Diels-Alder reaction absolute stereochemistry

The Diels-Alder reaction, now more than 60 years old, has regained new prominence with the ability to use asymmetric technology to control relative and absolute stereochemistry while creating two new carbon-carbon bonds.1 3-5 6 As a result of the diversity of dienes and dienophiles, the application of asymmetric methodology to the Diels-Alder reaction has lagged behind other areas such as aldol reactions.3 However, considerable advances have been made in recent years through the use of chiral dienophiles and catalysts.3 6 21... 

In search for control of absolute stereochemistry, the reaction of thio-chalcones was investigated with unsaturated amides bearing an Evans chiral oxazolidinone [223] and dimenthyl fumarate [224, 225]. For the first time with thiocarbonyl compounds, the efficiency of Lewis acid addition was demonstrated, and reactions could be conducted at room temperature. With EtAlCl2 (Table 4, entry 2) or A1C13 (entry 3), levels of induction up to 92% were attained for the endo isomer. Yb(OTf)3 in DMSO also caused the acceleration of the reaction with chiral acrylamides with p-facial selectivity [226]. This group has also reported [227] an intramolecular hetero Diels-Alder reaction with divinyl thioketones and the double bond of an allyloxy group (Table 4, entry 4). 

The diterpenoid (24) undergoes29 an unusual intramolecular Diels-Alder reaction to afford (25) in which the furan ring acts as a dienophile adding across the l(10),2(3)-double-bond isomer of the parent diterpenoid. The absolute stereochemistry of the trans-clerodane caryoptin (26) has been determined30 by conversion into a C-6 ketone and comparison of the o.r.d. and c.d. curves with those of similar derivatives obtained from clerodin. 

Highly diastereoselective Lewis acid mediated aza-Diels-Alder reactions of chiral auxiliary derivatized 2H-azirines have been studied (02T5983,03JOC9958,03CC1150). The cycloaddition proceeded with high diastereoselectivity (97% de), with the absolute stereochemistry of the major product confirmed by X-ray crystallography. Without the presence of a Lewis acid, no diastereoselectivity was obtained at room temperature. 

Mukaiyama Aldol Condensation. As expected, the chiral titanium complex is also effective for a variety of carbon-carbon bond forming processes such as the aldol and the Diels-Alder reactions. The aldol process constitutes one of the most fundamental bond constructions in organic synthesis. Therefore the development of chiral catalysts that promote asymmetic aldol reactions in a highly stereocontrolled and truly catalytic fashion has attracted much attention, for which the silyl enol ethers of ketones or esters have been used as a storable enolate component (Mukaiyama aldol condensation). The BINOL-derived titanium complex BINOL-TiCl2 can be used as an efficient catalyst for the Mukaiyama-ty pe aldol reaction of not only ketone si ly 1 enol ethers but also ester silyl enol ethers with control of absolute and relative stereochemistry (eq 11). ... 

The Diels-Alder reaction is one of the most powerful and efficient processes for formation of six-membered rings with the potential of controlling the relative and absolute stereochemistry at four newly created stereogenic centers [1]. Relative stereochemistry is usually well-defined because of the formation of a cyclic transition state arising from suprafacial-suprafacial interaction, with endo approach [2]. The reaction can be accelerated by Lewis acids, high pressure, or radical cations. Diels-Alder reactions catalyzed by Lewis acids are generally more regio- and stereoselective than their thermal counterparts [3]. 

We are concerned with the absolute stereochemistry of the product does epoxidation give 5a or 5b Does the Diels-Alder reaction give 7a or 7b There is also a small group of prochiral tetrahedral carbon atoms with enantiotopic functional groups such as the diester 8 or the diene 9. We shall meet examples of all these (and more ) in this chapter. 

Synthesis of cn-Atlantone from d-Limonene. The total synthesis of a-atlantone from isoprene shown in Figure 6.22, gave positive proof of the structure as far as atom connectivity is concerned. However, what it did not achieve was to demonstrate the absolute stereochemistry of the product as the Diels-Alder reaction was not stereoselective. In order to establish the absolute stereochemistry, Cookson carried out a partial synthesis of a-atlantone from d-limonene.6 4 This is shown in Figure 6.24. 

It appeared more attractive to carry out a Diels-Alder reaction with control of both, its regio- and stereo-chemistry. In 1975, Corey published a diastereose-lective Diels-Alder reaction with the use of 8-phenylmenthol as a chiral auxiliary. The Lewis acid fulfils two tasks on the one hand, it increases the reactivity by lowering the LUMO of the dienophile [219] on the other hand, it stabilises the s-trans conformation for steric reasons. The attack of the diene on the s-cis-dienophUe would lead to the opposite absolute stereochemistry in the product. The Diels-Alder reaction occurs diastereoselectively, because the Si-facial half of the prochiral double bond is effectively shielded by 7t-stacking with the phenyl ring of the auxiliary. In this reaction, four new stereogenic centres are generated all at once. The yield of the desired diastereomer amounts to 89 %. 

The Diels-Alder reaction of (-)-pentadienedioic acid (H02CCH=C=CH-CO2H) with cyclopentadiene yields an adduct (120) having the absolute stereochemistry shown. What is the absolute configuration of (—)-pentadie-nedioic acid ... 

In the synthesis of (-l-)-Minfiensine by MaeMillan and coworkers, a novel Diels-Alder/amine cyclisation sequenee is aehieved using n with TBA (tri-bromoacetic acid) as the coeatalyst, allowing the synthesis of the complex tetracyclic pyrrolindoline core of the target molecule (87% yield, 96% ee), with low loadings possible (5 mol%). Similarly, MacMillan and coworkers have described the short nine-step synthesis of (—)-Vincorine, in which they employ the catalyst II and HBF4 as a cocatalyst for the formation of three stereocentres with the correet absolute and relative stereochemistry. The combination of an intermolecular Diels-Alder reaction with an iminium cyclisation cascade allowed formation of the tetracyclic alkaloid core in one step (70% yield, 95% ee). ... 

The dienophile scope in Cu(II)-catalyzed enantioselective Diels-Alder reactions has been expanded to include P-(acyloxy)acrylates [74]. Cu(OTf)2/(49) and Cu(OTf)2/(35) are both efficient catalysts for cycloaddition of (238) to P-(acyloxy) acrylate (242) (Scheme 17.53). However, enantiomeric products are obtained with these catalyst combinations even though the bisoxazoline ligands have identical absolute configurations at C4. Distorted square-planar complexes with substrates tilted in opposite directions are proposed to account for the observed reversal in stereochemistry. 

Recent advances in the control of absolute stereochemistry in Diels-Alder reactions of 2-pyrones with dienophiles have been reviewed. The position of the electron-withdrawing group on simple y-pyrones is a decisive factor in the 4 - - 2-cycloaddition of y-pyrones with Danishefsky s diene and with azomethine ylides. The solid-state photo-4 -I- 2-cycloadditions of 2-pyrone-5-carboxylates with maleimides give only the... 

Path B works back through cyclohexene 111 and an intramolecular Diels-Alder reaction of dienamine 112. Once again, enamine tautomerization is likely to present big problems, but once again this can be overcome by using dienamide 113. This plan provides an opportunity to control absolute stereochemistry if 113 could be prepared in enantiopure form. The dienophile olefin geometry would afford the proper relative stereochemistry at C2 and C3, but stereochemistry relative to 5 and Cio is not guaranteed. 

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