Enantioselective synthesis of 1,2,3-trisubstituted cyclopropanes using gem-dizinc reagents

Article abstract of DOI:10.1021/ja906033g

(Chemical Equation Presented) The first asymmetric cyclopropanation of allylic alcohols using gem-dizinc carbenoids, which allows the synthesis of 1,2,3-substituted cyclopropane derivatives in high yields and excellent enantio- and diastereoselectivities,

Full text of DOI:10.1021/ja906033g

Published on Web 10/08/2009
Enantioselective Synthesis of 1,2,3-Trisubstituted Cyclopropanes Using
gem-Dizinc Reagents
Lucie E. Zimmer and Andre´ B. Charette*
De´partement de Chimie, UniVersite´ de Montre´al, P.O. Box 6138, Station Downtown, Montre´al,
Que´bec, Canada H3C 3J7
Received July 20, 2009; E-mail: andre.charette@umontreal.ca
Scheme 1. Stereoselective Synthesis of 1,2,3-Trisubstituted
The 1,2,3-trisubstituted cyclopropane subunit is present in
numerous natural and synthetic products possessing important
biological activities.1 This densely functionalized unit also finds
applications in drug discovery in the form of conformationally rigid
peptide isosters.2 1,2,3-Trisubstituted cyclopropanes are generally
synthesized by an addition/elimination sequence onto R,ꢀ unsatur-
ated systems3 or by the decomposition of diazo or iodonium ylides
promoted by a transition-metal catalyst.4 Although significant
improvements in the stereocontrol of these reactions have been
made recently, accessing interesting levels of enantio- and diaste-
reoselectivity remains the underlying challenge in intermolecular
versions of these transformations.5 The Simmons-Smith cyclo-
propanation has been sporadically used to generate this class of
compounds; however, the reaction typically displays a narrow
scope.6 We previously reported the use of an alkyl-substituted zinc
carbenoid reagent 2 in conjunction with dioxaborolane 1 for the
asymmetric cyclopropanation of allylic alcohols, leading to 1,2,3-
trisubstituted cyclopropane derivatives (Scheme 1).7 This method
enabled the preparation of enantioenriched cyclopropanes in good
yields with excellent diastereo- and enantiocontrol, where the
substituent derived from the zinc carbenoid bears a trans relationship
relative to the directing alcohol.
Cyclopropanes
Table 1. Optimization of the Zincocyclopropanation
We recently disclosed the formation of gem-dizinc carbenoids 3
and their use in the diastereoselective cyclopropanation of allylic
alcohols.8,9 In the course of this reaction, chelation of the proximal
basic group to one of the zinc atoms of the carbenoid results in its
incorporation as a substituent on the cyclopropane ring with a cis
relationship relative to the directing group. The ensuing cyclopro-
pylzinc compounds can be further functionalized into 1,2,3-
trisubstituted cyclopropanes with retention of stereochemistry.10
Herein we report the first enantioselective cyclopropanation method
involving gem-dizinc carbenoids.
The original method for preparing the gem-dizinc carbenoid was
revisited (Table 1), since previous studies on substrates other than
1,4-butenediol derivatives indicated significant amounts of byprod-
uct formation. Furthermore, these seminal conditions led to low
enantioselectivities when applied to the enantioselective cyclopro-
panation of allylic alcohols. A major competing reaction in the
zincocyclopropanation of alkenes bearing a single directing group
was the formation of iodocyclopropanes from the R-iodozinc
carbenoid (Scheme 1, R1 ) I) resulting from the incomplete
formation of the gem-dizinc reagent (Table 1, entry 1). To address
this problem, we decreased the CHI3/Et2Zn stoichiometric ratio in
order to facilitate the formation of the gem-dizinc carbenoid.
This markedly improved the cyclopropylzinc/iodocyclopropane
ratio, albeit at the expense of conversion (entry 1 vs 2). Our
reported modified protocol10 utilizing the more Lewis acidic
(IZn)2CHI·4Et2O in presence of ZnI2 yet again increased this ratio;
however, the reaction suffered from considerably lower conversions.
We then observed that the removal of the additive (ZnI2) dramati-
entry
“Zn” source
“Zn” (equiv)
CHI3 (equiv)
T (°C)
4/5/7 ratioa
1
Et2Zn
Et2Zn
IZnEt·2Et2O
IZnEt ·2Et2O
IZnEt ·2Et2O
IZnEt ·2Et2O
2.1
2.1
2.1
2.1
2.1
4.2
2.1
1.1
1.1
1.1
1.1
2.1
0
0
0
<1/65/35
38/14/48
51/8/42
18/7/75
11/<1/88
<1/<1/>98
2
3b
4
0
5
6
-40
-40
a Ratio determined by 1H NMR analysis. b With the addition of 1
equiv of ZnI2.
cally improved the conversion (entries 3 and 4). Additionally,
performing the reaction at lower temperature and increasing the
stoichiometric amount of the reagent inhibited the undesired reaction
involving the R-iodozinc carbenoid (entries 5 and 6). Iodination
experiments indicated that cyclopropylzinc 6 was produced as a
single diastereomer.
Having achieved the efficient zincocyclopropanation of alkenes
bearing a single directing group, we contemplated the possibility
of developing an enantioselective version of this reaction. Many
stoichiometric and catalytic chiral ligands have been developed for
enantioselective Simmons-Smith cyclopropanations.11 Of those
tested with the gem-dizinc reagent,12 only the dioxaborolane-based
ligand13,14 led to any promising results, although the original
protocol needed to be significantly modified to this effect. The initial
deprotonation of the alcohol with Et2Zn (instead of the gem-dizinc
reagent) was mandatory to prevent in situ formation of the
9
15624 J. AM. CHEM. SOC. 2009, 131, 15624–15626
10.1021/ja906033g CCC: $40.75  2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. In Situ Boron-Zinc Exchange
Table 2. Scope of the Reaction
entry
R1
R2
producta
yield (%)b
drc
ee (%)d
1
2
3
4
H
Ph
p-ClPh
o-ClPh
p-MeOPh
m-MeOPh
Pr
Pr
Pr
12a
12b
12c
12d
12e
12f
12f
12f
12g
12h
12i
59
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
92
94
91
89
89
94
80f
96g
91
93
94
97
97i
94
H
H
H
H
H
H
H
H
H
58e
59e
59e
49
5
6
51
7f
8g
9
85f
62g
79h
71
PhCH2CH2
Cy
10
11
12
13
14
Me (CH3)2CCH(CH2)2
64h
26
Pr
H
H
H
12j
12k
12l
Simmons-Smith reagent IZnCH2I (Scheme 2), which would have
led to a disubstituted cyclopropane (9a) rather than the desired
cyclopropylzinc. The reaction of the zinc alkoxide with the chiral
ligand presumably generates a tetracoordinated boron species that
reacts with the gem-dizinc carbenoid to produce the cyclopropylzinc.
These species were found to undergo a boron-zinc exchange to
generate the corresponding cyclopropyl borinate 11a.15,16 As such,
the stoichiometric enantiopure ligand not only goVerns the enan-
tioselectiVity of the reaction but also serVes as a stoichiometric
boron source for the in situ generation of a Very Versatile Suzuki
coupling partner.17 The ensuing cyclopropyl borinate is therefore
much easier to handle than the corresponding cyclopropylzinc
compound. As is the case with such intramolecular processes, the
boron-zinc exchange proceeded in a stereoselective manner.
TIPSO-CH2
Cl(CH2)4
57
61
a Absolute and relative stereochemistries were assigned according to
X-ray analysis of 12b. b Yield over two steps. Determined by H NMR
analysis. d Determined by SFC on a chiral stationary phase. e Yield after
dihydroxylation of the remaining traces of the starting allylic alcohol.
f Reaction was run on a 5 mmol scale. g Reaction was run on a 5 mmol
scale using 0.7 equiv of Et2Zn for the initial deprotonation and 1.6 equiv
of carbenoid. h The product was contaminated with the corresponding
disubstituted cyclopropane (∼10%). i Determined after removal of the
protecting group.
c
1
Scheme 3. Cyclopropanation of cis-3-Hexen-1-ol
Although the cyclopropyl borinate could in principle be isolated,
we elected to directly engage the crude reaction mixture in a
Suzuki-Miyaura cross-coupling reaction.18 This methodology
enabled the preparation of 1,2,3-trisubstituted cyclopropanes in good
yields over two steps with good to excellent enantioselectivities
(Table 2).
The reaction is efficient with trans-alkenes bearing either an aryl
(entries 1-5) or a primary or secondary alkyl group (entries 6,
9-11), leading to the corresponding 1,2,3-trisubstituted cyclopro-
panes in good yields over two steps with excellent diastereo- and
enantioselectivities. As expected, the reaction is selective for the
double bond bearing a directing group (entry 11). The reaction
conditions tolerate the presence of functional groups such as
aromatic or aliphatic chlorine atoms (entries 2, 3, and 14) as well
as protected alcohols (entry 13).
a
1H NMR yield using 1,3,5-trimethoxybenzene as an internal standard
Scheme 4. Particularity of cis-Cinnamyl Alcohol
The reaction of cis-alkyl-substituted allylic alcohols is more
problematic, and a relatively low yield of the desired coupling
product was observed (entry 12). In order to elucidate the reason
for such an outcome, the reaction mixture was quenched with iodine
prior to the cross-coupling step. Unexpectedly, we observed the
formation of a significant amount of trans-iodocyclopropane 13j,
indicating that the diastereoselectivity of the zincocyclopropanation
step was not high (Scheme 3). From this, we rationalized that since
the boron-zinc exchange occurs exclusively intramolecularly in a
stereospecific manner, as this exchange is not allowed because of
steric constraints in the case of the trans diastereoisomer, the trans-
cyclopropropylzinc is hydrolyzed during the reaction quench. Thus,
the decrease in the overall yield can be attributed in part to the
poorer diastereoselectivity of the zincocyclopropanation step.
Interestingly, cis-cinnamyl alcohol smoothly underwent the
zincocyclopropanation under the reaction conditions; however, the
boron-zinc exchange did not proceed. Quenching the crude reaction
mixture with iodine led to 14m in good yield and stereoselectivity
(Scheme 4). The surprisingly good diastereoselectivity of the
zincocyclopropanation step compared with that in the reaction with
8j can be explained by an interaction between the π system of the
phenyl group and the zinc atom or the iodide bonded to it.19 Since
the boron-zinc exchange reaction is an equilibrium,20 this coor-
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J. AM. CHEM. SOC. VOL. 131, NO. 43, 2009 15625

C O M M U N I C A T I O N S
Table 3. Other Electrophilic Partnersa
Org. Chem. 1984, 49, 2748. (f) Zubia, E.; Spinelle, A.; Giusto, G. B.;
Crispino, A.; Cimino, G. Tetrahedron Lett. 1994, 35, 8855. (g) Donaldson,
W. A. Tetrahedron 2001, 57, 8589, and references cited therein.
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J.-F. J. Am. Chem. Soc. 1991, 113, 8166. (b) Ukaji, Y.; Nishimura, M.;
Fujisawa, T. Chem. Lett. 1992, 21, 61. (c) Denmark, S. E.; Edwards, J.-P.
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T.; Murakami, Y.; Imai, N. Tetrahedron: Asymmetry 2006, 17, 3067. (k)
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(12) See the Supporting Information.
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11943.
(14) For a recent example using the chiral dioxaborolane ligand 1 to form
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Benoit, S.; Chen, C.-K.; Corbett, E. A.; Corbett, R. M.; DelMonte, A. J.;
Gingras, S.; Livingston, R. C.; Pendri, Y.; Sausker, J.; Soumeillant, M.
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entry
R4
yield (%)b
1
p-FPh (15a)
62
75
63
71
2
p-OMePh (15b)
CH2dCH (15c)
PhCHdCH (15d)
3c
4
a Absolute and relative stereochemistry were confirmed by X-ray
analysis of 12b. b Yield from 8f. c A solution of vinyl bromide in THF
was used.
dination presumably favors the thermodynamically more stable
cyclopropylzinc.
Besides phenyliodide, several coupling partners were submitted
to the Suzuki-Miyaura reaction with 11f. Iodoaryls bearing either
electron-withdrawing or -donating groups as well as vinyl bromide
and styryl iodide successfully reacted in the cross-coupling reaction
(Table 3).
In conclusion, we have developed the first asymmetric zinco-
cyclopropanation of allylic alcohols. The inexpensive stoichiometric
chiral ligand incorporated in this methodology exercises the dual
function of governing the enantioselectivity of the reaction and
serving as an electrophilic boron source for the boron-zinc
exchange leading to the Suzuki-Miyaura cross-coupling precursor.
This reaction has enabled the stereoselective synthesis of highly
functionalized 1,2,3-trisubstituted cyclopropanes that would be
difficult to access otherwise. Further studies into the functional-
ization of the borinate synthetic intermediates are underway and
will be reported in due course.
Acknowledgment. This work was supported by NSERC
(Canada), the Canada Foundation for Innovation, the Canada
Research Chair Program, and the Universite´ de Montre´al. The
authors are grateful to Dr. J.-F. Fournier for preliminary work and
L.-P. B. Beaulieu for helpful suggestions.
(16) 11B NMR (CDCl3, 96 MHz, BF3 · Et2O) for 11a: δ 53.0.
(17) For recent examples of the utility of cyclopropyl boronic acids and esters,
see: (a) Rubin, M.; Rubina, M.; Gevorgyan, V. Chem. ReV. 2007, 107,
3117. (b) Hohn, E.; Palecˇek, J.; Pietruszka, J. Synlett 2008, 971. (c)
Pietruszka, J.; Solduga, G. Synlett 2008, 1349. (d) Tsuritani, T.; Strotman,
N. A.; Yamamoto, Y.; Kawasaki, M.; Yasuda, N.; Mase, T. Org. Lett. 2008,
10, 1653. (e) Wong, D.-H.; Wasa, M.; Giri, R.; Yu, J.-Q. J. Am. Chem.
Soc. 2008, 130, 7190. (f) Be´nard, S.; Neuville, L.; Zhu, J. J. Org. Chem.
2008, 73, 6441.
Supporting Information Available: Experimental procedures for
the preparation of the compounds, characterization data, and crystal-
lographic data (CIF). This material is available free of charge via the
Internet at http://pubs.acs.org.
(18) Matos, K.; Soderquist, J. A. J. Org. Chem. 1998, 63, 461.
(19) Kim, H. Y.; Salvi, L.; Carroll, P. J.; Walsh, P. J. J. Am. Chem. Soc. 2009,
131, 954. For interactions between zinc and π systems, see: Bukhaltsev,
E.; Goldberg, I.; Cohen, R.; Vigalok, A. Organometallics 2007, 26, 4015.
Markies, P. R.; Schat, G.; Akkerman, O. S.; Bickelhaupt, F.; Smeets,
W. J. J.; Spek, A. L. Organometallics 1990, 9, 2243. For interactions
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