The present invention relates to novel key intermediates in the synthesis of an endothelin antagonist and the method for preparing these key intermediates of Formula I.
Two endothelin receptor subtypes ETA and ETB are known. The compounds of the present invention possess high affinity to at least one of two receptor subtypes, responsible for the dilation of smooth muscle, such as blood vessels or in the trachea. The endothelin antagonist compounds of the present invention provide a new therapeutic potential, particularly for the treatment of hypertension, pulmonary hypertension, Raynaud""s disease, acute renal failure, myocardial infarction, angina pectoris, cerebral infarction, cerebral vasospasm, arteriosclerosis, asthma, gastric ulcer, diabetes, restenosis, prostatauxe endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and/or cyclosporin-induced renal failure or hypertension.
Endothelin is a polypeptide composed of amino acids, and it is produced by vascular endothelial cells of human or pig. Endothelin has a potent vasoconstrictor effect and a sustained and potent pressor action (Nature, 332, 411-415 (1988)).
Three endothelin isopeptides (endothelin-1, endothelin-2 and endothelin-3), which resemble one another in structure, exist in the bodies of animals including human, and these peptides have vasoconstriction and pressor effects (Proc. Natl. Acad, Sci, USA, 86, 2863-2867 (1989)).
As reported, the endothelin levels are clearly elevated in the blood of patients with essential hypertension, acute myocardial infarction, pulmonary hypertension, Raynaud""s disease, diabetes or atherosclerosis, or in the washing fluids of the respiratory tract or the blood of patients with asthmaticus as compared with normal levels (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)).
Further, an increased sensitivity of the cerebral blood vessel to endothelin in an experimental model of cerebral vasospasm (Japan. Soc. Cereb. Blood Flow and Metabol., 1, 73 (1989)), an improved renal function by the endothelin antibody in an acute renal failure model (J. Clin, invest., 83, 1762-1767 (1989), and inhibition of gastric ulcer development with an endothelin antibody in a gastric ulcer model (Extract of Japanese Society of Experimental Gastric Ulcer, 50 (1991)) have been reported. Therefore, endothelin is assumed to be one of the mediators causing acute renal failure or cerebral vasospasm following subarachnoid hemorrhage.
Further, endothelin is secreted not only by endothelial cells but also by tracheal epithelial cells or by kidney cells (FEBS Letters, 255, 129-132 (1989), and FEBS Letters, 249, 42-46 (1989)).
Endothelin was also found to control the release of physiologically active endogenous substances such as renin, atrial natriuretic peptide, endothelium-derived relaxing factor (EDRF), thromboxane A2, prostacyclin, noradrenaline, angiotensin II and substance P (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)). Further, endothelin causes contraction of the smooth muscle of gastrointestinal tract and the uterine smooth muscle (FEBS Letters, 247, 337-340 (1989); Eur. J. Pharmacol., 154, 227-228 (1988); and Biochem. Biophys Res. Commun., 159, 317-323 (1989)). Further, endothelin was found to promote proliferation of rat vascular smooth muscle cells, suggesting a possible relevance to the arterial hypertrophy (Atherosclerosis, 78, 225-228 (1989)). Furthermore, since the endothelin receptors are present in a high density not only in the peripheral tissues but also in the central nervous system, and the cerebral administration of endothelin induces a behavioral change in animals, endothelin is likely to play an important role for controlling nervous functions (Neuroscience Letters, 97, 276-279 (1989)). Particularly, endothelin is suggested to be one of mediators for pain (Life Sciences, 49, PL61-PL65 (1991)).
Internal hyperplastic response was induced by rat carotid artery balloon endothelial denudation. Endothelin causes a significant worsening of the internal hyperplasia (J. Cardiovasc. Pharmacol., 22, 355-359 and 371-373(1993)). These data support a role of endothelin in the phathogenesis of vascular restenosis. Recently, it has been reported that both ETA and ETB receptors exist in the human prostate and endothelin produces a potent contraction of it. These results suggest the possibility that endothelin is involved in the pathophysiology of benign prostatic hyperplasia (J. Urology, 151, 763-766(1994), Molecular Pharmocol., 45, 306-311(1994)).
On the other hand, endotoxin is one of potential candidates to promote the release of endothelin. Remarkable elevation of the endothelin levels in the blood or in the culture supernatant of endothelial cells was observed when endotoxin was exogenously administered to animals or added to the culture endothelial cells, respectively. These findings suggest 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)).
Further, it was reported that cyclosporin remarkably increased endothelin secretion in the renal cell culture (LLC-PKL cells) (Eur. J. Pharmacol., 180, 191-192 (1990)). Further, dosing of cyclosporin to rats reduced the glomerular filtration rate and increased the blood pressure in association with a remarkable increase in the circulating endothelin level. This cyclosporin-induced renal failure can be suppressed by the administration of endothelin antibody (Kidney Int., 37, 1487-1491 (1990)). Thus, it is assumed that endothelin is significantly involved in the pathogenesis of the cyclosporin-induced diseases.
Such various effects of endothelin are caused by the binding of endothelin to endothelin receptors widely distributed in many tissues (Am. J. Physiol., 256, R856-R866 (1989)). It is known that vasoconstriction by the endothelins is caused via at least two subtypes of endothelin receptors (J. Cardiovasc. Pharmacol., 17(Suppl.7), S119-S121 (1991)). One of the endothelin receptors is ETA receptor Selective to ET-1 rather than ET-3, and the other is ETB receptor equally active to ET-1 and ET-3. These receptor proteins are reported to be different from each other (Nature, 348, 730-735 (1990)).
These two subtypes of endothelin receptors are differently distributed in tissues. It is known that the ETA receptor is present mainly in cardiovascular tissues, whereas the ETB receptor is widely distributed in various tissues such as brain, kidney, lung, heart and vascular tissues.
Substances which specifically inhibit the binding of endothelin to the endothelin receptors are believed to antagonize various pharmacological activities of endothelin and to be useful as a drug in a wide field. Since the action of the endothelins is caused via not only the ETA receptor but also the ETB receptor, novel non-peptidic substances with ET receptor antagonistic activity to either receptor subtype are desired to block activities of the endothelins effectively in various diseases.
Endothelin is an endogenous substance which directly or indirectly (by controlling liberation of various endogenous substances) induces sustained contraction or relaxation of vascular or non-vascular smooth muscles, and its excess production or excess secretion is believed to be one of pathogeneses for hypertension, pulmonary hypertension, Raynaud""s disease, bronchial asthma, gastric ulcer, diabetes, arteriosclerosis, restenosis, acute renal failure, myocardial infarction, angina pectoris, cerebral vasospasm and cerebral infarction. Further, it is suggested that endothelin serves as an important mediator involved in diseases such as restenosis, prostatauxe, endotoxin shock, endotoxin-induced multiple organ failure or disseminated intravascular coagulation, and cyclosporin-induced renal failure or hypertension.
Two endothelin receptors ETA and ETB are known so far. An antagonistic agent against the ETB receptor as well as the ETA receptor is useful as a drug. In the field of anti-endothelin agents, some non-peptidic compounds possessing antagonistic activity against endothelin receptors were already disclosed in patents (for example, EP 0526708 A1, WO 93/08799 A1). Accordingly, it is an object of the present invention to provide a novel therapeutics for the treatment of the above-mentioned various diseases by an invention of a novel and potent non-peptidic antagonist against either ETA or ETB receptor.
In order to accomplish the above object, the present inventors have developed an asymmetric conjugate addition which enables them to prepare compounds of Formula I 
and the sterioisomer with opposite stereochemistry at C*, wherein 
represents: 5- or 6-membered heterocyclyl, 5- or 6-membered carbocyclyl, or aryl;
R1 is: aryl, C1-C8 alkyl, or heteroaryl;
R2 is: OR4, N(R5)2, H, or OH;
R3 is: H, C1-C8 alkyl, C1-C8 alkoxy, halo, aryl, heteroaryl, or CHO;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl or aryl;
and use this key intermediate to prepare endothelin antagonists, such as the compound below (Ishikawa et al. U.S. Pat. No. 5,389,620): 
This invention relates to a key intermediate in the synthesis of an endothelin antagonist and the synthesis of this key intermediate via an asymmetric conjugate addition.
The instant invention relates to a compound of Formula I: 
and the sterioisomer with opposite stereochemistry at C*, wherein 
a) 5- or 6-membered heterocyclyl, wherein heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R10 substituents, wherein R is selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
c) aryl, wherein aryl is as defined below,
C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, OBenzyl, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R1 is:
a) aryl, wherein aryl is as defined above,
b) C1-C8 alkyl, or
c) heteroaryl;
heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R2 is:
a) OR4,
b) N(R5)2,
c) H, or
d) OH;
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl,
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, or
h) CHO;
n is: 0 to 5;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl, or aryl;
R6 is H, C1-C8 alkyl, and aryl; and
R7 is H, C1-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2.
The instant invention relates to a compound of Formula I: 
and the sterioisomer with opposite stereochemistry at the starred carbon (hereinafter referred to as C* and the carbon being identified in the structures with an asterix), wherein 
a) 5- or 6-membered heterocyclyl, wherein heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R10 substituents, where in R10 is selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
c) aryl, wherein aryl is as defined below,
C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, OBenzyl, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R1 is:
a) aryl, wherein aryl is as defined above,
b) C1-C8 alkyl, or
c) heteroaryl;
heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R2 is:
a) OR4,
b) N(R5)2,
c) H, or
d) OH;
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl,
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, or
h) CHO;
n is: 0 to 5;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl, or aryl;
R6 is H, C1-C8 alkyl, and aryl; and
R7 is H, C1-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2.
An embodiment of the invention includes a compound of Formula II: 
and the sterioisomer with opposite stereochemistry at C*, wherein
R2 is:
a) OR4,
b) N(R5)2,
c) H, or
d) OH;
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl,
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, or
h) CHO;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl or aryl; and
R10 is:
a) OH,
b) CO2R4,
c) halo, wherein halo is Br, Cl, F, or I,
d) CF3,
e) N(R5)2,
f) C1-C8 alkoxy,
g) C1-C8 alkyl,
h) C2-C8 alkenyl,
i) C2-C8 alkynyl,
j) C3-C8 cycloalkyl,
k) CO(CH2)nCH3, or
l) CO(CH2)nCH2N(R5)2.
An embodiment of the invention includes a compound of Formula III: 
and the sterioisomer with opposite stereochemistry at C*, wherein 
a) 5- or 6-membered heterocyclyl, wherein heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R10 substituents, wherein R is selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
c) aryl, wherein aryl is as defined below,
C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, OBenzyl, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R1 is:
a) aryl, wherein aryl is as defined above,
b) C1-C8 alkyl, or
c) heteroaryl;
heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl,
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, or
h) CHO;
n is: 0 to 5;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl, or aryl;
R6 is H, C1-C8 alkyl,or aryl;
R7 is H, C1-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R8 and R9 are independently:
a) aryl, wherein aryl is as defined in A(c) above,
b) heteroaryl, wherein heteroaryl is as defined in R1(b) above,
c) CH2OR4,
d) aryl-SCH3, wherein aryl is as defined in A(c) above,
e) C1-C8 alkyl, or
f) H, so long as both R8 and R9 are not both H at the same time.
Another embodiment of the invention is a compound of Formula IV: 
and the sterioisomer with opposite stereochemistry at C*, wherein
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl,
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, or
h) CHO;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl or aryl;
R8 and R9 are independently:
a) aryl, wherein aryl is as defined in A(c) above,
b) heteroaryl, wherein heteroaryl is as defined in R1(b) above,
c) CH2OR4,
d) aryl-SCH3, wherein aryl is as defined in A(c) above,
e) C1-C8 alkyl, or
f) H, so long as both R8 and R9 are not both H at the same time; and
R10 is:
a) OH,
b) CO2R4,
c) halo , wherein halo is Br, Cl, F, or I,
d) CF3,
e) N(R5)2,
f) C1-C8 alkoxy,
g) C2-C8 alkyl,
h) C2-C8 alkenyl,
i) C2-C8 alkynyl,
j) C3-C8 cycloalkyl,
k) CO(CH2)nCH3, or
l) CO(CH2)nCH2N(R5)2.
A further embodiment of the invention is a compound of Formula V 
or its enantiomer, wherein R3 is I, Br, Cl, F, CHO or C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens.
An embodiment of the invention is a process for the preparation of a compound of Formula I: 
and the sterioisomer with opposite stereochemistry at C*, wherein 
a) 5- or 6-membered heterocyclyl, wherein heterocyclyl is defined as a cyclic moiety containing one, two or three double bonds, but at least one double bond and 1, 2 or 3 heteroatoms selected from O, N and S, and the heterocyclyl is unsubstituted or substituted with one, two or three R10 substituents, wherein R10 is selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
b) 5- or 6-membered carbocyclyl, wherein carbocyclyl is defined as a cyclic moiety containing only carbon in the ring and containing one or two double bonds, but at least one double bond, the carbocyclyl is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
c) aryl, wherein aryl is as defined below,
C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, or C3-C8 cycloalkyl, are unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
aryl is defined as phenyl or naphthyl, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, OBenzyl, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2, and when two substituents are located on adjacent carbons they can join to form a 5- or 6-membered ring with one, two or three heteroatoms selected from O, N, and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: H, OH, CO2R6, Br, Cl, F, I, CF3, N(R7)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2,
R1 is:
a) aryl, wherein aryl is as defined above,
b) C1-C8 alkyl, or
c) heteroaryl,
heteroaryl is defined as a 5- or 6-membered aromatic ring containing 1, 2 or 3 heteroatoms selected from O, N and S, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;
R2 is:
a) OR4,
b) N(R5)2,
c) H, or
d) OH;
R3 is:
a) H,
b) C1-C8 alkyl,
c) C1-C8 alkoxy,
d) Br, Cl, F, I,
e) aryl,
f) heteroaryl, or
g) C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens;
n is: 0 to 5;
R4 is C1-C8 alkyl;
R5 is H, C1-C8 alkyl or aryl;
R6 is H, C1-C8 alkyl, or aryl; and
R7 is H, C1-C8 alkyl, or aryl, when there are two R7 substituents on a nitrogen they can join to form a 3- through 6-membered ring, which is unsubstituted or substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C1-C8 alkyl, C2-C8 alkenyl, C2-C8 alkynyl, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2;
comprising the steps of:
(1) reacting a vinyl-substituted, chiral oxazoline of Formula VI, 
wherein
R8 and R9 are independently:
a) aryl, wherein aryl is as defined in A(c) above,
b) heteroaryl, wherein heteroaryl is as defined in R1(b) above,
c) CH2OR4,
d) aryl-SCH3, wherein aryl is as defined in A(c) above,
e) C1-C8 alkyl, or
f) H, so long as both R8 and R9 are not both H at the same time;
with an amount of an organolithium compound, R1Li, in an aprotic solvent at a temperature between about xe2x88x92100xc2x0 to about 25xc2x0 C. to produce a chiral adduct; and
(2) hydrolyzing the chiral adduct with a hydrolyzing reagent to produce a compound of Formula I.
The process conditions for the process recited above, wherein the amount of R1Li added is between about 1 to about 4 equivalents, preferably about 2 to about 3 equivalents.
The process as recited above, wherein the suitable aprotic solvents include tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), benzene, toluene, pentane, hexane, dioxane and a mixture of said solvents, in addition to aprotic solvents that would be readily apparent to a person skilled in the art; and the temperature range is about xe2x88x92100xc2x0 C. to about 25xc2x0 C., and preferably about xe2x88x9278xc2x0 C. to about 0xc2x0C. 
A preferred embodiment of the invention is wherein the amount of R1Li added is between about 2 to about 3 equivalents, the aprotic solvent is tetrahydrofuran and the temperature range is between about xe2x88x9278xc2x0 C. to about 0xc2x0xc2x0C.
The process recited above, wherein the hydrolysis step is accomplished via heating with a hydrolyzing reagent such as protic acid in an alcohol solvent, which is further defined as H2SO4 and isopropyl alcohol. Suitable protic acids include H2SO4, H2NO3, HCl, acetic acid, trifluoroacetic acid, and other acids that would be readily apparent to those skilled in the art. Suitable alcohol solvents are C1-C8 straight-chain and branched alkyl alcohols, examples are methanol, ethanol, propanol, isopropanol, and butanol.
Alternatively, the hydrolysis step can be performed by treatment with other hydrolyzing reagents including, but not limited to, suitable electrophilic reagents, such as Lewis acids or alkylating agents. Suitable Lewis acids include TiCl4, BF3, BCl3, SnCl4, AlCl3, and TiCl2(OiPr)2. Suitable alkylating agents include alkyl iodides, alkyl triflates, and anhydrides, examples of these electrophilic reagents include methyl iodide, methyl triflate, ethyl iodide, ethyl triflate and triflic anhydride.
Yet another embodiment of the invention is the process recited above for the preparation of a compound of Formula II: 
and the sterioisomer with opposite stereochemistry at C*, wherein R2, R3, R4, R5 and n are as defined above; and
R10 is:
a) OH,
b) CO2R4,
c) halo, wherein halo is Br, Cl, F, or I,
d) CF3,
e) N(R5)2,
f) C1-C8 alkoxy,
g) C1-C8 alkyl,
h) C2-C8 alkenyl,
i) C2-C8 alkynyl,
j) C3-C8 cycloalkyl,
k) CO(CH2)nCH3, or
l) CO(CH2)nCH2N(R5)2;
comprising the steps of:
(1) reacting a vinyl-substituted, chiral oxazoline of Formula VII 
wherein R8 and R9 are as defined above;
with an amount of an organolithium compound of Formula VIII: 
in an aprotic solvent at a temperature between about xe2x88x9278xc2x0 and 0xc2x0 C. to produce a chiral adduct; and
(2) hydrolyzing the chiral adduct with a hydrolyzing reagent to produce a compound of Formula II.
A subembodiment of the invention is the process as recited above wherein the amount of the organolithium compound of Formula VIII used in step 1 is between about 2 to about 3 equivalents relative to the chiral oxazoline.
Another subembodiment is the process as recited above wherein the aprotic solvent used in step 1 is chosen from a group consisting of tetrahydrofuran, diethyl ether, MTBE (methyl t-butyl ether), benzene, toluene, pentane, hexane, dioxane and a mixture of said solvents.
Yet another subembodiment of the invention is the process as recited above wherein the hydrolyzing reagent used in step 2 is H2SO4.
Another embodiment of the invention is the process for the preparation of a compound of Formula IV 
and the sterioisomer with opposite stereochemistry at C*, wherein R3, R4, R5, R8, R9, R10, and n are as defined above which comprises reacting a vinyl-substituted, chiral oxazoline of Formula VII 
with at least 2 equivalents of an organolithium compound of Formula VIII 
in an aprotic solvent at a temperature between about xe2x88x9278xc2x0 and 0xc2x0 C.
The process as recited above, for the preparation of the compound of Formula IX: 
or its enantiomer, wherein R3 is I, Br, Cl, F or C(ORa)(ORb), wherein Ra and Rb are independently (C1-C5)alkyl and may be connected to form a 5- or 6-membered heterocyclic ring containing two oxygens, which comprises reacting a vinyl-substituted, chiral oxazoline of Formula X 
with at least 2 equivalents of an organolithium compound of Formula VIII 
in an aprotic solvent at a temperature between about xe2x88x9278xc2x0 and 0xc2x0 C.
It is further understood that the substituents recited above would include the definitions recited below.
The alkyl-substituents recited above denote straight and branched chain hydrocarbons of the length specified such as methyl, ethyl, isopropyl, isobutyl, tert-butyl, neopentyl, isopentyl, etc.
The alkenyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon double bond such as vinyl, allyl and 2-butenyl.
The alkynyl-substituents denote alkyl groups as described above which are modified so that each contains a carbon to carbon triple bond such as ethynyl,and propynyl.
Cycloalkyl denotes rings composed of 3 to 8 methylene groups, each of which may be substituted or unsubstituted with other hydrocarbon substituents, and include for example cyclopropyl, cyclopentyl, cyclohexyl and 4-methylcyclohexyl.
The alkoxy substituent represents an alkyl group as described above attached through an oxygen bridge.
Additionally, it is understood that the terms alkyl, alkenyl, akynyl, cycloalkyl and alkoxy can be substituted with one, two or three substituents selected from the group consisting of: OH, CO2R4, Br, Cl, F, I, CF3, N(R5)2, C1-C8 alkoxy, C3-C8 cycloalkyl, CO(CH2)nCH3, and CO(CH2)nCH2N(R5)2.
The heteroaryl substituent represents an carbazolyl, furanyl, thienyl, pyrrolyl, isothiazolyl, imidazolyl, isoxazolyl, thiazolyl, oxazolyl, pyrazolyl, pyrazinyl, pyridyl, pyrimidyl, purinyl. The heterocyclyl substituent represents a pyridyl, pyrimidyl, thienyl, furanyl, oxazolidinyl, oxazolyl, thiazolyl, isothiazolyl, pyrazolyl, triazolyl, imidazolyl, imidazoldinyl, thiazolidilnyl, isoxazolyl, oxadiazolyl, thiadiazolyl, morpholinyl, piperidinyl, piperazinyl, pyrrolyl, or pyrrolidinyl.
The vinyl-substituted, chiral oxazolines of Formula VI 
can generally be prepared by the following protocol. Scheme 1 below outlines the synthesis of the chiral auxiliary. 
Scheme 2 describes the addition of the chiral auxiliary 4 to form a vinyl-substituted, chiral oxazolines of Formula II. Unsaturated oxazoline 6 was prepared via the Homer-Emmons reaction of phosphonate 4 with bromopyridine aldehyde 5. 
Conjugate addition of the lithium anion of 4-bromo-1,2-(methylenedioxy)benzene 7 to 6 produced the desired adduct 8 in high diastereomeric excess. (Scheme 3) Hydrolysis of oxazoline 8 was accomplished by refluxing in isopropyl alcohol with concentrated sulfuric acid to yield the isopropyl ester 9, which is an example of a compound of Formula 1. Alternatively, the halide in compound 6 may be transformed into the corresponding carbonyl by methods well known in the literature and then protected as an acetal or another aldehyde equivalent. See, for example, Theodora W. Greene and Peter G. M. Wuts, Protective Groups in Organic Synthesis, John Wiley and Sons (1991). 
As previously mentioned, the compounds of Formula 1, such as compound 9, are useful intermediates in the syntheses of endothelin antagonists. Scheme 4 below outlines a synthesis of an endothelin antagonist using compound 9. 
Carbonylation of the isopropyl ester 9 using catalytic palladium in methanol produced diester 10. Inverse addition of the lithium anion of 14 to methyl ester 10 at xe2x88x9278xc2x0 C. generated the desired ketoester11. Compound 11 was then treated with aqueous HF to remove the silyl protecting group. The deprotected ketoester was then cyclized with sodium t-amylate to form aldol 12. Oxidation of 12 may then be accomplished using reagents well known in the art, such as Jone""s reagent (CrO3/H2SO4), to afford the carboxylic acid. Finally, the carboxylic acid analog of 12 can be deoxygenated by the action of TiCl4 and triethylsilane, for example, to produce 13. De-esterification then produces the target endothelin antagonist 15.