Enantioselective synthesis of β-trifluoromethyl α-amino acids

Article abstract of DOI:10.1021/ol100478d

Figure presented We report herein the three-step enantioselective synthesis of β-trifluoromethyl α-amino acids including trifluorovaline (TFV) using stereoselective hydrogenation with [((R)-trichickenfootphos)Rh(cod)] BF₄ catalyst as the key st

Full text of DOI:10.1021/ol100478d

ORGANIC
LETTERS
2010
Vol. 12, No. 9
2008-2011
Enantioselective Synthesis of
ꢀ-Trifluoromethyl r-Amino Acids
Cyril Benhaim,* Luc Bouchard, Guillaume Pelletier, John Sellstedt,
Livia Kristofova, and Sylvain Daigneault
Wyeth Research, 1025 Marcel-Laurin BouleVard, St-Laurent,
Que´bec H4R 1J6, Canada
benhaicy@wyeth.com
Received February 25, 2010
ABSTRACT
We report herein the three-step enantioselective synthesis of ꢀ-trifluoromethyl r-amino acids including trifluorovaline (TFV) using stereoselective
hydrogenation with [((R)-trichickenfootphos)Rh(cod)]BF4 catalyst as the key step.
An increasing number of fluorinated derivatives, particularly
amino acids,1 have found innovative and valuable applica-
tions in medicinal chemistry and biochemistry. Indeed, these
derivatives have the capacity to enhance helical protein
stability by taking advantage of the hydrophobicity of
fluorinated hydrocarbon chains, increasing the protein-protein
interaction’s selectivity in peptide and protein designs.2
Fluorine has been successfully used to increase drug activity
as it is capable of inhibiting pyridoxal enzymes.3 The small
sterical change and therefore minimal protein structural
perturbations involved in the use of fluorine has permitted
Tirell and co-workers to successfully insert 5,5,5-trifluoroi-
soleucine (TFI) in proteins and enzymes using in vitro and
in vivo protein engineering method using E. coli.4
fluorinated amino acids.5 Optically pure 4,4,4-trifluorovaline
(TFV) was first isolated by Kumar and co-workers using
enzymatic resolution.6 Later on, Qing and co-workers
developed a practical diastereoselective allylation method for
the synthesis of TFV and TFI.7 Recently, Hu and co-workers
were the first to report the application of chiral hydrogenation
technology to synthesize various fluoro-containing amino
acids.8 However, this hydrogenation was limited to trisub-
stituted alkenes. A three-step synthesis of TFV and analogues
using catalytic and asymmetric hydrogenation of tetrasub-
stituted trifluoromethyl alkene precursors as the key step is
reported. Numerous ligands, conditions, and their effects
upon the yield and selectivity of the process were examined
in this study.
The prochiral alkenes (Scheme 1) were prepared using
Schollkopf’s procedure,9 which generates a formyl protective
group on the nitrogen that requires very mild deprotection
conditions.
A benefit of using a formyl group versus an acetyl was
reported by Feringa and co-workers who observed no
racemization upon deprotection.10,11 Alkenes 1a-f were
There have been constant efforts in the development of
new methods for the synthesis of enantiomerically pure
(1) Jakowiecki, J.; Loska, R.; Makosza, M. J. Org. Chem. 2008, 73,
5436, and references cited therein.
(2) Chiu, H.-P.; Yuta, S.; Gullickson, D.; Ahmad, R.; Kokona, B.;
Fairman, R.; Cheng, R. P. J. Am. Chem. Soc. 2006, 128, 15556.
(3) (a) Bravo, P.; Capelli, S.; Meille, S. V.; Viani, F.; Zanda, M.; Kuhar,
V. P.; Soloshonok, V. A. Tetrahedron: Asymmetry 1994, 5, 2009. (b) Welch,
J. T.; Eswarakrishnan, S. Fluorine in Bioorganic Chemistry; John Wiley &
Sons: New York, 1991. (c) Sakai, T.; Yan, F.; Kashino, S.; Uneyama, K.
Tetrahedron 1996, 52, 233. (d) 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, 906.
(5) Kukhar, V. P.; Soloshonok, V. A. Fluorine Containing Amino Acids,
Synthesis and Properties; Wiley: New York, 1995.
(6) Xing, X.; Fichera, A.; Kumar, K. J. Org. Chem. 2002, 67, 1722.
(7) Chen, Q.; Qiu, X.-L.; Qing, F.-L. J. Org. Chem. 2006, 71, 3762.
(8) Hu, Z.; Han, W. Tetrahedron Lett. 2008, 49, 901.
(4) Wang, P.; Tang, Y.; Tirrell, D. A. J. Am. Chem. Soc. 2003, 125,
6900.
(9) Enders, D.; Chen, Z.-X.; Raabe, G. Synthesis 2005, 306.
10.1021/ol100478d  2010 American Chemical Society
Published on Web 03/26/2010

activity on tetrasubsituted dehydroamino acids.13,14 Unlike
the trend reported on similar substrates, these ligands gave
stereochemical induction of less than 15% ee. A secondary
screen was run using ferrocennyl-based ligands from Solvias.
Their long shelf life and stability to air makes them an
attractive set of ligands. Initially, low enantioselectivities
(<50% ee) were obtained using the Josiphos and Mandiphos
ligands.
Scheme 1
.
Synthesis of Prochiral Compounds Using
Schollkopf’s Procedure
However, more promising results were obtained using
ligands from the Walphos family (Figure 1).16 W003-1 (L1)
prepared in 60-80% yield and purified by chromatography
before being subjected to asymmetric hydrogenation.
It has been widely reported that only a few ligands are
able to achieve good enantioselectivity and conversion on
tetrasubstituted dehydroamino acids.12-14 Indeed, these
substrates are more challenging for chiral hydrogenation as
the olefin is sterically more hindered and electronically
enriched. These few ligands are very substrate specific, and
thus, a slight change in substrate can have a dramatic impact
on the performance of the hydrogenation.
Screening was carried out using two different condi-
tions: 120 psi with S/C 20 and 70 psi with S/C 100.15
A
summary of the best results obtained on alkene 1a is
reported in Table 1.
Table 1. Asymmetric Hydrogenation of 1a: Screening of
Various Conditions with Various Catalystsa
entry
catalyst
method convn (%)
ee (%)
1
2
3
4
5
6
7
L1 + Rh(nbd)2BF4
L2 + Rh(nbd)2BF4
B
B
B
A
A
B
B
100
85
95
100
100
100
100
79 (2S,3S)
72 (2R,3R)
87 (2R,3R)
89 (2S,3S)
78 (2S,3S)
92 (2S,3S)
>99 (2R,3R)
L3
L4
L5
L6
L7
Figure 1. Best chiral catalysts and ligands screened.
a Reactions were performed on 1 mmol of substrate at 60 °C with a
substrate concentration of 0.4 M. Method A is performed at 120 psi of H2
with S/C 20, and method B is performed at 70 psi of H2 with S/C 100.
Each reaction was stopped after 16 h. Enantiomeric excesses were
determined via chiral GC as described in the Supporting Information.
gave complete conversion with 79% ee (entry 1). Interest-
ingly, with an additionnal test using this ligand at 70 psi,
(10) Panella, L.; Aleixandre, A. M.; Kruidhof, G. J.; Robertus, J.; Feringa,
B. L.; De Vries, J. G.; Minnaard, A. J. J. Org. Chem. 2006, 71, 2026.
(11) Sheehan, J. C.; Yang, D.-D. H. J. Am. Chem. Soc. 1958, 80, 1154.
(12) (a) Burk, M. J.; Feaster, J. E.; Nugent, W. A.; Harlow, R. L. J. Am.
Chem. Soc. 1993, 115, 10125. (b) Burk, M. J.; Gross, M. F.; Martinez,
J. P. J. Am. Chem. Soc. 1995, 117, 9375.
Our initial screening comprised of Johnson-Matthey
ligands (Phanephos and Me-BoPhoz) known to have good
Org. Lett., Vol. 12, No. 9, 2010
2009

we were able to increase the S/C ratio to 1000 and still obtain
91% conversion with 75% ee. Our next catalyst screening
involved the well-known BINAP family. Higher selectivity
(86% ee) was obtained with [Binap-Ru] preformed complex
but with only a 45% conversion with S/C 50 in methanol.
The conversion was successfully increased to 95% by using
a more acidic solvent, trifluoroethanol. Unfortunately, it was
accompanied with a significant loss of selectivity (57% ee).
The best result from this series was using binaphane (L2)
with complete conversion at S/C 100 with reasonable
enantioselectivity (72% ee, entry 2). DUPHOS12 and BPE
are the most widely used family of ligands for asymmetric
hydrogenation of tetrasubstituted dehydroamino acids. There-
fore, it is with no surprise that we observed selectivities of
up to 89% using these ligands.
Table 2. Hydrogenation of (Z)-Alkyl- or
-Aryl-4,4,4-trifluoro-2-formamido-3-methylbut-2-enoatea
entry
catalyst
method
product
convn (%)
ee (%)
Ph-BPE (L3)-catalyzed reaction could be accomplished
with 1 mol % of catalyst. Higher pressure and higher catalytic
amounts seemed to be necessary for complete conversion
with both Me-Duphos (L4) and its analogue SK-P005 (L5)
(entries 3-5). Finally, high enantioselectivity (92% ee) was
obtained using Tangphos (L6) (entry 6),17 a ligand which
holds chirality on both carbon and phosphorus.Another chiral
phosphorus-type ligand was then screened: trichickenfoot-
phos-Rh, TCFP-Rh (L7). It was developed by Hoge and co-
workers18 who reported outstanding results such as high TON
(up to 27000) and nearly perfect enantioselectivity (>98%
ee) on various trisubstituted olefins and a few symmetrical
tetrasubstituted R-dehydroamino acids. We were able to
successfully use the L7 catalyst in the hydrogenation of
substrate 1a giving complete conversion and a very high
selectivity of above 99% ee (entry 7). We then decided to
extend the scope of our work by substituting the ꢀ-methyl
group with other alkyl or aryl groups (Table 2). A consistent
stereochemical induction was observed going from methyl-
substituted alkene 1a to ethyl-substituted akene 1b with
catalyst L7 (>99% ee, Table 2, entry 1).
The introduction of the benzyl group (1c) allowed for study
of steric effects, and once again, not only was the conversion
high but the selectivity was also found to be excellent (99%
ee, Table 2 entry 3). The benzyl and the hexafluoro olefin
(1c and 1h) seem to be very unique as most catalysts tested
apart from L7 gave conversion below 20% with low
selectivity (<20% ee). This was surprising as one can usually
expect to achieve some good conversions and potentially
some good selectivities in at least a couple of other similar
catalysts. We next investigated the impact of steric and
1
2
3
4
5
6
7
8
L7
L3
L7
L3
L7
L7
L3
L7
L3
L7
L3
B
B
B
B
B
C
C
C
C
C
C
2b
2b
2c
2c
2h
2d
2d
2e
2e
2f
100
100
100
0
100
78
100
14
100
65
>99
60
99
N/A
86
50
93
50
91
39
9
10
11
2f
100
90
a Reactions were performed on 1 mmol of substrate at 60 °C with a
substrate concentration of 0.4 M. Method B was performed at 70 psi of H2
with S/C 100 and method C at 250 psi of H2 with S/C 20. Each reaction
was stoppped after 16 h. Enantiomeric excesses were determined via chiral
GC or HPLC as described in the Supporting Information. Key: (a) for olefin
preparation, see the Supporting Information; (b) starting material and product
bearing an acetamide instead of formamide; (c) ethyl ester.
electronic effect using aromatic substituents (1d-f). First,
we demonstrated that the hydrogenation of these substrates
needed to be run with a mimimum of 5 mol % of catalyst
and higher pressure of 250 psi to get full conversion (method
C) in 16 h. Unfortunately, having the aryl directly attached
to the double bond seems to lower the reactivity of the
substrates toward the L7 catalyst. The reactions ranged from
14 to 78% completion within 16 h, with selectivities under
50% ee. The best results were obtained with L3, which gave
around 90% ee on three different substrates (Table 2, entries
7, 9, and 11). Having these results in hand, we concluded
that L7 requires a methylene group to get very high selectivity
and/or conversion (Scheme 2).
(13) (a) Pye, P. J.; Rossen, K.; Reamer, R. A.; Tsou, N. N.; Volante,
R. P.; Reider, P. J. J. Am. Chem. Soc. 1997, 6207. (b) Rossen, K.; Pye,
P. J.; DiMichele, L. M.; Volante, R. P.; Reider, P. J. Tetrahedron Lett.
1998, 6823.
Scheme 2. Generalized Reaction for Highly Stereoselective
Hydrogenation with [TCFP-Rh] (L7) Catalyst
(14) Boaz, N. W.; Debenham, S. D.; Mackenzie, E. B.; Large, S. E.
Org. Lett. 2002, 2421.
(15) S/C means substrate over catalyst ratio; S/C 20 ) 5 mol % of
catalyst; S/C 100 ) 1 mol % of catalyst.
(16) Sturm, T.; Weissensteiner, W.; Spindler, F. AdV. Synth. Catal. 2003,
345, 160.
(17) Yang, Q.; Shang, G.; Gao, W.; Deng, J.; Zhang, X. Angew. Chem.,
Int. Ed. 2006, 3832–3835.
(18) (a) Hoge, G.; Wu, H.-P.; Kissel, W. S.; Pflum, D. A.; Green, D. J.;
Bao, J. J. Am. Chem. Soc. 2004, 126, 5966. (b) Wu, H.-P.; Hoge, G. Org.
Lett. 2004, 6, 3645. (c) Gridnev, I. D.; Imamoto, T.; Hoge, G.; Kouchi,
M.; Takahashi, H. J. Am. Chem. Soc. 2008, 130, 2560.
2010
Org. Lett., Vol. 12, No. 9, 2010

Finally, we demonstrated that the asymmetric hydrogena-
tion approach could be used to generate enantiopure amino
acids. A simple treatment with concentrated HCl in acetone
afforded optically pure TFV from 2a (Scheme 3). The same
conditions applied on 2b would lead to enantiopure triflu-
oroisoleucine (TFI). It is also possible to generate many other
derivatives such as amino esters or N-formyl-protected amino
acids using simple transformations described in Scheme 3,
with preservation of stereochemical integrity.
Scheme 3. Synthesis of Enantiopure TFV and Derivatives
In conclusion, we report the first synthesis of ꢀ-trifluoro-
methyl-R-amino acid precursors (2a-g) using stereoselective
hydrogenation and its application to the synthesis of fluori-
nated amino acids such as TFV. We believe the same
approach can be used for the preparation of other analogues
such as TFI and/or aromatic analogues.
Acknowledgment. We acknowledge P. Crecca and M.
Konishi from Wyeth Research for their support and valuable
suggestions. We also acknowledge Wyeth for its continuing
support of this research.
During the hydrogenation screening of all alkenes, dias-
tereoisomers were never observed with chiral catalysts, but
a maximum of 40% de was obtained while preparing racemic
compounds (2a-f) with Pd/C for chiral HPLC references.19
Supporting Information Available: Experimental pro-
cedures and compound characterization data for all com-
pounds. This material is available free of charge via the
Internet at http://pubs.acs.org.
(19) Reactions were performed on 1 mmol of substrate at 60 °C with a
substrate concentration of 0.4 M in MeOH with 15% Pd/C (10%) at 250
psi of H2.
OL100478D
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