Total Syntheses of Zaragozic Acids A and C by a Carbonyl Ylide Cycloaddition Strategy

• Published in: Chemistry : a European journal Vol. 12; no. 35; pp. 8898 - 8925
• Main Authors: Hirata, Yuuki, Nakamura, Seiichi, Watanabe, Nobuhide, Kataoka, Osamu, Kurosaki, Takahiro, Anada, Masahiro, Kitagaki, Shinji, Shiro, Motoo, Hashimoto, Shunichi
• Format: Journal Article
• Language: English
• Published: Weinheim WILEY-VCH Verlag 04.12.2006; WILEY‐VCH Verlag; Wiley
• Subjects: Alkenes - chemistry; Bridged Bicyclo Compounds, Heterocyclic - chemical synthesis; carbonyl ylides; Catalysis; Chemistry; Chemistry, Multidisciplinary; Cross-Linking Reagents - chemistry; Cyclization; cycloaddition; diazo compounds; Enzyme Inhibitors - chemical synthesis; metathesis; Models, Chemical; Organometallic Compounds - chemistry; Physical Sciences; Science & Technology; Stereoisomerism; Tartrates - chemistry; total synthesis; Tricarboxylic Acids - chemical synthesis; SYMMETRY-BASED APPROACH; BICYCLIC ACETAL CORE; ENANTIOSELECTIVE SYNTHESIS; OLEFIN CROSS-METATHESIS; ABSOLUTE STEREOCHEMISTRY; carbonyl ylides; DIMETHYL SULFIDE COMPLEX; CATALYTIC SODIUM TETRAHYDROBORATE; FARNESYL-PROTEIN TRANSFERASE; SQUALENE SYNTHASE INHIBITOR; cycloaddition; metathesis; SIDE-CHAIN EQUIVALENT; total synthesis; diazo compounds
• ISSN: 0947-6539; 1521-3765
• DOI: 10.1002/chem.200601212

A carbonyl ylide cycloaddition approach to the squalene synthase inhibitors zaragozic acids A and C is described. The carbonyl ylide precursor 8 was synthesized starting from di‐tert‐butyl D‐tartrate (47) via an eleven‐step sequence involving the regioselective reduction of the mono‐MPM (MPM = 4‐methoxybenzyl) ether 48 with LiBH4 and the diastereoselective addition of sodium tert‐butyl diazoacetate to α‐keto ester 10. The reaction of α‐diazo ester 8 with 3‐butyn‐2‐one (40) in the presence of a catalytic amount of [Rh2(OAc)4] gave the desired cycloadduct 59 as a single diastereomer. The dihydroxylation of enone 59 followed by sequential transformations permitted the construction of the fully functionalized 2,8‐dioxabicyclo[3.2.1]octane core 5. Alkene 79 derived from 5 serves as a common precursor to zaragozic acids A (1) and C (2), since the elongation of the C1 alkyl side chain can be attained by olefin cross‐metathesis, especially under the influence of Blechert's catalyst (85). Stereocontrolled total syntheses of the squalene synthase inhibitors zaragozic acids A and C have been accomplished by a convergent strategy, wherein key steps involve a tandem [Rh2(OAc)4]‐catalyzed ester–carbonyl ylide formation/1,3‐dipolar cycloaddition and an olefin cross‐metathesis reaction.