Borane, chemoselectivity

Scheme 4 outlines the synthesis of key intermediate 7 in its correct absolute stereochemical form from readily available (S)-(-)-malic acid (15). Simultaneous protection of the contiguous carboxyl and secondary hydroxyl groups in the form of an acetonide proceeds smoothly with 2,2 -dimethoxypropane and para-toluene-sulfonic acid and provides intermediate 26 as a crystalline solid in 75-85 % yield. Chemoselective reduction of the terminal carboxyl group in 26 with borane-tetrahydrofuran complex (B H3 THF) affords a primary hydroxyl group that attacks the proximal carbonyl group, upon acidification, to give a hydroxybutyrolactone. Treat-... 

In continuation of our efforts to explore the utility of the SAMP/RAMP hydra-zone methodology, we developed the first asymmetric synthesis of a-phosphino ketones via formation of a carbon-phosphorus bond in the a-position to the carbonyl group [70]. The key step of this asymmetric C—P bond formation is the electrophilic phosphinylation of the ketone SAMP hydrazone 87, giving rise to the borane-adduct of the phosphino hydrazone 88 with excellent diastereoselectiv-ity (de = 95-98%). Since these phosphane-borane adducts are stable with respect to oxidation, the chemoselective cleavage of the chiral auxiliary by ozonolysis leading to the a-phosphino ketones (R)-89 could be accomplished with virtually no racemization. Using RAMP as a chiral auxiliary, the synthesis of the enantiomer (S)-89 was possible (Scheme 1.1.25). 

Borane also makes a good alternative to LiAlH4 for reducing amides as the two reagents have slightly different chemoselectivity—in this example borane reduces an amide in the presence of an ester. 

Borane is a highly chemoselective reagent for the reduction of carboxylic acids in the presence of other reducible functional groups such as esters, and even ketones. 

Zagorevskii et al. have observed the same stereoselective trans reduction with several tetrahydro-T-carbolines by generating the diborane from NaBIlt in situ (equation 79).As expected, treatment of these carbolines with pyridine-borane and acid gives the cw-fused isomers (equation 80).Bosch and coworkers have also utilized an in situ generation of diborane to effect the chemoselective reduction of the indole double bond during the synthesis of a new indolomorphan. 

The reactivity of boranes is dominated by the desire to accept an electron pair into the empty p-orbital. Therefore boranes reduce electron-rich carbonyl groups fastest. In the context of carboxylic acid reduction a triacylborate 35 is formed first. Compared to, for example, ketones, esters are less electrophilic because of conjugation between the carbonyl group and the lone pair of the sp -hybridized oxygen atom. However, in the case of boron esters such as 35, the oxygen next to the boron has to share its lone pair between the carbonyl group and the empty p-orbital of the boron. This fact makes them considerably more reactive than normal esters and allows the chemoselective reduction of carboxylic acids in the presence of esters or acyl chlorides. 

The facile reduction of the -COOH group by BHj THF or BH3 SMej has been employed for chemoselective reductions of the carboxyl group in the presence of ester or lactone functionalities using a stoichiometric quantity of the borane. The carbonyl group in triacylboranes resembles the reactivity of an aldehyde or a ketone more than of an ester (ester resonance) due to electron delocalization from the acyl oxygen into the p orbital of boron. 

Borane is typically used as a THF (BHs-THF) or dimethylsulfide complex (BH3 SMe2). Although the reactivity of the two complexes is similar, the boron dimethylsulfide species is more stable over longer periods of time. Borane will chemoselectively reduce a carboxylic acid in the presence of an ester or nitrile. Reviews (a) Seyden-Penne, J. Reductions by the Alumino- and Borohydrides in Organic Synthesis, Wiley-VCH New York, 1997, 2" edition, (b) Brown, H. C. ... 

Some amino alcohols react with borane to generate oxazaborolidines, which have been mainly used in asymmetric reduction of ketones (Section 3.2.3) and imines (Section 3.3.1) [NNl, S3]. In addition, they can also perform some chemoselective reductions [IWl]. 

For the synthesis of trialkylboranes. hydroboration is carried out with a borane solution in THF or with the borane-methyl sulfide complex (BMS) in THF, diethyl ether, or dichloromethane. Diborane reacts rapidly and quantitatively with alkenes to produce a solution of trialkylborane [16] (eq (13)). The addition of dialkylboranes. such as 9-borabicyclo[3.3.1]nonane (9-BBN. 3). disiamylborane (1), or dicyclohexylb-orane (2), to alkenes or alkynes gives mixed alkylboron compounds. The high regio-. stereo-, or chemoselectivity in the additions of these borane reagents unsaturated C—C bonds have been extensively used in organic syntheses. 

The way they solved the problem was this. (S )-(-)-Malic acid is available cheaply. Its dimethyl ester 127 could be chemoselectively reduced by borane to give 128. Normally borane does not reduce esters and clearly the borane first reacts with the OH group and then delivers hydride to the nearer carbonyl group. The primary alcohol was chemoselectively tosylated 129 and the remaining (secondary) OH protected with a silyl group 130 (TBDMS stands for t-butyldimethylsilyl and is sometimes abbreviated to TBS). Now the remaining ester can be reduced to an aldehyde 131 and protected 132. Displacement of tosylate by cyanide puts in the extra carbon atom 133 and reduction gives 134, that is the dialdehyde 126 in which one of the two aldehydes is protected. This compound was used in the successful synthesis of lipstatin. 

Alkenylzinc reagents. Hydroboration of pinacolatoborylalkynes with dicyclohexyl-borane affords 1,1-diboryl-l-alkenes. The dicyclohexylboryl group is selectively exchanged on treatment with Me2Zn, and the resulting species show differentiated chemoselectivity such that homologation/functionalization proceed in a desired manner. ... 

Thus, chemoselective reductions of ketones have been achieved in the absence of solvent 5. In general these reactions are performed at room temperature using 40-100% excess Alpine-Borane and typical ketones are reduced in 7-14 days. 

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