Mechanistic studies on a dipeptide-promoted asymmetric cyclopropanation of unfunctionalized olefins

Article abstract of DOI:10.1021/ol902150j

This paper describes mechanistic studies on a dipeptide-promoted asymmetric cyclopropanation system for unfunctionalized olefins. Zinc species generated from the deprotonation of the N-H of the dipeptide ligand have been investigated by NMR and X-ray stru

Full text of DOI:10.1021/ol902150j

ORGANIC
LETTERS
2009
Vol. 11, No. 22
5226-5229
Mechanistic Studies on a
Dipeptide-Promoted Asymmetric
Cyclopropanation of Unfunctionalized
Olefins
Jiang Long, Liang Xu, Haifeng Du, Kai Li, and Yian Shi*
Department of Chemistry, Colorado State UniVersity, Fort Collins, Colorado, 80523
yian@lamar.colostate.edu
Received September 17, 2009
ABSTRACT
This paper describes mechanistic studies on a dipeptide-promoted asymmetric cyclopropanation system for unfunctionalized olefins. Zinc
species generated from the deprotonation of the N-H of the dipeptide ligand have been investigated by NMR and X-ray structure studies and
are likely to be responsible for asymmetric cyclopropanation. ZnI2 plays an important role in promoting the reaction.
The asymmetric Simmons-Smith reaction presents an
important approach to the synthesis of optically active
cyclopropanes from olefins.1 Various effective systems have
been developed using chiral auxiliaries,2 reagents,3 or
catalysts.4 In most of these methods, substrates usually
contain heteroatoms as directing groups to enhance both
reactivity and stereocontrol. Asymmetric Simmons-Smith-
type cyclopropanation for prochiral olefins without effective
directing groups generally presents a formidable challenge.5
Our earlier studies have shown that encouragingly high
enantioselectivity (72-91% ee) can be achieved for the
cyclopropanation of unfunctionalized olefins using a sto-
ichiometric amount of dipeptide N-Boc-L-Val-L-Pro-OMe (1),
(1) For leading reviews, see: (a) Simmons, H. E.; Cairns, T. L.;
Vladuchick, S. A.; Hoiness, C. M. Org. React. 1973, 20, 1. (b) Hoveyda,
A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307. (c) Lautens, M.;
Klute, W.; Tam, W. Chem. ReV. 1996, 96, 49. (d) Denmark, S. E.; Beutner,
G. Cycloaddition Reactions in Organic Synthesis; Kobayashi, S., Jorgensen,
K. A., Eds.; Wiley-VCH Verlag GmbH & Co. KGaA: Weinheim, Germany,
2002; p 85. (e) Lebel, H.; Marcoux, J.-F.; Molinaro, C.; Charette, A. B.
Chem. ReV. 2003, 103, 977. (f) Pellissier, H. Tetrahedron 2008, 64, 7041.
(2) For leading references, see: (a) Arai, I.; Mori, A.; Yamamoto, H.
J. Am. Chem. Soc. 1985, 107, 8254. (b) Mash, E. A.; Nelson, K. A. J. Am.
Chem. Soc. 1985, 107, 8256. (c) Sugimura, T.; Futagawa, T.; Tai, A.
Tetrahedron Lett. 1988, 29, 5775. (d) Imai, T.; Mineta, H.; Nishida, S. J.
Org. Chem. 1990, 55, 4986. (e) Charette, A. B.; Coˆte´, B.; Marcoux, J.-F.
J. Am. Chem. Soc. 1991, 113, 8166. (f) Kang, J.; Lim, G. J.; Yoon, S. K.;
Kim, M. Y. J. Org. Chem. 1995, 60, 564. (g) Charette, A. B.; Coˆte´, B.
J. Am. Chem. Soc. 1995, 117, 12721. (h) Song, Z.; Lu, T.; Hsung, R. P.;
Al-Rashid, Z. F.; Ko, C.; Tang, Y. Angew. Chem., Int. Ed. 2007, 46, 4069.
(3) For leading references on chiral reagents for allylic alcohols, see:
(a) Ukaji, Y.; Nishimura, M.; Fujisawa, T. Chem. Lett. 1992, 61. (b)
Denmark, S. E.; Edwards, J. P. Synlett 1992, 229. (c) Ukaji, Y.; Sada, K.;
Inomata, K. Chem. Lett. 1993, 1227. (d) Charette, A. B.; Juteau, H. J. Am.
Chem. Soc. 1994, 116, 2651. (e) Kitajima, H.; Aoki, Y.; Ito, K.; Katsuki,
T. Chem. Lett. 1995, 1113. (f) Charette, A. B.; Juteau, H.; Lebel, H.;
Molinaro, C. J. Am. Chem. Soc. 1998, 120, 11943.
(4) For leading references on chiral catalysts for allylic alcohols, see:
(a) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S. Tetrahedron
Lett. 1992, 33, 2575. (b) Imai, N.; Sakamoto, K.; Takahashi, H.; Kobayashi,
S. Tetrahedron Lett. 1994, 35, 7045. (c) Denmark, S. E.; Christenson, B. L.;
Coe, D. M.; O’Connor, S. P. Tetrahedron Lett. 1995, 36, 2215. (d) Charette,
A. B.; Brochu, C. J. Am. Chem. Soc. 1995, 117, 11367. (e) Imai, N.;
Sakamoto, K.; Maeda, M.; Kouge, K.; Yoshizane, K.; Nokami, J. Tetra-
hedron Lett. 1997, 38, 1423. (f) Denmark, S. E.; O’Connor, S. P. J. Org.
Chem. 1997, 62, 3390. (g) Balsells, J.; Walsh, P. J. J. Org. Chem. 2000,
65, 5005. (h) Charette, A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc.
2001, 123, 12168. (i) Shitama, H.; Katsuki, T. Angew. Chem., Int. Ed. 2008,
47, 2450.
(5) (a) Sawada, S.; Oda, J.; Inouye, Y. J. Org. Chem. 1968, 33, 2141.
(b) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1968, 3495.
(c) Yang, Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39, 8621. (d)
Charette, A. B.; Francocur, S.; Martel, J.; Wilb, N. Angew. Chem., Int. Ed.
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10.1021/ol902150j CCC: $40.75
Published on Web 10/20/2009
 2009 American Chemical Society

ZnEt2, and CH2I2 (Scheme 1).6a Subsequent studies showed
that a catalytic process for this cyclopropanation is feasible
Scheme 1
when an achiral ligand such as ethyl methoxyacetate (EMA)
is added to coordinate with Zn(CH2I)2 to reduce background
reaction.6b,c,7 It was observed that addition of ZnI2 can
facilitate the cyclopropanation, particularly when the reaction
is carried out at low temperature.6b,c,8 A better mechanistic
understanding of this cyclopropanation system would be
beneficial for further development. Herein we wish to report
our preliminary efforts on this subject.
In contrast to dipeptide 1, no conversion was obtained for
1-phenyl-3,4-dihydronaphthalene when a methylated dipep-
tide, N-Boc-N-Me-L-Val-L-Pro-OMe (2), was used. This
indicates that the N-H of dipeptide 1 was important for the
asymmetric cyclopropanation. When dipeptide 1 was treated
with Zn(CH2I)2 at 0 °C, MeI was slowly formed as judged
by the 1H NMR spectrum, suggesting that compound 1 was
slowly deprotonated by Zn(CH2I)2 to form a peptide bound
zinc reagent, putatively drawn as 3 (Scheme 2). When the
Figure 1. Plot of the conversion of 1-phenyl-3,4-dihydronaphthalene
against time (h). The curves presented are: (A) Zn(CH2I)2 (1.0
equiv) + N-Boc-L-Val-L-Pro-OMe (1) (1.0 equiv); (B) L*-ZnCH2I
(3) (2.0 equiv); (C) L*-ZnCH2I (3) (2.0 equiv) + ZnI2 (0.4 equiv);
(D) L*-ZnCH2I (3) (2.0 equiv) + ZnI2 (1.0 equiv); (E) L*-ZnCH2I
(3) (1.0 equiv) + Zn(CH2I)2 (1.0 equiv); (F) L*-ZnI (9) (1.0 equiv)
+ Zn(CH2I)2 (1.0 equiv) (L* ) N-Boc-L-Val-L-Pro-OMe). All
reactions were carried out in CH2Cl2 at 0 °C.
Compound 3 can be generated more cleanly by treating
dipeptide 1 with ZnEt2, followed by CH2I2 (Scheme 3). The
Scheme 3
Scheme 2
cyclopropanation of 1-phenyl-3,4-dihydronaphthalene was
performed with 1.0 equiv of 1 and 1.0 equiv of Zn(CH2I)2,
30% conversion and 85% ee were obtained for the product
after 24 h at 0 °C (Figure 1, curve A). The product ee was
found to increase with time (from 70% ee at 1 h to 85% ee
at 14 h), indicating that more and more asymmetric cyclo-
propanation via a chiral species occurred with time, which
is consistent with compound 3 being involved for the
asymmetric cyclopropanation as it was formed gradually
from dipeptide 1 and Zn(CH2I)2.
transformations can be readily monitored by the formation
of CH3CH3 and EtI. The 1H and 13C NMR data are consistent
with the structures of compounds 3 and 4 (see Supporting
Information). For compound 3, the N-ZnCH2I signal over-
lapped with the signal of the Boc group. To avoid this
complication, a Cbz-protected dipeptide Cbz-L-Val-L-Pro-
OMe (5) was then used for further NMR study. In this case,
the methylene signal of N-ZnCH2I displayed two clear
doublets at ∼1.5 ppm (see Supporting Information), which
is consistent with the CH2 group being placed in a chiral
environment. Obtaining a crystal structure for compounds
3, 4, or related compounds proved to be extremely chal-
lenging. A suitable single crystal of 7 derived from ligand 6
and ZnEt2 was finally obtained after much experimentation.
The X-ray structure (Figure 2) shows that a dimer is formed
via a complexing carbonyl of the Boc and amide groups with
zinc atoms. At this moment, it is not clear whether the
dimerization plays an important role in catalysis. No
(6) (a) Long, J.; Yuan, Y.; Shi, Y. J. Am. Chem. Soc. 2003, 125, 13632.
(b) Long, J.; Du, H.; Li, K.; Shi, Y. Tetrahedron Lett. 2005, 46, 2737. (c)
Du, H.; Long, J.; Shi, Y. Org. Lett. 2006, 8, 2827.
(7) For recent reports on asymmetric cyclopropanation using chiral
phosphoric acid derived Zn reagents, see: (a) Lacasse, M.-C.; Poulard, C.;
Charette, A. B. J. Am. Chem. Soc. 2005, 127, 12440. (b) Voituriez, A.;
Charette, A. B. AdV. Synth. Catal. 2006, 348, 2363
.
(8) For theoretical studies and discussion on the effect of ZnX2, see: (a)
Nakamura, E.; Hirai, A.; Nakamura, M. J. Am. Chem. Soc. 1998, 120, 5844.
(b) Zhao, C.; Wang, D.; Phillips, D. L. J. Am. Chem. Soc. 2002, 124, 12903.
(c) Nakamura, M.; Hirai, A.; Nakamura, E. J. Am. Chem. Soc. 2003, 125,
2341
.
Org. Lett., Vol. 11, No. 22, 2009
5227

Scheme 4
the Zn atom for iodine to coordinate, activating the methylene
group toward cyclopropanation.5c
The cyclopropanation proceeded efficiently with 1.0 equiv
of 3 and 1 equiv of Zn(CH2I)2 without addition of ZnI2
(Figure 1, curve E), suggesting that ZnI2 or related species,
formed in situ from the decomposition and/or background
reaction of Zn(CH2I)2, was effective in promoting the
cyclopropanation. High ee’s obtained in this study also
suggested that the asymmetric process is faster than the
background reaction. When the cyclopropanation was per-
formed with 1.0 equiv of L*-ZnI (9) (L* ) N-Boc-L-Val-
L-Pro-OMe) and 1.0 equiv of Zn(CH2I)2, 99% conversion
and 86% ee were obtained after 24 h at 0 °C (Figure 1, curve
F). In this case, cyclopropanating species 3 was probably
generated in situ via the transmetalation between L*-ZnI (9)
and Zn(CH2I)2. NMR studies also indicated that L*-ZnI (9)
can undergo rapid transmetalation with Zn(CH2I)2.12 The
facile transmetalation between the chiral Zn species and
Zn(CH2I)2 was also observed in a deuterium labeling study
in which a mixture of labeled and unlabeled products was
formed regardless of whether L*-ZnCH2I (3) and Zn(CD2I)2
or L*-ZnCD2I (3′) and Zn(CH2I)2 were used (Scheme 5).
Figure 2. Structure of compound 7.
nonlinear effects were observed for the cyclopropanation of
1-phenyl-3,4-dihydronaphthalene with dipeptide 1.
Interestingly, compound 3 prepared via the aforementioned
method (Scheme 3) was not effective for cyclopropanation,
giving only 7% conversion (83% ee) for 1-phenyl-3,4-dihy-
dronaphthalene after 24 h at 0 °C (Figure 1, curve B). It was
surmised that higher reactivity obtained with 1.0 equiv of
Zn(CH2I)2 and 1.0 equiv of 1 (Figure 1, curve A) could be due
to the fact that the cyclopropanation might be facilitated by ZnI2
or related species resulting from the decomposition of
Zn(CH2I)29 and/or background reaction of the olefin with
Zn(CH2I)2. Subsequent studies showed that the cyclopropanation
with 3 was indeed enhanced by the addition of ZnI2 (Figure 1,
curves C and D), giving 89% conversion and 90% ee with 2.0
equiv of 3 and 1.0 equiv of ZnI2 after 24 h at 0 °C.
The effects of ZnX2 on Simmons-Smith cyclopropanation
have been described and discussed.4c,f,8,10 For example,
Denmark and co-workers reported that ZnI2 has a favorable
effect on the bissulfonamide-catalyzed cyclopropanation of
allylic alcohols.4c,f The increased reaction rate and enanti-
oselectivity caused by ZnI2 is attributed to the formation of
the more reactive and selective IZnCH2I species via a
Schlenk equilibrium. In their theoretical studies, Nakamura
and co-workers proposed that ZnX2 could accelerate the
cyclopropanation as a Lewis acid via a five-centered transi-
tion state.8a,c The precise role of ZnI2 in the current system
awaits further study.11 ZnI2 could activate 3 via a five-
membered species (8) (Scheme 4), following the proposed
model by Nakamura.8a,c ZnI2 could also facilitate the
cyclopropanation by breaking possible dimers analogous to
7, or it could facilitate the opening of a vacant orbital on
Scheme 5
(9) For a leading reference, see: Charette, A. B.; Marcoux, J.-F. J. Am.
Chem. Soc. 1996, 118, 4539.
On the basis of these results, a plausible catalytic cycle is
shown in Scheme 6. Compound 3, generated from dipeptide
1 by deprotonation with ZnEt2 and subsequent halogen
(10) For leading references on studies and discussion on the effect of
ZnX2, also see: (a) Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am.
Chem. Soc. 2001, 123, 8139. (b) Fournier, J.-F.; Charette, A. B. Eur. J.
Org. Chem. 2004, 1401
.
(11) Other Lewis acids can also promote the cyclopropanation of
1-phenyl-3,4-dihydronaphthalene at 0 °C, such as BF3·Et2O (72% conv.,
87% ee) and ZnBr2 (44% conv., 88% ee).
(12) For a leading reference on transmetallation of zinc reagents, see:
Dessy, R. E.; Coe, G. R. J. Org. Chem. 1963, 28, 3592.
5228
Org. Lett., Vol. 11, No. 22, 2009

Scheme 6
Scheme 7
exchange with CH2I2, is activated by XZnI to form complex
8, which then cyclopropanates the olefin to form 9. Active
species 8 is regenerated upon transmetalation between 9 and
Zn(CH2I)2 to complete the cycle. Alternatively, compound
9 could act as a chiral Lewis acid to activate XZnCH2I for
cyclopropanation (Scheme 7). Some zinc species involved
in the reaction pathways could also exist and/or function as
dimers structurally similar to compound 7. The dimer
structures may also be important for the creation of an
effective chiral environment for asymmetric induction. A
precise reaction mechanism awaits further study.
In summary, studies have shown that zinc species gener-
ated from the deprotonation of the N-H of dipeptide ligand
1 are likely to be responsible for asymmetric cyclopropa-
nation and that ZnI2 plays an important role in promoting
cyclopropanation. Rapid transmetalations among various zinc
species are involved in the catalytic cycle. These results
provide a better understanding for the peptide-promoted
asymmetric cyclopropanation and lay the foundation for
future development. Further search for an effective catalytic
process with high reactivity and enantioselectivity is currently
underway.
Acknowledgment. We are grateful to the generous
financial support from the National Science Foundation
CAREER Award program (CHE-9875497).
Supporting Information Available: The experimental
procedures for Figure 1 and Scheme 6, and NMR studies of
compounds 3, 4, and 9 along with the X-ray structure of
compound 7 and the NMR spectra of 3, 4, 9, and related
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
OL902150J
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