Brassard s diene

Asymmetric aza Diels-Alder reactions provide a useful route to optically active heterocyclics such as piperidines and tetrahydroquinolines.45 Although successful examples of diastereoselective approaches had been reported as early as 10 years ago,46 only recently have enantioselective reactions been accomplished.47 For example, the reaction of chiral amine-derived aromatic imine 115 with Brassard s diene 116 gives adduct 117 with up to 95% diaster-eoselectivity (Scheme 5-37).48... 

The same group expanded the scope of the aza-Diels-Alder reaction of electron-rich dienes to Brassard s diene 97 (Scheme 37) [60]. In contrast to Danishefsky s diene, it is more reactive, but less stable. Akiyama et al. found chiral BINOL phosphate (R)-3m (3 mol%, R = 9-anthryl) with 9-anthryl substituents to promote the [4 + 2] cycloaddition of A-arylated aldimines 94 and Brassard s diene 97. Subsequent treatment with benzoic acid led to the formation of piperidinones 98. Interestingly, the use of its pyridinium salt (3 mol%) resulted in a higher yield (87% instead of 72%) along with a comparable enantioselectivity (94% ee instead of 92% ee). This method furnished cycloadducts 98 derived from aromatic, heteroaromatic, a,P-unsaturated, and aliphatic precursors 94 in satisfactory yields (63-91%) and excellent enantioselectivities (92-99% ee). NMR studies revealed that Brassard s diene 97 is labile in the presence of phosphoric acid 3m (88% decomposition after 1 h), but comparatively stable in the presence of its pyridinium salt (25% decomposition after 1 h). This observation can be explained by the fact that the pyridinium salt is a weak Brpnsted acid compared to BINOL phosphate 3m. 

Scheme 37 Aza-Diels-Alder reaction of Brassard s diene...

Ding extended the scope of TADDOL catalyzed HDA reactions to the use of Brassard s diene with a variety of aromatic aldehydes (Scheme 5.54) [104]. Starting... 

Dihydropyran-4-ones can be prepared by addition of various nucleophiles to 3-ethoxy-5,6-dihydropyran-2-ones prepared from the hDA reaction between Brassard s diene and aldehydes <20050L2421>. 

Taddols can also catalyze the HDA reactions of other electron-rich dienes, as demonstrated by Ding and co-workers, who showed that taddol 119 catalyzed the cycloaddition of Brassard s diene with various aromatic aldehydes to give... 

The more recent work on this area deals predominantly with the asymmetric induction in aza Diels-Alder reactions in order to develop a novel powerful tool for the stereoselective synthesis of biologically active compounds. Thus, Wald-mann et al. demonstrated the utility of chiral imines derived from enantiopure amino acids by obtaining the cycloadduct 3-3 in very good diastereoselectivity from imine 3-1 and Brassard s diene 3-2 (Fig. 3-1) [181]. 

Among the more reactive and synthetically useful dienes are doubly and triply activated alkoxy- and amino-substituted dienes, such as ( )-l-methoxy-3-(trimethylsilyloxy)-1,3-butadiene (Danishefsky s diene),( )-l-(dimethylamino)-3-(fert-butyldimethylsilyloxy)-1,3-butadiene (Rawal s diene)-, and 1,3-dimethoxy-l-(trimethylsilyloxy)-1,3-butadiene (Brassard s diene). As illustrated below, the cyclo-addition products arising from these dienes can either be hydrolyzed or treated with fluoride ion to remove the silyl group, which is followed by (3-elimination to provide conjugated cyclohexenones. 

A chelation-controlled mechanism was discussed in the asymmetric hetero-Diels-Alder reaction of a-alkoxy aldehydes and A-protected amino aldehydes with Brassard s diene mediated by Eu(hfc)3 (eq. (9) BOC = r-butoxycarbonyl) [107]. 

Danishefsky s dienes and Brassard s dienes, with imines provides an efficient route... 

Chiral phosphoric add is also effective for aza-Diels-Alder reactions. Danishefsky s diene underwent aza-Diels-Alder reaction with aldimines by means of 21e in the presence of acetic add to give the cycloadduds with high enantios-eledivities (Equation 10.43) [89]. Brassard s diene also partidpated in the aza-Diels-Alder readion under the influence of 21j to give 5-ladams with excellent enantioselectivities [90]. 

A general procedure for the cycloaddition reactions of a-alkoxy aldehydes with Brassard s diene 7 using Eu(hfc), or magnesium bromide-diethyl ether complex as Lewis acid catalyst is given below. A comparison of substituent effects and catalyst influence is shown in the following table. 

To a solulion or suspension of Lewis acid [Eu(hfc)3 or MgBr2 OEt2 (0.05 equiv or l.l equiv. respectively)] and dry CH2Cl, is added 0.5 mmol of an a-alkoxy aldehyde 1. The solution or suspension is cooled to 0 C and stirred for 5 min. 1.2-1.3 Equiv of 1,3-dimethoxy-l-trimethyisilyloxy-l,3-butadiene (7, Brassard s diene) is added dropwise, and the mixture is allowed to warm to 20 °C. After stirring for 18-24 h at 20 JC, the reaction is quenched by addition of H20 and extracted with EtOAc. The combined extracts are washed with brine, dried over MgS04. filtered and concentrated in vacuo. The crude oil is purified by flash chromatography. 

To a solution of 1 mmol of aldehyde 17 in 10 mL of CH2C1., under N2, is added 1.1 equiv of 1,3-dime(hoxy-1-trimethylsilyloxy-1,3-butadiene (16, Brassard s diene). The solution is cooled to — 78 C and stirred for 10 min, and 1.1 equiv of a 1 M soln of F.i,AICI in hexane is added dropwise. The solution is stirred for 1 h and then allowed to warm to 20 C for 3 h. The reaction mixture is cooled again to 0 C, quenched with H,0, poured into a stirred solution of potassium sodium tartrate, and extracted with Et20. The combined organic layers are washed with brine, dried, and concentrated in vacuo. The crude oil is purified by flash chromatography (EtOAc/hexane 40-60%) to give a mixture of adducts 18 and 19. 

The [4 + 2] cycloaddition of A -benzylimine 1, derived in four steps from L-threonine, to Brassard s diene 2, catalyzed by diethylaluminum chloride gives lactam 3 (accompanied by the open-chain product 4) as a single diastereomer73. 

Asymmetric hetero-Diels-Alder reactions of Danishefsky s and Brassard s dienes with aldehydes 07SL2147. 

Enantiomerically pure Br0nsted acid catalysts are beginning to see application in the aza-Diels-Alder reaction. For example, the aza-Diels-Alder reaction of 2-hydroxyaniline-derived aromatic imines, including (8.151), with diene (8.123) proceeds with up to 91% ee in the presence of 10 mol% of the phosphoric acid (8.158). While the strong acidity of this catalyst precludes its use in reactions of labile substrates, the pyridinium salt of the related acid (8.159) catalyses the aza-Diels-Alder reaction with less stable dienes such as Brassard s diene (8.134) with ees between 92 and 99%. ... 

Reactions of imines derived from valine tert-butyl ester with Brassard s diene proceed highly stereoselective in the presence of Lewis acids, such as EtAlCl2, at low temperature. Removal of the chiral auxiliary is achieved via a Curtius rearrangement. 

Akiyama and his co-workers developed the aza-Diels-Alder reaction of Brassard s diene 93 with imines 92, catalyzed by a chiral Brpnsted acid 94 derived from (/ )-BINOL, to give dihydropyridone derivatives 95 with excellent enantiose-lectivities. Scheme 3.34 [49], To demonstrate the utility of the methodology, an experiment was performed on a gram scale. 

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