Butenolid

The most difflcult pharmaceutically relevant oxidation of steroids is the introduction of a 14 -hydroxyl group. This functional group is found in heart-active steroids (cardenolides) such as digitoxigenin, which also contain a 17/J-butenolide substituent. The 14/ -hydroxyl group is easily cleaved off by dehydration and must therefore not be treated with Lewis or... 

Pd hydride. Subsequent enolate formation, double bond isomerization, and carbonylation give the butenolide 582. 

The reaction of vinyloxiranes with malonate proceeds regio- and stereose-lectively. The reaction has been utilized for the introduction of a 15-hydroxy group in a steroid related to oogoniol (265)(156]. The oxirane 264 is the J-form and the attack of Pd(0) takes place from the o-side by inversion. Then the nucleophile comes from the /i-side. Thus overall reaction is sT -StM2 type, in the intramolecular reaction, the stereochemical information is transmitted to the newly formed stereogenic center. Thus the formation of the six-membered ring lactone 267 from 266 proceeded with overall retention of the stereochemistry, and was employed to control the stereochemistry of C-15 in the prostaglandin 268[157]. The method has also been employed to create the butenolide... 

Triethylammonium formate is another reducing agent for q, /3-unsaturated carbonyl compounds. Pd on carbon is better catalyst than Pd-phosphine complex, and citral (49) is reduced to citronellal (50) smoothly[55]. However, the trisubstituted butenolide 60 is reduced to the saturated lactone with potassium formate using Pd(OAc)2. Triethylammonium formate is not effective. Enones are also reduced with potassium formate[56]. Sodium hypophosphite (61) is used for the reduction of double bonds catalyzed by Pd on charcoal[57]. 

Butenolide, 2-hydroxy — see Isotetronic acids Butenolide, 3-hydroxy — see Tetronic acids But-2-enolide, 4-alkylidene-synthesis, 4, 697 Butenolides H NMR, 4, 578 mass spectrometry, 4, 585 structure, 4, 551 synthesis, 1, 416 trimethylsilylation... 

Furanones, previously named butenolides, are classified into three main types the 2(3//)-1, 2(5//)- 2, and the 3(2//)-furanones 3 (76CRV625). 

THF/liq. NH3, followed sequentially by oxidation and base-induced double bond isomerization, provides butenolide 33, a compound that possesses the lactone system of the steroidal cardiac aglycones. 

The diastereomeric lactones could be separated by chromatography and converted into optically active lactones by desulfurization with sodium amalgam or by pyrolysis to the corresponding butenolides. 

About 75 ml. of ethanol is used for every gram of butenolide to be dissolved. Clarification of the solution with charcoal should be avoided because the butenolide tends to separate from solution during filtration and clogs the steam-jacketed funnel. The crystallized butenolide melts at 150-152°. 

The method described above may be used for the preparation of a wide variety of butenolides substituted in the arylidene ring with either electron-withdrawing or electron-releasing substituents. y-Lactones such as a-benzylidene-7-phenyl-A 1 -bu-tenolide are isoelectronic with azlactones, but have received much less attention. Like the azlactone ring, the butenolide ring may be opened readily by water, alcohols, or amines to form keto acids, keto esters, or keto amides.7 a,-Benzylidene-7-phenyl-A3,1 -butenolide is smoothly isomerized by aluminum chloride to 4-phenyl-2-naphthoic acid in 65-75% yield via intramolecular alkylation. 

Butenolides from aryl aldehydes and 7-keto acids, 43, 5... 

Feringa-butenolide 114, in the presence of Dess-Martin periodinane reagent and 2,6-lutidine, gave the bis-ketone 115 which underwent intramolecular cycloaddition to afford endo-selectively the desired decalin-based lactone 116 (Equation 2.32) [114]. Double activation of butenolidic double bond strongly increases the reactivity of dienophile 115. 

Ogasawara and coworkers reported a concise route to (—)-kainic acid (Figure 6.51), an excitatory neurotransmitter of marine origin, via a lipase-mediated kinetic resolution of an N-Cbz aminocyclopentenol [139]. More recently, (—)-kainic acid was synthesized from an optically active butenolide prepared by enzymatic DKR [140]. 

Aldehyde (8) was needed for a butenolide synthesis. How would (8) be made ... 

C-(Trifluoromethyl)-gulo- (570) and -talo-furanosides 571 were pre-pared from 3-trifluoromethyl-A -butenolide (569) through a sequence of reactions. 

In some of the etherification reactions, the butenolide dimer XVIII was observed as a byproduct in yields up to 40%. The dimer... 

In preparation for scale-up of the strigol synthesis described by Sih (8), efforts were made to improve the yield of some of the seven steps involved in the scheme. Of these steps, nine are satisfactory from the standpoint of yield and experimental conditions. For three of the steps, we have improved the yield and/or experimental conditions such that the yield of (+ )-strigol would be raised to 2.85% overall from citral rather than 1.53% based on Sih s procedure and reported yields. Improvements were developed preparation of a-cyclocitral (III), the oxidation of the hydroxyaldehyde (V) to the ketoacid (VII), and for the preparation of the hydroxybutenolide (XVII). For the remaining five steps, our attempts to change experimental conditions have failed to improve, and in most cases to even obtain, the yields reported in the literature (8). We have considered the preparation of strigol analogs and determined the conditions and limitations for the preparation of a series of alkoxybutenolides (XVI) and a butenolide dimer (XVIII). Modification of the literature procedure (11) to eliminate the use of the mesylate (XX) and the use of polar aprotic solvents gave better yields of the 2-RAS (XXI). 

Hydroxymethylene formation proceeded in the standard fashion (7 ) to give a 93% yield of 22. Carcinogenic hexamethyl-phosphoric triamide was replaced by N-methylpyrrolidone as the solvent for the condensation reaction of 22 with the bromo-butenolide 23 in the presence of excess K.CO. and gave a mixture of racemic strigol (1) (35%) and 4 -epistrigol (25) (39%), which were readily separated by chromatography on silica gel. 

The A-D-ring analog 30a,b (mixture of epimers) has been prepared from the epoxide 3a,b by base catalyzed epoxide cleavage, hydroxymethylenation, and O-alkylation of the butenolide unit using standard conditions. Hydroxymethylenation of keto-ester 7 followed by butenolide addition provided the A-D-ring analog 31. 

Decarboxylation of 16 using the previously described NMP, lithium chloride method provided the dione 32. Selective reduction of the least hindered carbonyl was readily effected using sodium borohydride providing 33. Hydroxymethylenation followed by O-alkylation of the butenolide unit by standard procedures provided the A-B-D-ring analog 34a,b (racemic mixture of epimers). 

The final ring coupling reaction is usually an O-alkylation of the sodium enolate with a methyl sulfonate-, bromo-, or chloro-butenolide in acetonitrile or an ether solvent (8.22-24). Use of the methyl sulfonate derivative is least preferred because of its poor stability (9,24). The isolated hydroxymethylene lactone can be allowed to react with the bromobutenolide using potassium carbonate in hexamethylphosphoric triamide (caution a potential carcinogen). 

In the synthesis of butenolides substituted in a position adjacent to the carbonyl, the bis(dimethylamino)phosphinyloxy group has been employed for the direction of an incoming electrophile (Scheme 8). ... 

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