Tandem enantioselective conjugate addition--cyclopropanation. Application to natural products synthesis.

Article abstract of DOI:10.1021/jo026262w

A tandem asymmetric conjugate addition-cyclopropanation was developed, in which a cyclic or linear enone was converted to a TMS-protected 3-substituted-cyclopropanol in an efficient one-pot reaction. These compounds were then selectively cleaved to yield alpha-methyl-beta-alkyl ketones, alpha-methylene-enones, or chain extended gamma-alkyl-enones. This methodology was applied to the formal total synthesis of (-)-(S,S)-clavukerin A and (+)-(R,S)-isoclavukerin.

Full text of DOI:10.1021/jo026262w

Ta n d em En a n tioselective Con ju ga te Ad d ition -Cyclop r op a n a tion .
Ap p lica tion to Na tu r a l P r od u cts Syn th esis
Alexandre Alexakis* and Se´bastien March
Department of Organic Chemistry, University of Geneva, 30 quai Ernest-Ansermet,
Geneva 4, Switzerland CH-1211
alexandre.alexakis@chiorg.unige.ch
Received J uly 30, 2002
A tandem asymmetric conjugate addition-cyclopropanation was developed, in which a cyclic or
linear enone was converted to a TMS-protected 3-substituted-cyclopropanol in an efficient one-pot
reaction. These compounds were then selectively cleaved to yield R-methyl-â-alkyl ketones,
R-methylene-enones, or chain extended γ-alkyl-enones. This methodology was applied to the formal
total synthesis of (-)-(S,S)-clavukerin A and (+)-(R,S)-isoclavukerin.
In tr od u ction
Asymmetric carbon-carbon bond formation is still a
challenge in catalysis. Recent years have seen tremen-
dous advances in the 1,4-addition of organometallic
reagents to R,â-unsaturated ketones.1 We and others
have developed procedures for the use of catalytic copper
salts and chiral ligands (such as those illustrated in
Figure 1) with organozinc reagents, to give conjugate
addition products in good yield and ee.2
The nucleophilicity of the intermediate zinc enolate is
of interest. Noyori showed that aldehydes react with
these enolates,3 and we demonstrated that the reaction
could be extended to chiral acetals in the presence of a
Lewis acid such as BF3‚OEt2.4
F IGURE 1. Ligands used for the conjugate addition.
our group5 could be exploited to afford the desired zinc-
enolate substrate. A small modification was that 3 equiv
of diorganozinc reagent were used instead of the usual
ratio of 1.3. Thus, the only additional reactant needed to
afford the cyclopropanation was diiodomethane. Since the
cyclopropanol is known to be unstable,6 the possibility
of in situ silylation was examined. Conditions were found
that efficiently lead to enantiomerically pure or highly
enriched protected cyclopropanols in a single pot (Scheme
1).
In this paper, we report the use of the double bond of
this zinc enolate as a starting point for cyclopropanation.
The general conjugate addition conditions developed by
(1) For recent reviews see: (a) Alexakis, A.; Benhaim, C. Eur. J .
Org. Chem. 2002, 3221. (b) Krause, N.; Hoffmann-Ro¨der, A. Synthesis
2001, 171. (c) Sibi, M. P.; Manyem, S. Tetrahedron 2000, 56, 8033. (d)
Tomioka, K.; Nagaoka, Y. In Comprensive Asymmetric Catalysis I-III;
J acobsen, E. N., Pfaltz, A., Yamamoto, H., Eds.; Springer: New York,
1999; p 1105.
The cyclopropane rings were then selectively cleaved
in different ways (see Scheme 2). If the cleavage was
induced by a Lewis acid, an R-methyl-â-alkyl ketone was
cleanly obtained. Bromination followed by a dehydrobro-
mination step afforded selectively an R-methylene-â-alkyl
ketone. Radical-induced opening of the cyclopropane ring
led efficiently to a γ-alkyl expanded chain enone. In all
these opening reactions, the optical purity of the alkyl
group remained unchanged, allowing the products to be
used as valuable and easily accessible chiral building
blocks.
(2) (a) Alexakis, A. Pure Appl. Chem. 2002, 74, 37. (b) Degrado, S.
J .; Mizutani, H.; Hoveyda, A. H. J . Am. Chem. Soc. 2002, 124, 779. (c)
Degrado, S. J .; Mizutani, H.; Hoveyda, A. H. J . Am. Chem. Soc. 2001,
123, 755. (d) Alexakis, A.; Rosset, S.; Allamand, J .; March, S.; Guillen,
F.; Benhaim, C. Synlett 2001, 1375. (e) Yan, M.; Zhou, Z.-Y.; Chan, A.
S. C. Chem. Commun. 2000, 115. (f) Escher, I. H.; Pfaltz, A. Tetrahe-
dron 2000, 56, 2879. (g) Helmchen, G.; Pfaltz, A. Acc. Chem. Res. 2000,
33, 336. (h) Bennett, S. M. W.; Brown, S. M.; Cunningham, A.; Dennis,
M. R.; Muxworthy, J . P.; Oakley, M. A.; Woodward, S. Tetrahedron
2000, 56, 2847. (i) Alexakis, A.; Benhaim, C.; Fournioux, X.; Van der
Heuvel, A.; Leveˆque, J .-M.; March, S.; Rosset, S. Synlett 1999, 1811.
(j) Bennett, S. M. W.; Brown, S. M.; Conole, G.; Dennis, M. R.; Fraser,
P. K.; Radojevic, S.; McPartlin, M.; Topping, C. M.; Woodward, S. J .
Chem. Soc., Perkin Trans. 1 1999, 3127. (k) Bennett, S. M. W.; Brown,
S. M.; Muxworthy, J . P.; Woodward, S. Tetrahedron Lett. 1999, 40,
1767. (l) Reetz, M. T. Pure Appl. Chem. 1999, 71, 1503. (m) Hu, X.;
Chen, H.; Zhang, X. Angew. Chem., Int. Ed. 1999, 38, 3518. (n) Kno¨bel,
A. K. H.; Escher, I. H.; Pfaltz, A. Synlett 1997, 1429. (o) Feringa, B.
L.; Pineschi, M.; Arnold, L. A.; Imbos, R.; De Vries, A. H. M. Angew.
Chem., Int. Ed. 1997, 36, 2620.
Resu lts a n d Discu ssion
P r ep a r a tion of P r otected Cyclop r op a n ols. Pre-
liminary experiments following Saegusa’s procedure7
showed that cyclopropanation was best achieved in
(5) Alexakis, A.; Benhaim, C.; Rosset, S.; Humam, M. J . Am. Chem.
Soc. 2002, 124, 5262.
(3) (a) Kitamura, M.; Miki, T.; Nakano, K.; Noyori, R. Bull. Chem.
Soc. J pn. 2000, 73, 999. (b) Kitamura, M.; Miki, T.; Nakano, K.; Noyori,
R. Tetrahedron Lett. 1996, 37, 5141.
(4) Alexakis, A.; Trevitt, G. P.; Bernardinelli, G. J . Am. Chem. Soc.
2001, 123, 4358.
(6) (a) Gibson, D. H.; DePuy, C. H. Chem. Rev. 1974, 74, 605. (b)
DePuy, C. H. Acc. Chem. Res. 1968, 1, 33.
(7) (a) Ito, Y.; Fujii, S.; Nakatsuka, M.; Kawamoto, F.; Saegusa, T.
Org. Synth. 1980, 59, 113. (b) Ito, Y.; Fujii, S.; Saegusa, T. J . Org.
Chem. 1976, 41, 2073.
10.1021/jo026262w CCC: $22.00 © 2002 American Chemical Society
Published on Web 11/16/2002
J . Org. Chem. 2002, 67, 8753-8757
8753

Alexakis and March
SCHEME 1. Ta n d em Asym m etr ic Con ju ga te Ad d ition -Cyclop r op a n a tion
SCHEME 2. Selective Op en in g of th e
Cyclop r op a n e Rin g
SCHEME 3. Op en in g of th e Cyclop r op a n e Rin g
a
Mn(pic)3: manganese(III) pyridine-2-carboxylate.
dichloromethane rather than in ether or toluene although
the chemical yields were in all cases low. There are two
different ways to obtain the silylated cyclopropanol,
either the zinc enolate can be submitted to cyclopropa-
nation and then silylated or the zinc enolate can be first
silylated then cyclopropanated.
The first attempts of direct cyclopropanation on the
zinc enolate 5a followed by silylation were disappointing.
The reaction was not reproducible and once led to the
desired compound 6a , but another case gave the rear-
ranged derivative 7a .
in a single vessel, hence we needed to find conditions for
the silylation which were compatible with the excess of
diorganozinc used. In practice, the transformation of the
zinc enolate was very efficiently achieved with 1.5 equiv
of TMSOTf at room temperature.9 This reagent led to a
very efficient silylation of the conjugated adduct and did
not react at all with the excess of zinc reagent. The
formed silyl enol ether was then submitted to the
cyclopropanation conditions by simply adding 2 equiv of
diiodomethane. This part of the reaction proved to be
sensitive to the concentration. It did not take place if the
reaction mixture was too diluted and the optimum
conditions were found to be 1 mL of dichloromethane for
1 mmol of substrate.
When these conditions were met, we were delighted
to isolate the desired protected cyclopropanol 6a with
excellent yield (95%) and enantiomeric excess (98%) in a
one-pot procedure with cyclohexenone as starting mate-
rial (Table 1, entry 1).
This methodology has been extended, without diffi-
culty, to cycloheptenone as well as benzalacetone, an acy-
clic enone (entries 2 and 4). The face selectivity of the
cyclopropanation was high (de 60-84%), although not
perfect. The approach of the carbenoid reagent probably
occurs from the less hindered face, trans to the R-sub-
stituent. In the case of the acyclic benzalacetone, only
two diastereoisomers among the 4 theoretical (two for
each E or Z silyl enol ether) were formed, as an insepa-
rable mixture. Purification by column chromatography
with silica was not necessary since the crude mixture did
This isomerization has already been reported in the
literature during the course of a Simmons-Smith reac-
tion on the silyl enol ether of cyclohexanone.8 It is
believed to be induced by the zinc(II) iodide formed as
the reaction proceeds, and is dependent on the concentra-
tion. The authors found that the amount of this unex-
pected derivative increased as the proportion of the
solvent was decreased. However, any attempt to repro-
duce this rearrangement from our silylated cyclopropanol
6a failed and only gave the corresponding R-methyl-â-
ethyl ketone 8a (see Scheme 3) with complete conversion.
Since the direct cyclopropanation of the zinc enolate was
not satisfying, we focused on another route.
During his sequence, which led to a ring expansion,
Saegusa reported a cyclopropanation of a cyclic silyl enol
ether.7 We decided to change the order of our sequence
and proceed to the silylation step directly after the
conjugate addition (Scheme 1). With this modification,
the cyclopropanation would take place on the more stable
silicon enolate. However, we wanted to keep this reaction
(8) (a) Ryu, I.; Murai, S.; Otani, S.; Sonoda, N. Tetrahedron Lett.
1977, 23, 1995. (b) Murai, S.; Aya, T.; Renge, T.; Ryu, I.; Sonoda, N. J .
Org. Chem. 1974, 39, 858.
(9) Knopff, O.; Alexakis, A. Org. Lett. 2002, 4, 0000.
8754 J . Org. Chem., Vol. 67, No. 25, 2002

Tandem Asymmetric Conjugate Addition-Cyclopropanation
TABLE 1. Ta n d em Con ju ga te Ad d ition -Cyclop r op a n a -
SCHEME 4. En a n tioselective F or m a l Tota l
Syn th esis of (-)-(S,S)-Cla vu k er in A a n d
(+)-(R,S)-Isocla vu k er in
tion
entry
prod
L*
CuX
yield,a
%
ee,b
%
de,c %
1
2
3
4
6a
6b
6c
6d
2
1
2
3
CuTCd
95
97
91
97
98 S
93 S
97 S
89 R
77
84
71
60
CuTCd
Cu(OTf)2
Cu(OAc)2‚H2O
a
b
Isolated yield after chromatographic purification. Deter-
mined by chiral GC on a quenched aliquot of 5. The absolute
stereochemistry corresponds to the conjugated adduct. c Deter-
mined by 13C NMR on an average of three carbons. CuTC:
d
copper(I) thiophene-2-carboxylate.
TABLE 2. Op en in g of th e Cyclop r op a n e Rin g
loss of material by evaporation. The desired R-methylene-
â-ethyl ketone 9a was obtained in 75% yield, again
without any racemization. It was also important not to
extend the reaction time for the elimination of HBr since
methanol reacted slowly with the reactive Michael ac-
ceptor which had formed, to give the linear methyl ester
(S)-11a .12
entry
prod
conditionsa
yield,b %
ee,c %
5
6
7
8
9
8a
9a
10a
10b
10c
10d
A
B
C
C
C
C
81
55 (75)
79
79
90
97
97
97
92
96
87d
10
41 (61)
a
Condition A: ZnI2. Condition B: (i) Br2, (ii) NaOAc, MeOH.
b
Condition C: (i) FeCl3, (ii) NaOAc, MeOH. Isolated yield after
chromatographic purification, crude 1H NMR yield in parentheses.
d
c Determined by chiral GC. Determined by chiral SFC.
not contain any other byproducts. This mixture of dia-
stereomers was not detrimental to the next planned tran-
sformations, as these stereocenters will disappear (see
Scheme 3).
Yields for these reactions ranged from 95% to 97% and
enantiomeric excesses were only slightly lower than those
obtained in the classical conjugate addition conditions.5
This may be due either to a concentration or to a solvent
effect. As mentioned earlier, our reaction was performed
in dichloromethane rather than in ether or toluene and
in a much more concentrated medium than the typical
procedure for the conjugate addition.
Clea va ge of th e Cyclop r op a n e Rin g. Having these
valuable compounds in hand, several opening reactions
of the cyclopropane ring were considered (Scheme 2). The
first was a selective cleavage of the bond “i” induced by
a stoichiometric amount of a Lewis acid, such as ZnI2,8
in ether at room temperature (Scheme 3).
The use of a low boiling point solvent was crucial since
the R-methyl-â-ethyl ketone 8a formed, despite its rela-
tively high boiling point, appeared to be very volatile. The
reaction was quantitative and very selective, and no
racemization was observed. Once the solvent had been
carefully removed, the desired ketone 8a could be ob-
tained in 81% isolated yield10 (Table 2).
The last method of opening the cyclopropane ring
selectively cleaves the bond “ii”. It was inspired by the
sequence of Saegusa, which led to a ring-expanded enone
after elimination of an intermediate â-chloro ketone.7
Applying this ring-opening reaction to our cyclopropanol
bearing a â-alkyl group gave access to the unusual
γ-functionalized enone in a stereoselective manner.
Thus, the three cyclic cyclopropanols gave the corre-
sponding ring-expanded enones in good yields and with-
out loss of enantiomeric excess. As expected, cleavage of
6d occurred exclusively via the more stable secondary
radical to give the extended chain enone 10d after
elimination of HCl from the intermediate â-chloro ketone.
Only trans olefin was formed, as judged by the coupling
constant between the two vinylic protons (J ) 16.1 Hz).
Again, no racemization was observed but the yields were
slightly lower compared to the cyclic cyclopropanols.
F or m a l Syn th esis of (-)-(S,S)-Cla vu k er in A a n d
(+)-(R,S)-Isocla vu k er in . This methodology was suc-
cessfully applied to the asymmetric formal total synthesis
of (-)-(S,S)-clavukerin A (13) and of (+)-(R,S)-isoclavuk-
erin (15). These sesquiterpenes were isolated from the
Okinawan soft coral Clavularia koellikeri13 (Scheme 4).
So far, four syntheses of 1514,15 and six of 1315,16 have
been described, including four enantiocontrolled routes.
In all of them, the asymmetric centers were introduced
A second method, which also cleaves the bond “i”, was
taken under consideration. In this case, the reaction was
induced by free bromine.11 The use of an exact stoichi-
ometry and low temperature were found to be necessary
to avoid multiple bromination. First attempts to isolate
the resulting â-bromo ketone failed or resulted in very
low yields. Therefore, the dehydrobromination was car-
ried out directly on the crude mixture with a saturated
solution of sodium acetate in methanol at room temper-
ature. Again, special care had to be taken to avoid the
(12) The formation of (S)-11a may be explained by the following
mechanism:
(13) For the isolation and absolute configuration determination of
clavukerin A, see: Kobayashi, M.; Son, B. W.; Kido, M.; Kyogoku, Y.;
Kitawaga, I. Chem. Pharm. Bull. 1983, 31, 2160. For the absolute
configuration determination of isoclavukerin, see: Kusumi, T.; Ha-
mada, T.; Hara, M.; Ishitsuka, M. O.; Ginda, H.; Kakisawa, H.
Tetrahedron Lett. 1992, 33, 2019.
(10) The missing material is certainly due to unavoidable loss during
evaporation.
(11) Murai, S.; Seki, Y.; Sonoda, N. J . Chem. Soc., Chem. Commun.
1974, 24, 1032.
(14) Trost, B. M.; Higuchi, R. I. J . Am. Chem. Soc. 1996, 118, 10094.
J . Org. Chem, Vol. 67, No. 25, 2002 8755

Alexakis and March
bottom flask containing the copper salt (0.1 mmol) and the chiral
ligand (0.2 mmol). This mixture was stirred for 15 min at room
temperature and was then cooled to -30 °C. After 15 min, the
diethylzinc solution (0.8 M in hexane, 37.5 mL, 30 mmol) was
added, followed 20 min later by the enone (10 mmol). The
solution was stirred under these conditions until complete
consumption of the starting material. An analytical sample of 5
was hydrolyzed and taken for ee determination. TMSOTf (2.2
mL, 12 mmol) neutralized with 0.1 mL of Et2Zn solution was
then added and the reaction mixture was allowed to warm to
room temperature. Complete silylation was generally observed
in 3-4 h reaction time. Diiodomethane (1.6 mL, 20 mmol) was
then added and the reaction mixture was refluxed overnight. It
was then cooled to room temperature and hydrolyzed with a
saturated solution of NH4Cl. The organic layer was washed with
saturated NH4Cl then brine, dried with anhyd Na2CO3, filtered,
and concentrated in vacuo. The products were purified by flash
column chromatography (pentane then pentane/Et2O 9/1) to
afford the silylated cyclopropanols as colorless liquids.
through the chiral pool or through kinetic resolution. We
herein report the first synthesis where the chirality of
13 and 15 is introduced via a catalytic reaction.
To perform this synthesis, the only modification com-
pared to 10a was the use of dimethylzinc instead of its
ethyl derivative. Such a small change had, however, a
large impact on the cyclopropanol formation. When the
previous conditions were used (initial excess of dialkyl-
zinc), only incomplete reaction was obtained. This can
be ascribed to the lower reactivity of Me2Zn with CH2I2.
It was necessary to use only 1.3 equiv of Me2Zn for the
conjugate addition, then proceed to the silylation as
previously described and finally to the cyclopropanation
with 1.3 equiv of the more reactive diethylzinc. With
these new conditions, the methyl-cyclopropanol 6c was
isolated in 91% yield and 97% enantiomeric excess (see
Table 1, entry 3). The radical cleavage induced by FeCl3
followed by the elimination of the corresponding â-chloro
ketone led to the expected γ-methyl-enone 10c in very
good yield (90%). The elaboration of (()-clavukerin A and
(()-isoclavukerin from racemic 10c has been reported
earlier15a and therefore a formal asymmetric synthesis
of these two natural products has been achieved.
(+)-(5(S)-E t h ylb icyclo[4.1.0]h ep t -1-yloxy)t r im et h ylsi-
la n e (6a ): 1H NMR (400 MHz, CDCl3) δ 2.17 (d, J ) 12.9 Hz,
1H), 1.80 (td, J t ) 12.5 Hz, J d ) 5.4 Hz, 1H), 1.60 (m, 2H), 1.46
(m, 3H), 1.22 (m, 2H), 0.94 (t, J ) 7.3 Hz, 3H), 0.85 (m, 2H,),
0.29 (t, J ) 3.9 Hz, 1H), 0.14 (s, 9H). 13C NMR (100 MHz, CDCl3)
δ 57.2, 40.0, 32.0, 31.0, 29.7, 24.6, 21.2, 18.9, 11.9, 1.4. IR (CHCl3)
ν 2999, 2961, 2932, 2858 cm-1. HRMS m/z M+• calcd for C12H24
-
OSi 212.1596, found 212.1590. [R]20 +18.3 (c 1.0, CHCl3)
D
(determined on the cis/trans ratio). Ee of 98% for hydrolyzed 5a
was measured with a Lipodex E column (program 60-30-15-170-
0). RT ) 24.7 (R), 27.6 (S) min.
Con clu sion
A very efficient asymmetric one-pot synthesis of cyclic
and linear silylated cyclopropanols has been reported.
Three different cleavages of the cyclopropane ring were
applied leading to optically pure R-methyl-â-ethyl ke-
tones, R-methylene-â-ethyl ketones, or γ-alkyl-enones.
Finally, this last methodology has successfully been
applied to the asymmetric formal total synthesis of the
trinorguaiane sesquiterpenes (-)-(S,S)-clavukerin A and
(+)-(R,S)-isoclavukerin.
(+)-(6(S )-E t h ylb icyclo[5.1.0]oct -1-yloxy)t r im e t h ylsi-
la n e (6b): 1H NMR (400 MHz, CDCl3) δ 2.28 (dd, J ) 14.6, 6.6
Hz, 1H), 1.88 (m, 1H), 1.76 (m, 1H), 1.59 (m, 2H), 1.39 (m, 3H),
1,18 (m, 2H), 1.02 (m, 1H), 0.92 (t, J ) 7.6 Hz, 3H), 0.69 (m,
2H), 0.34 (t, J ) 5.5 Hz, 1H), 0.13 (s, 9H). 13C NMR (100 MHz,
CDCl3) δ 59.6, 45.6, 38.1, 35.6, 31.3, 30.5, 30.1, 25.1, 24.1, 12.1,
1.4. IR (CHCl3) ν 2994, 2961, 2927, 2875 cm-1. HRMS m/z M+•
calcd for C13H26OSi 226.1753, found 226.1757. [R]20 +34.7 (c
D
1.2, CHCl3) (determined on the cis/trans ratio). Ee of 93% for
hydrolyzed 5b was measured with a Lipodex E column (pro-
gram: 50-90-15-170-0). RT ) 92.2 (S), 92.8 (R) min.
(-)-[1-Met h yl-2-(1(R)-p h en ylp r op yl)cyclop r op oxy]t r i-
m eth ylsila n e (6d ): 1H NMR (400 MHz, CDCl3) δ 7.24 (m, 5H),
2.31 (m, 1H), 1.74 (m, 2H), 1.43 (s, 2.4H), 1.29 (s, 0.6H), 0.86 (t,
J ) 7.5 Hz, 3H), 0.77 (m, 1H), 0.69 (m, 0.2H), 0.51 (m, 1H), 0.30
(t, J ) 5.9 Hz, 0.8H), 0.18 (s, 7.2H), 0.11 (s, 1.8H). 13C NMR
(100 MHz, CDCl3) δ major diastereoisomer: 146.7, 128.1, 127.9,
125.6, 57.6, 45.9, 30.4, 30.0, 26.7, 19.1, 12.1, 1.3. 13C NMR (100
MHz, CDCl3) δ minor diastereoisomer: 146.3, 127.9, 127.8,
125.4, 56.6, 46.0, 30.4, 29.1, 26.4, 19.6, 12.1, 1.3. IR (CHCl3) ν
3065, 3009, 2962, 2930, 2874 cm-1. MS (EI) 247 (1), 233 (1), 159
Exp er im en ta l Section
Ma ter ia ls. Unless otherwise stated, reagents were obtained
commercially and were used without further purification. Cy-
cloheptenone was prepared according to the literature proce-
dure.17
Gen er a l P r oced u r es. CH2Cl2, DMF, and Et3N were distilled
from CaH2; diethyl ether was distilled from sodium benzophen-
one ketyl. 1H (300, 400, and 500 MHz) and 13C NMR (75, 100,
and 125 MHz) spectra were recorded in CDCl3, and chemical
shift (δ) are given in ppm relative to CHCl3. The high-resolution
mass spectra (HRMS) were recorded in the EI (70 eV) mode.
Optical rotations were measured at 20 °C in the stated solvent;
[R]D values are given in 10-1 deg cm2 g-1. Enantiomeric excesses
were determined by chiral-GC (capillary column, 10 psi H2) or
chiral-SFC with the stated column. Temperature programs are
described as follows: initial temperature (°C)-initial time
(min)-temperature gradient (°C/min)-final temperature (°C)-
final time (min)-retention times (RT) are given in min. Flash
column chromatography was performed with silica gel 32-63
mm, 60 Å, F254. All reactions were conducted under a nitrogen
atmosphere.
(5), 143 (100), 117 (10), 91 (12), 73 (91). [R]20 -57.7 (c 1.07,
D
CHCl3) (determined on the mixture of two diastereoisomers). Ee
of 89% for hydrolyzed 5d was measured with a Lipodex E column
(program: 60-50-1-70-0). RT ) 63.5 (S), 63.7 (R) min.
(+)-(5(S)-Meth ylbicyclo[4.1.0]h ep t-1-yloxy)tr im eth ylsi-
la n e (6c). Dry CH2Cl2 (10 mL) was added to a dry round-bottom
flask containing copper(II) triflate (36 mg, 0.1 mmol) and ligand
(R,R)-2 (94 mg, 0.2 mmol). This mixture was stirred for 15 min
at room temperature and was then cooled to 0 °C. Dimethylzinc
solution (2 M in toluene, 6.5 mL, 13 mmol) was added 15 min
later, followed 20 min later by 2-cyclohexenone (0.97 mL, 10
mmol). The solution was stirred under these conditions until
complete consumption of the starting material. An analytical
sample of 5c was hydrolyzed and taken for ee determination
and TMSOTf (2.2 mL, 12 mmol) neutralized with 0.1 mL of Et2-
Zn solution was then added. The reaction mixture was stirred
overnight at room temperature and diethylzinc (0.8 M in hexane,
16 mL, 13 mmol) followed by diiodomethane (1.6 mL, 20 mmol)
were then added. This solution was refluxed for 3.5 h, cooled to
room temperature, and hydrolyzed with a saturated solution of
NH4Cl. The organic layer was washed with saturated NH4Cl
then brine, dried with anhyd Na2CO3, filtered, and concentrated
in vacuo. The product was purified by flash column chromatog-
Gen er a l P r oced u r e for th e Con ju ga te Ad d ition -Cyclo-
p r op a n a tion . Dry CH2Cl2 (10 mL) was added to a dry round-
(15) (a) Friese, J . C.; Krause, S.; Scha¨fer, H. J . Tetrahedron Lett.
2002, 43, 2683. (b) Shimizu, I.; Ishikawa, T. Tetrahedron Lett. 1994,
35, 1905. (c) Asaoka, M.; Kosaka, T.; Itahana, H.; Takei, H. Chem.
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8756 J . Org. Chem., Vol. 67, No. 25, 2002

Tandem Asymmetric Conjugate Addition-Cyclopropanation
raphy (pentane then pentane/Et2O 9/1), to afford compound 6c
as a colorless liquid (91% yield). 1H NMR (400 MHz, CDCl3) δ
2.16 (dt, J ) 13.4, 3.7 Hz, 1H), 1.79 (m, 1H), 1.60 (m, 1H), 1.46
(m, 1H), 1.11 (d, J ) 6.6 Hz, 3H), 0.84 (m, 4H), 0.30 (t, J ) 5.0
Hz, 1H), 0.14 (s, 9H). 13C NMR (100 MHz, CDCl3) δ 57.4, 32.8,
32.0, 31.9, 26.1, 23.7, 21.3, 18.9, 1.4. IR (CHCl3) ν 2999, 2957,
2869 cm-1. HRMS m/z M+• calcd for C11H22OSi 198.1440, found
complete consumption of the starting material and was quenched
with saturated NH4Cl. The mixture was diluted with Et2O and
water and the organic layer was washed with saturated NH4Cl
and NaHCO3. Drying with anhydrous Na2CO3 and evaporation
in vacuo yielded the crude â-chloro ketone. This nearly colorless
liquid was then diluted in 3 mL of a saturated solution of
anhydrous sodium acetate in methanol and refluxed for 5 h.
Aqueous NH4Cl and Et2O were added and the organic layer was
washed twice with saturated NH4Cl. Careful removal of the
solvent in vacuo and purification by flash chromatography
(pentane/Et2O 9/1) gave pure γ-alkyl-enones 10a -d as colorless
liquids.
198.1438. [R]20 +22.4 (c 1.04, CHCl3) (determined on the cis/
D
trans ratio). Ee of 97% for hydrolyzed 5c was measured with a
Chiraldex B-TA column (program: 60-0-1-80-10). RT ) 17.6 (R),
18.2 (S) min.
(+)-3(S)-Eth yl-2(R)-m eth ylcycloh exan on e18 (8a). Dry Et2O
(1.4 mL) was added to a dry round-bottom flask containing
anhyd ZnI2 (638 mg, 2 mmol) at room temperature. Silylated
cyclopropanol 6a (425 mg, 2 mmol) was then added and the
reaction mixture was stirred for 20 h in these conditions. This
mixture was diluted with Et2O and water and the organic layer
was dried with anhyd Na2CO3. Careful evaporation of the solvent
and purification by flash chromatography (pentane/Et2O 9/1)
gave compound 8a (226 mg, 1.6 mmol, 81%) as a colorless
liquid.1H NMR (500 MHz, CDCl3) δ 2.38 (m, 1H), 2.26 (m, 1H),
2.16 (m, 1H), 2.04 (m, 1H), 1.89 (m, 1H), 1.62 (m, 2H), 1.36 (m,
3H), 1.02 (d, J ) 6.7 Hz, 3H), 0.90 (t, J ) 7.4 Hz, 3H). 13C NMR
(125 MHz, CDCl3) δ major diastereoisomer: 213.8, 49.5, 46.7,
41.5, 29.7, 26.2, 25.9, 11.8, 10.2. 3C NMR (125 MHz, CDCl3) δ
minor diastereoisomer: 214.8, 48.8, 43.9, 39.7, 26.5, 23.9, 21.9,
11.6, 11.3. IR (CHCl3) ν 2941, 2870, 1702 cm-1. HRMS m/z M+•
calcd for C9H16O 140.1201, found 140.1204. [R]20D +23.0 (c 1.02,
CHCl3). Ee of 97% for 8a was measured with a Hydrodex B-3P
column (program: 70-40-15-170-5). RT ) 32.3 (2S, 3R), 33.7 (2R,
3S) min.
(+)-4(S)-Eth ylcycloh ept-2-en on e (10a): 1H NMR (500 MHz,
CDCl3) δ 6.39 (dd, J ) 12.3, 4.1 Hz, 1H), 5.96 (dd, J ) 12.2, 2.4
Hz, 1H), 2.58 (m, 2H), 2.40 (m, 1H), 1.95 (m, 1H), 1.80 (m, 2H),
1.52 (m, 3H), 0.98 (t, J ) 7.4 Hz, 3H). 13C NMR (125 MHz,
CDCl3) δ 204.6, 150.7, 131.3, 43.3, 41.8, 31.3, 28.9, 20.5, 11.5.
IR (CHCl3) ν 3018, 2936, 1660 cm-1. HRMS m/z M+• calcd for
C9H14O 138.1045, found 138.1050. [R]20 +72.3 (c 1.7, CHCl3).
D
Ee of 97% for 10a was measured with a Lipodex E column
(program: 80-35-15-170-10). RT ) 21.3 (S), 25.9 (R) min.
(+)-4(S)-Eth ylcyclooct-2-en on e (10b): 1H NMR (500 MHz,
CDCl3) δ 6.10 (m, 2H), 2.94 (m, 1H), 2.84 (m, 1H), 2.51 (m, 1H),
1.82 (m, 1H), 1.69 (m, 2H), 1.59 (m, 1H), 1.48 (m, 3H), 1.27 (m,
1H), 0.96 (t, J ) 9.3 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ 204.3,
148.1, 133.6, 42.5, 40.3, 30.5, 30.5, 23.5, 23.1, 12.0. IR (CHCl3)
ν 3009, 2926, 1654 cm-1. HRMS m/z M+• calcd for C10H16
O
152.1201, found 152.1200. [R]20D +8.1 (c 0.16, CHCl3). Ee of 92%
for 10b was measured with a Lipodex E column (program: 110-
15-15-170-10). RT ) 4.9 (S), 6.9 (R) min.
(-)-4(S)-Meth ylcycloh ep t-2-en on e20 (10c): 1H NMR (400
MHz, CDCl3) δ 6.33 (dd, J ) 12.1, 3.8 Hz, 1H), 5.93 (dd, J )
12.1, 1.9 Hz, 1H), 2.60 (m, 3H), 1.95 (m, 1H), 1.81 (m, 2H), 1.52
(m, 1H), 1.17 (d, J ) 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ
204.4, 151.6, 130.6, 43.6, 35.7, 34.3, 21.9, 20.6. IR (CHCl3) ν 2964,
2934, 1657 cm-1. HRMS m/z M+• calcd for C8H12O 124.0888,
found 124.0899. [R]20D -138.4 (c 0.48, CHCl3). Ee of 96% for 10c
was measured with a Hydrodex B-3P column (program: 70-40-
15-170-5). RT ) 31.2 (S), 33.8 (R) min.
(+)-3(S)-Eth yl-2-m eth ylen ecycloh exa n on e19 (9a ). A solu-
tion of cyclopropanol 6a (425 mg, 2 mmol) in dry CH2Cl2 (2 mL)
was cooled to -78 °C. Bromine (100 µL, 2 mmol) in solution in
dry CH2Cl2 (1 mL) was added drop by drop over 10 min. Solid
sodium pyrosulfite was added 5 h later followed by 6 mL of a
saturated solution of sodium acetate in methanol. The reaction
was then allowed to warm to room temperature and was stirred
overnight. This mixture was diluted with Et2O and water and
the organic layer was dried with anhyd Na2CO3. Careful
evaporation of the solvent yielded crude compound 9a (343 mg,
75%) as a pale yellow liquid. 1H and 13C NMR revealed a good
purity. Purification by flash chromatography (pentane/Et2O 9/1)
gave pure compound 9a in 55% yield as a colorless liquid.1H
NMR (300 MHz, CDCl3) δ 5.77 (s, 1H), 5.09 (s, 1H), 2.42 (t, J )
6.6 Hz, 3H), 1.93 (m, 2H), 1.79 (m, 1H), 1.45 (m, 3H), 0.90 (t, J
) 7.4 Hz, 3H). 13C NMR (125 MHz, CDCl3) δ 203.2, 149.9, 118.9,
43.3, 40.6, 28.9, 26.1, 20.9, 11.3. IR (CHCl3) ν 3009, 2938, 1688
cm-1. HRMS m/z M+• calcd for C9H14O 138.1045, found 138.1049.
[R]20D +49.2 (c 1.0, CHCl3). Ee of 97% for 9a was measured with
a Hydrodex B-3P column (program: 70-50-15-170-5). RT ) 32.1
(R), 33.6 (S) min.
Gen er a l P r oced u r e for th e Rin g Hom ologa tion /Ch a in
Exten sion Rea ction s. Commercial anhydrous FeCl3 (1.43 g,
8.8 mmol) was further dried in vacuo for 0.5 h in a round-bottom
flask. Dry DMF (2.8 mL) was rapidly added at 0 °C, and the
brown suspension was stirred at room temperature until clear
(dissolution may be enhanced by ultrasonic irradiation). Dry
Et3N (0.56 mL, 4 mmol) was then added and neat cyclopropanol
6a -d (2 mmol) was slowly added via syringe-pump over 1 h at
0 °C. The solution was stirred under these conditions until
(-)-5(R)-P h en ylh ep t-3-en -2-on e (10d ): 1H NMR (500 MHz,
CDCl3) δ 7.36 (m, 2H), 7.28 (m, 1H), 7.21 (m, 2H), 6.91 (dd, J )
16.1, 7.8 Hz, 1H), 6.09 (d, J ) 16.1 Hz, 1H), 3.34 (m, 1H), 2.26
(s, 3H), 1.85 (m, 2H), 0.92 (t, J ) 7.4 Hz, 3H). 13C NMR (125
MHz, CDCl3) δ 198.7, 150.7, 142.0, 130.3, 128.7 (2), 127.7 (2),
126.8, 50.4, 27.8, 27.0, 12.1. IR (CHCl3) ν 3028, 3012, 2968, 1672
cm-1. HRMS m/z M+• calcd for C13H16O 188.1201, found 188.1192.
[R]20 -10.1 (c 1.0, CHCl3). Ee of 87% for 10d was measured by
D
chiral SFC with a Chiralcel OD-H column (1% MeOH, flow rate
2 mL/min). RT ) 4.48 (R), 4.88 (S) min.
Ack n ow led gm en t. The authors thank the Swiss
National Research Foundation No. 20-61891.00 and
COST action D12/0022/99 for financial support, and
Xavier Rathgeb for his very efficient synthetic help.
Su p p or tin g In for m a tion Ava ila ble: 1H and 13C spectra
for compounds 6a -d , 8a , 9a , and 10a -d plus Chiral GC for
compounds 5a -d (hydrolyzed to the corresponding ketone),
8a , 9a , and 10a -d . This material is available free of charge
via the Internet at http://pubs.acs.org.
J O026262W
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