Stemodane

Hanson JR, PB Reese, JA Takahashi, MR Wilson (1994) Biotransformation of some stemodane diterpenoids by Cephalosporium aphidicola. Phytochem 36 1391-1393. 

The key steps in the synthesis of the stemodane-type diterpenoids are again the retroaldol-aldol procedure. This was best demonstrated by the rearrangement of the ketal (103) to the epimeric alcohol (104), upon treatment with acid, in 60%... 

In a similar way, Malacria and colleagues accomplished the formation of the stemodan skeleton by a tandem [2 + 2 + 2]/[4 + 2] cycloaddition process348. 

Radical deoxygenation via thioimidazolyloxy derivatives is also found to be efficient process. Two examples are reported in Reactions (4.33) and (4.34) [70,71]. In particular, dideoxygenation was useful to prove the structure of the stemodane ring system, achieved by other routes. 

Toro, A. Nowak, P. Deslongchamps, P. (2000) Transannular Diels-Alder aitiy into stemodanes first asymmetric total synthesis of (+)-maritimol. J. Am. Chem. Soc., 122,4526-7. 

A regio- and stereo-controlled synthesis of the stemodane nucleus, utilizing a surprising selectivity of reagents, has been claimed.Readers are left to examine the paper and draw their own conclusions. 

The first asymmetric total synthesis of (+)-maritimol, a diterpenoid natural product that possesses a unique tetracyclic stemodane framework was accomplished by P. Deslongchamps. To introduce the C12 stereocenter, the Enders SAMP/RAMP hydrazone alkylation was used. This stereocenter played a crucial role in controlling the diastereoselectivity of the key transannular Diels-Alder reaction later in the synthesis. The required SAMP hydrazone was formed under standard conditions using catalytic p-toluenesulfonic acid. Subsequent protection of the free alcohol as a f-butyidiphenylsilyl ether, deprotonation of the hydrazone with LDA and alkylation provided the product in high yield and excellent diastereoselectivity. The hydrazone was converted to the corresponding nitrile by oxidation with magnesium monoperoxyphthalate. 

A study of the influence of silica gel surfaces on the photochemical addition of allene to a series of cyclic enones has been carried out. Using this technique cycloaddition occurs to the more hindered face of the enone. A typical example of allene addition, where addition takes place to the less hindered face, is reported by Piers et al. in the photoaddition to the enone (65) which affords the four isomeric products (66) in ratios of 40 51 6 3. The two major products (66a) and (66b) were used as starting materials for total syntheses of naturally occurring compounds of the stemodane type. ... 

The bis-E ck. cyclization of trienyl iodides has been applied as a key reaction by Overman to total syntheses of stemodane diterpenes and scopadulcic acid. Treatment of the 6R, %R epimer of the trienyl iodide intermediate 259 with Pd(dppb) in the presence of Ag2C03 in DMA provided two tricyclic products 260 (40 %) and 261 (25 %). The major product 260 has the stemodane skeleton [110]. On the other hand, w-cyclization of the 65, 8i epimer of the trienyl iodide 262 proceeded with complete stereo- and regioselectivity as shown by 263 and 264 to afford the tricycle of the scopadulan skeleton 266, from which total synthesis of scopadulcic acid A (267) was achieved. In the second cyclization as shown by 264, generation of the cyclohexylpalladium intermediate 265, having Pd attached to the secondary carbon center is favored to give 266 selectively. Formation of a stemodane skeleton is expected from the 6R, %R epimer [111]. 

The Thorpe-Ziegler reaction has been widely utilized in the synthesis of natural products. Deslongchamps and co-workers used the cyclization for construction of the D-ring of the stemodane skeleton in the natural product (-(-)-maritimol. (+)-Maritimol (36), isolated from Stemodia maritime was used as a Caribbean folk medicine for the treatment of venereal diseases. Cyclization of dinitrile 34 was followed by acidic hydrolysis to yield tetracycle 35, The synthesis of 35 represented a formal synthesis of the natural product, as this intermediate could be elaborated to 36 using conditions developed by Piers and co-workers. ... 

The Peterson olefination is known for its better performance compared to the corresponding Wittig process for hindered substrates. This is demonstrated in the first asymmetric synthesis of (+)-maritimol, a member of the stemodane diterpenoids (eq 66). Thus, the key step, a Thorpe-Ziegler annulation, requires a 1,5-dinitrile motif. This is achieved by the generation of an a-silyl boronate, obtained by BuLi deprotonation of trimethylsilylace-tonitrile and subsequent transmetalation with triisopropyl borate, which is then condensed with the tricyclic aldehyde. ... 

A one-step construction of the stemodane framework that resulted in a formal synthesis of the diterpene stemodin (185) was realized by the cobalt-mediated intramolecular cyclization of ene-diyne 182 (Scheme 7.40) [55], Three stereocenters in 183, two of them quaternary, were produced with complete specificity during this [2 - - 2 + 2] cycloaddition. 

Taking advantage of such biosynthetic abilities, Hanson s group has systematically investigated the biotransformation by C. aphidicola of some (more or less) related cyclic diterpenoids such as kaurane [63-65] or stemodane [66] derivatives. Interestingly, with most kaurane derivatives, the current hydroxylation at C-3 observed with the natural substrate was inhibited, but various other positions can be hydroxylated, including the 113, 16a, and 17 positions (Fig. 5), the later probably after the reduction of the 16,17 double bond took place. 

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