Mendeleev Communications Electronic Version, Issue 1, 2000 (pp. 1–42) Regioselective monophosphorylation of glycols containing primary and secondary hydroxyl groups Edward E. Nifantiev,*a Mikhail K. Gratcheva and Stephen F. Martinb a Department of Chemistry, Moscow State Pedagogical University, 119882 Moscow, Russian Federation. Fax: +7 095 248 0162; e-mail: chemdept@mtu-net.ru b Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, Texas 78712-1167, USA.Fax: +1 512 471 4180; e-mail: sfmartin@mail.utexas.edu DOI: 10.1070/MC2000v010n01ABEH001212 A new approach to the synthesis of monophosphorylated glycols with the use of PIII-benzimidazolide has been suggested. Regioselective phosphorylation of polyhydroxyl systems is an urgent problem of fine organic synthesis.Definite progress towards this direction was achieved using the preferable interaction of primary hydroxyl groups of polyols with sterically hindered amines, which are activators of the nucleophilicity of hydroxyl groups.1 For solving this problem, we suggest another way based upon the use of commonly available and highly reactive amides of trivalent phosphorus acids (ATPA) as phosphorylating agents.2 Note that in contrast to chlorophosphites and other widespread phosphorylating agents they can be dramatically different from each other in the spatial organization of a leaving (amine) group.This difference can be important in selecting reagents for the regioselective phosphorylation of nucleophiles having several reactive centres.Glycols with primary and secondary hydroxyl groups can serve as an example. ATPA with small amido groups do not exhibit selectivity with respect to such glycols. However, ATPA with bulky amido groups, which are responsible for steric hindrances during an attack on secondary hydroxyl groups, can provide high selectivity for the phosphorylation of only primary hydroxyl groups. In this connection, we decided on phospho(III)benzimidazolides3 in order to examine the regioselective monophosphorylation of glycols with primary and secondary hydroxyl groups. 1,3-Butylene glycol 1 was taken as a model substrate for the phosphorylation; diethylamide 2 and benzimidazolide 3 of neopentylenephosphorous acid served as phosphorylating agents. We found that the interaction of equimolecular quantities of 1 and 2 resulted in a mixture of two regioisomers 4 and 5, which exhibit dramatically different 31P NMR spectra (122 and 128 ppm, respectively, the integral ratio 1:1).† At the same time, according to 31P NMR data, the interaction of equimolecular quantities of 1 and 3 leads to only one product 4 (Scheme 1).In both cases, the complete disappearance of signals of phosphorylating reagents 2 and 3 (147 and 114 ppm, respectively) in the 31P NMR spectra of reaction mixtures was observed.Monophosphorylation product 4 was treated with sulfur to form thiophosphate 6, which was isolated in the individual form.‡ Note that diphosphite 7 was formed by the phosphorylation of glycol 1 by two moles of ATPA. The 31P NMR spectrum of the reaction mixture exhibited a signal at 128 ppm, which was previously observed in the phosphorylation of glycol 1 by amide † Dioxane, c 1 mol dm–3, 100 °C, 3 h.‡ An equimolar quantity of sulfur was added to the reaction mixture, and the contents were stirred at 20 °C for 12 h. Thiophosphate 6 was isolated by flash chromatography on silica gel with the eluent CHCl3– MeOH (7:1), Rf 0.5. Yield 70%, pale yellow viscous oil. 1H NMR (250 MHz, CDCl3, TMS as an internal standard) d: 0.88 (s, 3H, Mee cyclo), 1.13 (s, 3H, Mea cyclo), 1.17 (d, 3H, MeCH, 3JHCCH 6.4 Hz), 1.62–1.88 (m, 2H, CCH2C), 2.34 (br. s, 1H, OH), 3.80–4.03 (m, 6H, CH2Oacyclo, 3JHCOP 9.0 Hz; CH2Ocyclo, 3JHCOP 8.5 Hz), 4.08–4.35 (m, 1H, CH). 13C NMR (50.32 MHz, CDCl3, TMS as an internal standard) d: 20.97 (MeCH), 21.5 (Mee cyclo), 23.44 (Mea cyclo), 32.17 (MeCMe, 3JCCOP 6.6 Hz), 39.00 (CH2CH2CH, 3JCCOP 6.9 Hz), 63.97 (CH), 65.35 (CH2CCH2, 2JCOP 5.5 Hz), 77.61 (CH2CH2O, 2JCOP 5.6 Hz). 31P NMR (32.4 MHz, CDCl3, 85% H3PO4 as an external standard) d: 64. The elemental analysis data are consistent with the theoretical values. 2. Thus, we found that reagent 3 is capable of the regioselective phosphorylation of a primary hydroxyl group in the presence of secondary hydroxyl groups.An additional confirmation for the location of a phosphoruscontaining residue in compound 6 was obtained by an analysis of 1H and 13C NMR spectra measured under conditions of homoand heteronuclear double NMR. Thus, for example, spin–spin coupling constants (SSCC) of oxymethylene protons of 1,3-butylene glycol residue with phosphorus were present in the 1HNMR spectra, and SSCC of methine proton with phosphorus were absent.Analogously, SSCC of oxymethylene carbon with phosphorus were present in 13C NMR spectra and SSCC of methine carbon with phosphorus were absent.‡ We used the found regioselectivity for the directed phosphorylation of natural ceramide 8,§ which is of importance for lipidology.We found that ceramide 8 was regioselectively mono- § We used commercial ceramide 8 (Sigma), which had the following 1H NMR spectrum (250 MHz, CDCl3, TMS as an internal standard) d: 0.81 (t, 6H, Me1, 3JHCCH 7.2 Hz), 1.09–1.27 (m, 58H, CH2 2 ), 1.42–1.60 (m, 4H, CH2 3 ), 1.91–2.05 (m, 2H, CH2 4), 2.16 (t, 2H, CH2 8, 3JHCCH 7.1 Hz), 2.56 (br. s, 1H, CH2OH), 3.58–3.68 (m, 2H, CH2OH), 3.76–3.90 (m, 3H, CH2 5, NCH), 4.25 (br.s, 1H, HCOH), 5.25–5.30 (m, 1H, CH6), 5.39–5.51 (m, 1H, HCOH), 5.64–5.78 (m, 1H, CH7), 6.17 (d, 1H, NH, 3JHNCH 6.8 Hz). OH OH O O Et2NP 1:1 O O OP OH O O OP OH N N P O O 1 + 4 1:1 S O O OP OH S 1 + 2 1 2 4 5 O O P P O O O O 1:2 3 6 7 Scheme 1Mendeleev Communications Electronic Version, Issue 1, 2000 (pp. 1–42) phosphorylated by an equimolar quantity of phosphoamide 3 by analogy with the above reaction (Scheme 2).Phosphite 9 was treated in the reaction mixture by sulfur with the formation of thiophosphate 10, which was isolated in the individual form.¶ Its identity and structure were determined with using the above methodology. The synthesis of cyclothiophosphate 10 is not only principally important, but also synthetically useful since it opens the way for preparing various analogues of phosphosphingolipids (sphingomyelins).4 Thus, the traditional use of ATPA can find new applications, for example, to the regioselective phosphorylation of complex natural compounds containing different proton-donor groups. This work was supported by the International Science Foundation (ISF) and the U.S.Civilian Research and Development Foundation (CRDF) (grant no. RC1-177). References 1 K. Ishihara, H. Kurihara and H. Yamamoto, J. Org. Chem., 1993, 58, 3791. 2 E. E. Nifantiev and M. K. Gratchev, Usp. Khim., 1994, 63, 602 (Russ. Chem. Rev., 1994, 63, 575). 3 V. Yu. Iorish, M. K. Gratchev, A. R. Bekker and E. E. Nifantiev, Zh. Obshch. Khim., 1993, 63, 783 (Russ.J. Gen. Chem., 1993, 63, 551). 4 D. A. Predvoditelev and E. E. Nifantiev, Zh. Org. Khim., 1995, 31, 1761 (Russ. J. Org. Chem., 1995, 31, 1559). ¶ Phosphorylation conditions: dioxane–CH2Cl2 (4:1), c 0.1 mol dm–3, 45 °C, 12 h. 31P NMR of compound 9 (in the reaction mixture) d: 122. An equimolar quantity of sulfur was added to the reaction mixture at 45 °C for 12 h. Cyclothiophosphate 10 was isolated and purified by double flash chromatography on silica gel with the eluent CHCl3–MeOH (7:1), Rf 0.5; next, with the eluent C6H6–dioxane (3:1), Rf 0.6.Yield of compound 10 50%, pale yellow amorphous solid, mp 95–96 °C. 1H NMR (250 MHz, CDCl3, TMS as an internal standard) d: 0.84–0.92 (m, 9H, Me1, Mee cyclo), 1.16–1.36 (m, 61H, CH2 2, Mea cyclo), 1.56–1.70 (m, 4H, CH2 3), 1.95–2.09 (m, 2H, CH2 4), 2.22 (t, 2H, CH2 8, 3JHCCH 7.2 Hz), 3.67– 3.73 (m, 2H, CH2OP), 3.74–4.10 (m, 7H, CH2 5, NCH, CH2Ocyclo), 4.31 (br. s, 1H, HCOH), 5.33–5.37 (m, 1H, CH6), 5.46–5.58 (m, 1H, HCOH), 5.72–5.86 (m, 1H, CH7), 6.23 (d, 1H, NH, 3JHNCH 6.8 Hz). 31P NMR (32.4 MHz, CDCl3, 85% H3PO4 as an external standard) d: 63. The elemental analysis data are consistent with the theoretical values. CHOH CH CH CH2OH Me(CH2)9CH2CH2CH2C H NH Me(CH2)20CH2CH2C O 1 2 3 4 5 6 7 8 1 2 3 8 + 3 9 S CHOH CH CH H2C Me(CH2)9CH2CH2CH2C H NH Me(CH2)20CH2CH2C O 1 2 3 4 5 6 7 8 1 2 3 10 OP O O S Scheme 2 CHOH CH CH H2C Me(CH2)9CH2CH2CH2C H NH Me(CH2)20CH2CH2C O OP O O Received: 13th October 1999; Com. 99/1540