Improved Synthesis Strategy for <i>N</i> ‐Methoxy‐1,3‐oxazinane Nucleic Acids (MOANAs)

Dependence of the hydrolysis rate a series N-methoxy-2-phenyl-1,3-oxazinanes on Hammett substituent constant phenyl ring was determined, yielding reaction ρ=−1.40±0.05. Based this information, 4-(benzoyloxy)benzaldehyde selected as protecting group for new (2R,3S)-4-(methoxyamino)butane-1,2,3-triol phosphoramidite building block. The yield preparation block well its coupling in automated oligonucleotide synthesis were greatly improved compared to method reported previously. 2-[4-(benzoyloxy)phenyl]-1,3-oxazine protection persisted throughout short oligonucleotides but rapidly removed when released from solid support and dissolved water.