Advances in the Synthesis of Enantiomerically Pure Fluorinated Alcohols and Amines

Enantiomerically pure fluorinated alcohols and amines are invaluable building blocks for the medicinal chemistry community, finding application in the synthesis of a wide range of biologically active compounds. These building blocks enable the efficient synthesis of diverse fluorinated heterocycles, pharmaceuticals, and agrochemicals, taking advantage of the unique properties imparted by the fluorine substituent. The ability to rapidly access enantiomerically pure fluorinated alcohols and amines has had a profound impact on medicinal chemistry.

ATH of Fluorinated Ketones and Imines

Traditionally, the preparation of these versatile structures has relied on lengthy, multi-step sequences involving resolution of racemates or enzymatic kinetic resolutions. However, recent advancements in transition metal catalysis and organocatalytic reduction have revolutionized the field, providing efficient, direct access to these important targets.

One powerful approach has been the development of asymmetric transfer hydrogenation reactions of fluorinated ketones and imines. Asymmetric transfer hydrogenation (ATH) is an efficient, powerful and easy-to-operate method for the reduction of C=O, C= N and C=C bonds. Commonly used hydrogen sources, such as HCO₂H/Et₃N azeotropic mixtures, HCO₂Na and i-PrOH, are cost-effective and readily available.

Using chiral metal complexes or organocatalysts, the carbonyl or imine functionality can be selectively reduced, delivering the desired enantiomerically enriched alcohols and amines in high yields and enantioselectivities.

Fluorinated Ketones

Fluorinated ketones are widely used in organic synthesis reactions and can be used as key precursors for the synthesis of enantiomerically pure fluorinated alcohols. For example, Lassaletta and co-workers used ATH to obtain enantiomerically enriched fluorotetrahydrols^[1].

Fig.1 ATH/DKR to access enantiomerically enriched fluoro-tetralol.^[1]

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CAS NO.	Product Name
100361-18-0	7-Chloro-1-cyclopropyl-6-fluoro-1,4-dihydro-4-oxo-1,8-naphthyridine-3-carboxylic Acid
1007-15-4	3'-Bromo-4'-fluoroacetophenone
101975-15-9	4'-(1,1,2,2-Tetrafluoroethoxy)acetophenone
101975-16-0	3'-(1,1,2,2-Tetrafluoroethoxy)acetophenone
1060802-41-6	2,2,2-Trifluoro-1-(3-fluoropyridin-2-yl)ethanone
107368-61-6	Methyl perfluoro(1,4-dimethyl-2,5-dioxaoctyl) ketone
111141-00-5	8-Fluorochroman-4-one
111141-02-7	7-(Trifluoromethyl)chroman-4-one
1125812-58-9	1-(3-Chloro-5-(trifluoromethyl)phenyl)-2,2,2-trifluoroethanone
112811-71-9	Ethyl 1-cyclopropyl-6,7-difluoro-8-methoxy-4-oxo-1,4-dihydroquinoline-3-carboxylate
1147103-48-7	2,2,2-Trifluoro-1-(pyrazin-2-yl)ethanone
115665-92-4	(E)-4-(4-(Trifluoromethyl)phenyl)but-3-en-2-one
116707-09-6	1-(2-Fluorophenyl)-2-methylpropan-1-one
1185023-70-4	3,3-Dichloro-1,1,1-trifluoroacetone trihydrate
118803-81-9	1-Ethyl-6-fluoro-4-oxo-7-(piperazin-1-yl)-1,4-dihydroquinoline-3-carboxylic acid nicotinic acid salt
1191999-09-3	1-(2-Fluoro-3-hydroxyphenyl)ethanone
1204333-47-0	2-Bromo-1-(3-bromo-2-fluorophenyl)ethanone
121629-16-1	1-(4,4-Difluorocyclohexyl)ethanone

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Fluorinated Diketones

Fluorinated diketones can also be used as synthetic intermediates for the preparation of enantiomerically pure fluorinated alcohols and amines. It is hydrogenated by asymmetric transfer hydrogenation or other selective reduction strategies to produce fluorinated diols or amino alcohols, which can then be further processed into the desired fluorinated structural units. The presence of additional carbonyl functional groups in the diketone substrate may require customized catalyst systems or reaction conditions to achieve the desired chemical and stereoselectivity.

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CAS NO.	Product Name
141522-69-2	1-Phenyl-2H,2H-perfluoroundecane-1,3-dione
14324-82-4	Copper(II) 1,1,1-trifluoroacetylacetonate
146195-65-5	1,1,1-Trifluoro-5-methoxy-5-methylhexane-2,4-dione
14781-45-4	Copper(II) hexafluoroacetylacetonate hydrate
147874-76-8	3H,3H-Perfluorodecane-2,4-dione
15191-68-1	1-(4-Methoxyphenyl)-4,4,4-trifluorobutane-1,3-dione
1522-22-1	1,1,1,5,5,5-Hexafluoroacetylacetone
155311-12-9	Molybdenum(VI) dioxide bis(1,1,1-trifluoroacetylacetonate)
155662-73-0	Molybdenum(VI) dioxide bis(1,1,1,5,5,5-hexafluoroacetylacetonate)
168920-97-6	1-Phenyl-2H,2H-perfluoroheptane-1,3-dione
17524-05-9	Molybdenum(VI) dioxide bis(acetylacetonate)
17587-22-3	1,1,1,2,2,3,3-Heptafluoro-7,7-dimethyloctane-4,6-dione
18931-60-7	1-(4-Chlorophenyl)-4,4,4-trifluorobutane-1,3-dione
189347-40-8	4,4-Difluoro-1-(4-metoxyphenyl)butane-1,3-dione
203201-14-3	1H,1H,1H,3H,3H-Perfluorododecane-2,4-dione
20583-66-8	3H,3H-Decafluoroheptane-2,4-dione
20825-07-4	3H,3H-Octafluorohexane-2,4-dione
2145-68-8	6,6-Dimethyl-1,1,1,2,2-pentafluoroheptane-3,5-dione

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Fluorinated Imines

Similarly, the group of MacMillan demonstrated an organocatalytic reduction of fluorinated aromatic and aliphatic imines, furnishing the amine products with excellent enantioselectivity^[2].

Fig.2 Enantioselective thiourea-catalyzed polycyclization of hydroxylactam cations.^[2]

Beyond these seminal studies, significant progress has been made in expanding the substrate scope and improving the operational simplicity of these transformations. Transition metal catalysts based on iridium, rhodium, and other metals have been developed, allowing the reduction of an even broader array of fluorinated carbonyl and imine compounds. In the organocatalytic realm, the use of chiral Brønsted acids, phase-transfer catalysts, and other activation modes have further enhanced the utility and generality of these methods.

Unique Properties of Fluorine Substituents

• Enhanced Biological Activity

The introduction of fluorine can significantly impact the biological activity of the resulting compounds. Fluorine substituents can alter properties such as lipophilicity, metabolic stability, and binding affinity to biological targets, making these fluorinated building blocks valuable for the synthesis of diverse pharmaceuticals and agrochemicals.

• Metabolic Stability

Fluorine substitution can enhance the metabolic stability of the compounds by blocking or slowing down certain metabolic pathways, such as oxidation or hydrolysis. This can lead to improved pharmacokinetic profiles and increased drug efficacy.

• Conformational Effects

The presence of fluorine can influence the conformation and geometry of the molecules, which can be important for target binding and receptor interactions. This conformational control can be exploited in the design of biologically active compounds.

• Lipophilicity Modulation

The incorporation of fluorine can fine-tune the lipophilicity of the molecules, which can impact their solubility, cell permeability, and distribution within the body. This allows for optimization of the physicochemical properties to enhance the desired biological activity.

• Resistance to Enzymatic Degradation

Fluorine substitution can make the molecules less susceptible to enzymatic degradation, thereby increasing their stability and prolonging their efficacy in biological systems.

References

1. Ros A., et al. (2006). "Lassaletta J.M. Enantioselective Synthesis of Vicinal Halohydrins via Dynamic Kinetic Resolution." Org. Lett, 8, 127.
2. Knowles, R. R., et al. (2010). "Enantioselective Tail-to-Head Cyclizations Catalyzed by Dual-Hydrogen-Bond Donors." Journal of the American Chemical Society, 142(15), 6951-6956.