Tandem Enyneacetal-Nazarov Brønsted-Acid-Promoted Carbocyclizations Affording Hydroazulenones

The presence of hydroazulen(on)e skeletons in many bioactive natural products, such as guanacastepene[1] or pleocarpenone,[2] has resulted in sustained interest in their synthesis. A wide variety of approaches have been described.[3] The most common, other than the use of rearrangement reactions,[3,4] have started from the fivemembered ring, on which the seven-membered ring has been assembled by ring enlargement, reductive cyclization, metathesis or aldol condensation.[3, 5 ] Alternatives for constructing the fivemembered ring on the seven-membered ring have employed metathesis, aldol condensation, ring expansion or Nazarov cyclization.[3,6] Highly efficient approaches in which both rings are created in one pot have also been developed, most of them involving metalcatalyzed cycloaddition reactions (Scheme 1).[7-14] Thus Wender and coworkers have used both intramolecular Rh-catalyzed [5+2] cycloaddition (Scheme 1, path a)[7a] and intermolecular tandem Rhcatalyzed [5+2]/Nazarov cyclization;[7b] Trost and coworkers have explored [5+2] cyclization protocols using Ru catalysts;[ 8 ] Mascareñas and coworkers have employed Pdand Pt-catalyzed [4+3] cycloaddition[9] (Scheme 1, path b);[10] and Ahmar et al.,[11a] Brummond et al.[11b] and Mukai et al.[11c] have reported various approaches via allenic reactions of Pauson-Khand type (Scheme 1, path c).[12] Strategies based on the cyclization of acyclic dienynes, mediated[ 13a] or catalyzed[13b] by metal carbenes, have also been reported (Scheme 1, paths d and e).[14] As a contribution to the development of metal-free, environmentally less hazardous synthetic methods,[15] we recently described an efficient intramolecular cyclization of alkynals promoted by Brønsted acids.[16,17] Here we report its use in tandem with Nazarov cyclization[7b, 18 ] to construct hydroazulenone skeletons 2 from enyneacetals 1[19] (Scheme 1).[20] [5+2] [4+3]