Project description:The development of preparative methods for the synthesis of four-membered carbocycles is gaining increasing importance due to the widespread utility of cyclic compounds in medicinal chemistry. Herein, we report the development of a new methodology for the production of spirocyclic epoxides and aziridines containing a cyclobutane motif. In a two-step one-pot process, a bicyclo[1.1.0]butyl sulfoxide is lithiated and added to a ketone, aldehyde or imine, and the resulting intermediate is cross-coupled with an aryl triflate through C-C σ-bond alkoxy- or aminopalladation with concomitant epoxide or aziridine formation. After careful optimization, a remarkably efficient reaction was conceived that tolerated a broad variety of both aromatic and aliphatic substrates. Lastly, through several high yielding ring-opening reactions, we demonstrated the excellent applicability of the products as modular building blocks for the introduction of three-dimensional structures into target molecules.
Project description:Bicyclo[1.1.0]butanes (BCBs) have gained growing popularity in "strain release" chemistry for the synthesis of four-membered-ring systems and para- and meta-disubstituted arene bioisosteres as well as applications in chemoselective bioconjugation. However, functionalization of the bridge position of BCBs can be challenging due to the inherent strain of the ring system and reactivity of the central C-C bond. Here we report the first late-stage bridge cross-coupling of BCBs, mediated by directed metalation/palladium catalysis.
Project description:Rh(I)-catalyzed cycloisomerizations of bicyclo[1.1.0]butanes provide a fruitful approach to cyclopropane-fused heterocycles. Products and stereochemical outcome are highly dependent on catalyst. The triphenylphosphine (PPh3) ligand provides pyrrolidines, placing substituents anti to the cyclopropyl group. The 1,2-bis(diphenylphosphino)ethane (dppe) ligand yields azepanes with substituents syn to the cyclopropyl group. In this work, quantum mechanical DFT calculations pinpoint a reversal of regio- and diastereoselectivity, suggesting a concerted (double) C-C bond cleavage and rhodium carbenoid formation, driven by strain-release. The ligand-influenced cleavage step determines the regioselectivity of carbometalation and product formation, and suggests new applications of bicyclobutanes.
Project description:Bicyclo[1.1.0]butanes (BCBs) are increasingly valued as intermediates in 'strain release' chemistry for the synthesis of substituted four membered rings and bicyclo[1.1.1]pentanes, with applications including bioconjugation processes. Variation of the BCB bridgehead substituents can be challenging due to the inherent strain of the bicyclic scaffold, often necessitating linear syntheses of specific BCB targets. Here we report the first palladium catalyzed cross-coupling on pre-formed BCBs which enables a 'late stage' diversification of the bridgehead position, and the conversion of the resultant products into a range of useful small ring building blocks.
Project description:Bicyclo[1.1.0]butanes (BCBs), strained carbocycles comprising two fused cyclopropane rings, have become well-established building blocks in organic synthesis, medicinal chemistry, and chemical biology due to their diverse reactivity profile with radicals, nucleophiles, cations, and carbenes. The constraints of the bicyclic ring system confer high p-character on the interbridgehead C-C bond, leading to this broad reaction profile; however, the use of BCBs in pericyclic processes has to date been largely overlooked in favor of such stepwise, non-concerted additions. Here, we describe the use of BCBs as substrates for ene-like reactions with strained alkenes and alkynes, which give rise to cyclobutenes decorated with highly substituted cyclopropanes and arenes. The former products are obtained from highly stereoselective reactions with cyclopropenes, generated in situ from vinyl diazoacetates under blue light irradiation (440 nm). Cyclobutenes featuring a quaternary aryl-bearing carbon atom are prepared from equivalent reactions with arynes, which proceed in high yields under mild conditions. Mechanistic studies highlight the importance of electronic effects in this chemistry, while computational investigations support a concerted pathway and rationalize the excellent stereoselectivity of reactions with cyclopropenes.
Project description:The identification of spiro N-heterocycles as scaffolds that display structural novelty, three-dimensionality, beneficial physicochemical properties, and enable the controlled spatial disposition of substituents has led to a surge of interest in utilizing these compounds in drug discovery programs. Herein, we report the strain-release-driven Friedel-Crafts spirocyclization of azabicyclo[1.1.0]butane-tethered (hetero)aryls for the synthesis of a unique library of azetidine spiro-tetralins. The reaction was discovered to proceed through an unexpected interrupted Friedel-Crafts mechanism, generating a highly complex azabicyclo[2.1.1]hexane scaffold. This dearomatized intermediate, formed exclusively as a single diastereomer, can be subsequently converted to the Friedel-Crafts product upon electrophilic activation of the tertiary amine, or trapped as a Diels-Alder adduct in one-pot. The rapid assembly of molecular complexity demonstrated in these reactions highlights the potential of the strain-release-driven spirocyclization strategy to be utilized in the synthesis of medicinally relevant scaffolds.
Project description:By reacting [{Cp‴Fe(CO)2}2(µ,η1:1-P4)] (1) with in situ generated phosphenium ions [Ph2P][A] ([A]- = [OTf]- = [O3SCF3]-, [PF6]-), a mixture of two main products of the composition [{Cp‴Fe(CO)2}2(µ,η1:1-P5(C6H5)2)][PF6] (2a and 3a) could be identified by extensive 31P NMR spectroscopic studies at 193 K. Compound 3a was also characterized by X-ray diffraction analysis, showing the rarely observed bicyclo[2.1.0]pentaphosphapentane unit. At room temperature, the novel compound [{Cp‴Fe}(µ,η4:1-P5Ph2){Cp‴(CO)2Fe}][PF6] (4) is formed by decarbonylation. Reacting 1 with in situ generated diphenyl arsenium ions gives short-lived intermediates at 193 K which disproportionate at room temperature into tetraphenyldiarsine and [{Cp‴Fe(CO)2}4(µ4,η1:1:1:1-P8)][OTf]2 (5) containing a tetracyclo[3.3.0.02,7.03,6]octaphosphaoctane ligand.
Project description:Here we describe the development of a method for the Pd-catalyzed electrochemical acetoxylation of C-H bonds. The oxidation step of the catalytic cycle is probed through cyclic voltammetry and bulk electrolysis studies of a preformed palladacycle of 8-methylquinoline. A catalytic system for C-H acetoxylation is then developed and optimized with respect to the cell configuration, rate of oxidation, and chemistry at the counter electrode. This transformation is then applied to substrates containing various directing groups and to the acetoxylation of both C(sp2)-H and C(sp3)-H bonds.
Project description:The Sonogashira-type cross-coupling reaction is one of the most significant alkynylation transformations in organic chemistry. However, highly enantioselective alkynylation via the Sonogashira-type cross-coupling reaction is rather limited, mainly due to the difficulties in matching the stereoselective induction of chiral ligands with the combinational behavior of Pd/Cu-based bimetallic catalysts. We herein report novel enantioselective palladium/copper-catalyzed alkyl alkynylation of cyclobutanones with terminal alkynes via tandem C-C bond activation/Sonogashira-type cross coupling reaction, in which a novel chiral TADDOL-derived phosphoramidite ligand bearing fluorine and silicon-based bulky groups simplified as TFSi-Phos is found to be an efficient ligand for both C(sp2)-C(sp3) bond cleavage and new C(sp3)-C(sp) bond formation. A wide range of chiral alkynylated indanones bearing an all-carbon quaternary stereocenter are obtained efficiently with up to 97.5 : 2.5 er.
Project description:The title compound, C(24)H(56)N(4)P(6) or ((i)Pr(2)N)(2)P-P(4)-P(N(i)Pr(2))(2), adopts a butterfly structure, with planar environments for the N atoms and pyramidal environments for the P atoms. The structure studied has a 15% twin component that is related by a twofold rotation about [100].