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. ... 

The spirolactone is obtained in a diastereomeric ratio of 95 5 when the following dilithium reagent, available by double deprotonation of the acid, reacts with 2,2-dimcthylpropanal (pi-... 

An interesting suggestion was made by Levine in 1969. He supposed that the ketene formed photolytically from 1,2-naphthoquinone diazide could react with unreacted 1,2-naphthoquinone diazide to form a spirolactone-type addition product. This suggestion was tested experimentally almost twenty years later by Huang and Gu (1988). They irradiated 1,2-naphthoquinone diazide in dioxane in the presence of pyrene as sensitizer with a high-pressure mercury vapor lamp (Scheme 10-103). They did indeed obtain the spirolactonespiro(naphtho[4,5 2/,l/]furano-2-one)-3 T -inde-... 

Chapter 4 is concerned with a technically important group of leuco compounds which like the spiropyrans are not formed by reduction of the parent dye, but by formation of a spiro structure from the dye in such a way that the newly created sp3 center destroys the conjugation, and hence, the color of the chromophore. These are the phthalides (spirolactones) and the position of equilibrium is determined by pH rather than a redox process. Such materials are used mainly as color formers in pressure-sensitive... 

A catalytic system consisting of cat. Sml2, Zn/Hg, Lil, and Me3SiOTf induces spirolactonization (Scheme 20) [56]. Me3SiOTf plays a similar role in converting the intermediary alkoxides to the silyl ethers. The efficacy of Lil depends on the formation of Sml3 from Sm OTf, which facilitates reduction by Zn/Hg. The Lewis acidity of Zn(II) is reduced by conversion to a non-Lewis-acidic species such as Li2Znl2(OTf)2. 

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

C42 or in boiling toluene194 causes dimerization to spirolactone 257 (R = C6H5)195> 196. The formation of 257 can again be understood as an addition of one molecule of cyclopropenone through the C -CO bond to the C=0 group of a second molecule ... 

From phenyl cyclopropenone and enamines243 in addition to betaines (type 371), penta-2,4-diene amides (type 372), and j3-aminoenones (type 373), adducts from two moles of cyclopropenone and one mole of enamine are obtained as main products and were assigned the spirolactone structures 382 ... 

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).

A spirolactone 23 was prepared by electrooxidation of /V-carbomethoxy-tyrosine (63JA3702). 

The absolute configuration of the major isomers of spirolactone 102 and amide 103 was ISySRyl R, based on the known configuration of malic acid and determination of the relative configuration by an X-ray structure analysis of amide 103 [62]. 

Dioxocarboxylic acid 238 upon treatment with HTIB, cyclizes to dioxo-5-lactone 239 by intramolecular participation of the carboxylic group. When cyclic diketo acid 240 is the substrate, spirolactone 241 is obtained (90TL201). 

With R = CR R C02Me and R = (CH2)3+ OH, the obtained 5-iminooxazolines 42a could be converted into macrocyclodepsipeptides of type 46 as shown in Fig. 16. Saponification of the ester with KOH in Me0H/H20 followed by protonation of the exocychc imine and attack of the neighboring carboxyl oxygen led to the formation of spirolactone 48. Attack of the tethered OH and fragmentation generated the desired 14-, 15-, and 16-membered macrocycles in 27-54% yield [155]. 

The UV spectrum (/Imax 229, 288, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 290 showed the presence of a pyrrolo[2,3-c]carbazole framework with a spirolactone structure. The H-NMR spectrum indicated the presence of two... 

The UV spectrum (/Imax 229, 289, 324, 391, and 475 nm) of the pyrrolo[2,3-c]carbazole alkaloid 291 was identical to that of 290, indicating the presence of a similar pyrrolo[2,3-c]carbazole spirolactone framework. Comparison of the spectral data of this isolate with those of the pyrrolo[2,3-c]carbazole alkaloid 290 indicated it to be an acid form of 290. This was further established by the chemical conversion of 291 to the corresponding 7-hydroxy derivative. Based on these spectral data, and the close structural similarity to 290, the structure 291 was assigned to this compound (250) (Scheme 2.72). 

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. 

Castillo D, Arevalo J, Herrera F, Ruiz C, Rojas R, Rengifo E, Vaisberg A, Lock D, Le-mesre JL, Gomitzka H, Sauvain M. Spirolactone Iridoids might be responsible for the Antileishmanial Activity of a Peruvian Traditional Remedy Made with Himatanthus sucuuba (Apocynaceae). Journal of Ethnopharmacology 2007 112(2) 410-414. 

Wood CA, Lee K, Vaisberg AJ, Kingston DGI, Neto CC, Hammond GB. A Bioactive Spirolactone Iridoid and Tiiterpenoids from Himatanthus sucuuba. Chemical Pharmaceutical Bulletin 2001 49(11) 1477-1478. 

Yamaki, M., L. Bai, T. Kato, and . I. Tomita. 1993. Blespirol, a phenanthrene with a spirolactone ring from Bletilla striata. Phytochemistry 33 1497-1498. 

---