High endo selectivity

The TiX2-TADD0Late-catalyzed 1,3-dipolar q cloaddition reactions were extended to include an acrylate derivative [66]. In the absence of a catalyst, the reaction between nitrones 1 and acryloyl oxazolidinone 19b proceeded to give a mixture all eight regio-and stereoisomers (Scheme 6.23). However, application of in this case only 10 mol% of Ti(OTs)2-TADDOLate 23d as catalyst for the reaction of various nitrones 1 with alkene 19b, led to complete regioselectivity and high endo selectivity in the reaction and the endo products 21 were obtained with 48-70% ee (Scheme 6.23) [66]. 

The parent five-membered nitronate having no substituent at the 3-position was too unstable to be isolated. However, 3-substituted derivatives were highly stabilized. Especially, the 3-ethyl derivatives having a terminal electron-withdrawing substituent are readily available by the dehydrochlorination of 3-chloro-l-nitropropane in the presence of electron-deficient alkenes. It was our delight that the reaction of 3-al-kyl-substituted five-membered nitronates was also successfully catalyzed by R,R-DBFOX/Ph-Ni(SbFg)2 complex to at room temperature. This reaction was highly endo-selective (cisjtrans= 91 9) and enantioselective for the endo cycloadduct (92% ee). 

Optically active bicyclo[2.2,2]octanes can be obtained via diastercoselective MIMIRC reaction of lithium dienolates and a,/ -unsaturated esters of various chiral alcohols. Good yields (70-90%), high endo selectivities (> 95%) and diastereomeric ratios that depend on the auxiliary alcohol are found in these additions. The highest diastereomeric ratio reached was 18 82 using a camphor derived sulfonamide. The diastereomeric ratio could be improved (up to 9 91) by titanium(IV) chloride catalyzed addition of the corresponding silylenolates with the chiral a,/J-unsaturated esters358. 

A high endo selectivity is observed in the reaction of (phenylsulfonyl)allene (112) with furan (157) (equation 113)108. The endo adduct 158 can be readily transformed into highly substituted cyclohexenol 160 upon treatment with n-butyllithium after hydrogenation of the ring double bond (equation 114)108. 

Both inter- and intra- molecular Diels-Alder reactions of 2-benzopyran-3-ones occur with high endo-selectivity and have been used to synthesise (-)-podophyllotoxin (14) and 4a-substituted cis-BC fused hexahydrophenenthrenes (15), respectively <96JCS(P1)151, 96JCS(P1)705>. 

The reaction of 1-thiabuta-1,3-dienes with di-(-)-menthyl fumarate exhibits high endo-selectivity when carried out thermally or when catalysed by Lewis acids. In both cases, the preferred product is the 3,4-cis-dihydrothiopyran (23) which is a source of optically pure diols <96JCS(P1)1897>. 

Bis(oxazoline)-type complexes, which have been found useful for asymmetric aldol reactions, Diels-Alder, and hetero Diels-Alder reactions can also be used for inducing 1,3-dipolar reactions. Chiral nickel complex 180, which can be prepared by reacting equimolar amounts of Ni(C10)4 6H20 and the corresponding (J ,J )-4,6-dibenzofurandiyl-2,2 -bis(4-phenyloxazoline) (DBFOX/Ph) in dichloromethane, can be used for highly endo-selective and enantioselective asymmetric nitrone cycloaddition. The presence of 4 A molecular sieves is essential to attain high selectivities.88 In the absence of molecular sieves, both the diastereoselectivity and enantioselectivity will be lower. Representative results are shown in Scheme 5-55. 

The cycloaddition of allenes carrying an electron-withdrawing phosphorus substituent has also been studied [118]. Allenyl phosphine oxide 138 is prepared in a manner analogous to allenyl sulfoxide. The [4+ 2]-cycloaddition reaction of 138 with cyclopentadiene proceeded with a high endo selectivity. 

Sudo and Saigo153 reported the application of ds-2-amino-3,3-dimethyl-l-indanol derived l,3-oxazolidin-2-one 231 as a chiral auxiliary in asymmetric Diels-Alder reactions. The TV-crotonyl and TV-acryloyl derivatives were reacted with cyclopentadiene, 1,3-cyclohexadiene, isoprene and 2,3-dimethyl-l,3-butadiene, using diethylaluminum chloride as the Lewis acid catalyst. The reactions afforded the expected cycloadducts in moderate to high yields (33-97%) with high endo selectivities and high de values (92% to >98%). 

The authors investigated the salts in the Diels-Alder reaction. In analogy to the NMR experiments similar reactivities were found. As presented in Scheme 44, the salts gave up to 91% yield in high endo-selectivity with cyclopentadiene and an unsaturated amide in 4 h. The highest yield was obtained with salt 45, while for example salt 47 gave only 7% and salt 49 gave only traces. 

Also propiogeninic type macrolide moieties should be accessible via this inverse type hetero-Diels-Alder methodology. This was recently exhibited starting from cis-propenylether as heterodienophile (Schmidt, R.R. Haag-Zeino, B. Hoch, M. Liebigs Ann. Chem., in press). In a highly endo-selective cycloaddition reaction and in subsequent diastereoselective transformations of the methyl substituted dihydropyran obtained a 2,4-dimethyl-... 

Methyl (naphthylideneamino)acetate undergoes dimerization to produce a mixture of two diastereomeric imidazolidines when treated with Mg(C104)2 or C0CI2 (89). Other imines can also be used as acceptor molecules (Scheme 11.12). With the exception of azomethine ylides incorporating sodium and titanium ions, other N-metalated ylides undergo highly endo-selective cycloadditions with a,p-unsaturated... 

Enhanced reactivity as well as high endo-selectivity based on the rigid transition structure of N-metalated azomethine ylides is attractive for asymmetric 1,3-dipolar cycloaddition reactions. There are several reports known for the design of effective chiral nucleophiles in asymmetric cycloadditions. 

TADDOLate 245d (10 mol%) as catalyst for the reaction of various nitrones 225 with alkene 241b led to complete regioselectivity and high endo-selectivity in the reaction, and the endo-products 243 were obtained with 48-70% ee. 

Diels-Alder cyclization of IfiAO-undecatrienals.5 These unsaturated aldehydes undergo intramolecular Diels-Alder cyclization, particularly under Lewis acid catalysis. The reaction is highly endo-selective. Silyl-protected alcohol groups at C4 and Q can be present, and t-butyldimethylsilyl ethers show a strong axial preference. 

Chiral 4,4-dialkyl-l-cyclopentenones.1 The chiral bicyclic lactam 2, derived from levulinic acid and 1, on monoalkylation exhibits slight if any selectivity regardless of the electrophile. However, a second alkylation exhibits high endo-selectivity. This product (3), after reductive cleavage, furnishes a keto aldehyde that is cyclized by base to a chiral 4,4-disubstituted-2-cyclopentenone (4). Either antipode of 4 can be prepared by the sequence of alkylation. 

Heterobimetallic catalysts have also been examined as Lewis acids in the asymmetric Diels-Alder reaction. Thus LaLi3tris[(R)-6,6 -dibromobinaphthoxide] catalyzed the reaction of 172 with 170 to give 173 in high endo selectivity and in high enantiomeric excess (Figure 40). The same reaction promoted by LLB afforded 173 in 82% yield (endoiexo = 15 1) with 63% ee.94... 

Mukaiyama reported that 4—10 mol% of Ph2Sn=S and AgC104 catalyzed the Diels-Alder reaction between but-3-ene-2-one (183) or (E)-1 -phenylbut-2-en-1 -one (182) and unactivated dienes 184-186 to afford the products 187-192 in 57-95% yield (Scheme 2.48).80 The reaction with cyclic dienes 185 and 186 was highly endo-selective (dr 99 1). Naphthalene-1,4-dione also participated in the reaction with similar yields. 

---