CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

the unit-C contribute positively to their cytotoxic action. 151 In view of their potent
bioactivity, a large number of formal 152a-f and total 147a,153 syntheses of the cryptophycins
have been reported. Given the units B-D are easily available, particular attention was
focused to the synthesis of the octadienamide fragment (unit-A equivalent) of
desoxycryptophycins, leading to a number of interesting methodologies. 153a,154,155 A
strategical theme, common to majority of the syntheses of the epoxide-containing
cryptophycins had been the introduction of the epoxide pharmacophore in a single latestage
operation through the use of m-CPBA or dimethyl dioxirane. The reported
epoxidation methods proceeded with a diastereoselectivity of ~2-3:1, necessitating a
chromatographic separation of the desired (major) β-isomer. In contrast, the more efficient
protocols were based on prior introduction of the chiral diol unit at those centres. To this
end, we developed a novel asymmetric synthesis of unit-A equivalent, bearing the chiral
diol unit that can be elaborated to the cryptophycins.
O
O
O
O
O
O
O O HN
HN
X
O
O
O N
N O OMe
R 1 H
R 2 H
R
O
X
OMe
Cryptophycin-A (110): R 1 = Me, R 2 = H, X = Cl
Cryptophycin-24 (111): R 1 = R 2 = X = H
Cryptophycin-52 (112): R 1 = R 2 =Me, X = Cl
Cryptophycin-B (113): R 1 = Me, R 2 = H, X = H
Cryptophycin-C (114): R = Me, X = Cl
Cryptophycin-D (115): R = Me, X = Cl
Cryptophycin-29 (116): R = H, X = Cl
O
O
H O
2 N
X
OH
+
+
HO NH
+
2
OH OH
CO
HO O OMe
2 H
unit-A unit-B unit-C unit-D
Figure IV.2.1. Precursor units for convergent synthetic approach to cryptophycins.
148