Four Chiral Centers in a One Pot Procedure. Analogues of Isosorbide

Synthesis of analogues of isosorbide in one pot from 1-hydroxymethyl-4-phenylsulfonylbutadienes has been achieved. In the previous paper, we have described a simple way to obtain 1-sulfonyl-1,3-dienes with adequate functionalization. These compounds have been the object of numerous studies in the last years, above all as dienes or dienophiles.1 Furthermore, it should be noted that there are more examples with sulfoxides rather than sulfones due to the potential chirality that these substrates2 can possess. In our case, having developed a very easy way to get 1-sulfonyl-1,3dienes with an allylic alcohol, we wanted to exploit this feature to produce chiral compounds by way of the Sharpless enantioselective epoxidation.3 In this way, we planned to develop a short synthesis of analogues of isosorbide 1. Amino derivatives of 1 are being used as chiral auxiliaries4 in asymmetric synthesis while the dinitro derivative 2 and the piperazine derivative 3 possess antianginal activity5. 1, has been used recently as the starting material for the synthesis of novel bicyclic dideoxynucleosides as potential antiviral agents 4.6 All different routes to isosorbide analogues start from isosorbide 1 as the starting material. In this context, we have found a new and versatile method to obtain analogues with different stereochemistry and functionalization, which allows not only the use of SN2 type reactions but also the use electrophilic reagents. Results and discussion Compound 6 was easily obtained as described in the previous paper by treatment of sulfone 5 with n-BuLi/THF at -78° C (Scheme I). Treatment of 6 with n-BuLi/THF followed by addition of acetone as the electrophile gives compound 7 in excellent yields (90%). When 7 reacts with m-CPBA it afford compound 8 directly (77%). The second cyclization proved to be difficult, with bases such as NaH or KH giving inconsistant results. However, use of Craig s conditions7 (tBuOH/ tBuOK 5:1) gave satisfactory yields of 9 (83%). When 7 reacts under Sharpless conditions with L-(+)-DET, after the usual work up of the reaction only homochiral (-)-98 is isolated. The stereochemistry was established by study of N.M.R. spectra and n.O.e. studies. The CIS relationship between H-4 and H-5 (mechanism) was confirmed by the n.O.e observed (Scheme I) and the same relationship of H-5 and H-1 was established for the existence of another n.O.e. between them. The stereochemistry of H-8 was based on its coupling constant with H-1 ( J = 5.8 Hz ), the other stereochemistry would give a nearly zero coupling constant, (see ref 4). This was confirmed by the existence of n.O.e between H-1 and H-8 in the bencil derivative. So, in conclusion we have developed a short, and stereocontrolled way to obtain analogues of isosorbide. At the moment, we are trying to introduce further functionalization at C-8, and a range of electrophiles are being used in the addition step. Acknowledgement: This work was supported by Junta de Castilla y Leon (SA 44-96); M.E.C. and CICYT. References and Notes (1) a) Backwall, J.E.; Lofstrom, C.; Maffesal, M.; Lauger, V. Tetrahedron Lett. 1992, 33, 2417. b) Padwa, A.; Gareau, Y.; Harrison, B.; Norman, B.H. J. Org. Chem. 1991, 56, 2713. (2) a) Aversa, M. C.; Baratucci, A.; Bonaccorsi, P.; Gianneto, P. Tetrahedron Asymm. 1997, 9, 1339. b) Carreno, M. C. Chem. Rev. 1995, 95, 1717. (3) Gao, Y.; Hauson, R.M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.; Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765 (4) Tamion, R.; Marsais, F.; Ribereau, P.; Queguiner, G.; Abenhaim, D.; Loupy, A.; Munnier, L. Tetrahedron Asymm. 1993, 8, 1879. (5) Hayashi, H.; Keolo, J. I.; Kubo, K.; Mokiyama, J.; Karasama, A.; Suzuki, F. Chem. Pharm. Bull. 1993, 41, 1100 (6) Chao, Q.; Zhang, J.; Pickening, T. S.; Jahande, M.; Nair, V. Tetrahedron 1998, 54, 3113. (7) a) Craig, D.; Ikin, M. J.; Mathews, N.; Smith, A. M. Tetrahedron Lett. 1995, 41, 7531. b) Padwa, A.; Gareau, Y.; Harrison, B.; Norman, B. H. J. Org. Chem. 1991, 56, 2713. Scheme 1 D ow nl oa de d by : D on al d C ra ig . C op yr ig ht ed m at er ia l. December 1998 SYNLETT 1365 (8) Spectral data for 9: (-)-9: [α]D= -39.9 (c=1.0, CHCl3).; IR (cm-1): 2930, 2857, 1719, 1290, 1152, 1084.; 1H NMR (400MHz, CDCl3): δ 1.60 (3H, s, Me-C7), 1.61 (3H, s, Me-C7), 3.29 (1H, d, J=5.8Hz, H-8), 3.46 (1H, dd, J=9.5 and 6.6Hz, HB-3), 3.79 (1H, dd, J=9.5 and 5.5Hz, HA-3), 4.08 (1H, m, H-4), 4.60 (1H, t, J=5.8Hz, H-5), 5.22 (1H, t, J=5.8Hz, H-1), 7.60 (2H, m, Ar), 7.66 (1H, m, Ar), 7.91 (2H, m, Ar); 13C NMR (100Mhz, CDCl3): δ 23.1 (Me-C7), 28.6 (Me-C7), 70.5 (C8), 71.9 (C-3), 76.6 (C-4), 78.3 (C-5), 85.0 (C-1), 86.8 (C-7), 128.2 (2CHortho, Ar), 129.2 (2CHmeta, Ar), 133.9 (CHpara, Ar), 134.0 (Cipso, Ar). Anal. Calcd for C14H18O5S: C, 56.36; H, 6.08; Found: C, 56.35; H, 5.99. D ow nl oa de d by : D on al d C ra ig . C op yr ig ht ed m at er ia l.