Diastereoselective Total Synthesis of (±)‐Toxicodenane A

Abstract

The first total synthesis of tricyclic sesquiterpene (±)‐toxicodenane A has been accomplished. This synthetic work was completed in 12 steps from dimedone through diastereoselective reductive desymmetrization of 2,2‐disubstituted 5,5‐dimethylcyclohexane‐1,3‐dione, stereocontrolled allylation, ring‐closing metathesis of a diene compound to yield bicyclic compounds that bear a seven‐membered ring, and construction of the oxygen‐bridged moiety through neighboring group assisted ring‐opening reaction of an epoxide as key steps.

Metathesis Reactions in Natural Product Fragments and Total Syntheses

“…These molecules are organized under various transformations in the following sequence: 1) ring‐closing metathesis, 2) cross metathesis, 3) ring‐closing alkyne metathesis, and 4) ring‐closing enyne metathesis. 1) Ring‐closing metathesis : kanamienamide ( 37 ), [100] (+)‐chinensiolide B ( 38 ), [101] BMS‐846372 ( 39 ), [102] daphniyunnine B core ( 40 ), [103] clavilactone D ( 41 ), [104] pechueloic acid ( 42 ), [105] (−)‐deoxoapodine ( 43 ), [106] zephyranthine ( 44 ), [107] palodesangrens core ( 45 ), [108] (−)‐stemaphylline ( 46 ), [109] pavidolide B ( 47 ), [110] 7‐deoxypancratistatin ( 48 ), [111] (+)‐4‐ ɑ ‐dehydroxycrinamabine ( 49 ), [112] (−)‐elymoclavine ( 50 ), [113] viridin ( 51 ), [114] (−)‐crinane ( 52 ), [112] conduramine B‐1( 53 ), [115] ellipticine quinone ( 54 ), [116] (−)‐tegafur ( 55 ), [117] tetraponerine ( 56 ), [118] (−)‐cermizine B ( 57 ), [119] (Figure 7) (±)‐lycojaponicm ( 58 ), [120] (−)‐zeylenol ( 59 ), [121] aphanamal ( 60 ), [122] (+)‐epiquinamide ( 61 ), [123] erythrinane core ( 62 ), [124] (−)‐pseudodistomin E ( 63 ), [125] toxicodenane A ( 64 ), [126] ipomoeassin F ( 65 ), [127] scholarisine K ( 66 ), [128] panal core ( 67 ), [129] (+)‐crotanecine ( 68 ), [130] gagunin E analogue ( 69 ), [131] R‐(−)‐ ɑ ‐cuparenone ( 70 ), [132] citreamicin‐η core ( 71 ), [133] brianthein A core ( 72 ), [134] (+)‐cryptoconcatone H ( 73 ), [135] neomarchantin A ( 74 ), [136] (+)‐methynolide ( 75 ), [137] 10‐epi‐tirandamycin ( 76 ), [138] greensporone C ( 77 ), [139] 5′‐hydroxy‐zearalenone ( 78 ), [140] cheloviolene A ( 79 ), [141] crassifoside F c...…”

Enantioselective Total Synthesis and Absolute Configuration Assignment of (+)-Toxicodenane A

“…The NMR data of the synthesized product were identical to those of the racemic compound reported. 1,3 The absolute configuration of (+)-1 was assigned to be 4S,5S,8R,11R on the basis of the X-ray In summary, we have established a concise route that could achieve the first enantioselective total synthesis and absolute configuration of (+)-toxicodenane A (1) featuring an oxabridged [6.6.5]-tricyclic core via a longest linear sequence of nine steps from the commercially available material. This synthesis was highlighted by a P-stereogenic phosphinamidecatalyzed desymmetric enantioselective reduction of 1,3cyclohexanedione, a free hydroxy group-directed highly stereocontrolled Grignard reaction, and a Lewis acid-mediated cascade sequence of transacetalation and Prins cyclization.…”

“…Structural elucidation revealed that these sesquiterpenoids possess a [5.4.0]-, [6.3.0]-, or [5.3.0]-all-carbon bicyclic skeleton and bear four to seven continuous stereogenic centers. Specifically, toxicodenanes A (1), C (3), and E (4) feature the presence of a unique oxabridged tricyclic scaffold and an all-carbon quaternary chiral center at the ring junction. The relative stereochemistry of these compounds was established by a combination of multiple two-dimensional NMR spectroscopic analyses.…”

“…In addition to the intriguing structural features, biological evaluation for toxicodenanes B (2) and C (3) showed that these two compounds displayed significant inhibition activities for the overproduction of fibronectin, collagen IV, and IL-6 in high-glucose-induced mesangial cells in a dose-and timedependent manner. 1 These results imply that such types of sesquiterpenoids might potentially serve as a novel structural template for optimizing antidiabetic nephropathy drugs, albeit the biological activities of toxicodenanes A (1) and E (4) were not investigated.…”

“…3 accomplished the first total synthesis of racemic toxicodenane A (1) through a longest linear sequence of 12 steps. The key to their success involved a reductive desymmetrization of 2,2disubstituted 1,3-cyclohexanedione, stereocontrolled Grignard h i b i t e d .…”