Stereocontrolled asymmetric synthesis of α-hydroxy-β-amino acids. A stereodivergent approach

Article abstract of DOI:10.1021/ja0042332

The stereocontrolled asymmetric synthesis of α-hydroxy-β-amino acids has been investigated via the Lewis acid-promoted cyanation of (5R,6S)-2-acetoxy-4-(benzyloxycarbonyl)-5, 6-diphenyl-2,3,5,6-tetrahydro-4H-1,4-oxazines with trimethylsilyl cyanide. Base-

Full text of DOI:10.1021/ja0042332

3472
J. Am. Chem. Soc. 2001, 123, 3472-3477
Stereocontrolled Asymmetric Synthesis of R-Hydroxy-â-amino Acids.
A Stereodivergent Approach
Yutaka Aoyagi, Rajendra P. Jain, and Robert M. Williams*
Contribution from the Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado 80523
ReceiVed December 11, 2000
Abstract: The stereocontrolled asymmetric synthesis of R-hydroxy-â-amino acids has been investigated via
the Lewis acid-promoted cyanation of (5R,6S)-2-acetoxy-4-(benzyloxycarbonyl)-5,6-diphenyl-2,3,5,6-tetrahydro-
4H-1,4-oxazines with trimethylsilyl cyanide. Base-catalyzed hydrolysis of the resulting cyano compounds
proceeds with excellent stereoselectivity, providing access to diastereomerically pure oxazine-2-carboxylic
acids which were readily converted to each enantiomer of the R-hydroxy-â-amino acids isothreonine and nor-
C-statine.
Introduction
degrees of stereocontrol have been realized, multistep procedures
are typically required and there remains room for improving
access to this large family of compounds. Herein, we report a
unique stereodivergent approach to this class of compounds
(Figure 1) by using (5R,6S)-4-(benzyloxycarbonyl)-5,6-diphenyl-
2,3,5,6-tetrahydro-4H-1,4-oxazin-2-one (1a)18a as a starting
material.
The commercially available glycine templates such as 1 have
been extensively demonstrated to be versatile precursors for the
synthesis of a wide structural array of R-amino acids and peptide
Recently, much attention is being devoted to the design and
synthesis of nonscissile peptide mimics.1 Within this field,
enantiomerically pure R-hydroxy-â-amino acids constitute an
important class of organic substances due to their utility as
substrates for the synthesis of a wide variety of peptide isosteres2
and as being constituents of several natural products that exhibit
potent biological activity such as paclitaxel3 (an antitumor
agent), bestatin4 (an inhibitor of aminopeptidases), KRI 13145
(a renin inhibitor), microginin6 (an ACE inhibitor), and dideoxy-
kanamycin A7 (an antibacterial agent). The asymmetric synthesis
of R-hydroxy-â-amino acids has therefore attracted a consider-
able amount of interest in recent years and several approaches
have been developed for the synthesis of these materials.
Synthetic approaches include the following: (1) the nucleophilic
ring opening of chiral epoxides,8 (2) â-lactam synthon meth-
odologies,9 (3) hetero-Diels-Alder reactions,10 (4) aldol meth-
odologies,11 (5) electrophilic hydroxylation of chiral enolates,12
(6) diastereoselective alkylation of malic acid and subsequent
Curtius rearrangement,13 (7) addition of nucleophiles to chiral
R-amino aldehydes14 and imines,15 (8) halocyclocarbamation
of chiral allylamines,16 and (9) asymmetric aminohydroxylation
of olefins17 among other approaches. Although satisfactory
(9) (a) Bourzat, J. D.; Commerc¸on, A. Tetrahedron Lett. 1993, 34, 6049.
(b) Palomo, C.; Aizpurua, J. M.; Miranda, J. I.; Mielgo, A.; Odriozola, J.
M. Tetrahedron Lett. 1993, 34, 6325. (c) Georg, G. I.; Cheruvallath, Z. S.;
Harriman, G. C. B.; Hepperle, M.; Park, H. Biorg. Med. Chem. Lett. 1993,
3, 2467. (d) Holton, R. A.; Liu, J. H. Biorg. Med. Chem. Lett. 1993, 3,
2475. (e) Ojima, I.; Zucco, M.; Duclos, O.; Kuduk, S. D.; Sun, C. M.;
Park, Y. H. Biorg. Med. Chem. Lett. 1993, 3, 2479. (f) Ojima, I.; Habus, I.;
Zhao, M. J. Org. Chem. 1991, 56, 1681. (g) Ojima, I.; Park, Y. H.; Sun, C.
M.; Brigaud, T.; Zao, M. Tetrahedron Lett. 1992, 33, 5737.
(10) Swindell, C. S.; Tao, M. J. Org. Chem. 1993, 58, 5889.
(11) (a) Mukai, C.; Kim, I. J.; Furu, E.; Hanaoka, M. Tetrahedron 1993,
49, 8323. (b) Hattori, K.; Yamamoto, H. Tetrahedron 1994, 50, 2785. (c)
Barco, A.; Benetti, S.; De Risi, C.; Pollini, G. P.; Romagnoli, R.; Zanirato,
V. Tetrahedron Lett. 1994, 35, 9289.
(12) (a) Davis, F. A.; Reddy, R. T.; Reddy, R. E. J. Org. Chem. 1992,
57, 6387. (b) Bunnage, M. E.; Burke, A. J.; Davies, S. G.; Goodwin, C. J.
Tetrahedron: Asymmetry 1995, 6, 165. (c) Jefford, C. W.; Lu, Z.-H.; Wang,
J. B. Pure Appl. Chem. 1994, 66, 2075. (d) Escalante, J.; Juaristi, E.;
Tetrahedron Lett. 1995, 36, 4397.
(13) Norman, B. H.; Morris, M. L. Tetrahedron Lett. 1992, 33, 6803.
(14) (a) Herranz, R.; Castro-Pichel, J.; Vinuesa, S.; Garcia Lo´pez, M.
T. J. Org. Chem. 1990, 55, 2232. (b) Matsuda, F.; Matsumoto, T.; Ohsaki,
M.; Ito, Y.; Terashima, S. Chem. Lett. 1990, 723. (c) Denis, J.-N.; Correa,
A.; Greene, A. E. J. Org. Chem. 1991, 56, 6939. (d) Dondoni, A.; Perrone,
D.; Semola, T. Synthesis 1995, 181.
(1) Gante, J. Angew. Chem., Int. Ed. Engl. 1994, 33, 1699.
(2) For recent reviews, see: (a) Cole, D. C. Tetrahedron 1994, 50, 9517.
(b) Juaristi, E.; Quintana, D.; Escalante, J. Aldrichim. Acta 1994, 27, 3.
(3) (a) Ha, H.-J.; Park, G.-S.; Ahn, Y.-G.; Lee, G. S. Bioorg. Med. Chem.
Lett. 1998, 8, 1619. (b) Review: Nicolaou, K. C.; Dai, W.-M.; Guy, R. K.
Angew. Chem., Intl. Ed. Engl. 1994, 33, 15.
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29, 600. (b) Pearson, W. H.; Hines, J. V. J. Org. Chem. 1989, 54, 4235
and references therein.
(5) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota, T.;
Umeyama, H.; Kiso, Y. J. Chem. Soc., Chem. Commun. 1989, 1678.
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Lett. 1993, 34, 501.
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Chem. 1986, 51, 46. (b) Deng, L.; Jacobsen, E. N. J. Org. Chem. 1992, 57,
4320. (c) Commerc¸on, A.; Be´zard, D.; Bernard, F.; Bourzat, J. D.
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J. Org. Chem. 1993, 58, 1287. (e) Bonini, C.; Righi, G. J. Chem. Soc.,
Chem. Commun. 1994, 2767. (f) Grosjean, F.; Huche´, M.; Larcheveˆque,
M.; Legendre, J. J.; Petit, Y. Tetrahedron 1994, 50, 9325. (g) Pasto´, M.;
Castejo´n, P.; Moyano, A.; Perica`s, M. A.; Riera, A. J. Org. Chem. 1996,
61, 6033.
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(18) (a) The requisite diphenyloxazine (1a) and its antipode (1b) are
commercially available from Aldrich Chemical Co.: 1a, catalog No.
33185-6 (CAS Registry No. 105228-46-4); the antipode 1b, catalog No.
33187-2 (CAS Registry No. 100516-54-9). (b) Williams, R. M. Aldrichim.
Acta 1992, 25, 11. (c) Williams, R. M. In AdVances in Asymmetric Synthesis;
Hassner, A., Ed.; JAI Press: Stamford, CT, 1995; Vol. 1, pp 45-94. (d)
Williams, R. M., Synthesis of Optically ActiVe a-Amino Acids, in The
Organic Chemistry Series, Baldwin, J. E., Ed., Pergamon Press: Oxford,
1989.
10.1021/ja0042332 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/21/2001

Synthesis of R-Hydroxy-â-amino Acids
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3473
Figure 1.
Figure 2.
isosteres.18 The range of C-C bond-forming methodologies that
are accessible Via 1a (and its antipode 1b) and the corresponding
N-t-BOC congeners (1c,d) currently includes the following: (1)
the glycine electrophile,19 (2) the glycine enolate,20 (3) the
glycine radical,21 (4) glycine-based azomethine ylids,22 (5) the
glycine phosphonate23 that can be utilized to synthesize, and
(6) R,â-dehydro oxazinones that can be further functionalized
at both the R- and â-positions.23,24 More recently, the alkylated
oxazinones can be converted into the corresponding acetoxy
hemiacetals which, in the presence of Lewis acids, generates
the oxonium species that can be captured with a variety of
nucleophiles providing access to a range of peptide isosteres.25
These applications are outlined in Figure 2.18-25 No other amino
acid template or methodology, whether it be chiral auxiliary-
based or catalytic, presently offers this range of chemical and
structural versatility for the synthesis of amino acids and peptide
isosteres in optically active form.18d The results described here
seek to further extend the usefulness of these substances for
peptide isostere applications.
Results and Discussion
(19) (a) Sinclair, P. J.; Zhai, D.; Reibenspies, J.; Williams, R. M. J. Am.
Chem. Soc. 1986, 108, 1103. (b) Williams, R. M.; Sinclair, P. J.; Zhai, D.;
Chen, D. J. Am. Chem. Soc. 1988, 110, 1547. (c) Williams, R. M.; Sinclair,
P. J.; Zhai, W. J. Am. Chem. Soc. 1988, 110, 482.
(20) (a) Williams, R. M.; Im, M.-N. Tetrahedron Lett. 1988, 29, 6075.
(b) Williams, R. M.; Im, M.-N. J. Am. Chem. Soc. 1991, 113, 9276. (c)
Williams, R. M.; Im, M.-N.; Cao, J. J. Am. Chem. Soc. 1991, 113, 6976.
(d) Scott, J. D.; Tippie, T. N.; Williams, R. M. Tetrahedron Lett. 1998, 39,
3659.
(21) Williams, R. M.; Zhai, D.; Sinclair, P. J. J. Org. Chem. 1986, 51,
5021.
(22) (a) Williams, R. M.; Zhai, W.; Aldous, D. J.; Aldous, S. C. J. Org.
Chem. 1992, 57, 6527. (b) Sebahar, P.; Williams, R. M. J. Am. Chem. Soc.
2000, 122, 5666.
Oxazinone (1a) was alkylated at C3 with iodomethane and
cyclohexylmethyl triflate using the previously reported pro-
cedures20,25a to afford the corresponding anti-3-alkyl-oxazinones
(4) obtained as essentially single diastereomers (Scheme 1).
Treatment of 4a with KHMDS followed by addition of water
resulted in a complex mixture of products with the desired
compound 5a observable only as a minor product. This might
be a manifestation of the susceptibility of the lactone carbonyl
in 5a to the hydroxide ion generated in situ during the enolate
quench. This serious drawback was circumvented by bubbling
gaseous carbon dioxide into the mixture before quenching with
(23) (a) Williams, R. M.; Fegley, G. J. J. Am. Chem. Soc. 1991, 113,
8796. (b) Williams, R. M.; Fegley, G. J. J. Org. Chem. 1993, 58, 6933. (c)
Williams, R. M.; Fegley, G. J.; Pruess, D. L.; Schaeffer, F. Tetrahedron
1996, 52, 1149.
(25) (a) Williams, R. M.; Colson, P.-J.; Zhai, W. Tetrahedron Lett. 1994,
35, 9371. (b) Williams, R. M.; Aoyagi, Y. Tetrahedron 1998, 54, 10419.
(c) Aoyagi, Y.; Williams, R. M. Tetrahedron 1998, 54, 13045.
(24) Williams, R. M.; Fegley, G. J. Tetrahedron Lett. 1992, 33, 6755.

3474 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Aoyagi et al.
Scheme 1
Scheme 3
as a “buffer” or trap for hydroxide ion generated during the
course of the enolate quench producing equivalents of the milder
base bicarbonate. The 3-alkyl-oxazinones 4 and 5 were con-
verted into the corresponding acetoxy hemiacetals 6a, 6b,25b
7a, and 7b25b quantitatively by treatment with DIBAlH followed
by acetylation of the intermediate lactol with acetic anhydride
(Scheme 1).
Figure 3. PM3 geometry optimization of the putative oxocarbenium
ion intermediate using Spartan, C2 trivalent, and overall molecular
charge +1.
Scheme 2
Reaction of 7 with trimethylsilylcyanide in the presence of
BF3‚Et2O (MeCN, -20 °C) proceeded with a high degree of
diastereoselectivity to generate the desired coupling products 9
1
as single diastereomers (by H NMR analysis of the crude
reaction products) in essentially quantitative yields. The relative
stereochemistry of the newly created stereogenic center in 9
was assigned as being “R” on the basis of X-ray crystallographic
1
analysis of 9a and by H NMR nOe measurements on Cbz-
deprotected products derived from 9a and 9b (Scheme 2).
Modeling of the conformation of the putative oxocarbenium
ion intermediate that is presumed to result from Lewis acid-
mediated removal of the acetate group from 7 reveals that the
oxazinone ring adopts a boatlike conformation placing the “R”
group and the phenyl ring adjacent to the ring nitrogen atom in
pseudoequatorial dispositions mandating that the phenyl ring
adjacent to the ring oxygen atom adopt a pseudoaxial orientation
(Figure 3). The significantly less hindered face of this inter-
mediate thus suffers nucleophilic attack by cyanide to furnish
the anti-isomers 9. Treatment of the acetoxy hemiacetals 6 with
trimethlsilylcyanide in the presence of BF3‚Et2O under identical
conditions, however, generated the corresponding coupling
products 8 as diastereomeric mixtures at C2 in essentially
quantitative yield (Scheme 3). These results are summarized in
Table 1.
water. Thus, treatment of 4 with KHMDS followed by addition
of dry, gaseous CO2 and quenching the resulting mixture with
water led to clean epimerization of the C3 stereogenic center
to generate the corresponding all-syn isomers 5a and 5b25b in
excellent yields (82-91%) and as single diastereomers (by 1H
NMR analysis). Although the precise mechanism by which CO2
mediates this unexpectedly clean epimerization process has not
been clarified, it is reasonable to expect that CO2 might serve
The hydrolysis of the nitrile moiety in 8 and 9 proved to be
unexpectedly difficult under both harshly acidic as well as basic
conditions. However, we found that the removal of the Cbz-
group (1 atm of H2, Pd/C) from 8 and 9 proved beneficial for

Synthesis of R-Hydroxy-â-amino Acids
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3475
Table 1. Lewis Acid-Mediated Cyanation of Acetoxy Hemiacetals 6 and 7
entry
substrate
Lewis acid
solvent
temp, °C
product (% yield)
abs config
dra
1
2
3
4
5
6
6a
6b
7a
7b
7b
7b
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
BF3‚OEt2
TiCl4
MeCN
MeCN
MeCN
MeCN
CH2Cl2
MeCN
-20
8a (95)
8b (94)
9a (93)
9b (93)
9b (40)
9b (56)
3R,5R,6S
3R,5R,6S
2R,3S,5R,6S
2R,3S,5R,6S
2R,3S,5R,6S
2R,3S,5R,6S
2.8:1
1.2:1
-20
-20
-20
-78 to 0
-40
>95:5b
>95:5b
>95:5b
>95:5b
TMSOTf
1
a By H NMR analysis of the crude reaction products. b The minor diastereomer was not detectable.
Scheme 4
Scheme 5
Table 2
Table 3. Hydrogenolysis of Oxazine-2-carboxylic Acids 12 and 13
reaction
product
product
(% yield) abs config
entry substrate temp, °C (% yield)
abs config
dra
entry substrate
solvent
dr
1
2
3
4
10a
10b
11a
11b
150
170
150
170
12a (90) 2S,3R,5R,6S >95:5
12b (97) 2S,3R,5R,6S >95:5
13a (88) 2R,3S,5R,6S >95:5
13b (91) 2R,3S,5R,6S >95:5
1
2
3
4
5
6
12a
12b
13a
13b
12b
13b
1:1 THF:H2O 2a (98)
1:1 THF:H2O 2b (95)
1:1 THF:H2O 3a (95)
1:1 THF:H2O 3b (97)
2S,3R
2S,3R
2R,3S
2R,3S
2S,3R
2R,3S
>95:5a
95:5b
>95:5a
97:3b
MeOH
MeOH
16b (95)
17b (96)
94:6c
a By H NMR analysis of the crude reaction products; the minor
diastereomer was not detectable.
1
>95:5a
a Single diastereomer by 1H NMR. b By HPLC analysis. c By 1H
NMR analysis.
the subsequent basic hydrolysis of the corresponding deprotected
oxazinones 10 and 11. Treatment of 10 and 11 with KOH in
ethylene glycol at 150-170 °C for 40 h proceeded smoothly to
generate the corresponding carboxylic acids 12 and 13 in
excellent yields.
1
as a single diastereomer by H NMR analysis of crude 13),
epimerization was observed to occur during the hydrolysis of
10 (used as a diastereomeric mixture at C2) yielding the
corresponding carboxylic acids 12 with excellent diastereose-
lectivity (dr >95:5 by H NMR of crude 12, Scheme 4). The
results are summarized in Table 2.
1
Although the hydrolysis of 11 (single diastereomer) to 13
proceeded with net retention of configuration at C2 (obtained

3476 J. Am. Chem. Soc., Vol. 123, No. 15, 2001
Aoyagi et al.
recorded on Varian 300 or 400 MHz spectrometers. Mass spectra were
obtained on a Fisons VG Autospec. IR spectra were recorded on a
Perkin-Elmer 1600 series FT-IR spectrometer. Optical rotations were
obtained on a Rudolph Research automatic polarimeter Autopol III.
General procedure for C3-epimerization of 3-alkyl oxazinones
4: To a solution of oxazinone 4 (1 equiv) in anhydrous THF (2 equiv
of 18-crown-6 were added for oxazinone 4a) at -78 °C was rapidly
added a solution of KHMDS (0.5 M in toluene, 2 equiv) and the reaction
mixture was stirred for 1 min after which it was saturated with
anhydrous CO2 gas (bubbled through the reaction mixture for 5 min).
The mixture was quenched carefully with water and warmed to ambient
temperature. The aqueous layer was saturated with NaCl and extracted
with ethyl acetate. The combined organic layers were dried (Na2SO4)
and concentrated in vacuo to furnish the crude product which was
purified by flash chromatography on silica gel.
(3S,5R,6S)-3-Cyclohexymethyl-2-oxo-5,6-diphenylmorpholine-4-
carboxylic acid benzyl ester (5a): 5a was prepared from oxazinone
4a (0.1 g, 0.2 mmol) and 18-crown-6 (0.11 g, 0.41 mmol) in THF (4
mL) and KHMDS (0.5 M in toluene, 0.82 mL, 0.41 mmol) to furnish
the crude product that on purification by flash chromatography on silica
gel (eluted with 9:1 petroleum ether:ethyl acetate) gave 0.091 g of 5a
as a white foam (91% yield). [R]D25 -114.0 (c 1.03, CH2Cl2); 1H NMR
(300 MHz, DMSO-d6, 348 K) δ 7.44-7.09 (m, 15H), 6.20 (d, 1H, J
) 3.3 Hz), 5.89 (d, 1H, J ) 3.3 Hz), 5.25 (s, 2H), 4.86 (dd, 1H, J )
5.4, 6.9 Hz), 1.60-0.58 (m, 13H); 13C NMR (75 MHz, DMSO-d6, 353
K) δ 168.6, 154.1, 135.8, 135.4, 135.0, 128.4, 127.9, 127.7, 127.6,
127.3, 124.8, 79.7, 67.1, 55.8, 52.7, 41.5, 33.9, 32.4, 31.7, 25.4, 25.1,
25.0; IR (NaCl, neat) 1748, 1700 cm-1; HRMS (FAB+) calcd for
C31H34NO4 (m/z) 484.2488, found (m/z) 484.2499.
The stereochemistry at C2 in 12 (S) and 13 (R) was secured
through 1H NMR nOe measurements of 12 and 13. These
assignments were further confirmed by conversion of 12 and
13 into the known R-hydroxy-â-amino acids 2 and 3, respec-
tively. Thus, hydrogenolysis of 12a or 13a in THF:H2O (3 equiv
of PdCl2, 120 psi of H2, 75 °C, 3 h) cleanly generated the
corresponding (2S,3R)-nor-C-statine26 (2a) and (2R,3S)-nor-C-
statine5,9g,11b,14b,15a,17,27 (3a), respectively, in essentially quantita-
tive yields (as the hydrochloride salts, Scheme 5). The carboxylic
acids 12b and 13b were similarly converted into the corre-
sponding (2S,3R)-isothreonine7,15b,28 (2b) and (2R,3S)-isothre-
onine8f,29 (3b) in quantitative yields (as their hydrochloride salts).
The absolute stereochemistry of 2b and 3b was confirmed by
conversion into the known free amino acids 14b and 15b by
ion exchange filtration with use of DOWEX 50WX2-100 resin.
The diastereomeric ratios for 2a (dr ) >95:5), 2b (dr ) 95:5),
1
3a (dr ) >95:5), and 3b (dr ) 97:3) were determined by H
NMR and/or HPLC analysis. Hydrogenolysis of 12b and 13b
in methanol (3 equiv of PdCl2, 120 psi of H2, 75 °C, 24 h)
provided the corresponding isothreonine methyl esters 16b (dr
) 94: 6 by 1H NMR) and 17b (single diastereomer by 1H NMR)
in quantitative yields (as the corresponding hydrochloride salts).
The results are summarized in Table 3.
In summary, we have demonstrated an efficient and stereo-
divergent approach to (2S,3R)- and (2R,3S)-R-hydroxy-â-amino
acids from the commercially available template 1a. We have
defined an unexpectedly simple and mild method to effect the
clean kinetic protonation of the enolates derived from 4 in the
presence of dissolved, gaseous CO2. We are currently examining
the utility of this method in other kinetic protonation reactions.
Current efforts are directed toward the design and synthesis of
new candidates of this class utilizing this methodology, and we
are concurrently examining the utility of this approach to prepare
intermediates for the construction of complex molecules of
biological importance. Results of these studies will be reported
in due course.
(3S,5R,6S)-3-Methyl-2-oxo-5,6-diphenylmorpholine-4-carboxyl-
ic acid benzyl ester (5b):25b 5b was prepared from oxazinone 4b (0.12
g, 0.3 mmol) in THF (5 mL) and KHMDS (0.5 M in toluene, 1.2 mL,
0.6 mmol) to furnish the crude product which on purification by flash
chromatography on silica gel (9/1 petroleum ether/ethyl acetate) gave
0.99 g of 5b as a white foam (82% yield). Spectroscopic data was
identical with that previously reported.25b
General procedure for the Lewis acid promoted coupling
reactions of acetoxy hemiacetals 6 and 7 with trimethylsilyl cyanide:
To a solution of acetoxy hemiacetals 6 and 7 (1 equiv) in anhydrous
MeCN at -20 °C was added TMSCN (5 equiv), which was followed
by the slow addition (10 min) of BF3‚Et2O (1.5 equiv). The mixture
was stirred at the same temperature for an additional 30 min after which
it was quenched with saturated aqueous NaHCO3, warmed to ambient
temperature, and extracted with EtOAc. The combined organic layers
were dried over anhydrous Na2SO4 and concentrated to obtain the crude
product which was purified by flash chromatography on silica gel.
(3R,5R,6S)-2-Cyano-3-cyclohexylmethyl-5,6-diphenylmorpholine-
4-carboxylic acid benzyl ester (8a): 8a was prepared from 6a (0.512
g, 0.97 mmol), Me3SiCN (0.65 mL, 4.85 mmol), and BF3‚Et2O (0.19
mL, 1.5 mmol) in anhydrous MeCN (5 mL), yielding the crude product
that on purification by flash chromatography on silica gel (9:1 petroleum
ether:ethyl acetate) furnished 0.46 g (95%) of pure 8a (mixture of
Experimental Section
General Methods. All reactions requiring anhydrous conditions were
performed under a positive pressure of argon with oven-dried glassware
(120 °C) that was cooled under argon. THF was distilled from sodium
benzophenone ketyl, and dichloromethane and acetonitrile were distilled
from CaH2. Column chromatography was performed on Merck silica
gel Kieselgel 60 (230-400 mesh).1H NMR and 13C NMR spectra were
(26) (a) Matsuda, F.; Matsumoto, T.; Ohsaki, M.; Ito, Y.; Terashima, S.
Bull. Chem. Soc. Jpn. 1992, 65, 360. (b) Jefford, C. W.; McNulty, J.; Lu,
Z.-H.; Wang, J. B. HelV. Chim. Acta 1996, 79, 1203.
(27) (a) Harada, H.; Tsubaki, A.; Kamijo, T.; Iizuka, K.; Kiso, Y. Chem.
Pharm. Bull. 1989, 37, 2570. (b) Iizuka, K.; Kamijo, T.; Harada, H.;
Akahane, K.; Kubota, T.; Etoh, Y.; Shimaoka, I.; Tsubaki, A.; Murakami,
M.; Yamaguchi, T.; Iyobe, A.; Umeyama, H.; Kiso, Y. Chem. Pharm. Bull.
1990, 38, 2487. (c) Harada, H.; Iyobe, A.; Tsubaki, A.; Yamaguchi, T.;
Hirata, K.; Kamijo, T.; Iizuka, K.; Kiso, Y. J. Chem. Soc., Perkin Trans. 1
1990, 2497. (d) Iizuka, K.; Kamijo, T.; Harada, H.; Akahane, K.; Kubota,
T.; Umeyama, H.; Ishida, T.; Kiso, Y. J. Med. Chem. 1990, 33, 2707. (e)
Kobayashi, Y.; Matsumoto, T.; Takemoto, Y.; Nakatani, K.; Ito, Y.; Kamijo,
T.; Harada, H.; Terashima, S. Chem. Pharm. Bull. 1991, 39, 2550. (f)
Kobayashi, Y.; Takemoto, Y.; Kamijo, T.; Harada, H.; Ito, Y.; Terashima,
S. Tetrahedron 1992, 48, 1853. (g) Ojima, I.; Habus, I.; Zhao, M.; Zucco,
M.; Park, Y. H.; Sun, C. M.; Brigaud, T. Tetrahedron 1992, 48, 6985. (h)
Kang, S. H.; Ryu, D. H. Bioorg. Med. Chem. Lett. 1995, 5, 2959. (i)
Schwindt, M. A.; Belmont, D. T.; Carlson, M.; Franklin, L. C.; Hendrickson,
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Org. Chem. 1996, 61, 9564. (j) Sugimura, H.; Miura, M.; Yamada, N.
Tetrahedron: Asymmetry 1997, 8, 4089.
1
diastereomers at C2) as white foam. H NMR (300 MHz, DMSO-d6,
393 K) δ 7.30-7.03 (m, 15H), 5.64-4.95 (m, 5H), 4.31-4.07 (m,
1H), 2.21-0.67 (m, 13H); 13C NMR (75 MHz, DMSO-d6, 353 K) δ
154.7, 154.6, 136.9, 136.6, 136.3, 135.8, 135.6, 128.7, 128.0, 127.8,
127.7, 127.5, 127.4, 127.3, 127.2, 127,1, 126.9, 126.8, 126.7, 126.4,
125.2, 125.1, 117.9, 115.9, 75.5, 74.7, 67.9, 67.2, 66.7, 66.5, 60.7, 60.2,
50.6, 49.8, 41.1, 37.7, 33.6, 33.4, 32.3, 31.9, 31.8, 31.3, 25.4, 25.0; IR
(NaCl, neat) 1705 cm-1; HRMS (FAB+) calcd for C32H35N2O3 (m/z)
495.2647, found (m/z) 495.2630.
General procedures for hydrolysis of the cyano group in
morpholines 10 and 11: The mixture of nitriles 10 and 11 and KOH
(1 M solution in ethylene glycol, 20 equiv) was heated at 150 or 170
°C for 40 h after which it was cooled to ambient temperature, washed
with ether, and neutralized with 0.5 M aqueous HCl to furnish the crude
product which was purified by ion-exchange chromatography or flash
chromatography to obtain pure products.
(28) Cardillo, G.; Tolomelli, A.; Tomasini, C. Tetrahedron 1995, 51,
11831.
(29) (a) Shimohigashi, Y.; Waki, M.; Izumiya, N. Bull. Chem. Soc. Jpn.
1979, 52, 949. (b) Wolf, J.-P.; Pfander, H. HelV. Chim. Acta 1987, 70,
116.
(2S,3R,5R,6S)-3-Cyclohexylmethyl-5,6-diphenylmorpholine-2-
carboxylic acid (12a): 12a was prepared from 10a (0.065 g, 0.18
mmol) and KOH (1 M solution in ethylene glycol, 3.6 mL, 3.6 mmol)

Synthesis of R-Hydroxy-â-amino Acids
J. Am. Chem. Soc., Vol. 123, No. 15, 2001 3477
at 150 °C. After the reaction mixture was washed with ether and
neutralized with 0.5 M HCl, 5 mL of water was added and the resulting
mixture was extracted with ethyl acetate (3 × 15 mL). The combined
organic layer was washed with brine, dried (Na2SO4), and concentrated
under reduced pressure to furnish 62 mg (90%) of 12a as a white
amorphous solid (single diastereomer by 1H NMR). [R]D25 +54.8 (c 1,
pure 2a as white amorphous solid. [R]D25 +18.2 (c 0.63, 1 M HCl); 1H
NMR (300 MHz, D2O, 300K) δ 4.37 (d, 1H, J ) 3.3 Hz), 3.73-3.67
(dt, 1H, J ) 3.3, 7.2 Hz), 1.70-0.89 (m, 13H); 13C NMR (75 MHz,
D2O, 300K) δ 170.2, 65.0, 46.4, 31.9, 28.4, 28.1, 27.7, 21.4, 21.1, 21.0;
IR (KBr) 3330-2850, 1727, 1602, 1484 cm-1; HRMS (FAB+) calcd
for C10H20NO3 (m/z) 202.1443, found (m/z) 202.1445.
1
MeOH); H NMR (400 MHz, DMSO-d6, 300K) δ 7.52 (d, 2H, J )
7.6 Hz), 7.25-7.03 (m, 8H), 5.12 (d, 1H, J ) 2.8 Hz), 4.34 (d, 1H, J
) 2.8 Hz), 3.97 (d, 1H, J ) 10.0 Hz), 3.24-3.14 (m, 1H), 1.58-0.52
(m, 13H); 13C NMR (75 MHz, DMSO-d6, 300K) δ 171.1, 139.4, 139.0,
130.1, 127.6, 127.3, 126.5, 126.4, 125.2, 83.2, 78.3, 58.8, 45.9, 38.2,
33.9, 32.3, 31.4, 26.0, 25.7, 25.3; IR (CHCl3) 3018, 2923, 2852, 1693,
1606, 1496, 1450 cm-1; HRMS (FAB+) calcd for C24H30NO3 (m/z)
380.2225, found (m/z) 380.2223.
Acknowledgment. This work was supported by the National
Science Foundation (Grant CHE 9731947). We are very grateful
to Mr. Fukaya for X-ray crystallographic analysis. We are also
grateful to Steve Lenger for assistance with the PM3 geometry
optimization calculations. This paper is dedicated to Prof. Dave
Evans of Harvard University on the occasion of his 60th
birthday.
General procedure for the hydrogenolysis of oxazine-2-carboxylic
acids 12 and 13: A solution of 12 or 13 (1 equiv) in either THF:water
(1:1, v/v) or MeOH was hydrogenated with PdCl2 (3 equiv) at 75 °C
and 120 psi of H2. The mixture was then cooled to ambient temperature,
the catalyst was removed by filtration through a plug of glass wool,
and the filtrate was concentrated and triturated with Et2O to furnish
the corresponding products which were pure by NMR.
Supporting Information Available: Experimental methods
and spectroscopic data for compounds 2, 3, 5, 6a, 7a, and 8-17
1
and H and 13C NMR spectra for 5a, 6a, 7a, 8-13, 3b, and
17b (PDF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(2S,3R)-Nor-C-statin hydrochloride (2a):26 2a was prepared by
hydrogenolysis of 12a (0.04 g, 0.1 mmol) with PdCl2 (0.056 g, 0.31
mmol) in THF:water 1:1 (8 mL) for 3 h to provide 0.025 g (98%) of
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