With phenylmenthyl

A wide variety of tandem, triple [12], and even quadruple [13, 14] cyclizations can be performed with multiply unsaturated 1,3-dicarbonyl compounds as shown in Eq. (1) [14] this provide intermediates for steroid and terpene syntheses. High levels of asymmetric induction can be achieved with phenylmenthyl acetoacetate... 

A Lewis acid-mediated two-fold asymmetric Michael addition allows access to c( s-decalin derivatives. The reaction of the trimethylsilylenol ether of acety Icyclohexene with phenylmenthyl acrylate in the presence of Diethylaluminum Chloride (eq 7) yields the decalone in 64% yield (70% de). This has been shown not to be a Diels-Alder reaction. If the reaction is worked-up early, the initial Michael adduct can be isolated. ... 

The fact that only Grignard reagents add with high diastereoselectivity to the phenylmenthyl ester of glyoxylic acid, whereas methyllithium reacts nonstereoselectively, may be the result of a different aggregation of the reagents. This is supported by the tremendous improvement of the stereoselectivity when the addition of methyllithium is undertaken in the presence of lithium perchlorate13. 

Zamojski and coworkers have explored the use of the furan-carbonyl photocycloaddition in asymmetric synthesis, with somewhat limited success88. Irradiation of chiral glyoxylate derivative 196 [R = (R)(—)-menthyl and (R)(—)-8-phenylmenthyl] afforded... 

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%. 

This sequence was obviously not amenable to a synthesis of optically active a-allokainic acid given the fact that an aminomalonate group was necessary. After unfruitful assays with menthyl esters, the Swiss group was rewarded by the discovery that the phenylmenthyl group (180) brings sufficient asymmetry to the reaction intermediate to afford products with a high percentage of favorable diastereoisomer (Scheme 35) (181). 

Low-temperature photochemical cyclization of alkynes bearing a bulky substituent, mediated by CpCo(CO)2, proceeds with CO insertion to give cyclopentadienone complexes. Higher reaction temperatures lead to cyclotrimerization. The intramolecular variant of this reaction gives the bicyclic cyclopentadienones 139 and 139 (equation 19)142. Cyclization of unsymmetrically substituted diynes with the chiral R CpCo(CO)2 (R = 8-phenylmenthyl) leads to the formation of a mixture of diastereomers modest diastere-oselectivity was found. 

The diastereofacial selective imine-ene reactions with a-imino esters prepared from (—)-8-phenylmenthyl glyoxylate have provided an efficient entry to the asymmetric synthesis of a-amino acids, and a Lewis acid-mediated intramolecular imine-ene reaction has been used for the key spirocyclization step in a recent synthesis of (—)-perhydrohistrionicotoxin. Asymmetric azo-ene reactions have been effected using the chiral azo-enophile, di-(—)-(lR,2S)-2-phenyl-l-cyclohexyldiazenedicarboxylate. ... 

The formation of spirocyclopropanes from the reaction of diazodiphenylmethane and ( )-8-phenylmenthyl esters of acrylic acid and methyl fumarate occurred with a modest level of diastereofacial selectivity (136). In contrast, diastereoselectivities of 90 10 were achieved in the cycloadditions of diazo(trimethylsilyl)methane with acrylamides 65 derived from camphor sultam as the chiral auxiliary (137) (Scheme 8.16). Interestingly, the initial cycloadducts 66 afforded the nonconjugated A -pyrazolines 67 on protodesilylation the latter were converted into optically active azaproline derivatives 68. In a related manner, acrylamide 69 was converted into A -pyrazolines 70a,b (138). The major diastereoisomer 70a was used to synthesize indolizidine 71. The key step in this synthesis involves the hydrogenolytic cleavage of the pyrazoline ring. 

Nitrile oxides are relatively electron-deficient compounds that react smoothly with electron-rich vinyl ethers. Jenkins and co-workers (171) investigated the reactions of L-menthyl-, 8-phenylmenthyl- and S)-endo- >omy vinyl ethers with nitrile oxides, but generally the de values were <33%. However, use of the chiral vinyl ether 114 in the reaction with a number of alkyl and benzonitrile oxides provided product 115 with de values of up to 66% (Scheme 12.38). It is proposed that the syn-staggered conformation is preferred for the vinyl ether 114 as indicated... 

To a stirred solution of methyl 8-phenylmenthyl methylmalonate (250 mg, 0.72 mmol) in dry THF (5 mL) was added at — 78 C under argon 1 M LiHMDS in THF (1.1 mL, 1.1 mmol). The mixture was stirred for 30 min at — 78 C, after which l-fluoro-2,4,6-trimethylpyridinium triflate (Id 310mg. 1.1 mmol) was added in small portions. The resulting mixture was stirred for 15 h at — 78 C to rt, before dilution with benzene. The mixture was washed with 5 % aq KHS04 and brine, dried (MgS04). and evaporated. Column chromatography of the residue (silica gel, hexane/EtOAc 95 5) gave an epimeric mixture of the fluorides as an oil yield 225 mg (87%). 

An open-transition-state model is proposed for the Darzens condensation of ketones with (—)-8-phenylmenthyl a-chloroacetate the diastereoselectivity observed is explained in terms of a re-aryl interaction between the enolate and phenyl moieties.78... 

Asymmetric Diels-Alder reactions. The acrylate of (+ )-l is markedly superior to ( —)-menthyl acrylate in effecting asymmetric induction in Diels-Alder reaction with cyclopentadiene (Lewis acid catalysis, equation I). A chiral intermediate in Corey s prostaglandin synthesis was obtained by the reaction of (-1- )-8-phenylmenthyl acrylate with a cyclopentadiene derivative.1... 

Asymmetric Michael addition to enoatesThe known conjugate addition of RCu BF, (8, 324-325) to a,/(-unsaturated carbonyl compounds4 proceeds with high chiral induction to trans- )-8-phenylmenthyl crotonate (2). Addition to the isomeric ei.v-crotonate (5) is less selective, but results mainly in the enantiomeric acid (6). 

Diastereoselective alkylation of phenols.1 In the presence of TiCl4, phenols react with glyoxylates at -30 to 20° exclusively at the ortlio-position to form 2-hydroxymandelic esters. A substituent has no effect on the site of substitution. Use of a chiral glyoxylate, in particular (- )-8-phenylmenthyl glyoxylate, results in high... 

Fig. 11.19. Still-Gennari olefination of a racemic a-chi-ral aldehyde with an enan-tiomerically pure phosphonate as kinetic resolution I—Loss of the unreactive enantiomer ent-B of the aldehyde (R stands for the phenylmenthyl group in the Horner-Wadsworth-Emmons products the naming of the products in this figure is in agreement with the nomenclature of Figures 11.17 and 11.18).

By using a chiral a-oximino ester, an efficient asymmetric induction at the y-position to the carbalkoxy group was noted with several hypervalent iodine reagents, this substrate gave products with varying degrees of yield and diastereo-isomeric selectivity, as illustrated in the following scheme, where R is (— )-8-phenylmenthyl [17] ... 

Asymmetric Wittig-Homer reaction chiral olefinations. 2 Reaction of the chiral ketone 1 with the ylide from (- )-8-phenylmenthyl phosphonoacetate (2) at -30 to -60° gives the (E)-olefin in a 90 10 ratio. The geometry of the alkene is determined mainly by the chiral auxiliary. Use of ent-2 results in 3 with the E/Z... 

Asymmetric intramolecular double Michael reaction.3 Treatment of the 8-phenylmenthyl ot,(3-unsaturated amide ester (2) with r-butyldimethylsilyl triflate and triethylamine effects this Michael reaction with almost complete diastereose-lectivity to give the indolizidine 3, which was used for synthesis of (- )tylophorine (4). 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

Asymmetric versions of this fundamental way of making carbon-carbon bonds have attracted considerable attention lately. The diastereoselective version has proven successful in terms of high inductions and versatility of the substrate (unsaturated ketones, esters, amides, sultames, oxazolidines, aldimines. ..). The very large amount of data reported in this area precludes its coverage but excellent reviews are available143-145. The fine example displayed below, in which the intermediate enolate is trapped intramolecu-larly, illustrates the potency of this approach (Scheme 31)146. Similarly, good results were obtained with lithium enolates derived from (—)-8-phenylmenthyl esters147. 

A new diastereoselective and enantioselective synthesis of a-amino-y-oxo acid esters has been reported involving the alkylation of enamines with acyliminoacetates (78). The stereocontrol is attributed to formation of a Diels-Alder like transition state (79). Ring opening of the adduct leads to a zwitterion or alkylated enamine, hydrolysis of which gives the single diastereoisomer (80 de > 96%)174 (Scheme 71). The use of a chiral ester [R = ( + )- or ( —)-menthyl or (—)-8-phenylmenthyl] converted this process into an enantioselective reaction (de and ee 24-67%). Since the reaction proceeds with complete anti-diastereoselectivity the two stereoisomers, enantiomeric at the two new stereogenic centres, could readily be separated by fractional crystallization. The main isomer of 80 (X = CH2), obtained in 80% yield, was shown to have the (l S, 2R)-configuration174. 

Introduction of chiral auxiliaries in the starting materials is very attract for applications to organic synthesis. However, to be of synthetic interest, chiral auxiliaries have to be inexpensive, readily introduced on the starting ma rial, inert in the conditions of irradiation, and readily removed from the photo ducts. Even if the first requirements can be easily satisfied with chiral ket esters, and amides, it is often difficult to avoid side reactions involving auxiliary [63]. In order to control all the asymmetric centers created in the in molecular photocycloadditions of cyclic enones with alkenes, esters of c alcohols were first considered. Although menthyl and bomyl derivatives ga only low de, 8-phenylmenthyl esters produced a far better asymmetric inducti [64]. The facial selectivity was found to depend on the syn/anti nature of t cycloadducts and the structure and location of the chiral auxiliary on either tl enone or the alkenyl moiety. More surprisingly the selectivity also depe strongly on the nature of the solvent (Scheme 21). 

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