Dedicated to Professor Dieter Seebach on the occasion of his 70th birthday
With a practical synthesis of the ABCD aldehyde in hand (2, Scheme 1), [1] herein we describe our progress that culminated in the synthesis of (+)-azaspiracid-1 (1) in 26 linear steps and 2.7 % overall yield.
As outlined in Scheme 1, the addition of an anomeric sulfone anion derived from 3 to a C20-electrophile, as represented by aldehyde 2, could provide a highly convergent approach to the target. Since all nine rings of azaspiracid-1 (1) are formed prior to this final fragment coupling, the number of manipulations required after the coupling step would be minimal. Such anomeric sulfone anion additions have considerable precedent, both in the original investigations of anomeric sulfone anions derived from carbohydrates [2, 3] and subsequently in advanced fragment couplings in total synthesis, [4][5][6] although the crucial sulfone anion addition of 3 to electrophiles such as aldehyde 2 would represent the most complex anomeric sulfone anion addition to date.
Conformational analysis of the HI spiroaminal portion of pentacyclic sulfone 3 (Figure 1) suggests, on the basis of anomeric stabilization and an analysis of steric effects, that this synthon exists in its favored configuration. Therefore, a number of ketalization events were incorporated into the assembly of 3, in which the molecule is anticipated to spontaneously form the desired tetracyclic FGHI system under equilibrating conditions. The fragment couplings to construct intermediate 4 (Scheme 1) would involve a boronmediated addition of the C27-methyl ketone of the FG ring fragment 6 to the E ring aldehyde 5, while a chelatecontrolled Mukaiyama aldol addition [7] of the enolsilane derived from the C35-methyl ketone of 7 to the aldehyde of 6 was anticipated to establish the stereocenter at C34.
By inspection, two syn 1,3-dimethyl synthons of the same configuration are embedded in the azaspiracid structure in the E and the I rings. We were attracted to the possibility of constructing both of these subunits from the common Scheme 1. Retrosynthetic analysis of (+)-azaspiracid (1) and the EFGHI sulfone 3. See Ref.[8] for abbreviations.
Figure 1. Three-dimensional representation of the EFGHI sulfone 3.