Access to Chiral Cyclopentane Scaffolds by Enantioselective Nickel-Catalyzed Annulations

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.

Stereoselective synthesis of alkenes via base-metal-catalyzed addition reactions to alkynes and activation of hydrogen peroxide and carbon dioxide by iron complexes

Fedor Zhurkin

Alkene functionality can be found in the majority of natural products, drugs, catalysts and organic materials. Therefore, methods of C-C double bond formation constitute a cornerstone of organic synthesis. Selective formation of either (Z)- or (E)-isomer is especially desirable. 1,2-Addition to alkynes unites a large arsenal of methods of C-C double bond formation, among which the addition of carbon-centered species is the most interesting, since it offers a possibility of construction of the carbon skeleton. The first part of the present dissertation is devoted to the development of methods of selective addition of carbon reagents to alkynes. Chapter 1 reviews the existing methods of addition of carbon-centered species, generated from organometallic reagents, organic halides or carbonyl compounds to C-C triple bond with the accent on their stereoselectivity. Carbometalative mechanisms lay in the background of the majority of the reactions in this chemistry. The Z/E selectivity of 1,2-addition to triple bond can be controlled via predominance of either syn- or anti-addition or via Z/E isomerization of the addition intermediates. In Chapter 2 a novel method of disubstituted alkene synthesis via reductive addition of alkyl halides to terminal arylalkynes is described. The remarkable feature of this method is highly selective formation of (Z)-alkenes (generally Z/E > 10:1). Minor modifications of the reducing agent allowed the extension of the substrate scope to the primary alkyl iodides. Mechanistic studies revealed that this reaction proceeds as a formal anti-carbozincation. The resulting organozinc species form disubstituted (Z)-alkenes upon aqueous work-up. On the other hand, it would be interesting to utilize these species in cross-coupling reactions to allow the selective synthesis of trisubstituted alkenes. In Chapter 3 a catalytic system for highly regioselective copper-catalyzed allylation of these reagents is described. In Chapter 4 the results on stereoselective intermolecular addition of aldehydes and ketones to alkynes in the presence of zinc and trimethylchlorosilane are summarized. This reaction gives 1-chloro-1,3-dienes as products. The activation of small molecules has become an increasingly attractive area of research over the last years. In Chapter 5 an outline is given of the literature examples of small-molecule activation, namely activation of carbon dioxide and hydrogen peroxide, by iron complexes. In Chapter 6 the studies on small-molecule activation by iron-sulfur cubane clusters are presented. Electrochemical reduction of carbon dioxide and hydrogenation of alkenes were studied. As an additional result, synthesis and characterization of an unprecedented organic iron(I) ate-complex is reported. Structural modification of a non-heme iron complex with hydrogen-bond-donating substituents is described in Chapter 7. The deep impact of these modifications on the structure and reactivity of the resulting complex is discussed.

EPFL2017

Total Synthesis of Dolabriferol and Polypropionate Fragments Applying New Organic Chemistry of Sulfur Dioxide

Sylvain Claude Laclef

Polypropionates are common products of metabolism in bacteria, insects, fungi and marine organisms. They constitute an important class of products with a wide range of interesting biological activities. Our group has shown previously that 1-alkoxy-3-acyloxy-2-methyl-1,3-pentadienes can undergo hetero-Diels-Alder reactions with SO2, to give the corresponding sultines, which at low temperature in the presence of Lewis acids, can be opened to zwitterionic intermediates. The latter can be trapped by nucleophiles like enoxysilanes (oxyallylation) to generate the corresponding substituted silyl alkenylsulfinate. Desilylation of the latter under acidic conditions leads to intermediate allylsulfinic acids, which, after retro-ene desulfitation, provide a dipropionate stereotriad which is a useful fragment for polypropionate synthesis. Indeed this fragment obtained using this new SO2 reaction cascade, hetero-Diels-Alder addition/oxyallylation/retro-ene desulfitation (Vogel's cascade) is containing keto and enol ester fonctionality which allows the design of the asymmetric total synthesis of complicated polyketides fragments. Firstly a study was made in order to improve the way of synthesis of dienes and their use in Vogel's cascade to improve the diastereoselectivity of the oxyallylation step. The use of this methodology, using (E)-enoxysilanes as nucleophile for the oxyallylation step allowed us to obtain anti,anti-dipropionate stereotriad in high diastereoselectivity. This common subunit found in polyketide-derived natural products has generally been recognized to be difficult to synthesize. This fragment and its properties was used successfully in the first asymmetric total synthesis of the marine natural product dolabriferol. The use of Vogel's cascade with (Z)-enoxysilanes as nucleophile for the oxyallylation step is providing anti-syn-dipropionate stereotriad as major compound. Combination of this method and aldol chemistry allowed us the synthesis of polypropionate fragments in a short sequence. Efforts toward the synthesis of 6-deoxyrythronolide B, and analogues was presented. This strategy allowed us also, to synthesize, in a very efficient way, a lot of compound like lactones which are natural precursor of polypropionate with interesting biological activity or sulfonamide which are well known class of drugs.

EPFL2010

Palladium Catalysed Intramolecular Carbo-oxygenation of Propargylic Amines to Access 1,2-Amino Alcohols and alpha-Amino Ketones via in situ Tether Formation

Phillip Gulliver Dominic Greenwood

a-Amino ketones and 1,2-amino alcohols are important structural motifs in organic chemistry, that can be observed in natural products, pharmaceutically and bioactive compounds. For these reasons, they constitute privileged targets for the development of new and effective synthetic methods. The dual-functionalisation of unsaturated carbon-carbon bonds is a powerful approach to access these crucial motifs. In this context, Pd catalysis has been comprehensively investigated and has consistently demonstrated its capability. Methods enabling the concomitant formation of a carbonâ heteroatom and a carbonâcarbon bond are highly valuable, but the challenges of intermolecular reactions have led to the development of tether systems that require additional steps for their introduction and removal. In situ tethering strategies have previously been explored within the Waser group to circumvent these limitations. This approach relies on a one-pot, three component, Pd catalysed carboetherification or amination reaction, leading to rapidly increase in complexity of simple substrates. So far, the in situ methodologies developed by the Waser group have focused on the functionalisation of alkenes from allylic amines and alcohols. In this regard, the goal of my PhD was to expand the in situ tethering methodologies established within the Waser group, to the synthesis of a-amino ketones and 1,2-amino alcohols. Specifically, my focus was on the formation a trifluoromethyl hemiaminal with a propargylic amine and using the resulting aminal to direct the oxyalkynylation and oxyarylation of the alkyne substrate via a Pd catalysed transformation. Upon optimisation, the reaction of a protected terminal propargylamine, trifluoroacetaldehyde ethyl hemiacetal and silylbromoacetylene using a Pd0 complex with DPEPhos as the catalytic system and Cs2CO3 as the base gave the desired oxazolidine alkenes in high yields and E:Z selectivity. Substrates with substitution on the terminal position and at the propargylic required a change of ligand and base. The transformation was broadly tolerant towards substitution on the nitrogen and the alkyne. An oxyarylative variant was also developed, using Ruphos as ligand, and worked well with a range of iodoarene partners. The obtained oxazolidines could be conveniently orthogonally deprotected to access the a-amino ketone and terminal alkyne; the hydrogenation of the unsaturated oxazolidines has allowed access to 1,2-amino alcohol scaffolds and the application of gold catalysis converted the enyne-oxazolidine system into trisubstituted silyl furans. The identification of a sideproduct of the oxyalkynylation process led to the development of a carboxy-alkynylation reaction using a "CO2" unit derived from the carbonate base. Optimisation established CsHCO3 to the best base/"CO2" source, using DPEPhos as ligand. This transformation gave convenient access to diverse library of cyclic carbamates. Work is ongoing to achieve an enantioselective oxyarylation using chiral phosphine ligands. The asymmetric synthesis of oxazolidines, followed by the diastereoselective alkene hydrogenation and subsequent tether removal would allow the stereodivergent access to interesting diarylalkyl-1,2- amino alcohols. Most recently, the product was synthesised in 66% yield, with 66%ee using commercially available Trost ligand.

EPFL2020