Orthogonally protected glycerols and 2-aminodiols: useful building blocks in heterocyclic chemistry

The efficient synthesis of orthogonally protected glycerols,  -aminopropane-1,3-diols and 2-aminobutane-1,4-diols that can constitute useful tools in heterocyclic chemistry, is reported. These interesting tri-functionalized small synthons were easily prepared from serine or aspartic acid. In addition, these substrates can be readily transformed into their iodide derivatives in very good yields.


Introduction
Polyfunctionalized small molecules such as glycerols and -amino-alcohols are important and versatile units extensively used in the preparation of complex structures like macrolides, 1 morpholines, 2 hydroxyamidines 3 and antibiotics.Moreover, 1,2-diols can serve as precursors for the preparation of vic-halohydrins, useful molecules for synthetic transformations having importance, for example, in the synthesis of halogenated marine products. 4wing to their structures, these building blocks need at first to be protected with groups cleavable independently of the others.Lastly, synthesis of natural compounds required an enantioselective access to these substrates and that can be efficiently investigated starting from readily available natural amino acids.
In connection with our ongoing effort to synthesize spiroketals or analogues, based upon an iterative alkylation of acetone N,N-dimethylhydrazone with and -hydroxyiodides, 5 we were induced to develop approaches 5c,d to several orthogonally protected iodopropanediols, aminopropanols and aminobutanols starting from D-serine or from L-aspartic acid.We describe herein the synthesis and the characterization of orthogonally protected glycerols and 2-aminodiols, together with their efficient conversions into iodides.
Iodination of (S)-10b and (S)-10c was efficiently achieved using our standard conditions affording the polyfunctionalized substrates (R)-11b and (R)-11c.These iodo-compounds can be kept several weeks at 0 °C under argon but needed, as for iodides 1a and 1b, a filtration on flash silica gel column before use (Scheme 2).
L-Aspartic acid methyl ester was classically transformed into its known carbamate (S)-12. 15,16he selective reduction of the carboxylic acid of (S)-12 was then realized in two steps by activation with dicyclohexylcarbodiimide/N-hydroxysuccinimide followed by treatment with sodium borohydride, leading to (S)-13 17 in 79% yield.Alcohol (S)-13 was finally protected giving the pivotal tert-butyldiphenylsilyl ether (S)-14a in 98% yield using tert-butyldiphenylsilyl chloride/imidazole.This latter was further converted to the original esters 14b,c.Indeed, introduction of a second tert-butoxycarbonyl group on 14a was accomplished with di-tert-butyl dicarbonate/dimethylaminopyridine affording (S)-14b in 54% yield.Reaction of the carbamate (S)-14a with benzyl bromide in the presence of tetrabutylammonium iodide, furnished (S)-14c in 69% yield.
In a last step, all the alcohols 15 were transformed into their iodide derivatives 16a, 16b, 16c and 16d 19 in a range of 71-92% yields using our standard conditions for 16a,b,d and through its mesylate for 16c (Scheme 2).
Since compounds 5a, 9c, 10c, 11c, 14d, 15d, 16d were not fully described with regard to their characterisation data, and as some preparative procedures were different to those previously published, we report them in this paper, together with complete sets of data.

Conclusions
In conclusion, D-serine or L-aspartic acid constitute inexpensive commercially available substrates for the rapid and efficient synthesis of enantiomerically pure orthogonally protected glycerols and 2-aminodiols, applying short synthetic pathways and convenient transformations.Furthermore, these small polyfunctionalized synthons were efficiently transformed into their iodide derivatives.These products constitute useful building blocks for the elaboration of more complex structures.

Experimental Section
General.Melting points were measured using a Reichert melting point apparatus and are uncorrected.Infra-Red spectra were recorded on a Perkin-Elmer 881 instrument.Nuclear magnetic resonance spectra were obtained using BRUKER AC 400 spectrometer ( 1 H, 400 MHz, 13 C, 100 MHz).Chemical shifts ( values) are expressed in parts per million (ppm) with solvents as internal standards and coupling constants (J) are expressed in Hertz.Mass spectra were recorded with a Hewlett Packard 5989B instrument and high resolution mass spectra (HRMS) were performed with a Q-TOF micromass.Chromatography was performed using silica gel 60 (230-400 mesh) and thin layer chromatography (TLC) was performed on silica gel 60PF254 plates.Compounds were identified using UV fluorescence ( = 254 nm) and/or staining with a 5% phosphomolybdic acid solution in ethanol following by heating.Commercially reagents were used as received from the manufacturers except for tetrahydrofuran (distilled from potassium/benzophenone) and dichloromethane (dried over calcium hydride prior to use).

General procedure for the preparation of iodides
To a stirred solution of the appropriate alcohol (1.02 mmol) in a 3/2 mixture of diethyl ether/acetonitrile (15 mL) at 0 °C or in toluene (15 mL) at 20 °C were successively added imidazole (2.25 mmol), iodine (2.45 mmol) and triphenylphosphine (2.04 mmol).The stirring was maintained for 1 h at 0 °C and then for 24 h at 20 °C or directly at 20 °C for 24 h when toluene was used.The reaction was quenched by addition of a 10% aqueous sodium thiosulfate solution (6 mL) followed by saturated aqueous ammonium chloride solution (3 mL).The organic layer was extracted with ether, washed with a 10% aqueous sodium thiosulfate solution until the solution became colourless.Then it was washed with brine, dried (MgSO4) and concentrated under reduced pressure.The residue was purified by flash column chromatography using as solvents a mixture of ethyl acetate/cyclohexane to afford the corresponding iodide.

General procedure for reduction of esters: method A with LiBH4 in THF
To a stirred solution of the appropriate ester (1.04 mmol) in anhydrous tetrahydrofuran (20 mL), at 0 °C and under argon atmosphere, was dropwise added a 2.0 M lithium borohydride solution (1.56 mmol) in tetrahydrofuran.The resulting mixture was stirred for 12 h at 20 °C, quenched by addition of saturated aqueous ammonium chloride solution (1.0 mL).After extraction with ethyl acetate, the organic layer was washed with brine, dried (MgSO4) and concentrated under reduced pressure.The residue was then purified by flash column chromatography (ethyl acetate/cyclohexane) to afford the corresponding alcohol.

General procedure for reduction of esters: method B with LiBH4 in THF/EtOH
To a stirred solution of ester (1.56 mmol) in tetrahydrofuran/ethanol (v/v 1/9), at 0 °C and under argon atmosphere was dropwise added a 2.0 M lithium borohydride solution (0.78 mmol) in tetrahydrofuran.The resulting mixture was stirred for 12 h at 20 °C, and the reaction was stopped by addition of a 0.5 M hydrochloric acid solution.After extraction with diethyl ether, the organic layer was washed with saturated aqueous sodium bicarbonate solution, followed by brine, dried (MgSO4) and concentrated under reduced pressure.The residue was then purified by flash column chromatography (ethyl acetate/cyclohexane) to afford the corresponding alcohol.
General procedure for reduction of esters: method C with LiAlH4 in THF To a stirred solution of ester (1.94 mmol) in anhydrous tetrahydrofuran (5 mL), at 0 °C and under argon atmosphere, was dropwise added a 1.0 M lithium aluminium hydride solution in tetrahydrofuran (1.16 mmol).The resulting mixture was stirred for 12 h at 20 °C.The reaction was quenched at 0 °C by sequential addition of water, 15% sodium hydroxide solution and water.The resulting mixture was dried (MgSO4), filtered and the solvent was concentrated under reduced pressure to afford the corresponding pure alcohol.