Improved Stereoselective Syntheses of (+)‐Valiolamine and (+)‐Valienamine Starting from (–)‐Shikimic Acid

Abstract

Improved stereoselective syntheses of the target compounds (＋)-valiolamine 1 and (＋)-valienamine 2 starting from naturally abundant (-)-shikimic acid are described. A common key intermediate compound 7 was first synthesized from (-)-shikimic acid in 9 steps. The compound 7 was then converted to (＋)-valiolamine 1 in 3 steps, and was also converted to (＋)-valienamine 2 in 4 steps. In summary, (＋)-valiolamine 1 and (＋)-valienamine 2 were synthesized from (-)-shikimic acid in 12 (or 13) steps in 40% and 39% overall yields, respectively. The present syntheses are more practical and might be important for the potential industrial preparations of pharmaceutically valuable (＋)-valiolamine 1 and (＋)-valienamine 2.

Production and Synthetic Modifications of Shikimic Acid

“…Some of the potential of shikimic acid as an element of the chiral pool has been exploited in the total synthesis of many natural products, stretching from simpler C 7 N aminocyclitols − to more challenging esperamicin-A 1 , , even though the total synthesis of this natural antitumoral agent remains unforeseen. The comprehensive works of Usami and co-workers , on the synthesis of several cytotoxic pericosines from shikimic acid stand as examples of successful uses of this natural product in total synthesis.…”

“…C 7 N aminocyclitols such as (+)-valiolamine and (+)-valienamine are known to be strong inhibitors of glucosidases and structural components of several active pharmaceutical ingredients. Their total syntheses from shikimic acid have been reported by Shi and co-workers as well as the synthesis of (−)-1- epi -valiolamine. − The seminal 12-step synthesis of (+)-valiolamine from shikimic acid was refined by the same group in order to improve its practicality regarding the reactants. This resulted in an increase of the overall yield from 35 to 40% with the same number of steps.…”

“…Their total syntheses from shikimic acid have been reported by Shi and co-workers as well as the synthesis of (−)-1epi-valiolamine. 365−367 The seminal 12-step synthesis of (+)-valiolamine from shikimic acid 367 was refined by the same group 365 in order to improve its practicality regarding the reactants. This resulted in an increase of the overall yield from 35 to 40% with the same number of steps.…”

Stereodivergent Syntheses of All Stereoisomers of (−)‐Shikimic Acid: Development of a Chiral Pool for the Diverse Polyhydroxy‐cyclohexenoid (or ‐cyclohexanoid) Bioactive Molecules

“…(−)‐SA 1 is very useful material for syntheses of drugs and pharmaceutically valuable natural products. For examples, it has been extensively used in the syntheses of oseltamivir phosphate (Tamiflu), [7] valiolamine, [8] valienamine, [8a,9] NOV, [10] NOEV, [10] pericosines (A, B, D and E), [11] zeylenones, [12] (−)‐MK7607, [13] previtamin D 3 , [14] quercitols, [15] and (−)‐quinic acid [16] . (−)‐SA 1 and its derivatives might also be very important in drug discovery, since they have shown a wide range of physiological activities [17] such as antiviral, anti‐bacterial, anti‐fungi, anti‐osteoclastogenesis, anti‐platelet, anti‐thrombogenic, anti‐inflammatory, anti‐oxidant, and anti‐tumor activities.…”

Novel stereoselective syntheses of N-octyl-β-valienamine (NOV) and N-octyl-4-epi-β-valienamine (NOEV) from (−)-shikimic acid

“…Recently, we have been engaged in developing novel stereoselective syntheses of various pharmaceutically valuable molecules from (−)-shikimic acid. 20 To continue our research programs, we have just studied highly stereoselective, efficient and practical syntheses of NOV 1 and NOEV 2 by using (−)-shikimic acid as the starting material, and herein we want to report the details of these syntheses.…”