Chiral acids, protonation

Later, Corey reported that the bulky superacid triflylimide (Tf2NH) protonates chiral oxazaborolidines to form superactive, stable, chiral acids 11a and 11b, which are highly effective catalysts for a wide variety of enantioselective Diels-Alder reactions that were beyond the reach of synthetic chemists (Scheme... 

One of the first compounds to be introduced to the clinic, aztreonam (40-9), has been produced by total synthesis. Constmction of the chiral azetidone starts with amide formation of L-threonine (40-1) via its acid chloride treatment with ammonia leads to the corresponding amide (40-2). The primary amino group in that product is then protected as its carbobenzyloxy derivative (40-3). Reaction of that product with methanesulfonyl chloride affords the mesylate (40-4). Treatment of that intermediate with the pyridine sulfur trioxide complex leads to the formation of the A -sulfonated amide (40-5). Potassium bicarbonate is sufficiently basic to ionize the very acidic proton on the amide the resulting anion then displaces the adjacent mesylate to form the desired azetidone the product is isolated as its tetrabutyl ammonium salt (40-6). Catalytic hydrogenation over palladium removes the carbobenzyloxy protecting group to afford the free primary amine (40-7). The... 

The three acetylpyridines have been reduced in the presence of catalytic concentrations of different alkaloids in attempts to induce optical activity in the products 412 The reduction of 3-acetylpyridine gave optically inactive alcohols under all conditions employed, whereas optically active pyridyl-ethanols are produced from 2- and 4-acetylpyridine at 0°C, in a 1 1 aqueous-ethanolic acetate buffer with strychnine (5 x 10-4 M) as chiral catalyst. Under these conditions protonated, adsorbed strychnine is probably acting as a chiral acid. The pinacols obtained as side products were all optically inactive. 

The heterobimetallic multifunctional complexes LnSB developed by Shibasaki and Sasai described above are excellent catalysts for the Michael addition of thiols [40]. Thus, phenyl-methanethiol reacted with cycloalkenones in the presence of (R)-LSB (LaNa3tris(binaphthox-ide)) (10 mol %) in toluene-THF (60 1) at -40°C, to give the adduct with up to 90% ee. A proposed catalytic cycle for this reaction is shown in Figure 8D.9. Because the multifunctional catalyst still has the internal naphthol proton after deprotonation of the thiol (bold-H in I and II), this acidic proton in the chiral environment can serve as the source of asymmetric protonation of the intermediary enolate, which is coordinated to the catalyst II. In fact, the Michael addition of 4-/en-butylbenzcnethiol to ethyl thiomethacrylate afforded the product with up to 93% ee using (R)-SmSB as catalyst. The catalyst loading could be reduced to 2 mol % without affecting enantioselectivity of the reaction. 

Taddol has been widely used as a chiral auxiliary or chiral ligand in asymmetric catalysis [17], and in 1997 Belokon first showed that it could also function as an effective solid-liquid phase-transfer catalyst [18]. The initial reaction studied by Belokon was the asymmetric Michael addition of nickel complex 11a to methyl methacrylate to give y-methyl glutamate precursors 12 and 13 (Scheme 8.7). It was found that only the disodium salt of Taddol 14 acted as a catalyst, and both the enantio- and diastereos-electivity were modest [20% ee and 65% diastereomeric excess (de) in favor of 12 when 10 mol % of Taddol was used]. The enantioselectivity could be increased (to 28%) by using a stoichiometric amount of Taddol, but the diastereoselectivity decreased (to 40%) under these conditions due to deprotonation of the remaining acidic proton in products 12 and 13. Nevertheless, diastereomers 12 and 13 could be separated and the ee-value of complex 12 increased to >85% by recrystallization, thus providing enantiomerically enriched (2S, 4i )-y-methyl glutamic add 15. 

A major advantage is the potential to lock (and protect) written information in the photobistable material. A number of chemical gated systems involving mutual regulation of the photochromic event and, for instance, fluorescence, ion binding, or electrochemical properties have been reported.1501 Scheme 19 illustrates a chiral gated response system based on donor-acceptor substituted alkene 17.[511 The photochemical isomerization process of both the M-ds and the P-trans form was effectively blocked by the addition of trifluoroacetic acid. Protonation of the dimethyl-amine donor unit of M-rfs-17a and P-trons-17b resulted in an ineffective acceptor-acceptor (nitro and ammonium) substituted thioxanthene lower half. Since the stereoselective photoisomerization of 17 relies on the presence of both a donor and acceptor unit, photochemical switching could be restored by deprotonation by the addition of triethylamine. 

In 2005, both Rueping et al. and List et al. reported the first transfer hydrogenation with Hantzsch ester 1 of several N-protected ketimines catalyzed by chiral Bronsted acids derived from l,l -binaphthol [17, 18]. The reaction typically requires 1 to 20 mol% of catalyst, is performed in benzene at 60 °C, and enantio-selectivities of up to 90% are obtained. The chiral Bronsted acid protonates the lcetimine at nitrogen, giving an ion-pair which is reduced by Hantzsch ester 1. (For experimental details see Chapter 14.21.2). A preferred transition state has... 

Imines (98) may be lithiated66 if (a) they have no other acidic protons a to C=N and (b) they are A-methyl imines or they have other activation towards a-lithiation. The N-allyl amidines 99, for example, give interesting chiral organolithiums 100 with BuLi.67... 

V,5S)-5-Amino-4-phenyl-2,2-dimethyl-l,3-dioxane and (4i ,5i )-5-amino-(4 -biphenyl)-2,2-dimethyl-1,3-dioxane were synthesized and employed as chiral solvating agents for the ee determination of compounds bearing an acidic proton by means of NMR spectroscopy (99TA323). Based on the rigid conformation of the two amines, they are... 

Our research group developed catalytic enantioselective protonations of preformed enolates of simple ketones with (S,S)-imide 23 or chiral imides 25 and 26 based on a similar concept [29]. For catalytic protonation of a lithium eno-late of 2-methylcyclohexanone, chiral imide 26, which possesses a chiral amide moiety, was superior to (S.S)-imide 23 as a chiral acid and the enolate was pro-tonated with up to 82% ee. 

Enantioselective reactions have also been reported for the hydrolysis of enamines containing a chiral amine moiety via protonation or of prochiral enamines by the use of a chiral acid. Other asymmetric reactions are summarized in an excellent review by Seebach and coworkers179 and by Oare and Heathcock193. 

This method of deracemization by enantioselectivc protonation has been applied previously to carbonyl compounds. Thus hydrolysis of (E)- and (Z)-enamines of aldehydes or ketones in the presence of chiral acids results in preferential formation of one enantiomer. Reported optical yields are slight to moderate, ... 

Miscellaneous Applications. Only one attempt to use (R)-pantolactone as an enantioselective protonating agent for enolates has been reported. A series of structurally diverse chiral alcohols afforded modest ee s with (R)-pantolactone affording the largest ee noted for the series. The complexities of attempting a proto-nation of this sort in the presence of base and under exchanging conditions are discussed. Finally, the lactone has been used to resolve chiral acids by crystallization and chromatographic techniques applied to the (R)-pantolactone-derived esters. - ... 

The bimetallic complex (CO)5Cr =C(OMe)CH2—C6H7-77 - Fe(CO)3 (68a) was synthesized by reacting the anionic carbene precursor with the cationic cyclohexadienyl complex [Fe(7j -cyclohexadienyl)(CO)3]+ (197). Complex 68a is chiral, and a structure determination showed that both enantiomers are present in the unit cell. Deprotonation of a second acidic proton from the position a to the carbene carbon of 68a by -BuLi and subsequent treatment with another equivalent of the iron substrate afforded the trimetallic cr,Tr,7r complex (CO)5Cr=C(OMe)CH C6H7-7 -Fe(CO)3 2 (68b). The complex 68b has three chiral centers and can as a... 

Acetylation and ensuing cyclisation to the oxazolone also activates the a-proton (Figure 4.1) and provides the classical route from a natural L-a-amino acid to its dl form through hydrolysis of the derived oxazolone however, the re-protonation of a Schiff-base anion with a chiral acid (e.g. tartaric acid) gives an unequal mixture of d and l enantiomers. 

Yamamoto and co-workers have introduced a conceptually interesting series of catalysts that incorporate an acidic proton into the active catalyst. Termed Bronsted acid-assisted chiral Lewis acid (BLA), catalyst 14 selectively catalyzes a number of diene-aldehyde cycloadditions reactions (Scheme 16) [67]. While extremely selective for the substrates shown, no aldehydes lacking an a-substitu-ent were reported to be effective in this reaction. This feature was addressed in... 

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