Assembly-line synthesis of organic molecules with tailored shapes

Abstract

Molecular 'assembly lines', in which organic molecules undergo iterative processes such as chain elongation and functional group manipulation, are found in many natural systems, including polyketide biosynthesis. Here we report the creation of such an assembly line using the iterative, reagent-controlled homologation of a boronic ester. This process relies on the reactivity of α-lithioethyl tri-isopropylbenzoate, which inserts into carbon-boron bonds with exceptionally high fidelity and stereocontrol; each chain-extension step generates a new boronic ester, which is immediately ready for further homologation. We used this method to generate organic molecules that contain ten contiguous, stereochemically defined methyl groups. Several stereoisomers were synthesized and shown to adopt different shapes-helical or linear-depending on the stereochemistry of the methyl groups. This work should facilitate the rational design of molecules with predictable shapes, which could have an impact in areas of molecular sciences in which bespoke molecules are required.

Figure 1. Iterative approaches to assembly line synthesis

a Example of polyketide biosynthesis where successive cycles of chain extension and functional group interconversions generate a diverse array of complex molecules. b Proposed reagent controlled homologation of boronic esters where successive cycles of chain extension enable rapid and streamlined synthesis of stereodefined carbon chains.

Figure 2. Methodology used for homologation of boronic esters

a Method for the generation of Hoppe’s lithiated carbamate. b Method for the generation of α-lithiated hindered benzoate 6 with high e.r. from stannane 5. c Optimised protocol for iterative homologation of boronic esters. pin = pinacol. Carbenoid 2 was not suitable for iterative homologations whereas carbenoid 6 was suitable and the protocol for its successful use is shown in pane c. d Racemisation pathway for lithiated benzoate (S)-6 when an excess of stannane (R)-5 is present from the previous homologation. This example shows the ratio of products obtained from a mixture of lithiated benzoate (S)-6 (95%, 99.9:0.1 e.r.) and stannane (R)-5 (5%, 99.9:0.1 e.r.) which leads to lithiated benzoate and stannane of lower e.r. (~95:5 e.r.).

Figure 3. Iterative assembly line synthesis

a Synthesis of the all anti isomer boronic ester 11 and X-ray structure of the p-nitro benzoate derivative 12. b Synthesis of the all syn isomer boronic ester 13 and X-ray structure (two views) of the p-nitro benzoate derivative 15. c Synthesis of the alternating syn-anti isomer boronic ester 17 with X-ray structure (two views) and the MOM ether derivative 18. The X ray structures show that the all syn isomer adopts a helical conformation, the alternating syn-anti isomer adopts a linear conformation, and the all anti isomer does not adopt a regular conformation. Conditions for homologation: a) addition of boronic ester to lithiated benzoate, −78 °C, 30 min b) −42 °C, 1 h c) room temperature, 1 h, d) filter e) repeat. The ratios of boronic ester homologues were obtained by GCMS analysis (see SI). pin = pinacol; Ar = PhC₆H_4-; PNB = p-nitro benzoate; Aq/W = aqueous workup.

Figure 4. The effect of syn-pentane and other intramolecular steric interactions on conformation of molecules

a Energy penalty incurred with a syn-pentane interaction. b Expected helical conformation of the all syn isomer 13 where methyl groups along the carbon chain avoid syn-pentane interactions (red arrows). c Expected linear conformation of the alternating syn-anti isomer 17 where methyl groups along the carbon chain avoid syn-pentane interactions (red arrows). d Hoffmann’s examples of carbon chains bearing syn-1,3-dimethyl units and the percentage occupancy of a single dominant conformation. e Minor distortion in the conformation of the carbon chain of the all syn isomer 14 (helical molecule) as determined by NMR and computational analysis. Because of 1,4-steric interactions, the carbon chain is pushed further apart causing significant deviation from the idealised dihedral angles.

Figure 5. Solution conformations of compounds 14 and 18

a Theoretically predicted properties of the ensemble of conformations of model compounds 14a and 18a . Each populated conformer is shown as 9 dots, of size proportional to the calculated relative abundance of that conformer, and with a position defined by the calculated value of the corresponding backbone dihedral angle θ. b Correlation between theoretically predicted NMR properties (interproton-distance, green, and ¹H-¹H/¹H-¹³C scalar j-couplings, red and blue) for the ensemble of conformers of 14a and 18a and experimentally observed values (interproton-distance, bottom and scalar J-couplings, top) of 14 and 18. Each dot is shown with a radius related to the expected experimental deviation of the corresponding property. The calculations predict 14a to be predominantly helical in nature, with 18a overwhelmingly populating linear conformers, NMR measurements in solution are completely in line with this predicted behaviour. c Structure of the calculated dominant conformations of 14a and 18a.