Carboxylic acids, reduction with borane

The partial hydrolysis of 4a with methanolic potassium hydroxide followed by selective carboxylic acid reduction with excess borane and treatment of the resulting monoalcohol with methanesulfonyl chloride affords methyl 4-0-methanesulfonyl-2,3-0-isopropylidene-L-threonate (43). Facile displacement of the mesylate with azide followed by ester hydrolysis and catalytic reduction to an amine provides 4-amino-4-deoxy-2,3-0-isopropylidene-L-threonic acid (44). Mild acidic deprotection and ion-exchange desalting of 44 yields (2i ,3 S)-4-amino-4-deoxy-L-threonic acid (45), which has been utilized for the preparation of anthopleurine 46, the alarm pheromone of the sea anemone Anthopleura elegantissima [4] (Scheme 11). 

The use of hydride reagentsfor the reduction of carboxylic acids requires vigorous conditions because the carboxylatc anion, once formed, is resistant to further nucleophilic attack. An interesting exception to this is reduction with borane. A triacyloxyborane may be formed. Re.sonance involving the vacant orbitals of the boron and the lone pairs on the oxygen has the effect of making the attack of a nucleophilic hydride on the carbonyl carbon of the acid easier (see 3.21). 

Hydrazides (s. a. Carboxylic acid hydrazides) reduction with borane 26,56 Hydrazine (s. a. Wolff-Kishner reduction) 26,15 reaction with dicarboxylic acid anhydrides 8, 482... 

Scheme 9.111. The reduction of fra s-P-(2-carbomethoxycyclohexane)propanoic acid. The upper part of the scheme shows reduction with sodium (Na) in ethanol (CH3CH2OH) and liquid ammonia (NH3 (y), where the ester is reduced in preference to the carboxylic acid. The lower part of the scheme shows reduction with borane in THF (oxacyclopentane) where the opposite result obtains. For the preparation and reduction of trms- -(2-carbomethoxycyclohexane)propanoic acid, see Paquette, L. A. Nelson, N. A. /. Org. Chem., 1962,27, 2272.

Starting from MBHA resin 444, coupling of Boc-amino acid 445 in the presence of DIPCDI and HOBt in DMF, followed by removal of the Boc group in 55% TEA in DCM, afforded the resin-bound amino acid 446 (Scheme 9.54). Acylation with carboxylic acid 447 was carried out under the same coupling condition to give amide 448, which underwent exhaustive reduction with borane-THF complex to give diamine 449. Treatment with 10... 

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-... 

An indirect method ° of double-bond reduction involves hydrolysis of boranes (prepared by 15-16). Trialkylboranes can be hydrolyzed by refluxing with carboxylic acids,while monoalkylboranes RBH2 can be hydrolyzed with base. ° Triple bonds can be similarly reduced, to cis alkenes. °... 

Reduction of aromatic carboxylic acids to alcohols can be achieved by hydrides and complex hydrides, e.g. lithium aluminum hydride 968], sodium aluminum hydride [55] and sodium bis 2-methoxyethoxy)aluminum hydride [544, 969, 970], and with borane (diborane) [976] prepared from sodium borohydride and boron trifluoride etherate [971, 977] or aluminum chloride [755, 975] in diglyme. Sodium borohydride alone does not reduce free carboxylic acids. Anthranilic acid was reduced to the corresponding alcohol by electroreduction in sulfuric acid at 20-30° in 69-78% yield [979],... 

The key sequence in a somewhat involved stereospecihc total synthesis of a carbacephem starts by preparation of a chiral auxiliary. It is interesting to note that nitrogen is the only atom from this molecule retained in the hnal product. Constmction of this moiety starts with the formation of the carbethoxy derivative (37-2) from L(- -)-phenylglycine (37-1). Selective reduction of the free carboxyl group with borane. THF leads to the hydroxycarbamate (37-3). In a one-pot sequence, this is first cyclized to the corresponding oxazolidinone (37-4) by means of sodium hydride and then alkylated with ethyl bromoacetate (37-5). Saponification of the side chain then affords the chiral acetic acid (37-6). The carboxyl group is then activated by conversion to its acid chloride (37-7). 

Carboxylic acids can also be converted to alkanes, indirectly,570 by reduction of the corresponding tosylhydrazides RCONHNH2 with LiAlH4 or borane.571 OS VI, 747. 

Direct reduction of aldehydes with 2,3-dimethyl-2-butylborane proceeds rapidly and gives the corresponding alcohol. Nonetheless, reduction of carboxylic acids with the same borane (Section 18-3C) proceeds slowly and gives high yields of aldehydes. Explain why the reaction of RC02H with the 2,3-dimethyl-2-butylborane produces RCHO instead of RCH2OH. 

Alcohols are at a fairly low oxidation level compared to other oxygen-containing functional groups and consequently are readily prepared by reduction. Large numbers of reductive methods have been reported for the preparation of alcohols. Carboxylic acids and esters react vigorously with lithium aluminum hydride (LAH) to produce primary alcohols. Carboxylic acids, but not esters, are also reduced easily by borane, which is die only reducing agent diat reacts faster widi carboxylic acids dian widi esters or odier acid derivatives. 

Reduction of carboxylic acids with borane-dimethyl sulfide generally proceeds rapidly In connection with reduction experiments with p-hydroxybenzoic acid, it was found that this compound gave only low yields of p-hydroxybenzyl alcohol when treated with borane-dimethyl sulfide according to the procedure described by Knstersson et al (1980) This is in accordance with studies of the... 

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