Abstract:[reaction: see text] The first syntheses of 5,6-difunctionalized-2-azabicyclo[2.1.1]hexanes containing syn-hydroxy and syn-fluoro substituents have been effected in a stereocontrolled manner. The key reactions are regioselective additions to the aziridinium ions formed from 6-exo-iodo(bromo)-5-endo-X-2-azabicyclo[2.2.0]hexanes (X = F, OH) upon silver or mercury salt enhancement of iodide nucleofugacity.
“…12 Conversion of fluoroalcohol 18 to the thionocarbonate 19 using phenylchlorothionocarbonate 13 followed by reductive deoxygenation afforded the N -benzyloxycarbonyl fluoride 20 . Reductive removal of the protecting group using H 2 /Pd(OH) 2 in methanol in the presence of (BOC) 2 O afforded the N -BOC-5- syn -fluoro synthon 10a .…”
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.
“…12 Conversion of fluoroalcohol 18 to the thionocarbonate 19 using phenylchlorothionocarbonate 13 followed by reductive deoxygenation afforded the N -benzyloxycarbonyl fluoride 20 . Reductive removal of the protecting group using H 2 /Pd(OH) 2 in methanol in the presence of (BOC) 2 O afforded the N -BOC-5- syn -fluoro synthon 10a .…”
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.
“…15 Further studies revealed that the participation of both s and p electrons played an important role in controlling the stereochemistry of such rearrangements. 21 For such compounds, the silver-promoted rearrangement of each stereoisomer at the nitrogen atom (invertomers) proved to be dependent on the configuration at nitrogen.…”
“… N- Boc- and N- Cbz derivatives of the parent 2-azabicyclo[2.1.1]hexane derivatives have been described. 3a, …”
Section: Referencesmentioning
confidence: 99%
“…There has been substantial recent interest in the 2-azabicyclo[2.1.1]hexane ring system, which forms the basis for the nonproteinogenic amino acid 2,4-methanoproline . Early synthetic routes to the ring system were based on photochemical intramolecular [2 + 2] cycloaddition strategies, and there have been recent reports of alternative approaches, from 2-azabicyclo[2.2.0]hexane derivatives, 3-halomethyl-1-aminocyclobutanes, , and cis- cyclobutene dicarboxylic anhydrides so that the azabicyclic framework itself is now readily available. …”
Section: Introductionmentioning
confidence: 99%
“…Considerable recent effort has led to a significant widening of the range of methods for functionalization of the 2- and 5-/6-positions of the 2-azabicyclo[2.1.1]hexane ring system. , In particular, Krow has recently introduced attractive approaches to 5(6)- syn,anti- difunctional derivatives 3a and to control of lithiation at the 1- and 3-positions of N- Boc-2-azabicyclo[2.1.1]hexane leading to aldehydes and esters . Other alternatives to the carboxylic acid group at the 1-position include nitriles 1 and pyridine derivatives,2d and hydride reduction of the cyano group 1 has been reported.…”
Successful nucleophilic substitution at a methylene attached to the bridgehead (1-) position of the 2-azabicyclo[2.1.1]hexane ring system opens the way to construction of novel derivatives having a wider range of functional groups attached to the 1-position via a methylene "spacer" (including the beta-amino acid homologue of 2,4-methanoproline) and provides access to epibatidine analogues containing heterocyclic substituents and also to further homologation at the 1-position. Displacements with loss of a nucleofuge (e.g., loss of mesylate anion from the 1-mesyloxymethyl derivative) require thermal activation but proceed without the rearrangement initially anticipated in such a strained bicyclic ring system. A novel tricyclic carbamate intermediate 17 has been isolated; nucleophilic attack on 17 leads directly to the isolation of N-deprotected substitution products (with concomitant decarboxylation).
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