CHEM01200604012 Dibakar Goswami - Homi Bhabha National ...

IV.2.2: Previous syntheses of unit-A
Among different methodologies for the synthesis of unit-A, besides the lessdiastereoselective
last step epoxidation protocol, use of Shapless asymmetric
dihydroxylation (ADH) proceeded with good stereoselectivity, but moderate yield.
In the synthesis 153h of cryptophycin-A (111), Li et. al. relied on (R)-mandelic acid
as the sole source of asymmetry for unit-A. The syn-diol unit was introduced early in the
reaction sequence and was converted to the epoxide in the last step of the synthesis.
Pousset et al. 155a used O-protected methyl mandelate 117 for the synthesis of unit-
A. Reaction of the Al-salt, obtained by reaction DIBAL-H with 117, with magnesium
acetylide, followed by reduction under Denmark conditions afforded 118. Compound 118
was completely deprotected in acidic medium, and the resulting diol was selectively
protected as an acetonide. This, on Sharpless epoxidation gave 119 with 90% de. Epoxide
opening with trimethyl aluminum afforded diol 120, which was converted to hydroxyl
nitrile 121. This on DIBAL-H reduction and subsequent Wittig-Horner reaction furnished
the unit-A equivalent unsaturated ester 122 (Scheme IV.2.1).
O
O
OMOM
OMOM
O
i-ii iii-v vi
C
C 6 H 5 CO 2 Me C 6 H 5 OTPS
6 H 5
OTPS C 6 H 5
O
O OH
OH
117 118 119 120
O
O
vii-viii
ix-xi
C 6 H 5
CN C 6 H 5
CO 2 Me
O OH
O OH
121 122
OH
(i) (a) DIBAL-H, hexane, -78 o C, (b) Magnesium acetylide; (ii) Red-Al ® , Et 2 O, -20 o C; (iii)
2M HCl, MeOH, 40 o C; (iv) Acetone, CuSO 4 , cat. PPTS; (v) t-BuOOH, L -(+)-diisopropyl
149