One-pot Synthesis of the Tetracyclic Framework of the Aromatic Erythrina Alkaloids from Simple Furans

Abstract

Conversion of a simple furan into the intact erythrinane skeleton in one synthetic operation has been accomplished. The one-pot reaction sequence begins with singlet oxygen photooxygenation of the furan and proceeds via a 2pyrrolidinone formation, cyclization of the pendant aldehyde moiety and an N-acyliminium ion formation and terminates with a Pictet-Spengler-type aromatic substitution. The method has been used to achieve a rapid and highly effective formal synthesis of erysotramidine. The aromatic (D ring) erythrina alkaloids (Figure 1) have long captured researchers' imaginations due to their characteristic and wide-ranging profile which combines a complex web of biogenetic relationships, potent biological activities, and synthetically challenging polycyclic molecular architectures. 1 Strategies for the assembly of their tetracyclic frameworks are, as expected, numerous, 2, 3, 4 but, right from the outset, 5 construction Programme (FP7/2007-2013)/ERC grant agreement no. 277588 Supporting Information Available. Experimental procedures, full spectroscopic data and copies of 1 H and 13 C-NMR spectra for all new compounds. This material is available free of charge via the Internet at http://pubs.acs.org.

Singlet oxygen-mediated transformation of furans into aromatic nitrogen-containing polycycles in water

“…It shows how water is expected to participate as a reactant and why the use of water as solvent might cause a serious deviation from what had been accomplished previously. [22][23][24] Singlet oxygen, generated photochemically, typically first undergoes a [4+2]-cycloaddition with the furan substrate to give an ozonide (not shown). It is reasonable to suggest that the solvent, in this case water, might open the ozonide adduct to give a hydroxy-hydroperoxy intermediate B.…”

“…31 Under aqueous conditions, we propose that the equilibria between B, C and D is sidelined by the collapse of the open chain hydroperoxy ketone C affording the unsaturated keto-aldehyde E, which would in turn be the subject of an attack by the newly introduced amine (E → F). It should be emphasized here that no reductant (such as the Me 2 S utilized in such sequences [21][22][23][24] ) shall be used as an additive, thus the new protocol will not only be undertaken in an environmentally benign solvent, but will also work in a more succinct manner and have a reduced number of additives/reagents than previous methods. A series of reorganizing equilibria could then afford cation H, deprotonation of which affords the isolable, but fairly fragile, intermediate I that had been observed in previous studies.…”

“…A series of reorganizing equilibria could then afford cation H, deprotonation of which affords the isolable, but fairly fragile, intermediate I that had been observed in previous studies. [21][22][23][24] Since the last stages of this mechanistic analysis are common to the Pictet-Spengler reaction in methanol 22 the first and most important task was to validate the early steps of the proposed sequence. To this end, the simple furan 1a was photooxygenated using our standard conditions: bubbling oxygen through the reaction solution containing catalytic rose Bengal at 5 °C while irradiating with visible spectrum light (Scheme 2).…”

“…[15][16][17] Beyond its many advantages as a green reagent, singlet oxygen is an ideal player in sustainable chemistry because it is both highly selective in its reactions, which eliminates the need for protecting groups and non-strategic redox manipulations, 17 and because it readily initiates one pot reaction sequences that can accomplish dramatic increases in molecular complexity in a single operation. [18][19][20] Recently, we have explored ways to include basic nitrogen components in such sequences, [21][22][23][24] so that not only polyoxygenated, but also nitrogen-bearing, polycycles can be targeted. In a new method, 22,23 we combined the singlet oxygenphotooxidation of simple furans with the introduction into the reaction sequence of both a basic nitrogen reactant and a Pictet-Spengler cyclisation; [25][26][27] thus, affording in one operation various aromatic nitrogen containing-polycycles that are present in many natural products and other bioactive targets.…”

“…[18][19][20] Recently, we have explored ways to include basic nitrogen components in such sequences, [21][22][23][24] so that not only polyoxygenated, but also nitrogen-bearing, polycycles can be targeted. In a new method, 22,23 we combined the singlet oxygenphotooxidation of simple furans with the introduction into the reaction sequence of both a basic nitrogen reactant and a Pictet-Spengler cyclisation; [25][26][27] thus, affording in one operation various aromatic nitrogen containing-polycycles that are present in many natural products and other bioactive targets. This method, however, required the use of methanol and chlorinated solvents, neither of which can be part of a complete sustainable paradigm.…”