An Investigation of the Reactions between Azido Alcohols and Phosphoramidites

Abstract

The reactions of several β-, γ-, and δ-azido alcohols with dibenzyl and dimethyl N,N-diisopropylphosphoramidites were examined. Detailed analysis of the intermediates and products formed from the reactions under different conditions provided useful information to gain insights into their mechanisms involving intramolecular Staudinger reaction, as well as the structure–reactivity relationships of both substrates. The reactions of γ- and δ-azido alcohols with dibenzyl N,N-diisopropylphosphoramidite could produce 6- and 7-membered cyclic phosphoramidates, thereby providing a new synthetic method for these biologically important molecules.

Key words

Staudinger reaction - azido alcohol - phosphoramidite - ­cyclic phosphoramidate - cyclization

• References and Notes


New addresses:
• 1a Wu J., Progenra, Inc., 277 Great Valley Parkway, Malvern, PA 19355 USA.
• 1b L. Bishop, Lawrence Hall of ­Science, University of California, Berkeley, CA 94720, USA.
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• 16 General Experimental Procedure for the Reactions Listed in Table 2 To the solution of an azido alcohol 5 or 7 (0.774 mmol in 8 mL of anhydrous toluene) were added 1.2 equiv of dibenzyl N,N-diisopropylphosphoramidite (4, 0.32 mL, 0.929 mmol) and then 1.2 equiv of tetrazole (1.98 mL 0.47 M solution in acetonitrile, 0.929 mmol). After the solution was heated at 80 °C with stirring for 2 h, it was diluted with dichloromethane, washed with 20 mL of 10% sodium bicarbonate solution and two 20 mL portions of brine water, dried with Na₂SO₄, and concentrated under vacuum. Silica gel column chromatography of the residue gave the desired product 13 or 14. 3-Benzyloxy-3-oxo-1,4,5-trihydrobenzo[7]-2,4,3-oxazaphosphepine (13) White solid, 60% yield. ¹H NMR (300 MHz, CDCl₃): δ = 7.48–7.12 (m, 9 H), 5.22–5.05 (m, 4 H), 4.27 (ddd, J = 17.2, 10.4, 8.0 Hz, 1 H), 3.92 (ddd, J = 28.3, 17.2, 5.6 Hz, 1 H), 3.48–3.36 (m, 1 H). FAB-HRMS: m/z calcd for C₁₅H₁₇NO₃P [M + H]⁺: 290.0946; found: 290.0931. 2-Benzyloxy-2-oxo-5,5-dimethyl-1,3,2-oxazaphosphinane (14) White solid, 45% yield. ¹H NMR (300 MHz, CDCl₃): δ = 7.45–7.33 (m, 5 H), 5.04 (d, J = 10.0 Hz, 2 H), 3.98 (dd, J = 2.8, 14.0 Hz, 1 H), 3.84 (dd, J = 2.2, 11.2 Hz, 0.5 H), 3.73 (dd, J = 2.5, 11.4 Hz, 0.5 H), 3.26–3.10 (m, 1 H), 3.00 (dd, J = 4.6, 15.2 Hz, 1 H), 2.84 (ddd, J = 3.0, 7.0, 12.7 Hz, 0.5 H), 2.70 (ddd, J = 2.78, 7.5, 12.5 Hz, 0.5 H), 1.22 (s, 3 H), 0.79 (s, 3 H). FAB-HRMS: m/z calcd for C₁₂H₁₉NO₃P [M + H⁺]: 256.1103; found 256.1105.
• 17 Or YS, Ma J, Wang G. WO 2013173759, 2013