Asymmetric aldol reactions of an N -propionyl derivative of chiral auxiliary derived from terpene alcohol cis -myrtanol with benzaldehyde

The asymmetric aldol reaction was carried out by deprotonating an N -propionyl derivative of alcohol-derived terpene " cis -myrtanol", chiral auxiliary with lithium diisopropylamide (LDA), and then treating the Z -lithium enolate with benzaldehyde. Unfortunately, analysis of 1 H NMR spectrum of the crude aldol product showed poor diastereoselectivity. The boron enolate methodology was adopted to improve it. The boron enolate was generated by treatment of the N - propionyl derivative with Bu 2 BOTf and diisopropylethylamine and then treated with benzaldehyde. Analysis of 1 H NMR spectrum of the crude aldol product obtained revealed an excellent diastereoselectivity.


Introduction
The stereospecific intramolecular nitrene insertion process was chosen as a synthetic route for the synthesis of the chiral oxazolidinone auxiliaries [1][2][3][4][5][6][7] using as starting materials cheap, readily available chiral alcohol.This nitrene route to chiral oxazolidinones has been used previously by Paryzek 8 and by Alewood 9 in the field of steroid chemistry.The chiral substrate selected for investigation was the terpene alcohol cis-myrtanol 1 which is commercially available.This starting material was chosen and employed by Cadogan et al 7 for the synthesis of the chiral spiro-oxazolidinone auxiliary 4 (Scheme 1).Azidoformate 3 was synthesized from 1 according to the sequence shown in Scheme 1.The azidoformate 3 was subsequently thermally decomposed by flash vacuum pyrolysis (300°C, 0.1mmHg).This produced a mixture consisting of the spiro-oxazolidinone 4 and the six-membered oxazinone 5 in the ratio 4:1 respectively.Flash column chromatography of the crude mixture allowed the spiro-oxazolidinone 4 to be isolated in a yield of 56% 7 (Scheme 1).

Results and Discussion
The method used by Evans et al 10,11 was employed for the preparation of the N-propionyl derivative 7 of chiral auxiliary 4. In essence, solution of chiral auxiliary 4 in anhydrous THF (tetrahydrofuran) was treated with n-butyllithium at -78°C, followed by acylation of the resulting anion 6 with, cheap and readily available acylation reagent, freshly distilled propionic anhydride (Scheme 2), leading to an 80% yield of the desired N-propionyl derivative 7.

Scheme 2
The asymmetric aldol reaction was carried out by deprotonating N-propionyl derivative 7 with lithium diisopropylamide (LDA), and then treating the resulting Z-lithium enolate 8 with freshly distilled benzaldehyde (Scheme 3).The reaction was allowed to proceed for a period of 30 seconds in order to obtain a kinetic product mixture, rather than an equilibrated thermodynamic product.After work-up, the crude aldol product was isolated by flash column chromatography as a pale yellow gum in good yield (70%), and then examined by high field 1 H NMR spectroscopy.The resonances of interest were doublets in the chemical shift range 5.15-4.75ppm arising from the carbinol proton PhCHOH.Analysis revealed that only two syn diastereomers 9 and 10 ( 3 J = 3.9 and 5.9Hz) has been formed in a ratio of 70:30, respectively, giving a 40% diastereomeric excess (d.e.).The above assignments were made by measuring the vicinal coupling constants of the carbinol protons and using the known fact 12 that, for this proton, 3 J syn is typically 3-6 Hz, and 3 J anti is typically 7-9 Hz.It has been shown by a number of workers [13][14][15] that lithium-mediated aldol reactions exhibit poor levels of diastereoselection.It should be noted that the poor diastereoselectivity can be attributed to a less "tight" transition state compared to other enolate systems, e.g. that of boron, due to the relatively long Li-O bond length 16 .Furthermore, lithium does not possess true ligands, other than those of solvent, e.g.alkyl groups, which would make steric interactions in the aldol transition state greater.
After this slightly poor demonstration of selectivity with the lithium-based-enolate 8, attention was turned towards boron-mediated aldol reaction to improve the diastereoselectivity of this aldol reaction.In this procedure, the boron enolate 11 was generated by treatment of the Npropionyl derivative 7 with 1.1 equiv. of dibutylboron triflate (Bu 2 BOTf) and diisopropylethylamine and allowed to react with freshly distilled benzaldehyde for thirty minutes at -78°C (Scheme 4).Once complete, the solution was warmed to room temperature for one and three quarter hours and worked-up to yield the crude aldol product as a pale yellow oil in acceptable yield (65%).The crude product was purified by flash column chromatography to yield a single diastereomer (d.e.= >99%) as shown by high field 1 H NMR spectroscopy.Despite the poor yield (37%), the level of asymmetric induction imparted by the auxiliary 4 under these specific conditions is excellent and 13 C NMR spectroscopy indicated only one aldol product had been formed.Analysis of 1 H NMR 400 MHz spectrum confirmed that the product was a syn isomer due to the presence of small vicinal coupling constants (J= 3.9 Hz) with one doublet at 5.12 ppm arising from the PhCHOH proton.This high level of asymmetric induction imparted by oxazinone 4 in this model aldol reaction is attributed to formation of the six-membered Zimmerman-Traxler transition state 12 as shown in Scheme 5.
From a mechanistic viewpoint, when the dibutylboron triflate is added to 7, the boron initially co-ordinates to the N-acyl carbonyl groups in a tetrahedral fashion to form complex 13.Subsequent treatment with diisopropylethylamine forms the boron enolate 11 (Scheme 5).Upon benzaldehyde addition to 11, the B-O bond pertaining to the six-membered imide ring is cleaved, and the auxiliary rotates 180° about the N-C bond, allowing the boron to co-ordinate to the carbonyl oxygen of the incoming aldehyde.This results into the formation of the six-membered Zimmerman-Traxler transition state 12 as depicted in Scheme 5.It is worth noting that in the transition state 12, attack of the benzaldehyde occurs on the C α -re face of the enolate since the bulk of the auxiliary shields the C α -si face.The absolute stereochemistry of this single diastereomer 9 produced from the aldol reaction as expected from the mechanism discussed above has the syn (2'R,3'R) configuration, because it fits with the transition state 12 depicted in scheme 5.This indicates that the C α -re face of the enolate had been attacked by C α -si face of benzaldehyde.
After stirring for 30 minutes a solution of freshly distilled propionic anhydride (0.521g, 4.00mmol, 1.56 eq) in THF (5ml) was added dropwise via syringe.The resulting solution was stirred at -78°C for 5 minutes before being allowed to warm to room temperature and then stirred at this temperature for 30 minutes.TLC analysis revealed that the reaction was complete and quenching was effected with saturated aqueous sodium carbonate solution.After stirring for 10 minutes at room temperature, the layers were separated and the aqueous layer extracted with dichloromethane (3x20ml).The combined organic extracts were washed successively with saturated aqueous sodium bicarbonate solution and saturated aqueous sodium chloride solution, dried over (MgSO 4 ), filtered and evaporated to yield a pale yellow oil which was purified by flash chromatography (50g silica) using n-hexane:ether (3:1) as elution solvent, followed by Kugelrohr distillation to yield 7 as a colorless oil (0.512g, 80%); Bp= 105°C/0.03mmHg;[