Improved Synthesis Strategy for N-Methoxy-1,3-oxazinane Nucleic Acids (MOANAs)

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

Automated summary

The dependence of the hydrolysis rate of a series of N-methoxy-2-phenyl-1,3-oxazinanes on the Hammett substituent constant of the substituent of the phenyl ring was determined. Based on this information, 4-(benzoyloxy)benzaldehyde was selected as a protecting group for a new (2R,3S)-4-(methoxyamino)butane-1,2,3-triol phosphoramidite building block. The yield of the preparation of this building block as well as its coupling in automated oligonucleotide synthesis were greatly improved compared to the method reported previously.