J. Org. Chem. 1993,58, 7679-7684 7679 Phosphonomethylation of Cyclohexene Oxides Jean-Luc Montchamp, Marie E. Migaud, and John W. Frost. Department of Chemistry, Purdue University, West Lajayette, Indiana 47907 Received August 23, 19930 The tradeoff between synthetic directness and regioselectivity during oxirane ring opening is examined for two strategies used to phosphonomethylate cyclohexene oxide and substituted cyclohexene oxides derived from quinic acid and myo-inositol. Direct phosphonomethylation of the cyclohexene oxides utilizes diisopropyl lithiomethanephosphonate ((C3H70)2P(O)CH2Li)in combination with boron trifluoride. Another more indirect route to phosphonomethylation begins with reaction of the cyclohexene oxides with (1ithiomethyl)dimesitylborane (MeszBCHaLi). In both reactions, boron plays a key role as either a Lewis acid during opening of the oxirane (diisopropyl lithiomethane- phosphonate/boron trifluoride) or as a stabilizer of an adjacent carbanion in the attacking nucleophile [(lithiomethyl)dimesitylboranel. Regioselectivities for oxirane ring opening using diisopropyl lithiomethanephosphonate/boron trifluoride can be quite modest. By contrast, oxirane ring openings employing (1ithiomethyl)dimesitylborane are uniform in the high degree of regioselectivity which is achieved. Factors which might influence the observed regioselectivities during nucleophilic attack on the cyclohexene oxides are also discussed. During efforts to synthesizecarbaphosphonatesubstrate analogues for 3-dehydroquinate (DHQ) synthase, a one step phosphonomethylation procedure (step a, Scheme I) was developed.' Cyclohexene oxides derived from quinic acid (such as 2, Table I) were treated at -78 "C in tetrahydrofuran with an equimolar combination2 of di- isopropyl lithiomethanephosphonate and boron trifluoride etherak3 Ring opening proceeded with high regioselec- tivity and good overall yield. Phosphonomethyl products were ultimately converted into potent inhibitors of DHQ synthase.lt4 In route to synthesis of carbaphosphonate substrate analogues and reactive intermediate analogues for inhibition of myo-inositol phosphate synthase, phospho- nomethylation of a cyclohexene oxide (3, Table I) derived from myo-inositol was required. Reaction at -78 OC of the cyclohexene oxide derived from myo-inositol with a nearly stoichiometric concentration of the diisopropyl lithiomethanephosphonate and boron trifluoride combi- nation failed to afford any phosphonomethylated product. A survey of the literature to find a solution to this synthetic impasse failed to provide relevant alternatives. Since our initial report of direct phosphonomethylation of quinate- derived cyclohexene oxides,the only progress in extending the scope of the reaction had been in monosubstituted oxirane systems.6 This prompted a renewed examination of strategies relevant to phosphonomethylation of cyclo- hexene oxides. As a first step, parameters associated with reaction of the cyclohexene oxides with the diisopropyl lithio- methanephosphonate/ boron trifluoride combination were varied. The impact of reaction condition changes on both 0 Abstract published in Advance ACS Abstracts, November 15,1993. (1) (a) Montchamp, J.-L.; Piehler, L. T.; Frost, J. W. J. Am. Chem. SOC. 1992, 114, 4453. (b) Montchamp, J.-L.; Frost, J. W. J. Am. Chem. SOC. 1991,113,6296. (2) The complex of diisopropyl lithiomethanephosphonate and boron trifluoride etherate is also capableof openingoxetanee: Tanaka,H.;Fukui, M.; Haraguchi, K.; Masaki, M.; Miyasaka, T. Tetrahedron Lett. 1989,30, 2667. (3) For use of boron trifluoride in organolithiumreactions see: Eis, M. J.; Wrobel, J. E.; Ganem, B. J. Am. Chem. SOC. 1984, 106, 3693. (4) Montchamp, J.-L.;Piehler, L.T.;Tolbert,T. J.;Frost, J. W.BioMed. Chem. Lett. 1993, 3, 1403. (5) (a) Racha, S.; Li, Z.; El-Subbagh, H.; Abushanab, E. Tetrahedron Lett. 1992, 33, 6491. (b) Li, Z.; Racha, S.; Dan, L.; El-Subbagh, H.; Abushanab, E. J. Org. Chem. 1993,58, 6779. 0022-3263/93/1958-7679$04.00/0 R2 12, CH30Na,CH30H e X bH (i) H202, NaOH, THF dH (ii) TsCI, Pyr X - 1 or TsO (MW2 3 R l reactivity and regioselectivity were of particular interest. A less-direct route to phosphonomethylation was also examined (Scheme I) which employed initial reaction of the cyclohexene oxide with (lithiomethyl)dimesitylborane.6 Replacement of the dimesitylborane in the ring-opened intermediate with a suitable leaving group could be followed by Arbuzov' (steps c and d, Scheme I) or Michaelis-Becker7 methodology (steps e and f, Scheme I) to assemble the phosphonomethyl functionality. As with the diisopropyl lithiomethanephosphonate/boron triflu- oride combination, the reactivity of (1ithiomethyl)di- mesitylborane with cyclohexene oxide (1, Table I) and substituted cyclohexene oxides derived from quinic acid (2, Table I) and myo-inositol(3,Table I) was studied. The regioselectivities of oxirane ring openings were also es- tablished. (6) (a) Pelter, A.; Bugden, G.; Rower, R. Tetrahedron Lett. 1986,26, 5097. (b)Pelter, A.; Vaughan-Williams, G. F.; h er, R. M. Tetrahedron 1993,49, 3007. (7) (a) Bhattacharya,A. K.; Thyagarajan, G. Chem. Rev. 1981,81,415. (b) Kosolapoff, G. M. Org. React. 1981,6,273. (c) Arbuzov, B. A. Pure Appl. Chem. 1964,9,307. (d) Freedman, L. D.; Doak, G. 0. Chem. Rev. 1967,57,479. (e)Engel, R. Synthesis of Carbon-Phosphonur Bonds; CRC Press: Boca Raton, 1988. 0 1993 American Chemical Society