Catalytic asymmetric synthesis of highly functionalized cyclopentenes by a [3 + 2] cycloaddition [20]

Full text of DOI:10.1021/ja0160546

J. Am. Chem. Soc. 2001, 123, 7461-7462
Table 1. [3 + 2] Cycloadditions According to Eq 1
7461
Catalytic Asymmetric Synthesis of Highly
product
R1
R2
yield, %
ee, %a
Functionalized Cyclopentenes by a [3 + 2]
Cycloaddition
3a
3b
3c
3d
3e
3f
Me
Me
Me
n-Bu
H
Ph
79a,c
71b,d
49b,e
55b,b
61a,c
74b,e
98f
>99f
99f
p-BrPh
E-CHdCHEt
Ph
Huw M. L. Davies,* Bangping Xiang, Norman Kong, and
Douglas G. Stafford
>94g
82f
Ph
Department of Chemistry, UniVersity at Buffalo
The State UniVersity of New York
H
E-CHdCHEt
79f
a CH2Cl2 as reaction solvent. b Hexanes as reaction solvent. c Z/E
ratio of vinyl ether is 19:1. d Z/E ratio of vinyl ether is >19:1. e Z/E
ratio of vinyl ether is 1:1. f ee determined by HPLC using Chiralcel
OJ or OD columns, see Supporting Information for details. g ee
Buffalo, New York 14260-3000
ReceiVed April 20, 2001
ReVised Manuscript ReceiVed June 19, 2001
1
determined by H NMR using a chiral shift reagent.
The stereoselective construction of five-membered carbocycles
by means of [3 + 2] cycloadditions has been actively studied in
recent years.1 In this paper we describe a novel [3 + 2] cyclo-
addition protocol involving the metal-catalyzed decomposition
of vinyldiazocarbonyl derivatives in the presence of vinyl ethers.
The catalyst that is used in these reactions is Rh2(S-DOSP)4, which
has been shown to be exceptionally effective for the asymmetric
transformations of vinyldiazocarbonyl derivatives.2 Cyclopentene-
carboxylates are formed in 70-99% ee with full control of rela-
tive stereochemistry at up to three contiguous stereogenic centers
(eq 1). Furthermore, conjugate addition of nucleophiles to the
cyclopentenecarboxylates generates, stereoselectively, cyclopen-
tanes with up to five stereogenic centers.
diastereomer of the cyclopentene 3 was formed (79% yield), in
which all three substituents were in a cis arrangement. Also, even
though the reaction was carried out at room temperature, 3 was
formed in 98% ee. A further surprising feature of the reaction is
that a highly diastereoselective [3 + 2] cycloaddition is obtained,
even when the vinyl ether 2 is a mixture of double bond isomers,
because only the cis vinyl ether reacts with the carbenoid.
[3 + 2] cycloadditions have been observed previously in
reactions between vinyldiazoacetates and vinyl ethers4 but they
are likely to involve a different mechanism than the reactions
described herein. The previous [3 + 2] cycloadditions occurred
when the vinyl terminus of the vinyldiazoacetate was unsubsti-
tuted.4 These previous reactions were also nonstereospecific,
enhanced by bulky ester substituents on the vinyldiazoacetate,
and totally blocked when nonpolar solvents were used.4 On the
basis of these characteristics the reactions were considered to
involve stepwise ionic processes initiated by reaction of the vinyl
ether at the vinylogous position of the vinylcarbenoid. Further
confirmation that the formation of 3a occurs by a different
mechanism to the previously described [3 + 2] cycloadditions4
was obtained by repeating the reaction of 1 and 2 in hexane. The
solvent change had very little effect on the reaction as 3a was
formed in 86% yield and 95% ee.
Various highly functionalized cyclopentenecarboxylates can be
formed in this reaction as shown in Table 1. Very high
enantioselectivities (>94% ee) are obtained when the vinyldi-
azoacetates are substituted with an alkyl substituent at the vinyl
terminus position and the vinyl ethers are substituted with either
an aryl or a vinyl group. In all cases, the all cis products are
exclusively formed. An unsubstituted vinyldiazoacetate results in
the formation of the [3 + 2] cycloadduct 3e with lower
enantioselectivity (82% ee). An interesting example is shown in
eq 3, where a selective [3 + 2] cycloaddition by 5 occurs on the
The reaction of vinyldiazocarbonyl derivatives with vinyl ethers
is very sensitive to the structure of both reactants. Cyclopro-
panation of unsubstituted vinyl ethers with vinyldiazoacetates
substituted at the vinyl terminus is well established.3 In contrast,
Rh2(S-DOSP)4 catalyzed decomposition of the vinyldiazoacetate
1 at room temperature in CH2Cl2 in the presence of the vinyl
ether 2 (5 equiv) results in a remarkable reaction (eq 2). A single
vinyl ether component of 4 to form the cyclopentene 6 in 58%
yield. The absolute configuration of 3b was determined to be
(3R,4S,5R) by X-ray crystallography, while the absolute config-
uration of the other [3 + 2] cycloadducts is tentatively assigned,
assuming a similar mode of asymmetric induction.
(1) For recent examples, see: (a) Urabe, H.; Suzuki, K.; Saito, F. J. Am.
Chem. Soc. 1997, 119, 10014. (b) Chowdhury, S. K.; Amarasinghe, K. K.
D.; Heeg, M. J.; Montgomery, J. J. Am. Chem. Soc. 2000, 122, 6775. (c)
Hoffmann, M.; Buchert, M.; Reissig, H.-U. Angew. Chem., Int. Ed. Engl. 1997,
36, 283. (d) Barluenga, J.; Tomas, M.; Ballesteros, A.; Santamaria, J.; Brillet,
C.; Garcia-Granda, S.; Pinera-Nicolas, A.; Vazquez, J. T. J. Am. Chem. Soc.
1999, 121, 4516.
An especially attractive feature of this [3 + 2] cycloaddition
is that the resulting products are well-functionalized for further
(2) (a) Davies, H. M. L. Eur. J. Org. Chem. 1999, 2459. (b) Davies, H. M.
L. Aldrichim. Acta 1997, 30, 105.
(3) (a) Davies, H. M. L.; Kong, N.; Churchill. M. R. J. Org. Chem. 1998,
63, 6586. (b) Davies, H. M. L.; Hu, B. B. J. Org. Chem. 1992, 57, 3186.
(4) Davies, H. M. L.; Hu, B. B.; Saikali, E.; Bruzinski, P. R. J. Org. Chem.
1994, 59, 4535.
10.1021/ja0160546 CCC: $20.00 © 2001 American Chemical Society
Published on Web 07/07/2001

7462 J. Am. Chem. Soc., Vol. 123, No. 30, 2001
Communications to the Editor
elaboration. For example, reaction of 3a with L-selectride gener-
ated the cyclopentanecarboxylate 7 as a single diastereomer whose
configuration was assigned by nOe difference experiments (eq
4). Furthermore, addition of a higher order cuprate at -78 °C to
3a generates the cyclopentane 8 with full control of stereochem-
istry at five stereocenters (eq 5).
Figure 1. Model for the [3 + 2] cycloaddition.
the mechanistic details of this reaction are not well understood,
a plausible explanation for the relative stereochemistry of this
reaction is shown in Figure 1. The observed absolute stereo-
chemistry would require attack from the front face of the
carbenoid. The reaction may be considered a concerted process
in which the vinylcarbenoid substituent and the vinyl ether
functionality must point away from the catalyst “wall”. This would
explain why trans vinyl ethers are incapable of undergoing the
[3 + 2] cycloaddition. An alternative mechanism, whereby the
rhodium carbenoid undergoes a [4 + 2] cycloaddition to form a
metalacyclohexene followed by a reductive elimination, is also a
possibility.
The high asymmetric induction generated by the Rh2(S-DOSP)4
catalyst has been rationalized by assuming that the catalyst adopts
a D2-symmetric conformation and the arylsulfonyl groups act as
blocking groups. In this model, there is a blocking group behind
the carbenoid ester and in front of the carbenoid vinyl group, as
represented by the thickened and dotted vertical lines, respectively.
This model needs to be modified to rationalize the absolute
stereochemistry observed here because the blocking group in front
of the carbenoid vinyl group would preclude an effective approach
for a concerted reaction between the vinyl ether and the
vinylcarbenoid. For this model to remain viable for this chemistry,
it would be necessary for the blocking group in front of the
carbenoid vinyl group to be flexible and move away as the
reaction occurs. Some evidence to support this concept was seen
in carrying out the reaction of 1 with 2 using the bridged prolinate
catalyst Rh2(S-biTISP)2,5 which has a rigid structure. With this
catalyst only a trace of the [3 + 2] cycloaddition product 3a was
obtained in low ee (38%).
By using slightly more vigorous conditions to carry out the
cuprate additions, a conjugate addition followed by elimination
of methoxide occurs to form new unsaturated carboxylates 9 and
10. This is seen in the reaction of either 3a or 3e with either
butyl or phenyl higher order cuprates (eqs 6 and 7). In all cases,
the cuprate approaches from the opposite side to the all cis
substituents leading to single diastereomers of the products.
The highly stereoselective [3 + 2] cycloaddition reported herein
further demonstrates the breadth of diverse reactivity of carbenoids
derived from vinyldiazoacetates. Not only does the vinyl group
stabilize the carbenoid, leading to highly chemoselective reactions,
but it can also enter into new unprecedented carbenoid transfor-
mations. By combining the asymmetric [3 + 2] cycloadditions
with cuprate conjugate additions, a very general method for the
synthesis of cyclopetanecarboxylates with up to five stereogenic
centers can be readily achieved.
Finally, as the addition/elimination sequence generates a new
unsaturated carboxylate, a second cuprate addition can be carried
out. This is illustrated in the reaction of 9a with 2 equiv of the
higher order cuprate that leads to the stereoselective formation
of the pentasubstituted cyclopentane 11 (eq 8), again with full
control of relative stereochemistry.
Acknowledgment. This work was supported by the National Science
Foundation (CHE-0092490).
Supporting Information Available: Complete experimental data for
the [3 + 2] cycloadditions and X-ray crystallographic data for the
carboxylic acid derivative of 3b (PDF). This material is available free of
charge via the Internet at http://pubs.acs.org.
JA0160546
One of the most remarkable features of the [3 + 2] cycload-
dition is that the all cis products are formed in each case. Although
(5) Davies, H. M. L.; Panaro, S. A. Tetrahedron Lett. 1999, 40, 5287.