Synthesis of C3-symmetric star-shaped molecules containing α-amino acids and dipeptides via Negishi coupling as a key step

Article abstract of DOI:10.3762/bjoc.15.33

We demonstrate a new synthetic strategy toward star-shaped C₃-symmetric molecules containing α-amino acid (AAA) derivatives and dipeptides. In this regard, trimerization and Negishi cross-coupling reactions are used as the key steps starting fr

Full text of DOI:10.3762/bjoc.15.33

Synthesis of C3-symmetric star-shaped molecules containing
α-amino acids and dipeptides via Negishi coupling
as a key step
Sambasivarao Kotha* and Saidulu Todeti
Full Research Paper
Open Access
Address:
Beilstein J. Org. Chem. 2019, 15, 371–377.
Department of Chemistry, Indian Institute of Technology-Bombay,
Powai, Mumbai-400076, India, Fax: +91(22)-2572 7152
doi:10.3762/bjoc.15.33
Received: 16 October 2018
Accepted: 21 January 2019
Published: 08 February 2019
Email:
Sambasivarao Kotha* - srk@chem.iitb.ac.in
* Corresponding author
Associate Editor: D. Spring
Keywords:
© 2019 Kotha and Todeti; licensee Beilstein-Institut.
License and terms: see end of document.
amino acids; cyclotrimerization; Negishi coupling; peptide
Abstract
We demonstrate a new synthetic strategy toward star-shaped C3-symmetric molecules containing α-amino acid (AAA) derivatives
and dipeptides. In this regard, trimerization and Negishi cross-coupling reactions are used as the key steps starting from readily
available 4’-iodoacetophenone and L-serine. These C3-symmetric molecules containing AAA moieties are useful to design new
ligands suitable for asymmetric synthesis and peptide dendrimers.
Introduction
Optically active C3-symmetric molecules are valuable synthons tools. Moreover, C3-symmetric peptides are valuable in
to design dendrimers, chiral ligands, polymers, and supramole- studying the molecular interactions involving proteins that are
cules [1-4]. In this regard, 1,3,5-triarylbenzene derivatives are derived from trimers and synthetic access to such amino acids is
helpful to design star-shaped α-amino acids (AAAs) and they vital. In this regard, new star-shaped C3-symmetric molecules
play an important role in biological systems. The tumor necrosis [16-26] have been used in photovoltaics [27,28], organic light-
factor (TNF) superfamily belongs to trimeric ligands that form emitting diodes (OLEDs) [29,30], organic field-effect transis-
in the shape of C3-symmetric molecules [5]. Trimeric proteins tors (OFETs) [31,32] and electroluminescent devices [33]. To
containing star-shaped compounds are also involved in the com- address these challenges, we [34] and others [35,36] have syn-
plex interactions between cells and pathogens, e.g., the human thesized functionalized C3-symmetric molecules containing
immunodeficiency virus (HIV-1) [6]. The HIV-1 envelope pro- amino acids and peptides.
tein is present as a C3-symmetric trimer on the viruses’ surface
[7], and the virus entry into the cell is mediated by its interac- The Negishi cross coupling [37,38] is a reliable synthetic
tions with cellular receptors. To explore the structural and method, which involves palladium or nickel-catalyzed coupling
chemical nature of protein–protein interactions, synthetic of organozinc reagents [39,40] with various halo derivatives
peptides and unnatural AAAs [8-15] can be useful as molecular (e.g., aryl, vinyl, benzyl, or allyl) and has a broad scope to
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Beilstein J. Org. Chem. 2019, 15, 371–377.
assemble diverse targets. This reaction was first reported in (PPh3) and imidazole in CH2Cl2 at 0 °C to deliver the iodo de-
1977, and it is an elegant and versatile method that allows the rivative 6 in 63% yield [43,44]. Finally, the iodo compound 6
preparation of biaryls and olefins in good yields. To the best of was treated with freshly activated Zn in DMF at room tempera-
our knowledge only a limited number of reports is available for ture to afford the zinc insertion product 7 (Scheme 1) [43].
the synthesis of C3-symmetric peptides (Figure 1) [8,41]. To fill
this gap, we have explored a new synthetic strategy to star- With the organozinc compound 7 at hand we turned to the syn-
shaped C3-symmetric AAA derivatives and peptides by using thesis of the halide component for the attempted Negishi cou-
trimerization and the Negishi cross coupling as key steps.
pling. For this 4-iodoacetophenone (8) was treated with silicon
tetrachloride and ethanol (SiCl4/EtOH) at room temperature for
6 h to produce the iodonated trimerized product 9 in 71% yield
Results and Discussion
The required zinc insertion compound 7 was prepared from (Scheme 2) [45,46].
L-serine (3). Thus, commercially available L-serine (3) was
treated with acetyl chloride in methanol to give methyl ester 4, Then, the organozinc reagent 7 was coupled with triiodo
which was subjected to N-Boc protection with di-tert-butyl derivative 9 in the presence of tetrakis(triphenylphosphane)pal-
dicarbonate (Boc2O) and triethylamine in tetrahydrofuran ladium(0) (Pd(PPh3)4) as catalyst to provide the Negishi cou-
(THF) to obtain the N-Boc-serine methyl ester (5) in 93% yield pling product 10 (68%). Having the trimeric AAA derivative 10
[42]. Afterwards, the protected methyl ester 5 was subjected to in hand, it was treated with trifluoroacetic acid (TFA) in
iodination in the presence of iodine (I2), triphenylphosphane CH2Cl2 (1:1) at room temperature for 1 h to deliver the Boc-
Figure 1: Exemplar C3-symmetric peptide scaffolds reported in the literature.
Scheme 1: Preparation of compound 7 from L-serine (3).
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Beilstein J. Org. Chem. 2019, 15, 371–377.
directly treated with Boc-Val-OH or Boc-Phe-OH in the pres-
ence of HBTU and DIPEA in CH2Cl2 at room temperature for
5 h to give trimeric derivatives 12 (73%) and 13 (81%), respec-
tively. Further, trimer 12 was subjected to another Boc-depro-
tection to give the tris-amine 14 in 95% yield (Scheme 4).
Conclusion
We have demonstrated a simple synthetic strategy toward star-
shaped molecules containing unusual AAA units through
cyclotrimerization and Negishi cross-coupling reaction as key
steps under operationally simple reaction conditions. Here, we
have used the readily available starting materials 4-iodoace-
Scheme 2: Preparation of the trimerized product 9.
deprotected compound. Then, without further purification the tophenone (8) and L-serine (3). The C3-symmetric building
deprotected product was directly treated with thiophene-2- blocks prepared were coupled with different AAAs to produce
carboxylic acid in the presence of 2-(1H-benzotriazol-1-yl)- the C3-symmetric dipeptide trimers.
1,1,3,3-tetramethyluronium hexafluorophosphate (HBTU) and
Experimental
N,N-diisopropylethylamine (DIPEA) in CH2Cl2 at room tem-
perature for 5 h to give trimer 11 in 86% yield (Scheme 3).
General procedure
Commercially available starting materials were used without
In addition, different amino acids were incorporated in the star- further purification. Analytical thin layer chromatography
shaped molecule. In this regard, the Negishi cross-coupling (TLC) was performed on 7.5 × 2.5 cm glass plates coated with
product 10 was treated with TFA in CH2Cl2 at room tempera- Acme’s silica gel GF254 (containing 13% calcium sulfate as
ture for 1 h to give the Boc-deprotection product, which was binder) by using a suitable mixture of ethyl acetate and petro-
Scheme 3: Synthesis of compound 11 via Negishi cross-coupling reaction.
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Beilstein J. Org. Chem. 2019, 15, 371–377.
Scheme 4: Synthesis of C3-symmetric trimers 12, 13 and 14.
leum ether for development. The Negishi coupling was per- spectra were recorded on a Nicolet Impact-400 FTIR spectro-
formed in oven-dried glassware under argon or nitrogen atmo- meter. Specific rotation experiments were measured at 589 nm
sphere and the transfer of moisture-sensitive materials was (Na) and 25 °C (HPLC, CHCl3 stabilized with 0.7–1.0%
carried out in a glovebox by using standard syringe–septum ethanol). Proton nuclear magnetic resonance (1H NMR,
techniques. All purchased solvents (CH2Cl2, THF, acetonitrile, 400 MHz and 500 MHz) spectra and carbon nuclear magnetic
and DMF) were dried over calcium hydride (CaH2) or sodium. resonance (13C NMR, 100 MHz and 125 MHz) spectra were re-
Column chromatography was performed by using Acme’s silica corded on a Bruker spectrometer. The high-resolution mass
gel (100–200 mesh) with an appropriate mixture of ethyl measurements were carried out by using electrospray ionization
acetate, petroleum ether methanol and dichloromethane. The (ESI) spectrometer. Melting points were recorded on a Veego
coupling constants (J) are given in hertz (Hz) and chemical melting point apparatus.
shifts are denoted in parts per million (ppm) downfield from
internal standard, tetramethylsilane (TMS). The abbreviations, Negishi coupling product 10
s, d, t, q, m, and dd refer to singlet, doublet, triplet, quartet, Zinc (Zn) dust was activated by using 3 M aq HCl, then filtered
multiplet, and doublet of doublets, respectively. Infrared (IR) and washed with water (until neutral pH) followed by acetone.
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Beilstein J. Org. Chem. 2019, 15, 371–377.
Large particles were crushed until a fine powder was formed silica gel column chromatography (80% ethyl acetate/petro-
and transferred into a round-bottomed flask and dried under leum ether) to afford the C3-symmetric mono- and dipeptide de-
vacuum with heating and the flask was filled with nitrogen. A rivatives 11, 12 and 13, respectively.
portion of the activated Zn dust (500 mg, 7.65 mmol, 3 equiv)
was cooled to room temperature. Then, iodo compound 6 Peptide derivative 11
(842 mg, 2.55 mmol) was dissolved in DMF (10 mL) and added Colorless solid; yield 86% (89 mg, starting from 100 mg of 10);
dropwise to the freshly activated Zn powder under a nitrogen at- Rf = 0.46 (7:3 ethyl acetate/petroleum ether); mp 156–158 °C;
mosphere and the suspension was stirred at room temperature [α]D25 +25.07 (c 1.0, CHCl3); 1H NMR (500 MHz, CDCl3)
for 3 h. After completion of Zn insertion reaction, stirring was δ 7.71 (s, 3H), 7.60 (d, J = 8.0 Hz, 6H), 7.48 (q, J = 3.5 Hz,
stopped and the solid was allowed to settle down. The super- 6H), 7.24 (d, J = 8.0 Hz, 6H), 7.04 (t, J = 4.5 Hz, 3H), 6.64 (d,
natant was carefully transferred to a suspension of triiodo deriv- J = 7.5 Hz, 3H), 5.10 (q, J = 5.5 Hz, 3H), 3.79 (s, 9H),
ative 9 (500 mg, 0.73 mmol) in DMF (10 mL) at room tempera- 3.35–3.24 (m, 6H) ppm; 13C NMR (125 MHz, CDCl3) δ 172.0,
ture. Five mol % tetrakis(triphenylphosphane)palladium 161.5, 141.9, 139.9, 138.2, 135.3, 130.6, 129.9, 128.7, 127.8,
(Pd(PPh3)4) was added to this mixture under inert atmosphere 127.6, 125.0, 53.6, 52.6, 37.7 ppm; HRMS–ESI (Q-Tof, m/z):
and the reaction mixture stirred at 80 °C for 12 h. The reaction [M + H]+ calcd for C51H46N3O9S3, 940.2391; found, 940.2392;
mixture was cooled to room temperature and washed with IR (neat)
water, brine (3 × 15 mL), 1 M aq Na2S2O3 solution and
: 3769, 3327, 2932, 1664, 1169, 759 cm−1.
extracted with EtOAc (3 × 10 mL). The combined organic Dipeptide 12
layers were dried over Na2SO4 and concentrated at reduced Colorless solid; yield 73% (97 mg, starting from 100 mg of 10);
pressure. The crude was purified by silica gel column chroma- Rf = 0.59 (6:4 ethyl acetate/petroleum ether); mp <230 °C (dec);
tography (30% ethyl acetate/petroleum ether) to afford the [α]D25 +20.58 (c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3)
Negishi coupling product 10 (458 mg, 68%) as a colorless solid. δ 7.69 (s, 3H), 7.59 (d, J = 8.0 Hz, 6H), 7.21 (d, J = 7.6 Hz,
Rf = 0.73 (3:7 ethyl acetate/petroleum ether), [α]D25 +7.78 6H), 6.56 (d, J = 6.8 Hz, 3H), 5.12 (d, J = 7.2 Hz, 3H), 4.91 (d,
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.75 (s, 3H), J = 6.4 Hz, 3H), 3.95 (s, 3H), 3.72 (s, 9H), 3.16 (s, 6H), 2.09 (d,
7.64 (d, J = 8.0 Hz, 6H), 7.28 (d, J = 8.0 Hz, 6H), 5.14 (d, J = 6.0 Hz, 3H), 1.41 (s, 27 H), 0.92 (d, J = 6.8 Hz, 9H), 0.87
J = 8.0 Hz, 3H), 4.67 (d, J = 6.8 Hz, 3H), 3.77 (s, 9H), (d, J = 4.0 Hz, 9H) ppm; 13C NMR (100 MHz, CDCl3) δ 171.8,
3.24–3.11 (m, 6H), 1.45 (s, 27H) ppm; 13C NMR (100 MHz, 171.5, 155.9, 141.9, 139.9, 135.3, 129.8, 127.5, 124.9, 79.9,
CDCl3) δ 172.4, 155.2, 141.9, 139.8, 135.5, 129.9, 127.4, 60.0, 53.2, 52.4, 37.8, 31.0, 28.4, 19.3, 17.8 ppm; HRMS–ESI
124.9, 80.0, 54.5, 52.3, 38.0, 28.3 ppm; HRMS–ESI (Q-Tof, (Q-Tof, m/z): [M + Na]+ calcd for C66H90N6NaO15, 1229.6356;
m/z): [M + Na]+ calcd for C51H63N3NaO12, 932.4304; found, found, 1229.6359; IR (neat)
: 3342, 2938, 2332, 1742, 1635,
932.4302; IR (neat)
: 3661, 2349, 1716, 1495, 1163, 1044, 1534, 1213, 754 cm−1.
755 cm−1.
Dipeptide 13
General procedure for the mono- and dipeptide
products 11, 12 and 13
Colorless solid; yield 81% (96 mg, starting from 80 mg of 10);
Rf = 0.73 (6:4 ethyl acetate/petroleum ether); mp 204–206 °C;
Negishi coupling product 10 was dissolved in dichloromethane/ 1H NMR (500 MHz, CDCl3) δ 7.70 (s, 3H), 7.56 (d, J = 8.0 Hz,
trifluoroacetic acid (CH2Cl2/TFA 1:1) and the reaction mixture 6H), 7.27 (d, J = 7.6 Hz, 6H), 7.20 (t, J = 5.6 Hz, 9H), 7.10 (d,
was stirred at room temperature for 1 h. Then, the mixture was J = 8.0 Hz, 6H), 6.35 (d, J = 6.80 Hz, 3H), 4.98 (br, 3H), 4.83
concentrated at reduced pressure to remove the solvent and (d, J = 6.0 Hz, 3H), 4.35 (d, J = 5.20 Hz, 3H), 3.70 (s, 9H),
dried under vacuum. Later, without further purification the 3.10–3.00 (m, 12H), 1.34 (s, 27H) ppm; 13C NMR (100 MHz,
Negishi coupling deprotection product was reacted with 3 equiv CDCl3) δ 171.5, 171.0, 155.4, 142.0, 140.0, 136.6, 135.2,
of thiophene 2-carboxylic acid or amino acids (N-Boc-L-valine 129.9, 129.5, 128.8, 127.6, 127.1, 125.0, 80.4, 55.9, 53.5, 52.5,
or Boc-Phe-OH) in the presence of N,N-diisopropylethylamine 38.5, 37.8, 28.4 ppm; HRMS–ESI (Q-Tof, m/z): [M + Na]+
(DIPEA, 4 equiv), 2-(1H-benzotriazol-1-yl)-1,1,3,3-tetra- calcd for C78H90N6NaO15, 1373.6356; found, 1373.6359; IR
methyluronium hexafluorophosphate (HBTU, 9 equiv) in (neat)
CH2Cl2. Afterwards, the reaction mixture was stirred at room 751 cm−1.
temperature for 5 h under an inert atmosphere. After comple-
: 3738, 3644, 2919, 2850, 2343, 1666, 1517, 814,
tion of the reaction, the mixture was washed with water, brine Trisamine derivative 14
(3 × 10 mL) and extracted with CH2Cl2 (2 × 10 mL). The Compound 12 (95 mg, 0.07 mmol) was dissolved in CH2Cl2/
combined organic layer was dried over Na2SO4 and concen- TFA 1:1 and this mixture was stirred at room temperature for
trated at reduced pressure. The crude product was purified by 1 h. At the conclusion of the reaction (TLC monitoring), the
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Beilstein J. Org. Chem. 2019, 15, 371–377.
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Supporting Information File 1
Copies of 1H, 13C NMR and HRMS spectra of new
compounds.
[https://www.beilstein-journals.org/bjoc/content/
supplementary/1860-5397-15-33-S1.pdf]
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Acknowledgements
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We thank the Department of Science and Technology (DST),
New Delhi, India, for financial support and IIT Bombay, for
recording spectral data. S.K. thanks the Department of Science
and Technology for the award of a J. C. Bose fellowship (SR/
S2/JCB-33/2010), Praj industries, Pune, for Pramod Chaudhari,
Chair Professor (Green Chemistry) and CSIR (02(0272)/16/
EMR-II). S.T. thanks the IIT Bombay for the award of a
research fellowship.
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