8-phenylmenthol, as chiral auxiliary

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... 

The second approach to achieve asymmetric induction used (-)-(li ,3f ,45)-menthol or ( —)-(l/C3/C4S)-8-phenylmenthol as chiral auxiliary in diazenes 13 (Table 2, entries 10 and ll)23. In no case was the induced diastereoselectivity higher than a diastereomeric ratio of 53 47 and thus this route did not prove to be synthetically useful. Obviously, the auxiliary at the end of the tether plays no significant role in determining the direction of coiling of the acyclic chain 23. 

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. 

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... 

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... 

From the many examples of reactions with imines activated in various ways, we select the asymmetric synthesis of pipecolic acids by double diastereomeric induction using an activated imine 87 with two chiral auxiliaries - a-methylbenzylamine on the nitrogen atom and 8-phenylmenthol as esterifying group. Both these auxiliaries were discussed in earlier chapters (22 and 27). Acid-catalysed cycloaddition with normal dienes gives excellent asymmetric induction and reasonable yield. We show the matched case - the mismatched case is obviously worse.13... 

The [4 + 2] cycloaddition of 1-methoxy-l,3-butadiene (8) to (2/ )-/V-glyoxyloylbornane-10,2-sultam (7) leads to crystalline, easily separable adducts 9-12. In a noncatalyzed reaction (room temperature and high pressure) the diastereoselectivity obtained is moderate, but higher than that obtained when (-)-(/ )-menthol and (-)-(/ )-8-phenylmenthol arc used as chiral auxiliaries. The reaction is already catalyzed by very mild Lewis acids Eu(fod), yields adduct 9 with an excellent selectivity exceeding a d.r. 96 433. 

Excellent results are achieved when diene 11 [with (— )-8-phenylmenthol group as chiral auxiliary] reacts with a series of aldehydes 2a d under the influence of ( + )-Eu(hfc),. 

Esters of chiral alcohols are also used in radical reduction8, bromination 9, C S10 and C C bond formation reactions6 11 (sec Section D.l. 5.4.). Usually either 8-phenylmenthol (5)8,9> 11 or a sulfonamidoborneol. e.g., sulfonamidoisoborneol (6)10, is employed as chiral auxiliary. 

Scheme 6.20. 8-Phenylmenthol as a chiral auxiliary in the [2,3]-Wittig rearrangement [86]. Inset Rationale for the 5i-face selectivity of the enolate.

Scheme 6.52. Corey s synthetic approaches to prostaglandins (see also ref. [239], chapter 11) (a) Key hydroxy acid intermediate for the synthesis of PGF2 and PGE2. (b) Early synthesis that relied on resolution for obtaining enantiopure products [240]. (c) 8-Phenylmenthol as a chiral auxiliary [165]. (d) Acryloyl oxazolidinone as dienophile with a chiral catalyst [221,222]. (e) 2-Bromoacrolein as dienophile with a chiral catalyst [215],...

This alcohol when used as a chiral auxiliary in four test reactions shows higher asymmetric induction than tran5-2-phenylcyclohexanol or menthol. It is only slightly less effective than 8-phenylmenthol as a chiral auxiliary. ... 

Use as chiral auxiliary. Whitesell has reviewed use of this chiral alcohol (1), particularly as compared with that of (—)-menthol and (lR)-(+)-8-phenylmenthol. One advantage is that both enantiomers of 1 are available by resolution of trans-2-phenyl-cyclohexanol by means of enzymatic hydrolysis of the esters and that 2-substituted cyclohexanols are readily available. Although this chiral auxiliary was used originally for control of ene reactions of glyoxylates, it is also useful for asymmetric alkylation of enolates, and for control of various cycloaddition reactions. 

An asymmetric intramolecular Michael-aldol reaction which leads to nonracemic tricyclic cyclobutanes is performed by using TMSOTf andbis[(/ )-l-phenylethyl]amine as chiral amine, but only moderate enantioselectivities are reached (eq 68). A similar reaction sequence can also be carried out with TMSOTf and HMDS as base, with (—)-8-phenylmenthol as the chiral auxiliary however, the iodotrimethylsilane-HMDS system is more efficient in terms of yield and diastereoselectivity. The combination EtsN/TMSOTf (or some other trialkylsilyl triflates) has been used to accomplish an intramolecular Michael reaction, which was the key step for the synthesis of sesquiterpene (=E)-ricciocarpin A. ... 

It appeared more attractive to carry out a Diels-Alder reaction with control of both, its regio- and stereo-chemistry. In 1975, Corey published a diastereose-lective Diels-Alder reaction with the use of 8-phenylmenthol as a chiral auxiliary. The Lewis acid fulfils two tasks on the one hand, it increases the reactivity by lowering the LUMO of the dienophile [219] on the other hand, it stabilises the s-trans conformation for steric reasons. The attack of the diene on the s-cis-dienophUe would lead to the opposite absolute stereochemistry in the product. The Diels-Alder reaction occurs diastereoselectively, because the Si-facial half of the prochiral double bond is effectively shielded by 7t-stacking with the phenyl ring of the auxiliary. In this reaction, four new stereogenic centres are generated all at once. The yield of the desired diastereomer amounts to 89 %. 

This problem has been overcome by incorporating 8-phenylmenthol as a chiral auxiliary into a,/3-unsaturated carbene complexes their reaction with diazoalkanes results in the formation of single pyrazoline diastereomers [37]. This concept has been successfully extended to other types of 1,3-dipoles and their reaction with chiral carbene complexes. The one-pot reaction of the chromium ( )-menthyloxy-carbene 40 with nitrilimine 41 generated in situ affords a single diastereomer of -pyrazoline ester 42 after oxidative work-up neither regioisomer 43 nor its diastereomer could be detected (Scheme 11.16) [38]. 

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. 

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. 

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 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. 

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%. ... 

Chiral auxiliary-mediated diastereoselective allylations of a-bromoglycine derivatives 65 have also been established. 8-Phenylmenthol has been successfully employed as a chiral auxiliary in glycine allylations (Eq. (13.19)) [29]. The captoda-tive radical intermediate generated in this reaction benefits from the observation that a-amino acid radicals prefer an s-cis geometry about the single bond, presum-... 

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. 

In chapter 27 we recommended 8-phenylmenthol 21 as a chiral auxiliary. The three chiral centres in 8-phenylmenthol are made by from the terpene pulegone 22 (chiral pool) having only one chiral centre. The new chiral centres have 1,3- and 1,4-relationships to the centre already present in pulegone and the key to their successful control is conformational analysis. 8-Phenylmenthol has all three substituents equatorial. 

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