Efficient and Systematic Syntheses of Enantiomerically Pure and Regiospecifically Protected myo-Inositols

Efficient and systematic syntheses of a variety of enantiomerically pure and regiospecifically protected myo-inositols, which can be readily used as precursors for most natural and unnatural derivatives of myo-inositol, have been developed. The key strategies are the use of camphor as a protecting group and a chiral auxiliary and the development of regiospecific control in various steps. The diastereomerically pure 1 ~-2 ,3-O( l’R,2’R,4’R-1’,7’,7’-trimethyl[2.2.1] bicyclohept-2’-ylidene)-myo-inositol (la) was obtained in 3 1% yield via acetalization of myo-inositol with D-camphor dimethyl acetal followed by crystallization from methanol. In route A, silylation of tetrol la with tert-butyldiphenylsiyl chloride (TBDPS-C1) afforded l-OTBDPS-4,5,6-triol 7 exclusively, which served as a key intermediate. Further protection with other reagents, exhaustively or regiospecifically, combined with selective deprotecting steps, led to protected myo-inositols with free hydroxyls at 1-, 5-, 6-, 1,4-, 43-, 5,6-, 1,4,5-, and 1,4,6-positions. In route B, the diastereomeric camphor-protected tetrols 1 were protected with a bifunctional silylating agent, 1,3-dichloro-l,1,3,3-tetraisopropyldisiloxane (TIPDS-Cl2), to give diol 31. Subsequent protections/deprotections led to myo-inositols derivatives with free hydroxyls at 2-, 1,2-, 2,3-, 4 5 , 5,6-, 1,2,6-, and 1,3,4-positions. In route C the 4,5,6-triol 7 (from route A) was deacetalized to afford 1 -TBDPS-inositol. 1 -TBDPS-inositol after selective trisbenzoylation and alkylation followed by debenzoylation afforded 1,2,6-protected inositol (free hydroxyls at 3,4,5-positions). In route D the 4,5-diol 31 (from route B) was deacetalized to give 1,6-TIPDS-inositol. Alkylation or benzoylation of 1,6-TIPDS-inositol and subsequent desilylation afforded 1,6diols (protected at 2,3,4,5-positions). Overall, the various precursors of phosphoinositides were obtained in 4-8 steps from inositol in 5-25% yields. The various inositol phosphates and inositol phospholipids, including phosphatidylinositol (PI),] PI-4-phosphate (PI-CP), PI-4,5-bisphosphate (PI-4,5-P2), PI-3,4-bisphosphate (PI-3,4-P2), PI-3,4,5-trisphosphate (PI-3,4,5-P3), inositol 1-phosphate (IP), inositol 1 ,Cbisphosphate (1 ,4-IP2), inositol 1,4,5-trisphosphate ( i,4,5-IP3), inositol 1,3,4-trisphosphate ( 1,3,4-IP3), inositol 1,3,4,5-tetrakisphosphate (1 ,3,4,5-IP4), and the corresponding inositol 1 ,2-cyclic phosphates (IcP, IcP-4-P, and IcP-4,5-P2) have been found to trigger many important biological processes, through very complex pathways.2a-g In addition, membrane protein anchors contain a glucosylphosphatidylinositol (GPI) and glucosylinositol phosphate (GIP) is a partial structure of putative modulators involved in the cellular response to insulin.2k“ Apart from heterogeneity of fatty acids and carbohydrates in inositol phospholipids and inositol phosphoglycans, more than 20 different inositol phosphates have been identified in different cells.2eBg Interconversion between phosphoinositides is carried out by the large number of highly specific phospholipases, kinases, and ( I ) Abbreviations: GIP, 6-0-(2-amino-2-deoxy-~u-~-glucopyranosyl)inositol 1 -phosphate; GPI, 6-0-(2-amino-2-deoxy-a-o-glucopyranosyl)phosphatidylinositol; IP, inositol I-phosphate; 1 ,4-IP2, inositol 1,4-bisphosphate; 1 ,4,5-IP3, inositol 1,4,5-trisphosphate; 1 ,3,4-IP3, inositol 1,3,4-trisphosphate; 1,2,6-IP3, inositol 1,2,6-trisphosphate; 1 ,3,4,5-IP4, inositol 1.3.4,S-tetrakisphosphate; IcP, inositol 1.2-cyclic phosphate; IcP-4-P, inositol 1.2-cyclic phosphate-4-phosphate; IcP-4,5-P2, inositol 1,2-cyclic phosphate-4,S-bisphosphate; MOM-CI, methoxymethylene chloride; PI, phosphatidylinositol; PI-4-P, phosphatidylinositol 4-phosphate; PI-3,4-P2, phosphatidylinositol 3,4-bisphosphate; PI-4,5-P2, phosphatidylinositol 4,s-bisphosphate; PI-3,4,5-P3, phosphatidylinositol 3.4,s-trisphosphate; TBDMS-CI, tert-butyldimethylsilyl chloride; TBDPS-CI, tert-butyldiphenylsilyl chloride; TIPDS-C12, 1,3-dichloro-l,l,3,3-tetraisopropyldisiloxane; TMS-DEA, (diethy1amino)trimethylsilane; TMSOTf, trimethylsilyl triflate. (2) Recent reviews on phosphoinositide metabolism: (a) Berridge, M. J.; Irvine, R. F. Nature 1984, 312, 315-321. (b) Berridge, M. J. Biochem. J . 1984,220,345-360. (c) Hokin, R. H. Ann. Reu. Biochem. 1985,54,205-235. (d) Michell, R. H. Nature 1986, 319, 176-177. (e) Majerus, P. W.; Conolly, T. M.; Bansal, V. S.; Inhorn, R. C.; Ross, T. S.; Lips, D. L. J . Bid. Chem. 1988, 263, 3051-3054. (f) Berridge, M. J. Ann. Reu. Biochem. 1987, 56, 159-193. (g) Berridge, M. J.; Irvine, R. F. Nature 1989,341, 197-205. GPI as membrane protein anchors: (h) Ferguson, M. A. J.; Williams, A. F. Ann. Reu. Biochem. 1988,57, 285-320. (i) Low, M. G. Biochem. J . 1987, 244, 1-13. Q) Low, M. G. FASEBJ. 1989,3, 1600-1608. (k) Special Issue Cell. Bid. In!. Rep. 1991, 15, 739-1166. Insulin mimetics: ( I ) Romero, G.; Luttrell, L.; Rogol, A.; Zeller, K.; Hewlett, E.; Lamer, J. Science 1988, 240, 509-51 I . (m) Saltiel, A. R.; Cuatrecasas, P. Am. J . Physiol. 1988, 255, c l -c l l . (n) Farese, R. V. Proc. Soc. Exp. Bid. Med. 1990, 312-324. See, also: ref 2k. 0002-786319211514-6361$03.00/0 phosphatases.2g Most of these processes have been discovered in the past few years, and more are still forthcoming. Investigation of the chemical mechanism of these processes have been hampered by the difficulty in the synthesis of various substrates, substrate analogues, and inhibitors. Although the synthesis of these compounds has received extensive attention in recent years, many of the inositol derivatives and their analogues are not yet readily available. lo-myo-Inositol-I,5,6-triphosphate, for example, is one of the most expensive compounds ($89/10 pg) in the 1992 Sigma catalogue. The prices for one milligram of other inositol polyphosphates range from $100 to $5000, The main problem in such syntheses lies in the availability of properly protected and enantiomerically pure myo-inositol derivatives. Numerous syntheses of such phosphoinositide precursors have been reported to date.3 However, most of these procedures involve numerous protecting and optical resolution steps, which lead to low overall yields. In addition, many of the reported syntheses are aimed at specific phosphoinositides utilizing a speclfc starting material. The isomers of di-O-cy~lohexylidene-~ and di-0-isopropylidene-myo-ino~itol~ have found a widespread application as convenient starting derivatives. However, these compounds are synthesized from myo-inositol as a mixture of three positional isomers and separated by a combination of crystallization and chromat~graphy.~ ,~ The separated positional isomers are mixtures of enantiomers, which are generally resolved by further derivatization with a chiral auxiliary.3d This procedure lengthens the total synthesis by three steps: (i) derivatization of a racemic inositol derivative with a chiral auxiliary, (ii) separation (3) Reviews on synthesis of phosphoinositides and their precursors: (a) Potter, B. L. V. Nut. Prod. Rep. 1990, 1-24. (b) Billington, D. C. Chem. Soc. Reu. 1989, 18, 83-122. (c) Shvets, V. I.; Stepanov, A. E.; Krylova, V. N.; Gulak, P. V. Myo-Inositol and Phosphoinositides; Nauka Publishing House, Moscow, 1987. (d) Inositol Phosphates and Derivatives. Synthesis, Biochemistry and Therapeutic Potential; ACS Symposium Series 463; American Chemical Society: Washington, D.C., 1991. (e) Shvets, V. I. Usp. Khim. 1974.43, 1074-1101. (4) (a) Garegg, P. J.; Lindberg, B.; Kvarnstroem, I.; Svensson, S. C. T. Carbohydr. Res. 1985, 139, 209-215. (b) Garegg, P. J.; Iversen, T.; Johansson, R.; Lindberg, B. Carbohydr. Res. 1984, 1 30, 322-326. (c) Garegg, P. J.; Lindberg, B.; Kvarnstroem, I.; Svensson, S. C. T. Carbohydr. Res. 1988, ( 5 ) (a) Gigg, J.; Gigg, R.; Payne, S. ; Conant, R. Carbohydr. Res. 1985, 142, 132-134. (b) de la Paradilla, R. F.; Jaramillo, C.; Jimenez-Barbero, J.; Martin-Lomas, M.; Penades, S.; Zapata, A. Carbohydr. Res. 1990, 207, 249-257. 173, 205-216.