Synthetic studies on nogalamycin congeners [1] 1 chiral synthesis of the def-ring system of nogalamycin

Abstract

From the retrosynthetic perspective on nogalamycin congeners, the potent antitumor antibiotics of the anthra-cycline family, the regioselective Diels-Alder reaction employing the naphthoquinone (4), the CDEF-ring system of nogalamycin congeners, as a dienophile was anticipated to constitute the key step of one of the most convenient and flexible synthetic routes to their 11-deoxyanthracyclinone frameworks (3). As a model study to explore an efficient and reliable synthetic scheme to produce the characteristic bicyclic acetal structure of 4 in an optically active form, the preparation of the DEF-ring system (6) was first examined prior to the chiral synthesis of 4. The chiral synthesis of 6 accomplished starting from readily available (-)-D-arabinose (11), involves the following novel aspects: (1) synthesis of the suitably functionalized (-)-methylketone (18) from 11 through (-)-b-D-gentosaminide (14) which carries the stereochemistries at the C 2' -, C 3'-, and C 4'-positions, (2) stereoselective construction of the C5'-asymmetric center by chelation-controlled addition of the aryllithium [9 (M=Li)] to 18, (3) formation of the bicyclic acetal by treating the hydroquinone (28) with trimethylsilyl bromide.