Chiral auxiliary menthol

Chiral furanones (butanolides) such as 191 have been used as dipolarophUes in various 1,3-dipolar cycloadditions. The chiral 4-substituted butanolide 190 was prepared from 191 and the chiral auxiliary menthol (Scheme 12.55) (310,311). The single diastereomer 191 is obtained by crystallization and epimerization of the other diastereomer, as the amount of 191 in solution decreases. 1,3-Dipolar... 

In y-alkoxyfuranones the acetal functionality is ideally suited for the introduction of a chiral auxiliary simultaneously high 71-face selectivity may be obtained due to the relatively rigid structure that is present. With ( + )- or (—(-menthol as auxiliaries it is possible to obtain both (5S)- or (5/ )-y-menthyloxy-2(5//)-furanones in an enantiomerically pure form293. When the auxiliary acts as a bulky substituent, as in the case with the 1-menthyloxy group, the addition of enolates occurs trans to the y-alkoxy substituent. The chiral auxiliary is readily removed by hydrolysis and various optically active lactones, protected amino acids and hydroxy acids are accessible in this way294-29s-400. 

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... 

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%. 

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]. 

Optically pure 1,3-allenedicarboxylate 110c possessing central and axial chirality was prepared from dimethyl acetonedicarboxylate by incorporation of menthol as a chiral auxiliary [98]. The [4+2]-cycloaddition reaction of 110c with cyclopentadiene in the presence of A1C13 proceeded with high diastereoselectivity to afford adduct 115. 

Brimble and coworkers172 reported the asymmetric Diels-Alder reactions between quinones 265 bearing a menthol chiral auxiliary and cyclopentadiene (equation 73). When zinc dichloride or zinc dibromide was employed as the Lewis acid catalyst, the reaction proceeded with complete endo selectivity, but with only moderate diastereofacial selectivity affording 3 1 and 2 1 mixtures of 266 and 267 (dominant diastereomer unknown), respectively. The use of stronger Lewis acids, such as titanium tetrachloride, led to the formation of fragmentation products. Due to the inseparability of the two diastereomeric adducts, it proved impossible to determine which one had been formed in excess. 

Coordination of the aluminum atom of the reducing complex was proposed to take place both to the oxygen atom of the hydroxy group and to the nitrogen atom of the amino group. The asymmetric reduction of enamine perchlorates and ketimines with menthol and bomeol chiral auxiliary reagents (50,51) presumably involves coordination of aluminum to the nitrogen atom of the substrate. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

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. 

Other chiral auxiliaries have been used besides menthol. Sulfoxide Designations ... 

The use of ketocarbenoids with chiral auxiliaries has not been terribly effective at chiral induction. Menthol and bomeol esters of diazoacetates resulted in very low enantioselectivity.38 Some improvements were obtained by using the chiral amide (29 equation 13), but low overall yields were obtained due to competing intramolecular side reactions.39 Related studies with other types of carbenoids, however, have resulted in high enantioselectivity.60... 

Since its introduction in 1975 by E. J. Corey and H. E. Ensley3 8-phenylmenthol has found widespread use as a chiral auxiliary in organic syntheses. It has proved to be dramatically superior in diastereoface discriminating ability to the commonly used chiral auxiliaries such as menthol, borneol, etc. 

The reaction of glyoxylates with furan can also be performed using chiral glyox-ylate. In particular, the use of 7 -(-)-menthol, chiral 2-octanol, and chiral 2,2-dimethyl-3-butanol as chiral auxiliaries gave the corresponding oxetanes in high yields. These compounds can be converted into the corresponding... 

To prepare the enantiomerically pure iron acyl complex (R)-(39), a precursor diastereomeric menthoxyaUcyl complex was resolved and then manipulated (Scheme 14). More recently resolution of the chiral-at-metal acyl complexes themselves was achieved, and this has become the basis for a commercial preparation of the iron acyl developed for use as a chiral auxiliary (see below). Cationic iron complex (43) was treated with potassium L-mentholate to produce diastereomeric esters (44) that were not isolated but were reacted with LiBr/MeLi (Scheme 15). After chromatography and recrystallization the enantiomerically pure ironacyl complex (5 )-(39a) was obtained. It was suggested that only one diastereomeric ester can react (with inversion of configuration at iron, as shown) with the methyl nucleophile the unreactive diastereomer suffers from severe steric congestion about the electrophilic CO ligand. 

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. ... 

The terpene menthol is widely used in organic synthesis, and serves as a chiral auxiliary for several asymmetric reactions [39]. (-)-Menthol 53 could be produced in one step from isopulegol 55 by hydrogenation of the carbon-carbon double bond, and the latter compound could be prepared by a Lewis acid-induced carbonyl-ene reaction [40] of f-(y )-citronellal 54. Nakatani and Kawashima examined that the ene cyclization of citronellal to isopulegol with several Lewis acids in benzene (Sch. 22) [41]. The zinc reagents were far superior to other Lewis acids for obtaining... 

Table 10 summarizes the data for the addition of various achiral tetraalkylaluminates (23) to chiral keto esters as oudined in equation (9). Presumably, the observed diastereoselectivities will reflect the inherent facial bias of the controlling chiral element, namely menthol (R in Table 10). In this case the diastereoselectivities are moderate (67 to 75%), but, since Corey, Oppolzer and WhiteselP have observed superior inherent facial selectivity for the 8-substituted menthol chiral auxiliary, it would be interesting to attempt the alkyl aluminate additions on substrates incorporating this auxiliary.

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%. 

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. 

The cyclic monoterpenes are also very useful. Menthol 79 is very cheap and the ketones pulegone 81 and carvone 82 are moderately cheap. All are available as the other enantiomer, e.g. 80. An important application is as a chiral auxiliary, the favourite being 8-phenylmenthol 83 made from pulegone,23 see chapter 30. 

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