Lewis acid catalysis in heterolysis reactions of glycol ether radicals mimicking diol dehydratase-catalyzed reactions

Article abstract of DOI:10.1021/ol0481131

(Chemical equation presented) Zinc bromide-catalyzed heterolysis reactions of glycol ether radicals were studied by laser flash photolysis methods, which gave the binding constants and catalytic rate constants for fragmentation. The Lewis acid-catalyzed h

Full text of DOI:10.1021/ol0481131

ORGANIC
LETTERS
2004
Vol. 6, No. 24
4511-4514
Lewis Acid Catalysis in Heterolysis
Reactions of Glycol Ether Radicals
Mimicking Diol Dehydratase-Catalyzed
Reactions
Neil Miranda, Libin Xu, and Martin Newcomb*
Department of Chemistry, UniVersity of Illinois at Chicago, 845 W. Taylor Street,
Chicago, Illinois 60607
men@uic.edu
Received September 16, 2004
ABSTRACT
Zinc bromide-catalyzed heterolysis reactions of glycol ether radicals were studied by laser flash photolysis methods, which gave the binding
constants and catalytic rate constants for fragmentation. The Lewis acid-catalyzed heterolysis reactions mimic a putative reaction pathway in
diol dehydratase-catalyzed reactions and are potentially useful polar processes for incorporation into conventional radical chain reaction
sequences.
Coenzyme B12-dependent diol dehydratase enzymes catalyze
the conversion of a glycol to an aldehyde plus water via
radical intermediates.1,2 The reaction sequence (Scheme 1)
deoxyadenosin-5′-yl radical (Ado•). H-atom abstraction from
glycol substrate by Ado•, rearrangement of the glycol radical
to a â,â-dihydroxyalkyl radical, and H-atom transfer from
5′-deoxyadenosine gives a closed-shell aldehyde hydrate and
Ado•, which recombines with cobalt to regenerate coenzyme
B12. The aldehyde hydrate subsequently dehydrates to give
the aldehyde product.
Scheme 1
Although specific acid catalysis of glycol radical reactions
has been known for decades,3,4 the mechanistic details of
the conversion of the glycol radical to the â,â-dihydroxyalkyl
radical in diol dehydratase enzymes are not known.1,2 The
hydroxy group migration could occur in a concerted process
or by heterolytic fragmentation of the â-hydroxy group to
give hydroxide and an intermediate radical cation that
subsequently collapse to give the â,â-dihydroxy radical.
Irrespective of the mechanism, the rearrangement of a glycol
is a radical nonchain process initiated by homolysis of the
Co-C bond in coenzyme B12 (Ado-Cbl) to give the 5′-
(3) Buley, A. L.; Norman, R. O. C.; Pritchett, R. J. J. Chem. Soc., B
1966, 849-852.
(1) Toraya, T. Chem. ReV. 2003, 103, 2095-2127.
(2) Toraya, T. Chem. Rec. 2002, 2, 352-366.
(4) Walling, C.; Johnson, R. A. J. Am. Chem. Soc. 1975, 97, 2405-
2407.
10.1021/ol0481131 CCC: $27.50
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radical to an aldehyde hydrate radical appears to have
attractive potential in the context of synthetic analogues.
Specifically, conversions of glycol ether radicals to acetal
radicals or their equivalents might be useful additions to
radical-based synthetic methodology.
Scheme 3
Potassium ion or other Lewis acids are essential for
coenzyme B12-dependent diol dehydratase,5,6 and X-ray
crystal structures of a resting enzyme with bound substrate
show that potassium is complexed to both hydroxy groups
of glycol.7 The structure suggests that the Lewis acid has a
catalytic role in the enzyme, serving to stabilize hydroxide
in a fragmentation reaction. This possible reaction pathway
inspired us to study Lewis acid catalysis of radical reactions
of glycol ether radicals, and we report here ZnBr2-catalyzed
radical heterolysis reactions that mimic the putative frag-
mentation step of diol dehydratase.
in radicals 2 and 5 would give radicals 8, which are expected
to ring open to radicals 9 with rate constants of k ≈ 5 ×
1011 s-1.14
When radical 2 was produced in the absence of a catalyst
in various solvents, no signal from product radical 7 was
observed.10 In acetonitrile or in THF with ZnBr2 added,
however, results such as those shown in Figure 1A were
We studied the models for glycol radicals shown in
Scheme 2 in laser flash photolysis (LFP) experiments. The
Scheme 2
R,â-dimethoxy radical 2 was produced by 355 nm photolysis
of the PTOC ester precursor 1,8,9 which gave an acyloxyl
radical that rapidly decarboxylated to give radical 2.10 The
R-hydroxy-â-methoxy radical 4 was formed from phenyl-
selenyl precursor 3 by 266 nm photolysis to give cyclo-
propylcarbinyl radical 4 that rearranged to radical 5 in a fast
(k ≈ 1010 s-1)11,12 fragmentation reaction.
Figure 1. (A) Time-resolved growth spectrum from reaction of
radical 2 in CH3CN containing 0.01 M ZnBr2. (B) Observed rate
constants for reactions of 2 in CH3CN (red) and in THF (blue) in
the presence of ZnBr2; the lines are fits for the binding constants
and catalytic rate constants listed in the text. For the THF results,
the concentrations of ZnBr2 are 10 times the actual concentrations.
obtained. The growing signal with λmax ≈ 335 nm is
consistent with that expected for distonic radical cation 7
and quite similar to that observed from 2 in Brønsted acid-
catalyzed heterolysis reactions.10 The heterolysis reaction of
radical 2 was confirmed by conducting preparative reactions
with 1 in THF with 0.01 M ZnBr2 and Bu3SnH or
octadecane-1-thiol. The R,â-unsaturated ketone 10 and 1,2-
dimethoxy-1-(2,2-diphenylcyclopropyl)propane (from reduc-
tion of radical 2) were found in ca. 70% GC yield for the
thiol reaction (Scheme 4).
Radicals 2 and 5 contain diphenylcyclopropane reporter
groups for UV detection.13 Heterolysis of the â-methoxy
group in these radicals will give radical cation products (6)
that are expected to fragment rapidly to UV-detectable
distonic radical cations 7 (Scheme 3). This heterolysis
reaction sequence is known to occur for radical 2 in general
acid-catalyzed reactions.10 Alternatively, a migration reaction
(5) Lee, H. A., Jr.; Abeles, R. H. J. Biol. Chem. 1963, 238, 2367-2373.
(6) Toraya, T.; Sugimoto, Y.; Tamao, Y.; Shimizu, S.; Fukui, S.
Biochemistry 1971, 10, 3475-3484.
(7) Shibata, N.; Masuda, J.; Tobimatsu, T.; Toraya, T.; Suto, K.;
Morimoto, Y.; Yasuoka, N. Structure 1999, 7, 997-1008.
(8) Acronym PTOC is for pyridine-2-thioneoxycarbonyl. PTOC esters
were originally developed by Barton’s group and are also known as Barton
esters.9
Scheme 4
(9) Barton, D. H. R.; Crich, D.; Motherwell, W. B. Tetrahedron 1985,
41, 3901-3924.
(10) Newcomb, M.; Miranda, N. J. Org. Chem. 2004, 69, 6515-6520.
(11) Le Tadic-Biadatti, M.-H.; Newcomb, M. J. Chem. Soc., Perkin
Trans. 2 1996, 1467-1473.
(12) Martinez, F. N.; Schlegel, H. B.; Newcomb, M. J. Org. Chem. 1998,
63, 3618-3623.
(13) Newcomb, M.; Tanaka, N.; Bouvier, A.; Tronche, C.; Horner, J.
H.; Musa, O. M.; Martinez, F. N. J. Am. Chem. Soc. 1996, 118, 8505-
8506.
Acetal 11 was not observed in the preparative reactions,
although an authentic sample of 11 was adequately stable
4512
Org. Lett., Vol. 6, No. 24, 2004

to survive the reaction conditions. This result demonstrates
that the reaction involves the heterolysis pathway in Scheme
3 instead of the concerted migration reaction, but it does
not permit a complete mechanistic description. Specifically,
we cannot determine whether radical cation 6 (X ) Me) has
a finite lifetime. As an alternative, it is possible that distonic
radical cation 7 (X ) Me) is formed directly in the Lewis
acid-catalyzed heterolysis reaction of 2 by simultaneous
cleavage of two bonds.
Kinetic results for radical 2 in acetonitrile and in THF are
shown in Figure 1B. The increase in the rate constant for
reaction as a function of ZnBr2 concentration shows satura-
tion kinetics behavior consistent with reaction as shown in
Scheme 5. Solution of the data by nonlinear regression
Figure 2. Rate constants for reactions of radical 5 in acetonitrile
(A) and for reactions of radical 12 in THF (B); the lines are fits
for the binding constants and kinetic values given in the text.
kcat ) 2.8 × 104 s-1, but we note that the reaction of 5 was
suppressed by up to a factor of 2 at higher concentrations of
ZnBr2.
Scheme 5
Zinc bromide also catalyzed heterolysis of the acetate
group in radical 12. Radical 12 was previously found to react
by heterolysis in various organic solvents without catalysts.10
In THF containing ZnBr2, however, the reaction clearly was
catalyzed (Figure 2B). Solution of the data in Figure 2B
according to eq 2 gave Kbind ) 7.5 M-1, kcat ) 7.3 × 106
s-1, and kuncat ) 2 × 105 s-1. The rate constant found for the
uncatalyzed reaction of 12 in THF by this analysis is
the same as that previously reported for the uncatalyzed
heterolysis.10
analysis according to eq 1 gave Kbind ) 150 M-1 and kcat
)
4.3 × 104 s-1 for reactions in CH3CN. In THF, the data gave
Kbind ) 3500 M-1 and kcat ) 5 × 103 s-1.
kobs ) (kcatKbind[ZnBr2])/(Kbind[ZnBr2] + 1)
(1)
kobs ) (kuncat + kcatKbind[ZnBr2])/(Kbind[ZnBr2] + 1) (2)
The LFP rate constant for heterolysis of the complex of
radical 2 in THF was corroborated in an indirect kinetic
study.15 Reaction of PTOC ester 1 in THF with 0.01 M ZnBr2
and 2.5 mM octadecanethiol gave a 40:60 mixture of 10 and
1,2-dimethoxy-1-(2,2-diphenylcyclopropyl)propane. At this
concentration of ZnBr2, radical 2 is effectively completely
complexed with zinc ion. The rate constant for thiol trapping
of the complexed radical is likely to be different than that
for reaction of the uncomplexed radical, but, if one assumes
that it is not and uses the rate constant for reaction of an
R,â-dimethoxy radical with the thiol in THF (kH ) 2.1 ×
106 M-1 s-1),16 then the rate constant for heterolysis of the
ZnBr2 complex of 2 is kcat ≈ 3.5 × 103 s-1. Alternatively, if
the LFP rate constant for heterolysis of the complex is used
as the basis rate constant, the calculated rate constant for
reaction of the thiol with the ZnBr2 complex of 2 is kH ≈ 3
× 106 M-1 s-1.
The ZnBr2-catalyzed reaction of 2 appears to display
environment effects that are typical for radical heterolysis
reactions. The ca. 1 order of magnitude difference in rates
for reaction in the modest polarity solvent THF and the
medium polarity solvent CH3CN is similar to solvent effects
found in heterolysis reactions that give styrene radical
cations,17,18 enol ether radical cations,19 and alkene radical
cations,20 although relatively stable anionic leaving groups
were involved in these reactions. Rate constants for other
radical heterolysis reactions correlate with ET(30) solvent
polarity values;21 if the same holds for ZnBr2-catalyzed
heterolysis of methoxide in radical 2, then the reaction would
be expected to have a rate constant of kcat ≈ 1 × 106 s-1 in
Radical 5 behaved much like radical 2 in CH3CN. No
reaction was observed in the absence of catalyst, but reaction
was apparent in CH3CN with ZnBr2 present (Figure 2A).
The data shown in Figure 2A gives Kbind ) 1000 M-1 and
(17) Choi, S. Y.; Crich, D.; Horner, J. H.; Huang, X. H.; Newcomb, M.;
Whitted, P. O. Tetrahedron 1999, 55, 3317-3326.
(18) Bagnol, L.; Horner, J. H.; Newcomb, M. Org. Lett. 2003, 5, 5055-
5058.
(14) Newcomb, M.; Johnson, C. C.; Manek, M. B.; Varick, T. R. J. Am.
Chem. Soc. 1992, 114, 10915-10921.
(15) Newcomb, M. Tetrahedron 1993, 49, 1151-1176.
(16) Tronche, C.; Martinez, F. N.; Horner, J. H.; Newcomb, M.; Senn,
M.; Giese, B. Tetrahedron Lett. 1996, 37, 5845-5848.
(19) Horner, J. H.; Taxil, E.; Newcomb, M. J. Am. Chem. Soc. 2002,
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(21) Reichardt, C. Chem. ReV. 1994, 94, 2319-2358.
Org. Lett., Vol. 6, No. 24, 2004
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an environment as polar as water, whereas the rate constant
in a hydrocarbon solvent would be kcat ≈ 1000 s-1.
catalysis studied in this work is different in that it results
from stabilization of ionic leaving groups in heterolytic
radical reactions.
The cyclopropane reporter group in radical 2 has an
accelerating effect on heterolysis reactions that is similar to
the effects of cyclopropanes in heterolysis reactions of
closed-shell molecules. Specifically, when the same reporter
group was used in an alkyl radical with a â-phosphate leaving
group, the rate of heterolysis was accelerated by a factor of
35 in comparison with that for reaction of an alkyl radical
lacking the cyclopropane reporter.20 Thus, the ZnBr2-
catalyzed heterolysis of an R,â-dimethoxy radical without
the cyclopropyl reporter group is expected to have a rate
constant in the range of 1000-2000 s-1 in moderately polar
solvents such as acetonitrile and a rate constant exceeding 1
× 104 s-1 in highly polar media.
Radical heterolysis reactions involving relatively stable
anionic leaving groups have been incorporated into radical
chain reaction sequences and display attractive synthetic
potential.28-31 It is possible that related Lewis acid-catalyzed
radical heterolysis reactions can be developed, where the
leaving group is an inherently stable ether. In a similar
manner, Lewis acid catalysis of the acetate fragmentation
in radical 12 suggests a potential utility in catalyzing polar
reactions of radicals with modestly reactive leaving groups.
In regard to the radical rearrangement in diol dehydratase
that inspired this study, the demonstration of Lewis acid
catalysis in the heterolysis reactions studied here supports
the putative reaction pathway involving potassium ion-
catalyzed heterolysis.
Lewis acid catalysis of aminyl radical reactions via
complexation at the radical center is known,22 and Lewis
acid catalysis of radical reactions by complexation of a
molecule that reacts with a radical is possible.23 Lewis acids
also have been used to influence the stereochemical outcome
of radical homolytic substitution reactions, and the Lewis
acids appear to catalyze these reactions.24-27 The ZnBr2
Acknowledgment. This work was supported by a grant
from the National Science Foundation (CHE-0235293).
Supporting Information Available: Experimental de-
tails, kinetic data, and NMR spectra. This material is
available free of charge via the Internet at http://pubs.acs.org.
(22) Ha, C.; Musa, O. M.; Martinez, F. N.; Newcomb, M. J. Org. Chem.
1997, 62, 2704-2710.
OL0481131
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N. A. J. Org. Chem. 2002, 67, 6050-6054.
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ReV. 1997, 97, 3273-3312.
(29) Crich, D. In Radicals in Organic Synthesis; Renaud, P., Sibi, M.
P., Eds.; Wiley-VCH: Weinheim, 2001; Vol. 2, pp 188-206.
(30) Crich, D.; Shirai, M.; Rumthao, S. Org. Lett. 2003, 5, 3767-3769.
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Chem. Soc. 2003, 125, 7942-7947.
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