Asymmetric total synthesis of rollicosin

Article abstract of DOI:10.1021/ol047352l

(Chemical Equation Presented) The first total synthesis of rollicosin, a member of a rare subgroup of Annonaceous acetogenins containing two terminal γ-lactones, is reported. The approach features a highly reglo- and stereoselective tandem ring-closing/cr

Full text of DOI:10.1021/ol047352l

ORGANIC
LETTERS
2005
Vol. 7, No. 7
1243-1245
Asymmetric Total Synthesis of
Rollicosin
Kevin J. Quinn,* Andre´ K. Isaacs, Brian A. DeChristopher,
Stephanie C. Szklarz, and Rebecca A. Arvary
Department of Chemistry, College of the Holy Cross,
Worcester, Massachusetts 01610-2395
kquinn@holycross.edu
Received December 23, 2004
ABSTRACT
The first total synthesis of rollicosin, a member of a rare subgroup of Annonaceous acetogenins containing two terminal
γ-lactones, is
reported. The approach features a highly regio- and stereoselective tandem ring-closing/cross-metathesis reaction for construction of the
east-wing lactone and incorporation of the alkyl spacer. Establishment of the C4 stereocenter and addition of the west-wing lactone were
achieved by Sharpless asymmetric dihydroxylation and enolate alkylation.
The Annonaceous acetogenins are a class of polyketide
natural products with wide-ranging biological profiles,
including activity as antitumor, antiparasitic, insecticidal, and
immunosuppressive agents.1 Structural features common to
acetogenins are a terminal γ-lactone and a terminal aliphatic
side chain connected by a linker containing variously located
oxygenated functional groups and/or rings. Members of this
family are classified into several subtypes based on structural
features present in the linker and the nature of the terminal
γ-lactone.2
cell lines, suggesting potential of truncated acetogenins as
prototype anticancer agents and utility as SAR probes. Their
biological activities and limited availabilities make 1 and 2
excellent candidates for synthesis. To date, however, only
one approach has been reported, which culminated in the
synthesis of ent-2.5
Scheme 1. Retrosynthetic Analysis
Rollicosin (1, Scheme 1), isolated in low yield from
Rollinia mucosa in 2003, is one of two compounds in a new
subclass of acetogenins containing two terminal γ-lactones.3
Squamostolide (2), the other member, differs from 1 by only
the absence of the C4 hydroxyl,4 and both are likely derived
from oxidative cleavage of classical THF-containing aceto-
genins. In cytotoxicity assays, both 1 and 2 exhibited
significant in vitro inhibitory activity against human tumor
(1) For reviews, see: (a) Alali, F. Q.; Liu, X. X.; McLaughlin, J. L. J.
Nat. Prod. 1999, 62, 504. (b) Cave´, A.; Figade´re, B.; Laurens, A.; Cortes,
D. In Progress in the Chemistry of Natural Products; Herz, W., Kirby, G.
W., Moore, R. E., Steglich, W., Tamm, C., Eds.; Springer-Verlag: New
York, 1997; Vol. 70, pp 81-288.
(2) Figade´re, B. Acc. Chem. Res. 1995, 28, 359.
(3) Liaw, C. C.; Chang, F. R.; Wu, M. J.; Wu, Y. C. J. Nat. Prod. 2003,
66, 279.
(4) Xie, H. H.; Wei, X. Y.; Wang, J. D.; Liu, M. F.; Yang, R. Z. Chin.
Chem. Lett. 2003, 14, 588.
10.1021/ol047352l CCC: $30.25
© 2005 American Chemical Society
Published on Web 03/10/2005

We describe herein the asymmetric total synthesis of 1
highlighting our recently reported tandem ring-closing/cross-
metathesis (RCM/CM) strategy for allyl butenolide prepara-
tion.6 Our approach is outlined retrosynthetically in Scheme
1. We envisioned installation of the west-wing lactone by
alkylation of the enolate of (5S)-methyl-3-phenylsul-
fanyldihydrofuran-2-one 37 with triflate 4, which would arise
from 6 via Sharpless asymmetric dihydroxylation8 (SAD)
and subsequent selective diol activation/protection. Terminal
alkene 6 would, in turn, be available by straightforward
functionalization of 7. Butenolide 7 would be produced by
tandem RCM/CM with initial RCM9 of acrylate 9 preceding
CM10 with the benzyl ether of 10-undecen-1-ol (8). Hexa-
1,5-diene-3,4-diol 10,11 with the requisite (3R,4R) absolute
stereochemistry corresponding to C15 and C16 of rollicosin,
would serve as our starting material.
in the 1H and 13C NMR spectra. The (E)-stereochemistry of
the acyclic olefin was inferred from the H NMR spectrum
1
(J ) 15.4 Hz). Optimal yields were achieved by slow
addition of 11 to a 0.01 M solution of 9 and 3 equiv of 8 in
refluxing PhH via syringe pump. Despite the clear synthetic
utility of this process, surprisingly few examples of simple
triene RCM/CM reactions exist.13
It is notable that none of the dihydropyranone 12 was
isolated from the metathesis reaction, as it implies that 9
underwent initial RCM with complete regioselectivity for
generation of butenolide 13 (Scheme 3). The observed
Scheme 3. Regioselective RCM of 9
Metathesis substrate 9 could be prepared readily in
multigram quantities by mono-TBS protection of 10 and
subsequent acylation with acryloyl chloride (Scheme 2). We
Scheme 2. Preparation and RCM/CM of 9
regioselectivity can be rationalized by consideration of two
mechanistic pathways. The first is site-selective initiation by
the catalyst (LnM)) to produce intermediate 15 exclusively.14
The second is establishment of a pre-equilibrium between
intermediates 15 and 16 followed by fast formation of 13
(relative to 14) in an irreversible ring-closing step (kexchange
> k5 > k6).15 In the case of 9, the likely steric preference for
formation of 15 and the kinetic preference for five-membered
ring formation reinforce one another; thus, the observed
regiochemistry would be the predicted outcome of either
mechanistic scenario. RCM of the benzyl analogue of 9, in
which the nonacrylate olefins are not as clearly differentiated
by their steric environments, also proceeds with complete
regioselectivity for five-membered ring formation, however,
suggesting the second mechanistic pathway.6 Examples of
regioselective CM16 and chemoselectiVe RCM17 of 1,5-
hexadien-3-ol derivatives have been reported. To our knowl-
edge, however, only two other examples of regioselectiVe
RCM of 1,5-hexadien-3-yl acrylates such as 9 exist.6,13b
Studies to determine factors influencing (and thus, potential
means for manipulating) the regiochemical outcomes of such
reactions are currently underway.
were pleased to find that treatment of a solution of 9 and
coupling partner 8 with 10 mol % of second generation
Grubbs’ catalyst 1112 gave desired extended butenolide 7 as
the only isolable product in 64% yield. Assignment of the
tandem product as 7 rather than regioisomeric 12 was based
on the relatively large downfield chemical shifts of the
â-proton (7.44 ppm) and the carbonyl carbon (172.9 ppm)
(5) Lee, J. L.; Lin, C. F.; Hsieh, L. Y.; Lin, W. R.; Chiu, H. F.; Wu, Y.
C.; Wang, K. S.; Wu, M. J. Tetrahedron Lett. 2003, 44, 7833.
(6) Quinn, K. J.; Isaacs, A. K.; Arvary, R. A. Org. Lett. 2004, 6, 4143.
(7) White, J. D.; Somers, T. C.; Reddy, G. N. J. Org. Chem. 1992, 57,
4991.
With reliable access to 7 using our tandem RCM/CM
approach, we turned our attention to its functionalization to
(8) Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino, G. A.;
Hartung, J.; Jeong, K. S.; Kwong, H. L.; Morikawa, K.; Wang, Z. M.; Xu,
D.; Zhang, X. L. J. Am. Chem. Soc. 1992, 57, 2768.
(9) For a recent review on the use of RCM for synthesis of heterocycles,
see: Dieters, A.; Martin, S. F. Chem. ReV. 2004, 104, 2199.
(10) For a recent review of CM, see: Connon, S. J.; Blechert, S. Angew.
Chem., Int. Ed. 2000, 42, 1900.
(11) (a) Burke, S. D.; Sametz, G. M. Org. Lett. 1999, 1, 72. (b) Crombez-
Robert, C.; Benazza, M.; Frechou, C.; Demailly, G. Carbohydr. Res. 1997,
303, 359.
(13) (a) Virolleaud, M. A.; Bressy, C.; Piva, O. Tetrahedron Lett. 2003,
44, 8081. (b) Virolleaud, M. A.; Piva, O. Synlett 2004, 2087.
(14) Initiation of the acrylate olefin of 9 is not considered because of its
substantially reduced reactivity relative to the nonacrylate olefins.
(15) For a similar analysis of regioselective enyne RCM, see: Maifield,
S. V.; Miller, R. L.; Lee, D. J. Am. Chem. Soc. 2004, 126, 12228.
(16) BouzBouz, S.; Simmons, R.; Cossy, J. Org. Lett. 2004, 6, 3465.
(17) Numerous reports of chemoselective RCM of 1,5-hexadien-3-yl
acrylates for synthesis of dihydropyranones have been made. For a leading
reference, see: Falomir, E.; Murga, J.; Ruiz, P.; Carda, M.; Marco, J. A. J.
Org. Chem. 2003, 68, 5672.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
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Org. Lett., Vol. 7, No. 7, 2005

allow for incorporation of the west-wing lactone. To this
end, 7 was exposed to H2 in the presence of Pd/C to effect
removal of the benzyl ether and concomitant alkene reduction
to provide alcohol 17 in 86% yield (Scheme 4). TPAP
providing only minimal yields of 19 even in the presence of
HMPA or DMPU. Attempts to alkylate the enolate of 3 with
the epoxide of 6 met with failure due to formation of
mixtures of translactonization products.
The synthesis was completed as outlined in Scheme 5.
Scheme 4. Functionalization of 7
Scheme 5. Completion of the Synthesis
Oxidation of sulfide 19 to the sulfoxide and thermal
elimination gave 20, and TBS deprotection by treatment with
in situ generated HCl in MeOH provided rollicosin (1) in
76% over three steps. Synthetic 1 was isolated as a white
solid (mp ) 102-104 °C) and displayed spectral data (IR,
1H and 13C NMR) and optical rotation consistent with that
of naturally occurring rollicosin.3
In conclusion, the first total synthesis of rollicosin (1) was
accomplished in 9% yield over 12 steps from C2-symmetric
dienediol 10. Key to the overall efficiency of the route was
use of a highly regio- and stereoselective tandem RCM/CM
reaction for construction of the east-wing lactone and
incorporation of alkyl spacer. The synthesis provides con-
firmation of the structural assignment of 1, and the inherent
flexibility of this approach will make it useful for analogue
preparation.
oxidation to the corresponding aldehyde and one-carbon
Wittig homologation then gave terminal alkene 6 in 76%
over two steps and set up SAD. Treatment of 6 with AD-
mix-â provided diol 18 in 87% yield and proceeded with
excellent selectivity for establishment of the (R)-configured
C4 stereocenter. Only trace formation of the C4 epimer was
observed in the dihydroxylation, and the diastereomers could
be separated by column chromatography without difficulty.
Selective activation of the primary alcohol as a triflate and
subsequent silylation of the remaining secondary alcohol
were achieved in a one-pot process.18 Coupling of the triflate
with the enolate of 3 then provided 19 as an inseparable 12:1
mixture of diastereomers in 62% overall yield.19 As a result
of the low reactivity of the triflate as an alkylating agent,
extended reaction times were required, during which the yield
of 19 was somewhat diminished because of decomposition
of the triflate. The proper choice of enolate counterion proved
critical to the outcome of the reaction with lithium and
sodium enolates (formed with LDA, LHMDS, or NaHMDS)
Acknowledgment. We thank Professor Yang-Chang Wu
1
(Kaohsiung Medical University, Taiwan) for providing H
and 13C NMR spectra of natural rollicosin. This research was
supported by a Cottrell College Science Award from
Research Corporation. Additional financial support from the
Simeon J. Fortin Charitable Trust is gratefully acknowledged.
Mass spectral data were obtained at the University of
Massachusetts Mass Spectrometry Facility, which is sup-
ported, in part, by the National Science Foundation.
Supporting Information Available: Experimental pro-
cedures, characterization data, and 1H and 13C NMR spectra
for 1, 6, 7, 9, 17-20, and the mono-TBS ether of 10. This
material is available free of charge via the Internet at
http://pubs.acs.org.
(18) Mori, Y.; Yaegashi, K.; Furukawa, H. J. Am. Chem. Soc. 1996,
118, 8158.
(19) For alkylation of the enolate of 3 in the synthesis of other
4-hydroxylated acetogenins, see: (a) Schaus, S. E.; Brånalt, J.; Jacobsen,
E. N. J. Am. Chem. Soc. 1941, 63, 4876. (b) Marshall, J. A.; Piettre, A.;
Paige, M. A.; Valeriote, F. J. Org. Chem. 2003, 68, 1771. (c) Maezaki, N.;
Kojima, N.; Sakamota, A.; Tominaga, H.; Iwata, C.; Tanaka, T.; Monden,
M.; Damdensuren, B.; Nakamor, S. Chem. Eur. J. 2003, 9, 389.
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