Enantio-and diastereoselective iodocyclopropanation of allylic alcohols by using a substituted zinc carbenoid

Article abstract of DOI:10.1002/chem.200902228

The first enantioselective Simmons Smith iodocyclopropanation reaction, in which iodoform is used as the precursor to the substituted zinc carbenoid, was reported. The nature of the carbenoid was examined by quenching the preformed zinc carbenoid with D

Full text of DOI:10.1002/chem.200902228

COMMUNICATION
DOI: 10.1002/chem.200902228
Enantio- and Diastereoselective Iodocyclopropanation of Allylic Alcohols by
Using a Substituted Zinc Carbenoid
Louis-Philippe B. Beaulieu, Lucie E. Zimmer, and Andrꢀ B. Charette*[a]
In addition to being present in several bioactive natural
products,[1] 1,2,3-trisubstituted cyclopropanes embed signifi-
cant structural complexity that has prompted their use as
peptidomimetics,[2] and as substrates for various organic and
organometallic reactions.[3] 2,3-Disubstituted iodocyclopro-
panes have been shown to be versatile precursors to access
a multitude of highly functionalized cyclopropane units.[4]
However, few methods for their asymmetric synthesis have
been reported. Among them, Doyle and co-workers have
performed the rhodium-catalyzed enantioselective intramo-
lecular cyclopropanation of (Z)-3-iodo-2-propenyl diazoace-
tate.[5] The enantioselective, facially selective carbomagne-
siation of cyclopropenes by using N-methylprolinol as a
chiral ligand developed by Fox and Liu is an attractive route
to 2,3-disubstituted iodocyclopropanes, albeit being restrict-
ed to the use of methyl Grignard reagents.[6] Walsh and co-
workers have recently described a tandem enantioselective
diorganozinc addition–diastereoselective Simmons–Smith io-
docyclopropanation methodology towards the synthesis of
2,3-disubstituted iodocyclopropanes, whereby in most instan-
ces the iodine shows a syn relationship to the alkoxy group
in the major diastereomer.[7]
diiodoethane and from the required synthesis of these com-
pounds. A more convergent approach would rely on the syn-
thesis of 2,3-disubstituted iodocyclopropanes, which could
then be further derivatized. Herein we report the first enan-
tioselective Simmons–Smith iodocyclopropanation reaction,
in which iodoform is used as the precursor to the substituted
zinc carbenoid.
Since the pioneering efforts of Hashimoto and Miyano
and the recent contributions by Walsh and co-workers, there
has been very limited progress in the field of cyclopropana-
tion using a-iodozinc carbenoids.[7,9] A challenging aspect of
this reaction resides in its poor diastereoselectivity, which
stems from the two possible reactive conformers of the zinc
carbenoid (Scheme 1).
We envisioned that a versatile enantioselective iodocyclo-
propanation reaction would be a valuable addition to the
existing methodologies for the asymmetric synthesis of 2,3-
disubstituted iodocyclopropanes. We previously reported the
modified Simmons–Smith enantioselective cyclopropanation
of allylic alcohols using alkyl-substituted zinc carbenoids
and a stoichiometric dioxaborolane chiral ligand as a route
towards 1,2,3-trisubstituted cyclopropanes.[8] Despite its high
degree of stereoselectivity, this methodology suffered from
limited compatibility with other gem-diiodoalkanes than 1,1-
Scheme 1. Diastereoselectivity outcome dictated by the two reactive con-
formers of the zinc carbenoid.[9]
An additional complication lies in the development of
conditions favoring the formation of the a-iodozinc carbe-
noid over the more reactive gem-dizinc carbenoid
(Scheme 2).[10]
Bearing in mind that increasing the stoichiometric ratio of
R2Zn relative to CHI3 results in an increased proportion of
the gem-dizinc carbenoid relative to the a-iodozinc carbe-
noid,[11] we first examined the nature of the carbenoid by
quenching the preformed zinc carbenoid with D2O.[12] When
a 2:1 stoichiometric ratio of CHI3 relative to Et2Zn was
used, a ratio of CHI3 relative to CHDI2 of 1 was observed,
thus demonstrating that diethylzinc undergoes a single alkyl
[a] L.-P. B. Beaulieu, L. E. Zimmer, Prof. A. B. Charette
Dꢀpartement de Chimie
Universitꢀ de Montrꢀal
P.O. Box 6128, Station Downtown, Montrꢀal H3C 3J7 (Canada)
Fax : (+1) 714-343-5900
E-mail: andre.charette@umontreal.ca
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200902228.
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Table 2. Scope of the reaction.
Entry Product
Proc.[a] Yield [%][b] d.r.[c]
ee [%][d]
1
3a
A
B
A
A
B
A
A
B
B
B
B
B
B
66
73
81
70
64[e]
69
55
53
66
63
59
67
42
9:1
18:1
12:1
7:1
7:1
9:1
7:1
5:1
5:1
5:1
6:1
4:1
4:1
98
Scheme 2. Substituted zinc carbenoids formed by using iodoform as a
precursor.
2
3b
3c
3d
3e
3 f
3g
3h
3i
98
98
96
97
98
98
98
96
96[f]
95
95
99
exchange with iodoform to generate EtZnCHI2 (Hashimo-
toꢂs reagent).[9] While virtually only CHDI2 was observed
using a 2:1 stoichiometric ratio of CHI3 relative to Et2Zn,
up to 28% of the pool of deuterated iodomethane com-
prised CHD2I when a 1:1 stoichiometric ratio of these re-
agents was employed.
We then attempted the iodocyclopropanation reaction of
cinnamyl alcohol in the presence of the dioxaborolane 1
under various reaction conditions (Table 1). While a 1:1 stoi-
3
4
5
6
Table 1. Optimization of the iodocyclopropanation with RZnCHI2.[a]
7
8
9
Entry
CHI3
(x equiv)
Additive[b]
Conv.
[%][c]
Yield
[%][d]
d.r.[e]
ACHTUNGTRENNUNG
10
11
12
13
3j
1
2
2.2
4.4
4.4
2.2
2.2
–
–
–
I2
86
62
76
16
–
6:1
9:1
5:1
–
ꢀ98
ꢀ98
ꢁ5
ꢁ5
3[f]
4
3k
3l
5
CF3CH2OH
–
–
[a] Unless otherwise noted, the zinc carbenoid was formed by adding
neat Et2Zn to a suspension of CHI3 in CH2Cl2 at room temperature.
[b] A solution of CHI3 in CH2Cl2 was added to a preformed mixture of
Et2Zn and the additive (2.2 equiv) in CH2Cl2. [c] Determined by
1H NMR spectroscopy based on unreacted starting material. [d] 1H NMR
yield of the anti diastereomer using 1,3,5-trimethoxybenzene as an inter-
nal standard. [e] Determined by 1H NMR spectroscopy from the crude
reaction. [f] The reaction was performed in the absence of 1.
3m
14
15
3n
3o
B
65
68
16:1
91
chiometric ratio of CHI3 relative to Et2Zn did not ensure
complete conversion (Table 1, entry 1),[13] we were pleased
to observe complete conversion using a 2:1 stoichiometric
ratio of these reagents (Table 1, entry 2). High levels of dia-
stereoselectivity favoring the anti diastereomer were ob-
tained. Interestingly, a much lower yield and lower diaste-
reoselectivity were observed if the reaction was performed
in the absence of 1 (Table 1, entry 3). Furthermore, other
more electrophilic carbenoids such as IZnCHI2 (Table 1,
entry 4) and CF3CH2OZnCHI2 (Table 1, entry 5) were not
compatible with this methodology.
A
ꢀ20:1 93
[a] Procedure A: 0.1m relative to the allylic alcohol in CH2Cl2, room tem-
perature, 15 h. Procedure B: 0.2m in CH2Cl2, room temperature, 24 h.
[b] Isolated yield of the anti diastereomer. [c] Determined by 1H NMR
spectroscopy from the crude reaction. [d] Determined either by GC or
SFC on chiral stationary phase. [e] Yield after dihydroxylation of the re-
maining traces of the starting allylic alcohol. [f] Determined after remov-
al of the protecting group.
be highly enantioselective and displayed moderate to excel-
lent diasterometric ratio (d.r.), with modest to good isolated
yields of the anti diastereomer obtained over a range of sub-
strates.[14] Both electron- rich and poor (E)-3-aryl-2-propen-
The optimal reaction conditions (Table 1, entry 2) were
selected to elaborate the scope of this reaction (Table 2).
Gratifyingly, the iodocyclopropanation reaction proved to
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Enantio- and Diastereoselective Iodocyclopropanation of Allylic Alcohols
COMMUNICATION
1-ols (Table 2, entries 1–7), some of which contained greater
steric bulk (Table 2, entries 2 and 3), were well tolerated.
(E)-3-Alkyl-2-propen-1-ols (either primary or secondary,
Table 2, entries 9–12) underwent the iodocyclopropanation
reaction smoothly, although more forcing conditions were
needed to ensure complete conversion. Trisubstituted allylic
alcohols (Table 2, entries 14 and 15) gave excellent d.r. and
very good ee. In addition to being chemoselective towards
allylic alcohols (Table 2, entry 8), the reaction was compati-
ble with functionalities such as a nitro group (Table 2,
entry 5), aromatic or aliphatic chlorine atoms (Table 2, en-
tries 3, 6, 11) and a protected alcohol (Table 2, entry 10).
(Z)-2-Hexen-1-ol illustrated the profound impact of 1 on
the diastereoselectivity of the reaction, as none of the de-
sired anti diastereomer was obtained in its absence (Table 2,
entry 13). Although the diastereoselectivity of the reaction
was modest in some cases, it is worth noting that both dia-
stereomers were easily separated by flash chromatogra-
phy.[15]
clopropanation.[16] Of the two possible conformers that
could meet such a prerequisite, the conformer bearing an
iodine atom anti to the sterically encumbered dioxaboro-
lane–alkoxide complex would lead to the major diastereo-
mer.
To illustrate the versatility with which 2,3-disubstituted io-
docyclopropanes may be converted into several highly func-
tionalized 1,2,3-trisubstituted cyclopropanes, the iodocyclo-
propanes were submitted to a lithium–halogen exchange re-
action followed by treatment with an electrophile
(Scheme 3).[4] Additionally, the cyclopropyllithium was
The proposed transition state for the enantioselective io-
docyclopropanation of cinnamyl alcohol in the presence of
dioxaborolane 1 is illustrated in Figure 1. The zinc alkoxide
Scheme 3. Functionalization of the iodocyclopropanes.
transmetallated to zinc and employed in a Negishi Cou-
pling.[17] In all cases, the desired compounds were isolated as
single diastereomers with the overall retention of configura-
tion relative to the starting iodocyclopropane starting mate-
rial.
In conclusion, we have developed the first enantioselec-
tive Simmons–Smith iodocyclopropanation reaction. The use
of the 1,2,3-disubstituted iodocyclopropanes as versatile
enantioenriched building blocks has been demonstrated.
Figure 1. Chem 3D representation of the proposed transition state for the
enantioselective iodocyclopropanation reaction of allylic alcohols.
Acknowledgements
This work was supported by NSERC (Canada) , the Canada Research
Chair Program, the Canadian Foundation for Innovation and the Univer-
sitꢀ de Montrꢀal. L.-P.B.B. is grateful to NSERC and the Universitꢀ de
Montrꢀal for postgraduate scholarships. The authors are also grateful to
Dr. A. Gagnon for preliminary work and to Dr. J. A. Bull for useful dis-
cussions.
formed upon treatment of cinnamyl alcohol with diethylzinc
presumably reacts with the dioxaborolane to produce an ate
complex. It is postulated that the bulkier butyl substituent
on the dioxaborolane adopts the less sterically congested
pseudoequatorial position and the allylic alkoxide the more
favorable pseudoaxial position. The resulting ate complex is
believed to act as a bidentate ligand for the zinc carbenoid
involving the allylic alkoxide and the carbonyl amide moiet-
ies. The most suitable conformation for “CHI” delivery is
that in which the allylic chain is in its most stable conforma-
tion. It is generally accepted that the s*CÀI must be synperi-
planar to the pCÀC in the course of the Simmons–Smith cy-
Keywords: asymmetric synthesis · carbenoids · iodine ·
iodocyclopropanation · zinc
Chem. Eur. J. 2009, 15, 11829 – 11832
ꢁ 2009 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
11831

A. B. Charette et al.
[12] The full experimental details are disclosed in the Supporting Infor-
mation.
[13] Incomplete conversion could originate from the consumption of di-
ethylzinc during its reaction with the a-iodozinc carbenoid to form
the gem-dizinc carbenoid.
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[14] The absolute configuration of 3e was determined by X-ray crystal-
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the supplementary crystallographic data for this paper. These data
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Received: August 10, 2009
Published online: October 5, 2009
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Chem. Eur. J. 2009, 15, 11829 – 11832