Gold(III) Chloride Catalyzed Synthesis of Chiral Substituted 3‐Formyl Furans from Carbohydrates: Application in the Synthesis of 1,5‐Dicarbonyl Derivatives and Furo[3,2‐c]pyridine

Abstract

This report describes a gold(III)-catalyzed efficient general route to densely substituted chiral 3-formyl furans under extremely mild conditions from suitably protected 5-(1-alkynyl)-2,3-dihydropyran-4-one using H2 O as a nucleophile. The reaction proceeds through the initial formation of an activated alkyne-gold(III) complex intermediate, followed by either a domino nucleophilic attack/anti-endo-dig cyclization, or the formation of a cyclic oxonium ion with subsequent attack by H2 O. To confirm the proposed mechanistic pathway, we employed MeOH as a nucleophile instead of H2 O to result in a substituted furo[3,2-c]pyran derivative, as anticipated. The similar furo[3,2-c]pyran skeleton with a hybrid carbohydrate-furan derivative has also been achieved through pyridinium dichromate (PDC) oxidation of a substituted chiral 3-formyl furan. The corresponding protected 5-(1-alkynyl)-2,3-dihydropyran-4-one can be synthesized from the monosaccharides (both hexoses and pentose) following oxidation, iodination, and Sonogashira coupling sequences. Furthermore, to demonstrate the potentiality of chiral 3-formyl furan derivatives, a TiBr4 -catalyzed reaction of these derivatives has been shown to offer efficient access to 1,5-dicarbonyl compounds, which on treatment with NH4 OAc in slightly acidic conditions afforded substituted furo[3,2-c]pyridine.

Chiral Substituted 3‐Formylfurans from Carbohydrates: An Expedient Route via N‐Bromosuccinimide (NBS)‐Mediated Electrophilic Cyclization

“…To validate this idea (Scheme ), substituted 2‐iodoenones 1 were synthesized from the appropriately functionalized, readily available, and inexpensive monosaccharides or commercially available glycals ( d ‐glucose, d ‐galactose, l ‐fucose, l ‐rhamnose, and d ‐xylose) in a few steps according to the known literature procedures –. The 2‐alkenylated sugars were prepared by Pd‐catalyzed Heck coupling of 1 – with activated or unactivated terminal olefins .…”

“…In this case, product 3 ja was also isolated in 11 % yield as an inseparable mixture of α and β anomers in a 6:1 ratio, resulting from the conjugate addition of 3 j to 2 j via cyclic bromonium ion formation (see Scheme below). The major diastereomer was assigned as the α anomer by comparison of NMR data with known furo[3,2‐ c ]pyran derivatives . To determine the compatibility of a nitro‐substituted aromatic group with the reaction conditions, 2 n was examined.…”

“…This indeed afforded Heck‐coupled products ( cis and trans mixture) which were subjected to NBS/H 2 O‐mediated cyclization to afford the fully substituted chiral 3‐formylfuran 3 v in 30 % overall yield in two steps (Scheme ). It must be mentioned here that the synthesis of fully substituted chiral 3‐formylfuran by using this NBS/H 2 O/THF method provided a direct and strategic advantage over a gold(III) catalyst, as it might be relatively difficult to achieve by a gold‐catalyzed reaction.…”

“…However, no such oxidized products were isolated. Meanwhile, the structures of all compounds in Scheme were assigned by 2D NMR spectroscopy (see the Supporting Information) and comparison of NMR data with known derivatives …”

“…Recently, we have disclosed a gold(III)‐chloride‐catalyzed efficient route to substituted chiral 3‐formylfurans from suitably protected 5‐(1‐alkynyl)‐2,3‐dihydropyran‐4‐ones derived from carbohydrate scaffolds, utilizing H 2 O as a nucleophile . However, this method requires highly expensive and air‐sensitive gold catalysts, which limit its broad applicability.…”