Large-Scale Synthesis of All Stereoisomers of a 2,3-Unsaturated C-Glycoside Scaffold

Abstract

All stereoisomers of a highly functionalized 2,3-unsaturated C-glycoside can be accessed in 10-100 g quantities from readily available starting materials and reagents in 3-7 steps. These chiral scaffolds contain three stereogenic centers along with orthogonally protected functional groups for downstream reactivity.Due to their synthetic versatility and high level of stereochemical diversity carbohydrates have served as useful starting points for generating molecular diversity. 1 Carbohydratederived glycals in particular have been employed in multiple diversity-oriented synthesis (DOS) pathways. 2 Of interest to us was the utility of C-alkyl pseudoglycals for developing new build/couple/pair pathways in the context of library development. 3 In the present study, we focused on the synthesis of 2,3-unsaturated C-glycosides 1-4 ( Figure 1) which incorporate four chemical handles: (1) an ester, (2) an alkene, (3) a primary alcohol and (4) a secondary alcohol/primary amine, thereby, providing a range of options for subsequent modifications and/or functional group pairing reactions. 4 As part of our design strategy we sought to develop methods for the preparation of all eight stereoisomers of the C-glycoside template to enable the development of stereo/structure-activity relationships. 3b,5 Herein we describe the preparation of C-glycosides 1-4 on large (>50 g) scale.In order to introduce the ester functionality at C-1 we explored a type I Ferrier rearrangement 6 of tri-O-acetyl-D-and L-glucal to access C-glycosides 1-4. We elected to focus solely on optimizing the large-scale Ferrier reaction for the glucal series with the intention of accessing the galactal-derived material (2) via Mitsunobu inversion of the C-4 allylic alcohol. 7,8 Since we discovered that the α-and β-glycosides could be easily separated by silica gel chromatography and we required access to equal quantities of both anomers, we elected to develop reaction conditions that would achieve a closer to 1:1 α/β ratio.As shown in Table 1, we evaluated the Ferrier reaction of tri-O-acetyl-D-glucal with 5 under a range of conditions, mainly focused on varying the nature of the Lewis acid and solvent. Use of BF 3 ·Et 2 O as the Lewis acid in CH 2 Cl 2 led to the formation of C-glycoside 6 in 45% yield as a 1:2 mixture of anomers favoring the β-anomer (entry 1). Changing the Lewis acid to TMSOTf led to a higher isolated yield (73%) and a more favorable ratio of anomers 1:1.5 (entry 2). Using TMSOTf we next investigated the effect of solvent on reaction selectivity. When employing CH 3 CN as a solvent the formation of the α-anomer was slightly favored (α/β ratio = 1.5:1) and a lower yield was obtained (65%, entry 3). The yield of the glycosidation reaction could be improved to 77% on large scale (200 g), using CH 2 Cl 2 as a co-solvent (entries 4 and 5), providing a 1.2:1 mixture of anomers. The α/β isomers could be easily separated by silica gel chromatography to provide 42% of the α-anomer (α-D-6) and 35% of the β-anomer (β-D-6). 14 Deacetylation an...

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“…This ratio is identical to that reported in a related C-glycolsylation reaction of this type. 47 We found that cis - and trans - isomers of 12a and 12b were readily separated by flash chromatography to give the stereochemically pure products. The relative stereochemistry of both isomers was established by NOESY experiments and by single crystal X-ray structures of 4-nitrophenyl ester derivatives (see Figure 3 and SI).…”

“…We therefore pursued the alternative route to these intermediates that installed the desired stereochemistry and ester moiety in one step via a Ferrier-type rearrangement using a silylketene acetal. 45–47 The stereochemical outcome of this reaction has previously been shown to be highly dependent on the conditions employed. 49 We developed conditions for this transformation that provided a 2:1 mixture of cis - and trans -fused substituted dihydropyrans 12a (in 72% yield) and 12b (in 70% yield).…”

Fragment-based domain shuffling approach for the synthesis of pyran-based macrocycles

“…The synthesis of pyran fragments 1 and 2 initiated with C-glycoside 6 (Scheme 1), which itself was derived from tri-O-acetyl D-and L-glycals according to methods previously developed in our laboratory (31). Methylation of 6 with Meerwein's reagent in the presence of Proton Sponge gave rise to the corresponding methyl ether in 69-94% yield, which in turn was hydrogenated under standard conditions (Pd/C, MeOH, H 2 ) to afford pyrans 7 in 94-100% yield.…”

The carbon-Ferrier rearrangement: an approach towards the synthesis of C-glycosides

“…Marcaurelle et al 44 investigated the reaction of glucal 1 with ketene acetal 112 under various conditions, and found the reaction to be best carried out in the presence of TMSOTf in dichloromethane, yielding 73% of a 1:1.5 mixture of 108, favouring the β-anomer (Scheme 51).…”