A novel synthesis of enantiomerically pure 5,5,5,5',5',5'-hexafluoroleucine.

Article abstract of DOI:10.1021/ol015567e

[reaction in text] A novel, short, and efficient synthesis of (S)-5,5,5,5',5',5'-hexafluoroleucine (6) in greater than 99% ee starting from the protected oxazolidine aldehyde 1 is described. The enantiomeric excess of the product was calculated from an NMR analysis of a dipeptide formed by reaction with a protected L-serine derivative. Furthermore, a racemic sample of N-acylated hexafluoroleucine was enzymatically resolved by treatment with porcine kidney acylase I and was found to have the same optical rotation as a synthetic sample of 6.

Full text of DOI:10.1021/ol015567e

ORGANIC
LETTERS
2
001
Vol. 3, No. 9
285-1286
A Novel Synthesis of Enantiomerically
Pure 5,5,5,5′,5′,5′-Hexafluoroleucine
Xuechao Xing, Alfio Fichera, and Krishna Kumar*
1
Department of Chemistry, Tufts UniVersity, 62 Talbot AVenue,
Medford, Massachusetts 02155
kkumar01@tufts.edu
Received January 17, 2001
ABSTRACT
A novel, short, and efficient synthesis of (S)-5,5,5,5′,5′,5′-hexafluoroleucine (6) in greater than 99% ee starting from the protected oxazolidine
aldehyde 1 is described. The enantiomeric excess of the product was calculated from an NMR analysis of a dipeptide formed by reaction with
a protected L-serine derivative. Furthermore, a racemic sample of N-acylated hexafluoroleucine was enzymatically resolved by treatment with
porcine kidney acylase I and was found to have the same optical rotation as a synthetic sample of 6.
Selective fluorination of biologically active compounds is
often accompanied by dramatic changes in physiological
activities. Fluorinated amino acids have been synthesized
We have recently described the de novo design of peptides
based on the coiled coil motif where the residues lining the
4
1
1c-h,7
interface between helices have highly fluorinated side
5
and studied as potential inhibitors of enzymes and as
chains. These peptides form well-defined coiled coil struc-
2
therapeutic agents. Trifluoromethyl-containing amino acids
tures with higher thermal stability than their natural hydro-
carbon counterparts. To create protein structures with very
highly fluorinated cores, we required an efficient and
inexpensive synthesis of 6 in enantiomerically pure form.
Herein, we report a novel and efficient synthesis of (S)-
3
acting as potential antimetabolites have also been reported.
(1) (a) Welch, T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry;
Wiley-Interscience: New York, 1991 and references therein. (b) Fluorine-
containing Amino Acids; Kukhar′, V. P., Soloshonok, V. A., Eds.; John
Wiley & Sons: Chichester, 1994. (c) Williams, R. M. Synthesis of Optically
ActiVe R-Amino Acids; Pergamon Press: Oxford, 1989. (d) Ojima, I.; Kato,
K.; Nakahashi, K.; Fuchikami, T.; Fujita, M. J. Org. Chem. 1989, 54, 4511-
5
,5,5,5′,5′,5′-hexafluoroleucine starting from commerically
6
available D-serine. While there is one existing report of the
4
522. (e) Tsushima, T.; Kawada, K.; Ishihara, S.; Uchida, N.; Shiratori,
7
synthesis of racemic hexafluoroleucine and another recent
O.; Higaki, J.; Hirata, M. Tetrahedron 1988, 44, 5375-5387. (f) Weinges,
K.; Kromm, E. Liebigs Ann. Chem. 1985, 90-102. (g) Eberle, M. K.; Keese,
R.; Stoeckli-Evans, H. HelV. Chim. Acta 1998, 81, 182-186. (h) Tolman,
V. Amino Acids 1996, 11, 15-36.
8
report detailing the preparation of 6 in 81% ee, we sought
a better method to obtain hexafluoroleucine in >99% ee for
direct use in solid-phase peptide synthesis. Our synthesis
(2) Kollonitsch, J.; Patchett A. A.; Marburg, S.; Maycock, A. L.; Perkins,
L. M.; Doldouras, G. A.; Duggan, D. E.; Aster, S. D. Nature 1978, 274,
commenced from the oxazolidine aldehyde 1 (Garner alde-
9
1
06-908.
hyde) which served as a chiral, nonracemic synthon.9
(
3) (a) Walborsky, H. M.; Baum, M. E. J. Am. Chem. Soc. 1958, 80,
Aldehyde 1 is derived from D-serine, was obtained using a
87-192. (b) Walborsky, H. M.; Baum, M.; Loncrini, D. F. J. Am. Chem.
Soc. 1955, 77, 3637-3640. (c) Hill, H. M.; Towne, E. B.; Dickey, J. B. J.
Am. Chem. Soc. 1950, 72, 3289-3289.
slight modification of a published procedure, and is excep-
10
tionally stable toward racemization in subsequent steps. In
(4) (a) Crick, F. H. C. Acta Cyrstallogr. 1953, 6, 689. (b) O’Shea, E.
K.; Rutkowski, R.; Kim, P. S. Science 1989, 243, 538. (c) Lupas, A. Trends
Biochem. Sci. 1996, 21, 375-382. (d) Kohn, W. D.; Hodges, R. S. Trends
Biotechnol. 1998, 16, 379-389.
a key step, aldehyde 1 was converted to the bis-trifluorom-
(8) Zhang, C.; Ludin, C.; Eberle, M. K.; Stoeckli-Evans, H.; Keese, R.
HelV. Chim. Acta 1998, 81, 174-181.
(9) (a) Garner, P.; Park, J. M. J. Org. Chem. 1987, 52, 2361-2364. (b)
Garner, P.; Park, J. M. J. Org. Chem. 1988, 53, 2979-2984. (c) Garner,
P.; Park, J. M.; Malecki, E. J. Org. Chem. 1988, 53, 4395-4398. (d)
Angrick, M. Montash. Chem. 1985, 116, 645-649.
(
5) Bilgi c¸ er, B.; Fichera, A.; Kumar, K. J. Am. Chem. Soc., in press.
6) For synthesis of R-amino acids derived from D-serine using a serine
(
aldehyde equivalent, see: Blaskovich, M. A.; Lajoie, G. A. J. Am. Chem.
Soc. 1993, 115, 5021-5030.
(7) Lazar, J.; Sheppard, W. A. J. Med. Chem. 1968, 11, 138.
1
0.1021/ol015567e CCC: $20.00 © 2001 American Chemical Society
Published on Web 04/03/2001

ethyl olefin 2 by a Wittig reaction in 92% yield (Scheme
chloride salt of the desired R-amino acid 6. While the last
deprotection step was carried out in order to verify the optical
purity of 6, the Boc-protected amino acid 5 could be directly
used for solid-phase synthesis of peptides.
11
1). The ylide for this reaction is the phosphonium analogue
The optical purity of synthetic 6 was verified in two ways.
A racemic sample of 5 (prepared using a different route)
and 5 obtained through the scheme described here were
Scheme 1a
separately coupled to a protected methyl ester of L-serine
1
(
7), and the resulting dipeptide was analyzed using H NMR
spectroscopy. In the case of the dipeptide obtained from
racemic 5, three signals corresponding to the t-Boc group,
the methyl ester, and the tert-butyl ether were split into two
peaks presumably due to formation of two diastereomers,
whereas 5 from the present synthesis yielded a dipeptide with
only one set of signals for the three sets of protons described
above. Furthermore, racemic 6 was N-acylated and enzy-
matically resolved using porcine kidney acylase I [EC
a
Reagents and conditions: (a) PPh
3 3 2 2 2 2
, [(CF ) C] S , Et O, -78
°
C f rt, 3 d, 92%; (b) H
rt, 1 d, 80%; (d) PDC, DMF, 18 h, 75%; (e) 40% CF CO H/CH Cl ;
3 2 2 2
HCl, 10 min, rt, >95%.
2
, 10% Pd/C, THF, 98%; (c) TsOH, MeOH,
1
6
3
.5.1.14] to yield the R-S isomer exclusively. The optical
12
of Middleton’s phosphorane, generated in situ from tetrakis-
trifluoromethyl)-1,3-dithietane and triphenylphosphine.
rotation of 6 obtained in this manner and that of the synthetic
sample were identical. Thus, as far as we can tell, the
synthesis proceeds in >99% ee. The NMR data for 6 agree
13
14,15
(
The olefin 2 was reduced by catalytic hydrogenation over
Pd/C to give the suitably substituted oxazolidine 3 in 98%
yield. Next, the oxazolidine was subjected to acid-catalyzed
ring cleavage unmasking the alcohol 4. Alcohol 4 was
oxidized to the carboxylic acid 5 using pyridinium dichro-
mate, and in the final step, the tert-butyloxycarbonyl group
was removed using trifluoroacetic acid to yield the hydro-
8
,17
with those reported previously.
The construction of
5,5,5,5′,5′,5′-(R)-hexafluoroleucine is similarly achieved from
L-serine.
In summary, we have developed an efficient synthesis of
enantiomerically pure 5,5,5,5′,5′,5′-hexafluoroleucine. Studies
detailing the incorporation of this building block into peptides
and subsequent characterization will be reported shortly.
(10) Campbell, A. D.; Raynham, T. M.; Taylor, R. J. K. Synthesis 1998,
1
707-1709.
Acknowledgment. The authors thank the Faculty Re-
search Awards Committee (Tufts) and Tufts University for
support. We also thank Prof. Marc d’Alarcao for helpful and
stimulating discussions.
(
11) Korhummel, C.; Hanack, M. Chem. Ber. 1989, 122, 2187-2192.
Typical procedure for the coupling reaction: To a stirred solution of the
Garner aldehyde 1 (7.0 g, 31.0 mmol) and PPh3 (57 g, 217 mmol) in dry
Et2O (300 mL) was added 2,2,4,4-tetrakis(trifluoromethyl)-1,3-dithietane
(
3
39.5 g, 108.5 mmol) at -78 °C under argon. The mixture was stirred for
d while being slowly warmed to room temperature. The reaction slowly
accumulated an insoluble white solid which was filtered, and the filtrate
was concentrated. The residue was further dissolved in n-pentane (300 mL)
and filtered again to remove insoluble impurities. After removal of the
solvent, the residue was subjected to flash column chromatography using
n-pentane/Et2O (6/1) as eluant to give pure 2 as a pale yellow oil (10.4 g,
Supporting Information Available: Spectral character-
ization of compounds 2-6 and dipeptide 8 obtained from
the reaction of 7 and 6. This material is available free of
charge via the Internet at http://pubs.acs.org.
9
2%).
(
(
(
12) Middleton, W. J.; Sharkey, W. H. J. Org. Chem. 1965, 30, 1384.
13) Anello, L. G.; Vanderpuy, M. J. Org. Chem. 1982, 47, 377-378.
14) (a) Burton, D. J.; Yang, Z. Y.; Qiu, W. M. Chem. ReV. 1996, 96,
OL015567E
1
7
3
641-1715. (b) Dixon, D. A.; Smart, B. E. J. Am. Chem. Soc. 1986, 108,
172-7177. (c) Burton, D. J.; Inouye, Y. Tetrahedron Lett. 1979, 3397-
400.
(16) (a) Chenault, H. K.; Dahmer, J.; Whitesides, G. M. J. Am. Chem.
Soc. 1989, 111, 6354-64. (b) Fu, S. C. J.; Birnbaum, S. M. J. Am. Chem.
Soc. 1953, 75, 918-920.
(
15) Kobayashi, Y.; Nakajima, M.; Nakazawa, M.; Taguchi, T.; Ikekawa,
N.; Sai, H.; Tanaka, Y.; Deluca, H. F. Chem. Pharm. Bull. 1988, 36, 4144-
147.
(17) Both the synthetic sample and the enzyme-resolved samples of 6
26.0
had [R] D ) +5.6° (c 1, CH3OH), a value smaller in magnitude than that
4
reported previously (ref 8).
1286
Org. Lett., Vol. 3, No. 9, 2001