Synthesis of β-Cyclopropylalanines by Photolysis of Diacyl Peroxides

Article abstract of DOI:10.1021/ol035859a

(Matrix presented) Photolysis at 254 nm of neat (no solvent) unsymmetrical diacyl peroxides derived from cyclopropane carboxylic acids and L-aspartic acid generates protected β-cyclopropylalanines in reasonable yields. Orthogonally protected 3-(trans-2-am

Full text of DOI:10.1021/ol035859a

ORGANIC
LETTERS
2003
Vol. 5, No. 24
4669-4672
Synthesis of â-Cyclopropylalanines by
Photolysis of Diacyl Peroxides
Rajendra P. Jain and John C. Vederas*
Department of Chemistry, UniVersity of Alberta, Edmonton, Alberta, Canada T6G 2G2
john.Vederas@ualberta.ca
Received September 24, 2003
ABSTRACT
Photolysis at 254 nm of neat (no solvent) unsymmetrical diacyl peroxides derived from cyclopropane carboxylic acids and L-aspartic acid
generates protected â-cyclopropylalanines in reasonable yields. Orthogonally protected 3-(trans-2-aminocyclopropyl)alanine (21), a key constituent
of the antitumor agent belactosin A, as well as protected hypoglycin A (26), a causative agent of Jamaican vomiting sickness, is synthesized
by this approach with coupling of the intermediate substituted cyclopropyl radicals proceeding predominantly with retention of configuration
(dr g 95:5).
Recently, much attention has focused on amino acids
containing conformationally constrained cyclopropane rings
due to their important biological activities.1 For example,
â-cyclopropylalanine (12, 15, and 16, Scheme 3, n ) 1, R1
) R2 ) H) is a potent antagonist to E. coli ATCC 97232
and inhibits spore germination of Pyricularia oryzae Cav.,
the causative agent of rice blast disease.3 The cyclopropane
ring can be introduced into amino acids by a number of
methods, which include (1) metal-promoted cyclopropanation
or carbene addition reactions,4 (2) glycine enolate alkylation
with cyclopropylmethyl halides,5 and (3) Michael-induced
ring closure by glycine enolates.6
various functionalized amino acids in a concise manner and
with orthogonal protection. We envisaged that recombination
of cyclopropane radicals8,9 with an amino acid derived partner
could provide access to various cyclopropane amino acids
(Figure 1), but it was not initially obvious whether the special
properties of the cyclic radical10 would interfere in this
process.
We have recently reported7 the low-temperature photolysis
of diacyl peroxides in the absence of solvent to generate
Figure 1. Retrosynthesis of cyclopropane amino acids.
(1) (a) Williams, R. M. In Organic Chemistry Series, Volume 7: Synthesis
of Optically ActiVe R-Amino Acids; Baldwin, J. E., Magnus, P. D., Eds.;
Pergamon Press: Oxford, 1989. (b) Stammer, C. H.; Tetrahedron 1990,
46, 2231-2254. (c) Burgess, K.; Ho, K. K.; Moyesherman, D. Synlett 1994,
575-583. (d) Salau¨n, J.; Baird, M. S. Curr. Med. Chem. 1995, 2, 511-
542. (e) Salau¨n, J. Top. Curr. Chem. 2000, 207, 1-67. (f) Cativiela, C.;
Diaz-de-Viellgas, M. D. Tetrahedron: Asymmetry 2000, 11, 645-732.
(2) Meek, J. S.; Rowe, J. W. J. Am. Chem. Soc. 1955, 77, 6675-6677.
(3) (a) Ohta, T.; Nakajima, S.; Sato, Z.; Aoki, T.; Hatanaka, S.; Nozoe,
S. Chem. Lett. 1986, 511-512. (b) Hamon, C.; Rawlings, B. J. Synth.
Commun. 1996, 26, 1109-1115 and references cited therein.
(4) Rife, J.; Ortuno, R. M.; Lajoie, G. A. J. Org. Chem. 1999, 64, 8958-
8961.
Initial studies focused on the synthesis of protected
cyclopropane amino acids 12-16. Two different methods
(7) Spantulescu, M. D.; Jain, R. P.; Derksen, D. J.; Vederas, J. C. Org.
Lett. 2003, 5, 2963-2965.
(8) For review on cyclopropane radicals, see: Walborsky, H. M.
Tetrahedron, 1981, 37, 1625-1651.
(9) For other reactions of cyclopropane radicals, see: (a) Stefani, A. P.;
Chuang, L.-Y. Y.; Todd, H. E. J. Am. Chem. Soc. 1970, 92, 4168-4173.
(b) Stefani, A. P.; Todd, H. E. J. Am. Chem. Soc. 1971, 93, 2982-2986.
(c) Shono, T.; Nishiguchi, I.; Tetrahedron, 1974, 30, 2183-2190. (d) Clerici,
A.; Minisci, F.; Porta, O. J. Chem. Soc., Perkin Trans. 2 1974, 1699-
1701. (e) Herwig, K.; Lorenz, P.; Ru¨chardt, C. Chem. Ber. 1975, 108, 1421-
1436.
(5) (a) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119,
12414-12415. (b) Tzalis, D.; Knochel, P. Tetrahedron Lett. 1999, 40,
3685-3688.
(6) Pohlman, M.; Kazmaier, U. Org. Lett. 2003, 5, 2631-2633.
10.1021/ol035859a CCC: $25.00 © 2003 American Chemical Society
Published on Web 10/31/2003

were developed to synthesize the requisite precursor diacyl
peroxides 3-5 and 10-11. Thus, treatment of suitably
protected aspartic and glutamic acids (1a-c) with an Etheral
solution of cyclopropane percarboxylic acid11 (2, obtained
from cyclopropane carboxylic acid, concentrated H2SO4, and
H2O2, see the Supporting Information) in the presence of
DCC affords the diacyl peroxides 3-5 in 83-89% yield
(Scheme 1).
10, and 11 produces optically pure â-cyclopropylalanine
derivatives2,3 12, 15, and 16, respectively, with no detectable
crossover products. Similarly, photolysis of 4 and 5 at -78
°C generates one-carbon homologues 13 and 14, respectively
(Scheme 3).
Scheme 3
Scheme 1
Alternatively, DCC-mediated coupling of the protected
L-aspartic acid (1d and 1e) with 2-methoxyprop-2-yl hydro-
peroxide,12 acidic deprotection of the resultant peresters 6
and 7 (50% aq TFA/CHCl3 for 6, 50% aq AcOH for 7), and
acylation of the corresponding peracids 8 and 9 with
cyclopropane carbonyl chloride (py/CH2Cl2) generates the
diacyl peroxides 10 and 11 in good overall yields (Scheme
2). The diacyl peroxides 3-5 and 10-11 are stable to shock
and can be stored in non-nucleophilic organic solvents
(EtOAc, CHCl3) for several weeks at -20 °C without
decomposition.
This approach can be extended to the synthesis of the
orthogonally protected (2S,4R)-3-[trans-(2S)-aminocyclo-
propyl]alanine (21, Scheme 4), a key constituent of the
Scheme 4
Scheme 2
recently isolated metabolite belactosin A (17) produced by
Streptomyces sp. that exhibits antitumor activity.14 This also
provides an opportunity to examine the stereoselectivity of
coupling of cyclopropyl radicals (Scheme 4). We have
The photolysis reactions of the peroxides 3-5 and 10-
11 are done on neat substrates (solids and oils, no solvent)
at -78 °C with a 254 nm UV lamp.13 Thus, photolysis of 3,
(11) The pure peracid was not isolated from its solution due to its high
volatility, and to avoid possible explosion hazard, see: Swern, D. Organic
Peroxides; Wiley-Interscience: New York, 1970; pp 476-498. For
characterization purposes, a small aliquot of etheral solution was carefully
concentrated under positive pressure of Ar to obtain neat cyclopropane-
percarboxylic acid as clear colorless oil.
(10) Mann, D. J.; Hase, W. L. J. Am. Chem. Soc. 2002, 124, 3208-
3209.
(12) Dussault, P.; Sahli, A. J. Org. Chem. 1992, 57, 1009-1012.
4670
Org. Lett., Vol. 5, No. 24, 2003

recently demonstrated that secondary radicals bearing a
methyl substituent generated in this fashion can couple to
primary radicals with 5:1 retention of configuration at -196
°C.7 Earlier syntheses of 3-(trans-2-aminocyclopropyl)alanine
were reported by the groups of de Meijere15a and Armstrong16
using glycine enolate alkylation of the unstable iodide derived
from the alcohol 18. These routes rely on the generation of
C-2 chiral center of 3-(trans-2-aminocyclopropyl)alanine
either by use of a chiral glycine template15b or by chiral phase
transfer catalysis.16 In the present approach, the C-2 chiral
center is generated by incorporation of the existing stereo-
center of protected aspartic acid 1d (Scheme 4).
Scheme 5
arillus and seeds of unripe fruit of the Jamaican ackee tree
(Blighia sapida),19 hypoglycin A (23) is the causative agent
of Jamaican vomiting sickness.20 Natural hypoglycin A exists
as a mixture of diastereomers at C-4, with 17% diastereo-
meric excess favoring the (2S,4R) isomer.21
We followed the Wadsworth-Emmons cyclopropanation
protocol on benzyl (S)-(+)-glycidyl ether16 with a slight
change (final hydrogenolysis step is modified; 40 psi H2,
10% Pd-C, EtOAc, rt, 15 h, quant) in order to synthesize
requisite (S,S)-(trans-2-aminocyclopropyl)methanol deriva-
tive 18 (Scheme 4).
A recent synthesis of optically pure hypoglycin A21 relies
on the generation of C-2 chiral center by use of Scho¨llkopf
bis-lactim ether22 as chiral glycine template. As in case of
21, our approach for the synthesis of 26 is based on
generation of C-2 chiral center by incorporation of the
existing stereocenter of protected aspartic acid 1d (Scheme
5).
Thus, DCC-mediated coupling (-78 °C, 48 h) of 24,
obtained by modification of reported procedure23 (see the
Supporting Information), with 8 forms the diacyl peroxide
25 in 46% yield. Higher temperatures lower yields in this
reaction, probably due to peracid oxidation of the olefin and
subsequent decomposition. Photolysis of neat 25 at -78 °C
(30 h) produces 26 in 24% yield and with g95:5 diastere-
omeric ratio (by 1H NMR analysis in CDCl3 using Eu(Hfc)3,
as well as in DMSO-d6 at +100 °C, diastereomers insepa-
rable by silica gel chromatography).
Attempted oxidation of alcohol in 18 either by Jones
reagent or PDC could not generate the desired trans-â-
aminocyclopropane carboxylic acid derivative 19 in satisfac-
tory yield, possibly due to cyclopropane ring opening.17
18
However, oxidation of 18 with RuCl3/NaIO4 (MeCN/
CHCl3/H2O) cleanly produces 19 in 74% yield.
DCC-mediated coupling of 19 with 8 (R1 ) Cbz, R2 )
Me) forms the diacyl peroxide 20 in 83% yield.
Photolysis of neat 2013 at -78 °C (36 h) produces 21 in
47% yield and with g95:5 diastereomeric ratio (by 1H NMR
analysis in C6D6, diastereomers nonseparable by silica gel
chromatography), along with monodecarboxylation product
22 (41% yield). The retention of configuration at C-4 of 21
in the photolysis reaction is confirmed by NOE experiments.
In contrast to reaction at -78 °C, photolysis of neat 20 at
20 °C (4.5 h) in open atmosphere gives 18% yield of 21
along with 22 (29% yield). Photolysis of 20 at -196 °C is
sluggish (<20% conversion of 20 after 36 h).
Features of the photolytic decarboxylation-coupling reac-
tion that are critical for success are low temperature and
absence of solvent, as reported initially for simpler systems
by Scha¨fer and co-workers24 and extended by us to amino
acid derivatives.7 This reduces the mobility of the radical
We next examined the synthesis of protected (2S,4R)-
hypoglycin A (26, Scheme 5). Originally isolated from the
(13) All reactions were conducted with a 0.9 Amp UV lamp in 150 ×
75 mm crystallizing dish covered with a quartz plate and protected from
moisture. Reactions were performed on 0.07-0.93 mmol scale, but larger
scales are not problematic in our experience.
(14) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.; Mizukami, T.
J. Antibiot. 2000 53, 81-83.
(15) (a) Brandl, M.; Kozhushkov, S. I.; Loscha, K.; Kokoreva, O. V.;
Yufit, D. S.; Howard, J. A. K.; de Meijere, A. Synlett 2000, 1741-1744.
(b) Larionov, O. V.; Savel’eva, T. F.; Kochetkov, K. A.; Ikonnokov, N. S.;
Kozhushkov, S. I.; Yufit, D. S.; Howard, J. A. K.; Khrustalev, V. N.;
Belokon, Y. N.; de Meijere, A. Eur. J. Org. Chem. 2003, 869-877.
(16) Armstrong, A.; Scutt, J. N. Org. Lett. 2003, 5, 2331-2334.
(17) Cannon, J. G.; Garst, J. E. J. Org. Chem. 1975, 40, 182-184.
(18) (a) Carlsen, P. H. J.; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J.
Org. Chem. 1981, 46, 3936-3938. (b) Godier-Marc, E.; Aitken, D. J.;
Husson, H.-P. Tetrahedron Lett. 1997, 38, 4065-4068.
(19) (a) Hassall, C. H.; Reyle, K. Biochem. J. 1955, 60, 334-339. (b)
Fowden, L.; Pratt, H. M. Phytochemistry 1973, 12, 1677-1681.
(20) (a) Tanaka, K. In Handbook of Clinical Neurology; Vinken, P. J.,
Bruyn. G. W., Eds.; North-Holland: Amsterdam, 1979; Vol. 37, pp 511-
539.
(21) Baldwin, J. E.; Adlington, R. M.; Bebbington, D.; Russell, A. T.
Tetrahedron 1994, 50, 12015-12028.
(22) Scho¨llkopf, U. Top. Curr. Chem. 1983, 109, 65-84.
(23) Lai, M.-t.; Liu, L.-d.; Liu, H.-w. J. Am. Chem. Soc. 1991, 113,
7388-7397.
(24) Feldhues, M.; Scha¨fer, H. J. Tetrahedron 1985, 41, 4213-4235.
(b) Feldhues, M.; Scha¨fer, H. J. Tetrahedron 1986, 42, 1285-1290. (c)
Lomo¨lder, R.; Scha¨fer, H. J. Angew. Chem., Int. Ed. Engl. 1987, 26, 1253-
1254.
Org. Lett., Vol. 5, No. 24, 2003
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intermediates, thereby preventing formation of crossover
products, minimizing side reactions (e.g. hydrogen abstrac-
tion) and enhancing stereochemical control during coupling.
It is important to note that the cyclopropyl radical intermedi-
ate has a greater propensity to couple with retention of
configuration (dr g 95:5 in 21 and 26 at -78 °C) than the
more mobile acyclic secondary radicals (4.3:1 at -78 °C;
5:1 at -196 °C) produced in our earlier work.7 We believe
that in both cases the radical intermediates do not necessarily
retain their configuration (although cyclopropyl radicals are
more prone to do this). Instead, the lack of mobility of the
substituents (as well as of the whole molecules) in the frozen
matrix forces coupling to occur from the same side as the
departing carbon dioxide. Although it may be argued that
the bulky bis-(N-Boc-amino) substituent in 20 may direct
the stereochemical preference, previous work in our labora-
tory has shown that the effect of a â-chiral center on the
stereochemical outcome of the photolysis reaction is often
minimal.7 Whether the cis-amino cyclopropane diastereomer
of 21 can be generated with equal selection remains to be
determined. However, based on previous work, this method
should readily provide access to the C-2 epimer of 21 and
26 in high diastereomeric excess through the use of (R)-8.
The number of steps and overall yields leading to 21 and 26
are favorably competitive to those in the literature, and the
unique advantage of the present approach is incorporation
of the existing stereocenters and protecting groups of the
starting materials into final products.
In conclusion, photolysis of the unsymmetrical diacyl
peroxides derived from cyclopropanecarboxylic acids and
protected aspartic acid provides an access to various biologi-
cally interesting cyclopropylalanines. Current investigations
are focused on further extending the applications of the
methodology.
Acknowledgment. Financial support from Boehringer
Ingelheim Canada, the Natural Sciences and Engineering
Research Council of Canada (NSERC), and the Canada
Research Chair in Bioorganic and Medicinal Chemistry is
gratefully acknowledged.
Supporting Information Available: Experimental pro-
cedures and spectroscopic data of all new compounds. This
material is available free of charge via the Internet at
http://pubs.acs.org.
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