Fluorine-Containing Chiral Compounds of ... - ACS Publications

Chapter 1

Fluorine-Containing Chiral Compounds of Biomedical Interest Robert Filler

Downloaded by INDIANA UNIV PURDUE UNIV AT IN on October 13, 2012 | http://pubs.acs.org Publication Date: December 29, 1999 | doi: 10.1021/bk-2000-0746.ch001

Department of Biological, Chemical, and Physical Sciences, Illinois Institute of Technology, Chicago, I L 60616-3793

In recent years, there has been a plethora of publications on asymmetric syntheses and enzymic methods leading to fluorine-containing chiral compounds. This review, based on a detailed survey of recent literature, focuses on compounds of interest in bio-and medicinal chemistry, e.g., amino acids, anticancer agents, sugars, nucleosides, central nervous system agents, and anesthetics. Methods involving asymmetric aldol reactions, asymmetric alkylation, enantioselective fluorinating agents, and enzymically controlled reactions are presented. Bioactive fluorine-containing compounds have been known since the 1930s and 1940s, but the remarkable developments of the 1950s, including the fluorosteroids, inhalation anesthetics, such as halothane, and the anticancer agent 5-fluorouracil, heralded the subsequent rapid advances we have witnessed during the ensuing forty years. During the past decade, there has been an increased emphasis on new approaches to chiral compounds and asymmetric syntheses. This focus has been particularly pronounced in medicinal chemistry, where a specific enantiomer or diastereomer often exhibits enhanced therapeutic potency compared with the racemate. Organofluorine compounds have played a significant role in these advances. A n earlier report emphasized a range of methods for the synthesis of chiral bioactive fluoroorganic compounds (1). Since the intent of this paper is to provide an overview which captures the scope and flavor of these recent developments, it seems quite appropriate to briefly cite the fascinating range of research studies of the other contributors to this book. Bravo and co-workers report asymmetric syntheses of fluoroalkylamino compounds via chiral sulfoxides and the stereoselective synthesis of βfluoroalkyl-β-amino alcohol units using chiral sulfoxides and the Evans aldol reaction. Bégúe and colleagues discuss the stereoselective and enantioselective synthesis of trifluoromethyl amino alcohols and fluoroalkyl isoserinates. Hoffman reports the aysmmetric fluorination of α-aminoketones, while

© 2000 American Chemical Society

In Asymmetric Fluoroorganic Chemistry; Ramachandran, P.; ACS Symposium Series; American Chemical Society: Washington, DC, 1999.

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2 Soloshonok describes his continuing studies on a practical asymmetric methodology for the synthesis of enantiopure fluoro amines and amino acids. Chemical and biochemical approaches to non-racemic fluorinated catecholamines and amino acids are explored by Kirk and co-workers. Ramig discusses recent studies of the chiral fluorinated anesthetics, halothane, enflurane, isoflurane, and desflurane. Ojima and colleagues report exciting new results on the synthesis of enantiopure fluorine-containing analogs of paclitaxel and docetaxel and their use as anticancer agents and as important biochemical probes. In their studies of natural products containing fluorine, O'Hagan and Harper trace the biosynthetic origin of fluoroacetate and 4fluorothreonine in a Streptomyces bacterium. Iseki reports efficient asymmetric syntheses of fluorinated aldols and nitro aldols of high enantiomeric purity, while Yamazaki discusses the construction of chiral aldols with fluorine-containing methyl groups starting from D-glucose. Hamper and co-workers at Monsanto describe the synthesis and herbicidal activity of enantiomeric lactate derivatives of trifluoromethyl-substituted pyrazole herbicides. Resnati and colleagues discuss the resolution of racemic perfluorocarbon halides via self-assembly involving intermolecular electron donor-acceptor interactions. A variety of reactions leading to fluorinecontaining chiral molecules useful as liquid crystals are reported by Hiyama and co-workers. In the search for new antimicrobial agents bearing the βlactam moiety, Welch and co-workers report the preparation of a chiral 3fluoroazetidinone by cycloaddition of fluoroketene (from fluoroacetyl chloride and Et N) and an optically active arylimine. The azetidinone serves as a building block in a multistep synthesis of a new fluorine-containing tribactam (tricyclic β-lactam derivative). A n important feature is the dominance of the electronic effect of fluorine over the steric influence of a methyl group on the same carbon. Ramachandran and Brown review their applications of chiral organoboranes derived from α-pinene in a three-pronged approach for the preparation of asymmetric organofluorine compounds in very high enantiomeric excess. Reactions include (1) asymmetric reduction of fluorinated ketones, (2) asymmetric allylboration of fluorinated aldehydes, and (3) asymmetric enolboration-aldolization of fluoro aldehydes and ketones. Using B-chlorodiisocampheylborane, the stereochemical outcomes in reactions (1) and (3) are apparently influenced by the presence of fluorines in the molecules. Ramachandran and colleagues review and compare the MoritaBaylis-Hillman (MBH) reaction and vinylmetalation (aluminum and copper) of fluorocarbonyls as routes to achiral and chiral fluorinated allyl alcohols. Use of terpenyl alcohols as chiral auxiliaries in asymmetric M B H and vinylmetalation reactions is explored. Mikami reports the asymmetric synthesis of diastereomeric a- or β- C F liquid crystalline (LC) molecules by a carbonyl-ene reaction using fluoral in the presence of a chiral binaphtholderived titanium catalyst (BINOL-Ti). These LCs function as conformational 3

3


3


probes for ferroelectricity. The first example of spontaneous resolution of racemates in fluid L C phases has been observed with these diastereomers. Ishii and Mikami describe the first example of asymmetric catalysis (BINOLTi) in the Friedel-Crafts reaction of aryl compounds with fluoral to provide a practical route to chiral α-trifluoromethylbenzyl alcohols. Highly enantiopure β-trifïuoroaldols have also been prepared from vinyl ethers via sequential diastereoselective reactions. Fluoroamino Acids Fluorine-substituted amino acids have often been used as probes to follow biochemical reactions. During the past few years, asymmetric syntheses of fluoro α-amino acids have been the subject of intense activity. Thus, Soloshonok and co-workers (2) reported highly diastereoselective asymmetric aldol reactions between prochiral trifluoromethyl ketones and the N i (II)complex of the monochiral Schiff base of glycine (Figure 1) and established reaction conditions for preparative syntheses of diastereo- and enantiomerically enriched trifluoromethyl-substituted serines. Sting and Seebach (3) converted enantiopure (S) - 4,4,4 - trifluoro - 3 - hydroxybutanoic acid in several steps to dioxanones, whose enolates were stereoselectively aminated with di- tert - butyl azodicarboxylate, DBAD. Acidic ring-opening and removal of the N-Boc groups provided the corresponding α-hydrazino -β hydroxyesters which, on hydrogenolysis, gave the threonine analog (2R, 3S) - 2 - amino - 4,4,4 - trifluoro - 3- hydroxybutanoate methyl ester (1) (Figure 2). Previous synthetic and enzymatic approaches to trifluoromethyl analogs of threonine and allothreonine by other investigators are discussed in this paper (3). Enantiomerically enriched 3,3,3- trifluoroalanine (up to 63% ee) has been prepared by the asymmetric reduction of 2-(N-arylimino) - 3,3,3trifluoropropanoic acid esters with a chiral oxazaborolidine catalyst (equation 1)(4). In a novel approach, an enantiomerically pure derivative of 2-amino4,4,4trifluorobutanoic acid was synthesized via nucleophilic trifluoromethylation (Figure 3) (5). In the key step, Garner's aldehyde (2) (6), an oxazolidine derived from L-serine, reacted with the Ruppert-Prakash reagent, TMS-CF (a trifluoromethide equivalent) (7) and tetrabutylammonium fluoride. (S) - 5,5,5,5',5',5'- Hexafluoroleucine (3) (88% ee) was prepared in 18% overall yield from hexafluoroacetone and ethyl bromopyruvate in seven steps (8). The highly enantioselective reduction of the keto carbonyl group of 4 to the hydroxyester 5 either by baker's yeast and sucrose (91% ee) or by catecholborane and an oxazaborolidine catalyst (99% ee) was the pivotal reaction of the sequence. These workers (9) also prepared (-)-(R)- 4,4,4,4',4',4 -hexafluorovaline (6) (98% ee). The key step was the separation of the tosylate salts of the diastereomers formed by anti-Michael addition of (+)-(R)3

f


4


ο

90-98% de R= C H (a), C H (b), C H 3

4

g

7

I 5

(c), C H 8

1 7

(d), (CH ) Ph (e), C=C-Ph (I) 2

3

Figure 1. Highly diastereoselective asymmetric aldol reactions of chiral Ni(II)complex of glycine with CF3COR (2).

71-97%

BoeHN' diastereomeric ratio > 98:2 R = H, Me, Bu, Ph

1) H , Pt0 , MeOH

HCI, MeOH

2

2

2) NaHC0 CIH3N

F j C ' Y ^ O M e 3

NH

11-47%

2

1

Figure 2. Synthesis of (2R, 3S)-2-amino-3-trifluoromethyl-3-hydroxy alkanoic acid derivatives (3).

H . P h BHÇ0 Et 2

ζ

Ο

X

FaC^Np-MeOQ^

I —

Ο B

CO,Et F C^NHp-Me0C H 3

6

4

THF 93%

9

3

%

e

e

(R)


Fluorine-Containing Chiral Compounds of ... - ACS Publications

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