An amphiphilic, catalytically active, vitamin B12 derivative

Article abstract of DOI:10.1039/c4cc01064g

We performed the reaction of vitamin B₁₂ with N,N-dimethylformamide dimethyl acetal for primary amide activation, and added MeOH as a nucleophile, to afford cobalester, the first amphiphilic cobalamin derivative. The unique combination of redox properties and solubility represents an asset for its use as a catalyst in C-C bond forming reactions. This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01064g

Volume 50 Number 36 11 May 2014 Pages 4649–4764
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D. Gryko et al.
An amphiphilic, catalytically active, vitamin B12 derivative

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An amphiphilic, catalytically active, vitamin B12
derivative†
M. Giedyk,a S. N. Fedosovb and D. Gryko*a
Cite this: Chem. Commun., 2014,
50, 4674
Received 10th February 2014,
Accepted 25th February 2014
DOI: 10.1039/c4cc01064g
www.rsc.org/chemcomm
We performed the reaction of vitamin B12 with N,N-dimethyl- loop, possess chemical and physical properties different from those
formamide dimethyl acetal for primary amide activation, and added of the parent vitamin B12. Importantly, in alkylcobalamins, the
MeOH as a nucleophile, to afford cobalester, the first amphiphilic nucleotide enhances the ease of abstraction of the cobalt-alkyl
cobalamin derivative. The unique combination of redox properties group by an electrophile.8
and solubility represents an asset for its use as a catalyst in C–C
bond forming reactions.
We hypothesized that a hydrophobic derivative that retained the
nucleotide loop would provide a better model for such haloenzymes
and serve as better catalysts for organic reactions. This B12 derivative
Among many biologically important metals, Co, in the form of would require the conversion of the primary amide groups of
vitamin B12 (cyano-cobalamin 1), plays a unique role.1,2 B12 co- cobalamin into esters. Typically, transformation of primary carbox-
enzymes are indispensable for catalyzing enzymatic rearrangements amides into esters entails harsh reaction conditions. Brocchetta9
(coenzyme B12, adenosylcobalamin) and methylation reactions and Myers,10 however, showed that primary amides can be selec-
(methylcobalamin).1 The special ability of vitamin B12 (1) and other tively activated and transformed into esters or secondary amides
corrinoids to form a Co–C bond, combined with its facility in under mild conditions via the formation of formamidine, which
furnishing alkyl radicals via homolysis, has attracted the interest subsequently reacts with nucleophiles (Table 1). Because the sec-
of many researchers, because corrinoids can be used as catalysts for ondary amides remained intact, we reasoned that this methodology
C–C-bond forming reactions, which belong to the most challenging might be promising for selective modification of the primary
processes in organic synthesis.3 These catalytic reactions typically amides in vitamin B12 leaving the nucleotide unaffected.
involve alkyl-cobalt complexes, which are formed in reactions of
Co(I) species and an electrophile or a Co(II) and a radical.4 The most
common chemical procedure utilizes the ‘supernucleophilicity’ of
Table 1 Synthesis of cobalester (3) and cobinester (5)
the Co(I) species (B12s) toward alkylating agents, such as alkyl
halides. Homolysis of the Co–C bond generates a carbon-centered
radical, which can, in situ, disproportionate, abstract Hꢀ, or self-
couple. In these reactions, B12 alkyl derivatives can be considered
‘reversible carriers’ of an alkyl radical.
To study the catalytic function of corrinoids in the hydrophobic
microenvironment of enzyme active sites, Hisaeda and co-workers
used cobyrinic acid derivatives as artificial enzymes. They were
successfully used for dehalogenation, rearrangement, and ring
expansion reactions.4–7 These corrinoids, devoid of the nucleotide
Entry
R
X
Substrate
Product
a Institute of Organic Chemistry Polish Academy of Sciences, Kasprzaka 44/52,
01-224 Warsaw, Poland. E-mail: dorota.gryko@icho.edu.pl;
Web: http://ww2.icho.edu.pl/Gryko_group/index.html; Fax: +48 22 632 66 81
b Department of Engineering Science, Aarhus University, Denmark
† Electronic supplementary information (ESI) available: Detailed synthetic pro-
cedures, full characterisation of new compounds, biological tests and stability
tests. CCDC 981457. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/c4cc01064g
1
2
—
CN
1
4
3
5
H
4674 | Chem. Commun., 2014, 50, 4674--4676
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We report herein the synthesis of an amphiphilic, catalyti-
cally active, analogue of cobalamin (1), prepared via a one-step
procedure, starting with vitamin B12 (1).
Initially, CNCbl (1) was treated with DMF-DMA (2) in MeOH at
room temperature for up to 4 days. The reaction mainly led to
pentamethyl ester with an intact nucleotide loop. Upon increasing
the amount of the activating reagent and prolonging the reaction
Scheme 1 Homocoupling of benzyl bromide (4).
time, the desired cobalester (3) was obtained in very low amounts migrations,17 and alkene dimerization.18 Typical obstacles encountered
(1%). A substantial improvement in yield and selectivity was in B12-catalyzed reactions include the low solubility of vitamin B12 (1) in
achieved when HFIP (hexafluoroisopropanol) was used as a solvent; organic solvents, high catalyst loading, and a limited number of
this afforded cobalester (3) in 72% yield (for detailed optimization reducing agents suitable for synthetic applications.
studies, see the ESI†). The positive influence of this polar, low
The radical homocoupling of benzyl bromide (6) is a typical
nucleophilic solvent was previously reported; a similar effect was model reaction for measuring the catalytic activity of reduced
recently observed in hypervalent iodine-catalyzed reactions.11–13 Our vitamin B12 (1) (Scheme 1). It was previously found that,
method was also applied successfully to the synthesis of cobinester depending on the Co-catalyst (vitamin B12, salen, CoPcTS),
(5), a hydrophobic derivative of cobinamide (4).
the reaction furnishes either toluene (7) or bibenzyl (8) via an
The structure of cobalester (3) was confirmed by MS spectro- anionic or a radical pathway, respectively.19
metry, UV-Vis and NMR spectroscopy, and elemental analysis. The
The benzyl radical formed can undergo further reactions,
ESI-MS spectra showed a signal at m/z = 1445.57, which corre- such as H radical abstraction from a solvent, homocoupling, or
sponded to a pseudomolecular ion [M+H]+. In the 1H NMR spectra, addition to activated double bonds.15,19,20 The cobalamin-
six proton resonances at 3.45, 3.68, 3.71, 3.72, 3.75, and 3.76 ppm, catalyzed reaction predominantly afforded bibenzyl (8), but in
which were assigned to six –OMe groups, confirmed the replacement a moderate yield (64%).
of six –CONH2 with –CO2Me groups. Ultimately, crystallization of the
Tanaka et al. showed that benzyl radicals can also be obtained by
product by vapor diffusion of Et2O into EtOH gave crystals suitable the photoinduced cleavage of cobalt(III) complexes, cis-[R2Co(bpy)2]-
for X-ray analysis, which unambiguously confirmed its structure ClO4, in the presence of benzyl halides.21 Other methods for obtaining
(Fig. 1). As expected, product 3 displays UV-Vis characteristics that this conversion include the homocoupling of halides in the presence of
are nearly identical to the parent vitamin B12 (1), but significantly various metals22,23 (Ni, Mg, Mn, Zn, Cu, In, Cr, Fe, Ti), the homo-
different from heptamethyl cobyrinate ((CN)2Cby(OMe)7) (see ESI†). coupling of Grignard compounds,24 oxidative coupling,25 Heck cross
The spectrum also confirmed that cobalester (3) exists in a ‘base on’ coupling,26 the Wittig reaction followed by reduction27 etc. Though
form.14 Derivative 3 did not bind to the specific B12-transporting effective, these methods involve expensive reagents and/or ligands,
proteins at concentrations as high as 1 mM, which confirms the high catalyst loading, environmental hazards, and difficulties in
crucial role of side chain amides in the B12 binding.
The corrinoid catalysis proceeds via the reduced forms, Co(II) of new, environmentally-benign methods that address these issues.
and Co(I), whose formation depends on the nature of the axial In our studies, the chemical reduction of cob(III)alester (3) to Co(I)
catalyst recycling. Consequently, interest remains high for the discovery
ligands attached.1 In cobalamin and cobalester, these ligands species was performed using NaBH4/i-PrOH at an elevated tempera-
are identical; consequently, their reduction potentials are very ture; then, it was reacted with benzyl bromide (6). In a typical
similar. Both compounds displayed the same cathodic Epc* experiment, all reagents were placed in a flask and allowed to react
values of À1.04 V vs. Ag/AgCl electrode (see ESI†), measured in under deoxygenated conditions. The reaction at room temperature was
an aqueous solution ([Tris] = 0.2 M, pH = 8.0) using CV.
very sluggish, but under microwave irradiation, it quickly proceeded to
With this redox behavior and excellent solubility in a broad range of completion. A short optimization study demonstrated that the
organic solvents, the new amphiphilic ester 3 is capable of catalyzing cobalester-catalyzed, microwave-assisted reaction of benzylbromide
C–C bond forming reactions. Reduced cobalamin can serve as a catalyst (6) at 90 1C for 15 min furnished the desired bibenzyl (8) in 84% yield
in various organic reactions, including dehalogenation,15 cyclopropane (Table 2, entry 4). Gratifyingly, the catalyst loading could be as little as
ring cleavage,16 additions to activated alkenes,15 functional group 0.5 mol%, which represents the lowest amount required to date in
similar B12-catalyzed reactions. Surprisingly, when the reaction was
heated in an oil bath, it furnished bibenzyl (8) in a low yield, despite
the prolonged reaction time required for full conversion (entries 6, 7).
For a detailed description of the optimization studies, see ESI.†
These reaction conditions render the method significantly sim-
pler and more useful than other procedures reported to date, for
example requiring electrochemical reduction, which limits their
synthetic applicability.15,19–21,28 After establishing optimized reac-
tion conditions, we investigated the scope of benzyl bromide (6)
dimerization catalyzed by our cobalester (3). Benzyl bromides with
either electron donating or electron withdrawing substituent were
Fig. 1 X-ray structure of cobalester (3).
tested (Table 3).
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Table 2 Optimization studiesa
Table 4 Catalyst evaluationa
Catalyst loading
Temperature
Time
[min]
Catalyst
Entry
Conversion [%]
Yieldb [%]
Yieldb [%]
Entrya
[mol%]
[1C]
1
2
3
4
5
Vitamin B12 (1)
Cobinamide (4)
Cobalester (3)
Cobinester (5)
(CN)2Cob(OMe)7
38
43
100
100
100
15
21
84
60
62
1
2
3
4
1.5
0.5
0.25
0.5
0.5
0.5
0.5
120
120
120
90
60
Reflux
Reflux
15
15
15
15
15
15
60
84
86
42
84
10
5
a
6c
7c
Traces
Reactions were conducted with BnBr (0.25 mmol), i-PrOH (1 mL),
58d
NaBH4 (0.5 mmol), catalyst (0.5 mol%), at 90 1C (microwave heating) for
b
15 min. Isolated yields.
a
Reaction conditions: BnBr (0.25 mmol), i-PrOH (1 mL), NaBH4
(0.5 mmol), unless otherwise noted, the reactions were performed in
b
c
a microwave reactor. Isolated yields. An oil bath was used instead of
plays a role in the radical reactions catalyzed by vitamin B12
derivatives. The microwave-assisted homocoupling of benzyl-
bromide (6) catalyzed by cobalester (3) produced a higher yield
when compared to reactions catalyzed by reduced (CN)2Cob(OMe)7.
The amphiphilic character of this newly synthesized derivative (3)
will facilitate a broader range of applications for vitamin
d
microwave irradiation. Full conversion.
Table 3 Substrate scopea
R
Catalyst loading [mol%] T [1C] Product Yield [%]
Entry
1
2
3
4
5
6
7
8
H
4-I
3-I
4-NO2
4-NO2
2-CN
4-F
0.5
0.5
0.5
0.5
2.5
2.5
0.5
0.5
90
90
90
8
9
84
74
70
Traces
56
52
B
12-catalyzed reactions in organic synthesis.
We acknowledge the generous support from the Ministry of
10
11
11
12
13
14
Science and Higher Education, grant no. 0145/DIA/2012/41.
90
120
120
90
90
91
Notes and references
1 R. Banerjee, Chemistry and Biochemistry of B12, John Wiley & Sons, 1999.
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3-OMe
90
a
Reaction conditions: ArCH2Br (0.25 mmol), i-PrOH (1 mL), NaBH4
(0.5 mmol), 15 min; all reactions were performed in a microwave reactor.
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All reactions with cobalester (3) gave the desired products, with
yields exceeding 50%. Benzyl bromides with electron withdrawing
substituents initially formed toluene derivatives. However, an increase
in the catalyst loading (to 2.5%) and temperature (to 120 1C) led to the
formation of the desired products, 11 and 12 (entries 5 and 6). Although
the range of substrates was not exhaustive, the reaction appeared to be
quite general. It has been shown that intramolecular coordination of
the nucleotide function labilizes the organometallic C–Co bond in
alkylcobalamins, which facilitates subsequent reactions.2
With our series of vitamin B12 derivatives, with and without the
5,6-dimethylbenzimidazole moiety, we were in a position to verify this
hypothesis (assuming formation of benzyl-Cbl as an intermediate of
the reaction). We evaluated the effectiveness of catalysts in the
dimerization of benzyl bromide (6) under optimized conditions. A
comparison of reactions in the presence of reduced cobalester (3) and
(CN)2Cob(OMe)7 indicated that the nucleotide moiety increased the
yield of bibenzyl (Table 4, entries 3, 5). Interestingly, ester derivatives
´
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4676 | Chem. Commun., 2014, 50, 4674--4676
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