Chiral 8-phenylmenthol

Lewis acid-mediated asymmetric Diels-Alder reactions between 2H-azirines 59, bearing chiral auxiliaries, with enophiles such as 60 afforded mixtures of bicyclic aziridine-2-carboxylates 61 (Scheme 3.20) [68]. 8-Phenylmenthol appeared to be the auxiliary of choice in this reaction in terms of yield and diastereoselectivity. 

Mainly sulfoxide groups are introduced as chiral auxiliaries for the modification of a,/J-unsat-urated enones (see Section D.1.5.3.5.). Chiral imine derivatives have also been used (see Section D.1.5.3.1.). Various chiral alcohols, and in particular 8-phenylmenthol, have been successfully used as auxiliaries, mainly in two-fold Michael additions to a,/ -unsaturatcd esters. 

Alkenylcarbene complexes react with in situ-generated iodomethyllithium or dibromomethyllithium, at low temperature, to produce cydopropylcarbene complexes in a formal [2C+1S] cycloaddition reaction. This reaction is highly diastereoselective and the use of chiral alkenylcarbene complexes derived from (-)-8-phenylmenthol has allowed the enantioselective synthesis of highly interesting 1,2-disubstituted and 1,2,3-trisubstituted cyclopropane derivatives [31] (Scheme 9). As in the precedent example, this reaction is supposed to proceed through an initial 1,4-addition of the corresponding halomethyllithium derivative to the alkenylcarbene complex, followed by a spontaneous y-elimi-nation of lithium halide to produce the final cydopropylcarbene complexes. 

The reaction of alkenylcarbene complexes and imines in the presence of a Lewis acid generates pyrroline derivatives as a result of a [3C+2S] cyclisation process [76]. This reaction has been extended to an asymmetric version by the use of chiral alkenylcarbene complexes derived from several chiral alcohols. However, the best results are found when (-)-8-phenylmenthol-derived complexes are used and catalytic amounts of Sn(OTf)2 are added to the reaction. In these conditions high levels of trans/cis selectivity are achieved and the hydrolysis of the major tram diastereoisomers allows the preparation of optically pure 2,5-disubstituted-3-pyrrolidinone derivatives (Scheme 29). 

An 8-phenylmenthol ester was employed as the chiral auxiliary to achieve enantioselectivity in the synthesis of prostaglandin precursors.83 The crucial features of the TS are the anti disposition of the Lewis acid relative to the alcohol moiety and a tt stacking with the phenyl ring that provides both stabilization and steric shielding of the a-face. 

Substituted 3-hydroxy-2-pyrrolidinones were synthesised via 1,3-DC reactions of furfuryl nitrones with acrylates and subsequent intramolecular cyclisation after N-0 bond reduction. Addition of iV-acryloyl-(2/()-bomane-10,2-sultam to Z-nitrone 83 gave the endo/exo cycloadducts in 85 15 ratio with complete stereoface discrimination <00JOC1590>. The 1,3-DC of pyrroline A-oxide to chiral pentenoates using (-)-/rans-2-phenylcyclohexanol and (-)-8-phenylmenthol as chiral auxiliaries occurred with moderate stereocontrol (39% de and 57% de, respectively) and opposite sense of diastereoselectivity <00EJO3595>. The... 

Application of the above method to chiral 2-en-7-ynoates derived from optically active 8-phenylmenthol led to asymmetric ring-closure to give bicydic ketones bearing an angular substituent, with high ee values, as shown in Eq. 9.64, s.p. 349 [112]. 

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]. 

Taguchi and coworkers175 studied the Lewis acid catalyzed asymmetric Diels-Alder reactions of chiral 2-fluoroacrylic acid derivatives with isoprene and cyclopentadiene. When a chiral l,3-oxazolidin-2-one and diethylaluminum chloride were used as the chiral auxiliary and the Lewis acid catalyst, respectively, a de of 90% was observed for the reaction with isoprene. The reaction with cyclopentadiene afforded a 1 1 mixture of endo and exo isomers with de values of 95% and 96%, respectively. The endo/exo selectivity was improved by using 8-phenylmenthol as the chiral auxiliary. Thus, the reaction... 

The chiral TV-sulfmylcarbamate 248 derived from 8-phenylmenthol formed a mixture of two epimeric cycloadducts 249 and 250 with cyclohexa-1,3-diene (equation 132)124, whereas the reaction with (E, )-hexa-2,4-diene in the presence of tin(IV) chloride gave solely the epimer 251 (equation 133)125. 

In the course of examining the CAI effect of conformational restriction of the C3-side-chain, intermediate 24 was prepared. Shankar and co-workers (Shankar et al., 1996) demonstrated that 10, a key intermediate in the research synthesis could be accessed by Wacker oxidation of olefin 24 (Scheme 13.7). Additionally, an alternative chiral variant of the well-precedented addition of zinc enolates to imines was demonstrated. Treatment of the bromoacetate 25, derived from 8-phenylmenthol with zinc and sonication followed by imine addition afforded 26 in 55% yield with greater than 99% de. Ethyl magnesium promoted ring-closure followed by C3 alkylation with 28, intercepts the previously demonstrated route through formation of olefin 24 (Shankar et al., 1996). 

Diiodomethane-Diethylzinc, 276 2-Oxazolidones, chiral, 267 8-Phenylmenthol, 243 (S)-Prolinol, 261 Simmons-Smith reagent, 275 L-Valinol, 341 Amides... 

Methyl-5-phenyl-3-(3-phenylpro-pionyl)-2-oxazolidone, 24 (S)-l-[l-Methyl-2-pyrrolidinyl]-methylpiperidine, 116, 302 Methyl p-tolyl sulfoxide, 115 Norephedrine, 200 2-Oxazolidones, chiral, 24, 225, 267 (2R,4R)-Pentanediol, 205, 237 /r[Pg.403]

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. 

Oxidation of chiral esters of phenylacetic acids. These esters can be converted into acetates of mandelic esters by oxidation with DDQ in acetic acid. The reaction is diastereoselective when carried out on esters of chiral alcohols, of which 8-phenylmenthol is the most useful. The presence of substituents on the phenyl group has slight effect on the diastereoselectivity, which depends on formation of a donor-acceptor complex between the substrate and the quinone with removal of a hydrogen atom. The acetoxy group then enters from the opposite, more bulky face. 

YouwiHsee phenyimenthoi usedasa 0f a useful chiral molecule 8-phenylmenthol from the natural product (i )-(+)-pulegone. The first... 

Explain the stereochemistry and mechanism in the synthesis of the chiral auxiliary 8-phenylmenthol from (+)-pulegone. After the reduction with Na in i-PrOH, what is the minor (13%) component of the mixture ... 

Considerable work was done to induce chirality via chiral auxiliaries. Reac tions with aromatic a-ketoesters like phenylglyoxylates 21 and electron-rich al kenes like dioxoles 22 and furan 23 were particularly efficient (Scheme 6). Yield up to 99% and diastereoselectivities higher than 96% have been observed whet 8-phenylmenthol 21a or 2-r-butylcyclohexanol 21b were used as chiral auxiliarie [14-18]. It should be noted that only the exoisomers 24 and 25 were obtained from the reaction of dioxoles 22. Furthermore, the reaction with furan 23 wa regioselective. 24 were suitable intermediates in the synthesis of rare carbohydrate derivatives like branched chain sugars [16], Other heterocyclic compounds liki oxazole 28 [19] and imidazole 29 [20] derivatives as well as acyclic alkenes 3fl 31, and 32 [14,15,21,22] were used as olefinic partners. Numerous cyclohexane derived alcohols [18,21-24] and carbohydrate derivatives [25] were used as chiri... 

The Birch reduction has been applied to electron-deficient pyrroles substituted with a chiral auxiliary at the C(2)-position <1999TL435>. Using either (—)-8-phenylmenthol or (- -)-/ra /-2-(ot-cumyl)cyclohexanol as auxiliaries, high levels of stereoselectivity were obtained. Pyrrole 911, prepared from the l/7-pyrrole-2-carboxylic acid 910 in 90% yield, was reduced under modified Birch conditions (Scheme 176). The best conditions involved lithium metal (3 equiv), liquid ammonia and THE at —78°C. The addition of A, A -bis(2-methoxyethyl)amine (10 equiv) helped to reduce side reactions caused by the lithium amide formed in the reaction <1998TL3075>. After 15 min, the Birch reductions were quenched with a range of electrophiles and in each case 3,4-dehydroproline derivatives 912 were formed in excellent yields and with good diastereoselectivities. 

Asymmetric reactions of oc-keto esters of ( —)-l. Reduction of the a-keto ester (2) of (- )-8-phenylmenthol (1) with potassium triisopropoxyborohydride proceeds in 90% de to give the lactate ester (R)-3 with chirality opposite to that obtained by reaction of... 

By using chiral auxiliary groups derived from phenylmenthol or camphor, Lewis acid catalyzed Diels-Alder reactions gave an easy access to enantiomerically pure carbamate alcohols38,39. For example, the enantiomerically pure cycloadduct from cyclohexadiene and chiral IV-sulfinyl carbamate could be transformed into the bicyelic carbamate with complete transfer of chirality. 

Chiral Auxiliary for Asymmetric Induction. Numerous derivatives of (—)-8-phenylmenthol have been utilized for asymmetric induction studies. These include inter- and intramolecular Diels-Alder reactions, dihydroxylations, and intramolecular ene reactions of a,p-unsaturated 8-phenylmenthol esters. These reactions usually proceed in moderate to good yield with high diastereofacial selectivity. a-Keto esters of 8-phenylmenthol (see 8-Phenylmenthyl Pyruvate) have been used for asymmetric addition to the keto group, as well as for asymmetric [2 -F 2] photoadditions and nucleophilic alkylation. Ene reactions of a-imino esters of 8-phenylmenthol with alkenes provide a direct route to a-amino acids of high optical purity. Vinyl and butadienyl ethers of 8-phenylmenthol have been prepared and the diastereofacial selectivity of nitrone and Diels-Alder cycloadditions, respectively, have been evaluated. a-Anions of 8-phenylmenthol esters also show significant diastereofacial selectivity in aldol condensations and enantiose-lective alkene formation by reaction of achiral ketones with 8-phenylmenthyl phosphonoacetate gives de up to 90%. ... 

Hydroperoxide-n-Butyllithium gives 50% de. Chiral 3-amino esters of 8-phenylmenthol have been prepared in 50-60% de by the addition of amines to the re face of 8-phenylmenthyl crotonate under 14-15 kbar pressures (eq 2). Much higher (75 to >99%) de is obtained using 8-0-naphthyl)menthol crotonate. The 3-amino esters obtained are of the proper configuration for conversion to biologically active 3-lactams. ... 

Glyoxalate esters of phenylmenthols (83 equation 20) have been extensively used as chiral auxiliaries for a number of different reactions. Selective Grignard addition from the nt face of the molecule... 

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