Three-component synthesis of α,β-cyclopropyl-γ-amino acids

Article abstract of DOI:10.1021/ol0501525

(Chemical Equation Presented) The multicomponent coupling of alkenylzirconocenes with N-diphenylphosphinoyl imines provides rapid access to functionalized C-cyclopropylalkylamides which have been readily transformed into α,β-cyclopropyl-γ-amino acids. The

Full text of DOI:10.1021/ol0501525

ORGANIC
LETTERS
2005
Vol. 7, No. 6
1137-1140
Three-Component Synthesis of
-Cyclopropyl- -Amino Acids
r
,
â
γ
Peter Wipf* and Corey R. J. Stephenson
Department of Chemistry, UniVersity of Pittsburgh, Pittsburgh, PennsylVania 15260
pwipf+@pitt.edu
Received January 22, 2005
ABSTRACT
The multicomponent coupling of alkenylzirconocenes with N-diphenylphosphinoyl imines provides rapid access to functionalized
C-cyclopropylalkylamides which have been readily transformed into
in ca. 8 steps from commercially available alkynes.
r,â-cyclopropyl-γ-amino acids. These novel scaffolds are thus accessible
The use of modified amino acids in peptide strands allows
a greater control over chemical and conformational properties
of oligopeptides.1 The motivation for the development of
novel peptidomimetics stems from the high affinity and
selectivity of natural peptides for receptors and enzyme active
sites; the failure of peptides as drug candidates is a function
of their polarity and lack of stability to metabolic processes
peptidases. Modification of the peptide backbone offers the
promise of increased stability toward peptidases with the
potential to maintain biological activity. For example, (E)-
alkene isosteres can be used as geometric2 and electronic2f
replacements of the amide bond; however, alkenes are also
susceptible to a number of degradation pathways such as
isomerization and oxidation and in some cases even react
during chain elongation.2b
We have recently described new methodologies for the
preparation of allylic-,3 homoallylic-,4 C-cyclopropyl-
alkyl-3a,b and C,C-dicyclopropylalkylamides5 using multi-
component condensation reactions initiated by the dimeth-
ylzinc-mediated addition of alkenylzirconocenes to N-di-
phenylphosphinoyl imines. We were intrigued by the pos-
sibility of applying the methodology for C-cyclopropyl-
alkylamide synthesis to the preparation of a novel family of
backbone cyclopropane-extended amino acids (Figure 1).6,7
(1) (a) Cheng, R. P.; Gellman, S. H.; DeGrado, W. F. Chem. ReV. 2001,
101, 3219. (b) Hill, D. J.; Mio, M. J.; Prince, R. B.; Hughes, T. S.; Moore,
J. S. Chem ReV. 2001, 101, 3893.
(2) (a) Liang, G.-B.; Dado, G. P.; Gellman, S. H. J. Am. Chem. Soc.
1991, 113, 3994. (b) Hagihara, M.; Anthony, N. J.; Stout, T. J.; Clardy, J.;
Schreiber, S. L. J. Am. Chem. Soc. 1992, 114, 6568. (c) Liang, G.-B.;
Desper, J. M.; Gellman, S. H. J. Am. Chem. Soc. 1993, 115, 925. (d)
Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am. Chem. Soc. 1995, 117,
3280. (e) Wipf, P.; Henninger, T. C. J. Org. Chem. 1997, 62, 1586. (f)
Wipf, P.; Henninger, T. C.; Geib, S. J. J. Org. Chem. 1998, 63, 6088. (g)
Gardner, R. R.; Liang, G.-B.; Gellman, S. H. J. Am. Chem. Soc. 1999, 121,
1806. (h) Wipf, P.; Xiao, J. Org. Lett. 2005, 7, 103.
Figure 1. Backbone cyclopropane-extended amino acid residues.
The phenylglycine derivatives ∆Phg, âMe∆Phg, and
RMe∆Phg were chosen as representative examples that could
10.1021/ol0501525 CCC: $30.25
© 2005 American Chemical Society
Published on Web 02/18/2005

be readily prepared by multicomponent ZrfZn methodol-
ogy.8 These compounds should also exhibit the structural
rigidity that is paramount to the conformational mimicry of
the peptide strand.
group (HCl, MeOH) and precipitation with Et2O provided
the hydrochloride salts 8a and 8b. N-Protection (Cbz-Cl,
NaHCO3) led to the fully protected amino acids 9a and 9b
(Scheme 2).
Our initial approach to R,â-cyclopropyl-γ-amino acids
failed as the conversion of propargylic ether 1 stopped at
the allylic amine 2 (Scheme 1). Only traces of C-cycloprop-
ylalkyl amide product could be isolated after prolonged
reaction times.
Scheme 2. Synthesis of Cbz-dl-∆Phg-OMe and
Cbz-dl-∆Me∆Phg-OMe
Scheme 1. Propargyl Ether Approach
In contrast, the TBDPS-protected C-cyclopropylalkyl-
amides 4a and 4b were readily prepared on gram scale from
homopropargylic ethers 3a and 3b, respectively. Desilylation
(TBAF/AcOH) afforded 76% and 96% of alcohols 5a and
5b. Unfortunately, after conversion to the intermediate
selenide, oxidation and elimination9 afforded the desired
vinyl cyclopropanes 6a and 6b in poor yields. However, a
modification developed by Reich10 which involved oxidation
of the intermediate selenide with m-CPBA at low temperature
(-40 °C) followed by elimination in the presence of 5 equiv
of diisopropylamine afforded these alkenes in excellent yields
(82-88%, two steps). Ozonolysis in the presence of basic
methanol11 followed by N-deprotection of the phosphinoyl
R
The synthesis of the Me∆Phg residue necessitated the
combination of the water-accelerated methylalumination12
reaction with the Simmons-Smith cyclopropanation (Scheme
3).13 Carboalumination of 3a (Me3Al, Cp2ZrCl2, H2O)
followed by microwave-accelerated addition to diphenylphos-
phinoyl imine14 afforded the allylic amide 10. Treatment of
10 with Zn(CH2I)2‚DME complex15 afforded the desired
C-cyclopropylalkylamide 4c in excellent yield and dia-
stereoselectivity (>19:1 by 1H NMR). Desilylation (TBAF,
AcOH) followed by modified Grieco elimination led to 6c
which was transformed into the Cbz-protected 9c after
ozonolysis and an N-protective group switch.
(3) (a) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am. Chem. Soc.
2001, 123, 5122. (b) Wipf, P.; Kendall, C.; Stephenson, C. R. J. J. Am.
Chem. Soc. 2003, 125, 761. (c) Wipf, P.; Stephenson, C. R. J. Org. Lett.
2003, 5, 2449. (d) Wipf, P.; Janjic, J.; Stephenson, C. R. J. Org. Biomol.
Chem. 2004, 2, 443.
(4) Wipf, P.; Kendall, C. Org. Lett. 2001, 3, 2773.
(5) Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem. Soc. 2003,
125, 14694.
(6) For reviews on the synthesis of cyclopropyl amino acids, see (a)
Stammer, C. H. Tetrahedron 1990, 46, 2231. (b) Burgess, K.; Ho, K.-K.;
Moye-Sherman, D. Synlett 1994, 575.
(7) For examples of the use of cyclopropane-containing amino acids as
peptide mimics, see: (a) Burgess, K.; Ho, K.-K.; Pal, B. J. Am. Chem.
Soc. 1995, 117, 3808. (b) Martin, S. F.; Dorsey, G. O.; Gane, T.; Hillier,
M. C.; Kessler, H.; Baur, M.; Matha, B.; Erickson, J. W.; Bhat, T. N.;
Munshi, S.; Gulnik, S. V.; Topol, I. A. J. Med. Chem. 1998, 41, 1581. (c)
North, M. J. Peptide Sci. 2000, 6, 301. (d) Martin, S. F.; Dwyer, M. P.;
Hartmann, B.; Knight, K. S. J. Org. Chem. 2000, 65, 1305. (e) Hillier, M.
C.; Davidson, J. P.; Martin, S. F. J. Org. Chem. 2001, 66, 1657. (f) Davidson,
J. P.; Lubman, O.; Rose, T.; Waksman, G.; Martin, S. F. J. Am. Chem.
Soc. 2002, 124, 205. (g) Reichelt, A.; Gaul, C.; Frey, R. R.; Kennedy, A.;
Martin, S. F. J. Org. Chem. 2002, 67, 4062. (h) Headley, A. D.; Ganesan,
R.; Nam, J. Biorg. Chem. 2003, 31, 99.
(8) We selected the ∆-prefix to indicate amino acid residues that have a
cyclopropane ring inserted into the backbone chain between carbonyl-C
and R-C.
(9) (a) Sharpless, K. B.; Young, M. W. J. Org. Chem. 1975, 40, 947.
(b) Grieco, P. A.; Gilman, S.; Nishizawa, M. J. Org. Chem. 1976, 41, 1485.
(c) Kutney, J. P.; Singh, A. K. Can. J. Chem. 1983, 61, 1111.
(10) (a) Reich, H. J.; Renga, J. M.; Reich, I. L. J. Am. Chem. Soc. 1975,
97, 5434. (b) Reich, H. J.; Wollowitz, S.; Trend, J. E.; Chow, F.;
Wendelborn, D. F. J. Org. Chem. 1978, 43, 1697.
To examine the structural features of these new building
blocks in dipeptide conjugates, we prepared enantiomerically
pure derivatives by resolution of amine salts (Scheme 4).16
Hydrogenolysis (H2, Pd/C, MeOH) of 9a and 9c followed
(12) (a) Wipf, P.; Lim, S. Angew. Chem., Int. Ed. Engl. 1993, 32, 1068.
(b) Wipf, P.; Ribe, S. Chem. Commun. 2001, 299.
(13) (a) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1958, 80, 5323.
(b) Simmons, H. E.; Smith, R. D. J. Am. Chem. Soc. 1959, 81, 4256. (c)
Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1. (d) Lebel, H.;
Marcoux, J.-F.; Molinaro, C.; Charette, A. B. Chem. ReV. 2003, 103, 977.
(14) For the diastereoselective addition of alkenylalanes to N-sulfin-
ylimines using conventional reaction conditions, see: Wipf, P.; Nunes, R.
L.; Ribe, S. HelV. Chim. Acta 2002, 85, 3478. Microwave reactions were
performed in sealed tubes in a Biotage Emrys Optimizer at 300 W.
(15) Charette, A. B.; Prescott, S.; Brochu, C. J. Org. Chem. 1995, 60,
1081.
(11) (a) Marshall, J. A.; Garofalo, A. W.; Sedrani, R. C. Synlett 1992,
643. (b) Marshall, J. A.; Garofalo, A. W. J. Org. Chem. 1993, 58, 3675.
1138
Org. Lett., Vol. 7, No. 6, 2005

Cl, NaHCO3) of the tartrate salts followed by saponification
(KOTMS,18 Et2O or NaOH, MeOH/THF for 20) and
coupling with L-Phe-OMe‚HCl (EDCI, DMAP, DIPEA or
BOP, DIPEA, DMF for 20, Scheme 5). HPLC analysis of
Scheme 3. Synthesis of Cbz-dl-∆Me∆Phg-OMe
Scheme 5. Coupling Reactions of R,â-cyclopropyl-γ-amino
Acids
by formation of the corresponding l-tartaric acid ammonium
salts and fractional crystallization17 afforded the diastereo-
Scheme 4. Resolution of ∆Phg and ∆Me∆Phg Residues
the crude reaction mixtures indicated an excellent dia-
stereomeric purity for these dipeptides. The absolute con-
figuration19 of the cyclopropyl residues 13 and 14 was based
on the X-ray structure analysis of the p-bromobenzamide
derivative 21, prepared from 13 (p-BrC6H4COCl, DMAP)
in good yield. The phenylalanine derivative 19 was crystal-
lized from EtOAc/hexanes, and X-ray analysis confirmed
the syn-stereochemistry of the C-cyclopropylalkylamide
obtained in the Simmons-Smith step and allowed an
unequivocal assignment of the absolute configuration of the
amino acid precursors 15 and 16.
The strong preference for the syn-diastereoisomer that was
observed in the conversion of 10 to 4c is opposite to our
previous results in which (E)-disubstituted alkenes afforded
the anti-diastereoisomer (>19:1) under analogous reaction
conditions.3b The preference for the anti-isomer in (E)-
disubstituted allylic amides was rationalized using a model
akin to that proposed for the cyclopropanation of allylic
ethers (23),20 where nonbonded interactions between the
olefin and the diphenylphosphinoyl substituent disfavor
attack from the A1,3-minimized conformation 22. With (E)-
trisubstituted alkenes, however, the 1,3-allylic strain appears
to override this interaction leading to the syn-diastereomer
via 22 (Figure 2).
Interestingly, 19 adopts an extended conformation in the
solid state, crystallizing as an antiparallel dimer (Figure 3).
merically pure salts 13-16. Subsequently, phenylalanine
derivatives 17-20 were prepared by N-Cbz protection (Cbz-
(17) The salts were recrystallized until their optical rotation was constant
(ca. 3 times).
(18) Laganis, E. D.; Chenard, B. L. Tetrahedron Lett. 1984, 25, 5831.
(19) Flack, H. D. Acta Crystallogr. 1983, A39, 876.
(20) Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845.
(16) (a) Jacques, J.; Collet, A.; Wilen, S. H. Enantiomers, Racemates
and Resolutions; Wiley-Interscience: New York, 1981. (b) Eliel, E. L.;
Wilen, S. H. Stereochemistry of Organic Compounds; Wiley-Interscience:
New York, 1994.
Org. Lett., Vol. 7, No. 6, 2005
1139

positioning of the two amide groups in the solid state of 19.
This secondary structure preference is similar to that observed
by Schreiber and co-workers2b during their studies of
vinylogous amino acids. The geometric homology between
naturally occurring vinylogous amino acids and novel
backbone cyclopropane-extended residues such as 15 bodes
well for the use of the latter building blocks in the design of
conformationally preorganized peptide mimetics. â-Sheets
sheets are important for protein-protein and protein-DNA
interactions, and templates that induce these extended
conformations are useful tools in medicinal and host-guest
chemistry.21
In summary, we have developed an efficient approach for
the preparation of novel R,â-cyclopropyl-γ-amino acids
utilizing the one-pot, three-component reaction of alkenyl-
zirconocenes, diiodomethane, and benzaldimines. These
backbone-modified building blocks are now accessible on
multigram scale in ca. 8 steps and 35-50% overall yield
from simple alkynes. As part of these synthetic studies, we
have developed a new sequential water-accelerated meth-
ylalumination-imine addition-Simmons-Smith cyclopro-
panation strategy that provides syn-C-cyclopropylalkyl-
amides. At least some cyclopropane substitution motifs
appear to allow a control of secondary structure features.
The dipeptide 19 adopts an extended, â-sheet conformation
in the solid state, most likely due to a minimization of allylic
strain type interactions. Further studies into the solution and
solid state conformations of oligopeptides derived from R,â-
cyclopropyl-γ-amino acids are currently underway in our
laboratories and will be reported in due course.
Figure 2. Proposed transition states for stereoselective cyclopro-
panations of allylic phosphinoylamides.
In fact, the dihedral angles about the backbone cyclopropane-
extended amino acid residue are all greater than 135°,
minimizing allylic strain throughout the carbon chain. The
Newman projection in Figure 3b highlights the antiperiplanar
Acknowledgment. This work has been supported by the
NIH P50-GM067082 program. The authors thank Dr. S. J.
Geib for X-ray structure analyses of compounds 19 and 21.
Supporting Information Available: Experimental pro-
cedures and spectral data for all new compounds, including
copies of 1H and 13C NMR for 4b,c, 5-10, and 13-21 and
crystal information files (CIF) for 19 and 21. This material
is available free of charge via the Internet at http://pubs.acs.org
OL0501525
(21) (a) Phillips, S. T.; Rezac, M.; Abel, U.; Kossenjans, M.; Bartlett,
P. A. J. Am. Chem. Soc. 2002, 124, 58. (b) Nowick, J. S. Acc. Chem. Res.
1999, 32, 287. (c) Smith, A. B., III; Guzman, M. C.; Sprengeler, P. A.;
Keenan, T. P.; Holcomb, R. C.; Wood, J. L.; Carroll, P. J.; Hirschmann, R.
J. Am. Chem. Soc. 1994, 116, 9947.
Figure 3. (a) Stereoview of the X-ray crystal structure of 19. (b)
Newman projection of the C(â)-C(γ) bond in 19.
1140
Org. Lett., Vol. 7, No. 6, 2005