Enantioselective reactions chiral auxiliary

Moreover, this two-step equivalent of an aldol condensation can proceed with high enantioselectivity in the presence of a chiral auxiliary. Thus reaction of the enolate of chiral silyl ketene acetal (5) with isobutyryl chloride gives 6 in 89% yield and 94% ee after reduction of the intermediate. 

Since the middle of the 198O s remarkable progress has been achieved in the development of asymmetric aldol reactions of silyl enolates. In the beginning of this evolution, chiral auxiliary-controlled reactions were extensively studied for this challenging subject [106]. As new efficient catalysts and catalytic systems for the aldol reactions were developed, much attention focused on catalytic enantiocontrol using chiral Lewis acids and transition metal complexes. Thus, a number of chiral catalysts realizing high levels of enantioselectivity have been reported in the last decade. 

It has been observed that addition of Lewis acids to the free radical allylation improved the chemical yield [101]. When substrates with a chiral auxiliary were subjected to free radical allylation in the presence of a Lewis acid, the desired allylated products were obtained with high stereoselectivity [94 d]. In these reactions the Lewis acid plays a pivotal role in fixing the conformation of radical intermediates. Recently Sibi indicated that an elevated reaction temperature accelerated inversion of the stereochemistry of the radical-centered carbon giving rise to greater diastereoselectivity (Scheme 12.39) [102]. When enantiomerically pure Lewis acids were employed as chiral auxiliaries enantioselective free radical allylation of sulfones [103] and oxazolidinones [104] were realized. In the latter reaction two contiguous chiral centers were generated successfully in a single operation with excellent stereoselectivity via tandem C-C bond formation both enantiomers can be se-... 

This zinc-promoted reaction has been used with a variety of carbonyl compounds. Thus, the Luche conditions were applied in a synthesis of (-1-)-muscarine using an aldehyde derived from ethyl lactate [109]. Allyl halide condensation onto a-ketoamides of proline benzyl ester gave good diastereoselec-tivity when performed in the presence of zinc dust and pyridinium p-toluene-sulfonate in a water/THF mixture. In this way, a-hydroxy ketones were obtained with good enantioselectivity after removal of the chiral auxiliary [110]. Reactions of allyl bromide under the Luche conditions with y-aldo esters afforded y-hydroxy esters, which were converted in a one-pot reaction to y-allyl-y-butyro-lactones (Scheme 22) [111]. 

The first practical method for asymmetric epoxidation of primary and secondary allylic alcohols was developed by K.B. Sharpless in 1980 (T. Katsuki, 1980 K.B. Sharpless, 1983 A, B, 1986 see also D. Hoppe, 1982). Tartaric esters, e.g., DET and DIPT" ( = diethyl and diisopropyl ( + )- or (— )-tartrates), are applied as chiral auxiliaries, titanium tetrakis(2-pro-panolate) as a catalyst and tert-butyl hydroperoxide (= TBHP, Bu OOH) as the oxidant. If the reaction mixture is kept absolutely dry, catalytic amounts of the dialkyl tartrate-titanium(IV) complex are suflicient, which largely facilitates work-up procedures (Y. Gao, 1987). Depending on the tartrate enantiomer used, either one of the 2,3-epoxy alcohols may be obtained with high enantioselectivity. The titanium probably binds to the diol grouping of one tartrate molecule and to the hydroxy groups of the bulky hydroperoxide and of the allylic alcohol... 

Addition reactions to aldehydes in the presence of the tartaric acid derived chiral auxiliaries (.S ..S )-l,2,3,4-tetramethoxybutane (5), (S,.S)-2,3-dimethoxy-A%V,/V, A,, -tctramethyl-l,4-bu-tanediamine (6) and (5,5)-2,3-bis[2-(dimethylamino)ethoxy]-Af,yV,A. iV -tetramethyl-l,4-bu-tanediamine (7) have been studied in detail9" u. Again there was low enantioselection (generally 10-55% ee). 

A remarkable effect of the reaction temperature on the enantioselectivity of the addition of butyllithium to benzaldehyde was found with polystyrene-bound cvs-enofo-S-dimethylamino -(benzyloxy)bornane (8)12. When the soluble monomeric ligand 9 was tested, the enantioselectivity increased with decreasing temperature (53% ee at — 78 C). In contrast, the polymer-bound chiral additive 8 showed an optimum at — 20 C (32% ee). Although the enantioselectivity of this addition reaction is low, an advantage of a polymer-bound chiral auxiliary is that it can be removed by a simple filtration. 

In most cases homogeneous chiral catalysts afford higher enantioselectivities than heterogenous catalysts. Nevertheless, the development of heterogeneous chiral catalysts has attracted increasing interest because workup of the reaction, and recovery of often valuable chiral auxiliaries by simple filtration, is more convenient than in the case of homogeneous catalysts. 

The reaction of methyl 4-formyl-2-mcthylpentanoate and the chiral (Z)-2-butenylboronate clearly shows 52b-103, however, that the chiral auxiliary is not sufficiently enantioselective to increase the diastereoselectivity to >90% in either the matched [( + )-auxiliary] or mismatched [(—)-auxiliary] case. This underscores the requirement that highly enantioselective chiral reagents be utilized in double asymmetric reactions. 

Z)-l-Methyl-2-butenylboronate 7 undergoes an exceptionally enantioselective reaction with benzaldehyde (99% ee), propanal (79%. 98% ee), 2-methyl-2-propenal (85%, 99% ee), and ( )-2-methyl-2-pentenal (81 %, 99% ee)10 38. Excellent enantioselectivity is also realized in reactions of the analogous chiral a-methyl-) y-disubstituted allylboronate27 40. Whether the l,2-dicyclohexyl-l,2-ethanediol auxiliary plays a beneficial role in this reaction, as suggested above for the asymmetric allylboration reactions of 6, has not yet been determined. 

An excellent synthetic method for asymmetric C—C-bond formation which gives consistently high enantioselectivity has been developed using azaenolates based on chiral hydrazones. (S)-or (/ )-2-(methoxymethyl)-1 -pyrrolidinamine (SAMP or RAMP) are chiral hydrazines, easily prepared from proline, which on reaction with various aldehydes and ketones yield optically active hydrazones. After the asymmetric 1,4-addition to a Michael acceptor, the chiral auxiliary is removed by ozonolysis to restore the ketone or aldehyde functionality. The enolates are normally prepared by deprotonation with lithium diisopropylamide. 

Good results were obtained with (R)-0-acryloylpantolactone (4) in which the dienophile was incorporated with a smaller chiral auxiliary. Some results are reported in Table 4.4, where the cycloadditions catalyzed by Zn(II)-, Fe(II)- and Ti(IV)-K-10 exchanged montmorillonite calcined at 120 °C and 550 °C are compared with those that were not catalyzed and with TiCU- and EtAlCh-catalyzed reactions. Among the metal-clays activated, the Ti(IV)-K-10 was the best catalyst with high conversion and acceptable enantioselectivity obtained after 2 h. 

Abstract While the use of stoichiometric amounts of sparteine and related ligands in various asymmetric reactions often lead to highly enantioselective transformations, there have been far fewer applications of sparteine to asymmetric catalysis. The aim of this review is to highlight recent advances in the field of asymmetric transformations that use sparteine as chiral auxiliary, emphasizing the use of substoichiometric or catalytic amounts of this ligand. 

Enantioselective enolate alkylation can be done using chiral auxiliaries. (See Section 2.6 of Part A to review the role of chiral auxiliaries in control of reaction stereochemistry.) The most frequently used are the A-acyloxazolidinones.89 The 4-isopropyl and 4-benzyl derivatives, which can be obtained from valine and phenylalanine, respectively, and the c -4-methyl-5-phenyl derivatives are readily available. Another useful auxiliary is the 4-phenyl derivative.90... 

Stereochemical Control Through Chiral Auxiliaries. Another approach to control of stereochemistry is installation of a chiral auxiliary, which can achieve a high degree of facial selectivity.124 A very useful method for enantioselective aldol reactions is based on the oxazolidinones 10,11, and 12. These compounds are available in enantiomerically pure form and can be used to obtain either enantiomer of the desired product. 

Scheme 2.25 shows some examples of additions of enolate equivalents. A range of Lewis acid catalysts has been used in addition to TiCl4 and SnCl4. Entry 1 shows uses of a lanthanide catalyst. Entry 2 employs LiC104 as the catalyst. The reaction in Entry 3 includes a chiral auxiliary that controls the stereoselectivity the chiral auxiliary is released by a cyclization using (V-methylhydroxylamine. Entries 4 and 5 use the triphenylmethyl cation as a catalyst and Entries 6 and 7 use trimethylsilyl triflate and an enantioselective catalyst, respectively. 

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. 

Enantioselective Reactions of Organocopper Reagents. Several methods have been developed for achieving enantioselectivity with organocopper reagents. Chiral auxiliaries can be used for example, oxazolidinone auxiliaries have been utilized in conjugate additions. The outcome of these reactions can be predicted on the basis of steric control of reactant approach, as for other applications of the oxazolidinone auxiliaries. 

The following reactions use chiral auxiliaries to achieve enantioselectivity. By consideration of possible TSs, predict the absolute configuration of the major product of each reaction. 

Chapters 1 and 2 focus on enolates and other carbon nucleophiles in synthesis. Chapter 1 discusses enolate formation and alkylation. Chapter 2 broadens the discussion to other carbon nucleophiles in the context of the generalized aldol reaction, which includes the Wittig, Peterson, and Julia olefination reactions. The chapter and considers the stereochemistry of the aldol reaction in some detail, including the use of chiral auxiliaries and enantioselective catalysts. 

Dienes with Chiral Auxiliaries The use of dienes with the chiral auxiliary attached to the C-l position of the dienes is the most popular in asymmetric Diels-Alder reactions.59 In 1980, Trost reported high asymmetric induction in the Diels-Alder reaction using l-(S)-0-methylmandeloxy-l,4-butadiene59a However, the result obtained by Trost et al. has remained unique for more than a decade, at least in terms of enantioselectivity. The asymmetric Diels-Alder reaction of chiral diene-amines with nitroalkenes gives aminocyclohexenes with good diastereoselectivity (Eq. 8.37).60 The development in the area of chiral dienes is slow it may be due to the difficulty of preparing these compounds. 

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. 

This report prompted further study of asymmetric dihydroxylation, and higher enantioselect-ivity has been realized with various C2- or quasi-C2-symmetric diamines as the chiral auxiliaries.168-174 One example reported by Tomioka and Koga is shown in Scheme 43.170 Although the reaction is highly enantioselective, it needs the use of stoichiometric 0s04 and chiral diamine, because the diamine coordinates Osvl ion strongly and retards its reoxidation to Osvm ion. 

DHQD-CL or DHQ-CL) was used as the chiral auxiliary.175,176 However, the enantioselectivity observed under catalytic conditions was inferior to that observed under stoichiometric conditions. The addition of triethylammonium acetate, which increases the rate of hydrolysis of the Osvm-glycolate intermediate, improved enantioselectivity. A further improvement in enantioselectivity was brought about by the slow addition of substrates (Scheme 44).177 These results indicated that the hydrolysis of the Osvm-glycolate intermediate (57) was slow under those conditions and (57) underwent low enantioselective dihydroxylation (second cycle). Thus, Sharpless et al. proposed a mechanism of the dihydroxylation including a second cycle (Scheme 45).177 Slow addition reduces the amount of unreacted olefin in the reaction medium and suppresses the... 

The 9-O-substituent of the DHQD or DHQ ligand strongly influences both the enantioselectivity and the rate of the dihydroxylation reaction. Thus, enantioselectivity was further improved by introducing new chiral auxiliaries like DHQD-PHN and DHQD-MEQ (DHQ-PHN and... 

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