Total Synthesis of (+)-Phorboxazole A Exploiting the Petasis−Ferrier Rearrangement

Abstract

A highly convergent, stereocontrolled total synthesis of the potent antiproliferative agent (+)-phorboxazole A (1) has been achieved. Highlights of the synthesis include: modified Petasis-Ferrier rearrangements for assembly of both the C(11-15) and C(22-26) cis-tetrahydropyran rings; extension of the Julia olefination to the synthesis of enol ethers; the design, synthesis, and application of a novel bifunctional oxazole linchpin; and Stille coupling of a C(28) trimethyl stannane with a C(29) oxazole triflate. The longest linear sequence leading to (+)-phorboxazole A (1) was 27 steps, with an overall yield of 3%.

Kinetically Controlled Ring‐Closing Metathesis: Synthesis of a Potential Scaffold for 12‐Membered Salicylic Macrolides

“…The solvent was evaporated and the residue obtained was purified by chromatography on silica gel to afford the corresponding aldehyde (55 mg) as a colorless oil, which was used immediately for the next reaction. Compound 11: NaHMDS (1.0 m in THF, 4.49 mL, 4.49 mmol) was added dropwise to a stirred solution of alcohol 4 [22] (848 mg, 3.59 mmol) in anhydrous THF (20 mL) at 0 8C, and the mixture was stirred for 1 h. A solution of compound 10 (1.10 g, 2.99 mmol) in THF (10 mL) was added to the reaction mixture, which was stirred for 0.5 h at 0 8C and for an additional 2 h at room temperature. The reaction was quenched with 5 % HCl, the aqueous solution was extracted with AcOEt, and the combined organic layer was dried over MgSO 4 .…”

Enantioselective Alcohol C–H Functionalization for Polyketide Construction: Unlocking Redox-Economy and Site-Selectivity for Ideal Chemical Synthesis

“…43 Notably, the same C 2 -symmetric diol was prepared through a 7 step sequence involving 3 protecting group manipulations, two alcohol-to-aldehyde redox reactions and two carbonyl allylboration reactions (Scheme 5). 59 This bidirectional chain elongation can be deployed iteratively to form 1,3-polyol substructures evident in numerous oxo-polyene macrolides. 30c For example (+)-roxaticin 60 incorporates a C 2 -symmetric polyol substructure that is readily formed using three iterations of bidirectional alcohol C-H allylation.…”

Organotin Reagents in Cross‐Coupling Reactions

“…Smith et al [119] used a coupling between a vinyltin and an oxazole triflate as a key step in the 27-step total synthesis of the antiproliferative agent (−)-phorboxazole A. Buynak et al [120] used a number of coupling strategies involving vinyltin and other organotins (aryl and 2-pyridyl), as well as hexamethylditin, in the synthesis of 7-[(E)-alkylidene]cephalosporins, which are potential enzyme inhibitors. Kanekiyo et al [121] used couplings between vinyl-or alkynyltins and organoiodides in the total syntheses of three β-carboline alkaloids.…”