Lipase catalyzed regioselective lactamization as a key step in the synthesis of N-Boc (2R)-1,4-oxazepane-2-carboxylic acid

The synthesis of N-Boc (2R)-1,4-oxazepane-2-carboxylic acid was developed in 39% yield over seven steps starting from methyl (2R)-glycidate. The key step was a lipase-catalyzed regioselective lactamization performed using SpinChem® rotating bed reactor that simplified work up and recycling of the enzyme.

Abstract
“A synthesis of N-Boc (2R)-1,4-oxazepane-2-carboxylic acid 1 has been developed in 39% yield over seven steps starting from methyl (2R)-glycidate 2. The key step was a lipase-catalyzed regioselective lactamization of amino diester 5 into seven-membered lactam 6. The transformation was performed using SpinChem rotating flow cell technology which simplified the work up and the recycling of the enzyme. Subsequent N-Boc protection followed by chemoselective borane reduction of the lactam moiety afforded 4-tert-butyl 2-methyl (2R)-1,4-oxazepane-2,4-dicarboxylate 8. Finally, hydrolysis mediated by LiBr/Et3N in wet acetonitrile yielded the title compound (2R)-4-(tert-butoxycarbonyl)-1,4-oxazepane-2-carboxylic acid 1.”

Highlights:

• “After chromatography compound 6 was obtained in 61% yield. According to 1H NMR analyses, various polymeric byproducts accounted for the remaining 39%. Since stirring of the immobilized enzyme in standard batch mode generated fine particles causing blockage of the filter during workup, we decided to test a new rotating flow cell technology, SpinChem, which is a mechanical stirrer integrated with four compartments that can be charged with solids and resins (Figure 1).”
• “In fact the rotating flow cell is self-filtrating as any large particles will be sequestered in the rotating disc.”
• “We found this new technology very versatile, since no filtration of immobilized enzyme was necessary after completion of reaction and it was very convenient to reuse the enzyme already packed in the disc.”