Use of bis-(chiral α-methylbenzyl)glycine esters for synthesis of enantiopure β-hydroxyamino esters

Article abstract of DOI:10.1021/ol030085j

(Matrix presented) Aldol reactions using bis-(chiral α -methylbenzyl)glycine esters with aldehydes gave excellent diastereoselectivity. Thus, an enantiopure ribosylglycine was prepared for the synthesis of analogues of the natural antibiotics muraymycin.

Full text of DOI:10.1021/ol030085j

ORGANIC
LETTERS
2003
Vol. 5, No. 18
3305-3308
Use of Bis-(chiral
r-methylbenzyl)glycine Esters for
Synthesis of Enantiopure
â-Hydroxyamino Esters
Ayako Yamashita,* Emily B. Norton, R. Thomas Williamson, Douglas M. Ho,†
Sandra Sinishtaj,‡ and Tarek S. Mansour
Chemical Sciences, Wyeth Research, Pearl RiVer, New York 10965
yamasha@wyeth.com
Received July 9, 2003
ABSTRACT
Aldol reactions using bis-(chiral r-methylbenzyl)glycine esters with aldehydes gave excellent diastereoselectivity. Thus, an enantiopure
ribosylglycine was prepared for the synthesis of analogues of the natural antibiotics muraymycin. This method was extended for formation
of â-hydroxyamino esters.
Muraymycins (1, Figure 1), isolated from sp LL-AA896, form
a family of novel nucleoside-peptide antibiotics.1 Their core
skeleton consists of an unusual nucleotide disaccharide and
a lipophilic derivative of glycine linked to a unique dipeptide
urea.2 In the course of our work1c on the synthesis of
analogues of 1, we studied the enantioselective preparation
of intermediate 2. Although several methods for the forma-
tion of 2 have been reported,3 only a rather inconvenient
one achieves enantioselectivity.3c We now report our finding
that the aldol reaction of the chiral glycine ester 4 with the
enantiopure ribosyl aldehyde 34 produces enantiopure ribo-
sylglycine 2. This new method was extended to the prepara-
tion of enantiopure â-hydroxyamino esters using a number
of aldehydes.
The aldol reaction of 3 was first examined with nonchiral
dibenzylglycine ester 4a.5 The reaction conditions for aldol
reactions were examined with various bases [LDA, NaH,
NaHMDS, KHMDS], additives [crown ethers, HMPA], and
solvents [THF, HMPA]. The best result was obtained when
(3) (a) Paulsen, H.; Brieden, M.; Benz, G. Liebigs Ann. Chem. 1987,
565. (b) Hadrami, M. E.; Lavergne, J. P.; Viallefont, P.; Chiaroni, A.; Riche,
C.; Hasnaoui, A. Synth. Commun. 1993, 23, 157. (c) Bouifraden, S.;
Hadrami, M. E.; Ittobane, N.; Lavergne, J. P.; Viallefont, P. Synth. Commun.
1993, 23, 2559. (d) Borrachero, P.; Dianez, M. J.; Estrada, M. D.; Gomez-
Guillen, M.; Gomez-Sanchez, A.; Lopez-Castro, A.; Perez-Garrido, S.
Carbohydr. Res. 1995, 279, C9. (e) Czernecki, S.; Horms, S.; Valery, J.
M. J. Org. Chem. 1995, 60, 650. (f) Czernecki, S.; Franco, S.; Valery, J.
M. Tetrahedron Lett. 1996, 37, 4003. (g) Merrer, Y. L.; Gravier-Pelletier,
C.; Gerrouache, M.; Depezay, J. C. Tetrahedron Lett. 1998, 39, 385.
(4) Barrett, A. G. M.; Lebold, S. A. J. Org. Chem. 1990, 55, 3853.
(5) Preparation of 4a and use of 4a for aldol and Michael reactions,
etc.: (a) Scolastico, C. Tetrahedron Lett. 1987, 43, 2317. (b) Gray, B. D.;
Jeffs, P. W. J. Chem. Soc., Chem. Commun. 1987, 1329. (c) Guanti, G.;
Banfi, L.; Narisano, E.; Scolastico, C. Tetrahedron 1988, 44, 3671. (d) Elder,
T.; Gregory, L. C.; Orozco, A.; Pflug, J. L.; Wiens, P. S.; Wilkinson, T. J.
Synth. Commun. 1989, 19, 763. (e) Yamaguchi, M.; Torisu, K.; Minami,
T. Chem. Lett. 1990, 377.
† Director, Small Molecule X-ray Facility, Department of Chemistry,
Princeton University, Princeton, NJ 08544.
‡ Summer Intern, 2001.
(1) Biological activity of muraymycins and their analogues: (a) Singh,
G.; Yang, Y.; Rasmussen, B. A.; Petersen, P. J.; McDonald, L. A.;
Yamashita, A.; Lin, Y.-I.; Norton, E.; Francisco, G. D.; Li, Z.; Barbieri, L.
R. The 41st Interscience Conference on Antimicrobial Agents and Che-
motherapy, Chicago, IL; Abstract 1163; December 16-19, 2001. (b) Lin,
Y.-I.; Li, Z.; Francisco, G. D.; McDonald, L. A.; Davis, R. A.; Singh, G.;
Yang, Y.; Mansour, T. S. Bioorg. Med. Chem. Lett. 2002, 12, 2341. (c)
Yamashita, A.; Norton, E.; Petersen, P. J.; Rasmussen, B. A.; Singh, G.;
Yang, Y.; Mansour, T. S.; Ho, D. M. Bioorg. Med. Chem. Lett. 2003, 13,
in press, and other references therein.
(2) Isolation and structure determination of muraymycins: McDonald,
L. A.; Barbieri, L. R.; Carter, G. T.; Lenoy, E.; Petersen, P. P.; Siegel, M.
M.; Sign, G.; Williamson, R. T. J. Am. Chem. Soc. 2002, 124, 10260.
10.1021/ol030085j CCC: $25.00 © 2003 American Chemical Society
Published on Web 08/14/2003

Table 1. Aldol Reactions with 3 and Glycine Esters 4
yielda
ratiob
compd *R,*â
R1
R2
R3
Et
tBu
Et
(%)
products
(5:6)
4a
4b
H
H
Me
Me
H
H
H
H
92
80
76
77
76
71
5a /6a
5b/6b
5c/6c
5d /6d
5e/6e
5f/6f
4:1
1:1
2:1
2.5:1
1:199
5:2
4c
4d
4e
4f
S
R
SS
RR
Et
Me Me Et
Me Me Et
a Isolated yield as a mixture of 5 and 6. b Ratio of 5 and 6 was determined
1
by H NMR integration.
In a similar manner, aldol reaction of 3 using the tert-
butyl ester of glycine 4b7 was examined (Table 1). In contrast
to 4a, a 1:1 mixture of two diastereomers 5b (5R,6R) and
6b (5R,6S) was isolated.8 We then introduced one chiral
R-methylbenzyl group with either (S)- or (R)-configuration
[4c and 4d, respectively]. The aldol reactions of 3 with either
4c or 4d, however, showed little diastereoselectivity, giving
a 2:1 ratio for 5c/6c and a 2.5:1 for 5d/6d, respectively.9
The new glycine ester 4e, protected by two (S)-R-methyl-
benzyl groups, gave the remarkable result in the aldol
reaction with 3 in which essentially complete double dias-
tereoselectivity was obtained and only the (5R,6S)-diastere-
omer 6e was isolated. Surprisingly, the aldol reaction of 4f,
the glycine ester protected by two (R)-R-methylbenzyl
groups, resulted in practically no selectivity (2.5:1 ) 5f/6f).
The remarkable selectivity obtained from 4e prompted us
to study whether similar selectivity would be observed with
simple aldehydes (Scheme 2).
Figure 1.
LDA was used as a base in THF as the solvent. Thus, the
anion of 4a was generated by treatment with LDA [THF,
-78 °C] and reacted with 3 [-78 °C, 4 h] (Scheme 1). The
Scheme 1a
Scheme 2
a Reaction conditions: (a) (i) LDA, THF, -78 °C; (ii) 3, -30
°C, 4 h, 94%. (b) H2, 10% Pd/C, MeOH.
product was isolated as a 4:1 mixture of two inseparable
diastereomers (5a, 6a), which was directly hydrogenated, to
give the deprotected amines (7, 8). The absolute stereochem-
istry of the newly created chiral centers at C5 and C6 in 7
(a major component) was determined by X-ray analysis to
be (5R,6R)-. The minor product 8 (oil) was converted to the
para-nitrophenyl urea derivative 9a for X-ray analysis, which
revealed the stereochemistry at C5 and C6 as (5R,6S)-.6
Aldol reaction of 4e with sterically hindered trimethylac-
etaldehyde gave practically a single diastereomer 10a, the
(7) Banfi, L.; Cardani, S.; Potenza, D.; Scolastico, C. Tetrahedron 1987,
43, 2317. Other glycine esters 4c-f were prepared from ethyl bromoacetate
and appropriate chiral dibeznylamine derivatives.
(8) Relative stereochemistry of 5b and 6b was determined by NMR
spectroscopy through implementation of the J-configuration analysis
method: (a) Matsumori, N.; Kaneno, D.; Nakamura, H.; Tachibana, K. J.
Org. Chem. 1999, 64, 866. (b) Williamson, R. T.; Marquez, B. L.; Barrios
Sosa, A. C.; Koehn, F. K. Magn. Reson. Chem. 2003, 41, 379. This
technique was used for the structure determination of muraymycins: see
ref 2.
(6) Crystals of 7a suitable for X-ray were obtained as colorless prisms
from ether/hexanes. Crystals of the para-nitrophenyl urea derivative 9a of
8a were obtained as yellow prisms from methylene chloride/MeOH. The
supplementary publication numbers for the X-ray data are CCDC 214437
for 7a and CCDC 214438 for 9a.
3306
Org. Lett., Vol. 5, No. 18, 2003

Table 2. Aldol Reactions with 4e and 4f
compd
*R,*â
R4
yielda (%)
products
ratiob (10:11)
4e
4f
4e
4f
4e
SS
RR
SS
RR
SS
tBu
tBu
iPr
71
88
78
94
88
10a /11a
10b/11b
10c/11c
10d /11d
10e/11e
100:“0”
“0”:100
6:1
1:3
9:6c
iPr
Ph
a Isolated yield after column chromatography. b Determined by 1H NMR
integration. c Two other diastereomers were also isolated; thus, the ratio
was 9:6:1:1.
(2S,3S)-tert-butylserine ester10 (Table 2).11 In a similar
manner, reaction of 4f with the same aldehyde gave complete
selectivity, although, as expected, the absolute stereochem-
istry of the product, the (2R,3R)-â-hydroxyamino ester 11b,
was reversed. Reaction of 4e or 4f with the less hindered
isobutyraldehyde also gave good selectivities, giving the
â-hydroxyleucine esters12 in ratios of 6:1 (10c/11c13) and 1:3
(10d13/11d), respectively. Benzaldehyde gave little control
of selectivity, forming a mixture of four in a ratio14 of 9:6:
1:1. Alkylations using 4e and 4f were also examined. In
contrast to aldol reactions, however, no selectivity was
observed.
Figure 2. Crystal structure of 6e.
shape to the resulting transition state of the enolate A. An
aldehyde should approach from the side opposite from the
(S)-R-methyl at the bottom of the cup (B-1), due to steric
interaction between the methyl group and the alkyl group
of the aldehyde. This makes transition state B-1 more
favorable than transition state B-2. Thus, the (2S,3S)-â-
hydroxyamino ester 10 should be predominately formed from
B-1, and B-2 would lead to the minor product, the (2R,3R)-
isomer 11. This would be reversed in the case of 4f, to form
the (2R,3R)-â-hydroxyamino ester 11 (from B′-2) as the
favored product and the (2S,3S)-isomer 10 as the minor one
(from B′-1).
In an attempt to elucidate the transition state leading to
stereoselectivity, we submitted 6e to X-ray analysis.15 The
crystal structure of 6e reveals that the two phenyl rings in
the benzyl groups are perpendicular, and they are kept fairly
rigid by the two methyl groups (Figure 2).
In summary, we have developed a facile method for
synthesis of enantiopure â-hydroxyamino esters by the use
of bis (chiral R-methylbenzyl)glycine esters. Considering the
simplicity of preparing these glycine esters and the feasibility
of removing the benzyl group by hydrogenation, this method
should provide a useful tool for the synthesis of various
â-hydroxyamino esters.
A plausible rationale for diastereoselectivity is outlined
for 4e in Scheme 3. Treatment of the chiral glycine ester 4e
with LDA would generate the (E)-lithium enolate,16 which
could coordinate with one of the phenyl rings in the benzyl
groups.17 On the basis of the crystal structure of 6e, the (S)-
R-methyl substituent in the benzyl group would give a cup
Scheme 3
Org. Lett., Vol. 5, No. 18, 2003
3307

Acknowledgment. The authors are thankful for the
analytical support provided by Discovery Analytical Chem-
istry Department, Wyeth Research, Pearl River, NY, and
Princeton, NJ.
supporting analytical data; please also see ref 18. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL030085J
Supporting Information Available: Experimental pro-
cedures for the preparation of compounds 4-11 with
(13) Structures of compounds 11c and 10d were determined by their
X-ray analyses. Crystals suitable for 11c were obtained as colorless prisms
from ether/hexanes (supplementary publication number CCDC 214440).
Crystals suitable for 10d were also obtained as colorless prisms from ether/
hexanes (supplementary publication number CCDC 214439).
(14) We assumed that the (2S,3S)-diastereomer 10e was the major
component, along with the (2R,3R)-isomer 11e as the second major
component. Related references: (a) Suga, H.; Ikai, K.; Ibata, T. J. Org.
Chem. 1999, 64, 7040. (b) Tomasini, C.; Vecchione, A. Org. Lett. 1999, 1,
2153. (c) Markovic, D.; Hamersak, Z.; Visnjevac, A.; Kojic-Prodic, B.;
Sunjic, V. HelV. Chem. Acta 2000, 83, 603. (d) Davis, F. A.; Srirajan, V.;
Fanelli, D. L.; Portonovo. P. J. Org. Chem. 2000, 65, 7663 and other
references therein.
(9) Structure determination of products 5c-f and 6c-f from aldol
reactions of 4c-f was accomplished as follows: the isolated products were
subjected to catalytic hydrogenation using 10% Pd/C in absolute MeOH to
form the corresponding deprotected amines. Each amine was characterized
with two authentic samples (7a and 8a) by comparison with their 1H NMR
spectra and TLC analyses.
(10) (a)Soloshonok, V. A.; Avilov, D. V.; Kukhar, V. P. Tetrahedron:
Asymmetry 1995, 6, 1741. (b) Belokon, Y. N.; Kochetkov, K. A.; Ikonnikov,
N. S.; Strelkova, T. V.; Harutyunyan, S. R.; Saghiyan, A. S. Tetrahedron:
Asymmetry 2001, 12, 481.
(11) Stereochemistry of products 10a-d and 11a-d listed in Table 2
was determined by 1H NMR spectra and optical rotations. Also, the products
were deprotected by hydrogenation to give the corresponding amino esters.
1H NMR spectra and optical rotations of these free amino esters were used
for further confirmation of their stereochemistry.
(15) Crystals of 6e suitable for X-ray were obtained as colorless prisms
from ether/hexanes. The supplementary publication number for the X-ray
for 6e is CCDC 214436.
(16) Stereochemical outcome of the lithium enolate geometry of sub-
stituted esters in various solvent systems has been reported: (a) Jeffery, E.
A.; Meisters, A.; Mole, T. J. Organomet. Chem. 1974, 74, 373. (b) Dubois,
J. E.; Fellman, P. Tetrahedron Lett. 1975, 16, 1225. (c) Ireland, R. E.;
Willard, A. K. Tetrahedron Lett. 1975, 16, 3975. (d) Ireland, R. E.; Mueller,
R. H.; Willard, A. K. J. Am. Chem. Soc. 1976, 98, 2868. (e) Ireland, R. E.;
Thaisrivongs, S.; Vanier, N.; Wilcox, C. S. J. Org. Chem. 1980, 45, 48
and other references therein.
(17) A directing effect of neighboring aromatic groups on the regio-
chemistry of formation and on the stereochemistry of alkylation of lithium
enolates has been suggested: Posner, G. H.; Lentz, C. M. J. Am. Chem.
Soc. 1979, 101, 934. Other references therein.
(18) Crystallographic data for the compounds in this manuscript, which
were analyzed by X-ray, have been deposited at the Cambridge Crystal-
lographic Data Center, 12 Union Road, Cambridge CB2 1EW, UK. The
supplementary publication number for X-ray data for each compound is
individually listed in the footnote.
(12) Syntheses of â-hydroxy-leucines have been reported: (a) Jung, M.
E.; Jung, Y. H. Tetrahedron Lett. 1989, 30, 6637. (b) Hale, K. J.;
Manaviazar, S.; Delisser, V. M. Tetrahedron 1994, 50, 9181. (c) Yadav, J.
S.; Chandrasekhar, S.; Reddy, Y. R.; Rao, A. V. R. Tetrahedron 1995, 51,
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P. A.; Smith, A. B., III. J. Am. Chem. Soc. 1996, 118, 3584. (e) Kimura,
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