Fukuyama amine synthesis amines

The Fukuyama amine synthesis has seen wide application in the context of natural product synthesis. Complex polyamine natural products that highlight the orthogonal nature of the nosyl protecting group, such as lipogrammistin-A12 and various spider toxins,13 have been efficiently synthesized. This protocol has also been used in the context of medicinal chemistry,14 glucosylamines,15 and blasticidin amino acids.16... 

Despite the broad scope of the Fukuyama amine synthesis, there are possible complications that may arise. Common to any Mitsunobu reaction, there is the issue of purification that is often required in order to remove the copious amounts of Ph3P=0 that are generated. This can be difficult, but modifications to the phosphine base employed can mitigate this problem (vida infra). The Mitsunobu alkylation also oftentimes... 

The regioselectivity of the Fukuyama amine synthesis has also been examined. As shown, the NsCl (1 equiv) preferentially reacts with the primary amine of 45 despite the presence of a rather nucleophilic secondary nitrogen of the pyrrolidine to give 46 as the sole product.30... 

The Fukuyama amine synthesis can also be applied to protected hydroxylamines and hydroxamates.33 Various protected hydroxylamines 54 undergo clean reaction with NsCl giving 55. This N, O-protected hydroxylamine 55 may then react with a variety of alkyl halides to give fully protected hydroxylamines 56. 

This reaction was initially reported by Fukuyama and co-workers in 1995. It is a two-step conversion of primary amines into secondary amines via ortho-nitrobenzenesulfonation in conjunction with the Mitsunobu Reaction and subsequent removal of the o-nitrobenzenesulfonyl group by thiophenol. Therefore, this reaction is generally known as the Fukuyama amine synthesis. In addition, it is also referred to as the Fukuyama-Mitsunobu A -alkylation," Fukuyama-Mitsunobu alkylation, Fukuyama-Mitsunobu condition, Fukuyama-Mitsunobu procedure, or Fukuyama-Mitsunobu Reaction. In this reaction, the o-nitrobenzenesulfonyl-protected amine is alkylated with alcohol in the presence of PPhs and diethyl azodicarboxylate (DEAD) or diisopropyl azodicarboxylate (DIAD), and the deprotection occurs in a very mild condition (almost neutral ). The o-nitrobenzenesulfonyl group is simply called the Fukuyama sulfonamide protecting groupThis reaction has become a versatile method... 

Other references related to the Fukuyama amine synthesis are cited in the literature. 

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