Organocatalytic asymmetric sulfa-michael/michael addition reactions: A strategy for the synthesis of highly substituted chromans with a quaternary stereocenter

Article abstract of DOI:10.1002/anie.201004534

Simply complex: Diverse and structurally complex chroman derivatives with a quaternary stereocenter have been obtained through the titled reaction of thiols with nitroolefin enoates using the bifunctional catalyst 1. The reaction features simple experimental procedures, high yield, enantiomeric excess, and excellent diastereoselectivity.

Full text of DOI:10.1002/anie.201004534

Angewandte
Chemie
DOI: 10.1002/anie.201004534
Asymmetric Synthesis
Organocatalytic Asymmetric Sulfa-Michael/Michael Addition
Reactions: A Strategy for the Synthesis of Highly Substituted
Chromans with a Quaternary Stereocenter**
Xu-Fan Wang, Qiu-Lin Hua, Ying Cheng, Xiao-Lei An, Qing-Qing Yang, Jia-Rong Chen,* and
Wen-Jing Xiao*
Chromans form the core of numerous natural products and
synthetic analogues displaying a broad and interesting range
of biological activities.[1] In particular, the chiral chroman
skeleton plays an important role in various therapeutic
areas.[1d] For example, (À)-siccanin, isolated from the culture
broth of Heleminthosposium siccans, exhibited potent anti-
fungal activity against the pathogentic fungi Trichophyton
interdigitale, Trichophyton asteroids, Epidermophyton, and
Mycosporum (Figure 1).[2] Rubioncolin B belongs to a class of
methods for the construction of chromans remain largely
unexplored.[10]
The search for new efficient and highly enantioselective
approaches to complex molecular architectures, especially
those with multiple stereogenic carbon atoms and quaternary
stereocenters, continues to be a substantial challenge in both
academic and industrial domains.[11] In 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.[12] Of the catalytic strategies
developed for enantioselective cascade transformations,
bifunctional organocatalysts bearing both hydrogen-bond
donors and basic functional groups have formed a focal
point of attention in recent years.[13] Recently, our laboratory
implemented a novel formal inter-[4+1]/intra-[3+2] cycliza-
tion cascade of cycloadditions of sulfur ylides with nitroolefin
enoates to construct densely functionalized chromans
[Eq. (1)].[14] Notwithstanding the fascinating results, the
Figure 1. Examples of highly substituted biologically active chroman
derivatives.
unusual naphthohydroquinones that are administered in
traditional Chinese and Ayurvedic medicine,[3] and Gamma
secretase inhibitor is a candidate for use in Alzheimerꢀs
disease.[4] Therefore, these complex polycyclic frameworks
have become targets of interest in the organic synthetic
community. Recently, a number of catalytic asymmetric
methodologies using Lewis acids or transition-metal com-
plexes have been developed for the synthesis of this privileged
structural motif, including asymmetric epoxidation,[5] oxida-
tive cyclization,[6] allylic alkylation,[7] enyne cyclization,[8] and
others.[9] Despite these advances, organocatalytic asymmetric
development of an enantioselective version of this consec-
utive reaction remains extremely desirable. Therefore we
describe herein an alternative bifunctional organocatalyst for
the sulfa-Michael/Michael addition[15] reaction of thiols with
nitroolefin enoates to afford polyfunctionalized chroman
derivatives in a highly stereoselective manner [Eq. (2)]. The
notable features of this procedure include: 1) the generation
of three consecutive stereogenic carbon centers including one
quaternary stereocenter with high enantioselectivity (up to
96% ee) and excellent diastereoselectivity (> 95:5 d.r.), 2) no
reaction reversibility, which is usually found with hetero
nucleophiles,[16] 3) the cascade reaction adducts are the core
structural feature of the Gamma secretase inhibitor, and
[*] X.-F. Wang, Q.-L. Hua, Y. Cheng, X.-L. An, Q.-Q. Yang, Dr. J.-R. Chen,
Prof. Dr. W.-J. Xiao
Key Laboratory of Pesticide & Chemical Biology, Ministry of
Education, College of Chemistry, Central China Normal University
152 Luoyu Road, Wuhan, Hubei 430079 (China)
Fax: (+86)27-6786-2041
E-mail: wxiao@mail.ccnu.edu.cn
Homepage: http://chem-xiao.ccnu.edu.cn/default.aspx
[**] We are grateful to the National Science Foundation of China
(20872043) and the Program for Changjiang Scholars and Innova-
tive Research Team in University (IRT0953) for supporting this
research.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201004534.
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ꢀ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
8379

Communications
Table 1: Optimization of double Michael addition reaction conditions.[a]
4) more importantly, this double Michael addition reaction
proceeds efficiently even at a 0.5 mol% catalyst loading on a
gram scale.
Initially, we examined the feasibility of the proposed
cascade reaction by choosing para-thiocresol (1a) and nitro-
olefin enoate 2a as the model substrates to react in the
presence of various base/acid bifunctional organocatalysts in
CH2Cl2 at room temperature (Table 1). Catalyst F (Figure 2)
Entry
Catalyst
Solvent
t [h]
Yield [%][b]
ee [%][c]
d.r.[c]
1
2
3
4
5
6
7
8
A
B
C
D
E
F
F
F
F
F
F
F
F
F
F
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
DCE
12
8
6
2
2
75
85
88
93
85
93
82
89
75
81
90
43
93
91
70
53
82
82
86
84
89
80
79
72
76
72
66
90
90
91
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
2
8
Et2O
THF
10
10
10
2
10
8
9
10
11
12
13[d]
14[e]
15[e,f]
toluene
CH3CN
CH3OH
CH2Cl2
CH2Cl2
CH2Cl2
12
48
[a] Conditions: 1a (0.3 mmol), 2a (0.2 mmol), catalyst (20 mol%), and
solvent (1 mL). [b] Yield of isolated product. [c] Determined by chiral
HPLC methods. [d] Used 5 mol% F. [e] Used 3 mol% F. [f] The reaction
was carried out at 08C. DCE=1,2-dichloroethane, THF=tetrahydro-
furan.
Table 2: Double Michael addition reactions of thiols 1 to nitroolefin
enoate 2a with catalyst F.[a]
Figure 2. Bifunctional organocatalysts examined in this study.
Mes=2,4,6-trimethylphenyl, Ts=4-toluenesulfonyl.
proved to be the most efficient for this cascade procedure,
affording the desired product 3a with high yield, good
Entry
R1
Yield [%][b]
ee [%][c]
d.r.[c]
enantioselectivity,
and
excellent
diastereoselectivity
(Table 1, entry 6). Solvent screening demonstrated that
CH2Cl2 was the optimal reaction medium (Table 1,
entries 6–12). Additional efforts to improve the reaction
efficiency showed that the selectivity of 3a was slightly
increased when catalyst loading was decreased to 3 mol%
(Table 1, entry 14). Lowering the reaction temperature to 08C
resulted in a significant decrease in yield with comparable
enantioselectivity (Table 1, entries 15 versus 14).
With the optimal reaction conditions in hand, the general-
ity of this reaction was then explored using various thiols. As
shown in Table 2, for most arenethiols, regardless of their
substitution pattern and the electronic nature of their
aromatic system, the cascade sequence proceeded smoothly
to provide highly substituted chiral chromans with a quater-
nary stereocenter in good yield (74–91%), high enantiomeric
excess (89–92% ee), and excellent diastereoselectivity
(> 95:5 d.r.). For example, the reaction with arenethiols
bearing methyl or methoxy groups at the para, ortho, and
meta positions took place without loss of yield or selectivity
(Table 2, entries 1–5). Variation in the electronic contribution
of the aromatic systems also had a minimal impact upon the
reaction; as such, reactions with electron-rich (Table 2,
entries 1, 5, and 6), electron-deficient (Table 2, entries 7 and
8), and electron-neutral thiols (Table 2, entry 9), including
1[d]
2
3
4
5
6
7
8
9
10
11
12
13[e]
4-CH3C6H4 (1a)
3-CH3C6H4 (1b)
2-CH3C6H4 (1c)
2-CH3OC6H4 (1d)
4-CH3OC6H4 (1e)
4-tBuC6H4 (1 f)
4-FC6H4 (1g)
4-BrC6H4 (1h)
C6H5 (1i)
3,5-(CH3)2C6H3 (1j)
2-naphthyl (1k)
2-thienyl (1l)
91 (3a)
87 (3b)
77 (3c)
86 (3d)
82 (3e)
81 (3 f)
84 (3g)
78 (3h)
83 (3i)
79 (3j)
89 (3k)
74 (3l)
79 (3m)
90
91
91
90
89
92
91
91
90
91
91
92
95
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
4-CH3OBn (1m)
[a] Conditions: 1 (0.3 mmol), 2a (0.2 mmol), F (3 mol%), and CH2Cl2
(1.0 mL). [b] Yield of isolated product. [c] Determined by chiral HPLC
methods. [d] The absolute configuration of 3a was determined by X-ray
analysis; refer to reference [17]. [e] Run for 48 h. Bn=benzyl.
disubstituted and fused thiols (Table 2, entries 10 and 11), all
took place efficiently with excellent results. Moreover, the
heteroaromatic group (Table 2, entry 12) was also well
tolerated. Less reactive alkanethiols were also suitable
substrates, although the reaction time was somewhat longer.
For example, 4-methoxy benzyl mercapatan (1m) reacted
smoothly with nitroolefin enoate 2a to afford the correspond-
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ing chroman 3m with 95% ee and greater than 95:5 d.r.,
respectively (Table 2, entry 13). Notably, the absolute config-
uration of the product was determined as (2R,3R,4R) by using
X-ray crystallographic analysis of 3a (Figure 3).[17]
3u at moderate yield (72%), with excellent enantioselectivity
(92%) and poor diastereoselectivity (67:33). Linear aliphatic
substrates can also participate in this cascade sequence. For
example, nitroolefin enoate 2j underwent the double Michael
addition reaction and provided polyfunctionalized cyclohex-
ane in moderate yield (58% yield) with excellent enantiose-
lectivity (96% ee) and diastereoselectivity (> 95:5 d.r.)
[Eq. (3)].
In analogy to the bifunctional organocatalysts that
catalyzed the Michael addition reaction,[18] a plausible
catalytic cycle involving the double Michael addition reaction
of thiols with nitroolefin enoates is outlined in Scheme 1.
Firstly, catalyst F activates nitroolefin enoate 2a through a
hydrogen-bonding interaction, and its basic tertiary amino
moiety activates the nucleophilic para-thiocresol (1a),
thereby forming intermediate I, which undergoes the inter-
molecular sulfa-Michael addition to provide the intermediate
II. Another intramolecular Michael addition to this inter-
mediate generates a cyclized intermediate, and subsequent
proton transformation leads to the corresponding chroman 3a
with the release of catalyst F.
To validate the potential utility of this methodology, a
model reaction of the cascade process was carried out on a
gram scale. Notably, the reaction took place smoothly in the
presence of only 0.5 mol% F to afford a slightly better
product yield (95%) without any loss of stereoselectivity
[Eq. (4)].
Figure 3. X-ray crystal structure of compound 3a. The thermal ellip-
soids are drawn at 30% probability.
More importantly, a wide array of the nitroolefin enoates
was also suitable for this sulfa-Michael/Michael cascade
addition reaction. As illustrated in Table 3, in general, the
reaction proceeded efficiently to provide the desired multi-
substituted chiral chromans in high yield (66–92%) with
excellent stereoselectivity (88–92% ee, > 95:5 d.r.) in the
presence of 3 mol% of F. As highlighted in entry 8 of Table 3,
nitroolefin enoate 2h having a bulky benzyl group in the
a position was accommodated in this reaction, thus generat-
ing the corresponding adduct 3t at 81% yield, 96% ee, and
95:5 d.r. Aliphatic substrates were tolerated as well. For
example, nitroolefin enoate 2i underwent cyclization to give
Table 3: Double Michael addition reactions of 2-thionaphthol (1k) to
various nitroolefin enoates 2 with catalyst F.[a]
A demonstration of the synthetic value of the double
Michael addition reaction is described. For instance, the
cascade reaction adducts can be readily transformed into the
chroman ring containing g-amino acid ester 4 by reducing the
nitro group in the presence of SnCl2 [Eq. (5)]. Moreover,
oxidation of 3a by using H2O2 and NaWO4·2H2O can easily
produce the core structure of the Gamma secretase inhibitor 5
[Eq. (6)]. These results confirm that potential medicinal
candidates can be readily accessed with current methodology
from simple starting materials under benign conditions.
Perhaps more importantly, is that the extension of the
nucleophile scope in the present transformation has been
successfully achieved. For example, the reaction of nitroolefin
enoate 2a with 1H-benzo[d][1,2,3]triazole (6) worked very
Entry R2
R3
X
Yield [%][b] ee [%][c]
d.r.[c]
1
2
3
4
5
6
7
8
9
H
4-Me
4-MeO Me (2c)
4-F
4-Cl
4-Br
5-MeO Me (2g)
H
H
Me (2a)
Me (2b)
O
O
O
O
O
O
O
O
89 (3k)
84 (3n)
66 (3o)
87 (3p)
73 (3q)
90 (3r)
92 (3s)
81 (3t)
72 (3u)
91
88
92
92
92
92
92
96
92
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
>95:5
95:5
Me (2d)
Me (2e)
Me (2 f)
Bn (2h)
Me (2i)
CH2
67:33
[a] Conditions: 1k (0.3 mmol), 2 (0.2 mmol), F (3 mol%), and CH2Cl2
(1.0 mL). [b] Yield of isolated product. [c] Determined by chiral HPLC
methods.
Angew. Chem. Int. Ed. 2010, 49, 8379 –8383
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Communications
In summary we have developed a novel organocatalyzed
sulfa-Michael/Michael addition reaction of thiols with nitro-
olefin enoates, which provides rapid and efficient access to
highly substituted chromans with a quaternary stereocenter
from simple and readily available materials. The successful
extension of the scope to include divergent nitrogen sources
as nucleophiles has been achieved, which additionally dem-
onstrates the synthetic utilizability of the current process.
Additional investigations aimed at expanding the scope of the
application are underway.
Experimental Section
Representative procedure: A mixture of para-thio-
cresol (1a; 0.3 mmol, 37 mg), nitroolefin enoate 2a
(0.2 mmol, 55 mg), and catalyst F (0.006 mmol, 4 mg)
in CH2Cl2 (1 mL) was stirred at room temperature for
12 h. The crude reaction mixture was purified by flash
chromatography on silica gel (petroleum ether/ethyl
acetate 20:1–15:1) to give the desired product 3a as a
white solid in 91% yield, 90% ee, and > 95:5 d.r.
Received: July 23, 2010
Published online: July 7, 2010
Keywords: heterocycles · hydrogen bonds ·
.
Michael addition · organocatalysis ·
synthetic methods
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