Apoptolidins A-E are a family of macrolide natural products that have attracted considerable attention as highly selective apoptosis regulators.[1] The critical need for achieving greater selectivity in cancer chemotherapeutics has stimulated efforts to elucidate the mechanistic and structural basis for the apoptolidins unique pharmacological profile. These efforts include several total syntheses of apoptolidin A, each of which has provided invaluable insights into strategies for chemically modifying the natural product for expanded pharmacological profiling.[2] Similar considerations inspired our interest in developing an enantioselective synthesis of the apoptolidins exploring the capacity of catalytic asymmetric aldol reaction surrogates to facilitate the synthesis of these natural products. Toward this goal, we describe herein an enantioselective synthesis of apoptolidinone C (1), the apoptolidin C aglycone, wherein catalytic asymmetric CÀC bond constructions provide the conduit to all ten of the requisite stereogenic centers.Their utility in assembling acetate-or propionate-derived polyketide architecture is among the defining characteristics of modern aldol-based reaction technologies. There exists an array of aldol or aldol equivalents utilizing stoichiometric chiral controllers that provide exceptionally reliable and predictable methods for constructing complex polyacetate and polypropionate arrays.[3] For our purposes, the apoptolidin C aglycone provided a platform for evaluating whether similar levels of operational efficiency and expediency could be achieved in similar synthesis endeavors wherein stereocontrol would derive exclusively from catalyst-based substoichiometric chiral controllers. Specifically, catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions provide highly stereoselective acetate or propionate aldol equivalents using Al III -based Lewis acid or cinchona alkaloid Lewis base catalysts, respectively.[4] Complex polyketide assemblage predicated on the AAC methodology follows a reiterative pattern of catalyst controlled CÀC bond construction followed by b-lactone refunctionalization to the b-alkoxy aldehyde required for continued chain homologation in a sequence reminiscent of the iterative homologation-refunctionalization sequence observed in biosynthetic polyketide assembly.A synthesis of apoptolidinone C (1) emerges from the preceding analysis by disconnecting 1 across the C1ÀO and C11ÀC12 bonds to reveal the mixed acetate/propionatederived C12-C28 fragment 2 and the extensively dehydrated polypropionate C1-C11 fragment 3 (Scheme 1). The synthesis of lower fragment 2 highlights the iterative assembly of stereodefined polyketide units enabled by the AAC methodology. Thus, Al III -triamine (4)-catalyzed cyclocondensation of acetyl bromide with methoxyacetaldehyde provided b-lactone 5 as an acetate aldol equivalent (91 %, ! 95 % ee) (Scheme 2).[4] Converting lactone 5 to aldehyde 6 required for continued chain elongation involved amine-mediated ring opening (MeO(Me)NH,...

Apoptolidins A-E are a family of macrolide natural products that have attracted considerable attention as highly selective apoptosis regulators. [1] The critical need for achieving greater selectivity in cancer chemotherapeutics has stimulated efforts to elucidate the mechanistic and structural basis for the apoptolidins unique pharmacological profile. These efforts include several total syntheses of apoptolidin A, each of which has provided invaluable insights into strategies for chemically modifying the natural product for expanded pharmacological profiling. [2] Similar considerations inspired our interest in developing an enantioselective synthesis of the apoptolidins exploring the capacity of catalytic asymmetric aldol reaction surrogates to facilitate the synthesis of these natural products. Toward this goal, we describe herein an enantioselective synthesis of apoptolidinone C (1), the apoptolidin C aglycone, wherein catalytic asymmetric CÀC bond constructions provide the conduit to all ten of the requisite stereogenic centers.Their utility in assembling acetate-or propionate-derived polyketide architecture is among the defining characteristics of modern aldol-based reaction technologies. There exists an array of aldol or aldol equivalents utilizing stoichiometric chiral controllers that provide exceptionally reliable and predictable methods for constructing complex polyacetate and polypropionate arrays. [3] For our purposes, the apoptolidin C aglycone provided a platform for evaluating whether similar levels of operational efficiency and expediency could be achieved in similar synthesis endeavors wherein stereocontrol would derive exclusively from catalyst-based substoichiometric chiral controllers. Specifically, catalytic asymmetric acyl halide-aldehyde cyclocondensation (AAC) reactions provide highly stereoselective acetate or propionate aldol equivalents using Al III -based Lewis acid or cinchona alkaloid Lewis base catalysts, respectively. [4] Complex polyketide assemblage predicated on the AAC methodology follows a reiterative pattern of catalyst controlled CÀC bond construction followed by b-lactone refunctionalization to the b-alkoxy aldehyde required for continued chain homologation in a sequence reminiscent of the iterative homologation-refunc-tionalization sequence observed in biosynthetic polyketide assembly.A synthesis of apoptolidinone C (1) emerges from the preceding analysis by disconnecting 1 across the C1ÀO and C11ÀC12 bonds to reveal the mixed acetate/propionatederived C12-C28 fragment 2 and the extensively dehydrated polypropionate C1-C11 fragment 3 (Scheme 1). The synthesis of lower fragment 2 highlights the iterative assembly of stereodefined polyketide units enabled by the AAC methodology. Thus, Al III -triamine (4)-catalyzed cyclocondensation of acetyl bromide with methoxyacetaldehyde provided b-lactone 5 as an acetate aldol equivalent (91 %, ! 95 % ee) (Scheme 2). [4] Converting lactone 5 to aldehyde 6 required for continued chain elongation involved amine-mediated ring opening (MeO...