Matched and mismatched pairings in B-secotaxane construction: a structure elucidation study

The synthesis of the basic B-seco taxoid skeleton was achieved through a C10–C11 coupling of the A-ring segment (14S)-1 with the C-ring segments (10S) and (10R)-α-alkoxyorganolithium reagents, prepared in situ from 2 and 6 through nBuLi mediated transmetallation. The matched reactions of (14S)-1 with (10S)-2 and (10S)-6 displays an outstanding diastereoselectivity providing 12 and 34, respectively, as single isomers and hence allowing a convenient entry to highly functionalized taxoid diterpene frameworks. Significant mismatching was observed with the (10R)-epimer of 2 and 6 yielding little, if any, diastereoselectivity. The structures of B-secotaxanes were assigned on the basis of spatial proximity effects in the proton NMR spectrum. Assignment of the C10/C11 stereochemistry was made possible through conversion of the B-secotaxoid frameworks, derived from the matched and mismatched adducts, to the corresponding cyclic acetals. Configurational stability of α-alkoxyorganolithium derivatives was verified in all the cases investigated. Structure elucidation of these adducts was essential for the successful C1–C2 bonding via an intramolecular aldol reaction, given the fact that adducts containing a β-MOM substituent at C10 would be disfavored for such an endeavor.

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1-{2-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-4-(tert-butyl-dimethyl-silanyloxy)-2,6,6-trimethyl-cyclohex-2-enolC38H74O6Si2Ee ⩾ 97%[α]D20=+16 (c 2.0, CHCl3)Source of chirality:(S)-prolineAbsolute configuration (3S,7S,8S,10R,11S,14S)

4-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexylmethyl]-8-(tert-butyl-dimethyl-silanyloxy)-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-eneC37H70O5Si2Ee ⩾ 97%[α]D20=+14 (c 1.1, CHCl3)Source of chirality:(S)-prolineAbsolute configuration (3S,7S,8S,10R,11S,14S)

4-[6-tert-Butoxy-2-hydroxymethyl-1-methyl-3-methylene-cyclohexylmethyl-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-en-8-olC25H42O5Ee ⩾ 97%[α]D20=+51 (c 1.3, CHCl3)Source of chirality:(S)-prolineAbsolute configuration (3S,7S,8S,10R,11S,14S)

3-tert-Butoxy-2-methyl-6-methylene-2-(6,10,10-trimethyl-8-oxo-1,3-dioxa-spiro [4.5] dec-6-en-4-ylmethyl)-cyclohexane carbaldehydeC25H38O5Ee ⩾ 97%[α]D20=-84 (c 1.2, CHCl3)Source of chirality:(S)-prolineAbsolute configuration (3S,7S,8S,10R,11S)

4-(tert-Butyl-dimethyl-silanyloxy)-1-methoxymethoxymethyl-2,6,6-trimethyl-cyclohex-2-enolC18H36O4SiEe ⩾ 98%[α]D20=-5 (c 1.1, CHCl3)Source of chirality:[Rh (all-R-Et-DuPHOS)]BF4Absolute configuration (11S,14S)

4-(tert-Butyl-dimethyl-silanyloxy)-1-methoxymethoxymethyl-2,6,6-trimethyl-cyclohex-2-enolC18H36O4SiEe ⩾ 98%[α]D20=-40 (c 0.8, CHCl3)Source of chirality:[Rh (all-R-Et-DuPHOS)]BF4Absolute configuration (11R,14S)

6-(tert-Butyl-dimethyl-silanyloxy)-3-methoxymethoxymethyl-2,4,4-trimethyl-cyclohex-2-enoneC18H34O4SiEe ⩾ 98%[α]D20=-122 (c 1.5, CHCl3)Source of chirality: [Rh (all-R-Et-DuPHOS)]BF4Absolute configuration (14S)

3-Butyl-6-(tert-butyl-dimethyl-silanyloxy)-2,4,4-trimethyl-cyclohex-2-enoneC19H36O2SiEe ⩾ 98%[α]D20=-125 (c 1.4, CHCl3)Source of chirality: [Rh (all-R-Et-DuPHOS)]BF4Absolute configuration (6S)

1-{2-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-4-(tert-butyl-dimethyl-silanyloxy)-2,6,6-trimethyl-cyclohex-2-enolC38H74O6Si2Ee ⩾ 97%[α]D20=+286 (c 1.4, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S,14S)

1-{2-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-4-(tert-butyl-dimethyl-silanyloxy)-2,6,6-trimethyl-cyclohex-2-enolC38H74O6Si2Ee ⩾ 97%[α]D20=-53 (c 1.9, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R,14S)

4-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexylmethyl]-8-(tert-butyl-dimethyl-silanyloxy)-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-eneC37H70O5Si2Ee ⩾ 97%[α]D20=+5 (c 1.1, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S,14S)

4-[6-tert-Butoxy-2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexylmethyl]-8-(tert-butyl-dimethyl-silanyloxy)-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-eneC37H70O5Si2Ee ⩾ 97%[α]D20=-79 (c 2.1, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R,14S)

4-[6-tert-Butoxy-2-hydroxymethyl-1-methyl-3-methylene-cyclohexylmethyl-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-en-8-olC25H42O5Ee ⩾ 97%[α]D20=+24 (c 0.5, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S,14S)

4-[6-tert-Butoxy-2-hydroxymethyl-1-methyl-3-methylene-cyclohexylmethyl-6,10,10-trimethyl-1,3-dioxa-spiro [4.5] dec-6-en-8-olC25H42O5Ee ⩾ 97%[α]D20=-70 (c 0.8, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R,14S)

3-tert-Butoxy-2-methyl-6-methylene-2-(6,10,10-trimethyl-8-oxo-1,3-dioxa-spiro [4.5] dec-6-en-4-ylmethyl)-cyclohexane carbaldehydeC25H38O5Ee ⩾ 97%[α]D20=-165 (c 1.2, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S)

3-tert-Butoxy-2-methyl-6-methylene-2-(6,10,10-trimethyl-8-oxo-1,3-dioxa-spiro [4.5] dec-6-en-4-ylmethyl)-cyclohexane carbaldehydeC25H38O5Ee ⩾ 97%[α]D20=-248 (c 1.2, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R)

1-[2-(6-tert-Butoxy-2-hydroxymethyl-1-methyl-3-methylene-cyclohexyl)-1-methoxymethoxy-ethyl]-2,6,6-trimethyl-cyclohex-2-ene-1,4-diolC26H46O6Ee ⩾ 97%[α]D20=+71 (c 1.0, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S,14S)

1-[2-(6-tert-Butoxy-2-hydroxymethyl-1-methyl-3-methylene-cyclohexyl)-1-methoxymethoxy-ethyl]-2,6,6-trimethyl-cyclohex-2-ene-1,4-diolC26H46O6Ee ⩾ 97%[α]D20=-62 (c 1.1, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R,14S)

3-tert-Butoxy-2-[2-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-2-methoxymethoxy-ethyl]-2-methyl-6-methylene-cyclohexanecarbaldehydeC26H42O6Ee ⩾ 97%[α]D20=-111 (c 1.6, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11S)

3-tert-Butoxy-2-[2-(1-hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-2-methoxymethoxy-ethyl]-2-methyl-6-methylene-cyclohexanecarbaldehydeC26H42O6Ee ⩾ 97%[α]D20=-242 (c 2.3, CHCl3)Source of chirality: (S)-prolineAbsolute configuration (3S,7S,8S,10S,11R)

4-(tert-Butyl-dimethyl-silanyloxy)-1-{2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-2,6,6-trimethyl-cyclohex-2-enolC34H66O5Si2Ee ⩾ 97%[α]D20=-20 (c 1.6, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10R,11S,14S)

1-[2-(2-Hydroxymethyl-1-methyl-3-methylene-cyclohexyl)-1-methoxymethoxy-ethyl]-2,6,6-trimethyl-cyclohex-2-ene-1,4-diolC25H38O5Ee ⩾ 97%[α]D20=+2 (c 1.8, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10R,11S,14S)

2[2-(1-Hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-2-methoxymethoxy-ethyl]-2-methyl-6-methylene-cyclohexanecarbaldehydeC22H34O5Ee ⩾ 97%[α]D20=-64 (c 1.3, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10R,11S)

8-(tert-Butyl-dimethyl-silanyloxy)-4-[2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexylmethyl]-6,10,10-trimethyl-1,3-dioxa-spiro[4.5]dec-6-eneC33H62O4Si2Ee ⩾ 97%[α]D20=+10 (c 1.1, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10R,11S,14S)

4-(2-Hydroxymethyl-1-methyl-3-methylene-cyclohexylmethyl)-6,10,10-trimethyl-1,3-dioxa-spiro[4.5]dec-6-en-8-olC21H34O4Ee ⩾ 97%[α]D20=+38 (c 1.1, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10R,11S,14S)

4-(tert-Butyl-dimethyl-silanyloxy)-1-{2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-2,6,6-trimethyl-cyclohex-2-enolC34H66O5Si2Ee ⩾ 97%[α]D20=+14 (c 1.3, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11S,14S)

4-(tert-Butyl-dimethyl-silanyloxy)-1-{2-[2-(tert-butyl-dimethyl-silanyloxymethyl)-1-methyl-3-methylene-cyclohexyl]-1-methoxymethoxy-ethyl}-2,6,6-trimethyl-cyclohex-2-enolC34H66O5Si2Ee ⩾ 97%[α]D20=-55 (c 1.1, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11R,14S)

1-[2-(2-Hydroxymethyl-1-methyl-3-methylene-cyclohexyl)-1-methoxymethoxy-ethyl]-2,6,6-trimethyl-cyclohex-2-ene-1,4-diolC22H38O5Ee ⩾ 97%[α]D20=+54 (c 1.1, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11S,14S)

1-[2-(2-Hydroxymethyl-1-methyl-3-methylene-cyclohexyl)-1-methoxymethoxy-ethyl]-2,6,6-trimethyl-cyclohex-2-ene-1,4-diolC22H38O5Ee ⩾ 97%[α]D20=-70 (c 1.3, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11R,14S)

2-[2-(1-Hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-2-methoxymethoxy-ethyl]-2-methyl-6-methylene-cyclohexanecarbaldehydeC22H34O5Ee ⩾ 97%[α]D20=-68 (c 1.9, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and (S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11S)

2-[2-(1-Hydroxy-2,6,6-trimethyl-4-oxo-cyclohex-2-enyl)-2-methoxymethoxy-ethyl]-2-methyl-6-methylene-cyclohexanecarbaldehydeC22H34O5Ee ⩾ 97%[α]D20=-221 (c 1.1, CHCl3)Source of chirality: (R)-(+)-1-phenylethylamine and(S)-2-acetoxypropionyl chlorideAbsolute configuration (3S,8S,10S,11R)