Expeditious diastereoselective construction of a thiochroman skeleton via a cinchona alkaloid-derived catalyst

Article abstract of DOI:10.1039/c1ob06497e

An example of diastereoselective and enantioselective synthesis of thiochroman derivatives through a sulfa-Michael-Michael cascade sequence is disclosed. This is a significant complement of the quinine-thiourea catalyzed sulfa-Michael-Michael cascade reaction. The densely functionalized target thiochromans were obtained in high diastereoselectivities, and with high to excellent enantioselectivities.

Full text of DOI:10.1039/c1ob06497e

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Expeditious diastereoselective construction of a thiochroman skeleton via a
cinchona alkaloid-derived catalyst†
Zhiyun Du,a,b Chenggang Zhou,a Yaojun Gao,a Qiao Ren,a Kun Zhang,b Hansong Cheng,*a Wei Wang*c and
Jian Wang*a
Received 1st September 2011, Accepted 22nd September 2011
DOI: 10.1039/c1ob06497e
An example of diastereoselective and enantioselective syn-
thesis of thiochroman derivatives through a sulfa-Michael–
Michael cascade sequence is disclosed. This is a significant
complement of the quinine-thiourea catalyzed sulfa-Michael–
Michael cascade reaction. The densely functionalized target
thiochromans were obtained in high diastereoselectivities,
and with high to excellent enantioselectivities.
both hydrogen-bond donor and Brønsted base have generated a
focus of attention in recent years.3
The chemistry of sulfur based six-membered rings, thiopyrans,
has, to date, been less extensively studied than that of the analogous
pyrans.4 Although not particularly common throughout nature,
this class of sulfur-containing heterocycles is of synthetic and bi-
ological interest. 3,4-Dihydro-2H-1-benzothiopyrans, more com-
monly known as thiochromans, exhibit anti-inflammatory, anti-
pyretic, anti-depressant, and analgesic activities.4 For example,
compound A, CH4986399 (Fig. 1), exhibited high clinical efficacy
in tamoxifen and fulvestrant resistant ER-positive breast cancer
patients.5 Compound B was discovered as a 5-HT1A receptor
agonist for use in depression, schizophrenia and Parkinson’s
disease.6 Therefore, these complex polycyclic frameworks have
become targets of interest in the synthetic organic community.
Despite these advances, organocatalytic asymmetric methods for
the construction of thiochromans remain largely unexplored.
Introduction
Asymmetric organocatalysis is nowadays recognized as a fun-
damental synthetic strategy for efficient assembly of chiral
molecules.1 The rapid growth of organocatalysis over the last
decade has been warranted by many factors such as efficiency,
cost-effectiveness, low environmental impact, and operational
simplicity. All of these features have generated a remarkable
scientific competition, which has guided asymmetric organocatal-
ysis towards excellent levels of development and opened new
synthetic opportunities that were considered inaccessible a few
years ago. The extraordinary pace of innovation and progress
has been mainly dictated by the discovery of generic catalytic
modes that have enabled previously unknown transformations.
Consequently, venerable chemical transformations that lead to the
preparation of useful chiral building blocks have been generally
chosen as benchmarks for developing novel, more effective
catalysts and asymmetric transformations. Within this context,
the organocatalytic cascade reaction has recently emerged as a
powerful tool to facilitate a rapid increase in molecular complexity
and diversity from simple and readily available starting materials
by reducing the steps of manual operation as well as the generation
of waste.2 Of the catalytic strategies developed for enantioselec-
tive cascade transformation, bifunctional organocatalysts bearing
Fig. 1 Examples of biologically active thiochroman derivatives.
Wang et al. reported an example of the synthesis of densely
functionalized thiochromans via cascade thio-Michael–Michael
reactions of trans-3-(2-mercaptophenyl)-2-propenoic acid ethyl
esters with nitroalkenes (Fig. 2, A).8 Although it is a highly enan-
tioselective approach, the diastereomeric synthesis of thiochroman
derivatives continues to be a substantial challenge. In this context,
we document here a different asymmetric catalytic strategy for
the diastereoselective synthesis of thiochromans through a new
catalyst and a sulfa-Michael–Michael cascade sequence (Fig. 2, B).
In particular, the one-pot cascade process affords enantio-enriched
thiochromans with the creation of three new stereogenic centers
in remarkably high efficiency and stereoselectivity. Undoubtedly,
this method is a significant complement to previous synthetic
contributions.
aDepartment of Chemistry, National University of Singapore, 3 Science Drive
3, Singapore, 117543. E-mail: chmwangj@nus.edu.sg; Fax: +65 6779 1691;
Tel: +65 6516 1760
bFaculty of Chemical Engineering and Light Industry Guang Zhou University
of Technology, Guang Dong 510006, China
cDepartment of Chemistry & Chemical Biology, University of New Mexico,
MSC03 2060, Albuquerque, NM 87131-0001, USA
† Electronic supplementary information (ESI) available. CCDC reference
number 790476. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c1ob06497e
36 | Org. Biomol. Chem., 2012, 10, 36–39
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Table 1 Influence of chiral catalystsa
Entry
Cat.
Yield (%)b
d.r.c
ee (%)d
1
2
3
4
5
6
I
85
80
78
78
76
trace
—
—
—
83
—
—
18 : 1
20 : 1
12 : 1
16 : 1
16 : 1
n.d.e
—
—
—
20 : 1
—
—
68
75
73
82
76
74
—
—
—
-76
—
—
II
III
IV
V
VI
VII
VIII
IX
X
7f
8g
9g
10
11f
12h
Fig. 2 Overview of the H-bonding mediated sulfa-Michael–Michael
cascade reactions.
XI
XII
Results and discussion
a Reaction conditions: trans-b-nitrostyrene 1a (0.1 mmol, 1.0 equiv.), 3-(2-
mercapto-phenyl)-acrylic acid ethyl ester 2a (0. 12 mmol, 1.2 equiv.) and
10 mol% catalyst were dissolved in DCM (0.5 mL) at room temperature
for 36 h. b Yield of isolated product after column chromatography.
To probe the feasibility of the proposed cascade reaction, trans-
3-(2-mercaptophenyl)-2-propenoic acid ethyl ester 2a was treated
with trans-b-nitrostyrene 1a in the presence of catalyst I (Fig. 3)
in CH2Cl2 at room temperature. In contrast to quinine thiourea
catalyst (Fig. 2, A), there is a chiral center inversion on C9 of I.
Catalyst I is also a bifunctional catalyst, which bears a hydroxyl
group and a tertiary amine. It is surprising that 3a with a novel
diastereomeric structure was finally produced (Table 1, entry 1,
85%). Meanwhile, 3a was obtained in 68% ee and 18 : 1 d.r.
We envisioned that chiral inversion of C6 is the main element
for new diastereomer formation. We conclude that the dihedral
angle between two functional groups would be a decisive factor.
It is associated with the size of quinoline at the C9 position
which can directly affect the rotation between C9 and C8. To
validate our hypothesis, a series of cinchona alkaloid derivatives
were synthesized and applied to this reaction. Accordingly, some
bulky groups, such as OMe, OEt, OiPr, OcHex, and OTr, were
introduced to the C6¢ position of catalyst I to finally generate
catalysts II–VI (Fig. 3). The investigation based on catalysts II–
VI revealed that OiPr is the most appropriate size. In this case,
catalyst IV promoted the reaction smoothly to furnish the desired
diastereomer 3a in 78% yield and with good selectivity (16 : 1
d.r.; 82% ee) (Table 1, entry 4). More hindered catalysts (V and
VI) and less hindered catalysts (II and III) gave relatively low
1
c Determined by H NMR analysis of the crude mixture. d Enantiomeric
excess (ee) was determined by HPLC. e Not determined. f No desired prod-
uct. g Only Michael adduct was detected. h Different major diastereomer
was obtained (see Ref. 8).
enantioselectivities (73–76% ee) (Table 1, entries 2–3 and 5–6).
Further investigation on quinoline structure was also examined.
Catalyst VII (Fig. 3, cupreine) has a one more –OH group at
C6¢. Unfortunately, this acidic –OH group, as a potential H-
bonding donor, did not improve the stereo-selective performance
and afforded a non-desired diastereomer (entry 7). If the –OH
group (C9 position) was protected, reactions were sluggish and
only simple Michael adducts were generated (entries 8 and 9). In
addition, catalyst X (quinidine) was also examined, but no obvious
improvement was observed (entry 10, 82%, 20 : 1 d.r., -76% ee). To
understand the role of the –OH group in catalyzing the reaction,
we performed density functional theory (DFT) calculations under
the generalized gradient approximation (GGA). It was found that
the reaction between 1a and 2a is modestly exothermic with a
thermochemical energy of -7.4 kcal mol-1. In the absence of the
catalyst IV, the reactants approach each other, forming a transition
state that allows the H2a atom of 2a to migrate to C2a of 2a
assisted by the –NO2 group of 1a, leading to the completion
of the cycloaddition 3a. The calculated activation barrier of
29.1 kcal mol-1 is considerably high, suggesting the reaction is
kinetically difficult. In the presence of the catalyst IV, however,
we identified a transition state participated by 1a, 2a, and IV.
Here, H2a transfer from the H–S bond to C2a of 2a is facilitated
via H exchange mediated by the –OH group of the catalyst IV as
indicated in the optimized structure shown in Fig. 4. Consequently,
the activation barrier is substantially reduced to 15.9 kcal mol-1.
Upon completion of the reaction, the conformation of the catalyst
IV is recovered with the H atom of the –OH group pointing to
the NIV atom to take advantage of the H-bonding. To verify our
hypothesis, we did the following reactions. 1) catalyst IX (–OH
group at C9 was protected by –OBn, Fig. 3) was synthesized and
applied to this reaction. However, the experimental result showed
that the reaction only generated the Michael adduct and no desired
Fig. 3 Evaluated chiral catalysts.
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Table 2 Substrate scope
Fig. 4 The fully optimized transition state structure for the cascade
reaction of 1a and 2a catalyzed by IV.
product was finally achieved (Table 1, entry 9). 2) Catalyst VIII
(–OH group at C9 was protected by –OBn, but another –OH
group was introduced to C6 position, Fig. 3) was also synthesized
and applied to this reaction. Surprisingly, the experimental result
showed that the reaction is sluggish and no desired product was
detected. Based on the above experimental results, we predict that
the position of this –OH is very critical for catalytic activation.
3) In addition, we synthesized an epi-quinine thiourea catalyst XI
(a pseudo-enantiomer of quinine-thiourea catalyst XII,9 Fig. 3).
The catalyst XI has a bulky and more acidic thiourea group at
the C9 position. Interestingly, this thiourea catalyst XI caused a
sluggish reaction and gave no desired product (Table 1, entry 12).
In summary, we found that the –OH group at C9 was a unique
factor and played an irreplaceable catalytic function.
without substantial loss in yields (86–94%) or stereoselectivities
(80–90% ee, 15 : 1 to 99 : 1 d.r.). However, if there is an –OH group
at the p position of phenyl ring (Table 2, 3p), a moderate result (66%
ee and 2 : 1 d.r.) was obtained. The loss of stereoselectivity may
be caused by the additional hydrogen bonding between the –OH
group and catalyst IV, which might affect the relative orientation
of nucleophile and electrophile in this reaction. Moreover, a
heteroaromatic nitroolefin (Table 2, 3n) can also be tolerated.
A good ee value and diastereoselectivity were obtained in the
presence of a less reactive aliphatic nitroalkene (Table 2, 3o, 84%
ee and 15 : 1 d.r.). The absolute configuration of the products was
determined by single-crystal X-ray diffraction analysis (Fig. 5, a
sulfonate ester 3q) (for structure, see Supporting Information†).7
With regard to high stereo-control, further optimization was
performed by examining other parameters, such as solvent,
temperature and reaction concentration (Table 2). In contrast,
CH2Cl2 was revealed as the best media. For the purpose of high
enantioselectivity, we evaluated the reaction temperature (Table
2, entries 9–13). A higher stereo-control was achieved when the
temperature was locked at 0 ◦C (Table 2, entry 12, 25 : 1 d.r., 90%
◦
ee). A lower temperature (-30 C) slowed down the reaction but
without any obvious improvement in stereo-control (Table 2, entry
13, 79%, 25 : 1 d.r., 89% ee). If the concentration decreased from
0.2 M to 0.1 M or 0.05 M, improved results were not observed
(Table 2, entries 10 and 11, 83% ee and 82% ee, respectively).
Having established the optimal conditions, we then explored
the generality of this cascade process. Remarkably, this enantio-
and diastereo-selective cascade process served as a reliable syn-
thetic protocol for the preparation of densely functionalized
thiochromans (Table 2). Significantly, three new stereocenters were
efficiently created in good to high enantioselectivities, and excellent
diastereoselectivities in a one-pot process. It was found that an
extensive range of nitroalkenes can efficiently participate in the
process (Table 2, 3a–o), irrespective of the electronic nature and
the substitution pattern of the aromatic system. For example, the
reaction takes place with aromatic systems that possess electron-
neutral (Table 2, 3a), -withdrawing (Table 2, 3b–f), or -donating
(Table 2, 3g–l) groups at the o, m, or p positions of the nitroalkenes
Fig. 5 X-ray crystal structure of 3q.
Conclusions
In conclusion, we have developed a novel quinine derivative as an
effective catalyst to promote a one-pot cascade reaction for the
enantioselective and diastereoselective synthesis of thiochroman
derivatives. This is an important complement of the previ-
ous method of quinine-thiourea catalyzed thio-Michael–Michael
cascade reaction. The densely functionalized target thiochromans
38 | Org. Biomol. Chem., 2012, 10, 36–39
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were obtained in good to high yields, moderate to high di-
astereoselectivities, and good to high enantioselectivities. Further
applications of this mode, with regard to other transformations,
are under investigation in our laboratory.
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Acknowledgements
We gratefully acknowledge the National University of Singa-
pore and Singapore Ministry of Education for financial sup-
port of this work (Academic Research Grants: R143000408133,
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