Dipolar chiral auxiliaries

To control the stereochemistry of 1,3-dipolar cycloaddidon reacdons, chiral auxiliaries are introduced into either the dipole-part or dipolarophile A recent monograph covers this topic extensively ° therefore, only typical examples are presented here. Alkenes employed in asymmetric 1,3-cycloaddidon can be divided into three main groups (1) chiral allyhc alcohols, f2 chiral amines, and Hi chiral vinyl sulfoxides or vinylphosphine oxides. 

Asymmetric 1,3-dipolar cycloaddition of cyclic nitrones to crotonic acid derivatives bearing chiral auxiliaries in the presence of zinc iodide gives bicyclic isoxazolidines with high stereoselectivity (Eq. 8.51). The products are good precursors of (3-amino acids such as (+)sedridine.73 Many papers concerning 1,3-dipolar cycloaddition of nitrones to chiral alkenes have been reported, and they are well documented (see Ref. 63). 

Dipolar cycloaddition reactions are of main interest in nitrile oxide chemistry. Recently, reviews and chapters in monographs appeared, which are devoted to individual aspects of these reactions. First of all, problems of asymmetric reactions of nitrile oxides (130, 131), including particular aspects, such as asymmetric metal-catalyzed 1,3-dipolar cycloaddition reactions (132, 133), development of new asymmetric reactions utilizing tartaric acid esters as chiral auxiliaries (134), and stereoselective intramolecular 1,3-dipolar cycloadditions (135) should be mentioned. Other problems considered are polymer-supported 1,3-dipolar cycloaddition reactions, important, in particular, for combinatorial chemistry... 

However, most asymmetric 1,3-dipolar cycloaddition reactions of nitrile oxides with alkenes are carried out without Lewis acids as catalysts using either chiral alkenes or chiral auxiliary compounds (with achiral alkenes). Diverse chiral alkenes are in use, such as camphor-derived chiral N-acryloylhydrazide (195), C2-symmetric l,3-diacryloyl-2,2-dimethyl-4,5-diphenylimidazolidine, chiral 3-acryloyl-2,2-dimethyl-4-phenyloxazolidine (196, 197), sugar-based ethenyl ethers (198), acrylic esters (199, 200), C-bonded vinyl-substituted sugar (201), chirally modified vinylboronic ester derived from D-( + )-mannitol (202), (l/ )-menthyl vinyl ether (203), chiral derivatives of vinylacetic acid (204), ( )-l-ethoxy-3-fluoroalkyl-3-hydroxy-4-(4-methylphenylsulfinyl)but-1 -enes (205), enantiopure Y-oxygenated-a,P-unsaturated phenyl sulfones (206), chiral (a-oxyallyl)silanes (207), and (S )-but-3-ene-1,2-diol derivatives (208). As a chiral auxiliary, diisopropyl (i ,i )-tartrate (209, 210) has been very popular. 

Diastereoselective intramolecular 1,3-dipolar cycloadditions of alkylidene-cyclopropyl nitrones provide spirocyclopropylisoxazolidines. These compounds have been shown to undergo either thermally induced ring expansion to octahydro[l]pyrindin-4-ones or to acid induced ring contraction into fS-lactams with concomitant loss of ethylene (Scheme 2.218) (710-716). Use of chiral auxiliaries, that is (L)-2-acetoxylactate can lead to enantiomerically enriched heterocycles (715). 

The asymmetric 1,3-dipolar cycloaddition of nitrones (515), possessing an electron-withdrawing group, to allylic alcohols was achieved by using diisopropyl (/ ,/ )-tartrate [(R,R-DIPT)] as a chiral auxiliary. The isoxazolidines (516) and... 

The utility of a new fluorine supported chiral auxiliary was established in a series of catalyzed and uncatalyzed 1,3-dipolar cycloaddition reactions with diphenylnitrone (637b) (Scheme 2.281) (797). The yields and selectivities of the cycloadducts (645a—d) compare favorably with those obtained with conventional Evans-type auxiliaries (798). Purification of the products was greatly improved by using fluorous solid phase extraction (FSPE). 

The highly stereoselective 1,3-dipolar cycloaddition of C-phenyl-iV-glycosylnitrones (336) and (679) to dimethyl maleate D14, with the sugar moiety acting as a chiral auxiliary, has been used in enantioselective syntheses of isoxazolidines (678) and (678 ent) (Scheme 2.292) (118). 

Dipolar addition is closely related to the Diels-Alder reaction, but allows the formation of five-membered adducts, including cyclopentane derivatives. Like Diels-Alder reactions, 1,3-dipolar cycloaddition involves [4+2] concerted reaction of a 1,3-dipolar species (the An component and a dipolar In component). Very often, condensation of chiral acrylates with nitrile oxides or nitrones gives only modest diastereoselectivity.82 1,3-Dipolar cycloaddition between nitrones and alkenes is most useful and convenient for the preparation of iso-xazolidine derivatives, which can then be readily converted to 1,3-amino alcohol equivalents under mild conditions.83 The low selectivity of the 1,3-dipolar reaction can be overcome to some extent by introducing a chiral auxiliary to the substrate. As shown in Scheme 5-51, the reaction of 169 with acryloyl chloride connects the chiral sultam to the acrylic acid substrate, and subsequent cycloaddition yields product 170 with a diastereoselectivity of 90 10.84... 

Using a stoichiometric amount of (i ,i )-DIPT as the chiral auxiliary, optically active 2-isoxazolines can be obtained via asymmetric 1,3-dipolar addition of achiral allylic alcohols with nitrile oxides or nitrones bearing an electron-withdrawing group (Scheme 5-53).86a Furthermore, the catalytic 1,3-dipolar cycloaddition of nitrile oxide has been achieved by adding a small amount of 1,4-dioxane (Scheme 5-53, Eq. 3).86b The presence of ethereal compounds such as 1,4-dioxane is crucial for the reproducibly higher stereoselectivity. 

Another, slightly different method, is to use the resin to capture a molecule followed by release of a modified product. This is illustrated by the example shown in Scheme 13 where a nitrone undergoes a 1,3-dipolar cyclo-addition with an immobilized chiral auxiliary followed by a reductive cleavage to yield an isoxazoh-dine (Scheme 2.13) [32]. Here the polymer is acting as both an active reagent and as a purification technique [33]. 

E) configuration. The dipolar cycloaddition of 141 with a silyl nitronate shows a slight increase of facial selectivity over 132 (Eq. 2.9). Because the cycloadducts are converted directly to the corresponding isoxazolines, only the facial selectivity can be determined. It is believed that the cycloaddition proceeds on the Re face of the dipolarophile due to shielding of the Si face by the auxihary. Both chiral auxiliaries can be liberated from the cycloadduct upon reduction with L-Selectride. 

Akiyama et al. (180) overcame this problem by employing ch/ro-inositol derivatives as chiral auxiliaries for the acrylic ester, which afforded dipolar cycloadducts with a high degree of stereoselectivity (Scheme 6.34). Formation of the major products [(55)-isoxazoline-5-esters] was suggested to arise from the s-cis conformer of acrylate 27, the minor product being derived from the s-trans conformer 28. The bulky protective group (in this case tert-butyldiphenylsilyl) would effectively shield the Re face of the olefinic double bond and destabilize the s-trans conformer 28. 

In a related case, the use of dioxazaborocines as the chiral auxiliary with benzonitrile oxide gave dipolar cycloadducts with a poor diastereomeric ratio dr 68 32) (195). Similarly, the cycloaddition of benzonitrile oxide to vinyl ethers with a chiral appendage also proceeded with poor stereoselectivity (dr of 65 35) (196). 

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. 

The 1,3-dipolar cycloadditions of 1,3-dipoles with chiral alkenes has been extensively reviewed and thus only selected examples will be highlighted here. We have chosen to divide this section on the basis of the different types of alkenes rather than on the basis of the type of 1,3-dipole. For 1,3-dipolar cycloadditions, as well as for other reactions, it is important that the chiral center intended to control the stereoselectivity of the reaction is located as close as possible to the functional group of the molecule at which the reaction takes place. Hence, alkenes bearing the chiral center vicinal to the double bond are most frequently apphed in asymmetric 1,3-dipolar cycloadditions. Examples of the application of alkenes with the chiral center localized two or more bonds apart from the alkene will also be mentioned. Application of chiral auxiliaries for alkenes is very common and will be described separately in Section 12.3. 

Nitronates have also been applied in intramolecular 1,3-dipolar cycloaddition reactions. Denmark and Thorarensen (64) extensively studied the application of cyclic alkyl nitronates in tandem[4+2]/[3+2] cycloadditions of nitroalkanes. In most cases, the stereoselectivity of these reactions is directed by a chiral auxiliary and will thus be outlined in Section 12.3.4. The reader is also directed to the excellent chapter by Denmark in Chapter 2. 

Chiral auxiliaries are very often applied for induction of asymmetry in 1,3-dipolar cycloadditions. For most of the reactions described in this section, recovery of the chiral auxiliary has been demonstrated, but for some reactions the chiral moiety has the potential to be recovered, although it was not performed. Most frequently, the chiral auxiliary is connected to the dipolarophile, very often as a,p-unsaturated esters or amides. In a few cases, auxiliaries have been attached to the 1,3-dipole. 

Chiral furanones (butanolides) such as 191 have been used as dipolarophUes in various 1,3-dipolar cycloadditions. The chiral 4-substituted butanolide 190 was prepared from 191 and the chiral auxiliary menthol (Scheme 12.55) (310,311). The single diastereomer 191 is obtained by crystallization and epimerization of the other diastereomer, as the amount of 191 in solution decreases. 1,3-Dipolar... 

The use of chiral vinyl ethers in 1,3-dipolar cycloadditions with nitrones allows for the subsequent removal and recovery of the chiral group. Using the chiral vinyl ether 197 and the cyclic nitrone 77, the cycloaddition proceeded with high diastereoselectivity (Scheme 12.56). The endo/exo-selectivity was not given in this communication by Carmthers et al. (313), but this is of minor importance for the final outcome of this work, since one of the chiral centers was destroyed in the conversion of 198 into the final product 199. The chiral auxiliary can by recovered in this reaction sequence, and 199 was obtained with an optical purity of >95% ee. 

Baggiolini et al.216) have succeeded in synthesizing the vitamin d-bioiin from (RR)-cystine via intramolecular [3 + 2] cycloaddition with a d.s. value of 80%. Danishefsky et al.217) synthesized pretyrosine, the biosynthetic precursor of (S)-tyrosine, by a [4 + 2]-cycloaddition applying an (S)-glutamic acid derivative as chiral auxiliary. Phenylglycine was used as the source of the chiral information in an asymmetric variation of a 1,3-dipolar cycloaddition, as reported by Grigg and Kemp et al. 218>. 

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