Crotonates synthesis

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). 

NENITZESCU Indole Synthesis Indole synthesis trom quinones and amino crotonates... 

The synthesis of key intermediate 12, in optically active form, commences with the resolution of racemic trans-2,3-epoxybutyric acid (27), a substance readily obtained by epoxidation of crotonic acid (26) (see Scheme 5). Treatment of racemic 27 with enantio-merically pure (S)-(-)-1 -a-napthylethylamine affords a 1 1 mixture of diastereomeric ammonium salts which can be resolved by recrystallization from absolute ethanol. Acidification of the resolved diastereomeric ammonium salts with methanesulfonic acid and extraction furnishes both epoxy acid enantiomers in eantiomerically pure form. Because the optical rotation and absolute configuration of one of the antipodes was known, the identity of enantiomerically pure epoxy acid, (+)-27, with the absolute configuration required for a synthesis of erythronolide B, could be confirmed. Sequential treatment of (+)-27 with ethyl chloroformate, excess sodium boro-hydride, and 2-methoxypropene with a trace of phosphorous oxychloride affords protected intermediate 28 in an overall yield of 76%. The action of ethyl chloroformate on carboxylic acid (+)-27 affords a mixed carbonic anhydride which is subsequently reduced by sodium borohydride to a primary alcohol. Protection of the primary hydroxyl group in the form of a mixed ketal is achieved easily with 2-methoxypropene and a catalytic amount of phosphorous oxychloride. 

The reaction of /V-mcthyl mtropyrimidinone 76 with aminocrotonates has been used for the synthesis of 4-aminonicotinates. The only example using a dialkylamino crotonate gave a similar yield, but the equivalent reactions using aminoenones and 4-substituted aminocrotonates gave only very modest yields <06SL1437>. 

The double bond of certain a,p-unsaturated esters (e.g. crotonates, methacrylates) is so reactive that it tends to add the elements of the alcohol present as solvent the resulting p-alkoxy-substituted guanamines (LXXXV) (79) are therefore readily and cheaply produced, and the use of expensive p-alkoxycarboxylic esters required in the conventional synthesis (706) is avoided. Crotonic esters give the alkoxyguanamine... 

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... 

The second major class of enamines contains the enamino ketones, made from ammonia or an amine and a 1,3-diketone. By this route the same 1,3-diketone can provide both halves of the resulting pyridine such an example is provided by the synthesis of 5-benzoyl-2-phenylpyridine (444) (54YZ259). As in the case of the crotonates, the first examples of the condensation of an enamino ketone with an a,/ -unsaturated ketone were provided by Knoevenagel and Ruschhaupt (1898CB1025), who prepared the range of 3-acetyldihy-dropyridines (445) to (447). Similarly, Mumm and Bohme obtained the 3-acetyl- and 3-benzoyl-2,6-dimethylpyridines (448) and (449) from ethyl acetylpyruvate (21CB726). 

DL-Threonic acid (10) seemed to be a promising source of DL-threose. Therefore, other routes to 10 were elaborated. By a procedure consisting of five steps" 2-propenal (acrolein) — vinylglycoloni-trile — ethyl vinylglycolate — ethyl 4-bromocrotonate — 3-hydroxy-crotonic acid — 10, DL-threonic acid was obtained in an overall yield of 4.1%. Another synthesis of 10 was achieved17 in six steps starting... 

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). 

The synthesis of type III branched-chain sugars is based mainly on the use of ketosugars treated under Wittig-type conditions (see path a, Scheme 4) [13]. Several other methods, such as aldolization-crotonization or direct alkylidenation at the a-position of the carbonyl group of a keto sugar have been developed (path b). 

A double ir-face selective aptotic Michael addition of the lithium dienolate, derived from the chiral senecioate (119), to cyclopentenone served for the total synthesis of (-)-kushimone (120 Scheme 45).137-138 The selectivity of the key reaction was rationalized by the assumption of a transition state as shown in (121a). A related approach involves the Michael addition of enolates, derived from chiral propionates, to methyl ( )-crotonate (Scheme 46).139 The formation of the threo isomer (122) as the major product indicates a transition state structure as shown in (121b). This method was utilized in the synthesis of the marine natural product 7,20-diisocyanoadociane (123 Scheme 47).140... 

While sluggish under thermal conditions,274-275 the asymmetric conjugate addition of amines to alkyl crotonates is achieved at room temperature under high pressure (15 kbar).276 Thus, benzylamine can be added to the crotonate derived from 8-p-naphthyl menthol, with virtually complete diastereoselectivity. A related intramolecular 1,4-addition of an amine to a chiral enoate was used in a total synthesis of the alkaloid (-)-tylophorine.277 Additions of amines to chiral iron complexes of type (116) proceed with excellent selectivity and allow the preparation of homochiral p-lactams.l27128,l3() l32 In contrast, the addition of amine nucleophiles to chiral vinylic sulfoxides278-2811 and to chiral vinylsulfoximines281 proceeds with comparably low selectivities. 

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