Auxiliaries, chiral alcohols

One of the first examples of this type of reaction, using a chiral alcohol as an auxiliary, was the asymmetric synthesis of 2-hydroxy-2-phenylpropanoic acid (atrolactic acid, 3, R1 =C6H5 R3 = CH3) by diastereoselective addition of methyl magnesium iodide to the men-thyl ester of phcnylglyoxylie acid4,5 (Table 22). 

Compared to the lithium enolates of l and 5, the higher stereoselectivity obtained by the Mukaiyama variation is, in general, accompanied by reduced chemical yields. The chiral alcoholic moieties of the esters 3 and 7 can be removed either by reduction with lithium aluminum hydride (after protection of the earbinol group) or by aqueous alkaline hydrolysis with lithium hydroxide to afford the corresponding carboxylic acid. In both cases, the chiral auxiliary reagent can be recovered. 

Mainly sulfoxide groups are introduced as chiral auxiliaries for the modification of a,/J-unsat-urated enones (see Section D.1.5.3.5.). Chiral imine derivatives have also been used (see Section D.1.5.3.1.). Various chiral alcohols, and in particular 8-phenylmenthol, have been successfully used as auxiliaries, mainly in two-fold Michael additions to a,/ -unsaturatcd esters. 

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. 

An interesting approach to zr n.v-2,3-disubstituted cyeloalkanones is offered by auxiliary controlled intramolecular Michael additions. The diastereoselectivity depends on the chiral alcohol used193> l94. When the borneol derivative 7 was used as substrate, a single diastereomer of 8 resulted when the reaction was performed at 25 "C under thermodynamic control with a catalytic amount of sodium hydride in benzene. 

Optically active bicyclo[2.2,2]octanes can be obtained via diastercoselective MIMIRC reaction of lithium dienolates and a,/ -unsaturated esters of various chiral alcohols. Good yields (70-90%), high endo selectivities (> 95%) and diastereomeric ratios that depend on the auxiliary alcohol are found in these additions. The highest diastereomeric ratio reached was 18 82 using a camphor derived sulfonamide. The diastereomeric ratio could be improved (up to 9 91) by titanium(IV) chloride catalyzed addition of the corresponding silylenolates with the chiral a,/J-unsaturated esters358. 

The highly ordered cyclic TS of the D-A reaction permits design of diastereo-or enantioselective reactions. (See Section 2.4 of Part A to review the principles of diastereoselectivity and enantioselectivity.) One way to achieve this is to install a chiral auxiliary.80 The cycloaddition proceeds to give two diastereomeric products that can be separated and purified. Because of the lower temperature required and the greater stereoselectivity observed in Lewis acid-catalyzed reactions, the best diastereoselectivity is observed in catalyzed reactions. Several chiral auxiliaries that are capable of high levels of diastereoselectivity have been developed. Chiral esters and amides of acrylic acid are particularly useful because the auxiliary can be recovered by hydrolysis of the purified adduct to give the enantiomerically pure carboxylic acid. Early examples involved acryloyl esters of chiral alcohols, including lactates and mandelates. Esters of the lactone of 2,4-dihydroxy-3,3-dimethylbutanoic acid (pantolactone) have also proven useful. 

Selenski investigated the use of chiral enol ether auxiliaries in order to adapt method F-H for enantioselective syntheses. After surveying a variety of substituted and unsubstituted enol ethers derived from a vast assortment of readily available chiral alcohols, she chose to employ enol ethers derived from trans-1,2-phenylcyclohexanol such as 73 and 74 (Fig. 4.37). These derivatives were found to undergo highly diastereoselective cycloadditions resulting in the formation of 75 and 76 in respective... 

The introduction of various metal-catalyzed reactions, however, remarkably expanded the scope of the epoxidation of Q,.3-unsaturatcd ketones. Enders et al. have reported that a combination of diethylzinc and A-methyl-pseudoephedrine epoxidizes various o,. j-unsaturatcd ketones, under an oxygen atmosphere, with good to high enantioselectivity (Scheme 23).126 In this reaction, diethylzinc first reacts with the chiral alcohol, and the resulting ethylzinc alkoxide is converted by oxygen to an ethylperoxo-zinc species that epoxidizes the a,/3-unsaturated ketones enantioselectively. Although a stoichiometric chiral auxiliary is needed for this reaction, it can be recovered in almost quantitative yield. 

Chiral active pharmaceutical ingredients, 18 725-726. See also Enantio- entries Chiral additives, 6 75—79 Chiral alcohols, synthesis of, 13 667-668 P-Chiral alcohols, synthesis of, 13 669 Chiral alkanes, synthesis of, 13 668-669 Chiral alkenes, synthesis of, 13 668—669 Chiral alkoxides, 26 929 Chiral alkynes, synthesis of, 13 668-669 Chiral ammonium ions, enantiomer recognition properties for, 16 790 Chiral ansa-metallocenes, 16 90 Chiral auxiliaries, in oxazolidinone formation, 17 738—739... 

Asymmetric electroreduction of ketones to the corresponding chiral alcohols has recently been reported. Typical examples are the reduction of ketones bearing chiral auxiliaries [68, 69], and the indirect reduction of ketones with alcohol dehydrogenase (ADH), as a mediator (Scheme 32) [70]. 

Auxiliary-Induced Diastereoselection Esters of Nonracemic Chiral Alcohols... 

The formation of chiral alcohols from carbonyl compounds has been fairly widely studied by reactions of aldehydes or ketones with organometallic reagents in the presence of chiral ligands. Mukaiyama et al. 1081 obtained excellent results (up to 94% e.e.) in at least stoichiometric addition of the chiral auxiliary to the carbonyl substrate and the organometallic reagent. 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

Ketcnc equivalents, such as ketene acetals and thioacetals, can be used in cycloadditions to electron-deficient alkenes (see Sections 1.3.2.1. and 1.3.2.2.). In an example of a fumaric acid diester fitted with two chiral alcohol auxiliary groups, the aluminum(III)-catalyzed cycloaddition of 1,1-dimethoxyethene with di-(—)-menthyl fumarate (9) proceeds with > 99% diastereomeric excess. Intermediate 10 can be readily converted to cyclobutanone derivatives.17, 18... 

Asymmetric ethylidene transfer has been achieved in the reactions of 1-cyclohexenyl ethers carrying a chiral auxiliary with 1,1-diodoethane/diethylzinc 39. Asymmetric induction in the reaction of diazofluorene with fumaric esters bearing chiral alcohol moieties has been investigated (equation 84)140,141. Kinetics of intramolecular cyclopropanation in... 

Chiral halohydrins epoxides.1 The esters (2) of the chiral alcohol 1 derived from camphor-10-sulfonic acid, are converted to a-chloro esters (3) by O-silylation and reaction with NCS with high diastereoselectivity. Reduction of 3 with Ca(BH4)2 results in the recovered auxiliary and the chlorohydrin 4 with clean retention. Cyclization of 4 to the terminal epoxide 5 proceeds with clean inversion. 

Atorvastin (Lipitor, 13.40) is a cholesterol-lowering drug that has been synthesized as a single enantiomer through use of a chiral auxiliary (Scheme 13.6).16 Ester 13.36 contains the auxiliary, a chiral alcohol. Deprotonation of the ester forms an enolate (13.37). The enolate then attacks an aldehyde. The asymmetry of the stereocenter on the auxiliary causes the reaction to favor stereoisomer 13.38 over 13.39. Several recrystallizations are required to obtain 13.38 in high enantiomeric excess. Cleavage of the auxiliary from 13.38 and further manipulations of the side-chain afford atorvastin. 

If nitrogen is included in a chiral auxiliary, chirality is transferred with excellent enantiomeric excesses to the new C-C bond formed. Thus, alcohols are prepared with excellent enantioselectivity after oxidative cleavage of the Si-C bond, and a chiral 1,3-diol is obtained with high optical purity.297,298... 

Control over the absolute configuration in cyclohexenone photocycloadditions has been achieved by auxiliary-induced diastereoselectivity. In particular, esters related to compound 26, which are derived from a chiral alcohol but not from methanol, lend themselves as potential precursors, from which the chiral auxiliary can be effectively cleaved [42, 43]. In a recent study, the use of additives was advertised to increase the diastereomeric excess in these reactions [44], An intriguing auxiliary-induced approach was presented by Piva et al., who employed chiral 13-hydroxy-carboxylic adds as tethers to control both the regioselectivity and the diastereoselectivity of intramolecular [2 + 2]-photocycloaddition reactions [45]. In Scheme 6.14 the reaction of the (S)-mandelic acid derived substrate 38 is depicted, which led with very good stereocontrol almost exclusively to product 39a, with the other diastereoisomer 39b being formed only in minor quantities (39a/39b = 96/4). Other acids, such as (S)-lactic acid, performed equally well. The chiral tether could be cleaved under basic conditions to afford enantiomerically pure cydobutane lactones in good yields. 

The silylketene acetals derived from 10-(aminosulfonyl)-2-bomylesters were also good substrates in the electrophilic amination reactions using DTBAD. Enantiose-lective syntheses of a-amino acids were described by Oppolzer and co-workers [14]. The crystalline starting esters 33 were usually obtained in 82-96 % yield by reaction of acid chlorides with the chiral alcohol auxiliary 32 in the presence of AgCN (Scheme 13). 

Acryloyl and crotonoyl amides (9) derived from the sultam (8), available from ( + )-l, are somewhat more reactive dienophiles than the i orresponding esters (3) derived from 2. Diels-Alder reactions of 9 with cyclopentadiene catalyzed by TiCU or C2H,AIC1, proceed in high yield, with high endo selectivity ( 99%) ind diastereoselectivity of —95% de. The chiral auxiliary is removed by reduction witfi LiAIH4 to furnish 8 and the chiral alcohol in 89-95% yield.-... 

Nondestructive Removal of the Auxiliary. Primary alcohols are obtained by Lithium Aluminum Hydride reduction of the corresponding chiral esters. Also, hydrolysis of the auxiliary under basic conditions, 2N KOH in methanol, " provides the carboxylic acid and recovered alcohol (3). 

This type of reaction can also be performed with acrylates bearing chiral alcohol or amide auxiliaries (see Section 2.2.2.3.2.1.1.1.). For example, with l,l-dimethyl-2-methylenecyclo-propane (6) and the chiral acrylate 11, the [3 + 2] cycloadduct 12 can be obtained in 86 /o yield almost diastereospecifically. With chiral acrylic esters, diastereoselectivities are usually in the range of 30-85% de. ... 

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