Menthol as a Chiral Auxiliary

Although the other enantiomer is also commercially available, the natural isomer is usually employed in phosphine synthesis and is the only one considered here. 

The development of synthetic methods based on diastereomers containing this alcohol supposed a big step forward in the preparation of enantiopure P-stereogenic compounds because it allowed a much greater flexibility compared to previous methods. 

This method was described for the first time in the accounts of Mislow and co-workers ° and of Nudelman and Cram. These reports are classical papers in P-stereogenic chemistry. Table 2.8, which is not comprehensive, lists some of the phosphines prepared in the early reports about this method. 

The oxidative Cu-promoted dimerisation of PAMPO, obtained by the menthol method, provided enantiopure DiPAMP oxide, which was reduced with inversion of configuration to (i ,i )-DiPAMP. PAMPO has also been used by Johnson and Imamoto to prepare polydentate phosphines inspired by DiPAMP. 

Bodalski, Pietrusiewicz and co-workersreacted racemic butyl phosphinite 31 with menthyl bromoacetate to form the expected Michaelis-Arbuzov phosphine oxide 32. They found, serendipitously, that crystals of pure (5p)-32 precipitated from the crude oily product and could be easily isolated in 30% yield. This compound is a highly functionalised phosphine oxide which received 

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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. 

Dipolar addition of azomethine ylides to electron-deficient olefins is a versatile route to nitrogen-containing heterocycles. Applying this approach to ( )-ethyl 3-fluoroacrylates utilizing L-menthol as a chiral auxiliary provides a stereoselective and regioselective synthesis of enantiopure-fluorinated prolines 28 and 29. Careful... 

Upon initial examination, how one could control chirality in a reaction where the product is an alkene (no new sp centers are formed) which is inherently achiral could be asked. Despite this impression, asymmetric variations of the Wittig reaction have been reported. One approach is to use a chiral auxiliary in the ester moiety of a phosphonate. The first example of a chiral Witting made use of menthol as a chiral auxiliary Reaction of the ketone 86 with the chiral HWE reagent 87 gave rise to 88. However, the levels of chiral induction were not reported. 

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]. 

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. 

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. 

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... 

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. 

This alcohol when used as a chiral auxiliary in four test reactions shows higher asymmetric induction than trans-2-phcnylcyclohcxanol or menthol. It is only slightly less effective than 8-phcnylmenthol as a chiral auxiliary.1... 

Menthol [(—)-l] has been used as a chiral ligand for aluminum in Lewis acid catalyzed Diels-Alder reactions with surprising success2 (Section D.l.6.1.1.1.2.2.1). The major part of its application is as a chiral auxiliary, by the formation of esters or ethers. Esters with carboxylic acids may be formed by any convenient esterification technique. Esters with saturated carboxylic acids have been used for the formation of enolates by deprotonation and subsequent addition or alkylation reactions (Sections D.l.1.1.3.1. and D.l.5.2.3.), and with unsaturated acids as chiral dienes or dienophiles in Diels-Alder reactions (Section D. 1.6.1.1.1.), as chiral dipolarophiles in 1,3-dipolar cycloadditions (Section D.l.6.1.2.1.), as chiral partners in /(-lactam formation by [2 + 2] cycloaddition with chlorosulfonyl isocyanate (SectionD.l.6.1.3.), as sources for chiral alkenes in cyclopropanations (Section D.l.6.1.5.). and in the synthesis of chiral allenes (Section B.I.). Several esters have also been prepared by indirect techniques, e.g.,... 

In quantitative terms, menthol ranks as one ofthe major aroma chemicals. Apart from its use in perfumery / shower and shaving products (7%), menthol finds use in the manufacture of toothpaste, (28%), pharmaceuticals (27% cough medicine and nasal sprays), cigarettes (25 %), confectionery and chewing gum (11 %), liqueurs - and in chemistry as a chiral auxiliary. 

A stereoselective synthesis of 1-methoxyspiroindoline phytoalexin 63 has been disclosed (14TA1221). Bromine-mediated spirocyclization of 1-methoxybrassinin 60 in the presence of (-i-)-menthol as the chiral auxiliary gives 1-methoxyspirobrassinol menthyl ether 62 in good yield. Subsequent oxidation with PCC under microwave irradiation provides natural (R)-(- -)-l-methoxyspirobrassinin 63 in 68% yield. 

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. 

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. ... 

We illustrate an alternative strategy, namely asymmetric induction, by E. J. Corey s preparation of a key intermediate in his synthesis of prostaglandins. In asymmetric induction, the reactive functional group of an achiral molecule is placed in a chiral environment by reacting it with a chiral auxiliary. The strategy is that the chiral auxiliary then exerts control over the stereoselectivity of the desired reaction. The chiral auxiliary chosen by Corey was 8-phenylmenthol. This molecule has three chiral centers and can exist as a mixture of 2 = 8 possible stereoisomers. It was prepared in enantiomerically pure form from naturally occurring, enantiomeri-cally pure menthol. 

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-... 

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. 

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... 

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