The Fluorine Atom as a Cation-Stabilizing Auxiliary in Biomimetic Polyene Cyclizations:  Total Synthesis of dl-Dammarenediol¹

Abstract

Dammarenediols I (1a) and II (1b) were prepared by an efficient nonenzymatic biomimetic polyene tetracyclization route. The cyclization substrate, pentaenol 3, contains a tetramethylallylic alcohol initiator, an allyltrimethylsilane terminating group, and a fluorine atom at pro-C-13 to serve as a cation-stabilizing (C-S) auxiliary controlling the regiochemistry of the C/D ring juncture. The synthesis of 3 employed lithium−halogen exchange to create alcohols 10 and 19. The Z-fluoroalkene in 3 was introduced stereoselectively via the Trost palladium-catalyzed alkylation of allylic acetate 11 (Z/E: 4.6/1). The cyclization of 3 was most efficient (62% isolated yield) when it was added as a dilute solution in dichloromethane to trifluoroacetic acid at −45 °C to afford tetracyclic fluoro diene 24 possessing the trans−anti−trans−anti−trans ring stereochemistry of the dammaranes. Replacement of the fluorine atom of 24 with hydrogen with complete retention of configuration was accomplished using the Ohsawa−Oishi reagent (Na/K alloy and crown ether). Wacker oxidation of the resulting hydrocarbon provided ketone 28, which after ketalization was ozonolyzed with a reductive workup to give the 3β-alcohol 30. Ketal hydrolysis followed by Grignard reaction with isopentenylmagnesium bromide afforded the dammarenediols (1/3, 1a/1b).

Beyond the Isoprene Pattern: Bifunctional Polyene Cyclizations

“…As imilar polyene cascade reactionw as also applied to the total synthesis of dammarenediol II (3). [16] Next to heteroatom-substituted alkenes,t he Johnson group also investigated tetrasubstituted alkenes bearing all-carbon residues. [17] Based on these initial results, the Siegel group accomplished the total synthesis of triterpenoid natural products.…”

Polyfunctional Lithium Organometallics for Organic Synthesis

“…Treatment of the iodinated methoxy compound 230 with two equivalents of t-BuLi in heptane at ±78 C gave the e-functionalized organolithium compound 231, which upon addition of TMEDA, suffered intramolecular S N 2¢ cyclization to give the vinylcyclopropane 232 in almost quantitative yield (Scheme 2.30) [182]. On the other hand, the silyl-substituted vinyllithium 233, prepared by bromine±lithium exchange, did not cyclize and reacted with 3-fluoro-3-buten-2-one to give the corresponding alcohol, which was used in the synthesis of (±)-dammarenediol [183]. The e-oxido functionalized intermediate 234 was prepared from the corresponding chlorohydrine by a chlorine±lithium exchange with lithium naphthalenide after deprotonation, and reacted with iodoarenes to give the expected coupling products [184].…”

Functionalized organolithium compounds in total synthesis

“…An example can be seen in Scheme 30, where attack of acetylide 167 on an epimeric mixture of epoxides 168 has been used, after methoxide treatment and hydrogenolysis of the resulting alcohol 169, for the synthesis of (G)-pestalotin (170). 77 In addition, propiolate esters can be easily deprotonated with n-butyllithium to the corresponding lithium acetylides, being employed as nucleophiles in substitution reactions, as in the total synthesis of the alkaloid (G)-stemoamide, 78 in addition reactions to carbonyls, as in the total syntheses of the labdane diterpene (G)-forskolin, 79 the norsesquiterpene lactone (G)-senoxepin 80 or the macrolide (G)-81 and (C)-brefeldin A 82 or in epoxide ring opening, as in the total syntheses of lipoxins A4 and B4 83 or the ladybird alkaloid hyperaspine.…”

“…168 A recent example of the use of an sp 3 -hybridized hfunctionalized organolithium species is the lithiated acetal 398, prepared from the iodide using tert-butyllithium, and employed in a transmetalation to the corresponding organozinc reagent for a palladium-catalyzed cross-coupling reaction with a vinyl iodide, in a synthesis of the lipid chain-containing natural antifungal (C)-sphingofungin F. 169 In addition, the similarly prepared fluorosilylated organolithium species 399 has been employed as a nucleophile in an addition reaction to an aldehyde for the synthesis of (G)-dammarenediol. 170 The h-silylated organolithium reagent 401 has also been generated by tert-butyllithium-promoted iodine/lithium exchange and reacted with chiral Cbz-protected lactam 400 (CbzZbenzyloxycarbonyl), furnishing the intermediate alcohol 402, which was in situ exposed to boron trifluorideacetic acid complex to provide spirocycle 404 via an Nacyliminium ion/allylsilane internal cyclization from species 403 (Scheme 67). This spirocyclic compound 404 was converted, after several synthetic steps, into (K)-lepadiformine (405), a tricyclic alkaloid from the marine ascidian Clavelina cylindrica.…”