Silphinene synthesis

The key precursor in the silphinene synthesis, arene-alkene (95), is obtained in one step from commercial materials and provides, in accord with the above analysis, cycloadducts (96) and (97) (1 1) in 70% yield. Mode, regio-, exotendo- and stereo-selectivity are essentially complete. Transformation of cycloadduct (96) to silphinene involves reduction with lithium in methylamine, which proceeds with formation of the alkene radical anion and subsequent rupture of the better aligned cycloivopane bond (C-4—C-S > C-3—C-4). Requiring only three steps from commercial materials, this syntlwsis dramatically illustrates how complexity can be rapidly built up through strategies based on the meta cycloaddition. 

Scheme 13.1 New reactions and step economy a three-step total synthesis of silphinene.

Ito s regio- and stereoselective total synthesis relied on dicyclopentadiene as starting material The derived ketone 755 was cleaved to provide 756 which was crafted into 757 (Scheme LXXXV). FoUowing reduction of the carbomethoxy group, conversion to iodo ketone 758 was realked with trimethylsilyl iodide. Reaction of 758 with DBU resulted chiefly in conversion to 752 which was transformed into silphinene essentially as described above. 

Cyclopentane annelation.1 A recent synthesis of the sesquiterpene silphinene (7) used two cyclopentane annelations, both involving conjugate addition of the Grignard reagent derived from 1 in the presence of CuBr S(CH3)2 to an a,/ -enone. Thus 3, obtained as shown, undergoes dehydration to 4. This product was converted to 5, which undergoes a second cyclopentane annelation to give eventually 6, which has the carbon skeleton of 7. 

These intramolecular meta-addition processes were utilized in the key steps for the total synthesis of a-cedrene [245], isocomene [246], hirsutene [247], coriolin [248], silphinene [249], rudmollin [250], laurenene [251], and fenestranes [252-254], which were synthesized by Wender s and Keese s groups (Scheme 58). 

The Nazarov cyclization has been featured in a variety of synthetic endeavors involving both natural and unnatural products. In the area of polyquinane natural products ( )-hirsutene (88), ( )-mod-hephene (89), ( )-silphinene (90), ( )-A 2)-capnellene (91) and ( )-cedrene, have all been prepared (Scheme 37). The synthesis of (91) is noteworthy in the iterative use of the silicon-directed Nazarov cyclization. TIk divinyl ketones were constructed by the carbonylation-coupling of enol triflates (92) and (95) with the -silylvinylstannane (Scheme 38). llie diquinane (94), obtained from Nazarov cyclization of (93), was transformed into enol triflate (95) which was coupled with the -silylvinylstaimane as before. Silicon-directed Nazarov cyclization of (96) was highly diastereoselective to provide the cis,anti,cis isomer of (16). The synthesis was completed by routine manipulations. 

Additional applications of this intriguing method to create polyquinanes include synthesis of hirsutene, modhephen, and silphinene employing acid-induced or reductive cleavage of a vinylcyclopropane and opening of a cyclopropyl ketone with a... 

Similar methodology was used in a total synthesis of the angularly fused triquinane pentalenene (53) [65]. The known phenol 271 was used as the starting material. In this and the previous instance (viz. with 269) constant-current electrolyses were performed, this time converting 271 to a mixture of the desired adduct 272 (64%) as well as a material epimeric at the CH20Ac-bearing carbon (16%). The major adduct corresponds to one wherein the original olefin stereochemistry has been maintained. Conversion of 272 to the natural product followed chemistry similar to that used in the synthesis of silphinene (56). 

In the synthesis of angular triquinane ( )-silphinene by S. Yamamura et al., the Criegee oxidation was used to obtain a key bicyclic intermediate. ... 

Shizuri, Y., Ohkubo, M., Yamamura, S. Synthesis of ( )-silphinene using electrochemical method as a key step. Tetrahedron Lett. 1989, 30, 3797-3798. 

Miesch, M., Miesch-Gross, L., Franck-Neumann, M. Total synthesis of ( )-silphinene non photochemical cyclobutenic route to a crucial intermediate. Tetrahedron 1997, 53, 2103-2110. 

Silphinene (160), a constituent of the roots of Silphium perfoUatum, has attracted a considerable attention of synthetic chemists. Electrochemical methodology is used for its synthesis. On constant current electrolysis (1.18 mA -1-750-1200 mV V5. SCE) in AC2O, the phenol 161, readily prepared from 3,4-dimethoxyphenol, underwent intramolecular [5 -h 2] cycloaddition to give in 59% yield the desired tricyclic compound 162, which was successfully converted into silphinene through a bicyclic compound 163 (Scheme 32) . 

Sigmatropic rearrangement 677, 697 Sihca gel membranes 1082 Silphinene, electrosynthesis of 1183, 1187 Silver compounds, as oxidants 1307-1311 Silybin, synthesis of 1308, 1310 Silydianin 1180 Silylation, of phenols 934, 935 Silylcyanation, asymmetric 694, 695, 702 Simmons-Smith cyclopropanation, asymmetric 694... 

Wender and co-workers continue to make elegant synthetic use of the intramolecular meta photocycloaddition of phenyl-ethenyl non-conjugated bichromophoric systems and this year describe three such applications of the reaction. The synthesis of ( )-silphinene (40), the first member of a new family of tri-quinane natural products, has been achieved in three steps and... 

The cis-sclcctivc introduction of a cyclopentyl ring via a radical cyclization is the key step in the synthesis of ( )-silphinene. an angular fused triquinane48. Conversion of readily available 3,5.5-trimethylcyclohexenone to the radical precursor 3, followed by Barton deoxygenation16 generates the radical, which cyclizes stereoselectively to the tricyclopentanoid skeleton 4. 

Although a number of syntheses of the angular triquinane sesquiterpene isocomene (18) have now been published, the synthesis by Dreiding et al. is interesting since it features the sequential alkynone cyclisations (14)— -(15) and (16)——(17) as the two key 5-ring annulation reactions. In a new synthesis of the related sesquiterpene silphinene (23) intramolecular(2+2] photocycloaddition from (19) is first used to elaborate the tricycle (20), which on brief exposure to iodotrimethylsilane produces (21). Reduction of (21) to (22), and functional group elaboration then completed the... 

In a review article Synthesis, 1998, 1559), Chanon presents 8 different syntheses of silphinene and 18 different syntheses of hirsutene. Based on your definitions of efficiency, cost of starting materials, control of stereochemistry, and so on., compare and contrast these syntheses and draw a conclusion as to which you believe to be the best for each target. 

FIGURE 13.32 Bar graph showing sacrificial and building-up reaction proportions for each synthesis plan for silphinene. Plans are ranked according to kernel mass of waste produced per mole silphinene. 

The arene-olefin meta-photocycloaddition approach to triquinane natural products is further illustrated this year with a three-step total synthesis of ( )-silphinene (5) starting from 2-bromotoluene (1). Thus, irradiation of the arene-olefin (2) derived from (1) gave a 1 1 mixture of the photoadducts (3) and (4) in 70% yield. Regioselective reductive cleavage of the cyclopropane bond in (3),... 

One particularly elegant use of the silicon-directed Nazarov cyclization was in the synthesis of the angular triquinane silphinene (89), by Miesch and co-workers. Addition of a large excess of boron trifluoride etherate in refluxing ethylbenzene to 86 ensured annulation of the required third ring. Notably, the benzyloxy group was also eliminated imder the reaction conditions, and the product 88 was subsequently converted into the natural product 89. 

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