Stereoselective Total Synthesis of (−)‐Spirofungin A by Utilising Hydrogen‐Bond Controlled Spiroketalisation

Abstract

The stereoselective total synthesis of the spiroketal containing Streptomyces metabolite (-)-spirofungin A (1) is described. A key step involved a spiroketalisation controlled by an intramolecular H-bond which favoured the desired spiroketal 4 (13:1 ratio). The presence of the intramolecular H-bond in 4 is possibly due to a 1,5-alkyne-oxygen interaction. Other key steps include an efficient cross-metathesis to form the spiroketal precursor, a tin mediated syn-aldol reaction and a Stille cross-coupling reaction to create the C22C23 bond. A final Wittig extension followed by deprotection gave (-)-spirofungin A (1).

The modern interpretation of the Wittig reaction mechanism

“…44 -Recent synthetic applications including: photochromic dithienylethenes, 45 enantioselective synthesis of highly substituted cycloalkanes by organocatalysed domino M ichael-Wittig reactions, 46 one-step synthesis of Z-allylic 35 esters and alcohols by a SCOOPY-modified Wittig reaction, 47,48 and stereoselective total synthesis of (-)-spirofungin A (involving several Wittig reactions). 49 The scope of the related reaction of phosphonium y lides with 40 N-sulfonyl imines has also been very effectively broadened, with the development of reactions of non-stabilised 50 semi-stabilised 51 and stabilised 52 ylides that can be tuned to give complete E or Z selectivity by choice of the appropriate N-sulfonyl alkyl group. 45 …”

A Triphenylphosphine‐Based Microporous Polymer for a Wittig Reaction Cycle in the Solid State

“…Therefore, the Wittig reaction can be used to carry out late-stage functionalisation of molecules. [28,29] The underlying mechanism of the product formation remains the same in all cases. Typically, in the key step a triphenylphos-phonium salt is coupled with an aldehyde or a ketone forming the desired product and triphenylphosphine oxide as a byproduct in stoichiometric amounts.…”

“…What makes the Wittig reaction in general so attractive is the wide tolerance against functional groups such as alcohols, ethers, esters, epoxides, aromatic nitro groups as well as carbonyl/keto and nitrile groups. Therefore, the Wittig reaction can be used to carry out late‐stage functionalisation of molecules [28,29] . The underlying mechanism of the product formation remains the same in all cases.…”

Studies towards the Synthesis of (–)-Pulvomycin: Construction of the C12–C40 Segment by a Stereoselective Aldol Reaction

“…An (E)-selective hydrostannylation of the free alkyne was accomplished with tributylstannane in the presence of catalytic quantities of tris(dibenzylideneacetone)dipalladium (Pd 2 dba 3 ) and tricyclohexylphosphane (PCy 3 ). 27 The sterically encumbered phosphane ligand increases the regioselectivity by avoiding a stannylation at the internal carbon atom. 28 If palladium with a less bulky substituent, e.g.…”