A Desymmetrization Route to Fused Tröger's Base Analogues:  Synthesis, Isolation, and Characterization of the First Anti-Anti Diastereomer of a Fused Tris-Tröger's Base Analogue

Abstract

A desymmetrization route to fused Troger's base analogues was developed. In this way, the synthesis of the first example of an anti-anti diastereomer of a fused tris-Troger's base analogue was accomplished. The resulting compound 5b is a nonlinear symmetric regioisomer obtained from p-bromoaniline in 7% yield. The corresponding syn-anti diastereomer 5a was obtained in 4% yield.

Bromination and Iodination of 6H,12H‐5,11‐Methanodibenzo[b,f][1,5]diazocine: A Convenient Entry to Unsymmetrical Analogs of Tröger's Base

“…In addition, electrophilic halogenation followed by Pd-catalyzed amination [8] can be a very useful iterative strategy in the recently described rational synthesis of "fused tris-Tröger's bases". [21] The reported halogenation represents the first example of an electrophilic substitution of 6H,12H-5,11-methanodi-benzo[b,f][1,5]diazocine. Although our study revealed relatively low reactivity of this heterocyclic system compared to N,N-dialkylanilines, it clearly demonstrated the feasibility of the perfectly regioselective substitution in the para position to the nitrogen atom.…”

Determination of relative configuration of symmetrical bis-Tröger’s base derivatives

“…The otherwise usual approach based on weak allylic 4 J HH interaction constants and NOE measurements [14,15] fails due to the equivalency of hydrogen atoms in the case of symmetrical bisTB diastereoisomers [16]. Fortunately, the chemical shifts of syn and anti diastereoisomers of bisTB derivatives differ significantly, thus an empirical relationship between chemical shifts and stereostructure was suggested [17].…”

Prevention of postoperative adhesion formation by individual and combined administration of 4 per cent icodextrin and dimetindene maleate (Br J Surg 2009; 96: 1476–1483)

“…Fused tris‐TB analogues not sharing common benzenoid rings can variously form linear symmetric, non‐symmetric, or non‐linear symmetric regioisomers (Figure 13). 75…”

“…Our group contributed with another strategy to build fused tris‐TB analogues 75. Both the syn‐anti and the anti‐anti non‐linear symmetric fused tris‐TB analogues 43 and 44 (R = R′ = Br; Figure 14) were synthesized from the starting 2,8‐dibromo‐substituted TB analogue, and isolated by the desymmetrization route.…”

“…In our 2006 paper we thus reported a condensation between aniline 47 (Scheme ) and paraformaldehyde in TFA to afford the C 2 ‐symmetric dibromo‐substituted TB analogue 48 ,44 and this was then desymmetrized by application of our previously published conditions 46,75. TB analogue 48 was thus subjected to a single bromine/lithium exchange (1.1 equiv.…”