Enantioselective reduction of prochiral aryl ketones using a novel chiral auxiliary derived from a labdane diterpene

A novel chiral 2-methoxy-1,3,2-dioxaborolane derived from 2  ,3  -dihydroxycativic acid, a labdane-type diterpene isolated from aerial parts of Baccharis scandens DC., is reported as a highly effective chiral auxiliary. This compound has been successfully used in the borane dimethyl sulfide complex-mediated asymmetric reduction of prochiral aryl ketones at room temperature. Very good chemical yields (up to 89%) and high enantioselectivities were obtained.


Introduction
Stereoselective reduction of prochiral ketones to their corresponding enantiopure secondary alcohols is a key step in the preparation of a variety of pharmaceutical products. 1Introduction of chirality in organic molecules through the use of chiral reagents is a valuable synthetic tool in organic chemistry.As such, the development of chiral auxiliaries or catalysts to perform reductions with high enantioselectivity has attracted much attention.New methods such as asymmetric transfer hydrogenation, 2 metal catalyzed hydrogenations, 3 enzymatic reactions 4 and the use of metal hydride transfer reagents, 5 have been reported.
The use of chiral boron reagents has gained importance during the last decade, 6 and some oxazaborolidines function as excellent catalysts for enantioselective borane reduction of prochiral ketones. 7In addition, 1,3,2-dioxaborolanes and 1,3,2-dioxaborinanes are well known as chiral reagents in many regio-, stereo-and enantioselective reactions. 8,9n the other hand, numerous chiral auxiliaries and catalysts are derived from natural sources.Natural products isolated from plants are of particular interest because they can often mediate significant levels of stereoselection.In this way, boron reagents derived from chiral monoterpenes are useful in asymmetric synthesis; 10 versatile pinane-based reagents have been successfully applied to many chiral transformations. 11n this paper we describe the synthesis and the chiral properties of a novel 2-methoxy-1,3,2dioxaborolane employed in borane-mediated asymmetric reduction of prochiral ketones.The 5membered cyclic chiral borate was prepared from 2,3-dihydroxycativic acid, a labdane-type diterpene isolated from aerial parts of Baccharis scandens DC. and trimethoxyborane.The borane-dimethylsufide complex was used as the hydride source.The corresponding optically active alcohols were achieved in high chemical yields (89-99%) and good enantioselectivities (64-98% ee).Additionally, the effect of chiral auxiliary-substrate ratio and temperature on the enantioselectivity is discussed.

Results and Discussion
From aerial parts of B. scandens DC., a species that grows in the semi-arid western region of Argentina, was isolated 2,3-dihydroxycativic acid (45 mg/500 g plant) (1). 12Methylation of the dihydroxycativic acid 1 with diazomethane followed by Pd-catalyzed hydrogenation yielded the methyl ester 2. The corresponding 2-methoxy-1,3,2-dioxaborolane 3 was synthesized in situ from the methyl ester 2 with trimethoxyborane in dry toluene at reflux for 8 h (Scheme 1).Its structure was supported by IR, 1 H and 13 C NMR spectral data. 13 In order to study the potential of this boronate ester 3 in the borane-mediated asymmetric reduction, we selected a series of alkylaryl ketones 4-10 as substrates.The dioxaborolane 3 (10 mol %) was applied, without isolation, in the borane dimethylsulfide complex-mediated asymmetric reduction (Scheme 2).The corresponding optically active R-alcohols 11-17 were isolated in excellent chemical yields and good enantiopurity for sterically hindered ketones (Table 1).Absolute configurations determined by comparison of optical rotation with those described in the literature.d Absolute configurations determined by comparison of retention times by chiral GC analyses (Supelco -DEX 120 column).e Chemical yields of isolated products.
The results show that there is only marginal dependence of the ee from the amount of chiral catalyst.In addition, we also studied the effect of reaction temperature on ee and chemical yield (Table 3).a Chemical yields of isolated product.b Enantiomeric excesses were determinate by chiral HPLC using the chiral column, Chiralcel OD-H.Interestingly, room temperature seems optimal for the asymmetric reductions using compound 3 as the borane-coordinating auxiliary.The auxiliary may not be stable at 50 °C and at -78 °C the auxiliary formation may be too slow. 18

Conclusions
The asymmetric reduction of prochiral ketones 4-10 using a new chiral auxiliary, 2-methoxy-1,3,2-dioxaborolane 3, in the borane reduction was studied.The catalyst was derived from 2,3-dihydroxycativic acid, a natural product isolated from the aerial parts of Baccharis scandens DC.Steric and/or electronic factors were discussed.In the cyclic aryl ketones series, compound 3 reduced 1-indanone 9 and -tetralone 10 in excellent ee (95 and 96% ee, respectively).Aryl methyl ketones derived from acetophenone showed good chemical yields and moderated to good enantioselectivities.In addition, the effect of temperature and amount of chiral reagent on the enantioselectivity of the reduction were also reported.

Experimental Section
General.Ketones 1-8, borane-dimethylsulfide and trimethoxyborane were obtained from Aldrich Chemical Co.All reactions were carried out under a dry nitrogen atmosphere.The purity of all reagents was checked by NMR spectroscopy.Dry toluene was used.THF was freshly distilled over sodium before use.CC was performed on silica gel G 70-230 mesh. 1 H NMR spectra were recorded in CDCl3 at 200.13 MHz, whereas 13 C NMR spectra were obtained at 50.23 MHz on a Bruker AC-200 using TMS as an internal standard.Optical rotations were obtained on a Perkin-Elmer 341 polarimeter, and IR spectra were recorded on a Bruker IFS-2S spectrometer.Enantiomeric excesses were determined by HPLC with Daicel Chiralcel OD-H column or by CG with Supelco -DEX 120 column.

Typical procedure for the asymmetric reduction of ketones (1-8)
To a THF (1 mL) solution of dioxaborolane 3 (0.132 mg, 0.10 mmol) prepared above was added 2M BH3 .Me2S (28 L, 0.30 mmol).After being stirred at room temperature for 10 min, the solution of acetophenone 4 (120 L, 1 mmol) in THF (2 mL) was added via syringe pump over 1 h.The reaction mixture was stirred for 5 h at room temperature.The reaction mixture was quenched with MeOH (1 mL).Solvent was removed under reduced pressure.The residue was flash chromatographed though a small pad of silica gel using n-hexane/ethyl acetate (9:1) as solvent.

Table 2 .
Asymmetric reduction of α-tetralone 10 with varying amounts of chiral auxiliary 3 a Chemical yields of isolated product.b Enantiomeric excesses determined by chiral HPLC using the Chiralcel OD-H column.