Directing Effect of a Neighboring Aromatic Group in the Cyclopropanation of Allylic Alcohols

Full text of DOI:10.1021/jo9806815

5728
J . Org. Chem. 1998, 63, 5728-5729
Ta ble 1. Cyclop r op a n a tion of Allylic Alcoh ol 1 a n d
Der iva tives
Dir ectin g Effect of a Neigh bor in g Ar om a tic
Gr ou p in th e Cyclop r op a n a tion of Allylic
Alcoh ols
J anine Cossy,* Nicolas Blanchard, and
Christophe Meyer*
Laboratoire de Chimie Organique, Associe´ au CNRS, ESPCI,
10 rue Vauquelin, 75231-Paris Cedex 05, France
diastereo-
isomeric
ratioa
yieldb
(%)
substrate
reagents solvent
condns
2a /2b
Received April 14, 1998
1 (R ) H)
Et2Zn,
ICH2Cl
Et2Zn,
ICH2Cl
Et2Zn,
ICH2Cl
Et2Zn,
CH2I2
Et2Zn,
ICH2Cl
DCE
DCE
-23 °C, 1 h
80/20
83/17
85/15
50/50
80/20
80/20
30/70
20/80
88
A significant number of synthetic operations involving
organometallic species are depicted as heteroatom-directed
reactions.1 Their highly regio- and stereoselective character
result from a strongly stabilizing coordinative interaction
between the metal and the Lewis basic center. The basic π
electrons of unsaturated functional groups should act in the
same manner, as physical and experimental data have
evidenced the occurrence of metal-π interactions.2 How-
ever, their implications as key control elements in organic
synthesis have been relatively limited.
The directing effect of a neighboring aromatic group has
been illustrated in the regioselective formation and stereo-
selective alkylation of some â-aryl- and â-arylalkylcyclopen-
tanone lithium enolates.3 On the other hand, zinc-aryl,
-alkenyl, and, -alkynyl interactions have been invoked to
rationalize the stereochemical outcome of a 1,3-elimination
reaction from a dimetallic species.4 We report herein the
occurrence of a metal-π interaction in the zinc-promoted
cyclopropanation of a chiral racemic allylic alcohol bearing
a phenyl group at the remote allylic position.
1
-50 to -10 °C,
1 h
75
94
49
d
1
toluene -23 °C, 3 h
1
DCE -23 °C, 4 h
R ) Nac
CH2Cl2 -23 to -10 °C,
3 h
-23 °C, 2 h
3 (R ) TBS) Et2Zn,
ICH2Cl
Sm(Hg),
DCE
THF
THF
45e
74
40
1
1
-50 to +20 °C,
1 h 20 °C, 1 h
-50 to +20 °C,
1 h 20 °C, 2 h
ICH2Cl
Sm(Hg),
CH2I2
a
Ratio determined by 1H NMR and GC-MS analysis of the
b
crude reaction mixture. Isolated yield of analytically pure prod-
ucts. c One equivalent of sodium hydride was added to the
d
substrate prior to the cyclopropanation. 100% conversion. Iso-
lated yield was not determined. e Yield obtained after desilylation
with n-Bu4NF in THF.
prior to the cyclopropanation, indicating that the coordina-
tion of zinc to the hydroxy group was not a key control
element for the diastereoselectivity. We have to point out
that the use of diiodomethane (CH2I2) instead of ICH2Cl
resulted in a nonstereoselective reaction (Table 1).
A more striking result was observed when 1 was subjected
to the samarium-promoted cyclopropanation reaction in
THF.7 A diastereoisomeric mixture of 2a and 2b was
obtained in a 30/70 ratio (74% yield). Thus, Zn- and Sm-
promoted cyclopropanations exhibit opposite stereoselectivi-
ties in the case of substrate 1. To our knowledge, there is
no precedent for such results in the field of cyclopropana-
tions. Use of CH2I2 instead of ICH2Cl in the Sm-promoted
cyclopropanation resulted in an improved diastereoisomeric
ratio at the expense of a poorer yield (Table 1).
To elucidate the factors responsible for this selectivity
reversal, the stereochemical outcome of the cyclopropanation
of the chiral acyclic allylic alcohols 4-65 bearing a stereo-
genic center at the remote allylic position was investigated
(Table 2).
The Sm-promoted cyclopropanation of the (E)-isomer 4
proceeds without any stereoselectivity. On the contrary, the
Zn-promoted cyclopropanation of 4 exhibits a diastereoiso-
meric ratio of 7a /7b ) 75/25, comparable to the one observed
Treatment of the chiral racemic allylic alcohol 15 with
diethylzinc/chloroiodomethane (Et2Zn/ICH2Cl) in 1,2-dichlo-
roethane (DCE) at -23 °C6 afforded a mixture of two
diastereoisomeric cyclopropanated products 2a and 2b in a
80/20 ratio (88% yield). These products were easily sepa-
rated by flash chromatography, and the relative stereochem-
istry of the crystalline major diastereoisomer 2a was un-
ambiguously established by X-ray diffraction. The tem-
perature has little influence on the diastereoisomeric ratio,
but a slight improvement was observed by switching DCE
to toluene. The use of more coordinating solvents such as
diethyl ether was detrimental to the success of the cyclo-
propanation.6 Furthermore, the same diastereoisomeric
ratio was observed when the alcohol was protected as a TBS
ether (compound 3) or deprotonated with sodium hydride
* To whom correspondence should be addressed. (J .C.) Tel.: (33) 1 40
79 44 29. Fax: (33) 1 40 79 44 25. E-mail: janine.cossy@espci.fr.
(1) Hoveyda, A. H.; Evans, D. A.; Fu, G. C. Chem. Rev. 1993, 93, 1307-
1370.
(2) (a) St. Denis, J .; Oliver, J . P.; Dolzine, T. W.; Smart, J . B. J .
Organomet. Chem. 1974, 71, 315-323. (b) Oliver, J . P.; Smart, J . B.;
Emerson, M. T. J . Am. Chem. Soc. 1966, 88, 4101. (c) St. Denis, J .; Oliver,
J . P.; Smart, J . B. J . Organomet. Chem. 1972, 44, C32-C36. (d) Dolzine,
D. W.; Hovland, A. K.; Oliver, J . P. J . Organomet. Chem. 1974, 65, C1. (e)
Albright, M. J .; St. Denis, J .; Oliver, J . P. J . Organomet. Chem. 1977, 125,
1-7. (f) Haaland, A.; Lehmkuhl, H.; Nehl, H. Acta Chem. Scand. 1984, A38,
547-553. (g) Houk, K. N.; Rondan, N. G.; Schleyer, P. v. R.; Kaufmann, E.;
Clark, T. J . Am. Chem. Soc. 1985, 107, 2821-2823.
(7) (a) Molander, G. A.; Etter, J . B. J . Org. Chem. 1987, 52, 3942-3944.
(b) Molander, G. A.; Harring, L. S. J . Org. Chem. 1989, 54, 3525-3532.
(8) The relative stereochemistry of 7a and 7b was assigned by compari-
son with authentic samples prepared from 2a and 2b, respectively, using
the following sequence:
(3) Posner, G. H.; Lentz, C. M. J . Am. Chem. Soc. 1979, 101, 934-946.
(4) Beruben, D.; Marek, I.; Normant, J .-F.; Platzer, N. J . Org. Chem.
1995, 60, 2488-2501.
(5) (a) The (Z)-allylic alcohols 1, 5, and 6 were prepared by a three-step
homologation of the corresponding commercially available or known alde-
hydes: (i) PPh3, CBr4, CH2Cl2; (ii) n-BuLi (2 equiv), THF, then (CH2O)n;
(iii) Zn(Cu), i-PrOH, THF reflux. (b) For the preparation of aldehydes
involved in the synthesis of 5 and 6, see: Maruoka, K.; Itoh, T.; Sakurai,
M.; Nonoshita, K.; Yamamoto, H. J . Am. Chem. Soc. 1988, 110, 3588-3597.
(c) Smith, A. B., III; Qiu, Y.; J ones, D. R.; Kobayashi, K. J . Am. Chem. Soc.
1995, 117, 12011-12012. (d) For the preparation of 4, see: Desert, S.;
Metzner, P. Tetrahedron 1992, 47, 10327-10338.
(6) Denmark, S. E.; Edwards, J . P. J . Org. Chem. 1991, 56, 6974-6981.
S0022-3263(98)00681-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/25/1998

Communications
J . Org. Chem., Vol. 63, No. 17, 1998 5729
Ta ble 2. Cyclop r op a n a tion of Allylic Alcoh ols Bea r in g a
Rem ote Ster eocen ter
Sch em e 1. P ossible Tr a n sition Sta tes
metal interaction could be invoked to rationalize this ste-
rochemical outcome. There should be enough leeway for the
possible transition state A to reach conformation A′ or A′′,
in which the aromatic group directly coordinates the Zn
carbenoid leading to the major diastereoisomer 2a . Coor-
dination of the carbenoid to the hydroxy group is not
necessarily required as shown in conformation A′′, since TBS
ether 3 gave a similar diastereoisomeric ratio compared to
1. Finally, in the case of the (E)-allylic alcohol 4, the lack
of severe steric interactions in the different possible transi-
tion states leads to a stereorandom Sm-promoted cyclopro-
panation reaction, whereas the Zn-promoted one is appar-
ently directed by the phenyl group.
a
Determined by 1H NMR and GC-MS analysis of the crude
b
reaction mixture. Isolated yield of analytically pure material.
c These two diastereoisomers can be easily separated by flash
chromatography.
for the (Z)-isomer 1.8 In the case of compound 5 bearing a
cyclohexyl group, it is noteworthy that both Zn- and Sm-
promoted cyclopropanations exhibit comparable levels of
stereoselectivity without any reversal of stereochemistry.9
This result demonstrates the dramatic influence of the
aromatic group in the Zn-promoted cyclopropanation of 1
or 4. A reversal of selectivity between Zn- and Sm-promoted
cyclopropanations was also observed for compound 6 bearing
a p-methoxybenzyl group (CH2OPMB), although the dia-
stereoisomeric ratio was lower.10
The Lewis acidic character of Zn is an essential parameter
in these aryl-directed cyclopropanations. The use of CH2I2
instead of ICH2Cl resulted in a stereorandom cyclopropa-
nation in the case of 1 and might be due to the greater Lewis
acidic character of the chloromethylzinc carbenoid.12d,13
A
The stereochemical outcome of the cyclopropanations of
chiral allylic alcohols has been the subject of numerous
investigations and is now well-established.1,7,11 Whereas (Z)-
substituted olefins give high syn selectivities, for the (E)-
substituted ones the syn selectivities are usually modest. A
staggered model has been proposed to account for the
observed diastereoselectivities. In the case of substrates
bearing a stereocenter at the remote allylic position, mini-
mization of A-1,3 strain12 led us to consider two possible
transition states A and B for the cyclopropanation reactions
(Scheme 1).
Sm-promoted cyclopropanation led to the major diastere-
oisomers b irrespective of the nature of the R group. Unless
R contains an aromatic group, Zn-promoted cyclopropana-
tions exhibit the same stereoselectivities. In these cases,
the diastereoisomeric ratio probably reflects the preferential
approach of the carbenoid from the less crowded face of the
olefin in the transition state B and is related to the steric
bulk of the R substituent compared to the methyl group, as
it decreases ongoing from cyclohexyl, phenyl to CH2OPMB.
In the cyclopropanation of 1, 4, and 6 with Et2Zn/ICH2Cl,
the approach of the carbenoid is probably directed by the
aromatic group leading to a selectivity reversal. An aryl-
similar interaction with Sm might have been possible, but
since Sm-promoted cyclopropanation reactions are run in
THF, this solvent destroys the acidic character of the metal,
hence preventing such a kind of interaction. It can be
anticipated that coordinating solvents such as THF would
have the same effect in the Zn-promoted cyclopropanation
reaction, but they interfere as well with the reaction itself.6
Worthy of note is the fact that toluene as the solvent does
not apparently compete with this intramolecular aryl-metal
interaction.
In conclusion, we have shown that the cyclopropanation
of chiral acyclic allylic alcohols bearing a stereocenter at the
remote allylic position can proceed with synthetically useful
levels of stereoselectivity. When an aryl group was present
at this stereocenter, a reversal of selectivity has been
observed between the Sm- and the Zn-promoted cyclopro-
panation reactions, which has been interpreted by a π-metal
interaction resulting in a net directing effect of this sub-
stituent in the second case. We are currently performing
synthetic transformations on the cyclopropanated products
in order to exploit their potential in natural product syn-
thesis.
Ack n ow led gm en t. We thank the CNRS (ESA 7084),
the ESPCI for financial support and the Ministe`re de
l′Education Nationale de la Recherche et de la Technologie
for a grant (N.B.).
(9) The relative stereochemistry of 8a was assigned by comparison with
an authentic sample prepared from 2a (see the Supporting Information).
(10) The relative stereochemistry of 9a and 9b was assigned by convert-
ing them to the corresponding carboxylic acid and comparison with the acid
obtained from 2a by oxidation of the aromatic ring (see the Supporting
Information).
Su p p or tin g In for m a tion Ava ila ble: Full experimental pro-
cedures and spectroscopic data are available for compounds 1,
2a ,b, 3, 5, 6-12b, and intermediates involved in the preparation
of 1, 5, and 6, an ORTEP drawing for 2a , details of the data
acquisition, and descriptions of the assignment of the stereochem-
istry of 8a and 9a ,b (30 pages).
(11) (a) Ratier, M.; Castaing, M.; Godet, J .-Y.; Pereyre, M. J . Chem Res.,
Miniprint 1978, 2309-2315. (b) Ratier, M.; Castaing, M.; Godet, J .-Y.;
Pereyre, M. J . Chem Res., Synop. 1978, 179. (c) Charette, A. B.; Lebel, H.
J . Org. Chem. 1995, 60, 2966-2967. (d) Charette, A. B.; Marcoux, J .-F.
Synlett 1995, 1197-1207.
(12) Charette, A. B.; Marcoux, J .-F. Tetrahedron Lett. 1993, 34, 7157-
7160.
(13) Hoffmann, R. W. Chem. Rev. 1989, 89, 1841-1860.
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