trans-Cyclopropyl β-amino acid derivatives via asymmetric cyclopropanation using a (Salen)Ru(II) catalyst

Article abstract of DOI:10.1021/jo0344079

trans-Cyclopropyl β-amino acid derivatives can be synthesized in five steps with excellent enantioselectivities using a chiral (Salen)Ru(II) cyclopropanation catalyst in the key asymmetry-induction step. This facile synthesis proceeds with high overall yield and can be used to prepare a number of carbamate-protected (Cbz and Boc are demonstrated) β-amino acid derivatives.

Full text of DOI:10.1021/jo0344079

tr a n s-Cyclop r op yl â-Am in o Acid
Der iva tives via Asym m etr ic
Cyclop r op a n a tion Usin g a (Sa len )Ru (II)
Ca ta lyst
J ason A. Miller,‡ Edward J . Hennessy,‡
Will J . Marshall,† Mark A. Scialdone,*,† and
SonBinh T. Nguyen*,‡
F IGURE 1. N-Protected cycloalkyl â-amino acid derivatives.
Having an extra carbon atom between the N- and
C-termini, â-amino acids have a much greater potential
for structural diversity beyond that of monosubstituted
R-amino acids. In general, â-amino acids are also more
metabolically stable than their R-amino counterparts25
and have also been used for the preparation of modified
peptides.10,26,27 In particular, the nonnatural cyclic trans-
cyclohexyl and -cyclopentyl â-amino acids28 (Figure 1, 1
and 2 respectively), which restrict conformational mobil-
ity, have been successfully incorporated into â-peptide
designs by Gellman and co-workers.10
E. I. DuPont de Nemours and Company, Inc.,
Central Research & Development, Experimental Station,
Bldg 328, Wilmington, Delaware 19880-0328, and
Northwestern University, Department of Chemistry,
2145 Sheridan Rd., Evanston, Illinois 60208
mark.a.scialdone@usa.dupont.com;
stn@chem.northwestern.edu
Received March 28, 2003
Synthetic approaches toward the smaller-ring confor-
mationally constrained analogues, â-aminocyclobutyl car-
boxylic acid 329 and â-aminocyclopropyl carboxylic acid
(â-ACC) 4,29,30 have been reported. Reiser and co-workers
arrive at the N-protected derivative of 4 through the
ozonolytic cleavage of a N-protected pyrrole that has been
singly cyclopropanated in low yield with methyl diazoac-
etate. The isomers are then kinetically resolved (allowing
for a maximum 50% yield of the desired optically pure
isomer) by hydrolysis of the cyclopropylcarboxylic methyl
ester in the presence of lipase.31 We note that the Reiser
laboratory has also developed methods to incorporate 4
into peptides.32,33
Abstr a ct: trans-Cyclopropyl â-amino acid derivatives can
be synthesized in five steps with excellent enantioselectivi-
ties using a chiral (Salen)Ru(II) cyclopropanation catalyst
in the key asymmetry-induction step. This facile synthesis
proceeds with high overall yield and can be used to prepare
a number of carbamate-protected (Cbz and Boc are demon-
strated) â-amino acid derivatives.
The enantioselective synthesis of â-amino acids has
recently attracted considerable attention1-4 due to their
interesting structural properties and significant phar-
macological activities.5,6 â-Amino acids are found in
numerous biologically active compounds including â-
peptides,7-9 which have been shown to organize into well-
defined folded secondary and tertiary structures in
aqueous solution, similar to that observed for natural
proteins.10-14 â-Amino acids are also crucial structural
features of multiple natural products,15-21 â-lactams,22
and other pharmaceutical candidate compounds.23,24
Additionally, the Csuk and Ortun˜o groups have each
reported synthetic routes to enantiomerically enriched
4.34,35 These syntheses differed primarily in the cyclo-
propane-forming steps but both utilized pig liver esterase
(16) Zabriskie, T. M.; Klocke, J . A.; Ireland, C. M.; Marcus, A. H.;
Molinski, T. F.; Faulkner, D. J .; Xu, C.; Clardy, J . J . Am. Chem. Soc.
1986, 108, 3123-3124.
† E. I. DuPont de Nemours and Company, Inc., Contribution No.
8388.
(17) Kosemura, S.; Ogawa, T.; Totsuka, K. Tetrahedron Lett. 1993,
34, 1291-1294.
‡ Northwestern University.
(18) Davies, S. G.; Ichihara, O.; Walters, I. A. S. Synlett 1993, 461-
462.
(1) Abdel-Magid, A. F.; Cohen, J . H.; Maryanoff, C. A. Curr. Med.
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(19) Chemistry and Biochemistry of the Amino Acids; Barrett, G.
C., Ed.; Chapman and Hall: New York, 1985.
(2) Ng, J . S.; Topgi, R. S. Curr. Opin. Drug Discuss. Dev. 1998, 1,
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(3) Enantioselective Synthesis of â-Amino Acids; J uaristi, E., Ed.;
Wiley-VCH: New York, 1997.
In Curr. Med. Chem. 1999, 6(10), 905-1004.
(21) Cardillo, G.; Tomasini, C. Chem. Soc. Rev. 1996, 25, 117-128.
(22) The Chemistry of â-Lactams; Page, M. I., Ed.; Chapman and
Hall: London, 1993.
(4) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103, 1603-1623.
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Bristol-Myers Squibb Company, USA, 2002.
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10.1021/jo0344079 CCC: $25.00 © 2003 American Chemical Society
Published on Web 09/11/2003
7884
J . Org. Chem. 2003, 68, 7884-7886

F IGURE 2. (left) (Salen)Ru(II) cyclopropanation catalyst 5. (right) An ORTEP view of the crystal structure of 5 showing atom
labeling scheme.38 Thermal ellipsoids are drawn at 50% probability. Hydrogen atoms are omitted for clarity.
to arrive at the optically active product (through resolu-
tion of the two enantiomers of the cis-cyclopropane).
Unfortunately, isomerization and racemization, presum-
ably caused by heating in the synthetic pathway, led to
less than desirable ee’s for the final products. Low total
yields were also noted for both syntheses (50% loss in
the resolution step alone). Hence, a more straightforward
synthesis of trans-â-ACC 4 is desired.
Herein we report a high-yield synthesis of trans-â-ACC
derivatives, where the amino group is protected as the
N-Cbz (4a ) and N-Boc (4b) moieties, employing the highly
enantioselective (salen)Ru(II) cyclopropanation catalyst
536 developed in our laboratory (Figure 2).37
be cyclopropanated in good yields but with poor diaste-
reoselectivity and no enantioselectivity. In our hands, a
series of commercially available Doyle’s chiral dirhodium
catalysts42 (containing the MEPY, MIPPM, and MEOX
ligands) showed similar results (low diastereoselectivity
and no enantioselectivity). These poor results prompted
us to investigate other methods to synthesize the target
trans-cyclopropyl â-amino acids.
We postulated that it would be advantageous to exploit
the outstanding combination of diastereoselectivity (cis:
trans ) 1:11) and enantioselectivity (96% ee for cis, 99%
ee for trans) in the cyclopropanation of styrene with EDA
using our (salen)Ru(II) catalyst 5 (eq 2).36 The product
It has been established that the amino group of 4 needs
to be protected with an electron-withdrawing group such
as a carbamate because of its vicinal donor-acceptor
substitution pattern, which can result in rapid ring
opening and subsequent hydrolysis or condensation reac-
tions.29,39,40 Thus, we selected the benzyl carbamate (Cbz)
and tert-butyl carbamate (Boc) N-protected cyclopropanes
(4a and 4b, respectively) as our synthetic targets. Cbz
and Boc protecting groups were chosen on the basis of
their contrasting chemical stabilities (N-Cbz is stable to
most acidic conditions and is cleaved by catalytic hydro-
genolysis, whereas N-Boc is stable to most basic condi-
tions and is cleaved by acidic hydrolysis) and ease of
introduction.41
of this reaction, chirally pure cyclopropane 10, can be
obtained in quantitative yield (99%) and serve as an
excellent intermediate for our planned synthesis (Scheme
1). Oxidative degradation of the phenyl moiety of 10 to a
carboxylic acid employing ruthenium tetraoxide, as de-
scribed by Sharpless and co-workers43 and applied to a
phenyl-substituted cyclopropane by J ørgensen and
Sydnes,44 would furnish a pseudo-C2 symmetric trans-
acid ester, which can be transformed to an azide and
undergo Curtius rearrangement to an isocyanate, with
retention of configuration. The cyclopropyl isocyanate
could then be converted to the target carbamate via
reaction with an alcohol of choice (e.g., tBuOH or BnOH).
Indeed, application of the Sharpless oxidative degrada-
tion of the phenyl group of phenyl cyclopropane 10 with
ruthenium tetroxide furnishes the cyclopropane ester-
Our first attempt to produce the enantiomerically pure
trans-â-ACC derivatives employed the direct cyclopro-
panation of the corresponding vinyl carbamates 6 and 7
with ethyl diazoacetate (EDA) in the presence of 5 (eq
1). While cyclopropanation of the Boc-protected olefin 7
resulted in no reaction, the Cbz-protected olefin 6 can
(35) Martin-Vila`, M.; Muray, E.; Aguado, G. P.; Alvarez-Larena, A.;
Branchadell, V.; Minguillon, C.; Giralt, E.; Ortun˜o, R. M. Tetrahe-
dron: Asymmetry 2000, 11, 3569-3584.
(36) Miller, J . A.; J in, W.; Nguyen, S. T. Angew. Chem., Int. Ed.
2002, 41, 2953-2956.
(37) Katsuki and co-workers have also reported salen-based Ru and
Co cyclopropanation catalysts. See: Uchida, T.; Irie, R.; Katsuki, T.
Tetrahedron 2000, 56, 3501-3509. Fukuda, T.; Katsuki, T. Synlett
1995, 825-826.
(38) Single crystals of 5 were obtained by slow diffusion of methanol
into a toluene solution of 5 at low temperature inside a drybox. The
catalyst crystallized in an orthorhombic unit cell, space group Pna21
with formula weight ) 1078.45, a ) 19.208(3) Å, b ) 15.746(2) Å, c )
19.587(3) Å, and Dcalc ) 1.209 g/cm3 for Z ) 4, T ) -100 °C.
(39) Wheeler, J . W.; Shroff, C. C.; Stewart, W. S.; Uhm, S. J . J . Org.
Chem. 1971, 36, 3356-3361.
(40) Cannon, J . G.; Garst, J . E. J . Org. Chem. 1975, 40, 182-184.
(41) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; Wiley-Interscience: New York, 1991.
(42) Doyle, M. P.; Brandes, B. D.; Kazala, A. P.; Pieters, R. J .;
J arstfer, M. B.; Watkins, L. M.; Eagle, C. T. Tetrahedron Lett. 1990,
31, 6613-6616.
(43) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(44) J ørgensen, E.; Sydnes, L. K. J . Org. Chem. 1986, 51, 1926-
1928.
J . Org. Chem, Vol. 68, No. 20, 2003 7885

SCHEME 1. Sch em e for tr a n s-Cyclop r op yl
â-Am in o Acid Der iva tive Syn th esisa
HMPA at low temperatures showed no improvement over
the noncatalyzed reaction, although this catalyst system
has been found to be effective for carbamate synthesis
with other substrates.45 However, copper(I) chloride-
catalyzed addition of the alcohol46 to 13 proved to be
t
highly successful for both BnOH and BuOH. This high-
yield (94%) reaction proceeds at room temperature, thus
minimizing the chance of isomerization or racemization.
Analysis of the final N-Cbz- and N-Boc-protected (1R,2R)-
trans-cyclopropyl â-amino acid derivatives 8 and 9 by
chiral HPLC and GC, respectively, showed a slight
decrease in ee (99% to 90% ee) in comparison to that of
10. This is most likely due to a small amount of racemi-
zation that presumably occurred via thermal rearrange-
ment.34,35 Following the synthesis in Scheme 1 with
further trans-enriched cyclopropane 10 (cis:trans ratio of
1:17, obtained by vacuum distilling off a small amount
of predominately the cis isomer, which has a higher vapor
pressure) also yielded final enantiomeric excesses of 90%
for the trans isomer with no change in the product cis:
trans ratio.
a
Conditions: (a) RuCl3‚xH2O, NaIO4, CCl4/CH3CN/H2O, rt, 3
days. (b) (i) EtOC(O)Cl, Et3N, acetone, 0 °C, 1 h; (ii) NaN3, H2O,
rt, 1 h. (c) Toluene, 85 °C, 1 h. (d) CuCl, ROH, toluene/DMF, rt,
1.5 h.
We note that use of the (S,S)-cyclohexyl analogue of
catalyst 5 in the styrene cyclopropanation reaction (eq
2) results, as expected, in the same selectivities but
opposite product absolute configurations. Thus, use of the
(S,S)-5 would allow for easy production of the (S,S)
enantiomers of the trans-cyclopropyl â-amino acid de-
rivatives synthesized in Scheme 1.
In conclusion, chiral (salen)Ru(II) cyclopropanation
catalysts can be successfully used in the key chirality-
induction step for the synthesis of highly enantiomeri-
cally enriched trans-cyclopropyl â-amino acid derivatives.
Our high-yield synthesis proceeds with a large amount
of retention of the high enantio- and diastereoselectivities
introduced initially in the cyclopropanation of styrene
with EDA by 5. Further saponification and in situ
N-deprotection of these cyclopropyl â-amino acid deriva-
tives could lead to a number of synthetically and biologi-
cally important products.
acid 11 in near quantitative yield (96%) (Scheme 1, (a)).
Azide transfer to 11 (Scheme 1, (b)) was attempted with
diphenyl phosphoryl azide (DPPA)34 but yielded no
product. However, the acyl azide intermediate 12 can be
obtained in high yield (96%) using ethyl chloroformate
in the presence of triethylamine followed by reaction with
sodium azide in a one-pot synthesis.35 The Curtius
rearrangement of the acyl azide 12 (Scheme 1, (c)) was
carried out thermally in a toluene solution. Precise
control of reaction time and temperature is crucial in
order to preserve the optical purity of the â-amino acid
derivatives. To optimize conditions for this reaction, it
was followed closely by solution IR spectroscopy. Disap-
pearance of the azide stretching peak at 2148 cm-1
corresponds simultaneously to the appearance of the
isocyanate stretching peak at 2279 cm-1. With this
monitoring, optimal reaction time was found to be 1 h at
85 °C. Both longer reaction times and higher reaction
temperature resulted in a loss of ee in the final products
due to racemization, which is in accordance with obser-
vations by others where thermally induced racemization
of the cyclopropane results in an overall loss in optical
purity.34,35
Ack n ow led gm en t. This work was supported by the
National Institute of Health and the DuPont Central
Research & Development. S.T.N. is an Alfred P. Sloan
research fellow. We also thank the Dreyfus Foundation,
Union Carbide, the Beckman Foundation, and the
Packard Foundation for partial financial support.
After the Curtius rearrangement, the toluene solution
of 13 was used directly for the carbamate synthesis
(Scheme 1, (d)) without isolation. Initially, direct nucleo-
philic attack of the alcohols on 13 was attempted without
a catalyst. This proved to be an inefficient process that
was plagued by low yields (<30% for reaction of BnOH
Su p p or tin g In for m a tion Ava ila ble: General procedures
for the syntheses and characterization of the cyclopropanes
(together with all GC and HPLC methods) and the X-ray
structural data for 5. A combined X-ray crystallographic file
for the structure determination of 5 is available in CIF format.
This material is available free of charge via the Internet at
http://pubs.acs.org.
t
and <10% with BuOH) and enantioselectivity due to the
necessary heating required for carabamate formation. In
an effort to improve the overall carbamate yield while
at the same time reducing the need for heating, we
decided to make use of a Lewis acid catalyst for this
reaction. Employing samarium diiodide as a catalyst with
J O0344079
(45) Kim, Y. H.; Park, H. S. Synlett 1998, 261-262.
(46) Duggan, M. E.; Imagire, J . S. Synthesis 1989, 131-132.
7886 J . Org. Chem., Vol. 68, No. 20, 2003