An efficient chiral synthesis of fluoro-containing amino acids: N-benzyloxycarbonyl-2-amino-4,4-difluorobutyric acid methyl ester and its analogs

Article abstract of DOI:10.1016/j.tetlet.2007.11.163

Fluoro-containing amino acids, N-benzyloxycarbonyl-2-amino-4,4-difluorobutyric acid methyl ester and analogs, were prepared in high enantiomeric excess. Incorporation of 2-amino-4,4-difluoro butyric acid as P1 group provided a potent HCV NS3 protease inhi

Full text of DOI:10.1016/j.tetlet.2007.11.163

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Tetrahedron Letters 49 (2008) 901–902
An efficient chiral synthesis of fluoro-containing amino acids:
N-benzyloxycarbonyl-2-amino-4,4-difluorobutyric
acid methyl ester and its analogs
Zilun Hu *, Wei Han
Department of Discovery Chemistry, Research and Development, Bristol-Myers Squibb Company, PO Box 5400, Princeton, NJ 08543, USA
Received 27 February 2007; revised 16 November 2007; accepted 27 November 2007
Available online 4 December 2007
Abstract
Fluoro-containing amino acids, N-benzyloxycarbonyl-2-amino-4,4-difluorobutyric acid methyl ester and analogs, were prepared in
high enantiomeric excess. Incorporation of 2-amino-4,4-difluoro butyric acid as P1 group provided a potent HCV NS3 protease
inhibitor.
Ó 2007 Elsevier Ltd. All rights reserved.
Keywords: 2-Amino-4,4-difluorobutyric acid; Fluoro amino acid; HCV protease inhibitor
Fluorinated amino acids possess interesting biological
activities, and are frequently used as replacements for
natural amino acids in drug discovery.1 In the process of
optimizing a HCV NS3 protease inhibitor, we were in need
of (S)-2-amino-4,4-difluorobutyric acid (diFAbu) as a
replacement for cysteine in the substrate.2 Literature
reports on the preparation of this fluorinated amino acid
are limited.3 In this Letter, we report an efficient two-step
synthesis of benzyloxycarbonyl (Cbz) protected (S)- and
(R)-2-amino-4,4-difluorobutyric acid methyl ester and its
analogs in high enantiomeric excess.
Scheme 1. Reagents and conditions: (a) KOtBu, THF, À78 °C to rt (64%);
(b) H2, 55 psi, [(S,S)-Et-Duphos-Rh]+CF3SO À, MeOH (>95%).
Scheme 1 outlines the synthesis of S(+)-N-Cbz-2-amino-
4,4-difluoro butyric acid methyl ester. The condensation of
commercially available N-Cbz-phosphonoglycine trimethyl
ester (1) with 2,2-difluoroacetaldehyde ethyl hemiacetal (2)
in the presence of potassium tert-butoxide in THF gave
methyl 2-Cbz-lamino-4,4-difluorobut-2-enoate (3) as a 9:1
Z/E mixture in 64% yield. When the reaction was
performed in dichloromethane, as usually used for this type
of reaction, a 4:1 Z/E mixture of 3 was obtained in 24%
3
yield. Asymmetric hydrogenation of Z/E-3 catalyzed by
(+)-1,2-bis((2S,5S)-2,5-diethylphospholano)benzene(cyclo-
octadiene)rhodium(I)trifluoro-methanesulfonate ([Rh(COD)-
(S,S-Et-Duphos)]+CF3SO
)
provided Cbz protected
À
3
S(+)-diFAbu methyl ester (S(+)-4a) with excellent enantio-
selectivity (>98% ee) in quantitative yield. The enantio-
selectivity is independent of the composition of Z/E
isomers.4 Similarly, the corresponding R isomer of 4a was
obtained using [Rh(COD)(R,R-Et-Duphos)]+CF3SO
À
*
Corresponding author. Tel.: +1 609 818 5290.
3
E-mail address: zilun.hu@bms.com (Z. Hu).
as the catalyst. The asymmetric hydrogenation was
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.11.163

902
Z. Hu, W. Han / Tetrahedron Letters 49 (2008) 901–902
2. (a) Han, W.; Hu, Z.; Jiang, X.; Wasserman, Z. R.; Decicco, C. P.
Bioorg. Med. Chem. Lett. 2003, 13, 1111; (b) Han, W.; Jiang, X.; Hu,
Z.; Wasserman, Z. R.; Decicco, C. P. Bioorg. Med. Chem. Lett. 2005,
15, 3487–3490.
3. (a) Winkler, D.; Burger, K. Synthesis 1996, 1419; (b) Tsushima, T.;
Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori, O.; Higaki, J.; Hirata,
M. Tetrahedron 1988, 44, 5375.
4. Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am. Chem.
Soc. 1993, 115, 10125.
5. Procedures: N-Benzyloxycarbonyl-2-amino-4,4-difluoro-2-butenoic acid
methyl ester (3): N-Z-Phosphonoglycine trimethyl ester (35.5 g,
Scheme 2. Reagents and conditions: (a) KOtBu, THF, À78 °C to rt (78%);
(b) H2, 55 psi, [(S,S)-Et-Duphos-Rh]+CF3SO À, MeOH (>95%), (i) Dess–
107 mmol) was added to
a solution of potassium tert-butoxide
3
Martin, DCM, rt, (ii) KOtBu, THF, À78 °C to rt (38%).
(13.2 g, 118 mmol) in THF (200 mL) at À78 °C. The resulting
suspension was stirred at À78 °C for 20 min, and 2,2-difluoroacetal-
dehyde ethyl hemiacetal (2) (15.0 g, 119 mmol) was added slowly. The
reaction was warmed up to room temperature slowly and stirred for
22 h. The mixture was poured into ethyl acetate, washed with cold
water. The organic phase was separated and dried over magnesium
sulfate, filtered, and the solvent was removed under reduced pressure.
The crude product was purified by flash chromatography (silica gel,
10–15% ethyl acetate–hexanes) to give a 9:1 Z/E mixture of the desired
product as a clear oil 19.63 g (64%). Isomer Z: 1H NMR (300 MHz,
CDCl3, ppm): d 3.84 (s, 3H), 5.18 (s, 2H), 6.32 (dt, 1H, J = 10.8 Hz,
5.4 Hz), 6.70 (dt, 1H, J = 55.2 Hz, 5.4 Hz), 7.02 (b, 1H), 7.38 (b, 5H).
19F NMR (282 MHz, CDCl3, ppm): d À115.50 (dd, 2F, J = 55.0 Hz,
10.7 Hz). Isomer E: 1H NMR (300 MHz, CDCl3, ppm): d 3.91 (s, 3H),
5.17 (s, 2H), 7.00 (dt, 1H, J = 56.1 Hz, 6.9 Hz), 7.09 (dt, 1H,
J = 10.4 Hz, 6.9 Hz), 7.22 (b, 1H), 7.38 (b, 5H). 19F NMR
(282 MHz, CDCl3, ppm): d À108.28 (dd, 2F, J = 56.4 Hz, 10.7 Hz).
(S)-(+)-N-Benzyloxycarbonyl-2-amino-4,4-difluorobutyric acid methyl
ester (S(+)-4a): A solution of 3 (0.90 g, 3.16 mmol) in MeOH (20 mL)
was deÀgassed with nitrogen, and Rh(COD)(S,S-Et-Duphos)]+
CF3SO3 (25 mg, 1 mol %) was added. The solution was stirred under
hydrogen (55 psi) for 15 h. The solvent was removed under reduced
pressure and the residue was passed through a pad of silica gel eluting
with 30% EtOAc in hexanes to remove small amount of catalyst to
leave a product as a white solid, 0.91 g (100%). [a]25 +3.0 (c = 0.362,
chloroform). ee% 98.5. 1H NMR (300 MHz, CDCl3, ppm): d 2.20–2.55
(m, 2H), 3.78 (s, 3H), 4.56 (dd, 1H, J = 12.9 Hz, 7.2 Hz), 5.13 (s, 2H),
5.51 (d, 1H, J = 6.9 Hz), 5.94 (tt, 1H, J = 56.1 Hz, 4.8 Hz), 7.36 (b,
Scheme 3. Reagents and conditions: (a) DiBAL, CH2Cl2, À78 °C, 30 min
(89%); (b) LiC(SMe)3, THF, À64 °C to À30 °C, 1 h (85%); (c) HgCl2/
HgO, MeOH/H2O, rt, 2 h (96%); (d) Ref. 2.
efficient for scales up to 200 g with no detectable decreased
enantioselectivity.
This approach was applied to the synthesis of other
fluoro-containing amino acid analogs. Examples such as
S(+)- and R(À)-N-Cbz-2-amino-4,4,4-trifluorobutyric acid
methyl ester (4b), and S(+)-N-Cbz-2-amino-4,4,5,5-tetra-
fluoro-2-pentanoic acid methyl ester (4c) were synthesized
in high enantiomeric excess (>98% ee) as shown in
Scheme 2.5
With S(+)-4a available, we incorporated it as P1 group
to our HCV NS3 protease inhibitors. As outlined in
Scheme 3, methyl ester 4a was reduced to the correspond-
ing aldehyde 9. Aldehyde 9 was treated with tris(methyl-
thio) methyl lithium followed by HgCl2/HgO to provide
a-hydroxyl ester 10 in good yield. Using the procedures
previously described by us, 10 was then converted to a
tetrapeptide-based a-ketoamide HCV NS3 protease inhib-
itor 11, which has an IC50 of 0.06 lM.2
5H). 19F NMR (282 MHz, CDCl3, ppm):
d
À116.63 (dt, 2F,
J = 56.4 Hz, 16.9 Hz). 13C NMR (75 MHz, CDCl3, ppm): d 36.67 (t,
J = 22.44 Hz), 49.43, 52.85, 67.28, 115.13 (t, J = 239.56 Hz), 128.11,
128.29, 128.55, 135.96, 155.76, 171.20. Anal. Calcd for C13H15F2NO4:
C, 54.36; H, 5.26; N, 4.88. Found: C, 54.62; H, 5.38; N, 4.68. R(À)-4a:
[a]25 À2.7 (c = 0.942, chloroform). ee% 95.5. S(+)-N-Benzyloxy-
carbonyl-2-amino-4,4,4-trifluoro-2-butyric acid methyl ester (S(+)-4b)
[a]25 +6.2 (c = 0.280, chloroform). ee% 97.1. 1H NMR (300 MHz,
CDCl3, ppm): d 2.62–2.85 (m, 2H), 3.79 (s, 3H), 4.64 (q, 1H,
J = 12.6 Hz, 6.3 Hz), 5.13 (s, 2H), 5.51 (d, 1H, J = 7.8 Hz), 7.36 (b,
5H). 19F NMR (282 MHz, CDCl3, ppm): d À63.58 (t, 3F, J = 9.3 Hz).
13C NMR (75 MHz, CDCl3, ppm): d 35.62 (q, J = 28.3 Hz), 48.99,
52.96, 67.27, 125.51 (q, J = 277.58 Hz), 128.03, 128.26, 128.53, 135.97,
155.56, 170.26. Anal. Calcd for C13H14F3NO4: C, 51.15; H, 4.62; N,
4.60. Found: C, 51.06; H, 4.58; N, 4.55. R(À)-4b: [a]25 À6.4 (c = 0.168,
CHCl3). ee% 98.3. Anal. Calcd for C13H14F3NO4: C, 51.15; H, 4.62; N,
4.60. Found: C, 51.22; H, 4.60; N, 4.53. (S)-(+)-N-Benzyloxycarbonyl-
2-amino-4,4,5,5-tetrafluoropentanoic acid methyl ester (S(+)-4c)
[a]25 +5.4 (c = 0.968, chloroform). ee% 98.4. 1H NMR (300 MHz,
CDCl3, ppm): d 2.46–2.70 (m, 2H), 3.77 (s, 3H), 4.70 (dd, 1H,
J = 12.3 Hz, 7.5 Hz), 5.13 (s, 2H), 5.63 (d, 1H, J = 8.1 Hz), 5.74 (tt,
53.7 Hz, 2.7 Hz), 7.35 (b, 5H). 19F NMR (282 MHz, CDCl3, ppm): d
À115.31 (m, 2F), À136.09 (dd, 2F, J = 53.4 Hz, 5.9 Hz). 13C NMR
(75 MHz, CDCl3, ppm): d 31.79 (t, J = 21.4 Hz), 48.46, 52.91, 67.25,
109.70 (tt, J = 150.0 Hz, 40.1 Hz), 117.19 (tt, J = 248.5 Hz, 29.6 Hz),
128.03, 128.24, 128.52, 136.00, 155.61, 170.86. Anal. Calcd for
In summary, an efficient chiral method for the synthesis
of diFAbu derivative and structural related fluoro-contain-
ing analogs was described. DiFAbu was evaluated as P1
group of HCV NS3 protease inhibitor.
References and notes
1. (a) Fluorine in Bioorganic Chemistry; Welch, J. T., Eswarakrishnan, S.,
C
13H14F3NO4: C, 49.86; H, 4.48; N, 4.15. Found: C, 49.85; H, 4.42;
Eds.; John Wiley
& Sons: New York, 1991; (b) Welch, J. T.
N, 3.97.
Tetrahedron 1987, 43, 3123.