Azotides as Modular Peptide-Based Ligands for Asymmetric Lewis Acid Catalysis

Article abstract of DOI:10.1021/acs.joc.9b00732

Synthesis of azotides and evaluation of these as ligands for enantioselective Lewis acid catalysis is reported. The ligands were readily prepared from the chiral pool of amino acids and perform well in the cobalt(II)-catalyzed formation of asymmetric hete

Full text of DOI:10.1021/acs.joc.9b00732

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Article
Azotides as Modular Peptide-Based Ligands
for Asymmetric Lewis Acid Catalysis
Christian Borch Borch Jacobsen, Daniel Steen Nielsen, Morten Meldal, and Frederik Diness
J. Org. Chem., Just Accepted Manuscript • Publication Date (Web): 29 Apr 2019
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The Journal of Organic Chemistry
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Azotides as Modular Peptide-Based Ligands for Asymmetric Lewis
Acid Catalysis
Christian Borch Jacobsen, Daniel Steen Nielsen, Morten Meldal* and Frederik Diness*
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Center for Evolutionary Chemical Biology, Department of Chemistry, University of Copenhagen, Universitetsparken 5,
2100 Copenhagen, Denmark
O
S
Easy synthesis
R
O
N
O
N
Co2+
HN
O
Modulable ligands
O
ABSTRACT: Synthesis of azotides and evaluation of these as ligands for enantioselective Lewis Acid catalysis is reported. The
ligands were readily prepared from the chiral pool of amino acids. The ligands perform well in the cobalt(II) catalyzed formation of
asymmetric hetero Diels-Alder adducts. A rational for the observed enantioselectivity and conversion rate supported by
computational calculations is provided.
Introduction
azolines that can act as metal-coordinating moieties, this
class of compounds does appear to be intriguing starting
points for developing green ligands for asymmetric metal
catalysis.
Azotides,1 peptides with azole or azoline moieties in the
backbone, are commonly found natural products (Figure 1)
produced by a broad range of cyanobacteria and other
microorganisms.2 Despite their abundance, little is known
about their functions, though, several of the naturally
occurring azotides has been found to have potent
antibacterial or anticancer activity.3 Since the first gene
clusters responsible for their biosynthesis were discovered
in 2009,4 interest in this class of compounds has increased
as their ribosomal origin facilitates bioengineering of
analogues being potential pharmaceuticals.5 In relation to
this we have previously reported on the synthesis of natural
azotides and their oral bioavailability.1 Another interesting
property of the azotides, is their versatile ability to
coordinate metal ions (Figure 1).6 Thus, it has been
suggested that metal binding is involved in the biological
function of some azotides.7 Many synthetic chiral
oxazolines derived from amino acid also bind metal ions
and the (Py)BOX type ligands (Figure 1) have found broad
Thiazole-thiazoline
motif
NH
Thiazole-
oxazoline motif
O
O
O
S
S
S
N
Me
O
N
N
H
NH
N
N
O
N
S
S
N
N
N
S
S
O
S
O
O
HN
O
MeO
S
N
N
H
N
O
N
NH HN
OHO
OH
O
O
Largazole
Histone
deacetylase
inhibitor
GE2270A
Inhibitor of bacterial elongation factor Tu
Thiazole
Oxazoline
O
O
Oxazoline
O
O
N
CuII
O
S
N
N
R
N
N
O
R
NH
HN
O
BOX ligands
applications
in
metal
catalyzed
asymmetric
O
O
CuII
N
transformations.8 From a green chemistry perspective,
application of natural products as chiral ligands is
attractive. Compounds such as single amino acids, tartaric
acid, quinine and other cinchona alkaloids have been
applied as chiral ligands; however, these are very difficult
to engineer on the biosynthetic level.9 In contrast, azotides
are readily diversified by simple editing of their genetic
encoded lead sequences. As they contain azoles and
N
Oxazoline
S
N
O
O
O
N
O
N
N
R
R
Crystalized Cu(II) complex of
Ascidiacyclamide
PyBOX ligands
Figure 1. Natural azotides and amino acid-derived metal ligands.
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In this communication, the feasibility of this concept is
Page 2 of 8
82% ee (Scheme 2). On the other hand, the combination of
L-valine thiazole and L-serine oxazoline (2) gave the
opposite enantiomer, but only in 12% ee and with modest
conversion. Several other Lewis acidic metal salts were
also tested under identical conditions. Exchanging the
counter anion by using cobalt(II) acetylacetonate gave high
conversion of >90 %, whereas cobalt(III) acetylacetonate
lead to minimal conversion. However, both catalytic
systems provided no enantioselectivity. Applying other
metal triflate salts had a large effect on the conversion
rates. Copper(II) triflate gave <10 % conversion, whereas
zinc(II) triflate led to high conversion of >90 %. Copper(I)
triflate led to a complex mixture of products which
indicates that this acted not only as Lewis acid catalyst. All
these other metal triflate salts provided no or negligible
enantioselectivity. Hence, cobalt(II) triflate was selected
for further studies of the ligands.
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demonstrated through the use of azotides as cobalt(II)
ligands for a Lewis acid catalyzed asymmetric hetero
Diels-Alder reaction. Hetero Diels-Alder reactions are
powerful tools for building heterocyclic structures,10 and
constitute a common platform for evaluation of ligand-
metal catalysts’ ability to control enantioselectivity,
including the BOX type ligands (Figure 1).11 Hetero Diels-
Alder reactions are a part of Nature’s own chemical
toolbox and it is well recognized that the pyridine
substructure in GE2270A (Figure 1) and other thiopeptides
originate from such reactions.12 In nature, the
transformation has been demonstrated to be enzyme
catalyzed, however, it is unknown if metal coordination
plays a role in this process. In this work we took inspiration
from the core oxazoline-thiazole structural motif in
GE2270A (Figure 1). This motif comprises structural
elements from the (Py)BOX ligands and is relative simple
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O
,
to generate chemically.1 13
S
*
R
N
O
N
R'
O
O
HN
Results and Discussion
OTMS
O
+
O
*
1. CoIITf2/Ligand, THF, rt
All the azotide ligands (1-11) were synthesized via a
modified Hantzsch thiazole synthesis followed by an amide
coupling and oxazoline formation. Starting from Cbz-
protected amino acid amides these were converted to
thioamides by reaction with Lawesson’s reagent followed
by alkylation and cyclization with ethyl bromo pyruvate
finalized by dehydration with trifluoroacetic anhydride
NO2
MeO
2. TFA
13
12
NO2
14
1
Using ligand : 92 % yield
O
N
O
O
N
S
S
S
O
O
O
N
O
N
O
N
N
O
HN
O
HN
O
HN
O
O
O
O
,
(Scheme 1).1 14 The previously reported method was
3
2
1
slightly modified for synthesis of the bulky tert-butyl
glycine thioamide as this (CH2Cl2, 12 h, rt) led to poor
conversion. The obstacle was solved by rising the reaction
temperature to 60°C which demanded using THF instead of
CH2Cl2. We attribute the sluggishness of this reaction to
the sterically bulkiness of the tert-butyl group when
combined with the relative bulky Lawesson’s reagent. All
of the obtained thiazole building blocks were then
saponified, coupled to serine, or other amino alcohols
followed by oxazoline formation through DAST-mediated
cyclization (Scheme 1).15
71% conv 7% ee
55% conv ent-12% ee
>95% conv 82% ee
O
O
O
S
S
O
S
O
O
O
N
O
N
N
O
N
N
O
N
HN
O
HN
O
HN
O
O
O
O
6
4
5
76 % conv 17 % ee
90 % conv 34 % ee
88 % conv 64 % ee
O
O
S
S
H
O
N
O
O
N
O
N
N
O
N
O
HN
O
HN
O
O
O
1) Lawesson's reagent
2) BrCH2COCO2Et, KHCO3,
then (CF3CO)2O, 2,6-lutidine
3) NaOH (aq), THF
S
R
O
O
R
NH2
O
N
O
OH
7
8
HN
HN
80 % conv 48 % ee
>95% conv 61% ee
Reference 1 and 14
O
O
O
O
O
N
S
S
S
N
O
N
N
O
N
N
O
O
N
S
HN
HN
HN
1) ClCO2Et, DIPEA, then amino alcohol
2) DAST, DCM, then NaHCO3 (aq)
*
R
N
O
R'
O
O
O
HN
10
>95% conv 35% ee
9
11
>95% conv 57% ee
O
>95% conv 50% ee
1-11
Scheme 2. Ligand 1-11 investigated as ligands in a cobalt catalyzed
Scheme 1: Synthesis of the azotide ligands.
asymmetric Diels-Alder reaction.
Initially, the two L-valine-(D- or L)-serine derived ligands (1
and 2) in combination with cobalt(II) triflate were studied
as catalysts for a hetero Diels-Alder reaction.16 This
revealed a high degree of cooperation between the two
stereocenters in dictating the enantioselectivity. Applying
the L-valine-D-serine adduct (1) provided full conversion of
the starting material and led to a high enantioselectivity of
The impact on conversion rate and enantioselectivity of the
side chain on the thiazole building was investigated.
Inspired by the Jacobsen thiourea catalysts17 introduction of
an additional methyl group on the β-carbon (3) was tested,
but this led to only negligible stereoselectivity and reduced
rate of conversion. Various other modifications at the β-
carbon (4-7) also led to reduced stereoselectivity and
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incomplete conversion. Interestingly, it was found that
1
2
3
4
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7
8
omitting a substituent at the α-carbon in the thiazole amino
acid building block (8), and thereby having one less stereo
center in the ligand, led to only 21% reduction of
enantiomeric excess as compared to ligand 1, while full
conversion was still achieved. These results demonstrated
that the substituent on the oxazoline stereo center plays a
major role in dictating the enantioselectivity. A small series
of azotide ligands (9-11) without coordinating groups in
this position was synthesized and investigated in order to
explore if the effect was mediated through steric bulk or via
the additional coordination of the ester carbonyl to the
cobalt(II) ion. All of these ligands (9-11) led to only
modest ee as compared to the parent ligand 1, while
complete conversion was maintained.
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In order to understand the observed effects of ligand
variations, computational studies of the ligand-cobalt-
complexes were performed by molecular dynamic
simulations combined with structure energy minimizations.
All the generated structures maintained
a
stable
coordination of the cobalt(II) ion to the nitrogen atoms of
the two azoles as well as to the carbonyl of the carbamate
group (Figure 2). Structures displaying metal coordination
to the ester carbonyl were retrieved from the dynamics of
all serine derived ligands (1-8) although this coordination
was less prevalent. The structure populations segregated
into two major conformations with the cobalt(II) ion
orientated either slightly above or slightly below the
thiazole-oxazoline plane (see e.g. 11, Figure 2), with the
carbamate group coordinating from below or above,
respectively. Only the D-serine derived ligand (1) of the
two initial valine-serine derived ligands (1 and 2) yield low
energy structures with all the four heteroatoms coordinating
to cobalt (Figure 2, compound 1).
Figure 2. Computational investigation of the ligand structures’ influence
on cobalt coordination. Examples of low energy structures of ligands with
three or four coordinating groups. Example of the two structure
populations depicted for ligand 11.
Hence, the L-serine derived ligand (2) give rise to a less
stable cobalt(II) complex, compared to the corresponding
D-serine derived ligand (1) which is supported by the
molecular dynamics (Figure 3). The relatively high
flexibility of 2 observed in silico may contribute to the
reduced stereoselectivity observed with this ligand as
compared to 1.
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close to the catalytic center. As it was found that cobalt(II)
Page 4 of 8
1
2
3
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5
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8
triflate catalyzed the reaction well even in the absence of
ligand, it is possible that the modest selectivity of some of
the ligands including the more steric congested ligands 3
(Figure 2) originate from competing background reaction
with minute amounts of the free cobalt(II) ions. Hence,
several factors may be the origin of that the isopropyl
substituent is the optimal structural motif among the tested
amino acid side chains. In ligand 1 this balances shielding
sides of the cobalt(II) ion in order to induce
enantioselectivity, while still leaving room for substrate
binding and high catalytic turnover.
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In conclusion, inspired by a structural motif in the naturally
occurring azotide GE2270A (Figure 1), we have
synthesized a library of azotides and demonstrated their
enantio-selectivity inducing capacity when used as ligands
in a cobalt(II)-catalyzed hetero Diels-Alder reaction. These
readily available chiral ligands can be easily diversified and
take advantage of the inherent chirality of α-amino acids.
The relative enantioselectivity and catalytic capacity has
been correlated to computational studies of the ligand-
metal complexes. The results provide an optimal base for
developing more advanced synthesized or expressed
azotide ligands, and apply these in green and benign
enantioselective catalysis.
Experimental details
All purchased chemicals were used without further
purification. All solvents were HPLC-grade. Flash
chromatography (FC) was carried out on Merck silica gel
60 (0.040-0.063 mm). NMR spectra were recorded on a
Bruker ADVANCE III 500 MHz CRYO probe instrument.
Chemical shifts are reported in ppm relative to residual
solvent signals (CHCl3, 7.26 ppm; DMSO-d6, 2.50 ppm)
Figure 3. Simulated molecular dynamics annealing of complexes of ligand
1, 2 and 5 represented by distance variation between the β-carbon of the
amino acid in the thiazole part and the carbon equivalent to the carbonyl
carbon in the serine residue (see complex structures in Figure 2). The
simulation was maintained at 750 K for 3000 ps and then cooled to 230 K
over 2000 ps and then equilibrated at 230 K for 3000 ps (see also
supporting information).
1
for H NMR spectra and relative to the central solvent
resonance (CDCl3, 77.0 ppm; DMSO-d6, 39.5 ppm) for 13
C
NMR spectra. The following abbreviations are used to
1
indicate the multiplicity in H and 13C NMR spectra: s,
singlet; d, doublet; t, triplet; q, quartet; dd, doublet of
doublets; ddd, doublet of doublet of doublets; dt, doublet of
triplets; tt, triplet of triplets; m, multiplet. 13C NMR spectra
were acquired in broadband decoupled mode. High
resolution mass spectrometry (HRMS) was performed on a
Bruker micro-TOF using positive electrospray ionization.
Enantiomeric excesses were determined by chiral HPLC on
a Waters 600 system (Waters 60F solvent pump; Waters
2996 photodiode array detector) using a Lux 5 μm
Cellulose-1 LC column 250 x 4.6 mm from Phenomenex
and eluting with an isocratic eluent of 60% isopropanol in
heptane with a flow-rate of 1.0 mL/min. The reference
racemic sample was prepared using Co(OTf)2 without
ligand as a catalyst.
It was noted that the L-valine-D-serine derived ligand (1)
has the most stable structure in silico, as compared to
compounds where the thiazole moiety were generated from
other amino acids than L-valine (e.g. 5, Figure 2). This is
likely adding to the superior enantioselectivity of ligand 1.
Hence, a major disadvantage of the extended side chain
found in ligand 4-7 may be reduced conformation stability
as a consequence of the random rotations of the relative
heavy flexible α-carbon substituent. This is in line with the
general trend of efficient ligands for asymmetric synthesis
which rarely have large substituent with connected
, ,
,
rotational bonds.8 9 10 11 The coordination of the cobalt(II)
ion to the carbonyl substituent on the oxazoline is clearly
imperative in guiding the enantioselectivity. Absence of
this carbonyl leads to a less shielded catalytic site with the
substituent on the 4-position on the oxazoline pointing
away from the cobalt (see 11, Figure 2). Interestingly, even
the complex of 1 appears to have a relative open face with
the isopropyl side chain pointing away from the cobalt(II)
ion. The less hindered access to the cobalt could be crucial
in order to accommodate both the aldehyde and the diene
General procedure for the formation of ligands 1 - 11
The Cbz-protected thiazole building blocks (Cbz-X-Thz-
OH, where X indicates the designated amino acid) were
prepared as their ethyl esters by a literature procedure,
followed by ester hydrolyzed as previously described.1 The
ligands 1 - 11 were all isolated as clear viscous oils and
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The Journal of Organic Chemistry
Hz, 1H), 1.32 (t, J = 7.1 Hz, 3H), 0.95 (d, J = 6.8 Hz, 3H),
prepared by the following procedure using Ligand 1 as an
example: DIPEA (610 L, 3.5 mmol) was added to a
stirred solution of Cbz-Val-Thz-OH (334 mg, 1.0 mmol) in
THF (10 mL) then ethyl chloroformate (190 L, 2.0 mmol)
was added. The solution was stirred for 30 minutes prior to
addition of D-serine ethyl ester hydrochloride (339 mg, 2.0
mmol) as a solid. The reaction was stirred at room
temperature overnight. Citric acid (20% aq., 20 mL) was
added and the product was extracted with EtOAc (2x 10
mL). The combined organic phases were concentrated and
the residual Cbz-Val-Thz-D-Ser-OEt was purified by
column chromatography (369 mg, 82% yield). The
intermediate (369 mg, 0.82 mmol) was dissolved in CH2Cl2
(5.0 mL) and cooled to -40 °C. Diethylaminosulfur
trifluoride (145 L, 1.1 mmol) was added to the stirred
solution. The reaction was stirred at -20 °C for 1 hour.
NaHCO3 (sat. aq., 2.0 mL) was added and the reaction
allowed to reach room temperature. The solution was
extracted with EtOAc (2x10 mL). The solvent was
removed in vacuo and the product was purified by flash
column chromatography using a gradient of EtOAc in
heptane, from 1:4 to 1:1. The product (1) was collected as a
clear syrup upon evaporation (332 mg, 0.76 mmol, 94%
yield). The yields (unoptimized) for the remaining ligands
2-11 are reported below as the overall yields for the
combined synthetic steps on a 1.0 mmol scale.
0.93 (d, J = 6.8 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 172.3, 170.9, 161.3, 156.0, 143.6, 136.2, 128.5, 128.2,
128.1, 124.1, 70.0, 68.7, 67.1, 61.8, 58.6, 33.5, 19.5, 17.6,
14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C21H26N3O5S+ 432.1588; Found 432.1558.
1
2
3
4
5
6
7
8
Ethyl (S)-5-(2-((S)-1-(((benzyloxy)carbonyl)amino)-2-
methylpropyl)thiazol-4-yl)-3,4-dihydro-2H-pyrrole-2-
carboxylate (2):
9
1
Yield: 296 mg, 0.69 mmol, 69%. H NMR (500 MHz,
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CDCl3) δ 7.96 (s, 1H), 7.42 – 7.29 (m, 5H), 5.56 (d, J = 9.3
Hz, 1H), 5.17 – 5.06 (m, 2H), 5.01 – 4.87 (m, 2H), 4.70 (t,
J = 8.4 Hz, 1H), 4.61 (dd, J = 10.5, 8.7 Hz, 1H), 4.26 (p, J
= 7.2 Hz, 2H), 2.44 (dt, J = 13.6, 6.8 Hz, 1H), 1.32 (t, J =
7.1 Hz, 3H), 0.97 (d, J = 6.9 Hz, 3H), 0.92 (d, J = 6.8 Hz,
3H). 13C{1H} NMR (126 MHz, CDCl3) δ 172.6, 170.9,
161.4, 156.0, 143.7, 136.2, 128.5, 128.2, 128.1, 124.0,
70.1, 68.8, 67.2, 61.9, 58.6, 33.4, 19.5, 17.5, 14.2. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C21H26N3O5S+
432.1588; Found 432.1556.
Ethyl (R)-2-(2-((S)-1-(((benzyloxy)carbonyl)amino)-2,2-
dimethylpropyl)thiazol-4-yl)-4,5-dihydrooxazole-4-
carboxylate (3):
1
Yield: 170 mg, 0.38 mmol, 38%. H NMR (500 MHz,
CDCl3) δ 7.99 (s, 1H), 7.40-7.31 (m, 1H), 5.89 (d, J = 9.7
Hz, 1H), 5.16-5.07 (m, 2H), 4.97 (dd, J = 10.5, 8.1 Hz,
1H), 4.93 (d, J = 9.6 Hz, 1H), 4.70 (t, J = 8.4 Hz, 1H), 4.63
(dd, J = 10.5, 8.7 Hz, 1H), 4.29 (t, J = 6.8 Hz, 2H), 1.34 (t,
J = 7.1 Hz, 3H), 1.04 (s, 9H). 13C{1H} NMR (126 MHz,
CDCl3) δ 170.9, 169.8, 161.4, 156.1, 143.3, 136.3, 128.5,
128.1, 128.0, 124.1, 70.0, 68.8, 67.0, 61.9, 61.1, 35.7, 26.6,
14.2. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H28N3O5S+ 446.1744; Found 446.1750.
Procedure for the formation of (S/R)-2-(4-nitrophenyl)-
2,3-dihydro-4H-pyran-4-one (14) by a cobalt-catalyzed
hetero-Diels-Alder reaction:
Co(OTf)2 was synthesized by dissolving anhydrous CoCl2
(65 mg, 0.5 mmol) in acetonitrile (25 mL) and adding
AgOTf (257 mg, 1.0 mmol) to the mixture. A white solid
formed that was filtered off after 1 h. The light pink
Co(OTf)2 catalyst was isolated by evaporation of the
solvent and stored under nitrogen. A vial containing
Co(OTf)2 (3.6 mg, 10 mol%, 0.01 mmol) and the ligand
(one of compound 1 – 11) (15 mol%, 0.015 mmol) in dry
Ethyl (R)-2-(2-((S)-1-(((benzyloxy)carbonyl)amino)-3-
methylbutyl)thiazol-4-yl)-4,5-dihydrooxazole-4-
carboxylate (4):
o
THF (0.20 mL) was heated in an oil bath to 50 C under
1
nitrogen for 10 min to allow complex formation. The vial
was cooled to room temperature then 4-nitrobenzaldehyde
(0.10 mmol) and Danishefsky´s diene (0.15 mmol) was
added. The reaction was stirred under nitrogen for 16 h at
room temperature. Trifluoroacetic acid (0.10 mL) was
added and the reaction stirred for 1 hour. The mixture was
loaded direct onto a silica column and the product eluted
with EtOAc/heptane 1:4. The product (14) was obtained in
a maximum yield of 92% (20.2 mg, 0.092 mmol), and
enantiomeric excess of 83% using ligand 1. The
enantiomeric excess was assessed by chiral HPLC analysis
of a sample in isopropanol/heptane 3:2 as described above.
Yield: 272 mg, 0.61 mmol, 61%. H NMR (500 MHz,
CDCl3) δ 7.90 (s, 1H), 7.39 – 7.27 (m, 5H), 5.50 (d, J = 9.0
Hz, 1H), 5.17 – 5.03 (m, 3H), 4.92 (dd, J = 10.5, 8.1 Hz,
1H), 4.66 (t, J = 8.4 Hz, 1H), 4.58 (dd, J = 10.5, 8.6 Hz,
1H), 4.28 – 4.18 (m, 2H), 1.96 – 1.86 (m, 1H), 1.83 – 1.73
(m, 1H), 1.72 – 1.62 (m, 1H), 1.29 (t, J = 7.1 Hz, 3H), 0.97
– 0.89 (m, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 173.6,
170.8, 161.2, 155.6, 143.5, 136.1, 128.4, 128.0, 127.9,
124.0, 69.9, 68.7, 66.9, 61.7, 51.5, 44.4, 24.8, 22.8, 21.7,
14.0. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C22H28N3O5S+ 446.1744; Found 446.1713.
Ethyl (R)-2-(2-((R)-1-(((benzyloxy)carbonyl)amino)-2-
phenylethyl)thiazol-4-yl)-4,5-dihydrooxazole-4-
carboxylate (5):
Ethyl (R)-2-(2-((S)-1-(((benzyloxy)carbonyl)amino)-2-
methylpropyl)thiazol-4-yl)-4,5-dihydrooxazole-4-
carboxylate (1):
1
Yield: 254 mg, 0.53 mmol, 53%. H NMR (500 MHz,
1
Yield: 332 mg, 0.76 mmol, 76%. H NMR (500 MHz,
CDCl3) δ 7.88 (s, 1H), 7.36 – 7.26 (m, 4H), 7.25 – 7.18 (m,
4H), 7.09 – 7.04 (m, 2H), 5.67 (d, J = 8.6 Hz, 1H), 5.33 (q,
J = 7.5 Hz, 1H), 5.06 (s, 2H), 4.95 (dd, J = 10.5, 8.1 Hz,
1H), 4.69 (t, J = 8.4 Hz, 1H), 4.61 (dd, J = 10.5, 8.6 Hz,
1H), 4.30 – 4.20 (m, 2H), 3.36 – 3.29 (m, 2H), 1.31 (t, J =
CDCl3) δ 7.96 (s, 1H), 7.43 – 7.29 (m, 5H), 5.58 (d, J = 9.2
Hz, 1H), 5.12 (d, J = 2.7 Hz, 2H), 4.94 (ddd, J = 10.3, 8.0,
3.7 Hz, 2H), 4.69 (t, J = 8.4 Hz, 1H), 4.62 (dd, J = 10.5, 8.7
Hz, 1H), 4.40 – 4.14 (m, 2H), 2.43 (dq, J = 10.4, 5.2, 3.8
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7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 172.3,
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C21H28N3O3S+
402.1846; Found 402.1820.
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2
3
4
170.8, 161.2, 155.5, 143.4, 136.1, 136.0, 129.3, 128.6,
128.4, 128.1, 127.9, 127.0, 124.3, 70.0, 68.7, 67.0, 61.8,
54.3, 41.6, 14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd
for C25H26N3O5S+ 480.1588; Found 480.1551.
Benzyl
((S)-2-methyl-1-(4-((S)-4-phenyl-4,5-
dihydrooxazol-2-yl)thiazol-2-yl)propyl)carbamate (10):
1
5
Yield: 166 mg, 0.38 mmol, 38%. H NMR (500 MHz,
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8
9
Ethyl (R)-2-(2-((R)-1-(((benzyloxy)carbonyl)amino)-2-
(tert-butoxy)ethyl)thiazol-4-yl)-4,5-dihydrooxazole-4-
carboxylate (6):
CDCl3) δ 7.96 (s, 1H), 7.43 – 7.27 (m, 10H), 5.64 (d, J =
9.3 Hz, 1H), 5.41 (dd, J = 10.2, 8.3 Hz, 1H), 5.12 (d, J =
1.1 Hz, 2H), 4.96 (dd, J = 9.0, 6.0 Hz, 1H), 4.82 (dd, J =
10.2, 8.4 Hz, 1H), 4.32 (t, J = 8.4 Hz, 1H), 2.45 (dq, J =
13.3, 6.6 Hz, 1H), 0.97 (d, J = 6.7 Hz, 3H), 0.94 (d, J = 6.9
Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3) δ 172.2, 159.8,
156.0, 144.2, 141.8, 136.2, 128.7, 128.5, 128.1, 128.0,
127.7, 126.8, 123.3, 75.0, 70.2, 67.0, 58.6, 33.5, 19.5, 17.6.
HRMS (ESI-TOF) m/z: [M + H]+ Calcd for C24H26N3O3S+
436.1689; Found 436.1659.
1
Yield: 257 mg, 0.54 mmol, 54%. H NMR (500 MHz,
CDCl3) δ 8.13 (s, 1H), 7.48 – 7.31 (m, 5H), 5.99 (s, 1H),
5.24 (s, 1H), 5.16 (s, 2H), 4.99 (dd, J = 10.5, 8.0 Hz, 1H),
4.75 (t, J = 8.4 Hz, 1H), 4.70 – 4.64 (m, 1H), 4.37 – 4.24
(m, 2H), 3.95 – 3.86 (m, 1H), 3.74 – 3.66 (m, 1H), 1.35 (t,
J = 7.1 Hz, 3H), 1.11 (d, J = 1.7 Hz, 9H). 13C{1H} NMR
(126 MHz, CDCl3) δ 172.4, 170.8, 161.3, 161.3, 155.7,
143.0, 136.1, 128.5, 128.2, 124.5, 73.8, 69.9, 68.7, 67.1,
63.5, 61.7, 54.0, 27.2, 14.1. HRMS (ESI-TOF) m/z: [M +
H]+ Calcd for C23H30N3O6S+ 476.1850; Found 476.1815.
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Benzyl
((S)-1-(4-((S)-4-benzyl-4,5-dihydrooxazol-2-
yl)thiazol-2-yl)-2-methylpropyl)carbamate (11):
1
Yield: 207 mg, 0.46 mmol, 46%. H NMR (500 MHz,
CDCl3) δ 7.86 (s, 1H), 7.40 – 7.28 (m, 6H), 7.25 – 7.16 (m,
4H), 5.62 (d, J = 9.2 Hz, 1H), 5.12 (d, J = 1.9 Hz, 2H), 4.95
(dd, J = 9.3, 6.2 Hz, 1H), 4.67 – 4.56 (m, 1H), 4.36 (t, J =
8.9 Hz, 1H), 4.19 – 4.10 (m, 1H), 3.34 (dd, J = 13.8, 4.7
Hz, 1H), 2.73 (dd, J = 13.8, 9.5 Hz, 1H), 2.44 (dq, J = 13.5,
6.7 Hz, 1H), 0.95 (dd, J = 9.8, 6.8 Hz, 6H). 13C{1H} NMR
(126 MHz, CDCl3) δ 172.1, 159.2, 156.0, 144.3, 137.8,
136.2, 129.1, 128.6, 128.5, 128.1, 128.0, 126.5, 122.9,
72.2, 68.0, 67.1, 58.5, 41.6, 33.6, 19.4, 17.6. HRMS (ESI-
TOF) m/z: [M + H]+ Calcd for C25H28N3O3S+ 450.1846;
Found 450.1813.
Ethyl (S)-2-(2-((R)-3,11-dioxo-1,13-diphenyl-2,12-dioxa-
4,10-diazatridecan-5-yl)thiazol-4-yl)-4,5-
dihydrooxazole-4-carboxylate (7):
1
Yield: 137 mg, 0.23 mmol, 23%. H NMR (500 MHz,
CDCl3) δ 7.90 (s, 1H), 7.36 – 7.27 (m, 10H), 5.85 (d, J =
8.0 Hz, 1H), 5.18 – 4.95 (m, 5H), 4.90 (dd, J = 10.5, 8.1
Hz, 1H), 4.65 (t, J = 8.4 Hz, 1H), 4.56 (dd, J = 10.6, 8.6
Hz, 1H), 4.29 – 4.18 (m, 2H), 3.25 – 3.05 (m, 2H), 2.15 –
1.98 (m, 1H), 1.98 – 1.80 (m, 2H), 1.60 – 1.34 (m, 4H),
1.29 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126 MHz, CDCl3)
δ 173.5, 170.8, 161.2, 161.1, 156.6, 155.9, 143.4, 136.5,
136.1, 128.4, 128.4, 128.1, 128.0, 128.0, 124.1, 69.9, 68.6,
67.0, 66.5, 61.7, 53.2, 40.1, 34.8, 29.2, 22.4, 14.0. HRMS
(ESI-TOF) m/z: [M + H]+ Calcd for C30H35N4O7S+
595.2221; Found 595.2169.
Molecular dynamics annealing of Co2+ triflate in
complex with ligands 1 – 11.
The dynamic behavior of the catalyst complexes obtained
from the ligands and Co2+OTf2 was studied by performed
MD-annealing in suite Molecular Operating Environment
(MOE from CCG) of the complexes from 750 K to 230 K
by empirical methods using the Amber 10 force field18 in
the default Amber 10:ETH setting. The solvated complexes
(in a droplet of CHCl3, 12 layers) were constructed in the
molecule builder and all major conformations of each
complex were visited and energy minimized. Based on
potential energy calculation low energy conformers of the
complexes were extracted. In order to follow the dynamics
of the interchange between these conformers a distance
between the carbonyl carbon of the ester (or equivalent
carbon in ligand 9-11) and the Cβ of the chiral center
connected to the thiazole was monitored during a simulated
MD-annealing process. The process started at 750 K for
3000 ps in order to establish the population of the two
conformers as well as the relative barrier of interchange.
This was followed by a cooling period of 2000 ps to 230 K
and an equilibration period of 3000 ps at this temperature
to find the low energy conformations at low temperature.
The distance in Å between the two carbon atoms (one
carbon and one hydrogen for ligand 8) over time are
depicted for each ligand complex.
Ethyl
(R)-2-(2-
((((benzyloxy)carbonyl)amino)methyl)thiazol-4-yl)-4,5-
dihydrooxazole-4-carboxylate (8):
1
Yield: 238 mg, 0.61 mmol, 61%. H NMR (500 MHz,
CDCl3) δ 7.98 (s, 1H), 7.42 – 7.31 (m, 5H), 5.53 (s, 1H),
5.15 (s, 2H), 4.94 (dd, J = 10.5, 8.1 Hz, 1H), 4.71 (dd, J =
9.6, 7.3 Hz, 3H), 4.61 (dd, J = 10.5, 8.7 Hz, 1H), 4.34 –
4.16 (m, 2H), 1.32 (t, J = 7.1 Hz, 3H). 13C{1H} NMR (126
MHz, CDCl3) δ 170.7, 169.1, 161.2, 156.2, 143.2, 136.0,
128.6, 128.3, 128.1, 124.9, 70.1, 68.7, 67.3, 61.9, 42.6,
14.1. HRMS (ESI-TOF) m/z: [M + H]+ Calcd for
C18H20N3O5S+ 390.1118; Found 390.1093.
Benzyl ((S)-1-(4-((S)-4-isopropyl-4,5-dihydrooxazol-2-
yl)thiazol-2-yl)-2-methylpropyl)carbamate (9):
1
Yield: 237 mg, 0.57 mmol, 57%. H NMR (500 MHz,
CDCl3) δ 7.88 (s, 1H), 7.47 – 7.28 (m, 5H), 5.63 (d, J = 9.3
Hz, 1H), 5.11 (d, J = 1.7 Hz, 2H), 4.95 (dd, J = 9.2, 6.1 Hz,
1H), 4.50 – 4.38 (m, 1H), 4.20 – 4.05 (m, 2H), 2.43 (dq, J
= 13.5, 6.8 Hz, 1H), 1.91 (dqt, J = 13.1, 9.4, 4.8 Hz, 1H),
1.04 (d, J = 6.8 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H), 0.92 (d, J
= 6.8 Hz, 6H). 13C{1H} NMR (126 MHz, CDCl3) δ 172.1,
158.6, 156.0, 144.4, 136.2, 128.5, 128.1, 128.0, 122.8,
72.6, 70.3, 67.1, 58.6, 33.6, 32.5, 19.5, 19.2, 17.9, 17.5.
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The Journal of Organic Chemistry
Morten Meldal: 0000-0001-6114-9018
Frederik Diness: 0000-0001-5098-7198
Supporting Information
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NMR spectra and computational data (PDF). The Supporting
Information is available free of charge on the ACS Publications
website.
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Notes
The authors declare no competing financial interest
AUTHOR INFORMATION
Corresponding Author
ACKNOWLEDGMENT
The University of Copenhagen is acknowledged for funding of
the Center for Evolutionary Chemical Biology (CECB). The
authors are grateful to the Villum Foundation for postdoctoral
grants to C.B.J. and D.S.N.
* Email: meldal@nano.ku.dk, fdi@chem.ku.dk
ORCID
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Christian Borch Jacobsen: 0000-0002-7502-9831
Daniel S. Nielsen: 0000-0001-7851-1538
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