Role of Noncovalent Sulfur···Oxygen Interactions in Phenoxyl Radical Stabilization: Synthesis of Super Tocopherol-like Antioxidants

Article abstract of DOI:10.1021/acs.orglett.6b02557

Noncovalent sulfur···oxygen interactions can increase the stability of chalcogen ortho-substituted phenoxyl radicals. This effect contributes to transforming the 7-hydroxybenzo[b]thiophene moiety in a privileged structural motif to enhance the activity of

Full text of DOI:10.1021/acs.orglett.6b02557

Letter
pubs.acs.org/OrgLett
Role of Noncovalent Sulfur···Oxygen Interactions in Phenoxyl Radical
Stabilization: Synthesis of Super Tocopherol-like Antioxidants
Stefano Menichetti,*,† Riccardo Amorati,*,§ Valentina Meoni,† Lorenzo Tofani,† Gabriella Caminati,†,‡
and Caterina Viglianisi*,†
†Department of Chemistry “U. Schiff”, University of Florence, Via della Lastruccia 13, 50019 Sesto Fiorentino, Italy
‡CSGI, University of Florence, Via della Lastruccia 3, 50019 Sesto Fiorentino, Italy
§Department of Chemistry “Ciamician”, University of Bologna, Via San Giacomo 11, 40126 Bologna, Italy
S
* Supporting Information
ABSTRACT: Noncovalent sulfur···oxygen interactions can
increase the stability of chalcogen ortho-substituted phenoxyl
radicals. This effect contributes to transforming the 7-
hydroxybenzo[b]thiophene moiety in a privileged structural
motif to enhance the activity of phenolic antioxidants. A
cascade of five consecutive electrophilic reactions occurring in
one pot afforded potent and biocompatible α-tocopherol-like
antioxidants.
henols (ArOH) are probably the most important class of
natural and synthetic antioxidants used for the protection
P
of manmade items and living tissues from oxidation.1 Nature
selected α-tocopherol (α-TOH), the main component of
vitamin E (Vit E), as the most potent lipophilic chain-breaking
antioxidant for the protection of cell membranes and LDL from
autoxidation.2 This ability depends on the easy transfer of an H
atom from α-TOH to, typically, peroxyl radicals (ROO•) with
formation of a relatively safe phenoxyl radical (α-TO•). This
can be reduced by various reductants (such as ascorbate,
vitamin C) in a synergetic red-ox cycle.3 Ingold and co-workers
studied the stereoelectronic issues that make α-TOH the model
for lipophilic antioxidants, and their pioneering achievements
inspired improvements on this topic. Considering the key H•
transfer process, the lower the bond dissociation energy (BDE)
of the phenolic O−H, the higher is the rate constant (kinh) of
the reaction with ROO•.4 Thus, any stabilization of the starting
phenol, for example, the involvement of the phenolic OH in a
H bond,5 will hamper the process, while any stabilization of the
Ar−O• will facilitate it. The transformation of Ar−OH into
Ar−O• means transforming an electron-donating (ED) group
into an electron-withdrawing (EW) group.5e Therefore, ED
groups on the aromatic ring (i.e., as in α-TOH) strongly
stabilize the Ar−O•, facilitating the H• transfer.5 The p-alkoxy
group plays a relevant role, but resonance stabilization requires
a correct conformation; i.e., one lone pair of the alkoxy oxygen
should be parallel to the aromatic π orbitals. Actually, this
situation takes place when the Ar−O−R dihedral angle is near
to 0°, a situation that is facilitated by the alkoxy oxygen inserted
in a benzo-fused six-membered ring (as in α-TOH) or, even
better, in a five-membered ring as in the dihydrobenzo[b]-
furanol (DhyBF) (Figure 1).5,6
Figure 1. Benzo-fused phenolic antioxidants.
(DhyBF) since the five-membered ring is almost coplanar
with the aromatic ring (Figure 1).5,6 Several years ago, Ingold
also demonstrated that benzo[b]furanol (BF), despite its
complete planarity, shows an important decrease (roughly 10
times) of the H• transfer ability.7 This was explained by
considering that aromatization reduced the ED ability of the
endocyclic O atom.7 Thus, in the design of new phenolic
antioxidants inspired by α-TOH, aromatic benzo-fused
heterocyclic systems have been barred since a decreasing ability
in the stabilization of the Ar−O• is expected.8 We demonstrate
here that the situation changes with benzo[b]thiophenes.
Introduction of chalcogens in the skeleton of phenolic
antioxidants and, in particular, in that of α-TOH can offer
the opportunity to link the chain-breaking antioxidant to the
(catalytic) hydroperoxide quencher ability of chalcogens
(mainly Se and Te).9 During our research, we pointed out a
peculiar behavior of sulfur-substituted phenolic antioxidants
Accordingly, kinh increases from 5,7,8-trimethyl-6-hydrox-
ychromane (as in α-TOH) to dihydrobenzo[b]furanol
Received: August 26, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
bearing the sulfur atom ortho to the phenolic OH and inserted
in a benzoxathiine heterocyclic system. In these derivatives, the
sulfur is a poor acceptor of intramolecular H bonds,10 while it
maintains its ED character and the ability of stabilizing Ar−O•.
This allowed us to propose a rationale for the post-translational
cysteine−tyrosine linkage in the galactose oxidase (GAO)
active site11 and to prepare, in several steps and low overall
yields, potent antioxidants12 (like compound 1 Figure 1) with
kinh equivalent to that of α-TOH (kinh = 3.2 × 106 M−1 s−1).
Recently, exploiting a procedure based on an acid-mediated
benzoxathiine−dihydrothiophene rearrangement (Scheme 1),
Table 1. Calculated ArO-H BDE and Most Positive σ-Hole
Electrostatic Potentials on S and Se Atom
Scheme 1. From 1,4-Benzo[b]oxathiines to 7-
Hydroxybenzo[b]thiophenes
a
b
kcal/mol. Calculated on an isodensity surface corresponding to
c
0.005 au by Multiwfn software (ref 14c). Relative to the most stable
conformer with the O−H bond pointing opposite to S or Se atom, as
shown in Figure 2 (bottom). See the Supporting Information for
details.
we efficiently prepared 7-hydroxydihydrobenzo[b]thiophenes
like 2 and 3 (Figure 1) showing, in turn, high kinh (∼1.4 × 106
M−1 s−1).13 While studying the benzoxathiine−dihydrothio-
phene rearrangement, we discovered that under harsher acid
conditions, i.e., using triflic acid (TfOH) as promoter,
dihydrobenzo[b]thiophenes 3 and 4 are transformed into
benzo[b]thiophenes 4 and 5, which can be also directly
obtained from the benzoxathiine derivatives without isolation of
intermediates 2 and 3 (Scheme 1).
more clear that aromatization causes an “unexpected”
stabilization of the o-phenoxyl radical. Enthalpy differences
between the phenoxyl radicals of 5- and 7-hydroxy isomers
show that o-dihydro radicals are less stable than para radicals
(up to 3.6 kcal/mol for furans), while ortho “heteroaromatic”
radicals are more stable than para radicals (more than 3 kcal/
mol for thiophenes and selenophenes (Figure 7SI)).
We hypothesized this was the fingerprint of an intra-
molecular interaction between an electron-deficient area on the
surface of the covalently bonded chalcogen (S or Se) and the
negative surface of the O atom.16 Analysis of the electrostatic
potential surfaces of the investigated compounds indicated, on
the sulfur and selenium atoms, the presence of σ-holes17 as two
regions of positive potential along the outer sides of the
carbon−chalcogen σ-bonds (Figure 2 and Figure 4SI).
Despite being synthetically useful, taking into consideration
the previously reported evidence on the dihydrobenzo[b]furan
vs benzo[b]furan pair,7 the transformation reported in Scheme
1 appeared to be detrimental for antioxidant activity.
Surprisingly, measured kinh of 4 and 5 were up to three times
higher than those of the corresponding dihydro precursors 2
and 3 (see Table 2). Since a benzo[b]thiophene is, at least, as
“aromatic” as a benzo[b]furan, a rationale for this result
requires envisaging some additional effect responsible for the
extra stabilization of the Ar−O• involving the sulfur atom. We
initially evaluated the BDE(OH) of these phenols by
theoretical calculations.14 Phenols 4 and 5 showed identical
BDE(OH) values (74.6 kcal/mol) that were 3.2 kcal/mol lower
than 2 or 3 (77.8 kcal/mol) and 1.0 kcal/mol lower than
2,2,5,7,8-pentamethylchroman-6-ol (PMC, a “calculation
friendly” analogue of α-TOH) (75.6 kcal/mol). The good
agreement between calculated BDE(OH) and kinetic results
encouraged us to investigate at this level of theory the
BDE(OH) of parent 5- and 7-hydroxybenzo-fused five-
membered heterocycles containing O, S, and Se15 atoms (see
Table 1). For 5-hydroxy derivatives (i.e., the endocyclic
heteroatom is para to the OH), aromatization has a negative
impact on the BDE(OH), in particular for furans, in line with
Ingold’s result.7 On the other hand, for 7-hydroxy derivatives
(i.e., the endocyclic heteroatom is ortho to the OH),
aromatization has either no effect, as for oxygen, or a BDE-
lowering effect as for sulfur and selenium. Obviously, calculated
BDEs reported in Table 1 depend on several factors
contributing to the stabilization of the parent phenols and of
the phenoxyl radicals (Figures 5SI and 6SI). However, focusing
on the relative stability of phenoxyl radicals, it appears even
Figure 2. (Top) Molecular electrostatic potential showing the σ-hole
position (blue, positive potential; red, negative potential). (Bottom)
Preferential stabilization of the phenoxyl radical by the interaction
between the sulfur σ-hole and the oxygen atom.
Quantitative analysis of electrostatic potential surfaces,14c
reported in Table 1, showed that the σ-hole increased (i)
with the atomic number of the chalcogen atom, (ii) with
aromatization, and (iii) by passing from phenols to phenoxyl
radicals. These observations agree with the known determining
factors of σ-hole magnitude,17 which are size and polarizability
of the chalcogen atom and electron density removal, due to the
inclusion into an aromatic system or to the presence of
B
DOI: 10.1021/acs.orglett.6b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
electron-withdrawing groups. Figure 2 (top) shows that one σ-
hole on the S atom points toward the phenoxyl oxygen, whose
surface is largely negative. In recent years, noncovalent sulfur···
oxygen interactions have been used to rationalize the receptor−
drug binding18 or the preferred conformation of polythio-
phenes in organic electronic devices,19 even though, to the best
of our knowledge, the stabilization of a radical intermediate is
unknown. Actually, alignment between the σ-hole and the
oxygen lone pair is not optimal in our systems for an oxygen···
sulfur σ-hole interaction. However, NBO perturbation theory
analysis revealed a weak interaction between an oxygen lone
pair and the σ*(S−C2) in the 7-benzothiophenoxyl radical (0.16
and 0.18 kcal/mol for α and β spin sets, respectively). This
interaction is absent in the 7-benzofuranoxyl radical. Likewise,
in the structurally related 2-acetylthiophene, the occurrence of a
weak chalcogen bond is invocated to justify the preference for
the s-cis conformation.20 Upon closer inspection, several other
examples of “directionally unfavorable” intramolecular inter-
actions are available in literature.18,19 Additionally, an oxygen···
sulfur σ-hole interaction is also present when approaching
parent phenoxyl radical and thiophene, a simplified inter-
molecular model that we investigated to support our hypothesis
following the appreciated suggestion of a reviewer (Figure 8SI).
Thus, reasonably, the high reactivity and low BDE(OH) of 5
and 6 can be also attributed to a weak S···O chalcogen bond,
whose strength increases upon passing from the parent phenol
to the phenoxyl radical (Figure 2 (bottom)). These results
prompted us to explore the preparation of a family of super Vit
E like phenolic antioxidants by properly introducing the
benzo[b]thiophene structural motif in the α-TOH skeleton
(Scheme 2). We started studying the building of the chroman
promoted transposition process (Scheme 1SI). However, the
tert-butyl group, inserted to ensure the regioselective closure of
the chromanic ring, should be removed to allow the
dihydrobenzothiophene ring closure. Additionally, the acid
conditions required for transposition should preserve the
chroman ring. To our satisfaction, we verified that both
achievements (i.e., de-tert-butylation and chroman ring
conservation) could be accomplished under the reaction
conditions effective for the transposition (Scheme 2). Thus,
by reacting oxathiines 6 and 7 with 1 equiv of TfOH in CHCl3
at 60 °C, we observed the initial formation of dihydro
derivatives 10 and 11 followed by benzo[b]thiophenes 8 and 9.
Modulating the reaction times, it was possible to isolate
mixtures largely enriched in the required thiophenes (8 vs 10 or
9 vs 11;22 see the Supporting Information for details).
Remarkably, the formation of benzo[b]thiophenes 8 and 9 is
the result of five consecutive electrophilic events (i.e., de-tert-
butylation, benzoxathiine ring opening, dihydrobenzothiophene
ring closure, retro-alkylation, and deprotonative aromatization)
occurring in one pot (Scheme 2). As expected, the chromanic
and the thiophenic fused rings together in the right position
ensured a remarkable antioxidant activity with kinh of 8 and 9 up
to three times higher than those of 10, 11, and α-TOH (Table
2).
Table 2. Reactivity toward Peroxyl Radicals (kinh) and
Affinity to α-Tocopherol Transfer Protein (α-TTP)
a
b
substrate
kinh /106 (M−1 s−1
)
R
c
2
1.5
c
3
1.4
4
5.0
5.9
3.2
2.9
7.4
9.8
5
Scheme 2. Mechanism and Synthesis of Tocopherols
Containing the Benzo[b]thiophene Structural Motif
10
11
8
1.8
0.8
1
9
d
all-rac-α-TOH
3.2
a
Measured by studying the inhibited autoxidation of styrene in PhCl,
initiated by AIBN at 30 °C. The stoichiometry of radical trapping was
b
∼2 (see the Supporting Information). R = Kd (ligand)/Kd (all-rac-α-
c
d
TOH). From ref 13. From ref 6a.
Eventually, we measured the binding of α-tocopherol transfer
protein23,24 (α-TTP) to 8 and 9 to verify whether introduction
of the benzo[b]thiophene moiety on the α-TOH skeleton is a
tolerable modification at the biological level.
Thus, we measured the tryptophan fluorescence quenching
caused by the enzyme−substrate interaction. As discussed in
the Supporting Information, due to the known dependence of
Kd on experimental conditions,25 we decided to express the
dissociation constant of the antioxidant molecules with respect
to that of natural all-rac-α-TOH.26 The dissociation constant
ratio, R, reported in Table 2, shows how the insertion of an
unsubstituted (8) or a 2-methyl-substituted benzo[b]thiophene
(9) moiety in the α-TOH skeleton was well tolerated, resulting
in similar binding affinities.
7-Hydroxybenzo[b]thiophene is a privileged structure for the
construction of potent Vit E like phenolic antioxidants. A
noncovalent interaction between the ArO• group and the sulfur
σ-hole ensures extra stabilization of the phenoxyl radical that
lowers the phenolic BDE(O−H) and increases the reactivity
toward ROO•. A smart, one-pot procedure consisting of a
ring by cross-cyclic addition to the suitable phenol (Scheme
1SI).21 Thus, tert-butylation of 2-methylhydroquinone followed
by reaction with phythol allowed the regioselective preparation
of the 2-phythylchromane-substituted phenol. Using our well-
established methodology,8b,11−13 the phenol was transformed
into benzoxathiines 6 and 7 as suitable substrates for the acid-
C
DOI: 10.1021/acs.orglett.6b02557
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
(9) (a) Robillard, B.; Hughes, L.; Slaby, M.; Lindsay, D. A.; Ingold, K.
U. J. Org. Chem. 1986, 51, 1700−1704. (b) Malmstrom, J.; Jonsson,
M.; Cotgreave, J. A.; Hammarstrom, L.; Sjodin, M.; Engman, L. J. Am.
Chem. Soc. 2001, 123, 3434−3440. (c) Shanks, D.; Amorati, R.; Fumo,
M. G.; Pedulli, G. F.; Valgimigli, L.; Engman, L. J. Org. Chem. 2006, 71,
1033−1038. (d) Amorati, R.; Cavalli, A.; Fumo, M. G.; Masetti, M.;
Menichetti, S.; Pagliuca, C.; Pedulli, G. F.; Viglianisi, C. Chem. - Eur. J.
2007, 13, 8223−8230. (e) Menichetti, S.; Amorati, R.; Bartolozzi, M.
G.; Pedulli, G. F.; Salvini, A.; Viglianisi, C. Eur. J. Org. Chem. 2010,
cascade of five consecutive electrophilic transformations,
occurring one pot, provided two benzo[b]thiophene tocopher-
ols, perfectly recognized by α-TPP, with kinh three times higher
than that of α-TOH.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02557.
́
2010, 2218−2225. (f) Amorati, R.; Diner, P.; Bakhtiari, K.; Saeedi, M.;
Valgimigli, L.; Engman, L. Chem. - Eur. J. 2013, 19, 7510−7522.
(g) Poon, J-f.; Singh, V. P.; Yan, J.; Engman, L. Chem. - Eur. J. 2015,
21, 2447−2457.
Experimental procedures, including synthesis of inter-
mediates, kinh and Kd measurement, and calculation
details (PDF)
(10) (a) Schaefer, T.; Wildman, t. A.; Salman, S. R. J. Am. Chem. Soc.
1980, 102, 107−110. (b) Amorati, R.; Fumo, M. G.; Menichetti, S.;
Mugnaini, V.; Pedulli, G. F. J. Org. Chem. 2006, 71, 6325−6332.
(c) Howard, D. L.; Kjaergaard, H. G. Phys. Chem. Chem. Phys. 2008,
10, 4113−4118.
AUTHOR INFORMATION
■
(11) Amorati, R.; Catarzi, F.; Menichetti, S.; Pedulli, G. F.; Viglianisi,
C. J. Am. Chem. Soc. 2008, 130, 237−244.
(12) Viglianisi, C.; Menichetti, S.; Amorati, R.; Pedulli, G. F.;
Bartolozzi, M. G. Chem. - Eur. J. 2011, 17, 12396−12404.
(13) Viglianisi, C.; Di Pietro, L.; Amorati, R.; Menichetti, S. Chem. -
Eur. J. 2015, 21, 16639−16645.
(14) Geometries, frequencies, and natural bond orbital (NBO)
analysis were calculated in the gas phase at the M062X/aug-cc-pVDZ
level of theory. (a) Bauza, A.; Alkorta, I.; Frontera, A.; Elguero, J. J.
Chem. Theory Comput. 2013, 9, 5201−5210. (b) Nziko, V. de P. N.;
Scheiner, S. J. Org. Chem. 2015, 80, 2356−2363. (c) Lu, T.; Chen, F. J.
Comput. Chem. 2012, 33, 580−592.
(15) Calculations on selenophenes were actually carried out to
support the possible role of chalcogen bond in ArO• stabilization.
(16) Amorati, R.; Pedulli, G. F.; Valgimigli, L.; Johansson, H.;
Engman, L. Org. Lett. 2010, 12, 2326−2329.
Corresponding Authors
*E-mail: stefano.menichetti@unifi.it.
*E-mail: riccardo.amorati@unibo.it.
*E-mail: caterina.viglianisi@unifi.it.
Notes
The authors declare no competing financial interest.
REFERENCES
■
(1) (a) Ingold, K. U. Chem. Rev. 1961, 61, 563−589. (b) Al-Malaika,
S. In Comprehensive Polymer Science; Allen, G., Bevington, J. C., Eds.;
Eastwood, G. C., Ledwith, A., Russo, S., Sigwalt, P., Volume Eds.;
Pergamon Press: New York, 1989; Vol. 6, pp 539−576. (c) de Fat
́
ima
Poca
̧
s, M. F.; Hogg, T. Trends Food Sci. Technol. 2007, 18, 219−230.
(d) Halliwell, B.; Gutteridge, J. Free Radicals in Biology and Medicine,
4th ed.; Oxford University Press: Oxford, 2007. (e) Ingold, K. U.;
Pratt, D. A. Chem. Rev. 2014, 114, 9022−9046.
(17) (a) Politzer, P.; Murray, J. S.; Clark, T. Phys. Chem. Chem. Phys.
2013, 15, 11178−11189. (b) Murray, J. S.; Lane, P.; Clark, T.; Politzer,
P. J. Mol. Model. 2007, 13, 1033−1038.
̀
(2) (a) Brigelius-Flohe, R.; Traber, M. G. FASEB J. 1999, 13, 1145−
(18) (a) Beno, B. R.; Yeung, K.-S.; Bartberger, M. D.; Pennington, L.
D.; Meanwell, N. A. J. Med. Chem. 2015, 58, 4383−4438. (b) Fick, R.
J.; Kroner, G. M.; Nepal, B.; Magnani, R.; Horowitz, S.; Houtz, R. L.;
Scheiner, S.; Trievel, R. C. ACS Chem. Biol. 2016, 11, 748−754.
(19) (a) Turbiez, M.; Frere, P.; Allain, M.; Videlot, C.; Ackermann, J.;
Roncali, J. Chem. - Eur. J. 2005, 11, 3742−3752. (b) Murray, J. S.;
Lane, P.; Politzer, P. Int. J. Quantum Chem. 2008, 108, 2770−2781.
(c) Fanfrlik, J.; Prada, A.; Padelkova, Z.; Pecina, A.; Machacek, J.;
Lepsik, M.; Holub, J.; Ruzicka, A.; Hnyk, D.; Hobza, P. Angew. Chem.,
Int. Ed. 2014, 53, 10139−10142. (d) Nziko, V. de P. N.; Scheiner, S. J.
Org. Chem. 2015, 80, 2356−2363. (e) Kremer, A.; Fermi, A.; Biot, N.;
Wouters, J.; Bonifazi, D. Chem. - Eur. J. 2016, 22, 5665−5675.
(20) Rittner, R.; Ducati, L. C.; Tormena, C. F.; Fiorin, B. C.; Braga,
C. B. Spectrochim. Acta, Part A 2011, 79, 1071−1076.
(21) (a) Ishino, Y.; Mihara, M.; Hayakawa, N.; Miyata, T.; Kaneko,
Y.; Miyata, T. Synth. Commun. 2001, 31, 439−448. (b) Huang, Z.; Cui,
Q.; Xiong, L.; Wang, Z.; Wang, K.; Zhao, Q.; Bi, F.; Wang, Q. J. Agric.
Food Chem. 2009, 57, 2447−2456.
(22) A slight increase of the final yields of 8 and 9 was achieved with
isolated dihydrothiophenes 10 and 11 as starting materials.
(23) Panagabko, C.; Morley, S.; Neely, S.; Lei, H.; Manor, D.;
Atkinson, J. Protein Expression Purif. 2002, 24, 395−403.
(24) (a) Nam, T-g.; Rector, C. L.; Kim, H-y.; Sonnen, A. F-P.;
Meyer, R.; Nau, W. M.; Atkinson, J.; Rintoul, J.; Pratt, D. A.; Porter, N.
P. J. Am. Chem. Soc. 2007, 129, 10211−10219. (b) Li, B.; Harjani, J. R.;
Cormier, N. S.; Madarati, H.; Atkinson, J.; Cosa, G.; Pratt, D. A. J. Am.
Chem. Soc. 2013, 135, 1394−1405.
1155. (b) Traber, M. G.; Atkinson, J. Free Radical Biol. Med. 2007, 43,
4−15. (c) Azzi, A. Free Radical Biol. Med. 2007, 43, 16−21.
(3) (a) Golumbic, C.; Mattill, H. A. J. Am. Chem. Soc. 1941, 63,
1279−1280. (b) Amorati, A.; Ferroni, F.; Lucarini, M.; Pedulli, G. F.;
Valgimigli, L. J. Org. Chem. 2002, 67, 9295−9303. (c) Zhou, B.; Wu,
L.-M.; Yang, L.; Liu, Z.-L. Free Radical Biol. Med. 2005, 38, 78−84.
(d) Eggersdorfer, M.; Laudert, D.; Letinois, U.; McClymont, T.;
́
Medlock, J.; Netscher, T.; Bonrath, W. Angew. Chem., Int. Ed. 2012, 51,
12960−12990.
(4) (a) Wright, J. S.; Carpenter, D. J.; McKay, D. J.; Ingold, K. U. K. J.
Am. Chem. Soc. 1997, 119, 4245−4252. (b) Burton, G. W.; Ingold, K.
U. J. Am. Chem. Soc. 1981, 103, 6472−6477. (c) Wright, J. S.; Johnson,
E. R.; Di Labio, G. A. J. Am. Chem. Soc. 2001, 123, 1173−1183.
(d) Lucarini, M.; Pedulli, G. F. Chem. Soc. Rev. 2010, 39, 2106−2119.
(5) (a) Barclay, L. R. C.; Edwards, C. E.; Vinqvist, M. R. J. Am. Chem.
Soc. 1999, 121, 6226−6231. (b) Lucarini, M.; Mugnaini, V.; Pedulli, G.
F.; Guerra, M. J. Am. Chem. Soc. 2003, 125, 8318−8329.
(d) Litwinienko, G.; Ingold, K. U. Acc. Chem. Res. 2007, 40, 222−
230. (e) Foti, M. C.; Amorati, R.; Pedulli, G. F.; Daquino, C.; Pratt, D.
A.; Ingold, K. U. J. Org. Chem. 2010, 75, 4434−4440.
(6) (a) Burton, G. W.; Le Page, Y.; Gabe, E. J.; Ingold, K. U. J. Am.
Chem. Soc. 1980, 102, 7791−7792. (b) Doba, T.; Burton, G. W.;
Ingold, K. U. J. Am. Chem. Soc. 1983, 105, 6505−6506. (c) Lucarini,
M.; Cipollone, M.; Pedulli, G. F. J. Org. Chem. 1994, 59, 5063−5070.
(7) Zahalka, H. A.; Robillard, B.; Hughes, L.; Lusztyk, J.; Burton, G.
W.; Janzen, E. G.; Kotake, Y.; Ingold, K. U. J. Org. Chem. 1988, 53,
3739−3745.
(8) (a) Mukai, K.; Kageyama, Y.; Ishida, T.; Fukuda, K. J. Org. Chem.
1989, 54, 552−556. (b) Hussain, H. H.; Babic, G.; Durst, T.; Wright, J.
S.; Flueraru, M.; Chichirau, A.; Chepelev, L. L. J. Org. Chem. 2003, 68,
7023−7032. (c) Gregor, W.; Grabner, G.; Adelwohrer, C.; Rosenau,
T.; Gille, L. J. Org. Chem. 2005, 70, 3472−3483.
(25) Martina, M. R.; Tenori, E.; Bizzarri, M.; Menichetti, S.;
Caminati, G.; Procacci, P. J. Med. Chem. 2013, 56, 1041−1051.
(26) The natural ligand of α-TTP is (R,R,R)-α-TOH. We use all-rac-
α-TOH since to have a realistic comparison with racemic 8 and 9.
D
DOI: 10.1021/acs.orglett.6b02557
Org. Lett. XXXX, XXX, XXX−XXX