Prolinols derivatives

High anti selectivity combined with induced diastereoselectivity is also provided by the prolinol derived siloxane 5 which reacts with benzaldehyde to give predominantly the adduct 6l06h. 

Kobayashi and colleagues227 prepared chiral boron reagent 355 from BBr3 and chiral prolinol derivative 354 (equation 100). This catalyst afforded the exo Diels-Alder adduct of cyclopentadiene and methacrolein with 97% cc (equation 101). In the same way, norbomene (2/J)-357 was obtained from 356 and cyclopentadiene. 

Borane reduction catalyzed by chiral oxazaborolidines (CBS reduction, CBS = Corey, Bakshi, and Shibata) exhibits excellent enantio- and chemoselectiv-ity for a wide variety of ketonic substrates (Figure 1.27). This reaction was originally developed as a stoichiometric system consisting of diphenylvalinol and borane, ° but was later extended to a useful catalytic method. Because of the high efficiency of this reaction, many chiral oxazaborolidines have been synthesized from p-amino alcohols.Among them the prolinol-derived oxazaboro-lidine is one of the most widely used catalysts. ... 

Prolinol derived catalyst 30 has also been used in the [3+2] cycloaddition of nitrones with a,P-unsaturated aldehydes (Scheme 10) [69]. Importantly, the reactions proceed at room temperature in just 24 h, showing excellent levels of cata-lystactivity, withuniformly high endo exo ratios (11.5 1-99 1) andenantioselectivity... 

The alkylated pyrrolo[l,2-c]oxazolone 5, obtained from the reaction with 3-bromocyclohexene, can be converted to the trans-prolinol derivative 6 by treatment with lithium aluminum hydride in tetrahydrofuran at reflux temperature, then further reduced with palladium on charcoal to provide the cyclohexane derivative 7. 

Asymmetric Michael addition to to-nitrostyrenes,2 The enamine (2) formed from cyclohexanone and this prolinol derivative reacts with 2-aryl-1-nitroethylenes (3) to form, after acid hydrolysis of the primary adduct, essentially only one (4) of the four possible y-nitro ketones. 

The bis-prolinol-derived phenol (156) has been designed to facilitate the formation of heterodinuclear complexes based upon the large difference in pKH of the phenolic OH group and the tertiary OH groups. The first examples of its application involve hydroxyacetophenones (157) as donors in the asymmetric Michael addition to nitroalkene acceptors (158) the best stereocontrol was observed with a zinc- magnesium dinuclear complex, where enantiomeric excesses ranged up to 92% for the major anti diastereoisomer (159).212... 

Other centrally chiral amine catalysts reported for kinetic resolution of alcohols include the (S)-prolinol-derived dihydroisoindolines 12a,b (Scheme 12.4), devel-... 

Readily available from BINOL and prolinol derivatives, respectively... 

In the pioneering studies of Melchiorre and Jorgensen and colleagues, a variety of pyrrolidine-derived catalysts was tested (Scheme 2.51) [40]. Whilst modest selectivity was obtained with proline, and unhindered prolinol derivatives, (S)-2-(bis(phenyl)methyl)pyrrolidine derivative, 45c, allowed good conversion and enantio selectivity in the addition of linear aldehydes to methyl-vinyl ketone (MVK) (revalues up to 85%). Cyclic enones as well as -substituted enones afforded no, or perhaps poor, results. 

Kim et al have recently reported also the preparation and application of prolinol derivatives on mesoporous silicas43. In this case, higher enantioselectivities were obtained mainly due to the higher intrinsic efficiency of the chiral auxiliary and to the addition of butyl lithium as extra-metal reagent. 

Other nucleophiles that have been used in this context are acetylides (alkynes). The addition of those to iminium cations generated in situ from aldehydes and secondary amines accomplishes a gold(III)-catalyzed three-component coupling for the synthesis of propargylamines, as can be observed in equation (124). The reactions are performed in water or in tetrahydrofuran (THF) when supported catalysts are employed.Chiral prolinol derivatives as... 

Chiral Amines with C2 Symmetry, trans-2,5-Dimethylpyrrolidine (1) was the first chiral amine possessing C2 symmetry used as a chiral auxiliary in asymmetric synthesis. Since that time a number of related systems have been developed including the title compound (2) and (4). These amines were developed as C2-symmetric analogs to the commercially available prolinol derivative (5). While proline-derived chiral auxiliaries have been widely used in asymmetric synthesis, the C2-symmetric chiral auxiliaries often give enhanced stereoselectivity when compared directly to the prolinol derivatives. Unfortunately the preparation of the C2-symmetric compounds is more tedious and, at the time of writing, none are commercially available. For example, the standard route to chiral pyrrolidines (2) and (3) involves the resolution of tranf-N-benzylpyrrolidine-2,5-dicarboxylic acid, although other preparations have been... 

Mukaiyama and co-workers have reported that prolinol derivatives combined with BBrs produce promising catalysts for some Diels-Alder reactions [26]. Methacrolein and cyclopentadiene, for example, afford the exo adduct (exoiendo > 99 1) in 97 % ee (reaction at -78 °C in dichloromethane with 20 mol % catalyst). The chiral catalyst is believed to be the HBr adduct salt of the amino boron derivative (Eq. 26). 

The first report of a polymer-supported approach to this reaction appeared in 1987 [48]. Enantiopure amino alcohols such as ephedrine, prolinol, and 3-exo-amino-isoborneol were attached to Merrifield polymer. The use of polymer-supported 3-exo-aminoisoborneol 40 resulted in quite high enantioselectivity ( 95 % ee) in the ethylation of aldehydes with diethylzinc (Eq. 15), a result comparable with those obtained from the corresponding low-molecular-weight catalyst system (Eq. 16). A similar system was also reported in 1989, this time using ephedrine derivatives (41,42) and prolinol derivative (43) [49]. A methylene spacer was introduced between the polymer and the amino alcohol to improve activity [50]. Despite this the selectivity was always somewhat lower than that obtained from the low-molecular-weight catalyst (44). These chiral polymers were all prepared by the chemical modification method using Merrifield polymer. 

Asymmetric ethylation of benzaldehyde was conducted in the presence of 5 mol% of the ferrocenylzinc complex 5 in toluene or hexane (Scheme 3-6). Results are listed in Table 3-1. The iodoferrocene 4a itself bearing a simple iV-methyl-aminoalcohol side chain showed poor catalytic effect (entry 1) however, by chelation with zinc metal enantioselectivity was doubled (entry 2). With (S)-prolinol derivatives 4b and 4d, 1-phenylpropanol with R configuration was formed (entries... 

The most preparatively useful enantioselective allylation of aldehydes in this domain involves dialkoxyallylchromium (III) complexes. These stoichiometric reagents are prepared by treatment of CrCl2 with lithium alkoxides of chiral alcohols [151]. From a variety of chiral modifiers, the iV-benzoyl-L-prolinol derivatives are found to give the best yields and enantioselectivities (Scheme 10-84). 

Scheme 8). Conjugate addition of the resulting enamine-silyl ether to methyl a-trimethylsilylvinyl ketone in the presence of MgCl2 provided the cyclohex-enones. Using the prolinol-derived enamine, the annelated product was obtained with 77% ee.

Application of the prolinol-derived lithium amide 11 (Scheme 9)in the asymmetric synthesis of (-F)-confertin was successful with the addition of isoprope-nyllithium to 2-methylcyclopentenone being a key step [37]. 

Chiral boronales are generated m situ by reaction of binaphthols 3.7 (R = H, Ph) [231] with BH3 in the presence of acetic acid [778], with H BBr [781] or with B(OPh)3 [782, 783], Chiral borates are formed by reactions of substituted (S)-prolinol derivative 2.13 (R =- CPl OH) and BBr3 [784], These boronates and borates are valuable catalysts in asymmetric Diels-Alder reactions [73, 231, 601, 780], Tartaric acid derivatives, such as borate 3.8 and acyloxyboranes 3.9 recommended by Yamamoto and coworkers [73,601,778,780,785-791], are very efficient catalysts in asymmetric Diels-Alder reactions and in condensations of aldehydes with allylsilanes, enoxysilanes or ketene acetals. These catalysts are generated in situ from substituted monobenzoates of (RJl)- or (S -tartaric acid and BH3 (R = H) or an arylboric acid (R = Ar). The best asymmetric inductions are observed with catalysts 3.9, R = /-Pr. 1,3,2-OxazaboroMnes 3.10, prepared from a-aminoacids [44, 601, 780, 792, 793], are efficient catalysts in asymmetric Diels-Alder reactions. The catalyst generated from A -tosyltrytophan 3.11 is more efficient than borolidines 3.10 (R = Et, /-Pr). The catalysts 3.10 prepared from 3.11, 3.12 and 3.13 are also useful in asymmetric condensations of aldehydes with ketene acetals [794-797]. 

Most reactions of tertiary enamines have been performed with (5)-prdine derivatives. The first examples of 1,4-additions to a, 3-unsaturated aldehydes and ketones exhibited mediocre selectivities (ee < 60%) [173]. However, the reactions of two enamines of cyclohexanone, 7.109 and 7.110, with methylacrylate lead to the expected adducts with a high enantiomeric excess but a poor chemical yield [173] (Figure 7.72). The addition of an (.S)-prolinol-derived enamine to an a-tri-methylsilyl-a,P-unsaturated ketone also gives useful selectivity [162]. Seebach and coworkers reacted enamine 7.110 (R = Me) with a,P-unsaturated gem-diesters or 2-aryl-l-nitroethylenes and obtained the expected 1,4-adducts with a high selectivity [162] (Figure 7.72). Martens and Lubben [294] proposed the use of enamine 7.111 for similar purposes, but the selectivity was not as high as with 7.110 (R = Me) (Figure 7.72). 

Asymmetric iodolactonization on solid support was carried out using a C2-sym-metric chiral auxiliary 35 [13, 22], The prolinol derived precursor was allylated, followed by treatment with iodine and H 20. The resulting lactone (36) was obtained with exclusive trans selectivity and 87% ee (Scheme 12.16). 

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