An enantioselective cascade reaction between α,β-unsaturated aldehydes and malonic half-thioesters: A rapid access to chiral δ-lactones

Article abstract of DOI:10.1039/c4cc01736f

We disclose a novel efficient enantioselective organocatalytic cascade reaction for the preparation of δ-lactones in good to excellent yields (69-93%) and with high to excellent enantioselectivities (88-96% ee). This journal is the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01736f

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An enantioselective cascade reaction between
a,b-unsaturated aldehydes and malonic half-
thioesters: a rapid access to chiral d-lactones†
Cite this: Chem. Commun., 2014,
50, 6137
Received 7th March 2014,
Accepted 15th April 2014
Qiao Ren,ab Shaofa Sun,*a Jiayao Huang,b Wenjun Li,b Minghu Wu,a Haibing Guoa
and Jian Wang*ab
DOI: 10.1039/c4cc01736f
www.rsc.org/chemcomm
We disclose a novel efficient enantioselective organocatalytic cascade
reaction for the preparation of d-lactones in good to excellent yields
(69–93%) and with high to excellent enantioselectivities (88–96% ee).
The assembly of O-heterocycles is an important field of research
due to their prevalence in natural products and drugs.1 Of the
O-heterocycles, d-lactones are well-known six-membered oxygen-
containing heterocycles that form the structural scaffold of many
biologically active molecules;2 hence, they are widely used in
medicinal chemistry as important structural elements. Notably,
a large number of d-lactones involved with biologically active
important molecules exist in a single enantiomer.2,3 As exempli-
fied in Fig. 1, lovastatin4 a marketed by Merck under the trade
name Mevacor, is a member of the drug class of statins, used in
the treatment of dyslipidemia and the prevention of cardiovas-
cular disease. Artemisitene5 b, isolated from Artemisia annua L.,
Fig. 1 Examples of natural products or drugs contacting the d-lactone
moiety.
has been shown to possess antimalarial activity. Crassin acetate6 c, surrounding two enantiomers often show distinct biological
a lactonic cembrane diterpene, has been shown to be the principal activity, the development of effective protocols to access optical
antineoplastic agent present in marine invertebrates. Leioderma- pure d-lactones would be extremely desirable to further study the
tolide7 d is a structurally unique macrolide isolated from the deep- correlation between the chirality of these compounds and their
water marine sponge Leiodermatium sp. which exhibits potent propensities for biological activities to seek more potent and/or
antiproliferative activity against a range of human cancer cell lines appropriate pharmaceutical candidates. In our continued effort
and drastic effects on spindle formation in mitotic cells.
towards the development of new approaches for the stereo-
Notably, chiral pharmaceuticals are figuring largely in the drug selective construction of enantiopure synthetically useful building
market. Most beneficial drugs are sold as a single enantiomeric blocks,9 we thought about expanding the scope of organocatalytic
form because of the higher efficiency compared to its mirror decarboxylative reactions10,11 to a,b-unsaturated aldehydes.12
image enantiomer and displaying a better fit to its receptor. Although many methods have been reported on chiral d-lactone
In addition, harmful results may even be encountered upon synthesis, most of them were prepared for the assembly of a,b- or
using the other enantiomers.8 Given the fact that within a chiral g,d-unsaturated d-lactones.13,14 Herein, we disclose a direct and
efficient enantioselective cascade strategy for the saturated func-
tional d-lactone synthesis (Scheme 1).
a Hubei Collaborative Innovation Centre for Non-power Nuclear Technology, College
of Chemistry and Biological Sciences, Hubei University of Science and Technology,
Hubei Province 437100, People’s Republic China
b Department of Chemistry, National University of Singapore, Block S15, Level 5,
3 Science Drive 3, Singapore 117543, Singapore. E-mail: chmwangj@nus.edu.sg;
Fax: +65-6779-1691
During our initial studies on the feasibility of amine-catalyzed
intermolecular reactions of malonic acid mono-protected esters
(2a–b) with cinnamaldehyde (1a), no decarboxylative adducts
were observed (Scheme 2). In the context of exploring a plausible
catalytic process, we turned our attention to investigate malonic
acid analogs. As shown in Scheme 2, the malonic half-thioester
(2c) was found to be a suitable partner to allow the reaction to
† Electronic supplementary information (ESI) available. CCDC 856259. For ESI
and crystallographic data in CIF or other electronic format see DOI: 10.1039/
c4cc01736f
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Table 2 Optimization of other reaction parametersa
Entry
Additive
Solvent
3acb (%)
3ac eec (%)
1
2
3
4
TEA
DCM
DCM
DCM
Toluene
THF
51
22(4)
37
53
47
47
57
82
89
18
78
81
84
89
89
92
Na2CO3
TBDg
TEA
TEA
TEA
TEA
TEA
Scheme 1 Efficient synthesis of chiral d-lactones and related transformations.
5
6
IPA f
7d
8d,e
DCM
DCM
a
Reactions were performed with 1a (0.20 mmol), 2c (0.24 mmol),
b
c
additive (0.20 mmol) in the solvent (1.0 mL). Isolated yield. Deter-
d
mined by chiral HPLC analysis. 2c (0.50 mmol), TEA (0.50 mmol).
e
TEA dissolved in 0.50 mL of DCM was added dropwise in 10 min, 0 1C.
f
g
Isopropanol. 1,5,7-Triazabicyclo[4.4.0]dec-5-ene.
Gratifyingly, the dropwise addition pattern of TEA gave better
results (92% ee, 82% yield). Controlled experiments indicated
that one-pot addition of TEA could cause a rapid decomposition
of the malonic half-thioester 2c.
Scheme 2 Initial experiments. Reaction conditions: 1a (0.20 mmol), 2
(0.24 mmol), TEA (0.20 mmol), Cat. II (0.20 mmol), DCM (1.0 mL), 72 h,
room temperature.
After having optimized the conditions for the cascade reaction,
the scope of the methodology was evaluated. Initially, various
a,b-unsaturated aldehydes 1 with different substitution pat-
terns and electronic properties were examined (Table 3). The
substitution patterns of malonic half-thioesters had a limited
impact on the yields or enantioselectivities, thereby providing
the only regioisomer with ee values ranging from 91 to 94%
(Table 3, 3ac–ah, all dr 4 20 : 1). Pleasingly, a,b-unsaturated
aldehydes 1a–h bearing different electron-withdrawing substi-
tuents on the aromic ring reacted easily under the established
reaction conditions (3ac–hc). In most of the cases, good yields
and high steroselectivities were obtained.17 Additionally, a,b-
Table 1 Screened catalysts
Table 3 Substrate scope of a,b-unsaturated aldehydesa–d
Reaction conditions: 1a (0.20 mmol), 2a (0.24 mmol), TEA (1.0 equiv.),
Cat. I–VI (20 mol%), DCM (1.0 mL), 72 h, room temperature.
proceed smoothly in the presence of the prolinol catalyst II
(Table 1). Interestingly, an unexpected d-lactone (3ac) was iden-
tified as a major product (59% yield, 72% ee). Screening of
catalysts revealed that the size of the silyl ether moiety in the
catalysts (Cat. I–VI) is critical for stereocontrol. As outlined in
Table 1, the most bulky catalyst tert-butyltrimethylsilane ether VI
(TBDMS) gave the best results (Table 1, 89% ee, 51% yield).
Subsequent solvent survey (Table 2, entries 1 and 4–6) indicated
that DCM is an ideal medium for this asymmetric transforma-
tion (entry 7, 89% ee). Other parameters (e.g. bases) showed no
improvement in the ee values (Table 2, entries 2 and 3). It is
noteworthy that acyclic 3-phenyl 1-aldehyde 5-thioester 4 was
formed as a major product when Na2CO3 was used instead TEA.
a
Reaction conditions: 1a–k (0.20 mmol), 2c–h (0.50 mmol), TEA
(0.50 mmol) and catalyst VI (0.04 mmol), DCM (1.0 mL), 0 1C for 24 h. b Isolated
yield. c Determined by chiral HPLC analysis. d All dr 4 20 : 1.
6138 | Chem. Commun., 2014, 50, 6137--6140
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´
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(3)
A further application study was embarked upon examining
the applicability of our method to the concise synthesis of
(À)-paroxetine, marketed as Paxil/Seroxat (Scheme 3). The
reaction of 1m with 2c catalyzed by VI and TEA gave the
corresponding 3mc in 72% yield and 91% ee (Scheme 3). Next,
the Ni-catalyzed ring opening reaction gave the corresponding
3-substituted 1,5-dicarbonyl 17, and the subsequent reduction
of 17 afforded the key intermediate 18. According to a reported
procedure,16 the intermediate 18 can be converted to target
(À)-paroxetine, an antidepressant drug.
In summary, we have established a new method for the
enantioselective cascade synthesis of d-lactone in the presence of
chiral prolinol or cinchona alkaloid amine organocatalysts. Our
methodology provided a straightforward way to generate a valuable
chiral d-lactone scaffold, which has potential biological significance
in the field of medicinal chemistry. The ready accessibility of the
starting materials makes the current methodology particularly
attractive in organic synthesis. Studies towards expanding the
synthetic utility of this strategy are currently underway.
Financial support from Singapore Ministry of Education
(Academic Research Grant: R143000443112, R143000532112)
and the China Hubei Collaborative Innovation 2011 Project and
the National Nature Science Foundation of China (21202136) are
greatly appreciated.
12 There is no reported enantioselective decarboxylative reaction
of a,b-unsaturated carbonyls and half-thioesters catalyzed by
secondary amine.
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6140 | Chem. Commun., 2014, 50, 6137--6140
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