COMMUNICATION One-pot Transformation of Simple Furans into Octahydroindole Scaffolds Dimitris Kalaitzakis, Myron Triantafyllakis, Georgios I. Ioannou and Georgios Vassilikogiannakis * Dedication ((optional)) Abstract: A highly efficient and general singlet-oxygen initiated one- pot transformation of readily accessible furans into octahydroindole scaffolds has been developed. How to increase the molecular complexity of a simple precursor in a minimum number of synthetic operations is one of the foremost considerations of synthetic chemists today. One-pot reaction sequences [1] not only usually increase molecular complexity substantially and reduce the steps of a synthetic sequence (step economy), [2] but also demonstrate synthetic elegance and creativity. [3] Furthermore, the avoidance of protecting groups, nonstrategic redox manipulations and other functional group interconversions is also very important in order to shorten synthetic approaches. [4] The quality of a new method may be correlated to the number of non-concessionary bonds generated in a single synthetic operation. [5] With these criteria in mind, carbo-[3+3] annulations seem to be packed with potential because of their ability to form multiple bonds simultaneously with excellent stereochemical control. [6] The most common products of these reactions are bicyclo- [3.3.1] adducts [7] or cyclohexane derivatives. [8] Even though the diversity of the structures that can be assembled is potentially huge, to the best of our knowledge, these reactions have never Scheme 1. General structures of natural alkaloids containing the octahydroindole scaffold. [9] been investigated for the construction of fused 1-azabicyclic systems. The 1-azabicyclic [4.3.0] system is the core structural unit of a wide range of biologically active natural products and is usually given the term octahydroindole (OHI, Scheme 1). [9] The ubiquity of the scaffold has prompted the development of several efficient methodologies for the synthesis of octahydroindoles. [10] Nevertheless, various complexities associated with accessing OHI scaffolds, have rendered the development of more versatile and sustainable synthetic approaches starting from readily accessible precursors, highly imperative. Herein, we introduce an innovative methodology for the synthesis of a wide variety of OHI motifs. The key synthetic intermediate is the 2-pyrrolidinone of type 3 derived from the reaction of singlet oxygen with simple furans 1 [11] followed by treatment with Me2S and primary amines 2 (Scheme 2). [12] Specifically, we had envisioned that 2-pyrrolidinone 3 could serve as an electron rich dienophile, and, consequently, participate in an inverse electron demand hetero Diels-Alder reaction [13] with electron poor α,β-unsaturated carbonyl partner compounds 4. [14] Although the expected tetrahydropyranopyrrolone (THPP) product 5 (Scheme 2) is itself an important structural unit, [15] investigation of the potential rearrangement of 5 to the desired OHI scaffolds of type 6 through the intermediates 5i and 5ii was our primary intention. The transformation of 2-pyrrolidinone 3 into the final product 6 (Scheme 2) can be considered to be a [3+3]-annulation. Initially, we studied the first part of the proposed transformation (1 → 5). In particular, we investigated the progress of the Diels-Alder reaction of 2-pyrrolidinone 3a [derived from 2-methylfuran (1a) and benzylamine (2a) using our standard singlet oxygen protocol] [12] with acrolein (4a) in different Scheme 2. Envisioned scenario for the synthesis of octahydroindole scaffolds from furans. [a] Dr. D. Kalaitzakis, M. Triantafyllakis, G. I. Ioannou, Prof. Dr. G. Vassilikogiannakis Department of Chemistry, University of Crete Vasilika Vouton, 71003, Iraklion, Crete, Greece E-mail: vasil@chemistry.uoc.gr Homepage: www.chemistry.uoc.gr/vassilikogiannakis Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))