Dissymmetrical Double-Chain Elongation Approach to the Asymmetric Synthesis of Long-Chain Polypropionates

Polyketides show interesting biological activities and therefore represent an important class of natural products. The necessity of their diastereo- and enantioselective synthesis led to the development of numerous methodologies. A brief overview of this topic is presented. The research carried out in our group has led to the development of a C-C-bond forming reaction involving Umpolung of a chiral, electron rich 1,3-dioxy-1,3-diene due to hetero-Diels-Alder reaction with sulphur dioxide. The so-formed six-membered sultines (6-alkoxy-3,6-dihydro-1,2-oxatiin-2-oxides) can be ionized into a zwitterion in the presence of a Lewis acid promoter, which can be trapped by nucleophiles, e.g. enoxy- or allylsilanes, to generate the corresponding alkenylsulfinates. Protolysis of the latter to sulfinic acids initiates retro-ene desulfitation to produce polyketide- or polypropionate fragments. Studies towards the influence of electronic and steric effects on the diastereoselectivity of the SO2-reaction cascade between 1,3-dioxy-1,3-dienes and enoxysilanes have been performed. A novel series of chiral, p-substituted 1-arylethoxy-3-acyloxy-1,3-dienes has been synthesised and their reactivity and diastereoselectivity in the SO2-cascade has been studied. Enoxysilanes and silyl-based Lewis acid promoters of different steric bulk have been employed in the SO2-cascade with the aim to improve the diastereoselectivity of the reaction. The utility of the SO2-methodology is demonstrated by the short and selective synthesis of several natural and unnatural δ-lactones with various relative configurations from the same starting materials (stereodiversity). The stereoselectivity of the reaction cascade has been verified to be governed exclusively by the chiral auxiliary, even in the presence of additional stereocentres. The methodology has been extended to the synthesis of pseudo-C2- or -CS-symmetrical, long-chain polyketide precursors via bidirectional elongation strategy, either through multistep or one-pot operations employing 1,3-dienes of the novel series and allylsilanes in the first case or allylbissilanes in the second. The so-obtained products are readily desymmetrised and have been shown to undergo selective chain elongations in both directions, which allow for the selective formation of advanced polyketide fragments.

Access to Chiral Cyclopentane Scaffolds by Enantioselective Nickel-Catalyzed Annulations

Joachim Sven Ernst Ahlin

The cyclopentane scaffold has attracted much attention due to its ubiquity in numerous bioactive natural products such as prostaglandins and polyquinanes. However, despite a plethora of available procedures to access this motif, a lack of methods that rival the generality of the Diels-Alder reaction for the synthesis of six-membered rings represents an important gap. Thus, the development of protocols providing efficient access to functionalized chiral cyclopentanes from simple and readily accessible starting materials is highly desirable. In this respect, the tremendous advances in the development of nickel-catalyzed carbon-carbon bond-forming reactions, combined with the unique properties of N-heterocyclic carbenes have led to the development of new approaches to five-membered carbocyclic rings. These include nickel-catalyzed reductive couplings and reductive [3+2] cycloadditions. These strategies are attractive, as functionalized five-membered carbocyclic rings can be accessed from two simple pi-components without any changes in atom connectivity. Despite the recent development of numerous chiral N-heterocyclic carbenes and their successful application in various transition metal-catalyzed reactions, applications in asymmetric nickel catalysis remain scarce. This thesis describes the development of efficient enantioselective nickel-catalyzed methodologies for the formation of five-membered carbocycles from readily accessible and inexpensive starting materials, enabled by two novel chiral N-heterocyclic carbene ligands. First, the development of an intermolecular enantioselective nickel-catalyzed reductive [3+2] cycloaddition of unsaturated aromatic esters and internal alkynes for the synthesis of cyclopentenones is described. For this scalable methodology, a bulky chiral C1-symmetric N-heterocyclic carbene ligand was shown to facilitate the efficient asymmetric synthesis of cyclopentenones from a wide range of mesityl enoates and internal alkynes under mild conditions. Unsymmetrically substituted alkynes were incorporated in a regioselective fashion and the cyclopentenones were synthesized in high yields and enantioselectivity. As a second methodology for the construction of chiral cyclopentane scaffolds, an intermolecular diastereoselective and enantioselective nickel-catalyzed reductive three-component coupling of various aryl aldehydes, norbornene derivatives and silanes is described, which gives access to synthetically valuable silyl-protected indan-1-ols via an aromatic C(sp2)-H functionalization. A bulky chiral C2-symmetric N-heterocyclic carbene ligand possessing a 1,2-(dinaphthalen-1-yl)ethylene diamine scaffold provided the silylated indan-1-ols under mild and scalable conditions, as a single diastereoisomer, in high enantioselectivity and good regioselectivity in the case of meta-substituted aryl aldehydes.

EPFL2016

Isocyanoacetates as Synthetic Platform Towards Natural Products and Biologically Relevant Scaffolds

Thomas Bertrand Pascal Marie Buyck

My PhD work started with the development of a racemic access to trigonoliimine B, an hexacyclic alkaloid isolated in 2010. After having explored different strategies, we reported a 7-step synthesis of this natural product. This synthesis features a challenging and unprecedented Bischler-Napieralski reaction for the formation of a 7-membered ring with the concurrent creation of an exocyclic imine at the last step. The choice of sulfolane as solvent for this transformation was critical to the success. Aiming at upgrading our synthesis towards an enantioselective version, we developed an enantioselective synthesis of α-quaternary α-amino acids. The Michael addition between α-aryl isocyanoacetates and phenyl vinyl selenone catalyzed by a quinine derivative affords enantioenriched Michael adducts. Due to the nature of the functional groups, these adducts are easily transformed to useful scaffolds such as pyrrolidinones and oxindoles. We also demonstrated the synthetic utility of this transformation by using it for the enantioselective total synthesis of (+)- and (-)-trigonoliimine A. With the idea to further demonstrate the efficiency of this reaction for natural product synthesis, we are trying to develop the first total synthesis of (+)-hinckdentine A. Finally, during our investigations on the Michael adduct, we observed the formation of 1,3-oxazinan-2-one. We implemented an integrated one-pot process to access biologically relevant 1,3-oxazinan-2-one. We also studied the reaction mechanism demonstrating an unprecedented triple role of phenyl selenonyl group as an electron withdrawing group, a leaving group and a latent oxidant.

EPFL2014

Enantioselective Total Synthesis of (+)-Alstilobanine C, (+)-Undulifoline, and (-)-Alpneumine H

Nicolas David Gaeng, Guang Li, Cyril Piemontesi, Qian Wang, Jieping Zhu

We report herein the enantioselective total synthesis of three monoterpene indole alkaloids, namely, (+)-alstilobanine C, (+)-undulifoline, and (-)-alpneumine H. The key features of our synthesis include: a) introduction of chirality via enantioselective deprotonation of a prochiral 4-substituted cyclohexanone; b) use of methoxymethyl (MOM) ether as both a hydroxyl protective group and a latent oxonium species for the formation of bridged oxepane and c) domino double reductive cyclization to build both the indole and the piperidine ring at the end of the synthesis. The synthesis confirmed the absolute configuration of these natural products assigned based on the biogenetic hypothesis.

WILEY-V C H VERLAG GMBH2021

Access to Chiral Cyclopentane Scaffolds by Enantioselective Nickel-Catalyzed Annulations

Joachim Sven Ernst Ahlin

EPFL2016