Chiral nitrones 1,3-dipolar cycloaddition

Other approaches to (36) make use of (37, R = CH ) and reaction with a tributylstannyl allene (60) or 3-siloxypentadiene (61). A chemicoen2ymatic synthesis for both thienamycia (2) and 1 -methyl analogues starts from the chiral monoester (38), derived by enzymatic hydrolysis of the dimethyl ester, and proceeding by way of the P-lactam (39, R = H or CH ) (62,63). (3)-Methyl-3-hydroxy-2-methylpropanoate [80657-57-4] (40), C H qO, has also been used as starting material for (36) (64), whereas 1,3-dipolar cycloaddition of a chiral nitrone with a crotonate ester affords the oxa2ohdine (41) which again can be converted to a suitable P-lactam precursor (65). 

Gothelf presents in Chapter 6 a comprehensive review of metal-catalyzed 1,3-di-polar cycloaddition reactions, with the focus on the properties of different chiral Lewis-acid complexes. The general properties of a chiral aqua complex are presented in the next chapter by Kanamasa, who focuses on 1,3-dipolar cycloaddition reactions of nitrones, nitronates, and diazo compounds. The use of this complex as a highly efficient catalyst for carbo-Diels-Alder reactions and conjugate additions is also described. 

The above described reaction has been extended to the application of the AlMe-BINOL catalyst to reactions of acyclic nitrones. A series chiral AlMe-3,3 -diaryl-BINOL complexes llb-f was investigated as catalysts for the 1,3-dipolar cycloaddition reaction between the cyclic nitrone 14a and ethyl vinyl ether 8a [34], Surprisingly, these catalysts were not sufficiently selective for the reactions of cyclic nitrones with ethyl vinyl ether. Use of the tetramethoxy-substituted derivative llg as the catalyst for the reaction significantly improved the results (Scheme 6.14). In the presence of 10 mol% llg the reaction proceeded in a mixture of CH2CI2 and petroleum ether to give the product 15a in 79% isolated yield. The diastereoselectiv-ity was the same as in the acyclic case giving an excellent ratio of exo-15a and endo-15a of >95 <5, and exo-15a was obtained with up to 82% ee. 

Several titanium(IV) complexes are efficient and reliable Lewis acid catalysts and they have been applied to numerous reactions, especially in combination with the so-called TADDOL (a, a,a, a -tetraaryl-l,3-dioxolane-4,5-dimethanol) (22) ligands [53-55]. In the first study on normal electron-demand 1,3-dipolar cycloaddition reactions between nitrones and alkenes, which appeared in 1994, the catalytic reaction of a series of chiral TiCl2-TADDOLates on the reaction of nitrones 1 with al-kenoyloxazolidinones 19 was developed (Scheme 6.18) [56]. These substrates have turned out be the model system of choice for most studies on metal-catalyzed normal electron-demand 1,3-dipolar cycloaddition reactions of nitrones as it will appear from this chapter. When 10 mol% of the catalyst 23a was applied in the reaction depicted in Scheme 6.18 the reaction proceeded to give a yield of up to 94% ee after 20 h. The reaction led primarily to exo-21 and in the best case an endo/ exo ratio of 10 90 was obtained. The chiral information of the catalyst was transferred with a fair efficiency to the substrates as up to 60% ee of one of the isomers of exo3 was obtained [56]. 

A quite different type of titanium catalyst has been used in an inverse electron-demand 1,3-dipolar cycloaddition. Bosnich et al. applied the chiral titanocene-(OTf)2 complex 32 for the 1,3-dipolar cycloaddition between the cyclic nitrone 14a and the ketene acetal 2c (Scheme 6.25). The reaction only proceeded in the presence of the catalyst and a good cis/trans ratio of 8 92 was obtained using catalyst 32, however, only 14% ee was observed for the major isomer [70]. 

A mechanism for this reaction has been proposed [75], The first key intermediate in the reaction is the copper(I) acetylide 42. The additional ligand may be solvent or H2O. The acetylene moiety in 42 is activated for a 1,3-dipolar cycloaddition with the nitrone to give intermediate 43, with introduction of chirality in the product. A possible route to ris/traws-41 might be via intermediate 44. Finally, the cis isomer is isomerized into the thermally more stable trans-41. It should be mentioned that the mechanism outlined in Scheme 6.32 was originally proposed for a racemic version of the reaction to which water was added. 

In 1997 the application of two different chiral ytterbium catalysts, 55 and 56 for the 1,3-dipolar cycloaddition reaction was reported almost simultaneously by two independent research groups [82, 83], In both works it was observed that the achiral Yb(OTf)3 and Sc(OTf)3 salts catalyze the 1,3-dipolar cycloaddition between nitrones 1 and alkenoyloxazolidinones 19 with endo selectivity. In the first study 20 mol% of the Yb(OTf)2-pyridine-bisoxazoline complex 55 was applied as the catalyst for reactions of a number of derivatives of 1 and 19. The reactions led to endo-selective 1,3-dipolar cycloadditions giving products with enantioselectivities of up to 73% ee (Scheme 6.38) [82]. In the other report Kobayashi et al. described a... 

The mechanism of 1,3-dipolar cycloaddition can be found in Ref. 63 and the references within. The reaction of nitrone with 1,2-disubstituted alkenes creates three contiguous asymmetric centers, in which the geometric relationship of the substituents of alkenes is retained. The synthetic utility of nitrone adducts is mainly due to their conversion into various important compounds. For instance, P-amino alcohols can be obtained from isoxazolidines by reduction with H2-Pd or Raney Ni with retention of configuration at the chiral center (Eq. 8.44). 

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). 

Various kinds of chiral acyclic nitrones have been devised, and they have been used extensively in 1,3-dipolar cycloaddition reactions, which are documented in recent reviews.63 Typical chiral acyclic nitrones that have been used in asymmetric cycloadditions are illustrated in Scheme 8.15. Several recent applications of these chiral nitrones to organic synthesis are presented here. For example, the addition of the sodium enolate of methyl acetate to IV-benzyl nitrone derived from D-glyceraldehyde affords the 3-substituted isoxazolin-5-one with a high syn selectivity. Further elaboration leads to the preparation of the isoxazolidine nucleoside analog in enantiomerically pure form (Eq. 8.52).78... 

Enantioselective total synthesis of antifungal agent Sch-38516 is reported. Stereocontrolled carbohydrate synthesis is based on the 1,3-dipolar cycloaddition of chiral nitrone to vinylene carbonate, as shown in Eq. 8.53.79... 

Intramolecular cycloadditions of chiral nitrones provide a useful tool for the preparation of bioactive heterocyclic compounds.63 Shing et al. demonstrated that 1,3-dipolar cycloaddition of nitrones derived from 3-0-allyl-hexoses is dependent only on the relative configuration at C-2,3, as shown in Scheme 8.16. Thus 3-0-allyl-D-glucose and -D-altrose (both with threo-configuration at C-2,3) produce oxepanes selectively, whereas 3-O-allyl-D-allose and -D-man-nose (both with erythro-configuration at C-2,3) give tetrahydropyranes selectively.80... 

An optically active cyclic nitrone in 1,3-dipolar cycloaddition was first reported by Vasella in 1985. 81A variety of optically active cyclic nitrones have been devised since then. Some typical chiral nitrones described in Ref. 63c are shown in Scheme 8.17. Applications of these nitrones are also presented in this review. 

Asymmetric 1,3-dipolar cycloaddition of nitronates using chiral alkenes has been reported,... 

Scheme 60). 1,3-Dipolar cycloaddition reactions of nitrones with olefins are catalyzed by a chiral Ni11 or Pd11 catalyst.283,284... 

In a related area, a novel 1,3-dipolar cycloaddition strategy involving 1,2-isopropylidene furanoside-fused oxepane derivatives and 4-0-allyl nitrone or nitrile oxide species to give chiral oxepinopyran and oxepinooxepane systems has been described <00TL10135>. 

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... 

Dipolarophiles D4. 1,3-Dipolar cycloaddition between acrylonitrile (D4) and chiral nonracemic nitrones is a key step in an efficient synthetic route to isoxa-zolidinyl analogs of thiazofurin (540) (Scheme 2.253). Opposite diastereofacial induction was observed when the chiral group was placed at either the carbon or the nitrogen atom of the nitrone function (753). 

Dipolarophiles D5. Electron-deficient alkenes based on acrolein and its analogs are widely used as dipolarophiles. To carry out asymmetrical 1,3-dipolar cycloadditions between various nitrones and acrolein, the bis-titanium catalyst (543) (Fig. 2.37) was used as the chiral Lewis acid (Table 2.22) (754a). 

To carry out 1,3-dipolar cycloadditions with alkyl acrylates, nitrones of various structures such as ferrocenylnitrones (141), nitrones derived from chiral amino acids (210), L-serine-derived nitrones (660) and N -substituted C -phosphorylated nitrones (263) have been used. 

The 1,3-dipolar cycloaddition of nitrones to vinyl ethers is accelerated by Ti(IV) species. The efficiency of the catalyst depends on its complexation capacity. The use of Ti( PrO)2Cl2 favors the formation of trans cycloadducts, presumably, via an endo bidentate complex, in which the metal atom is simultaneously coordinated to the vinyl ether and to the cyclic nitrone or to the Z-isomer of the acyclic nitrones (800a). Highly diastereo- and enantioselective 1,3-dipolar cycloaddition reactions of nitrones with alkenes, catalyzed by chiral polybi-naphtyl Lewis acids, have been developed. Isoxazolidines with up to 99% ee were obtained. The chiral polymer ligand influences the stereoselectivity to the same extent as its monomeric version, but has the advantage of easy recovery and reuse (800b). 

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... 

Mukai et al.85 reported an asymmetric 1,3-dipolar cycloaddition of chromium(0)-complexed benzaldehyde derivatives. As shown in Scheme 5 52, heating chiral nitrone 171a, derived from Cr(CO)3-complexed benzaldehyde, with electron-rich olefins such as styrene (173a) or ethyl vinyl ether (173b) generates the corresponding chiral a.v-3,5-disubstitutcd isoxazolidine adduct 174 or... 

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. 

A diastereoselective dipolar cycloaddition of chiral nitrone 80 with alkene dipolarophiles afforded imidazo[ 1,2-3]-isoaxazole (Scheme 9). The conversion via N-O reduction of this ring system with Raney-Ni in methanol gave the corresponding pyrrolo[l,2-A imidazole in 66% yield. The structure has been confirmed by X-ray diffraction crystal stmcture analysis <2000SL967>. 

Finally, the catalytic enantioselective 1,3-dipolar cycloaddition reaction has recently been developed to be a highly selective reaction of nitrones with electron-deficient alkenes activated by chiral Lewis acids. High levels of regio-, diastereo-, and enantioselectivities can now be reached using catalysts 89 <2000JOC9080>, 90 <2002JA4968>, or 91 <2005JA13386> (Scheme 29). 

Abstract 1,3-Dipolar cycloaddition reactions (DCR) are atom-economic processes that permit the construction of heterocycles. Their enantioselective versions allow for the creation of up to four adjacent chiral centers in a concerted fashion. In particular, well-defined half-sandwich iridium (111) catalysts have been applied to the DCR between enals or methacrylonitrile with nitrones. Excellent yield and stereoselectivities have been achieved. Support for mechanistic proposals stems from the isolation and characterization of the tme catalysts. 

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