A New Synthesis of α-Amino Acid Derivatives Employing Methyl Nitroacetate as a Versatile Glycine Template

Full text of DOI:10.1021/jo980477h

3528
J . Org. Chem. 1998, 63, 3528-3529
Ta ble 1. Kn oeven a gel Con d en sa tion s/Con ju ga te
Ad d ition sa
A New Syn th esis of r-Am in o Acid Der iva tives
Em p loyin g Meth yl Nitr oa ceta te a s a Ver sa tile
Glycin e Tem p la te
Richard S. Fornicola, Eric Oblinger, and
J ohn Montgomery*
Department of Chemistry, Wayne State University,
Detroit, Michigan 48202-3489
Received March 16, 1998
Non-natural R-amino acids are highly versatile building
blocks in the preparation of a variety of pharmaceutically
significant molecules.1,2 Applications include small molecule
drug discovery3 and the preparation of peptides constructed
of nonproteinogenic amino acids.4 For these applications,
considerable effort has been directed toward the develop-
ment of multicomponent syntheses of amino acids.5 Most
methods, such as the elegant solid-phase Ugi condensation
recently reported by Armstrong, involve diversity introduc-
tion largely at the carboxyl and amino termini of the amino
acid, with the R-carbon substituent itself being derived from
a single component.5a,b The recently reported method of
Petasis, involving Mannich condensations with organobo-
ronic acids, is an efficient example in which the R-carbon
substituent of an R-amino acid is derived from two compo-
nents.5c To provide rapid access to an increasingly diverse
range of unnatural amino acids, we have developed a direct
linear sequence in which the amino acid framework is
derived from a nitroacetate, and the R-carbon diversity is
derived from three widely available components: an alde-
hyde, an organozinc, and a reactive electrophile (eq 1). The
method provides very simple access to a broad spectrum of
highly functionalized nonnatural R-amino acids.
a
Reagents and Conditions: (i) TiCl4, N-methylmorpholine,
THF, 0-25 °C; (ii) R2Li or R2MgBr, ZnCl2, THF, 0-25 °C.
catalysis is required in organozinc conjugate additions to the
highly electrophilic unsaturated nitroacetates (Table 1).7 In
all cases examined, the uncatalyzed conjugate additions
proceeded in good to excellent yield at 0 °C in THF to give
a 1:1 mixture of diastereomers. To our knowledge, this
report constitutes the first examples of conjugate additions
of unstabilized carbon nucleophiles with unsaturated ni-
troacetates.8
A variety of methods for quaternization of the R-position
of the functionalized nitroacetates are possible. In an
important early study by Bergbreiter and Wong, a number
of procedures for alkylation of R-methyl nitroacetates were
developed;9 however, functionally elaborate R-alkyl nitroac-
etates were not available at the time of their study.
Representative alkylation procedures that we examined
include palladium-catalyzed allylic alkylations (eq 2),10
phosphine-promoted Michael additions to acrylates and
Highly electrophilic R,â-unsaturated nitroacetates are
readily assembled by the Lehnert modification of the Kno-
evenagel condensation employing TiCl4 in the presence of
N-methylmorpholine in THF (Table 1).6 Aromatic and
aliphatic aldehydes were tolerated in the sequence in
moderate to good yield. The unsaturated nitroacetates were
then directly functionalized with transmetalation-derived
organozincs in THF (prepared in situ from a 1.5:1 ratio of
organolithiums or Grignard reagents and zinc chloride). No
(1) (a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Williams, R. M.
Synthesis of Optically-Active R-Amino Acids; Pergamon Press: Oxford, 1989.
(2) For an overview of heterocycle syntheses employing proteinogenic
amino acids, see: Sardina, F. J .; Rapoport, H. Chem. Rev. 1996, 96, 1825.
(3) For representative examples, see: (a) Ellman, J . A. Acc. Chem. Res.
1996, 29, 132. (b) Gordon, E. M.; Gallop, M. A.; Patel, D. V. Acc. Chem.
Res. 1996, 29, 144. (c) Bolton, G. L.; Hodges, J . C.; Rubin, J . R. Tetrahedron
1997, 53, 6611. (d) Szardenings, A. K.; Burkoth, T. S.; Lu, H. H.; Tien, D.
W.; Campbell, D. A. Tetrahedron 1997, 53, 6573.
(4) See refs 1 and 2 of the following manuscript: Myers, A. G.; Gleason,
J . L.; Yoon, T.; Kung, D. W. J . Am. Chem. Soc. 1997, 119, 656.
(5) (a) Armstrong, R. W. Acc. Chem. Res. 1996, 29, 123. (b) Tempest, P.
A.; Brown, S. D.; Armstrong, R. W. Angew. Chem., Int. Ed. Engl. 1996, 35,
640. (c) Petasis, N. A.; Zavialov, I. A. J . Am. Chem. Soc. 1997, 119, 445.
(6) (a) Lehnert, W. Tetrahedron 1972, 28, 663. (b) Dauzonne, D.; Royer,
R. Synthesis 1987, 399.
(7) For other examples of uncatalyzed organozinc conjugate additions,
see: Reddy, C. K.; Devasagayaraj, A.; Knochel, P. Tetrahedron Lett. 1996,
37, 4495.
(8) For additions of stabilized nucleophiles to unsaturated nitroacetates,
see: (a) Rodriguez, R.; Diez, A.; Rubiralta, M. Heterocycles 1996, 43, 513.
(b) Dornow, V. A.; Menzel, H. Liebigs Ann. Chem. 1954, 588, 40. (c) Somei,
M.; Tokutake, S.; Kaneko, C. Chem. Pharm. Bull. 1983, 31, 2153.
(9) Lalonde, J . J .; Bergbreiter, D. E.; Wong, C.-H. J . Org. Chem. 1988,
53, 2323.
(10) Ferroud, D.; Genet, J . P.; Muzart, J . Tetrahedron Lett. 1984, 25,
4379.
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Published on Web 05/12/1998

Communications
J . Org. Chem., Vol. 63, No. 11, 1998 3529
enones (eq 3),11 and arylations employing triphenylbismuth
dichloride (eq 4).12 Generally, diastereomeric ratios in the
substrates 9a and 11 due to overreduction and product
decomposition. In these cases, reduction with Sn0 or Zn0 in
AcOH was particularly effective with more desirable chemose-
lectivities than with catalytic hydrogenation.14 For instance,
the alkene of 12 and benzylic amine of 13 are unaffected in
the tin or zinc-based reductions (eq 5). The nitro reduction
products were directly derivatized with acetyl chloride and
pyridine in dichloromethane prior to isolation.
In summary, a concise method for the preparation of
structurally diverse R-amino acids has been developed by a
linear sequence involving Knoevenagel condensation, orga-
nozinc conjugate addition, and nitroacetate R-alkylation.15
The method offers significant advantages over most alterna-
tive procedures in terms of efficiency, simplicity, and poten-
tial for diversity generation. Future efforts will focus on
further refinements of the scope and diastereoselectivity of
the methodology, enantioselective applications, and solid-
and solution-phase combinatorial applications in the prepa-
ration of various heterocyclic structures.
Ack n ow led gm en t. Parke-Davis Pharmaceutical Re-
search and the National Institutes of Health are acknowl-
edged for support of this research. J .M. acknowledges
receipt of a New Faculty Award from 3M Pharmaceuticals,
a CAREER Award from the National Science Foundation,
and a Camille Dreyfus Teacher-Scholar Award.
range of 1:1 or 1:2 were observed. However, we did observe
in the case of the arylation procedure that base structure
displayed a dramatic effect on the diastereoselectivity of the
process. Tetramethylguanidine (TMG), which was originally
employed by Bergbreiter and Wong,9 afforded quite low
diastereoselectivities in arylations of nitroacetates bearing
chirality at the â-position. However, beginning with a 1:1
ratio of diastereomers of compound 6a , arylation with
diazabicycloundecene (DBU) as the base afforded compound
11 with a diastereomeric ratio of 11:1,13 suggesting that a
more extensive examination of base structure may improve
diastereoselectivities in other variants.
Su p p or tin g In for m a tion Ava ila ble: Experimental proce-
dures and 1H NMR spectra for all reported compounds (34 pages).
J O980477H
(14) (a) For a zinc-based procedure, see: Battersby, A. R.; Baker, M. G.;
Broadbent, H. A.; Fookes, J . R.; Leeper, F. J . J . Chem. Soc., Perkin Trans.
1 1987, 2027. (b) For a tin-based reduction procedure, see: Baldwin, J . E.;
Haber, S. B.; Hoskins, C.; Kruse, L. I. J . Org. Chem. 1977, 42, 1239.
(15) For representative methods for preparing R-amino acids that rely
on conjugate addition chemistry, see: (a) Cardellicchio, C.; Fiandanese, V.;
Marchese, G.; Naso, F.; Ronzini, L. Tetrahedron Lett. 1985, 26, 4387. (b)
Lander, P. A.; Hegedus, L. S. J . Am. Chem. Soc. 1994, 116, 8126. (c) Han,
Y.; Qiu, W.; Cai, C.; Hruby, V. J . Tetrahedron Lett. 1997, 5135. (d) Ring-
openings of â-lactones also allow â-carbon functionalization by nucleophiles.
Arnold, L. D.; May, R. G.; Vederas, J . C. J . Am. Chem. Soc. 1988, 110, 2237.
(e) Ring-openings of aziridines also allow â-carbon functionalization by
nucleophiles. Baldwin, J . E.; Spivey, A. C.; Schofield, C. J .; Sweeney, J . B.
Tetrahedron 1993, 49, 6309. (f) Church, N. J .; Young, D. W. Tetrahedron
Lett. 1995, 36, 151.
The nitro functionality of nitroacetates may be effectively
reduced to the primary amine by a variety of catalytic
hydrogenation methods. However, yields were low with
(11) White, D. A.; Baizer, M. M. Tetrahedron Lett. 1973, 3597.
(12) Barton, D. H. R.; Finet, J . P. Pure Appl. Chem. 1987, 59, 937.
(13) The relative stereochemistry of the major isomer of 11 was not yet
determined.