Scheme 1
Figure 1. Structures of γ and R amino acid residues.
γ-amino acid building blocks with diverse conformational
constraints.
Here we describe asymmetric synthetic routes to γ-amino
acids with a cyclohexyl constraint at the CRꢀCβ bond
(ζ torsion angle). Michael addition of nitromethane to
cyclohexene-1-carboxaldehyde, facilitated via organocataly-
sis, provides access to protected derivatives of the cis and
trans γ-amino acid diastereomers, each in highly enantioen-
riched form.8 Ultimately, this route enables us to incorporate
γ residues of types II and III into R/γ-peptides. The cis
residue (II) is shown to support helical secondary structure.
Our γ-amino acid synthesis efforts were motivated by
results from Hayashi et al.9 and Wang et al.;10 these groups
simultaneously reported that pyrrolidine A catalyzes a
highly enantioselective Michael addition of nitromethane
to β-substituted propenal derivatives. Use of benzoic acid
as a cocatalyst proved to be necessary for high yields, and
simple alcohols were superior as reaction media to non-
polar or polar aprotic solvents. Most of the reported
examples involved β-aryl propenals as the Michael accep-
tors; propenal derivatives bearing bulkier β-alkyl substi-
tuents required longer reaction times.9 It was unclear from
these precedents whether cyclohexene-1-carboxaldehyde
would be an effective Michael acceptor, since the enal unit
bears both β-alkyl and R-alkyl substituents, which could
sterically hinder the desired reactivity.
Reaction of nitromethane and cyclohexene-1-carboxal-
dehyde (3:1 ratio) in the presence of 20 mol % Aand 10 mol %
benzoic acid provided a pair of isomeric γ-nitro alde-
hyde products in an ∼4.5:1 ratio, based on NMR analysis
(Scheme 1). The total yield was 90%. These aldehydes were
immediately reduced to the corresponding trans and cis
γ-nitro alcohols 1t and 1c; HPLC analysis indicated that
each diastereomer was generated in >95% ee. Reduction
was employed to avoid epimerization adjacent to the
aldehyde group. The catalytic mechanism underlying the
Michael addition presumably involves formation of an
iminium ion via condensation of the starting aldehyde and A.
Diastereomers 1t and 1c were difficult to separate on a
preparative scale, so the mixture of these δ-nitro alcohols
was treated with H2Cr2O7 in acetone, which quantitatively
generated the corresponding γ-nitro carboxylic acids 2t
and 2c. These diastereomers could be separated by chro-
matography and crystallization (major isomer 2t is a white
solid, while 2c is an oil). The absolute configuration of 2t
was established as (R,R) via the crystal structure of
L-phenylalanine/γ-dipeptide derivative 4 (Figure 2). We
observed that the minor γ-nitro aldehyde stereoisomer
generated by the Michael addition could be converted to
themajor γ-nitro aldehyde isomerbytreatment withDBU,
which suggests that γ-nitro carboxylic acid 2c has the
S configuration at the ring carbon bearing the carboxyl
group. This deduction was confirmed by oligomer crystal
structures discussed below.
(4) (a) Raguse, T. L.; Lai, J. R.; Gellman, S. H. J. Am. Chem. Soc.
2003, 125, 5592. (b) Schmitt, M. A.; Choi, S. H.; Guzei, I. A.; Gellman,
S. H. J. Am. Chem. Soc. 2005, 127, 13130. (c) Horne, W. S.; Gellman,
S. H. Acc. Chem. Res. 2008, 41, 1399. (d) Horne, W. S.; Johnson, L. M.;
Ketas, T. J.; Klasse, P. J.; Lu, M.; Moore, J. P.; Gellman, S. H. Proc.
Natl. Acad. Sci. U.S.A. 2009, 106, 14751. (e) Price, J. L.; Hadley, E. B.;
Steinkruger, J. D.; Gellman, S. H. Angew. Chem., Int. Ed. 2010, 49, 368.
(5) Woll, M. G.; Lai, J. R.; Guzei, I. A.; Taylor, S. J. C.; Smith,
M. E. B.; Gellman, S. H. J. Am. Chem. Soc. 2001, 123, 11077.
(6) Qureshi, M. K. N.; Smith, M. Chem. Commun. 2006, 5006.
(7) (a) Guo, L.; Chi, Y.; Almeida, A. M.; Guzei, I. A.; Parker, B. K.;
Gellman, S. H. J. Am. Chem. Soc. 2009, 131, 16018. (b) Guo, L.;
Almeida, A. M.; Zhang, W.; Reidenbach, A. G.; Choi, S. H.; Guzei,
I. A.; Gellman, S. H. J. Am. Chem. Soc. 2010, 132, 7868. (c) Sawada, T.;
Gellman, S. H. J. Am. Chem. Soc. 2011, 133, 7336. (d) Guo, L.; Zhang,
W.; Reidenbach, A. G.; Giuliano, J. W.; Guzei, I. A.; Spencer, L. C.;
Gellman, S. H. Angew. Chem., Int. Ed. 2011, 50, 5843. (e) For an
altertnative synthesis of γ amino acids of type I, see: Nodes, W. J.; Nutt,
D. R.; Chippindale, A. M.; Cobb, A. J. A. J. Am. Chem. Soc. 2009, 131,
16016.
The high levels of enantiopurity generated for both
product diastereomers in the Michael addition allowed
us to evaluate the resulting γ-amino acids as foldamer
building blocks. Boc-protected γ-amino acids 3t and 3c
were readily prepared from γ-nitro acids 2t and 2c, respec-
tively. We prepared R/γ-peptides with 1:1 R/γ alterna-
tion, 5ꢀ8 (Figure 2), because computational studies by
Hofmann et al.3e and basic principles of conformational
analysis suggested that such systems might display discrete
(8) For racemic synthesis of γ-amino acids corresponding to residues
II and III, see: Johnson, M. R.; Gauuan, J. F.; Guo, C.; Guzzo, P. R.; Le,
V.-D.; Shenoy, R. A.; Hamby, J.; Roark, H.; Stier, M.; Mangette, J. E.
Synth. Commun. 2011, 41, 2769. For asymmetric synthesis of the
ꢀ
cyclobutane analogue of 3c, see: Andre, V.; Vidal, A.; Ollivier, J.; Robin,
S.; Aitken, D. J. Tetrahedron Lett. 2011, 52, 1253.
(9) Gotoh, H.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2007, 9, 5307.
(10) Zu, L.; Xie, H.; Li, H.; Wang, J.; Wang, W. Adv. Synth. Catal.
2007, 349, 2660.
Org. Lett., Vol. 14, No. 10, 2012
2583