Dedicated to Professor Zdenek Valenta on the occasion of his 80th birthdayOuabain (1 a), a cardioactive glycoside isolated from the bark of the African ouabio tree (Acokanthera ouabio) by Arnaud in 1888), [1] has received considerable attention since it was discovered that an ouabain-like compound occurs naturally in mammals and acts as an endogenous digitalis as proposed by Szent-Gyorgyi.[2] After some debate, it was established that the endogenous and plant derived ouabain are in fact identical.[3] Ouabagenin (1 b), the aglycone of ouabain, was isolated for the first time in 1942 by Mannich and Siewert, [4] who proposed a structure for the aglycone, and the structure for ouabain, which was later proven to be correct. [5] Progress towards the construction of these highly oxygenated steroids has been made recently, [6][7][8] but to date no total synthesis has been reported. Our foray into this field was based on a hypothesis that the polyanionic cyclization (double-Michael addition followed by aldol condensation) methodology developed by our research group [9] would allow facile access to an appropriately functionalized tetracyclic intermediate with the desired A/B cis, B/C trans, and C/D cis ring junctions. Our initial studies [9,10] suggested a promising synthetic route towards 14-b-OH steroidal intermediates, and herein we report the completion of the first total synthesis of ouabagenin (1 b) and in turn ouabain (1 a).Our strategy was based on the initial rapid construction of densely functionalized tetracycle D, (Scheme 1), which contains, in principle, the functionalities required for ouabagenin (1 b) and in turn ouabain (1 a). Tetracycle D would be readily available from tricycle C, which in turn could be produced from the condensation of chiral building blocks A and B.The initial steps of the synthesis, drawn from our previous studies on steroid skeleton synthesis, [9][10][11] were successful (Scheme 2). Thus, the union of Nazarov substrate 3[10b] with freshly prepared cyclohexenone 2 [11,12] in the presence of Cs 2 CO 3 at 0 8C followed by decarboxylation afforded tricycle 4 with an overall yield of 78 %. Reduction of the resulting aldehyde with Li(Et 3 CO) 3 AlH [13] and then protection of the alcohol as its PMB ether [14] afforded aldol precursor 5 in 74 % yield over two steps The aldol reaction to form the desired tetracycle 6 in 83% yield occurred in the presence of KHMDS. In order to reduce the ketone at C1 to give the desired b stereochemistry, it was necessary to first deprotect the alcohol at C11, by saponification of the acetate, which assisted the subsequent surprisingly facile reduction of the C1 ketone with NaBH 4 in EtOH at À78 8C to produce 7 with an overall yield of 95 %.Oxidation of PMB ether 7 was carried out in a CH 2 Cl 2 solution, which was rigorously dried with molecular sieves prior to addition of DDQ, to afford orthoester 8 in 84 % yield. [15,16] From orthoester 8, formation of a silyl enol ether using excess TBSOTf and oxidation to the enone with DDQ [17] proceeded smoothly to aff...

Hg(II) salts are identified as highly efficient catalysts for the versatile construction of spiroketals from alkyne diols in aqueous conditions. Monounsaturated spiroketals and furans were accessed with equal ease when propargylic triols (or propargylic diols) were subjected to similar conditions. Even the semiprotected alkyne diols gave the corresponding spiroketals with the same ease in a cascade manner. The reactions are instant and high yielding at ambient temperatures. Regioselectivity issues are well addressed.

A regioselective arylative cyclization of ortho functional diaryl acetylenes for the synthesis of selectively substituted diaryl pyridine and indene derivatives is accomplished through an electrophile driven alkyne polarization.

The steroidal natural product hippuristanol targets eukaryotic translation initiation factor (eIF)4A which plays a pivotal role in translation in eukaryotic cells. Now an efficient synthesis of hippuristanol from 11-ketotigogenin is reported. The synthesis features a rapid construction of a spiroketal unit via Hg(OTf)(2)-catalyzed oxidation/spiroketalization of the 3-alkyn-1,7-diol motif.