The enantioselective synthesis of anti-β-hydroxy-α-amino acids via the reaction of lithium enolates of glycine bearing an oxazolidine chiral auxiliary with aldehydes

Article abstract of DOI:10.1055/s-1998-1736

A new anti-selective aldol reaction utilizing 2,4-disubstituted oxazolidine functionalized-glycine ester 1 is described. The corresponding lithium enolate of 1, has been demonstrated to undergo a highly anti-diastereoselective aldol reation with a variety of aldehydes. Facile removal of the chiral auxiliary allows for the efficient preparation of chiral β-hydroxy-α-amino acids of erythro stereochemistry.

Full text of DOI:10.1055/s-1998-1736

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LETTERS
SYNLETT
The Enantioselective Synthesis of anti-β-Hydroxy-α-Amino Acids via the Reaction of Lithium
Enolates of Glycine Bearing an Oxazolidine Chiral Auxiliary with Aldehydes
Edwin J. Iwanowicz , Peter Blomgren , Peter T. W. Cheng , Kennith Smith , Wan F. Lau , Yolanda Y. Pan , Henry H. Gu , Mary F. Malley and Jack
a*
a
a
b
a
a
a
a
a
Z. Gougoutas
a)
Bristol-Myers Squibb Pharmaceutical Research Institute, Princeton, NJ 08543-4000, USA
Fax: (609) 252-6601; E-mail: iwanowicz@bms.com
b)
General Electric Company, Corporate Research and Development, Schenectady, NY 12301, USA
Received 8 August 1997
Abstract:A new anti-selective aldol reaction utilizing 2,4-disubstituted
oxazolidine functionalized-glycine ester
1
is described. The
corresponding lithium enolate of 1, has been demonstrated to undergo a
highly anti-diastereoselective aldol reation with a variety of aldehydes.
Facile removal of the chiral auxiliary allows for the efficient preparation
of chiral β-hydroxy-α-amino acids of erythro stereochemistry.
As part of an effort to construct analogs and develop new molecular
frameworks for thrombin active site inhibitors we examined the
behavior of the lithium enolate derived from 1 in an aldol process. Based
upon the crystallographic structure of BMS 183,507 complexed with
human α-thrombin we observed the methyl group of the allo-threonine
residue was positioned over the specificity pocket proximal to the
1
guanidine moiety. This spatial relationship would allow for the direct
attachment of a guanidine residue to the allo-threonine moiety via the
insertion of an alkyl chain. Preparation of inhibitors based upon this
structural motif required an efficient method for the preparation of
derivatives of allo-threonine.
Various aldehydes were condensed with 2 and the results are
summarized in Table 1. The crude reaction products 3-7 contained
varying amounts of the minor isomers. Recrystallization of the crude
o
mixture of 7a and 7b from hexanes provided pure 7a, [α] +51.7 (c
D
2.0, acetone) in 83 % yield, the only crystalline analog of this series.
The relative stereochemical assignment of the C-2 asymmetric center of
phenylglycinol-derived oxazolidines formed by condensation with an
7
1
aldehyde has been controversial. Recent H NMR studies suggest that a
8
cis relationship between the C-2 and C-4 residues predominates.
Compound 7a was subjected to single crystal X-ray analysis.
Substituents at the C-2 and the C-4 asymmetric centers (both in the R
configuration) of the oxazolidine ring are on the same face. The nitrogen
has pyramidal geometry (S configuration) with the lone electron pair cis
The development of methods for the preparation of nonproteinogenic α-
amino acids continues to be an active area of research. Although many
2
9
to the phenyl and benzhydryl substituents.
methods for the construction of a variety of α-amino acids have been
described, a chiral glycine equivalent that efficiently undergoes a highly
anti-selective aldol reaction in high yield has remained an elusive
To determine the relative stability of the various isomers and related
conformers of 6, molecular mechanics calculations were performed on
the model structures 8 -11 using the MM2 molecular mechanics force
3,4
target. Reported here is the development of a novel oxazolidine-based
10
field as implemented in the MACROMODEL software package. For
chiral glycine equivalent of high isomeric purity which addresses this
issue.
each molecule, Monte Carlo searching (MACROMODEL) of
conformational space was used to calculate all possible low energy
Oxazolidines derived from optically active phenylglycinol have been
utilized as chiral auxiliaries or reactants for the formation of chiral
11
conformers within 10 kcal/mol. The bond between O-1 and C-5 in the
oxazolidine ring was defined as the ring closure bond for the purpose of
MC torsion angle searching. The torsion angles that defined the atoms in
the ring, the tert-butyl group and the phenyl group were varied. The
relative energies of the respective lowest energy conformers are given in
Table 2. The relative energy difference between the cis 8 and trans 10
conformers is 2.7 kcal/mol, which predicts a theoretical ratio of 67/1
5
products. We have prepared several 2,4-disubstituted oxazolidine-
functionalized glycine tert-butyl esters in an attempt to find an
appropriate combination of high diastereomeric purity and required
steric bulk necessary for good diastereofacial selectivity in subsequent
6
aldol reactions.
o
12
respectively, at 50 C. In addition, the residues at C-2 and C-4 and the

June 1998
SYNLETT
665
lone pair of electrons of structure 8, are on the same face, which is
consistent with the solid state structure of 7a.
Compound 7a readily epimerizes via an acid catalyzed process to give
the thermodynamic ratio of products. Exposure to either CDCl with
3
trace DCl or MgSO /CH Cl gave a 38/1 mixture of 7a and 7b,
4
2
2
13
respectively. However, the stereochemical integrity of 7a was easily
preserved by avoiding exposure to acids.
Treatment of 7a or 12 with lithium diisopropylamide (LDA) in THF (1h
o
at -78 C), followed by the reaction of the resultant lithium enolate with
14
various aldehydes gave aldol products 13-18. The crude reaction
1
products were examined by H NMR under neutral conditions (acetone-
o
d at 55 C) to ascertain the ratios of diastereomers. The diastereomeric
6
product ratios and the purified yields are given in Table 3. The reaction
of the lithium enolate of 12 with isobutyraldehyde (1.0 M, THF) gave a
mixture of all four possible diastereomers. Contrary to this result, the
reaction of the lithium enolate derived from 7a when reacted with
various aldehydes led predominantly to a single diastereomeric product.
Reactions involving sterically hindered aldehydes, entries 15 and 16,
displayed the highest selectivity (99/1) whereas a decrease in steric bulk
about the carbonyl group led to
a reduction in diastero- and
enantioselectivity. The reactions gave the isolated aldol product in good
1
to excellent yields; in many cases 7a was not observed by H NMR in
the crude reaction mixtures.
In addition to the acid-catalyzed isomerization of the oxazolidine
moiety described earlier, a second isomerization gave a trisubstituted
oxazolidine. The aldol product 15 was found to equilibrate through an
acid catalyzed reaction to give a 55/45 mixture of the two oxazolidines
15 and 19 respectively, as shown in Figure 2. This equilibration process
provided additional complexity for the direct determination of the ratio
of diastereomeric aldol products by methods other than NMR in neutral
solvents. Irradiation of H with subsequent observation of a nuclear
3
Overhauser effect (NOE) at H and H establishes that the substituents
1
4
at C-2, C-4 and C-5 are on the same face of the oxazolidine ring
confirming the relative anti-stereochemistry for the aldol process.
However this study provided no details as to the absolute
stereochemistry of these asymetric centers.
The aldol product 18 was converted to the corresponding amino diol
Scheme 3
9,15
which was examined by single crystal X-ray analysis.
The two
contiguous asymmetric centers were found to be R in configuration,
relative to the known asymmetric center (R) contained in the phenyl
glycinol residue, thus confirming the anti-stereochemistry for the aldol
reaction.

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SYNLETT
The aldol product 15 was converted to the corresponding amino acid via
a three step procedure. The optical rotation determined for this acid
N.; Cao, J. J. Am. Chem. Soc. 1991, 113, 6976-6981. c) El
Hadrami, M.; Lavergne, J.-P.; Viallefont, Ph.; Chiaroni, A.; Riche,
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d) Kanemasa, S.; Mori, T.; Tatsukawa, A. Tetrahedron Lett. 1993
34, 8293-8296.
15
compared favorably with the data reported by Kanemasa et al for the
4d,15
enantiomerically pure amino acid.
A re (enolate)/si (aldehyde) combination yields the observed aldol
products 14-18. We believe the enolate/aldehyde complex adopts a
configuration that would minimize the non-bonded interactions between
5.
Recent examples: a) Porter, N. A.; Rosenstein, I. J.; Breyer, R. A.;
Bruhnke, J. D.; Wu, W-X.; McPhail, A. T. J. Am. Chem. Soc.
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the large bulky residues and this would result in the pre-aldol complex
16,17,18
given in Figure 3.
Studies are now ongoing to determine the
steric requirements of the chiral auxiliary with regard to stereochemical
control of the aldol process.
6.
7.
Compound 2 was prepared by the reaction of (R)-(-)-2-
phenylglycinol and t-butyl bromoacetate. A manuscript describing
the preparation of 2 and 7a has been submitted: Iwanowicz, E. J.;
Smith, K. Synth. Commun.
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Arseniyadis, S.; Huang, P. Q.; Morellet, N.; Beloeil, J-C.; Husson,
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In conclusion, as part of our effort to prepare potent novel inhibitors of
thrombin catalytic activity, we have developed an easily prepared chiral
glycine equivalent. The lithium enolate derived from this ester reacts
with a variety of aldehydes in an enantio- and diastereoselective manner
to afford aldol products of erythro stereochemistry. In addition, we have
demonstrated that these adducts are easily converted to the
corresponding amino acids under mild conditions.
Fractional atomic coordinates have been deposited with the
Cambridge Crystallographic Datacenter.
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References and Notes
1.
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S. M. J. Med. Chem.. 1994, 37, 2122-2124, b)Tabernero, L.;
Chang, C. Y.; Ohringer, S.; Lau, W.; Iwanowicz, E. J.; Han, W-C.;
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E. J. Bioorganic and Medicinal Chemistry 1995, 3, 1039-1048.
12. Value calculated from Æ G = -RTlnK at 298 K.
1
o
13. Determined by H NMR in CD COCD at 50 C.
3
3
14. A 1.0 M solution of LDA in THF was used that contains 0.4 M
hexanes. The aldol reactions were quenched with saturated
NaHCO , extracted with ethyl acetate and dried over NaSO .
3
4
15) Degradation sequences for 15 and 18.
2.
3.
Williams, R. M. The Synthesis of Optically Active α-Amino Acids.
Pergamon Press: Oxford, 1989.
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2
2
2
c) anhydrous HF at 0oC, 15min. d) Dowex-1.
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4.
Enantioselective: a) Reno, D. S.; Lotz, B. T.; Miller, M. J.
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