Synthesis of Conformationally Constrained 5-Fluoro- and 5-Hydroxymethanopyrrolidines. Ring-Puckered Mimics of Gauche- and Anti-3-Fluoro- and 3-Hydroxypyrrolidines

Abstract

N-Acetylmethanopyrrolidine and its four 5-syn/anti-fluoro and hydroxy derivatives have been synthesized from 2-azabicyclo[2.2.0]hex-5-ene, a 1,2-dihydropyridine photoproduct. These conformationally constrained mimics of idealized Cβ-gauche and Cβ-anti conformers of pyrrolidines were prepared in order to determine the inherent bridge bias and subsequent heteroatom substituent effects upon trans/cis amide preferences. The bridgehead position and also the presence of gauche(syn)/anti-5-fluoro or 5-hydroxy substituents have minimal influence upon KT/C values of N-acetylamide conformers in both CDCl3 (43–54% trans) and D2O (53–58% trans). O-Benzoylation enhances the trans amide preferences in CDCl3 (65% for a syn-OBz, 61% for a trans-OBz) but has minimal effect in D2O. The synthetic methods developed for N-BOC-methanopyrrolidines should prove useful in the synthesis of more complex derivatives containing α-ester substituents. The KT/C results obtained in this study establish baseline amide preferences that will enable determination of contributions of α-ester substituents to trans-amide preferences in methanoprolines.

Synthesis of 5-Fluoro- and 5-Hydroxymethanoprolines via Lithiation of N-BOC-methanopyrrolidines. Constrained Cγ-Exo and Cγ-Endo Flp and Hyp Conformer Mimics

“…The results are shown by entries 1-4 in Table 3 13 . The percentages of trans isomers obtained from averaged separate 1 H NMR integrations are reliable to ±1.2% or better.…”

“…10 We now report a different synthetic approach to methanoprolines using directed lithiations of isomeric N -Boc-5-fluoro and 5-hydroxymethanopyrrolidines to introduce the 3-ester substituent. 12,13 By this method, we have synthesized and characterized in detail ex-MetFlp 6 and en-MetFlp 7 that contain embedded exo and endo conformations of Flp 1 . We have also prepared ex-MetHyp 8 and en-MetHyp 9 that contain exo and endo conformations of Hyp 2 (see Figure 1).…”

A Proline Mimetic for the Design of New Stable Secondary Structures: Solvent-Dependent Amide Bond Isomerization of (S)-Indoline-2-carboxylic Acid Derivatives

“…Both these features make (2 S )-Ind a good candidate for the investigation of its conformational properties. Contrary to the many studied proline analogues with substituents at position C4 and C5, − pseudoprolines, or other bicyclic proline derivatives, , (2 S )-Ind cannot undergo stabilization or destabilization by ring puckering, as the 5-membered ring is intrinsically quasiplanar.…”

Recent Applications of the (TMS)3SiH Radical-Based Reagent

“…Examples of dehalogenation (Cl, Br and I) and reductive removal of chalcogen groups (SR and SeR) are well known [ 1 , 2 , 3 , 4 , 5 ]. Scheme 2 shows some recent examples of debromination starting from bromide 1 [ 6 ], 2 [ 7 ] or 3 [ 8 ]. The most popular thermal initiator is azobisisobutyronitrile (AIBN), with a half-life of 1 h at 81 °C.…”