Asymmetric construction of spirocyclohexanonerhodanines catalyzed by simple diamine derived from chiral tert-leucine

Article abstract of DOI:10.1039/c2cc34321e

A diamine-catalyzed asymmetric tandem reaction between α,β- unsaturated ketones and rhodanine derivatives has been developed to synthesize various spirocyclic compounds with high stereoselectivities (up to 99% ee and >20:1 dr). The products obtained contain two pharmaceutically relevant features: the biologically active rhodanine moiety embedded in a spirocyclic unit.

Full text of DOI:10.1039/c2cc34321e

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COMMUNICATION
Asymmetric construction of spirocyclohexanonerhodanines catalyzed by
simple diamine derived from chiral tert-leucinew
Wenbin Wu, Huicai Huang, Xiaoqian Yuan, Kailong Zhu and Jinxing Ye*
Received 16th June 2012, Accepted 23rd July 2012
DOI: 10.1039/c2cc34321e
A diamine-catalyzed asymmetric tandem reaction between
a,b-unsaturated ketones and rhodanine derivatives has been
developed to synthesize various spirocyclic compounds with high
stereoselectivities (up to 99% ee and 420 : 1 dr). The products
obtained contain two pharmaceutically relevant features: the
biologically active rhodanine moiety embedded in a spirocyclic
unit.
In 2009, Melchiorre8 demonstrated that the organocascade
reaction of a,b-unsaturated ketones proceeded via a tandem
iminium and enamine activation sequence catalyzed by a
cinchona alkaloid hydroquinine-derived primary amine
catalyst and this strategy was applied in the asymmetric
synthesis of spirocyclic oxindoles.9 Later, Gong’s group10
developed an approach for the direct construction of spiro-
[4-cyclohexanone-1,30-oxindoline] derivatives via the bifunctional
organocatalytic [4+2] cycloaddition of Nazarov reagents.
Shortly after, chiral spiro[cyclohexane-1,30-indoline]-20,3-diones
and spirocyclic benzofuranone cyclohexanones were syn-
thesized by Wang11 and Melchiorre,12 respectively, employing
somewhat similar strategies.
Spirocompounds, which have received increasing interest from
synthetic organic chemists, feature in a large number of
natural products, new ligands and catalysts due to the unique
structural properties of spirocycles.1 Particularly, heterocyclic
spiro-type molecules are very attractive to pharmacological
scientists. Recently, 2-thioxo-1,3-thiazolidin-4-one (rhodanine),
1,3-thiazolidine-2,4-dione and 2-thioxoimidazolidin-4-one have
become a very important group of heterocyclic compounds in
drug discovery and development.2 The rhodanine derivative
epalrestat, thiazolidine-2,4-dione derivatives, glitazones
(Avandia, Rezulin, and Actos) and the 2-thioxoimidazolidin-
4-one derivative dilantin have been introduced to clinical use
for treatment of diabetic complications, type II diabetes,
mellitus and epilepsy, respectively.3 5-substituted benzyl
thiazolidine-2,4-dione and 5-octylthiazolidine-2,4-dione have
demonstrated potential applications as GPR40 agonists.4
Interestingly, the 5S enantiomers of glitazone compounds with
the methyl group in the 5-position have been found to have
enhanced anti-inflammatory activity over the corresponding
5R enantiomers.5 The relationship between the biological
and pharmacological activities and the stereoconfiguration
prompted us to focus on developing new methodologies for
the direct construction of novel, stereoriched and architecturally
complex molecular scaffolds with these biologically attractive
heterocyclic backbones.6
In our initial study, a series of chiral primary amines were
chosen as catalysts to evaluate the reaction. Moderate diastereo-
selectivities and enantioselectivities were observed using 10 mol%
(R,R)-1,2-cyclohexanediamine and (R,R)-1,2-diphenylethylene-
diamine as catalysts, coordinating with 20 mol% benzoic acid.
When the quinidine-derived catalyst 9-amino(9-deoxy)epi-
quinine 3 was employed in the reaction, the desired spiro
product was afforded with a good yield, while only with
75% ee and 3 : 1 dr.
We envisaged that a catalyst with neighboring bulky sub-
stituents of the primary amine group could improve the
enantioselectivity based on the above results. Diamine (primary-
secondary or primary-tertiary) was chosen as the catalyst
backbone, which was readily available from inexpensive amino
acids.13 Initially, the tert-butyl group was introduced into the
catalyst scaffold to investigate the effects of secondary and
tertiary amines. Dimethylamine and piperidine derived catalysts
4a and 4b gave poor results (Table 1, entries 4 and 5), while
cyclohexylamine derived catalyst 4c revealed excellent controlling
ability in regulating the enantioselectivity, affording 99% ee and
69/31 dr. Comparing the effect of neighboring substituents of the
primary amine group, tert-butyl was obviously much better
than the isopropyl and benzyl groups in catalysts 4d and 4e
(Entries 6–8). To our delight, the diastereoselectivity was
dramatically improved through acid screening. Satisfactory results
(90% yield, 98% ee and 420 : 1 dr) were obtained when the
combination of 10 mol% catalyst 4c and 20 mol% 2-methoxy-
benzoic acid or N-Boc-L-tryptophan was employed, and the
reaction was performed in toluene at 30 1C for 24 hours.
After the optimal conditions had been established, the
generality of the tandem reaction was investigated by using
Since the elegant tandem reaction of a,b-unsaturated
ketones was reported by Barbas III and Cabal,7 enones have
been employed in the synthesis of spirocyclic compunds.
Engineering Research Centre of Pharmaceutical Process Chemistry,
Ministry of Education, School of Pharmacy, East China University of
Science and Technology, 130 Meilong Road, Shanghai 200237, China.
E-mail: yejx@ecust.edu.cn
w Electronic supplementary information (ESI) available: Experimental
procedures, crystal data and characterization of the Michael addition
products. CCDC 882323. For ESI and crystallographic data in CIF or
other electronic format see DOI: 10.1039/c2cc34321e
c
9180 Chem. Commun., 2012, 48, 9180–9182
This journal is The Royal Society of Chemistry 2012

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Table 1 Screening of chiral amino catalysts and acidic additivesa
Table 2 Generality of organocatalytic tandem reactions
Entry Cat. Additive
Yieldb (%) eec (%) drd
1
2
3
4
5
6
7
8
1
2
3
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
PhCO2H
N-Boc-L-Phg
N-Boc-L-Trp
o-F-C6H4CO2H
o-CH3O-C6H4CO2H 90
p-NO2-C6H4CO2H 92
52
69
86
46
27
89
83
87
88
87
88
ꢀ23
ꢀ22
75
ꢀ15
ꢀ27
99
70/30
73/27
3/1
75/25
76/24
69/31
3/1
3/1
10/1
420/1
6/1
4a
4b
4c
4d
4e
4c
4c
4c
4c
4c
ꢀ9
70
83
9
10
11
12
13
98
93
98
98
420/1
13/1
a
Reaction conditions: 5a (0.10 mmol, 1.0 eq), 6a (0.15 mmol, 1.5 eq),
catalyst (10 mol %) and acid (20 mol%) in toluene (C = 0.5 M) at
b
30 1C for 24 h. Yield of isolated product after chromatography.
Enantiomeric excess was determined by chiral HPLC. Determined
c
d
by 1H NMR and chiral HPLC of the crude reaction mixture.
rhodanine derivatives (compound 5). As summarized in
Table 2, a,b-unsaturated ketones with electron-withdrawing
and electron-donating substituents at different positions
on the aromatic ring and neutral and heteroaromatic
a,b-unsaturated ketones turned out to be tolerant of the
reaction, affording up to 499% ee and 420 : 1 dr. When
(E)-ethyl 4-oxopent-2-enoate was involved in the tandem
reaction, the yield decreased to 35%. Unexpectedly, the
enantioselectivity of the cascade product of the cyclic
a,b-unsaturated ketone dropped to 0. Changing the ester
group into aromatic groups decreased the reactivity of the
rhodanine derivatives because of the weaker electron attrac-
tion. In spite of this, substrates with different electron-
withdrawing aromatic substituents at the terminal carbon
atom of the double bond yielded the desired products with
94–99% ee and 420 : 1 dr by extending the reaction time to
48 hours and increasing the temperature to 50 1C. In contrast,
the electron-donating aromatic substituted substrates afforded
poor yields because the reaction rate of the first-step Michael
addition was greatly influenced. The relative and absolute
configurations of the sequential reaction products were assigned
on the basis of X-ray crystal structural analysis of the product
7c (see the ESIw).
a
Reaction conditions. 5 (0.30 mmol, 1.0 eq), 6 (0.45 mmol, 1.5 eq),
Cat. 4c (10 mol%) and o-CH3O-C4H6CO2H (20 mol%) in PhCH3
b
(C = 0.5 M) at 30 1C for 24 h. Cat. 4c (10 mol%) and N-Boc-L-Trp
(20 mol%) in CHCl3 (C = 0.5 M) at 50 1C for 48 h. 50 1C for 72 h.
Cat. 4c (30 mol%) and N-Boc-L-Trp (60 mol%) for 72 h.
c
d
e
5 (0.30 mmol, 1.0 eq), 6 (0.60 mmol, 2.0 eq), Cat. 4c (10 mol%)
and N-Boc-L-Trp (20 mol%) in CHCl3 (C = 0.5 M) at 50 1C for 72 h.
the same and the reaction proceeded smoothly, giving the
desired products with satisfactory results (7a, 7o to 7r).
In the further exploration, the construction of spirocyclo-
hexanonerhodanines with four chiral consecutive centers was
focused upon, which remains challenging in asymmetric syn-
thesis. As shown in Table 3, introducing alkyl groups such as
methyl and ethyl into the fourth chiral center of the spiro-
backbone gave 43 to 87% yields, 93 to 99% ee and 5 : 1 to
12 : 1 dr.
Next, the attention was turned to evaluate the substituents
on the nitrogen atom of substrates 5. The reactivity of
substrates 5 with different substituents (phenyl, isopropyl,
cyclohexyl or hydrogen) on the nitrogen atom were almost
c
This journal is The Royal Society of Chemistry 2012
Chem. Commun., 2012, 48, 9180–9182 9181

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Table 3 Construction of spirocompounds with four consecutive
chiral centers
In summary, rhodanine derivatives 5 were successfully
applied in cascade reactions for the construction of spiro-
cyclohexanonerhodanines with multiple consecutive chiral
centers catalyzed by a simple diamine, providing products in
good yields and high stereoselectivities (up to 99% ee and
420 : 1 dr).
We thank Shanghai Municipal Education Commission
(11ZZ56), the National Natural Science Foundation of China
(20902018), the Fundamental Research Funds for the Central
Universities and the Shanghai Committee of Science and
Technology (11DZ2260600) for financial support.
Notes and references
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9182 Chem. Commun., 2012, 48, 9180–9182
This journal is The Royal Society of Chemistry 2012