Highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids by addition of benzylzinc reagents to chiral imines of trifluoropyruvate

Article abstract of DOI:10.1016/j.tetlet.2011.07.006

An effective and facile method for highly diastereoselective synthesis of quaternary α-trifluoromethyl α-amino acids was developed in good yields with high diastereoselectivity (dr >20:1) via MgCl₂- accelerated addition of benzylzinc reagents (

Full text of DOI:10.1016/j.tetlet.2011.07.006

Tetrahedron Letters 52 (2011) 4675–4677
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Highly diastereoselective synthesis of quaternary
a-trifluoromethyl a-amino
acids by addition of benzylzinc reagents to chiral imines of trifluoropyruvate
Jie Yang a, Qiao-Qiao Min b, Yi He a,c, Xingang Zhang b,
⇑
a School of Chemistry and Chemical Engineering, Southwest Petroleum University, 8 Xindu Avenue, Chengdu, Sichuan 610500, China
b Key Laboratory of Organofluorine Chemistry, Shanghai Institute of Organic Chemistry, Chinese Academy of Sciences, 345 Lingling Road, Shanghai 200032, China
c State Key Lab of Oil and Gas Reservoir Geology and Exploitation, Southwest Petroleum University, 8 Xindu Avenue, Chengdu, Sichuan 610500, China
a r t i c l e i n f o
a b s t r a c t
Article history:
An effective and facile method for highly diastereoselective synthesis of quaternary
a-trifluoromethyl
Received 3 May 2011
Revised 25 June 2011
Accepted 1 July 2011
Available online 8 July 2011
a-amino acids was developed in good yields with high diastereoselectivity (dr >20:1) via MgCl2-acceler-
ated addition of benzylzinc reagents (Knochel type organozinc reagents) to (R)-phenylglycinol methyl
ether based imines of trifluoropyruvate.
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
Benzylzinc reagents
Diastereoselective synthesis
Ketoimine esters
Quaternary
a-trifluromethyl a-amino acids
Trifluoropyruvate
Fluorinated compounds have drawn extensive attention owing
to their importance in materials and life sciences.1 Among them,
organometallic reagents remains a problem. This is mainly because
of the challenges in highly stereoselective construction of quater-
nary chiral center with a CF3 group.7 For example, the additions
quaternary
a-trifluoromethyl a-amino acids (a-Tfm-AAs) consti-
tute a distinct class of fluorinated compounds. Because the unique
properties of the CF3 group,2 such as high electronegativity, high
lipophilicity, and steric hindrance that non-linearly increases with
the number of fluorine atoms, can make such a special class of fluo-
rinated amino acids greatly influence the bioavailability of peptides
by improving enzymatic stability and enhancing in vivo absorption
as well as drug permeability through certain body barriers.3 In
of chiral p-toluenesulfinyl a-CF3 ketoimine ester with benzyl or al-
kyl magnesium halides only led to poor to moderate diastereose-
lectivity (dr 2.3–6.7).8 In this regard, recently, we developed an
efficient method for highly diastereoselective synthesis of quater-
nary a-allyl a-Tfm-AAs via indium mediated allylation of (R)-phe-
nylglycinol methyl ether based imines of trifluoropyruvate 1.9 To
continue our research interest, herein, we report an effective meth-
od for highly diastereoselective addition of benzylzinc reagents
addition, due to the existence of quaternary chiral center in
a-
Tfm-AAs, once there is appropriate incorporation of -Tfm-AAs into
a
(Knochel type organozinc reagents)10 to chiral
a-CF3 ketoimine es-
peptides, severe conformational restrictions are exerted on the
peptide chains and thus can enhance the biological activity of the
peptides by helping to pre-organize the optimum conformation
for binding or by inhibiting metabolic degradation.4 As a result,
they can be used as peptidomimetics and therapeutic agents.5 Fur-
thermore, because of the abundance of 19F in nature, CF3 group can
be used as a probe for kinetic and structural studies through 19F
NMR.6 Hence, it is of great synthetic interest to develop an efficient
method to synthesize these valuable fluorinated amino acids.
Although the most common method to non-racemic quaternary
ter 1, which provides a facile access to a-Tfm-AAs (Scheme 1).
Considering that the low diastereoselectivity resulted from the
addition of Grignard or organolithium reagents to chiral imines
may arise from the active reactivities of these organometallic
reagents, we envisioned that using a relatively ‘inert’ nucleophile
to react with (R)-phenylglycinol methyl ether based imines of
Ph
OMe
Ph
HN
OMe
.
ZnCl MgCl2
N
a-Tfm-AAs relies on the addition of organometallic reagents to
THF
temp
F3C
CO2R1
R2
+
chiral
a
-CF3 ketoimine ester, the access of such a class of fluori-
F3C
CO2R1
nated amino acids in high diastereoselectivity using sp3 hybridized
R2
1
2
3
⇑
Corresponding author. Tel.: +86 21 5492 5333; fax: +86 21 6416 6128.
E-mail address: xgzhang@mail.sioc.ac.cn (X. Zhang).
Scheme 1. Diastereoselective synthesis of quaternary
acids.
a-trifluoromethyl
a-amino
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.07.006

4676
J. Yang et al. / Tetrahedron Letters 52 (2011) 4675–4677
Table 1
1). Although, initially a poor diastereoselectivity (dr 1.9:1) was
provided when the reaction was carried out with 1 (1.0 equiv),
benzyl zinc reagent 2a11 (1.8 equiv) in THF at room temperature
(Table 1, entry 1), we were pleased to observe the formation of
3a in high dr value (dr >20:1, determined by 19F NMR) when the
reaction was run at À10 °C with utilization of 1.2 equiv of 2a, albeit
in a low yield (42%) (Table 1, entry 2). Further optimization re-
vealed that increasing the loading amount of 2a benefited the reac-
tion yield with no erosion of the diastereoselectivity (Table 1,
entries 3–7), and high reaction yield could be obtained when
3.5–4.0 equiv of 2a was used (Table 1, entries 6–7). Further
increasing the reaction temperature to 0 °C with utilization of
3.5 equiv of 2a still afforded 3a in high diastereoselectivity with
good yield (Table 1, entry 9). Interestingly, when 1a was treated
with only benzyl zinc reagent without MgCl2, poor yield and dia-
stereoselectivity were obtained (Table 1, entry 10). While, a higher
yield and dr value were provided, when MgCl2 was added (Table 1,
entry 11). This finding demonstrated that MgCl2 is essential for the
reaction efficiency and diastereoselectivity, and may function as a
Lewis acid.10b However, decreasing the loading amount of 2a to
1.5 equiv in combination of 2.0 equiv of MgCl2 only led to a low
yield with a maintained diastereoselectivity (Table 1, entry 12),
thus suggesting that an organozinc-magnesium complex is critical
for the reaction. But the reason why excessive 2a was required re-
mains elusive and will be addressed in the future.
Optimization of diastereoselective addition of benzyl zinc reagent 2a to chiral
a-CF3
ketoimine ester 1aa
Ph
OMe
Ph
HN
F3C
OMe
.
N
ZnCl MgCl2
THF
temp
CO2Et
+
F3C
CO2Et
1a
2a
3a
b
Entry
2a (equiv)
Temp (°C)
dr
3a, yield (%)c
1
2
3
4
5
6
7
8
1.8
1.2
1.5
2.0
3.0
3.5
4.0
3.0
3.5
3.5
1.5
1.5
25
À10
À10
À10
À10
À10
À10
0
1.9:1
84
42
54
66
90
93
97
90
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
4.3:1
9
0
0
94 (93)
9
21
10d
11e
12f
À10
>20:1
>20:1
À10
47
a
Unless otherwise noted, the reaction was carried out by using 1a (0.5 mmol,
1 equiv), 2a (1.2–4.0 equiv) in a 0.17 M THF solution (based on 1a) for 8–9 h. For
clarity complexed LiCl has been omitted.
b
Determined by 19F NMR before column chromatography.
c
NMR yield determined by 19F NMR, yield in parentheses was isolated yield.
d
To ascertain the scope of this methodology, a variety of benzyl-
Benzyl zinc (3.5 equiv) was used without MgCl2.
Benzyl zinc (1.5 equiv) in conjunction with MgCl2 (3.5 equiv) was used.
Compound 2a (1.5 equiv) in conjunction with MgCl2 (2.0 equiv) was used.
e
zinc reagents 2 and chiral
a-CF3 ketoimine esters 1 were investi-
f
gated (Table 2). Generally, excellent yields and high
diastereoselectivities were obtained. For the electron-deficient
benzylzinc reagents 2f and 2g, due to the formation of side prod-
ucts under the standard conditions, increasing loading amount of
2f and 2g to 4.0–5.0 equiv was found to benefit the reaction effi-
ciency and diastereoselectivity (Table 2, entries 5–6). para- And
meta-methyl benzylzinc reagents furnished the reaction smoothly
with good yields and high dr values (Table 2, entries 1 and 3), but
ortho-methyl substituted 2c failed to give product 3c, because of its
poor reactivity (Table 2, entry 2). 2-Trimethylsilylethyl (TMSE), al-
trifluoropyruvate 1 would help. In addition, the chelation of metal
with N/O atoms in the compound 1 would lead to a rigid chelated
transition state, as a result, a high diastereoselectivity would be ob-
served. Recently, an important progress has been made by Knochel
and coworkers,10b in which the addition of alkyl and benzyl zinc
reagents to aldehydes or ketones could be realized by the presence
of MgCl2. Inspired by their research work, we began our studies of
diastereoselective addition of chiral
choosing Knochel type benzyl zinc reagent 2a as nucleophile (Table
a-CF3 ketoimine ester 1 by
lyl and propargyl
a-CF3 ketoimine esters 1b–d are also suitable
substrates for the reactions, affording desired products in excellent
Table 2
Diastereoselective addition of benzyl zinc reagents 2 to chiral
a
-CF3 ketoimine ester 1a
Ph
OMe
Ph
Ph
HN
OMe
OMe
.
N
N
ZnCl MgCl2
THF
temp
F3C
CO2R1
R2
R2
+
F3C
CO2R1
Ph
CO2Et
1f
1
2
3
Entry
1 R1
2 R2
Temp (°C)
Time (h)
drb
3, yieldc (%)
1
1a, Et
1a, Et
1a, Et
1a, Et
1a, Et
1a, Et
2b, 4-Me
2c, 2-Me
2d, 3-Me
2e, 4-OMe
2f, 4-F
0
0
8
>20:1
—
>20:1
>20:1
>20:1
>20:1
3b, 92
3c, N.R.
3d, 95
3e, 81
3f, 91
2
24
12
8
8
12
3d
4
À10
0
5e
6d
À10
À10
0
0
0
2g, 4-Cl
3g, 88
7e
2a, H
2a, H
2a, H
8
>20:1
>20:1
>20:1
3h, 95
3i, 81
3j, 70
1b
1c
1d
TMS
8
12
12
9
10
11
1e, Bn
1f
2a, H
2a, H
0
25
12
12
>20:1
—
3k, 95
3l, <10
a
Unless otherwise noted, the reaction was carried out by using 1 (0.5 mmol, 1 equiv), 2 (3.5 equiv) in a 0.17 M THF solution (based on 1). For clarity complexed LiCl has
been omitted. N.R., no reaction.
b
Determined by 19F NMR before column chromatography.
Isolated yield.
Using 5.0 equiv of 2, the reaction was run in a 0.08–0.10 M THF solution (based on 1).
Using 4.0 equiv of 2, the reaction was run in a 0.15–0.17 M THF solution (based on 1).
c
d
e

J. Yang et al. / Tetrahedron Letters 52 (2011) 4675–4677
4677
Ph
Ph
OMe
OMe
HN
F3C
HN
KOH
CO2Et
F3C
CO2H
MeOH/H2O
99%
3a (dr > 20:1)
4
NH2
CO2H
F3C
Pd/C, H2 (10 atm),
MeOH, 85%
5
Scheme 2. Synthesis of (S)-a-Tfm-Phe 5 and X-ray crystal structure of compound 4.
Supplementary data
R1O
Cl Zn
F3C
O
Ph
Cl
Mg
Ph
OMe
HN
F3C
Supplementary data (detailed experimental procedures, and
characterization data for new compounds) associated with this
article can be found, in the online version, at doi:10.1016/
j.tetlet.2011.07.006.
Cl
O
H
CO2R1
R
N
R2
Scheme 3. The mechanistic proposal on stereocontrol.
References and notes
yields with high dr values (Table 2, entries 7–10). It is noteworthy
that these functional groups, TMSE, allyl, and propargyl, in -Tfm-
AAs can subsequently be applied for further functionalization, pro-
viding opportunities to access diverse -Tfm-AAs derivatives.
Unfortunately, when -phenyl ketoimine ester 1f was investigated,
poor yield was obtained even at room temperature, thus indicating
that an electron-deficient group, such as CF3, in the ketoimine, is
critical for the reaction efficiency (Table 2, entry 11).
1. For recent reviews, see: (a) Smart, B. E. J. Fluorine Chem. 2001, 109, 3; (b)
Maienfisch, P.; Hall, R. G. Chimia 2004, 58, 93; (c) Special issue on ‘‘Fluorine in
the Life Sciences’’, ChemBioChem 2004, 5, 557.; (d) Purser, S.; Moore, P. R.;
Swallow, S.; Gouverneur, V. Chem. Soc. Rev. 2008, 37, 320; (e) Amii, H.;
Uneyama, K. Chem. Rev. 2009, 109, 2119.
2. (a) Kirsch, P. Modern Fluoroorganic Chemistry: Synthesis, Reactivity, Applications;
Wiley-VCH: Weinheim, 2004; (b) Hiyama, T.; Kanie, K.; Kusumoto, T.;
Morizawa, Y.; Shimizu, M. Organofluorine Compounds Chemistry and
Applications; Springer: Berlin, 2000; (c)Biomedical Frontiers of Fluorine
Chemistry, ACS Symposium Series 639; Ojima, I., McCarthy, J. R., Welch, J. T.,
Eds.; American Chemical Society: Washington, DC, 1996.
a
a
a
The absolute configuration of quaternary chiral center in a-ben-
3. (a) Welch, J. T.; Gyenes, A.; Jung, M. J. In General Features of Biological Activity of
Fluorinated Amino Acids: Design, Pharmacology and Biochemistry; Kuhhar, V. P.,
Soloshonok, V. A., Eds.; John Wiley & Sons: Chichester, 1995; pp 311–331; (b)
Smits, R.; Koksch, B. Curr. Top. Med. Chem. 2006, 16, 1483.
zyl
a-Tfm-AAs 3 was determined to be S by the X-ray crystallo-
graphic analysis of 4.12 As depicted in Scheme 2, compound 4
was synthesized from 3a (dr >20:1) by treatment of KOH. Subse-
quently, hydrogenation of 4 in the presence of Pd/C afforded enan-
4. (a) Pozzo, A. D.; Ni, M.; Muzi, L.; Castiglione, R.; Mondelli, R.; Mazzini, S.; Penco,
S.; Pisano, C.; Castorina, M.; Giannini, G. J. Med. Chem. 2006, 49, 1808; (b)
Burger, K.; Mutze, K.; Hollweck, W.; Koksch, B. Tetrahedron 1998, 54, 5915.
5. (a) Bravo, P.; Buche, L.; Pesenti, C.; Viani, F.; Volonterio, A.; Zanda, M. J. Fluorine
Chem. 2011, 112, 153; (b) Margiotta, N.; Papadia, P.; Lazzaro, F.; Crucianelli, M.;
De Angelis, F.; Pisano, C.; Vesci, L.; Natile, G. J. Med. Chem. 2005, 48, 7821.
6. Yoder, N. C.; Kumar, K. Chem. Soc. Rev. 2002, 31, 335; Lazzaro, F.; Crucianelli, M.;
De Angelis, F.; Frigerio, M.; Malpezzi, L.; Volonterio, A.; Zanda, M. Tetrahedron:
Asymmetry 2004, 15, 889; Papeo, G.; Giordano, P.; Brasca, M. G.; Buzzo, F.;
Caronni, D.; Ciprandi, F.; Mongelli, N.; Veronesi, M.; Vulpetti, A.; Dalvit, C. J. Am.
Chem. Soc. 2007, 129, 5665.
7. For reviews, see: (a) Smits, R.; Cadicamo, C. D.; Burger, K.; Koksch, B. Chem. Soc.
Rev. 2008, 37, 1727; (b) Fustero, S.; Sanz-Cervera, J. F.; Acena, J. L.; Sanchez-
Rosello, M. Synlett 2009, 525.
8. (a) Bravo, P.; Crucianelli, M.; Vergani, B.; Zanda, M. Tetrahedron Lett. 1998, 39,
7771; (b) Asensio, A.; Bravo, P.; Crucianelli, M.; Farina, A.; Fustero, S.; Soler, J.
G.; Meille, S. V.; Panzeri, W.; Viani, F.; Volonterio, A.; Zanda, M. Eur. J. Org. Chem.
2001, 1449.
9. Min, Q.-Q.; He, C.-Y.; Zhou, H.; Zhang, X. Chem. Commun. 2010, 46, 8029.
10. (a) Piller, F. M.; Metzger, A.; Schade, M. A.; Haag, B. A.; Gavryushin, A.; Knochel,
P. Chem. Eur. J. 2009, 15, 7192; (b) Metzger, A.; Bernhardt, S.; Manolikakes, G.;
Knochel, P. Angew. Chem., Int. Ed. 2010, 49, 4665; For diastereoselective
addition of Knochel type benzylzinc reagents to N-tert-butanesulfinyl
aldimines, see: (c) Buesking, A. W.; Baguley, T. D.; Ellman, J. A. Org. Lett.
2011, 13, 964.
11. Benzylzinc reagents were prepared according Knochel’s procedure, see Ref. 10.
12. CCDC 821663 contains the supplementary crystallographic data for compound
4. This data can be obtained free of charge from the Cambridge
Crystallographic Data Centre via www.ccdc.cam.ac.uk/data_request/cif.
13. The configuration of ketoimine ester 1a is E. For the assignment of the
configuration of 1a, see: Chaume, G.; Van Severen, M.-C., Marinkovic, S.;
Brigaud, T. Org. Lett. 2006, 8, 6123. However, in our previous work (see Ref. 9), a
Z configuration of 1a was drawn in the transition state. In this case, we thought
that probably, there is an equilibrium between E-1a and Z-1a under the
reaction conditions, and Z configuration is preferred in the transition state.
However, an alternative transition state might be possible, see Supplementary
data.
tioenriched (S)-a
-Tfm-Phe 58 in 85% yield, demonstrating the
synthetic utility of this method.
On the basis of our preliminarily results and Knochel’s research
work that MgCl2 may function as Lewis acid and can chelate with
carbonyl group to form a six-member ring chelation state,10b we
proposed a highly restricted chair transition state for explanation
of the high diastereoselectivity obtained in the reaction, in which
Mg coordinates with C@N, MeO of imine, and carbonyl group of es-
ter, which induces the benzylzinc reagents to attack the steric less
hindered Re face to generate S configuration stereoselectively13
(Scheme 3).
In conclusion, we have developed an effective and facile method
for highly diastereoselective synthesis of quaternary a-Tfm-AAs in
good yields with high diastereoselectivities by addition of Knochel
type benzylzinc reagents to (R)-phenylglycinol methyl ether based
imines of trifluoropyruvate. Although 3.0–5.0 equiv of benzyl zinc
reagents were used, the low cost and ready availability of benzyl
chlorides and the ease of preparation of Knochel type benzylzinc
reagents make this protocol useful for application in peptides
and related chemistry. Further studies to expand the substrates
scope and their applications in synthesis and evaluation of bioac-
tive compounds are currently in progress.
Acknowledgments
The NSFC (Nos. 20902100 and 20832008), the Shanghai Rising-
Star Program (09QA1406900) and SIOC are greatly acknowledged
for funding this work.