Asymmetric Fluoroorganic Chemistry - American Chemical Society

Chapter 13

The Synthesis of a Series of Fluorinated Tribactams 1

2

Ferenc Gyenes, Andrei Kornilov , and John T. Welch

Downloaded by UNIV LAVAL on October 10, 2015 | http://pubs.acs.org Publication Date: December 29, 1999 | doi: 10.1021/bk-2000-0746.ch013

Department of Chemistry, University at Albany, Albany, NY 12222

A fluorinated building block was converted in a concise series of steps to a new series of fluorinated tribactams. During the course of the synthesis an interesting stereoselective addition, presumably influenced by the presence of fluorine was discovered. The products were carefully characterized by 2D N M R spectroscopic methods.

The search for novel antimicrobial agents containing the β-lactam motif has produced a plethora of novel chemical entities many of which are presently marketed as antibiotic agents. The report of the discovery of thienamycin opened a new frontier in β-lactam research. Since then, other advances in the chemistry and biology of the carbapenems have followed. Recently, scientists at Glaxo Wellcome have discovered the "trinem" family(l-5) of synthetic β-lactams (See below). Functionalization at the C-4 position of a cyclohexane ring fused to the carbapenem nucleus has been very effective at modifying the activity of the trinems. The main structural features of these tricyclic β-lactam derivatives (also known as tribactams) are the presence of a reactive β-lactam ring (A) with hydroxyethyl substituent, an unsaturated five-membered ring (B), and a six-membered carbocyclic ring (C).

COOH

Current address: Institute of Bioorganic Chemistry and Petrochemistry, National Academy of Science of the Ukraine, 1 Murmanskaya, Kiev 94, Ukraine 253660. Corresponding author.

182

© 2000 American Chemical Society

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

183 Typically trinems have been prepared with optically active 4-acetoxy-2azetidinone 1 as the crucial building block.


OLi

1

2

(2*5)-3

(27?)-3

(2'S)-3 COOH

COOH

(8S)-4

(8#)-4

The more active β isomer (8S)-4 was only slightly less than active than the clinical agent imipenem(6) 5 while the α isomer (8R)-4 was less active. HO

5 Imipenem

After establishing the optimum stereochemistry at C-8, modification of the C ring at position 4 led to the synthesis of 4-substituted derivatives. Of the four possible isomers the 4-a (4S), 8-β (8S) series of derivatives(7-9) has a comparable level of activity to imipenem 6.

6a R = Η 6bR = S C H 6cR = O C H 6d R = NHCH 3

3


184 Compound 6c, also known as Sanfetrinem combines a particularly broad spectrum (including gram-negative and gram-positive aerobes and anaerobes) with high potency, resistance to β-lactamases, the bacterial enzymes that hydrolyze β-lactam antibiotics, and stability to dehydropeptidases.


Antimicrobial Activity Sanfetrinem has in vitro activity equivalent to that of imipenem, equivalent to or better than that of a combination of Amoxicillin and clavulanic acid, and superior to that of ciprofloxacin, and erythromycin. Against gram-negative bacteria, this tribactam possessed activity similar to that of imipenem and cefpiran, but its activity was superior to that of a combination of Amoxicillin and clavulanic acid. Sanfetrinem is stable to all clinically relevant β-lactamases and is rapidly lethal to susceptible bacteria. Nonetheless, expression of β-lactamases is the likely means by which bacteria might develop resistant to Sanfetrinem. These enzymes are widely produced by gram-positive and gram-negative organisms and may be encoded either chromosomally or extrachromosomally, that is by means of plasmids or transposons.(7-9) Chromosomal β-lactamases are inducible enzymes but can be constituitively expressed (i.e., stable activated and expressed at all times) and are found in almost all gram-negative bacteria. Inducible chromosomal β-lactamases are especially problematic in the clinical setting. Since the induction of a β-lactamase is a chromosomal trait, all the organisms in a population produce the enzyme. Chromosomal β-lactamases are often resistant to inhibition by mechanism-based inactivators and unfortunately, the addition of a second antibiotic to the treatment regimen seems to have has little or no effect on the rate of emergence of resistance. β-Lactamase Sensitivity. Although carbapenems have remained relatively insensitive to the hydrolytic action of many clinically relevant β-lactamases, a number of carbapenem-hydrolyzing enzymes have been reported in recent years. Carbapenemhydrolyzing β-lactamases include the more recently described penicillin-interactive proteins.(lO) The number of these enzymes relative to the variety of other βlactamases remains low, only 17 carbapenem-hydrolyzing enzymes were included in the recent compilation of 190 functionally or molecularly distinct β-^3ηΜ8β8.(11) Most carbapenem-hydrolyzing β-lactamases confer resistance not only to carbapenems, but also to other β-lactams. Since the majority of the carbapenem-hydrolyzing βlactamase genes are chromosomally encoded this has certainly mediated the spread of these enzymes, with a concomitant slow increase in β-lactamase-mediated resistance to carbapenems in clinical applications. Two strategies have been employed to counter the problem of β-lactamasemediated resistance. One approach to overcome the destructive acylation of the βlactam is alteration of the β-lactam structure, rendering it insensitive to hydrolysis by the β-lactamase while maintaining potency as an antibiotic. Alternatively, an auxiliary agent that inactivates the β-lactamase can be employed, in synergy with a β-lactam antibiotic that is otherwise susceptible to the enzyme. The strategy proposed in this work is to combine the two effects by preparing a series of fluorine-containing trinems


185 7. Attempted modifications of penicillin and cephalosporin often led to molecules that were more resistant to the β-lactamase but were unfortunately less effective antibiotics. This is not surprising since at least some of the enzymes of cell-wall biosynthesis which are acylated by penems show a convincing homology(12) with residues involved in


COOCH3

7

acyl-enzyme formation by the P-lactamase.(13) Carbapenems generally satisfy the requirements necessary for an inhibitor, ready acylation of the active site of βlactamases, but sluggish deacylation, combined with antibacterial activity. The trinems also possess these desirable features.(l-5) Synthesis of A Fluorinated Tribactam Our synthesis of the β-lactam nucleus was based upon the highly efficient [2+2] cycloaddition approach.(14) Thus fluoroacetyl chloride is allowed to react with an optically active imine 8, which was obtained by condensation of p-anisidine with (D)glyceraldehyde acetonide. The product of this cycloaddition reaction, a single diastereomer of 3-fluoro-2-azetidinone 9, was formed in 68% yield in 99% ee.(14) The absolute stereochemistry of this product was confirmed by single-crystal X-ray diffraction studies.(14)

Ο

/

CI

+

\

Et N/CH Cl 34-36 °C 3

2

68.0% ee>99%

F?

2

X \

/

H-" O'

OCH3

\)CH

3

The high stereoselectivity observed, was previously discussed and may be rationalized as a consequence of the anti addition of the imine 8 to a single face of the fluoroketene.(14) The intermediate zwitterionic species 10 is postulated to collapse with 1,2-lk, ul topicity(15) i . e., antiperiplanar to the adjacent carbon-oxygen bond via a conrotatory ring closure forming 9 for stereoelectronic reasons.


186 H CQ 3

(Re,Re-S)


10

The chiral 3-fluoroazetidinone 9 was deprotonated with L D A at -90 °C and methylated without loss of stereochemical integrity at the fluorinated carbon as determined by l ^ F N M R spectroscopy of the reaction mixture.(14) The very high stereoselectivity at C-3 in the ring could be explained by the steric demand of the bulky dioxolane ring at the C-4 position which directs electrophilic attack.

X

Ο

Ο LDA/THF/-95 ° C

CH3I Ο

7Κ>PMP

93%

PMP

\ J

F CU

PMP = 4-methoxyphenyl

O'

11 The transformation of 11 to the aldehyde 12 can proceed via either of two pathways. Cleavage of the acetal group with 70% acetic acid(16) followed by sodium periodate oxidative cleavage(17-18) of the formed diol 13, furnished the aldehyde 12 in 88% yield. Alternatively, this conversion was realized in a single flask by simple treatment of 11 with periodic acid in dry ether.(19) The isolated yield, 83%, is comparable with the 88% yield of the two-step process.

X

HO

OH U

F

70%CH COOH 3

CH

CH,

reflux 94%

cr

Ο

PMP

PMP 13 NaI0 rt/CH Cl 4

2

2

94%

NCHO

N

CHi

7X

PMP

O'

12

The aldehyde 12 was easily oxidized by potassium permanganate to the corresponding carboxylic acid(20) 13 in nearly quantitative yield. As mentioned previously, the 4-acetoxy derivatives of β-lactams are the key intermediates for the synthesis of thienamycin and related penems. In our case the conversion of the acid 13


187 to O-acetyl derivative decarboxylation.(20)

rH3

^Y

was

performed

by

Hunsdiecker

oxidative

CHQ

KMn0 /K C0 4

i - i Ο

14

2

3r

C

H

C

^ , -

3

O

O

H

THF/H 0/rt 2

PMP

99%

Ο

PMP

F H PrXOAc) /70°C


4

C

H

l

CH3COOH/DMF 80% (4R)-U

The reaction presumably proceeds via a radical mechanism with complete loss of the optical activity at C-4 to afford a 1:1 mixture of two diastereoisomers. Two resonances are observed in the N M R spectrum of this mixture: a quartet, corresponding to the (S) configuration at C-4, and a second resonance, a doublet of quartets that corresponds to the (R) configuration at C-4. Deprotection of the β-lactam nitrogen by treatment with eerie ammonium nitrate(21) (CAN) forms the N-dearylated product 15.

1 4

CAN/0

°c

3

Y

cn -4-f

w

3

CH CN/H 0

X-N

2

74%

Ο S

O

H

15

The introduction of the cyclohexanone ring at C-4 was affected by an additionelimination under the two different reaction conditions. Initially, the Lewis acid catalyzed process, which requires TBDMS protection(22) of the β-lactam nitrogen, was explored. The protected product 16 was obtained smoothly in 90% yield from 15.

i 5

TB

D M S

CVEt N 3

l y y C H ,

t

CH Cl /DMAP/rt 2

I

2

9

0

%

^

ο N

3

-ΝΟ

COOCH

3

Characterization of the Product. While cyclohexanone addition afforded only two diastereomers are observed after cyclization, fluorine and proton N M R resonances attributable to more than two diastereoisomers. Possibly, epimerization of position four occurs during the acylation of the lactam nitrogen. The presence of fluorine on the adjacent carbon atom may make this hydrogen sufficiently acidic to be abstracted by triethylamine, in contrast to the original trinem. The final product was characterized using 500 M H z N M R spectroscopy. The individual methylene resonances of the cyclohexane ring as well as the remaining resonances were identified by two-dimensional proton-proton chemical shift correlation spectroscopy (COSY), which provided a map of coupling networks between protons in the molecule. The coupling pathway was determined by correlating the chemical shifts of coupled spins in a stepwise manner. Three resonances can be assigned from the lD-^H-NMR. The first two of the three resonances can be attributed to methyl groups. One methyl is attached to C-10, the other is the methyl group of the ester function attached at C-2. The third resonance is derived from the proton attached to C-9. However, the information from the first two sets of hydrogens is limited since they do not have any cross peaks in the COSY spectrum. The proton on C-9 was the starting point for determining which protons


190 are located on the six-membered ring. The only cross peak corresponding to H 9 is at δ 2.90-2.70 ppm. This chemical shift belongs to H-8. Continuing the connectivity analysis, the protons from H-7 through H-4 were identified (Table I).

a


Table I. N M R spectroscopic data for compound 7 as a mixture of diastereomers

COOCH

3

7

Position* 4 5 6 7 8 9 12 13

^HCOSY ^(ppm) 1.95-1.80, br H-5 1.80-1.50, br H-6 1.80-1.50, br H-7 2.50-2.30, br H-8 2.90-2.70, m H-9 4.30-4.05, m 1.74, d, 23.1; 1.73, d, 23.2; 1.71, d, 22.2; 1.69, d, 23.1; 3.83, 3.81, 3.80, 3.78, s N M R spectra recorded at 500 MHz..

iH^HTOCSY H-5, H-6, H-8, H-9 H-6, H-7 H-7, H-8, H-9 H-8, H-9 H-9, H-12 H-12

a

For the confirmation of the structure, 2D TOCSY (2D totally correlated spectroscopy) was performed as well. In this spectrum, the long range couplings of H-9 can be clearly seen to H-7, H-4, H-6 and H-12 (the methyl group on C-10). The methyl on C-10 is also coupled with H-8. The couplings of H-8 to H-4 and H-6 are also detectable from the spectrum. From the two dimensional N M R spectra it is possible to assign a resonance to each hydrogen in the mixture of four diastereomers that were formed in a ratio of 1:1:2:6. Conclusion A fluorinated version of a "trinem" β-lactam was synthesized bearing a methyl group at position three instead of a hydroxyethyl unit. The electronic effect of the fluorine was observed during nucleophilic addition to the adjacent in situ -formed sp2 carbon which resulted in exclusively trans addition to the carbon-fluorine bond. The electronic effect of fluorine dominates the steric influences of the methyl group at the same site. The addition of methyl oxalyl chloride in the cyclization process under basic conditions promotes epimerization of the C-4 stereocenter. The biological testing of the final compound is under investigation.


191 Acknowledgments. Financial Support of this work by NSF Grant Number C H E 9413004 and NIH Grant Number AI4097201 is gratefully acknowledged


Literature Cited 1. Perboni, Α.; Tamburini, B . ; Rossi, T.; Tarzia, G.; Gaviraghi, G. In Recent Advances in the Chemistry of Anti-infective Agents; Bentley, P.H.; Ponsford, R., Eds.; RSC: Cambridge, 1993; pp 21-35. 2. Wollmann, T.; Gerlach, U . ; Horlein, R.; Krass, N.; Lattrell, R.; Limbert, M . ; Markus, A . In Recent Advances in the Chemistry of Anti-infective Agents; Bentley, P.H.; Ponsford, R., Eds.; RSC: Cambridge, 1993; pp 50-66. 3. Tamburini, B.; Perboni, Α.; Rossi, T.; Donati, D.; Andreotti, D.; Gaviraghi, G.; Carlesso, R.; Bismara, C. Eur. Pat. Appl. EP0416953 A2, 1991; Chem. Abstr. 1992, 116, 23533t. 4. Perboni, Α.; Rossi, T.; Gaviraghi, G.; Ursini, Α.; Tarzia, G. WO 9203437, 1992; Chem. Abstr. 1992,117,7735m. 5. Biondi, S.; Rossi, T.; Contini, S. A . EP 617017, 1994; Chem. Abstr. 1994, 121, 280531r. 6. Brown, A. G.; Pearson, M. J.; Southgate, R. In Agents Acting on Cell Walls; Wiley and Sons: New York, 1995; ρ 655. 7. Matthew, M. J. Antimicrob. Chemother. 1979, 5, 349. 8. Roy, C.; Foz, Α.; Segura, C.; Tirado, M.; Fuster, C.; Reig, R. J. Antimicrob. Chemother. 1983,12, 507. 9. Skyes, R. B.; Matthew, M. J. Antimicrob. Chemother. 1976, 2, 115. 10. Rasmussen, Β. Α.; Bush, K . Antimicrob. Agents Chemother. 1997, 223. 11. Bush, K . ; Jacoby, G. Α.; Medeiros, A . A . Antimicrob. Agents Chemother. 1995, 39, 1211. 12. Yocum, R. R.; Waxman, D. J.; Rasmussen, J. R.; Stromiger, J. L . Proc. Natl. Acad. Sci. U.S.A. 1979, 76, 2730. 13. Fisher, J. F.; Belasco, J. G.; Khosla, S.; Knowles, J. R. Biochemistry 1980, 19, 2895. 14. Welch, J. T.; Araki, K . ; Kawecki, R.; Wichtowski, J. A . J. Org. Chem. 1993, 58, 2454. 15. Seebach, D.; Prelog, V . Angew. Chem., Int. Ed. Engl. 1982, 21, 654. 16. Ho, P-T. Tetrahedron Lett. 1978, 37, 1623. 17. Bunton, C. A . In Oxidation in Organic Chemistry; Wiberg, K . B . , Ed.; Academic: New York, 1965; Part A . pp 367-388. 18. Perlin, A. S. In Oxidation; Augustine, R. L., Ed.; Marcel Dekker: New York, 1969; Vol. 1, pp 189-204. 19. Wu, Y - L . ; Wu, W-l. J. Org. Chem. 1993, 58, 2760. 20. Georg, G. I.; Kant, J.; Gill, H . S. J. Am. Chem. Soc. 1987, 109, 1129. 21. Kronenthal, D. R.; Han, C. Y.; Taylor, M . K . J. Org. Chem. 1982, 47, 2765. 22. Hart, D. J.; Lel, C. S.; Pirkle, W. H.; Hyon, M. H.; Tsipouras, A . J. Am. Chem. Soc. 1986, 108, 6054. 23. Rossi, T.; Marchioro, Α.; Paio, Α.; Thomas, R. J.; Zarantonello, P. J. Org. Chem. 1997, 62, 1653. 24. Tirpak, R. E.; Rathke, M . W. J. Org. Chem. 1982, 47, 5099.



192 25. Brownbridge, P. Synthesis 1983, 1. 26. Murata, S. Tetrahedron, 1988, 44, 4259. 27. Kowalski, C.; Creary, X . ; Rollin, A . J.; Burke, C. M. J. Org. Chem. 1978, 43, 2601. 28. Andreotti, D.; Rossi, T.; Gaviraghi, G.; Donati, D.; Marchioro, C.; D i Modugno, E.; Perboni, A . Bioorg. Med. Chem. Lett. 1996, 6, 491. 29. Jackson, P. M.; Roberts, S. M.; Davalli, S.; Donati, D.; Marchioro, C.; Perboni, Α.; Proviera, S.; Rossi, T. J. Chem. Soc., Perkin Trans. 1. 1996, 2029. 30. Pentassuglia, G.; Tarzia, G.; Andreotti, D.; Bismara, C.; Carlesso, R.; Donati, D.; Gaviraghi, G.; Perboni, Α.; Pezzoli, Α.; Rossi, T.; Tamburini, B.; Ursini, A . J. Antibiotics 1995, 48, 399. 31. Greenlee, M . L.; DiNinno, F. P.; Salzmann, T. N. Heterocycles 1989, 28, 195. 32. Yoshida, Α.; Hayashi, T.; Takeda, N.; Oida, S.; Ohki, E. Chem. Pharm. Bull. 1983, 31, 768. 33. Guthikonda, R. N.; Cama, L. D.; Quesada, M.; Woods, M. F.; Salzmann, T. N.; Christensen, B. G. J. Med. Chem. 1987, 30, 871. 34. Hayashi, T.; Yoshida, Α.; Takeda, N . ; Oida, S.; Sugawara, S.; Ohki, E. Chem. Pharm. Bull. 1981, 29, 3158. 35. Yoshida, Α.; Hayashi, T.; Takeda, N . ; Oida, S.; Ohki, E. Chem. Pharm. Bull. 1983, 31, 768. 36. Battistini, C.; Scarafile, C.; Foglio, M.; Franceschi, G. Tetrahedron Lett. 1984, 25, 2395. 37. Yoshida, Α.; Tajima, Y . ; Takeda, N . ; Oida, S. Tetrahedron Lett. 1984, 25, 2793. 38. Pfaendler, H . R.; Gosteli, J.; Woodward, R. B. J. Am. Chem. Soc. 1980, 102, 2039. 39. Afonso, Α.; Hon, F.; Weinstein, J.; Ganguly, A . K . J. A m . Chem. Soc. 1982, 104, 6139. 40. Padova, Α.; Roberts, S. M.; Donati, D.; Perboni, Α.; Rossi, T. J. Chem. Soc., Chem. Commun. 1994, 441.


Asymmetric Fluoroorganic Chemistry - American Chemical Society

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