An Expedient and Practical Method for the Synthesis of A Diverse Series of Cyclopropane α-Amino Acids and Amines

Article abstract of DOI:10.1021/jo035596y

A practical synthesis for the preparation of a diverse series of cyclopropane α-amino acids is described. Nitrocyclopropane carboxylates can be readily prepared through treatment of α-nitroesters and iodobenzene diacetate or α-nitro-α-diazoesters with a R

Full text of DOI:10.1021/jo035596y

An Exp ed ien t a n d P r a ctica l Meth od for th e Syn th esis of a Diver se
Ser ies of Cyclop r op a n e r-Am in o Acid s a n d Am in es
Ryan P. Wurz and Andre´ B. Charette*
De´partement de Chimie, Universite´ de Montre´al, P.O. Box 6128, Station Downtown,
Montre´al, Que´bec, Canada H3C 3J 7
andre.charette@umontreal.ca
Received October 30, 2003
A practical synthesis for the preparation of a diverse series of cyclopropane R-amino acids is
described. Nitrocyclopropane carboxylates can be readily prepared through treatment of R-nitro-
esters and iodobenzene diacetate or R-nitro-R-diazoesters with a Rh(II) catalyst and an olefin.
Reduction of the nitro group using zinc/HCl in i-PrOH affords substituted cyclopropane R-amino
esters in modest to high yields (54-99%). A “one-pot” procedure involving sequential cyclopro-
panation and reduction is described. The method can also be applied to the preparation of
arylcyclopropyl amines (three examples).
In tr od u ction
Considerable interest has been drawn to cyclopropane
R-amino acids (ACCs) in recent years on account of their
diverse biological activities as low molecular weight
inhibitors or as nonproteogenic components in peptides.
Substituted ACCs represent challenging synthetic targets
due to their chiral quaternary center and the presence
of an often sensitive cyclopropane subunit. There have
been many methods developed for their preparation,1 yet
few methods allow facile preparation of a diverse series
of derivatives from readily available starting materials.
Furthermore, only a few compounds are naturally occur-
ring, making their isolation from these sources incon-
venient for large-scale production.
The parent compound 1-amino-1-cyclopropane car-
boxylic acid (ACC) occurs naturally2 as the immediate
biosynthetic precursor of the plant hormone ethylene,3
and also displays properties of pharmaceutical interest
when incorporated into peptides. A variety of other
naturally occurring substituted ACCs exist including
coronatine, a novel phytotoxin produced by Pseudomonas
syringae,4 and carnosadine, a natural product isolated
from the red algae Grateloupia carmasa which can be
F IGURE 1. Naturally occurring cyclopropane amino acids.
regarded as the cyclopropane analogue of arginine (Fig-
ure 1).5
Perhaps, the greatest pharmacological potential of
ACCs exists in the field of conformationally constrained
peptide mimetics.6 It has been observed that their
incorporation into peptides affects the 3-dimensional
conformation, leading to more compact structures. This
compression of the peptide results in reduced rates of
hydrolysis, resulting in increased bioavailability of the
peptide.7 In principle, replacement of any amino acid by
its cyclopropane analogue could potentially lead to desir-
able modifications to the peptide’s conformation.
Synthetic ACCs have also been shown to have impor-
tant biological activities including m-tyrosine cyclopro-
pane amino acid (cyclo-m-Tyr), which is a competitive
* To whom correspondence should be addressed. Phone: (514) 343-
2432. Fax: (514) 343-5900.
(1) For reviews see: (a) Burgess, K.; Ho, K.-K.; Moye-Sherman, D.
Synlett 1994, 575. (b) Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetra-
hedron: Asymmetry 2000, 11, 645. (c) Salau¨n, J . Top. Curr. Chem.
2000, 207, 1. (d) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Najera, C.
J . Org. Chem. 2000, 65, 3034.
(2) For the first isolation see: (a) Burroughs, F. Nature 1957, 179,
360. (b) Va¨ha¨talo, M. L.; Virtanen, A. I. Acta Chem. Scand. 1957, 11,
741.
(3) For the mechanism of ethylene biosynthesis see: (a) Zhou, J .;
Rocklin, A. M.; Lipscomb, J . D.; Que, L., J r.; Solomon, E. I. J . Am.
Chem. Soc. 2002, 124, 4602. (b) Pirrung, M. C. Acc. Chem. Res. 1999,
32, 711.
(5) (a) Wakamiya, T.; Nakamoto, H.; Shiba, T. Tetrahedron Lett.
1984, 25, 4411. (b) Wakamiya, T.; Oda, Y.; Fujita, H.; Shiba, T.
Tetrahedron Lett. 1986, 27, 2143.
(6) (a) J ime´nez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J . Am.
Chem. Soc. 1998, 120, 9452. (b) Gademann, K.; Ha¨ne, A.; Rueping,
M.; J aun, B.; Seebach, D. Angew. Chem., Int. Ed. 2003, 42, 1534. (c)
Bednarek, M. A.; MacNeil, T.; Kalyani, R. N.; Tang, R.; Van der Ploeg,
L. H. T.; Weinberg, D. H. J . Med. Chem. 2001, 44, 3665. (d) D´ıaz, M.;
J ime´nez, J . M.; Ortun˜o, R. M. Tetrahedron: Asymmetry 1997, 8, 2465.
(e) D´ıaz, M.; Ortun˜o, R. M.; Tetrahedron: Asymmetry 1996, 7, 3465.
(7) (a) Burgess, K.; Ho, K.-K.; Pettitt, B. M. J . Am. Chem. Soc. 1995,
117, 54. (b) Burgess, K.; Ke, C.-Y. J . Org. Chem. 1996, 61, 8627. (c)
Kimura, H.; Stammer, C. H.; Ren-Lin, C.; Stewart, J . Biochem.
Biophys. Res. Commun. 1983, 115, 112. (d) Ogawa, T.; Shimohigashi,
Y.; Yoshitomi, H.; Sakamoto, H.; Kodama, H.; Waki, M.; Stammer, C.
H. Pept. Chem. 1988, 25. (e) Ogawa, T.; Shimohigashi, Y.; Shiota, M.;
Waki, M.; Stammer, C. H.; Ohno, M. Pept. Chem. 1989, 43.
(4) (a) Ichihara, A.; Shiraishi, K.; Sato, H.; Sakamura, S.; Nishiyama,
K.; Sakai, R.; Furusaki, A.; Matsumoto, T. J . Am. Chem. Soc. 1977,
99, 636. (b) Bender, C. L.; Alarcon-Chaidez, F.; Gross, D. C. Microbiol.
Mol. Biol. Rev. 1999, 63, 266.
10.1021/jo035596y CCC: $27.50 © 2004 American Chemical Society
Published on Web 01/22/2004
1262
J . Org. Chem. 2004, 69, 1262-1269

Synthesis of Cyclopropane R-Amino Acids and Amines
SCHEME 1
Furthermore, these reactions are often tedious and
proceed with only modest yields. One of the most expedi-
ent and reliable approaches to date involves the method
reported by Davies and co-workers which employs a
Curtius rearrangement for the incorporation of the
quaternary amine (Scheme 1).13b,c Cyclopropanation of an
alkene with vinyldiazo ester 1 and a chiral rhodium(II)
carboxylate catayst proceeds in high yields and enantio-
selectivities for a variety of alkenes. The quaternary
amine is then incorporated in a sequence involving
oxidative cleavage of the vinylcyclopropane 2, followed
by a Curtius rearrangement with the resulting carboxylic
acid, leading to the protected aminocyclopropane ester 3
in modest yields for the two-step sequence (Scheme 1).
In an attempt to reduce the number of required steps
for the synthesis of cyclopropane R-amino acids and allow
for the synthesis of substituted ACCs with sensitive
functionalities, we envisioned a metal-catalyzed cyclo-
propanation of an R-nitro-R-diazocarbonyl, 4,16 affording
the nitrocyclopropane carboxylate 5 (Table 1).16a,17 We
recently described an alternative cyclopropanation pro-
cedure to avoid the potentially dangerous R-nitro-R-
diazocarbonyl substrates. In this method, iodobenzene
diacetate was used to directly effect a cyclopropanation
reaction between R-nitrocarbonyls 6 and olefins in the
presence of a catalyst (Table 1). This cyclopropanation
presumably proceeds via an iodonium ylide intermediate
formed in situ.18 In both of these methods, the diazo
substrate 4 and the R-nitroester 6 are readily available,
along with a wide variety of olefinic substrates. The
strategy would then afford the corresponding cyclopro-
pane amino acids through reduction of the nitro group
and saponification of the ester.
F IGURE 2. Biologically active products containing cyclopro-
pane amino acid subunits.
inhibitor of pig liver L-aromatic amino acid decarboxylase
(Dopa decarboxylase, DCC) against D-m-tyrosine.8 Re-
searchers at Boehringer-Ingelheim recently incorporated
substituted ACCs into small peptides9 and macrocycles,10
resulting in potent NS3 protease inhibitors against
hepatitis C. The cyclopropane derivative of penicillin G,
(2,3)-â-methylenepenam, serves as a probe for the â-
lactamase mechanism of action and was found to be a
â-lactamase inhibitor (Figure 2).11
Resu lts a n d Discu ssion
There are four general strategies for the synthesis of
functionalized ACCs including (a) cyclopropanation of
functionalized R,â-dehydro amino acids,12 (b) Curtius or
Hofmann rearrangements of carboxylic acid containing
cyclopropanes,13 (c) double alkylation of glycine anion
equivalents,14 and (d) cyclopropanation using amino acid
equivalents.15 Using the latter approach as a synthetic
strategy, unmasking an amine equivalent could avoid the
additional steps required when Curtius or Hofmann
rearrangements are employed in the synthetic strategy.
(8) Ahmad, S.; Phillips, R. S.; Stammer, C. H. J . Med. Chem. 1992,
35, 1410.
(9) Poupart, M.-A.; Cameron, D. R.; Chabot, C.; Ghiro, E.; Goudreau,
N.; Goulet, S.; Poirier, M.; Tsantrizos, Y. S. J . Org. Chem. 2001, 66,
4743.
(10) (a) Lamarre, D.; Anderson, P. C.; Bailey, M.; Beaulieu, P.;
Bolger, G.; Bonneau, P.; Bo¨s, M.; Cameron, D. R.; Cartier, M.;
Cordingley, M. G.; Faucher, A.-M.; Goudreau, N.; Kawai, S. H.; Kukolj,
G.; Lagace´, L.; Laplante, S. R.; Narjes, H.; Poupart, M.-A.; Rancourt,
J .; Sentjens, R. E.; St. George, R.; Simoneau, B.; Steinmann, G.;
Thibeault, D.; Tsantrizos, Y. S.; Weldon, S. M.; Yong, C.-L.; Llina`s-
Brunet, M. Nature 2003, 426, 186-189. (b) Tsantrizos, Y. S.; Bolger,
G.; Bonneau, P.; Cameron, D. R.; Goudreau, N.; Kukolj, G.; LaPlante,
S. R.; Llina`s-Brunet, M.; Nar, H.; Lamarre, D. Angew. Chem., Int. Ed.
2003, 42, 1355.
(11) (a) Keith, D. D.; Tengi, J .; Rossman, P.; Tobaro, L.; Weigele,
M. Tetrahedron 1983, 39, 2445. (b) Atherton, F. R.; Hassall, C. H.;
Lambert, R. W. J . Med. Chem. 1986, 29, 29. (c) Adlington, R. M.;
Baldwin, J . E.; Challis, G. L.; Tetrahedron Lett. 1998, 39, 8537. (d)
Sebffleber, F. C.; Geiger, W. E., J r. J . Am. Chem. Soc. 1975, 97, 5020.
(12) (a) Adams, L. A.; Aggarwal, V. K.; Bonnert, R. V.; Bressel, B.;
Cox, R. J .; Shepherd, J .; de Vicente, J .; Walter, M.; Whittingham, W.
G.; Winn, C. L. J . Org. Chem. 2003, 68, 9433. (b) Aggarwal, V. K.;
Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew.
Chem., Int. Ed. 2001, 40, 1433. (c) Chinchilla, R.; Falvello, L. R.;
Galindo, N.; Na´jera, C. J . Org. Chem. 2000, 65, 3034. (d) King, S. W.;
Riordan, J . M.; Holt, E. M.; Stammer, C. H. J . Org. Chem. 1982, 47,
3270. (e) Calmes, M.; Daunis, J .; Escale, F. Tetrahedron: Asymmetry
1996, 7, 395.
(13) For asymmetric syntheses see: (a) Charette, A. B.; Coˆte´, B. J .
Am. Chem. Soc. 1995, 117, 12721. (b) Davies, H. M. L.; Cantrell, W.
R., J r. Tetrahedron Lett. 1991, 32, 6509. (c) Davies, H. M. L.; Bruzinski,
P. R.; Lake, D. H.; Kong, N.; Fall, M. J . J . Am. Chem. Soc. 1996, 118,
6897.
(14) (a) Aitken, D. J .; Royer, J .; Husson, H.-P. J . Org. Chem. 1990,
55, 2814.
(15) For racemic syntheses see: (a) Barluenga, J .; Aznar, F.;
Gutie´rrez, I.; Garcia-Granda, S.; Llorca-Baragan˜o, M. A. Org. Lett.
2002, 4, 4273. (b) Bertus, P.; Szymoniak, J . J . Org. Chem. 2002, 67,
3965. (c) Scho¨llkopf, U.; Hauptreif, M.; Dippel, J .; Nieger, M.; Egert,
E. Angew. Chem., Int. Ed. Engl. 1986, 25, 192.
Cyclopropanation using methods A and B allows access
to a diverse series of nitrocyclopropane carboxylates 5.
In most cases, similar chemical yields and diastereo-
selectivities19 can be obtained for a variety of substrates
using either method A or method B. Electron-rich and
-deficient styrene derivatives are well tolerated by both
methods (Table 1, entries 1-4). Two noteworthy excep-
tions include the sterically hindered styrene derivative20
(Table 1, entry 3) and 4-phenyl-1-butene (Table 1, entry
5) for which method B gave only modest yields (ca. 50%)
and completely failed, respectively, even under forcing
(16) For preparation of these reagents see: (a) Charette, A. B.; Wurz,
R. P.; Ollevier, T. Helv. Chim. Acta 2002, 85, 4468. (b) Charette, A.
B.; Wurz, R. P.; Ollevier, T. J . Org. Chem. 2000, 65, 9252. (c) O’Bannon,
P. E.; Dailey, W. P. Tetrahedron Lett. 1989, 30, 4197. (d) Scho¨llkopf,
U.; Toone, P. Ann. Chem. 1971, 753, 135. (e) Scho¨llkopf, U.; Markusch,
P. Ann. Chem. 1971, 753, 143. (f) Scho¨llkopf, U.; Toone, P.; Schaefer,
H.; Markusch, P. Ann. Chem. 1969, 722, 45.
(17) (a) O’Bannon, P. E.; Dailey, W. P. J . Org. Chem. 1989, 54, 3096.
(b) O’Bannon, P. E.; Dailey, W. P. Tetrahedron 1990, 46, 7341.
(18) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327.
(19) The diastereoselectivities for the two methods vary less than
(2%.
(20) The steric bulk associated with the TBDPS ether appears to
be the only factor influencing the reduced chemical yield when using
method B. It should be noted that 4-vinylanisole undergoes efficient
cyclopropanations using methods A and B (see ref 18).
J . Org. Chem, Vol. 69, No. 4, 2004 1263

Wurz and Charette
TABLE 1. P r ep a r a tion of Su bstitu ted Nitr ocyclop r op a n e Ca r boxyla tes
a
b
d
The major isomer is depicted. Isolated yields after purification by flash chromatography. c Reaction allowed to stir overnight. Five
equivalents of alkene used. e Refers to the exo:endo ratio. f Reaction required heating at 40 °C for 3 h.
TABLE 2. P r ep a r a tion of Sym m etr ic Nitr ocyclop r op a n e
Ca r boxyla tes
conditions.21 However, when R-stabilized electron-rich
olefins are used (e.g., the olefin in entry 8 is more
R-stabilized than that in entry 5), the in situ procedure
can be scaled up with ease, even with reduced catalyst
loadings.22
A series of cyclic cis-olefins were also good substrates
for the cyclopropanation reaction with R-nitro-R-diazo-
carboxylates 4, with the reaction yields varying as a
function of ring size. Cyclopropanation of cyclopentene
afforded excellent yields of the corresponding cyclopro-
pane 5i, with preference for the exo-diastereomer (Table
2, entry 1). In contrast, cyclohexene proved to be less
cyclopropane
exo:endo
ratio
yielda
(%)
entry
n
R
5
1
2
3
4
5
1
2
2
Bn
Me
Bn
Bn
Bn
5i
5j
5k
5l
5m
87:13
88:12
86:14
80:20
74:26
81
55
39
66
71
4
(21) A variety of additives were tested including toluene, KBr
aqueous solutions, molecular sieves, MgO, etc.
4b
a
Isolated yields after purification by flash chromatography.
Alkene derived from cyclooctadiene.
(22) Ethyl nitroacetate and styrene undergo a cyclopropanation
reaction when treated with PhI(OAc)2 (1.05 equiv) and [Rh(Octan-
oate)2]2 (0.04 mol %) on a 3.0 g scale. The reaction was heated at 40
°C for 4.5 h, affording 79% isolated yield of cyclopropane 5a in a 92:8
E:Z ratio. For a recent example of reduced catalyst loadings in Rh(II)-
catalyzed cyclopropanation reactions see: Davies H. M. L.; Venkat-
aramani, C. Org. Lett. 2003, 5, 1403.
b
reactive under the cyclopropanation conditions and gave
disappointing yields of the corresponding cyclopropane
1264 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Cyclopropane R-Amino Acids and Amines
5j or 5k (Table 2, entries 2 and 3).23 Cyclooctene- and
cyclooctadiene-derived cyclopropanes could also be pre-
pared with acceptable yields (Table 2, entries 4 and 5).
Attempts to cyclopropanate these substrates using iodo-
benzene diacetate derived conditions resulted in only
modest yields, between 45% and 50%, of the correspond-
ing cyclopropanes 5i and 5m after 24 h at 40 °C in sealed
tubes.
SCHEME 2
With two reliable methods for the preparation of a
variety of nitrocyclopropane carboxylates 5 in modest to
high yields, we then sought a method for the reduction
of the nitro group. Although there exist several reported
examples concerning the reduction of nitrocyclopro-
panes,24 to the best of our knowledge, only two examples
exist for the reduction of nitrocyclopropane carboxylates.
The first example was reported by Seebach and Ha¨ner25
involving the parent compound 7 (eq 1), while the second
example was recently reported by Kuznetsova and co-
workers involving spirohexane amino acids.26 It is also
noteworthy to mention the absence of reports in the
literature for the reduction of nitrocyclopropanes contain-
ing aromatic groups.
SCHEME 3
drogenolysis efficiency could be derived from the aromatic
substituent in the 2-position. Thus, 2-phenylcyclopropane
carboxylate ethyl ester (12) was subjected to the above
reaction conditions, resulting in high yields of the opened
product 13 (Scheme 3). Cyclopropane 5e, which does not
contain an aromatic group directly attached to the
cyclopropane ring, was also submitted to the reduction
conditions, and only small quantities of the desired amino
ester could be recovered (Scheme 3).28
Clearly, the reduction was problematic using Pd cata-
lysts for these cyclopropanes, so a variety of reducing
conditions for nitro groups were screened including
Raney Ni,29 Fe/HCl,24a and Zn/Ac2O.30 All these conditions
led to unidentifiable products. The ease of rearrangement
of activated (aromatic containing) nitrocyclopropane car-
boxylates to isoxazoline N-oxides16a under mildly acidic
conditions and their efficient ring opening with a variety
of nucleophiles30,31 further impose the necessity for mild
reducing conditions. Lewis acids have also been found
to induce rearrangements.17b
When methyl 2-phenyl-1-nitrocyclopropane carboxylate
(9) was submitted to the above reaction conditions (Pd/
C, H2, 1 atm), amine 11, resulting from the hydrogenoly-
sis of the cyclopropane, was isolated in low yields.
Ammonium formate was then used as a “H2” source and
led to isolation of hydroxylamine 10 in good yields
(Scheme 2). It has been suggested that Pd catalysts are
preferable for partial reduction of R-carboxy nitro groups
to hydroxyamines probably due to the resulting stabiliza-
tion imparted by the intramolecular hydrogen bonding.27
Higher pressures of H2 with Pd(OH)2/C led to the hydro-
genolysis of the cyclopropane ring, affording amine 11
in 74% isolated yield (Scheme 2). The hydrogenolysis of
the cyclopropane ring was found to be regiospecific as
only one of the two possible products was observed in the
crude reaction mixtures.
We then turned to zinc(0) due to its success in reduc-
tions involving sterically encumbered R,R-disubstituted
nitro carboxylates27a and various other tertiary and
quaternary nitro groups.32 A variety of acid sources
(NH4Cl, AcOH, HCl) were screened along with various
stoichiometries of acid and zinc. Finally, 20 equiv of zinc
(dust) with 10 equiv of aqueous 1 N HCl in methanol
We then wondered if hydrogenolysis resulted from the
presence of radical species on the nitro group R to the
cyclopropane ring during reduction. Alternatively, hy-
(23) The benzyl ester was used to reduce the volatility of the
corresponding cyclopropyl amine upon reduction.
(24) For nitrocyclopropane reduction with Fe/HCl see: (a) Hass, H.
B.; Shechter, H. J . Am. Chem. Soc. 1953, 75, 1382. Pd/C see: (b)
Brandl, M.; Kozhushkov, S. I.; Loscha, K.; Kokoreva, O.; Yufit, D. S.;
Howard, J . A. K.; Meijere de, A. Synlett 2000, 1741. (c) Zindel, J .;
Meijere de, A. Synthesis 1994, 190. For Raney nickel see: (d) Yun, Y.
K.; Godula, K.; Cao, Y.; Donaldson, W. A. J . Org. Chem. 2003, 68, 901.
(25) Seebach, D.; Ha¨ner, R. Chimia 1985, 39, 356.
(26) Conditions: 10% Pd/C, NH4CO2H (10 equiv), 40 h, rt, EtOH.
See: Yashin, N. V.; Averina, E. B.; Gerdov, S. M.; Kuznetsova, T. S.;
Zefirov, N. S. Tetrahedron Lett. 2003, 44, 8241.
(28) It is noteworthy to mention that Stammer et al. have reported
the cleavage of the benzyl ester of benzyl (Z)-2-phenyl-1-amino-1-
carboxylate in high yields without hydrogenolysis of the cyclopropane
ring. See: King, S. W.; Riordan, J . M.; Holt, E. M.; Stammer, C. H. J .
Org. Chem. 1982, 47, 3270.
(29) For reduction of nitro groups with Raney nickel see: Norris,
T.; Braish, T. F.; Butters, M.; DeVries, K. M.; Hawkins, J . M.; Massett,
S. S.; Rose, P. R.; Santafianos, D.; Sklavounos, C. J . Chem. Soc., Perkin
Trans. 1 2000, 1615 (also includes examples of reductions with Zn/
methanesulfonic acid and Pt/H2).
(27) (a) Fu, Y.; Hammarstro¨m, L. G. J .; Miller, T. J .; Fronczek, F.
R.; McLaughlin, M. L.; Hammer, R. P. J . Org. Chem. 2001, 66, 7118.
(b) Freifelder, M. Catalytic Hydrogenation in Organic Synthesis,
Procedures and Commentary; J ohn Wiley & Sons: New York, 1978;
pp 26-39. (c) Rylander, P. Catalytic Hydrogenation in Organic
Synthesis; Academic Press: New York, 1979; pp 113-125. (d) Boger,
D. L.; Lerner, R. A.; Cravatt, B. F. J . Org. Chem. 1994, 59, 5078.
(30) For nitro reductions with Zn/Ac2O see: Seebach, D. v.; Ha¨ner,
R.; Vettiger, T. Helv. Chim. Acta 1987, 70, 1507.
(31) Vettiger, T.; Seebach, D. Liebigs Ann. Chem. 1990, 195.
(32) For Zn/HOAc see: (a) Battersby, A. R.; Baker, M. G.; Broadbent,
H. A.; Fookes, C. J . R.; Leeper, F. J . J . Chem. Soc., Perkin Trans. 1
1987, 2027. (b) Fornicola, R. S.; Oblinger, E.; Montgomery, J . J . Org.
Chem. 1998, 63, 3528.
J . Org. Chem, Vol. 69, No. 4, 2004 1265

Wurz and Charette
TABLE 3. Zin c(0) Red u ction of Nitr ocyclop r op a n e
Ca r boxyla tes
TABLE 4. Zin c(0) Red u ction of Sym m etr ic
Nitr ocyclop r op a n e Ca r boxyla tes
entry
n
R
product 14
yielda (%)
1
2
3
4
5
1
2
3
Bn
Me
Bn
Bn
Bn
14i
14j
14k
14l
14m
88
74b
87
>99
94
4
4c
a
Isolated yields after purification by flash chromatography.
Product was found to be volatile. c Alkene derived from cyclo-
b
octadiene.
result was probably due to the low solubility of the
cyclopropane in methanol, resulting in conglomeration
of the reactants. Thus, replacement of the methanol with
2-propanol gave more general reduction conditions. Fi-
nally, the best results (77%, Table 3, entry 3) were
obtained when the zinc dust was added in small portions
over 15 min (reaction is exothermic) to the acidic alcohol
solution containing the cyclopropane. In contrast, how-
ever, slow addition of 1 N HCl to the heterogeneous
mixture of cyclopropropane, alcohol, and zinc dust gave
increased degradation. Other zinc(0) sources, including
zinc powder, were also tested and found to give inferior
results.
Cyclopropane 5b underwent smooth reduction, afford-
ing the corresponding amino ester 14b in 76% yield.
Cyclopropane 5c, in 2-propanol, gave acceptable yields
of 74% and serves as a precursor to cyclo-m-Tyr (Figure
2). E- and Z-isomers of cyclopropane 5e, which do not
contain an aromatic substituent directly attached to the
cyclopropane ring, gave excellent yields (93%) of the
corresponding amino ester (Table 3, entry 7). It is
noteworthy to mention that the E- and Z-isomers (of 14e)
could now be easily separated by flash chromatography.
Cyclopropane 5f, derived from indene, and its homologue
5g, underwent smooth reductions, affording 79% and 86%
yields, respectively, of the corresponding amino esters 14f
and 14g. Surprisingly, the reduction of cyclopropane 5h
under the standard reduction conditions yielded only a
modest 54% yield of the pure amino ester 14h (Table 3,
entry 10). Attempts to reduce cyclopropane 5h under the
conditions reported by Kuznetsova and co-workers26
yielded only traces of the desired amino ester 14h in
addition to hydroxy amines and products resulting from
the hydrogenolysis of the cyclopropane. The nitrocyclo-
propyl lactone prepared by intramolecular cyclopro-
panation was also reduced successfully to its amine 14n
(70%, Table 3, entry 11).33
a
Isolated yields after purification by flash chromatography.
AcOH used as acid. c MeOH used as solvent.
b
(0.05 M) afforded clean reactions with only traces of the
hydrogenolysis product. 2-Propanol was found to be a
superior solvent, upon further optimization, as it aided
in the solubility and led to an increase in yields of 5-10%
when compared to methanol. The scope of the reaction
was then examined for a variety of structurally diverse
nitrocyclopropane carboxylates (Table 3).
Initially, when acetic acid and 2-propanol were used,
nitrocyclopropane carboxylate 5a was reduced, affording
ethyl 2-phenyl-1-aminocyclopropane carboxylate (14a ) in
49% yield (Table 3, entry 1). Upon changing the acid
source to HCl, an isolated yield of 67% of 14a could be
obtained in methanol (Table 3, entry 2). This protocol
gave acceptable yields for most of the examples tested,
except 5c, which only gave 32% isolated yield of 14c. This
Zinc(0) reduction of the symmetric cyclopropanes pro-
ceeded in excellent yields, affording the corresponding
amino esters (Table 4). The minor endo-diastereomer can
now be easily separated from the major exo-diastereomer.
Cyclopropane 5j, derived from cyclohexene, was found to
be volatile, affording amino ester 14j in 74% yield (Table
4, entry 2), whereas the less volatile benzyl ester 14k
(33) Charette, A. B.; Wurz, R. P. J . Mol. Catal. A 2003, 196, 83.
1266 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Cyclopropane R-Amino Acids and Amines
TABLE 5. P r ep a r a tion of Ar om a tic Su bstitu ted
tr a n s-Am in ocyclop r op a n es
afforded 87% yield (Table 4, entry 3). Satisfyingly,
reduction of the unsaturated nitrocyclopropane 5m re-
sulted in the chemospecific reduction of the nitro group
in the presence of the alkene, and the corresponding
amino ester 14m was isolated in 94% yield (Table 4, entry
5).
The reduction of more sensitive cyclopropanes such as
2,2-diphenyl-1-nitrocyclopropane carboxylate represents
a more challenging example as they readily rearrange
to the corresponding N-oxides on silica gel if it is not
pretreated with triethylamine.16a,17 To avoid decomposi-
tion during purification, the products were prepared
using the standard cyclopropanation reaction, the solvent
was removed, and then the crude material was subjected
directly to the reduction conditions, yielding the cyclo-
propane amino esters. Modest yields were obtained (62%
and 57%, respectively) for the two-step sequence, with
the total reaction time amounting to only 4 h (eq 2).
reduction
yield
decarboxylation trans:cis
entry
R
yield of 17 (%)
ratio
of 18a (%)
1
2
3
phenyl (9)
1-naphthyl (5b)
4-chlorophenyl (5d )
91 (17a )
79 (17b)
96 (17c)
81:19
82:18
83:17
60 (18a )
61 (18b)
67 (18c)
a
Refers to the isolated yield for two steps on reduction of pure
trans-isomer only.
Finally, the amino esters can be converted to the
corresponding amino acids by saponification of the ester,
according to previously reported methods.12b,26
There has been much interest in the preparation of
cyclopropyl amines as they are found in a number of
biologically active products.36 We also wondered if this
reduction could be applied to aromatic substituted nitro-
cyclopropanes, again noting the absence of reports in the
literature concerning reduction of these compounds.
There are a variety of methods for the preparation of
nitrocyclopropanes37 including the decarboxylation of
nitrocyclopropane carboxylates 5 as reported by O’Bannon
and Dailey.38 Using a slight modification of the procedure
reported by O’Bannon and Dailey, the nitrocyclopropane
carboxylates 9, 5b, and 5d were treated with NaOH in a
mixture of DMSO/H2O and heated to 80 °C for 2 h,
resulting in the saponification and then decarboxylation
of the nitrocyclopropane carboxylate. Upon extraction, the
corresponding nitrocyclopropanes 17 were afforded in
high yields with slight erosion of their stereochemical
integrity.39 These cyclopropanes were found to efficiently
yield the corresponding cyclopropyl amines under the
standard reduction conditions. The amines were pro-
tected as their tert-butyl carbamates (Boc) for ease of
purification (Table 5).
This one-pot cyclopropanation/reduction procedure can
also be applied to biphasic, aqueous cyclopropanations.34
To illustrate this, an aqueous solution of methyl nitro-
diazoacetate 4 was added over 30 min to a mixture of
styrene (2 equiv) and catalyst, effecting an efficient
cyclopropanation reaction. Treatment of the reaction
mixture after 2 h with 2-propanol, 1 N HCl, and zinc(0)
afforded the corresponding aminocyclopropane carbox-
ylate 16 in 66% yield for two steps (eq 3).35
The reduction of trans-1-nitro-2-phenylcyclopropane
(17a ) affords the corresponding amine, which represents
(36) For recent syntheses of biologically active amino cyclopropanes
see: (a) Aggarwal, V. K.; de Vincente, J .; Bonnert, R. V. Org. Lett.
2001, 3, 2785. (b) Armstrong, A.; Scutt, J . N. Org. Lett. 2003, 5, 2331.
(c) Kazuta, Y.; Hirano, K.; Natsume, K.; Yamada, S.; Kimura, R.;
Matsumoto, S.; Furuichi, K.; Matsuda, A.; Shuto, S. J . Med. Chem.
2003, 46, 1980. (d) Chem. Eng. News 2003, May 23, 31.
(37) (a) Kai, Y.; Knochel, P.; Kwiatkowski, S.; Dunitz, J . D.; Oth, J .
F.; Seebach, D.; Kalinowski, H.-O. Helv. Chim. Acta 1982, 65, 137. (b)
Yu, J .; Falck, J . R.; Mioskowski, C. J . Org. Chem. 1992, 57, 3757. (c)
Aggarwal, V. K.; Smith, H. W.; Hynd, G.; J ones, R. V. H.; Fieldhouse,
R.; Spey, S. E. J . Chem. Soc., Perkin Trans. 1 2000, 3267. (d) Asunskis,
J .; Shretcher, H. J . Org. Chem. 1968, 33, 1164. (e) Russel, G. A.;
Makosza, M.; Hershberger, J . J . Org. Chem. 1979, 44, 1195. (f) Arai,
S.; Nakayama, K.; Hatano, K.; Shioiri, T. J . Org. Chem. 1998, 63, 9572.
(g) Galley, G.; Hu¨ner, J .; Anklam, S.; J ones, P. G.; Pa¨tzel, M.
Tetrahedron Lett. 1996, 37, 6307.
In
a similar fashion, the cyclopropanation using
iodonium ylides could also be applied (eq 4). This practi-
cal method offers the advantage of avoiding the handling
of the potentially dangerous diazo compounds and does
not require purification of the nitrocyclopropane.
(38) (a) O’Bannon, P. E.; Dailey, W. P. J . Org. Chem. 1990, 55, 353.
(b) O’Bannon, P. E.; Dailey, W. P. J . Am. Chem. Soc. 1989, 111, 9244.
See also: (c) Ivanova, O. A.; Yashin, N. V.; Averina, E. B.; Grishin, Y.
K.; Kuznetsova, T. S.; Zefirov, N. S. Russ. Chem. Bull. Int. Ed. 2001,
50, 2101.
(39) The cis- and trans-isomers of the nitrocyclopropanes can be
easily separated by column chromatography. Only the pure trans-
isomers were submitted to the reduction conditions.
(34) Wurz, R. P.; Charette, A. B. Org. Lett. 2002, 4, 4531.
(35) There is some erosion of the stereochemical integrity (ca. 10-
15%) for styrene-derived cyclopropanes during the course of the nitro
reduction. The implicated mechanism pertaining to this surprising
observation is under closer examination.
J . Org. Chem, Vol. 69, No. 4, 2004 1267

Wurz and Charette
oil (148 mg, 90%) in a 93:7 E:Z ratio. Separation of the
diastereomers is possible using a less polar eluent (3% EtOAc/
hexane).
an intuitively straightforward, yet novel synthesis of the
antidepressant (()-transcycloamine.40 Typically, the cy-
clopropyl amine is prepared via a Curtius rearrangement
from the corresponding acid and often results in low
isolated yields.41 Reductions involving nitrocyclopropanes
17b and 17c also proceed with similar efficiencies,
affording >60% yield for the two-step sequence.
Gen er a l P r oced u r e for th e in Situ Rh od iu m (II) Ca r -
boxyla te-Ca ta lyzed Cyclop r op a n a tion s of Alk en es w ith
r-Nitr oester s a n d P h I(OAc)2 (Ta ble 1). Styrene (587 mg,
0.65 mL, 5 equiv) was added to a 25 mL round-bottomed flask
containing the required amount of [Rh(OPiv)2]2 catalyst (3.4
mg, 5.6 × 10-3 mmol, 0.5 mol %) and ethyl nitroacetate (150
mg, 1.13 mmol, 1 equiv). Iodobenzene diacetate (400 mg, 1.24
mmol, 1.1 equiv) was then added in one portion and the
mixture allowed to stir for 2 h open to air. The crude reaction
mixture was then chromatographed directly on silica gel, first
eluting with hexane (to remove excess alkene) and then with
5% EtOAc/hexane, affording 5a as a clear, colorless oil (223
mg, 84%) in a 92:8 E:Z ratio.
Gen er al Redu ction P r ocedu r e (Tables 3 an d 4). 2-Phen-
yl-1-nitrocyclopropane carboxylate ethyl ester (5a ) (104 mg,
0.44 mmol) was dissolved in 8.8 mL of i-PrOH (0.05 M) and
treated with 1 N HCl (4.4 mL, 10 equiv). Zinc dust (578 mg,
8.80 mmol, 20 equiv) was then added in small portions over
10-15 min and the solution allowed to stir for 2 h at room
temperature. The suspension was quenched by addition of a
saturated solution of NaHCO3 (15 mL), stirred for 15 min, and
filtered through a small plug of Celite, washing with EtOAc
(20 mL). The aqueous phase was further extracted with
dichloromethane (2 × 10 mL), the combined organic extracts
were dried over anhydrous MgSO4 and filtered, and the solvent
was removed under reduced pressure. The crude residue was
then chromatographed on silica gel pretreated with 1:5:19
Et3N/EtOAc/hexane, rinsed with 20% EtOAc/hexane, and
eluted with a 20-80% gradient of EtOAc/hexane. The E- and
Z-diastereomers were easily separated and the appropriate
fractions combined (ninhydrin used as a developer), affording
the corresponding amino esters 14a (70 mg, 77%).
Con clu sion s
In summary, the above methodology represents a rapid
and efficient method for the preparation and reduction
of a diverse series of aminocyclopropane carboxylates and
aromatic substituent containing aminocyclopropanes. It
represents an attractive method to access symmetric and
racemic substituted ACCs from commercially available
R-nitroesters and -olefins. Modest to high yields of
aminocyclopropane carboxylates can be obtained in short
reaction times. The asymmetric version of this reaction
proceeds with modest enantioselectivities, up to 72% ee,
and is still under examination.33 Furthermore, a variety
of methods exist for the resolution of cyclopropane amino
acids and can be applied to access the enantiomerically
enriched materials.42
Exp er im en ta l Section
See the Supporting Information for general synthetic meth-
ods and materials.
Nitr ocyclop r op a n e Ca r boxyla tes. Cyclopropanes 5a ,17a
5d ,18 5f,16a 5h ,18 5j,17a 5n ,33 9,16a and 17a ,38 have been previ-
ously reported. See the Supporting Information for the char-
acterization data (1H and 13C NMR spectra) of new nitro- and
aminocyclopropanes.
Da ta for (E)-Eth yl 1-Am in o-2-p h en yl-1-cyclop r op a n e-
ca r boxyla te ((E)-14a ): pale yellow oil; Rf 0.16 (60% EtOAc/
hexane); 1H NMR (400 MHz, CDCl3) δ 7.16-7.27 (m, 5H),
3.68-3.83 (m, 2H), 2.66 (t, J ) 8.7 Hz, 1H), 2.20 (s (br), 2H),
1.99 (dd, J ) 7.9, 5.0 Hz, 1H), 1.45 (dd, J ) 9.5, 5.0 Hz, 1H),
0.77 (t, J ) 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 173.7,
136.9, 129.4, 128.1, 126.7, 60.8, 43.2, 36.4, 20.0, 13.8; IR (film)
Ca u tion . Although we have not experienced any problems
in the handling of these compounds (trifluoromethanesulfonyl
azide and the R-nitro-R-diazocarbonyl derivatives), extreme care
should be taken when they are manipulated due to their
explosive nature.
3374 (NH), 1713 (CdO), 1144 cm-1
.
Gen er a l P r oced u r e for R h od iu m (II) Ca r b oxyla t e-
Ca ta lyzed Cyclop r op a n a tion s of Alk en es w ith r-Nitr o-
r-d ia zoester s (Ta bles 1 a n d 2). Styrene (145 mg, 0.16 mL,
2 equiv) was added to a 10 mL round-bottomed flask contain-
ing the required amount of [Rh(Octanoate)2]2 catalyst (2.7 mg,
3.5 × 10-3 mmol, 0.5 mol %). Ethyl nitrodiazoacetate (111 mg,
0.70 mmol, 1 equiv) was dissolved in anhydrous CH2Cl2 (0.70
mL, 1.0 M) and added slowly dropwise to the alkene/catalyst
solution, allowing for a controlled rate of N2 evolution (over
ca. 15-20 min). CH2Cl2 (0.5 mL) was then used to rinse the
flask containing the diazo to ensure complete transfer of
material. The reaction was allowed to stir for 2-4 h and then
concentrated under reduced pressure. The diastereoselectivity
of the cyclopropanation was determined by 1H NMR of the
crude reaction mixture. Purification by chromatography on
silica gel, first eluting with hexanes (to remove excess alkene)
and then 5% EtOAc/hexane, afforded 5a as a clear, colorless
Da ta for (Z)-Eth yl 1-Am in o-2-p h en yl-1-cyclop r op a n e-
ca r boxyla te ((Z)-14a ): pale yellow oil; Rf 0.57 (80% EtOAc/
hexane); 1H NMR (400 MHz, CDCl3) δ 7.28-7.35 (m, 2H),
7.23-7.27 (m, 3H), 4.22 (q, J ) 7.1 Hz, 2H), 2.82 (t, J ) 9.5
Hz, 1H), 1.84 (dd, J ) 9.6, 4.9 Hz, 1H), 1.56 (s (br), 2H), 1.44
(dd, J ) 7.6, 4.9 Hz, 1H), 1.31 (t, J ) 7.1 Hz, 3H); 13C NMR
(100 MHz, CDCl3) δ 175.6, 136.0, 129.4, 128.3, 127.0, 61.5,
41.3, 33.2, 22.1, 14.5; IR (film) 3384 (NH), 1717 (CdO), 1262,
1148, 834 cm-1; LRMS (APCI, Pos) m/z calcd for C12H15NO2
[M + H]+ 206.3, obsd 206.1.
“On e-P ot” Cyclop r op a n a tion Red u ction P r oced u r e
for th e P r ep a r a tion of Sen sitive Cyclop r op a n es 15a a n d
15b (Eq 2). [Rh(Octanoate)2]2 (4.5 mg, 0.5 mol %) was added
to a 100 mL round-bottomed flask, followed by 1,1-diphenyl-
ethene (415 mg, 2.30 mmol, 2 equiv). Methyl nitrodiazoacetate16a
(167 mg, 1.15 mmol, 1 equiv) was then added slowly dropwise
as a solution in CH2Cl2 (1.2 mL, 1.0 M) to the catalyst/alkene
mixture over 20 min. The solution was allowed to stir at room
temperature for 2 h, and then the CH2Cl2 was removed under
reduced pressure. The crude residue was dissolved in i-PrOH
(23 mL, 0.05 M) and treated with 1 N HCl (11.5 mL, 10 equiv).
Zinc dust (1.50 g, 23.0 mmol, 20 equiv) was added in small
portions over 10-15 min, and the resulting suspension was
allowed to stir for an additional 2 h. It was quenched by the
addition of a saturated solution of NaHCO3 (ca. 15 mL) and
allowed to stir for 15 min. The suspension was filtered through
a small Celite plug, washing with EtOAc (25 mL). After
separation of the organic phase, the aqueous phase was re-
extracted with CH2Cl2 (2 × 15 mL), and the combined organic
(40) A monoaminooxidase inhibitor (MAOI), tranylcypromine (Par-
nate, J atrosom N), which is an oral MAOI-type antidepressant, is used
to treat major depression in patients who have not responded to other
antidepressant therapies.
(41) (a) Shu, F.-C.; Zhou, Q.-L. Synth. Commun. 1999, 29, 567. (b)
Csuk, R.; Schabel, M. J .; Scholz, Y. v. Tetrahedron: Asymmetry 1996,
7, 3505. (c) Wang, M.-X.; Feng, G.-Q. Tetrahedron Lett. 2000, 41, 6501.
(42) (a) Wakamiya, T.; Oda, Y.; Fujita, H.; Shiba, T. Tetrahedron
Lett. 1986, 27, 2143. (b) Shiraishi, K.; Ichihara, A.; Sakamura, S. Agric.
Biol. Chem. 1977, 41, 2497. (c) Baldwin, J . E.; Adlington, R. M.;
Rawlings, B. J .; J ones, R. H. Tetrahedron Lett. 1985, 26 485. (d)
Kimura, H.; Stammer, C. H. J . Org. Chem. 1983, 46, 2440. (e) Kimura,
H.; Stammer, C. H.; Shimohigashi, Y.; Ren-Lin, C.; Stewart, J .
Biochem. Biophys. Res. Commun. 1983, 115, 112.
1268 J . Org. Chem., Vol. 69, No. 4, 2004

Synthesis of Cyclopropane R-Amino Acids and Amines
extracts were dried over MgSO4, filtered, and concentrated
under reduced pressure. Purification of the crude residue by
chromatography on silica gel pretreated with 1:5:19 Et3N/
EtOAc/hexane was achieved by eluting with a gradient of 10-
40% EtOAc/hexane, affording pure 15a (174 mg, 57%). The
same procedure was repeated for the preparation of 15b.
On e-P ot Cyclop r op a n a tion Red u ction P r oced u r e for
Rh od iu m (II) Ca r boxyla te-Ca ta lyzed Cyclop r op a n a tion
of Styr en e w ith Meth yl Nitr od ia zoa ceta te in Wa ter (Eq
3). Styrene (158 mg, 0.17 mL, 2 equiv) was added to a 100 mL
round-bottomed flask containing the required amount of
[Rh(OPiv)2]2 catalyst (2.3 mg, 3.8 × 10-3 mmol, 0.5 mol %) and
distilled water (0.5 mL). Methyl nitrodiazoacetate16a (110 mg,
0.76 mmol, 1 equiv) was dissolved in hot water (4.0 mL, at 40
°C), cooled, and added slowly dropwise to the aqueous catalyst/
styrene mixture over 30 min. After being stirred for an
additional 2 h, the reaction mixture was diluted with i-PrOH
(15 mL, 0.05 M) and treated with 1 N HCl (7.6 mL, 10 equiv).
Zinc dust (987 mg, 15.1 mmol, 20 equiv) was added to the
solution over 10-15 min in small portions, and the resulting
suspension was allowed to stir for an additional 2 h. It was
quenched by the addition of a saturated solution of NaHCO3
(ca. 15 mL) and stirred for an additional 15 min. The
suspension was filtered through a small Celite plug, washing
with EtOAc (25 mL). After separation of the organic phase,
the aqueous phase was re-extracted with CH2Cl2 (2 × 15 mL),
and the combined organic extracts were dried over MgSO4,
filtered, and concentrated under reduced pressure. Purification
of the crude residue by chromatography on silica gel pretreated
with 1:5:19 Et3N/EtOAc/hexane and eluting with a gradient
of 20-80% EtOAc/hexane afforded pure 16 (96 mg, 66%, 71:
29 E/Z).
On e-P ot Cyclop r op a n a tion Red u ction P r oced u r e for
Rh od iu m (II) Ca r boxyla te-Ca ta lyzed Cyclop r op a n a tion
of Styr en e w ith Meth yl Nitr oa ceta te a n d P h I(OAc)2 (Eq
4). Styrene (525 mg, 0.58 mL, 5 equiv) was added to a 100 mL
round-bottomed flask containing the required amount of
[Rh(OPiv)2]2 catalyst (3.1 mg, 5.0 × 10-3mmol, 0.5 mol %) and
methyl nitroacetate (120 mg, 1.01 mmol, 1 equiv). Iodobenzene
diacetate was then added (357 mg, 1.11 mmol, 1.1 equiv) in
one portion and the mixture allowed to stir for 2.5 h. The
reaction mixture was then concentrated under reduced pres-
sure to remove iodobenzene and excess alkene. The crude
residue was suspended in i-PrOH (20 mL, 0.05 M) and treated
with 1 N HCl (10.1 mL, 10 equiv). Zinc dust (1.32 g, 20.2 mmol,
20 equiv) was then added in small portions over 10-15 min
and the solution allowed to stir for 2 h at room temperature.
The suspension was quenched by addition of a saturated
solution of NaHCO3 (ca. 15 mL), stirred for 15 min, and filtered
through a small plug of Celite, washing with EtOAc (25 mL).
The aqueous phase was further extracted with CH2Cl2 (2 ×
15 mL), the combined organic extracts were dried over
anhydrous MgSO4 and filtered, and the solvent was removed
under reduced pressure. The crude product was then chro-
matographed on silica gel pretreated with 1:5:19 Et3N/EtOAc/
hexane, eluting with a 20-80% gradient of EtOAc/hexane. The
E- and Z-diastereomers were easily separated and the ap-
propriate fractions combined (ninhydrin used as a developer),
affording the corresponding amino esters 16 (125 mg, 65%).
Typ ica l P r oced u r e for th e Syn th esis of Nitr ocyclo-
p r op a n es. Cyclopropane 5d 18 was treated with DMSO (7.0
mL) and NaOH (62.6 mg, 1.57 mmol, 1 equiv) dissolved in
distilled water (2.5 mL). The reaction mixture was heated to
80 °C for 2 h and then quenched with a saturated solution of
NH4Cl (15 mL). The aqueous phase was extracted with Et2O
(2 × 20 mL), washed with distilled water (3 × 25 mL) and
brine (1 × 25 mL), and dried over MgSO4. Filtration and
removal of the solvent under reduced pressure afforded the
crude nitrocyclopropane 17c. It was purified by column chro-
matography on silica gel using a 4-10% gradient of EtOAc/
hexane, allowing separation of the trans- and cis-diastereomers
of 17c (301 mg, 96%, 83:17 trans/cis).
Typ ica l P r oced u r e for th e Syn th esis of Boc-P r otected
tr a n s-Am in ocyclop r op a n es. The standard reduction pro-
cedure was followed as described above. The crude residue was
dissolved in anhydrous THF and treated with Et3N (1.0 equiv),
while being cooled in an ice bath. Boc2O (1.1 equiv) was added
in one portion, and the solution was allowed to stir in an ice
bath for an additional 10 min before it was removed and
allowed to stir at room temperature overnight. The reaction
mixture was then concentrated and the residue dissolved in
EtOAc. The solution was washed with 10% citric acid (2 × 15
mL) and brine (1 × 25 mL) before being dried over MgSO4.
Filtration, removal of the solvent under reduced pressure, and
purification by column chromatography on silica gel using a
5-15% gradient of EtOAc/hexane afforded the pure Boc-
protected cyclopropanes.
Ack n ow led gm en t. This work was supported by
NSERC (Canada), Merck Frosst, Boehringer Ingelheim
(Canada) Ltd., and the Universite´ de Montre´al. R.P.W.
is grateful to NSERC (PGS B) for a postgraduate
fellowship. We also thank Prof. J ean Lessard and his
students for helpful discussions.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal procedures and 1H and 13C NMR spectra of all new
compounds (PDF). This material is available free of charge
via the Internet at http://pubs.acs.org.
J O035596Y
J . Org. Chem, Vol. 69, No. 4, 2004 1269