Deracemization of α-aryl hydrocoumarins via catalytic asymmetric protonation of ketene dithioacetals

Article abstract of DOI:10.1021/ja3096202

An unprecedented catalytic asymmetric protonation of ketene dithioacetals is described. Various racemic α-aryl hydrocoumarin derivatives are transformed into enantioenriched dithioacetal-protected hydrocoumarins in the presence of a chiral Br?nsted acid catalyst. A newly developed phosphoric acid, featuring the 3,5-bis(pentafluorothio)phenyl (3,5-(SF₅) ₂C₆H₃) substituent, is introduced. The obtained products can be easily converted into either hydrocoumarins or the corresponding chromans via simple hydrolysis or hydrogenation, respectively.

Full text of DOI:10.1021/ja3096202

Communication
pubs.acs.org/JACS
Deracemization of α‑Aryl Hydrocoumarins via Catalytic Asymmetric
Protonation of Ketene Dithioacetals
Ji-Woong Lee and Benjamin List*
Max-Planck-Institut fur Kohlenforschung, Kaiser-Wilhelm-Platz 1, D-45470 Mulheim an der Ruhr, Germany
̈
̈
S
* Supporting Information
may be an effective and general tool for the deracemization of
enantiopure α-substituted cyclic esters.8 In particular, we
expected this reaction design to lead to an efficient approach
to α-arylated hydrocoumarins9,10 and related chroman
derivatives (isoflavonoids),11 as these compound classes include
naturally abundant agents possessing antioxidant and various
other biological activities (Figure 1).
ABSTRACT: An unprecedented catalytic asymmetric
protonation of ketene dithioacetals is described. Various
racemic α-aryl hydrocoumarin derivatives are transformed
into enantioenriched dithioacetal-protected hydrocoumar-
ins in the presence of a chiral Brønsted acid catalyst. A
newly developed phosphoric acid, featuring the 3,5-
bis(pentafluorothio)phenyl (3,5-(SF5)2C6H3) substituent,
is introduced. The obtained products can be easily
converted into either hydrocoumarins or the correspond-
ing chromans via simple hydrolysis or hydrogenation,
respectively.
symmetric protonations of enolate equivalents, at least in
A
principle, offer a highly straightforward approach to
enantioenriched α-tertiary carbonyl compounds. Since pioneer-
ing investigations by Duhamel and Yoshikawa,1,2 such reactions
have typically relied on a stoichiometric chiral proton source,
although catalytic asymmetric versions have also been
described.3−5 In the context of a different project, we were in
need of enantiomerically pure α-aryl hydrocoumarins (1).
Despite their high relevance as biologically active compounds,
however, nonracemic α-aryl hydrocoumarins (1) have been entirely
unknown. Here we report a highly enantioselective, catalytic,
asymmetric protonation-induced cyclization of ketene dithio-
acetals 2 to easily hydrolyzable ortho esters 3. The overall
sequence described here provides for an efficient entry toward
enantiomerically pure α-aryl hydrocoumarins via an effective
deracemization.
Figure 1. Selected examples of chiral α-aryl hydrocoumarins and
chromans.
Syntheses of enantioenriched α-arylated hydrocoumarins
have not been reported previously, and even relatively obvious
approaches such as asymmetric α-arylations and hydrogenation
reactions are completely unknown. Recently, an access to
chromanones via a highly enantioselective NHC-catalyzed
intramolecular Stetter reaction has been described.12 Also,
enantioselective Brønsted acid catalysis has been utilized in the
synthesis of chroman derivatives from an activated allylic
alcohol substrate via intramolecular allylic substitution.13
Our own studies commenced with the investigation of model
substrate 2a, which is obtained in quantitative yield by reacting
3-phenylhydrocoumarin with in situ-generated bis-
(dimethylaluminum) 1,3-propanedithiolate (see Supporting
Information). Encouraged by recent breakthroughs in asym-
metric Brønsted acid catalysis,14 we first tested catalytic
In addition to their use in carbonyl protection and umpolung
activation,6 dithioacetals have been used by Corey et al. as
protecting groups for lactones and esters.7 Interestingly, it was
found that dithioacetal protection of γ-valerolactone in
chloroform led to an instantaneous and presumably acid-
catalyzed cyclization of the ketene dithioacetal to the
corresponding ortho ester. We envisioned that the reaction
sequence of ketene dithioacetal formation, asymmetric
Brønsted acid-catalyzed protonative cyclization, and hydrolysis
Received: September 28, 2012
Published: October 29, 2012
© 2012 American Chemical Society
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Journal of the American Chemical Society
Communication
a b
,
amounts of chiral phosphoric acids 5. These investigations
revealed the facile catalyst 5a-mediated cyclization of ketene
dithioacetal 2a to the protected hydrocoumarin derivative 3a in
excellent yield but disappointing enantioselectivity (Table 1,
Chart 1. Substrate Scope
a
Table 1. Establishing Suitable Reaction Conditions
b
c
entry
catalyst
time
conv
er
1
2
3
4
5
5a (10 mol%)
5b (10 mol%)
5c (10 mol%)
5d (10 mol%)
5e (10 mol%)
5e (5 mol%)
5e (0.5 mol%)
5f (5 mol%)
8 h
45 h
8 h
90%
93%
91%
31%
95%
98%
53:47
65:35
74:26
54:46
90:10
91:9
2 h
2 h
d
6
18 h
2.5 d
7 d
e
g
7
df
,
93%
99%
93.5:6.5
95:5
8
a
Unless otherwise indicated, all reactions were carried out with
substrate 2a (0.016 mmol) and 5 mg of molecular sieves (4 Å) in
b
cyclohexane (0.5 mL, 0.032 M). Conversion determined by 1H NMR
c
analysis of the crude reaction mixture. Enantiomeric ratio determined
d
e
by HPLC analysis. Reaction carried out at 0.008 M. Reaction carried
f
out with 2 mmol of substrate 2a (at 0.002 M). Reaction carried out
without molecular sieves. Isolated yield.
g
entry 1, 53:47 er). Similarly, with sterically hindered phosphoric
acids 5b−d, only moderate enantioselectivities were observed
(entries 2−4). Further screening of catalyst structures revealed
that commercially available acid 5e, featuring electron-with-
drawing 3,5-bis(trifluoromethyl)phenyl substituents, was opti-
mal in terms of reactivity and enantioselectivity (90:10 er, entry
5). By decreasing the catalyst loading to 5 mol% and diluting
the reaction mixture, we could obtain orthoester 3a with
slightly higher enantioselectivity (91:9 er, entry 6). Moreover,
the catalyst loading could be decreased to 0.5 mol% to afford
product 3a with similar enantioselectivity on a 2 mmol scale
(entry 7). Gratifyingly, the enantioselectivity could be further
improved by using a novel catalyst, acid 5f, which displays the
new 3,5-bis(pentafluorothio)phenyl substituent in its 3,3′-
position.15 The pentafluorothio group has recently been
utilized in the context of medicinal chemistry as an alternative
and larger substitute for the common trifluoromethyl
group.15c,d Indeed, very high enantioselectivity was obtained
with phosphoric acid 5f (95:5 er), although this catalyst proved
to be slightly less active (entry 8).
With the development of suitable reaction conditions and the
identification of acids 5e and 5f as highly enantioselective
catalysts, we next began investigating the substrate scope of this
new asymmetric protonation-induced cyclization reaction
(Chart 1).
The required racemic α-arylated hydrocoumarins can be
easily obtained via condensation of salicylaldehyde derivatives
and α-aryl acetyl chloride and subsequent reduction (see
Supporting Information).16 The corresponding ketene dithio-
acetals (2b−o) were then obtained in typically quantitative
a
Isolated yields (%) and enatiomeric ratios (er); see Supporting
b
Information and Table S1 for the experimental details. Enantiomeric
ratio determined by HPLC analysis. Reactions carried out with 1 mol
% of catalyst at 25 mM 2g. Reaction carried out with the (S)-
enantiomer of the catalyst to afford (R)-3g.
c
d
yields. As shown in Chart 1, various ketene dithioacetals were
converted into the corresponding dithioacetal-protected hydro-
coumarin derivatives with good to excellent enantioselectivity
in the presence of catalytic amounts of a phosphoric acid 5e or
5f. The desired products 3b−o were obtained with generally
good to excellent yields and enantioselectivities and essentially
unaffected by electronic or steric properties of the ketene
dithioacetals. It is noteworthy that thioacetal 3g was obtained
with an outstanding yield and enantioselectivity (98% yield,
>99:1 er) with only 1 mol% catalyst loading. In this case, the
opposite enantiomer was also prepared with excellent
enantioselectivity (1:99 er) by using the enantiomeric (S)-
configured catalyst. The structures of a starting material (2g)
and a product (3k), including its absolute configuration, were
assigned unambiguously by X-ray crystallography (see Support-
ing Information).
To demonstrate the practical utility of our deracemization
protocol, we examined the preparation of an optically enriched
hydrocoumarin on a gram scale. As shown in Scheme 1,
racemic hydrocoumarin 1g could be transformed into the
achiral ketene thioacetal intermediate 2g and isolated by
precipitation in cold diethyl ether. Thioacetal 2g was then
treated with a catalytic amount of phosphoric acid (0.5 mol%)
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Journal of the American Chemical Society
Communication
acknowledged. We thank our analytical departments (mass
spectroscopy and X-ray analysis) for their excellent support.
Scheme 1. Gram-Scale Deracemization of Hydrocoumarin
1g without Purification
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enantiopure hydrocoumarin (S)-1g in quantitative yield (see
Supporting Information).
Finally, the dithioacetal protecting group can also be
removed reductively using Raney-Ni under a hydrogen
atmosphere, affording valuable chroman or isoflavonoid
derivatives. As illustrated in Scheme 2, dithioacetal-protected
hydrocoumarin derivative 3e was converted into the
enantioenriched non-steroidal estrogen (S)-Equol via hydro-
genation and demethylation.17
Scheme 2. Application to the Synthesis of (S)-Equol
In conclusion, we have developed a deracemization approach
to enantiopure α-arylated hydrocoumarin derivatives that is
based on an enantioselective protonation in the presence of
commercially available phosphoric acid catalyst 5e or the novel
SF5-substituted phosphoric acid catalyst 5f. The operationally
simple protocol allows facile catalysis at ambient reaction
conditions. The obtained thioacetal-protected enantioenriched
products can be easily transformed to hydrocoumarins and
chromans via simple deprotection steps without loss of
enantiopurity. Further application of our protocol to various
lactones and biologically active target molecules is currently
under investigation.
ASSOCIATED CONTENT
* Supporting Information
Experimental procedures and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
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AUTHOR INFORMATION
Corresponding Author
list@mpi-muelheim.mpg.de
■
Notes
The authors declare no competing financial interest.
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