Abstract:
The deoxy derivative of pancratistatin 1.10 was prepared in good yield through
the use of a [4+2] Diels-Alder cycloaddition and Bischler-Napieralski cyclization
approach. The Bischler-Napieralski cyclization was shown to yield two additional side
products 2.9, 2.10, however, under slightly modified hydrolysis conditions, the
tetracyclic product 2.11 was obtained exclusively in greater than 84% yield. Initial
screening of the di-hydroxylatgd derivative, and the other complementary pair
analogue 1.10' previously prepared in our laboratories gave interesting results. Both of
these compounds were shown to exhibit cytostatic activity; the mono-alcohol was
marginally active while the di-hydroxylated analogue proved to be more potent
although one to two magnitudes less potent than pancratistatin itself Human tumour
cell line assay results indicated that the di-hydroxylated derivative exhibited selective
cytotoxic inhibition in the following cell lines: non-small cell lung cancer line
NCI-H226 (ED50 - 0.65 ^g/mL), leukemia cell lines CCRF-CEM (ED30 = 0.55
Hg/mL) and HL-60(TB) (ED50 = 0.89^ig/mL). Our results demonstrated that the
pharmacophore is not a mono-alcohol, and that the minimum pharmacophore contains
the hydroxyl group at the C4 position in addition to either, or both, of the hydroxyl
groups present at C2 and C3.' The minimum pharmacophore has been narrowed to only
three possibilities which are current synthetic targets in several research groups. The controlled Grignard addition to the tartaric acid derived bis-Weinreb
amide 1.25 afforded a direct entry to a host of 1,4-diflferentiated tartaric acid derived
intermediates (2.12-2.18). This potentially usefiil methodology was demonstrated
through the efficient synthesis of the naturally occurring lactone 2.23, which bears the
inherent syn-dio\ subunit. Based on this result, a similar approach to the synthesis of
syn-dio\ bearing natural products looks very promising? A direct 2,3-diol desymmetrization method using TIPS-triflate was shown to be
effective on the selective differentiation of Z,-methyl tartrate (and diisopropyl tartrate).
The mono-silyl-protected intermediates 2.31 also proved to be useful when they were
selectively differentiated at the 1,4-carboxyl position (2.35, 2.36) through the use of a
borohydride reducing agent. Furthermore, the mono-silyl-protected derivative
underwent periodate cleavage affording two synthetically useful a,P-unsaturated
esters 2.43, 2.44, with one of esters being obtained via a silyl-migration method.''
