Iron-Catalyzed Diastereoselective Synthesis of Unnatural Chiral Amino Acid Derivatives

Article abstract of DOI:10.1021/acs.orglett.6b01493

An iron-catalyzed diastereoselective synthesis of unnatural chiral (S)-α-amino acids with γ-quaternary carbon centers has been developed. The protocol uses inexpensive iron salt as the catalyst, readily available 2-phthaloyl acrylamide and alkenes as the starting materials, and phenylsilane as the reductant, and the reactions were performed well in mixed solvent of 1,2-dichloroethane and ethylene glycol at room temperature. The method shows some advantages including simple and wide substrates, mild conditions, high diastereoselectivity, and easy workup procedures.

Full text of DOI:10.1021/acs.orglett.6b01493

Letter
pubs.acs.org/OrgLett
Iron-Catalyzed Diastereoselective Synthesis of Unnatural Chiral
Amino Acid Derivatives
Hao Zhang, Haifang Li, Haijun Yang, and Hua Fu*
Key Laboratory of Bioorganic Phosphorus Chemistry and Chemical Biology (Ministry of Education), Department of Chemistry,
Tsinghua University, Beijing 100084, P. R. China
*
S Supporting Information
ABSTRACT: An iron-catalyzed diastereoselective synthesis of
unnatural chiral (S)-α-amino acids with γ-quaternary carbon centers
has been developed. The protocol uses inexpensive iron salt as the
catalyst, readily available 2-phthaloyl acrylamide and alkenes as
the starting materials, and phenylsilane as the reductant, and the
reactions were performed well in mixed solvent of 1,2-dichloroethane
and ethylene glycol at room temperature. The method shows some
advantages including simple and wide substrates, mild conditions, high diastereoselectivity, and easy workup procedures.
mino acids, especially chiral α-amino acids (α-AAs), are
Table 1. Optimization of Conditions on Iron-Catalyzed
A
one of the most powerful and versatile building blocks in
Reaction of 2-Phthaloyl Acrylamide (1a−c) with 1-Methyl-1-
1
a
nature. Compared with the common proteinogenic amino acids,
unnatural chiral α-AAs exhibit unique functions. For example, the
peptides incorporating unnatural α-AAs can resist hydrolysi2s
of proteinases and show interesting pharmacological activity.
The α-AAs are widely used in synthesis of natural products,
cyclohexene (2a) in the Presence of Phenylsilane (PhSiH )
3
3
4
biomolecules, and the chiral catalysts and ligands. Therefore,
the chemical synthesis of these valuable compounds has received
tremendous interest. The previous methods for synthesis of
5
6
α-AAs mainly include the asymmetric Strecker reaction, the
asymmetric alkylation of glycine derivatives employing chiral
7
8
auxiliaries or chiral phase-transfer catalysts, and the enantiose-
9
lective hydrogenation of dehydroamino acid precursors.
Recently, palladium-catalyzed direct C−H functionalization on
ratio
(1:2a)
change from the standard
conditions
dr
yield of 3a
(%)
the side chains of natural α-amino acids to access their unnatural
b
c
entry
1
(3a/3′a)
10
counterparts has gained great progress. The unnatural chiral
1
2
3
4
5
6
7
8
9
1a
1b
1c
1c
1c
1c
1c
1c
1c
1c
1:3
1:3
1:3
1:5
1:5
1:5
1:5
1:5
1:5
1:5
none
4:1
51
none
2.4:1
>20:1
>20:1
56
none
31
none
55
FeSO ·7H O as the catalyst
trace
trace
NR
NR
62
4
2
FeCl as the catalyst
3
Fe (SO ) ·H O as the catalyst
2
4
3
2
no catalyst
EtOH as the solvent, 2 h
11:1
13:1
1
0
80 °C, 1 h
50
a
Reaction conditions: under nitrogen atmosphere, 2-phthaloyl acrylamide
1) (0.2 mmol), 1-methyl-1-cyclohexene (2a) (0.6−1.0 mmol), iron
catalyst (0.06 mmol), 1,2-dichloroethane (DCE) (1.5 mL), ethylene glycol
(
(
EG) (0.3 mL), temperature (25 or 80 °C), time (6 h) in a sealed Schlenk.
b
Diastereoselective ratio (dr value) was determined according to the
1
H NMR peak areas of α-H in 3a and 3′a from the reaction mixture
c
of 1 with 2a. Isolated yield. acac = acetylacetonate. NR = no reaction.
Figure 1. Unnatural α-amino acids with γ-quaternary carbon centers.
(
a) The biologically active unnatural α-amino acids with γ-quaternary
carbon centers. (b) Our strategy for synthesis of unnatural α-amino
acids with γ-quaternary carbon centers.
Received: May 24, 2016
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b01493
Org. Lett. XXXX, XXX, XXX−XXX

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Letter
a
Table 2. Iron-Catalyzed Synthesis of Unnatural Chiral α-Amino Acid Derivatives (3)
a
Reaction conditions: under nitrogen atmosphere, 1c (0.2 mmol), alkene (2) (1.0 mmol), Fe(acac) (0.06 mmol), PhSiH (0.3 mmol), 1,2-dichloroethane
3
3
b
(1.5 mL), ethylene glycol (0.3 mL), temperature (room temperature, ∼25 °C), time (6−12 h) in a sealed Schlenk tube. Diastereoselective ratio
1
c
(
dr value) was determined according to the H NMR peak areas of α-H in 3 and 3′ from the reaction mixture of 1c with 2. Isolated yield.
α-AAs with γ-quaternary carbon centers display various interest-
ing biological activity. For example, compounds containing A
residue are azepanone inhibitors of human cathepsin S, and
However, the methods using radicals as the partners are very
16
rare for the synthesis of chiral unnatural α-AAs. To the best
of our knowledge, synthesis of unnatural chiral α-AAs using
2-aminoacrylic acid derivatives as the radical acceptors and
alkenes as the donators has not been reported. Herein, we report
an efficient and practical iron-catalyzed diastereoselective
synthesis of unnatural chiral α-AAs (3) with γ-quaternary carbon
centers via reaction of 2-phthaloyl acrylamide (1) with chiral
auxiliaries with alkenes (2) at room temperature (Figure 1b).
At first, we investigated three Evans-oxazolidinones as the
11a
molecules containing B−E residues are used as the ligands of
1
1b,c
glutamate and NMDA receptors.
Compound with F residue
11d
is a potent inhibitor of tyrosine kinase, and compounds with
G residue are applied as the potent N-methyl-D-aspartic acid
11e
receptor agonists (Figure 1a). Unfortunately, the methods
for their synthesis are very limited thus far, and the synthetic
11,12
pathways usually are fussy.
Therefore, it is highly desirable to
17
develop an efficient and practical diastereoselective approach to
unnatural chiral α-AAs with γ-quaternary carbon centers.
Iron is an abundant and inexpensive metal on earth, and the
chiral auxiliaries, (S)-4-benzyloxazolidin-2-one (a), (S)-4-
phenyloxazolidin-2-one (b), and (S)-4-tert-butyloxazolidin-2-one
(c), and they were installed on N-phthaloyl dehydroalanine to give
the corresponding 2-phthaloyl acrylamides (1a−c). As shown in
Table 1, reaction of 1c with 1-methyl-1-cyclohexene (2a) gave
the highest diastereoselective ratio of 3a/3′a (dr > 20:1) using
Fe(acac) as the catalyst in the presence of PhSiH in mixed
13
iron catalysts are widely used in organic synthesis. Very recently,
Baran and co-workers have developed an interesting reductive
coupling of olefins through carbon−carbon bond formation, and
14
various novel compounds were prepared. 2-Aminoacrylic acid
derivatives are important precursors, and their Michael addition
3
3
14b
solvent of 1,2-dichloroethane (DCE) and ethylene glycol (EG)
15
reaction with nucleophiles provides amino acid derivatives.
at room temperature (entry 3), and 3a with S-configuration could
B
DOI: 10.1021/acs.orglett.6b01493
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
easily be isolated by column chromatography on silica gel using
petroleum ether/ethyl acetate as the eluent. Unfortunately, the
yield was only 31%. When amount of 1-methyl-1-cyclohexene
Scheme 2. Reaction of 1c with 2a in the Presence of
Ethylene Glycol-d under the Standard Conditions
2
(2a) was increased, the yield greatly improved with homocou-
pling of alkene occurring (entry 4). Other iron catalysts were
attempted (entries 5−7), and they gave poor results. No target
products (3a and 3′a) were found in the absence of catalyst
(entry 8). Effect of solvents was investigated, and the mixed
solvent of DCE and EG was suitable (compare entries 4 and 9).
The diastereoselectivity decreased when temperature was raised
to 80 °C (entry 10). In order to confirm whether other transition
metals are involved in the reaction, the solvent in the resulting
solution of entry 4 was removed by a rotary evaporator, and the
residue was determined by ICP mass spectrometry. Cu, Co, Mn,
Pd, Rh, and Ru almost were not observed (data determined by
ICP mass spectrometry: Cu = 0.3 ppm, Co = 3.0 ppb, Mn =
was first investigated as shown in Scheme 2. Reaction of 1c
with 2a was carried out under the standard conditions using
9.0 ppb, Pd = 2.0 ppb, Rh = 0.3 ppb, and Ru = 0.2 ppb). The result
displays that the present reaction is an iron-catalyzed process.
Having identified the optimal conditions, we next examined
the scope of alkenes for the iron-catalyzed synthesis of unnatural
chiral α-amino acid derivatives (3). As shown in Table 2, 11
alkenes with different-sized rings (2a−k) were attempted, and
they provided good to excellent yields with high diastereose-
lectivity in which the larger cyclic substrates gave higher
diastereoselectivity because of bigger steric effect (see 3a−k
in Table 2). For noncyclic alkenes 2l−u, the substrates with
smaller steric substituents such as methyl in 2p−t afforded
slightly lower diastereoselectivity. Interestingly, 2u also gave
a high diastereoselective ratio (dr >20:1). The iron-catalyzed
synthesis of unnatural chiral α-amino acid derivatives (3)
showed tolerance of some functional groups including amides,
ethers, esters, and hydroxyl. Therefore, the present methods can
easily afford diverse unnatural chiral α-amino acid derivatives.
As shown in Scheme 1, we attempted synthesis of 3b, 3i, and
ethylene glycol-d instead of ethylene glycol in Table 2, and
H NMR showed that mixtures of 3a and 4 were obtained after
purification, and 4 was a major product. Subsequently, a radical
2
1
trapping experiment was performed. 1,1-Diphenylethylene as a
18
radical-trapping reagent was added to the system of 1-methyl-
1
-cyclohexene (2a), PhSiH , and Fe(acac) in DCE/ethylene
3 3
glycol, and adduct of 1,1-diphenylethylene and 2a was observed
by GC−MS (see Supporting Information for the details). The
result exhibited that iron-catalyzed reaction of 2a with PhSiH
3
first formed a radical intermediate VII in Scheme 3.
Therefore, a plausible mechanism is proposed in Scheme 3
using reaction of 1c with 2a in mixed solvent of DCE and
Scheme 3. Plausible Mechanism for the Iron-Catalyzed Coupling
of 1c and 2a in Mixed Solvent of DCE and Ethylene Glycol-d2
3q on gram-scale under the standard conditions, and the results
showed the present method was also effective.
In order to explore the reaction mechanism on the iron-catalyzed
synthesis of unnatural chiral α-amino acid derivatives (3), two
control experiments were performed. A deuterium-labeled study
Scheme 1. Iron-Catalyzed Synthesis of 3b, 3i, and 3q on
Gram-Scale under the Standard Conditions
ethylene glycol-d as an example of this novel iron-catalyzed process
2
14
according to the results above and the previous references. First,
treatment of iron catalyst L Fe(III) with PhSiH and ethylene
3
3
glycol-d2 (DOCH CH OD) provides L Fe(III)-H (I), PhSi-
2
2
2
H OCH CH OD (II), and III, and isomerization of III leads to
2
2
2
IV and V. Reaction of I with 2a gives L Fe(II) (VI) and radical
2
VII, and Michael addition of VII to 1c yields VIII. Redox between
14b
VI and VIII produces L Fe(III) (X) and anion XI. Treatment
2
of X, XI with DOCH CH OD or III, V affords products 3a
2
2
(
minor) and 4 (major) regenerating iron-catalyst (L Fe(III)).
Hydrolysis of 3i was performed in mixed solvent of THF and
3
water in the presence of H O and LiOH at 0 °C for 2 h, and 5
2
2
was obtained in 91% yield (Scheme 4). In order to confirm
C
DOI: 10.1021/acs.orglett.6b01493
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(
(
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Scheme 4. Hydrolysis of 3i Leading to 5
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whether the procedure led to racemization of 5, a pair of
racemates, Rac-5, was first prepared (see Supporting Information
for details). Next, HPLC analysis of Rac-5 and 5 was performed
with CHIRALPAK QN-AX (QN07163) chiral column using
methanol/acetic acid/triethylamine (100:2:0.2) as the mobile
phase (flow rate = 0.5 mL/min). The results displayed that
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for the details). In addition, single crystal of 5 was prepared, and
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analysis (see Supporting Information for details). It is known
that deprotection of the phthalimido amino acids with hydrazine
2
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19
can get free amino acid without erosion of chirality.
(11) (a) Kerns, J. K.; Nie, H.; Bondinell, W.; Widdowson, K. L.;
In summary, we have developed a convenient, efficient, and
practical iron-catalyzed method for diastereoselective synthesis
of unnatural chiral α-(S)-amino acids with γ-quaternary
carbon centers. The protocol uses inexpensive iron salt as the
catalyst, readily available 2-phthaloyl acrylamide with (S)-4-tert-
butyloxazolidin-2-one chiral auxiliary and alkenes as the starting
materials, and phenylsilane as the reductant, and the reactions
were performed well in mixed solvent of 1,2-dichloroethane and
ethylene glycol at room temperature under nitrogen atmosphere.
The method shows some advantages including simple and wide
substrates, mild conditions, high diastereoselectivity, and easy
workup procedures. Therefore, the present method provides
a novel and valuable strategy for synthesis of diverse unnatural
chiral α-amino acids.
Yamashita, D. S.; Rahman, A.; Podolin, P. L.; Carpenter, D. C.; Jin, Q.;
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ASSOCIATED CONTENT
Supporting Information
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c) Plietker, B. Iron Catalysis in Organic Chemistry; Wiley-VCH:
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■
*
S
(
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b01493.
2
2
014, 516, 343. (b) Lo, J. C.; Yabe, Y.; Baran, P. S. J. Am. Chem. Soc.
014, 136, 1304.
General procedures, characterization data, and NMR
spectra of obtained compounds (PDF)
̃
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Chem. Commun. 2002, 2440. (c) Navarre, L.; Martinez, R.; Genet, J.-
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AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: fuhua@mail.tsinghua.edu.cn.
(
16) (a) Yim, A.-M.; Vidal, Y.; Viallefont, P.; Martinez, J.
Notes
Tetrahedron: Asymmetry 2002, 13, 503. (b) Gasanov, R. G.;
Ilinskaya, L. V.; Misharin, M. A.; Maleev, V. I.; Raevski, N. I.;
Ikonnikov, N. S.; Orlova, S. A.; Kuzmina, N. A.; Belokon, Y. N. J.
Chem. Soc., Perkin Trans. 1 1994, 3343.
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Porter, N. A. Acc. Chem. Res. 1999, 32, 163.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
The authors wish to thank the National Natural Science
Foundation of China (Grant Nos. 21372139 and 21221062),
and Shenzhen Sci & Tech Bureau (CXB201104210014A) for
financial support.
(
18) Liu, D.; Liu, C.; Li, H.; Lei, A. Angew. Chem., Int. Ed. 2013, 52,
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DOI: 10.1021/acs.orglett.6b01493
Org. Lett. XXXX, XXX, XXX−XXX