Crotonate compounds synthesis

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). 

A synthesis of this compound was devised by Ohmizu, Iwasaki and co-workers and featured a three-component tandem conjugate addition/enolate trapping as key step (Scheme 12.24) [82]. In this synthesis, the acyl anion equivalent cyanohydrin 165 was first treated with LDA and allowed to react with methyl crotonate 166. The resulting enolate was trapped with 2,3,5-trimethoxy benzylbromide 168 to afford crude intermediate 169, which was immediately deprotected in situ to afford ketone product 170. Both the ester and the ketone functionalities were then reduced at low temperature to afford the corresponding diol 171. Upon treatment with trifluoroacetic acid, the desired Friedel-Craft cyclization adduct 172 was obtained. The latter tricyclic compound was then further elaborated to the final target 164 through a short sequence of standard transformations. 

Amino-3-cyanopyrroles (326) are versatile starting materials for the easy synthesis of 4-amino-7//-pyrrolo[2,3-d]pyrimidines (327) by treatment with triethyl orthoformate and ammonia.183,184 The l,2-diamino-3-cyanopyrrole 328 affords with diacetyl in acetic acid a pyrrolo [ 1,2-6]-as-triazine (329)184 (Scheme 93). Malonodinitrile, sulfur, and bases afford the diaminodicyano-thiophenes 330 and 331.166 Compound 331 yields, with 2 equivalents of formamide, 4,9-diaminothieno[2,3-d 4,5-d ]dipyrimidines (332)185 (Scheme 94). Furthermore, 2-amino-3-cyanothiophenes (333) react with ethyl amino-crotonate. Cyclization of the intermediate 334 with sodium ethoxide gives... 

The gross structures of the three compounds were confirmed as correctly represented by CVI, CVII, and CVIII by the unequivocal synthesis of ( )-pseudoheliotridane by Leonard and Felley (151, 152). The synthesis involved three steps (a) the Michael addition of nitro-methane to ethyl crotonate or diethyl ethylidenemalonate (CIX) ... 

Direct reaction of 191 with acrylic acid resulted in efficient formation of 192 (eq. 41).66 Subsequent dehydrogenation at elevated temperatures provided the aromatic species 193, which was a key intermediate in the synthesis of 194, a compound that displays strong p-blocking activity. Under similar conditions, reaction of 191 with crotonic acid, cinnamic acid, and ethyl acrylate did not generate the corresponding bicyclic alkaloid skeletons. 

In addition, bio-based green solvents can be generated from PHAs after their utilization via pyrolysis. This way, unsaturated compounds such as crotonic acid and 2-pentenoic acid needed for synthesis of lactones are generated. 

In an early application, the aqueous Diels-Alder reaction of diene carboxy-lates was used to effect a very concise synthesis of the vemolepin precursor 5.2 [60]. This compound had previously been prepared by Schlessinger via another route in 11 steps from ethyl crotonate [61]. Reaction of the substituted methacrolein 5.3 with sodium ( )-3,5-hexadienoate (5.4) in water proceeded at 50 C to give the Diels-Alder endo adduct 5.5 along with a minor amount of the exo adduct (not shown) quantitatively in a ratio of 10/1 (Scheme 1.4). Sodium borohydride was added directly to this reaction mixture to produce the 6-hydroxycarboxylate 5.6, which lactonized spontaneously upon acidic workup. This one-pot operation resulted in the isolation of vemolepin AB-ring... 

Compound 20 is a 1,5-difunctional compound. Therefore one can design a synthesis that proceeds via intermediates that only contain odd difimctional relationships. Propose such a synthesis and indicate potential problems with your approach. If you can t get started, have a look at the following reference Ballester, P Costa, A. Raso, A. G. Gomez-Solivellas, A. Mestres, R. Dienediolates from Unsaturated Carboxylic Acids. Michael Addition of Dilithium 1,3-Butadiene-1,1-diolate (from Crotonic Acid) to Unsaturated Ketones J. Chem. Soc., Perkin 1 Organic and Bio-Oi anic Chemistry 1988, 1711-1717. (Unnatural Products-2)... 

One should keep in mind that further functionalization can also be built-in function on the substrate itself. Thus, for instance, acetals upon acidic hydrolysis allow an intramolecular aldolization-crotonization. This transformation produces chiral bicyclic a,p-unsaturated compoimds. These compounds are important intermediates for the synthesis of sesquiterpene derivatives. For instance, this procedure has been recently used in the alternative synthesis of axane derivatives [87] isolated from the marine sponge Axinella cannabia (Scheme 22) [33]. 

The methods of cyclization with the participation of nonaromatic carbonyl and dicarbonyl compounds that are widely used in total steroid synthesis are not very diverse they comprise only the intramolecular alkylation of ketones and crotonic condensation. 

A preliminary communication of the first synthesis by Wettstein s group (Scheme 66) was published in 1955 [131]. By this method, the atom is first introduced by etho grcarbonylation and then the C20, and C21 atoms by alkylation with methallyl iodide, and, finally, the Cg and Cxg atoms with ethoxyethnylmagnesium bromide. Ring D is formed by the intramolecular crotonic condensation of the 16,20-dicarbonyl compounds. 

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