Angewandte
Chemie
concentration without base. Optimization of the substitution
pattern of the Maruoka-type chiral ammonium precatalysts[10]
showed that best enantioselectivities were achieved with
perfluoroalkyl-containing substituted binaphthyl units.
Under optimized conditions cycloetherification of pre-
cursor 3 in the presence of 1 mol% (R,R)-5 yielded (S)-
chroman derivative 4 in 98% yield and 93% ee, and it was
further transformed to intermediate 6 (Scheme 1). The
syntheses of (S)-Trolox (8), (2R,4’R,8’R)-a-tocopherol (1a),
and (2R,3’E,7’E)-a-tocotrienol (2a) were completed by using
established methods. Also differently substituted chroman
building blocks 7 could be obtained analogously with ee
values of 85–93% and they served as intermediates in the
syntheses of the homologous b-, g-, and d-tocopherols (1b–d)
as well as several structurally related pharmaceuticals. The
catalyst turnover numbers (TONs) of up to 200 (loading of
0.5 mol%) are notably high for such transformations, and
a TON value of 2000 (corresponding to a loading of
0.05 mol%) was reported for a catalyst structurally closely
related to (R,R)-5 in the much faster cyclization of a corre-
sponding b-(2-hydroxyphenyl)ketone to five-membered ben-
zofuran 9 (R5 = Ts).
Without a doubt this work belongs to the most innovative
approaches for the enantioselective preparation of the chro-
man (and benzofuran) skeleton in the past few years and
represents a considerable step forward in the field. Never-
theless, some limitations at the current status should be
mentioned. Starting material 3 contains both a large auxiliary
(Z) and protective (Ts) group, and is (currently) prepared in
six steps from commercially available materials. The synthesis
of the phase-transfer catalyst also requires multiple steps.
Although the 1 mol% loading of (R,R)-5 is already rather
low, it still corresponds to a high weight proportion since the
catalyst contains 52 fluorine atoms and has a molecular mass
exceeding 2000. The impressive but still insufficient level of
stereoselectivity (up to 93% ee) must be increased by
recrystallization, and additional manipulations in down-
stream chemistry are required to arrive at the target
product(s). Finally, the new methodology can offer “only”
a possible solution for the generation of the chiral chroman
core structure.
In commentaries on the contribution of the Nagoya
research group,[9b,c] discussions have been started on whether
this work is a low-cost and “green” synthesis method for
making tocopherols, and whether this route can compete with
work published earlier. It must be clearly stated that no
simple and precise answer regarding a practical, that is,
commercially viable solution is apparent. In general, the
overall route to a product has to fulfill all requirements in
terms of cost and environmental sustainability. It is known
from experience that considerable effort in process research
and development is necessary to translate a scientific break-
through into a large-scale process. This concerns not only the
number of steps, yields, and selectivities, but also issues such
as availability, stability, and recyclability of auxiliaries,
reagents, catalysts, and solvents, energy consumption, and
waste formation. Often catalyst activity and productivity
become major challenges and determine whether a process is
economical.
Scheme 1. Asymmetric hypoiodite-catalyzed chroman ring closure.
a) Cumene hydroperoxide (2 equiv), K2CO3 (1 equiv), Et2O, (R,R)-5
(1 mol%), 258C, 10 h; b) MeOTf (5 equiv), CH2Cl2, 258C, 1 h, then
DBU (1.2 equiv), MeOH, 258C, 1 h, then recrystallization (hexane/
EtOAc); c) Mg (10 equiv), MeOH, 258C, 2 h; Ts=para-toluenesulfonyl,
Tf =trifluoromethanesulfonyl, DBU=1,8-diazabicyclo[5.4.0]undec-7-
ene.
group as an auxiliary at the g-(2-hydroxyphenyl)ketone
moiety, protection of the remote phenolic hydroxy group of
the hydroquinone as a sulfonic ester, the stoichiometric use of
an alkyl hydroperoxide in combination with an inorganic
base, and the catalysis induced by 0.05–10 mol% of a chiral
ammonium iodide based on a binaphthyl structural motif in
an aliphatic ether (tert-butyl methyl ether or, preferably,
diethyl ether) as the solvent.
During the investigation, several difficulties had to be
overcome. The OTs (O-para-toluenesulfonyl) group proved
to be sufficiently stable towards the oxidative conditions
while the initially used tert-butyldimethylsilyl ether was
oxidized to dearomatized quinone and peroxyquinol side
products. Generally, the weak oxidant cumene hydroperoxide
was superior to tert-butyl hydroperoxide and 30% aqueous
hydrogen peroxide. According to detailed mechanistic inves-
tigations of the catalytic cycle (Scheme 2) the presence of
potassium carbonate (1 equiv) was essential to suppress the
ꢀ
formation of the inactive I3 species, which can be trans-
formed (back) to the catalytically active IOꢀ salt by alkaline
hydrolysis. Indeed no conversion was detected at low catalyst
Scheme 2. Proposed catalytic cycle for enantioselective cyclization.
Angew. Chem. Int. Ed. 2014, 53, 2 – 5
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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These are not the final page numbers!
Netscher, Thomas
