Cobalamin-Catalysed Chemical Reactions: Probing the Role of the Nucleotide Loop

Article abstract of DOI:10.1002/ejoc.201800877

The nucleotide loop in the vitamin B₁₂ structure affects its biological and physicochemical properties, but its role in cobalamin-catalysed reactions still remains disputable. Herein, we show the synthesis of a series of model compounds includi

Full text of DOI:10.1002/ejoc.201800877

A Journal of
Accepted Article
Title: Cobalamin-catalysed chemical reactions - probing the role of
nucleotide loop
Authors: Dorota Gryko, Maksymilian Karczeski, and Michał Ociepa
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10.1002/ejoc.201800877
European Journal of Organic Chemistry
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Cobalamin-catalysed chemical reactions – probing the role of
nucleotide loop
Maksymilian Karczewski,[a] Michał Ociepa,[a] and Dorota Gryko*[a]
Abstract: The nucleotide loop in the vitamin B12 structure affects its
biological and physicochemical properties, but its role in cobalamin-
catalysed reactions still remains disputable. Herein, we show the
synthesis of
a
series of model compounds including
N-methylcobalamin (NMICbl) in a base-off form with the nucleotide
attached. The structure-activity relationship studies reveal that in the
studied cobalamin-catalysed reaction, the reduction step is not a
rate-determining.
Introduction
Fine tuning of ligands’ properties is a challenging task in the field
of organometallic catalysis and changing their electronic and
steric features are often required to achieve a suitable balance
between the stability and reactivity of a catalyst.[1] Vitamin B12 (1,
cobalamin), one of the most intriguing catalysts provided by
Nature itself, is a Co-complex with highly functionalised corrin
ring as an equatorial ligand and two distinct axial ligands (Figure
1). In mammalian cells it plays an important role of a cofactor in
Figure 1. Structure of vitamin B12 (1, cobalamin).
increasing basicity of an α-axial ligand, the energy required to
break the Co-C bond increases.[9] The trans-effect of the DMB
ligand on the Co-β-ligand bond length was confirmed by X-ray
analysis of various cobaloximes and vitamin B12 derivatives.[10,11]
In this line, Zelder studied a model complex with imidazole as
the α-axial ligand and showed that deprotonation of the nitrogen
atom stabilizes the Co ion on the +3 oxidation state.[12] Réthey
prepared compounds possessing 4-methylphenol in place of the
heterocycle - DMB.[13] This artificial coenzyme proves not only to
catalyse the metylmalonyl-CoA rearrangement, but also to have
higher affinity towards methylmalonyl-CoA mutase itself.
Cobinamide – a Cbl derivative lacking DMB, ribose and
phosphate units – was as well used to study the AdCH2-Co
binding.[14-19]
Finke et al. focused on the radical chemistry behind the
cleavage of the Co-C bond and found that the DMB base-on
form favours Co-C homolysis over heterolysis. Though the
presence of the nucleotide loop is not absolutely necessary for
the Co-C homolytic step, it plays an essential role in preventing
the radical intermediates from undergoing side reactions.[16] Our
previous results suggest that the loop plays a vital role in
reactions catalysed by Co(I) vitamin B12.[7] The catalytic activity
of an amphiphilic derivative of cobalamin – cobalester (Cble)
was compared to that of cobinamide and heptamethyl
cobyrinates (Cby) lacking the nucleotide loop, in a dimerization
of benzyl bromide.[7] In this case, Cble proves superior to Cbi,
however the lack of the loop in Cbi and Cby derivatives makes
them imperfect models for base-off form of vitamin B12, as they
do not entirely reflect steric effects of the loop in natural
cobalamin. Therefore, we believe that the question ‘if the
nucleotide loop provided to the vitamin B12 by Nature grants it
superior catalytic properties’ can only be answered by
comparing native vitamin B12 to model compounds (4-6)
bearing all structural elements of cobalamin, but being either
permanently locked in the base-off form (6) or possessing axial
processes such as methylmalonyl-coenzyme
A
(CoA)
rearrangements,[2] or methyl transfer reactions.[3] The catalytic
activity of vitamin B12, relying mainly on the redox chemistry of
the central cobalt atom, enables successful application of this
compound in synthetically useful reactions: dehalogenation, ring
expansion, C-H activation, cyclopropanation.[4-7] However, due to
its structural complexity, cobalamin is rarely perceived as a
catalyst which catalytic efficacy can be improved via structure
modifications. Although this may seem a challenging task, we
believe that knowing the structure-activity relationship for
cobalamin derivatives is essential for better understanding of
their catalytic properties. One of the most characteristic
structural features of native vitamin B12 is the so-called
“nucleotide loop”, located at the α face of the corrin ring with
5’,6’-dimethylbenzimidazol (DMB) moiety as an α-axial ligand.
The importance of the loop corroborates itself in the
methylmalonyl-coenzyme A (CoA) rearrangement. Halpern and
co-workers showed that in these reactions switching between
base-on and base-off forms of the cofactor changes the strength
of the Co-C bond enabling cobalamin to play a role of a
“reversible free radical carrier”.[8] The process is initiated by the
homolytic dissociation of 5’-deoxyadenosyl-cobalt bond with the
estimated energy of 109 kJ·mol-1 and proceeds via a radical
mechanism. Furthermore, it has been reported that with an
[a]
M. Karczewski, M. Ociepa, D. Gryko
Institute of Organic Chemistry, Polish Academy of Sciences
Kasprzaka 44/52
01-224 Warsaw, Poland
E-mail: dorota.gryko@icho.edu.pl
Supporting information for this article is given via a link at the end of
the document.
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10.1002/ejoc.201800877
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Figure 1 Comparison of structural features of our model compounds..
ligands and three cobinamide derivatives with different moieties
at the hydroxyl group (4-5, Figure 2). Consequently, the effects
of those changes were examined in the reductive dimerization of
1,1-diphenylethylene.
Trimethyl esters of phosphorus inorganic acids are known as
methylating agents for nitrogen bases.[22,23] Intriguingly, the
reported reaction of P(OMe)3 with (CN)1 at room temperature
-
leads only to the ligand exchange - from CN- to P(O)(OMe)2
giving red complex (P(O)(OMe)2)1 (Scheme 1). Its
crystallographic structure clearly evidences longer Co-DMB
bond (2.20 Å) in comparison to (CN)1 (2.01 Å), thus more
susceptible to chemical modifications.[24] However, when (CN)1
and P(OMe)3 were reacted in DMF at elevated temperature both
the methylation of DMB moiety and the ligand exchange
occurred (Scheme 1). Mild reaction temperature (45 °C) as well
as the addition of Lewis acid (BF3∙OEt2) led only to complex
(P(O)(OMe)2)1, but reactions under microwave irradiation of
either (CN)1 or (P(O)(OMe)2)1 with P(OMe)3 at 110 °C yielded a
mixture of compounds with (P(O)(OMe)2)2 predominating. Other
products, according to MS analysis, included derivatives bereft
of the “nucleotide loop” – cobinamides (3) possessing various
axial ligands. Subsequently, the reaction conditions were
optimized and the desired compound (P(O)(OMe)2)2 was
obtained in 17% yield. For reactions on 100 mg scale, the
reaction time was prolonged to 40 min, to assure full conversion.
An alternative methodology employed aquacobalamian ((H2O)1)
as a starting material (Scheme 2). Initially, complex (H2O)1 while
reacted with reagent 7 formed a stable yellow complex of
coblamin in a semi-base-off form, with the DMB moiety being
protonated. The stability of this compound seems to arise from
the intramolecular hydrogen bond formation with the α-ligand.
The comparison of the experimental UV/Vis spectra of NHI-
(P(O)Ph2)1 to the computed ones for four diastereoisomers
differentiating in the side of a ligand attachment (α or β) and the
atom coordinating to cobalt ion (phosphorus or oxygen)
suggests the existence of this bond (Figure 3). Whereas binding
of the phosphorous ligand on the β-face of macrocycle would
result in a bathochromic shift (green and blue lines) in
comparison to the native cobalamin, a hypsochromic shift was
observed (orange line). Additionally, the shape experimental
spectrum resembles the computed one for the diastereoisomer
with the Co-P bond at the site resembled (pink). Complex NHI-
(P(O)Ph2)1 could be methylated with as little as 10 equivalents
of methyl iodide (compared to more than 100 equiv. of P(OMe)3
and 6x105 of MeI as reported by Zelder),[21] offering an facile
access to base-off complex 2.
Results and Discussion
Synthesis of N-methylated cobalamins (2). To the best of our
knowledge the only stable base-off form of cobalamin was
obtained by Friedrich and Bernhauer in 1956 by methylating the
nitrogen atom of the DMB moiety, then the methodology was
further explored by Zelder.[20,21] However, previously published
procedures were not suitable for the synthesis on a preparative
scale, consequently we devised a new method of quaternization
of DMB nitrogen atom by employing trimethylphosphite along
with microwave irradiation (Scheme 1).
Scheme 1. Synthesis of (P(O)(OMe)2)2 directly from (CN)1 or via
(P(O)(OMe)2)1.
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Synthesis of cobinamides with
a “non-natural loop”.
Although performing reactions at the secondary, terminal OH
group of cobinamide (3) was a challenging task, activation by
CDT (1,1’-carbonyldi(1,2,4-triazole)) at elevated temperature
and the subsequent reaction with primary amines allowed
functionalisation of the macrocycle at the f-side chain (Scheme
4).
Scheme 2. Synthesis of (P(O)Ph2)2 directly from (H2O)1 via semi-base-off
NHI-(P(O)Ph2)1.
Scheme 3. Exchange of phosphate ligand to molecule of solvent or cyanide
ligand.
Figure 3. UV/Vis spectra for truncated structure of complex NHI-(P(O)Ph2)1
and four possible diastereoisomers (experimental (MeOH, CM = 1.65 x 10-5 M)
and computed (BP86/6-31G(d)/def2TZVP)
Anionic ligands are not desirable for the purpose of catalysis,
as proved by Zhang et al.[25] and Zelder et al.,[26] hence the
synthesized complex 2 was irradiated with light that led to
products possessing molecule of water coordinated to the
central atom. As the conversion was not quantitative, we
addressed this issue by developing an efficient strategy for the
replacement of the anionic ligands with a molecule of solvent
(Scheme 3), which also proved to be a valuable tool for the
quantitative transformation of (CN)1 to (H2O)1 (See supporting
information).
Scheme 4. Modification of cobinamide (3) with amines.
Electrochemical behaviour of synthesised derivatives.
The catalytic efficacy of cobalamin-type catalysts strongly
depends on their redox properties. Therefore, we explored
electrochemical characteristics of the base-off model
compounds on the basis of a series of cyclic voltammograms
(Table 1). The obtained results clearly shows that the
coordination of the cobalt ion by DMB moiety decreases
susceptibility of the coordination centre to reduction, as shown
by the negative shift in redox potentials values for the
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corresponding compounds in base-on forms (compare entries 2
with 5, 6 and 1with 4).
Base-off compounds (H2O)2, (CN)2 and (P(O)(OMe)2)2 show
similar Epc values to that of cobinamide (3), indicating that the
cobalt centre does not experience significant electronic effects
from the presence of the blocked nucleotide loop. Diaqua
complex (H2O)2 with two labile ligands undergoes reduction via
analogous mechanism to that of aquacobalamin (1) with well
separated redox couples Co(III)/Co(II) and Co(II)/Co(I).
Moreover, CV for compound (CN)2 evidences the existence of
an equilibrium between (CN)(H2O)NMICbl and (CN)2NMICbl
which is distinct from the redox behaviour of cyanocobalamin (2)
but similar to that of cobyrinic acid derivatives.
Scheme 5. Typical catalytic cycle of the cobalamin-catalysed radical reactions
(E – electrophile).
The reduction potential of compound (CN)4 and native
cobalamin (CN)1 differ by 0.13 V although they both possess the
same base - DMB, this suggests that not only the base itself
affects the reduction potential, but also the structure of a linker
connecting the base and the corrin, as reported by Zelder et
al.[27]
Table 1. Reduction potentials for different cobalamin derivatives in MeOH (vs.
Ag/AgCl)
Entry
Catalyst
(H2O)1
base-off
No
EPc(CoIII→CoII)
+0.10
EPc(CoII→CoI)
-0.86
1
2
3
4
5
6
7
8
9
(CN)1
No
-1.01
-1.01
(P(O)(OMe)2)1
(H2O)2
No
-1.03
-1.03
Yes
Yes
Yes
Yes
Yes
Yes
Yes
+0.25
-0.73
(CN)2
-0.49 (-1.24)[a]
-0.77
-0.74 (-1.24)[a]
-0.77
Scheme 6. Model reaction chosen for comparison of cobalamin-like catalysts -
reductive dimerization of 1,1-diphenylethylene (8) and a plausible mechanism
proposed by van der Donk.[29]
(P(O)(OMe)2)2
(CN)4
-0.57
-0.88
(CN)5
-0.38
-0.77
The dimerization was affected by the presence of the
nucleotide loop, but not its basicity, contrary to the phenomena
of well-studied trans-effect. The highest yield was obtained when
native cobalamian (1) served as a catalyst for the discussed
reaction in either the cyano or aqua form, (Table 2, entries 1, 2).
However once the “loop” was unable of donating the lone
electron pair to the central atom, the yield decreased (entry 3, 4).
Both derivatives (H2O)1 and (CN)1 are in base-on form and
though they have different electrochemical behaviour as
depicted by cyclic voltammetry, they yielded almost the same
quantity of products (entry 1, 2). This result indicates that in the
studied reaction, the reduction step is not a rate-determining.
Moreover, green colour of the reaction mixture (characteristic for
Co(I) form of cobalamins), indicates that the complex B is a
steady-state of a catalyst during the reaction (see SI).
(CN)6
-0.56
-0.73
10
[a]
(CN)(H2O)3
-0.51 (-1.20)[a]
-0.73 (-1.20)[a]
Peaks corresponding to reduction of dicyano form.
Catalytic activity studies
In a typical cobalamin-catalysed reaction, the most important
steps featuring Cbl are its reduction to the Co(I) form and
homolytic cleavage of the Co-C bond, which can undergo via
photolytic or thermolytic pathway (Scheme 5).
Due to the fact that all studied compounds are polar, model
reaction had to be performed in a highly polar solvent in order to
exclude any solubility issues. Therefore, we examined the
synthesised set of cobalt catalysts in a reductive dimerization
1,1-diphenylethylene (Scheme 6), which could be performed in
EtOH, as reported by van der Donk et. al.[28,29] Mechanistic
studies of cobalamin-catalysed reactions of alkenes (including
styrene derivatives)[29,30] proves that the active form of the
catalyst is its Co(I) form B and is likely to proceed via the
formation of Co-C complex C (Scheme 6).
Interestingly, when the reaction was extended to 24 h, there
was little to no change in the yield for native cobalamin (1, entry
1
in parentheses) in contrast to catalyst 3 (entry 4 in
parentheses) for which the yield increased to 99%, suggesting
that with an increased rate of the dimerization, side products
started forming (see SI). The cobinamide derivative 5 with a
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As a consequence, the binding of the loop to the cobalt ion
facilitates formation of the Co-C bond. Moreover, they point to
the possible dependence of catalytic properties on the
nucleotide ligand.
primary amine serving as the axial ligand, was the least efficient
catalyst, presumably due to presence of the -NH2 group (entry 7).
Table 2. Yields of dimer 9 obtained in model reaction.
Entry
Catalyst
(CN)1
base-off
No
Yield [%]
1
2
3
4
5
6
80 (78)[a]
Conclusions
(H2O)1
(H2O)2
(CN)(H2O)3
(CN)6
No
77
In conclusion, new N-methylated cobalamins 2 with four different
-
-
axial ligands – CN-, P(O)(OMe)2 , P(O)Ph2 and H2O, were
synthesised by two different methods - a) microwave irradiation
of methanol solution of P(OMe)3 and cyanocobalamin ((CN)1),
b) by the formation of the semi-base-off form and the
subsequent methylation with methyl iodide. Three different
models - cobinamide derivatives (4-6), with an extended f-side
chain were obtained.
Yes
Yes
Yes
Yes
Yes
65
68 (99)[a]
74
75
8
(CN)4
7
(CN)5
Catalytic activity of cobalt catalysts were tested in the model
reductive dimerization of 1,1-diphenylethylene (8). The data
obtained in catalytic experiments suggests that in dimerization,
complexation of the cobalt ion plays a vital role, influencing the
reaction yield. The base-on derivatives proved to react with
alkene 8 with higher rate, however more controlled reaction with
base-off derivatives allowed to obtain exclusively dimerization
product 9 without the formation of side products. The results
obtained for reactions catalyzed by compounds 2, 4, 6 suggest
that the sole presence of the nucleotide loop in the structure of a
catalyst has an impact on their catalytic property and the
outcome of the reaction.
[a]
Yield after 24 h;
DFT calculations
In order to determine how binding of a loop influences the Co-C
bond strength in the plausible intermediate C (Scheme 6), we
performed calculations of the Co-C bond dissociation energy
using the method BP86/TZVP and truncated structures of base-
on and base-off forms of cobalamin (Scheme 7) proposed by
Kozlowski et al.[9]
Our findings provide new insights into properties of base-off
form of vitamin B12. We expect that the greater understanding of
the influence of the nucleotide loop on catalytic properties of
vitamin B12 and its derivatives will soon result in a development
of new cobalamin catalysed reactions of general use.
Experimental Section
Scheme 7. Truncated structures of base-on and base-off forms of vitamin B12
used in calculations.
General information
Commercially available reagents and solvents were used as received. 1H
and 13C NMR spectra were recorded at room temperature on a Bruker
or Varian 500 MHz spectrometer with the residual solvent peak as an
internal standard. Data are reported as follows: chemical shift, peak
multiplicity (s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet),
coupling constants (Hz) and the number of protons. UV-visible spectra
were recorded on a Jenway 7315 spectrophotometer. High resolution
In the case of base-off form EtOH was chosen as an α-axial
ligand as our model reaction was performed in this solvent. The
results of DFT calculations confirmed that the coordination by
the nucleotide ligand leads to the formation of more stable Co-C
complex. Substitution of DMB with EtOH significantly increases
the distance between α-ligand and the central cobalt atom, while
the trans-effect manifests itself in a decrease of the bond
dissociation energy of Co-C bond by 75 kJ/mol (Table 3).
ESI mass spectra were recorded on
a Mariner and SYNAPT
spectrometer. All the reactions and products purities were monitored
using RP HPLC technique. Preparative chromatography was performed
using Knauer RP C-18 column, 250x20 mm, with flow rate of 9 ml min-1
with water purified by reverse osmosis and HPLC grade MeCN or MeOH
as eluents. HPLC analytical measurement conditions: column, Kromasil
Eternity-5-C18, 250 mm × 4.6 mm with a precolumn; UV/vis detection,
temperature, 30 °C; wavelengths 254 nm and 361 nm, flow rates 1 ml
min-1. Compounds 3 and 7 were synthesised according to the literature
procedures.[31,32] Calculations were performed using Gaussian 09 E.01,
using BP86 method with 6-31G(d) basis set for C,H,N,O and def2TZVP
for cobalt.[33]
Table 3. Calculated bond dissociation energies and bond lengths for model
catalysts.
Entry
α-ligand
Co-Cβ/
Co-α ligand/
ECo-C/ kJ·mol-1
Å
Å
1
2
DMB
1.976
1.977
2.235
2.473
170.3
95.0
EtOH
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Analytical chromatography gradient
Program 1
General procedure for reductive dimerization of 8
Freshly activated zinc dust (98 mg, 1.5 mmol), NH4Cl (45 mg, 1.7 mmol),
a catalyst (2.5 μmol) and EtOH (2.5 mL) were placed in a test tube and
sealed with septum. The reaction was degassed using ultrasounds with
argon being passed through the reaction mixture. Once the colour
change was observed, 1,1-diphenylethylene (8, 45 μL, 0.25 mmol) was
added via septum. The reaction was irradiated with visible light (LED,
300 lm, warm) with vigorous stirring to assure good zinc dispersion and
for either 1 hour or 24 hours. The crude reaction mixture was diluted with
Et2O (20 mL) and filtered through a pad of celite. The resulting filtrate
was concentrated under reduced pressure and purified by flash
chromatography using hexanes:AcOEt mixture (97:3) as an eluent.
Appropriate fractions were collected, solvents removed under reduced
pressure and the resulting white solid was dried in vacuo.
Entry
H2O (0.5‰ TFA) [%]
MeCN [%]
Time [min]
1
2
3
4
99
85
20
99
1
15
80
1
0
5
30
35
Program 2
Entry
H2O (0.5‰ TFA) [%]
MeCN [%]
Time [min]
Cyclic voltammetry
1
2
90
30
10
70
0
A cylindrical three-electrode cell was equipped with a glassy carbon
working electrode, a 25 mm platinum wire as the counter electrode and
an Ag/AgCl (3.0 M NaCl) electrode as the reference electrode. The scan
rate for a typical experiment was 100 mV·s−1. The solution of the vitamin
15
Preparative chromatography gradient
−
B12 derivative (2.0 × 10−3 M) and n-Bu4N+ClO4 (1.0 × 10−1 M) in dry
Entry
H2O (0.5‰ TFA) [%]
MeOH [%]
Time [min]
MeOH was deaerated by Ar gas bubbling before the measurements, and
the cyclic voltammetry was carried out under an Ar gas atmosphere at
room temperature. The E1/2 value of the ferrocene–ferrocenium (Fc/Fc+)
in MeOH was +0.44 V vs. Ag/AgCl with this setup.
1
2
3
4
99
57
50
99
1
43
50
1
0
60
70
75
Compound (P(O)(OMe)2)2
Synthesis from (CN)1 Cyanocobalamin (92 mg, 68 μmol) was evenly
distributed among seven microwave vessels equipped with stirring bars.
The substrate was dissolved in a mixture of MeOH (0.6 mL) and P(OMe)3
(0.1 mL, 0.8 mmol). Each vessel was irradiated with microwaves at 110
˚C for 25 min. After workup and HPLC (RP) 20 mg (17%, 13 μmol) of
yellow-brown solid was obtained.
General work up procedure prior to RP chromatography
All reactions requiring HPLC (RP) purification were diluted with 10-fold
excess of Et2O and poured on a pad of celite. The solid residue was
washed twice with 2-fold excess of Et2O, and flushed with MeOH.
Solvents were evaporated and the residue was dissolved in a minimal
amount of MeOH, transferred to 50 mL falcon tube, diluted with Et2O and
centrifuged. Resulting solid was washed with Et2O, n-pentane and dried
in vacuo.
Synthesis from (P(OMe)2)1 Substrate (30 mg, 21 μmol) was dissolved
in a mixture of MeOH (1.8 mL) and P(OMe)3 (0.15 mL, 1.2 mmol). The
reaction was irradiated with microwaves maintaining temperature of
110 C for 10 min. After workup and HPLC (RP) 5 mg (17%, 3 μmol) of
̊
yellow-brown solid was obtained.
General procedure for the synthesis of aqua complexes
1H NMR (DMSO-d6, 600 MHz) δ 9.59 (s, 1H), 7.99 (t, J = 4.8 Hz, 1H),
7.74( d, J = 10.8 Hz, 2H), 7.67 (d, J = 14.4 Hz, 2H), 7.56 (s, 1H), 7.49 (s,
1H), 7.39(s, 1H), 7.32 (s, 1H), 7.24 (s, 1H), 7.06 (s, 1H), 6.96 (s, 1H),
6.81 (s, 2H), 6.73 (s,1H), 6.71 (s, 1H), 6.50 (d, J = 4.2 Hz, 1H), 4.89 (d, J
= 5.8 Hz, 1H), 4.63 - 4.57(m, 1H), 4.57 - 4.51 (m, 2H), 4.50 (d, J = 9.0 Hz,
1H), 4.32 (d, J = 10.6 Hz, 1H), 4.40 (d, J = 2.9 Hz, 1H), 4.15 (quint, J =
6.1 Hz, 1H), 4.08 - 4.00 (m, 1H), 4.02(s, 3H), 3.58 (td, J1 = 3.73 Hz, J2 =
12.0 Hz, 3H), 3.34 (d, J = 3.0 Hz, 2H), 3.25(d, J = 10.9 Hz, 1H), 3.10 (d, J
= 10.9 Hz, 3H), 3.16 - 3.02 (m, 2H), 3.00 - 2.94 (m, 1H), 2.97 (d, J = 11.0
Hz, 3H), 2.86 (s, 1H), 2.61 (d, J = 1.8 Hz, 1H), 2.59 (s, 1H), 2.55 (s, 1H),
2.52 (dd, J1 = 2.2 Hz, J2 = 4.1, 1H), 2.40 (d, J = 14.2 Hz, 5H), 2.33 (s,
3H), 2.31 (s, 1H), 2.30 (s, 3H), 2.21 (d, J = 8.2 Hz, 2H), 2.26 - 2.16 (m,
1H), 2.11 - 2.03 (m, 1H), 2.02 - 1.91 (m, 3H), 1.91 - 1.72 (m, 4H), 1.67 (s,
3H), 1.55 (s, 3H), 1.59 -1.47 (m, 1H), 1.43 (d, J = 8.1 Hz, 1H), 1.31 (s,
5H), 1.28 - 1.13 (m, 2H), 1.06 (d, J = 6.3 Hz, 2H), 1.04 (s, 2H), 0.99 (s,
2H), 0.86 (t, J = 7.2 Hz, 1H), 0.80 (d, J = 6.4 Hz, 1H). 13C NMR (DMSO-
d6, 150 MHz) δ 177.3, 175.7, 174.7, 174.2, 173.9, 173.5, 173.3, 173.2,
173.2, 172.9, 171.4, 163.7, 163.3, 157.9, 157.7, 140.7, 135.9, 135.8,
130.1, 129.2, 114.1, 112.8, 107.7, 106.0, 97.2, 87.8, 86.6, 86.5, 85.7,
75.0, 74.1, 72.1, 70.0, 61.0, 54.3, 54.2, 53.7 (d, J = 42 Hz), 53.4 (d, J =
To remove the cyanide ligand from cobalamin and its derivatives, a
sample of cyano complex (22 μmol) was dissolved in H2O (50 mL) and
Na2SO3 (0.5 g, 3.9 mmol) was added. The resulting mixture was stirred
for 1 hour. Than it was diluted with H2O (100 mL) and solvents were
removed under reduced pressure. The resulting crude was redissolved in
EtOH and filtered through a pad of celite. Again solvent was removed
under reduced pressure; the resulting solid was dissolved in H2O (22 mL)
and irradiated with visible light (LED, 300 lm, warm). Thereafter solvent
was evaporated and the crude was purified by chromatography.
General procedure for CDT coupling
(CN)(H2O)3 (30 mg, 27 μmol) and CDT (80 mg, 487 μmol) were placed in
a tube with a Teflon screw and flushed with argon prior to addition of dry
NMP (1 mL). The reaction was put in a preheated oil bath for 50 ˚C, for
30 min. Afterwards an amine (600 μmol) was added in a stream of argon
and the resulting mixture was heated for another hour. The crude mixture
was purified by column chromatography.
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10.1002/ejoc.201800877
European Journal of Organic Chemistry
FULL PAPER
36 Hz), 52.5, 49.9, 46.7, 45.6, 45.2, 41.7, 41.2, 38.7, 35.3, 33.2, 32.9,
32.5, 32.2, 30.7, 27.5, 26.4, 25.7, 23.8, 20.1, 20.0, 19.4, 19.0, 17.3, 16.6,
15.71, 15.70, 15.2. 31P NMR (DMSO-d6, 288 MHz) δ 34.1, 0.1. HRMS
87.0, 84.8, 75.8, 75.0, 74.8, 72.3, 71.4, 65.5, 61.3, 59.4, 57.2, 56.9, 56.0,
55.5, 54.1, 49.8, 44.6, 42.1, 41.2, 39.6, 39.1, 35.2, 33.9, 32.9, 32.5, 32.2,
31.9, 30.1, 26.7, 25.8, 22.0, 21.1, 19.2, 19.1, 18.5, 18.3, 18.0, 17.1, 16.7,
16.1, 15.2, 14.0, 13.0. HRMS (ESI-TOF) m/z calcd for
C63H91CoN14O14PCo [M]+ 1343.5878, found 1343.5874. IR (KBr, cm−1):
3348, 3198, 2973, 2936, 2875, 1669, 1621, 1580, 1502, 1452, 1401,
1335, 1283, 1200, 1138, 1069, 993, 951, 886, 841, 801, 722, 584. UV/vis
(H2O) λmax (nm) (ε, M−1 cm−1): 223 (3.5×104), 274 (1.7×104), 349
(1.8×104), 403 (3.2×103), 494 (7.3×103), 518 (7.6×103). HPLC: tanalytical 1
= 12.1 min, tpreparative = 60.7 min.
- +
(ESI-TOF) m/z calcd for C65H97CoN13O17P2Co [M-CF3CO2 ] : 1452.5933,
found 1452.5894. IR (KBr, cm−1 ): 3376, 3196, 2976, 2947, 1667, 1621,
1573, 1496, 1452, 1406, 1350, 1221, 1205, 1153, 1118, 1069, 1029,
1002, 951, 884, 785, 731, 566. UV/vis (H2O) λmax (nm) (ε, M−1 cm−1):219
(2.6×103), 258 (1.8×103), 279 (1.6×103), 318 (1.2×103), 345 (1.1×103),
401 (7.1×102), 437 (7.1×102). HPLC: tanalytical 1 = 16.2 min, tpreparative
=
15.32 min.
Compound (CN)2
Compound (P(O)(OMe)2)1[24]
(P(O)(OMe)2)2 (40 mg, 26 μmol) was transformation to aqua complex
according to the general procedure described above and the resulting
crude was dissolved in MeOH (5 mL) and NaCN (6 mg) was added. The
resulting mixture after work-up was purified by HPLC (RP) yielding 16 mg
of red solid (41%, 11 μmol).
(CN)1 (102 mg, 75 μmol) was dissolved in MeOH (6 mL) and P(OMe)3
(0.25 mL, 2.1 mmol) followed up with addition of BF3∙OEt2 (0.25 mL,
2.mmol). After stirring for 1 hour the reaction was worked up as
described above and purified using HPLC (RP) yielding 61 mg of red
solid (57%, 43 μmol).
1H NMR (CD3OD, 500 MHz) δ 9.42 (d, J = 8.4 Hz, 1H), 7.71 (d, J = 4.8
Hz, 1H), 7.66 (d, J = 9.4 Hz, 1H), 6.55 (s, 1H), 6.50 (d, J = 5.4 Hz, 1H),
6.47 (t, J = 2.4 Hz, 1H), 4.71 (s, 1H), 4.50 (d, J = 9.2 Hz, 1H), 4.31 (d, J =
9.3 Hz, 2H), 4.11 (d, J = 4.3 Hz, 3H), 4.07 (d, J = 10.4 Hz, 1H), 3.89 (dd,
J = 10.1, 5.1 Hz, 1H), 3.78 (s, 2H), 3.71 (dd, J = 6.1, 4.9 Hz, 1H), 3.54 (s,
1H), 3.45 - 3.40 (m, 1H), 3.28 (d, J = 5.0 Hz, 1H), 3.25 - 3.11 (m, 1H),
2.78 (d, J = 14.1 Hz, 1H), 2.75 - 2.70 (m, J = 6.1 Hz, 1H), 2.65 (d, J =
14.0 Hz, 1H), 2.61 - 2.49 (m, 3H), 2.48 (s, 5H), 2.46 (d, J = 2.6 Hz, 3H),
2.43 (s, 3H), 2.40 (s, 3H), 2.37 - 1.84 (m, 8H), 1.83 (s, 2H), 1.78 - 1.72
(m, 1H), 1.71 (s, 1H), 1.67 (s, 1H), 1.60 (s, 3H), 1.57 (d, J = 5.0 Hz, 2H),
1.39 (s, 2H), 1.37 (s, 3H), 1.34 (s, 1H), 1.32 - 1.23 (m, 3H), 1.21 (dd, J =
8.5, 6.4 Hz, 3H), 1.15 (s, 1H), 0.90 (t, J = 7.1 Hz, 3H). 13C NMR (CD3OD,
125 MHz) δ 180.4, 179.9, 179.7, 178.9, 178.7, 178.5, 177.5, 175.8, 175.6,
174.6, 165.9, 165.7, 165.3, 142.0, 132.0, 131.2, 114.9, 113.6, 108.3,
106.7, 96.1, 94.8, 89.1, 88.5, 87.0, 85.0, 76.8, 76.3, 73.8, 72.8, 62.8,
61.0, 60.4, 58.6, 57.7, 57.4, 57.0, 55.5, 55.3, 52.2, 46.7, 46.2, 43.9, 42.8,
40.7, 40.2, 36.4, 36.2, 35.3, 34.2, 33.9, 33.4, 33.2, 33.0, 31.7, 28.3, 28.1,
28.0, 27.6, 27.1, 26.8, 25.0, 23.4, 22.9, 21.8, 20.5, 20.3, 20.0, 19.8, 19.6,
18.0, 17.7, 17.39, 16.5, 16.4, 14.4. HRMS (ESI-TOF) m/z calcd for
C64H91CoN14O14PCo [M]+ 1369.5909, found 1369.5900. IR (KBr, cm−1):
3333, 3190, 2966, 2876, 2135, 1667, 1614, 1577, 1499, 1449, 1396,
1357, 1311, 1219, 1153, 1116, 1069, 993, 951, 845, 581. UV/vis (H2O)
λmax (nm) (ε, M−1 cm−1): 221 (4.7×104), 277 (1.7×104), 354 (2.6×104),
498 (8.8×103), 525 (8.3×103). HPLC: tanalytical 1 = 14.70 and 15.00 min,
tpreparative = 57.9 and 63.2 min.
1H NMR (DMSO-d6, 500 MHz) δ 7.71 (s, 1H), 7.65 (s, 1H), 7.57 (d, J =
22.1 Hz, 3H), 7.32 (s, 1H), 7.23 (s, 1H), 7.11 (s, 1H), 7.01 (d, J = 10.8 Hz,
2H), 6.89 (d, J = 6.4 Hz, 2H), 6.74 (s, 1H), 6.57 (s, 1H), 6.50 (s, 1H), 6.35
(s, 1H), 6.19 (s, 1H), 6.10 (s, 1H), 5.99 (s, 1H), 5.95 (s, 1H), 4.53 (d, J =
8.6 Hz, 1H), 4.49 (s, 1H), 4.12 (d, J = 6.6 Hz, 1H), 4.03 (d, J = 10.6 Hz,
1H), 3.92 (d, J = 3.9 Hz, 2H), 3.72 – 3.64 (m, 1H), 3.53 (d, J = 18.9 Hz,
3H), 3.22 (d, J = 10.4 Hz, 3H), 3.10 (d, J = 10.4 Hz, 4H), 2.74 (s, 1H),
2.64 (d, J = 11.6 Hz, 2H), 2.43 (s, 5H), 2.39 (s, 5H), 2.35 – 2.19 (m, 5H),
2.17 (s, 4H), 2.16 (s, 4H), 2.08 (d, J = 12.6 Hz, 1H), 2.06 – 1.92 (m, 2H),
1.85 (s, 1H), 1.75 (d, J = 12.6 Hz, 2H), 1.67 (s, 5H), 1.56 (dd, J = 14.9,
7.6 Hz, 1H), 1.33 (s, 3H), 1.26 (s, 3H), 1.25 – 1.19 (m, 2H), 1.16 (s, 3H),
1.09 (t, J = 5.7 Hz, 1H), 1.05 (s, 3H), 0.84 (s, 1H), 0.30 (s, 3H). HRMS
(ESI-TOF) m/z calcd for C64H94CoN13O17P2CoNa [M+Na]+ 1460.5596
found 1460.5583. HPLC: tanalytical 1 = 13.95 min, tpreparative = 14.2 min.
Compound NHI-(P(O)Ph2)1
(H2O)1 (50 mg, 36 μmol) was put in a vial and dissolved in DMSO (2 mL),
followed by addition of compound 7 (117 mg, 420 μmol). The vial was
kept in a heating mantel with temperature set for 50 ˚C for 16 hours. The
crude was diluted with 2 ml of AcOEt and worked up as described above,
followed by HPLC (RP) yielding 30 mg (54%, 20 μmol) yellow-brown
solid.
1H NMR (DMSO-d6, 600 MHz) δ 8.96 (s, 1H), 7.85 (s, 2H), 7.64 (d, J =
36.4 Hz, 5H), 7.56 (s, 2H), 7.41 (d, J = 20.6 Hz, 5H), 7.34 (s, 3H), 7.24 –
7.11 (m, 13H), 7.08 (t, J = 6.3 Hz, 4H), 6.90 (d, J = 22.6 Hz, 3H), 6.82 (s,
2H), 6.80 – 6.74 (m, 4H), 6.69 (s, 1H), 6.43 – 6.37 (m, 4H), 4.67 (d, J =
10.4 Hz, 2H), 4.65 (s, 1H), 4.61 (s, 1H), 4.58 (s, 1H), 4.44 (d, J = 9.8 Hz,
1H), 4.24 (t, 1H), 3.95 – 3.91 (m, 1H), 3.59 (s, 3H), 3.56 (d, J = 8.9 Hz,
2H), 3.23 (d, J = 13.2 Hz, 1H), 3.14 (s, 3H), 2.71 (s, 2H), 2.43 – 2.34 (m,
3H), 2.31 (s, 5H), 2.28 (s, 8H), 2.18 (d, J = 16.5 Hz, 6H), 2.17 – 2.06 (m,
12H), 2.04 – 1.88 (m, 10H), 1.83 (d, J = 9.3 Hz, 4H), 1.69 (dd, J = 32.3,
8.6 Hz, 6H), 1.63 (s, 6H), 1.51 (d, J = 7.1 Hz, 4H), 1.46 (d, J = 6.9 Hz,
9H), 1.31 – 1.25 (m, 2H), 1.22 (s, 5H), 1.13 – 1.07 (m, 6H), 0.86 (t, J =
7.2 Hz, 2H), 0.60 (d, J = 14.9 Hz, 4H), 0.44 (s, 4H), 0.16 (d, J = 13.9 Hz,
1H). 13C NMR (150 MHz, DMSO-d6) δ 177.55, 176.18, 175.32, 175.07,
173.83, 173.60, 173.52, 173.44, 172.58, 171.35, 171.26, 165.37, 164.49,
163.66, 159.54, 157.66, 140.01, 136.42 (d, J = 53.7 Hz), 135.26 (d, J =
55.9 Hz), 133.38, 130.41, 129.87, 129.23, 128.85 (d, J = 5.3 Hz), 128.48
(d, J = 10.5 Hz), 127.88 (d, J = 11.1 Hz), 127.71 (d, J = 11.8 Hz), 118.65,
115.10, 112.58, 110.03, 108.21, 98.92, 87.30, 86.51, 85.66, 75.37, 74.33,
71.65, 71.07, 64.80, 60.94, 58.72, 54.22, 53.84, 51.88, 48.56, 46.24,
45.42, 44.45, 33.39, 32.44, 32.22, 32.10, 32.01, 31.71, 30.24, 27.19,
Compound (H2O)2
(P(O)(OMe)2)2 or (P(O)Ph2)2 (40 mg, 26 μmol) were transform into aqua
complexes according to the general procedure described above and
purified using HPLC (RP) yielding either 26 mg (76%, 20 μmol) or 13 mg
(40%, 10 μmol) of red solid respectively.
1H NMR (CD3OD, 500 MHz) δ 9.45 (s, 1H), 7.72 (s, 1H), 7.66 (s, 1H),
6.52 (s, 1H), 6.50 (s, 1H) 4.93 (s, 1H), 4.71 (s, 1H), 4.55 (s, 1H), 4.34 (t,
J = 5.5 Hz, 1H), 4.11 (s, 3H), 3.80 (t, J = 3.5 Hz, 2H), 3.69 (d, J = 19 Hz,
1H), 3.43 (s, 3H), 3.21 (d, J = 12.5 Hz, 1H), 2.83 (s, 1H), 2.77 (s, 1H),
2.62 - 2.48 (m, 12H), 2.46 (s, 3H), 2.45 (s, 3H), 2.41 - 2.26 (m, 3H), 2.26
- 2.12 (m, 4H), 1.85 - 1.79 (m, 3H), 1.81 (s, 3H), 1.66 (s, 3H), 1.63 (s, 4H),
1.45 (d, J = 7.6 Hz, 3H), 1.32 (d, J = 6.3 Hz, 2H), 1.30 (d, J = 1.5 Hz, 1H),
1.28 (s, 3H), 1.26-1.23 (m, 1H), 1.20 (s, 1H), 1.192 (s, 1H), 1.188 (s, 1H),
1.17 (s, 2H), 1.16 (s, 1H), 0.89 (t, J = 7.0 Hz, 1H). 13C NMR (CD3OD, 125
MHz) δ 181.0, 180.9, 176.2, 174.7, 173.9, 173.6, 164.5, 164.3, 162.8,
140.6, 136.9, 130.6, 129.5, 113.4, 112.2, 104.9, 103.3, 92.8, 87.8, 87.2,
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10.1002/ejoc.201800877
European Journal of Organic Chemistry
FULL PAPER
26.12, 25.82, 23.50, 21.62, 21.59, 20.03, 19.55, 19.09, 18.67, 17.46,
16.24, 15.55, 15.47, 15.06, 13.79. 31P NMR (243 MHz, DMSO-d6) δ
66.42, -1.30; HRMS (ESI-TOF) m/z calcd for C74H99CoN13O15P2Na
[M+Na+]2+ 776.8093 found 776.8040; UV/vis (MeOH) λmax (nm) (ε, M−1
Compound (CN)5
Compound (CN)5 was synthesized according to the general procedure
described for CDT coupling yielding 6.5 mg (18%, 4.9 μmol) of red solid.
cm−1): 265 (2.5×104), 327 (2.0×104), 433 (1.1×104); HPLC:
=
1
tanalytical
15.14 min, tpreparative = 16.0 min.
1H NMR (500 MHz, CD3OD) δ 7.28 (dd, J = 14.7, 7.2 Hz, 2H), 7.22 (d, J
= 7.4 Hz, 1H), 7.17 (d, J = 7.6 Hz, 1H), 5.81 (s, 1H), 4.27 (q, 2H), 4.12 (d,
J = 9.0 Hz, 1H), 3.79 (d,J = 10.7 Hz, 1H), 3.76 (s, 2H), 3.56 (d, J = 4.7 Hz,
1H), 3.39 (dd, J = 14.0, 4.1 Hz, 1H), 3.24 (dd, J = 13.9, 7.3 Hz, 1H), 3.15
(s, 1H), 3.01 – 2.93 (m, 1H), 2.63 (dd, J = 14.0, 9.7 Hz, 2H), 2.59 – 2.55
(m, 1H), 2.52 (d, J = 13.8 Hz, 2H), 2.48 (dd, J = 10.6, 4.8 Hz, 1H), 2.38
(ddd, J = 24.8, 14.0, 8.4 Hz, 3H), 2.30 (s, J = 7.4 Hz, 3H), 2.28 (s, 3H),
2.26 – 2.14 (m, 2H), 2.12 (d, J = 9.2 Hz, 1H), 2.10 (s, 1H), 2.08 – 1.88 (m,
3H), 1.88 – 1.79 (m, 2H), 1.70 (s, 3H), 1.51 (t, J = 6.6 Hz, 4H), 1.42 (s,
3H), 1.35 – 1.28 (m, 2H), 1.25 (d, J = 12.5 Hz, 3H), 1.22 (d, J = 6.2 Hz,
3H), 1.19 (s, 3H), 1.17 (d, J = 7.0 Hz, 2H), 1.15 (d, J = 6.2 Hz, 1H), 0.90
(t, J = 7.1 Hz, 2H); 13C NMR (126 MHz, CD3OD) δ 176.88, 176.81,
176.71, 176.19, 174.41, 174.30, 173.54, 172.36, 163.42, 163.01, 157.22,
142.58, 139.39, 128.31, 126.03, 125.80, 125.48, 104.74, 102.74, 90.69,
83.15, 75.10, 69.81, 65.46, 58.68, 56.89, 56.35, 55.24, 53.55, 49.08,
46.41, 46.04, 45.25, 44.07, 43.60, 43.35, 41.30, 38.76, 34.83, 33.89,
32.79, 32.08, 31.54, 31.27, 31.17, 30.37, 27.00, 25.26, 21.96, 21.47,
18.43, 17.99, 16.93, 16.84, 15.91, 14.73, 14.51, 14.01, 12.93; HRMS
(ESI-TOF) m/z calcd for C58H82CoN14O9 [M]+ 1177.5721 found
1177.5712; UV/vis (MeOH) λmax (nm) (ε, M−1 cm−1): 277 (1.7×104), 354
Compound (P(O)Ph2)2
(P(O)Ph2)1 (20 mg, 16 μmol) was put in a vial and dissolved in DMSO (2
mL), followed by addition of MeI (15 μL, 160 μmol) The vial was kept in a
heating mantel with temperature set for 50 ˚C for 16 hours. The crude
was diluted with AcOEt (2 mL) and worked up as described above,
followed by purification using HPLC (RP) yielding 10 mg (50%, 8 μmol)
yellow-brown solid.
1H NMR (500 MHz, CD3OD) δ 9.41 (s, 1H), 7.72 – 7.62 (m, 2H), 7.39 (t, J
= 7.3 Hz, 1H), 7.34 – 7.23 (m, 3H), 7.15 (dd, J = 7.4, 5.5 Hz, 3H), 6.86
(dd, J = 10.9, 8.2 Hz, 2H), 6.47 (t, J = 8.5 Hz, 2H), 4.78 – 4.72 (m, 1H),
4.67 (d, J = 4.1 Hz, 1H), 4.64 (s, 1H), 4.47 (d, J = 9.0 Hz, 1H), 4.30 (t,
1H), 4.09 (s, J = 7.0 Hz, 2H), 4.07 – 4.02 (m, 1H), 3.85 (d, J = 4.9 Hz,
1H), 3.74 (t, 1H), 3.31 (dt, J = 3.2, 1.6 Hz, 3H), 3.26 (d, J = 4.9 Hz, 1H),
3.19 (d, J = 14.7 Hz, 1H), 2.88 (t, 1H), 2.62 (ddd, J = 24.4, 16.2, 10.5 Hz,
1H), 2.56 – 2.48 (m, J = 16.0, 6.3 Hz, 1H), 2.45 (d, J = 14.2 Hz, 6H), 2.40
(s, 3H), 2.35 (dd, J = 9.5, 4.3 Hz, 1H), 2.32 (s, 3H), 2.30 – 2.25 (m, 2H),
2.25 – 2.11 (m, 2H), 2.11 – 2.01 (m, 2H), 2.01 – 1.95 (m, 2H), 1.91 –
1.82 (m, 2H), 1.80 (s, 4H), 1.76 (d, J = 11.9 Hz, 1H), 1.67 – 1.63 (m, 1H),
1.62 (d, J = 4.5 Hz, 3H), 1.61 (s, 3H), 1.42 (t, 2H), 1.39 – 1.23 (m, 2H),
1.19 (s, 1H), 1.17 (s, 3H), 1.16 (s, 3H), 0.90 (t, J = 7.1 Hz, 1H), 0.73 (s,
3H), 0.65 (s, 3H), 0.36 (d, J = 14.3 Hz, 1H); 13C NMR (126 MHz, CD3OD)
δ 178.04, 176.90, 176.55, 176.22, 175.96, 175.86, 174.95, 174.24,
173.39, 173.27, 165.49, 164.49, 140.57, 136.86, 136.30 (d, J = 56.2 Hz),
134.69 (d, J = 58.2 Hz), 131.22, 131.06, 130.57, 129.74, 129.01, 128.96
(d, J = 10.3 Hz), 128.60 (d, J = 10.1 Hz), 128.11, 128.02, 113.40, 112.22,
111.37, 110.06, 109.99, 109.48, 100.03, 88.51, 87.95, 87.71, 87.27,
87.07, 75.67, 74.90, 72.27, 71.30, 65.47, 61.32, 59.62, 55.39, 54.75,
52.55, 49.27, 45.74, 44.73, 41.04, 40.93, 38.85, 34.64, 33.89, 32.45,
32.32, 31.95, 31.88, 31.18, 27.12, 26.41, 26.09, 23.44, 21.96, 20.85,
19.18, 19.11, 18.37, 17.64, 15.81, 15.28, 14.95, 14.02, 12.94; HRMS
(ESI-TOF) m/z calcd for C75H101CoN13O15P2Na [M+Na+]2+ 783.8117
found 783.8114; UV/vis (MeOH) λmax (nm) (ε, M−1 cm−1): 266 (2.4×104),
(2.6×104), 495 (8.4×103), 523 (8.4×104); HPLC: tanalytical = 6.00 min,
2
tpreparative = 10.23 min.
Compound (CN)6
Compound (CN)6 was synthesized according to the general procedure
described for CDT coupling yielding 16 mg (43%, 12 μmol) of red solid.
1H NMR (500 MHz, CD3OD) δ 7.32 (d, J = 8.1 Hz, 1H), 7.25 (d, J = 2.8
Hz, 1H), 7.08 (t, 1H), 6.97 (d, J = 7.0 Hz, 1H), 6.57 (t, J = 5.7 Hz, 1H),
5.78 (s, 1H), 4.63 (d, J = 14.9 Hz, 1H), 4.56 (dd, J = 14.6, 6.4 Hz, 1H),
4.50 (d, J = 14.9 Hz, 1H), 4.12 (d, J = 8.7 Hz, 1H), 3.77 (d, J = 10.6 Hz,
1H), 3.58 – 3.52 (m, 1H), 3.42 (dd, J = 14.0, 3.2 Hz, 1H), 3.34 (s, 1H),
3.17 (dd, J = 13.9, 8.0 Hz, 1H), 2.93 (dd, J = 10.4, 5.8 Hz, 1H), 2.87 (s,
1H), 2.60 (d, J = 4.5 Hz, 2H), 2.56 (d, J = 12.9 Hz, 1H), 2.51 (d, J = 13.6
Hz, 3H), 2.46 (d, J = 4.8 Hz, 1H), 2.42 – 2.37 (m, 1H), 2.36 (s, 1H), 2.27
(s, J = 11.1 Hz, 2H), 2.24 – 2.13 (m, 3H), 2.11 (s, 3H), 2.10 – 2.04 (m, J
= 11.0, 6.5 Hz, 2H), 2.01 – 1.91 (m, 3H), 1.86 – 1.77 (m, 2H), 1.69 (s, J =
17.3 Hz, 3H), 1.48 (s, 3H), 1.46 (s, 2H), 1.41 (dd, J = 19.5, 8.5 Hz, 2H),
1.36 ( s, 2H), 1.29 (dd, J = 18.9, 9.5 Hz, 2H), 1.26 – 1.20 (m, 3H), 1.19 (s,
1H), 1.17 (s, 2H), 1.16 (s, 3H), 0.90 (t, J = 6.8 Hz, H); 13C NMR (126
MHz, CD3OD) δ 178.41, 178.32, 178.23, 178.15, 178.11, 177.64, 175.84,
175.69, 174.97, 173.69, 164.80, 164.36, 158.64, 137.72, 131.27, 127.96,
125.63, 122.27, 119.02, 111.73, 106.12, 104.17, 100.61, 92.06, 84.55,
76.43, 71.25, 66.89, 60.06, 57.73, 56.64, 54.82, 50.51, 47.74, 47.46,
45.11, 44.77, 44.05, 42.71, 40.07, 36.25, 34.25, 33.42, 32.97, 32.74,
32.48, 31.83, 28.41, 26.66, 26.44, 23.69, 22.85, 19.85, 19.41, 18.35,
18.27, 17.32, 16.15, 15.83, 15.43, 14.41; HRMS (ESI-TOF) m/z calcd for
C59H80CoN14O9 [M]+ 1187.5565 found 1187.5555; UV/vis (MeOH) λmax
(nm) (ε, M−1 cm−1): 277 (1.7×104), 354, (2.6×104), 495 (8.4×103), 523
(8.4×104); HPLC: tanalytical 2 = 6.82 min, tpreparative = 11.04 min.
325 (1.9×104), 431 (1.2×104); HPLC: tanalytical 1 = 15.32 min, tpreparative
16.2 min.
=
Compound (CN)4
Compound (CN)4 was synthesized according to the general procedure
described for CDT coupling yielding 17 mg (46%, 13 μmol) of red solid.
1H NMR (500 MHz, CD3OD) δ 8.08 (s, 1H), 7.43 (s, 1H), 7.36 (s, 1H),
5.80 (s, 1H), 4.28 (t, J = 7.1 Hz, 2H), 4.10 (d, J = 8.7 Hz, 1H), 3.77 (d, J =
10.7 Hz, 1H), 3.58 – 3.55 (m, 1H), 3.46 – 3.40 (m, 1H), 3.35 (s, J = 8.0
Hz, 1H), 3.16 (ddd, J = 27.3, 13.9, 7.2 Hz, 4H), 3.09 (s, 1H), 2.96 (s, 1H),
2.59 (s, 3H), 2.52 (d, J = 13.9 Hz, 1H), 2.46 (d, J = 9.4 Hz), 2.40 (s, 3H),
2.37 (s, 3H), 2.27 (d, J = 6.6 Hz, 7H), 2.22 – 2.14 (m, 2H), 2.14 – 2.00 (m,
5H), 2.00 – 1.78 (m, 3H), 1.70 (s, J = 5.0 Hz, 3H), 1.46 (s, 3H), 1.41 (s,
2H), 1.31 (dd, J = 13.9, 7.1 Hz, 2H), 1.24 (s, 2H), 1.21 (d, J = 6.3 Hz, 3H),
1.19 (d, J = 7.1 Hz, 2H), 1.17 (d, J = 1.9 Hz, 2H), 1.16 (s, 3H), 1.15 (s,
4H), 0.90 (t,
J = 7.1 Hz, 2H); HRMS (ESI-TOF) m/z calcd for
Acknowledgements
C62H87CoN15O9 [M]+ 1244.6143 found 1244.6135; UV/vis (MeOH) λmax
(nm) (ε, M−1 cm−1): 279 (1.7×104), 361 (2.6×104), 519 (8.4×103), 540
(8.4×104); HPLC: tanalytical 2 = 7.47 min, tpreparative = 12.86 min.
Financial support for this work was provided by the National Science
Centre (OPUS 2012/07/B/ST5/02016) and the Ministry of Science
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10.1002/ejoc.201800877
European Journal of Organic Chemistry
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Nakajima, Y. Honda, O. Kitao, H. Nakai, T. Vreven, J. A. Montgomery,
Jr., J. E. Peralta, F. Ogliaro, M. Bearpark, J. J. Heyd, E. Brothers, K. N.
Kudin, V. N. Staroverov, T. Keith, R. Kobayashi, J. Normand, K.
Raghavachari, A. Rendell, J. C. Burant, S. S. Iyengar, J. Tomasi, M.
Cossi, N. Rega, J. M. Millam, M. Klene, J. E. Knox, J. B. Cross, V.
Bakken, C. Adamo, J. Jaramillo, R. Gomperts, R. E. Stratmann, O.
Yazyev, A. J. Austin, R. Cammi, C. Pomelli, J. W. Ochterski, R. L.
Martin, K. Morokuma, V. G. Zakrzewski, G. A. Voth, P. Salvador, J. J.
Dannenberg, S. Dapprich, A. D. Daniels, O. Farkas, J. B. Foresman, J.
V. Ortiz, J. Cioslowski, and D. J. Fox, Gaussian, Inc., Wallingford CT,
2013.
and Higher Education (M.O. grant no. 0141/DIA/2015/44).
Calculations have been carried out at the Wroclaw Centre for
Networking and Supercomputing (http://www.wcss.pl), grant no. 432.
Keywords: cobalamin • vitamin B12 • catalysis • base-off •
cobinamide
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