Borane, reduction

COREY Enalioselaclive borane reduction Enantioselective reduction ol ketones by borane or catecholborane catalyzed by oxazaborolldine 3... 

This is one of the few methods available for the direct and efficient conversion of an acid, via the acid chloride, to an ortho ester. The preparation of the oxetane is straightforward, and a large number of oxetanes have been prepared [triol, (EtO)2CO, KOH]." In addition, the -butyl analogue has been used for the protection of acids. During the course of a borane reduction, the ortho ester was reduced to form a ketal. This was attributed to an intramolecular delivery of the hydride. ... 

Scheme 10.54 Borane reduction of acetophenone with sulfoximine ligand.

Scheme 10.55 Borane reductions of ketones with p-hydroxy sulfoximine ligand.

In order to avoid the use of a rather expensive and potentially dangerous borane complex, Bolm et al. have developed an improved procedure for the borane reduction of ketones, which involved two inexpensive reagents namely NaBH4 and TMSCI. The reduction of a series of ketones was examined applying these novel reaction conditions and the same p-hydroxy sulfoximine ligand to that described above (Scheme 10.56). For most ketones, both the level of asymmetric induction and the yield compared favorably to the precedent results. 

In 1994, the scope of this p-hydroxy sulfoximine ligand was extended to the borane reduction of ketimine derivatives by these workers. The corresponding chiral amines were formed with enantioselectivities of up to 72% ee, as shown in Scheme 10.57. It was found that the A -substituent of the ketimine had a major influence on the asymmetric induction, with a ketoxime thioether (SPh) being the most successful substrate. 

Scheme 10.57 Borane reductions of ketimine derivatives with P-hydroxy sulfoximine ligand.

Other S/N ligands have been investigated in the enantioselective catalytic reduction of ketones with borane. Thus, Mehler and Martens have reported the synthesis of sulfur-containing ligands based on the L-methionine skeleton and their subsequent application as new chiral catalysts for the borane reduction of ketones." The in situ formed chiral oxazaborolidine catalyst has been used in the reduction of aryl ketones, providing the corresponding alcohols in nearly quantitative yields and high enantioselectivities of up to 99% ee, as shown in Scheme 10.60. 

Scheme 10.58 Borane reductions of meso A -phenylimides with thiazazincolidine complex.

Scheme 10.60 Borane reductions of ketones with L-methionine-derived S/N ligand.

Scheme 10.63 Borane reductions of aryl methyl ketones with MerCO ligand.

Scheme 10.64 Heterogeneous borane reduction of acetophenone with MerCO ligand.

Scheme 10.65 Ga-catalysed borane reductions of ketones with MTBH2 ligand.

The section will cover various aspects of the synthetic route development and the scale up to make several kilograms of final compound 1. As will be seen, a novel sulfoxide-directed stereospecific borane reduction was discovered in this effort and the scope and application of this reaction will be discussed in Section 5.2 [5],... 

Prior literature indicated that olefins substituted with chiral sulfoxides could indeed be reduced by hydride or hydrogen with modest stereoselectivity, as summarized in Scheme 5.10. Ogura et al. reported that borane reduction of the unsaturated sulfoxide 42 gave product 43 in 87 13 diastereomer ratio and D20 quench of the borane reduction mixture gave the product 43 deuterated at the a-position to the sulfoxide, consistent with the hydroboration mechanism [10a]. In another paper, Price et al. reported diastereoselective hydrogenation of gem-disubstituted olefin rac-44 to 45 with excellent diastereoselectivity using a rhodium catalyst [10b],... 

On the other hand, borane reduction of sulfoxide 46 gave a mixture of 47 and 48 in equal amounts and, more interestingly, no reaction of 47 occurred with borane under the same conditions. These results indicated that borane reduction of the olefin in 46 required the activation and potential direction by the sulfoxide oxygen. 

A novel, unprecedented sulfoxide-directed borane reduction of the a,P-unsaturated sulfoxide to the saturated sulfide was discovered. 

Initially, two plausible mechanisms were considered, as depicted in Scheme 5.16. The first was a hydroboration route (a), where the B-H bond was added across the olefin from the same face of S-0 and upon aqueous work-up, the resulting C-B bond was replaced with a C-H bond. The tis B-H addition to the olefin led to the cis-stereochemistry of the two adjacent aryl substituents. The reduction of the sulfoxide oxygen occurs in the next step. The alternative mechanism was the borane reduction route (h), which was similar to 1,4-addition of hydride,... 

Scheme 5.16 Two plausible mechanistic pathways for the borane reduction.

Application of the Sulfoxide-Directed Borane Reduction to Other Similar Compounds... 

We have developed the efficient synthesis of the SERM drug candidate 1 and successfully demonstrated the process on a multiple kilogram scale to support the drug development program. A novel sulfoxide-directed borane reduction of vinyl sulfoxides was discovered. The mechanistic details of this novel reaction were explored and a plausible mechanism proposed. The sequence of asymmetric oxidation of vinyl sulfoxides followed by stereospecific borane reduction to make chiral dihydro-1,4-benzoxathiins was applied to the asymmetric synthesis of a number of other dihydro-1,4-benzoxathiins including the sweetening agent 67. 

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