Oligocyclopropane structural units from cationic intermediates

Article abstract of DOI:10.1021/ol990221d

(matrix presented) syn-and anti-bis-cyclopropanes have been efficiently prepared through two distinct routes via the trapping of cyclopropylcarbinyl cationic intermediates. A ring-closing olefin metathesis for the formation of the necessary allylsilane pr

Full text of DOI:10.1021/ol990221d

ORGANIC
LETTERS
1999
Vol. 1, No. 8
1257-1260
Oligocyclopropane Structural Units from
Cationic Intermediates
Richard E. Taylor,* F. Conrad Engelhardt, and Haiqing Yuan
Department of Chemistry and Biochemistry, 251 Nieuwland Science Hall,
UniVersity of Notre Dame, Notre Dame, Indiana 46556-5670
taylor.61@nd.edu
Received August 10, 1999
ABSTRACT
syn- and anti-bis-cyclopropanes have been efficiently prepared through two distinct routes via the trapping of cyclopropylcarbinyl cationic
intermediates. A ring-closing olefin metathesis for the formation of the necessary allylsilane precursors highlights the initial route. The
cyclopropanation step proceeds in good yield to provide exclusively trans-vinylcyclopropanes. Iteration of the sequence has provided an
efficient route to bis-cyclopropanes. The stereospecificity of the second cyclization was shown to be dependent on distal functionality. An
alternative approach produces these interesting structural units from skipped dienes in a single step.
Two natural products have recently been isolated which
contain remarkable contiguous cyclopropane structural units.
FR-900848 is a nucleoside analogue isolated from the
fermentation broth StreptoVerticillium ferVens.1 This interest-
ing compound has shown potent selective activity against
filamentous fungi, but is surprisingly inactive against bacteria
and nonfilamentous fungi. More recently U-106305, a
cholesteryl ester transfer protein inhibitor, was reported
containing a structurally related lipid side chain.2 The
oligocyclopropanes ideal targets for synthetic methodological
development. Several groups have reported synthetic efforts
for the preparation of these novel compounds3-6 with
strategies largely based on the stereoselective cyclopropa-
nation of cyclopropyl-substituted olefins using modified
Simmons-Smith methodology. In contrast, we have been
investigating an approach based on the iterative generation,
stabilization, and trapping of cyclopropylcarbinyl cationic
intermediates.7,8
(3) For papers describing the total synthesis of FR-900848, see: (a)
Barrett A. G. M.; Kasdorf, K. J. Chem. Soc. Chem. Commun. 1996, 325-
326. (b) Barrett A. G. M.; Kasdorf, K. J. Am. Chem. Soc. 1996, 118, 11030-
11037. (c) Falck, J. R.; Mekonnen, B.; Yu, J.; Lai, J.-Y. J. Am. Chem. Soc.
1996, 118, 6096-6097.
(4) For the total synthesis of U-106305, see: (a) Barrett, A. G. M.;
Hamprecht, D.; White, A. J. P.; Williams, D. J. J. Am. Chem. Soc. 1996,
118, 7863-7864. (b) Barrett, A. G. M.; Hamprecht, D.; White, A. J. P.;
Williams, D. J. J. Am. Chem. Soc. 1997, 119, 8608-8615. (c) Charette, A.
B.; Lebel, H. J. Am. Chem. Soc. 1996, 118, 10327-10328.
(5) For alternative approaches to oligocyclopropane structural units using
modified Simmons-Smith technology on cyclopropyl-substituted alkenes,
see: (a) McDonald, W. S.; Verbicky, C. A.; Zercher, C. K. J. Org. Chem.
1997, 63, 1215-1222. (b) Therberge, C. R.; Verbicky, C. A.; Zercher, C.
K. J. Org. Chem. 1996, 62, 8792-8798. (c) Theberge, C. R.; Zercher, C.
K. Tetrahedron Lett. 1995, 36, 5495-5498. (d) Armstrong, R. W.; Maurer,
K. W. Tetrahedron Lett. 1995, 36, 357-360. (e) Theberge, C. R.; Zercher,
C. K. Tetrahedron Lett. 1994, 35, 9181.
(6) For additional examples oligocyclopropane preparation, see: (a) Itoh,
T.; Emoto, S.; Kondo, M.; Tetrahedron 1998, 54, 5225-5232. (b) Charette,
A. B.; DeFreitas-Gil, R. P. Tetrahedron Lett. 1997, 38, 2809-2812. (c)
Cebula, R. E. J.; Hanna, M. R.; Theberge, C. R.; Verbicky, C. A.; Zercher,
C. K. Tetrahedron Lett. 1996, 37, 8341. (d) O’Bannon, P. E.; Dailey, W.
P. J. Am. Chem. Soc. 1989, 111, 9244-9245.
combination of their interesting biological activity, novel
structural and conformational properties, and their potential
utility as scaffolds for combinatorial chemistry, molecular
recognition, catalysis design, and nanotechnology make
(1) Yoshida, M.; Ezaki, M.; Hashimoto, M.; Yamashita, M.; Shigematsu,
N.; Okuhara, M.; Kohsaka, M.; Horikoshi, K. J. Antibiot. 1990, 43, 748-
754.
(2) Kuo, M. S.; Zielinski, R. J.; Cialdella, J. I.; Marschke, C. K.; Dupuis,
M. J.; Li, G. P.; Kloosterman, D. A.; Spilmann, C. H.; Marshall, V. P. J.
Am. Chem. Soc. 1995, 117, 10629-10634.
10.1021/ol990221d CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/18/1999

Recently, we reported a route to trans-syn-trans and trans-
anti-trans bis-cyclopropanes through an efficient sequence
of steps as outlined in Scheme 1.7,9 The cyclopropanation
(vinylMgBr, CuI) from commercially available benzyl gly-
cidyl ether. Protection of the secondary alcohol was
accomplished with allylchlorodimethylsilane. The resulting
bis-olefin was subjected to Grubbs’ ruthenium alkylidene
catalyst, providing silyoxycycloheptene 6 in excellent yield.10
Exposure of the cyclic silyl ether 6 to methyllithium provided
the allylsilane derivative 7a, qualitatively identical to com-
pound 1 prepared by our previously reported acetylene
sequence. Not surprisingly, activation of alcohol 7a, with
trifluoromethanesulfonic anhydride provides the trans-vinyl-
cyclopropane 8 in 77% yield for the two steps. Alternatively,
silyl ether 6 could be fragmented by exposure to HF‚pyr,
providing 7b, which upon subsequent activation yielded 8
in 71% yield for the two-step sequence. These complemen-
tary cleavage conditions provide opportunities to prepare
more functionalized cyclopropane derivatives. The general
sequence allows for the efficient conversion of easily
accessible homoallylic alcohols to corresponding trans-
vinylcyclopropanes.
Scheme 1a
a (a) Propargyl-TMS, BuLi, THF, -78 °C; BF3‚OEt2; then
epoxide; (b) H2, Lindlar; (c) Tf2O, CH2Cl2, 2,6-lutidine.
At this point we can exploit the potential of the strategy
by iteration of the synthetic sequence. Vinylcyclopropane 8
underwent clean oxidative cleavage to the corresponding
aldehyde by treatment with OsO4/NaIO4, Scheme 3. The
was achieved by the activation of a homoallylic alcohol 1
with triflic anhydride. Rapid cyclization occurred to form
an intermediate cyclopropylcarbinyl cation, which was
stabilized and trapped by the presence of a â-trimethylsilyl
group. The ring closure proceeded in excellent yield and
provided exclusively trans-vinylcyclopropane 2. Epoxidation
followed by reiteration of the methodology provided efficient
access to diastereomerically pure syn- and anti-bis-cyclo-
propanes 4.
Scheme 3
Since this preliminary report we have developed an
alternative, more versatile route to similar cyclization precur-
sors. The new sequence begins with an easily accessible
starting material, homoallylic alcohol 5, Scheme 2. While a
Scheme 2
necessary homoallylic alcohol was prepared by exposure to
allylmagnesium bromide at low temperature. The homoallylic
(8) For examples of chemical approaches to cyclopropanes via cyclo-
propylcarbinyl cationic intermediates, see: (a) Krief, A.; Provins, L. Synlett
1997, 505-507. (b) Hannesian, S.; Reinhold, U.; Ninkovic, S. Tetrahedron
Lett. 1996, 37, 8971-8974. (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.; Hana, Y.; Onoguchi, Y.; Ohba, S.; Suzuki, S. Synlett 1995,
739. (f) White, J. D.; Jensen, M. S. J. Am. Chem. Soc. 1993, 115, 2970.
(9) 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, 717-723.
diverse range of homoallylic alcohols are available from the
allylation of aldehydes, 5 was prepared in a single step
(7) Taylor, R. E.; Ameriks, M. K.; LaMarche, M. J. Tetrahedron Lett.
1997, 38, 2057-2060.
1258
Org. Lett., Vol. 1, No. 8, 1999

alcohol 9a,b was obtained as a mixture of diastereomers
(1:1) in >90% yield from 8. While the separation of these
alcohols was fairly tedious, each diastereomer could be
obtained with >95% stereoisomeric purity through the use
of flash chromatography. While it is expected that stereo-
selective allylation of the cyclopropylaldehyde could be
accomplished using reagent-based methods,11 a stereorandom
allylation enabled us to test the stereospecificity of a second
ring closure.
Scheme 4a
The final sequence of steps is presented for each diaste-
reomer in Scheme 3. After silylation and ring-closing
metathesis, the fragmentation proceeded smoothly for each
isomer, yielding the cyclopropanation precursors 10a and
10b. Activation of either diastereomeric homoallylic alcohol
under our standard conditions provided high yields of the
bis-cyclopropane products. The only byproduct of this
reaction is the trimethylsilyl ether of 10a and 10b, which
can be isolated in as high as 20% yield. Apparently, the
cyclization step, which generates an equivalent of TMSOTf
is extremely fast relative to the generation of the triflate.
Although the formation of the bis-cyclopropanes was
extremely efficient, we were surprised to isolate an identical
1:1 (syn:anti) mixture of diastereomers from the reaction of
each precursor, 10a and 10b.12 This suggests that the second
ring closure is slower than ionization of the intermediate
triflate, formation of a cyclopropylcarbinyl cation, and loss
of the stereochemical integrity of the starting homoallylic
alcohol stereogenic center.
The lack of stereospecificity in the second cyclization
strongly contrasts our previously published work,13 which
contained a distal phenoxy group in place of the benzyl ether
(Scheme 1). A potential explanation is that benzyl ether
assists in the ionization of the secondary triflate and
stabilization of the homoallylic carbocation14 through pro-
posed intermediate A which then undergoes sequential
cyclizations to provide the mixture of diastereomeric bis-
cyclopropanes. On the basis of this hypothesis, it should be
possible to generate multiple cyclopropanes in a single step
from an acyclic skipped diene structure.
a (a) BuLi, THF, -78 °C; BF3‚OEt2; phenylglycidyl ether, 58%,
(b) pTsOH, CH3OH; 89%; (c) CBr4, Ph3P, CH2Cl2; 98%; (d)
Na2CO3, TBAI, CuI, DMF, propargyl-TMS; 67%; (e) H2, Lindlar,
pyr; 76%; (f) Tf2O, CH2Cl2, 2,6-lutidine; 69%.
mediately followed by acid-catalyzed deprotection. The
primary alcohol underwent selective conversion to the
propargylic bromide 12 in good yield. A skipped diyne was
then prepared by condensation of propargyltrimethylsilane
with the bromide under the conditions reported by Jeffery
et al.15 The diyne was then selectively reduced to the Z,Z-
diene 13 via Lindlar hydrogenation in the presence of
pyridine. Exposure of the 13 to the standard actiVation
conditions proVided the bis-cyclopropane 14 as a 1:1 mixture
of diastereomers in a remarkable 69% yield. Only minor
uncharacterizable byproduct formation was observed in the
1H NMR of the crude reaction mixture. Presumably, the bis-
cyclopropane forms via trapping of the intermediate cyclo-
propylcarbinyl cation.14 This appears to be faster than
trapping of the related homoallylic cation to form a ther-
modynamically more stable cyclohexene isomer through a
six-membered ring transition state. Alternatively, both carbon-
carbon bonds could be forming in a more concerted fashion
without the generation of a discrete cyclopropylcarbinyl
cation.
In summary, we have developed a practical method for
the conversion of readily available homoallylic alcohols to
trans-vinylcyclopropanes and oligocyclopropanes based upon
novel reactive intermediates. A ring-closing olefin metathesis
and an intramolecular displacement of a homoallylic triflate
with an allylsilane nucleophile highlight the efficient four-
step sequence. The route is general and applicable to the
stereocontrolled preparation of 1,2,3-trisubstituted cyclopro-
panes, which will be reported in a subsequent publication.
The stereospecificity of the second cyclization was shown
to be dependent upon the nature of functionality distal to
the cyclopropylcarbinyl triflate. The tandem cationic cy-
clization, reminiscent of the elegant work of W. S. Johnson16
is extraordinarily facile. We are continuing to explore many
aspects of this work and related synthetic and mechanistic
challenges.
Skipped diene 13 was efficiently prepared through the
sequence shown in Scheme 4. Epoxide fragmentation with
the alkynyl anion of O-THP-propargyl alcohol was im-
(10) For the preparation of olefinic diols via similar silyloxycycloalkenes,
see: Chang, S.; Grubbs, R. H. Tetrahedron Lett. 1997, 38, 4757-4760.
For the preparation of tetrahydrofurans and pyrans via similar silyloxycy-
cloalkenes, see: Meyer, C.; Cossy, J. Tetrahedron Lett. 1997, 38, 7861-
7864.
(11) (a) Keck, G. E.; Geraci, L. S. Tetrahedron Lett. 1993, 34, 7827-
7828. (b) Racherla, U. S.; Brown, H. C. J. Org. Chem. 1991, 56, 401-
404. (c) Roush, W. R.; Hoong, L. K.; Palmer, M. A. J.; Park, J. C. J. Org.
Chem. 1990, 55, 4109-4117.
(12) The relative stereochemistry of the diastereomeric homoallylic
alcohols 9a and 9b was determined by chemical correlation to previously
reported compounds. See: Mohapatra, D. K.; Datta, A. J. Org. Chem. 1998,
63, 642-646.
(13) (a) We have more recently repeated these experiments and have
shown that the phenoxy series is ∼80% stereospecific. (b) We do not believe
that the benzyl ether has an effect on the initial cyclopropanation reaction
(7 to 8, Scheme 2).
(14) The “classic” and “nonclassic” carbocationic behavior of homoallyl-
cyclopropyl carbinyl-cyclobutyl cations has recently been reviewed: Olah,
G. A.; Reddy, V. P.; Surya Prakash, G. K. Chem. ReV. 1992, 92, 69-95.
For a seminal discussion of these intermediates, see: Roberts J. D.; Mazur,
R. H. J. Am. Chem. Soc. 1951, 73, 2509.
Acknowledgment. We gratefully acknowledge support
from the National Science Foundation through an Early
Career Award (CHE97-33253). This work is also supported
(15) Jeffery, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett. 1992,
33, 5757-5760.
(16) Johnson, W. S. Acc. Chem. Res. 1968, 54, 4731.
Org. Lett., Vol. 1, No. 8, 1999
1259

by the Petroleum Research Fund as administered by the
American Chemical Society (31817-G1).
This material is available free of charge via the Internet at
http://pubs.acs.org.
Supporting Information Available: 1H and 13C NMR
spectra and full experimental details for all new compounds.
OL990221D
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