Asymmetric Synthesis of N-Fmoc-(S)-7-aza-tryptophan via Alkylation of Chiral Nucleophilic Glycine Equivalent

Article abstract of DOI:10.1002/ejoc.202100485

Ni(II)-complexes, derived from glycine Schiff bases with chiral tridentate ligands, have been used as powerful tools for the synthesis of structurally diverse tailor-made amino acids. In this manuscript, asymmetric alkylation reaction between chiral nucleophilic glycine derived Ni-complex and 3-(chloromethyl)-1H-pyrrolo[2,3-b]pyridine has been developed under convenient conditions, which affords the corresponding alkylated Ni-complex in 74 % yield and excellent diastereoselectivity (only one isomer). This reaction features convenient conditions and completely controlled diastereoselectivity, which provides a highly valuable approach for asymmetric synthesis of 7-aza-tryptophan.

Full text of DOI:10.1002/ejoc.202100485

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Asymmetric Synthesis of N-Fmoc-(S)-7-aza-tryptophan via
Alkylation of Chiral Nucleophilic Glycine Equivalent
Authors: Yupiao Zou, Ryosuke Takeda, Jianlin Han, Hiroyuki Konno,
Hiroki Moriwaki, Hidenori Abe, Kunisuke Izawa, and Vadim A.
Soloshonok
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01/2020

10.1002/ejoc.202100485
European Journal of Organic Chemistry
COMMUNICATION
Asymmetric Synthesis of N-Fmoc-(S)-7-aza-tryptophan via
Alkylation of Chiral Nucleophilic Glycine Equivalent
Yupiao Zou,[a] Ryosuke Takeda,[b] Jianlin Han,*[a] Hiroyuki Konno,[c] Hiroki Moriwaki,[b] Hidenori Abe,*[b]
Kunisuke Izawa,[b] and Vadim A. Soloshonok*[d,e]
[a]
Y. Zou, Prof. Dr. J. Han
Jiangsu Co-Innovation Center of Efficient Processing and Utilization of Forest Resources, International Innovation Center for Forest Chemicals and
Materials, College of Chemical Engineering
Nanjing Forestry University
159 Longpan Road, 210037, Nanjing, China
E-mail: hanjl@njfu.edu.cn; homepage: hg.njfu.edu.cn
Dr. R. Takeda, Dr. H. Moriwaki, Dr. H. Abe, Dr. K. Izawa
Hamari Chemicals Ltd., 1-4-29 Kunijima, Higashi-Yodogawa-ku, Osaka 533-0024, Japan
Email: hidenori-abe@hamari.co.jp
[b]
[c]
Prof. Dr. H. Konno
Department of Biological Engineering, Graduate School of Science and Engineering
Yamagata University
Yonezawa, Yamagata 992-8510, Japan
[d]
[e]
Prof. Dr. V. A. Soloshonok
Department of Organic Chemistry I, Faculty of Chemistry
University of the Basque Country UPV/EHU
Paseo Manuel Lardizábal 3, 20018 San Sebastián, Spain
Email: vadym.soloshonok@ehu.es; homepage: http://www.ikerbasque.net/vadym.soloshonok
IKERBASQUE, Basque Foundation for Science
Alameda Urquijo 36-5, Plaza Bizkaia, 48011 Bilbao, Spain
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
Abstract: Ni(II)-complexes, derived from glycine Schiff bases with
chiral tridentate ligands, have been used as powerful tools for the
synthesis of structurally diverse tailor-made amino acids. In this
manuscript, asymmetric alkylation reaction between chiral
nucleophilic glycine derived Ni-complex and 3-(chloromethyl)-1H-
pyrrolo[2,3-b]pyridine has been developed under convenient
conditions, which affords the corresponding alkylated Ni-complex in
74% yield and excellent diastereoselectivity (only one isomer). This
reaction features convenient conditions and completely controlled
diastereoselectivity, which provides a highly valuable approach for
asymmetric synthesis of 7-aza-tryptophan.
genus acylase,[10] L-amino acid oxidase[11] or tryptophan synthase
from Salmonella typhimurium[12] as biocatalyst (Scheme 1b). Thus,
there is a room for the development of convenient, efficient, and
easy scalable methods for preparation of chiral 7-aza-tryptophan.
Amino acids (AAs) belong to the most ubiquitous class of naturally
occurring compounds,[1] which have been used as an important
type of structural units in the design of modern drugs due to
several advantageous features, such as high structural diversity,
wide scope of functional groups, good solubility in aqueous media,
and few safety concerns.[2] Currently, a number of small-molecule,
peptidomimetics, and peptide containing residues of tailor-made
AAs or their derivatives serve as key structural features in many
blockbuster drugs.[3] Among these natural and non-natural AAs,
7-aza-tryptophan occupies an important position, which has been
widely used as biological fluorescent probes,[4] antiplasmodial
compounds,[5] and inhibitors of checkpoint kinase 1.[6,7] Although
there have been several reports on the synthesis of aza-
tryptophanes,[8] the synthesis of 7-aza-tryptophan still remained
less developed, in particular in the asymmetric mode. One of the
first asymmetric methods was based on alkylation reaction
between (1R,4R)-camphor imine and tert-butylglycinate, which
proceeded with poor chemical yield (Scheme 1a).[9]
Chemoenzymatic synthesis represents an alternative strategy for
the preparation of optical pure 7-aza-tryptophan using aspergillus
Scheme 1. Asymmetric synthesis of 7-aza-tryptophan.
Consistent with our long-standing interest in preparation of
tailor-made AAs, in particular phosphorus-[13] and fluorine-
1
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10.1002/ejoc.202100485
European Journal of Organic Chemistry
COMMUNICATION
containing derivatives,[14] we were developing general approach
for asymmetric synthesis of AAs via Ni(II) complexes of chiral
Schiff bases.[15] Typically, chiral ligands (S)-5-7 are used for the
preparation of nucleophilic glycine-based Ni-complex for the
introduction of the desired side-chain(s) (Figure 1).[16] Several
types of reactions of these nucleophilic Ni-complexes have been
developed, such as alkyl halide alkylations[17] aldol,[18] Mannich[19]
and Michael[20] addition reactions. Based on the literature data
and our own experience in application of Ni(II)-complexes of
Schiff bases for the synthesis of “Tailor-Made Amino
Acids™”,[21,22] we eversion that reaction between Ni-complex and
suitable alkyl halide would provide a method to chiral 7-aza-
tryptophan. Herein, report an asymmetric method for the
synthesis of chiral 7-aza-tryptophan via an alkylation of chiral Ni-
complex with corresponding alkyl chloride (Scheme 1c).
developed a one-pot procedure for the synthesis of pure alkylated
Ni-complex 4a. The Boc remaining protected product 4b was
completely converted to compound 4a by the treatment of the
crude reaction mixture with MeOH.
Thus, the reaction was conducted in 2.0 g scale of (S)-2, 0.8
equiv of alkyl chloride 3, 1.5 equiv of NaOH, in DMSO (40 mL)
under nitrogen atmosphere at room temperature for 1.5 h. The
resulted reaction mixture was treated with MeOH (40 mL) and
o
o
stirred at 20 C for 2 h, and then heated to 60 C for 1 h, which
afforded the corresponding product 4a in 74% yield and
completely controlled stereochemical outcome.
Figure 1. Chiral tridentate ligands 5-7.
Scheme 2. Alkylation of chiral glycine-Ni(II) complex 2 with compound 3.
Ligand (S)-6 derived glycine Ni-complex 2 was chosen as the
starting material for this alkylation reaction (Scheme 2), which
usually shows enhanced stereocontrolling properties due to a
parallel displaced type of aromatic interactions between the
selectively chlorinated o-amino-benzophenone and Pro N-benzyl
rings.[23] The desired alkyl chloride 3, Boc-protected 3-
(chloromethyl)-1H-pyrrolo[2,3-b]pyridine, was prepared with 1H-
pyrrolo[2,3-b]pyridine-3-carbaldehyde as the starting reagent (for
details, see SI file).
Having prepared alkyl chloride 3, we then studied its alkylation
reaction with Ni(II)-complex 2 (Scheme 2). To find an optimal
reaction condition to achieve high selectivity and clean conversion
to the desired Ni (II) complex 4a, several screens were carried out.
The optimization study led to the very specific condition using
DMSO as a reaction solvent, which had rarely been used in the
past applications of this methodology.[21] Using DMSO showed a
significant difference in purity of the product 4a during the reaction,
exhibiting the high diastereomeric selectivity as well as the
lowering impurities formation. After more refining studies were
conducted to find an optimal stoichiometry of base and alkyl
chloride minimizing the key bis-alkylation byproduct, we found
that the reaction with DMSO as a solvent in the presence of NaOH
(1.5 equiv) and alkyl chloride (0.8 equiv) provided the best yield
and diastereoselectivity. To address this question, we added the
following sentence: The beneficial effect of DMSO on the reaction
outcome is likely multifactorial. However, what could be clearly
noticed is a significantly reduced amount of the oxidation products
that usually observed under strongly basic reaction conditions.[24]
During the workup procedure, surprisingly, the Boc group was
partially removed during the reaction even under basic conditions
providing a mixture of compounds (4a and 4b). Thus, we
The alkylated Ni (II) complex (S,2S)-4a was then disassembled
in the presence of 3N HCl (aqueous) with 1,2-dimethoxyethane
(DME) as a solvent, which afforded the corresponding free amino
acid, (S)-7-aza-tryptophan (1) hydrochloric acid salt in 95% yield
(Scheme 3). DME was chosen as a solvent, instead of methanol,
although methanol has been generally employed for this step.[22]
This is because the use of methanol as solvent for this
disassembly procedure was found to cause undesired
esterification. The reaction proceeded smoothly and the isolation
of the amino acid was successfully carried out by filtering off most
of the chiral ligand precipitated after the reaction and partitioning
between water and dichloromethane to sequester the residual
ligand into organics. C18 flash column chromatography was
utilized to remove the residual Ni2+ prior to the following Fmoc
protection. It should be pointed out the C18 flash column method
was used during this trace experiment. This is proved to be the
most straightforward for small scale, which worked well to provide
the desired amino acid 1 in good yield and high purity. It should
be emphasized that chiral ligand (S)-6, as well as Ni(II), can be
recycled and reused for continuous production of this and other
types of AAs, as illustrated in the recent publications.[22,25]
2
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Scheme 3. Disassembly of Ni-complex 4a.
The Fmoc protection was carried out employing general
conditions using Fmoc-OSu in the presence of sodium carbonate
(Scheme 4). The reaction proceeded smoothly and furnished the
desired Fmoc-L-7-AzaTrp-OH (8) in 70% yield. It should be
mentioned that the residual Ni2+ seems to complicate the Fmoc
reaction and care must be taken to remove Ni2+ completely before
this step. The crystalline product 8 was easy to isolate from the
reaction. For the purification, the hydrolyzed impurity derived from
unreacted Fmoc-OSu was effectively sequestered by the
trituration with toluene. The synthesized compound 1 could be
1
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We gratefully acknowledge the financial support from the National
Natural Science Foundation of China (No. 21761132021) and
IKERBASQUE, Basque Foundation for Science.
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Keywords: Tailor-Made Amino Acids™ • aza-tryptophanes •
Schiff bases • asymmetric synthesis • chiral tridentate ligands
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4
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Entry for the Table of Contents
Efficient method for synthesis of (S)-7-aza-tryptophan via tridentate chiral auxiliary derived Ni(II)-complexes has been developed. The
three-step synthesis includes alkylation, disassembly and Fmoc-protection, affording Fmoc-L-7-AzaTrp-OH in over 49% yield and
excellent diastereoselectivity.
5
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