A convergent coupling strategy for the formation of polycyclic ethers: Stereoselective synthesis of the BCDE fragment of brevetoxin A

Article abstract of DOI:10.1021/ol051543m

(Chemical Equation Presented) A stereoselective synthesis of the BCDE fragment of brevetoxin A has been completed. anti-Glycolate aldol, glycolate alkylation, and ring-closing metathesis reactions were employed as key bond-forming events. A convergent ass

Full text of DOI:10.1021/ol051543m

ORGANIC
LETTERS
2005
Vol. 7, No. 18
4033-4036
A Convergent Coupling Strategy for the
Formation of Polycyclic Ethers:
Stereoselective Synthesis of the BCDE
Fragment of Brevetoxin A
Michael T. Crimmins,* Patrick J. McDougall, and Kyle A. Emmitte
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received June 30, 2005
ABSTRACT
A stereoselective synthesis of the BCDE fragment of brevetoxin A has been completed. anti-Glycolate aldol, glycolate alkylation, and ring-
closing metathesis reactions were employed as key bond-forming events. A convergent assembly strategy was employed that relied on a
Horner−Wadsworth−Emmons union of two complex fragments. Subsequent cyclization and dehydration led to efficient generation of an
intermediate endocyclic enol ether, which was advanced to a tetracyclic fragment.
The impressive collection of architecturally diverse metabo-
lites produced by marine organisms includes the polycyclic
ethers, or ladder toxins, which are some of the largest and
most complex natural products.1 The unique structures of
the ladder toxins have inspired a variety of synthetic
strategies2 resulting in several total syntheses.3 Arguably, one
of the more daunting polycyclic ethers is the marine biotoxin
brevetoxin A4 (Figure 1), a neurotoxic metabolite of the
notorious red tide dinoflagellates. Unique to the polyether
Figure 1. Brevetoxin A.
subclass, brevetoxin A contains five-, six-, seven-, eight-,
and nine-membered rings, two of which are unsaturated.
There has been comparatively little activity concerning the
synthesis of brevetoxin A, with the exception of the notable
total synthesis accomplished by Nicoloau in 1998.3a-e
Our previous syntheses of Laurencia metabolites have led
to strategic advances in methods for the construction of
medium ring ethers.5 Recently, we initiated a program toward
the total synthesis of brevetoxin A6 based on our established
strategy for the synthesis of complex medium ring ethers
through a ring-closing metathesis of diene fragments gener-
ated from chiral auxiliary mediated aldol and alkylation
reactions. Additionally, anti-selective glycolate aldol addi-
tions,7 which generate differentiated anti-1,2-diols, are
(1) (a) Yasumoto, T.; Murata, M. Chem. ReV. 1993, 93, 1897. (b) Murata,
M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293.
(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.
10.1021/ol051543m CCC: $30.25
© 2005 American Chemical Society
Published on Web 08/09/2005

of the mixed anhydride of the acid with (R)-lithio-4-
isopropyl-2-oxazolidinone provided the imide 5 in good
overall yield. Alkylation10 of the sodium enolate of imide 5
with benzyl iodomethyl ether (prepared in situ) proceeded
to give a single detectable diastereomer in 93% yield.
Reductive removal of the auxiliary gave primary alcohol 6,
which was oxidized under Swern conditions.11 The aldehyde
was treated with vinylmagnesium bromide to yield a 3:1
inseparable mixture of diastereomers favoring the (R)-
configuration. Ring-closing metathesis utilizing Grubbs
catalyst12 [Cl2(Cy3P)(sIMes)RudCHPh] cleanly furnished the
separable oxocenes 7 and 8 in good yield. The undesired
isomer 8 could be inverted to alcohol 7 by the Mitsunobu
protocol.13
Scheme 1. Convergent Coupling Strategy
To establish the C6 stereocenter, a substrate-controlled
selective hydrogenation of the trisubstituted olefin was
investigated. As expected, the configuration of the C8
hydroxyl directly influenced the facial selectivity. Whereas
oxocene 8 underwent hydrogenation selectively from the
undesired face, hydrogenation of 7 using Crabtree’s catalyst14
at reduced temperature provided the oxacane 9 with the
desired C6 configuration as a single observable diastereomer
in excellent yield (Scheme 2). Similar directing effects have
been noted in the cyclopropanation and epoxidation of
medium ring allylic alcohols.15 Oxidation of alcohol 9 to
the ketone16 preceded a highly selective addition of methyl-
magnesium chloride to deliver the tertiary alcohol 10.
Selective cleavage of the benzyl ether was followed by
oxidation of the resultant alcohol to aldehyde 11 in prepara-
tion for the HWE coupling.
particularly suited to formation of the trans-fused ring
junctions common to the ladder toxins.
A highly convergent approach was envisoned for the
assembly of polycyclic ethers, which would rely on a
Horner-Wadsworth-Emmons (HWE) reaction between two
appropriately functionalized precursors leading to an inter-
mediate enone (Scheme 1). Conjugate reduction of the enone
and cyclization to the hemiacetal would permit an endo-
selective dehydration to form a cyclic enol ether. Consider-
able precedent exists for the further oxidation of the
endocyclic enol ether to allow closure of the remaining
ring.2b-e,3k,m,n,o
For the BCDE fragment of brevetoxin A, suitably func-
tionalized B ring and E ring units were required to implement
the planned assembly. Synthesis of the B ring aldehyde,
required for the HWE coupling, commenced with an aldol
addition of the chlorotitanium enolate of the thioimide 2
(Scheme 2) with 3-methyl-3-butenal8 to provide the anti
adduct 3 in 64% isolated yield (3:other anti:syn ) 87:2:11).
Reductive removal of the chiral auxiliary followed by
protecting group manipulations gave the allyl ether 4.
Selective removal of the allyl group,9 alkylation of the
resultant alcohol with sodium bromoacetate, and treatment
The synthesis of the E ring precursor of brevetoxin A is
shown in Scheme 3. Oxidation of the known alcohol 1217
and subsequent propionate aldol addition18 yielded the Evans
syn adduct 13 in high yield and excellent diastereoselectivity
(>98:2). Reductive removal of the chiral auxiliary and
(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) Crimmins, M. T.; Cleary, P. A. Heterocycles 2003, 61, 87.
(7) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591.
(8) Available from oxidative cleavage of symmetrical diol: See Sup-
porting Information and ref 5h.
(9) Lee, J.; Cha, K. Tetrahedron Lett. 1996, 37, 3663.
(10) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165.
(11) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(12) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(13) See Supporting Information for details.
(14) Crabtree, R. H.; Felkin, H.; Fillebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183.
(15) (a) Poulter, C. D.; Friedrich, E. C.; Winstein, S. J. Am. Chem. Soc.
1969, 91, 6892. (b) Itoh, T.; Jitsukawa, K.; Kaneda, K.; Teranishi, S. J.
Am. Chem. Soc. 1979, 101, 159.
(16) (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.
(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. (f) Brevetoxin B: (g) Nicolaou, K.
C. Angew. Chem., Int. Ed. Engl. 1996, 35, 589. (h) Matsuo, G.; Kawamura,
K.; Hori, N.; Matsuo, G.; Kawamura, K.; Hori, N.; Matsukura, H.; Nakata,
T. J. Am. Chem. Soc. 2004, 126, 14374. (i) Kadota, I.; Takamura, H.; Nishii,
H.; Yamamoto, Y. J. Am. Chem. Soc. 2005, 27, 9246. (j) Hemibrevetoxin
B: Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003, 125,
7822 and references therein. (k) Ciguatoxin CTX3C: Inoue, M.; Hirama,
M. Acc. Chem. Res. 2004, 37, 961. Gambierol: (l) Kadota, I.; Takamura,
H.; Sato, K.; Ohno, A.; Matsuda, K.; Yamamoto, Y. J. Am. Chem. Soc.
2003, 125, 46. (m) Fuwa, H.; Kainuma, N.; Tachibana, K.; Sasaki, M. J.
Am. Chem. Soc. 2002, 124, 14983. (n) Johnson, H. W. B.; Majumder, U.;
Rainier, J. D. J. Am. Chem. Soc. 2005, 127, 848. (o) Gymnocin A: Tsukano,
C.; Ebine, M.; Sasaki, M. J. Am. Chem. Soc. 2005, 127, 4326.
(17) Available from alkylation of oxazolidinethione benzyl glycolate;
see ref 10 for synthesis of the enantiomer. Previous synthesis: Mulzer, J.;
Angermann, A. Tetrahedron Lett. 1983, 24, 2843.
(18) Crimmins, M. T.; King, B. W.; Tabet, E. A.; Chaudhary, K. J. Org.
Chem. 2001, 66, 894.
(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.
4034
Org. Lett., Vol. 7, No. 18, 2005

Scheme 2. Synthesis of the B Ring of Brevetoxin A
selective protection of the primary alcohol as the TIPS ether
droboration-oxidation of enol ethers similar to 21 have
appeared; however, selective hydroboration of the enol ether
could not be achieved under a variety of conditions. An
alternateoxidativeprotocolusingdimethyldioxirane(DMDO)3n,21
resulted in exclusive oxidation of the enol ether; however,
the resulting epoxide proved unstable above -78 °C, making
isolation difficult. Fortunately, this problem was overcome
using “acetone-free” DMDO,22 which allowed for an in situ
reductionoftheepoxidewithi-Bu2AlHatreducedtemperature.3n
Oxidation of the resultant alcohol 22 revealed the presence
of two C12 epimers in a 4:1 ratio favoring the undesired
configuration. Complete isomerization of the undesired
isomer was possible by exposure of the ketone to DBU. The
E ring was completed by treatment of the diene with Grubbs
catalyst24 to generate the intermediate tricyclic ketone 23.
Selective removal of the PMB groups with CF3CO2H gave
the keto alcohol 24 necessary for cyclization of the D ring.
A two-step procedure via the intermediate dimethyl ketal
led to the formation of the desired mixed methyl ketal 25
with moderate success. Reduction of the methyl ketal
proceeded smoothly upon exposure to BF3-OEt2 and Et3-
SiH to give the completed BCDE ring fragment 1 as a single
diastereomer. Stereochemical confirmation was obtained
through extensive 2-D NMR experiments on the triacetate
and tribenzoate derivatives.25
provided alcohol 14. Alkylation of the secondary alcohol with
sodium bromoacetate and coupling of the resultant acid to
(R)-4-benzyl-2-oxazolidinethione gave thioimide 15. An anti-
selective aldol addition of thioimide 15 to 3-butenal5h
provided aldol adduct 16. Although the yield and diastereo-
selectivity (50%, 80% brsm, 5:1 dr) were modest in this
complex system, rapid access was gained to the diene
precursor of the E ring. Completion of the required keto
phosphonate from aldol adduct 16 is illustrated in Scheme
3. Removal of the auxiliary, cleavage of the benzyl ether,
and protection of the three hydroxyls gave the TIPS ether
17. The silyl ether was removed, whereupon the primary
hydroxyl was converted to the nitrile 18 via the intermediate
iodide. Hydrolysis of the nitrile efficiently provided the
carboxylic acid, and formation of the corresponding methyl
ester proceeded smoothly. The desired â-keto phosphonate
19 was obtained upon treatment of the ester with LiCH2P-
(O)(OMe)2.
The HWE coupling between the two fragments 11 and
19
19 in the presence of Ba(OH)2 provided enone 20 in
excellent yield (Scheme 3). Selective reduction of the enone
empoying catalytic Stryker’s reagent20 gave the saturated
ketone, which upon treatment with PPTS produced the
endocyclic enol ether 21 exclusively. The overall efficiency
for the formation of the bicyclic enol ether from the
individual rings was consistently high and serves as a
testament to the potential of this coupling strategy.
The subsequent transformation of the C ring enol ether to
a suitable precursor for D ring cyclization was considerably
more problematic. Several reports2e,3m,o of successful hy-
In summary, we have developed an enantioselective
synthesis of the BCDE fragment of brevetoxin A. anti-
Glycolate aldol, syn-propionate aldol, and glycolate alkylation
reactions were used to form key carbon-carbon bonds and
(21) Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki, K.; Hirama, M. J.
Org. Chem. 2004, 69, 2797.
(22) Gilbert, M.; Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetra-
hedron 1997, 53, 8643.
(23) Johnson, H. W. B.; Majumder, U.; Rainier, J. D. J. Am. Chem. Soc.
2005, 127, 848.
(24) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108.
(25) See Supporting Information.
(19) (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.
(20) (a) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291. (b) Lipshutz, B. H.; Keith, J.; Papa, P.; Vivian, R.
Tetrahedron Lett. 1998, 39, 4627.
Org. Lett., Vol. 7, No. 18, 2005
4035

Scheme 3. Synthesis of the E Ring and Completion of the BCDE Fragment
set the stage for ring-closing metathesis to generate the
is acknowledged with thanks. Special thanks to Henry
Johnson and Professor Jon Rainier for their helpful discus-
sions regarding the oxidation of enol ether 21 and reduction
of the ensuing enol ether epoxide.
medium ring ethers, B and E. A convergent coupling strategy
was developed for the synthesis of polycyclic ethers in a
highly efficient manner. Application of this strategy toward
the GHIJ fragment of brevetoxin A is also currently
underway in our laboratory.
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.
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM60567)
OL051543M
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Org. Lett., Vol. 7, No. 18, 2005