Stereocontrolled synthesis of 3-(trans-2-aminocyclopropyl)alanine, a key component of belactosin A

Article abstract of DOI:10.1021/ol0346887

(Matrix presented) Herein we report a concise synthesis of 3-(trans-2-aminocyclopropyl)alanine, a component of belactosin A, using asymmetric alkylation of a glycine enolate in the presence of chiral phase-transfer catalysts to control the configuration at C2. Reaction of protected glycidol with triethyl phosphonoacetate (Wadsworth-Emmons cyclopropanation) is used for enantiospecific preparation of an intermediate cyclopropanecarboxylate that is converted to a cyclopropylamine via Curtius rearrangement.

Full text of DOI:10.1021/ol0346887

ORGANIC
LETTERS
2003
Vol. 5, No. 13
2331-2334
Stereocontrolled Synthesis of
3-(trans-2-Aminocyclopropyl)alanine, a
Key Component of Belactosin A
Alan Armstrong* and James N. Scutt
Department of Chemistry, Imperial College London, South Kensington,
London SW7 2AZ, UK
a.armstrong@imperial.ac.uk
Received April 24, 2003
ABSTRACT
Herein we report a concise synthesis of 3-(trans-2-aminocyclopropyl)alanine, a component of belactosin A, using asymmetric alkylation of a
glycine enolate in the presence of chiral phase-transfer catalysts to control the configuration at C2. Reaction of protected glycidol with triethyl
phosphonoacetate (Wadsworth−Emmons cyclopropanation) is used for enantiospecific preparation of an intermediate cyclopropanecarboxylate
that is converted to a cyclopropylamine via Curtius rearrangement.
Belactosin A 1 is a recently isolated Streptomyces metabolite
that mediates cell-cycle progression via inhibition of cyclin-
cdk complexes and is therefore of interest as a potential
antitumor agent.1 Reports in the patent literature also suggest
that this compound and analogues effect proteasome
inhibition.1b
reported to date has come from the de Meijere group2a as
part of their significant contributions to the synthesis of
functionalized cyclopropanes.2 However, their route to 2
required resolution by recrystallization to give enantiomeri-
cally pure material and prepared the compound as an
inseparable mixture of diastereomers at the C2-stereocenter.
We envisaged that reagent-controlled catalytic asymmetric
alkylation of a glycine enolate equivalent would allow
separate preparation of either C2-diastereomer, as well as
provide a test of the methodology in a highly demanding
molecular environment. Among several routes evaluated for
the synthesis of the aminocyclopropane unit, the most concise
appeared to proceed via Curtius rearrangement of the ester
3, which we hoped could be accessed by reaction of the
enantiomerically pure protected glycidol 4 with a phospho-
nate carbanion (Scheme 1). This reaction, which we term
A particularly interesting feature of 1 is the presence of
the unique central (2S,1′R,2′S)-3-(trans-2-aminocyclopropyl)-
alanine amino acid 2. An efficient stereocontrolled route to
2 with the flexibility to provide other stereoisomers in a
controlled fashion would provide access to an expanded
range of important compounds for screening and be ap-
plicable to a total synthesis of 1. The only synthesis of 2
(2) (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) Wiedemann, S.; Frank, D.; Winsel, H.; de Meijere, A. Org. Lett. 2003,
5, 753-755. (c) 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. (d) Zindel, A.; de Meijere, A. J. Org. Chem. 1995, 60, 2968-
2073. (e) Zindel, J.; Zeeck, A.; Ko¨nig, W. A.; de Meijere, A. Tetrahedron
Lett. 1993, 34, 1917-1920.
(1) (a) Asai, A.; Hasegawa, A.; Ochiai, K.; Yamashita, Y.; Mizukami,
T. J. Antibiot. 2000, 53, 81-83. (b) Asai, A.; Mizukami, T.; Yamashita,
Y.; Akinaga, S.; Ikeda, S.; Kanda, Y. Eur. Patent 1166781, 2002; Chem.
Abstr. 2002, 133, 120677.
10.1021/ol0346887 CCC: $25.00 © 2003 American Chemical Society
Published on Web 05/22/2003

Encouraged by this result, we proceeded with the synthesis
of 2 by applying the reaction to commercially available (S)-
glycidol benzyl ether, ent-4 (Scheme 3). Screening of a range
Scheme 1
Scheme 3a
the Wadsworth-Emmons cyclopropanation, has rarely been
exploited in synthesis.3 Here we report successful imple-
mentation of this strategy, leading to enantioselective
synthesis of either C2-epimer of ent-2.
a Conditions: (a) triethyl phosphonoacetate, NaH, toluene, 110
°C, 14 h, 63%; (b) NaOH (aq), EtOH, 96%; (c) DPPA, BuOH,
NEt3, 53%; (d) Boc2O, MeCN, DMAP, 95%; (e) Pd/C, H2, cat.
AcOH, THF, 98%; (f) Bu4NI, DDQ, PPh3, CHCl3, rt.
t
At the outset of our studies, the degree of stereospecificity
of the Wadsworth-Emmons cyclopropanation reaction (and
hence its applicability to complex total synthesis of this type)
had not been determined, although optical rotation measure-
ments suggested that the transformation proceeds with some
degree of inversion at the epoxide stereocenter.3b,c We
addressed this issue by demonstrating that enantiomerically
pure (R)-styrene oxide 5 could be converted to the (S, S)-
trans-2-phenylcyclopropanecarboxylate 6 of >95% ee, thus
demonstrating essentially complete inversion of the epoxide
configuration. This is in accord with the proposed mechanism
(Scheme 2), which involves epoxide opening followed by
of solvents, bases, and temperatures (see Supporting Infor-
mation) revealed that the highest yields were obtained using
2 equiv of phosphonate and NaH in toluene at 110 °C,
providing the desired ent-3 in 63% yield and >95% ee
1
(analysis by H NMR in the presence of Eu(hfc)3 as chiral
shift reagent). NOE studies confirmed the trans relative
configuration of the cyclopropane. This reaction was per-
formed equally successfully on (R)-glycidol benzyl ether 4,
providing 3 (>95% ee), which possesses the same absolute
configuration as the natural product. With the aim of
preparation of novel material for biological testing, we
proceeded in the synthesis with the unnatural enantiomer ent-
3. Pleasingly, hydrolysis of ent-3 followed by Curtius
rearrangement of the derived azide and Boc-protection
afforded the cyclopropylamine 7. Removal of the benzyl
ether protecting group furnished (1′R,2′R)-(aminocyclopro-
pyl)methanol 8.
Scheme 2a
Exploratory work on the glycine enolate alkylation reaction
established a need for iodide 9 as the electrophile, since other
leaving groups (e.g., OMs, OTs) did not provide the
necessary reactivity. However, preparation of 9 from 8 using
several methods proved to be problematic due to the
instability of 9. Pleasingly, we were able to effect this
transformation cleanly and in high yield using Ph3P/DDQ/
Bu4NI,5 with 9 being used directly due to its sensitivity upon
chromatography and storage, as noted for its dideutero
analogue.2a We next studied the alkylation of iodide 9 with
the O’Donnell glycine equivalent 10 under phase-transfer
conditions, with a view to eventually using chiral catalysts.
We initially employed racemic 9 in order to ascertain the
level of any intrinsic 1,3-asymmetric induction in the
alkylation. However, attempts to perform the reaction under
liquid-liquid PTC conditions (50% aqueous KOH, toluene)
failed. Better results were obtained under solid-liquid-phase
transfer conditions (Bu4NBr catalyst). In CH2Cl2 as a solvent,
however, the inseparable protected (aminocyclopropyl)-
a Conditions: (a) triethyl phosphonoacetate, NaH, xylenes, 135
°C, 51%.
migration of the phosphonate group from carbon to oxygen
and subsequent SN2 ring closure. Recently, workers at
Bristol-Myers Squibb have reported similar cyclopropanation
of an aryl epoxide, confirming clean stereochemical inver-
sion.4
(3) (a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc. 1961, 83,
1733-1738. (b) Tomoskozi, I. Tetrahedron 1966, 22, 179-182. (c) Izydore,
R. A.; Ghirardelli, R. D. J. Org. Chem. 1973, 38, 1790-1793. (d)
Fitzsimmons, B. J.; Fraser-Reid, B. Tetrahedron 1984, 40, 1279-1287. (e)
Clive, D. L. J.; Daigneault, S. J. Chem. Soc., Chem. Commun. 1989, 332-
335. (f) Petter, R. C. Tetrahedron Lett. 1989, 30, 399-402. (g) Petter, R.
C.; Banerjee, S.; Englard, S. J. Org. Chem. 1990, 55, 3088-3097. (h) Jacks,
T. E.; Nibbe, H.; Wiemer, D. F. J. Org. Chem. 1993, 58, 4584-4588. (i)
Robl, J. A.; Sieber-McMaster, E.; Sulsky, R. Tetrahedron Lett. 1996, 37,
8985-8988. (j) Meul, T.; Kampfen, U. U.S. Pat. 5149869, 1992; Chem.
Abstr. 1992, 118, 38500. (k) Padmavathi, V.; Sharmila, K.; Reddy, A. S.;
Reddy, D. B. Ind. J. Chem. B. 2001, 40, 11-14.
(4) Singh, A. K.; Rao, M. N.; Simpson, J. H.; Li, W.; Thornton, J. E.;
Kuehner, D. E.; Kacsur, D. J. Org. Proc. Res. DeV. 2002, 6, 618-620.
(5) Iranpoor, N.; Firouzabadi, H.; Aghapour, Gh; Vaez zadeh, A. R.
Tetrahedron 2002, 58, 8689-8693.
2332
Org. Lett., Vol. 5, No. 13, 2003

Scheme 4a
Table 1. Alkylation of 10 with 9 Catalyzed by 14a
entry temp/°C [9] /M equiv of 10
time
ded yielde/%
1b
2
3
4
5c
-20
-20
-40
-40
-40
0.09
0.09
0.07
0.33
0.22
1.0
1.0
2.0
2.0
2.0
3 days
3 days
7 days >95
6 days >95
29
38
27
40
28
50
66
40 h
>95
a 14 (10 mol % with respect to 10), PhCH3, 4 Å molecular sieves.
b Molecular sieves omitted. c PhCH3/CH2Cl2 (1:1) was used as a solvent.
1
d Estimated by integration of the H NMR spectrum. e Yield from 8.
addition of 4 Å molecular sieves (entry 2). This effect has
previously been attributed to a closer contact cation-anion
pair being generated in the absence of water.10 Through
further lowering of the temperature to -40 °C, a dramatic
increase in selectivity was observed (>95% de, entry 3).
However, the reaction was prohibitively slow, with only ca.
53% conversion after 7 days. Increasing the concentration
of reactants increased the conversion but only to ca. 70%
after 6 days (entry 4). We reasoned that the reduced reaction
rate was due to the limited solubility of catalyst 14 in the
toluene solvent. As a consequence, a 1:1 toluene/CH2Cl2
solvent mixture was utilized in the hope of improving catalyst
solubility. In addition, a high iodide concentration was
utilized to minimize any CH2Cl2 bis-alkylation. Gratifyingly,
the desired iodide alkylation was complete in 40 h at -40
°C to give protected (aminocyclopropyl)alanine 12 in 66%
yield and 97:3 dr (entry 5 and Scheme 5). In addition, the
diastereoisomer with the natural relative configuration at C2,
11, was successfully synthesized in 52% yield and 6:94 dr
utilizing the pseudoenantiomeric catalyst 15 under the same
conditions (Scheme 5). In this case, a single recrystallization
provided diastereomerically pure material, and crystal-
lographic analysis of 11 (Figure 1) also confirmed that the
a Conditions: (a) 2 equiv of 10, KOH (s), 10 mol % Bu4NBr,
CH2Cl2, rt, 14 h, 30% 11/12 (from 8), 51% 13 (meso:C2 87:13);
(b) 1 equiv of 10, KOH (s), 10 mol % Bu4NBr, toluene, rt, 14 h,
55% 11/12 (from 8).
alanines 11 and 12 were obtained in only 30% yield in a
53:47 ratio, confirming a lack of 1,3-induction. Interestingly,
a major side product was the 1,3-diamino acid derivative
13, which formally arises from double alkylation of dichlo-
romethane. While side-products of this type have been
observed in phase-transfer-catalyzed alkylations using other
nucleophiles,6 to the best of our knowledge, it has not been
reported previously in alkylations of 10 and serves as a
warning of the potential reactivity of CH2Cl2 solvent when
relatively unreactive electrophiles are employed. Switching
to toluene solvent afforded a yield of 55% (44:56 dr) of (()-
11/12 over two steps from alcohol 8 (Scheme 4).
With success in the racemic alkylation, we now turned
our attention to asymmetric catalysis using quaternary
ammonium salts derived from cinchona alkaloids. Following
the pioneering work of O’Donnell et al.,7 important structural
modifications made independently by Corey and Lygo8 have
led to exceptional enantioselectivities using third-generation
catalysts such as the O(9)-allyl-N-(9-anthracenylmethyl)-
cinchonidinium (14) and cinchonium (15)9 bromides. We
began by using 14, which precedent suggested should provide
the (2S)-stereoisomer. However, extensive optimization was
required in order to accomplish efficient reaction with the
demanding electrophile 9 (Table 1). Toluene was selected
initially as a solvent in order to avoid the bis-alkylation of
CH2Cl2 observed in the racemic series. With 10 mol %
catalyst 14 (with respect to glycine) and 10 equiv of solid
CsOH‚H2O at -20 °C in toluene, only 29% de was observed
(entry 1), but this was improved to 38% de through the
(6) Dehmlow, E. V.; Dehmlow, S. S. Phase Transfer Catalysis; VCH:
Weinheim, Germany, 1993; p 72. Dalgaard, L.; Jensen, L.; Lawesson, S.-
O. Tetrahedron 1974, 30, 93-104. Vinogradova, N. M.; Artyushin, O. I.;
Kalyanova, R. M.; Lyssenko, K. A.; Petrovskii, P. V.; Mastryukova, T. A.;
Kabachnik, M. I. Russ. Chem. Bull. 1998, 47, 960-966.
(7) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353-2355. O’Donnell, M. J.; Wu, S.; Huffman, J. C. Tetrahedron
1994, 50, 4507-4518.
Figure 1. X-ray crystal structure of 11.
(8) Corey, E. J.; Xu, F.; Noe, M. C. J. Am. Chem. Soc. 1997, 119, 12414-
12415. Lygo, B.; Wainwright, P. G. Tetrahedron Lett. 1997, 38, 8595-
8598.
relative stereochemical outcome of asymmetric alkylation
was in line with precedent. At this stage, correlation with
(9) O’Donnell, M. J.; Delgado, F.; Pottorf, R. S. Tetrahedron 1999, 55,
6347-6362.
Org. Lett., Vol. 5, No. 13, 2003
2333

Scheme 5a
a Conditions: (a) Bu4NI, DDQ, PPh3, CHCl3, rt; (b) 2 equiv of 10, 20 mol % 14, 10 equiv of CsOH‚H2O (s), 1:1 toluene/CH2Cl2, -40
°C, 40 h; (c) 2 equiv of 10, 20 mol % 15, 10 equiv of CsOH‚H2O (s), 1:1 toluene/CH2Cl2, -40 °C, 40 h; (d) 1.2 M HCl (aq)/THF, rt, 48
h.
the reported data for the natural product was possible via
global deprotection of 11 and 12 and comparison with H
cyclopropanation of (R)-glycidol benzyl ether, which we have
already shown to be feasible. Further studies in this area will
be reported in due course.
1
NMR data for 3-(2-aminocyclopropyl)alanine‚HCl obtained
1
by degradation of the natural product. Gratifyingly, the H
NMR spectrum of ent-2 was in very good agreement with
that of the genuine sample,1b confirming the reported
stereochemical assignment.
Acknowledgment. We thank the EPSRC (studentship to
J.N.S.) for support of this work. We are grateful to Pfizer,
Merck Sharp and Dohme, AstraZeneca, and Bristol-Myers
Squibb for unrestricted support of our research programs.
We thank Dr. A. Asai of Kyowa Hakko Kogyo Co., Ltd.,
for supplying 1H NMR data for 2 and Dr. A. J. P. White for
the X-ray structure determination.
In conclusion, we have developed a concise synthesis of
either C2-epimer of the unusual cyclopropylamine amino acid
ent-2. The synthesis highlights the under-exploited Wad-
sworth-Emmons procedure for the enantiospecific formation
of cyclopropanes, as well as the extension of catalytic
asymmetric alkylation of glycine enolate equivalents to
highly functionalized, relatively unreactive electrophiles. We
anticipate that selective removal of the imine functionality
in 11 and mono-Boc-deprotection will allow ent-2 to be
incorporated into biologically significant analogues of be-
lactosin A. The total synthesis of the natural product will
require the synthesis of 2 and will thus proceed via
Supporting Information Available: Experimental pro-
cedures and spectroscopic characterization information;
details of optimization of reaction conditions for formation
of ent-3 and ee determination; 1H NMR spectrum and NOE
1
data for ent-3; NOE data for 7; H NMR spectra of 11, 12,
ent-2‚xHCl, 16‚xHCl; and X-ray structural data of 11. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(10) Chen, G.; Deng, Y.; Gong, L.; Mi, A.; Cui, X.; Jiang, Y.; Choi, M.
C. K.; Chan, A. S. C. Tetrahedron: Asymmetry 2001, 12, 1567-1571.
OL0346887
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Org. Lett., Vol. 5, No. 13, 2003