Stereospecific Synthesis of α-Substituted syn-α,β-Diamino Acids by the Diaza-Cope Rearrangement

Abstract

Diaza-Cope rearrangement is used to make a variety of alpha-substituted syn-alpha,beta-diamino acids. The rearrangement takes place with complete transfer of stereochemical integrity (>97% de and >98% ee) giving only one of four possible stereoisomers as determined by X-ray crystallography, (1)H NMR, and chiral HPLC. The observed stereospecificity can be explained in terms of DFT computation. This represents the first 1,4-diaza-Cope rearrangement with a ketone.

Synthesis of Enantiopure Mixed Alkyl-Aryl Vicinal Diamines by the Diaza-Cope Rearrangement: A Synthesis of (+)-CP-99,994

“…Thus, enantiopure hpen (>99% ee) was used to make a variety of enantiopure diaryl vicinal diamines (>99% ee) ,− with electron-donating, electron-withdrawing, and sterically bulky groups, as well as enantiopure dialkyl vicinal diamines . In addition, this procedure was extended to make unsymmetrical vicinal diamines through a sequential addition of two different aldehydes to hpen. , Indeed, we showed that aryl aldehydes, conjugate aldehydes, and ketones can be used to make unsymmetrical vicinal diamines in moderate to good yields (52–91%).…”

“…Instead, we proposed an alternative, efficient, and scalable procedure to make chiral vicinal diamines by the diaza-Cope rearrangement (DCR) (Figure d). − In our procedure, a single enantiopure diamine, 1,2-bis­(2-hydroxyphenyl)-1,2-diaminoethane (hpen, 1 ) was used as a template for the coupling of imines. We have shown that the resonance-assisted hydrogen bonds (RAHBs) provide a sufficient thermodynamic driving force and the chair-transition state allows inversion of stereochemistry in the rearrangement without any loss of enantiopurity.…”

“…10 In addition, this procedure was extended to make unsymmetrical vicinal diamines through a sequential addition of two different aldehydes to hpen. 11,12 Indeed, we showed that aryl aldehydes, conjugate aldehydes, 13 and ketones 14 can be used to make unsymmetrical vicinal diamines in moderate to good yields (52−91%).…”

Short Synthesis of Enantiopure trans-3-Arylpiperazine-2-carboxylic Acid Derivatives via Diaza-Cope Rearrangement

“…15 The rearrangement reaction was nicely extended to a stereospecific "one pot" route to Rsubstituted syn-R,β-diamino esters. 16 We envisioned that the chiral nonsymmetrical 1,2-disubstituted vicinal diamines synthesized by diaza-Cope rearrangement (DCR) could serve as suitable intermediates for the preparation of chiral nonsymmetrical 2,3-substituted piperazines. Herein, we report on the development of an efficient route to enantiopure trans-3-arylpiperazine-2-carboxylic acids starting from optically pure HPEN via DCR using various aryl aldehydes and trans-cinnamaldehyde.…”

Asymmetric Synthesis of Quaternary β‐Perfluorophenyl‐β‐amino‐indolin‐2‐ones

“…Similar to the 2,2,2‐trifluoro‐1‐(amino)ethyl [CF 3 CH(NH 2 )‐] moiety, the [C 6 F 5 CH(NH 2 )‐] structural feature is expected to have pharmacophoric properties and is found in some compounds showing various types of bioactivity . Consequently, the synthesis of compounds possessing the [C 6 F 5 CH(NH 2 )‐] fragment has received some attention in the past, but still remains largely underdeveloped, especially with respect to asymmetric versions . Considering the current upsurge in the development of fluoro‐organic methodology and the vital role of fluorine in modern energy, food, and healthcare industries, the ready availability of compounds bearing the [C 6 F 5 ‐CH(NH 2 )‐] moiety will be desirable for a systematic study of their advanced properties and applications.…”