One-Step Regioselective Functionalization of myo-Inositol by Dissolution Strategy

Abstract

Functionalizations of hydroxy groups of myo-inositol were usually nonselective due to its poor solubility. By dissolving myo-inositol in DMSO or LiCl-N,N-dimethylacetamide, we have achieved regioselective acylation, silylation, sulfonylation, phosphinylation to give the corresponding 1,3-di-O-substituted products in good yields.

Key words

acylation - regioselectivity - substitutions - inositol - DMA

References and Notes

• 1 Berridge MJ. Nature (London)  1993,  361:  315 
• 2a Billington DC. The Inositol Phosphates, Chemical Synthesis and Biological Significance   Wiley-VCH; Weinheim: 1993. 
• 2b Watanabe Y. Selective Reactions and Total Synthesis of Inositol Phosphates, In Studies in Natural Products Chemistry, Stereoselective Synthesis (Part K)   Vol. 18:  . Elsevier; Amsterdam: 1996.  p.391-456  
• 3a Reitz AB. Inositol Phosphates and Derivatives, Synthesis, Biochemistry, and Therapeutic Potential   American Chemical Society; Washington DC: 1991. 
• 3b Potter BVL. Lampe D. Angew. Chem., Int. Ed. Engl.  1995,  34:  1933 
• 3c Morgan AJ. Komiya S. Xu Y. Miller SJ. J. Org. Chem.  2006,  71:  6923 
• 4a Gigg J. Gigg R. Top. Curr. Chem.  1990,  154:  77 
• 4b Prestwich GD. Acc. Chem. Res.  1996,  29:  503 
• 4c Bruzik KS. Phosphoinositides: Chemistry, Biochemistry and Biomedical Applications   American Chemical Society; Washington DC: 1998. 
• 4d Xu Y. Sculimbrene BR. Miller SJ. J. Org. Chem.  2006,  71:  4919 
• 5a Praefcke K. Kohne B. Psaras P. Hempel J. J. Carbohydr. Chem.  1991,  10:  523 
• 5b Praefcke K. Marquardt P. Kohne B. Stephan W. J. Carbohydr. Chem.  1991,  10:  539 
• 5c Praefcke K. Blunk D. Liquid Cryst.  1993,  14:  1181 
• 6a Kim SC. Kim TY. Lee SY. Roh SH. Nam KD. Kongop Hwahak  1994,  5:  573 
• 6b Tsuzuki W. Kitamura Y. Suzuki T. Kobayashi S. Biotechnol. Bioeng.  1999,  64:  267 
• 6c Blunk D. Bierganns P. Bongartz N. Tessendorf R. Stubenrauch C. New J. Chem.  2006,  30:  1705 
• 6d Catanoiu G. Gärtner V. Stubenrauch C. Blunk D. Langmuir  2007,  23:  12802 
• 6e Neto V. Granet R. Mackenzie G. Krausz P. J. Carbohydr. Chem.  2008,  27:  231 
• 7a Sureshan KM. Shashidhar MS. Varma AJ. J. Org. Chem.  2002,  67:  6884 
• 7b Dixit SS. Shashidhar MS. Devaraj S. Tetrahedron  2006,  62:  4360 
• 8a Hosoda A. Miyake Y. Nomura E. Taniguchi H. Chem. Lett.  2003,  32:  1042 
• 8b Watanabe Y. Miyasou T. Hayashi M. Org. Lett.  2004,  6:  1547 
• 8c Sureshan KM. Yamaguchi K. Sei Y. Watanabe Y. Eur. J. Org. Chem.  2004,  4703 
• 9a Chida N. J. Synth. Org. Chem. Jpn.  2000,  58:  642 
• 9b Suzuki T. Suzuki ST. Yamada I. Koashi Y. Yamada K. Chida N. J. Org. Chem.  2002,  67:  2874 
• 10 Kwon Y.-K. Lee C. Chung S.-K. J. Org. Chem.  2002,  67:  3327 
• 11 Sureshan KM. Shashidhar MS. Praveen T. Das T. Chem. Rev.  2003,  103:  4477 
• 12 Suami T. Ogawa S. Oki S. Bull. Chem. Soc. Jpn.  1971,  44:  2824 
• 13 Angyal SJ. Bender V. Curtin JH. J. Chem. Soc.  1966,  798 
• 14 Chung S.-K. Chang Y.-T. Bioorg. Med. Chem. Lett.  1997,  7:  2715 
• 15 Kuhn R. Trischmann H. Chem. Ber.  1963,  96:  284 
• 16 Wewers W. Gillandt H. Traub HS. Tetrahedron: Asymmetry  2005,  16:  1723 
• In addition to refs. 2-4, see:
• 17a Angyal SJ. Tate ME. Gero SD. J. Chem. Soc.  1961,  4116 
• 17b Suami T. Ogawa S. Tanaka T. Otake T. Bull. Chem. Soc. Jpn.  1971,  44:  835 
• 17c Chung S.-K. Ryu Y. Carbohydr. Res.  1994,  258:  145 
• 17d Kubiak RJ. Bruzik KS. J. Org. Chem.  2003,  68:  960 
• 17e Watanabe Y. Kiyosawa Y. Hyodo S. Hayashi M. Tetrahedron Lett.  2005,  46:  281 
• 18a Braz GI. Voznesenskaya NN. Yakubovich AY. J. Org. Chem. USSR (Engl. Transl.)  1973,  9:  114 
• 18b A related reaction of ethyl chloroformate with DMA in the presence of triethylamine followed by reaction with benzoyl chloride was reported: Kira MA. Zayed AA. Fathy NM. Egypt. J. Chem.  1983,  26:  253 
• 19 McCormick CL. Dawsey TR. Newman JK. Carbohydr. Res.  1990,  208:  183 
• 20a Bordwell FG. Pitt BM. J. Am. Chem. Soc.  1955,  77:  572 
• 20b Dilworth BM. McKervey MA. Tetrahedron  1986,  42:  3731 
• 22 Watanabe Y. Mitani M. Morita T. Ozaki S. J. Chem. Soc., Chem. Commun.  1989,  482 

21

When a solution of dinaphthoate in EtOAc was washed with H₂O, the dinaphthoate could be recovered completely in the organic layer. However, the presence of DMA in the solution resulted in the loss of about 10% of the dinaphthoate into the aqueous layer.

23

myo-Inositol was dried prior to the reaction. Commercial myo-inositol was first dried by heating at 200 ˚C for 12 h under reduced pressure (0.5 mmHg) and secondly, the inositol was treated three times with pyridine (1 g Ins/5 mL Py) under atmospheric pressure to remove azeotropically a trace of H₂O. The resulting inositol was finally heated at 120 ˚C for 12 h under reduced pressure (0.5 mmHg). Anhydrous DMA and DMSO were obtained by treating with powdered CaH₂ and BaO overnight, respectively, and subsequent distillation (1 and 20 mmHg). LiCl is so hygroscopic that it was weighed in a reaction vessel and dried by application of heat at about 300-400 ˚C under reduced pressure (0.5 mmHg).
Typical Procedure for the Synthesis of 1,3-Di- O -benzoyl- myo -inositol (2a): To a reaction flask containing LiCl (400 mg, 9.44 mmol) were added inositol (100 mg, 0.55 mmol) and DMA (5 mL), and the mixture was heated at about 120 ˚C until the mixture became a clear solution (about 3 min). After addition of Et₃N (391 mg, 3.89 mmol), the resulting solution was kept at -10 ˚C, and then benzoyl chloride (234 mg, 1.67 mmol) was added. The mixture was stirred at the same temperature for 4 h, and pyridine (2 mL) and TMSCl (1 mL, 7.82 mmol) were carefully added. The mixture was stirred at 0 ˚C for 5 h, and diluted with H₂O and EtOAc. After partition to two layers, the aqueous layer was extracted with EtOAc (3 ×), and the organic layers combined with the initial organic one were washed successively with H₂O (2 ×), 0.5 N HCl solution, H₂O, sat. NaHCO₃ solution, H₂O, and then brine. The organic layer was dried over Na₂SO₄, filtered and evaporated. The residue was dissolved in a small volume of CHCl₃ (1 mL), and MeOH (5 mL) and CF₃CO₂H (74 mg, 0.64 mmol) were added. The solution was stirred for 4 h at r.t., and the volatile materials were all distilled off under reduced pressure (1.0 mmHg). The residue was subjected to a column chromatography on silica gel (MeOH-CHCl₃, 1:10) to give crystalline 1,3-di-O-benzoate (205 mg, 95% yield): R _f 0.5 (MeOH-CHCl₃, 1:5); mp 174.5-175.0 ˚C (EtOAc-hexane). ^¹H NMR (400 MHz, CD₃OD): δ = 3.44 (1 H, t, J = 9.8 Hz, InsH₅), 4.08 (2 H, t, J = 9.8 Hz, InsH_4,6), 4.43 (1 H, t, J = 2.6 Hz, InsH₂), 5.01 (2 H, dd, J = 9.8, 2.6 Hz, InsH_1,3), 7.47 (4 H, t, J = 8.0 Hz, H _m ), 7.60 (2 H, t, J = 8.0 Hz, H _p ), 8.00 (4 H, d, J = 8.0 Hz, H _o ). ^¹³C NMR (100 MHz, CD₃OD): δ = 69.29, 71.89, 75.90, 76.52 (6 × C, InsC), 129.42 (4 × C, C_ar3), 130.88 (4 × C, C_ar2), 131.50 (2 × C, C_ar1), 134.26 (2 × C, C_ar4), 167.69 (2 × C, CO). MS (FAB⁺, m-nitrobenzyl alcohol): m/z = 389 [M + H]⁺. Anal. Calcd for C₂₀H₂₀O₈˙1/2H₂O: C, 60.45; H, 5.33. Found: C, 60.09; H, 5.13.
1,3-Di- O -(1-naphthoyl)- myo -inositol (2b): As described above, a solution of inositol (100 mg, 0.55 mmol) and LiCl (400 mg, 9.44 mmol) in DMA (5 mL) was prepared. After addition of Et₃N (391 mg, 3.89 mmol), the resulting solution was kept at -10 ˚C, and then 1-naphthoyl chloride (317 mg, 1.67 mmol) was added. The mixture was stirred at the same temperature for 20 h. H₂O (about 0.1 mL) was added and the mixture was stirred for 10 min, and then partitioned to EtOAc and H₂O layers. The aqueous solution was extracted with EtOAc (3 ×). The combined extract was washed with H₂O (3 ×) and brine, dried over Na₂SO₄, filtered, and then evaporated. The residue was recrystallized from EtOAc-hexane to give crystals of 2b (193 mg, 71%). The remaining dinaphthoate (32 mg, 12%) was isolated from the mother liquor by a flash column chromatography on silica gel (MeOH-CHCl₃, 1:14): R _f 0.4 (MeOH-CHCl₃, 1:10); mp 195.5-196.0 ˚C (EtOAc-hexane). ^¹H NMR (270 MHz, CD₃OD): δ = 3.61 (1 H, t, J = 9.6 Hz, InsH₅), 4.23 (2 H, t, J = 9.6 Hz, InsH_4,6), 4.73 (1 H, t, J = 2.4 Hz, InsH₂), 5.26 (2 H, dd, J = 9.6, 2.4 Hz, InsH_1,3), 7.61 (6 H, complex, aromatic H_3,6,7), 7.96 (2 H, d, J = 8.0 Hz, aromatic H₅), 8.11 (2 H, d, J = 8.4 Hz, aromatic H₄), 8.41 (2 H, d, J = 7.2 Hz, aromatic H₂), 9.00 (2 H, d, J = 8.4 Hz, aromatic H₈). ^¹³C NMR (100 MHz, CDCl₃): δ = 69.58 (C, InsC₂), 72.26 (2 × C, InsC_4,6), 76.30 (2 × C, InsC_1,3), 77.04 (C, InsC₅), 125.9, 127.2, 127.6, 128.8, 128.9, 129.9, 131.9, 132.9, 134.8, 135.5 (10 × C, aromatic), 169.0 (C=O). MS (FAB⁺, m-nitrobenzyl alcohol): m/z = 689 [M + H]⁺. Anal. Calcd for C₂₈H₂₄O₈: C, 68.85; H, 4.95. Found: C, 68.56; H, 4.91.
The other compounds were identified similarly by spectros-copic data (^¹H NMR and ^¹³C NMR, FAB-MS) and elemental analysis.