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 Csp3–C bonds would expand access to many important types of functional organic molecules1. Previously, methyliminodiacetic acid (MIDA) boronates were used to orchestrate the formation of Csp2–Csp2 bonds and were effective building blocks for automating the synthesis of many small molecules2, but they are incompatible with stereospecific Csp3–Csp2 and Csp3–Csp3 bond-forming reactions3,4,5,6,7,8,9,10. 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 analysis11,12,13 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 cage2, which are essential for generalized automated synthesis, are retained by TIDA boronates. This enabled Csp3 boronate building blocks to be assembled using automated synthesis, including the preparation of natural products through automated stereospecific Csp3–Csp2 and Csp3–Csp3 bond formation. These findings will enable increasingly complex Csp3-rich small molecules to be accessed via automated assembly.
Automated iterative assembly of chemical building blocks broadens access to innovation at the molecular scale1. Methods for reversibly attenuating the reactivity of the functional group handles used to link such blocks are critical for these platforms. For unsaturated (Csp2-rich) organic small molecules, such lego-like assembly in automated and/or manual fashion has been achieved by many different research groups worldwide using N-methyliminodiacetic acid (MIDA) boronates2,14,15,16, which are compatible with anhydrous basic Csp2 cross-coupling conditions (Fig. 1a). An important advantage of MIDA relative to other ligands that attenuate boronic acid reactivity (for example, 1,8-diaminonaphthalene, anthranilamide, ethanolamine, fluoride)17 is that MIDA boronates display a tuneable affinity for silica gel, which permits generalized automated purification2. This unique feature enabled assembly of 14 distinct classes of small organic molecules using one automated process2.
Important areas of chemical space remain inaccessible with this first-generation platform, particularly for molecules rich in non-planar and potentially stereogenic sp3-hybridized carbon atoms (Csp3). This represents a substantial limitation, because Csp3-rich molecules constitute some of the most notable natural products, medicines18, biological probes and functional materials19. An important goal is thus to expand automated modular synthesis to include Csp3-rich small molecules.
Many recent breakthroughs in stereospecific formation of Csp3–C bonds through Suzuki–Miyaura couplings6,7 and 1,2-metallate rearrangements8,9,10 stand to enable advances in this direction (Fig. 1b). However, most of these reactions require either aqueous basic conditions that hydrolyse MIDA boronates, or nucleophilic reagents that react with MIDA boronates (Fig. 1c). In both cases loss of the MIDA protecting group will lead to uncontrolled couplings and form complex mixtures and/or oligomeric products. We thus sought hyperstable boronates to enable lego-like small-molecule synthesis via iterative Csp3–C bond formation.
Identifying a hyperstable boronate
Mechanistic studies on MIDA boronate hydrolysis provided a foundation for developing hyperstabilized variants20. There are two mechanisms for MIDA boronate hydrolysis. The first involves frustrated Lewis pair-like activation of water by the dative N–B bond. The second mechanism involves ester hydrolysis-like cleavage of a MIDA carbonyl (C=O) group by hydroxide. Steric shielding would probably protect the carbonyl carbons from hydroxide and nucleophiles, yet steric effects are known to activate frustrated Lewis pair behaviour of N–B bonds21,22,23. Although hydrolysis studies of MIDA boronates20 indicated electronic tuning of the N–B bond could be achieved via modifying the organic group attached to boron, we required a building block-independent solution. So, at the outset it was unclear whether steric or electronic effects could be leveraged to create a more stable ligand.
Using [18O]water to probe the hydrolysis of MIDA boronate 1a20, we first established the N–B bond as the primary hydrolysis mechanism under aqueous basic Csp3–Csp2 Suzuki–Miyaura coupling conditions (THF/H2O, K2CO3, 60 °C) (Fig. 2a). We thus required a MIDA derivative that could suppress the frustrated Lewis pair like reactivity of the N–B bond. To better understand this behaviour, we used 1H NMR to study the stability of a range of substituted MIDA derivatives (1b, 3–9) in deuterated solvent (THF-d8/D2O, K2CO3, 60 °C) (Fig. 2b).
Consistent with earlier precedent22,23, bulky groups on nitrogen (Fig. 2b3–5 and Supplementary Fig. 2a) increased the rate of hydrolysis relative to MIDA (1b), probably increasing N–B frustrated Lewis pair-like behaviour. Remarkably, appending two n-butyl groups (6) to the iminodiacetic acid backbone caused almost no change in hydrolysis rate relative to MIDA (1b). Reducing the size of these substituents to ethyl groups (7) and methyl groups (8) provided impressive stabilization. Finally, we prepared a boronate derived from a highly sterically hindered tetramethylated variant of N-methyliminodiacetic acid 9 (TIDA) and, surprisingly, found it was highly stable under aqueous basic Csp3-Csp2 cross-coupling conditions, with more than 99% remaining after 6 h (Fig. 2b).
Additional hydrolysis studies of TIDA boronate 21 under these conditions in protic solvent (Supplementary Figs. 3, 4), [18O] labelling (Supplementary Fig. 5) and neutral hydrolysis (Supplementary Fig. 6) indicated that TIDA boronates were cleaved via N–B bond water activation. The hyperstable TIDA boronate was retained during Csp3-Csp2 Suzuki–Miyaura reaction between Csp3 boronate 10 and bifunctional halo-TIDA boronate 11b to provide 12, whereas MIDA boronate 11a (Fig. 2c) and related N-2-benzyloxycyclopentyliminodiacetic acid (BIDA) boronate SI-14 (Supplementary Fig. 2b) gave no desired product.
Encouraged by these results, we tested the stability of TIDA boronates to iPrMgCl·LiCl, which promotes stereospecific Csp3–Csp3 bond-forming 1,2-metallate rearrangements10 (Fig. 2d). TIDA boronate 14b resists cleavage by iPrMgCl·LiCl to form the target product 15 in high yield, whereas MIDA boronate 14a is cleaved under these conditions. Remarkably, TIDA boronates even tolerated highly reactive tBuLi, enabling the formation of 18 and 19 with excellent diastereocontrol (Fig. 2e). Providing an additional practical advantage, our bifunctional sulfoxide10 TIDA boronate building blocks (that is, 14, 16 and 17) are easily handled, bench-stable solids (Supplementary Fig. 1).
X-ray crystallographic studies
The stability of 9 towards aqueous base is surprising considering the strong precedent for increased reactivity of frustrated Lewis pairs derived from tetramethylpiperidine21. Hints at the origin of this stability were found on X-ray crystallographic analysis of single crystals of MIDA boronate 1c (Fig. 3a, inset) and TIDA boronate 20 (Fig. 3b, inset), which revealed a torsional shift of greater than 10° along the N–B axis in TIDA 20 relative to MIDA 1c.
Torsional effects can substantially influence24 the magnitude of hyperconjugative stabilization (that is, staggered versus eclipsed ethane25). Torsional shifts in 20 bring three donor N–C bonds nearly antiperiplanar to three acceptor bonds (two B–O bonds and one B–C bond), potentially elevating hyperconjugation across the N–B bond. Backbone methylation would probably increase N–C donor ability, and internal angle compression in 20 (approximately 5°) suggests thermodynamic Thorpe–Ingold effects make the framework more rigid (Extended Data Fig. 1a). Both effects probably reinforce putative hyperconjugation across the N–B bond in 20. We thus questioned whether stabilizing hyperconjugative interactions across the N–B bond in TIDA boronates drives a reduction in the rate of N–B hydrolysis.
Electron distribution analysis
To probe electronic effects experimentally, we performed quantum theory of atoms in molecules (QTAIM)-based charge density analysis11,12,13 on X-ray crystal structures of MIDA boronate 1c and TIDA boronate 20. Multiple lines of evidence revealed that the dramatic reduction in hydrolysis for TIDA boronates is attributable to hyperconjugation-mediated redistribution of electron density that increases the covalency of the N–B bond.
Topology maps of crystallographically determined bonding electron density, ρ, demonstrated electron redistribution across planar slices spanning the iminodiacetic acid rings of MIDA 1c and TIDA 20 (Fig. 3a, b). Notable features of TIDA 20 included increased electron density spanning the N–B interatomic space (Fig. 3b and Extended Data Fig. 2j), and formation of a contiguous ring of electron density around the iminodiacetic acid cage (Fig. 3b). The stabilizing nature of electronic redistribution with the N–B bond of TIDA 20 was supported by a negative Laplacian of electron density ∇2ρ(r) at boron and nitrogen valence shell charge concentrations (Extended Data Fig. 3j). TIDA 20 therefore possesses an N–B bond of substantially increased covalent character.
Elongation of nitrogen-attached donor bonds and boron-attached acceptor bonds (Extended Data Fig. 1b), consistent with previous studies of anomeric26 and gauche effects27, supports threefold hyperconjugation along the N–B linkage. Anticipated increased π-character manifested localized increased ellipticity (ε)11 (Extended Data Fig. 4c, f, g, j, l, m), and redistributed electron density was supported by changes in ∇2ρ(r) (Extended Data Fig. 3e, f, k)28. Electrostatic potential maps, reduced polarization of the N–B bond29 and 11B/13C NMR shifts were also consistent with electron redistribution (Extended Data Fig. 5). Additional stabilizing electronic redistributions were found on examination of ρ, ∇2ρ(r) and ε surrounding boron-attached oxygens O1 and O4, which revealed more equal distribution of electron density directed towards boron and the carbonyl carbons for TIDA 20 compared to MIDA 1c (Extended Data Figs. 2b, c, h, i, 3b, c, h, i, 4c, d, i, j and 6).
Increased electron sharing30 is consistent with reduced propensity for frustrated Lewis pair activity31,32,33, and rationalizes the increased robustness of TIDA boronates towards N–B bond hydrolysis. Remarkably, these stark differences in N–B bond character are contrasted with similar bond lengths (MIDA 1c: 1.6613(7) Å; TIDA 20: 1.6632(5) Å).
Steric shielding of TIDA boronates
Crystallographic data for TIDA 20 also indicated that the stability of TIDA boronates towards carbon nucleophiles (iPrMgCl·LiCl and tBuLi) arises from shielding of all four π-faces of the carbonyls by the attached methyl groups (Fig. 3c and Extended Data Fig. 7a34). Comparison with organolithium-stable Beak-type benzoates35 revealed that 20 mirrors Beak-like shielding interactions via a transannular methyl group spanning the back face of the iminodiacetic acid cage (Extended Data Fig. 7b).
Synthetic utility of TIDA boronates
Reversible ligation is a requirement for deploying TIDA boronates in iterative cross-coupling-based building block assembly. An orthogonal pathway for hydrolysis involving C=O attack (Supplementary Fig. 7 and Extended Data Fig. 8a) enabled TIDA boronates (21) to be deprotected to boronic acids (22), trifluoroboronate salts (23), and boronic esters36 (24, 25) by simply using aqueous basic or protic conditions at elevated temperature (Fig. 3d).
TIDA boronates retain all other key features of their MIDA boronate counterparts that enabled automated building block-based synthesis2: TIDA ligand is accessible on the kg scale (Extended Data Fig. 8b), TIDA boronates are prepared from boronic acids under Dean–Stark conditions or by using a dehydrated form of TIDA (Extended Data Fig. 8c), TIDA boronates are stable to a wide range of common cross-coupling reactions (that is, Stille, Suzuki, Sonogashira, Heck, photochemical; see Extended Data Fig. 9) and chemical transformations (that is, oxidation, reduction, borylation, olefination; see Extended Data Fig. 10). Representative TIDA boronates retain a tuneable affinity for silica gel, being minimally mobilized in Et2O and rapidly eluted in THF (Extended Data Fig. 8d). This feature enables the TIDA boronate group to act as a tag for generalized and automated catch-and-release purification2. The heightened stability of TIDA boronates further enabled us to create a self-contained next-generation synthesis machine (Supplementary Figs. 8–11 and 13) to enable automated iterative assembly of Csp3 boronate building blocks (Fig. 4a, d).
Having established an iterative synthesis platform (Fig. 4a), we investigated a series of stereospecific Csp3–Csp2 cross-coupling reactions with bifunctional halo-TIDA boronates (Fig. 4b). Across a range of carbonate-promoted aqueous/protic stereospecific Csp3 cross-coupling reactions6,7, MIDA boronates were fully hydrolysed, whereas the corresponding TIDA boronates universally provided the desired products in good yields both in manual and automated formats (12, 26, 27 and 28). The increased stability of TIDA boronates also permitted use of stronger bases KOH (31)5 and Ag2O (30)4.
Leveraging automated Csp3–Csp2 couplings with TIDA boronates, we targeted a lego-like total synthesis of ieodomycin C37 (Fig. 4c). Building block 31 (97:3 enantiomeric ration (e.r.)) underwent automated stereospecific Csp3 cross-coupling with bifunctional TIDA boronate 32 to provide 33 in >95:5 e.r. and 50% isolated yield after automated purification. TIDA boronate enabled functional group interconversion followed by deprotection (34), and Suzuki–Miyaura cross-coupling with vinyl halide 35 furnished diene 36 and ieodomycin C after deprotection.
The tolerability of TIDA boronates to iPrMgCl·LiCl enabled 1,2-metallate rearrangements to be executed with bifunctional sulfoxide-TIDA boronate building blocks in manual and automated formats (Fig. 4d) to prepare a variety of Csp3–Csp3 bonds in excellent yields (Fig. 4e, 15 and 37-42). A triply boron-selective reaction was also achieved in the diastereospecific preparation of 43 and 44. Csp2 boronic esters were also effective (45, 46).
Reactivity differences between unhindered/hindered boronic esters38,39 suggested potential for iteration-enabling kinetic selectivity within Csp3–Csp3 bond formation. Accordingly, we investigated the lego-like automated synthesis of macrocyclic antifungal natural product sch725674 (ref. 40) (Fig. 4f). Demonstrating the advantage ofour approach over previous strategies41 to access sch725674, our bifunctional sulfoxide-TIDA boronate 14b enabled recursive application of the same assembly chemistries to form Csp3–Csp3 bonds. Additionally, the inclusion of a TIDA boronate enabled this entire process of multiple building block assembly via iterative Csp3–Csp3 bond formation to be executed in a fully automated and uninterrupted fashion (Supplementary Figs. 14 and 15). n-Pentyl pinacol boronic ester 47 was subject to 1,2-metallate rearrangement with sulfoxide-boronate 14b to afford the target TIDA boronate 48 in high stereocontrol (>95:5 e.r.). Automated deprotection to the corresponding pinacol boronic ester 49 was followed by automated boronic ester-selective reaction with sulfoxide 50 to provide the core carbon scaffold of sch725674 (52) after oxidation of bisboronate 51. Deprotection (TBAF, 53), oxidative modification, macro-lactonization and final deprotection furnished sch725674 in only seven steps from bench-stable building blocks.
X-ray crystal structure data are available free of charge on the Cambridge Crystallographic Data Centre under the following accession numbers: 4-bromophenylboronic acid MIDA ester 1c: structure 2087874, multipole refinement 2087875; 4-bromophenylboronic acid TIDA ester 20: structure 2087872, multipole refinement 2087873; 3-bromophenylboronic acid dimethyl-MIDA ester SI-10: structure 2087648; ethynylboronic acid TIDA ester SI-47: structure 2087715; cis-2-bromovinylboronic acid TIDA ester SI-49: structure 2087714; trans-2-bromovinylboronic acid TIDA ester 32: structure 2087712; sulfinyl benzoate anti-SI-25: structure 2087716; TIDA anhydride: structure 2120500. All other data are available in the main text or supplementary materials.
Trobe, M. & Burke, M. D. The molecular industrial revolution: automated synthesis of small molecules. Angew. Chem. Int. Edn 57, 4192–4214 (2018).
Li, J. et al. Synthesis of many different types of organic small molecules using one automated process. Science 347, 1221–1226 (2015).
Imao, D., Glasspoole, B. W., Laberge, V. S. & Crudden, C. M. Cross coupling reactions of chiral secondary organoboronic esters with retention of configuration. J. Am. Chem. Soc. 131, 5024–5025 (2009).
Lehmann, J. W. et al. Axial shielding of Pd(II) complexes enables perfect stereoretention in Suzuki–Miyaura cross-coupling of Csp3 boronic acids. Nat. Commun. 10, 1263 (2019).
Mlynarski, S. N., Schuster, C. H. & Morken, J. P. Asymmetric synthesis from terminal alkenes by cascades of diboration and cross-coupling. Nature 505, 386–390 (2013).
Ma, X., Murray, B. & Biscoe, M. R. Stereoselectivity in Pd-catalysed cross-coupling reactions of enantioenriched nucleophiles. Nat. Rev. Chem. 4, 584–599 (2020).
Cherney, A. H., Kadunce, N. T. & Reisman, S. E. Enantioselective and enantiospecific transition-metal-catalyzed cross-coupling reactions of organometallic reagents to construct C–C bonds. Chem. Rev. 115, 9587–9652 (2015).
Leonori, D. & Aggarwal, V. K. Lithiation-borylation methodology and its application in synthesis. Acc. Chem. Res. 47, 3174–3183 (2014).
Sharma, H. A., Essman, J. Z. & Jacobsen, E. N. Enantioselective catalytic 1,2-boronate rearrangements. Science 374, 752–757 (2021).
Casoni, G. et al. α-Sulfinyl benzoates as precursors to Li and Mg carbenoids for the stereoselective iterative homologation of boronic esters. J. Am. Chem. Soc. 139, 11877–11886 (2017).
Bader, R. F. W., Slee, T. S., Cremer, D. & Kraka, E. Description of conjugation and hyperconjugation in terms of electronic distributions. J. Am. Chem. Soc. 105, 5061–5068 (1983).
Bader, R. F. W. Ed. Atoms in Molecules–A Quantum Theory (Oxford Univ. Press, 1990).
Koritsanszky, T. S. & Coppens, P. Chemical applications of X-ray charge-density analysis. Chem. Rev. 101, 1583–1628 (2001).
Fujita, K., Matsui, R., Suzuki, T. & Kobayashi, S. Concise total synthesis of (−)-myxalamide A. Angew. Chem. Int. Edn 51, 7271–7274 (2012).
Seo, K.-B., Lee, I.-H., Lee, J., Choi, I. & Choi, T.-L. A rational design of highly controlled Suzuki–Miyaura catalyst-transfer polycondensation for precision synthesis of polythiophenes and their block copolymers: marriage of palladacycle precatalysts with MIDA-boronates. J. Am. Chem. Soc. 140, 4335–4343 (2018).
Angelone, D. et al. Convergence of multiple synthetic paradigms in a universally programmable chemical synthesis machine. Nat. Chem. 13, 63–69 (2021).
Lennox, A. J. J. & Lloyd-Jones, G. C. Selection of boron reagents for Suzuki–Miyaura coupling. Chem. Soc. Rev. 43, 412–443 (2014).
Lovering, F., Bikker, J. & Humblet, C. Escape from flatland: increasing saturation as an approach to improving clinical success. J. Med. Chem. 52, 6752–6756 (2009).
Worch, J. C. et al. Stereochemical enrichment of polymer properties. Nat. Rev. Chem. 3, 514–535 (2019).
Gonzalaez, J. A. et al. MIDA boronates are hydrolysed fast and slow by two different mechanisms. Nat. Chem. 8, 1067–1075 (2016).
Stephan, D. W. & Erker, G. Frustrated Lewis pairs: metal-free hydrogen activation and more. Angew. Chem. Int. Edn 49, 46–76 (2010).
Mancilla, T. & Contreras, R. New bicylic organylboronic esters derived from iminodiacetic acids. J. Organomet. Chem. 307, 1–6 (1986).
Mancilla, T., de los Ángeles Calixto Romo, M. & Delgado, L. A. Synthesis and characterization of (N→B) phenyl[N-alkyl-N-(2-alkyl)aminodiacetate-O,O′,N]boranes and phenyl[N-alkyl-N-(2-alkyl)aminodiacetate-O,O′,N]boranes. Polyhedron 26, 1023–1028 (2007).
Wu, J. I.-C. & von Ragué Schelyer, P. Hyperconjugation in hydrocarbons: not just a “mild sort of conjugation”. Pure Appl. Chem. 85, 921–940 (2013).
Pophristic, V. & Goodman, L. Hyperconjugation not steric repulsion leads to the staggered structure of ethane. Nature 411, 565–568 (2001).
Senderowitz, H., Golender, L. & Fuchs, B. New supramolecular host systems. 2. 1,3,5,7-Tetraoxadecalin, 1,2-dimethoxyethane and the gauche effect reappraised. Theory vs. experiment. Tetrahedron 32, 9707–9728 (1994).
Hoffman, R. W., Hrovat, D. A. & Borden, W. T. Is hyperconjugation responsible for the “gauche effect’ in 1-fluoropropane and other 2-subsituted-1-fluoroethanes? J. Chem. Soc. Perkin Trans. 2 12, 1719–1726 (1999).
Scherer, W. et al. Valence-shell charge concentrations and electron delocalization in alkyllithium complexes: negative hyperconjugation and agnostic bonding. Chem. Eur. J. 8, 2324–2334 (2002).
Hirschfeld, F. L. Bonded-atom fragments for describing molecular charge densities. Theor. Chim. Acta 44, 129–138 (1977).
Jonas, V., Frenking, G. & Reetz, M. T. Comparative theoretical study of Lewis acid–base complexes of BH3, BF4, BCl3, AlCl3, and SO2. J. Am. Chem. Soc. 116, 8741–8753 (1994).
Skara, G., de Vleeschouwer, F., Geerlings, P., de Proft, F. & Pinter, B. Heterolytic splitting of molecular hydrogen by frustrated and classical Lewis pairs: a unified reactivity concept. Sci. Rep. 7, 16024 (2017).
Schürmann, C. J. et al. Experimental charge density study on FLPs and a FLP reaction product. Z. Kristallogr. Crystall. Mater. 233, 723–731 (2018).
Ullrich, M., Lough, A. J. & Stephan, D. W. Dihydrogen activation by B(p-C6F4H)3 and phosphines. Organometallics 29, 3647–3654 (2010).
Falivene, L. et al. Towards the online computer-aided design of catalytic pockets. Nat. Chem. 11, 872–879 (2019).
Beak, P. & Carter, L. G. Dipole-stabilized carbanions from esters: α-oxo lithiations of 2,6-substituted benzoates of primary alcohols. J. Org. Chem. 46, 2363–2373 (1981).
Landry, M. L., Hu, D. X., McKenna, G. M. & Burns, N. Z. Catalytic enantioselective dihalogenation and the selective synthesis of (−)-deschloromytilipin A and (−)-danicalipin A. J. Am. Chem. Soc. 138, 5150–5158 (2016).
Mojid Mondol, M. A. et al. Ieodomycins A–D, antimicrobial fatty acids from a marine Bacillus sp. J. Nat. Prod. 74, 1606–1612 (2011).
Blakemore, P. R., Marsden, S. P. & Vater, H. D. Reagent-controlled asymmetric homologation of boronic esters by enantioenriched main-group chiral carbenoids. Org. Lett. 8, 773–776 (2006).
Roesner, S., Blair, D. J. & Aggarwal, V. K. Enantioselective installation of adjacent tertiary benzylic stereocentres using lithiation-borylation-protodeboronation methodology. Application to the synthesis of bifluranol and fluorohexestrol. Chem. Sci. 6, 3718–3723 (2015).
Yang, S.-W. et al. Structure elucidation of sch725674 from Aspergillus sp. J. Antibiot. 58, 535–538 (2005).
Fawcett, A. et al. Regio- and stereoselective homologation of 1,2-bis(boronic esters): stereocontrolled synthesis of 1,3-diols and sch725674. Angew. Chem. Int. Edn 55, 14663–14667 (2016).
Momma, K. & Izumi, F. VESTA 3 for three-dimensional visualization of crystal, volumetric and morphology data. J. Appl. Crystallogr. 44, 1272–1276 (2011).
O’Brien, N. J. et al. Synthesis, structure and reactivities of pentacoordinated phosphorus-boron bonded compounds. Eur. J. Inorg. Chem. 20, 1995–2003 (2020).
Uno, B. E., Gillis, E. P. & Burke, M. D. Vinyl MIDA boronate: a readily accessible and highly versatile building block for small molecule synthesis. Tetrahedron 65, 3130–3138 (2009).
Ma, Y. et al. Radical C–N borylation of aromatic amines enabled by a pyrylium reagent. Chem. Eur. J. 26, 3738–3743 (2020).
Neuvonen, H., Neuvonen, K., Koch, A., Kleinpeter, E. & Pasanen, P. Electron-withdrawing substituents decrease the electrophilicity of the carbonyl carbon. An investigation with the aid of 13C NMR chemical shifts, ν(C=O) frequency values, charge densities, and isodesmic reactions to interpret substituent effects on reactivity. J. Org. Chem. 67, 6995–7003 (2002).
Aspin, S., Goutierre, A.-S., Larini, P., Jazzar, R. & Baudoin, O. Synthesis of aromatic α-aminoesters: palladium-catalyzed long-range arylation of primary Csp3-H bonds. Angew. Chem. Int. Edn 51, 10808–10811 (2012).
Li, G., Ji, C.-L., Hong, X. & Szostak, M. Highly chemoselective, transition-metal-free transamidation of unactivated amides and direct amidation of alkyl esters by N-C/O-C cleavage. J. Am. Chem. Soc. 141, 11161–11172 (2019).
Xie, X. & Stahl, S. S. Efficient and selective Cu/nitroxyl-catalyzed methods for aerobic oxidative lactonization of diols. J. Am. Chem. Soc. 137, 3767–3770 (2015).
Yamamato, Y., Nemoto, H., Kikuchi, R., Komatsu, H. & Suzuki, I. A conformationally rigid acyclic molecule. J. Am. Chem. Soc. 112, 8598–8599 (1990).
Ueki, Y., Ito, H., Usui, I. & Breit, B. Formation of quaternary carbon centers by highly regioselective hydroformylation with catalytic amounts of a reversibly bound directing group. Chem. Eur. J. 17, 8555–8558 (2011).
We thank F. Sun and H. Yao at the UIUC Mass Spectrometry Facility, D. Olson, L. Zhu and N. Duay at the School of Chemical Sciences NMR Laboratory at UIUC for NMR services, and members of the Burke laboratory for discussions related to this project. The Bruker 500 MHz NMR spectrometer was obtained with the financial support of the Roy J. Carver Charitable Trust, Muscatine, Iowa, USA. D.J.B. thanks the Damon-Runyon Cancer Research Foundation for additional support during the COVID-19 pandemic. S. Denmark is acknowledged for manuscript review. We thank P.-J. Chen, Y. Tong, A. Blake, H. Auby and D. Szczepankiewicz for technical assistance. Support was provided by the following sources: M.D.B.: NIH (GM118185), NSF (CHE-1955838); D.J.B.: Illini 4000 Fellow of the Damon-Runyon Cancer Research Foundation DRG-2290-17; S.C.: ACS Division of Organic Chemistry Summer Undergraduate Research Fellowship, Henry Luce Foundation and the Illinois Scholars Undergraduate Research Program; M.B.T.: Erwin Schrödinger Post-Doctoral Fellow, Austrian Science Fund (FWF) (J3960-N34).
The University of Illinois has filed patent applications related to MIDA and TIDA boronates. M.D.B. is a founder, shareholder and consultant for REVOLUTION Medicines.
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Extended data figures and tables
Extended Data Fig. 1 Structural consequences of backbone substitution on iminodiacetic acid boronates.
a, Internal angle compression from MIDA 1c to dimethyl-MIDA SI-10 to TIDA 20 suggest thermodynamic Thorpe–Ingold effects might further support hyperconjugative interactions by rigidifying the iminodiacetic acid cage of TIDA. b, Increases in nitrogen attached donor and boron attached acceptor bond lengths for TIDA 20 compared to MIDA 1c support hyperconjugative transfer of electron density along the N-B bond (lengths in Å).
Extended Data Fig. 2 Bond path total electron density for MIDA boronate 1c and TIDA boronate 20.
a, Legend and numbered molecular structures. b–i Follow anticlockwise around the iminodiacetic acid cage. j–l, The N-B, N-Me, and C-B bonds are also included. The maximum displayed value of the electron density (y-axis) is capped at 4 eA−3 to best capture the interatomic bonding region.
Extended Data Fig. 3 Bond path Laplacian profiles comparing MIDA boronate 1c and TIDA boronate 20.
a, Legend and labelled structures. b–i Follow an anticlockwise path around MIDA 1c and TIDA 20 as well as the N-B, N-Me, and C-B bonds (j–l).
Extended Data Fig. 4 Bond path ellipticity profiles for MIDA boronate 1c and TIDA boronate 20.
a, Schematic representation of ellipticity (ε), which reflects an increase in directionality of electron density and is characteristic of increased π-character. b, Legend for sections c–m. Pronounced changes in ellipticity can be seen for TIDA boronate 20 compared to MIDA boronate 1c particularly for the N-C2/3 (f, g), B-O1/4 (c, j), and N-B bonds, which are consistent with observations of redistributions of electron density around the N-B bond (see Fig. 3a, b). Ellipticity profiles (c–j) follow an anticlockwise path around the iminodiacetic acid rings of 1c and 20 starting with B-O1 (c) and ending with O4-B (j). Profiles for the N-B, N-Me, and C-B bonds (k–m) are also included.
Extended Data Fig. 5 Charge analysis of MIDA boronate 1c and TIDA boronate 20.
a, Electrostatic potential surface for MIDA 1c, showing side on and bottom perspectives. b, Electrostatic potential surface for TIDA 20, showing side on and bottom perspectives. c, Stockholder charges comparing MIDA 1c (black) and TIDA 20 (green), values shown are in electrons. d, Integrated charge comparing MIDA 1c (black) and TIDA 20 (green), values shown are in electrons. TIDA backbone methyl groups were omitted for clarity on the charge plots. e, A downfield shift for TIDA boronates carbonyl carbons indicates a net electron depletion relative to MIDA boronates. Similarly, there is an up-field shift for the boron atoms in TIDA boronates relative to MIDA boronates indicating increased boronate complex-like character and elevated electronic shielding43,44,45. f, Trends in 13C NMR carbonyl chemical shifts in CDCl3 on sequential substitution of the α-carbon with methyl groups and/or lactone formation and/or addition of an α-dimethylamino group are provided for comparison46,47,48,49,50,51.
Extended Data Fig. 6 Laplacian and electron density isosurfaces support redistributed density around the O4-B-O1 linkage of TIDA 20.
a, The Laplacian at isosurface value -80 eA−5 (shown in yellow) for MIDA 1c indicates an isolated valence shell charge concentration (VSCC) at O4 (i.e. minimal lone-pair interactions). b, Unlike at O4 the Laplacian at O1 for MIDA 1c reveals coalescence of lone-pair VSCC and the O1-C1 VSCC, pointing toward interaction between O1 and C1 (the adjacent carbonyl). c, End-on view of deformation density (isosurface value of 0.0034 eA−3 in blue) down O4 in MIDA 1c provides further evidence for charge localization at O4. d, In contrast to O4 the end-on view of deformation density down O1 for MIDA 1c reveals the electron distribution along B-O1-C1, favours O1-C1. e, The Laplacian of TIDA 20 reveals interaction between lone-pair VSCC and both C4-O4/O4-B VSCCs. f, In contrast to MIDA 1c the lone-pair VSCC of TIDA 20 at O1 coalesces with the B-O1 VSCC and not the O1-C1 VSCC. g, h, Consistent with these changes in VSCCs, deformation density at O4 (g) and O1 (h) for TIDA 20 supports electronic redistribution about the C4-O4-B-O1-C1 network compared to MIDA 1c. Prepared using VESTA 3 (ref. 42).
Extended Data Fig. 7 Robust steric shielding suppresses carbonyl attack on TIDA boronates.
a, Topological steric maps34 of the plane perpendicular to the carbonyl carbons enable comparison of MIDA (1c), dimethyl-MIDA (SI-10), and TIDA (20). MIDA boronates (left column) experience minimal steric shielding, and methyl groups introduced in dimethyl-MIDA (A’ and B’) occupy pseudo-equatorial positions, minimally impacting carbonyl approach (centre column). The two additional methyl groups in TIDA (A and B) occupy pseudo-axial positions and establish transannular steric shielding interactions between A and the carbonyl on the opposite side of the TIDA framework (right column). Additionally, A and B shield their adjacent carbonyls towards approach at the Burgi-Dunitz angle. b, The transannular influence of methyl group A mirrors that of Beak-type 2,4-6-triisopropyl benzoates which are resistant to carbon centred nucleophiles.
Extended Data Fig. 8 TIDA boronates retain all required properties to enable generalized automated synthesis.
a, TIDA boronate 21 is hydrolysed by NaOH primarily via the ester hydrolysis mechanism. b, TIDA ligand and TIDA boronates can be prepared on scale. c, TIDA anhydride provides an alternative method to prepare TIDA boronates. d, TIDA boronates possess a binary affinity for silica gel, agnostic of the attached carbon fragment. They are minimally mobilized in Et2O and rapidly eluted in THF, enabling generalized and automatable catch-and-release purification. tol, para-toluene.
Extended Data Fig. 9 TIDA boronates tolerate a diverse range of cross-coupling chemistry.
a, Suzuki–Miyaura cross-coupling. b, Heck coupling. c, Sonogashira coupling. d, Photochemical Suzuki–Miyaura cross-coupling. e, Photochemical thioetherification. f, Stille coupling leading to bis-borylated dienes. g, Stille coupling leading to germylated dienes.
Extended Data Fig. 10 Functional group interconversion of TIDA boronate building blocks.
a, Ethynylboronic acid TIDA ester is readily converted into E- and Z- 2-bromovinylboronic acid TIDA esters with excellent stereocontrol. Images of X-ray crystal structures shown inset. b, Reduction of ethynylboronic acid TIDA ester furnishes vinylboronic acid TIDA ester which participates in epoxidation and Grubbs metathesis. c, Common functional group interconversion reactions are well tolerated by TIDA including oxidation, reduction, halogenation, reductive amination, Evans aldol and Takai olefination. d–g, A wide range of borylation chemistries are tolerated by TIDA boronates to produce mono-protected polyborylated building blocks, including Miyaura (d), C-H borylation (e), diboration (f), and copper catalysed borylation (g).
Procedures for chemical synthesis, automated synthesis and mechanistic data.
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Blair, D.J., Chitti, S., Trobe, M. et al. Automated iterative Csp3–C bond formation. Nature 604, 92–97 (2022). https://doi.org/10.1038/s41586-022-04491-w
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