Chiral auxiliary camphorsultam

The first diastereoselective synthesis of a tetrahydrothiophene derivative was reported by Karlsson and Hdgberg (32,95). The parent ylide la was added to a variety of C,C-dipolarophiles (79) bearing (—)-(15)-2,10-camphorsultam as the chiral auxiliary group to exclusively give trans-cycloadducts 80a,b with high diastereoselectivity [diastereomeric ratio (dr) 9 1], (Scheme 5.28). 

The enantiomeric synthesis of rranj-3,4-disubstituted tetrahydrothiophenes using a sulfur ylide cycloaddition has been reported <990L1667>. The sulfur ylide derived from the action of cesium fluoride on sulfide 111 underwent an asymmetric cycloaddition with chiral a,p-unsaturated camphorsultam amide 112 giving tetrahydrothiophene 113 (80% de). The configuration was confirmed by cleavage of the chiral auxiliary followed by reductive desulfurization with Raney-Ni which gave known carboxylic acid 114. 

A practicable strategy to provide access to chiral pyrazolidine-3-carboxylic acid (16) makes use of asymmetric dipolar cycloaddition of diazoalkanes to u,p-unsaturated carboxylic acid derivatives. For this purpose a chiral auxiliary of the alkene component is used, e.g. Op-polzer s1166 1671 (lf )-2,10-camphorsultam.t164l As shown in Scheme 7, by reaction of (tri-methylsilyl)diazomethane (41) with /V-( aery I oy I )cam p h ors u 11 am (42), the AL(4,5-dihy-dropyrazoline-5-carbonyl)camphorsultam (43) is obtained. Reduction of 44 with sodium cyanoborohydride leads to A-(pyrazolidine-3-carbonyl)camphorsultam (45) as the 35-dia-stereoisomer (ee 9 1) in 65 to 80% yields.[164] The camphorsultam 45 is then converted into the methyl ester 46 by reaction with magnesium methylate without racemizationj1641... 

Oppolzefs chiral auxiliary,6 (-)-2,10-camphorsultam, is useful in the asymmetric Diels-Alder reaction,3 4 and for the preparation of enantiomerically pure p-substituted carboxylic acids7 and diols,8 in the stereoselective synthesis of A2-isoxazolines,9 and in the preparation of N-fluoro (-)-2,10-camphorsultam, an enantioselective fluorinating reagent.10... 

Many chiral auxiliaries are derived from 1,2-amino alcohols.7 These include oxazolidinones (l),7-9 oxazolines (2),10 11 bis-oxazolines (3),1213 oxazinones (4),14 and oxazaborolidines (5).15-17 Even the 1,2-amino alcohol itself can be used as a chiral auxiliary.18-22 Other chiral auxiliaries examples include camphorsultams (6),23 piperazinediones (7),24 SAMP [(S)-l-amino-2-methoxy-methylpyrrolidine] (8) and RAMP (ent-8),25 chiral boranes such as isopinocampheylborane (9),26 and tartaric acid esters (10). For examples of terpenes as chiral auxiliaries, see Chapter 5. Some of these auxiliaries have been used as ligands in reagents (e.g., Chapters 17 and 24), such as 3 and 5, whereas others have only been used at laboratory scale (e.g., 6 and 7). It should be noted that some auxiliaries may be used to synthesize starting materials, such as an unnatural amino acid, for a drug synthesis, and these may not have been reported in the primary literature. 

Smith exploited a Lewis-acid-mediated asymmetric Diels-Alder reaction34 between 1,3-butadiene and the Oppolzer acryloyl camphorsultam 78 to set the remote C(29) stereocentre in phenylsulfone 57 (Scheme 17.17). This tactic procured acid 8 in 93% enantiomeric excess (ee), after base-promoted hydrolysis of the chiral auxiliary. Utilising a procedure published by Martin and co-workers,35 Smith iodolactonised acid 8, and... 

The chiral auxiliary approach. Poncas group has worked with chiral sulfur moieties like 10-methylthioisoborneol, Oppolzer s camphorsultam or chiral oxazolidinones which gave excellent results in stereo control and yields [95-100]. Recently they have reported that chiral alkynylthiols like 46 exhibit excellent diastereoselectivities in both inter- and intramolecular PKR, and have used this approach for the synthesis of 47, an intermediate in the synthesis of (+)-15-nor-pentelenene (48) (Scheme 15) [101,102]. 

Introduction. The toluene-2,a-sultams are recently introduced relatives of the well established 10,2-Camphorsultam chiral auxiliary and have been designed to provide similar high levels of face discrimination in reactions of pendent prochiral functionality. Feamres that distinguish them include high crystallinity and facile NMR and HPLC analysis of derivatives, favorable acylation and aldolization characteristics of derived Al-acyl enolates, and improved cleavage characteristics. 

Although Me2CuLi-mediated reductive defluorination of 42, followed by a-alkylation with alkyl halide, gave product 45 in high yield and in Z-selective manner, the relative stereochemistry at C-5 and C-2 was not controlled (see Scheme 10.12). For the stereo-controlled alkylation at C-2, a chiral auxiliary at the carboxyl moiety was used, and relatively high diastereoselectivity was realized in the case of camphorsultam derivative 46 (see Scheme 10.14) [23]. 

Palladium-catalyzed cyclopropanation using diazomethane has been achieved stereoselectively on a series of a,)9-unsaturated carboxylic acids derivatized with camphorsultam as a chiral auxiliary. The selectivity of the reaction produces cyclopropanated products 22 with the absolute configuration. The stereoselectivity of the reactions is temperature dependent. Several A-enoylsultams 21 were successfully cyclopropanated in this manner. It was found that branching at the a- or /i-carbons disfavors complete conversion an electron-withdrawing substituent at the )9-position is particularly unfavorable. The chiral auxiliary was removed by using titanium(IV) isopropoxide in benzyl alcohol followed by alkaline hydrolysis of the intermediate ester providing cyclopropanated derivatives 23b of high diastereomeric purity. ... 

Camphorsultam, a frequently used chiral auxiliary in diastereoselective syntheses [101], has also been applied in radical reactions [99]. Heterocoupling reactions with 42, 43, and the coacids 33 and 35, afforded the products 44-48 (Eq. 7). The results demonstrate that the diastereoselectivity strongly increases with the steric bulk of the 2-substituent in the malonates 42 and 43, namely 79.5% de with R = tBu and 41.3% de with R = iPr. With increasing bulk of the substituents in the coacid, hydrogen abstraction of the auxiliary substituted radical becomes a major competing reaction leading to 47 and 48. 

Chiral auxiliary approaches have been examined for the production of enantioenriched products through [2,31-rearrangements. For example, Sweeney and coworkers treated N,N-dimethylammonium salts 186 with sodium hydride to generate ammonium ylides bearing Oppolzer s camphorsultam, which underwent diastereoselective [2,31-Stevens rearrangements to enantioenriched products 187 [Scheme 1S.44. Eq. Oppolzer s camphorsultam was also compatible with our group s palladium-catalyzed tandem allylic amination/[2,31-Stevens rearrangement of tertiary amines [Scheme 1S.44. Eq. 2) ... 

The related phthallmldyl dlazoacetate (25) has yielded series of dlazoacetamldes bearing Oppolzer s camphorsultam chiral auxiliary (eq 17). ... 

Of great interest is the use of Oppolzer s camphorsultam as chiral auxiliary in a zinc-mediated allylation of oximes in the Luche conditions ... 

Permanganate was the first reagent that was demonstrated to have the ability to carry out the oxidative cyclization of 1,5-dienes [47]. Brown and coworkers have continued the development of this area by discovering a diastereoselective KMn04-mediated 1,5-diene cyclization that leads to 2,5-cis-tetrahydrofuran derivatives. They have used a camphorsultam chiral auxiliary to ccaitrol the facial selectivity and have found that polyunsaturated substrates can be chemoselectively manipulated. As an... 

Oppolzer s acylated camphorsultams (147, Equation 12) remain a classic among chiral auxiliaries for asymmetric synthesis and have been successfully applied in a variety of mechanistically distinct chemical transformations [88, 91]. The corresponding enolates can readily be prepared with a variety of strong bases and have been shown to undergo diastereoselective alkylation with a range of activated and non-activated electrophilic reagents. An illustrative example is the formation of 149 in dr >99 1 [91]. The sense... 

The use of amides and imides as chiral auxiliaries in [4 + 2]-cycloadditions has been the subject of numerous investigations. Oppolzer reported the use of camphorsultam 112 in asymmetric Diels-Alder reactions [26, 67. 68], The camphor sultam is readily available in both enantiomeric forms from cam-phorsulfonyl chloride. Acrylate 113 was found to react with cyclopentadiene in the presence of EtAlCl2 to give 115 with high selectivity (endo/exo = 99.5 0.5, dr = 97.5 2.5, Equation 10) [67]. Oppolzer also reported that triene 116 participated in an intramolecular Diels-Alder cycloaddition reaction to afford endo product 117 in 71 % yield and 96.5 3.5 dr (Scheme 17.19) [69]. This bicyclic product was subsequently converted into the pyridine alkaloid (-)-pulo upone (118). 

Lewis acid catalyzed asymmetric IMDA reactions of trienes bearing a chiral camphorsultam auxiliary have been described102. 

As one of the pioneering works on asymmetric synthesis, Evans and coworkers reported diastereoselective Diels-Alder reaction of acryloyl oxazolidinones mediated by Et2AlCl [140]. Intramolecular version of this cycloaddition was also reported, in which interesting stereochemical difference depending on substituents at oxazo-lidinone ring was found. As an another excellent example, Oppolzer and coworkers reported diastereoselective Diels-Alder reaction of chiral dienophiles equipped with camphorsultam auxiliary [141]. Recently, these diastereoselective reactions were applied to enantioselective synthesis of ceralure Bl, known as Mediterranean fruit fly attr actant (Scheme 6.118) [142]. 

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