title: Total synthesis of (+)-rishirilide B: development and application of general processes for enantioselective oxidative dearomatization of resorcinol derivatives.
abstract: A concise synthesis of (+)-rishirilide B (2) is described. This is the first synthesis to be reported for the (+)-enantiomer of rishirilide B (2) as found in nature. The strategy accentuates the valuable combination of a method for o-quinone methide coupling with a method for enantioselective resorcinol dearomatization, which provides a densely functionalized chiral building block. The convergent synthesis illustrates several improvements and refinements to these methods and their supporting chemistries. Among these is the in situ generation of PhI[OTMS]OTf. Combination of this oxidant with phenol 31 constitutes the first example of a diastereoselective oxidative dearomatization of a resorcinol displaying a 2-alkyl substituent. In addition, the preparation of the cyclic sulfone 34 is reported. As a new dimethide precursor expressing a readily cleavable O-benzyl residue, sulfone 34 should prove useful in future endeavors. A protocol using the aluminum amide of dimethylhydrazine for opening and cleavage of a [1,4]-dioxan-2-one is also described. This procedure unmasks the hydroxy dione 36 by jettisoning the chiral directing group. Regioselective O-carbamylation of the 1,3-dione 36 enables the transformation of the remaining carbonyl into the alpha-hydroxy carboxylic acid found in 2. The total synthesis of (+)-rishirilide B (2) requires 15 pots from benzaldehyde 17 and 13 pots from benzaldehyde 32. The final product emerges in yields of 12.5% and 20.3% from compounds 17 and 32, respectively. The longest linear sequence requires eight chromatographies. Important observations leading to the development of the principle asymmetric method are described within the context of the total synthesis.
authors.affiliation: Department of Chemistry and Biochemistry, University of California at Santa Barbara, Santa Barbara, California 93106, USA.
authors.forename: Lupe H
authors.initials: LH
authors.lastname: Mejorado
authors.forename: Thomas R R
authors.initials: TR
authors.lastname: Pettus
mesh_terms: D019813:1,2-Dimethylhydrazine / Q000737:chemistry; D000535:Aluminum / Q000737:chemistry; D000577:Amides / Q000737:chemistry; D000873:Anthracenes / Q000138:chemical synthesis*; D001547:Benzaldehydes / Q000737:chemistry; D001688:Biological Products / Q000138:chemical synthesis*; D004146:Dioxanes / Q000737:chemistry; D008956:Models, Chemical; D010084:Oxidation-Reduction; D012118:Resorcinols / Q000737:chemistry*; D013237:Stereoisomerism; D013302:Streptomyces / Q000737:chemistry*
chemical_list: D000577:Amides; D000873:Anthracenes; D001547:Benzaldehydes; D001688:Biological Products; D004146:Dioxanes; D012118:Resorcinols; C043480:rishirilide B; D000535:Aluminum; D019813:1,2-Dimethylhydrazine; C032175:benzaldehyde; C031389:resorcinol