Unusual Dimethyl Ketal from Cycloadduct of 4,6-O-Benzylidene-D-allal and Dichloroketene

Abstract

Glycal derivatives are useful building blocks in organic synthesis as well as in carbohydrate chemistry. Cycloadditions of dichloroketene to tri-O-benzyl or tri-O-acetylD-glucal and D-galactal were reported to produce α-oriented cyclobutanone ring, and the resulting bicyclic cyclobutanones were converted into lactone compounds by oxidation. Although they showed high stereo and regioselectivity with moderate yield, this methodology has not been widely applied for synthetic purpose. For the last few years, we have studied the cycloaddition of ketene to glucal, galactal, and allal derivatives and their application for the synthesis of C-glycoside derivatives and modified nucleosides. Even though, in case of allal, β-oriented cyclobutane ring formation is reported, no direct evidence supporting the face selectivity of dichloroketene cycloaddition to allal derivatives has been reported yet. Thus herein we report the X-ray structure of an unusual ketal from allal-derivative as the evidence that the facial selectivity of cycloaddition to glycal is controlled by the stereochemistry of C-3 constituent and discuss the mechanism for the formation of the unsual dimethyl ketal. To substantiate the evidence for facial selectivity, glucal and allal derivatives (1 and 3, respectively) were subject to dichloroketene cycloaddition reaction and treated with sodium methoxide in methanol. As expected, 3-O-benzyl4,6-O-benzilidene-D-glucal (1) was converted to C-1 and C-2 dialkylated C-glycoside, 3-O-benzyl-4,6-O-benzylidene1-dichloromethyl-2-methoxycarbonyl-1,2-dideoxy-α-D-glucopyranoside (2) in 73% yield. To our surprise, 3-O-benzyl4,6-O-benzylidene-D-allal (3) provided two products, O-benzyl-4,6-O-benzylidene-1-dichloromethyl-2-methoxycarbonyl-1,2-dideoxy-β-D-altropyranoside (4a) and dimethyl ketal (5a), in 36% and 29% isolated yield from allal (3), respectively (Scheme 1). The stereochemistry of C2 of 2 was determined by coupling constant between H2 and H3 (9.3 Hz, 1,2-diaxial orientation) and the previous results from glucal and galactal. Although C-glycoside from allalderivative has not been reported in the literature, methoxy carbonyl group on C2 of 4a was determined to orient axially based on coupling constant between H2 and H3 (3 Hz, 1,2diequatorial). This assignment of stereochemistry of C2 was confirmed by X-ray structure of 5a. In solid state the ketal (5a) has chair conformation of benzlylidene unit, twisted chair conformation of six membered sugar ring, and axial orientation of C3 benzyloxy substituent. Besides, more importantly, cyclobutanone is located on β-face of sugar ring, showed in Figure 1. This stereochemistry is attributed to the steric hindrance of bulky group on C3, which prevented dichloroketene from reacting on the α-face of allal effectively. To the best of our knowledge, the x-ray structure of allal-derived cycloaddition products has not been disclosed yet. Accordingly, we can