Noniterative approach to the total asymmetric synthesis of 15-carbon polyketides and analogs with high stereodiversity

Starting from inexpensive furan and furfuryl alcohol, a noniterative approach to the synthesis of pentadeca-1,3,5,7,9,11,13,15-octols and their derivatives has been developed. The method relies upon the double [4+3]-cycloaddition of 1,1,3-trichloro-2-oxylallyl cation with 2,2'-methylenedifuran and conversion of the adducts into meso and (±)-threo-1,1'-methylenebis (cis- and trans-4,6-dihydroxycyclohept-1-ene) derivatives. The latter undergo oxidative cleavage of their alkene moieties, generating 5-hydroxy-7-oxoaldehydes that are reduced diastereoselectively into either syn or anti-5,7-diols. Asymmetry is realized using either chiral desymmetrization with Sharpless asymmetric dihydroxylation or by kinetic resolution of polyols using lipase-catalyzed acetylations. All of the possible stereomeric pentadeca-1,3,5,7,9,11,13,15-octols and derivatives can be obtained with high stereoselectivity applying simple operations, thus demonstrating the high stereodiversity of this new, noniterative approach to the asymmetric synthesis of long-chain polyketide

Synthesis of the Bis-spiroacetal Moiety of Spirolides B and D

An enantioselective synthesis of the bis-spiroacetal fragment of spirolides B and D is reported. The carbon framework was constructed via Barbier reaction of dihydropyran 3 with aldehyde 4, followed by a double oxidative radical cyclization to construct the bis-spiroacetal. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor. The initial unsaturated bis-spiroacetals 2a−d underwent equilibration during epoxidation to trans-epoxide 14 that was converted to a tertiary alcohol

Synthesis of the Bis-spiroacetal Moiety of Spirolides B and D

An enantioselective synthesis of the bis-spiroacetal fragment of spirolides B and D is reported. The carbon framework was constructed via Barbier reaction of dihydropyran 3 with aldehyde 4, followed by a double oxidative radical cyclization to construct the bis-spiroacetal. A silyl-modified Prins cyclization and enantioselective crotylation successfully installed the stereocenters in the cyclization precursor. The initial unsaturated bis-spiroacetals 2a−d underwent equilibration during epoxidation to trans-epoxide 14 that was converted to a tertiary alcohol

Non-iterative asymmetric synthesis of C-15 polyketide spiroketals

The 2,2'-methylenebis[furan] (1) was converted to 1-{(4R,6S))-6-[(2R)-2,4-dihydroxybutyl]-2,2-dimethyl-1,3-dioxan-4-yl}-3- [(2R,4R)-tetrahydro-4,6-dihydroxy-2H-pyran-2-yl)propan-2-one ((+)-18) and its (4S)-epimer (-)-19 with high stereo- and enantioselectivity (Schemes 1-3). Under acidic methanolysis, (+)-18 yielded a single spiroketal, (3R)-4-1(1R,3S,4'R,5R,6'S,7R)-3',4',5',6'-tetrahydro-4'-hydroxy-7-methox yspiro[2,6-dioxabicyclo[3.3.1]nonane-3,2'-[2H]pyran]-6'-yl]butane-1,3-di ol ((-)-20), in which both O-atoms at the spiro center reside in equatorial positions, this being due to the tricyclic nature of (-)-20 (methyl pyranoside formation). Compound (-)-19 was converted similarly into the (4'S)-epimeric tricyclic spiroketal (-)-21 that also adopts a similar (3S)-configuration and conformation. Spiroketals (-)-20, (-)-21 and analog (-)-23, i.e., (1R,3S,4'R,5R,6'R)-3',4',5',6'-tetrahydro-6'-[(2S)-2-hydroxybut-3-enyl]- 7-methoxyspiro[2,6-dioxabicyclo[3.3.1]nonane-3,2'-[2H]pyran]-4'-ol, derived from (-)-20, were assayed for their cytotoxicity toward marine P388 lymphocytic leukemia and six human cancer cell lines. Only racemic ()-21 showed evidence of cancer-cell-growth inhibition (P388, ED50: 6.9 mug/ml)

Asymmetric synthesis of polycyclic polyketides via the double Diels-Alder addition of 2,2 '-ethylidenebis[3,5-dimethylfuran]

The Diels-Alder adduct 3 of 2,2'-ethylidenebis(3,5-dimethylfuran) to diethyl (E,E)-4-oxohepta-2,5-diene-1,7-dioate was converted into meso-(1R,2R,4R,4aR,5S,7S,8S,8aS,9aS,10aS)- 1,8-bis(acetoxymethyl)- 1,3,4,5,6,7,8,8a,9,9a-decahydro-2,4,5,7,10 -pentamethyl-3,6,9-trioxo-2H,10H-2,4a:7,10a-diepoxy-anthracene (9). Enantioselective monoreduction of 9 with BH3. Me2S and a catalytic amount of methyloxazaborolidine derived from L-diphenylprolinol gave (1S,2S,4S,4aS,5S,6R,7R,8R,8aS,9aR,10R,10aS)-1,8-bis(acetoxymethyl-1,3,4, 5,6,7,8,8a,9,9a-decahydro-6- methyl-3,9-dioxo-2N,10H-2,4a:7,10a-diepoxyanthracene with 90% ee. Its absolute configuration was established by single crystal X-ray diffraction studies of the camphanate (-)-13 (1S,2S,4S,4aS,5S,6S,7R,8R,8aS,9aR,10R,10aS)- 8-acetoxymethyl-1-[(2'S,5'R)-camphanoyloxymethyl]-1,3,4,5,6,8,8a,9,9a-de cahydro-6-(methoxymethyl)-2,4,5,7,10-penta 2H,10H-2,4a:7,10a-diepoxyanthracene). Basic treatment of (-)-10 led to regioselective ethereal ring opening of the 7-oxabicyclo[2.2.1] heptan-2-one moiety at C-1,2,3,4,4a,9a with formation of (1R,2R,3R,4S,4aR,5S,7S,8S,9aS,10S)-1,8-diacetoxymethyl-1,3,4,5,6,7,8,9,9 a,10-decahydro-3,7-dihydroxy-2,4,5,7,10-pentamethyl methyl-6,9-dioxo-2H-2,4a-epoxyanthracen. Thus, desymmetrization of 9 via enantioselective triketone reduction allows the preparation of polycyclic polyketides with high stereochemical complexity and with high stereo- and enantioselectivity