Guanidines as Asymmetric Organocatalysts

School of Physical Mathematical Sciences, Division of Chemistry and Biological Chemistry, Nanyang Technological University, 21 Nanyang Link, Singapore 637371, Singapore Email choonhong ntu.edu. sg 

Sustainable Catalysis Without Metals or Other Endangered Elements, Part 2 

The E-factor, which was introduced by Sheldon, is a more elaborate metric to estimate the amount of waste generated per unit of products. Waste is defined as everything except the desired product. This could include solvents, reagents, inorganic salts, fuel, It should be noted that quantification of waste such as fuel used for power generation can he difficult. 

There are other metrics that are closely related to the E-factor. For example, reaction mass efficiency is defined by Hudliclqr and coworkers as the percentage of mass of product, relative to the mass of all nonbenign materials used in its synthesis. However, the definition of nonbenign materials is debatable and we will not discuss this metric in this chapter. 

Mass index (MI) is defined as the total mass used in a process/process step divided by the mass of product and it is approximately the E-factor plus one. A software package, the Environmental Assessment Tool for Organic Syntheses (EATOS), has been designed to calculate some of these metrics. More elaborate assessments such as life cycle assessment (LCA), could be performed, but this is also beyond the scope of this chapter. Our objective is to provide a preliminary assessment for the community to determine if further development of any guanidine organocatalysis is appropriate for use in green chemistry. 

---

Numerous 2-substituted pyrrolidine organocatalysts have been prepared from L-proline and its derivatives, and have been proven to be highly efficient for many asymmetric reactions. Representative organocatalysts have been selected and categorised on the basis of the 2-substituted group that includes di- and tri-amine (la-m), dithioacetal (2a-f), guanidine (2g-i), sulfonamide (3a-j), amide and thioamide (3k-n), urea (4a and 4e), thiourea (4b-d, f-j) and heterocycles such as tetrazole (5a,b), triazole (5c-g), imidazole (5h-j) and benzoimidazole (5k) (Figure 9.1). 

Over the past decade, rapid growth has been achieved in organocatalytic asymmetric Diels-Alder and hetero-Diels-Alder reactions. Numerous organocatalysts such as chiral amines, guanidines, N-heterocyclic carbenes, Bronsted acids, and bifunctional catalysts have been successfully developed. The activation modes for these catalysts, such as imine-catalysis, enamine-catalysis, dienamine catalysis. 

---