Chiral menthol-derived

For acrylates, or type I reagents, applied in asymmetric Diels-Alder reactions, several chiral auxiliaries such as menthol derivatives, camphor derivatives,16,3 and oxazolidinones4 are available. Carbohydrate compounds have also been reported as chiral auxiliaries in a recent publication, although the stereoselectivity was not good.5 Here are examples in which asymmetric Diels-... 

Early work on the asymmetric Darzens reaction involved the condensation of aromatic aldehydes with phenacyl halides in the presence of a catalytic amount of bovine serum albumin. The reaction gave the corresponding epoxyketone with up to 62% ee.67 Ohkata et al.68 reported the asymmetric Darzens reaction of symmetric and dissymmetric ketones with (-)-8-phenylmenthyl a-chloroacetate as examples of a reagent-controlled asymmetric reaction (Scheme 8-29). When this (-)-8-phenyl menthol derivative was employed as a chiral auxiliary, Darzens reactions of acetone, pentan-3-one, cyclopentanone, cyclohexanone, or benzophenone with 86 in the presence of t-BuOK provided dia-stereomers of (2J ,3J )-glycidic ester 87 with diastereoselectivity ranging from 77% to 96%. 

Chiral alkenes derived from ot,p-unsaturated aldehydes have also been applied in asymmetric 1,3-dipolar cycloadditions (142). Soucy et al. (142) used (—)-8-(benzylamino)menthol (94) and acrolein for the exclusive formation of 95 having an equatorial C(2) vinyl group (Scheme 12.31). The 1,3-dipolar cycloaddition of acetonitrile oxide with 95 gave 96 with a selectivity of > 90% de. 

The technique of chiral auxiliaries was exploited in a synthesis of cholesterol absorption inhibitors, based on an imino-Reformatsky reaction between bromoacetates of chiral alcohols (e.g. 69a and 69b) and imine 70. Virtual complete asymmetric induction was found with (-)-trans-2-phenylcyclohexanol and (—)-phenyl substituted menthol derived chiral auxiliaries (equation 43)126. 

Boron enolates bearing menthol-derived chiral ligands have been found to exhibit excellent diastereo- and enantio-control on reaction with aldehydes34 and imines.35 Highly diastereo- and enantio-selective aldol additions of geometrically defined trichlorosilyl ketone enolates (31) and (32) have been achieved by promoting the reactions with chiral Lewis bases, of which (,S., S )-(33) proved to be the most effective.36 Moderate enantiomeric excesses have been achieved by using chiral ammo alcohols as catalysts for the Baylis-Hillman condensation of aldehydes with methyl vinyl ketone the unexpected pressure effect on the reaction has been rationalized.37... 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

Although a large number of chiral dienophiles have been developed (Table 26.2), their ability to provide high asymmetric induction appears to be limited to specific dienes. However, there are some dienophiles that tolerate a wider variety of dienes including menthol derivatives,117 118 camphor derivatives,6 39 40 105 107-113 181 182 and oxazolidinones.120 165 183 184 It should be noted that even these auxiliaries would require an efficient recycle protocol for economic scale up. One exception is the use of sacrificial chiral oxazolidinones, which are relatively inexpensive. This approach has been used in the large-scale preparation of the base cyclohexane unit of Ceralure Bj.168 A procedure has been developed for the preparation of (75,25)-5-norbomene-2-carboxylic acid where the D-panta-lactone auxiliary can be recycled efficiently.185186... 

Bach and co-workers developed the axially chiral N-arylthiazolium catalyst 41 bearing a menthol-derived backbone (Fig. 9.6) [45]. Using 20 mol% of this catalyst, they were able to isolate the Stetter product 30 (R = Me) in 75% yield with 50% ee. The low stereoselectivity was ascribed to an atropo-isomerization of the catalyst during the course of the reaction. 

Other previously described chiral allenyllithiums derived from aminoalcohols 761-764, menthol 765 and sugars 766-7681087 1,189 have been prepared by deprotonation with n-BuLi in ether at —40°C for 15 min. They reacted with carbonyl compounds giving, after hydrolysis, enantioenriched a-hydroxy ketones. 

Less than 5% enantiomeric excess was obtained in the osmium-catalyzed oxyamination of 2-phenyl-l-propene when chiral carbamates derived from 1-menthol and 1-borneol were used96, but the structures of the resulting products were not reported. 

The use of the corresponding thiourea in this reaction leads to equal amounts of both diastereomers, that is, no stereoselectivity is observed48. Chiral carbamates, derived from (-)-menthol and (+ )-camphor, give, in a similar reaction, a-aminoalkanephosphonic acids with optical purity up to 42 %71. 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization of 175, which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid (see Eq. (13.55)). The enantioselective variant simply utilizes an achiral template 188 in conjunction with a bulky chiral binol-derived aluminum Lewis acid 189 (Eq. (13.59)) [75]. Once again the steric bulk of the chiral aluminum Lewis acid complex favors the s-trans rotamer of the acceptor olefin. Facial selectivity of the radical addition can then be controlled by the chiral Lewis acid. The highest selectivity (48% ee) was achieved with 4 equivalents of chiral Lewis acid, providing a yield of 63%. 

In principle, the menthol recovered in Fig. 13 could be recycled, which makes the use of the chiral agent derived from nature truly minimal, but in practice it has not been worth the effort. More useful is the recovery by hydrolysis of the phosphinic acid from the (R)-menthyl ester (Fig. 12). 

Stork and coworkers [624e] have introduced enamines as a nucleophilic substitute of enols, and a few asymmetric aldol reactions have been performed with enamines. Scolastico and coworkers [1311] have reacted morpholine enamines with chiral oxazolidine 1.84 (EWG = Ts), and in some cases they obtained higher sdectivities than those obtained from enoxysilanes ( 6.9.3) (Figure 6.102). Chiral enamines derived from pyrrolidine 1.64 (R = MeOCI ) react with acyliminoesters of chiral alcohols at -100°C [1313], Double diastereodifferentiation is at work so that from matched reagents, for example the pyrrolidine enamine and iminoester 6.126 shown in Figure 6.102, P-keto-a-aminoesters are obtained with a high diastereo- and enantioselectivity. The esters of either enantiomer of menthol or of achiral alcohols give mediocre asymmetric induction. 

Extremely high diastereomeric excesses are observed with chiral phenylglyoxylates derived from 8-phenylmenthol and are independent of the nature of the olefin (Table 7) however, de values for the corresponding menthol derivatives vary with the structure of the olefin. Remarkable is the high selectivity obtained with 2,2-dimethyl-1,3-dioxole in both cases (entry 2). The tWo-phenyl selective formation of oxetanes with cyclic olefins is of note and resembles the results reported by Griesbeck32 34 In addition various olefins demonstrate the influence of C2 symmetry and the stereoselectivity with respect to regiomeric oxetanes. 

Few examples have been reported demonstrating enantioselective cyclization methodology. One known example, however, is similar to the diastereoselective cyclization which uses a menthol-derived chiral auxiliary and a bulky aluminum Lewis acid to impart selective cyclization [30[. The enantioselective variant simply... 

Utilizing the menthol-derived chiral tin reagents 77-80 in conjunction with bulky Lewis acids such as zirconocene dichloride or a manganese-salen complex, selective reductions of esters (81a-d) offered excellent levels of selectivity up to 96% ee in a 75% yield (for reduction of 81c) [36], Chiral stannane 80 offered the most consistent high levels of enantioselectivity for reduction of all substrates, ranging from 62% ee to above 90% ee in many cases with a bulky Lewis acid additive. 

Semmelhack s results in this area are centered on menthol derived chiral auxiliaries [23]. Product yields are good but diastereoselectivity in these reactions are modest (<48% ee). The example in Scheme 6 shows that higher enantiomeric excesses are obtained at elevated temperatures (0 °C as opposed to -78 °C) and this could be indicative of a change in the reaction from kinetic control at low temperature to thermodynamic control at the higher temperature. This is in keeping with the ready reversibiUty of nucleophilic addition of nitrile stabilized carbanions at temperatures above -70 °C [24,25]. 

In the past Lewis acid-catalyzed [4+2] cycloaddition reactions of chiral alkyl acrylates have been systematically studied. Chiral auxiliaries derived from camphor, menthol and amino acids or from carbohydrates have been developed. Stereochemical and theoretical aspects of these chiral inductors have been intensively reviewed (see. Chapter 6). Asymmetric Diels-Alder reactions of chiral acrylamides derived from Ca-symmetrical secondary amines lead selectively to the cycloadducts in the presence of Lewis acids such as AICI3. In reactions of chiral auxiliaries derived from (iS)-proline and (iS)-prolinol excellent endo/exo selectivities and diastereoselectivities were obtained in the presence of catalytic amounts of Et2AlCl or TiCL. Cycloadducts of chiral crotonoyl derivatives derived from oxazolidinones 62, sultam 63 or for example (S)-lactate IS were obtained with high selectivities in the presence of Lewis acids such as Et2AICl. 

Other different chiral carbene catalysts have been developed by other authors and tested specifically in intramolecular Stetter reactions (Scheme 6.10). This is the case of menthol-derived thiazolium salt 121 ° and tripeptide 122 incorporating a thiazolylalanine amino acid as constituents, which were used as pre-catalysts in the same reaction shown in Schemes 6.3 and 6.4 leading to chromanones. However, these two new catalytic systems, although active and able to promote rather efficiently the reaction, only furnished moderate levels of enantioselection. In a different approach, a C2-symmetric imidazoli-dinium salt 123 has been employed to generate the corresponding catalytically active carbene species and employed in the cyclization of 7-oxo-2-pentenoates leading to chiral cyclopentenones. In this case, this intramolecular Stetter reaction proceeded with moderate to good yields and enantioselectivities up to 80% ee. 

The asymmetric hydrovinylation reaction was first reported as early as 1972 by the Wilke group. By utilizing the menthol-derived chiral phosphonite LI as the ligand, they realized the Ni-catalyzed asymmetric hydrovinylation of... 

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