MOP and EE Protecting Groups in Synthesis of α- or β-Naphthyl-C-Glycosides from Glycals

Abstract

The development of effective protection strategies is essential in the synthesis of complex carbohydrates and glycomimetics. This article describes a versatile four-stage protocol for the synthesis of α- or β-aryl- C -glycosides from unprotected d -glycals using two acetal protecting groups, ethoxyethyl and methoxypropyl, which are stable under harsh basic conditions and convenient for the C-1 metalation of glycals. Their stability was investigated in subsequent cross-coupling reactions with 1-iodonaphthalene followed by oxidative/reductive transformations to naphthyl- C -glycosides.

Facile Approach toC‐Glucosides by Using a Protecting‐Group‐Free Hiyama Cross‐Coupling Reaction: High‐Yielding Dapagliflozin Synthesis

“…The reaction of 2‐methoxypropene in the presence of pyridinium tosylate afforded MOP‐ d ‐glucal 2 in an excellent yield of 84 %. As we reported before, [9a] MOP acetal protecting groups represent an efficient strategy for transient protection of glycals. Their use is favourable for several reasons, such as their easy introduction and removal, compatibility with silyl groups, low cost, and stability under harsh basic conditions, which are required for C‐1 derivatization.…”

“…As we published before, [4,9a,15a] the protected unsaturated pseudo‐ C ‐glycosides are suitable substrates for further stereoselective transformations, which produced α‐ or β‐ C ‐glycosides and 2‐deoxy‐β‐ C ‐glycosides in high yields. As most of the naturally occurring aryl C ‐glycosides exist with β‐configuration at the pseudoanomeric centre, selected unprotected cross‐coupling products 5 a – d were directly converted to β‐ C ‐glucosides 7 a – d (Table 3.…”

“…For efficiency reasons, we aimed for a one‐pot sequence [9a] of hydroboration followed by oxidation with alkaline hydrogen peroxide. The resulting products 7 a – d were obtained in moderate yields (46–66 %) with only β‐selectivity.…”

“…Consequently, many successful strategies to provide a synthetic access to aryl C ‐glycosides in a direct or de novo manner have been already developed [1] . Notable strategies to construct these saccharide mimetics by transition‐metal‐mediated coupling reactions include Heck, [8] Stille, [9] Suzuki‐Miyaura, [4,9a,10] Negishi [10b,11] and Hiyama‐Denmark cross‐coupling reactions (Figure 1). [12] All of these methodologies were applied almost exclusively to O ‐protected (mostly benzylated and silylated) 1‐substituted glycals except for the Stille cross‐coupling reaction of aryl halides with glycosyl stannanes, described by Walczak et al [13] .…”

“…Therefore, a straightforward access to unprotected aryl C ‐glycosides in high yield is advantageous. In continuation of our interest in the synthesis of C ‐glycosides, [4,9a,15] we report access to diverse (hetero)aryl C ‐glycosides via a key Hiyama cross‐coupling reaction of 1‐diisopropylsilyl‐ d ‐glucal 4 with different (hetero)aryl halides under mild conditions. Herein, to the best of our knowledge, the most suitable and practical synthesis of dapagliflozin 8 n and its derivatives 7 n and 10 n is also described.…”