Multicomponent synthesis of cyclic depsipeptide mimics by Ugi reaction including cyclic hemiacetals derived from asymmetric organocatalysis

Article abstract of DOI:10.1021/acs.joc.5b02158

The synthesis of novel cyclic depsipeptide mimics by means of an organocatalytic conjugate addition, leading to chiral cyclic hemiacetals, followed by a multicomponent reaction with α-amino acids and isocyanides, is described. The initial organocatalytic step is employed for the asymmetric derivatization of α,β-unsaturated aldehydes to 4,5-disubstituted 2-hydroxytetrahydropyrans, which are next used as chiral bifunctional substrates on the Ugi five-center three-component reaction, giving rise to nine-membered-ring lactones. This sequential approach proved to be suitable for the rapid generation of molecular complexity through the combination of aliphatic, dipeptidic, glucosidic, and lipidic isocyanides with several amino acids, thus giving access to amido-, glyco-, and lipo-depsipeptide scaffolds featuring natural product-like structures.

Full text of DOI:10.1021/acs.joc.5b02158

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Article
Multicomponent synthesis of cyclic depsipeptide mimics by Ugi reaction
including cyclic hemiacetals derived from asymmetric organocatalysis
Alexander Fernandez de la Torre, Daniel G. Rivera, Odette Concepción,
Radell Echemendía , Arlene G. Corrêa, and Marcio W. Paixao
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.5b02158 • Publication Date (Web): 31 Dec 2015
Downloaded from http://pubs.acs.org on January 3, 2016
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Multicomponent synthesis of cyclic depsipeptide mimics by Ugi reaction
including cyclic hemiacetals derived from asymmetric organocatalysis
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Alexander F. de la Torre,† Daniel G. Rivera,†,‡,* Odette Concepción,‡ Radell Echemendia,†,‡
Arlene G. Correa† and Márcio W. Paixão†,*
†Departamento de Química, Universidade Federal de São Carlos, São Carlos, SP, 13565ꢀ905,
Brazil.
‡Center for Natural Products Research, Faculty of Chemistry, University of Havana, Zapata y
G, 10400, La Habana, Cuba.
Corresponding Authors *Emails: dgr@fq.uh.cu (D. G. Rivera); mwpaixao@ufscar.br (M.
W. Paixão). Tel. and Fax: +55ꢀ16ꢀ33518450.
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Graphical Abstract
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Abstract
The synthesis of novel cyclic depsipeptide mimics by means of an organocatylic conjugate
addition leading to chiral cyclic hemiacetals followed by a multicomponent reaction with αꢀ
amino acids and isocyanides is described. The initial organocatalytic step is employed for the
asymmetric derivatization of α,βꢀunsaturated aldehydes to 4,5ꢀdisubstituted 2ꢀ
hydroxytetrahydropyrans, which are next used as chiral bifunctional substrates on the Ugi
fiveꢀcenter threeꢀcomponent reaction, giving rise to nineꢀmembered ring lactones. This
sequential approach proved to be suitable for the rapid generation of molecular complexity
through the combination of aliphatic, dipeptidic, glucosidic and lipidic isocyanides with
several amino acids, thus giving access to amidoꢀ, glycoꢀ and lipoꢀdepsipeptide scaffolds
featuring natural productꢀlike structures.
Keywords: multicomponent reactions, organocatalysis, Michael addition, amino acids,
peptidomimetics
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Introduction
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Isocyanideꢀbased multicomponent reactions (IꢀMCRs) traditionally stand among the most
versatile methods to produce mediumꢀsize and macrocyclic peptidomimetics.1 These
processes not only comprise great chemical efficiency and atom economy, but also enable the
easy implementation of the diversityꢀoriented synthesis (DOS) concept to cover the wider
chemical space.2 Among the IꢀMCRs, the Ugi fourꢀcomponent reaction3 – i.e., the
condensation of a primary amine, a carboxylic acid, an aldehyde/ketone and an isocyanide
leading to Nꢀsubstituted dipeptide – has been the most powerful synthetic tool to produce
naturally occurring cyclic peptides and peptidomimetics.1,2 An outstanding variation of the
Ugi reaction is the soꢀcalled Ugi fiveꢀcenter fourꢀcomponent reaction (Ugiꢀ5Cꢀ4CR),
developed in 1996.4 Ugiʼs concept behind this remarkable process was the utilization of αꢀ
amino acids as bifunctional scaffolds, leading to sixꢀmembered ring αꢀadducts that evade the
classic Mumm rearrangement, enabling the attack of a nucleophilic solvent like methanol.
Applications of this reaction include the design of chiral ligands for asymmetric catalysis5 and
of inhibitors of metalloꢀaminopeptidases6 based on the resulting 1,1´ꢀiminodicarboxylic acid
platform. Also, variants of this reaction include the Lewis acidꢀcatalyzed diastereoselective
version7 and the replacement of methanol by a further amine component for the design of a
new fourꢀcomponent reaction leading to 1,1´ꢀiminodicarboxamides.8
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An important modification of this reaction that gives access to cyclic scaffolds was developed
by Ugi himself using trifunctional scaffolds like the amino acid lysine.9 In this new variant,
named Ugi fiveꢀcenter threeꢀcomponent reaction (Ugiꢀ5Cꢀ3CR), the αꢀadduct evolves through
an intramolecular acylation of the side chain amino group leading to an αꢀaminoꢀεꢀlactam
derivative (scheme 1A). The same approach was also implemented by Kim and coworkers for
the synthesis of αꢀaminobutyrolactones using αꢀhomoserine as trifunctional scaffold.10 The
authors took advantage of the feasible intramolecular acylation also with a primary alcohol,
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and designed a new variant of the Ugiꢀ5Cꢀ3CR based on the utilization of two different
bifunctional scaffolds (i.e., a glycoaldehyde and αꢀamino acid) along with the isocyanide
component.11 An important improvement of this latter concept was made by Yudin et al. with
the development of an Ugiꢀ5Cꢀ3CR using an aziridine aldehyde and αꢀamino acids.12
Remarkably, such a chiral amphoteric scaffold enabled the highly stereoselective synthesis of
pirazinones (scheme 1B) and macrocyclic peptidomimetics, while allowing a variety of
derivatizations toward cyclopeptidic architectures.13 Just recently, both unprotected
carbohydrates and αꢀamino acids were employed as chiral bifunctional substrates for this type
of procedure, leading to the diastereoselective formation of novel cyclic glycopeptides.14
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Scheme 1. Synthetic variants of the Ugiꢀ5Cꢀ3CR with: A) a trifunctional amino acid, B and
C) two chiral bifunctional substrates.
Herein we describe a novel approach for the Ugiꢀmulticomponent synthesis of cyclic
depsipeptide mimics employing 4,5ꢀdisubstituted 2ꢀhydroxytetrahydropyrans as chiral
bifunctional substrates (scheme 1C). The overall strategy involves an initial asymmetric
organocatalytic conjugate addition of nitroethanol to α,βꢀunsaturated aldehydes followed by
an Ugiꢀ5Cꢀ3CR including the chiral cyclic hemiacetals and a variety of amino acids and
isocyanides. Recently, we initiated a synthetic program aiming at the development of new
multicomponent approaches derived from chiral hemiacetals previously generated by
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aminocatalytic transformations.15 This concept is inserted in an international endeavor to
combine the diversity and complexityꢀgenerating character of MCRs with the high
stereoselection provided by organocatalysis.16
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Results and Discussion
Our synthetic design relying on the use of chiral hemiacetals as IꢀMCR inputs seeks the
implementation of ideally oneꢀpot,15 or eventually consecutive reaction sequences leading to
complex small or mediumꢀsize heterocyclic compounds. In this study, we implement an
asymmetric conjugate addition leading to an enantioenriched cyclic hemiacetal, as this
scaffold can be included into an Ugiꢀ5Cꢀ3CR pathway by reaction with an αꢀamino acid and
an isocyanide. The rationale of using 2ꢀhydroxytetrahydropyran lies at its bifunctional
character, as the aldehyde group may react with the other Ugi components to form the αꢀ
adduct, while the appendage primary hydroxyl group undertakes the intramolecular acylation
leading to a completely new type of depsipeptide mimic (see scheme 2).
We chose an efficient approach previously developed by Hayashi and coꢀworkers as initial
organocatalytic step towards cyclic hemiacetals.17 This process comprises the conjugate
addition of nitroethanol to α,βꢀunsaturated aldehydes catalyzed by a diphenylprolinol silyl
ether, which after cyclization renders the enantioenriched 4,5ꢀdisubstituted 2ꢀ
hydroxytetrahydropyrans 1. Our original idea was to perform the organocatalytic step and the
IꢀMCR as a oneꢀpot process, but this turned out to be impractical due to the low
diastereoselectivity of the organocatalytic conjugate addition/acetalization. In their seminal
paper, Hayashi and coꢀworkers found that basedꢀmediated isomerization (i.e., stirring in a
methanolic NaHCO3 solution) after hemiacetal formation significantly favors the conversion
of the cis isomer into the more stable trans isomer, thus leading to a marked improvement in
the diastereoselectivity. This result was corroborated by our laboratory, and thus prompted the
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design of a sequential procedure instead of a oneꢀpot sequence, since the excess of base would
be adverse for the subsequent Ugiꢀ5Cꢀ3CR.
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However, the reported reaction conditions based on the use of 10 mol% of the chiral
diarylprolinol silyl ether organocatalyst and 20 mol% of benzoic acid as coꢀcatalyst at 25 °C,
did not reproduce the excellent enantioselectivity originally reported (i.e., 95% ee).17 As
shown in Table 1, good yield and diastereoselectivity were achieved with those conditions,
but only up to 83% ee was obtained after several attempts (entry 1). Consequently, further
screenings of the reaction conditions and substrate scope were carried out, keeping the
original stoichiometry, reaction time and solvent from the reported procedure.17 Thus, we
found that carrying out the reaction at 10 °C led to an important increment in enantiomeric
excess up to 95%, while both the yield and diastereoselectivity remained high (entry 2). The
decrease of the temperature to ꢀ10°C did not lead to further improvement (entry 3), while
lowering the catalyst loading to 5 mol% provoked a drop in yield, enantioꢀ and
diastereoselectivity (entry 4). The reaction conditions of entry 2, standardized for
cinammaldehyde, were also employed for the organocatalytic conjugate addition to other α,βꢀ
unsaturated aldehydes, generally resulting in good to excellent yields and stereoselectivity. A
poorer enantioselectivity was obtained for pꢀmethoxyꢀcinammaldehyde (entry 6), which also
is in contradiction with the previously reported results.17
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Once we were capable of reproducing these results and thus have access to a pool of
enantioenriched 4,5ꢀdisubstituted 2ꢀhydroxytetrahydropyrans, we turned our attention to the
synthesis of cyclic depsipeptide mimics by the Ugiꢀ5Cꢀ3CR with such chiral hemiacetals.
Cyclic depsipeptides are naturally occurring peptides composed of amino acids and at least
one hydroxy acid as amino acid surrogate, thus enabling the formation of a lactone bond in
the cyclic skeleton. A variety of natural cyclic depsipeptides have been shown to possess
antitumor, antimicrobial and antiꢀinflammatory activities,18 what makes them important
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targets for sythetic methods development in drug discovery approaches. IꢀMCRs have been
used to produce macrocyclic lactams resembling naturally occurring depsipeptides,19 but in
most cases the IꢀMCR is not responsible for the ring closure step and has never been used to
produce mediumꢀsize lactone rings.
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Table 1. Screening of reaction conditions and substrate scope of the asymmetric conjugate
addition of nitroethanol to α,βꢀunsaturated aldehydes, catalyzed by diphenylprolinol silyl
ether.
Entrya
R
Temp. (ºC) Compound Yield (%)c
drd
ee (%)e
83
1
2
Ph
25
10
ꢀ10
10
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10
10
1a
1a
1a
1a
1b
1c
1d
1e
96
95
95
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82
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88:12
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73:27
84:16
84:16
93:7
Ph
95
3
4 b
Ph
94
Ph
83
5
pꢀBrC6H4
pꢀMeOC6H4
pꢀNO2C6H4
C2H5
92
6
59
7
92
8
75:25
92
a) Reactions using 0.9 mmol (1.5 equivalents) of nitroethanol and 0.6 mmol of the
α,βꢀunsaturated aldehyde. b) Reaction using 5 mol% of catalyst. c) Yield of isolated
pure product. d) dr anti/syn determined by 1H NMR of the crude product. e)
Determined by chiralꢀphase HPLC analysis of the anti isomer.
As depicted in scheme 2, hemiacetal 1a was initially reacted with glycine in the presence of
cyclohexylisonitrile or methyl isocyanoacetate at room temperature to afford nineꢀmembered
ring depsipeptides 2a and 2b, respectively, in moderate yields after 24 h of reaction. Whereas
compounds 2a and 2b were produced with very low diastereoselectivity, this suggests that the
stereogenic centers at the hemiacetal exert no stereocontrol over the Ugiꢀmulticomponent
reaction. Unfortunately, the combination of this chiral hemiacetal with chiral αꢀamino acids
also led to poor diastereoselectivity in the formation of the new stereogenic center in
compounds 2cꢀq. However, results of marked relevance were obtained from the study of the
substrate scope, which showed that a wide range of peptidic, monosaccharidic and lipidic
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isocyanides could be efficiently combined with a variety of αꢀamino acids and hemiacetals. In
all cases, the reactions were conducted at 0.25 mol.Lꢀ1 in trifluoroethanol (TFE), conditions
that comprise the initial insolubility of the starting materials and their gradual solubilization
during the first hours of reaction.
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Scheme 2. Multicomponent synthesis of cyclic depsipeptides by Ugiꢀ5Cꢀ3CR between
cyclic chiral hemiacetals, αꢀamino acids and isocyanides.
LꢀAlanine (Ala) was chosen to assess the reaction efficiency upon variation of the isocyanide
component and 4ꢀarylꢀsubstituted 2ꢀhydroxytetrahydropyrans, in all cases providing moderate
to good yields in the Ugiꢀ5Cꢀ3CR (2c-2h, 51ꢀ77% yield). However, the use of a 2ꢀ
hydroxytetrahydropyran bearing an aliphatic group in position 3 led to the lowest product
yield (2i, 41% yield) among all hemiacetals combined with Ala. Variation of the amino acid
component further proved the potential of this protocol to produce diverse natural productꢀ
like skeletons (2j-2n); as shown, either amino acids bearing aromatic and aliphatic
hydrocarbon side chains such as Val, Leu, Phe, PhGly or those having heteroatomꢀ
functionalized side chains such as Met, His and Trp readily led to the desired nineꢀmembered
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ring lactones. The caseof compounds 2k and 2n – derived from PhGly and Trp, respectively –
that were produced only in moderate yield, parallel experiments proved that the reaction
efficiency can be enhanced up to ca. 70% yield with 72 h of reaction. However, it was not
possible to further increase the reaction yield even with longer reaction times. Finally, we
proved that this approach is well suited for the rapid generation of molecular complexity by
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the combination of a dipeptidic, a
Dꢀglucosidic and a lipidic isocyanide with varied amino
acids (2o, 2p and 2q, respectively). For compounds 2o and 2q, the yield could be increased by
setting up the reaction time at 72 h. For the synthesis of glycodepsipeptide 2p, though, the
yield could not be further improved with a longer reaction time.
Aiming to improve the diastereoselectivity of this reaction, we carried out experiments using
5 mol% of the Lewis acid catalyst Ti(OCH(CH3)2)4, which was previously reported to
effectively enhance the diastereoselection of the classic Ugiꢀ5Cꢀ3CR of amino acids with
aromatic aldehydes.7 However, even after several attempts and screening of reaction
conditions, there was no improvement in the diastereoselectivity, as it is the case of several
Ugiꢀmulticomponent processes for which there are no available stereoselective versions.
Conclusions
We have designed and implemented a new reaction sequence combining organocatalysis and
a multicomponent reaction to provide structurally novel cyclic depsipeptide mimics. The
sequential approach was initiated with an asymmetric organocatalytic conjugate addition of
nitroethanol to α,βꢀunsaturated aldehydes, followed by baseꢀmediated isomerization to the
trans isomer of 4,5ꢀdisubstituted 2ꢀhydroxytetrahydropyrans. Such enantiomerically enriched
cyclic hemiacetals were combined in an Ugi reaction with a wide variety of αꢀamino acids
and isocyanides of aliphatic, peptidic, glycosidic and lipid nature to produce polysubstituted
nineꢀmembered ring lactones featuring natural productꢀlike architectures. Whereas the
multicomponent step showed poor diastereoselectivity, the overall strategy proved a
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remarkable complexityꢀgenerating ability with the creation of three new stereocenters and the
incorporation of four components into the final cyclic depsipeptide scaffolds. The presence of
a nitro group makes these compounds suitable for further derivatization such as reduction and
coupling to amino acids for enlarging the peptide chain by the western part. Overall, the
synthetic scope of this method further proves the potential of combining the organocatalytic
functionalization of carbonyls with their subsequent multicomponent derivatization.
Experimental Section
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General
Melting points are uncorrected. 1H NMR and 13C NMR spectra were recorded at 400 MHz for
1H and 100 MHz for 13C, respectively. Chemical shifts (δ) are reported in parts per million
relative to the residual solvent signals chemical shifts are given relative to tetramethylsilane
(TMS), and coupling constants (J) are reported in hertz. High resolution ESI mass spectra
were obtained from a Fourier transform ion cyclotron resonance (FTꢀICR) mass spectrometer,
an RFꢀonly hexapole ion guide and an external electrospray ion source. Flash column
chromatography was carried out using silica gel 60 (230ꢀ400 mesh) and analytical thin layer
chromatography (TLC) was performed using silica gel aluminum sheets. HPLC
chromatograms were obtained on an apparatus with a LCꢀ10AT Pump, SPDꢀ10A UVꢀVis
Detector, SCLꢀ10A System Controller, using a Chiralpak ADꢀH (4,6 mmØ × 250 mmL,
particle size 5 ꢁm). Optical rotations were measured with a Polarimeter at 589 nm, 23 °C.
General procedure for the organocatalytic conjugate addition: Diphenylprolinol silylether
(0.06 mmol, 10 mol%) and the α,βꢀunsaturated aldehyde (0.6 mmol, 1.0 equivalent) were
dissolved in MeOH (1.2 mL). The solution was cooled to 10 °C and PhCO2H (0.12 mmol, 20
mol%) and 2ꢀnitroethanol (0.9 mmol, 3.0 equivalent) were added. The reaction mixture was
stirred for 24 h at 10 °C, then treated with NaHCO3 (3.0 mmol, 5.0 equivalent) and stirred for
another 48 h at room temperature. The resulting mixture was quenched with phosphate buffer
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(pH 7.0) and the organic material was extracted with AcOEt (3 × 3 mL), dried over anhydrous
Na2SO4 and then concentrated under reduced pressure. The resulting crude product was
purified by flash column chromatography on silica gel using nꢀhexane/EtOAc as eluent to
furnish the corresponding 5ꢀnitroꢀ4ꢀarylꢀ2ꢀhydroxytetrahydropyran. The NMR and physical
data of chiral 2ꢀhydroxytetrahydropyrans are in agreement with published data,17 see the
Supporting Information. The enantiomeric excess was determined by chiralꢀphase HPLC
analysis through comparison with the authentic racemic material. Assignment of the
stereoisomers was performed by comparison with literature data.17
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General procedure for the Ugi-5C-3CR: To a suspension of the corresponding 4,5ꢀ
disubstituted 2ꢀhydroxytetrahydropyran (0.25 mmol) and the αꢀamino acid (0.25 mmol) in
TFE (1 mL) was added slowly the isocyanide component (0.25 mmol). The resulting mixture
was stirred for 24 h at 25 °C. The volatiles were removed under pressure and the crude
product was purified by flash column chromatography on silica gel using nꢀhexane/EtOAc as
eluent. The diastereomeric ratio of final compounds was determined by 1H NMR.
Compound 2a: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol), glycine
(18.7 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted in TFE (1
mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column chromatography
purification (nꢀhexane/EtOAc 1:1) afforded 2a (57mg, 60%) as a colorless oil. Rf = 0.25 (nꢀ
hexane/EtOAc 1:1). Four diastereomers were detected. 1H NMR (400 MHz, CDCl3) δ = 7.39ꢀ
7.23 (m, 5H), 7.04, 6.96, 6.76 (3×d, J = 8.4 Hz, 1H), 4.76 (m, 1H), 4.49 (m, 1H), 4.44ꢀ4.37
(m, 1H), 3.88ꢀ3.74 (m, 1H), 3.69ꢀ3.48 (m, 1H), 3.38, 3.30, 3.24, 3.18 (4×d, J = 18.0 Hz, 2H),
2.85, 2.75, 2.68 (3×dd, J = 8.8, 3.6 Hz, J = 8.8, 5.1 Hz, J = 10.4, 2.6 Hz, 1H), 2.33, 2.18, 1.97
(3×m, 2H), 1.88ꢀ1.55 (m, 6H), 1.34 (m, 2H), 1.21ꢀ1.03 (m, 3H). 13C NMR (100 MHz, CDCl3)
δ = 171.9, 171.5, 170.9, 170.3, 137.7, 137.0, 129.5, 129.4, 129.2, 129.1, 128.4, 128.3, 128.2,
94.0, 93.3, 62.7, 62.4, 61.6, 61.2, 60.88, 60.79, 60.5, 60.4, 60.2, 60.0, 48.7, 48.6, 48.1, 47.9,
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43.2, 42.9, 37.1, 36.09, 34.4, 33.0, 25.55, 24.83. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for
C20H26N3O5: 388.18779, found 388.18710.
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Compound 2b: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
glycine (18.7 mg, 0.25 mmol), and methylisocyanoacetate (22.7 µL, 0.25 mmol) were reacted
in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2b (54 mg, 57%) as a colorless
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oil. Rf = 0.23 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.56, 7.47 (2×t, J = 5.8 Hz, 1H), 7.40ꢀ7.23 (m, 5H), 4.83ꢀ4.74 (m, 1H),
4.53ꢀ4.47 (m, 1H), 4.41 (q, J = 8.4 Hz, 1H), 4.06, 4.02, 3.99, 3.93 (4×d, J = 6.4 Hz, 2H), 3.82,
3.54 (m, 1H), 3.75, 3.74, 3.73 (3×s, 3H), 3.63ꢀ3.48, 3.44, 3.36, 3.27 (4×d, J = 18.1 Hz, 2H),
3.00, 2.95, 2.88, 2.80 (4×dd, J = 7.7, 5.7 Hz, J = 9.0, 3.6 Hz, J = 8.6, 4.9 Hz, J = 10.4, 2.6 Hz,
1H), 2.34, 2.16, 2.00, 1.78 (4×m, 2H), 1.43, 1.34, 1.26 (3×s, 1H). 13C NMR (100 MHz,
CDCl3) δ = 173.6, 173.1, 170.95, 170.4, 170.3, 137.5, 136.9, 129.5, 129.4, 129.2, 129.1,
128.4, 128.4, 94.0, 62.7, 62.3, 61.6, 60.9, 60.8, 60.5, 60.4, 59.9, 59.7, 52.5, 48.6, 43.0, 42.7,
40.9, 40.7, 36.5, 35.9. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C17H20N3O7: 378.13067, found
378.13116.
Compound 2c: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
alanine (22.3 mg, 0.25 mmol), and tertꢀbutylisocyanide (28 µL, 0.25 mmol) were reacted in
TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2c (60 mg, 64%) as a colorless
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oil. Rf = 0.57 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.44ꢀ7.18 (m, 5H), 7.04, 6.82, 6.65 (s, 1H), 4.79ꢀ4.74 (m, 1H), 4.40, 4.29
(2×m, 2H), 3.83 (m, 1H), 3.52 (m, 1H), 3.19ꢀ3.12 (m, 1H), 2.87, 2.76, 2.67, 2.56 (4×dd, J =
8.2, 3.5 Hz, J = 7.3, 6.3 Hz, J = 10.3, 2.7, J = 9.4, 4.8 Hz, 1H), 2.37, 2.18, 1.98, 1.82 (4×dd, J
= 14.5, 12.0, 2.7 Hz, 2H), 1.33, 1.28 (2×s, 9H, CH3), 1.22, 1.17, 1.03 (3×d, J = 7.1 Hz, 3H,
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CH3). 13C NMR (100 MHz, CDCl3) δ = 173.5, 172.5, 172.0, 137.7, 136.9, 129.7, 129.2,
129.0, 128.5, 128.4, 128.1, 94.0, 93.9, 93.4, 62.4, 61.7, 60.8, 60.7, 60.4, 60.3, 59.7, 59.2, 58.7,
55.2, 50.9, 50.7, 43.0, 42.8, 42.4, 37.9, 35.4, 29.8, 28.7, 28.6, 28.4, 19.5, 18.4. HRMS (ESIꢀ
FTꢀICR) [MꢀH]ꢀ calcd. for C19H26N3O5: 376.18779, found 376.18704
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Compound 2d: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
alanine (22.3 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted in
TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2d (78 mg, 77%) as a colorless
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oil. Rf = 0.50 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.46ꢀ7.20 (m, 5H, Ph), 7.25, 7.02, 6.84, 6.72 (4×d, J = 8.3 Hz, 1H), 4.77
(m, 1H, Hꢀ8), 4.21ꢀ4.12 (m, 2H, Hꢀ9), 3.82 (m, 1H, Hꢀ7), 3.69ꢀ3.62 (m, 1H, Hꢀ13), 3.21ꢀ3.19
(m, 1H, Hꢀ3), 2.96, 2.82, 2.78, 2.65 (4×dd, J = 7.9, 3.7 Hz, J = 7.6, 5.9 Hz, J = 10.2, 2.8 Hz, J
= 9.2, 4.8 Hz, 1H), 2.38, 2.18, 2.03 (3×m, 2H, Hꢀ6), 1.94ꢀ1.56 (m, 6H), 1.36ꢀ1.00 (m, 5H),
1.22, 1.14, 0.99 (3×d, J = 7.1 Hz, 3H, Hꢀ10). 13C NMR (100 MHz, CDCl3) δ= 173.5, 173.1,
173.0 (C=O, Cꢀ2), 172.4, 172.2, 171.8 (C=O, Cꢀ11), 138.3, 137.6, 137.0 (C, Cꢀ19), 129.6,
129.3, 129.2, 129.0, 128.5, 128.4, 128.1 (CH, Cꢀ20ꢀ24), 94.1, 94.0, 93.5 (CH, Cꢀ8), 62.5,
62.4, 61.8, 60.7, 60.4, 60.3 (CH2, Cꢀ9), 59.7, 59.2, 59.1, 58.6 (CH, Cꢀ5), 55.3, 55.1 (CH, Cꢀ3),
48.3, 48.1, 47.7 (CH, Cꢀ13), 43.0, 42.8, 42.4 (CH, Cꢀ7), 37.6, 36.4, 35.3 (CH2, Cꢀ6), 33.5,
33.0, 32.7 (CH2), 25.5, 24.8 (CH2), 19.4, 19.3, 18.4, 18.1 (CH3, Cꢀ10). HRMS (ESIꢀFTꢀICR)
[MꢀH]ꢀ calcd. for C21H28N3O5: 402.20344, found 402.20197.
Compound 2e: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
alanine (22.3 mg, 0.25 mmol), and methylisocyanoacetate (22.7 µL, 0.25 mmol) were reacted
in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2e (65.9 mg, 67%) as a light
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yellow oil. Rf = 0.20 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR
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(400 MHz, CDCl3) δ = 7.68, 7.51 (2×t, J = 6.0 Hz, 1H), 7.42ꢀ7.23 (m, 5H), 4.77 (m, 1H),
4.54, 4.41 (2×m, 2H), 4.29ꢀ4.22 (m, 1H), 3.95 (t, J = 5.8 Hz, 1H), 3.75, 3.72, 3.71 (4×s, 1H),
3.65ꢀ3.43 (m, 2H), 3.27 (m, 1H), 3.04, 2.94, 2.87, 2.79 (4×dd, J = 8.3, 3.6 Hz, J = 7.7, 5.5 Hz,
J = 10.1, 2.8 Hz, J = 8.9, 4.8 Hz, 1H), 2.42, 2.27, 1.95, 1.83 (m, 2H), 1.47, 1.42, 1.17, 1.05
(4×d, J = 7.0 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 174.2, 174.0, 173.7, 173.24, 173.20,
171.3, 170.2, 137.5, 136.9, 129.7, 129.3, 129.2, 128.6, 128.5, 128.4, 128.2, 94.1, 93.9, 93.6,
93.5, 62.5, 62.3, 61.8, 61.7, 60.9, 60.7, 60.5, 60.3, 59.0, 58.4, 56.3, 55.4, 55.0, 54.8, 52.6,
52.5, 52.4, 42.8, 42.7, 42.4, 42.0, 41.0, 40.9, 40.7, 40.3, 37.0, 35.2, 33.7, 32.2, 21.1, 19.4,
18.3, 18.1, 16.9, 14.2. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C18H22N3O7: 392.14632, found
392.14630.
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Compound 2f: 4ꢀ(4ꢀbromophenyl)ꢀ5ꢀnitrotetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1b, 32.3 mg, 0.125
mmol), Lꢀalanine (22.3 mg, 0.125 mmol), and cyclohexylisocyanide (14 µL, 0.125 mmol)
were reacted in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash
column chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2f (84 mg, 70%) as a
colorless oil. Rf = 0.30 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. 1H NMR
(400 MHz, CDCl3) δ = 7.53, 7.49, 7.48 (3×d, J = 8.4 Hz, 2H), 7.20, 7.15, 7.11 (3×d, J = 8.4
Hz, 2H), 6.94, 6.89, 6.77 (3×d, J = 8.1 Hz, 1H), 4.71 (m, 1H), 4.49ꢀ4.42 (m, 2H), 4.25 (m,
1H), 4.12 (m, 1H), 3.77 (m, 1H), 3.60 (m, 1H), 3.52 (m, 1H), 3.19 (m 1H), 2.95, 2.75, 2.61
(3×dd, J = 7.7, 4.4 Hz, J = 10.1, 2.9 Hz, J = 9.9, 4.5 Hz, 1H), 2.33, 2.12, 2.03 (3×m, 2H), 1.79
(m, 2H), 1.35 (m, 4H), 1.24, 1.19, 1.11 (3×d, J = 7.2 Hz, 3H, CH3), 1.28ꢀ1.07 (m, 3H). 13C
NMR (100 MHz, CDCl3) δ = 173.7, 172.0, 171.5, 137.3, 136.6, 136.1, 132.8, 132.5, 132.4,
130.3, 130.1, 93.6, 93.4, 92.9, 62.2, 61.7, 60.9, 60.5, 58.9, 58.6, 55.4, 55.1, 48.2, 47.7, 42.2,
42.1, 41.8, 37.5, 35.4, 33.0, 32.8, 25.5, 24.8, 19.6, 18.5, 18.3. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ
calcd. for C21H27BrN3O5: 480.11396, found 480.11322.
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Compound 2g: 4ꢀ(4ꢀmethoxyphenyl)ꢀ5ꢀnitrotetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1c, 63.3 mg, 0.25
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chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2g (57 mg, 51%) as a colorless
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oil. Rf = 0.50 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.20, 7.16, 7.13 (3×d, J = 8.8 Hz, 2H), 6.91, 6.88, 6.87 (3×d, J = 8.7 Hz,
2H), 7.07, 6.83 (d, J = 8.2 Hz, 1H), 4.71 (m, 1H), 4.52 (m, 1H), 4.39 (m, 1H), 4.31ꢀ4.20 (m,
1H), 4.16ꢀ4.10 (m, 1H), 3.81, 3.79, 3.78 (3×s, 3H), 3.58 (m, 1H), 3.35 (m, 1H), 3.24ꢀ3.12 (m,
1H), 2.95, 2.85, 2.78, 2.68 (4×dd, J = 8.1, 3.6 Hz, J = 11.5, 6.2 Hz, J = 10.1, 2.5 Hz, J = 9.1,
4.8 Hz, 1H), 2.38, 2.20, 2.05 (3×m, 2H), 1.91ꢀ1.56 (m, 6H), 1.43ꢀ1.03 (m, 5H), 1.22, 1.17,
1.06 (3×d, J = 7.1 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 173.6, 173.2, 172.4, 171.8,
159.6, 159.3, 129.5, 129.4, 128.5, 115.0, 114.7, 114.6, 94.1, 93.6, 62.5, 62.4, 61.8, 60.8, 60.5,
59.2, 58.78, 58.70, 58.5, 55.4, 55.3, 55.2, 48.1, 47.7, 42.3, 42.0, 41.7, 37.6, 35.4, 33.7, 33.0,
32.8, 29.8, 25.5, 24.8, 19.5, 18.4, 18.2. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C22H30N3O6:
432.21401, found 432.21249.
Compound 2h: 4ꢀ(4ꢀnitrophenyl)ꢀ5ꢀnitrotetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1d, 67 mg, 0.25 mmol),
Lꢀalanine (22.3 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted
in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2h (45 mg, 71%) as a colorless
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oil. Rf = 0.30 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 8.19, 8.17, 8.14 (3×d, J = 8.7 Hz, 2H), 7.47, 7.43, 7.36 (3×d, J = 8.8 Hz,
2H), 6.92, 6.89, 6.82 (3×d, J = 8.7 Hz, 1H, NH), 4.70 (m, 1H), 4.43, 4.19 (m, 2H), 3.64 (m,
1H), 3.54 (m, 1H), 3.19 (q, J = 7.2 Hz, 1H), 3.10, 2.85, 2.66, 2.49 (4×dd, J = 14.7, 6.6 Hz, J =
8.2, 4.8 Hz, J = 9.8, 3.2 Hz, J = 10.2, 4.3 Hz, 1H), 2.31, 2.11, 1.90 (3×m, 2H), 1.90ꢀ1.50 (m,
6H), 1.19, 1.15, 1.10 (3×d, J = 7.1 Hz, 3H, CH3), 1.36ꢀ0.99 (m, 5H). 13C NMR (100 MHz,
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CDCl3) δ = 173.6, 173.0, 171.7, 171.2, 147.8, 147.6, 145.1, 144.8, 129.6, 129.5, 129.4, 124.5,
124.2, 124.1, 93.0, 92.8, 92.4, 61.9, 58.6, 58.3, 55.3, 54.9, 48.1, 47.6, 42.1, 37.3, 35.6, 33.0,
32.9, 32.7, 25.4, 24.7, 19.5, 18.3, 18.2. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C21H27N4O7:
447.18852, found 447.18777.
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Compound 2i: 4ꢀethylꢀ5ꢀnitrotetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1e, 15 mg, 0.07 mmol), Lꢀalanine (5
mg, 0.07 mmol), and cyclohexylisocyanide (7 µL, 0.07 mmol) were reacted in TFE (1 mL)
according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column chromatography
purification (nꢀhexane/EtOAc 1:1) afforded 2i (10.2 mg, 41%) as a colorless oil. Rf = 0.50 (nꢀ
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hexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400 MHz, CDCl3) δ =
7.11, 7.06, 6.92, 6.73 (d, J = 8.8 Hz, 1H), 4.84ꢀ4.36 (m, 2H), 4.25ꢀ4.00 (m, 1H), 3.89 (m, 1H),
3.73 (m, 1H), 3.50, 3.35 (2×m, 1H), 3.27, 3.16, 3.07, 2.98 (4×dd, J = 8.0, 6.1 Hz, J = 13.3, 6.9
Hz, J = 8.2, 5.6 Hz, 1H), 2.22 (m, 1H), 1.97ꢀ1.09 (m, 13H), 1.40, 1.36 (2×d, J = 7.0 Hz, 3H),
0.97 (dt, J = 14.4, 4.7 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 174.0, 173.9(C=O), 172.8,
172.8 (C=O), 90.9, 90.5, 90.2 (CH), 61.2, 61.0, 60.8 (CH2), 59.8, 58.7 (CH), 55.4, 55.2 (CH),
48.0, 47.8, 47.2 (CH), 37.4, 37.2, 36.8 (CH), 34.9, 34.6 (CH2), 33.1, 32.8 (CH2), 25.5, 24.9,
24.8 (CH2), 24.3, 23.7, 23.3, 23.1 (CH2), 19.7, 18.0 (CH3), 11.1, 11.0, 10.8 (CH3). HRMS
(ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C17H28N3O5: 354.20344, found 354.20346.
Compound 2j: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
valine (29.3 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted in
TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2j (75mg, 70%) as a colorless
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oil. Rf = 0.45 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.42ꢀ7.19 (m, 5H), 7.05, 6.91, 6.58 (d, J = 8.8 Hz, 1H), 4.79ꢀ4.70 (m, 1H),
4.51, 4.35 (2×dd, J = 12.7, 8.5 Hz, 1H), 4.21ꢀ4.06 (m, 1H), 3.89ꢀ3.75 (m, 1H), 3.73ꢀ3.50 (m,
1H), 2.97, 2.89, 2.70, 2.59 (4×dd, J = 9.9, 2.7 Hz, J = 9.6, 4.8 Hz, 1H), 2.32, 2.18, 2.08
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(3×ddd, J = 14.5, 11.8, 2.9 Hz, 3H), 1.93ꢀ1.60 (m, 6H), 1.45ꢀ0.76 (m, 5H), 1.04 (d, J = 6.8
Hz, 1H), 0.97, 0.90, 0.80 (3×d, J = 6.9 Hz, 6H), 0.92, 0.77 (2×d, J = 7.0 Hz, 3H). 13C NMR
(100 MHz, CDCl3) δ = 172.9, 172.6, 172.4, 171.6, 137.4, 129.6, 129.2, 128.6, 128.5, 128.4,
128.1, 94.1, 93.9, 66.4, 65.6, 62.50, 60.57, 60.1, 59.2, 48.2, 47.8, 43.0, 42.8, 38.0, 36.3, 33.1,
32.8, 31.8, 31.3, 25.6, 24.8, 19.8, 18.7, 18.4, 17.4. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for
C23H32N3O5: 430.23474; found 430.23441.
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Compound 2k: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
methionine (37.3 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were
reacted in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2k (75 mg, 72%) as a colorless
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oil. Rf = 0.45 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.46ꢀ7.19 (m, 5H), 6.86, 6.82, 6.48 (3×d, J = 8.3 Hz, 1H), 4.74 (m, 1H),
4.51 (dd, J = 12.7, 8.4 Hz, 1H), 4.40 (dd, J = 12.7, 8.4 Hz, 1H), 4.22, 4.12 (2×dd, J = 16.7, 8.4
Hz, 1H), 3.78 (m, 1H), 3.69ꢀ3.50 (m, 2H), 3.31 (m, 1H), 2.74, 2.65, 2.54, 2.50 (4×dd, J =
12.8, 8.1 Hz, J = 11.9, 5.9 Hz, J = 8.3, 5.1 Hz, J = 8.3, 5.1 Hz, 1H), 2.31, 2.09 (2×m, 1H),
2.07, 2.05, 2.04, 2.03 (4×s, 3H), 1.67 (m, 8H), 1.23 (m, 6H). 13C NMR (100 MHz, CDCl3) δ =
172.6, 172.1, 137.3, 129.7, 129.2, 128.6, 128.4, 93.9, 62.5, 59.2, 58.9, 48.3, 42.7, 36.3, 33.1,
32.90, 32.10, 30.0, 25.5, 24.9, 15.3. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C23H32N3O5S:
462.20627, found 462.20670.
Compound 2l: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
phenylglycine (37.8 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were
reacted in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2l (63mg, 54%) as a colorless
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oil. Rf = 0.40 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ = 7.49ꢀ6.88 (m, 10H), 4.95ꢀ4.61 (m, 1H), 4.58ꢀ4.21 (m, 1H), 4.21ꢀ3.91 (m,
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1H), 3.84 (m, 1H), 3.73ꢀ3.41 (m, 1H), 3.37ꢀ2.69 (m, 3H), 2.68ꢀ2.22 (m, 1H), 2.00ꢀ1.45 (m,
7H), 1.44ꢀ0.91 (m, 8H). 13C NMR (100 MHz, CDCl3) δ= 172.3, 171.6, 137.9, 129.8, 129.2,
129.0, 128.9, 128.3, 128.1, 127.5, 93.4, 62.3, 61.7, 51.1, 48.9, 48.2, 47.2, 43.3, 42.3, 39.2,
34.7, 33.1, 32.6, 25.5, 24.8. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C26H30N3O5: 464.21800,
found 464.21838.
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Compound 2m: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol), Lꢀ
histidine (38.8 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted
in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2m (82mg, 70%) as an orange
solid. Mp = 96ꢀ99 °C. Rf = 0.45 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected.
1H NMR (400 MHz, CDCl3) δ = 7.70, 7.68, 6.94, 6.91 (4×s, 1H), 7.54, 7.51, 6.77, 6.72 (4×d,
J = 2.98 Hz, 1H), 7.45ꢀ7.25 (m, 5H), 7.09, 7.00 (2×d, J = 6.9 Hz, 1H), 4.73 (m, 1H), 4.54ꢀ
4.40 (m, 1H), 4.36ꢀ4.24 (m, 1H), 4.01 (m, 1H), 3.81, 3.71 (2×d, J = 8.6 Hz, 2H), 3.64ꢀ3.36
(m, 2H), 3.25ꢀ2.95 (m, 1H), 2.91, 2.81, 2.71, 2.65 (4×dd, J = 14.5, 8.7 Hz, J = 7.9 Hz, 10.5
Hz, 1H), 2.36, 2.25 (2×m, 2H), 1.94ꢀ1.56 (m, 6H), 1.36ꢀ1.00 (m, 5H). 13C NMR (100 MHz,
CDCl3) δ = 173.0, 172.9, 172.6, 137.9, 137.1, 137.1, 136.1, 135.3, 129.5, 129.1, 128.9, 128.3,
128.1, 128.0, 124.2, 121.4, 116.1, 112.7, 94.5, 94.5, 94.4, 62.3, 61.6, 61.3, 60.7, 60.4, 60.0,
59.6, 48.3, 43.0, 42.6, 37.2, 36.0, 32.9, 32.8, 32.6, 30.5, 25.5, 25.4, 24.93, 24.89. HRMS (ESIꢀ
FTꢀICR) [MꢀH]ꢀ calcd. for C24H30N5O5: 468.22469, found 468.22278.
Compound 2n: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
tryptophan (51.1 mg, 0.25 mmol), and cyclohexylisocyanide (31 µL, 0.25 mmol) were reacted
in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2n (54 mg, 42%) as a yellow
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solid. Mp = 90ꢀ95 °C. Rf = 0.10 (Hex/EtOAc 1:1). Four diastereoisomers were detected. H
NMR (400 MHz, CDCl3) δ = 8.77, 8.26, 8.07 (3×s, 1H), 7.70ꢀ7.64 (m, 1H), 7.51ꢀ7.41 (m,
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1H), 7.39ꢀ7.05 (m, 7H), 7.01, 6.59 (d, J = 6.6 Hz, 1H, NH(amide)), 6.35, 6.33, 6.32 (3×s, 1H),
4.77ꢀ4.69 (m, 1H), 4.53, 4.32 (2×m, 2H), 4.54ꢀ4.38 (m, 1H), 2.88, 2.81, 2.74, 2.64 (4×dd, J =
14.5, 10.4 Hz, J = 10.6, 3.9 Hz, J = 14.6, 9.6 Hz, J = 9.3, 4.7 Hz, 1H), 2.40, 2.20 (2×m, 2H),
1.86ꢀ1.41 (m, 8H), 1.38ꢀ1.05 (m, 6H). 13C NMR (100 MHz, CDCl3) δ = 173.2, 173.0, 172.6,
171.8, 138.2, 137.2, 136.7, 136.4, 129.1, 128.9, 128.6, 128.2, 127.2, 123.6, 123.2, 122.8,
122.5, 120.1, 118.7, 118.5, 112.1, 111.6, 111.0, 110.2, 93.6, 93.5, 93.5, 61.9, 61.7, 61.3,
61.30, 60.33, 59.7, 48.3, 47.5, 47.2, 43.2, 42.4, 36.4, 34.7, 33.1, 32.6, 32.0, 29.7, 29.3, 25.5,
24.8. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for C29H33N4O5: 517.24564, found 517.24359.
Compound 2o: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 27.9 mg, 0.1 mmol), Lꢀ
leucine (16.4 mg, 0.1 mmol), and CNꢀGlyꢀPheꢀOMe15 (30.8 mg, 0.1 mmol) were reacted in
TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2o (26.8 mg, 46%) as a yellow
solid. Mp = 82ꢀ86 °C. Rf = 0.15 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected.
1H NMR (400 MHz, CDCl3) δ = 7.55 (dt, J = 10.5, 5.3 Hz, 1H), 7.44ꢀ6.98 (m, 10H), 6.65,
6.54, 6.43, 6.36 (4×d, J = 6.8 Hz, 1H), 4.93ꢀ4.66 (m, 1H), 4.48ꢀ4.20 (m, 1H), 4.16ꢀ3.93 (m,
1H), 3.73, 3.70, 3.69 (3×s, 3H), 3.87ꢀ3.44 (m, 1H), 3.26ꢀ2.96 (m, 1H), 3.08, 2.84, 2.73, 2.70
(4×dd, J = 14.0, 5.9 Hz, 1H), (d, J = 4.9 Hz, 1H), (dd, J = 8.9, 3.5 Hz, 1H), (dd, J = 10.4, 2.9
Hz, 1H), 2.41, 2.18, 2.00 (3×m, 2H), 1.81ꢀ1.15 (m, 5H), 0.93, 0.90 (2×d, J = 6.4 Hz, 3H),
0.87, 0.80 (2×d, J = 6.6 Hz, 3H). 13C NMR (100 MHz, CDCl3) δ = 174.1, 173.3, 171.8, 171.6,
170.5, 168.6, 137.0, 135.88, 135.85, 129.8, 129.5, 129.3, 129.2, 128.7, 128.6, 128.5, 127.4,
127.3, 127.1, 93.9, 93.9, 93.8, 62.5, 62.3, 59.5, 59.3, 59.1, 53.5, 53.4, 53.1, 52.6, 52.5, 52.4,
43.1, 42.8, 42.6, 37.90, 37.86, 37.1, 36.4, 24.8, 24.7, 22.8, 22.6, 22.5. HRMS (ESIꢀFTꢀICR)
[MꢀH]ꢀ calcd. for C30H37N4O8: 581.26031; found 581.26169.
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Compound 2p: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
phenylalanine (41.3 mg, 0.25 mmol), and βꢀ
D
ꢀglucosyl isocyanide20 (89.3 mg, 0.25 mmol)
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were reacted in TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash
column chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2p (58.2 mg, 32%) as a
light yellow solid. Mp = 91ꢀ96 °C. Rf = 0.5 (nꢀhexane/EtOAc 1:1). Four diastereoisomers
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1
were detected. H NMR (400 MHz, CDCl3) δ = 7.45ꢀ7.22 (m, 10H), 7.00, 6.83 (2×d, J = 9.2
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Hz, 1H, NH), 5.28 (dd, J = 15.2, 5.7 Hz, 1H), 5.12 (dd, J = 9.3 Hz, 1H), 5.07 (m, 1H), 4.87
(dd, J = 9.5 Hz, 1H), 4.61 (m, 1H), 4.50 (dd, J = 12.7, 8.5 Hz, 1H), 4.32ꢀ4.21 (m, 2H), 4.05
(dd, J = 12.4, 2.0 Hz, 1H), 3.78 (m, 1H), 3.68 (dd, J = 12.4, 8.3 Hz, 1H), 3.45 (dd, J = 12.4,
2.0 Hz, 1H), 3.17ꢀ3.10 (m, 1H), 2.99, 2.78, 2.59 (3×dd, J = 13.8, 4.7 Hz, J = 13.7, 9.0 Hz, J =
10.9, 4.1 Hz, 1H), 2.06 (s, 3H), 2.03 (s, 3H), 2.02 (s, 3H), 2.01 (s, 3H), 1.65 (d, J = 7.4 Hz,
3H), 1.53ꢀ1.10 (m, 3H). 13C NMR (100 MHz, CDCl3) δ= 174.2, 171.9, 171.1, 170.7, 170.0,
169.6, 137.0, 136.7, 129.79, 129.71, 128.9, 128.5, 128.1, 127.3, 93.8, 78.3, 73.7, 72.8, 70.7,
68.1, 62.5, 61.6, 60.6, 58.8, 42.2, 39.2, 36.8, 20.7. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for
C35H40N3O14: 726.25103; found 726.25049.
Compound 2q: 5ꢀnitroꢀ4ꢀphenylꢀtetrahydroꢀ2Hꢀpyranꢀ2ꢀol (1a, 55.8 mg, 0.25 mmol),
Lꢀ
alanine (22.3 mg, 0.25 mmol), and nꢀoctylisocyanide15 (44 µL, 0.25 mmol) were reacted in
TFE (1 mL) according to the general Ugiꢀ5Cꢀ3CRꢀbased procedure. Flash column
chromatography purification (nꢀhexane/EtOAc 1:1) afforded 2q (55 mg, 51%) as a colorless
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oil. Rf = 0.50 (nꢀhexane/EtOAc 1:1). Four diastereoisomers were detected. H NMR (400
MHz, CDCl3) δ= 7.42ꢀ7.19 (m, 5H), 7.12, 6.96, 6.86 (3×t, J = 5.6 Hz, 1H), 4.77 (m, 1H),
4.51, 4.40 (2×m, 2H), 4.28 (m, 1H), 3.82 (m, 1H), 3.53 (m, 1H), 3.23 (m, 1H), 2.98, 2.87,
2.78, 2.69 (4×dd, J = 7.6, 3.8 Hz, J = 11.2, 5.1 Hz, J = 10.1, 2.7 Hz, J = 9.0, 4.9 Hz, 1H),
2.38, 2.18, 1.86, 1.78 (4×m, 2H), 1.45 (m, 2H), 1.27 (br. s, 8H), 1.21, 1.15, 1.00 (3×d, J = 7.0
Hz, 3H, CH3), 0.88 (t, J = 7.1, 3.4 Hz, 3H, CH3). 13C NMR (100 MHz, CDCl3) δ= 173.6,
173.3, 173.2, 173.1, 172.6, 138.4, 137.7, 137.0, 129.6, 129.4, 129.2, 129.1, 128.9, 128.6,
128.5, 128.4, 128.1, 127.3, 94.1, 94.0, 93.5, 62.5, 62.4, 61.8, 60.8, 60.7, 60.5, 60.3, 59.3, 59.1,
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58.6, 55.4, 55.2, 55.1, 43.2, 43.0, 42.8, 42.4, 39.6, 39.4, 39.1, 37.4, 35.3, 33.4, 31.8, 29.59,
29.52, 29.3, 27.0, 22.7, 19.4, 18.4, 18.1, 14.1. HRMS (ESIꢀFTꢀICR) [MꢀH]ꢀ calcd. for
C23H34N3O5: 432.25039; found 432.25018.
9
Acknowledgements
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A. F. de la Torre and R. Echemendia are grateful to CNPq and CAPES, respectively, for PhD
fellowships. D. G. Rivera thanks FAPESP for a Visiting Professor grant. We also gratefully
acknowledge financial support from CNPq (INCTꢀCatálise), CAPES (CAPESꢀMES/Cuba
Program) and FAPESP (14/50249-8 and 15/17141-1).
1
Supporting Information. H, 13C NMR and HRMS (ESIꢀFTꢀICR) m/z spectra of medium
sized cyclic peptidomimetics and chiralꢀphase HPLC analysis of Michael adducts. This
material is available free of charge via the Internet at http://pubs.acs.org.
References
1. (a) Rotstein, B. H.; Zaretsky, S.; Rai, V.; Yudin, A. K. Chem. Rev. 2014, 114, 8323. (b)
Koopmanschap, G.; Ruijter, E.; Orru, R. V. A. Beilstein J. Org. Chem. 2014, 10, 544. (c)
White, C. J.; Yudin, A. K. Nature Chem. 2011, 3, 509. (d) Masson, G.; Neuville, L.; Bughin,
C.; Fayol, A.; Zhu, J. Top. Heterocycl. Chem. 2010, 25, 1. (e) Wessjohann, L. A.; Rhoden, C.
R. B.; Rivera, D. G.; Vercillo, O. E. Top. Heterocycl. Chem. 2010, 23, 19. (f) Wessjohann, L.
A.; Rivera, D. G. Vercillo, O. E. Chem. Rev. 2009, 109, 796.
2. (a) Brauch, S.; van Berkel, S. S.; Westermann, B. Chem. Soc. Rev. 2013, 42, 4948. (b)
Dömling, A.; Wang, W.; Wang, K. Chem. Rev. 2012, 112, 3083. (c) Ruijter, E.; Scheffelaar,
R.; Orru, R. V. A. Angew. Chem. Int. Ed. 2011, 50, 6234. (d) Dömling, A. Chem. Rev. 2006,
106, 17. (e) Dömling, A.; Ugi, I. Angew. Chem. Int. Ed. 2000, 39, 3168.
3. Ugi, I.; Meyr, R.; Fetzer, U.; Steinbrücker, C. Angew. Chem. 1959, 71, 386.
4. Demharter, A.; Hörl, W.; Herdtweck, E.; Ugi, I. Angew. Chem. Int. Ed. Engl. 1996,35,
173.
5. Dycker, G.; Breitenstein, K.; Henke, G. Tetrahedron: Asymmetry 2002, 13, 1929.
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Page 22 of 23
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5
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7
6. (a) Méndez, Y.; PérezꢀLabrada, K.; GonzálezꢀBacerio, J.; Valdés, G.; de los Á. Chávez, M.;
Osuna, J.; Charli, J.ꢀL.; Pascual, I. Rivera, D. G. ChemMedChem 2014, 9, 2351. (b)
Thormann, M.; Almstetter, M. WO 2004099124.
8
9
7. Godet, T.; Bonvin, Y.; Vincent, G.; Merle, D.; Thozet, A.; Ciufolini, M. A. Org. Lett.
2004, 6, 3281.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
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41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
8. (a) Sinha, M. K.; Khoury, K.; Herdtweck, E.; Dömling, A. Org. Biomol. Chem. 2013, 11,
4792. (b) Khoury, K.; Sinha, M. K.; Nagashima, T.; Herdtweck, E.; Dömling, A. Angew.
Chem. Int. Ed. 2012, 51, 10280.
9. Ugi, I.; Demharter, A.; Hörl, W.; Schmidt, T. Tetrahedron 1996, 52, 11657.
10. Park, S. J.; Keum, G.; Kang, S. B.; Koh, H. Y.; Kim, Y.; Lee, D. H. Tetrahedron Lett.
1998, 39, 7109.
11. Kim, Y. B.; Choi, E. H.; Keum, G.; Kang, S. B.; Lee, D. H.; Koh, H. Y.; Kim, Y. Org.
Lett. 2001, 3, 4149.
12. Hili, R.; Rai, V.; Yudin, A. K. J. Am. Chem. Soc. 2010, 132, 2889.
13. (a) White, C. J.; Hickey, J. L.; Scully, C. C. G.; Yudin, A. K. J. Am. Chem. Soc. 2014,
136, 3728. (b) Zaretsky, S.; Scully, C. C. G.; Lough, A. J.; Yudin, A. K. Chem. Eur. J. 2013,
19, 17668. (c) Scully, C. C. G.; Rai, V.; Poda, G.; Zaretsky, S.; Burns, D. C.; Houliston, R. S.;
Lou, T.; Yudin, A. K. Chem. Eur. J. 2012, 18, 15612.
14. Voigt, V.; Mahrwald, R. Org. Lett. 2015, 17, 2606.
15. Echemendía, R.; de la Torre, A. F.; Monteiro, J. L.; Pila, M.; Corrêa, A. G.; Westermann,
B.; Rivera, D. G.; Paixão, M. W. Angew. Chem. Int. Ed. 2015, 54, 7621.
16. (a) Banfi, L.; Basso, A.; Moni, L.; Riva, R. Eur. J. Org. Chem. 2014, 1989. (b) Moni, L.;
Banfi, L.; Basso, A.; Galatini, A.; Spallarossa, M.; Riva, R. J. Org. Chem. 2014, 79, 339. (c)
Morana, F. ; Basso, A.; Riva, R.; Rocca, V.; Banfi, L. Chem. Eur. J. 2013, 19, 4563. (d)
Deobald, A. M.; Correa, A. G.; Rivera, D. G.; Paixão, M. W. Org. Biomol. Chem. 2012, 10,
7681. (e) Dickmeiss, G.; Jensen, K. L.; Worgull, D.; Franke, P. T.; Jørgensen, K. A. Angew.
Chem. Int. Ed. 2011, 50, 1580. (f) Riguet, E. J. Org. Chem. 2011, 76, 8143. (g) Umbreen, S.;
Brockhaus, M.; Ehrenberg, H.; Schmidt, B. Eur. J. Org. Chem. 2006, 4585.
17. Gotoh, H.; Okamura, D.; Ishikawa, H.; Hayashi, Y. Org. Lett. 2009, 11, 4056.
18. (a) Blunt, J. W.; Copp, B. R.; Munro, M. H. G.; Northcote, P. T.; Prinsep, M. R. Nat.
Prod. Rep. 2010, 27, 165. (b) Sarabia, F.; Chammaa, S.; Ruiz, A. S.; Ortiz, L. M.; Herrera, F.
22
ACS Paragon Plus Environment

Page 23 of 23
The Journal of Organic Chemistry
1
2
3
4
5
6
7
8
9
J. L. Curr. Med. Chem. 2004, 11, 1309. (c) Hamel, E.; Covell, D. G. Curr. Med. Chem.: Antiꢀ
Cancer Agents 2002, 2, 19. (d) Takusagawa, F. J. Antibiot. 1985, 38, 1596.
19. (a) Barreto, A. F. S.; Vercillo, Wessjohann, L. A.; Andrade, C. K. Z. Beilstein J. Org.
Chem. 2014, 10, 1017. (b) Socha, A. M.; Tan, N. Y.; LaPlante, K. L.; Sello, J. K. Bioorg.
Med. Chem. 2010, 18, 7193. (c) León, F.; Rivera, D. G.; Wessjohann, L. A. J. Org. Chem.
2008, 73, 1762. (d) Beck, B.; Larbig, G.; Mejat, B.; MagninꢀLachaux, M.; Picard, A.;
Herdtweck, E.; Dömling, A. Org. Lett. 2003, 5, 1047. (e) Zhao, G.; Sun, X.; Bienaymé, H.;
Zhu, J. J. Am. Chem. Soc. 2001, 123, 6700.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
20. (a) Ichikawa, Y.; Nishiyama, T.; Isobe, M. Synlett., 2000, 9, 1253. (b) Badía, C.; Souard,
F.; Vicent, C. J. Org. Chem., 2012, 77, 10870.
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