Chiral 2-amino alcohols

For other chiral reagents and application of this method to other classes of compounds, such as a-amino esters, a-hydroxy esters, amino alcohols, chiral a-deuterated benzylamine, phosphorus compounds, and the use of nuclei other than hydrogen (l3C, 19F), see reference 186 and Section D.4.1. 

One of the early syntheses of orlistat (1) by Hoffmann-La Roche utilized the Mukaiyama aldol reaction as the key convergent step. Therefore, in the presence of TiCU, aldehyde 7 was condensed with ketene silyl acetal 8 containing a chiral auxiliary to assemble ester 9 as the major diastereomer in a 3 1 ratio. After removal of the amino alcohol chiral auxiliary via hydrolysis, the a-hydroxyl acid 10 was converted to P-lactone 11 through the intermediacy of the mixed anhydride. The benzyl ether on 11 was unmasked via hydrogenation and the (5)-7V-formylleucine side-chain was installed using the Mitsunobu conditions to fashion orlistat (1). 

In general, the chiral hydride reagent is generated in situ by reaction of a suitable metal hydride with chiral ligands such as alkaloids , sugar derivatives , amino alcohol chiral oxazolines tartaric acid derivatives chiral amines and chiral diols... 

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 hydride-donor class of reductants has not yet been successfully paired with enantioselective catalysts. However, a number of chiral reagents that are used in stoichiometric quantity can effect enantioselective reduction of acetophenone and other prochiral ketones. One class of reagents consists of derivatives of LiAlH4 in which some of die hydrides have been replaced by chiral ligands. Section C of Scheme 2.13 shows some examples where chiral diols or amino alcohols have been introduced. Another type of reagent represented in Scheme 2.13 is chiral trialkylborohydrides. Chiral boranes are quite readily available (see Section 4.9 in Part B) and easily converted to borohydrides. 

The configuration of the amine was retained, except in the case of amino acid derivatives, which racemized at the stage of the pyridinium salt product. Control experiments showed that, while the starting amino acid was configurationally stable under the reaction conditions, the pyridinium salt readily underwent deuterium exchange at the rz-position in D2O. In another early example, optically active amino alcohol 73 and amino acetate 74 provided chiral 1,4-dihydronicotinamide precursors 75 and 76, respectively, upon reaction with Zincke salt 8 (Scheme 8.4.24). The 1,4-dihydro forms of 75 and 76 were used in studies on the asymmetric reduction of rz,>S-unsaturated iminium salts. 

Chiral boron(III) complexes can catalyze the cycloaddition reaction of glyoxy-lates with Danishefsky s diene (Scheme 4.18) [27]. Two classes of chiral boron catalyst were tested, the / -amino alcohol-derived complex 18 and bis-sulfonamide complexes. The former catalyst gave the best results for the reaction of methyl glyoxylate 4b with diene 2a the cycloaddition product 6b was isolated in 69% yield and 94% ee, while the chiral bis-sulfonamide boron complex resulted in only... 

Quite a number of asymmetric thiol conjugate addition reactions are known [84], but previous examples of enantioselective thiol conjugate additions were based on the activation of thiol nucleophiles by use of chiral base catalysts such as amino alcohols [85], the lithium thiolate complex of amino bisether [86], and a lanthanide tris(binaphthoxide) [87]. No examples have been reported for the enantioselective thiol conjugate additions through the activation of acceptors by the aid of chiral Lewis acid catalysts. We therefore focussed on the potential of J ,J -DBFOX/ Ph aqua complex catalysts as highly tolerant chiral Lewis acid catalyst in thiol conjugate addition reactions. 

As described in Section 2.3.2, vinylaziridines are versatile intermediates for the stereoselective synthesis of (E)-alkene dipeptide isosteres. One of the simplest methods for the synthesis of alkene isosteres such as 242 and 243 via aziridine derivatives of type 240 and 241 (Scheme 2.59) involves the use of chiral anti- and syn-amino alcohols 238 and 239, synthesizable in turn from various chiral amino aldehydes 237. However, when a chiral N-protected amino aldehyde derived from a natural ot-amino acid is treated with an organometallic reagent such as vinylmag-nesium bromide, a mixture of anti- and syn-amino alcohols 238 and 239 is always obtained. Highly stereoselective syntheses of either anti- or syn-amino alcohols 238 or 239, and hence 2,3-trans- or 2,3-as-3-alkyl-2-vinylaziridines 240 or 241, from readily available amino aldehydes 237 had thus hitherto been difficult. Ibuka and coworkers overcame this difficulty by developing an extremely useful epimerization of vinylaziridines. Palladium(0)-catalyzed reactions of 2,3-trons-2-vinylaziri-dines 240 afforded the thermodynamically more stable 2,3-cis isomers 241 predominantly over 240 (241 240 >94 6) through 7i-allylpalladium intermediates, in accordance with ab initio calculations [29]. This epimerization allowed a highly stereoselective synthesis of (E) -alkene dipeptide isosteres 243 with the desired L,L-... 

Since the addition of dialkylzinc reagents to aldehydes can be performed enantioselectively in the presence of a chiral amino alcohol catalyst, such as (-)-(1S,2/ )-Ar,A -dibutylnorephedrine (see Section 1.3.1.7.1.), this reaction is suitable for the kinetic resolution of racemic aldehydes127 and/or the enantioselective synthesis of optically active alcohols with two stereogenic centers starting from racemic aldehydes128 129. Thus, addition of diethylzinc to racemic 2-phenylpropanal in the presence of (-)-(lS,2/ )-Ar,W-dibutylnorephedrine gave a 75 25 mixture of the diastereomeric alcohols syn-4 and anti-4 with 65% ee and 93% ee, respectively, and 60% total yield. In the case of the syn-diastereomer, the (2.S, 3S)-enantiomer predominated, whereas with the twtf-diastereomer, the (2f ,3S)-enantiomer was formed preferentially. 

Another chiral auxiliary used in diastereoselective addition reactions is the 1,3-oxazine derivative 4a which shows a close structural resemblance to the 1,3-oxathiane 16 (vide supra). However, in contrast to the oxathiane, 4a cannot be readily acylatcd in the 2-position. Therefore, the benzoyl derivative 4b was prepared by condensing amino alcohol 3 with phenylglyoxal. 

Cleavage of the addition product 5 can be easily performed by treatment with dilute ( 1 %) aqueous alcoholic hydrochloric acid which liberates the chiral amino alcohol 3 and an a-hydroxy aldehyde. The latter can be further oxidized to the oc-hydroxy carboxylic acid 6 with sodium chlorite33. 

Simple Amines, Alcohols and Amino Acid Derived Amino Alcohols as Chiral Catalysts... 

To obtain information about the structural requirements of a ligand capable of catalyzing the addition of dialkylzincs to aldehydes, various simple amines, alcohols and amino acid derived amino alcohols were tested as chiral catalysts (Table 27). 

In general, an ethyl(monoalkoxy)zinc is formed with amino alcohols6. Therefore, in the presence of an equimolar amount of chiral amino alcohol, a slow reduction of benzaldehyde to benzyl alcohol is observed rather than alkylation1. Alkylation only occurs with a ratio of diethylzinc to amino alcohol greater than equimolar. Consequently, a two-zinc species is postulated to be the actual catalyst1, n. 

Although it is known that in some cases the lithium salts of chiral amino alcohols are even better catalysts than the chiral ligands themselves, the use of metals other than lithium has rarely been investigated. The oxazaborolidines A and B and the aluminum analog C have been used as catalysts for the enantioselective addition of diethylzinc to benzaldehyde35 (Table 32). 

The reaction of triallylborane31 with diols or acidic amino alcohols provides a convenient method of synthesis of allylboron reagents, especially when the diol or amino alcohol is a valuable chiral auxiliary32-34. Two representative cases arc summarized below. 

A number of chiral alcohols and amino alcohols have been applied as auxiliaries to enolates. The induction may be explained by the shielding of one of the faces of the cnolate by a bulky alkoxy or aryl substituent. Representative examples, together with the results in diastereoselec-tive 1,4-additions with different Michael acceptors, are given in the following. 

A variety of chiral amides as well as oxazolidones388 and imidazolidones389,390 may easily be prepared from amino alcohols that are derived from amino acids391 392. The addition of the lithium enolates of these amides under kinetically controlled conditions to a,/i-unsaturated esters yields optically active pentanedioates. Both syn- and //-5-amino-5-oxopcntanoates may be obtained with good diastereomeric ratios192. 

Several methods for asymmetric C —C bond formation have been developed based on the 1,4-addition of chiral nonracemic azaenolates derived from optically active imines or enamines. These methods are closely related to the Enders and Schollkopf procedures. A notable advantage of all these methods is the ready removal of the auxiliary group. Two types of auxiliaries were generally used to prepare the Michael donor chiral ketones, such as camphor or 2-hydroxy-3-pinanone chiral amines, in particular 1-phenylethanamine, and amino alcohol and amino acid derivatives. 

In some cases the yields were poor due to competing deprotonation of the substrate by the organolithium reagent. Deprotonation was the predominant reaction with methyllithium or when (Z)-2-(l-alkenyl)-4,5-dihydrooxazoles were employed. The stereochemical outcome has been rationalized as occurring from a chelated transition state. The starting chiral amino alcohol auxiliary can also be recovered without racemization for reuse. 

Epoxidations of chiral allenamides lead to chiral nitrogen-stabilized oxyallyl catioins that undergo highly stereoselective (4 + 3) cycloaddition reactions with electron-rich dienes.6 These are the first examples of epoxidations of allenes, and the first examples of chiral nitrogen-stabilized oxyallyl cations. Further elaboration of the cycloadducts leads to interesting chiral amino alcohols that can be useful as ligands in asymmetric catalysis (Scheme 2). 

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