Dipolar diastereoselective with chiral auxiliary

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). 

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... 

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. 

Benzoyl nitrene 247 (R = Ph) generated by photolysis of benzoyl azide in the presence of carbonyl compounds affords 1,4,2-dioxazolines 248-251 (Scheme 34). Moderate yields are obtained upon irradiation at 254 nm, while better yields are obtained upon irradiation at 365 nm in the presence of a sensitizer, such as Michler s ketone, which diminishes the photo-Curtius side reaction of acylnitrene to isocyanate. With ethoxycarbonylnitrene 247 (R=—OEt) and acetone, compounds 251 and 252 are obtained the latter is possibly formed from acetone and the dipolar intermediate 252 <1995T7181>. In another report on reactions of chiral aroylnitrene 254, the obtained dioxazolines 255 do not show any diastereoselectivity, although the presence of a chiral auxiliary in the ortfe-position ensures its vicinity to the reaction center (Scheme 35) <2001S1125>. 

Related a,p-Unsaturated Esters. Similar a,p-unsaturated esters bearing a heterocyclic chiral auxiliary of a-amino acid origin at the p-position are known and have been utilized in asymmetric synthesis. Effective asymmetric conjugate additions of cuprates to (2), (3), and (5)J epoxidations of (3), and dipolar cycloadditions of (2) have been reported. Although oxazoli-dine (4) is only obtained as an 86 14 equilibrating mixture of stereoisomers, reactions with the lithium (Z)-enolate of methyl N-benzylideneglycinate (see Ethyl N-Benzylideneglycinate) are exclusively diastereoselective. 

A non-biomimetic synthesis of /J-(-)-horsfiline (57) has also been recently reported which was based on a thermal intermolecular 1,3-dipolar cycloaddition reaction as outlined in Scheme 7 [63J. The reaction of the optically active menthyl ester 67 acting as a dipolarophile, with the JV-methylazomethine ylide 68 (thermally generated in situ from sarcosine and formaldehyde) proceeded with n-facial diastereoselectivity to produce a chromatographically separable mixture of 69 and the unwanted diastereomer. Subsequent cleavage of the chiral auxiliary, followed by removal of the carboxylic acid group by the Barton radical method provided J7-(-)-horsfiline. 

Our initial improvement in the synthesis of pyrrolidine acid 3 relied on a racemic 1,3 dipolar cycloaddition followed by resolution. Attempts to devise asymmetric protocols of this reaction using chiral auxiliaries were not productive. The results from our laboratories were consistent with literature findings, with a moderate diastereoselectivity of 3 to 4 1 at best obtained even when double chiral auxiliaries were used. Several other approaches, such as Aza-Cope/Mannich reaction, intramolecular C-H insertion, and asymmetric aryl 1,4 addition, did not bear fruit. 

Scheme 18.14). Upon treatment of ketones or aldehydes with 62, condensation reactions lead to the formation of nitrones including 63 [71, 72]. Such nitrones were observed to participate in dipolar cycloadditions with olefin 64 and to furnish the corresponding isoxazolidines (cf. 65) in a diastereoselective manner. Facile removal of the chiral carbohydrate-derived auxiliary was effected upon exposure of the adduct to acidic hydrolysis, providing the chiral isoxazolidine 66 (> 90% ee). 

The amino acid derived chiral oxazolidinone 188 is a very commonly used auxiliary in Diels-Alder and aldol reactions. However, its use in diastereoselective 1,3-dipolar cycloadditions is less widespread. It has, however, been used with nitrile oxides, nitrones, and azomethine ylides. In reactions of 188 (R = Bn, R =Me, R = Me) with nitrile oxides, up to 92% de have been obtained when the reaction was performed in the presence of 1 equiv of MgBr2 (303). In the absence of a metal salt, much lower selectivities were obtained. The same observation was made for reactions of 188 (R = Bn, R = H, R = Me) with cyclic nitrones in an early study by Murahashi et al. (277). In the presence of Znl2, endo/exo selectivity of 89 11 and up to 92% de was observed, whereas in the absence of additives, low selectivities resulted. In more recent studies, it has been shown for 188 (R =/-Pr, R = H, R =Me) that, in the presence of catalytic amounts of Mgl2-phenanthroline (10%) (16) or Yb(OTf)3(20%) (304), the reaction with acyclic nitrones proceeded with high yields and stereoselectivity. Once again, the presence of the metal salt was crucial for the reaction no reaction was observed in their absence. Various derivatives of 188 were used in reactions with an unsubstituted azomethine ylide (305). This reaction proceeded in the absence of metal salts with up to 60% de. The presence of metal salts led to decomposition of the azomethine ylide. 

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