Prolinol derivative reactions

Cycloaddition reactions. Asymmetric induction in cycloaddition of enals is based on the formation of conjugated iminium salts with bulky prolinol derivatives. Reaction partners include enamides and cyclopentadiene. The Diels-Alder reaction (catalyst 3B) is exo-... 

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. 

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... 

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. 

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). 

Redox reactions. Two prolinol derivatives and 6 with polyfluorinated a-substituents have been developed for use in the CBS-type reduction. Immobilization of 6 in hydrofluoroether perhaps contributes to the attainment of high ee of the reduction and it facilitates recovery of the adjuvant (for reuse). 

By complete analogy to the ephedrine derivatives discussed in Section 2.2., a dwert-butylhy-droxyphenylmethyl substituent can be attached to prolinol by reaction with 2,4-di- ert-butyl-6-(4-nitrobenzoyloxy)methylphenol20. The compound (S -IS was used for the same purpose as TV-mcthylprolinol. 

Many supported or heterogeneous catalysts used for Diels-Alder reactions are known to give better results than their non-supported analogues. Nevertheless, chiral catalysts for asymmetric Diels-Alder reactions are scarce. Mayoral, Luis and coworkers studied the use of a variety of chiral polymer-bound amino alcohols as catalysts in cycloaddition reactions. Reaction of cyclopentadiene with methacrolein in the presence of (S)-prolinol-derived resin 81 proceeded with excellent yield (98%) but poor enantioselectivity (14% e.e.) as shown in Scheme 3.6.8. Once again, extrapolation from solution phase chemistry to a solid-supported reaction proved difficult. 

Some years later, further developments by Alexakis et al. have shown that prolinol derivative 22a (10 mol%) is a better catalysts for the reaction [89]. The results vary from good, for conjugate addition of linear aldehydes to l,l-bis(benzenesulfonyl) ethylene (77-90% yields 76-93% ee), to moderate (12-91% ee) when using a-branched aldehydes as nucleophiles. Catalyst 22a has been also used by Palomo et al. for the enantioselective conjugate addition of linear and 3-branched aldehydes to E-a-ethoxycarbonyl vinyl sulfones and -a-cyano vinyl sulfones [90], derivatives that after further transformations, which usually involve a reductive desulfonylation process [91], have made possible the synthesis of different interesting chiral building blocks. 

Fustero et al. noticed that fluorinated imines lOg-h had received little attention so far in literature. In particular, the synthesis of the corresponding anti-Mannich adducts had never been explored previously. By employing Jprgensen s diphenyl-prolinol derivative 41, highly enantioselective one-pot reactions between aldehydes 2 and the fluoroaldimines lOg-h were conducted [31], leading to the fluorinated P-aUcyl-y-amino alcohols 42a-e in a highly selective anh-manner (Scheme 5.23). 

In 2005, J0rgensen and co-workers [170] developed the first asymmetric organo-catalytic epoxidation of a-p-unsamrated aldehydes using a chiral amine and H2O2 as the oxidant (Scheme 12.30). Prolinol derivative 32a turned out to be an excellent catalyst for the reaction. Although CH2CI2 was the solvent of choice to study the... 

Vinylsulfone acceptors A conjugate addition of aldehydes (203) to l,3-bis(sulfonyl) butadienes (202), catalysed by the Jprgensen-Hayashi prolinol derivative (123a), followed by cyclization, has been reported to produce cyclohexadiene derivatives (204) with <95% ee. The reaction is assumed to proceed via the usual enamine... 

The Michael addition-a-amination sequence to produce the a-hydrazino aldehydes bearing a quaternary stereocentre (228) has been attained with <98% ee on reaction of propanal, nitrostyrenes, and CbzN=NCBz, catalysed by a combination of the prolinol derivative (123a) and the cinchonine-derived primary amine (162). ... 

In 2008, Li et al. reported a copper-catalyzed amine-alkyne-alkyne addition reaction as an efficient method for the synthesis of Y,5-alkynyl-p-amino acid derivatives 102 (Scheme 3.52) [137]. In this case, the first step of the reaction is proposed to be the hydroamination of the electron-deficient alkyne 100, which plays the role of the aldehyde component. Subsequent reaction of the resultant intermediate XXX with alkyne 101 would afford intermediate XXXI, which would be then protonated to give an iminium intermediate XXXII. Finally, an intramolecular transfer of the alkyne moiety to the iminium ion would yield the 7,8-alkynyl-p-amino ester 102 and regenerate the catalyst. The reaction was later extended using chiral prolinol derivatives as the amine component, which afforded the corresponding Y,5-alkynyl-p-amino acid derivatives with excellent diaste-reoselectivities (up to >99 1) [138]. 

The domino Michael/aldol reaction of 3-halogeno-l,2-diones (273) (X = Cl, F) to a,fi-unsaturated aldehydes RCH=CHCH=0 (R = aryl, heteroaryl), catalysed by the prolinol derivatives (256), has been developed as a method for the construction of cyclopen- tanones (274) with four contiguous stereogenic centres (<94% ee, >20 1 dr)P ... 

Addition of aldehydes (360) to / -nitrostyrene (361), catalysed by the prolinol derivative (256a) and followed by the reaction with PhNHOH, afforded isoxazolidines (362). ° The prolinethiol ether (253), mentioned earlier, catalysed the Michael addition of ketones R CH2COR to halogenated nitroalkenes ArCH=C(X)CH=CHN02 (X = halogen) under solvent-free conditions with up to >99% ee and >99 1 drp ... 

Besides proline and MacMillan et al. s imidazolidi-nones, prolinol derivatives (Scheme 10.10) and corresponding diamines have been employed as catalysts in aldol reactions. 

The metal-free intramolecular 5 Nf-exo-trig aminohydroxylation of Al-alkenyl-sulfonamides (81) can be effected by oxone activated with Brpnsted acid as catalyst. The reaction thus proceeds via (83) and affords the prolinol derivatives (82). Although the scheme suggests that the reaction should be diastereoselective, this issue has not been addressed and there is also an incorrect use of curly arrows in this paper. 

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