Total synthesis of (5 S ,6 S )-6-amino-2,8-dimethylnonan-5-ol and (5 S ,6 S )-6-amino-7-cyclohexyl-2-methylheptan-5-ol

A stereoselective synthesis of two complex 1,2-dialkyl-2-amino-1-ethanols [(5 S ,6 S )-6-amino- 2,8-dimethylnonan-5-ol and (5 S ,6 S )-6-amino-7-cyclohexyl-2-methylheptan-5-ol] is described from 5-azido-3,5,6-trideoxy-6-isopropyl-L -idose and 5-azido-3,5,6-trideoxy-6-cyclohexyl-L - idose respectively.


Introduction
The Chiron Approach 1 to the synthesis of chiral target molecules from carbohydrates is now a well established tool in organic chemistry and this approach recently allowed us to make new contributions to the field of carbasugars consisting of new syntheses of cyclohexane α-amino acids 2 , dehydrohydroxymethylinositols 3 and cyclopentane β-amino acids 4 , among others.The large number of additional synthetic applications for this strategy include the transformation of D-ribose into compound 2 5 , an isostere incorporated in several type 1 renin inhibitors 5,6 currently used as agents to lower blood pressure.However, other type 2 compounds have yet to be prepared from carbohydrates.In connection with this work and as a part of our ongoing programme aimed at the design, synthesis and pharmacological evaluation of new β-secretase inhibitors for the treatment of Alzheimer's disease, we became interested in the preparation of aminoalcohols 4a and 4b 7 , which were efficiently prepared from D-glucose.

Results and Discussion
We first studied the preparation of amino alcohol 4a starting from the known azidofuranose 5a 8 , which is easily prepared from D-glucose.Removal of the acetonide protecting group of 5a using a standard procedure 9 provided lactol 6a as an unstable gum, which was directly reduced 10 with NaBH 4 to the corresponding azidotriol 7a.In accordance with our synthetic plan, we proceeded to carry out an indirect selective protection of the hydroxyl group at position C 4 of compound 7a in a three-step sequence.Once the terminal 1,2-diol system of this compound was selectively protected as the acetonide by treatment with 2,2-dimethoxypropane and p-toluensulfonic acid 10 , the free OH group of the resulting compound 8a was protected 11 as the benzyloxy derivative and, finally, the fully protected compound 9a readily provided the desired 1,2-diol-5-azido derivative 10a by removal 11 of the acetonide protecting group.The mass spectrum of 8a confirmed the molecular formula C 12 H 23 N 3 O 3 and the selective protection of its 1,2-diol system was easily established from the 1 H NMR spectrum, which showed two singlets at 1.37 and 1.44 ppm corresponding to the two methyl groups of the acetonide subunit.The presence of the free OH group at C 4 was easily deduced from the presence of a band at 3475 cm -1 in the IR spectrum.In addition, protection of this free OH group as the benzyloxy derivative was confirmed by the expected signals for the benzyl group in the 1 H NMR spectrum of 9a: two doublets at 4.55 and 4.60 ppm corresponding to the two protons of the methylene subunit together with a multiplet at 7.34-7.36ppm due to the five protons of the benzene ring.Finally, the molecular formula C 16 H 25 N 3 O 3 established for compound 10a from its mass spectrum confirmed the desired selective deprotection of the 1,2-diol system, a situation further confirmed by the spectroscopic data, mainly from the 1 H NMR spectrum, which showed the expected signals for all twenty five protons, including two doublets at 4.58 and 4.64 ppm corresponding to two protons and a multiplet at 7.29-7.36ppm due to five protons.Both of these signals are due to the benzyloxy substituent.A broad singlet was also observed at 2.90 ppm due to a free OH group and a multiplet at 3.38-3.87ppm corresponding to the second free OH group and the five protons at positions C 1 , C 2 , C 4 and C 5 .
We next reacted diol 10a with NaIO 4 to produce the key aldehyde 11a, 11 which was subjected to a Wittig olefination 12 by treatment with Ph 3 P=C(CH 3 ) 2 in THF.The molecular formula (C 18 H 27 N 3 O) of the resulting olefin 12a was confirmed by the mass spectrum (m/z = 302, MH + ) and the presence of a double bond was easily established from the 1 H NMR spectrum: a singlet due to three protons was observed at 1.64 ppm along with a second singlet (three protons) at 1.71 ppm -these two signals correspond to the two methyl groups at position C 2 .A multiplet corresponding to one proton was seen at 5.09-5.17ppm and this is due to proton H 3 .The presence of a strong band at 2105 cm -1 in the IR spectrum confirmed that the azide substituent at position C 6 remained unaltered during the synthetic sequence leading to olefin 12a.
In summary, we have demonstrated that the Chiron Approach is a useful strategy for the efficient stereospecific synthesis of complex 1,2-disusbtituted-1,2-aminoalcohols of interest for chemical and biological purposes.Work is currently in progress aimed at the incorporation of compounds 4a and 4b as isosteres in a panel of peptides for subsequent evaluation as anti-Alzheimer agents.

Experimental Section
General Procedures.Melting points were determined on a Kofler Thermogerate apparatus and are uncorrected.Infrared spectra were recorded on a MIDAC FTIR spectrophotometer.Nuclear magnetic resonance spectra, unless otherwise specified, were recorded on a Bruker DPX-250 apparatus using deuterochloroform solutions containing tetramethylsilane as internal standard.Mass spectra were obtained on a HP 5988A mass spectrometer.Thin layer chromatography (tlc) was performed using Merck GF-254 type 60 silica gel and hexane/ethyl acetate mixtures as eluant; tlc spots were visualized with ultraviolet light or Hanessian mixture.Column chromatography was carried out using Merck type 60 230-400 mesh silica gel.Solvents were purified as per ref.14.Solutions of extracts in organic solvents were dried with anhydrous sodium sulfate.

5-Azido-3,5,6-trideoxy-6-isopropyl-1,2-O-isopropylidene-L-iditol
( 8a).2,2-Dimethoxypropane (45 mL), copper sulfate (1 g) and p-toluensulfonic acid monohydrate (0.04 g, 0.23 mmol) were added to a solution of triol 7a (0.49 g, 2.26 mmol) in dry acetone (30 mL) and the suspension was stirred at room temperature for 24 h.The reaction mixture was neutralized with saturated aqueous sodium bicarbonate solution, filtered through Celite and the solids washed with dichloromethane.The solvent was evaporated and the residue was dissolved in water (30 mL) and extracted with dichloromethane (3 x 30 mL).The combined organic layers were dried over anhydrous sodium sulfate, filtered, evaporated in vacuo and the resulting residue and tetrabutylammonium iodide (0.003 g, 0.008 mmol) was added.A solution of compound 8a (0.21 g, 0.80 mmol) in dry THF (2 mL) was added to the above suspension at 0 ºC and the mixture was stirred for 10 min and then allowed to warm up to room temperature.Benzyl bromide (0.11 mL, 0.88 mmol) was added and the resulting reaction mixture was heated at 50 ºC for 3 h.Methanol (1 mL) was added and the heating was maintained for a further 2 h.The reaction mixture was filtered through Celite, the solids washed with dichloromethane, and the filtrate evaporated to dryness.The residue was dissolved in dichloromethane (10 mL) and washed with water (2 x 10 mL).The combined organic layers were dried with anhydrous sodium sulfate, filtered and evaporated in vacuo to give 5-azido-4-O-benzyl-3,5,6-trideoxy-6-isopropyl-1,2-O-isopropylidene-L-iditol (9a) as a yellow oil (0.27g, 97% yield).