Total Synthesis of Cyanolide A in the Absence of Protecting Groups, Chiral Auxiliaries, or Premetalated Carbon Nucleophiles

Abstract

No protection, no problem: The C2‐symmetric macrodiolide cyanolide A is prepared in six steps from neopentyl glycol and allyl acetate by iridium‐catalyzed double asymmetric allylation and a tandem cross‐metathesis/oxa‐Michael cyclization to form the substituted pyran. The synthesis is accomplished in the absence of any protecting groups, chiral auxiliaries, or premetalated carbon nucleophiles in fewer than half the steps of any prior approach.

Direct Generation of Triketide Stereopolyads via Merged Redox-Construction Events: Total Synthesis of (+)-Zincophorin Methyl Ester

“…In the present study, hydrogenative couplings that exploit alcohol-to-carbonyl oxidation as a driver for carbanion generation, 4 are used to directly generate triketide stereopoly-ads that would otherwise require lengthy multi-step syntheses. As demonstrated here and in prior work, 7 these methods have availed a “step-function” change in efficiency across diverse contexts, bringing us one step closer to the Hendricksonian ideal. 31 More immediately, the concise nature of the present route to (+)-zincophorin methyl ester will enable access to material that will allow for a more complete investigation into its biological properties; studies which are currently underway.…”

“…Most importantly, such redox-triggered carbonyl additions enable transformations and strategies beyond those accessible via conventional carbanion chemistry. Indeed, as borne out in total syntheses of roxaticin, 7a bryostatin 7, 7b trienomycins A and F, 7c cyanolide A, 7d and 6-deoxyerythronolide B, 7e application of these methods have availed a “step-function increase” in efficiency – in each case, the synthetic route was significantly more concise than in any prior approach. 4b These studies brought to light an especially powerful protocol for the direct assembly of acetate- or propionate-based triketide stereopolyads 2a or 2b involving the bidirectional enantioselective double allylation 8a or anti -crotylation 8b of 1,3-diols 1a or 1b , respectively (eq.…”

“…Key C-C bond formations include Breit’s method for the stereospecific substitution of α-hydroxy ester triflates with Grignard reagents to create the C22 stereocenter, 15 stereoselective Wittig olefination, 17 which defines the geometry of the trisubstituted olefin, and direct redox-triggered anti -crotylation of allylic alcohol 5 to form the C18-C19 stereodiad. 18 The synthesis of Fragment B takes advantage of the two-directional double anti -crotylation of 2-methyl-1,3-propane diol 1b to form adduct 2b , 7e,8b which directly establishes the triketide stereopolyad spanning C6-C10. Cross-metathesis is used to introduce the C12-C13 carbon atoms of allyl alcohol 8 , and hydroformylation is used to forge the C3-C4 bond of Fragment B .…”

“…7e,8b Iodoetherification defines the chirotopic nonstereogenic center of diol 2b at C8, and serves to differentiate the terminal olefin moieties. The pseudo - C -symmetric diol 2b is produced as a single enantiomer due to Horeau’s principle, 21 that is, the minor enantiomer of the intervening mono-adduct is converted to the pseudo - meso -diastereomer.…”

Corrigendum to “Protecting group-free syntheses of natural products and biologically active compounds” [Tetrahedron 70 (2014) 8183–8218]

“…1 The first step in the retrosynthetic analysis of this compound by Krische and Waldeck simplifies the C 2 symmetric target molecule into monomer 508, which also contains a hidden element of symmetry, as revealed by subsequent application of a metathesis/cyclization transform (508/509). 2 The key step in the synthesis is the assembly of intermediate 509 by double hydrogen-transfer asymmetric allylation of diol 510da reaction previously developed by the authors 3 and successfully applied in total syntheses of several natural products. 4 This initial transformationdthe reaction of 1,3-propanediol 510 with allyl acetate in the presence of chiral iridium complexdis remarkable for several reasons: it formally represents allylation by CeH functionalization of alcohols that avoids the existance of highly unstable 1,3-dialdehyde, which could not be successfully allylated.…”