Prolinol-derived 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... 

SCHEME 14.17. Enantioselective synthesis of thiochromenes through sulfa-Michael-aldol cascade process using cycloalkenones, promoted hy different prolinol-derived catalysts. 

Recently, and co-workers [41] Zhang reported the first highly efficient protocol for the synthesis of a-amino esters with prolinol-derivated catalyst. The (9-pivaloyl 7ra 5-4-hydroxyproline derivative (Cat. 10) achieved best results. Crucial for efficiency was the addition of small quantities of pentanoic acid. Through this approach, a broad range of chiral a-amino esters were synthesized in good yields (up to 97%) and with high levels of enantioselectivity (up to 93%) (Scheme 15.14). 

An organo-metal synergistic catalysis has been developed (Scheme 19) for the construction of the spirocyclopentene oxindole derivatives (502). Here, the cinnamic aldehyde (498) is first activated through the in situ catalytic formation of the highly electrophilic iminium ion (499) with the Hayashi-Jprgensen prolinol-derived catalyst (325)... 

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. ... 

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

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. 

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]. 

Prolinol derivatives of boron tribromide 4 give excellent results in the [4 + 2] cycloaddition of methacrolein (8a) to cyclopentadiene (exojendo ratio 99 1, 97% ee)21. Several boron catalysts derived from /V-sulfonamides of a-amino acids 7a-d have been developed. In the cycloaddition of methacrolein (8a) or croton aldehyde (8b) to cyclopentadiene these catalysts produce enan-tioselectivities ranging from medium to good8-22 23. Chiral oxazaborolidinone 6 is an excellent catalyst for the addition of 2-bromoacrolein (8e) to various dienes24 (see table overleaf)-... 

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-... 

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. 

This transformation proved to be rather general with respect to the enoliz-able aldehyde and the enal, with higher yields obtained when aliphatic a,p-unsaturated aldehydes were employed. On the other hand, all the nitroalkenes tested were nitrostyrene derivatives, with no data provided with regard to the use of the more problematic aliphatic nitroalkenes. In addition, several selective transformations were carried out on the compounds obtained by this methodology, therefore proving the possibility of chemical manipulation of the different functionalities present in their structure. A version involving the use of recyclable polystyrene-supported prolinol-based catalysts has also been reported furnishing similar yields to those obtained by Enders in solution for a comparative example. 

The TIPS-protected L-prolinol derivative A (see Chapter 8) gave superior enantioinduction however, only 44% enantiomeric excess was still obtainable. Tetrazole-derived catalyst B (see Chapter 9) gave the highest yield (98% yield). Figure 5.9 illustrates the difference in reactivity and enantioselectivities between L-proline, and proline-derived catalysts A and B. 

Wang and coworkers utilized a chiral Cu-prolinol derivative complex to catalyze a similar transformation and 2-alkylated pyrroles were obtained in good yields and enantioselectivities (63—96% yields 91—98% ee) (20150L4018). This catalyst was observed to be tolerant of both electron withdrawing and donating groups but gave superior yields with the former. More importantly, the researchers were able to develop a sequential... 

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. 

The utilization of bifunctional thiourea catalyst containing a chiral secondary amine was first reported by Peng and co-workers [45], The prolinol-derived thiourea catalyst 72 has been successfully appUed to the ATift-selective direct asymmetric... 

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... 

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]. 

Finally, a remarkable four-component tandem Michael-aza-Henry-hemi-aminalisation-dehydration tandem reaction was recently developed by Lin and co-workers on the basis of a dual organocatalysis involving a chiral diaryl prolinol trimethylsilyl ether and a chiral cinchona alkaloid." As shown in Scheme 2.37, the reaction began with the Michael addition of an aldehyde to a nitroalkene catalysed by the L-proline-derived catalyst, giving the corresponding intermediate aldehyde. The latter intermediate... 

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