Studies Directed to the Synthesis of the Unusual Cardiotoxic Agent Kalmanol. Enantioselective Construction of the Advanced Tetracyclic 7-Oxy-5,6-dideoxy Congener

Abstract

The first synthesis of a highly functionalized B-homo-C-nor grayanotoxin closely related to kalmanol is reported. An enantiocontrolled route to the diquinane sector was first developed from (4R)-(+)-tert-butyldimethylsiloxycyclopentenone by taking advantage of the Michael acceptor properties of this enone and an α,β-unsaturated ester subsequently derived from it, viz., 4 → 7 → 8. These experiments formed the basis for more advanced substitution of the bicyclo[3.3.0]octane core. In fact, ready access was gained to the α-hydroxy esters 24−27. In these advanced intermediates, it is imperative that the acetyl and carbomethoxy groups bear a trans 1,3-relationship. The neighboring OR substituent should preferably be larger than methoxy in order to guarantee 100% facial selectivity during the ensuing capture by 1 (as its lithiated derivative). This condensation leads unidirectionally to tricyclic lactones represented by 30 and 31 and sets the stage for implementation of sequential Tebbe olefination and Claisen rearrangement. This pivotal two-step process gives rise directly to the targeted tetracyclic framework. The further oxygenation of 35 can be accomplished in a highly stereoselective manner to give 3. The characteristics of the [3.3] sigmatropic event that results in ring expansion plays a significant role in defining absolute configuration at key carbon centers which would otherwise be difficult to establish unequivocally. A total of 25 synthetic steps was involved.

Titanium reagents for the alkylidenation of carboxylic acid and carbonic acid derivatives

“…Similarly, the key steps in Paquette's approach to the tetracyclic framework of kalmanol were Tebbe methylenation of lactone 336 followed by Claisen rearrangement to give tetracycle 337 in 86% yield (Scheme 142). 166 The stereochemistry of the newly formed ring junction is a result of the thermodynamic preference for a Z double bond in the cyclooct-4-enone ring and the chair-like nature of the Claisen rearrangement's transition state. Later, Paquette et al employed the same approach as an early step in their syntheses of (ϩ)-epoxydictymene 342.…”

Facile access to cyclooctanoid ring systems via microwave-assisted tandem 6-exo dig cyclization–rearrangement sequence

“…The reason for the reaction to fail is almost certainly due to the inability of the 5-alkyn-1-ol 1 to undergo the initial 6-exo cyclization. In fact, Paquette et al 13 and Petasis 14 have previously demonstrated that preformed allyl vinyl ether precursors with terminal exocyclic double bonds, prepared from δ-valerolactone derivatives via the Tebbe 15 or Petasis 14 reactions, are indeed capable of undergoing [3,3]-sigmatropic rearrangements. The failure of the examined 5-alkyn-1-ol system 1 to cyclize is consistent with the observed trend that 6-exo isomerizations are generally more sluggish than the corresponding 5-exo processes.…”

Reactivity versus Stability of Oxiranes under Palladium‐Catalyzed Reductive Conditions

“…Working towards the total synthesis of kalmanol, Borrelly and Paquette, in 1996, confirmed the pronounced selectivity dependency on the phosphane ligand by using the Shimizu/Tsuji procedure to reduce the multifunctionalized β-alkenyl-α,β-epoxy ester shown in Equation (63). [144] Alicyclic γ,δ-epoxy-α,β-unsaturated ketones are rather reluctant to react. The complete conversion is attained with difficulty, [134,145] and a mixture of homoallylic and allylic alcohols is obtained.…”