Diels-Alder reactions chiral dienes

The most important development within the field of Diels-Alder chemistry during the past two decades must be considered to be the design and application of chiral Lewis acid catalysts. From the mid 80s on, the number of literature reports about the design and application of chiral Lewis acids in the synthesis of chiral Diels-Alder adducts from achiral precursors grew exponentially, but it started to level off and decrease again in the mid 90s. Several excellent reviews about the application of chiral Lewis acids in Diels-Alder reactions have been published41,43 44. In this section, the recent literature about the chiral Lewis acid catalyzed all-carbon Diels-Alder reactions of dienes with dienophiles is reviewed, which, as such, has not been reviewed before. 

The asymmetric Diels-Alder reaction of diene and cyclopentenone derivatives can be promoted by a chiral titanium catalyst prepared in situ from (Pr 0)2TiCl2 and a tartrate-derived o.,a,a, a -tetraalkyl-l,3-dioxolane-4,5-dimethanol [54] (Eq. 8A.31). The resulting adducts can easily be tranformed to estrogens and progestogens. 

Saigo and co-workers reasoned that, by analogy, high levels of diastereofacial discrimination could be achieved in the Lewis acid-mediated Diels-Alder reaction of dienes with oxazolidinone 108-derived dienophiles. Indeed, excellent regioselectivities (endo. exo) and diastereoselectivities were reached in the Diels-Alder reaction of 109 with cyclic and acyclic dienes using Et2AlCl as the activator (Scheme 24.28).107 The selectivities obtained actually surpassed those reported with cis-1 -amino-2-indanol 1 as the chiral auxiliary (93% de) (see Scheme 24.16).82 The additional bulk... 

In order to test the iminium-activation strategy, MacMillan first examined the capacity of various amines to enantioselectively catalyze the Diels-Alder reaction between dienes and a,/ -unsaturated aldehyde dienophiles [6]. Preliminary experimental findings and computational studies proved the importance of four objectives in the design of a broadly useful iminium-activation catalyst (1) the chiral amine should undergo efficient and reversible iminium ion formation (2) high... 

The moderate Lewis acidity of ruthenium complexes was used to promote catalytic Diels-Alder reaction of dienes and acrolein derivatives [21-23]. The enantioselective Diels-Alder reaction of methacrolein with dienes was catalyzed with cationic ruthenium complexes containing an arene or cyclo-pentadienyl (Cp) ligand and a chiral ligand such as phosphinooxazoline, pyridyl-oxazoline, monoxidized 2,2 -bis(diphenylphosphino)-1, T-binaphthyl (BINPO)or l,2-bis[bis(pentafluorophenyl)phosphanyloxy]-l,2-diphenylethane (BIPHOP-F). The reaction gave the cycloadduct in high yields with excellent... 

More recently, a fluorous organocatalyst has been used to perform selective Diels-Alder reactions of dienes with oc,(3-unsaturated aldehydes in acetonitrile-water. The chiral fluorous imidazolidinone catalyst can be recovered using fluorous silica (80-90% recovery efficiency) and reused. Figure 7.10. Further organocatalytic reactions are presented later in this chapter. 

Diels-Alder Reactions. Chiral a,p-unsaturated imides participate in Lewis acid-promoted Diels-Alder cycloaddition reactions to afford products in uniformly excellent endo/exo and endo diastereoselectivities (eq 50 and 51). Unfortunately, this reaction does not extend to certain dienophiles, including methacryloyl imides, p,3-dimethylacryloyl imides, or alkynic imides. Cycloadditions also occur with less reactive acyclic dienes with high diastereoselectivity (eq 52). Of the auxiliaries surveyed, the phenylalanine-derived oxazolidinones provided the highest diastereoselectivities. This methodology has been recently extended to complex intramolecular processes (eq 53). In this case, use of the unsubstituted achiral oxazolidinone favored the undesired diastereomer. 

Asymmetric Diels-Alder reactions of dienes substituted widi a removable chiral moiety with prochiral dienophiles have been much less extensively studied. Hie few successful examples involve ester or ether derivatives of 1,3-dienols. 

Chiral alkyldihaloboranes are among the most powerful chiral Lewis acids. In general, however, because alkyldihaloboranes readily decompose to alkanes or alkenes as a result of protonolysis or /3-hydride elimination, it is difficult to recover them quantitatively as alkylboronic acids. Aryldichloroborane is relatively more stable and can be reused as the corresponding boronic acid. We have developed chiral aryldichlorobor-anes 23 bearing binaphthyl skeletons with axial chirality as asymmetric catalysts for the Diels-Alder reaction of dienes and a,/3-unsaturated esters (see, e.g., Eq. 37) [36]. 

Stereoselective oxycarborative addition is also achieved in cycloaddition and cyclooligomeriza-tion reactions. Thus, hetero-Diels-Alder reactions of dienes and aldehydes are not only catalyzed by main group Lewis acids, but also by transition metal complexes 10°. Tris[3-(heptafluoropropyl-hydroxymethylene)-( + )-camphorato]europium [( + )-Eu(hfc)3] and similar vanadium complexes have been used as the chiral catalyst in [4 + 2] cycloadditions of various achiral and chiral dienes to aldehydes63 67-101. With achiral silyloxydienes only moderate asymmetric inductions are observed, however, with chirally modified dienes, high double diastereoselectivities are achieved. Thus, the reaction of benzaldehyde with 3-terf-butyldimethylsilyloxy-l-(/-8-phenvl-menthoxy)-l.3-butadiene (1) gives (2/ .6/ )-4-wf-bntyldimethylsilyloxy-5,6-dihydro-6-phenyl-2-[(17 ,3/ ,45 )-8-phenylmenthoxy]-2f/-pyran (2) in 95% yield with a diasteieoselectivity of 25 1 ss. After crystallization and hydrolysis with trifluoroacetic acid, optically pure (2/ )-2,3-di-hydro-2-phenyl-4-(4//)-pyranone (3) is obtained in 87% yield. 

An alternative synthesis of pumiliotoxin C makes use of a related, but intramolecular Diels-Alder reaction. The diene 39, prepared in optically active form from (5)-norvaline, cyclized to the octahydroquinoline 40 with high selectivity (3.40). In this chemistry, the chiral centre in 39 controls the formation of the three new developing centres in 40. 

In addition, theoretical frameworks for Diels-Alder reactions of dienes, such as cm, had been adumbrated by Houk [30] and Hehre [31]. Therefore, it was an opportune time for experimental clarification of 7c-facial selectivity in the Diels-Alder reaction of homochiral dienes containing an allylic chiral center. 

Asymmetric Diels-Alder reactions with dienes bearing chiral auxiliaries have been studied less extensively. One example exploits some interesting cycloreversion chemistry. [52] The source of asymmetry for diene (120) is (5)-mandelic acid. 

The moderate Lewis acidity of ruthenium complexes was used to promote catalytic Diels Alder reactions, and notably, enantioselective Diels Alder reactions were performed with ruthenium containing a cyclopentadienyl or indenyl ligand and a chiral P,P-ligand such as (/ )-BINOP-F or 1,2-bis(diphenylphosphinamino) cyclohexane [128-132]. These mild chiral Lewis acids proved to be excellent catalysts for the intermolecular Diels Alder reactions of dienes with acrolein derivatives [128-130] [Eq. (61)] and enones [131] as well as for the intramolecular Diels Alder reaction of suitable trienes [132] [Eq. (62)]. 

In 2003, Rawal reported the use of TADDOLs 177 as chiral H-bonding catalysts to facilitate highly enantioselec-tive hetero-Diels-Alder reactions between dienes 181 and different aldehydes 86 (Scheme 6.29A) [82], and also BINOL-based catalysts 178 were found to facilitate this reaction with excellent selectivities [83]. TADDOLs were also successfully used as organocatalysts for other asymmetric transformations like Mukaiyama aldol reactions, nitroso aldol reactions, or Strecker reactions to mention a few examples only [84]. In addition, also BINOL derivatives have been employed as efficient chiral H-bonding activators as exemplified in the Morita-Baylis-Hilhnan reaction of enone 184 with different carbaldehydes 86 [85]. The use of chiral squaramides for asymmetric reactions dates back to 2005 when Xie et al. first used camphor-derived squaric amino alcohols as ligands in borane reductions [86]. The first truly organocatalytic application was described by Rawal et al. in 2008 who found that minute amounts of the bifunctional cinchona alkaloid-based squaramide 180 are... 

An early example of chiral alcohol-based hydrogen bonding catalysts is the work by Braddock and coworkers in which they used paracydophanediols (PHANOLs) as dual H-bond donors [65, 66]. Significant rate enhancements were obtained in the Diels-Alder reactions of dienes with a,P-unsaturated aldehydes and ketones and in the epoxide-opening reactions with amines. However, little or no asymmetric induction was obtained when a chiral PHANOL catalyst was used. 

The monocyclopentadienyliron complexes with chiral bidentate phosphorus ligand such as 177 and 178 are suitable Lewis acid catalysts for Diels-Alder reaction of dienes with acryl aldehydes. The reaction proceeds under mild conditions with high yields and ees. In some cases the complex 178 gave better results than 177. Some representative examples of enantioselective Diels-Alder reaction of various acroleins with dienes are given in Table 35 [ 116]. Similar results can be achieved with the ruthenium complexes 179 [117]. 

A great advantage of catalyst 24b compared with other chiral Lewis acids is that it tolerates the presence of ester, amine, and thioether functionalities. Dienes substituted at the 1-position by alkyl, aryl, oxygen, nitrogen, or sulfur all participate effectively in the present asymmetric Diels-Alder reaction, giving adducts in over 90% ee. The reaction of l-acetoxy-3-methylbutadiene and acryloyloxazolidinone catalyzed by copper reagent 24b, affords the cycloadduct in 98% ee. The first total synthesis of ewt-J -tetrahydrocannabinol was achieved using the functionalized cycloadduct obtained [23, 33e] (Scheme 1.39). 

Although furan is usually a poor diene in the Diels-Alder reaction, the chiral copper reagent 24b promotes its asymmetric addition to acryloyloxazolidinone to afford the 7-oxabicyclo[2.2.1]hept-2-ene derivative in high optical purity (Scheme 1.40). Because a retro-Diels-Alder reaction occurs above -20 °C, the reaction must be performed at low temperature (-78 °C) to obtain a high optical yield. The bicy-... 

The Diels-Alder reaction catalyzed by this chiral titanium catalyst 31 has wide generality (Scheme 1.53, 1.54, Table 1.22, 1.23). Acryloyl- and fumaroyl-oxazolidinones react with isoprene giving cycloadducts in high optical purity. 2-Ethylthio-l,3-buta-diene can also be successfully employed as the diene [42]. 

Several highly enantioselective Diels-Alder reactions are known for which the di-enophile does not fit any of the above classes. Corey and coworkers applied the chiral aluminum reagent 36 with a C2-symmetric stilbenediamine moiety (videsu-pra) to the Diels-Alder reaction of maleimides as dienophiles [54] (Scheme 1.68). In most asymmetric Diels-Alder reactions the reactants are usually relatively simple dienes such as cyclopentadiene or monosubstituted butadienes, and unsym-... 

In all the reactions described so far a chiral Lewis acid has been employed to promote the Diels-Alder reaction, but recently a completely different methodology for the asymmetric Diels-Alder reaction has been published. MacMillan and coworkers reported that the chiral secondary amine 40 catalyzes the Diels-Alder reaction between a,/ -unsaturated aldehydes and a variety of dienes [59]. The reaction mechanism is shown in Scheme 1.73. An a,/ -unsaturated aldehyde reacts with the chiral amine 40 to give an iminium ion that is sufficiently activated to engage a diene reaction partner. Diels-Alder reaction leads to a new iminium ion, which upon hydrolysis af-... 

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