Concise Total Syntheses of (+)-Haplocidine and (+)-Haplocine via Late-Stage Oxidation of (+)-Fendleridine Derivatives

Abstract

We report the first total syntheses of (+)-haplocidine, and its N1-amide congener (+)-haplocine. Our concise synthesis of these alkaloids required the development of a late-stage and highly selective C–H oxidation of complex aspidosperma alkaloid derivatives. A versatile, amide directed ortho-acetoxylation of indoline amides enabled our implementation of a unified strategy for late-stage diversification of hexacyclic C19-hemiaminal ether structures via oxidation of the corresponding pentacyclic C19-iminium ions. An electrophilic amide activation of a readily available C21-oxygenated lactam, followed by transannular cyclization and in situ trapping of a transiently formed C19-iminium ion, expediently provided access to hexacyclic C19-hemiaminal ether alkaloids (+)-fendleridine, (+)-acetylaspidoalbidine, and (+)-propionylaspidoalbidine. A highly effective enzymatic resolution of a non-β-branched primary alcohol (E=22) allowed rapid preparation of both enantiomeric forms of a C21-oxygenated precursor for synthesis of these aspidosperma alkaloids. Our synthetic strategy provides succinct access to hexacyclic aspidosperma derivatives, including the antiproliferative alkaloid (+)-haplocidine.

Boron-mediated directed aromatic C–H hydroxylation

“…To further demonstrate the potential synthetic applications of this method, we showed three examples to compare existing strategies with our developed C-H hydroxylation method. Previously, using N-acetylindoline 70 as a model substrate for the total synthesis of the potent caspase-8 inhibitor (+)-haplocidine and its N1-amide congener (+)-haplocine, the precursor acetoxy-indoline 71′ was generated with a 84% yield by the palladium-catalysed C7 hydroxylation of indoline 60 . Based on the boron-mediated strategy, we prepared product 71 from substrate 70 with a 71% yield, in which N-acetyl can be used as a directing group (Fig.…”

Enantioselective Total Synthesis of (−)‐Deoxoapodine

“…(>98 % conversion, 22 °C, 3 h). Notably, lactam (−)‐ 13 correlates well with a key intermediate in our synthesis of haplocidine and related aspidosperma alkaloids, thus enabling an enantioselective approach to these alkaloids as well. As our planned synthesis of (−)‐deoxoapodine ( 1 ) required the opposite enantiomer of the RCM product, the use of ent ‐ Mo‐3 (5 mol %) under the optimal conditions allowed conversion of lactam 12 into the desired diene (+)‐ 13 in 92 % yield (94:6 e.r.…”

“…Given the ready availability of lactam 12 (Scheme ), which can be prepared in seven steps from crotonyl chloride, we focused on its RCM to afford lactam 13 in enantiomerically enriched form. We chose to explore the utility of molybdenum monoaryloxide pyrrolide (Mo‐MAP) complexes for the anticipated catalytic desymmetrization reaction.…”

“…We next focused on the synthesis of pentacycle (+)‐ 16 from lactam (+)‐ 13 (Scheme ). The necessary C21‐oxygenation was introduced through Wacker–Tsuji oxidation of lactam (+)‐ 13 and subsequent reduction of the resulting C21‐aldehyde to furnish the corresponding primary alcohol (79 % yield) . This alcohol was converted into the corresponding para ‐nitrobenzoate ester (+)‐ 14 (95 % yield) to set the stage for pentacycle formation.…”

“…In the early stages of our studies, we secured the oxolane F‐ring of deoxoapodine ( 1 ) by employing an oxymercuration step to introduce the C6‐ether (Scheme ). Removal of the para ‐nitrobenzoyl group of pentacyclic ester (±)‐ 16 , prepared as described previously with a second‐generation Ru catalyst for the RCM of triene 12 , provided the pentacyclic alcohol (±)‐ 17 . Exposure of alcohol (±)‐ 17 to mercury(II) trifluoroacetate at 23 °C in tetrahydrofuran led to oxymercuration, which was followed by reductive demercuration with sodium borohydride and sodium hydroxide to give the desired hexacyclic product in 20–40 % yield.…”