Spirolactone derivatives

Grassy, G., Trape, R, Bompart, J., Calas, B. and Auzou, G. (1995). Variable Mapping of Structure-Activity Relationships. Application to 17-Spirolactone Derivatives with Mineralocorti-coid Activity. J.Mol.Graphics, 13, 356-367. 

Schenkel, L., Kraehenbuehl, C., Biollaz, M. et ol. (1987) Three new epoxy-spirolactone derivatives characterization in vivo and in vitro. Journal of Pharmacology and Experimental Therapeutics, 240, 650-656. 

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]. 

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). 

Benzo[6]thienyl)propionic acid is obtained by dehydrogenation of the spirolactone (144) it undergoes cyclization in the presence of liquid hydrogen fluoride to give the isomeric ketones (307 and 308).447 j9-(3-Benzo[6]thienyl)propionyl chloride and its a-methyl derivative... 

The alkylation of ( )-spirolactones (34a) and (34b) with higher diastereoface selectivity has been modelled by geometry-optimized ab initio 4-31G calculations which suggest that approach of the electrophile occurs at an angle of ca 80° to the plane of the enolate and with some displacement away from the oxygen linked to the metal ion.41 Asymmetric a-methylation of phenylalanine derivatives has been achieved with 82% ee and retention of configuration in the absence of any external chiral source.42... 

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. 

SPIRO(17H-CYCLOPENTA(a)PHENAN-THRENE-17,2 (5 H)FURAN), PREGN-4-ENE-21-CARBOXYLIC ACID DERIV. SPIROLACTONE SPIROLAKTON SPIROLANG SPIRONE SPIRONOLACTONE SPIRONOLACTONE A URACTONE VEROSPIRON... 

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. 

More recently, quinonoidal spirolactones (LV), which can react with amino acid esters to give dipeptides, have been conveniently prepared via anodic oxidation of tyrosine derivatives (LIV) [Eq. (24)] [54]. Anodic phenolic coupling of tyrosine and phenylglycine derivatives to afford isodityrosine, dityrosine, and related compounds has also been recently reported [55]. 

A very interesting phenanthrene derivative with a spirolactone ring, named dendrochrysanene (444), was isolated from the stems of Dendrobium chrysanthum. Its structure was established by NMR, mass spectrometry and X-ray analyses [201]. 

A route to spirolactams involves oxidation of oxazolines derived from t)rosine. Simple amides give the corresponding spirolactones. ... 

Tyrosine spirolactones are not only promising synthetic intermediates for bioactive natural products such as alkaloids and antibiotics but also synthons useful in peptide chemistry. For example, N-protected tyrosine derivatives 104 and 105, prepared from 2,6-di(ferf-butyl)-4-chloromethylphenol, were electrolyzed at a controlled potential (+1.3-1.4 V Vi. Ag/Ag+) in MeCN to give spirolactones 106 and 107 (64 and 85%, respectively). These spirolactones are used for peptide synthesis, as shown in Scheme 19. 

A similar oxidation of tyrosine derivative 244 with an excess of (diacetoxyiodo)benzene in cold acetonitrile followed by quenching with aqueous sodium bromide furnished brominated spirolactone 246 in 80% overall yield. A plausible mechanism for this reaction involves the iodonium derivative245 as an intermediate product and subsequent substitution of each phenyliodonium group with a bromide anion (Scheme 3.100) [311]. 

Branched-chain sugar spirolactones 26 and 27, potential inhibitors of ATPase, have been derived in very high yields from isoxazolines 24 and 25, respectively by treatment with aqueous acetic acid. The structure of 26 was confirmed by X-ray crystallography (see also Chapters 10 and 21). 

The NMR spectra of enmein-type diterpenoids in which 6a-H is part of a hemiacetal contain only a singlet assignable to this proton because of its ca. 90° dihedral angle with 5-H [e.g. isodocarpin (64), carpalasionin (77) in Table VIII, and enmein (62), isodotricin (65) etc. in Table II]. In spirolactone-type diterpenoids having a hemiacetal function 6-H is a doublet [e. g. trichorabdal E (96) in Table VIII and trichorabdals F (97) and G (98) in Table II]. In the enmein-type diterpenoids of this group, C-6 is R except for rabdosin A (73), while the spirolactone-type diterpenoids occur as a mixture of 6R- and 6S-isomers 81). Shikodonin has been reported to have structure (88) on the basis of X-ray analyses of its 6-O-methyl and 6-0-ethyl derivatives, but our experimental results are inconsistent with this proposal, and thus the stereochemistries of C-5 and C-6 in (88) seem questionable. 

This type of conversion is easily achieved by periodate oxidation of a 6,20-dihydroxy-7-oxokaurene derivative. The 6,7-secokaurene-type product from this reaction is either of the enmein-type or the spirolactone-type when the starting material has a hydroxy group at C-I, an enmein-type compound is produced when it has no hydroxy group at C-1, a spirolactone-type product is formed (see Scheme 26). 

The antitumor activity of spirolactone-type diterpenoids has also been studied. Shikodonin (88) had antitumor activity 64). Very recently in vivo antitumor activity has been reported for trichorabdals A-C (92-94) and related diterpenoids against Ehrlich ascites carcinoma in the mouse. The trichorabdals exhibited greater activity than oridonin and while the activity of their dihydro derivatives was greatly reduced, they were still active, in contrast to dihydroenmein and its analogs which are inactive. Hence, the trichorabdals may possess a second active site, presumably the spirolactone aldehyde part, and it was assumed that the enhanced activity of the trichorabdals is due to synergism between the two active sites 82, 142). 

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