Method for constructing continuous chiral center allyl alcohol derivative

Abstract

The invention provides a method for constructing a continuous chiral center allyl alcohol derivative, which comprises the following step: in a solvent and a system, a compound I, a compound II and a compound III are subjected to a reaction as shown in the specification to obtain a compound A. The invention further provides a preparation method of the continuous chiral center allyl alcohol derivative. According to the method disclosed by the invention, stable and easily available racemic alpha-branched chain aldehyde and alkyne are taken as substrates, only a catalytic system of a compound as shown in a formula IV and Ni (cod) 2 is used, a reductive coupling reaction of dynamic dynamics can be completed under a mild condition, and the method has very high enantioselectivity, diastereoselectivity and regioselectivity; and the configuration of the product can be changed by adjusting the configuration of the ligand, so that the product with high ee, dr and rr values can be directly obtained. The method provided by the invention has the advantages of high yield, simple operation, mild reaction conditions, high selectivity, strong chiral control ability and wide substrate applicability, and has high academic and application values.

Description

TECHNICAL FIELD

[0001] The present application belongs to the field of organic chemical synthesis, and particularly relates to a method for constructing allyl alcohol derivatives with continuous chiral centers. BACKGROUND

[0002] Building carbon-carbon bond (C-C) is a long-term goal pursued by organic chemists, and asymmetric C-C bond formation reaction can achieve efficient synthesis of chiral molecules, which is an important research frontier. Secondary alcohol with continuous chiral centers is an important structure, which widely exists in various life active substances and is an important building block in organic synthesis, and the development of efficient asymmetric synthesis strategy for this structure is still limited.

[0003] Traditional asymmetric catalytic reaction mostly focuses on the formation of a single chiral center, and the research on the construction of two continuous chiral centers by one-step reaction is relatively less. Limited synthesis methods are the use of chiral substrate-induced diastereoselective synthesis, which requires the pre-synthesis of chiral aldehyde which is difficult to prepare, and the chiral aldehyde is prone to racemization, which is not conducive to storage, and the substrate range and selectivity of the reaction are greatly limited.

[0004] Enantioconvergent catalysis refers to the process of converting racemic substrate into a single chiral product with 100% theoretical yield by one-step reaction under the action of chiral catalyst, and can simultaneously construct two continuous chiral centers, which is an efficient synthesis strategy. As an efficient strategy for synthesizing secondary alcohol with a single chiral center, the asymmetric reductive coupling reaction of aldehyde-yne and the asymmetric addition reaction of aldehyde have been developed, but the enantioconvergent reductive coupling reaction / addition using alpha-branched aldehyde as substrate has not been reported. The difficulty of the reaction lies in the simultaneous control of enantioselectivity, diastereoselectivity and chemical selectivity, and the enantioconvergent reductive coupling reaction of aldehyde-yne also needs to efficiently control the regioselectivity and syn-anti selectivity, which has a high requirement for the catalyst, and suitable conditions need to be found to make the substrate racemize quickly.

[0005] Therefore, there is an urgent need in the art to develop a method for synthesizing allyl alcohol structure with continuous chiral center, which has simple synthesis route, mild reaction condition, high selectivity, strong chiral control ability and wide substrate applicability. SUMMARY

[0006] The present application aims to provide a method for synthesizing allyl alcohol structure with continuous chiral center, which has simple synthesis route, mild reaction condition, high selectivity, strong chiral control ability and wide substrate applicability. Specifically, it relates to a method for constructing allyl alcohol derivatives with continuous chiral centers.

[0007] In a first aspect of the present application, there is provided a method for constructing a continuous chiral center allyl derivative, said method comprising the step of: carrying out a reaction as shown below in a solvent, in a system, of compound I, compound II and compound III to obtain compound A:

[0008]

[0009] said system is compound IV and bis(1,5-cyclooctadiene)nickel;

[0010] wherein R 1 , R 2 are each independently H, substituted or unsubstituted C 1-7 alkyl, substituted or unsubstituted C 3-10 cycloalkyl, substituted or unsubstituted C 3-10 heterocycloalkyl, substituted or unsubstituted C 6-10 aryl, substituted or unsubstituted 5-13 membered heteroaryl, substituted or unsubstituted 7-13 membered arycycloalkyl, substituted or unsubstituted C 6-13 aryheterocycloalkyl, substituted or unsubstituted 7-13 membered heteroarylcycloalkyl, substituted or unsubstituted 7-13 membered heterocycloalkylaryl, -NR a R b , -OMe, -OCPh3;

[0011] or R 1 , R 2 and the CH to which they are attached together form a structure selected from the group consisting of substituted or unsubstituted 5-13 membered heteroaryl, substituted or unsubstituted 7-13 membered arycycloalkyl, substituted or unsubstituted C 6-13 aryheterocycloalkyl, substituted or unsubstituted 7-13 membered heteroarylcycloalkyl, substituted or unsubstituted 7-13 membered heterocycloalkylaryl;

[0012] wherein said substitution means that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, C 2-7 alkenyl, C 6-13 aryl, C 1-7 alkoxy, C 3-10 cycloalkyl, C 3-10 heterocycloalkyl, -OMe, -NMe2, -SMe, -CF3, -COCF3, -CN, -CO2Me, -C(O)NMe2, -C(O)NEt2, -CH2CHMe2, benzoyl, t-butylcarbonyl (-Boc), benzyloxycarbonyl (-Cbz), triphenylmethyl ether (-OTr);

[0013] R a , R beach independently selected from the group consisting of -C(O)-O-(CH2) n -C(CH3)3, -C(O)-O-(CH2) m -C 6-12 aryl, -(CH2) p -C 6-12 aryl, -C(O)-C 6-12 aryl, C 6-10 aryl, wherein n, m, p are each independently 0, 1, 2, 3, 4, 5, 6 or 7; or R a , R b and the N adjacent thereto together form a 3-10 membered ring structure;

[0014] R 3 , R 4 each independently selected from the group consisting of H, C 6-10 aryl, C 1-10 alkyl, C 3-12 cycloalkyl, -SiMe3, -(CH2) x -O-SiMe2-C4alkyl, -(CH2) y -C 6-10 aromatic ring; wherein x, y are each independently 0, 1, 2, 3, 4, 5, 6 or 7;

[0015] wherein each of said heterocycloalkyl or heteroaromatic ring independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0016] In another preferred embodiment, the compound IV has the structure:

[0017]

[0018] wherein,

[0019] R 9a , R 9b , R 9c and R 9d are each independently substituted or unsubstituted C 1-6 alkyl, substituted or unsubstituted C 6-14 aryl, wherein said substitution means that one or more hydrogen atoms on the group are each independently replaced with a substituent selected from the group consisting of halogen, C 1-4 alkyl, C 6-14 aryl;

[0020] R 7a , R 7b , R 7c , R 8a , R 8b and R 8c are each independently selected from the group consisting of hydrogen, halogen, C1-4 alkyl;

[0021] R 5 and R 6 are each independently selected from the group consisting of hydrogen, C 1-4 alkyl, halogen, C 6-10 aryl; wherein R 5-1 and R 5 -2 are each independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl; or R 5 , R 6 together with the carbon atom to which they are attached form a

[0022] said is a single or double bond;

[0023] said Y - is a monovalent anion.

[0024] In another preferred embodiment, the system is compound IV, potassium tert-butoxide, bis(1,5-cyclooctadiene)nickel.

[0025] In another preferred embodiment, R 1 , R 2 are each independently selected from the group consisting of C 1-7 alkyl, -NR a R b , -OMe, -OCPh3, C 6-10 aromatic ring, substituted or unsubstituted 5-13 membered aromatic heterocycle, substituted or unsubstituted naphthyl, substituted or unsubstituted benzopyrrolyl, substituted or unsubstituted benzo 3-7 cycloalkyl, substituted or unsubstituted C 3-7 heterocycloalkyl and phenyl, substituted or unsubstituted furano 3-7 cycloalkyl, C 1-1 alkyl substituted with 1, 2 or 3 R 1-7 alkyl and R 1-2 cycloalkyl substituted with 1, 2 or 3 R 6-10 aromatic ring;

[0026] or R 1 , R 2 and the CH to which they are attached together form a structure selected from the group consisting of substituted or unsubstituted C 6-10 aromatic ring, substituted or unsubstituted 5-13 membered aromatic heterocycle, substituted or unsubstituted naphthyl, substituted or unsubstituted benzopyrrolyl, substituted or unsubstituted benzo 3-7 cycloalkyl, substituted or unsubstituted furano 3-7 cycloalkyl;

[0027] Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, C 2-7 Alkenyl, C 6-13 Aryl, C 1-7 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -OMe, -NMe2, -SMe, -CF3, -COCF3, -CN, -CO2Me, -C(O)NMe2, -C(O)NEt2, -CH2CHMe2, benzoyl, tert-butylcarbonyl (-Boc), benzyloxycarbonyl (-Cbz), triphenylmethylether (-OTr);

[0028] R 1-1 For halogen, vinyl, -OCH2-, C 3-7 Cycloalkyl;

[0029] R 1-2 is a halogen, containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. 3-10 Heteroaromatic ring, -OMe, -NMe2, -SMe, -O-CH2-O-, -CF3, -OCF3, -CN, -CO2Me, -C(O)NEt2, -CH2CHMe2, phenyl, benzoyl;

[0030] R a 、R b Each independently selected from the group consisting of benzyl, -C(O)-OC(CH3)3, phenyl, benzoyl, or R a 、R b Together with the adjacent N, it forms a 3-7 membered ring structure;

[0031] Wherein, each of the heterocycloalkyl groups or heteroaromatic rings independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

[0032] In another preferred embodiment, R 3 、R 4 Each independently selected from the group consisting of: H, C 6-10 Aryl, C 1-5 Alkyl, C 3-8 Cycloalkyl, -SiMe3, -(CH2) x -O-SiMe2-C4 alkyl, -(CH2) y -C 6-10 An aromatic ring, wherein x and y are each independently 0, 1, 2, 3 or 4.

[0033] In another preferred embodiment, R 1 Independently C 1-7 Alkyl, 1, 2 or 3 R 1-1 Substituted C1-7 alkyl, R 1-1 Cl, vinyl, aryl ring, -OCH2-;

[0034] R 2 independently C 6-10 aryl ring, 5-13 membered heteroaryl ring, substituted with 1, 2, or 3 R 1-2 substituted C 6-10 aryl ring, R 1-2 F, Cl, Br, I, aryl ring, -OMe, -NMe2, -SMe, -O-CH2-O-, -CF3, -OCF3, -CN, -CO2Me, -CONEt2;

[0035] R 3 , R 4 H, C6 aryl, C 1-5 alkyl, C 3-12 cycloalkyl, -SiMe3, -CH2-O-SiMe2-CMe3 (-OTBS), benzyl.

[0036] In another preferred embodiment, R 1 independently C 1-7 alkyl, C 1-1 substituted C 1-7 alkyl;

[0037] R 2 independently -NR a R b , -OMe, -OCPh3, wherein said R a and R b are each independently selected from the group consisting of -CO-O-CMe3, -CO-O-CH2-C 6-12 aryl, -CH2-C 6-12 aryl, -CO-O-C 6-12 aryl, C6 aryl;

[0038] R 3 , R 4 are each independently selected from the group consisting of phenyl, C 1-5 alkyl, C 3-12 cycloalkyl, -SiMe3, -CH2-O-SiMe2-CMe3, -CH2-C6 aryl ring.

[0039] In another preferred embodiment, R 1 independently C 1-7 alkyl, C 1-7 alkyl;

[0040] R 2 independently C 1-7alkyl, C1-7alkyl substituted with 1, 2, or 3 C6aryl;

[0041] R 3 , R 4 is C6aryl, C 1-5 alkyl, 12-membered cycloalkyl, -SiMe3, -CH2-O-SiMe2-CMe3, -CH2-C6aryl.

[0042] In another preferred embodiment, the structure of the compound IV is selected from the following structures:

[0043]

[0044] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d are the same or different.

[0045] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d are each independently selected from the group consisting of: C 1-6 alkyl, C 6-10 aryl, or C 1-4 alkyl substituted with 1 or 2 C 6-10 aryl.

[0046] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d are each independently selected from the group consisting of: C 1-6 alkyl, C 6-10 aryl, wherein said R 9a-1 is C 1-4 alkyl.

[0047] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d , said C 6-14 aryl ring is a C 6-10 aryl ring, preferably a benzene ring or a naphthalene ring.

[0048] In another preferred embodiment, each R 9a-1 is independently selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl, or t-butyl; preferably methyl or t-butyl.

[0049] In another preferred embodiment, R 9a , R 9b , R9c and R 9d each independently is selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

[0050] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d are identical and are selected from the group consisting of:

[0051] In another preferred embodiment, R 9a , R 9b , R 9c and R 9d are identical and are selected from the group consisting of:

[0052] In another preferred embodiment, R 7a , R 7b , R 7c , R 8a , R 8b and R 8c are identical or different.

[0053] In another preferred embodiment, R 7a , R 7b , R 7c , R 8a , R 8b and R 8c are identical and are selected from the group consisting of hydrogen, methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

[0054] In another preferred embodiment, R 7a , R 7c , R 8a and R 8c are all hydrogen, R 7b , R 8b are identical and are selected from the group consisting of methyl, ethyl, n-propyl, i-propyl, n-butyl, i-butyl or t-butyl.

[0055] In another preferred embodiment, R 5 and R 6 are each independently C 6-10 aryl, or R 5 and R 6 together with the carbon atom to which they are attached form a

[0056] In another preferred embodiment, R 9a , R 9b , R 9c and R9d is unsubstituted or replaced by R 9a-1 Substituted C 6-14 When aryl, R 5 and R 6 Together with the carbon atoms to which it is attached,

[0057] In another preferred embodiment, when R 9a 、R 9b 、R 9c and R 9d C 1-6 When alkyl, R 5 and R 6 Each independently is C 6-10 Aryl.

[0058] In another preferred embodiment, Y - F - 、Cl - Br - , I - or BF4 - ; preferably Cl - or BF4 - .

[0059] In another preferred embodiment, the compound I is selected from any one of the following compounds:

[0060]

[0061] In another preferred embodiment, the compound II is selected from any one of the following compounds:

[0062]

[0063] In another preferred embodiment, the compound IV is selected from any one of the following compounds:

[0064]

[0065] In another preferred embodiment, the reaction is as follows:

[0066]

[0067] Among them, R 1 、R 2 、R 3 、R 4 Compound IV is as described above;

[0068] “-” is a bold bond, indicating a racemic form.

[0069] In another preferred embodiment, the ee value of the compound A is more than 80%, preferably more than 90%, preferably more than 95%, for example 91%, 92%, 93%, 94%, 95%.

[0070] In another preferred embodiment, the compound A is selected from the group consisting of:

[0071]

[0072]

[0073] In another preferred embodiment, the compound A is selected from the group consisting of:

[0074]

[0075]

[0076]

[0077]

[0078]

[0079]

[0080] In another preferred embodiment, the molar ratio of the compound I to the compound II is 10:1 to 1:10, preferably 8:1 to 1:5, for example 6:1, 4:1, 2:1, 1:1, 1:2, 1:5.

[0081] In another preferred embodiment, the molar ratio of the compound I to the compound III is 10:1 to 1:10, preferably 5:1 to 1:5, for example 4:1, 2:1, 1:1, 1:2, 1:3, 1:5.

[0082] In another preferred embodiment, the molar ratio of the compound I to the bis(1,5-cyclooctadiene)nickel is 1:0.01 to 0.5, preferably 1:0.01 to 0.1, for example 60:1, 50:1, 30:1, 20:1, 10:1.

[0083] In another preferred embodiment, the molar ratio of the compound IV to the bis(1,5-cyclooctadiene)nickel is 0.5 to 2:0.5 to 2, preferably 0.8 to 1.2:0.8 to 1.2, for example 1:1.

[0084] In another preferred embodiment, the solvent is an alkane solvent, an ether solvent, or a combination thereof.

[0085] In another preferred embodiment, the solvent is selected from the group consisting of n-hexane, n-heptane, cyclohexane, cycloheptane, tetrahydrofuran, 1,4-dioxane, or a combination thereof.

[0086] In another preferred embodiment, the reaction temperature of the reaction is 10-60°C, preferably 20-50°C, for example 30°C.

[0087] In another preferred embodiment, the reaction time of the reaction is 12-48h; for example 24h.

[0088] In another preferred embodiment, the feeding process of the method is carried out in a protective atmosphere.

[0089] In another preferred embodiment, the protective gas is selected from the group consisting of nitrogen, helium, argon, or a combination thereof.

[0090] In another preferred embodiment, the method comprises mixing compound IV, potassium tert-butoxide, bis(l,5-cyclooctadiene)nickel and a solvent under a protective atmosphere, then sequentially adding compound I, II and compound III thereto, and then optionally removing the protective atmosphere and carrying out the reaction at room temperature.

[0091] In another preferred embodiment, in the method, compound III needs to be slowly added into the system for about 40 minutes.

[0092] In another preferred embodiment, the reaction is carried out under stirring.

[0093] In another preferred embodiment, the stirring speed is 100-1500 rpm.

[0094] It should be understood that, within the scope of the present application, all the technical features of the present application described above and those described in detail hereinafter (such as the examples) can be combined with each other to form new or preferred technical solutions. Due to the limited space, they will not be listed one by one here. DETAILED DESCRIPTION

[0095] The present inventors have made extensive and in-depth studies, and through a large number of experimental screenings, for the first time, a method for constructing a polysubstituted allyl alcohol structure with consecutive chiral centers which is difficult to synthesize by traditional strategies is accidentally developed. In the present application, stable and readily available racemic α-branched aldehyde and alkyne are used as substrates, only a catalytic system of compound IV and Ni(cod)2 is used, and the dynamic kinetic reductive coupling reaction can be completed under mild conditions, and has very high enantiomeric, diastereomeric and regioselectivity; and the present application can also change the configuration of the product by adjusting the configuration of the ligand, and directly obtain a product with high ee, dr and rr values. The polysubstituted allyl alcohol compound with consecutive chiral centers prepared by the present application can be applied to the late-stage modification of drug molecules and the form synthesis of biologically active molecules, and the method has the advantages of high yield, simple operation, mild reaction conditions, high selectivity, strong chiral control ability and wide substrate applicability, and has high academic and application values. On this basis, the present inventors complete the present application.

[0096] Term Explanation

[0097] Unless otherwise defined, all technical and scientific terms used herein have the same meaning as commonly understood by one of ordinary skill in the art to which this application belongs. As used herein, the terms have the following meanings unless otherwise indicated:

[0098] In the present application, the term "internal olefin" includes, but is not limited to, the structure shown in compound I in the present application.

[0099] The term "halogen" refers to fluorine, chlorine, bromine or iodine.

[0100] The term "alkyl" refers to a straight-chain or branched-chain hydrocarbon group having the specified number of carbon atoms (e.g., C 1-20 ) alkyl groups include, but are not limited to, methyl, ethyl, n-propyl, isopropyl, n-butyl, t-butyl, isobutyl, sec-butyl, n-pentyl and n-hexyl, etc.

[0101] The term "cycloalkyl" refers to a cyclic hydrocarbon group consisting only of carbon atoms having the specified number of carbon atoms (e.g., C 3-20 ) cycloalkyl groups can include fused cycloalkyl groups, bridged cycloalkyl groups or spirocycloalkyl groups, preferably, the cycloalkyl groups include, but are not limited to, cyclopropyl, cyclobutyl, cyclopentyl and cyclohexyl, etc.

[0102] The term "aromatic ring" refers to a cyclic hydrocarbon group having the specified number of carbon atoms (e.g., C 6-14) consisting solely of carbon atoms, which is either monocyclic or polycyclic, and at least one of which is aromatic (complies with Huckel's rule). Aryl groups include, but are not limited to, phenyl, naphthyl, anthryl, and the like.

[0103] The term "heteroaromatic ring" refers to a cyclic hydrocarbon group having a specified number of carbon atoms (e.g., 5-16 membered), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S), which is either monocyclic or polycyclic, and at least one of which is aromatic (complies with Huckel's rule). Heteroaromatic rings preferably include 3- to 20-membered, or 3- to 12-membered, or 3- to 10-membered, or 3- to 8-membered, or 3- to 6-membered heteroaromatic rings, which can include fused, bridged, or spiro rings, and preferably include, but are not limited to, furan, pyrrole, thiophene, pyrazole, imidazole, oxazole, thiazole, pyridine, pyrimidine, and indole rings, and the like.

[0104] The term "heterocycloalkyl" refers to a saturated cyclic hydrocarbon group having a specified number of carbon atoms (e.g., C 3-20 ), a specified number of heteroatoms (e.g., 1, 2, or 3), a specified type of heteroatoms (one or more of N, O, and S). Heterocycloalkyl groups preferably include 3- to 20-membered, or 3- to 12-membered, or 3- to 10-membered, or 3- to 8-membered, or 3- to 6-membered heterocycloalkyl groups, which can include fused, bridged, or spiro heterocycloalkyl groups, and preferably include, but are not limited to, piperidine, piperazine, pyrrolidine, tetrahydrofuran, tetrahydropyran, and the like.

[0105] It will be understood by those skilled in the art that, as used in the structural formulas describing the groups herein, the use of a line indicating that a bond is made to a particular atom means that the corresponding group R is attached to the rest of the molecule at that point.

[0106] A "-" at the end of a group means that the group is attached to the rest of the molecule at that point. For example, -OCH3 means methoxy, where the oxygen is attached to the rest of the molecule.

[0107] When any variable (e.g., R Ar ) occurs more than one time in a compound, its definition in each occurrence is independent of its meaning in every other instance. Thus, if a group is substituted with 1, 2, or 3 R Ar groups, then at each occurrence it is independently substituted with up to 3 R Ar groups. Also, combinations of substituents and / or variables are permissible only if such combinations result in stable compounds. Ar Ar

[0108] ​​The above-mentioned preferred conditions can be combined arbitrarily to obtain preferred examples of the present application without departing from the common knowledge in the art.

[0109] Compared with the prior art, the present application has the following advantages:

[0110] (1) In the present application, stable and readily available racemic α-branched aldehyde and alkyne are used as substrates to efficiently synthesize allyl alcohol derivatives with consecutive chiral centers. The products obtained by the reaction have excellent regioselectivity and stereoselectivity, and can be applied to drug molecule derivatization and form synthesis of biologically active molecules, which is of great significance for efficiently and accurately synthesizing small molecules with complex structures.

[0111] (2) In the method of the present application, the yield of the chiral allyl alcohol compound prepared is high, the diastereoselectivity of the reaction is high, most of which is above 20 / 1, the enantioselectivity of the reaction is high, and most of the ee value is above 90%.

[0112] (3) The substrate of the method of the present application has very wide applicability, and has wide compatibility with various functional groups and heterocyclic structures. The chiral allyl alcohol product synthesized has various structures.

[0113] The present application will be further described below in conjunction with specific examples. It should be understood that these examples are only used to illustrate the present application and not to limit the scope of the present application. The experimental methods in the following examples are not specified, which are usually carried out according to conventional conditions or according to the conditions recommended by the manufacturer. Unless otherwise specified, percentages and parts are by weight.

[0114] Example 1:

[0115]

[0116] General Method A: In a 4 mL vial, compound IV-1 (3.7 mg, 0.004 mmol, 2 mol%), potassium tert-butoxide (1.6 mg, 0.014 mmol, 7 mol%), Ni(cod)2 (1.1 mg, 0.004 mmol, 2 mol%) (system), and 0.2 mL of tetrahydrofuran (solvent) were added in a glove box filled with nitrogen, and stirred at room temperature for 2 hours. Then compound I (0.2 mmol) (aldehyde as substrate) and compound II (0.22 mmol) (alkyne) and compound III (0.4 mmol) (triethylsilane with strong reducing property) were sequentially added, and then the glove box was removed, and the reaction was carried out at room temperature for 12 hours. After the reaction was completed, the product was separated directly by column chromatography.

[0117] wherein the structural formula of compound IV-1 is:

[0118]

[0119] General Procedure B: In a nitrogen filled glove box, to a 4 mL vial was added compound IV-1 (9.4 mg, 0.01 mmol, 5 mol%), potassium tert-butoxide (2.2 mg, 0.02 mmol, 10 mol%), Ni(cod)2(2.8 mg, 0.01 mmol, 5 mol%), and 0.2 mL tetrahydrofuran, stirred at room temperature for 2 hours. Then to it was added compound I (0.2 mmol) and compound II (0.22 mmol) and compound III (0.4 mmol) sequentially, after which the glove box was removed, and reacted at room temperature for 12 hours. After the reaction was completed, the product was isolated directly by column chromatography.

[0120]

[0121] General Procedure C: In a nitrogen filled glove box, to a 4 mL vial was added compound IV-1 (9.4 mg, 0.01 mmol, 5 mol%), potassium tert-butoxide (7.8 mg, 0.07 mmol, 35 mol%), Ni(cod)2(2.8 mg, 0.01 mmol, 5 mol%), and 0.2 mL tetrahydrofuran, stirred at room temperature for 2 hours. Then to it was added compound I (0.2 mmol) and compound II (0.22 mmol) and compound III (0.4 mmol) sequentially, after which the glove box was removed, and reacted at room temperature for 24 hours. After the reaction was completed, the product was isolated directly by column chromatography.

[0122]

[0123] General Procedure D: In a nitrogen filled glove box, to a 4 mL vial was added compound IV-1 (9.4 mg, 0.01 mmol, 5 mol%), potassium tert-butoxide (23.5 mg, 0.21 mmol, 105 mol%), Ni(cod)2(2.8 mg, 0.01 mmol, 5 mol%), and 0.2 mL tetrahydrofuran, stirred at room temperature for 2 hours. Then to it was added compound I (0.2 mmol) and compound II (0.22 mmol) and compound III (0.4 mmol) sequentially, after which the glove box was removed, and reacted at room temperature for 24 hours. After the reaction was completed, the product was isolated directly by column chromatography.

[0124] Using the above general procedures A-C, substituting the following starting materials, the corresponding products were obtained:

[0125]

[0126]

[0127] Compound 1-1 : Prepared according to General Method A as a colorless liquid in 93% yield (>20:1 dr).

[0128] 1 HNMR (400 MHz, CDC13) δ 7.28 - 7.11 (m, 5H), 5.22 (t, J = 7.4 Hz, 1H), 4.08 (d,

[0129] J = 5.4 Hz, 1H), 2.91 - 2.78 (m, 1H), 2.15 - 1.79 (m, 4H), 1.22 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.6 Hz, 3H), 0.90 - 0.77 (m, 12H), 0.54 - 0.33 (m, 6H). HPLC analysis (OJ-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 97% ee: tR(minor) = 4.5 min, tR(major) = 4.8 min.

[0130] Compound 1-2: Prepared according to General Method A as a colorless liquid in 92% yield (>20:1 dr).

[0131] 1 HNMR (400 MHz, CDC13) δ 7.28 - 7.11 (m, 5H), 5.22 (t, J = 7.4 Hz, 1H), 4.08 (d,

[0132] Compound 1-3: Prepared according to General Method B as a colorless liquid in 92% yield (>20:1 dr).

[0133] 1 HNMR (400 MHz, CDC13) δ 7.28 - 7.11 (m, 5H), 5.22 (t, J = 7.4 Hz, 1H), 4.08 (d,

[0134] δ 7.72 (d, J = 6.9 Hz, 1 H), 7.59-7.40 (m, 4 H), 5.44 (t, J = 7.4 Hz, 1 H), 4.36 (d, J = 4.5 Hz, 1 H), 3.95-3.71 (m, 1 H), 2.33-2.14 (m, 1 H), 2.13-1.88 (m, 3 H), 1.39 (d, J = 6.9 Hz, 3 H), 1.02 (t, J = 7.6 Hz, 3 H), 0.90 (t, J = 7.5 Hz, 3 H), 0.79 (t, J = 7.9 Hz, 9 H), 0.44-0.23 (m, 6 H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) 84% ee: tR(major) = 8.8 min, tR(minor) = 12.3 min.

[0135] Compound 1-4: Prepared according to General Method A as a colorless liquid in 91% yield (19:1 dr).

[0136] 1 HNMR (400 MHz, CDC13) δ 7.10 (d, J = 8.4 Hz, 2 H), 6.85-6.78 (m, 2 H), 5.23 (t, J = 7.4 Hz, 1 H), 4.06 (d, J = 5.5 Hz, 1 H), 3.79 (s, 3 H), 2.83 (p, J = 6.9 Hz, 1 H), 2.17-1.77 (m, 4 H), 1.22 (d, J = 7.0 Hz, 3 H), 0.99 (t, J = 7.6 Hz, 3 H), 0.95-0.81 (m, 12 H), 0.58-0.37 (m, 6 H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) 97% ee: tR(major) = 14.1 min, tR(minor) = 16.7 min.

[0137] Compound 1-5: Prepared according to General Method A as a colorless liquid in 87% yield (14:1 dr).

[0138] 1HNMR (400 MHz, CDC13) δ 7.06 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.05 (d, J = 5.7 Hz, IH), 2.90 (s, 6H), 2.78 (p, J = 6.8 Hz, IH), 2.15-1.79 (m, 4H), 1.21 (d, J = 7.0 Hz, 3H), 1.02-0.95 (m, 3H), 0.89 (m, 12H), 0.48 (m, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 7.7 min, tR(minor) = 9.1 min.

[0139] 93% ee: tR(major) = 8.7 min, tR(minor) = 9.3 min.

[0140] Compound 1-6: Prepared according to General Method B as a colorless liquid in 78% yield (>20:1 dr).

[0141] 1 HNMR (400 MHz, CDC13) δ 7.06 (d, J = 8.4 Hz, 2H), 6.69 (d, J = 8.2 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.05 (d, J = 5.7 Hz, IH), 2.90 (s, 6H), 2.78 (p, J = 6.8 Hz, IH), 2.15-1.79 (m, 4H), 1.21 (d, J = 7.0 Hz, 3H), 1.02-0.95 (m, 3H), 0.89 (m, 12H), 0.48 (m, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 7.7 min, tR(minor) = 9.1 min.

[0142] Compound 1-7: Prepared according to General Method A as a colorless liquid in 95% yield (>20:1 dr).

[0143] 1H NMR (400 MHz, CDC13) δ 6.71 (dd, J = 4.9, 3.1 Hz, 2H), 6.63 (dd, J = 8.0, 1.7 Hz, 1H), 5.90 (s, 2H), 5.24 (t, J = 7.4 Hz, 1H), 4.09 - 3.97 (m, 1H), 2.86 - 2.72 (m, 1H), 2.16 - 1.77 (m, 4H), 1.18 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 8.0 Hz, 12H), 0.57 - 0.36 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) 98% ee: tR(minor) = 8.4 min, tR(major) = 8.8 min.

[0144] 1.0 mL / min, 220 nm) 98% ee: tR(minor) = 8.4 min, tR(major) = 8.8 min.

[0145] Compound 1-8: Prepared according to General Method A as a colorless liquid in 78% yield (13: 1 dr).

[0146] 1 H NMR (400 MHz, CDC13) δ 6.71 (dd, J = 4.9, 3.1 Hz, 2H), 6.63 (dd, J = 8.0, 1.7 Hz, 1H), 5.90 (s, 2H), 5.24 (t, J = 7.4 Hz, 1H), 4.09 - 3.97 (m, 1H), 2.86 - 2.72 (m, 1H), 2.16 - 1.77 (m, 4H), 1.18 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.88 (t, J = 8.0 Hz, 12H), 0.57 - 0.36 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) 98% ee: tR(minor) = 8.4 min, tR(major) = 8.8 min.

[0147] Compound 1-9: Prepared according to General Method A as a colorless liquid in 95% yield (>20: 1 dr).

[0148] 1HNMR (400 MHz, CDC13) δ 7.19-7.08 (m, 2H), 6.94 (t, J = 8.7 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.04 (d, J = 5.4 Hz, IH), 2.92-2.77 (m, IH), 2.16-1.77 (m, 4H), 1.20 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.92 - 0.80 (m, 12H), 0.56 - 0.34 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 94% ee: tR(major) = 6.8 min, tR(minor) = 7.8 min.

[0149] 96% ee: tR(major) = 7.6 min, tR(minor) = 8.7 min.

[0150] Compound 1-10: Prepared according to General Method B as a colorless liquid in 88% yield (>20:1 dr).

[0151] 1 HNMR (400 MHz, CDC13) δ 7.19-7.08 (m, 2H), 6.94 (t, J = 8.7 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.04 (d, J = 5.4 Hz, IH), 2.92-2.77 (m, IH), 2.16-1.77 (m, 4H), 1.20 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.92 - 0.80 (m, 12H), 0.56 - 0.34 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 94% ee: tR(major) = 6.8 min, tR(minor) = 7.8 min.

[0152] Compound 1-13: Prepared according to General Method A as a colorless liquid in 97% yield (>20:1 dr).

[0153] 1HNMR (400 MHz, CDC13) δ 7.51 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.09 (d, J = 5.3 Hz, IH), 3.02 - 2.86 (m, IH), 2.18 - 1.80 (m, 4H), 1.24 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.92 - 0.73 (m, 12H), 0.54 - 0.32 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 254 nm) gave 99% purity, 99% ee with tR(major) = 7.1 min and tR(minor) = 7.8 min.

[0154] 96% ee: tR(major) = 7.1 min, tR(minor) = 7.8 min.

[0155] Compound 1-14: Prepared according to General Method A as a colorless liquid in 95% yield (>20:1 dr).

[0156] 1 HNMR (400 MHz, CDC13) δ 7.51 (d, J = 8.1 Hz, 2H), 7.30 (d, J = 8.1 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.09 (d, J = 5.3 Hz, IH), 3.02 - 2.86 (m, IH), 2.18 - 1.80 (m, 4H), 1.24 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.92 - 0.73 (m, 12H), 0.54 - 0.32 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 254 nm) gave 99% purity, 99% ee with tR(major) = 7.1 min and tR(minor) = 7.8 min.

[0157] 93% ee: tR(major) = 14.0 min, tR(minor) = 15.7 min.

[0158] Compound 1-16: Prepared according to General Method B as a colorless liquid in 89% yield (>20:1 dr).

[0159] 1HNMR (400 MHz, CDC13) δ 7.93 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.09 (d, J = 5.4 Hz, IH), 3.90 (s, 3H), 2.91 (p, J = 6.8 Hz, IH), 2.15 - 1.77 (m, 4H), 1.22 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.9 Hz, 12H), 0.54 - 0.23 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 9.6 min, tR(minor) = 10.2 min.

[0160] Compound 1-17: Prepared according to General Method B as a colorless liquid in 84% yield (>20:1 dr).

[0161] 1 HNMR (400 MHz, CDC13) δ 7.93 (d, J = 7.9 Hz, 2H), 7.24 (d, J = 8.0 Hz, 2H), 5.23 (t, J = 7.4 Hz, IH), 4.09 (d, J = 5.4 Hz, IH), 3.90 (s, 3H), 2.91 (p, J = 6.8 Hz, IH), 2.15 - 1.77 (m, 4H), 1.22 (d, J = 6.9 Hz, 3H), 0.98 (t, J = 7.6 Hz, 3H), 0.85 (t, J = 7.9 Hz, 12H), 0.54 - 0.23 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 9.6 min, tR(minor) = 10.2 min.

[0162] Compound 1-18: Prepared according to General Method A as a colorless liquid in 80% yield (>20:1 dr).

[0163] 1HNMR (400 MHz, CDC13) δ 8.14 (s, IH), 7.52 (d, J = 7.7 Hz, IH), 7.34 (s, IH), 7.28 (ddd, J = 8.3, 7.2, 1.4 Hz, IH), 7.25 - 7.19 (m, IH), 5.40 (t, J = 6.9 Hz, IH), 4.27 (d, J = 3.2 Hz, IH), 3.20 - 3.06 (m, IH), 2.15 (dt, J = 15.0, 7.6 Hz, IH), 2.06 - 1.88 (m, 3H), 1.66 (s, 9H), 1.25 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H),

[0164] 0.90 (t, J = 7.5 Hz, 3H), 0.81 (t, J = 7.9 Hz, 9H), 0.48 - 0.26 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 254 nm) gave 98% ee: tR(minor) = 7.1 min, tR(major) = 7.7 min.

[0165] Compound 1-19: Prepared according to General Method A as a colorless liquid in 87% yield (>20:1 dr).

[0166] 1 HNMR (400 MHz, CDC13) δ 8.14 (s, IH), 7.52 (d, J = 7.7 Hz, IH), 7.34 (s, IH), 7.28 (ddd, J = 8.3, 7.2, 1.4 Hz, IH), 7.25 - 7.19 (m, IH), 5.40 (t, J = 6.9 Hz, IH), 4.27 (d, J = 3.2 Hz, IH), 3.20 - 3.06 (m, IH), 2.15 (dt, J = 15.0, 7.6 Hz, IH), 2.06 - 1.88 (m, 3H), 1.66 (s, 9H), 1.25 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H),

[0167] Compound 1-20: Prepared according to General Method A as a colorless liquid in 98% yield (8:1 dr).

[0168] 1HNMR (400 MHz, CDC13) δ 7.23 - 7.14 (m, 1H), 7.03 - 6.87 (m, 2H), 5.26 (t, J = 7.3 Hz, 1H), 4.08 (d, J = 5.2 Hz, 1H), 2.99 (p, J = 6.6 Hz, 1H), 2.15 - 1.92 (m, 3H), 1.86 (dq, J = 14.8, 7.6 Hz, 1H), 1.22 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.94 - 0.82 (m, 12H), 0.56 - 0.30 (m, 6H). HPLC analysis (OJ-H, 5% IPA in hexanes, 0.5 mL / min, 254 nm) gave 93% ee: tR(minor) = 4.6 min, tR(major) = 4.9 min.

[0169] 1.0 mL / min, 254 nm) measured 93% ee: tR(minor) = 4.6 min, tR(major) = 4.9 min.

[0170] Compound 1-21 : Prepared as a colorless liquid in 91% yield (>20:1 dr) following General Method B.

[0171] 1 HNMR (400 MHz, CDC13) δ 7.23 - 7.14 (m, 1H), 7.03 - 6.87 (m, 2H), 5.26 (t, J = 7.3 Hz, 1H), 4.08 (d, J = 5.2 Hz, 1H), 2.99 (p, J = 6.6 Hz, 1H), 2.15 - 1.92 (m, 3H), 1.86 (dq, J = 14.8, 7.6 Hz, 1H), 1.22 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.94 - 0.82 (m, 12H), 0.56 - 0.30 (m, 6H). HPLC analysis (OJ-H, 5% IPA in hexanes, 0.5 mL / min, 254 nm) gave 93% ee: tR(minor) = 4.6 min, tR(major) = 4.9 min.

[0172] Compound 1-22: Prepared as a colorless liquid in 96% yield (>20:1 dr) following General Method B.

[0173] 1HNMR (400 MHz, CDC13) δ 7.33-7.00 (m, 5H), 5.11 (t, J = 7.3 Hz, IH), 4.06 (d, J = 6.5 Hz, IH), 2.74-2.58 (m, IH), 2.08-1.95 (m, IH), 1.94-1.75 (m, 4H), 1.64-1.51 (m, IH), 1.19-0.99 (m, 2H), 0.99-0.84 (m, 12H), 0.84-0.74 (m, 6H), 0.60-0.40 (m, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 0.5 mL / min, 220 nm) gave 99% ee: tR(minor) = 11.4 min, tR(major) = 11.9 min.

[0174] >99% ee: tR(major) = 20.1 min.

[0175] Compound 1-23: Prepared according to General Method B as a colorless liquid in 87% yield (9: 1 dr).

[0176] 1 HNMR (400 MHz, CDC13) δ 7.33-7.00 (m, 5H), 5.11 (t, J = 7.3 Hz, IH), 4.06 (d, J = 6.5 Hz, IH), 2.74-2.58 (m, IH), 2.08-1.95 (m, IH), 1.94-1.75 (m, 4H), 1.64-1.51 (m, IH), 1.19-0.99 (m, 2H), 0.99-0.84 (m, 12H), 0.84-0.74 (m, 6H), 0.60-0.40 (m, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 0.5 mL / min, 220 nm) gave 99% ee: tR(minor) = 11.4 min, tR(major) = 11.9 min.

[0177] J = 5.1 Hz, IH), 2.13-1.86 (m, 4H), 1.77 (dq, J = 14.8, 7.5 Hz, IH), 1.31-1.15 (m, IH), 1.05-0.92 (m, 3H), 0.91-0.79 (m, 12H), 0.61-0.29 (m, 8H), 0.25-0.12 (m, IH), -0.11-0.23 (m, IH). HPLC analysis (OJ-H, 0.5% IPA in hexanes, 0.5 mL / min, 254 nm) gave 98% ee: tR(minor) = 11.4 min, tR(major) = 11.9 min.

[0178] Compound 1-24: Prepared according to General Method B as a colorless liquid in 99% yield (15: 1 dr).

[0179] 1HNMR (400 MHz, CDC13) δ 7.27-7.20 (m, 2H), 7.18-7.08 (m, 3H), 5.14 (t, J = 7.4 Hz, IH), 4.07 (d, J = 6.2 Hz, IH), 3.43 (t, J = 6.7 Hz, 2H), 2.71-2.58 (m, IH), 2.14-1.97 (m, 2H), 1.96-1.76 (m, 3H), 1.77-1.62 (m, IH), 1.61-1.47 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.9 Hz, 9H), 0.79 (t, J = 7.5 Hz, 3H), 0.58-0.39 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 9.4 min, tR(major) = 15.3 min.

[0180] 92% ee: tR(minor) = 9.4 min, tR(major) = 15.3 min.

[0181] Compound 1-25: Prepared according to General Method B as a colorless liquid in 93% yield (>20:1 dr).

[0182] 1 HNMR (400 MHz, CDC13) δ 7.27-7.20 (m, 2H), 7.18-7.08 (m, 3H), 5.14 (t, J = 7.4 Hz, IH), 4.07 (d, J = 6.2 Hz, IH), 3.43 (t, J = 6.7 Hz, 2H), 2.71-2.58 (m, IH), 2.14-1.97 (m, 2H), 1.96-1.76 (m, 3H), 1.77-1.62 (m, IH), 1.61-1.47 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.9 Hz, 9H), 0.79 (t, J = 7.5 Hz, 3H), 0.58-0.39 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 9.4 min, tR(major) = 15.3 min.

[0183] 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 9.4 min, tR(major) = 15.3 min.

[0184] Compound 1-26: Prepared according to General Method B as a colorless liquid in 97% yield (>20:1 dr).

[0185] 1 HNMR (400 MHz, CDC13) δ 7.27-7.20 (m, 2H), 7.18-7.08 (m, 3H), 5.14 (t, J = 7.4 Hz, IH), 4.07 (d, J = 6.2 Hz, IH), 3.43 (t, J = 6.7 Hz, 2H), 2.71-2.58 (m, IH), 2.14-1.97 (m, 2H), 1.96-1.76 (m, 3H), 1.77-1.62 (m, IH), 1.61-1.47 (m, 2H), 0.95 (t, J = 7.6 Hz, 3H), 0.89 (t, J = 7.9 Hz, 9H), 0.79 (t, J = 7.5 Hz, 3H), 0.58-0.39 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 9.4 min, tR(major) = 15.3 min.

[0186] J = 6.3 Hz, 1 H), 3.33 (d, J = 13.7 Hz, 1 H), 3.02 - 2.88 (m, 1 H), 2.74 (t, J = 12.6 Hz, 1 H), 2.17 - 1.76 (m, 4 H), 1.04 - 0.78 (m, 15 H), 0.64 - 0.43 (m, 6 H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 97% ee: tR(major) = 18.5 min, tR(minor) = 27.5 min.

[0187] Compound 1-27: Prepared according to General Method B as a colorless liquid in 99% yield (>20:1 dr).

[0188] 1 HNMR (400 MHz, CDC13) δ 7.15 - 6.78 (m, 9 H), 5.24 (t, J = 7.6 Hz, 1 H), 4.18 (d,

[0189] J = 6.3 Hz, 1 H), 3.33 (d, J = 13.7 Hz, 1 H), 3.02 - 2.88 (m, 1 H), 2.74 (t, J = 12.6 Hz, 1 H), 2.17 - 1.76 (m, 4 H), 1.04 - 0.78 (m, 15 H), 0.64 - 0.43 (m, 6 H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 97% ee: tR(major) = 18.5 min, tR(minor) = 27.5 min.

[0190] Compound 1-28: Prepared according to General Method B as a colorless liquid in 99% yield (>20:1 dr).

[0191] 1 HNMR (400 MHz, CDC13) δ 7.15 - 6.78 (m, 9 H), 5.24 (t, J = 7.6 Hz, 1 H), 4.18 (d,

[0192] 98% ee: tR(major) = 7.5 min, tR(minor) = 10.7 min.

[0193] Compound 1-29: Prepared according to General Method B as a colorless liquid in 93% yield (>20:1 dr).

[0194] 1 HNMR (400 MHz, CDC13) δ 7.09 (dd, J = 8.2, 5.5 Hz, 1H), 6.98 - 6.77 (m, 2H), 5.38 (t, J = 7.3 Hz, 1H), 4.17 (d, J = 4.9 Hz, 1H), 3.35 - 3.16 (m, 1H), 2.99 - 2.80 (m, 1H), 2.79 - 2.62 (m, 1H), 2.27 - 1.92 (m, 6H), 1.13 - 0.95 (m, 6H), 0.83 (t, J = 7.9 Hz, 9H), 0.53 - 0.31 (m, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 0.5 mL / min, 220 nm) gave >99% ee: tR(major) = 37.1 min.

[0195] Compound 1-30: Prepared according to General Method B as a colorless liquid in 54% yield (12:1 dr).

[0196] 1 HNMR (400 MHz, CDC13) δ 7.09 (dd, J = 8.2, 5.5 Hz, 1H), 6.98 - 6.77 (m, 2H), 5.38 (t, J = 7.3 Hz, 1H), 4.17 (d, J = 4.9 Hz, 1H), 3.35 - 3.16 (m, 1H), 2.99 - 2.80 (m, 1H), 2.79 - 2.62 (m, 1H), 2.27 - 1.92 (m, 6H), 1.13 - 0.95 (m, 6H), 0.83 (t, J = 7.9 Hz, 9H), 0.53 - 0.31 (m, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 0.5 mL / min, 220 nm) gave >99% ee: tR(major) = 37.1 min.

[0197] Compound 1-31: Prepared according to General Method C as a colorless liquid in 96% yield (>20:1 dr).

[0198] 1HNMR (400 MHz, CDC13) δ 7.39 - 7.09 (m, 5H), 5.36 (t, J = 7.4 Hz, IH), 4.63 - 4.26 (m, 3H), 4.13 (s, 0.6H), 3.78 (s, 0.4H), 2.22 - 1.84 (m, 4H), 1.53 (s, 3.8H), 1.32 (s, 5.2H), 1.10 - 0.87 (m, 18H), 0.60 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) 94% ee: tR(major) = 13.3 min, tR(minor) = 17.7 min.

[0199] Compound 1-32: Prepared according to General Method C as a colorless liquid in 87% yield (>20:1 dr).

[0200] 1 HNMR (400 MHz, CDC13) δ 7.39 - 7.09 (m, 5H), 5.36 (t, J = 7.4 Hz, IH), 4.63 - 4.26 (m, 3H), 4.13 (s, 0.6H), 3.78 (s, 0.4H), 2.22 - 1.84 (m, 4H), 1.53 (s, 3.8H), 1.32 (s, 5.2H), 1.10 - 0.87 (m, 18H), 0.60 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) 94% ee: tR(major) = 13.3 min, tR(minor) = 17.7 min.

[0201] Compound 1-33: Prepared according to General Method C as a colorless liquid in 73% yield (>20:1 dr).

[0202] 1 HNMR (400 MHz, CDC13) δ 7.39 - 7.09 (m, 5H), 5.36 (t, J = 7.4 Hz, IH), 4.63 - 4.26 (m, 3H), 4.13 (s, 0.6H), 3.78 (s, 0.4H), 2.22 - 1.84 (m, 4H), 1.53 (s, 3.8H), 1.32 (s, 5.2H), 1.10 - 0.87 (m, 18H), 0.60 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) 94% ee: tR(major) = 13.3 min, tR(minor) = 17.7 min.

[0203] Compound 1-34: Prepared according to General Method C as a colorless liquid in 96% yield (>20:1 dr).

[0204] 1 HNMR (400 MHz, CDC13) δ 7.32-7.03 (m, 7H), 6.73-6.54 (m, 3H), 5.32 (t, J = 7.3 Hz, IH), 4.69 (d, J = 17.8 Hz, IH), 4.41 (d, J = 17.7 Hz, IH), 4.32 (d, J = 4.8 Hz, IH), 4.21-4.09 (m, IH), 2.23-2.09 (m, IH), 2.08-1.86 (m, 3H), 1.21 (d, J = 6.7 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.91 (t, J = 7.8 Hz, 12H), 0.55 (q, J = 8.2 Hz, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 11.3 min, tR(minor) = 12.8 min.

[0205] Compound 1-35: Prepared according to General Method C as a colorless liquid in 74% yield (>20:1 dr).

[0206] 1 HNMR (400 MHz, CDC13) δ 7.32-7.03 (m, 7H), 6.73-6.54 (m, 3H), 5.32 (t, J = 7.3 Hz, IH), 4.69 (d, J = 17.8 Hz, IH), 4.41 (d, J = 17.7 Hz, IH), 4.32 (d, J = 4.8 Hz, IH), 4.21-4.09 (m, IH), 2.23-2.09 (m, IH), 2.08-1.86 (m, 3H), 1.21 (d, J = 6.7 Hz, 3H), 1.03 (t, J = 7.6 Hz, 3H), 0.91 (t, J = 7.8 Hz, 12H), 0.55 (q, J = 8.2 Hz, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 11.3 min, tR(minor) = 12.8 min.

[0207] Compound 1-36: Prepared according to General Method C as a colorless liquid in 87% yield (>20:1 dr).

[0208] 1HNMR (400 MHz, CDC13) δ 7.49 - 7.03 (m, 10H), 5.46 (t, J = 7.4 Hz, 0.42H), 5.37 - 5.23 (m, 1.13H), 4.73 - 4.55 (m, 0.84H), 4.43 - 4.23 (m, IH), 4.22 - 3.93 (m, 1.57H), 2.27 - 1.72 (m, 3H), 1.48 (dq, J = 14.7, 7.5 Hz, 0.6H), 1.25 - 0.89 (m, 17H), 0.74 - 0.53 (m, 7H). HPLC analysis (OD-H, 5% IPA in hexanes, 1.0 mL / min, 254 nm) 90% ee: tR(minor) = 12.5 min, tR(major) = 14.2 min.

[0209] Compound 1-37: Prepared according to General Method C as a colorless liquid in 98% yield (>20:1 dr).

[0210] 1 HNMR (400 MHz, CDC13) δ 7.49 - 7.03 (m, 10H), 5.46 (t, J = 7.4 Hz, 0.42H), 5.37 - 5.23 (m, 1.13H), 4.73 - 4.55 (m, 0.84H), 4.43 - 4.23 (m, IH), 4.22 - 3.93 (m, 1.57H), 2.27 - 1.72 (m, 3H), 1.48 (dq, J = 14.7, 7.5 Hz, 0.6H), 1.25 - 0.89 (m, 17H), 0.74 - 0.53 (m, 7H). HPLC analysis (OD-H, 5% IPA in hexanes, 1.0 mL / min, 254 nm) 90% ee: tR(minor) = 12.5 min, tR(major) = 14.2 min.

[0211] 1.0 mL / min, 210 nm) 96% ee: tR(major) = 6.9 min, tR(minor) = 7.3 min.

[0212] Compound 1-38: Prepared according to General Method C as a colorless liquid in 94% yield (>20:1 dr).

[0213] 1HNMR (400 MHz, CDC13) δ 5.26 (t, J = 7.2 Hz, IH), 4.42 (d, J = 9.2 Hz, IH), 4.09 (d, J = 11.5 Hz, IH), 3.96 - 3.52 (m, 3H), 3.50 - 3.31 (m, 2H), 3.15 - 2.92 (m, IH), 2.15 - 1.88 (m, 4H), 1.45 (s, 9H), 1.09 - 0.84 (m, 15H), 0.61 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 210 nm) gave 94% ee: tR(major) = 8.1 min, tR(minor) = 8.8 min.

[0214] Compound 1-39: Prepared according to General Method C as a colorless liquid in 92% yield (>20:1 dr).

[0215] 1 HNMR (400 MHz, CDC13) δ 5.26 (t, J = 7.2 Hz, IH), 4.42 (d, J = 9.2 Hz, IH), 4.09 (d, J = 11.5 Hz, IH), 3.96 - 3.52 (m, 3H), 3.50 - 3.31 (m, 2H), 3.15 - 2.92 (m, IH), 2.15 - 1.88 (m, 4H), 1.45 (s, 9H), 1.09 - 0.84 (m, 15H), 0.61 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 210 nm) gave 94% ee: tR(major) = 8.1 min, tR(minor) = 8.8 min.

[0216] Compound 1-39: Prepared according to General Method C as a colorless liquid in 92% yield (>20:1 dr).

[0217] 1 HNMR (400 MHz, CDC13) δ 5.26 (t, J = 7.2 Hz, IH), 4.42 (d, J = 9.2 Hz, IH), 4.09 (d, J = 11.5 Hz, IH), 3.96 - 3.52 (m, 3H), 3.50 - 3.31 (m, 2H), 3.15 - 2.92 (m, IH), 2.15 - 1.88 (m, 4H), 1.45 (s, 9H), 1.09 - 0.84 (m, 15H), 0.61 (q, J = 8.0 Hz, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 210 nm) gave 94% ee: tR(major) = 8.1 min, tR(minor) = 8.8 min.

[0218] Compound 1-41 : Prepared according to General Method C as a colorless liquid in 88% yield (>20:1 dr).

[0219] 1 HNMR (400 MHz, CDC13) δ 7.22 - 7.02 (m, 4H), 5.46 - 5.27 (m, IH), 4.97 (d,

[0220] J = 16.1 Hz, 0.55H), 4.75 (d, J = 16.3 Hz, 0.45H), 4.37 - 4.02 (m, 3H), 3.13 - 2.98 (m, IH), 2.75 (td, J = 16.4, 6.3 Hz, IH), 2.31 - 1.94 (m, 4H), 1.54 - 1.39 (m, 9H), 1.05 (t, J = 7.6 Hz, 3H), 1.00 (t, J = 7.5 Hz, 3H), 0.86 (td, J = 8.0, 2.4 Hz, 9H), 0.56 - 0.39 (m, 6H). HPLC analysis (ID, hexanes, 1.0 mL / min, 220 nm) gave 93% ee: tR(minor) = 9.2 min, tR(major) = 11.3 min.

[0221] 93% ee: tR(minor) = 9.2 min, tR(major) = 11.3 min.

[0222] Compound 1-42: Prepared according to General Method C as a colorless liquid in 81% yield (>20:1 dr).

[0223] 1 HNMR (400 MHz, CDC13) δ 7.22 - 7.02 (m, 4H), 5.46 - 5.27 (m, IH), 4.97 (d,

[0224] Compound 1-43: Prepared according to General Method C as a colorless liquid in 77% yield (>20:1 dr).

[0225] 1HNMR (400 MHz, CDC13) δ 5.53 - 5.40 (m, IH), 4.57 - 4.05 (m, 2H), 3.83 - 3.51 (m, 2H), 2.40 - 1.73 (m, 6H), 1.50 - 1.35 (m, 9H), 1.04 - 0.86 (m, 15H), 0.58 (q, J = 7.8 Hz, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 220 nm) 50% ee: tR(major) = 12.1 min, tR(minor) = 17.8 min.

[0226] Compound 1-44: Prepared according to General Method C as a colorless liquid in 85% yield (3:1 dr).

[0227] 1 HNMR (400 MHz, CDC13) δ 5.53 - 5.40 (m, IH), 4.57 - 4.05 (m, 2H), 3.83 - 3.51 (m, 2H), 2.40 - 1.73 (m, 6H), 1.50 - 1.35 (m, 9H), 1.04 - 0.86 (m, 15H), 0.58 (q, J = 7.8 Hz, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 220 nm) 50% ee: tR(major) = 12.1 min, tR(minor) = 17.8 min.

[0228] Compound 1-45: Prepared according to General Method C as a colorless liquid in 93% yield (19:1 dr).

[0229] 1HNMR (400 MHz, CDC13) δ 7.59 (dt, J = 7.8, 1.0 Hz, IH), 7.31 (d, J = 8.1 Hz, IH), 7.25 - 7.18 (m, IH), 7.15 - 7.08 (m, IH), 7.06 (s, IH), 5.54 - 5.39 (m, IH), 4.51 (qd, J = 6.9, 4.1 Hz, IH), 4.34 - 4.24 (m, IH), 2.37 (d, J = 1.0 Hz, 3H), 2.28 - 2.16 (m, IH), 2.08 - 1.97 (m, 2H), 1.96 - 1.84 (m, IH), 1.51 (d, J = 6.9 Hz, 3H), 1.05 (t, J = 7.6 Hz, 3H), 0.96 - 0.81 (m, 12H), 0.53 - 0.37 (m, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 254 nm) gave 92% ee: tR(major) = 5.9 min, tR(minor) = 9.2 min.

[0230] Compound 1-46: Prepared according to General Method C as a colorless liquid in 86% yield (>20:1 dr).

[0231] 1 HNMR (400 MHz, CDC13) δ 7.59 (dt, J = 7.8, 1.0 Hz, IH), 7.31 (d, J = 8.1 Hz, IH), 7.25 - 7.18 (m, IH), 7.15 - 7.08 (m, IH), 7.06 (s, IH), 5.54 - 5.39 (m, IH), 4.51 (qd, J = 6.9, 4.1 Hz, IH), 4.34 - 4.24 (m, IH), 2.37 (d, J = 1.0 Hz, 3H), 2.28 - 2.16 (m, IH), 2.08 - 1.97 (m, 2H), 1.96 - 1.84 (m, IH), 1.51 (d, J = 6.9 Hz, 3H), 1.05 (t, J = 7.6 Hz, 3H), 0.96 - 0.81 (m, 12H), 0.53 - 0.37 (m, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 254 nm) gave 92% ee: tR(major) = 5.9 min, tR(minor) = 9.2 min.

[0232] J = 7.5 Hz, 2H), 5.10 (t, J = 7.4 Hz, IH), 4.85 - 4.64 (m, 2H), 2.04 (dq, J = 14.9, 7.5 Hz, IH), 1.77 (d, J = 6.1 Hz, 3H), 1.68 (dq, J = 24.6, 7.3 Hz, 3H), 0.94 (dt, J = 18.4, 7.8 Hz, 12H), 0.61 (q, J = 7.9 Hz, 6H), 0.47 (t, J = 7.5 Hz, 3H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 254 nm) gave 94% ee: tR(minor) = 9.8 min, tR(major) = 15.9 min.

[0233] Compound 1-50: Prepared according to General Method D as a colorless liquid in 95% yield (>20:1 dr).

[0234] 1HNMR (400 MHz, CDC13) δ 5.32 (t, J = 7.3 Hz, IH), 3.99 (d, J = 4.1 Hz, IH), 2.12-1.97 (m, 3H), 1.92-1.72 (m, 3H), 1.73-1.44 (m, 6H), 1.36 (td, J = 6.9, 4.2 Hz, IH), 1.23-1.06 (m, 2H), 1.02-0.88 (m, 15H), 0.77 (d, J = 6.7 Hz, 3H), 0.64-0.51 (m, 6H). HPLC analysis (AD-H, 0.2% IPA in hexanes, 0.5 mL / min, 210 nm) gave 96% ee: tR(major) = 7.3 min, tR(minor) = 9.6 min.

[0235] 93% ee: tR(major) = 18.0 min, tR(minor) = 22.5 min.

[0236] Compound 1-51 : Prepared according to General Method D as a colorless liquid in 86% yield (>20:1 dr).

[0237] 1 HNMR (400 MHz, CDC13) δ 5.32 (t, J = 7.3 Hz, IH), 3.99 (d, J = 4.1 Hz, IH), 2.12-1.97 (m, 3H), 1.92-1.72 (m, 3H), 1.73-1.44 (m, 6H), 1.36 (td, J = 6.9, 4.2 Hz, IH), 1.23-1.06 (m, 2H), 1.02-0.88 (m, 15H), 0.77 (d, J = 6.7 Hz, 3H), 0.64-0.51 (m, 6H). HPLC analysis (AD-H, 0.2% IPA in hexanes, 0.5 mL / min, 210 nm) gave 96% ee: tR(major) = 7.3 min, tR(minor) = 9.6 min.

[0238] Compound 1-52: Prepared according to General Method D as a colorless liquid in 98% yield (>20:1 dr).

[0239] 1HNMR (400 MHz, CDC13) δ 7.42-7.33 (m, 2H), 7.32-7.18 (m, 6H), 7.18-7.07 (m, 2H), 5.38 (td, J = 7.4, 1.4 Hz, IH), 4.12-4.01 (m, IH), 3.86 (d, J = 11.1 Hz, IH), 2.44 (dqd, J = 11.2, 6.6, 1.6 Hz, IH), 2.20-1.97 (m, 3H), 1.91-1.77 (m, IH), 0.97 (t, J = 7.5 Hz, 3H), 0.93-0.82 (m, 12H), 0.65 (d, J = 6.7 Hz, 3H), 0.45 (q, J = 8.0 Hz, 6H). HPLC analysis (IC, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 4.9 min, tR(major) = 6.7 min.

[0240] Compound 1-53: Prepared according to General Method D as a colorless liquid in 81% yield (>20:1 dr).

[0241] 1 HNMR (400 MHz, CDC13) δ 7.42-7.33 (m, 2H), 7.32-7.18 (m, 6H), 7.18-7.07 (m, 2H), 5.38 (td, J = 7.4, 1.4 Hz, IH), 4.12-4.01 (m, IH), 3.86 (d, J = 11.1 Hz, IH), 2.44 (dqd, J = 11.2, 6.6, 1.6 Hz, IH), 2.20-1.97 (m, 3H), 1.91-1.77 (m, IH), 0.97 (t, J = 7.5 Hz, 3H), 0.93-0.82 (m, 12H), 0.65 (d, J = 6.7 Hz, 3H), 0.45 (q, J = 8.0 Hz, 6H). HPLC analysis (IC, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 98% ee: tR(minor) = 4.9 min, tR(major) = 6.7 min.

[0242] Compound 1-54: Prepared according to General Method D as a colorless liquid in 87% yield (16:1 dr).

[0243] 1HNMR (400 MHz, CDC13) δ 7.28-7.05 (m, 5H), 5.35 (t, J = 7.2 Hz, IH), 4.10 (d, J = 5.3 Hz, IH), 2.93 (dd, J = 14.6, 3.6 Hz, IH), 2.42 (dd, J = 14.7, 7.7 Hz, IH), 2.16-1.98 (m 3H), 1.92 (dq, J = 14.9, 7.7 Hz, IH), 1.81-1.62 (m, 2H), 1.05-0.89 (m, 15H), 0.85 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7.3 Hz, 3H), 0.66-0.50 (m, 6H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 84% ee: tR(minor) = 7.9 min, tR(minor) = 9.0 min.

[0244] Compound 1-55: Prepared according to General Method D as a colorless liquid in 97% yield (1.5:1 dr).

[0245] 1 HNMR (400 MHz, CDC13) δ 7.28-7.05 (m, 5H), 5.35 (t, J = 7.2 Hz, IH), 4.10 (d, J = 5.3 Hz, IH), 2.93 (dd, J = 14.6, 3.6 Hz, IH), 2.42 (dd, J = 14.7, 7.7 Hz, IH), 2.16-1.98 (m 3H), 1.92 (dq, J = 14.9, 7.7 Hz, IH), 1.81-1.62 (m, 2H), 1.05-0.89 (m, 15H), 0.85 (d, J = 6.6 Hz, 3H), 0.81 (d, J = 7.3 Hz, 3H), 0.66-0.50 (m, 6H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 84% ee: tR(minor) = 7.9 min, tR(minor) = 9.0 min.

[0246] J = 6.0 Hz, 0.6H), 3.77 (d, J = 6.9 Hz, 0.4H), 3.18 (dd, J = 13.2, 3.1 Hz, 0.4H),

[0247] 2.77 (dd, J = 13.5, 4.1 Hz, 0.6H), 2.25-1.74 (m, 6H), 1.11-0.88 (m, 15H), 0.76 (d, J = 6.9 Hz, 1.8H), 0.68 (dd, J = 7.8, 3.3 Hz, 1.2H), 0.65-0.54 (m, 6H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 0.5 mL / min, 220 nm) gave 97% ee 1 : tR(minor) = 15.9 min, tR(major) = 16.7 min, 98% ee 2: tR(minor) = 18.0 min, tR(major) = 20.6 min.

[0248] Compound 1-56: Prepared according to General Method A as a colorless liquid in 85% yield (>20:1 dr).

[0249] 1HNMR (400 MHz, CDC13) δ 7.18 - 6.93 (m, 4H), 5.26 (t, J = 7.4 Hz, IH), 4.08 (d, J = 5.0 Hz, IH), 2.85 (p, J = 6.8 Hz, IH), 2.45 (d, J = 7.1 Hz, 2H), 2.23 - 1.76 (m, 5H), 1.22 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.95 - 0.74 (m, 18H), 0.55 - 0.29 (m, J = 7.6 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) 98% ee: tR(major) = 6.6 min, tR(minor) = 7.5 min.

[0250] Compound 1-57: Prepared according to General Method A as a colorless liquid in 84% yield (>20:1 dr).

[0251] 1 HNMR (400 MHz, CDC13) δ 7.18 - 6.93 (m, 4H), 5.26 (t, J = 7.4 Hz, IH), 4.08 (d, J = 5.0 Hz, IH), 2.85 (p, J = 6.8 Hz, IH), 2.45 (d, J = 7.1 Hz, 2H), 2.23 - 1.76 (m, 5H), 1.22 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.95 - 0.74 (m, 18H), 0.55 - 0.29 (m, J = 7.6 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) 98% ee: tR(major) = 6.6 min, tR(minor) = 7.5 min.

[0252] Compound 1-58: Prepared according to General Method A as a colorless liquid in 95% yield (>20:1 dr).

[0253] 1 HNMR (400 MHz, CDC13) δ 7.18 - 6.93 (m, 4H), 5.26 (t, J = 7.4 Hz, IH), 4.08 (d, J = 5.0 Hz, IH), 2.85 (p, J = 6.8 Hz, IH), 2.45 (d, J = 7.1 Hz, 2H), 2.23 - 1.76 (m, 5H), 1.22 (d, J = 7.0 Hz, 3H), 1.00 (t, J = 7.6 Hz, 3H), 0.95 - 0.74 (m, 18H), 0.55 - 0.29 (m, J = 7.6 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) 98% ee: tR(major) = 6.6 min, tR(minor) = 7.5 min.

[0254] J = 8.4, 1.8 Hz, IH), 7.14 (d, J = 9.1 Hz, 2H), 5.30 (t, J = 7.3 Hz, IH), 4.21 (d,

[0255] J = 5.4 Hz, IH), 3.93 (s, 3H), 3.02 (p, J = 6.7 Hz, IH), 2.12 (dt, J = 15.2, 7.6 Hz, IH), 2.05 - 1.83 (m, 3H), 1.34 (d, J = 6.9 Hz, 3H), 1.02 (t, J = 7.6 Hz, 3H), 0.93 - 0.77 (m, 12H), 0.57 - 0.35 (m, J = 7.5 Hz, 6H). HPLC analysis (AD-H, 2% IPA in hexanes, 1.0 mL / min, 254 nm) gave 96% ee: tR(major) = 16.4 min, tR(minor) = 17.8 min.

[0256] Compound 1-59: Prepared according to General Method B as a colorless liquid in 76% yield (>20: 1 dr).

[0257] 1 HNMR (400 MHz, CDC13) δ 7.79 (d, J = 7.6 Hz, 2H), 7.65 (s, IH), 7.57 (d, J = 7.7 Hz, 2H), 7.53 - 7.40 (m, 3H), 7.36 (t, J = 7.6 Hz, IH), 5.25 (t, J = 7.4 Hz, IH), 4.10 (d, J = 5.3 Hz, IH), 2.95 (p, J = 6.7 Hz, IH), 2.20 - 1.75 (m, 4H), 1.24 (d, J = 7.0 Hz, 3H), 0.99 (t, J = 7.6 Hz, 3H), 0.91 - 0.70 (m, 12H), 0.54 - 0.30 (m, J = 7.6 Hz, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 254 nm) gave 98% ee: tR(minor) = 12.8 min, tR(major) = 15.3 min.

[0258] Compound 2-1 : Prepared according to General Method A as a colorless liquid in 99% yield (9: 1 dr).

[0259] 1HNMR (400 MHz, CDC13) δ 7.16 (m, 5H), 5.11 (q, J = 6.9 Hz, IH), 3.98 (d, J = 7.8 Hz, IH), 2.85 (q, J = 7.2 Hz, IH), 1.49 (s, 3H), 1.37 (d, J = 6.7 Hz, 3H), 1.32-1.01 (m, 3H), 1.00-0.64 (m, 9H), 0.61-0.18 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 84% ee: tR(minor) = 8.2 min, tR(major) = 10.0 min.

[0260] Compound 2-2: Prepared according to General Method A as a colorless liquid in 98% yield (>20:1 dr).

[0261] 1 HNMR (400 MHz, CDC13) δ 7.16 (m, 5H), 5.11 (q, J = 6.9 Hz, IH), 3.98 (d, J = 7.8 Hz, IH), 2.85 (q, J = 7.2 Hz, IH), 1.49 (s, 3H), 1.37 (d, J = 6.7 Hz, 3H), 1.32-1.01 (m, 3H), 1.00-0.64 (m, 9H), 0.61-0.18 (m, 6H). HPLC analysis (AD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 84% ee: tR(minor) = 8.2 min, tR(major) = 10.0 min.

[0262] Compound 2-3: Prepared according to General Method A as a colorless liquid in 99% yield (>20:1 dr).

[0263] 1HNMR (400 MHz, CDC13) δ 7.31 - 7.08 (m, 5H), 5.24 (t, J = 7.4 Hz, IH), 4.08 (d, J = 5.3 Hz, IH), 2.93 - 2.79 (m, IH), 2.11 - 1.73 (m, 4H), 1.45 - 1.25 (m, 5H), 1.24 - 1.17 (m, 6H), 0.88 (dt, J = 26.1, 7.4 Hz, 15H), 0.50 - 0.33 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 94% ee: tR(minor) = 5.1 min, tR(major) = 5.7 min.

[0264] Compound 2-4: Prepared according to General Method A as a colorless liquid in 99% yield (>20:1 dr).

[0265] 1 HNMR (400 MHz, CDC13) δ 7.31 - 7.08 (m, 5H), 5.24 (t, J = 7.4 Hz, IH), 4.08 (d, J = 5.3 Hz, IH), 2.93 - 2.79 (m, IH), 2.11 - 1.73 (m, 4H), 1.45 - 1.25 (m, 5H), 1.24 - 1.17 (m, 6H), 0.88 (dt, J = 26.1, 7.4 Hz, 15H), 0.50 - 0.33 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 94% ee: tR(minor) = 5.1 min, tR(major) = 5.7 min.

[0266] Compound 2-5: Prepared according to General Method A as a colorless liquid in 85% yield (>20:1 dr).

[0267] 1HNMR (400 MHz, CDC13) δ 7.35 - 7.06 (m, 5H), 5.44 (dd, J = 10.5, 5.7 Hz, IH), 4.20 (d, J = 4.1 Hz, IH), 2.92 (qd, J = 7.0, 4.0 Hz, IH), 2.44 - 2.28 (m, IH), 2.26 - 2.13 (m, IH), 1.96 - 1.69 (m, 2H), 1.57 - 1.23 (m, 16H), 1.16 (d, J = 7.0 Hz, 3H), 0.81 (t, J = 7.9 Hz, 9H), 0.45 - 0.21 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 96% ee: tR(minor) = 7.1 min, tR(major) = 8.0 min.

[0268] Compound 2-6: Prepared according to General Method B as a colorless liquid in 41% yield (>20:1 dr).

[0269] 1 HNMR (400 MHz, CDC13) δ 7.35 - 7.06 (m, 5H), 5.44 (dd, J = 10.5, 5.7 Hz, IH), 4.20 (d, J = 4.1 Hz, IH), 2.92 (qd, J = 7.0, 4.0 Hz, IH), 2.44 - 2.28 (m, IH), 2.26 - 2.13 (m, IH), 1.96 - 1.69 (m, 2H), 1.57 - 1.23 (m, 16H), 1.16 (d, J = 7.0 Hz, 3H), 0.81 (t, J = 7.9 Hz, 9H), 0.45 - 0.21 (m, 6H). HPLC analysis (OD-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 96% ee: tR(minor) = 7.1 min, tR(major) = 8.0 min.

[0270] Compound 2-7: Prepared according to General Method B as a colorless liquid in 39% yield (>20:1 dr).

[0271] 1HNMR (400 MHz, CDC13) δ 7.20 (m, 5H), 5.54 (t, J = 6.0 Hz, IH), 4.36-4.09 (m, 4H), 3.92 (d, J = 12.2 Hz, IH), 2.91 (p, J = 6.8 Hz, IH), 1.21 (d, J = 7.0 Hz, 3H), 0.85 (m, 27H), 0.48-0.29 (m, J = 7.5 Hz, 6H), 0.06 (d, J = 6.5 Hz, 12H). HPLC analysis (OD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 86% ee: tR(minor) = 20.1 min, tR(major) = 23.4 min.

[0272] Compound 2-8: Prepared according to General Method B as a colorless liquid in 79% yield (18: 1 dr).

[0273] 1 HNMR (400 MHz, CDC13) δ 7.20 (m, 5H), 5.54 (t, J = 6.0 Hz, IH), 4.36-4.09 (m, 4H), 3.92 (d, J = 12.2 Hz, IH), 2.91 (p, J = 6.8 Hz, IH), 1.21 (d, J = 7.0 Hz, 3H), 0.85 (m, 27H), 0.48-0.29 (m, J = 7.5 Hz, 6H), 0.06 (d, J = 6.5 Hz, 12H). HPLC analysis (OD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 86% ee: tR(minor) = 20.1 min, tR(major) = 23.4 min.

[0274] Compound 2-9: Prepared according to General Method B as a colorless liquid in 95% yield (16: 1 dr, 15: 1 rr).

[0275] 1 HNMR (400 MHz, CDC13) δ 7.20 (m, 5H), 5.54 (t, J = 6.0 Hz, IH), 4.36-4.09 (m, 4H), 3.92 (d, J = 12.2 Hz, IH), 2.91 (p, J = 6.8 Hz, IH), 1.21 (d, J = 7.0 Hz, 3H), 0.85 (m, 27H), 0.48-0.29 (m, J = 7.5 Hz, 6H), 0.06 (d, J = 6.5 Hz, 12H). HPLC analysis (OD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 86% ee: tR(minor) = 20.1 min, tR(major) = 23.4 min.

[0276] J = 4.8 Hz, 1 H), 4.19 (d, J = 11.6 Hz, 1 H), 3.92 (d, J = 11.7 Hz, 1 H), 3.03-2.88 (m, 1 H), 2.04 (m, 2 H), 1.20 (d, J = 7.0 Hz, 3 H), 0.91 (s, 12 H), 0.82 (t, J = 7.9 Hz, 9 H), 0.48-0.28 (m, J = 7.8 Hz, 6 H), 0.08 (d, J = 6.7 Hz, 6 H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(major) = 11.8 min, tR(minor) = 14.1 min.

[0277] Compound 2-10: Prepared according to General Method B as a colorless liquid in 72% yield (14:1 dr, >20:1 rr).

[0278] 1 HNMR (400 MHz, CDC13) δ 7.39-7.30 (m, 2 H), 7.30-7.24 (m, 1 H), 7.23-7.09 (m, 5 H), 7.04-6.99 (m, 2 H), 5.78 (qd, J = 7.0, 1.3 Hz, 1 H), 4.49 (dq, J = 3.8, 1.2 Hz, 1 H), 2.62 (m, 1 H), 1.60-1.52 (m, 3 H), 1.18 (d, J = 7.0 Hz, 3 H), 0.86 (m, 9 H), 0.54-0.32 (m, 6 H). HPLC analysis (OJ-H, 5% IPA in hexanes, 1.0 mL / min, 254 nm) gave 84% ee: tR(minor) = 6.2 min, tR(major) = 7.7 min.

[0279] Compound 2-11: Prepared according to General Method B as a colorless liquid in 60% yield (9:1 dr, >20:1 rr).

[0280] 1HNMR (400 MHz, CDC13) δ 7.32-7.08 (m, 5H), 6.23 (s, IH), 4.27 (d, J = 4.8 Hz, IH), 2.84-2.69 (m, IH), 1.73 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 0.83 (t, J = 8.0 Hz, 9H), 0.45-0.29 (m, J = 6.9 Hz, 6H), 0.16 (s, 9H). HPLC analysis (OJ-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 77% ee: tR(minor) = 11.7 min, tR(major) = 14.0 min.

[0281] Compound 2-12: Prepared according to General Method B as a colorless liquid in 73% yield (1.2:1 dr, 94:6 rr).

[0282] 1 HNMR (400 MHz, CDC13) δ 7.32-7.08 (m, 5H), 6.23 (s, IH), 4.27 (d, J = 4.8 Hz, IH), 2.84-2.69 (m, IH), 1.73 (d, J = 6.9 Hz, 3H), 1.18 (d, J = 7.0 Hz, 3H), 0.83 (t, J = 8.0 Hz, 9H), 0.45-0.29 (m, J = 6.9 Hz, 6H), 0.16 (s, 9H). HPLC analysis (OJ-H, 1% IPA in hexanes, 1.0 mL / min, 220 nm) gave 77% ee: tR(minor) = 11.7 min, tR(major) = 14.0 min.

[0283] Compound 2-13: Prepared according to General Method B as a colorless liquid in 74% yield (1.2:1 dr, >20:1 rr).

[0284] 1HNMR (400 MHz, CDC13) δ 7.32-7.07 (m, 10H), 5.59-5.25 (m, 2H), 4.08-4.01 (m, IH), 2.81-2.61 (m, 2H), 2.54 (t, J = 7.8 Hz, IH), 2.37-2.18 (m, 2H), 1.28-1.23 (m, 2H), 1.15 (d, J = 7.1 Hz, IH), 0.95-0.75 (m, 9H), 0.58-0.33 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 79% ee 1 : tR(minor) = 8.3 min, tR(major) = 9.2 min, 85% ee 2: tR(minor) = 9.7 min, tR(major) = 10.6 min.

[0285] Compound 2-14: Prepared according to General Method C as a light pink liquid in 89% yield (9: 1 dr).

[0286] 1 HNMR (400 MHz, CDC13) δ 7.32-7.07 (m, 10H), 5.59-5.25 (m, 2H), 4.08-4.01 (m, IH), 2.81-2.61 (m, 2H), 2.54 (t, J = 7.8 Hz, IH), 2.37-2.18 (m, 2H), 1.28-1.23 (m, 2H), 1.15 (d, J = 7.1 Hz, IH), 0.95-0.75 (m, 9H), 0.58-0.33 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 79% ee 1 : tR(minor) = 8.3 min, tR(major) = 9.2 min, 85% ee 2: tR(minor) = 9.7 min, tR(major) = 10.6 min.

[0287] Compound 2-14: Prepared according to General Method C as a light pink liquid in 89% yield (9: 1 dr).

[0288] 1 HNMR (400 MHz, CDC13) δ 7.32-7.07 (m, 10H), 5.59-5.25 (m, 2H), 4.08-4.01 (m, IH), 2.81-2.61 (m, 2H), 2.54 (t, J = 7.8 Hz, IH), 2.37-2.18 (m, 2H), 1.28-1.23 (m, 2H), 1.15 (d, J = 7.1 Hz, IH), 0.95-0.75 (m, 9H), 0.58-0.33 (m, 6H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 79% ee 1 : tR(minor) = 8.3 min, tR(major) = 9.2 min, 85% ee 2: tR(minor) = 9.7 min, tR(major) = 10.6 min.

[0289] Compound 2-16: Prepared according to General Method C as a light pink liquid in 86% yield (>20:1 dr).

[0290] 1 HNMR (400 MHz, CDC13) δ 5.33 (t, J = 7.3 Hz, IH), 4.31 (d, J = 6.9 Hz, IH), 4.18-3.72 (m, 2H), 2.98-2.68 (m, IH), 2.14-1.83 (m, 5H), 1.71-1.23 (m, 22H), 0.91 (m, 15H), 0.57 (q, J = 7.9 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min) 98% ee: tR(major) = 12.4 min, tR(minor) = 16.1 min.

[0291] Compound 2-17: Prepared according to General Method C as a light pink liquid in 91% yield (>20:1 dr).

[0292] 1 HNMR (400 MHz, CDC13) δ 5.33 (t, J = 7.3 Hz, IH), 4.31 (d, J = 6.9 Hz, IH), 4.18-3.72 (m, 2H), 2.98-2.68 (m, IH), 2.14-1.83 (m, 5H), 1.71-1.23 (m, 22H), 0.91 (m, 15H), 0.57 (q, J = 7.9 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min, 210 nm) 98% ee: tR(major) = 11.7 min, tR(minor) = 14.6 min.

[0293] Compound 2-18: Prepared according to General Method C as a light pink liquid in 96% yield (>20:1 dr).

[0294] 1HNMR (400 MHz, CDC13) δ 5.60 - 5.39 (br, IH), 4.50 - 4.33 (br, IH), 4.19 - 3.73 (m, 2H), 3.12 - 2.81 (m, IH), 2.36 - 2.20 (m, IH), 2.19 - 2.04 (m, IH), 2.02 - 1.77 (m, 3H), 1.65 - 1.24 (m, 30H), 0.94 (t, J = 7.9 Hz, 9H), 0.58 (q, J = 7.7 Hz, 6H). HPLC analysis (OD-H, 0.5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 96% ee: tR(minor) = 12.2 min, tR(major) = 14.3 min.

[0295] Compound 2-19: Prepared according to General Method C as a colorless liquid in 54% yield (>20:1 dr).

[0296] 1 HNMR (400 MHz, CDC13) δ 7.39 - 7.19 (m, 5H), 7.06 (dd, J = 5.2, 2.0 Hz, 3H), 6.91 (dd, J = 7.0, 2.9 Hz, 2H), 6.73 (s, IH), 4.88 - 4.75 (m, IH), 4.14 - 4.04 (m, IH), 3.80 (d, J = 13.6 Hz, IH), 2.82 (td, J = 13.5, 12.8, 3.2 Hz, IH), 2.48 - 2.30 (br, IH), 2.02 (dt, J = 12.5, 4.5 Hz, IH), 1.81 - 1.66 (m, IH), 1.57 - 1.27 (m, 13H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(minor) = 12.8 min, tR(major) = 14.8 min.

[0297] Compound 2-21: Prepared according to General Method C as a light pink liquid in 82% yield (>20:1 dr, 7:1 rr). 1HNMR (400 MHz, CDC13) δ 5.42 (q, J = 7.0 Hz, IH), 4.30 (d, J = 7.0 Hz, IH), 4.24-3.74 (m, 2H), 2.95-2.60 (m, IH), 2.11-1.85 (m, 3H), 1.61-1.25 (m, 23H), 1.00-0.82 (m, 12H), 0.57 (q, J = 7.6 Hz, 6H). HPLC analysis (AD-H, 0.5% IPA in hexanes, 1.0 mL / min, 210 nm) gave 95% ee: tR(minor) = 18.5 min, tR(major) = 21.0 min.

[0298] Compound 2-22: Prepared according to General Method C as a colorless liquid in 46% yield (>20:1 dr, >20:1 rr). 1 HNMR (400 MHz, CDC13) δ 7.48-7.32 (m, 3H), 7.29-7.07 (m, 7H), 6.97-6.85 (m, 2H), 6.51 (t, J = 7.2 Hz, IH), 6.10 (d, J = 8.2 Hz, 2H), 5.80 (q, J = 6.9 Hz, IH), 4.86 (d, J = 18.1 Hz, IH), 4.81-4.72 (m, IH), 4.30 (d, J = 18.1 Hz, IH), 3.90 (qd, J = 6.7, 2.8 Hz, IH), 1.60 (d, J = 7.0 Hz, 3H), 1.18 (d, J = 6.8 Hz, 3H), 0.95 (t, J = 7.9 Hz, 9H), 0.63 (q, J = 8.1 Hz, 6H). HPLC analysis (AD-H, 5% IPA in hexanes,

[0299] 1.0 mL / min, 254 nm) gave 90% ee: tR(major) = 9.8 min, tR(minor) = 12.3 min.

[0300] Compound 2-23: Prepared according to General Method C as a colorless liquid in 72% yield (>20:1 dr, 10:1 rr).

[0301] 1HNMR (400 MHz, CDC13) δ 7.39 (d, J = 7.0 Hz, 4H), 7.31 (t, J = 7.4 Hz, 4H), 7.27 - 7.20 (m, 2H), 5.45 (t, J = 7.3 Hz, IH), 4.39 (d, J = 5.7 Hz, IH), 3.88 (d, J = 11.6 Hz, IH), 3.81 - 3.69 (m, 3H), 3.54 (d, J = 14.0 Hz, 2H), 2.71 (p, J = 6.5 Hz, IH),

[0302] 2.18 (dh, J = 22.0, 7.4 Hz, 2H), 1.11 (d, J = 6.6 Hz, 3H), 1.05 - 0.93 (m, 12H), 0.92 (s, 9H), 0.69 - 0.59 (m, 6H), 0.04 (s, 3H), 0.00 (s, 3H). HPLC analysis (AD-H, 5% IPA in hexanes, 1.0 mL / min, 220 nm) gave 95% ee: tR(minor) = 17.0 min, tR(major) = 14.4 min.

[0303] Compound 2-24: Prepared according to General Method C as a colorless liquid in 73% yield (>20:1 dr, 12:1 rr).

[0304] 1 HNMR (400 MHz, CDC13) δ 7.39 (d, J = 7.0 Hz, 4H), 7.31 (t, J = 7.4 Hz, 4H), 7.27 - 7.20 (m, 2H), 5.45 (t, J = 7.3 Hz, IH), 4.39 (d, J = 5.7 Hz, IH), 3.88 (d, J = 11.6 Hz, IH), 3.81 - 3.69 (m, 3H), 3.54 (d, J = 14.0 Hz, 2H), 2.71 (p, J = 6.5 Hz, IH),

[0305] Compound 2-25: Prepared according to General Method D as a colorless liquid in 93% yield (>20:1 dr, 7:1 rr).

[0306] 1HNMR (400 MHz, CDC13) δ 7.35 (d, J = 6.8 Hz, 2H), 7.30 - 7.17 (m, 6H), 7.16 - 7.06 (m, 2H), 5.47 (q, J = 8.4, 7.6 Hz, 0.87H), 5.40 - 5.34 (m, 0.13H), 4.06 (s, 0.87H), 3.98 (s, 0.13H), 3.89 - 3.79 (m, IH), 2.52 - 2.38 (m, IH), 2.19 - 1.95 (m, IH), 1.85 - 1.73 (m, IH), 1.60 (d, J = 6.9 Hz, 2.6H), 1.55 (s, 0.4H), 1.39 - 1.17 (m, 6H), 0.94 - 0.81 (m, 12H), 0.69 (d, J = 6.7 Hz, 0.4H), 0.64 (d, J = 6.7 Hz, 2.6H), 0.45 (q, J = 7.9 Hz, 6H). HPLC analysis (IC, 0.2% IPA in hexanes, 0.5 mL / min, 220 nm) gave 90% ee 1 : tR(minor) = 30.4 min, tR(major) = 41.2 min, 89% ee 2: tR(minor) = 27.5 min, tR(major) = 34.8 min.

[0307] Compound 2-27: Prepared according to general procedure C as a colorless liquid in 50% yield (>20:1 dr, >20:1 rr).

[0308] 1 HNMR (400 MHz, CDC13) δ 7.35 (d, J = 6.8 Hz, 2H), 7.30 - 7.17 (m, 6H), 7.16 - 7.06 (m, 2H), 5.47 (q, J = 8.4, 7.6 Hz, 0.87H), 5.40 - 5.34 (m, 0.13H), 4.06 (s, 0.87H), 3.98 (s, 0.13H), 3.89 - 3.79 (m, IH), 2.52 - 2.38 (m, IH), 2.19 - 1.95 (m, IH), 1.85 - 1.73 (m, IH), 1.60 (d, J = 6.9 Hz, 2.6H), 1.55 (s, 0.4H), 1.39 - 1.17 (m, 6H), 0.94 - 0.81 (m, 12H), 0.69 (d, J = 6.7 Hz, 0.4H), 0.64 (d, J = 6.7 Hz, 2.6H), 0.45 (q, J = 7.9 Hz, 6H). HPLC analysis (IC, 0.2% IPA in hexanes, 0.5 mL / min, 220 nm) gave 90% ee 1 : tR(minor) = 30.4 min, tR(major) = 41.2 min, 89% ee 2: tR(minor) = 27.5 min, tR(major) = 34.8 min.

[0309] The compounds of the present application are shown in Table 1 below:

[0310] Table 1 List of compounds of the present application

[0311]

[0312]

[0313]

[0314]

[0315]

[0316]

[0317]

[0318]

[0319]

[0320]

[0321]

[0322]

[0323]

[0324]

[0325] In summary, the method of the present application has good substrate universality, and the product can be obtained with very high selectivity, thus being very suitable for the preparation of allyl alcohol derivatives with double chiral centers.

[0326] All documents mentioned in the present application are incorporated herein by reference. In addition, it is to be understood that the application can admit of various changes and modifications and also various alternatives, all falling within the frame of the claims appended hereto.

Claims

1. A method for constructing a continuous chiral center allyl alcohol derivative, characterized in that: The method comprises the following steps: in a solvent, in a system, reacting compound I, compound II and compound III as shown below to obtain compound A: The system is compound IV and bis(1,5-cyclooctadiene)nickel; Among them, R 1 、R 2 are each independently H, substituted or unsubstituted C 1-7 Alkyl, substituted or unsubstituted C 3-10 Cycloalkyl, substituted or unsubstituted C 3-10 Heterocycloalkyl, substituted or unsubstituted C 6-10 Aryl, substituted or unsubstituted 5-13 membered heteroaryl, substituted or unsubstituted 7-13 membered aromatic ring and cycloalkyl, substituted or unsubstituted C 6-13 Aromatic and heterocyclic alkyl, substituted or unsubstituted 7-13 membered heteroaromatic and cycloalkyl, substituted or unsubstituted 7-13 membered heterocyclic alkyl and aryl, -NR a R b , -OMe, -OCPh3; or R 1 、R 2 and the CH connected thereto together form a structure selected from the group consisting of: a substituted or unsubstituted 5-13 membered heteroaryl group, a substituted or unsubstituted 7-13 membered aromatic ring and cycloalkyl group, a substituted or unsubstituted C 6-13 Aromatic and heterocycloalkyl, substituted or unsubstituted 7-13 membered heteroaromatic and cycloalkyl, substituted or unsubstituted 7-13 membered heterocycloalkyl and aryl; Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, C 2-7 Alkenyl, C 6-13 Aryl, C 1-7 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -OMe, -NMe2, -SMe, -CF3, -COCF3, -CN, -CO2Me, -C(O)NMe2, -C(O)NEt2, -CH2CHMe2, benzoyl, tert-butylcarbonyl (-Boc), benzyloxycarbonyl (-Cbz), triphenylmethylether (-OTr); R a 、R b Each independently selected from the group consisting of: -C(O)-O-(CH2) n -C(CH3)3, -C(O)-O-(CH2) m -C 6-12 Aryl, -(CH2) p -C 6-12 Aryl, -C(O)-C 6-12 Aryl, C 6-10 Aryl, wherein n, m, and p are each independently 0, 1, 2, 3, 4, 5, 6, or 7; or R a 、R b Together with the adjacent N, it forms a 3-10-membered ring structure; R 3 、R 4 Each independently selected from the group consisting of: H, C 6-10 Aryl, C 1-10 Alkyl, C 3-12 Cycloalkyl, -SiMe3, -(CH2) x -O-SiMe2-C4 alkyl, -(CH2) y -C 6-10 Aromatic ring; wherein x and y are each independently 0, 1, 2, 3, 4, 5, 6 or 7; Wherein, each of the heterocycloalkyl groups or heteroaromatic rings independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

2. The method according to claim 1, characterized in that The structure of compound IV is: in, R 9a 、R 9b 、R 9c and R 9d are each independently substituted or unsubstituted C 1-6 Alkyl, substituted or unsubstituted C 6-14 Aryl, wherein the substitution refers to one or more hydrogen atoms on the group being independently substituted by a substituent selected from the group consisting of halogen, C 1-4 Alkyl, C 6-14 aryl; R 7a 、R 7b 、R 7c 、R 8a 、R 8b and R 8c are independently selected from the group consisting of hydrogen, halogen, C 1-4 alkyl; R 5 and R 6 are independently selected from the group consisting of hydrogen, C 1-4 Alkyl, halogen, C 6-10 Aryl; wherein R 5-1 and R 5-2 are independently selected from the group consisting of hydrogen, halogen, C 1-4 Alkyl; or, R 5 , R 6 Together with the carbon atoms to which it is attached, The Is: single bond or double bond; The Y - It is a monovalent anion.

3. The method according to claim 1, wherein R 1 、R 2 Each independently selected from the following group: C 1-7 Alkyl, -NR a R b ,-OMe,-OCPh3,C 6-10 Aromatic ring, substituted or unsubstituted 5-13 membered aromatic heterocycle, substituted or unsubstituted naphthyl, substituted or unsubstituted benzopyrrolyl, substituted or unsubstituted benzo C 3-7 Cycloalkyl, substituted or unsubstituted C 3-7 Heterocycloalkylphenyl, substituted or unsubstituted furano C 3-7 Cycloalkyl, 1, 2 or 3 R 1-1 Substituted C 1-7 Alkyl and R 1-2 Substituted C 6-10 aromatic rings; or R 1 、R 2 and the CH connected thereto together form a structure selected from the group consisting of: substituted or unsubstituted C 6-10 Aromatic ring, substituted or unsubstituted 5-13 membered aromatic heterocycle, substituted or unsubstituted naphthyl, substituted or unsubstituted benzopyrrolyl, substituted or unsubstituted benzo C 3-7 Cycloalkyl, substituted or unsubstituted furano C 3-7 Cycloalkyl; Wherein, the substitution refers to that one or more hydrogen atoms on the group are replaced by a substituent selected from the group consisting of halogen, C 2-7 Alkenyl, C 6-13 Aryl, C 1-7 Alkoxy, C 3-10 Cycloalkyl, C 3-10 Heterocycloalkyl, -OMe, -NMe2, -SMe, -CF3, -COCF3, -CN, -CO2Me, -C(O)NMe2, -C(O)NEt2, -CH2CHMe2, benzoyl, tert-butylcarbonyl (-Boc), benzyloxycarbonyl (-Cbz), triphenylmethylether (-OTr); R 1-1 For halogen, vinyl, -OCH2-, C 3-7 Cycloalkyl; R 1-2 is a halogen, containing 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen. 3-10 Heteroaromatic ring, -OMe, -NMe2, -SMe, -O-CH2-O-, -CF3, -OCF3, -CN, -CO2Me, -C(O)NEt2, -CH2CHMe2, phenyl, benzoyl; R a 、R b Each independently selected from the group consisting of benzyl, -C(O)-OC(CH3)3, phenyl, benzoyl, or R a 、R b Together with the adjacent N, it forms a 3-7 membered ring structure; Wherein, each of the heterocycloalkyl groups or heteroaromatic rings independently contains 1 to 4 heteroatoms selected from oxygen, sulfur and nitrogen.

4. The method according to claim 2, wherein The structure of the compound IV is selected from the following structures:

5. The method according to claim 1, wherein The compound I is selected from any one of the following compounds:

6. The method according to claim 1, wherein The compound II is selected from any one of the following compounds:

7. The method according to claim 1, wherein The compound A is selected from the following group of compounds:

8. The method according to claim 1, wherein The molar ratio of the compound I to the compound II is 10:1 to 1:10, preferably 8:1 to 1:

5.

9. The method according to claim 1, wherein The molar ratio of the compound I to the compound III is 10:1 to 1:10, preferably 5:1 to 1:

5.

10. The method according to claim 1, wherein The molar ratio of the compound I to the bis(1,5-cyclooctadiene)nickel is 1:0.01-0.5, preferably 1:0.01-0.

1.

11. The method according to claim 1, wherein The molar ratio of the compound IV to the bis(1,5-cyclooctadiene)nickel is 0.5-2:0.5-2, preferably 0.8-1.2:0.8-1.

2.

12. The method according to claim 1, wherein The solvent is an alkane solvent, an ether solvent, or a combination thereof.

13. The method according to claim 1, wherein The reaction temperature is 10-60°C, preferably 20-50°C.

14. The method according to claim 1, wherein The reaction time of the reaction is 12-48h.

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