Asymmetric Diels-Alder reaction complex

Kanemasa et al. discovered an asymmetric Diels-Alder reaction of acryloyl-oxazolidi-none and cyclopentadiene catalyzed by a chiral aqua complex of 4,6-dibenzofurani-dyl-2,2 -bis(4-phenyloxazoline) 16 (vide infra) [22]. Unlike the Diels-Alder reaction of acryloyloxazolidinone, for which NiBr2/AgC104 and Znl2/AgC104 are the most suitable sources of the central metal, the best for the Diels-Alder reaction of a-bromo-... 

Table 1.12 Asymmetric Diels-Alder reactions catalyzed by the Cr-salen complex 15 [21]...

Since Evans s initial report, several chiral Lewis acids with copper as the central metal have been reported. Davies et al. and Ghosh et al. independently developed a bis(oxazoline) ligand prepared from aminoindanol, and applied the copper complex of this ligand to the asymmetric Diels-Alder reaction. Davies varied the link between the two oxazolines and found that cyclopropyl is the best connector (see catalyst 26), giving the cycloadduct of acryloyloxazolidinone and cyclopentadiene in high optical purity (98.4% ee) [35] (Scheme 1.45). Ghosh et al., on the other hand, obtained the same cycloadduct in 99% ee by the use of unsubstituted ligand (see catalyst 27) [36] (Scheme 1.46, Table 1.19). 

Many chiral metal complexes with Lewis acid properties have been developed and applied to the asymmetric Diels-Alder reaction. High enantioselectivity is, of course, one of the goals in the development of these catalysts. Enantioselectivity is not, however, the only factor important in their design. Other important considerations are ... 

The complexation procedure included addition of an equimolar amount of R,R-DBFOX/Ph to a suspension of a metal salt in dichloromethane. A clear solution resulted after stirring for a few hours at room temperature, indicating that formation of the complex was complete. The resulting solution containing the catalyst complex was used to promote asymmetric Diels-Alder reactions between cyclopen-tadiene and 3-acryloyl-2-oxazolidinone. Both the catalytic activity of the catalysts and levels of chirality induction were evaluated on the basis of the enantio-selectivities observed for the endo cycloadduct. 

Effect of water additive was examined in the asymmetric Diels-Alder reactions catalyzed by the J ,J -DBF0X/Ph-Ni(C104)2 complex. After addition of an appropriate amount of water to the anhydrous complex A, the reaction with an excess amount of cyclopentadiene was performed at room temperature. Enantioselectivity was as high as 93% ee for the endo cycloadduct up to five equivalents of water added and the satisfactory level of 88% ee was maintained when 10 equivalents were added. However, enantioselectivity gradually decreased with the increased amounts of water added 83 and 55% ee from 15 and 50 equivalents, respectively (Scheme 7.11). When the reaction temperature went down to -40 °C, the enantioselectivity as high as 98% ee resulted up to 15 equivalents of water additive. The effect of methanol at room temperature was even more surprising. In the presence of 15 and 100 equivalents of methanol, high levels of enantioselectivities of 88% and 83% ee, respectively, were recorded for the reactions at room temperature. 

Ghosh et al. [70] reviewed a few years ago the utihty of C2-symmetric chiral bis(oxazoline)-metal complexes for catalytic asymmetric synthesis, and they reserved an important place for Diels-Alder and related transformations. Bis(oxazoline) copper(II)triflate derivatives have been indeed described by Evans et al. as effective catalysts for the asymmetric Diels-Alder reaction [71]. The bis(oxazoline) Ugand 54 allowed the Diels-Alder transformation of two-point binding N-acylimide dienophiles with good yields, good diastereos-electivities (in favor of the endo diastereoisomer) and excellent ee values (up to 99%) [72]. These substrates represent the standard test for new catalysts development. To widen the use of Lewis acidic chiral Cu(ll) complexes, Evans et al. prepared and tested bis(oxazoHnyl)pyridine (PyBOx, structure 55, Scheme 26) as ligand [73]. 

Several groups have reported the use of rare earth complexes as catalysts for asymmetric Diels-Alder reaction. Qian and Wang described thus the preparation and use of Yb complexes chelated by Pr-PyBOx to successfully achieve the hetero-Diels-Alder reaction of methyl glyoxylate with Danishefsky s diene in 77% ee and 73% yield (Scheme 37) [98]. 

Fukuzawa et al. [99] found analogous scandium(III)triflate/ Pr-PyBOx complex as efficient catalyst for the asymmetric Diels-Alder reaction between cyclopentadiene or acyclic dienes and acyl-l,3-oxazohdin-2-ones with up to 90% ee. They latter described the same reaction in super critical CO2 in the presence of MSdA [ 100] that proceeded more rapidly than in CH2CI2 leading to the expected product with analogous selectivity. 

Zeijden [112] used chiral M-functionalized cyclopentadiene ligands to prepare a series of transition metal complexes. The zirconium derivative (82 in Scheme 46), as a moderate Lewis acid, catalyzed the Diels-Alder reaction between methacroleine and cyclopentadiene, with 72% de but no measurable enantiomeric excess. Nakagawa [113] reported l,T-(2,2 -bis-acylamino)binaphthalene (83 in Scheme 46) to be effective in the ytterbium-catalyzed asymmetric Diels-Alder reaction between cyclopentadiene and crotonyl-l,3-oxazolidin-2-one. The adduct was obtained with high yield and enantioselectivity (97% yield, endo/exo = 91/9, > 98% ee for the endo adduct). The addition of diisopropylethylamine was necessary to afford high enantioselectivities, since without this additive, the product was essentially... 

In 2005, Carretero et al. reported a second example of chiral catalysts based on S/P-coordination employed in the catalysis of the enantioselective Diels-Alder reaction, namely palladium complexes of chiral planar l-phosphino-2-sulfenylferrocenes (Fesulphos). This new family of chiral ligands afforded, in the presence of PdCl2, high enantioselectivities of up to 95% ee, in the asymmetric Diels-Alder reaction of cyclopentadiene with A-acryloyl-l,3-oxazolidin-2-one (Scheme 5.17). The S/P-bidentate character of the Fesulphos ligands has been proved by X-ray diffraction analysis of several metal complexes. When the reaction was performed in the presence of the corresponding copper-chelates, a lower and opposite enantioselectivity was obtained. This difference of results was explained by the geometry of the palladium (square-planar) and copper (tetrahedral) complexes. 

Chiral (Acyloxy)borane Complex Catalyzed Asymmetric Diels-Alder Reaction (1 R)-1,3,4-Trimethyl-3-cyclohexene-1-carboxaldehyde. 

Ghosh et al.32 have demonstrated another bis(oxazoline) derivative chiral ligand 86 for asymmetric Diels-Alder reaction and obtained excellent results. Reaction of an equimolar mixture of chiral ligand 86 and Cu(C104)2 6H20 produces the aqua complex 87 (w being water molecule), which shows excellent catalytic power in asymmetric Diels-Alder reactions. As depicted in Scheme 5 27, the reaction of 88 with cyclopentadiene gives product 89 with more than 80% yield, over 99 1 diastereoselectivity and up to 99% ee. 

Kobayashi s chiral lanthanide complex 63 has been used for asymmetric Diels-Alder reactions, and very good results have been obtained (see Section 5.4.2). This kind of complex is also effective in asymmetric 1,3-dipolar reactions.87 The chiral ligand is prepared in situ by mixing Yb(OTf)3,... 

In summary, asymmetric cycloadditions are powerful methods for the synthesis of complex chiral molecules because multiple asymmetric centers can be constructed in one-step transformations. Among them, reactions using chiral catalysts are the most effective and promising, and fruitful results have been reported in asymmetric Diels-Alder reactions. 

Collins and co-workers have performed studies in the area of catalytic enantioselective Diels—Alder reactions, in which ansa-metallocenes (107, Eq. 6.17) were utilized as chiral catalysts [100], The cycloadditions were typically efficient (-90% yield), but proceeded with modest stereoselectivities (26—52% ee). The group IV metal catalyst used in the asymmetric Diels—Alder reaction was the cationic zirconocene complex (ebthi)Zr(OtBu)-THF (106, Eq. 6.17). Treatment of the dimethylzirconocene [101] 106 with one equivalent of t-butanol, followed by protonation with one equivalent of HEt3N -BPh4, resulted in the formation of the requisite chiral cationic complex (107),... 

CHIRAL (ACYLOXY)BORANE COMPLEX-CATALYZED ASYMMETRIC DIELS-ALDER REACTION (1R)-1,3,4-TRIMETHYL-3-CYCLOHEXENE-1-CAR BOX ALDEHYDE (3-Cyclohexene-1-carboxaldehyda, 1,3,4-trlmethyl-, (-)-)... 

Density functional theory has been used to investigate the Diels-Alder reactions of triazolinedione with s-cis- and. y-fran -butadiene. " Combined quantum mechanics-molecular mechanics calculations have been used to investigate the asymmetric Diels-Alder reaction of cyclopentadiene with the complex dienophiles AICI3-methyl acrylate and methoxyaluminium dichloride-acrolein.Equilibrium constants have been determined for the molecular complexes formed from 1-alkyl-1-(2-naphthyl)ethenes and 1-vinylnaphthalene with TCNE in C1(CH2)2C1 at 27.1 °C ... 

Other than hydrogen transfer reactions, catalytic applications of Cp lr complexes for the deuteration of organic molecules [81-84], asymmetric Diels-Alder reactions [85, 86],... 

The characteristic feature of the aforementioned oxazaborolidine catalyst system consists of a-sulfonamide carboxylic acid ligand for boron reagent, where the five-membered ring system seems to be the major structural feature for the active catalyst. Accordingly, tartaric acid-derived chiral (acyloxy)borane (CAB) complexes can also catalyze the asymmetric Diels-Alder reaction of a,P-unsaturated aldehydes with a high level of asymmetric induction [10] (Eq. 8A.4). Similarly, a chiral tartrate-derived dioxaborolidine has been introduced as a catalyst for enantioselective Diels-Alder reaction of 2-bromoacrolein [11] (Eq. 8A.5). 

A titanium complex derived from chiral /V-arencsulfonyl-2-amino-1 -indanol [20], a cationic chiral iron complex [21], and a chiral oxo(salen)manganese(V) complex [22] have been developed for the asymmetric Diels-Alder reaction of oc,P-unsaturated aldehydes with high asymmetric induction (Eq. 8A.11). In addition, a stable, chiral diaquo titanocene complex is utilized for the enantioselective Diels-Alder reaction of cyclopentadiene and a series of a.P Unsaturated aldehydes at low temperature, where catalysis occurs at the metal center rather than through activation of the dienophile by protonation. The high endo/exo selectivity is observed for a-substituted aldehydes, but the asymmetric induction is only moderate [23] (Eq. 8A. 12). 

With Tartrate-Derived Chiral 1,4-Diol/Ti Complexes A catalytic asymmetric Diels-Alder reaction is promoted by the use of a chiral titanium catalyst prepared in situ from (Pr O TiC and a tartrate-derived (2.R,3.R)-l,l>4,4-tetraphenyl-2,3-0-(l-phenylethylidene)-l,2,3,4-butanetetrol. This chiral titanium catalyst, developed by Narasaka, has been successfully executed with oxazolidinone derivatives of 3-borylpropenoic acids as P-hydroxy acrylic acid equivalents [40] (Eq. 8A.21). The resulting chiral adduct can be utilized for the first asymmetric total synthesis of a highly oxygenated sesquiterpene, (-i-)-Paniculide. 

Chiral bis-sulfoxides with a C2 symmetry axis can be readily prepared from the known (W)-methyl p-tolyl sulfoxide and commercially available methyl (S)-p-toluenesulfinate. Such chiral ligands are very attractive because of their easy synthesis and their ready availability in both enantiomers from inexpensive starting materials. Their complexes with Fel3 are shown to be good chiral catalysts for asymmetric Diels-Alder reactions [48] (Eq. 8A.26). 

With Chiral Al Complexes Chiral bis(silyl)binaphthol-modified aluminum catalyst, which is originally developed for asymmetric hetero-Diels-Alder reaction [50], is successfully applied to asymmetric Diels-Alder reaction of cyclopentadiene with methyl acrylate or methyl propio-late [51 ] (Eq. 8A.28). The latter is a rather rare example in the literatures. 

With Chiral DiolTTi Complexes Harada investigated the influence of the torsional angles of biaryl rings on the enantioselecdvity in the asymmetric Diels-Alder reaction of cyclopentadiene with methyl acrylate catalyzed by a series of Ti complexes possessing chiral 2,2 -biaryldiols. The best results were obtained by the use of chiral binaphthol or 6,6 -hexylenedioxy-2,2 -biphenyldiol [52] (Eq. 8A.29). 

Chiral Ti complex, derived from hydrobenzoin dilithium salt and TiCl4, can be used for the asymmetric Diels-Alder reaction of several dienes with fumarate [53] (Eq. 8A.30). However, attempted use of acrylate as dienophile resulted in low enantioselectivity. 

Chiral bis(oxazoline)/Copper(II) complexes are evaluated for asymmetric Diels-Alder reaction of naphthoquinone derivatives, and moderate levels of enantiomeric excess are observed in certain cases [56] (Eq. 8A.33). 

Kobayashi reported an asymmetric Diels-Alder reaction catalyzed by a chiral lanthanide(III) complex 24, prepared from ytterbium or scandium triflate [ Yb(OTf)3 or Sc(OTf)3], (Zf)-BINOL and tertiary amine (ex. 1,2,6-trimethylpiperidine) [30], A highly enantioselective and endose-lective Diels-Alder reaction of 3-(2-butenoyl)-l,3-oxazolidin-2-one (23) with cyclopentadiene (Scheme 9.13) takes place in the presence of 24. When chiral Sc catalyst 24a was used, asymmetric amplification was observed with regard to the enantiopurity of (/ )-BINOL and that of the endoadduct [31 ]. On the other hand, in the case of chiral Yb catalyst 24b, NLE was affected by additives, that is, when 3-acetyl-l,3-oxazolidin-2-one was added, almost no deviation was observed from linearity, whereas a negative NLE was observed with the addition of 3-pheny-lacetylacetone. 

The total synthesis proceeds in >10 steps on solid phase and includes various transformations, including an asymmetric Diels-Alder reaction, oxidation with singlet oxygen, and olefin metathesis. This synthesis sequence is among the most advanced and demanding solid-phase syntheses developed so far for chemical genomics experiments. It demonstrates that the total synthesis of complex natural products in multi-step sequences on solid phase is feasible. 

Furuta, K. Gao, Q.-Z. Yamamoto, H. Chiral (acyloxy)borane complex catalyzed asymmetric Diels-Alder reaction (lR)-l,3,4-trimethyl-3-cyclohexene-l-carboxaldehyde. Org. Synth. 1998, Coll. Vol. IX, 722-727. 

Asymmetric Diels-AUer reactions The observation that simple acyloxy-boranes such as H2BOCOCH=CH2, prepared by reaction of BH3 with acrylic acid, can serve as Lewis acid catalysts for reactions of the a,P-unsaturated acids with cyclopentadiene (15, 2) has been extended to the preparation of chiral acyloxy-boranes derived from tartaric acid. The complex formulated as 3, prepared by reaction of BH3 with the monoacylated tartaric acid 2, catalyzes asymmetric Diels-Alder reactions of a,P-enals with cyclopentadiene with high enantioselectivity. The process is applicable to various dienes and aldehydes with enantioselectivities generally of 80-97 % ee. 

The discovery that chiral Lewis acids can catalyze the asymmetric Diels-Alder reaction is a major milestone for the scale up and practice of this reaction on an industrial scale. The use of such a catalyst obviates the need for a chiral auxiliary on the diene or dienophile. The vast majority of chiral auxiliaries that have been used in the Diels-Alder reaction are either not commercially available or are expensive. In addition, the chemical steps needed to attach and remove the chiral auxiliary increase the cost and complexity of the synthesis. Chiral catalysts may also be recovered or recycled, further decreasing cost.47 Research in this area is very active, and catalysts based on a number of metals (Table 26.1) have shown encouraging asymmetric induction.21 Our understanding of the role these catalysts play in the asymmetric induction of Diels-Alder reactions is increasing, and more general reagents should appear. 27-48 54... 

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