Synthesis of cyclopropene α-amino acids via enantioselective desymmetrization

Article abstract of DOI:10.1021/ol060847l

The preparation of cyclopropene α-amino acids via the enantioselective desymmetrization of cyclopropene bis-carboxylic acid derivatives is described. The amino acids are stable to harsh reaction conditions, and a derivative has been incorporated into a tripeptide using conventional methods for peptide synthesis.

Full text of DOI:10.1021/ol060847l

ORGANIC
LETTERS
2006
Vol. 8, No. 14
2965-2968
Synthesis of Cyclopropene
Acids via Enantioselective
Desymmetrization
r-Amino
Fan Zhang and Joseph M. Fox*
Brown Laboratories, Department of Chemistry and Biochemistry,
UniVersity of Delaware, Newark, Delaware 19716
jmfox@udel.edu
Received April 7, 2006
ABSTRACT
The preparation of cyclopropene
r-amino acids via the enantioselective desymmetrization of cyclopropene bis-carboxylic acid derivatives is
described. The amino acids are stable to harsh reaction conditions, and a derivative has been incorporated into a tripeptide using conventional
methods for peptide synthesis.
Small ring analogues of amino acids allow peptide structures
to be tuned with exquisite precision because they provide
exact control over the orientation of side chains with a
minimal change to the remaining structure.1,2 Despite their
geometrical niche for aligning the side chains ∼90° relative
to the main chain, the chemistry of cyclopropene amino acids
is not well developed.3 In the only report on enantiomerically
enriched cyclopropene R-amino acids, Scho¨llkopf used his
elegant bis-lactim ether methodology to access several
cyclopropene analogues of phenylalanine.3a However, that
method has not been extended to other side chains, and
cyclopropene R-amino acids have never been incorporated
into peptides. We therefore considered a new method that
would make these valuable components more broadly
available.
Described herein is a concise and highly enantioselective
synthesis of cyclopropene R-amino acids (Scheme 1). The
key step is the desymmetrization of malonate-derived cy-
clopropene bis-carboxylic acids. Furthermore, it is demon-
strated that cyclopropene R-amino acids and their precursors
are stable in the presence of many harsh reagents (e.g., TFA,
ethanolic KOH) and can be incorporated into synthetic
peptides using conventional coupling strategies.
Chiral oxazolidinones are powerful tools for asymmetric
synthesis.4 In recent years, elegant studies from the labs of
Davies, Eames, and Fukuzawa have shown oxazolidinones
(1) (a) Salaun, J. Top. Curr. Chem. 2000, 207, 1. (b) Stammer, C. H.
Tetrahedron 1990, 46, 2231. (c) Gnad, F.; Reiser, O. Chem. ReV. 2003,
103, 1603.
(2) Lead examples of secondary structures that are stabilized by
cyclopropane R-amino acids: (a) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J.
Am. Chem. Soc. 1994, 116, 799. (b) Burgess, K.; Ho, K.-K.; Pettitt, B. M.
J. Am. Chem. Soc. 1995, 117, 54. (c) Burgess, K.; Ho, K.-K.; Pal, B. J.
Am. Chem. Soc. 1995, 117, 3808. (d) Burgess, K.; Ke, C.-Y. J. Org. Chem.
1996, 61, 8627. (e) Moye-Sherman, D.; Jin, S.; Li, S.; Welch, M. B.;
Reibenspies, J.; Burgess, K. Chem. Eur. J. 1999, 5, 2730. (f) Jime´nez, A.
I.; Ballano, G.; Cativiela, C. Angew. Chem., Int. Ed. 2005, 44, 396. (g)
Jime´nez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J. Am. Chem. Soc.
1998, 120, 9452.
(3) Cyclopropene R-amino acids: (a) Scho¨llkopf, U.; Hupfeld, B.; Ku¨per,
S.; Egert, E.; Dyrbusch, M. Angew. Chem., Int. Ed. Engl. 1988, 27, 433.
(b) Wheeler, T. N.; Ray, J. J. Org. Chem. 1987, 52, 4875. (c) McGregor,
S. D.; Jones, W. M. J. Am. Chem. Soc. 1968, 90, 123. (d) Domnin, I. N.;
Zhuravleva, E. F.; Komendantov, M. I.; Ritari, A. EÄ . Zh. Org. Khim. 1977,
13, 1789; J. Org. Chem. USSR 1977, 13, 1656. For the synthesis of
cyclopropene γ-amino acids, see: (e) Mu¨ller, P.; Imoga¨ı, H. Tetrahedron:
Asymmetry 1998, 9, 4419.
10.1021/ol060847l CCC: $33.50
© 2006 American Chemical Society
Published on Web 06/10/2006

derivatives with structure 5 as shown in Scheme 2. High
Scheme 1. Enantioselective Desymmetrization Approach to
Cyclopropene R-Amino Acids
Scheme 2. Enantioselective Desymmetrization of
Bis-pentafluorophenylesters
to be useful tools for the kinetic resolution of chiral
carboxylic acid derivatives.5 We recently described a parallel
kinetic resolution strategy for resolving cyclopropene car-
boxylic acids as quasienantiomeric N-acyloxazolidinones.6
Given the generality of the kinetic resolution, we envisioned
the enantioselective desymmetrization7 approach to nonra-
cemic cyclopropene R-amino acid derivatives 3 shown in
Scheme 1. Thus, activation of both acid functions of 1
followed by desymmetrization would provide enantiomeri-
cally enriched 2. A second acyl transfer with azide, subse-
quent Curtius rearrangement8 and alcoholysis would provide
protected amino acid 3. This approach would have virtue
because it is short and uses an inexpensive9 oxazolidinone
as the source of asymmetry and because diverse types of
prochiral cyclopropenes 1 are readily available on large scale
from the Rh-catalyzed addition of diazomalonate to alkynes.10
It is shown here that high enantioselectivity can indeed
be realized by the desymmetrization of bis-pentafluorophe-
nylesters 4, substances that are available in one step from
their corresponding diacids (1).11 Under optimal conditions,12
bis-pentafluorophenylester 4 is combined with the Li-salt of
4-phenyloxazolidinone at -78 °C in CH2Cl2. These condi-
tions were applied for the preparation of a series of
diastereomer ratios were observed for a range of side chain
functionalites. Particularly high selectivities were observed
for the phenylalanine analogue 5b (dr 99.5:0.5), the p-
fluorophenylalanine analogue 5d (dr 99:1), and the leucine
analogue 5c (dr 99:1). In each case, the major diastereomer
could easily be separated from the minor diastereomer by
column chromatography.
Having demonstrated the generality of the enantioselective
desymmetrization, we sought to establish a short sequence
by which enantiomerically enriched cyclopropenes 5 could
be converted into protected amino acids. This was demon-
strated for 5a and 5b as shown in Scheme 3. Thus, acyl
azides 6a and 6b were produced in excellent yield upon
treatment with NaN3 and catalytic DMAP in wet THF.
Curtius rerrangement and subsequent ester and carbamate
formation with p-methoxybenzyl alcohol gave the protected
amino acids 7a and 7b. The modest yields of derivatives 7
from 6 should be considered in the context that three distinct
transformations (Curtius rearrangement, ester formation,
carbamate formation) take place with only one purification.
Multigram quantities of 7a were prepared by this method,
and (4S)-4-phenyloxazolidione could be recovered in 75%
yield. It is also pointed out that p-methoxybenzyl alcohol
(4) (a) Evans, D. A.; Ennis, M. D.; Mathre, D. J. J. Am. Chem. Soc.
1982, 104, 1737. (b) Ager, D. J.; Prakash, I.; Schaad, D. R. Aldrichimica
Acta 1997, 30, 3.
(5) (a) Bew, S. P.; Davies, S. G.; Fukuzawa, S.-i. Chirality 2000, 12,
483. (b) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Motevalli,
M.; Northen, J.; Yohannes, Y. Synlett 2006, 101. (c) Coumbarides, G. S.;
Eames, J.; Flinn, A.; Northen, J.; Yohannes, Y. Tetrahedron Lett. 2005,
46, 849. (d) Coumbarides, G. S.; Dingjan, M.; Eames, J.; Flinn, A.; Northen,
J.; Yohannes, Y. Tetrahedron Lett. 2005, 46, 2897. (e) Fukuzawa, S.-i.;
Chino, Y.; Yokoyama, Y. Tetrahedron: Asymmetry 2002, 13, 1645. For
examples of asymmetric acyl transfer reactions in which oxazolidiones or
oxazolidinethiones are leaving groups, see: (f) Notte, G. T.; Sammakia, T.
J. Am. Chem. Soc. 2006, 128, 4230. (g) Nagao, Y.; Inoue, T.; Hashimoto,
K.; Hagiwara, Y.; Ochiai, M.; Fujita, E. J. Chem. Soc., Chem. Commun.
1985, 1419. (h) Hashimoto, N.; Ishizuka, T.; Kunieda, T. Tetrahedron Lett.
1998, 39, 6317.
(6) (a) Liao, L.-a.; Zhang, F.; Dmitrenko, O.; Bach, R. D.; Fox, J. M. J.
Am. Chem. Soc. 2004, 126, 4490. For an earlier study in which cyclopropene
carboxylic acids were resolved via their N-acyloxazolidinones, see: (b) Liao,
L.-a.; Zhang, F.; Yan, N.; Golen, J. A.; Fox, J. M. Tetrahedron 2004, 60,
1803.
(7) (a) Willis, M. C. J. Chem. Soc., Perkin Trans. 1 1999, 1765-1784.
Enzymatic desymmetrization: (b) Schoffers, E.; Golebiowski, A.; Johnson,
C. R. Tetrahedron 1996, 52, 3769.
(8) The Curtius rearrangment has been applied to the synthesis of the
parent cyclopropene amino acid. See ref 3b.
(9) (S)-4-Phenyloxazolidinone costs less than $1/g when purchased by
the kilogram (Chemicrea Inc, Tokyo, Japan).
(10) See ref 6b and (a) Muller, P.; Granicher, C. HelV. Chim. Acta 1993,
76, 521. (b) Rubina, M.; Rubin, M.; Gevorgyan, V. J. Am. Chem. Soc.
2003, 125, 7198. (c) Rubin, M.; Gevorgyan, V. Synthesis 2004, 796.
(11) Bis-pentafluorophenylesters were prepared from the corresponding
diacids and CF3CO2C6F5. See: Green, M.; Berman, J. Tetrahedron Lett.
1990, 31, 5851.
(12) Desymmetrization reactions with the bis-acid chloride or bis-
ethylcarbonic anhydride of 1 proceeded in very low dr (<2:1). Our efforts
to prepare the mixed anhydride of 1 from either t-BuCOCl or 1-adamantoyl
chloride were unsuccessful. The products of attempted mixed anhydride
formation had extremely broad 1H NMR spectra, a possible indication that
the materials were polymeric.
2966
Org. Lett., Vol. 8, No. 14, 2006

corresponding bis-lactim ether under relatively mild condi-
tions (0.1 M HCl, rt).3a However, in a prior study on a
cyclopropene γ-amino acid,3e protecting group manipulation
presented major difficulties. Ultimately, deprotection of a
Teoc derivative with TBAF was successful, but alternative
strategies (e.g., TFA cleavage of a Boc derivative) were very
low yielding.3e
Scheme 3. Synthesis of Protected Cyclopropene R-Amino
Acids
Given the uncertainity surrounding the stability of cyclo-
propene amino acid dervatives, it was notable that the
derivatives in Scheme 4 are tolerant of harsh conditions (i.e.,
KOH/MeOH, 20% TFA in CH2Cl2). The residues are also
compatible with commonly used conditions for peptide
synthesis. Thus, it was possible to incorporate 8a into
tripeptide 14 using HCTU-mediated peptide bond-forming
reactions (Scheme 5). A reaction sequence was specifically
was more efficient than t-BuOH in trapping the sterically
encumbered tertiary isocyanate. Subsequent reactivity paral-
lels Boc chemistry, as Moz13 carbamates cleave under acidic
conditions similar to those used to cleave Boc carbamates.13
The bis-p-methoxybenzyl-protected cyclopropenes 7 serve
as intermediates to a number of useful amino acid derivatives.
Thus, the free amino acids 10a and 10b were obtained upon
simple treatment with 20% TFA in CH2Cl2 (Scheme 4).
Scheme 5. Incorporation of a Cyclopropene R-Amino Acid
into a Peptide
Scheme 4. Synthesis of Cyclopropene R-Amino Acid
Derivatives
chosen to demonstrate compatibility both with piperidine-
mediated deprotection of a Fmoc group and with TFA/
anisole-mediated deprotection of the Moz group. The latter
conditions are also commonly used in the removal of Boc
protecting groups.
The sense of asymmetric induction for the formation of
5b is the reverse of that observed in the parallel kinetic
resolution of 1,2-diphenylcycloprop-2-ene-1-carboxylic acid.6a,15
The major difference in the two procedures is that carboxylic
acids were activated as mixed anhydrides in the kinetic
resolution, whereas the bis-carboxylic acids in the present
study were activated as their pentafluorophenyl esters. In an
earlier computational study at the B3LYP/6-31+G(d,p) level
of theory,6a,16 we proposed a transition state for the kinetic
resolution in which the carbonyl oxygens of the oxazolidi-
none and the carboxylate leaving group formed a chelate to
the lithium counterion. As the pentafluorophenyl esters
cannot form such a chelate, it seems reasonable that the sense
of asymmetric induction would differ. Unfortunately, efforts
to prepare the mixed anhydrides from 1 and either pivaloyl
chloride or 1-adamantoyl chloride were unsuccessful,12 so a
Furthermore, the Fmoc-protected amino acid 9a was obtained
upon sequential treatment of 7a with TFA and FmocOSu,
and the Moz13-protected amino acid 8a was obtained upon
saponification of 7a.
Because of the strain that is inherent to cyclopropenes,14
there was concern that cyclopropene R-amino acids might
be too reactive for applications. Wheeler and Ray had earlier
prepared the parent cyclopropene R-amino acid by depro-
tection of the Boc-protected acid but noted that they were
unable to prepare analogues bearing alkyl substituents on
the cyclopropene ring.3b Scho¨llkopf prepared methyl 1-amino-
2-phenylcyclopropene-1-carboxylate via hydrolysis of the
(13) Moz ) p-methoxybenzylcarbamate. For cleavage of Moz esters,
see: (a) Weygand, F.; Hunger, K. Chem. Ber. 1962, 95, 1. (b) Greene, T.
W.; Wuts, P. G. M. ProtectiVe Groups in Organic Synthesis, 3nd ed.;
Wiley: New York, 1999; pp 537-538.
(14) (a) Bach, R. D.; Dmitrenko, O. J. Am. Chem. Soc. 2004, 126, 4444.
(b) Wiberg, K. B. Angew. Chem., Int. Ed. Engl. 1986, 25, 312.
(15) (4S)-4-Phenyl-3-[(1S)-1,2-diphenylcycloprop-2-en-1-oyl]oxazolidi-
none is formed preferentially in the reaction of (4S)-4-phenyloxazolidinone
with the mixed anhydride from 1,2-diphenylcycloprop-2-ene-1-carboxylic
acid and 1-adamantoyl chloride.6a
(16) Fox, J. M.; Dmitrenko, O.; Liao, L.-a.; Bach, R. D. J. Org. Chem.
2004, 69, 7317.
Org. Lett., Vol. 8, No. 14, 2006
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direct comparison to the desymmetrization of bis-pentafluo-
rophenyl esters 4 is not yet possible. In future work, the
dependence of asymmetric induction on the nature of the
leaving group will be further explored through experiment
and computation.
methods for peptide synthesis. Efforts to utilize cyclopropene
R-amino acids in de novo peptide design are underway.
Acknowledgment. For financial support of this work we
thank NIGMS (NIH R01 GM068650-01A1) and the NIH
COBRE program of the NCRR (P20 RR017716-01).
In summary, a new route to enantiomerically enriched
cyclopropene R-amino acids is reported. The key step is a
highly enantioselective desymmetrization of cyclopropene-
bis-carboxylic acids. Derivatives of cyclopropene R-amino
acids are shown to be stable to harshly acidic and basic
reaction conditions (TFA, NaOH), and one derivative has
been incorporated into a tripeptide using conventional
Supporting Information Available: Full experimental
1
and characterization details, H and 13C NMR spectra, and
X-ray data for the stereochemical assignment of 5b. This
material is available free of charge via the Internet at
http://pubs.acs.org.
OL060847L
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Org. Lett., Vol. 8, No. 14, 2006