Tunable Cinchona-Based Thioureas-Catalysed Asymmetric Epoxidation to Synthetically Important Glycidic Ester Derivatives

Article abstract of DOI:10.1002/adsc.201700146

A novel class of synthetically important glycidic esters has been obtained via an asymmetric epoxidation of trans-α-cyano-α,β-unsaturated esters catalysed by a multifunctional Cinchona alkaloid-derived thiourea/tert-butyl hydroperoxide (TBHP) system. The glycidic esters, isolated in excellent yield with complete trans-diastereocontrol and high enantioselectivity, proved to be versatile building blocks to access challenging small targets bearing a quaternary stereocenter. (Figure presented.).

Full text of DOI:10.1002/adsc.201700146

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DOI: 10.1002/adsc.201700146
Tunable Cinchona-Based Thioureas-Catalysed Asymmetric
Epoxidation to Synthetically Important Glycidic Ester Derivatives
Sara Meninno,a Luca Zullo,a Jacob Overgaard,b and Alessandra Lattanzia,*
a
Dipartimento di Chimica e Biologia “A. Zambelli”, Universitꢀ di Salerno, Via Giovanni Paolo II, 84084 Fisciano, Italy
Fax : (+39)-089-969-603; phone: (+39)-089-969-563; e-mail: lattanzi@unisa.it
Department of Chemistry, Aarhus University, Langelandsgade 140, 8000 Aarhus, Denmark
b
Received: February 5, 2017; Revised: February 14, 2017; Published online: && &&, 0000
Supporting information for this article can be found under http://dx.doi.org/10.1002/adsc.201700146.
Abstract: A novel class of synthetically important
glycidic esters has been obtained via an asymmetric
epoxidation of trans-a-cyano-a,b-unsaturated esters
catalysed by a multifunctional Cinchona alkaloid-
derived thiourea/tert-butyl hydroperoxide (TBHP)
system. The glycidic esters, isolated in excellent
yield with complete trans-diastereocontrol and high
enantioselectivity, proved to be versatile building
blocks to access challenging small targets bearing
a quaternary stereocenter.
turated esters. This is not surprising since these al-
kenes are “borderline substrates” in terms of reactivi-
ty, being challenging for either an electrophilic or nu-
cleophilic oxidative system. Chiral ketone-derived di-
oxiranes, Mn(III)-salen/NaOCl and yttrium-chiral bi-
phenyldiol/Ph3AsO/TBHP
systems
developed,
respectively, by Shiꢁs,[8] Jacobsenꢁs[9] and Shibasakiꢁs[10]
groups afforded glycidic esters in generally good yield
and good to excellent enantioselectivity. A few indi-
rect oxidative methods were also reported.[11] The
value of optically active glycidic esters, has been dem-
onstrated in the asymmetric synthesis of important
pharmaceuticals, namely the blood pressure lowering
agent Diltiazem,[12] the phenylisoserine Taxol side-
chain,[12] the antibiotic Chloramphenicol A[13] and nat-
ural products.[14]
Keywords: amine-thiourea catalysts; asymmetric
catalysis; electron-deficient compounds; epoxida-
tion; glycidic esters; organocatalysis
We recently disclosed the ability of Cinchona alka-
loid-derived thioureas to catalyse a highly enantiose-
The development of new stereoselective methodolo- lective epoxidation of a-aroyl acrylamides with TBHP
gies for the epoxidation of alkenes is at the forefront to afford terminal epoxides.[15] Prompted by our inter-
of asymmetric catalysis.[1] The importance of epoxides est in developing asymmetric epoxidation reactions[16]
is widely recognised in the realm of natural products and with the knowledge that Cinchona alkaloid-de-
and as versatile intermediates in several total synthe- rived thioureas behave as effective bifunctional cata-
ses of biologically active compounds. Given the feasi- lysts in nucleophilic epoxidations, we chose a-cyano-
bility of stereocontrolled ring-opening reactions, sev- a,b-unsaturated esters as our playground. At the
eral small building blocks such as 1,2-functionalised outset of this work an asymmetric version for this
products can be attained.[2] Since the pivotal discover- class of alkenes was still unknown, likewise the syn-
ies in the 1980s, intensive investigations have focused thetic potential of this class of epoxides.[17] Herein, we
on the development of efficient systems for the epoxi- report the first asymmetric epoxidation of trans-a-
dation of functionalised alkenes, namely allylic and cyano-a,b-unsaturated esters, which proceeded with
homoallylic alcohols and unfunctionalised alkenes by complete diastereocontrol, high conversion and enan-
metal-catalysed[3] and organocatalytic systems.[4] In tioselectivity when using multifunctional Cinchona al-
the case of epoxides deriving from electron-poor al- kaloid-derived thioureas. Moreover, further elabora-
kenes, additional transformations are possible via ma- tions of the enantioenriched epoxides showed that
nipulation of the electron-withdrawing group.[5]
A
these epoxides can be valuable intermediates to
multitude of methods exists to effect the asymmetric access small chiral targets that are difficult to prepare
epoxidation of trans-acyclic enones,[6] far less are by alternative methods.
available for aliphatic and cyclic enones[4f–h] and dif-
Initial studies focused on the screening of different
ferently substituted enals[4a,i,7] and only a few have bifunctional organocatalysts in the epoxidation of the
been reported for mono- and disubstituted a,b-unsa- model trans-a,b-unsaturated ester 1a using TBHP in
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Table 1. Catalyst screening.[a]
Entry
R
Cat. [mol%]
Time [h]
Yield [%][b]
er[c]
1
2
3
4
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Et
Bn
t-Bu
Me
QN
eQNT
eHQNU
eQDT
eQDU
eQNS
3
4a
4b
4c
4d
5a
5b
5c
5d
5e
5e
5e
5e
25
60
17
24
24
64
41
20
40
23
70
17
19
41
110
17
23
46
23
2a, 54
2a, 59
2a, 60
2a, 22
2a, 53
2a, 6
2a, 52
2a, 30
2a, 30
2a, 76
2a, 8
2a, 81
2a, 60
2a, 13
2a, <5
2a, 88
2b, 70
2c, 60
2d, 96
63:37
24:76
23:77
61:39
51:49
45:55
75:25
35:65
45:55
13:87
nd
84:16
67:33
60:40
nd
89:11
89:11
83:17
89.5:10.5
5
6[d]
7
8
9
10
11
12
13
14
15
16
17
18
19
[a]
Reaction consitions: 0.05 mmol scale of 1 (C 0.2M) using TBHP (1.2 equiv.) at room temperature.
Determined by H NMR analysis with 1,3,5-(MeO)3C6H3 as an internal standard.
Determined by chiral HPLC analysis.
Reaction performed with 5 mol% of catalyst in CHCl3 as solvent.
[b]
[c]
[d]
1
toluene at room temperature (Table 1). The quinine showing that the nature of the H-bonding donor
(QN)-mediated epoxidation proceeded with complete group played a major role in the catalysis (entry 6).
diastereocontrol to trans-epoxide 2a, which was isolat-
The presence of additional chiral moieties, bearing
ed in acceptable yield, albeit in low enantioselectivity Brønsted acid groups, in proline or Cinchona alka-
(entry 1). Among the classical Cinchona alkaloid-de- loid-derived thiourea catalysts improved their activity
rived bifunctional organocatalysts, eQNT and and enantiocontrol, by virtue of supplementary H-
eHQNU enabled the formation of the opposite enan- bonding and matching effects established in the cata-
tiomer of 2a in satisfactory yield and comparable lyst-reagent reactive complex.[18] Inspired by these
enantiocontrol (entries 2 and 3). eQDT and eQDU findings, we checked Cinchona alkaloid-derived thio-
were less efficient catalysts, with eQDU affording an ureas incorporating 1,2-diarylethylenediamine or 1,2-
almost racemic product (entries 4 and 5). The qui- diphenylethyleneamino alcohol groups. The (R,R)-
nine-derived squaramide was totally uneffective, 1,2-diphenylethylenediamine unit in catalyst
3
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Table 2. Scope of the asymmetric epoxidation of alkenes
1.[a,b,c]
(entry 7) remarkably affected the sense of asymmetric
induction displayed by the eQNT scaffold (entry 2),
leading to the opposite enantiomer. A decreased ac-
tivity and moderate mismatching effect were also ob-
served when the (S,S)-enantiomer was incorporated
into catalyst 4a (entry 8) and with catalyst 4b, bearing
the (S,S)-amino alcohol portion (entry 9), attesting
the importance of the polar group. However, a match-
ing effect was observed with catalyst 4c, bearing a ster-
ically demanding (S,S)-1,2-di-1-naphthylethylenedi-
ACHTUNGTRENNUNGamine unit, with the product being recovered in
better yield and up to 87:13 er (entry 10). A compari-
son of the activity of catalysts 4a and 4d (entries 8
and 11), showed the urea analogue 4d to be almost
unreactive even after a prolonged reaction time.[19]
Hence, we chose the thiourea-based catalysts for fur-
ther investigations. We next explored the “pseudoe-
nantiomeric” series based on the eQD scaffold. Inter-
estingly, the presence of the (R,R)-diamine unit in
catalyst 5a assured a significant matching effect
(entry 12) when compared to the modest performance
observed with eQDT (entry 4). Replacing the primary
amine with a secondary amine, a hydroxy or a me-
thoxy group, respectively in catalysts 5b–d, dramati-
cally depressed the efficiency and enantiocontrol
through to a complete loss of activity (entries 13–15).
These findings confirmed the essential role played by
the polar groups in the catalysis and they could be in-
terpreted in view of a better ability of the primary
amine to be engaged in an H-bonding network with
the reagents.[20] The most hindered catalyst 5e afford-
ed the best result in terms of yield and enantioselec-
tivity (entry 16). The nature of the ester group in the
starting alkenes was next investigated. Alkenes bear-
ing more sterically demanding groups were more
[a]
Reaction conditions: 0.1 mmol scale of 1 (c 0.025M)
using TBHP (1.2 equiv.) and 20 mol% of 5e at À208C.
[b]
Product isolated after flash chromatography.
[c]
Determined by chiral HPLC analysis. Absolute configu-
ration determined by X-ray crystallography.
slowly converted into the corresponding epoxides 2p). Interestingly, the epoxidation could be applied
which showed slightly lower ee values (entries 17 and with success to less reactive b-alkyl-substituted a-
18). The a,b-unsaturated methyl ester was converted cyano-a,b-unsaturated esters. Indeed, the correspond-
into the epoxide 2d best, in terms conversion and ing epoxides 2q and 2r were obtained in 96% and
level of enantiocontrol (entry 19). Further optimisa- 77% yields, 96.5:3.5 er and 88.5:11.5 er, respectively.
tion of the hydroperoxide nature and reaction condi-
The absolute configuration of epoxide 2e was un-
tions led to a significant improvement in the epoxida- ambiguously determined to be (2S,3R) by X-ray crys-
tion of trans-methyl 2-cyano-3-phenylacrylate, whose tallographic analysis, and the configurations of the
epoxide 2d was obtained with 94.5:5.5 er, when work- other epoxides were assigned by analogy (Figure 1).[22]
ing at a 20 mol% loading of 5e, with TBHP as the ox-
To assess the synthetic potential of this new class of
idant at À208C in the presence of molecular sieves.[21] optically active epoxides, we envisaged some useful
With the optimised conditions in hand, we next exam- transformations to prepare products of great interest,
ined the applicability of the epoxidation (Table 2).
Pleasingly, a broad range of differently substituted
a-cyanocinnamates with electron-poor or electron-
rich substituents was converted into the trans-epox-
ides with excellent yield (76–99%) and high enantio-
control (up to 97.5:2.5 er). The ortho-substituted ep-
oxides (2h and 2o) were formed with somewhat
lower, but fairly good levels of enantioselectivity. Al-
kenes bearing double aryl substitution and heteroaro-
matic residues gave good results (epoxides 2n and soids drawn at 50% probability.
Figure 1. X-ray crystal structure of (2S,3R)-2e, thermal ellip-
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AHCTUNGTREGUNiNN soflavonoids, compounds endowed with a broad
range of biological activities.[25b] Tosylation of diol 9
followed by base-promoted ring-closure led to chal-
lenging terminal epoxy methyl ester 11 in 65% two-
step overall yield and 94.5:5.5 er, attesting that no rac-
emisation occurred over the entire sequence. (S)-Ep-
oxide 11 is a particularly attractive and versatile com-
pound, used as building block for the synthesis of
a new class of HIV-1 protease inhibitors, analogues of
Indinavir.[27] Moreover, (S)-epoxide 11 can be em-
ployed as a key intermediate for the synthesis of Bica-
lutamide-like molecules, which displayed very promis-
ing activity toward prostate cancer cell lines.[28]
To rationalise the stereoselectivity of the reaction,
we propose a tentative transition state model for the
oxa-Michael addition step, which should be the rate-
and stereoselectivity-determining step of the process
(Figure 2). A fast ring closure to the epoxide would
Scheme 1. Synthetic elaborations of glycidic esters 2.
Figure 2. Proposed stereochemical model.
starting from model epoxide 2d, via chemo- and re-
gioselective reactions at the functional groups
(Scheme 1).
be in agreement with the observed complete control
Treatment of enantioenriched epoxide 2d with of the diastereoselectivity. The crucial importance of
NaBH4 affected selective reduction of the ester group the NH2 and thiourea groups in tuning the enantiose-
in almost quantitative yield to give the cyano epoxy lectivity might be ascribed to cooperative H-bonding
alcohol 6.[23] The previously reported stoichiometric engagement with the cyano and ester groups of the
Sharpless Ti/tartrate-mediated asymmetric epoxida- alkene.[29] The NH2 unit of the sterically encoumbered
tion of poorly reactive 2-cyanoallylic alcohols leading C2-symmetrical diamine portion would act as a confor-
to compounds 6,[24] suffered from modest conversions. mationally rigid H-bonding handle, fixing the orienta-
Epoxide 6 was hydrolysed to the corresponding cis-a- tion of the alkene toward a preferential attack of the
amido epoxide 7 in 84% yield. The following regiose- alkene Re-face by the alkyl hydroperoxide.[30,31]
lective ring-opening reaction, performed under cata-
In conclusion, we have developed the first asym-
lytic hydrogenation conditions, gave the a,b-dihy- metric epoxidation of a-cyano-a,b-unsaturated esters
droxy amide 8, bearing a tetrasubstituted carbon, in by using a multifunctional Cinchona alkaloid-derived
90% yield. This compound was also readily trans- thiourea, bearing a 1,2-diamine chiral unit. The epox-
formed into methyl ester 9. Products of the types 8 ides were obtained in excellent yield, complete diaste-
and 9 can be accessed by Sharpless asymmetric dihy- reoselectivity and very good to high enantiocontrol.
droxylation of the corresponding 2-substituted acryl- Importantly, optically active a-cyano glycidic esters
ates or acrylamides.
are useful building blocks to prepare small targets of
However, the asymmetric induction appears to be high synthetic value. Finally, it is interesting to point
highly dependent on the nature of the a-substituent out that this study has wider implications in non-cova-
and ester groups.[25] In the case of a-substituted acryl- lent organocatalysis. Up to now, bi- and multifunc-
amides, only Weinreb amides afforded high enantiose- tional organocatalysts, bearing primary amines, have
lectivity.[26] Esters of type 9 have been used as starting been extensively used almost exclusively in covalent
material to synthesise Eucomols, a subclass of homo- organocatalysis,[32] the so-called aminocatalysis, ex-
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ploiting the iminium-enamine activation of carbonyl
compounds. A primary amine, which can be readily
installed in multifunctional organocatalysts, can also
provide helpful donor-acceptor H-bonding interac-
tions, still rarely explored in the non-covalent activa-
tion strategy.[20]
Experimental Section
General Procedure for the Asymmetric Synthesis of
Glycidic Esters 2
A sample vial was charged with the (E)-2-cyano acrylate
1 (0.10 mmol) and catalyst 5e (13.6 mg, 0.02 mmol) in anhy-
drous toluene (4 mL). Then activated molecular sieves
(ꢀ40 mg) and finally TBHP (ꢀ5.5M in decane, 22 mL,
0.12 mmol) were added. The mixture was stirred at À208C
until completion, as monitored by TLC. Purification of the
crude mixture by flash chromatography (eluting in gradient
from PE/diethyl ether 98/2 to 70/30) gave enantioenriched
epoxides 2d–r.
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G. A. Molander, P. A. Evans), Thieme, Stuttgart, 2011,
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Acknowledgements
We thank MIUR, University of Salerno, POR Regione Cam-
pania FESR 2007-2013-O.O. 2.1 (FarmaBioNet) and the
Danish National Research Foundation (DNRF-93) for finan-
cial support. We thank Dr. P. Iannece (University of Salerno)
for assistance with mass spectra and elemental analyses.
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[21] See the Supporting Information for more details.
[22] CCDC 1523834 contains the supplementary crystallo-
graphic data for this paper. These data can be obtained
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Tunable Cinchona-Based Thioureas-Catalysed Asymmetric
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