Aminocatalyzed asymmetric Diels-Alder reaction of 2,4-dienals and rhodanine/hydantoin derivatives

Article abstract of DOI:10.1039/c3cc00023k

Aminocatalyzed asymmetric Diels-Alder reaction between 2,4-dienals and rhodanine/hydantoin derivatives via trienamine mechanism has been developed to synthesize various spirocyclic compounds with good yields (up to 98%) and excellent stereoselectivities (

Full text of DOI:10.1039/c3cc00023k

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Aminocatalyzed asymmetric Diels–Alder reaction of
2,4-dienals and rhodanine/hydantoin derivatives†
Cite this: Chem. Commun., 2013,
49, 2157
Kailong Zhu, Huicai Huang, Wenbin Wu, Yuan Wei and Jinxing Ye*
Received 2nd January 2013,
Accepted 23rd January 2013
DOI: 10.1039/c3cc00023k
www.rsc.org/chemcomm
Aminocatalyzed asymmetric Diels–Alder reaction between 2,4-dienals
and rhodanine/hydantoin derivatives via trienamine mechanism
has been developed to synthesize various spirocyclic compounds
with good yields (up to 98%) and excellent stereoselectivities
(up to 99% ee and >19 : 1 dr).
Rhodanine (2-thioxo-1,3-thiazolidin-4-one) as a compound of
great importance in medicinal chemistry has been intensively
explored by pharmacological scientists for a long time.1 As a
privileged scaffold in new drug discovery, structural modifica-
tions of rhodanine have led to the development of many potent
and selective drugs.2 For instance, rhodadyns that are formed
through the condensation of rhodanine with active carbonyl
compounds have recently attracted tremendous attention.2
Fig. 1 Selected bioactive substances containing the rhodanine/hydantoin
structure.
Typically, compound 1a, known as BH3I-1, is a widely used far outweighs the androgenic effect. What’s more, the differ-
inhibitor of the Bcl-2 protein that plays an important role in ence in biological activities between enantiomers has also been
cancer treatment;3 1b–1d have been identified as potent anti- identified. For instance, the enantiomer of 2c was proved to be
bacterial drugs.4 However, it should also be noted that the inactive. This makes the asymmetric synthesis of structures
reactivities of this group of compounds as Michael addition which contain the N-aryl-hydantoin motif meaningful. This
acceptors may, in some occasions, complicate their use in cell- prompted us to develop new strategies for the convenient
based assays or in vivo. Antibacterial drug 1b, for example, can constructions of new scaffolds that incorporate the structural
react with glutathione and other free thiols within a cell.5 Thus elements of rhodanine9 and hydantoin derivatives.
it seems that further structural modifications of rhodadyns are
desirable.
Diels–Alder cycloaddition is one of the most powerful
methods in the construction of six-membered carbo- or
As structural analogues of rhodanine, hydantoins and their heterocycles.10 In most traditional asymmetric Diels–Alder
derivatives are a class of bioactive molecules that are widely reactions, chiral catalysts catalyzed the cycloaddition process
used in medicinal chemistry6 and agrochemistry7 (2a–c, Fig. 1). by employing a LUMO-lowering strategy as means of activating
Most recently, Deprez and co-workers8 demonstrated that electron-deficient dienophiles11 rather than taking advantage of
N-aryl-hydantoin derivatives (2b, 2c) can be used as nonsteroidal, the alternative strategy of HOMO-raising activation of electron-
selective androgen receptor modulators (SARM). Compared to rich dienes.12 Very recently, Chen and Jørgensen13 jointly demon-
the traditional steroidal androgen receptor modulator, they strated that an aminocatalyst was able to promote the Diels–Alder
exhibited higher oral bioavailability and the anabolic activity reaction between dienal and dienophile through a trienamine
intermediate that formed between the catalyst and the dienal,
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
† Electronic supplementary information (ESI) available. Experimental proce-
dures, crystal data and characterization of the Michael addition products. CCDC
917401. For ESI and crystallographic data in CIF or other electronic format see
DOI: 10.1039/c3cc00023k
in which process the catalyst activated the dienal by rising
the HOMO of the dienal. This newly developed method has
been proved to be a very powerful protocol in the stereo-
selective construction of densely functionalized cyclic scaffolds
and spirocyclic compounds.14,15 In this paper, rhodanine/
hydantoin derivatives 5 were successfully employed as dienophiles
c
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Table 1 Screening of reaction conditionsa
Table 2 Generality of organocatalytic Diels–Alder reaction
Entry Solvent
Additive
Yieldb (%) eec (%) drd
1
2
3
4
5
6
7
8
9
Toluene o-F-C6H4CO2H
Dioxane o-F-C6H4CO2H
63
60
40
40
90
52
89
88
73
89
94
93
94
93
93
93
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
>19 : 1
CH3CN
CPME
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
CDCl3
o-F-C6H4CO2H
o-F-C6H4CO2H
o-F-C6H4CO2H
o-NO2-C6H4CO2H
p-MeO-C6H4CO2H 78
C6H5CO2H
N-Boc-L-Phe
N-Boc-L-Trp
87
57
73
10
a
Reaction conditions: 5a (0.10 mmol, 1.0 eq.), 4a (0.20 mmol, 2.0 eq.),
catalyst 3 (20 mol%) and acid (20 mol%) in solvent (1.0 mL) at 50 1C for
b
c
72 h. Yield of the isolated product. Enantiomeric excess was deter-
mined by chiral HPLC after 6a was converted into the corresponding
d
a,b-unsaturated ester (Ph3PQCH2CO2Me, THF, r.t.). Determined by
1H NMR analysis of the crude reaction mixture. CPME = cyclopentyl
methyl ether.
to participate in the asymmetric Diels–Alder reaction with
various 2,4-dienals 4, leading to the construction of structurally
complex compounds containing the rhodanine/hydantoin
motif.
We initially performed the asymmetric Diels–Alder reaction
between rhodadyn 5a and dienal 4a in different solvents, in the
presence of 20 mol% of diphenylprolinol silyl ether 3 and
20 mol% of o-F-C6H4CO2H as a combination of catalyst.16
It was gratifying to see that in all cases excellent diastereo-
selectivities (dr >19 : 1) were observed, and the ee values were
satisfying (Table 1, entries 1, 2, 4 and 5) with the exception of
CH3CN (entry 3). However, the isolated yields of the asymmetric
process varied greatly, depending on the solvents used. For
example, only 40% of yield was observed when the reactions
were carried out in CH3CN and CPME (entries 3 and 4), and
moderate yields were obtained in the cases of toluene and
dioxane (entries 1 and 2). In contrast, when the reaction was
carried out using CDCl3 as solvent,17 the yield of the isolated
product was dramatically improved to 90% (entry 5). In our
opinion, such enormous variation could mainly be attributed to
the difference of the solubility of 5a in these solvents. Having
the optimized solvent ascertained, we subsequently turned our
attention to the effect of acid additives on this asymmetric
procedure. The results demonstrated that additives did not play
an important role in the controlling of stereoselectivities,
and all other acid additives probed failed to give a better
Reaction conditions: 5 (1.0 mmol, 1.0 eq.), 4 (2.0 mmol, 2.0 eq.), cat 3
(20 mol%) and o-F-C6H4CO2H (20 mol%) in CDCl3 (C = 0.1 M) at 50 1C
for specified time, in reaction leading to 6j, 3.0 mmol (3.0 eq.) of 4a was
used. The yields are those of isolated products. The dr values were
determined by 1H NMR analysis of the crude reaction mixture. The ee
values were determined by chiral HPLC after the product was converted
into the corresponding ester (Ph3PQCH2CO2Me, THF, r.t.).
result compared to that of o-F-C6H4CO2H in terms of the yield reaction substantially with respect to the reaction rate. When
(entries 6–10).
R3QCO2Et, the reactions completed smoothly just after 2–4 hours,
With the optimal reaction condition in hand, the substrate leading to products 6g, 6l, 6p and 6s in good yields and
scope of the reaction was then investigated by employing excellent diastereo-(dr >19 : 1) and enantioselectivities (up to
various combinations of 2,4-dienals 4 and rhodanine deriva- 99% ee). However, the reactions turned out to be much slower
tives 5, and the results are summarized in Table 2. It should be when the R3 substituent was exchanged by various aro-
noted that the R3 substituent of substrate 5 affected the matic rings (72–96 h). It appeared that the properties of the
c
2158 Chem. Commun., 2013, 49, 2157--2159
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Scheme 1 Elaboration of the Diels–Alder cycloaddition product.
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substituent on the aromatic rings had very limited influence on
the reaction in terms of stereoselectivities, while the electron-
donating substituent afforded relatively low yield (6e, 64% yield).
Interestingly, rhodanine derivatives with R3 substituent of the
p-F-C6H4 group afforded the desired products with slightly
decreased dr values (6b, 6k, 10 : 1 dr). The substituents on the
nitrogen atom of 5 barely affected the asymmetric process.
We then paid our attention to the substrate scope of the
2,4-dienals. Gratifyingly, when 4-ethyl-2,4-dienal was employed,
products 6o to 6r were obtained with much higher yields and
enantioselectivities compared to that of 4a. It was noteworthy
that structurally more complicated 4-phenyl-2,6-dienal gave the
desired products 6s–6v with almost perfect stereoselectivities.
Products 6k–6n that bore four consecutive chiral centers could
also be easily prepared using 4,6-disubstitued-2,4-hexadienal as
diene, with up to 98% yield and excellent diastereo- and
enantioselectivities. It should be noted that the established
method was also applicable to the reaction with the N-aryl-
thiohydantoin derivative. As shown in Table 2, products (6w, 6x)
could be easily prepared in good yields with excellent enantio-
(>90% ee) and slightly decreased diastereoselectivities (10 : 1 dr).
The relative and absolute configurations of the sequential
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manipulation (Scheme 1).
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2,4-dienals 4 and rhodanine derivatives has been established
with high yield and excellent diastereo- and enantioselectivities.
The optimized reaction condition was also applicable to the
reaction of 2,4-dienals and thiohydantoin derivatives, the
adducts of which may serve as valuable scaffolds in new drug
discovery and natural product synthesis. Exploration of the
application of the Diels–Alder cycloaddition product in medicinal
chemistry is currently under way in our laboratories.
We thank the National Natural Science Foundation of China
(20902018, 21272068), Shanghai Municipal Education Commis-
sion (11ZZ56), the Fundamental Research Funds for the Central
Universities, and 111 project (B07023) for financial support.
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c
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Chem. Commun., 2013, 49, 2157--2159 2159