Cycloaddition crotonate

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). 

An ANRORC mechanism has also been proposed (besides an inverse cycloaddition reaction) in the conversion of 1-methylpyrimidinium iodide into 3-ethoxycarbonyl-2-methylpyridine on treatment with ethyl -amino-crotonate (95RCB1272) (Scheme 23a). The reaction starts by addition of the -carbon of the crotonate at the electron-deficient 4-position of the... 

Cycloaddition reactions of (E)-l-acetoxybutadiene (18a) and (E)-l-methoxy-butadiene (18b) with the acrylic and crotonic dienophiles 19 were studied under high pressure conditions [9] (Table 5.1). Whereas the reactions of 18a with acrylic dienophiles regioselectively and stereoselectively afforded only ortho-enJo-adducts 20 in fair to good yields, those with crotonic dienophiles did not work. Similar results were obtained in the reactions with diene 18b. The loss of reactivity of the crotonic dienophiles has been ascribed to the combination of steric and electronic effects due to the methyl group at the )S-carbon of the olefinic double bond. 

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). 

Hawkins and Loren225 reported simple chiral arylalkyldichloroborane catalysts 352 which were effectively used in the cycloadditions of acrylates lib and 350 to cyclopen-tadiene, affording adducts 351a and 351b, respectively (equation 99). A crystal structure of the molecular complex between methyl crotonate and the catalyst allowed the authors to rationalize the outcome of the reaction. One face of methyl crotonate is blocked by tt-tt donor-acceptor interactions, as becomes clear from the structure of complex 353. The cycloadduct of methyl acrylate and cyclopentadiene (5 equivalents) was obtained with 97% ee, using the same catalyst. Three years later, the authors reported that the cycloadduct was obtained with 99.5% ee in the presence of 10 equivalents of cyclopentadiene226. 

But there are many cases known where the (4+2) cycloaddition fails even with siloxy-activated dienes, e.g., methyl (E)-crotonate does not react with diene 1 at normal pressure and elevated temperature llO C), whereas the aprotic double Michael addition does give the desired bicyclo[2.2.2]octane in high yield. This reaction gives mainly (92%) bicyclic esters with the endo configuration. 

Weinreb and co-workers (16) reported a high-pressure-induced 1,3-dipolar cycloaddition of alkyl and phenyl azides with electron-deficient alkenes at ambient temperature. As a representative example, phenyl azide underwent cycloaddition with methyl crotonate (69) at 12 kbar to give the triazoline 70 (43%) and the p-amino diazoester 71 (53%). The high-pressure conditions resulted in high yield and a shorter reaction time (Scheme 9.16). 

Among the most commonly applied chiral moiety for nitrones (2) is the N-a-methylbenzyl substituent (Scheme 12.6) (18-25). The nitrones 8 with this substituent are available from 1 -phenethylamine, and the substituent has the advantage that it can be removed from the resulting isoxazolidine products 9 by hydrogeno-lysis. This type of 1,3-dipole has been applied in numerous 1,3-dipolar cycloadditions with alkenes such as styrenes (21,23), allyl alcohol (24), vinyl acetate (20), crotonates (22,25), and in a recent report with ketene acetals (26) for the synthesis of natural products. Reviewing these reactions shows that the a-methylbenzyl group... 

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). 

Other nitrones (21-23) having the chiral moiety located at the carbon atom have been applied in reactions with various alkenes (Scheme 12.10) (33-35). Nitrone 21 offered poor discrimination in 1,3-dipolar cycloadditions with benzyl crotonate, as all four diastereomers were obtained in both reactions (33). The fluorinated nitrone... 

The formal total synthesis of the novel /3-lactam antibiotic thienamycin has been accomplished from an isoxazoline derivative generated by [3 + 2] dipolar cycloaddition <79H(l2)l 183). Reaction of the nitrile oxide derived from 3-nitropropanal dimethyl acetal with methyl crotonate gave the isoxazoline (477) regio- and stereo-selectively. The isoxazoline was converted to amino ester (478) by hydrogenation and then to /3-lactam (479) by ester saponification and ring closure with DCC. Treatment of (479) with p-nitrobenzyl chloroformate and reaction of the derived acetal (480) with excess N-p-nitrobenzyloxycar-bonylcysteamine gave thioacetal (481), a compound which has previously been converted into ( )-(8S )-thienamycin (Scheme 106). 

Another possible route to thienamycin (487) has utilized the dipolar cycloaddition of 1-pyrroline 1-oxide (482) with methyl crotonate (79TL4359). The reaction is highly stereoselective due to the operation of secondary orbital effects. The isoxazolidine (483), produced in 90% yield, was subjected to hydrogenolysis, and the resulting amino alcohol (484) was selectively blocked with hexamethyldisilazane to give (485). Treatment with ethylmagnesium bromide then gave /3-lactam (486 Scheme 107). 

Chiral crotonates derived from S-citroncllol, l-(—)-menthol, and S-solketol undergo 1,3-dipolar cycloaddition with cyclic and acyclic nitrones.66 Asymmetric 1,3-dipolar cycloaddition of optically active hifluoromethylated a, /l-unsaturated aiyl sulfones (43) with nitrones yield the corresponding isoxazolidmes (44) and (45) with high regio- and... 

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