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Fully automated synthetic chemistry would substantially change the field by providing broad on-demand access to small molecules. However, the reactions that can be run autonomously are still limited. Automating the stereospecific assembly of C sp 3 –C bonds would expand access to many important types of functional organic molecules 1 . Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of C sp 2 –C sp 2 bonds and were effective building blocks for automating the synthesis of many small molecules 2 , but they are incompatible with stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 3 bond-forming reactions 3 , 4 , 5 , 6 , 7 , 8 , 9 – 10 . Here we report that hyperconjugative and steric tuning provide a new class of tetramethyl N -methyliminodiacetic acid (TIDA) boronates that are stable to these conditions. Charge density analysis 11 , 12 – 13 revealed that redistribution of electron density increases covalency of the N–B bond and thereby attenuates its hydrolysis. Complementary steric shielding of carbonyl π-faces decreases reactivity towards nucleophilic reagents. The unique features of the iminodiacetic acid cage 2 , which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled C sp 3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific C sp 3 –C sp 2 and C sp 3 –C sp 3 bond formation. These findings will enable increasingly complex C sp 3 -rich small molecules to be accessed via automated assembly. Identification of a hyperstable boronate enables automated lego-like synthesis to access a wider range of three-dimensionally complex small organic molecules rich in C sp 3 –C bonds. 

Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the highly customized approach that is currently used to synthesize this class of chemical matter. An alternative ‘building block approach’ — that is, generalized iterative assembly of interchangeable parts — has now proved to be a highly efficient and flexible method of constructing things ranging from skyscrapers and macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that already improve access to specific classes of small molecules. There has also been substantial recent progress towards the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small-molecule synthesis may be within reach. Iterative approaches to synthesis have revolutionized the preparation and study of peptides, nucleic acids and sugars. This Review discusses whether and how such iterative syntheses can be applied more broadly towards an ultimate goal of developing a building block approach to the synthesis of most small organic molecules.

Stereocontrolled Csp 3 cross-coupling can fundamentally change the types of chemical structures that can be mined for molecular functions. Although considerable progress in achieving the targeted chemical reactivity has been made, controlling stereochemistry in Csp 3 cross-coupling remains challenging. Here we report that ligand-based axial shielding of Pd(II) complexes enables Suzuki-Miyaura cross-coupling of unactivated Csp 3 boronic acids with perfect stereoretention. This approach leverages key differences in spatial orientation between competing pathways for stereoretentive and stereoinvertive transmetalation of Csp 3 boronic acids to Pd(II). We show that axial shielding enables perfectly stereoretentive cross-coupling with a range of unactivated secondary Csp 3 boronic acids, as well as the stereocontrolled synthesis of xylarinic acid B and all of its Csp 3 stereoisomers. We expect these ligand design principles will broadly enable the continued search for practical and effective methods for stereospecific Csp 3 cross-coupling. Despite the progress in C(sp 3 ) cross-coupling reactions, full control over the stereochemistry remains a challenge. Here, the authors show that phosphine-containing axially shielded Pd(II) complexes enable Suzuki-Miyaura cross-couplings of unactivated C(sp 3 ) boronic acids with perfect stereoretention.

An ancient resistance mechanism poses a problem when using streptogramin antibiotics. A modular approach to drug synthesis exploits this same mechanism to generate an antibiotic that avoids the emergence of resistance. A resistance-evading streptogramin antibiotic.

[...]modularity is a powerful enabler of creativity: because many variants can be rapidly assembled and tested, researchers can make almost any target that they want. [...]unlike conventional small-molecule synthesis, the price of failure is not high - it doesn't matter if any given compound lacks the desired biological activity, because many others can be prepared, thereby increasing the likelihood of finding active small molecules. [...]the allyl group points towards the binding site for group B streptogramins in the exit tunnel, and seems to make favourable contacts with three nucleotides in the tunnel that are not contacted by VM2. Li et al. also obtained an X-ray crystal structure of the new compound bound to VatA, which revealed a potential clash between the allyl group and an amino-acid residue (designated Leu 110) in the enzyme.

The automated synthesis of small organic molecules from modular building blocks has the potential to transform our capacity to create medicines and materials 1 , 2 – 3 . Disruptive acceleration of this molecule-building strategy broadly unlocks its functional potential and requires the integration of many new assembly chemistries. Although recent advances in high-throughput chemistry 4 , 5 – 6 can speed up the development of appropriate synthetic methods, for example, in selecting appropriate chemical reaction conditions from the vast range of potential options, equivalent high-throughput analytical methods are needed. Here we report a streamlined approach for the rapid, quantitative analysis of chemical reactions by mass spectrometry. The intrinsic fragmentation features of chemical building blocks generalize the analyses of chemical reactions, allowing sub-second readouts of reaction outcomes. Central to this advance was identifying that starting material fragmentation patterns function as universal barcodes for downstream product analysis by mass spectrometry. Combining these features with acoustic droplet ejection mass spectrometry 7 , 8 we could eliminate slow chromatographic steps and continuously evaluate chemical reactions in multiplexed formats. This enabled the assignment of reaction conditions to molecules derived from ultrahigh-throughput chemical synthesis experiments. More generally, these results indicate that fragmentation features inherent to chemical synthesis can empower rapid data-rich experimentation. Mass spectrometry fragmentation patterns define analytical barcodes for the rapid, quantitative analysis of high-throughput chemical synthesis experiments.

Nature Reviews Chemistry 2, 0115 (2018) The author affiliations were incorrect and should read as follows: Jonathan W. Lehmann1, Daniel J. Blair1 and Martin D. Burke1,2,3* 1Department of Chemistry, University of Illinois at Urbana-Champaign, 454 Roger Adams Laboratory, Urbana, IL, USA. 2Department of Biochemistry, University of Illinois at Urbana-Champaign, Urbana, IL, USA.

Automated iterative small-molecule synthesis has the potential to advance and democratize the discovery of new medicines, materials and many other classes of functional chemical matter. To date, however, this approach has been limited because each carbon–carbon bond-forming step takes about a day. Here we report a next-generation small-molecule synthesizer that operates an order of magnitude faster than previous systems through improvements in both chemistry and engineering. Key advances include the discovery that rapid Suzuki–Miyaura cross-couplings under homogeneous conditions, although not tolerated by N-methyliminodiacetic acid boronates, are fully compatible with their more stable tetramethyl-N-methyliminodiacetic acid boronate counterparts, and the development of optimized cartridges for rapid catch-and-release purification. These findings move the field of small-molecule synthesis a step closer to democratizing its core discovery engine.Automated iterative small-molecule synthesis has generally been limited to around one carbon–carbon bond-forming step per day. Now, a next-generation automated synthesizer enables rapid, automated, iterative synthesis of a variety of small molecules. Improvements to chemistry and automation leads to a tenfold decrease in reaction time over previous automated platforms.

Small molecules have extensive untapped potential to benefit society, but access to this potential is too often restricted by limitations inherent to the customized approach currently used to synthesize this class of chemical matter. In contrast, the \"building block approach\", i.e., generalized iterative assembly of interchangeable parts, has now proven to be a highly efficient and flexible way to construct things ranging all the way from skyscrapers to macromolecules to artificial intelligence algorithms. The structural redundancy found in many small molecules suggests that they possess a similar capacity for generalized building block-based construction. It is also encouraging that many customized iterative synthesis methods have been developed that improve access to specific classes of small molecules. There has also been substantial recent progress toward the iterative assembly of many different types of small molecules, including complex natural products, pharmaceuticals, biological probes, and materials, using common building blocks and coupling chemistry. Collectively, these advances suggest that a generalized building block approach for small molecule synthesis may be within reach.