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Oligomethylene-Bridged Vitamin B12 Dimers.

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Oligomethylene-Bridged Vitamin B
Dimers""
Bernhard Krautler,* Tomas Dkrer, Pingli Liu, Walter
Miihlecker, Michael Puchberger, Karl Gruber, and
Christoph Kratky"
Dedicated to Profbssor Karl Sclilogl
on the occasion of lzis 70th hirtlzda!
,
Organometallic vitamin B I Zderivatives such as coenzyme B,
and methylcobalainin are cofactors of considerable biological
importance either as "reversible sources of an alkyl radical"[']
or as intermediates in methyl group transfer reactions.[21Owing
to their stability in protic environment, organometallic B,
derivatives also hold a large potential for preparative radical
reactions.[31 We report here on oligomethylene-bridged B,,
dimers such as the tetramethylene-1 ,4-di-Cop-cobalamin D4,[41
organometallic B,, derivatives of a novel structural type. Such
binuclear B,, derivatives, which contain two thermally and photochemically labile organometallic bonds, may be considered
"latent alkanediyl d i r a d i ~ a l s " . [ ~ ~
In methanolic solution and under inert atmosphere 0.5 mole
equivalents of 1,4-dibromobutane were added to electrochemically produced Co' cobalamin. The color of the reaction mixture
changed rapidly from green to red, indicating the alkylation of
cobalt. Upon aqueous workup under exclusion of light, dark
red, prismatic crystals of chromatographically uniform dimer
D4 were obtained (60% yield).
In contrast and as expected. the addition of 1,4-dibromobutane in about a hundredfold excess and under inert
atmosphere to electrochemically produced Co' cobalamin led to
the almost exclusive foimation of monomeric Cop-4-bromobutylcobalamin M4. After crystallization, M4 was isolated in
about 80 o/o yield.['] Use of homologous 1.5-dibromopentane
and 1 ,6-dibromohexane, but not of 1,3-dibr0mopropane,['~
resulted in analogous organometallic B,, dimers (D5in 75%
yield, D6 in 78 'YO yield).
Characteristic UV/Vis and CD spectra of the dimers D4-D6
as well as of the monomer M4 indicated the presence of
organometallic B, derivatives with only weak interactions
between the chromophores of the dimer moieties. In the
OH:
I
+
I
M3 : 11 = 3
M4:n=4
M5 : ti = 5
M6: I! = 6
D4 : 11 = 4
D5:r1=5
D6:n=6
D4
[*] Prof. Dr. B. Kriutler, Dip].-Ing. T. Derer. Dr. M. Puchbergei
Mag. W. Miihlecker
Institut fur Organische Chemie der Universitit
lnnrain 52a. A-6020 Innsbruck (Austria)
Telefax: Int. code (512)507-2892
Prof. Dr. C. Kratky. Mag. K. Gruber
lnstitut fur Physikalische Chemie der Universitit
Heinrichstrasse 28, A-8010 Graz (Austria)
Telefax: Int. code (316)322248
Dr. P. Liu
Dipartement de Chimie Organique. Universite de Geneve. (Switzerland)
+
+
[**I
We would like to thank Dr. E. Hoffmann (Varian. Darmstadt. Germany) and
Dr. D. Moskau (Bruker-Spektrospin. Fillanden. Switzerland) for ineiisuring
the 500 MHz ' H NMR spectrti. Dr. W.Amreiu and R. Hiifliger (ETH. Zurich)
for the FAB inass spectra. and H. Hediger and R. Dohner (ETH, Zurich) For
recording the C D spectra. This work was supported financially by the Swiss
National Science Foundation (Proj.-Nr. 20.29850.90) and by the Austrian
National Science Foundation FWF (Proj.-Nr. P-9334 and P-9542).
FAB = fast atom bombardment. C D = circular dichroism. NOE = nuclear
Overhauser enhancement. NOBA = or-rlx-nitrobenzyl alcohol.
~
84
FAB mass spectra (besides signals of fragments) the diagnostic
signals of the respective molecule ions were observed (in the case
of D4 at rniz = 2714).
Owing to the effective C , symmetry of the dimers D4-D6, the
number of signals of chemically inequivalent protons in the
'H N M R spectra was reduced (Fig. 1). The N M R spectroscopic
analysis of dimer D4 by means of homonuclear (DQF-COSY
and ROESY) and heteronuclear correlations (HMQC and H M BC spectra)[*] allowed complete assignment of the 'H and l3C
signals; for example, the signals at high field were attributed to
the protons of the cobalt-bound alkanediyl chain (four broad
sigllals at 6 = - 0.50 [H;,(A2)]- -o.04 [Hb(A2)1, o.20
and 0.97 [H,(Al)]). The observation of NOE effects between
groups bonded on the c,ndo side of the hydrocarbon-bridged
cobalamin halves of D4 (for example, between the singlet at
6 = 1.23 [CH,(17B)I and the signals at 6 = 2.56 [s, CH,(j1)1 and
6 = 1.85/2.20 [AB system, CH,(7')]), indicated spatial prox-
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Table 1 . Selected spectroscopic data for D4. D5. 0 6 . and \I4 [a1
~~
~~
35
D4: red crystals. UV:Vis: Ama,(lgi:)= 264 (4.60). 279 (4.53). 289 (4.50). 3105 (4.36).
318 (4.38). 373s (4.21). 450s (3.81). 514 (4.13). CD: i(Ar.1 = 252 ( - 5.76), 270
(19.5). 298 (9.67). 329 ( - X.23). 355 (-18.10). 388 ( I 3 60). 435 (-11.10). 496
(17.90). 557(-17.50): i,):
259,316, 373. 405.457. 524: ' I 1 N M R : 6 = - 0 . 5 0 ( m .
2 H ) . -0.04(m,2H).0.20(m.2H).0.53(s.6H).0.97(ni.2H).1.00(s.6H).1.10
(in. 4H).1.23 (s. 6 H ) . 1.29 (d. 6 H ) . 1.38 ( s + m. XH). 1.5: ( 5 , 6H).1.73 (m.
2H).
1.8 -2.0 (m. 6 H ) und 1.88 (s. 6H). 2.0-2.2 (m,8 H ) . 2.24 tin. 4 H ) . 2.30 (s. I 2 H ) .
235~2.6(m,4H),2.49(~.6H)und2.56(~.6H).2.63(m.311).2.80(tn.2H).307
(dd.2H).3.21(d.2H).3.49(m.2H).3.60~3.80~in.8H).iY4(d.2H).4.0(d.2H).
4.17 (m. 2 H ) . 4.26 (m.2H).4.3 4.5 (m, 4H).4.73 (rn.?!I). 6 08 (9. 2 H ) . 6.23 (d.
~ H ) , ~ . ~ ~ ( S . ? H ) . ~ . O ~ ( S . ~ H ) , ~ . ~ O ( ~ , ? 16.6(2q).
H ) : " C NIX.4(q),18.6
MR.~~
( q ) . 19.9(q),20.1 (q).20.3(q).20.6(q).20.9(q).22.3(~~).
~7.4it).37.6(t).28.7(t).
29.1 (t). 32.4 (I).
32.9 (t). 33.0 (q). 33.3 (ti. 33.4 (ti. 33.6 (11, 35.5 ( t ) , 36.7 (t), 40.6
(d).44.3(t).45.1 ( t ) , 4 6 . 4 ( t ) , 4 7 . 9 ( ~ ) , 4 8 . 0 ( s ) , 5 2 . 0 ( ~ ) . 5 4 . 357.0(d).57.5(d),
(d),
59.0 is), 62.9 (1). 71 .I (d), 13.4 (d).75.0 (d), 75.9 (d). 83.4 ( d ) , 87 0 ( 5 ) . X7.5 (d), 95.5
(d). 105 (s), 108 (s). I12 (d), 120 (d), 133 (3s). 135 (sl. 141 I \ ) . 143 ( d ) . 164 (s), 165
(s). 171 ( s ) ; 175 (s).177 (2s): FAB-MS: / ) I ; : ( % ) :
2716 5( 12)
m': = 371
2657.9(5). 1330.3(100) [C,,,H,,,Co,N,,,O,,P,:
0 5 : redcrystals. UV:Vis: j . m a x ( l g i : )= 240 (4.65). 265 (4.59). 31Os(4.39). 318 (4.40).
343 (4.34). 370s (4.22). 450s (3.83). 514 (4.16): CD. ;.(A>.) = 25X ( - 16.0). 272 (8.5).
287 (3.5).298 (12.5). 330 ( - 6 . 5 ) . 358 (-16.0). 3x7 (16.0). 43X ( - 9.51. 498 (12.5).
554 (-18.0); FAB-MS: /n/:(%): 2729.5 (8.1). 2728.5 (8 51. 2727.5 (3 7), 2658.6
(3.6). 1330.3 (100) [CIL4H,,,Co,N,,O,,P,: / ) I ) : = 2727.2lJ3l.
D6 red crystals. UV;Vis: &,ax(lp~)
= 266 (4.56). 279 (4.51). 2x9 (4.49). 310s (4.40).
315 (4.41). 344 (4.34). 370s (4.21). 450s (3.XS). 511 (4.17). CD: ~ . ( A L=
) 256
(-11.7). 298 (10.1). 329(- 6.1). 358 ( - 14 4). 388 (14 4).J.:X ( 11.4).496 (15.5).
555 (-16.8): FAB-MS' i ? 7 : : ( % ) : 27445 (X.7). 2743 5 (6..31. 2741.5 (6.4). 2658.6
( 1 . 7 ) .1330.3 (ion) [c,,,H,,,co,N,,o,,P,:
w Z= n i . ? ~
M4 red crystals. UV:Viu: j.m4x(lpc)= 266(4.21). 280 (4.161.289(4.14). 309(4.06).
316 (4.06). 343 (3.99). 372s (3.88).450s (3.53). 512 ( 3 X3): CL): ~ ( A I =
: ) 256 ( - 8 . 2 ) .
273 ( 2 . 3 ) . 297 (4.6). 327 ( - 2.9). 358 ( - 6.9). 387 (5.7). 43s (~ 5.21. 496 (9.2). 558
( - 5 0): FAB MS: ni;:(%): 1466.2(32). 1465.2(28). 1.33,3(100) [('~~,,H,,~,7"B~-CoN,,O,,P: /~7:: = 1463.541.
4 0
[a]: UV:VIS. ca. 5 x I t l - ' ~ in
5 0 4 5 4 0 3 5 3 0 2 5 2 0 1 5 1 0 0 5 0 0 -05
051
-O-j
1.5:
..Oj
2.5
'
co
I
3
0 - 4
H,O.KONTRON-UVIKO%860. CD spectra: c : ~ .
5 x I O - ' M in H,O: JOBlN-YVON Dichropraph. M a r k l l l . N M R i n C'D,OD. ca.
26 C: Varian UNlTYplus (500 M H r ) : 'H O(C.I),ODI = 3 3 5 . '"C.
b(CD,OD) = 49.0; FAB-MS: ZAB-2SEQ (NOBA matrix)
4.53
5 . 0 4.5 4.0 3.5 3.0 2.5 2.0 1.5 1.0 0.5 0.0 -0.5
- 6
Fig. 1. Top. 500 M H z ' H N M R spectrum of D4 in CD,OD; bottom: ROESY
spectrum of D4 i n CD,OD (see text and Table I for further details).
imity of these groups in D4 (Fig. 1, bottom) due to the tetramethylene bridge.
The X-ray analysis of a single crystal of D4 confirmed the
spectroscopically deduced constitution and configuration of
this dimer. as well as its effective C,-symmetric conformation
(Fig. 2).["] The structure of the cobalamin moieties of D4 is
similar to that of monomeric, organometallic B,, derivatives.
The ligand planes of the two cobalamin halves of D4 are almost
parallel (tilt of 2.3'). The corrin ligands form a torsional angle
of about 27 with respect to the cobalt-cobalt axis. which is
close to perpendicular with respect to the ligand planes. This
arrangement results in a rather tight packing of the two substituted corrin units without any noticeable buildup of strain on
the rnrlo side. Indeed. the
of the corrin ligands in D4
amounts to 16.5' and is practically identical to that of methylcobalamin." Oh]
The tetramcthylene chain that bridges the two cobalt centers at
a distance of 6.95 A is shielded laterally by the corrin substituents
located on the cmdo side. The tetramethylene chain occurs in a
close-to-staggered conformation. The two terminal C-Co bonds
are both 2.00 A long and positioned antiperiplanar with respect
to the central C(A2)-C(A2') bond. The torsion angle with respect
to the latter bond amounts to S0(2)0, such that in this open-chain
system an unusual synclinal conformation is observed.
Exploratory thermolytic investigations provided no hint of
possible strain that might accelerate the decomposition of D4.
This dimer decomposed five and eight times slower than its
homologues DS and D6, respectively,[' when heated at 1 10 "C
in oxygen-free ethylene glycol solution. Under these conditions
the dimers D5 and D6 decomposed into Co" cobalamin (UVi
Vis) and cyclopentane or cyclohexane. respectively ('H NMR).
Photolysis of D5 (oxygen-free aqueous solution. room temperature) also led to cyclopentane ( ' H N M R . GCiMS) and Co"
cobalamin (UV/Vis)."21 Formation of cycloalkanes from the
penta- and hexamethylene bridges of DS and D6, respectively.
most probably proceeds by a yet-undocumented, but thermodynamically favorable route leading to the formation of a C-C
bond by homolytic substitution: It results from the attack of an
alkyl radical at the saturated carbon center of the metal-bonded
alkyl ligand and occurs with simultaneous loss o f a Co" corrin.
Dinuclear hydrocarbon-bridged complexes often display unusual rea~tivities.'~, The bridging tetramethylene ligand of
the dimer D4 appears to be conformationally strained as a result
of its constitution and of intramolecular packing effects. In D4
a remarkable situation therefore exists that may model possible
mechanisms of enzyme activation.'" 14'
Oligomethylene-bridged B,, dimers such as 115 and D6 may
also allow the study ofthe formation of C--C bonds by reactions
between alkyl radical and saturated organometallic functions, a
subject that appears to be of interest from mechanistic and
biological points of view.[15] Under mild conditions and in
aqueous media D5 and D6 provide easy access to an extraordinary range of radical chemistry. Indeed, homolysis of the two
C-Co bonds of such dimers can be initiated thermally and with
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141 Formation of dimer D4 through a reaction of Co'
cobdunin with 1,4-dihromohutane was first suggested in
1964. although with n o evidence concerning its structure:
E. L. Smith. L. Mervin. P. W. Muggleton. A. W. Johnson.
N . Shaw. Aii~i.N. X A u i d S1.i. 1974, 565-574.
[5] a ) A summary or alkanediyl-bridged metal complexes:
C. P. Cdsey. J. D. Audett. Cheni. Rev. 1986, X6.339-352; W.
Beck, B. Niemer. M. Wieser. A n g m . . C%rri?.1993. /Y7.
969- 996; .AiJ,qeii,. ~ h l ~ i l /JI ? / . ti/.Enfi/. 1993. 32. 923; b)
alkanediyl-bridged porphinoid iron complexes: K. Shin.
BS:
Yli. H. M Goff, /Jlllrp. Chmi 1990. 29. 889- 890: C)
oligoinethylene-bridged cohaloxime dimers: K. P. Finch,
J. R. Moss. .I Or,qurioiiie/.Chiwi. 1988, 346. 253-266.
(61 The addition of one mole equivalent of CoI,-4-broinohutylcobaliimin M4 to ii solution of electrochemically
produced Co' cohalainin similarly led to the formation of
the dimer D4 in approximately 70% yield: the use of Cop3'-hroinopropylcoh;ilamin M3 led only to dealkylation.
[7] A bridging triinethylene group would he expected to result
in a considerable increase of strain (cf. discussion i n ref.
1411.
[XI N M R techniques: cf. fnr example: H. Kessler, M. Gehrke.
C Griesinger. Anp. Chwii. 1988. /OO. 507; Aiigeu. C h m .
/ ~ i / . GI. G i p l . 1988. 27, 490: DQF-COSY (Douhle Quantum Filtered Correlation Spectroscopy): U . Piantini. W. 0.
Sorcnsen. R. R. Ernst. J. .4im C h c ~ iSuc.
.
1982. 104. 6800:
ROESY (Rotating Frame Nuclear Overhauser Spectroscopy): A . A. Bothner-By, R. L. Stephens. J. M . Lee.
ihrd. 1984. 106, 811 : HMQC (Heteronuclear Multiple
Quantum Coherence): M. I-.. Summers. G . L. Marzilli, A.
Bax. [hid. 1986. fON. 2093: HMBC (HeterOnUdedr Multiple Bond Correlation): A. Bax. M. F. Summers. ihid. 1986.
Fig 2. Cr>stal structiirc of the diiner D4 191. Left: hall-and-stick model: right: space-tilling model.
I O N . 2093
[Y] a ) X-ray analysis of D 4 . 6 3 H 2 0 : prismatic crystals from
H,O: spacegroup P4,2,2.a = 1 6 . 1 3 5 ( 4 ) , ~=70.902(14) A.
k'=18461(7)ff3. 2 = 4 . { J ~ , , , ~ < , = 1 . 3 8 5 g c r 1 - ~ ,~ i ( C u , , ) = 2 . 4 8 m m - ' . T =
visible light, and (formally) releases two organic radical centers.
Mi?) K . Dnta collection on ii inodilicd STOE diffractometer (Cu,, radiation
Depending on the sequence of homolysis events (either stepwise
i = 1.5418
Ni filter); Structure determination with ii totel of 12540 meaor synchronous). the oligomethylene bridge leads either to an
sured reflections, l 1389 unique (R,,,, = 0.0616): structure solutmn with Patterson methods: refinement versus F:. c , J R ,= 0.275 for a11 11 3x9 reflections
(intermediate) organometallic alkyl radical or to a (1 .w)-alkyl
(iri-'
= c z ( F t )+ (0.lXP)'. P =1,'3milx(0.F;) + 2,'3$); R1 = 0.097for6263
diradical.
observed reflections (6: > 4a(F:j): cnipirical absorption and volume corrections [Sc]. computer programs in ref. [9ii-c]. Further details of the crystal
structure investigation are available on request from the Director of the CamExperirnenral Procedure
bridge Crystallographic Data Centre, 12 Union Road, GB-Cambridge CB2
D4: Under inert 31s (glovehox. < 10 ppm 02).
aquocobalamin chloride (100 mg.
I E Z ( U K ) . on quoting the full journal citation. hj SHELXTL 4.1. Siemens
7.13 x lo-' mol: Roussel Uclaf apyrogenc) was dissolved in 4 m L of a 0.1 M solution
Ci-ystallogaphic Research System, 1990: c) SHELXL-93: G. Sheldrick. Uniof tetrabutylainmoniuin hexafluorophosphate in methanol and reduced with stirversity of Gdttingeii, 1993: d) DIFABS: N. Wilkcr. D. Stuart. Acta CystaiIoring at a mercury cathode ( - I .I V vei-sus 0.1 V calomel electrode: residual current:
gr. Sw/. A 1983. 39. 158 - 166.
approximately 0.05 mA). The solution then contained Co' cohalamin (UV.'Visj. I t
[I01 :I) V. B. Petl. M. N. Liebman. P Murray-Rust. K. Prasad, J. Gluaker. J AM.
was protected froin light and 1.4-dihromobutane (4.3 pL. 0.5 mol equivj was added.
C h < ~ Si .i x . 1987. 1W. 3207: h) M. R o w . J. P. Glusker. L. Randaccio, M . E
The rcsction mixture was reduced further a t - 1 .0 V (total consumption: 16.5 C
Summers, P. J. Toscano, L. G . Marzilli, hid. 1985, 109, 7894.
versus 14.OC in theory). Under protection from light. the solutioii w a s added
[I I] Rates ofdecoinpnsition [ s - ' ] during thermolysis (1 I 0 C. ethylene glycol): D4:
Ig h = - 4.09; DS. Ig h =
3.3X; D6: Ig X = 3.17.
to 20 inL of distilled watcr and extracted with three portions of 20 inL ofmethylenc
chloride. The dark red. tiqueoiis phase was then concentrated. Dimer D4crystallired
[12] Interestingly, ;in aii;ilogous formation ofcyclohexane could not be observed in
at 0 5 C from concentrated. q i i e o u s solutions to give 58.5 mg of D4 (60% yield).
exploratory photolysis experiments with D6.
[13] See for example H Lang. A i i g n v . Chriii 1994, 106. 569; Aiipov. Cheni. I n / . Ed.
DS wiis prepared in analogy to D4 with 0.5 equivalents of 1.5-dihroniopentane.
Eli'ql 1994, -13. 547.
Ci-ystallizition from water:acetone yielded 74 ing (75.5%) of D5.
(141 J. Ri'tey. Aiiprii.. Chcm. 1990. 102. 573 379: .4li,fyu.. Cheni./nr. Ed. D i g / . 1990.
D6 was prepared in aiidogy to D4 uitli 0.5 equivalents of 1 .6-dibromohexane
3.355.
Crystallizition from water,'acetone yielded 78 mg (78.5%) of D6.
[IS] See D. Arigoni. P. K . Galliker. unpublished: cf. P. K. Galhker "Zur BioM4 %:IS prepared i n analog) to D4. except for the addition of 100 equivalents of
synthese der Etherlipide a u s Methanohacterium thermoautotrophicum".
1.4-dibromobutaiie at the beginning of the electrochemical reduction ;it - 1 .O V.
Dissertation ETH-Zurich. Nr. 9119. 1990.
The yield of iM4 obtaincd from water.'xetoiie WIS 83.5 mg (79%)
A,
~
Recei\ed: July 21. 1994 (Z7152IE]
Gel-man versioii: Aiigoii.. Chrvii. 1995. fO7. 66
Keywords: alkanediyl-bridged complexes cobalt compounds
vitamin B l z
*
[ I ] a ) J. Halperii. Srirriw 1985. 227. 869-875, b) 8 . T. Gelding. D. N . R. Rao iii
i?JIZj'rlll~ iMrrhrrnisnn (Eds.: M . 1. Page. A. Williams). Royal Society of Chemistry. London. 1987. p. 404.
[2] a j R. G . M'itthcws. V. J. Banerjee. S. W. Rngsdide. BioFwior.\ 1990. 2. 147; hj
B. Krautler in Thf>B i o i o g i d A / k l ~ i l ~ ~ iof
~ JH
i l c i m E / L ~ I ~(Eds.:
J ~ ~ P.
I ~J.~ Craip.
s
F. G l o c k l i n ~ ) Roy;d
.
Society of Chemistry. London, 1988, p. 168.
[3] S. Bus;ito. 0 . Tincmhart. 2. Thang. R Scheffold. ??trohrr/ro,i 1990. 46, 31 55
3 166.
86
~
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