"Divergent Total Synthesis of (-)-Rhazinilam, (-)-Leucomidine B and (+)-Leuconodine F" and "Synthetic Studies Towards Sarpagine-Related Indoles"

The work presented in this thesis focuses on the synthesis of monoterpene indole alkaloids. The first part describes the divergent total synthesis of (-)-rhazinilam, (-)-leucomidine B and (+)-leuconodine F, three structurally distinct natural products of the Aspidosperma family. The key step involves the heteroannulation of an advanced tetrahydropyridine with bromoacetaldehyde or oxalyl chloride in order to afford the corresponding tetrahydroindolizine and 2,3-dioxopyrrole moieties, respectively. By fine tuning of the reaction conditions, the former was converted into rhazinilam while the latter led to the syntheses of leucomidine B and leuconodine F. In the case of leucomidine B, the development of a substrate-directed diastereoselective reduction of a sterically unbiased double bond is also discussed. The second part details the synthetic studies towards various members of the Sarpagan family. After the exploration of several strategies and indoles alkaloids, the enantioselective total synthesis of N(1)-demethyl-3,5-diepi-alstolactone was accomplished. This synthesis features three key points: 1) the incorporation of a vinyl ketone function in the C-2 position of indole by using the Liebeskind-Srogl coupling in order to afford, after ring-closing metathesis, an advanced eight-membered cyclic enone, 2) a highly diastereoselective intramolecular Michael addition and 3) the formation of an azabicyclo[3.3.1]nonane bridged system from the corresponding eight-membered ring via a dehydration / transannular cyclization process.

Towards the Sarpagine-Ajmaline-Macroline Family of Indole Alkaloids: Enantioselective Synthesis of an N-Demethyl Alstolactone Diastereomer

Dylan Jean Robert Dagoneau, Qian Wang, Jieping Zhu

the strategy involving the use of functionalized tetrahydro-6H-cycloocta[b]indol-6-one is reported as a key intermediate for synthesis of members of the sarpagine-ajmaline-macroline family of monoterpene indole alkaloids. The desired tricycle was synthesized through the following key steps: 1) Evans' syn-selective aldolization; 2) Liebeskind-Srogl cross-coupling using the phenylthiol ester of 3-chloropropanoic acid as a surrogate of acrylic thioester for the synthesis of 2,3-disubstituted indoles; and 3) ring-closing metathesis (RCM) for the formation of the eight-membered ring. An N-allylation followed by intramolecular 1,4-addition was planned for synthesis of the vobasine class of natural products. However, attempted cyclizations under a diverse set of conditions involving anionic, radical, and organopalladium/organonickel species failed to produce the bridged ring system. On the other hand, esterification of the pendant primary alcohol function with acetoacetic acid, followed by intramolecular Michael addition, afforded the desired tetracycle with excellent diastereoselectivity. Subsequent functional group manipulation and transannular cyclization of the amino alcohol afforded the N(1)-demethyl-3,5-diepi-alstolactone. We believe that the same synthetic route would afford the alstolactone should the amino alcohol with appropriate stereochemistry be used as the starting material.

WILEY-V C H VERLAG GMBH2020

Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

The development of a titanium(III)-mediated cascade electrocyclisation/rearrangement for theenantioselective total synthesis of indole alkaloids (+)-condyfoline and (-)-tubifoline serve as the basisof the first chapter of this thesis. An introduction will focus on the use of domino sequencesincorporating a 1,2-shift in the context of complex natural product synthesis. The design of such adomino process is then presented, along with preliminary results originating from our research groupconcerning the titanium(III)-mediated Cadogan cyclisation. This novel domino sequence enabled thefirst enantioselective total synthesis of (+)-condyfoline. These results provided insights into themechanistic nature of the formal 1,2-shift, indicating that the formal 1,2-migration most likelyproceeds via 1,5-sigmatropic rearrangement rather than retro-Mannich/Mannich sequence. Theisolation of (+)-condyfoline enabled a re-investigation of its isomerisation process to Strychnos isomer(-)-tubifoline. The chapter concludes with synthetic studies towards (+)-tronoharine and (+)-tubotaiwine.The second chapter of this thesis deals with the development of an integratedOxidation/Reduction/Cyclisation (iORC) sequence for the enantioselective total synthesis of the Uleinefamily of monoterpene indole alkaloids. A brief introduction will review our group's previous effortsto implement iORC sequences for the total synthesis of alkaloids. The step-by-step development of theiORC sequence is described, along with the endgame strategy for the synthesis of (+)-nordasycarpidone, (+)-dasycarpidone, (-)-dasycarpidol and (+)-uleine. The chapter ends with theattempted titanium(III)-mediated cyclisation/rearrangement sequence towards (+)-uleine, andattempted iORC sequence towards (+)-condyfoline.The third chapter of this thesis reports a novel synthesis of benzofuro[3,2-b]indolines from onitrostylbene precursors using a titanium(III)-mediated interrupted Cadogan reaction. A rapidinvestigation of the substrate scope is presented. The remaining of the chapter reports our efforts toapply this newly developed transformation for the total synthesis of bis-indole alkaloid phalarine.The last chapter is dedicated to our synthetic studies towards (+)-pestalustaine A, a recently isolatedsesquiterpene possessing a unique 5/6/7-fused tricyclic system. A designed formal [3+2] reaction wasenvisioned to provide access to this novel sesquiterpene, but resulted in the isolation of a Wilson-Clokerearrangement product.

EPFL2022

Enantioselective Total Syntheses of (−)-Rhazinilam, (−)-Leucomidine B, and (+)-Leuconodine F

Dylan Jean Robert Dagoneau, Qian Wang, Zhengren Xu, Jieping Zhu

A divergent total synthesis of three structurally distinct natural products from imine 9 was accomplished through an approach featuring: 1) a Pd-catalyzed decarboxylative cross-coupling, and 2) heteroannulation of 9 with bromoacetaldehyde and oxalyl chloride to give tetrahydroindolizine 6 and dioxopyrrole 7, respectively. The former was converted into (-)-rhazinilam, while the latter was converted into (-)-leucomidine B and (+)-leuconodine F. A substrate directed highly diastereoselective reduction of a sterically unbiased double bond by using a homogeneous palladium catalyst was developed. A self-induced diastereomeric anisochronism (SIDA) phenomenon was observed for leucomidine B.

Wiley-Blackwell2016

Asymmetric Total Synthesis of Indole Alkaloids (+)-Condyfoline, (-)-Tubifoline, (+)-Dasycarpidone and (+)-Uleine

Bastien Delayre

EPFL2022