A Mild and Efficient CH₂‐Extrusion Reaction for the Enantiospecific Synthesis of Highly Configurationally Stable Tröger Bases

Abstract

An ovel CH 2 -extrusion reaction leading to the transformation of ethano-Trçger bases into disubstituted methano derivatives is reported (yields up to 93 %). Under mild and metal-free oxidative conditions,aloss of CH 2 and aring contraction are provoked. Despite two bond cleavages at stereogenic nitrogen and carbon centers and at emporary rupture of the bicyclic structure,avery high enantiospecificity (es ! 98 %) is observed for this unusual reaction.Extrusion reactions,w hich are formally the reverse of insertion processes,a re characterized by the removal of an atom or ag roup of atoms from ag iven combination of functional groups and by the reformation of abond between the atoms to which the departing moiety was attached.[1] Such processes are relatively common in organometallic and chalcogen chemistry. [2,3] With more classical organic substrates,only few CH 2 extrusions are reported using metal-free conditions and activated benzylamines and a-hydroxy carbonyl compounds as substrates.[4] Herein, in the context of nitrogen stereochemistry and Tr çger base (TB) derivatives in particular,wereport anovel methylene extrusion which sees the enantiospecific transformation of the ethano-TB 1 into the disubstituted methano-TB 2 (Scheme 1, top). Under mild oxidative conditions,the loss of CH 2 occurs with yields of up to 93 %. Importantly,avery high enantiospecificity (es ! 98 %) is obtained in this reaction which proceeds with retention of configuration through ar ing opening and two bond cleavages at stereogenic nitrogen and carbon centers.Recently,i tw as shown that Tr çger bases of type 3 (Scheme 1, bottom), [5] which are classical chiral molecules as aresult of the presence of stereogenic nitrogen atoms,react in as ingle step with metal carbenes to afford ethano-Trçger bases of type 1.[6] With donor-acceptor diazo reagents as precursors,t he enantiospecificity of the ring expansion is excellent (es 97-99 %

Absolute Configurations of Synthetic Molecular Scaffolds from Vibrational CD Spectroscopy

“…Compounds 91 and 92 are derivatives of Troger's base, which were obtained by a novel mild CH 2 -extrusion reaction (91) 130 and resolution of the racemic mixtures by chiral HPLC (92), 131 respectively. In both cases, AC determination was based on VCD, and ECD and X-ray crystallography were carried out in addition to VCD for 92.…”

Synthesis of 3,3′-bisindoles via demethylenation

“…Demethylenation (CH 2 -extrusion reaction) as an important part of extrusion reactions involves the removal of a methylene unit from a given combination of functional groups. 1 In recent years, much attention has been paid to demethylenation since it enables a great number of readily available substances in chemical transformations via cleavage of the C-C and/or Cheteroatom bond. 2 However, with more classical organic substrates, reports on their demethylenation are rare, 3 especially under additive-free and metal-free conditions (Fig.…”

Synthesis of Tröger’s Base Analogues via a Phase-Transfer-Catalyzed Double Aza-Michael Reaction under Base-Free Conditions

“…Applying the same chemical principle, Wilcox and Sergeyev designed a stepwise method to access unsymmetrically substituted TB analogues by tethering two differently substituted aniline derivatives. 11 A conceptually different strategy for the construction of the methanodiazocine scaffold is the shortening of a twocarbon bridge 12 or the introduction of the bridge between the nitrogen atoms of a tetrahydrodiazocine 13 either by a reaction with carbonyl compounds 14 or as demonstrated by our group via a double aza-Michael addition (DAMA). 15 As this method represents a concise approach to access a variety of diastereomerically or enantiomerically pure TB analogues with a functionalized bridge, we wished to expand its scope and evaluate other activated alkynes.…”