Stereoselective synthesis of enantiopure analogues of (−)-cephalotaxine

The asymmetric total synthesis of three analogues of (−)-cephalotaxine with structural modification of the aromatic ring was achieved in 16 steps and acceptable overall yields. The procedure used was quite similar to that reported by our group for the total synthesis of (−)-cephalotaxine in 2004. The enantiopure spiranic compound 4 is a common intermediate on which various aromatic groups can be introduced. Unexpected and interesting different chemical behaviors were observed during these syntheses.

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(6R)-7-Phenethyl-1,4-dioxa-7-aza-dispiro[4.0.4.3]tridecan-8-oneC18H23NO3Ee = 98%[α]D23=-52.6 (c 1.12, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (6R)

(6R)-7-(2-Naphthalen-2-yl-ethyl)-1,4-dioxa-7-aza-dispiro [4.0.4.3]tridecan-8-oneC22H25NO3Ee = 98%[α]D23=-29.9 (c 0.83, CHCl3Source of chirality: asymmetric synthesisAbsolute configuration: (6R)

(5R)-1-Phenethyl-1-aza-spiro[4.4] nonane-2,6-dioneC16H19NO2Ee = 98%[α]D23=-16.5 (c 0.94, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R)

(5R)-1-(2-Naphthalen-2-yl-ethyl)-1-aza-spiro[4.4] nonane-2,6-dioneC20H21NO2Ee = 98%[α]D23=-18.5 (c 0.92, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R)

(5S)-1-Phenethyl-1-aza-spiro[4.4] non-7-ene-2,6-dioneC16H17NO2Ee = 98%[α]D23=-293.6 (c 0.93, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5S)

(5S)-1-(2-Naphthalen-2-yl-ethyl)-1-aza-spiro[4.4]non-7-ene-2,6-dioneC20H19NO2Ee = 98%[α]D23=-138.6 (c 0.35, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (5R)

(4S,5S)-2,3-Dehydro-15,16-desmethylenedioxy-cephalotaxan-8-oneC16H17NOEe = 98%[α]D23=-108.7 (c 0.96, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(4S,5S)-2,3-Dehydro-19,20-desmethylenedioxy-14,19-benzo-cephalotaxan-8-oneC20H19NOEe = 98%[α]D23=-128.5 (c 0.75, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(2S,3R,4S,5S)-2,3-Dihydroxy-15,16-desmethylenedioxy-cephalotaxan-8-oneC16H19NO3Ee = 98%[α]D23=+53.4 (c 0.95, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,4S,5S)

(2S,3R,4S,5S)-2,3-Dihydroxy-19,20-desmethylenedioxy-14,19-benzocephalotaxan-8-oneC20H21NO3Ee = 98%[α]D20=+177.9 (c 1.06, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (2S,3R,4S,5S)

(4S,5S)-1,2-Dehydro-2-methoxy-15,16-desmethylenedioxy-cephalotaxan-8-oneC17H17NO3Ee = 98%[α]D23=-78.7 (c 0.91, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(4S,5S)-1,2-Dehydro-2-methoxy-19,20-desmethylenedioxy-14,19-benzocephalotaxan-8-oneC21H19NO3Ee = 98%[α]D23=+59.0 (c 1.00, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (4S,5S)

(3S,4S,5S)-1,2-Dehydro-2-methoxy-3-hydroxy-15,16-desmethylenedioxy cephalotaxaneC17H21NO2Ee = 98%[α]D23=-150.4 (c 0.75, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5S)

(3S,4S,5S)-1,2-Dehydro-2-methoxy-3-hydroxy-19,20-desmethylenedioxy-14,19-benzo-cephalotaxaneC21H23NO2Ee = 98%[α]D23=-90.4 (c 0.24, CHCl3)Source of chirality: asymmetric synthesisAbsolute configuration: (3S,4S,5S)