Enantioselective Synthesis of Substituted δ-Lactones by Cooperative Oxidative N-Heterocyclic Carbene and Lewis Acid Catalysis

Article abstract of DOI:10.1021/acs.orglett.5b01932

Efficient construction of complex cylcopentane- or cyclohexane-fused δ-lactones employing redox activation of enals using a chiral N-heterocyclic carbene and LiCl as cooperative catalysts is described. The organocascade proceeds with excellent diastereo- (>99:1) and enantioselectivity (up to >99% ee) and comprises the formation of three bonds with three contiguous stereocenters.

Full text of DOI:10.1021/acs.orglett.5b01932

Letter
pubs.acs.org/OrgLett
Enantioselective Synthesis of Substituted δ‑Lactones by Cooperative
Oxidative N‑Heterocyclic Carbene and Lewis Acid Catalysis
Srikrishna Bera, Constantin G. Daniliuc, and Armido Studer*
Organisch-Chemisches Institut, Westfalische Wilhelms-Universitat, Corrensstraße 40, 48149 Munster, Germany
̈
̈
̈
S
* Supporting Information
ABSTRACT: Efficient construction of complex cylcopentane- or
cyclohexane-fused δ-lactones employing redox activation of enals
using a chiral N-heterocyclic carbene and LiCl as cooperative catalysts
is described. The organocascade proceeds with excellent diastereo-
(>99:1) and enantioselectivity (up to >99% ee) and comprises the
formation of three bonds with three contiguous stereocenters.
everal powerful strategies have been developed for the
stereoselective construction of complex molecules starting
Scheme 1. NHC-Catalyzed Reactions
S
from readily accessible materials using organocatalysis.1 Along
these lines, N-heterocyclic carbene (NHC) catalyzed cascade
reactions have been found to be highly valuable.2 Stereoselective
construction of highly substituted five- and six-membered
carbocycles by NHC catalysis is a highly active research area.
Notably, such carbocycles can be found as important
substructures in many bioactive natural products3 and
pharmaceuticals.
For example, iridoids are a class of compounds consisting of a
cyclopentane ring fused to a six-membered oxygen heterocycle
(Figure 1). Iridoids are monoterpenoid natural products with
Figure 1. Biologically active iridoids.
over 250 known members occurring in marine and terrestrial
ecosystems.4a They have gained widespread attention due to
their diverse pharmacological effects, showing anticancer,
antibacterial, and antiflammatory activities.4b,c,5 Surprisingly,
only a few methods are known for the synthesis of iridoid type
lactones which mostly require multiple synthetic steps.6
We report herein a strategy for the construction of the iridoid
core structure using oxidative NHC catalysis.7,8 NHC-catalysis
has been successfully used to build up 5-membered carbocycles
via conjugate addition reactions. For example, in 2007 Scheidt
and co-workers published an elegant NHC-catalyzed sequence
for the preparation of disubstituted indanes using intramolecular
homoenolate chemistry (Scheme 1).9 Four years later, we
disclosed an efficient organocascade for the synthesis of 1,2,3-
substituted indanes by oxidative NHC catalysis.10 In this work,
the two Michael acceptors used in the cascade to build up the 5-
membered carbocycle are integrated into the same molecule
separated from each other by an arene moiety. This particular
substrate design restricts the method to the preparation of indane
derivatives, and fully saturated cyclopentane compounds cannot
be accessed by this approach. We also showed that α-substituted
malonates react by oxidative NHC catalysis with enals to give
highly substituted cyclopentanes bearing a β-lactone moiety.11
LiCl was used as a cooperative catalyst, and only a single Michael
acceptor is involved in the cascade.
As a further extension, we planned to design an intermolecular
organocascade with two separated Michael acceptors as reaction
partners. As compared to the previous reports, substrates are
more readily prepared and the iridoid skeleton should be easily
accessible via this double Michael pathway using oxidative NHC
catalysis. The organocascade involves the formation of two C−C
Received: July 6, 2015
© XXXX American Chemical Society
A
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Letter
bonds along with one C−O bond with three contiguous
stereogenic centers. Notably, there are only a few examples of
double Michael addition reactions using α,β-unsaturated acyl
azoliums as intermediates.12
Investigations of this organocascade commenced with
cinnamaldehyde 1a and malonate 2a as the model substrates.
Bisquinone 313 (1.2 equiv) was chosen as the oxidant, and
triazolium salts A14 and B15 were selected as achiral and chiral
NHC precatalysts in the optimization studies. It was found that,
with achiral triazolium salt A (10 mol %) and DBU as a base in
THF, 4aa comprising the core structure of the iridoid natural
products was obtained in 65% yield (Table 1, entry 1). Lactone
was isolated) (Table 1, entry 6). A far better outcome (nearly
quantitative yield and an increase in ee from 74% to 88%) was
observed upon switching to iPr2EtN as a base in THF (Table 1,
entry 7). Other solvents such as CH2Cl2, toluene, and MeCN in
combination with iPr2EtN did not provide better results (Table
1, entries 8−10). With Cs2CO3 in THF, selectivity remained high
but the yield slightly decreased (Table 1, entry 11). The best
result was achieved with 1,4-diazabicyclo[2.2.2]octane
(DABCO) as a base in THF, and 4aa was isolated in an
excellent yield (97%) and high enantioselectivity (90% ee)
(Table 1, entry 12). Reducing the loading of LiCl provided a
lower yield and a lower selectivity (Table 1, entry 13).
With optimized reaction conditions in hand, we explored the
scope and limitations of the organocascade (Scheme 2). Keeping
Table 1. Reaction Optimization
Scheme 2. Scope of the Reaction and X-ray Structure of 4ba
(Structure Is Shown with 50% Probability)
LiCl
time
(h)
yield
a
ee
b
entry (mol %)
base
DBU
cat.
solvent
(%)
(%)
c
1
−
−
−
−
20
20
20
20
20
20
20
20
10
A
THF
3
65
−
c
2
DBU
B
THF
24
24
4
trace
trace
15
n.d.
n.d.
n.d.
74
c
3
DBU
B
CH2Cl2
toluene
THF
c
4
DBU
B
c
5
DBU
B
2.5
1
65
c
6
DBU
B
CH2Cl2
THF
13
n.d.
88
7
iPr2EtN
iPr2EtN
iPr2EtN
iPr2EtN
Cs2CO3
DABCO
DABCO
B
B
B
B
B
B
B
2
97
8
CH2Cl2
toluene
MeCN
THF
5.5
7
62
87
9
49
84
10
11
12
13
7
<15
86
n.d.
88
5
THF
0.5
2
97
90
d
THF
78
82
a
Yield of the isolated product, and all reactions were run with 0.1
b
mmol of 2a. Determined by HPLC (see Supporting Information).
c
d
10 mol % catalyst was used. n.d. = not determined. Run with 0.2
mmol of 2a.
4aa was formed with complete diastereocontrol. Disappoint-
ingly, the enantioselective version upon switching from catalyst A
to B (10 mol %) provided only a trace amount of the desired
bicycle 4aa. Varying solvents from THF to toluene and
prolonging the reaction time afforded a slightly improved result.
However, a poor yield (15%) was still obtained in the best case
and decomposition of the starting material was noticed under the
applied conditions (Table 1, entries 2−4).
To increase reactivity, LiCl was added as a Lewis acid because
we and others have shown that cooperative Lewis acids improve
the efficiency of such organocascades.11,16 LiCl as a cocatalyst
should have the ability to interact with both the substrate 2a as
well as the in situ generated acyl azolium ion (LUMO activation).
Pleasingly, in the presence of 20 mol % LiCl and DBU as a
stoichiometric base, lactone 4aa was formed with chiral catalyst B
in 65% yield with complete diastereocontrol and 74%
enantioselectivity (Table 1, entry 5). Varying the solvent from
THF to CH2Cl2 provided a diminished result (only 13% of 4aa
substrate 2a as a ketone component, various enals were tested
first. We found that cinnamaldehyde derivatives bearing electron-
donating substituents at the para-position of the arene ring are
working well while a slight decrease in ee was observed for the
corresponding derivatives bearing para-electron-withdrawing
substituents. In particular the para-chloro-substituted compound
provided a lower ee (see 4ea). The absolute configuration of 4ba
was unambiguously assigned by X-ray crystallography (see
Scheme 2). The configuration of all other iridoid type lactones 4
prepared in this study was assigned in analogy. Notably, all
compounds prepared in this series were formed with complete
B
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diastereocontrol. The 2-furylenal 1f also delivered the targeted
lactone 4fa which was isolated in 86% yield with 91% ee. A lower
selectivity was achieved with crotonal (see 4ga) showing the aryl
substituent in the cinnamaldehyde derivatives positively
influences selectivity.
Our suggested reaction mechanism for the formation of
lactone products of type 4 is depicted in Scheme 4. Formation of
Scheme 4. Suggested Mechanism
We next investigated the effect of the ester groups in the
malonate component 2 on the selectivity and found that benzyl
malonate 2b (R2 = Bn, R3 = Me) provides the lactones 4ab−4cb
and 4eb in the reaction with enals 1a−c and 1e, as compared to
the ethyl malonates with slightly improved enantioselectivities. A
malonate of type 2 bearing two different ester groups (CO2Et,
CO2Bn) reacted with 1a in low diastereoselectivity with respect
to the quaternary malonate C-center (dr = 1.6:1, 63%, ee = 87%
for each isomer; not shown in Scheme 2, see Supporting
Information). We next replaced the methyl group in vinyl ketone
2a by an aryl substituent. Reactivity in the reaction with 1a was
lower, but selectivity remained high for the phenyl or p-
methoxyphenyl-substituted vinyl ketones 2c and 2d (see 4ac and
4ad).
To demonstrate flexibility, we tested homologue 5 in the
reaction with various enals under the optimized conditions which
should deliver bicyclic lactones comprising two 6-membered
rings (Scheme 3). Gratifyingly, with cinnamaldehyde 1a the
Scheme 3. Synthesis of Cyclohexane-Fused δ-Lactones
homologues 6 works in analogy. At first, enal 1 reacts with
carbene B′ generated by deprotonation of B to generate the
Breslow intermediate which is oxidized by 3 to provide the
corresponding acyl azolium ion 7. Deprotonated 2 then engages
in a 1,4 addition8f to the acylazolium species to give enolate 8.
Michael-type cyclization of the enolate onto the enone moiety
affords 9 which eventually undergoes intramolecular lactoniza-
tion to release the product and catalyst B′. Alternatively, enolate
8 can undergo an endo-hetero-Diels−Alder reaction which after
fragmentation of B′ also delivers the product 4.
The absolute stereochemistry can be explained by considering
model 11, where the Li-ion interacts with both the acylazolium
and malonate. The cis-selective second C−C bond formation is
controlled by complexation of the Li-enolate with the enone
oxygen atom (see 12). The significantly higher enantioselectiv-
ities obtained for the 6,6-bicyclic systems 6 as compared to those
of compounds 5 deserve some comments. It is not obvious why
the initial conjugate addition of the malonate derived from 5
occurs with far higher stereoselectivity than the initial addition of
the 2-derived malonates. We currently assume that in both cases
the addition is not perfectly stereoselective. In the case of
intermediate 8, cis-5-exo cyclization is fast for both diaster-
eoisomers and the initial selectivity is reflected by the ee obtained
for the final product. However, for the corresponding enolate
derived from 5, only the major diastereoisomer cyclizes after
lactonization eventually leading to 6. The minor diastereoisomer
likely undergoes a retro-Michael-addition to 7 and 5-Li. Hence,
the nonperfect selectivity is corrected by the reversibility of the
initial Michael addition accompanied by an inefficient (very
slow) cis-cyclization of the minor diasteroisomer enolate. This
error correction10 ensures high selectivity and also allows very
high overall yields to be obtained.
targeted cyclohexane-fused δ-lactone 6a was formed in 98% yield
with excellent diastereoselectivity (99:1) and excellent enantio-
selectivity (99% ee).
The higher reactivity and selectivity obtained with 5 as
compared to the lower homologues 4 are general as could be
shown by the reactions of enals 1b and 1c bearing electron-rich
substituents at the para-position of the aryl group. The lactones
6b and 6c were isolated in excellent yields and enantioselectiv-
ities (>99% ee). The relative and absolute configurations of 6b
were assigned on the basis of X-ray analysis (see Supporting
Information), and the other derivatives were assigned in analogy.
Also the more electron-poor enal 1d with the p-nitro substituent
(a problematic substrate with 2a) gave, in the reaction with 5, the
corresponding lactone 6d with high yield and selectivity, and
even the para-chloro substituted cinnamaldehyde 1e showed, in
the formation of 6e, good yield and selectivity. Moreover, a very
good result was also achieved with the furyl substituted enal 1f to
provide 6f with complete diastereocontrol with 98% ee and high
isolated yield (90%).
C
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(5) Willot, M.; Radtke, L.; Konning, D.; Frohlich, R.; Gessner, V. H.;
̈
̈
In summary, the introduced organocascade utilizing NHC and
LiCl as cooperative catalysts offers an efficient approach to
cyclopentane- and cyclohexane-anellated δ-lactones by succes-
sive formation of three new σ-bonds along with three
stereocenters and two rings in a single sequence from readily
prepared starting materials. LiCl turned out to be essential for
obtaining high yields in the enantioselective version of the
cascade. Our approach opens novel routes to the synthesis of
valuable natural product analogues containing substituted
cyclcopentanes and cyclohexanes fused with a lactone moiety.
The described organocascade reactions are experimentally easy
to perform by simply mixing the catalyst, substrates, and reagents
at ambient temperature. All reactions occur with complete
diastereocontrol with good to excellent enantioselectivity.
Strohmann, C.; Christmann, M. Angew. Chem., Int. Ed. 2009, 48, 9105.
(6) (a) Candish, L.; Lupton, D. W. Org. Lett. 2010, 12, 4836. (b) Lee,
S.; Paek, S.-M.; Yun, H.; Kim, N.-J.; Suh, Y.-G. Org. Lett. 2011, 13, 3344.
(c) Hilgraf, R.; Zimmermann, N.; Lehmann, L.; Troger, A.; Francke, W.
Beilstein J. Org. Chem. 2012, 8, 1256.
(7) For recent reviews, see: (a) Knappke, C. E. I.; Imami, A.; von
Wangelin, A. J. ChemCatChem 2012, 4, 937. (b) De Sarkar, S.; Biswas,
A.; Samanta, R. C.; Studer, A. Chem. - Eur. J. 2013, 19, 4664.
(c) Albanese, D. C. M.; Gaggero, N. Eur. J. Org. Chem. 2014, 2014, 5631.
(8) For selected recent reports on NHC catalyzed generation of α,β-
unsaturated acyl azoliums and their reactions, see: (a) De Sarkar, S.;
Studer, A. Angew. Chem., Int. Ed. 2010, 49, 9266. (b) Mahatthananchai,
J.; Zheng, P.; Bode, J. W. Angew. Chem., Int. Ed. 2011, 50, 1673.
(c) Lyngvi, E.; Bode, J. W.; Schoenebeck, F. Chem. Sci. 2012, 3, 2346.
(d) Kravina, A. G.; Mahatthananchai, J.; Bode, J. W. Angew. Chem., Int.
Ed. 2012, 51, 9433. (e) Biswas, A.; De Sarkar, S.; Tebben, L.; Studer, A.
Chem. Commun. 2012, 48, 5190. (f) Samanta, R. C.; Maji, B.; De Sarkar,
ASSOCIATED CONTENT
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S
* Supporting Information
S.; Bergander, K.; Frohlich, R.; Muck-Lichtenfeld, C.; Mayr, H.; Studer,
̈
̈
A. Angew. Chem., Int. Ed. 2012, 51, 5234. (g) Candish, L.; Lupton, D. W.
J. Am. Chem. Soc. 2013, 135, 58. (h) Yetra, S. R.; Kaicharla, T.; Kunte, S.
S.; Gonnade, R. G.; Biju, A. T. Org. Lett. 2013, 15, 5202. (i) Cheng, J.;
Huang, Z.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 8592. (j) Mo, J.;
Shen, L.; Chi, Y. R. Angew. Chem., Int. Ed. 2013, 52, 8588. (k) Candish,
L.; Levens, A.; Lupton, D. W. J. Am. Chem. Soc. 2014, 136, 14397.
(l) Mondal, S.; Yetra, S. R.; Patra, A.; Kunte, S. S.; Gonnade, R. G.; Biju,
A. T. Chem. Commun. 2014, 50, 14539. (m) Yetra, S. R.; Mondal, S.;
Suresh, E.; Biju, A. T. Org. Lett. 2015, 17, 1417.
(9) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. Angew. Chem.,
Int. Ed. 2007, 46, 3107.
(10) Biswas, A.; De Sarkar, S.; Frohlich, R.; Studer, A. Org. Lett. 2011,
13, 4966.
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.5b01932.
Experimental details, characterization data for the
products (PDF)
Supplementary crystallographic data (CCDC-1414262
and CCDC-1414263) (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: studer@uni-muenster.de.
Notes
(11) See also: Bera, S.; Samanta, R. C.; Daniliuc, C. G.; Studer, A.
Angew. Chem., Int. Ed. 2014, 53, 9622.
(12) (a) Zhang, H.-R.; Dong, Z.-W.; Yang, Y.-J.; Wang, P.-L.; Hui, X.-P.
Org. Lett. 2013, 15, 4750. (b) Fang, X.; Jiang, K.; Xing, C.; Hao, L.; Chi,
R. Y. Angew. Chem. 2011, 123, 1950.
(13) (a) De Sarkar, S.; Grimme, S.; Studer, A. J. Am. Chem. Soc. 2010,
132, 1190. (b) De Sarkar, S.; Studer, A. Org. Lett. 2010, 12, 1992.
(14) Ling, K. B.; Smith, A. D. Chem. Commun. 2011, 47, 373.
(15) Struble, J. R.; Bode, J. W. Org. Synth. 2010, 87, 362.
(16) For NHC catalysis in the presence of Lewis acids as cocatalysts,
see: (a) Raup, D. E. A.; Cardinal-David, B.; Holte, D.; Scheidt, K. A. Nat.
Chem. 2010, 2, 766. (b) Cohen, D. T.; Scheidt, K. A. Chem. Sci. 2012, 3,
53. (c) Mo, J.; Chen, X.; Chi, Y. R. J. Am. Chem. Soc. 2012, 134, 8810.
(d) Dugal-Tessier, J.; O'Bryan, E. A.; Schroeder, T. B. H.; Cohen, D. T.;
Scheidt, K. A. Angew. Chem., Int. Ed. 2012, 51, 4963. (e) Zhang, Y.; Lu,
Y.; Tang, W.; Lu, T.; Du, D. Org. Biomol. Chem. 2014, 12, 3009. (f) Xiao,
Z.; Yu, C.; Li, T.; Wang, X.-S.; Yao, C. Org. Lett. 2014, 16, 3632.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
This work was financially supported by the SFB858 and the
NRW Graduate School of Chemistry.
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REFERENCES
■
(1) For selected reviews on organocatalytic cascade reactions, see:
(a) Enders, D.; Grondal, C.; Huttl, M. R. Angew. Chem., Int. Ed. 2007, 46,
1570. (b) Walji, A. M.; MacMillan, D. W. C. Synlett 2007, 2007, 1477.
(c) Yu, X.; Wang, W. Org. Biomol. Chem. 2008, 6, 2037. (d) Zhou, J.
Chem. - Asian J. 2010, 5, 422. (e) Grossmann, A.; Enders, D. Angew.
Chem., Int. Ed. 2012, 51, 314.
(2) For reviews on NHC catalysis, see: (a) Enders, D.; Niemeier, O.;
Henseler, A. Chem. Rev. 2007, 107, 5606. (b) Marion, N.; Diez-
Gonzalez, S.; Nolan, S. P. Angew. Chem., Int. Ed. 2007, 46, 2988. (c) Nair,
V.; Vellalath, S.; Babu, B. P. Chem. Soc. Rev. 2008, 37, 2691. (d) Moore, J.
L.; Rovis, T. Top. Curr. Chem. 2009, 291, 77. (e) Nair, V.; Menon, R. S.;
Biju, A. T.; Sinu, C. R.; Paul, R. R.; Jose, A.; Sreekumar, V. Chem. Soc. Rev.
2011, 40, 5336. (f) Bugaut, X.; Glorius, F. Chem. Soc. Rev. 2012, 41,
3511. (g) Douglas, J.; Churchill, G.; Smith, A. D. Synthesis 2012, 44,
2295. (h) Vora, H. U.; Wheeler, P.; Rovis, T. Adv. Synth. Catal. 2012,
354, 1617. (i) Mahatthananchai, J.; Bode, J. W. Acc. Chem. Res. 2014, 47,
696. (j) Hopkinson, M. N.; Richter, C.; Schedler, M.; Glorius, F. Nature
2014, 510, 485. (k) Yetra, S. R.; Patra, A.; Biju, A. T. Synthesis 2015, 47,
1357. (l) Flanigan, D. M.; Romanov-Michailidis, F.; White, N. A.; Rovis,
T. Chem. Rev. 2015, 115, 9307. (m) Menon, R. S.; Biju, A. T.; Nair, V.
Chem. Soc. Rev. 2015, 44, 5040.
(3) Barrero, A.; Quilez del Moral, J. F.; Herrador, M. M.; Rodriguez,
H.; Morales, M. C. P. Curr. Org. Chem. 2009, 13, 1164.
(4) For reports on iridoids, see: (a) El-Naggar, L. J.; Beal, J. L. J. Nat.
Prod. 1980, 43, 649. (b) Dinda, B.; Chowdhury, D. R.; Mohanta, B. C.
Chem. Pharm. Bull. 2009, 57, 765. (c) Dinda, B.; Debnath, S.; Banik, R.
Chem. Pharm. Bull. 2011, 59, 803. (d) Tundis, R.; Loizzo, M. R.;
Menichini, F.; Statti, G. A. Mini-Rev. Med. Chem. 2008, 8, 399.
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