Diels-Alder reaction endo stereochemistry

The first papers dealing with the use of optically active sulfinyl nitroalkenes were published by Fuji et al. in 1991 [71,72]. These papers describe the reaction of Danishefsky s diene with compound 70 (the dienophile containing a six-membered ring does not react) to afford a 1 1 mixture of two compounds (endo-71 and exo-71) resulting from desulfinylation of the endo t) and exo(t) adducts. The optical purity of these compounds ee > 95 %) indicates a complete 7r-facial selectivity in the cycloaddition. X-ray diffraction studies of dienophile 70 showed the s-trans conformation of the sulfinyl oxygen (like that depicted in Scheme 38) in the solid state. By assuming steric approach control for the Diels-Alder reaction, the stereochemistry of endo-71 and exo-71 suggests that such a con-... 

These two aspects of the Dids-Alder are both iteroospecific (Chapter 12) in that the stereochemistry of the product is determined simply by the stereochemistry of the starting materials and not at all by how favourable one reaction pathway may be. There is one more stereochemical aspect of the Diels-Alder reaction—endo selectivity—and that is a stereose/ectiveaspect. 

Note that the stereochemistry comes out right. H s a and b are cis because they were cis in the starting quinone and the Diels-Alder reaction is stereospecific in this respect. H is also cis to and H " because the Diels-Alder reaction is stereoselectively endo. These points are described in more detail in Norman p.284-6 and explained in Ian Fleming Frontier Orbitals and Organic Chemical Reactions, Wiley 1976, p. 106-109. How would you make diene A ... 

Another stereochemical feature of the Diels-Alder reaction is that the diene and dienophile partners orient so that the endo product, rather than the alternative exo product, is formed. The words endo and exo are used to indicate relative stereochemistry when referring to bicyclic structures like substituted norbornanes (Section 4.9). A substituent on one bridge is said to be exo if it is anti (trans) to the larger of the other two bridges and is said to be endo if it is syn (cis) to the larger of the other two bridges. 

Diels-Alder reaction, 492 characteristics of, 492-497 dienes in, 496-497 dienophiles in. 493-494 electrostatic potential map of. 493 endo stereochemistry of, 495 HOMO in. 1188-1189 LUMO in. 1188-1189 mechanism of. 493 s-cis diene conformation in, 496-497... 

Enantiotopic (NMR), 455 Endergonic. 153 Endergonic reaction, Hammond postulate and, 197-198 Endo stereochemistry, Diels-Alder reaction and, 495 Endothermic, 154 -ene, alkene name ending, 176 Energy difference, equilibrium position and, 122... 

The synthesis of chaparrinone and other quassinoids (naturally occurring substances with antileukemic activity) is another striking example [16a-c]. The key step of synthesis was the Diels-Alder reaction between the a,/l-unsaturated ketoaldehyde 1 (Scheme 6.1) with ethyl 4-methyl-3,5-hexadienoate 2 (R = Et). In benzene, the exo adduct is prevalent but it does not have the desired stereochemistry at C-14. In water, the reaction rate nearly doubles and both the reaction yield and the endo adduct increase considerably. By using the diene acid 2 (R = H) the reaction in water is 10 times faster than in organic solvent and the diastereoselectivity and the yield are satisfactory. The best result was obtained with diene sodium carboxylate 2 (R = Na) when the reaction is conducted 2m in diene the reaction is complete in 5h and the endo adduct is 75% of the diaster-eoisomeric reaction mixture. 

Diels-Alder reaction is one of the most fundamental reactions for organic synthesis. Its synthetic utility is unquestioned. The stereochemistry of the reactions has attracted much attention. The retention of stereochemistry in the diene and the dienophile, the predominant formation of endo-attack products in the reactions of cyclic dienes, and highly controlled regioselectivity in the reactions of substimted dienes and... 

The stereoselectivity of some Diels-Alder reactions was also strongly affected in water.26 At low concentrations, in which both components were completely dissolved, the reaction of cyclopentadiene with butenone gave a 21.4 1 ratio of endo/exo products when they were stirred at 0.15 M concentration in water, compared to only a 3.85 1 ratio in excess cyclopentadiene and an 8.5 1 ratio with ethanol as the solvent. Aqueous detergent solution had no effect on the product ratio. The stereochemical changes were explained by the need to minimize the transition-state surface area in water solution, thus favoring the more compact endo stereochemistry. The results are also consistent with the effect of polar media on the ratio.27... 

Subsequent monosilylation and Wittig reaction furnished unsymmetrical double diene 170. The synthesis of the other Diels-Alder partner started from bromophenol 173 (prepared in three steps from dimethoxytoluene), which was doubly metalated and reacted with (S,S)-menthylp-toluenesulfinate 173. CAN oxidation delivered quinone 171, which underwent a Diels-Alder reaction with double diene 170 to give compound 175 possessing the correct regio- and stereochemistry. Upon heating in toluene the desired elimination occurred followed by IMDA reaction to adduct 176, which was obtained in an excellent yield and enantioselectivity. Both Diels-Alder reactions proceeded through an endo transition state the enantioselectivity of the first cyclization is due to the chiral auxiliary, which favors an endo approach of 170 to the sterically less congested face (top face) (Scheme 27). 

For an unsymmetrical dienophile, there are two possible stereochemical orientations with respect to the diene. The two possible orientations are called endo and exo, as illustrated in Fig. 6.3. In the endo transition state, the reference substituent on the dienophile is oriented toward the % orbitals of the diene. In the exo transition state, the substituent is oriented away from the % system. For many substituted butadiene derivatives, the two transition states lead to two different stereoisomeric products. The endo mode of addition is usually preferred when an electron-attracting substituent such as a carbonyl group is present on the dienophile. The empirical statement which describes this preference is called the Alder rule. Frequently, a mixture of both stereoisomers is formed, and sometimes the exo product predominates, but the Alder rule is a useful initial guide to prediction of the stereochemistry of a Diels-Alder reaction. The endo product is often the more sterically congested. The preference for the endo transition state... 

Theoretical work on the gas-phase hetero-Diels-Alder reaction of A -sulfinyl dienophiles was used to study both endo- and o-modes of cycloaddition for both (E)-29 and (Z)-30 dienophiles at the B3LYP/6-31G level (Scheme 2) <2000JOC3997>. In summary, these calculations have predicted that (1) the A -sulfinyl dienophiles prefer the (Z)-30 orientation over (E)-29 stereochemistry by 5-7 kcalmoP, (2) the transition state is concerted but nonsynchronous, and (3) an lYo-transition state with diene 31 is favored over the fvo-approach both kinetically and thermodynamically. 

In 1993, Evans and co-workers examined phe-box 6, /-pr-box 45, and bu-box 3 ligands in the Diels-Alder reaction of cyclopentadiene 68 and 3-acryloyl-l,3-oxazolidin-2-one 69 using a weak Lewis acid such as copper(II) triflate." The results are summarized in Table 9.9. The reaction was carried out between —50 and —78 °C for 3-18 h and achieved selectivities of up to 98 2 (endo/exo) with an endo ee of >98% (using bu-box 3). Interestingly, the enantiomer produced in these reactions was the (25) configuration, compared to the (2K) isomer obtained with iron(III) and magnesium(II) as reported by Corey. This observed stereochemistry was explained by the chelation model of the copper(II) complex 74 (Fig. 9.23)... 

Ghosh and co-workers have also demonstrated that the Cu(II)-bis(oxazoline) complexes of conformationally constrained inda-box ligands 9a and ent-9a are excellent catalysts for the enantioselective Diels-Alder reaction. Using copper(II) trrflate as the metal source, the reaction resulted in selectivities up to >99 1 endo/ exo ratio with endo ee up to 99% (2R isomer), as shown in Table 9.10 (Fig. 9.24). Of particular interest, Cu(II)-phe-box ligand 6-derived catalyst complex exhibited considerably lower enantioselectivity (30%)." Furthermore, they have shown that the use of Mg(II) as the chelating metal resulted in a reversal of stereochemistry [up to 98 2 endo/exo and 61% endo ee for the (25) isomer]. Davies also showed that the use of copper(II) triflate with his stmcturally related inda-box ligands 9b and 34a led to similar selectivities. 

The Diels-Alder reaction is stereo specific. The stereochemistry of the dienophile is retained in the product i.e., cis and trans dienophiles produce different diastereoisomers in the product. For example, freshly distilled cyclopentadiene, having s-cis configuration, reacts with maleic anhydride to give c/ -norbornene-Sjh-endo-dicarboxylic anhydride. 

The cycloaddition reactions of 368 (X = CO) with 7V-phenylmaleimide, p-benzoquinone, dimethyl acetylenedicarboxylate, and tetracyanoethylene afforded [4 + 2]-cycloadducts with endo-stereochemistry ethyl acrylate gave two isomers (probably endo and exo). l,4-Dihydro-l,4-oxidonaph-thalene (19) yielded the endo-exo isomer. The Diels-Alder reaction of 368 (X = SO2) with ethyl acrylate gave a mixture of isomers, from which the higher melting product could be isolated in pure form. ... 

However, this route fails because the Diels-Alder reaction with the particular set of reagents has a very unfavorable equilibrium constant. Even if the addition were successful, it is possible also that the stereochemistry (exo or endo) of the adduct would not be the same as that of the natural product. 

From the stereochemical structure of the adduct it can be inferred that the initial ortho photocycloaddition occurs with exo stereochemistry, whereas the subsequent Diels-Alder reaction of the ortho adduct with a second molecule of maleic anhydride proceeds with endo stereochemistry. 

The stereochemistry of the cycloadducts in intramolecular Diels-Alder reactions depends upon the different geometry of the possible transition states 37—40 whose nomenclature can be explained as follows The orientation with the chain connecting the diene and dienophile lying under or above the diene is called endo. The opposite means exo. E and Z mark the geometry of the diene double bond which is connected with the chain. Syn and anti describe the arrangement of the hydrogen atoms (or substituents) at the prestereogenic centers which are involved in the C-C bond formation.12... 

The uncoordinated portion of the 3-vinylpyrrole complexes described above resembles an electron-rich diene, and undergoes a Diels-Alder reaction under mild conditions with electron-deficient alkenes and al-kynes to give functionalized 5,6,7,7a-tetrahydroindole complexes 122 and 149-164 in moderate to excellent yields (Table 10). In most cases, only one stereoisomer is observed even though up to four new stereocenters are formed. For tetrahydroindole complexes 122 and 150, relative stereochemistry has been assigned and is consistent with cycloaddition occurring through an endo-transition state as well as dienophile attack occurring anti to metal coordination. Furthermore, no isomerization occurs to the 4,5,6,7-tetrahydroindole system, which predominates for uncoordinated tetrahydroindoles.23... 

From the unequivocally established syn relationship between hydroxy and amino groups in 137, the same relative stereochemistry of the sulfoxide and amino functions in the precursor adducts 136 may be inferred based upon the stereospecific character of the rearrangement. On this basis, it could be concluded that Diels-Alder reaction of sulfinyldiene 134 took place with complete control of endo and regioselectivities. 

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 stereochemistry of the cycloadducts in hetero Diels-Alder as well as of the all-carbon Diels-Alder reactions depends upon the different geometry of the possible transition structures [3,12,38]. According to an endo- or exo-orientation of the dienophile and an (E)- or (Z)-configuration of the diene, four different transition structures have to be discussed which are shown exemplary for 1-oxa-1,3-butadienes in the inter- and intramolecular mode (Schemes 1-2 and 1-3). 

Draw a final diagram of the product with the stereochemistry of the other substituents shown too in the usual way. This is the endo product of the Diels-Alder reaction... 

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