Toward Generalization of Iterative Small Molecule Synthesis

Abstract

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.

Figure 1. Modularity in small molecules

a Biosynthesis of natural products from building blocks. b Coverage of > 75% of polyene natural product chemical space using 12 bifunctional halo MIDA boronate building blocks. c Common heteroaryl motifs found in pharmaceuticals. d Modularity in organic materials.

Figure 2. Customized iterative synthesis of naturally occurring small molecules

a Aldohexose synthesis via iterative Sharpless epoxidation. b Formal synthesis of 6-deoxyerythronolide B via iterative aldol reactions. c Passifloricin A synthesis via iterative allylboration. d |(+)-Roxaticin via iterative C-C bond forming transfer hydrogenation. e (−)-Borrelidin via iterative Myers’ alkylation. f Phthioceranic acid via iterative conjugate addition. g Iterative synthesis of polydeoxypropionates via stereospecific displacement of tosylates. h (+)-Kalkitoxin via iterative homologation of boronic esters. i Coenzyme Q₁₀ via iterative palladium-catalyzed couplings of alkylzinc reagents. j Amphotericin B via iterative Horner-Wadsworth-Emmons olefinations. k Synthesis of goniocin via iterative THF ring formation. l ABCDEF ring system of yessotoxin and adriatoxin via iterative oxiranyl anion strategy. m Halichondrin B via iterative NHK reactions.

Figure 2. Customized iterative synthesis of naturally occurring small molecules

a Aldohexose synthesis via iterative Sharpless epoxidation. b Formal synthesis of 6-deoxyerythronolide B via iterative aldol reactions. c Passifloricin A synthesis via iterative allylboration. d |(+)-Roxaticin via iterative C-C bond forming transfer hydrogenation. e (−)-Borrelidin via iterative Myers’ alkylation. f Phthioceranic acid via iterative conjugate addition. g Iterative synthesis of polydeoxypropionates via stereospecific displacement of tosylates. h (+)-Kalkitoxin via iterative homologation of boronic esters. i Coenzyme Q₁₀ via iterative palladium-catalyzed couplings of alkylzinc reagents. j Amphotericin B via iterative Horner-Wadsworth-Emmons olefinations. k Synthesis of goniocin via iterative THF ring formation. l ABCDEF ring system of yessotoxin and adriatoxin via iterative oxiranyl anion strategy. m Halichondrin B via iterative NHK reactions.

Figure 2. Customized iterative synthesis of naturally occurring small molecules

a Aldohexose synthesis via iterative Sharpless epoxidation. b Formal synthesis of 6-deoxyerythronolide B via iterative aldol reactions. c Passifloricin A synthesis via iterative allylboration. d |(+)-Roxaticin via iterative C-C bond forming transfer hydrogenation. e (−)-Borrelidin via iterative Myers’ alkylation. f Phthioceranic acid via iterative conjugate addition. g Iterative synthesis of polydeoxypropionates via stereospecific displacement of tosylates. h (+)-Kalkitoxin via iterative homologation of boronic esters. i Coenzyme Q₁₀ via iterative palladium-catalyzed couplings of alkylzinc reagents. j Amphotericin B via iterative Horner-Wadsworth-Emmons olefinations. k Synthesis of goniocin via iterative THF ring formation. l ABCDEF ring system of yessotoxin and adriatoxin via iterative oxiranyl anion strategy. m Halichondrin B via iterative NHK reactions.

Figure 3. Customized iterative synthesis of non-natural small molecules

a Iterative arene homologation. b Iterative synthesis of octacene. c Iterative convergent synthesis of phenylacetylene oligomers. d Iterative convergent synthesis of hydrocarbon dendrimers. e Iterative synthesis of extended iptycenes. f Iterative arylation of multiply borylated compounds. g Iterative synthesis of rotaxanes.

Figure 4. Approaches to Iterating Metal-Mediated Coupling Reactions

a Reversible attenuation of organometallic reactivity enables iterative coupling. b Iterative Hiyama couplings by reversible silane activation. c Iterative Suzuki couplings by reversible protection with 1,8-diaminonaphthalene (dan). d Iterative Suzuki couplings by reversible protection with N-methyliminodiacetic acid (MIDA).

Figure 5. Reaction conditions that tolerate. MIDA boronates

a Oxidations. b Reductions. c Protections and Deprotections. d Nucleophilic Displacements. e Addition across multiple bonds. f Reactions of aldehydes with nucleophiles. g Transition metal-catalyzed reactions. h Electrophilic substitution reactions. i Heterocycle formation reactions. j Cycloadditions. k Reactions of α-boryl aldehydes. l Stereoselective synthesis with chiral MIDA variants

Figure 5. Reaction conditions that tolerate. MIDA boronates

a Oxidations. b Reductions. c Protections and Deprotections. d Nucleophilic Displacements. e Addition across multiple bonds. f Reactions of aldehydes with nucleophiles. g Transition metal-catalyzed reactions. h Electrophilic substitution reactions. i Heterocycle formation reactions. j Cycloadditions. k Reactions of α-boryl aldehydes. l Stereoselective synthesis with chiral MIDA variants

Figure 6

Small molecules made via iterative cross-coupling with MIDA boronate building blocks.

Figure 7. Illustrative examples of iterative cross-coupling

a Ratanhine. b Mixalamide A. c Glucagon receptor inhibitor. d Histamine H3 antagonist. e Peridinin. f Secodaphnane core via biomimetic linear-cyclized strategy. g Cryptobeilic acid D methyl ester. h C35-deoxy amphotericin B.

Figure 8. Automated Synthesis Machine

a Binary affinities of MIDA boronates for silica gel enable catch-and-release purification. b Design of a machine for automated iterative cross-coupling. c Linear small molecules prepared by using automated iterative cross-coupling. d Automated synthesis of ratanhine and 19 derivatives. e Linear-to-cyclized strategy for automated synthesis of complex natural products.