Pantolactone Diels-Alder reactions

Brimble and coworkers176 studied the asymmetric Diels-Alder reactions of cyclopentadiene with chiral naphthoquinones 272 bearing different chiral auxiliaries. The highest endo and facial selectivities were obtained using zinc dichloride as the Lewis acid catalyst and (—)-pantolactone as the chiral auxiliary. Thus, the reaction between cyclopentadiene and 272 afforded a 98 2 mixture of 273 and 274 (equation 76). The chiral auxiliary was removed easily by lithium borohydride reduction. 

Mark6 and colleagues178 studied the Eu(hfc)3 catalyzed inverse electron demand Diels-Alder reactions between (—)-pantolactone derived chiral a-pyrones 279 and vinyl ethers and thio ethers 280. This auxiliary proved superior to other auxiliaries in these reactions. The reactions generally proceeded with high yields, affording the endo adducts 281 with de values generally above 95%. The de proved independent of the chirality or achirality of the Lewis acid employed, as (+)-Eu(hfc)3, (—)-Eu(hfc)3 and Eu(fod)3 all afforded the same diastereomer with >95% de (equation 78, Table 13). 

At Tokyo College of Pharmacy [284], esters of 2-(trifluoromethyl)propenoic acid were used to synthesise 16,16,16-trifluororetinal (Eq. 101). Intermolecular Lewis acid-catalysed Diels-Alder reaction with a pantolactone chiral auxiliary allowed the diastereoselective construction of the core cyclohexenone portion with the quaternary centre set in the desired absolute configuration. 

Use as a Chiral Auxiliary. (5)-Ethyl lactate has been used as a chiral auxiliary in a variety of simple Diels-Alder reactions. As the fumaric acid diester, the de employing cyclopentadiene can almost be completely reversed by addition of Titanium(IV) Chloride (eq 8). In general, superior de values are achieved using (R)-Pantolactone in this context, and also for base-mediated addition to ketenes. ... 

Diels-Alder Reactions. (i )-Pantolactone is one of the most effective chiral auxiliaries for preparative scale Diels-Alder additions of simple enoate esters in the presence of Lewis acids (eq 1). ... 

Interestingly, the Diels-Alder reaction of the acrylate of o-pantolactone and cyclopentadiene in the presence of 2 equiv. MAD results in high diastereoselectivity which is the opposite of that encountered with ordinary Lewis acids. The low-temperature NMR spectrum of the Lewis acid complex of the acrylate of D-pantolactone showed that an ordinary Lewis acid such as SnCU forms the chelate complex [O] (Sch. 132). In the 1 1 acrylate-MAD complex, structure [P], although predominant, seems to be in equilibrium with the minor complex [Q] with s-cis conformation this... 

Control of the stereochemistry of the Diels-Alder reaction by means of a chiral center in the substrate is a versatile means of synthesizing cychc systems stereoselec-tively [347]. For preparation of ring systems with multi-stereogenic centers, in particular, the diastereoselective Diels-Alder reaction is, apparently, one of the most dependable methods. The cyclization of optically active substrates has enabled asymmetric synthesis. Equation (147) shows a simple and very efficient asymmetric Diels-Alder reaction, starting from commercially available pantolactone [364,365], in which one chlorine atom sticking out in front efficiently blocks one side of the enone plane. A fumarate with two chiral auxiliaries afforded virtually complete stereocontrol in a titanium-promoted Diels-Alder reaction to give an optically active cyclohexane derivative (Eq. 148) [366,367]. A variety of diastereoselective Diels-Alder reactions mediated by a titanium salt are summarized in Table 13. 

Diels-Alder reactions with Oppolzer s chiral sultam Diels-Alder reactions with pantolactone as chiral auxiliary Chiral auxiliaries attached to the diene Improved Oxazolidinones SuperQuats Asymmetric Michael (Conjugate) Additions... 

Diels-Alder reactions with pantolactone as chiral auxiliary... 

We saw pantolactone 156 acting as a reagent in chapter 26. Here it esterifles an unsaturated acid to control a Diels-Alder reaction. It has two main advantages. It is easy to use on a large scale and it is easily removed from the product. The simple acrylate derivative 157 reacts with cyclopentadiene to give essentially pure (by HPLC) adduct 158 in 81% yield after two recrystallisations.20... 

Successful polymer supported stereoselective Diels-Alder reaction was performed using immobilized enantiopure 4-(3-hydroxy-4,4-dimethyl-2-oxopyrro-lidin-l-yl)benzoic acid 12 as a chiral auxiliary [15]. The corresponding resin-bound acrylate derivate has been applied as the dienophile 13. Preparation of the precursor started with the combination of pantolactone 10 and the sodium salt of 4-aminobenzoic acid. Conversion into the corresponding benzyl ester followed. The obtained racemate was esterified with (lS)-camphanic acid chloride to a dia-stereomeric mixture to gain the enantiopure compounds by chromatographic separation. After subsequent saponification of the camphanic acid moiety and hydrolysis of the benzyl ester the (R)-enantiomer 11 was coupled to Rink amide resin (Scheme 12.6). 

Diels-Alder reactions of cyclopentadiene with methyl acrylate [19], (-)-menthyl acrylate, or other chiral dienophiles [20-23] catalyzed by cation-exchanged KIO montmorillonites were thoroughly investigated by Mayoral and co-workers. The structures of the chiral dienophiles are depicted in Figure 1. Moderate diastereo-selectivities were obtained with (-)-menthyl acrylate (54 %) and (7 )-f -acryloyl-pantolactone (53 %) in reactions catalyzed by zinc(II)-exchanged KIO montmoril-lonite at —20 °C. 

Asymmetric Diels-Alder reactions. Single-sited coordination of chiral dienophiles (e.g., the acrylate of ti-pantolactone) confers diastereoselectivity to the cycloaddition. 

It is clear that a restricted orientation of the dienophile is crucial to the success of the asymmetric Diels-Alder reaction. A good method to lock the conformation is to use an auxiliary containing a carbonyl group, such that the two carbonyl groups of the dienophile can chelate to a Lewis acid. Thus, high levels of diastereofacial selectivity can be achieved in Diels-Alder reactions of the acrylates of ethyl lactate or of pantolactone, in the presence of the Lewis acid TICU (3.91). The adduct 124 is formed almost exclusively (93 7 ratio of diastereomers) using butadiene and the acrylate of (/f)-pantolactone and can be purified easily by crystallization. Simple hydrolysis gives enantiomerically pure carboxylic acid 125. In such chelated systems, the metal is co-ordinated anti to the alkene of the dienophile and the acrylate therefore adopts the s-cis conformation 126. 

Other optically active alcohols have been employed as auxiliaries in diastereoselective, auxiliary-controlled Diels-Alder cycloaddition reactions. Helm-chen has pioneered the use of pantolactone as a chiral auxiliary that has the ability to form chelates with appropriate Lewis acids [64, 65]. Thus, treatment of 106 with isoprene and TiCl4 furnished 108 as a 97 3 mixture of dia-stereomers (Equation 8) [65]. The Ti chelate 107 was proposed as a key intermediate, leading to superb levels of asymmetric induction in the cycloaddition. 

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