New β-Carboline Derivatives by Double-Cyclization of Chiral α-Heteroarylmethylamino Esters

Abstract

Dialkylation of amino esters 2 with o-bromobromomethylheteroaromatics 1 and double-cyclization of the resulting N,N-disubstituted esters 3 via bromo-lithium exchange to tetrahydropyridine rings gives access to dicondensed 5-hydroxy-1-azabicyclo[3.3.1]nonanes 4, mostly ß-carboline derivatives. The synthesis is highly stereoselective affording optically active products.Dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 (X = CH=CH) have gained interest as antihistaminic compounds 1 and as starting materials for the synthesis of Amaryllidaceae alkaloids. 2,3 Several synthetic methods have been reported for this class of condensed heterocycles and related heterocyclic analogues. Thus acid catalyzed double-cyclization of α-dibenzylaminoaldehydes, acetals 2, 4-6 or ketones 7,8 afford 8 (X = CH=CH, R = H, alkyl or aryl) with a hydrogen atom, an alkyl or an aryl substituent at position 5. In this synthesis the first cyclization represents a hydroxyalkylation and gives intermediate 2-benzyl-4-hydroxy or 4-alkoxy-2-benzyl-tetrahydroisoquinolines that subsequently cyclize by intramolecular Friedel-Crafts like alkylation. Likewise 2-benzyltetrahydroisoquinolines with hydroxy, acyloxy or methoxy groups in position 4 give dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 upon treatment with acids. 4,9,10 These last two methods were also used in the thieno series. 11 5-Methyl-dibenzo[c,f]-1-azabicyclo[3.3.1]nonanes 8 (X = CH=CH, R = Me) were obtained by double-cyclization of N,Ndibenzyl-2-propinylamine in the presence of triflic acid. 12 Finally, acid treatment of oxygenated dihydro-2-benzylisoquinolines 9, 13 or reaction of 4-aryl-tetrahydroisoquinolines with formaldehyde / formic acid gave access to 8 (X = CH=CH). 14 An asymmetric synthesis of the dibenzo[c,f]-1-azabicyclo[3.3.1]nonane 8 (X = CH=CH) or related heterocyclic analogues 8 (X = N, S, O) skeleton has not been reported so far. One optically active member in this series was obtained by resolution of the corresponding racemate. 2 We report now the first synthesis of optically active [c,f]-dicondensed 1-azabicyclo[3.3.1]nonane 4 giving access to 5-hydroxy substituted compounds. Again a double-cyclization strategy was pursued. But unlike in the known syntheses using Friedel-Crafts methodology an activation of the aromatic ring by bromo-lithium exchange was employed now. Esters of natural amino acids 2 were dialkylated with obromo-bromomethyl hetarenes 1. 15 The resulting N,N-dialkylaminoesters 3 gave the 1-azabicyclo[3.3.1]nonane 4 in a straightforward manner after treatment with n-BuLi or t-BuLi. Double cyclization most probably proceeds by prior bromo-lithium exchange followed by attack of the ester moiety by the o-lithiated carbons of both heterocyclic substituents. 16 In a similar manner monocyclization has been reported before with N-monosubstituted amino esters 6 giving rise to the formation of condensed dihydropyridin-3-ones 7. 17 Compound 4e as a member of asymmetrically condensed 1-azabicyclo[3.3.1]nonanes 4 (X 1 ≠ X 2 ) could be obtained from the corresponding N-skatyl-N-thie...

Double Cyclization of Bis(α‐hetarylmethyl)amino Esters to Optically Active Bridged N‐Heterocycles of HIV‐Inhibiting Activity

“…[2] We recently found a novel stereoselective chiral pool synthesis of heterocyclic analogues 6 of 1-azadibenzo[c,f]bicyclo[3.3.1]nonanes (most of the analogues were β-carboline derivatives). [14] Our synthesis starts with amino esters 2, which are dialkylated by o-bromobenzyl halides or their heterocyclic analogues 1 to afford 5. After the exchange of bromide by lithium with butyllithium, double cyclization occurs under very mild conditions (Ϫ100°C) to afford chiral polycyclic hydroxytetrahydropyridines 6 via intermediate monocyclization products 8.…”

Synthesis of Optically Active Condensed Tetrahydropyridines from α-Amino Esters

“…Alternatively, condensed dihydropyridones 6 with an o-bromobenzyl or heterocyclic analogous substituent R 2 could be treated with butyllithium. 32,33 The products exhibited a novel mode of HIV-inhibition by blocking the RNase-H and DNA-polymerase activity of the reverse transcriptase. 32,33 Here we give a full report on the synthesis of condensed dihydropyridones 6 and their precursors i.e., the N-protected amino esters 5 and the N-unprotected members 4.…”

“…32,33 The products exhibited a novel mode of HIV-inhibition by blocking the RNase-H and DNA-polymerase activity of the reverse transcriptase. 32,33 Here we give a full report on the synthesis of condensed dihydropyridones 6 and their precursors i.e., the N-protected amino esters 5 and the N-unprotected members 4. Furthermore, reactions of the condensed dihydropyridones 6 with organometallics and with reducing reagents resulting in a transformation of the carbonyl group into hydroxy compounds 7 or 8 and halocyclization of allyl and homoallyl compounds 8 to 1,3-bridged cyclization products 9 and 10 are reported (Scheme 2).…”

“…Reaction of amino esters 2 with two equivalents of the alkylation reagent 1 promotes the double alkylation to become the major reaction. 32,33 The N-monobenzylated amino esters 4 could be N-Cbz-protected (5j) or allylated (5c, 5n) in high yields providing an access (Method C) to products 5 as an alternative to direct Route B.…”