Imines Derived from Chiral Aldehydes

Reports of diastereoselective additions to chiral ketimines are much more rare. 

One example describes the sequential addition of two different nucleophiles 

Imines Bearing a Chiral Protect ng/Activating Croup 

The imine 19 derived from a phenylethylamine has been reported to react with various nucleophiles, such as organolithium reagents and cuprates, to generate the diastereoenriched amine following hydrogenolysis (H2/Pd) of the chiral auxiliary. However, the diastereoselectivities of these reactions are typically modest [36 38]. The seminal works of Takahashi [39] and later Pridgen [40] demonstrated that higher 

Chiral Hydrazones Chiral Oxime Ethers APSulfinyl Aldimines 

---

In 2000, the group of Banik et al. reported the enantiospecific synthesis of 3-hydroxy-2-azetidinones by microwave assisted Staudinger reaction [51]. Chiral imines, derived from chiral aldehydes and achiral amines, reacted with methoxy- or acet-oxy-acetyl chloride to afford a single, optically pure c/s-p-lactam, (Scheme 7). 

Cycloaddition of diverse types of ketenes and imines leading to the formation of P-lactams is reported. The reactions of chiral ketenes with achiral imines, chiral imines with achiral ketenes, chiral imines with chiral ketenes, and catalytic asymmetrical Staudinger reactions have been investigated. In general, a higher level of asymmetric induction is achieved using either chiral ketenes or chiral imines derived from chiral aldehydes in comparison to the use of a chiral imine derived from an achiral aldehyde with an achiral ketene. Both carboxylic acid chlorides and carboxylic acids themselves have been used as ketene precursors. 

Double asymmetric induction operates when the azomethine compound is derived from a chiral a-amino aldehyde and a chiral amine, e.g., the sulfin-imine 144 [70]. In this case, the R configuration at the sulfur of the chiral auxihary, N-tert-butanesulfinamide, matched with the S configuration of the starting a-amino aldehyde, allowing complete stereocontrol to be achieved in the preparation of the diamine derivatives 145 by the addition of trifluo-romethyl anion, which was formed from trifluoromethyltrimethylsilane in the presence of tetramethylammonium fluoride (Scheme 23). The substituents at both nitrogen atoms were easily removed by routine procedures see, for example, the preparation of the free diamine 146. On the other hand, a lower diastereoselectivity (dr 80 20) was observed in one reaction carried out on the imine derived from (it)-aldehyde and (it)-sulfinamide. 

To solve this problem, Pericas and co-workers have introduced a dual catalytic system consisting of a chiral amino alcohol 2, to control the enantioselectivity of the addition process, and a bulky silylating agent, to further activate the inline substrate (Scheme 1) [7]. When the 2/TIPSC1 system was used to promote the addition to imines derived from aromatic aldehydes, the addition reactions took place with good yield (63-75%) and high enantioselectivities (72-91%). Even in this case, a substoichiometric amount of chiral amino alcohol is required for a satisfactory result. 

In 1998, Yamamoto et al. reported the first catalytic enantioselective allylation of imines with allyltributylstannane in the presence of a chiral 7i-allylpalladium complex 23 (Scheme 9) [15]. The imines derived from aromatic aldehydes underwent the allylation with high ee values. Unfortunately, the allylation reaction of aliphatic imines resulted in modest enantioselectivities. They proposed that a bis-Jt-allylpalladium complex is a reactive intermediate for the allylation and reacts with imines as a nucleophile. The bis-Jt-allylpalladium complex seemed the most likely candidate for the Stille coupling [16]. Indeed, the Stille coupling reaction takes place in the presence of triphenylphosphine even if imines are present, whereas the allylation of imines occurs in the absence of the phosphine [17]. They suggested the phosphine ligand played a key role in controlling the... 

In 1997, Kobayashi and colleagues reported the first truly catalytic enantioselective Mannich-type reactions of aldimines 24 with silyl enolates 37 using a novel chiral zirconium catalyst 38 prepared from zirconium (IV) fert-butoxide, 2 equivalents of (R)-6,6 -dibromo-l,l -bi-2-naphthol, and N-methylimidazole (Scheme 13) [27, 28], In addition to imines derived from aromatic aldehydes, those derived from heterocyclic aldehydes also worked well in this reaction, and good to high yields and enantiomeric excess were obtained. The hydroxy group of the 2-hydroxyphenylimine moiety, which coordinates to the zirconium as a bidentate ligand, is essential to obtain high selectivity in this method. 

In 1997, the first truly catalytic enantioselective Mannich reactions of imines with silicon enolates using a novel zirconium catalyst was reported [9, 10]. To solve the above problems, various metal salts were first screened in achiral reactions of imines with silylated nucleophiles, and then, a chiral Lewis acid based on Zr(IV) was designed. On the other hand, as for the problem of the conformation of the imine-Lewis acid complex, utilization of a bidentate chelation was planned imines prepared from 2-aminophenol were used [(Eq. (1)]. This moiety was readily removed after reactions under oxidative conditions. Imines derived from heterocyclic aldehydes worked well in this reaction, and good to high yields and enantiomeric excesses were attained. As for aliphatic aldehydes, similarly high levels of enantiomeric excesses were also obtained by using the imines prepared from the aldehydes and 2-amino-3-methylphenol. The present Mannich reactions were applied to the synthesis of chiral (3-amino alcohols from a-alkoxy enolates and imines [11], and anti-cc-methyl-p-amino acid derivatives from propionate enolates and imines [12] via diastereo- and enantioselective processes [(Eq. (2)]. Moreover, this catalyst system can be utilized in Mannich reactions using hydrazone derivatives [13] [(Eq. (3)] as well as the aza-Diels-Alder reaction [14-16], Strecker reaction [17-19], allylation of imines [20], etc. 

In general, the level of asymmetric induction achieved with imines derived from achiral aldehydes and chiral amines is lower than that observed when a chiral aldehyde or chiral ketene is used. Nevertheless, threonine-derived imines 52 give the cis-P-lactams 53 with diastereoselectivity which increases as the size of the protecting group on the hydroxyl group increases <00SC3685>. 

In 2011, WulfTdescribed the first three-component catalytic asymmetric aziridi-nation reaction of an aldehyde 92, bis(dimethylanisyl)methylamine (163), and ethyl diazoacetate (164) to provide the corresponding chiral aziridine-2-carboxylic esters (165) [55]. When promoted by a chiral boroxinate catalyst in situ generated from B(OPh)3 and chiral Hgand (S)-VAPOL (2,2 -diphenyl-(4-biphenanthrol)), the reaction afforded products 165 with good yields and excellent diastereoselectivities and enantioselectivities (Scheme 11.36). This novel methodology furnished an effective solution to the problem of unstable imines derived from aliphatic aldehydes that cannot be purified. 

The use of a chiral amine to generate a chiral imine is obviously attractive. Chiral amines (and amino alcohols) are readily available, and they have been used successfully in numerous enantioselective methodologies. However, imines derived from chiral amines and achiral aldehydes have generally afforded disappointing levels of asymmetric induction. This is perhaps to be expected because the imine A -substituent is relatively remote from the C3 and C4 substituents in the assembled transition state. For example, modest diastereoselectivity was observed with the use of the imine 13, which is derived from a commercially available aminodiol. ... 

Ketene-imine cycloaddition involving an imine derived from cinnam-aldehyde and a D-glucosamine derivative led stereoselectively to the p-lactam (110) the chiral auxiliary could be disconnected from the p-lactam by base treatment. Cycloaddition of methyl acrylate and an N-glycosyl dihydropyridine gave adduct (111) and its diastereomer in the azabicyclic ring system. Removal of the chiral auxiliary from each diastereomer then gave the enantiomeric isoquinuclidines. ... 

Chiral imines derived from 1-phenylethanone and (I. Sj-exo-l, 7,7-trimethyIbicyclo-[2.2.1]heptan-2-amine [(S)-isobornylamine], (.S>1-phenylethanamine or (R)-l-(1-naphthyl) ethanamine are transformed into the corresponding (vinylamino)dichloroboranes (e.g., 3) by treatment with trichloroborane and triethylamine in dichloromethane. Reaction of the chiral boron azaenolates with aromatic aldehydes at 25 "C, and subsequent acidic hydrolysis, furnishes aldol adducts with enantiomeric excesses in the range of 2.5 to 47.7%. Significantly lower asymmetric inductions are obtained from additions of the corresponding lithium and magnesium azaenolates. Best results arc achieved using (.S )-isobornylamine as the chiral auxiliary 3. 

Shi and Xu reported that the chiral amine catalyst 142 also performs quite efficiently in the related addition of N-tosyl aryl imines to methyl vinyl ketone (MVK), to methyl acrylate, and to acrylonitrile (Scheme 6.61) [155]. As shown in Scheme 6.61, enantiomeric excesses > 95% were achieved for several />-N-tosylamino enones 147 obtained by addition of aryl imines (146) to MVK, > 80% for addition to methyl acrylate, and 55% ee (max.) for addition to acrylonitrile (not shown in Scheme 6.61). Reaction times were typically 1-3 days. N-Sulfonylimines derived from aliphatic aldehydes gave rise to complex product mixtures. Under the reaction conditions shown in Scheme 6.61 addition of p-nitrobenzaldehyde to MVK proceeded with only 20% ee. 

Axially chiral bis-isoquinoline N,N -bisoxide (S)-17 has been reported to promote the addition of Me3SiCN (1.5-2.0 equiv.) to imines 78, derived from aromatic aldehydes (Scheme 7.17) here, CH2CI2 was identified as an optimal solvent. The reaction is stoichiometric in 17, and exhibits partial dependence on the imine electronics (62-78% ee), but much less than that observed for the allylation of PhCHO catalyzed by QINOX (24) (vide supra). The o-substitution had a positive effect in the case of Cl (95% ee), but a very negative effect in the instance of MeO (12% ee). Chelation of the silicon by the N-oxide groups was suggested to account for the stereochemical outcome. Analogues of 17 were much less successful [75]. 

Ester-Mannich Additions. The E 0) enolate (7) reacts with A-allyl or A-benzyl aldimines to afford chiral p-amino esters (eq 11). As with the aldol reactions, best selectivities are achieved with imines derived from aromatic or unsaturated aldehydes. The... 

On the basis of these results, we have developed the first method for the enantiose-lective synthesis of chiral /3-amino acid esters from achiral imines and ketene silyl acetals using BLA 28. The enantioselectivity of the aldol-type reaction is dramatically increased by using sterically bulky A-substituents. Condensation of the imine derived from benzhydrylamine occurs with high enantioselectivity (90 % ee) (Eq. 80). Furthermore, the best result (96 % ee) is achieved by use of a 1 1 (v/v) mixture of toluene and dichloromethane as solvents. Thus, excellent enantioselectivity (95 % ee or better) has been achieved in reactions of aromatic aldehyde-derived imines... 

In addition to chiral PTCs, cinchona-based thioureas have also been proved to serve as catalysts for nitro-Mannich reactions. In 2006, Ricci and coworkers first reported that the quinine-based thiourea 40 (20mol%) can catalyze the aza-Henry reaction between nitromethane and the N-protected imines 93 derived from aromatic aldehydes [40]. N-Boc-, N-Cbz-, and N-Fmoc protected imines gave the best results in terms of the chemical yields and enantioselectivities (up to 94% ee at —40°C) (Scheme 8.30). 

Kobayashi has demonstrated that a chiral zirconium catalyst derived from 3,3 dibromo or 3,3 dichloro BINOL can catalyze the addition of substituted allyl stannanes to the imines derived from 2 hydroxyaniline and aryl or hetereoaryl substituted aldehydes (Scheme 1.25) [95]. The active catalyst is possibly generated by the bonding of the alcohol functionalities of the imine and of allylstarmane to the zirconium center. 

The various possibilities for the preparation of chiral allylic amines or a aryl substituted amines are outlined in Figure 1.9. Although the addition reaction of a carbon nucleophile to an imine derived from an aryl substituted aldehyde is very efficient (B), the related addition to an a,p unsaturated imine (A) can sometimes proceed via a 1,4 addition pathway. Similarly, the asymmetric C=N reduction reaction (C and D) is sometimes hampered by the possibility of either obtaining conjugate reduction (in the case of C) or low enantioselectivities (in D when R = aryl). The addition of sp hybridized carbanions to imines (E) is a particularly effective... 

The imine (101) derived from a 2-aryltryptamine and ethyl glyoxylate undergoes a diastereo-selective spirocyclization to the indolenine (102) (Equation (27)). Replacement of the ethyl ester by chiral esters, such as the 8-phenylmenth-3-yl ester, leads to asymmetric induction at the spiro carbon atom <90HCA439>. Imines derived from tryptophan esters have also been studied as substrates for the Pictet-Spengler cyclization (e.g., <87tlii31 . Enantioselective cyclizations have made use of enantiomerically pure aldehydes and tryptophan esters <92H(34)517, 93JCS(pi)43i, 93T8589>. 

---