A cyclopropanol-based strategy for subunit coupling: Total synthesis of (+)-spirolaxine methyl ether

Article abstract of DOI:10.1021/ol0710111

Equation Presented A strategy for ketone synthesis with cyclopropanols as intermediates and its application to (+)-spirolaxine methyl ether is described. The synthesis also features an application of Fu's alkyl-alkyl Suzuki coupling.

Full text of DOI:10.1021/ol0710111

ORGANIC
LETTERS
2007
Vol. 9, No. 14
2717-2719
A Cyclopropanol-Based Strategy for
Subunit Coupling: Total Synthesis of
(+)-Spirolaxine Methyl Ether
Katie A. Keaton and Andrew J. Phillips*
Department of Chemistry and Biochemistry, UniVersity of Colorado at Boulder,
Boulder, Colorado 80309-0215
andrew.phillips@colorado.edu
Received May 1, 2007
ABSTRACT
A strategy for ketone synthesis with cyclopropanols as intermediates and its application to (+)-spirolaxine methyl ether is described. The
synthesis also features an application of Fu’s alkyl−alkyl Suzuki coupling.
In the course of studies directed toward the synthesis of
polyketide natural products, we sought a convenient method
for the reductive coupling of an olefin with an ester. Although
current dogma dictates that this process is best achieved by
a multistep sequence involving conversion of the olefin to a
main group organometallic and reaction with a Weinreb
amide, we were attracted to a straightforward alternative that
consists of sequencing a Kulinkovich cyclopropanation1,2 and
subsequent cyclopropanol opening (Scheme 1).3-5
in producing 2.7 After exploring acidic and basic conditions
for the opening of cyclopropanol 2, we settled on the Fe-
(III)-based conditions first promulgated by DePuy8 and
Saegusa.9,10 In the presence of Bu3SnH, Fe(NO3)3 provided
3 in 86% yield. Other hydrogen atom or hydride donors11
such as 1,3-cyclohexadiene or Et3SiH were also suitable,
although with lower yield in this example (50 and 37%,
respectively).
Our initial studies focused on the combination of olefin 1
with ethyl acetate (Scheme 2). Although a variety of
conditions for the Kulinkovich reaction are known, the
straightforward application of cyclohexylmagnesium bro-
mide6 as reductant in the presence of Ti(i-PrO)4 was effective
Scheme 1
(1) (a) Kulinkovich, O. G.; Sviridov, S. V.; Vasilevskii, D. A.; Pri-
tytskaya, T. S. Zh. Org. Chim. 1989, 25, 2244. (b) Cha, J. K.; Kim, H.;
Lee, J. J. Am. Chem. Soc. 1996, 118, 4198.
(2) For review of the Kulinkovich cyclopropanation, see: de Meijere,
A.; Kulinkovich, O. G. Chem. ReV. 2000, 100, 2789.
(3) A substantial portion of the early work on cyclopropanols was carried
out by DePuy and co-workers. For a review, see: Gibson, D. H.; DePuy,
C, H. Chem. ReV. 1974, 74, 605.
(4) For a recent review of the chemistry of cyclopropanols, see:
Kulinkovich, O. G. Chem. ReV. 2003, 103, 2597.
(5) For other examples of Ti-based subunit couplings, see: (a) Keaton,
K. A.; Phillips, A. J. J. Am. Chem. Soc. 2006, 128, 408. (b) Reichard, H.
A.; Micalizio, G. C. Angew. Chem., Int. Ed. 2007, 46, 1440.
10.1021/ol0710111 CCC: $37.00
© 2007 American Chemical Society
Published on Web 06/09/2007

Scheme 2
Table 1. Ketone Synthesis by Kulinkovich
Reaction-Cyclopropanol Opening
Some measure of the utility of this reaction for the
acylation of other homoallylic alcohols is provided in Table
1. As can be seen from this survey presented, there is
tolerance of simple functionality, and the yields for the two-
step process range from ∼50 to 80% (an average of 75-
90% each step).
In parallel studies, we have applied this strategy to a
remarkably direct synthesis of the spiroketal domain of (+)-
spirolaxine methyl ether (Scheme 3) en route to a total
synthesis.12 The spirolaxines were isolated from various
strains of white rot fungi (genera Sporotrichum and Phan-
erochaetei) and have potent activity against Helicobacter
pylori.13 Spirolaxine 1 has also been reported to lower
cholesterol and to inhibit the growth a variety of cell lines.14
Some recent attention from the synthesis community has
resulted in total syntheses of (+)-spirolaxine methyl ether
by Brimble and co-workers15 and Dallavalle and co-work-
ers.16
The synthesis commences with the coupling of readily
available olefin 417 with commercially available (R)-γ-
(6) Lee, J.; Kim, H.; Cha, J. K. J. Am. Chem. Soc. 1996, 118, 4198.
(7) The Kulinkovich cyclopropanation generally provides cis-cyclopro-
panols, although more highly substituted substrates can give mixtures of
cis- and trans-cyclopropanols. For mechanistic studies, see: (a) Casey, C.
P.; Strotman, N. A. J. Am. Chem. Soc. 2004, 126, 1699. (b) Wu, Y.-D.;
Yu, Z.-X. J. Am. Chem. Soc. 2001, 123, 5777.
(8) DePuy, C. H.; Van Lanen, R. J. J. Org. Chem. 1974, 39, 3360.
(9) It is known that FeCl3 and Fe(NO3)3 cleave (trimethylsilyl) cyclo-
propanols to give the enone or the â-chloroketone: (a) Ito, Y.; Fujii, S.;
Saegusa, T. J. Org. Chem. 1976, 41, 2073. (b) Blanco, L.; Mansour, A.
Tetrahedron Lett. 1988, 29, 3239. (c) For the opening and subsequent 5-exo
cyclization of trimethylsilylcyclopropanol-derived radicals, see: Booker-
Milburn, K. I.; Jones, L. J.; Sibley, G. E. M.; Cox, R.; Meadows, J. Org.
Lett. 2003, 5, 1107 and references cited therein.
(10) (a) For the photosensitized oxidation and opening of aminocyclo-
propanes, see: Lee, H. B.; Sung, M. J.; Blackstock, S. C.; Cha, J. K. J.
Am. Chem. Soc. 2001, 123, 11322. (b) For the opening of cyclopropanols
to enones, see: Lysenko, I. L.; Lee, H. G.; Cha, J. K. Org. Lett. 2006, 8,
2671.
(11) Two possible limiting scenarios can be envisaged: radical opening
of the cyclopropanol to give the â-keto radical and subsequent reaction
with Bu3SnH or oxidation of the â-keto radical to the cation and then
reaction with Bu3SnH in a polar manifold. Mechanistic studies will be
reported in due course.
a c-C6H11MgBr (6 equiv), Ti(i-PrO)4 (3 equiv), PhMe, 25 °C. b The
acylating agent was methyl isobutyrate.
valerolactone in the presence of cyclohexylmagnesium
bromide and Ti(i-PrO)4 in toluene at room temperature to
afford cyclopropanol 5 in 92% yield (Scheme 3). Immediate
exposure of this material to Fe(NO3)3 and Bu3SnH provided
ketone 6 in 75% yield. Removal of the TBS ethers and
concomitant cyclic ketal formation proceeded smoothly upon
exposure of 6 to HF to yield 7 (89%). Subsequent Appel
reaction with NBS and PPh3 proceeded in quantitative yield
to give primary bromide 8.
At this juncture, we were presented with an opportunity
to evaluate the alkyl-alkyl Suzuki coupling recently reported
by Fu for the union of the two halves of the target.18 To this
end, a solution of olefin 11 in THF (prepared from 9 by
(12) (a) Arnone, A.; Assante, G.; Nasini, G.; Vajna de Pava, O.
Phytochemistry 1990, 29, 613. (b) Gaudliana, M. A.; Huang, L. H.; Kaneko,
T.; Watts, P. C. PCT Int. Appl. W0 9605204, 1996. (c) Adachi, T.; Takagi,
I.; Kondo, K.; Kawashima, A.; Kobayashi, A.; Taneoka, I.; Morimoto, S.;
Hi, B. M.; Chen, Z. PCT Int. Appl. W0 9610020, 1996.
(13) (a) Blaser, M. J. Clin. Infect. Dis. 1992, 15, 386. (b) Walsh, J. H.;
Peterson, W. L. New Engl. J. Med. 1995, 333, 984. (c) Rathbone, B. Scrip
Magazine 1993, 25.
(16) Nannei, R.; Dallavalle, S.; Merlini, L.; Bava, A.; Nasini, G. J. Org.
Chem. 2006, 71, 6277.
(17) Blakemore, P. R.; Browder, C. C.; Hong, J.; Lincoln, C. M.;
Nagornyy, P. A.; Robarge, L. A.; Wardrop, D. J.; White, J. D. J. Org.
Chem. 2005, 70, 5449.
(18) Netherton, M. R.; Dai, C.; Neuschutz, K.; Fu, G. C. J. Am. Chem.
Soc. 2001, 123, 10099.
(14) Bava, A.; Clericuzio, M.; Giannini, G.; Malpezzi, L.; Valdo Meille,
S.; Nasini, G. Eur. J. Org. Chem. 2005, 2292.
(15) Robinson, J. E.; Brimble, M. A. Chem. Commun. 2005, 1560.
(19) This material was identical to the reported data for (+)-spirolaxine
methyl ether (see refs 12 and 15).
2718
Org. Lett., Vol. 9, No. 14, 2007

Scheme 3
Brimble’s route as shown) was treated with 9-BBN at 25
Acknowledgment. This material is based upon work
supported by the National Science Foundation under CHE-
0645787. Spectra were obtained using NMR facilities
purchased partly with funds from an NSF Shared Instru-
mentation Grant (CHE-0131003).
°C to yield intermediate borane 12, which was coupled with
alkyl bromide 8 in the presence of aqueous Cs2CO3, Pd-
(OAc)2 (5 mol %), and Cy3P (10 mol %) in dioxane to
directly yield spirolaxine methyl ether in 79% yield after
workup and chromatography.19
Supporting Information Available: Experimental pro-
cedures, characterization data, and copies of spectra for
compounds 3 and 5-12, spirolaxine and the final compounds
in Table 1. This material is available free of charge via the
Internet at http://pubs.acs.org.
In conclusion, we have described a new strategy for the
synthesis of ketones and its application to a very concise
synthesis of spirolaxine methyl ether. As well as highlighting
the utility of this approach for subunit couplings, the
synthesis also features a complex example of Fu’s alkyl-
alkyl Suzuki coupling.
OL0710111
Org. Lett., Vol. 9, No. 14, 2007
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