Enol lactonization

In the presence of a double bond at a suitable position, the CO insertion is followed by alkene insertion. In the intramolecular reaction of 552, different products, 553 and 554, are obtained by the use of diflerent catalytic spe-cies[408,409]. Pd(dba)2 in the absence of Ph,P affords 554. PdCl2(Ph3P)3 affords the spiro p-keto ester 553. The carbonylation of o-methallylbenzyl chloride (555) produced the benzoannulated enol lactone 556 by CO, alkene. and CO insertions. In addition, the cyclobutanone derivative 558 was obtained as a byproduct via the cycloaddition of the ketene intermediate 557[4I0]. Another type of intramolecular enone formation is used for the formation of the heterocyclic compounds 559[4l I]. The carbonylation of the I-iodo-1,4-diene 560 produces the cyclopentenone 561 by CO. alkene. and CO insertions[409,4l2]. 

The unsaturated c.vo-enol lactone 17 is obtained by the coupling of propargylic acetate with 4-pentynoic acid in the presence of KBr using tri(2-furyl)-phosphine (TFP) as a ligand. The reaction is explained by the oxypalladation of the triple bond of 4-pentynoic acid with the ailenyipailadium and the carbox-ylate as shown by 16, followed by reductive elimination to afford the lactone 17. The ( -alkene bond is formed because the oxypalladation is tnins addition[8]. 

The enol lactone (12.7 g) is added to 157 ml of 0.5 M perbenzoic acid in benzene and allowed to stand at 25° for 140 hr. The solution is cooled to 15° and 15% sodium bisulfite solution is added to neutralize the excess peracid. The organic layer is separated and washed with saturated sodium bicarbonate solution and water. The benzene solution is dried over anhydrous sodium sulfate, filtered and concentrated to 30 ml. The product is crystallized by adding 80 ml of petroleum ether, filtered and washed with petroleum ether to yield 12.8 g (98%) of 3a,20,23-trihydroxy-16a-methyl-17(20)-oxido-ll-oxo-21-norchol-22-enoic acid-24(20)-lactone 3,23-diacetate mp 225-227°. 

Photochemical rearrangements of enol esters, enol lactones, and enol ethers... 

Photochemical oxacarbene formation, 307 Photochemical rearrangements of cross-conjugated cyclohexadienones, 330 Photochemical rearrangements of enol esters and enol lactones, 339... 

It has been reported that concentrated H2SO4 (98%) promotes conversion of 3,5-dibromolevulinic acid 47 into 4-bromo-5-(bromomethylene)-2(5// )-furanones 48 (R = Br R = H) along with minor products, while similar treatment using 20% oleum gives the isomeric 5-(dibromomethylene)-2(5// )-furanone 49 (R = H R = Br) as the major product (63AJC165). Spectroscopic data and chemical structures were not provided for the minor substances, but the formation of the major product was explained on the basis of the enol-lactonization process followed by oxidation (63AJC165). 

Dimethyldioxirane DMDO discovered by Murray and coworkers, is a superior choice for the epoxidation of most olefins, giving comparable or higher yields than m-CPBA-based epoxidation [21]. Proceeding rapidly under neutral and mild conditions, it is especially well suited for the synthesis of sensitive epoxides of enol esters, enol lactones [22], and enol ethers [23]. The reaction is stereospecific, gen-... 

Auch Natriumboranatgreift bei 2H-Pyronendie Ather-Bindungan (s. S. 445), wahrend 6-Trichlormethyl-2H-pyrone zu Diolen reduziert werden5. Bei der Reduktion polycycli-scher d-Enol-lactone mit komplexen Methallhydriden tritt oft Umlagerung ein6. 

Enol-lactone der 2H-Pyron-Reihe werden unter Hydrogenolyse der Enol-Bindung zu ungesattigten Carbonsauren reduziert. So erhalt man z. B. aus 4,6-Dimethyl-2H-pyron mit Lithiumalanat in 47%iger Ausbeute 3 -Melhyl-hexadien- (2,4) -satire11 ... 

Base-catalyzed condensation between phenylacetic acid and phthalic acid produces enol lactone 78, which is reduced to benzoate 79 with HI and phosphorous. Friedel-Crafts cyclization by polyphosphoric acid followed by reduction produces alcohol 80. This alcohol forms ethers exceedingly easily, probably via the carbonium ion. Treatment with N-methyl-4— piperidinol in the presence 6f acid leads to the antidepressant hepzidine (81). 

This arrangement of subgroups is due to the hypothetical biosynthetic sequence. It assumes that precursors for these alkaloids are the Af-methylphth-alideisoquinolinium salts, whose presence in plants is well documented. Enol lactones may be the initial degradation products formed in a Hofmann-type jft-elimination process. They could be hydrated to the keto acids and in the next step oxidated in air to the diketo acids. Diketo adds may undergo further oxidative cleavage to yield simple alkaloids of the fumariflorine (87) type 85,86), which seem to be the final products of the metabolism of phthalideiso-quinoline alkaloids. 

In Table VI secophthalideisoquinoline alkaloids and their precursors are presented. They form four series of seco bases from enol lactones to diketo adds ending with ene lactams, which in all probability are not true alkaloids but products arising during the extraction process. The classic precursors of... 

Parent phthalideisoquinoline alkaloid Configuration Enol lactone Configuration Keto acid Diketo acid Ene lactam Configuration... 

In this chapter the proposed (5) division of secophthalideisoquinolines into the four subgroups and the nomenclature have been preserved. Since the publication of the most recent review (5), information about the synthesis of the missing ( )-narceine enol lactone (102) (87), the isolation of ( )-fumaramine (112) from Fumaria vailanti (88), and the discovery of a new seco alkaloid, coryrutine (118), from Corydalis rutifolia (89) has appeared. In the former plant fumaramine (111) (55) and in the latter N-methylhydrasteine... 

The secophthalideisoquinoline enol lactones may exist as Z or geometric isomers. Three pairs of such isomers are known aobamidine (96) (Z) and adlumidiceine enol lactone (97) ( ), /V-methylhydrastine (98) (Z) and (E)-N-methylhydrastine (99) ( ), (Z)-narceine enol lactone (101) and ( )-narceine enol lactone (102). Three of these enol lactones (99, 101, 102) are synthetic products. Lists of these alkaloids, the plant species in which they occur, as well as their spectral data and other references are provided in the review papers (4,5,8). Narceine enol lactones (101 and 102) are described in Refs. 87 and 90. 

Enol lactones are assumed to form from iV-methylisoquinolinium salts as a result of a Hofmann-type degradation process. This P elimination is a highly stereospecific reaction in which Z isomers are produced from precursors of erythro configuration and isomers from threo diastereomers(5,97). This fact seems to suggest that syn rather than the more usual anti elimination takes place. Examination of models indicates, however, that there is a preferred conformation in which the C-8 hydrogen is in the syn and coplanar position to the quaternary nitrogen. This hypothesis was proved correct in experiments carried out in vitro (5,14,15,91-94). 

The stereochemistry of the enol lactones was established by correlation with the structure of derivative 121, prepared from bicuculline (88), whose configuration as Z was determined by X-ray analysis (95). In this correlation... 

The enol lactones were synthesized by Hofmann degradation of metho salts of classic phthalideisoquinoline alkaloids. The biogenetically relevant transformations were highly stereospecific. In this way aobamidine (96) was obtained from the methiodide of (erythro) bicuculline (88) (2), and ad-lumidiceine enol lactone (97) was produced from both (threo) isomeric adlumidiceine (89) and capnoidine (90) methiodides (14,15,91-93). (Z)- (98) and ( )-N-methylhydrastine (99) were obtained from / - (91, erythro) and a-N-methylhydrastinium (92, threo) iodides (5,87,91,96-98), respectively, as were (Z)- (101) and (JE)-narceine enol lactones (102) synthesized from a- (94, erythro) and /J-narcotine (95, threo) quaternary N-metho salts (87,90), respectively. In a similar process /J-hydrastine (91) JV-oxide heated in chloroform yielded enol lactone 124 of Z configuration (99) however, a-narcotine (94) N-oxide was transformed to benzoxazocine 125 (99). ... 

Enol lactones can also be obtained from keto acids by enolization-dehydration. Adlumidiceine (103) as well as N-methylhydrasteine (104) when heated in toluene with acetic anhydride or p-toluenosulfonic acid were transformed to enol lactones 97 (97) and 98 (5,102), respectively. Narceine (106) under the influence of PC13 yielded 101 (87,100). 

Both Z and E isomeric enol lactones undergo photoisomerization to yield mixtures of isomers (5,14,87) in which the thermodynamically more stable one prevails. It is the Z form in hydrastine series (5) and the E isomer in the more hindered narcotine series (87). Relative stabilities of isomeric enol lactones (98 versus 99 and 101 versus 102) were determined by comparing their rates of methanolysis. Keto esters of type 126 were formed (87). It turned out that both ( )-N-methylhydrastine enol lactone (99) and (Z)-narceine enol lactone (101) solvolyzed faster than their geometric partners. 

In a hydrolytic environment enol lactones can be easily hydrolyzed to the corresponding keto acids. Both Ai-methylhydrastines (98 and 99) when allowed to stand in aqueous acetone gave rise to N-methylhydrasteine (104) (5). 

Secophthalideisoquinoline enol lactones of type 128 were used by Klotzer et al. (95,103-105) for the synthesis of benzazepine system 129 which was further transformed to alkaloids of rhoeadine type. 

Secophthalideisoquinoline keto acids are postulated to be biosynthesized from phthalideisoquinoline metho salts via enol lactones. Such transformations occur easily in laboratory experiments (Section III,B,1). There are... 

Mass spectra of these alkaloids are almost identical with the mass spectra of their enol lactone precursors. It may be assumed that the molecular ions, recorded only in spectra of 104 and 106, can be easily dehydrated under electron impact (4,107,108). 

Steric hindrances may also be the reason why quaternary salts of 8-alkylnarcotoline (130) were transformed during Hofmann degradation to analogous keto acids (131) (111,112) and not to the enol lactones (Scheme 24). In some cases (5,87) the keto acids and their esters have been synthesized from the corresponding enol lactones by hydration (Section III,A,2). Nornarceine (107) was prepared from JV-benzyl-(—)-a-narcotinium bromide (139, X = Br) by Hofmann degradation followed by N-debenzylation and ester hydrolysis (109). 

Keto acids can be dehydrated to enol lactones (Section III,A,1). They may also undergo esterification with alcohols e.g., /V-methylhydrasteine (104) in methanol at room temperature gave the expected keto ester 126 (R + R = CH2, R1 = CH3) (5,87). Sodium borohydride reduction of keto acid 104 supplies the saturated y-lactone 132 identical with that obtained from enol lactone 98 (5). 

It has been postulated that secophthalideisoquinoline ene lactams and hydroxy lactams are most probably artifacts of isolation resulting from the reaction of enol lactones or keto acids with ammonia during the extraction process. The hydroxy lactams are probably formed initially and then undergo dehydration to give ene lactams (5,8). For this reason, this section covers the hydroxy lactams in addition to the ene lactams. The hydroxy lactams are... 

As in the case of enol lactones, the stereochemistry of the ene lactams may be deduced from the UV and H-NMR spectral data. Details about the... 

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