Compound having il-17 production-inducing activity and use thereof

Abstract

To provide an α-GalCer analogue that induces Th17-selective cytokine production.SOLUTION: The present invention provides a compound represented by the formula (I) in the figure (where A represents an α- or β-D-glycopyranosyl group, R1 represents an acyl group derived from a linear fatty acid monosubstituted with a hydroxy or nitro group, and R2 represents a linear aliphatic group which may be monosubstituted with a hydroxy group).SELECTED DRAWING: None

Description

[Technical Field]

[0001] The present invention relates to a compound capable of inducing IL-17 production and uses thereof. [Background technology]

[0002] The lipid antigen-presenting protein CD1d is a type of protein expressed primarily on the surface of antigen-presenting cells such as dendritic cells and is known to recognize glycolipids as ligands. The CD1d-glycolipid complex is recognized by natural killer T (NKT) cells via the T cell receptor (TCR). NKT cells that recognize the CD1d-ligand complex stimulate undifferentiated naive Th cells by inducing various cytokines. When Th1 cytokines, such as IFN-γ, are induced by ligand recognition, naive Th cells differentiate into Th1 cells, which are involved in cellular immunity related to tumor immunity. On the other hand, when Th2 cytokines, such as IL-4, are induced, naive Th cells differentiate into Th2 cells, which are involved in humoral immunity related to allergies (Non-Patent Document 1). It is also known that the balance of cytokine induction varies depending on the structure of the glycolipid ligand. Therefore, the development of novel CD1d ligands that can control this balance is expected to lead to the development of antitumor drugs and therapeutic agents for autoimmune diseases.

[0003] A representative CD1d ligand is α-GalCer (KRN7000), which is known to have little Th1 / Th2 selectivity in cytokine induction (Non-Patent Document 2). It has also been revealed that the fatty acid moiety of the two lipid chains of α-GalCer binds to the hydrophobic A' pocket of CD1d, and the sphingosine moiety binds to the hydrophobic F' pocket.

[0004] [ka]

[0005] Previously, attempts have been made to achieve Th1 or Th2 selectivity by modifying the fatty acid moiety of α-GalCer, and Wong, Tsuji et al. (Non-Patent Document 3) and Porcelli et al. (Non-Patent Document 4) synthesized α-GalCer analogs that selectively induce cytokines in either Th1 or Th2, respectively.

[0006] Based on the report by Kelly et al. (Non-Patent Document 5) that hydrogen bonds within the hydrophobic pocket of proteins are stronger than normal hydrogen bonds, and the report by Barril et al. (Non-Patent Document 6) that hydrogen bonds deep within the binding pocket are stronger than normal hydrogen bonds, the present inventors have been developing α-GalCer analogs focusing on hydrophilic amino acid residues present deep within the hydrophobic A' pocket. In particular, by introducing an amide group (α-GalCer-amide) or an amino group (α-GalCer-amine) into the fatty acid moiety and further varying the length of the fatty acid moiety, Th2-selective cytokine induction has been successfully achieved (Non-Patent Documents 7 and 8). In particular, α-GalCer analogs containing an amide group exhibited strong cytokine-inducing activity, and molecular dynamics simulations suggested that the hydrophilic amino acid residue Ser28 present in the hydrophobic A' pocket interacts strongly with the amide group via hydrogen bonds (Non-Patent Document 7).

[0007] IL-17 is produced primarily by activated T cells and is known to induce inflammation by acting on fibroblasts, epithelial cells, vascular endothelial cells, macrophages, and the like to induce various factors such as inflammatory cytokines, chemokines, and cell adhesion molecules (Non-Patent Documents 9 and 10). Recently, it has been discovered that IL-17-producing T cells are not produced from the previously known T cell subsets called Th1 cells or Th2 cells, but from a new subset called Th17 cells, and the role of this cell population in inflammation and infection defense has attracted considerable attention.

[0008] As mentioned above, α-GalCer analogs that induce Th1- or Th2-selective cytokine production have been developed, but no α-GalCer analogs that induce Th17-selective cytokine production are known. [Prior art documents] [Non-patent literature]

[0009] [Non-Patent Document 1] Nat. Rev. Immunol. 2007, 7, 505-518 [Non-patent document 2] J. Med. Chem. 1995, 38, 2176-2187 [Non-patent document 3] Proc. Natl. Acad. Sci. USA 2010, 107, 13010-13015 [Non-patent document 4] Immunity 2009, 30, 888-898 [Non-Patent Document 5] Nat. Struct. Mol. Biol. 2009, 16, 684-690 [Non-patent document 6] J. Am. Chem. Soc. 2011, 133, 18903-18910 [Non-Patent Document 7] ACS Chem. Biol. 2016, 11, 3132-3139 [Non-patent document 8] Angew. Chem. Int. Ed. 2018, 57, 9655-9659 [Non-Patent Document 9] J. Leukoc. Biol. 2002, 71, 1-8 [Non-Patent Document 10] Immunity 2004;21:467-76 Summary of the Invention [Problem to be solved by the invention]

[0010] An object of the present invention is to provide an α-GalCer analog that induces Th17-selective cytokine production. [Means for solving the problem]

[0011] The present inventors have conducted extensive research to solve the above-mentioned problems, and as a result of further investigation, have discovered that by introducing a hydroxyl group or a nitro group into the fatty acid moiety of α-GalCer, an α-GalCer analogue with Th17-selective cytokine induction ability can be obtained, thereby completing the present invention.

[0012] That is, the present invention relates to the following. [1] A compound represented by the following formula (I):

[0013] [ka]

[0014] (In formula (I), A is an α- or β-D-glycopyranosyl group; R 1 is an acyl group derived from a straight-chain fatty acid monosubstituted with a hydroxyl group or a nitro group, R 2 is a linear aliphatic group which may be mono-substituted with a hydroxyl group. [2]R 1 is a compound of [1], which is an acyl group derived from a straight-chain fatty acid having 12 to 26 carbon atoms and mono-substituted with a hydroxyl group. [3] The compound of [2], wherein any one of carbon atoms at positions 8 to 17 of the fatty acid is substituted with a hydroxyl group. [4]R 2 is a compound of [2] or [3], in which the first carbon atom is a straight-chain alkyl group substituted with a hydroxyl group. [5]R 2 is a compound of [2] or [3], which is a straight-chain alkenyl group containing a double bond between the 1st and 2nd carbon atoms. [6]R 1 is a compound of formula [1], which is an acyl group derived from a straight-chain fatty acid having 12 to 26 carbon atoms and monosubstituted with a nitro group. [7] The compound of [6], wherein any one of carbon atoms at positions 9 to 16 of the fatty acid is substituted with a hydroxyl group. [8]R 2 is a compound of [6] or [7], in which the first carbon atom is a straight-chain alkyl group substituted with a hydroxyl group. [9]R 2 is a compound of [6] or [7], which is a straight-chain alkenyl group containing a double bond between the 1st and 2nd carbon atoms.

[10] The compound according to any one of [1] to [9], wherein A is an α- or β-D-galactopyranosyl group or an α- or β-D-glucopyranosyl group.

[11] A pharmaceutical composition comprising any one of the compounds of [1] to

[10] .

[12] The pharmaceutical composition of

[11] , which is an immunostimulatory agent.

[13] An IL-17A production promoter comprising any one of the compounds described in [1] to

[10] . [Effects of the Invention]

[0015] The present invention provides α-GalCer analogs that induce Th17-selective cytokine production. Because IL-17 is thought to play an important role in defense against infection, these α-GalCer analogs may be useful as anti-infective agents or immunostimulants. [Brief explanation of the drawings]

[0016] [Figure 1] FIG. 1 shows the results of comparing the relative IL-17A production induction ability (IL-17A / IFNγ) of the compounds of the present invention with that of α-GalCer. [Figure 2] FIG. 2 shows the results of comparing the relative IL-17A production induction ability (IL-17A / IFNγ) of the compounds of the present invention with that of α-GalCer. [Figure 3] FIG. 3 shows the results of comparing the relative IL-4 production-inducing ability (IL-4 / IFNγ) and the relative IL-17A production-inducing ability (IL-17A / IFNγ) of the compounds of the present invention with α-GalCer. [Figure 4]FIG. 4 shows the results of mouse splenocyte IL-17A production induced by the compounds of the present invention compared with α-GalCe (KRN7000). [Figure 5] FIG. 5 shows the results of mouse splenocyte IL-17A production induced by the compounds of the present invention compared with α-GalCe (KRN7000). [Figure 6] FIG. 6 shows the results of analyzing the interaction between the compound of the present invention and CD1d by AlphaScreen. [Figure 7] FIG. 7 shows the results of mouse splenocyte IL-17A production induced by the compounds of the present invention compared with α-GalCer (KRN7000). [Figure 8] FIG. 8 shows the results of analyzing the interaction between the compound of the present invention and CD1d by AlphaScreen. [Figure 9] FIG. 9 shows the results of mouse splenocyte IL-17A production induced by the compounds of the present invention compared with α-GalCer (KRN7000). [Figure 10] FIG. 10 shows the results of an APC-free assay comparing the induction of IL-2 production by the compounds of the present invention with that by α-GalCer (KRN7000). [Figure 11] FIG. 11 shows the results of analyzing the interaction between the compound of the present invention and CD1d by AlphaScreen. DETAILED DESCRIPTION OF THE INVENTION

[0017] <Compound> The present invention provides a compound represented by the following formula (I) (hereinafter referred to as "the compound of the present invention"):

[0018] [ka]

[0019] (In formula (I), A is an α- or β-D-glycopyranosyl group; R1 is an acyl group derived from a straight-chain fatty acid monosubstituted with a hydroxyl group or a nitro group, R 2 is a linear aliphatic group which may be mono-substituted with a hydroxyl group.

[0020] Examples of the glycopyranosyl group of A include, but are not limited to, a galactopyranosyl group, a glucopyranosyl group, a 6'-deoxygalactopyranosyl group, etc. The glycopyranosyl group is preferably a galactopyranosyl group or a glucopyranosyl group. The glycopyranosyl group may be either an α-anomer or a β-anomer. Without being bound by theory, the α-anomer is expected to have a stronger intermolecular interaction between the compound of the present invention and CD1d than the β-anomer, thereby enhancing the IL-17 production-promoting effect. From this perspective, the glycopyranosyl group is preferably an α-anomer. In one aspect, the glycopyranosyl group of A is preferably an α-D-galactopyranosyl group, a β-D-galactopyranosyl group, an α-D-glucopyranosyl group, or a β-D-glucopyranosyl group, and more preferably an α-D-galactopyranosyl group or an α-D-glucopyranosyl group.

[0021] R 1The "acyl group derived from a straight-chain fatty acid mono-substituted with a hydroxyl group or a nitro group" refers to an acyl group obtained by removing a hydroxyl group from a carboxylic acid contained in the "straight-chain fatty acid mono-substituted with a hydroxyl group or a nitro group." The length (number of carbon atoms) of the straight-chain fatty acid in the "straight-chain fatty acid mono-substituted with a hydroxyl group or a nitro group" may be sufficient to bind to the hydrophobic A' pocket of CD1d, and is usually 8 or more, preferably 12 or more, and more preferably 15 or more. In one aspect, the length (number of carbon atoms) of the straight-chain fatty acid is 12 to 26 (i.e., 12, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26), preferably 15 to 26 (i.e., 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, or 26). The straight-chain fatty acid may be saturated or unsaturated. When the straight-chain fatty acid is unsaturated, the number of double bonds contained therein may be one (i.e., monounsaturated fatty acid) or two or more (i.e., polyunsaturated fatty acid), and is not particularly limited, but is preferably one or two. The double bond may be cis or trans. The position of the double bond is not particularly limited, but for example, it may be between the 9th and 10th carbon atoms (Δ 9 ), between the 10th and 11th carbons (Δ 10 ), between the 11th and 12th carbons (Δ 11 ), between the 12th and 13th carbons (Δ 12 ), between the 13th and 14th carbons (Δ 13 ), between the 14th and 15th carbons (Δ 14 ), between the 15th and 16th carbons (Δ 15 In this specification, the structure of a straight-chain fatty acid may be expressed in terms of "number of carbon atoms: number of double bonds (position of cis or trans-unsaturated bonds)".

[0022] Saturated straight-chain fatty acids include Lauric acid (12:0), Myristic acid (14:0), Palmitic acid (16:0), stearic acid (18:0), arachidic acid (20:0), Behenic acid (22:0), lignoceric acid (24:0), Cerotinic acid (26:0) These can include, but are not limited to:

[0023] Unsaturated straight-chain fatty acids include: cis-12-pentadecenoic acid (15:1 (cis-Δ 12 )) Oleic acid (cis-9-octadecenoic acid) (18:1 (cis-Δ 9 )) Elaidic acid (trans-9-octadecenoic acid) (18:1 (trans-Δ 9 )) cis-11-octadecenoic acid (18:1 (cis-Δ 11 )) cis-12-octadecenoic acid (18:1 (cis-Δ 12 )) cis-13-Octadecenoic acid (18:1 (cis-Δ 13 )) cis-11-Eicosenoic acid (20:1 (cis-Δ 11 )) cis-12-Eicosenoic acid (20:1 (cis-Δ 12 )) cis-13-Eicosenoic acid (20:1 (cis-Δ 13 )) Nervonic acid (cis-15-tetracosenoic acid) (24:1 (cis-Δ 15 )) trans-15-tetracosenoic acid (24:1 (trans-Δ 15 )) cis-11-Hexacosenoic acid (26:1 (cis-Δ 11 )) cis-12-Hexacosenoic acid (26:1 (cis-Δ 12 )) cis-13-Hexacosenoic acid (26:1 (cis-Δ 13 )) Linoleic acid (cis, cis-9,12-octadecadienoic acid) (18:2 (cis-Δ 9 , cis-Δ12 )) cis,trans-9,11-octadecadienoic acid (18:2 (cis-Δ 9 , trans-Δ 11 )) trans,cis-10,12-octadecadienoic acid (18:2 (trans-Δ 10 , cis-Δ 12 )) cis,trans-11,13-Eicosadienoic acid (20:2 (cis-Δ 11 , trans-Δ 13 )) trans,cis-12,14-Eicosadienoic acid (20:2 (trans-Δ 12 , cis-Δ 14 )) These can include, but are not limited to:

[0024] In a straight-chain fatty acid, the carbon position substituted with a hydroxyl group or nitro group is not particularly limited, but is preferably any one of the carbons at positions 8 to 17 (i.e., positions 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) of the fatty acid. Without being bound by theory, superior IL-17A selectivity can be expected when the hydroxyl group or nitro group is bonded to a carbon relatively far from the carboxyl group (positions 8 to 17) of the fatty acid, rather than to a carbon relatively close to the carboxyl group (positions 2 to 7). From this perspective, the carbon position substituted with a hydroxyl group or nitro group is more preferably any one of the carbons at positions 8 to 17 (i.e., positions 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) of the straight-chain fatty acid.

[0025] Furthermore, without being bound by theory, a higher amount of IL-17A can be expected to be produced when the hydroxyl or nitro group is bound to a carbon atom relatively far from the carboxyl group of the fatty acid (carbon atoms at positions 11 to 17) than when it is bound to a carbon atom relatively close to the carboxyl group of the fatty acid (carbon atoms at positions 8 to 10). From this perspective, the carbon atom substituted with the hydroxyl or nitro group is more preferably any one of carbon atoms at positions 11 to 17 (i.e., positions 11, 12, 13, 14, 15, 16, or 17) of the straight-chain fatty acid.

[0026] When an asymmetric carbon is generated by substitution of a hydroxyl group or a nitro group, the configuration thereof is not particularly limited as long as the compound of the present invention exhibits the activity of inducing IL-17 production, and may be either R or S. Furthermore, the compound of the present invention may be provided as a racemate without separating the R and S forms.

[0027] Specific examples of the straight-chain fatty acid monosubstituted with a hydroxyl group include the following: 8-Hydroxystearic acid (18:0, 8-OH) 11-Hydroxystearic acid (18:0, 11-OH) 8-Hydroxyoleic acid (8-hydroxy-cis-9-octadecenoic acid) (18:1 (cis-Δ 9 )) 11-Hydroxyelaidic acid (11-hydroxy-trans-9-octadecenoic acid) (18:1 (trans-Δ 9 ), 11-OH) 14-Hydroxynervonic acid (14-hydroxy-cis-15-tetracosenoic acid) (24:1 (cis-Δ 15 ), 14-OH) 17-Hydroxy-trans-15-tetracosenoic acid (24:1 (trans-Δ 15 ), 17-OH) 13-Hydroxy-cis,trans-9,11-octadecadienoic acid (18:2 (cis-Δ 9 , trans-Δ 11 ), 13-OH) 9-Hydroxy-trans,cis-10,12-octadecadienoic acid (18:2 (trans-Δ 10 , cis-Δ 12 ), 9-OH) 15-Hydroxy-cis,trans-11,13-icosadienoic acid (20:2 (cis-Δ 11 , trans-Δ 13 ), 15-OH) 11-Hydroxytrans,cis-12,14-icosadienoic acid (20:2 (trans-Δ 12 , cis-Δ 14 ), 11-OH)

[0028] Specific examples of the straight-chain fatty acid monosubstituted with a nitro group include the following: 13-nitro-cis-12-pentadecenoic acid (15:1 (cis-Δ 12 ), 13-NO2) 11-Nitro-cis-11-octadecenoic acid (18:1 (cis-Δ 11 ), 11-NO2) 13-nitro-cis-12-octadecenoic acid (18:1 (cis-Δ 12 ), 13-NO2) 13-Nitro-cis-13-octadecenoic acid (18:1 (cis-Δ 13 ), 13-NO2) 11-Nitro-cis-11-icosenoic acid (20:1 (cis-Δ 11 ), 11-NO2) 13-Nitro-cis-12-icosenoic acid (20:1 (cis-Δ 12 ), 13-NO2) 13-Nitro-cis-13-icosenoic acid (20:1 (cis-Δ 13 ), 13-NO2) 15-Nitro-nervonic acid (15-nitro-cis-15-tetracosenoic acid) (24:1 (cis-Δ 15 ), 15-NO2) 16-Nitro-nervonic acid (16-nitro-cis-15-tetracosenoic acid) (24:1 (cis-Δ 15 ), 16-NO2) 11-nitro-cis-11-hexacosenoic acid (26:1 (cis-Δ 11 ), 11-NO2) 13-nitro-cis-12-hexacosenoic acid (26:1 (cis-Δ 12 ), 13-NO2) 13-Nitro-cis-13-hexacosenoic acid (26:1 (cis-Δ13 ), 13-NO2)

[0029] R 2 is a straight-chain aliphatic group which may be mono-substituted with a hydroxyl group. Examples of the aliphatic group include saturated aliphatic groups such as alkyl groups, and unsaturated aliphatic groups such as alkenyl groups and alkynyl groups. In the case of an unsaturated aliphatic group, it may have one or more (e.g., 1, 2, 3, 4, or 5) unsaturated bonds within the molecule and / or at the terminal, but preferably has only one unsaturated bond within the molecule or at the terminal. The aliphatic group is preferably an alkyl group or an alkenyl group. The unsaturated bond (double bond) contained in the alkenyl group may be either cis or trans, but is preferably trans. The position of the unsaturated bond in an alkenyl group having only one unsaturated bond is not particularly limited, but is preferably 1-position from the viewpoint of structural similarity to sphingosine.

[0030] R 2 When is a linear aliphatic group mono-substituted with a hydroxyl group, the position of the hydroxyl group in the aliphatic group is not particularly limited as long as the compound of the present invention exhibits the activity of inducing IL-17 production, but from the viewpoint of structural similarity to phytosphingosine, the hydroxyl group is preferably substituted at carbon atom 1. When an asymmetric carbon is generated by the substitution of the hydroxyl group, the configuration thereof is not particularly limited as long as the compound of the present invention exhibits the activity of inducing IL-17 production, and it may be either R- or S-configuration.

[0031] The length of the linear aliphatic group (i.e., the number of carbon atoms) is not particularly limited as long as the compound of the present invention exhibits the effect of inducing IL-17 production, and may be, for example, within the range of 2 to 50. However, from the viewpoint of structural similarity to sphingosine, the length is preferably 13 to 17 (i.e., 13, 14, 15, 16, or 17), and most preferably 15.

[0032] In one embodiment, R 2 is 1-hydroxypentadecyl or trans-1-pentadecenyl.

[0033] [ka]

[0034] In one embodiment, the compound of the present invention is a compound represented by the following formula (I-1) or (I-2):

[0035] [ka]

[0036] (In formula (I-1) or (I-2), A and R 1 The definitions of are the same as those in formula (I).

[0037] In one embodiment, the compound of the present invention is a compound represented by the above formula (I-1), A is an α-D-galactopyranosyl group, R 1 is an acyl group derived from a straight-chain fatty acid having 12 to 26 carbon atoms (e.g., 12, 14, 16, 18, 20, 22, 24, or 26) (preferably, 18 to 24) in which one carbon atom at any one of positions 8 to 17 (i.e., position 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) (preferably position 11 to 17) is mono-substituted with a hydroxyl group.

[0038] In this embodiment, R 1 The straight-chain fatty acid from which the acyl group of is derived is a saturated straight-chain fatty acid or an unsaturated straight-chain fatty acid containing only one double bond. The position of the double bond in an unsaturated straight-chain fatty acid is Δ 9 , Δ 10 , Δ 11 , Δ 12 , Δ 13 , Δ 14 or Δ 15 is.

[0039] In one embodiment, the compound of the present invention is a compound represented by the above formula (I-1), A is an α-D-galactopyranosyl group, R 1is an acyl group derived from a straight-chain fatty acid having 12 to 26 carbon atoms (e.g., 12, 14, 16, 18, 20, 22, 24, 26), in which one carbon atom at any one of positions 9 to 16 (i.e., position 9, 10, 11, 12, 13, 14, 15, or 16) is mono-substituted with a nitro group.

[0040] In this embodiment, R 1 The straight-chain fatty acid from which the acyl group of is derived is a saturated straight-chain fatty acid or an unsaturated straight-chain fatty acid containing only one double bond. The position of the double bond in an unsaturated straight-chain fatty acid is Δ 9 , Δ 10 , Δ 11 , Δ 12 or Δ 13 is.

[0041] In one embodiment, the compound of the present invention is a compound represented by the above formula (I-2), A is an α-D-galactopyranosyl group, a β-D-galactopyranosyl group, an α-D-glucopyranosyl group, or a β-D-glucopyranosyl group, R 1 is an acyl group derived from a straight-chain fatty acid having 18 to 24 carbon atoms in which one carbon atom at any of positions 8 to 17 (i.e., positions 8, 9, 10, 11, 12, 13, 14, 15, 16, or 17) (preferably positions 11 to 17) is mono-substituted with a hydroxyl group.

[0042] In this embodiment, R 1 The straight-chain fatty acids from which the acyl groups of the formula (I) are derived are saturated straight-chain fatty acids or unsaturated straight-chain fatty acids containing only one or two double bonds. The position of the double bond in unsaturated straight-chain fatty acids is Δ 9 , Δ 10 , Δ 11 , Δ 12 , Δ 13 , Δ 14 or Δ 15 is.

[0043] In one embodiment, the compound of the present invention is a compound represented by the above formula (I-2), A is an α-D-galactopyranosyl group, a β-D-galactopyranosyl group, an α-D-glucopyranosyl group, or a β-D-glucopyranosyl group, R 1 is an acyl group derived from a straight-chain fatty acid having 18 to 26 carbon atoms in which one carbon atom at any one of positions 9 to 16 (i.e., positions 9, 10, 11, 12, 13, 14, 15, or 16) (preferably positions 11 to 16) is mono-substituted with a nitro group.

[0044] In this embodiment, R 1 The straight-chain fatty acid from which the acyl group of is derived is a saturated straight-chain fatty acid or an unsaturated straight-chain fatty acid containing only one double bond. The position of the double bond in an unsaturated straight-chain fatty acid is Δ 9 , Δ 10 , Δ 11 , Δ 12 , Δ 13 , Δ 14 or Δ 15 is.

[0045] <Manufacturing method> 1. Preparation of the Compounds of the Present Invention The compound of the present invention is a condensation product of glycopyranose and a linear aliphatic amino alcohol and a fatty acid R 1 It can be produced by condensing with OH.

[0046] [ka]

[0047] (In the formula, A, R 1 and R 2 The definitions of are the same as those in formula (I).

[0048] The method for producing the compounds of the present invention will be described in more detail, focusing on the synthesis of the following compounds (I-1-A) and (I-2-A) as the compounds of the present invention.

[0049] [ka]

[0050] Compound (I-1-A) is a compound in which A is an α-D-galactopyranosyl group, R 2 is 1-hydroxypentadecyl.

[0051] Compound (I-1-A) is obtained by reacting intermediate (II) with fatty acid R 1 It can be synthesized by condensing with OH.

[0052] [ka]

[0053] Intermediate (II) can be synthesized from D-galactose and phytosphingosine according to a known method (Tetrahedron 2005, 61, 1855-1862). Specifically, compound (III) is synthesized from D-galactose in four steps, and compound (IV) is synthesized from phytosphingosine in four steps. Compound (III) is then iodized to obtain iodide, which is then glycosylated to give compound (V).

[0054] [ka]

[0055] The benzyl protecting group in compound (V) is then removed, and the azide group is reduced to an amino group to obtain intermediate (II). For example, compound (V) is catalytically reduced in the presence of palladium on carbon to obtain intermediate (II).

[0056] [ka]

[0057] Intermediate (II) and fatty acid R 1The condensation with OH can be carried out using a condensing agent. For example, DMT-MM(OTf) (Tetrahedron Lett. 2002, 43, 3323-3326), in which the counter ion of DMT-MM is replaced from chloride ion to triflate anion, is used as a condensing agent to carry out an amide-selective condensation reaction, thereby obtaining intermediate (II) and fatty acid R 1 Condensation with OH gives compound (I-1-A).

[0058] [ka]

[0059] In the process of obtaining compound (V) from compound (III), condensation of compound (III) with compound (IV) results in a mixture of α and β anomers, which can be separated using a silica gel column or the like to isolate only the α anomer, thereby obtaining purified compound (V). On the other hand, isolating the β anomer instead of the α anomer can obtain the β anomer of compound (V), and using this β anomer to perform the same process as for compound (V), can obtain the β anomer of compound (I-1-A).

[0060] In addition, by using D-glucose instead of D-galactose as the starting material, A is an α-D-glucopyranosyl group and R 2 In addition, as in the case of D-galactose, the β-anomer can be isolated instead of the α-anomer to obtain the β-anomer isomer of the intermediate. By using this β-anomer intermediate, it is possible to obtain the compound of the present invention in which A is a β-D-glucopyranosyl group and R 2 is 1-hydroxypentadecyl.

[0061] Compound (I-2-A) is a compound in which A is an α-D-galactopyranosyl group, R 2is trans-1-pentadecenyl.

[0062] Compound (I-2-A) can be prepared by reacting intermediate (VI) with fatty acid R 1 It can be synthesized by condensing with OH.

[0063] [ka]

[0064] The intermediate (VI) can be produced, for example, as follows.

[0065] First, the hydroxyl group at the carbon atom 1 of galactose (J. Carbohydr. Chem. 2007, 26, 91-106) (compound VII), in which the hydroxyl group is protected with a p-methoxyphenyl (PMP) group, is protected with an allyl group (e.g., benzyl group). For example, by reacting with allyl bromide in the presence of sodium hydride in DMF, the allyl-protected compound (VIII) is obtained.

[0066] [ka]

[0067] Next, the PMP group is removed from compound (VIII). For example, compound (VIII) is reacted with ceric ammonium nitrate (IV) (CAN) in a MeCN / water mixed solvent to obtain compound (IX).

[0068] [ka]

[0069] Next, compound (IX) is reacted with 2,2,2-trifluoro-N-phenylacetimidoyl chloride to obtain trifluoroacetyl-N-phenylimidate sugar (X). For example, compound (IX) is reacted with 2,2,2-trifluoro-N-phenylacetimidoyl chloride, DIPEA, and DMAP in dichloromethane to obtain trifluoroacetyl-N-phenylimidate sugar (X).

[0070] [ka]

[0071] On the other hand, the hydroxyl group of sphingosine derivative (XI) (J. Org. Chem. 2009, 74, 8669), in which the terminal hydroxyl group is protected with a trityl group and the amino group is substituted with an azide group, is protected with an allyl group. For example, sphingosine derivative (XI) is reacted with allyl bromide in the presence of sodium hydride in DMF to obtain sphingosine derivative (XII), in which the hydroxyl group is protected with an allyl group.

[0072] [ka]

[0073] Next, the trityl group in the sphingosine derivative (XII) is removed, for example, by reacting the sphingosine derivative (XII) with p-toluenesulfonic acid in a dichloromethyl / water mixed solvent to deprotect the sphingosine derivative (XIII). [ka]

[0074] Then, compound (X) is condensed with sphingosine derivative (XIII). For example, a solution of compound (X) and sphingosine derivative (XIII) in dichloromethane solvent is stirred in the presence of molecular sieves (e.g., MS 4A), and then trimethylsilyl trifluoromethanesulfonate (TMSOTf) is added. When compound (X) and sphingosine derivative (XIII) are condensed, a mixture of α anomer and β anomer is obtained. This mixture is separated using a silica gel column or the like, and only the α anomer is isolated to obtain purified compound (XIV).

[0075] [ka]

[0076] Furthermore, the allyl protecting group in compound (XIV) is removed by, for example, treating compound (XIV) with trifluoroacetic acid in the presence of a ruthenium catalyst (e.g., [CpRu(CH)(CHNCOO)]PF) in a trichloromethyl / methanol mixed solvent, to remove the allyl protecting group from compound (XIV) and obtain compound (XV).

[0077] [ka]

[0078] The azide group in compound (XV) is then reduced to give intermediate (VI). For example, compound (XV) is treated with a zinc catalyst in a mixed solution of THF, MeOH, and acetic acid, whereby the azide group is reduced to an amino group to give intermediate (VI).

[0079] [ka]

[0080] Intermediate (VI) and fatty acid R 1Condensation with OH can be carried out using a condensing agent. For example, DMT-MM(OTf) (Tetrahedron Lett. 2002, 43, 3323-3326), in which the counter ion of DMT-MM is replaced from chloride ion to triflate anion, is used as a condensing agent to carry out an amide-selective condensation reaction, thereby obtaining intermediate (VI) and fatty acid R 1 Condensation with OH gives compound (I-2-A).

[0081] [ka]

[0082] In the process of obtaining compound (XIV) from compound (X), condensation of compound (X) with sphingosine derivative (XIII) results in a mixture of α- and β-anomers, which can be separated using a silica gel column or the like to isolate only the α-anomer, thereby obtaining purified compound (XIV). On the other hand, isolating the β-anomer instead of the α-anomer can obtain the β-anomer isomer of compound (XIV), and using this β-anomer to carry out the same process as for compound (XIV), can obtain the β-anomer isomer of compound (I-2-A).

[0083] In addition, by using D-glucose instead of D-galactose as the starting material, A is an α-D-glucopyranosyl group and R 2 In addition, as in the case of D-galactose, the β-anomer can be isolated instead of the α-anomer to obtain the β-anomer isomer of the intermediate. By using this β-anomer intermediate, it is possible to obtain the compound of the present invention in which A is a β-D-glucopyranosyl group and R 2 is 1-hydroxypentadecyl.

[0084] 2. Preparation of mono-nitro-substituted straight-chain fatty acids As a method for producing a linear fatty acid monosubstituted with a nitro group, the following method for producing nitrated lipids (XVI-A) and (XVI-B) will be mainly described.

[0085] [ka]

[0086] Nitrated lipids (XVI-A) and (XVI-B) can be synthesized by the nitroaldol reaction. First, fatty acid (XVII) is tert-butyl esterified to protect the carboxylic acid, yielding ester compound (XVIII).

[0087] [ka]

[0088] Nitrolipids (XVI-A) and (XVI-B) have nitro groups at different positions on the double bond, so the structures of the nitro-side raw materials and the aldehyde-side raw materials are different when performing the nitroaldol reaction.

[0089] To synthesize the nitrated lipid (XVI-A), the synthesized ester (XVIII) is iodized and then nitrated to synthesize the nitroester (XIX).

[0090] [ka]

[0091] Following the microwave-assisted nitroaldol reaction reported by Wang et al. (Synlett 2006, 3, 387-390), the nitroaldol reaction of nitroester (XIX) with aldehyde (XX) gave β-nitroalcohol (XXI), which was then dehydrated with Martin's sulfurane (J. Am. Chem. Soc. 1974, 96, 4604-4611) to afford E-form compound (XXII) with high selectivity (J. Org. Chem. 2016, 81, 532-544; Org. Lett. 2008, 10, 1291-1294). Acid-assisted deprotection of the tert-butyl ester from E-form compound (XXII) afforded nitrated lipid (XVI-A).

[0092] [ka]

[0093] Nitrated lipid (XVI-B) can be synthesized in the same manner as nitrated lipid (XVI-A). For example, the ester (XVIII) is formylated to give aldehyde (XXIII).

[0094] [ka]

[0095] In addition, bromoalkanes can be iodinated and then nitrated to give nitroalkanes (XXIV).

[0096] [ka]

[0097] As with the nitrated lipid (III-A), a nitroaldol reaction is carried out between the aldehyde (XXIII) and the nitroalkane (XXIV) to obtain a β-nitroalcohol, which is then dehydrated using Martin's sulfrane to obtain an E-form compound, which is then deprotected with an acid to remove the tert-butyl ester to obtain the nitrated lipid (XVI-B).

[0098] [ka]

[0099] The method for producing a straight-chain fatty acid mono-substituted with a nitro group is not limited to the above, and a person skilled in the art can introduce a nitro group into a desired carbon of the straight-chain fatty acid. The straight-chain fatty acid mono-substituted with a nitro group produced in this way is called fatty acid R 1 By using OH in the production method of the present invention, R 1 is an acyl group derived from a straight chain fatty acid monosubstituted with a nitro group.

[0100] 3. Preparation of mono-hydroxyl-substituted straight-chain fatty acids By treating the unsaturated fatty acid ester (XXV) with selenium dioxide in the presence of t-butyl hydroperoxide, the allylic CH is oxidized to give a mixture of mono-substituted hydroxyl unsaturated fatty acids (XXVI-a) and (XXVI-b). By purifying the mixture by column chromatography using silica gel or the like, the unsaturated fatty acids (XXVI-a) and (XXVI-b) can be separated and isolated individually.

[0101] [ka]

[0102] An unsaturated fatty acid having a mono-substituted hydroxyl group can be obtained by hydrolyzing an unsaturated fatty acid ester having a mono-substituted hydroxyl group with a base such as LiOH.

[0103] [ka]

[0104] A saturated fatty acid ester having a mono-substituted hydroxyl group can be obtained by reducing the unsaturated bond of an unsaturated fatty acid ester having a mono-substituted hydroxyl group through catalytic reduction using palladium on carbon.

[0105] [ka]

[0106] A saturated fatty acid ester in which a hydroxyl group is mono-substituted can be hydrolyzed with a base such as LiOH to obtain a saturated fatty acid in which a hydroxyl group is mono-substituted.

[0107] [ka]

[0108] Furthermore, a mixture of polyunsaturated fatty acid esters with various mono-substituted hydroxyl groups can be obtained by incubating and oxidizing a polyunsaturated fatty acid ester with 4-CF3-NMBHA, MeOAMVN, and PhCl / MeCN, and then hydrolyzing this with a base such as LiOH to obtain a mixture of polyunsaturated fatty acids with various mono-substituted hydroxyl groups. Purification by column chromatography on silica gel or the like allows the separation and isolation of the mono-substituted polyunsaturated fatty acids (XXXI-a) to (XXXI-d).

[0109] [ka]

[0110] The method for producing a straight-chain fatty acid mono-substituted with a hydroxyl group is not limited to the above, and a person skilled in the art can introduce a hydroxyl group to a desired carbon of the straight-chain fatty acid. The straight-chain fatty acid mono-substituted with a hydroxyl group produced in this way is called fatty acid R 1 By using OH in the production method of the present invention, R 1 However, the compound of the present invention can be produced in which the acyl group is derived from a straight-chain fatty acid and mono-substituted with a hydroxyl group.

[0111] <Pharmaceutical Composition> The present invention also provides a pharmaceutical composition containing the compound of the present invention. The pharmaceutical composition of the present invention may be formulated. The dosage form is not particularly limited, and may be formulated into, for example, an injection (intravenous injection (including drip infusion), intramuscular injection, intraperitoneal injection, subcutaneous injection, etc.), tablet, capsule, liquid, suppository, ointment, etc., and in the case of an injection preparation, it may be provided in the form of a unit-dose ampule or a multi-dose container. These various formulations can be produced by conventional methods using, as appropriate, excipients, fillers, binders, wetting agents, disintegrants, lubricants, surfactants, dispersants, buffers, preservatives, solubilizers, antiseptics, flavoring agents, soothing agents, stabilizers, isotonicity agents, etc. that are commonly used in formulations. The pharmaceutical composition of the present invention may or may not contain these additives for the purpose of formulation in addition to the compound of the present invention. The content of the compound of the present invention in the pharmaceutical composition is not particularly limited, and is, for example, about 0.00001 to 100% by weight, or 0.0001 to 99.9% by weight, of the total pharmaceutical composition. The method of administration of the pharmaceutical composition of the present invention is not particularly limited, and may be oral or parenteral administration, which can be appropriately selected depending on the dosage form.

[0112] <Application> The compounds of the present invention can activate NKT cells and thus can be used as components of NKT cell activators. In the present invention, "NKT cell activation" refers to either or both of enhancing the activity of NKT cells or promoting the proliferation of NKT cells. By activating NKT cells, the compounds of the present invention can induce the production of various cytokines (IFN-γ, IL-4, IL-17A, etc.) in the immune system, and are particularly excellent in promoting Th17-selective cytokine production (e.g., IL-17A production). Therefore, the compounds of the present invention can be used as IL-17A production promoters.

[0113] The compounds of the present invention can activate NKT cells and induce the production of various cytokines in the immune system, making the compounds of the present invention and pharmaceutical compositions containing the compounds useful as immunostimulants. The compounds of the present invention are particularly effective in promoting Th17-selective cytokine production (e.g., IL-17A production). Therefore, an effective amount of the compounds of the present invention can be administered to patients with diseases for which Th17 activation or induction of IL-17A production is expected to have a direct or indirect therapeutic or preventive effect, or to humans at risk of such diseases, to activate their immune system and thereby treat or prevent (reduce the risk of onset) the disease. Diseases for which Th17 activation or induction of IL-17A production is expected to have a direct or indirect therapeutic or preventive effect include, but are not limited to, infections caused by extracellular bacteria such as Klebsiella pneumoniae, Streptococcus pneumoniae, and mycobacteria, intracellular parasitic bacteria such as Salmonella, and fungi such as Candida albicans. The compounds of the present invention can also be expected to induce cytotoxic T cells (CTLs).

[0114] All references cited herein, including publications, patent documents, and the like, are incorporated herein by reference to the same extent as if each was individually and specifically incorporated by reference and the contents thereof were specifically set forth in their entirety.

[0115] The present invention will be explained in more detail below with reference to examples, but the present invention is not limited thereto. [Example]

[0116] <Production example> <Sphingosine-type GlcCer(OH)>

[0117] [ka]

[0118] Compound 1-6-1 To a stirred solution of 1-5-1 (J. Carbohydr. Chem. 2007, 26, 91-106) (1.00 g, 3.49 mmol) in anhydrous DMF (15.2 mL) was added a 60% paraffin oil suspension of NaH (616 mg, 15.4 mmol) and AllylBr (1.28 mL, 14.7 mmol) at 0 °C, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with ice-water, and the whole was extracted with EtO, washed with HO and saturated brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 7 / 1) to give 1-6-1 (1.23 g, 79%) as a clear oil.

[0119] 1H NMR (CDCl3) δ 7.06-6.97 (m, 2H), 6.81 (d, J = 8.5 Hz, 2H), 6.06-5.84 (m, 4H), 5.34-5.23 (m, 4H), 5.18-5.15 (m, 4H), 4.47-4.39 (m, 1H), 4.30 (ttt, J = 21.3, 7.4, 2.3 Hz, 3H), 4.21-4.11 (m, 2H), 4.08-3.80 (m, 3H), 3.76 (t, J = 3.1 Hz, 3H), 3.63 (dt, J = 11.9, 4.1 Hz, 1H), 3.58-3.51 (m, 2H), 3.45 (t, J = 4.6 Hz, 2H); 13 C NMR (CDCl3) δ 155.2, 154.9, 150.7, 135.3, 134.9, 134.7, 134.4, 118.4, 118.1, 117.6, 117.3, 117.1, 116.9, 116.8, 116.5, 102.7, 96.5, 84.1, 81.4, 79.3, 75.0, 74.5, 73.9, 72.4, 70.6, 68.2, 55.6; HRMS (ESI-QTOF) calcd for C 25 H 34 O7[M+Na] + 469.2197, found 469.2203.

[0120] Compound 1-6-2 1-5-2 in anhydrous DMF (60.7 mL) To a stirred solution of 1-6-2 (J. Carbohydr. Chem. 2007, 26, 91-106) (4.00 g, 14.0 mmol), a 60% paraffin oil suspension of NaH (2.46 g, 61.5 mmol) and AllylBr (5.32 mL, 61.5 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 18 h. The reaction was quenched with ice-water, and the whole was extracted with EtO, washed with HO and saturated brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 7 / 1) to give 1-6-2 (5.16 g, 83%) as a clear oil.

[0121] 1 H NMR (CDCl3) δ 7.05-6.92 (m, 2H), 6.84-6.68 (m, 2H), 6.03-5.73 (m, 4H), 5.46-5.43 (m, 1H), 5.36-5.09 (m, 8H), 4.77-4.72 (m, 1H), 4.44-3.87 (m, 13H), 3.84-3.79 (m, 1H), 3.70-3.54 (m, 1H), 3.49-3.30 (m, 1H); 13 C NMR (CDCl3) δ 155.2, 151.8, 135.5, 135.4, 135.3, 135.2, 135.1, 135.0, 134.5, 118.7, 118.7, 117.4, 117.2, 117.1, 116.8, 116.7, 116.5, 114.5, 114.4, 103.2, 97.6, 81.5, 79.0, 78.3, 76.1, 74.5, 74.2, 74.0, 73.6, 72.5, 72.3, 72.0, 71.8, 69.7, 68.5, 55.7; HRMS (ESI-QTOF) calculation for C 25 H 34 O7[M+Na] + 469.2197, found 469.2203.

[0122] [ka]

[0123] Compound 1-7-1 To a stirred solution of 1-6-1 (30.4 mg, 0.068 mmol) in MeCN (419 μL) and HO (419 μL) was added CAN (73.5 mg, 0.134 mmol), and the mixture was stirred at 0 °C for 15 min. The mixture was diluted with brine, and the whole was extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 2 / 1) to give 1-7-1 (19.9 mg, 86%) as a brown solid.

[0124] 1 H NMR (CDCl3) δ: 6.02-5.86 (m, 4H), 5.27 (dt, J = 17.2, 5.1 Hz, 4H), 5.14 (m, 4H), 4.39-3.93 (m, 9H), 3.74-3.58 (m, 3H), 3.38 (m, 2H), 3.24-3.14 (1H, m); 13 C NMR (CDCl3) δ 135.7, 135.4, 115.8, 115.6, 115.4, 115.2, 89.6, 80.4, 79.6, 77.5, 73.5, 72.9, 72.8, 72.5, 72.4, 71.1, 70.3, 69.1; HRMS (ESI-QTOF) calcd for C 18 H 28 O6[M+Na] + 363.1778, found 363.1787.

[0125] Compound 1-7-2 To a stirred solution of 1-6-2 (2.42 g, 5.42 mmol) in MeCN (33.9 mL) and HO (33.9 mL), CAN (5.94 g, 10.8 mmol) was added, and the mixture was stirred at 0 °C for 15 min. The mixture was diluted with brine, and the whole was extracted with EtOAc, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue, which was purified by silica gel column chromatography (n-hexane / EtOAc = 2 / 1) to give 1-7-2 (1.55 g, 84%) as a brown solid.

[0126] 1 H NMR (CDCl3) δ: 6.00-5.86 (m, 4H), 5.42-5.10 (m, 9H), 4.97-4.76 (m, 1H), 4.60 (dd, J = 7.5, 1.5 Hz, 1H), 4.42-3.94 (m, 9H), 3.84-3.81 (m, 1H), 3.78-3.67 (m, 2H), 3.67-3.54 (m, 1H); 13 C NMR (CDCl3) δ 135.3, 134.9, 134.7, 134.3, 117.8, 117.5, 117.4, 116.9, 116.7, 97.6, 92.0, 74.5, 74.0, 72.7, 72.5, 71.6, 69.4, 68.9; HRMS (ESI-QTOF) calcd for C 18 H 28 O6[M+Na] + 363.1778, found 363.1787.

[0127] [ka]

[0128] Compound 1-8-1 To a stirred solution of 1-7-1 (261 mg, 0.767 mmol) in CHCl (15.3 mL), 2,2,2-trifluoro-N-phenylacetimidoyl chloride (145 μL, 0.922 mmol), DIPEA (261 μL, 1.53 mmol), and DMAP (81.5 mg, 0.667 mmol) were added. The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 9 / 1) to give 1-8-1 (373 mg, 95%) as a yellow oil.

[0129] 1 H NMR (CDCl3) δ: 7.28 (dd, J = 13.2, 4.9 Hz, 2H), 7.09 (t, J = 7.3 Hz, 1H), 6.83 (d, J = 7.3 Hz, 2H), 6.03-5.84 (m, 4H), 5.32-5.26 (m, 4H), 5.19 (tt, J = 9.0, 3.6 Hz, 4H), 4.41-3.98 (m, 9H), 3.85 (s, 1H), 3.74 (q, J = 7.8 Hz, 1H), 3.66 (dd, J = 12.7, 8.3 Hz, 2H), 3.52 (dd, J = 21.5, 11.7 Hz, 2H); 13 C NMR (CDCl3) δ 135.0, 134.7, 134.5, 134.4, 129.1, 128.7 (3C), 127.4, 120.6, 117.6 (2C), 117.5, 117.2, 117.1 (2C), 116.8 (2C), 116.7, 80.3, 74.4, 74.1, 73.9, 73.0, 72.5, 72.4; HRMS (ESI-QTOF) calcd for C 26 H 32 F3O6[M+Na] + 534.2174, found 534.2074.

[0130] Compound 1-8-2 To a stirred solution of 1-7-2 (1.10 g, 3.23 mmol) in CHCl (64.6 mL) was added 2,2,2-trifluoro-N-phenylacetimidoyl chloride (558 μL, 3.55 mmol), DIPEA (1.10 mL, 6.46 mmol), and DMAP (276 mg, 2.26 mmol). The mixture was stirred at room temperature for 4 hours and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 9 / 1) to give 1-8-2 (1.40 g, 85%) as a yellow oil.

[0131] 1 H NMR (CDCl3) δ 7.34-7.03 (m, 4H), 7.10-6.98 (m, 1H), 6.80 (d, J = 7.2 Hz, 2H), 5.98-5.82 (m, 4H), 5.42-5.14 (m, 8H), 4.41-4.34 (m, 1H), 4.27-3.91 (m, 8H), 3.80-3.74 (m, 2H), 3.67-3.53 (m, 2H); 13 C NMR (CDCl3) δ 135.3, 135.2, 134.9, 134.8, 134.7 (2C), 134.4 (3C), 129.5, 128.8, 128.7, 126.5, 124.2, 120.5, 119.6, 119.4, HRMS (ESI-QTOF) calcd for C 26 H 32 F3O6[M+Na] + 534.2174, found 534.2074.

[0132] [ka]

[0133] Compound 1-10 Compound 1-9 (J. Org. Chem. 2009, 74, 8669) To a stirred solution of 1-10 (877 mg, 1.55 mmol) in DMF (15.5 mL), a 60% paraffin oil suspension of NaH (99.2 mg, 2.48 mmol) and AllylBr (201 μL, 2.32 mmol) were added at 0 °C, and the mixture was stirred at room temperature for 23 h. The whole was extracted with EtO, washed with HO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 15 / 1) to give 1-10 (891 mg, 95%) as a white solid.

[0134] 1 H NMR (CDCl3) δ 7.51-7.41 (m, 5H), 7.35-7.22 (m, 10H), 5.80 (dq, J = 11.1, 5.4 Hz, 1H), 5.68-5.61 (m, 1H), 5.30-5.11 (m, 2H), 4.01 (dd, J = 13.1, 5.0 Hz, 1H), 3.90 (dd, J = 8.4, 5.7 Hz, 1H), 3.76 (dd, J = 12.9, 5.7 Hz, 1H), 3.63-3.56 (m, 1H), 3.30 (dd, J = 9.7, 6.6 Hz, 1H), 3.21 (q, J = 4.7 Hz, 1H), 2.05-1.98 (m, 2H), 1.44-1.16 (m, 20H), 0.93-0.84 (m, 3H); 13 C NMR (CDCl3) δ 143.8 (3C), 137.7, 134.7 (2C), 128.8, 127.9, 127.2, 127.1, 126.0, 116.7, 87.1, 79.6, 77.5, 77.1, 76.8, 69.0, 65.0, 63.1, 53.5, 32.4, 32.0, 29.8 (2C), 29.7, 29.6 (2C), 29.5, 29.3, 29.1, 22.8, 14.3; HRMS (ESI-QTOF) calcd for C40 H 53 O2[M+Na] + 630.4030, found 630.4022.

[0135] [ka]

[0136] Compound 1-11 To a stirred solution of compound 1-10 (810 mg, 1.33 mmol) in CHCl (6.8 mL) and MeOH (3.4 mL), p-TsOH·HO (278 mg, 1.46 mmol) was added, and the mixture was stirred at room temperature for 2.5 h. The mixture was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 5 / 1) to give 1-11 (443 mg, 91%) as a colorless oil.

[0137] 1 H NMR (CDCl3) δ 5.94-5.84 (m, 1H), 5.77 (dt, J = 15.1, 6.8 Hz, 1H), 5.39 (q, J = 8.0 Hz, 1H), 5.29-5.18 (m, 2H), 4.16-4.07 (m, 1H), 3.92-3.80 (m, 2H), 3.80-3.70 (m, 2H), 3.50 (q, J = 5.4 Hz, 1H), 2.17 (t, J = 6.3 Hz, 1H), 2.10 (q, J = 6.8 Hz, 2H), 1.41 (t, J = 6.8 Hz, 2H), 1.27-1.20 (m, 20H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3) δ 138.2, 134.3, 126.1, 117.3, 80.9, 77.4, 77.1, 76.8, 69.1, 66.0, 62.7, 32.4, 32.0, 29.7 (3C), 29.5 (2C), 29.5 (2C), 29.2, 29.0, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 21 H 39 O2[M+Na] + 388.2934, found 388.2930.

[0138] [ka]

[0139] Compound 1-12-1 A solution of compound 1-8-1 (294 mg, 0.57 mmol) and compound 1-11 (268 mg, 0.44 mmol) in CHCl (8.8 mL) was stirred for 30 min in the presence of MS 4A. The mixture was cooled to -30 °C, and TMSOTf (27 μL, 0.15 mmol) was added. After stirring for 7 h, the reaction was quenched with EtN, the mixture was filtered, and the solvent was concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 6 / 1) to give 1-12-1a (α anomer) (160 mg, 53%) as a yellow solid and 1-12-1b (β anomer) (121 mg, 40%) as a yellow oil.

[0140] 1-12-1-1a: 1H NMR (CDCl3) δ 5.96-5.78 (m, 5H), 5.73-5.65 (m, 1H), 5.37-5.17 (m, 5H), 5.16-5.05 (m, 5H), 4.34-4.13 (m, 6H), 4.12-3.96 (m, 5H), 3.91-3.73 (m, 3H), 3.70-3.50 (m, 4H), 3.39-3.31 (m, 3H), 3.20-3.09 (m, 1H), 2.08-1.95 (m, 2H), 1.34 (d, J = 5.0 Hz, 2H), 1.31-1.23 (m, 20H), 0.85 (t, J = 6.9 Hz, 3H); 13 C NMR (CDCl3) δ 135.3, 135.1 (2C), 134.9 (2C), 134.8 (2C), 129.3, 126.2, 120.7, 117.1, 117.0, 116.9, 116.8, 116.7, 103.4, 84.2, 81.5, 77.5, 77.3, 77.1, 76.8, 75.0, 74.9, 74.5, 73.9, 72.5, 69.0, 68.9, 32.4, 32.0, 29.7 (3C), 29.5 (2C), 29.4 (2Cs), 29.3, 29.2, 29.1, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 39 H 65 N3O 87 [M+Na] + 710.4715, found 710.4711;

[0141] 1-14-1-1b: 11H NMR (CDCl3) δ 5.99 - 5.82 (m, 5H), 5.75 - 5.66 (m, 1H), 5.38 - 5.30 (m, 1H), 5.28 - 5.22 (m, 5H), 5.18 - 5.13 (m, 5H), 4.39 - 4.21 (m, 5H), 4.19 - 3.97 (m, 5H), 3.93 - 3.77 (m, 3H), 3.69 - 3.51 (m, 4H), 3.36 - 3.31 (m, 3H), 3.22 - 3.17 (m, 1H), 2.09 - 2.03 (m, 2H), 1.37 (t, J = 7.0 Hz, 2H), 1.26 - 1.21 (m, 20H), 0.87 (t, J = 6.8 Hz, 3H); 13 13C NMR (CDCl3) δ 138.0, 137.8, 135.3, 135.2, 134.9, 134.8, 134.4, 117.1, 117.0, 116.9, 116.8, 116.7, 84.2, 84.1, 81.5, 79.7, 79.5, 77.5, 77.2, 76.8, 75.0, 74.9, 74.4, 73.9, 73.7, 72.5, 69.0, 67.5, 64.4, 58.5, 53.5, 49.6, 32.4, 32.0, 29.7, 29.5, 29.4, 29.3, 29.2, 29.1, 22.7, 14.2; HRMS (ESI - QTOF) calcd for C 39 H[[ID=�]] 65 N3O 8\7 [M + Na] + 710.4715, found 710.4720.

[0142] Compound 1 - 12 - 2 A solution of compound 1-8-2 (1.63 g, 3.19 mmol) and compound 1-11 (1.06 g, 2.90 mmol) in CHCl (44.6 mL) was stirred for 30 min in the presence of MS 4A. The mixture was cooled to -30 °C, and TMSOTf (136 μL, 0.75 mmol) was added. After stirring for 15 h, the reaction was quenched with EtN, the mixture was filtered, and the solvent was concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 6 / 1) to give 1-12-2a (α anomer) (734 mg, 37%) as a yellow solid and 1-12-2b (β anomer) (861 mg, 43%) as a yellow oil.

[0143] 1-12-2a: 1 H NMR (CDCl3) δ 5.98-5.81 (m, 5H), 5.75-5.68 (m, 1H), 5.38-4.97 (m, 14H), 4.37-4.29 (m, 2H), 4.24-4.10 (m, 4H), 4.06-3.95 (m, 2H), 3.95-3.68 (m, 4H), 3.66-3.47 (m, 5H), 3.37-3.29 (m, 1H), 2.20-2.04 (m, 2H), 1.55-1.11 (m, 22H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl3) δ 138.1, 135.5, 135.4, 135.1, 135.0, 134.8, 134.4, 129.5, 128.0, 126.5, 125.6, 120.6, 117.6, 117.1, 116.8, 116.7, 116.6, 103.8, 81.6, 79.6, 79.0, 74.1, 74.0, 73.4, 73.2, 72.5, 71.9, 69.0, 68.6, 64.4, 32.5, 32.0, 29.8, 29.6, 29.5, 29.3, 29.1, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 44 H 69 N3O8[M+Na] +710.4715, found 710.4519.

[0144] 1-12-2b: 1 H-NMR (CDCl3) δ 6.00 - 5.81 (m, 5H), 5.78 - 5.66 (m, 1H), 5.38 - 5.18 (m, 10H), 5.16 - 5.09 (m, 4H), 4.93 (d, J = 3.6 Hz, 1H), 4.37 (q, J = 6.0 Hz, 1H), 4.23 - 4.16 (m, 1H), 4.15 - 4.08 (m, 1H), 4.06 - 3.96 (m, 2H), 3.96 - 3.86 (m, 1H), 3.84 - 3.76 (m, 4H), 3.75 - 3.68 (m, 1H), 3.63 - 3.54 (m, 2H), 3.51 (dd, J = 9.3, 6.1 Hz, 1H), 2.09 - 1.92 (m, 3H), 1.40 - 1.36 (m, 2H), 1.26 (d, J = 16.3 Hz, 22H), 0.87 (t, J = 6.8 Hz, 3H); 13 C NMR (CDCl3) δ 137.9, 135.5, 135.3, 135.2, 134.7, 134.6, 129.1, 128.0, 127.7, 127.3, 126.2, 117.3, 117.1, 116.7, 116.4 (2C), 98.7, 79.3, 78.1, 76.2, 74.8, 74.1, 72.5, 72.2, 71.8, 69.6, 69.1, 68.8, 67.9, 64.3, 32.4, 32.0, 29.8, 29.6, 29.5, 29.3, 29.1, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 44 H 69 N3O8[M+Na] + 710.4715, found 710.4709.

[0145]

Chem.

[0146] Compound 1-13-1a To a stirred solution of 1-12-1a (148 mg, 0.22 mmol) in CHCl3 (6.5 mL), MeOH (0.65 mL), and TFA (72 μL) was added [CpRu(C3H5)(C9H6NCOO)]PF6 (Org. Lett. 2017, 19, 6482-6485; Org. Lett. 2004, 6, 1873-1875; Sci. Rep. 2017, 7, 9472; Chemistry a European Journal 2017, 23, 8304-8308). (9.0 mg, 17.2 μmol) was added, and the mixture was stirred at room temperature for 15 hours. The reaction was quenched with SilicaMet® DMT, and the mixture was stirred at room temperature for 30 minutes. After filtration, the solvent was concentrated to give a residue, which was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1) to give 1-13-1a (α anomer) (97.4 mg, 93%) as a brown solid.

[0147] 1 H NMR (CD3OD) δ: 5.72-5.64 (m, 1H), 5.43 (dd, J = 15.4, 7.5 Hz, 1H), 4.72 (dd, J = 9.5, 5.7 Hz, 1H), 4.09 (t, J = 6.1 Hz, 1H), 3.80-3.75 (m, 1H), 3.70 (dd, J = 11.8, 2.4 Hz, 1H), 3.58 (dt, J = 15.1, 4.5 Hz, 1H), 3.54-3.42 (m, 2H), 3.32-3.28 (m, 1H), 3.20 (dq, J = 9.7, 2.7 Hz, 3H), 1.98 (q, J = 6.7 Hz, 2H), 1.31 (d, J = 6.3 Hz, 2H), 1.19 (s, 20H), 0.82-0.77 (m, 3H); 13C NMR (CDCl3) δ 135.8, 129.8, 101.0, 74.9, 74.0 (2C), 73.5, 73.4 (2C), 71.6 (2C), 68.8, 67.2, 62.5 (2C), 33.4, 33.1, 30.8 (2C), 30.6, 30.5, 30.3, 30.2, 23.7; HRMS (ESI-QTOF) calcd for C 24 H 45 N3O7[M+Na] + 510.3150, found: 510.3164.

[0148] Compound 1-13-1b To a stirred solution of 1-12-1-1b (244.3 mg, 0.36 mmol) in CHCl (10.8 mL), MeOH (1.1 mL), and TFA (118 μL) was added [CpRu(C3H5)(CH6NCOO)]PF6 (14.9 mg, 28.4 μmol), and the mixture was stirred at room temperature for 16 h. The reaction was quenched with SilicaMet® DMT, and the mixture was stirred at room temperature for 30 min. The mixture was filtered, and the solvent was concentrated to give a residue that was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1) to give 1-13-1b (β anomer) (150 mg, 87%) as a brown solid.

[0149] 1 H NMR (CD3OD) δ: 5.70-5.63 (m, 1H), 5.41 (dd, J = 15.4, 7.5 Hz, 1H), 4.19 (t, J = 9.6 Hz, 1H), 4.08 (dd, J = 7.3, 5.5 Hz, 1H), 3.83-3.75 (m, 2H), 3.61-3.51 (m, 3H), 3.28-3.14 (m, 3H), 3.10 (dd, J = 8.8, 7.9 Hz, 1H), 1.97 (q, J = 7.0 Hz, 2H), 1.30 (d, J = 6.7 Hz, 2H), 1.14 (d, J = 36.8 Hz, 20H), 0.80 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3) δ 135.9, 129.6, 104.5, 78.0 (2C), 75.0, 73.5 (2C), 71.5 (2C), 70.1, 67.3, 62.7 (2C), 33.4, 33.1, 30.8 (2C), 30.6, 30.5, 30.3, 30.2, 23.7, 14.5; HRMS (ESI-QTOF) calcd for C 24 H 45 N3O7[M+Na] + 510.3150, found 510.3163.

[0150] Compound 1-13-2a To a stirred solution of 1-12-2a (448 mg, 0.65 mmol) in CHCl3 (19.8 mL), MeOH (1.98 mL), and TFA (217 μL) was added [CpRu(C3H5)(C9H6NCOO)]PF6 (Org. Lett. 2017, 19, 6482-6485; Org. Lett. 2004, 6, 1873-1875; Sci. Rep. 2017, 7, 9472; Chemistry a European Journal 2017, 23, 8304-8308). The reaction was quenched with SilicaMet® DMT, the mixture was stirred at room temperature for 30 minutes, filtered, and the solvent was concentrated to give a residue, which was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1) to give 1-13-2a (α anomer) (259 mg, 82%) as a brown solid.

[0151] 1H-NMR (CD3OD) δ 5.78-5.70 (m, 1H), 5.51-5.46 (m, 1H), 4.22 (d, J = 7.7 Hz, 1H), 4.17 (dd, J = 7.0, 5.7 Hz, 1H), 3.90-3.83 (m, 2H), 3.78-3.71 (m, 2H), 3.70-3.59 (m, 2H), 3.55-3.44 (m, 2H), 3.29-3.28 (m, 1H), 2.07-1.99 (m, 2H), 1.38 (q, J = 6.8 Hz, 2H), 1.32-1.21 (m, 20H), 0.87 (t, J = 7.0 Hz, 3H); 13 C NMR (CDCl3) δ 134.5, 128.3, 103.8, 75.2 (3C), 73.6, 72.2, 71.1(2C), 69.1, 68.7, 66.0, 61.2 (2C), 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 47.0, 32.1, 31.8, 29.5, 29.3, 29.2, 28.9, 28.9, 22.4, 13.2; HRMS (ESI-QTOF) calcd for C 24 H 45 N3O7[M+Na] + 510.3150, found: 510.3164.

[0152] Compound 1-13-2b 1-12-1-2b (448 mg, 0.65 mmol) in CHCl3 (21.5 mL), MeOH (2.15 mL) and TFA (237 μL), [CpRu(C3H5)(C9H6NCOO)]PF6 (Org. Lett. 2017, 19, 6482-6485; Org. Lett. 2004, 6, 1873-1875; Sci. Rep. 2017, 7, 9472; Chemistry a European Journal 2017, 23, 8304-8308) (30.0 mg, 57.0 μmol) was added, and the mixture was stirred at room temperature for 18 hours. The reaction was quenched with SilicaMet® DMT, and the mixture was stirred at room temperature for 30 minutes. After filtration, the solvent was concentrated to give a residue, which was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1) to give 1-13-2b (β anomer) (264 mg, 76%) as a brown solid.

[0153] 1 H-NMR (CD3OD) δ 5.79-5.72 (m, 1H), 5.53-5.47 (m, 1H), 4.83 (d, J = 3.2 Hz, 1H), 4.17 (t, J = 6.6 Hz, 1H), 3.91-3.89 (m, 1H), 3.89-3.86 (m, 1H), 3.85-3.79 (m, 1H), 3.79-3.76 (m, 1H), 3.75-3.66 (m, 2H), 3.59-3.54 (m, 1H), 3.49 (td, J = 6.2, 3.5 Hz, 1H), 3.29-3.28 (m, 1H), 2.05 (q, J = 6.9 Hz, 2H), 1.38 (q, J = 6.8 Hz, 2H), 1.29 (d, J = 20.8 Hz, 20H), 0.87 (t, J = 7.0 Hz, 3H); 13 C NMR (CDCl3) δ 134.3, 128.7, 99.9, 71.9 (2C), 71.2, 70.0, 69.8, 68.8, 67.7, 65.6, 61.4 (2C), 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 47.0, 32.1, 31.8, 29.5 (3C), 29.3, 29.2, 28.9, 28.9, 22.4, 13.1; HRMS (ESI-QTOF) calcd for C 24 H 45 N3O7[M+Na] + 510.3150, found: 510.3164.

[0154] [ka]

[0155] Compound 1-14-1a Compound 1-13-1a (68.1 mg, 0.14 mmol) in THF (7.4 mL), MeOH (12.9 mL), and AcOH (5.5 mL) was added with zinc powder (1.84 g, 28.3 mmol). The mixture was sonicated for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and treated with aqueous NHOH at room temperature for 1 hour. The solvent was removed under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH / HO = 60 / 25 / 4) to give compound 1-14-1a (α anomer) (59.5 mg, 92%) as a purple oil.

[0156] 1 H NMR (CD3OD) δ: 5.81-5.74 (m, 1H), 5.39 (dd, J = 15.2, 6.6 Hz, 1H), 4.73 (d, J = 3.6 Hz, 1H), 4.23 (dd, J = 12.2, 6.8 Hz, 1H), 3.94-3.84 (m, 1H), 3.71 (dd, J = 11.8, 1.8 Hz, 1H), 3.55 (dt, J = 16.9, 6.0 Hz, 2H), 3.42 (m, 3H), 3.29 (t, J = 5.0 Hz, 1H), 3.19 (dt, J = 14.3, 6.7 Hz, 1H), 2.00 (q, J = 6.9 Hz, 2H), 1.30 (s, 2H), 1.19 (s, 20H), 0.80 (t, J = 6.8 Hz, 3H); 13 C NMR (CD3OD) δ 136.7, 126.1, 100.6, 74.9, 74.2, 73.3, 71.4 (2C), 62.5, 57.0, 33.4, 33.1, 30.9, 30.8 (3C), 30.7 (2C), 30.5, 30.4 (2C), 30.2, 23.7, 14.5; HRMS (ESI-QTOF) calcd for C 24 H47 NO7[M+Na] + 484.3245, found: 484.3241.

[0157] Compound 1-14-1b To compound 1-13-1b (10.7 mg, 22.0 μmol) in THF (1.2 mL), MeOH (2.0 mL), and AcOH (870 μL) was added zinc powder (290 mg, 4.43 mmol). The mixture was sonicated for 30 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and treated with aqueous NHOH at room temperature for 1 hour. The solvent was removed under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH / HO = 60 / 25 / 4) to give 1-14-1b (β anomer) (6.3 mg, 62%) as a purple oil.

[0158] 1 H-NMR (CD3OD) δ: 5.80-5.72 (1H, m), 5.39 (1H, dd, J = 15.4, 6.8 Hz), 4.21 (1H, t, J = 6.3 Hz), 3.83 (3H, ddd, J = 19.1, 13.5, 4.9 Hz), 3.56 (1H, dd, J = 11.6, 5.7 Hz), 3.30-3.11 (6H, m), 2.00 (2H, q, J = 6.9 Hz), 1.32 (2H, t, J = 7.5 Hz), 1.19 (20H, s), 0.80 (3H, t, J = 6.8 Hz); 13 C NMR (CD3OD) δ 136.5, 128.5, 104.1, 78.1, 77.8, 74.8, 71.5, 71.1, 62.5, 56.7, 35.4, 33.4, 33.1, 30.9, 30.8 (3C), 30.7, 30.5 (2C), 30.4, 30.2, 23.7, 14.5; HRMS (ESI-QTOF) calcd for C 24 H 47 NO7[M+Na] + 484.3245, found 484.3243.

[0159] Compound 1-14-2a To compound 1-13-2a (148 mg, 0.30 mmol) in THF (11.1 mL), MeOH (19.4 mL), and AcOH (1.0 mL) was added zinc powder (4.0 g, 60.8 mmol). The mixture was sonicated for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and treated with aqueous NHOH at room temperature for 1 hour. The solvent was removed under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH / HO = 60 / 25 / 4) to give compound 1-14-2a (α anomer) (67.9 mg, 48%) as a purple oil.

[0160] 1 H-NMR (CD3OD) δ 5.83 (dd, J = 15.0, 7.0 Hz, 1H), 5.47 (dd, J = 15.4, 6.6 Hz, 1H), 4.84 (d, J = 3.6 Hz, 1H), 4.30 (t, J = 5.5 Hz, 1H), 4.02-3.97 (m, 1H), 3.88 (t, J = 3.1 Hz, 1H), 3.82 (dd, J = 10.1, 3.6 Hz, 1H), 3.76-3.64 (m, 3H), 3.50-3.43 (m, 1H), 3.38 (dd, J = 7.5, 4.4 Hz, 1H), 3.30-3.27 (m, 1H), 2.07 (q, J = 6.7 Hz, 2H), 1.91 (d, J = 7.2 Hz, 2H), 1.39 (d, J = 6.1 Hz, 2H), 1.27 (s, 22H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (CD3OD) δ 135.3, 127.0, 99.6, 71.6 (2C), 69.9, 69.6, 68.8, 64.5, 61.4, 55.5, 48.4, 48.1, 47.9, 47.7, 47.5, 47.3, 47.1, 32.1, 31.8, 29.5 (3C), 29.4 (2C), 29.2, 29.1, 28.9, 22.4, 21.8, 13.2; HRMS (ESI-QTOF) calcd for C 24 H 47 NO7[M+Na] + 484.3245, found: 484.3241.

[0161] Compound 1-14-2b To compound 1-13-2b (662 mg, 1.36 mmol) in THF (24.0 mL), MeOH (43.0 mL), and AcOH (23.3 mL) was added zinc powder (17.7 g, 271 mmol). The mixture was sonicated for 20 minutes, filtered, and the filtrate was concentrated under reduced pressure. The residue was dissolved in MeOH and treated with aqueous NHOH at room temperature for 1 hour. The solvent was removed under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH / HO = 60 / 25 / 4) to give compound 1-14-2b (β anomer) (430 mg, 69%) as a purple oil.

[0162] 1 H-NMR (CD3OD) δ 5.88-5.81 (m, 1H), 5.47 (dd, J = 15.3, 6.7 Hz, 1H), 4.31-4.23 (m, 2H), 3.96-3.92 (m, 2H), 3.81-3.69 (m, 3H), 3.58-3.46 (m, 3H), 3.38-3.33 (m, 1H), 3.30-3.28 (m, 1H), 2.08 (q, J = 7.0 Hz, 2H), 1.95 (d, J = 8.3 Hz, 2H), 1.39 (d, J = 6.3 Hz, 2H), 1.27 (s, 22H), 0.88 (t, J = 6.8 Hz, 3H);13 C NMR (CD3OD) δ 135.4, 127.0, 103.2, 75.6, 73.4, 71.1(2C), 69.6, 69.0, 65.9, 61.3, 55.7, 48.3, 48.1, 47.9, 47.7, 47.5, 47.3, 47.0, 32.0, 31.7 (3C), 29.5, 29.3, 29.2, 29.1, 28.8, 22.4, 20.0, 13.1; HRMS (ESI-QTOF) calcd for C 24 H 47 NO7[M+Na] + 484.3245, found: 484.3241.

[0163] [ka]

[0164] Compounds 1-16a and 1-16b To a stirred solution of compound 1-15 (305 mg, 0.80 mmol) in CHCl (1.0 mL) was added SeO (48.7 mg, 0.44 mmol) in CHCl (53.0 mL) and decane at room temperature. t A solution of 5.0M-6.0M BuOOH (630 μL, 3.13 mmol) was added, followed by AcOH (3.0 μL, 0.75 μmol). The mixture was stirred at room temperature for 63 h. The solvent was removed under reduced pressure, and the whole was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 8 / 1) to give the mixed compound 1-16a-b as a colorless oil. The mixed compound 1-16a-b was purified by HPLC (5SL-II column, 10 ID × 250 mm, eluted with A / B = 99.8:0.2 at 5 mL / min). A: hexane, B: 2-propanol, λ = 205 nm, t = 31.4 min (21a), t = 38.6 min (21b).

[0165] 1-16a: 1H-NMR (CDCl3) δ 5.66-5.59 (m, 1H), 5.44 (dd, J = 15.4, 7.1 Hz, 1H), 4.03 (d, J = 6.5 Hz, 1H), 3.67 (s, 3H), 2.30 (t, J = 7.5 Hz, 2H), 2.02 (q, J = 7.0 Hz, 2H), 1.63-1.25 (m, 34H), 0.88 (t, J = 6.7 Hz, 3H); 13 C-NMR (CDCl3) δ 174.4, 133.0, 132.2, 73.2, 51.4, 37.2, 34.1, 32.2, 31.8, 29.6 (4C), 29.5 (2C), 29.4, 29.3, 29.2 (2C), 29.1 (2C), 25.5, 24.9, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 25 H 48 O3: [M+Na] + , 419.3496; found: 403.3554.

[0166] 1-16b: 1 H-NMR (CDCl3) δ 5.62 (dt, J = 21.1, 7.0 Hz, 1H), 5.47-5.40 (m, 1H), 4.02 (t, J = 6.4 Hz, 1H), 3.66 (t, J = 3.3 Hz, 3H), 2.29 (dd, J = 14.4, 7.0 Hz, 2H), 2.02 (q, J = 7.0 Hz, 2H), 1.63-1.25 (m, 34H), 0.87 (q, J = 6.5 Hz, 3H); 13 C-NMR (CDCl3) δ 174.4, 133.0, 132.2, 73.2, 51.4, 37.2, 34.1, 32.2, 31.9 (2C), 29.6, 29.5, 29.4, 29.3 (2C), 29.2 (2C), 29.1 (2C), 25.5 (2C), 24.9 (2C), 22.7, 14.1; HRMS (ESI-QTOF) calcd for C 25 H 48O3: [M+Na] + , 419.3496; found: 403.3554.

[0167] [ka]

[0168] Compound 1-17c To a solution of compound 1-16a (12.0 mg, 0.03 mmol) in THF (300 μL) was added 2M LiOH aq. (300 μL, 0.60 mmol). After stirring at room temperature for 22 hours, the reaction mixture was acidified with 1 M HCl, and the whole was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 1 / 1) to give compound 1-17c (8.2 mg, 71%) as a white solid.

[0169] 1 H NMR (CDCl3) δ 5.63 (t, J = 7.7 Hz, 1H), 5.44 (dd, J = 15.6, 7.1 Hz, 1H), 4.03 (d, J = 6.3 Hz, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.01 (t, J = 7.2 Hz, 2H), 1.45 (dt, J = 93.3, 30.6 Hz, 18H), 0.88 (t, J = 6.6 Hz, 3H); 13 C-NMR (CDCl3) δ 178.9, 132.9, 132.3, 73.3, 37.3, 33.9, 32.2, 31.9, 29.5 (2C), 29.4 (2C), 29.3, 29.2 (3C), 29.0 (2C), 25.5, 24.7, 22.7, 14.1; HRMS (ESI-QTOF) calcd for C 24 H 46 O3: [MH] - , 381.3374; found: 381.3378.

[0170] [ka]

[0171] Compound 1-17d To a solution of compound 1-16b (12.6 mg, 0.03 mmol) in THF (310 μL) was added 2M LiOH aq. (310 μL, 0.62 mmol). After stirring at room temperature for 22 hours, the reaction mixture was acidified with 1 M HCl, and the whole was extracted with EtOAc, washed with brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 1 / 1) to give compound 1-17d (10.0 mg, 82%) as a white solid.

[0172] 1 H-NMR (CDCl3) δ 5.62 (dt, J = 21.1, 7.0 Hz, 1H), 5.47-5.40 (m, 1H), 4.02 (t, J = 6.4 Hz, 1H), 3.66 (t, J = 3.3 Hz, 3H), 2.29 (dd, J = 14.4, 7.0 Hz, 2H), 2.02 (q, J = 7.0 Hz, 2H), 1.63-1.25 (m, 41H), 0.87 (q, J = 6.5 Hz, 3H); 13 C-NMR (CDCl3) δ 179.0, 132.9, 132.3, 73.3, 37.3, 33.9, 32.2, 31.8, 29.6 (2C), 29.5 (2C), 29.4, 29.3, 29.2 (3C), 29.1, 29.0 (2C), 25.5, 24.7, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 24 H 46 O3: [MH] - , 381.3374; found: 381.3375.

[0173] [ka]

[0174] Compounds 1-19a and 1-19b A mixture of 1-18a-b (43.7 mg, 0.14 mmol) and Pd(OH) (20% wt on carbon, 10.9 mg, 0.016 mmol) in MeOH (2.8 mL) was stirred under a H atmosphere (0.1 MPa) at room temperature for 20 hours. The mixture was filtered and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (n-hexane / EtOAc = 7 / 1) to give compounds 1-19a (15.9 mg, 45%) and 1-19b (15.6 mg, 43%) as white solids.

[0175] 1-19a: 1 H-NMR (CDCl3) δ: 3.67 (s, 3H), 3.58 (s, 1H), 2.30 (t, J = 7.7 Hz, 2H), 1.61 (d, J = 7.2 Hz, 2H), 1.36 (d, J = 58.0 Hz, 27H), 0.88 (t, J = 6.8Hz, 3H); 13 C-NMR (CDCl3)δ 174.3, 72.0, 51.4, 37.5, 37.4, 34.1, 31.8, 29.7, 29.6, 29.5, 29.3 (2C), 29.2, 29.1, 25.6 (2C), 24.9, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 19 H 38 O3: [M+Na] + ,337.2713; found: 337.2718.

[0176] 1-19b: 1 H-NMR (CDCl3) δ: 3.58 (s, 1H), 2.31 (t, J = 7.5 Hz, 2H), 1.63 (s, 2H), 1.35 (m, 27H), 0.88 (t, J = 6.8 Hz, 3H);13 C-NMR (CDCl3)δ 174.3, 71.9, 51.4, 37.5, 37.3, 34.0, 31.9, 29.7, 29.6 (2C), 29.3 (2C), 29.1 (2C), 25.6, 25.4, 24.8, 22.7, 14.1; HRMS (ESI-QTOF) calcd for C 19 H 38 O3: [M+Na] + ,337.2713; found: 337.2715.

[0177] [ka]

[0178] Compound 1-17e To a solution of compound 1-19a (33.0 mg, 0.11 mmol) in THF (1.0 mL) was added 2M LiOH aq. (1.0 mL, 2.0 mmol). After stirring at room temperature for 22 hours, the reaction mixture was acidified with 1 M hydrochloric acid, and the whole was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-17e (38.6 mg) as a white solid, which was used in the next reaction without further purification.

[0179] 1 H-NMR (CDCl3) δ: 3.59 (s, 1H), 2.34 (t, J = 7.6 Hz, 2H), 1.63 (t, J = 7.3 Hz, 2H), 1.35 (m, 27H), 0.88 (t, J = 6.8 Hz, 3H); 13 HRMS (ESI-QTOF) calcd for C 18 H 36 O3: [MH] - , 299.2592; found: 299.2597.

[0180] [ka]

[0181] Compound 1-17f To a solution of compound 1-19b (21.3 mg, 0.068 mmol) in THF (0.7 mL) was added 2M LiOH aq. (1.0 mL, 1.4 mmol). After stirring at room temperature for 22 hours, the reaction mixture was acidified with 1 M hydrochloric acid, and the whole was extracted with EtOAc, washed with brine, dried over anhydrous Na2SO4, filtered, and concentrated under reduced pressure to give 1-17f (19.1 mg) as a white solid, which was used in the next reaction without further purification.

[0182] 1 H-NMR (CDCl3) δ: 3.59 (s, 1H), 2.34 (t, J = 7.6 Hz, 2H), 2.18 (s, 4H), 1.63 (t, J = 7.3 Hz, 3H), 1.36 (d, J = 59.5 Hz, 28H), 0.88 (t, J = 6.8Hz, 3H); 13 HRMS (ESI-QTOF) calcd for C 18 H 36 O3: [MH] - ,299.2592; found: 299.2601.

[0183] [ka]

[0184] [ka]

[0185] Compounds 1-17g and 1-17h A mixture of methyl linoleate (5.88 g, 20.0 mmol), 4-CF3-NMBHA (4.40 g, 20.0 mmol), MeOAMVN (616 mg, 2.00 mmol), and PhCl / MeCN (100 mL) was stirred under air for 3 days. PPh3 (5.24 g, 20.0 mmol) was then added, and the mixture was stirred for 30 min. The whole was concentrated under reduced pressure to give a crude oil. This was purified by silica gel column chromatography (n-hexane / EtOAc = 6:1) to give a mixture of compounds 1-20a-d (3.15 g) as a pale yellow oil. The product ratio of 1-20a-d was determined to be 50.4 / 47.8 / 1.1 / 0.7 by HPLC analysis (COSMOSIL 5SL-II column, 4.6 ID x 250 mm, elution at 1 mL / min with A / B = 97.5:2.5; A: hexane, B: hexane / 2-propanol = 80:20; λ = 220 nm; t1 = 13.9 min for 1-20a, t2 = 16.4 min for 1-20c, t3 = 19.7 min for 1-20b, t4 = 21.8 min for 1-20d). A solution of 1-20a and 1-20b (containing small amounts of 1-20c and 1-20d; 3.15 g, 10.1 mmol) in THF (60 mL) was added to 2 M LiOH aq. (40.0 mL, 80.8 mmol) was added. After stirring at room temperature overnight, the reaction mixture was acidified with 1 M HCl, and the mixture was extracted three times with EtOAc. The extract was dried over anhydrous Na2SO4 and concentrated under reduced pressure to give a crude oil. This was purified by silica gel column chromatography (n-hexane / EtOAc = 4:1 → 1:1) to give 1-17g (1.14 g, 19% over two steps) and 1-17h (990 mg, 17% over two steps) as pale yellow oils.

[0186] 1-17g: 1H NMR (CDCl3, 400 MHz) δ 6.49 (dd, J = 15.1, 11.1 Hz, 1H), 5.98 (t, J = 10.9 Hz, 1H), 5.67 (dd, J = 15.3, 6.7 Hz, 1H), 5.44 (dd, J = 18.4, 7.6 Hz, 1H), 4.20-4.10 (m, 1H), 2.35 (t, J = 7.4 Hz, 2H), 2.20-2.17 (m, 2H), 1.65-1.47 (m, 4H), 1.37-1.28 (m, 14H), 0.89 (t, J = 6.7 Hz, 3H); 13 C NMR (CDCl3, 100 MHz) δ 179.4, 135.6, 132.7, 127.8, 125.8, 72.9, 37.1, 34.0, 31.7, 29.3, 28.9, 28.8 (2C), 27.5, 25.0, 24.6, 22.5, 14.0; HRMS (ESI-QTOF) calcd C 18 H 31 O3: [M-H] - , 295.2279; found: [M-H] - , 295.2276. 1-17h: 1 H NMR (CDCl3, 400 MHz) δ 6.48 (dd, J = 15.1, 11.1 Hz, 1H), 5.97 (t, J = 10.9 Hz, 1H), 5.65 (dd, J = 15.0, 7.0 Hz, 1H), 5.45 (dd, J = 18.4, 7.6 Hz, 1H), 4.14 (dt, J = 20.7, 6.8 Hz, 1H), 2.34 (t, J = 7.5 Hz, 2H), 2.17 (q, J = 7.4 Hz, 2H), 1.63-1.60 (m, 4H), 1.42-1.17 (m, 14H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (CDCl3, 100 MHz) δ 179.6, 135.5, 133.0, 127.6, 125.9, 72.9, 37.1, 34.0, 31.4, 29.2, 29.1, 28.9 (2C), 27.7, 25.3, 24.6, 22.5, 14.0; HRMS (ESI-QTOF) calcd C 18 H 31 O3: [MH] - , 295.2279; found: [MH] - , 295.2278.

[0187] [ka]

[0188] Compound 1-1a To a stirred solution of compound 1-14-1a (10.6 mg, 23.0 μmol) and compound 1-17a (J. Am. Chem. Soc. 1994, 116, 6690) (7.55 mg, 25.3 μmol) in EtOH (215 μL) and CHCl (72 μL) was added DMT-MM(OTf) (European Journal of Organic Chemistry 2015, 2015, 401-408) (10.8 mg, 27.6 μmol) at room temperature. The mixture was stirred at room temperature for 19 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1 → 5 / 1) to give 1-1a (5.4 mg, 32%) as a white solid.

[0189] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.61 (m, 1H), 5.48 (m, 1H), 5.32 (ddd, J = 6.9 Hz, 2H), 4.71 (d, J = 3.7 Hz, 1H), 4.00 (m, 1H), 3.86 (m, 2H), 3.60 (dd, J = 43.9, 11.9 Hz, 4H), 3.39 (d, J = 31.6 Hz, 2H), 3.27 (t, J = 9.6 Hz, 2H), 2.08 (d, J = 7.8 Hz, 2H), 1.91 (s, 4H), 1.49 (s, 2H), 1.12 (t, J = 14.9 Hz, 42H), 0.77 (d, J = 6.4 Hz, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 133.7, 132.5, 131.3, 128.8, 99.0, 73.4, 72.5, 71.7, 71.6, 69.7, 66.8, 61.0, 57.1, 53.2, 36.8, 35.9, 32.0, 31.8, 31.5, 31.4, 29.3 (2C), 29.2 (2C), 29.1 (2C), 28.9 (4C), 28.8 (2C), 28.6 (2C), 25.4, 25.1, 22.2 (2C), 17.3, 13.5 (2C); HRMS (ESI-QTOF) calcd for C 42 1H 79 14NO9: [M+Na] + , 764.5647; found: 764.5719.

[0190] Compound 1-2a To a stirred solution of compound 1-14-1b (7.58 mg, 16.4 μmol) and compound 1-17a (4.90 mg, 16.4 μmol) in EtOH (175 μL) and CHCl (60 μL) at room temperature, DMT-MM(OTf) (11.0 mg, 28.2 μmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2a (4.0 mg, 33%) as a white solid.

[0191] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.64-5.58 (m, 1H), 5.54-5.49 (m, 1H), 5.39-5.30 (m, 2H), 4.18 (d, J = 7.7 Hz, 1H), 4.07 (dd, J = 10.0, 4.6 Hz, 1H), 4.01 (t, J = 7.3 Hz, 1H), 3.90 (t, J = 6.6 Hz, 2H), 3.78 (dd, J = 12.0, 2.6 Hz, 1H), 3.63 (dd, J = 12.2, 5.3 Hz, 1H), 3.49 (dd, J = 10.0, 3.2Hz, 1H), 3.31 (dq, J = 26.4, 5.6 Hz, 3H), 3.22-3.16 (m, 1H), 2.09 (t, J = 7.6 Hz, 2H), 1.92 (t, J = 11.5 Hz, 4H), 1.50 (m, 2H), 1.26 (dd, J = 55.1, 28.2 Hz, 42H), 0.80 (t, J = 6.6 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 134.0, 132.5, 131.4, 128.8, 102.7, 75.8, 73.2, 72.5 (2C), 71.8, 69.7, 68.2, 61.1, 52.9, 36.8, 36.0, 32.0, 31.8, 31.5, 31.4, 29.3 (2C), 29.2 (2C), 29.1 (2C), 29.0 (2C), 28.9 (4C), 28.8 (2C), 28.6, 25.5, 25.1, 22.3, 22.2, 13.5 (2C); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.4754.

[0192] Compound 1-3a To a stirred solution of compound 1-14-1a (14.4 mg, 29.6 μmol) and compound 1-17a (J. Am. Chem. Soc. 1994, 116, 6690) (10.6 mg, 35.5 μmol) in EtOH (277 μL) and CHCl (92 μL) was added DMT-MM(OTf) (European Journal of Organic Chemistry 2015, 2015, 401-408) (13.9 mg, 35.5 μmol) at room temperature. The mixture was stirred at room temperature for 19 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl3 / MeOH = 7 / 1 → 5 / 1) to give 1-3a (5.6 mg, 26%) as a white solid.

[0193] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.62 (d, J = 15.9 Hz, 1 H), 5.54-5.49 (m, 1H), 5.37 (q, J = 7.6 Hz, 2H), 4.18 (d, J = 7.2 Hz, 1 H), 4.03 (t, J = 6.8 Hz, 1 H), 3.94 (d, J = 15.4 Hz, 2H), 3.77 (d, J = 12.7 Hz, 1 H), 3.67-3.63 (m, 1 H), 3.35-3.29 (m, 4H), 3.21-3.16 (m, 2H), 2.09 (t, J = 7.5 Hz, 2H), 1.93 (t, J = 7.0 Hz, 4H), 1.51 (s, 2H), 1.18 (s, 42H), 0.80 (t, J = 6.6 Hz, 6H); 13 C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.5, 134.0, 133.0, 131.9, 128.8, 99.9, 73.1, 72.8, 70.4, 70.3, 69.8, 68.9, 67.8, 61.9, 53.5, 37.3, 36.5 (2C), 32.4 (2C), 32.1 (2C), 32.0, 31.9 (2C), 29.7 (2C), 29.7 (2C), 29.6 (2C), 29.4 (2C), 29.3 (2C), 29.1, 28.8, 25.7, 25.5, 22.7, 22.7, 14.1 (2C); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.5655.

[0194] Compound 1-4a To a stirred solution of compound 1-14-1b (13.7 mg, 28.1 μmol) and compound 1-17a (10.1 mg, 33.7 μmol) in EtOH (263 μL) and CHCl (88 μL) at room temperature, DMT-MM(OTf) (13.2 mg, 33.7 μmol) was added. The mixture was stirred at room temperature for 10 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-4a (11.1 mg, 53%) as a white solid.

[0195] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.65-5.49 (m, 2H), 5.36 (td, J = 15.2, 7.1 Hz, 2H), 4.13 (d, J = 7.0 Hz, 1 H), 4.09-4.03 (m, 2H), 3.97-3.91 (m, 2H), 3.77 (dd, J = 11.8, 6.4 Hz, 1 H), 3.68 (dd, J = 11.7, 4.9 Hz, 1 H), 3.44 (dd, J = 12.0, 9.5 Hz, 3H), 3.31-3.30 (m, 2H), 2.10 (t, J = 7.5 Hz, 2H), 1.95 (dd, J = 13.1, 6.2 Hz, 4H), 1.52 (s, 2H), 1.33-1.19 (m, 42H), 0.86-0.79 (m, 6H); 13C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.5, 134.3, 132.9, 131.9, 128.9, 103.7, 74.8, 73.0, 72.2, 71.3, 69.1, 68.7, 61.6, 55.9, 53.3, 37.2 (2C), 36.4 (2C), 32.4 (2C), 32.1 (2C), 31.9 (2C), 31.8 (2C), 29.7 (2C), 29.7, 29.5, 29.3, 29.3, 29.1, 28.9, 25.7, 25.5, 22.7, 14.0 (2C); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.5648.

[0196] Compound 1-1b To a stirred solution of compound 1-14-1a (10.3 mg, 22.3 μmol) and compound 1-17b (J. Am. Chem. Soc. 1994, 116, 6690) (7.31 mg, 24.5 μmol) in EtOH (210 μL) and CHCl (70 μL) was added DMT-MM (OTf) (10.5 mg, 26.8 μmol) at room temperature. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1b (3.9 mg, 24%) as a white solid.

[0197] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.67 - 5.61 (m, 1H), 5.55 - 5.49 (m, 1H), 5.39 - 5.30 (m, 2H), 4.74 (d, J = 3.7 Hz, 1H), 4.19 (dd, J = 7.4, 3.4 Hz, 1H), 4.02 (t, J = 7.0 Hz, 1H), 3.92 - 3.87 (m, 1H), 3.69 (d, J = 2.6 Hz, 2H), 3.65 (dt, J = 15.2, 4.9 Hz, 2H), 3.58 (t, J = 9.3 Hz, 1H), 3.46 (td, J = 4.9, 2.1 Hz, 1H), 3.37 (dd, J = 9.6, 3.9 Hz, 1H), 3.30 - 3.26 (m, 2H), 2.11 (t, J = 7.6 Hz, 2H), 1.97 - 1.91 (m, 4H), 1.51 (s, 2H), 1.43 - 1.18 (m, 42H), 0.85 - 0.76 (m, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 173.8, 133.3, 131.8, 130.9, 128.6, 98.5, 72.8, 71.8, 71.2, 71.1, 69.2, 66.9, 66.2, 60.4, 52.7, 38.0, 36.3, 35.4, 31.4, 31.3, 31.0, 29.6, 28.8, 28.7, 28.6, 28.5, 28.5, 28.4, 28.3 (4C), 28.2, 28.0, 24.9, 24.4, 23.0, 22.0, 21.7 (2C), 12.9 (2c); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.5688.

[0198] Compound 1 - 2b To a stirred solution of compound 1-14-1b (8.7 mg, 18.8 μmol) and compound 1-17b (5.60 mg, 18.8 μmol) in EtOH (175 μL) and CHCl (60 μL) at room temperature, DMT-MM (OTf) (11.0 mg, 28.2 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2b (2.9 mg, 21%) as a white solid.

[0199] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.65-5.49 (m, 2H), 5.35 (td, J = 15.9, 7.2 Hz, 2H), 4.19 (t, J = 6.6 Hz, 1H), 4.09-4.04 (m, 1H), 4.02 (t, J = 7.2 Hz, 1H), 3.90 (dt, J = 17.5, 5.8 Hz, 2H), 3.78 (dd, J = 12.0, 2.5 Hz, 1H), 3.63 (dd, J = 12.0, 5.2 Hz, 1H), 3.50 (dd, J = 10.0, 3.2 Hz, 1H), 3.31 (tt, J = 13.1, 5.5 Hz, 3H), 3.22-3.15 (m, 1H), 2.09 (t, J = 7.7 Hz, 2H), 1.91 (tt, J = 14.3, 4.8 Hz, 4H), 1.51 (m, 2H), 1.21 (t, J = 11.6 Hz, 42H), 0.80 (t, J = 6.8 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 133.9 ,132.3, 131.5, 128.8, 102.7, 76.0, 75.8, 73.2, 72.4, 71.8, 69.7, 68.1, 61.0, 53.0, 36.8, 36.0, 32.0, 31.8, 31.5 (2C), 29.3 (4C), 29.2 (2C), 29.1 (2C), 29.0 (2C), 28.9 (3C), 28.8 (2C), 25.4, 24.9, 22.3, 22.2, 13.5 (2C); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.5681.

[0200] Compound 1-3b To a stirred solution of compound 1-14-1a (14.7 mg, 30.2 μmol) and compound 1-17b (J. Am. Chem. Soc. 1994, 116, 6690) (10.8 mg, 36.2 μmol) in EtOH (283 μL) and CHCl (94 μL) at room temperature, DMT-MM (OTf) (14.1 mg, 36.2 μmol) was added. The mixture was stirred at room temperature for 18 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-3b (10.4 mg, 46%) as a white solid.

[0201] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.62 (d, J = 15.0 Hz, 2H), 5.37 (q, J = 7.7 Hz, 2H), 4.18 (d, J = 8.6 Hz, 2H), 4.03 (s, 1H), 3.94 (d, J = 15.0 Hz, 2H), 3.78 (d, J = 12.2 Hz, 1 H), 3.35-3.29 (m, 4H), 3.18 (t, J = 8.4 Hz, 2H), 2.10 (d, J = 7.7 Hz, 2H), 1.99-1.93 (m, 4H), 1.52 (s, 2H), 1.32-1.12 (m, 42H), 0.90-0.79 (m, 6H); 13 C NMR (CDCl3 / CD3OD = 10 / 1) δ 168.4, 134.0, 132.7, 132.2, 131.9, 128.8, 99.9, 72.7, 69.7, 68.9, 67.7, 65.4, 61.8, 57.8, 55.9, 53.6, 37.2 (2C), 36.4 (2C), 34.2 (2C), 32.4 (2C), 32.2 (2C), 31.9 (2C), 31.9 (2C), 29.7, 29.6, 29.5, 29.4, 29.3, 29.3, 26.4, 25.7, 25.2, 22.7, 17.9, 14.0 (2C); HRMS (ESI-QTOF) calcd for C 42 H 79 NO9: [M+Na] + , 764.5647; found: 764.5650.

[0202] Compound 1-4b To a stirred solution of compound 1-14-1b (13.6 mg, 27.9 μmol) and compound 1-17b (10.0 mg, 33.5 μmol) in EtOH (261 μL) and CHCl (87 μL) at room temperature, DMT-MM (OTf) (13.1 mg, 33.5 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-4b (5.0 mg, 24%) as a white solid.

[0203] 1 1H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.61 (d, J = 14.8 Hz, 2H), 5.36 (t, J = 7.9 Hz, 2H), 4.12 (d, J = 6.7 Hz, 1 H), 4.04 (d, J = 5.2 Hz, 2H), 3.94 (d, J = 7.6 Hz, 1 H), 3.81 (d, J = 2.0 Hz, 1 H), 3.78 - 3.65 (m, 1 H), 3.46 - 3.40 (m, 2H), 3.30 - 3.28 (m, 4H), 2.10 (d, J = 5.2 Hz, 2H); 13 13C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.5, 134.3, 132.7, 132.0, 128.9, 103.7, 74.7, 73.4, 72.4, 71.4, 71.3, 69.1, 69.0, 61.7, 53.3, 43.3, 37.5, 37.3, 37.1, 36.5, 36.4, 36.2, 36.1, 35.4, 32.4, 32.2, 31.9, 31.8, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.0, 26.5, 26.4, 25.7, 25.2, 22.7, 14.1; HRMS (ESI - QTOF) calcd for C 42 H 79 NO9: [M + Na] + , 764.5647; found: 764.5649.

[0204] Compound 1 - 1c To a stirred solution of compound 1-14-1a (16.7 mg, 36.0 μmol) and compound 1-17c (13.8 mg, 36.0 μmol) in EtOH (340 μL) and CHCl (110 μL) at room temperature, DMT-MM (OTf) (42.4 mg, 109 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1c (8.6 mg, 33%) as a white solid.

[0205] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.68-5.48 (m, 2H), 5.39-5.29 (m, 2H), 4.74 (d, J = 3.8 Hz, 1H), 4.18 (t, J = 6.5 Hz, 1H), 4.01 (t, J = 7.3 Hz, 1H), 3.95 (d, J = 5.6 Hz, 1H), 3.91-3.86 (m, 1H), 3.68 (dq, J = 19.2, 5.0 Hz, 2H), 3.62-3.55 (m, 1H), 3.47 (dq, J = 9.9, 2.5 Hz, 1H), 3.36 (dd, J = 9.6, 3.6 Hz, 1H), 3.28 (dd, J = 13.1, 5.3 Hz, 2H), 2.10 (t, J = 7.7 Hz, 2H), 1.95 (d, J = 7.0 Hz, 4H), 1.43 (ddd, J = 25.2, 15.8, 10.9 Hz, 2H), 1.23 (dd, J = 22.8, 18.3 Hz, 54H), 0.88-0.78 (m, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 133.7, 132.3, 131.3, 129.0, 98.9, 73.2, 72.3, 71.7, 71.6, 71.2, 69.6, 67.3, 60.8, 55.1, 53.2, 38.4, 36.7, 35.9, 35.8, 31.8, 31.6, 31.3 (3C), 30.0, 29.1 (2C), 29.0 (2C), 28.9 (3C), 28.8 (4C), 28.7 (2C), 28.6, 28.4, 25.4, 24.9, 23.4, 22.3, 22.1, 22.0 13.2 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6586.

[0206] Compound 1-2c To a stirred solution of compound 1-14-1b (12.0 mg, 26.0 μmol) and compound 1-17c (10.0 mg, 26.0 μmol) in EtOH (240 μL) and CHCl (80 μL) at room temperature, DMT-MM (OTf) (11.2 mg, 28.6 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2c (6.7 mg, 31%) as a white solid.

[0207] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.65 (dt, J = 35.8, 7.7 Hz, 2H), 5.43 (dt, J = 25.8, 9.5 Hz, 2H), 4.30-4.26 (m, 1H), 4.18 (t, J = 5.0 Hz, 1H), 4.09 (t, J = 7.9 Hz, 1H), 4.04-3.96 (m, 4H), 3.87 (d, J = 11.9 Hz, 1H), 3.71 (dd, J = 12.0, 5.3 Hz, 1H), 3.58 (d, J = 10.1 Hz, 1H), 3.43-3.24 (m, 2H), 2.18 (t, J = 7.5 Hz, 2H), 2.02 (m 4H), 1.59 (m, 2H), 1.31 (d, J = 30.5 Hz, 54H), 0.90 (t, J = 9.9 Hz, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 133.9, 132.4, 131.5, 128.8, 102.6, 76.0, 75.8, 73.2, 72.5, 69.7, 68.1, 66.2, 61.0, 55.3, 52.9, 36.8, 36.0, 31.9, 31.8, 31.5, 31.4, 29.2 (6C), 29.1 (2C), 29.0 (4C), 28.9 (4C), 28.8 (5C), 28.7, 28.6, 25.5, 25.1, 22.2, 13.4 (2C); HRMS (ESI-QTOF) calcd for C 48 1 91 1 + H

[0208] Compound 1-3c To a stirred solution of compound 1-14-1a (8.9 mg, 18.3 μmol) and compound 1-17c (7.0 mg, 18.3 μmol) in EtOH (171 μL) and CHCl (57 μL) at room temperature, DMT-MM (OTf) (7.9 mg, 20.1 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-3c (2.2 mg, 15%) as a white solid.

[0209] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.66-5.50 (m, 2H), 5.41-5.31 (m, 2H), 4.19 (d, J = 7.6 Hz, 1 H), 4.07-3.99 (m, 2H), 3.97-3.90 (m, 2H), 3.78 (dd, J = 12.2, 2.8 Hz, 1 H), 3.66 (dd, J = 12.0, 4.8 Hz, 1 H), 3.52 (dd, J = 10.2, 3.3 Hz, 1 H), 3.39-3.30 (m, 4H), 2.14-2.08 (m, 2H), 1.97-1.92 (m, 4H), 1.51 (s, 2H), 1.28 (d, J = 80.3 Hz, 54H), 0.85-0.79 (m, 6H); 13C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.8, 134.0, 132.7, 131.9, 128.9, 99.8, 72.9, 72.3, 70.5, 70.1, 69.7, 68.9, 67.9, 61.7, 55.7, 37.4, 37.1, 36.4 (2C), 32.5 (2C), 32.3 (2C), 32.1 (2C), 31.8 (2C), 31.7 (2C), 31.6, 29.5 (2C), 29.2 (2C), 29.1, 26.3, 26.2, 26.0, 25.8, 25.5, 25.4, 25.2, 22.6, 22.5, 22.4, 13.8 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6592.

[0210] Compound 1-4c To a stirred solution of compound 1-14-1b (5.6 mg, 11.5 μmol) and compound 1-17c (4.4 mg, 11.5 μmol) in EtOH (107 μL) and CHCl (36 μL) at room temperature, DMT-MM (OTf) (4.9 mg, 12.6 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-4c (2.0 mg, 21%) as a white solid.

[0211] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.64-5.50 (m, 2H), 5.43-5.30 (m, 2H), 4.18-4.01 (m, 3H), 3.93-3.86 (m, 2H), 3.81 (d, J = 2.9 Hz, 1H), 3.53-3.41 (m, 4H), 3.30-3.28 (m, 2H), 2.09 (t, J = 7.6 Hz, 2H), 1.96-1.89 (m, 4H), 1.52 (d, J = 7.6 Hz, 2H), 1.22 (d, J = 35.7 Hz, 54H), 0.80 (t, J = 6.8 Hz, 6H); 13 C NMR (CDCl3 / CD3OD = 10 / 1) δ 172.4, 132.8, 132.2, 130.8, 128.9, 103.6, 74.8, 73.3, 71.3, 71.2, 69.1, 68.7, 61.7, 59.1, 53.6, 38.7, 38.2, 37.2, 36.5, 35.7, 35.3, 34.8, 33.5, 32.4, 32.2, 31.9, 31.8, 31.6, 30.1, 29.9, 29.7, 29.6 (2C), 29.5, 29.3 (2C), 29.2, 29.1, 28.6, 27.4, 26.7, 26.3, 25.9, 25.5, 22.9, 22.7, 14.0 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6593.

[0212] Compound 1-1d To a stirred solution of compound 1-14-1a (4.9 mg, 10.6 μmol) and compound 1-17d (4.06 mg, 10.6 μmol) in EtOH (130 μL) and CHCl (30 μL) at room temperature, DMT-MM (OTf) (12.4 mg, 31.8 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1d (3.8 mg, 43%) as a white solid.

[0213] 1 H-NMR (CDCl3 / CD3OD = ¾) δ 5.67 - 5.48 (m, 2H), 5.34 (ddd, J = 19.0, 14.6, 5.0 Hz, 2H), 4.74 (d, J = 3.6 Hz, 1H), 4.01 (t, J = 7.3 Hz, 1H), 3.88 (q, J = 6.2 Hz, 1H), 3.71 - 3.55 (m, 4H), 3.46 (dt, J = 9.9, 3.6 Hz, 1H), 3.36 (dd, J = 9.6, 3.8 Hz, 1H), 3.30 - 3.25 (m, 3H), 2.10 (t, J = 7.7 Hz, 2H), 1.94 (t, J = 6.5 Hz, 4H), 1.50 (m, 2H), 1.18 (m, 54H), 0.79 (t, J = 6.8 Hz, 6H); 13 C-NMR (CDCl3 / CD3OD = ¾) δ 174.2, 133.7, 132.4, 131.3, 128.8, 98.9, 73.3, 72.3, 71.7, 71.6, 71.2, 70.0, 66.6, 60.8, 53.1, 36.7, 35.8, 31.8, 31.7, 31.4, 31.3 (2C), 29.1 (4C), 29.0 (2C), 28.9 (4C), 28.8 (4C), 28.7 (3C), 28.6, 25.8, 25.4, 25.0, 22.1, 13.2 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6594.

[0214] Compound 1-2d To a stirred solution of compound 1-14-1b (10.7 mg, 23.2 μmol) and compound 1-17d (8.86 mg, 23.0 μmol) in EtOH (220 μL) and CHCl (70 μL) at room temperature, DMT-MM (OTf) (9.88 mg, 25.3 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2d (6.7 mg, 52%) as a white solid.

[0215] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.65 (dtd, J = 29.7, 10.1, 5.3 Hz, 2H), 5.43 (ddt, J = 22.7, 15.0, 3.1 Hz, 2H), 4.28-4.25 (m, 1H), 4.17 (dd, J = 5.9, 3.9 Hz, 1H), 4.11-4.07 (m, 1H), 4.04-3.97 (m, 3H), 3.87 (d, J = 11.9 Hz, 1H), 3.74-3.70 (m, 1H), 3.58 (t, J = 5.0 Hz, 1H), 3.44-3.34 (m, 2H), 3.27 (dt, J = 15.3, 4.8 Hz, 1H), 2.17 (t, J = 5.9 Hz, 2H), 1.99 (d, J = 20.2 Hz, 4H), 1.58 (m, 2H), 1.36 (t, J = 34.9 Hz, 54H), 0.88 (dt, J = 7.3, 2.9 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 174.3, 133.9, 132.4, 131.5, 128.8, 102.6, 76.0, 73.2, 72.5, 71.6, 69.7, 68.1, 66.2, 61.0, 55.3, 36.8, 36.0, 31.9, 31.8, 31.5, 31.4, 29.2 (6C), 29.1 (2C), 29.0 (4C), 28.9 (4C), 28.8 (4C), 28.7, 28.6, 25.5, 25.1, 22.2, 13.4 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6593.

[0216] Compound 1-3d To a stirred solution of compound 1-14-1a (9.9 mg, 20.4 μmol) and compound 1-17d (7.8 mg, 20.6 μmol) in EtOH (191 μL) and CHCl (64 μL) at room temperature, DMT-MM (OTf) (8.8 mg, 22.4 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-3d (3.6 mg, 21%) as a white solid.

[0217] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.65-5.50 (m, 2H), 5.41-5.31 (m, 2H), 4.19 (d, J = 7.6 Hz, 1 H), 4.07-4.01 (m, 2H), 3.97-3.90 (m, 3H), 3.78 (dd, J = 12.0, 2.8 Hz, 1H), 3.66 (dd, J = 12.1, 4.9 Hz, 1 H), 3.52 (dd, J = 10.3, 3.4 Hz, 1 H), 3.39 - 3.30 (m, 3H), 2.14 - 2.08 (m, 2H), 1.97 - 1.90 (m, 4H), 1.52 (d, J = 7.6 Hz, 2H), 1.22 (d, J = 35.0 Hz, 54H), 0.80 (t, J = 6.8 Hz, 6H); 13 C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.3, 134.1, 132.7, 132.1, 128.8, 99.8, 73.0, 69.7, 68.9, 67.9, 67.6, 65.4, 57.7, 55.8, 53.6, 38.8, 38.6, 38.5, 37.2, 36.5, 36.0, 34.7, 34.7, 32.3, 32.2, 31.9, 31.8, 29.8, 29.7, 29.6, 29.5, 29.3, 29.2, 28.9, 27.4 (2C), 26.8, 26.7, 26.3, 26.1, 25.8, 25.6, 25.4, 22.6, 17.8, 14.0 (2C); HRMS (ESI - QTOF) calcd for C 48 H 91 NO9: [M + Na] + , 848.6586; found: 848.6594.

[0218] Compound 1 - 4d To a stirred solution of compound 1-14-1b (8.9 mg, 18.3 μmol) and compound 1-17d (7.0 mg, 18.3 μmol) in EtOH (172 μL) and CHCl (57 μL) at room temperature, DMT-MM (OTf) (7.9 mg, 20.1 μmol) was added. The mixture was stirred at room temperature for 22 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-4d (2.1 mg, 14%) as a white solid.

[0219] 1 H NMR (CDCl3 / CD3OD = 10 / 1) δ 5.44-5.70 (2H), 5.28-5.42 (2H), 4.08-4.16 ( 1 H), 3.99-4.09 (2H), 3.86-3.97 (2H), 3.81-3.86 ( 1 H), 3.73-3.80 ( 1 H), 3.62-3.72 ( 1 H), 3.39-3.57 (3H), 3.27-3.34 ( 1 H), 2.00-2.15 (2H), 1.85-2.00 (4H), 1.43-1.57 (2H), 1.08-1.32 (54H), 0.71-0.86 (6H); 13C NMR (CDCl3 / CD3OD = 10 / 1) δ 174.4, 132.8, 132.2, 128.9, 128.6, 103.7, 73.3, 73.1, 72.4, 71.3, 69.1, 68.8, 61.8, 58.5, 53.2, 37.2, 36.6, 32.4, 32.2, 31.9, 31.8, 31.3, 30.8, 30.3, 29.9, 29.7 (2C), 29.5, 29.4, 29.3, 29.2, 28.9, 28.0, 27.2, 26.8, 26.4, 26.2, 25.9, 25.8, 25.5, 24.8, 24.7, 24.2, 23.9, 22.7, 22.3, 14.1 (2C); HRMS (ESI-QTOF) calcd for C 48 H 91 NO9: [M+Na] + , 848.6586; found: 848.6595.

[0220] Compound 1-1e To a stirred solution of compound 1-14-1a (15.1 mg, 32.6 μmol) and compound 1-17e (10.4 mg, 34.5 μmol) in EtOH (310 μL) and CHCl (100 μL) at room temperature, DMT-MM (OTf) (15.6 mg, 40.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1e (10.1 mg, 42%) as a white solid.

[0221] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.65 - 5.58 (m, 1H), 5.35 (dd, J = 15.5, 7.4 Hz, 1H), 4.72 (t, J = 3.7 Hz, 1H), 4.19 (t, J = 2.9 Hz, 1H), 4.00 (t, J = 7.7 Hz, 1H), 3.85 (t, J = 4.0 Hz, 1H), 3.67 (J = 3.4 Hz, d, 2H), 3.59 - 3.50 (m, 1H), 3.44 (dq, J = 13.7, 4.2 Hz, 1H), 3.31 (dd, J = 9.6, 3.6 Hz, 1H), 2.15 - 2.07 (m, 2H), 1.93 (t, J = 7.1 Hz, 2H), 1.50 (m, 2H), 1.41 - 1.19 (m, 48H), 0.84 (dq, J = 24.3, 6.2 Hz, 10H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 135.1, 130.6, 100.9, 77.1, 75.0, 73.9, 73.6, 72.4, 71.6, 68.7, 62.5, 55.2, 40.3, 38.5 (2C), 37.3, 33.5, 33.1 (2C), 31.7, 30.9 (5C), 30.8 (FC), 30.7 (2C), 30.6, 30.5 (2C), 30.4, 27.1, 26.9, 26.7, 23.8, 14.5, 11.4; HRMS (ESI-QTOF) calcd for C 42 1H 81 29O9: [M+Na] + , 766.5804; found: 766.5805.

[0222] Compound 1 - 2e To a stirred solution of compound 1-14-1b (20.6 mg, 44.6 μmol) and compound 1-17e (8.04 mg, 26.8 μmol) in EtOH (420 μL) and CHCl (140 μL) at room temperature, DMT-MM (OTf) (15.6 mg, 40.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2e (11.5 mg, 58%) as a white solid.

[0223] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.62-5.55 (m, 1H), 5.39-5.32 (m, 1H), 4.19 (dd, J = 5.6, 1.1 Hz, 1H), 4.16 (d, J = 7.9 Hz, 1H), 4.05 (dd, J = 10.1, 4.7 Hz, 1H), 3.97 (t, J = 8.0 Hz, 1H), 3.90 (dd, J = 11.0, 6.3 Hz, 1H), 3.77 (d, J = 11.0 Hz, 1H), 3.56 (dd, J = 11.7, 5.4 Hz, 1H), 3.51 (dd, J = 10.0, 3.3 Hz, 1H), 3.39 (d, J = 6.1 Hz, 1H), 3.29-3.09 (m, 3H), 2.08 (t, J = 7.5 Hz, 2H), 1.92 (t, J = 7.0 Hz, 2H), 1.45 (dd, J = 21.5, 13.9 Hz, 2H), 1.39-1.19 (m, 48H), 0.84 (dq, J = 24.3, 6.2 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 135.0, 131.3, 104.7, 78.0, 77.1, 75.2, 73.1, 72.4, 71.6, 69.9, 68.7, 62.7, 38.5 (2C), 37.4, 33.5, 33.1, 31.7, 31.1, 30.9 (3C), 30.8 (3C), 30.7, 30.5 (3C), 30.4, 30.2, 27.1, 26.9, 26.8 (2C), 26.7, 25.1, 24.0, 23.8, 14.5, 14.4; HRMS (ESI-QTOF) calcd for C 42 H 81 O9: [M+Na] + , 766.5804; found: 766.5805.

[0224] Compound 1-1f To a stirred solution of compound 1-14-1a (15.1 mg, 32.6 μmol) and compound 1-17f (8.18 mg, 27.2 μmol) in EtOH (310 μL) and CHCl (100 μL) at room temperature, DMT-MM (OTf) (15.6 mg, 40.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1f (8.38 mg, 41%) as a white solid.

[0225] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.74 - 5.67 (m, 1H), 5.44 (dd, J = 15.1, 7.3 Hz, 1H), 4.82 (d, J = 3.9 Hz, 1H), 4.09 (t, J = 7.8 Hz, 1H), 3.95 (t, J = 7.1 Hz, 1H), 3.77 (dd, J = 10.7, 2.9 Hz, 4H), 3.67 - 3.62 (m, 2H), 3.53 (dt, J = 9.4, 3.3 Hz, 1H), 3.49 (m, 1H), 3.40 (dd, J = 9.5, 3.7 Hz, 1H), 2.18 (t, J = 7.6 Hz, 2H), 2.03 (q, J = 6.8 Hz, 2H), 1.58 (m, 2H), 1.42 - 1.28 (m, 48H), 0.89 (t, J = 6.8 Hz, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 135.0, 131.3, 100.9, 77.1 (2C), 75.0, 73.9, 72.6, 72.4, 71.6, 72.4, 71.6, 62.5, 55.2, 38.5, 37.4, 33.5, 33.1 (2C), 30.9 (6C), 30.8 (4C), 30.7 (2C), 30.6 (2C), 30.5 (4C), 30.4, 27.2, 26.9, 23.8, 14.5 (2C); HRMS (ESI-QTOF) calcd for C 42 H 81 O9: [M+Na] + , 766.5804; found: 766.5805.

[0226] Compound 1-2f To a stirred solution of compound 1-14-1b (19.5 mg, 42.3 μmol) and compound 1-17f (10.2 mg, 33.8 μmol) in EtOH (400 μL) and CHCl (130 μL) at room temperature, DMT-MM (OTf) (15.6 mg, 40.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2f (7.5 mg, 30%) as a white solid.

[0227] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 5.62-5.55 (m, 1H), 5.35 (dd, J = 15.4, 7.7 Hz, 1H), 4.16 (d, J = 7.6 Hz, 1H), 4.06 (dd, J = 10.1, 4.9 Hz, 1H), 3.97 (t, J = 8.0 Hz, 1H), 3.87 (td, J = 8.5, 3.9 Hz, 1H), 3.77 (d, J = 10.3 Hz, 1H), 3.55 (t, J = 5.9 Hz, 1H), 3.50 (dd, J = 10.1, 3.1 Hz, 1H), 3.22-3.20 (m, 2H), 3.17 (dd, J = 6.3, 5.2 Hz, 2H), 3.11 (dd, J = 9.1, 7.7 Hz, 1H), 2.07 (t, J = 7.5 Hz, 2H), 1.96-1.90 (m, 2H), 1.48 (m 2H), 1.33-1.19 (m, 48H), 0.80 (t, J = 6.7 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 135.0, 131.3, 104.7, 78.0, 77.9, 75.2, 73.1, 72.4, 71.6, 69.9, 62.7, 54.8, 38.5, 37.4, 33.5, 33.1 (2C), 30.9 (5C), 30.8 (3C), 30.7, 30.6 (2C), 30.5 (4C), 30.4 (2C), 27.2, 26.9 (2C), 23.8 (2C), 14.5 (2C); HRMS (ESI-QTOF) calcd for C 42 H 81 O9: [M+Na] + , 766.5804; found: 766.5805.

[0228] Compound 1-1g To a stirred solution of compound 1-14-1a (15.7 mg, 33.9 μmol) and compound 1-17g (20.1 mg, 67.8 μmol) in EtOH (320 μL) and CHCl (110 μL) at room temperature, DMT-MM (OTf) (21.1 mg, 74.6 μmol) was added. The mixture was stirred at room temperature for 19 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1g (6.8 mg, 27%) as a colorless oil.

[0229] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 6.39 (dd, J = 15.1, 11.1 Hz, 1H), 5.88 (t, J = 11.0 Hz, 1H), 5.64 - 5.49 (m, 2H), 5.33 (dt, J = 25.0, 8.4 Hz, 2H), 4.73 (d, J = 3.6 Hz, 1H), 4.01 (tt, J = 17.7, 5.9 Hz, 2H), 3.77 (d, J = 10.5 Hz, 1H), 3.68 (dd, J = 11.3, 3.0 Hz, 1H), 3.51 (ddt, J = 30.9, 17.6, 6.0 Hz, 3H), 3.20 (dtt, J = 40.3, 18.2, 5.7 Hz, 4H), 2.08 (dd, J = 12.0, 7.3 Hz, 2H), 1.93 (m, 2H), 1.49 (m, 4H), 1.23 (t, J = 17.4 Hz, 38H), 0.80 (td, J = 6.8, 3.2 Hz, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 137.4, 135.0, 132.9, 131.3, 129.4, 126.5, 100.9, 78.0, 77.9, 77.1 (2C), 75.2, 73.6, 73.4, 71.6, 56.2, 38.5, 37.3, 33.5, 33.1, 33.0 (2C), 30.9, 30.8 (5C), 30.5 (2C), 30.4 (2C), 30.2 (2C), 28.7, 27.1, 26.3, 23.8, 23.7, 14.5, 14.4; HRMS (ESI-QTOF) calcd for C 42 1H 77 9O: [M+Na] + , 762.5491; found: 762.5492.

[0230] Compound 1-2g To a stirred solution of compound 1-14-1b (19.4 mg, 41.9 μmol) and compound 1-17g (24.8 mg, 83.8 μmol) in EtOH (390 μL) and CHCl (130 μL) at room temperature, DMT-MM(OTf) (28.5 mg, 73.0 μmol) was added. The mixture was stirred at room temperature for 19 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2g (10.1 mg, 32%) as a colorless oil.

[0231] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 6.39 (dd, J = 15.3, 11.0 Hz, 1H), 5.88 (t, J = 11.1 Hz, 1H), 5.56 (tt, J = 22.8, 7.2 Hz, 2H), 5.38-5.27 (m, 2H), 4.16 (d, J = 7.6 Hz, 1H), 4.05 (dd, J = 10.1, 4.9 Hz, 1H), 4.00-3.95 (m, 2H), 3.77 (d, J = 10.3 Hz, 1H), 3.58-3.54 (m, 1H), 3.50 (dd, J = 10.1, 3.4 Hz, 1H), 3.26 (td, J = 8.6, 5.2 Hz, 1H), 3.22 (dt, J = 6.1, 2.5 Hz, 2H), 3.17 (dd, J = 6.6, 5.3 Hz, 1H), 3.14-3.09 (m, 1H), 2.12-2.08 (m, 2H), 1.96-1.89 (m, 2H), 1.48 (d, J = 7.0 Hz, 4H), 1.29-1.19 (m, 38H), 0.81 (td, J = 6.8, 3.3 Hz, 6H); 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.0, 137.4, 135.0, 132.9, 131.3, 129.4, 126.5, 104.7, 77.9, 77.1, 75.2, 73.4, 71.6, 62.7, 56.3, 54.9, 54.8, 38.5, 37.4, 37.3, 33.5, 33.1, 33.0, 30.9, 30.8 (3C), 30.7 (2C), 30.5 (2C), 30.4 (2C), 30.3, 30.2, 28.7, 27.1, 26.3, 23.8, 23.7, 14.5, 14.4; HRMS (ESI-QTOF) calcd for C 42 H 77 O9: [M+Na] + , 762.5491; found:762.5489.

[0232] Compound 1-1h To a stirred solution of compound 1-14-1a (15.3 mg, 33.2 μmol) and compound 1-17h (19.7 mg, 66.4 μmol) in EtOH (310 μL) and CHCl (100 μL) at room temperature, DMT-MM(OTf) (28.5 mg, 73.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-1h (8.6 mg, 35%) as a colorless oil.

[0233] 11H-NMR (CDCl3 / CD3OD = 3 / 1) δ 6.39 (tt, J = 12.6, 4.2 Hz, 1H), 5.88 (t, J = 10.8 Hz, 1H), 5.65 - 5.58 (m, 1H), 5.51 (dd, J = 15.3, 6.7 Hz, 1H), 5.38 - 5.28 (m, 2H), 4.7 (t, J = 12.3 Hz, 1H), 4.02 - 3.95 (m, 1H), 3.85 (dd, J = 10.8, 6.3 Hz, 1H), 3.68 (dd, J = 11.4, 2.9 Hz, 2H), 3.59 - 3.53 (m, 1H), 3.45 (dq, J = 9.9, 2.5 Hz, 1H), 3.31 (dd, J = 9.6, 3.8 Hz, 1H), 3.18 (dq, J = 14.4, 4.3 Hz, 4H), 2.12 - 2.06 (m, 2H), 1.94 (dd, J = 13.8, 6.6 Hz, 2H), 1.49 - 1.39 (m, 4H), 1.33 - 1.15 (m, 38H), 0.80 (td, J = 6.8, 2.0 Hz, 6H); 13 13C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.1, 137.3, 135.0, 133.0, 131.3, 129.3, 126.5, 100.9, 77.1, 75. 1, 73.9, 73.6, 73.4, 72.7, 71.6, 62.5, 56.4, 38.5, 38.4, 33.5, 33.1, 32.6 (2C), 30.9, 30.8 (2C), 30.6, 30.5 (3C), 30.4, 30.2, 28.6 (2C), 27.1, 26.6, 26.5, 26.2, 23.8, 23.6, 14.5, 14.4; HRMS (ESI-QTOF) calcd for C 42 1H 77 19O9: [M+Na] + , 762.5491; found: 762.5492.

[0234] Compound 1-2h To a stirred solution of compound 1-14-1b (20.5 mg, 44.4 μmol) and compound 1-17h (26.3 mg, 88.8 μmol) in EtOH (420 μL) and CHCl (140 μL) at room temperature, DMT-MM(OTf) (28.5 mg, 73.0 μmol) was added. The mixture was stirred at room temperature for 17 hours. The reaction was quenched with saturated aqueous NaHCO, and the whole was extracted with EtOAc, washed with saturated aqueous NaHCO and brine, dried over anhydrous NaSO, filtered, and concentrated under reduced pressure to give a residue. This was purified by silica gel column chromatography (CHCl / MeOH = 7 / 1 → 5 / 1) to give 1-2h (10.0 mg, 30%) as a colorless oil.

[0235] 1 H-NMR (CDCl3 / CD3OD = 3 / 1) δ 6.39 (dd, J = 15.3, 11.0 Hz, 1H), 5.88 (t, J = 11.2 Hz, 1H), 5.55 (tt, J = 20.0, 6.6 Hz, 2H), 5.38-5.28 (m, 2H), 4.16 (d, J = 7.6 Hz, 1H), 4.05 (dd, J = 10.0, 4.8 Hz, 1H), 3.99-3.95 (m, 2H), 3.90 (dd, J = 10.3, 6.7 Hz, 1H), 3.77 (d, J = 11.7 Hz, 1H), 3.57-3.49 (m, 2H), 3.29-3.09 (m, 4H), 2.18-2.06 (m, 2H), 1.93 (dd, J = 15.0, 8.1 Hz, 2H), 1.44 (t, J = 19.6 Hz, 4H), 1.24 (tt, J = 24.1, 11.2 Hz, 38H), 0.80 (td, J = 6.9, 2.2 Hz, 6H); 1313C-NMR (CDCl3 / CD3OD = 3 / 1) δ 176.1, 137.3, 135.0, 133.0, 131.3, 129.3, 126.5, 104.7, 78.0, 77.1, 75.2, 73.4, 73.1, 71.6, 69.9, 62.7, 54.8, 38.5, 37.4, 37.3, 33.4, 33.1, 32.6, 30.9, 30.8 (5C), 30.6 (3C), 30.5, 30.4, 28.6, 27.1, 26.6, 26.5, 23.8, 23.6, 14.5, 14.4; HRMS (ESI-QTOF) calcd for C 42 H 77 NO9: [M+Na] + , 762.5491; found: 762.5490.

[0236] <KRN7000-type GalCer(NO2)>

[0237]

Chem.

[0238]

Chem.

[0239]

Chem.

[0240] Compound 2-14a 2-13a (8.00 g, 24.9 mmol) was dissolved in 80 mL of dichloromethane and the solution was cooled to 0 °C. Trifluoroacetic anhydride (7.62 mL, 54.8 mmol) was added dropwise to the solution at 0 °C, and the mixture was stirred at room temperature for 2 h. t-Butanol (8.52 mL, 89.6 mmol) was then added to the reaction solution, and the mixture was stirred for an additional 2 h. Water was added to quench the reaction, followed by extraction with dichloromethane and washing with saturated brine. The mixture was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-14a as a white solid (8.26 g, 88% yield).

[0241] 1 H-NMR (400 MHz, CDCl3) δ 3.40 (t, J = 7.0 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.88-1.81 (m, 2H), 1.44-1.39 (m, 12H), 1.26 (d, J = 7.2 Hz, 19H); 13 C-NMR (100 MHz, CDCl3) δ 173.5, 80.0, 35.7, 34.2, 32.9, 29.7 (2C), 29.6 (4C), 29.5 (2C), 29.4, 29.2, 28.9, 28.3, 28.2, 25.2; HRMS (ESI-QTOF) calcd for C 19 H 37 BrNaO2: [M+Na] + , 399.1869; found: 399.1871.

[0242] [ka]

[0243] Compound 2-14b 2-13b (3.22 g, 11.0 mmol) was dissolved in 36 mL of dichloromethane and the solution was cooled to 0 °C. Trifluoroacetic anhydride (3.37 mL, 24.2 mmol) was added dropwise to the solution at 0 °C, and the mixture was stirred at room temperature for 2 h. t-Butanol (3.76 mL, 39.6 mmol) was then added to the reaction solution, and the mixture was stirred for an additional 2 h. Water was added to quench the reaction, followed by extraction with dichloromethane and washing with saturated brine. The mixture was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-14b as a white solid (3.47 g, 90% yield).

[0244] 1 H-NMR (400 MHz, CDCl3) δ 3.40 (t, J = 7.0 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 1.88-1.80 (m, 2H), 1.59-1.52 (m, 2H), 1.47-1.37 (m, 10H), 1.26 (s, 17H); 13 C-NMR (100 MHz, CDCl3) δ 173.4, 80.0, 35.7, 34.2, 32.9, 29.6 (4C), 29.5 (2C), 29.4, 29.2, 28.9, 28.3, 28.2, 25.2; HRMS (ESI-QTOF) calcd for C 17 H 33 BrNaO2: [M+Na] + , 371.1556; found: 371.1561.

[0245] [ka]

[0246] Compound 2-14c 12-Bromododecanoic acid (2-13c, 2.50 g, 8.95 mmol) was dissolved in 30 mL of dichloromethane and the solution was cooled to 0 °C. Trifluoroacetic anhydride (2.80 mL, 19.7 mmol) was added dropwise to the solution at 0 °C, and the mixture was stirred at room temperature for 2 h. t-Butanol (3.10 mL, 32.2 mmol) was then added to the reaction solution, and the mixture was stirred for an additional 2 h. Water was added to quench the reaction, followed by extraction with dichloromethane and washing with saturated brine. The mixture was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-14c as a white solid (3.02 g, quantitative yield).

[0247] 1 H NMR (400 MHz, CDCl3) δ 3.41 (t, J = 6.8 Hz, 2H), 2.20 (t, J = 7.3 Hz, 2H), 1.89-1.82 (m, 2H), 1.63-1.57 (m, 4H), 1.46-1.43 (m, 12H), 1.29-1.26 (m, 9H).

[0248] [ka]

[0249] Compound 2-14d 11-Bromoundecanoic acid (2-13d, 5.00 g, 18.8 mmol) was dissolved in 60 mL of dichloromethane and the solution was cooled to 0 °C. Trifluoroacetic anhydride (5.80 mL, 41.5 mmol) was added dropwise to the solution at 0 °C, and the mixture was stirred at room temperature for 2 h. tert-Butanol (6.50 mL, 67.9 mmol) was then added to the reaction solution, and the mixture was stirred for an additional 2 h. Water was added to quench the reaction, followed by extraction with dichloromethane and washing with saturated brine. The mixture was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-14d as a white solid (5.44 g, 90% yield).

[0250] 1 H NMR (400 MHz, CDCl3) δ 3.41 (t, J = 6.8 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.89-1.82 (m, 2H), 1.59-1.57 (m, 2H), 1.47-1.42 (m, 12H), 1.34-1.25 (m, 9H).

[0251] [ka]

[0252] Compound 2-14e 9-Bromonoic acid (2-13e, 528 mg, 2.23 mmol) was dissolved in 7.5 mL of dichloromethane and the solution was cooled to 0 °C. Trifluoroacetic anhydride (681 mL, 4.90 mmol) was added dropwise to the solution at 0 °C, and the mixture was stirred at room temperature for 2 h. tert-Butanol (763 mL, 8.03 mmol) was then added to the reaction solution, and the mixture was stirred for an additional 2 h. Water was added to quench the reaction, followed by extraction with dichloromethane and washing with saturated brine. The mixture was dried over sodium sulfate, concentrated under reduced pressure, and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-14e as a white solid (644 mg, 99% yield).

[0253] 1 H NMR (400 MHz, CDCl3) δ 3.41 (t, J = 6.8 Hz, 2H), 2.20 (t, J = 7.6 Hz, 2H), 1.89-1.81 (m, 2H), 1.57 (t, J = 6.6 Hz, 2H), 1.43 (d, J = 8.3 Hz, 8H), 1.31 (s, 9H).

[0254] [ka]

[0255] Compound 2-7a 2-14a (3.53 g, 9.35 mmol) and sodium iodide (2.11 g, 14.1 mmol) were dissolved in 37 mL of acetone. The mixture was refluxed for 24 h in the dark, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1). Silver nitrite (5.71 g, 37.1 mmol) was added and dissolved in 37 mL of water. The mixture was stirred at 60 °C in the dark for 24 h, then ethyl acetate was added and filtered. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-7a as a white solid (1.27 g, 40% yield).

[0256] 1 H-NMR (400 MHz, CDCl3) δ 4.38 (t, J = 7.1 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 2.04-1.97 (m, 2H), 1.44 (s, 10H), 1.36-1.25 (m, 21H); 13C-NMR (100 MHz, CDCl3) δ 173.5, 80.0, 35.7, 29.7 (3C), 29.5 (2C), 29.4 (2C), 29.3 (2C), 29.2 (2C), 28.9, 28.2, 27.5, 26.3, 25.2; HRMS (ESI-QTOF) calcd for C 19 H 37 NNaO4: [M+Na] + , 366.2615; found: 366.2623.

[0257] [ka]

[0258] Compound 2-7b 2-14b (3.22 g, 9.21 mmol) and sodium iodide (2.07 g, 13.8 mmol) were dissolved in 40 mL of acetone. The mixture was refluxed for 24 h in the dark, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1). Silver nitrite (5.67 g, 36.8 mmol) was added and dissolved in 40 mL of water. The mixture was stirred at 60 °C for 24 h in the dark, then ethyl acetate was added and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-7b as a white solid (1.51 g, 52% yield).

[0259] 1 H-NMR (400 MHz, CDCl3) δ 4.37 (t, J = 7.1 Hz, 2H), 2.19 (t, J = 7.5 Hz, 2H), 2.03-1.96 (m, 2H), 1.45-1.42 (m, 10H), 1.40-1.25 (m, 17H); 13 C-NMR (100 MHz, CDCl3) δ 173.4, 80.0, 35.7, 29.6 (3C), 29.5 (2C), 29.4 (2C), 29.3, 29.2, 28.9, 28.2, 27.5, 26.3, 25.2; HRMS (ESI-QTOF) calcd for C 17 H 33 NNaO4: [M+Na] + , 338.2302; found: 338.2310.

[0260] [ka]

[0261] Compound 2-7d 2-14d (4.00 g, 12.4 mmol) and sodium iodide (2.79 g, 18.7 mmol) were dissolved in 50 mL of acetone. The mixture was refluxed for 24 h in the dark, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added and the mixture was filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1). Silver nitrite (7.63 g, 49.6 mmol) was added and dissolved in 50 mL of water. The mixture was stirred at 60 °C in the dark for 24 h, then ethyl acetate was added and the mixture was filtered. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-7d as a white solid (2.65 g, 74% yield).

[0262] 1 H NMR (400 MHz, CDCl3) δ 4.38 (t, J = 7.1 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 2.03-1.98 (m, 2H), 1.63-1.53 ​​(m, 2H), 1.52-1.41 (m, 6H), 1.40-1.24 (m, 15H); 13 C NMR (100 MHz, CDCl3) δ 173.3, 79.9, 35.6, 29.2 (3C), 28.9 (4C), 28.8, 28.1, 27.4, 26.2, 25.0; HRMS (ESI-QTOF) calcd for C 15 H 29 NNaO4: [M+Na] + , 310.1989; found: 310.1998.

[0263] [ka]

[0264] Compound 2-7e 2-14e (500 mg, 1.71 mmol) and sodium iodide (383 mg, 2.56 mmol) were dissolved in 70 mL of acetone. The mixture was refluxed for 24 h in the dark, cooled to room temperature, and concentrated under reduced pressure. Ethyl acetate was added and filtered. The filtrate was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1). Silver nitrite (1.02 g, 6.64 mmol) was added and dissolved in 70 mL of water. The mixture was stirred at 60 °C for 24 h in the dark, then ethyl acetate was added and filtered. The filtrate was extracted with ethyl acetate, and the extract was washed with saturated brine and dried over sodium sulfate. The mixture was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-7e as a white solid (344 mg, 78% yield).

[0265] 1 H NMR (400 MHz, CDCl3) δ: 4.38 (t, J = 7.1 Hz, 2H), 2.20 (t, J = 7.4 Hz, 2H), 2.05-1.97 (m, 2H), 1.59-1.55 (m, 2H), 1.45-1.44 (m, 8H), 1.41-1.24 (m, 9H); 13 C NMR (100 MHz, CDCl3) δ 173.2, 79.9, 35.5, 28.9, 28.8, 28.6 (4C), 28.1, 27.3, 26.1, 25.0; HRMS (ESI-QTOF) calcd for C 13 H 25 NNaO4: [M+Na] + , 282.1676; found: 282.1685.

[0266] [ka]

[0267] Compound 2-8a 2-14a (3.00 g, 7.95 mmol), sodium bicarbonate (668 mg, 7.95 mmol), and sodium iodide (1.2-10 g, 7.76 mmol) were dissolved in 40 mL of DMSO and stirred at 120 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, and diethyl ether and saturated aqueous sodium bicarbonate were added. The solution was extracted with n-hexane-ethyl acetate (4:1). The extract was washed with saturated brine and water, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-8a as a colorless oil (1.75 g, 71% yield).

[0268] 1 H-NMR (400 MHz, CDCl3) δ 9.77 (t, J = 1.9 Hz, 1H), 2.42 (td, J = 7.3, 1.9 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.60 (qd, J = 14.7, 7.4 Hz, 4H), 1.40-1.25 (m, 27H); 13 C-NMR (100 MHz, CDCl3) δ 203.1, 173.4, 80.0, 44.0, 35.7, 29.7 (2C), 29.5 (2C), 29.4 (2C), 29.2 (2C), 28.2 (2C), 25.2 (2C), 22.2 HRMS (ESI-QTOF) calcd for C 19 H 36 NaO3: [M+Na] + , 335.2557; found: 335.2561.

[0269] [ka]

[0270] Compound 2-8c 2-14c (1.20 g, 3.58 mmol), sodium bicarbonate (300 mg, 3.58 mmol), and sodium iodide (536 mg, 3.58 mmol) were dissolved in 15 mL of DMSO and stirred at 120 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature and diluted with diethyl ether and saturated aqueous sodium bicarbonate. The solution was extracted with n-hexane-ethyl acetate (4:1). The extract was washed with saturated brine and water, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-8c as a colorless oil (630 mg, 65% yield).

[0271] 1 H NMR (400 MHz, CDCl3) δ 9.75 (s, 1H), 2.42 (t, J = 7.5 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.62-1.56 (m, 6H), 1.48-1.40 (m, 4H), 1.39-1.27 (m, 15H).

[0272] [ka]

[0273] Compound 2-8e 2-14e (1.49 g, 5.08 mmol), sodium bicarbonate (427 mg, 5.08 mmol), and sodium iodide (761 mg, 5.08 mmol) were dissolved in 25 mL of DMSO and stirred at 120 °C for 5 h. After the reaction was complete, the mixture was cooled to room temperature, and diethyl ether and saturated aqueous sodium bicarbonate solution were added. The whole was extracted with n-hexane-ethyl acetate (4:1). The extract was washed with saturated brine and water, dried over sodium sulfate, and concentrated under reduced pressure. This was purified by silica gel column chromatography using n-hexane-ethyl acetate (20:1) to give 2-8e as a colorless oil (1.06 g, 91% yield).

[0274] 1 H NMR (400 MHz, CDCl3) δ 1 H-NMR (CDCl3) δ: 9.77 (s, 1H), 2.43 (t, J = 7.3 Hz, 2H), 2.20 (t, J = 7.5 Hz, 2H), 1.61-1.54 (m, 5H), 1.51-1.38 (m, 6H), 1.37-1.24 (m, 8H).

[0275] <General Procedure for the Synthesis of Compounds 2-11>

[0276] [ka]

[0277] 2-7, 2-9, triethylamine, 1,2-dichloroethane, and lithium bromide were added in this order to a microwave-safe glass vial. The mixture was stirred for 30 seconds and then heated to 80 °C using 300 W of microwave irradiation. After stirring for 20 minutes, the mixture was cooled to room temperature, dichloromethane was added, and the solvent was washed three times with water. The combined aqueous layers were extracted with dichloromethane and dried over sodium sulfate. The extract was concentrated, dichloromethane was added, and the solution was cooled to 0 °C. Martin's sulfurane dissolved in dichloromethane was added to this, and the mixture was stirred at 0 °C for an additional 10 minutes, then returned to room temperature and stirred for 3 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (24:1). Dichloromethane, followed by TFA, was added to this and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated by azeotropy with toluene and purified by silica gel column chromatography using n-hexane-ethyl acetate (4:1) to obtain compound 2-11.

[0278] [ka]

[0279] Compound 2-11a 2-11a was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7a (477.5 mg, 1.39 mmol), 2-9d (nonanal, 95.3 μL, 0.556 mmol), triethylamine (116 μL, 0.863 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 560.9 mg (0.863 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 30 mL of dichloromethane and 6.0 mL of TFA were used to obtain compound 2-11a as a yellow oil (138.7 mg, yield: 61%).

[0280] 1 H-NMR (400 MHz, CDCl3) δ 7.07 (t, J = 8.0 Hz, 1H), 2.56 (t, J = 7.5 Hz, 2H), 2.35 (t, J = 7.5 Hz, 2H), 2.21 (q, J = 7.6 Hz, 2H), 1.66-1.59 (m, 2H), 1.50-1.43 (m, 4H), 1.30-1.24 (m, 28H), 0.88 (t, J = 6.8 Hz, 3H); 13 C-NMR (100 MHz, CDCl3) δ 179.2, 152.0, 136.6, 77.4, 77.1, 76.8, 33.9, 31.9, 29.7, 29.6, 29.5, 29.4, 29.4, 29.3, 29.3, 29.1, 28.6, 28.1, 28.0, 26.4, 24.8, 22.7, 14.2; HRMS (ESI-QTOF) calcd for C 24 H 44NO4: [MH] - , 410.3276; found: 410.3283.

[0281] [ka]

[0282] Compound 2-11b 2-11b was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7b (438.5 mg, 1.39 mmol), 2-9c (110.3 mg, 0.556 mmol), triethylamine (116 μL, 0.863 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 560.9 mg (0.863 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 30 mL of dichloromethane and 6.0 mL of TFA were used to obtain compound 2-11b as a yellow oil (131.8 mg, yield: 54%).

[0283] 1 H-NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.9 Hz, 1H), 2.56 (t, J = 7.5 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.20 (q, J = 7.6 Hz, 2H), 1.66-1.59 (m, 2H), 1.50-1.45 (m, 4H), 1.25 (m, 32H), 0.87 (t, J = 6.8 Hz, 3H); 13C-NMR (100 MHz, CDCl3) δ 179.2, 151.9, 136.6, 34.0, 32.0, 29.7 (3C), 29.6 (4C), 29.4 (3C), 29.3 (2C), 29.1 (2C), 28.6, 28.1, 28.0, 26.4, 24.8, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 26 H 48 NO4: [MH] - , 438.3589; found: 438.3596.

[0284] [ka]

[0285] Compound 2-11c 2-11c was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7b (438.5 mg, 1.39 mmol), 2-9f (heptanal, 78.4 μL, 0.556 mmol), triethylamine (116 μL, 0.863 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 560.9 mg (0.863 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 30 mL of dichloromethane and 6.0 mL of TFA were used to obtain compound 2-11c as a yellow oil (108.7 mg, yield: 55%).

[0286] 13C-NMR (100 MHz, CDCl3) δ 179.8, 152.0, 136.6, 34.1, 31.6, 29.6 (3C), 29.5 (2C), 29.3 (2C), 29.1 (2C), 28.6, 28.1, 28.0, 26.4, 24.7, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 20 H 36 NO4: [MH] - , 354.2650; found: 354.2658.

[0287] [ka]

[0288] Compound 2-11d 2-11d was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7b (438.5 mg, 1.39 mmol), 2-9h (pentanal, 59.1 μL, 0.556 mmol), triethylamine (116 μL, 0.863 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 560.9 mg (0.863 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 30 mL of dichloromethane and 6.0 mL of TFA were used to obtain compound 2-11c as a yellow oil (108.7 mg, yield: 55%).

[0289] 1H-NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.9 Hz, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.22 (q, J = 7.5 Hz, 2H), 1.61 (q, J = 7.3 Hz, 2H), 1.51-1.26 (m, 20H), 0.93 (t, J = 7.2 Hz, 3H); 13 C-NMR (100 MHz, CDCl3) δ 179.6, 152.0, 136.5, 34.0, 30.7, 29.6 (2C), 29.5 (3C), 29.3, 29.1, 28.0, 27.8, 26.4, 24.7, 22.5, 13.9; HRMS (ESI-QTOF) calcd for C 18 H 32 NO4: [MH] - , 326.2337; found: 326.2332.

[0290]

change

[0291] Compound 2-11e 2-11e was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7d (811.0 mg, 2.83 mmol), 2-9a (251.6 mg, 1.11 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 50 mL of dichloromethane and 10 mL of TFA were used to obtain compound 2-11e as a yellow oil (227.3 mg, yield: 47%).

[0292] 1 H-NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.9 Hz, 1H), 2.55 (t, J = 7.7 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.20 (q, J = 7.6 Hz, 2H), 1.65-1.58 13C-NMR (100 MHz, CHLOROFORM-D) δ 179.7, 151.9, 136.6, 34.0, 32.0, 29.7 (3C), 29.6 (4C), 29.5 (2C), 29.4 (2C), 29.3 (2C), 29.1, 28.6, 28.1, 28.0, 26.4, 24.7, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 26 H 48 NO4: [MH] - , 438.3589; found: 438.3596.

[0293] [ka]

[0294] Compound 2-11f 2-11f was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7d (580 mg, 2.02 mmol), 2-9d (nonanal, 140 μL, 0.807 mmol), triethylamine (168 μL, 1.21 mmol), 1,2-dichloroethane (480 μL), and LiBr (35.1 mg, 0.404 mmol). For the second step, the residue obtained by concentration was dissolved in 22.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 814 mg (1.21 mmol) of Martin's sulfurane in 3.2 mL of dichloromethane. For the third step, 40 mL of dichloromethane and 8.0 mL of TFA were used to obtain compound 2-11f as a yellow oil (185.7 mg, yield: 64%).

[0295] 1 H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.7 Hz, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.42-2.31 (m, 2H), 2.21 (q, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.50-1.47 (m, 4H), 1.24-1.09 (m, 20H), 0.88 (t, J = 6.6 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 179.8, 151.8, 136.5, 33.9, 31.8, 29.3 (3C), 29.2 (2C), 29.1 (2C), 29.0, 28.5, 28.0, 27.9, 26.3, 24.6, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 20 H 36NO4: [MH] - , 354.2650; found: 354.2652.

[0296] [ka]

[0297] Compound 2-11g 2-11g was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7d (400 mg, 1.39 mmol), 2-9f (heptanal, 77.4 μL, 0.556 mmol), triethylamine (116 μL, 0.834 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 561 mg (0.834 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 37.5 mL of dichloromethane and 7.5 mL of TFA were used to obtain compound 2-11g as a yellow oil (132.3 mg, yield: 73%).

[0298] 1 H NMR (400 MHz, CDCl3) δ 7.09 (t, J = 7.9 Hz, 1H), 2.57 (t, J = 7.6 Hz, 2H), 2.39-2.32 (m, 2H), 2.22 (q, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.53-1.46 (m, 4H), 1.26 (m, 16H), 0.89 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.7, 151.8, 136.5, 33.9, 31.5, 29.2 (3C), 29.1 (2C), 29.0, 28.5, 28.0, 27.9, 26.3, 24.6, 22.5, 14.0; HRMS (ESI-QTOF) calcd for C 18 H 32 NO4: [MH] - , 326.2337; found: 326.2329.

[0299] [ka]

[0300] Compound 2-11h 2-11h was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-7e (361 mg, 1.39 mmol), 2-9d (nonanal, 96.4 μL, 0.556 mmol), triethylamine (116 μL, 0.834 mmol), 1,2-dichloroethane (330 μL), and LiBr (24.2 mg, 0.278 mmol). For the second step, the residue obtained by concentration was dissolved in 15.5 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 561 mg (0.834 mmol) of Martin's sulfurane in 2.2 mL of dichloromethane. For the third step, 25 mL of dichloromethane and 5.0 mL of TFA were used to obtain compound 2-11h as a yellow oil (111.8 mg, yield: 61%).

[0301] 11H NMR (400 MHz, CDCl3) δ: 7.09 (t, J = 7.7 Hz, 1H), 2.57 (t, J = 7.5 Hz, 2H), 2.36 - 2.35 (m, 2H), 2.22 (q, J = 7.2 Hz, 2H), 1.64 - 1.63 (m, 2H), 1.50 - 1.48 (m, 4H), 1.32 - 1.29 (m, 16H), 0.90 - 0.88 (m, 3H); 13 13C NMR (100 MHz, CDCl3) δ 179.7, 151.7, 136.6, 33.9, 31.8, 29.3 (2C), 29.1 (2C), 29.0, 28.9, 28.5, 28.0, 27.8, 26.3, 24.5, 22.6, 14.1; HRMS (ESI - QTOF) calcd for C 18 1H 32 NO4: [M - H] - , 326.2337; found: 326.2341.

[0302] <General procedure for the synthesis of compound 2 - 12>

[0303]

Chem.

[0304] 2-8, 2-10, triethylamine, 1,2-dichloroethane, and lithium bromide were added in this order to a microwave-safe glass vial. The mixture was stirred for 30 seconds and then heated to 80 °C using 300 W of microwave irradiation. After stirring for 20 minutes, the mixture was cooled to room temperature, dichloromethane was added, and the solvent was washed three times with water. The combined aqueous layers were extracted with dichloromethane and dried over sodium sulfate. The extract was concentrated, dichloromethane was added, and the solution was cooled to 0 °C. Martin's sulfurane dissolved in dichloromethane was added to this, and the mixture was stirred at 0 °C for an additional 10 minutes, then returned to room temperature and stirred for 3 hours. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with dichloromethane. The organic layer was washed with saturated brine and dried over sodium sulfate. The solution was concentrated under reduced pressure and purified by silica gel column chromatography using n-hexane-ethyl acetate (24:1). Dichloromethane, followed by TFA, was added to this and the mixture was stirred at room temperature for 2 hours. After the reaction was completed, the solution was concentrated by azeotropy with toluene and purified by silica gel column chromatography using n-hexane-ethyl acetate (4:1) to obtain compound 2-12.

[0305] [ka]

[0306] Compound 2-12a 2-12a was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-10d (481.7 mg, 2.78 mmol), 2-8a (346.9 mg, 1.11 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 20 mL of dichloromethane and 4.0 mL of TFA were used to give compound 2-12a as a yellow oil (174.5 mg, yield: 48%).

[0307] 1 H-NMR (400 MHz, CDCl3) δ 7.07 (t, J = 8.0 Hz, 1H), 2.56 (t, J = 7.6 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.21 (q, J = 7.6 Hz, 2H), 1.62 (q, J = 13C-NMR (99 MHz, CHLOROFORM-D) δ 178.8, 152.0, 136.6, 33.9, 31.9, 29.7, 29.6 (3C), 29.5, 29.4 (2C), 29.3 (3C), 29.1, 28.6, 28.1, 28.0, 26.4, 24.8, 22.7, 14.2; HRMS (ESI-QTOF) calcd for C 24 H 44 NO4: [MH] - , 410.3276; found: 410.3283.

[0308] [ka]

[0309] Compound 2-12b 2-12b was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-10b (676.6 mg, 2.78 mmol), 2-8c (300.8 mg, 1.11 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 30 mL of dichloromethane and 6.0 mL of TFA were used to give compound 2-12b as a yellow oil (174.5 mg, yield: 48%).

[0310] 1 H-NMR (400 MHz, CDCl3) δ 7.07 (t, J = 7.7 Hz, 1H), 2.55 (t, J = 7.7 Hz, 2H), 2.34 (t, J = 7.5 Hz, 2H), 2.20 (q, J = 7.6 Hz, 2H), 1.66-1.58 13C-NMR (100 MHz, CHLOROFORM-D) δ 180.0, 152.0, 136.5, 34.1, 32.0, 29.7 (3C), 29.6 (2C), 29.5 (3C), 29.4 (3C), 29.3 (2C), 29.1, 28.6, 28.1, 28.0, 26.4, 24.7, 22.8, 14.2; HRMS (ESI-QTOF) calcd for C 26 H48 NO4: [MH] - , 438.3589; found: 438.3590.

[0311] [ka]

[0312] Compound 2-12c 2-12c was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-10e (443 mg, 2.78 mmol), 2-8c (301 mg, 1.11 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 40 mL of dichloromethane and 8.0 mL of TFA were used to give compound 2-12c as a yellow oil (123.3 mg, yield: 31%).

[0313] 1 H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.2 Hz, 1H), 2.57 (t, J = 7.0 Hz, 2H), 2.35 (t, J = 7.0 Hz, 2H), 2.22 (q, J = 7.2 Hz, 2H), 1.65-1.63 (m, 2H), 1.49-1.48 (m, 4H), 1.29-1.24 (m, 20H), 0.88 (t, J = 6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 179.7, 151.9, 136.4, 33.9, 31.7, 29.4, 29.3 (3C), 29.2 (2C), 29.0, 28.9, 28.5, 28.0, 27.9, 26.3, 24.6, 22.6, 14.2; HRMS (ESI-QTOF) calcd for C 20 H 36 NO4: [MH] - , 354.2650; found: 354.2647.

[0314] [ka]

[0315] Compound 2-12d 2-12d was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-10g (1-nitrohexane, 388 μL, 2.78 mmol), 2-8c (317.5 mg, 1.17 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 25 mL of dichloromethane and 5.0 mL of TFA were used to give compound 2-12d as a yellow oil (148.5 mg, yield: 41%).

[0316] 1H NMR (400 MHz, CDCl3) δ 7.08 (t, J = 7.9 Hz, 1H), 2.57 (t, J = 7.6 Hz, 2H), 2.37-2.31 (m, 2H), 2.25-2.19 (m, 2H), 1.67-1.60 (m, 2H), 1.53-1.46 (m, 4H), 1.32-1.25 (m, 20H), 0.90 (t, J = 6.8 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 180.0, 151.9, 136.4, 33.4, 31.3, 29.4 (2C), 29.3 (2C), 29.2, 29.0, 28.5, 28.0, 27.6, 26.2, 24.6, 22.3, 13.9; HRMS (ESI-QTOF) calcd for C 18 H 32 NO4: [MH] - , 326.2337; found: 326.2334.

[0317]

change

[0318] Compound 2-12e 2-12e was synthesized according to the general procedure described above. The amounts of compounds and reagents used in the first step were as follows: 2-10d (482 mg, 2.78 mmol), 2-8c (254 mg, 1.11 mmol), triethylamine (232 μL, 1.67 mmol), 1,2-dichloroethane (660 μL), and LiBr (48.4 mg, 0.556 mmol). For the second step, the residue obtained by concentration was dissolved in 31.0 mL of dichloromethane. A solution of Martin's sulfurane in dichloromethane was prepared by dissolving 1.12 g (1.67 mmol) of Martin's sulfurane in 4.4 mL of dichloromethane. For the third step, 20 mL of dichloromethane and 4.4 mL of TFA were used to give compound 2-12e as a yellow oil (174.5 mg, yield: 48%).

[0319] 1 H NMR (400 MHz, CDCl3) δ: 7.07 (t, J = 7.9 Hz, 1H), 2.57 (t, J = 7.7 Hz, 2H), 2.40-2.30 (m, 2H), 2.22 (q, J = 7.6 Hz, 2H), 1.67-1.59 (m, 2H), 1.53-1.43 (m, 4H), 1.40-1.22 (m, 16H), 0.88 (t, J = 6.7 Hz, 3H); 13 C NMR (100 MHz, CDCl3) δ 179.7, 151.9, 136.2, 33.9, 31.8, 29.2 (2C), 29.1 (2C), 29.0, 28.8, 28.4, 27.9 (2C), 26.3, 24.5, 22.6, 14.1; HRMS (ESI-QTOF) calcd for C 18 H 32 NO4: [MH] - , 326.2337; found: 326.2334.

[0320] [ka]

[0321] Compound 2-1a 2-4 (20.0 mg, 19.1 mmol) and palladium hydroxide (20% wt on carbon, 20.2 mg) were added to a reaction vessel and dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 22 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11b (10.9 mg, 24.8 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (10.4 mg, 26.7 mmol) was added and stirred overnight at room temperature. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-1a as a white solid (3.76 mg, 22% yield).

[0322] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.18 (t, J = 8.0 Hz, 1H), 4.99 (d, J = 3.8 Hz, 1H), 4.11 (s, 1H), 4.02-3.95 (m, 2H), 3.90-3.74 (m, 6H), 3.62-3.60 (m, 2H), 2.67 (t, J = 7.6 Hz, 2H), 2.35-2.26 (m, 4H), 1.75-1.34 (m, 64H), 0.96 (t, J = 6.7 Hz, 6H) 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.8, 152.1, 137.1, 100.0, 75.0, 72.2, 71.0, 70.5, 70.0, 69.2, 67.6, 62.1, 50.6, 36.7, 32.9, 32.2, 29.9 (9C), 29.8 (5C), 29.6 (7C), 28.7, 28.3 (2C), 28.2 (2C), 26.6 (2C), 26.1 (2C), 22.9 (2C), 14.2 (2C); HRMS (ESI-QTOF) calcd for C 50 H 96 N2NaO 11 : [M+Na] + , 923.6906; found: 923.6912.

[0323] [ka]

[0324] Compound 2-1b 2-4 (20.0 mg, 19.1 mmol) and palladium hydroxide (20% wt on carbon, 21.2 mg) were added to a reaction vessel and dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 22 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-12b (10.9 mg, 24.8 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (10.4 mg, 26.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-1b as a white solid (3.40 mg, 20% yield).

[0325] 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 8.11 (m, 1H), 7.10 (t, J = 8.0 Hz, 1H), 4.90 (m, 1H), 4.03 (m, 1H), 3.94-3.87 (m, 2H), 3.79-3.70 (m, 6H), 3.55-3.51 (m, 2H), 2.58 (t, J = 6.5 Hz, 2H), 2.27-2.19 (m, 4H), 1.70-1.49-1.28 (m, 64H), 0.90-0.87 (m, 6H); 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.7, 152.1, 137.0, 100.0, 75.0, 72.2, 71.0, 70.5, 70.0, 69.2, 67.6, 62.1, 50.7, 36.7, 32.9, 32.2, 31.0, 29.9 (7C), 29.8 (5C), 29.7 (2C), 29.6 (3C), 29.5 (2C), 29.4 (2C), 28.8, 28.3 (2C), 28.1 (2C), 26.6 (2C), 26.1 (2C), 22.9 (2C), 14.2 (2C); HRMS (ESI-QTOF) calculation for C 50 H 96 N2NaO 11 : [M+Na] + , 923.6906; found: 923.6915.

[0326]

change

[0327] Compound 2-1c 2-4 (20.0 mg, 19.1 mmol) and palladium hydroxide (20% wt on carbon, 22.6 mg) were added to a reaction vessel and dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 24 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11e (11.3 mg, 24.9 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (10.4 mg, 26.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-1c as a white solid (5.29 mg, 31% yield).

[0328] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.11 (t, J = 8.0 Hz, 1H), 4.91 (d, J = 4.0 Hz, 1H), 4.03 (s, 1H), 3.94 (d, J = 3.1 Hz, 1H), 3.89 (dd, J = 10.3, 4.7 Hz, 1H), 3.82-3.66 (m, 6H), 3.54 (d, J = 4.5 Hz, 2H), 2.61-2.57 (m, 2H), 2.27-2.19 (m, 4H), 1.67-1.20 (m, 64H), 0.69 (t, J = 6.6 Hz, 6H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.7, 152.1, 137.1, 100.0, 75.0, 72.2, 71.0, 70.5, 70.0, 69.2, 67.6, 62.1, 50.7, 36.7, HRMS (ESI-QTOF) calcd for C 50 H 96 N2NaO 11 : [M+Na] + , 923.6906; found: 923.6910.

[0329] [ka]

[0330] Compound 2-2a 2-4 (20.0 mg, 19.1 mmol) and palladium hydroxide (20% wt on carbon, 22.6 mg) were added to a reaction vessel and dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 22 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11c (8.32 mg, 24.8 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (10.4 mg, 26.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-2a as a white solid (2.96 mg, 19% yield).

[0331] 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 8.0 Hz, 1H), 4.91 (d, J = 3.8 Hz, 1H), 4.03 (d, J = 1.8 Hz, 1H), 3.94 (d, J = 2.9 Hz, 1H), 3.88 (dd, J = 10.8, 4.7 Hz, 1H), 3.82 - 3.66 (m, 6H), 3.54 (d, J = 5.2 Hz, 2H), 2.59 (t, J = 7.6 Hz, 2H), 2.27 - 2.19 (m, 4H), 1.70 - 1.22 (m, 64H), 0.92 - 0.87 (m, 6H); 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.4, 151.7, 136.7, 99.6, 74.6, 71.9, 70.6, 70.1, 69.6, 68.8, 67.2, 61.8, 55.7, 36.4, 32.5, 31.8, 31.4, 29.6 (6C), 29.5 (4C), 29.4 (4C), 29.3, 29.2, 29.1, 28.9, 28.4, 27.9, 27.8, 26.2, 25.8, 22.6, 22.4, 13.9 (2C); HRMS (ESI-QTOF) calcd for C 44 H 84 N2NaO 11 : [M+Na] + , 839.5967; found: 839.5976.

[0332]

Chem.

[0333] Compound 2-2b 2-4 (63.9 mg, 61.1 mmol) and palladium hydroxide (20% wt on carbon, 64.3 mg) were added to a reaction vessel and dissolved in a mixture of 3 mL of ethanol and 1 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 22 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-12c (43.4 mg, 0.122 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (54.8 mg, 0.145 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-2b as a white solid (9.40 mg, 19% yield).

[0334] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.40 (d, J = 8.2 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.19 (m, 1H), 3.93-3.88 (m, 2H), 3.82-3.67 (m, 6H), 3.55-3.54 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.28-2.19 (m, 4H), 1.60-1.36 (m, 52H), 0.89 (t, J = 7.1 Hz, 6H); 13C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.2, 151.4, 136.5, 99.4, 74.3, 71.6, 70.5, 69.9, 69.4, 68.6, 66.8, 61.6, 56.9, 36.1, 32.3, 32.2, 31.6, 31.3, 29.4 (6C), 29.3 (4C), 29.2, 29.1, 29.0 (2C), 28.8, 28.6, 28.2, 27.7, 27.5, 25.9, 25.5 (2C), 22.3, 22.2, 13.6 (2C); HRMS (ESI-QTOF) calculation for C 44 H 84 N2NaO 11 : [M+Na] + , 839.5967; found: 839.5969.

[0335]

change

[0336] Compound 2-2c 2-4 (127.7 mg, 0.122 mmol) and palladium hydroxide (20% wt on carbon, 134.1 mg) were added to a reaction vessel and dissolved in a mixture of 6 mL of ethanol and 2 mL of dichloromethane. The mixture was stirred at room temperature for 22 hours under a hydrogen atmosphere of 0.8 MPa and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11f (56.5 mg, 0.159 mmol) were dissolved in a mixture of 4.5 mL of ethanol and 1.5 mL of dichloromethane. DMT-MM(OTf) (66.7 mg, 0.171 mmol) was added and the mixture was stirred overnight at room temperature. The mixture was then heated to 40 °C and stirred for an additional 7 hours. 2-11f (33.3 mg, 0.0936 mmol) and DMT-MM(OTf) (45.0 mg, 0.115 mmol) were added and stirred for 2 hours. After the reaction was completed, the reaction was quenched by adding saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-2c as a white solid (36.8 mg, 47% yield).

[0337] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.37 (d, J = 8.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.24-4.16 (m, 1H), 4.05-3.85 (m, 2H), 3.82-3.66 (m, 6H), 3.56-3.54 (m, 2H), 2.59 (t, J = 7.7 Hz, 2H), 2.27-2.21 (m, 4H), 1.71-1.23 (m, 52H), 0.90-0.87 (m, 6H); 13C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.2, 151.5, 136.5, 99.4, 74.5, 71.7, 70.4, 69.9 (2C), 68.6, 66.9, 61.6, 55.5, 36.1, 32.2, 31.6, 29.4 (8C), 29.3 (4C), 29.0 (2C), 28.9, 28.8, 28.1, 27.7, 27.6, 26.0, 25.5 (2C), 22.3 (2C), 13.6 (2C); HRMS (ESI-QTOF) calcd for C 44 H 84 N2NaO 11 : [M+Na] + , 839.5967; found: 839.5972.

[0338] [ka]

[0339] Compound 2-3a 2-4 (20.0 mg, 19.1 mmol) and palladium hydroxide (20% wt on carbon, 22.6 mg) were added to a reaction vessel and dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 22 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11d (8.12 mg, 24.8 mmol) were dissolved in a mixture of 150 mL of ethanol and 50 mL of dichloromethane. DMT-MM(OTf) (10.4 mg, 26.7 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3a as a white solid (4.11 mg, 37% yield).

[0340] 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.10 (t, J = 7.9 Hz, 1H), 4.90 (d, J = 3.8 Hz, 1H), 4.18 (d, J = 4.3 Hz, 1H), 3.93 (d, J = 2.9 Hz, 1H), 3.87 (dd, J = 10.7, 4.6 Hz, 1H), 3.81 - 3.65 (m, 6H), 3.54 (d, J = 4.0 Hz, 2H), 2.58 (t, J = 7.5 Hz, 2H), 2.22 (td, J = 14.9, 7.6 Hz, 4H), 1.69 - 1.25 (m, 48H), 0.96 - 0.86 (m, 6H); 13C-NMR (99 MHz, CHLOROFORM-D) δ 174.4, 151.8, 136.7, 99.6, 74.6, 71.9, 70.6, 70.1, 69.7 (2C), 68.8, 61.8, 50.3, 36.4, 32.5, 31.8, 30.5, 29.6 (8C), 29.5 (6C), 29.4 (5C), 29.3 (4C), 29.2 (2C), 29.1 (2C), 27.8, 27.6, 26.2, 25.8, 22.6, 22.3, 13.9, 13.6; HRMS (ESI-QTOF) calcd for C 42 H 80 N2NaO 11 : [M+Na] + , 811.5654; found: 811.5663.

[0341]

Chem.

[0342] Compound 2 - 3b 2-4 (95.9 mg, 0.0916 mmol) and palladium hydroxide (20% wt on carbon, 96.5 mg) were added to a reaction vessel and dissolved in a mixture of 4.5 mL of ethanol and 1.5 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 23 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-12d (33.0 mg, 0.101 mmol) were dissolved in a mixture of 600 mL of ethanol and 200 mL of dichloromethane. DMT-MM(OTf) (46.8 mg, 0.120 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3b as a white solid (6.41 mg, 9% yield).

[0343] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.43 (d, J = 8.6 Hz, 1H), 7.10 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.19 (m, 1H), 3.93-3.86 (m, 2H), 3.77-3.67 (m, 6H), 3.55 (m, 2H), 2.59 (t, J = 7.7 Hz, 2H), 2.28-2.19 (m, 4H), 1.66-1.16 (m, 48H), 0.92-0.87 (m, 6H); 13C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.2, 151.5, 136.4, 99.4, 74.3, 71.6, 70.4, 69.9, 69.4, 68.6, 67.0, 61.4, 57.2, 36.1, 32.1, 31.6, 31.0, 29.5 (5C), 29.4 (5C), 29.3, 29.2, 29.1, 29.0, 28.9, 28.1, 27.7, 27.2, 25.9, 25.5, 22.2, 22.0, 17.4, 13.6, 13.4; HRMS (ESI-QTOF) calcd for C 42 H 80 N2NaO 11 : [M+Na] + , 811.5654; ​​found: 811.5656.

[0344] [ka]

[0345] Compound 2-3c 2-4 (132.3 mg, 0.127 mmol) and palladium hydroxide (20% wt on carbon, 134.1 mg) were added to a reaction vessel and dissolved in a mixture of 6 mL of ethanol and 2 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 23 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-11g (83.2 mg, 0.254 mmol) were dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. DMT-MM(OTf) (69.5 mg, 0.178 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3c as a white solid (22.3 mg, 22% yield).

[0346] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.39 (d, J = 8.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.20-4.19 (m, 1H), 4.01-3.86 (m, 2H), 3.82-3.66 (m, 6H), 3.55-3.54 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.28-2.19 (m, 4H), 1.52-1.29 (m, 48H), 0.90-0.88 (m, 6H); 13 C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.5, 151.5, 136.5, 99.4, 74.5, 72.6, 71.7, 70.5, 69.5, 68.6, 67.2, 61.5, 57.4, 36.1, HRMS (ESI-QTOF) calcd for C 42 H 80 N2NaO 11 : [M+Na] + , 811.5654; ​​found: 811.5656.

[0347]

change

[0348] Compound 2-3d 2-4 (73.8 mg, 0.0705 mmol) and palladium hydroxide (20% wt on carbon, 74.3 mg) were added to a reaction vessel and dissolved in a mixture of 3.8 mL of ethanol and 1.2 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 23 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-12d (30.0 mg, 0.0916 mmol) were dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. DMT-MM(OTf) (38.5 mg, 0.0987 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3d as a white solid (6.54 mg, 12% yield).

[0349] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.40 (d, J = 8.6 Hz, 1H), 7.09 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 3.6 Hz, 1H), 4.20 (m, 1H), 3.93-3.88 (m, 2H), 3.84-3.67 (m, 6H), 3.55-3.53 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.30-2.22 (m, 4H), 1.54-1.27 (m, 48H), 0.89-0.88 (m, 6H); 13C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.0, 151.6, 136.3, 99.4, 74.4, 71.6, 70.4, 69.9, 69.4, 68.6, 67.1, 61.5, 55.4, 36.0, 32.3, 31.6, 31.4, 29.4 (6C), 29.3 (3C), 29.0, 28.9 (2C), 28.8 (2C), 28.2, 27.8, 27.7, 27.5, 25.9, 25.4, 22.3, 22.2, 13.6 (2C); HRMS (ESI-QTOF) calcd for C 42 H 80 N2NaO 11 : [M+Na] + , 811.5654; ​​found: 811.5659.

[0350] [ka]

[0351] Compound 2-3e 2-4 (132.3 mg, 0.127 mmol) and palladium hydroxide (20% wt on carbon, 134.1 mg) were added to a reaction vessel and dissolved in a mixture of 6 mL of ethanol and 2 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 23 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and a mixture of 2-11h (83.2 mg, 0.254 mmol) were dissolved in a mixture of 900 mL of ethanol and 300 mL of dichloromethane. DMT-MM(OTf) (69.5 mg, 0.178 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3e as a white solid (16.9 mg, 16% yield).

[0352] 1 H NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.38 (d, J = 8.6 Hz, 1H), 7.11 (t, J = 7.9 Hz, 1H), 4.91 (d, J = 2.7 Hz, 1H), 4.20 (m, 1H), 3.94-3.87 (m, 2H), 3.81-3.67 (m, 6H), 3.53 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.25-2.21 (m, 4H), 1.58-1.38 (m, 48H), 0.97-0.87 (m, 6H); 13 C NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.0, 151.4, 136.6, 99.4, 74.8, 71.7, 70.4, 69.9, 69.4, 69.0, 68.6, 67.0, 61.5, 55.3, 36.0, 32.5, 31.6, 31.5, 29.5 (6C), 29.4 (3C), 29.3, 29.0 (2C), 28.9, 28.8, 28.7, 28.2, 27.7, 27.6, 26.0, 25.5, 25.4, 22.3(2C), 13.6(2C); HRMS (ESI-QTOF) calculation for C 42 H 80 N2NaO 11 : [M+Na] + , 811.5654; ​​found: 811.5653.

[0353]

change

[0354] Compound 2-3x 2-4 (39.3 mg, 0.0402 mmol) and palladium hydroxide (20% wt on carbon, 8.44 mg) were added to a reaction vessel and dissolved in a mixture of 2.1 mL of ethanol and 0.7 mL of dichloromethane. The mixture was stirred at room temperature under a hydrogen atmosphere of 0.8 MPa for 23 hours and then filtered through Celite. The filtrate was concentrated, and the resulting residue and 2-12e (14.9 mg, 0.0523 mmol) were dissolved in a mixture of 300 μL of ethanol and 100 μL of dichloromethane. DMT-MM(OTf) (22.0 mg, 0.0563 mmol) were added, and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched with saturated aqueous sodium bicarbonate and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-3x as a white solid (19.2 mg, 64% yield).

[0355] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.08 (t, J = 8.0 Hz, 1H), 4.91 (d, J = 3.8 Hz, 1H), 4.20 (t, J = 4.5 Hz, 1H), 3.94 (m, 1H), 3.88 (m, 1H), 3.84-3.79 (m, 2H), 3.77-3.73 (m, 2H), 3.72-3.65 (m, 2H), 3.55-3.54 (m, 2H), 3.37-3.35 (m, 1H), 2.65-2.58 (m, 2H), 2.28-2.17 (m, 4H), 1.70-1.45 (m, 6H), 1.43-1.26 (m, 42H), 1.14-1.10 (m, 3H), 0.88 (t, J = 6.8 Hz, 3H) LRMS calcd. for C 39 H 74 N2O 11 Na: [M+Na] + , 769.5190; found: 769.4221.

[0356] <Sphingosine-type GlcCer(NO2)>

[0357] [ka]

[0358] Compounds 2-15a and 2-15b 34a (10.0 mg, 21.7 mmol) and 2-12a (10.7 mg, 26.0 mmol) were dissolved in 150 μL of EtOH and 50 μL of dichloromethane. DMT-MM (OTf) (12.7 mg, 32.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-15a as a white solid (6.89 mg, 37% yield).

[0359] 1 H-NMR (392 MHz, CDCl3:CD3OD = 3:1) δ 7.02 (t, J = 8.0 Hz, 1H), 5.68-5.61 (m, 1H), 5.36 (dd, J = 15.5, 7.0 Hz, 1H), 4.73 (d, J = 3.6 Hz, 1H), 4.02 (t, J = 6.8 Hz, 1H), 3.92-3.86 (m, 2H), 3.72-3.68 (m, 3H), 3.67-3.56 (m, 1H), 3.48-3.44 (m, 1H), 3.37 (dd, J = 9.5, 3.7 Hz, 1H), 3.30 (t, J = 9.3 Hz, 3H), 2.50 (t, J = 7.5 Hz, 2H), 2.19-2.09 (m, 4H), 1.95 (q, J = 7.0 Hz, 2H), 1.51-1.18 (m, 62H), 0.80 (t, J = 6.6 Hz, 6H) 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.6, 151.8, 136.7, 134.1, 129.0, 99.3, 73.7, 71.9 (2C), 70.0, 67.2, 61.3 (2C), 53.4, 36.3, 32.3, 31.8, 31.7, 29.6 (4C), 29.5 (2C), 29.4 (3C), 29.3 (4C), 29.2, 29.1 (4C), 28.4, 27.9, 27.8, 26.2, 25.8, 22.6, 22.5, 13.9 (2C); HRMS (ESI-QTOF) calcd for C 48 H 90 N2NaO 10 : [M+Na] + : 877.6488; found: 877.6497.

[0360] 34b (7.50 mg, 16.2 mmol) and 2-12a (8.01 mg, 19.4 mmol) were dissolved in 112 μL of EtOH and 38 μL of dichloromethane. DMT-MM (OTf) (9.50 mg, 24.3 mmol) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-15b as a white solid (1.39 mg, 10% yield).

[0361] 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 8.0 Hz, 1H), 5.73-5.66 (m, 1H), 5.45 (q, J = 7.7 Hz, 1H), 4.16 (dd, J = 10.1, 4.3 Hz, 1H), 4.09 (t, J = 7.3 Hz, 1H), 4.01-3.96 (m, 1H), 3.86 (dd, J = 12.1, 2.5 Hz, 1H), 3.72 (dd, J = 11.9, 5.2 Hz, 1H), 3.58 (dd, J = 10.0, 3.0 Hz, 1H), 3.41 (q, J = 8.8 Hz, 3H), 3.31-3.24 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.27-2.15 (m, 4H), 2.05-1.96 (m, 2H), 1.60-1.19 (m, 62H), 0.88 (t, J = 6.5 Hz, 6H); 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.5, 151.8, 136.7, 134.3, 129.0, 102.9, 73.4, 72.1 (2C), 69.9, 68.5, 61.3 (2C), 53.2, 36.4, 32.3, 31.8, 31.7, 29.6 (9C), 29.5 (3C), 29.4, 29.3 (2C), 29.1 (4C), 28.4, 27.9, 27.8, 26.2, 25.8, 22.6, 22.5, 13.8 (2C); HRMS (ESI-QTOF) calcd for C 48 H 90 N2NaO 10 : [M+Na] + : 877.6488; found: 877.6495.

[0362]

change

[0363] Compound 2-16aおよび2-16b 34a (10.0 mg, 21.7 mmol) and 2-11a (10.7 mg, 26.0 mmol) were dissolved in 150 μL of EtOH and 50 μL of dichloromethane, and DMT-MM (OTf) (12.7 mg, 32.5 mmol) was added. The mixture was stirred at room temperature for 24 h. After the reaction was completed, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-16a as a white solid (5.37 mg, 29% yield).

[0364] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 8.0 Hz, 1H), 5.77-5.70 (m, 1H), 5.45 (dd, J = 15.3, 7.0 Hz, 1H), 4.82 (d, J = 3.8 Hz, 1H), 4.10 (t, J = 6.8 Hz, 1H), 4.00-3.94 (m, 1H), 3.81-3.77 (m, 2H), 3.75-3.64 (m, 3H), 3.57-3.53 (m, 1H), 3.45 (dd, J = 9.6, 3.8 Hz, 1H), 3.41-3.35 (m, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.27-2.17 (m, 4H), 2.06-1.99 (m, 2H), 1.61-1.26 (m, 62H), 0.89 (t, J = 6.9 Hz, 6H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.6, 151.7, 136.7, 134.1, 129.0, 99.3, 73.7, 71.9 (2C), 70.0, 67.2, 61.3 (2C), 53.4, 36.3, 32.3, 31.8, 31.7, 29.6 (4C), 29.5 (7C), 29.4 (3C), 29.3 (2C), 29.2 (3C), 29.0, 28.4, 27.9, 27.8, 26.2, 25.8, 22.5, 22.5, 13.9, 13.8; HRMS (ESI-QTOF) calcd for C 48 H 90 N2NaO 10 : [M+Na] + : 877.6488; found: 877.6496.

[0365] 34b (7.50 mg, 16.2 mmol) and 2-11a (8.00 mg, 19.4 mmol) were dissolved in 112 μL of EtOH and 38 μL of dichloromethane. DMT-MM (OTf) (9.50 mg, 24.3 mmol) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-16b as a white solid (2.60 mg, 19% yield).

[0366] 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 8.0 Hz, 1H), 5.73-5.66 (m, 1H), 5.45 (dd, J = 15.4, 7.3 Hz, 1H), 4.16 (dd, J = 10.0, 4.4 Hz, 1H), 4.09 (t, J = 7.4 Hz, 1H), 4.01-3.97 (m, 1H), 3.86 (dd, J = 12.1, 2.5 Hz, 1H), 3.73 (dd, J = 12.1, 4.9 Hz, 1H), 3.57 (dd, J = 10.1, 3.1 Hz, 1H), 3.45-3.35 (m, 3H), 3.26 (t, J = 8.2 Hz, 2H), 2.59 (t, J = 7.5 Hz, 2H), 2.27-2.15 (m, 4H), 2.02 (q, J = 7.1 Hz, 2H), 1.60-1.26 (m, 62H), 0.90-0.87 (m, 6H); 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.5, 151.8, 136.7, 134.3, 129.0, 102.9, 73.4, 72.1 (2C), 69.9, 68.5, 61.3 (2C), 53.2, 36.4, 32.3, 31.8, 31.7, 29.6 (8C), 29.5 (4C), 29.2 (4C), 29.1 (3C), 29.0, 28.4, 27.9, 27.8, 26.2, 25.8, 22.6, 22.5, 13.8 (2C); HRMS (ESI-QTOF) calcd for C 48 H 90 N2NaO 10 : [M+Na] + : 877.6488; found: 877.6495.

[0367]

change

[0368] Compound 2-17aおよび2-17b 34a (20.0 mg, 43.3 mmol) and 2-12c (18.5 mg, 52.0 mmol) were dissolved in 300 μL of EtOH and 100 μL of dichloromethane. DMT-MM (OTf) (27.2 mg, 69.7 mmol) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-17a as a white solid (6.56 mg, 19% yield).

[0369] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 8.0 Hz, 1H), 5.77-5.70 (m, 1H), 5.45 (dd, J = 15.3, 7.0 Hz, 1H), 4.82 (d, J = 3.6 Hz, 1H), 4.11 (t, J = 6.8 Hz, 1H), 4.00-3.95 (m, 1H), 3.82-3.77 (m, 2H), 3.75-3.64 (m, 3H), 3.57-3.53 (m, 1H), 3.45-3.36 (m, 5H), 2.59 (t, J = 7.5 Hz, 2H), 2.22 (td, J = 15.1, 7.8 Hz, 4H), 2.06-2.01 (m, 2H), 1.60-1.26 (m, 54H), 0.90-0.87 (m, 6H) 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.9, 152.1, 137.0, 134.4, 129.3, 99.6, 72.3, 72.2 (2C), 70.4, 67.6, 61.7 (2C), 53.7, 36.6, 32.6, 32.1, 31.9, 29.9 (6C), 29.7 (4C), 29.6 (2C), 29.5 (2C), 29.4, 29.2, 28.8, 28.3, 28.1, 26.5, 26.1, 22.9, 22.8, 14.2 (2C); HRMS (ESI-QTOF) calcd for C44 H 82 N2NaO 10 : [M+Na] + : 821.5862; found: 821.5870.

[0370] 34b (20.0 mg, 43.3 mmol) and 2-12c (18.5 mg, 52.0 mmol) were dissolved in 300 μL of EtOH and 100 μL of dichloromethane. DMT-MM (OTf) (28.4 mg, 72.8 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate and concentrated under reduced pressure. The resulting residue was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-17b as a white solid (4.84 mg, 14% yield).

[0371] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.10 (t, J = 7.8 Hz, 1H), 5.76-5.68 (m, 1H), 5.49-5.43 (m, 1H), 4.19-4.09 (m, 2H), 4.02-3.99 (m, 1H), 3.90-3.84 (m, 3H), 3.75-3.72 (m, 1H), 3.45-3.40 (m, 2H), 3.31-3.24 (m, 2H), 2.61-2.57 (m, 2H), 2.27-2.16 (m, 4H), 2.03 (m, 2H), 1.59-1.50 (m, 6H), 1.28 (m, 48H), 0.89 (m, 6H). 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.8, 152.1, 137.0, 134.6, 129.3, 103.2, 73.8, 72.5, 70.3, 69.4, 68.8, 61.8, 61.6, 53.8, 36.7, 32.6, 32.1, 31.9, 29.9 (6C), 29.8 (4C), 29.7 (4C), 29.6, 29.5, 29.4, 29.2, 28.8, 28.3, 28.1, 26.5, 26.1, 22.9, 22.8, 14.2 (2C); HRMS (ESI-QTOF) calcd for C 44 H 82 N2NaO 10 : [M+Na] + : 821.5862; found: 821.5870.

[0372] [ka]

[0373] Compounds 2-18a and 2-18b 34a (10.0 mg, 21.7 mmol) and 2-12e (9.53 mg, 29.1 mmol) were dissolved in 150 μL of EtOH and 50 μL of dichloromethane. DMT-MM (OTf) (12.7 mg, 32.5 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-18a as a white solid (6.40 mg, 38% yield).

[0374] 1H-NMR (400 MHz, CHLOROFORM-D) δ 7.01 (t, J = 8.0 Hz, 1H), 5.69-5.61 (m, 1H), 5.36 (dd, J = 15.4, 7.1 Hz, 1H), 4.73 (d, J = 3.8 Hz, 1H), 4.02 (t, J = 6.8 Hz, 1H), 3.91-3.87 (m, 1H), 3.73-3.68 (m, 2H), 3.67-3.56 (m, 3H), 3.48-3.44 (m, 1H), 3.39-3.27 (m, 2H), 2.50 (t, J = 7.5 Hz, 2H), 2.19-2.10 (m, 5H), 1.95 (q, J = 7.0 Hz, 2H), 1.54-1.11 (m, 50H), 0.80 (m, 6H). 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.4, 151.8, 136.5, 134.0, 129.0, 99.3, 73.7, 72.0, 71.9 (2C), 70.0, 67.2, 61.3, 53.4, 36.2, 32.3, 31.8, 31.7, 29.6 (3C), 29.5 (4C), 29.2 (4C), 29.1, 29.0, 28.4, 27.9, 27.8, 26.2, 25.7, 22.6, 22.5, 13.9 (2C); HRMS (ESI-QTOF) calcd for C 42 H 78 N2NaO 10 : [M+Na] + : 793.5549; found 793.5549.

[0375] 34b (7.50 mg, 16.2 mmol) and 2-12e (6.35 mg, 19.4 mmol) were dissolved in 112 μL of EtOH and 38 μL of dichloromethane. DMT-MM (OTf) (9.50 mg, 24.3 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-18b as a white solid (2.37 mg, 19% yield).

[0376] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.09 (t, J = 7.9 Hz, 1H), 5.73-5.66 (m, 1H), 5.45 (q, J = 7.5 Hz, 1H), 4.16 (dd, J = 10.1, 4.5 Hz, 1H), 4.10 (t, J = 7.3 Hz, 1H), 4.02-3.98 (m, 1H), 3.86 (dd, J = 12.1, 2.2 Hz, 1H), 3.73 (dd, J = 12.0, 5.0 Hz, 1H), 3.58 (dd, J = 10.0, 3.0 Hz, 1H), 3.41 (q, J = 8.8 Hz, 3H), 3.26 (t, J = 8.2 Hz, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.27-2.16 (m, 4H), 2.02 (q, J = 7.0 Hz, 2H), 1.62-1.26 (m, 50H), 0.90-0.87 (m, 6H); 13C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.7, 152.1, 136.8, 134.6, 129.3, 103.2, 73.8, 72.4 (2C), 70.3, 68.8, 61.6 (2C), 53.5, 36.6, 32.6, 32.1, 32.0, 29.9 (6C), 29.8 (3C), 29.6 (3C), 29.5 (2C), 29.4, 28.8, 28.3, 28.1, 26.5, 26.0, 22.9, 22.8, 14.2 (2C); HRMS (ESI-QTOF) calcd for C 42 H 78 N2NaO 10 : [M+Na] + : 793.5549; found 793.5553.

[0377] [ka]

[0378] Compounds 2-19a and 2-19b 34a (20.0 mg, 43.3 mmol) and 2-11h (12.0 mg, 36.6 mmol) were dissolved in 225 μL of EtOH and 75 μL of dichloromethane. DMT-MM (OTf) (20.2 mg, 51.8 mmol) was added, and the mixture was stirred at room temperature for 24 h. After the reaction was completed, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-19a as a white solid (8.22 mg, 32% yield).

[0379] 1H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.11 (t, J = 7.9 Hz, 1H), 5.77-5.70 (m, 1H), 5.45 (dd, J = 15.3, 7.0 Hz, 1H), 4.82 (d, J = 3.8 Hz, 1H), 4.11 (t, J = 6.6 Hz, 1H), 4.02-3.95 (m, 1H), 3.81-3.77 (m, 2H), 3.75-3.64 (m, 3H), 3.57-3.53 (m, 1H), 3.47-3.35 (m, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.27-2.18 (m, 4H), 2.03 (q, J = 6.8 Hz, 2H), 1.60-1.26 (m, 50H), 0.90-0.87 (m, 6H). 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.4, 151.6, 136.8, 134.1, 129.0, 99.3, 73.7, 71.9 (2C), 70.0, 67.2, 61.3 (2C), 53.4, 36.2, 32.3, 31.8, 31.7, 29.6 (7C), 29.5 (3C), 29.4 (3C), 29.2, 29.0, 28.4, 27.9, 27.8, 26.2, 25.7, 22.5 (2C), 13.8 (2C). HRMS (ESI-QTOF) calcd for C 42 H 78 N2NaO 10 : [M+Na] + : 793.5549; found 793.5553.

[0380] 34b (15.0 mg, 32.4 mmol) and 2-11h (14.8 mg, 45.2 mmol) were dissolved in 225 μL of EtOH and 75 μL of dichloromethane. DMT-MM (OTf) (21.4 mg, 54.8 mmol) was added, and the mixture was stirred at room temperature for 24 h. After completion of the reaction, saturated aqueous sodium bicarbonate was added, and the mixture was extracted with ethyl acetate. The residue obtained by concentration under reduced pressure was purified by silica gel column chromatography using chloroform-methanol (19:1→9:1) to give 2-19b as a white solid (4.90 mg, 20% yield).

[0381] 1 H-NMR (400 MHz, CDCl3:CD3OD = 3:1) δ 7.11 (t, J = 8.0 Hz, 1H), 5.71 (m, 1H), 5.46 (dd, J = 15.4, 7.3 Hz, 1H), 4.18-4.08 (m, 2H), 4.02-3.97 (m, 1H), 3.90-3.87 (m, 2H), 3.85-3.84 (m, 1H), 3.75-3.70 (m, 1H), 3.45-3.36 (m, 2H), 3.31-3.24 (m, 2H), 2.58 (t, J = 7.6 Hz, 2H), 2.27-2.16 (m, 4H), 2.03-2.00 (m, 2H), 1.59-1.48 (m, 6H), 1.34-1.26 (m, 44H), 0.89 (m, 6H); 13 C-NMR (100 MHz, CDCl3:CD3OD = 3:1) δ 174.7, 152.0, 137.1, 134.6, 129.3, 103.7, 73.8, 72.6, 72.4, 70.3, 69.4, 68.8, 61.8, 53.5, 36.6, 32.6, 32.2, 32.0, 29.9 (4C), 29.8 (3C), 29.6 (2C), 29.5, 29.4 (2C), 29.3, 28.7, 28.3, 28.2, 26.5, 26.1, 22.9 (2C) 14.2 (2C); HRMS (ESI-QTOF) calcd for C 42 H78 N2NaO 10 : [M+Na] + : 793.5549; found 793.5555.

[0382] <Sphingosine-type GalCer(NO2)>

[0383] [ka]

[0384] Compound 3-1 A mixture of 3-3 (15.0 mg, 30.8 mmol) and 2-11g (11.1 mg, 33.9 mmol) was dissolved in a mixed solvent of 288 mL of ethanol and 96.1 mL of dichloromethane. DMT-MM(OTf) (13.2 mg, 33.9 mmol) was then added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-1a as a white solid (3.19 mg, 13% yield).

[0385] 1 H-NMR (396 MHz, CDCl3) δ 7.11-7.00 (m, 1H), 5.80-5.73 (m, 1H), 5.45 (dd, J = 15.4, 5.9 Hz, 1H), 4.93 (s, 1H), 4.22 (s, 1H), 4.06 (d, J = 20.4 Hz, 2H), 3.87-3.81 (m, 6H), 3.68 (d, J = 10.9 Hz, 1H), 2.56 (t, J = 7.5 Hz, 2H), 2.22 (q, J = 7.6 Hz, 4H), 2.03 (d, J = 7.7 Hz, 2H), 1.72 (s, 3H), 1.60 (s, 2H), 1.48 (q, J = 7.1 Hz, 3H), 1.31-1.25 (m, 42H), 0.88 (td, J = 6.9, 2.4 Hz, 6H);13 C-NMR (99 MHz, CDCl3) δ 173.9, 151.8, 136.9 134.3, 128.5, 100.0, 77.4-76.4(2C), 73.3, 70.4, 62.9, 53.3, 36.8, 32.5-31.9 (4C), 29.8-28.0 (16C), 26.4, 25.7, 22.8(2C), 14.2 (2C).

[0386] Compound 3-2 A mixture of 3-3 (15.0 mg, 30.8 mmol) and 2-12d (11.1 mg, 33.9 mmol) was dissolved in a mixed solvent of 288 mL of ethanol and 96.1 mL of dichloromethane. DMT-MM(OTf) (13.2 mg, 33.9 mmol) was added and the mixture was stirred at room temperature overnight. After completion of the reaction, the reaction was quenched by adding saturated aqueous sodium bicarbonate solution and extracted with ethyl acetate. The extract was concentrated under reduced pressure and purified by silica gel column chromatography using chloroform-methanol (7:1) to give 2-1a as a white solid (1.89 mg, 8% yield).

[0387] 1 H-NMR (392 MHz, CDCl3) δ 7.06 (t, J = 7.9 Hz, 1H), 6.39 (s, 1H), 5.75 (s, 1H), 5.48-5.42 (m, 1H), 4.93 (s, 1H), 4.23 (s, 1H), 4.09 (s, 1H), 3.83 (d, J = 18.4 Hz, 5H), 3.69 (s, 2H), 2.57-2.54 (m, 2H), 2.21 (q, J = 7.2 Hz, 4H), 2.02 (d, J = 8.5 Hz, 2H), 1.65 (s, 4H), 1.46 (t, J = 6.8 Hz, 3H), 1.28 (d, J = 27.2 Hz, 43H), 0.92-0.85 (m, 6H); 13C-NMR (100 MHz, CDCl3) δ 173.7, 152.0, 139.1, 136.4, 134.3, 128.5, 78.1-76.8 (3C), 69.9 , 69.2, 63.1(2C), 53.2, 36.8, 32.5-31.9 (3C), 29.8-29.3 (16C), 28.6 (2C), 28.0, 26.5, 25.7, 22.8-22.6 (2C), 14.2 (2C).

[0388] The compounds of the present invention produced in the above Production Examples are summarized as follows: When an asymmetric carbon atom is generated in the fatty acid side chain by introducing a hydroxyl group or a nitro group into the fatty acid side chain, the pharmacological activity of the compounds of the present invention was evaluated as racemates without separating the optical isomers.

[0389] [Table 1]

[0390] [Table 2]

[0391] [Table 3]

[0392] [Table 4]

[0393] <Test Example 1> Evaluation of selective induction of IL-17A production using mouse spleen cells Spleen cells (6 × 10 ) extracted from C57BL / 6J mice were incubated in various ligand solutions (10 nM). 5The IL-17A / IFN-γ ratio was calculated for each ligand, and the relative value was determined when the IL-17A / IFN-γ ratio for α-GalCer (KRN7000) was set to 1. As a result, selective induction of IL-17A production was observed for each ligand (Figures 1 to 3).

[0394] <Test Example 2> The following compounds were synthesized and their ability to induce IL-17A production was examined using mouse spleen cells.

[0395] [Table 5]

[0396] Introduction of a hydroxyl group into the fatty acid side chain enhanced the ability to induce IL-17A production (Figure 4).

[0397] Furthermore, the introduction of a nitro group into the fatty acid side chain also enhanced the ability to induce IL-17A production. The introduction of a nitro group into the 11th to 13th carbon atoms resulted in a stronger ability to induce IL-17A production than the introduction of a nitro group into the 9th or 10th carbon atoms (Figure 5).

[0398] The binding affinity of synthetic ligands to CD1d was analyzed using AlphaScreen®. Ligands 3q, 3r, 3s, 3w, 3x, 3y, 3z, 3aa, and 3ab, which possess a nitro group at position 11 or 13, showed stronger interactions than α-GalCer. This tendency was observed regardless of the number of carbon atoms in the fatty acid (18-26 carbon atoms). These results suggest that the presence of a nitro group enhances binding affinity. On the other hand, ligands 3ac and 3ad, which possess a nitro group at position 9 or 10, showed significantly reduced interaction with CD1d, suggesting that this reduced binding affinity to CD1d is the cause of their reduced ability to induce IL-17A production (Figure 6).

[0399] <Test Example 3> The following compounds were synthesized and their ability to induce IL-17A production was examined using mouse spleen cells.

[0400] [Table 6]

[0401] The longer the fatty acid side chain, the stronger the induction of IL-17A production. Furthermore, the introduction of a nitro group at carbon positions 15 and 16 was more potent than the introduction of a nitro group at carbon positions 9 and 10 (Fig. 7).

[0402] The binding affinity of synthetic ligands to CD1d was analyzed using AlphaScreen®. Ligands 1t, 1u, 2t, and 2u, which have a nitro group at position 15 or 16, exhibited stronger interactions than α-GalCer. This result suggests that the presence of a nitro group enhances binding affinity. On the other hand, ligands 1ac, 1ad, 2ac, and 2ad, which have a nitro group at position 9 or 10, exhibited weaker interactions with CD1d than 1t, 1u, 2t, and 2u, suggesting that their lower binding affinity to CD1d is responsible for their lower ability to induce IL-17A production (Figure 8).

[0403] <Test Example 4> The ability of Example compounds 2-3e, 2-2c, 2-3c, 2-3d, 2-2b, and 2-3b to induce IL-17A production in mouse spleen cells was examined. All compounds showed a greater ability to induce IL-17A production than α-GalCer (Figure 9).

[0404] <Test Example 5> The following compounds were synthesized and their ability to induce IL-2 production was examined using mouse spleen cells. All compounds showed a greater ability to induce IL-2 production than α-GalCer (Figure 10).

[0405] [ka]

[0406] Furthermore, the binding ability of the synthetic ligands to CD1d was analyzed using AlphaScreen®, and the results showed that all compounds bound very strongly to CD1d (Figure 11). [Industrial Applicability]

[0407] The present invention provides α-GalCer analogs that induce Th17-selective cytokine production. Because IL-17 is thought to play an important role in defense against infection, these α-GalCer analogs may be useful as anti-infective agents or immunostimulants.

Claims

1. A compound represented by the following formula (I): 【Chemical 1】 (In formula (I), A is an α- or β-D-glycopyranosyl group; R 1 is an acyl group derived from a straight-chain fatty acid monosubstituted with a hydroxyl group or a nitro group, R 2 is a linear aliphatic group which may be mono-substituted with a hydroxyl group.

2. R 1 is an acyl group derived from a linear fatty acid having 12 to 26 carbon atoms and mono-substituted with a hydroxyl group.

3. 3. The compound according to claim 2, wherein any one of carbons at positions 8 to 17 of the fatty acid is substituted with a hydroxyl group.

4. R 2 The compound according to claim 2, wherein is a straight-chain alkyl group in which the carbon at position 1 is substituted with a hydroxyl group.

5. R 2 3. The compound of claim 2, wherein is a straight chain alkenyl group containing a double bond between the 1- and 2-carbon atoms.

6. R 1 is an acyl group derived from a linear fatty acid having 12 to 26 carbon atoms and mono-substituted with a nitro group.

7. 7. The compound according to claim 6, wherein any one of carbons at positions 9 to 16 of the fatty acid is substituted with a hydroxyl group.

8. R 2 The compound according to claim 6, wherein is a straight-chain alkyl group in which the carbon at position 1 is substituted with a hydroxyl group.

9. R 2 7. The compound of claim 6, wherein is a straight chain alkenyl group containing a double bond between the 1- and 2-carbon atoms.

10. 2. The compound of claim 1, wherein A is an α- or β-D-galactopyranosyl group or an α- or β-D-glucopyranosyl group.

11. A pharmaceutical composition comprising a compound according to any one of claims 1 to 10.

12. 12. The pharmaceutical composition of claim 11, which is for immunostimulation.

13. An IL-17A production promoter comprising the compound according to any one of claims 1 to 10.

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