Prolines, Proline Analogs

Proline is a bifunctional compound with two active sites of carboxyl and amino groups, so it can act as both an acid and a base to adapt to more catalytic reaction conditions. The organic small molecule chiral catalysts such as L-proline and its derivatives have simple structure, low cost, easy availability, non-toxicity, and wide adaptability. It can be used to catalyze asymmetric aldol reactions such as Aldol reaction, Michael, and Diels-Alder reaction. It is widely used in the organic chemical synthesis of natural and non-natural products.

Figure 1. L-proline

Applications

The single-centered L-proline chiral catalyst has only one catalytic active center. This type of catalyst can not only catalyze a single reaction such as Aldol, Michael, but also catalyze the series reaction of Michael/Aldol. The bicentered L-proline chiral catalyst has two catalytically active centers. Such catalysts are generally used to catalyze tandem reactions due to the synergistic effect of the two centers, which can increase the reactivity and selectivity.

• Catalytic epoxidation reaction: Some researchers have reported that the L-proline derivative 3,5 bistrifluoromethylprolinol catalyst can directly catalyze the epoxidation of unsaturated aldehydes, and the target product has high selectivity.

Figure 2. 3,5 bistrifluoromethylprolinol catalyst

• Catalytic Michael reaction: Some researchers have directly catalyzed the Michael reaction using a diphenyl-meronyl silyl ether catalyst, and the corresponding selectivity of the target product obtained is as high as 97%.

Figure 3. Asymmetric Michael reaction

• Catalytic asymmetric Aldol reaction: Some researchers have reported an N-acylsulfonamide organic small molecule catalyst based on L-proline synthesis and applied it to the catalytic study of asymmetric Aldol reaction. The N-acylsulfonamide catalyst exhibits excellent catalytic performance, and the ee value of the related Aldol reaction product can reach 98%. It may be because the benzene ring in N-acylsulfonamide has a good shielding effect on the side of the aldehyde, thereby promoting the nucleophilic attack of the intermediate enamine from the surface of the aldehyde, forming a corresponding reaction product with high activity and high selectivity.

Figure 4. Proline-derived N-acylsulfonamide catalyst

Classification:

Proline is usually in three forms, namely DL-proline, L-proline, and D-proline. According to the atom or functional group at the carboxyl end of L-proline, the derivative of L-proline can be divided into 4-hydroxy-L-proline, prolinol ether, proline amide, proline amines, proline thioureas, proline sulfonyl groups, and the like. The L-proline based catalyst can be further classified into a single-center (acid/base) chiral catalyst and a dual-center (acid-base synergistic) chiral catalyst according to the number of catalytically active centers of the chiral molecule catalyst.

Production:

• Direct fermentation method: L-proline is obtained by microbial fermentation using glucose and yellow Brevibacterium mutant strain or wild strain of Corynebacterium glutamicum.
• Chemical synthesis: Glutamic acid and absolute ethanol are esterified under sulfuric acid catalysis, and aminoethanol sulfate is released by adding triethanolamine to obtain glutamic acid-δ-ethyl ester. The glutamic acid-δ-ethyl ester is then reduced with a metal reducing agent potassium borohydride to obtain a crude proline. Finally, the crude proline is obtained by separation and purification.
• Plant synthesis: One way is to synthesize proline with glutamic acid (Glu) as a substrate, and the other is to synthesize proline with ornithine as a substrate. Usually, when plants are stressed or nitrogen-deficient, the main source of proline is the glutamate synthesis pathway. In the case of sufficient nitrogen supply, the main synthetic pathway for proline is the synthesis of ornithine as a substrate.

References

1. Soti P L, Yamashita H, Sato K.(2016)."Synthesis of a self-assembling gold asymmetric aldol Reactions". Tetrahedron, 72(16): 1984-1990.
2. Jones M, Mersmann S, Raabe G.(2013)."Organocatalytic solvent-free hydrogen bonding mediated asymmetric Michael additions under ball milling conditions".Green Chem., 15(3): 612-616.
3. Li X J, Yang B L, Zhang S L,(2017). "Hairy nanoparticle-supported MacMillan and its application to Diels-Alder reaction in the water". Colloid Polym. Sci., 295(4): 573-582.