Synthetic methodology for the construction of structurally diverse cyclopropanes

Article abstract of DOI:10.1021/ja0037163

Practical and efficient routes for the stereoselective conversion of homoallylic alchols to diastereomerically pure cis-, trans-1,2-disubstituted, and 1,2,3-trisubstituted cyclopropanes have been developed. The routes are highlighted by olefin metathesis

Full text of DOI:10.1021/ja0037163

2964
J. Am. Chem. Soc. 2001, 123, 2964-2969
Synthetic Methodology for the Construction of Structurally Diverse
Cyclopropanes
Richard E. Taylor,* F. Conrad Engelhardt, Michael J. Schmitt, and Haiqing Yuan
Contribution from the Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall,
UniVersity of Notre Dame, Notre Dame, Indiana 46556-5670
ReceiVed October 18, 2000
Abstract: Practical and efficient routes for the stereoselective conversion of homoallylic alchols to
diastereomerically pure cis-, trans-1,2-disubstituted, and 1,2,3-trisubstituted cyclopropanes have been developed.
The routes are highlighted by olefin metathesis strategies and the stabilization of an intermediate cyclopro-
pylcarbinyl cation by the â-silicon effect. The stereospecificity of the key cyclization step has been rationalized
by transition-state models in which the important determinants include (i) a minimization of the steric interactions
about the forming cyclopropane bond and (ii) an inversion of stereochemistry at the activated homoallylic
alcohol position. The cyclopropane product chirality is ultimately controlled by the choice of homoallylic
alcohol starting material. Through this method nonracemic, diasteromerically pure homoallylic alcohols can
be converted in two steps to nonracemic, diasteromerically pure cyclopropane structural units. The scope and
limitations of this versatile methodology have also been investigated.
The cyclopropyl group has played a prominent role in organic
Scheme 1
chemistry for many reasons. Its strained structure, interesting
bonding characteristics, and its use as an internal mechanistic
probe continue to draw the attention of the physical organic
community.1 In addition, the prevalence of cyclopropane-
containing compounds with biological activity, whether isolated
from natural sources or rationally designed pharmaceutical
agents, has inspired chemists to find novel and diverse ap-
proaches to their synthesis. Progress in the area of diastereo-
and enantioselective methods for cyclopropane construction has
been largely focused on the modification of allylic alcohols
through intramolecular carbenoid intermediates2 or intermo-
lecular Simmons-Smith chemistry.3 In contrast, we have been
investigating the ready conversion of simple structures such as
homoallylic alcohols to enantiomerically and diastereomerically
pure cyclopropanes.4 The key step in our route involves the
generation, stabilization, and trapping of cyclopropylcarbinyl
cations.5 The stereochemistry of the resulting cyclopropane
product, both absolute and relative, is controlled by the
homoallylic alcohol 1 and the constraints of transition state A,
Scheme 1. The presence of a carbocationic-stabilizing group Y
allows for efficient, stereospecific cyclization through an
inversion of the activated homoallylic alcohol, and the formation
of unsaturation traps the cyclopropylcarbinyl cation before
fragmentation, rearrangement, or potential loss of stereochem-
istry.
For our first generation approach we chose Y ) CH2SiR3 to
exploit the cation stabilization of the â-silicon effect, 2.6,7 In
this account, we introduce the application of olefin cross-
metathesis for the preparation of our cyclization precursors. This
process has now allowed the preparation of nonracemic,
diasteromerically pure cyclopropanes in just two steps from
readily available chiral precursors. We now present the synthetic
and mechanistic details of this highly efficient route together
with its scope and limitations.
(1) (a) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809. (b)
Nonhebel, D. C. Chem. Soc. ReV. 1993, 22, 347.
(2) Doyle, M. P.; Austin, R. E.; Bailey, A. S.; Dwyer, M. P.; Dyatkin,
A. B.; Kalinin, A. V.; Kwan, M. M. Y.; Liras, S.; Oalmann, C. J.; Pieters,
R. J.; Protopopova, M. N.; Raab, C. E.; Roos, G. H. P.; Zhou, Q.-L.; Martin,
S. F. J. Am. Chem. Soc. 1995, 117, 5763 and references therein.
(3) Charette, A. B.; Juteau, H.; Lebel, H.; Molinaro, C. J. Am. Chem.
Soc. 1998, 117, 11943 and references therein.
Results
Ring-Closing Metathesis. There are numerous published
methods for the preparation of homoallylic alcohols.8 A repre-
sentive series of homoallylic alcohol starting materials were
(4) (a) Taylor, R. E.; Schmitt, M. J.; Yuan, H. Org. Lett. 2000, 2, 601.
(b) Taylor, R. E.; Engelhardt, F. C.; Yuan, H. Org. Lett. 1999, 1, 1257. (c)
Taylor, R. E.; Ameriks, M. K.; LaMarche, M. J. Tetrahedron Lett. 1997,
38, 2057.
(5) For examples of chemical approaches to cyclopropanes via cyclo-
propylcarbinyl cationic intermediates, see: (a) Krief, A.; Provins, L. Synlett
1997, 505. (b) Hanessian, S.; Reinhold: U.; Ninkovic, S. Tetrahedron Lett.
1996, 37, 8971. (c) White, J. D.; Jensen, M. S. Synlett 1996, 31. (d) White,
J. D.; Jensen, M. S. J. Am. Chem. Soc. 1995, 117, 6224. (e) Nagasawa, T.;
Handa, Y.; Onoguchi, Y.; Ohba, S.; Suzuki, K. Synlett 1995, 739. (f) White,
J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993, 115, 2970.
(6) Schaumann has previously reported the preparation of vinylcyclo-
propanes from similar starting materials through an allylic anion-mediated
process. For a lead reference, see: Schaumann, E.; Kirschning, A.; Narjes,
F. J. Org. Chem. 1991, 56, 717.
(7) (a) For an excellent review of the chemistry of allylsilanes, see:
Fleming, I. Org. React. 1989, 37, 57. (b) Lambert, J. B.; Zhao, Y.; Emblidge,
R. W.; Salvador, L. A.; Liu, X.; So, J.-H.; Chelius, E. C. Acc. Chem. Res.
1999, 32, 183.
10.1021/ja0037163 CCC: $20.00 © 2001 American Chemical Society
Published on Web 03/09/2001

Construction of Structurally DiVerse Cyclopropanes
Table 1. Silylation and Ring Closing Metathesis
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2965
Scheme 2
cleave the silyloxepene ring 5a but, in addition, induced proto-
desilylation leading to isolation of the terminal olefin 6, Scheme
2. In response, numerous methods were systematically explored
to provide the desired allylsilane homoallylic alcohol. It was
discovered that HF‚pyr worked beautifully and provided the
fluorosilane 7a in quantitative yield. Alternatively, subjecting
the cyclic silyl ether 5a to milder conditions, basic methanol
(K2CO3) provided methyl ether 7b through a trans-etherification
reaction. It is important to note that silanes 7a and 7b are not
chromatographically stable with silica gel. Attempted purifica-
tion of fluorosilane 7a led to quantitiative protodesilylation and
isolation of 6. In contrast, silica gel chromatography of methyl
ether 7b provided a mixture of silanol 7d and silyloxycyclo-
heptene 5a through acid-induced cyclization. Ultimately, it was
discovered that treatment of 5a with excess methyllithium in
diethyl ether at room temperature provided the chromatographi-
cally stable trimethylsilane 7c in high yields. The complementary
nature of these silicon-oxygen cleavage conditions (HF‚pyr or
MeLi) provides the opportunity to prepare a variety of func-
tionalized cyclopropane precursors.
At this point we envisioned that activation of the homoallylic
alcohol by any of numerous methods would lead to vinylcy-
clopropane formation through a silicon-stabilized cyclopropyl-
carbinyl cationic intermediate 2. In fact, activation of alcohol
7a, with trifluoromethanesulfonic anhydride in the presence of
2,6-lutidine provided exclusively the trans-vinylcyclopropane
8a in 71% yield from 5a. Additionally, trimethylsilane 7c
provided 8a in 77% yield for the two-step sequence. In each
case only the trans-vinylcyclopropane was observed, presumably
controlled by a minimization of steric interactions as in transition
state A, Scheme 1.5e Most importantly, a synthetic derivative
of vinylcyclopropane 8a was compared by chiral gc analysis
(Cyclodex-B, J&W Scientific) to racemic material and shown
to have retained the enantiomeric purity of the glycidol starting
material. As shown in Scheme 3, vinylcyclopropane 8a was
converted to the previously prepared (-)-(1R,3R)-1,3-bis-
(hydroxymethyl)cyclopropane14 through a three-step sequence.
The terminal olefin was cleaved by OsO4/NaIO4 and the
resulting aldehyde reduced by NaBH4. Hydrogenolysis of the
benzyl ether provided the desired material, [R]23D ) -16.3, lit.
prepared, Table 1. Enantiomerically enriched benzyl ether 4a
was prepared in a single step (vinylMgBr, CuI) from com-
mercially available, (R)-(-)-benzylglycidyl ether. Crotylation
of hydrocinnamaldehyde provided anti-4b and syn-4c from
crotylbromide/CrCl2 and crotylstannane/BF3‚OEt2,10 respec-
9
tively. A chromatographically separable mixture of anti-4d and
syn-4e (3:1) was obtained from ethyl bromocrotonate/In(0),11
and enantiomerically pure alcohol 4f was prepared from the
corresponding crotyl imide through the boron enolate methodol-
ogy developed in the Evans’ laboratory.8b For each homoallylic
alcohol, incorporation of the necessary cation-stabilizing group
(Y ) CH2SiMe3) was accomplished by a two-step protocol.
Protection of the secondary hydroxyl group of 4a-f was
accomplished with allylchlorodimethylsilane in the presence of
imidazole. The resulting bis-olefin was then subjected to Grubbs’
bis-(tricyclohexylphospine) ruthenium alkylidene catalyst12 which
provided silyloxycycloheptenes 5a-f in excellent yield.13
Our next goal was to cleave the silyloxycycloheptene ring to
expose the cyclization precursor 1. Initially, we explored the
use of tetrabutylammonium fluoride (TBAF). TBAF did indeed
enantiomer [R]25 ) +16.1.14a This sequence was carried out
D
for both the allyldimethylfluorosilane 7a as well as the allyl-
trimethylsilane 7c (prepared via cross-metathesis as an insepa-
rable E:Z mixture (2.3:1), vide infra 15a). Despite the expected
electronic and reactivity differences between allylsilanes 7a and
(8) (a) For a recent review of the reaction of aldehydes with allylic metals,
see: Yamamoto, Y.; Asao, N. Chem. ReV. 1993, 93, 2207. (b) For an
alternative preparation of homoallylic alcohols using chiral crotonate
enolates, see: Evans, D. A.; Sjogren, E. B.; Bartroli, J.; Dow, R. L.
Tetrahedron Lett. 1986, 27, 4957.
(9) Okude, Y.; Hirano, S.; Hiyama, T.; Nozaki, H. J. Am. Chem. Soc.
1977, 99, 3179.
(10) Keck, G. E.; Savin, K. A.; Cressman, E. N. K.; Abbott, D. E. J.
Org. Chem. 1994, 59, 7889 and references therein.
(11) Li, C. J.; Chan, T. H. Tetrahedron Lett. 1991, 32, 7017.
(12) (a) Nguyen, S. T.; Johnson, L. K.; Grubbs, R. H. J. Am. Chem.
Soc. 1992, 114, 3974. (b) Schwab, P. E.; Grubbs, R. H.; Ziller. J. W. J.
Am. Chem. Soc. 1996, 118, 100.
(13) For the preparation of olefinic diols via similar silyloxycycloalkenes,
see: Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757. For the
preparation of tetrahydrofurans and pyrans via similar silyloxycycloalkenes,
see: Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861.
(14) (a) McDonald, W. S.; Verbicky, C. A.; Zercher, C. K. J. Org. Chem.
1997, 62, 1215. (b) Takahashi, H.; Yoshioka, M.; Ohno, M.; Kobayashi, S.
Tetrahedron Lett. 1992, 33, 2575.

2966 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Taylor et al.
Scheme 3
7c, the successful preparation of (-)-(1R,3R)-1,3-bis(hydroxy-
methyl)cyclopropane, in high enantiomeric purity with both
substrates, is supportive of an efficient inversion process
(transition state A, Scheme 1).
provided a single, diastereomerically pure vinylcyclopropane,
we originally believed that the C2 substituent played no role in
the product stereochemistry. We have now unequivocally
established that this is not the case.
Despite the expected deactivating effect, fluorosilanes 9a-e
provided 1,2,3-trisubsituted cyclopropanes 10a-e under the
identical activation conditions. The yields provided in Table 2
are for both steps (HF‚pyr of 5b-f; Tf2O.) The diastereomeric
anti and syn “propionates” 9a and 9b cyclized efficiently, to
provide the 1,2,3-trisubstituted cyclopropanes 10a and 10b,
respectively. In addition, the carboalkoxy-substituted systems
9c, 9d, and 9e provided access to their corresponding function-
alized trisubstituted cyclopropanes. Each of these reactions was
completely diastereospecific, providing a single trisubsituted
vinylcyclopropane. The successful preparation of an enantio-
merically pure 1,2,3-trisubstituted cyclopropane was demon-
strated by the conversion of hydrocinnamaldehyde to diastereo-
merically pure 10e through the Evans’ aldol intermediate 4f.
On the basis of the fact that these reactions proceed with
inversion of stereochemistry two transition states are possible:
(1) B-1 which has a trans relationship between C1 and C3 and
(2) B-2 which has a cis relationship between C1 and C3, Figure
1. Substrates 7a and 7c (R1 ) R2 ) H) appear to proceed
through B-1 providing exclusively trans-vinylcyclopropanes.
Homoallylic alcohols 9a, 9c, and 9e (R1 ) alkyl, R2 ) H) also
proceed through transition state B-1. However, this transition
state is disfavored for substrates 10b and 10d. In contrast, these
substrates prefer to adopt a conformation which minimizes the
steric interactions between the C2 and C3 position such as seen
in B-2 (R1 ) H, R2 ) alkyl). Presumably, the longer C1-C3
bond length at the transition state can better accommodate a
cis relationship.
Table 2. Cyclopropane Formation
Figure 1. Transition state leading to 1,2,3-trisubstituted cyclopropanes.
Attempts to generate trisubstituted cyclopropanes from the
trimethylsilane derivatives proved problematic, Scheme 4.
Silyloxycycloheptene 5b was efficiently cleaved by exposure
to methyllithium in tetrahydrofuran, providing trimethylsilane
11 in 94% yield. However, in contrast to the successful
cyclization of fluorosilane 9a, exposure of 11 to our standard
conditions cleanly provided an equal mixture of desired cyclo-
propane 10a and silylated material 12. While trimethylsilyl
triflate is produced as a product of the cyclization, <5%
silylation was observed in the conversion of allylsilane 7c to
1,2-disubstituted vinylcyclopropane 8. It appears that in more
hindered homoallylic alcohols such as 11 activation with triflic
anhydride is slow, relative to cyclization, allowing for competi-
tive silylation to occur. However, this silylation problem could
be circumvented with the use of an alternative, activating agent.
In fact, no silylation was observed when thionyl chloride was
used in the presence of pyridine or 2,6-lutidine at room
temperature. Thionyl chloride activation of homoallylic alcohol
11 provided the trans-vinylcyclopropane 10a in 81% yield.
There are several potential reasons for the lack of silylation with
thionyl chloride: (1) a decrease in the rate of cyclization relative
to rate of hydroxyl activation, (2) the presence of chloride ion
which assists in the desilylation step, or (3) silyl ether 12 may
not be stable to the reaction conditions. The first suggestion is
a Tf2O, 2,6-lutidine, -78 °C.
Confirmation of the stereochemical assignments of each 1,2,3-
trisubstituted cyclopropane came from an examination of the
vicinal 1H-1H coupling constants for the ring protons. In
general, cyclopropyl protons with a cis relationship have larger
coupling constants (7-10 Hz) than those in a trans relationship
(3-7 Hz). Vinylcyclopropanes 10b and 10d have revised
stereochemical assignments from our original communication.4a
Since each substrate, regardless of relative stereochemistry,

Construction of Structurally DiVerse Cyclopropanes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2967
supported by the fact that the deactivated fluorosilane intermedi-
ates 9 do not cyclize efficiently with thionyl chloride. Whatever
the rationale, these conditions substantially improve the prac-
ticality of our process efficiently, providing the cyclopropane
products via an inexpensive activating agent under noncryogenic
conditions.
with only a small amount of reductive cleavage observed.
Activation of the homoallylic alcohol gave cis-cyclopropanes
14c and 14d in excellent yield. Here, the presence of the
silyloxycycloheptene ring constrains the substituents in a cis
orientation about the forming ring, Figure 2 (transition state C.)
The closure is remarkably efficient despite the less than optimal
orbital alignment between the ring carbon-silicon σ-bond and
the developing cyclopropylcarbinyl cation.7b
Scheme 4
Figure 2. Transition state leading to cis-vinylcyclopropanes.
Cross Metathesis. A more efficient approach to the cyclo-
propane precursors was envisioned by considering an inter-
molecular metathesis reaction (cross-metathesis) between
homoallylic alcohols 4a-f and allyltrimethylsilane, Table 4. In
fact, Crowe recently reported that cross-metathesis is an
excellent method for the preparation of functionalized allylsi-
lanes.15 As the results in Table 4 clearly indicate, cross-
metathesis between allyltrimethylsilane (4 equiv) and homoal-
lylic alcohols 4a-f, catalyzed by the Grubbs’ 1,3-dimesityl-
4,5-dihydroimidazol-2-ylidene ruthenium catalyst16 efficiently
provided the cyclopropane precursors in good yield with varying
selectivity, but always favoring the E-isomer. The use of only
2 equiv of allyltrimethylsilane was still effective, but the reaction
rate was markedly slower. Interestingly, the E/Z ratio of the
cross-metathesis products was affected by the relative stereo-
chemistry of the chiral precursors. The anti diastereomers, 4b,
4d, and 4f provided the product allylsilanes in a >11:1 ratio in
favor of the presumed thermodynamically more stable E
isomer.17 In contrast, both syn diastereomers, 4c and 4e, were
less selective, <4:1. Most importantly, activation of the ho-
moallylic alcohols with thionyl chloride led to isolation of
diastereomerically pure vinylcyclopropanes without competitive
silylation of starting material and verified the generality of the
milder activating conditions. Finally, it is important to note that
based on the successful results outlined in Table 4, olefin
geometry (of the intermediate allylsilane) appears to have no
effect on the efficiency of the cyclization.
In addition to providing access to the 1,2,3-trisubstituted
compounds (10c, 10d) the ester-substituted silyloxepenes 5d
and 5e have also provided access to both cis- and trans-1,2-
disubstituted cyclopropanes, Table 3. In each case, reduction
of the ethyl ester by exposure to excess DIBAL (5 equiv) yielded
the isolable silanes 13a and 13b. Presumably, formation of the
diol occurs through reductive cleavage of the silyloxepene ring
after reduction of the ester functionality. Selective activation
of the primary alcohol of 13a and 13b, easily accomplished
with triflic anhydride at -78 °C, provided the trans-vinylcy-
clopropanes 14a and 14b, respectively, in good yield. The
selective formation of exclusively trans-stereochemistry can
again be rationalized by a minimization of steric interactions
during ring closure.
Table 3. Formation of cis- and trans-1,2-Disubstituted
Cyclopropanes
Summary
The synthetic utility of this new methodology for the
preparation of enantio- and diastereomerically pure vinylcyclo-
(15) (a) Crowe, W. E.; Goldberg, D. R.; Zhang, Z. J. Tetrahedron Lett.
1996, 37, 2117. In this paper Crowe uses the Schrock molybdenum-based
metathesis catalysts. While we originally explored the use of Grubbs’ bis-
Cy3P-ruthenium catalyst, we have more recently found the dihydroimida-
zolylidene-ruthenium complex16 remarkably efficient (vide infra). (b) While
we have successfully prepared the dihydroimidazolylidene-Ru catalyst in
our laboratories on a gram-scale, it is now commercially available from
Strem Chemicals, Newburyport, MA.
(16) (a) Scholl, M.; Ding, S.; Lee C. W.; Grubbs, R. H. Org. Lett. 1999,
1, 953-956. (b) Chatterjee, A. K.; Grubbs, R. H. Org. Lett. 1999, 1, 1751-
1753. (c) Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R. H. J.
Am. Chem. Soc. 2000, 122, 3783-3784. (d) Morgan, J. P.; Grubbs, R. H.
Org. Lett. 2000, 2, 3153.
(17) The E:Z ratios shown in Table 4 appear to be a result of a kinetically
controlled process. Prolonged exposure of pure-Z-15b to the identical
reaction conditions provided a 1:1 ratio of olefin isomers. A more detailed
discussion of the factors controlling the cross-metathesis olefin geometry
will be published elsewhere: Engelhardt, F. C.; Schmitt, M. J.; Taylor, R.
E. Manuscript in preparation.
a DIBAL (2 equiv). b DIBAL (5 equiv). c Tf2O, 2,6-lutidine, -78
°C.
Alternatively, reduction of silyloxepenes 5d and 5e with
DIBAL (2 equiv) provided the primary alcohols 13c and 13d

2968 J. Am. Chem. Soc., Vol. 123, No. 13, 2001
Table 4. Cross Metathesis Route to Vinylcyclopropanes
Taylor et al.
1069. HRMS calculated for C18H28OSi (M + H)+ m/z 289.1988, found
289.2018. The syn-silyl ether (125 mg, 0.43 mmol) was then diluted
in anhydrous CH2Cl2 (50 mL) and refluxed to which was added bis-
tricyclohexylphosphinebenzylidene ruthenium chloride (Grubbs’ cata-
lyst, 70 mg, 0.085 mmol) via cannula in CH2Cl2 (1 mL). The solution
was stirred at reflux overnight. The solvent was removed in vacuo,
and the residue was purified by flash column chromatography (silica
gel, hexanes f 5% Et2O in hexanes) to give the syn-silyloxycyclo-
1
heptene 5c (99 mg, 88%) as an oil. H NMR (300 MHz, CDCl3) δ
(ppm) 7.33-7.20 (m, 5H), 5.77 (m, 1H), 5.29 (m, 1H), 3.94 (m, 1H),
2.87 (m, 2H), 2.58 (m, 1H), 1.86 (m, 2H), 1.65 (m, 1H), 1.30 (dd, J )
15, 8.7, 1H), 1.00 (d, J ) 7.2, 3H), 0.23 (s, 3H), 0.17 (s, 3H). 13C
NMR (75 MHz, CDCl3) δ (ppm) 142.9, 133.5, 128.7, 128.5, 126.2,
125.8, 77.3, 39.9, 34.8, 33.3, 18.4, 16.3, -0.24, -0.20. FTIR (cm-1
)
3026, 2958, 2875, 1636, 1604, 1496, 1454, 1250, 1095. HRMS
calculated for C16H24OSi (M + H)+ m/z 261.1675, found 261.1663.
Representative Methyl Lithium-Induced Silicon-Oxygen Bond
Cleavage Followed by Cyclopropanane Formation. Preparation of
(2-Vinyl-cyclopropylmethoxymethyl)-benzene (8a). In a 50 mL
round-bottom flask, the seven-membered silyloxycycloheptene 5a (310
mg, 1.18 mmol) was diluted in THF (10 mL). The flask was then
flushed of all air and kept under an atmosphere of nitrogen. Then a
1.6 M solution of methyllithium (2.22 mL, 3.55 mmol) was added via
syringe. Over the next 15 min the flask contents darkened to a
transparent brown-orange. The reaction appeared complete at this point
by TLC and was quenched with ammonium chloride. It was stirred for
15 min at room temperature after which the bulk of the THF was
rotovapped off. Then the product was extracted with EtOAc (2 × 30
mL) and washed with brine. This methylated intermediate 7c is stable
to silica gel and can be purified before generating the cyclopropane;
however, it was shown in subsequent reactions that purification was
not necessary for the success of the cyclopropanation reaction. Thus,
taking the crude mixture (336 mg, 1.2 mmol) in a 50 mL round-bottom
flask, it was diluted in CH2Cl2 (10 mL). 2,6-lutidine (198 µL, 1.70
mmol) was added, and the reaction mixture was cooled to -78 °C.
Quickly, the triflic anhydride was added to the reaction mixture followed
immediately (within five minutes) by a quench Hunig’s base (large
excess). Again, the color change from yellow to red/purple was
observed. Slowly the reaction mixture was allowed to warm to room
temperature during which the reaction contents darkened. The product
was isolated as a crude residue by removing the solvent under reduced
pressure and was purified using a flash chromatography (silica gel,
6% EtOAc in hexanes) to give the enantiopure benzyl vinylcyclopro-
propanes has been demonstrated. Each simple and efficient
sequence allows the preparation of structurally complex cyclo-
propanes from readily available homoallylic alcohols. The ring-
closing metathesis route is highlighted by the preparation of
trans- and cis-1,2-disubstituted and 1,2,3-trisubstituted cyclo-
propanes in just two steps from a common intermediate.
Additionally, the cross-metathesis route provides trans-1,2-
disubstituted and 1,2,3-trisubstituted systems in just two steps
from starting homoallylic alcohols. In comparison to our
previous reported conditions, activation with inexpensive thionyl
chloride at room temperature represents a significant improve-
ment in the development of the process. The versatility of
methodology demonstrated herein makes this chemistry a useful,
practical alternative to other methods for cyclopropane construc-
tion. Most importantly, this investigation sets the stage for the
application of the methodology to solid-phase synthesis and,
ultimately, the generation of combinatorial libraries based on
cyclopropane scaffolds.
1
pane 8a (175 mg, 77%) as a clear oil. H NMR (300 MHz, CDCl3) δ
(ppm) 7.35-7.34 (m, 5H), 5.48-5.36 (m, 1H), 5.07 (dd, J ) 1.7, 17,
1H), 4.88 (dd, J ) 1.7, 10.3, 1H), 4.54 (d, J ) 12.0, 1H), 4.53 (d, J )
12.0, 1H), 3.41 (dd, J ) 6.6, 10.4, 1H), 3.35 (dd, J ) 6.6, 10.4, 1H),
1.38-1.29 (m, 1H), 1.22-1.13 (m, 1H), 0.68 (t, J ) 6.9, 2H). 13C
NMR (75 MHz, CDCl3) δ (ppm) 140.7, 138.4, 128.3, 127.7, 127.5,
112.2, 73.2, 72.4, 20.8, 20.2, 11.9. FTIR (cm-1) 3067, 3004, 1720,
1637, 1497, 1454. HRMS (CI) calcd for C13H16O (M + H)+ m/z
189.1279, found 189.1281.
Experimental Section
Representative Allylsilane Protection of a Homoallylic Alcohol
Followed by a Ring-Closing Metathesis (RCM) Reaction. Prepara-
tion of syn-2,2,6-Trimethyl-7-phenethyl-2,3,6,7-tetrahydro-[1,2]oxa-
silepine (5c). To a solution of syn-4-methyl-1-phenyl-hex-5-ene-3-ol
4c (133 mg, 0.70 mmol) in anhydrous DMF (2 mL) was added
imidazole (238 mg, 3.5 mmol) and allylchlorodimethylsilane (200 µL,
1.3 mmol). The mixture was stirred at room temperature for overnight.
The reaction mixture was diluted with Et2O, washed with H2O. The
aqueous layer was extracted with Et2O (2 × 20 mL). The combined
organic layers were washed with brine, dried over MgSO4, and
concentrated in vacuo. The crude product was purified by flash column
chromatography (silica gel, hexanes f 5% EtOAc in hexanes) to give
Representative Fluoride Silicon-Oxygen Bond Cleavage Fol-
lowed by Cyclopropanane Formation. Preparation of syn-[2-(2-
Methyl-3-vinyl-cyclopropyl)-ethyl]-benzene (10b). To a solution of
the syn-[1,2]oxasilepine 5c (23 mg, 0.088 mmol) in anhydrous THF
(1 mL) was added HF/Pyridine (50 µL, ∼1.9 mmol). The reaction
mixture was stirred at room temperature for 10 min and was diluted
with Et2O and washed with H2O. The aqueous layer was extracted with
Et2O (2 × 10 mL). The combined organic layers were washed with
brine, dried over MgSO4, and concentrated in vacuo. The crude product
(23 mg, 100%) was directly subjected to the next reaction without
1
further purification. H NMR (300 MHz, CDCl3) δ (ppm) 7.32-7.19
(m, 5H), 5.48 (m, 1H), 5.22 (m, 1H), 3.43 (m, 1H), 2.87 (m, 1H), 2.65
(m, 1H), 2.56 (m, 1H), 1.88 (m, 1H), 1.79-1.57 (m, 4H), 0.99 (d, J )
6.9, 3H), 0.24 (d, J ) 7.5, 6H). 13C NMR (75 MHz, CDCl3) δ (ppm)
142.5, 131.7, 128.64, 128.58, 126.0, 123.8, 75.5, 37.9, 36.0, 32.7, 18.8
(d, J ) 13.6), 16.5, -1.3 (d, J ) 15.1), -1.4 (d, J ) 14.6). FTIR
(cm-1) 3586, 3392, 2961, 2930, 2872, 1497, 1455, 1257. HRMS
calculated for C16H25FOSi (M + H)+ m/z 281.1737, found 281.1710.
To a solution of the crude fluorosilane 9b (22 mg, 0.079 mmol) in
1
syn-silyl ether (127 mg, 63%) as a colorless oil. H NMR (300 MHz,
CDCl3) δ (ppm) 7.38-7.22 (m, 5H), 5.96-5.82 (m, 2H), 5.15-4.93
(m, 4H), 3.68 (m, 1H), 2.81 (m, 1H), 2.62 (m, 1H), 2.41 (m, 1H), 2.12
(m, 1H), 1.80 (m, 1H), 1.73 (d, J ) 8.1, 2H), 1.08 (d, J ) 6.9, 3H),
0.22 (s, 6H). 13C NMR (75 MHz, CDCl3) δ (ppm) 142.8, 141.2, 134.5,
128.6, 128.5, 125.9, 114.7, 113.9, 76.3, 43.6, 35.8, 32.1, 25.5, 15.7,
-1.3. FTIR (cm-1) 3064, 3027, 2959, 1631, 1604, 1496, 1454, 1254,

Construction of Structurally DiVerse Cyclopropanes
J. Am. Chem. Soc., Vol. 123, No. 13, 2001 2969
anhydrous CH2Cl2 (1 mL) at -78 °C was added 2,6-lutidine (18 µL,
0.16 mmol) followed by trifluoromethanesulfonic anhydride (20 µL,
0.12 mmol). The reaction was stirred at -78 °C for 25 min and was
quenched by H2O (200 µL) and warmed to room temperature. Et2O
and H2O were added, and layers were separated. The aqueous layer
was extracted with Et2O (2 × 10 mL). The combined organic layers
were washed with brine, dried over MgSO4, and concentrated in vacuo.
The crude product was purified by flash column chromatography (silica
gel, hexanes) to give syn-3-methyl-2-(2-phenylethyl)-vinylcyclopropane
2.64-2.46 (m, 2H), 1.99-1.87 (m, 1H), 1.80-1.65 (m, 2H), 1.54-
1.44 (m, 2H), 0.20 (s, 3H), 0.16 (s, 3H). 13C NMR (75 MHz, CDCl3)
δ (ppm) 142.5, 128.6, 128.5, 128.3, 128.2, 125.7, 71.9, 63.2, 50.3, 38.1,
32.4, 17.7, -0.8, -1.1. FTIR (cm-1) 3392, 3025, 1639, 1604, 1496,
1454. HRMS calculated for C16H24O2Si (M + H)+ m/z 276.1546, found
276.1526.
Representative Cross-Metathesis Reaction of a Homoallylic
Alcohol with Allyltrimethylsilane. Preparation of (E)- and (Z)-anti-
4-Methyl-1-phenyl-7-(trimethyl-silanyl)-hept-5-en-3-ol (15b). A solu-
tion of anti-4-methyl-1-phenyl-hex-5-ene-3-ol 4b (40.2 mg, 0.212
mmol) was diluted in CH2Cl2 (5 mL) in a 25 mL flask and warmed to
reflux under an atmosphere of nitrogen. The solution was allowed to
reflux for 30 min, and then allyltrimethylsilane (134 µL, 0.846 mmol)
was added via syringe to the reaction vessel, followed by the solid
addition of Grubbs’ 1,3-dimesityl-4,5-dihydroimidazol-2-ylidene ru-
thenium carbene (9 mg, 5 mol %). The solution immediately took on
a transparent rose color and was stirred under reflux. The reaction was
complete after 3 h (TLC), and the solution had taken on a clear gold
color. The reaction vessel was removed from heat and stirred open to
the air for several hours. During this time the solution darkened to an
opaque brown color. The reaction volume was reduced to 1 mL by
evaporation, and the residue was flushed through a plug of silica gel
using CH2Cl2 (5 mL) followed by 16% EtOAc in hexanes (10 mL).
The resulting light brown solution was concentrated in vacuo and
purified by flash column chromatography through a pipet column (silica
gel, 6% EtOAc in hexanes) to give an inseparable mixture of E and Z
isomers (∼92:8) 15b (50.1 mg, 86%) as a colorless oil. 1H NMR (300
MHz, CDCl3) δ (ppm) -CH(OH)CH(CH3)CH-: E-isomer 0.99 (d,
J ) 7.0, 3H), Z-isomer 0.95 (d, J ) 6.7, 3H); -Si(CH3)3: (E) 0.01 (s,
9H), (Z) 0.02 (s, 9H). All Peaks: 13C NMR (75 MHz, CDCl3) δ (ppm)
142.5, 130.1, 129.2, 128.4, 128.3, 125.7, 74.7, 74.3, 43.8, 37.8, 36.1,
35.8, 32.5, 32.2, 32.1, 23.0, 18.9, 17.1, 16.9, -1.8, -2.0. HRMS
calculated for C17H28OSi (M + H)+ m/z 277.1988, found 277.1997.
1
10b (9 mg, 62%) as a colorless oil. H NMR (300 MHz, CDCl3) δ
(ppm) 7.30-7.18 (m, 5H), 5.57 (ddd, J ) 17.1, 10.2, 9.3, 1H), 5.09
(ddd, J ) 17.1, 2.1, 0.9, 1H), 4.95 (dd, J ) 10.2, 1.8, 1H), 2.68 (m,
2H), 1.65 (m, 2H), 1.2 (ddd, J ) 4.4, 8.8, 8.8, 1H), 1.05 (d, J ) 5.8,
3H), 0.71 (m, 1H), 0.57 (ddq, J ) 5.3, 5.3, 5.8, 1H). 13C NMR (75
MHz, CDCl3) δ (ppm) 142.7, 138.4, 128.7, 128.4, 125.8, 113.7, 36.1,
31.2, 28.7, 27.3, 21.5, 18.7. FTIR (cm-1) 3083, 2999, 2927, 2860, 1633,
1496, 1454, 1076, 988. HRMS calculated for C14H18 (M + H)+ m/z
187.1487, found 187.1463.
Representative Ethyl Ester Reduction and Silyloxy Ring Cleav-
age with DIBAL. Preparation of anti-2-[3-(Dimethyl-silanyl)-
propenyl]-5-phenyl-pentane-1,3-diol (13a). A nitrogen-flushed solu-
tion of ethyl ester 13c (100 mg, 0.31 mmol) in methylene chloride
(2.5 mL) was cooled to -78 °C, to which was added dropwise a 1 M
solution of DIBAL (1.55 mL) via syringe. The reaction was allowed
to come to room temperature over 5 h. The reaction was quenched
with a saturated solution of Rochelle salt. The resultant salts were
filtered and washed with ethyl acetate. The organic layer was dried
with MgSO4 and concentrated in vacuo. The residue was purified by
flash column chromatography (silica gel, 25% ether in hexanes) to
afford 13a (77 mg, 88%) as a clear oil; crystallization to a white solid
occurred upon long periods of standing. Spectra for 13a: 1H NMR
(300 MHz, CDCl3) δ (ppm) 7.32-7.15 (m, 5H), 5.73 (td, J ) 8.7,
11.1, 1H), 5.32 (dd, J ) 11.1, 11.0, 1H), 3.90-3.63 (m, 4H), 2.89-
2.78 (m, 1H), 2.71-2.61 (m, 1H), 1.89-1.52 (m, 5H), 0.102 (d, J )
3.6, 6H). 13C NMR (75 MHz, CDCl3) δ (ppm) 142.0, 130.4, 128.4,
Acknowledgment. This paper is dedicated to the memory
of Arthur G. Schultz. We gratefully acknowledge support from
the National Science Foundation through an Early Career Award
(CHE97-33253). This work has also been supported by the
Petroleum Research Fund as administered by the American
Chemical Society (31817-G1). F.C.E. acknowledges a Rohm
& Haas Graduate Fellowship (2000-2001; UND). M.J.S.
acknowledges an Amoco Graduate Fellowship (2000-2001;
UND). R.E.T. is an Eli Lilly Grantee award recipient.
128.4, 125.8, 123.1, 72.8, 65.0, 44.3, 36.4, 32.3, -4.5. FTIR (cm-1
)
3305, 3013, 2114, 1604, 1497, 1454. HRMS calculated for C16H26O2-
Si (M + H)+ m/z 279.1780, found 279.1770.
Representative Ethyl Ester Reduction with DIBAL. Preparation
of anti-(2,2-Dimethyl-7-phenethyl-2,3,6,7-tetrahydro-[1,2]oxasilepin-
6-yl)-methanol (13c). A nitrogen flushed solution of ethyl ester 13c
(75 mg, 0.24 mmol) in methylene chloride (5 mL) was cooled to -78
°C, to which was added dropwise a 1 M solution of DIBAL (0.53 mL)
via syringe. The reaction was closely monitored for disappearance of
starting ester. After 2 h at -78 °C the reaction was quenched with a
saturated solution of Rochelle salt, and the resultant salts were filtered
and washed with ethyl acetate. The organic layer was dried with MgSO4
and concentrated in vacuo. The residue was purified by flash column
chromatography (silica gel, 25% ether in hexanes) to afford 13c as a
clear oil. Spectra for 13c: 1H NMR (300 MHz, CD Cl3) δ (ppm) 7.31-
7.14 (m, 5H), 5.99-5.90 (m, 1H), 5.41 (ddd, J ) 11.2, 6.3, 1.2, 1H),
4.03 (td, J ) 9.6, 2.4, 1H), 3.66 (d, J ) 3.9, 2H), 2.97-2.86 (m, 1H),
Supporting Information Available: Full characterization
data for compounds 4a-f, 5a, 5b, 5d-f, 9a, 10a, 10c-e, 13b,
1
13d, 14a, 14b, 14c, 14d, 15a, 15c-f and H- and 13C NMR
spectra for all new compounds (PDF). This material is available
free of charge via the Internet at http://pubs.acs.org.
JA0037163