Exploiting Natural Complexity: Synthetic Terpenoid‐Alkaloids by Regioselective and Diastereoselective Hydroaminoalkylation Catalysis

Abstract

We report a catalytic and atom‐economic approach for the addition of N‐methyl groups to unactivated alkene‐containing terpenes to generate a library of synthetic terpenoid‐alkaloids. This catalysis was accomplished using Ta(CH2SiMe3)3Cl2 in combination with a new chiral ureate salt for highly chemo‐, regio‐, and diastereoselective hydroaminoalkylation reactions. The desired products are easily isolated and purified from unreacted starting materials to give aminated terpenes in one catalytic step. Starting material enantiopurity is completely retained, and stereoselective catalysis results to give enantiopure products. Absolute stereochemistry was determined by X‐ray crystallography and is consistent with regio‐ and stereoselective alkene insertion into a catalytically active tantallaziridine intermediate.

Direct, Catalytic α-Alkylation of N-Heterocycles by Hydroaminoalkylation: Substrate Effects for Regiodivergent Product Formation

“…Attempts to achieve this transformation with the known simple tantalum complex Ta­(NMe 2 ) 5 ,, were unsuccessful under any reaction conditions. Using a known organometallic tantalum starting material, Ta­(CH 2 SiMe 3 ) 3 Cl 2 , , the benchmark reaction with piperidine over 24 h at 165 °C gave only 6% conversion, as determined by 1 H NMR spectroscopy . None of the established amidate, pyridonate ligand salts ( L12 , L13 ) could be used for any reactivity with this challenging N -heterocycle substrate. ,, Only starting material remained by NMR spectroscopy after heating.…”

“…Our group recently showed that highly active tantalum and titanium ureate hydroaminoalkylation catalysts can be prepared in situ for the efficient alkylation of both aryl and alkyl N -methylated secondary amines. − Although reactivity with N -heterocycles was not achieved, this earlier work showcased the tunable nature of ureate ligand salts to improve catalytic activity and enhance substrate scope. Here, we report a tantalum ureate catalyst for the rapid α-C–H alkylation of saturated N -heterocycles with activated and unactivated alkene coupling partners (Figure c).…”

New Titanium Complexes and Their Use in Hydroamination and Hydroaminoalkylation Reactions

“…Eisen′s titanium mono(formamidinate) complex 1 (Scheme ) has previously been reported as a highly active hydroaminoalkylation catalyst that converts secondary amines and simple 1‐alkenes (R 1 = alkyl) into branched hydroaminoalkylation products with high selectivity while on the other hand, corresponding reactions of styrenes (R 1 = aryl) usually give mixtures of a branched and a linear product. From a mechanistic point of view, it is generally accepted that the catalytically active species of hydroaminoalkylation reactions are titanaaziridines (Scheme ) possessing two spectator ligands which do not participate in the catalytic reaction but determine the activity as well as the selectivity of the catalyst.…”

Commodity Polymers to Functional Aminated Materials: Single-Step and Atom-Economic Synthesis by Hydroaminoalkylation

“…HAA is a transition-metal catalyzed, green, amination method that operates by activating the C–H bond α to an amine nitrogen and adding it across a carbon–carbon unsaturation . Advances in HAA catalyst design have enabled the coupling of a broad scope of commercial amines and small molecule alkenes. − Efforts to apply HAA for the functionalization of macromolecules with first generation HAA catalysts showed promise but suffered from long reaction times, of at least 18 h, and were limited to N -methylaniline. − Our group has developed a highly active N , O -chelated tantalum catalyst ( [Ta] , Scheme ), which promotes catalysis in minutes and displays excellent reactivity with both aryl and alkyl amines. Here we show that this improved catalyst is efficient for catalytic postpolymerization amination to prepare functional materials, with no byproduct formation, thereby affording polymers suitable for further synthetic elaboration.…”