Enediyne-Comprising Amino Aldehydes in the Passerini Reaction

Article abstract of DOI:10.1021/acscombsci.7b00167

Multicomponent reactions represent a highly efficient approach to a broad spectrum of structurally diverse compounds starting from simple and affordable compounds. A focused library of tweezers-like compounds is prepared by employing the multicomponent Passerini reaction comprising enediyne-derived amino aldehydes. The reaction proceeds under mild conditions yielding Passerini products in good to excellent yields. Postcondensation modifications of Passerini products are demonstrated through a simple deprotection/coupling approach comprising amino functionality, furnishing enediyne cores with highly decorated arms.

Full text of DOI:10.1021/acscombsci.7b00167

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Article
Enediyne-comprising amino aldehydes in the Passerini reaction
Mladena Glavaš, Matija Gredi#ak, and Ivanka Jeric
ACS Comb. Sci., Just Accepted Manuscript • DOI: 10.1021/acscombsci.7b00167 • Publication Date (Web): 17 Jan 2018
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Enediyneꢀcomprising amino aldehydes in the
Passerini reaction
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Mladena Glavaš, Matija Gredičak, and Ivanka Jerić*
Division of Organic Chemistry and Biochemistry, Ruđer Bošković Institute, Bijenička cesta 54,
10000 Zagreb, Croatia
KEYWORDS: multicomponent reactions, enediynes, Passerini reaction, receptors.
ABSTRACT: Multicomponent reactions represent a highly efficient approach to a broad
spectrum of structurally diverse compounds starting from simple and affordable compounds. A
focused library of tweezersꢀlike compounds is prepared by employing the multicomponent
Passerini reaction comprising enediyneꢀderived amino aldehydes. The reaction proceeds under
mild conditions yielding Passerini products in good to excellent yields. Postꢀcondensation
modifications of Passerini products are demonstrated through a simple deprotection/coupling
approach comprising amino functionality, furnishing enediyne cores with highly decorated arms.
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Introduction
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Isolation of biologically active acetyleneꢀcontaining compounds from natural sources in 1980s
boosted the research efforts in different areas of organic chemistry, biochemistry, natural product
synthesis, medicinal chemistry, material science, and others. Enediyne anticancer antibiotics
isolated from marine and terrestrial plant sources represent a class of antitumor/antimicrobial
agents with high cytotoxic activity.1 The remarkable activity and a striking mode of action made
enediyne compounds an attractive target molecules. Motivated by their biological importance,
many cyclic and acyclic enediyne derivatives were prepared and their biological activities
evaluated.1ꢀ5 Apart from their role in biologically relevant processes, enediynes are versatile
building blocks for the construction of complex aromatic systems through thermal or
photochemical activation.6ꢀ11 Furthermore, rigid, stable and spatially wellꢀdirected enediyne
motif can be exploited as an inducer of turnꢀlike conformation. In our previous studies, we
showed that enediyneꢀbased small molecule tweezers are efficient Cu(II) atom binders.12
Comparing stability of studied complexes with those reported for histidineꢀrich peptide
fragments with high affinity for copper(II), revealed that enediyne tweezers effectively mimic
properties of copper(II) binding peptides. It is noteworthy that in many proteins, the proline
residue is found in the vicinity of Cu(II) binding site, mostly preceding histidine residue. We
therefore, concluded that structural rigidity of enediyne tweezers significantly enhances
coordination properties of the receptor, thus conforming importance of the turnꢀlike peptide
conformation for the copper(II) binding. Furthermore, we demonstrated that amino acidꢀderived
enediyne ligands account for high enantioselectivities observed in a rhodiumꢀcatalyzed
asymmetric hydrogenation reaction.13 In both cases, enediyne unit acts as structural element,
while function is determined by groups attached at the terminal positions. We are therefore
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interested to explore further the potential of enediyne compounds primarily as receptors. In that
sense, conjugation of enediynes with peptideꢀlike structures is particularly interesting, since the
presence of different functional groups on the periphery of the synthetic receptors, especially
chiral ones, is often the key factor for the recognition and/or discrimination of different
ligands.14ꢀ18 A nice example is recent study of Delsuc et al. where two peptide segments attached
to a rigid template are designed to hybridize with a guest peptide molecule into a collagenꢀlike
triple helix.17 Also, Faggi et al. described a family of pseudopeptidic cage receptors with a
remarkable selectivity for Nꢀprotected dipeptides with an aromatic amino acid at the Cꢀ
terminus.18 Although cyclic and macrocyclic structures hold a prominent position as receptors
for chiral molecules15 and probes for proteinꢀprotein interactions,19 tweezersꢀlike compounds
with cavities of flexible size proved to be effective synthetic receptors as well.14,20 The main
advantage of tweezersꢀlike receptors is adaptability of the receptor geometry to the ligand
topology. While size and shape of the receptor cavity is influenced by the template, selectivity of
the receptor depends on the properties of its arms.
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As a part of our ongoing research in enediyne chemistry, we explored methodologies for the
easy construction of structurally diverse enediyne cores for the binding of different ligands.
Multicomponent reactions (MCRs) offer rapid, efficient and reliable approach to libraries of
structurally diverse compounds starting from simple and affordable compounds. Isocyanideꢀ
based MCRs, like Passerini and Ugi reaction21 are exceptionally useful for the assembly of
chimeras composed of enediynes and peptideꢀlike structures. Among different approaches, we
opted for bifunctional enediyne cores, particularly amino aldehydes 1 and 2 (Figure 1) equipped
with two different functional groups that can be used in stepꢀbyꢀstep diversification process.
Aldehyde group takes part in the first MCR, while amine group is available, (after deprotection)
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for the second MRC, or standard peptide coupling reaction. Our main motivation was to build a
reliable and robust strategy toward library of receptors for different ligands. In this work, we
explored the reactivity of aldehyde group in enediynes 1 and 2 in the Passerini reaction
comprising various acids and isocyanides Thus obtained Passerini products can be further
functionalized to give tweezers with highly decorated arms available for even further
modifications.
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Figure 1. Structures of amino aldehydes 1 and 2.
Results and Discussion
Boc protected amino aldehydes 1 and 2 were prepared by a straightforward procedure
comprising two consecutive Sonogashira couplings22 followed by an oxidation (Scheme 1).
Crossꢀcoupling of Bocꢀprotected propargyl amine with 1,2ꢀdiiodobenzene gave Sonogashira
product 3 in 50 % yield. Next, coupling of 3 with either pentꢀ4ꢀynꢀ1ꢀol or propꢀ2ꢀynꢀ1ꢀol gave
amino alcohols 4 and 5 in excellent yields (87 and 98 %, respectively). Finally, oxidation with
Dess Martin periodane proceeded smoothly providing enediyneꢀbridged Bocꢀprotected amino
aldehydes 1 (80 % yield) and 2 (87 % yield) (Scheme 1).
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Scheme 1. Synthesis of amino aldehydes 1 and 2
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a) tertꢀbutyl propꢀ2ꢀynylcarbamate, CuI (10 mol %), Pd(PPh3)4 (3 mol %), in TEA, RT, under
Ar, 24 h, 50 % yield; b) pentꢀ4ꢀynꢀ1ꢀol or propꢀ2ꢀynꢀ1ꢀol (2 equiv.), CuI (3 mol %),
PdCl2(PPh3)2 (3 mol %), in TEA, RT, under Ar, 24 , 87 % and 98 % yield, respectively; c)
DMP (2 equiv) in DCM, RT, 3 h.
In our initial experiments, Passerini reaction was performed with equimolar amounts of amino
aldehyde 1, benzoic acid and cyclohexyl isocyanide, and after 3 days in different solvents (DCM,
ethyl acetate, THF) at room or elevated temperature, still showed presence of starting material.
Reactions performed with excess of acid and isocyano components proceeded faster; reaction
was completed in 24 h and the Passerini product 6 was obtained in 63 % yield (Chart 1).
Therefore, optimized reaction conditions for the Passerini reaction include 3.1 equivalent of acid
and isocyanide and reaction were carried out in DCM at room temperature until the consumption
of the aldehyde component, typically 24ꢀ48h. Three additional isocyanides were used as
nucleophiles; with tertꢀbutyl isocyanide Passerini product 7 was gained in a 56 % yield, while a
highly branched 1,1,3,3ꢀtetramethylbutyl isocyanide gave Passerini products 8 in 81 % yield.
Finally, methyl isocyanoacetate was used as a representative of amino acidꢀderived isocyanides,
and the corresponding Passerini product was obtained in a 76 % yield. A robust methodology for
the synthesis of libraries should tolerate a broad range of substrates with different electronic and
steric features. Therefore, benzoic acids with different electronic properties were tested in the
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Passerini reaction. As seen in Chart 1, benzoic acid with strong electronꢀwithdrawing group at
the paraꢀposition gave product 10 in the same yield (65 %) as benzoic acid with strong electronꢀ
donating group at the same position (product 11, 67 %). Therefore, electronic properties of the
acid component do not affect its reactivity in the Passerini reaction. When halogen atoms were
introduced at the para position of the benzoic acid aromatic ring, isolated yields were slightly
lower (29ꢀ53 % for products12ꢀ15), regardless of isocyanide used (Chart 1). Next, aliphatic
carboxylic acids were investigated. Acetic and isobutyric acid reacted with 1,1,3,3ꢀ
tetramethylbutyl isocyanide and gave rise to Passerini products 16 and 17 in 51 % and 72 %
yield, respectively. Amino acids are preferable building blocks in multicomponent reactions,
since they provide possibility for multiple postꢀcondensation modifications, mainly through
deprotection/cyclization protocols. Moreover, as discussed previously, amino acids and peptides
are often key elements important for recognition of different ligands. Three Bocꢀprotected amino
acids were used as acid components: cyclic amino acid proline, aromatic phenylalanine and
aliphatic lysine. Cyclohexyl isocyanide was used in all three reactions and Passerini products 18ꢀ
20 were isolated in 63ꢀ92 % yield as a 1:1 mixture of two diastereoisomers. It is known that
stereoselectivity of the Passerini reaction performed with chiral components is mainly influenced
by the aldehyde component, while contribution of acid and isocyanide is generally negligible.21
Therefore, the absence of stereoselectivity in the reaction performed with achiral amino aldehyde
1 is expected.
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Next, we examined the reactivity of amino aldehyde 2 in the Passerini reaction with selected
carboxylic acid and isocyanides. All reactions proceeded smoothly and Passerini products were
isolated in 54ꢀ91 % yield (Chart 2). The influence of scaleꢀup on the efficiency of the presented
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methodology was also examined. Reaction performed with 1 mmol of aldehyde 2, 3.1 mmol of
Bocꢀprotected phenylalanine and cyclohexyl isocyanide gave Passerini product 25 in 87 % yield.
An interesting feature of Passerini products 21ꢀ26 is presence of triple bond attached to the sp3
carbon atom. Recently, synthesis of structurally analogous propargylic alcohol derivatives by a
copperꢀcatalyzed oxyꢀalkynylation of diazo compounds with hypervalent iodine reagents was
reported.23 Here, presented Passerini reaction comprising easy accessible aldehyde 2 offers an
alternative, metalꢀfree approach to spꢀsp3 carbon bonds in very good yields and under mild
reaction conditions.
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Chart 1. Passerini reactions performed with aldehyde 1a
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aReactions were performed with ~ 0.05 mmol of 1, 3.1 equiv. of acid and 3.1 equiv. of
isocyanide component. Isolated yields are given in parentheses.
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Chart 2. Passerini reactions performed with aldehyde 2a
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a
Reactions were performed with ~ 0.05 mmol of 2, 3.1 equiv. of acid and 3.1 equiv. of
isocyanide component. Isolated yields are given in parentheses.
Increasing the structural complexity of receptor is often needed to increase the binding
selectivity, especially in competitive solvents, and can be achieved by adding new “arm” through
a straightforward approach.18 Multicomponent approach coupled with postꢀcondensation
modification(s) provides efficient strategy for the synthesis of structurally and functionally
different receptors, where binding site can be crafted by careful selection of starting compounds.
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Thus, multipleꢀarm receptors carrying hydrophobic or hydrophilic peripheral structures can be
designed to probe binding of different ligands. To demonstrate the susceptibility of prepared
Passerini products toward further modifications, we subjected compound 24 to Boc deprotection
under acid conditions followed by coupling with Nꢀterminally protected phenylalanine, and
compound 27 was obtained in 50 % yield over two steps. Thus, presented Passerini
reaction/postꢀPasserini coupling of enediyneꢀrelated amino aldehydes can be used as synthetic
tool to produce tweezersꢀlike molecules with tailored binding site. Synthesis of multipleꢀarm
derivatives through here presented strategy, as well as a thorough complexation study of
prepared Passerini compounds with a range of metal ions is currently underway, and will be
published in due course.
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Scheme 2. PostꢀPasserini modification
a) TFA/H2O (9/1) RT, 30 min; b) BocꢀPheꢀOH (1.2 equiv), BOP (1.5 equiv.), HOBt (1.5
equiv.), NMM (2 equiv.), in DMF, RT, overnight
Conclusions
In summary, we successfully introduced Bocꢀprotected enediyneꢀrelated amino aldehydes as
carbonyl components in the Passerini reaction. Reactions were performed under mild reaction
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conditions affording Passerini products in good to excellent yields. The reaction was tolerant of
aromatic and aliphatic carboxylic acids, including amino acids, as well as of various isocyanides.
Furthermore, we demonstrated that Passerini products can be additionally modified by a
deprotection/coupling approach through their amino functionality.
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Experimental procedures
General procedure for the Passerini reaction (Charts 1 and 2) Compound 1 or 2 (~ 0.05
mmol) were dissolved in dichloromethane under argon. Carboxylic acid (3.1 equiv.) and
isocyanide (3.1 equiv.) were added and the reaction mixture was stirred at room temperature
until the consumption of the aldehyde component, typically 24ꢀ48h. The reaction was quenched
with saturated NaHCO3 and the product was extracted with dichloromethane. Organic layer was
washed with brine and water, dried over Na2SO4 and concentrated under reduced pressure. The
product was obtained by flash column chromatography (petrol/ethyl acetate (v/v = 2/1)) to afford
corresponding products 6 – 26.
Representative example of the Passerini product (Chart 1)
6-(2-(3-(tert-butoxycarbonylamino)prop-1-ynyl)phenyl)-1-(cyclohexylamino)-1-oxohex-5-
yn-2-yl benzoate (6) Compound 6 was obtained from tertꢀbutyl 3ꢀ(2ꢀ(5ꢀhydroxypentꢀ1ꢀ
ynyl)phenyl)propꢀ2ꢀynylcarbamate (1) (23 mg), benzoic acid (28 mg) and cyclohexyl isocyanide
(28 µL) according to the general procedure in 63% yield (25 mg, 0.046 mmol) as a yellow oil;
1H NMR (600 MHz, CDCl3): δ = 8.08 (d, J = 7.6 Hz, 2H), 7.58 (t, J = 7.4 Hz, 1H), 7.44 (t, J =
7.7 Hz, 2H), 7.38 (s, 1H), 7.32 – 7.30 (m, 1H), 7.20 – 7.18 (m, 2H), 6.12 (s, 1H), 5.57 (d, J =
30.9 Hz, 2H), 4.21 (s, 2H), 3.84 – 3.79 (m, 1H), 2.66 (t, J = 6.8 Hz, 2H), 2.41 – 2.28 (m, 2H),
1.90 (t, J = 11.5 Hz, 2H), 1.68 – 1.65 (m, 3H), 1.45 (s, 9H), 1.35 – 1.33 (m, 2H), 1.16 – 1.10 ppm
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(m, 3H); C NMR (151 MHz, CDCl3): δ = 167.9, 165.1, 133.1, 131.7, 131.3, 129.4, 128.6,
128.1, 127.4, 126.9, 125.4, 124.7, 91.6, 89.1, 81.0, 80.0, 79.1, 73.1, 59.9, 47.7, 32.4, 32.3, 30.3,
27.9, 24.9, 24.2, 24.1, 15.3 ppm; HRMS (M + Na+) calculated 565.2678, found 565.2660; IR:
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max = 3307, 2930, 1714, 1407, 1249, 814, 710 cm–1.
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ῦ
Representative example of the Passerini product (Chart 2)
4-(2-(3-(tert-butoxycarbonylamino)prop-1-ynyl)phenyl)-1-oxo-1-(2,4,4-trimethylpentan-
2-ylamino)but-3-yn-2-yl benzoate (21) Compound 21 was obtained from tertꢀbutyl 3ꢀ(2ꢀ(3ꢀ
oxopropꢀ1ꢀynyl)phenyl)propꢀ2ꢀynylcarbamate (2) (32 mg), benzoic acid (30 mg) and 1,1,3,3ꢀ
tetramethylbutyl isocyanide (42 µL) according to the general procedure in 54 % yield (33 mg,
1
0.061 mmol) as a yellow oil; H NMR (300 MHz, CDCl3): δ = 8.15 – 8.12 (m, 2H), 7.65 – 7.60
(m, 1H), 7.51 – 7.40 (m, 4H), 7.32 – 7.22 (m, 2H), 6.36 (s, 1H), 6.15 (s, 1H), 5.78 (s, 1H), 4.20
13
(s, 2H), 1.77 (d, J = 4.9 Hz, 2H), 1.49 – 1.47 (m, 15H), 1.01 ppm (s, 9H); C NMR (151 MHz,
CDCl3): δ = 164.3, 162.8, 133.3, 131.2, 129.5, 128.5, 128.3, 128.1, 127.4, 125.8, 123.8, 90.0,
85.6, 85.4, 80.6, 65.0, 55.4, 51.6, 30.9, 30.8, 28.5, 28.3, 27.9 ppm; HRMS (M + Na+) calculated
567.2835, found 567.2831; IR: ῦmax = 3324, 3127, 2953, 1681, 1409, 1366, 1246, 1303, 1026,
898, 710 cm–1.
ASSOCIATED CONTENT
Supporting Information. General methods, synthetic procedures, characterization data and
copies of 1H, 13C and HRMS spectra are included in the SI file (PDF).
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AUTHOR INFORMATION
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Corresponding Author
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*Eꢀmail address: ijeric@irb.hr
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Author Contributions
The manuscript was written through contributions of all authors. All authors have given approval
to the final version of the manuscript.
ACKNOWLEDGMENT
We thank the Croatian Science Foundation, Grant number 3102 for financial support.
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tethering group for efficient inhibition of tumor cell viability J. Mater. Chem. B 2015, 3,
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