Effect of 9,10-Cyclic Acetal Stereochemistry on Feasible Operation of the α-Ketol Rearrangement in Highly Functionalized Paclitaxel (Taxol) Precursors

Abstract

The convergent, stereocontrolled synthesis of enantiopure stereoisomeric 9,10-cyclic acetals, whose designed role was to serve as potential precursors to Taxol, is reported. These advanced intermediates are multiply functionalized and carry a bridgehead alpha-ketol array which was key to isomerization into the proper framework. In agreement with relative strain energy values obtained by MM3 calculations, a dichotomy was observed between these two families. While the trans-fused acetals failed to undergo bridge migration, their cis counterparts did so efficiently. In fact, isomerization was sufficiently rapid that oxygenation at C2 was now precluded. The operation of several unusual transannular hydride shifts is also detailed.

Total Synthesis of (−)-Mitrephorone A Enabled by Stereoselective Nitrile Oxide Cycloaddition and Tetrasubstituted Olefin Synthesis

“…α-Oxidation of 42 (O 2 , KOt-Bu, then PPh 3 ) gave α-hydroxyketone 43 in 72% yield (Scheme 10). 33 Treatment with DMP furnished hydroxydiosphenol 44 in 74% yield. It is worth noting that oxidation of 42 to diosphenol 44 was carried out in an efficient sequence with the tertiary alcohol being unprotected.…”

Synthesis of the Aliphatic Subunit of the Macrolide LL‐Z 1640‐2 via Vasella Ring Opening of a 6‐Iodo‐4‐deoxy‐D‐mannose

“…The aldehyde 4 was reacted with the lithium reagents, prepared in situ by treatment of alkyne 5 [23] or vinyl iodide 6 with n-BuLi (Sch. 3).…”

“…Iodoalkene 6 (1.2 g, 60%) was isolated as a colorless liquid after distillation at reduced pressure. 1 (5S)-1-((4R,5S)-5-Allyl-2,2-dimethyl-1,3-dioxolan-4-yl)-5-(tertbutyldimethylsilyloxy)hex-2-yn-1-ol (7) n-Buthyllithium (1.6 M in hexane, 0.45 mL, 0.5 mmol) was added slowly at -608C to the solution of (S)-isopropyldimethyl(pent-4-yn-2-yloxy)silane (5) [23] (90 mg, 0.5 mmol) in dry THF (20 mL). The reaction mixture was stirred for 15 min at -608C.…”

Catalytic asymmetric total synthesis of (+)-artalbic acid

“…First, we attempted the addition of vinyllithium derivative 15, which was derived from the corresponding known vinyl bromide 9 and t-BuLi, to isopropyl ester derivative (+)-4. However, despite many trials, the desired adduct was not obtained.…”

“…In summary, the first asymmetric total synthesis of artalbic acid (1) was accomplished in 12 steps with 12.5% overall yield from isopropyl acetoacetate (9). This synthesis featured the asymmetric allylation of compound 8 with allyl iodide derivative 11 using phase-transfer catalyst (S,S)-10, construction of the cyclopentane core via intramolecular aldol condensation of aldehyde (+)-6 under diluted conditions, stereocontrolled 1,4addition of an isopropenyl group to α,β-unsaturated ketone (+)-5, stereoselective reduction of ketone (+)-13, and side chain construction by addition of vinyllithium derivative 15 to aldehyde (+)-17 followed by Jones oxidation of the resulting adduct.…”