Prins reaction and intermediates for the synthesis of spongistatin macrolides and their analogues

Abstract

The present invention relates to the Prins reaction and intermediates that can be used for the synthesis of spongistatin macrolides and their analogs. Specifically, the present invention provides a method for synthesizing spongistatin macrolide or its analogs through a cyclization reaction strategy. The strategy of the present invention includes subjecting an intermediate to Prins reaction conditions to obtain a macrolide. The present invention also provides compounds that can be used as intermediates for the synthesis of spongistatin macrolide or its analogs and methods for their preparation.

Description

[0001] This application is a divisional application of the invention patent application with the application date of June 30, 2017, application number 201780052964.2, and title "Prins Reactions and Intermediates for the Synthesis of Halichondrin Macrolides and Analogs Thereof". Background

[0002] The present invention relates to intermediates useful for the synthesis of pharmaceutically active macrolide compounds, and methods for synthesizing macrolide compounds. Halichondrin B is an effective anti-cancer agent initially isolated from the sponge Halichondria okadai Halichondria okadai ) and subsequently found in South China Sea sponges Axinella sp. ), East Indian Ocean sponges Phakellia carteri ), and Lissodendoryx sp. . The total synthesis of Halichondrin B was published in 1992 (Aicher, T.D. et al., J. Am. Chem. Soc. 114:3162 - 3164). Further studies on synthesis and structure - activity relationships are disclosed in U.S. Patent Nos. 5,338,865 and 5,436,238, and in Towle et al. Annual Meeting of the American Association for Cancer Research , April 6 - 10, 2002, 5721 and Wang et al. Bioorg. Med. Chem. Lett. , 10:1029 - 1032, 2000. Eribulin mesylate (also known as Halaven®, E7389, and the mesylate of B1939) is a non - taxane microtubule dynamics inhibitor, which is a structurally simplified synthetic analog of Halichondrin B. Methods and intermediates for the synthesis of certain Halichondrin B analogs and intermediates are described in: International Publication Nos. WO 2005 / 118565, WO 2009 / 046308, WO 2009 / 064029, and WO 2009 / 124237; U.S. Patent No. 6,214,865; Austad et al., Synlett 24(3):333 - 337, 2013; Austad et al., Synlett. 24(3):327 - 332, 2013; and Chase et al., Synlett 24(3):323 - 326, 2013. There is a need for new methods for synthesizing Halichondrin and its analogs (such as macrolide analogs). Summary of the Invention

[0003] Generally, the present invention provides methods for preparing macrocyclic intermediates in the synthesis of halichondrin macrocycles or analogs thereof. In particular, the methods disclosed herein can be used to prepare halichondrin macrocycles or analogs thereof by forming a C.26-C.27 bond through an allene-Prins reaction conducted on the intermediate. The present invention also provides intermediates that can be used in the reactions described herein.

[0004] In one aspect, the present invention provides a method for preparing a macrocyclic intermediate in the synthesis of a halichondrin macrocycle or an analog thereof, the method comprising reacting an intermediate of formula (IA) with R 12 OH and a Lewis acid, the reaction generating a macrocyclic intermediate by forming a bond in the structure of the halichondrin macrocycle or an analog thereof.

[0005] wherein R 12 is an optionally substituted acyl group;

[0006] wherein the compound of formula (IA) is:

[0007]

[0008] or a salt or tautomer thereof,

[0009] wherein

[0010] D and D’ are each independently H, an optionally substituted alkyl group, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, an alkyl group or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon backbone, said backbone being unsubstituted or having 1-10 substituents independently selected from: cyano, halogen, azido, oxo and Q 1 , said group of formula (1) having the structure:

[0011]

[0012] wherein

[0013] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0014] R 1 is H, or R 1 and P 1 combine to form a bond;

[0015] (i) R 2is H, where P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

[0016] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , where P 3 is an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is an N-protecting group, or (b) P 2 and P 4 combine to form an alkylidene;

[0017] (iii) R 2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo; or

[0018] (iv) R 2 and P 2 combine to form an optionally substituted ethylene or a structure selected from:

[0019]

[0020]

[0021] where each P’ is independently H or a hydroxyl protecting group;

[0022] E is H, optionally substituted alkyl or optionally substituted alkoxy;

[0023] G is O, S, CH 2 or NR N , where R N is H, an N-protecting group or optionally substituted alkyl;

[0024] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0025] n, when present, is 0, 1 or 2;

[0026] k is 0 or 1;

[0027] X 1 is –CH(Y)–, –CH 2 – or –O–,

[0028] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 )–; where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or –SR X1 ; where each R X1 is independently optionally substituted alkyl, or two R X1 combine to form optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O;

[0029] Y is SO 2 R C or COOR C , where when Y is SO 2 RC When R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when Y is COOR C then R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl;

[0030] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0031] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxy protecting group, and R 8 is H;

[0032] Or

[0033] A 1 is H or OP”, and:

[0034] (a) P 7 is H or a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached combine to form a double bond;

[0035] Or

[0036] (b) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0037] (i) Each P 6 is independently H or a hydroxy protecting group, or two P 6 together with the atoms to which they are attached combine to form a ketal or an acetal; X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxy protecting group; and each R 11 is –OP 10 or two R 11 combine to form an oxo, where P 10 is an alkyl or a hydroxy protecting group;

[0038] (ii) P 6 and X each combine with the atom to which they are attached to form a ketal, and P 7 and R 7 combine to form a bond, and R 8 is H or OP”; and each R 11 is –OP 10 or two R 11 combine to form an oxo, where P 10 is an alkyl or a hydroxy protecting group; or

[0039] (iii) Two P 6 and two R 11 combine with the atoms to which they are attached to form an acetal; and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxy protecting group;

[0040] R 9 is H, OP” or Y, and R 10 is H; or R 9 and R 10 combine with the atoms to which they are attached to form a double bond;

[0041] Each P” is independently H or a hydroxy protecting group when present; and

[0042] P 8 is H or a silyl; and

[0043] wherein the macrocyclic intermediate in the synthesis of halichondrin macrolide or its analogs is a compound of formula (IB):

[0044]

[0045] or a salt or tautomer thereof.

[0046] In some embodiments, the Lewis acid is an oxygenophilic Lewis acid (e.g., boron trifluoride or its solvate).

[0047] In another aspect, the present invention provides a method for preparing halichondrin macrolide or its analogs or salts thereof:

[0048]

[0049] wherein

[0050] D and D’ are each independently H, an optionally substituted alkyl, or OP 1 , provided that only one of D and D’ is OP 1, where P 1 is H, an alkyl or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or a C 2-6 unsaturated hydrocarbon backbone, said backbone being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azido, oxo and Q 1 , said group of formula (1) having the structure:

[0051]

[0052] where

[0053] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0054] R 1 is H, or R 1 and P 1 combine to form a bond;

[0055] (i) R 2 is H, where P 2 is absent, H, an optionally substituted alkyl, or a hydroxy protecting group;

[0056] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , where P 3 is H or an N - protecting group, and (a) P 2 is absent, H, an optionally substituted alkyl, or a hydroxy protecting group, and P 4 is H or an N - protecting group, (b) P 2 and P 4 combine to form an alkylene group, or (c) P 2 and P 4 are each H;

[0057] (iii) R 2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, an optionally substituted alkyl, or a hydroxy protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, a cyclic carbonate, a dicarbonyl - dioxo or a silylene - dioxo; or

[0058] (iv) R 2 and P 2 combine to form an optionally substituted ethylene group or a structure selected from the following:

[0059]

[0060]

[0061] wherein each P’ is independently H or a hydroxyl protecting group;

[0062] A 1 、A 2 and A 3 are each independently H or OP”, where each P” is independently H or a hydroxyl protecting group;

[0063] E is H, an optionally substituted alkyl group or an optionally substituted alkoxy group;

[0064] G is O, S, CH 2 or NR N , where R N is H, an N - protecting group or an optionally substituted alkyl group;

[0065] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently H, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an aryl group, a haloaryl group, a hydroxyaryl group, an alkoxyaryl group, an arylalkyl group, an alkylaryl group, a haloarylalkyl group, an alkylhaloaryl group, an (alkoxyaryl)alkyl group, a heterocyclic group or a heterocyclic - alkyl group;

[0066] n is 0, 1 or 2 when present;

[0067] k is 0 or 1;

[0068] X 1 is –CH 2 – or –O–, and

[0069] X 2 is =O;

[0070] The method is carried out as follows:

[0071] (A) A compound of formula (IA) and R 12 OH yield a compound of formula (IB), wherein R 12 is an optionally substituted acyl group, and the compound of formula (IA) has the following structure:

[0072]

[0073] or a salt or tautomer thereof,

[0074] wherein

[0075] D and D’ are each independently H, an optionally substituted alkyl group, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, an alkyl group or a hydroxyl protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azide, oxo and Q 1 , said group of formula (1) having the structure:

[0076]

[0077] wherein

[0078] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0079] R 1 is H, or R 1 and P 1 combine to form a bond;

[0080] (i) R 2 is H, wherein P 2 is absent, H, an optionally substituted alkyl group, or a hydroxyl protecting group;

[0081] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , where P 3 is an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxy-protecting group, and P 4 is an N-protecting group, or (b) P 2 and P 4 combine to form an alkylene group;

[0082] (iii) R 2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, optionally substituted alkyl, or a hydroxy-protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxy-protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo; or

[0083] (iv) R 2 and P 2 combine to form an optionally substituted ethylene group or a structure selected from:

[0084]

[0085]

[0086] where each P’ is independently H or a hydroxy-protecting group;

[0087] E is H, optionally substituted alkyl, or optionally substituted alkoxy;

[0088] G is O, S, CH 2 or NR N , where R N is H, an N-protecting group or optionally substituted alkyl;

[0089] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NRB (CO)R A 、NR B (CO)(CO)R A 、

[0090] NR B (CO)NR B R A 、NR B (CO)OR A 、(CO)OR A 、O(CO)R A 、(CO)NR B R A or O(CO)NR B R A wherein R A and R B are each independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group, or heterocyclic group-alkyl;

[0091] n is 0, 1 or 2 when present;

[0092] k is 0 or 1;

[0093] X 1 is –CH(Y)–, –CH 2 – or –O–,

[0094] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 )–; wherein each R X is independently H, –OR X1 or –SR X1 provided that at least one R X is –OR X1 or –SR X1 when present; wherein each R X1 is independently optionally substituted alkyl, or two R X1 combine to form optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O;

[0095] Y is SO 2 R C or COOR C wherein, when Y is SO 2 R C then RC is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when Y is COOR C then R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl;

[0096] R 3 and R 5 together form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached form a double bond, and the remaining R 4 or R 6 is H;

[0097] A 1 and R 7 together form an oxo, P 7 is H or a hydroxy protecting group, and R 8 is H;

[0098] or

[0099] A 1 is H or OP”, and:

[0100] (a) P 7 is H or a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached form a double bond;

[0101] or

[0102] (b) P 7 and R 7 together form a bond, and R 8 is H or OP”;

[0103] (i) Each P 6 is independently H or a hydroxy protecting group, or two P 6 together with the atoms to which they are attached form a ketal or an acetal; X is =O or X together with the carbon atom to which it is attached forms –(CH(OP 9 ))–, where P 9 is H or a hydroxy protecting group; and each R 11 is –OP 10 or two R 11 together form an oxo, where P 10 is an alkyl or a hydroxy protecting group;

[0104] (ii) P 6 and X each combine with the atoms to which they are attached to form a ketal, and P 7 and R 7 combine to form a bond, and R 8 is H or OP″; and each R 11 is –OP 10 or two R 11 combine to form an oxo, where P 10 is an alkyl or a hydroxyl protecting group; or

[0105] (iii) Two P 6 and two R 11 combine with the atoms to which they are attached to form an acetal; and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group;

[0106] R 9 is H, OP″ or Y, and R 10 is H; or R 9 and R 10 combine with the atoms to which they are attached to form a double bond;

[0107] Each P″, when present, is independently H or a hydroxyl protecting group; and

[0108] P 8 is H or a silyl group;

[0109] and

[0110] The compound of formula (IB) has the following structure:

[0111]

[0112] or a salt or tautomer thereof;

[0113] wherein

[0114] R 12 is an optionally substituted acyl group; and

[0115] (B) Generating the halichondrin macrolide or an analog thereof from the compound (IB).

[0116] In certain embodiments, generating the compound of formula (IB) includes reacting the compound of formula (IA) with R 12 OH and a Lewis acid (such as an oxygenophilic Lewis acid (e.g., boron trifluoride or a solvate thereof)). In a particular embodiment, generating the halichondrin macrolide or an analog thereof includes reacting the compound of formula (IB) with an allylic reducing agent. In a further embodiment, R3 and R 5 combine to form a bond, and R 4 and R 6 are each H. In some embodiments, R 5 and R 6 together with the atoms to which they are attached combine to form a double bond, R 4 is H, and R 3 is a hydroxyl protecting group. In other embodiments, each P 6 is a hydroxyl protecting group, and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–. In still other embodiments, R 7 and P 7 combine to form a bond, and R 8 is H. In yet other embodiments, P 7 is a hydroxyl protecting group, and R 7 and R 8 together with the atoms to which they are attached combine to form a double bond. In some embodiments, R 9 is H or SO 2 R C and R 10 is H. In other embodiments, P 8 is silyl. In certain embodiments, each R 11 is –OP 10 where P 10 is alkyl. In some embodiments, G is O. In further embodiments, D is H. In still further embodiments, D’ is OP 1 where P 1 is alkyl. In other embodiments, the stereocenter designated by a is ( R ) and A has the following structure:

[0117] .

[0118] In still other embodiments, k is 0 and X 1 is –CH 2 –. In yet other embodiments, R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 where n is 0. In further embodiments, A and D combine to form the following structure:

[0119]

[0120] wherein the bond connecting the oxygen atom originates from the carbon atom to which D in formula (IA) is attached, and

[0121] wherein R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , where n is 2.

[0122] In some embodiments, k is 1, and E is an optionally substituted alkyl. In certain embodiments, X 1 is –O–.

[0123] The method of the present invention can be used to prepare eribulin or a salt thereof (e.g., eribulin mesylate). Compounds of formula (IA), (IB), (IC), (IE), (IJ), or (IN), wherein k is 0, X 1 is –CH(Y)– or –CH 2 –, D is H, D' is OP 1 , G is O, and A has the following structure:

[0124]

[0125] wherein

[0126] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is H or an N-protecting group, and P 2 and P 4 combine to form an alkylene group or P 2 is H, an optionally substituted alkyl, or a hydroxyl-protecting group, and P 4 is an N-protecting group; or

[0127] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 is H, an optionally substituted alkyl, or a hydroxyl-protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxyl-protecting group; or P 2 and P 5Combined with the atoms to which they are respectively attached to form a ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo;

[0128] It can be used for the synthesis of eribulin or its salts (for example, eribulin mesylate).

[0129] In certain embodiments of formula (IA), (IB), (IC), (IE), (IJ), or (IN), k is 0, X 1 is –CH(Y)– or –CH 2 –, D is H, D’ is OP 1 , G is O, and A has the following structure:

[0130]

[0131] where

[0132] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is an N-protecting group, and P 2 and P 4 combine to form an alkylene group; or

[0133] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 is H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 Combined with the atoms to which they are respectively attached to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo;

[0134] It can be used for the synthesis of eribulin or its salts (for example, eribulin mesylate).

[0135] On the other hand, the present invention provides compounds of formula (IA), (IB), (IC), (ID), (IDa), (IDb), (IDc), (IDd), (IE), (IF), (IH), (IHa), (IHb), (IJ), or (IN).

[0136] The structure of the compound of formula (IA) is as follows:

[0137]

[0138] or a salt or tautomer thereof,

[0139] wherein

[0140] D and D’ are each independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, alkyl or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azido, oxo and Q 1 , said group of formula (1) having the structure:

[0141]

[0142] wherein

[0143] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0144] R 1 is H, or R 1 and P 1 combine to form a bond;

[0145] (i) R 2 is H, wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group;

[0146] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , wherein P 3 is an N - protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 4 is an N - protecting group, or (b) P 2 and P 4 combine to form an alkylene;

[0147] (iii) R 2 is –(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 5is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached form a ketal, cyclic carbonate, dicarbonyl-dioxo or silyl-dioxo; or

[0148] (iv) R 2 and P 2 combine to form an optionally substituted ethylene or a structure selected from:

[0149]

[0150]

[0151] where each P’ is independently H or a hydroxyl protecting group;

[0152] E is H, optionally substituted alkyl or optionally substituted alkoxy;

[0153] G is O, S, CH 2 or NR N , where R N is H, an N-protecting group or optionally substituted alkyl;

[0154] each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0155] n is 0, 1 or 2 when present;

[0156] k is 0 or 1;

[0157] X 1 is –CH(Y)–, –CH 2 – or –O–;

[0158] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X ) 2 )–; where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X is –OR X1 or –SR X1 when present; where each R X1 is independently optionally substituted alkyl or two R X1 combine to form optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O;

[0159] Y is SO 2 R C or COOR C , where, when Y is SO 2 R C is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR C is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl; C is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl; C R

[0160] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxyl protecting group, R 5 and R 4 and R 6 in which one of them together with the atoms to which it is attached combines to form a double bond, and the remaining R 4 or R 6 is H;

[0161] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxyl protecting group, and R8 is H;

[0162] or

[0163] A 1 is H or OP”, and:

[0164] (i) P 7 is H or a hydroxyl protecting group, and R 7 and R 8 together with the atoms to which they are attached form a double bond;

[0165] or

[0166] (ii) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0167] (i) Each P 6 is independently H or a hydroxyl protecting group, or two P 6 together with the atoms to which they are attached form a ketal or an acetal; X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group; and each R 11 is –OP 10 or two R 11 combine to form an oxo group, where P 10 is an alkyl group or a hydroxyl protecting group;

[0168] (ii) P 6 and X both together with the atoms to which they are attached form a ketal, P 7 and R 7 combine to form a bond, and R 8 is H or OP”; and each R 11 is –OP 10 or two R 11 combine to form an oxo group, where P 10 is an alkyl group or a hydroxyl protecting group; or

[0169] (iii) Two P 6 and two R 11 together with the atoms to which they are attached form an acetal; and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group;

[0170] R 9 is H, OP” or Y, and R 10 is H; or R9 and R 10 together with the atoms to which they are attached form a double bond;

[0171] Each P″, when present, is independently H or a hydroxy protecting group; and

[0172] P 8 is H or silyl.

[0173] The structure of the compound of formula (IB) is as follows:

[0174]

[0175] or a salt or tautomer thereof,

[0176] wherein

[0177] D and D′ are each independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D′ is OP 1 , wherein P 1 is H, alkyl, or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azido, oxo, and Q 1 , said group of formula (1) having the structure:

[0178]

[0179] wherein

[0180] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0181] R 1 is H, or R 1 and P 1 combine to form a bond;

[0182] (i) R 2 is H, wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group;

[0183] (ii) R 2 is –(CH 2 ) n NP 3 P 4 wherein P 3 is an N - protecting group, and (a) P 2is absent, H, an optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is an N-protecting group or (b) P 2 and P 4 combine to form an alkylene group;

[0184] (iii) R 2 is –(CH 2 ) n OP 5 wherein P 2 is absent, H, an optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silyl-dioxo; or

[0185] (iv) R 2 and P 2 combine to form an optionally substituted ethylene or a structure selected from:

[0186]

[0187]

[0188] where each P’ is independently H or a hydroxyl protecting group;

[0189] E is H, an optionally substituted alkyl or an optionally substituted alkoxy;

[0190] G is O, S, CH 2 or NR N where R N is H, an N-protecting group or an optionally substituted alkyl;

[0191] each Q 1 is independently OR A 、SR A 、SO 2 R A 、OSO 2 R A 、NR B R A 、NR B (CO)R A 、NR B (CO)(CO)R A 、NR B (CO)NR B R A 、NR B (CO)OR A, (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , wherein R A and R B are each independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0192] n, when present, is 0, 1 or 2;

[0193] k is 0 or 1;

[0194] X 1 is –CH(Y)–, –CH 2 – or –O–;

[0195] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 )–; wherein each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or –SR X1 ; wherein each R X1 is independently optionally substituted alkyl or two R X1 combine to form optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O;

[0196] Y is SO 2 R C or COOR C , wherein when Y is SO 2 R C , R C is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR C , R C is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl;

[0197] R 3 and R 5 combine to form a bond, and R 4 and R6 each is H; or R 3 is H or a hydroxyl protecting group, R 5 and R 4 and R 6 one of and the atoms to which it is attached together form a double bond, and the remaining R 4 or R 6 is H;

[0198] A 1 and R 7 combine to form oxo, P 7 is H or a hydroxyl protecting group, and R 8 is H;

[0199] or

[0200] A 1 is H or OP”, and:

[0201] (a) P 7 is H or a hydroxyl protecting group, and R 7 and R 8 and the atoms to which they are attached together form a double bond;

[0202] or

[0203] (b) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0204] (i) Each P 6 is independently H or a hydroxyl protecting group or two P 6 and the atoms to which they are attached together form a ketal or acetal; X is =O or X and the carbon atom to which it is attached form –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group; or

[0205] (ii) P 6 and X both and the atoms to which they are attached together form a ketal, P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0206] R 9 is H, OP” or Y, and R 10 is H; or R 9 and R 10 and the atoms to which they are attached together form a double bond;

[0207] Each P” when present is independently H or a hydroxyl protecting group; and

[0208] R 12 is an optionally substituted acyl group.

[0209] The structure of the compound of formula (IC) is as follows:

[0210]

[0211] or a salt or tautomer thereof,

[0212] wherein

[0213] D and D’ are each independently H, an optionally substituted alkyl group, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, an alkyl group or a hydroxyl protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azide, and Q 1 , said group of formula (1) having the structure:

[0214]

[0215] wherein

[0216] L is –(CH(OP 2 ))– or –C(O)–;

[0217] R 1 is H, or R 1 and P 1 combine to form a bond;

[0218] (i) R 2 is H, wherein P 2 is absent, H, an optionally substituted alkyl group, or a hydroxyl protecting group;

[0219] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , wherein P 3 is an N - protecting group, and (a) P 2 is absent, H, an optionally substituted alkyl group, or a hydroxyl protecting group, and P 4 is an N - protecting group, or (b) P 2 and P 4 combine to form an alkylene group;

[0220] (iii) R2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 5 is optionally substituted alkyl or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached form a ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo; or

[0221] (iv) R 2 and P 2 combine to form an optionally substituted ethylene or a structure selected from the following:

[0222]

[0223]

[0224] where each P’ is independently a hydroxy protecting group;

[0225] E is H, optionally substituted alkyl or optionally substituted alkoxy;

[0226] G is O, S, CH 2 or NR N , where R N is H, an N-protecting group or optionally substituted alkyl;

[0227] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and RB Each is independently an alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0228] n, when present, is 0, 1 or 2;

[0229] k is 0 or 1;

[0230] X 1 is –CH(Y)– or –CH 2 –;

[0231] X 2 is =O, or X 2 together with the carbon atom to which it is attached is -(C(R X )) 2 )–; where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or -SR X1 ; where each R X1 is independently an optionally substituted alkyl or two R X1 combine to form an optionally substituted alkylene;

[0232] Y is SO 2 R C or COOR C , where, when Y is SO 2 R C , R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when Y is COOR C , R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl;

[0233] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 in one of them together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0234] (a) Each P6 is independently a hydroxyl protecting group, or two Ps 6 together with the atoms to which they are attached form a ketal or an acetal;

[0235] each R 11 is independently –OP 10 , or

[0236] two Rs 11 combine to form an oxo, where P 10 is an alkyl or a hydroxyl protecting group;

[0237] or

[0238] (b) two Ps 6 and two Rs 11 together with the atoms to which they are attached form an acetal;

[0239] R 13 is H or –CH 2 P(O)(OR E ) 2 , where each R E , when present, is independently an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted arylalkyl;

[0240] X is =O or X together with the carbon atom to which it is attached forms –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group;

[0241] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxyl protecting group, and R 8 is H;

[0242] or

[0243] A 1 is H or OP”, and:

[0244] (i) P 7 is H or a hydroxyl protecting group, and Rs 7 and R 8 together with the atoms to which they are attached form a double bond;

[0245] or

[0246] (ii) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0247] and

[0248] Each P”, when present, is independently H or a hydroxyl protecting group.

[0249] The structure of the compound of formula (ID) is as follows:

[0250]

[0251] wherein

[0252] P 8 is H or a hydroxyl protecting group; and

[0253] R 9 is SO 2 R C or COOR C and when R 9 is SO 2 R C then R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when R 9 is COOR C then R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl.

[0254] The structure of the compound of formula (IDa) is as follows:

[0255]

[0256] wherein R 9 is SO 2 R C or COOR C and when R 9 is SO 2 R C then R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when R 9 is COOR C then R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl.

[0257] The structure of the compound of formula (IDb) is as follows:

[0258]

[0259] wherein R 9 ’ and R 10 are both H, or R 9 ’ and R 10 combine to form a double bond; R 14 is a hydroxyl, a halogen (such as iodine) or a pseudohalogen (trifluoromethanesulfonate); and R 9 is SO2 R C or COOR C , when R 9 For SO 2 R C When R C is optionally substituted aryl or optionally substituted non-enolate alkyl, and when R 9 For COOR C When R C is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl.

[0260] The structure of the compound of formula (IDc) is as follows:

[0261]

[0262] Where R 16 is H, a hydroxyl protecting group or an optionally substituted alkyl group.

[0263] The structure of the compound of formula (IDd) is as follows:

[0264]

[0265] Where X 6 =–C(R 17 )=CH 2 or –C(O)–Me, where R 17 is a pseudohalogen (e.g., a triflate) or a halogen; and R 16 is H, a hydroxyl protecting group or an optionally substituted alkyl group.

[0266] The structure of the compound of formula (IE) is as follows:

[0267]

[0268] or a salt or a tautomer thereof,

[0269] in

[0270] D and D' are each independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D' is OP 1 , where P 1 is H, an alkyl group or a hydroxyl protecting group; and A is a group of formula (1) or C 1-6 Saturated or C 2-6 An unsaturated hydrocarbon skeleton, which is unsubstituted or has 1-10 substituents, which are independently selected from: cyano, halogen, azido and Q 1 , the group of formula (1) has the structure:

[0271]

[0272] wherein

[0273] L is –(CH(OP 2 ))– or –C(O)–;

[0274] R 1 is H, or R 1 and P 1 combine to form a bond;

[0275] (i) R 2 is H, where P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group;

[0276] (ii) R 2 is –(CH 2 ) n NP 3 P 4 where P 3 is an N-protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 4 is an N-protecting group or (b) P 2 and P 4 combine to form an alkylene group;

[0277] (iii) R 2 is –(CH 2 ) n OP 5 where P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 5 is optionally substituted alkyl or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo; or

[0278] (iv) R 2 and P 2 combine to form an optionally substituted ethylene group or a structure selected from:

[0279]

[0280]

[0281] where each P’ is independently a hydroxy protecting group;

[0282] E is H, optionally substituted alkyl, or optionally substituted alkoxy;

[0283] G is O, S, CH 2 or NR N , where R N is H, an N - protecting group or an optionally substituted alkyl group;

[0284] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an aryl group, a haloaryl group, a hydroxyaryl group, an alkoxyaryl group, an arylalkyl group, an alkylaryl group, a haloarylalkyl group, an alkylhaloaryl group, an (alkoxyaryl)alkyl group, a heterocyclic group or a heterocyclic - alkyl group;

[0285] n, when present, is 0, 1 or 2;

[0286] k is 0 or 1;

[0287] X 1 is –CH(Y)– or –CH 2 –;

[0288] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X ) 2 )–; where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or –SR X1 ; where each RX1 Each is independently an optionally substituted alkyl group, or two Rs X1 combine to form an optionally substituted alkylene group;

[0289] Y is SO 2 R C or COOR C , where when Y is SO 2 R C , R C is an optionally substituted aryl group or an optionally substituted non-enolizable alkyl group, and when Y is COOR C , R C is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group;

[0290] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0291] R 7 and P 7 combine to form a bond, and R 8 is H; or P 7 is a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached combine to form a double bond;

[0292] (i) Each P 6 is independently a hydroxy protecting group, or two Ps 6 together with the atoms to which they are attached combine to form a ketal or an acetal;

[0293] Each R 11 is independently –OP 10 , or

[0294] Two Rs 11 combine to form an oxo group, where P 10 is an alkyl group or a hydroxy protecting group;

[0295] or

[0296] (ii) Two Ps 6 and two Rs 11 together with the atoms to which they are attached combine to form an acetal; and

[0297] X 3 is –CH 2 OP A , –CH=CH 2 or –CH(OP A )CH 2 OP A , where each R E is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl, and where each P A is independently H or a hydroxyl protecting group, or two P A combine to form a protected cyclic diol.

[0298] The structure of the compound of formula (IF) is as follows:

[0299]

[0300] where

[0301] X 3 is –CHO, –CH 2 OP A , –CH=CH 2 or –CH(OP A )CH 2 OP A ;

[0302] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxyl protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0303] R 7 and P 7 combine to form a bond, and R 8 is H; or P 7 is a hydroxyl protecting group, and R 7 and R 8 together with the atoms to which they are attached combine to form a double bond; and

[0304] each P 6 is independently a hydroxyl protecting group, or two P 6 together with the atoms to which they are attached combine to form a ketal or an acetal.

[0305] The structure of the compound of formula (IH) is as follows:

[0306]

[0307] or a salt thereof,

[0308] wherein

[0309] X 3 is –CHO, –CH 2 OP A –, –CH=CH 2 – or –CH(OP A )CH 2 OP A ;

[0310] X 4 is =O, or X 4 together with the carbon atom to which it is attached forms –CH 2 –;

[0311] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and one of R 6 together with the atoms to which they are attached form a double bond, and the remaining R 4 or R 6 is H;

[0312] R 7 and P 7 combine to form a bond, and R 8 is H; or P 7 is a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached form a double bond;

[0313] Each P 6 is independently a hydroxy protecting group, or two P 6 together with the atoms to which they are attached form a ketal or an acetal;

[0314] Each P A is independently H or a hydroxy protecting group, or two P A combine to form a protected cyclic diol; and

[0315] P B is H, a hydroxy protecting group or an optionally substituted alkyl group.

[0316] The structure of the compound of formula (IHa) is as follows:

[0317]

[0318] wherein

[0319] a the carbon-oxygen bond is defined as or ,

[0320] X 3 is –CHO, –CH 2 OP A , –CH=CH 2 or –CH(OP A )CH 2 OP A ;

[0321] X 5 is –CH=CH 2 or –CH(R 4 )–CH(R 5 )–CH(R 6 )–C(X 4 )OP B ;

[0322] X 4 is =O, or X 4 together with the carbon atom to which it is attached forms –CH 2 –;

[0323] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 one of which together with the atoms to which it is attached forms a double bond, and the remaining R 4 or R 6 is H;

[0324] P 6 is a hydroxy protecting group, or two P 6 ;

[0325] Each P A is independently H or a hydroxy protecting group, or two P A combine to form a protected cyclic diol; and

[0326] P B is H, a hydroxy protecting group or an optionally substituted alkyl group.

[0327] The structure of the compound of formula (IHb) is as follows:

[0328]

[0329] wherein

[0330] X 5 is –CH=CH 2 or –CH(R 4 )–CH(R 5 )–CH(R 6 )–C(X 4 )OP B ;

[0331] X 4 is =O, or X 4 together with the carbon atom to which it is attached forms –CH 2 –;

[0332] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxyl protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached form a double bond, and the remaining R 4 or R 6 is H; and

[0333] P 6 and P 7 are each independently a hydroxyl protecting group, or one P 6 and P 7 together with the atoms to which they are attached form a ketal (for example, one P 6 and P 7 combine to form cyclohexylidene) and the remaining P 6 is a hydroxyl protecting group; or both P 6 together with the atoms to which they are attached form a ketal, and P 7 is a hydroxyl protecting group.

[0334] The structure of the compound of formula (IJ) is as follows:

[0335]

[0336] wherein

[0337] D and D’ are each independently H, optionally substituted alkyl, or OP 1, provided that only one of D and D’ is OP 1 , wherein P 1 is H, alkyl or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or a C 2-6 unsaturated hydrocarbon backbone, said backbone being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azido and Q 1 , the group of formula (1) having the structure:

[0338]

[0339] wherein

[0340] L is –(CH(OP 2 ))– or –C(O)–;

[0341] R 1 is H, or R 1 and P 1 combine to form a bond;

[0342] (i) R 2 is H, wherein P 2 is absent, H, optionally substituted alkyl or a hydroxy protecting group;

[0343] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , wherein P 3 is an N - protecting group, and (a) P 2 is absent, H, optionally substituted alkyl or a hydroxy protecting group, and P 4 is an N - protecting group, or (b) P 2 and P 4 combine to form an alkylene;

[0344] (iii) R 2 is –(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl or a hydroxy protecting group, and P 5 is an optionally substituted alkyl or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl - dioxo or silylene - dioxo; or

[0345] (iv) R 2 and P 2Combine to form an optionally substituted ethylene group or a structure selected from the following:

[0346]

[0347]

[0348] where each P’ is independently a hydroxyl protecting group;

[0349] E is H, an optionally substituted alkyl group or an optionally substituted alkoxy group;

[0350] G is O, S, CH 2 or NR N , where R N is H, an N - protecting group or an optionally substituted alkyl group;

[0351] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an aryl group, a haloaryl group, a hydroxyaryl group, an alkoxyaryl group, an arylalkyl group, an alkylaryl group, a haloarylalkyl group, an alkylhaloaryl group, an (alkoxyaryl)alkyl group, a heterocyclic group or a heterocyclic - alkyl group;

[0352] When present, n is 0, 1 or 2;

[0353] k is 0 or 1;

[0354] X 1 is –CH(Y)–, –CH 2 – or –O–;

[0355] X 2 is =O, or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 ); where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or –SR X1 ; where each R X1 is independently an optionally substituted alkyl group, or two R X1 combine to form an optionally substituted alkylene group, provided that when X 1 is –O–, X 2 is =O;

[0356] Y is SO 2 R C or COOR C , where, when Y is SO 2 R C , R C is an optionally substituted aryl group or an optionally substituted non-enolizable alkyl group, and when Y is COOR C , R C is an optionally substituted alkyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group;

[0357] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and one of R 4 and R 6 combine with the atoms to which they are respectively attached to form a double bond, and the remaining R 4 or R 6 is H;

[0358] (i) Each P 6 is independently a hydroxy protecting group, or two P 6 combine with the atoms to which they are respectively attached to form a ketal or an acetal;

[0359] Each R 11 is independently –OP 10 , or

[0360] two R 11 combine to form an oxo group, where P 10 is an alkyl group or a hydroxy protecting group;

[0361] or

[0362] (ii) Two P 6 and two R 11 together with the atoms to which they are attached form an acetal;

[0363] P 7 is a hydroxyl protecting group; and

[0364] X 2 is a halogen or a pseudohalogen.

[0365] The structure of the compound of formula (IN) is as follows:

[0366]

[0367] or a salt or tautomer thereof,

[0368] wherein

[0369] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxyl protecting group, R 5 and R 4 and R 6 one of them together with the atoms to which they are attached form a double bond, and the remaining R 4 or R 6 is H;

[0370] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxyl protecting group, and R 8 is H;

[0371] or

[0372] A 1 is H or OP”, and:

[0373] (i) P 7 is H or a hydroxyl protecting group, and R 7 and R 8 together with the atoms to which they are attached form a double bond;

[0374] or

[0375] (ii) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0376] Each P", when present, is independently H or a hydroxy protecting group;

[0377] Each P 6 is independently H or a hydroxy protecting group, or two Ps 6 together with the atoms to which they are attached form a ketal or an acetal, and X is =O or X together with the carbon atom to which it is attached forms –(CH(OP 9 ))–, where P 9 is H or a hydroxy protecting group; or P 6 and X both together with the atoms to which they are attached form a ketal; wherein, when P 6 and X both together with the atoms to which they are attached form a ketal, P 7 and R 7 combine to form a bond, and R 8 is H or OP";

[0378] R 9 is H, SO 2 R C or COOR C and R 10 is H; or R 9 and R 10 together with the atoms to which they are attached form a double bond, wherein, when R 9 is SO 2 R C then R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when R 9 is COOR C then R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl;

[0379] R 15 is H or –OP 11 where P 11 is H, a hydroxy protecting group or an optionally substituted alkyl;

[0380] X 4 is =O or together with the carbon atom to which it is attached is –CH 2 –, provided that when R 15 is H, X 4 is =O; and

[0381] P 8 is H or a silyl.

[0382] In some embodiments, each P A is H, or two Ps A combine to form a protected cyclic diol. In other embodiments, A 1is H. In still other embodiments, each R 11 is –OP 10 , where P 10 is alkyl. In still other embodiments, R 9 is H or SO 2 R C , and R 10 is H. In certain embodiments, R 9 is SO 2 R C . In a further embodiment, P 8 is silyl. In a particular embodiment, P 6 is a hydroxyl protecting group, and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–. In certain embodiments, R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H. In a further embodiment, R 5 and R 6 combine with the atoms to which they are respectively attached to form a double bond, R 4 is H, and R 3 is a hydroxyl protecting group. In still further embodiments, R 7 and P 7 combine to form a bond, and R 8 is H. In still further embodiments, P 7 is a hydroxyl protecting group, and R 7 and R 8 combine with the atoms to which they are respectively attached to form a double bond. In certain embodiments, A 3 is H. In a particular embodiment, A 2 is H.

[0383] In a further embodiment, the stereocenter designated by a is ( R ), and A has the following structure:

[0384] .

[0385] In still further embodiments, k is 0 and X 1 is –CH 2 –. In still further embodiments, R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP5 , where n is 0.

[0386] In other embodiments, A and D combine to form the following structure:

[0387]

[0388] where the bond connecting the oxygen atom originates from the carbon atom to which D is attached in formula (IA), and where R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , where n is 2.

[0389] In still other embodiments, k is 1, and E is an optionally substituted alkyl group. In yet other embodiments, X 1 is –O–.

[0390] In certain embodiments of the compounds of formula (IA), (IB), (IC), (IE), (IJ) or (IN), k is 0, D is H, D’ is OP 1 , and A has the following structure:

[0391]

[0392] where

[0393] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is H or an N-protecting group, and P 2 and P 4 combine to form an alkylene group; or

[0394] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 is H, an optionally substituted alkyl group, or a hydroxyl protecting group, and P 5 is H, an optionally substituted alkyl group, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo.

[0395] In certain embodiments of the compounds of formula (IA), (IB), (IC), (IE), (IJ), or (IN), k is 0, D is H, and D’ is OP 1 and A has the following structure:

[0396]

[0397] wherein

[0398] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is an N-protecting group, and P 2 and P 4 combine to form an alkylene group; or

[0399] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 and P 5 are each independently H, an optionally substituted alkyl group, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo group.

[0400] In another aspect, the present invention provides compounds 1, 2, 3, 5, 7, 7a, 8, 9, 10, 11, 12, 13, 14, 15, 16, 17, 18, 21, 23, 24, 25, 27, 28, 29, 31, 32, 33, 34, 35, 36, 36b, 36c, 37, 38, 39, 40, 41, 43, 44, 44a, 45, 47, 47a, 47b, 47c, 48, 49, 50, 50a, 51, 52, 53, 54, 55, 56, 57, 58, 59, 61, 62, 63, 66, 67, 68, 69, 70, 71, 72, 73, 77, 78, 79, 80, 81, 82, 83, 84, 85, 86, and 87.

[0401] Definition

[0402] The compounds useful in the present invention can be isotopically labeled compounds. Useful isotopes include hydrogen, carbon, nitrogen, and oxygen (e.g., 2 H, 3 H, 13 C, 14 C, 15 N,18 O and 17 O). Isotopically labeled compounds can be prepared by using readily available isotopically labeled reagents in place of non-isotopically labeled reagents to synthesize the compounds.

[0403] For any of the following chemical definitions, the number following the atomic symbol represents the total number of atoms of that element present in a particular chemical moiety. As will be appreciated, other atoms (e.g., hydrogen atoms) or substituents as described herein may be present as needed to satisfy the valency of the atoms. For example, unsubstituted C 2 alkyl has the formula -CH 2 CH 3 . When used in conjunction with the groups defined herein, reference to the number of carbon atoms includes the divalent carbon in acetal and ketal groups, but does not include the carbonyl carbon in acyl, ester, carbonate, or carbamate groups. Reference to the number of oxygen, nitrogen, or sulfur atoms in a heteroaryl refers only to those atoms that form part of the heterocycle.

[0404] "Acetal" means –O–(CHR)–O–, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or the R group is a bond attached to a carbon atom enumerated within the intermediate or within the soft spongin macrolide or its analog as shown in Figure 1.

[0405] "Acetyl" means an acyl group where R is –CX n H 3-n , where n is 0, 1, 2, or 3, and each X is independently alkoxy or halogen, provided that when n is 3, each X is independently halogen, and when n is 2, the two X groups are both independently halogen or the two X groups are both independently alkoxy. The acetyl group can be substituted (i.e., n is 1, 2, or 3) or unsubstituted (i.e., n is 0).

[0406] "Acyl" means -C(O)R, where R is H, alkyl, alkenyl, aryl, or arylalkyl. In exemplary acyl groups, R is H, C 1-12 alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 or C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 , C 2-6 , C 2-4 , C 3-12 or C 3-6 alkenyl), C 6-20 aryl (e.g., C 6-14 , C 6-10 , C 8-20or C 8-14 aryl), monocyclic C 1-6 heteroaryl (e.g., monocyclic C 1-4 or C 2-6 heteroaryl), C 4-19 heteroaryl (e.g., C 4-10 heteroaryl), (C 6-14 )aryl(C 1-6 )alkyl, (C 1-6 )heteroaryl(C 1-6 )alkyl, or (C 4-9 )heteroaryl(C 1-6 )alkyl. As defined herein, any heteroaryl present in the acyl group has 1 - 4 heteroatoms independently selected from O, N, and S. The acyl group can be unsubstituted or substituted (e.g., optionally substituted acyl group). In the optionally substituted acyl group, the substituent R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl. In some embodiments, the acyl group is C 2-10 acyl group.

[0407] "Acylating agent" refers to a compound that reacts with an amine or a hydroxyl group to form an amide or an ester, respectively. The acylating agent has the formula R - LG, where R is an acyl group and LG is a halogen, a carbonate, or - OR', where R' is an acyl group.

[0408] "Alcoholate" refers to the anionic compound RO - , where R is an alkyl group. The counterion of the alcoholate can be an alkali metal cation, an alkaline earth metal cation, or a tetraalkylammonium cation. The alcoholate can be optionally substituted in the same manner as the alkyl group.

[0409] "Alkoxy" refers to - OR, where R is an alkyl group. The alkoxy group can be optionally substituted in the same manner as the alkyl group.

[0410] "Alkoxyalkyl" refers to - OR, where R is an alkyl group substituted with an alkoxy group. Each part of the alkoxyalkyl can be optionally substituted in the same manner as the alkyl group.

[0411] "Alkoxyaryl" refers to - R'(R")[[]] n , where n is 1 or 2, R' is an arylene group and R" is an alkoxy group as defined herein. R' can also be optionally substituted in the same manner as the aryl group. R" can be optionally substituted in the same manner as the alkyl group.

[0412] "Alkoxyarylalkyl" refers to - R'(R"(R"')[[]] n), where n is an integer from 1 to 3, R' is an alkylene group, R" is an arylene group, and R''' is an alkoxy group as defined herein. R' may be optionally substituted in the same manner as an alkyl group. R" may also be optionally substituted in the same manner as an aryl group. R''' may be optionally substituted in the same manner as an alkyl group.

[0413] Unless otherwise specified, "alkyl" refers to a straight-chain, branched-chain, saturated cyclic (i.e., cycloalkyl), or acyclic hydrocarbon group having 1 to 12 carbons. In some embodiments, the alkyl group is C 1-6 alkyl. Exemplary alkyl groups include C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 , and C 3-6 alkyl. Specific examples include methyl, ethyl, 1-propyl, 2-propyl, 2-methyl-1-propyl, 1-butyl, 2-butyl, etc. The alkyl group may be optionally substituted with 1, 2, 3, or 4 substituents selected from halogen, hydroxy, alkoxy, aryloxy, arylalkyloxy, amino, oxo, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azide.

[0414] "Alkylamino" refers to -NHR, where R is an alkyl group. "[Alkenyl]alkylamino" refers to -NRR', where R is an alkyl group and R' is an alkenyl group. "[Aryl]alkylamino" refers to -NRR', where R is an alkyl group and R' is an aryl group. "[Arylalkyl]alkylamino" refers to -NRR', where R is an alkyl group and R' is an arylalkyl group. "Dialkylamino" refers to -NR 2 , where each R is independently selected alkyl.

[0415] "Alkylaryl" refers to -R'(R") n , where n is an integer from 1 to 3, R' is an arylene group, and R" is an alkyl group. The alkylaryl group may be optionally substituted in the same manner as defined for each R' and R" group.

[0416] "Alkylene" refers to a polyvalent alkyl group. The alkylene group may be optionally substituted in the same manner as an alkyl group. The alkylene group may be a divalent alkylene group. For example, C 1 alkylene is -CH 2 -.

[0417] "Alkylenedithio" refers to -S-alkylene-S-. The alkylenedithio group may be optionally substituted in the same manner as an alkylene group.

[0418] "Alkylhaloaryl" refers to -R'(R") n-R”’, where n is an integer from 1 to 5 and R’ is arylene, R” is halogen, and R”’ is alkylene, as defined herein. R’ may also be optionally substituted in the same manner as aryl. R”’ may also be optionally substituted in the same manner as alkyl.

[0419] “Alkylthio” means -SR, where R is alkyl. Alkylthio may be optionally substituted in the same manner as alkyl.

[0420] Unless otherwise specified, “alkenyl” means a straight-chain, branched-chain, cyclic or acyclic hydrocarbyl group having 2 to 12 carbons and containing one or more carbon-carbon double bonds. In some embodiments, alkenyl is C 2-6 alkenyl. Exemplary alkenyls include C 2-8 , C 2-7 , C 2-6 , C 2-4 , C 3-12 and C 3-6 alkenyl. Specific examples include ethenyl (i.e., vinyl), 1-propenyl, 2-propenyl (i.e., allyl), 2-methyl-1-propenyl, 1-butenyl, 2-butenyl (i.e., crotyl), etc. Alkenyl may be optionally substituted in the same manner as alkyl. Alkenyl as used in any context herein may also be substituted by aryl.

[0421] “Amido” means -NHR, where R is acyl. Amido may be optionally substituted in the same manner as acyl.

[0422] “Acetalamine” means -O-CR 2 -NR’-, where each R is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl, or the two R groups together are optionally substituted alkylene, and R’ is H or N -protecting group. In particular, R’ may be N -protecting group (e.g., Boc).

[0423] “Amino” means -NR 2 , where N combines with R 2 to form an azide group, or each R is independently H or N -protecting group, or the two Rs combine to form N -protecting group. When each R is H, the amino group may be unmasked, or when at least one R is not H, it is masked. Thus, an optionally masked amino group may be a masked or unmasked amino group.

[0424] “Aminoalkyl” means -R’(R”) n, where n is 1 or 2, R’ is an alkylene group, and R” is an amino group as defined herein. R’ may be optionally substituted in the same manner as an alkyl group.

[0425] "Aryl" refers to a monocyclic or polycyclic ring system having one or more aromatic rings, wherein the ring system is carbocyclic. Exemplary aryl groups include C 6-20 , C 6-15 , C 6-10 , C 8-20 and C 8-15 aryl groups. Preferred aryl groups are C 6-10 aryl groups. Specific examples of carbocyclic aryl groups include phenyl, indanyl, indenyl, naphthyl, phenanthryl, anthracenyl, and fluorenyl. The aryl group may be optionally substituted with 1, 2, 3, 4, or 5 substituents selected from alkyl, alkenyl, aryl, arylalkyl, halogen, alkoxy, aryloxy, arylalkyloxy, alkylthio, alkylenedithio, alkylamino, [alkenyl]alkylamino, [aryl]alkylamino, [arylalkyl]alkylamino, dialkylamino, silyl, sulfonyl, cyano, nitro, carboxyl, and azide.

[0426] "Arylalkyl" refers to -R’R”, where R’ is an alkylene group and R” is an aryl group. The arylalkyl group may be optionally substituted in the same manner as defined for each R’ and R” group.

[0427] "Arylalkyloxy" refers to -OR, where R is an arylalkyl group. The arylalkyloxy group may be optionally substituted in the same manner as defined for the arylalkyl group.

[0428] "Arylene" refers to a polyvalent aryl group. The arylene group may be optionally substituted in the same manner as the aryl group. For example, C 6 arylene is phenylene.

[0429] "Aryloxy" refers to -OR, where R is an aryl group. The aryloxy group may be optionally substituted in the same manner as the aryl group.

[0430] "Azide" refers to -N 3 .

[0431] "Boronate" refers to –OB(R)O–, where R is an alkyl, alkenyl, aryl, arylalkyl, alkoxy, or 2,6-diethylamidophenyl group. The boronate may be substituted when R is a substituted alkyl, substituted alkenyl, substituted aryl, substituted arylalkyl, or substituted alkoxy group. Alternatively, the boronate may be unsubstituted when R is an unsubstituted alkyl, unsubstituted alkenyl, aryl, unsubstituted arylalkyl, unsubstituted alkoxy, or 2,6-diethylamidophenyl group.

[0432] "Carbamate" refers to the following group: when it is a hydroxyl protecting group, it has the formula -OC(O)NR2 or, when an amine protecting group, has the formula -NR'-C(O)OR, where each R and R' is independently H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted arylalkyl.

[0433] "Carbonate" means -OC(O)OR, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted arylalkyl.

[0434] "Carbonyl" means -C(O)-.

[0435] "Carboxyl" means -C(O)OH in free acid, ionized or salt form.

[0436] "Carboxylic acid" means R-OH, where R is optionally substituted acyl.

[0437] "Carboxylic anhydride" means R-O-R, where each R is independently optionally substituted acyl.

[0438] "Cyclic carbonate" means -OC(O)O- as part of a ring.

[0439] "Dicarbonyl" means -C(O)-C(O)-. Dicarbonyl-dioxo is -OC(O)-COO-.

[0440] "Ester" means -OC(O)R, where -C(O)R is optionally substituted acyl.

[0441] "Ether" means -OR, where R is alkyl, alkenyl, arylalkyl, silyl or 2-tetrahydropyranyl. The ether can be optionally substituted as defined for each R group.

[0442] "Halichondrin macrolide" means a lactone including the carbon 1-30 structure shown in Figure 1, where carbons 29 and 30 form part of a five- or six-membered ring.

[0443] "Haloalkyl" means -R'(R") n , where n is an integer from 1 to 5 and R' is alkylene and R" is halogen, as defined herein. R' can also be optionally substituted in the same manner as alkyl.

[0444] "Haloaryl" means -R'(R") n , where n is an integer from 1 to 5 and R' is arylene and R" is halogen, as defined herein. R' can also be optionally substituted in the same manner as aryl.

[0445] "Haloarylalkyl" means -R'(R"(R"')) n), where n is an integer from 1 to 5 and R’ is an alkylene group, R” is an arylene group, and R”’ is a halogen, as defined herein. R’ may also be optionally substituted in the same manner as an alkyl group. R” may also be optionally substituted in the same manner as an aryl group.

[0446] "Halogen" means fluorine, chlorine, bromine or iodine.

[0447] "Heterocyclic group" means a 5-, 6- or 7-membered ring which, unless otherwise specified, contains one, two, three or four heteroatoms independently selected from nitrogen, oxygen and sulfur. The 5-membered ring has zero to one double bond, and the 6- and 7-membered rings have zero to two double bonds. Some heterocyclic groups contain 1 to 9 carbon atoms. Other such groups may contain up to 12 carbon atoms. The term "heterocyclic group" also represents a heterocyclic compound having a bridged polycyclic structure in which one or more carbon and / or heteroatoms bridge two non-adjacent monocyclic members, such as quinuclidinyl. The term "heterocyclic group" includes bicyclic, tricyclic and tetracyclic groups in which any of the above heterocycles is fused to one, two or three carbocyclic rings (such as an aromatic ring, a cyclohexane ring, a cyclohexene ring, a cyclopentane ring, a cyclopentene ring), or fused to another monocyclic heterocycle such as indolyl, quinolyl, isoquinolyl, tetrahydroquinolyl, benzofuranyl, benzothiophenyl, etc. Examples of fused heterocycles include tropane and 1,2,3,5,8,8a-hexahydroindolizine. Heterocyclic groups include pyrrolyl, pyrrolinyl, pyrrolidinyl, pyrazolyl, pyrazolinyl, pyrazolidinyl, imidazolyl, imidazolinyl, imidazolidinyl, pyridyl, piperidinyl, homopiperidinyl, pyrazinyl, piperazinyl, pyrimidinyl, pyridazinyl, oxazolyl, oxazolidinyl, isoxazolyl, isoxazolidinyl, morpholinyl, thiomorpholinyl, thiazolyl, thiazolidinyl, isothiazolyl, isothiazolidinyl, indolyl, quinolyl, isoquinolyl, benzimidazolyl, benzothiazolyl, benzoxazolyl, furyl, thienyl, thiazolidinyl, isothiazolyl, isoindazolyl, triazolyl, tetrazolyl, oxadiazolyl, purinyl, thiadiazolyl (such as 1,3,4-thiadiazole), tetrahydrofuryl, dihydrofuryl, tetrahydrothienyl, dihydrothienyl, dihydroindolyl, tetrahydroquinolyl, tetrahydroisoquinolyl, pyranyl, dihydropyranyl, dithiazolyl, benzofuranyl, benzothiophenyl, etc. Other examples of heterocyclic groups also include: 2,3,4,5-tetrahydro-2-oxo-oxazolyl; 2,3-dihydro-2-oxo-1H-imidazolyl; 2,3,4,5-tetrahydro-5-oxo-1H-pyrazolyl (such as 2,3,4,5-tetrahydro-2-phenyl-5-oxo-1H-pyrazolyl); 2,3,4,5-tetrahydro-2,4-dioxo-1H-imidazolyl (such as 2,3,4,5-tetrahydro-2,4-dioxo-5-methyl-5-phenyl-1H-imidazolyl); 2,3-dihydro-2-thioxo-1,3,4-oxadiazolyl (such as 2,3-dihydro-2-thioxo-5-phenyl-1,3,4-oxadiazolyl); 4,5-dihydro-5-oxo-1 H -triazolyl (such as 4,5-dihydro-3-methyl-4-amino-5-oxo-1 H-triazolyl); 1,2,3,4-tetrahydro-2,4-dioxopyridinyl (such as 1,2,3,4-tetrahydro-2,4-dioxo-3,3-diethylpyridinyl); 2,6-dioxopiperidinyl (such as 2,6-dioxo-3-ethyl-3-phenylpiperidinyl); 1,6-dihydro-6-oxopyrimidinyl; 1,6-dihydro-4-oxopyrimidinyl (such as 2-(methylthio)-1,6-dihydro-4-oxo-5-methylpyrimidin-1-yl); 1,2,3,4-tetrahydro-2,4-dioxopyrimidinyl (such as 1,2,3,4-tetrahydro-2,4-dioxo-3-ethylpyrimidinyl); 1,6-dihydro-6-oxopyridazinyl (such as 1,6-dihydro-6-oxo-3-ethylpyridazinyl); 1,6-dihydro-6-oxo-1,2,4-triazinyl (such as 1,6-dihydro-5-isopropyl-6-oxo-1,2,4-triazinyl); 2,3-dihydro-2-oxo-1 H -indolyl (such as 3,3-dimethyl-2,3-dihydro-2-oxo-1 H -indolyl and 2,3-dihydro-2-oxo-3,3'-spiropropane-1 H -indol-1-yl); 1,3-dihydro-1-oxo-2 H -isoindolyl; 1,3-dihydro-1,3-dioxo-2 H -isoindolyl; 1 H -benzopyrazolyl (such as 1-(ethoxycarbonyl)-1 H -benzopyrazolyl); 2,3-dihydro-2-oxo-1 H -benzimidazolyl (such as 3-ethyl-2,3-dihydro-2-oxo-1 H -benzimidazolyl); 2,3-dihydro-2-oxobenzoxazolyl (such as 5-chloro-2,3-dihydro-2-oxobenzoxazolyl); 2,3-dihydro-2-oxobenzoxazolyl; 2-oxo-2H-benzopyranyl; 1,4-benzodioxanyl; 1,3-benzodioxanyl; 2,3-dihydro-3-oxo,4 H -1,3-benzothiazinyl; 3,4-dihydro-4-oxo-3 H -quinazolinyl (such as 2-methyl-3,4-dihydro-4-oxo-3 H -quinazolinyl); 1,2,3,4-tetrahydro-2,4-dioxo-3 H -quinazolinyl (such as 1-ethyl-1,2,3,4-tetrahydro-2,4-dioxo-3 H -quinazolinyl); 1,2,3,6-tetrahydro-2,6-dioxo-7 H -purinyl (such as 1,2,3,6-tetrahydro-1,3-dimethyl-2,6-dioxo-7 H-purinyl); 1,2,3,6-tetrahydro-2,6-dioxo-1 H -purinyl (such as 1,2,3,6-tetrahydro-3,7-dimethyl-2,6-dioxo-1 H -purinyl); 2-oxobenz c,d indolyl; 1,1-dioxo-2H-naphtho[1,8- c,d isothiazolyl; and 1,8-naphthylenedicarboxamido. Also included are heterocyclic groups of the following formula:

[0448] wherein

[0449] F′ is selected from -CH 2 -, -CH 2 O-, and -O-, and G′ is selected from -C(O)- and -(C(R’)(R”)) v -, where each R’ and R” is independently selected from hydrogen or alkyl of one to four carbon atoms, and v is from 1 to 3, and including groups such as 1,3-benzodioxolyl, 1,4-benzodioxanyl, etc. Any heterocyclic group mentioned herein may be optionally substituted by one, two, three, four, or five substituents independently selected from the following: (1) alkanoyl (such as formyl, acetyl, etc.); (2) alkyl (such as alkoxyalkyl, alkylsulfinylalkyl, aminoalkyl, azidoalkyl, acylalkyl, haloalkyl (such as perfluoroalkyl), hydroxyalkyl, nitroalkyl, or thioalkoxyalkyl); (3) alkenyl; (4) alkynyl; (5) alkoxy (such as perfluoroalkoxy); (6) alkylsulfinyl; (7) aryl; (8) amino; (9) aryl-alkyl; (10) azido; (11) cycloalkyl; (12) cycloalkyl-alkyl; (13) cycloalkenyl; (14) cycloalkenyl-alkyl; (15) halo; (16) heterocyclic group (such as heteroaryl); (17) (heterocyclic group)oxy; (18) (heterocyclic group)aza; (19) hydroxy; (20) oxo; (21) nitro; (22) thio; (23) thioalkoxy; (24) -(CH 2 ) q CO 2 R A , where q is an integer from 0 to 4, and R A is selected from (a) alkyl, (b) aryl, (c) hydrogen, and (d) aryl-alkyl; (25) -(CH 2 ) q CONR B R C , where q is an integer from 0 to 4 and where R B and R CIndependently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene; (26)-(CH 2 ) q SO 2 R D , where q is an integer from 0 to 4 and where R D is selected from (a) alkyl, (b) aryl, and (c) aryl-alkylene; (27)-(CH 2 ) q SO 2 NR E R F , where q is an integer from 0 to 4 and where each R E and R F is independently selected from (a) hydrogen, (b) alkyl, (c) aryl, and (d) aryl-alkylene; (28) mercapto; (29) aryloxy; (30) cycloalkyloxy; (31) arylalkyloxy; (31) heterocyclic-alkylene (such as heteroaryl-alkylene); (32) silyl; (33) cyano; and (34)-S(O)R H , where R H is selected from (a) hydrogen, (b) alkyl, (c) aryl and (d) aryl-alkylene. In some embodiments, these groups may each be further substituted as described herein. For example, the alkylene of the aryl-C 1 -alkylene or heterocyclic-C 1 -alkylene may be further substituted with an oxo group to give the corresponding aroyl and (heterocyclic) acyl (oyl) substituents. In addition, when a heterocyclic group is present in the bio-reversible group of the present invention, it may be substituted with an ester, thioester or disulfide group as defined herein that is linked to a conjugate moiety, a hydrophilic functional group or a helper moiety.

[0450] As used herein, "heterocyclic alkyl" means an alkyl group substituted with a heterocyclic group. The heterocyclic group and the alkyl moiety may be substituted as described herein for each group.

[0451] "Hydroxyalkyl" means -R'(R") n , where n is 1 or 2, R' is alkylene and R" is hydroxy, as defined herein. R' may also be optionally substituted in the same manner as alkyl.

[0452] "Hydroxyaryl" means -R'(R") n , where n is 1 or 2, R' is arylene and R" is hydroxy, as defined herein. R' may also be optionally substituted in the same manner as aryl.

[0453] "Hydroxy" means -OH.

[0454] "Hydroxy protecting group" refers to any group that can protect the oxygen atom to which it is attached from reaction or bonding. Hydroxy protecting groups are known in the art; see, for example, Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary protecting groups (with the oxygen atom to which they are attached) are independently selected from esters, carbonates, carbamates, sulfonates, and ethers. In exemplary ester hydroxy protecting groups, the R of the acyl group is C 1-12 alkyl (e.g., C 1-8 、C 1-6 、C 1-4 、C 2-7 、C 3-12 and C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 、C 2-6 、C 2-4 、C 3-12 and C 3-6 alkenyl), carbocyclic C 6-20 aryl (e.g., C 6-15 、C 6-10 、C 8-20 and C 8-15 aryl), monocyclic C 1-6 heteroaryl (e.g., C 1-4 and C 2-6 heteroaryl), C 4-19 heteroaryl (e.g., C 4-10 heteroaryl), (C 6-15 ) aryl (C 1-6 ) alkyl, (C 4-19 ) heteroaryl (C 1-6 ) alkyl or (C 1-6 ) heteroaryl (C 1-6 ) alkyl. Specific examples of acyl groups for esters include formyl, benzoylformyl, acetyl (e.g., unsubstituted or chloroacetyl, trifluoroacetyl, methoxyacetyl, triphenylmethoxyacetyl, and p-chlorophenoxyacetyl), 3-phenylpropionyl, 4-oxopentanoyl, 4,4-(ethylenedithio)pentanoyl, pivaloyl (Piv), vinylpivaloyl, crotonoyl, 4-methoxy-crotonoyl, naphthoyl (e.g., 1- or 2-naphthoyl), and benzoyl (e.g., unsubstituted or substituted, e.g., p-methoxybenzoyl, phthaloyl (including salts, e.g., triethylamine and potassium salts), p-bromobenzoyl, and 2,4,6-trimethylbenzoyl). As defined herein, any heteroaryl present in an ester has 1-4 heteroatoms independently selected from O, N, and S. In exemplary carbonate hydroxy protecting groups, R is C1-12 alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 and C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 , C 2-6 , C 2-4 , C 3-12 and C 3-6 alkenyl), carbocyclic C 6-20 aryl (e.g., C 6-15 , C 6-10 , C 8-20 and C 8-15 aryl), monocyclic C 1-6 heteroaryl (e.g., C 1-4 and C 2-6 heteroaryl), C 4-19 heteroaryl (e.g., C 4-10 heteroaryl), (C 6-15 )aryl(C 1-6 )alkyl, (C 4-19 )heteroaryl(C 1-6 )alkyl or (C 1-6 )heteroaryl(C 1-6 )alkyl. Specific examples include methyl, 9-fluorenylmethyl, ethyl, 2,2,2-trichloroethyl, 2-(trimethylsilyl)ethyl, 2-(phenylsulfonyl)ethyl, vinyl, allyl, tert-butyl, p-nitrobenzyl, and benzyl carbonates. As defined herein, any heteroaryl present in a carbonate has 1-4 heteroatoms independently selected from O, N, and S. In exemplary carbamate hydroxy protecting groups, each R is independently H, C 1-12 alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 and C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 , C 2-6 , C 2-4 , C 3-12 and C 3-6 alkenyl), carbocyclic C 6-20 aryl (e.g., C 6-15 , C 6-10 , C 8-20 and C 8-15 aryl), monocyclic C 1-6 heteroaryl (e.g., C 1-4 and C 2-6heteroaryl), C 4-19 heteroaryl (e.g., C 4-10 heteroaryl), (C 6-15 )aryl(C 1-6 )alkyl, (C 4-19 )heteroaryl(C 1-6 )alkyl or (C 1-6 )heteroaryl(C 1-6 )alkyl. Specific examples include carbamates of N-phenyl and N-methyl-N-(o-nitrophenyl). As defined herein, any heteroaryl present in the carbamate group has 1-4 heteroatoms independently selected from O, N, and S. Exemplary ether hydroxyl protecting groups include C 1-12 alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 and C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 , C 2-6 , C 2-4 , C 3-12 and C 3-6 alkenyl), (C 6-15 )aryl(C 1-6 )alkyl, (C 4-19 )heteroaryl(C 1-6 )alkyl, (C 1-6 )heteroaryl(C 1-6 )alkyl, (C 1-6 )alkoxy(C 1-6 )alkyl, (C 1-6 )alkylthio(C 1-6 )alkyl, (C 6-10 )aryl(C 1-6 )alkoxy(C 1-6 )alkyl and silyl (e.g., tris(C 1-6 alkyl)silyl, tris(C 6-10 aryl or C 1-6 heteroaryl)silyl, di(C 6-10 aryl or C 1-6 heteroaryl)(C 1-6 alkyl)silyl and (C 6-10 aryl or C 1-6 heteroaryl)di(C 1-6 alkyl)silyl). Specific examples of alkyl ethers include methyl and tert-butyl, and an example of an alkenyl ether is allyl. The ether hydroxyl protecting group can be used to protect a carboxyl group (e.g., with C 1-12 alkyl (e.g., C 1-8 , C 1-6 、C1-4 , C 2-7 , C 3-12 and C 3-6 alkyl), (C 6-15 ) aryl(C 1-6 ) alkyl, (C 1-6 ) alkoxy(C 1-6 ) alkyl, (C 1-6 ) alkylthio(C 1-6 ) alkyl, or (C 6-10 ) aryl(C 1-6 ) alkoxy(C 1-6 ) alkyl). Examples of alkoxyalkyl and alkylthioalkyl groups that can be used as ether hydroxyl protecting groups include methoxymethyl, methylthiomethyl, (2 - methoxyethoxy)methyl, and β - (trimethylsilyl)ethoxymethyl. Examples of arylalkyls that can be used as ether hydroxyl protecting groups include benzyl, p - methoxybenzyl (MPM), 3,4 - dimethoxybenzyl, triphenylmethyl (trityl), o - nitrobenzyl, p - nitrobenzyl, p - halobenzyl, 2,6 - dichlorobenzyl, p - cyanobenzyl, naphthylmethyl, and 2 - and 4 - pyridylmethyl ethers. Specific examples of silyl ethers include trimethylsilyl (TMS), triethylsilyl (TES), tert - butyldimethylsilyl (TBS), tert - butyldiphenylsilyl (TBDPS), triisopropylsilyl (TIPS), and triphenylsilyl (TPS) ethers. An example of an arylalkyloxyalkyl ether is benzyloxymethyl ether. As defined herein, any heteroaryl present in the ether group has 1 - 4 heteroatoms independently selected from O, N, and S. Vicinal or 1,3 - diols can be protected with diol protecting groups (e.g., to form a “cyclic protected diol”), such as acetals (e.g., containing C 1-6 alkylene), ketals (e.g., containing C 3-6 alkylene or C 3-6 cycloalkyl), cyclic silylene, cyclic carbonate, and cyclic borate. Examples of acetal and ketal groups include methylene - dioxy, ethylidene - dioxy, benzylidene - dioxy, isopropylidene - dioxy, cyclohexylidene - dioxy, and cyclopentylidene - dioxy. An example of cyclic silylene is di - tert - butylsilylene. Another diol protecting group is 1,1,3,3 - tetraisopropylsiloxanediyl. Examples of cyclic borates include methyl, ethyl, phenyl, and 2,6 - diacetamidophenyl borate. Protecting groups can be substituted as known in the art; for example, aryl and arylalkyl (e.g., phenyl, benzyl, naphthyl, or pyridyl) can be substituted with C 1-6 alkyl, C 1-6substituted with an alkoxy, nitro, cyano, carboxyl or halogen group. Alkyl groups (such as methyl, ethyl, isopropyl, n-propyl, tert-butyl, n-butyl and sec-butyl) and alkenyl groups (such as vinyl and allyl) may also be substituted with oxo, arylsulfonyl, halogen and trialkylsilyl groups. Preferred protecting groups are TBS and Piv. Removal of orthogonal protecting groups under different conditions is known in the art.

[0455] "Imido" means -NR 2 , where each R is independently an optionally substituted acyl group.

[0456] "Ketal" means -O-CR 2 -O-, where each R is independently an optionally substituted alkyl group, an optionally substituted alkenyl group, an optionally substituted aryl group or an optionally substituted arylalkyl group, or the two R groups together are an optionally substituted alkylene group, or each R group is a bond attached to a carbon atom listed in the intermediate or in the soft spongin macrolide or its analog as shown in Figure 1.

[0457] "Macrocycle" means a compound containing at least one n -membered ring, where n is equal to or greater than 10.

[0458] "Non-enolizable" means a group that cannot form an enol by a deprotonation / reprotonation sequence, either alone or in combination with the groups to which it is attached. For example, a "non-enolizable alkyl" may be bonded to a sulfone group or a carbonyl group through a quaternary carbon atom (i.e., a carbon atom not bonded to a hydrogen atom).

[0459] " N -Protecting group" means a group that protects the nitrogen atom in a molecule from participating in one or more unwanted reactions (e.g., oxidation reactions or certain nucleophilic and electrophilic substitutions) during chemical synthesis. Commonly used N -protecting groups are disclosed in Wuts, Greene's Protective Groups in Organic Synthesis, Wiley-Interscience, 4th Edition, 2006. Exemplary N- Protecting groups include: acyl groups (e.g., formyl, acetyl, trifluoroacetyl, propionyl, pivaloyl, t-butylacetyl, 2-chloroacetyl, 2-bromoacetyl, trifluoroacetyl, trichloroacetyl, phthaloyl, o-nitrophenoxyacetyl, α-chlorobutyryl, benzoyl, 4-chlorobenzoyl, and 4-bromobenzoyl); sulfonyl-containing groups (e.g., benzenesulfonyl, p-toluenesulfonyl, o-nitrobenzenesulfonyl, and p-nitrobenzenesulfonyl); groups forming carbamates (e.g., benzyloxycarbonyl, p-chlorobenzyloxycarbonyl, p-methoxybenzyloxycarbonyl, p-nitrobenzyloxycarbonyl, 2-nitrobenzyloxycarbonyl, p-bromobenzyloxycarbonyl, 3,4-dimethoxybenzyloxycarbonyl, 3,5-dimethoxybenzyloxycarbonyl, 2,4-dimethoxybenzyloxycarbonyl, 4-methoxybenzyloxycarbonyl, 2-nitro-4,5-dimethoxybenzyloxycarbonyl, 3,4,5-trimethoxybenzyloxycarbonyl, 1-(p-biphenylyl)-1-methylethoxycarbonyl, α,α-dimethyl-3,5-dimethoxybenzyloxycarbonyl, diphenylmethoxycarbonyl, t-butoxycarbonyl, diisopropylmethoxycarbonyl, isopropoxycarbonyl, ethoxycarbonyl, methoxycarbonyl, allyloxycarbonyl, 2,2,2-trichloroethoxycarbonyl, phenoxycarbonyl, 4-nitrophenoxycarbonyl, fluoren-9-ylmethoxycarbonyl, cyclopentyloxycarbonyl, adamantyloxycarbonyl, cyclohexyloxycarbonyl, and phenylthiocarbonyl); arylalkyls (e.g., triphenylmethyl); silyls (e.g., trimethylsilyl); and groups forming imines (e.g., diphenylmethylene). Preferred N - protecting groups are acetyl, benzoyl, phenylsulfonyl, p-toluenesulfonyl, p-nitrobenzenesulfonyl, o-nitrobenzenesulfonyl, t-butoxycarbonyl (Boc), and benzyloxycarbonyl (Cbz).

[0460] "oxo" or (O) means =O.

[0461] "Pharmaceutically acceptable salts" refer to salts within the scope of reasonable medical judgment that are suitable for contact with the tissues of humans and animals without excessive toxicity, irritation, allergic reaction, etc., and that exhibit a reasonable benefit / risk ratio. Pharmaceutically acceptable salts are well known in the art. For example, pharmaceutically acceptable salts are described in: Berge et al., J. Pharmaceutical Sciences 66: 1-19, 1977, and Pharmaceutical Salts: Properties, Selection, and Use (Eds. P.H. Stahl and C.G. Wermuth), Wiley-VCH, 2008. Representative acid addition salts include acetate, adipate, alginate, ascorbate, aspartate, benzenesulfonate, benzoate, bisulfate, borate, butyrate, camphorate, camphorsulfonate, citrate, cyclopentanepropionate, digluconate, dodecyl sulfate, ethanesulfonate, fumarate, glucoheptonate, glycerophosphate, hemisulfate, heptanoate, hexanoate, hydrobromide, hydrochloride, hydroiodide, 2-hydroxyethanesulfonate, lactobionate, lactate, laurate, lauryl sulfate, malate, maleate, malonate, methanesulfonate, 2-naphthalenesulfonate, nicotinate, nitrate, oleate, oxalate, palmitate, pamoate, pectinate, persulfate, 3-phenylpropionate, phosphate, picrate, pivalate, propionate, stearate, succinate, sulfate, tartrate, thiocyanate, toluenesulfonate, undecanoate, valerate, etc. Preferred is methanesulfonate.

[0462] "Pseudohalogen" refers to –O–SO 2 R, where R is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted arylalkyl. Non-limiting examples of pseudohalogens include trifluoromethanesulfonate and nonaflate.

[0463] "Silyl" refers to -SiR 3 , where each R is independently an alkyl, alkenyl, aryl, or arylalkyl. Examples of silyls include tris(C 1-6 alkyl)silyl, tris(C 6-10 aryl or C 1-6 heteroaryl)silyl, bis(C 6-10 aryl or C 1-6 heteroaryl)(C 1-6 alkyl)silyl, and (C 6-10 aryl or C 1-6 heteroaryl)bis(C 1-6(alkyl)silyl. It is to be understood that when the silyl group includes two or more alkyl, alkenyl, aryl, heteroaryl or arylalkyl groups, these groups are independently selected. As defined herein, any heteroaryl group present in the silyl group has 1 - 4 heteroatoms independently selected from O, N and S. The silyl group may be optionally substituted in the same manner as defined for each R group.

[0464] “Methylsilylene” means -SiR 2 -, where each R is independently alkyl, alkenyl, aryl, arylalkyl or alkoxy. “Dialkylmethylsilylene” means a methylsilylene group in which each R is alkyl. The methylsilylene group may be optionally substituted in the same manner as defined for each R group. “Methylsilylene - dioxy” is a group having the formula -O - SiR 2 -O-.

[0465] “Strong base” means a Brønsted base whose conjugate acid has a pKa greater than or equal to 13. Non - limiting examples of strong bases include alkyl alkali metals (e.g., butyllithium or Schlosser’s base), Grignard reagents (e.g., alkylmagnesium halides), alkali metal or alkaline earth metal alkoxides (e.g., tertiary alkoxides, such as tert - butoxide), alkali metal or alkaline earth metal amides (e.g., diisopropylamide, tetramethylpiperidine or bis(trimethylsilyl)amide), and phosphazene bases (e.g., Schwesinger base). Non - limiting examples of alkali metal amides are lithium diisopropylamide, lithium tetramethylpiperidine, lithium bis(trimethylsilyl)amide, sodium bis(trimethylsilyl)amide, and potassium bis(trimethylsilyl)amide.

[0466] “Sulfonamide” means -NR, where R is a sulfonyl group.

[0467] “Sulfonate” means -OS(O) 2 R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl or optionally substituted arylalkyl. In an exemplary sulfonate, R is C 1-12 alkyl (e.g., C 1-8 , C 1-6 , C 1-4 , C 2-7 , C 3-12 or C 3-6 alkyl), C 2-12 alkenyl (e.g., C 2-8 , C 2-6 , C 2-4 , C 3-12 or C 3-6 alkenyl), carbocyclic C 6-20 aryl (e.g., C 6-15 , C 6-10 , C8-20 or C 8-15 aryl), monocyclic C 1-6 heteroaryl (e.g., C 1-4 and C 2-6 heteroaryl), C 4-19 heteroaryl (e.g., C 4-10 heteroaryl), (C 6-15 )aryl(C 1-6 )alkyl, (C 4-19 )heteroaryl(C 1-6 )alkyl or (C 1-6 )heteroaryl(C 1-6 )alkyl. As defined herein, any heteroaryl in a sulfonate group has 1 - 4 heteroatoms independently selected from O, N, and S.

[0468] "sulfonyl" means -S(O) 2 R, where R is optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, optionally substituted arylalkyl, or silyl. Preferred R groups for sulfonyl are the same as those described above for sulfonate.

[0469] "thioacetal" means -S-(CHR)-S-, where R is H, optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

[0470] "thioketal" means -S-(CR 2 )-S-, where each R is independently optionally substituted alkyl, optionally substituted alkenyl, optionally substituted aryl, or optionally substituted arylalkyl.

[0471] "triflate" means trifluoromethanesulfonate.

[0472] Unless otherwise stated, the pKa values recited herein refer to the pKa values of the conjugate Brønsted acids in water at room temperature.

[0473] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this disclosure belongs. Although methods and materials similar or equivalent to those described herein can be used to practice the disclosed methods and compositions, exemplary methods, devices, and materials are described herein.

[0474] For the purposes of this disclosure, any term that exists in the art and is the same as any term clearly defined in this disclosure will be defined in all respects by the term definition presented in this disclosure. Detailed Description of the Invention

[0475] The present invention provides a method for synthesizing halichondrin macrocycles or analogs thereof (see Figure 1). Preferably, the halichondrin macrocycle analog is eribulin. Preferably, the halichondrin macrocycle is halichondrin B macrocycle. The method of the present invention includes subjecting an intermediate to Prins reaction conditions. The carbon atom numbering scheme of halichondrin macrocycles and their analogs is shown in Figure 1.

[0476] Figure 1

[0477]

[0478] or a salt or tautomer thereof,

[0479] wherein D and D’ are each independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, alkyl, or a hydroxyl protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, which is unsubstituted or has 1 - 10 substituents, and the substituents are independently selected from: cyano, halogen, azide, oxo, and Q 1 , and the group of formula (1) has the structure:

[0480]

[0481] wherein

[0482] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))–, or –C(O)–;

[0483] R 1 is H, or R 1 and P 1 combine to form a bond;

[0484] (i) R 2 is H, wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

[0485] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , wherein P 3 is H or an N - protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is H or an N - protecting group, or (b) P2 and P 4 combine to form an alkylidene, or (c) P 2 and P 4 are each H;

[0486] (iii) R 2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, an optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, a cyclic carbonate, a dicarbonyl-dioxo, or a silyl-dioxo; or

[0487] (iv) R 2 and P 2 combine to form an optionally substituted ethylene or a structure selected from the following:

[0488]

[0489]

[0490] where each P’ is independently H or a hydroxyl protecting group;

[0491] A 1 , A 2 and A 3 are each independently H or OP”, where each P” is independently H or a hydroxyl protecting group;

[0492] E is H, an optionally substituted alkyl, or an optionally substituted alkoxy;

[0493] G is O, S, CH 2 or NR N , where R N is H, an N-protecting group, or an optionally substituted alkyl;

[0494] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)RA , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , wherein R A and R B are each independently H, alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0495] k is 0 or 1; and

[0496] n is 0, 1 or 2.

[0497] The preparation of halichondrin macrolide or its analogs comprises the reaction between a compound of formula (IA), R 12 OH (R 12 may be an optionally substituted acyl group) and a Lewis acid (e.g., an oxophilic Lewis acid (e.g., boron trifluoride or its solvate)) to form a compound of formula (IB). The compound of formula (IA) has the following structure:

[0498]

[0499] or its salt or tautomer,

[0500] wherein

[0501] D and D’ are each independently H, optionally substituted alkyl, or OP 1 , provided that only one of D and D’ is OP 1 , wherein P 1 is H, alkyl, or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1-10 substituents, said substituents being independently selected from: cyano, halogen, azide, oxo and Q 1 , and the group of formula (1) has the structure:

[0502]

[0503] wherein

[0504] L is –(CH(OP 2 ))–, –(C(OH)(OP 2 ))– or –C(O)–;

[0505] R 1 is H, or R 1 and P 1 combine to form a bond;

[0506] (i) R 2 is H, where P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group;

[0507] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , where P 3 is an N - protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 4 is an N - protecting group, or (b) P 2 and P 4 combine to form an alkylene group;

[0508] (iii) R 2 is –(CH 2 ) n OP 5 , where P 2 is absent, H, optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl - dioxo or silylene - dioxo; or

[0509] (iv) R 2 and P 2 combine to form an optionally substituted ethylene group or a structure selected from:

[0510]

[0511]

[0512] where each P’ is independently H or a hydroxyl protecting group;

[0513] E is H, optionally substituted alkyl or optionally substituted alkoxy;

[0514] G is O, S, CH 2 or NRN , wherein R N is H, an N-protecting group or an optionally substituted alkyl group;

[0515] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , wherein R A and R B are each independently H, an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an aryl group, a haloaryl group, a hydroxyaryl group, an alkoxyaryl group, an arylalkyl group, an alkylaryl group, a haloarylalkyl group, an alkylhaloaryl group, an (alkoxyaryl)alkyl group, a heterocyclic group or a heterocyclic-alkyl group;

[0516] n, when present, is 0, 1 or 2;

[0517] k is 0 or 1;

[0518] X 1 is –CH(Y)–, –CH 2 – or –O–, and X 2 is =O or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 )–; wherein each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or -SR X1 ; wherein each R X1 is independently an optionally substituted alkyl group, or two R X1Combine to form an optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O; and wherein Y is SO 2 R C or COOR C , wherein when Y is SO 2 R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when Y is COOR C is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted arylalkyl; C is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted arylalkyl; C is an optionally substituted alkyl, an optionally substituted aryl, or an optionally substituted arylalkyl;

[0519] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached form a double bond, and the remaining R 4 or R 6 is H;

[0520] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxy protecting group, and R 8 is H;

[0521] or

[0522] A 1 is H or OP”, and:

[0523] (i) P 7 is H or a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached form a double bond;

[0524] or

[0525] (ii) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0526] (i) Each P 6 is independently H or a hydroxy protecting group, or two P 6 together with the atoms to which they are attached form a ketal or an acetal; X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP9 ))–, wherein P 9 is H or a hydroxyl protecting group; and each R 11 is –OP 10 ; or two Rs 11 combine to form oxo, wherein P 10 is an alkyl or a hydroxyl protecting group (e.g., silyl);

[0527] (ii) P 6 and X both combine with the atoms to which they are attached to form a ketal, P 7 and R 7 combine to form a bond, and R 8 is H or OP”; and each R 11 is –OP 10 ; or two Rs 11 combine to form oxo, wherein P 10 is an alkyl or a hydroxyl protecting group (e.g., silyl); or

[0528] (iii) two Ps 6 and two Rs 11 combine with the atoms to which they are attached to form an acetal; and X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, wherein P 9 is H or a hydroxyl protecting group;

[0529] R 9 is H, OP” or Y, and R 10 is H; or R 9 and R 10 combine with the atoms to which they are attached to form a double bond;

[0530] P 8 is H or silyl; and

[0531] each P” when present is independently H or a hydroxyl protecting group.

[0532] The compound of formula (IB) has the following structure:

[0533]

[0534] or a salt or tautomer thereof,

[0535] wherein R 12 is an optionally substituted acyl group, and all other variables are as defined for the compound of formula (IA).

[0536] Typically, the reaction conditions for converting the compound of formula (IA) to the compound of formula (IB) are those known in the art for the Prins reaction.

[0537] The preparation of halichondramide macrolide or its analogs from the compound of formula (IB) further comprises reacting the compound of formula (IB) with an allyl reducing agent to produce halichondramide macrolide or its analogs.

[0538] In halichondramide macrolide, its analogs, formula (IA) or formula (IB), G can be O. In halichondramide macrolide, its analogs, formula (IA) or formula (IB), D can be H. In halichondramide macrolide, its analogs, formula (IA) or formula (IB), D’ can be OP 1 , where P 1 can be an alkyl group (e.g., methyl).

[0539] In the halichondramide macrolide analogs, formula (IA) or formula (IB), k can be 0, and X 1 can be –CH 2 –. In halichondramide macrolide, formula (IA) or formula (IB), k can be 1, and X 1 can be –O–.

[0540] In halichondramide macrolide, its analogs, formula (IA) or formula (IB), E can be an optionally substituted alkyl group.

[0541] In halichondramide macrolide, its analogs, formula (IA) or formula (IB), A 1 can be H.

[0542] In halichondramide macrolide, its analogs, formula (IA) or formula (IB), the a stereocenter specified by R can be (

[0543] ), and A can have the following structure:

[0544] In a further embodiment of halichondramide macrolide, its analogs, formula (IA) or formula (IB), k is 0 and X 1 is –CH 2 –. In yet a further embodiment of halichondramide macrolide, its analogs, formula (IA) or formula (IB), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , where n is 0.

[0545] Alternatively, in the halichondramide macrolactone, its analogs, formula (IA) or formula (IB), A and D can combine to form the following structures:

[0546]

[0547] wherein the bond connecting the oxygen atom originates from the carbon atom connected to D in the halichondramide macrolactone, its analogs, formula (IA) or formula (IB). In still further embodiments of the halichondramide macrolactone, its analogs, formula (IA) or formula (IB), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , and n is 2.

[0548] In other embodiments of the halichondramide macrolactone, its analogs, formula (IA) or formula (IB), k is 1, and E is an optionally substituted alkyl group. In still other embodiments of the halichondramide macrolactone, its analogs, formula (IA) or formula (IB), X 1 is –O–.

[0549] If in the compound of formula (IA), R 3 is H or a hydroxyl protecting group, R 5 and R 4 and one of R 6 combine with their respective connected atoms to form a double bond, and the remaining R 4 or R 6 is H, then treating the compound of formula (IA) with a Lewis acid (e.g., an oxygenophilic Lewis acid) and R 12 OH can generate the compound of formula (IB), wherein R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H.

[0550] The preparation of the halichondramide macrolactone or its analogs can include further steps, depending on the properties of A 1 , R 3 , R 4 , R 5 , R 6 , R 7 , R 8 , R 9 , R 10 , R 1 , P 6 and P 7 .

[0551] The preparation of certain compounds of formula (IA) or formula (IB) may further comprise converting a compound of formula (IA) or formula (IB) wherein A 1 is H and R 7 and R 8 combine to form a double bond) into a compound of formula (IA) or formula (IB) wherein R 7 and A 1 combine to form O). In a non-limiting example, a nucleophilic peroxide reagent such as tert-butyl hydroperoxide can be used to convert the enone in a compound of formula (IA) or formula (IB) wherein R 7 and R 8 combine to form a double bond) into a C.12-C.13 epoxide, which can then be converted into a compound of formula (IA) or formula (IB) wherein A 1 and R 7 combine to form an oxo) using methods known in the art (e.g., by reaction with a bidentate phosphine ligand and a Pd(0) source) (see, e.g., Muzart, J., Eur. J. Org. Chem. , 4717-4741, 2011). Thus, compounds of formula (IA) or formula (IB) wherein A 1 is OP” can be prepared. Other transformations may include α-oxidation to generate compounds of formula (IA) or formula (IB) wherein R 8 and / or R 9 is OP”.

[0552] If, in a compound of formula (IA) or formula (IB), X 1 is –CH(Y)– and / or R 9 is SO 2 R C or COOR C , then the synthesis of the halichondrin macrolide or an analogue thereof may further comprise the decarboxylation reaction described herein (when X 1 is –CH(Y)– and Y is COOR C and / or R 9 is COOR C ) or desulfonation reaction (when X 1 is –CH(Y)– and Y is SO 2 R C and / or R 9 is SO 2 R C ). The decarboxylation or desulfonation reaction can be carried out on the compound of formula (IA) or formula (IB) or on a downstream intermediate of the compound of formula (IB) (e.g., after reacting the compound of formula (IB) with an allyl reducing agent).

[0553] If, in the compound of formula (IA) or formula (IB), wherein R 9 and R 10 together with the atoms to which they are attached form a double bond, the synthesis of the halichondrin macrolide or its analog can further comprise a 1,4-reduction as described herein (e.g., using Stryker's reagent). The 1,4-reduction can be carried out on the compound of formula (IA) or formula (IB) or on a downstream intermediate of the compound of formula (IB). Thus, a compound of formula (IA) or formula (IB) can be prepared in which both R 9 and R 10 are H.

[0554] If, in the compound of formula (IA) or formula (IB), X together with the carbon atom to which it is attached forms –(CH(OP 9 ))–, where P 9 is H, the synthesis of the halichondrin macrolide or its analog can further comprise reacting the compound of formula (IB) with an oxidizing agent capable of converting an alcohol to a carbonyl group to produce a compound of formula (IB) in which X is =O. Alternatively, treatment with an oxidizing agent capable of converting an alcohol to a carbonyl group can be carried out on a downstream intermediate of the compound of formula (IB) (e.g., after reacting the compound of formula (IB) with an allyl reducing agent). The reaction in which X is converted to oxo can also be carried out on the compound of formula (IA) prior to the macrolactonization reaction.

[0555] If, in the compound of formula (IB), each P 6 is H and X is =O, the synthesis of the halichondrin macrolide or its analog can further comprise reacting the compound of formula (IB) with a Bronsted acid (e.g., a Bronsted acid having a pKa of 5 ± 3) to produce a compound of formula (IB) in which both P 6 and X together with the atoms to which they are attached form a ketal. Alternatively, treatment with a Bronsted acid (e.g., a Bronsted acid having a pKa of 5 ± 3) can be carried out on a downstream intermediate of the compound of formula (IB) (e.g., after reacting the compound of formula (IB) with an allyl reducing agent).

[0556] If, in the compound of formula (IB), each P 6 is a hydroxy protecting group (e.g., silyl) and X is =O, the synthesis of the halichondrin macrolide or its analog can further comprise reacting the compound of formula (IB) with a hydroxy protecting group removing agent (e.g., a fluoride source if P 6 is silyl) to produce a compound of formula (IB) in which each P 6When H and X are =O, it can then be treated with a Bronsted acid (e.g., a Bronsted acid having a pKa of 5 ± 3) to produce a compound of formula (IB), wherein P 6 and X both combine with the atoms to which they are attached to form a ketal. Alternatively, treatment with a hydroxy protecting group remover (e.g., a fluoride source, if P 6 is a silyl group) can be carried out on the downstream intermediate of the compound of formula (IB) (e.g., after reacting the compound of formula (IB) with an allyl reducing agent).

[0557] If, in the compound of formula (IB), each P 6 is H, X is =O, P 7 is H, and R 7 and R 8 combine with the atoms to which they are attached to form a double bond, the synthesis of halichondrin macrolide or an analogue thereof can further include reacting the compound of formula (IB) with a Bronsted acid (e.g., a Bronsted acid having a pKa of 5 ± 3) to produce a compound of formula (IB), wherein P 6 and X both combine with the atoms to which they are attached to form a ketal, and R 7 and R 8 combine with the atoms to which they are attached to form a double bond. Alternatively, treatment with a Bronsted acid (e.g., a Bronsted acid having a pKa of 5 ± 3) can be carried out on the downstream intermediate of the compound of formula (IB) (e.g., after reacting the compound of formula (IB) with an allyl reducing agent).

[0558] If the halichondrin macrolide analogue contains A, which is a group of formula (1), wherein L is –CH(OH)-, R 1 is H, and R 2 is –(CH 2 ) n NP 3 P 4 (e.g., eribulin or a salt thereof), and in the compound of formula (IB), A is a group of formula (1), wherein L is –CH(OH)-, R 1 is H and R 2 is –(CH 2 ) n OP 5 wherein P 5 is H, the synthesis of the halichondrin macrolide analogue can include the amination described herein. In some embodiments, the halichondrin macrolide analogue is eribulin or a salt thereof (e.g., eribulin mesylate).

[0559] If the halichondrin macrolide analogue is eribulin mesylate, the synthesis can further include the salification of eribulin described herein.

[0560] Given the invention disclosed herein and the knowledge in the art, additional protecting group manipulations can be readily identified. In particular, those skilled in the art will recognize that if an alcohol is protected with a hydroxy protecting group, the conversion in which the alcohol is oxidized to a carbonyl group may require deprotection of the alcohol (e.g., by treatment with a hydroxy protecting group removing agent), unless such deprotection occurs in situ under the oxidation reaction conditions. Similarly, those skilled in the art will recognize that an oxidative transformation of a compound containing a primary or secondary alcohol may require protection of the primary or secondary alcohol if such an alcohol is to be retained and if the primary or secondary alcohol is prone to oxidation under the conditions present for the oxidative transformation.

[0561] Synthesis of Intermediates

[0562] The compounds of formula (IA) can be prepared using, for example, the methods and intermediates disclosed in the following: U.S. Patent Nos. 5,338,865; 5,436,238; and 6,214,865; International Patent Application Publication Nos. WO 2015 / 066729 and WO 2016 / 179607; and Towle et al., Annual Meeting of the American Association for Cancer Research , April 6 - 10, 2002, 5721; Wang et al., Bioorg. Med. Chem. Lett. , 10:1029 - 1032, 2000; Aicher et al., J. Am. Chem. Soc. , 114:3162 - 3164, 1992; Ueda et al., J. Am. Chem. Soc. , 136:5171 - 5176; and Yamamoto et al., J. Am. Chem. Soc. , 134:893 - 896, 2012; each of which is incorporated herein by reference in its entirety.

[0563] Synthesis of the compound according to formula (IC)

[0564] The compounds of formula (IA) wherein X 1 is –CH(Y)– or –CH 2 –) can be prepared by reacting a compound of formula (IC) wherein R 13 is H with a compound of formula (ID), treating it with a strong base (e.g., an alkali metal amide or an alkyllithium).

[0565] The compounds of formula (IC) have the following structure:

[0566]

[0567] wherein

[0568] D and D’ are each independently H, an optionally substituted alkyl, or OP1 provided that only one of D and D' is OP 1 , wherein P 1 is H, alkyl, or a hydroxy protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon backbone, said backbone being unsubstituted or having 1 - 10 substituents, said substituents being independently selected from: cyano, halogen, azido, and Q 1 , the group of formula (1) having the structure:

[0569]

[0570] wherein

[0571] L is –(CH(OP 2 ))– or –C(O)–;

[0572] R 1 is H, or R 1 and P 1 combine to form a bond;

[0573] (i) R 2 is H, wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group;

[0574] (ii) R 2 is –(CH 2 ) n NP 3 P 4 , wherein P 3 is an N - protecting group, and (a) P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 4 is an N - protecting group, or (b) P 2 and P 4 combine to form an alkylene group;

[0575] (iii) R 2 is –(CH 2 ) n OP 5 , wherein P 2 is absent, H, optionally substituted alkyl, or a hydroxy protecting group, and P 5 is optionally substituted alkyl or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl - dioxo, or silylene - dioxo; or

[0576] (iv) R 2 and P2 Combine to form an optionally substituted ethylene group or a structure selected from the following:

[0577]

[0578]

[0579] where each P’ is independently a hydroxyl protecting group;

[0580] E is H, an optionally substituted alkyl group or an optionally substituted alkoxy group;

[0581] G is O, S, CH 2 or NR N , where R N is H, an N - protecting group or an optionally substituted alkyl group;

[0582] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A , NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently an alkyl group, a haloalkyl group, a hydroxyalkyl group, an aminoalkyl group, an aryl group, a haloaryl group, a hydroxyaryl group, an alkoxyaryl group, an arylalkyl group, an alkylaryl group, a haloarylalkyl group, an alkylhaloaryl group, an (alkoxyaryl)alkyl group, a heterocyclic group or a heterocyclic - alkyl group;

[0583] When present, n is 0, 1 or 2;

[0584] k is 0 or 1;

[0585] X 1 is –CH(Y)– or –CH 2 –

[0586] X 2 is =O, or X 2 together with the carbon atom to which it is attached is -(C(R X )) 2 ); where each R X is independently H, -OR X1 or -SR X1 , provided that at least one R X , when present, is -OR X1 or -SR X1 ; where each R X1 is independently optionally substituted alkyl, or two R X1 combine to form optionally substituted alkylene;

[0587] Y is SO 2 R C or COOR C , where, when Y is SO 2 R C , R C is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR C , R C is optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl;

[0588] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 in one of them together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0589] R 13 is H or -CH 2 P(O)(OR E ) 2 , where each R E , when present, is independently optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl;

[0590] (i) Each P 6 is independently a hydroxy protecting group, or two P 6 together with the atoms to which they are attached combine to form a ketal or an acetal;

[0591] Each R 11 is independently -OP10 , or

[0592] two Rs 11 combine to form an oxo, where P 10 is an alkyl or hydroxyl protecting group (e.g., silyl);

[0593] or

[0594] (ii) two Ps 6 and two Rs 11 together with the atoms to which they are attached combine to form an acetal;

[0595] X is =O or X together with the carbon atom to which it is attached forms –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group;

[0596] A 1 and R 7 combine to form an oxo, P 7 is H or a hydroxyl protecting group, and R 8 is H;

[0597] or

[0598] A 1 is H or OP”, and:

[0599] (i) P 7 is H or a hydroxyl protecting group, and R 7 and R 8 together with the atoms to which they are respectively attached combine to form a double bond;

[0600] or

[0601] (ii) P 7 and R 7 combine to form a bond, and R 8 is H or OP”;

[0602] and

[0603] each P” when present is independently H or a hydroxyl protecting group.

[0604] In formula (IC), the stereocenter designated by a can be ( R ), and A can have the following structures:

[0605] .

[0606] In certain embodiments of formula (IC), k is 0 and X 1 is –CH 2 –. In a particular embodiment of formula (IC), R 2is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , where n is 0.

[0607] Alternatively, in formula (IC), A and D may combine to form the following structures:

[0608]

[0609] where the bond connecting the oxygen atom originates from the carbon atom connected to D in formula (IC). In some embodiments of formula (IC), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , and n is 2.

[0610] In other embodiments of formula (IC), k is 1, and E is an optionally substituted alkyl. In still other embodiments of formula (IC), X 1 is –O–.

[0611] The compound of formula (ID) has the following structure:

[0612]

[0613] where

[0614] P 8 is H or a hydroxyl protecting group; and

[0615] R 9 is SO 2 R C or COOR C , when R 9 is SO 2 R C , R C is an optionally substituted aryl or an optionally substituted non-enolizable alkyl, and when R 9 is COOR C , R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl.

[0616] Alternatively, the compound of formula (IA) (where X 1 is –CH(Y)– or –CH 2–) can be prepared by reacting a compound of formula (IC) wherein X is =O and R 13 is –CH 2 P(O)(OR E ) 2 ) with a compound of formula (ID’) under Horner-Wadsworth-Emmons reaction conditions.

[0617] The compound of formula (ID’) has the following structure:

[0618]

[0619] wherein P 8 is H or a hydroxy protecting group.

[0620] A compound of formula (IC) wherein X is =O and R 13 is H can be reacted with (R E O) 2 P(O)-CH=N + =N – (e.g., Seyferth-Gilbert reagent) to produce a compound of formula (IC) wherein X is =O and R 13 is -CH 2 P(O)(OR E ) 2 .

[0621] The compound of formula (IC) can be prepared from a compound of formula (IE)

[0622]

[0623] wherein

[0624] X 3 is –CH 2 OP A 、–CH=CH 2 or –CH(OP A )CH 2 OP A , wherein each P A is independently H or a hydroxy protecting group, or two P A combine to form a protected cyclic diol; R 7 and P 7 combine to form a bond, and R 8 is H; or P 7 is a hydroxy protecting group, and R 7 and R 8 together with the atoms to which they are attached combine to form a double bond; and all other variables are as defined for the compound of formula (IC).

[0625] The preparation of a compound of formula (IC) from a compound of formula (IE) can be carried out by reacting a compound of formula (IE) in which X 3 is –CH(OP A )CH 2 OP A , and both P A are H) with a diol cleavage agent (such as periodic acid or its salts such as NaIO 4 ) to produce a compound of formula (IC) in which X is =O, and R 13 is H).

[0626] The preparation of certain compounds of formula (IC) can further include converting a compound of formula (IC) in which A 1 is H, R 7 and R 8 combine to form a double bond, and X is =O) into a compound of formula (IC) in which R 7 and A 1 combine to form O. In a non-limiting example, a nucleophilic peroxide reagent such as tert-butyl hydroperoxide can be used to convert the enal in a compound of formula (IC) in which R 7 and R 8 combine to form a double bond) into a C.12-C.13 epoxide, which can then be converted into a compound of formula (IC) in which A 1 and R 7 combine to form an oxo using methods known in the art (see, for example, Muzart, J., Eur. J. Org. Chem. , 4717-4741, 2011). Thus, a compound of formula (IC) in which A 1 is OP” can be prepared. Other transformations can include α-oxidation to produce a compound of formula (IC) in which R 8 is OP”.

[0627] If, in the compound of formula (IE), at least one P A is a hydroxyl protecting group, or the two P A combine to form a protected cyclic diol, the compound of formula (IE) can be treated with a hydroxyl protecting group removing agent (such as Bronsted acid (such as p -TsOH), if the two P A combine to form a diol protected as a ketal) to prepare a compound of formula (IE) in which the two P A are H.

[0628] The compound of formula (IE) can be prepared by reacting a compound of formula (IF) with a compound of formula (IG), treating it with a strong base (such as an alkali metal amide or an alkyllithium). Before this reaction, according to the following procedure, a compound of formula (IF) (where X 3 is –CH(OP A )CH 2 OP A , and both P A are H) can be converted into a compound of formula (IF) (where X 3 is –CH 2 OP A , where P A is a hydroxyl protecting group). A compound of formula (IF) (where X 3 is –CH(OP A )CH 2 OP A , and both P A are H) can react with a diol cleavage agent (such as periodic acid or its salt, such as NaIO 4 ) to form a compound of formula (IF) (where X 3 is –CHO), which can provide a compound of formula (IF) (where X 3 is –CH 2 OP A , where P A is a hydroxyl protecting group) when reduced with a 1,2-reducing agent and protected with a hydroxyl protecting group. For the reduction step, the aldehyde adjacent to R 6 in formula (IF) can be protected with a protecting group suitable for protecting carbonyl groups known in the art.

[0629] The compound of formula (IF) has the following structure:

[0630]

[0631] where X 3 is –CHO, –CH 2 OP A , –CH=CH 2 or –CH(OP A )CH 2 OP A , and all other variables are as defined for the compound of formula (IE).

[0632] The compound of formula (IG) has the following structure:

[0633]

[0634] where all variables are as defined in formula (IE).

[0635] In formula (IG), the stereocenter specified by a can be ([[]] R ), and A can have the following structures:

[0636] .

[0637] In certain embodiments of formula (IG), k is 0 and X 1 is –CH 2 –. In specific embodiments of formula (IG), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , where n is 0.

[0638] The compounds of formula (IG) can be prepared using methods known in the art such as those described in WO 2015 / 066729.

[0639] The compounds of formula (IF) can be prepared by reacting a compound of formula (IH) in which X 4 together with the carbon atom to which it is attached forms –CH 2 – with an oxidizing agent capable of oxidizing an alcohol to a carbonyl group. Alternatively, the compounds of formula (IF) can be prepared by reacting a compound of formula (IH) in which X 4 is =O and P B is a hydroxyl protecting group or an optionally substituted alkyl group with a 1,2-reducing agent (such as DIBAL).

[0640] The compounds of formula (IH) have the following structure:

[0641]

[0642] where P B is H, a hydroxyl protecting group or an optionally substituted alkyl group, X 4 is =O or X 4 together with the carbon atom to which it is attached forms –CH 2 –, and all the remaining variables are as defined for the compounds of formula (IF).

[0643] In some embodiments of formula (IH), R 3 and R 5 combine to form a bond. In specific embodiments, P 7 and R 7 combine to form a bond.

[0644] Compounds of formula (IH) wherein R 7 and P 7 combine to form a bond) can be prepared from compounds of formula (IHa)

[0645]

[0646] wherein X 5 is –CH=CH 2 or –CH(R 4 )–CH(R 5 )–CH(R 6 )–C(X 4 )OP B , a identifying the carbon-oxygen bond as or , and the remaining variables are as defined for the compounds of formula (IH).

[0647] In some embodiments of formula (IHa), X 3 is –CH 2 OP A . In certain embodiments, R 8 is H.

[0648] Compounds of formula (IHa) can be reacted with a hydrosilane (e.g., Et 3 SiH, Ph 2 SiH 2 , Ph 2 MeSiH or PMHS) and an acid (e.g., a Brønsted acid (such as trifluoroacetic acid) or a Lewis acid (such as boron trifluoride diethyl etherate)) to reduce the ketal, thereby generating a compound of formula (IH), if X 5 is –CH(R 4 )–CH(R 5 )–CH(R 6 )–C(X 4 )OP B . If X 5 in the compound of formula (IHa) is –CH=CH 2 , then the preparation of the compound of formula (IH) can further include operation X 5 , whereby –CH=CH 2 is converted to –CH(R 4 )–CH(R 5 )–CH(R 6 )–C(X 4 )OP B . For example, the conversion can include hydroboration / oxidation followed by an olefination reaction (e.g., with P B O–C(O)–CH 2–P(O)(OR P ) 2 in a Horner-Wadsworth-Emmons reaction, where R P is an optionally substituted alkyl).

[0649] If the bond in formula (IHa) is determined as a , the compound of formula (IHa) can be epimerized (e.g., using a reaction sequence including oxidizing the group –CH(OP )– to a carbonyl group, then reducing it, and protecting it with a hydroxy protecting group) to provide a compound of formula (IHa) where 6 is a for .

[0650] A compound of formula (IHa) where X 3 is –CH 2 OP A ) can be prepared from a compound of formula (IHb):

[0651]

[0652] where P 6 and P 7 are each independently a hydroxy protecting group, or P 6 and P 7 together with the atoms to which they are attached form a ketal (e.g., one P 6 and P 7 combine to form a cyclohexylidene), and the remaining P 6 is a hydroxy protecting group; or two P 6 together with the atoms to which they are attached form a ketal, and P 7 is a hydroxy protecting group.

[0653] The compound of formula (IHb) can undergo an oxa-Michael addition, and then the hydroxy protecting groups are removed from OP 6 and OP 7 while a ketalization reaction is carried out (e.g., using a hydroxy protecting group removing agent (e.g., Bronsted acid (such as p-toluenesulfonic acid)) to provide a compound of formula (IHa).

[0654] Compounds of formula (IH) can also be prepared using methods known in the art, such as those described in WO 2015 / 066729 and WO2005 / 118565.

[0655] A compound of formula (ID) can be prepared from a compound of formula (Ii):

[0656]

[0657] wherein

[0658] P 8 is H or a hydroxyl protecting group;

[0659] (i) P C is H or a hydroxyl protecting group, and R D is –CH 2 OP D wherein P D is H or a hydroxyl protecting group; or P C and P D combine to form a protected cyclic diol; or

[0660] (ii) P C and R D together with the atoms to which they are attached combine to form a carbonyl group.

[0661] The synthesis of a compound of formula (ID) from a compound of formula (Ii), wherein P 8 is a hydroxyl protecting group, and P C and R D together with the atoms to which they are attached combine to form a carbonyl group, may include reacting the compound of formula (Ii) with deprotonated R 9 -CH 2 -P(O)(OR E ) 2 to produce a product, which is treated with a 1,4 - reducing agent (such as LiHBEt 3 ) to obtain a compound of formula (ID), wherein R E is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl; and R 9 is SO 2 R C or COOR C , wherein, when R 9 is SO 2 R C , R C is an optionally substituted aryl or an optionally substituted non - enolizable alkyl, and when R 9 is COOR C , R C is an optionally substituted alkyl, an optionally substituted aryl or an optionally substituted arylalkyl. The compound of formula (Ii) and R 9 -CH 2 -P(O)(OR E ) 2The reaction between can be carried out under reductive conditions known in the art for the Horner-Wadsworth-Emmons reaction. For example, a strong base (such as an alkali metal amide) can be used to deprotonate R in situ 9 -CH 2 -P(O)(OR E ) 2 , and then the compound of formula (Ii) is added.

[0662] If in the compound of formula (Ii), P C is H and R D is –CH 2 OP D , where P D is H, the synthesis of the compound of formula (ID) or formula (ID’) can include reacting the compound of formula (Ii) with a diol cleavage agent (such as periodic acid or its salt, such as NaIO 4 ) to form a compound of formula (Ii) in which P C and R D together with their respective attached atoms form a carbonyl group.

[0663] The compound of formula (ID’) corresponds to the compound of formula (Ii) in which P C and R D together with their respective attached atoms form a carbonyl group.

[0664] The compound of formula (Ii) can be prepared by methods known in the art such as those described in WO 2015 / 066729 and WO 2005 / 118565.

[0665] Alternatively, the compound of formula (ID) can be prepared from the compound of formula (IDa):

[0666]

[0667] where R 9 is as defined in formula (ID).

[0668] The compound of formula (IDa) can be epimerized from a secondary alcohol (for example, by a Mitsunobu reaction with P 8 -OH, where P 8 is a hydroxyl protecting group, such as p-nitrobenzyl)) to form a compound of formula (ID) in which P 8 is a hydroxyl protecting group. If a compound of formula (ID) in which P 8 is H is desired, then the compound of formula (ID) (where P 8 is a hydroxyl protecting group) can be treated with a hydroxyl protecting group removing agent to form a compound in which P 8A compound of formula (ID) wherein is H.

[0669] The compound of formula (IDa) can be prepared by subjecting a compound of formula (IDb) wherein R 14 is a halogen (e.g., iodine) or a pseudohalogen, and R 9 ’ and R 10 are each H) to Vasella fragmentation reaction conditions (e.g., Zn and aqueous acetic acid). The compound of formula (IDb) has the following formula:

[0670]

[0671] wherein R 9 ’ and R 10 are both H, or R 9 ’ and R 10 combine to form a double bond; R 14 is a hydroxyl group, a halogen (e.g., iodine) or a pseudohalogen (e.g., trifluoromethanesulfonate); and R 9 is as defined in formula (ID).

[0672] The compound of formula (IDb) wherein R 9 ’ and R 10 are both H) can be prepared by treating a compound of formula (IDb) wherein R 4 ’ and R 9 combine to form a double bond) with a 1,4 - reducing agent (e.g., LiBH 10 ).

[0673] The compound of formula (IDb) wherein R 14 is a hydroxyl group) can be converted to a compound of formula (IDb) wherein R 14 is a pseudohalogen) by reaction with a suitable pseudohalogen anhydride (e.g., trifluoromethanesulfonic anhydride) under basic conditions (e.g., in the presence of a bulky base such as Hünig's base). The compound of formula (IDb) wherein R 14 is a pseudohalogen) can be treated with a halide salt (e.g., sodium iodide or tert - butylammonium iodide) to produce a compound of formula (IDb) wherein R 14 is a halogen (e.g., iodine). The two reactions can be carried out in a one - pot process.

[0674] The compound of formula (IDb) wherein R 14 is a hydroxyl group, and R 9 ’ and R 10 combine to form a double bond) can be prepared by reaction with R 9 –CH 2 –P(O)(OR E ) 2 (wherein each R EThe Horner-Wadsworth-Emmons reaction is carried out independently for optionally substituted alkyl) from the compound of formula (IDc) (wherein R 16 is H). The compound of formula (IDc) has the following formula:

[0675]

[0676] wherein R 16 is H, a hydroxyl protecting group or an optionally substituted alkyl.

[0677] The compound of formula (IDc) (wherein R 16 is a hydroxyl protecting group or an optionally substituted alkyl) can be converted to the compound of formula (IDc) (wherein R 16 is H) by using acid-catalyzed hydrolysis (for example, using a mixture of a Brønsted acid aqueous solution and a polar organic solvent such as THF).

[0678] The compound of formula (IDc) (wherein R 16 is an optionally substituted alkyl or a hydroxyl protecting group) can be prepared from the compound of formula (IDd) (wherein X 17 is –C(R 6 )=CH 17 ) by metal-catalyzed net elimination of H-R 2 (for example, using Pd(0), a MOP ligand and Hünig base). The compound of formula (IDd) has the following formula:

[0679]

[0680] wherein X 6 is –C(R 17 )=CH 2 ), –C(O)–Me or cyano, wherein R 17 is a pseudohalogen (such as trifluoromethanesulfonate) or a halogen; and R 16 is as defined in formula (IDc).

[0681] The compound of formula (IDd) (wherein R 16 is H and X 6 is cyano) is known in the art (for example, in WO 2009 / 046308). The compound of formula (IDd) (wherein R 16 is H) can be reacted with an excess of R 16 -OH under acid catalysis to obtain the compound of formula (IDd) (wherein R 16 is a hydroxyl protecting group or an optionally substituted alkyl). The compound of formula (IDd) (wherein X 6 is cyano, and R 16(wherein X is a hydroxyl protecting group or an optionally substituted alkyl group) can react with a nucleophilic source of methyl (such as MeLi·LiBr) to obtain a compound of formula (IDd) (wherein X 6 is –C(O)–Me). The compound of formula (IDd) (wherein X 6 is –C(O)–Me) can react with an electrophilic source of pseudohalogen (such as PhNTf 2 and a bulky base such as NaHMDS) or an electrophilic source of halogen (such as triphenyl phosphite, elemental halogen, and a base (such as triethylamine)) to obtain a compound of formula (IDd) (wherein X 6 is –C(R 17 )=CH 2 ).

[0682] Synthesis of the compound according to formula (IJ)

[0683] The compound of formula (IA) can be prepared by reacting a compound of formula (IJ) with a compound of formula (IK) under the Nozaki-Hiyama-Kishi reaction conditions described herein. The compound of formula (IJ) has the following formula:

[0684]

[0685] where

[0686] D and D’ are each independently H, an optionally substituted alkyl group, or OP 1 , provided that only one of D and D’ is OP 1 , where P 1 is H, an alkyl group or a hydroxyl protecting group; and A is a group of formula (1) or a C 1-6 saturated or C 2-6 unsaturated hydrocarbon skeleton, said skeleton being unsubstituted or having 1-10 substituents, said substituents being independently selected from: cyano, halogen, azide, and Q 1 , said group of formula (1) having the structure:

[0687]

[0688] where

[0689] L is –(CH(OP 2 ))– or –C(O)–;

[0690] R 1 is H, or R 1 and P 1 combine to form a bond;

[0691] (i) R 2 is H, where P 2is absent, an optionally substituted alkyl, or a hydroxy protecting group;

[0692] (ii) R 2 is –(CH 2 ) n NP 3 P 4 wherein P 3 is absent, H, an optionally substituted alkyl, or a hydroxy protecting group, and (a) P 2 is absent, H, an optionally substituted alkyl, or a hydroxy protecting group, and P 4 is an N-protecting group, or (b) P 2 and P 4 combine to form an alkylene group;

[0693] (iii) R 2 is –(CH 2 ) n OP 5 wherein P 2 is absent, an optionally substituted alkyl, or a hydroxy protecting group, and P 5 is an optionally substituted alkyl or a hydroxy protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo, or silylene-dioxo; or

[0694] (iv) R 2 and P 2 combine to form an optionally substituted ethylene group or a structure selected from:

[0695]

[0696]

[0697] wherein each P’ is independently a hydroxy protecting group;

[0698] E is H, an optionally substituted alkyl, or an optionally substituted alkoxy;

[0699] G is O, S, CH 2 or NR N wherein R N is H, an N-protecting group, or an optionally substituted alkyl;

[0700] Each Q 1 is independently OR A , SR A , SO 2 R A , OSO 2 R A , NR B R A, NR B (CO)R A , NR B (CO)(CO)R A , NR B (CO)NR B R A , NR B (CO)OR A , (CO)OR A , O(CO)R A , (CO)NR B R A or O(CO)NR B R A , where R A and R B are each independently alkyl, haloalkyl, hydroxyalkyl, aminoalkyl, aryl, haloaryl, hydroxyaryl, alkoxyaryl, arylalkyl, alkylaryl, haloarylalkyl, alkylhaloaryl, (alkoxyaryl)alkyl, heterocyclic group or heterocyclic group-alkyl;

[0701] n, when present, is 0, 1 or 2;

[0702] k is 0 or 1;

[0703] X 1 is –CH(Y)–, –CH 2 – or –O–, and X 2 is =O or X 2 together with the carbon atom to which it is attached is –(C(R X )) 2 )–; where each R X is independently H, –OR X1 or –SR X1 , provided that at least one R X , when present, is –OR X1 or –SR X1 ; where each R X1 is independently optionally substituted alkyl, or two R X1 combine to form optionally substituted alkylene, provided that when X 1 is –O–, X 2 is =O; and where Y is SO 2 R C or COOR C , where when Y is SO 2 R C , R C is optionally substituted aryl or optionally substituted non-enolizable alkyl, and when Y is COOR C , R Cis an optionally substituted alkyl, optionally substituted aryl or optionally substituted arylalkyl;

[0704] R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 4 and R 6 together with the atoms to which they are attached combine to form a double bond, and the remaining R 4 or R 6 is H;

[0705] (i) Each P 6 is independently a hydroxy protecting group, or two P 6 together with the atoms to which they are attached combine to form a ketal or acetal;

[0706] Each R 11 is independently –OP 10 , or

[0707] two R 11 combine to form an oxo group, where P 10 is an alkyl or hydroxy protecting group (such as silyl);

[0708] Or

[0709] (ii) Two P 6 and two R 11 together with the atoms to which they are attached combine to form an acetal;

[0710] Each P 7 is independently a hydroxy protecting group; and

[0711] X 2 is a halogen or pseudohalogen.

[0712] In formula (IJ), the stereocenter designated by a can be ( R ), and A can have the following structures:

[0713] .

[0714] In certain embodiments of formula (IJ), k is 0 and X 1 is –CH 2 –. In a particular embodiment of formula (IJ), R 2 is –(CH 2 ) n NP 3 P 4or –(CH 2 ) n OP 5 , where n is 0.

[0715] Alternatively, in formula (IJ), A and D may combine to form the following structure:

[0716]

[0717] where the bond connecting the oxygen atom originates from the carbon atom to which D is attached in formula (IJ). In some embodiments of formula (IJ), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , and n is 2.

[0718] In other embodiments of formula (IJ), k is 1, and E is an optionally substituted alkyl. In still other embodiments of formula (IJ), X 1 is –O–.

[0719] The compound of formula (IK) has the following structure:

[0720]

[0721] where P 8 is a hydroxyl protecting group.

[0722] The compound of formula (IK) can be prepared using methods known in the art, such as those described in WO 2015 / 066729 and WO 2005 / 118565.

[0723] The compound of formula (IJ) (where X 1 is –CH(Y)– or –CH 2 –) can be prepared from the compound of formula (IG) and the compound of formula (IL) (where R 15 is H, and X 4 is =O). The compound of formula (IL) has the following structure:

[0724]

[0725] or a salt thereof,

[0726] where R 15 is H or –OP 11 , and P 11 is H, a hydroxyl protecting group, or an optionally substituted alkyl; X 4is =O, or together with the carbon atom to which it is attached is –CH 2 –; and all remaining variables are as defined for the compounds of formula (IJ); provided that when R 15 is H, X 4 is =O.

[0727] The compounds of formula (IL) can be prepared using methods known in the art, such as those described in International Patent Application Nos. WO2005 / 118565 and WO 2015 / 066729 and U.S. Patent Nos. 5,338,865; 5,436,238; and 6,214,865.

[0728] The synthesis of the compounds of formula (IJ) in which X 1 is –CH(Y)– or –CH 2 –) involves reacting a compound of formula (IL) in which R 15 is H, and X 4 is =O) with a compound of formula (IG), treating it with a strong base (such as an alkali metal amide or an alkyllithium) and then oxidizing the alcohol formed from the aldehyde group using an oxidizing agent capable of converting an alcohol to a carbonyl group (such as Dess-Martin periodinane).

[0729] If a compound of formula (IJ) in which X 1 is –CH 2 –) is to be prepared, the synthesis of this compound of formula (IJ) can further involve subjecting a compound of formula (IJ) in which X 1 is –CH(Y)–) to the decarboxylation (if Y is COOR C ) or desulfonation (if Y is SO 2 R C ) reaction conditions described herein.

[0730] The compounds of formula (IJ) in which X 1 is –O–) can be prepared by reacting a compound of formula (IL) in which R 15 is –OP 11 , P 11 is H, and X 4 together with the carbon atom to which it is attached is –CH 2 –) with a compound of formula (IM) under esterification reaction conditions (such as the Yamaguchi esterification described herein or using EDCI / DMAP, as described in Namba and Kishi, J. Am. Chem. Soc. ,127:15382-15383, 2005).

[0731] The compounds of formula (IL) in which R 15 is –OP 11, P 11 is H, and X 4 together with the carbon atom to which it is attached is –CH 2 –) can react with an oxidizing agent capable of oxidizing a hydroxyl group to a carbonyl group to obtain a compound of formula (IL) (wherein R 15 is H and X 4 is =O). The compound of formula (IL) (wherein R 15 is H and X 4 is =O) can be oxidized using Pinnick oxidation to obtain a compound of formula (IL) (wherein R 15 is –OP 11 , P 11 is H and X 4 is =O). The compound of formula (IL) (wherein X 4 is =O, R 15 is –OP 11 , and P 11 is a hydroxyl protecting group or an optionally substituted alkyl group) can be treated with a 1,2 - reducing agent (such as DIBAL) to obtain a compound of formula (IL) (wherein R 15 is –OP 11 , P 11 is H, and X 4 together with the carbon atom to which it is attached is –CH 2 –). The compound of formula (IL) (wherein X 4 is =O, and R 15 is H) can be prepared by reacting the compound of formula (IL) (wherein X 4 is =O, R 15 is –OP 11 , and P 11 is a hydroxyl protecting group or an optionally substituted alkyl group) with a 1,2 - reducing agent under conditions known in the art for converting an ester to an aldehyde (such as reacting with DIBAL at low temperature (such as about - 80 °C to about - 50 °C)).

[0732] The compound of formula (IM) has the following structure:

[0733]

[0734] wherein each R 11 is independently –OP 10 , or two R 11 combine to form oxo, wherein P 10 is an alkyl group or a hydroxyl protecting group (such as silyl); and all remaining variables are as defined in formula (IM).

[0735] In formula (IM), A and D can combine to form the following structure:

[0736]

[0737] The bond connecting the oxygen atom originates from the carbon atom to which D is attached in formula (IM). In some embodiments of formula (IM), R 2 is –(CH 2 ) n NP 3 P 4 or –(CH 2 ) n OP 5 , and n is 2.

[0738] In other embodiments of formula (IM), k is 1, and E is an optionally substituted alkyl group. In still other embodiments of formula (IM), X 1 is –O–.

[0739] The compounds of formula (IL) and (IM) can be prepared using methods known in the art, such as those described in International Patent Application Nos. WO 2005 / 118565 and WO 2015 / 066729, and U.S. Patent Nos. 5,338,865 and 5,436,238.

[0740] Synthesis of the compound according to formula (IN)

[0741] The compound of formula (IA) (wherein X 1 is –O–) can be prepared by reacting a compound of formula (IN) (wherein R 15 is –OP 11 and P 11 is H) with a compound of formula (IM). This reaction can be carried out using esterification reaction conditions known in the art (such as Yamaguchi esterification, which can include the use of 2,4,6-trichlorobenzoyl chloride, an amine base (such as Hünig base), and a catalytic amount of 4-dimethylaminopyridine). The Yamaguchi esterification reaction conditions are described, for example, in Aicher et al., J. Am. Chem. Soc. , 114:3162 - 3164, 1992. Alternatively, the esterification conditions can include the use of a carbodiimide reagent (such as EDCI) and a Lewis base catalyst (such as DMAP); non-limiting examples of this transformation are described in Namba and Kishi, J. Am. Chem. Soc. , 127:15382 - 15383, 2005.

[0742] The compound of formula (IA) (wherein X 1 is –CH(Y)–) can be prepared by reacting a compound of formula (IN) (wherein R 15is prepared by reacting with a compound of formula (IG) and treating it with a strong base (such as an alkali metal amide or an alkyllithium).

[0743] The compound of formula (IN) has the following structure:

[0744]

[0745] or a salt thereof,

[0746] wherein R 15 is H or –OP 11 wherein P 11 is H, a hydroxyl protecting group, or an optionally substituted alkyl; X 4 is =O or together with the carbon atom to which it is attached is –CH 2 –; and all remaining variables are as defined in formula (IA); provided that when R 15 is H, X 4 is =O.

[0747] The compound of formula (IN) wherein R 15 is –OP 11 wherein P 11 is H, and X 4 together with the carbon atom to which it is attached is –CH 2 –) can be reacted with an oxidizing agent capable of oxidizing a hydroxyl group to a carbonyl group to obtain a compound of formula (IN) wherein R 15 is H, and X 4 is =O). The compound of formula (IN) wherein R 15 is H, and X 4 is =O) can be oxidized using Pinnick oxidation to obtain a compound of formula (IN) wherein R 15 is –OP 11 wherein P 11 is H, and X 4 is =O). The compound of formula (IN) wherein X 4 is =O, R 15 is –OP 11 and P 11 is a hydroxyl protecting group or an optionally substituted alkyl) can be treated with a 1,2 - reducing agent (such as DIBAL) to obtain a compound of formula (IN) wherein R 15 is –OP 11 wherein P 11 is H, and X 4 together with the carbon atom to which it is attached is –CH 2 –). The compound of formula (IN) wherein X 4 is =O, and R 15 is H) can be obtained by reacting a compound of formula (IN) wherein X4 is =O, R 15 is –OP 11 , and P 11 is a hydroxyl protecting group or an optionally substituted alkyl group) is prepared by reacting with a 1,2 - reducing agent under conditions known in the art for converting an ester to an aldehyde (e.g., reacting with DIBAL at low temperature (e.g., about - 80 °C to about - 50 °C)).

[0748] The compound of formula (IN) (wherein R 15 is –OP 11 , and P 11 is a hydroxyl protecting group or an optionally substituted alkyl group) can be prepared from a compound of formula (ID) and a compound of formula (IH) (wherein P B is a hydroxyl protecting group or an optionally substituted alkyl group, X 3 is –CHO, and X 4 is =O).

[0749] Synthesizing the compound of formula (IN) from a compound of formula (IH) and a compound of formula (ID) (wherein R 15 is –OP 11 ) can include reacting the compound of formula (IH) with the compound of formula (ID), treating it with a strong base (e.g., an alkali metal amide or an alkyllithium) to generate a product containing an alcohol, removing P B (e.g., if P B is an acyl group (e.g., pivaloyl), using a 1,2 - reducing agent) and then oxidizing (e.g., performing sequential oxidation using an oxidizing agent capable of converting an alcohol to a carbonyl group and then Pinnick oxidation) can provide the compound of formula (IN).

[0750] Alternatively, the compound of formula (IN) can be prepared from a compound of formula (IL) and a compound of formula (IK). For example, the compound of formula (IL) (wherein X 4 is =O, R 15 is –OP 11 , and P 11 is a hydroxyl protecting group) can be reacted with the compound of formula (IK) under Nozaki - Hiyama - Kishi reaction conditions to generate the compound of formula (IN) (wherein R 15 is –OP 11 , and P 11 is a hydroxyl protecting group; R 7 and R 8 together with the atoms to which they are attached form a double bond; and X is attached to the carbon atom to form –(CH(OP 9 ))–, wherein P 9For H). Then, deprotection and reaction with an oxidizing agent capable of converting an alcohol to a carbonyl can provide a compound of formula (IN) (where X is =O and R 15 is –OP 11 , and P 11 is H).

[0751] The preparation of certain compounds of formula (IN) can further include converting a compound of formula (IN) (where A 1 is H, R 7 and R 8 combine to form a double bond, and X is =O) to a compound of formula (IN) where R 7 and A 1 combine to form O. In a non-limiting example, a nucleophilic peroxide reagent such as tert-butyl hydroperoxide can be used to convert the enal in a compound of formula (IN) (where R 7 and R 8 combine to form a double bond) to a C.12-C.13 epoxide, which can then be converted to a compound of formula (IN) (where A 1 and R 7 combine to form oxo) using methods known in the art, for example, by reaction with a bidentate phosphine ligand and a Pd(0) source (see, e.g., Muzart, J., Eur. J. Org. Chem. , 4717-4741, 2011). Thus, compounds of formula (IN) where A 1 is OP” can be prepared. Other transformations can include α-oxidation to generate compounds of formula (IN) where R 8 and / or R 9 is OP”.

[0752] In certain embodiments of formula (IA), (IB), (IC), (IE), (IJ), or (IN), k is 0, X 1 is –CH(Y)– or –CH 2 –, D is H, D’ is OP 1 , G is O, and A has the following structure:

[0753]

[0754] where

[0755] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is H or an N-protecting group, and P 2 and P 4 combine to form an alkylene or P2 is H, an optionally substituted alkyl or a hydroxyl protecting group, and P 4 is an N-protecting group; or

[0756] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 is H, an optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached form a ketal, cyclic carbonate, dicarbonyl-dioxo or silyl-dioxo;

[0757] can be used for the synthesis of eribulin or its salt (such as eribulin mesylate).

[0758] In certain embodiments of formula (IA), (IB), (IC), (IE), (IJ) or (IN), k is 0, X 1 is –CH(Y)– or –CH 2 –, D is H, D’ is OP 1 , G is O, and A has the following structure:

[0759]

[0760] where

[0761] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is an N-protecting group, and P 2 and P 4 combine to form an alkylene or P 2 is H, an optionally substituted alkyl or a hydroxyl protecting group, and P 4 is an N-protecting group; or

[0762] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 is H, an optionally substituted alkyl, or a hydroxyl protecting group, and P 5 is H, an optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5Together with the atoms to which they are attached, they combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo;

[0763] It can be used for the synthesis of eribulin or its salts (such as eribulin mesylate).

[0764] In a further embodiment of the compounds of formula (IA), (IB), (IC), (IE), (IJ) or (IN), k is 0, D is H, D' is OP 1 , and A has the following structure:

[0765]

[0766] where

[0767] (i) R 2 is –(CH 2 ) n NP 3 P 4 , where n is 0, P 3 is an N-protecting group, and P 2 and P 4 combine to form an alkylene group; or

[0768] (ii) R 2 is –(CH 2 ) n OP 5 , where n is 0, P 2 and P 5 are each independently H, optionally substituted alkyl, or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached combine to form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo.

[0769] Masked amines and amine unmasking agents

[0770] The compounds used in the methods of the present invention may contain masked or unmasked amines (e.g., at the C.35 carbon of the structure of a halichondrin macrolide analogue, such as eribulin). An unmasked amine is –NH 2 . The amines can be masked using methods known in the art, such as by protecting the amines with an N-protecting group. Alternatively, the amines can be masked as nitrogen-containing groups that can react with an amine unmasking agent to provide the amine. Non-limiting examples of nitrogen-containing groups include azides and imides (such as phthalimide). The amine unmasking agent can be one known in the art for removing N-Those of the protecting groups. In a non-limiting example, the Boc group can be removed using amine-exposing agents known in the art, such as brequinar acid (e.g., HCl in 1,4-dioxane or trifluoroacetic acid). When the amine is masked as an azide, the amine can be exposed by subjecting the compound containing the masked amine to Staudinger reaction conditions (e.g., by reacting with a phosphine, such as a trialkylphosphine, a dialkylarylphosphine, an alkyldiarylphosphine, or a triarylphosphine) or by reacting the compound containing the masked amine with a reducing agent (e.g., LiAlH 4 ) to expose the amine. When the amine is masked as an imide (e.g., phthalimide), the amine can be exposed by reacting with an amine-exposing agent known in the art, such as hydrazine.

[0771] Oxidizing agents capable of converting an alcohol to a carbonyl group

[0772] Oxidizing agents capable of converting an alcohol to a carbonyl group are known in the art. Non-limiting examples of such oxidizing agents include Dess-Martin periodinane, TEMPO (in the presence of bleach or BAIB), dimethylsulfonium compounds (e.g., dimethylsulfonium monochloride), trialkoxyaluminum with an excess of a ketone (e.g., acetone) and catalytic tetrapropylammonium perruthenate (TPAP) (in N -methylmorpholine N-oxide). The dimethylsulfonium compound can be prepared in situ under conditions known for Parikh-Doering oxidation, Swern oxidation, Corey-Kim oxidation, or Pfitzner-Moffatt oxidation. Alternatively, the dimethylsulfonium compound can be prepared in situ by the reaction between trichloroacetic anhydride and dimethyl sulfoxide. The oxidation of an alcohol to a carbonyl group (e.g., a ketone) can be carried out using trialkoxyaluminum and an excess of a ketone (e.g., acetone) under conditions known in the art for Oppenauer oxidation. Allylic and benzylic alcohols can also be oxidized with MnO 2 .

[0773] Reducing agents

[0774] Reducing agents that can be used in the methods of the present invention are those known in the art. The reducing agent can be an electron transfer reducing agent, a metal hydride, or a non-metal hydride. Non-limiting examples of electron transfer reducing agents include alkali metals in the oxidation state (0), alkaline earth metals in the oxidation state (0), basic arenides, lanthanide (II) salts (e.g., SmI 2 ), Zn(0), Fe(0), and Mn(0). Non-limiting examples of metal hydrides and non-metal hydrides include borohydride compounds (e.g., NaBH 4 , LiBH 4 , LiHBEt 3, selectrides (e.g., lithium tri-sec-butylborohydride (L-selectride)) and boranes (e.g., 9-BBN and alpine borane), aluminum hydride compounds (e.g., LiAlH 4 , Red-Al®, and alanes (e.g., diisobutylaluminum hydride (DIBAL))), hydrosilanes (e.g., PMHS and Ph 2 SiH 2 ), hydrostannane (e.g., Bu 3 SnH), copper hydride complexes (e.g., Stryker's reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes. The reducing agent can be formed in situ. For example, a copper hydride complex can be formed by the reaction of a copper salt with, for example, a borohydride compound or a hydrosilane. Thus, some reducing agents (e.g., borohydride compounds, hydrosilanes, and hydrostannanes) can be used in combination with a catalytic amount of a metal salt (e.g., a Cu, Pd, Pt, Ir, Rh, or Ru salt). Alternatively, a catalytic reducing agent can be a metal salt combined with an alcohol (e.g., aluminum isopropoxide or a ruthenium complex), which performs transfer hydrogenation of a carbonyl compound without an intermediate metal hydride. Non-limiting examples of transfer hydrogenation reactions include Meerwein-Ponndorf-Verley reduction (e.g., using aluminum isopropoxide / isopropanol) and Ru-catalyzed transfer hydrogenation (e.g., Hashiguchi et al., J. Am. Chem. Soc., 117:7562-7563, 1995).

[0775] When the substrate is an α,β-unsaturated carbonyl or sulfone compound (e.g., an α,β-enone or vinyl sulfone), the reducing agent can be a 1,2-reducing agent or a 1,4-reducing agent. For example, the reaction between an α,β-unsaturated carbonyl compound and a 1,2-reducing agent can provide, for example, an allylic alcohol (or allylic amine if the starting compound is an enamide), while the reaction between an α,β-unsaturated carbonyl compound and a 1,4-reducing agent can provide an α,β-saturated compound and keep the carbonyl intact after work-up of the reaction mixture. Non-limiting examples of 1,2-reducing agents include metal hydrides and non-metal hydrides, such as aluminum hydride compounds, borohydride compounds (e.g., CeCl 4 having NaBH 3 ) and ruthenium hydride complexes. Non-limiting examples of 1,4-reducing agents include borohydride compounds (e.g., LiHBEt 3and lithium tri-sec-butylborohydride (L-selectride), stannane hydride, copper hydride complexes (e.g., Stryker's reagent), palladium hydride complexes, platinum hydride complexes, iridium hydride complexes, rhodium hydride complexes, and ruthenium hydride complexes.

[0776] Compounds having an allylic leaving group (e.g., a carboxylic acid ester group, a halogen, or a sulfonate group) can be treated with an allylic reducing agent to replace the leaving group with a hydrogen atom. Non-limiting examples of allylic reducing agents are palladium salts or complexes (e.g., Pd(PPh 3 ) 4 ) in combination with a formate (e.g., trialkylammonium formate).

[0777] Hydroxy protecting groups and hydroxy protecting group removing agents

[0778] Hydroxy protecting groups can be as defined herein. In particular, hydroxy protecting groups can be acyl, sulfonyl, arylalkyl (e.g., benzyl or p-methoxybenzyl), aryl (e.g., p-methoxyphenyl), or optionally substituted silyl (e.g., TMS, TES, TBS, TIPS, TBDPS, or TPS). The hydroxy protecting group, hydroxy protecting agent, and hydroxy protecting reaction conditions can be selected to selectively protect a particular hydroxy group in a compound while leaving other hydroxy groups unprotected. Selection of the hydroxy protecting group for a compound can facilitate subsequent deprotection strategies since some hydroxy protecting groups can be removed in the presence of other hydroxy protecting groups using a suitable hydroxy protecting group removing agent. Some of these strategies involving the selection of silyl hydroxy protecting groups are described, for example, in Silicon-Based Blocking Agents, Gelest, Inc., 2011.

[0779] Hydroxy protecting group removing agents are those reagents that can react with a compound having a protected hydroxy group to provide a compound having a deprotected hydroxy group. Hydroxy protecting group removing agents and deprotection reaction conditions can be those known in the art. In one non-limiting example, a hydroxy group masked as a silyl ether can be de-masked by reaction with a fluoride source (e.g., a fluoride salt, such as KF or TBAF). Alternatively, a hydroxy group protected as a TMS or TES ether can be deprotected by reaction with a Brønsted acid (e.g., a carboxylic acid). In another non-limiting example, a hydroxy group protected as an ester can be deprotected by reaction with a base (e.g., an alkali metal hydroxide (such as lithium hydroxide, sodium hydroxide, or potassium hydroxide)) or a C 1-6 alkoxide (e.g., an alkali metal C 1-6 alkoxide or an alkaline earth metal C 1-6deprotected by reaction with an alcoholate). Alternatively, a hydroxyl group protected as an ester (e.g., a pivaloyl ester) can be deprotected by reaction with a 1,2 - reducing agent (e.g., DIBAL - H). In yet another non - limiting example, a hydroxyl group protected as an arylalkyl ether (e.g., a 1 - arylalk - 1 - yl ether) can be deprotected using a reduction reaction (e.g., with Pd / C and H 2 , or with Na / NH3). Alternatively, a hydroxyl group protected as an alkoxy - arylalkyl ether (e.g., an MPM ether) can be deprotected by reaction with 2,3 - dichloro - 5,6 - dicyano - 1,4 - benzoquinone (DDQ). In yet another non - limiting example, a hydroxyl group protected as an alkoxyalkyl ether (e.g., a 1 - alkoxyalk - 1 - yl) or a THP ether can be deprotected by reaction with Bronsted acid. A cyclic protected diol (e.g., an acetal or a ketal (e.g., a 2 - alkyl - 1,3 - dioxolane, a 2,2 - dialkyl - 1,3 - dioxolane, a 2 - alkyl - 1,3 - dioxane, or a 2,2 - dialkyl - 1,3 - dioxane)) can be deprotected by reaction with a Bronsted acid (e.g., a carboxylic acid).

[0780] Decarboxylation and desulfonation

[0781] The conditions for decarboxylation can be those known in the art, such as Krapcho decarboxylation or a sequence involving deprotection, if R C is not H, by converting R C to H and then performing typical protodecarboxylation. The conditions for desulfonation can be those known in the art. For example, the desulfonation reaction can involve contacting a compound of formula (IA) or formula (IB) or a downstream intermediate of a compound of formula (IA) or formula (IB) with an electron - transfer reducing agent (e.g., SmI 2 ; a Cr(III) salt and Mn(0); or Mg(0)). For exemplary desulfonation conditions, see WO2009 / 064029.

[0782] Nozaki - Hiyama - Kishi reaction

[0783] The Nozaki-Hiyama-Kishi reaction conditions useful for the transformations described herein can be those known in the art. The Nozaki-Hiyama-Kishi reaction can include reacting a substrate (an aldehyde and a vinyl halide or pseudohalide) with a Cr(II) salt and a Ni(II) salt. A co-ligand can be used in combination with the metal salts. In one non-limiting example, a substituted 1,10-phenanthroline can be used in combination with the Ni(II) salt. A chiral co-ligand can be used to render the reaction stereoselective. In one non-limiting example, chiral N-(dihydrooxazolyl-phenyl)-sulfonamides can be used with the Cr(II) salt to control the stereochemistry of the carbonyl carbon to which a vinyl nucleophile is added during the course of the Nozaki-Hiyama-Kishi reaction.

[0784] Salt formation

[0785] Salt formation reaction conditions are known in the art. Salt formation of eribulin can provide a pharmaceutically acceptable salt of eribulin (e.g., eribulin mesylate). In particular, the salt formation reaction can include contacting eribulin with brequinar acid (e.g., a pharmaceutically acceptable brequinar acid such as mesylic acid) to provide a pharmaceutically acceptable salt of eribulin (e.g., Handbook of Pharmaceutical Salts: Properties, Selection and Use, ed.: Stahl and Wermuth, Wiley-VCH / VHCA, Weinheim / Zurich, 2002). A pharmaceutically acceptable salt of eribulin, such as eribulin mesylate, can be formed by methods known in the art, such as in situ formation during the final isolation and purification of the compound, or separately by reacting the free base moiety with a suitable organic acid. In one example, eribulin is treated with a solution of MsOH and NH 4 OH in water and acetonitrile. The mixture is concentrated. The residue is dissolved in DCM-pentane and the solution is added to anhydrous pentane. The resulting precipitate is filtered and dried under high vacuum to provide eribulin mesylate.

[0786] Epimerization

[0787] Epimerization reactions can be used to transform stereogenic centers having undesired stereochemical characteristics. For example, by epimerization, an R stereogenic center can be converted to an S stereogenic center and vice versa. A stereoisomer bonded to a hydrogen atom and a hydroxyl group sp 3-Epimerization of carbon can be achieved by a reaction sequence that includes oxidizing a hydroxyl group to a carbonyl group followed by a 1,2-reduction reaction. The 1,2-reduction reaction can provide the desired stereochemistry diastereoselectively, or the reaction can be accomplished using a chiral catalyst, a chiral auxiliary, or a chiral reducing agent. Non-limiting examples of chiral reducing agents include alpine borane and prapine borane. Non-limiting examples of 1,2-reduction reactions that include a chiral catalyst are the Corey-Bakshi-Shibata reduction, the Noyori hydrogenation, and the Noyori transfer hydrogenation. The oxidation / reduction reaction sequence can be carried out in situ using dynamic kinetic resolution. The dynamic kinetic resolution can further include reacting with a hydroxyl protecting agent that removes the desired stereoisomer from the reduction / oxidation equilibrium. In one non-limiting example, the dynamic kinetic resolution of a chiral secondary alcohol can include: utilizing the reduction / oxidation equilibrium of η 5 -Ph 5 CpRu(CO) 2 H, which is combined with the enantioselective esterification of isopropyl acetate catalyzed by a lipase (e.g., lipase B from Candida Antarctica, see, for example, Martin-Matute et al., J. Am. Chem. Soc. , 127:8817-8825, 2005).

[0788] Epimerization can also be carried out on compounds containing a tetrahydropyran-2-yl-acetaldehyde moiety, where carbon 2 of the pyran ring exhibits an undesired stereochemistry. Contacting the compound with L-proline can provide an equilibrium between the two stereoisomers. Otherwise, an unbalanced stereogenic center is present in the compound, and the most stable stereoisomer will be present in a larger amount relative to one or more other stereoisomers that are in equilibrium with the most stable stereoisomer.

[0789] The following examples are intended to illustrate the invention. They are not intended to limit the invention in any way. Examples

[0790] Example 1 - Preparation of halichondrin macrolide analogues via the compound of formula (IC)

[0791]

[0792] (S)-1-((2S,5R)-5-((R)-1,2-Dihydroxyethyl)-3-methylenetetrahydrofuran-2-yl)-5-methylhepta-5,6-dien-3-yl 4-nitrobenzoate

[0793]

[0794] To a solution of (S)-1-((2S,5R)-5-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-methylenetetrahydrofuran-2-yl)-5-methylhepta-5,6-dien-3-yl 4-nitrobenzoate (0.70 g, 1.53 mmol) in acetic acid (8 mL) was added water (2 mL). The resulting mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, the reaction mixture was concentrated in vacuo and azeotroped with toluene twice to afford 0.62 g of the title product.

[0795]

[0796] (S)-5-methyl-1-((2S,5R)-3-methyl-5-((E)-2-(phenylsulfonyl)vinyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl 4-nitrobenzoate

[0797]

[0798] At ambient temperature, (S)-1-((2S,5R)-5-((R)-1,2-dihydroxyethyl)-3-methylenetetrahydrofuran-2-yl)-5-methylhepta-5,6-dien-3-yl 4-nitrobenzoate (0.62 g, 1.49 mmol) was dissolved in THF (12.4 mL). Then water (6.20 mL) and sodium periodate (0.953 g, 4.46 mmol) were added. The resulting mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, the reaction mixture was diluted with MTBE (30 mL), washed twice with 30% (w / v) aqueous NaCl solution (15 mL), and dried over MgSO 4 4-nitrobenzoate (0.62 g, 1.49 mmol) was dissolved in THF (12.4 mL). Then water (6.20 mL) and sodium periodate (0.953 g, 4.46 mmol) were added. The resulting mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, the reaction mixture was diluted with MTBE (30 mL), washed twice with 30% (w / v) aqueous NaCl solution (15 mL), and dried over MgSO 4The reaction was quenched with an aqueous solution of Cl (9 mL) and water (3 mL). The resulting mixture was warmed to ambient temperature and extracted twice with MTBE (12 mL each time). The combined organic layers were washed with an aqueous solution of 30% NaCl (10 ml) and dried over MgSO 4 438 mg of the title compound as a colorless oil was obtained by filtration, concentration in vacuo and purification by silica gel column chromatography using a gradient of 20 - 50% ethyl acetate / n-heptane as eluent.

[0799]

[0800] (S)-5-Methyl-1-((2S,5R)-3-methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-ol

[0801]

[0802] (S)-5-Methyl-1-((2S,5R)-3-methylene-5-((E)-2-(phenylsulfonyl)vinyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl 4-nitrobenzoate (438 mg, 0.837 mmol) was dissolved in THF (15 mL) and cooled to 0 °C. 1.0 M Lithium triethylborohydride (Super hydride) / THF (3.35 mL, 3.35 mmol) was added and the resulting mixture was allowed to warm to ambient temperature. After complete consumption of the starting material, saturated NH 4 Cl aqueous solution (30 mL) was added. The resulting mixture was extracted twice with MTBE (30 mL each time). The combined organic layers were washed with an aqueous solution of 30% (w / v) NaCl (10 mL) and dried over MgSO 4 280 mg of the title compound as a colorless oil was obtained by filtration, concentration in vacuo and purification by silica gel column chromatography using a gradient of 30 - 50% ethyl acetate / n-heptane as eluent.

[0803]

[0804] Triethyl(((S)-5-methyl-1-((2S,5R)-3-methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl)oxy)silane

[0805]

[0806] At 0 °C, imidazole (101 mg, 1.4 mmol) and triethylchlorosilane (0.127 mL, 0.744 mmol) were added to a solution of (S)-5-methyl-1-((2S,5R)-3-methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-ol (0.14 g, 0.372 mmol) in dichloromethane (4 mL). The resulting reaction mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, the reaction was quenched with saturated NH 4 Cl solution (10 mL). The resulting mixture was extracted with MTBE (20 mL), washed with 30% (w / v) aqueous NaCl solution (5 mL) and dried over MgSO 4 . Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 0 - 25% gradient of ethyl acetate / heptane as eluent afforded 128 mg of the title product as a colorless oil.

[0807]

[0808] 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde

[0809]

[0810] At -78 °C, 1.0 M Dibal-H / toluene (0.214 mL, 0.214 mmol) was added to a solution of 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (0.100 g, 0.107 mmol) in dichloromethane (2.0 mL). The reaction mixture was stirred at -78 °C until all starting materials had been consumed. Upon completion, the reaction was quenched with a solution of methanol (0.043 mL, 1.07 mmol) and Rochelle salt (0.453 g) in water (2.0 mL). The resulting mixture was allowed to warm to ambient temperature overnight. The organic layer was set aside and the aqueous layer was extracted twice with dichloromethane (4.00 mL). The combined organic layers were dried over MgSO 4Drying, filtration and vacuum concentration afforded 89 mg of [2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethanol]. The crude product was dissolved in dichloromethane (1.8 mL) at ambient temperature and treated with sodium bicarbonate (43.9 mg, 0.523 mmol) and Dess-Martin periodinane (111 mg, 0.261 mmol). Once the reaction was complete, MTBE (1.8 mL), saturated aqueous NaHCO 3 aqueous solution (8% w / v) (1 mL), water (0.5 mL) and sodium thiosulfate (165 mg, 1.05 mmol) were added. The resulting mixture was stirred at ambient temperature for 1 h and the layers were separated. The organic layer was washed with 30% aqueous NaCl (1 mL) and dried over MgSO 4 . Filtration, vacuum concentration and purification by silica gel column chromatography using a 2 / 1 mixture of n-heptane and ethyl acetate as eluent afforded 73 mg of the title product as a white foam solid.

[0811]

[0812] (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

[0813]

[0814] To a solution of (S)-3-((2R,3R,4S,5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (593 mg, 0.946 mmol) in THF (3.6 mL) at -78 °C was added 0.35 M lithium diisopropylamide (LDA) / THF (2.65 mL, 0.927 mmol). After 1 h, a solution of 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde (358 mg, 0.422 mmol) in n-heptane (5.4 mL) was added. The reaction mixture was stirred at -78 °C until all the aldehyde had been consumed. Upon completion, the reaction was quenched with saturated NH 4 Cl aqueous solution (7 mL). The resulting mixture was extracted twice with MTBE (50 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (4 mL) and dried over MgSO 4 . Filtration, concentration in vacuo and purification by silica gel column chromatography using a gradient of 33 - 66% ethyl acetate / n-heptane as eluent afforded 576 mg of (2R)-3-((2R,3R,4S,5S)-4-((1S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate contaminated with by-products. The crude product (658 mg) was dissolved in dichloromethane (13 mL) at ambient temperature and treated with sodium bicarbonate (0.187 g, 2.229 mmol) and Dess-Martin periodinane (0.473 g, 1.115 mmol). The reaction mixture was stirred at ambient temperature until all the starting materials had been consumed. Upon completion, MTBE (30 mL), saturated NaHCO 3 aqueous solution (15 mL), saturated Na 2 S 2 O 3An aqueous solution (10 mL) and water (10 mL). The resulting mixture was stirred at ambient temperature for 1 h and the layers were separated. The organic layer was set aside and the aqueous layer was extracted with MTBE (30 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (10 mL) and dried over MgSO 4 4. A solution of (R)-3-((2R,3R,4S,5S)-4-((S)-3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxo-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (0.590 g) in THF / methanol (9 / 6 mL) was cooled to -78 °C. 0.1 M SmI 2 2 in THF (18.0 mL, 1.80 mmol) was added until the green color persisted. Once the reaction was complete, saturated Rochelle's salt solution (30 mL), MTBE (7.2 mL) and water (4 mL) were added. The resulting mixture was warmed to ambient temperature over 4 h. The organic layer was separated and the aqueous layer was extracted with MTBE (7.2 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (2.4 mL) and dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using a gradient of 33 - 88% ethyl acetate / heptane as eluent to give 353 mg of the title product as a white foam solid.

[0815]

[0816] (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-((R)-2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate. Compound 7a

[0817]

[0818] To a solution of (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(((R)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (87 mg, 0.065 mmol) in methanol (5 mL) was added p-toluenesulfonic acid monohydrate (3.10 mg, 0.016 mmol). The reaction mixture was stirred until all starting materials had been consumed. Upon completion, the reaction was quenched with saturated NaHCO 3 aqueous solution (5 mL) and water (5 mL). The resulting mixture was extracted twice with MTBE (10 mL each time), and the combined organic layers were washed with 30% (w / v) aqueous NaCl solution (2 mL) and dried over MgSO 4 . The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using a 50 – 100% gradient of ethyl acetate / heptane as the eluent to afford 51 mg of the target product.

[0819]

[0820] (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

[0821]

[0822] To a solution of (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-((R)-2,3-dihydroxypropyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (51 mg, 0.039 mmol) in THF (2 mL) was added water (0.7 mL, 39 mmol) and sodium periodate (50.6 mg, 0.237 mmol). The reaction mixture was stirred until all starting materials had been consumed. Upon completion, the reaction was quenched with 30% (w / v) aqueous NaCl solution (5 mL). The resulting mixture was extracted with MTBE (12 mL) and the organic layer was washed twice with 30% (w / v) aqueous NaCl solution (3 mL) and dried over MgSO 4 48 mg of the title product as a white foam solid was provided after filtration and concentration in vacuo. The crude product was used in the next step without further purification.

[0823]

[0824] (2R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

[0825]

[0826] To a solution of triethyl(((S)-5-methyl-1-((2S,5R)-3-methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl)oxy)silane (25.09 mg, 0.051 mmol) in THF (1.5 mL) at -78 °C was added 0.35 M LDA / THF (0.156 mL, 0.055 mmol). After 30 min at -78 °C, a solution of (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (43 mg, 0.034 mmol) in THF (1.5 mL) was added. After stirring for 30 min at -78 °C, the reaction mixture was treated with saturated NH 4 Cl aqueous solution (3 mL), water (2 mL), and MTBE (5 mL). The resulting mixture was allowed to warm to ambient temperature and the layers were separated. The aqueous layer was extracted with MTBE (10 mL) and the combined organic layers were washed twice with 30% (w / v) NaCl aqueous solution (2 mL) and dried over MgSO 4 4. Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 15 – 50% gradient of ethyl acetate / heptane as eluent afforded 36 mg of a mixture of (2R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxy-4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate and the starting aldehyde, which was used in the next step without further purification.

[0827] To a solution of the crude product (1 mL of dichloromethane) at ambient temperature was added sodium bicarbonate (10.35 mg, 0.123 mmol) and Dess-Martin periodinane (26.1 mg, 0.062 mmol). After stirring for 6 h, the reaction mixture was diluted with MTBE (5 mL) and treated with saturated NaHCO 3 aqueous solution (3 mL) and saturated Na 2 S 2 O 3 aqueous solution (2 mL). The resulting mixture was stirred for 20 min and the layers were separated. The aqueous layer was extracted with MTBE (12 mL) and the combined organic layers were washed twice with 30% (w / v) aqueous NaCl solution and dried over MgSO 4 . Filtration, concentration in vacuo, and purification by silica gel column chromatography using a gradient of 33–50% ethyl acetate / heptane as eluent afforded 24 mg of the title product as a 1:1 diastereomeric mixture.

[0828]

[0829] Compound 14

[0830]

[0831] To a solution of dibenzoic acid (2R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (12 mg, 5.484 µmol) in dichloromethane (2.4 mL) at -18 °C was added methoxyacetic acid (0.017 mL, 0.219 mmol) and BF 3 .OEt 2 (5.6 µL, 0.044 mmol). The reaction mixture was stirred at -25 °C to -15 °C until cyclization was complete. After completion, it was treated with saturated NaHCO 3The reaction was quenched with aqueous solution (5 mL). The resulting mixture was extracted twice with MTBE (10 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (3 mL) and dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using a 10–40% gradient of ethyl acetate / heptane as eluent to afford 5.5 mg of the title compound as a 3:2 diastereomeric mixture.

[0832]

[0833] Compound 16

[0834]

[0835] To a solution of compound 14 (5.5 mg, 3.309 μmol) in THF (1 mL) was added formic acid (6.35 μL, 0.165 mmol), triethylamine (0.023 mL, 0.165 mmol) and a solution of Pd(Ph 3 P) 4 (1.147 mg, 0.993 μmol) and triphenylphosphine (1.041 mg, 3.971 μmol) in THF (0.1 mL). The resulting mixture was stirred at 60–65 °C overnight and cooled to ambient temperature. The reaction mixture was diluted with MTBE (10 mL), washed with saturated aqueous NaHCO 3 3 solution (3 mL) and dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using a 30–50% gradient of ethyl acetate / heptane as eluent to afford 1.8 mg of the title compound as a 2:1 diastereomeric mixture.

[0836]

[0837] Compound 17

[0838]

[0839] At -78 °C, 0.1 M samarium diiodide / THF (0.057 mL, 5.718 µmol) was added to a solution of compound 16 (1.8 mg, 1.144 µmol) in THF (0.5 mL) / methanol (0.25 mL) until the green color persisted. The reaction mixture was stirred at -78 °C for 10 min and treated with saturated Rochelle's salt aqueous solution (3 mL), MTBE (5 mL), and water (2 mL). The resulting mixture was warmed to ambient temperature and then extracted with MTBE (7 mL). The organic layer was washed with 30% (w / v) aqueous NaCl solution (3 mL) and dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo, and purified by silica gel column chromatography using a gradient of 10 – 33% ethyl acetate / heptane as the eluent to afford 1.4 mg of the desired product.

[0840]

[0841] Compound 18

[0842]

[0843] At ambient temperature, THF (280 µL) and N,N-dimethylacetamide (98 µL) were added to compound 17 (1.4 mg, 0.976 µmol) in a vial. A mixture of TBAF (1.0 M in THF, 49 µL, 0.049 mmol) and imidazole hydrochloride (2.6 mg, 0.024 mmol) was added. The resulting mixture was stirred at ambient temperature for 15 h and then treated with 30% (w / v) aqueous NaCl solution (2 mL) and MTBE (3 mL). The layers were separated and the aqueous layer was extracted twice with MTBE (3 mL each time). The combined organic layers were concentrated in vacuo. The residue was dissolved in dichloromethane (0.5 mL) at ambient temperature and PPTS (0.9 mg, 3.6 µmol) was added. Once the starting material had been consumed, the reaction mixture was purified by silica gel column chromatography using heptane / ethyl acetate (1 / 1) and ethyl acetate as the eluents to afford 0.6 mg of the desired product, which was confirmed by NMR analysis using an authentic sample.

[0844] (S)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2S,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxobutyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate

[0845]

[0846] To a solution of (S)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl dibenzoate (12 mg, 6.856 μmol) in THF (1.2 mL) / methanol (0.4 mL) was added a THF solution of samarium diiodide (0.1 M, 0.34 mL, 34 μmol) until the green color persisted. The reaction mixture was stirred at -78 °C for 10 min and treated with saturated Rochelle's salt solution (1.5 mL), MTBE (3 mL), and water (1 mL). The resulting mixture was warmed to ambient temperature and extracted with MTBE (7 mL). The organic layer was washed with 30% (w / v) aqueous NaCl solution (3 mL) and dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo, and purified by silica gel column chromatography using a 33–50% gradient of ethyl acetate / heptane as the eluent to afford 6.0 mg of the title product.

[0847]

[0848] Compound 15

[0849]

[0850] To a solution of di-benzoic acid (R)-3-((2R,3R,4S,5S)-4-(3-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2S,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxobutyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (6.0 mg, 3.726 µmol) in dichloromethane (1.8 mL) was added methoxyacetic acid (8.6 µL, 0.112 mmol) and BF 3 ·OEt 2 (3.8 µL, 0.03 mmol). The reaction mixture was stirred at -20 °C to -15 °C and monitored by TLC. After completion, the reaction was quenched with saturated NaHCO 3 aqueous solution (2 mL). The resulting mixture was extracted twice with MTBE (10 mL). The combined organic layers were washed with 30% (w / v) NaCl aqueous solution (2 mL) and dried over MgSO 4 . Filtered, concentrated in vacuo, and purified by silica gel column chromatography using a 10–40% gradient of ethyl acetate / heptane as the eluent to afford 2.8 mg of the target product.

[0851]

[0852] Compound 17

[0853]

[0854] To a solution of Compound 15 (1.3 mg, 0.85 µmol) in THF (0.5 mL) was added formic acid (1.6 µL, 0.043 mmol), triethylamine (6.0 µL, 0.043 mmol), and a solution of Pd(Ph 3 P) 4 (0.5 mg, 0.42 µmol) and triphenylphosphine (0.5 mg, 1.7 µmol) in THF (0.1 mL). The resulting mixture was stirred at 60 - 65 °C overnight and cooled to ambient temperature. The reaction mixture was diluted with MTBE (5 mL) and washed with saturated NaHCO 3 aqueous solution (1 mL) and 30% (w / v) NaCl aqueous solution (1 mL), and dried over MgSO4 Dry. Filter, concentrate in vacuo, and purify by silica gel column chromatography using a 20–50% gradient of ethyl acetate / heptane as eluent to afford 0.2 mg of the title product, which was confirmed by comparison of its NMR with an authentic sample.

[0855] Alternative synthesis via compound (IC)

[0856] Compound 17 can also be prepared from compound 8 according to the following reaction sequence.

[0857]

[0858] As illustrated in the above scheme, compound 8 can react with Seyferth–Gilbert reagent 20 in the presence of SnCl 2 to afford compound 21, which can be converted to compound 23 after reaction with a strong base (e.g., LiHMDS) and compound 22. Compound 23 can be subjected to a Prins reaction with an oxophilic Lewis acid and a carboxylic acid to give compound 24, which is converted to compound 17 after allylic reduction (e.g., Pd-catalyzed allylic reduction) and 1,4-reduction (e.g., with Stryker's reagent).

[0859] Example 2 - Preparation of halichondrin macrolide analogues via the compound of formula (IJ)

[0860]

[0861]

[0862] Dibenzoic acid (2 S )-3-((2 R, 3 R, 4 S, 5 S )-4-((1 R )-3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S,E )-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester

[0863] Dibenzoic acid (S)-3-((2 R, 3 R, 4 S,The solution of (5S)-5-(2,2-dimethoxyethyl)-3-methoxy-4-((phenylsulfonyl)methyl)tetrahydrofuran-2-yl)propane-1,2-diyl ester (4.95 g, 7.89 mmol) (azeotroped with THF twice) in THF (40.5 mL) was cooled to -78 °C and treated with freshly prepared lithium diisopropylamide (LDA, 19.7 mL, 0.40 M), maintaining the internal temperature below -68 °C. After stirring for 30 min at -78 °C, the mixture was treated with a solution of 2-((2 R, 4a S, 6 S, 7 R, 8 S, (8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S,E )-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)acetaldehyde (4.50 g, 6.07 mmol) in n-heptane (54.0 mL) for 15 min, maintaining the internal temperature below -65 °C. The mixture was stirred at -78 °C for 2 h, at which point the reaction was quenched with saturated aqueous NH 4 Cl (45.0 mL) and extracted twice with methyl tert-butyl ether (MTBE, 45.0 mL). The organic layers were combined, dried over MgSO 4 and concentrated in vacuo to afford the title compound (8.6 g, 104%).

[0864]

[0865] Dibenzoic acid ( S )-3-((2 R, 3 R, 4 S, (5S)-4-((R)-3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S, (E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxo-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester

[0866] The crude dibenzoic acid (2 R )-3-((2 R, 3 R,4 S, 5 S )-4-((1 S )-3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S,E )-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-hydroxy-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (10.8 g, 7.88 mmol) in CH 2 Cl 2 (162 mL) was treated with Dess-Martin periodinane (4.01 g, 9.45 mmol) and stirred at room temperature for 2 h. The reaction was quenched with saturated NaHCO 3 aqueous solution (86 mL) and 20% (w / v) Na 2 SO 3 aqueous solution (86 mL). The mixture was extracted twice with MTBE (86 mL). The organic layers were combined, dried over MgSO 4 and concentrated in vacuo to afford the title compound (11.23 g, 104%).

[0867]

[0868] Dibenzoic acid ( S )-3-((2 R, 3 R, 4 S, 5 S )-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S, E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester

[0869] The crude dibenzoic acid (R)-3-((2 R, 3R, 4 S, 5 S )-4-(( S )-3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S, E)-1-((tert-butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxo-1-(phenylsulfonyl)propyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (10.75 g, 7.87 mmol) in a solution of a mixture of THF (82 mL) and methanol (56 mL) was cooled to -78 °C and treated with 0.1 M SmI 2 / THF (197 mL, 19.7 mmol) for 40 min while maintaining the internal temperature below -60 °C. The resulting mixture was stirred at -78 °C for 1 h. The reaction was quenched with an aqueous solution of 40% (w / v) Rochelle salt (153 mL), and the resulting mixture was warmed to room temperature. After treatment with potassium carbonate (32.6 g, 236 mmol), the mixture was stirred at room temperature for 30 min and extracted twice with MTBE (108 mL). The organic layers were combined, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 25%) to give the title compound (6.65 g, 69%, over 3 steps).

[0870]

[0871]

[0872] Dibenzoic acid (2 R )-3-((2 R, 3 R, 4 S, 5 S )-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((1 S,E )-1-((tert-butyldimethylsilyl)oxy)-4-hydroxy-6-((2 S, 5S )-5-(( S )-5-Methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)hex-2-en-1-yl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester

[0873] Purge the three-necked flask with nitrogen and charge it with ( S )- N -(2-(4-Isopropyl-4,5-dihydrooxazol-2-yl)-6-methylphenyl)methanesulfonamide ((S)-ligand, 2.42 g, 8.16 mmol). After purging with nitrogen for 5 min, add chromium(II) chloride (1.00 g, 8.16 mmol). After purging with nitrogen for 5 min, heat the mixture to 35 °C and treat it with Et 3 N (1.14 mL, 8.16 mmol), maintaining the internal temperature below 35 °C. Stir the mixture at 30 - 35 °C for 1 h. After cooling to 0 °C, treat the mixture with nickel(II) 2,9-dimethyl-1,10-phenanthroline complex (0.069 g, 0.20 mmol), and 3-((2 S, 5 S )-5-(( S )-5-Methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)propanal (1.066 g, 2.815 mmol) and dibenzoic acid( R )-3-((2 R, 3 R, 4 S, 5 S )-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-Bis((tert-butyldimethylsilyl)oxy)-6-(( S,E)-1-((tert-Butyldimethylsilyl)oxy)-3-iodoallyl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (2.5 g, 2.04 mmol) in THF (11.25 mL) was treated. The mixture was stirred at 0 °C for 5 min and at room temperature for 16 h. After cooling to 0 °C, the mixture was treated with 1,2-ethylenediamine (2.05 mL, 30.6 mmol) and stirred at room temperature for 1 h. The mixture was treated with water (25 mL) and n-heptane (37.5 mL). The organic layer was separated, and the aqueous layer was extracted twice with MTBE (30.0 mL). The organic layers were combined, dried over MgSO 4 and concentrated in vacuo. The residue was treated with 2-propanol (ca. 10 mL) and stirred at room temperature for 1 h. The precipitated ligand was filtered off and rinsed with 2- propanol. The filtrate was concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 40%) to afford the title compound (1.398 g, 46%, a mixture of two isomers).

[0874]

[0875]

[0876] (R)-3-((2 R, 3 R, 4 S, 5S)-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, 8aS)-7,8-Bis((tert-butyldimethylsilyl)oxy)-6-(( S,E )-1-((tert-butyldimethylsilyl)oxy)-6-((2 S, 5S)-5-((S)-5-Methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-4-oxohex-2-en-1-yl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester

[0877] Di-benzoic acid 2R )-3-((2 R, 3 R, 4 S,(5S)-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, (8aS)-7,8-bis((tert-butyldimethylsilyl)oxy)-6-((1 S, (E)-1-((tert-butyldimethylsilyl)oxy)-4-hydroxy-6-((2 S, (5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)hex-2-en-1-yl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (0.957 g, 0.647 mmol) in CH 2 Cl 2 (9.6 mL) was treated with aqueous sodium bicarbonate (0.163 g, 1.94 mmol) and Dess-Martin periodinane (0.33 g, 0.78 mmol). The mixture was stirred at room temperature for 40 min. The reaction was quenched with 20% (w / v) Na 2 SO 3 aqueous solution (7.66 mL) and saturated NaHCO 3 aqueous solution (7.66 mL). The mixture was extracted twice with MTBE (9.57 mL). The organic layers were combined, washed with brine (9.6 mL), and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 40%) to afford the title compound (828 mg, 87%).

[0878]

[0879]

[0880] Compound 33. Dibenzoic acid ( R )-3-((2 R, 3 R, 4 S, 5 S )-4-(3-((2 R, 4a S, 6 S, 7 R, 8 S, 8a S )-7,8-bis((tert-butyldimethylsilyl)oxy)-6-(( S,E)-1-((tert-Butyldimethylsilyl)oxy)-6-((2 S, (5S)-5-(( S )-5-Methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-4-oxohex-2-en-1-yl)octahydropyrano[3,2-b]pyran-2-yl)-2-oxopropyl)-5-(2,2-dimethoxyethyl)-3-methoxytetrahydrofuran-2-yl)propane-1,2-diyl ester (0.10 g, 0.068 mmol) in CH 2 Cl 2 (22 mL) was cooled to -25 °C and treated with methoxyacetic acid (0.104 mL, 1.36 mmol) and BF 3 ·OEt 2 (0.026 mL, 0.20 mmol). The mixture was stirred at -25 °C to -15 °C for 3 h. Additional BF 3 ·OEt 2 (0.017 mL, 0.135 mmol) was added and stirring was continued at -15 to -25 °C for an additional 1 h. The reaction was quenched with saturated NaHCO 3 aqueous solution (20 mL). The mixture was extracted twice with MTBE (20 mL). The organic layers were combined, washed with brine, and concentrated in vacuo. The residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 40%) to afford the title compound (26 mg, 28%).

[0881]

[0882]

[0883] Compound 34. To a mixture of Pd(Ph 3 P) 4 (2.1 mg, 1.80 µmol) and triphenylphosphine (1.9 mg, 7.2 µmol) in THF (1.0 mL) was added a solution of compound 33 (25 mg, 0.018 mmol) in THF (1.0 mL), formic acid (0.017 mL, 0.45 mmol), and triethylamine (0.063 mL, 0.45 mmol). The mixture was stirred at 60 °C for 3 days (d). Additional Pd(Ph 3 P) 4(2.1 mg, 1.8 µmol), triethylamine (0.063 mL, 0.45 mmol), and formic acid (0.017 mL, 0.45 mmol), and the mixture was stirred at 60 °C for an additional 1 day. The mixture was diluted with MTBE and washed with saturated NaHCO 3 aqueous solution. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% - 25%) to give the title compound (17 mg, 73%).

[0884]

[0885]

[0886] Compound 18. A mixture of imidazole hydrochloride (0.011 g, 0.11 mmol) and 1 M tetrabutylammonium fluoride (TBAF) / THF (0.23 mL, 0.23 mmol) was diluted with THF (0.46 mL) and treated with a solution of compound 34 (0.023 g, 0.018 mmol) in THF (0.69 mL). After stirring at room temperature for 2 days, the mixture was treated with toluene (2.3 mL) and water (1.2 mL). The organic layer was separated and the aqueous layer was extracted twice with a mixture of toluene (1.2 mL) and THF (1.2 mL). The organic layers were combined and concentrated in vacuo. The residue was azeotroped twice with acetonitrile (1.2 mL).

[0887] The residue was dissolved in CH 2 Cl 2 (3 mL), treated with PPTS (0.045 g, 0.18 mmol), and stirred at room temperature for 1 day. The mixture was concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 80%) to give the title compound (12 mg, 72%).

[0888]

[0889] Compound 19. A solution of compound 18 (0.012 g, 0.013 mmol) in a mixture of THF (0.024 mL) and methanol (0.48 mL) was treated with 6 - 10% (w / v) Mg(OMe) 2 / methanol (0.051 g, 0.038 mmol), and the resulting mixture was stirred at room temperature for 20 h. Additional 6 - 10% Mg(OMe) 2 / methanol (0.051 g, 0.038 mmol) and stirred for an additional 1 day at room temperature. After concentration, the mixture was purified by silica gel column chromatography (ethyl acetate / n-heptane = 30% - 100%, then 5% MeOH / ethyl acetate) to afford the title compound (4 mg, 43%).

[0890]

[0891] Compound 35. A mixture of imidazole hydrochloride (0.022 g, 0.21 mmol) and 1 M TBAF / THF (0.44 mL, 0.44 mmol) was diluted with THF (0.94 mL) and treated with a solution of compound 33 (0.094 g, 0.068 mmol) in THF (2.256 mL). The mixture was stirred at room temperature for 7 days. After dilution with toluene (2.35 mL) and water (2.35 mL), the organic layer was separated, and the aqueous layer was extracted twice with a mixture of toluene (1.6 mL) and THF (1.6 mL). The combined organic layers were concentrated in vacuo and azeotroped twice with acetonitrile (4.7 mL).

[0892] The residue was dissolved in CH 2 Cl 2 (3.55 mL), treated with pyridinium p-toluenesulfonate (PPTS, 0.094 g, 0.37 mmol), and stirred at room temperature for 1 day. Additional PPTS (0.094 g, 0.37 mmol) was added and stirring was continued at room temperature for an additional 3 days. After concentration, the mixture was dissolved in ethyl acetate and filtered through a glass filter to remove the insoluble solid (PPTS). The filtrate was concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 80%) to afford the title compound (18 mg, 26%).

[0893]

[0894]

[0895] Compound 18. To Pd(Ph 3 P) 4A solution of compound 35 (0.018 g, 0.018 mmol), formic acid (0.013 mL, 0.35 mmol) and triethylamine (0.049 mL, 0.35 mmol) in THF (0.72 mL) was added to a mixture of (2.0 mg, 1.8 µmol) and triphenylphosphine (1.8 mg, 7.0 µmol) in THF (0.72 mL). The mixture was stirred at 60 °C for 20 h. Additional triethylamine (0.049 mL, 0.35 mmol) and formic acid (0.013 mL, 0.35 mmol) were added and stirring was continued at 60 °C for an additional 2.5 days. After dilution with MTBE, the mixture was washed with saturated NaHCO 3 aqueous solution. The organic layer was concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 80%) to give the title compound (18 mg).

[0896]

[0897]

[0898] Compound 19. A solution of compound 18 (0.018 g, 0.019 mmol) in a mixture of THF (0.045 mL) and methanol (0.9 mL) was treated with 6 - 10% (w / v) Mg(OMe) 2 / methanol (0.186 mL, 0.134 mmol) and stirred at room temperature for 3 days. After concentration, the mixture was purified by silica gel column chromatography (ethyl acetate / n-heptane = 30% to 100% and 5% MeOH / ethyl acetate) to give the title compound (3 mg, 23%, over 2 steps).

[0899]

[0900] Example 3 - Preparation of halichondrin macrolide analogues via the compound of formula (IJ)

[0901]

[0902] Exemplary compounds of formula (IA) can be prepared as shown in the above scheme. Compound 36 can be homologated in the following order: Swern oxidation, Horner-Wadsworth-Emmons reaction (Masamune / Roush conditions), reduction with DIBAL-H and with MnO 2Oxidation. Then the homologated compound 36 is treated with compound 6 and can be deprotonated, for example, with LDA or LiHMDS to give compound 37. Reacting compound 37 with compound 30 under Nozaki-Hiyama-Kishi reaction conditions provides compound 38 (an exemplary compound of formula (IA)). Then compound 38 is oxidized with Dess-Martin periodinane to give compound 39 (another exemplary compound of formula (IA)). Compound 39 can be converted to compound 40 (an exemplary compound of formula (IB)) by reaction with methoxyacetic acid and BF 3 ·OEt 2 (exemplary Prins reaction conditions).

[0903]

[0904] Exemplary halichondrin macrolide analogs can be prepared from the compound of formula (IB) as shown in the above scheme. Two routes are provided herein that can be used to obtain compound 18 from compound 40. In one method, compound 40 can be reacted with an allyl reducing agent (e.g., Pd(PPh 3 ) 4 / HCO 2 H / Et 3 N) to give compound 41, which can be converted to compound 18 after global desilylation with a fluorine source (e.g., TBAF buffered with imidazolium hydrochloride), PPTS-catalyzed ketalization, and reductive desulfonation (e.g., with SmI 2 ). Alternatively, compound 40 can first be converted to compound 35 by global desilylation with a fluorine source (e.g., TBAF buffered with imidazolium hydrochloride), PPTS-catalyzed ketalization, and reductive desulfonation (e.g., with SmI 2 ). Reacting compound 35 with an allyl reducing agent (e.g., Pd(PPh 3 ) 4 / HCO 2 H / Et 3 N) gives compound 18 as described in Example 2. Compound 18 is converted to compound 19 as described in Example 1.

[0905] Example 4 - Preparation of halichondrin via the compound of formula (IN)

[0906]

[0907] 2-((2R,3R,4aS,6S,7R,8R,8aS)-3-(benzyloxy)-6-(2,2-dimethoxyethyl)-7-((4-methoxybenzyl)oxy)-8-methyloctahydropyrano[3,2-b]pyran-2-yl)ethanol

[0908]

[0909] At 0 °C, imidazole (0.397 g, 5.83 mmol) and triethylchlorosilane (0.652 mL, 3.89 mmol) were added to a solution of methyl 2-((2S,3R,4R,4aS,6R,7R,8aS)-7-(benzyloxy)-6-(2-hydroxyethyl)-3-((4-methoxybenzyl)oxy)-4-methyloctahydropyrano[3,2-b]pyran-2-yl)acetate (1.0 g, 1.94 mmol) in dichloromethane (10.00 mL, 155.417 mmol). The resulting mixture was stirred at ambient temperature for 1 h and then treated with MTBE (20 mL) and saturated aqueous NH 4 Cl (15 mL). The organic layer was separated, washed twice with 30% (w / v) aqueous NaCl (10 mL), and dried over MgSO 4 . Filtration and concentration in vacuo afforded 1.329 g of methyl 2-((2S,3R,4R,4aS,6R,7R,8aS)-7-(benzyloxy)-3-((4-methoxybenzyl)oxy)-4-methyl-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)acetate. The crude product was dissolved in dichloromethane (24 mL) and cooled to -78 °C. 1.0 M DIBAL-H / toluene (3.08 mL, 3.077 mmol) was added while maintaining the internal temperature below -74 °C. After stirring at -78 °C for 2 h, the reaction was quenched with methanol (0.778 mL, 19.231 mmol) and Rochelle salt solution (30 mL) and water (20 mL) were added. The resulting mixture was warmed to ambient temperature overnight. The layers were separated and the aqueous layer was extracted twice with dichloromethane (30 mL). The combined organic layers were dried over MgSO 4 , filtered, and concentrated in vacuo to afford 1.314 g of crude 2-((2S,3R,4R,4aS,6R,7R,8aS)-7-(benzyloxy)-3-((4-methoxybenzyl)oxy)-4-methyl-6-(2-((triethylsilyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-2-yl)acetaldehyde. The crude product was dissolved in methanol (20 mL) at ambient temperature. Trimethyl orthoformate (2 mL) and p-toluenesulfonic acid monohydrate (0.018 g, 0.097 mmol) were added to the resulting solution. The reaction mixture was stirred at ambient temperature overnight and quenched with saturated NaHCO 3Treated with aqueous solution (34.7 mL) and water (12 mL). The resulting mixture was extracted three times with MTBE (40 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (20 mL) and dried over MgSO 4 and filtered, concentrated in vacuo and purified by silica gel column chromatography using a 50–100% gradient of ethyl acetate / heptane as eluent to afford 0.79 g of the title product.

[0910]

[0911] (2R,3R,4aS,6S,7R,8R,8aS)-6-(2,2-Dimethoxyethyl)-7-((4-methoxybenzyl)oxy)-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl 4-nitrobenzoate

[0912]

[0913] To a solution of 2-((2R,3R,4aS,6S,7R,8R,8aS)-3-(benzyloxy)-6-(2,2-dimethoxyethyl)-7-((4-methoxybenzyl)oxy)-8-methyloctahydropyrano[3,2-b]pyran-2-yl)ethanol (0.77 g, 1.451 mmol) in methanol (31 mL) was added a slurry of Raney-Nickel in water (ca. 8 mL). The resulting mixture was stirred under H 2 (balloon) until all starting materials had been consumed. Upon completion, the mixture was diluted with MeOH and filtered through a pad of Celite, then rinsed with MeOH until all soluble products had been removed. Concentration of the filtrate afforded 0.639 g of (2R,3R,4aS,6S,7R,8R,8aS)-6-(2,2-dimethoxyethyl)-2-(2-hydroxyethyl)-7-((4-methoxybenzyl)oxy)-8-methyloctahydropyrano[3,2-b]pyran-3-ol. The crude product was dissolved in pyridine (12.8 ml) at ambient temperature and treated with 4-nitrobenzoyl chloride (1.077 g, 5.802 mmol) and 4-dimethylaminopyridine (0.018 g, 0.145 mmol). The resulting mixture was stirred until all starting materials had been consumed. Upon completion, the reaction mixture was diluted with EtOAc (30 mL) and washed with saturated NaHCO 3Treat with aqueous solution (40 mL) and water (10 mL). Separate the layers, and extract the aqueous layer twice with a mixture of EtOAc / MTBE (1 / 1, 30 mL each time). Wash the combined organic layers with 30% (w / v) aqueous NaCl solution (25 mL) and dry over MgSO 4 Dry. Filter, concentrate in vacuo and purify by silica gel column chromatography using a gradient of 25–50% ethyl acetate / heptane as eluent to give 0.72 g of the title product.

[0914]

[0915] (2R,3R,4aS,6S,7R,8R,8aS)-6-(2,2-Dimethoxyethyl)-7-hydroxy-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl 4-nitrobenzoate

[0916]

[0917] To a solution of (2R,3R,4aS,6S,7R,8R,8aS)-6-(2,2-Dimethoxyethyl)-7-((4-methoxybenzyl)oxy)-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl 4-nitrobenzoate (0.70 g, 0.948 mmol) in dichloromethane (22.4 mL) at ambient temperature was added tert-butanol (0.224 mL), pH 7 phosphate buffer (2.2 mL) and DDQ (0.430 g, 1.895 mmol). Stir the resulting mixture at ambient temperature until all starting materials have been consumed (ca. 2 h). Upon completion, treat the reaction mixture with saturated NaHCO 3 aqueous solution (30 mL). Separate the layers and extract the aqueous layer twice with CH 2 Cl 2 (30 mL each time). Wash the combined organic layers with 30% NaCl aqueous solution (10 mL) and dry over MgSO 4 Dry. Filter, concentrate in vacuo and purify by silica gel column chromatography using a gradient of 50–80% ethyl acetate / heptane as eluent to give 574 mg of the title product as a white solid.

[0918]

[0919] 1-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-7-(2-hydroxyethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-3-(phenylsulfonyl)butan-2-ol. Compound 44a

[0920]

[0921] To a solution of triethyl(((S)-5-methyl-1-((2S,5R)-3-methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-yl)oxy)silane (178 mg, 0.363 mmol) in THF (4.6 mL) at -78 °C was added potassium tert-butoxide (1.0 M in THF, 0.363 mL, 0.363 mmol) and n-BuLi (1.6 M in hexanes, 0.227 mL, 0.363 mmol). The resulting mixture was stirred at -78 °C for 10 min and treated with a solution of 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-oxoethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (116 mg, 0.134 mmol) in THF (3 mL). The resulting reaction mixture was stirred at -78 °C until all aldehyde had been consumed. Upon completion, the reaction was quenched with saturated NH 4 Cl aqueous solution (4 mL) and water (2 mL). The resulting mixture was diluted with MTBE (5 mL) and warmed to ambient temperature. The layers were separated and the aqueous layer was extracted with MTBE (10 mL). The combined organic layers were washed twice with 30% (w / v) aqueous NaCl solution (4 mL) and dried over MgSO 4 4. Filtration and concentration in vacuo afforded 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(2-hydroxy-4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)ethyl pivalate (MS m / z 1376.8 [M+Na]+ )。The crude product (theoretically 182 mg) was dissolved in dichloromethane (8 mL) and cooled to -78 °C. 1.0 M DIBAL-H / toluene (0.672 mL, 0.672 mmol) was added and the resulting solution was stirred at -78 °C for 1.5 h. The reaction was then quenched with methanol (0.27 mL, 6.72 mmol) and saturated Rochelle salt solution (10 mL). The resulting mixture was diluted with dichloromethane (10 mL) and warmed to ambient temperature overnight. The layers were separated and the aqueous layer was extracted with dichloromethane (5 mL). The combined organic layers were dried over MgSO 4 4. The mixture was filtered, concentrated in vacuo and purified by silica gel column chromatography using a gradient of 20 – 50% ethyl acetate / heptane as eluent to afford 148 mg of the title product as a mixture of four diastereoisomers (MS m / z 1291.7 [M+Na] + ).

[0922] 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-Bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetic acid

[0923]

[0924] To a solution of 1-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-7-(2-hydroxyethyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-2-yl)-4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-3-(phenylsulfonyl)butan-2-ol (148 mg, 0.117 mmol) in dichloromethane (4.4 mL) at ambient temperature was added sodium hydrogen carbonate (78 mg, 0.932 mmol) and Dess-Martin periodinane (198 mg, 0.466 mmol). The resulting mixture was stirred at ambient temperature for 4 h and quenched with saturated NaHCO 3 aqueous solution (6 mL) and saturated Na 2 2 2 SO 3Treat with aqueous solution (6 mL). Dilute the resulting mixture with MTBE (15 mL) and stir for 30 min. Separate the layers and extract the aqueous layer with MTBE (10 mL). Wash the combined organic layers twice with 30% (w / v) aqueous NaCl solution (5 mL each time) and dry over MgSO 4 Dry. Filter and concentrate in vacuo to afford 148 mg of 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetaldehyde (MS m / z 1287.6 [M+Na] + ). To the crude product, add tert-butanol (4.4 mL) and n-pentene (0.444 mL, 4.19 mmol). Treat the resulting mixture with an aqueous solution (2.2 mL) of sodium dihydrogen phosphate (49.1 mg, 0.409 mmol) and sodium chlorite (31.7 mg, 0.351 mmol). Stir the reaction mixture at ambient temperature until all starting materials have been consumed. Upon completion, dilute the mixture with MTBE (15 mL) and treat with saturated NH 4 Cl aqueous solution (10 mL). Separate the organic layer and extract the aqueous layer with MTBE (10 mL). Wash the combined organic layers twice with 30% (w / v) aqueous NaCl solution (5 mL each time) and dry over MgSO 4 Dry. Filter, concentrate in vacuo and purify by silica gel column chromatography using a 33–75% gradient of ethyl acetate / n-heptane as eluent to afford 118 mg of the title product, which is a 1:1 mixture of two diastereomers (MS m / z 1303.8 [M+Na] + ).

[0925]

[0926] (2R,3R,4aS,6S,7R,8S,8aS)-7-(2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-Bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-Methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetoxy)-6-(2,2-dimethoxyethyl)-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl 4-nitrobenzoate

[0927]

[0928] To a solution of 4-nitrobenzoic acid 2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (118 mg, 0.092 mmol) and (2R,3R,4aS,6S,7R,8R,8aS)-6-(2,2-dimethoxyethyl)-7-hydroxy-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl ester (159 mg, 0.258 mmol) in dichloromethane (3.0 mL) was added triethylamine (TEA, 0.026 mL, 0.184 mmol), 6-nitro-2-methylbenzoic anhydride (47.5 mg, 0.138 mmol) and 4-dimethylaminopyridine (5.62 mg, 0.046 mmol). After stirring overnight, the reaction mixture was concentrated in vacuo. Purification by silica gel column chromatography using a gradient of 33 - 66% ethyl acetate / heptane as eluent afforded 152 mg of the title compound as a 1:1 mixture of diastereomers.

[0929]

[0930] Compound 49

[0931]

[0932] To a solution of (2R,3R,4aS,6S,7R,8S,8aS)-7-(2-((2R,3S,3aR,4aS,7R,8aS,9S,9aR)-3,9-bis((tert-butyldiphenylsilyl)oxy)-2-(4-((2R,5S)-5-((S)-5-methyl-3-((triethylsilyl)oxy)hepta-5,6-dien-1-yl)-4-methylenetetrahydrofuran-2-yl)-2-oxo-3-(phenylsulfonyl)butyl)decahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetoxy)-6-(2,2-dimethoxyethyl)-8-methyl-2-(2-((4-nitrobenzoyl)oxy)ethyl)octahydropyrano[3,2-b]pyran-3-yl 4-nitrobenzoate (76 mg, 0.04 mmol) in dichloromethane (38 mL) was added methoxyacetic acid (0.155 mL, 2.02 mmol) and BF 3 ·OEt 2 (51 µL, 0.40 mmol). The reaction mixture was stirred at -20 °C to -10 °C and the reaction was monitored by TLC and LCMS. Upon completion, the reaction was quenched with saturated NaHCO 3 aqueous solution (20 mL). The organic layer was separated and washed with 30% (w / v) NaCl aqueous solution (5 mL) and dried over MgSO 4 . Filtered, concentrated in vacuo and purified by silica gel column chromatography using a 50–66% gradient of ethyl acetate / heptane as eluent to afford 58 mg of the title product as a 1:1 diastereomeric mixture.

[0933]

[0934] Compound 50

[0935]

[0936] At ambient temperature, to a solution of Pd(Ph 3 P) 4 (8.05 mg, 6.967 µmol) and triphenylphosphine (7.31 mg, 0.028 mmol) in THF (1.0 mL) was added a solution of compound 49 (25 mg, 0.014 mmol) in THF (0.5 mL). Formic acid (3.2 µL, 0.084 mmol) and triethylamine (0.012 mL, 0.084 mmol) were added via syringe. The resulting mixture was stirred at 60 - 65 °C for 15 h and cooled to ambient temperature. The reaction mixture was diluted with MTBE (10 mL) and washed with saturated NaHCO3 Washed with aqueous solution (3 mL) and dried over MgSO 4 Dried. Filtered, concentrated in vacuo and purified by silica gel column chromatography using a 25–60% gradient of ethyl acetate / n-heptane as eluent to afford 10 mg of the title product, which is a 2:1 mixture of diastereomers.

[0937]

[0938] Compound 50a

[0939]

[0940] To a solution of compound 50 (10 mg, 5.861 μmol) in MeOH (0.5 mL, 12.359 mmol) and THF (0.20 mL, 2.441 mmol) at ambient temperature was added magnesium methoxide solution (3.88 μL, 2.931 μmol). The reaction was monitored by LCMS and TLC, and an additional magnesium methoxide solution (0.16 mL) was added over 6 days. The resulting mixture was diluted with EtOAc (6 ml) and washed with saturated NH 4 Cl aqueous solution (5 mL). The aqueous layer was extracted with EtOAc (5 mL), and the combined organic layers were washed with 30% aqueous NaCl solution (2 mL) and dried over MgSO 4 Dried. Filtered, concentrated in vacuo and purified by silica gel column chromatography using a 50–100% gradient of ethyl acetate / n-heptane as eluent to afford 5 mg of the title product.

[0941]

[0942] Compound 51

[0943]

[0944] To a solution of compound 50a (5.0 mg, 3.551 μmol) in THF (0.9 mL) / methanol (0.3 mL) at -78 °C was added a THF solution of 0.1 M samarium diiodide (0.2 mL, 0.02 mmol). After 10 min, saturated Rochelle salt solution (1.5 mL), MTBE (3 mL) and water (1 mL) were added. The resulting mixture was warmed to ambient temperature and extracted with MTBE (5mL). The organic layer was washed with 30% (w / v) aqueous NaCl solution (3 mL) and dried over MgSO 4Dry. Filter, concentrate in vacuo and purify by silica gel column chromatography using a 50–75% gradient of ethyl acetate / heptane as eluent to afford 4.0 mg of the title product as a foamy solid.

[0945]

[0946] Compound 52

[0947]

[0948] To a vial containing compound 51 (2.5 mg, 3.2 μmol) at ambient temperature was added THF (0.8 mL) and N , N N,N-dimethylacetamide (0.28 mL). TBAF (1.0 M in THF, 95 μL, 0.095 mmol) and imidazole hydrochloride (5.0 mg, 0.047 mmol) were added. The resulting mixture was stirred at ambient temperature for 2 days. Aqueous 30% (w / v) NaCl solution (2.0 mL) was added and the resulting mixture was extracted twice with a mixture of THF (5.0 mL) and toluene (5.0 mL). The combined organic layers were concentrated under a stream of nitrogen. The residue was dissolved in dichloromethane (1.5 mL) at ambient temperature and PPTS (33 mg, 132 μmol) was added. Once all starting materials had been consumed, the reaction mixture was purified by silica gel column chromatography using a 0–10% gradient of methanol / ethyl acetate as eluent to afford 0.7 mg of the title product, confirmed by LCMS (MS m / z 795.4 [M+Na] + ) and comparison of the 1 1H NMR with that previously reported 1 1H NMR.

[0949]

[0950] Example 5 - Preparation of halichondrin macrolide via the compound of formula (IJ)

[0951]

[0952] Exemplary compounds of formula (IA) can be prepared as shown in the above scheme. Compound 52 is reacted with compound 53 via Yamaguchi esterification to give compound 54 which is reacted with compound 30 under Nozaki-Hiyama-Kishi reaction conditions to give compound 55 (an exemplary compound of formula (IA)). Oxidation of compound 55 with Dess-Martin periodinane gives compound 56 (another exemplary compound of formula (IA)).

[0953] Exemplary spongistatin macrolides can be prepared as shown in the above schemes. Compound 56 can be converted to compound 57 by reaction with methoxyacetic acid and BF 3 ·OEt 2 (exemplary Prins reaction conditions). Two routes for obtaining exemplary spongistatin macrolide 51 from compound 57 are provided herein. In one method, compound 57 can be reacted with an allyl reducing agent (e.g., Pd(PPh 3 ) 4 / HCO 2 H / Et 3 N) to generate compound 58, which can be converted to compound 51 after global desilylation with a fluorine source (e.g., TBAF buffered with imidazolium hydrochloride) and PPTS-catalyzed ketalization. Alternatively, compound 57 can be globally desilylated with a fluorine source (e.g., TBAF buffered with imidazolium hydrochloride), followed by PPTS-catalyzed ketalization and reaction with an allyl reducing agent (e.g., Pd(PPh 3 ) 4 / HCO 2 H / Et 3 N) to obtain compound 51.

[0954] In some embodiments, P is PNB.

[0955] Example 6 - Preparation of halichondrin via the compound of formula (IN)

[0956]

[0957] Exemplary compounds of formula (IA) can be prepared as shown in the above schemes. Reacting compound 60 with compound 30 under Nozaki-Hiyama-Kishi reaction conditions gives compound 61 (exemplary compound (IN)). Hydrolysis of the ester in compound 61 provides compound 62. Oxidation of compound 62 (e.g., with Dess-Martin periodinane) gives compound 63. Yamaguchi esterification of compound 63 with compound 52 gives compound 56 (exemplary compound of formula (IA)). The Prins reaction of compound 56 (methoxyacetic acid and BF 3 ·OEt 2 ; exemplary Prins reaction conditions) provides compound 57 (exemplary compound of formula (IB)).

[0958] Example 7 - Preparation of compound (IH)

[0959]

[0960] Methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((R)-3,3,8,8-tetraethyl-4,7-dioxa-3,8-disiladecan-5-yl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate

[0961]

[0962] At 0 °C, imidazole (0.775 g, 11.4 mmol) and triethylchlorosilane (1.19 ml, 7.12 mmol) were added to a solution of methyl 2-((3aR,4S,5aS,8R,9aS,9bS)-4-((R)-1,2-dihydroxyethyl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate (1.1 g, 2.847 mmol) in dichloromethane (11.0 mL). The resulting mixture was warmed to ambient temperature and stirred until all starting materials had been consumed. Upon completion, the reaction was quenched with saturated aqueous NH 4 Cl (10 mL). The resulting mixture was extracted with MTBE (20 mL). The organic layer was washed with 30% (w / v) aqueous NaCl (5 mL) and dried over MgSO 4 . Filtered, concentrated in vacuo and purified by silica column chromatography using a 0 – 25% gradient of ethyl acetate / heptane as eluent to afford 1.64 g of the title compound as a colorless oil.

[0963]

[0964] Methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((S)-2-oxo-1-((triethylsilyl)oxy)ethyl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate

[0965]

[0966] At -70 °C, a solution of oxalyl chloride (2.67 mL, 5.33 mmol, 2.0 M in dichloromethane) was added dropwise to a solution of DMSO (0.76 mL, 10.7 mmol) in dichloromethane (4.1 mL). After 15 min, methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((R)-3,3,8,8-tetraethyl-4,7-dioxa-3,8-disiladecan-5-yl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate (0.82 g, 1.33 mmol) in dichloromethane (4.1 mL) was added. The reaction solution was stirred at -70 °C for 20 min and at -40 °C for 20 min, cooled to -78 °C, and treated with TEA (2.2 mL, 16.0 mmol). The resulting mixture was warmed to ambient temperature, treated with water (16.4 mL), and extracted with MTBE (32.8 mL). The organic layer was washed three times with 30% (w / v) aqueous NaCl solution (24.6 mL) and twice with water (25 mL) and dried over MgSO 4 Drying. Filtration and concentration in vacuo afforded the title product as an oil (assuming 100% theoretical yield), which was used in the next step without further purification.

[0967] Methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((S)-2-oxo-1-((triethylsilyl)oxy)but-3-en-1-yl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate

[0968]

[0969] Methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((S)-2-oxo-1-((triethylsilyl)oxy)ethyl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate (0.666 g, 1.33 mmol) was dissolved in THF (13 mL), and the resulting solution was cooled to -25 °C and treated with vinylmagnesium bromide (1.0 M in THF, 1.6 mL, 1.6 mmol). If needed, additional vinyl Grignard reagent was added until all starting material had been consumed. Upon completion, saturated NH 4The reaction was quenched with an aqueous solution of Cl (15 mL) and water (5 mL). The resulting mixture was extracted twice with MTBE (20 mL each time). The combined organic layers were washed with an aqueous solution of 30% (w / v) NaCl (10 mL) and dried over MgSO 4 To provide methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((1R)-2-hydroxy-1-((triethylsilyl)oxy)but-3-en-1-yl)octahydrospiro[[1,3]dioxoleno[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate (assuming 100% theoretical yield), which was used in the next step without further purification.

[0970] The crude product was dissolved in dichloromethane (14 mL). To the solution was added Dess-Martin periodinane (1.01 g, 2.38 mmol) and sodium bicarbonate (0.556 g, 6.62 mmol). The resulting mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, MTBE (20 mL), saturated Na 2 S 2 O 3 aqueous solution (20 ml) and water (10 mL) were added. The resulting mixture was stirred for 1 h. The layers were separated and the aqueous layer was extracted with MTBE (20 mL). The combined organic layers were washed with saturated NaHCO 3 aqueous solution (10 mL) and 30% (w / v) NaCl aqueous solution (10 mL), and dried over MgSO 4 To provide 369 mg of the target product as a colorless oil, which was purified by silica gel column chromatography using a 20–66% gradient of ethyl acetate / heptane as the eluent.

[0971]

[0972] Methyl 2-((2R,3S,3aS,4aS,7R,8aS,9S,9aR)-2-(2-(benzyloxy)ethyl)-3-hydroxydodecahydro-2,9-epoxypyrano[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0973]

[0974] To a solution of methyl 2-((3aR,4R,5aS,8R,9aS,9bS)-4-((S)-2-oxo-1-((triethylsilyl)oxy)but-3-en-1-yl)octahydrospiro[[1,3]dioxolano[4,5-d]pyrano[3,2-b]pyran-2,1'-cyclohexane]-8-yl)acetate (0.123 g, 0.234 mmol) in toluene (6 mL) was added benzyl alcohol (0.3 mL, 2.89 mmol) and p-toluenesulfonic acid monohydrate (8.92 mg, 0.047 mmol). The reaction mixture was heated at 70 - 80 °C for 5 h, cooled to ambient temperature, and diluted with MTBE (20 mL). The resulting mixture was washed with saturated NaHCO 3 aqueous solution (5 mL), 30% (w / v) NaCl aqueous solution (5 mL), and water (5 mL), and dried over MgSO 4 . Filtration, concentration in vacuo, and purification by silica gel column chromatography using a 40 – 80% gradient of ethyl acetate / heptane as the eluent afforded 40 mg of the title compound as a white solid.

[0975]

[0976] Methyl 2-((2S,3aR,4aS,7R,8aS,9S,9aS)-2-(2-(benzyloxy)ethyl)-3-oxodecahydro-2,9-epoxydifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0977]

[0978] To a solution of methyl 2-((2R,3S,3aS,4aS,7R,8aS,9S,9aR)-2-(2-(benzyloxy)ethyl)-3-hydroxydodecahydro-2,9-epoxydifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (13 mg, 0.031 mmol) in dichloromethane (1 mL) at ambient temperature was added Dess-Martin periodinane (26.2 mg, 0.062 mmol) and sodium bicarbonate (12.99 mg, 0.155 mmol). After stirring for 1 h, the reaction mixture was diluted with MTBE (5 mL) and treated with saturated Na 2 S 2 O 3 aqueous solution (3 mL) and water (1 mL). After stirring for 30 min, the organic layer was separated, washed with 30% (w / v) NaCl aqueous solution, and dried over MgSO 4Dry. Filter and concentrate in vacuo to afford 11 mg of the title compound.

[0979]

[0980] Methyl 2-((2R,3R,3aS,4aS,7R,8aS,9S,9aR)-2-(2-(benzyloxy)ethyl)-3-hydroxydodecahydro-2,9-epoxydifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0981]

[0982] To a solution of methyl 2-((2S,3aR,4aS,7R,8aS,9S,9aS)-2-(2-(benzyloxy)ethyl)-3-oxododecahydro-2,9-epoxydifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (11 mg, 0.026 mmol) in methanol (1 mL) at 0 °C was added sodium borohydride (2.98 mg, 0.079 mmol). After 15 min, the reaction was quenched with saturated aqueous NH 4 Cl (2 mL) and water (1 mL). The resulting mixture was extracted three times with EtOAc (5 mL each). The combined organic layers were washed with brine (2 mL) and dried over MgSO 4 Dry. Filter, concentrate in vacuo, and purify by silica gel column chromatography using a 50–80% gradient of ethyl acetate / heptane as eluent to afford 8.0 mg of the title compound as a colorless oil.

[0983]

[0984] Methyl 2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-(2-(benzyloxy)ethyl)-3,9-dihydroxydodecahydrodifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0985]

[0986] To a solution of methyl 2-((2R,3R,3aS,4aS,7R,8aS,9S,9aR)-2-(2-(benzyloxy)ethyl)-3-hydroxydodecahydro-2,9-epoxydifuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (8 mg, 0.019 mmol) in dichloromethane (1 mL) was added triethylsilane (0.1 mL, 0.626 mmol). The resulting solution was cooled to 0 °C and treated with BF 3 ·OEt 2Treated with (0.012 mL, 0.095 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred until all starting materials had been consumed. Upon completion, the reaction was quenched with saturated NaHCO 3 aqueous solution (1 mL) and 30% (w / v) NaCl aqueous solution (1 mL). The resulting mixture was extracted twice with EtOAc (5 mL). The combined organic layers were washed with 30% (w / v) NaCl aqueous solution (3 mL) and dried over MgSO 4 . Filtered, concentrated in vacuo and purified by silica gel column chromatography using a gradient of 50 – 100% ethyl acetate / heptane, then a gradient of 0 – 20% methanol / ethyl acetate as eluent to afford 3.0 mg of the title product.

[0987]

[0988] Methyl 2-((2R,3R,3aS,4aS,7R,8aR,9S,9aS)-2-(2-(benzyloxy)ethyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0989]

[0990] To a solution of methyl 2-((2R,3S,3aS,4aS,7R,8aS,9S,9aR)-2-(2-(benzyloxy)ethyl)-3-hydroxydecahydro-2,9-epoxyfuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (13 mg, 0.031 mmol) in dichloromethane (1 mL) was added triethylsilane (0.1 mL, 0.626 mmol). The resulting solution was cooled to 0 °C and treated with BF 3 ·OEt 2 (0.020 mL, 0.155 mmol). The reaction mixture was allowed to warm to ambient temperature and stirred until all starting materials had been consumed. Upon completion, the reaction was quenched with saturated NaHCO 3 aqueous solution (1 mL) and 30% (w / v) NaCl aqueous solution (1 mL). The resulting mixture was extracted twice with EtOAc (5 mL). The combined organic layers were washed with 30% (w / v) NaCl aqueous solution (3 mL) and dried over MgSO 4 . Filtered, concentrated in vacuo and purified by silica gel column chromatography using a gradient of 60 – 100% ethyl acetate / heptane as eluent to afford 8.0 mg of the title product.

[0991]

[0992] Methyl 2-((2R,3aR,4aS,7R,8aS,9aR)-2-(2-(benzyloxy)ethyl)-3,9-dioxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0993]

[0994] To a solution of methyl 2-((2R,3R,3aS,4aS,7R,8aR,9S,9aS)-2-(2-(benzyloxy)ethyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (4 mg, 9.468 μmol) in dichloromethane (1 mL) was added Dess-Martin periodinane (12 mg, 0.028 mmol) and sodium bicarbonate (4 mg, 0.047 mmol). After stirring for 2 h, the reaction mixture was diluted with MTBE (5 mL) and treated with saturated Na 2 S 2 O 3 aqueous solution (3 mL) and water (1 mL). After stirring for 30 min, the organic layer was separated, washed with 30% (w / v) aqueous NaCl solution, and dried over MgSO 4 4.0 mg of the title product was provided by filtration and concentration in vacuo.

[0995]

[0996] Methyl 2-((2R,3S,3aS,4aS,7R,8aR,9S,9aS)-2-(2-(benzyloxy)ethyl)-3,9-dihydroxydecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate

[0997]

[0998] To a solution of methyl 2-((2R,3aR,4aS,7R,8aS,9aR)-2-(2-(benzyloxy)ethyl)-3,9-dioxodecahydrofuro[3,2-b]pyrano[2,3-e]pyran-7-yl)acetate (4 mg, 9.464 μmol) in THF (1 mL) was added 1.0 M lithium tri-tert-butoxyaluminum hydride (0.047 mL, 0.047 mmol) at 0 °C. The reaction mixture was stirred at ambient temperature until all starting materials had been consumed. Upon completion, the reaction mixture was treated with saturated Rochelle salt solution (3 mL) and extracted twice with EtOAc (5 mL). The combined organic layers were washed with 30% (w / v) aqueous NaCl solution (2 mL) and dried over MgSO 4 4. Filtration, concentration in vacuo, and purification by silica gel column chromatography using a gradient of 50–100% ethyl acetate / heptane followed by a gradient of 0–20% methanol / ethyl acetate as eluent afforded 3.1 mg of the title product.

[0999] Example 8 - Preparation of compound (ID)

[1000]

[1001] (R)-3-((2 R, 3 R, 5a R, 7 R, 9aS)-3-methoxyhexahydro-5H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-2-methylpropanenitrile

[1002]

[1003] A solution of ([[]] R )-3-((2 R, 3 R, 5a R, 7 R, 9a S )-3-hydroxyhexahydro-2H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-2-methylpropanenitrile (20 g, 79 mmol) in methanol (200 mL) was treated with p- TsOH (0.751 g, 3.95 mmol) and stirred at 40 °C for 22 h. The mixture was concentrated in vacuo, evaporated again with methanol (100 mL), and azeotroped with toluene (100 mL). The residue was treated with saturated NaHCO 3 3 aqueous solution (100 mL) and extracted twice with MTBE (160 mL). The organic layers were combined and dried over MgSO4 Dry and concentrate in vacuo. Dissolve the residue in MTBE (30 mL) under heating to obtain a clear solution and treat with n-heptane (60 mL). Stir the resulting suspension at 65 °C (bath) for 30 min and cool slowly to room temperature over 1 day. Filter the precipitate, wash with MTBE / heptane = 1 / 5, and dry under a nitrogen stream to obtain the title compound (16.94 g, 80%).

[1004]

[1005] 4-((2 R, 3 R, 5a R, 7 R, (9aS)-3-methoxyhexahydro-5H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-3-methylbutan-2-one

[1006]

[1007] A solution of R ()-3-((2 R, 3 R, 5a R, 7 R, 9a S )-3-methoxyhexahydro-2H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-2-methylpropanenitrile (7.0 g, 26 mmol) in THF (105 mL) was cooled to -35 °C and treated with 1.5 M methyllithium-lithium bromide complex / ether (21.0 mL, 31.4 mmol) while maintaining the internal temperature below -30 °C. Stir the mixture at -30 °C for 2 h. Quench the reaction with saturated aqueous NH 4 Cl (70 mL) and warm to room temperature with stirring over 10 min. Extract the mixture twice with MTBE (56 mL). Combine the organic layers, dry over MgSO 4 and concentrate in vacuo to obtain the title compound as a mixture of two isomers (3.43 g 105%).

[1008] 4-((2 R, 3 R, 5a R, 7 R, (9aS)-3-methoxyhexahydro-5H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-3-methylbut-1-en-2-yl ester

[1009]

[1010] 4-((2 R, 3 R, 5a R, 7 R, 9aS)-3-methoxyhexahydro-2H-2,5a-methanopyrano[3,2-e][1,4]dioxepin-7-yl)-3-methylbutan-2-one (0.13 g, 0.46 mmol) in THF (3.3 mL) was cooled to -78 °C and treated with 1 M NaHMDS / THF (0.50 mL, 0.50 mmol) for 10 min while maintaining the internal temperature below -65 °C. The mixture was stirred at -78 °C for 30 min. 1,1,1-Trifluoro- N -phenyl- N -(trifluoromethyl)sulfonylmethanesulfonamide (0.245 g, 0.686 mmol) in THF (1.0 mL) was added and stirring was continued at -78 °C for 1 h. Additional 1 M NaHMDS / THF (0.091 mL, 0.091 mmol) was added and stirring was continued at -78 °C for an additional 1 h. The reaction was quenched with saturated NH 4 Cl aqueous solution (1.3 mL) and extracted twice with n-heptane (0.9 mL). The organic layers were combined, washed with brine, concentrated in vacuo, and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 30%) to afford the title compound as a mixture of two isomers (130 mg, 68%).

[1011] (2 R, 3 R, 5a R, 7 R, 9aS)-3-methoxy-7-(2-methylbuta-2,3-dien-1-yl)hexahydro-5H-2,5a-methanopyrano[3,2-e][1,4]dioxepin

[1012]

[1013] A 100 mL flask was charged with Pd 2 (dba) 3 (0.088 g, 0.096 mmol), ([[]] S )-(-)-(diphenylphosphino)-2'-methoxy-1,1'-binaphthalene (0.180 g, 0.384 mmol) and n-heptane (32 mL), and heated to 55 °C for 5 min. The mixture was treated with 4-((2 R, 3 R, 5a R, 7R, 9a S )-3-Methoxyhexahydro-2 H -2,5a-methano-2H-pyrano[3,2-e][1,4]dioxepin-7-yl)-3-methylbut-1-en-2-yl ester (2.0 g, 4.8 mmol) and N, N- A mixture of diisopropylethylamine (1.7 mL, 9.6 mmol) in n-heptane (15 mL) was treated. The mixture was stirred at 55 °C for 24 h. After cooling to room temperature, the mixture was filtered through a pad of diatomaceous earth and rinsed with n-heptane. The filtrate was concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 40%) to give the title compound (700 mg, 55%).

[1014]

[1015] (2 R, 3 R, 5a R, 7 R, (9aS)-7-(2-Methylbuta-2,3-dien-1-yl)hexahydro-5H-2,5a-methano-2H-pyrano[3,2-e][1,4]dioxepin-3-ol

[1016]

[1017] (2 R, 3 R, 5a R, 7 R, 9a S )-3-Methoxy-7-(2-methylbuta-2,3-dien-1-yl)hexahydro-2 H -2,5a-methano-2H-pyrano[3,2-e][1,4]dioxepine (0.60 g, 2.25 mmol) was dissolved in THF (9 mL) and treated with 6 N HCl (9.0 mL, 54 mmol). The mixture was stirred at room temperature for 14 h. The mixture was extracted twice with ethyl acetate (9 mL). The organic layers were combined, washed with saturated NaHCO 3 aqueous solution (9 mL), dried over MgSO 4 and concentrated in vacuo to give the title compound as a mixture of two anomers (630 mg, 110%).

[1018] ((2 R, 3a R, 5 R,7aS)-5-(2-Methylbuta-2,3-dien-1-yl)-2-((E)-2-(phenylsulfonyl)vinyl)hexahydro-3aH-furo[3,2-b]pyran-3a-yl)methanol

[1019]

[1020] The mixture of (2 R, 3 R, 5a R, 7 R, 9a S )-7-(2-Methylbuta-2,3-dien-1-yl)hexahydro-2 H -2,5a-Methanopyrano[3,2-e][1,4]dioxepin-3-ol (0.68 g, 2.7 mmol), diethyl ((phenylsulfonyl)methyl)phosphonate (0.87 g, 3.0 mmol) and lithium chloride (0.17 g, 4.0 mmol) in acetonitrile (13.6 mL) was cooled to 0 °C and treated with N,N- diisopropylethylamine (0.75 mL, 4.3 mmol). The mixture was stirred at 0 °C for 1 h and at room temperature for 4 h. Additional phosphonate (157 mg), lithium chloride (34 mg) and N,N- diisopropylethylamine (0.14 mL) were added and stirring was continued at room temperature for an additional 15 h. The reaction mixture was poured into water (6.8 mL) and extracted twice with MTBE (10 mL). The organic layers were combined, dried over MgSO 4 and concentrated in vacuo and purified by silica gel column chromatography (ethyl acetate / heptane = 10% to 50%) to give the title compound (548 mg, 55%, over 2 steps).

[1021]

[1022] ((2 R, 3a R, 5 R, 7aS)-5-(2-Methylbuta-2,3-dien-1-yl)-2-(2-(phenylsulfonyl)ethyl)hexahydro-3aH-furo[3,2-b]pyran-3a-yl)methanol

[1023]

[1024] The mixture of ((2 R, 3a R, 5 R, 7a S )-5-(2-Methylbuta-2,3-dien-1-yl)-2-((E)-2-(phenylsulfonyl)vinyl)hexahydro-2H A solution of (2 4 ,3a 3 ,5

[1025]

[1026] (2 R, 3a S, 5 R, (2,3a,5,7aS)-3a-(iodomethyl)-5-(2-methylbuta-2,3-dien-1-yl)-2-(2-(phenylsulfonyl)ethyl)hexahydro-2H-furo[3,2-b]pyran

[1027]

[1028] A solution of ((2 R ,3a R ,5 R ,7a S )-5-(2-methylbuta-2,3-dien-1-yl)-2-(2-(phenylsulfonyl)ethyl)hexahydro-2 H -furo[3,2-b]pyran-3a-yl)methanol (0.37 g, 0.94 mmol) in CH 2 Cl 2 (3 mL) was cooled to -5 °C and treated with 2,6-lutidine (0.33 mL, 2.8 mmol) and 1 M Tf 2 O / CH 2 Cl 2 (1.4 mL, 1.4 mmol). After stirring at -5 °C for 1.5 h, the mixture was diluted with DMF (2.78 mL) and treated with sodium iodide (0.42 g, 2.8 mmol). The mixture was stirred at room temperature for 20 h. The mixture was diluted with MTBE (19 mL) and successively washed with water (5.6 mL), 1 N HCl (5.6 mL), saturated NaHCO 3An aqueous solution (3.7 mL) and 20% (w / v) Na 2 S 2 O 3 / water (3.7 mL) wash. After concentration, the residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 40%) to give the title compound (140 mg, 30%).

[1029]

[1030] (R)-5-Methyl-1-((2 S, (5R)-3-Methylene-5-(2-(phenylsulfonyl)ethyl)tetrahydrofuran-2-yl)hepta-5,6-dien-3-ol

[1031]

[1032] A suspension of zinc powder (0.128 g, 1.95 mmol) in water (0.9 mL) was cooled to 0 °C and treated with acetic acid (0.019 mL, 0.33 mmol). After stirring for 10 min, the mixture was treated with a solution of (2 R ,3a S ,5 R ,7a S )-3a-(Iodomethyl)-5-(2-methylbuta-2,3-dien-1-yl)-2-(2-(phenylsulfonyl)ethyl)hexahydro-2 H -furo[3,2-b]pyran (0.14 g, 0.28 mmol) in THF (1.4 mL). After stirring at 0 °C for 1 h, the reaction was quenched with 20% (w / v) aqueous citric acid (0.84 mL) and stirred at 0 °C for 10 min. The mixture was filtered through a pad of diatomaceous earth to remove the insoluble zinc and rinsed with MTBE (14 mL). The organic layer was separated and washed with saturated NaHCO 3 (1.4 mL) and brine (1.4 mL). After concentration, the residue was purified by silica gel column chromatography (ethyl acetate / n-heptane = 10% to 50%) to give the title compound (76 mg, 72%).

[1033]

[1034] Other embodiments

[1035] Various modifications and variations of the compositions and methods of the present invention will be apparent to those skilled in the art without departing from the scope and spirit of the invention. Although the invention has been described in connection with specific embodiments, it should be understood that the claimed invention should not be unduly limited to these specific embodiments. Indeed, various modifications of the described modes for carrying out the invention that are obvious to those skilled in the art are intended to fall within the scope of the invention.

[1036] Other embodiments are in the claims.

Claims

1. A compound of formula (IC) or a salt or tautomer thereof, wherein D and D' are each independently H or OP 1 , provided that only one of D and D' is OP 1 , where P 1 is H or C 1-6 alkyl; and A is a group of formula (1): wherein L is –(CH(OP 2 ))-; R 1 is H, or R 1 and P 1 combine to form a bond; R 2 is –(CH 2 ) n OP 5 , where P 2 is H or a hydroxyl protecting group, and P 5 is H or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached form a ketal, cyclic carbonate, dicarbonyl-dioxo or silylene-dioxo; E is C 1-6 alkyl; G is O; n is 0, 1 or 2; k is 0 or 1; X 1 is –CH(Y)– or –CH 2 – or -O-; X 2 is =O; Y is SO 2 R C , where R C is C 6-10 aryl; R 3 and R 5 combine to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxyl protecting group, R 5 and R 6 together with the atoms to which they are respectively attached combine to form a double bond, and R 4 is H; Each P 6 is independently a hydroxyl protecting group, or two Ps 6 together with the atoms to which they are respectively attached form a ketal or an acetal; each R 11 is independently –OP 10 , or Two Rs 11 combine to form an oxo, where P 10 is C 1-6 alkyl; R 13 is H or -CH 2 P(O)(OR E ) 2 , wherein each R E is independently C 1-6 alkyl when present; X is =O or X combines with the carbon atom to which it is attached to form –(CH(OP 9 ))–, where P 9 is H or a hydroxyl protecting group; A 1 is H, and: P 7 and R 7 combine to form a bond, and R 8 is H.

2. A compound of formula (IE): or a salt or tautomer thereof, wherein D and D' are each independently H or OP 1 , provided that only one of D and D' is OP 1 , where P 1 is H or C 1-6 alkyl; and A is a group of formula (1): wherein L is –(CH(OP 2 ))–; R 1 is H, or R 1 and P 1 combine to form a bond; R 2 is –(CH 2 ) n OP 5 , where P 2 is H or a hydroxyl protecting group, and P 5 is H or a hydroxyl protecting group; or P 2 and P 5 together with the atoms to which they are attached form a ketal, cyclic carbonate, dicarbonyl-dioxo or silyl-dioxo; E is H or C 1-6 alkyl; G is O; n is 0, 1 or 2; k is 0 or 1; X 1 is –CH(Y)– or –CH 2 – or -O-, X 2 is =O; Y is SO 2 R C , wherein R C is C 6-10 aryl; R 3 combines with R 5 to form a bond, and R 4 and R 6 are each H; or R 3 is H or a hydroxy protecting group, R 5 and R 6 together with the atoms to which they are respectively attached combine to form a double bond, and R 4 is H; R 7 and P 7 combine to form a bond, and R 8 is H; Each P 6 is independently a hydroxyl protecting group, or two Ps 6 together with the atoms to which they are respectively attached form a ketal or an acetal; each R 11 is independently –OP 10 , or Two Rs 11 combine to form an oxo, where P 10 is C 1-6 alkyl; X 3 is –CH 2 OP A , –CH=CH 2 or –CH(OP A )CH 2 OP A , where each P A is independently H or a hydroxyl protecting group, or two P A combine to form an acetal, a ketal, a cyclic silylene, a cyclic carbonate or a cyclic borate.

3. The compound according to claim 2, wherein each P A is H, or two P A combine to form an acetal, a ketal, a cyclic silylene, a cyclic carbonate or a cyclic borate.

4. The compound according to any one of claims 1 to 3, wherein each R 11 is –OP 10 , wherein P 10 is C 1-6 alkyl.

5. The compound according to any one of claims 1 to 3, wherein the stereocenter designated by a is (R), and A has the following structure:

6. The compound according to any one of claims 1 to 3, wherein k is 0 and X 1 is –CH 2 –.

7. The compound according to any one of claims 1 to 3, wherein n is 0.

8. The compound according to any one of claims 1 to 3, wherein A and D combine to form the following structure: wherein the bond connecting the oxygen atom originates from the carbon atom to which D is attached, and wherein n is 2.

9. The compound according to any one of claims 1 to 3, wherein k is 1.

10. The compound according to any one of claims 1 to 3, wherein X 1 is –O–.

11. The compound according to any one of claims 1 to 3, wherein R 5 and R 6 together with the atoms to which they are attached form a double bond, R 4 is H, and R 3 is a hydroxyl protecting group.

12. A compound selected from:

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