Tsuji–Trost Cyclization of Disulfonamides: Synthesis of 12-Membered, 11-Membered, and Pyridine-Fused Macrocyclic Triamines

Abstract

Macrocyclic triamine disulfonamides can be synthesized by double Tsuji–Trost N-allylation reaction of open-chain disulfonamides with 2-alkylidene-1,3-propanediyl bis(carbonates). The previously used Atkins–Richman macrocyclization method generally gives lower yields and requires more tedious purification of the product. Solvent, palladium source, ligand, and concentration have all been varied to optimize the yields of two key 12-membered ring bioactive compounds, CADA and VGD020. The new approach tolerates a wide range of functional groups and gives highest yields for symmetrical compounds in which the acidities of the two sulfonamide groups are matched, although the yields of unsymmetrical compounds are still generally good. The method has also been extended to the synthesis of 11-membered rings, pyridine-fused macrocycles, and products bearing an ester or aryl substituent on the exocyclic double bond.

Annulative Allylic Alkylation Reactions between Dual Electrophiles and Dual Nucleophiles: Applications in Complex Molecule Synthesis

“…For example, Trost and co-workers synthesized the novel bicyclic isoxazoline-2-oxide 51 by coupling meso-dibenzoate 49 with lithium nitronate 50,w hich underwent intermolecularCalkylation followed by intramolecular O-alkylation in the same pot (Scheme13). Treatmentw ith Pd 0 ionized the vinyl epoxide in 62 to afford an alkoxide (63), which was trapped by tosyl isocyanate. Hydride reduction of 52 followed by acylation afforded dicarbonate 53,s etting the stage fora nother Pd-catalyzed allylic alkylation reaction.…”

“…[60] The HIV inhibitory properties of macrocyclic polyamines such as cyclotriazadisulfonamide (CADA, 167 a)c oupled with their highly modularn ature makes these molecules attractive candidates fors tructure-activity relationship studies. [63] Scheme36. Slow additions are required and the need for high dilutionn ecessitatesl arge volumes of DMF, which complicates workup.…”

“…As before, the sequence commencedw ith ad oublea llylic alkylation reaction between (phenylsulfonyl)nitromethane 59 and meso-dibenzoate 58.T he first ionization and subsequenti ntermolecular coupling was facile and highly enantioselective, but unlike five-membered electrophile 49,t he second ionization-which is mismatchedw ith the chiral catalyst-wass luggish and the addition of an achiral palladium source was necessary.Athreestep reduction sequence identicalt ot he one described above transformed isoxazoline-2-oxide 60 into hydroxyester 61, which was further elaborated into epoxide 62 using standard oxidation chemistry.As econd annulative allylic alkylation was used to install the two remaining heteroatoms. Treatmentw ith Pd 0 ionized the vinyl epoxide in 62 to afford an alkoxide (63), which was trapped by tosyl isocyanate. The amide anion in the resultantspecies 64 cyclized onto the pendant p-allyl to generate ac yclic carbamate (65), which upon reduction and deprotection gave rise to 66.…”

“…Unfortunately,w ith electron-deficient sulfonamides (167 c)o runsymmetrically substituteds ubstrates (167 d), the yields for the annulative allylic alkylation reaction are much lower. [63] Scheme36. Synthesis of the macrolide antibiotic EDP-420.…”

“…This protocol also enabled a high‐yielding synthesis of 167 b , which could not be synthesized using the Atkins‐Richman method. Unfortunately, with electron‐deficient sulfonamides ( 167 c ) or unsymmetrically substituted substrates ( 167 d ), the yields for the annulative allylic alkylation reaction are much lower …”