Fukuyama-Mitsunobu reactions

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

Synthesis of Fmoc-(Me)Xaa1-OH by On-Resin Methylation Using the Fukuyama/Mitsunobu Reactions General Procedure 92 ... 

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... 

Synthesis of Amines, Amides, Ureas, Thioamides, and Thioureas. The Fukuyama-Mitsunobu reaction is the best method to synthesize secondary amines from primary amines, avoiding formation of undesired tertiary amines and/or the quaternary ammonium salts (eq 1). ... 

Additional examples of the Fukuyama-Mitsvmobu variant are shown below. Lemoine et al. used the more activated dinitrosulfonamide amine equivalent for the Mitsunobu reaction to prepare 176 the subsequent hydrolysis was carried out using mercaptoacetic acid. Hovinen and Sillanpaa found that azamacrocycles like 177 could be prepared under carefully controlled conditions. In a similar context, azamacrocycle 178 was prepared in excellent yield using the tributylphopshine/DIAD pairing. These conditions were better than TPP/DEAD or TBP/ADDP for this particular substrate class. The intramolecular Fukuyama-Mitsunobu reaction was of great use in the preparation of a series of heterocyclic peptidomimetics like the D-tryptophan-based example 179 shown below. ... 

Scheme 17.1 Bidirectional solid-phase total synthesis of AigTX-636. The monoprotected diamine was anchored to the resin by reduced amination, followed by adding the amino acid linker and aromatic head group under the standard coupling condition. The polyamine backbone was prolonged by repeated Fukuyama-Mitsunobu reactions. After adding the terminal arginine to the intermediate, the protected resin-bound molecule was released from the resin, and then the protecting group was removed to obtain the nature ArgTX-636...

The first synthesis of optically pure N-methylated derivatives of Ala, Leu, Phe, and Tyr was published by Fischer and Lipschitz in 1915 73 using the sulfonamide method. Two main developments have ensured that this method remains useful for the preparation of TV-alkyl amino acids both in solution and solid phase (1) the introduction of the Mitsunobu reaction for the alkylation step and (2) the introduction of replacements for Tos (such as the Fukuyama Nbs) that allow easy removal of the sulfonamide protecting group after the alkylation step. Sulfonamide-protected amino acid derivatives can be alkylated in two different ways. Because of the acidity of the sulfonamide hydrogen it is possible to introduce the N-substituent either by direct alkylation (e.g., alkyl halides) or by the Mitsunobu reaction 74 (Scheme 4). 

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... 

Activated amines tethered to solid supports have found ready application in the preparation of primary amines or Boc-protected amines. These approaches usually rely on doubly activated amines or a Fukuyama style approach. The figure below lists two amine synthesis precursors (186, 187) after Mitsunobu reaction, appropriate deprotection conditions yield the desired amines. Additional examples for the synthesis of Fmoc-iV-methyl amino acids are also known. ... 

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