Chiral reduction

The enantioselective introduction of chiral centres into an achiral molecule can nowadays be achieved most easily using chiral reductants or oxidants. 

The copper-catalyzed chiral reduction of -substituted ,/Tunsaturated lactones with PMHS and (S)-/ -Tol-BINAP in the presence of a hindered alcohol can be carried out in moderate to good yields with moderate ee values.599 The reaction is useful for both butenolides and pentenolides. Inferior results are realized with diphenylsilane as the reducing agent. Excellent results employing PMHS and the DTBM-SEGPHOS ligand are possible (Eq. 354).598... 

The chiral reduction of -substituted a,/3-unsaturated lactams with PMHS in the presence of (S)-/ -Tol-BINAP as the chiral ligand with a copper catalyst results in -substituted lactams in excellent yield and with greater than 90% ee.599 This method has been applied in an efficient enantioselective synthesis of the antidepressant (-)-paroxetine (Eq. 356). 

One exception to the use of primary phosphines is in the reported syntheses of the catASium M dass of ligands 20 [46-49]. In one report, reaction of the cyclic sulfate with P(TMS)3 yields the TMS-protected secondary phospholane, which could then be reacted with the appropriate 1,2-dichloro spedes [46]. An alternative procedure to the same intermediate involves preparation of 1-phenyl-phospholane via the bismesylate, subsequent lithium-induced P-Ph deavage, and quenching with TMSC1 [49]. The ligand based on 2,3-dichloromaleic anhydride (20a originally referred to as MalPHOS [46]) has been shown to be effective for the chiral reduction of a- and /1-deliydroarnino acid derivatives and itaconate derivatives. 

Chemical catalysts for transfer hydrogenation have been known for many decades [2e]. The most commonly used are heterogeneous catalysts such as Pd/C, or Raney Ni, which are able to mediate for example the reduction of alkenes by dehydrogenation of an alkane present in high concentration. Cyclohexene, cyclo-hexadiene and dihydronaphthalene are commonly used as hydrogen donors since the byproducts are aromatic and therefore more difficult to reduce. The heterogeneous reaction is useful for simple non-chiral reductions, but attempts at the enantioselective reaction have failed because the mechanism seems to occur via a radical (two-proton and two-electron) mechanism that makes it unsuitable for enantioselective reactions [2 c]. 

Hydrogen atom transfer implies the transfer of hydrogen atoms from the chain carrier, which is the stereo-determining step in enantioselective hydrogen atom transfer reactions. These reactions are often employed as a functional group interconversion step in the synthesis of many natural products wherein an alkyl iodide or alkyl bromide is converted into an alkane, which, in simple terms, is defined as reduction [ 19,20 ]. Most of these reactions can be classified as diastereoselective in that the selectivity arises from the substrate. Enantioselective H-atom transfer reactions can be performed in two distinct ways (1) by H-atom transfer from an achiral reductant to a radical complexed to a chiral source or alternatively (2) by H-atom transfer from a chiral reductant to a radical. 

Scheme 12 Memory of chirality reduction of Barton esters...

The chiral reduction of phenacyl chloride (2) was run using either the methyl- or methoxy- oxazaborolidine (3) as the catalyst. After optimization of the reaction... 

Therefore better methods for the chiral reduction of indole-2-carboxylic acid derivatives would provide an elegant synthesis of this intermediate. A study by Kuwano and Kashiwabara of the reduction of indole derivatives into the corresponding indohnes found that a range of the more common ligand systems gave almost no enantioselectivity but the TRAP ligand gave the chiral indolines in up to 95 % ee for reduction of the methyl ester (B, R=Me, R =H). Further developments are awaited. 

The drug candidate OPC-51803 is the first nonpeptide vasopressin V2-receptor-selective agonist that is in phase II clinical trials and the best chiral reduction to the intermediate acid (E) was with ruthenium acetate-[(5)-H8-BlNAP] that gave a 77 % ee (Figure 1.10). An improved catalyst system will be needed for large scale production. 

Good methods for the chiral reduction of tetrasubstituted and terminal alkenes have yet to be fully developed. 

Asymmetric reduction of a,/l-unsaturated aldehydes with transition metal catalysts has not yet proven ready for widespread industrial application. One area, namely the chiral reduction of enals to yield chiral alcohols using bakers yeast has been... 

Figure 7.32 Chiral reduction to (S)-metolachlor with organometallic catalyst.

In addition, monoterpenes can provide some useful chiral reagents, such as the pinene-based organoborane reagents for chiral reductions, which have been reviewed extensively.42 Camphor-derived organic acids such as camphenesulfonic acid can be used for the resolution of racemic bases and is a common practice in industry (Chapter 6). 

Scheme 13 Option. A great deal of work was carried out to find a reduction procedure for the chiral reduction of the readily available R-aminoketone (IX). In addition, despite the benzyl blocking group, the R-aminoketone (XVII) was also the subject of chiral reduction work.

Delorme and coworkers have published a stereoselective route that is effective with a wide range of amines, including those without a stereocenter on the amine (Scheme 8) [43]. Chiral reduction of the appropriate benzophe-none (as a chromium tricarbonyl complex) using Corey s oxazaborolidine approach afforded the benzhydrol with 91% ee. Treatment with tetrafluo-roboric acid followed by the piperazine gave the desired benzhydryl piperazine without any erosion of stereochemical purity after decomplexation. In addition to simplifying analogue synthesis, these two complementary routes provide a useful base for the future development of stereoselective manufacturing routes. 

Further results on asymmetric hydrogenations of activated carbonyl compounds catalyzed by bis(dimethylglyoximato) cobalt (Il)-chiral amine complexes have been reported (55,56). Some chiral reductive dimerizations were observed (55). 

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