Pergamon Tetrahedron Letters, Vol. 38, No. 34, pp. 5933-5936, 1997 © 1997 Elsevier Science Ltd All fightsreserved. Printedin Great Britain PII: S0040-4039(97)01325-7 0040-4039/97 $17.00 + 0.00 A New Approach to the Pancratistatin C-Ring from D-Glucose: Ferrier Rearrangement, Pseudoinversion and Pd-Catalyzed Cyclizations Gregory K. Friestad and Bruce P. Branchaud* Department of Chemistry, University of Oregon, Eugene, OR 97403-1253, USA Abstract: A Ferrier rearrangement and [~-hydroxyketone transposition are key steps in a route to a pancratistatin C-ring precursor. A key feature of the strategy is the pseudoinversion accomplished by ~- hydroxyketone transposition, which allows convenient access from methyl (z-D-glucopyranoside. Arylations of the C-ring by intramolecular reductive or non-reductive Pd-catalyzed conjugate addition have been demonstrated, utilizing the C 1 hydroxyl to deliver the tethered aryl synthon. © 1997 Elsevier Science Ltd. The biological activity, scarcity and structural complexity .OH .OH of Amaryllidaceae alkaloids 1-4 have prompted numerous f ~ . . f o 8 -~ : H ~ O H 10 synthetic studies toward functionalized phenanthridone ring o8 ( =- OH systems, 1,2 including several total syntheses of lycoricidine (1). With six contiguous stereogenic centers in their C rings, 7- R O R O deoxypancratistatin (3) and pancratistatin (4) present 1 (R=H) 3 (R=H) considerable synthetic challenges, including stereocontrolled 2 (R = OH) 4 (R = OH) introduction of the C10b aryl substituent. Recently, the first successful syntheses of 7-deoxypancratistatin (3) and pancratistatin (4) have been reported.3,4, 5 Our efforts in this area focused on a synthesis of 7-deoxy- pancratistatin (3) which would be capable of general access to highly oxygenated members of the phenanthridone alkaloids, including (+)-pancratistatin (4). Notable features of our strategy (Scheme 1) include the utilization of the C1 ~- hydroxyl to deliver a tethered aryl synthon to the 13 face at C10b resulting in a cis-fused ring system, subsequent electrophilic enolate amination on the convex face, and an endgame based on a lactone ---> lactam isomerization (5 --->3). 6 To support the development of the strategy shown in Scheme 1, we recently described model studies of intramolecular palladium-catalyzed .OH : OH 0 3 Scheme 1 OBn .OH o A .OBn ~~.. (~n ~.0.~1~ OBn ::~ ~ o S ,.o OBn ArCI'-~O,~,.~ OBn HO" v - 0 Ipseudoinversion via 7 ,', J p-hydroxyketone ",::,` [ transposition -:,. OBn ArC~2:O~'~OBn 10 derived from 2-O-alkyl L-glucose OBn ArCH2~fB n 8 4) .OBn 9 derived from 4-O-alkyl D-glucose pseudosymmetry aryl iodide-enone conjugate addition reactions of 4-iodobenzyloxycyclohexenone U to selectively form tricyclic arylation products 12 or 13 (Scheme 2). 7 Importantly, the reductive cyclization product 12 was formed with complete selectivity for the cis ring junction as required for pancratistatin synthesis (>95% by IH NMR spectroscopy, no trans product detected); these results encouraged us to pursue the application of this stereoselective arylation reaction to the synthesis of 7-deoxypancratistatin (3). 5933