Enantiomerically enriched .alpha.,.alpha.-distributed amino acids and method

FIELD OF THE INVENTION
The present invention relates to the preparation of enantiomerically enriched 4,4-disubstituted-5(4H)-oxazolones, which can be transformed into enantiomerically enriched .alpha.,.alpha.-disubstituted amino acids.
BACKGROUND OF THE INVENTION
.alpha.,.alpha.-Disubstituted amino acids are of great interest for a variety of reasons. They have been shown to be effective inhibitors of enzymes which normally metabolize the corresponding proteinogenic amino acids (Almond et al., Biochem., 1, 243 (1962); Pankaskie et al., J. Med. Chem., 23, 121 (1980)). The additional substituent of such amino acids can have a marked effect on the conformation of peptide structure, thus they can be utilized to modify physiologically important peptides to stabilize preferred conformations (Burgess, Proc. Natl. Acad. Sci. USA, 91, 2649 (1994)). They also occur as constituent parts of interesting natural products (Koert, Nachr. Chem. Tech. Lab., 43, 347 (1995)). As such any effective preparation of .alpha.,.alpha.-disubstituted amino acids, in an enantiocontrolled fashion, is highly desirable.
5(4H)-Oxazolones have been known for some time, and are prepared by the direct dehydration of N-acylated .alpha.-amino acids. These 5(4H)-oxazolones are readily substituted in the 4-position. Subsequent hydrolysis of 4,4-disubstituted-5(4H)-oxazolone ring results in .alpha.,.alpha.-disubstituted amino acids. However, it has not been previously known to substitute the ring system in an stereospecific fashion so as to generate enantiomerically enriched, .alpha.,.alpha.-disubstituted amino acids.
SUMMARY OF THE INVENTION
The present invention relates compositions and methods for the preparation of enantiomerically enriched .alpha.,.alpha.-disubstituted amino acid precursors.
In one aspect of the present invention, methods for preparing enantiomerically enriched .alpha.,.alpha.-disubstituted amino acids precursors are presented. Briefly, allylic electrophiles are alkylated with oxazolones in the presence of a base and catalytic quantities of a transition metal complex incorporating a chiral phosphine ligand. In addition to the surprising degree of enantioselectivity, a high degree of diastereoselectivity may also be achieved with the appropriate choice of substrate, base and solvent.
A particularly preferred chiral phosphine ligand for practicing the present invention is Compound 1. ##STR1##
Preferred oxazolones for the practice of the present invention are compounds of Formula 3 ##STR2## wherein R.sup.1 is selected from a group consisting of hydrogen, substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls and R.sup.2 is an amino acid side-chain, a substituted amino acid side-chain or is selected from a group consisting of substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls. Particularly preferred oxazolones are where R.sup.1 is phenyl and R.sup.2 is an amino acid side-chain.
Preferred allylic electrophiles (R.sup.3 -L) are compounds of Formula 4 and Formula 6. ##STR3## When the allylic electrophile is cyclic, then n=1-6 and L is any ionizable group (also referred to as a leaving group). Illustrative examples of leaving groups include but are not limited to halides, esters, carbonates, and carboxylates. A particularly preferred cyclic allylic electrophile is where n=1 and L is acetate.
When the allylic electrophile is acyclic, two leavings groups L are present, and after reaction with an oxazolone of Formula 3, one of the leaving groups L is retained in the product. Similarly to cyclic allylic electrophiles, illustrative examples of leaving groups include but are not limited to halides, esters, carbonates, and carboxylates. The substituent R.sup.4 is selected from a group consisting of hydrogen, substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls. A particularly preferred acyclic allylic electrophile is where L is acetate are acetate and R.sup.4 is either hydrogen or a phenyl.
DESCRIPTION OF THE PREFERRED EMBODIMENTS
This invention is based on the discovery that allylic electrophiles may be alkylated with 5(4H)-oxazolones with high enantioselectivity, in the presence of a base and catalytic quantities of a transition metal complex incorporating a chiral phosphine ligand. This reaction results in enantiomerically enriched 4,4-disubstituted-5(4H)-oxazolones which may be subsequently transformed to yield enantiomerically enriched .alpha.,.alpha.-disubstituted amino acids.
As used in this disclosure, "enantiomerically enriched" refers to products whose enantiomeric excess is greater than zero. Enantiomeric excess (ee) is the "excess" of one enantiomer over the other. As a result, since both enantiomers are present in equal amounts in a racemic mixture, the enantiomeric excess would be zero (0% ee). However, if one enantiomer is enriched such that it constitutes 95% of the product, then the enantiomeric excess would be 90% ee (95% -5% (the amount of the enriched enantiomer minus the amount of the other enantiomer)). In general, higher enantiomeric purity (>about 50% ee) is preferred with enantiomeric excess of between about 75% ee and about 90% ee being more preferred and enantiomeric excess of greater than about 90% ee being particularly preferred.
Suitable transition metal complexes for practicing the invention are those based on Pd, W, Mo, Rh, Ni, and mixtures thereof (e.g. Pd and Rh). Especially preferred in the practice of the present invention are complexes of Pd(0) with C2-symmetric bidentate diphosphines containing a pair of metal binding moieties of the type C(.dbd.O)--Ar--P--(Ar').sub.2, wherein Ar and Ar' are aryl or heteroaryl groups, optionally comprising fused rings, as disclosed by Trost and Bunt in Wo-A-9609306, published Mar. 8, 1996. A particularly preferred ligand is compound (1). Such C2-symmetric ligands are available in both enantiomeric forms, thereby allowing with equal facility the preparation of a chosen enantiomer of a target compound. ##STR4## 5(4H)-Oxazolones are well known in the literature. As illustrated by Scheme 1, one general method for their preparation is the direct dehydration of the corresponding N-acylated .alpha.-amino acid (2). Briefly, N-acyl .alpha. amino acids (2) are treated with N,N'-dicyclohexylcarbodiimide (DCC) in THF for 24 hours. The only by-product, N,N'-dicyclohexyl urea (DCU), may be removed by simple filtration at low temperature which results in high yields of pure 5(4H)-oxazolones (3). However, although Scheme 1 has been described, oxazolones may be prepared using any synthesis known in the art. ##STR5##
Preferred oxazolones for the practice of the present invention are compounds of Formula 3 (as illustrated by Scheme 1) wherein R.sup.1 is selected from a group consisting of hydrogen, substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls and R.sup.2 is an amino acid side-chain, a substituted amino acid side-chain or is selected from a group consisting of substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls. Particularly preferred oxazolones are where R.sup.1 is phenyl and R.sup.2 is an amino acid side-chain.
In one embodiment of the present invention, cyclic allylic electrophiles are used. As shown by Scheme 2, cyclic allylic electrophiles are alkylated with 5(4H)-oxazolones in the presence of a base and a catalytic amount of a Pd(0)-diphosphine complex to give novel products of the formula (5). The enantiomeric purity of the 4, 4-disubstituted-5(4H)-oxazolones (5) is typically high and often exceed 95% ee. The diastereomeric ratio is largely dependent upon the substrate, solvent and base and ranges between 1:1 to only a single diastereomer being observed. ##STR6##
When the allylic electrophile is cyclic, then n=1-6 and L is any ionizable group (also referred to as a leaving group). Illustrative examples of leaving groups include but are not limited to halides, esters, carbonates, and carboxylates. A particularly preferred cyclic allylic electrophile is where n=1 and L is acetate. The 5(4H)-oxazolones are as previously defined.
In addition to the surprising degree of enantioselectivity in the synthetic methods of the present invention, a high degree of diastereoselectivity may also be achieved with the appropriate choice of substrate, base, and solvent. Suitable solvent and base combinations include: THF and DME with NaH; CH.sub.2 Cl.sub.2, CH.sub.3 CN, DMF, DMSO with Et.sub.3 N (and other tertiary amines), or Cs.sub.2 CO.sub.3. For example, in the case when the catalyst is a Pd(0) complex of the ligand (1), R.sup.1 =phenyl, R.sup.2 =methyl, n=2, and L=acetate with CH.sub.2 Cl.sub.2 (solvent) and Et.sub.3 N (base), the product (5) is obtained in a diastereomeric ratio of 2.75:1, with each diastereomer having 99% ee. In contrast, when R.sup.1 =phenyl, R.sup.2 =CH(CH.sub.3).sub.2, n=2, and L=acetate with CH.sub.3 CN and Et.sub.3 N, only a single diastereomer is observed having 99% ee.
In another embodiment of the invention, the reaction is as in Scheme 2 except that acyclic allylic electrophiles are used. As shown by Scheme 3, each L group is a leaving group. Suitable examples of leaving groups include but are not limited to halides, esters, carbonates, and carboxylates. The substituent R.sup.4 is selected from a group consisting of hydrogen, substituted and unsubstituted C.sub.1 -C.sub.20 alkyls, substituted and unsubstituted C.sub.1 -C.sub.20 aryls, and substituted and unsubstituted C.sub.1 -C.sub.20 heteroaryls. A particularly preferred acyclic allylic electrophile is where L=acetate and R.sup.4 is either hydrogen or phenyl. ##STR7##
The product of this reaction (7) is also novel. Typically, the enantiomeric purity of the 4,4-disubstituted-5(4H)-oxazolones (7) is high and often exceeds 95% ee. The diastereomeric ratio is largely dependant upon the substrate, solvent and base, and ranges between 1:1 and to only a single diastereomer being observed. For example, when the catalyst is a Pd(0) complex of the ligand (1), R.sup.1 and R.sup.4 =phenyl, R.sup.2 =methyl, and L=acetate with CH.sub.2 Cl.sub.2 (solvent) and Et.sub.3 N (base), then the product (7) is obtained in a diastereomeric ratio of 4.4:1, each diastereomer having 83% ee and 40% ee, respectively. In contrast, when the catalyst is Pd(0) complex of ligand (1), R.sup.1 and R.sup.4 =phenyl, R.sup.2 =CH(CH.sub.3).sub.2, and L=acetate with DME and NaH, only a single diastereomer is observed having 99% ee.
The enantiomerically enriched 4,4-disubstituted 5(4H)-oxazolones may be readily transformed into enantiomerically enriched .alpha.,.alpha.-disubstituted amino acids of Formula 8 (where R.sup.3 and R.sup.2 are as previously defined) using well known reactions (including enzymatic reactions) known in the art. For example, hydrolysis of the heterocyclic ring affords an N-acyl .alpha.-amino acid. Similarly, alcoholysis of the heterocyclic ring affords an N-acyl .alpha.-amino ester. ##STR8##
Aspects of the present invention will now be illustrated by the following examples. It will be understood that these examples are intended to illustrate, and not limit, the present invention.

EXAMPLE 1
All reactions were carried out under Ar atmosphere using standard syringe, septum equipment, and dried solvents which were bubbled with Ar prior use unless otherwise noted. THF, diethyl ether, dimethoxyethane, and dioxane were distilled over sodium benzophenone ketyl; benzene CH.sub.2 Cl.sub.2 distilled from CaH.sub.2 ; acetonitrile, DMSO and DMF were dried over molecular sieves. 2-Cyclopentenol, 2-cyclopentenyl acetate, 2-cyclohexenyl acetate, and bis(.eta..sup.3 -allyl)di-.mu.-chloro- dipalladium(II) were prepared by literature methods. Melting points were taken on a Thomas-Hoover melting point apparatus in open capillaries and are uncorrected. .sup.1 H NMR (300 MHz) and .sup.13 C NMR (75 MHz) were obtained on a Varian Gemini 300 spectrometer. NMR spectra were recorded in CDCl.sub.3, and chemical shifts were reported in parts per million relative to tetramethylsilane or CDCl.sub.3 (77.0 ppm, .sup.13 C). Infrared spectra were recorded on a Perkin Elmer Paragon 500. Optical rotations were measured at 23-25.degree. C. in CH.sub.2 Cl.sub.2 on a JASCO DIP-360. Enantiomeric excess were determined by chiral HPLC (Chiracel.RTM. OD or Chiralpak.RTM. AD column, detection at 254 nm and flow rate 1 mL/min). Flash chromatography was performed on silica gel (Merck Kiegel 60, 230-400 mesh).
EXAMPLE 2
2-Oxazolin-5-ones. General Procedure.
A solution of 1,3-dicyclohexylcarbodiimide (DCC, 5.21 g, 25.0 mmol) in THF (25 mL) was added dropwise to a suspension of N-acyl-amino acid (25.0 mmol) in THF (25 mL) at 0.degree. C. under Ar. After stirring overnight at room temperature, the suspension was filtered at -40.degree. C. under Ar and the precipitate was washed twice with THF (2.times.20 mL) also at -40.degree. C. The combined organic layer was evaporated to dryness and the obtained 2-oxazolin-5-one was not further purified.
4-Methyl-2-phenyl-2-oxazolin-5-one: m.p.: 37-39.degree. C. (lit. 37-38.degree. C.). IR (neat film from CDCl.sub.3): 3064, 2986, 2939, 1822, 1731, 1652, 1580, 1527, 1496, 1451, 1323, 1308, 1258, 1156, 1111, 1048, 999, 912, 879, 809, 780, 696 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.01-7.98 (m, 2H), 7.59 (m, 1H), 7.52-7.46 (m, 2H), 4.46 (q, J=7.6 Hz, 1H), 1.60 (d, J=7.6 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.0, 161.8, 132.9, 128.9, 127.9, 60.9, 16.7.
2(2'-Methoxyphenyl)-4-methyl-2-oxazolin-5-one: Oil. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.83 (m, 1H), 7.52 (m, 1H), 7.07-7.02 (m, 2H), 3.96 (s, 3H), 4.48 (q, J=7.6 Hz, 1H), 1.61 (d, J=7.6 Hz, 3H).
2-Tert-Butyl-4-methyl-2-oxazolin-5-one: Oil. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 4.21 (q, J=7.5 Hz, 1H), 1.47 (d, J=7.5 Hz, 3H), 1.29 (s, 9H).
4-Benzyl-2-phenyl-2-oxazolin-5-one: m.p.: 68-70.degree. C. (lit. 68-70.degree. C.). .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.93-7.90 (m, 2H), 7.54 (m, 1H), 7.47-7.42 (m, 2H), 7.27-7.22 (m, 5H), 4.69 (dd, J=6.7, 5.0 Hz, 1H), 3.37 (dd, J=14.0, 5.0 Hz, 1H), 3.18 (dd, J=6.7 Hz, 14.0 Hz, 1H).
4-Isopropyl-2-phenyl-2-oxazolin-5-one: m.p.: 48-50.degree. C. (lit. 48-51.degree. C.). IR (neat film from CDCl.sub.3): 2967, 2934, 2877, 1822, 1654, 1581, 1495, 1452, 1325, 1297, 1246, 1148, 1131, 1044, 1021, 885, 780, 701 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.02-8.00 (m, 2H), 7.57 (m, 1H), 7.51-7.46 (m, 2H), 4.29 (d, J=4.6 Hz, 1H), 2.38 (m 1H), 1.15 (d, J=6.9 Hz, 3H), 1.02 (d, J=6.9 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.9, 161.8, 132.7, 128.8, 127.9, 126.0, 70.6, 31.1, 18.6, 17.4.
4-Isobutyl-2-phenyl-2-oxazolin-5-one: m.p.: 53-55.degree. C. (lit. 45-56.degree. C.). IR (KBr) : 2961, 2930, 2876, 1820, 1655, 1580, 1492, 1473, 1452, 1321, 1302, 1279, 1239, 1155, 1077, 1043, 1020, 897, 882, 851, 818, 782, 697, 659 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.01-7.99 (m 2H), 7.57 (m, 1H), 7.51-7.46 (m, 2H), 4.42 (dd, J=9.1, 5.5 Hz, 1H), 2.06 (m, 1h), 1.85 (m, 1H), 1.68 (m, 1H), 1.04 (d, J=6.9 Hz, 3H), 1.01 (d, J=7.0 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.1, 161.5, 132.6, 128.8, 127.9, 126.1, 63.9, 40.7, 25.1, 22.6. 21.8. ##STR9##
______________________________________R R' N-acyl-AA Yield (g)______________________________________Methyl Phenyl 4.83 g 99% (4.34 g) Methyl.sup.a,d 2-Methoxyphenyl.sup.e 2.72 g 100% (2.53 g) Methyl.sup.b,d tert-Butyl.sup.f 2.45 g 90% (1.96 g) Methyl.sup.c,d 2-Pyridyl.sup.g 0.479 g -- Benzyl Phenyl 6.73 g 89% (5.61 g) Isobutyl.sup.a Phenyl 2.94 g 83% (2.26 g) Isopropyl.sup.a Phenyl 2.61 g 83% (2.11 g)______________________________________ .sup.a Scaled to 1/2; .sup.b Scaled to 3/5; .sup.c Scaled to 1/10; .sup.d Prepared from DLalanine methyl ester hydrochloride; .sup.e Prepared from the corresponding acid and DCCEt.sub.3 N; .sup.f Prepared from pivaloyl chloride and Et.sub.3 N; .sup.g Prepared from the corresponding acid and DCCEt.sub.3 N.
EXAMPLE 3
Asymmetric Alkylation of 2-Cyclohexenyl Acetate with 4-Methyl-2-phenyl-oxazolin-5-one. General Procedure.
2-Cyclohexenyl acetate (14 mg, 100 .mu.mol was added to a solution (0.5 mL) of amine (200 .mu.mol) and 4-methyl-2-phenyl-2 oxazolin-5-one (39.4 mg, 225 .mu.mol). Then a preformed solution (0.5 mL) of bis(.eta..sup.3 -allyl)di-.mu.-chlorodipalladium (II) (0.9 mg, 2.5 .mu.mol) and chiral ligand (7.5 .mu.mol) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 20 ml) and extracted with CH.sub.2 Cl.sub.2 (3.times.15 mL). The combined organic layer were dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) or hexane-AcOEt (95:5) to give an oil as a non-separable diastereomeric mixture of 4(2'-cyclohexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one. Then, enantiomeric and diastereomeric excess were determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.9:0.1), t.sub.R (major)=8.5 (1'R, 4R), 14.0 (1'S, 4S), t.sub.R (minor)=10.5 (1'S, 4R), 16.3 (1'R, 4S). Further separation could be accomplished by careful flash chromatography on silica gel eluting with petroleum ether-AcOEt (97:3).
(1'S, 4S)-4(2'-Cyclohexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one: Oil. [.alpha.].sub.D -82.4 (c=1.03, CH.sub.2 Cl.sub.2). IR (neat film from CDCl.sub.3): 3031, 2936, 2862, 1820, 1655, 1581, 1494, 1451, 1320, 1291, 1003, 920, 873, 779, 704, 692, 668 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.01-7.98 (m, 2H), 7.56 (m, 1H), 7.50-7.45 (m, 2H), 5.84 (m, 1H), 5.53 (m, 1H), 2.64 (m, 1H), 1.98-1.93 (m, 3H), 1.85 (m, 1H), 1.59-1.49 (m, 2H), 1.54 (s, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 180.7, 159.6, 132.6, 131.4, 128.8, 128.0, 126.1, 124.8, 71.9, 43.1, 24.7, 23.5, 21.4, 20.9. Anal. Calcd for C.sub.16 H.sub.17 NO.sub.2 ; C, 75.27; H, 6.71; N, 5.49. Found: C, 75.46; H, 6.75; N, 5.58.
(1'S, 4R)-4(2'-Cyclohexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one: Oil. [.alpha.].sub.D -96.2 (c=1.25, CH.sub.2 Cl.sub.2). IR (neat film from CDCl.sub.3): 3029, 2935, 2861, 1818, 1654, 1581, 1494, 1451, 1321, 1291, 1002, 922, 876, 702, 692 cm.sup.-1. .sup.1 H NMR (300 MHZ, CDCl.sub.3) .delta.: 8.03-8.00 (m, 2H), 7.58 (m, 1H), 7.51-7.46 (m, 2H), 5.88 (m, 1H), 5.65 (m, 1H), 2.64 (m, 1H), 1.98-1.96 (m, 2H), 1.84-1.78 (m, 2H), 1.58-1.49 (m, 2H), 1.56 (s, 3H). .sup.13 C NMR (75.5 MHZ, CDCl.sub.3) .delta.: 180.4, 160.1, 132.7, 131.5, 128.8, 128.0, 126.0, 124.1, 71.8, 42.4, 24.8, 23.3, 21.6, 21.2. Anal. Calcd for C.sub.16 H.sub.17 NO.sub.2 ; C, 75.27; H, 6.71; N, 5.49. Found: C, 75.33; H, 6.74; N, 5.43. ##STR10##
______________________________________Solvent Amine Time Amount Yield D.r.(e.e)______________________________________CH.sub.2 Cl.sub.2 Et.sub.3 N 18 h 29 .mu.L 94% 2.75:1 (24.1 mg) (99)(99) CH.sub.2 Cl.sub.2 Hydroquinidine 4 h 100 mg 87% 2.83:1 9-phenanthryl ether (22.2 mg) (99)(99) CH.sub.2 Cl.sub.2 (DHQD).sub.2 PHAL 4 h 78 mg 76% 2.84:1 (19.3 mg) (99)(99) CH.sub.2 Cl.sub.2 (DHQ).sub.2 PYR 4 h 88 mg 94% 2.97:1 (23.9 mg) (99)(99) CH.sub.2 Cl.sub.2 (-)-N-Methyl- 7 h 36.6 mg 72% 2.92:1 ephedrine (18.4 mg) (99)(99) CH.sub.2 Cl.sub.2 Chirald .RTM. 7 h 56.7 mg 82% 2.97:1 (20.9 mg) (99)(99) CH.sub.2 Cl.sub.2 4-DMAP 9 h 24.4 mg 55% 2.92:1 (13.8 mg) (99)(99) CH.sub.2 Cl.sub.2 2,2,6,6-Tetramethyl 5 h 36.2 mg 57% 2.96:1 piperidine (14.5 mg) (99)(99) CH.sub.2 Cl.sub.2 (-)-Quinine 9 h 64.9 mg 50% 2.96:1 (12.8 mg) (98)(98) CH.sub.2 Cl.sub.2 (-)-Sparteine 9 h 46.9 mg 66% 2.89:1 (16.9 mg) (99)(98) CH.sub.2 Cl.sub.2 Quinidine 9 h 64.9 mg 60% 2.92:1 (15.4 mg) (99)(99) CH.sub.2 Cl.sub.2 (-)-Nicotine 18 h 32.5 mg 48% 2.99:1 (12.2 mg) (99)(99)CH.sub.2 Cl.sub.2 Triethanolamine 3 h 27.mu. 88% 2.78:1 (22.4 mg) (99)(99) CH.sub.2 Cl.sub.2 DBU 6 h 61.mu. 30% 2.69:1 (15.3 mg) (99)(99) Toluene Et.sub.3 N 18 h 29.mu. 45% 2.75:1 (11.6 mg) (99)(99) Toluene (-)-Nicotine 24 h 32.mu. 53% 2.83:1 (13.4 mg) (99)(99)______________________________________ ##STR11##
______________________________________Ligand Yield Time D.r. (e.e.)______________________________________2.sup.a 85% 2 h 1.25:1 (11.0 mg) (43.2 mg) (78) (68) 3.sup.a 95% 2 h 30' 2.55:1 (15.0 mg) (48.7 mg) (62) (62) 4 76% 14 h 2.55:1 (5.9 mg) (19.3 mg) (90) (92)______________________________________ .sup.a Reaction scaled .times. 2. ##STR12##
______________________________________Solvent.sup.a Yield D.r. (e.e.)______________________________________CH.sub.3 CN 90% 8.67:1 (45.8 mg) (99) (97) DMF 94% 4.43:1 (48.0 mg) (98) (96) DMSO 41% 4.24:1 (20.9 mg) (98) (95)______________________________________ .sup.a Reaction scaled .times. 2.
EXAMPLE 4
Asymmetric Alkylation of 2-Cyclohexenyl Acetate with 4-Alkyl-2-phenyl-2-oxazolin-5-one. General Procedure.
2-Cyclohexenyl acetate (28 mg, 200 .mu.mol) was added to a solution of triethylamine (56 .mu.L, 400 .mu.mol) and 4-alkyl-2-phenyl-2-oxazolin-5-one (450 .mu.mol) in acetonitrile (1 mL). Then a preformed solution of bis(.eta..sup.3 -allyl)di-.mu.-chlorodipalladium (II) (1.8 mg, 4.9 .mu.mol) and ligand 1 (10.4 mg, 15.1 .mu.mol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH.sub.2 Cl.sub.2 (3.times.30 mL). The combined organic layer were dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt to give an oil of 4-alkyl-4(2'-cyclohexenyl)-2-phenyl-2-oxazolin-5-one. ##STR13##
______________________________________R Time Yield.sup.a D.r. (e.e.)______________________________________--CH.sub.3 4 h 90% 8.7:1 (78.8 mg) (45.8 mg) (99) (97) --CH.sub.2 Ph 2 h 74%.sup.d 12.4:1 (113.1 mg) (48.9 mg) (99) -- --CH.sub.2 CH(CH.sub.3).sub.2 2 h 30' 77%.sup.b 13.3:1 (97.8 mg) (45.9 mg) (99) -- --CH(CH.sub.3).sub.2 6 h 91% >19:1 (91.5 mg).sup.c (51.4 mg) (95) --______________________________________ .sup.a Mixture yield; .sup.b Major isomer yield, .sup.c Racemic ligand 1, .sup.d In CH.sub.2 Cl.sub.2 74% yield 4.21(98):1(96).
(1'S, 4S)-4-Benzyl-4(2'-cyclohexenyl)-2-phenyl-2-oxazolin-5-one: Petroleum ether--AcOEt (95:5) for chromatography. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propenyl 99.9:0.1), t.sub.R =13.0 (1'S, 4S), 15.3 (1'R, 4R). [.alpha.].sub.D =-221.8 (c=1.45, CH.sub.2 Cl.sub.2, for 99.1% e.e.). Oil. IR (neat film from CDCl.sub.3): 3063, 3031, 2930, 2861, 2838, 1815, 1655, 1603, 1581, 1495, 1452, 1320, 1293, 1103, 1055, 1026, 967, 889, 873, 778 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.82-7.80 (m, 2H), 7.48 (m, 1H), 7.40-7.35 (m, 2H), 7.17-7.09 (m, 5H), 5.85 (m, 1h), 5.60 (m, 1H), 3.33 (d, J=13.2 Hz, 1H), 3.18 (d, J=13.2 Hz, 1H), 2.83 (m, 1H), 2.08-1.99 (m, 3H), 1.88 (m, 1H), 1.71-1.52 (m, 2H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.4, 159.6, 134.6, 132.41 131.3, 130.3, 128.6, 128.1, 127.8, 127.1, 125.9, 124.9, 77.4, 42.7, 40.4, 24.8, 23.8, 21.5. Anal. Calcd for C.sub.22 H.sub.21 NO.sub.2 ; C, 79.73; H, 6.39; N, 4.23. Found: C, 79.79; HI 6.35; N, 4.23.
(1'S, 4R)-4-Benzyl-4(2'-cyclohexenyl)-2-phenyl-2-oxazolin-5-one: Petroleum ether-AcOEt (95:5) for chromatography. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.9:0.1), t.sub.R =15.8 (1'R, 4S), 19.6 (1'S, 4R). [.alpha.].sub.D =+37.7 (c=0.71, CH.sub.2 Cl.sub.2 for 98.7% e.e.). Oil. IR (neat film from CDCl.sub.3): 3063, 3031, 2931, 2860, 1814, 1654, 1603, 1581, 1495, 1451, 1321, 1293, 1104, 1055, 1039, 966, 884, 778 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.85-7.82 (m, 2H), 7.51 (m, 1H), 7.43-7.27 (m, 2H), 7.18-7.10 (m, 5H), 5.92 (m, 1H), 5.74 (m, 1H), 3.36 (d, J=13.2 Hz, 1H), 3.23 (d, J=13.2 Hz, 1H), 2.82 (m, 1H), 2.04-1.98 (m, 2H), 1.96-1.82 (m, 2H), 1.69-1.52 (m, 2H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.1, 160.1, 134.5, 132.5, 131.6, 130.3, 128.7, 128.1, 127.9, 127.1, 125.7, 124.3, 77.3, 42.0, 40.6, 24.8, 23.6, 21.6. Anal. Calcd for C.sub.22 H.sub.21 NO.sub.2 ; C, 79.73; H, 6.39; N, 4.23. Found: C, 79.62; H, 6.26; N, 4.17.
(1'S, 4S)-4(2'-Cyclohexenyl)-4-isobutyl-2-phenyl-2-oxazolin-5-one (major isomer): Petroleum ether-AcOEt (97:3) for chromatography. Diastereomeric excess was determined by HPLC (Microsorb.RTM. Si 80-125-C5, flow 2 mL/min, 254 nm, heptane/AcOEt 98:2, t.sub.R (major)=4.1, t.sub.R (minor)=4.9). Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. AD column, heptane/2-propenyl 99.9:0.1), t.sub.R =6.9 (1'S, 4S), 7.8 (1'R, 4R). [.alpha.].sub.D =-108.4 (c=1.20, CH.sub.2 Cl.sub.2). Oil. IR (neat film from CDCl.sub.3): 3032, 2956, 2871, 1814, 1654, 1581, 1495, 1451, 1320, 1290, 1156, 1098, 1037, 1023, 959, 882, 778, 705, 692, 668 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.02-7.99 (m, 2H), 7.57 (m, 1H), 7.51-7.46 (m, 2H), 5.85 (m, 1H), 5.59 (m, 1H), 2.63 (m, 1H), 2.09-1.80 (m, 6H), 1.63-1.44 (m, 3H), 0.89 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 180.8, 159.4, 132.5, 131.51 128.8, 128.0, 126.2, 124.8, 75.5, 44.0, 43.0, 24.8, 24.0, 23.6, 23.1, 21.6. Anal. Calcd for C.sub.19 H.sub.23 NO.sub.2 ; C, 76.74; H, 7.79; N, 4.71. Found: C, 76.75; H, 7.95; N, 4.58.
(1'S, 4R)-4(2 '-Cyclohexenyl)-4-isobutyl-2-phenyl-2-oxazolin-5-one (minor isomer): Petroleum ether-AcOEt (97:3) for chromatography. An analytical sample was purified by semipreparative HPLC (Microsorb.RTM. Si 80- 199-C5, flow 2 mL/min, 254 nm, heptane/AcOEt 98:2). Oil. IR (neat film from CDCl.sub.3): 2925, 2853, 1814, 1654, 1581, 1451, 1320, 1290, 1056, 1037, 1024, 957, 882, 778, 702 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.04-8.01 (m, 2H), 7.59 (m, 1H), 7.56-7.47 (m, 2H), 5.85 (m, 1H), 5.56 (m, 1H), 5.56 (m, 1H), 2.63 (m, 1H), 2.10-1.79 (m, 6H), 1.65-1.45 (m, 3H), 0.90 (d, J=6.6 Hz, 3H), 0.85 (d, J=6.6 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 180.4, -, 132.7, 131.6, 128.9, 128.1, -, 124.3, 75.3, 43.2, 43.0, 24.8, 24.1, 23.0, 23.0, 21.7.
4(2'-Cyclohexenyl)-4-isopropyl-2-phenyl-2-oxazolin-5-one (single isomer): Petroleum ether-AcOEt (98:2) for chromatography. Oil. IR (neat film from CDCl.sub.3): 3032, 2969, 2937, 2878, 1813, 1655, 1581, 1494, 1470, 1451, 1389, 1321, 1292, 1073, 1040, 1022, 944, 879, 780, 706, 692, 670 cm.sup.1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.02-7.99 (m, 2H), 7.57 (m, 1H), 7.54-7.45 (m, 2H), 5.84 ((m, 1H), 5.52 (m, 1H), 2.84 (m, 1H), 2.44 (hp, J=6.8 Hz, 1H), 2.01-1.95 (m, 2H), 1.89-1.78 (m, 2H), 1.61-138 (m, 2H), 1.01 (d, J=6.8 Hz, 3H), 0.99 (d, J=6.8 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.8, 159.9, 132.5, 131.3, 128.8, 128.0, 126.0, 124.5, 79.1, 39.4, 31.2, 24.8, 23.9, 21.6, 16.7, 16.3. Anal. Calcd for C.sub.18 H.sub.21 NO.sub.2 : C, .delta.; 76.30; H, 7.47; N, 4.94. Found: C, 76.56; H. 7.47; N, 5.00.
EXAMPLE 5
Asymmetric Alkylation of 2-Cyclopentenyl Acetate or Tert-butyl 2-Cyclopentenyl Carbonate with 4-Benzyl-2-phenyl-2-oxazolin-5-one.
2-Cyclopentenyl acetate (25.2 mg, 200 .mu.mol) or tert-butyl 2-cyclopentenyl carbonate (36.8 mg, 200 .mu.mol) was added to a solution of triethylamine (56 .mu.L, 400 .mu.mol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (113.1 mg, 450 .mu.mol) in acetonitrile (1 mL). Then a preformed solution of bis(.eta..sup.3 -allyl)di-.mu.-chlorodipalladium (II) (1.8 mg, 4.9 .mu.mol) and ligand 1 (10.4 mg, 15.1 .mu.mol) in acetonitrile (1 mL) was added via cannula. After 3 hours the reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH.sub.2 Cl.sub.2 (3.times.30 mL). The combined organic layer were dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (97:3) to give two fractions: the first one was the major isomer, the second one was a mixture of 4-benzyl-2-phenyl-2-oxazolin-5-one and the minor isomer that could be partially separated. ##STR14##
______________________________________R Yield.sup.a D.r..sup.b (e.e.).sup.c [.alpha.].sub.D .sup.d______________________________________--Ac 71% 5.4:1 -290.7 (45.0 mg) (93) -- (c = 0.99, CH.sub.2 Cl.sub.2) --Boc 69% 5.4:1 -301.5 (43.8 mg) (95) -- (c = 0.98, CH.sub.2 Cl.sub.2)______________________________________ .sup.a Isolaled major isomer; .sup.b Determined by HNMR; .sup.c Determined by chiral HPLC, .sup.d Major isomer.
4-Benzyl-4(2'-cyclopentenyl)-2-phenyl-2-oxazolin-5-one (major isomer): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.9:0.1), t.sub.R (major)=15.3, t.sub.R (minor)=22.4. IR (neat film from CDCl.sub.3): 3062, 3032, 2926, 2850, 1814, 1655, 1603, 1580, 1496, 1452, 1320, 1291, 1234, 1177, 1159, 1094, 1048, 1009, 972, 888, 778, 700 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.82-7.79 (m, 2H), 7.49 (m, 1H), 7.41-7.36 (m, 2H), 7.18-7.10 (m, 5H), 5.90 (m, 1H), 5.60 (m, 1H), 3.55 (m, 1H), 3.31 (d, J=13.4 Hz, 1H), 3.19 (d, J=13.4 Hz, 1H), 2.50-2.27 (m, 2H), 2.19-1.98 (m, 2H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.4, 159.7, 135.3, 134.7, 132.4, 130.2, 128.6, 128.2, 128.1, 127.8, 127.1, 125.9, 77.2, 53.2, 41.5, 32.2, 24.9. Anal. Calcd for C.sub.22 H.sub.21 NO.sub.2 ; C, 79.47; H, 6.03; N, 4.41. Found: C, 79.84; H, 6.08; N, 4.28.
4-Benzyl-4(2'-cyclospentenyl)-2-phenyl-2-oxazolin-5-one (minor isomer): Oil. IR (neat film from CH.sub.2 Cl.sub.2): 3062, 3032, 2925, 2851, 1814, 1654, 1603, 1581, 1495, 1452, 1320, 1292, 1097, 1060, 1049, 1013, 968, 990, 779, 700 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.86-7.83 (m, 2H), 7.52 (m, 1H), 7.44-7.39 (m, 2H), 7.18-7.11 (m, 5H), 5.97 (m, 1H), 5.75 (m, 1H), 3.36 (m, 1H), 3.30 (d, J=13.3 Hz, 1H), 3.23 (d, J=13.3 Hz, 1H), 2.50-2.28 (m, 2H), 2.15-1.90 (m, 2H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.1, 160.1, 135.5, 134.7, 132.5, 130.3, 128.7, 128.2, 128.2, 127.9, 127.1, 125.8, 77.0, 52.6, 41.4, 32.4, 24.2. Calcd for C.sub.21 H.sub.19 NO.sub.2 : 317.1416. Found: 317.1413.
EXAMPLE 6
Asymmetric Alkylation of Allylic Acetate with 4-Benzyl-2-phenyl-2-oxazolin-5-one.
Allyl acetate (21.6 .mu.L, 200 .mu.mol) was added to a solution of triethylamine (56 .mu.L, 400 .mu.mol) or pentamethylguanidine (51.7 mg, 400 .mu.mol) and 4-benzyl-2-phenyl-2-oxazolin-5-one (450 .mu.mol) in acetonitrile (1 mL). Then a preformed solution of bis(.eta..sup.3 -allyl)di-,.mu.-chlorodipalladium (II) (1.8 mg, 4.9 .mu.mol) and ligand 1 (10.4 mg, 15.1 .mu.mol) in acetonitrile (1 mL) was added via cannula. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH.sub.2 Cl.sub.2 (3.times.30 mL). The combined organic layer was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5) to give 4-allyl-4-benzyl-2-phenyl-2-oxazolin-5-one. ##STR15##
______________________________________Base Time Yield.sup.a E.e..sup.b [.alpha.].sub.D______________________________________Et.sub.3 N 2 h 30' 98% 40% -31.1 (57.5 mg) (c = 1.10, CH.sub.2 Cl.sub.2) Pentamethyl- 5 h 70%.sup.d 30% -25.4 guanidine (45.0 mg) (c = 0.98, CH.sub.2 Cl.sub.2)______________________________________ .sup.a Not including the catalyst; .sup.b Determined by chiral HPLC.
4-Allyl-4-benzyl-2-phenyl-2-oxazolin-5-one: Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propenyl 99.9:0.1), t.sub.R (major)=14.3, t.sub.R (minor)=17.4. IR (neat film from CH.sub.2 Cl.sub.2): 3064, 3032, 2922, 1817, 1656, 1603, 1581, 1495, 1452, 1436, 1321, 1292, 1176, 1137, 1087, 1046, 977, 929, 890, 780, 738, 700, 665 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.86-7.83 (m, 2H), 7.52 (m, 1H), 7.41 (m, 2H), 7.18-7.13 (m, 5H), 5.68 (m, 1H), 5.24-5.10 (m, 2H), 3.24 (d, J=13.4 Hz, 1H), 3.16 (d, J=13.4 Hz, 1H), 2.80-2.67 (m, 2H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.3, 160.0, 134.4, 132.6, 130.8, 103.2, 128.7, 128.2, 127.9, 127.3, 125.7, 120.6, 74.8, 43.1, 41.3. Anal. Calcd for C.sub.19 H.sub.17 NO.sub.2 ; C, 78.33; H, 5.88; N, 4.81. Found: C, 78.25; H, 5.94; N, 4.81.
EXAMPLE 7
Asymmetric Alkylation of 3,3-Diacetoxy-1-phenyl-1-propene with 4-Alkyl-2-phenyl-2-oxazonlin-5-one. General Procedure.
A solution (1.0 mL) of 4-alkyl-2-phenyl-2-oxazolin-5-one (450 .mu.mol) was added to NaH (95% in oil, 10.1 mg, 400 .mu.mol) at -78.degree. C. and warmed to room temperature. When the bubbling stopped, a solution (0.5 mL) of bis(.eta..sup.3 -allyl)di-.mu.-chlorodipalladium (II) (1.8 mg, 4.9 .mu.mol) and ligand 1 (10.4 mg, 15.1 .mu.mol). Finally, another solution (1.0 mL) of 3,3 diacetoxy-1-phenylpropene (46.9 mg, 200 .mu.mol) was added at the desired temperature. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 mL) and extracted with CH.sub.2 Cl.sub.2 (3.times.30 mL). The combined organic layer was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt. ##STR16##
__________________________________________________________________________R Sol.(T) Time Base Yield.sup.a E.e..sup.b D.r..sup.c [.alpha.].sub.D.sup.e__________________________________________________________________________--CH.sub.3 CH.sub.2 Cl.sub.2 18 h Et.sub.3 N 73% (50.9 mg) 83% 4.4:1 -193.5 (2.84) 78.8 mg r.t. 16% (11.4 mg) 40% -37.9 (0.86) --CH.sub.3 THF 18 h NaH 38% (26.4 mg) 98% --:-- -221.0 (2.20) 78.8 mg r.t. 6% (4.5 mg) 91% -82.2 (0.27) --CH.sub.3 DME 5 h NaH 60% (42.1 mg) 99% 6.6:1 -227.7 (4.21) 78.8 mg r.t. 9% (6.4 mg) 96% -92.6 (0.64) --CH.sub.2 Ph DME 5 h NaH 67% (57.2 mg) 98% 7.8:1 -283.5 (2.67) 113.1 mg r.t. 7% (6.3 mg) 94% +19.1 (0.62) --CH.sub.2 Ph DME 24 h NaH 75% (64.2 mg) 99% 9.7:1 -290.1 (1.08) 113.1 mg 0-5.degree. C. 6% (4.9 mg) 96% +21.5 (0.22) --CH.sub.2 Ph DME 24 h NaH 67% (56.7 mg) 99% 11.2:1 -289.3 (1.52) 113.1 mg -20.degree. C. 5% (5.9 mg) 98% +25.5 (0.46) Isobutyl DME 3 h NaH 91% (71.1 mg) 99% 15:1 -235.2 (1.02) 97.8 mg 0-5.degree. C. 6% (4.7 mg) 95% -40.5 (0.41) Isopropyl DME 2 h NaH 88% (66.4 mg) 99% >19:1 -208.0 (1.02) 91.5 mg 0-5.degree. C. 4% (4.4 mg).sup.d -- --__________________________________________________________________________ .sup.a Isolated yield; .sup.b Determined by chiral HPLC; .sup.c Determined by HNMR; .sup.d 2% of the other regioisomer; .sup.e Conc. in CH.sub.2 Cl.sub.2.
(E, 1'R, 4S)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-methyl-2-phenyl-2-oxazolin-5-one: (major isomer, first fraction). Petroleum ether-AcOEt (9:1) for chromatography. M.p.: 138-139.degree. C. (isopropanol). Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99:1), t.sub.R (minor)=11.6, t.sub.R (major)=13.7. IR(neat film from CH.sub.2 Cl.sub.2): 3601, 3029, 2985, 2936, 1827, 1749, 1656, 1581, 1495, 1451, 1371, 1322, 1294, 1223, 1179, 1092, 1071, 1007, 971, 904, 781, 743, 694 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.10-8.07 (m, 2H), 7.65-7.45 (m, 5H), 7.38-7.26 (m, 3H), 6.88 (d, J=15.9 Hz, 1H), 6.32 (dd, J=15.9, 8.8 Hz, 1H), 5.66 (d, J=8.8 Hz, 1H), 1.96 (s, 3H), 1.50 (s, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 178.9, 169.4, 161.3, 138.4, 135.7, 133.0, 128.9, 128.7, 128.6, 128.2, 127.1, 125.8, 121.3, 77.6, 72.2, 20.8, 20.3. Anal. Calcd for C.sub.21 H.sub.19 NO.sub.4 : C, 72.19; H, 5.48; N, 4.01. Found: C, 72.32; H. 5.62; N, 4.01.
(E, 1'R, 4R)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-methyl-2-phenyl-2-oxazolin-5-one (minor isomer, second fraction). Petroleum ether-AcOEt (9:1) for chromatography. M.p.: 142-144.degree. C. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol.99:1), t.sub.R (major)=12.8, t.sub.R (minor)=15.6. IR (neat film from CH.sub.2 Cl.sub.2): 3061, 3029, 2935, 1822, 1748, 1655, 1581, 1494, 1451, 1372, 1322, 1294, 1226, 1150, 1115, 1094, 1072, 1008, 971, 906, 882, 782, 746, 694 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.03-8.00 (m, 2H), 7.63-7.42 (m, 5H), 7.36-7.28 (m, 3H), 6.81 (d, J=15.9 Hz, 1H), 6.36 (dd, J=15.9, 8.9 Hz, 1H), 5.71 (d, J=8.9 Hz, 1H), 1.94 (s, 3H), 1.53 (s, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 178.1, 169.5, 161.5, 137.6, 135.7, 133.1, 129.0, 128.7, 128.7, 128.1, 127.1, 125.6, 120.5, 77.3, 71.7, 20.8, 20.3. Anal. Calcd for C.sub.21 H.sub.19 NO.sub.4 ; C, 72.19; H, 5.48; N, 4.01. Found: C, 72.38; H, 5.57; N, 4.00.
(E, 1'R, 4S)-4-(1-Acetoxy-3'-phenyl-2'-propenyl)-4-benzyl-2-phenyl-2-oxazolin-5-one (major isomer, first fraction). Petroleum ether-AcOEt (9:1) for chromatography on silica gel (2% Et.sub.3 N). M.p.: 138-140.degree. C. (isopropanol). Enantiomeric excess was determined by chiral, HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99:1), t.sub.R (minor)=17.2, t.sub.R (major)=21.5. IR (neat film from CDCl.sub.3): 3031, 1820, 1748, 1655, 1496, 1451, 1370, 1322, 1293, 1227, 1053, 1023, 971, 693 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.91-7.88 (m, 2H), 7.57-7.27 (m, 8H), 7.14-7.11 (m, 5H), 6.95 (d, J=16.0 Hz, 1H), 6.42 (dd, J=16.0, 8.9 Hz, 1H), 5.84 (d, J=8.9 Hz, 1H), 3.21 (d, J=13.3 Hz, 1H), 3.12 (d, J=13.3 Hz, 1H), 1.96 (s, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.6, 169.41 161.31 138.4, 135.7, 133.3, 132.8, 130.3, 128.7, 128.2, 128.1, 127.4, 127.1, 125.6, 121.6, 77.5, 77.2, 39.9, 20.9. Anal. Calcd for C.sub.27 H.sub.23 NO.sub.4 ; C, 76.22; H, 5.45; N, 3.29. Found; C, 76.37; H, 5.30; N., 3.24.
(E, 1'R, 4R)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-benzyl-2-phenyl-2-oxazolin-5-one (minor isomer, second fraction). Petroleum ether-AcOEt (9:1) for chromatography on silica gel (2% Et.sub.3 N). Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. AD column, heptane/2-propanol 9:1), t.sub.R (major)=7.6, t.sub.R (minor)=13.7. IR (neat film from CDCl.sub.3): 3031, 1817, 1748, 1655, 1496, 1451, 1371, 1322, 1293, 1226, 1051, 988, 694 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.87-7.84 (m, 2H), 7.57-7.30 (m, 8H), 7.18-7.13 (m, 5H), 6.84 (d, J=15.9 Hz, 1H), 6.47 (dd, J=15.9, 9.0 Hz, 1H), 5.87 (d, J=9.0 Hz, 1H), 3.25 (d, J=13.5 Hz, 1H), 3.19 (d, J=13.5 Hz, 1H), 1.96 (s, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.0, 169.5, 161.5, 137.8, 135.7, 133.5, 132.9, 130.4, 128.8, 128.3, 128.0, 127.4, 127.1, 125.4, 120.6, 77.2, 76.9, 39.9, 20.8. HRMS Calcd for C.sub.27 H.sub.24 NO.sub.4 (M+1); 426.1705. Found: 426.1720.
(E, 1'R, 4S)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-isobutyl-2-phenyl-2-oxazolin-5-one (major isomer, first fraction). Petroleum ether-AcOEt (95.5 to 9:1) for chromatography. M.p.: 164-165.degree. C. (racemic, heptane/2-propanol, 9:1). Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. AD column, heptane/2-propanol 99.5:0.5), t.sub.R (major)=15.7, t.sub.R (minor)=19.1. IR (neat film from CH.sub.2 Cl.sub.2): 3061, 3028, 2959, 2873, 1819, 1747, 1655, 1601, 1580, 1495, 1451, 1370, 1321, 1295, 1222, 1159, 1046, 1023, 969, 917, 885, 779, 744, 708, 693, 669 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.11-8.01 (m, 2H), 7.63 (m, 1H), 7.56-7.46 (m, 4H), 7.38-7.26 (m, 3H), 6.86 (d, J=15.9 Hz, 1H), 6.30 (dd, J=15.9, 8.8 Hz, 1H), 5.61 (d, J=8.8 Hz, 1H), 1.95 (dd, J=14.0, 7.1 Hz, 1H), 1.95 (s, 3H), 1.79' (dd, J=14.0, 7.1 Hz, 1H), 1.57 (m, 1H), 0.85 (m, J=6.5 Hz, 3H), 0.84 (m, J=6.6 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.2, 169.3, 161.3, 138.4, 135.8, 133.0, 128.9, 128.7, 128.6, 128.3, 127.1, 125.9, 121.7, 78.0, 75.9, 42.0, 24.5, 23.8, 23.0, 20.9. Anal. Calcd for C.sub.24 H.sub.25 NO.sub.4 ; C, 73.64; H, 6.44; N, 3.58. Found: C, 73.44; H, 6.19; N, 3.68.
(E, 1'R, 4R)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-isobutyl-2-phenyl-2-oxazolin-5-one (minor isomer, second fraction). Petroleum ether-AcOEt (95:5 to 9:1) for chromatography. Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. AD column, heptane/2-propanol 95:5), t.sub.R (major)=8.2, t.sub.R (minor)=10.0. IR (neat film from CDCl.sub.3): 3062, 3029, 2960, 2927, 2873, 1818, 1749, 1655, 1602, 1580, 1495, 1451, 1371, 1322, 1293, 1225, 1040, 1025, 982, 912, 885, 782, 745, 702 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.04-8.02 (m, 2H), 7.61 (m 1H), 7.54-7.44 (m, 4H), 7.38-7.30 (m, 3H), 6.80 (d, J=15.9 Hz, 1H), 6.39 (dd, J=15.9, 9.1 Hz, 1H), 5.70 (d, J=9.1 Hz, 1H), 1.94 (dd. J=13.8, 4.8 Hz, 1H), 1.88 (s, 3H), 1.79 (dd, J=13.8, 4.8 Hz, 1H), 1.67 (m, 1H), 0.89 (m, J=6.5 Hz, 3H), 0.83 (m, J=6.5 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 178.5, 169.4, 161.4, 137.6, 135.7, 133.0, 129.0, 128.7, 128.7, 128.1, 127.1, 125.7, 120.3, 77.6, 75.0, 42.4, 24.7, 24.0, 22.6, 20.8. HRMS (CI): Calcd for C.sub.22 H.sub.12 NO.sub.3 (M-COCH.sub.3): 348.1600. Found: 348.1587.
(E, 1'R, 4S)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-isopropsyl-2-phenyl-2-oxazolin-5-one (major isomer, first fraction). Petroleum ether-AcOEt (95:5 to 9:1) for chromatography. Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.8:0.2), t.sub.R (major)=22.4, t.sub.R (minor)=27.5. IR (neat film from CDCl.sub.3): 3061, 3028, 2973, 2881, 1814, 1747, 1656, 1602, 1580, 1495, 1451, 1371, 1321, 1294, 1229, 1177, 1161, 1087, 1044, 1022, 969, 939, 913, 883, 782, 750, 733, 693 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.10-8.07 (m, 2H), 7.61 (m, 1H), 7.55-7.49 (m, 2H), 7.46-7.43 (m, 2H), 7.36-7.26 (m, 3H), 6.91 (d, J=16.1 Hz, 1H), 6.33 (dd, J=16.1, 8.8 Hz, 1H), 5.92 (d, J=8.8 Hz, lH), 2.29 (hp, 1H), 1.96 (s, 3H), 1.18 (d, J=6.9 Hz, 3H), 0.91 (d, J=6.9 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.4, 169.5, 161.4, 137.8, 135.8, 132.9, 128.9, 128.7, 128.6, 128.2, 127.0, 125.8, 121.8, 78.9, 75.3, 31.8, 20.9, 17.0, 15.5. Anal. Calcd for C.sub.23 H.sub.23 NO.sub.4 ; C, 73.19; H, 6.14; N. 3.71. Found: C, 73.33; H, 5.94; N, 3.56.
(E, 1'R, 4R)-4-(1'-Acetoxy-3'-phenyl-2'-propenyl)-4-isopropyl-2-phenyl-2-oxazolin-5-one (minor isomer, third fraction). Petroleum ether-AcOEt (95:5 to 9:1) for chromatography. Oil impurified with the other regioisomer. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.06-8.03 (m, 2H), 7.61 (m, 1H), 7.55-7.44 (m, 4H), 7.38-7.28 (m, 3H), 6.88 (d, J=15.8 Hz, 1H), 6.49 (dd, J=15.8, 9.3 Hz, 1H), 5.87 (d, J=9.3 Hz, 1H), 2.30 (hp, 1H), 1.87 (s, 3H), 1.16 (d, J=6.7 Hz, 3H), 0.85 (d, J=6.7 Hz, 3H).
4-(3'-Acetoxy-1'-phenyl-2'-prospenyl)-4-isopropyl-2-phenyl-2-oxazolin-5-one (second fraction, only one diastereoisomer). Petroleum ether-AcOEt (95:5 to 9:1) for chromatography. Oil impurified with the other regioisomer. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.87-7.85 (m, 2H), 7.61-7.44 (m, 6H), 7.17-7.10 (m, 3H), 6.07 (dd, J=12.6, 10.7 Hz, 1H), 3.99 (d, J=10.7 Hz, 1H), 2.38 (hp, 1H), 2.13 (s, 3H), 1.27 (d, J=6.9 Hz, 3H), 0.86 (d, J=6.9 Hz, 3H).
EXAMPLE 8
Asymmetric Alkylation of 1,1-Diacetoxy-2-hexene with 4-Alkyl-2-phenyl-2-oxazolin-5-one. General Procedure.
A solution of 4-alkyl-2-phenyl-2-oxazolin-5-one (450 .mu.mol) was added to NaH (95% in oil, 10.1 mg, 400 .mu.mol) at -78.degree. C. and warmed to room temperature in DME (1.0 mL). When the bubbling stopped, a solution of bis(.eta..sup.3 -allyl)di-.mu.-chlorodipalladium (II) (1.8 mg, 4.9 .mu.mol) and ligand 1 (10.4 mg, 15.1 .mu.mol) in DME (1.5 mL). Finally, 1,1-diacetoxy-2-hexene (40.0 mg, 200 .mu.mol) was added dropwise at 0.degree. C. The reaction mixture was quenched with aqueous phosphate buffer (pH 7, 40 ml) and extracted with CH.sub.2 Cl.sub.2 (3.times.30 mL). The combined organic layer was dried over Na.sub.2 SO.sub.4 and concentrated in vacuo. The residue was purified by flash chromatography on silica gel eluting with petroleum ether-AcOEt (95:5). ##STR17##
______________________________________R Time Yield.sup.b E.e..sup.c D.r..sup.a [.alpha.]______________________________________--CH.sub.3 6 hr 22% (13.7 mg) 86% 1:1.sup.d -71.5 (c = 0.81) (78.8 mg) 22% (13.7 mg) 97% -40.9 (c = 0.49) --CH.sub.2 Ph 2 hr 39% (30.4 mg) 91% 1.2:1 -161.2 (c = 1.90) (113.1 mg) 33% (25.7 mg) 97% +90.4 (c = 1.67)______________________________________ .sup.a Determined by HNMR; .sup.b Isolated yield; .sup.c Determined by chiral HPLC; .sup.d The other regioisomer was obtained in 20% (12.5 mg) yield and d.r.(e.e.) 3.1(71%):1(65%).
4-(1'-Acetoxy-2'-hexenyl)-4-benzyl-2-phenyl-2-oxazolin-5-one (major isomer, first fraction): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.5:0.5), t.sub.R (minor)=10.9, t.sub.R (major)=15.5. IR (neat film from CDCl.sub.3): 3064, 3033, 2959, 2929, 2872, 1822, 1750, 1656, 1602, 1581, 1496, 1452, 1370, 1322, 1293, 1229, 1120, 1054, 1024, 973, 894, 779, 736, 702 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.88-7.85 (m, 2H), 7.54 (m, 1H), 7.46-7.41 (m, 2H), 7.14-7.10 (m, 5H), 6.07 (m, 1H), 5.72-5.61 (m, 2H), 3.18 (d, J=13.4 Hz, 1H), 3.09 (d, J=13.4 Hz, 1H), 2.16-2.09 (m, 2H), 1.96 (s, 3H), 1.45 (m, 1H), 0.91 (t, J=7.3 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.8, 169.4, 161.1, 140.8, 133.5, 132.7, 130.3, 128.7, 128.2, 128.0, 127.4, 125.7, 123.0, 77.4, 77.3, 39.9, 34.3, 21.8, 20.8, 13.5. Anal. Calcd for C.sub.24 H.sub.25 NO.sub.4 ; C, 73.64; H, 6.44; N, 3.58. Found: C, 73.45; H, 6.19; N, 3.37.
4-(1'-Acetoxy-2'-hexenyl)-4-benzyl-2-phenyl-2-oxazolin-5-one (minor isomer, second fraction): Oil. Enantiomeric excess was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.5:0.5), t.sub.R (major)=10.7, t.sub.R (minor)=14.9. IR (neat film from CDCl.sub.3): 3064, 3033, 2959, 2930, 2872. 1818, 1750, 1655, 1602, 1581, 1496, 1452, 1371, 1321, 1293, 1228, 1045, 1022, 985, 892, 779, 745, 700 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 7.85-7.82 (m, 2H), 7.53 (m, 1H), 7.44-7.39 (m, 2H), 7.17-7.11 (m, 5H), 5.96 (m, 1H), 5.75-5.67 (m, 2H), 3.20 (d, J=13.4 Hz, 1H), 3.15 (d, J=13.4 Hz, 1H), 2.13-2.06 (m, 2H), 1.95 (s, 3H), 1.43 (m, 1H), 0.89 (t, J=7.3 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 177.0, 169.5, 161.2, 140.2, 133.7, 132.8, 130.3, 128.7, 128.2, 127.9, 127.3, 125.5, 122.0, 76.9, 77.1, 39.8, 34.2, 21.8, 20.9, 13.4. Anal. Calcd for C.sub.24 H.sub.25 NO.sub.4 ; C, 73.64; H, 6.44; N, 3.58. Found: C, 73.56; H, 6.44; N, 3.58.
4-(1'-Acetoxy-2'-hexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one (first fraction): Oil. Enantiomeric excess (86%) was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.5:0.5), t.sub.R (minor)=8.0, t.sub.R (major)=10.3. IR (neat film from CDCl.sub.3): 2960, 2933, 2873, 1828, 1750, 1657, 1452, 1371, 1322, 1294, 1226, 1185, 1007, 973, 904, 781, 744, 701 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.06-8.03 (m, 2H), 7.61 (m, 1H), 7.54-7.48 (m, 2H), 6.00 (m, 1H), 5.58 (m, 1H), 5.45 (d, J=8.8 Hz, 1H), 2.13-2.05 (m, 2H), 1.95 (s, 3H), 1.46 (s, 3H), 1.49-1.37 (m, 2H), 0.89 (t, J=7.4 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 179.1, 169.4, 161.1, 140.8, 132.9, 128.9, 128.2, 125.9, 122.5, 77.7, 72.1, 34.3, 21.8, 20.9, 20.3, 13.5. HRMS (CI): Calcd for C.sub.18 H.sub.22 NO.sub.4 (M+1): 316.1549. Found: 316.1550.
4-(3'-Acetoxy-1'-propenyl-2'-prospenyl)-4-methyl-2-phenyl-2-oxazolin-5-one (second fraction): Mixture of two diastereoisomers: A(major) and B(minor). Diastereomeric and enantiomeric excess were determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.8:0.2), t.sub.R (A, major)=10.6, t.sub.R (A, minor)=12.1, t.sub.R (B, minor)=13.71, t.sub.R (B, major)=18.2. Spectral data of the mixture (only A is shown): IR (neat film from CDCl.sub.3): 2960, 2932, 2873, 1822, 1760, 1655, 1582, 1495, 1452, 1371, 1321, 1293, 1220, 1167, 1100, 1069, 1004, 943, 893, 781, 749, 701, 670 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.03-8.00 (m, 2H), 7.57 (m, 1H), 7.52-7.47 (m, 2H), 7.21 (d, J=12.6 Hz, 1H), 5.37 (dd, J=12.6, 10.0 Hz, 1H), 2.40 (m, 1H), 2.15 (s, 3H), 1.46 (s, 3H), 1.40-1.14 (m, 4H), 0.82 (t, J=7.1 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 181.1, 168.1, 160.2, 138.2, 132.8, 128.9, 128.1, 125.9, 112.6, 72.2, 45.5, 31.9, 22.9, 20.6, 20.2, 13.6. HRMS (CI): Calcd for C.sub.18 H.sub.21 NO.sub.4 (M+1); 316.1549. Found. 316.1559.
4-(1'-Acetoxy-2'-hexenyl)-4-methyl-2-phenyl-2-oxazolin-5-one (third fraction): Oil. Enantiomeric excess (97%) was determined by chiral HPLC (Chiracel.RTM. OD column, heptane/2-propanol 99.5:0.5), t.sub.R (major)=9.1, t.sub.R (minor)=13.2. IR (neat film from CH.sub.2 Cl.sub.2): 2960, 2933, 2873, 1823, 1750, 1656, 1602, 1582, 1451, 1372, 1322, 1294, 1228, 1131, 1093, 1007, 974, 881, 781, 756, 699 cm.sup.-1. .sup.1 H NMR (300 MHz, CDCl.sub.3) .delta.: 8.01-7.99 (m, 2H), 7.60 (m, 1H), 7.52-7.47 (m, 2H), 5.93 (m, 1H), 5.65-5.50 (ml 2H), 2.10-2.02 (m, 2H), 1.93 (s, 3H), 1.49 (s, 3H), 1.47-1.35 (m, 2H), 0.88 (t, J=7.4 Hz, 3H). .sup.13 C NMR (75.5 MHz, CDCl.sub.3) .delta.: 178.2, 169.6, 161.2, 139.9, 133.0, 128.8, 128.1, 125.9, 121.8, 77.4, 71.7, 34.2, 21.8, 20.8, 20.2, 13.4. HRMS (CI): Calcd for C.sub.18 H.sub.22 NO.sub.4 (M+1): 316.1549. Found: 316.1555.
It is to be understood that while the invention has been described above in conjunction with preferred specific embodiments, the description and examples are intended to illustrate and not limit the scope of the invention, which is defined by the scope of the appended claims.

Number	Name	Date
3440278	Kallischnigg	Apr 1969
4264771	Steglich	Apr 1981
4339589	Steglich	Jul 1982
4508921	Amato	Apr 1985
4981972	Kobori	Jan 1991
5039813	Fazio	Aug 1991
5691278	Park	Nov 1997

Number	Date	Country
0344963	Dec 1989	EPX
19533617	Mar 1997	DEX
1469307	Apr 1977	GBX
9512573	May 1995	WOX
9609306	Mar 1996	WOX

Enantiomerically enriched .alpha.,.alpha.-distributed amino acids and method

Information

Patent Number

Date Filed

Date Issued

Inventors

Original Assignees

Examiners

Agents

CPC

US Classifications

Field of Search

US

International Classifications

Abstract

Description

Claims

US Referenced Citations (7)

Foreign Referenced Citations (5)

Non-Patent Literature Citations (27)

Entry
Bartlett et al., "Ester-Enolate Claisen Rearrangement of Alpha-Amino Acid Derivatives", Journal of Organic Chemistry, vol. 47, No. 20, Sep. 24, 1982, pp. 3933-3941.
Trost et al., "Catalytic Asymmetric Alkylation of Nucleophiles: Asymmetric Synthesis of Alpha-Alkylated Amino Acids", Angewandte Chemie. International Edition, vol. 36, No. 23, Dec. 15, 1997, pp. 2635-2637.
Chemical Abstracts 98:53740, abstract of Heterocyclis, (1982), vol. 19(10), pp. 1823-1828, Tsuge.
Chemical Abstracts 90:23638, 1978.
CA 113:168298, 1990.
CA 100:121298, 1983.
CA 126:59963, 1996.
CA 113:152213, 1990.
CA 106:85002, 1986.
CA 103:22934, 1985.
CA 102:96084, 1984.
CA 101:151379, 1984.
CA 101:131107, 1984.
CA 101:73096, 1984.
CA 95:187613, 1981.
CA 91:21019, 1979.
CA 90:39214, 1978.
CA 70:106832, 1969.
CA 125:104859, 1996.
CA 123:144634, 1994.
CA 122:4968, 1993.
CA 117:146711, 1992.
CA 73:131303, 1970.
Almond et al., "Interaction of .alpha.-Chrmotrypsin with Several .alpha.-Methyl-.alpha.-Acylamino Acid Methyl Esters," Biochemistry, 1:2 (Mar. 1962), pp. 243-249.
Pankaskie et al., "Inhibitors of Polyamine Biosynthesis. 8. Irreversible Inhibition of Mammalian S-Adenosyl-L-methionine Decarboxylase by Substrate Analogues," J. Med. Chem., 23 (1980), pp. 121-127.
Burgess, Antony W., "Designing Amino Acids to Determine the Local Conformations of Peptides," Proc. Natl. Acad. Sci. USA, 91, (Mar. 1994), pp. 2649-2653.
Koert, Ulrich, "Oligo-(thiazolin)-Naturstoffsynthese," Nachr. Chem. Tech. Lab., 43 (1995), pp. 347-354.