A General Strategy for Synthesis of Both (6Z)- and (6E)-Cladiellin Diterpenes:  Total Syntheses of (−)-Cladiella-6,11-dien-3-ol, (+)-Polyanthellin A, (−)-Cladiell-11-ene-3,6,7-triol, and (−)-Deacetoxyalcyonin Acetate

Abstract

The first total synthesis of an (E)-cladiellin diterpene, (-)-cladiella-6,11-diene-3-ol (1), was accomplished featuring an intramolecular amide enolate alkylation-intramolecular Diels-Alder strategy. In addition, a highly stereo-, regio-, and chemoselective synthetic strategy for other members of the cladiellin diterpenes such as (+)-polyanthellin A (2), (-)-cladiell-11-ene-3,6,7-triol (3), and (-)-deacetoxyalcyonin acetate (4) was developed utilizing the synthetic (E)-cladiellin 1 as a common intermediate by taking advantage of the unique chemical properties of its C(6)-(E)-oxatricyclic skeleton.

Asymmetrische Totalsynthese und Festkörperstruktur des marinen cytotoxischen Diterpens (+)‐Vigulariol

“…[2] (+)-1 wirkt cytotoxisch gegen die menschliche Lungenkarzinom-A-549-Zellkultur (IC 50 = 18.33 mg mL À1 ). [1] Zwei weitere Vertreter dieser in Weichkorallen vorkommenden Diterpene, Sclerophytin A (2) [3,4] und Polyanthellin A (3), [5,6] zeigten hohe Cytotoxizität und AntimalariaAktivität. Die faszinierenden Strukturen und die vielfältigen biologischen Aktivitäten dieser Naturstoffklasse gaben den Anlass zu mehreren Totalsynthesen durch die Arbeitskreise von Paquette, [3a,c] Overman, [3b,c, 7] Crimmins [8] und Kim.…”

“…Die faszinierenden Strukturen und die vielfältigen biologischen Aktivitäten dieser Naturstoffklasse gaben den Anlass zu mehreren Totalsynthesen durch die Arbeitskreise von Paquette, [3a,c] Overman, [3b,c, 7] Crimmins [8] und Kim. [5] (+)-1 wurde bereits vor seiner Entdeckung als Naturstoff von Paquette et al im Rahmen der Synthese von 2 als Nebenprodukt erhalten und nicht vollständig charakterisiert.…”

Intramolecular Enolate Alkylation: From Steroids through Cladiellins to Isolaurallene

“…(-)-cladiella-6,11-dien-3-ol (65), for which we believe our approaches have a distinct edge. 33 As shown in Scheme 26, (Z)-C-3 tertiary (3°)/α,α′-cissyn-oxonene (Z)-67 could be constructed efficiently by applying our IAEA to (Z)-allylic chloride (Z)-66. Incidentally, the product of the Superhydride reduction of (Z)-oxonene (Z)-67 is a known Crimmins intermediate for (-)-ophirin B (64).…”

“…For instance, we can construct (Z)-as well as (E)-oxonenes specifically, as previously illustrated in our synthesis of (-)-cladiella-6,11-dien-3-ol (65). 33 Furthermore, the oxocene core in bermudenynol (99), which also contains a vinyl chloride moiety, could be constructed using our IAEA methodolo- When I gave lecture presentations, I would compare our substrate-controlled approach 47 with the asymmetric strategy used by the Crimmins group, as illustrated in Scheme 39, 46a,b and would claim that our entirely substrate-based approach enabled us to achieve the more concise synthesis. Now, I spy Professor Scott Snyder of Columbia University over my shoulder as he describes syntheses of the (our!)…”

Recent progress in the synthesis of oxepanes and medium ring ethers

“…While intramolecular enolate alkylation has not found widespread use for the preparation of medium ring ethers, Kim has extensively developed an intramolecular amide enolate alkylation as a key macrocyclization strategy for the syntheses of several cladiellin diterpene 47 …”