Diastereoselectivity chiral dipolarophiles

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... 

Although the first attempts at asymmetric azomethine ylide cycloadditions were reported by Padwa s group (92), the acyclic azomethine ylides chosen, bearing an a-chiral alkyl substituent on the nitrogen, showed poor diastereoselectivities (93,94). When the chiral center is fixed in a cyclic structure (95) or when chirality is introduced in an intramolecular cycloaddition system (96-98), high selectivities have been accomplished. There are only a few examples known of asymmetric cycloadditions of achiral azomethine ylides to chiral dipolarophiles where cyclic azomethine ylides (99,100) or cyclic chiral dipolarophiles (94) were used. 

Chiral dipolarophiles such as 43 <03TL1071> and 45 <03SL1358>, derived from carbohydrates, react with nitrile oxides to afford spiro- and bicyclic-isoxazolines 44 and 46, respectively, with high regio- and diastereoselectivity. 

Most of the efforts toward stereocontrolled syntheses of 2-isoxazolines have been based on reactions between chiral dipolarophiles and achiral dipoles. This approach is exemplified by some selected examples in Schemes 112-114 and Equation (80). Enantiopure dipolarophiles such as 485 <2003TL1071> and 487 <2003SL1358>, derived from carbohydrates, reacted with nitrile oxides to afford spiro- and bicyclic-isoxazolines 486 and 488, respectively, with high regio- and diastereoselectivity (Scheme 112). 

Whitney and coworkers [48] reported diastereoselective reactions between chiral nitrones and chiral dipolarophiles. The reaction of Vasella s nitrone 56 with the protected vinylglycine derivative 57 afforded isoxazolidines 58 with high diastereoselectivity (19 1) (Scheme 10.19). After removal of the glycosyl residue, the major isoxazolidine was converted into the antibiotic acivicin [48]. 

The asymmetric induction on the 1,3-dipolar cycloaddition reaction of carbonyl ylides has also been studied using chiral dipolarophile. The Rh2(OAc)4-catalyzed reactions of o-(methoxycarbonyl)diazoacetophenone 89 with enantiomerically pure vinyl sulfoxides 103 afforded 4,10-epoxybenzo-[4,5]cyclohepta[l,2-c]furan-3,9-dione 105, in good or moderate yield with complete regioselectivity [113]. The endo stereoisomer 105a is favored with respect to the exo isomer 105b and interestingly, high diastereoselectivity and complete enantioselectivity have been achieved (Scheme 32). 

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>. 

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>. 

In an analogous approach, the chiral stabilized azomethine ylide 165, generated in situ via Lewis acid-catalyzed condensation of (53 )-5-phenylmorpholin-2-one 164 with 2,2-dimethoxypropane, was trapped diastereoselectively with singly and doubly activated dipolarophiles such as the acrylate (Scheme 24). The cycloadduct 84 was then employed to furnish enantiomerically pure 5,5-dimethylproline derivatives (see Section 11.11.6.3), <2001SL1836>. 

The first diastereoselective synthesis of a tetrahydrothiophene derivative was reported by Karlsson and Hdgberg (32,95). The parent ylide la was added to a variety of C,C-dipolarophiles (79) bearing (—)-(15)-2,10-camphorsultam as the chiral auxiliary group to exclusively give trans-cycloadducts 80a,b with high diastereoselectivity [diastereomeric ratio (dr) 9 1], (Scheme 5.28). 

A new dipolarophile bearing a chirality-controlling heterocyclic auxiliary at the p-position is readily accessible from (5)-A -benzylvalinol and methyl ( )-4-oxo-2-propenoate. However, the dipolarophile is available only as an 86 14 equilibrium mixture of trans and cis stereoisomers (Scheme 11.20) (84). When this is used without separation in the reaction with the Al-hthiated azomethine ylide derived from methyl (benzylideneamino)acetate in THE at 78 °C for 3.5 h, a mixture of two diastereomeric cycloadducts (75 25) was obtained in 82% yield. These two cycloadducts are derived from the trans and cis isomers of acceptor, indicating that both cycloadditions were highly diastereoselective. 

Yamamoto and co-workers (135,135-137) recently reported a new method for stereocontrol in nitrile oxide cycloadditions. Metal ion-catalyzed diastereoselective asymmetric reactions using chiral electron-deficient dipolarophiles have remained unreported except for reactions using a-methylene-p-hydroxy esters, which were described in Section 11.2.2.6. Although synthetically very useful and, hence, attractive as an entry to the asymmetric synthesis of 2-isoxazohnes, the application of Lewis acid catalysis to nitrile oxide cycloadditions with 4-chiral 3-(2-aIkenoyl)-2-oxazolidinones has been unsuccessful, even when > 1 equiv of Lewis acids are employed. However, as shown in the Scheme 11.37, diastereoselectivities in favor of the ffc-cycloadducts are improved (diastereomer ratio = 96 4) when the reactions are performed in dichloromethane in the presence of 1 equiv of MgBr2 at higher than normal concentrations (0.25 vs 0.083 M) (140). The Lewis acid... 

Results of a similar study on the enantiospecific synthesis of a glycosidase inhibitor, using chiral (3-benzyloxy acrylamide, show that even electron-rich alkenes can serve as dipolarophiles. A large influence of the polarity of the solvent is observed the greater the polarity the greater is the diastereoselectivity. Thus, DMF and acetonitrile are found to be the best solvents. On the basis of these observations, the desired enantiomerically pure glycosidase inhibitor, (3R. 4R)-4-(hydroxymethyljpyrrolidin-3-ol, could be prepared in two steps in 87% overall yield.436... 

The reaction of 3,4-dihydroisoquinoline A-oxide (74) and methacrylonitrile in the presence of cationic half-sandwich rhodium and iridium complexes containing a chiral diphosphine ligand was analyzed. The cycloadditions occurred with excellent regio- and diastereoselectivity and low-to-moderate enantioselectivity. Analysis of the catalytic system showed the formation of two epimeric complexes 75 containing the dipolarophile methacrylonitrile. The reaction of one of the isolated diastereopure complexes 75 with 74 afforded cycloadduct 76 with high enantioselectivity. A recycling procedure was developed in order to increase the adduct/catalyst ratio <07CEJ9746>. 

Catalytic asymmetric 1,3-dipolar cycloaddition of a nitrone with a dipolarophile has been performed using a chiral scandium catalyst [31]. The chiral catalyst, which was effective in asymmetric Diels-Alder reactions, was readily prepared from Sc(OTf)3, (7 )-(-i-)-BINOL, and d5 -l,2,6-trimethylpiperidine. The reaction of benzylbenzylide-neamine A-oxide with 3-(2-butenoyl)-l,3-oxazolidin-2-one was performed in the presence of the chiral catalyst to yield the desired isoxazolidine in 69 % ee with perfect diastereoselectivity (endolexo = > 99 1) (Sch. 8) [31,46], It was found that reverse enantioselectivity was observed when a chiral Yb catalyst, prepared from Yb(OTf)3, the same (i )-(-i-)-BINOL, and cd-l,2,6-trimethylpiperidine, was used instead of the Sc catalyst under the same reaction conditions. 

Homochiral 4,5-dihydroimidazolium ylides 595 derived from chiral l-benzyl-4-phenyl-2-imidazoline 594, undergo diastereoselective endo 1,3-dipolar cycloaddition with a range of alkene dipolarophiles to form hexahydropyrrolo[l,2- t]-imidazoles 596. These reactions are best carried out in one pot by refluxing a mixture of 594, bromoacetate, and a dipolarophile in the presence of DBU (Scheme 142) <1996TL1707, 1998J(P1)2061>. Bicyclic adducts 596 are readily converted into enantiopure pyrrolidines in a two-step procedure <1996TL1711>. An intramolecular system (597 to 598) provided a rapid assembly of 2,3,4-trisubstituted pyrrolidines <1997TL1647>. 

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. 

Better diastereoselectivities were achieved with dipolarophiles such as unsaturated esters that bear a chiral auxiliary297-298. For instance, cycloaddition of the EVE-azomethine ylide, generated from the following imine by metalation, with the chiral alkene (27 )-2-(2-methoxycar-bonylethenyl)-3-phenyl-l,3-diazabicyclo[3.3.0]octane affords the pyrrolidine derivative as a single regio- and stereoisomer297. 

The oldest known type of diastereoselectivity is the addition to dipolarophiles that form chiral centers at the reacting atoms. In the context of Buchner s pioneering work on cycloaddition of diazoalkanes (see Sects. 1.1 and 6.2), Buchner investigated the reactions of methyl diazoacetate with ethyl (E)-3-phenylprop-2-enoate (ethyl cinnamate) and of ethyl diazoacetate with methyl ( )-3-phenylprop-2-enoate (Scheme 6-31) with his coworkers Dessauer (1893) and von der Heide (1902). They found two isomeric 4,5-dihydro-3//-pyrazoles 6.69 and 6.70 which, on dehydrogenation, gave the same prototropic mixture of ethyl methyl 4-phenylpyrazole-3,5-dicarboxylates (6-32). The ratio found was 80 20. Ihis surprising result was rationalized 78 years after Buchner s discovery ... 

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