Total synthesis of Brevetoxin A

Article abstract of DOI:10.1021/ol802710u

(Chemical Equation Presented) A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were effectively united via a Horner-Wittig olefination. The resulting octacycle was prog

Full text of DOI:10.1021/ol802710u

ORGANIC
LETTERS
2009
Vol. 11, No. 2
489-492
Total Synthesis of Brevetoxin A
Michael T. Crimmins,* J. Lucas Zuccarello, J. Michael Ellis, Patrick J. McDougall,
Pamela A. Haile, Jonathan D. Parrish, and Kyle A. Emmitte
Department of Chemistry, Venable and Kenan Laboratories of Chemistry, UniVersity of
North Carolina at Chapel Hill, Chapel Hill, North Carolina 27599-3290
crimmins@email.unc.edu
Received November 26, 2008
ABSTRACT
A total synthesis of brevetoxin A is reported. Two tetracyclic coupling partners, prepared from previously reported advanced fragments, were
effectively united via a Horner-Wittig olefination. The resulting octacycle was progressed to substrates that were explored for reductive
etherification, the success of which led to a penultimate tetraol intermediate. The tetraol was converted to the natural product through an
expeditious selective oxidative process followed by methylenation.
The exquisite structures of marine polycyclic ether natural
products have captured the imagination of synthetic chemists
for over two decades. The structures of the polyether ladder
toxins characteristically contain a linear series of trans-fused
ether rings of varying sizes from five to nine members with
assorted methyl and hydroxyl substituents appended. As
novel technologies for the convergent preparation of these
targets have emerged, a number of total syntheses of the
ladder toxins have been completed.1 The structure of
brevetoxin A (1), a representative member of this class, was
first elucidated in 1986 by Shimizu2a,b and co-workers by
X-ray analysis and independently determined by Nakanishi
through spectroscopic studies.2c Brevetoxin A (1) contains
10 rings (including five-, six-, seven-, eight, and nine-
membered oxacycles) fused in a linear array adorned by 22
tetrahedral stereocenters. A metabolite of Karenia breVis,
brevetoxin A is a toxic component of the infamous red tide
phenomenon, which has been responsible for massive fish
kills as well as neurotoxic shellfish poisoning and bronchial
irritation in humans.3 The potent activity of brevetoxin A is
attributed to strong binding to the R subunit of the voltage-
sensitive sodium ion channels effecting an increase in the
mean channel open time and inhibiting channel inactivation.3a
To date, the landmark total synthesis reported by Nicolaou
stands as the only completed synthesis of this intriguing
target.4
The planned approach for the total synthesis of brevetoxin
A5 focused on a versatile endgame that would exploit the
selective manipulation of tetraol 2 (Scheme 1), which would
derive from mixed methyl ketal 3 via stereoselective reduc-
tive etherification. Ketal 3 would be obtained through the
(2) (a) Shimizu, Y.; Chou, H. N.; Bando, H.; Vanduyne, G.; Clardy,
J. C. J. Am. Chem. Soc. 1986, 108, 514. (b) Shimizu, Y.; Chou, H.-N.;
Bando, H.; Van Duyne, G.; Clardy, J. C. J. Chem. Soc., Chem. Commun.
1986, 1656. (c) Pawlak, J.; Tempesta, M. S.; Golik, J.; Zagorski, M. G.;
Lee, M. S.; Nakanishi, K.; Iwashita, T.; Gross, M. L.; Tomer, K. B. J. Am.
Chem. Soc. 1987, 109, 1144.
(3) (a) Michelliza, S.; Abraham, W. M.; Jacocks, H. M.; Schuster, T.;
Baden, D. G. ChemBioChem 2007, 8, 2233. (b) Naar, J. P.; Flewelling,
L. J.; Lenzi, A.; Abbott, J. P.; Granholm, A.; Jacocks, H. M.; Gannon, D.;
Henry, M.; Pierce, R.; Baden, D. G.; Wolny, J.; Landsberg, J. H. Toxicon
2007, 50, 707. (c) Kirkpatrick, B.; Fleming, L. E.; Backer, L. C.; Bean,
J. A.; Tamer, R.; Kirkpatrick, G.; Kane, T.; Wanner, A.; Dalpra, D.; Reich,
A.; Baden, D. G. Harmful Algae 2006, 5, 526. (d) Fleming, L. E.; Backer,
L. C.; Baden, D. G. EnViron. Health Persp. 2005, 113, 618, and references
therein.
(1) (a) Fuwa, H.; Sasaki, M. Curr. Opin. Drug DiscoVery DeV. 2007,
10, 784. (b) Inoue, M. Chem. ReV. 2005, 105, 4379. (c) Nakata, I. Chem.
ReV. 2005, 105, 4314. (d) Kadota, I.; Yamamoto, Y. Acc. Chem. Res. 2005,
38, 423. (e) Sasaki, M.; Fuwa, H. Synlett 2004, 11, 1851. (f) Evans, P. A.;
Delouvrie´, B. Curr. Opin. Drug DiscoVery DeV. 2002, 5, 986. (g) Marmsa¨ter,
F. P.; West, F. G. Chem.sEur. J. 2002, 8, 4346. (h) Mori, Y. Chem.sEur.
J. 1997, 3, 849. (i) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.;
Mart´ın, J. D. Chem. ReV. 1995, 95, 1953.
10.1021/ol802710u CCC: $40.75
Published on Web 12/19/2008
2009 American Chemical Society

been previously prepared in significant quantities through
similar highly convergent [X + 2 + X] strategies based on
a Horner-Wadsworth-Emmons coupling of the B and E
ring units (and the G and J subunits) and subsequent
construction of the central CD and HI rings.5a,b
Scheme 1. Retrosynthetic Analysis of Brevetoxin A
The conversion of diol 7 to phosphine oxide 5 (Scheme
2) commenced with protection of diol 7 as the bis-p-
Scheme 2. Formation of Phosphine Oxide 5
stereoselective Horner-Wittig coupling6 of phosphine oxide
5 and aldehyde 6. This route was attractive not only because
it allowed for optimal convergence by simplifying the natural
product into two halves of similar complexity but also
because it found precedent in the strategy previously reported
by Nicolaou.4 Further, it was reasoned that the dithioketal
moiety of aldehyde 6 could serve as a stabilized precursor
to mixed ketal 3 or lead to sulfone 4 in the event that
formation or reductive etherification of mixed ketal 3 proved
problematic. The Horner-Wittig coupling partners 5 and 6
would be obtained from advanced fragments 7 and 8,
respectively. The BCDE fragment 7 and GHIJ subunit 8 had
methoxybenzyl ether and subsequent reductive cleavage of
the benzyl ethers with LiDBB to form diol 9.7 Diol 9 was
protected as the bis-TBS ether, whereupon selective cleavage
of the primary TBS ether with HF·pyr afforded alcohol 10.
Alcohol 10 was smoothly transformed to phosphine oxide
11 via a sequence which involved mesylation of the alcohol,
nucleophilic displacement of the mesylate to provide the alkyl
diphenylphosphine, and finally, oxidative workup of the
phosphine with H2O2.4,6 Cleavage of the TBS ether with
n-Bu4NF and formation of the methoxypropyl (MOP) acetal
delivered the required phosphine oxide 5 in high yield.8
For aldehyde 6, GHIJ tetracycle 8 was treated with
n-Bu4NF to cleave the TIPS ether, and the resultant second-
ary alcohol was oxidized to ketone 12 with Dess-Martin
periodinane (Scheme 3).9 Treatment of ketone 12 with
Zn(OTf)2 and EtSH produced the dithioketal,10 and reductive
cleavage of the pivaloate ester with LiAlH4 delivered alcohol
13. While a host of conditions proved unsuitable for the
subsequent oxidation of the primary alcohol to aldehyde 6,
due to undesired oxidation of the dithioketal, the use of
(4) (a) Nicolaou, K. C.; Yang, Z.; Shi, G.-Q.; Gunzner, J. L.; Agrios,
K. A.; Ga¨rtner, P. Nature 1998, 392, 264. (b) Nicolaou, K. C.; Bunnage,
M. E.; McGarry, D. G.; Shi, S.; Somers, P. K.; Wallace, P. A.; Chu, X.-J.;
Agrios, K. A.; Gunzner, J. L.; Yang, Z. Chem.sEur. J. 1999, 5, 599. (c)
Nicolaou, K. C.; Wallace, P. A.; Shi, S.; Ouellette, M. A.; Bunnage, M. E.;
Gunzner, J. L.; Agrios, K. A.; Shi, G.-q.; Ga¨rtner, P.; Yang, Z. Chem.sEur.
J. 1999, 5, 618. (d) Nicolaou, K. C.; Shi, G.-q.; Gunzner, J. L.; Gärtner, P.;
Wallace, P. A.; Ouellette, M. A.; Shi, S.; Bunnage, M. E.; Agrios, K. A.;
Veale, C. A.; Hwang, C.-K.; Hutchinson, J.; Prasad, C. V. C.; Ogilvie,
W. W.; Yang, Z. Chem.sEur. J. 1999, 5, 628. (e) Nicolaou, K. C.; Gunzner,
J. L.; Shi, G.-q.; Agrios, K. A.; Ga¨rtner, P.; Yang, Z. Chem.sEur. J. 1999,
5, 646.
(5) (a) Crimmins, M. T.; McDougall, P. J.; Ellis, J. M. Org. Lett. 2006,
8, 4079. (b) Crimmins, M. T.; Zuccarello, J. L.; Cleary, P. A.; Parrish,
J. D. Org. Lett. 2006, 8, 15. (c) Crimmins, M. T.; McDougall, P. J.; Emmitte,
K. A. Org. Lett. 2005, 7, 4033. (d) Crimmins, M. T.; Cleary, P. A.
Heterocycles 2003, 61, 87.
(7) (a) Freeman, P. K.; Hutchinson, L. L. J. Org. Chem. 1980, 45, 1924.
(b) Ireland, R. E.; Smith, M. G. J. Am. Chem. Soc. 1988, 110, 854.
(8) Attempts to prepare the phosphine oxide with the C21 hydroxyl or
MOP acetal directly were hampered by purification difficulties and lower
yields, respectively.
(6) (a) Horner, L. L.; Hoffmann, H.; Wippel, H. G.; Klahre, G.
Chem.Ber. 1959, 92, 2499. (b) Buss, A. D.; Warren, S. J. Chem. Soc., Perkin
Trans. 1 1985, 2307, and references therein. (c) For the use of LDA in
Horner-Wittig reactions, see: Earnshaw, C.; Wallis, C. J.; Warren, S.
J. Chem. Soc., Perkin Trans. 1 1979, 3099.
(9) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(10) Corey, E. J.; Shimoji, K. Tetrahedron Lett. 1983, 24, 169.
490
Org. Lett., Vol. 11, No. 2, 2009

to dialkyl ketals,12 we reasoned that exposure of olefin 14
to the hypervalent iodine reagent in MeOH would lead to
the dimethyl ketal 15, or to mixed ketal 3 directly. In the
event, treatment of thioketal 14 with (F3CCO2)2IPh in MeOH
rapidly removed the MOP protecting group, and led to a
mixture of the expected ketal products in a 4:1 ratio favoring
the dimethyl ketal 15.13 Exposure of the unpurified mixture
to PPTS and trimethyl orthoformate in toluene provided an
80% overall yield of cyclic mixed methyl ketal 3.
Scheme 3. Preparation of Aldehyde 6
Drawing upon previous successes in our laboratory
involving the reductive etherification of precursors to the
BCDE and GHIJ fragments,5a,b it was anticipated that
treatment of ketal 3 with an appropriate Lewis acid in the
presence of a trialkylsilane would deliver the expected
nonacycle 16 (Scheme 4). Despite extensive screening of
Lewis acids (BF3·OEt2, TiCl4, TMSOTf), solvents, silanes
(Et3SiH, Me2PhSiH), and drying agents (4 Å MS, BaO), only
traces of the desired reduction product 16 were obtained.
Instead, hydrolysis of the ketal, via interception of the
oxocarbenium ion by adventitious water, cleavage of the
oxocene (producing the C27 methyl ether), and intractable
decomposition were repeatedly observed. The use of
i-Bu2AlH as the reducing agent also failed to bring about
the intended reduction.
stoichiometric n-Pr4NRuO4 reproducibly provided the desired
aldehyde with minimal byproducts.11
With both phosphine oxide 5 and aldehyde 6 in hand, their
assembly under Horner-Wittig conditions was explored
(Scheme 4).6 After some experimentation, addition of 3 equiv
of LDA to a solution of phosphine oxide 5 and aldehyde 6
at -78 °C was found to produce 63% of the Horner-Wittig
adduct. It is worthy of note that no epimerization of aldehyde
6 was observed, despite the presence of superstoichiometric
base. Exposure of the intermediate hydroxyphosphine oxide
to KHMDS provided the desired Z-olefin 14 in 74% yield.
Having effectively coupled the BCDE and GHIJ frag-
ments, we wished to examine the mixed methyl ketal 3 as a
precursor to the targeted nonacycle 16 (Scheme 4). Despite
the dearth of literature examples for the conversion of
7-hydroxy ketones or ketals to eight-membered cyclic ketals,
we believed that the formation of mixed ketal 3 would be
possible due to the structural preorganization present in olefin
14. In particular, the newly formed Z-olefin, along with the
cyclic conformational constraints about the C21-C22 and
C26-C27 bonds, would be expected to assist in the required
cyclization event. Additionally, based upon the reported use
of (F3CCO2)2IPh in alcoholic solvent to convert dithioketals
Borrowing from precedent in the Nicolaou synthesis,
attention was turned to the reductive etherification of sulfone
4 rather than the ketal 3 in an attempt to increase the lability
of the leaving group at C27.4,14 Removal of the MOP acetal
from olefin 14 (Scheme 5) under acidic conditions followed
by treatment of the hydroxy dithioketal with AgClO4
provided the cyclic mixed S,O-ketal 18. Upon obtaining
sulfone 4 via oxidation with m-CPBA, reductive etherifica-
tion with concomitant removal of the PMB protecting groups
was readily accomplished, furnishing diol 16 in 85% yield.
Initial attempts to complete the synthesis of brevetoxin A
from diol 16 focused on the formation of the A ring lactone
followed by removal of the J ring benzyl ethers and
functionalization of the J ring side chain. While the A ring
lactone could be readily constructed by treatment of diol 16
with n-Pr4NRuO4, subsequent attempts to cleave the J ring
Scheme 4. Coupling of Tetracyclic Fragments 5 and 6
Org. Lett., Vol. 11, No. 2, 2009
491

2 to PhI(OAc)2 in the presence of catalytic TEMPO15 served
to selectively form the A ring lactone and the C44 aldehyde
while leaving the axially disposed C39 secondary alcohol
unaffected. The unpurified decacyclic aldehyde 19 was
treated with Eschenmoser’s salt in the presence of Et3N4,16
to complete the synthesis of brevetoxin A (1). Synthetic
brevetoxin A (1) was identical in all respects (1H and 13C
NMR, IR, HRMS, [R]D) to an authentic sample.4,17
Scheme 5. Completion of Brevetoxin A (1)
In summary, the total synthesis of brevetoxin A was
completed from aldehyde 6 and phosphine oxide 5 through
a stereoselective Horner-Wittig olefination to assemble two
advanced tetracycles. The uncommon cyclization of a
medium ring mixed methyl ketal was accomplished, and the
mixed methyl ketal was assessed as a substrate for a reductive
etherification of an oxocene. Ultimately, a sulfone-based
approach proved superior and set the stage for a selective
oxidation strategy of tetraol 2, allowing the completion of
the second total synthesis of brevetoxin A (1).
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM60567)
is acknowledged with thanks. We are grateful to Professor
Daniel G. Baden and Dr. Andrea Bourdelais (University of
North Carolina at Wilmington) for kindly providing an
1
authentic sample as well as 13C and H NMR spectral data
of brevetoxin A.
Supporting Information Available: Experimental details
and spectral data for new compounds as well as brevetoxin
A. This material is available free of charge via the Internet
at http://pubs.acs.org.
benzyl ethers under a host of reductive or Lewis acidic
conditions met with failure due to significant amounts of
decomposition. Ultimately, a strategy involving the selective
oxidation of tetraol 2 was examined. Unlike the A ring
lactone derived from diol 16, the J ring benzyl ethers could
be readily cleaved from diol 16 itself to deliver tetraol 2.
Thus, brevetoxin A (1) was accessed in three straightforward
operations from diol 16 (Scheme 5). Reductive cleavage of
the J ring benzyl ethers and subsequent exposure of tetraol
OL802710U
(12) Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287.
(13) The 4:1 ratio of products appears to be the kinetic ratio, since
resubjecting either of the isolated ketal products to the (CF3CO2)2IPh/MeOH
conditions did not cause equilibration.
(14) Nicolaou, K. C.; Prasad, C. V. C.; Hwang, C.-K.; Duggan, M. E.;
Veale, C. A. J. Am. Chem. Soc. 1989, 111, 5321.
(15) Hansen, T. M.; Florence, G. J.; Lugo-Mas, P.; Chen, J. H.; Abrams,
J. N.; Forsyth, C. J. Tetrahedron Lett. 2003, 44, 57.
(11) (a) Griffith, W. P.; Ley, S. V.; Whitcombe, G. P.; White, A. D.
J. Chem. Soc., Chem. Commun. 1987, 1625. (b) Griffith, W. P.; Ley, S. V.
Aldrichim. Acta 1990, 23, 13.
(16) Schreiber, J.; Maag, H.; Hashimoto, N.; Eschenmoser, A. Angew.
Chem., Int. Ed. Engl. 1971, 10, 330
.
(17) See the Supporting Information.
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Org. Lett., Vol. 11, No. 2, 2009