Chiral auxiliary 8-phenylmenthol

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 ... 

The first asymmetric synthesis of (20 S)-camptothecin using catalytic asymmetric induction was achieved by Fang et al. in 1994 [74], They carried out a catalytic enantioselective synthesis of Comins s intermediate (23) in order to avoid the use of the expensive chiral auxiliary, 8-phenylmenthol, or similar compound. Intramolecular Heck reaction of pyridine derivative (26) gave the cyclic olefins (27) and (28) in a ratio 1 8. The allylic ether (27) can be isomerized to (28) upon treatment with Wilkinson s catalyst [75], Asymmetric Sharpless dihydroxylation of (28) proceeded successfully when 2,5-diphenyl-4,6-bis(9-0-dihydroquinidyl)pyrimidine [(DHQD)2-PYR] was used as the chiral catalyst [76], and subsequent oxidation gave (29) in 94% ee. Treatment of (29) with acid gave the target molecule (23, Scheme 2.5), which was converted to (20S)-camptothecin in 2 steps using the Comins s procedure [73]. 

From 1988 to 1990, Ihara and co-workers modified the above synthesis approach to develop an asymmetric total synthesis of (-)-tylophorine [(-)- ] via an intramolecular double Michael reaction of a,p-imsaturated esters. Their work proved that the absolute configuration of naturally occurring (-)-tylophorine is (R). Two different chiral auxiliaries, (-)-phenylmenthol [52, 53] or (2R,4S,5R)-(-)-4-(tert-butyldimethylsiloxymethyl)-5-hydroxy-2-phenyl-1,3-dioxane(BDH), were employed [53, 54]. The reactions are summarized in Scheme (2). The resulting (E, E)-esters (26) and (27) underwent a double Michael reaction through proposed transition states (A) (B), respectively, to give a highly enantioselective product (28 and 29, respectively). (-)-... 

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. 

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... 

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... 

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. 

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. 

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%. ... 

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... 

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. 

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),. 

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