Cycloaddition reactions chiral dipolarophiles

To control the stereochemistry of 1,3-dipolar cycloaddition reactions, chiral auxiliaries are introduced into either the dipole-part or dipolarophile. A recent monograph covers this topic extensively 70 therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddition can be divided into three main groups (1) chiral allylic alcohols, (2) chiral amines, and (3) chiral vinyl sulfoxides or vinylphosphine oxides.63c... 

Nitrones were the first as well as the most widely used dipoles in asymmetric cycloadditions. The first report on the use of enantiomerically pure vinylsulf-oxides as dipolarophiles was due to Koizumi et al. [153], who described in 1982 the reaction of (-R)-vinyl p-tolyl sulfoxide 1 with acyclic nitrones 191. The reactions required 20 h in refluxing benzene to be completed, yielding a mixture of only two compounds, 192 and 193 (Scheme 91). They exhibited identical endo or exo stereochemistry (which was not unequivocally assigned), deduced from the fact that their reduction yielded enantiomeric thioethers. The major component, 192, exhibits (S) configuration at C-3, determined by chemical correlation. The authors claim this paper [153] to be the first example of 1,3-dipolar cycloaddition using chiral dipolarophiles. 

The cyclodehydration of 2-substituted-A/-acylthiazolidine-4-carboxylic acids yields bicyclic munchnones. This mesoionic ring system acts as a cyclic azomethine ylid and can undergo 1,3-dipolar cycloaddition reactions with dipolarophiles. A range of chiral pyrrolo[l,2-c]thiazoles have been prepared by this method both intermolecularly and intramolecularly. 

Kobayashi and co-workers reported similar enantioselectivity switch in the bi-nol-yterrbium(III) triflate complex-catalyzed cycloaddition reactions [69] between N-benzylidenebenzylamine N-oxide and 3-crotonoyl-2-oxazolidinone [70]. The reaction in the presence of MS 4 A showed an exclusively high enantioselectivity of 96% ee, while that in the absence of MS 4 A (-50% ee) or in the presence of pyridine N-oxide (-83% ee) had the opposite enantioselectivity (Scheme 7.24). This chirality switch happens generally for the combination of a wide variety of nitrones and dipolarophiles. 

The enantioselectivity of [3+ 2]-cycloaddition reactions is determined by the preference of a particular facial attack of the reagents containing chiral inductors. Most of such reactions proceed in the absence of a catalyst and, consequently, the inductor should be present in either the dipole or the dipolarophile. 

Silyl nitronates containing chiral inductors have not been as yet used in intermolecular [3 + 2]-cycloaddition reactions. In this case, the facial discrimination was generally created by introducing chiral nonracemic fragments into dipolarophiles (see review 433). 

This section shall consider the effects of substitution on both the nitronate as well as the dipolarophile, as they relate to both the inter- and intramolecular versions of the dipolar cycloaddition. Also included will be a discussion of facial selectivity in the reaction of a chiral dipolarophile. 

Koizumi and co-workers (38) reported the first asymmetric synthesis of (15)-(—)-a-tropanol (149) via a 1,3-dipolar cycloaddition protocol. Treatment of the chiral dipolarophile 150 with 151 in tetrahydrofuron (THF) delivered cycloadducts exo-152 and endo-153. Although the reaction proceeded with low facial selectivity,... 

The azomethine ylide was generated by treatment of A -benzyl-Af-(methoxy-methyl)-trimethylsilylmethylamine (155) with TFA and underwent the required cycloaddition step with chiral dipolarophile 156, stereocontrol being induced by Evan s auxiliary. The ot, p-unsaturated acid dipolarophile was tethered to a chiral oxazoladine in two easy, high-yielding steps. The auxiliary served three purposes to give asymmetric control to the reaction, to allow for separation of the reaction products by generating column separable diastereoisomers, and hnally to activate the olefin in the cycloaddition step (Scheme 3.45). 

In synthetic efforts toward the DNA reactive alkaloid naphthyridinomycin (164), Gamer and Ho (41) reported a series of studies into the constmction of the diazobicyclo[3.2.1]octane section. Constmction of the five-membered ring, by the photolytic conversion of an aziridine to an azomethine ylide and subsequent alkene 1,3-dipolar cycloaddition, was deemed the best synthetic tactic. Initial studies with menthol- and isonorborneol- tethered chiral dipolarophiles gave no facial selectivity in the adducts formed (42). However, utilizing Oppolzer s sultam as the chiral controlling unit led to a dramatic improvement. Treatment of ylide precursor 165 with the chiral dipolarophile 166 under photochemical conditions led to formation of the desired cycloadducts (Scheme 3.47). The reaction proceeded with an exo/endo ratio of only 2.4 1 however, the facial selectivity was good at >25 1 in favor of the desired re products. The products derived from si attack of the ylide... 

The reaction was further developed to form a wide range of p-lactam-based products (52). Treatment of the racemic ylide processor 186 with suitable sulfur-based thiocarboxylate or thiocarbonate dipolarophiles gave rise to the expected racemic penams 189 and 190 and penems as single regioisomers (Scheme 3.54). Once again, the use of the chiral dipolarophile 186 furnished the cycloaddition product 191 with complete enantiomeric integrity. Similarly, the use of aldehydes... 

Chiral bicyclic lactams have been successfully utilized by Meyers as chiral dipolarophiles in highly diastereoselective azomethine ylide cycloadditions (73). Treatment of the ylide precursor 218 with the unsaturated, non-racemic dipolar-ophile 219 in the presence of a catalytic amount of TFA led to the formation of tricyclic adducts 220 and 221 in excellent yields (85-100%). The diastereofacial preference for the reaction was dependent on the nature of R with a methyl group... 

The relative rate constants (fe ) do not account for the fact that approach of the nitrile oxide to the 7i-bond can occur from both olefinic diastereofaces with two regioisomeric modes of reaction (Scheme 6.14). In the case of achiral 1-alkenes, only one regioisomer is formed. With chiral dipolarophiles, preference for one of the two is usually found (diastereodifferentiation). The relative diastereofacial reactivity (fejH) is used to evaluate this effect (121). With ethylene, there are four possibilities of attack (two for each face corresponding to the different regio-isomers), and the of each is set as 0.25. In diastereodifferentiating cycloadditions, such as those with a-chiral alkenes, the major isomer generally results... 

The most common method for inducing asymmetry in 1,3-dipolar cycloadditions is by the application of chiral 1,3-dipoles, chiral dipolarophiles, or both, the latter always being the case for intramolecular reactions (5). First the reaction of chiral 1,3-dipoles will be described, then the reactions of chiral dipolarophiles, and finally the intramolecular reactions. In this chapter we have chosen to treat the diaster-eoselective reactions employing chiral auxiliaries separately in Section 12.3. 

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