Reactions spirolactonization

The much simpler steroid, 253, was fortuitously found to fulfill this role when injected into animals. Its lack of oral activity was overcome by incorporation of the 7a-thioacetate group. Reaction of the ethisterone intermediate, 77b, with a large excess of an organomagnesium halide leads to the corresponding acetylide salt carbonation with CO2 affords the carboxyllic acid, 251. This is then hydrogenated and the hydroxy acid cy-clized to the spirolactone. Oppenauer oxidation followed by treatment with chloranil affords the 4,6-dehydro-3-ketone (254). Conjugate addition of thiolacetic acid completes the synthesis of spironolactone (255), an orally active aldosterone antagonist. ... 

Scheme 7.23. Domino oxidation/spirolactonization/Diels-Alder reaction sequence.

Novel bridged spirolactones have been synthesized via tandem radical cycli-zations of enol ether radical. In Reaction (7.85) the first 5-exo spirocyclization is followed by a 6-endo cyclization to give the bridged derivative as a single diastereoisomer [96]. 

Fig. 14. A mechanism to explain heme modification in the P. vitcde catalase and possibly E. coli HPII. For simplicity, the phenyl ring of T3rr415 is not shown, and only ring III of the heme and the heme iron are shown. Compound I is an oxyferryl species formed, along with water, in the reaction of one H2O2 with the heme. The iron is in a formal Fe oxidation state, but one oxidation equivalent is delocalized on the heme to create the 0x0-Fe" -heme cation, shown as the starting species, compound I. A water on the proximal side of the heme is added to the heme cation species of compound 1 shown in A to generate a radical ion in B. The electron flow toward the oxo-iron would generate the cation shown in (C), leading to the spirolactone product shown in D. In E, an alternate mechanism for the His-Tyr bond formation in HPII is presented that could occur independently of the heme modification reaction. Reprinted with permission of Cambridge University Press from Bravo et al. (93).

Fig. 15. A proposed mechanism coupling the formation of the His-Tyr bond to the oxidation of ring III of the heme in HPII. The mechanism begins with the formation of compound I shown in A. A concerted series of reactions, possibly triggered by either Aspl97/His395 or by a putative anionic species bound to compound I, results in the transfer of a hydroxyl to the heme from the H2O2 shown in C, which would facilitate spirolactone cyclization to form the final product containing the His-Tyr bond and the modified heme shown in D. Reprinted with permission of Cambridge University Press from Bravo et al. (.93).

In 1994, Quayle et al. reported the application of this cyclic Fischer-carbene synthesis from 3-butynols to spirolactone synthesis, although the process was stepwise and a stoichiometric amount of the complex was employed [17]. The key transformation was the chromium or tungsten carbene complex formation followed by the CAN oxidation of the complex to give y-lactone. The reaction was further applied to the synthesis of andirolactone and muricatacin, the former being shown in Scheme 5.14. 

Cyclopentenones. The anion of 1 (LDA, THF, —78") is susceptible to attack by electrophiles at either the a- or /-position. At temperatures of - 78° the reaction occurs at the former position at temperatures near 0" the product is a spirolactone. These lactones are converted into cyclopentenones when heated at 60° with P205 in methanesulfonic acid. 

Spirolactones may also be prepared from cyclic anhydrides by the action of 1,5-bis(bromomagnesio)pentane (8lJOC309l>. The reaction proceeds through the keto acid... 

The reaction of 3-(3,4-dimethoxyphenyl)propanoic acid with thallium(III) trifluoroace-tate in the presence of boron trifluoride etherate leads to a mixture of the dihydrocoumarin (574) and the spirolactone (572) (78JOC3632). It is suggested that these products arise through an initial one-electron oxidation to the radical cation, the fate of which may vary. Thus, intramolecular reaction with the carboxyl group gives the radical (571) and eventually the spirolactone. Alternatively, capture of the radical ion by solvent and further oxidation affords the radical (573), whereupon an intramolecular Michael addition to the carboxyl group and aromatization lead to the dihydrocoumarin (Scheme 218) (81JA6856). 

The intermediacy of a metallacyclobutene is proposed upon reaction of the diphenylcy-clopropenone dimer spirolactone with CpCo(CO)2, ultimately yielding a >j4-vinylketene complex (equation 23 l)295a. Unlike the analogous iron complex (Section IV.B.2.a), no vinyl carbene complex was observed, and hence formation of the metallacyclobutene seems to be more likely. 

Spirolactones result from the reaction of epoxides with (2-buten-1,4-diyl) magnesium complexes and subsequent carbonation (95JOC5143). 

This reaction applied to diallyllactones allowed the diastereoselective preparation of exo-methylene spirolactones [ 14] (Eq. 9). 

Fukuzawa44,45 and Inanaga46 showed that the coupling of ketones and aldehydes with acrylates mediated by Sml2 generally leads to y-lactones due to cyclisation of the intermediate alkoxide produced from the carbon-carbon bond-forming step. This is illustrated by the reaction of cyclooctanone with methyl acrylate to provide the spirolactone 27 in high yield (Scheme 5.22). 

In light of the above results it is interesting to note that the reaction of diphenylcyclo-propenone dimer spirolactone with ironenneacarbonyl yields a mixture of ring-opened vinyl carbene and -vinylketene complexes, and these interconvert under addition (or removal) of CO (equation 225) . A possible pathwav to vinylketene Fe-complexes, prepared earlier from cyclopropenes and ironcarbonyls " , may thus involve initial f -coordination, followed by ring cleavage to vinyl carbene and finally carbonylation to the ketene iron // -complexes. An analogous // -manganese complex is prepared similarly by the reaction of CpMn(CO),THF with 3,3-dimethylcyclopropene complex (equation 226) . ... 

Cyanation of acetals. Reaction of acetals with t-butyl isocyanide catalyzed by TiCU results in cyanohydrin ethers in high yield. A similar reaction with ethylene acetals results in spirolactones. 

Oxidative laetonization. A recently discovered group of mycotoxins known as tryptoquivalineS has a novel spirolactone unit derived from N-acyltryptophans. A typical member of the group, tryptoquivaline G (1), has now been synthesized by Biichi and co-workers and has been shown to be derived from D-tryptophan. A key step involves oxidation of a derivative (2) of L-tryptophan with DMSO and methanesulfonic anhydride (2 equiv.) to 3 and 4. NBS has been used for such a reaction, but it can also effect undesired nuclear bromination. The main product 3 was converted in several steps into tryptoquivaline L, the C,9 epimer of 1. Contra-thermodynamic epimerization (KH, then protonation) converted this isomer into 1 and thus proved the absolute configuration. 

In the case of steroidal propargylic alcohols the first rearrangement produced a mixture of allenyl sulfoxides, epimeric at the sulfur atom, which reacted with an added nucleophile to produce substituted allylic sulfoxides. Rearrangement of the sulfoxide resulted in the exclusive formation of a-hydroxy derivatives. This reaction sequence has been applied in a synthesis of hydrocortisone acetate74 (Nu = OCH3) from androstene-3,17-dione and in a transformation of mesantrol75 (Nu = malonate) to a spirolactone. 

Under similar conditions, reduction of an Qr,)6-unsaturated lactone linked to a linear a,)6-unsaturated ester gave modest yields of two isomeric spirolactones, [Eq. (17)]. CV of simple monofunctional compounds indicates that in this case the a,)6-unsaturated ester function is the electrophore [159]. The regioselective coupling ip to the ester group) and the presence of a proton donor (diethyl malonate) indicate that the probable reaction pathway is a-protonation of the radical anion, further reduction, and Michael addition of the resulting )6-anion to the lactone. 

Spirolactone moieties are important components of some biologically active steroids that possess antitumor activity. A prelude to formation of the spiro unit is the introduction of an allyl side chain into a steroidal ketone. This reaction can be accomplished in good yield by the Barbier reaction of allyl bromide, ketone, and iodine-activated magnesium in ether. With 5a-cholestan-3-one, 51 and 48% of the epimeric allyl alcohols are isolated. With 3(i-(tetrahydropyran-2-yloxy)-5a-androstan-17-one, 98% of the allyl alcohol is isolated [39]. 

Similar condensations can be accomplished with other types of stabilized carbanions, e.g. sulfonyl anions, as illustrated by equation (81). The resulting sulfonyl lactone (228) eliminates sulfinic acid on treatment with p-TsOH to furnish the a,3-unsaturated system (229).Spirolactonization is the result of the Reformatsky reaction of ester (231) with cyclic ketones. In equation (82), this reaction is applied to the synthesis of the lysergic acid precursor (232), which is formed stereoselectively from (230). ... 

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