Amino acids borane reduction

The most successful of the Lewis acid catalysts are oxazaborolidines prepared from chiral amino alcohols and boranes. These compounds lead to enantioselective reduction of acetophenone by an external reductant, usually diborane. The chiral environment established in the complex leads to facial selectivity. The most widely known example of these reagents is derived from the amino acid proline. Several other examples of this type of reagent have been developed, and these will be discussed more completely in Section 5.2 of part B. 

The utilization of a-amino acids and their derived 6-araino alcohols in asymmetric synthesis has been extensive. A number of procedures have been reported for the reduction of a variety of amino acid derivatives however, the direct reduction of a-am1no acids with borane has proven to be exceptionally convenient for laboratory-scale reactions. These reductions characteristically proceed in high yield with no perceptible racemization. The resulting p-amino alcohols can, in turn, be transformed into oxazolidinones, which have proven to be versatile chiral auxiliaries. Besides the highly diastereoselective aldol addition reactions, enolates of N-acyl oxazolidinones have been used in conjunction with asymmetric alkylations, halogenations, hydroxylations, acylations, and azide transfer processes, all of which proceed with excellent levels of stereoselectivity. 

An even more efficient approach to enantioselective reduction is to use a chiral catalyst. One of the most promising is the oxazaborolidine I, which is ultimately derived from the amino acid proline.96 The enantiomer is also available. A catalytic amount (5— 20 mol %) of this reagent along with BH3 as the reductant can reduce ketones such as acetophone and pinacolone in >95% e.e. An adduct of borane and I is the active reductant. 

Support-bound 1,2-diamines can be readily converted into imidazolidinones by treatment with carbonyl diimidazole [128,129]. The required diamines have been prepared on cross-linked polystyrene by reduction of peptides bound to MBHA resin with borane. Similarly, bicyclic imidazolines have been prepared from triamines and thiocarbonyl diimidazole (Entry 10, Table 14.3). Dehydration of polystyrene-bound monoacyl ethylene-1,2-diamines yields 4,5-dihydroimidazoles (cyclic amidines, Entry 5, Table 13.18). Several groups have reported the synthesis of 2-aminoimidazol-4-ones from resin-bound amino acid derivatives (e.g., Entry 6, Table 15.11). Most of these compounds are, however, unstable, and slowly decompose if dissolved in DMSO (Jesper Lau, private communication). 

The oxazolidin-2-ones 53 (R = H=CCH=CH2 or COEt) are obtained in a one-pot reaction of amino alcohol carbamates 52 with sodium hydroxide, followed by allyl bromide or propi-onyl chloride (94TL9533). A modified procedure for the preparation of chiral oxazolidin-2-ones 56 from a-amino acids 54, which avoids the hazardous reduction of the acids with borane and the intermediacy of water-soluble amino alcohols, is treatment of the methyl ester of the amino acid with ethyl chloro-formate to give 55, followed by reduction with sodium borohydride and thermal ring-closure of the resulting carbamate f95SC561). The 2-prop-ynylcarbamates 57 (R = Ts, Ac, Bz, Ph or allyl) cyclize to the methyleneoxazolidinones 58 under the influence of silver cyanate or copper(I) chloride/triethylamine (94BCJ2838). 

Reduction of amino acids. The ethyl ester hydrochlorides of amino acids can be reduced to the corresponding amino alcohols wtihout racemization by borane-dimethyl sulfide in yields of about 50% (distilled). The rate is enhanced if the dimethyl sulfide is allowed to escape during the reaction. 

The C-4 acids (183 and 184) have also been subjected to borane reduction conditions to afford alcohol 195 in 23-50% yield or 64% yield as the C-8 epimeric mixture (195 and 196, Scheme 29) [34, 49, 64]. The C-8 alcohol epimers 195 and 196 have been treated separately as a common intermediate for a number of C-4 derivatives including esters, ethers, and amines [34, 49, 64], Alcohols 195 and 196 was subjected to DCC, DMAP, and desired acid chloride or carboxylic acid in CH2CI2 affording ester analogs in 50-92% yield [64], Esters prepared include alkyl, aryl, and fluorenylmethyloxycarbonyl (Fmoc) protected amino acid derivatives (197 and 198) [64]. Ethers were prepared with various alkyl halides and Ag20 in CH3CN at 40 °C. Alkyl, allyl, and benzyl ethers were prepared in 45-80% yield (199 and 200) [34,64]. Alcohols 195 and 196 were then activated to the triflates and displaced by a variety of amines by treatment with trifluoromethanesulfonic anhydride and desired amine in 22% - quantitative yield over two steps (201 and 202)... 

As in other electroless processes, chemical reduction of ions such as Fe2+, Cu2+, Ag+, Au+, Pd2+, and Pt4+ from their aqueous solutions is carried out using various reducing agents to produce different shapes of nanoparticles. Depending on metal, typical reducing agents involve borohydride, dimethyl amino borane, ascorbic acid, hydrazine, formaldehyde, etc. 

With respect to reactivity, the amine-boranes lie somewhere between BHj-THF and NaBH4. They reduce aldehydes and ketones without affecting ester, ether, SPh, and NOj groups (Section 3.2,1), The reduction of ketones can be accelerated by the addition of Lewis acids or when carried out in acetic acid [PSl], On alumina or silica supporrts, amine-boranes can selectively reduce aldehydes without affecting keto groups (Section 3.2.1) [BSl], Chiral amino acids can be reduced to amino alcohols without epimerization [PSl],... 

Reduction of amino acids (usually with borane) gives amino alcohols such as valinol 27, prolinol 28 or phenylalaninol 30 they have the general structure 51. 

A variety of optically active amines and amino alcohols have been used as chiral auxiliaries for borane reductions. With few exceptions9, early results gave poor to modest asymmetric induction. For example, a variety of amino alcohols derived from a-amino acids gave reduction products of up to 60% ee1U. These reagents presumably used one equivalent of borane per mole of amino alcohol. In 1983 it was shown that the ratio of borane to amino alcohol was important and that two equivalents of borane were required for maximum asymmetric induction. It was postulated that an amino-borane complex of an oxazaborolidinc was involved in the reduction11. 

The first attempt to use a chiral ligand to modify borane was Kagan s attempt at enantioselective reduction of acetophenone using amphetamine-borane and desoxy-ephedrine-borane in 1969 [18]. However, both reagents afforded 1-phenyl ethanol in <5% ee. The most successful borane-derived reagents are oxazaborolidines, introduced by Hirao in 1981, developed by Itsuno, and further developed by Corey several years later (reviews [19,20]). Figure 7.2 illustrates several of the Hirao-Itsuno and Corey oxazaborolidines that have been evaluated to date. All of these examples are derived from amino acids by reduction or Grignard addition. Hirao... 

By similar reduction procedures, amino alcohols can be derived from almost every amino acid. (S)-Valinol [(S)-4], (S)-leucinol [(S)-5], and (S -zm-leucinol [(S) ] are prominent examples of these compounds. A detailed procedure for the reduction of (S)-valine to (S)-valtnol by borane-dimethyl sulfide/boron trifluoride-diethyl ether complex has been reported6, as well as details on the preparation of (5)-leucinol2 and (S)-/m-leucinol ... 

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