Chiral Carbocyclic Nucleosides from d-Glucose:  Enantiodivergent Synthesis and One-Pot Entry of Dimethylamino Functionality in the Purine Rings

Abstract

Cyclization of appropriately designed enose−nitrones derived from d-glucose, having nitrone at C-5 or C-1 and allylic/homoallylic functionalities at C-3 of the sugar backbone, afforded polyhydroxylated aminocarbocycles which were subsequently used as the precursors for carbocyclic nucleoside analogues (11, 13, 16, 21, and 23). The enantiodirecting synthesis of both the enantiomeric pairs of nucleoside analogues 11 and 13, 21a and 23a, and 21c and 23c, has also been demonstrated by judiciously applying intramolecular nitrone cycloaddition (INC) reaction. An interesting observation was that in the cyclization reaction of pyrimidine ring to purine ring in DMF solvent, the substitution of C-6 chloro group with a dimethylamino functionality also occurred spontaneously under mild condition, though similar reactions are reported to occur at higher temperature. The hydrogen bonding between N-3 of the purine ring and an appropriate hydroxy substituent in the carbocycle seems to play a crucial role in this reaction.

Stereo‐ and Regioselectivity in an Intramolecular Nitrone–Alkene Cycloaddition of Hept‐6‐enoses with a trans‐Acetonide Blocking Group

“…The results are summarized in Table 1. The INAC reactions of heptenoses 12,16, or 20 proceeded with excellent yields and cycloheptanes (endo product) 23, 25, or 27, respectively, were obtained as the major cycloadducts (entries [1][2][3]. As the size of the OR4 group increases from OH to OTBS, the endo selectivity increases from 86:14 (entry 1) to 92:8 (entry 3).…”

Sequential Ring-Closing Metathesis and Nitrone Cycloaddition on Glucose-Derived Substrates: A Divergent Approach to Analogues of Spiroannulated Carbanucleosides and Conformationally Locked Nucleosides

“…The chloronucleoside 26 on ammonolysis with a saturated solution of ammonia in methanol furnished 28 in good yield. The formation of 27 could be rationalized via nucleophilic displacement of the chloro group by dimethylamine generated in the reaction medium from DMF 5 …”

Allyloxy and Propargyloxy Group Migration: Role of Remote Group Participation in the Synthesis of 5-C-Nucleosides and Other Sugar Derivatives

“…It is interesting to note that the 6-chloro group was replaced by a dimethylamino functionality during this transformation. This can be attributed to the generation of dimethylamine from DMF under reflux conditions, as previously observed by us . The formation of 10 is due to formation of an allyloxonium ion intermediate (Figure ), generated through participation of the allyloxy group during the displacement of the substituent at C(2) of the sugar moiety; this then suffered subsequent attack by the purine base at C(5), leading to migration of the allyloxy group to the C(2) position.…”