Improved synthesis of the ABCDE fragment of brevetoxin A

Article abstract of DOI:10.1021/ol0615782

A second-generation synthesis of the BCDE fragment of brevetoxin A is described. Novel reactions were developed that extend the utility of the asymmetric glycolate alkylation reaction and improve scale-up to provide gram quantities of the B and E subunits

Full text of DOI:10.1021/ol0615782

ORGANIC
LETTERS
2006
Vol. 8, No. 18
4079-4082
Improved Synthesis of the ABCDE
Fragment of Brevetoxin A
Michael T. Crimmins,* Patrick J. McDougall, and J. Michael Ellis
Venable and Kenan Laboratories of Chemistry, UniVersity of North Carolina at
Chapel Hill, Chapel Hill, North Carolina 27599
crimmins@email.unc.edu
Received June 27, 2006
ABSTRACT
A second-generation synthesis of the BCDE fragment of brevetoxin A is described. Novel reactions were developed that extend the utility of
the asymmetric glycolate alkylation reaction and improve scale-up to provide gram quantities of the B and E subunits. Significant improvements
to the convergent assembly of the tetracycle were also realized. In addition, formation of the A ring lactone was accomplished to complete
the ABCDE pentacycle.
Brevetoxin A (Figure 1), a ladder ether toxin which is a
metabolite of the notorious Karenia breVis, possesses a
fragments of brevetoxin A. These reports highlighted the
development of a highly efficient coupling strategy5 centered
around a Horner-Wadsworth-Emmons union of two com-
plex ring units followed by a cyclodehydration of a keto-
alcohol to form an intermediate cyclic enol ether. The original
synthesis of the BCDE fragment focused on the application
of our anti-glycolate aldol reaction6 to establish four stereo-
genic centers. Although this approach proved useful, it
ultimately provided the BCDE fragment 1 (Figure 2)
Figure 1. Brevetoxin A.
topographically daunting structure containing 10 rings and
22 stereogenic centers.1,2 In previous communications, we
disclosed successful approaches to the BCDE3 and GHIJ4
(1) Isolation: (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.
Figure 2. Previous synthesis of the BCDE fragment.
(2) Previous synthesis: Nicolaou, K. C.; Yang, Z.; Shi, G.-q.; Gunzner,
J. L.; Agrios, K. A.; Ga¨rtner, P. Nature 1998, 392, 264. Nicolaou, K. C.
Gunzner, J. L.; Shi, G.-q.; Agrios, K. A.; Ga¨rtner, P.; Yang, Z. Chem.-
Eur. J. 1999, 5, 646 and references therein.
(3) Crimmins, M. T.; McDougall, P. J.; Emmitte, K. A. Org. Lett. 2005,
7, 4033.
truncated by two carbons (C1 and C24). Consequently, a
revised route to the BCDE fragment was envisioned that
would obviate a late-stage homologation yet apply the insight
gained from our previous synthesis. We report herein an
10.1021/ol0615782 CCC: $33.50
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Scheme 1
improved, scalable route to the BCDE fragment of brevetoxin
A and formation of the ABCDE lactone.
this time with benzyl iodomethyl ether (prepared in situ), to
provide a single detectable diastereomer in good yield.
Reductive removal of the chiral auxiliary provided alcohol
7, which was oxidized under Swern conditions.8 The resultant
aldehyde was treated with vinylmagnesium bromide to yield
a 3:1 inseparable mixture of diastereomers favoring the
desired configuration. Treatment of the mixture of dienes
with the Grubbs second-generation catalyst10 provided
oxocenes 8 and 9. The diastereomers were easily separable
at this point, and the minor isomer 9 was inverted to the
desired alcohol 8 by sequential Swern oxidation8 and Luche
reduction.11
Treatment of oxocene 8 with Crabtree’s catalyst12 under
an atmosphere of hydrogen at low temperature provided a
single detectable diastereomer of the oxacane in excellent
yield. The secondary alcohol was oxidized under Swern
conditions,8 and the resultant ketone 10 was treated with
methylmagnesium chloride to provide the tertiary alcohol
in 88% yield. Selective cleavage of the benzyl ether was
achieved via hydrogenation in the presence of Raney nickel.13
Finally, Dess-Martin oxidation14 of the resultant primary
alcohol provided aldehyde 11. This approach has allowed
preparation of multigram quantities of the B ring subunit 11
in a single run through the sequence.
To address the issue of incorporating the required C1 and
C24 carbons, an asymmetric glycolate alkylation7 strategy
was employed rather than the anti-glycolate aldol approach.
To this end, the sodium enolate of glycolate 2 (Scheme 1)
was alkylated with methallyl iodide to provide a single
diastereomer in 78% yield. An unprecedented Claisen
condensation of the N-acyloxazolidinone with the lithium
enolate of ethyl acetate provided â-keto ester 3 directly in
high yield. The inductive effect of the ether oxygen likely
allows for direct displacement of the oxazolidinone chiral
auxiliary by the lithiated nucleophile by increasing the
electrophilicity of the adjacent carbonyl. Following reduction
of both carbonyl functionalities with LiAlH4, the primary
alcohol of the resultant diol was selectively protected as the
triisopropylsilyl ether. Oxidation of the secondary alcohol
under Swern conditions8 provided the ketone 4. A chelation-
controlled reduction using zinc borohydride9 provided the
alcohol 5 in 79% yield (>15:1 dr).
Because alcohol 5 was homologous to an intermediate in
our first-generation synthesis, a similar strategy was utilized
for the completion of the B ring subunit. The alcohol 5 was
alkylated with sodium bromoacetate, and the mixed anhy-
dride of the resultant glycolic acid was treated with (R)-
lithio-4-isopropyl-2-oxazolidinone to provide imide 6 in 90%
yield. Exploiting the asymmetric glycolate alkylation strat-
egy7 once again, the sodium enolate of imide 6 was alkylated,
The revised E ring synthesis followed the initial stages of
the previous approach3 to generate the advanced glycolyl
imide 12 (Scheme 2). To install the requisite two-carbon unit
at C22, a novel alkylation using bromoacetonitrile was
employed to give the alkylated adduct in good yield and
(4) Crimmins, M. T.; Zuccarello, J. L.; Cleary, P. A. Org. Lett. 2006, 8,
159.
(5) For a recent review on convergent strategies for synthesis of
polycyclic ethers, see: Inoue, M. Chem. ReV. 2005, 105, 4379.
(6) Crimmins, M. T.; McDougall, P. J. Org. Lett. 2003, 5, 591.
(7) Crimmins, M. T.; Emmitte, K. A.; Katz, J. D. Org. Lett. 2000, 2,
2165.
(10) Scholl, M.; Ding, S.; Lee, C. W.; Grubbs, R. H. Org. Lett. 1999, 1,
953.
(11) Gemal, A. L.; Luche, J. L. J. Am. Chem. Soc. 1981, 103, 5454.
(12) Crabtree, R. H.; Felkin, H.; Fillebeen-Khan, T.; Morris, G. E. J.
Organomet. Chem. 1979, 168, 183.
(13) Horita, K.; Yoshioka, T.; Tanaka, T.; Oikawa, Y.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021.
(14) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
(8) Mancuso, A. J.; Huang, S.; Swern, D. J. Org. Chem. 1978, 43, 2480.
(9) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
4080
Org. Lett., Vol. 8, No. 18, 2006

Scheme 2
excellent diastereoselectivity (>98:2 dr). Reductive removal
yield. Reduction of the nitrile to the aldehyde using i-Bu2-
AlH, followed by the addition of lithiated dimethyl methyl
phosphonate, gave an inconsequential mixture of â-hydroxy
phosphonates in good yield. Oxidation of the â-hydroxy
phosphonates to the â-keto phosphonate was readily ac-
complished using the Dess-Martin reagent.14 Finally, closure
of the E ring was accomplished upon exposure of the diene
to the Grubbs first-generation catalyst16 to give the completed
E ring fragment 17. The yields of these final steps were
highly reproducible and readily amenable to scale-up.
Union of the revised B and E rings proceeded smoothly
by exposure of aldehyde 11 and phosphonate 17 to aqueous
Ba(OH)2 to give the enone 18 in excellent yield (Scheme
2).17 Although our original route relied upon the highly air-
sensitive Stryker’s reagent18 for the selective reduction of
the enone C-C π bond, an alternative protocol was
developed with the use of Wilkinson’s catalyst in the
presence of a silane source.19 The addition of PPTS directly
of the auxiliary provided the primary alcohol 13. Oxidation
of the alcohol under Swern conditions8 followed by Felkin-
Anh-controlled allylation using allyltributylstannane and
trimethylaluminum15 delivered the product with the highest
levels of diastereoselection (>7:1 dr). Treatment of the
mixture of diastereomers with HCl in methanol at 65 °C
resulted in hydrolysis of the nitrile, cleavage of the TIPS
and PMB ethers, and lactonization leading to lactone 14.
Separation of the two diastereomers was readily achieved at
this stage.
It was anticipated that protecting group choice would be
critical to a successful coupling strategy and material
throughput. Thus, protection of the C13, C16 diol as the bis-
TBS ether was followed by subsequent reduction of the
lactone using LiAlH4 to give the C21, C24 diol in excellent
yield. Orthogonal protection of the C21, C24 diol as the
bisbenzyl ether led to the fully protected E ring fragment
15. Treatment with HF-pyridine selectively removed the
C13 silyl ether to give 72% of the desired primary alcohol
along with 16% of the C13, C16 diol, which could be easily
recycled.
(15) (a) Crimmins, M. T.; Stanton, M. G.; Allwein, S. P. J. Am. Chem.
Soc. 2002, 124, 5958. (b) Keck, G. E.; Abbott, D. E. Tetrahedron Lett.
1984, 25, 1883.
(16) Miller, S. J.; Kim, S.-H.; Chen, Z.-R.; Grubbs, R. H. J. Am. Chem.
Soc. 1995, 117, 2108.
(17) (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.
(18) Mahoney, W. S.; Brestensky, D. M.; Stryker, J. M. J. Am. Chem.
Soc. 1988, 110, 291.
Preparation of the â-keto phosphonate 17 was examined
under a variety of conditions. The most reliable and efficient
route began with formation of the alkyl iodide followed by
displacement with cyanide to give the nitrile 16 in excellent
Org. Lett., Vol. 8, No. 18, 2006
4081

to the reaction mixture following enone consumption allowed
for a one-pot, efficient conversion of enone 18 to the desired
enol ether 19. Conversion of enol ether 19 to ketone 21
utilized an in situ epoxidation-reduction protocol,20 which
was adopted as a result of the highly sensitive nature of the
epoxy enol ether. This procedure required DMDO solutions
that were nearly free of acetone to minimize the amount of
i-Bu2AlH required. However, inconsistencies in the reaction
were observed, likely the result of varying concentrations
of acetone present in the DMDO solution. A simple
modification to the original extraction procedure,21 utilizing
CH2Cl2-pentane solvent mixtures, gave DMDO solutions
that were superior in the aforementioned reaction. In practice,
oxidation of the enol ether followed by the addition of i-Bu2-
AlH led to a diastereomeric mixture of alcohols in good,
reproducible yield. The configuration of the diastereomers
that were formed was not ascertained at this stage of the
synthesis. However, subsequent oxidation to the ketones
using Dess-Martin periodinane revealed the presence of two
C12 epimers 20 and 21 in an approximate 3:1 ratio favoring
the undesired epimer 20.
The next challenge in the synthesis required identification
of an efficient method for the isomerization of the C12
epimer 20 to the desired diastereomer 21. The use of several
bases, including DBU,22 NaOMe, LiOMe, and imidazole
resulted in either significant decomposition or very slow
isomerization. Fortunately, the use of potassium carbonate
in methanol at 65 °C, resulted in isomerization at C12 with
minimal decomposition. One exposure of ketone 20 to the
isomerization conditions led to 66% of the ketone 21
accompanied by 22% of ketone 20. The mixture was readily
separated, and ketone 20 was resubjected to the reaction
conditions. The desired isomer 21 was obtained in 78% yield
after recycle.
required a three-step sequence from the protected keto
alcohol. However, after considerable experimentation, it was
found that simply treating ketone 21 with camphorsulfonic
acid in methanol led to a remarkably efficient transformation
involving cleavage of the silyl ethers and direct cyclization
to the mixed ketals 22 and 23 (inconsequential partial loss
of the PMB group was also observed). Reduction of both
mixed methyl ketals (R ) PMB or H) using BF3-OEt2 and
Me2PhSiH led to the formation of the BCDE fragment 24
in good yield and as a single detectable isomer. In an effort
to explore the formation of the A ring lactone, the diol 24
was treated with tetrapropylammonium perruthanate (TPAP)
and stoichiometric 4-methylmorpholine N-oxide (NMO)23 to
give exclusive formation of the ABCDE lactone 25 in 63%
yield. Stereochemical confirmation of the ABCDE fragment
was obtained using 2D NMR.
In summary, a highly stereoselective synthesis of the
ABCDE fragment of brevetoxin A has been completed. This
second-generation approach proved far more amenable to
scale-up enabling the preparation of significant quantities of
the BCDE fragment. To date, more than three grams of
aldehyde 11 and five grams of phosphonate 17 have been
prepared by the sequence described herein. During the course
of these studies, several novel transformations were disclosed,
including a direct displacement of an oxazolidinone chiral
auxiliary with a lithium enolate and a glycolate alkylation
using bromoacetonitrile. Our convergent coupling strategy
was again employed for the formation of the C and D rings,
this time providing the BCDE fragment more efficiently than
previously reported. Efforts toward the completion of the
total synthesis of brevetoxin A are ongoing.
Acknowledgment. Financial support of this work by the
National Institute of General Medical Sciences (GM60567)
is acknowledged with thanks.
Previous efforts to cyclize the remaining D ring to the
mixed methyl ketal were rather inefficient (∼30%) and
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.
(19) Ojima, I.; Kogure, T. Organometalics 1982, 1, 1390.
(20) Johnson, H. W. B.; Majumder, U.; Rainier, J. D. J. Am. Chem. Soc.
2005, 127, 848.
OL0615782
(21) Gilbert, M.; Ferrer, M.; Sanchez-Baeza, F.; Messeguer, A. Tetra-
hedron 1997, 53, 8643.
(22) Inoue, M.; Yamashita, S.; Tatami, A.; Miyazaki, K.; Hirama, M. J.
Org. Chem. 2004, 69, 2797.
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J. Am. Chem. Soc. 1996, 118, 5620. Griffith, W. P.; Ley, S. V.; Whitcombe,
G. P.; White, A. D. J. Chem. Soc. Chem. Commun. 1987, 1625.
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Org. Lett., Vol. 8, No. 18, 2006