A titanium naphtholate approach for the synthesis of analogues of griseusin A †

Abstract

The synthesis of analogues of the spiroketal-containing pyranonaphthoquinone antibiotic griseusin A 1 is described. The key disconnection focused on hydroxyalkylation of naphthol 21 with aldehyde 12. Aldehyde 12 was prepared from oxazolidinone 5 and (R)-aldehyde 6. Aldol condensation of oxazolidinone 5 with aldehyde 6 using tin(II) triflate and tetramethylethylenediamine afforded adduct 8 with the required 2′,3′-anti 3′,5′-syn stereochemistry as the major product. Aldol adduct 8 was then converted into aldehyde 12. The titanium naphtholate generated from naphthol 21 using TiCl3OiPr then afforded alcohol 26 upon addition of aldehyde 12. Oxidation of alcohol 26 afforded ketone 29 which underwent acetylation to acetate 31. Conversion of naphthol acetate 31 into naphthoquinone 33 followed by addition of 2-(trimethylsilyloxy)furan effected furofuran annulation to a 1∶1 inseparable mixture of adducts 34. Ceric ammonium nitrate oxidative rearrangement of this mixture of adducts produced lactol 35 which underwent cyclization to a 3.2∶1 mixture of spiroketals 36a and 36b wherein epimerization at C-3′ had occurred.