Synthesis of the C(1)–C(13) Fragment of Leiodermatolide via Hydrogen-Mediated C–C Bond Formation

Abstract

The C(1)–C(13) fragment of the antimitotic marine macrolide leiodermatolide is prepared in 7 steps (LLS) via hydrogenative and transfer hydrogenative reductive C-C couplings. A hydrogen-mediated reductive coupling of acetylene with a Roche-type aldehyde is used to construct C(7)–C(13). A 2-propanol-mediated reductive coupling of allyl acetate with (E)-2-methylbut-2-enal at low loading of iridium (1 mol %) is used to construct C(1)–C(6), which is converted to an allylsilane using Oestereich’s copper-catalyzed allylic substitution of Si-Zn reagents. The union of the C(1)–C(6) and C(7)–C(13) fragments is achieved via stereoselective Sakurai allylation.

Synthesis of a Leiodermatolide Analogue with a Dienyl Side Chain

“…Prior to their total synthesis, the Paterson group had described a synthesis of the macrolactone core of ent ‐ 1 . In 2017 the Krische group published a conceptually interesting approach to a C1/C13 fragment where in a key step the C6/C7 bond is formed by addition of a chiral allylsilane to an aldehyde …”

Total Synthesis of Leiodermatolide A via Transfer Hydrogenative Allylation, Crotylation, and Propargylation: Polyketide Construction beyond Discrete Allyl- or Allenylmetal Reagents

“…In the specific context of type I polyketides, which are ubiquitous in human medicine, commercial manufacturing routes rarely exploit de novo chemical synthesis, highlighting the need for more efficient and process-relevant synthetic methods. Inspired by the broad use of hydrogenation and transfer hydrogenation in the production of clinical candidates, we have advanced a suite of catalytic enantioselective carbonyl reductive couplings based on alcohol mediated hydrogen transfer. , Using these methods, an initial (but unsuccessful) campaign toward leiodermatolide A was undertaken . Here, we disclose a more fruitful approach employing catalytic enantioselective transfer hydrogenative allylation, , crotylation, − and propargylation , that has resulted in a 13 step longest linear sequence (LLS) total synthesis of leiodermatolide A, constituting the most concise route to this compound reported, to date.…”

“…Retrosynthetically, leiodermatolide A was envisioned to arise through a polyconvergent assembly of Fragments A , B , and C (Figure ). Fragment A is accessible through the Hosomi–Sakurai reaction of aldehyde 8 (prepared by catalytic enantioselective transfer hydrogenative crotylation of acetylentic aldehyde 5 ), with allylsilane 4 (prepared by enantioselective transfer hydrogenative allylation of tiglic aldehyde 1 ). ,− Fragment B is generated via transfer hydrogenative carbonyl propargylation employing an enyne pronucleophile. , Finally, Fragment C is prepared by Mukaiyama aldol reaction of phenyl acrylate 11 with propanal 12 to give the anti -aldol , followed by kinetic resolution via asymmetric acetylation using Birman’s catalyst, and then Dieckmann condensation-ketone allylboration. , …”

“…The synthesis of Fragment A begins with the conversion of tiglic aldehyde 1 to allyl silane 4 (Scheme ). Using 1.25 mol% loadings of the π-allyliridium- C , O -benzoate modified by ( S )-BINAP, 2-propanol-mediated reductive coupling of tiglic aldehyde 1 with allyl acetate delivers the homoallylic alcohol 2 in 78% yield and 92% ee. , As shown, the chromatographically stable iridium catalyst could be recovered in 39% yield and recycled without erosion in performance. Conversion of alcohol 2 to aldehyde 3 is achieved via benzoylation of secondary alcohol followed by chemoselective anti -Markovnikov Wacker oxidation of the less substituted olefin.…”

“…With allyl silane 4 and aldehyde 8 in hand, Hosomi–Sakurai reaction was attempted. Upon evaluation of different Lewis acids, it was found that chelation-controlled addition could be achieved in 62% yield using AlEtCl 2 (250 mol%). Exhaustive deprotection of the Hosomi–Sakurai product delivers Fragment A .…”