Enantioselective synthesis of 2-arylbicyclo[1.1.0]butane carboxylates

Article abstract of DOI:10.1021/ol303217s

The rhodium-catalyzed reaction of 2-diazo-5-arylpent-4-enoates can be controlled by the appropriate choice of catalyst and catalyst loading to form either 2-arylbicyclo[1.1.0]butane carboxylates or cyclohexene derivatives. Both products are produced in a

Full text of DOI:10.1021/ol303217s

ORGANIC
LETTERS
XXXX
Vol. XX, No. XX
000–000
Enantioselective Synthesis of
2‑Arylbicyclo[1.1.0]butane Carboxylates
Changming Qin and Huw M. L. Davies*
Department of Chemistry, Emory University, 1515 Dickey Drive, Atlanta,
Georgia 30322, United States
hmdavie@emory.edu
Received November 21, 2012
ABSTRACT
The rhodium-catalyzed reaction of 2-diazo-5-arylpent-4-enoates can be controlled by the appropriate choice of catalyst and catalyst loading to
form either 2-arylbicyclo[1.1.0]butane carboxylates or cyclohexene derivatives. Both products are produced in a highly diastereoselective
manner, with 2-arylbicyclo[1.1.0]butane carboxylates preferentially formed under low catalyst loadings. When the reaction is catalyzed by Rh2(R-
BTPCP)4, the 2-arylbicyclo[1.1.0]butane carboxylates are generated with high levels of asymmetric induction (70À94% ee).
The bicyclo[1.1.0]butane ring system has fascinated che-
mists because it challenges chemical bonding models1 and
offers utility in complex molecule synthesis.2 General syn-
thetic routes to access bicyclo[1.1.0]butanes include Wurtz
coupling, reductive dehalogenation of 1,3-dihalocyclobu-
tanes, anionic-type ring closure, and 1,3 γ-silyl elimination.3
The metal-catalyzed synthesis of the bicyclo[1.1.0]butane
system is relatively undeveloped. Previous approaches in-
clude the cyclopropanation of cyclopropenes4 and intra-
molecular cyclopropanation of R-allyl diazo compounds,5
neither of which has been conducted in an enantioselective
manner. Herein, we report the asymmetric synthesis of
bicyclo[1.1.0]butanes rings by the rhodium-catalyzed de-
composition of 2-diazo-5-arylpent-4-enoates (eq 1).
(1) Important contributions to bicyclo[1.1.0]butanes chemistry.
Experiment: (a) Wiberg, K. B.; Ciula, R. P. J. Am. Chem. Soc. 1959,
81, 5261. (b) Wiberg, K. B.; Lampman, G. M.; Ciula, R. P.; Connor,
D. S.; Schertler, P.; Lavanish, J. Tetrahedron 1965, 21, 2749. (c) Walters,
V. A.; Hadad, C. M.; Thiel, Y.; Colson, S. D.; Wiberg, K. B.; Johnson,
P. M.; Foresman, J. B. J. Am. Chem. Soc. 1990, 112, 4782. (d) Blanchard,
E. P., Jr.; Carncross, A. J. Am. Chem. Soc. 1966, 88, 487. (e) Becknell,
A. F.; Berson, J. A.; Srinivasan, R. J. Am. Chem. Soc. 1985, 107, 1076.
(f) Adam, W.; Oppenlander, T.; Zang, G. J. Am. Chem. Soc. 1985, 107,
3921. (g) Closs, G. L.; Pfeffer, P. E. J. Am. Chem. Soc. 1968, 90, 2452.
(h) Wiberg, K. B.; Lavanish, J. M. J. Am. Chem. Soc. 1966, 88, 5272.
Theory: (i) Nguyen, K. A.; Gordon, M. S.; Boatz, J. A. J. Am. Chem.
Soc. 1994, 116, 9241. (j) Shevlin, P. B.; McKee, M. L. J. Am. Chem. Soc.
1988, 110, 1666. (k) Dewar, M. J. S.; Kirschner, S. J. Am. Chem. Soc.
1975, 97, 2931. (l) Sbevlin, P. B.; Mckee, M. L. J. Am. Chem. Soc. 1988,
110, 1666. (m) Gassman, P. G.; Greenlee, M. L.; Dixon, D. A.;
Richtsmeier, S.; Gougoutas, J. Z. J. Am. Chem. Soc. 1983, 105, 5865.
(n) Schmidt, M. W.; Nguyen, K. A; Gordon., M. S.; Montgomery, J. A.,
Jr. J. Am. Chem. Soc. 1991, 113, 5998. (o) Nguyen, K. A; Carroll, M. T.;
Gordon, M. S. J. Am. Chem. Soc. 1991, 113, 7924. (p) Nguyen, K. A;
Gordon, M. S.; Boatz, J. A. J. Am. Chem. Soc. 1994, 116, 9241. Review:
(q) Hoz, S. In The Chemistry of the Cyclopropyl Group; Rappoport, Z.,
Ed.; Wiley: Chichester, 1987; Part 2, Chapter 19.
Our initial studies began with the rhodium-catalyzed de-
composition of R-cinnamyldiazoacetate 1. 1,2-Hydride mi-
gration could be a competing process in this transformation,6
(2) (a) Ueda, M.; Walczak, M. A. A.; Wipf, P. Tetrahedron Lett.
2008, 49, 5986. (b) Walczak, M. A. A.; Wipf, P. J. Am. Chem. Soc. 2008,
130, 6924. (c) Wipf, P.; Walczak, M. A. A. Angew. Chem., Int. Ed. 2006,
45, 4172. (d) Wipf, P.; Stephenson, C. R. J.; Okumura, K. J. Am. Chem.
Soc. 2003, 125, 14694. (e) Gaoni, Y. Tetrahedron 1989, 45, 2819.
(3) (a) Wiberg, K. B.; Lampman, G. M. Tetrahedron Lett. 1963, 30,
2173. (b) Wiberg, K. B.; Lampman, G. M.; Ciula, R. P.; Connor, D. S.;
Schertler, P.; Lavanish, J. Tetrahedron 1965, 21, 2749. (c) Sieja, J. B.
J. Am. Chem. Soc. 1971, 93, 130. (d) Rifi, M. R. J. Am. Chem. Soc. 1967,
89, 4442. (e) Kelly, C. B.; Colthart, A. M.; Constant, B. D.; Corning,
S. R.; Dubois, L. N. E.; Genovese, J. T.; Radziewicz, J. L.; Sletten, E. M.;
Whitaker, K. R.; Tilley, L. J. Org. Lett. 2011, 13, 1646.
(4) (a) Baird, M. S.; Hussain, H. H. Tetrahedron 1987, 43, 215.
(b) Mahler, W. J. Am. Chem. Soc. 1962, 84, 4600. (c) Corey, E. J.;
Jautelat, M. J. Am. Chem. Soc. 1967, 89, 3912. (d) Masamune, S. J. Am.
Chem. Soc. 1964, 86, 735. (e) Small, A. J. Am. Chem. Soc. 1964, 86, 2091.
(f) Jautelat, M.; Schwarz, V. Tetrahedron Lett. 1966, 7, 5101.
(5) (a) Shi, W.; Xiao, F.; Wang, J. J. Org. Chem. 2005, 70, 4318.
(b) Ikota, N.; Takamura, N.; Young, S. D.; Ganem, B. Tetrahedron Lett.
1981, 22, 4163.
(6) Taber, D. F.; Herr, R. J.; Pack, S. K.; Geremia, J. M. J. Org.
Chem. 1996, 61, 2908.
r
10.1021/ol303217s
XXXX American Chemical Society

but recent studies by Fox suggested that it would be pos-
sible to circumvent this problem with the use of very bulky
dirhodium catalysts.7 Consequently, we began our inveti-
gation with Rh2(TPA)4, an electron-rich and sterically
crowded catalyst (Scheme 1). Although Rh2(TPA)4 cata-
lyzed the decomposition of 1, the catalyst failed to provide
the desired bicyclo[1.1.0]butane product. Instead, a mix-
ture of diene 2 and cyclohexene 48 was obtained. Cyclo-
hexene 4, isolated in 69% yield, was presumably formed by
dimerization of the diene 3, which was produced in situ.
Table 1. Catalyst Loading Evaluation
cat. loading
yield ratio
(2/4/5)a
yield
(%)b
entry
catalyst
(mol %)
1
2
3
4
5
6
Rh2(OPiv)4
Rh2(OPiv)4
Rh2(OOct)4
Rh2(OOct)4
Rh2(TPA)4
Rh2(TPA)4
1.0
10/10/80
4/trace/96
16/18/66
2/trace/98
25/64/11
8/33/59
62
80
60
85
10
47
0.01
1.0
Scheme 1. Rh2(TPA)4-Catalyzed Decomposition of 1
0.01
1.0
0.01
a Ratio was calculated from the NMR of the reaction mixture prior
to chromatographic purification and takes into account that 2.0 equiv of
1 are required for the formation of 4. b Isolated yield of 5 (>20:1 dr).
Further exploratory studies revealed that the product
outcome was dependent on the reaction solvent, time, and
catalyst (Scheme 2). When the reaction with Rh2(TPA)4
was conducted in hexane at room temperature in 12 h,
cyclohexene 4 could be isolated in 80% yield; however,
when Rh2(OAc)4 was used as catalyst in dichloromethane,
the desired 2-phenyl bicyclo[1.1.0]butane carboxylate 5
was obtained in 87% yield.
Having developed a practical entry into the bicyclo-
[1.1.0]butane system, we subsequently focused on achiev-
ing an asymmetric version of this process with a chiral
dirhodium catalyst (Figure 1) at a very low catalystloading
(0.01 mol %). The standard chiral dirhodium tetracarbox-
ylatecatalysts,9 Rh2(R-DOSP)4, Rh2(S-PTAD)4, and Rh2-
(S-PTTL)4, resulted in the effective formation of 5, but the
level of enantioinduction was relatively low in each case
(Table 2, entries 1À3). The dirhodium tetracarboxamidate
catalyst, Rh2(4S-MEOX)4,10 a less reactive catalyt, also
resulted in the formation of 5 with a higher catalyst loading
(0.5 mol %), but bicyclo[1.1.0]butane carboxylate 5 was
still produced with low levels of enantioselectivity (Table 2,
entry 4). The breakthough catalyst for high asymmetric
induction was the triarylcyclopropane carboxylate com-
plexRh2(R-BTPCP)4,11 which provided 5in72%yield and
90% ee in dichloromethane (Table 2, entry 5). Furthermore,
when ethyl acetate was used as solvent, the asymmetric
induction of this transformation can be improved to 94% ee
(Table 2, entry 8).
Scheme 2. Divergent Synthesis of 4 and 5
As Rh2(OAc)4 is only partially soluble in dichloro-
methane, we reasoned that only a trace amount of catalyst
may be required to decompose the diazo compound 1 and
generate the bicyclobutane 5, but 5 may be undergoing a
slower rhodium-catalyzed rearrangement to 3 and subse-
quent dimerization into product 4. On the basis of this
hypothesis, we examined a series of catalysts at standard
(1.0 mol %) and low catalyst loadings (0.01 mol %) (Table 1).
As shown in Table 1, the formation of bicyclo[1.1.0]butane
was favored at low catalyst loadings in all cases. Under
conditions with 0.01 mol % of Rh2(OOct)4, 5 was formed
in 85% isolated yield.
Rh2(R-BTPCP)4 proved to be an effective catalyst
for the asymmetric synthesis of a range of 2-arylbicyclo-
[1.1.0]butane carboxylates as summarized in Scheme 3.
Generally, 2-arylbicyclo[1.1.0]butane carboxylates were
(9) (a) Davies, H. M. L.; Beckwith, R. E. J. Chem. Rev. 2003, 103,
2861. (b) Hansen, J. H.; Davies, H. M. L. Coord. Chem. Rev. 2008, 252,
545. (c) Reddy, R. P.; Davies, H. M. L. Org. Lett. 2006, 8, 5013.
(d) Reddy, R. P.; Lee, G. H.; Davies, H. M. L. Org. Lett. 2006, 8, 3437.
(e) Minami, K.; Saito, H.; Tsutsui, H.; Nambu, H.; Anada, M.; Hashimoto,
S. Adv. Synth. Catal. 2005, 347, 1483. (f) Tsutsui, H.; Yamaguchi, Y.;
Kitagaki, S.; Nakamura, S.; Anada, M.; Hashimoto, S. Tetrahedron:
Asymmetry 2003, 14, 817. (g) Saito, H.; Oishi, H.; Kitagaki, S.;
Nakamura, S.; Anada, M.; Hashimoto, S. Org. Lett. 2002, 4, 3887.
(h) DeAngelis, A.; Dmitrenko, O.; Yap, G. P. A.; Fox, J. M. J. Am.
Chem. Soc. 2009, 131, 7270.
(10) (a) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.;
Dyatkin, A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann,
C. J. J. Am. Chem. Soc. 1995, 117, 5763. (b) Doyle, M. P.; Forbes, D. C.
Chem. Rev. 1998, 98, 911.
(11) Qin, C.; Boyarskikh, V.; Hansen, J. H.; Hardcastle, K. I.;
Musaev, D. G.; Davies, H. M. L. J. Am. Chem. Soc. 2011, 133, 19198.
(7) (a) DeAngelis, A.; Panne, P.; Yap, G. P.; Fox, J. M. J. Org. Chem.
2008, 73, 1435. (b) Panne, P.; DeAngelis, A.; Fox, J. M. Org. Lett. 2008,
10, 2987. (c) DeAngelis, A.; Taylor, M. T.; Fox, J. M. J. Am. Chem. Soc.
2009, 131, 1101.
(8) The crystal structures of 4 and 7h have been deposited at the
Cambridge Crystallographic Data Centre, and the deposition numbers
CCDC 910504 and 910501, were allocated, respectively. For X-ray
crystallographic data of 4 and 7h, see the Supporting Information.
The quality of the data for 7h is not sufficient for an unabiguous
assigment of the absolute configuration, but further analysis by deter-
mining the Hooft parameter (using Platon software) confirmed the
tentative assignment.
B
Org. Lett., Vol. XX, No. XX, XXXX

formed in good yield (61%À74%) with high levels of
enantioinduction (>90% ee). However, lower enantios-
electivity was observed when the ester group was tert-butyl
(70% ee) or when the aryl ring was electron rich such as
p-methoxyphenyl (85% ee) or was changed to a benzyl
substituent (51% ee). The absolute configuration of 2-aryl
bicyclo[1.1.0]butane carboxylate 7h was assigned with a
relatively high level of confidencebyX-ray crystallography
(see Supporting Information).8 The configuration of the
other bicylco[1.1.0]butane products are tentatively assigned
by analogy.
Even though bicyclobutanes could be isolated in high
yield, these products could be totally eliminated when 1.0
mol % of Rh2(TPA)4 and extended reaction times were
used. Under these conditions, cyclohexenes 8 were ob-
tained in good yields (81À89%) for a variety of methyl
cinnamyldiazoacetate 6 (Scheme 4). Increasing the size of
the ester from methyl, iso-propyl to tert-butyl caused a
steady drop in the isolated yield of 8 (Scheme 4, 8a: 80%,
8b: 46%, 8c: 20%).
Figure 1. Chiral dirhodium catalysts.
Table 2. Chiral Catalyst Evaluation
Scheme 4. Cyclohexene Formation
yield
(%)a
ee
(%)b
entry
catalyst
solvent
1
2
3
4c
5
6
7
8
Rh2(R-DOSP)4
Rh2(S-PTAD)4
Rh2(S-PTTL)4
Rh2(4S-MEOX)4
Rh2(R-BTPCP)4
Rh2(R-BTPCP)4
Rh2(R-BTPCP)4
Rh2(R-BTPCP)4
DCM
65
64
69
42
72
64
60
70
<5
47
52
À23
90
88
94
94
DCM
DCM
DCM
DCM
hexane
acetone
EtOAc
a Isolated yield. b Analysis by chiral HPLC column, >20:1 dr. c 0.5
mol % catalyst loading.
In order to probe the cause in the change in product
distribution, further control experiments were conducted
as illustrated in Scheme 5. The Rh2(TPA)4-catalyzed reac-
tion of 1 was re-examined under short (40 min) and long
(12 h) reaction times. After 40 min a mixture of the three
products (2, 4, 5) is present, but no 2-phenyl bicyclo-
[1.1.0]butane carboxylate 5 is present in the reaction
mixture after 12 h. Under these conditions, cyclohexene 4
is isolated in 80% yield. Product 5 is stable in solution in
the absence of catalyst for several days. However, when
exposed to Rh2(TPA)4, within 40 min, over half of the
material rearranges to diene 2 and the cycloadduct 4. After
12h, noneof5 remains and 4 isisolatedin72%yield. These
experiments show that Rh2(TPA)4 catalyzes the ring open-
ing of 5. However, as the ratio of 4 formed after 40 min is
higher when starting from the diazo compound 1 than
when starting from 5, it appears that at least some of the
product 4 is formed directly from the carbenoid derived
from 1.
Scheme 3. Bicyclo[1.1.0]butane Carboxylate Formation
Org. Lett., Vol. XX, No. XX, XXXX
C

Scheme 5. Control Experiments for Mechanistic Study
Scheme 6. Proposed Mechanism for the Reactions of 1
A reasonable series of mechanisms for these transforma-
tions isshowninScheme 6. Dienes2and 3 can begenerated
directly from the allyl carbenoid 9 via a 1,2-shift of either a
hydride or a styryl group. Direct cyclopropanation of 9
would generate the bicyclo[1.1.0]butane 5. The bicyclo-
[1.1.0]butane carboxylate is also unstable in the presence of
the dirhodium catalysts, undergoing ring opening to inter-
mediate 10 and then bond breaking to form either 2 by a
ring openingÀhydride shift mechanism or 3 (electron
movement “a”). The rhodium catalyzed ring opening of
5 is slower than the rhodium-catalyzed nitrogen extrusion
to form the carbenoid intermediates. Therefore, when a
very low catalyst loading and relatively short reaction
times are used, the bicyclo[1.1.0]butane 5 can be selectively
isolated.
decomposition of R-allyldiazoesters. Furthermore, an en-
antioselective synthesis of 2-arylbicyclo[1.1.0]butane car-
boxylates was achieved by the use of Rh2(R-BTPCP)4 as a
catalyst under low catalyst loadings.
Acknowledgment. This work was supported by the
National Science Foundation (CHE 1213246). We thank
Dr. John Bacsa, Emory University, for the X-ray crystal-
lographic analysis.
Supporting Information Available. Experimental pro-
cedures, characterization, and spectral data for new com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
In summary, we have developed a divergent and highly dia-
steroselective synthesis of 2-arylbicyclo[1.1.0]butane carbox-
ylate and cyclohexene derivatives via a dirhodium-catalyzed
The authors declare no competing financial interest.
D
Org. Lett., Vol. XX, No. XX, XXXX