Exploiting Pd^II and Ti^III Chemistry To Obtain γ-Dioxygenated Terpenoids:  Synthesis of Rostratone and Novel Approaches to Aphidicolin and Pyripyropene A

Abstract

In nature there are several terpenoids with a characteristic gamma-dioxygenated system on the A ring, and many of them show interesting pharmacological properties. We have developed a novel strategy for the synthesis of these terpenoids involving three stages: (a) the selective epoxidation of commercial polyenes, (b) titanium(III)-catalyzed cyclization of the epoxypolyprenes thus obtained, and (c) Pd-mediated remote functionalization of the equatorial methyl group attached at C-4 on ring A of the cyclic terpenoid thus formed. This strategy has proved to be useful for the synthesis of the natural labdane rostratone (1) and related terpenoids, as well as for advanced synthetic approaches toward the pharmacologically active products aphidicolin (2) and pyripyropene A (3).

Total synthesis and antiviral activity of indolosesquiterpenoids from the xiamycin and oridamycin families

“…These functionalized decalin systems are expected to arise from a cascade cyclization of dienylepoxide precursors, such as 9 and 10 . This type of radical cyclization may be initiated by reduction of the epoxide by a Ti(III) species32333435363738394041424344454647, although, to our knowledge, α,β-epoxy esters/ketones have not been fully explored as the substrates for such cyclization1448. Notably, Cuerva and coworkers49 disclosed that enol radicals derived from α,β-unsaturated ketones inhibit the cyclization reaction.…”

“…Starting from optically active epoxide 11 (96% ee)50, a sequence of 2-azaadamantane N -oxyl (AZADO) oxidation5152 and esterification led to compound 12 in 76% overall yield. On the basis of seminal work on the Ti(III)-catalysed bioinspired epoxypolyene cyclization by Cuerva and Oltra38394041, we investigated the cyclization of the α,β-epoxy ester 12 . Under the optimized conditions [Cp 2 TiCl 2 (20 mol%), Mn, i Pr 2 NEt, TMSCl], the desired trans -decalin 13 was obtained as a single diastereomer.…”

Reactions of m-chloroperoxybenzoic acid with dimeric cyclopalladated complexes derived from 2-phenyl-2-oxazolines

“…Reactions at the C-Pd bond of cyclopalladated complexes (CPCs) [1][2][3][4][5] (e.g., phosphination [6][7][8][9][10], chlorination [11][12][13][14], iodination [15][16][17][18][19], bromination [15,16], acetoxylation [20][21][22][23][24][25] and other transformations [15,[26][27][28][29][30][31]) represent an attractive method for highly regioselective functionalization of organic compounds. These Pd-mediated transformations are gaining importance as a synthetic method, providing access to new organic and organometallic compounds not readily available by other methods.…”

“…However, in spite of the number of studies focused on reactions of CPCs with m-CPBA, only a few rather similar types of palladacycles have been tested: (1) dinuclear complexes of the CN type derived from azoarenes ( Fig. 1, type A) [36,44,45], (2) mononuclear complexes based on azoarenes and having an additional cyclopentadienyl ligand (B) [20,39], (3) mononuclear complexes based on azoarenes with an SR (C) [40][41][42][43] or other chelating substituent (D) [34,35], (4) dinuclear complexes of the CS type obtained from dibenzyl sulfide, benzyl phenyl sulfide and benzyl phenyl sulfoxide (E) [38] and (5) mononuclear complexes derived from 2-(dimethylamino)methylnaphthalene (F) [47]. In this paper, we report our data for the reactions of m-CPBA with dimeric dichloro-and diacetato-bridged CPCs derived from 2-phenyl-2-oxazolines.…”

Titanium‐Catalyzed Enantioselective Synthesis of α‐Ambrinol

“…[2] This reagent has since become a powerful tool in organic synthesis, [3] especially after the catalytic version developed by Gansäuer et al, which uses 2,4,6-collidine hydrochloride as titanocene-regenerating agent. [4] Subsequently we developed an alternative titanocene-regenerating agent, a mixture of Me 3 SiCl and 2,4,6-collidine, [5] which has been used both by us and other authors for the total synthesis of several C-3 hydroxylated terpenoids in racemic form, including monoterpenoids such as karahanaenone, [6] sesquiterpenoids such as trans-4(11),8-daucadiene, [6] isodri-> menediol, [7] and 3b-hydroxydihydroconfertifolin, [7] diterpenoids such as 3b-hydroxymanool, [8] rostratone, [9] barekoxide, [6] laukarlaool, [6] and sclareol oxide, [10] meroterpenoids such as zonarone and zonarol, [11] and triterpenoids such as 3b-hydroxymalabarica-14 (26),17E,21-triene [8] and achilleol A. [12] In contrast, Cp 2 TiCl has scarcely been used for the enantioselective synthesis of natural products.…”