Table 1. Acetylide Addition Route to L-Serine Amino Acid Analogs
a Key: (i) LDA (4 equiv), THF, DMPU, -50 °C, then E+ (4 equiv); (ii) LDA (3 equiv), THF, DMPU, -50 °C, then E+ (4 equiv) and warm to rt; (iii)
CuI, toluene, NEt3, 65 °C.
in 80% ee through a PLE-catalyzed enzymatic desymmetri-
zation of the corresponding diacetate, was recently developed
in this laboratory and utilized in the synthesis of constrained
analogues of the R-N-acetylgalactosaminyl serine glyco-
peptide substructure.8 Our goal was to recruit 1 as an
intermediate for the stereoselective preparation of a variety
of novel R-substituted serine analogues. Unfortunately,
neither compound 1 nor any other intermediates were
crystalline, so the ee could not be enhanced further.
The method bears notable advantages over previous ones.
First, the divergent method is flexible. The terminal alkyne
functional group in 1 is amenable to a variety of synthetic
transformations, which facilitates the propagation of diversity
at CR. Specifically, compounds 2 and 3, enantiomers
available from 1 by a benzylation-deacylation-silylation
or silylation-deacylation-benzylation sequence, respectively
(Scheme 1),8 can undergo acetylide additions to a variety of
electrophiles. Compound 4, also available from 1,8 is
amenable to palladium-catalyzed Sonogashira couplings9
with a variety of aryl halides. The orthogonal protecting
groups in 2-4 provide selective access to both D- and
L-amino acid configurations. Second, enantioselectivities are
consistent. Compounds 2-4 were previously shown to
maintain the enantiomeric ratio established in intermediate
1. Therefore, all amino acid products arising from these
intermediates would possess this ratio as well. This is
advantageous since the enantioselectivity of a desymmetri-
zation process is highly dependent on substrate structure.10
Finally, the strategy avoids problems associated with sub-
strate compatibility in the desymmetrization process. The
method provides access to compounds that may not be
directly available through an enzymatic desymmetrization.
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(6) Davis, F. A.; Zhang, Y.; Rao, A.; Zhang, Z. Tetrahedron 2001, 57,
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(7) Fukuyama, T.; Xu, L. J. Am. Chem. Soc. 1993, 115, 8449.
(8) Lane, J. W.; Halcomb, R. L. J. Org. Chem. 2003, 68, 1348.
(9) Hundertmark, T.; Littke, A. F.; Buchwald, S. L.; Fu, G. C. Org. Lett.
2000, 2, 1729 and references therein.
(10) (a) Wong, C.-H.; Whitesides, G. M. Enzymes in Synthetic Organic
Chemistry; Elsevier: New York, 1994. (b) Ohno, M.; Otsuka, M. In Organic
Reactions: Chiral Synthons by Ester Hydrolysis Catalyzed by Pig LiVer
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