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Regio- and Enantioselective Synthesis of 1,2-Diamines by Formal Hydroamination of Enamines : Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis-Piperazines as a Privileged Scaffold

Mohiti, Maziar LU ; Lu, Yu LU ; He, Hui ; Ni, Shao Fei and Somfai, Peter LU (2024) In Chemistry - A European Journal
Abstract

We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the “click-type” synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1′-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the... (More)

We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the “click-type” synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1′-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.

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author
; ; ; and
organization
publishing date
type
Contribution to journal
publication status
epub
subject
keywords
asymmetric catalysis, computational study, diamines, enamines, hydroamination
in
Chemistry - A European Journal
publisher
Wiley-Blackwell
external identifiers
  • pmid:38205968
  • scopus:85183917616
ISSN
0947-6539
DOI
10.1002/chem.202303078
language
English
LU publication?
yes
id
68ad81e5-3117-4ff5-92ff-296203f27646
date added to LUP
2024-02-27 15:08:33
date last changed
2024-04-26 18:56:08
@article{68ad81e5-3117-4ff5-92ff-296203f27646,
  abstract     = {{<p>We have previously reported the first formal hydroamination of enamines for the synthesis of chiral 1,2-diamines. Here, we describe: (i) the discovery, optimization, and substrate expansion of this reaction; (ii) a novel and straightforward protocol for the “click-type” synthesis of enamines in quantitative yield utilizing sodium sulfate in a dual role as an ancillary and dehydrating agent without the need for workup or purification; (iii) the application of this methodology to the first enantioselective synthesis of orthogonally protected 1,1′-(1-(4-fluorophenyl)ethane-1,2-diyl) piperazines, a scaffold for rapid lead optimization in drug discovery; (iv) a computational investigation into the mechanism and rationalization of the enantioselectivities of the reaction.</p>}},
  author       = {{Mohiti, Maziar and Lu, Yu and He, Hui and Ni, Shao Fei and Somfai, Peter}},
  issn         = {{0947-6539}},
  keywords     = {{asymmetric catalysis; computational study; diamines; enamines; hydroamination}},
  language     = {{eng}},
  publisher    = {{Wiley-Blackwell}},
  series       = {{Chemistry - A European Journal}},
  title        = {{Regio- and Enantioselective Synthesis of 1,2-Diamines by Formal Hydroamination of Enamines : Scope, Mechanism, and Asymmetric Synthesis of Orthogonally Protected Bis-Piperazines as a Privileged Scaffold}},
  url          = {{http://dx.doi.org/10.1002/chem.202303078}},
  doi          = {{10.1002/chem.202303078}},
  year         = {{2024}},
}