Total Synthesis of Ambruticin

Abstract

Highly stereoselective radical cyclization and olefin metathesis reactions for the construction of oxacyclic building blocks were key steps in the convergent total synthesis of the orally active antifungal agent ambruticin (1).

Diene, Enyne, and Diyne Metathesis in Natural Product Synthesis

“…7. Intermediate 64 284 J. Mulzer · E. Öhler Scheme 11 RCM-based synthesis of dihydropyran fragments 56 [48] and 58 [49] in total synthesis of the antifungal agent ambruticin S (59) Fig. 7 Advanced dihydropyran fragments used in total syntheses of laulimalide (65) was prepared by twodirectional RCM under high dilution from the corresponding d-mannose-derived tetraene, and served as an efficient precursor for the volatile dihydropyran carboxaldehyde [53].…”

“…In Martin's synthesis [48], secondary alcohol 55 was used as the metathesis substrate, and the reaction led to ketone 56 in 60% yield after TPAP oxidation (substrate concentration, catalyst loading, and reaction time were not given). In Lee's work [49], the ring closure of diene 57 was effected under high dilution with catalyst A, leading to cyclization product 58 in 98% yield, when Pb(OAc) 4 was added to the reaction mixture before workup to remove traces of ruthenium and phosphine by-products derived from the catalyst [50].…”

“…Scheme 49 Total syntheses of epo490 (240d) and epoD (237d) by diene-ene RCM between C10 and C11: favorable influence of solvent toluene or unprotected hydroxy groups in metathesis substrates 239 [113] Scheme 50 Epothilone synthesis via RCM between C9 and C10: dependence of chemoselectivity on the size of the C12 substituent in metathesis substrates 244 [117] Alternatively, diene-ene 244b was also efficiently cyclized in the presence of catalyst C to produce macrolides 245b (E/Z mixture at the newly formed double bond) in 75% yield. Global deprotection of 245b, followed by a sequence of selective hydrogenation at C9-C10, Sharpless asymmetric epoxidation, and deoxygenation of the primary hydroxy group provided an alternative route to epoB (238b).…”

Diene, Enyne, and Diyne Metathesis in Natural Product Synthesis

“…In Martin's synthesis [48], secondary alcohol 55 was used as the metathesis substrate, and the reaction led to ketone 56 in 60% yield after TPAP oxidation (substrate concentration, catalyst loading, and reaction time were not given). In Lee's work [49], the ring closure of diene 57 was effected under high dilution with catalyst A, leading to cyclization product 58 in 98% yield, when Pb(OAc) 4 was added to the reaction mixture before workup to remove traces of ruthenium and phosphine by-products derived from the catalyst [50].…”

The chemistry of the carbon–transition metal double and triple bond: annual survey covering the year 2002

“…100) [311]; (8) formation of six-membered ring lactones for fostriecin total synthesis [312,313]; (9) diastereoselective formation of bicyclic six-membered ring containing oxygen heterocycles (e.g. 101) [314,315]; (10) formation of six-membered ring ␣,␤-unsaturated lactones [316][317][318][319][320]; (11) formation of six-membered ring ␣,␤-unsaturated lactones for total synthesis of methynolide [321], goniodiol (see 102) [322], and osmundalatone [323]; (12) formation of ␤,␥-unsaturated six-membered ring lactones [324]; (13) formation of six-membered ring cyclic ethers for total synthesis of ambruticin [325]; (14) tandem alkene-isomerization and RCM to form various cyclic enol ethers (e.g. 103) from the corresponding acyclic allylic ethers (e.g.…”