Chiral nitrones, cycloaddition

Induced Diastereoselection in Nitrone Cycloadditions Chiral Nitrones... 

H. Martin, Verbesserung der Totalsynthese von Thienamy-cin durch diastereoselektive 1,3-dipolare Cycloaddition chiraler Nitrone, Doctoral Thesis, Technical University of Munich, 1987. 

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). 

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... 

Kibayashi and coworkers have used enantiometrically pure allylic silyl ethers obtained from amino acids in cycloaddition with nitrones (Eq. 8.49).71 Cyclic nitrone reacts with a chiral allyl ether to give selectively the exo and erythro isomer (de 90%). Optically active alkaloids containing a piperidine ring such as (+)-monomorine,71c (+)-coniine,71a and (-)-oncinotine71b have been prepared from the addition product. 

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,... 

Nitrone 1,3-DC reactions are still the most general approach to isoxazolidines. The stereocontrol is usually achieved by the use of chiral nitrones and/or dipolarophiles, but new interesting achievements on Lewis acid catalyzed cycloadditions are also frequently reported. Tris(6,6,7,7,8,8,8-heptafluoro-2,2-dimethyl-3,5-octanatedionate) europium(III) [Eu(fod)3] selectively activated the Z-isomer of C-alkoxycarbonyl nitrone 75 existing as an E,Z-equilibrium mixture by forming the (Z)-75-Eu(fod)3 complex. (Z)-75-Eu(fod)3 reacted with electron-rich dipolarophiles such as vinyl ethers to give the trans-adducts with excellent diastereoselectivity <06T12227>. 

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... 

Cycloaddition of nitrone (26) to allylamine (538) leads to the synthesis of chiral tetracyclic isoxazolidine (539) which is used in the preparation of compound R107500. This compound has been found to be active as an antiolytic and antidepressant. It also has the potential to inhibit drug abuse (Scheme 2.252) (80). 

Chiral nitrones derived from L-valine (62a-c) react with methyl acrylate to afford the corresponding diastereomeric 3,5-disubstituted isoxazolidines (565a-c) to (568a-c). The dibenzyl substituted nitrone (62a) also gave 3,4-disubstituted isoxazolidine (569) in 4% yield. The stereoselectivity was dependent on the steric hindrance of the nitrone and on reaction conditions. High pressure decreased the reaction time of the cycloadditions. The major products were found to have the C-3/C-6 erythro and C-3/C-5 Irons configuration (Scheme 2.262) (771). 

For example, cycloaddition of nitrone (643, R1 =Ph, R2 = Me) to DIO, catalyzed by chiral phosphine-palladium complexes (Fig. 2.42), gave isoxazolidines (644) in high yield with high enantioselectivity (794). 

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... 

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>. 

Over the last years, one of the most studied DCR has been the asymmetric version of the cycloaddition of nitrones with alkenes. This reaction leads to the construction of up to three contiguous asymmetric carbon centers (Scheme 4). The resulting five-membered isoxazolidine derivatives may be converted into amino alcohols, alkaloids, or p-lactams. Several chiral metal complexes have been used as catalysts for this process [13-15, 18-22]. However, the employment of iridium derivatives is very scarce. 

The above-mentioned complexes are the sole iridium derivatives applied to DCR, and the cycloaddition of nitrones to enals or methacrylonitrile, the unique process studied. We think that iridium-based catalysts are underrepresented in 1,3-dipolar cycloaddition chemistry. For example, no iridium (1) systems have been developed to this end. It can be anticipated that the (bidentate ligand)lr(l) fragment could be active (and stereoselective if chiral bidentate ligands are used) in DCR such as those involving azomethine ylides. 

Chiacchio et al. (43,44) investigated the synthesis of isoxazolidinylthymines by the use of various C-functionalized chiral nitrones in order to enforce enantioselec-tion in their cycloaddition reactions with vinyl acetate (Scheme 1.3). They found, as in the work of Merino et al. (40), that asymmetric induction is at best partial with dipoles whose chiral auxiliary does not maintain a fixed geometry and so cannot completely direct the addition to the nitrone. After poor results with menthol ester-and methyl lactate-based nitrones, they were able to prepare and separate isoxazo-lidine 8a and its diastereomer 8b in near quantitative yield using the A-glycosyl... 

The continued importance of 3-lactam ring systems in medicine has encouraged a number of research groups to investigate their synthesis via a nitrone cycloaddition protocol. Kametani et al. (60-62) reported the preparation of advanced intermediates of penems and carbapenems including (+)-thienamycin (29) and its enantiomer (Scheme 1.7). They prepared the chiral nitrone 30 from (—)-menthyl... 

This chapter is divided into four major sections. The first (Section 2.1) will deal with the structure of both alkoxy and silyl nitronates. Specifically, this section will include physical, structural, and spectroscopic properties of nitronates. The next section (Section 2.2) describes the mechanistic aspects of the dipolar cycloaddition including both experimental and theoretical investigations. Also discussed in this section are the regio- and stereochemical features of the process. Finally, the remaining sections will cover the preparation, reaction, and subsequent functionalization of silyl nitronates (Section 2.3) and alkyl nitronates (Section 2.4), respectively. This will include discussion of facial selectivity in the case of chiral nitronates and the application of this process to combinatorial and natural product synthesis. 

The number of investigations on the enantioselective dipolar cycloaddition of nitronates is still rather limited. In the case of simple alkyl nitronates, the facial selectivity is controlled solely by the steric environment about the two faces of the chiral unit. For example, the reaction of steroid dipolarophile 270 proceeds with the nitronate approaching the Re face of the alkene (Eq. 2.23) (234). The facial selectivity is controlled by the C(19) methyl group, which blocks the Si face of the dipolarophile. Similarly, exposure of 279 to ethyl acrylate at 40 °C for 24 h, provides a single nitroso acetal (Scheme 2.21) (242). The facial selectivity is presumed to arise from steric shielding by the menthol group, however the full stereostructure has not been established. 

The majority of asymmetric dipolar cycloadditions have been investigated in the context of the tandem [4 + 2]/[3 + 2]-nitroalkene cycloaddition. The chiral nitronate is prepared by using either a chiral nitroalkene, vinyl ether, or Lewis acid in the hrst cycloaddition. The acetal center at C(6) of the nitronate provides important steric and electronic effects that control the subsequent dipolar cycloaddition. Subsequently, in the cycloadditions of the chiral nitroalkenes 281 and 284, the dipolarophile approaches from the side distal to that of the substituent at C(4) and the acetal center at C(6) (Eq. 2.27 and Table 2.53) (90,215). 

The dipolar cycloaddition of nitronates has been applied to the synthesis of several natural products in the context of the tandem [4+2] / [3 + 2] nitroalkene cycloaddition process. All of these syntheses have focused on the construction of pyrrolidine, pyrrolizidine, and indolizidine alkaloids. For example, the synthesis of ( )-hastanecine (316), a necine alkaloid, involves the elaboration of a p-benzoy-loxynitroalkene 311 via [4 + 2] cycloaddition with a chiral vinyl ether (312) in the presence of a titanium based Lewis acid, to provide the nitronate 313 with high diastereo- and facial selectivity (Scheme 2.30) (69). The dipolar cycloaddition of... 

The tandem transesterification/[3 + 2]-cycloaddition methodology is be a powerful synthetic tool, since it guarantees high diastereoselectivity even under thermal conditions. It has been successfully apphed to synthetic work of the N-terminal amino acid component of Nikkomycin Bz (Scheme 11.53) (173). Thus, the sugar-based oxime is condensed with a glyoxylate hemiacetal to produce a chiral nitrone ester, which is then reacted with ( )-p-niethoxycinnamyl alcohol in the presence of a catalytic amount of TiCU at 100 °C. After the intramolecular cycloaddition, the... 

Achiral ester-substituted nitrones as well as chiral nitrones can be employed in diastereoselective asymmetric versions of tandem transesterification/[3 + 21-cycloaddition reactions, as shown in Scheme 11.54 (174). High diastereoselectivity and excellent chemical yields have been observed in the reaction with a (Z)-allylic alcohol having a chiral center at the a-position in the presence of a catalytic amount of TiCl4- On the other hand, the reaction with an ( )-allylic alcohol having a chiral center at the a-position, under similar conditions, affords very low selectivities. Tamura et al. has solved this problem with a double chiral induction method. Thus, high diastereoselectivity has been attained by use of a chiral nitrone. 

Saito et al. (32) developed a tartaric acid derived chiral nitrone 18. In the reaction of 18 with methyl crotonate 19, the 1,3-dipolar cycloaddition product 20 was obtained in an endo/exo ratio of 10 1 and with high diastereofacial induction to give the endo-isomer (Scheme 12.9). 

The power of cyclic chiral nitrones in synthesis was demonstrated by Nagasawa et al. (52) by the synthesis of the enantiomerically pure pentacyclic guanidine derivative 38 (Scheme 12.14). The 1,3-dipolar cycloaddition of 27b with 34 took... 

Another type of chiral alkene applied in 1,3-dipolar cycloadditions are vinyl groups attached to chiral phosphine oxides or sulfoxides. Brandi et al. (150,151) used chiral vinyl phosphine oxide derivatives as alkenes in 1,3-dipolar cycloadditions with chiral nitrones. This group also studied reactions of achiral nitrones with chiral vinyl phosphine oxide derivatives. Using this type of substrate, fair endo/exo-selectivities were obtained. In reactions involving optically pure vinyl phosphine oxides, diastereofacial selectivities of up to 42% de were obtained. Chiral vinyl... 

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. 

Cyclic alkyl nitronates may be used in tandem [4+2]/[3+2] cycloadditions of nitroalkanes, and this reaction has been extensively studied by Denmark et al. (64,333-335). In recent work, they developed the silicon-tethered heterodiene-alkene 219 (Scheme 12.63). Steric hindrance and the fact that both the nitroalkene and the a,p-unsaturated ester in 219 are electron deficient renders the possibility of self-condensation. Instead, 219 reacts with the electron-rich chiral vinyl ether 220 in the presence of the catalyst 224 to form the intermediate chiral nitronate 221. The tandem reaction proceeds from 221 with an intramolecular 1,3-dipolar cycloaddition to form 222 with 93% de. Further synthetic steps led to the formation of ( )-detoxinine 223 (333). A similar type of tandem reaction has also been applied by Chattopadhyaya and co-workers (336), using 2, 3 -dideoxy-3 -nitro-2, 3 -didehydrothymidine as the starting material (336). 

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