The "Other" Inositols and Their Phosphates: Synthesis, Biology, and Medicine (with Recent Advances in myo-Inositol Chemistry)

Abstract

Cell signaling via inositol phosphates, in particular via the second messenger myo-inositol 1,4,5-trisphosphate, and phosphoinositides comprises a huge field of biology. Of the nine 1,2,3,4,5,6-cyclohexanehexol isomers, myo-inositol is pre-eminent, with "other" inositols (cis-, epi-, allo-, muco-, neo-, L-chiro-, D-chiro-, and scyllo-) and derivatives rarer or thought not to exist in nature. However, neo- and d-chiro-inositol hexakisphosphates were recently revealed in both terrestrial and aquatic ecosystems, thus highlighting the paucity of knowledge of the origins and potential biological functions of such stereoisomers, a prevalent group of environmental organic phosphates, and their parent inositols. Some "other" inositols are medically relevant, for example, scyllo-inositol (neurodegenerative diseases) and d-chiro-inositol (diabetes). It is timely to consider exploration of the roles and applications of the "other" isomers and their derivatives, likely by exploiting techniques now well developed for the myo series.

Keywords: cyclitols; inositol; isomers; phosphates; synthetic methods.

Figure 1. The structures of the inositol isomers.

Three projections of each of the inositols are shown. The first column is a Mills projection. The second column is a Haworth projection. The third column shows a more realistic three-dimensional structure (not necessarily the most stable structure) for each of the inositols. The numbering of the carbons in the ring is shown.

Scheme 1

Reaction conditions: (a) OsO₄, NMO, acetone (aq).

Scheme 2

Reaction conditions: (a) I₂, Ag₂O, dioxane (aq), 90°C, (b) CF₃COOH(aq), THF, 50°C.

Scheme 3

Reaction conditions: (a) PTSA, MeOH, reflux; (b) BzCl, pyr., 91%; (c) Pd(OH)₂/C, MeOH, (50 psi) H₂, 96%; (d) Tf₂O, CH₂Cl₂, pyr., –42°C→ rt, 89%; (e) KOBz, DMSO, 100°C 32%; (f) base (step not shown in original literature).

Scheme 4

Reaction conditions: (a) 5% mol PdCl₂, Dioxane-H₂O, 4:1, 81%; (b) 5% mol PdCl₂, dioxane-H₂O, 2:1.

Scheme 5

Reaction conditions: (a) NaBH₄, MeOH, 0°C, 30 min; up to 99:1 of desired product; (b) Me₄NBH(OAc)₃, 5.0 eq, MeCN, AcOH, 0°C, 3 h, up to 99:1 of desired product; (c) NaOH, MeOH, 0°C, then Pd(OH)₂, H₂, MeOH.

Scheme 6

Reaction conditions: (a) NaBH₄, MeOH, 0°C, 30 min., 97%; (b) Pd(OH)₂ on carbon, H₂, MeOH, 12 h, quantitative yield; (c) H₂SO₄ (conc.), Me₂C=O, 0°C, 1 h 83%; (d) Tf₂O, pyridine, CH₂Cl₂, rt, 1 h, 89%; (e) CF₃CO₂Cs, 18-crown-6, toluene, DMF, 80°C, 1.5 h, then saturated NaHCO₃, rt, 1 h, 78% from 57; (f) TFA, MeOH, 60°C, 3 h.

Scheme 7

Reaction conditions: (a) Br₂, CHCl₃, 0°C, (98%); (b) NaBH₄, Et₂O, –20°C to rt (88%); (c) pyridine, acetic anhydride, overnight, (68%); (d) PPL phosphate buffer (pH 7), 4 days (38% of each).

Scheme 8

Reaction conditions (a) NaOAc, AcOH (95%), 10 days, 125°C; Ac₂O, CH₂Cl₂, DMAP; (b) RuCl₃, NaIO₄, MeCN; (c) NaOMe, MeOH; (d) (CF₃CO)₂O, H₂O₂, CH₂Cl₂, NaHCO₃; (e) Ac₂O, pyridine; (f) NaOMe, MeOH, then water/NaOH; (g) NaOBn, BnOH/THF; (h) (CF₃CO)₂O, H₂O₂, CH₂Cl₂, Na₂CO₃; (i) H₂SO₄, dioxane, H₂O; (j) Pd/C, H₂, ethanol/water.

Scheme 9

Reaction conditions: (a) 2,2-dimethoxypropane, acetone, PPTS, (b) 1. NaOAll, 90°C, 2. HCl; (c) 1. Pd/C, MeOH; 2. HCl, 3. Pd/C, H₂.

Scheme 10

Reaction conditions: (a) RuCl₃, NaIO₄, acetonitrile; (b) Ac₂O, pyridine; (c) Zn, Et₂O, AcOH; (d) 1. RuCl₃, NaIO₄, acetonitrile; 2 Ac₂O, pyridine; (e) NaOMe, MeOH.

Scheme 11

Reaction conditions: (a) CH₂=PPh₃, THF, 45°C, 10 h; then COCl₂, Me₂SO, CH₂Cl₂, –78°C, 20 min, Et₃N, –78°C to rt; (b) vinyl magnesium bromide, MgBr₂·OEt₂, –78°C, CH₂Cl₂, 3 h; (c) (CyP)₂RuCl₂(CHPh), 10 mol %, CH₂Cl₂, 15 min, 99%; (d) BnBr, DMF, NaH, 94%; (e) OsO₄, NMO, Me₂C=O/H₂O, 93%; (f) TIPS-Cl, DMF, AgNO₃, Separate compounds, (yield not given for this step, but 54% over 3 preceding steps); (g) O₃, CH₂Cl₂, pyridine, then Me₂S, (h) SmI₂, tert-BuOH, THF, –78°C, 3 h, then 20°C, O/N.

Scheme 12

Reaction conditions: (a) NaH, BzCl, DMF, rt; (b) Tosyl chloride, Pyr. 80-100°C; (c) iso-butylamine, MeOH, reflux; (d) (COCl)₂, DMSO, CH₂Cl₂, –78°C, then Et₃N, rt; (e) NaBH₄, MeOH-THF, rt; (f) NaOMe, MeOH, reflux; (g) TFA-water (4:1).

Figure 2. The conversion of myo-inositol to scyllo-inositol via myo-inosose

Figure 3

1-deoxy-1-fluoro-scyllo-inositol (96); 1,4-dideoxy-1,4-dimethyl-scyllo-inositol (97); Oxime derivatives of scyllo-inositol (98). R = H or up to 3 hydroxyl substituents on the ring.

Figure 4

scyllo-Inositol-1,2,4,5-tetrakisphosphate. (99), l-scyllo-Inositol-1,2,4-trisphosphate (100), scyllo-Inositol-1,2,3,4,5-pentakisphosphate (101).

Scheme 13

Reaction conditions: (a) 2,2-Dimethoxypropane, PTSA; (b) KMnO₄, MgSO₄, aqueous acetone, 8:1, ratio of compound 104 to compound 105, 60%; (c) AIBN, tris(trimethylsilyl)silane, toluene, 42%; (d) H₂O, sodium benzoate, 77% yield, >95% purity.

Figure 5

d-chiro-inositol-1,3,4,6-tetrakisphosphate (107); d-chiro-inositol-2,3,4,5-tetrakisphosphate (108); d-chiro-inositol-1,3,4-trisphosphate (109).

Figure 6

INS-2 Pinitol β-1,4-galatosamine

Scheme 14

Reaction conditions: (a) Toluene dioxygenase; (b) 2,2-dimethoxypropane, TsOH, rt; (c) MCPBA, CH₂Cl₂, 96%; (d) PhCH₂OH, BF₃:Et₂O, –10°C, 85%; (e) n-Bu₃SnH, AIBN, THF, 78%; (f) OsO₄, acetone, H₂O, NMO, 75%; (g) HCl, EtOH, 79%; (h) 10% Pd/C, H₂, H₂O, 81%, (30% overall yield from 114).

Figure 7

l-chiro-inositol-2,3,5-trisphosphate (117) l-chiro-inositol-2,3,5-trisphosphorothioate (118) l-chiro-inositol-1,4,6-trisphosphate (119) l-chiro-inositol-1,4,6-trisphosphorothioate (120).

Figure 8

l-chiro-inositol-1,3,4,6-tetrakisphosphate (121); l-chiro-inositol-2,3,4,5-tetrakisphosphate (122); l-chiro-inositol-1,3,4-trisphosphate (123).

Scheme 15

Reaction conditions: epi-Inositol Synthesis: (a) TrCl, pyr. Reflux, 1.5 h, 93%; (b) BnBr, NaH, Bu₄NI, THF, 25°C, 6 h, reflux 19 h, 85%; (c) CH₂Cl₂-MeOH (2:1), TFA, 18 h, 79%; (d) (i) (COCl)₂, DMSO, CH₂Cl₂, –78°C, 25 min; (ii) Et₃N, –78°C to 25°C, 1.5 h, 88%; (e) Catalyst 124 or 125, Et₃N, 14%; (f) EtOH, NaBH₄, 1 h, reflux; (g) PdCl₂, EtOH, H₂, 78% for steps f and g.

Scheme 16

Reagents and conditions: (a) Butanedione, MeOH, CH(OMe)₃, (±)-10-camphorsulfonic acid, reflux; (b) Trifluoromethanesulphonic anhydride, pyridine, CH₂Cl₂, –78°C to rt; (c) 50:1 dimethylacetamide-water, 50°C; (d) NaOMe, MeOH, reflux; (e) 4:1 AcOH-water, reflux.

Figure 9

neo-inositol hexakisphosphate (137) 2-diphospho-neo-inositol 1,3,4,5,6-pentakisphosphate (138), 2,5-bisdiphospho-neo-inositol 1,3,4,6-tetrakisphosphate (139).

Scheme 17

Reaction conditions: (a) 10% aqueous KOH, H₂O, DME, 87%; (b) n-Bu₃SnH, AIBN, THF, 90%; (c) MCPBA, CH₂Cl₂, 71%; (d) 10% aqeous H₂SO₄, 78%; (e) Amberlyst A-27, H₂O, 89%.

Scheme 18

Reagents and conditions: allo-Inositol Synthesis: (a) TrCl, pyr. Reflux, 1.5 h, 97%; (b) BnBr, NaH, Bu₄NI, THF, 25°C, 6 h, reflux 19 h, 90%; (c) CH₂Cl₂-MeOH (2:1), TFA, 18 h, 86%; (d) (i) (COCl)₂, DMSO, CH₂Cl₂, –78°C, 25 min; (ii) Et₃N, –78°C to 25°C, 1.5 h, 99%; (e) Catalyst 124 or 125 Et₃N, 54%; (f) EtOH, NaBH₄, 1 h, reflux; (g) PdCl₂, EtOH, H₂, 81% for 2 steps f and g.

Figure 10

The black dashed line indicates an apparent plane of symmetry that does not really exist: the hydroxyl on one side of the line is equatorial while the equivalent hydroxyl on the other side of the line is axial. The lack of any plane of symmetry in allo-inositol means that the conformational isomers are also enantiomers.

Scheme 19

Reaction conditions: (a) Cyclohexanone, benzene, reflux, PTSA, 59%; (b) Light petroleum, benzene, PTSA/EtOH 71%; (c) Pyridine, benzoyl chloride, 70-75°C, 5 h, 51%; (d) Benzene, DMSO, Ac₂O 17 h, 62%; (e) Chloroform/methanol NaBH₄, 2h, 96%; (f) Sodium, dry MeOH, 99%; (g) 80% acetic acid, heat, 76%.

Figure 11

Scheme 20

Reaction conditions: (a) DIBAL-H (2.7 eq), CH₂Cl₂, –78°C; (b) PMB-Cl, NaH, DMF; (c) PTSA (cat), MeOH/H₂O, 5 min., reflux; (d) compound 163 (3 equivalents), mix with reagent 164, 5-p-F-Ph-1H-tetrazole, CH₃CN, then, 0°C, mCPBA; 1:1 mixture of 165 and 166, separated by chromatography or recrystallization and yield based upon consumption of P(III) reagent (164). (e) TFA (2.5%) in CHCl₃; (f) P(III) reagent 167 (10 eq), 4,5-dicyanoimidazole (15 eq), 0°C, CH₃CN, then MCPBA (10 eq).

Scheme 21

Reaction conditions: Pyrophosphate formation- (a) DBU, then BSTFA in CH₃CN to give intermediate 171; (b) TFA in Methanol then remove solvent; (c) P(III) reagent 173, 1H-tetrazole/CH₃CN, then MCPBA. B = DBU.

Scheme 22

Reaction conditions: (a) H₂, palladium black or PtO₂, 80 bar, tert-BuOH/H₂O, 4/1 to 1/1, NaHCO₃, 3 h, recrystallise product.

Scheme 23

Reaction conditions: Reagent 164, (1 eq) 179 (3 eq), DCI CH₃CN, 0°C, tert-BuOOH, (5.5 M in nonane), 45% for (180), 36% for (181) and resolved by chromatography and re-crystallisation (high purity), yield based upon consumption of reagent 164; (b) PTSA (cat), MeOH/CH₂Cl₂, recrystallize; (c) reagent 167, DCI, 0°C, CH₃CN, 0°C, MCPBA, recrystallise.

Scheme 24

Reaction conditions: (a) see Scheme 21; (b) H₂, palladium black or PtO₂, 80 bar, tert-BuOH/H₂O, 4/1 to 1/1, NaHCO₃, 3 h, recrystallize product.

Scheme 25

Reaction conditions: (a) BnBr, NaH, DMF; (b) reagent 190, CH₂Cl₂, 5-Ph-1H-tetrazole, then MCPBA, –40°C→rt; (c) 90% TFA(aq), 1:1; (d) reagent 173, CH₂Cl₂, 5-Ph-1H-tetrazole; (e) MCPBA, –40°C→rt; (f) DBU then BSTFA; (g) TFA, MeOH; (h) reagent 173, CH₂Cl₂, 5-Ph-1H-tetrazole; (i) MCPBA, –40°C→rt; (j) Pd(OH)₂, H₂, tert-BuOH, H₂O (196 was prepared in the presence of DBU to inhibit O-benzyl deprotection).

Scheme 26

Reaction conditions: (a) reagent 198, tert-BuOOH, 1 h, (b) PTSA, CH₂Cl₂, MeOH, Δ, 10 min; (c) reagent 164, 1H-tetrazole, CH₃CN, then MCPBA; (d) 5% TFA, CHCl₃, 4 h, recrystallize; (e) reagent 167, DCI, CH₃CN, then MCPBA.

Scheme 27

Reaction conditions: (a) See Scheme 21 for reaction conditions; (b) Pd/C, H₂ (180 bar), tertBuOH, H₂O, NaHCO₃.

Scheme 28

Reaction conditions: (a) (BnO)₂P(O)CH₂CO₂H, DCC, CH₂Cl₂, 73%; (b) TFA, H₂O, 5 min, up to 62%; (c) reagent 173, 5-Ph-1H-tetrazole, CH₂Cl₂, then 3-chloroperoxybenzoic acid, CH₂Cl₂, up to 93%; (d) H₂, Palladium hydroxide/carbon, MeOH, H₂O, 50 psi, 92%; (e) BnBr, NaH, DMF, 55%; (f) (BnO)₂P(O)CH₂CO₂H, EDAC, DMAP, CH₂Cl₂, 95%; (g) H₂, Palladium hydroxide/carbon, MeOH, TEAB(aq) 79%; (h) H₂, Palladium hydroxide/carbon, MeOH, H₂O, 50 psi, 79%.

Scheme 29

Reaction conditions: (a) Benzyl((bis(benzyloxy)phosphoryl)methyl)-phosphonochloridate, KHMDS, THF, –78°C → rt, O/N; (b) Sodium methoxide, MeOH, rt, O/N, then p-toluenesulfonic acid, H₂O, (CH₃)₂CO, O/N; (c) reagent 167, MeCN, 1H-tetrazole, 0°C→rt, 1.5 days, then 3-chloroperoxybenzoic acid, MeCN, 0°C→rt, 3 h; (d) H₂, Palladium black, NaHCO₃, t-BuOH/H₂O, rt, O/N; (e) NH₃(aq) conc, 4 days, then H⁺-Dowex.

Scheme 30

Reagents and conditions: (a) DIPE, MeOH, 14 h 36°C; (b) (bis(benzyloxyphosphoryloxy)methyl) phosphoryl chloride, DBU, 1H-tetrazole, CH₂Cl₂, 0°C→rt, O/N; (c) DIBAL-H, CH₂Cl₂, –78°C, 6 min; (d) TFA-MeOH-CH₂Cl₂, 0°C, 3h; (e) Reagent 167, 5-Ph-1H-tetrazole, CH₂Cl₂, 0°C→rt, 18 h, then MCPBA oxidation, 78°C→rt, 3h; (f) H₂, Palladium black, NaHCO₃, H₂O-^tBuOH, rt, O/N; (g) NH₃(aq) conc., rt, 4 days, then Dowex H⁺ form.

Scheme 31

Reagents and conditions: (a) Bis[6-trifluoromethyl)benzotriazol-1-yl)]methylphosphonate, pyridine, then BnOH, deprotect using palladium black, H₂, H₂O, NaHCO₃; (b) SO₃, pyr.; then tert-butanol, H₂O, NaHCO₃; (c) RuCl₃.H₂O, CCl₄, NaIO₄, MeCN, H₂O; deprotection for (b) and (c) as for (a).

Scheme 32

Reagents and conditions: (a) TBAF in THF; then reagent 173, CH₂Cl₂, 1H-tetrazole, then MCPBA; (b) ceric ammonium nitrate, MeCN, H₂O; then (MeO)(BnO)PNⁱPr₂, CH₂Cl₂, 1H-tetrazole; then MCPBA; (c) palladium black, H₂, tert-butanol, H₂O, NaHCO₃.

Figure 12

Inositol phosphate ligands evaluated at PPIP5K2; compound 245 is the most potent ligand.

Scheme 33

Reagents and conditions: (a) EtⁱPr₂N-MeOH, (1:4), 36°C, 11 h, 91%; (b) Reagent 248, 4,5-dicyanoimidazole, CH₂Cl₂, 0°C, to rt, 20 min., then AcOOH, –18°C, to rt, 1 h, 70%; (c) Formic acid-CH₂Cl₂ (7:3), rt, 3.5 h; (d) Reagent 198, 4,5-dicyanoimidazole, CH₂Cl₂/MeCN, 4:1, rt, 1 h, then AcOOH, –18°C, to rt, 1.5 h, 48% (over 2 steps); (e) Formic acid/CH₂Cl₂, 95:5, 4.5 h; (f) 1,1-Dimethoxybutane, CH₂Cl₂, jandajel pyridinium trifluoroacetate, rt, 23 h, Dowex 50WX8, H⁺, 1 h; (g) Reagent 251 4,5-dicyanoimidazole, CH₂Cl₂-MeCN, rt, 30 min, then AcOOH, –18°C, to rt, 30 min, 46% (over 3 steps); (h) CH₂Cl₂, piperidine, rt, 1 h; (i) bromomethyl acetate, EtⁱPr₂N, MeCN, rt, 10 h, 16% (over 2 steps).

Figure 13

Caged C₈-PtdIns(3,4,5)P₃ (253) protected with acetoxymethyl groups that are enzymatically hydrolyzed to give a photolabile derivative (254) prior to uncaging.

Scheme 34

Reagents and conditions: (a) BzCl in CHCl₃, pyr. –40°C, 1 h; (b) MEM-Cl, Hünigs base, CHCl₃, Δ, 48h; (c) 65% HCOOH, in MeOH, rt, 48h; (d) 4-(dimethoxymethyl)phenol, CH₂Cl₂, PPTS, rt, 24 h, then 40 °C for 4 h; (e) Wang alcohol resin, DIAD, triphenylphosphine, THF, rt, 48 h; (f) DIBAL-H, CH₂Cl₂, −78°C → −30°C, 3 h; (g) reagent 173, DCI, CH₂Cl₂, CH₃CN, 24 h, then peracetic acid, −30°C → rt, 1 h; (h) TASF in DMF, 32 h; (i) glycerol diester phosphoramidite, DCI, CH₂Cl₂, MeCN, 24 h, then peracetic acid −30°C → rt, 1 h; (j) DDQ, CH₂Cl₂, H₂O; (k) TMSBr, rt, 1h.

Figure 14

The structure of a mammalian phospholipid (260) compared to the newly discovered plasmanylinositol (261) found in Dictyostelium.

Figure 15

The structures of benzene polyphosphates showing agonist behavior and antagonist behavior at the Ins(1,4,5)P₃ receptor.