DOI: 10.1002/adsc.201200045 Copper Carbenoid, Reactant and Catalyst for One-Pot Diazo Ester Coupling Cascade Rearrangement of Enediynes: Formation of Two Contiguous Tetrasubstituted Stereocenters Shovan Mondal, a Malek Nechab, a, * Damien Campolo, a Nicolas Vanthuyne, b and Michle P. Bertrand a, * a Aix-Marseille UniversitØ, CNRS, Institut Chimie Radicalaire (ICR), UMR 7273, 13397 Marseille Cedex 20, France E-mail: malek.nechab@univ-amu.fr or michele.bertrand@univ-amu.fr b Aix-Marseille UniversitØ, CNRS, ISM2 UMR 7313, 13397 Marseille Cedex 20, France Received: January 17, 2012; Published online: July 2, 2012 Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200045. Abstract: The copper-catalyzed reaction of ene- diynes with diazo esters leads to cyclic amino esters bearing two contiguous tetrasubstituted stereogenic centers through a one-pot, five-step cascade. Copper iodide catalyzes the formation of an intermediate 3- alkynoate and copper carbenoid promotes its reversi- ble isomerization to the corresponding allenoate. The alkynoate-allenoate equilibrium is completely shifted to the right by the rapid consumption of the allenoate by Myers–Saito cyclization. This is fol- lowed by 1,5-H atom transfer and recombination of the resulting biradical. Memory of chirality phenom- enon explains the high enantioselectivity. Keywords: allenes; carbenoids; diazo compounds; enediyne rearrangement; memory of chirality; radi- cal reactions Introduction Interest in the chemistry of enediynes and enyne-al- lenes has dramatically increased since the discovery of the antitumor activity of natural enediynes. [1] The bioactivity of enediyne-connected amino esters, nota- bly the evaluation of enediyne peptide conjugates as DNA damaging and protein cleavage agents, has been the subject of recent interest. [2] However, their chemi- cal reactivity has hardly been explored. [3–6] Investigations of the enantioselective rearrange- ment of this type of enediynes were recently started in our group. [7,8] The Myers–Saito cycloaromatization of substrates where the formation of the key allenic motive is activated by a base-catalyzed 1,3-proton shift from a propargylic sulfone was investigated first. [7] These reactions were shown to lead to cyclic amino esters bearing a tetrasubstituted stereogenic center adjacent to a tertiary one, in good yields and with a high level of enantioselectivity based on memory of chirality phenomenon. [9] The CrabbØ ho- mologation of related terminal enediynes leads direct- ly through a one-pot procedure to polycyclic amino esters with a very high stereocontrol of the unique tetrasubstituted center. [8] Searching to devise a one-pot route to potentially bioactive analogues [10] bearing two contiguous tetra- substituted stereocenters, we were interested in apply- ing the strategy published in 2004 by Fu for the prep- aration of 3-alkynoates. [11a] As exemplified in Scheme 1, in this very simple procedure alkyne 1, 1 equivalent of ethyl diazoacetate (Figure 1), and Scheme 1. Cu-catalyzed coupling of phenylacetylene with ethyl diazo ester. Figure 1. Structures of diazo esters 7. Adv. Synth. Catal. 2012, 354, 1987 – 2000 # 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 1987 FULL PAPERS