Stereoselectivity in Diels-Alder

Aqueous cycloaddition using glyco-organic substrates. Facial stereoselectivity in Diels-Alder reactions of a chiral diene derived from D-glyceraldehyde [102]... 

Table 9-5 Regio and Stereoselectivity in Diels-Alder Cycloadditions of Substituted Cyclopentadienes with Acrylonitrile ... 

SchneidCT, H.-J. Sangwan, N. K. Changes of stereoselectivity in Diels-Alder reactions by hydrophobic solvent effects and by p-cyclodextrin, Angew. Chem. Int. Ed. Engl 1987,26, 896-897. 

Hajduch, J. Paleta, O. Kvicala, J. Haufe, G. Fluorinated furan-2(5H)ones reactivity and stereoselectivity in Diels-Alder reactions. Eur. J. Org. Chem. 2007, 5101-5111. 

H.-J. Schneider, N. K. Sangwan, Diels-Alder reactions in hydrophobic cavities a quantitative correlation with solvophobicity and rate enhancements by macrocycles, J. Chem. Soc., Chem. Commun., 1986, 1787-1789 H.-J. Schneider, N. K. Sangwan, Changes of stereoselectivity in Diels-Alder reactions by hydrophobic solvent effects and by )S-cyclodextrin, Angew. Chem. Int. Ed. Engl, 1987, 26, 896-897. 

Bulky aluminum Lewis acid, such as MAD and ATPH, also showed interesting stereoselectivity in Diels-Alder chemistry. For example, in the presence of stoichiometric amount of MAD the reaction of tert-butyl methyl fumarate with cyclopentadiene selectively gave methoxycarbonyl endo-adduct through selective coordination ofless bulky methoxycarbonyl group to MAD (Scheme 6.123) [147]. 

Two approaches to convergent steroid syntheses are based on the thermal opening of benzocyclobutenes to the o-quinodimethane derivatives (see p. 80 W. Oppolzer, 1978 A) and their stereoselective intramolecular Diels-Alder cyclizations. T, Kametani (1977 B, 1978) obtained (+ )-estradiol in a six-step synthesis. The final Diels-Alder reaction occurred regio- and stereoselectively in almost quantitative yield, presumably because the exo transition state given below is highly favored over the endo state in which rings A and D would stcrically inter-... 

In Diels-Alder reactions a nitroolefin may function as an electron-deficient ene com-onent or a 1,2-dihydropyridine derivative may be used as a diene component. Both types of iactants often yield cyclic amine precursors in highly stereoselective manner (R.K. Hill, 1962 i. BOchi, 1965, 1966A). 

It has been established that alkoxy alkenylcarbene complexes participate as dienophiles in Diels-Alder reactions not only with higher rates but also with better regio- and stereoselectivities than the corresponding esters [95]. This is clearly illustrated in Scheme 51 for the reactions of an unsubstituted vinyl complex with isoprene. This complex reacts to completion at 25 °C in 3 h whereas the cycloaddition reaction of methyl acrylate with isoprene requires 7 months at the same temperature. The rate enhancement observed for this complex is comparable to that for the corresponding aluminium chloride-catalysed reactions of methyl acrylate and isoprene (Scheme 51). 

Highly stereoselective hetero Diels-Alder reactions of a chiral liirylaldehyde (22) with Danishefiky s dioie were reported. In the presoice of Ln(OTf), exclusively 23 was obtained, while the reaction in the presence of Eu(thd)j produced 24 as the major product <96TA1199>. 

Nitroalkenes with Chiral Auxiliaries The use of carbohydrates as chiral auxiliary in Diels-Alder reactions for the stereoselective preparation of carbocyclic and heterocyclic chiral rings is well documented.48 For example, D-manno-nitroalkene reacts with 2,3-dimethyl-1,3-butadiene to give a 65 35 mixture of adducts, as shown in Eq. 8.29. The configurations at C-4 and C-5 have been determined to be (4R,5R) and (45,55), respectively. Hydrolysis of the product followed by degradative oxidation of the sugar side chains leads to enantiomerically... 

In stereoselective reactions, Zn11 Lewis acids work well to achieve high selectivities (Scheme 54). Chiral complexes of Zn11 with chiral bis(oxazoline) ligands act as effective catalysts in Diels-Alder reactions of reactive dienes with dienophiles having bidentate chelating moieties such as... 

Six-membered rings. Selenoketones react as dienophiles with conjugated die-nes24,89,223 233 234 in Diels-Alder [4+2] cycloadditions to form 3,6-dihydro-2H-selenapyrans. Reaction of arylselenoketones92with /ra ,v,/ra .v-2,4-hexadiene proceeds in a completely stereospecific way to yield the corresponding cis-selenapyran, while with cw,tra i-2,4-hexadiene it proceeds stereoselectively, forming cis-selenapyran with small amounts of the /nmv-selenapyran isomers, Scheme 30. 

Another total synthesis of pamamycin-607 (lb) was reported in 2001 by our own group [6] at about the same time as the Lee synthesis. Here, the approach was based on the stereoselective intramolecular Diels-Alder reaction of vinyl-sulfonates and novel methods for elaboration of the resulting sultones [13,14]. 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

Stereoselective intramolecular Diels-Alder reactions The reaction of Meldrum s acid (1) with (R)-citronellal (2) in the presence of ethylenediammonium acetate (EDDA)2 at 15-20° results in the tricyclic dihydropyran 3 as the major product with an optical purity of >98%. The product evidently results from an intramolecular hetero-Diels-Alder addition. It can be converted by acid into the optically pure a-methoxycarbonyllactone 4. 

Stereospecificity, stereoselectivity and regioselectivity combined in Diels-Alder reactions give unprecedented control and you should now see why it is so important. The analgesic tilidine 47, effective in cases of severe pain, is an obvious Diels-Alder product.8 The regioselectivity is correctly ortho and the endo transition state 51 shows that the trans -enamine 49 is needed. This is the geometry we get when the enamine is made in the normal way from the enal 50 and Me2NH. 

The reactivity of 47/-benzopyran-4-ones in Diels-Alder reactions is well documented <1987T3075>, and recently high asymmetric induction has been achieved in the reaction of 3-alkoxycarbonyl-substituted chromones with chiral auxiliaries and Danishefsky s diene <1991JOC2058>. It should be noted that 3-formylchromones can react as heterodienes in the stereoselective inverse electron Diels-Alder reaction with enol ethers <1994T11755> to provide a route to pyrano[4,3-A][l]benzopyrans a heterocyclic nucleus which occurs naturally in the fungal metabolite fulvic acid <1984CC1565>. The thermal Diels-Alder reaction of 477-pyran-4-one 405 in the presence of an excess of Danishefsky s diene 404 provided cycloadduct 406 (Equation 32) <1996H(43)745>. 

Stereoselectivity is also observed in Diels-Alder reactions of dienophiles, which contain a stereogenic C=C double bond (Figure 15.15). A cis,trans-pair of such dienophiles, moreover,... 

Despite the low reactivity and poor stereoselectivity of compound 1 as a di-enophile, the main interest of the Maignan and Raphael s paper [5] derives from the fact that it was the first one involving the use of enantiomerically pure sulfoxides in Diels-Alder reaction, which would be used profusely later in asymmetric synthesis. For this reason it deserves some additional comments. From Scheme 2 can be deduced a moderate endo orientating character of the sulfinyl group [endo-adducts are the major ones (66%) in the mixture]. Although no explanation about the stereochemical behavior of compound 1 was offered in... 

These results indicate that the sulfinyl group seems to be much more efficient in the control of the stereoselectivity of 1,3-dipolar cycloadditions (endo or exo adducts are exclusively obtained in de> 80%) than in Diels-Alder processes (mixtures of all four possible adducts were formed). Additionally, complete control of the regioselectivity of the reaction was observed. Despite these clearly excellent results, the following paper concerning asymmetric cycloaddition of cyclic nitrones and optically pure vinyl sulfoxides was reported nine years later [154]. (Meanwhile, only one paper [155], related to the synthesis of /1-nicotyri-nes, described the use of reaction of nitrones with racemic vinyl sulfoxides, but these substrates were merely used as a masked equivalent of acetylene dipolaro-phile). In 1991, Koizumi et al. described the reaction of one of the best dipolarophiles, the sulfinyl maleimide 109, with 3,4,5,6-tetrahydropyridine 1-oxide 194 [154]. It proceeded in CH2C12 at -78 °C to afford a 60 20 10 6 mixture of four products in ca. 90 % yield (Scheme 92). 

A similar approach to the synthesis of tetracyclic indole alkaloid derivatives has been described [182], and the use of reactive chiral iminium ions allows the realisation of stereoselective aza Diels-Alder reactions even in aqueous solution [183,184]. Nevertheless it should be noted that reactions of electron-rich dienes with imines e. g. derived from amino acids do not necessarily proceed via a Diels-Alder mechanism. They may as well undergo a domino-Mannich-Michael sequence which also efficiently leads to useful nitrogen heterocycles [185-188]. 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

As a current example of a stereoselective intramolecular Diels-Alder reaction using nitroso dienophiles, Kibayashi s studies aimed at the enantioselective total sysnthesis of (-)-pumiliotoxin C 4-31 shall be discussed here [356, 357]. The chiral nitroso compound 4-30 derived from L-malic acid was generated in situ... 

The Stereoselectivity of Diels-Alder Reactions. One of the most challenging stereochemical findings is Alder s endo rule for Diels-Alder reactions. The favoured transition structure 6.180 has the electron-withdrawing substituents in the more hindered environment, under the diene unit, giving the kinetically more favourable but thermodynamically less favourable adduct 6.181. Heating eventually equilibrates the adducts in favour of the exo adduct 6.182, by a retro-cycloaddition re-addition pathway. 

Evans et al. also showed that the 1 1 mixture of BAN and (3, y-distearoyl-phos-photidylcholine (DSPC) gives a smectic A texture in the temperature range of 57.3 to 100°C [21]. This is the first notice of lyotropic lamellar liquid crystals formed in the ionic medium. Additionally, Seddon et al. [28] and Neve et al. [29] have described the long-chained A-alkylpyridinium or l-methyl-3-alkylimidazolium ions to display smectic liquid-crystalline phases above their melting points, when Cl or tetrachloro-metal anions like CoCl " and CuCl " are used as the counter ions. Lin et al. have also noted the liquid crystal behavior of 1-alkylimidazolium salts and the effect on the stereoselectivity of Diels-Alder reactions [30]. However, liquid crystals are classified as ionic liquid crystals (ILCs), and they are distinguished from liquid crystals that are dispersed in ionic liquids. Although the formation of micelles and liquid crystal phases in ionic liquids have been thus reported, there has been no mention of the self-assembly of developed nano-assemblies that are stably dispersed in ionic liquids. In the next section the formation of bilayer membranes and vesicles in ionic liquids is discussed. 

Both (+)-nootkatone (566) and its (+)-4-isomer (565) have been synthesized from (+)-nopinone (564) (Scheme 69). ° On the other hand, Hiyama et have used a completely different approach for the synthesis of nootkatone (566) (Scheme 70) which involves as a key step the acid-induced cyclopentenone annulation. In an alternative route to eremophilane and valencane sesquiterpenes, NM et have used a stereoselective intramolecular Diels-Alder... 

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