Isosteviol

Mosettig and Ness determined that steviol and isosteviol were diterpenoid acids with the former containing a 2,11-cyclopentanoperhydro-phenanthrene skeleton, a hydroxyl acid and a terminal methylene group. It was in 1963 that Mosettig and his colleagues finally showed the unambiguous structure of stevioside. 

The reverse rearrangement, involving the conversion of the kaurene skeleton to that of the beyerene series, is found in the steviol-isosteviol and gibberellin-8,13-isogibberellin rearrangements (see Scheme 22). Apart from their mechanistic interest, these rearrangements were used in partial syntheses directed at structural correlations. 

Aniline, (V.iV-dimethylaniline and toluene form molecular complexes with (4a, b,13b)-13-methyl-16-oxo-17-norkaurane-18-carboxylic acid (isosteviol) (93) investigated by X-ray diffraction159. 93 forms individual 2 1 molecular complexes with aniline or N,N-dimethylaniline and toluene. The supramolecular crystal structure of these complexes is formed by chiral double helices involving isosteviol molecules. The helices are linked together by intermolecular hydrogen bonds between the carboxy and the carbonyl groups160. 

Figure 1 is a drawing of the supramolecular complexes between double helices of isosteviol with aniline (structure 94) or toluene and (V.iV-dimethylaniline (structure 95). 

FIGURE 1. Supramolecular structure of the complexes between isosteviol and aniline (94), N,N-dimethylaniline (X = N(CH3)2) or toluene (X = CH3) (95). Isosteviol is represented as ribbon helices. Adapted from Reference 159... 

The oxidation of cnt-kaurene is inhibited by the plant-growth regulator ancymidol at 10 mol 1 the drug blocks the formation of ent-kaurenol and at 10 mol it stops the conversion of MVA into ent-kaurene. These effects are completely reversed by the addition of gibberellic acid. Isosteviol (84) and steviol acetate (85) are effectively metabolized by cultures of mycelia of a G. fujikuroi... 

Korochkina, M. Fontanella, M. Casnati, A. Arduini, A. Sansone, F. Ungaro, R. Latypov, S. Kataev, V. Alfonsov, V., Synthesis and spectroscopic studies of isosteviol-calix[4]arene and -calix[6]arene conjugates, Tetrahedron. 2005, 61, 5457-5463... 

Kataev VE, Strobykina lY, MUitsina OI, Korochkina MG, Fedorova OV, Ovchinnikova IG, Valova MS, Rusinov GL. Isosteviol and some of its derivatives as receptors and carriers of amino acid picrates Tetrahedron Lett 47 2006 2137-2139. 

Snider was interested in the synthesis of tetracyclic diterpenes. For that purpose, he examined the radical cyclization of tetraene precursor 55 to give highly valuable intermediate 56 for the total synthesis of isosteviol and beyer-15-ene-3,19-diol (Scheme 19). After the initial 6-enr/o-trig cyclization, a subsequent i-endo-ing cyclization involving the unsubstituted ene partner was responsible for the erosion of the yield [33]. 

The modification of isosteviol leading to the introduction of substituents at C-12 and C-14 has been described. The products from the carbonium ions (80)... 

Scheme 10.34 Three-component Mannich reaction cataiyzed by isosteviol-derived amino acids.

On the other hand, selective Beckmann fragmentation was achieved with this scaffold by reaction of isosteviol oxime 110 with acetic anhydride in acetonitrile, yielding the corresponding acetate. Subsequent treatment with p-toluenesulfonic acid produced the A olefinic nitriles 111 and 114 in an 8 1 ratio of, respectively (Scheme 5.271. 

Complete a-selectivity was observed in the isosteviol-derived amino-thiourea 24-catalyzed conjugate addition-aromatization reaction of azlactone with a,-P-unsaturated pyrazolones (Scheme 22) [39]. Although generally good to excellent chemical yield and stereoselectivity were obtained with C2-aryl azlactones, the reaction failed with C2-alkyl azlactone (Ar = u, = Pr) even at room temper-... 

Stevioside and five metabolites (isosteviol, steviabioside, 15a-hydroxysteviol, steviol-16,17a-epoxide, steviol) were isolated firom urine and blood and separated on a Ci8 column (.i = 210nm) using a 20-min 70/30 35/65 water/acetonitrile... 

Closer examination, however, will reveal that the approaches used to date represent only a few drops in the vast ocean of organic chemistry. Synthesis strictly from first principles is still a remarkably rare occurrence. More frequently, a combination of clues from the literature, past experience, and personal intuition is employed. Consider the potent convulsant anisatin 104 and the antihypertensive diterpenoid isosteviol 105 (Figure 28), both of which have been found to behave as clathrands. We can understand after the event why this took place, but their behavior certainly could not have been anticipated with confidence—let alone accurate prediction be made of the precise supramolecular details of inclusion. 

Figure 28 One of the clathrates formed by the antihypertensive diterpenoid isosteviol 105, namely (105)2-(benzene). Color code H, light blue O, red host C, green and guest C, purple. Interhost C=0- -H-0 hydrogen bonding is indicated by dashed lines.

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