Short, enantioselective total synthesis of aflatoxin B2 using an asymmetric [3+2]-cycloaddition step

Article abstract of DOI:10.1021/ja054503m

A highly enantioselective [3+2]-cycloaddition reaction of 2,3-dihydrofuran with 1,4-benzoquinones using a chiral oxazaborolidinium triflimidate as catalyst has been developed which allows rapid access to a variety of chiral phenolic tricycles (enantiomeric excesses ranging from 91 to 98%). The utility of this new methodology is demonstrated by a short synthesis of the important pentacyclic natural product, aflatoxin B₂. This exploratory study indicates that an even broader application of these catalysts to enantioselective cycloadditions may be possible. Copyright

Full text of DOI:10.1021/ja054503m

Published on Web 08/09/2005
Short, Enantioselective Total Synthesis of Aflatoxin B2 Using an Asymmetric
[3+2]-Cycloaddition Step
Gang Zhou and E. J. Corey*
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received July 7, 2005; E-mail: corey@chemistry.harvard.edu
[3+2]-Cycloaddition reactions are among the most powerful tools
for chemical synthesis because they provide unique access to
numerous five-membered ring systems and allow a rapid buildup
of molecular complexity. However, enantioselective versions of
these processes have just begun to emerge.1 We report herein a
novel enantioselective addition of 1,4-benzoquinones with vinyl
ethers catalyzed by the chiral oxazaborolidinium ion A (or the
enantiomer; see Scheme 1), a reagent that has previously been
shown to be exceedingly effective for the control of absolute
stereochemistry for many types of Diels-Alder reactions,2 and the
application of this methodology to a short enantioselective total
synthesis of the potent naturally occurring mutagen aflatoxin B2
(1, Scheme 1). Since the first synthesis of racemic aflatoxins by
the groups of Bu¨chi and Roberts,3 there have been numerous
syntheses of the racemates,4 but only recently has an enantiose-
lective route been described.5
The synthesis of aflatoxin B2 is summarized in Scheme 1.
Reaction of 2-methoxy-1,4-benzoquinone with 2,3-dihydrofuran
(1.5 equiv) in the presence of the (R)-oxazaborolidinium triflimide
A (0.2 equiv) in 1:1 CH2Cl2-CH3CN as solvent at -78 to 23 °C
over 7 h produced the [3+2]-cycloadduct 2 as the major product
(65% isolated yield) along with the regioisomer produced by [3+2]-
cycloaddition to O-1 and C-6 of the quinone as the minor product
(32% isolated yield) after chromatography on silica gel.6-8 The
structure and absolute configuration of 2 was determined by X-ray
crystallographic analysis both of 2 and the 4-bromobenzoate ester.6
The enantiomeric purity of 2 was determined to be 92% by GC
analysis; after one recrystallization from ether, enantiomerically pure
2, mp 151-152 °C, [R]23 -96 (c ) 1.0, CHCl3), was obtained.
D
An explanation for the absolute stereochemical course of the
formation of 2 is presented in Scheme 2. The phenolic cycloadduct
2 was transformed into the aldehyde 3 by sequential orthoformy-
lation (ca. 40%)6,7 and triflate ester formation (ca. 80%).6,7
Conversion of the aldehyde to the corresponding methyl ketone
(4) was effected by treatment with MeMgBr and subsequent
oxidation (85%). Baeyer-Villiger oxidation of 4 and reductive
removal of the triflate group together with deacetylation gave the
tricyclic phenol 5 (ca. 40% overall).6,7 Treatment of 5 with the
â-bromo-R,â-enone 6 (1.2 equiv) in the presence of ZnCO3 in CH2-
Cl2 as solvent at 23 °C for 24 h produced aflatoxin B2 (36% yield),
having physical properties identical with those reported.3a,b,6
A variety of solvents were tested for the critical [3+2]-
cycloaddition reaction leading to adduct 2. Although good enan-
tioselectivity was obtained with toluene or CH2Cl2 as solvent, the
reactions were slower than with 1:1 CH2Cl2-CH3CN as solvent.
The use of CH3CN or Me2CHCN as solvent was slightly inferior
with regard to product enantiomeric excess than was 1:1 CH2Cl2-
CH3CN.
The scope of the [3+2]-cycloaddition reaction was examined
with a number of substrates using the S-enantiomer of catalyst A.
The results are summarized in Table 1. The symmetrical quinones,
1,4-benzoquinone and 2,3-dimethyl-1,4-benzoquinone, gave a single
[3+2]-cycloadduct, as expected (Table 1, entries 4 and 5). The
unsymmetrical quinones shown in entries 1-3 of Table 1 generally
Scheme 1. Synthesis of Aflatoxin B2
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10.1021/ja054503m CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Enantioselective [3+2] Reactions of 1,4-Benzoquinones
and 2,3-Dihydrofuran
Scheme 2. Rational Pathway for the Formation of 2 and 11 via 12
with Catalyst A
1
a Isolated yield. b Ratios of regioisomers were determined by H NMR
analysis at 400 MHz. c Enantioselectivities were determined by GC analysis
or HPLC analysis using chiral columns.6 d Structures proved by X-ray
crystallographic analysis.6
and 11 are formed from that dipolar intermediate, as shown in
Scheme 2 (see also refs 1a-1h).
The enantioselective and unusually short synthesis of aflatoxin
B2 shown in Scheme 1 illustrates the utility of the new methodology
described herein.
afforded two regioisomers, with the major regioisomer being 7
(corresponding to 2 of Scheme 1). The formation of two regio-
isomers for entries 1-3 can be understood in terms of two different
pathways involving catalyst coordination to each of the two different
quinone oxygens. Although coordination to the more basic oxygen
may predominate, the other mode of coordination probably leads
to a faster [3+2]-cycloaddition rate.2h The structures of both adducts
of entry 1 were determined unambiguously by X-ray crystal-
lographic analyses, as was the structure of the major adduct of entry
2.
Supporting Information Available: Additional experimental pro-
cedures and spectral data for reaction products (22 pages, print/PDF).
X-ray crystallographic data for 2, the 4-bromobenzoate of 2, 11, and
the products of entries 1 and 2 of Table 1. This material is available
free of charge via the Internet at http://pubs.acs.org.
References
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In another example, the reaction of 2-methoxy-1,4-benzoquinone
with 5-dimethylphenylsilyl-2,3-dihydrofuran under the standard
conditions of Table 1 provided the [3+2]-cycloadduct 9 in 82%
yield (only regioisomer formed) and 98% ee. It is clear from this
result that additional substitution on the olefinic linkage of the vinyl
ether component is tolerated in the cycloaddition process and also
that very high regioselectivity is possible with unsymmetrical
components. Finally, when the reaction of 2-methyl-5-isopropyl-
6-methoxy-1,4-benzoquinone and 2,3-dihydrofuran was carried out
with 0.2 equiv of the S-catalyst ent-A, the [2+2]-cycloadduct 10
was obtained as the major product (25% isolated yield, 99% ee).8
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A mechanistically powerful result for understanding the pathway
of the [3+2]-cycloaddition reaction leading to 2 has been obtained
by a simple trapping experiment. When the reaction of 2-methoxy-
1,4-benzoquinone and 2,3-dihydrofuran was carried out with 10
equiv of the latter and 0.2 equiv of catalyst A, the major products
were 2 (53% isolated yield, 91% ee) and the 2:1 adduct 11 (41%,
85% ee), with the structure of 11 being fully confirmed by X-ray
crystallographic analysis.6 We believe that the formation of 11
results from the trapping of a 1:1 dipolar intermediate (12 in Scheme
2) in the [3+2]-cycloaddition process. It is possible that both 2
(5) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2003, 125, 3090-3100.
(6) See Supporting Information for full details.
(7) Yield not optimized.
(8) For a discussion relevant to the regiochemistry of the [3+2]-cycloaddition
reactions reported herein, see ref 2h. For Ti-catalyzed [2+2]-cycloadditions
to 1,4-benzoquinones, see: Engler, T. A.; Letavic, M. A.; Rajesh, I.; La
Tessa, K. O.; Reddy, J. P. J. Org. Chem. 1999, 64, 2391-2405.
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