Asymmetric michael addition of substituted rhodanines to α,β-unsaturated ketones catalyzed by bulky primary amines

Article abstract of DOI:10.1021/ol300489q

A bulky group was introduced by design into a diamine catalyst, and a series of robust and tunable bulky chiral primary amine catalysts were developed and successfully applied in the direct conjugate addition of substituted rhodanines to α,β-unsaturated ketones. High yields (up to 99%) and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 98% ee) were observed.

Full text of DOI:10.1021/ol300489q

ORGANIC
LETTERS
2012
Vol. 14, No. 8
2038–2041
Asymmetric Michael Addition of Substituted
Rhodanines to r,β-Unsaturated Ketones
Catalyzed by Bulky Primary Amines
Feng Yu, Haoxiang Hu, Xiaodong Gu, and Jinxing Ye*
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
yejx@ecust.edu.cn
Received March 5, 2012
ABSTRACT
A bulky group was introduced by design into a diamine catalyst, and a series of robust and tunable bulky chiral primary amine catalysts were
developed and successfully applied in the direct conjugate addition of substituted rhodanines to r,β-unsaturated ketones. High yields (up to 99%)
and excellent diastereoselectivities (up to 99:1 dr) and enantioselectivities (up to 98% ee) were observed.
It has been discovered that five-membered rhodanines
and structurally analogous scaffolds play an important
role in medicinal chemistry and drug discovery, behaving
as small molecule inhibitors of numerous targets because
of their wide range of pharmacological activities. Several
rhodanine derivatives have entered into clinical trials
showing antibacterial, antiviral, antimalarial, and antitu-
mor activities.1 A schematic representation of the 5-aryli-
dene rhodanine skeleton is provided in Scheme 1A.
Epalrestat is one of the most well-known examples of a
drug product containing a 5-arylidene rhodanine moiety,
and the compound is currently commercially available
for the treatment of diabetic neuropathy. A schematic
representation of the corresponding nonconjugated struc-
ture, which contains a stereocenter at the 5-position of the
heterocyclicsystem, isshown inScheme 1B.2 Rosiglitazone
and pioglitazone are both derived from 4-thiazolidone-
dione and show great therapeutic effects in type 2 diabetes
mellitus. A challenging problem for the nonconjugated
rhodanines and analogous 4-thiazolidinone systems is
the relative ease with which enolization can occur at the
5-position under physiological conditions, which makes
the stereochemistry difficult to maintain at this position.
Kawamatsu3 and Oschkinat2a have successively demon-
strated that the enantiomers of ciglitazone and 5-aryl-2-
thioxo-4-thiazolidinones can easily racemize. Only one
enantiomer, however, showed biological activity. We were
intrigued by the challenges presented by these idiosyncratic
defects and developed a great interest in the development
of reliable and highly stereoselective methods for the
synthesis of chiral rhodanine structures.4
(1) (1) For reviews, see: (a) Lesyk, R. B.; Zimenkovsky, B. S. Curr.
Org. Chem. 2004, 8, 1547. (b) Masic, L. P.; Tomasic, T. Curr. Med.
Chem. 2009, 16, 1596.
(2) For selected examples, see: (a) Joshi, M.; Vargas, C.; Boisguerin,
P.; Diehl, A.; Krause, G.; Schmieder, P.; Moelling, K.; Hagen, V.;
Schade, M.; Oschkinat, H. Angew. Chem., Int. Ed. 2006, 45, 3790. (b)
Powers, J. P.; Piper, D. E.; Li, Y.; Mayorga, V.; Anzola, J.; Chen, J. M.;
Jaen, J. C.; Lee, G.; Liu, J.; Peterson, M. G.; Tonn, G. R.; Ye, Q.;
Walker, N. P. C; Wang, Z. J. Med. Chem. 2006, 49, 1034. (c) Gilbert,
A. M.; Bursavich, M. G.; Lombardi, S.; Georgiadis, K. E.; Reifenberg,
E.; Flannery, C. R.; Morris, E. A. Bioorg. Med. Chem. Lett. 2007, 17,
1189. (d) Sonawane, N. D.; Verkman, A. S. Bioorg. Med. Chem. 2008,
Inspired by several excellent privileged ligands and
catalysts containing large bulky groups, such as the bisox-
azoline ligand with its bulky tert-butyl group (t-Bu-Box),5
Jacobsen’s thiourea catalysts with their tert-leucine amide
ꢀ
ꢀ ꢁ
ꢀ
16, 8187. (e) Zidar, N.; Tomasic, T.; Sink, R.; Rupnik, V.; Kovac, A.;
(3) Sohda, T.; Mizuno, K.; Kawamatsu, Y. Chem. Pharm. Bull. 1984,
32, 4460.
(4) For an opening example of our group, see:Huang, H.; Zhu, K.;
Wu, W.; Jin, Z.; Ye, J. Chem. Commun. 2012, 48, 461.
Turk, S.; Patin, D.; Blanot, D.; Martel, C. C.; Dessen, A.; Premru,
ꢀ ꢀ
M. M.; Zega, A.; Gobec, S.; Masic, L. P.; Kikelj, D. J. Med. Chem. 2010,
53, 6584. (f) Prashantha Kumar, B. R.; Nanjan, M. J. Bioorg. Med.
Chem. Lett. 2010, 20, 1953.
r
10.1021/ol300489q
Published on Web 04/06/2012
2012 American Chemical Society

Diamines derived from amino acids are attractive com-
pounds for catalyst design because of the rich availability
of the chiral amino acid starting materials.11 We therefore
prepared a series of diamines from L-valine (1a), L-phenyla-
lanine (1b), L-tert-leucine (1cÀ1f), and D-serine (1gÀ1i).
A series of chiral primary amine catalysts were first applied
in the conjugate addition of substituted rhodanine 3a to
benzalacetone. The results are summarized in Table 1.
Catalysts 1aÀc, which contained a tertiary amine moiety
derived from piperidine, clearly demonstrated behavior
consistent with catalytic activity and produced some en-
couraging results. These catalysts provided the anticipated
products in near complete conversion with excellent diaster-
eomeric ratios. Interestingly, the enantioselectivity of the
reaction was observed to be greatly dependent on the steric
hindrance around the primary amine group (Table 1, entries
1À3, from 0 to 70%). In contrast to catalysts containing the
piperidine moiety, the use of the more hindered diisopropy-
lamine moiety, as in catalyst 1e, destroyed the catalytic
activity, and only trace conversion was observed (Table 1,
entry 5). The use of the secondary diamine derived from
cyclohexamine, as in catalysts 1f and 1i, also gave poor
diastereoselectivity results (Table 1, entries 6 and 9). Pleas-
ingly, replacement of the tert-butyl group with the more
hindered methoxy-diphenylmethyl group led to significant
improvements in the levels of enantioselectivity observed.
For example, catalysts 1g and 1h provided the product with
an enantioselectivity of 88% ee in both cases. At the same
time, the diastereomeric ratios were maintained (dr 96:4),
and moderate to good levels of conversion were observed in
both cases (Table 1, entries 7 and 8). It is worthy of note that
extended reaction times were needed to obtain a good levels
of conversion. On the basis of these results, a 10 mol %
loading of catalyst 1h was selected for further screening.
Several different reaction solvents were assessed, and di-
chloroethane (DCE), methyl t-butyl ether (MTBE), hexane,
dioxane, and xylene were all found to be suitable
for the model reaction. In contrast, the polar solvent
i-PrOH did not provide good levels of stereoselectivity
(Table 1, entry 15). Xylene was found to be the best solvent
with an enantioselectivity of 96% ee and a diastereo-
selectivity of 99:1 dr (Table 1, entry 14). The addition
of an acidic cocatalyst to the catalytic system also produced
the same high level of stereoselectivity in the Michael product
at a similar reaction rate (Table 1, entry 16), and the
enantioselectivity was slightly lower when compared with
the corresponding reaction performed without the acid.
Under the optimized reaction conditions, which included
a 10 mol % loading of catalyst 1h at 40 °C in xylene, the
scope of the reaction between different R,β-unsaturated
ketones 2 and rhodanine derivatives 3 was investigated
(Table 2). A variety of different substituents and different
positions of the aromatic rings on the enones were well
Scheme 1. Several Pharmaceutically Active Molecules That
Contain the Fragments of Rhodanine and Thiazolidonedione
Derivatives
structural motifs,6 MacMillan’s imidazolidinone with its
tert-butyl group7 and Jørgensen and Hayashi’s diarylproli-
nol silyl ether catalyst,8 we were interested in incorporat-
ing bulky groups into diamine catalysts. Furthermore,
we were interested in integrating iminium activation, avail-
ability, and tunability. Frequently used diamines, such as
1,2-diaminocyclohexane and 1,2-diphenyl-ethylenedia-
mine are rigid trans-diamines.9 In recent years, 9-amino-
9-deoxy-epi-cinchona alkaloids have emerged as one of
the most successful primary amine catalysts.10 However,
it is very difficult to introduce bulky groups into all three
of the backbones present within these systems to allow for
the introduction of tunable reactivity and stereoselectivity.
(5) (a) Jørgensen, K. A.; Johannsen, M.; Yao, S.; Audrain, H.;
Thorhauge, J. Acc. Chem. Res. 1999, 32, 605. (b) Johnson, J. S.; Evans,
D. A. Acc. Chem. Res. 2000, 33, 325.
(6) (a) Sigman, M. S.; Jacobsen, E. N. J. Am. Chem. Soc. 1998, 120,
4901. (b) Huang, H.; Jacobsen, E. N. J. Am. Chem. Soc. 2006, 128, 7107.
(c) Doyle, A. G.; Jacobsen, E. N. Chem. Rev. 2007, 107, 5713.
(7) (a) Austin, J. F.; MacMillan, D. W. C. J. Am. Chem. Soc. 2002,
124, 1173. (b) Ouellet, S. G.; Walji, A. M.; MacMillan, D. W. C. Acc.
Chem. Res. 2007, 40, 1327.
(8) (a) Marigo, M.; Wabnitz, T. C.; Fielenbach, D.; Jørgensen, K. A.
Angew. Chem., Int. Ed. 2005, 44, 794. (b) Hayashi, Y.; Gotoh, H.;
Ha-yashi, T.; Shoji, M. Angew. Chem., Int. Ed. 2005, 44, 4212. (c) Jensen,
K. L.; Dickmeiss, G.; Jiang, H.; Alberecht, Ł.; Jørgensen, K. A. Acc.
Chem. Res. 2012, 45, 248.
(9) For selected organocatalytic Michael reactions, see: (a) Kim, H.; Yen,
C.; Preston, P.; Chin, J. Org. Lett. 2006, 8, 5239. (b) Wang, J.; Wang, X.; Ge,
Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 46, 1751. (c) Wang, J.; Qi, C.;
Ge, Z.; Cheng, T.; Li, R. Chem. Commun. 2010, 46, 2124.
(10) For selected examples catalyzed by 9-amino-9-deoxy-epi-cinch-
ona alkaloid, see: (a) Xie, J.; Chen, W.; Li, R.; Du, W.; Chen, Y.; Wu, Y.;
Zhu, J.; Deng, J. Angew. Chem., Int. Ed. 2007, 46, 389. (b) McCooey,
S. H.; Connon, S. J. Org. Lett. 2007, 9, 599. (c) Singh, R. P.; Bartelson,
K.; Wang, Y.; Su, H.; Lu, X.; Deng, L. J. Am. Chem. Soc. 2008, 130,
2422. (d) Wang, X.; Reisinger, C. M.; List, B. J. Am. Chem. Soc. 2008,
130, 6070. (e) Bencivennia, G.; Galzeranoa, P.; Mazzantia, A.; Bartolia,
G.; Melchiorreb, P. Proc. Natl. Acad. Sci. U. S. A. 2010, 107, 20642. (f)
Kwiatkowski, P.; Beeson, T. D.; Conrad, J. C.; MacMillan, D. W. C.
J. Am. Chem. Soc. 2011, 133, 1738.
(11) For selected examples of nonbulky diamine catalysts derived
from amino acids, see: (a) Ishihara, K.; Nakano, K. J. Am. Chem. Soc.
2005, 127, 10504. (b) Yang, Y.-Q.; Zhao, G. Chem.;Eur. J. 2008, 14,
10888. (c) Hong, L.; Sun, W.; Liu, C.; Wang, L.; Wong, K.; Wang, R.
Chem.;Eur. J. 2009, 15, 11105. (d) Huang, H.; Jin, Z.; Zhu, K.; Liang,
X.; Ye, J. Angew. Chem., Int. Ed. 2011, 50, 3232.
Org. Lett., Vol. 14, No. 8, 2012
2039

Table 1. Optimization of Reaction Parametersa
Table 2. Scope of Direct Conjugate Addition of Various
R,β-Unsaturated Ketonesa
entry
cat
t/h
solvent
conv (%)b
drc
ee (%)d
1
1a
1b
1c
1d
1e
1f
24
24
24
24
72
24
48
48
72
48
48
48
48
48
48
48
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
CHCl3
DCE
99
99
97:3
94:6
97:3
97:3
0
33
70
68
2
3
99
4e
5
99
trace
99
6
65:35
96:4
56
88
88
77
91
92
93
92
96
66
94
7
1g
1h
1i
62
8
82
96:4
9
42
76:24
96:4
a All reactions were carried out using 1.0 equiv of 3 (0.20 mmol), 2.0 equiv of
R,β-unsaturated ketone 2(0.40 mmol), and 0.10 equiv of the catalyst 1h in xylene
(0.4 mL). b Isolated yield. c Determined by GC and confirmed by 1H NMR of
the crude reaction mixture. d Determined by chiral HPLC. e Catalyst loading of
20 mol %. f Reaction time:24 h. g Reaction time:72 h. h Reaction time:96 h.
10
11
12
13
14
15
16e
1h
1h
1h
1h
1h
1h
1h
79
MTBE
hexane
EtOAc
xylene
i-PrOH
xylene
95
98:2
90
96:4
94
96:4
96
>99:1
87:13
99:1
Other nucleophiles bearing different R2 group, including
i-Pr, Bn, and p-methoxyphenyl were also compatible with
the reaction conditions (Table 2, entries 13À17). Increasing
the steric hindrance of the enone group by introducing
an n-propyl group adjacent to the carbonyl carbon led to a
reduction in activity, although a good yield and high diaster-
eo- and enantioselectivities were still obtained with a 20 mol %
loading of catalyst 1h (Table 2, entry 18). The results
obtained for the ethyl-substituted rhodanine 3e were excellent
(Table 2, entries 19À21). When a rhodanine substrate with a
branched alkyl chain (i-Pr) was used, a slower rate of reaction
was observed, and a moderate enantioselectivity (71% ee)
with a good diastereoselectivity (dr 93:7) was obtained when
a 20 mol % loading of catalyst was used (Table 2, entry 22).
To further expand the scope of the process, other types
of R,β-unsaturated ketones were investigated for the
Michael reaction with 3a (Scheme 2). The more sterically
hindered chalcone led to a sluggish reaction under the
optimized reaction conditions, and it was speculated that
the rate of formation of the iminium intermediate with
catalyst 1h was reduced by the steric interaction occurr-
ing between the bulky methoxy-diphenylmethyl group of
catalyst and the phenyl group of chalcone. Therefore, we
switched our attention back to the diamine catalyst derived
from L-tert-leucine, which contained the less hindered
90
96
a Unless otherwise stated, all reactions were carried out using 1.0 equiv of
3a (0.20 mmol), 2.0 equiv of 2a (0.40 mmol), and 0.10 equiv of catalyst in 0.4
mL of solvent. b Conversion was determined by GC. c Diastereomeric ratios
(dr) were determined by GC and confirmed by 1H NMR of the crude
reaction mixture. d Enantiomeric excess (ee) values were determined by
chiral HPLC. e With 10 mol % addition of benzoic acid.
tolerated, furnishing the corresponding Michael addition
products in good yields with excellent diastereo- and
enantioselectivities (Table 2, entries 2À7). Slightly higher
reaction activities were observed for the enones bearing
electron-withdrawing groups (Table 2, entries 4À6)
compared with those functionalized with electron-donat-
ing groups (Table 2, entries 2 and 3). Heterocyclic thio-
phene and furan enones also worked well without any loss
in the diastereo- or enantioselectivities (Table 2, entries 8, 9).
When aliphatic enones were employed, moderate yields
and good ee values were obtained (Table 2, entries 10
and 11). It is worthy of note that the functionalized enone
containing an alkenyl moiety reacted with 3a in good yield
and high diastereo- and enantioselectivity (Table 2, entry 12).
This alkylated adduct is of great value because the CdC
bond provides a good handle for further transforma-
tions and the generation of other useful functional groups.
2040
Org. Lett., Vol. 14, No. 8, 2012

Scheme 2. Scope of Direct Michael Reation of Chalcones and
Cyclic Enonesa,b,c
Scheme 3. Derivatization of the Michael Addition Product
a Experimental condition: 1.0 equiv of 3a (0.20 mmol) and 2.0 equiv
of R,β-unsaturated ketone (0.40 mmol) in xylene (0.40 mL).
b Diastereomeric ratios (dr) were determined by GC and confirmed
by 1H NMR of the crude reaction mixture. c Enantiomeric excess (ee)
values were determined by chiral HPLC. d The dr values in parenth-
eses were obtained after silica gel chromatography. Method A: 20 mol %
catalyst 1c with 20 mol % Boc-L-tert -leucine, 40 °C; Method B:
10 mol % catalyst 1f with 10 mol % Boc-L-tert-leucine, 0 °C.
recognized as a privileged scaffold for drug discovery.1a The
reaction between the 4-thiazolidonedione substrate and
benzalacetone was slow under the optimized reaction con-
ditions, whereas compound 6 was easily obtained in a high
yield of 95% following oxidization of the corresponding
rhodanine product 4n with CrO3 in acetic acid.12 This also
provided an effective and indirect method to access the chiral
4-thiazolidone core compounds. Thus, the thiocarbonyl
group of 4a could be effectively reduced by zinc dust in
acetic acid, affording the compound 7 containing the chiral
skeleton of thiazolidinone.13 The substituted tetrahydrothio-
phene 8 was obtained in 92% yield following treatment of 4a
with aqueous basic NaOH through thermodynamic control
of enolization.14 Interestingly, when 4a was treated with the
strong base LDA at À78 °C, a fused heterocyclic product 9
bearing two adjacent quaternary stereocenters was obtained
in 62% yield by means of a kinetically controlled enolization.
Crystals of the products 8 and 9 were subjected to X-ray
analysis to determine the absolute configuration.
In conclusion, a strategy of steric hindrance has been
successfully applied to the design of a series of novel chiral
diamines from amino acids, and a series of robust and tunable
bulky chiral primary amine catalysts have been developed and
applied in the direct diastereo- and enantioselective Michael
addition of substituted rhodanines to R,β-unsaturated ke-
tones. The reactions proceeded well, and a variety of different
enones were well tolerated, providing access to a wide range of
enantioenriched rhodanine derivatives, which were proven to
be valuable scaffolds in biochemistry and medicinal chemistry.
tert-butyl group. Fortunately, catalyst 1c promoted the
reaction dramatically, and the addition product 5a was
obtained in good yield with a high level of stereocontrol
(dr 30:1, 93% ee). Furthermore, it was observed that the
addition of a suitable acid facilitated the formation of
the iminium ion. Several differentially substituted chalcones
were well tolerated by the catalytic system, and high yields
and excellent diastereo- and enantioselectivities were
achieved (Scheme 2; 5b and 5c). The cyclic enones effectively
containing Z-alkenes showed different behavior from the
acyclic enones, which effectively contained E-alkenes, and
the tertiary diamine catalyst 1c provided poor results. Pleas-
ingly, the secondary diamine catalyst 1f performed much
more effectively when used in conjunction with an additional
proper organic acid in a 1:1 ratio (10 mol %) (Scheme 2,
5dÀf). The reactions proceeded smoothly at 0 °C to give the
corresponding products with satisfying results in terms of
efficiency and enantioselectivity. The diastereoselectivities
varied from 1:1 to 6:1 for different cyclic enones. The
absolute configuration of the asymmetric Michael addition
products 4a and 5e were determined by X-ray crystal-
lographic analysis (see the Supporting Information).
The Michael reaction between the substituted rhodanines
and various R,β-unsaturated ketones has been developed
with satisfactory results, and the chiral center at the C-5
position of the heterocycle was successfully constructed in a
highly efficient and stereoselective manner. Further efforts to
demonstrate the utility of the current method were carried
out (Scheme 3). The 4-thiazolidonedione core has also been
Acknowledgment. This work was partially supported by
the Fundamental Research Funds for the Central Universities.
Supporting Information Available. Experimental proce-
dures, structural proofs, NMR spectra, and HPLC chroma-
tograms of the products and CIF files demonstrating the
enantiopurity. This material is available free of charge via the
Internet at http://pubs.acs.org.
(12) El-Aasar, N. K.; Saied, K. F. J. Sulfur Chem. 2008, 29, 43.
(13) (a) Hansen, M. M.; Harkness, A. R. Tetrahedron Lett. 1994, 35,
6971. (b) Slattery, B. J.; Kjell, D. P.; Copp, J. D.; Ginah, F. O.; Hansen,
M. M.; Stirm, S. C. Org. Process Res. Dev. 2000, 4, 295.
(14) Makosza, M.; Krylova, I. V. Eur. J. Org. Chem. 1998, 222.
The authors declare no competing financial interest.
Org. Lett., Vol. 14, No. 8, 2012
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