Chiral aldehydes, dienophiles

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... 

A high asymmetric induction in intramolecular hetero Diels-Alder reactions was found using chiral 1-oxa-1,3-butadienes with a stereogenic center in the tether [54]. Such compounds can easily be obtained by a Knoevenagel condensation of a 1,3-dicarbonyl compound such as iV,N-dimethylbarbituric acid with a chiral aldehyde bearing a dienophile moiety [169 a] (Scheme 2-3). With the stereogenic center in a-position relative to the oxadiene or dienophile moiety an excellent induced diastereoselectivity is obtained for the nearly exclusively formed trans-cycloadduct (simple diastereoselectivity = 97.9 2.1 and 98.3 1.7,... 

Chiral Aldehydes as Dienophiles Synthesis of Long-Chain Sugars... 

Yamamoto and coworkers have developed a practical Diels-Alder catalyst for aldehyde dienophiles. Treatment of a monoacylated tartaric acid with borane released ca. 2.2 equiv of H2 gas, affording a complex that has been assigned structure 7. Circrunstantial evidence for structure 7 was found in the comparable enan-tioselectivity of a catalyst in which the free carboxyl group was esterified (see below). The chiral (acyloxy)borane (CAB) complex is effective in catalyzing a number of aldehyde-based Diels-Alder reactions (Scheme 9) [56]. Reactions with... 

Nonauxiliary-Controlled Dienophiles Cycloaddition to Chiral Aldehydes... 

Similarly, pyran rings are a common early-stage synthetic intermediate in a variety of syntheses. In Kutay and Gademann s synthesis of anguinomycin C, they prepare the heterocyclic portion of the target by combination an electron-rich diene with an unsaturated aldehyde in the presence of Jacobsen s chromium (III) catalyst. Ghosh used the same asymmetric catalyst to promote the reaction of an aldehyde and an electron-rich diene in his synthesis of brevisamide. Rawal synthesized a pyranone for use in his synthesis of pederin by combination of a chiral dienophile with Danishefsky s diene. In his synthesis of phorboxazole B, Burke treated Brassard diene 119 with chiral aldehyde 118 and a europium catalyst to yield pyranone 120. ... 

Chiral Lewis acid-catalyzed HDA reactions have foimd application in the asymmetric synthesis of THP-containing natural products. Chiral chromium complexes, especially the adamantyl-Cr(III) complexes discovered by Jacobsen et al., have been applied to the use of unactivated aldehyde dienophiles with various diene partners [111]. Paterson and coworkers employed this variation in the synthesis of... 

To overcome these problems with the first generation Brmsted acid-assisted chiral Lewis acid 7, Yamamoto and coworkers developed in 1996 a second-generation catalyst 8 containing the 3,5-bis-(trifluoromethyl)phenylboronic acid moiety [10b,d] (Scheme 1.15, 1.16, Table 1.4, 1.5). The catalyst was prepared from a chiral triol containing a chiral binaphthol moiety and 3,5-bis-(trifluoromethyl)phenylboronic acid, with removal of water. This is a practical Diels-Alder catalyst, effective in catalyzing the reaction not only of a-substituted a,/ -unsaturated aldehydes, but also of a-unsubstituted a,/ -unsaturated aldehydes. In each reaction, the adducts were formed in high yields and with excellent enantioselectivity. It also promotes the reaction with less reactive dienophiles such as crotonaldehyde. Less reactive dienes such as isoprene and cyclohexadiene can, moreover, also be successfully employed in reactions with bromoacrolein, methacrolein, and acrolein dienophiles. The chiral ligand was readily recovered (>90%). 

Among the many chiral Lewis acid catalysts described so far, not many practical catalysts meet these criteria. For a,/ -unsaturated aldehydes, Corey s tryptophan-derived borane catalyst 4, and Yamamoto s CBA and BLA catalysts 3, 7, and 8 are excellent. Narasaka s chiral titanium catalyst 31 and Evans s chiral copper catalyst 24 are outstanding chiral Lewis acid catalysts of the reaction of 3-alkenoyl-l,2-oxazolidin-2-one as dienophile. These chiral Lewis acid catalysts have wide scope and generality compared with the others, as shown in their application to natural product syntheses. They are, however, still not perfect catalysts. We need to continue the endeavor to seek better catalysts which are more reactive, more selective, and have wider applicability. 

Entry 9 uses the oxaborazolidine catalysts discussed on p. 505 with 2-bromopropenal as the dienophile. The aldehyde adopts the exo position in each case, which is consistent with the proposed TS model. Entry 10 illustrates the use of a cationic oxaborazolidine catalyst. The chirality is derived from trans-1,2-diaminocyclohcxanc. Entry 12 shows the use of a TADDOL catalyst in the construction of the steroid skeleton. Entry 13 is an intramolecular D-A reaction catalyzed by a Cu-Ws-oxazoline. Entries 14 and 15 show the use of the oxazaborolidinone catalyst with more complex dienes. 

Chiral dienophiles, prepared from an aldehyde and asparagine in water followed by reacting with acryloyl chloride, reacted with cyclopentadiene at room temperature in water or ethanol-water to provide cycloadducts diastereoselectively and chiral products upon separation and hydrolysis (47-64% ee for the endo isomers endo/exo 82 18) (Eq. 12.18).61... 

The types of dienophiles which have been studied most are acrylic aldehydes, acrylates and 3-acryloyl-l,3-oxazolidines. The latter have been used predominantly in copper, magnesium, zinc and lanthanide catalyzed reactions in which the chiral Lewis acid binds in an rj2 fashion to the dienophile (complexation to both carbonyls). 

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). 

An important challenge in the asymmetric catalytic Diels-Alder reaction is the use of simple ketone dienophiles to obtain high enantioselectivity. Indeed, the success of chiral Lewis acid-mediated Diels-Alder reactions is founded upon the use of dienophiles such as aldehydes, esters, quinones [36-43], and bidentate chelating carbonyls [44-47], where high levels of lone pair discrimination are achieved in the metal association step, an organizational event that is essential for enantiocontrol. In contrast, Lewis acid coordination to ketone dienophiles is generally non-selective, since the participating lone pairs are positioned in similar steric and electronic environments (Eq. 4). The ability for diastereomeric activa-... 

Several Ru-based transition metal complexes catalyze the hetero Diels-Alder reaction between aldehydes, in particular benzaldehyde and Danishefsky s diene. Using the [Ru(Cp)(CHIRAPHOS)] (18) complex, a modest e.e. value of 25% is obtained (Entry 1, Scheme 10.25) [48]. This reaction is also catalyzed by irradiating the chiral complex (3) in the presence of the diene and the hetero-dienophile. The product is obtained with a good chiral induction (Entry 2, Scheme 10.25) [49, 50],... 

The absolute stereochemical selectivities achieved in these reactions can be explained in terms of the nnf/-exo-transition-state models 16, 17, and 18, which are analogous to those previously proposed for the reaction of dienes and olefinic dienophiles (Fig. 8) [12,27d]. These transition-state models are based on three assumptions (i) the substituent in the chiral ligand blocks the same enantiofacial side of the carbonyl in the Diels-Alder reactions of acetylenic and olefinic aldehydes (ii) exo-transition structures predominate and (hi) anh-coordination of the bulky chiral Lewis acid to carbonyl is preferred in the transition state. 

Trace amounts of complexes 3 and 20 promote the synthesis of optically pure, multiply functionalized, versatile intermediates such as pyrones or lactones from activated, acid-labile siloxydienes with aldehydes. The reagents typically work under mild conditions and therefore promote the survival of valuable functionality in the dienophile, the diene, and cycloadduct [105-107]. As a consequence this procedure is applied in the total synthesis of various natural products, often requiring an intramolecular Diels-Alder approach [106]. Specific interactivity of the chiral precatalyst Eu(hfc)3 (hfc = 3-(heptafluorpropylhydroxymethylene)-D-camphorate with Danishefsky s diene bearing a chiral auxiliary resulted in cycloaddition products of high diastereofacial excess (95 % eq. (8)) [105]. 

---