Diastereo- And enantioselective synthesis of β-Hydroxy-α-amino acids: Application to the synthesis of a key intermediate for lactacystin

Article abstract of DOI:10.1021/jo8023973

The development of a highly efficient and stereoselective methodology for the preparation of β-hydroxy-α- amino acids is described. Nucleophilic addition of enolates of tricyclic iminolactones 1a and 1b to aldehydes in the presence of 6 equiv of lithium chloride in THF at -78 °C leads to aldol adducts in good yield (63-86%) and high diastereoselectivity (up to >25:1 dr). Subsequently, hydrolysis of the aldol adducts under acidic conditions leads to the corresponding β-hydroxy-a-amino acids in good yields (up to 83%) and excellent enantiomeric excesses (99% ee) with good recovery yields of the chiral auxiliaries 6 and 7. This methodology was applied to the facile synthesis of the key intermediate for lactacystin along with several isomers.

Full text of DOI:10.1021/jo8023973

Diastereo- and Enantioselective Synthesis of ꢀ-Hydroxy-r-Amino
Acids: Application to the Synthesis of a Key Intermediate for
Lactacystin
Qiong Li,† Shao-Bo Yang,† Zhihui Zhang,‡ Lei Li,† and Peng-Fei Xu*,†
State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering,
Lanzhou UniVersity, Lanzhou 730000, PRC
xupf@lzu.edu.cn
ReceiVed October 27, 2008
The development of a highly efficient and stereoselective methodology for the preparation of ꢀ-hydroxy-R-
amino acids is described. Nucleophilic addition of enolates of tricyclic iminolactones 1a and 1b to aldehydes
in the presence of 6 equiv of lithium chloride in THF at -78 °C leads to aldol adducts in good yield (63-86%)
and high diastereoselectivity (up to >25:1 dr). Subsequently, hydrolysis of the aldol adducts under acidic
conditions leads to the corresponding ꢀ-hydroxy-R-amino acids in good yields (up to 83%) and excellent
enantiomeric excesses (99% ee) with good recovery yields of the chiral auxiliaries 6 and 7. This methodology
was applied to the facile synthesis of the key intermediate for lactacystin along with several isomers.
Introduction
6519 by Omura et al.4 Its interesting structure contains hydroxyls
at both ꢀ-positions of the R-amino acid. As a consequence of
the essential role played by ꢀ-hydroxy-R-amino acids in
biological systems and their utilities as synthetic building blocks,
a number of useful strategies utilizing chemical and enzymatic
methods have been devised for their preparations.5 However,
some problems limit these protocols for the synthesis of
enantioenriched ꢀ-hydroxy-R-amino acids. For example, the
generation of enantioenriched products has been achieved
through dynamic kinetic resolution of racemic precursors, while
other synthetic approaches afford only one of the diastereomers
(threo- or erythro-ꢀ-hydroxy-R-amino acid).6 Therefore, meth-
ods that can control the stereochemistry of R- and ꢀ-positions
of ꢀ-hydroxy-R-amino acids would be highly useful. Our group
ꢀ-Hydroxy-R-amino acids are important constituents of
peptides and related compounds1 as well as other complex
natural products.2 Additionally, they may serve as useful
precursors and chiral auxiliaries in organic synthesis.3 For
example (+)-lactacystin is a potent and selective proteasome
inhibitor isolated from the culture broth of Streptomyses sp. OM-
* Corresponding author. Tel: 86-931-8912281. Fax: 86-931-8915557.
† Lanzhou University.
‡ Current address: Department of Chemistry, Emory University, 1515 Dickey
Drive, Atlanta, GA 30322.
(1) (a) Blaskovich, M. A.; Evindar, G.; Rose, N. G. W.; Wilkinson, S.; Luo,
Y.; Lajoie, G. A. J. Org. Chem. 1998, 63, 3631–3646. (b) Palian, M. M.; Polt,
R. J. Org. Chem. 2001, 66, 7178–7183. (c) Belokon, Y. N.; Kochetkov, K. A.;
Ikonnikov, N. S.; Strelkova, T. V.; Harutyunyan, S. R.; Saghiyan, A. S.
Tetrahedron: Asymmetry 2001, 12, 481–485.
(2) (a) Amador, M.; Ariza, X.; Garcia, J.; Sevilla, S. Org. Lett. 2002, 4,
4511–4514. (b) Mettath, S.; Srikanth, G. S. C.; Dangerfield, B. S.; Castle, S. L.
J. Org. Chem. 2004, 69, 6489–6492. (c) Willis, M. C.; Cutting, G. A.; Piccio,
V. J.-D.; Durbin, M. J.; John, M. P. Angew. Chem. 2005, 117, 1567-1569;
Angew. Chem., Int. Ed. 2005, 44, 1543-1545. (d) Shibasaki, M.; Kanai, M.;
Fukuda, N. Chem. Asian J. 2007, 2, 20–38.
(4) (a) Omura, S.; Fujimoto, T.; Otoguro, K.; Matsuzaki, K.; Moriguchi, R.;
Tanaka, H.; Sasaki, Y. J. Antibiot. 1991, 44, 113–116. (b) Omura, S.; Matsuzaki,
K; Fujimoto, T.; Kosuge, K.; Furuya, T.; Fujita, S.; Nakagawa, A. J. Antibiot.
1991, 44, 117–118.
(5) (a) Herbert, R. B.; Wilkinson, B.; Ellames, G. J.; Kunec, E. K. J. Chem.
Soc., Chem. Commun. 1993, 205–206. (b) Li, G.; Chang, H.-T.; Sharpless, K. B.
Angew. Chem. 1996, 108, 449-452; Angew. Chem., Int. Ed. 1996, 35, 451-
454. (c) Kimura, T.; Vassilev, V. P.; Shen, G. J.; Wong, C. H. J. Am. Chem.
Soc. 1997, 119, 11734–11742. (d) Kuwano, R.; Okuda, S.; Ito, Y. J. Org. Chem.
1998, 63, 3499–3503. (e) Wang, M.-X.; Deng, G.; Wang, D.-X.; Zheng, Q.-Y.
J. Org. Chem. 2005, 70, 2439–2444.
(3) (a) Evans, D. A.; Dinsmore, C. J.; Ratz, A. M.; Evrard, D. A.; Barrow,
J. C. J. Am. Chem. Soc. 1997, 119, 3417–3418. (b) Badorrey, R.; Cativiela, C.;
D´ıaz-de-Villegas, M. D. J.; Ga´lvez, A. Tetrahedron: Asymmetry 2000, 11, 1015–
1025.
10.1021/jo8023973 CCC: $40.75
Published on Web 01/13/2009
2009 American Chemical Society
J. Org. Chem. 2009, 74, 1627–1631 1627

Li et al.
TABLE 1. Aldol Reaction of Tricyclic Iminolactones 1a and 1b
with Aldehydes
TABLE 2. Aldol Reaction of Tricyclic Iminolactones 1a and 1ba
with Aldehydes
yield
entry
additive
substrate
R
products (%)a threo/erythrob
1
2
3
1a
1a
1a
Cyc 2d + 2d′ 80
Cy 2d + 2d′ 81
Cy 2d + 2d′ 80
1:4
1:4
1:6
HMPA (3 equiv)
HMPA (3 equiv),
LiCl (3 equiv)
LiCl (3 equiv)
LiCl (6 equiv)
entry substrate
R
yield (%)b
product
threo/erythroc
4
5
6
7
8
9
1a
1a
1a
1a
1a
1b
Cy 2d + 2d′ 83
Cy 2d + 2d′ 82
Ph 2e + 2e′ 70
Ph 2e + 2e′ 76
Ph 2e + 2e′ 75
Cy 3e + 3e′ 82
1:15
1
2
3
4
5
6
7
8
1a
1a
1a
1a
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
1b
1b
Me
85
80
84
82
80
75
73
78
63
80
86
83
82
83
82
80
77
2a + 2a′
2b + 2b′
2c + 2c′
2d + 2d′
2e + 2e′
2f + 2f′
2g + 2g′
2h + 2h′
3a + 3a′
3b + 3b′
3c + 3c′
3d + 3d′
3e + 3e′
3f + 3f′
3g + 3g′
3h + 3h′
3i + 3i′
1:6
1:15
<1:25
1.5:1
6:1
10:1
<1:25
n-propyl
i-propyl
Cyd
<1:25
<1:25
10:1
>25:1
>25:1
12:1
1:6
1:19
<1:25
1:19
<1:25
>25:1
>25:1
>25:1
19:1
LiCl (4 equiv)
LiCl (6 equiv)
LiCl (6 equiv)
Ph
o-F-Ph
o-Cl-Ph
o-MeO-Ph
Me
n-propyl
i-propyl
n-hexyl
Cy
a The reported yields are isolated combined yields after column
chromatographic separation, except for entry 5. b The ratios were
estimated by 1H NMR integrations of the crude reaction mixtures on a
400 NMR spectrometer. c Cy: cyclohexyl.
9
10
11
12
13
14
15
16
17
has developed an aldol reaction between aldehydes and the
enolates of tricyclic iminolactones 1a and 1b, which are derived
from natural (1R)-(+)-camphor as chiral glycine templates,7,8
to generate optically pure ꢀ-hydroxy-R-amino acids in good
yield and high diastereoselectivity (up to >25:1 dr) and applied
this methodology to the synthesis of the key intermediate of
(+)-lactacystin along with several isomers. In addition, an
interesting reversal of diastereoselectivity between alkyl and aryl
aldehydes was observed with our methodology.
Ph
o-F-Ph
o-Cl-Ph
p-MeO-Ph
a The reaction was carried out in the presence of 6 equiv of LiCl.
b The reported yields are isolated major single product yields after
column chromatographic separation, except for entries 1 and 9. c The
ratios were estimated by 1H NMR integrations of the crude reaction
mixtures on
a 400 NMR spectrometer (<1:25 means only one
diastereomer was found). d Cy: cyclohexyl.
Results and Discussion
Encouraged by the above results, a series of aldol reactions
were then conducted using the above optimized conditions, and
the results are summarized in Table 2. All aldol reactions were
conducted at -78 °C in THF in the presence of 6 equiv of
lithium chloride (LiCl) as the additive with 1.1 equiv of LDA
as the base. As anticipated, these reactions furnished the aldol
adducts in good yields with high stereochemical control of the
two newly formed chiral centers.
The aldol reactions were carried out at -78 °C in THF using
LDA as the base, and we observed that the stereoselectivity of
the product was strongly dependent on the additives applied.
In an attempt to improve the yield and diastereoselectivity, we
carried out a series of experiments varying the additives used.
The results in Table 1 clearly demonstrate that the addition of
6 equiv of lithium chloride (LiCl) leads to remarkably improved
diastereoselectivity.
In principle, the aldol reaction of any tricyclic iminolactone
(1a or 1b) with an aldehyde can form four diastereoisomeric
products resulting from two newly formed chiral centers.
However, in our reactions, the exclusively endo addition of the
nucleophile to the aldehyde leads to the production of only two
diastereomers. It is presumably due to the steric hindrance of
the C12-methyl, which effectively blocks the approach from the
exo-face and thus favors the attack of the electrophile from the
endo-face of the enolate.9 Additionally, the lone pair of electrons
on the auxiliary nitrogen fuses the iminolactone into a boat
conformation. However, it is very difficult to confirm the
absolute configuration of the newly formed hydroxyl carbon
directly from NMR spectral analysis. Therefore, these configu-
rations were determined by hydrolysis of aldol adducts to the
known amino acids (see below). Furthermore, the structures of
the aldol products 2c′, 3c′ (please see the Supporting Informa-
(6) For recent examples, see: (a) Kobayashi, J.; Nakamura, M.; Mori, Y.;
Yamashita, Y.; Kobayashi, S. J. Am. Chem. Soc. 2004, 126, 9192–9193. (b)
Makino, K.; Goto, T.; Hiroki, Y.; Hamada, Y. Angew. Chem. 2004, 116, 900-
902; Angew. Chem. Int. Ed. 2004, 43, 882-884. (c) Bourdon, L. H.; Fairfax,
D. J.; Martin, G. S.; Mathison, C. J.; Zhichkin, P. Tetrahedron: Asymmetry 2004,
15, 3485–3487. (d) Makino, K.; Hiroki, Y.; Hamada, Y. J. Am. Chem. Soc. 2005,
127, 5784–5785. (e) Makino, K.; Fujii, T.; Hamada, Y. Tetrahedron Lett. 2006,
17, 481–484. (f) Chrich, D.; Banerjee, A. J. Org. Chem. 2006, 71, 7106–7109.
(7) (a) Xu, P.-F.; Chen, Y.-S.; Lin, S.-I.; Lu, T.-J. J. Org. Chem. 2002, 67,
2309–2314. (b) Xu, P.-F.; Lu, T.-J. J. Org. Chem. 2003, 68, 658–661. (c) Li,
S.; Hui, X.-P.; Yang, S.-B.; Jia, Z.-J.; Xu, P.-F.; Lu, T.-J. Tetrahedron: Asymmetry
2005, 16, 1729–1731. (d) Xu, P.-F.; Li, S.; Lu, T.-J.; Wu, C.-C.; Fan, B.; Golfis,
G. J. Org. Chem. 2006, 71, 4364–4373. (e) Wang, P.-F.; Gao, P.; Xu, P.-F.
Synlett 2006, 7, 1095–1099. (f) Zhang, H.-H.; Hu, X.-Q.; Wang, X.; Luo, Y.-
C.; Xu, P.-F. J. Org. Chem. 2008, 73, 3634–3637. (g) Wang, H.-F.; Ma, G.-H.;
Yang, S.-B.; Han, R.-G.; Xu, P.-F. Tetrahedron: Asymmetry 2008, 19, 1630–
1635. From (1R)-(+)-camphor, we can prepare both 1a and 1b (1:1.59) and
only need four steps with 55% overall yield. .
(8) For references to early work on asymmetric synthesis of ꢀ-hydroxy-R-
amino acids through glycine enolates, see: (a) Belokon, Y. N.; Bulychev, A. G.;
Vitt, S. V.; Struchkov, Y. T.; Batsanov, A. S.; Timofeeva, T. V.; Tsyryapkin,
V. A.; Ryzhov, M. G.; Lysova, L. A.; Bakhmutov, V. I.; Belikov, V. M. J. Am.
Chem. Soc. 1985, 107, 4252–4259. (b) Evans, D. A.; Weber, A. E. J. Am. Chem.
Soc. 1986, 108, 6757–6761. (c) Horikawa, M.; Busch-Petersen, J.; Corey, E. J.
Tetrahedron Lett. 1999, 40, 3843–3846.
(9) The theoretical explanation for the high stereoselectivity of substitution
reactions of 1a and 1b with alkyl halides has been made by quantum chemistry
study; see ref 6d.
1628 J. Org. Chem. Vol. 74, No. 4, 2009

Synthesis of ꢀ-Hydroxy-R-Amino Acids
TABLE 3. Hydrolysis of Aldol Products
a
D
entry substrate
R
product yield (%)
[R]20
ee (%)
FIGURE 1. Proposed mechanism of the aldol reaction of 1a with
aliphatic aldehydes.
1
2
3
4
5
6
7
8
2a′
2c′
2d′
2e
Me
i-propyl
Cy
4a
4c
4d
4e
4f
4g
5c
5d
5e
5f
77
87
74
65
70
76
84
81
76
80
83
81
+8.9b (+8.7)
+20b (+22)
+33c
-30b d (-32.8) 99:1
,
Ph
-20b d (-18.5) 99:1
,
2f
o-F-Ph
o-Cl-Ph
i-propyl
n-hexyl
Cy
Ph
o-F-Ph
o-Cl-Ph
-34b d
99:1
,
2g
3c′
3d′
3e′
3f
3g
3h
-20c
-6.7c
c
d
,
9
-33 ,
,
10
11
12
+31b d (+30.6) 99:1
+21b d (+20.6) 99:1
,
5g
5h
+34b d
99:1
,
a Literature values are in parentheses. b The optical rotations were
recorded in H2O solution. c The optical rotations were recorded in
aqueous HCl. d Compounds 4e, 4f, 4g, 5f, 5g, and 5h were determined
by HPLC analysis on a CR (+) column.
FIGURE 2. Proposed mechanism of the aldol reaction of 1a with
aromatic aldehydes.
precursors. The structures of ꢀ-hydroxy-R-amino acids were further
tion), 2d′, 2f, 2h, 3f, 3g, and 3i were unambiguously ascertained
via X-ray crystallography.10
1
confirmed by comparison of their optical rotations and H NMR
data with those of the corresponding amino acids reported in the
literature.13 In addition, the chiral auxiliaries 6 and 7 were recovered
in excellent yield. The recovered chiral auxiliaries 6 and 7 were
recycled to prepare the tricyclic iminolactones 1a and 1b, which
exhibited the same optical purity as that of the one derived from
freshly synthesized compounds 6 and 7.
It is noteworthy that the aldol reactions of aromatic aldehydes
with 1a produced predominantly threo-adducts, while reactions
of aliphatic aldehydes gave exclusively erythro-adducts. Simi-
larly, 1b reacts with aromatic aldehydes to yield threo-adducts,
while its reaction with aliphatic aldehydes gave erythro-adducts
with good stereoselectivities. The reason for this selectivity
pattern can be explained by the theory of Zimmerman and
Denmark11 (Figure 1), where pathway 2 details the orientation
for erythro-adducts in the aldol reactions of aliphatic aldehydes
with 1a. In this case, the stereoselectivity comes from minimiza-
tion of nonbonded interaction in the form of a chairlike transition
state, in which the alkyl group of aldehyde (R1) assumes a
pseudoequatorial position. For the reactions of aromatic alde-
hydes (Figure 2), the transition state in pathway 2 would enforce
a π-π interaction between the benzene ring and the π system
of the iminolactone. As a result, the benzene ring can adjust to
be parallel with the iminolactone ring, as shown in pathway 1,
to reduce the steric interaction. Therefore, pathway 1 is more
favorable than pathway 2 in the reactions of aromatic aldehydes.
The hydrolysis of the isolated single aldol products was carried
out by heating in 6 N HCl at 80 °C for 3 h12 to afford the
corresponding ꢀ-hydroxy-R-amino acids in good yields with
enantiomeric excess (Table 3). The configurations of the R-positions
and ꢀ-positions of the ꢀ-hydroxy-R-amino acids are consistent with
the stereochemistry assigned to the respective tricyclic iminolactone
The 20S proteasome is essential for the turnover of cellular
proteins and for removing damaged, misfolded, and mistrans-
lated proteins in cells. It also plays a vital role in the turnover
of many regulatory proteins that control cell growth and
metabolism.14 So, (+)-lactacystin may have a therapeutic use
in animal models of myocardial infarction, stroke, asthma, and
arthritis. (+)-Lactacystin’s unusual structure and remarkable
biological activity has caught the attention of many synthetic
chemists. Many have used oxazoline 9 derived from hydroxy-
leucine as a key intermediate in their total synthesis, including
Adams, Corey, and others.15 Fortunately, we found that using
our methodology we can prepare either (2S,3S)- or (2R,3R)-3-
hydroxyleucine only with two steps from tricyclic iminolactone
1a or 1b. We can easily prepare trans-oxazoline 9 and the other
three isomers. trans-Oxazoline 9 was frequently used in the
synthesis of (+)-lactacystin, and it was envisaged based upon
an asymmetric aldol reaction using a tricyclic iminolactone. The
(13) (a) Sheehan, J. C.; Maeda, K.; Sen, A. K.; Stork, J. A. J. Am. Chem.
Soc. 1962, 84, 1303–1305. (b) Yasuo, A.; Naohiko, Y.; Tetsuo, Y. Bull. Chem.
Soc. Jpn. 1974, 47, 326–330. (c) Guanti, G.; Banfi, L.; Narisano, E. Tetrahedron
1988, 44, 5553–5562. (d) Blaser, D.; Seebach, D. Liebigs Ann. Chem. 1991,
1067–1078. (e) Soloshonok, V. A.; Kukhar, V. P.; Galushko, S. V.; Svistunova,
N.; Avilov, D. V.; Kuzmina, N. A.; Raevski, N. I.; Struchkov, Y. T.; Pysarevsky,
A. P.; Belokon, Y. N. J. Chem. Soc., Perkin Trans. 1993, 3143–3155. (f) Hale,
K. J.; Manaviazar, S.; Delisser, V. M. Tetrahedron 1994, 50, 9181–9188. (g)
Alker, D.; Hamblett, G.; Harwood, L. M.; Robertson, S. M.; Watkin, D. J.;
Williams, C. E. Tetrahedron 1998, 54, 6089–6098. (h) Davis, F. A.; Srirajan,
V.; Fanelli, D. L.; Portonovo, P. J. Org. Chem. 2000, 65, 7663–7666.
(10) The X-ray structure of aldol products CCDC Nos. 266588 (2c′), 266589
(3c′), 221192 (2d′), 221193 (2f), 266590 (3f), 266591 (3g), 221191 (2h), and
266592 (3i) contain the supplementary crystallographic data. These data can be
obtained free of charge from www.ccdc.cam.ac.uk/conts/ retrieving.html [or from
the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge, CB2
1EZ, U.K. Fax: (+44) 1223/336-033.
(11) (a) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920–1923. (b) Denmark, S. E.; Henke, B. R. J. Am. Chem. Soc. 1989, 111,
8032–8034.
(14) (a) Rock, K. L.; Gramm, C.; Rothstein, L.; Clark, K.; Stein, R.; Dick,
L.; Hwang, D.; Goldberg, A. L. Cell 1994, 78, 761–771. (b) King, R. W.;
Deshaies, R. J.; Peters, J. M.; Kirschner, M. W. Science 1996, 274, 1652–1659.
(12) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Na´jera, C. Tetrahedron:
Asymmetry 1998, 9, 2223–2227.
J. Org. Chem. Vol. 74, No. 4, 2009 1629

Li et al.
SCHEME 1. Synthesis of trans-Oxazoline 9 and Its Diastereoisomer 10
SCHEME 2. Synthesis of the Other Two Isomers of trans-Oxazoline 9
synthesis of trans-oxazoline 9 and its diastereoisomer 10 is
outlined in Scheme 1. Treatment of iminolactone 1b with LDA
at -30 °C generated the corresponding anions that reacted with
isobutyraldehyde at -78 °C to form compound 3c′ with good
yields and diastereoselectivity. Subsequent hydrolysis of com-
pound 3c′ in a 6 N HCl solution at 80 °C for 3 h afforded the
corresponding (2R,3R)-3-hydroxyleucine 5c. Esterification of
5c into its methyl ester through acidic methanolysis proceeded
in quantitative yield. The resultant product was then N-acylated
with benzoyl chloride in methanol at 0 °C to form the amide 8,
which underwent cyclization to oxazoline 9 via reaction with
1.5 equiv of thionyl chloride. Syntheses of the other two isomers
of oxazoline 9 were accomplished only by using the corre-
sponding tricyclic iminolactone 1a as shown in Scheme 2.
from inexpensive and readily available (1R)-(+)-camphor. The
transformations, which occur via the coupling of aldehydes with
tricyclic iminolactones 1a and 1b, proceed with good diaste-
reoselectivity and yield to afford the corresponding aldol
products. Additionally, the chiral auxiliaries (6 and 7) can be
recovered in high yield and preserve their stereochemical
integrity throughout the reaction sequence. Moreover, a stereo-
selective rule can be deduced as: (1) For tricyclic iminolactone
1a, the threo-isomers are the major products after the aldol
reactions with aromatic aldehydes, and the adducts have S,R-
configuration, while the erythro-isomers are the major products
in the reactions of aliphatic aldehydes and the adducts have S,S-
configuration. (2) For tricyclic iminolactone 1b, the adducts of
tricyclic iminolactone 1b with aromatic aldehydes have R,S-
configuration, and the adducts of tricyclic iminolactone 1b with
aliphatic aldehydes have R,R-configuration. Therefore, we can
control the configuration of the ꢀ-position for new ꢀ-hydroxy-
R-amino acids using this rule. Application of this method to
total synthesis of several natural products, such as sphingofun-
gins, polyoxins, lactacystin, will be reported in due course.
Conclusion
In summary, we have developed a novel and practical method
for the preparation of enantioenriched ꢀ-hydroxy-R-amino acids
(15) (a) Sunazuka, T.; Nagamitsu, T.; Matsuzaki, K.; Tanaka, H.; Omura, S.
J. Am. Chem. Soc. 1993, 115, 5302–5302. (b) Nagamitsu, T.; Sunazuka, T.;
Tanaka, H.; Omura, S.; Sprengeler, P. A.; Smith, A. B, III. J. Am. Chem. Soc.
1996, 118, 3584–3590. (c) McCormack, T. A.; Adams, J.; Plamondon, L. J. Am.
Chem. Soc. 1999, 121, 9967–9976. (d) Saravanan, P.; Corey, E. J. J. Org. Chem.
2003, 68, 2760–2764. (e) Panek, J. S.; Masse, C. E. Angew. Chem. 1999, 111,
1161-1163; Angew. Chem. Int. Ed. 1999, 38, 1093-1095.
Experimental Section
General Procedure for Aldol Reaction of Iminolactone and
Aldehydes: Preparation of iminolactones 1a and 1b is described
1630 J. Org. Chem. Vol. 74, No. 4, 2009

Synthesis of ꢀ-Hydroxy-R-Amino Acids
in the literature.7 Lithium chloride (383 mg, 9 mmol, 6 equiv) was
added to a dry 50 mL long-neck flask under argon. Diisopropy-
lamine (0.234 mL, 1.65 mmol, 1.1 equiv) was added to dry THF
(8 mL) in a long-neck flask. After the solution was cooled to -30
°C, n-BuLi (2.8 M, 0.589 mL, 1.65 mmol, 1.1 equiv) was added
dropwise. The reaction mixture was stirred at -30 °C for 30 min.
Tricyclic iminolactone (310 mg, 1.5 mmol) in dry THF (10 mL)
was added dropwise over a period of 10 min into the above freshly
prepared LDA solution at -30 °C, and then the reaction mixture
was subsequently cooled to -78 °C and stirring was continued for
30 min followed by the addition of the solution of aldehyde (1.8
mmol) in dry THF (10 mL) over a period of 10 min. The well-
stirred reaction was kept at -78 °C for another 1-12 h (after TLC
analysis showed the reaction was complete). Saturated NH4Cl (1
mL) solution was added to the mixture to quench the reaction. The
reaction was warmed up to rt; the solvent was removed under
reduced pressure, and the residue was diluted with water and
extracted with ethyl acetate (3 × 15 mL). The combined organic
phase was washed with water and brine, dried (MgSO4), and
concentrated to give the crude product. The crude product was
purified by column chromatography to yield desired compounds.
(1S,2R,5S,8R,1′S)-5-(1′-Hydroxyethyl)-1,11,11-trimethyl-3-
oxa-6-azatricyclo[6.2.1.02,7]undec-6-en-4-one (2a′): White solid
(320 mg, 85%); [R]20D +52 (c 1.61, CHCl3); mp 139-141 °C; IR
(KBr) 3354 (s), 2990 (m), 1745 (s), 1702 (s) cm-1; 1H NMR (400
MHz, CDCl3) δ 4.78 (s, 1H), 4.43 (d, J ) 4.4 Hz, 1H), 4.18-4.17
(m, 1H), 2.20 (d, J ) 4.8 Hz, 1H), 2.10-2.02 (m, 2H), 1.81-1.74
(m, 1H), 1.66-1.59 (m, 1H), 1.46 (d, J ) 6.8 Hz, 3H), 1.41-1.35
(m, 2H), 1.07 (s, 3H), 0.97 (s, 3H), 0.81 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 182.7, 169.8, 80.1, 69.4, 68.2, 52.9, 48.4, 47.7,
29.3, 25.9, 21.8, 20.1, 19.5, 10.1; HRMS (ESI) calcd for C14H22NO3
[M + H]+ 252.1597, found 252.1594.
General Procedure for Hydrolysis of Aldol Products: The
aldol product (1.2 mmol) was dissolved in 6 N HCl (3 mL) in a
sealed tube with a Teflon screw cap and heated at 80 °C for 3 h.
After cooling to rt, water (5 mL) was added and the mixture was
extracted with diethyl ether (3 × 5 mL). The chiral auxiliary 6 or
7 was recovered when the ether layer was concentrated. The
aqueous layer was evaporated under reduced pressure, and the
residue was dissolved in EtOH (5 mL). Propylene oxide (3 mL)
was then added and stirred at rt for 30 min during which time white
solids precipitated. The precipitate was collected by filtration,
washed successively with cold EtOH (2 × 2 mL) and Et2O (1 × 4
mL), and air-dried to give the desired free ꢀ-hydroxy-R-amino acids.
(2S,3S)-2-Amino-3-hydroxybutanoic Acid (4a): White solid (97
mg, 77%); [R]20D +8 (c 1.1, H2O); mp 264-266 °C; 1H NMR (400
MHz, D2O) δ 4.37 (dd, J ) 6.4, 4 Hz, 1H), 3.84 (d, J ) 4 Hz,
1H), 1.20 (d, J ) 6.4 Hz, 3H); 13C NMR (100 MHz, D2O) δ 171.8,
65.3, 59.6, 16.1.
(2R,3R)-3-Hydroxyleucine (5c): White solid (148 mg, 84%);
1
[R]20 -20 (c 1.26, H2O); mp 187 °C (dec); H NMR (400 MHz,
D
D2O) δ 3.92 (d, J ) 3.2 Hz, 1H), 3.53 (dd, J ) 9.2, 3.2 Hz, 1H),
1.94 (m, 1H), 0.98 (m, 6H); 13C NMR (100 MHz, D2O) δ 171.7,
76.1, 57.1, 30.2, 18.5.
Methyl (4R,5S)-5-Isopropyl-2-phenyl-4,5-dihydrooxazole-4-
carboxylate 9: A solution of amide 8 (398 mg, 1.5 mmol) in THF
(15 mL) was cooled to 0 °C. Thionyl chloride (0.16 mL, 2.25 mmol)
was added to the solution at 0 °C. The reaction mixture was warmed
gradually to 25 °C. After stirring 12 h, the reaction mixture was
heated to 60 °C for 1.5 h. Then the reaction mixture was cooled to
0 °C and quenched with saturated NaHCO3 (15 mL). The aqueous
phase was extracted with ethyl acetate (3 × 15 mL). The combined
organic phase was washed with H2O (10 mL) and brine (10 mL),
dried over Na2SO4, filtered, and concentrated. Flash chromatography
(8:1 petrol ether/EtOAc) afforded 9 (330 mg, 89%) as light yellow
oil: [R]20D -113 (c 0.04, CHCl3); IR υmax (film) 2922, 1741, 1646,
1449, 1385; 1H NMR (400 MHz, CDCl3) δ 1.00 (d, J ) 6.4 Hz,3H),
1.03 (d, J ) 6.4 Hz, 3H), 1.94-1.99 (m, 1H), 3.81 (s, 3H), 4.57
(d, J ) 7.2 Hz, 1H), 4.68 (apparent t, J ) 6.8 Hz, 1H), 7.40-7.43
(m, 2H), 7.48-7.52 (m, 1H), 7.98-8.00 (m, 2H); 13C NMR (100
MHz, CDCl3) δ 17.2, 17.4, 32.4, 52.6, 71.3, 87.2, 127.2, 128.3,
128.5, 131.7, 165.7, 172.0; HRMS (ESI) calcd for C14H18NO3 [M
+ H]+ 248.1281, found 247.1283.
(1S,2R,5S,8R,1′R)-5-(1′-Hydroxy-o-fluorobenzyl)-8,11,11-tri-
methyl-3-oxa-6-azatricyclo [6.2.1.02,7]undec-6-en-4-one (2f):
White solid (372 mg, 75%); [R]20 -33 (c 1.24, CHCl3); mp
D
138-140 °C; IR (KBr) 3194 (b), 2990 (m), 1740 (s), 1690 (s) cm-1
;
1H NMR (400 MHz, CDCl3) δ 7.47-7.43 (m, 1H), 7.33-7.26 (m,
1H), 7.19-7.15 (m, 1H), 7.05-7.00 (m, 1H), 5.63 (d, J ) 4 Hz,
1H), 4.82 (d, J ) 4.4 Hz, 1H), 4.30 (s, 1H), 3.06 (s, 1H), 2.13 (d,
J ) 4.4 Hz, 1H), 2.04-1.97 (m, 1H), 1.78-1.71 (m, 1H),
1.62-1.55 (m, 1H), 1.27-1.21 (m, 1H), 1.00 (s, 3H), 0.93 (s, 3H),
0.76 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 183.5, 170.3, 129.9,
128.1, 127.0, 124.4, 115.4, 115.2, 79.8, 69.4, 66.9, 53.1, 48.2, 47.7,
29.3, 26.0, 20.1, 19.5, 10.1; HRMS (ESI) calcd for C19H23FNO3
[M + H]+ 332.1656, found 332.1660.
Methyl (4R,5R)-5-Isopropyl-2-phenyl-4,5-dihydrooxazole-4-
carboxylate 13: Following the procedure described for 9, the only
change was (2R,3R)-3-hydroxyleucine 5c into (2S,3S)-3-hydroxyleu-
cine 4c: Colorless oil; [R]20 + 113 (c 0.04, CHCl3); IR υmax (film)
D
1
2923, 1733, 1636, 1439, 1383; H NMR (400 MHz, CDCl3) δ 0.98
(1R,2S,5R,8S,1′R)-5-(1′-Hydroxyethyl)-1,11,11-trimethyl-3-
oxa-6-azatricyclo[6.2.1.02,7]undec-6-en-4-one (3a′): Oil (237 mg,
(d, J ) 6.8 Hz, 3H), 1.02 (d, J ) 6.8 Hz, 3H), 1.92-1.97 (m, 1H),
3.79 (s, 3H), 4.56 (d, J ) 6.8 Hz, 1H), 4.66 (apparent t, J ) 6.8 Hz,
1H), 7.38-7.41 (m, 2H), 7.46-7.50 (m, 1H), 7.97-7.99 (m, 2H);
13C NMR (100 MHz, CDCl3) δ 17.2, 17.3, 32.3, 52.5, 71.2, 87.1, 127.1,
128.2, 128.5, 131.7, 165.7, 172.0; HRMS (ESI) calcd for C14H18NO3
[M + H]+ 248.1281, found 247.1286.
1
63%); IR (KBr) 3385 (s), 2964 (m), 1743 (s), 1704 (s) cm-1; H
NMR (400 MHz, CDCl3) δ 4.60 (s, 1H), 4.38 (d, J ) 4.4 Hz, 1H),
4.16 (m, 1H), 2.43 (d, J ) 4.4 Hz, 1H), 2.05-1.98 (m, 1H),
1.92-1.87 (m, 1H), 1.63-1.57 (m, 1H), 1.45 (d, J ) 6.4 Hz, 3H),
1.42-1.36 (m, 1H), 1.05 (s, 3H), 0.97 (s, 3H), 0.85 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 181.2, 169.5, 82.0, 69.2, 68.0, 53.9,
49.5, 48.2, 34.5, 21.8, 21.4, 20.0, 19.3, 9.7; HRMS (ESI) calcd for
C14H22NO3 [M + H]+ 252.1594, found 252.1588.
Acknowledgment. We are grateful for the financial support
of the National Natural Science Foundation of China (NSFC,
20572039, 20772051), the Program for NCET-05-0880, and the
Doctoral Funds from Chinese Ministry of Education of P.R.
China. We also thank Professor T.-J. Lu for his support.
(1R,2S,5R,8S,1′S)-5-(1′-Hydroxybenzyl)-1,11,11-trimethyl-3-
oxa-6-azatricyclo[6.2.1.02,7]undec-6-en-4-one (3f): White solid
(389 mg, 83%); [R]20D +93 (c 2.52, CH2Cl2); mp 152-153 °C; IR
1
(KBr) 3245 (s), 2960 (s), 1744 (s), 1697 (s) cm-1; H NMR (400
Supporting Information Available: General methods for the
synthesis of racemic ꢀ-hydroxy-R-amino acids, spectra data for
compounds 2d′, 2e′, 2g, 2h, 3a, 3d′, 3e′, 3h, 3i, 4e-4g, 5e-5h,
MHz, CDCl3) δ 7.34-7.32 (m, 3H), 7.28-7.26 (m, 2H), 5.23 (t,
J ) 4.4 Hz, 1H), 4.70 (d, J ) 3.6 Hz, 1H), 3.59 (s, 1H), 3.40 (d,
J ) 4.8 Hz, 1H), 2.32 (d, J ) 4.4 Hz, 1H), 1.96-1.88 (m, 1H),
1.80-1.72 (m, 1H), 151-1.45 (m, 1H), 1.12-1.03 (m, 1H), 0.94
(s, 3H), 0.89 (s, 3H), 0.75 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
181.8, 170.7, 139.8, 128.42, 128.40, 126.3, 81.7, 75.1, 67.1, 53.9,
49.1, 48.0, 34.5, 21.3, 19.8, 19.1, 9.5; HRMS (ESI) calcd for
C19H24NO3 [M + H]+ 314.1751, found 314.1759.
1
and 11-13, as well as copies of H and 13C NMR spectra and
HPLC results. This material is available free of charge via the
Internet at http://pubs.acs.org.
JO8023973
J. Org. Chem. Vol. 74, No. 4, 2009 1631