New preorganized γ-amino acids as foldamer building blocks

Article abstract of DOI:10.1021/ol3008815

An asymmetric synthesis of two new diastereomeric γ-amino acids is described. Both molecules contain a cyclohexyl ring to limit conformational flexibility about the C_α-C_β bond; they differ in having cis vs trans stereochemistry on th

Full text of DOI:10.1021/ol3008815

ORGANIC
LETTERS
2012
Vol. 14, No. 10
2582–2585
New Preorganized γ-Amino Acids as
Foldamer Building Blocks
Li Guo,† Weicheng Zhang, Ilia A. Guzei, Lara C. Spencer, and Samuel H. Gellman*
Department of Chemistry, University of Wisconsin, Madison, Wisconsin 53706,
United States
gellman@chem.wisc.edu
Received April 6, 2012
ABSTRACT
An asymmetric synthesis of two new diastereomeric γ-amino acids is described. Both molecules contain a cyclohexyl ring to limit conformational
flexibility about the CrꢀCβ bond; they differ in having cis vs trans stereochemistry on the ring. Residues derived from the cis γ isomer are shown
to support helical secondary structures in r/γ-peptide oligomers.
Peptidic oligomers that contain γ-amino acid residues
have become increasingly popular as subjects for foldamer
research.1ꢀ3 γ-Amino acid building blocks in which a ring
constrains at least one backbone bond are of particular
interest because cyclic constraints have proven to be useful
in stabilizing specific secondary structures among folda-
mers that contain β-amino acid residues.4 We previously
found that a five-membered ring incorporated via CR and
Cγ promotes a γ-peptide sheet secondary structure,5 and
comparable observations have been reported by Smith et al.
for γ residues in which a cyclopropyl ring links CR and
Cβ.6 More recently we have shown that a γ residue of
type I (Figure 1), with a cis cyclohexyl constraint at the
CβꢀCγ bond (θ torsion angle), supports helical secondary
structures among γ-, R/γ-, β/γ-, and R/β/γ-peptides.7
Identification of additional γ-containing foldamers will
require the development of a methodology to prepare new
(3) Selected examples with γ residues in heterogeneous backbones:
(a) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.; Schreiber, S. L.
J. Am. Chem. Soc. 1992, 114, 6568. (b) Karle, I. L.; Pramanik, A.;
Banerjee, A.; Bhattacharjya, S.; Balaram, P. J. Am. Chem. Soc. 1997,
119, 9087. (c) Ananda, K.; Vasudev, P. G.; Sengupta, A.; Raja, K. M. P.;
Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2005, 127, 16668.
(d) Qureshi, M. K. N.; Smith, M. Chem. Commun. 2006, 5006.
(e) Baldauf, C.; Gunther, R.; Hofmann, H. J. J. Org. Chem. 2006, 71,
1200. (f) Sharma, G. V. M.; Jadhav, V. B.; Ramakrishna, K. V. S.;
Narsimulu, K.; Subash, V.; Kunwar, A. C. J. Am. Chem. Soc. 2006,
128, 14657. (g) Baruah, P. K.; Sreedevi, N. K.; Gonnade, R.;
Ravindranathan, S.; Damodaran, K.; Hofmann, H. J.; Sanjayan, G. J.
J. Org. Chem. 2007, 72, 636. (h) Vasudev, P. G.; Ananda, K.; Chatterjee,
S.; Aravinda, S.; Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2007,
129, 4039. (i) Chatterjee, S.; Vasudev, P. G.; Raghothama, S.;
Ramakrishnan, C.; Shamala, N.; Balaram, P. J. Am. Chem. Soc. 2009,
† Current address: The Dow Chemical Company, 1712 Building, Office
21-5, Midland, Michigan 48674, United States.
(1) Recent reviews: (a) Guichard, G.; Huc, I. Chem. Commun. 2011,
47, 5933. (b) Hecht, S., Huc, I., Eds. Foldamers: Structure, Properties and
Applications; Wiley-VCH: Weinheim, Germany, 2007. (c) Seebach, D.;
Beck, A. K.; Bierbaum, D. J. Chem. Biodiversity 2004, 1, 1111.
(2) Selected γ-peptide examples: (a) Hanessian, S.; Luo, X.; Schaum,
R.; Michnick, S. J. Am. Chem. Soc. 1998, 120, 8569. (b) Hintermann, T.;
Gademann, K.; Jaun, B.; Seebach, D. Helv. Chim. Acta 1998, 81, 983.
(c) Seebach, D.; Brenner, M.; Rueping, M.; Schweizer, B.; Jaun, B.
Chem. Commun. 2001, 207. (d) Baldauf, C.; Gunther, R.; Hofmann, H. J.
Helv. Chim. Acta 2003, 86, 2573. (e) Farrera-Sinfreu, J.; Zaccaro, L.;
Vidal, D.; Salvatella, X.; Giralt, E.; Pons, M.; Albericio, F.; Royo, M. A.
J. Am. Chem. Soc. 2004, 126, 6048. (f) Claudon, P.; Violette, A.; Lamour,
K.; Decossas, M.; Fournel, S.; Heurtault, B.; Godet, J.; Mely, Y.;
Jamart-Gregoire, B.; Averlant-Petit, M.-C.; Briand, J.-P.; Duportail,
G.; Monteil, H.; Guichard, G. Angew. Chem., Int. Ed. 2010, 49, 333.
€
€
131, 5956. (j) Araghi, R. R.; Jackel, C.; Colfen, H.; Salwiczek, M.; Vokel,
A.; Wagner, S. C.; Wieczorek, S.; Baldauf, C.; Koksch, B. ChemBio-
Chem 2010, 11, 335. (k) Araghi, R. R.; Baldauf, C.; Gerling, U. I. M.;
Cadicamo, C. D.; Koksch, B. Amino Acids 2011, 41, 733.
r
10.1021/ol3008815
Published on Web 05/08/2012
2012 American Chemical Society

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

Figure 2. Structures of R/γ peptides 4ꢀ8 (arrows indicate
H-bonds in the crystal structures 5 and 6).
Figure 3. Crystal structures of 5 (left), 6 (right): (top) views
perpendicular to helical axes; (bottom) views along the helical
axes.
folding propensities. Residues derived from γ-amino acid
3c (type II; as in R/γ-peptides 5 and 6) are expected to
display gaucheþ torsion angles about the θ and ζ backbone
bonds. The computational studies predict that a local gþ,
gþ torsion angle sequence should promote formation of
an R/γ-peptide helix that contains CdO(i)--H-N(iþ3)
H-bonds. This “12-helix” (so-named because the H-bonds
occur in 12-atom rings) has previously been documented
among R/γ-peptides.3i,7a In contrast, residues derived from
γ-amino acid 3t (type III; as in R/γ-peptides 7 and 8) are
expected to display an anti torsion angle for θ and a
gaucheꢀ torsion angle for ζ. The local a,gꢀ torsion angle
sequence, which is observed for the single γ residue of type
III in dipeptide 4, is predicted to be consistent with
an R/γ-peptide helix that contains CdO(i)--H-N(iꢀ4)
H-bonds.3e This helix has never been documented experi-
mentally. It should be noted that the absolute configura-
tion is R at Cβ of each γ residue in R/γ-peptides 4ꢀ7,
because all of these residues derive from Michael reactions
catalyzed by A (S configuration). On the other hand,
L-R-amino acid residues were used for 5 and 6, but D-R-
amino acid residues were used for 7 and 8, based on the
computational predictions of Hofmann et al.3e
CdO(i)--H-N(iþ3) pattern; however, the other H-bond
has the pattern CdO(i)--H-N(iꢀ1), a 10-membered ring
interaction. This secondary structure has been designated
the 12/10-helix; the different orientations of the 12- and
10-membered ring H-bonds cause this helix to have
only a small net dipole. The 12/10-helix has previously
been proposed by Sharma, Kunwar et al. based on NMR
analysis of R/γ-peptides containing acyclic γ residues.3f
Hexamer 6 formed the expected 12-helix conformation
in the solid state; all four possible CdO(i)--H-N(iþ3)
H-bonds were formed. The crystal contains three indepen-
dent molecules, but all three conformations are very
similar to one another. Balaram et al. have previously
proposed a 12-helical conformation for R/γ-peptides in
which the γ residues are derived from gabapentin (spiro
cyclohexyl ring at Cβ), based on NMR data.3i We have
recently provided crystallographic evidence for the 12-helix
in R/γ-peptides that contain γ residues with a cis cyclohexyl
constraint on the CβꢀCγ bond.7a
High-quality crystals of R/γ-peptides 5 and 6 were
grown by slow evaporation of chloroform/heptanes/ether
or chloroform/heptanes solutions, respectively, and the
structures of these oligomers were solved based on X-ray
diffraction data. Unfortunately, we were unable to crystal-
lize either 7 or 8, despite extensive effort. Thus, at present
we haveno insight on the secondary structural propensities
of these R/γ-peptides containing γ residues with the trans
cyclohexyl constraint (type III).
The solid state conformations of R/γ-peptides 5 and 6
revealed two different helical secondary structures (Figure 3),
both of which were first proposed by Hofmann et al.
based on computational studies.3e Tetramer 5 forms
two intramolecular H-bonds. The H-bond involving
the N-terminal Boc carbonyl conforms to the expected
Table 1 compares backbone torsion angles for the R and
γ residues observed in crystal structures of R/γ-peptides
5 and6, which contain cis γresidues(II), and the analogous
data for the lone trans γ residue (III) in dimer 4. For
comparison, backbone torsion angles are given for a
previously reported 1:1 R/γ-peptide crystal structure that
contains γ residues of type I;7a this example contains the
(R,R,R)-γ residueand D-alanine. Each ofthe γ residues in6
displays a gþ,gþ local conformation about the CRꢀCβ (ζ)
and CβꢀCγ (θ) bonds, and ψ and φ torsion angles near
ꢀ120°, with a somewhat wider distribution for the latter
torsion angle. In contrast, the previously described γ
residues of type I display gꢀ,gꢀ local conformations. For
both type I and type II γ residues, the crystal structures
are consistent with the CdO(i)--H-N(iþ3) H-bonded
2584
Org. Lett., Vol. 14, No. 10, 2012

Table 1. Backbone Torsion Angles (deg) for R/γ-Peptides
Table 2. Average Parameters for i, iþ3 H-Bonded Helices
helix res/turn rise/turn rise/res radius
˚
˚
˚
backbone
type
n
p (A)
d (A)
r (A)
1:1 R/γ-peptides
(γ-residues II)
1:1 R/γ-peptides
(γ-residues I)
R-peptides
12
2.9
5.4
6.1
5.8
1.9
2.0
1.8
2.5
2.5
2.0
12
3.0
3.2
310
for two other helices that contain CdO(i)--H-N(iþ3)
hydrogen bonds: the 1:1 R/γ-peptide 12-helix containing
γ residues of type I and the R-peptide 310-helix. The
parameters for all three helices are quite similar, although
it is intriguing that the 12-helix containing γ residues of
type II has a somewhat smaller rise-per-turn than the
12-helix containing γ residues of type I.
We have developed a short, asymmetric route to γ-
amino acids that feature a cyclohexyl constraint on the
CRꢀCβ bond. Both cis and trans diastereomers can be
produced in highly enantiopure forms. Preliminary eva-
luation of the foldamer potential of these γ-amino acids
was carried out via synthesis and examination of oligomers
with a 1:1 R/γ backbone. Crystal structures revealed a
strong helix-forming propensity for the cis γ residue, but
no insights could be gleaned regarding the trans γ residue.
Further use of the cis γ residues for fundamental foldamer
research would be facilitated by improvements in the
synthetic route, since the required protected γ-amino acid
is derivedfrom the minordiastereomer produced in thekey
Michael addition. We anticipate that incorporation of the
new γ residues into other types of heterogeneous peptidic
backbones will give rise to new types of foldamers.
helical conformation for 1:1 R/γ-peptides predicted by
Hofmann et al.3f The R residue ψ torsion angles in our
crystal structures (near ꢀ30° for L-Ala) are similar to
those observed for a canonical 310-helix, which shares the
CdO(i)--H-N(iþ3) H-bonding pattern.
Acknowledgment. This research was supported by the
NSF (CHE-0848847). NMR spectrometers were purchased
with partial support from the NIH and NSF.
Average parameters for the CdO(i)--H-N(iþ3) H-bonded
helices formed by 1:1 R/γ-peptides were derived from
the structural data as described previously11 and are
presented in Table 2. Each helical parameter was calcu-
lated from the R-carbons of four consecutive residues
(for γ residues, Cβ was used as an imaginary R-carbon).
Nonhelical residues at C-termini were excluded from these
calculations. Table 2 includes, for comparison, parameters
Supporting Information Available. Full experimental
details, characterization data for all compounds includ-
ing 1H and 13C NMR and crystallographic data for 5 and
6 (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org. The authors declare no
competing financial interest.
(11) (a) Barlow, D. J; Thorton, J. M. J. Mol. Biol. 1988, 5, 601.
(b) Sugeta, H.; Miyazawa, T. Biopolymers 1967, 5, 673. (c) Kahn, P. C.
Comput. Chem. 1989, 13, 185.
The authors declare no competing financial interest.
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