Cyclopropanation of protected chiral, acyclic allylic alcohols: Expedient access to the anti-cyclopropylcarbinol derivatives

Article abstract of DOI:10.1021/ol0264051

(matrix presented) The diastereoselective cyclopropanation of silyl-protected chiral allylic alcohols using Shi's carbenoid (TFA-Et₂Zn-CH₂I₂) gave access to the anti-cyclopropylcarbinyl silyl ethers with excellent diastereocontrol. The level of stereocontrol was shown to depend on the sizes of the protective group and the allylic substituent.

Full text of DOI:10.1021/ol0264051

ORGANIC
LETTERS
2002
Vol. 4, No. 20
3351-3353
Cyclopropanation of Protected Chiral,
Acyclic Allylic Alcohols: Expedient
Access to the anti-Cyclopropylcarbinol
Derivatives
Andre´ B. Charette* and Marie-Christine Lacasse
De´partement de Chimie, UniVersite´ de Montre´al, P.O. 6128 Station Downtown,
Montre´al, Que´bec, Canada H3C 3J7
andre.charette@umontreal.ca
Received June 21, 2002
ABSTRACT
The diastereoselective cyclopropanation of silyl-protected chiral allylic alcohols using Shi’s carbenoid (TFA−Et2Zn−CH I ) gave access to the
2 2
anti-cyclopropylcarbinyl silyl ethers with excellent diastereocontrol. The level of stereocontrol was shown to depend on the sizes of the
protective group and the allylic substituent.
The directed cyclopropanation of chiral, acyclic allylic
alcohols is a well-documented process,1 and many reagents
and reaction conditions are known to lead to cyclopropyl-
carbinols. The presence of a proximal basic group plays a
predominant role in assisting the delivery of the carbenoid.
For example, acyclic chiral allylic alcohols can be converted
effectively to the syn isomer under the appropriate reaction
conditions.2,3 However, few methods are known for the
synthesis of the related acyclic anti-cyclopropylcarbinol
derivatives.4 During our investigation of the relative directing
abilities of oxygenated groups in the cyclopropanation of
chiral allylic compounds, we observed that the reaction of
O-benzyl-protected (E)-allylic secondary alcohols with Fu-
rukawa’s reagent5 gave access to the anti-cyclopropylcarbinyl
ethers with modest levels of diastereoselection (Scheme 1).4c
Scheme 1
(1) For a comprehensive review of substrate-directable reactions, see:
Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. ReV. 1993, 93, 1307.
(2) (a) Ratier, M.; Castaing, M.; Godet, J.-Y.; Pereyre, M. J. Chem. Res.,
Miniprint 1978, 2309. (b) Scho¨llkopf, U.; Tiller, T.; Bardenhagen, J.
Tetrahedron 1988, 44, 5293. (c) Molander, G. A.; Etter, J. B. J. Org. Chem.
1987, 52, 3942. (d) Molander, G A.; Harring, L. S. J. Org. Chem. 1989,
54, 3525. (e) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1992, 57,
798. (f) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1995, 60, 2474.
(g) Charette, A. B.; Lebel, H. J. Org. Chem. 1995, 60, 2966. (h) Charette,
A. B.; Molinaro, C.; Brochu, C. J. Am. Chem. Soc. 2001, 123, 12160.
(3) For a recent review on Simmons-Smith cyclopropanation, see:
Charette, A. B.; Beauchemin, A. Org. React. 2001, 58, 1.
The anti selectivities were greatly improved if one of the
two antipodes of a chiral dioxaborolane ligand was added.
Herein, we report that the cyclopropanation of acyclic allylic
silyl ethers with the appropriate zinc carbenoid reagent results
in a new simple and direct way to access anti-cyclopropyl-
(4) (a) Delanghe, P. H. M.; Lautens, M. Tetrahedron Lett. 1994, 35,
9513. (b) Lautens, M.; Delanghe, P. H. M. J. Org. Chem. 1995, 60, 2474.
(c) Charette, A. B.; Lebel, H.; Gagnon, A. Tetrahedron 1999, 55, 8845.
10.1021/ol0264051 CCC: $22.00 © 2002 American Chemical Society
Published on Web 08/31/2002

carbinol derivatives. We also show that the level of diaste-
reocontrol is highly dependent on the nature of the protective
groups.
Table 1. Effect of the Nature of the Reagent
We envisioned that the introduction of a bulky protective
group may actually prevent preassociation of the zinc reagent
with the substrate and thus lead to the formation of the anti
diastereomer through a transition structure that minimizes
steric interactions between the reagent and the substituents
(Figure 1, A is favored over B). The ground-state conforma-
entry
reagent
IZnCH2Id
conversion (%)b
anti:sync
1
2
3
4
5
6
7
8
8
48
44
92
88
60
52
>99
84:16
92:8
90:10
94:6
97:3
89:11
93:7
EtZnCH2I
Zn(CH2I)2
e
EtZnCH2Cl
e
Zn(CH2Cl)2
2,4,6,-Cl3C6H2OZnCH2I
2,4,6,-F3C6H2OZnCH2I
CF3CO2ZnCH2I
>99:1
a Reaction conditions: substrate is added to 2.0 equiv of preformed
reagent, CH2Cl2, 0 °C to room temperature. b Determined by 1H NMR using
an internal standard. c Determined by GC analysis of the corresponding
acetate derivatives. d Formed by treating 2.0 equiv of I2 with 2.0 equiv of
Et2Zn and 2.0 equiv of CH2I2. e 1.0 equiv of reagent was used.
useful conversions and diastereoselectivities were observed
with the Denmark’s procedure (entries 4-5).8 The aryloxide-
derived carbenoids9 gave lower conversions, probably due
to the bulkiness of the reagent making the approach to the
alkene more difficult (entries 6-7). A highly activated
reagent prepared from trifluoroacetic acid10 (Shi’s reagent)
gave the best conversion and diastereoselectivity, making it
the optimal carbenoid for the following studies.
Figure 1. Postulated transition structures for directed vs non-
directed cyclopropanation reactions.
tion in which the silyloxy group is synclinal to the alkene
has been proposed by Gung to be the most stable for small
R4 substituents.6 Nonassisted attack of the carbenoid on this
favored conformer (which should also be the most reactive
on the basis of stereoelectronic arguments) should lead to
the anti isomer. This approach contrasts with the cyclopro-
panation of unprotected allylic alcohols in which minimiza-
tion of the A-1,3 strain is the main controlling element for
good diastereocontrol (Figure 1, D is favored over C). One
potential problem with this approach is the lack of reactivity
of the classical zinc carbenoid reagents, which sometimes
are not sufficiently reactive to cyclopropanate alkenes that
do not contain basic proximal groups. However, several
improved versions of the reagent have recently been reported
and should prove to be sufficiently reactive to provide the
cyclopropane product in good yields with this class of
substrates.
The reaction was initially performed by reacting the chiral
racemic triisopropylsilyl ether derived from (E)-4-phenylbut-
3-en-2-ol to different zinc carbenoids (Table 1). As expected,
the classical Simmons-Smith reagent7 gave only poor
conversion, though the selectivity was in favor of the desired
anti diastereomer (entry 1). The selectivities increased with
Furukawa-type carbenoids (entries 2-5), and synthetically
The next step was to study the effect of the protective
group on the selectivity of the reaction (Table 2). We
compared the level of diastereoselection as a function of the
size of the silyl ether protective group. Gratifyingly, all but
two substrates gave the anti diastereomer as a major product
with an excellent ratio (anti:syn ratio superior to 94:6) when
treated with Shi’s reagent. It is also apparent that the
diastereoselectivities usually increased by increasing the
steric bulk of the silyl ether, the triisopropylsilyl being the
optimal protective group for maximizing the anti:syn ratio.11
As expected, the nature of the allylic substituent (R4) also
influences the ratio considerably (entries 6-9). While the
small methyl and ethyl allylic substituents allowed excellent
diastereoselectivities, the level was lower in the case of
isopropyl (entries 2 and 7 vs 8). Conversely, the presence
of a methyl substituent at the R3 position did not seem to
affect the level of diastereoselection, yielding the corre-
sponding trisubstituted cyclopropylcarbinyl silyl ethers in
good yields and excellent diastereomeric ratios (entries 10-
11).
It is well established that (Z)-allylic secondary alcohols
give high levels of syn selectivity when treated under the
(8) Denmark, S. E.; Edwards, J. P. J. Org. Chem. 1991, 56, 6974.
(9) Charette, A. B.; Francoeur, S.; Martel, J.; Wilb, N. Angew. Chem.,
Int. Ed. 2000, 39, 4539.
(10) (a) Yang. Z.; Lorenz, J. C.; Shi, Y. Tetrahedron Lett. 1998, 39,
8621. (b) Charette, A. B.; Beauchemin, A.; Francoeur, S. J. Am. Chem.
Soc. 2001, 123, 8139.
(11) Reaction of a bulkier allylic tert-butyldiphenylsilyl ether led mostly
to decomposition of the starting material, which in this case probably occurs
faster than the cyclopropanation under these Lewis-acidic conditions.
(5) (a) Furukawa, J.; Kawabata, N.; Nishimura, J. Tetrahedron Lett. 1966,
3353; (b) Tetrahedron 1968, 24, 53.
(6) (a) Gung, B. W.; Melnick, J. P.; Wolf, M. A.; King, A. J. Org. Chem.
1995, 60, 1947. (b) Khan, S. D.; Pau, C. F.; Chamberlin, A. R.; Hehre, W.
J. J. Am. Chem. Soc. 1987, 109, 650.
(7) Simmons, H. E.; Cairns, T. L.; Vladuchick, S. A.; Hoiness, H. M.
Org, React. 1973, 20, 1.
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Org. Lett., Vol. 4, No. 20, 2002

In general, the reaction times were short, especially when
the cyclopropanations were performed at 0 °C. We observed
in some cases that the reactions were cleaner when performed
at -20 °C (entries 5, 6, and 8-11) although longer reaction
times were required.
Table 2. Cyclopropanation of Acyclic Allylic Silyl Ethers
The π-facial selectivity can be accounted for by the models
presented in Figure 1 by considering the most stable ground
state conformations. Further evidence for this is provided
by looking at the coupling constants between the allylic
proton and the vicinal alkene proton of various starting
materials (Figure 2). The observed values are in agreement
Figure 2.
with Gung’s conclusions6a indicating that a smaller value is
consistent with an increase in the population of conformer
in which the C-O bond is eclipsed with the CdC bond.
In summary, we have developed a simple methodology
for accessing the cyclopropylcarbinyl silyl ethers of anti
relative stereochemistry with good yields and good to
excellent diatereoselectivities.12 The diastereoselectivities
depend on the substitution pattern of the olefinic substrates,
but synthetically useful levels are attained in most cases.
Further studies are underway to determine the effect of other
types of substituent on the allylic ethers in order to expand
the scope of the Simmons-Smith cyclopropanation and will
be reported in due course.
Acknowledgment. This work was supported by grants
from the National Science and Engineering Research Council
(NSERC) of Canada and the Universite´ de Montre´al.
a Isolated yield of both diastereomers. b Determined by GC analysis of
the corresponding acetate derivatives.
Supporting Information Available: Experimental pro-
cedures and characterization data for the new compounds.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Simmons-Smith conditions, due to the strong preference
for an hydroxy-directed process on the A-1,3 minimized
conformer in the transition structure (D in Figure 1).2,4b
Therefore, we were pleased to observe that the cyclopropa-
nation of a (Z)-allylic silyl ether gave the anti product as
the major diastereomer (entry 12). However, the introduction
of a more sterically demanding R1 substituent led to an
inversion of the selectivity, which shows the importance of
the conformation adopted by the substrate when reacting with
the zinc carbenoid (entry 13).
OL0264051
(12) The sense of induction appears to be highly dependent upon the
nature of the alkene substituent. It has been observed that the cyclopropa-
nation of a â-chloro allylic ethers under the conditions reported here led
preferentially to the syn diastereoisomer: Evans, D. A.; Burch, J. D. Org.
Lett. 2001, 3, 503.
Org. Lett., Vol. 4, No. 20, 2002
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