Synthesis of β-Hydroxy-α,α-disubstituted Amino Acids through the Orthoamide-Type Overman Rearrangement of an α,β-Unsaturated Ester and Stereodivergent Intramolecular SN2′ Reaction: Development and Application to the Total Synthesis of Sphingofungin F

Abstract

The development of a two-step synthesis for β-hydroxy-α,α-disubstituted amino acid derivatives from cyclic orthoamide is reported. The first step is the orthoamide-type Overman rearrangement of an α,β-unsaturated ester to give a sterically hindered α,α-disubstituted amidoester. The α,β-unsaturated ester is known to be a challenging substrate in the conventional Overman rearrangement due to the competitive aza-Michael reaction. However, suppression of the aza-Michael reaction is realized by two factors; 1) the high reaction temperature, and 2) an alkyl substituent at the α-position. The second step is stereodivergent intramolecular SN2′ reaction for the installation of a hydroxy group at the β-position. Either syn- or anti-type SN2′ reaction is possible by simply changing the reaction conditions. The developed method can provide all four possible stereoisomers of the β-hydroxy-α,α-disubstituted amino acid, and is successfully applied to the total synthesis of sphingofungin F.

A Modular Approach to the Antifungal Sphingofungin Family: Concise Total Synthesis of Sphingofungin A and C

“… [35] and Sugai et al. [36] in 2018 (Figure 1 C ). Despite these tremendous achievements, most synthetic routes require ten or more synthetic steps in the longest linear synthetic sequence and often require the preparation of elaborate starting materials as well as several protecting group transformation steps causing very low overall yields.…”

“…[2] While sphingofungin At oDmainly differ in the position of the acetyl and guanin group,r espectively,s phingofungins Ea nd Fc ontain aq uaternary stereo center at the a-position, and ak eto functionality at C-14. Due to their intriguing structural features and important pharmacological properties,s phingofungins became quickly popular total synthetic targets.U ntil today,14distinct synthetic strategies have been applied in the total synthesis of sphingofungins B, D, E, and F, with the last syntheses of sphingofungin Ea nd Fb eing reported in 2017 by Noda et al [35] and Sugai et al [36] in 2018 (Figure 1C). Despite these tremendous achievements,m ost synthetic routes require ten or more synthetic steps in the longest linear synthetic sequence and often require the preparation of elaborate starting materials as well as several protecting group transformation steps causing very low overall yields.In addition, the syntheses of sphingofungin A, C, G, and H remained elusive until today.T hus,a ccess to material and derivatives for biological and biochemical studies has been al imiting factor and hampered further progress in understanding the biology and functions of this compound class.…”

“…Due to their intriguing structural features and important pharmacological properties, sphingofungins became quickly popular total synthetic targets. Until today, 14 distinct synthetic strategies have been applied in the total synthesis of sphingofungins B, D, E, and F,[ 12 , 13 , 14 , 15 , 16 , 17 , 18 , 19 , 20 , 21 , 22 , 23 , 24 , 25 , 26 , 27 , 28 , 29 , 30 , 31 , 32 , 33 , 34 , 35 , 36 ] with the last syntheses of sphingofungin E and F being reported in 2017 by Noda et al. [35] and Sugai et al.…”

A Modular Approach to the Antifungal Sphingofungin Family: Concise Total Synthesis of Sphingofungin A and C

“…Due to their intriguing structural features and important pharmacological properties, sphingofungins became quickly popular total synthetic targets. Until today, 14 distinct synthetic strategies have been applied in the total synthesis of sphingofungins B, D, E, and F, [12–36] with the last syntheses of sphingofungin E and F being reported in 2017 by Noda et al [35] . and Sugai et al [36] .…”

“…Until today, 14 distinct synthetic strategies have been applied in the total synthesis of sphingofungins B, D, E, and F, [12–36] with the last syntheses of sphingofungin E and F being reported in 2017 by Noda et al [35] . and Sugai et al [36] . in 2018 (Figure 1 C).…”