Facile, Efficient, and Enantiospecific Syntheses of 1,1‘-N-Linked Pseudodisaccharides as a New Class of Glycosidase Inhibitors

Abstract

This article describes an efficient synthesis of a potent trehalase inhibitor, 1,1'-N-linked pseudodisaccharide 1 (consisting of two valienamines), in 14 steps with an overall yield of 12% and a first synthesis of 2 (consisting of two 2-epi-valienamines) in 15 steps with an overall yield of 24% from (-)-quinic acid. The synthesis involves a stereospecific palladium-catalyzed coupling reaction between an allylic amine and an allylic chloride as the crucial step. The acetonide blocking groups were shown to be the best hydroxyl protecting groups, compatible with the palladium-catalyzed allylic amination reaction that afforded high yields of the 1,1'-N-linked pseudodisaccharides with a minimum amount of an elimination diene side product.

Genetically engineered production of 1,1′-bis-valienamine and validienamycin in Streptomyces hygroscopicus and their conversion to valienamine

“…Subsequently, 3 was converted to its peracetate derivative and its optical rotation was measured. The [α] D value of the product is +107.3, which is consistent with that reported by Ogawa ([α] D +109) (Ogawa et al 1993) and somewhat similar to that reported by Shing ([α] D +92) (Shing et al 2004). …”

“…1,1′-bis-Valienamine ( 3 ) was previously reported as a synthetic compound, derived from (−)-quinic acid in 14 steps, and shown to be a potent trehalase inhibitor (Shing et al 2004). The fact that 3 can now be produced by fermentation is noteworthy, as it can be used as an alternative source of valienamine.…”

“…(Shing et al 2004) [α] D 20 +47.1 ( c = 1.0 in MeOH)}*; IR (thin film): n =3349, 2920, 1656, 1408, 1310, 1097, 1012 cm −1 . 1 H NMR (300 MHz, D 2 O, 23 °C, DSS): δ=3.56 (dd, J = 4.7, 4.8 Hz, 2H; H-1 and H-1′), 3.66 (dd, J = 4.7, 10.0 Hz, 2H; H-2 and H-2′), 3.73 (dd, J = 6.5, 10.0 Hz, 2H; H-3 and H-3′), 4.07 (d, J = 6.5 Hz, 2H; H-4 and H-4′), 4.12 (d, J = 13.9 Hz, 2H; H-7a and H-7′a), 4.24 (d, J = 13.9 Hz, 2H; H-7b and H-7′b), 5.95 (brd, J = 4.8 Hz, 2H; H-6 and H-6′).…”

“…ESI(+)-MS: m/z : 334.13 [M+H] + ; HRMS (ESI+): m/z : 356.1341 (calcd for C 14 H 23 NO 8 Na: 356.1321). *To address the discrepancy between our [α]D value with the reported value (Shing et al 2004), the experiments were repeated three times in two different polarimeters. However, our [α] D reading was consistently measured around +144 in all of the experiments.…”

Amine-linked diglycosides: Synthesis facilitated by the enhanced reactivity of allylic electrophiles, and glycosidase inhibition assays

“…After the coupling reaction, dihydroxylation of the C=C double bond would restore the carbohydrate structure (Scheme 1) [17]. As well as Mitsunobu chemistry [18], the allylic nature of the electrophile opens up the way for transition-metal-catalysed allylic amination reactions [19–21] as a possible coupling method. We report our investigations into this area in this paper.…”