Formal (4 + 1)-Addition of Allenoates to o-Quinone Methides

Abstract

The first (4 + 1)-annulation of o-quinone methides with α-branched allenoates as C1 synthons has been developed. This operationally simple protocol gives access to highly functionalized dihydrobenzofurans in an unprecedented fashion with excellent diastereoselectivities and high yields.

Enantioselective Catalytic [4+1]‐Cyclization of ortho‐Hydroxy‐para‐Quinone Methides with Allenoates

“…Two years ago we reported the first highly enantioselective synthesis of compounds 1 by reacting preformed chiral ammonium ylides with in situ formed o ‐QMs 2 . More recently we found that the highly functionalized allenoates 4 can undergo a very unique (and up to then unprecedented) formal [4+1]‐cyclization with acceptors 2 in the presence of a stoichiometric amount of PPh 3 (Scheme C) . The (unexpected) outcome of this reaction was in sharp contrast to other previously described reactions between o ‐QMs 2 and (differently substituted) allenoates, which all resulted in formal [4+2]‐annulations .…”

“…The (unexpected) outcome of this reaction was in sharp contrast to other previously described reactions between o ‐QMs 2 and (differently substituted) allenoates, which all resulted in formal [4+2]‐annulations . Unfortunately however, we were only able to carry out this reaction in racemic manner, as even the use of a stoichiometric amount of different commonly used chiral phosphine catalysts gave low yields and poor enantioselectivities only . In especially we found that the in situ formed o ‐QMs 2 decomposed rather rapidly under the previously developed reaction conditions, thus making a catalytic approach difficult.…”

“…By testing other bases, K 2 CO 3 turned out to be the most promising (entry 7). It should be noted that other simple trialkylphosphines were tested as well, but in analogy to our previous observation these did not allow for this [4+1]‐annulation.…”

“…Mechanistically this is a rather complex reaction and it should be admitted that so far, we only have some hints that may allow us to postulate the mechanistic scenario depicted in Scheme . This proposal is also based on our recent observations made for the racemic [4+1]‐annulation of o ‐QMs 2 where we found that intramolecular rapid proton transfers are crucial to explain the outcome of this [4+1]‐cyclization …”

“…The 2,3-dihydrobenzofuran scaffold is ap rominent structural motif foundi nn umerous biologically active (natural) compounds [1] and the development of novel synthesis strategies to access these targets has been ah eavily investigatedt opic over the last years. [2][3][4][5][6][7][8] One especially appealing approach to access chiral 2,3-dihydrobenzofurans is the formal [4+ +1]-cyclization [9] between as uitable C1 buildingb lock and ac arefully chosen (maybe in situ generated)a cceptor-donor containing C4 building block. The mostv ersatile class of C4 building blocks used to obtain the dihydrobenzofuran skeleton 1 via af ormal [4+ +1]cyclization are ortho-quinone methides (o-QMs) 2.…”