Synthetic Studies on Furanosteroids: Construction of the Viridin Core Structure via Diels–Alder/retro-Diels–Alder and Vinylogous Mukaiyama Aldol-Type Reaction

The synthesis of the viridin class of furanosteroids core skeleton from the readily available 2,3-dihydro-4-hydroxyinden-1-one (6) is described. Our strategy was broken down into three parts: (1) Synthesis of functionalized alkyne oxazoles of type 5; (2) intramolecular Diels–Alder/retro-Diels–Alder reaction of 5 followed by tautomerization and elaboration of R to give silylated furanonaphthols 4 bearing an aldehyde side chain; and (3) annulation of ring A by intramolecular vinylogous Mukaiyama aldol-type cyclization. Two major challenges were faced in the last step: (i) furanonaphthol derivatives bearing a β-hydroxyaldehyde functionality (R1 = OH) suffered from dehydration to the E-enal, which is geometrically incapable of cyclization, and (ii) the functionality at C17 had a strong influence on the conversion of 4 to 3, as exemplified by the failure of the free ketone (X = O) or its derivatives (X = H, OH; X = H, OAc) to cyclize. In the end, success was realized with the analogous C17-norketone (X = H, H).

本文报道了以易得的2,3-二氢-4-羟基茚-1-酮(6)为起始原料，合成绿胶霉素类呋喃甾体(furanosteroids)核心骨架的研究工作。本研究的合成策略可分为三个部分：(1) 制备官能团化的5型炔基恶唑(alkyne oxazoles)；(2) 对化合物5进行分子内狄尔斯-阿尔德/逆狄尔斯-阿尔德(intramolecular Diels–Alder/retro-Diels–Alder)反应，随后经互变异构化(tautomerization)以及对R基团的结构修饰，得到带有醛基侧链的硅基化呋喃萘酚(silylated furanonaphthols)4；(3) 通过分子内插烯Mukaiyama羟醛型环化(intramolecular vinylogous Mukaiyama aldol-type cyclization)完成A环的构建。在最终步骤中，我们面临两大核心挑战：(i) 带有β-羟基醛(β-hydroxyaldehyde)官能团(R1=OH)的呋喃萘酚衍生物易发生脱水反应生成E型烯醛(E-enal)，该产物因几何构型限制无法进行环化；(ii) C17位的官能团对化合物4转化为3的反应进程具有显著影响，例如游离酮(X=O)及其衍生物(X=H,OH；X=H,OAc)均未能实现环化。最终，我们通过采用类似结构的C17降酮(X=H,H)成功完成了目标环化反应。