&Mannich Reaction Iridium-Catalyzed Reductive Nitro-Mannich Cyclization

A new chemoselective reductive nitro-Mannich cyclization reaction sequence of nitroalkyl-tethered lactams has been developed. Relying on the rapid and chemoselective iridium(I)-catalyzed reduction of lactams to the corresponding enamine, subsequent nitro-Mannich cyclization of tethered nitroalkyl functionality provides direct access to important alkaloid natural-product-like structures in yields up to 81% and in diastereoselectivities that are typically good to excellent. An in-depth understanding of the reaction mechanism has been gained through NMR studies and characterization of reaction intermediates. The new methodology has been applied to the total synthesis of (œ)-epi-epiquinamide in four steps. Reaction cascades are becoming mainstream in organic synthesis, allowing the synthesis of advanced structures with fewer purification steps, increased speed and efficiency. 2] The development of new cascade sequences can be either methodologyor target-driven and in a few cases they can provide the critical link from a late stage intermediate to the end-game sequence in a total synthesis. To this end we recently reported an unprecedented chemoselective reductive nitro-Mannich cyclization of 1 proceeding via a putative iminium intermediate to form the B ring in manzamine A (2) (Scheme 1). Recognising the synthetic potential of this novel annulation strategy, we wanted to investigate whether an analogous reductive nitro-Mannich cyclization of N-linked lactam substrates of type 3 was feasible. Such chemistry would allow direct access to fused nitrogen-containing bicycles of type 5 via reactive iminium ion intermediates 4 (Scheme 2). These motifs are abundant in nature, making up major classes of alkaloid natural products which show important biological activity. 10] In addition, the presence of the versatile nitro group could be exploited as a handle to access, for example, ketone and amine functionality. As such the new methodology would be useful for natural product and library synthesis alike. Herein we wish to report our findings. Readily prepared caprolactam-derived substrate 3a was selected as a model system and initially subjected to the modified Buchwald conditions used in the synthesis of manzamine A. 13] Pleasingly we were able to isolate the desired bicycle 5a albeit in only 17% yield (Table 1, entry 1). A range of typical hydridic reducing agents including DIBAL (diisobutylaluminiumhydride) and Schwartz reagent ([ZrCl(C5H5)2H]) were screened. Unfortunately, in all cases poor yields and/or full reduction products were observed. However, inspired by the work of Nagashima, an attempted reduction of 3a using substoichiometric Vaska’s complex [IrCl(CO)(PPh3)2] [15] (2.5 mol%) and silane (TMDS or PMDS) resulted in the desirable formation of 5a in 23 and 36% yield, respectively (Table 1, entries 2 and 3). Quenching the reaction with 1m HCl allowed efficient removal of excess silane and its by-products. Basification, extraction and purification afforded 5a in improved yield (Table 1, entry 4). With this promising method in hand we attempted to lower the catalyst loading (Table 1, entries 4–6). Pleasingly lowering to 0.1% had little detrimental impact on the yield; however, for practicality (in weighing out the catalyst) we chose to use 0.5 mol% of Vaska’s complex. A solvent screen (Table 1, entries 7–9) revealed that toluene was indeed the best solvent. The concentration of the reaction was an important parameter, with high dilution leading to an inScheme 1. Reductive nitro-Mannich cascade in the total synthesis of manzamine A. Scheme 2. Proposed partial reductive nitro-Mannich cyclization concept. [a] A. W. Gregory, A. Chambers, Dr. A. Hawkins, Dr. P. Jakubec, Prof. Dr. D. J. Dixon Department of Chemistry, Chemistry Research Laboratory University of Oxford, Mansfield Road, Oxford OX1 3TA (UK) E-mail : [email protected] Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/chem.201405256. Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH & Co. KGaA. This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. Chem. Eur. J. 2015, 21, 111 – 114 Ó 2015 The Authors. Published by Wiley-VCH Verlag GmbH&Co. KGaA, Weinheim 111 Communication DOI: 10.1002/chem.201405256