trans-directing ability of the amide group: Enabling the enantiocontrol in the synthesis of 1,1-dicarboxy cyclopropanes. Reaction development, scope, and synthetic applications

Article abstract of DOI:10.1021/jo902066y

(Chemical Equation Presented) In this article, we describe our efforts toward the enantioselective formation of 1,1-cyclopropane diesters via the metal-catalyzed cyclopropanation of olefins. The strategies envisioned to achieve such a goal are discussed a

Full text of DOI:10.1021/jo902066y

pubs.acs.org/joc
trans-Directing Ability of the Amide Group: Enabling the Enantiocontrol
in the Synthesis of 1,1-Dicarboxy Cyclopropanes. Reaction Development,
Scope, and Synthetic Applications
ꢀ
David Marcoux, Sebastien R. Goudreau, and Andre B. Charette*
ꢀ
ꢀ ꢀ ꢀ
Departement de Chimie, Universite de Montreal, P.O. Box 6128, Station Downtown, Montreal (Quebec),
Canada H3C 3J7
ꢀ
ꢀ
andre.charette@umontreal.ca
Received September 25, 2009
In this article, we describe our efforts toward the enantioselective formation of 1,1-cyclopropane
diesters via the metal-catalyzed cyclopropanation of olefins. The strategies envisioned to achieve such
a goal are discussed as well as the results that led us to the discovery of the powerful trans-directing
ability of the amide group in Rh(II)-catalyzed cyclopropanation reactions. We show how this feature
enables a solution for the stereoselective synthesis of 1,1-dicarboxy cyclopropane derivatives. The
scope and limitations are discussed as well as the demonstration that these newly formed cyclopro-
panes display reactivity similar to that of 1,1-cyclopropane diesters. Conversely, 1,1-cyclopropane
diesters could be accessed in two steps from commercially available alkenes. The potential utility of
this methodology is illustrated by several functional group transformations and its use in the
expedient stereoselective formal synthesis of (S)-(þ)-curcumene, (S)-(þ)-nuciferal, (S)-(þ)-nuciferol,
(þ)-erogorgiaene, (()-xanthorrhizol, and (()-2-hydroxycalamenene.
1. Introduction
different nucleophiles and, thus, are known as electrophilic
cyclopropanes.2 Recently, there has been a growing interest in
the reactivity of 1,1-cyclopropane diesters. Indeed, they have
been exploited in cycloaddition reactions with imines,3 alde-
hydes,4 nitrones,5 and others6 to afford a variety of useful
building blocks (Scheme 1). Cylopropane 1 has also been
shown to react with nucleophiles7 such as organocuprate
The cyclopropane ring has been shown to undergo a wide
variety of transformations due to its high Baeyer strain.1 Ofall
cyclopropanes, those bearing two geminal acceptor groups
have been widely studied due to their ability to react with
(1) (a) de Meijere, A. Angew. Chem., Int. Ed. 2005, 44, 7836. (b) Rappoport,
Z., Ed. The Chemistry of the Cyclopropyl Group; Wiley-Interscience: New York,
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Chem., Int. Ed. 2003, 42, 3023.
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Zimmer, L. E.; Charette, A. B. Org. Lett. 2008, 10, 689. (b) Ivanova, O. A.;
Budynina, E. M.; Grishin, Y. K.; Trushkov, I. V.; Verteletskii, P. V. Eur. J.
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Kerr, M. A. J. Am. Chem. Soc. 2008, 130, 4196. (d) Dias, D. A.; Kerr, M. A.
Org. Lett. 2009, 11, 3694. (e) Lebold, T. P.; Leduc, A. B.; Kerr, M. A. Org.
Lett. 2009, 11, 3770. (f) Lebold, T. P.; Kerr, M. A. Org. Lett. 2009, 11, 4354.
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(2) For reviews on the chemistry of donor-acceptor and electrophilic
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DOI: 10.1021/jo902066y
r
Published on Web 11/06/2009
J. Org. Chem. 2009, 74, 8939–8955 8939
2009 American Chemical Society

Marcoux et al.
JOCFeatured Article
SCHEME 1. Reactivity and Synthetic Applications of 1,1-Cyclo-
propane Diesters
the most straightforward route to 1,16 no highly enantiose-
lective methods have been reported to date.17 Indeed, the
best catalyst, Rh2(S-MEAZ)4, performs this reaction with
only 44% ee on styrene (eq 1).18 Muller has also described the
€
in situ formation of the phenyliodonium ylide variants and
obtained 82% ee on styrene employing Rh2(S-4-BrNTTL)4
as the catalyst (eq 2).19
reagents (Scheme 1).8 This unique reactivity has been utilized as
a key step in the efficient synthesis of structurally complex
molecules (Figure 1).9 Cyclopropane 1 is also a useful inter-
mediate for the synthesis of biologically relevant molecules
such as R-amino acid10 and β-amino acid cyclopropanes
(Scheme 1).11,12 Importantly, all of these derivatizations and
reactivities are realized with preservation of the stereochemical
information, further validating 1 as a very attractive target.
Although 1,1-cyclopropane diesters have been shown to
be valuable chiral intermediates, their asymmetric synthesis
still remains an important challenge. Several multistep
syntheses have been reported (Scheme 2). For example, they
can be accessed through the asymmetric Simmons-Smith
cyclopropanation13 or the Davies Rh(II)-catalyzed cyclo-
propanation14 in four and three steps from the correspond-
ing alkene, respectively. Likewise, the Sharpless dihydro-
xylation has also been utilized to afford enantioenriched
1,1-cyclopropane diesters in three steps.15 Kinetic resolution
of 15a and cocrystallization of the 1,1-diacid derivatives with
a chiral amine4f have also been described. In these cases, the
overall yields range from 15 to 48%.
Herein, we report the discovery of the powerful trans-
directing ability of the amide group that led to the first highly
enantio- and diastereoselective Rh(II)-catalyzed cyclopro-
panation with diazo reagents bearing two acceptor groups.
The trans-directing ability of different groups in Rh(II)-
catalyzed cyclopropanation is detailed, and the demonstra-
tion that the trans-directing group must adopt an out-of-
plane conformation is described. We demonstrate how this
feature can be applied to enable a solution to the enantio-
control issue in the synthesis of 1,1-cyclopropane diesters.
Finally, the scope of this new reaction as well as the synthetic
utility of these novel cyclopropanes is discussed.20,21
2. Results and Discussion
Even though the metal-catalyzed cyclopropanation be-
tween diazomalonate 2 and commercially available olefins is
Because of the growing interest in chiral, nonracemic 1,1-
cyclopropane diesters, we investigated the transition metal-cata-
lyzed formation of 4a. According to the literature precedent (vide
supra), rhodium-based catalysts were unsuitable for the highly
enantioselective synthesis of 1,1-cyclopropane diesters from
diazomalonates.18,19 Recently, we reported a highly enantio-
and diastereoselective formation of 1-nitro-1-cyclopropane
(8) Corey, E. J.; Gant, T. G. Tetrahedron Lett. 1994, 35, 5373.
(9) (a) Carson, C. A.; Kerr, M. A. Org. Lett. 2009, 11, 777. (b) Young,
I. S.; Kerr, M. A. J. Am. Chem. Soc. 2007, 129, 1465. (c) England, D. B.; Kuss,
T. D. O.; Keddy, R. G.; Kerr, M. A. J. Org. Chem. 2001, 66, 4704. (d) Leduc,
A. B.; Kerr, M. A. Angew. Chem., Int. Ed. 2008, 47, 7945. (e) Young, I. S.;
Williams, J. L.; Kerr, M. A. Org. Lett. 2005, 7, 953. (f) Carson, C. A.; Kerr,
M. A. Angew. Chem., Int. Ed. 2006, 45, 6560. (g) Carson, C. A.; Kerr, M. A.
Chem. Soc. Rev. 2009, 38, 3051.
(10) For biological purposes, see: (a) Brackmann, F.; de Meijere, A.
Chem. Rev. 2007, 107, 4538. (b) Gnad, F.; Reiser, O. Chem. Rev. 2003, 103,
1603. (c) Reichelt, A.; Martin, S. F. Acc. Chem. Res. 2006, 39, 433.
(d) Jimenez, A. I.; Cativiela, C.; Aubry, A.; Marraud, M. J. Am. Chem.
Soc. 1998, 120, 9452.
(11) For their synthesis, see: (a) Moreau, B.; Charette, A. B. J. Am. Chem.
Soc. 2005, 127, 18014. (b) Davies, H. M. L.; Bruzinski, P.; Hutcheson, D. K.;
Kong, N.; Fall, M. J. J. Am. Chem. Soc. 1996, 118, 6897. (c) Burgess, K.; Ho,
K.-K.; Moye-Sherman, D. Synlett 1994, 575. (d) Cativiela, C.; Diaz-de
Villegas, M. Tetrahedron: Asymmetry 2000, 11, 645. (e) Aggarwal, V. K.;
Alonso, E.; Fang, G.; Ferrara, M.; Hynd, G.; Porcelloni, M. Angew. Chem.,
Int. Ed. 2001, 40, 1433. (f) Adams, L. A.; Aggarwal, V. K.; Bonnert,
R. V.; Bressel, B.; Cox, R. J.; Shepherd, J.; de Vincente, J.; Walter, M.;
Whittingham, W. G.; Winn, C. L. J. Org. Chem. 2003, 68, 9433.
(12) Kozikowski, A. P.; Zhao, L.; Zhang, A.; Wang, C. Z.; Flippen-
Anderson, J.; Johnson, K. M. ChemMedChem 2006, 1, 58.
(16) For recent review on the stereoselective metal-catalyzed cyclopropa-
nation, see: (a) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. Rev. 2003, 103, 977. (b) Doyle, M. P.; McKervey, M. A.; Ye, T. Modern
Catalytic Methods for Organic Synthesis with Diazo Compounds: From
Cyclopropanes to Ylides; Wiley: New York, 1998. (c) Davies, H. M. L.;
Antoulinakis, E. G. Org. React. (N.Y.) 2001, 57, 1. (d) Pellissier, H. Tetrahedron
2008, 64, 7041.
(17) (a) Doyle, M. P. J. Org. Chem. 2006, 71, 9253. (b) Doyle, M. P.
Angew. Chem., Int. Ed. 2009, 48, 850.
(18) (a) Doyle, M. P.; Hu, W. ARKIVOC 2003, 15. (b) Doyle, M. P.;
Davies, S. B.; Hu, W. Org. Lett. 2000, 2, 1145. (c) Davies, H. M. L.;
Bruzinski, P.; Fall, M. J. Tetrahedron Lett. 1996, 37, 4133.
€
(19) Muller, P.; Ghanem, A. Org. Lett. 2004, 6, 4347. In our hands, we
obtained 10% ee in the cyclopropanation of styrene with Rh2(4-Br-S-
NTTL)4. A screening of Rh(II) catalyst did not improve the enantioselec-
tivity.
(20) For preliminary results on the trans-directing ability of amide, see:
Marcoux, D.; Charette, A. B. Angew. Chem., Int. Ed. 2008, 47, 10155.
(21) For an other application of the trans-directing ability of amide, see:
Marcoux, D.; Azzi, S.; Charette, A. B. J. Am. Chem. Soc. 2009, 131, 6970.
^ ꢀ
(13) Charette, A. B.; Cote, B. J. Am. Chem. Soc. 1995, 117, 12721.
(14) (a) See ref 11b. (b) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459.
(15) Sapeta, K.; Kerr, M. A. J. Org. Chem. 2007, 72, 8597.
8940 J. Org. Chem. Vol. 74, No. 23, 2009

Marcoux et al.
JOCFeatured Article
FIGURE 1. Structurally diverse products synthesized from a substituted 1,1-cyclopropane diesters.
SCHEME 2. Asymmetric Synthesis of 1,1-Cyclopropane Diesters
SCHEME 3. Cu(I)-Catalyzed Formation of 4a via Iodonium
Ylide Reagents
obtained with L2 (31 vs 71%) is a result of the ligand’s
greater steric hindrance. Further optimization demonstrated
that L7 gave improved enantioselectivity (60%, 66% ee).
Among all solvents studied with L7 (entries 10-17), no
significant increase in enantioselectivity was observed,
though the yield improved to 70% when the reaction was
performed in toluene (entry 12). A variety of Cu sources
and counterions were next considered (entries 18-24). Cu-
(II)SbF6 did not catalyze the reaction, while the counterion
of Cu(I) played an important role, with SbF6- providing the
best results. A control experiment showed that CuCl did
catalyze the reaction, though it yielded a racemic product
(entry 24). This result suggests an important background
reaction if the complex is not suitably preformed. It should
also be highlighted that AgSbF6 is not an effective catalyst in
this reaction. Finally, lowering the temperature to 0 °C
afforded the desired cyclopropane in 88% yield and 75%
ee (entry 25), while lower temperature led to decreased yield
(<20%). Different symmetrical and asymmetrical malo-
nates were considered, but none led to a better enantioselec-
tivity (entries 25-29). Nonetheless, the result obtained with
L7 (entry 25) represents the highest enantioselectivity re-
ported to date for the Cu(I)-catalyzed cyclopropanation of
styrene with a malonate carbene precursor. To achieve a
more enantioselective process, we envisioned the use of
different transition metals. However, Co(II)/Salen24 and
Ru(II)/Pybox25 complexes were found to be ineffective at
decomposing diazo 2 or iodonium ylides 6a at room temp-
erature.
carboxylates using a Cu(I)/bisoxazoline complex.11a We, there-
fore, envisioned that such complexes could enable a solution for
the enantiocontrol issue in preparing cyclopropane 4a. Unfor-
tunately, Cu(I)OTf was not effective at decomposing diazo-
malonate 2, affording <10% of the desired cyclopropane with
recovery of the unreacted diazo reagent. We thus turned our
attention toward the use of the phenyliodonium ylide deriva-
tives, as they are known to be more prone to metal-catalyzed
decomposition.22 As shown by Dauban, Cu(acac)2 successfully
catalyzed the reaction using the in situ generated iodonium
ylides (Scheme 3).22l This strategy required a large quantity of
molecular sieves that makes the reaction difficult to perform on
larger scale and may explain the requirement for high catalyst
loading (10 mol %) (Scheme 3). We recently reported an
efficient method to isolate the corresponding phenyliodonium
ylide.23 The use of this isolated phenyliodonium ylide afforded
a promising result toward the development of an asymmetric
variant using only 1 mol % of catalyst (Scheme 3).
2.1. Cu(I)-Catalyzed Asymmetric Cyclopropanation. With
our previously developed conditions,11a several symmetric
and asymmetric bisoxazoline and Pybox ligands were first
tested (entries 1-9, Table 1). Bisoxazolines L1 and L2 were
both effective, affording the desired cyclopropane in 60% ee
(entries 1 and 2). We presume that the decreased yield
2.2. Mechanistic Considerations. Cu(I) and Rh(II) do not
seem suitable for the highly enantioselective formation of
1,1-cyclopropane diesters from malonates using known
ligands. As such, we decided to go back on the proposed
mechanism to fully understand this problem. Both the
(22) For examples of cyclopropanation reactions using iodonium ylides,
€
see: (a) Muller, P; Allenbach, Y. F.; Chappelet, S.; Ghanem, A. Synthesis
2006, 1689. (b) Wurz, R. P.; Charette, A. B. Org. Lett. 2005, 7, 2313.
(c) Ghanem, A.; Lacrampe, F.; Schuring, V. Helv. Chim. Acta 2005, 88,
(24) (a) Ikeno, T.; Sato, M.; Yamada, T. Chem. Lett. 1999, 1345.
(b) Yamada, T.; Ikeno, T.; Sekino, H.; Sato, M. Chem. Lett. 1999, 719.
(c) Ikeno, T.; Nishizuka, A.; Sato, M.; Yamada, T. Synlett 2001, 406.
(d) Ikeno, T.; Sato, M.; Sekino, H.; Nishizuka, A.; Yamada, T. Bull. Chem.
Soc. Jpn. 2001, 74, 2139. (e) Ikeno, T.; Iwakura, I.; Yamada, T. Bull. Chem.
Soc. Jpn. 2001, 74, 2151. (f) Ikeno, T.; Iwakura, I.; Yabushita, S.; Yamada, T.
Org. Lett. 2002, 4, 517. (g) Fukuda, T.; Katsuki, T. Synlett 1995, 825.
(h) Fukuda, T.; Katsuki, T. Tetrahedron 1997, 53, 7201.
(25) (a) Nishiyama, H.; Park, S. B.; Haga, M.; Aoki, K.; Itoh, K. Chem.
Lett. 1994, 1111. (b) Nishiyama, H.; Itoh, Y.; Matsumoto, H.; Park, S.-B.;
Itoh, K. J. Am. Chem. Soc. 1994, 116, 2223. (c) Nishiyama, H.; Itoh, Y.;
Sugawara, Y.; Matsumoto, H.; Aoki, K.; Itoh, K. Bull. Chem. Soc. Jpn. 1995,
68, 1247. (d) Nishiyama, H. Enantiomer 1999, 4, 569.
€
€
216. (d) Ghanem, A.; Muller, P. Chirality 2005, 17, 44. (e) Muller, P. Acc.
Chem. Res. 2004, 37, 243. (f) Muller, P.; Allenbach, Y.; Robert, E. Tetra-
€
€
hedron: Asymmetry 2003, 14, 779. (g) Muller, P.; Ghanem, A. Synlett 2003,
12, 1830. (h) Wurz, R. P.; Charette, A. B. Org. Lett. 2003, 5, 2327. (i) Batsila,
C.; Kostakis, G.; Hadjiarapoglou, L. P. Tetrahedron Lett. 2002, 43, 5997.
€
(j) Muller, P.; Bolea, C. Helv. Chim. Acta 2001, 84, 1093. (k) Georgakopoulou,
G.; Kalogiros, C.; Hadjiarapoglou, L. P. Synlett 2001, 1843. (l) Dauban, P.;
Saniere, L.; Tarrade, A.; Dodd, R. H. J. Am. Chem. Soc. 2001, 20, 5189.
€
ꢀ
(m) Muller, P.; Fernandez, D. Helv. Chim. Acta 1995, 78, 947. (n) Moriarty,
R. M.; Vaid, R. K. Synthesis 1990, 431 and references cited therein.
(23) Goudreau, S. R.; Marcoux, D.; Charette, A. B. J. Org. Chem. 2009,
74, 470.
J. Org. Chem. Vol. 74, No. 23, 2009 8941

Marcoux et al.
JOCFeatured Article
TABLE 1. Optimization of the Cu(I)-Catalyzed Cyclopropanation
entry
6a
Cub
L
solvent
yield (%)c
ee (%)d
1
2
3
4
5
6
7
8
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6a
6b
6c
6d
6e
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
Cu(SbF6)2
CuClO4
CuOOCCF3
CuOTf
L1
L2
L3
L4
L5
L6
L7
L8
L9
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
L7
PhH
PhH
PhH
PhH
PhH
PhH
PhH
PhH
71
31
12
17
21
88
60
56
38
60
53
70
49
55
53
6
38
<5
43
12
81
5
55
65
88
23
41
77
60
60
60
47
50
62
17
66
42
0
51
48
67
60
63
51
59
57
-
59
0
63
50
57
0
75
34
35
7
9
PhH
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25e
26e
27e
28e
29e,f
DCM
DCE
PhMe
PhCl
PhCF3
PhNO2
THF
dioxane
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
PhMe
CuBF4
CuPF6
CuCl
CuSbF6
CuSbF6
CuSbF6
CuSbF6
CuSbF6
54
aAdded in one portion. bMade from CuCl (2 mol %) and AgX (2.4 mol %). cIsolated yield. dDetermined by SFC analysis on chiral stationary phase.
eReaction performed at 0 °C. fA 85:15 dr mixture was isolated.
Cu- and Rh(II)-catalyzed decompositions of diazo reagents are
known to proceed via a metal carbene that reacts in an asyn-
chronous [2 þ 1] transition state with an olefin (Scheme 4).16
With diazoacetate reagents, it has been postulated that the
ester on the metal carbene adopts an out-of-plane conforma-
tion26 that places the carbonyl group in a position that
stabilizes the developing Markovnikov positive charge in
the transition state.27,28 The largest substituent on the alkene is
oriented to minimize steric interactions, affording the major
trans-isomer. The ester can thus be seen as a trans-directing
group. This situation is more complicated for carbenes posses-
sing two electron-withdrawing groups, as at least three different
conformations can be envisioned for carbenes derived from
malonates (out-out, in-out, in-in, Figure 2). The out-out
(26) This out-of-plane conformation has been demonstrated by different
calculation for Cu(I)- and Rh(II)-catalyzed cyclopropanation. For examples,
(27) (a) Doyle, M. P.; Griffin, J. H.; Bagheri, V.; Dorow, R. L. Organo-
metallics 1984, 3, 53. (b) See ref 16b
.
see: (a) Fraile, J. M.; Garcı
´
a, J. I.; Martı
´
nez-Merino, V.; Mayoral, J. A.;
(28) Although we are not aware of any calculation that validates this
trans-directing ability neither for Cu(I)- nor Rh(II)-catalyzed cyclopropana-
tion, we believe that this stabilization has not been explicitly searched (see ref
26). Work toward the demonstration of this stabilization by calculation is
ongoing in our group.
Salvatella, L. J. Am. Chem. Soc. 2001, 123, 7616. (b) Straub, B. F.; Gruber, I.;
Rominger, F.; Hofmann, P. J. Organomet. Chem. 2003, 684, 124. (c) Nowlan,
D. T.; Gregg, T. M.; Davies, H. M. L.; Singleton, D. A. J. Am. Chem. Soc.
2003, 125, 15902.
8942 J. Org. Chem. Vol. 74, No. 23, 2009

Marcoux et al.
JOCFeatured Article
SCHEME 4. Cu(I)-andRh(II)-Catalyzed Cyclopropanation Tran-
sition State Structures with Diazoacetates as Carbene Precursor
greater trans-directing ability of the COR group. (4) The use of a
metal that reacts in a more synchronous matter or through a
different mechanism. From these four hypotheses, it appeared
to us that the use of a carbene precursor possessing two groups
with different trans-directing abilities was the most promising,
and we decided to investigate it further (Scheme 6).
2.2.1. trans-Directing Ability of the Amide Group. Our
initial work focused on establishing a relative trend of the
trans-directing ability of various carboxyl groups. As such,
we investigated the Rh2(oct)4-catalyzed cyclopropanation of
styrene with a variety of substituted R-carbonyl diazaoace-
tate reagents (Scheme 7). We were excited by the result
obtained with R-amido-R-diazoacetate derivatives 8. Indeed,
this class of compounds led to very high levels of diaster-
eocontrol. The trans-relationship between the phenyl group
and the ketone has been unambiguously established by X-ray
analysis of cyclopropane 9c.30 Interestingly, it was found
that, as postulated, the polarity of the carbonyl has an
important influence on the diastereoselectivities of the reac-
tions. By varying the p-substituent on the phenylketone
(diazo 7b-d), different levels of diastereocontrol were ob-
served. Since all three phenylketone derivatives possess
similar steric constraints around the metal carbene, the
interpretation of these results must rely on electronic considera-
tions. It is known that CdO IR stretching vibration gives
insight into the polarity of the CdO bond, and it was found
that it also gives a qualitative prediction of the trans-directing
ability of different groups. Indeed, the more polar the CdO
bond, the better the diastereoselectivity (Figure 3).31 Interest-
ingly, the methyl ketone 7a follows the diastereoselectivity
trend even though it is sterically less congested than phenyl
ketones 7b-d. To demonstrate further reliability of this trans-
directing ability, we envisioned the synthesis of a carbene
precursor that would not be capable to adopt an out-of-plane
conformation. Strikingly, the submission of diazo 8b led to a
low diastereoselectivity (58:42 dr), indicating that the trans-
directing group must adopt an out-of-plane conformation to
induce high diastereoselectivities (eq 3).
conformation is believed to constitute the ground state, as
corroborated by Nishiyama’s X-ray structure of a Ru-malonate
carbene.29 We also postulate that this conformation is nonreac-
tive due to steric repulsion with an approaching alkene. We
hypothesize that the in-out conformation is operative as
placing one group in the same plane of the metal carbene
liberates space for an alkene to approach and enhances the
FIGURE 2. Different possible conformations of a malonate-derived
metal carbene with chiral ligands.
electrophilicity of the metal carbene. The out-of-plane substi-
tuent can act as a trans-directing group, and in the case of
malonates, transition state structures C-F would be plausible
(Scheme 5). Assuming that the use of a chiral catalyst would be
effective at blocking the pro-S face, we found that the four
possible transition state structures would lead to a pair of
enantiomers (Scheme 5). This may explain the low enantiocon-
trol obtained to date with malonates. Therefore, we envisioned
several strategies for the development of a highly enantioselec-
tive version of this reaction: (1) The use of a chiral ligand that
would be large enough to efficiently control the selectivity of the
longer C-C bond formation in the asynchronous [2 þ 1]
transition state. This would probably be detrimental to the
isolated yield as can be seen with the bulkier catalyst derived
from L2 (entry 2, Table 1). (2) The use of a chiral ligand that
would control the conformation of the carbene as well as favor
reaction on one of the two prochiral faces (discrimination
between C,D and E,F, Scheme 5). (3) The use of a carbene pos-
sessing two different groups that have different trans-directing
abilities in combination with a catalyst that would be effective
at blocking one of the two prochiral faces (Scheme 6). Transi-
tion state structures I,J would not be accessible due to the
2.3. Optimization of the Reaction. Now that we did succeed
in finding a carbene precursor possessing two different
acceptor groups with different trans-directing abilities and
exhibiting outstanding levels of diastereocontrol, we studied
different chiral catalysts. In our first attempt, Cu(I)/bisox-
azolines were ineffective at decomposing diazo 8a. The use of
the in situ generated iodonium ylides did not afford the
corresponding cyclopropane, and we have not been success-
ful in isolating the corresponding iodonium ylides in good
yield and purity. The use of Rh(II) dimers, known to be more
reactive catalysts than the copper-based system, was there-
fore investigated despite the fact that these complexes have
never been reported to produce high enantioselectivities in
(29) Nishiyama, H.; Aoki, K.; Itoh, H.; Iwamura, T.; Sakata, N.;
Kurihara, O.; Motoyama, Y. Chem. Lett. 1996, 1071.
(30) See Supporting Information for further details.
(31) IR stretching vibration according to the Sadtler database.
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SCHEME 5. Cu(I)- and Rh(II)-Catalyzed Cyclopropanation Transition State Structures with Diazomalonates as Carbene Precursor
JOCFeatured Article
SCHEME 6. Proposed Strategy with a Metal Carbene Possessing Two Different Groups with Different trans-Directing Abilities
SCHEME 7. Cyclopropanation of Styrene with a Variety of
Carboxy Diazoacetate Reagents
FIGURE 3. Graphical representation of the diastereoselectivity of
the reaction as a function of the carbonyl IR stretching frequency of
the trans-directing group.
reactions involving metal carbenes bearing two acceptor
groups. We first considered the effect of a variety of chiral
ligands using diazo reagent 8a in CH2Cl2 at 25 °C (entries
1-10, Table 2). Though the diastereoselectivity remained
high in all cases, the different ligands had a drastic effect on
optimization. We next turned our attention to study struc-
turally different R-amido diazoacetate reagents 8, and it was
found that their structure greatly affected the enantioselec-
tivity and yield of the reaction (entries 11-19). More pre-
cisely, we were pleased to find that the pyrrolidine amide 8h
gave excellent enantiocontrol (95% ee) regardless of the
structure of the ester (entries 17-19). To the best of our
knowledge, these results represent the first example of a
highly selective Rh(II)-catalyzed cyclopropanation with a
carbene possessing two acceptor groups. The reduced yield
with the Et and i-Pr ester (entries 18 and 19) is explained by
the presence of a secondary and tertiary carbon that under-
goes C-H insertion to form the corresponding β-lactone
(eq 4).34 Interestingly, diazo 8h did not undergo this type of
reaction when mixed alone with Rh2(S-NTTL)4, and the
unreacted diazo was recovered. This special feature has
also been reported by Box using diazo 8h and Rh2(OAc)4
as catalyst.35 Surprisingly, changing the amide for the
piperidine amide 8e and azepane amide 8f led to very low
both the yield and the enantioselectivity. Hashimoto’s32
33
€
(L13-L15) and Muller’s (L10-L12) ligands were found
to be the most promising. In general, increasing the size of the
side chain from Bn to t-Bu led to improved enantiocontrol,
with L12 and L15 being the most interesting, affording the
corresponding cyclopropane in 75 and 70% ee, respectively
(entries 3 and 6). Many solvents were tested, but none was
found to have a significant positive effect on the selectivity
compared to CH2Cl2. Decreasing the temperature to 0 °C led
to no conversion, and the diazo could be recovered. This is a
particular feature as Rh(II)-based catalysts have been shown
to be highly effective at decomposing diazo reagents even at
low temperatures.16 The time of addition of the diazo reagent
had little or no impact on the efficiency of the reaction, as
similar results were obtained when the reagent was added
over a 2, 10, or 24 h period, but 10 h was chosen for the
(32) (a) Hashimoto, S.; Watanabe, N.; Ikegami, S. Tetrahedron Lett.
1990, 31, 5173. (b) Hashimoto, S.; Watanabe, N.; Ikegami, S. Synlett 1994,
353. (c) Yamawaki, M.; Tsutsui, H.; Kitagaki, S.; Anada, M.; Hashimoto, S.
Tetrahedron Lett. 2002, 43, 9561.
(34) Unfortunately, enantiomeric excesses of these β-lactones could not
be determined.
€
(33) Muller, P.; Bernardinelli, G.; Allenbach, Y. F.; Ferri, M.; Flack,
H. D. Org. Lett. 2004, 6, 1725.
(35) Box, V. G. S.; Marinovic, N.; Yiannikouros, G. P. Heterocycles
1991, 32, 245.
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TABLE 2. Optimization of the Rh(II)-Catalyzed Cyclopropanation
entry
8a
L
solvent
yield (%)b
ee (%)d
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23f
24
8a
8a
8a
8a
8a
8a
8a
8a
8a
8a
8b
8c
8d
8e
8f
L10
L11
L12
L13
L14
L15
L16
L17
L18
L19
L12
L12
L12
L12
L12
L12
L12
L12
L12
L12
L12
L12
L12
L12
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
DCM
EtOAc
PhMe
DCE
61
83
71
63
69
76
52
45
33
54
75
45
30
70
-30
-23
0
-
-
85
80
15
-
54
95
94
97
86
81
96 (96)e
96
67
NR
<10
35
24
29
<10
48
71
45
19
8g
8h
8i
8j
8a
8a
8a
8a
8a
54
49
75 (77)e
79
<10
DCE
THF
-
aAddition over 10 h. bIsolated yields. cDetermined by 1H NMR and GC/MS analysis of the crude reaction mixture. dDetermined by SFC analysis on
chiral stationary phase. eYield and ee in parentheses correspond to a 5 mmol scale reaction. f3 equiv of 9h and 1 equiv of 3a were used.
asymmetric induction and no conversion, respectively
(entries 15 and 16). Optimization of the solvent (entries
20-22 and 24) showed that DCE gave a slight increase in
enantioselectivity to 96% ee. When expensive olefins are
cyclopropanated, the alkene can be used as the limiting
reagent with 3 equiv of 8h to afford the desired cyclopro-
pane with a slightly increased yield (79 vs 75%) and with the
same level of selectivity (entry 23). Conversely, when the
olefin is inexpensive as styrene (3a), a 5-fold excess was used.
In both cases, the unreacted olefin was recovered in nearly
quantitative yield following completion of the reaction.
Using 5-fold excess of styrene (3a) (entry 22), cyclopro
pane 10h could be obtained in 77% yield (96% ee, >30:1
dr) using 1 g (ca. 5 mmol) of diazo 8h when added over a
10 h period.
2.3.1. Scope of the Cyclopropanation Reaction. With these
optimal conditions in hand (entry 23, Table 2), we studied the
scope of the reaction beginning with the effect of different
p-substituted styrenes (entries 1-13, Table 3). Electron-rich
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TABLE 3. Scope of the Reaction
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TABLE 3. Continued
aIsolated yields. bDetermined by 1H NMR and GC/MS analysis of the crude reaction mixture. cDetermined by SFC analysis on chiral stationary
phase. d2 mol % of catalystwas used. eReaction performed at 50 °C. f6 equiv of 8h were used. gThe diazoreagent was added over 48 h. h5 mol % of catalyst
was used. iYield of the mixture of diastereomer. jee of the trans-isomer is in parentheses.
(entries 10, 23, and 24) and electron-neutral styrenes (entries
1-9 and 13) underwent the reaction in high yields (75-92%)
and high enantioselectivities (93-97% ee). Electron-poor
styrenes did give the corresponding cyclopropane derivatives
in high enantioselectivities (95% ee) but were found to be less
reactive as decreased yields were observed (31-55%) (entries
11 and 12). Moving the electron-withdrawing group from the
para to the meta position led to a better isolated yield in the
case of the nitro group (51%) (entry 15) while having no
significant effect for the CF3 group (49%) (entry 16). Steri-
cally hindered o-substituted styrenes reacted in yields ran-
ging from 24 to 43% but with high enantiocontrol (entries
17-21). Even the presence of an o-basic Br group did not
affect the selectivity. The same substrate was reported to give
low enantiocontrol as a result of the proximity to the double
bond.33 It should be noted that, in the cases of less reactive
styrenes, a non-negligible amount of unreacted diazo 8h was
recovered after a reaction time of 16 h. This unusual feature
can, in part, account for the decreased isolated yields
due to the similar Rf of diazo 8h and the corresponding
cyclopropanes. To overcome this, the use of 2 mol % of cata-
lyst or longer addition time can be used to fully consume
diazo 8h and increase the isolated yield. For example, with
o-fluorostyrene (entries 17 and 18) and o-chlorostyrene
(entries 19 and 20), the yield can be improved if the addition
time is increased to 48 h (from 43 to 72% and from 35 to
52%, respectively). It is believed that a high concentration of
unreacted diazo 8h poisons the catalyst by complexation
with the highly basic amide oxygen that bears a negative
charge on the R-carbon. Interesting results were encountered
when m-MeO styrene derivatives were submitted to the
reaction (entries 14 and 22-24), as both the selectivity and
the isolated yields were lower even when the reaction was
performed at 50 °C. 1-Naphthyl-substituted olefins also
reacted in 86% and high enantioselectivity (entry 25). The
1,1- and 1,2-(Z)-disubstituted styrene derivatives afforded
the corresponding cyclopropanes in moderate yields (51-
63%) and excellent to good enantioselectivities (84-95% ee)
(entries 26-29). Non-styryl olefins also reacted under
these optimal conditions. Indeed, N-Me-2-vinylpyrrole and
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Marcoux et al.
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butylvinyl ether both reacted in low and good yields, respec-
tively, to afford the desired cyclopropanes with good selectiv-
ities (entries 30 and 34). Surprising results were observed using
N-protected 3-vinylindole (entries 31-33) as low diastereo-
selectivities (1:1 dr) were found with Ts, Boc, and Bn
as protecting groups, though excellent enantioselectivities
(95-96% ee) were observed in the cases of the N-Boc- and
N-Ts-protected adducts. The exact explanation for the low
diastereoselectivity remains unclear. Aryl-substituted dienes
as well as an alkyl-substituted diene provided the corres-
ponding cyclopropanes in moderate to excellent yields
(45-90%) and with selectivities ranging from 6:1 dr and
75% ee to 22:1 dr and 85% ee (entries 35-38). Aliphatic
olefins, which are less reactive substrates in Rh(II)-catalyzed
cyclopropanation, did not react under these conditions.
However, they can be accessed after cyclopropanation
of the less hindered double bond of a diene followed
by hydrogenation (eq 5). Pd(OH)2 and EtOAc were found
to be crucial in this hydrogenation as other solvents and
Pd sources gave competing side reactions leading to the
opened cyclopropane presumably through π-allyl chemis-
try.36 Finally, the absolute and relative stereochemistry
of these cyclopropanes was determined using known acid
13 (eq 6).30
SCHEME 8. Functional Group Transformations on Cyclopro-
pane 10h
been widely used for their biological properties.10,11 The acid
obtained after ester hydrolysis was decarboxylated under
heating at 180 °C to afford 17 in 76% yield (85:15 dr). The cis-
stereochemistry of the major product was assigned by convert-
ing the amide to the known ethyl ester 19 using a methodology
previously reported by our group (Scheme 9).39 The cis-stereo-
chemistry obtained can be explained by a protonation from
the less sterically hindered face since that the reaction is not
under thermodynamic control. Indeed, treating cyclopropane
cis-17 in i-PrOH/AcOH at 180 °C for 1 h did not lead to the
trans-isomer. However, epimerization could be performed in
basic medium (Scheme 9).40 Unfortunately, the decarboxyla-
tion reaction afforded 17 with loss of the stereochemical
information. We know that 17 does not racemize under the
reaction conditions and that the ester hydrolysis is performed
with complete retention of ee. Conversely, the amide acid
intermediate is configurationally unstable at 180 °C and race-
mizes prior to decarboxylation.4f,15 The amide could also be
hydrolyzed to afford the valuable 1,1-cyclopropane diesters 4a
in 75% yield after in situ methylation with Me2SO4.41 Though
cyclopropane 4a could be rapidly accessed, we wondered if the
presence of the amide on cyclopropane 10h affected its electro-
philicity.
2.3.2. Synthetic Utility. As we validated the efficiency of the
reaction, we wished to demonstrate the versatility of these
newly formed cyclopropanes (Scheme 8). The amino alcohol
14 was obtained upon treatment with LAH. Interestingly, such
cyclopropanes possess biological activity as selective serotonin
reuptake inhibitors.12 The amide could be reduced with ex-
We therefore studied its reactivity toward organocuprate
reagents. The reaction of 10h with 2 equiv of Bu2CuLi2CN
did not afford the desired product. Instead, the organocup-
rate reagent reacted with the ester, affording the tertiary
alcohol 18 in 77% yield (Scheme 8). As shown in eq 7, this
reagent reacted smoothly with diester 4a to afford the linear
product. Different Cu sources and cuprates were investi-
cellent chemoselectively using BH3 THF in moderate yield.37
3
β-Aminoester derivatives such as 15 are important derivatives
extensively used in peptide mimetic chemistry10,11 and as
selective serotonin reuptake inhibitors.12 The ester could be
selectively hydrolyzed and converted to the N-Boc cyclopropyl
amine 16 following a Curtius rearrangement.38 Cyclopropane
16 was recrystallized from Et2O, and X-ray analysis unambigu-
ously showed the cis-relationship between the amine and
the phenyl group.30 Such R-amino acid derivatives have also
gated, and we were pleased to observe that BuCu LiCN
3
reacted with cyclopropane 10h to give 21 in 70% yield with
(36) Parsons, A. T.; Campbell, M. J.; Johnson, J. S. Org. Lett. 2008, 10,
2541.
(37) (a) Kornet, M. J.; Thio, P. A.; Tan, S. I. J. Org. Chem. 1968, 33, 3637.
(b) Brown, H. C.; Heim, P. J. Org. Chem. 1973, 38, 912.
(38) Ninomiya, K.; Shiori, T.; Yamada, S. Tetrahedron 1974, 30, 2151.
(39) Charette, A. B.; Chua, P. Synlett 1998, 163.
(40) Yamaguchi, K.; Kazuta, Y.; Abe, H.; Matsuda, A.; Shuto, S. J. Org.
Chem. 2003, 68, 9255.
(41) Gassman, P. G.; Hodgson, P. K. G.; Balchunis, R. J. J. Am. Chem.
Soc. 1976, 98, 1275.
8948 J. Org. Chem. Vol. 74, No. 23, 2009

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SCHEME 9. Epimerization of Amide 17 and Its Conversion to an Ethyl Ester
SCHEME 10. Formal Synthesis of Bisabolane-Type Natural Products
SCHEME 11. Formal Synthesis of (()-Xanthorrhizol and (()-3-Hydroxycalamenene
trace amounts of alcohol 18 (eq 8). We thus believe that
cyclopropanes 10 have a similar reactivity to diester 1 and 4a,
therefore making them a good alternative to study the
reactivity of electrophilic cyclopropanes bearing gem-dicar-
boxy groups.
characterized by a chiral benzylic aliphatic substituent.
They have been found in many different natural sources42
and displayed a myriad of biological features ranging
from olfactive properties43 to antibabesial activities.44 Their
simple structures have captured the attention of synthetic
chemists as exemplified by the large number of reported
(42) (a) Sakai, T.; Nishimura, K.; Hirose, Y. Bull. Chem. Soc. Jpn. 1965,
38, 381. (b) Honwad, V. K.; Rao, A. S. Tetrahedron 1964, 20, 2921.
(c) Damodaran, N. P.; Dev, S. Tetrahedron 1968, 24, 4113. (d) Nagumo,
S.; Irie, S.; Hayashi, K.; Akita, H. Heterocycles 1996, 43, 1175. (e) Vyvyan,
J. R.; Loitz, C.; Looper, R. E.; Mattingly, C. S. J. Org. Chem. 2004, 69, 2461.
(43) (a) Stevens, K. L.; Lundin, R. E.; Teranishi, R. J. Org. Chem. 1965,
30, 381. (b) Flath, R. A.; Lundin, R. E.; Teranishi, R. Tetrahedron Lett. 1966,
295. (c) Thomas, A. F. Chem. Commun. 1967, 947. (d) Bertele, E.; Schudei, P.
Helv. Chim. Acta 1967, 50, 2445.
(44) (a) Bohlman, F.; Lonitz, M. Chem. Ber 1978, 111, 843. (b) McEnroe,
F. J.; Fenical, W. Tetrahedron 1978, 34, 1661. (c) Fusetani, N.; Sugano, M.;
Matsunaga, S.; Hashimoto, K. Experientia 1987, 43, 1234. (d) Wright, A. E.;
Pomponi, S. A.; McConnell, O. J.; Kohmoto, S.; McCarthy, P. J. J. Nat.
Prod. 1987, 50, 976. (e) Ohno, M.; Todoriki, R.; Yamamoto, Y.; Akita, H.
Chem. Pharm. Bull. 1994, 42, 1590. (f) Asaoka, M.; Shima, K.; Fujii, N.;
Takei, H. Tetrahedron 1988, 44, 4757. (g) Rucker, G.; Breitmaier, E.; Manns,
D.; Maier, W.; Marek, A.; Heinzmann, B.; Heiden, K.; Seggewies, S. Arch.
Pharm. 1997, 330, 12. (h) Mayer, A. M. S.; Jacobson, P. B.; Fenical, W.;
Jacobs, R. S.; Glaser, K. B. Life Sci. 1998, 62, 401.
We were excited by this result, as it provides a route to the
expedient synthesis of a variety of molecules from the
bisabolane family. These natural products are sesquiterpenes
J. Org. Chem. Vol. 74, No. 23, 2009 8949

Marcoux et al.
JOCFeatured Article
shown in Table 3. For example, treatment of cyclopropane
(()-10ab through the same synthetic sequence gave access
to the formal synthesis of (()-xanthorrhizol50 and (()-2-
hydroxycalamenene51 (Scheme 11).
3. Conclusion
Herein we have described our efforts toward the highly
enantio- and diastereoselective synthesis of 1,1-dicarboxy
cyclopropane derivatives. We elaborated the concept of the
trans-directing ability of different groups in Rh(II)-catalyzed
cyclopropanation and demonstrated that the trans-directing
group must adopt an out-of-plane conformation. The scope
and the limitations of the reaction between diazo reagent 8h
and a variety of mono- and disubstituted alkenes were also
studied, which represents the first highly stereoselective Rh-
(II)-catalyzed cyclopropanation with a carbene possessing
two acceptor groups. Finally, the resulting cyclopropanes
have been used in further synthetic transformations as well as
in the formal synthesis of six natural products. Other appli-
cations of this trans-directing ability of amides in cyclopro-
panation will be reported in due course.
FIGURE 4. Versatility of chiral, nonracemic cyclopropane amide
esters.
total syntheses. Within the bisabolane family, (S)-(þ)-cur-
cumene,45 (S)-(þ)-nuciferal,46 (S)-(þ)-nuciferol,46 and (þ)-
erogorgiaene47 attracted our attention. Indeed, it was found
that all four natural products could be accessed from the
same intermediate 23. To date, the fastest route to form 23
was reported by Pan and required six steps from p-methyl-
styrene (90% ee).46d We envisioned that 23 could come
from a three-step sequence involving the MeCu LiCN ring
3
opening of cyclopropane 10o, decarboxylation, and reduc-
tion of the amide 22 to aldehyde 23 using LiAlH(OEt)3, a
reagent developed by Brown (Scheme 10).48 Aldehyde 23 was
thus accessed in four steps (37% overall yield) from commer-
cially available p-methylstyrene. To the best of our know-
ledge, this synthetic sequence represents to date the fastest
route to 23.
Experimental Section
General Procedure of the Optimized Condition for the Synth-
esis of Enantioenriched Cyclopropanes (Table 3). A 10 mL
microwave tube was charged with Rh2(S-NTTL)4 (2.9 mg,
0.002 mmol, 1 mol %) and a magnetic stir bar. The tube was
sealed with a Teflon septum and purged with argon. DCE
(1 mL) and the corresponding alkene (0.20 mmol, 1.00 equiv)
were then added. The diazo compound (0.60 mmol, 3.00 equiv)
dissolved in 1 mL of DCE was added to the reaction mixture
over a period of 10 h using a syringe pump at 25 °C. Following
complete addition, the resulting mixture was stirred for an
additional 6 h at 25 °C. After complete consumption of the
diazo reagent, the reaction mixture was put directly on a silica
gel column and eluted with 100% hexane to 100% Et2O. In
ases where the rhodium dimer is complexed to the product, the
green mixture was dissolved in DCM and poly(4-vinylpyridine)
(≈20 mg) was added. The color of the mixture turned from green
to red, and the mixture was then filtered through Celite to afford
a rhodium-free product following concentration under reduced
pressure.
Interestingly, this synthetic route appears to be extremely
versatile for SAR studies (Figure 4). Indeed, the aldehyde
group comes from an amide that is a highly useful functional
group that can be converted into several other useful func-
tionalities.49 The aliphatic side chain at the benzylic position
can be installed using the appropriate organocuprate reagent
(eq 8). Finally, the aromatic moiety can be modified as
(45) (a) Kamal, A.; Malik, M. S.; Shaik, A. A.; Azeeza, S. Tetrahedron:
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J. Chem. Res 2006, 15. (d) Du, Z. T.; She, X. G.; Yue, G. R.; Ma, J. Y.; Li,
Y.; Pan, X. F. Chin. Chem. Lett. 2004, 15, 1389. (e) Zhang, A. B.; RajanBabu,
T. V. Org. Lett. 2004, 6, 3159. (f) Du, Z. T.; Yue, G. R.; Ma, J. Y.; She, X. G.;
Wu, T. X.; Pan, X. F. J. Chem. Res 2004, 427. (g) Harmata, M.; Hong, X. C.;
Barnes, C. L. Tetrahedron Lett. 2003, 44, 7261. (h) Vickers, T. D.; Keay, B. A.
Synlett 2003, 1349. (i) Hagiwara, H.; Okabe, T.; Ono, H.; Kamat, V. P.;
Hoshi, T.; Suzuki, T.; Ando, M. J. Chem. Soc., Perkin Trans. 1 2002, 895.
(j) Serra, S. Synlett 2000, 890. (k) Fuganti, C.; Serra, S.; Dulio, A. J. Chem.
Soc., Perkin Trans. 1 1999, 279. (l) Fuganti, C.; Serra, S. Synlett 1998, 1252.
(m) Meyers, A. I.; Stoianova, D. J. Org. Chem. 1997, 62, 5219. (n) Asaoka,
M.; Shima, K.; Fujii, N.; Takei, H. Tetrahedron 1988, 44, 4757. (o) Kametani,
T.; Kawamura, K.; Tsubuki, M.; Honda, T. J. Chem. Soc., Perkin Trans. 1
1984, 1305. (p) Kametani, T.; Tsubuki, M.; Nemoto, H. J. Chem. Soc., Perkin
Trans. 1 1980, 759. (q) Zilenovski, J. S. R.; Hall, S. S. Synthesis 1979, 698.
(r) Tamao, K.; Hayashi, T.; Matsumoto, H.; Yamamoto, H.; Kumada, M.
Tetrahedron Lett. 1979, 2155.
(46) (a) Yoneda, R.; Harusawa, S.; Kurihara, T. J. Chem. Soc., Perkin
Trans. 1 1988, 3163. (b) Lee, W. Y.; Lee, Y. Y.; Lim, K. S.; Goo, Y. M.; Park,
O. S. Bull. Korean Chem. Soc. 1988, 9, 379. (c) Takano, S.; Goto, E.;
Ogasawara, K. Tetrahedron Lett. 1982, 23, 5567. (d) Blanco, L.; Slougui,
N.; Rousseau, G.; Conia, J. M. Tetrahedron Lett. 1981, 22, 645.
(47) (a) Harmata, M.; Hong, X.; Schreiner, P. R. J. Org. Chem. 2008, 73,
1290. (b) Yadav, J. S.; Basak, A. K.; Srihari, P. Tetrahedron Lett. 2007, 48,
2841. (c) Harmata, M.; Hong, X. C. Tetrahedron Lett. 2005, 46, 3847.
(d) Davies, H. M. L.; Walji, A. M. Angew. Chem., Int. Ed. 2005, 44, 1733.
(e) Cesati, R. R.; de Armas, J.; Hoveyda, A. H. J. Am. Chem. Soc. 2004, 126,
96.
(1R,2R)-Methyl 2-phenyl-1-(pyrrolidine-1-carbonyl)cyclopropane-
carboxylate (10h). Prepared according to the general procedure.
The product was isolated as a white solid: yield 79%; diastere-
omeric ratio (>30:1) was determined by GC/MS analysis of the
crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to 270 °C,
63 psi H2, tr (minor) 32.3 min, tr (major) 33.3 min); enantiomeric
excess (96% ee) was determined by SFC analysis on chiral phase
(Chiralpak AD-H 25 cm, 4% i-PrOH, 5 mL/min, 30 °C, 200 psi,
tr (major) 13.9 min, tr (minor) 16.8 min); mp 73-75 °C; Rf 0.35
1
(100%, Et2O); [R]20 = þ113 (c 1.18, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.30-7.22 (m, 5H), 3.78-3.50 (m, 3H), 3.42
(s, 3H), 3.41-3.27 (m, 2H), 2.21 (dd, J = 4.7 Hz, J = 7.9 Hz,
1H), 2.01-1.87 (m, 4H), 1.53 (dd, J = 4.7 Hz, J = 9.1 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 168.7, 166.5, 135.4, 129.2 (2C),
128.1 (2C), 127.2, 52.4, 46.6, 46.5, 38.8, 31.5, 26.2, 24.3, 17.8; IR
(film) 3039, 3008, 2946, 2884, 1715, 1638, 1511, 1434, 1334, 1135
cm-1; HRMS (ES, Pos) calcd for C16H19N1O3 [M þ H]þ
274.1438, found 274.1437.
(48) Brown, H. C.; Tsukamoto, A. J. Am. Chem. Soc. 1964, 87, 1089.
(49) Zabicky, J., Ed. The Chemistry of Amides; Wiley-Interscience: New
York, 1970.
(50) (a) Lujan-Montelongo, J. A.; Covarrubias-Zuniga, A.; Romero-
Ortega, M.; Avila-Zarraga, J. G. Lett. Org. Chem. 2008, 5, 470. (b) Sirat,
H. M.; Hong, N. M.; Jauri, M. H. Tetrahedron Lett. 2007, 48, 457. (c) Sato,
K.; Bando, T.; Shindo, M.; Shishido, K. Heterocycles 1999, 50, 11.
(d) Nagumo, S.; Irie, S.; Hayashi, K.; Akita, H. Heterocycles 1996, 43, 1175.
Methyl 2-(4-tert-butylphenyl)-1-(pyrrolidine-1-carbonyl)cyclo-
propanecarboxylate (10k). Prepared according to the general
(51) Krause, W.; Bohlmann, F. Tetrahedron Lett. 1987, 28, 2575.
8950 J. Org. Chem. Vol. 74, No. 23, 2009

Marcoux et al.
JOCFeatured Article
procedure. The product was isolated as a white solide: yield
89%; diastereomeric ratio (>30:1) was determined by GC/MS
analysis of the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from
40 to 270 °C, 63 psi H2, tr (minor) 37.3 min, tr (major) 38.7 min);
enantiomeric excess (96% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 5% MeOH, 3 mL/min,
(m, 4H), 1.54 (dd, J = 4.9 Hz, J = 9.2 Hz, 1H); 13C NMR (75
MHz, CDCl3) δ 168.8, 166.6, 136.7, 132.3, 129.1 (2C), 128.9
(2C), 52.4, 46.7, 46.6, 38.8, 31.3, 26.3, 24.3, 21.3, 17.8; IR (film)
3050, 3010, 2951, 2876, 1731, 1641, 1429, 1317, 1144 cm-1
;
HRMS (ES, Pos) calcd for C17H21N1O3 [M þ H]þ 288.1594,
found 288.1593.
30 °C, 200 psi, tr (minor) 5.4 min, tr (major) 6.6 min); mp 78-80
D
Methyl 2-(4-methoxyphenyl)-1-(pyrrolidine-1-carbonyl)cyclo-
propanecarboxylate (10o). Prepared according to the general
procedure. The product was isolated as a white solid: yield 92%;
diastereomeric ratio (50:1) was determined by GC/MS analysis
of the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to
270 °C, 63 psi H2, tr (minor) 36.5 min, tr (major) 37.9 min);
enantiomeric excess (93% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 10% i-PrOH, 3 mL/
min, 25 °C, 200 psi, tr (minor) 6.7 min, tr (major) 7.8 min); mp
78-81 °C; Rf 0.28 (100%, Et2O); [R]20D = þ70 (c 0.98, CHCl3);
1H NMR (300 MHz, CDCl3) δ 7.20 (d, J = 8.6 Hz, 2H), 6.80
(d, J = 8.7 Hz, 2H), 3.78 (s, 3H), 3.76-3.48 (m, 3H), 3.43
(s, 3H), 3.32-3.25 (m, 2H), 2.14 (dd, J = 4.9 Hz, J = 8.0 Hz,
1H), 2.03-1.82 (m, 4H), 1.51 (dd, J = 4.9 Hz, J = 9.2 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 168.8, 166.6, 158.7, 130.3 (2C),
127.4, 113.6 (2C), 55.3, 52.4, 46.6, 46.5, 38.8, 31.0, 26.3, 24.3,
18.0 ; IR (film) 3050, 3010, 2952, 2877, 1729, 1638, 1516, 1429,
1316, 1248, 1143 cm-1; HRMS (ES, Pos) calcd for C17H21N1O4
[M þ Na]þ 326.1363, found 326.1359.
1
°C; Rf 0.36 (100%, Et2O); [R]20 = þ124 (c 0.35, CHCl3); H
NMR (300 MHz, CDCl3) δ 7.31 (d, J = 6.4 Hz, 2H), 7.24 (d,
J = 7.3 Hz, 2H), 3.71-3.54 (m, 3H), 3.42 (s, 3H), 3.38-3.28 (m,
2H), 2.19 (dd, J = 4.9 Hz, J = 8.1 Hz, 1H), 2.01-1.85 (m, 4H),
1.54 (dd, J = 4.9 Hz, J = 9.2 Hz, 1H), 1.31 (s, 9H); 13C NMR
(75 MHz, CDCl3) δ 168.8, 166.6, 150.0, 132.3, 128.9 (2C), 125.0
(2C), 52.3, 46.7, 46.6, 38.8, 34.6, 31.5 (3C), 31.3, 26.3, 24.4, 17.9;
IR (film) 3038, 3009, 2956, 2879, 1729, 1644, 1432, 1319, 1139
cm-1; HRMS (ES, Pos) calcd for C20H27N1O3 [M þ H]þ
330.2064, found 330.2062.
Methyl 2-(4-fluorophenyl)-1-(pyrrolidine-1-carbonyl)cyclopropane-
carboxylate (10l). Prepared according to the general procedure.
The product was isolated as a white solid: yield 77%; diastere-
omeric ratio (>30:1) was determined by GC/MS analysis of
the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to 270 °C,
63 psi H2, tr (minor) 34.4 min, tr (major) 35.5 min); enantiomeric
excess (97% ee) was determined by SFC analysis on chiral phase
(Chiralpak AD-H 25 cm, 4% MeOH, 3 mL/min, 40 °C, 210 psi,
tr (minor) 5.8 min, tr (major) 6.9 min); mp 68-72 °C; Rf 0.36
Methyl 2-(4-nitrophenyl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10p). Prepared according to the general pro-
cedure with a reaction temperature of 50 °C. The product was
isolated as a colorless oil: yield 31%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture,
and enantiomeric excess (95% ee) was determined by SFC
analysis on chiral phase (Chiralpak OD-H 25 cm, 5% MeOH,
3 mL/min, 30 °C, 210 psi, tr (minor) 6.9 min, tr (major) 7.8 min);
Rf 0.25 (100%, Et2O); [R]20D = þ99 (c 1.22, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 8.15 (d, J = 8.8 Hz, 2H), 7.46 (d, J =
8.6 Hz, 2H), 3.63-3.49 (m, 3H), 3.47-3.38 (m, 4H), 3.31-3.20
(m, 1H), 2.26 (dd, J = 5.1 Hz, J = 8.1 Hz, 1H), 2.07-1.84 (m,
4H), 1.64 (dd, J = 5.1 Hz, J = 9.2 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 168.9, 166.3, 147.8, 144.0, 130.8 (2C), 124.0 (2C), 53.4,
47.4, 47.2, 40.2, 31.7, 26.9, 25.0, 18.8; IR (film) 3050, 3010, 2951,
2876, 1731, 1641, 1521, 1429, 1317, 1144, 870 cm-1; HRMS (ES,
Pos) calcd for C16H18N2O5 [M þ H]þ 319.1289, found 319.1289.
Methyl 1-(pyrrolidine-1-carbonyl)-2-(4-(trifluoromethyl)phenyl)-
cyclopropanecarboxylate (10q). Prepared according to the general
procedure with a reaction temperature of 50 °C. The product
was isolated as a colorless oil: yield 55%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture, and
enantiomeric excess (95% ee) was determined by SFC analysis
on chiral phase (Whelk-O 25 cm, 7% i-PrOH, 3 mL/min, 40 °C,
150 psi, tr (minor) 9.8 min, tr (major) 12.1 min); Rf 0.42 (100%,
1
(100%, Et2O); [R]20 = þ79 (c 1.12, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.29-7.26 (m, 2H), 6.98 (t, J = 8.7 Hz, 2H),
3.53-3.49 (m, 3H), 3.45 (s, 3H), 3.37-3.28 (m, 2H), 2.17 (dd,
J = 4.9 Hz, J = 8.0 Hz, 1H), 2.03-1.87 (m, 4H), 1.54 (dd, J =
4.9 Hz, J = 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.3,
166.9, 162.7 (d, J = 243.9 Hz, 1C), 131.8 (d, J = 3.2 Hz, 1C),
131.5 (d, J = 8.1 Hz, 2C), 115.7 (d, J = 21.3 Hz, 2C), 53.1, 47.3,
47.2, 39.5, 31.4, 26.9, 25.0, 18.6; 19F NMR (282 MHz, CDCl3) δ
-116.95; IR (film) 3050, 3012, 2953, 2878, 1728, 1632, 1513,
1434, 1316, 1145 cm-1
; HRMS (ES, Pos) calcd for
C16H18N1O3F1 [M þ Na]þ 314.1163, found 314.1162.
Methyl 2-(4-chlorophenyl)-1-(pyrrolidine-1-carbonyl)cyclopropane-
carboxylate (10m). Prepared according to the general procedure.
The product was isolated as a white solid; yield 81%; diastere-
omeric ratio (>30:1) was determined by GC/MS analysis of
the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to 270 °C,
63 psi H2, tr (minor) 36.0 min, tr (major) 36.6 min); enantiomeric
excess (96% ee) was determined by SFC analysis on chiral phase
(Chiralcel OD-H 25 cm, 10% MeOH, 2 mL/min, 30 °C, 150 psi,
tr (minor) 3.7 min, tr (major) 4.8 min); mp 72-75 °C; Rf 0.36
1
(100%, Et2O); [R]20 = þ88 (c 1.08, CHCl3); H NMR (300
D
MHz, CDCl3) δ 7.27-7.19 (m, 4H), 3.62-3.49 (m, 3H), 3.45
(s, 3H), 3.33-3.24 (m, 2H), 2.16 (dd, J = 5.0 Hz, J = 8.0 Hz,
1H), 2.00-1.86 (m, 4H), 1.54 (dd, J = 5.0 Hz, J = 9.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 168.6, 166.2, 134.0, 133.1, 130.6
(2C), 128.4 (2C), 52.6, 46.7, 46.6, 39.0, 30.9, 26.3, 24.3, 17.9; IR
Et2O); [R]20 = þ79 (c 1.91, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.51-7.47 (m, 2H), 7.38-7.34 (m, 2H), 3.54-3.49 (m,
3H), 3.47-3.38 (m, 4H), 3.31-3.20 (m, 1H), 2.19 (dd, J = 5.0
Hz, J = 8.0 Hz, 1H), 1.93-1.84 (m, 4H), 1.54 (dd, J = 5.0 Hz,
J = 9.1 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.4, 166.0,
139.7, 129.6 (2C), 126.3 (q, J =, 1C), 125.0 (m, 1C), 122.6 (2C),
52.6, 46.7, 46.5, 39.2, 31.1, 26.3, 24.3, 17.9; IR (film) 2954,
2878, 1730, 1640, 1433, 1324, 1116, 1068 cm-1; HRMS (ES,
Pos) calcd for C17H18N1O3F3 [M þ H]þ 342.1312, found
342.1319.
(film) 3050, 3010, 2951, 2876, 1727, 1635, 1427, 1314, 1143 cm-1
;
HRMS (ES, Pos) calcd for C16H18N1O3Cl1 [M þ H]þ 308.1048,
found 308.1048.
Methyl 1-(pyrrolidine-1-carbonyl)-2-p-tolylcyclopropanecar-
boxylate (10n). Prepared according to the general procedure.
The product was isolated as a white solid: yield 82%; diastere-
omeric ratio (>30:1) was determined by GC/MS analysis of the
crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to 270 °C,
63 psi H2, tr (minor) 33.8 min, tr (major) 35.2 min); enantiomeric
excess (96% ee) was determined by SFC analysis on chiral phase
(Chiralpak AD-H 25 cm, 5% MeOH, 3 mL/min, 30 °C, 200 psi,
Dimethyl 2,20-(biphenyl-4,40-diyl)bis((pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate) (10r). Prepared according to the
general procedure. The product was isolated as a white solid:
1
tr (minor) 7.5 min, tr (major) 9.2 min); mp 72-74 °C; Rf 0.35
yield 62%; diastereomeric ratio (25:1) was determined by H
1
(100%, Et2O); [R]20 = þ85 (c 0.83, CHCl3); H NMR (300
NMR of the crude mixture, and enantiomeric excess (>99% ee)
was determined by SFC analysis on chiral phase (Chiralpak
AD-H 25 cm, 20% MeOH, 3 mL/min, 30 °C, 210 psi, tr (minor)
13.9 min, tr (major) 16.4 min); mp 194-197 °C; Rf 0.35 (100%,
D
MHz, CDCl3) δ 7.19 (d, J = 8.0 Hz, 2H), 7.10 (d, J = 7.9 Hz,
2H), 3.68-3.49 (m, 3H), 3.45 (s, 3H), 3.38-3.28 (m, 2H), 2.33
(s, 3H), 2.18 (dd, J = 4.9 Hz, J = 8.1 Hz, 1H), 2.03-1.87
J. Org. Chem. Vol. 74, No. 23, 2009 8951

Marcoux et al.
JOCFeatured Article
EtOAc); [R]20D = þ209 (c 1.03, CHCl3); 1H NMR (300 MHz,
CDCl3) δ 7.52 (d, J = 8.2 Hz, 4H), 7.35 (d, J = 8.2 Hz, 4H),
3.54-3.49 (m, 6H), 3.47-3.34 (m, 8H), 3.31-3.19 (m, 2H), 2.23
(dd, J = 5.0 Hz, J = 8.0 Hz, 2H), 2.06-1.87 (m, 8H), 1.54 (dd,
J = 5.0 Hz, J = 9.1 Hz, 2H); 13C NMR (75 MHz, CDCl3) δ
168.7 (2C), 166.5 (2C), 139.5 (2C), 134.5 (2C), 129.7 (4C), 126.7
(4C), 52.5 (2C), 46.7 (2C), 46.6 (2C), 39.1 (2C), 31.4 (2C), 26.3
(2C), 24.4 (2C), 18.0 (2C); IR (film) 3044, 2952, 2877, 1727, 1629,
1433, 1312, 1144, 908 cm-1; HRMS (ES, Pos) calcd for
C32H36N2O6 [M þ H]þ 545.2646, found 545.2642.
(>30:1) was determined by 1H NMR of the crude mixture,
and enantiomeric excess (94% ee) was determined by SFC
analysis on chiral phase (Chiralpak AD-H 25 cm, 7% i-PrOH,
3 mL/min, 40 °C, 150 psi, tr (minor) 9.8 min, tr (major) 11.4 min);
Rf 0.35 (100%, Et2O); mp 88-91 °C; [R]20 = þ121 (c 0.74,
D
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.24-7.16 (m, 2H),
7.06-6.95 (m, 2H), 3.60-3.45 (m, 3H), 3.44 (s, 3H), 3.43-3.38
(m, 1H), 3.22 (app t, J = 8.8 Hz, 1H), 2.13 (dd, J = 5.0 Hz, J =
8.1 Hz, 1H), 1.97-1.87 (m, 4H), 1.63 (dd, J = 5.1 Hz, J = 9.2
Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.0, 166.2, 162.0 (d,
J = 1C), 130.8 (d, J = 1C), 129.0 (d, J = 1C), 123.6 (d, J = 1C),
122.8 (d, J = 1C), 115.2 (d, J = 1C), 52.5, 46.7, 46.4, 37.9, 26.3,
26.2, 24.3, 18.3; IR (film) 2952, 2876, 1727, 1637, 1428, 1319,
1145 cm-1; HRMS (ES, Pos) calcd for C16H18N1O3F1 [M þ H]þ
292.1344, found 292.1349.
Methyl 2-(3-methoxyphenyl)-1-(pyrrolidine-1-carbonyl)cyclo-
propanecarboxylate (10s). Prepared according to the general
procedure with a reaction temperature of 50 °C. The product
was isolated as a colorless oil: yield 78%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture, and
enantiomeric excess (96% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 7% i-PrOH, 3 mL/min,
Methyl 2-(2-chlorophenyl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10w). Prepared according to the general pro-
cedure with a reaction temperature of 50 °C. The product was
isolated as a white solid: yield 35%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture,
and enantiomeric excess (94% ee) was determined by SFC
analysis on chiral phase (Chiralpak AD-H 25 cm, 7% i-PrOH,
3 mL/min, 40 °C, 150 psi, tr (minor) 14.1 min, tr (major) 22.8
min); Rf 0.35 (100%, Et2O); mp 96-98 °C; [R]20D = þ49 (c 1.00,
40 °C, 150 psi, tr (minor) 13.8 min, tr (major) 14.9 min); Rf 0.34
D
1
(100%, Et2O); [R]20 = þ73 (c 1.54, CHCl3); H NMR (300
MHz, CDCl3) δ 7.18-7.13 (m, 1H), 6,85-6.80 (m, 2H),
6.76-6.72 (m, 1H), 3.75 (s, 3H), 3.54-3.49 (m, 3H), 3.41
(s, 3H), 3.31-3.218 (m, 2H), 2.13 (dd, J = 5.1 Hz, J = 8.1
Hz, 1H), 1.94-1.84 (m, 4H), 1.44 (dd, J = 5.1 Hz, J = 9.2 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 168.7, 166.5, 159.5, 137.2,
129.2, 121.6, 114.8, 113.1, 55.4, 52.5, 46.7, 46.6, 38.9, 31.6, 26.3,
24.4, 18.0; IR (film) 2951, 2876, 1730, 1638, 1429, 1315, 1143,
1046 cm-1; HRMS (ES, Pos) calcd for C17H21N1O4 [M þ H]þ
304.1543, found 304.1551.
1
CHCl3); H NMR (300 MHz, CDCl3) δ 7.37-7.33 (m, 1H),
7.23-7.19 (m, 3H), 3.88-3.54 (m, 3H), 3.52-3.45 (m, 4H),
3.32-3.28 (m, 1H), 2.21 (dd, J = 5.1 Hz, J = 8.1 Hz, 1H),
2.01-1.85 (m, 4H), 1.60 (dd, J = 5.1 Hz, J = 9.2 Hz, 1H); 13
C
Methyl 2-(3-nitrophenyl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10t). Prepared according to the general pro-
cedure with a reaction temperature of 50 °C. The product was
isolated as a colorless oil: yield 51%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture,
and enantiomeric excess (96% ee) was determined by SFC
analysis on chiral phase (Whelk-O 25 cm, 5% MeOH, 3 mL/
min, 40 °C, 150 psi, tr (minor) 13.8 min, tr (major) 21.8 min); Rf
0.21 (100%, Et2O); [R]20D = þ42 (c 2.38, CHCl3); 1H NMR (300
MHz, CDCl3) δ 8.13 (s, 1H), 8.10 (d, J = 8.8 Hz, 1H), 7.62 (d,
J = 8.6 Hz, 1H), 7.43 (t, J = 8.8 Hz, 1H), 3.57-3.43 (m, 3H),
3.42 (s, 3H), 3.38 (app t, J = 8.0 Hz, 1H), 3.31-3.20 (m, 1H),
2.21 (dd, J = 5.0 Hz, J = 8.0 Hz, 1H), 1.97-1.84 (m, 4H), 1.61
(dd, J = 5.0 Hz, J = 9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
168.4, 165.7, 148.2, 137.9, 135.7, 129.1, 124.2, 122.4, 52.8, 46.8,
46.5, 39.1, 30.8, 26.3, 24.3, 18.1; IR (film) 2953, 2877, 1728, 1640,
1529, 1432, 1349, 1147 cm-1; HRMS (ES, Pos) calcd for
C16H18N2O5 [M þ H]þ 319.1289, found 319.1297.
NMR (75 MHz, CDCl3) δ 168.9, 166.1, 136.2, 133.8, 130.6,
129.4, 128.6, 126.3, 52.5, 46.7, 46.4, 38.1, 30.4, 26.3, 24.3, 18.5;
IR (film) 2951, 2877, 1728, 1642, 1432, 1317, 1148 cm-1; HRMS
(ES, Pos) calcd for C16H18N1O3Cl1 [M þ H]þ 308.1048, found
308.1054.
Methyl 2-(2-bromophenyl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10x). Prepared according to the general pro-
cedure at 50 °C instead of 25 °C. The product was isolated as a
colorless oil: yield 24% (85% brsm); diastereomeric ratio
(>30:1) was determined by GC/MS analysis of the crude
mixture (30 m ꢀ 0.25 mm, 5 °C/min from 40 to 270 °C, 63 psi
H2, tr (minor) 36.2 min, tr (major) 37.3 min); enantiomeric excess
(94% ee) was determined by SFC analysis on chiral phase
(Chiralpak AS-H 25 cm, 10% i-PrOH, 2 mL/min, 25 °C, 150
psi, tr (minor) 8.4 min, tr (major) 10.2 min); Rf 0.32 (100%,
Et2O); [R]20 = þ73 (c 0.35, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.55 (dd, J = 1.1 Hz, J = 7.9 Hz, 1H), 7.29-7.20 (m,
2H), 7.15-7.09 (m, 1H), 3.66-3.52 (m, 3H), 3.50-3.43 (m, 4H),
3.33-3.24 (m, 1H), 2.20 (dd, J = 4.8 Hz, J = 8.1 Hz, 1H),
Methyl 1-(pyrrolidine-1-carbonyl)-2-(3-(trifluoromethyl)phenyl)-
cyclopropanecarboxlate (10u). Prepared according to the general
procedure with a reaction temperature of 50 °C. The product
was isolated as a colorless oil: yield 49%; diastereomeric ratio
(>30:1) was determined by 1H NMR of the crude mixture, and
enantiomeric excess (95% ee) was determined by SFC analysis
on chiral phase (Whelk-O 25 cm, 7% i-PrOH, 3 mL/min, 40 °C,
150 psi, tr (minor) 8.6 min, tr (major) 13.4 min); Rf 0.25 (100%,
2.04-1.82 (m, 4H), 1.59 (dd, J = 4.8 Hz, J = 8.9 Hz, 1H); 13
C
NMR (75 MHz, CDCl3) δ 168.8, 166.0, 135.5, 132.5, 130.8,
128.9, 126.9, 126.4, 52.5, 46.7, 46.4, 38.3, 32.7, 26.3, 24.3, 18.9;
IR (film) 3050, 3010, 2950, 2877, 1731, 1639, 1413, 1297, 1148
cm-1; HRMS (ES, Pos) calcd for C16H18Br1N1O3 [M þ H]þ
351.0470, found 351.0475.
Methyl 2-(3,5-dimethoxyphenyl)-1-(pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate (10y). Prepared according to the gene-
ral procedure with a reaction temperature of 50 °C. The product
was isolated as a colorless oil: yield 54%; diastereomeric ratio
Et2O); [R]20 = þ70 (c 0.83, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.51 (s, 1H), 7.46-7.43 (m, 2H), 7.38-7.34 (m, 1H),
3.57-3.46 (m, 3H), 3.42-3.36 (m, 4H), 3.31-3.24 (m, 1H), 2.17
(dd, J = 5.1 Hz, J = 8.1 Hz, 1H), 1.97-1.86 (m, 4H), 1.52 (dd,
J = 5.1 Hz, J = 9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
168.4, 166.0, 136.7, 132.7, 130.7 (q, J = Hz, 1C), 128.6, 126.1,
124.0, 122.4, 52.5, 46.7, 46.5, 39.0, 30.9, 26.2, 24.3, 17.8; 19F
NMR (182 MHz, CDCl3) δ -117.0; IR (film) 2953, 2878, 1730,
1640, 1429, 1326, 1122 cm-1; HRMS (ES, Pos) calcd for
C17H18N1O3F3 [M þ H]þ 342.1312, found 342.1319.
1
(22:1) was determined by H NMR of the crude mixture, and
enantiomeric excess (90% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 7% MeOH, 3 mL/min,
40 °C, 150 psi, tr (minor) 6.0 min, tr (major) 12.5 min); Rf 0.22
1
(100%, Et2O); [R]20D = þ89 (c 1.11, CHCl3); H NMR (300
MHz, CDCl3) δ 6.41 (dd, J=8.8 Hz, J=1.1 Hz, 2H), 6.29 (t,
J=8.8 Hz, 1H), 3.72 (s, 6H), 3.60-3.44 (m, 3H), 3.44 (s, 3H),
3.33-3.19 (m, 2H), 2.10 (dd, J = 5.0 Hz, J = 8.0 Hz, 1H),
2.07-1.84 (m, 4H), 1.44 (dd, J=5.0 Hz, J=9.2 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 168.7, 166.4, 160.5 (2C), 138.0, 107.2
(2C), 99.6, 55.5 (2C), 52.5, 46.7, 46.5, 38.8, 31.6, 26.2, 24.3, 18.0;
Methyl 2-(2-fluorophenyl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10v). Prepared according to the general pro-
cedure with a reaction temperature of 50 °C. The product was
isolated as a white solid: yield 43%; diastereomeric ratio
8952 J. Org. Chem. Vol. 74, No. 23, 2009

Marcoux et al.
JOCFeatured Article
1
IR (film) 2951, 2877, 2840, 1729, 1636, 1594, 1425, 1425, 1310,
1203, 1151 cm-1; HRMS (ES, Pos) calcd for C18H23N1O5
[M þ H]þ 334.1649, found 334.1660.
(100%, Et2O); [R]20D = þ90 (c 0.85, CHCl3); H NMR (300
MHz, CDCl3) δ 7.34-7.23 (m, 5H), 3.76-3.72 (m, 1H),
3.64-3.59 (m, 3H), 3.42 (s, 3H), 2.16 (d, J=4.6 Hz, 1H), 2.05-
1.96 (m, 4H), 1.66 (d, J = 4.6, 1H), 1.49 (s, 3H); 13C NMR
(75 MHz, CDCl3) δ 170.1, 166.5, 142.6, 129.1 (2C), 129.1 (2C),
127.9, 52.9, 48.1, 47.2, 42.1, 38.9, 27.1, 26.5, 26.3, 25.0; IR (film)
Methyl 1-(pyrrolidine-1-carbonyl)-2-(3,4,5-trimethoxyphenyl)-
cyclopropanecarboxylate (10z). Prepared according to the gene-
ral procedure with a reaction temperature of 50 °C. The product
was isolated as a colorless oil: yield 29%; diastereomeric ratio
3038, 3009, 2956, 2879, 1729, 1644, 1432, 1319, 1139 cm-1
;
1
(24:1) was determined by H NMR of the crude mixture, and
HRMS (ES, Pos) calcd for C17H21N1O3 [M þ H]þ 288.1594,
enantiomeric excess (59% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 15% MeOH, 3 mL/
min, 40 °C, 150 psi, tr (minor) 2.3 min, tr (major) 3.1 min); Rf 0.21
found 288.1593.
Methyl-1-(pyrrolidine-1-carbonyl)-1,1a,6,6a-tetrahydrocyclo-
propana[a]indene-1-carboxylate (10ad). Prepared according to
the general procedure. The product was isolated as a white solid:
yield 51%; diastereomeric ratio (>30:1) was determined by GC/
MS analysis of the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min
from 40 to 270 °C, 63 psi H2, tr (minor) 37.8 min, tr (major) 38.5
min); enantiomeric excess (84% ee) was determined by SFC
analysis on chiral phase (Chiralpak AD-H 25 cm, 5% MeOH,
3 mL/min, 30 °C, 200 psi, tr (minor) 6.0 min, tr (major) 7.0 min);
mp 71-73 °C; Rf 0.37 (100%, Et2O); [R]20D = þ43 (c 0.53,
(100%, Et2O); [R]20D = þ47 (c 1.12, CHCl3); H NMR (300
1
MHz, CDCl3) δ 6.45 (s, 2H), 3.78 (s, 6H), 3.75 (s, 3H), 3.60-3.43
(m, 3H), 3.42 (s, 3H), 3.42 (app t, J=8.8 Hz, 1H), 3.38-3.24
(m, 1H), 2.10 (dd, J=5.1 Hz, J=8.1 Hz, 1H), 1.92-1.84 (m, 4H),
1.42 (dd, J=5.1 Hz, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3)
δ 168.6, 166.4, 153.1 (2C), 137.1, 131.3, 106.1 (2C), 61.0, 56.4
(2C), 52.5, 46.7, 46.4, 38.9, 31.6, 26.2, 24.3, 18.0; IR (film) 3050,
3010, 2951, 2876, 1731, 1641, 1521, 1429, 1317, 1144, 870 cm-1
;
HRMS (ES, Pos) calcd for C19H25N1O6 [M þ H]þ 363.1760,
CHCl3); H NMR (300 MHz, CDCl3) δ 7.40-7.37 (m, 1H),
1
found 363.1764.
7.18-7.12 (m, 3H), 3.71-3.60 (m, 1H), 3.60-3.46 (m, 4H),
3.43-3.24 (m, 5H), 2.50 (t, J=6.5 Hz, 1H), 2.01-1.86 (m, 4H);
13C NMR (75 MHz, CDCl3) δ 168.2, 166.8, 145.5, 139.8, 127.8,
127.1, 125.9, 124.7, 52.7, 47.5, 47.4, 40.6, 38.9, 34.0, 31.4, 27.0,
24.9; IR (film) 3050, 3010, 2950, 2877, 1731, 1639, 1413, 1297,
1148 cm-1; HRMS (ES, Pos) calcd for C17H19N1O3 [M þ Na]þ
308.1257, found 308.1258.
Methyl 2-(3-methoxy-4-methylphenyl)-1-(pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate (10aa). Prepared according to the gen-
eral procedure with a reaction temperature of 50 °C. The pro-
duct was isolated as a white solid: yield 64%; diastereomeric
ratio (25:1) was determined by 1H NMR of the crude mixture,
and enantiomeric excess (81% ee) was determined by SFC
analysis on chiral phase (Chiralpak AD-H 25 cm, 15% MeOH,
3 mL/min, 40 °C, 150 psi, tr (minor) 2.3 min, tr (major) 4.3 min);
mp 105-108 °C; Rf 0.29 (100%, Et2O); [R]20D =þ49 (c 2.00,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.98 (d, J=8.8 Hz, 1H),
6.76-6.70 (m, 2H), 3.77 (s, 3H), 3.61-3.48 (m, 3H), 3.48 (s, 3H),
3.36-3.19 (m, 2H), 2.18-2.10 (m, 4H), 1.97-1.80 (m, 4H), 1.44
(dd, J=5.1 Hz, J=9.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
168.8, 166.6, 157.5, 134.2, 130.2, 125.5, 120.8, 111.1, 55.4, 52.5,
46.6, 46.5, 38.8, 31.6, 26.2, 24.3, 18.0, 16.1; IR (film) 3050, 3010,
Methyl 2-(1-methyl-1H-pyrrol-2-yl)-1-(pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate (10ae). Prepared according to the gen-
eral procedure. The product was isolated as a colorless oil: yield
31%; diastereomeric ratio (>30:1) was determined by 1H NMR
analysis of the crude mixture, and enantiomeric excess (90% ee)
was determined by SFC analysis on chiral phase (R,R-Welko
25 cm, 7% MeOH, 3 mL/min, 40 °C, 160 psi, tr (minor) 14.3 min,
tr (major) 17.9 min); Rf 0.37 (100%, Et2O); [R]20D=þ97 (c 0.93,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 6.56 (t, J=2.2 Hz, 1H),
6.10-6.00 (m, 1H), 5.95-5.90 (m, 1H), 3.68 (s, 3H), 3.64-3.49
(m, 3H), 3.48 (s, 3H), 3.28-3.15 (m, 2H), 2.16 (dd, J=4.7 Hz, J=
7.8 Hz, 1H), 2.02-1.86 (m, 4H), 1.50 (dd, J=4.7 Hz, J=9.2 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 168.4, 166.3, 127.4, 122.5,
108.0, 106.7, 52.5, 46.6, 46.3, 38.2, 33.8, 26.2, 24.3, 23.9, 17.7; IR
2951, 2876, 1731, 1641, 1521, 1429, 1317, 1144, 870 cm-1
;
HRMS (ES, Pos) calcd for C18H23N1O4 [M þ H]þ 318.1700,
found 318.1700.
Methyl 2-(naphthalen-1-yl)-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10ab). Prepared according to the general
procedure. The product was isolated as a white foam: yield
86%; diastereomeric ratio (>30:1) was determined by GC/MS
analysis of the crude mixture (30 m ꢀ 0.25 mm, 5 °C/min from
40 to 270 °C, 63 psi H2, tr (minor) 37.7 min, tr (major) 38.2 min);
enantiomeric excess (95% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 15% MeOH, 3 mL/
min, 30 °C, 200 psi, tr (minor) 3.6 min, tr (major) 7.8 min); mp
83-85 °C; Rf 0.39 (100%, Et2O); [R]20D=-28 (c 1.67, CHCl3);
1H NMR (300 MHz, CDCl3) δ 8.67 (d, J=8.5 Hz, 1H), 7.80 (d,
J=8.0 Hz, 1H), 7.76 (d, J=7.6 Hz, 1H), 7.60 (t, J=1.4 Hz, 1H),
7.50-7.28 (m, 3H), 3.77 (app t, J=8.5 Hz, 1H), 3.65-3.53 (m,
3H), 3.27-3.22 (m, 1H), 3.11 (s, 3H), 2.42 (dd, J=4.7 Hz, J=
8.1 Hz, 1H), 2.03-1.89 (m, 4H), 1.64 (dd, J = 4.7 Hz, J =
8.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 168.7, 166.8,
133.5, 133.3, 132.0, 128.2, 128.0, 126.5, 126.4, 126.0, 125.3,
125.1, 52.2, 46.6, 46.3, 38.3, 30.3, 26.2, 24.4, 17.9; IR (film)
(film) 2951, 2876, 1723, 1635, 1430, 1313, 1295, 1142 cm-1
;
HRMS (ES, Pos) calcd for C15H20N2O3 [M þ H]þ 277.1558,
found 277.1547.
tert-Butyl 3-(2-(methoxycarbonyl)-2-(pyrrolidine-1-carbonyl)-
cyclopropyl)-1H-indole-1-carboxylate (10af). Prepared accord-
ing to the general procedure. The product was isolated as a white
solid: yield 54%; diastereomeric ratio (1.2:1) was determined by
1H NMR of the crude mixture, and enantiomeric excess (96 and
88% ee) was determined by SFC analysis on chiral phase
((major) Chiralcel AS-H 25 cm, 5% MeOH, 3 mL/min, 35 °C,
150 psi, tr (minor) 9.7 min, tr (major) 11.7 min; (minor) Chiralcel
OB-H 25 cm, 5% MeOH, 3 mL/min, 40 °C, 150 psi, tr (minor)
3.0 min, tr (major) 3.8 min); mp 165-168 °C; Rf 0.15 (100%,
Et2O); [R]20D = þ28 (c 0.90, CHCl3); 1H NMR (300 MHz,
CDCl3) δ (major) 8.08 (br s, 1H), 7.79 (d, J=8.8 Hz, 1H), 7.43
(br s, 1H), 7.33-7.22 (m, 2H), 3.67-3.51 (m, 3H), 3.37 (s, 3H),
3.34-3.22 (m, 2H), 2.16 (dd, J = 4.6 Hz, J = 8.0 Hz, 1H),
2.07-1.84 (m, 4H), 1.68 (s, 9H), 1.58 (dd, J=4.6 Hz, J=9.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ (major) 171.3, 168.8, 166.5,
130.8, 124.6, 122.7, 119.8, 116.1, 115.2, 83.7, 66.0, 53.6, 46.6,
46.4, 37.6, 28.4 (3C), 26.2, 35.5, 22.8, 18.1; IR (film) 2975, 2877,
1725, 1631, 1451, 1371, 1309, 1179 cm-1; HRMS (ES, Pos) calcd
for C23H28N2O5 [M þ H]þ 413.2071, found 413.2078.
3050, 3010, 2951, 2875, 1733, 1639, 1429, 1315, 1140 cm-1
;
HRMS (ES, Pos) calcd for C20H21N1O3 [M þ H]þ 324.1594,
found 324.1597.
Methyl 2-methyl-2-phenyl-1-(pyrrolidine-1-carbonyl)cyclopro-
panecarboxylate (10ac). Prepared according to the general
procedure. The product was isolated as a colorless oil after
purification by HPLC prep: yield 63%; diastereomeric ratio
(>20:1) was determined by 1H NMR of the crude mixture, and
enantiomeric excess (95% ee) was determined by SFC analysis
on chiral phase (Chiralpak AD-H 25 cm, 5% MeOH, 3 mL/min,
30 °C, 210 psi, tr (major) 7.7 min, tr (minor) 9.3 min); Rf 0.33
Methyl 1-(pyrrolidine-1-carbonyl)-2-(1-tosyl-1H-indol-3-yl)-
cyclopropanecarboxylate (10ag). Prepared according to the gen-
eral procedure. The product was isolated as a white solid: yield
58%; diastereomeric ratio (1.2:1) was determined by 1H NMR
J. Org. Chem. Vol. 74, No. 23, 2009 8953

Marcoux et al.
JOCFeatured Article
of the crude mixture, and enantiomeric excess (95 and 83% ee)
was determined by SFC analysis on chiral phase (Chiralpak
OD-H 25 cm, 10% MeOH, 3 mL/min, 30 °C, 150 psi, tr (minor
trans) 6.7 min, tr (major trans) 7.9 min, tr (major cis) 9.3 min, tr
(minor cis) 12.6 min); mp 125-127 °C; Rf 0.25 (100%, EtOAc);
by SFC analysis on chiral phase (Chiralpak OD-H 25 cm, 5%
MeOH, 3 mL/min, 30 °C, 150 psi, tr (major) 10.2 min, tr (minor)
23.8 min); Rf 0.48 (100%, Et2O); mp 72-75 °C; [R]20D=þ116
(c 0.58, CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.39-7.23 (m,
5H), 6.68 (d, J=15.9 Hz, 1H), 6.21 (dd, J=9.3 Hz, J=15.9 Hz,
1H), 3.75 (s, 3H), 3.54-3.50 (m, 3H), 3.41-3.37 (m, 1H), 2.62
(app q, J=9.3 Hz, J=15.6 Hz, 1H), 1.97-1.91 (m, 4H), 1.84 (dd,
J=4.8 Hz, J=7.5 Hz, 1H), 1.68 (dd, J=4.8 Hz, J=9.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 169.8, 166.4, 137.2, 133.3, 128.7
(2C), 127.6, 126.3 (2C), 125.7, 52.8, 46.8, 46.5, 37.8, 31.7, 26.2,
24.4, 21.5; IR (film) 3024, 2959, 2874, 1726, 1633, 1416, 1312,
1139 cm-1; HRMS (ES, Pos) calcd for C18H21N1O3 [M þ H]þ
300.1594, found 300.1596.
1
mp 180-183 °C; [R]20D=-26 (c 2.95, CHCl3); H NMR (300
MHz, CDCl3) δ (major þ minor) 8.05-8.00 (m, 1H), 7.89-7.85
(m, 1H), 7.78-7.65 (m, 5H), 7.63-7.55 (m, 1H), 7.35-7.09
(m, 10H), 3.74 (s, 3.74), 3.58-3.47 (m, 4H), 3.24-3.09 (m, 3H),
3.12 (s, 3H), 3.07-2.91 (m, 2H), 2.61-2.50 (m, 1H), 2.31 (s, 3H),
2.28 (s, 3H), 2.16-2.04 (m, 2H), 1.96-1.84 (m, 4H), 1.81 (dd, J=
5.1 Hz, J=8.1 Hz, 1H), 1.53 (dd, J=5.1 Hz, J=9.2 Hz, 1H),
1.45-1.33 (m, 4H); 13C NMR (75 MHz, CDCl3) δ 171.1, 168.3,
166.2, 163.3, 135.4, 135.3, 135.1, 135.0, 131.3, 130.9, 130.0 (2C),
129.9 (2C), 127.1 (2C), 127.0 (2C), 125.7, 125.1, 125.0, 123.5,
123.4, 121.9, 120.3, 118.9, 118.0, 117.3, 113.9, 113.6, 53.6, 52.9,
52.3, 46.6, 46.4, 46.3, 45.8, 39.6, 38.2, 30.5, 26.2, 25.3, 24.3, 23.7,
23.0, 22.4, 21.7, 21.1, 17.9; IR (film) 3050, 3010, 2951, 2876,
1731, 1641, 1600, 1521, 1429, 1317, 1144, 870 cm-1; HRMS (ES,
Pos) calcd for C25H26N2O5S1 [M þ H]þ 467.1634, found
467.1635.
Methyl 2-(2,2-diphenylvinyl)-1-(pyrrolidine-1-carbonyl)cyclo-
propanecarboxylate (10ak). Prepared according to the general
procedure. The product was isolated as a white solid: yield 90%;
1
diastereomeric ratio (6:1) was determined by H NMR of the
crude mixture, and enantiomeric excess (75 and 53% ee) was
determined by SFC analysis on chiral phase (Chiralpak OD-H
25 cm, 7% i-PrOH, 2 mL/min, 35 °C, 150 psi, tr (minor trans)
15.7 min, tr (major trans) 18.8 min, tr (minor cis) 20.3 min, tr
(major cis) 23.4 min); mp 115-118 °C; Rf 0.45 (100%, Et2O);
Methyl 2-(1-benzyl-1H-indol-3-yl)-1-(pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate (10ah). Prepared according to the
general procedure. The product was isolated as a colorless oil:
1
[R]20D=þ44 (c 1.83, CHCl3); H NMR (300 MHz, CDCl3) δ
(major) 7.51-7.21 (m, 10H), 6.13 (d, J=13.1 Hz, 1H), 3.79 (s,
3H), 3.42-3.31 (m, 3H), 3.20-3.09 (m, 1H), 2.64-2.53 (m, 1H),
1.97-1.63 (m, 6H), (minor) 7.51-7.21 (m, 10H), 5.44 (d, J=13.1
Hz, 1H), 3.69 (s, 3H), 3.45-3.34 (m, 3H), 3.34-3.19 (m, 1H),
2.81-2.70 (m, 1H), 1.97-1.63 (m, 6H); 13C NMR (75 MHz,
CDCl3) δ (major þ minor) 171.6, 171.5, 170.6, 167.0, 145.7,
145.6, 142.9, 142.7, 140.2, 140.0, 131.1 (2C), 130.7, 139.4, 129.2
(2C), 129.1, 128.9 (2C), 128.4, 128.4, 128.3, 128.2 (2C), 128.1,
128.0, 126.1, 125.2, 53.5, 53.4, 47.3, 47.2, 47.1, 47.0, 38.7, 38.4,
29.9, 29.2, 26.9, 26.7, 26.9, 26.7, 25.1, 24.9, 23.7, 23.1; IR (film)
3057, 3010, 2952, 2877, 1726, 1639 cm-1; HRMS (ES, Pos) calcd
for C24H25N1O3 [M þ H]þ 376.1907, found 376.1919.
1
yield 88%; diastereomeric ratio (1.5:1) was determined by H
NMR of the crude mixture, and enantiomeric excess (50 and
41% ee) was determined by SFC analysis on chiral phase
((major) Chiralpak AD-H 25 cm, 20% MeOH, 3 mL/min,
35 °C, 150 psi, tr (minor) 5.7 min, tr (major) 12.2 min; (minor)
Chiralpak AD-H 25 cm, 20% MeOH, 3 mL/min, 35 °C, 150 psi,
tr (minor) 3.7 min, tr (major) 4.2 min); Rf 0.25 (100%, Et2O);
1
[R]20D=þ39 (c 1.25, CHCl3); H NMR (300 MHz, CDCl3) δ
(Major) 7.80 (d, J=8.8 Hz, 1H), 7.78-6.93 (m, 9H), 5.29-5.23
(m, 2H), 3.61-3.3.52 (m, 3H), 3.39 (app t, J = 8.7 Hz, 1H),
3.30-3.20 (m, 4H), 2.08 (dd, J = 4.9 Hz, J = 8.0 Hz, 1H),
1.95-1.83 (m, 4H), 1.57 (dd, J=4.9 Hz, J=9.2 Hz, 1H), (minor)
7.77 (d, J=8.8 Hz, 1H), 7.48-7.07 (m, 8H), 6.84 (s, 1H), 5.24
(dd, J=4.5 Hz, J=9.2, 2H), 3.79 (s, 3H), 3.40 (app t, J=8.9 Hz,
1H), 3.33-3.14 (m, 2H), 3.08-2.94 (m, 1H), 2.77-2.70 (m, 1H),
2.14 (dd, J=4.9 Hz, J=8.0 Hz, 1H), 1.88 (dd, J=4.9 Hz, J=9.2
Hz, 1H), 1.57-1.35 (m, 3H), 0.52-0.37 (m, 1H); 13C NMR (75
MHz, CDCl3) δ (major) 169.0, 166.9, 137.9, 136.6, 129.0, 128.9
(2C), 127.7, 127.3, 126.9 (2C), 122.0, 119.8, 119.5, 110.2, 109.7,
52.3, 50.1, 46.6, 46.5, 38.4, 26.2, 24.4, 23.7, 18.6; IR (film) 2949,
2874, 1726, 1630, 1432, 1308, 1145, 732 cm-1; HRMS (ES, Pos)
calcd for C25H26N2O3 [M þ H]þ 403.2016, found 403.2031.
Methyl 2-butoxy-1-(pyrrolidine-1-carbonyl)cyclopropanecar-
boxylate (10ai). Prepared according to the general procedure
using the alkene with a 10-fold excess. The product was isolated
as a colorless oil: yield 70%; diastereomeric ratio (89:11) was
determined by 1H NMR analysis of the crude mixture, and
enantiomeric excess (89% ee) was determined by SFC analysis
on chiral phase (R,R-Welko 25 cm, 7% MeOH, 3 mL/min,
40 °C, 160 psi, tr (minor) 10.3 min, tr (major) 15.7 min); Rf 0.38
Methyl 2-((E)-1-phenylprop-1-en-2-yl)-1-(pyrrolidine-1-carbonyl)-
cyclopropanecarboxylate (10al). Prepared according to the gen-
eral procedure. The product was isolated as a colorless oil: yield
73%; diastereomeric ratio (14:1) was determined by 1H NMR of
the crude mixture, and enantiomeric excess (85% ee) was
determined by SFC analysis on chiral phase (Chiralpak AD-H
25 cm, 3% MeOH, 3 mL/min, 40 °C, 150 psi, tr (major) 5.7 min,
tr (minor) 6.9 min); Rf 0.33 (100%, Et2O); [R]20D=-83 (c 1.08,
CHCl3); 1H NMR (300 MHz, CDCl3) δ 7.35-7.12 (m, 5H), 6.36
(s, 1H),3.63 (s, 3H), 3.60-3.39 (m, 3H), 3.29-3.17 (m, 1H), 2.85
(app t, J=9.2 Hz, 1H), 2.03 (dd, J=4.8 Hz, J=8.1 Hz, 1H),
1.96-1.78 (m, 7H), 1.32 (dd, J=4.8 Hz, J=8.7 Hz, 1H); 13C
NMR (75 MHz, CDCl3) δ 169.1, 166.6, 137.9, 132.4, 129.0 (2C),
128.5, 128.3 (2C), 126.5, 52.6, 46.7, 46.4, 37.8, 35.7, 30.5, 26.3,
24.3, 18.6; IR (film) 3057, 3010, 2952, 2877, 1726, 1639 cm-1
;
HRMS (ES, Pos) calcd for C19H23N1O3 [M þ H]þ 314.1756,
found 314.1760.
Methyl 2-((E)-2,6-dimethylhepta-1,5-dienyl)-1-(pyrrolidine-1-
carbonyl)cyclopropanecarboxylate (10am). Prepared according
to the general procedure. The product was isolated as a colorless
oil: yield 45%; diastereomeric ratio (22:1) was determined by
1H NMR of the crude mixture, and enantiomeric excess (90%
ee) was determined by SFC analysis on chiral phase (Chiralpak
AD-H 25 cm, 5% MeOH, 10 mL/min, 40 °C, 150 psi, tr (minor)
3.9 min, tr (major) 5.2 min); Rf 0.54 (100%, Et2O); [R]20D=-32
(c 2.70, CHCl3); 1H NMR (300 MHz, CDCl3) δ 5.05-5.00 (m,
2H), 3.67 (s, 3H), 3.53-3.39 (m, 3H), 3.29-3.15 (m, 1H),
2.52-2.50 (m, 1H), 2.10-1.76 (m, 8H), 1.74 (s, 3H),
1.67-1.60 (m, 4H), 1.56 (s, 3H), 1.43 (dd, J = 4.5 Hz, J =
9.0 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 169.9, 166.8, 140.7,
131.6, 124.1, 119.7, 52.4, 46.5, 46.3, 39.7, 37.6, 27.1, 26.7, 26.1,
25.8, 24.3, 21.1, 17.8, 16.8; IR (film) 2970, 2890, 1729, 1643,
1
(100%, Et2O); [R]20D = þ64 (c 0.91, CHCl3); H NMR (300
MHz, CDCl3) δ 4.09 (dd, J=5.4 Hz, J=7.0 Hz, 1H), 3.76 (s,
3H), 3.65-3.60 (m, 1H), 3.56-3.42 (m, 3H), 3.26-3.23 (m, 1H),
2.06 (app t, J=5.4 Hz, 1H), 1.97-1.86 (m, 4H), 1.58-1.51 (m,
2H), 1.37-1.22 (m, 4 H), 0.90 (t, J=7.4 Hz, 3H); 13C NMR (75
MHz, CDCl3) δ 168.0, 165.8, 71.5, 64.1, 52.7, 46.4, 46.2, 37.1,
31.6, 26.1, 24.3, 20.3, 19.4, 14.0; IR (film) 2955, 2873, 1732, 1634,
1433, 1307, 1147 cm-1; HRMS (ES, Pos) calcd for C14H23N1O4
[M þ H]þ 270.1700, found 270.1703.
Methyl 1-(pyrrolidine-1-carbonyl)-2-styrylcyclopropanecarboxy-
late (10aj). Prepared according to the general procedure. The
product was isolated as a white solid: yield 77%; diastereomeric
1
ratio (9:1) was determined by H NMR analysis of the crude
mixture, and enantiomeric excess (87% ee) was determined
8954 J. Org. Chem. Vol. 74, No. 23, 2009

Marcoux et al.
JOCFeatured Article
DeSeve Foundation for postgraduate fellowships. Francine
1434, 1310, 1138, 911 cm-1; HRMS (ES, Pos) calcd for
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C19H29N1O3 [M þ H]þ 320.2223, found 320.2220.
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Belanger and Jad Tannous (Universite de Montreal) are
acknowledged for X-ray and SFC analysis, respectively.
Acknowledgment. This work was supported by NSERC
(Canada), the Canada Research Chair Program, the Canada
Supporting Information Available: Experimental proce-
dures for the preparation of all the compounds and characteri-
zation data for each reaction and detailed structural assignment.
This material is available free of charge via the Internet at http://
pubs.acs.org.
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Foundation for Innovation, and the Universite de Montreal.
D.M. is grateful to NSERC (PGS D), the Universite de
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Montreal, and the Financiere Manuvie for postgraduate fel-
lowships. S.R.G. is grateful to NSERC (PGS D) and the J.A.
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J. Org. Chem. Vol. 74, No. 23, 2009 8955