Auxiliaries, chiral menthol derivatives

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%. 

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. 

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... 

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%. 

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... 

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. 

The Diels-Alder reaction of simple alkoxy alkenylcarbene complexes leads to mixtures of endo and exo cycloadducts, with the endo isomer generally being the major one [96,97]. Asymmetric examples of endo Diels-Alder reactions have also been reported by the use of chiral auxiliaries both on the carbene complex and the diene. Thus, the reaction of cyclopentadiene with chiral alkenylcarbene complexes derived from (-)-menthol proceeds to afford a 4 1... 

A satisfactory result was obtained with the ligand 4 [43], which was synthesized from neo-menthol and contains an equatorial cyclopentadienyl group. The enantioselectivity of the opening attained synthetically useful levels (97 3) and the isolated yields were reasonable. Complex 5 [44], incorporating a ligand derived from phenylmenthone, also performed well. An enantioselectivity of 96.5 3.5 was observed. Phenylmenthol has already been extensively and successfully used as a chiral auxiliary [45]. 

Poor (<4% de) to modest (56% de) amounts of diastereofacial selection is observed in the cycloaddition of nitrile oxides to optically active acrylates. The plan in each case, of course, was to use a chiral auxiliary which would preferentially shield one of the two ir-faces of the dipolarophile. Of the auxiliaries used, the sulfonamide esters derived from (+)-camphorsulfonyl chloride worked best, the menthyl esters derived from (-)-menthol the poorest (<4% de). As illustrated in Table 19, changes in both temperature and solvent had either no or little affect on the product ratios. Unlike Diels-Alder reactions, the addition of Lewis acids, specifically Et2AlCl, EtAlCh and TiCL, resulted in significant decreases in both the rate of cycloaddition and isolated yield, without an appreciable change in diastereomer ratio. ... 

To explore the viability of chiral auxiliaries in the vinyl phosphate-p-ketophosphonate rearrangement, a series of vinyl phosphates derived from ephedrine, pseudoephedrine, (lR,2S,5R)-(-)-menthol, (15,25,35,57 )-(-i-)-isopinocampheol, (5)-(-)-2-methylbutanol, binaphtol, and (2R,4R)- or (25,45)-pentane-2,4-diol have been examined. (5)-(-)-2-methylbutanol and 2,4-pentane-2,4-diol derivatives appear as the most attractive chiral auxiliaries. 

A cyclic compound 131 derived flora menthol 1.4 (R = H) has seen interesting applications [73, 137, 202, 203] in [4+2] cycloaddition reactions and in 1,3-dipolar cycloaddition reactions, as well as in the synthesis of enantioenriched aminoalcohols or aminoacids. These reactions are highly stereoselective, and the chiral auxiliaries are easily recovered by methanolysis (Figure 1.4). 

Diastereoselective [2+2] photocycloaddition of a polymer-supported cyclic chiral enone with ethylene has been reported (Scheme 12.33) [43]. The auxiliary was derived from (-)-8-(p-methoxyphenyl) menthol (87). Protection of the secondary alcohol and demethylation were carried out to give (-)-8-(p-hydroxyphenyl)menthyl acetate (88). An alkyl linker was introduced and finally loaded to poly (ethylene glycol) grafted Wang resin. Deprotection of the alcohol functionality was followed by esterification with cyclohexen-3-one-l-carboxylic acid to provide the chiral enone 89. The photochemical reaction with ethylene was performed by irradiating with light (k > 280 nm). Trifluoroacetic acid (TFA) or aqueous hydrolysis with... 

Chiral alkoxy-l,3-cyclohexadienes 1 add to 1,4-naphthoquinone (2) yielding 3 with moderate to very high diastereomcric ratios. The best results (d.r. 97.5 2.5) are achieved for dienes le and lf(l,2 5,6 -di-O-isopropylidene-a-D-glucopyranoside as an auxiliary). Diene Id (2.3,4,6-tetra-0-methyl-/(-D-glucopyranoside as auxiliary) gives a d.r. of only 58.5 41.5. Terpene derivatives as auxiliary alcohols do not work much better d.r. 63 27, 53 47, 64 36 are obtained for la [(-)-borneol], lb [( — )-menthol] and lc [(—)isopinocampheol], respectively18. 

In 1989, Prakash and co-workers reported that (trifluoro-methyl)trimethylsilane can be activated by a Lewis base to form the trifluoromethyl anion in situ, which could subsequently add to both carbonyls and imines. More recently, it has been demonstrated that the asymmetric addition of the trifluoromethyl anion to imines can be directed by sulfinyl chiral auxiliaries, whereas the addition to ketones can be controlled through the use of menthol " and isosorbide ° derived chiral auxiliaries. 

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