Synthesis of Novel Derivatives of (1S,4S)‐2,5‐Diazabicyclo[2.2.1]heptane and Their Evaluation as Potential Ligands in Asymmetric Catalysis

Abstract

Thirty-seven (most of them novel) chiral derivatives of (1S,4S)-2,5-diazabicyclo[2.2.1]heptane (2-36, 38, 39) were prepared from (S)-trans-4-hydroxyproline. A selection of these chiral ligands were examined as potential ligands in the preparation of catalysts for the enantioselective addition of diethylzinc to aldehydes and as chiral Lewis acid activators in the asymmetric Diels-Alder reaction. In the former system, diamine 30 induced up to 92 % enantiomeric excess in the formation of (S)-phenyl ethyl carbinol, whereas in the case of the cycloaddition reaction between cyclopentadiene and 3-acryloyloxazolidin-2-one the catalytic complex formed

Use of (R)-Mandelic Acid as Chiral Co-Catalyst in the Michael Addition Reaction Organocatalyzed by (1S,4S)-2-Tosyl-2,5-diazabicyclo[2.2.1]heptane under Solvent-Free Conditions

“…Brought to you by | Yale University Authenticated Download Date | 7/27/15 1:56 PM Organocatalyst 2 was prepared from trans-4-hydroxy-(S)-proline following the method reported by MelgarFernández, et al,[42] affording the N-benzylated precursor (1S,4S)-5-benzyl-2-tosyl-2,5-diazabicyclo[2.2.1] heptane (1), which was then debenzylated by hydrogenolysis over Pd/C 10% to give compound 2 (Scheme 1).…”

Optimized Methodologies in Asymmetric Organic Synthesis Applying Microwaves

“…Diazabicyclo [2.2.1]heptanes have emerged as an attractive framework in the area of asymmetric catalysis, mainly when acting as ligands. Some features of these compounds are their structural rigidity, the presence of two stereogenic centers, and suitable coordination sites, that render them as attractive analogs of the steroid sparteine [14]. The conventional route for the synthesis of (1S,4S)-2,5-diazabicyclic derivatives described by Portoghese [15a] and Braish [15b] involves tosylation of the amino group in the (S)-trans-4-hydroxyproline 1, followed by reduction of the carboxylic acid fragment with sodium borohydride.…”

“…Scheme 1) motivated the search for alternative strategies; indeed, the use of microwave irradiation turned out to be an ideal option. Thus, the first and final steps were optimized with microwave irradiation: the tosylation of the amino group in 1 was realized in 30 min instead of 48 h and the cyclization step was carried out in 30-90 min instead of 2-24 h. Desired 5a-c derivatives were obtained in good overall yields (Scheme 2) [14].…”

Synthesis of Ranolazine Derivatives Containing the (1S,4S)‐2,5‐Diazabicyclo[2.2.1]Heptane Moiety and Their Evaluation as Vasodilating Agents

“…Acetamide ( S , S )‐4 was prepared from the aniline 1 , which in the presence of bromoacetyl bromide yielded the bromoacetamide 2 ; this upon reaction with 2‐benzyl‐DBH [prepared according to Melgar‐Fernandez et al . ] afforded the protected diamine ( S , S )‐3, which produced, by palladium‐catalyzed hydrogenolysis, the intermediate (S,S)‐4, which reacted with racemic epoxide 7 to give the epimeric mixture of ( S , S , S ) ‐ 5 and ( S , S , R ) ‐ 5 .…”