Complexation of Vinylcyclopropanes with Zirconocene - 1-butene Complex: Application to the Stereocontrolled Synthesis of Steroidal Side Chains

Article abstract of DOI:10.1021/jo962064r

Reactions of vinylcyclopropane derivatives with a zirconocene-1-butene complex ("Cp₂Zr") caused regioselective cleavage of the cyclopropyl bond to give η³ π-allylic and/or η¹ σ-allylic complexes. The regioselectivity of the bond cleavage and the formation of a η³ π-allylic or η¹ σ-allylic complex depend on the bulkiness of the substituents on the cyclopropyl group and the presence of leaving functionality. A catalytic use of "Cp₂Zr" in the presence of excess Grignard reagent also caused a ring opening of the vinylcyclopropane derivatives with the same sense of regiochemical selectivity. The reaction of the thermally equilibrated "Cp₂Zr"-propenylcyclopropane complex with acetone indicated the possibility for the synthesis of the steroidal side chain in either natural or unnatural forms. The synthetic utility of the present μCp₂Zr"-vinylcyclopropane chemistry was ascertained by the stereocontrolled preparation of the C-20, C-24 dimethylated steroidal side chain which is identical to the active metabolite of vitamin D₂.

Full text of DOI:10.1021/jo962064r

3
994
J . Org. Chem. 1997, 62, 3994-4001
Com p lexa tion of Vin ylcyclop r op a n es w ith Zir con ocen e-1-bu ten e
Com p lex: Ap p lica tion to th e Ster eocon tr olled Syn th esis of
Ster oid a l Sid e Ch a in s
Susumu Harada, Hiromichi Kiyono, Ryoko Nishio, Takeo Taguchi,* and Yuji Hanzawa*,†
School of Pharmacy, Tokyo University of Pharmacy and Life Science, 1432-1, Horinouchi,
Hachioji, Tokyo 192-03, J apan
Motoo Shiro
Rigaku Corporation, Matsubara-cho 3-9-12, Akishima, Tokyo 196, J apan
Received November 4, 1996X
Reactions of vinylcyclopropane derivatives with a zirconocene-1-butene complex (“Cp
2
Zr”) caused
3
1
regioselective cleavage of the cyclopropyl bond to give η π-allylic and/or η σ-allylic complexes.
3
1
The regioselectivity of the bond cleavage and the formation of a η π-allylic or η σ-allylic complex
depend on the bulkiness of the substituents on the cyclopropyl group and the presence of leaving
functionality. A catalytic use of “Cp
ring opening of the vinylcyclopropane derivatives with the same sense of regiochemical selectivity.
The reaction of the thermally equilibrated “Cp Zr”-propenylcyclopropane complex with acetone
indicated the possibility for the synthesis of the steroidal side chain in either natural or unnatural
forms. The synthetic utility of the present “Cp Zr”-vinylcyclopropane chemistry was ascertained
by the stereocontrolled preparation of the C-20, C-24 dimethylated steroidal side chain which is
2
Zr” in the presence of excess Grignard reagent also caused a
2
2
2
identical to the active metabolite of vitamin D .
In tr od u ction
procedure developed by Negishi et al.3 The zirconocene-
-butene complex is known to undergo a ligand exchange
with external unsaturation to give a new zirconocene
complex by releasing the 1-butene ligand. Therefore, the
zirconocene-1-butene complex can be regarded as a
zirconocene itself and is often termed a zirconocene
1
Transition metal-mediated transformations of organic
molecules is a major and important discipline in modern
organic chemistry, and a large number of new synthetic
works committed to transition metal complexes have
been reported. Recent progress in synthetic chemistry
using early-transition metal complexes, especially orga-
nozirconocene derivatives, reveals a wide-ranging pos-
equivalent, which is abbreviated to “Cp
discovery of a very practical method to generate “Cp
2
Zr”. Since the
3
2
-
Zr”, the chemistry of the zirconocene complex has quickly
developed and been applied to the preparation of many
1
sibilities for organic synthesis. In our search for new
reactions, we have been devoting much time to synthetic
use of a zirconocene-1-butene complex, which can be
2 2
generated in situ from zirconocene dichloride (Cp ZrCl )
types of organic molecules, including complex natural
2
products.4 Herein, we report a full account of vinylcy-
clopropane reactions with “Cp
Cp Zr”-vinylcyclopropane chemistry to stereocontrolled
preparations of steroidal side chains.
2
Zr” and the application of
and n-butyllithium in an aprotic solvent according to the
“
2
5
†
Phone:
81-426-76-3274.
Fax:
81-426-76-3257.
E-mail:
hanzaway@ps.toyaku.ac.jp.
X
Abstract published in Advance ACS Abstracts, May 15, 1997.
(1) For reviews, see: (a) Wailes, P. C.; Coutts, P. S. P.; Weigold, H.
Organometallic Chemistry of Titanium, Zirconium and Hafnium;
Academic Press: New York, 1974. (b) Cardin, D. J .; Lappert, M. F.;
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Wilkinson, G., Stone, F. G. A., Abel, E. W., Eds.; Pergamon: Oxford,
1
982; Vol. 3, p 549. (c) Schwartz, J .; Labinger, J . A. Angew. Chem.,
Int. Ed. Engl. 1976, 15, 333. (d) Weidmann, B.; Seebach, D. Angew.
Chem., Int. Ed. Engl. 1983, 22, 31. (e) Negishi, E.; Takahashi, T.
Aldrichim. Acta 1985, 18, 31. (f) Yasuda, H.; Tatsumi, K.; Nakamura,
A. Acc. Chem. Res. 1985, 18, 120. (g) Yasuda, H.; Nakamura, A.
Angew. Chem., Int. Ed. Engl. 1987, 26, 732. (h) Negishi, E.; Takahashi,
T. Synthesis 1988, 1. (i) Buchwald, S. L.; Nielsen, R. B. Chem. Rev.
1
988, 88, 1047. (j) Erker, G.; Berlerkamp, M.; L o´ pez, L.; Grehl, M.;
Sch o¨ necker, B.; Krieg, R. Synthesis 1994, 212. (k) Negishi, E.;
Takahashi, T. Acc. Chem. Res. 1994, 27, 124. (l) Lipshutz, B. H.;
Bhandari, A.; Lindsley, C.; Keil, R.; Wood, M. R. Pure Appl. Chem.
1
994, 66, 1493. (m) Negishi, E. In Comprehensive Organic Synthesis;
Paquette, L. A., Ed.; Pergamon Press: New York, 1991; Vol. 5, p 1163.
2) (a) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992, 33,
(3) Negishi, E.; Cederbaum, F. E.; Takahashi, T. Tetrahedron Lett.
1986, 27, 2829.
(
1
295. (b) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1992,
3, 7873. (c) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y.
(4) (a) Wender, P. A.; McDonald, F. E. J . Am. Chem. Soc. 1990, 112,
4956. (b) Angel, G.; Negishi, E. J . Am. Chem. Soc. 1991, 113, 7424.
(c) Angel, G.; Owczarczyk, Z.; Negishi, E. Tetrahedron Lett. 1991, 32,
1543. (d) Mori, M.; Uesaka, N.; Shibasaki, M. J . Org. Chem. 1992,
57, 3519. (e) Uesaka, N.; Saito, F.; Mori, M.; Shibasaki, M.; Okamura,
K.; Date, T. J . Org. Chem. 1994, 59, 5633.
(5) Preliminary communications, see: (a) Hanzawa, Y.; Harada, S.;
Nishio, R.; Taguchi, T. Tetrahedron Lett. 1994, 35, 9421. (b) Harada,
S.; Kiyono, H.; Taguchi, T.; Hanzawa, Y.; Shiro, M. Tetrahedron Lett.
1995, 36, 9489.
3
Tetrahedron Lett. 1992, 33, 3769. (d) Ito, H.; Taguchi, T.; Hanzawa,
Y. J . Org. Chem. 1993, 58, 774. (e) Ito, H.; Motoki, T.; Taguchi, T.;
Hanzawa, Y. J . Am. Chem. Soc. 1993, 115, 8835. (f) Ito, H.; Ikeuchi,
Y.; Taguchi, T.; Hanzawa, Y.; Shiro, M. J . Am. Chem. Soc. 1994, 116,
5
469. (g) Ito, H.; Taguchi, T.; Hanzawa, Y. Tetrahedron Lett. 1993,
4, 7639. (h) Ito, H.; Nakamura, T.; Taguchi, T.; Hanzawa, Y.
3
Tetrahedron 1995, 51, 4507. (i) Hanzawa, Y.; Ito, H.; Taguchi, T.
Synlett 1995, 299.
S0022-3263(96)02064-6 CCC: $14.00 © 1997 American Chemical Society

Complexation of Vinylcyclopropanes with Zirconocene-1-Butene
J . Org. Chem., Vol. 62, No. 12, 1997 3995
Sch em e 1
Sch em e 2
Vinylcyclopropane is often used as a favorable molecule
for the study of complexations with transition metals and
a number of examples using various transition metals
6
have been reported. It is considered significant to
examine the reactivity of vinylcyclopropane derivatives
toward “Cp
and/or trans substituted vinylcyclopropane derivatives
a -e which were easily prepared by the sequences
shown in Scheme 1.
2
Zr”. As model compounds, we selected cis
1
Ta ble 1. Rea ction P r od u cts of Vin ylcyclop r op a n es w ith
“
Cp 2Zr ” a n d Ca r bon yls
entry
starting material
carbonyl
acetone
product
yield (%)
1
2
3
4
5
6
7
8
9
cis-1a
trans-1a
cis-1b
5a
86
48
84
45
93
80
41
80
26
5b
5c
trans-1b
cis-1c
trans-1ca
1d
Resu lts a n d Discu ssion
Treatment of cis- or trans-1a with “Cp
PhCHO
7
10
cis-1e
trans-1e
2
Zr” (see the
Experimental Section) in tetrahydrofuran (THF), or
toluene, followed by acidic (1 M HCl) workup of the
reaction mixture, yielded ring-opened compounds 3 (50%)
a
trans/ cis ) 7.6.
than reactions with trans-isomers (entries 1, 3, 5, and
). In all cases examined, a regioselective cyclopropyl
bond-scission with “Cp Zr” occurred at the less sterically
crowding cyclopropyl bond. The presence of an oxygen
functionality which is able to coordinate to zirconium
metal does not affect the regioselectivity of the cyclopro-
pyl bond cleavage (entries 1, 2, 8, and 9).
The incorporation of two deuteriums into 3 (X ) D),
the formation of 5, and the NMR spectrum of the eight-
membered oxazirconacycle 4 suggest the formation of an
(Scheme 2). Since the reaction of the cyclopropyl com-
8
pound which has no vinyl group ended in recovery of the
starting material under the same reaction conditions, the
double bond is an essential factor in bringing about the
2
2
ring opening of 1a with “Cp Zr”. In the reaction of 1a ,
addition of 10% deuterium chloride in deuterium oxide
to the reaction mixture revealed an efficient incorporation
of the two deuteriums, one by one, into each methyl group
of 3 (X ) D) (60% yield). Adding acetone to the reaction
mixture of 1a and “Cp
the mixture yielded an eight-membered oxazirconacyclic
compound 4 (R ) CH OBn) containing an E-double bond
J ) 15.1 Hz) in the ring (Scheme 2). The oxazircona-
2
Zr” followed by concentration of
3
η π-allylic zirconocene complex 2 in the reaction of 1 with
Cp Zr” (Scheme 2). Although we could not obtain a clear
2
NMR spectrum of 2a due to its diastereomeric and/or
unstable nature, the η π-allylic structures of 2a was
“
2
(
3
cyclic compound 4 was quantitatively converted to 5 by
the addition of 1 M HCl.
Results of the reactions of vinylcyclopropane deriva-
1
13
confirmed by characteristic H- and C-chemical shifts
3
8
3
of the η π-allylic portion (Scheme 2). The dimethyl η
π-allylic zirconocene complex 6 which is generated from
d showed a clearer NMR spectrum than 2a (Scheme 3).
E-Stereochemistry of η π-allylic complexes 2a , 6 was
deduced by coupling constants (J ) 16.1 and 16.9 Hz,
respectively) between two vinyl protons (Schemes 2 and
). In the reaction of 1e, the initially formed η π-allylic
complex 8 is converted to the σ-allylic complex 9 through
a facile â-elimination of the benzyloxy group.
structure of the zirconocene intermediate 9 was con-
firmed to be E σ-allylic complex (J olefinic ) 15.3 Hz) from
tives with “Cp
2
Zr” are listed in Table 1. Reactions with
1
cis-isomers generally give higher yields of the products
3
(6) For reviews and lead references, see: (a) Wender, P. A.; Taka-
hashi, H.; Witulski, B. J . Am. Chem. Soc. 1995, 117, 4720. (b)
Khusuntdinov, R. I.; Dzhemilev, U. M. J . Organomet. Chem. 1994, 471,
3
3
1
. (c) Aumann, R.; Averbeck, H. J . Organomet. Chem. 1978, 160, 241.
(d) Salzer, A. J . Organomet. Chem. 1976, 117, 245. (e) Hudlicky, T.;
Reed, J . W. In Comprehensive Organic Synthesis; Trost, B. M., Fleming,
I., Paquette, L. A., Eds.; Pergamon Press: New York, 1991; Vol. 5, p
2a
The
8
5
99. (f) Doyle, M. P.; van Leusen, D. J . Am. Chem. Soc. 1981, 103,
917. (g) Doyle, M. P.; van Leusen, D. J . Org. Chem. 1982, 47, 5326.
(
h) Hudlicky, T.; Koszyk, F. J .; Kutchan, T. M.; Sheth, J . P. J . Org.
Chem. 1980, 45, 5020. (i) Hiroi, K.; Arinaga, Y. Tetrahedron Lett. 1994,
5, 153. (j) Murakami, M.; Nishida, S. Chem. Lett. 1979, 927. (k)
Morizawa, Y.; Oshima, K.; Nozaki, H. Tetrahedron Lett. 1982, 23, 2871.
l) Grimme, W. Chem. Ber. 1967, 100, 113. (m) Liotta, F. J ., J r.;
Carpenter, B. K. J . Am. Chem. Soc. 1985, 107, 6426.
3
(7) Salomon, R. G.; Salomon, M. F.; Heyne, T. R. J . Org. Chem. 1975,
40, 756.
(8) Dimmock, P. W.; Whitby, R. J . J . Chem. Soc., Chem. Commun.
1994, 2323.
(

3
996 J . Org. Chem., Vol. 62, No. 12, 1997
Harada et al.
Sch em e 3
Sch em e 4
stable complex (E,E)-13 by equilibrium through the
assumed σ-allylic zirconocene species (15, 16, and 17)
(Figure 2). Heating of π-complexes 13 at 70 °C for 12 h
and the subsequent reaction with acetone gave a single
diastereomer 14a in 50% yield. The 1,4-relative config-
uration of the dimethyl groups in product 14a was
confirmed to be (1R*,4R*)-configuration with X-ray analy-
sis of the 3,5-dinitrobenzoate of 14a .9 The selective
formation of (1R*,4R*)-dimethyl compound 14a as a
single product can be explained as a result of the reaction
between the thermodynamically stable σ-allylic zir-
conocene 18 and acetone through a six-membered chair-
form cyclic transition state which is considered the most
favorable energetically (Figure 3). In the reaction of the
equilibrated (70 °C, 12 h) π-complexes 13 with acetone,
the lowered yield (50%) and the exclusive formation of
NMR data (Scheme 3).2h The reactions of 6 and 9 with
benzaldehyde showed formations of homoallylic alcohol
7
and 10 in 41% and 80% yields, respectively (entries 7
and 8, Table 1). In the reaction of 1e with “Cp Zr”, the
2
gem-dimethyl group is considered bulky enough to force
cleavage of the (benzyloxy)methyl-substituted σ-bond of
the cyclopropyl ring. The regioselective bond scission of
2
substituted vinylcyclopropane with “Cp Zr” indicates the
influence of substituent bulkiness on the cyclopropyl ring.
The observation that the cis-isomer of 1 generally gives
a higher yield of the product than the trans-isomer might
be a reflection of the steric effect during complexation.
An experiment which was essentially the same was
independently reported by Whitby’s group.8 They sug-
gested the possibility that the participation of the prefer-
able conformation A over B of the zirconacyclopropane
1
4a compared to those (85% yield, 14a :14b ) 1:1) under
nonequilibrium conditions might indicate a possibility for
selective decomposition of the thermodynamically un-
stable zirconocene complex, which leads to 14b, during
the thermal equilibration process.
3
intermediate 11 forms the E-stereochemical η π-allylic
complex (Figure 1).
F igu r e 2. Thermal isomerization of allylic zirconocene spe-
cies.
F igu r e 1. Whitby’s proposal for the formation of the π-allylic
8
zirconocene complex.
2 2
The catalytic use of Cp ZrCl or its optically active
Complexation of cis- or trans-(1-propenyl)cyclopropane
derivatives 12 (a mixture of E/ Z olefinic isomers) with
derivative has become a very challenging task in modern
chemical synthesis.10 The bond scission of vinylcyclo-
propane derivatives 1a was also carried out with a
“
Cp
a diastereomeric mixture (Scheme 4). As expected from
the results of the reactions of “Cp Zr” with vinylcyclo-
2
Zr”, followed by treatment with acetone, gave 14 as
(9) Crystals for X-ray analysis were prepared by the reaction of 19a
2
with 3,5-dinitrobenzoyl chloride in the presence of DMAP in pyridine,
and the crystals were recrystallized from hexane-ethyl acetate, mp
83-86 °C. Cu KR radiation (n ) 1.54178 Å). Crystal data: empirical
propane derivatives 1, the cis-substituted isomer cis-12
gave a much higher yield of diastereomeric products 14
formula C22
H N O ; monoclinic; space group p2 (no. 14); a ) 6.321(4)
3
0
2
6
1
(63-85%) than the trans-12 (<10%). The diastereomeric
3
Å, b ) 9.721(6) Å, c ) 37.452(3) Å, â ) 92.66(2)°, V ) 2298(1) Å , Z )
ratio of 14, while disappointing, was suggested to be
dependent on the olefinic geometry of the starting mate-
rial cis-12 (Scheme 4). Thus, according to Whitby’s
3
4
, D ) 1.209 g/cm . A total of 3032 unique reflections were collected.
The final R factor was 0.064. The author has deposited atomic
coordinates for this structure with the Cambridge Crystallographic
Data Centre. The coordinates can be obtained, on request, from the
Director, Cambridge Crystallographic Data Centre, 12 Union Road,
Cambridge, CB2 1EZ, UK.
8
proposal, the geometrical and diastereomeric mixture of
complexes 13 was converted to the thermodynamically

Complexation of Vinylcyclopropanes with Zirconocene-1-Butene
J . Org. Chem., Vol. 62, No. 12, 1997 3997
F igu r e 3. Transition state model for the reaction of the
thermally stable complex with acetone.
Ta ble 2. Rin g Op en in g of Vin ylcyclop r op a n es w ith
Ca ta lytic “Cp 2Zr ”
F igu r e 4. A catalytic cycle for the ring opening of 1a with
2
“Cp Zr”.
chain analog for steroids because the carbon-zirconium
bond is easily converted to a carbon-oxygen or halogen
bond.1 The construction of the steroidal side chain has
attracted much attention not only from a biological view
point, but also in the stereocontrolled synthesis of the
acyclic system. Although a number of methods have been
reported for stereocontrolled construction of the side
Cp2ZrCl2
(mol %)
reaction
time (h)
entry
vinylcyclopropane
yield (%)
1
2
3
cis-1a
cis-1a
trans-1a
10
30
30
8
0.3
0.3
30
56
38
2 2
catalytic amount of Cp ZrCl (10-30 mol %) and n-
butylmagnesium chloride (3 mol equiv) in THF or tolu-
ene; however, yields of product 19 (38-56%) were low
2
Table 2). Addition 10% DCl-D O to the reaction
mixture gave a monodeuterated compound of 19 (X ) D).
These results support the formation of a “Cp Zr” catalytic
2
chain of active vitamin D metabolite, to our knowledge,
there are no reports about the simultaneous construction
of two methyl groups at C-20 and C-24 positions in a
(
1
2
stereocontrolled manner.
To synthesis the steroidal
side chain, steroid 2113 was chosen as the target.
2
cycle. Under catalytic conditions, formation of olefinic
compound 19, which is an isomer of 3, and the incorpora-
tion of monodeuterium into the methyl group of 19
suggest Grignard reagent 20 is generated during the
course of the catalytic reaction (Figure 4).
To apply “Cp
tempted stereocontrolled construction of the steroidal side
chain, which is identical to the active vitamin D me-
tabolite.11 The present “Cp
Zr”-vinylcyclopropane chem-
istry also indicates the possibility of preparing the side
2
Zr”-vinylcyclopropane chemistry, we at-
2
2
(
10) (a) Hoveyda, A. H.; Morken, J . P. Angew. Chem., Int. Ed. Engl.
1
996, 35, 1262. (b) Negishi, E. Pure Appl. Chem. 1981, 53, 2333. (c)
Dzhemilev, U. M.; Vostrikova, O. S.; Tolstikov, G. A. J . Organomet.
Chem. 1986, 304, 17. (d) Takahashi, T.; Seki, T.; Nitto, Y.; Saburi,
M.; Rousset, C. J .; Negishi, E. J . Am. Chem. Soc. 1991, 113, 6266. (e)
Knight, K. S.; Waymouth, R. M. J . Am. Chem. Soc. 1991, 113, 6268.
It is obvious that the diastereoselective introduction
of the cyclopropyl ring into a steroidal side chain is crucial
to a stereocontrolled construction of the 20,24-dimethyl
(
f) Lewis, D. P.; Muller, P. M.; Whitby, R. J .; J ones, R. V. H.
side chain with our present “Cp Zr”-vinylcyclopropane
2
Tetrahedron Lett. 1991, 32, 6797. (g) Didiuk, M. T.; J ohannes, C. W.;
Morken, J . P.; Hoveyda, A. H. J . Am. Chem. Soc. 1995, 117, 7097. (h)
Visser, M. S.; Heron, N. M.; Diduk, M. T.; Sagal, J . F.; Hoveyda, A. H.
J . Am. Chem. Soc. 1996, 118, 4291 and the references cited therein.
chemistry. The diastereoselective Simmons-Smith cy-
14
clopropanation (10 equiv of diethyl zinc and 10 equiv
(
1
i) Visser, M. S.; Harrity, J . P. A.; Hoveyda, A. H. J . Am. Chem. Soc.
996, 118, 3779. (j) Uesaka, N.; Mori, M.; Okamura, K.; Date, T. J .
of diiodomethane in toluene at -30 °C) of Z-allylic alcohol
15
2
3 which can be prepared from aldehyde 22 gave an
Org. Chem. 1994, 59, 4542. (k) Suzuki, N.; Kondakov, D. Y.; Taka-
hashi, T. J . Am. Chem. Soc. 1993, 115, 8485. (l) Kondakov, D. Y.;
Negishi, E. J . Am. Chem. Soc. 1995, 117, 10771. (m) Houri, A. F.;
Diduk, M. T.; Xu, Z.; Horan, N. R.; Hoveyda, A. H. J . Am. Chem. Soc.
inseparable mixture of 24 and 25 in a ratio of 78:22 in
84% yield (Scheme 5). Separation of the diastereomeric
mixture was carried out at the final stage of preparing
1
993, 115, 6614. (n) Hoveyda, A. H.; Xu, Z.; Morken, J . P.; Houri, A.
2
1 and 28 (vide infra). The Simmons-Smith reaction
F. J . Am. Chem. Soc. 1991, 113, 8950. (o) Hoveyda, A. H.; Xu, Z. J .
Am. Chem. Soc. 1991, 113, 5079. (p) Houri, A. F.; Xu, Z.; Cogan, D.
A.; Hoveyda, A. H. J . Am. Chem. Soc. 1995, 117, 2943.
in the presence of 1 equiv of L-dibutyl tartrate in THF
gave 24 as the major isomer at more than 94% de in 87%
yield.16 The stereochemistry of 24 as the major isomer
was confirmed by converting the mixture to the known
(11) Ikekawa, N.; Ishizuka, S. In Molecular Structure and Biological
Activity of Steroids; Bohl, M., Duax, W. L., Eds.; CRC: Boca Raton,
FL, 1991; p 293.

3
998 J . Org. Chem., Vol. 62, No. 12, 1997
Harada et al.
Sch em e 5
2
5-OH, C-20 epi steroid 2812v (60% based on the calcu-
carried out by the Simmons-Smith reaction in the
presence of D-diisopropyl tartrate (2-3 equiv) as a
stereocontrolling agent to give 24 and 25 in a 27:73 ratio
in 76-83% yield. The improved ratio of 25 (24:25 ) 11:
89) was obtained by Charette’s enantioselective Sim-
mons-Smith cyclopropanation17 of 23 using a chiral
dioxaborolane ligand derived from (R,R)-(+)-N,N,N′,N′-
tetramethyltartaric acid diamide. Configuration of the
cyclopropyl ring of 25 was confirmed by converting the
lated amount of 27) via compounds 26 and 27 by (i) the
Dess-Martin oxidation of 24, (ii) Wittig olefination of 26
+
-
3 3 2
(Ph P CH Br /nBuLi), (iii) “Cp Zr” complexation of 27
followed by the addition of acetone, (iv) deprotection and
separation of the diastereomer. In order to prepare a
steroid, which has a natural configuration at C-20, the
requisite introduction of the cyclopropyl ring into 23 was
(
12) (a) Batcho, A. D.; Berger, D. E.; Davoust, S. G.; Wovkulich, P.
mixture to the C-20 naturally configured steroid 21 (R′
M.; Uskokovic, M. R. Helv. Chem. Acta 1981, 64, 1682. (b) Dauben,
W. G.; Brookhart, T. J . Am. Chem. Soc. 1981, 103, 237. (c) Batcho, A.
D.; Berger, D. E.; Uskokovic, M. R.; Snider, B. B. J . Am. Chem. Soc.
12v
)
H) (47% yield based on the calculated amount of 30)
in the same way as the preparation of 28. To prepare
21, compound 25 (24:25 ) 27:73) was oxidized with the
Dess-Martin reagent to aldehyde and the subsequent
1
981, 103, 1293. (d) Mikami, K.; Kawamoto, K.; Nakai, T. Tetrahedron
Lett. 1985, 26, 5799. (e) Mikami, K.; Kawamoto, K.; Nakai, T.
Tetrahedron Lett. 1986, 27, 4899. (f) Castedo, L.; Granja, J . R.;
Mouri n˜ o, A. Tetrahedron Lett. 1985, 26, 4959. (g) Mikami, K.;
Kawamoto, K.; Nakai, T. Chem. Lett. 1985, 115. (h) Tanabe, M.;
Hayashi, K. J . Am. Chem. Soc. 1980, 102, 862. (i) Koreeda, M.;
Tanaka, Y.; Schwartz, A. J . Org. Chem. 1980, 45, 1172. (j) Trost, B.
M.; Verhoeven, T. R. J . Am. Chem. Soc. 1976, 98, 630. (k) Trost, B.
M.; Verhoeven, T. R. J . Am. Chem. Soc. 1978, 100, 3435. (l) Takahashi,
T.; Ootake, A.; Tsuji, J . Tetrahedron Lett. 1984, 25, 1921. (m)
Takahashi, T.; Ootake, A.; Tsuji, J .; Tachibana, K. Tetrahedron 1985,
+
-
Wittig olefination (Ph
as an E/ Z mixture (E:Z ) 22:78). Heating (70 °C, 12 h)
the “Cp Zr” complex generated from 31 in THF, followed
by the reaction with acetone, and deprotection, gave 21
R′ ) CH ). All of the synthesized steroids (28, 21 R′ )
H, R′ ) CH ) were identical in every respect to the
reported spectral data in the literature.
In summary, an efficient complexation of vinylcyclo-
propane derivatives with a stoichiometric amount of “Cp
3 2 3
P CH CH Br /nBuLi) to give 31
2
(
3
3
1
2v,13
4
7
1, 5747. (n) Temple, J . S.; Schwartz, J . J . Am. Chem. Soc. 1980, 102,
381. (o) Riediker, M.; Schwartz, J . Tetrahedron 1981, 22, 4655. (p)
Marino, J . P.; Abe, H. J . Am. Chem. Soc. 1981, 103, 2907. (r) Schmuff,
N. R.; Trost, B. M. J . Org. Chem. 1983, 48, 1404. (s) Wicha, J .; Bal,
K. J . Chem. Soc., Perkin Trans. 1 1978, 1282. (t) Midland, M. M.;
Kwon, Y. C. J . Am. Chem. Soc. 1983, 105, 3725. (u) Midland, M. M.;
Kwon, Y. C. Tetrahedron Lett. 1985, 26, 5017. (v) Mandai, T.;
Matsumoto, T.; Kawada, M.; Tsuji, J . Tetrahedron 1994, 50, 475.
2
-
Zr” was established to give zirconocene complexes through
a regioselective ring-opening of the vinylcyclopropane
derivative. The regioselective cleavage of the cyclopropyl
3
1
(
13) (a) Anjaneyulu, V.; Radhika, P.; Babu, J . S.; Krishna, M. M.
bond and the formation of η π-allylic complex and/or η
Indian J . Chem. 1994, 33B, 901. (b) Sardina, F. J .; Mouri n˜ o, A.;
Castedo, L. Tetrahedron Lett. 1983, 24, 4477.
(
σ-allylic complex depend upon the bulkiness of the
substituents on the cyclopropyl ring. With a catalytic
14) For recent reviews, see: (a) Charette, A. B.; Marcoux, J .-F.
Synlett 1995, 1197. (b) Motherwell, W. B.; Nutley, C. J . Contemp. Org.
Synth. 1994, 1, 219 and the references cited therein.
2
amount of “Cp Zr” and 3 equiv of Grignard reagent, the
same sense of regioselective cleavage of vinylcyclopropane
(
15) Mauvais, A.; Burger, A.; Roussel, J . P.; Hetru, C.; Luu, B.
Bioorg. Chem. 1994, 22, 36.
16) (a) Ukaji, Y.; Sada, K.; Inomata, K. Chem. Lett. 1993, 1227.
b) Ukaji, Y.; Nishiyama, M.; Fujisawa, T. Chem. Lett. 1992, 61.
(
(17) Charette, A. B.; Prescott, S.; Brochu, C. J . Org. Chem. 1995,
60, 1081.
(

Complexation of Vinylcyclopropanes with Zirconocene-1-Butene
J . Org. Chem., Vol. 62, No. 12, 1997 3999
was observed. Extension of this chemistry to the ste-
reocontrolled preparation of the steroidal side chain in
natural and/or unnatural form showed a high possibility
M in hexane, 1.8 mL, 2.79 mmol), and the resulting solution
was stirred for 1 h at -78 °C. A solution of 1a (200 mg, 1.06
mmol) in THF (3 mL) was added and the reaction mixture was
warmed to room temperature. After 3 h, acetone (0.16 mL,
.18 mmol) was added dropwise while cooling to 0 °C, and the
mixture was stirred for 5 h at room temperature. The mixture
was quenched with aqueous HCl (1 M) while cooling on an ice
of constructing the analog of the steroidal side chain.
2
Exp er im en ta l Section
bath and extracted with Et
washed with water, NaHCO3 and brine, dried (MgSO ),
2
O. The organic extracts were
All nonaqueous reactions were carried out under an argon
atmosphere with dry, freshly distilled solvents under anhy-
4
filtered, and concentrated in vacuo to give a crude oil.
drous conditions. Tetrahydrofuran (THF), diethyl ether (Et
and dimethoxyethane (DME) were distilled from sodium
benzophenone ketyl. Dichloromethane (CH Cl ) and toluene
2
O),
Purification by column chromatography (hexane:EtOAc ) 20:1
1
f 5:1) yielded 5a (228 mg, 86%) as a colorless oil.
H NMR
2
2
(400 MHz, CDCl ) δ 1.03 (d, J ) 6.7 Hz, 3 H), 1.19 (s, 3 H),
3
were distilled from calcium hydride. NMR spectra were
1.20 (s, 3 H), 1.63 (bs, 1 H), 2.17 (d, J ) 6.7 Hz, 2 H), 2.47 -
2.57 (m, 1 H), 3.31 (dd, J ) 6.7, 8.9 Hz, 1 H), 3.35 (dd, J ) 6.7,
8.9 Hz, 1 H), 4.51 (s, 2 H), 5.47 (dd, J ) 6.7, 15.5 Hz, 1 H),
1
measured at 300 and 400 MHz for H and 75.5 or 100.6 MHz
1
3
for C. Materials were obtained from commercial suppliers
and used without further purification unless otherwise noted.
n-Butyllithium was purchased from Aldrich Chemical Co. as
a 1.6 M solution in hexane. Fuji silysia silica gel BW80S was
used for column chromatography, and prepacked columns
CPS-223L-1 (Kusano Kagaku Kikai Works Co., J apan) were
used for medium pressure liquid chromatography (MPLC).
5.54 (ddd, J ) 6.7, 15.5, 15.5 Hz, 1 H), 7.26-7.36 (m, 5 H); 13
C
NMR (75.5 MHz, CDCl ) δ 17.2, 28.9, 29.1, 37.1, 46.9, 70.2,
3
72.9, 75.2, 125.2, 127.5, 127.6, 128.3, 137.7, 138.5; IR (neat) ν
3393 (br), 2969, 1096 cm-1; EIMS m/ z 230 (M
+
- H O). Anal.
2
Calcd for C H O : C, 77.38; H, 9.74. Found: C, 77.64; H,
1
6
24
2
9.66.
(
E)-2-[(Ben zyloxy)m eth yl]-3-p en ten e (3, X ) H). To a
solution of zirconocene dichloride (403 mg, 1.38 mmol) in THF
3 mL) cooled to -78 °C was added dropwise nBuLi (1.41 M
(E)-2,6-Dim et h yl-8-p h en yl-4-oct en -2-ol (5b ). Experi-
mental procedure was same as the procedure described for 5a .
1
(
H NMR (400 MHz, CDCl ) δ 1.04 (d, J ) 6.7 Hz, 3 H), 1.22
3
in hexane, 2.0 mL, 2.82 mmol), and the resulting solution was
stirred for 1 h at -78 °C. A solution of 1a (200 mg, 1.06 mmol)
in THF (3 mL) was added, and the reaction mixture was
warmed to room temperature. After stirring for 5 h, the
mixture was quenched with aqueous HCl (1 M) while cooling
(s, 6 H), 1.48 (bs, 1 H), 1.57-1.62 (m, 2 H), 2.15-2.22 (m, 1
H), 2.19 (d, J ) 6.2 Hz, 2 H), 2.53-2.66 (m, 2 H), 5.40-5.46
(m, 1 H), 5.49 (dd, J ) 6.5, 15.3 Hz, 1 H), 7.15-7.29 (m, 5 H);
1
3
C NMR (75.5 MHz, CDCl ) δ 20.9, 29.1, 33.8, 36.6, 38.8, 47.0,
3
70.5, 81.2, 124.1, 125.6, 128.3, 128.4, 140.7, 142.7; IR (neat) ν
-
1
+
to 0 °C and extracted with Et
washed with water, NaHCO
2
O. The organic extracts were
and brine, dried (MgSO ),
3382 (br), 2968, 699 cm ; EIMS m/ z 217 (M - CH ). Anal.
3
3
4
Calcd for C H24O: C, 82.70; H, 10.41. Found: C, 82.35; H,
1
6
filtered, and concentrated in vacuo to give a crude oil.
10.60.
Purification by column chromatography (hexane:EtOAc ) 20:
(E)-6-Cycloh exyl-2-m eth yl-4-h ep ten -2-ol (5c). Experi-
mental procedure was same as the procedure described for 5a .
1
) followed by MPLC (hexane:EtOAc ) 100:1) yielded 3 (X )
1
1
H) (97 mg, 48%) as a colorless oil. H NMR (300 MHz, CDCl
3
)
H NMR (400 MHz, CDCl ) δ 0.92-0.97 (m, 2 H), 0.96 (d, J )
3
δ 1.01 (d, J ) 6.8 Hz, 3 H), 1.67 (d, J ) 6.0 Hz, 3 H), 2.41 -
6.9 Hz, 3 H), 1.08-1.24 (m, 4 H), 1.20 (s, 6 H), 1.50 (bs, 1 H),
1.62-1.73 (m, 5 H), 1.92-2.00 (m, 1 H), 2.16 (d, J ) 6.0 Hz, 2
H), 5.38 (dt, J ) 6.0, 15.3 Hz, 1 H), 5.43 (dd, J ) 6.9, 15.3 Hz,
2
9
5
1
.50 (m, 1 H), 3.26 (dd, J ) 7.1, 9.1 Hz, 1 H), 3.35 (dd, J ) 6.4,
.1 Hz, 1 H), 4.52 (s, 2 H), 5.33-5.56 (m, 2 H), 7.26-7.35 (m,
1
3
13
H); C NMR (75.5 MHz, CDCl
3
) δ 17.3, 18.1, 36.9, 72.9, 75.5,
1 H); C NMR (75.5 MHz, CDCl ) δ 17.9, 26.6, 26.7, 29.1, 30.4,
3
+
24.6, 127.4, 127.5, 128.3, 133.9; EIMS m/ z 190 (M ); HRMS
18O: 190.1358, found: 190.1360.
30.5, 42.6, 43.1, 47.0, 70.4, 124.0, 140.0; IR (neat) ν 3373 (br),
-
1
+
calcd for C13
H
2925, 2852 cm ; EIMS m/ z 195 (M - CH ). Anal. Calcd
3
(
E)-1-(Ben zyloxy)-2-m eth yl-d -3-p en ten e-5-d (3, X ) D).
for C14H26O: C, 79.94; H, 12.46. Found: C, 79.54; H, 12.33.
3
The reaction mixture, which was obtained by the procedure
(E)-η -π-Allylzir con ocen e 6. Sample was prepared as in
the case of 4 except for the addition of acetone. H NMR (400
1
as described for compound 3 (X ) H), was quenched with DCl/
D
2
O (10%) while cooling to 0 °C. Extraction and purification
MHz, C D ) δ -0.94 (d, J ) 10.0 Hz, 1 H), -0.81 (d, J ) 10.0
6
6
by column chromatography yielded 3 (X ) D) (90 mg, 59%) as
Hz, 1 H), 1.00 (s, 3 H), 1.28 (dd, J ) 4.5, 14.2 Hz, 1 H), 1.37 (s,
3 H), 2.21 (dd, J ) 4.5, 7.7 Hz, 1 H), 3.03 (d, J ) 16.9 Hz, 1
H), 4.21 (ddd, J ) 7.7, 14.2, 16.9 Hz, 1 H), 5.19 (s, 5 H), 5.27
(s, 5 H); 13C NMR (100.6 MHz, C D ) δ -14.8, 26.1, 33.4, 37.2,
1
a colorless oil. H NMR (400 MHz, CDCl ) δ 1.00-1.05 (m, 2
3
H), 1.64-1.69 (m, 2 H), 2.41-2.50 (m, 1 H), 3.27 (dd, J ) 7.1,
9
5
.1 Hz, 1 H), 3.36 (dd, J ) 6.4, 9.1 Hz, 1 H), 4.53 (s, 2 H),
6
6
13
.37-5.54 (m, 2 H), 7.26-7.38 (m, 5 H); C NMR (100.6 MHz,
) δ 17.0 (t), 17.8 (t), 36.8, 72.9, 75.5, 124.6, 127.4, 127.5,
40.6, 83.5, 104.0, 104.2, 104.5.
3
(E)-5,5-Dim eth yl-1-p h en yl-3-h exen -1-ol (7). 1H NMR
CDCl
28.3, 133.9, 138.7; EIMS m/ z 192 (M ); HRMS calcd for
O: 192.1483, found: 192.1485.
OBn ). To a solution of
+
1
(400 MHz, CDCl ) δ 1.00 (s, 9 H), 2.08 (bs, 1 H), 2.38-2.49
3
C
13
H
16
D
2
(m, 2 H), 4.68 (dd, J ) 4.9, 7.8 Hz, 1 H), 5.32 (ddd, J ) 6.6,
Oxa zir con a cycle 4 (R ) CH
2
7.7, 15.6 Hz, 1 H), 5.59 (dt, J ) 1.2, 15.6 Hz, 1 H), 7.25-7.36
(m, 5 H); 13C NMR (100.6 MHz, CDCl
) δ 29.6, 33.1, 42.9, 73.5,
zirconocene dichloride (322 mg, 1.10 mmol) in THF (3 mL)
3
cooled to -78 °C was added dropwise nBuLi (1.56 M in hexane,
120.0, 125.8, 127.3, 128.3, 144.0, 146.3; IR (neat) ν 3421 (br),
-
1
+
1
1
.4 mL, 2.18 mmol), and the resulting solution was stirred for
h at -78 °C. A solution of vinylcyclopropane 1a (1.00 mmol)
2960, 701 cm ; EIMS m/ z 204 (M ); HRMS calcd for
20O: 204.1514, found: 204.1499.
14
C H
1
in THF (3 mL) was added, and the reaction mixture was
warmed to room temperature. After 6 h, acetone (0.15 mL,
(E)-η -σ-a llylzir con ocen e 9. Sample was prepared as in
1
6 6
the case of 6. H NMR (400 MHz, C D ) δ 1.31 (s, 6 H), 1.96
2
.04 mmol) was added dropwise while cooling to 0 °C, and the
(dd, J ) 1.2, 8.5 Hz, 2 H), 4.88 (s, 2 H), 5.04 (dd, J ) 1.6, 10.5
Hz, 1 H), 5.17 (dd, J ) 1.6, 17.4 Hz, 1 H), 5.21 (dt, J ) 1.2,
15.3 Hz, 1 H), 5.78 (s, 10 H), 5.91 (dt, J ) 8.5, 15.3 Hz, 1 H),
mixture was stirred for 3 h at room temperature. The solvent
was then concentrated to dryness in vacuo, and the residue
1
13
was dissolved in benzene-d
6
(2 mL). H NMR (400 MHz, C
6
D
6
)
6.11 (dd, J ) 10.5, 17.4 Hz, 1 H), 7.16-7.31 (m, 5 H); C NMR
δ 0.59 (dd, J ) 2.8, 12.2 Hz, 1 H), 0.98 (s, 3 H), 1.05 (s, 3 H),
.25 (t, J ) 12.2 Hz, 1 H), 1.71 (t, J ) 11.5 Hz, 1 H), 2.09 (dd,
J ) 3.8, 11.5 Hz, 1 H), 2.93-3.00 (m, 1 H), 3.48 (dd, J ) 8.0,
(100.6 MHz, C D ) δ 28.4, 39.3, 44.2, 75.7, 109.3, 111.2, 111.7,
6
6
1
126.5, 127.1, 128.5, 134.9, 143.3, 149.5.
3,3-Dim eth yl-1-p h en yl-2-vin yl-4-p en ten -1-ol (10). Mp
1
9
.1 Hz, 1 H), 3.57 (dd, J ) 5.4, 9.1 Hz, 1 H), 4.62 (s, 1 H), 4.86
37.3-39.0 °C; H NMR (300 MHz, CDCl ) δ 1.11 (s, 3 H), 1.14
3
(
1
dd, J ) 10.1, 15.1 Hz, 1 H), 5.21 (ddd, J ) 3.8, 11.5, 15.1 Hz,
(s, 3 H), 1.99 (d, J ) 3.5 Hz, 1 H), 2.06 (dd, J ) 2.2, 10.2 Hz,
1 H), 4.67 (dd, J ) 2.2, 17.2 Hz, 1 H), 5.08-5.14 (m, 4 H), 5.93
1
3
H), 5.73 (s, 5 H), 5.76 (s, 5 H), 7.15-7.50 (m, 5 H); C NMR
) δ 30.1, 32.2, 36.2, 46.2, 47.7, 73.0, 79.5, 79.8,
09.7, 110.7, 122.8, 123.4, 127.8, 128.5, 140.1, 143.5.
E)-7-(Ben zyloxy)-2,6-d im eth yl-4-h ep ten -2-ol (5a ). To
1
3
(100.6 MHz, C
6
D
6
(dt, J ) 10.2 Hz, 1 H), 6.04 (dd, J ) 10.5, 17.9 Hz, 1 H);
C
1
NMR (75.5 MHz, CDCl ) δ 25.0, 26.6, 39.2, 61.9, 73.2, 112.0,
3
(
119.6, 125.8, 126.7, 127.7, 133.0, 144.6, 147.3; IR (KBr) ν 3358
-1
+
a solution of zirconocene dichloride (403 mg, 1.38 mmol) in
THF (3 mL) cooled to -78 °C was added dropwise nBuLi (1.55
(br), 2965, 918 cm ; EIMS m/ z 107 (M - H
2
7 7
O - C H ). Anal.
Calcd for C15H20O: C, 83.29; H, 9.32. Found: C, 82.92; H, 9.40.

4
000 J . Org. Chem., Vol. 62, No. 12, 1997
3R *,6R *)-(E )-6-Cycloh e xyl-2,3-d im e t h yl-4-h e p t e n -
-ol (14a ). To a solution of zirconocene dichloride (380 mg,
.30 mmol) in THF (3 mL) cooled to -78 °C was added
Harada et al.
7.26-7.36 (m, 5 H); 13C NMR (75.5 MHz, CDCl
(
3
) δ 16.5 (t),
33.3, 38.0, 73.0, 75.3, 115.9, 127.4, 127.5, 128.3, 137.0, 138.8;
2
1
+
EIMS m/ z 191 (M ); HRMS calcd for C13H17DO: 191.1420,
dropwise nBuLi (1.64 M in hexane, 1.6 mL, 2.62 mmol), and
the resulting solution was stirred for 1 h at -78 °C. A solution
of cis-12 (Z/ E ) 2.8, 164 mg, 1.00 mmol) in THF (3 mL) was
added, and the reaction mixture was warmed to room tem-
perature. After stirring for 5 h, the mixture was heated to
reflux at 70 °C for 12 h. Acetone (0.15 mL, 2.04 mmol) was
added dropwise while cooling to 0 °C, and the mixture was
stirred for 5 h at room temperature. The mixture was
quenched with aqueous HCl (1 M) while cooling on an ice bath
found: 191.1422.
Cyclop r op a n a tion of 23. By Ta r tr a te Ad d ition . To a
solution of 23 (200 mg, 0.45 mmol) in toluene cooled to -30
°C were added a solution of (+)-L-dibutyl tartrate (118 mg, 0.45
mmol) in toluene (5 mL) and diethylzinc (1.0 M solution in
hexane, 4.5 mL, 4.5 mmol), and the resulting mixture was
stirred for 15 min at -30 °C. While cooling to -30 °C,
diiodomethane (0.36 mL, 4.5 mmol) was added, and the
mixture was stirred for 6 h at -30 °C. The mixture was
quenched with aqueous HCl (1 M) on an ice bath and extracted
and extracted with Et
with water, NaHCO and brine, dried (MgSO
2
O. The organic extracts were washed
3
4
), filtered, and
with toluene. The organic extracts were washed with Na
2
-
concentrated in vacuo to give a crude oil. Purification by
SO , NaHCO and brine, dried (MgSO ), filtered, and concen-
3
3
4
column chromatography (hexane:EtOAc ) 10:1 f 3:1) yielded
trated in vacuo to give a crude solid. Purification by column
chromatography (toluene:EtOAc ) 10:1) yielded an inseparable
mixture of 24 and 25 (187 mg, 91%, 24:25 ) 97:3 ratio). The
same procedure in the presence of 2-3 equiv of (-)-D-
diisopropyl tartrate instead of (+)-L-dibutyl tartrate gave
R-cyclopropanemethanol 25 as a major product (24:25 ) 27:
73) in 76-83% yield.
1
alcohol 14a (112 mg, 50%) as a colorless oil. H NMR (300
MHz, CDCl
3
) δ 0.85-1.02 (m, 2 H), 0.95 (d, J ) 6.9 Hz, 3 H),
1
1
6
)
2
1
.01 (d, J ) 6.9 Hz, 3 H), 1.05-1.22 (m, 4 H), 1.13 (s, 3 H),
.17 (s, 3 H), 1.57-1.73 (m, 6 H), 1.93 (m, 1 H), 2.14 (dq, J )
.9, 8.5 Hz, 1 H), 5.28 (dd, J ) 8.5, 15.4 Hz, 1 H), 5.41 (dd, J
1
3
3
7.9, 15.4 Hz, 1 H); C NMR (75 MHz, CDCl ) δ 15.9, 17.9,
6.3, 26.6, 26.7, 27.0, 30.4, 30.5, 42.5, 43.1, 48.4, 72.3, 130.4,
By Ch a r ette’s Meth od .17 To a mixture of dioxaborolane
(134 mg, 0.5 mmol), 23 (200 mg, 0.45 mmol), and molecular
sieves (4 Å) (20 mg) in CH Cl (3 mL) cooled to -15 °C was
-
1
37.6; IR (neat) ν 3431 (br), 2927, 2853 cm ; EIMS m/ z 209
+
(M
- CH
Found: C, 79.90; H, 12.58.
3R*,6R*)-(E)-6-Cycloh exyl-2,3-d im et h yl-2-[(3,5-d in i-
3
). Anal. Calcd for C15H28O: C, 80.29; H, 12.58.
2
2
added the previously prepared solution of Zn(CH I) ‚DME
2
2
(
complex (2.25 mmol in 3 mL of CH
mixture was stirred at -15 °C for 6 h. The mixture was then
quenched with aqueous NH Cl, and the layers were separated.
2 2
Cl ), and the resulting
tr oben zoyl)oxy]-4-h ep ten e. To a solution of alcohol 14a (32
mg, 0.14 mmol) and 4-(dimethylamino)pyridine (1 mg) in dry
pyridine (3 mL) was added slowly 3,5-dinitrobenzoyl chloride
4
The aqueous layer was extracted with toluene, and the
combined organic extracts were stirred vigorously for 12 h with
aqueous KOH (5 M). The layers were separated, and the
(
5
49 mg, 0.21 mmol), and the resulting mixture was heated at
0 °C for 24 h. After being quenched with water, the mixture
was extracted with CH Cl , and the organic extracts were
washed with aqueous HCl (10%), distilled water, and NaHCO
dried (MgSO ), filtered, and concentrated in vacuo to give a
2
2
organic layer was washed with aqueous HCl (1 M), NaHCO
3
,
3
,
water and brine, dried (MgSO ), filtered, and concentrated in
4
4
vacuo to give a crude solid. Purification by column chroma-
crude solid. Purification by column chromatography (hexane:
EtOAc ) 20:1 f 10:1) followed by recrystallized (hexane-
EtOAc) yielded benzoate (47 mg, 79%) as colorless crystals.
tography (toluene:EtOAc ) 10:1) yielded 24 and 25 (186 mg,
90%, 24:25 ) 11:89, inseparable mixture) as a white solid.
1
Cyclop r op a n em eth a n ol 24: H NMR (400 MHz, CDCl
3
) δ
1
Mp 83.1-86.3 °C; H NMR (300 MHz, CDCl
3
) δ 0.83 (d, J )
-0.06 (dd, J ) 5.5, 9.9 Hz, 1 H), 0.02-0.06 (m, 1 H), 0.05 (s,
6 H), 0.72 (s, 3 H), 0.89 (s, 9 H), 1.01 (s, 3 H), 3.33-3.40 (m, 1
H), 3.42-3.53 (m, 1 H), 3.78-3.84 (m, 1 H), 5.31-5.32 (m, 1
6
.9 Hz, 3 H), 0.82-0.89 (m, 2 H), 1.05-1.16 (m, 5 H), 1.10 (d,
J ) 6.9 Hz, 3 H), 1.56-1.67 (m, 4 H), 1.59 (s, 3 H), 1.61 (s, 3
H); 13C NMR (100.6 MHz, CDCl
) δ -4.6, 7.5, 13.0, 16.2, 18.3,
H), 1.89 (m, 1 H), 2.97 (dq, J ) 6.9, 8.0 Hz, 1 H), 5.29 (dd, J
3
)
8.2, 15.4 Hz, 1 H), 5.43 (dd, J ) 8.0, 15.4 Hz, 1 H), 9.07 (d,
19.0, 19.5, 20.9, 24.4, 25.9, 28.8, 31.9, 32.1, 36.7, 37.4, 38.1,
42.1, 42.8, 50.1, 50.4, 56.1, 63.8, 72.6, 121.0, 141.6.
1
3
J ) 2.1 Hz, 2 H), 9.19 (t, J ) 2.1 Hz, 1 H); C NMR (75.5
MHz, CDCl ) δ 15.9, 17.7, 23.4, 23.6, 26.58, 26.64, 30.39, 30.44,
2.5, 43.0, 45.3, 89.0, 121.9, 129.0, 129.2, 135.8, 135.5, 148.5,
1
3
Cyclop r op a n em eth a n ol 25: H NMR (400 MHz, CDCl )
3
4
1
δ 0.06 (s, 6 H), 0.74 (s, 3 H), 0.89 (s, 9 H), 1.01 (s, 3 H), 3.42-
-
1
+
13
61.2; IR (KBr) ν 1714, 1542, 1346 cm ; CIMS m/ z 417 (M
1). Anal. Calcd for C22 : C, 63.14; H, 7.23; N, 6.69.
Found: C, 63.06; H, 7.31; N, 6.63.
-(Ben zyloxy)-2-m eth yl-4-p en ten e (19, X ) H). To a
3.53 (m, 1 H), 3.57-3.61 (m, 1 H), 5.31-5.32 (m, 1 H); C NMR
-
H
30
N
2
O
6
(100.6 MHz, CDCl ) δ -4.6, 8.2, 13.0, 16.1, 16.2, 18.3, 19.5,
3
20.8, 24.8, 25.9, 28.8, 31.9, 32.0, 32.1, 36.7, 37.4, 38.4, 42.8,
43.0, 50.2, 50.6, 63.4, 72.6, 121.1, 141.6.
1
solution of 1a and zirconocene dichloride (44 mg, 30 mol %) in
THF (3 mL) cooled to 0 °C was added dropwise nBuMgCl (0.90
M in THF, 1.7 mL, 1.53 mmol), and the resulting solution was
heated to reflux for 20 min. The reaction mixture was
quenched with aqueous HCl (1 M) while cooling to 0 °C and
P r ep a r a tion s of 27, 30. To a solution of a mixture of 24
and 25 (24:25 ) 97:3 or 11:89) (133 mg, 0.29 mmol) in CH Cl
2
2
(10 mL) cooled to 0 °C was added Dess-Martin periodinane
(185 mg, 0.44 mmol), and the resulting mixture was stirred
for 2 h at 0 °C. The mixture was quenched with Na S O and
2
2
3
extracted with Et
water, NaHCO
concentrated in vacuo to give a crude oil. Purification by
2
O. The organic extracts were washed with
and brine, dried (MgSO ), filtered, and
extracted with toluene. The organic extracts were washed
with NaHCO and brine, dried (MgSO ), filtered, and concen-
3
4
3
4
trated in vacuo to give a crude solid 26 or 29 (ca. 120 mg). To
a suspension of methyltriphenylphosphonium bromide (156
mg, 0.44 mmol) in THF (5 mL) cooled to 0 °C was added nBuLi
(1.43 M, 0.31 mL, 0.44 mmol), and the resulting mixture was
stirred for 1 h at 0 °C. A solution of crude aldehyde 26 or 29
(50 mg, 0.11 mmol) in THF (5 mL) was added via a cannula,
and the mixture was stirred for additional 12 h at room
column chromatography (hexane:EtOAc ) 30:1) yielded 19 (X
1
)
H) (53 mg, 56%) as a colorless oil. H NMR (300 MHz,
CDCl ) δ 0.94 (d, J ) 6.5 Hz, 3 H), 1.82-1.98 (m, 2 H), 2.18-
3
2
9
7
.28 (m, 1 H), 3.28 (dd, J ) 6.0, 9.0 Hz, 1 H), 3.35 (dd, J ) 6.3,
.0 Hz, 1 H), 4.51 (s, 2 H), 4.99-5.05 (m, 2 H), 5.79 (ddt, J )
.0, 10.1, 17.1 Hz, 1 H), 7.26-7.36 (m, 5 H); 13C NMR (75.5
MHz, CDCl
3
) δ 16.8, 33.4, 38.1, 73.0, 75.3, 115.9, 127.4, 127.5,
temperature. The mixture was quenched with NH Cl and
4
+
1
C
28.3, 137.0, 138.8; EIMS m/ z 190 (M ); HRMS calcd for
18O: 190.1358, found: 190.1344.
extracted with toluene. The organic extracts were washed
13
H
with brine, dried (MgSO ), filtered, and concentrated in vacuo
4
1
-(Ben zyloxy)-2-m eth yl-d -4-p en ten e (19, X ) D). The
to give a crude solid. Purification by column chromatography
(toluene) yielded vinylcyclopropane 27 or 30 (48 mg, 96%) as
a white solid. Vin ylcyclop r op a n e 27: H NMR (300 MHz,
reaction mixture, which was obtained by the procedure as
described for compound 19 (X ) H), was quenched with DCl/
O (10%) while cooling to 0 °C. Extraction and purification
1
D
2
3
CDCl ) δ 0.06 (s, 6 H), 0.14-0.19 (m, 1 H), 0.71 (s, 3 H), 0.89
by column chromatography yielded 19 (X ) D) (32%) as a
(s, 9 H), 1.00 (s, 3 H), 3.42-3.53 (m, 1 H), 4.90 (dd, J ) 2.0,
10.2 Hz, 1 H), 5.04 (dd, J ) 2.0, 17.0 Hz, 1 H), 5.31-5.32 (m,
1
colorless oil. H NMR (300 MHz, CDCl ) δ 0.91-0.95 (m, 2
3
1
3
H), 1.83-1.98 (m, 2 H), 2.19-2.28 (m, 1 H), 3.28 (dd, J ) 6.0,
1 H), 5.58 (ddd, J ) 8.9, 10.2, 17.0 Hz, 1 H); C NMR (75.5
9
4
.0 Hz, 1 H), 3.34 (dd, J ) 6.1, 9.0 Hz, 1 H), 4.51 (s, 2 H),
.99-5.05 (m, 2 H), 5.79 (ddt, J ) 6.9, 10.2, 17.0 Hz, 1 H),
MHz, CDCl
3
) δ -4.6, 10.8, 13.0, 18.3, 19.3, 19.5, 20.4, 20.8,
24.6, 26.0, 28.6, 32.0, 32.1, 36.7, 37.4, 38.5, 42.5, 42.8, 50.0,

Complexation of Vinylcyclopropanes with Zirconocene-1-Butene
0.5, 56.2, 72.6, 112.7, 121.1, 140.0, 141.6. Vin ylcyclop r o-
J . Org. Chem., Vol. 62, No. 12, 1997 4001
5
Purification by column chromatography (toluene:EtOAc ) 5:1)
followed by recrystallization (MeOH) yielded pure 28 (12 mg,
60% yield from the calculated amount of 27) as a white solid.
The NMR spectra of the synthesized product 28 was identical
1
p a n e 30: H NMR (300 MHz, CDCl
J ) 5.0, 9.3 Hz, 1 H), 0.73 (s, 3 H), 0.89 (s, 9 H), 1.02 (s, 3 H),
.43-3.54 (m, 1 H), 4.94 (dd, J ) 2.1, 10.2 Hz, 1 H), 5.08 (dd,
J ) 2.1, 17.0 Hz, 1 H), 5.31-5.32 (m, 1 H), 5.61 (ddd, J ) 8.5,
3
) δ 0.06 (s, 6 H), 0.33 (dd,
3
2
7
to the authentic sample: mp 204.5-207.1 °C, [R] ) -54.48°
D
0.2, 17.0 Hz, 1 H); 13C NMR (75.5 MHz, CDCl
) δ -4.6, 11.7,
12v
1
1
3
1
3
(c 0.41, CHCl ) {lit.
mp 205-205.5 °C, [R]D ) -54.35° (c
3
3.0, 17.6, 18.3, 19.1, 19.5, 20.8, 24.7, 25.9, 27.9, 31.9, 32.0,
2.1, 36.7, 37.4, 38.4, 42.8, 50.6, 50.9, 55.9, 72.6, 113.6, 121.1,
38.8, 141.6. Anal. Calcd for C30H50OSi: C, 79.23; H, 11.08.
0.471, CHCl )}.
3
Ster oid 21 (R′ ) H). The experimental procedure was the
same as that described for the preparation of 28. The major
isomeric mixture of vinylcyclopropane 30 (15 mg, 0.03 mmol,
Found: C, 79.01; H, 10.86 (as a mixture of 29 and 32).
P r ep a r a tion of 31. To a suspension of ethyltriphenylphos-
phonium bromide (163 mg, 0.44 mmol) in THF (5 mL) cooled
to 0 °C was added nBuLi (1.43 M, 0.31 mL, 0.44 mmol), and
the resulting mixture was stirred for 1 h at 0 °C. A solution
of crude aldehyde 27 (50 mg, 0.11 mmol, 26:29 ) 27:73) in
THF (5 mL) was added, and the mixture was stirred for 12 h
2
7:30 ) 27:73) was treated with “Cp
to give acetone-adduct. The adduct was deprotected by HF-
CH CN-toluene, and the resulting crude solid was purified
2
Zr” followed by acetone
3
and recrystallized (MeOH) to give pure 21 (R′ ) H) (5 mg, 47%
yield from the calculated amount of 32). The synthesized
material 21 (R′ ) H) was identical to an authentic sample:
at room temperature. The mixture was quenched with NH
Cl and extracted with toluene. The organic extracts were
washed with brine, dried (MgSO ), filtered, and concentrated
4
-
mp 175.0-177.3 °C, [R]28
) -51.42° (c 0.35, CHCl
) -51.38° (c 0.253, CHCl )}.
). The experimental procedure was
) {lit.
12v
D
3
mp 178.0-178.5 °C, [R]
Ster oid 21 (R′ ) CH
D
3
4
3
in vacuo to give a crude solid. Purification by column chro-
matography (toluene) yielded (1-propenyl)cyclopropane (51 mg,
the same as that described for the preparation of 14a . The
E/ Z mixture of (1-propenyl)cyclopropane 31 (11 mg, 0.02
9
3
5
9%, E:Z ) 22:78, inseparable mixture) as a white solid. (Z)-
1
mmol) was treated with “Cp
ization and the addition of acetone to give acetone-adduct (6
mg, 45%). The adduct was deprotected by HF-CH CN-
toluene, and the resulting crude solid was purified and
recrystallized (MeOH) to give pure 21 (R′ ) CH ). The
2
Zr” followed by thermal isomer-
1: H NMR (300 MHz, CDCl
3
) δ 0.06 (s, 6 H), 0.21 (dd, J )
.2, 9.7 Hz, 1 H), 0.73 (s, 3 H), 0.89 (s, 9 H), 1.01 (s, 3 H), 1.71
(
1
dd, J ) 1.6, 6.8 Hz, 3 H), 3.43-3.53 (m, 1 H), 5.10 (ddq, J )
3
.6, 9.1, 10.6 Hz, 1 H), 5.31-5.32 (m, 1 H), 5.37-5.55 (m, 1
1
3
H); the characteristic C NMR signals (75.5 MHz, CDCl
1
1
characteristic H NMR signals of (E)-31: H NMR (300 MHz,
CDCl
8
3
) δ
52OSi: C, 79.42; H,
1.18. Found: C, 79.23; H, 11.10 (as an E/ Z mixture). The
3
3
synthesized material 21 (R′ ) CH ) was identical to an
21.1, 124.2, 130.7. Anal. Calcd for C31H
3
0
authentic sample: mp 166.6-168.0 °C, [R]
D
) -92.86° (c
1
1
0.11, CHCl ) (lit.13 mp 168.5-169.5 °C).
3
3
) δ 1.67 (dd, J ) 1.6, 6.4 Hz, 3 H), 5.22 (ddq, J ) 1.6,
.5, 15.2 hz, 1 H).
P r ep a r a tion of Ster oid s 28, 21. Ster oid 28. Compound
7 (32 mg, 0.07 mmol) was treated with “Cp Zr” and acetone
Su ppor tin g In for m ation Available: Procedures and char-
acterization data of the intermediates for 1, 12, and 23, copies
2
2
1
13
of H and C NMR spectra for all new compounds without
elementary analysis data and synthesized steroids (21, 28),
and an ORTEP drawing for 3,5-dinitrobenzoate of 14a (64
pages). This material is contained in libraries on microfiche,
immediately follows this article in the microfilm version of the
journal, and can be ordered from the ACS; seen any current
masthead page for ordering information.
as described for 5a to give acetone-adduct (25 mg, 68%). To a
solution of acetone-adduct (19 mg, 0.03 mmol) in toluene (1
mL) and CH CN (1 mL) cooled to 0 °C was added dropwise
3
aqueous HF (46%, 0.11 mL), and the resulting mixture was
stirred for 2 h at room temperature. The mixture was diluted
with toluene and water, separated, and extracted with toluene.
The organic extracts were washed with water, dried (MgSO
4
),
filtered, and concentrated in vacuo to give a crude solid.
J O962064R