High-turnover hypoiodite catalysis for asymmetric synthesis of tocopherols

Article abstract of DOI:10.1126/science.1254976

The diverse biological activities of tocopherols and their analogs have inspired considerable interest in the development of routes for their efficient asymmetric synthesis. Here, we report that chiral ammonium hypoiodite salts catalyze highly chemo- and enantioselective oxidative cyclization of γ-(2-hydroxyphenyl)ketones to 2-acyl chromans bearing a quaternary stereocenter, which serve as productive synthetic intermediates for tocopherols. Raman spectroscopic analysis of a solution of tetrabutylammonium iodide and tert-butyl hydroperoxide revealed the in situ generation of the hypoiodite salt as an unstable catalytic active species and triiodide salt as a stable inert species. A high-performance catalytic oxidation system (turnover number of ~200) has been achieved through reversible equilibration between hypoiodite and triiodide in the presence of potassium carbonate base.We anticipate that these findings will open further prospects for the development of high-turnover redox organocatalysis.

Full text of DOI:10.1126/science.1254976

High-turnover hypoiodite catalysis for asymmetric synthesis of
tocopherols
Muhammet Uyanik et al.
Science 345, 291 (2014);
DOI: 10.1126/science.1254976
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22. J. A. D. Matthew, M. Komninos, Surf. Sci. 53, 716–725 (1975).
23. F. Tarantelli, L. S. Cederbaum, Phys. Rev. Lett. 71, 649–652
(1993).
24. T. D. Thomas et al., Phys. Rev. Lett. 89, 223001 (2002).
25. A. Niehaus, J. Phys. At. Mol. Opt. Phys. 19, 2925–2937 (1986).
26. V. May, O. Kühn, Charge and Energy Transfer Dynamics in
Molecular Systems, (Wiley-VCH, Weinheim, 2011).
27. E. Hamilton et al., Phys. Rev. A 72, 043402 (2005).
28. V. Averbukh, L. S. Cederbaum, J. Chem. Phys. 123, 204107 (2005).
29. M. Krikunova et al., New J. Phys. 11, 123019 (2009).
Department of Energy Office of Science by Stanford University.
We acknowledge the Max Planck Society for funding the
sample selection, and to the SLAC staff for their support and
hospitality during the beamtime. We thank R. Moshammer,
K. Schnorr A. Senftleben, and T. Pfeifer for fruitful discussions and
for the idea to adapt the classical over-the-barrier model for the
interpretation of the data presented in this manuscript.
development and operation of the CFEL-ASG-Multi-Purpose
(CAMP) instrument within the Advanced Study Group at CFEL. A.R.
acknowledges the support from Chemical Sciences, Geosciences,
and Biosciences Division, Office of Basic Energy Sciences, Office of
Science, U.S. Department of Energy and from Kansas National
Science Foundation Experimental Program to Stimulate
SUPPLEMENTARY MATERIALS
www.sciencemag.org/content/345/6194/288/suppl/DC1
Materials and Methods
Figs. S1 to S4
Tables S1 to S3
References (30–39)
Competitive Research (NSF EPSCoR) “First Award”; D.R.
acknowledges support from the Helmholtz Gemeinschaft through
the Young Investigator Program. J. K and S. T. acknowledge support
from the excellence cluster “The Hamburg Centre for Ultrafast
Imaging - Structure, Dynamics and Control of Matter at the Atomic
Scale” of the Deutsche Forschungsgemeinschaft. We are grateful
to C. Schmidt for technical support, to M. Cryle for help with
ACKNOWLEDGMENTS
Parts of this research were carried out at the Linac Coherent
Light Source (LCLS) at the SLAC National Accelerator Laboratory.
LCLS is an Office of Science User Facility operated for the U.S.
19 March 2014; accepted 9 June 2014
10.1126/science.1253607
ASYMMETRIC CATALYSIS
activated receptor–a/g dual agonist and exhibits
substantial antihyperglycemic and hypolipidemic
activities (13).
Natural D-a-tocopherol is formally (2R,4'R,8'R)-
2,5,7,8-tetramethyl-2-(4',8',12'-trimethyltridecyl)-6-
chromanol. The (2R)-configuration at the chroman
ring among the three stereocenters of a-tocopherol
is critical for its bioactivity; (2S)-stereoisomers
are not accepted by the tocopherol transfer pro-
tein (5). Thus, asymmetric construction of the
chroman ring has been an important challenge
(1, 2). Enantioselective processes have been de-
veloped to address this need by using chiral
transition metal complexes (Pd or Ru) (14–16)
or organocatalysts (17, 18). However, the low cat-
alytic activities and/or moderate enantioselec-
tivities have limited their utility (2). Here, we
report a transition metal–free (19) approach for
the enantioselective synthesis of tocopherols and
their analogs by using chiral hypoiodite catalysts
(20, 21) generated in situ from the corresponding
quaternary ammonium iodide with alkyl hydro-
peroxides as environmentally benign co-oxidants
(Fig. 1B). Chemoselective oxidative cyclization of
hydroquinone-derived g-(2-hydroxyphenyl)ketones
High-turnover hypoiodite catalysis for
asymmetric synthesis of tocopherols
Muhammet Uyanik,1 Hiroki Hayashi,1 Kazuaki Ishihara1,2
*
The diverse biological activities of tocopherols and their analogs have inspired considerable
interest in the development of routes for their efficient asymmetric synthesis. Here, we
report that chiral ammonium hypoiodite salts catalyze highly chemo- and enantioselective
oxidative cyclization of g-(2-hydroxyphenyl)ketones to 2-acyl chromans bearing a quaternary
stereocenter, which serve as productive synthetic intermediates for tocopherols.
Raman spectroscopic analysis of a solution of tetrabutylammonium iodide and tert-butyl
hydroperoxide revealed the in situ generation of the hypoiodite salt as an unstable catalytic
active species and triiodide salt as a stable inert species. A high-performance catalytic
oxidation system (turnover number of ~200) has been achieved through reversible
equilibration between hypoiodite and triiodide in the presence of potassium carbonate
base. We anticipate that these findings will open further prospects for the development of
high-turnover redox organocatalysis.
iologically active compounds containing
a chiral chroman skeleton are abundant
in nature (1). One of the most prominent
chiral chromans is a-tocopherol, which
is in the same family as vitamin E, to-
affecting cell viability (12). C48 developed by
Merck research laboratories (Rahway, New Jersey)
is a potent, selective peroxisome proliferator–
B
gether with b-, g-, and d-tocopherols and the cor-
responding a-, b-, g-, and d-tocotrienols (Fig. 1A)
(2). a-Tocopherol acts as a lipid-soluble, chain-
breaking antioxidant by capturing free radicals or
singlet oxygen formed by oxidative metabolism
in tissues (3). Furthermore, tocopherols show
physiologically diverse properties, including anti-
tumor, anti-inflammatory, anti-atherosclerosis,
and cell-signaling activities (4–8). Various non-
natural tocopherol analogs have also been devel-
oped because of their potency and distinct
structural features. For example, trolox and its
derivatives have been used as a chiral derivatizing
reagent (9) and NO-releasing drug candidates
(10). Dihydrodaedalin A, a syntheticintermediate
for the natural product daedalin A (11), is a potent
tyrosinase inhibitor and has been shown to
suppress melanogenesis in human skin without
1Graduate School of Engineering, Nagoya University, Furo-cho,
Chikusa, Nagoya 464-8603, Japan. 2Core Research for
Evolutional Science and Technology, Japan Science and
Technology Agency, Furo-cho, Chikusa, Nagoya 464-8603,
Japan.
Fig. 1. A catalytic route to the tocopherol core. (A) Biologically active tocopherols and other chromans.
(B) Enantioselective oxidative cycloetherification of γ-(2-hydroxyphenyl)ketones 1 to 2-acyl chromans 2 by
in situ–generated chiral hypoiodite catalysts.
*Corresponding author. E-mail: ishihara@cc.nagoya-u.ac.jp
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gives >95% yield of the corresponding 2-acyl
chromans; with the quaternary stereocenter set
in high enantioselectivity, these products are poised
for elaboration to a range of tocopherols.
Previously, we developed in situ–generated chi-
ral quaternary ammonium hypoiodite (R4NOI) ca-
talysis for the enantioselective oxidative cyclization
of b-(2-hydroxyphenyl)ketones to the five-membered
ring products 2-acyl-2,3-dihydrobenzofurans with
hydrogen peroxide or tert-butyl hydroperoxide
(TBHP) as co-oxidants (20). The use of chiral
binaphthyl-based quaternary ammonium (22) io-
dide as a precatalyst and an N-phenylimidazol-2-yl
(Z) (23) group as an auxiliary of b-(2-hydroxyphenyl)
ketones was effective for inducing high enantio-
selectivities. We envisioned that the enantioselec-
tive oxidative cyclization of g-(2-hydroxyphenyl)
ketones (1) would give the desired six-membered
ring 2-acyl chromans (2) (Fig. 1B).
To begin our investigation, we compared the
enantioselective oxidative cyclization of (5-tert-
butyldimethylsilyloxy-2-hydroxyphenyl)ketones
(1a and 3a) derived from trimethyl hydroquinone
(Fig. 2A). Oxidative cyclization of 3a under pre-
vious conditions by using 10 mole percent
(mol %) of ammonium iodide (R,R)-5a and
hydrogen peroxide (2 equivalents) as an oxidant
in methyl tert-butyl ether (MTBE) gave five-
membered ring dihydrobenzofuran (R)-4a in 95%
yield with 93% enantiomeric excess (ee). In sharp
contrast, oxidative cyclization of 1a to the six-
membered ring under the same conditions was
sluggish, and only a trace amount of the desired
2-acyl chroman 2a was obtained together with a
small amount (10% yield) of phenol-oxidation
product 6a.
The posited catalytic mechanism and side-
reaction pathway are summarized in Fig. 2B.
The above results and competition experiments
(table S1) suggested that oxidative cyclization
to a six-membered ring was much slower than
cyclization to a five-membered ring. Thus, un-
desired side reactions, such as the dearomati-
zation of 1a, preferentially proceeded to give
side-products 6a and/or 6b, presumably via
phenoxenium ion 7 (24). The cyclization step
might be rate-limiting for six-membered ring
oxidative cyclization. Consequently, the in situ–
generated catalytic active species (hypoiodite)
was easily converted to an inert species such as
triiodide salts, as confirmed with Raman analy-
sis. For the construction of an efficient catalytic
cycle, the oxidative cyclization step should not
be rate-limiting. To address this issue, the oxi-
dation of iodide (path a) should be decelerated,
oxidative cyclization (path b) should be accel-
erated, or the inactivation (path c) should be
suppressed or reversed. The use of TBHP as a
weaker oxidant (25) instead of hydrogen per-
oxide solved this problem partially by decel-
eration of the generation of active species.
Substrate 1a was consumed within 1 hour; how-
ever, the desired product 2a was obtained in
only 15% yield with 18% ee (Fig. 2A). Undesired
dearomatization dominated again, and quinone
6a and peroxy quinol 6b were obtained in a
combined yield of 65%.
Fig. 2. Investigation of six-membered ring oxidative cyclization. (A) Comparison of five- and six-
membered enantioselective oxidative cyclizations. Isolated yields of 2a, 4a, and 6 are reported. TBS,
tert-butyldimethylsilyl. (B) Proposed catalytic mechanism and side-reaction pathway. “X” (in XOOH),
H or alkyl. (C) Investigation of reaction parameters toward a-tocopherol. Isolated yields of 2b and 4b
are reported. ee was determined by means of chiral stationary-phase high-performance liquid chro-
matography (HPLC). The absolute configuration of 2b was determined by comparing the optical
rotation of 9 (Fig. 3B) derived from 2b with the literature value (31), and all other chromans 2 were
assigned through analogy. The absolute configurations of 4a and 4b were determined by using their
known analogs (20).
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To prevent undesired dearomatization and ac-
celerate the desired cyclization path, a para-
toluenesulfonyl (Ts) group was introduced as an
electron-withdrawing protective group in place
of the silyl group of 1a. As expected, the oxida-
tive cyclization of 1b with 10 mol % of (R,R)-5a
gave desired (R)-2b quantitatively, with 60% ee
(Fig. 2C, entry 1). The 3,3′-substituents of the
binaphthyl moiety of (R,R)-5 had a dramatic
Fig. 3. Application to structurally diverse sub-
strates. (A) Enantioselective oxidative cycloether-
ification of various γ-(2-hydroxyphenyl)ketones
1 to chromans 2. Unless otherwise noted, 1 mol %
of (R,R)-5a or (R,R)-5d was used in the presence
of potassium carbonate. Asterisk indicates that
the reaction was performed by using 10 mol % (R,R)-
5a in the absence of K2CO3 with TBHP instead of
CHP at 0°C. Dagger symbol indicates that (R)-2h
and (S)-2h were obtained in optically pure forms
after a single re-crystallization. (B) Asymmetric
formal syntheses of (S)-trolox, D-a-tocopherol, and
D-a-tocotrienol. MeOTf, methyl trifluoromethane-
sulfonate; DBU, 1,8-diazobicyclo[5.4.0]undec-7-ene.
Fig. 4. Probing the active catalyst. (A) Detection of catalytic
species. A series of Raman spectra (a to c) obtained upon
the addition of sodium hydroxide to
a solution of n-
tetrabutylammonium iodide and TBHP are shown. (B)
Control experiments with n-tetrabutylammonium triiodide
in the presence or absence of potassium carbonate.
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effect on enantioselectivity and reactivity (Fig.
2C, entries 1 to 4). To our surprise, the use of
(R,R)-5b in place of (R,R)-5a gave (S)-2b as an
opposite enantiomer, with higher enantioselec-
tivity (86% ee) (Fig. 2C, entry 2). The opposite
absolute stereoselectivity was observed with the
use of not only (R,R)-5b but also (R,R)-5c and
(R,R)-5d, which have biphenyl groups at the 3,3′
positions (Fig. 2C, entries 2 to 4). The best result
(96% yield, 89% ee) was obtained after a shorter
reaction time with perfluoroalkyl-substituted am-
monium iodide (R,R)-5d (Fig. 2C, entry 4). Be-
cause the oxidative cyclization step might not
be rate-limiting for 1b, which was more reactive
than 1a, hydrogen peroxide could be used as an
oxidant, albeit with a slightly reduced enantio-
selectivity (Fig. 2C, entry 5). When cumene hydro-
peroxide (CHP) was used as an oxidant in diethyl
ether, the reaction was complete in 45 min, and
(S)-2b was obtained quantitatively, with 93% ee
(Fig. 2C, entry 6).
A reduction in the catalyst loading might
cause competition between inactivation (path c)
and oxidative cyclization (path b) in this catalytic
system (Fig. 2B). When 1 mol % of 5d was used,
no reaction occurred, and the starting material
was recovered fully (Fig. 2C, entry 7). To overcome
this problem, suppression or reversible control of
the inactivation path was considered. It is known
that hypoiodite salts can be prepared with the
hydrolysis of triiodide salts in alkaline solutions,
and these species are in equilibrium under basic
conditions (26). We envisioned that the hypoio-
dite species might be regenerated from triiodide
species in the presence of appropriate base addi-
tives under our catalytic conditions. After the in-
vestigation of various organic and inorganic base
additives (table S4), we succeeded in developing
a high-performance catalytic oxidation system in
the presence of an inorganic base such as potas-
sium carbonate. Thus, the catalyst loading could
be reduced to 1 or even 0.5 mol % [turnover num-
ber (TON) of the catalyst = 200] for the oxidation
of 1b in the presence of one equivalent of potas-
sium carbonate without reducing the chemical
yield or enantioselectivity (Fig. 2C, entries 8 and 9).
Furthermore, the TON of the catalyst was 2000
for the five-membered oxidative cyclization of 3b
(Fig. 2C, entry 10). These reaction conditions were
compatible with gram-scale synthesis (Fig. 2C,
entries 8 and 10).
with high enantioselectivities. The optically pure
enantiomers 2h could be obtained after a single
recrystallization.
6. M. Tomasetti, J. Neuzil, Vitam. Horm. 76, 463–491
(2007).
7. A. C. Howard, A. K. McNeil, P. L. McNeil, Nat. Commun. 2, 597
(2011).
8. P.-H. Huang et al., Sci. Signal. 6, ra19 (2013).
9. W. Walther, W. Vetter, T. Netscher, J. Micro. Sep. 4, 45–49
(1992).
10. G. V. López et al., Bioorg. Med. Chem. 13, 5787–5796
(2005).
11. M. Sekimoto, Y. Hattori, K. Morimura, M. Hirota,
H. Makabe, Bioorg. Med. Chem. Lett. 20, 1063–1064
(2010).
12. Y. Morimura, M. Hirota, Y. Hattori, H. Makabe, “Chroman
compound and method for preparing the same,” Japan patent
5212969 (2013).
13. H. Koyama et al., J. Med. Chem. 47, 3255–3263
(2004).
14. B. M. Trost, H. C. Shen, L. Dong, J.-P. Surivet, C. Sylvain, J. Am.
Chem. Soc. 126, 11966–11983 (2004).
15. L. F. Tietze, K. M. Sommer, J. Zinngrebe, F. Stecker,
Angew. Chem. Int. Ed. Engl. 44, 257–259 (2004).
16. S. Tanaka, T. Seki, M. Kitamura, Angew. Chem. Int. Ed. Engl.
48, 8948–8951 (2009).
17. A. Chougnet, K. Liu, W.-D. Woggon, Chimia (Aarau) 64,
303–308 (2010) and references therein.
18. S. Tokunou, W. Nakanishi, N. Kagawa, T. Kumamoto, T. Ishikawa,
Heterocycles 84, 1045–1056 (2012).
19. B. List, K. Maruoka, Eds., Science of Synthesis:
Asymmetric Organocatalysis (George Thieme Verlag,
Stuttgart, 2012).
20. M. Uyanik, H. Okamoto, T. Yasui, K. Ishihara, Science 328,
1376–1379 (2010).
21. M. Uyanik, K. Ishihara, ChemCatChem 4, 177–185
(2012).
22. T. Ooi, K. Maruoka, Angew. Chem. Int. Ed. Engl. 46, 4222–4266
(2007).
23. D. A. Evans, K. R. Fandrick, H.-J. Song, K. A. Scheidt, R. Xu,
J. Am. Chem. Soc. 129, 10029–10041 (2007).
24. D. Magdziak, S. J. Meek, T. R. R. Pettus, Chem. Rev. 104,
1383–1430 (2004).
25. R. D. Cadle, H. Huff, J. Phys. Colloid Chem. 54, 1191–1195
(1950).
The formal syntheses of D-a-tocopherol, D-
a-tocotrienol, and (S)-trolox were also achieved
(Fig. 3B). The (N-phenylimidazol-2-yl)carbonyl
group of product 2b was easily transformed (23)
to the methyl ester (8), which could be obtained
in optically pure form after a single recrystalliza-
tion. Subsequent deprotection of the tosyl group
of 8 under mild conditions gave 9 in high chem-
ical yield. The ester 9 is a common synthetic inter-
mediate for D-a-tocopherol (27), D-a-tocotrienol
(28), and (S)-trolox (29). Other tocopherols and
their biologically active analogs could be easily
prepared in a similar manner.
To gain insight into the catalytic mechanism,
we performed various control experiments and
spectroscopic analysis (Fig. 4, tables S5 and S6,
and figs. S1 to S8). A series of Raman spectra
obtained upon the addition of sodium hydroxide
to a solution of n-tetrabutylammonium iodide
(Bu4NI) and TBHP is shown in Fig. 4A. To our
delight, we detected unstable hypoiodite [IO]–
and hypoiodous acid [IOH] species (30). Spec-
trum a, which includes three main bands at 110,
417, and 438 cm–1, was recorded immediately af-
ter the mixing of Bu4NI with TBHP. The other
bands were attributed to the solvents and re-
agents used. The band at 110 cm–1 is character-
istic of [I3]–. The bands at 417 and 438 cm–1 were
assigned to [IO]– and [IOH] species, respective-
ly, on the basis of the literature (30) and our
control experiments (figs. S4 to S7). These two
species might be in equilibrium under these
conditions and disappeared steadily with time,
and only a band of triiodide was observed after
2 hours (spectrum b). No other inert species such
as iodate and periodate were observed at this
time. The band of triiodide decreased immedi-
ately under basic conditions (spectrum c). A new
band at 768 cm–1, which is characteristic of the
iodate [IO3]– spectrum, was observed (30). This
indicated the rapid generation and subsequent
disproportionation of hypoiodite species (30).
These results revealed that hypoiodite is an un-
stable catalytic active species and that triiodide
is a stable inert species under our conditions
(Fig. 2B). Although iodite species [IO2]– could
not be detected, we could not completely rule out
a catalytic role of [IO2]–. The regeneration of hy-
poiodite from triiodide was also confirmed with
control experiments (Fig. 4B and table S6). Oxi-
dative cyclization of 1h did not occur with the
use of n-tetrabutylammonium triiodide but pro-
ceeded in the presence of potassium carbonate
under identical conditions.
26. Y.-T. Chia, thesis, University of California, Berkeley
(1958).
27. M. Nozawa, K. Takahashi, K. Kato, H. Akita, Chem. Pharm. Bull.
(Tokyo) 48, 272–277 (2000).
28. R. Chênevert, G. Courchesne, N. Pelchat, Bioorg. Med. Chem.
14, 5389–5396 (2006).
29. A. Ida, Y. Kyuko, T. Hidaka, “Method of producing (S)-(–)-6-
hydroxy-2,3,7,8-tetramethylchromane-2-carboxylic acid and
product obtained by the method,” U.S. Patent 8,080,676
(2011).
30. J. C. Wren, J. Paquette, S. Sunder, B. L. Ford, Can. J. Chem. 64,
2284–2296 (1986).
31. H. Yoda, K. Takabe, Chem. Lett. 18, 465–466 (1989).
ACKNOWLEDGMENTS
Financial support for this project was partially provided by the
Japan Society for the Promotion of Science, Grant-in-Aid for
Scientific Research (KAKENHI) (24245020, 22750087, and
25105722), and Program for Leading Graduate Schools
“Integrative Graduate Education and Research in Green Natural
Sciences,” Ministry of Education, Culture, Sports, Science and
Technology, Japan. Metrical parameters for the structure of
compound 2h are available free of charge from the Cambridge
Crystallographic Data Centre under reference number CCDC
996935. M.U. and K.I. developed the concept and conceived the
experiments. H.H. performed the experiments. H.H. and M.U.
analyzed the data. M.U. and K.I. prepared the manuscript, with
assistance from H.H.
We examined several g-(2-hydroxyphenyl)
ketones 1 under optimized conditions (Fig. 3A).
(S)-2-Acylchromans 2c–e, which would be a syn-
thetic intermediate for b-, g-, and d-tocopherols,
were obtained quantitatively with high enantio-
selectivities by using 1 mol % of (R,R)-5d.
The reactions of g-[5-(4-chlorobenzoyloxy)-2-
hydroxyphenyl]ketone 1f and g-(4-tosyloxy-2-
hydroxyphenyl)ketone 1g by using (R,R)-5a gave
(R)-2f and (R)-2g, respectively. Compounds (R)-
2f and (R)-2g would potentially offer a different
route to dihydrodaedalin A (11, 12) and Merck’s
compound C48 (13), respectively. The oxidative
cyclizations of 1h by using 1 mol % of (R,R)-5a
and (R,R)-5d under the same conditions pro-
vided both enantiomers of the chroman 2h
SUPPLEMENTARY MATERIALS
REFERENCES AND NOTES
www.sciencemag.org/content/345/6194/291/suppl/DC1
1. H. C. Shen, Tetrahedron 65, 3931–3952 (2009) and references
therein.
2. T. Netscher, Vitam. Horm. 76, 155–202 (2007) and references
therein.
3. J. E. Packer, T. F. Slater, R. L. Willson, Nature 278, 737–738
(1979).
4. The Alpha-Tocopherol Beta Carotene Cancer Prevention Study
Group, N. Engl. J. Med. 330, 1029–1035 (1994).
5. D. H. Blatt, W. A. Pryor, J. E. Mata, R. Rodriguez-Proteau,
J. Nutr. Biochem. 15, 380–395 (2004).
Materials and Methods
Tables S1 to S7
Figs. S1 to S9
HPLC Traces
NMR Chart
References (32–53)
18 April 2014; accepted 10 June 2014
10.1126/science.1254976
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