Mitsunobu reaction ester synthesis

The Wenker aziridine synthesis entails the treatment of a P-amino alcohol 1 with sulfuric acid to give P-aminoethyl sulfate ester 2 which is subsequently treated with base to afford aziridine 3. Before the discovery of the Mitsunobu reaction, wbicb transforms an amino alcohol into an aziridine in one step under very mild conditions, the Wenker reaction was one of the most convenient methods for aziridine synthesis. However, due to the involvement of strong acid and then strong base, its utility has been limited to substrates without labile functionalities. 

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 ... 

Smidt and Langner111"1 in their synthesis of the natural calcium blocker leualacin utilized the Mitsunobu reaction for the construction of the linear depsipeptide N-(tert-but oxycarbony I) -(3-alanyl-O-D-leucic acid benzyl ester in 69% yield. Higher yields (94-96%) were reported for two didepsipeptide units N-(/er/-butoxycarbonyl)-./V-methylleucyl-D-lactic acid diphen-ylmethyl ester and iV-(/er/-butoxycarbonyl)-yV-methylleucyl-D-phenyllactic acid diphe-nylmethyl ester in the course of the total synthesis of the anthelmintic cyclooctadepsipeptide PF1022A based on the Mitsunobu reaction.1102 ... 

Once again, the drive for improved performance in transition metal ion-catalysed processes has continued to stimulate the synthesis of new types of organophosphine and tervalent phosphorus-ester and -amide ligands. Activity in the chemistry of heteroaromatic phosphorus ring systems and low-coordination number p -bonded systems has also remained at a high level. New mechanistic insights into the Mitsunobu reaction have been reported, and interest in synthetic applications of Staudinger/Mitsunobu procedures has continued to develop. 

In the stereoselective total synthesis of ( )-14-deoxyisoamijiol by G. Majetich et al., the last step was the epimerization of the C2 secondary allylic alcohol functionality. The Mitsunobu reaction resulted only in a poor yield (30%) of the inverted product, so the well-established sulfoxide-sulfenate rearrangement was utilized. The allyic alcohol was first treated with benzenesulfenyl chloride, which afforded the thermodynamically more stable epimeric sulfenate ester via an allylic sulfoxide intermediate. The addition of trimethyl phosphite shifted the equilibrium to the right by consuming the desired epimeric sulfenate ester and produced the natural product. 

Winterfeldf s synthesis of brefeldin A (Scheme 1.36) also entailed use of a Michael addition in an anti fashion to a 4-substituted cyclopentenone. Dithiane anion 217 was added in a 1,4 sense to enone 216 to give, after elimination of acetic acid, cyclopentenone 218. Addition of cuprate 219 to 218 in the expected anti manner cleanly afforded the trans cyclopentane 220. Hydride reduction gave the unnatural P-alcohol, which was inverted by a Mitsunobu reaction and the resulting ester cleaved to the desired a-alcohol 221. Protection of the alcohol... 

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