Nonnatural amino acid synthesis by using carbon-hydrogen bond functionalization methodology

Article abstract of DOI:10.1002/anie.201200731

Taking direction well: Substituted phenylalanine derivatives were prepared by C-H bond functionalization (see scheme). The syntheses are highly convergent and employ an N-phthaloylalanine with a 2-thiomethylaniline directing group. The use of an 8-aminoquinoline directing group allows for the diarylation of methyl and the diastereoselective arylation of methylene groups. Copyright

Full text of DOI:10.1002/anie.201200731

Angewandte
Chemie
DOI: 10.1002/anie.201200731
À
C H Bond Functionalization
Nonnatural Amino Acid Synthesis by Using Carbon–Hydrogen Bond
Functionalization Methodology**
Ly Dieu Tran and Olafs Daugulis*
During recent years, transition-metal-catalyzed functionali-
zation of carbon–hydrogen bonds has become a rapidly
monoarylation of methylene groups. The arylation regio-
selectivity results from the formation of the double five-
membered chelate 1.
Several other research groups have used these directing
groups in the synthesis of natural products.[5] Corey and co-
workers have used the 8-aminoquinoline auxiliary to arylate
expanding area of research.[1] Functionalization of the C H
À
bond is appealing, because it allows for shorter and simpler
reaction pathways. However, most of the reports that deal
with the conversion of carbon–hydrogen bonds into carbon–
carbon bonds involve either method development or mech-
anistic investigations. Their applications in the synthesis of
natural products, or their analogues, are rare.[2] The limited
3
3
[5a]
À
sp C(sp ) H bonds in amino acid derivatives. However,
the monoarylation of alanine derivatives was not demon-
strated and the stereochemical integrity of the arylation
products, as well as removal of the directing group, was not
reported. Developing new methods for synthesis of non-
natural amino acids is important, because they are used in
drug discovery, protein engineering, peptidomimetics, glyco-
peptide synthesis, and click chemistry in biologically relevant
systems.[6,7] Methods for the preparation of chiral, nonrace-
mic, nonnatural a-amino acids involve the synthesis of
racemates followed by resolution, use of chiral auxiliaries,
À
use of C H bond functionalization may be explained by the
following issues. First, methods that result in the functional-
ization of C H bonds of alkanes are relatively rare.[3] Second,
À
harsh reaction conditions are typically used that may be
incompatible with sensitive functionalities. Third, methods
are often not broadly applicable and require nonremovable
directing groups.
We have reported the b arylation of carboxylic acid and
g arylation of amine derivatives by employing an 8-amino-
quinoline or picolinic acid auxiliary, a catalytic amount of
Pd(OAc)2, and an aryl iodide coupling partner (Scheme 1).[4a]
asymmetric hydrogenation, and biological approaches.[8]
A
general synthesis of nonnatural amino acids from the chiral
pool would greatly expand the methods that are available for
their preparation. We report herein the palladium-catalyzed
À
synthesis of protected, nonnatural amino acids by C H bond
functionalization, which employs readily available starting
materials derived from the chiral pool.
À
The functionalization of amino acid C H bonds requires
installation of a directing group and protection of the amino
group. A phthaloyl group was chosen for protection of the
amino functionality.[9] The directing group was installed by
treating phthaloylamino acid chlorides[10] with 8-aminoquino-
line or 2-thiomethylaniline. The N-phthaloylalanine deriva-
tive 2 was arylated with phenyl iodide (PhI) in the presence of
a palladium catalyst and base. Subsequently, the directing
group was removed by treatment with BF3·Et2O in methanol
at 1008C (Table 1).[11] Compound 4 was obtained in a nearly
identical enantiomeric excess when AgOAc, AgOCOCF3, or
CsOAc were used as the base at 60–708C (entries 3–8).
Higher reaction temperatures resulted in a lower enantio-
meric excess of 4 (entries 1, 4, and 9), as did the addition of
pivalic acid (entry 2). The optimal combination of yield and
enantiomeric excess was obtained by employing palladium
acetate as the catalyst in combination with AgOAc at 608C
(entry 5).
À
Scheme 1. Auxiliaries for C H bond arylation. L=ligand; X=CH2, CO,
aromatic tether; Y=CH2, CO; R=alkyl.
Subsequently, several other auxiliaries were investigated for
the b arylation of carboxylic acids.[4b] The use of a 2-thio-
methylaniline auxiliary results in the selective monoarylation
of methyl groups. In contrast, the use of an 8-aminoquinoline
auxiliary allows either diarylation of methyl groups or
[*] L. D. Tran, Prof. Dr. O. Daugulis
Department of Chemistry, University of Houston
Houston, TX 77204-5003 (USA)
E-mail: olafs@uh.edu
The use of a 2-thiomethylaniline derivative allows for
a
selective monoarylation of the methyl group in 2
(Scheme 2). Arylation of 2 with iodobenzene affords 3 in
78% yield. 4-Methoxyiodobenzene is also reactive and the
arylation product 5 was isolated in 68% yield. 2-Iodonaph-
thalene and 2-iodobenzothiophene afforded the products 6
and 7, respectively, in good yields. b-(2-Naphthyl)alanine-
containing peptides are highly specific Pin1 (peptidyl prolyl
[**] We thank the Welch Foundation (Grant No. E-1571), NIGMS (Grant
No. R01GM077635), and Camille and Henry Dreyfus Foundation for
supporting this research. We also thank Dr. James Korp for
collecting and solving the X-ray structure of 21.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201200731.
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Table 1: Reaction optimization.
Entry
Base
T [8C]
3 conv [%]
4 ee [%]
1[a]
CsOAc
CsOAc
CsOAc
AgOAc
110
90
60
70
60
70
60
70
110
68[c]
61[c]
51
77
55
92
88
92
91
92
93
67
2[a,b]
3[a]
4[d]
90
5[d]
AgOAc
78[c]
78
6[d]
AgOCOCF3
AgOCOCF3
AgOCOCF3
AgOCOCF3
7[d]
77
8[d,e]
9[d–f]
59
82[c]
[a] Toluene as solvent. [b] Pivalic acid added. [c] Yield of isolated
product. [d] No solvent. [e] Pd(OCOCF3)2 as catalyst. [f] Reaction time
12 h. See the Supporting Information for details. Phth=phthaloyl.
Scheme 2. Synthesis of modified phenylalanine derivatives.
cis/trans isomerase) inhibitors.[12] Interestingly, 3-iodo-1-
methylindole can be coupled with 2 to give N-methylated
tryptophan derivative 8 in 61% yield. An azido functionality
is tolerated on the aryl iodide, and the 3-azidophenylalanine
derivative 9 was obtained in 81% yield. Thus, a wide variety
of substituted phenylalanines can be made in a convergent
fashion from a readily available, single starting material 2.
The directing group in two of the arylated derivatives was
cleaved, with N-phthaloylphenylalanine methyl ester 4 being
obtained in 87% yield and 90% ee, and the benzothiophene
derivative 10 in 80% yield.
Scheme 3. Aminoquinoline auxiliary.
plished with 3,4-dimethyl-1-iodobenzene to give 12 and 4-
iodobenzoic acid ethyl ester to give 13, with both the products
being isolated in excellent yields. Interestingly, the arylation
of methylene groups occurs with high diastereoselectivity, in
favor of the anti diastereomers. Protected phenylalanine can
also be arylated with 4-iodoanisole to give 14 in 91% yield,
with a crude diastereomer ratio of 24:1. Similarly, the
arylation with 2-iodothiophene results in the formation of
An 8-aminoquinoline directing group can be used for the
diarylation of methyl and monoarylation of methylene
functionalities (Scheme 3). The diarylation of 11 was accom-
2
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the single diastereomer 15 in 95% yield. Protected lysine can
be arylated with 4-iodoanisole and 2-iodothiophene to give 16
and 17 in high yields and diastereoselectivities. The arylation
of a leucine derivative affords products 18 and 19 in high
yields. The reactions were typically run on a 0.5 mmol scale,
but 5.55 mmol scale p-methoxyphenylation of the leucine
derivative afforded 18 in 67% yield. Cleavage of the directing
group was investigated for 12 and 18. Methyl esters 20 and 21
were obtained in yields of 80 and 58%, respectively. Com-
pound 21 was produced with 86% ee, but could be increased
to 95% ee (85% recovery) by one recrystallization. Addi-
tionally, the relative stereochemistry of 21, which is a deriv-
ative of highly-constrained b-isopropyltyrosine,[13] was veri-
fied by X-ray crystallography (see Supporting Information).
Preliminary results on the alkylation and acetoxylation of
À
C H bonds of amino acid are reported in Scheme 4. Thus,
alanine derivative 11 was alkylated with 1-iodooctane to
Scheme 5. Mechanistic considerations. RE=reductive elimination.
In conclusion, we have shown that the synthesis of
a number of substituted phenylalanine derivatives is possible
À
Scheme 4. Alkylation and acetoxylation.
by using C H bond functionalization. The syntheses are
highly convergent and employ N-phthaloylalanine with 2-
thiomethylaniline as a directing group. The use of an 8-
aminoquinoline directing group allows for the diarylation of
methyl groups and diastereoselective monoarylation of
methylene groups of amino acids. The acetoxylation and
afford 22 in 42% yield. Compound 22 is a derivative of
a lipidic amino acid, which has been shown to inhibit the
growth of tumor cells.[14] Acetoxylation of 23 gave 24 in 53%
yield.[15,16]
À
alkylation of C H bonds in amino acid derivatives are also
The diastereoselectivity of the arylation occurs either at
possible.
À
the C H activation step or, less likely, at the reductive
elimination step.[17] The H/D exchange in 23 was examined by
heating the substrate with a catalytic amount of Pd(OAc)2 in
a CD3CO2D/[D8]toluene mixture (Scheme 5). After 5 h at
1008C, 64% of deuterium incorporation was observed at 3S
position with minimal (< 10%) incorporation at 3R position.
From this information, a generalized reaction mechanism can
be proposed. Formation of a palladium amide 23a is followed
Experimental Section
7: (S)-N-(2-Phthalimidopropionyl)-2-methylthioaniline (170 mg,
0.5 mmol), Pd(OAc)2 (6 mg, 0.027 mmol), 2-iodobenzothiophene
(785 mg, 3.0 mmol), AgOAc (209 mg, 1.25 mmol), and toluene
(0.4 mL) were added to a 1-dram vial. The mixture was stirred at
608C for 64 h, then cooled to room temperature and diluted with
CH2Cl2 (25 mL). The reaction mixture was then extracted with brine
(15 mL), and the aqueous layer extracted with CH2Cl2 (2 ꢀ 15 mL).
The combined organic layers were dried over MgSO4. Evaporation to
remove the organic solvents, followed by purification by flash
chromatography with hexanes/EtOAc (100% hexanes to 3:1), and
preparative HPLC with hexanes/EtOAc 4:1 gave 175 mg of 7 as
a colorless oil (74%). Rf = 0.45 (SiO2, 2:1 hexanes/EtOAc); 1H NMR
(500 MHz, CDCl3): d = 8.95 (s, 1H), 8.37–8.31 (m, 1H), 7.87–7.82 (m,
2H), 7.75–7.67 (m, 3H), 7.62–7.58 (m, 1H), 7.45–7.41 (m, 1H), 7.33–
7.20 (m, 4H), 7.80–7.04 (m, 1H), 5.40 (dd, 1H, J = 5.7, 10.3 Hz), 4.03
(dd, 1H, J = 5.1, 14.9 Hz), 4.11 (dd, 1H, J = 10.9, 15.5 Hz), 2.13 ppm
(s, 3H); 13C NMR (125 MHz, CDCl3): d = 167.8, 165.8, 140.1, 139.9,
138.0, 134.7, 133.6, 131.5, 129.4, 125.5, 125.0, 124.3, 124.1, 123.9, 123.4,
123.3, 122.3, 120.6, 55.9, 29.7, 19.2 ppm; the signal for one carbon
À
by the C H activation that affords 23b. Complex 23b can
then be protonated or deuterated, leading to 25. Since
protonation likely occurs with retention of configuration,[18]
it can be assumed that 23b has a trans arrangement of the
phthaloyl and phenyl groups and that the diastereoselectivity
of the arylation is established at the palladation step.
Oxidative addition to give a high-valent[19] Pd intermediate
26 is followed by a reductive elimination that proceeds with
retention of configuration. Oxidative addition of aryl iodides
to palladium(II) centers may be facilitated by the silver salts,
because they are known to complex aryl iodides.[20] Ligand
exchange affords 27 and regenerates 23a.
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atom could not be located; FTIR (neat): 1715, 1513, 1436, 1380 cmÀ1
.
Inoue, Y. Fukumoto, N. Chatani, J. Am. Chem. Soc. 2011, 133,
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Elemental analysis calcd (%) for C26H20N2O3S2 (472.58 gmolÀ1): C
66.08, H 4.27, N 5.93, found: C 65.82, H 4.45, N 5.72.
Received: January 26, 2012
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Published online: && &&, &&&&
À
À
Keywords: amino acids · C C coupling · C H activation ·
palladium
.
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4
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Communications
À
C H Bond Functionalization
L. D. Tran, O. Daugulis*
&&&& — &&&&
Nonnatural Amino Acid Synthesis by
Using Carbon–Hydrogen Bond
Functionalization Methodology
Taking direction well: Substituted phe-
nine with a 2-thiomethylaniline directing
nylalanine derivatives were prepared by
group. The use of an 8-aminoquinoline
directing group allows for the diarylation
of methyl and the diastereoselective ary-
lation of methylene groups.
À
C H bond functionalization (see
scheme). The syntheses are highly con-
vergent and employ an N-phthaloylala-
Angew. Chem. Int. Ed. 2012, 51, 1 – 5
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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5
These are not the final page numbers!