KR20000070085A - Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive - Google Patents

Abstract

The present invention relates to a process for preparing a compound of formula (I) which is a major intermediate in the synthesis of endothelin antagonists using chiral adducts to carry out asymmetric conjugated addition reactions.

Formula I

Description

Endothelin intermediates by asymmetric conjugate addition reaction using a chiral additive

The present invention relates to novel main intermediates in the synthesis of endothelin antagonists and methods of preparing such main intermediates of formula (I).

Compounds containing a high affinity for at least one of the two receptor subtypes are involved in the expansion of smooth muscle, such as in blood vessels or conduits. Endothelin antagonist compounds include, in particular, hypertension, pulmonary hypertension, Raynaud's disease, acute kidney disease, myocardial infarction, angina pectoris, cerebral infarction, cerebrovascular spasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatic hypertrophic endotoxin shock, endotoxin -Potentially new therapeutic targets for the treatment of induced multiple organ disease or diffuse vascular coagulation, and / or cyclosporin-induced kidney disease or hypertension.

Endothelin is a polypeptide consisting of amino acids and is produced by vascular endothelial cells of human or swine. Endothelin has a potential vasoconstrictor effect and a sustained and latent boosting action (Nature, 332, 411-415 (1988)).

Three endothelin isopeptides (endothelin-1, endothelin-2, and endothelin-3) that are similar in structure to each other are present in the body of animals, including humans, and these peptides have vasoconstrictive and boosting effects. Literature: Proc. Natl. Acad, Sci, USA, 86, 2863-2867 (1989).

As reported, endothelin levels are significantly higher in blood of patients with hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud's disease, diabetes or atherosclerosis, or in airways or blood lavage of patients with asthma. [Japan, J. Hypertension, 12, 79, (1989), J. Vascular medicine Biology, 2, 207 (1990), Diabetologia, 33, 306-310 (1990), J. Am. Med. Association, 264, 2868 (1990), and The Lancet, ii, 747-748 (1989) and ii, 1144-1147 (1990).

In addition, increased sensitivity of cerebrovascular to endothelin in subjects of cerebrovascular spasm [Japan: Japan. Soc. Cereb. Blood Flow & Metabol., 1, 73 (1989)], improved renal action by endothelin antibodies in subjects with acute kidney disease [J. Clin, invest., 83, 1762-1767 (1989)] and gastric ulcers Inhibition of gastric ulcer development using endothelin antibodies in subjects. Extract of Japanese Society of Experimental Gastric Ulcer. 50 (1991). Thus, endothelin is presumed to be one of the mediators of acute kidney disease or cerebrovascular concomitant with subarachnoid hemorrhage.

In addition, endothelin is secreted by endothelial cells as well as organ endothelial cells or kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).

Endothelin is also used in physiologically active endogenous substances such as renin, atrial sodium excretion peptides, endothelial-induced relaxation factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P. It has been found to modulate release. Biochem. Biophys, Res. Commun., 157, 1164-1168 (1988); Biochem. Biophys, Res. Commun., 155, 20 167-172 (1989); Proc. Natl. Acad. Sci. USA, 85 1 9797-9800 (1989); J. Cardiovasc. Pharmacol., 13, S89-S92 (1989); Japan. J. Hypertension, 12, 76 (1989) and Neuroscience Letters, 102, 179-184 (1989)]. In addition, endothelin causes contractions of the smooth and uterine smooth muscle of the gastrointestinal tract [FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res. Commun., 159, 317-323 (1989). Endothelin has also been shown to promote the proliferation of rat vascular smooth muscle cells, suggesting a possible validity for arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Endothelin may also play an important role in regulating neuronal activity, since endothelin receptors are present in high density in the central nervous system as well as in peripheral tissues and cerebral administration of endothelin leads to behavioral changes in animals. Neuroscience Letters, 97, 276-279 (1989). In particular, endothelin is shown to be one of the mediators for pain (Life Science, 49, PL61-PL65 (1991)).

Internal proliferative responses are induced by rat carotid artery endogenous epidermal detachment. Endothelin significantly exacerbates internal hyperplasia [J. Cardiovasc. Pharmocol., 22, 355-359 & 371-373 (1993). These data support the role of endothelin in the pathogenesis of vascular restenosis. Recently, it has been reported that both ET _A and ET _B receptors are present in human prostate and endothelin causes its potential contraction. These results indicate the possibility that endothelin is involved in the pathogenesis of benign prostatic hyperplasia (J. Urology, 151, 763-766 (1994), Molecular Pharmocol., 45, 306-311 (1994)).

Endotoxins are also one of the potential factors for promoting the release of endothelin. Significant increases in endothelin levels in the culture supernatant of blood or endothelial cells are observed when endotoxins are externally administered to animals or applied to cultured endothelial cells, respectively. This finding suggests that endothelin is an important mediator for endotoxin-induced diseases. Biochem. Biophys. Commun., 161, 1220-1227 (1989); and Acta Physiol. Scand., 137, 317-318 (1989).

Cyclosporine has also been reported to significantly increase endothelin secretion in renal cell medium (LLC-PKL cells). Eur. J. Pharmacol., 180, 191-192 (1990)]. In addition, administration of cyclosporin to rats reduces the rate of glomerular filtration and increases blood pressure in association with a marked increase in circulating endothelin levels. Such cyclosporin-induced kidney disease can be lowered by the administration of endothelin antibodies (Kidney Int., 37, 1487-1491 (1990)). Thus, endothelin is presumed to be deeply involved in the pathogenesis of cyclosporin-induced diseases.

These various effects of endothelin are generated by binding the endothelin to the endothelin receptors widely distributed in various tissues. Am. J. Physiol., 256, R856-R866 (1989)].

Vasoconstriction by endothelin is known to occur through two or more subtypes of endothelin receptors. See J. Cardiovasc. Pharmacol., 17 (Suppl. 7), S119-S121 (1991). One of the endothelin receptors is an ET _A receptor that is selective for ET-1 over ET-3, and the other is an ET _B receptor that is equally active for ET-1 and ET-3. These receptor proteins are reported to be different from one another (Nature, 348, 730-735 (1990)).

These two subtypes of endothelin receptors are distributed differently in tissues. It is known that ET _A receptors are mainly present in cardiovascular tissues, while ET _B receptors are widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.

Substances that specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as pharmaceuticals in a wide range of fields. Because the action of endothelin occurs not only through the ET _A receptor but also through the ET _B receptor, new nonpeptidic substances with ET receptor antagonistic activity against any receptor subtype are required to effectively block the activity of endothelin in various diseases. .

Endothelin is an endogenous substance that induces continuous contraction or relaxation of vascular or non-vascular smooth muscle either directly or indirectly (by regulating the release of various endogenous substances), and its excessive production or excessive secretion is caused by hypertension, pulmonary hypertension, and Raynaud's disease. It is believed to be one of the etiologies for bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute kidney disease, myocardial infarction, angina pectoris, cerebrovascular spasm and cerebrovascular infarction. In addition, endothelin plays an important role in mediating diseases such as restenosis, prostatic hypertrophy, endotoxin shock, endotoxin-induced multiple organ disease or diffuse endothelial coagulation, and cyclosporin-induced kidney disease or hypertension. Is presented.

Two endothelin receptors ET _A and ET _B are known to date and antagonists of these receptors appear to be potential drug targets. EP 0526708 Al and WO 93/08799 Al are representative examples of patent applications that describe non-peptidic compounds with asserted activity as endothelin receptor antagonists.

The present invention has a structure Asymmetric conjugated addition reactions for the preparation of compounds of formula (I) which are key intermediates in the synthesis of phosphorus endothelin antagonists are described.

In the above formula,

Represents 5- or 6-membered heterocyclyl, 5- or 6-membered carbocyclyl and aryl,

R ¹ is C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, aryl or heteroaryl,

R ² is OR ⁴ and N (R ⁵ ) ₂ ,

R ^3b is aryl or heteroaryl,

R ⁴ is C ₁ -C ₈ alkyl,

R ⁵ is C ₁ -C ₈ alkyl or aryl.

Summary of the Invention

The invention relates to α, β-unsaturated esters or amides To a organolithium compound, R ¹ Li, in the presence of a chiral adduct and an aprotic solvent in the temperature range of about −78 ° C. to about 0 ° C.

Formula I

In the above formula,

Is

a) a 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds and containing at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, wherein hetero Cyclyl may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C _{8 cycloalkyl, CO (CH 2) n CH} 3 , and _{CO (CH 2) n CH 2} N (R 5) 1, 2 are selected from the group consisting of ₂ Or substituted with 3 substituents,

b) 5- or 6-membered carbocyclyl containing one or two double bonds, but containing at least one double bond, wherein carbocyclyl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F , I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl , CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ and substituted with 1, 2 or 3 substituents selected from the group consisting of

c) aryl, unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₃ -C _{8 as defined below} C ₁ -C ₈ alkoxy, C ₁ substituted with 1, 2 or 3 substituents selected from the group consisting of cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, wherein aryl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is substituted with one, two or three substituents selected from the group consisting of two substituents Can be combined to form a 5- or 6-membered ring having 1, 2 or 3 heteroatoms selected from O, N and S, which may be unsubstituted or substituted with H, OH, CO ₂ R ⁶ , Br , Cl, F, I, CF ₃ , N (R ⁷ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Defined as phenyl or naphthyl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ ; ,

R ¹ is

a) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl,

b) aryl, or

c) contains 1, 2 or 3 heteroatoms selected from O, N and S and is unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is a heteroaryl defined as a 5- or 6-membered aromatic ring substituted with 1, 2 or 3 substituents selected from the group consisting of

R ² is OR ⁴ or N (R ⁵ ) ₂ ,

R ³ is

a) H,

b) C ₁ -C ₈ alkyl,

c) C ₁ -C ₈ alkenyl,

d) C ₁ -C ₈ alkynyl,

e) C ₁ -C ₈ alkoxyl,

f) C ₃ -C ₇ cycloalkyl,

g) S (O) _t R ⁵ ,

h) Br, Cl, F, I,

i) aryl,

j) heteroaryl,

k) N (R ⁵ ) ₂ ,

l) NH ₂ ,

m) CHO,

n) -CO-C ₁ -C ₈ alkyl,

o) -CO-aryl,

p) -CO-heteroaryl,

q) -CO ₂ R ⁴ , or

r) protected aldehydes,

X and Y are independently O, S or NR ⁵ ,

n is 0 to 5,

t is 0, 1 or 2,

R ⁴ is C ₁ -C ₈ alkyl,

R ⁵ is C ₁ -C ₈ alkyl or aryl,

R ⁶ is H, C ₁ -C ₈ alkyl or aryl,

R ⁷ is H, C ₁ -C ₈ alkyl, and unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ Aryl which may be substituted with one, two or three substituents selected from the group consisting of ₂ ), or when two R ⁷ substituents are present in the same nitrogen to combine with each other to form a 3 to 6 membered ring.

The invention relates to α, β-unsaturated esters or amides To a organolithium compound, R ¹ Li, in the presence of a chiral adduct and an aprotic solvent in the temperature range of about −78 ° C. to about 0 ° C.

Formula I

In the above formula,

Is

a) a 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds and containing at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, wherein hetero Cyclyl may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C _{8 cycloalkyl, CO (CH 2) n CH} 3 , and _{CO (CH 2) n CH 2} N (R 5) 1, 2 are selected from the group consisting of ₂ Or substituted with 3 substituents,

b) 5- or 6-membered carbocyclyl containing one or two double bonds, but containing at least one double bond, wherein carbocyclyl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F , I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl , CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ and substituted with 1, 2 or 3 substituents selected from the group consisting of

c) aryl, unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₃ -C _{8 as defined below} C ₁ -C ₈ alkoxy, C ₁ substituted with 1, 2 or 3 substituents selected from the group consisting of cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, wherein aryl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is substituted with one, two or three substituents selected from the group consisting of two substituents Can be combined to form a 5- or 6-membered ring having 1, 2 or 3 heteroatoms selected from O, N and S, which may be unsubstituted or substituted with H, OH, CO ₂ R ⁶ , Br , Cl, F, I, CF ₃ , N (R ⁷ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Defined as phenyl or naphthyl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ ; ,

R ¹ is

a) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl,

b) aryl, or

c) contains 1, 2 or 3 heteroatoms selected from O, N and S and is unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is a heteroaryl defined as a 5- or 6-membered aromatic ring substituted with 1, 2 or 3 substituents selected from the group consisting of

R ² is OR ⁴ or N (R ⁵ ) ₂ ,

R ³ is

a) H,

b) C ₁ -C ₈ alkyl,

c) C ₁ -C ₈ alkenyl,

d) C ₁ -C ₈ alkynyl,

e) C ₁ -C ₈ alkoxyl,

f) C ₃ -C ₇ cycloalkyl,

g) S (O) _t R ⁵ ,

h) Br, Cl, F, I,

i) aryl,

j) heteroaryl,

k) N (R ⁵ ) ₂ ,

l) NH ₂ ,

m) CHO,

n) -CO-C ₁ -C ₈ alkyl,

o) -CO-aryl,

p) -CO-heteroaryl,

q) -CO ₂ R ⁴ , or

r) protected aldehydes,

X and Y are independently O, S or NR ⁵ ,

n is 0 to 5,

t is 0, 1 or 2,

R ⁴ is C ₁ -C ₈ alkyl,

R ⁵ is C ₁ -C ₈ alkyl or aryl,

R ⁶ is H, C ₁ -C ₈ alkyl or aryl,

R ⁷ may be bonded to each other when H, C ₁ -C ₈ alkyl, and two R ⁷ substituents are each present in nitrogen to form a 3 to 6 membered ring, and may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br , Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Aryl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ .

In the process as mentioned above, the equivalent value of the organolithium compound, R ¹ Li, is from 1 to about 4, preferably from about 1.5 to about 2.5.

In the process as mentioned above, the chiral adduct is a chiral compound that can coordinate with the chiral adduct,

a) (-)-spartane,

b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or

c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H at the same time and R ¹⁰ is C ₁ -C ₆ alkyl or aryl Compounds such as are useful in this method. The amino alcohols represented by the above-mentioned structures are believed to have one or more, potentially two chiral centers.

In the process as mentioned above, the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane and dioxane or mixtures of the above solvents. . Preferred aprotic solvents in the above-mentioned methods are toluene.

Solvent mixtures useful in this process are hexane and toluene using catalytic amounts of tetrahydrofuran and pentane and toluene using catalytic amounts of tetrahydrofuran, preferably hexane and toluene using catalytic amounts of tetrahydrofuran.

In the process as mentioned above, the temperature range is from about -78 ° C to about -20 ° C, preferably from about -78 ° C to about -50 ° C.

Aspects of the invention

1) α, β-unsaturated esters or amides Wherein R ³ is CH (OR ⁴ ) ₂ in the presence of a chiral adduct and an aprotic solvent in the temperature range of about −78 ° C. to about 0 ° C. to react with the organolithium compound, R ¹ Li Forming water, and

2) removing the aldehyde protecting group with an acid to obtain a compound of formula I wherein R ³ is CHO.

Formula I

In the above formula,

Is

a) a 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds and containing at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, wherein hetero Cyclyl may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C _{8 cycloalkyl, CO (CH 2) n CH} 3 , and _{CO (CH 2) n CH 2} n (R 5) 1, 2 are selected from the group consisting of ₂ Or substituted with 3 substituents,

b) 5- or 6-membered carbocyclyl containing one or two double bonds, but containing at least one double bond, wherein carbocyclyl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F , I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl , CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ and substituted with 1, 2 or 3 substituents selected from the group consisting of

c) aryl, unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₃ -C _{8 as defined below} C ₁ -C ₈ alkoxy, C ₁ substituted with 1, 2 or 3 substituents selected from the group consisting of cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, wherein aryl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is substituted with one, two or three substituents selected from the group consisting of two substituents Can be combined to form a 5- or 6-membered ring having 1, 2 or 3 heteroatoms selected from O, N and S, which may be unsubstituted or substituted with H, OH, CO ₂ R ⁶ , Br , Cl, F, I, CF ₃ , N (R ⁷ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Defined as phenyl or naphthyl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ ; ,

R ¹ is

a) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl,

b) aryl, or

c) contains 1, 2 or 3 heteroatoms selected from O, N and S and is unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is a heteroaryl defined as a 5- or 6-membered aromatic ring substituted with 1, 2 or 3 substituents selected from the group consisting of

R ² is OR ⁴ or N (R ⁵ ) ₂ ,

R ³ is

a) CHO,

b) CH (OR ⁴ ) ₂ ,

n is 0 to 5,

t is 0, 1 or 2,

X and Y are independently O, S or NR ⁵ ,

R ⁴ is C ₁ -C ₈ alkyl,

R ⁵ is C ₁ -C ₈ alkyl or aryl,

R ⁶ is H, C ₁ -C ₈ alkyl and aryl,

R ⁷ may be bonded to each other when H, C ₁ -C ₈ alkyl, and two R ⁷ substituents are each present in nitrogen to form a 3 to 6 membered ring, and may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br , Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Aryl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ .

In the process as mentioned above, the equivalent value of the organolithium compound, R ¹ Li, is from 1 to about 4, preferably from about 1.5 to about 2.5.

In the process as mentioned above, the chiral adduct is a chiral compound that can coordinate with the chiral adduct,

a) (-)-spartane,

b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or

c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H at the same time and R ¹⁰ is C ₁ -C ₆ alkyl or aryl Compounds such as are useful in this method.

In the process as mentioned above, the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane and dioxane or mixtures of the above solvents. . Preferred aprotic solvents in the process as mentioned above are toluene.

Solvent mixtures useful in this process are hexane and toluene using catalytic amounts of tetrahydrofuran and pentane and toluene using catalytic amounts of tetrahydrofuran, preferably hexane and toluene using catalytic amounts of tetrahydrofuran.

Solvent mixtures useful in this process are hexane and toluene using catalytic amounts of tetrahydrofuran and pentane and toluene using catalytic amounts of tetrahydrofuran, preferably hexane and toluene using catalytic amounts of tetrahydrofuran.

In the process as mentioned above, the temperature range is from about -78 ° C to about -20 ° C, preferably from about -78 ° C to about -50 ° C.

Embodiments of the invention provide an α, β-unsaturated ester or amide Organolithium compounds in the presence of chiral adducts and aprotic solvents at temperatures ranging from about -78 ° C to about -20 ° C. Protected aldehydes, including reaction with It is a method of manufacturing.

In the process as mentioned above, the equivalent value of the organolithium compound, R ¹ Li, is from 1 to about 4, preferably from about 1.5 to about 2.5.

In the process as mentioned above, the chiral adduct is a chiral compound that can coordinate with the chiral adduct,

a) (-)-spartane,

b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or

c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H at the same time and R ¹⁰ is C ₁ -C ₆ alkyl or aryl Compounds such as are useful in this method.

In the process as mentioned above, the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), toluene, benzene, hexane, pentane and dioxane or mixtures of the above solvents. . Preferred aprotic solvents in the process as mentioned above are tetrahydrofuran.

Solvent mixtures useful in this process are hexane and toluene using catalytic amounts of tetrahydrofuran and pentane and toluene using catalytic amounts of tetrahydrofuran, preferably hexane and toluene using catalytic amounts of tetrahydrofuran.

In the process as mentioned above, the temperature range is from about -78 ° C to about -20 ° C, preferably from about -78 ° C to about -50 ° C, most preferably from about -78 ° C to about -70 ° C.

It is also contemplated that the aforementioned substituents may include the definitions mentioned below.

By alkyl substituents mentioned above are meant straight or branched chain hydrocarbons of specified length such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl and the like.

Alkenyl substituents refer to alkyl groups as described above that contain modified carbon to carbon double bonds such as vinyl, allyl and 2-butenyl, respectively.

Cycloalkyl means a ring consisting of 3 to 8 methylene groups, each of which may be unsubstituted or substituted with other hydrocarbon substituents, and includes, for example, cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.

Alkoxy substituents represent alkyl groups as described above attached through an oxygen bridge.

Heteroaryl substituents include carbazolyl, furanyl, thiethyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, furinyl do.

Heterocyclyl substituents include pyridyl, pyrimidyl, thienyl, furanyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazolidinyl, thiazolidinyl, Isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl or pyrrolidinyl.

Protected aldehydes are CH (OC ₁ -C ₈ alkyl) ₂ , or Acetals such as

α, β-unsaturated esters or amides Is usually

1) Coupling Reaction at One Point of Ring A

(Wherein R ³ is CHO, Z is a leaving group such as Br, Cl, I, Otripryl, Otosyl or Omesyl and R ² is OR ⁴ or N (R ⁵ ) ₂ ), and

2) two steps of conversion of an aldehyde, wherein R ³ is CHO, to the desired protected aldehyde, wherein R ³ is CH (OR ⁴ ) ₂ and R ⁴ is C ₁ -C ₈ alkyl. Can be.

Commercially available pyridone 1 is alkylated with propyl bromide via divalent anion and then the product is converted to bromopyridine 3a using a brominating agent such as PBr ₃ . Nitrile 3a is then reduced to aldehyde 3 using diisobutyl aluminum hydride (DIBAL). The aldehyde is then refluxed through a Heck reaction with t-butyl acrylate using NaOAc, (allyl) ₂ PdCl ₂ , tri-o-tolylphosphine, toluene to yield unsaturated ester 4a in high yield. The unsaturated ester 4a is then treated with alcohol (R ⁴ OH) and aqueous acid to give acetal-receptor 5a.

A commercially available acid 10 is reduced to alcohol 11 using BH ₃ · SMe ₂ and then converted to bromide 13 through mesylate 12 using mesyl chloride, triethylamine, followed by NaBr and dimethylacetamide ( DMAC).

Commercially available 1,2-amino indanol is acylated (propionyl chloride, K ₂ CO ₃ ) to give amide 8, which is then acetonide 9 (2-methoxypropene, pyridinium p-toluene- Sulfonate (PPTS)). Acetonide 9 is then alkylated with bromide 13 (LiHMDS) to afford 14 which is then hydrolyzed (H ⁺ , MeOH) to give a mixture 15 of acid and methyl ester. The ester / acid mixture is reduced (LAH) to give alcohol 16 in high yield and optical purity. Alcohol 16 (TBSCl, imidazole) is protected to give bromide 17, a precursor to organolithium 17a.

Chiral adducts such as compound 17a and spatein are added to α, β-unsaturated ester 5a at -78 ° C to -50 ° C. Work up with water to give compounds 6a and 6b. The mixture of compounds 6a and 6b is treated with TBAF or aqueous acid to deprotect the silylated alcohols or acetals and silylated alcohols.

The invention can be further understood by the following examples which do not limit it.

Example 1

1, manufacture

Compound 1 is a commercially available starting material (Aldrich Chemical Company, Milwaukee, WI, USA 53201).

Example 2

2, manufacturing

Diisopropyl amine (MW 101.19, d 0.772, 2.1 equ, 20.54 mL) in 200 mL THF was cooled to -50 ° C and n-BuLi (1.6 M in hexane, 2.05 equ, 96 mL) was added and the solution was -20 ° C. Allow to warm up. Aged at 0-3 [deg.] C. for 15 minutes, then cooled to -30 [deg.] C. and 1 (MW 134.14, 75 mmol, 10.0 g) is added. Aged at 0 ° C. to 43 ° C. for 2 hours. Cool to −50 ° C. and add bromopropane (MW 123.00, d 1.354, 1.0 equ, 6.8 mL). Warm to 25 ° C. over 30 minutes and aged for 30 minutes. NH ₄ Cl and CH ₂ Cl ₂ are added. The organics are dried (magnesium sulfate) and then evaporated in vacuo to give 61% of 2.

Example 3

3, manufacturing

2 (MW 176.22, 46 mmol) and PBr ₃ (MW 270.70, d 2.880, 2.5 equi, 10.8 mL) were mixed and aged at 160 ° C. After 2 hours, it is cooled to 25 ° C. and a small amount of CH ₂ Cl ₂ is added. Quench slowly while adding water. The layers are separated and the aqueous layer is washed twice with CH ₂ Cl ₂ . The organic layers are combined and dried (magnesium sulfate). Concentrate and separate the solid in 60% yield (MW 239.12, 6.60 g) by silica gel chromatography (90:10 hexanes: ethyl acetate).

The product of bromination reaction (MW 239.12, 27.6 mmol, 6.60 g) is dissolved in 66 mL of toluene and cooled to -42 ° C. DIBAL (1.5 M in toluene, 2 equ, 37 mL) was added slowly and aged at -42 ° C for 1 hour. HCl (2N, 10equ, 134 mL) was added and vigorously stirred for 30 minutes. Dilute with ethyl acetate, separate the layers and wash the aqueous layer with ethyl acetate. The organic layers are combined, dried (magnesium sulfate) and concentrated in vacuo to give 90% of 3 (MW 242.11, 6.01 g).

Example 4a

Manufacture of 4a

3 (MW 242.11, 24.8 mmol, 6.01 g) is dissolved in 75 ml of toluene. Sodium acetate (MW 82, 3equ, 6.13g), t-butyl acrylate (MW 128.17, d 0.875, 2.5equ, 9.08ml), P (o-tolyl) ₃ (MW 304.38, 10mol%, 755mg) and allyl Palladium chloride dimer (MW 365.85, 5 mol%, 455 mg) is added. Aged at reflux for 24 hours. Cool, filter and evaporate in vacuo. 4a (MW 289.37) is separated by silica gel chromatography (92: 8 hexanes: ethyl acetate) in 80% yield (5.74 g).

Example 4b

Manufacture of 4b

3 (MW 242.11, 24.8 mmol, 6.01 g) is dissolved in 75 ml of toluene. Sodium acetate (MW 82, 3equ, 6.13g), dimethylacrylamide (MW 99.13, d 0.962, 1equ, 2.55ml), PPh ₃ (MW 262.29, 10mol%, 653mg) and allyl palladium chloride dimer (MW 365.85, 5mol %, 455 mg) was added. Aged for 24 hours at 140 ° C in a sealed tube. Cool, filter and evaporate in vacuo. 4b (MW 260.34) is separated by silica gel chromatography (80:20 hexanes: ethyl acetate) in 70% yield (4.52 g).

Example 5a

Manufacture of 5a

16.0 g (55.36 mmol) of aldehyde 4a and 1.4 g (5.54 mmol) of PPTS in 280 mL of MeOH are heated at reflux for 2.5 h. After cooling to room temperature, the solvent is evaporated in vacuo. The residue is dissolved in EtOAc and washed with saturated sodium bicarbonate solution. The organic layer is concentrated to give 18.2 g of the desired product 5a in 98% yield.

¹ H NMR (CDCL ₃ ) δ: 7.95 (d, 1H), 7.80 (d, 1H), 7.12 (d, 1H), 7.04 (d, 1H), 5.09 (1H), 3.45 (s, 6H), 2.80 (t, 2H), 1.73 (m, 2H), 1.54 (s, 9H), 1.40 (m, 2H), 0.95 (t, 3H) ppm.

Example 6

Step A: Preparation of 6a and 6b

To a solution of 17 (2.23 g, 5.97 mmol), (-)-spatane (1.37 mL, 5.97 mmol) and THF (73 μL, 0.896 mmol) in 20 mL of toluene at −78 ° C., t-BuLi (1.7 M in hexane) , 7.0 ml, 11.94 mmol) is added dropwise. The solution is aged at −78 ° C. for 30 minutes. A solution of unsaturated t-butyl ester 5a (1.0 g, 2.98 mmol) in 5 ml of toluene was added dropwise at −78 ° C. over 10 minutes. After 20 minutes at −78 ° C., the reaction is quenched with water. The organic phase is separated and dried over anhydrous sodium sulfate. The crude product is purified by silica gel chromatography (EtOAc / Hex, 2:98) to give 1.52 g of the desired products 6a and 6b in 81% yield.

For major diastereomer 6b: ¹ H NMR (CDCL ₃ ) δ: 7.24 (dd, 1H), 7.00 (d, 1H), 6.84 (d, 1H), 6.70 (d, 1H), 6.55 (dd, 1H) ), 5.74 (s, 1H), 5.02 (m, 1H), 3.72 (s, 3H), 3.55 (m, 4H), 3.22 (s, 3H), 2.92 (s, 3H), 2.80 (t, 2H) , 2.50 (m, 2H), 2.12 (m, 1H), 1.75 (m, 2H), 1.40 (m, 2H), 1.28 (s, 9H), 0.95 (m, 6H), 0.90 (s, 9H), 0.09 (s, 3H), 0.08 (s, 3H) ppm.

To determine the ratio of the two diastereomers 6a and 6b, the compound is further deprotected by treatment with TBAF in THF or HCl or pTSA in aqueous acetone.

Step B: Preparation of 6c and 6d (Method A)

A solution of 500 mg (0.8 mmol) of the product 6a and 6b and 0.96 mL of TBAF (1.0 M in THF) in 6 mL of THF is allowed to stir at room temperature for 4 hours. The reaction solution is then washed with water and dried over sodium sulfate. The product is analyzed by H ¹ NMR. The ratio of the two diastereomers is determined by integrating a single peak at 5.42 ppm (major diastereomer) and 5.38 ppm (subsidiary diastereomer).

Step C: Preparation of 6e and 6f (Method B)

A solution of 100 mg (0.16 mmol) of the above products 6a and 6b in 3 ml of acetone and 1 ml of 5% HCl or 45 mg of pTSA in 3 ml of acetone and 1 ml of water is allowed to stir at room temperature for 5 hours. The solvent is evaporated in vacuo. The residue is dissolved in EtOAc and washed with 10% sodium carbonate. The product is concentrated and analyzed by H ¹ NMR. The ratio of the two diastereomers is determined by integrating a single peak at 10.35 ppm (major diastereomer) and 10.20 ppm (ancillary diastereomer).

Example 7

7, manufacturing

Compound 7 is a commercially available starting material. See DSM Andeno, Grubbenvorsterweg 8, P.O. Box 81, 5900 AB Venlo, The Netherlands.

Example 8

8, manufacturing

Na ₂ CO ₃ (MW 105.99, 1.5 equ, 8.8 g) is dissolved in 82 ml of water. A solution of (1R, 2S) amino indanol 7 (MW 149.19, 55.0 mmol, 8.2 g) in 160 mL CH ₂ Cl ₂ is added. Cool to −5 ° C. and propionyl chloride (MW 92.53, d 1.065, 1.3 equi, 6.2 mL) is added. Warm to 25 ° C. and age for 1 hour. The layers are separated and the organics are dried (magnesium sulfate). Concentration in vacuo gave 8 (MW 205.26, 10 g) in 89% independent yield.

Example 9

9, manufacturing

In a solution of 8 (MW 205.26, 49.3 mmol, 10 g) in 200 mL of THF, pyridinium p-toluenesulfonate (PPTS) (MW 251.31, 0.16 equ, 2 g) was followed by methoxypropene (MW 72.11, d 0.753, 2.2 equ, 10.4 ml) is added. After aging at 38 ° C. for 2 hours, aqueous sodium bicarbonate and ethyl acetate are added. The organic layer is dried (magnesium sulfate). After concentration in vacuo, 9 (MW 245.32, 12.09 g) is formed in stoichiometric yield.

Example 10

10, manufacturing

Compound 10 is a commercially available starting material. Lancaster Synthesis, P.O. Box 1000, Windham, NH 03087-9977 or Ryan Scientific, Inc., P.O. Box 845, Isle of Palms, SC 29451-0845.

Example 11

Manufacture of 11

BH ₃ -SMe ₂ (3equ, 25.2 mL) was added to 10 (MW 231.05, 130 mmol, 30.0 g) in 300 mL of CH ₂ Cl ₂ at 0 ° C. and aged at 25 ° C. for 2 hours. Quench with aqueous 2N HCl and separate layers. The organics are dried (magnesium sulfate) and concentrated in vacuo to give 11 (MW 217.06, 25.5 g) in 94% yield.

Example 12

Manufacture of 12

11 (MW 217.06, 47.2 mmol, 10.24 g) is dissolved in 55 mL CH ₂ Cl ₂ and cooled to -20 ° C. DIEA (MW 129.25, d 0.742, 1.3 equ, 10.69 mL) is added followed by methane sulfonyl chloride (MsCl) (MW 114.55, d 1.480, 1.2 equ, 4.38 mL). Aged at −5 ° C. to 0 ° C. for 1 hour and then quenched with 55 ml of water. Extract with CH ₂ Cl ₂ and then rinse with 1N H ₂ SO ₄ (40 mL) followed by brine. The organic layer is dried (magnesium sulfate) and concentrated in vacuo to give 12 (MW 295.15, 13.23 g) in 95% yield.

Example 13

Manufacture of 13

To 12 (MW 295.15, 44.8 mmol, 13.23 g) in 44 ml of dimethylacetamide (DMAC) was added NaBr (MW 102.90, 2equ, 9.22 g) and aged for 1 hour. 88 ml of water is added and the solid is recovered by filtration. The mass is washed with water and suction dried. A stoichiometric yield of 13 (MW 279.96, 12.54 g) is obtained.

Example 14

Manufacture of 14

9 (MW 245.32, 1.1 equ, 89.1 g) in 1 L of THF is cooled to -50 ° C. LiHMDS (1.0 M in THF, 1.5 equ, 545 mL) was added and aged for 1.5 h and warmed to -30 ° C. 13 (MW 279.96, 327 mmol, 91.3 g) in 300 mL of THF was added and aged at −35 ° C. for 1 hour. Warm to −10 ° C. over 1 hour and then quench with aqueous NH ₄ Cl. The layers are separated and extracted with ethyl acetate. The organics are dried and concentrated in vacuo to afford crude 14 (MW 444.37).

Example 15

Manufacture of 15

14 in 1 L of MeOH is cooled to 10 ° C. The reaction is bubbled in HCl gas for 1 hour until the reaction is complete. ₂ L of H ₂ 0 are added and the product is filtered. The mass is washed with H ₂ O and dried to give product hydroxyamide, which is then dissolved in 1 L of MeOH and 1.5 L of 6N HCl and refluxed overnight. The mixture is cooled to 25 ° C. and extracted with CH ₂ Cl ₂ , concentrated to give compound 15 (60 g, 64% from bromide 13).

Example 16

Manufacture of 16

Lithium aluminum hydride (LiAlH ₄ ) (1M in THF, 2equ, 53.76 ml) is added over 15 minutes (mixture of acid and ester, 26.88 mmol) in 150 ml THF at −78 ° C. Warm to 25 ° C. over 1 h and then quench with aqueous NH ₄ Cl. Ethyl acetate is added and ethyl acetate is extracted. The organics are washed with brine, dried (magnesium sulfate) and concentrated in vacuo to give 16 (MW 259.14, 6.62 g) in 95% yield.

Example 17

Manufacture of 17

16 (MW 259.14, 25.54 mmol, 6.62 g) in 35 mL of CH ₂ Cl ₂ is cooled to 0 ° C. Imidazole (MW 68.08, 2.5 equ, 4.35 g) is added followed by tert-butyldimethylsilyl chloride (TBSCl) (MW 150.73, 1 equ, 3.85 g). Aged at 25 ° C. for 1 h, then quenched with aqueous NaHCO ₃ and ethyl acetate was added. After extraction with ethyl acetate, the organic layer is dried (magnesium sulfate) and concentrated in vacuo to give 17 (MW 373.41, 9.54 g) in stoichiometric yield.

¹ H NMR (CDCl ₃ ): 7.41 (d, J = 8.74, 1H), 6.77 (d, J = 3.04, 1H), 6.63 (dd, J = 8.73, 3.06, 1H), 3.78 (s, 3H), 3.50 (d, J = 5.75, 2H), 2.89 (dd, J = 13.31, 6.15, 1H), 2.45 (dd, J = 13.30, 8.26, 1H), 2.03 (m, 1H), 0.94 (s, 9H) , 0.92 (d, J = 5.01, 3H), 0.07 (s, 6H).

¹³ C NMR (CDCl ₃ ): 159.1, 141.6, 133.2, 117.0, 115.4, 113.2, 67.4, 55.4, 39.7, 36.3, 26.0 (3C), 18.4, 16.5, -5.3 (2C).

Examples 18-22

According to the method described in Example 6, the indicated diastereomeric ratios of compounds 6a to 6b are obtained with the following chiral adducts.

Claims (18)

α, β-unsaturated esters or amides Reacting an organolithium compound, R ¹ Li, in the presence of a chiral adduct and an aprotic solvent in the temperature range of about -78 ° C to about 0 ° C. Formula I In the above formula, Is a) a 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds and containing at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, wherein hetero Cyclyl may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C _{8 cycloalkyl, CO (CH 2) n CH} 3 , and _{CO (CH 2) n CH 2} N (R 5) 1, 2 are selected from the group consisting of ₂ Or substituted with 3 substituents, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but containing at least one double bond, wherein carbocyclyl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F , I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl , CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ and substituted with 1, 2 or 3 substituents selected from the group consisting of c) aryl, unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₃ -C _{8 as defined below} C ₁ -C ₈ alkoxy, C ₁ substituted with 1, 2 or 3 substituents selected from the group consisting of cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, wherein aryl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is substituted with one, two or three substituents selected from the group consisting of two substituents Can be combined to form a 5- or 6-membered ring having 1, 2 or 3 heteroatoms selected from O, N and S, which may be unsubstituted or substituted with H, OH, CO ₂ R ⁶ , Br , Cl, F, I, CF ₃ , N (R ⁷ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Defined as phenyl or naphthyl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ ; , R ¹ is a) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, b) aryl, or c) contains 1, 2 or 3 heteroatoms selected from O, N and S and is unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is a heteroaryl defined as a 5- or 6-membered aromatic ring substituted with 1, 2 or 3 substituents selected from the group consisting of R ² is OR ⁴ or N (R ⁵ ) ₂ , R ³ is a) H, b) C ₁ -C ₈ alkyl, c) C ₁ -C ₈ alkenyl, d) C ₁ -C ₈ alkynyl, e) C ₁ -C ₈ alkoxyl, f) C ₃ -C ₇ cycloalkyl, g) S (O) _t R ⁵ , h) Br, Cl, F, I, i) aryl, j) heteroaryl, k) N (R ⁵ ) ₂ , l) NH ₂ , m) CHO, n) -CO-C ₁ -C ₈ alkyl, o) -CO-aryl, p) -CO-heteroaryl, q) -CO ₂ R ⁴ , or r) protected aldehydes, X and Y are independently O, S or NR ⁵ , n is 0 to 5, t is 0, 1 or 2, R ⁴ is C ₁ -C ₈ alkyl, R ⁵ is C ₁ -C ₈ alkyl or aryl, R ⁶ is H, C ₁ -C ₈ alkyl or aryl, R ⁷ may be bonded to each other when H, C ₁ -C ₈ alkyl, and two R ⁷ substituents are each present in nitrogen to form a 3 to 6 membered ring, and may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br , Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Aryl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ . The method of claim 1 wherein the organolithium compound, R ¹ Li, is equivalent to about 1 to about 4. 5. The method of claim 2 wherein the chiral adduct is a) (-)-spartane, b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H simultaneously and R ¹⁰ is H, C ₁ -C ₆ alkyl or aryl Selected from the group consisting of: 4. The process of claim 3 wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane and dioxane or mixtures of said solvents. The method of claim 4, wherein the temperature range is from about −78 ° C. to about −20 ° C. 6. 1) α, β-unsaturated esters or amides Wherein R ³ is CH (OR ⁴ ) ₂ in the presence of a chiral adduct and an aprotic solvent in the temperature range of about −78 ° C. to about 0 ° C. to react with the organolithium compound, R ¹ Li Forming water, and 2) removing the protecting group with an acid to obtain a compound of formula I wherein R ³ is CHO. Formula I In the above formula, Is a) a 5- or 6-membered heterocyclyl containing 1, 2 or 3 double bonds and containing at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, wherein hetero Cyclyl may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C _{8 cycloalkyl, CO (CH 2) n CH} 3 , and _{CO (CH 2) n CH 2} N (R 5) 1, 2 are selected from the group consisting of ₂ Or substituted with 3 substituents, b) 5- or 6-membered carbocyclyl containing one or two double bonds, but containing at least one double bond, wherein carbocyclyl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F , I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl , CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ and substituted with 1, 2 or 3 substituents selected from the group consisting of c) aryl, unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₃ -C _{8 as defined below} C ₁ -C ₈ alkoxy, C ₁ substituted with 1, 2 or 3 substituents selected from the group consisting of cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, wherein aryl is unsubstituted or OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is substituted with one, two or three substituents selected from the group consisting of two substituents Can be combined to form a 5- or 6-membered ring having 1, 2 or 3 heteroatoms selected from O, N and S, which may be unsubstituted or substituted with H, OH, CO ₂ R ⁶ , Br , Cl, F, I, CF ₃ , N (R ⁷ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Defined as phenyl or naphthyl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ ; , R ¹ is a) C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl, C ₃ -C ₈ cycloalkyl, b) aryl, or c) contains 1, 2 or 3 heteroatoms selected from O, N and S and is unsubstituted or substituted with OH, CO ₂ R ⁴ , Br, Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C ₃ -C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ and CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ is a heteroaryl defined as a 5- or 6-membered aromatic ring substituted with 1, 2 or 3 substituents selected from the group consisting of R ² is OR ⁴ or N (R ⁵ ) ₂ , R ³ is a) CHO, b) CH (OR ⁴ ) ₂ , n is 0 to 5, t is 0, 1 or 2, X and Y are independently O, S or NR ⁵ , R ⁴ is C ₁ -C ₈ alkyl, R ⁵ is C ₁ -C ₈ alkyl or aryl, R ⁶ is H, C ₁ -C ₈ alkyl and aryl, R ⁷ may be bonded to each other when H, C ₁ -C ₈ alkyl, and two R ⁷ substituents are each present in nitrogen to form a 3 to 6 membered ring, and may be unsubstituted or substituted with OH, CO ₂ R ⁴ , Br , Cl, F, I, CF ₃ , N (R ⁵ ) ₂ , C ₁ -C ₈ alkoxy, C ₁ -C ₈ alkyl, C ₂ -C ₈ alkenyl, C ₂ -C ₈ alkynyl or C _3- Aryl substituted with 1, 2 or 3 substituents selected from the group consisting of C ₈ cycloalkyl, CO (CH ₂ ) _n CH ₃ , CO (CH ₂ ) _n CH ₂ N (R ⁵ ) ₂ . 7. The method of claim 6, wherein the organolithium compound, R ¹ Li, is equivalent to about 1 to about 4. 8. The method of claim 7, wherein the chiral adduct is a) (-)-spartane, b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H simultaneously and R ¹⁰ is H, C ₁ -C ₆ alkyl or aryl Selected from the group consisting of: The method of claim 8, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, hexane, pentane and dioxane or mixtures of the above solvents. The method of claim 9, wherein the temperature range is from about −78 ° C. to about −20 ° C. 11. α, β-unsaturated esters or amides Organolithium compounds in the presence of chiral adducts and aprotic solvents at temperatures ranging from about -78 ° C to about -20 ° C. Including reacting with, How to prepare. 12. The method of claim 11 wherein the organolithium compound, R ¹ Li, is equivalent to about 1 to about 4. The method of claim 11, wherein the chiral adduct is a) (-)-spartane, b) N, N, N ', N'-tetra (C ₁ -C ₆ ) -alkyltrans-1,2-diamino-cyclohexane, or c) R ⁸ and R ⁹ are each H, C ₁ -C ₆ alkyl, C ₃ -C ₇ cycloalkyl or aryl, provided that R ⁸ and R ⁹ cannot be H at the same time and R ¹⁰ is C ₁ -C ₆ alkyl or aryl Selected from the group consisting of: The method of claim 13, wherein the aprotic solvent is selected from the group consisting of tetrahydrofuran, diethyl ether, methyl t-butyl ether, benzene, toluene, pentane, hexane and dioxane or mixtures of said solvents. The method of claim 14, wherein the temperature range is from about −78 ° C. to about −50 ° C. 16. The method of claim 15, wherein the organolithium compound, R ¹ Li, has an equivalent value of 1.5 to about 2.5. The method of claim 16, wherein the aprotic solvent is a toluene or toluene-hexane- (catalytic) tetrahydrofuran mixture. The method of claim 17, wherein the temperature range is from about −78 ° C. to about −70 ° C. 18.