Research Progress of C—H Bond Asymmetric Hydroxylation

doi:10.6023/cjoc202412014

Abstract

Chiral alcohol derivatives are an important class of molecules that exist in many bioactive substances and natural products, and are also an important class of organic synthetic intermediates used to synthesize many important organic compounds. Biomimetic catalysis has been emerging as a very powerful tool for catalytic asymmetric hydroxylation after biocatalysis, and this type of reaction is mainly innovative in the design of novel ligands and their application in asymmetric catalytic reactions. Therefore, it is of great significance to develop efficient, green and stereoselective methods for the synthesis of chiral alcohols. In this paper, the asymmetric hydroxylation of C—H bonds over the past two decades is summarized, and such reactions are classified and summarized according to the types of catalysts, which are mainly divided into two categories of biocatalysis and biomimetic catalysis.

Key words: asymmetric hydroxylation, enantioselectivity, enzymatic catalysis, biomimetic catalysis, chiral ligands

Cite this article

Ye Wu, Chunxia Chen, Jinsong Peng. Research Progress of C—H Bond Asymmetric Hydroxylation[J]. Chinese Journal of Organic Chemistry, 2025, 45(8): 2726-2745.

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Fig. & Tab. 48

Figure 1. Natural active substances containing chiral alcohol structural units

Scheme 1. P450-CAM-catalyzed hydroxylation of 1R-(＋)- camphor

Scheme 2. Mechanism of asymmetric hydroxylation of alkanes catalyzed by P450-CAM

Scheme 3. P450-catalyzed the hydroxylation of myristate at three sites

Scheme 4. Asymmetric hydroxylation of substrates 19 and 20 was catalyzed by mutants

Scheme 5. LG-23 mutants catalyze asymmetric hydroxylation of six steroids

Scheme 6. Asymmetric hydroxylation of β-halogenated aromatics by E. coli P450PL2-4

Scheme 7. Bimodal mechanism of asymmetric hydroxylation of ethylbenzene and 1-phenylethanol in the presence of H216O2 or H218O2

Scheme 8. Symmetric hydroxylation of lactone substrates catalyzed by filamentous fungal enzymes

Scheme 9. Non-heme oxygenase-catalyzed C—H asymmetric hydroxylation of amino acids

Scheme 10. Hydroxylation process based on the consensus mechanism of α-KG dependent enzymes

Scheme 11. Regionally and stereoselectively hydroxylation of steroid substrates was performed using β-cyclodextrin-Mn-porphyrin catalysts

Scheme 12. Asymmetric epoxidation of olefin and hydroxylation catalyzed by water-soluble Mn-porphyrin

Scheme 13. Mn-porphyrin catalyzed asymmetric hydroxylation of 3,4-dihydroquinolones

Scheme 14. M(P3)Cl catalyzed asymmetric hydroxylation at benzyl site

Scheme 15. Asymmetric hydroxylation of allyl catalyzed by Fe-porphyrins

Scheme 16. Ru(P5)(CO) catalyzed asymmetric hydroxylation at the benzylic site

Scheme 17. Ru(P4)(CO)(EtOH)-catalyzed asymmetric hydroxylation of benzyl C—H bond

Scheme 18. Regional selective hydroxylation catalyzed by Os- (TMP)(CO)

Scheme 19. Asymmetric benzyl C—H hydroxylation catalyzed by Mn(III)-Salen complex

Scheme 20. Chiral concave Mn(III)-Salen catalyst

Scheme 21. Fe(III)-Salan catalyzed asymmetric hydroxylation of β-ketoesters

Scheme 22. Zr(lV)-Salan catalyzed asymmetric hydroxylation of β-ketoesters

Scheme 23. Modified Zr(lV)-Salan catalyzed asymmetric hydroxylation of β-ketoesters

Scheme 24. Reaction mechanism of asymmetric hydroxylation of β-keto esters catalyzed by Zr(lV)-Salan

Scheme 25. The novel nitro-substituted Ti-Salalen-catalyzes the asymmetric hydroxylation of benzyl C—H

Figure 2. The catalyst structure of Ti-Salalen dimer

Scheme 26. Asymmetric hydroxylation of tertiary propargyl C(sp3)—H bonds catalyzed by Mn-Salen

Scheme 27. Transition metal catalysts based on aminopyridines

Scheme 28. Fe-aminopyridine catalyzes the hydroxylation of alkyl C—H bond

Entry	Product	Isolated yield/% (rsm^a)
1		46 (26)
2		53 (43)
3		60 (18)
4		43 (33)
5		52 (21)
6		57 (27)
7		43 (42)
8		33 (67) 90*^,^b(8)
9		52 (20)
10		92*

Table 1. Range of 98 for different types of substrates

Scheme 29. Order of C—H bond reactivity under the influence of EWG

Scheme 30. Stereospecific tertiary C—H hydroxylation of cis-1,2-dimethyl cyclohexane

Scheme 31. 101 catalyzed aliphatic C—H oxidation

Scheme 32. C—H bond oxidation catalyzed by 102-104

Scheme 33. Selective oxidation of (＋)-neomenthol neopentanoate 136

Scheme 34. Selective oxidation of (＋)-neomenthol neopentanoate 138

Entry	Cat.	Conv/%	Total yield (isolated yield)/%	C6/C7/C12/C14
1	107c	85	70 (50)	75/5/23/—
2	107d	86	80 (71)	11/1/88/—
3	108c	83	60 (49)	82/12/3/3
4	108d	50	48 (33)	22/6/69/3

Table 2. Oxidation of trans-androsterone acetate

Scheme 35. (a) Schematic diagram of the polarity reversal concept; (b) C—H hydroxylation mechanism entailing hydrogen atom transfer

Scheme 36. Mn catalyzed asymmetric benzyl hydroxylation in fluorinated ethanol

Scheme 37. Highly enantioselective oxidation of helicoidal hydrocarbons

Scheme 38. Enantioselective benzyl C—H oxidation of spirocycles

Scheme 39. Mn-catalyzed asymmetric benzyl hydroxylation of indene derivatives and mechanism

Scheme 40. C—H oxidation of (－)-norambergris ether and its derivatives

Scheme 41. C—H hydroxylation of estrone 3-acetate, 17α- and 17β-estradiol 3-acetate substrates

Scheme 42. Asymmetric oxidation of C—H bonds of unactivated methylene

Scheme 43. Nondirected enantioselective hydroxylation of the unactivated tertiary C—H bond

Scheme 44. HFIP-assisted distant C—H hydroxylation of heteroaromatic substrates

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C—H键不对称羟基化反应的研究进展