Diels-Alder reaction substrate controlled

Alkylation to form substrates which undergo intramolecular Diels-Alder reaction is controlled by choice of metal (Pd, Mo, W) template . [MoCp(cyclohexadiene) (CO)2 J" " may be used to control functionalisation of the 6-membered ring in particular a novel stereocontrolled lactone synthesis O effects of m- or p-... 

The reactivity in Diels-Alder reactions is controlled by the HOMO-LUMO energy gap between the reagents. Generally, the small energy-separation is found between the HOMO of the diene and the LUMO of the dienophile and we talk about normal Diels-Alder reactivity. High HOMO dienes and low LUMO dienophiles are ideal substrates for these types of reactions. By contrast, electron-deficient dienes like 1 have low HOMOs and are more prone to participate in inverse electron demand Diels-Alder. In these cases the interaction HOMO dienophile-LUMO diene controls the process. 

In the 1,3-dipolar cycloaddition reactions of especially allyl anion type 1,3-dipoles with alkenes the formation of diastereomers has to be considered. In reactions of nitrones with a terminal alkene the nitrone can approach the alkene in an endo or an exo fashion giving rise to two different diastereomers. The nomenclature endo and exo is well known from the Diels-Alder reaction [3]. The endo isomer arises from the reaction in which the nitrogen atom of the dipole points in the same direction as the substituent of the alkene as outlined in Scheme 6.7. However, compared with the Diels-Alder reaction in which the endo transition state is stabilized by secondary 7t-orbital interactions, the actual interaction of the N-nitrone p -orbital with a vicinal p -orbital on the alkene, and thus the stabilization, is small [25]. The endojexo selectivity in the 1,3-dipolar cycloaddition reaction is therefore primarily controlled by the structure of the substrates or by a catalyst. 

The classic method for controlling stereochemistry is to perform reactions on cyclic substrates. A rather lengthy but nonetheless efficient example in the prostaglandin field uses bicyclic structures for this purpose. Bisacetic acid derivative S is available in five steps from Diels-Alder reaction of trans-piperylene and maleic anhydride followed by side-chain homologation. Bromolactonization locks the molecule as bicyclic intermediate Esterification, reductive dehalogen-... 

Uncatalysed Diels-Alder reactions usually have to be carried out at relatively high temperatures (normally around 100 °C)73, often leading to undesired side reactions and retro-Diels-Alder reactions which are entropically favoured. The Diels-Alder reaction became applicable to sensitive substrates only after it was realized that Lewis acids (e.g. A Clg) are catalytically active56. As a consequence, Diels-Alder reactions can now be carried out at temperatures down to — 100°C85. The use of Lewis acid catalysts made the [4 + 2]-cycloaddition applicable to the enantioselective synthesis of many natural compounds51,86. Nowadays, Lewis acid catalysis is the most effective way to accelerate and to stereochemically control Diels-Alder reactions. Rate accelerations of ten-thousand to a million-fold were observed (Table 7, entries A and B). 

Highly enantioselective 1,5-substitution reactions of enyne acetates are also possible under carefully controlled conditions (Eq. 4.31) [46]. For example, treatment of enantiomerically pure substrate 70 with the cyano-Gilman reagent tBu2CuLi-LiCN at —90 °C provided vinylallene 71 as a 1 3 mixture of E and 2 isomers with 20% and 74% ee, respectively. This mediocre selectivity might be attributable to race-mization of the allene by the cuprate or other reactive copper species formed in the reaction mixture. The use of phosphines as additives, however, can effectively prevent such racemizations (which probably occur by one-electron transfer steps) [47]. Indeed, vinylallene 71 was obtained with an ee of 92% for the E isomer and of 93% for the 2 isomer if the substitution was performed at —80 °C in the presence of 4 eq. of nBusP. Use of this method enabled various substituted vinylallenes (which are interesting substrates for subsequent Diels-Alder reactions Sect. 4.2.2) to be prepared with >90% ee. 

As we have shown, the sulfinyl group has been widely used as a chiral inductor in Diels-Alder reactions when bonded to the dienophilic double bond, due to its strong ability to control the 7r-facial selectivity. However, only a small number of papers on the use of sulfinyl dienes in asymmetric synthesis have been written, perhaps due to the poor reactivity of many of these substrates and the complex course of their reactions (mainly in the case of 1-sulfinyl dienes, see later). Additionally, the fact that synthetic methods to obtain enantiomerically pure sulfinyl dienes have been available only in the last six years would also explain the low number of papers concerning these asymmetric Diels-Alder reactions. During the preparation of this account, an excellent review on the synthesis and asymmetric Diels-Alder reactions of chiral 1,3-sulfinyl dienes has been published [11]. 

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. 

Lewis acids have been widely used to catalyze Diels-Alder reactions when thermal conditions were not efficient [43]. A limitation of the Lewis acid catalyzed Diels-Alder cycloaddition reaction has often been found to be due to the sensitivity of the substrates to the strongly acidic media. For instance, when considering the addition of phenylacetylene derivatives to 1-silyloxypyrrole, it was found that the Lewis acids (AICI3, BF3, TiCU) led to decomposition of starting materials, while the thermal processes afforded only negligible amounts of the desired cycloadduct [44]. The successful preparation of the cycloadduct product was achieved with lithium perchlorate in ether. This approach did not produce a very acidic reaction medium, but considerably lowered the LUMO pyrrole energy, almost as much as protonation by itself (Table 14). The final effect was that the reaction became a strongly LUMO diene controlled Diels-Alder reaction. 

This implies all chiral centers are created at the time of the Diels-Alder reaction, but some are formed prior to the Diels-Alder and some after. It is important to specify the timing of the reactions and their sequence. If chiral centers are created from prochiral substrates, control of the geometry of diene and alkene is important. If chiral centers are incorporated into the diene and alkene, an asymmetric synthesis is required, possibly using a chiral starting material. 

A new approach to determination of partial rate constants for reactions of conformers has been developed on the basis of constituents of the Gibbs energy of activation for reactions of a series of conformationally heterogeneous substrates. The proposed model allows solving of formal kinetic tasks under conditions of thermodynamic control and in the absence of diastereoisomeric products. The p-values and partial rate constants have been determined for the chair and twist conformers of a series of 2-substituted l,3-dioxacyclohept-5-enes in the model Diels-Alder reaction with l,2,4>5-tetrazine-3,6-dicarboxylate in two solvents. In dioxane, the chair conformer reacts 3.4 times faster and, in acetone, 1.4 times faster than does the twist conformer <1996RJC477>. 

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