Hetero-Diels—Alder reactions chiral auxiliaries

Although the reactions of carbonyl compounds with dienes follow a stepwise addition, the overall stereochemical outcome mimics that of the Diels-Alder reaction.1 2 5 242-244 The products of the hetero Diels-Alder reaction have been used as substrates for a wide variety of transformations and natural products syntheses.242,245-258 Many hetero Diels-Alder reactions use chiral auxiliaries or catalysts that have been successful for the Diels-Alder reaction. 

For the diastereoselective hetero Diels-Alder reaction of carbonyl compounds using removable chiral auxiliaries, intensive studies of the uncatalyzed... 

Recently, Breitmaier et al. [94] showed that in the hetero Diels-Alder reaction of triketones such as indantrione 2-34 and alloxane with the chiral 2-methyl-1-(1-phenylalkoxy)-1,3-butadienes 2-35 a good diastereoselectivity can be obtained. The cycloaddition proceeded regioselectively with increasing facial selectivity in correlation to the steric demand of the alkyl group at the benzylic position in the auxiliary to give the dihydropyran 2-36 as the major and 2-37 as the minor product (Fig. 2-10). 

Numerous further chiral imines activated by electron-withdrawing substituents have been investigated in order to carry out stereoselective aza Diels-Alder reactions. In these studies, Bailey et al. have recently introduced the use of two inducing stereocenters in the imine. This approach proved to yield excellent diastereoselectivities thus, imine 3-12 bearing a (,R)-8-phenylmenthyl auxiliary gave the essentially pure cycloadduct 3-13 upon hetero Diels-Alder reaction with cyclopentadiene (Fig. 3-4) [194-196]. 

Cyclic nitrones generated by [4+ 2]-cycloaddition of nitroalkenes undergo various, synthetically very valuable reactions. Thus, Denmark et al. have developed an elegant access to different enantiopure, 3- and 3,4-substituted pyrrolidine derivatives by reductive ring contraction of the cyclic nitrone resulting from a hetero Diels-Alder reaction [389,390]. Upon reaction of -2-nitrostyrene 4-51 with the chiral enol ether 4-52 in the presence of the bulky Lewis acid MAPh (4-53), three diastereomeric cycloadducts 4-54, 4-55 and 4-56 were formed. Hydrogenolysis of the main product 4-54 yielded the desired pyrrolidine 4-57 in excellent optical purity and allowed nearly quantitative recovery of the chiral auxiliary (Fig. 4-12) [391]. It is noteworthy that the nature of the Lewis acid catalyst, especially its steric demand, decisively influences the stereochemical course of such cycloadditions [392]. 

In a more recent study, Koizumi et al. employed terpene derivatives as chiral auxiliaries attached to thioaldehydes [405], but these heterodienophiles gave only moderate diastereoselectivities in reactions with cyclopentadiene. Mazzan-ti et al. have investigated the hetero Diels-Alder reaction of thioketones bearing an asymmetric silicon atom directly attached to the thiocarbonyl moiety which induced diastereoselectivities up to 50% de [406]. 

N-Acylimines which may react as l-oxa-3-aza-l,3-butadienes represent a class of heterodienes which exhibit a close relationship to l-thia-3-aza-l,3-butadienes [13]. A very impressive application of such an l-oxa-3-aza-l,3-butadiene has been worked out by Swindell et al.[445]. The asymmetric hetero Diels-Alder reaction described therein opens a very elegant approach to the A-ring side chain of taxol. This synthesis takes advantage of the bulky chiral auxiliary attached to the dienophile 6-5 which upon cycloaddition with the l-oxa-3-aza-1,3-butadiene 6-4 yielded the 1,3-oxazine derivative 6-6. Subsequent hydrolysis, hydrogenolysis and transesterification gave the methyl ester of the taxol A-ring side chain 6-7 in good endo and excellent zr-facial selectivity (Fig. 6-2). 

Bednarski, M, Danishefsky, S, On the interactivity of chiral auxiliaries with chiral catalysts in the hetero Diels-Alder reaction a new route to L-glycoUpids, J. Am. Chem. Soc., 105, 6968-6969, 1983. 

The hetero-Diels-Alder reaction with inverse electron demand is an attractive route for the synthesis of 3.4-dihydro-2//-pyrans. Enone 7, esterified with D-mandelic acid as chiral auxiliary, adds to ethyl vinyl ether (8) to give a 2 1 mixture of 9 and 10 [d.r. (2S,4S) (2RAR) 67 33]1. The enone 11 requires high pressure to add to the much less reactive enol ether 12, yielding a 2 3 mixture of 13 and 14 [d.r. (2S, 3S,45 )/(21 ,37 ,4/ ) 40 60]8. The introduction of the additional stereogenic center in the enone 15 leads to a substantially improved diastereofacial selectivity, and adducts 16 and 17 are obtained as a 1 10 mixture [d.r. (2S.4S) (2RAR) 9 91]9. 

The hetero-Diels-Alder reaction of chiral sulfines 24, bearing the relatively cheap (S)-proline as chiral auxiliary, with 2,3-dimethyl-l,3-butadiene (17) proceeds with low to moderate diastereoselectivity66. 

A number of examples have been reported of the asymmetric hetero Diels-Alder reaction of heterodienes or heterodienophiles such as imines, nitroso or carbonyl compounds.The chiral auxiliary is commonly attached to the nitrogen atom of the imine or nitroso compound, or a chiral ester or amide substituent may provide the necessary asymmetric induction. As an example, the a-cWoronitroso dienophile 132, bearing a sugar-derived auxiliary, has been found to be effective for the formation of cyclic hydroxylamines with high optical purity (3.95). The initial cycloadduct breaks down readily (see Scheme 3.32), via an iminium ion with subsequent methanolysis to release the chiral auxiliary and the product 133. 

The hetero Diels-Alder reaction <01H1591, 01TL5693> and dipolar cycloadditions continue to constitute important approaches to piperidines. Kibayashi and co-workers used an intramolecular acylnitroso Diels-Alder reaction to synthesize (-)-lepadins A,B, and C from an acyclic precursor <01JOC3338>. An intramolecular nitrone cycloaddition was used by Machetti and co-workers to produce both enantiomers of 4-oxopipecolic acid <01T4995>. Their synthesis proceeds from a nitrone bearing an a-methylbenzylamine chiral auxiliary. Noteworthy in this report is the presence of large-scale experimental procedures the nitrone formation and cycloaddition reactions were performed on 285 mmol and 226 mmol scales, respectively. 

The cycloadditions of aldehydes with chiral siloxydienes, bearing the chiral substituent at the 1-position, proceed with moderate selectivities in the presence of Eu(fod)3 or Eu(hfc)3 at low temperature. Asymmetric thermal hetero Diels-Alder reaction of triketones with 2-methyl-l-(l-phenylalkoxy)-1,3-butadienes bearing the chiral alcohols 16 or 17 (Chapter 6) as auxiliaries lead highly selective to the cycloadducts. ... 

Hetero-Diels-Alder reactions have been used in the construction of amino-sugars, asymmetry being induced by the use of either a chiral Lewis acid catalyst or a chiral auxiliary. Thus, the 3-amino-hexuronic acid derivatives 61 were obtained with high de and ee using a copper(II) triflate catalyst with a chiral bisoxazoline ligand. 4-Amino-4-deoxy-D-erythrose and 4-amino-4,5-dideoxy-L-lyxose (63), the latter a potent inhibitor of a-L-fucosidase, were obtained from the D-pyroglutamic add-containing diene 62 (Scheme 19). ... 

Swindell CS, Tao M (1993) Chiral Auxiliary-Mediated Asymmetric Induction in a Thermal Inverse Electron Demand Hetero-Diels-Alder Reaction - Enantioselective Synthesis of the Taxol A-Ring Side Chain. J Org Chem 58 5889... 

Yb(OTf)3 was effective for asymmetric induction in hetero Diels-Alder reaction of thiabutadiene and electron-deficient olefin bearing chiral auxiliary [37]. 10 mol% of catalyst effected the reaction into giving cycloadduct in excellent Tc-facial selectivity, whereas selectivity was reversed with modest degree in the absence of the catalyst (Scheme 13.15). The reaction in which a coordinative solvent such as dimethylsulfoxide (DMSO) or dimethylformamide (DMF) displayed similar selectivity came from that of noncatalyzed reaction, suggesting well-organized coordination of substrates to Yb. 

---