Enantioselective reactions Diels-Alder additions

Diels-Alder disconnection will have been eliminated, and the rctrosynthetic search becomes highly focused. Having selected both the transform and the mapping onto the TGT, it is possible to sharpen the analysis in terms of potentially available dienophile or diene components, variants on the structure of the intermediate for Diels-Alder disconnection, tactics for ensuring stereocontrol and/or position control in the Diels-Alder addition, possible chiral control elements for enantioselective Diels-Alder reaction, etc. 

To date, hydrogen bond catalysis has been successfully utilized to facilitate enantioselective Michael additions, Baylis-Hillman reactions, Diels-Alder cycloadditions, and additions of 7i-nucleophiles to imines. 

As in intermolecular reactions, enantioselectivity can be enforced in intramolecular Diels-Alder additions by use of chiral structures. For example, the dioxolane rings in 2 and 3 result in transition-state structures that lead to enantioselective reactions.72... 

J0rgensen successfully determined the structure of a Ti-TADDOLate/dienophile complex by X-ray crystallography and proposed a possible reaction mechanism for the enantioselective Diels-Alder addition of cyclopentadiene to /V-acyloxazolidinones using the Ti-TADDOLate catalyst [43],... 

Chiral (.S, .S )-diazaaluminolidine catalyst brought about the first highly enantioselective catalytic Diels-Alder reaction of an achiral C2v-symmetric dienophile with an achiral diene. Addition of 2-methoxybutadiene to A-o-tolylmaleimide in the presence of 20 mol % (5,5)-diazaaluminolidine gave rise to the cycloadduct in 98% yield and 93% ee one recrystallization from i-PrOH-hexane furnished the enantiomerically pure compound [57] (Eq. 8A.34). The Diels-Alder reaction of 2-((trimethylsilyl)methyl)butadiene and A-aryimaleimide promoted by this catalyst has been successfully applied to the enantioselective total synthesis of Gracilins B and C [58],... 

Apart form the aforementioned highly enantioselective hetero-Diels-Alder reactions, that proceed with very low catalyst loadings, the catalytically accessible enolates have also been used for related intramolecular Michael reactions (Philips et al. 2007) and for the desym-metrization of 1,3-diketones yielding cyclopentenes via an intramolecular aldol reaction (Wadamoto et al. 2007). The formation of cyclopentenes, however, presents a special case, so—depending on the stereochemical nature of the enone substrates (s-cis or s-trans) and the stereochemistry of the final products—two different mechanisms are discussed in the literature. Whereas /ran.v-cycl open (cries are proposed to be available upon conjugate addition of a homoenolate to chalcones,... 

Tridentate salen ligands (10) derived from 1 have given excellent results in the enantiocontrol of the hetero Diels-Alder addition reaction of dienes with aldehydes (eq 7) and in the asymmetric additions of TMS-azide to mc5o-epoxide and trimethylsilyl cyanide to benzaldehyde (up to 85% ee). Phosphino-oxazolines derived from 1 have been employed for the asymmetric control of palladium-catalyzed allylic substitution reactions products of 70-90% ee were obtained. Photolysis of crystalline adducts of enantiomerically pure 1 with prochiral alcohols results in asymmetric inductions of up to 79% in a rare example of a solid-state enantioselective reaction. ... 

Reaction of (R)-3,3 -bis(2-hydroxyphenyl)-2,2 -dihydroxy-l,l -binaphthyl with B(OMe)3 in dichloromethane under reflux and with removal of methanol gives a white precipitate of (R)-4. Extremely high enantioselectivity (> 99 to 92 % ee) and exo selectivity (> 99 to 97 % exo) are obtained for Diels-Alder additions of a-substi-tuted a,/ -enals with dienes in the presence of the catalyst (R)-4 [27a],... 

Five months later, Corey and Lee reported the enantioselective Diels-Alder reaction between cyclopentadiene and a,/ -acetylenic aldehydes catalyzed by a chiral cationic oxazaborinane catalyst [33]. Although initial studies of the Diels-Alder reaction between cyclopentadiene and 2-butyn-l-al or 2-octyn-l-al with 20 mol % catalyst at -94 °C to -78 °C revealed only 3-5 % conversion to product over a 24-h period, replacement of the /3-alkyl substituent on the aldehyde component by RsSi or RsSn groups resulted in much faster Diels-Alder addition (Eq. 33). The greater yield with 3-tributylstannyl-2-propyn-l-al, compared with the 3-silyl analogs, results from the rate of reaction with the former. In each instance, good enantioselectivity (80-87 % ee) was obtained. 

Lanthanide Lewis acids catalyze many of the reactions catalyzed by other Lewis acids, for example, the Mukaiyama-aldol reaction [14], Diels-Alder reactions [15], epoxide opening by TMSCN and thiols [14,10], and the cyanosilylation of aldehydes and ketones [17]. For most of these reactions, however, lanthanide Lewis acids have no advantages over other Lewis acids. The enantioselective hetero Diels-Alder reactions reported by Danishefsky et al. exploited one of the characteristic properties of lanthanides—mild Lewis acidity. This mildness enables the use of substrates unstable to common Lewis acids, for example Danishefsky s diene. It was recently reported by Shull and Koreeda that Eu(fod)3 catalyzed the allylic 1,3-transposition of methoxyace-tates (Table 7) [18]. This rearrangement did not proceed with acetates or benzoates, and seemed selective to a-alkoxyacetates. This suggested that the methoxy group could act as an additional coordination site for the Eu catalyst, and that this stabilized the complex of the Eu catalyst and the ester. The reaction proceeded even when the substrate contained an alkynyl group (entry 7), or when proximal alkenyl carbons of the allylic acetate were fully substituted (entries 10, 11 and 13). In these cases, the Pd(II) catalyzed allylic 1,3-transposition of allylic acetates was not efficient. 

Roberson, M., Jepsen, A. S., Jorgensen, K. A. On the mechanism of catalytic enantioselective hetero-Diels-Alder reactions of carbonyl compounds catalyzed by chiral aluminum complexes-a concerted, step-wise or Mukaiyama-aldol pathway. Tetrahedron 2001, 57, 907-913. Monnat, F., Vogel, P., Rayon, V. M., Sordo, J. A. Ab Initio and Experimental Studies on the Hetero-Diels-Alder and Cheletropic Additions of Sulfur Dioxide to (E)-I-Methoxybutadiene A Mechanism Involving Three Molecules of S02. J. Org. Chem. 2002, 67, 1882-1889. 

Preparation of enantiopure intermediates by the use of oxidation reactions was not limited to the synthesis of AB segment (J )-10. The synthesis of the modified daimomycinone, 9-deacetyl-ll-deoxy-9-hydroxymethyldauno-mycinone 44 by Naruta et al. provides an example of enantioselective epox-idation at the stage of a tetracycHc intermediate (Scheme 8) [56]. TetracycUc quinone 42, with the required stereochemistry of the C-4 and C-9 substituents and a protected phenolic hydroxyl group, was prepared in a tandem Michael-Diels-Alder addition of pentadienyltin with acryoylquinone 40 mediated by Lewis acid [57], followed by demethylation, acetylation, and selective hydrolysis. Sharpless enantioselective epoxidation [58] of 42 yielded epoxide 43 in 80% yield and 96% ee. Further transformations of 43 by known procedures, indicated in Scheme 8, furnished the target anthracyclinone 44 in 36% yield from 42. 

In addition, chiral zirconium-containing systems catalyze enantioselective aza-Diels-Alder reactions (137). 

Following this route, the authors achieved the synthesis of 10 analogues of compound 58, in a high global yield, where the crucial step of this total synthesis was the efficient catalytic enantio-, regio-, EIZ-, and diastereoselective three-component inverse electron demand hetero-[4+2] cycloaddition/allylboration sequence. This key process provides a rare example of an enantioselective hetero-Diels-Alder reaction involving acyclic 2-substituted enol ethers. Additionally, these compounds were evaluated for antimicrobial activity, and two of them showed more activity than the original thiomarinol H. 

Chiral Lewis acids derived from complexes between copper(I) chloride with phosphino sulfenyl ferrocenes are efficient catalysts for enantioselective aza-Diels-Alder reaction of A-sulfonyl imines with Danishefsky-type dienes (eq 47), and asymmetric conjugate addition of Grignard reagents to cyclic enones (eq 48).136... 

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