Oxidative Entry into the Illicium Sesquiterpenes: Enantiospecific Synthesis of (+)-Pseudoanisatin

Abstract

Illicium sesquiterpenes have been the subject of numerous synthetic efforts due to their ornate and highly oxidized structures as well as significant biological activities. Herein we report the first chemical synthesis of (+)-pseudoanisatin from the abundant feedstock chemical cedrol (~$50 USD/kg) in 12-steps using extensive site-selective C(sp3)–H bond functionalization. Significantly, this work represents a novel oxidative strategic template for future approaches to these natural products and their analogs.

Total Syntheses of (−)-Majucin and (−)-Jiadifenoxolane A, Complex Majucin-Type Illicium Sesquiterpenes

“…This procedure delivered 7 in 67% yield and on 120 mmol scale. 11 Diverging from past work, in which an olefin oxidative cleavage reaction was used to generate a keto acid, 10 we found that 7 could be converted into ketone 8 directly via a hydroboration/double oxidation sequence (BH 3 ·THF/CrO 3 ·2pyr.). The use of Collin’s reagent avoided hydrolysis of the acetate protecting group as compared to many other oxidants examined.…”

“…10 During our work, iron- and radical-mediated oxidations of the cedrol C-4 methine (shown in green) and C-14 methyl positions (shown in blue) respectively were employed as key steps. In extending this strategy to the more highly oxidized majucinoids, such as 1 and 2 , it is also necessary to oxidize all the C–H bonds of the C-12 methyl group and the indicated C–H bond of the C-10 methylene (both shown in magenta, seco -prezizaane numbering).…”

A One Pot Synthesis of Dehydrohedione (DHH) from a Hedione® Precursor

“…More recently, during a synthesis of Me‐jasmonate via the α ‐halogenation/dehydrohalogenation of 2‐(pent‐2‐yn‐1‐yl)cyclopentan‐1‐one, we encountered the additional problem of endo/exo ‐cyclic regioselectivity during the dehydrohalogenation, and could only minimize this drawback under neutral conditions . We thus similarly applied the Kochi 's methodology to 2a ,, and, to our delight, we obtained directly and cleanly, in a one pot, DHH 1a . This domino reaction, constitutes the shortest synthesis of 1a , thus avoiding trans ‐ Hedione ® 6a as a starting material for either halogenation/dehydrohalogenation,, or enol acetate formation/epoxidation/rearrangement, or HIO 3 oxidation,, , as key intermediate for the final hydrogenation towards the olfactively more appreciated cis ‐ Hedione ® 6b , or its even more powerful enantiomer (+)‐(1 R ,2 S )‐ cis ‐ 6b , named Paradisone ® ,…”

“…2 More recently, during a synthesis of Me-jasmonate via the a-halogenation/dehydrohalogenation of 2-(pent-2-yn-1-yl)cyclopentan-1-one, we encountered the additional problem of endo/exo-cyclic regioselectivity during the dehydrohalogenation, and could only minimize this drawback under neutral conditions. [17] We thus similarly applied the Kochi's methodology to 2a, [17][18][19][20][21][22][23][24][25][26][27][28][29][30][31][32][33], 3 and, to our delight, we obtained directly and cleanly, in a one pot, DHH 1a. This domino reaction, constitutes the shortest synthesis of 1a, thus avoiding trans-Hedione â 6a as a starting material for either halogenation/dehydrohalogenation, [31][33] [34],4 1 For the diethyl 2-(3-oxo-2-pentylcyclopentyl)malonate analogue, see.…”

“…Halogenation of ketones under these conditions is less regio‐selective in MeCN, as compared to the optimized co‐solvent conditions AcOEt/CHCl 3 1:1 . For the use of t BuOH, see . For analogous basic conditions (CuBr 2 , NaH, DMSO, or CuBr 2 , CaCO 3 , THF) on other substrates, see …”