Scalable Syntheses of Chirally Pure Mono-protected and Orthogonally Di-protected cis-3,4-Diaminotetrahydrofurans

Abstract

Scalable and chromatography-free syntheses of chirally pure and orthogonally protected cis-3,4-diaminotetrahydrofurans prepared from a single starting material, 3,4-epoxytetrahydrofuran, are presented.

Key words

chiral - linker - cis-diamino - TCI - orthogonal - protecting groups

• References


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• 5 90–95% conversion and ca. 48:52 desired vs. undesired trans diastereomers as determined by ¹H NMR spectroscopic analysis.
• 6 Optical purities of enantiomers 2 and 3 were determined by HPLC-UV analyses of their N-benzoyl derivatives. Similarly, the absolute configuration of 2 prepared from 11 was correlated to 2 prepared independently by following references 2c and 3.
• 7 Product isolated in the presence of 2-propanol was more crystalline and filtered better than the product crystallized directly from water.
• 8 Theory is 0.47 mole H₂; some debenzylation likely occurred during H₂ purging. No unreacted 11 was observed by ¹H NMR spectroscopic analysis.
• 9 Additional 5% yield of a pure second crop was recovered from the filtrate.
• 10 Analysis of extracts indicated some loss of 12 due to partial opening of the phthalimide ring by aqueous carbonate employed to wash out excess phthalimide. Although this degradation was minor, there was concern that losses would be higher at larger scale. In further improvements, the Mitsunobu reaction was run using 1.00–1.05 equiv of phthalimide at 40–50 °C to afford the same or higher conversions to 12. Elimination of the base wash afforded material that contained <6 wt% phthalimide, which was effectively removed by suspending crude 4 in toluene at 80 °C, then filtering.
• 11 Ethylenediamine was employed because it is a less hazardous reagent on scale than hydrazine hydrate. Five equivalents were employed in initial batches. In subsequent batches, 1.0–1.5 equiv of ethylenediamine were successfully employed with good reaction performance and minimal caking onto reactor surfaces.
• 12 Washes were employed to remove ethylenediamine. 1 N NaOH was chosen for these washes to enhance phase separations and minimize product loss in the aqueous phases.