Enantioselective de Novo Synthesis of 4-Deoxy-d-hexopyranoses via Hetero-Diels–Alder Cycloadditions: Total Synthesis of Ezoaminuroic Acid and Neosidomycin

Abstract

The de novo synthesis of carbohydrates constitutes an important aspect of organic chemistry, and its application toward deoxy sugars is particularly noteworthy in targeting biologically active compounds. The enantioselective preparation of 4-deoxy-D-ribo-, 4-deoxy-D-lyxo-, and 4-deoxy-D-xylo-hexopyranosides, along with their uronate counterparts has been successfully accomplished using hetero-Diels-Alder reactions as the key step. Jacobsen chromium(III) catalyst and a titanium-binaphthol complex have been used to successfully catalyze diene and aldehyde cycloadditions, leading to optically active dihydropyran templates. 6-Hydroxydesosamine, orthogonally protected ezoaminuroic acid, and neosidomycin were synthesized using a comparative study. Also, a novel chiron approach to 4-deoxy-lyxo-hexopyranosiduronic acid methyl ester derivatives was efficiently accomplished starting from readily accessible starting materials. This work represents a systematic and comprehensive study toward a de novo synthesis of 4-deoxy-hexopyranoses via enantioselective hetero-Diels-Alder reactions.

De Novo Synthesis of Mono‐ and Oligosaccharides via Dihydropyran Intermediates

“…Roy et al used Jacobsen's chromium(III) catalyst( Scheme 16) and at itanium-binaphthol complex (Scheme17) to control the stereochemistry of dihydropyran products (95-99% ee,9 5-99 %de) derived from HDA cycloadditions. [42] 4-Deoxy-d-ribo-, 4-deoxy-d-lyxo-, and 4-deoxy-d-xylohexopyranosidesc ould be easily synthesized in af ew steps from the HDAc ycloaddition product. De novo synthesis of protected ezoaminuroica cid and neosidomycin was also accomplished by using this strategy (Scheme17).…”

“…De novo synthesis of protected ezoaminuroica cid and neosidomycin was also accomplished by using this strategy (Scheme17). [42] Inverse-electron-demand HDA cycloadditions have also been appliedt ot he synthesis of monosaccharides via dihydropyran intermediates. In 1988, Boger and Robarge reported the de novo synthesis of racemic mannopyranosides throughah ighly endo-selective inverse-electron-demand HDA cycloaddition from b,g-unsaturated a-keto esters.…”

“…Roy et al. used Jacobsen's chromium(III) catalyst (Scheme ) and a titanium–binaphthol complex (Scheme ) to control the stereochemistry of dihydropyran products (95–99 % ee , 95–99 % de) derived from HDA cycloadditions . 4‐Deoxy‐ d ‐ribo‐, 4‐deoxy‐ d ‐lyxo‐, and 4‐deoxy‐ d ‐xylohexopyranosides could be easily synthesized in a few steps from the HDA cycloaddition product.…”

“…4‐Deoxy‐ d ‐ribo‐, 4‐deoxy‐ d ‐lyxo‐, and 4‐deoxy‐ d ‐xylohexopyranosides could be easily synthesized in a few steps from the HDA cycloaddition product. De novo synthesis of protected ezoaminuroic acid and neosidomycin was also accomplished by using this strategy (Scheme ) …”

Recent applications of the hetero Diels–Alder reaction in the total synthesis of natural products

“…The compound 305 gave neosidomycin 302 aer 3 reaction steps. 312 The rst total synthesis of (+)-keto-deoxyoctulosonate (308, (+)-KDO) is relied on the HDA reaction of a-selenoaldehyde 309 to the a-furylsubstituted diene 310. 313 The reaction provides an adduct mixture which upon treatment with CF 3 COOH gives a 5 : 1 mixture of cis/trans dihydropyrones 311 and 312.…”