The natural products containing α,α-disubstituted α-amino acid structures attracted significant attention because of their interesting biological activities such as antifungal, immunosuppressive, enzyme inhibitory and neurotrophic factor activities. We report here a synthetic protocol for such natural products using rearrangement of allylic trichloroacetimidates (Overman rearrangement) derived from aldohexoses, and total syntheses of myriocin (1) from D-mannose and sphingofungin E (2) from D-glucose. Myriocin (1) is an antimicrobial and immunosuppressive agent isolated from Myriococcum, Myceria, and Isaria. The amino acid precursor 10 was prepared in 7: 1 stereoselectivity by using Overman rearrangement of the (E)-allylimidate derived from D-mannose. Ozonolysis of 10 followed by oxidation and esterification afforded diastereomeric pure ester 13, which was converted to (E)-allylbromide 16 in 5 steps. The sulfone 17, an aliphatic part of myriocin, was lithiated with nBuLi and reacted with 16 to afford the coupling product 18. Saponification and subsequent Birch reduction gave crude carboxylic acid, whose protecting groups were removed to afford the known lactone 20. Final saponification furnished the total synthesis of myriocin. Sphingofungin E (2) isolated from Paecilomyces, is a novel antifungal agent, and known as a strong inhibitor of serinepalmitoyl transferase. Stereoselective synthesis of sphingofungin E with the similar synthetic procedures to those employed for the synthesis of myriocin was explored. Overman rearrangement of (Z)-allylimidate prepared from D-glucose in 8 steps, showed moderate stereoselectivity, and gave rearranged product 23a, whose structure was determined by X-ray analysis of 24, as the major product,. Ozonolysis of 23a followed by reduction gave carbinol 25, which was converted into allylbromide 27 stereoselectively. Coupling reaction of 27 with sulfone 17 afforded the backbone of sphingofungin E 28. Treatment of 28 with lithium naphthalide followed by oxidation gave carboxylic acid 29. Acid hydrolysis of 29, followed by saponification completed the total synthesis of sphingofungin E.
