Following the asymmetric formal synthesis of (+)-corynoline using the carbiodination methodology of synthesizing enantioenriched dihydroisoquinolinones in a highly diastereoselective manner, the efficiency of the path to the natural product was re-examined. Within the route to (+)-corynoline, a nucleophilic displacement of the neopentyl alkyliode with KCN and 18-crown-6 ether under reflux was performed (Scheme 2). To avoid using these toxic and forcing conditions and to further increase the efficiency of the formal synthesis, the diastereoselective Pd-catalyzed arylcyanation/heteroarylcyanation was developed to furnish the desired nitrile-containing dihydroisoquinolinone.
The preactivation time must be kept at a minimum when generating the Fmoc-Arg(Pmc,Pbf)-OBt derivative as the activated Arg derivatives may cyclize yielding an unreactive lactam.
Interested in these dearomatization products, this project evolved into the study of other potential coupling partners. We developed a 1,2-diarylation of these substrates by using easily accessible boroxines. As seen below, these -diarylated indoline scaffolds were formed in good yields and diastereoselectivity. Moreover, the short reaction times, exceedingly broad scope and derivitizable products could allow this method to be utilized in natural product synthesis.
For the coupling of very bulky amino acids such as N-alkylamino acids or α-dialkylamino acids, the moderately reactive TBTU should be replaced by more potent reagents such as HATU , TATU, or PyBOP .
In recent years acylphosphonium (BOP, PyBOP) [24,25] and acyluronium/aminium salts (HBTU, TBTU)  have become extremely popular coupling agents in SPPS.
It is necessary to carry out the preactivation step when working with uronium derivatives such as TBTU or TATU as they can react with the free amino group of the peptide-resin to yield substituted guanidines .
After our success in arylcyanation of -allylcarboxamides, our group searched for a broader application of this useful reaction. Adapting our method to indoles led to the dearomative -1,2-arylcyanation product, thus constructing highly substituted indoline frameworks which have desirable biological activity. As seen in the reaction below, these rigid products are highly functionalized. The indoline core contains a tetrasubstituted tertiary carbon, a functionalizable acidic alpha proton, and a highly versatile nitrile group. Additionally, these scaffolds are synthesized in high yield and diastereoselectivity.
The use of multiple catalysts in a reaction vessel in organic synthesis has recently gained significant interest, as multi-catalytic systems can achieve superior reactivity and synthetic efficiency that are unmatched with single catalytic systems. Important advantages include new modes of substrate activation, new bond forming transformations, and efficient complexity generation processes that lead to waste reduction in synthesis and minimized environmental impact (Scheme 1). For example, the use of multiple metals in catalysis has provided powerful transformations such as the Wacker process and the Sonogashira cross coupling. Thus, in comparison to the traditional approach of using a single metal catalyst to perform a reaction, taking the multi-metal catalysis approach toward synthesis can be highly effective.
The same is true for the activation of Fmoc-His(Trt)-OH since racemization catalyzed by the nitrogen of the imidazole ring may occur. For the coupling of especially bulky amino acids such as Aib, Tic, ... or in the case of recognized difficult coupling we recommend the replacement of HOBt by HOAt, or the use of other activating agents.
As ligands are integral in providing reactivity and controlling selectivity in metal-catalyzed reactions, their inclusion enables a broad range of useful transformations. The use of multiple ligands in multi-metal catalysis can facilitate optimization, improve reaction efficiency, and allow systematic ligand screening to fine-tune reactivity. Taking advantage of the dynamics and reactivity of multiple metal-ligand interactions may unlock new reactions in a variety of modes of multi-metal catalysis (Scheme 2).
The palladium-catalyzed intramolecular Mizoroki-Heck reaction has been an interest to many groups throughout the years, since it is an effective method for installing new carbon−carbon bonds. Under standard conditions, the catalytic cycle is terminated by β-hydride elimination, which reforms an olefin moiety—a useful functional group handle in organic synthesis (Scheme 1). In the absence of a suitable β-hydrogen, the generated alkyl palladium intermediate can be terminated with varying nucleophiles resulting in a functionalized carbon quaternary center that would otherwise be difficult to install.
We reported the use of rhodium and palladium with a combination of two ligands, BINAP and XPhos, in the catalytic synthesis of dihydroquinolines (Scheme 3). We were interested in the Rh-catalyzed formal hydroarylation of an aryl chloride containing alkyne. In situ functionalization of the alkyne delivered an alkene for a Pd-catalyzed cross coupling. The selective formation of the desired dihydroquinoline product implied that the reaction pathway must be highly controlled. Our investigation of the mechanism led us to two observations that were important for the development of multi-metal-catalyzed reactions.