Convergent, stereoselective synthesis of the GHIJ fragment of brevetoxin A

Article abstract of DOI:10.1021/ol0526625

(Chemical Equation Presented) A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation, ring-closing metathesis, and Hosomi-Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which were united through a Horner-Wadsworth-Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.

Full text of DOI:10.1021/ol0526625

ORGANIC
LETTERS
2006
Vol. 8, No. 1
159-162
Convergent, Stereoselective Synthesis
of the GHIJ Fragment of Brevetoxin A
Michael T. Crimmins,* J. Lucas Zuccarello, Pamela A. Cleary, and
Jonathan D. Parrish
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received November 2, 2005
ABSTRACT
A stereoselective synthesis of the GHIJ fragment of brevetoxin A utilizing a convergent assembly strategy is described. Glycolate alkylation,
ring-closing metathesis, and Hosomi Sakurai reactions were central operations in the construction of the G ring and J ring subunits, which
were united through a Horner Wadsworth Emmons coupling. Subsequent dehydrative cyclization produced an endocyclic enol ether that
−
−
−
was further elaborated to the tetracyclic GHIJ fragment of brevetoxin A.
Among the wealth of structurally unique metabolites pro-
duced by marine organisms, the ladder ether toxins stand as
a prominent illustration of the remarkable complexity of
molecules produced by Nature.1 The challenging architecture
of the ladder toxins has inspired a variety of approaches to
their synthesis,2 and several noteworthy total syntheses have
been reported.3 Brevetoxin A (Figure 1),4 a neurotoxin
of brevetoxin A reported in 1998 by the Nicolaou laboratory
stands as the only total synthesis to date.3
Strategic advances from our laboratory in methods for the
construction of medium ring ethers, in particular, the ring-
(2) (a) Alvarez, E.; Candenas, M.-L.; Pe´rez, R.; Ravelo, J. L.; Mart´ın, J.
D. Chem. Rev. 1995, 95, 1953. (b) Mori, Y. Chem. Eur. J. 1997, 3, 849.
(c) Evans, P. A.; Delouvrie´, B. Curr. Opin. Drug DiscoVery DeV. 2002, 5,
986. (d) Marmsa¨ter, F. P.; West, F. G. Chem. Eur. J. 2002, 8, 4346. (e)
Sasaki, M.; Fuwa, H. Synlett 2004, 11, 1851. (f) Kadota, I.; Yamamoto, Y.
Acc. Chem. Res. 2005, 38, 423.
(3) Brevetoxin A: (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. Eur. 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. Eur. J. 1999, 5, 618. (d) Nicolaou, K. C.; Shi, G.-q.;
Gunzner, J. L.; Ga¨rtner, 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. Eur. J. 1999, 5, 628.
(e) Nicolaou, K. C. Gunzner, J. L.; Shi, G.-q.; Agrios, K. A.; Ga¨rtner, P.;
Yang, Z. Chem. Eur. J. 1999, 5, 646. Brevetoxin B: (f) Nicolaou, K. C.
Angew. Chem., Int. Ed. Engl. 1996, 35, 588. (g) Matsuo, G.; Kawamura,
K.; Hori, N.; Matsukura, H.; Nakata, T. J. Am. Chem. Soc. 2004, 126, 14374.
(h) Kadota, I.; Takamura, H.; Nishii, H.; Yamamoto, Y. J. Am. Chem. Soc.
2005, 127, 9246. Hemibrevetoxin B: (i) Zakarian, A.; Batch, A.; Holton,
R. A. J. Am. Chem. Soc. 2003, 125, 7822 and references therein. Ciguatoxin
CTX3C: (j) Inoue, M.; Hirama, M. Acc. Chem. Res. 2004, 37, 961.
Gambierol: (k) Kadota, I.; Takamura, H.; Sato, K.; Ohno, A.; Matsuda,
K.; Yamamoto, Y. J. Am. Chem. Soc. 2003, 125, 46. (l) Fuwa, H.; Kainuma,
N.; Tachibana, K.; Sasaki, M. J. Am. Chem. Soc. 2002, 124, 14983. (m)
Johnson, H. W. B.; Majumder, U.; Rainier, J. D. J. Am. Chem. Soc. 2005,
127, 848. Gymnocin A: (n) Tsukano, C.; Ebine, M.; Sasaki, M. J. Am.
Chem. Soc. 2005, 127, 4326.
Figure 1. Brevetoxin A.
produced by the red tide dinoflagellates, is one of the more
daunting members of the ladder toxins from a synthetic
perspective. Brevetoxin A contains 22 tetrahedral stereogenic
centers, as well as 10 rings including at least one of five,
six, seven, eight, and nine members. The landmark synthesis
(1) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897. (b) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293.
10.1021/ol0526625 CCC: $33.50
© 2006 American Chemical Society
Published on Web 12/06/2005

phonate 1 and a J ring aldehyde 2 through a Horner-
Wadsworth-Emmons (HWE) reaction, which would produce
an enone intermediate 3 (Scheme 1). Subsequent 1,4-
reduction followed by an endo-selective dehydrative cycliza-
tion would lead to an enol ether 4, which could then be
oxidized and further advanced to the desired tetracyclic
fragment 5.
Scheme 1. Convergent Assembly Strategy
As shown in Scheme 2, the synthesis of the requisite G
ring â-keto phosphonate began with the oxidation of known
alcohol 67 under Swern conditions.8 Addition of the resulting
aldehyde to the lithium enolate of tert-butyl acetate provided
efficient access to alcohol 7 (inconsequential mixture of
diastereomers). Reduction of the ester to the primary alcohol
with LiAlH4 and selective protection of the resultant primary
alcohols as the triisopropylsilyl ether produced alcohols 8.
The diastereomeric mixture was then converged to a single
ketone by oxidation under Dess-Martin conditions.9 Che-
lation-controlled addition of methylmagnesium chloride
afforded tertiary alcohol 9 as a single isomer in excellent
yield.
To establish the C26 stereocenter, tertiary alcohol 9 was
alkylated with sodium bromoacetate, whereupon the glycolic
acid was converted to the mixed anhydride with pivaloyl
chloride and treated with (S)-lithio-4-isopropyl-2-oxazolidi-
none to produce imide 10 in good overall yield. Alkylation7
of the sodium enolate of imide 10 with benzyl iodomethyl
ether (prepared in situ) followed immediately by reductive
removal of the chiral auxiliary with LiBH4 afforded alcohol
11 in 69% yield (>98:2 dr).
closing metathesis of diene intermediates assembled through
chiral auxiliary mediated aldol and alkylation reactions, have
been realized concomitantly with our syntheses of Laurencia
metabolites.5 Further probing the utility of these methods in
solving complex synthetic problems, we have initiated a
program toward the total synthesis of brevetoxin A.6 To this
end, we recently described a successful approach to the
BCDE fragment of brevetoxin A that combined our synthetic
methods for medium ring ether synthesis with a convergent
assembly strategy.6b We report here the extension of our
convergent assembly strategy to the synthesis of the GHIJ
fragment of brevetoxin A.
Dess-Martin oxidation of alcohol 11 produced the cor-
responding aldehyde, which when exposed to vinylmagne-
sium bromide delivered the diene as a mixture of C27
epimers, setting the stage for closure of the oxocene. Ring-
Analogous to our synthesis of the BCDE fragment, we
envisioned the assembly of an advanced G ring ketophos-
Scheme 2. Synthesis of the G Ring of Brevetoxin A
160
Org. Lett., Vol. 8, No. 1, 2006

Scheme 3. Synthesis of the J Ring and Completion of the GHIJ Fragment
closing metathesis was then accomplished smoothly using
inconsequential for the overall synthetic plan, the diastere-
omers were converged to a single isomer for convenience.
To this end, oxidation of the alcohols to the ketone with
Dess-Martin periodinane, followed by reduction with i-Bu2-
AlH, yielded alcohol 13 as a single isomer, presumably due
to the facial bias of the oxocane ring.
the Grubbs catalyst10 [Cl2(Cy3P)(sIMes)RudCHPh], provid-
ing oxocene 12 in 61% overall yield for three steps. Exposure
of oxocene 12 to Crabtree’s catalyst11 selectively hydroge-
nated the C28-C29 double bond without cleavage of the
benzyl ether. Although the mixture of epimers at C27 was
Finally, to complete the â-keto phosphonate G ring
fragment, a series of protecting group manipulations were
carried out to produce oxacane 14. Selective removal of the
primary triisopropylsilyl protecting group under acidic condi-
tions followed by a two-step oxidation process provided
carboxylic acid 15 in high yield. Conversion to the methyl
ester and treatment with lithio dimethyl methylphosphonate
furnished the desired â-keto phosphonate 1 in 77% yield.12
The synthesis of the J ring aldehyde 2 commenced with
the conversion of known alcohol 1613 to mixed acetal 17
(Scheme 3). Ring-closing metathesis with Grubbs catalyst14
and oxidation of the resulting glycal with RuCl3/NaIO4
(4) (a) Shimizu, Y.; Chou, H.-N.; Bando, H. J. Am. Chem. Soc. 1986,
108, 514. (b) 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.
(5) (a) Crimmins, M. T.; Brown, B. H. J. Am. Chem. Soc. 2004, 126,
10264. (b) Crimmins, M. T.; DeBaillie, A. C. Org. Lett. 2003, 5, 3009. (c)
Crimmins, M. T.; Powell, M. T. J. Am. Chem. Soc. 2003, 125, 7592. (d)
Crimmins, M. T.; Emmitte, K. A.; Choy, A. L. Tetrahedron 2002, 58, 1817.
(e) Crimmins, M. T.; Tabet, E. A. J. Am. Chem. Soc. 2000, 122, 5473. (f)
Crimmins, M. T.; Emmitte, K. A. Org. Lett. 1999, 1, 2029. (g) Crimmins,
M. T.; Choy, A. L. J. Am. Chem. Soc. 1999, 121, 5653. (h) Crimmins, M.
T.; Choy, A. L. J. Org. Chem. 1997, 62, 7548.
(6) (a) Crimmins, M. T.; Cleary, P. A. Heterocycles 2003, 61, 87. (b)
Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005, 7,
4033.
(7) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165.
(8) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(9) (a) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155; J. Am.
Chem. Soc. 1991, 113, 7277. (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993,
58, 2899.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(11) Crabtree, R. H.; Felkin, H.; Fillebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183.
(12) Careful addition of lithiated dimethyl methylphosphonate solution
at -78 °C to the methyl ester of acid 15 allowed for selective addition into
the methyl ester over the pivaloyl ester.
Org. Lett., Vol. 8, No. 1, 2006
161

produced diol 18 in 71% yield. Protection of the diol as the
carbonate using 1,1′-carbonyldiimidazole preceded a high
yielding Hosomi-Sakurai reaction15 to afford pyran 19, thus
installing C42-C44 and setting the C41 stereocenter (dr >
10:1). The carbonate group was then removed under basic
conditions, and the resulting diol was reprotected as the
acetonide. Hydroboration of the terminal olefin with 9-BBN
gave the primary alcohol 20 exclusively. Protection of the
C44 primary alcohol as its benzyl ether and removal of the
C36 TBDPS group with n-Bu4NF, followed by TEMPO
oxidation, furnished aldehyde 2 in 76% overall yield.
The HWE coupling of â-keto phosphonate 1 and aldehyde
conditions in 96% yield, whereas undesired alcohol diaste-
reomer 23 was converted to ketone 24 in modest yield by
oxidation followed by isomerization under basic conditions.
Oxidative removal of the PMB group from ketone 24 with
DDQ and treatment of the resulting hemiketal with PPTS in
MeOH effected nearly complete conversion to mixed meth-
oxy ketal 25 in 67% yield over two steps (72% brsm).
Reduction of the ketal with BF3‚Et2O and Et3SiH yielded
the GHIJ fragment 5 as a single isomer in 96% yield; 1H,13C,
and 2-D NMR spectral analysis of an acetate derivative
provided structural verification.19
To summarize, we have completed an efficient synthesis
of the GHIJ fragment of brevetoxin A that draws upon our
synthetic methods for medium ring ether synthesis. Asym-
metric glycolate alkylation, along with the Hosomi-Sakurai
reaction, formed key carbon-carbon bonds stereoselectively
to generate G and J ring precursors for ring closing
metathesis. The G and J subunits were united via a HWE
coupling, and subsequent cyclodehydration formed the I ring,
paving the way for completion of the tetracyle. Assembly
of the BCDE and GHIJ fragments for the completion of
brevetoxin A will be reported in due course.
16
2 with Ba(OH)2 proceeded smoothly, generating enone 3
in 80% yield. Subsequent 1,4-reduction of the enone with
Stryker’s reagent17 and removal of the acetonide group
produced diol 21, setting the stage for intramolecular
cyclization of the I ring. Due to the observed sensitivity of
this reaction, a number of acids, solvents, and temperatures
were screened; optimized cyclization conditions18 realized
the endocyclic enol ether as the sole observable product, with
recovery of a small amount of starting material. Protection
of the remaining secondary alcohol as the benzyl ether
afforded tricycle 4 in 64% overall yield (70% brsm).
The critical oxidation of the enol ether was accomplished
through hydroboration with BH3‚THF,3f,l,n which after alka-
line peroxide workup gave a 3:1 mixture of desired diaste-
reomer 22 and undesired 23 in 79% combined yield. Alcohol
22 was oxidized to the ketone 24 under Dess-Martin
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM60567)
is acknowledged with thanks.
Note Added after ASAP Publication. There was an
incorrect stereochemical assignment in the brevetoxin GHIJ
fragment at C27 on the G ring structure shown in the
graphical abstract and Schemes 1-3 in the version published
ASAP December 6, 2005; the corrected version was pub-
lished ASAP December 13, 2005.
(13) Previous synthesis: Bergmeier, S. C.; Stanchina, D. M. J. Org.
Chem. 1999, 64, 2852-2859. For an alternative preparation used in the
present work work, see Supporting Information.
(14) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108.
(15) Hosomi, A.; Sakata, Y.; Sakurai, H. Tetrahedron Lett. 1984, 25,
2383.
(16) (a) Alvarez-Ibarra, C.; Arias, S.; Ban˜on, G.; Fernandez, M. J.;
Rodriguez, M.; Sinisterra, V. J. Chem. Soc., Chem. Commun. 1987, 1509.
(b) Paterson, I.; Yeung, K.-S.; Smaill, J. B. Synlett 1993, 774.
(17) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291.
Supporting Information Available: Experimental details
and spectral data for new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
(18) Conditions: PPTS, benzene, 40 °C, aspirator vacuum. See Sup-
porting Information for more detail. See: Allwein, S. P.; Cox, J. M.;
Howard, B. E.; Johnson, H. W. B.; Rainier, J. D. Tetrahedron 2002, 58,
1997. Kawamura, K.; Hinou, H.; Matsuo, G.; Nakata, T. Tetrahedron Lett.
2003, 44, 5259.
OL0526625
(19) See Supporting Information.
162
Org. Lett., Vol. 8, No. 1, 2006