Organic chemists are now able to synthesize small quantities of almost any known natural product, given sufficient time, resources and effort. However, translation of the academic successes in total synthesis to the large-scale construction of complex natural products and the development of large collections of biologically relevant molecules present significant challenges to synthetic chemists. Here we show that the application of two nature-inspired techniques, namely organocascade catalysis and collective natural product synthesis, can facilitate the preparation of useful quantities of a range of structurally diverse natural products from a common molecular scaffold. The power of this concept has been demonstrated through the expedient, asymmetric total syntheses of six well-known alkaloid natural products: strychnine, aspidospermidine, vincadifformine, akuammicine, kopsanone and kopsinine.

A highly efficient synthesis of sitagliptin, a potent and selective DPP-4 inhibitor for the treatment of type 2 diabetes mellitus (T2DM), has been developed. The key dehydrositagliptin intermediate 9 is prepared in three steps in one pot and directly isolated in 82% yield and >99.6 wt % purity. Highly enantioselective hydrogenation of dehydrositagliptin 9, with as low as 0.15 mol % of Rh(I)/(t)Bu JOSIPHOS, affords sitagliptin, which is finally isolated as its phosphate salt with nearly perfect optical and chemical purity. This environmentally friendly, 'green' synthesis significantly reduces the total waste generated per kilogram of sitagliptin produced in comparison with the first-generation route and completely eliminates aqueous waste streams. The efficiency of this cost-effective process, which has been implemented on manufacturing scale, results in up to 65% overall isolated yield.

An enantioselective total synthesis of the Strychnos alkaloid (+)-minfiensine has been accomplished. Prominent features of this synthesis include (i) a new enantioselective organocatalytic Diels–Alder/amine cyclization sequence to build the central tetracyclic pyrroloindoline framework in four steps from commercial materials and (ii) a 6-exo-dig radical cyclization to forge the final piperidinyl ring system. This total synthesis of (+)-minfiensine was completed in nine chemical steps and 21% overall yield.

Keywordscascade reactions; enantioselectivity; natural products; organocatalysisThe discovery of new strategies that emulate nature's capacity to rapidly construct architectural complexity continues to be a central focus for research and development in the chemical sciences.[1] Recently, our laboratory disclosed the concept of organocascade catalysis,[2-4] a new chemical paradigm that combines two modes of catalyst activation (iminium and enamine catalysis) into one mechanism, thereby allowing the rapid conversion of simple achiral starting materials into stereochemically complex, single-enantiomer products (≥99% ee,Scheme 1a).[5] As a critical design feature, we revealed that the merger of these two activation modes can render a variety of transformations that are not yet possible using monocyclic catalysis pathways (e.g. enantioselective HCl, HF, and aryl-Cl addition across olefins).[2] Moreover, we realized the ideal of cycle-specific catalysis, wherein each cycle in the cascade sequence is moderated by a different chiral amine catalyst, a scenario that enables selective access to any product enantiomer or diastereomer by judicious catalyst selection. Our initial studies on cycle-specific catalysis employed a combination of two chiral imidazolidinone catalysts, a system that was particularly effective for olefin hydrohalogenation.[3a] Herein we describe the use of imidazolidinone 1[6] and proline (2) [7] as a dual-catalyst system that allows access to a greatly expanded array of valuable transformations including olefin hydroamination, hydro-oxidation, and aminooxidation. As a further milestone, we report the first use of this organocascade catalysis as a strategy for natural product synthesis by the enantioselective construction of the sesquiterpene (−)-aromadendranediol.Over the last 10 years, imidazolidinones (such as 1) have been established as LUMOlowering iminium catalysts that can be employed in a wide variety of enantioselective transformations including conjugate additions, Friedel-Crafts alkylations, hydrido reductions, and cycloadditions.[8] While imidazolidinones can also serve as enamine catalysts,[9] they do not contain the necessary structural features to participate in bifunctional enamine catalysis (wherein activation of the electrophilic reaction partner is

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