Cyclopropane compatibility with oxidative carbocation formation: Total synthesis of clavosolide A

Article abstract of DOI:10.1021/ol302744t

Cyclopropane-substituted allylic ethers react with 2,3-dichloro-5,6- dicyano-1,4-benzoquinone to form oxocarbenium ions with no competitive ring cleavage. This reaction can be used for the preparation of cyclopropane- substituted tetrahydropyrans. The pro

Full text of DOI:10.1021/ol302744t

ORGANIC
LETTERS
2012
Vol. 14, No. 21
5614–5617
Cyclopropane Compatibility with
Oxidative Carbocation Formation:
Total Synthesis of Clavosolide A
GuangRong Peh and Paul E. Floreancig*
Department of Chemistry, University of Pittsburgh, Pittsburgh, Pennsylvania 15260,
United States
florean@pitt.edu
Received October 4, 2012
ABSTRACT
Cyclopropane-substituted allylic ethers react with 2,3-dichloro-5,6-dicyano-1,4-benzoquinone to form oxocarbenium ions with no competitive ring
cleavage. This reaction can be used for the preparation of cyclopropane-substituted tetrahydropyrans. The protocol was used as a key step in the
total synthesis of the sponge-derived macrolide clavosolide A.
The strain energy of approximately 27 kcal/mol in
cyclopropanes provides a driving force for several ring-
opening reactions that are not observed in less strained
cycloalkanes.1 Cyclopropane cleavage is commonly en-
countered when a reactive intermediate such as a carbe-
nium ion is introduced on an adjacent atom.2 These ring
cleavage processes limit the reaction conditions that can
be utilized in the presence of cyclopropanes and often
mandate that the synthesis of cyclopropane-containing
products employ cyclopropanation reactions at a late stage
in the sequence.
material. Indeed Taylor and co-workers have demonstrated4
that cyclopropanes can be formed from intramolecular
additions of electron-rich alkenes into cationic intermedi-
ates, a process that is the microscopic reverse of cation-
induced cyclopropane opening.
Scheme 1. Energetics of Cyclopropyl Carbinyl Cation Ring
Opening
Cationic cyclopropane-opening reactions can be sup-
pressed by sufficiently stabilizing the reactive intermediate
to counterbalance the energetic benefit of strain release.3
This is illustrated in Scheme 1, whereby the cleavage of
a cyclopropane with an adjacent oxocarbenium ion is
postulated to be disfavored because the product contains
a far less stabilized cation in comparison to the starting
The stability of cyclopropane-substituted oxocarbenium
ions creates opportunities for functionalization through
nucleophilic addition reactions. The products of these
additions, however, would still be susceptible to cyclopro-
pane opening through ionization of the product alkoxy
group if classical Lewis acid mediated protocols are em-
ployed for oxocarbenium ion generation. This suggests that
electrophile formation under nonacidic conditions would
provide strategic benefits for the functionalization of cy-
clopropane-containing molecules. Oxidative carbocation
(1) de Meijere, A. Angew. Chem., Int. Ed. 1979, 18, 809.
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Angew. Chem., Int. Ed. 2004, 43, 6671.
r
10.1021/ol302744t
Published on Web 10/24/2012
2012 American Chemical Society

formation provides an alternative to Lewis acid mediated
ionization and has been used in the synthesis of complex
structures that contain sensitive groups such as acetals and
epoxides.5 We have been engaged in developing oxidative
carbonÀhydrogen bond cleavage reactions to generate
stabilized carbocations under nonacidic conditions.6 These
processes proceed through reactions of allylic, benzylic,
and vinylic ethers, amides, and sulfides with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ). In this manuscript
we report that cyclopropane-substituted R,β-unsaturated
oxocarbenium ions can be prepared through allylic ether
oxidation and that the resulting intermediates can be
trapped to form tetrahydropyrans with no evidence of ring
opening, as shown in the generic conversion of 1 to 2 to 3
in Scheme 2. This process is used as the key step in a
convergent synthesis of the macrodiolide clavosolide A.
not quantitative, the remainder of the mass can be attrib-
uted to nonspecific decomposition pathways rather than
cyclopropane ring opening. These results provided a sui-
table precedent for the application of the protocol in a
more complex setting.
Scheme 3. Oxidative Cyclization of Cyclopropane-Containing
Substrates
Scheme 2. Oxidative Synthesis of Cyclopropane-Containing
Tetrahydropyrans
We chose clavosolide A, 9 (Scheme 4), as a target to
highlight the utility of the protocol. The Faulkner group
isolated clavosolide A from a sponge off the coast of the
Phillipines,8 but limited quantities have precluded a thor-
ough examination of its biological activity. A revision of
the stereostructure was proposed by Willis9 and was con-
firmed through a total synthesis from the Lee group.10
Several total and formal syntheses of clavosolide A have
subsequently been reported,11 with the majority employing
a late stage introduction of the cyclopropyl group to avoid
the potential for ring opening. Smith and co-workers
introduced the cyclopropane at an early stage but noted
the Lewis acid sensitivity of the group and cautioned against
prolonged reaction times and the use of strong acids.11b Our
objective was to demonstrate that the oxidative cyclization
conditions allow the cyclopropane unit of clavosolide A
to be introduced at an early stage in the synthesis, thereby
providing an attractive strategy for a convergent synthesis.
We envisioned 9 as arising from cyclopropyl tetrahydropyr-
an 10, which can be accessed from ether 11 through an
oxidative cyclization. This ether can arise from the union of
subunits 12 and 13.
The initial demonstrations of this transformation are
shown in Scheme 3. Vinylsilanes were selectedassubstrates
because they can be converted stereoselectively to second-
ary alcohols through a short sequence6d and they are
readily accessed with high geometric control from alkynes
through hydrosilylation reactions7 with ruthenium or
platinum catalysts. Enol acetates were used as the nucleo-
philes because they are oxidatively stable enolate surro-
gates. Exposing Z-vinylsilane 4 to DDQ at 45 °C provided
oxocarbenium ion 5 en route to the formation of tetrahy-
dropyrone 6. While many DDQ-mediated oxocarbenium
ion formations proceed at ambient temperature or below,
the vinylsilanes generally require higher temperatures be-
cause steric bulk interferes with their association with
the oxidant.6d The oxidation of (E)-isomer 7 proceeds with
similar efficiency to form 8. These reactions provided
inseparable diastereomeric mixtures of products, showing
that the cyclopropyl group does not promote remote
stereoinduction. While the yields of these reactions were
The synthesis of the cyclopropane-containing subunit
(Scheme 5) employed Feringa’s elegant asymmetric 1,4-
addition protocol12 as the key step. Conjugate addition
of MeMgBr to chloro enone 14, prepared in one step from
(5) (a) Wan, S.; Gunaydin, H.; Houk, K. N.; Floreancig, P. E. J. Am.
Chem. Soc. 2007, 129, 7915. (b) Green, M. E.; Rech, J. C.; Floreancig,
P. E. Angew. Chem., Int. Ed. 2008, 47, 7317. (c) Clausen, D. J.; Wan, S.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2011, 50, 5178.
(6) (a) Tu, W.; Liu, L.; Floreancig, P. E. Angew. Chem., Int. Ed. 2008,
47, 4184. (b) Tu, W.; Floreancig, P. E. Angew. Chem., Int. Ed. 2009, 48,
4567. (c) Liu, L.; Floreancig, P. E. Org. Lett. 2009, 11, 3152. (d) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 3069. (e) Liu, L.;
Floreancig, P. E. Angew. Chem., Int. Ed. 2010, 49, 5894. (f) Brizgys, G. J.;
Jung, H. H.; Floreancig, P. E. Chem. Sci. 2012, 3, 438. (g) Cui, Y.;
Floreancig, P. E. Org. Lett. 2012, 14, 1720. (h) Han, X.; Floreancig, P. E.
Org. Lett. 2012, 14, 3808. (i) Clausen, D. J.; Floreancig, P. E. J. Org.
Chem. 2012, 77, 6574.
(8) Rao, M. R.; Faulkner, D. J. J. Nat. Prod. 2002, 65, 386.
(9) Barry, C. S.; Bushby, N.; Charmant, J. P. H.; Elsworth, J. D.;
Harding, J. R.; Willis, C. L. Chem. Commun. 2005, 5097.
(10) Son, J. B.; Kim, S. N.; Kim, N. Y.; Lee, D. H. Org. Lett. 2006, 8,
661.
(11) (a) Barry, C. S.; Elsworth, J. D.; Seden, P. T.; Bushby, N.;
Harding, J. R.; Alder, R. W.; Willis, C. L. Org. Lett. 2006, 8, 3319. (b)
Smith, A. B., III; Simov, V. Org. Lett. 2006, 8, 3315. (c) Chakraborty,
T. K.; Reddy, V. R.; Gajula, P. K Tetrahedron 2008, 64, 5162. (d)
Carrick, J. D.; Jennings, M. P. Org. Lett. 2009, 11, 769.
ꢀ
(12) den Hartog, T.; Rudolph, A.; Macia, B.; Minnaard, A. J.;
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Feringa, B. L. J. Am. Chem. Soc. 2010, 132, 14349.
Org. Lett., Vol. 14, No. 21, 2012
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The synthesis of the cyclization precursor is shown in
Scheme 6. Coupling mesylate 17, in which the stereocenter
can be conveniently prepared through a Noyori reduc-
tion,16 with aldehyde 18 under Marshall’s conditions17
provided homopropargylic alcohol 19 with good enantio-
and diastereocontrol. Deprotonation followed by the
addition of mesylate 16 under modified Williamson
conditions18 provided the expected ether with concomitant
cleavageof the alkynylsilane group. The addition ofHOAc
through standard ruthenium-catalyzed conditions19 pro-
vided a mixture of the expected enol acetate 20 (55%)
and dienol acetate 21 (27%). This procedure is generally
quite selective for terminal alkynes in preference to internal
Scheme 4. Retrosynthetic Analysis of Clavosolide A
Scheme 6. Synthesis of the Cyclization Substrates
allyl chloride and acetyl chloride,13 in the presence of CuI
and (R)-tolylBINAP provided a chloro enolate that could
either be warmed to generate cyclopropane 15 directly or
quenched at low temperature and subjected to base to effect
the cyclopropanation in >90% ee.14 We found that the yield
and reproducibility were superior for the two-step protocol.
Scheme 5. Synthesis of the Cyclopropane-Containing Subunit
alkynes,6d,h indicating that the cyclopropane group plays
an activating role. The cis-addition across the internal
alkyne was confirmed through NOESY experiments on
a subsequent intermediate. Subjecting 20 to hydrosilyla-
tion under Trost’s conditions20 provided vinylsilane 22
in 71% yield. Since 21 could in principle also suffice for
our synthetic objectives, we exposed the diyne to a higher
catalyst loading and a longer reaction time to provide the
diaddition product in 69% yield.
The oxidative cyclization reactions are shown in
Scheme 7. Exposing 21 to DDQ at rt for 1.5 h provided
23 as a single stereoisomer in 62% yield. The cyclization of
22 required heating to 40 °C for 6 h to provide a 51% yield
of 24. No attempt was made to optimize the yield for the
cyclization of 22 in consideration of material accessibility
and the superiority of 21 as a substrate. The cyclization
of 21 is significant in that it highlights the utility of enol
The methyl ketone was converted to a propargyl alcohol
through Negishi’s method15 in which the enolate was
quenched with diethylphosphoryl chloride and the result-
ing phosphonate was subjected to excess LDA to generate
the alkynyl anion. Quenching the alkynyl anion with
paraformaldehyde completed the construction of the pro-
pargyl alcohol. Converting the hydroxy group to a leaving
group proved to be challenging due to cyclopropane
opening upon exposure to common halogenating agents.
However mesylation under standard conditions could be
achieved to form 16. This species should be prepared
shortly before the subsequent step due to its propensity
for ionization and decomposition.
(16) Matsumura, K.; Hashiguchi, S.; Ikariya, T.; Noyori, R. J. Am.
Chem. Soc. 1997, 119, 8738.
(17) Marshall, J. A.; Adams, N. D. J. Org. Chem. 1998, 63, 3812.
(18) Aspinall, H. C.; Greeves, N.; Lee, W.-M.; McGiver, E. G.;
Smith, P. M. Tetrahedron Lett. 1997, 38, 4679.
(19) Goossen, L. J.; Paetzold, J.; Koley, D. Chem. Commun. 2003,
706.
(20) Trost, B. M.; Ball, Z. T. J. Am. Chem. Soc. 2005, 127, 17644.
(13) Kulinkovich, O. G.; Tischenko, I. G.; Sorokin, V. L. Synthesis
1985, 1058.
(14) An exact value for the ee could not be obtained because of
overlapping peaks in the HPLC trace. Please see the Supporting
Information for details.
(15) Negishi, E.; King, A. O.; Klima, W. L.; Patterson, W.; Silveira,
A., Jr. J. Org. Chem. 1980, 45, 2526.
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Org. Lett., Vol. 14, No. 21, 2012

acetates as stabilizing groups for oxidative carbocation
formation, thereby providing an additional option for the
formation of functionalized alkenyl tetrahydropyrans that
can be used for subsequent diversification studies.
Scheme 8. Completion of the Synthesis
Scheme 7. Comparison of Oxidative Cyclization Substrates
The completion of the synthesis is shown in Scheme 8.
Ketone reduction of 23 with NaBH4 smoothly provided
the equatorial alcohol on the tetrahydropyran. The enol
acetate was then cleaved with K2CO3 and MeOH to yield
the corresponding ketone. Glycosidation was conducted at
this point in accord with syntheses of related struc-
tures,10,21 because the glycosyl group can effectively serve
as a hydroxyl protecting group. Additionally, three
anomeric stereoisomers can form if glycosidation is con-
ducted after macrodiolide formation, resulting in a low
product yield and a significant separation problem if
the glycosylation reaction shows poor selectivity. Adding
the tetrahydropyranol to trichloroacetimidate 259 in the
presence of TMSOTf provided glycoside 26 (52%) along
with significant amounts of its anomer. The reduction
of a similar ketone group has been reported11c to proceed
with useful substrate-directed stereocontrol, but we found
superior results could be attained through reagent-directed
stereocontrol. Exposing 26 to BH3•SMe2 and catalyst 2722
provided the desired secondary alcohol in high yield and
with good diastereocontrol. Removal of the silyl protect-
ing group was achieved with HCl in EtOH. Selective
oxidation of the primary alcohol23 yielded carboxylic acid
monomer 28. Macrodiolide formation under Yamaguchi’s
conditions24 completed the synthesis of clavosolide A.
We have shown that cyclopropanes are compatible
with oxocarbenium ion formation through CÀH bond
oxidation and have applied this result to the synthesis
of cyclopropane-substituted tetrahydropyrans. The func-
tional group tolerance of the oxidative cyclization allowed
for a convergent total synthesis of clavosolide A. Key steps
in the sequence include an early stage Feringa asymmetric
cyclopropanation reaction and the oxidation of of an
acetoxy-substituted allylic ether as a precursor to a func-
tionalized unsaturated oxocarbenium ion. The capacity
to introduce cyclopropane groups at an early stage of a
synthetic sequence that eventually proceeds through a
carbocation-forming reaction adds to the unique strategic
options that oxidative CÀH bond functionalization offers
for complex molecule synthesis.
Acknowledgment. We thank the National Institutes
of Health (GM062924) for generous support of this work.
We thank Professor T. K. Chakraborty and Dr. R. Reddy
Vakiti (CentralDruginstitute, Lucknow, India) for helpful
discussions and sharing spectra.
(21) (a) Kim, H.; Hong, J. Org. Lett. 2010, 12, 2880. (b) Seden, P. T.;
Charmant, J. P. H.; Willis, C. L. Org. Lett. 2008, 10, 1637.
(22) (a) Corey, E. J.; Helal, C. J. Tetrahedron Lett. 1995, 36, 9153.
(b) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(23) Anelli, P. L.; Biffi, C.; Montanari, F.; Quici, S. J. Org. Chem.
1987, 52, 2559.
Supporting Information Available. Experimental pro-
cedures for cyclization reactions and characterization
data for all new compounds. This information is available
free of charge via the Internet at http://pubs.acs.org.
(24) Inanaga, J.; Hirata, K.; Saeki, H.; Katzuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 21, 2012
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