Total Synthesis and Structural Elucidation of the Antifungal Agent Papulacandin D

Abstract

Condensation of the aryllithium reagents, prepared from the bromides 10 and 11 and tert-butyllithium, with lactone 19 and acid-catalyzed spirocyclization gave the papulacandin spiroketals 14 and 15. Subsequent protection using di-tert-butylsilyl bis(trifluoromethanesulfonate) gave the diols 31 and 30. Isoleucine (37) was converted using a double Wittig reaction sequence and propargylation of the intermediate aldehyde 46 into the alkynol 47. Separation of the C-7 epimers of 47 was achieved using kinetic resolution via Sharpless epoxidation. Both alkynol epimers 53 and 57 were converted into the papulacandin side chain esters 65 and 66 using a hydrozirconation and palladium(0)-catalyzed coupling sequence. Comparisons of Mosher ester derivatives of 65 and 66 with the Mosher ester derivative of the natural papulacandin side chain and further degradation were consistent with the stereochemistry of the natural product being 7S,14S. Esterification of the spiroketals with the mixed anhydride 70 and global deprotection gave papulacandin D (1).

Palladium‐Catalyzed Cross‐Coupling Reactions in Total Synthesis

“…A selection of other architecturally intriguing natural products that have been the target of total syntheses involving Negishi couplings as key carbon-carbon bond-forming steps are highlighted in Scheme 57: reveromycin B (320) (Theodorakis and Drouet, 1999), [253] papulacandin D (321) (Barrett and co-workers, 1996), [254] longithorone A (322) (Shair and coworkers, 2002), [255] and xerulin (323) (Negishi and co-workers, 2000). [256] The carbon-carbon bond(s) formed in each case is(are) shown, and while such a cursory overview of the state of the art can neither be comprehensive nor do full justice to the remarkable developments in the field and the efforts of the many researchers involved who could not be acknowledged, it can hopefully serve to emphasize how the Negishi Scheme 56.…”

“…[252] Scheme 57. Selected examples of natural products syntheses employing Negishi reactions (the CÀC bonds formed by this cross-coupling process are highlighted with circles): reveromycin B (320) (Theodorakis and Drouet, 1999), [253] papulacandin D (321) (Barrett et al, 1996), [254] longithorone A (322) (Shair et al, 2002), [255] and xerulin (323) (Negishi et al, 2000). [256] coupling reaction offers the synthetic chemist a plethora of opportunities for carbon-carbon bond-forming operations.…”

Palladiumkatalysierte Kreuzkupplungen in der Totalsynthese

“…(Theodorakis und Drouet, 1999), [253] Papulacandin D (321) (Barrett und Mitarbeiter, 1996), [254] Longithoron A (322) (Shair und Mitarbeiter, 2002) [255] und Xerulin (323) (Negishi und Mitarbeiter, 2000). [256] Die durch Negishi-Kupplung erzeugten Kohlenstoff-Kohlenstoff-Bindungen sind jeweils markiert.…”

“…¾hnlich wie die Grignard-, die Diels- Drouet, 1999), [253] Papulacandin D (321) (Barrett et al, 1996), [254] Longithoron A (322) (Shair et al, 2002) [255] und Xerulin (323) (Negishi et al, 2000). [256] C-C-Kupplungen …”

Carbanion generation through tin-lithium exchange of vinyl-, aryl-, and hetarylstannanes

“…(E)-1-Tributylstannyl-2-(trimethylsilyl)ethylene was reacted with BuLi to give the lithium reagent which was then reacted with (4S)-methylhexanal to give the corresponding alcohol in 82% yield (Scheme 11). 45 This step was part of the total synthesis Li …”