Expedient synthesis of cyclopropane α-amino acids by the catalytic asymmetric cyclopropanation of alkenes using iodonium ylides derived from methyl nitroacetate

Article abstract of DOI:10.1021/ja056192l

A highly enantioselective (up to 97.5% ee) and diastereoselective (95:5 dr trans/cis) Cu(I)-catalyzed cyclopropanation of alkenes using phenyliodonium ylide generated in situ from iodosobenzene and methyl nitroacetate is reported. The cyclopropanation took place with high enantioselectivity for a wide range of alkenes, and the reaction was performed at room temperature. 1-Nitrocyclopropyl esters are versatile building blocks to access the corresponding cyclopropane amino esters and aminocyclopropanes in two and three steps, respectively, from commercially available products. Copyright

Full text of DOI:10.1021/ja056192l

Published on Web 12/01/2005
Expedient Synthesis of Cyclopropane r-Amino Acids by the Catalytic
Asymmetric Cyclopropanation of Alkenes Using Iodonium Ylides Derived
from Methyl Nitroacetate
Benoˆıt Moreau and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
Received September 15, 2005; E-mail: andre.charette@umontreal.ca
The asymmetric synthesis of cyclopropane R-amino acids is an
important process due to the occurrence of this moiety in natural
products1 and in several bioactive unnatural analogues.2 The
sterically restrained cyclopropane amino acid is known to induce
changes in conformation2b such as â-turns2c and to bring stability
toward enzymatic hydrolysis.2d,e Although several approaches have
been designed toward their asymmetric synthesis,3,4 the transforma-
tion remains a great synthetic challenge since control of both
Figure 1. Important cyclopropane amino acids and amines.
diastereoselectivity and enantioselectivity in the cyclopropane
formation step is required. Moreover, few methods allow expedient
preparation of a wide series of derivatives from readily available
starting materials. Furthermore, the related chiral aminocyclopro-
panes5 are widely found in potential drugs (Figure 1).6
Figure 2. Various classes of metal (M) carbenes in cyclopropanations.
Scheme 1. Approach toward Cyclopropyl Amino Acids
Our research group has been developing a general expedient
approach for the synthesis of the cyclopropyl amino acid unit, using
either diazo (2b) or phenyliodonium ylide (2a) derivatives of R-nitro
ester 1 (Scheme 1).7 The Rh- or Cu-catalyzed cyclopropanation of
these species with alkenes affords substituted 1-nitro-cyclopropyl
carboxylates7,8 in good yields and diastereocontrol but with poor
enantiocontrol (e72% ee).7d
This is not surprising since, even though the transition-metal-
catalyzed cyclopropanation reactions of metal carbenes bearing
either an acceptor group (EWG) (A) or both acceptor and donor
(EDG) groups (B)4d have provided high enantiocontrol, similar
reactions of metal carbenes substituted by two acceptor groups (C)
have given much lower ee’s (Figure 2).3a
Table 1. Optimization of Reaction Conditions for the
Cyclopropanation of Styrene (3a) with Cu(I)
We herein report that a Cu(I)-bis(oxazoline) complex is highly
efficient in the catalytic asymmetric cyclopropanation of phenyl-
iodonium ylides.9
This study was initiated using styrene, PhIdO, and molecular
sieves to scavenge water. Commercially available isopropylidene
bis(4-phenyl-2-oxazoline) (5) and Cu(MeCN)4PF6 were used as
catalyst precursors (Table 1, entry 1).
yielda
drb
eec
An encouraging 10% yield (22% conversion + remaining
unreacted 1a) of the desired cyclopropanation adduct was obtained
using 5 mol % of the catalyst, which showed that the presence of
iodosobenzene, an oxidizing agent, did not shut down the Cu(I)
catalytic pathway. Furthermore, the enantioselectivities (75% ee)
were similar to those previously observed with the parent diazo
compound with 5 as the ligand.7d Our next goal was to find
conditions to fully consume methyl nitroacetate 1a. The use of
Na2CO3 (2.3 equiv) as an additive was found to be optimal for the
full consumption of the starting material, although no improvement
in the yield was observed. It was assumed that the low catalyst
activity was responsible for the low yield (entry 3). In contrast to
the cyclopropanation reaction of the parent diazo compound, use
of ethyl diazoacetate (EDA) was not required to activate the Cu(I)
catalyst (entry 2). Upon screening the Cu(I) source, we observed a
tremendous effect of the catalyst counterion on the reactivity.10
Among those tested, the hexafluoroantimonate (SbF6) counterion
entry
additive
solvent
Cu(I) (x mol %)
1
2
3
4
5
6
7
8
9
none
EDA (0.2)d
Na2CO3 (2.3) CH2Cl2
Na2CO3 (2.3) CH2Cl2
Na2CO3 (2.3) toluene
CH2Cl2
CH2Cl2
Cu(MeCN)4PF6 (5) 10 85:15 75
Cu(MeCN)4PF6 (5) 13 85:15 75
Cu(MeCN)4PF6 (5) 11 92:8
74
82
89
90
91
91
91
CuSbF6 (5)e
CuSbF6 (5)
58 92:8
65 92:8
35 92:8
73 93:7
79 93:7
52 93:7
Na2CO3 (2.3) o-xylene CuSbF6 (5)
Na2CO3 (2.3) C6H6
Na2CO3 (2.3) C6H6
Na2CO3 (2.3) C6H6
CuSbF6 (5)
CuSbF6 (2)
CuSbF6 (1)
a Isolated yield. b Diastereomeric ratio was determined by 1H NMR.
c Enantiomeric excesses (ee) were determined by SFC on chiral stationary
phase. d Ethyl diazoacetate was premixed with the catalyst. e CuSbF6 was
generated from CuCl (1 equiv) and AgSbF6 (1.2 equiv).
resulted in an increased yield (58%) of the resulting cyclopropane
and improved enantioselectivity (82% ee) (entry 4). The solvent
effect on the enantioselectivity was then studied, and several trends
were observed. Acetonitrile (either added or from Cu(MeCN)4PF6)
9
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J. AM. CHEM. SOC. 2005, 127, 18014-18015
10.1021/ja056192l CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 2. Scope for the Cyclopropanation of Alkenes (3a-j) with
In conclusion, a three-step synthesis of enantiomerically enriched
cyclopropane R-amino acid esters was developed using the Cu(I)-
catalyzed asymmetric cyclopropanation reaction of phenyliodonium
ylides with alkenes. The method is efficient and practical, and it
should find wide application in synthesis. Efforts to access the other
diastereomeric cyclopropane R-amino acids are in progress and will
be reported in due course.
Cu(I)
entry
alkene
yielda
drb
eec
1
2
3
4
5
6
7
8
9
10
PhCHdCH2 (3a)
82e
45
71f
76
53
74
54
80
72
84
94:6
92:8
93:7
93:7
93:7
91:9
95:5
93:7
95:5
82:18
91
91
68d
92
91
91
93
90
98d
90
4-Cl-PhCHdCH2 (3b)
4-MeO-PhCHdCH2 (3c)
4-Me-PhCHdCH2 (3d)
1-NaphthCHdCH2 (3e)
2-NaphthCHdCH2 (3f)
2,4,6-Me3C6H2CHdCH2 (3g)
4-tBu-PhCHdCH2 (3h)
indene (3i)
Acknowledgment. This work was supported by NSERC
(Canada), Merck Frosst Canada, Boehringer Ingelheim (Canada)
Ltd., and the Universite´ de Montre´al. B.M. is grateful to Boehringer
Ingelheim for a postgraduate fellowship.
Supporting Information Available: Experimental procedures for
the preparation of all the compounds and characterization data for each
reaction and detailed structural assignment. This material is available
free of charge via the Internet at http://pubs.acs.org.
1,3-butadiene (3j)
a Isolated yield. b Diastereomeric ratio was determined by 1H NMR.
c Enantiomeric excesses (ee) were determined by SFC on chiral stationary
phases. d Enantiomeric excesses (ee) were determined on a derivative.
e Reaction was performed on 10 mmol scale. f Yield by 1H NMR with
internal standard.
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To demonstrate the versatility of the nitrocyclopropyl carboxy-
lates 4 as chiral building blocks, methyl 1-nitro-2-phenylcyclopropyl
carboxylate (4a) was converted into important unnatural cyclopro-
panes 6a2c and 7a6a (Scheme 2). A simple two-step process was
used to decarboxylate and reduce the nitroester 4a into the amine
7a. The most stable trans isomer of the 1-aminocyclopropane 7a
was obtained through thermodynamic equilibration of the 1-nitro-
cyclopropane. Similarly, the aminoester 6a was obtained in high
yield from 4a by a simple Zn-mediated reduction.7a In both cases,
the high enantioselectivity was preserved.
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Scheme 2. Derivatization of 1-Nitrocyclopropyl Carboxylate 4a
(11) See Supporting Information for details.
(12) Major diastereomer cis determined by NOE experiment. See Supporting
Information for details.
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