The first solvent-directed regioselective ketal reduction of unsymmetrical glycols

摘要

J. CHEM. SOC. PERKIN TRANS. 1 1991 The First Solvent -d i rected Reg iosel ect ive Ket aI Red uct ion of UnsymmetricaI Glycols Roger Hunter' and Birgit Bartels Chemistry Dept., University of Cape Town, Rondebosch 7700, South Africa Borane-dimethyl sulphide/TMSOTf in TH F reduces ketals of unsymmetrical vicinal diols with much higher regioselectivity than with CH,CI, as solvent. Considerable interest has been shown recently in the chemo- selective protection of unsymmetrical vicinal diols to afford the thermodynamically and kinetically less stable secondary protected derivative. All of the procedures owe their success to the site selectivity of the oxygen attached to the primary carbon atom of an appropriate cyclic derivative towards an electro- philic reagent.Cyclic derivatives studied to date have been stannylene derivatives,' phosphoranes,2 and acetals and ketal~.~,~We have recently reported that boranedimethyl sulphide/trimethylsilyl trifluoromethanesulphonate (TMSOTf) is a novel, highly potent reagent combination for reductive ketal opening. In this communication we report on the use of this reagent in the first solvent controlled regioselective ketal reduction and comment on the mechanistic implications (Scheme 1). 2 3 Scheme 1 Reagents and conditions: i, BH,-SMe,/THF or CH,Cl,/ TMSOTf/ -78 "C; ii, NaHCO,/H,O; iii, Ac,O/pyridine/DMAP (cat). A study was undertaken to ascertain the influence of various reaction conditions and substrate structure on the reaction outcome.The dimethyl and diethyl ketals of 1 -phenylethane- 1,2-diol and the diethyl and dibenzyl ketals of hexane-1,2-diol were reduced in both THF and CH,Cl,, and as seen in Table 1 the isomer ratio improved in favour of the secondary protected derivatives 2 with increasing steric bulk of the ketal groups. Furthermore, improvement in regioselectivity for 2 was more pronounced in THF. The reaction product was acetylated in each case and isomer ratios were ascertained using 'H NMR and GC. Use of bulkier reagents, e.g. tert-butyldimethylsilyl trifluoromethanesulphonate (TBDMSOTf) or 1,1,2-trimethyl- propylborane (thexylborane) resulted in a modest preference for the unwanted primary protected derivative 3. The most pronounced regioselectivity was observed using THF as solvent which resulted in higher regioselectivities compared with CH,C12 in spite of the higher temperature required for reaction.For instance, the product ratio for the reduction of the diethyl ketal of l-phenylethane-1,2-diol improved from 63 :37 to 98 :2 in favour of the desired secondary protected derivative 2 by changing from CH,Cl, to THF (Entries 3 and 4, Table 1). Similarly, for hexane-1,2-diol diethyl ketal it improved from 27: 73 to 83: 17. The glycerol dioxolane derivatives (Entries 9 and 10) with R as CH20Bn were reduced in CH,Cl, to afford almost exclusively6 the primary protected derivative 3 derived by chelation controlled (uiu Ci-I,OBn) silylation of the oxygen bonded to the secondary carbon. By comparison, in THF (entry 1 l), the ratio shifts significantly to give some secondary protected derivative 2 in which the directing influence of THF competes with the chelation controlled process.Other solvents (toluene, acetonitrile, diisopropyl ether, diethyl ether) did not influence the isomer ratio in favour of the secondary protected derivative. Slightly higher ratios were obtained by adding the borane dimethyl sulphide first, while use of 2 equiv. of borane did not influence the isomer ratio significantly, but did help to reduce the reaction time. Table 1 Product yields and isomer ratios from reductive cleavage of ketals 1 using borane dimethyl sulphide and TMSOTf (2 equiv.) followed by acet ylation Entry R R' Solvent T/"C Ratio 2-3 Yield () 1 2 Ph Ph Me Me CH,Cl, THF -78 -78 to + 10 63 :37 81 :19 60 67 3 Ph Et CH,CI, -78 to -30 63:37 84 4 Ph Et THF -78 to +10 98:2 88 5 Bu Et CH,CI, -78 to -20 27 :73 73 6 Bu Et THF -78 to +4 83: 17 72 7 Bu CH,Ph CH,Cl, -78 to -20 31:69 91 8 Bu CH2Ph THF -78 to RT 90: 10 87 9 CH,OBn Me CH,CI, -78 to -70 5:95 86 10 CH,OBn CH,Ph CH,C1, -78 to -30 5:95 69 11 CH,OBn Me THF -78 to -70 27 :73 72 12 Ph Et ether -78 to 0 63 :37 76 13 14 Ph Bu CH,Ph Et diisopropyl ether ether -78 to 0 -78 to RT 62: 38 38 :62 84 83 Mechanistically, the most plausible explanation for the solvent effect is that the Lewis basic THF assists in the silylation process, acting as a sterically demanding silylating agent.Other ethereal solvents (diethyl and diisopropyl ether, Entries 12-14) gave approximately the same ratio as the corresponding CHzClzcases which may be due to their lower Lewis basicity compared with THF. The THF is unlikely to exert a steric influence in the reduction step since this probably involves TfOBH,. This is also borne out by the result with thexyl- borane in which no improvement in isomer ratio was observed favouring the desired isomer. Hence, increasing the steric bulk of the reductant does not result in production of more of the secondary protected derivative. Yamamoto has recently shown that solvent has a marked effect on the stereoselectivity of reduction of a symmetrical bicyclic ketal using diisobutylalu- minium hydride (DIBAH), but in this case the two oxygen atoms were equivalent and oxygen site selectivity was not an issue.In conclusion, this result highlights the importance of solvent in this reaction for controlling site selectivity and points the way towards the design of more effective reagents for the transformation. We are currently working towards a more useful protecting group using this reagent and results will be communicated in due course. Experimental Typical Procedure.--To a solution of ketal (1 mmol) in dry THF or CH,Cl, (3 cm3) at -78 "C was added TMSOTf (2 mmol) followed by borane dimethyl sulphide (2 mmol). The reduction was followed to completion by TLC whereupon saturated aqueous sodium hydrogencarbonate (5 cm3) was J. CHEM.SOC. PERKIN TRANS. I 1991 added and the organic material extracted into ethyl acetate and dried (MgSO,). Removal of solvent gave an oil which was acetylated using pyridine (1 cm3) and acetic anhydride (1 cm3) with a catalytic amount of 4-dimethylaminopyridine. After the normal work-up, the final product was isolated by column chromatography and analysed by 'H NMR and GC in appropriate cases. Acknowledgements We thank the FRD, Pretoria, for financial support. References and notes 1 (a) C. W. Holzapfel, J. M. Koekemoer and C. F. Marais, S. Afr. J. Chem., 1984, 37, 19; (b) S. David and S. Hanessian, Tetrahedron, 1985, 41, 643; (c) G. Reginato, A. Ricci, S. Roelens and S. Scapecchi, J. Org. Chem., 1990,55, 5132. 2 A. M. Pautard and S. A. Evans Jr., J. Org. Chem., 1988,53,2300. 3 For an interesting case of site selectivity in sugar derivatives see: W. V. Dahlhoff, Liebigs Ann. Chem., 1990, 1025, and references cited therein. 4 (a)Y. Guindon, Y. Girard, S. Berthiaume, V. Gorys, R. Lemieux and C. Yoakim, Can. J. Chem., 1990, 68, 897; (h) R. Johansson and B. Samuelsson, J. Chem. Soc., Perkin Trans. 1, 1984, 2371. 5 R. Hunter, B. Bartels and J. P. Michael, Tetrahedron Lett., 1991, 32, 1095. 6 In the original paper (ref. 5 above), it was stated that 3 was obtained exclusively for the bis-dibenzyl dioxolane. The ratio has now been more accurately determined to be 2/3 = 5 :95. We apologise for this error. 7 K. Ishihara, A. Mori and H. Yamamoto, Tetrahedron, 1990,46,4595. Paper 1/04385D Received 1 5th August 1991 Accepted 23rd August 1991