Chiral azadienes

Two general approaches to aza-Diels-Alder reactions have been reported. One incorporates the requisite nitrogen atom into the 2rt component (imine), while the other incorporates the requisite nitrc en in the 4rt component (azadiene). Chiral copper Lewis acids have been used with success in both approaches. Jorgensen and coworkers reported enantioselective imino Diels-Alder reactions catalyzed by CuC104 MeCN in the presence of phosphino-oxazoline (287) or BINAP (290) (Scheme 17.64) [93]. Phosphino-oxazoline (287) proved to be the ligand of choice in the aza-Diels-Alder reaction of N-tosyl a-imino ester (142) with Danishefsky s diene (286), while BINAP (290) gave the highest selectivity when dimethyl-substituted Danishefsky s diene (289) was used. 

In 1996, the first example of the catalytic enantioselective aza Diels-Alder reactions of azadienes using a chiral lanthanide catalyst was reported [4], In this article, successful examples of such catalytic reactions are surveyed. 

In the presence of 10 mol% chiral Cu(II) catalyst 25, 2-azadienes 26 reacted with dienophiles 27 to afford the corresponding piperidone derivatives in high yields... 

Another successful aza Diels-Alder reaction involves 2-azadienes of type 125 with dienophile 126 in the presence of bis(oxazoline) catalyst 106a.53 Product 127 is obtained in a high exo endo ratio, as well as high enantiomeric excess for the exo-isomer of 127. The high enantioselectivity and high yield rely on the chiral catalyst 106a, which activates the dienophile by complexation with an appropriate functional group and does not irreversibly coordinate with the... 

Ghosez and co-workers (223) illustrated that azadienes could be efficiently used as heterodienes with acryloylimide dienophiles in the presence of chiral cationic Cu(II) catalysts, Eq. 183. The reaction was found to be highly exo- and enantiose-lective, provided the azadiene contains an aryl or vinyl group in the 1-position. Acryloylimide as dienophile affords equal enantioselectivities albeit reduced dias-tereoselectivities (typically 6 1). 

Motorina and Grierson (224) examined the use of bis(oxazoline)-Cu(II) complexes as chiral Lewis acids in the intramolecular heterocycloaddition of azadienes, Eq. 184. Very low selectivities are observed in the cycloaddition of 326. The authors speculate that monodentate coordination of the substrate to copper is responsible for the low selectivity. 

In the reaction of benzylideneaniline with cyclopentadiene, the imine functions as an azadiene to yield the rearranged Diels-Alder adduct 77 (equation SI)44,453. In a study of the effect of various Lewis acids (ZnCl2, TiCU, Et2AlCl and SnCU) on diastereoselective cycloadditions of Danishefsky s diene to the imines 79, obtained from the chiral aldehydes 78 (R = MeO or Cl), it was found that SnCLj was the most effective, giving the optically active products in high yields and excellent ee values (equation 52)46. 

The fact that these adducts were diastereoisomerically pure (deduced from the reported melting points and NMR spectra) suggests that these reactions took place with a complete control of the diastereoselectivity. Bearing this in mind, in 1989 Waldner [64] synthesized optically pure sulfoxide 55 (by MCPBA oxidation of the corresponding chiral thioether and further separation from the epimeric mixture so obtained) and studied its reactions with dienes and aza-dienes (Scheme 29). A high 7r-facial selectivity (almost complete with cyclopen-tadiene and azadienes) was observed in all cases, the approach of the diene from the dienophilic face supporting the lone pair of electrons at sulfur being favored. In the case of the reaction with cyclopentadiene, the endo-selectivity was complete as well. 

He M, Bode JW (2005) Catalytic synthesis of y-lactams via direct annulations of enals and N-sulfonylimines. Qrg Lett 7 3131-3134 He M, Struble JR, Bode JW (2006) Highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral N-heterocyclic carbenes. J Am Chem Soc 128 8418-8420... 

ORGANOMETALUC ADDITIONS TO AZADIENES 1.12.7.1 Chiral a,fi-Unsaturated Aldimines... 

An inverse electron demand aza D A reaction of electron rich alkenes with N aryl imines as 2 azadiene (Povarov reaction) provides tetrahydroquinolines. Reactions catalyzed by chiral phosphoric acids yielded different absolute ste reochemical outcomes when ethyl vinyl efher and enecarbamate are employed as electron rich alkenes, although chiral phosphoric acids have the same axial chirality in both cases (see Scheme 3.26). 

Ghosez and Gouvemeur [272, 1593] usedtiie same chiral auxiliary to promote uncatalyzed cycloadditions of nitrosoamide 9.64. With cyclic dienes, reactions occur near room temperature, while 2-azadienes 9.65 react at -78°C (Figure 9.32). The cycloadducts formed with 9.65 are precursors of (/ )-a-aminoacids [861], The observed selectivities are interpreted by the endo approach of the diene to the least hindered face of the dienophile in the s-cis conformation (see above). 

Recently, Ghosez and Beaudegnies [319] recommended chiral azadienes 9.102 derived from a,P-unsaturated aldehydes and Enders s hydrazines 1.76. To observe a high face selectivity in the cydoadditions with maleimides or maleic anhydride conducted at room temperature, the side chain of the hydrazines must be bulky (R = Me) (Figure 9.50). The cleavage of the auxiliary is accomplished with Zn-AcOH, but this also saturates the double bond, and diastereoisomers are formed. Unfortunately, this cydoaddition does not work with acrylates or fu-marates. 

The Diels-Alder reaction of 2-azadienes also benefits from the presence of an electron-donating substituent, to enhance the reactivity with electron-deficient dienophiles. Cycloaddition with alkynyl dienophiles and aromatization leads to substituted pyridines (3.54). Silyloxy-substituted 2-azadienes such as 68 are effective dienes and have been used to prepare substituted 2-pyridones and piperidones after methanolysis (3.55). Asymmetric hetero Diels-Alder reactions with the chiral Lewis acid catalyst 66 provide access to the piperidone products with very high enantioselectivity. ... 

Bode, et al. developed a highly enantioselective azadiene Diels-Alder reactions catalyzed by chiral A-heterocyclic carbenes. Scheme 3.28 [43]. Reactions of alkyl fra -4-oxo-2-butenoate 80 with A-sulfonyl imines 81 and catalyst 82 (10-15 mol%), DIPEA (10 mol%) in toluene-THF (10 1) at room temperature afforded the dihydopyridinones 83 in excellent diastereo- and enantioselectivity (>50 1 cw-diastereoselectivity, 99% ee). The LUMO -controUed inverse electron demand Diels-Alder cycloaddition was facilitated by NHC-carbene catalyst 82. Similar reactions without the catalyst would require high pressure (12 bar) or high temperature. The high cw-diastereoselectivity which would arise from (Z)-enolate reacting with the dienophile is rationalized as depicted in Scheme 3.28. 

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