Mitsunobu reaction sulfonamide, synthesis

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). 

The pK.d values of TV-methyltrifluoromethanesulfonamide (TfNHMe = 7.5) and TV-meth-yltoluenesulfonamide (TosNHMe= 11.7) have been examined and it was found that these sulfonamides are applicable to the Mitsunobu reaction conditions. 80 A modified Mitsunobu reaction has been used for the synthesis of A7"-alkyl amino acid esters 81,82 this method is only applicable to amino acid esters and not to the free acids. Thus, TV-Tos amino acid esters are condensed with MeOH, EtOH, or iPrOH in the presence of TPP and DEAD. The Tos group is deprotected by sodium in liquid ammonia or with sodium amalgam. 83 The deprotection of the Tos group has also been achieved electrochemically under mild conditions and in good yields. 84 ... 

A novel route for the synthesis of piperazin-2-ones on a solid support relies on an intramolecular Mitsunobu reaction [111]. First, commercially available amino alcohols are attached to an aldehyde resin by reductive ami-nation. The alcohol function is protected and the secondary amine obtained is acylated with an amino add. Sulfonamide activation of the free amino group allows intramolecular alkylation through a Mitsunobu reaction, and thereby the formation of a derivatized ring. 

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... 

In both cases described above, the newly formed amides stayed untouched but, in a more recent study Kakuchi and Theato demonstrated synthetic routes for the insertion of further functionalities at an amide position when switching to the synthesis of polymeric sulfonamides [12]. Therefore, the starting polymer poly (pentafluorophenyl-4-vinylbenzene sulfonate) was aminolyzed to obtain the corresponding sulfonamide. A subsequent Mitsunobu reaction led to doubly functionalized side chains (Scheme 6). This succession enabled the double functionalization of each repeating unit with a huge library of different amines and alcohols in almost quantitative yields. 

Resin 23 was first swollen in CH2CI2 and, in a manner that parallels the route employed in the solution-phase synthesis, was reacted with a selected benzylsulfonyl chloride and t-BuOLi as a base to afford the corresponding sulfonamide resin 28, containing the first diversity element R. The sulfonamide resin 28 was then reacted under Mitsunobu conditions (PPha (triphenyl phosphine), DIAD (diisopropyl azodicarboxylate), THE, room temperature) with the appropriate alcohols. This process efficiently produced resin 29 and introduced the second diversity element R. Cyclization reaction of resin 29 was promoted by sodium hydride in DMF and led to the formation of the desired thiazolo[4,5-c] [l,2]thiazine resin 30. Treatment of resin 30 with mCPBA in CH2CI2 generated the resin-bound cyclic sulfonamide 31. Finally, the thiazolo[4,5-c][l,2]thiazine derivatives 5 were formed and cleaved from the resin (in a traceless manner" ) by treatment of resin 31 with the corresponding amines (R R" N diversity elements) in respectable yields (34 examples, from 11% to 29% for seven linear steps starting with Merrifield resin 1, Table 10.4). 

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