We thank the National Institute of General Medical Sciences (NIGMS) (GM72586) for support. AM acknowledges NIGMS for a Diversity Supplement (GM72586-S1).
Dedicated to the memory of our dear friend and colleague Keith Fagnou
Abstract
Herein, we report a simple and noninvasive experimental protocol in which a series of relative reaction rates may be obtained by way of single competition experiments. This approach permits a quantitative comparison of any given number of chiral catalysts relative to a ‘benchmarking’ chiral catalyst – a particularly useful tool since catalyst design and selection have remained largely dependent on chemical intuition. We apply this benchmarking approach towards an asymmetric N-heterocyclic carbene (NHC) catalyzed intramolecular Stetter reaction as a proof-of-concept study. In doing so, we demonstrate a rapid method to assess the complex interplay between catalyst reactivity and stereoelectronic effects – an analytical approach that has heretofore not been attempted for NHCs. To showcase the generality of this method, we apply it to an enantioselective Rh(I)-catalyzed [2+2+2] cycloaddition of alkenyl isocyanates and aryl alkynes for a series of chiral phosphoramidite ligands. The results described herein demonstrate that this inexpensive and easily adoptable protocol can reveal complex yet subtle steric and stereoelectronic effects of vastly different chiral catalyst structures, which can further aid with catalyst development and selection for a clearly defined application.
In this regard, over 50 unique structures are known for triazolium precatalysts, alone (see reference 9). For selected papers dedicated to the synthesis of unique structures, see:
14a
Brand JP,
Siles JI. O,
Waser J.
Synlett 2010; 881
14b
Rong ZQ,
Li Y,
Yang GQ,
You S.-L.
Synlett 2011; 1033
14c
Rafínśki Z,
Kozakiewicz A,
Rafinśka K.
ACS Catal. 2014; 4: 1404
16 Recently, a study that combines modifications of NHCs in combination with machine-learning techniques in order to study NHC structural effects appeared, see:
Ghayalan V,
Gadekar SC,
Alassad Z,
Milo A.
Nat. Chem. 2019; 11: 543
27 Taken in part from:
Munoz A.
The Development of Novel N-Heterocyclic Carbenes and Tools for Assessing Structural Variation Effects Upon Catalyst Reactivity 2018
28Typical Procedure: Stock solutions of 10 (1.0 M in toluene), C-1 (0.1 M in toluene), C-5 (0.1 M in toluene), and KHMDS (0.1 M in toluene) were freshly prepared inside a glovebox under N2 atmosphere. From these stock solutions, C-1 (3.45 mL, 2.5 mol%) and C-5 (3.45 mL, 2.5 mol%) were dosed inside a scrupulously dried 1-dram vial, into which 600 mL of degassed and anhydrous toluene (0.023 M) was added. KHMDS (6.9 mL from 0.1 M stock solution, 5 mol%) was added and the reaction was stirred for 5 minutes. Substrate 10 was then dosed (13.8 mL from 0.1 M stock solution, 5 mol%) and the reaction was stirred for 1 hour. The reaction mixture was then concentrated to dryness in vacuo. The crude reaction mixture was filtered over a Celite plug with DCM and then subject to analysis by chiral-phase HPLC.
