Asymmetric synthesis of α-amino acids under operationally convenient conditions

Article abstract of DOI:10.1002/adsc.201400405

A new multipurpose glycine equivalent for the general asymmetric synthesis of α-amino acids is introduced. The chiral reagent can be transformed to various amino acids by alkylations with alkyl halides as well as aldol and Michael addition reactions under operationally convenient reaction conditions at room temperature with virtually complete stereochemical control.

Full text of DOI:10.1002/adsc.201400405

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DOI: 10.1002/adsc.201400405
Asymmetric Synthesis of a-Amino Acids under Operationally
Convenient Conditions
Manuel Jçrres,a Xia Chen,b Josꢀ Luis AceÇa,c Carina Merkens,d Carsten Bolm,a,*
Hong Liu,b,* and Vadim A. Soloshonokc,e,*
a
Institute of Organic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
Fax : (+49)-241-809-2391; e-mail: carsten.bolm@oc.rwth-aachen.de
Key Laboratory of Receptor Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, 555 Zu
b
Chong Zhi Road, Shanghai 201203, Peopleꢁs Republic of China
Fax : (+86)-21-5080-7042; e-mail: hliu@mail.shcnc.ac.cn
Department of Organic Chemistry I, Faculty of Chemistry, University of the Basque Country UPV/EHU, Paseo Manuel
c
Lardizꢂbal 3, 20018 San Sebastiꢂn, Spain
Fax : (+34)-94-301-5270; e-mail: vadym.soloshonok@ehu.es
Institute of Inorganic Chemistry, RWTH Aachen University, Landoltweg 1, 52074 Aachen, Germany
IKERBASQUE, Basque Foundation for Science, Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bibao, Spain
d
e
Received: April 24, 2014; Published online: && &&, 0000
Dedicated to Professor Yuri Nikolaevich Belokon on the occasion of his 75th birthday.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201400405.
Abstract: A new multipurpose glycine equivalent
for the general asymmetric synthesis of a-amino
acids is introduced. The chiral reagent can be trans-
formed to various amino acids by alkylations with
alkyl halides as well as aldol and Michael addition
reactions under operationally convenient reaction
conditions at room temperature with virtually com-
plete stereochemical control.
the known chemical methods prohibitively expensive
as compared to their enzyme-based counterparts.[8]
Considering the growing importance of a-AAs in the
de novo design of peptides, peptidomimetics and
pharmaceuticals,[9] the cost-per-structure issue is a key
factor in the quality assessment of a new synthetic
method. Particularly, a high degree of stereocontrol
accessible under operationally convenient conditions,
such as an easily maintainable temperature and the
use of air- and moisture-stable reagents,[10] is unargua-
bly an essential requirement of a truly practical
method. Taking all such aspects into account, one of
the most economically sound chemical asymmetric
syntheses of a-AAs is the one reported by Maruoka,
who developed alkylations of achiral glycine Schiff
Keywords: amino acids; asymmetric synthesis; cen-
tral and axial chirality; nickel; Schiff bases
a-Amino acids (a-AAs) can be found in nature as bases 1 under phase-transfer catalysis (PTC) with
structural units of peptides and proteins leading to chiral quaternary amines (Figure 1).[3b,11] Although
countless biological functions in living beings.[1] Con-
sequently, the search for efficient asymmetric synthe-
ses of a-AAs has always been a goal of paramount
importance for synthetic chemists. The wealth of
methodology available to date for accessing a-AAs
features true synthetic ingenuity allowing the prepara-
tion of virtually any tailor-made[2] structurally/func-
tionally complex a-AA.[3,4] Methods include stoichio-
metric as well as catalytic approaches.[1,3–5] Some, such
as the asymmetric hydrogenation of dehydroamino
acid derivatives utilizing rhodium- or ruthenium-
based catalytic systems, have already been applied on
(multi-)kilogram scales.[6,7] Aspects of practicality and
Figure 1. Achiral and chiral glycine equivalents of practical
cost, however, have often been neglected rendering significance.
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Manuel Jçrres et al.
synthetically highly valuable, this process has still seri- reoselectivity, the generation of the chiral axis is less
ous drawbacks related to the high cost of the chiral determined (at the required elevated temperature of
catalysts and the incomplete yields (~80%). Here, we the metal complexation in methanol) resulting in the
report on an alternative protocol, featuring excellent formation of two diastereomeric complexes 6 and 7,
stereochemical control achieved under PTC condi- which are formed in about a 1:2 ratio in high overall
tions at room temperature. The approach relies on yield. Column chromatography allows separation of
the use of a specially designed and inexpensive gly- both complexes providing 6 and 7 in diastereomerical-
cine equivalent 2 possessing two elements of chirality: ly pure form. Their relative configurations were un-
stereogenic centers and a chiral axis.[12]
ambiguously determined by X-ray crystal structure
It is demonstrated that in the matched case of these analyses.[17] Accordingly, 6 and 7 have S and R config-
stereocontrolling elements alkylations as well as aldol urations, respectively, at the chiral axes.
and Michael addition reactions can be conducted with
PTC benzylations were chosen as model reactions
virtually complete stereochemical control leading in order to determine the inductive potential of 6 and
to excellent stereoselectivities [of commonly dr= 7 in diastereoselective alkylations. The standard con-
>98:2]. Because Schiff bases 2 are hydrolytically ditions involved the addition of tetrabutylammonium
stable under PTC conditions, high chemical yields can iodide (TBAI, 10 mol%), NaOH (30% aqueous), and
be achieved. Drawing inspiration from the many ap- 1,2-dichloroethane.[18] As shown in Scheme 2, the dia-
plications of glycine Schiff base Ni(II) complexes[13,14] stereoselectivities in the benzylation reactions of 6
for general asymmetric a-AA synthesis,[15] we de- and 7 differed significantly. Whereas the former led to
signed proline-derived amide (S)-5 as a new type of a single product (8a) in high chemical yield, the latter
potential nickel chelator (Scheme 1). The synthesis of afforded a diastereomeric mixture of the two corre-
(S)-5 involved a simple condensation of commercially sponding benzylated products (9) in a 43:57 ratio.
available (S)-N-benzylproline [(S)-3] and 2-amino-
2’,5-dichlorobenzophenone (4), which led to (S)-5 in erated (matched case), whereas in 7 this beneficial
89% yield.[16]
effect was missing (mismatched case). Consequently,
Thus, in complex 6 the stereogenic elements coop-
The central feature of (S)-5 is that upon formation complex 6 was considered valuable for the subsequent
of the Schiff base with glycine and subsequent in situ alkylation studies.
complexation of the resulting imine with an Ni(II)
The optimization of the PTC conditions revealed
salt, a metal complex is generated that bears two new that the alkylation reactions of 6 could be carried out
elements of chirality. First, a stereogenic center at the under solid-liquid phase-transfer conditions, allowing
prolinyl nitrogen and, second, a chiral axis between avoidance of water as additional reaction medium. In
the imine carbon and the ortho-chlorophenyl group terms of the substrate scope we were pleased to find
resulting from hindered rotation around the respec- that most products were formed with excellent diaste-
À
tive C C bond. Whereas the new stereogenic center reoselectivities (>98:2) in good yields after short re-
is cleanly induced with R configuration in high diaste- action times (Table 1). All reactions of 6 with sym-
metrically substituted benzyl bromides gave the corre-
sponding alkylation products (8a–h) in good yields
with virtually complete stereoselectivity, regardless of
the electronic nature of the substituents (Table 1, en-
tries 1–8). ortho- and meta-substituted benzyl bro-
mides reacted with the same efficiency in both yield
and diastereoselectivity (Table 1, entries 9–13). Use of
unsaturated alkyl bromides such as allyl and proparg-
Scheme 1. Synthesis of Ni(II) complexes 6 and 7 containing
elements of central and axial chirality.
Scheme 2. Benzylations of Ni(II) complexes 6 and 7 under
PTC conditions.
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Asymmetric Synthesis of a-Amino Acids
Table 1. Alkylations of Ni(II) complex 6 under PTC condi-
tions.[a]
Scheme 3. Disassembly of 8a to give (S)-phenylalanine [(S)-
10].
Entry
R
dr[b]
Yield[c] [%]
1
2
3
4
5
6
7
8
C6H5CH2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
>98:2
97:3
>98:2
>98:2
>97:3
>98:2
>97:3
>98:2
>98:2
>98:2
>98:2
94:6
73 (8a)
80 (8b)
77 (8c)
81 (8d)
73 (8e)
89 (8f)
88 (8g)
84 (8h)
83 (8i)
91 (8j)
90 (8k)
83 (8l)
89 (8m)
76 (8n)
88 (8o)
89 (8p)
81 (8q)
96 (8r)
87 (8s)
90 (8t)
to our delight, the yield significantly improved from
73% to 96%. By treatment of 8a with 6N HCl in
methanol under standard conditions,[19] the complex
could be degraded leading to (S)-phenylalanine [(S)-
10] with an er of 98:2 in 72% yield after purification
by cation exchange resin (Dowex). Chiral amide (S)-5
was recovered in 95% yield (Scheme 3).
4-F3C-C6H4CH2
4-Br-C6H4CH2
4-NO2-C6H4CH2
4-BrCH2C6H4CH2
3,5-F2-C6H3CH2
3,5-(MeO)2-C6H3CH2
2,3,4,5,6-F5C6CH2
2-Br-C6H4CH2
2-I-C6H4CH2
Considering the importance of bis-amino acids,[20]
the alkylation of 6 with a,a’-dibromo-para-xylene (11)
was studied (Scheme 4). Both electrophilic sites of 11
reacted well furnishing aryl-bridged dinickel complex
12 as a single product with a dr of >98:2 in 89%
yield.
9
10
11
12
13
14
15
16
17
18
19
20[d]
3-F-C6H4CH2
3-MeO-C6H4CH2
3-NO2-C6H4CH2
À
CH2=CH CH2
À
PhCH=CH CH2
Aldol addition reactions of chiral glycine equiva-
lents open a reliable and straightforward access to
biologically important a-amino-b-hydroxy acids.[21] To
illustrate the directing power of the newly developed
system in such reactions, nickel complex 6 was treated
with NaOMe in methanol and reacted under homoge-
neous conditions with n-butyraldehyde and 2-methyl-
propanal. As a result, the corresponding products 14a
and 14b were obtained in 74% and 71% yields, re-
spectively (Scheme 5). Under thermodynamic control,
the stereoselectivity was complete leading to a single
one out of the four theoretically possible diastereo-
mers in both cases.[22]
ꢀ À
HC C CH2
ꢀ À
CH3CH2C C CH2
MeO2CCH2
2-naphthyl CH2
Me
À
[a]
Use of 6 (0.07 mmol), alkyl bromide (0.17 mmol), NaOH
(2.7 mmol) and (n-Bu)4NI (0.007 mmol) in 1,2-dichloro-
ethane (0.7 mL) at room temperature.
[b]
[c]
[d]
1
Determined by H NMR spectroscopy.
After column chromatography.
Use of methyl iodide as alkylating agent.
yl bromides also worked well leading to products
The relative stereochemistry of product 14a was de-
8n–q in yields reaching 89% and excellent stereose- termined by X-ray crystal structure analysis,[17] which
lectivities (Table 1, entries 14–17). Particularly note- revealed that the newly formed stereogenic centers
worthy is the alkylation of 6 with methyl bromoace-
tate, which led to aspartic acid derivative 8r with a dr
of >98:2 in almost quantitative yield (Table 1,
entry 18). Finally, reactions of 6 with 2-(bromome-
thyl)naphthalene and methyl iodide afforded the cor-
responding products 8s and 8t as single diastereomers
in 87% yield and as 94:6 diastereomeric mixtures in
90% yield, respectively (Table 1, entries 19 and 20).
The S-configuration of the newly created stereogen-
ic center was established by X-ray crystal structure
analysis of propargylinated complex 8p.[17]
Increasing the scale of the reaction and applying
1 g of 6 in the alkylation with benzyl bromide afford-
ed 8a with the same excellent diastereoselectivity as
on the smaller scale (>98:2, cf. Table 1, entry 1), and, (11).
Scheme 4. Alkylation of 6 with a,a’-dibromo-para-xylene
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Manuel Jçrres et al.
Scheme 5. Aldol additions of Ni(II) complex 6.
had
R and S configurations (as indicated in a single diastereomer was observed (91% yield).
Scheme 5). This result suggests the intermediacy of Using chiroptical properties and spectral data,[2,27]
a complex of type 13,[23] in which the alkoxy moiety is both new stereogenic centers were determined to
bound to the central nickel ion. As a consequence, have S configurations.
the sodium carboxylate group points down, away
Having proven that nickel complex 6 was highly ef-
from the stereochemistry-controlling chloro substitu- fective in controlling the stereochemistry in alkyla-
ent of the arene, and the R substituent at the alkoxy- tion, aldol and Michael addition reactions, we won-
bearing carbon is in the sterically favourable trans-po- dered about a possible use of its diastereomer 7,
sition to the COONa group. Upon protonation, com- which was formed in significant quantities during the
plex 13 rearranges to the final product 14. As a result, complex formation (Scheme 1). To this end we finally
the stereochemical preference in the aldol process is could demonstrate that under microwave irradiation
the same as that in the alkylation of complex 6 al- a clean epimerization (by rotation around the chiral
though the absolute configuration at the newly axis) occurred allowing us to convert pure diastereo-
formed stereogenic center is opposite.
mer 7 into a 55:45 mixture of 6 and 7. Chromato-
Michael additions are other important homologa- graphic separation of the two diastereomers increased
tion reactions of glycine equivalents.[24] They give rise the overall yield of 6, which proved beneficial for the
À
to a variety of structurally complex amino acids, such aforementioned applications in asymmetric C C bond
as b-substituted, c-constrained derivatives with rele- formations.
vance for the design of de novo peptides.[25] In our
In summary, we have developed a new chiral gly-
study, we chose the addition of 6 to crotonic acid cine equivalent having a combination of stereogenic
methyl ester (15) as a test reaction, as it is known to centers and chiral axis and proved its applicability in
be a difficult transformation due to the formation of a variety of representative alkylations with alkyl hal-
two consecutive stereogenic centers and the minimal ides, as well as in aldol and Michael addition reac-
steric impact of the methyl group.[26] To our delight, tions. Of particular significance is the exceptional
the Michael addition proceeded smoothly in acetoni- combination of virtually complete stereochemical
trile with DBU as base (Scheme 6), and as in the control with operationally convenient room tempera-
other processes, the reaction was clean occurring at ture conditions. Further applications of this syntheti-
a high rate. The stereocontrol was complete, and only cally interesting reagent are currently on-going in our
laboratories.
Experimental Section
Experimental procedures, full characterization of new prod-
ucts, copies of NMR spectra, er determinations and X-ray
crystal data for 6, 7, 8p and 14a (CIF) can be found in the
Supporting Information.
General Procedure for the Alkylation of Nickel
Complexes 6 and 7
Scheme 6. Representative Michael addition of Ni(II) com-
plex 6.
In a Schlenk flask equipped with a magnetic stirrer bar the
Ni(II) complex (37.8 mg, 0.07 mmol), TBAI (2.5 mg,
4
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Asymmetric Synthesis of a-Amino Acids
0.007 mmol, 0.1 equiv.) and crushed NaOH (106.7 mg,
2.7 mmol, 40 equiv.) were dissolved in 1,2-dichloroethane
(0.7 mL) under an argon atmosphere. The alkylation reagent
(0.17 mmol, 2.5 equiv.) was added to the reaction mixture
(liquid alkyl halides were dissolved in a small amount of 1,2-
dichloroethane). The reaction was followed by TLC
(DCM:acetone 4:1) until completion (30–60 min). The reac-
tion mixture was washed with AcOH (5% aqueous solution,
5 mL) and the separated aqueous layer was extracted with
CH2Cl2 (3ꢄ5 mL each). The combined organic phases were
dried over Na2SO4, filtered, and concentrated under
vacuum. The product was purified by column chromatogra-
phy (DCM:acetone 4:1 or 7:1).
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Acknowledgements
We thank IKERBASQUE, Basque Foundation for Science,
the Basque Government (SAIOTEK S-PE13UN098), and
Hamari Chemicals (Osaka, Japan) for financial support. We
are also grateful to SGIker (UPV/EHU) for HR-MS analy-
ses. M. J. acknowledges DAAD (German Academic Ex-
change Service) and the Forschungscluster SusChemSys,
which is co-financed by the Regional Development Fund –
investing in your future – of the European Union and the
State of North Rhine Westphalia, for stipends. H.L. and X.C.
are grateful for financial support from the National Natural
Science Foundation of China (Grant 81025017).
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6
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Adv. Synth. Catal. 0000, 000, 0 – 0
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COMMUNICATIONS
Asymmetric Synthesis of a-Amino Acids under
7
Operationally Convenient Conditions
Adv. Synth. Catal. 2014, 356, 1 – 7
Manuel Jçrres, Xia Chen, Josꢀ Luis AceÇa, Carina Merkens,
Carsten Bolm,* Hong Liu,* Vadim A. Soloshonok*
Adv. Synth. Catal. 0000, 000, 0 – 0
ꢃ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
asc.wiley-vch.de
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ÞÞ
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