Chapter 8
Terminal Fluoroolefins Synthesis and Application to Mechanism-Based Enzyme Inhibition
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Philippe Bey, James R. McCarthy, and Ian A. McDonald Merrell Dow Research Institute, 2110 East Galbraith Road, Cincinnati, OH 45215
The incorporation of a f l u o r o o l e f i n f u n c t i o n a l i t y into a substrate of a p a r t i c u l a r enzyme is often an e f f e c t i v e way to design a mechanism-based i n h i b i t o r of an enzyme that catalyzes an oxidation step during turnover of substrate to product. A review of published synthetic methods leading to f l u o r o o l e f i n s i s presented with p a r t i c u l a r focus on examples relevant to enzyme inhibition. Over the past 15 years, the concept of mechanism-based i n h i b i t i o n has been exploited successfully to develop a wealth of new enzyme i n h i b i t o r s of therapeutic relevance ( 1 ) . The prototype of mechanism-based i n h i b i t o r s i s the suicide i n h i b i t o r . Suicide i n h i b i t o r s are chemically unreactive pseudo-substrates of the target enzymes which incorporate i n t h e i r structures a latent reactive group. A c t i v a t i o n of the latent group during enzymatic turnover generates a species that eventually inactivates the target enzyme, usually through formation of a covalent bond with a residue of the active s i t e of the enzyme or of the cofactor. The f u n c t i o n a l i t i e s s u i t a b l e as latent reactive groups obviously depend upon the mechanism of action of the target enzymes. For example, double bonds have proven useful i n the design of mechanism-based i n h i b i t o r s for enzymes that catalyze an oxidation step during turnover of substrates to products ( 2 ) . when the double bond i s located on the carbon atom of the substrate next to the function that i s oxidized, an e l e c t r o p h i l i c Michael acceptor i s generated i n the enzyme's active s i t e , provided that the modified unsaturated substrate i s s t i l l turned over by the target enzyme. The Michael acceptor can eventually a l k y l a t e an adventitious n u c l e o p h i l i c residue i n the active s i t e , r e s u l t i n g i n the formation of a covalent adduct between the i n h i b i t o r and enzyme which leads to i n a c t i v a t i o n of the target enzyme. In p r i n c i p l e , the chemical r e a c t i v i t y of the double bond can be manipulated by adding a f l u o r i n e atom on the d i s t a l carbon atom of the double bond; the 0097-6156/91/0456-0105$08.25/0 © 1991 American Chemical Society
In Selective Fluorination in Organic and Bioorganic Chemistry; Welch, John T.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
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SELECTIVE FLUORINATION IN ORGANIC AND BIOORGANIC CHEMISTRY
f l u o r i n e atom i s s i m i l a r to an hydrogen atom i n terms of s t e r i c hindrance (3). The fluorinated unsaturated d e r i v a t i v e can, therefore, be expected to be a substrate f o r the target enzyme i f the corresponding unsaturated d e r i v a t i v e i s also a substrate. The ^ - f l u o r i n a t e d Michael acceptor that would be formed i s more e l e c t r o p h i l i c and consequently more reactive towards a n u c l e o p h i l i c residue than the non-fluorinated system. Moreover, the β-fluoroα,β-unsaturated system can add the enzyme n u c l e o p h i l i c residue i n a Michael-type addition-elimination reaction as indicated i n Figure 1. A p o t e n t i a l advantage i s that the r e s u l t i n g covalent bond between the enzyme and the i n h i b i t o r would be more stable since a retro-Michael reaction i s no longer possible. In t h i s chapter, we discuss the synthetic methodologies used to prepare f l u o r o o l e f i n s and present examples of mechanism-based i n h i b i t o r s of amine oxidases, γ-aminobutyric acid transaminase and S-adenosylhomocysteine hydrolase which incorporate t h i s s t r u c t u r a l f u n c t i o n a l i t y . Ve have r e s t r i c t e d our discussion to the syntheses of terminal mono-, d i - and t r i f l u o r o o l e f i n s , omitting the large body of synthetic endeavour directed towards other fluoro o l e f i n s (4). V i t t i g Reactions and Organometallic Approaches to Fluoroolefins
The V i t t i g reaction has served as a v e r s a t i l e method to mono- and d i f l u o r o o l e f i n s . Fuqua (5,6) and Burton (7 8) f i r s t applied t h i s reaction to the synthesis of d i f l u o r o o l e f i n s (3) by the i n s i t u generation of triphenyldifluoromethylenephosphorane ( 2 ) from sodium chlorodifluoroacetate ( 1 ) and triphenylphosphine i n tEe presence of aldehydes (7,8) or ketones (6) (Scheme 1). When the reaction was c a r r i e d out with an unsaturated carbonyl compound no d i f l u o r o c y c l o propanes were formed (8), suggesting the absence a d i s c r e t e difluorocarbene intermediate. At the time t h i s method was developed there were no other simple general methods to d i f l u o r o o l e f i n s {9,10). The synthesis of fluoromethyltriphenylphosphonium iodide (5) from fluoroiodomethane ( 4 ) provided a d i r e c t route to monofluoro-substituted o l e f i n s (11,T2). The scope of the reaction, as w e l l as alternate methods f o r the synthesis of 5 and fluoromethylenetriphenylphosphorane ( 6 ) , were studied by Burton and Greenlimb (13) (Scheme 2). Although improved y i e l d s of f l u o r o o l e f i n s 7 (from 5) were r e a l i z e d when potassium t-butoxide was used i n adïïition to n-butyllithium, these were generally less than 50%. Moreover, extremely dry solvents were required to obtain reproducible y i e l d s and the a v a i l a b i l i t y and expense of the s t a r t i n g halofluoromethanes, Cfl FI and CHFI , l i m i t e d the u t i l i t y of the method. Replacement of iodofluoromethane ( 4 ) i n Scheme 2 with dibromodifluoromethane ( 9 ) provided a new route to the V i t t i g reagent Ph P=CF ( 2 ) (14J". I n contrast to 2 (obtained from 1 0 ) , which appears best suited f o r reaction with aldehydes, (dimethylamino)difluoromethylenephosphorane ( 1 1 ) adds to both aldehydes and unactivated ketones (Scheme 3). The reaction conditions, however, are s t i l l extremely s e n s i t i v e to moisture. Difluoromethylenation of the activated ketone 12 was achieved chemoselectively with Ph P/CF Br /Zn (Scheme 4); thêTïactone carbonyl was unreactive (15). However, the reagent generated from CF Br /(Me N) P reacted with a formate ester ( 1 4 ) i n high y i e l d (Scheme 5) (16) and the lactone ( 1 6 ) could be converted to 17 by f
2
3
2
3
2
2
2
2
2
2
3
In Selective Fluorination in Organic and Bioorganic Chemistry; Welch, John T.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
8.
Terminal Fluoroolefins
BEY ET AL
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Nu-Enz
Nu-Enz
Figurel.
Rational
for the design
enzyme
inhibitors
PPh
CICF C0 Na 2
of fluoroolefin-containing
3
Ph P = CF
2
3
160"
1
mechanism-based
RFVC=0 -
2
RR'C=CF
2
2 Scheme 1
IFCH
PPh
3
[Ph PCH F]
2
3
2
+ I
BuLi
Ph P = CHF 3
4
6 RR'C=0 PPh
Zn (Cu)
3
CHFlo
[Ph PCHFI] l" +
3
-
RR'C=CHF 7
8 Scheme 2
2 (Me N) P 2
(Me N) P = CF 2
3
11
2
PPh
3
2
Zn
3
CBr F 2
[Ph PCBrF2] Br
Ph P = CF
10
2
3
9 Scheme 3
In Selective Fluorination in Organic and Bioorganic Chemistry; Welch, John T.; ACS Symposium Series; American Chemical Society: Washington, DC, 1991.
3
2
108
SELECTIVE FLUORINATION IN ORGANIC AND BIOORGANIC CHEMISTRY
treatment with (Me N) P/CF Br /Zn (Scheme 6) (17). The silylated (IS) or acylated (19) forms of 1,1-difluoro-l-alken-3-ols (19 and 20) were obtained from the respective s i l y l or acyl protected α-hydroxy -aldehyde or -ketone (19) by reaction with the Wittig reagent generated in situ with CF Br /(Me N) P (Scheme 7). Perfluoroalkyl acyl fluorides react with the fluoro diphosphonium salt 22 to provide vinyl phosphonium salts (23) in good yields (20) (ScHeme 8); hydrolysis gave (E)-l,2-difluoro olef ins (24). Alternatively, 22 could be reacted with aldehydes to provide tHê fluoroalkenylphosphonium salt (25) which, when treated with aqueous sodium hydroxide, affords a convenient one pot synthesis of fluoroolefins (26)(21). The unexpected Ζ stereoselec tivity observed in the synthesis of 26a (E/Z = 13/87) was rationalized on the basis of through space charge-transfer complexes between the pi electrons of the aromatic ring of the aldehyde and the positive charge of one of the tri-n-butylphosphonium groups. The Vadsworth-Emmons reagent 27 has been used successfully to prepare difluoroolefins (3) (Scheme 9) (22,23). Furthermore, when the trimethylsilyl derivative 30 is used in place of 27, the condensation reaction can be performed under very mil
