and S,S-TADDOL (entry 9) delivered a 5:1 mixture favoring
the anti diastereomer. Unfortunately, R,R-TADDOL gave
only a 2:1 preference for the syn diastereomer (entry 10).
Satisfactory diastereoselection was ultimately obtained
taking advantage of Carreira’s catalyst (Figure 2),10 which
Scheme 3. Hetero-Diels-Alder Cycloaddition
Figure 2. Carreira’s catalyst.
to effect the hetero-Diels-Alder reaction using triethylsilyl13
and tert-butyldimethylsilyl ethers at C5 resulted in formation
of â-keto lactone 20 presumably via interception of the acyl
ketene by the C5 ether oxygen followed by loss of the labile
silicon protecting group (Scheme 4, path b).14 Incorporating
the more robust benzyloxymethyl group precluded formation
of the â-keto lactone 20.
has been reported to effect enantioselective Mukiayama aldol
additions of silyl dienolate 11 with a variety of achiral
aldehydes. Use of the Carreira protocol with dienolate 11
and aldehyde 6 allowed access to either the syn diastereomer
12s or anti diastereomer 12a in high yield and selectivity
with low catalyst loadings. Using the (+)-enantiomer of 13
(entry 12) led to formation of a 10:1 mixture of aldol adducts
favoring the desired syn diastereomer 12s (95% yield), while
(-)-13 produced the anti diastereomer 12a (entry 11) as the
major product (8.6:1 dr, 81% yield).
Scheme 4. Side Reactions of Acyl Ketene Intermediate
Having accomplished an efficient synthesis of the desired
dioxinone 12s, its conversion to the required pyrone was
investigated. An extension of the method reported by
Coleman and Grant11 to include more complex substrates,
by performing a hetero-Diels-Alder reaction of an acyl
ketene with butyl vinyl ether, was envisioned for conversion
of dioxinone 12s to the desired pyrone. To this end, the C5
hydroxyl was readily protected as a benzyloxymethyl ether
to provide hetero-Diels-Alder precursor 14 (Scheme 3).
Heating dioxinone 14 in toluene in the presence of butyl
vinyl ether led to formation of butyl acetal 16 presumably
through a hetero-Diels-Alder reaction of intermediate acyl
ketene 15 with butyl vinyl ether. Immediate exposure of the
butyl acetal to p-TsOH in THF led to rapid elimination of
butanol to produce pyrone 17 (65% over two steps).12
Efficient conversion of the dioxinone 14 to the butyl acetal
16 required that all materials be rigorously dried to avoid
trapping of the acyl ketene intermediate by advantitious
water. Failure to scrupulously dry the dioxinone, the solvent,
or butyl vinyl ether led to formation of â-keto acid 19
(Scheme 4, path a). Additionally, the choice of protecting
group on the C5 hydroxyl group was critical. Early attempts
Taking advantage of the chemistry previously employed
in the total synthesis of spongistatin, the p-methoxybenzyl
group was removed by the action of DDQ to provide the
free alcohol at C3 (Scheme 5). Exposure of the hydroxy-
pyrone to catalytic trifluoroacetic acid in benzene provided
spiroenone 21 in 64% yield after recycle. The minor
diastereomer (<10% which had been introduced in the
Mukaiyama aldol addition) could be readily removed after
the spiroketalization. Treatment of the spiroenone 21 with
the vinyl cuprate reagent formed from vinylmagnesium
bromide and tetrakis[copper(I) iodide-tributylphosphine] led
to the formation of alkene 22 as the major diastereomer (5:1
dr). The C9 tertiary carbinol was introduced by addition of
methylmagnesium iodide to the C9 ketone. Cleavage of the
(10) Singer, R. A.; Carreira, E. M. J. Am. Chem. Soc. 1995, 117, 12360-
61.
(11) Coleman, R. S.; Grant, E. B. Tetrahedron Lett. 1990, 31, 3677-
80. See also: Sato, M.; Ogasawara, H.; Kato, K.; Sakai, M.; Kato, T. Chem.
Pharm. Bull. 1983, 31, 4300-05.
(12) Zawacki, F. J.; Crimmins, M. T. Tetrahedron Lett. 1996, 37, 6499-
6502.
(13) Katz, J. D. Thesis, University of North Carolina.
(14) Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Heterocycles 1995,
41, 1435-44. Sato, M.; Sunami, S.; Sugita, Y.; Kaneko, C. Chem. Pharm.
Bull. 1994, 42, 839-45.
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