Enantio- and diastereoselective access to distant stereocenters embedded within tetrahydroxanthenes: Utilizing ortho-quinone methides as reactive intermediates in asymmetric bronsted acid catalysis

Article abstract of DOI:10.1002/anie.201406587

A protocol for the highly enantioselective synthesis of 9-substituted tetrahydroxanthenones by means of asymmetric Bronsted acid catalysis has been developed. A chiral binolbased N-triflyphosphoramide was found to promote the in situ generation of ortho-quinone methides and their subsequent reaction with 1,3-cyclohexanedione to provide the desired products with excellent enantioselectivities. In addition, a highly enantio- and diastereoselective Bronsted acid catalyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl substrates with ortho-quinone methides gives rise to valuable tetrahydroxanthenes containing two distant stereocenters.

Full text of DOI:10.1002/anie.201406587

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Chemie
DOI: 10.1002/anie.201406587
Organocatalysis
Enantio- and Diastereoselective Access to Distant Stereocenters
Embedded within Tetrahydroxanthenes: Utilizing ortho-Quinone
Methides as Reactive Intermediates in Asymmetric Brønsted Acid
Catalysis**
Chien-Chi Hsiao, Hsuan-Hung Liao, and Magnus Rueping*
Abstract: A protocol for the highly enantioselective synthesis
of 9-substituted tetrahydroxanthenones by means of asymmet-
ric Brønsted acid catalysis has been developed. A chiral binol-
based N-triflyphosphoramide was found to promote the in situ
generation of ortho-quinone methides and their subsequent
reaction with 1,3-cyclohexanedione to provide the desired
products with excellent enantioselectivities. In addition,
a highly enantio- and diastereoselective Brønsted acid cata-
lyzed desymmetrization of 5-monosubstituted 1,3-dicarbonyl
substrates with ortho-quinone methides gives rise to valuable
tetrahydroxanthenes containing two distant stereocenters.
T
he development of simplified and atom-economic strat-
egies for rapid access to complex enantiomerically enriched
structural motifs featured in natural products is one of the
main tasks in synthetic chemistry.[1] For example, 4H-chro-
mene is an intriguing core structure which is present in many
fascinating natural products having remarkable biological and
pharmacological properties.[2] While procedures for the syn-
thesis of chiral chromenes have been reported,[3] the direct
asymmetric synthesis of more complex and representative
target scaffolds, such as tetrahydroxanthenes embedding one
or two stereocenters (Figure 1), has not been described.
ortho-Quinone methides (o-QMs) were introduced by
Fries,[4] and are widely exploited as useful synthetic inter-
mediates for the construction of complex natural products
and bioactive compounds.[5,6] o-QMs can be obtained by
a variety of methods[7] including oxidation,[7a] thermolysis,[7b]
photolysis,[7c] transition-metal catalysis,[8] and base-[7d] and
acid-mediated transformations.[7e] o-QMs have been mainly
applied in Michael addition reactions, 6p electrocyclizations
or [4+2] cycloadditions, and often lead to the synthesis of
chromane and chromene skeletons.[9] Given the inherently
transient nature of o-QMs, a feature resulting from their
tendency of rearomatization or dimerization, the generation
of enantiomerically enriched products still remains a great
challenge.[9–12]
Figure 1. Natural products with 9-substituted tetrahydro-1H-xanthene-
1-one core.
Thus we decided to develop a new asymmetric Brønsted
acid catalyzed process for a fast and streamlined synthesis of
valuable tetrahydroxanthenes by using o-QMs as reactive
intermediates.
Despite the flourishing advancement of asymmetric
Brønsted acid catalysis over the past decade,[13,14] the majority
of the developed transformations involve species which have
good coordination ability to the catalyst, for example, imines,
carbonyl groups, and oxocarbenium ions. Inspired by DFT
computational studies described by Freccero in 2001,[15] who
reported that hydrogen bonding by water or acid catalysis can
enhance the reactivity of o-QMs, we questioned whether
asymmetric Brønsted acid catalysis could be extended to
reactions involving o-QMs (Scheme 1). Typically, Brønsted
[*] M. Sc. C.-C. Hsiao, M. Sc. H.-H. Liao, Prof. Dr. M. Rueping
Institute of Organic Chemistry, RWTH Aachen University
Landoltweg 1, 52074 Aachen (Germany)
E-mail: magnus.rueping@rwth-aachen.de
[**] H.-H.L. and C.-C.H. were supported by DAAD fellowships. We
gratefully acknowledge financial support from the DFG.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201406587.
Scheme 1. o-QMs as reactive intermediates in Brønsted acid catalyzed
asymmetric synthesis.
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Table 1: Optimization of the Brønsted acid catalyzed addition with
in situ generated o-QM.
acid promoted enantioselective reactions including desym-
metrizations[16] establish stereocenters in close proximity
(e.g., 1,2- or 1,3-relationship). To the best of our knowledge,
the establishment of more distant stereocenters using this
catalytic mode has never been reported. Often, compounds
which bear two remote stereocenters are obtained from pre-
established chiral precursors under remote asymmetric
induction.[17,18]
Herein, we document a new catalytic asymmetric desym-
metrization of meso-1,3-dicarbonyl compounds with in situ
generated o-QMs to provide a distant relationship of two
stereocenters in tetrahydroxanthene derivatives (3- and 9-
positions) with excellent diastereomeric ratio and enantio-
meric excess. Furthermore, the highly enantioselective syn-
thesis of tetrahydroxanthenes bearing a chiral center in the 9-
position is also described. To avoid limitations in substrate
scope resulting from the difficulty of isolating o-QMs, we
decided to use hydroxybenzyl alcohol derivatives as precur-
sors for o-QMs. These have been used in the photolytic and
thermal in situ generation of o-QMs with the advantage of
being readily prepared in one step from commercially
available salicylaldehydes and arylmagnesium bromide.
Guided by our previous research interest in cascade trans-
formations we chose 2a (see Table 1) as a nucleophile for
initial investigations.
Thus, we began our studies by examining the Brønsted
acid catalyzed reaction of the hydroxybenzyl alcohol 1a with
1,3-diketone 2a as model substrates. Initially, an array of
chiral N-triflylphosphoramides (NTPAs)[14] (4a–i) was eval-
uated (Table 1, entries 1–9) with the 3,3’-bis(2-naphthyl)-
substituted NTPA 4h providing good results for both
enantioselectivity and yield (entry 8). Further optimization
was carried out by employing different solvents. Use of o-
Entry[a]
Solvent
T [8C]
4
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
toluene
CH2Cl2
m-xylene
o-xylene
o-xylene
o-xylene
o-xylene
o-xylene
0
0
0
0
0
0
0
0
0
0
0
0
0
À10
À10
À10
4a
4b
4c
4d
4e
4 f
4g
4h
4i
4h
4h
4h
4h
4h
4h
–
64
66
56
67
71
70
68
73
69
85
71
73
74
71
62
–
57
77
0
83
89
89
85
91
86
43
85
93
94
98
90
–
9
10
11
12
13[d]
14[d]
15[d,e]
16[f]
[a] Reactions were performed with the alcohol 1a (0.07m concentration),
cyclohexane-1,3-dione 2a (3 equiv), and 5 mol% 4. The solution was
stirred at the indicated temperature for 8 h, and then at RT for another
8 h. [b] Yield of isolated product after column chromatography.
[c] Enantiomeric excess was determined by HPLC on chiral stationary
phase. [d] Addition of MgSO4. [e] Reaction was performed with 2 mol%
of catalyst. [f] Without any catalyst. Tf=trifluoromethanesulfonyl.
xylene resulted in
a slightly better enantioselectivity
(entry 12). With MgSO4 as an additive, a slight increase in
both yield and selectivity was observed (entry 13), and
lowering the temperature to À108C provided higher enan-
tiomeric excess without affecting the yield (entry 14). A
control experiment without catalyst revealed that the NTPA
is essential for the reaction to occur (entry 16).
tinued to explore the generation of o-QMs with the 1,3-
dioxole-substituted hydroxybenzyl alcohols 1k and 1l, which
also gave good results. We have also evaluated different R2
substitution at either ortho or para positions (1m–p) and all
substrates furnished the corresponding products with good
yields and good enantiomeric excesses. The absolute config-
uration of the products has been determined by X-ray single-
crystal structure analysis of product 3a.[19] Furthermore, 5,5-
dimethyl-1,3-cyclohexanedione (2b) has also been applied in
this newly developed organocatalytic procedure and the
desired product 3q was obtained with 72% yield and 86% ee
(Scheme 2). Noteworthy is that the cycloadduct 3q is very
similar to the structural motif found in important biologically
Then we turned our attention to explore the generality of
the Brønsted acid catalyzed addition/cyclization cascade
reaction of o-QMs and dicarbonyl analogues. In general,
cycloadducts with high enantiomeric excesses are obtained in
good yields regardless of their electronic properties (Table 2).
Firstly, a wide variety of p-methoxy-substituted hydroxyben-
zyl alcohols with nonsubstituted (1a), electron-donating (1b,
1c), and electron-withdrawing (1d) substituents were tested
and all substrates participated smoothly in this cascade
reaction, thus furnishing the corresponding cycloadducts
3a–d with good yields (68–79%) and excellent enantioselec-
tivities (93–98% ee). 1-Napthalene hydroxylbenzyl alcohol
(1e), a more sterically demanding substrate, furnished the
product 3e with a slightly diminished yield and good
enantiomeric excess. Next, substrates with an OAllyl group
in the para-position have been tested. Various hydroxybenzyl
alcohols (1 f–j) bearing either an electron-withdrawing or
electron-donating group in different positions of the quinone
methide fragment, all functioned efficiently. We then con-
Scheme 2. Brønsted acid catalyzed asymmetric synthesis of important
structural motifs with anticancer activity. M.S.=molecular sieves.
2
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Table 2: Substrate scope of Brønsted acid catalyzed enantioselective
addition/cyclization reaction.
After optimizing the reaction conditions, this new desym-
metrization strategy was tested for its generality. Essentially,
high diastereomeric ratios and enantiomeric excesses for the
desired cycloadducts bearing aromatic and heteroaromatic
substituents, as well as aliphatic functional groups at the 9-
position were obtained (Table 3). Firstly, p-methoxy-substi-
tuted hydroxybenzyl alcohols with different substituents (R1)
were used and the adducts 5a–c were isolated as a single
Table 3: Substrate scope of Brønsted acid catalyzed enantioselective
addition/desymmetrization reaction.
[a] Reactions were performed with the alcohol 1, cyclohexane-1,3-dione
2a (3 equiv), and 5 mol% 4h. The solution was stirred at À108C for 8 h,
and then at RT until cyclization was complete.
active molecules with antiproliferative activity for human
cancer.[20]
After evaluating a wide array of o-QMs with 1,3-diketone
nucleophiles (2a,b) which afforded the cycloadducts 3a–q
bearing a single stereocenter (Table 2 and Scheme 2), we
considered the possibility of developing a protocol for the
generation of products with a set of two stereocenters by
using meso-5-monosubstituted-1,2-cyclohexanediones in the
reaction. If this proposal would be realized under Brønsted
acid catalysis, valuable tetrahydro-1H-xanthen-1-one deriva-
tives bearing stereocenters at the 3- and 9-positions would be
obtained.
[a] Reactions were performed with the alcohol 1, cyclohexane-1,3-dione 2,
and 5–10 mol% 4j. The solution was stirred at À208C until completion.
The excess 1,3-dione nucleophile was removed and FeCl3 (0.1 equiv), 4 ꢀ
M.S. and toluene were added and the solution was stirred at RT until
completion.
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diastereomer in good yields (61–73%) and with excellent
enantioselectivies (90–93% ee). We then focused on employ-
ing different 5-aryl-substituted 1,3-cyclohexanedione nucleo-
philes in the reaction with various o-QMs and the corre-
sponding adducts 5d–h were obtained as single diastereomers
in moderate to high yields (45–83%) and excellent enantio-
selectivities (88–95% ee).
We also prepared the o-methoxy-substituted hydroxyben-
zyl alcohol and the appropriate product 5i was obtained as
single diastereomer in 53% yield and 90% ee. Aliphatic
groups in the 5-position of the 1,3-dione were also tolerated in
this new desymmetrization protocol. Particularly noteworthy
is the excellent enantioselectivity observed in the case of
small methyl substituent on the dione nucleophile with
different o-QMs substrates (5j–l; 90–96% ee). 1,3-Diones
with longer aliphatic carbon chains reacted efficiently and
afforded the corresponding products 5m and 5n with slightly
diminished diastereo- and enatioselectivities.
As the reaction is believed to follow an asymmetric
Brønsted acid catalyzed 1,4-addition/cyclization pathway we
tried to isolated the hemiacetal intermediate. Indeed, we were
able to isolate and identify the proposed intermediates 6a and
6d. Subsequent subjection to FeCl3 catalysis afforded the
tetrahydroxanthene products 5a and 5d in full conversion and
with retention of configuration (Scheme 3). The configuration
at the 9-position in the products 5 has been assigned in
analogy to the products 3. The configuration at the 3-position
has been assigned according to NOE experiments, which
showed a cis relationship for the protons in the 3- and 9-
positions.[19]
Figure 2. Plausible transition states for the chiral Brønsted acid
catalyzed reaction.
binol-based N-triflyphosphoramide was found to promote the
in situ generation of o-QMs and their subsequent asymmetric
reaction with 1,3-cyclohexanedione to deliver the desired
products with excellent enantioselectivities. In addition,
a highly enantio- and diastereoselective Brønsted acid
catalyzed desymmetrization of 5-monosubstituted-1,3-dicar-
bonyl substrates with o-QMs has been developed. A broad
range of valuable tetrahydroxanthenes with two embedded
distant stereocenters were synthesized according to this newly
developed method. Notably, a chiral binol phosphoric acid
catalyst proved to participate extensively in this catalytic
cycle, through generation of o-QMs, activation of 1,3-
dicarbonyl compounds, control of Michael addition, and
desymmetrization of meso 1,3-dicarbonyl compound. Given
the value of the products and the wide applicability of o-QMs
in organic synthesis, further investigation regarding the
detailed mechanism and utilization of this organocatalytic
procedure in the preparation of natural products and
bioactive compounds[22] is underway.
Received: June 25, 2014
Published online: && &&, &&&&
Keywords: cyclization · enantioselectivity · heterocycles ·
.
organocatalysis · synthetic methods
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4
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[21] During the preparation of this manuscript, a similar protocol
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Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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.
Angewandte
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6
www.angewandte.org
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
These are not the final page numbers!

Angewandte
Chemie
Communications
Organocatalysis
C.-C. Hsiao, H.-H. Liao,
M. Rueping*
&&&& — &&&&
Enantio- and Diastereoselective Access to
Distant Stereocenters Embedded within
Tetrahydroxanthenes: Utilizing ortho-
Quinone Methides as Reactive
Intermediates in Asymmetric Brønsted
Acid Catalysis
Protocols for the Brønsted acid catalyzed
asymmetric synthesis of 9-substituted
tetrahydroxanthenones and 3,9-disubsti-
tuted tetrahydroxanthenone derivatives
have been developed. The protocols are
based on the in situ generation of ortho-
quinone methides and their subsequent
reaction with 1,3-dicarbonyl compounds.
The reaction provides products with
a high level of asymmetric induction.
Angew. Chem. Int. Ed. 2014, 53, 1 – 7
ꢀ 2014 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
7
These are not the final page numbers!