Diastereoselective cycloaddition

Danishefsky et al. were probably the first to observe that lanthanide complexes can catalyze the cycloaddition reaction of aldehydes with activated dienes [24]. The reaction of benzaldehyde la with activated conjugated dienes such as 2d was found to be catalyzed by Eu(hfc)3 16 giving up to 58% ee (Scheme 4.16). The ee of the cycloaddition products for other substrates was in the range 20-40% with 1 mol% loading of 16. Catalyst 16 has also been used for diastereoselective cycloaddition reactions using chiral 0-menthoxy-activated dienes derived from (-)-menthol, giving up to 84% de [24b,c] it has also been used for the synthesis of optically pure saccharides. 

Yaodong Huang, while pursuing the synthesis of ( + )-berkelic acid (69), reported a diastereoselective cycloaddition using method H that leads to another type of 5,6-aryloxy spiroketals (Fig. 4.36).32 For example, addition of three equivalents of t-butyl magnesium bromide to alcohol 70 in the presence of the exocyclic enol ether 71 proceeds in a 72% yield to the spiroketal 72 with a 4.5 1 selectivity favoring the endo approach (Fig. 4.36). Additional experiments suggest the bromine atom decreases the HOMO-LUMO band gap and improves diastereoselectivity. 

Selenski investigated the use of chiral enol ether auxiliaries in order to adapt method F-H for enantioselective syntheses. After surveying a variety of substituted and unsubstituted enol ethers derived from a vast assortment of readily available chiral alcohols, she chose to employ enol ethers derived from trans-1,2-phenylcyclohexanol such as 73 and 74 (Fig. 4.37). These derivatives were found to undergo highly diastereoselective cycloadditions resulting in the formation of 75 and 76 in respective... 

FIGURE 4.36 A diastereoselective cycloaddition strategy for (+ )-berkelic acid 69. 

FIGURE 4.37 Some examples of diastereoselective cycloadditions using chiral auxiliaries. 

Acetylenic ethers 7 can be hydrozirconated, and subsequent iododezirconation leads to (fc)-iodo enol ethers 8 (Scheme 4.4) [18], These species undergo efficient Sonogashira couplings to give (E)-enynes, which are ultimately converted to stereodefined dienol ethers. These dienes have proven useful in studies of diastereoselective cycloaddition reactions with singlet oxygen, where R in 8 is a nonracemic auxiliary (e. g., menthyl) (Procedure 3, p. 140). 

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 diastereoselective cycloaddition of 2-phenyl-4-dimethylamino-l-thia-3-azabuta-l,3-diene with a choice of dienophiles and in the presence of a Lewis acid provides a convenient route to 5,6-dihydro-4//-l,3-thiazines <2002TL6067, 2004T1827>. The more stable /ra r-adducts are produced exclusively. The approach using (4A)-3-acryloyl-4-benzyloxazolidin-2-one 198 provides access to the chiral 5,6-dihydro-4//-l,3-thiazine 199 <2004T1827>. The exceptional level of selectivity is only achieved when magnesium bromide is used. The chiral auxiliary was removed by reaction with lithium benzoxide to give the benzyl ester 200, and reaction with catalytic amount of samarium triflate and methanol provides the methyl ester 201 (Scheme 21). 2-Substituted-5,6-dihydro-l,3-thiazines are conveniently synthesized from nitriles or thiocyanates and 4-mercapto-2-methylbutan-2-ol to produce... 

Planar chiral arene Cr(CO)3 complexes have been shown to undergo highly diastereoselective cycloadditions and Kiindig has extended this protocol to the [3+2] cycloadditions of azomethine ylides (96). Enantiopure ortho- substituted p -benzaldehyde complex 337 underwent condensation with an ot-amino ester to afford imine 338 in the presence of EtaN. Subsequent treatment with methyl acrylate at ambient temperamre in the presence of LiBr and EtaN delivered cycloadduct 339, with excellent stereoinduction and high material yield. Photoinduced oxidative decomplexation in air furnished the final arylpyrrolidines (Scheme 3.114). 

The formation of five-membered tetrahydrothiophene rings using nonsymme-trical reaction partners usually occurs with high regioselectively. In most cases, a stereospecific reaction was observed (9,27,94). Recently, a diastereoselective cycloaddition of the parent species la to various chiral a,p-unsaturated amides was also reported (32,95). 

Reactants of type 303 gave similar reactions and, interestingly, the enantiomeri-cally pure example 304 reacted via a fully diastereoselective cycloaddition in the first step leading to 305 (66%) (189). 

Acetyl-2(3//)-oxazolone 84 serves as a good 1,3-dipolarophile in the [3+2] cycloaddition to A-alkyl-a-phenylnitrones 239, giving a mixture of the four possible isomers 240-243, but with the predominant formation of the exo-syn adduct 240 (Fig. 5.59). Diastereoselective cycloadditions proceed when mixtures of optically active 3-(2-exo-alkoxy-l-apocamphanecarbonyl)-2(3/7)-oxazolones and A-benzyl- and A-ferf-butyl-a-phenylnitrones are heated at 110 °C ... 

The formation of hydrogen bond to direct the Patemd-Btichi reaction has been considered by other researchers. Diastereoselective cycloaddition has... 

Wagner, P.J. and McMahon, K. (1994) Chiral auxiliaries promote both diastereoselective cycloaddition and kinetic resolution of products in the ortho photocycloaddition of double bonds to benzene rings. Journal of the American Chemical Society, 116, 10827-10828. 

The one-pot reaction of 0-BOC protected salicylaldehydes and salicyl alcohols with electron-rich alkenes and a Grignard reagent involves a diastereoselective cycloaddition to an o-quinone methide and offers access to a wide range of 4-substituted chromans <02JOC6911>. 

Table 10. Diastereoselective Cycloaddition Reactions of Danishefsky s Diene with 2-Formyl-2-methyl-1,3-dithiane 1 -Oxide...

Cheletropic reactions, dimethylgermylene to 1-azabuta-1,3-dienes. 57, 5 Chemotherapeutic agents isoxazolines. 60, 297 thiopyrylium salts, 60, 172 Chiral auxiliaries, in diastereoselective cycloadditions of nitrile oxides, 60, 286-94... 

The allenic ester 4 of (R)-l also undergoes a highly diastereoselective cycloaddition with cyclopentadiene to afford the e do-adduct 5 almost exclusively and in 99% de. The adduct provides a chiral intermediate to natural (- i-P-santalene (6).-... 

Oxabicyclo[2.2.1]hept-5-cn-2-one derivatives (ketals, cyanohydrins) were prepared in an optically pure form, hence optically pure -functionalized amines can be prepared via the diastereoselective cycloaddition of organic azides. Such transformations have been described for ethoxycarbonyl azide and /ert-butoxycarbonyl azide54, 5. For example 3-amino-3-deoxy-a-altropyranoside hydrochloride 20 was prepared from the dibenzyl acetal 19ss. 

The highly strained twist" and chair bicyclic trans-cyclooctenes 17 and 18 underwent an exceptionally regioselective and diastereoselective cycloaddition with phenyl azide, the stereochemistry of the dihydrotriazoles was fully retained in the thermal decomposition to aziridi-nes107. Furthermore no imine is produced. 

Cyclopentadienes, unsymmetrically substituted at C-5, can be prepared at low temperature without isomerization and undergo diastereoselective cycloadditions of diazenes (see p 5475). 

Cyclobutene-fused tetrahydropyridazines 1 and 2 are prepared by the diastereoselective cycloaddition of acyldiazenes to 1,2-diethylidenecyclobutanes. They can be converted to bicyclic diazenes 3, which are readily isomerized to the hydrazones f Pyrolysis of the bicyclic diazenes 3 affords 2,6-octadienes 4 with >99.9% stereospecificity. 

Chlorocyclononatetraene undergoes a rapid rearrangement in liquid sulfur dioxide to the l-c/.v-chloro-3a,7a-c/.v-dihydro-1 //-indene (24), which, after replacement of the solvent with dichloromethane at the same temperature, undergoes diastereoselective cycloaddition of 4-phenyl-3//-1,2.4-triazole-3,5(4//)-dionc (anti to the cyclohexadienc ring substituents) to give 2535. 

Similar anti-azomethine ylides 76 (EWG = COOR, R = MeO) bearing an ylide-stabilizing ester moiety are involved in the diastereoselective cycloadditions to 3,4-dihydroisoquinolines and N-(arylmethylene)methylamines to provide stereoselective imidazolidine-fused cycloadducts 259 and 260 (82LA924, 82LA2146). As imines and ylides 76 bear extremely different LUMO and HOMO coefficients on each termini, uniformly high regioselec-tion is not surprising. endo-Approach of the dihydroisoquinolines to the... 

Treatment of r -(EBIH)ZrMe2 954 with [HNMe3]Cl yields the chlorozirconocene methyl derivative rac-(EBIH)Zr(Cl)Me 955, which is subsequently treated with LiHNAr in THF to afford the imido complex r -(EBIH)Zr(=NAr)(THF)2 956727 (Scheme 240). This racemic imido complex undergoes highly diastereoselective cycloadditions reactions with 1 equiv. of racemic disubstituted allenes to yield single diastereomeric azametallacycle products 957. The use of the enantiopure zirconocene imido complex... 

There is no doubt that the field of asymmetric induction occupies a very important place in modem synthetic methodology. Elegant protocols designed to cany out dipolar cycloadditions have been developed and important advances in the theoretical description of these processes have taken place as a consequence (vide infra) Diastereoselective cycloadditions have been carried out between optically active nitrile oxides, nitrones,azomethine ylides and achiral dipolarophiles, and between optically active dipolarophiles and achiral nitrile oxides and achiral nitrones. The products have b n put to good use, either by translating the cycloaddition diastereoselectivity to the construction of useful optically active acyclic intermediates, or in Ae total synthesis of natural products (vide infra) ... 

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