Univocal syntheses of 2- and 3-hydroxymethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridine enantiomers

The enantiomers of 2- and 3-hydroxymethyl substituted 2,3-dihydro[1,4]dioxino[2,3-b]pyridine 1 and 2, important chiral building blocks for the preparation of several biologically active compounds, were synthesized. (S)- and (R)-1 were obtained from either one or both the enantiomers of benzylglycerol, while (S)- and (R)-2 were obtained from (R)- and (S)-isopropylideneglycerol, respectively. The novel efficient synthetic strategies, which do not follow routes already reported for the corresponding racemates, ensure very high regioselectivity and maintenance of the enantiomeric purity of the starting materials. The enantiomeric composition of the title compounds was determined by chiral HPLC or NMR. The key intermediate in the synthesis of non-racemic 1, namely 1-benzyl-2-mesyl-3-tritylglycerol, is a new high melting chiral C3 synthon, worth considering for its stability, versatility, easy isolation by simple crystallization and, potential of configuration inversion through a simple one-pot reaction sequence.

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(R)-2-Hydroxymethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridineC8H9NO3Ee = 99.3% [by chiral HPLC][α]D25=+32.6 (c 0.5, EtOH)Source of chirality: (R)-1-benzylglycerolAbsolute configuration: R

(R)-3-Hydroxymethyl-2,3-dihydro[1,4]dioxino[2,3-b]pyridineC8H9NO3Ee >98% [by 1H NMR in the presence of a chiral solvating agent][α]D25=+28.1 (c 0.5, EtOH)Source of chirality: (R)-1-tosyl-2,3-isopropylideneglycerolAbsolute configuration: R

(S)-1-Benzyl-2-mesyl-3-tritylglycerolC30H30O5S[α]D25=-8.8 (c 1, CHCl3)Source of chirality: (R)-1-benzylglycerolAbsolute configuration: S