Synthesis of Many Different Types of Organic Small Molecules Using One Automated Process

RESEARCH | REPORTS ORGANIC SYNTHESIS ally synthesized in prior studies using this strategy (16–19). With this promising starting point, we set out Synthesis of many different types of to expand the scope of this platform to include all of the structures shown in Fig. 1A. Csp3-rich cyclic and polycyclic natural product frameworks such organic small molecules using one as 10 to 14 represent especially challenging tar- getsandthusrequiredastrategicadvance.Be- automated process causemanyofthesemoleculesarebiosynthesized via cyclization of modular linear precursors derived from iterative building block assembly Junqi Li,* Steven G. Ballmer,* Eric P. Gillis, Seiko Fujii, Michael J. Schmidt, (10–12), we hypothesized that an analogous linear- Andrea M. E. Palazzolo, Jonathan W. Lehmann, Greg F. Morehouse, Martin D. Burke† to-cyclized strategy might enable this platform to access many such structures. In this approach, Small-molecule synthesis usually relies on procedures that are highly customized for each the same building block assembly process is used target. A broadly applicable automated process could greatly increase the accessibility to generate a linear precursor, which is then of this class of compounds to enable investigations of their practical potential. Here (poly)cyclized into the topologically complex pro- we report the synthesis of 14 distinct classes of small molecules using the same fully duct. The stereochemical information in the build- automated process. This was achieved by strategically expanding the scope of a building ing blocks is first translated into linear precursors block–based synthesis platform to include even Csp3-rich polycyclic natural product via stereospecific couplings and then into the tar- frameworks and discovering a catch-and-release chromatographic purification protocol geted products via stereospecific and/or stereo- applicable to all of the corresponding intermediates. With thousands of compatible selective (poly)cyclization reactions. To enable building blocks already commercially available, many small molecules are now accessible such cyclizations, such linear precursors must be with this platform. More broadly, these findings illuminate an actionable roadmap to a suitably flexible and, therefore, rich in sp3 hybrid- more general and automated approach for small-molecule synthesis. ized carbons. Building block–based assembly of these precursors thus requires many Csp3 cou- mall molecules perform many important sents a major challenge. However, like peptides, plings, which can be challenging. functions in nature, medicine, and tech- oligonucleotides, and oligosaccharides, most nat- To test this linear-to-cyclized strategy, we targeted on September 14, 2015 nology. However, efforts to discover and ural products (such as 1 to 4) are biosynthesized the manual synthesis of the highly complex pen- S optimize new small-molecule function are via the iterative assembly of a small set of build- tacyclic secodaphnane alkaloid core 14.Thiscore often impeded by limitations in synthetic ing blocks, such as malonyl coenzyme A, iso- can, in theory, be derived from a much simpler access to this class of compounds. For peptides pentenyl pyrophosphate, and pyruvic acid (8). linear precursor 15 via a bioinspired cyclization (1) and oligonucleotides (2), the development of Many materials and pharmaceuticals (such as 5 cascade involving amine condensation and intra- automated synthesis platforms removed this bot- to 9) comprise collections of aryl and/or hetero- molecular Diels-Alder and Prins cyclizations (20). tleneck. The resulting expanded access to these aryl components (9). Even topologically complex In turn, 15 was targeted via the iterative assembly molecules permitted widespread exploration and natural products containing macrocyclic or poly- of building blocks 16 to 18 in which all of the re- applications of their functional potential. Substan- cyclic frameworks (such as 10 to 14) are usually quired double bond stereochemistry is preinstalled. www.sciencemag.org tial progress has also been made toward automat- biosynthesized via an iterative building block– Csp3 coupling of 16 and 17 generates MIDA bo- ing the synthesis of oligosaccharides (3). In each based assembly of linear precursors, which are ronate intermediate 19.Deprotectionof19 yields a of these cases, automation was enabled by the then (poly)cyclized to yield more complex mo- free boronic acid, which is engaged in another Csp3 development of a general building block–based lecular architectures (10–12). This analysis suggests coupling with 18 to complete the iterative assembly synthesis strategy and a common purification pro- that many small molecules might be accessible of linear precursor 15. The aforementioned diaster- cess for the corresponding intermediates. Such via a common, biosynthesis-inspired strategy in- eoselective cyclization cascade is then used to standardization reduced the number of processes volving the iterative assembly of building blocks. transform 15 into the pentacyclic alkaloid (T)-14. employed and thus decreased the number of chal- Supporting this notion, we recently demonstrated Having established a strategy to access even lenges involved in automating the synthesis plat- that more than 75% of all polyene natural product topologically complex small molecules using the Downloaded from form. In contrast, despite tremendous progress motifs can be prepared using just 12 building same building block–based approach, we next in the field, small-molecule syntheses typically blocks and one coupling reaction (13). questioned whether a common purification pro- employ strategies and purification methods that That study employed a synthesis platform anal- tocol could also be developed and thereby enable are highly customized for each target, thus re- ogous to iterative peptide coupling that sequential- this platform to be automated. Small-molecule quiring automation solutions to be developed ly assembles bifunctional N-methyliminodiacetic synthesis typically involves purifications custom- on an ad hoc basis (4–7). To enable the more gen- acid (MIDA) boronates (Fig. 1B) (14). Iterative ized for each intermediate, such as chromatog- eralized automation of small-molecule synthesis, cycles of coupling and deprotection are enabled raphy with eluents optimized for each compound. we asked whether many different types of small by the MIDA ligand, which attenuates the re- Such customization is incompatible with gener- molecules could be prepared using a common activity of boronic acids and thus prevents un- alized automated purification. Solid-phase syn- building block–based strategy and a common pu- desired oligomerization. This approach is both thesis can address this problem for peptides (1), rification process. efficient and flexible because all of the required oligonucleotides (2), oligosaccharides (3), and some Small molecules can be very diverse in struc- functional groups, oxidation states, and stereo- organic polymers (21). In some cases, syntheses ture, as illustrated by representative compounds chemical elements are preinstalled into the build- of natural products and pharmaceuticals have 1 to 14 in Fig. 1A. Synthesis of this entire set of ing blocks. These features are then faithfully also been aided by solid-phase methods (22). This targets using a common approach thus repre- translated into the products using the same approach is well established, is compatible with a mild and stereospecific coupling chemistry (15). wide range of chemistries, and has been employed Hundreds of MIDA boronates and thousands in industry (23). However, small molecules do not Howard Hughes Medical Institute (HHMI), Department of of additional halide and boronic acid building possess a common functional group handle for Chemistry, University of Illinois at Urbana-Champaign, blocks are now commercially available, and attachment to solid support, which precludes gen- Urbana, IL 61801, USA. *†These authors contributed equally to this work. †Corresponding natural products from most major biosynthetic eralized application of this approach. Thus, we author. E-mail: [email protected] pathways, including 1 to 4, have been manu- needed a different solution. SCIENCE sciencemag.org 13 MARCH 2015 • VOL 347 ISSUE 6227 1221 RESEARCH | REPORTS Fig. 1. Common building block–based approach for making many different types of small molecules. (A) A collection of compounds representing the structural and functional diversity of small molecules. tBu, tert-butyl. (B) Analogous building block–based strategies for the synthesis of peptides and small molecules. R, amino acid side chains. (C)SynthesisoftheCsp3-rich pentacyclic secodaphnane core (T)-14 via iterative Csp3 couplings to yield a linear precursor followed by biosynthesis-inspired cascade polycyclization. An x-ray crystallographic study of the N-bromoacyl derivative of 14 unambiguously confirmed the structure of 14. TIPS, triisopropylsilyl; Ph, phenyl; DMSO, dimethyl sulfoxide. We recognized that each iteration of building the eluent to THF. The MIDA boronate motif The coupling module then heats and stirs a so- block assembly in our platform generates a MIDA can thus serve as both a latent reactive function- lution of the next building block and the coupling boronate as the key intermediate (Fig. 1, B and C). al group for iterative coupling and a traceless reagents. The synthesizer then adds the freshly This led us to question whether the MIDA bo- common functional group handle for general- prepared

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