Optically active secondary

An optically active, secondary terpene alcohol. ( —)-Piperilol is found in various eucalyptus oils and (-l-) piperitol in the oil from a species of Andropogon. A somewhat viscous oil of pleasant smell. It yields piperitone on oxidation with chromic acid. 

With optically active secondary alcohols the reaction proceeds with predominant, but incomplete, inversion of configuration. 

Allylsilanes are available by treatment of allyl acetates and allyl carbonates with silyl cuprates17-18, with antarafacial stereochemistry being observed for displacement of tertiary allyl acetates19. This reaction provides a useful asymmetric synthesis of allylsilanes using esters and carbamates derived from optically active secondary alcohols antarafacial stereochemistry is observed for the esters, and suprafacial stereochemistry for the carbamates20,21. 

Claisen and Carroll rearrangements of hydroxyalkenylsilanes provide an asymmetric synthesis of allylsilanes from optically active secondary alcohols39,40. 

Scheme 17. Improved synthesis of optically active secondary phosphine-boranes...

Two contrasting conclusions have been reported in the reactions of lithium aluminium hydride in THF with phosphine oxides and phosphine sulphides respectively. The secondary oxide, phenyl-a-phenylethylphos-phine oxide (42), has been found to be racemized very rapidly by lithium aluminium hydride, and this observation casts some doubt on earlier reports of the preparation of optically active secondary oxides by reduction of menthyl phosphinates with this reagent. A similar study of the treatment of (/ )-(+ )-methyl-n-propylphenylphosphine sulphide (43) with lithium aluminium hydride has revealed no racemization. These results have been rationalized on the basis of the preferred site of attack of hydride on the complexed intermediate (44), which, in the case of phosphine oxides (X = O), is at phosphorus, and in the case of the sulphides (X = S), is at sulphur. Such behaviour is comparable to that observed during the reduction of phosphine oxides and sulphides with hexachlorodisilane. ... 

The reaction of organometalic compounds with nitrones can be applied not only to the synthesis of stable nitroxyl radicals but also to the preparation of optically active secondary amines (Scheme 2.162) (617, 618). 

Hu S, Tat D, Martinez C, Yazbeck D, Tao J (2005) An efficient and practical chemoenzymatic method for preparing optically active secondary amines. Org Lett 7 4329-4331... 

Catalytic asymmetric hydrosilylation of prochiral olefins has become an interesting area in synthetic organic chemistry since the first successful conversion of alkyl-substituted terminal olefins to optically active secondary alcohols (>94% ee) by palladium-catalyzed asymmetric hydrosilylation in the presence of chiral monodentate phosphine ligand (MOP, 20). The introduced silyl group can be converted to alcohol via oxidative cleavage of the carbon-silicon bond (Scheme 8-8).27... 

Menthol ester (20) with (l/ S)-frans-2,2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (19) has been utilized to produce ( R)-trans-2, 2-dimethyl-3-(2,2-dichloroethenyl) cyclopropanecarboxylic acid (21), an acid moiety of transfluthrin (22) [9]. Matsuo et al. surveyed various optically active secondary alcohols for their potential in the optical resolution of (lRS)-trans-chrysanthemic acid [10] (Scheme 2). 

It is well known that bakers yeast is capable of reducing a wide range of ketones to optically active secondary alcohols. A recent example involves the preparation of the (R)-alcohol (7) (97 % ee) (a key intermediate to ( norephedrine) from the corresponding ketone in 79 % yield1281. Other less well-known organisms are capable of performing similar tasks for instance, reduction of 5-oxohexanoic acid with Yamadazyma farinosa furnishes (R)-5-hydroxyhexanoic acid in 98 % yield and 97 % ee[29]. 

It is possible to use isolated, partially purified enzymes (dehydrogenases) for the reduction of ketones to optically active secondary alcohols. However, a different set of complications arises. The new C H bond is formed by delivery of the hydrogen atom from an enzyme cofactor, nicotinamide adenine dinucleotide (phosphate) NAD(P) in its reduced form. The cofactor is too expensive to be used in a stoichiometric quantity and must be recycled in situ. Recycling methods are relatively simple, using a sacrificial alcohol, or a second enzyme (formate dehydrogenase is popular) but the real and apparent complexity of the ensuing process (Scheme 8)[331 provides too much of a disincentive to investigation by non-experts. 

Hydrogenation of imines, e.g. 45-48, with a chiral titanocene catalyst at 2000 psig gave the corresponding optically active secondary amines in high enantiomeric excess74. Imines are reduced to amines by trichlorosilane/boron trifluoride etherate in benzene75. 

Extension (70) of this investigation to the reduction of A-phenylazomethines with 36d-LAH gave optically active secondary amines (eq. [IS]). The products had the S configuration, as predicted by reference to Scheme 9, with hydride transfer of the less shielded H2 occurring preferentially when the phenyl points away from the shielding 3-O-benzyl group of the sugar derivative. 

This acylating agent has also been used in the resolution of indolines see Gotor-Fernandez, V., Rebolledo, F. and Gotor, V., Chemoenzymatic preparation of optically active secondary amines a new efficient route to enantiomerically pure indolines. Tetrahedron Lett., 2006,17, 2558. 

The enantioselective addition of alkyllithium to aldehyde in the presence of the lithium salt of diaminoalcohol (94) yielded optically active secondary alcohols as shown in Table 2. 

One popular method that has been apphed to industrial processes for the enantio-selective reduction of prochiral ketones, leading to the corresponding optically active secondary alcohols, is based on the use of chiral 1,3,2-oxazaborolidines. The original catalyst and reagent system [diphenyl prolinol/methane boronic acid (R)] is known as the Corey-Bakshi-Shibata reagent. Numerous examples... 

Microbial reduction of ketones is a useful method for the preparation of optically active secondary alcohols. Recently, both enantiomers of secondary alcohols were prepared by reduction of the corresponding ketones with a single microbe.Thus, reduction of aromatic ketones with Geotrichum candidum IFO 5767 afforded the corresponding 5-alcohols in an excellent ee when Amberlite XAD-7, a hydro-phobic polymer, was added to the reaction system the same microbe afforded... 

The transesterification reaction does not involve fission of the C—O bond of the alcohol, and therefore optically active secondary alcohols yield optically active orthoformates [34, 38, 45-48]. 

As a consequence of steric congestion in the transition state, ketones generally require high pressures to increase the reaction rate but yield optically active secondary alcohols in high . Thus, acetophenone yields 100% . of (S -l-phenylethanol at 2000 atm ... 

The racemization of an optically active secondary halide with the chiral carbon carrying the halogen (e.g., 2-chlorobutane) may occur ift solution and, usually, the more polar and better ionizing the solvent is, the more readily the substance is racemized. Ionization of the halide by an SK1 process probably is responsible, and this certainly would be promoted by polar solvents (see Section 8-6). All indications are that an alkyl carbocation once dissociated from its accompanying anion is planar and, when such an ion recombines with the anion, it has equal probability of forming the d and L enantiomers ... 

Carbonyl Addition Diethylzinc has been added to benzaldehyde at room temperature in the presence of an ephedra-derived chiral quat (8) to give optically active secondary alcohols, a case in which the chiral catalyst affords a much higher enantioselectivity in the solid state than in solution (47 to 48, Scheme 10.6) [30]. Asymmetric trifluoromethylation of aldehydes and ketones (49 to 50, Scheme 10.6 [31]) is accomplished with trifluoromethyl-trimethylsilane, catalyzed by a quaternary ammonium fluoride (3d). Catalyst 3d was first used by the Shioiri group for catalytic asymmetric aldol reactions from silyl enol ethers 51 or 54 (Scheme 10.6) [32]. Various other 1,2-carbonyl additions [33] and aldol reactions [34] have been reported. 

Application of this sequence to alkyl aryl ketones generally gives the tertiary alcohols in 85-99% optical purity. However, separation of the adducts of prochiral dialkyl ketones is generally difficult. The resolution of adducts of aldehydes by chromatography is impractical desulfuration of the unresolved adducts results in optically active secondary methylcarbinols in only 25-45% optical purity. 

Hydrogenation of acyclic aromatic (V-arylimines, to the corresponding optically active secondary amines with up to 99% ee, is catalysed by an iridium(I) complex... 

In summary, this organocatalytic alkylation of aldehydes and ketones is a promising route for preparation of optically active secondary and tertiary alcohols and is of general interest. Certainly, improvement of the asymmetric induction as well as applications of other nucleophiles will be the next major challenge in this field to make this synthetic concept competitive with alternative routes. 

Optically active amino thiocyanate derivatives of (—)-norephedrine [e.g. (44)] have been found to act as effective aprotic ligands for enantioselective addition of diethylzinc to aldehydes.115 This reaction has provided optically active secondary alcohols with ee up to 96%. 

OH - —NTfCHj. Primary or secondary alcohols are converted to protected secondary amines by this triflamide under Mitsunobu conditions (triphenylphos-phine, diethyl azodicarboxylate) in 70-86% yield. The reaction proceeds with inversion, and is useful for preparation of optically active secondary amines. 

---