Synthesis of Illudinine from Dimedone

Abstract

A total synthesis of the illudalane sesquiterpene illudinine was realized in eight steps and 14% overall yield from commercially available dimedone. The approach features tandem fragmentation/Knoevenagel-type condensation and microwave-assisted oxidative cycloisomerization to establish the isoquinoline core. Completion of the synthesis involves a recently reported cascade SAr/Lossen rearrangement on a densely functionalized aryl bromide and an optimized procedure for O-methylation of 8-hydroxyisoquinolines. The oxidative cycloisomerization proceeds by way of a novel inverse-demand intramolecular dehydro-Diels-Alder cycloaddition, which has a potentially broader appeal for preparing substituted isoquinolines.

Microwave Heating Outperforms Conventional Heating for a Thermal Reaction that Produces a Thermally Labile Product: Observations Consistent with Selective Microwave Heating

“…This reaction system is our first example that (1) demonstrates a strategic advantage of MW heating, and that (2) we consider to be of practical synthetic utility (e.g., because of its central role in our illudinine synthesis). Our previous reports feature highly specialized reaction designs of limited synthetic utility in order to observe significant MW‐specific rate accelerations: open quartz glassware, unusual hydrocarbon solvents (e.g., p ‐xylene and naphthalene), dilute reaction conditions, and dynamic temperature and/or power profiles that can be sensitive to equipment parameters and variables like flask size and shape, wall thickness, etc.…”

“…Observed reaction yields were higher at am easured bulk temperature of 200 8Ct han at 180 8C or 220 8C; at 24 hours than at earliero rl ater time points; and when the reaction solution was heatedu sing MW energy as opposedt oC ONV heating with am etal heat block. Selective MW heating of polar solutea ggregates is postulated to explain these observations.We recently reported as ynthesis of illudinine [1] in conjunction with broader efforts to produce targets of interestb earing neopentylene ring fusions. [2] Previously reported syntheses of illudinine required 14 [3] to 16 [4] steps, many of which were dedicated to craftingt he neopentylene ring fusion.…”

“…So-called "non-thermal" effectst hat relate to quantum mechanical resonant-energy transfer process have been discussed in detail elsewhere; [7,16,17] they are not invoked here and are dubiousi na ny case of MW heating.I nt he selective heating model, thermalr eactivity deviates from temperature-based expectations because the measured system temperatured oes not fully reflect the thermal energy of the selectively heated components. [19] Selectiveh eating can provide strategica dvantages in chemical synthesis.This reactions ystem is our first example that (1) demonstratesastrategic advantageo fM Wh eating,a nd that (2) we considert ob eo fp ractical synthetic utility [18] (e.g.,b ecause of its central role in our illudinine synthesis [1] ). Our previousr eports [13, 14] feature highlys pecialized reactiond esignso fl imited synthetic utility in order to observe significant MW-specific rate accelerations:open quartz glassware, unusualhydrocarbon solvents (e.g., p-xylene and naphthalene), dilute reactionc onditions, and dynamic temperature and/orp ower profilest hat can be sensitive to equipment parameters and variables like flask size ands hape, wall thickness, etc.…”

“…We recently reported as ynthesis of illudinine [1] in conjunction with broader efforts to produce targets of interestb earing neopentylene ring fusions. [2] Previously reported syntheses of illudinine required 14 [3] to 16 [4] steps, many of which were dedicated to craftingt he neopentylene ring fusion.…”

A Catalytic Strategy for α,ω‐Functionalization: NHC‐Mediated Fragmentation/Umpolung Cascades to Access Hydroxytrifluoromethyl Ynones and Allenones

“…[1] Aside from approaches using well-established aldehyde/ bisulfite adducts and paraldehyde or paraformaldehyde depolymerization, Dudley and co-workers recently have introduced vinylogous hemiacetal triflates (VHATs) as corresponding advanced precursor systems yielding instable ynals by basemediated, heterolytic Grob-fragmentation (Scheme 1, I). [2,3] Being only isolable in unsatisfactory yields, the aldehydes were trapped in situ within reaction cascades employing stoichio-metric or excess amounts of different nucleophiles in classical, non-catalytic transformations, including Grignard additions, Horner-Wadsworth-Emmons or Knoevenagel reactions (Scheme 1, II) [4][5][6] With cascade reactions generally holding obvious advantages over multistep procedures such as the avoidance of intermittent isolations or costly protection group chemistry, this concept affords a variety of ynols and enynes in only one single step. [7] To further broaden the scope of this elegant approach and in the context of our program on NHC catalysis in multicatalytic settings, [8] we became interested whether these stoichiometric follow-up reactions could be replaced by the implementation of catalytic CÀ C-bond formations.…”