Vinylogous Reactivity of Cyclic 2-Enones: Organocatalysed Asymmetric Addition to 2-Enals to Synthesize Fused Carbocycles

Article abstract of DOI:10.1002/anie.201901902

A method for asymmetric and site selective annulations at the γ and γ′ positions of cyclic 2-enones with α,β-unsaturated aldehydes has been developed. The organocatalysed [3+3]-annulations proceed with high levels of regio-, diastereo-, and enantioselectivity, affording a series of high value fused carbocycles. Further elaboration gave key lactones (both bridged and fused).

Full text of DOI:10.1002/anie.201901902

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Accepted Article
Title: Vinylogous Reactivity of Cyclic 2-Enones: Organocatalysed
Asymmetric Addition to 2-Enals to Synthesize Fused Carbocycles
Authors: Manolis Sofiadis, Dimitris Kalaitzakis, John Sarris, Tamsyn
Montagnon, and Georgios Vassilikogiannakis
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10.1002/anie.201901902
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Vinylogous Reactivity of Cyclic 2-Enones: Organocatalysed
Asymmetric Addition to 2-Enals to Synthesize Fused Carbocycles
Manolis Sofiadis, Dimitris Kalaitzakis, John Sarris, Tamsyn Montagnon and Georgios
Vassilikogiannakis*
Dedication
Abstract: Asymmetric and site selective annulations from the  and
' positions of cyclic 2-enones with ,-unsaturated aldehydes have
been developed. The organocatalysed [3+3]-annulations proceeded
with high levels of regio- diastereo- and enantioselectivity affording a
series of high value fused carbocycles. Further elaboration gave key
lactones (both bridged and fused).
Currently, there is a strong drive to find new ways to achieve
rapid enhancement in molecular complexity in order to maximize
synthetic efficiency and minimize waste. In this context, one-pot
cascade reaction sequences have proven to be a potent tool
because they form multiple covalent bonds in a single synthetic
operation.[1] Furthermore, when these sequences are designed
to include asymmetric organocatalysis,[2] stereochemically
dense, as well as, skeletally complex molecules can be
accessed very rapidly from simple precursors in a highly
controlled manner.[3] In this work, we sought to develop novel
enantioselective one-pot reaction sequences using a double
vinylogous addition reaction.[4] We were drawn to this particular
reaction type due to its inherent advantages and the power it
Scheme 1. Organocatalytic functionalizations of cyclic 2-enones.
has to form key bonds, as exemplified by the major contributions
it has already made in the synthesis of complex targets.[4]
vinylogous ' position (Scheme 1, path c).[8] Interestingly, no
Cyclic 2-enones (I, Scheme 1) are valuable starting
studies have been conducted which look at selectively
materials for generating complexity due to the multiplicity and
functionalising cyclic 2-enones at both the  and ' positions in
differential reactivity of their reaction sites. In order to access
potential nucleophilicity, an amine organocatalyst has been
order to synthesize fused carbocycles; a deficit we now address
albeit through a new reaction mode (vide infra).
harnessed; for example, dienamine organocatalysis may
activate the ',[5]  and ' positions of I (Scheme 1). Only very
Firstly, we devised a new plan that involved a switch in
strategy towards relying on a LUMO-lowering effect for the direct
 and ' functionalization of cyclic enones. In order to apply such
an effect, however, it was calculated that two major criteria must
be met; namely, the use of a LUMO-lowered electrophile in
conjunction with an easily enolizable cyclic enone (we proposed
adding an ester handle). Of relevance to the discussion here, is
the reactivity of malononitrile derivatives of type II with ,-
unsaturated aldehydes (Scheme 1, path d and e) which was
described by Zanardi and Chen.[9] In this case, the activation of I
by derivatization (Scheme 1, I→II)[10] was essential in order to
increase the acidity of the  and ' protons, and, thus, facilitate
certain annulation reactions (path d, e). This chemistry was
restricted to cyclohexyl starting materials.[9]
recently, this HOMO-activation approach has been exploited in
vinylogous addition reactions; thus, addressing the principal
challenges associated with the regio- and stereo-selective
functionalization of 5- and 6-membered cyclic 2-enones.[6-8] In
particular, the asymmetric reaction of the  carbon of 2-
cyclohexenones with various electrophiles, in the presence of
cinchona alkaloid-based primary amine derivatives, was
reported by Melchiorre and Bencivenni (Scheme 1, path a).[6]
A
dual dienamine activation mode was exploited by Chen and Gao
in which cyclic 2-enones produced annulated products by
reaction from the ' and ' positions (Scheme 1, path b).[7] Later,
using different primary amine catalysts, Ye demonstrated the
regioselective functionalization of 2-cyclopentenones from the
Herein, we describe how we have implemented the
conceptual design described above and in so-doing have
developed a novel double vinylogous reactivity for cyclic 2-
enones with LUMO-lowered 2-enals under mild conditions. In
detail, we envisioned that the presence of an ester group at the
-position of the cyclic 2-enones 1 or 2 (Scheme 2) might
facilitate their nucleophilic addition to 2-enals of type 3.
Moreover, in the readily accessible keto esters 1 and 2, both
the and ' positions would be activated meaning that they
[]
M. Sofiadis, Dr. D. Kalaitzakis, J. Sarris, Dr. T. Montagnon, Prof. Dr.
G. Vassilikogiannakis
Department of Chemistry, University of Crete
Vasilika Vouton, 71003, Iraklion, Crete, Greece
E-mail: vasil@uoc.gr
ID:
Georgios Vassilikogiannakis: 0000-0002-9099-383X
Supporting information for this article is given via a link at the end of
the document.
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Scheme 2. Envisioned [3+3]-annulation of cyclic 2-enones with ,-
unsaturated aldehydes using a LUMO-lowering strategy.
would constitute excellent substrates for the formation of [3+3]-
annulated products with dielectrophilic enals 3. The successful
implementation of this methodology constitutes the first example
of an organocatalysed functionalization of cyclic 2-enones at the
 and ' positions, leading to the high value bicyclo[4,3,0]nonane
and bicyclo[4,4,0]decane frameworks (68, Scheme 2) that are
present in numerous natural products.[11]
Scheme 3. Optimization of the conditions for the synthesis of 6a from 1. [a]
Determined by 1H-NMR. [b] Determined by chiral HPLC analysis of the final
product 6a. [c] These conditions were applied after cond. 8. [d] When Et3N, or
the acids (PTSA or TFA) were used, the reaction time was 5 h. In the case of
the anhydrides (Ac2O or TFAA), the reaction time was 0.5 h and 4-DMAP (0.2
equiv) was added (see the SI for experimental details). [e] Isolated yields.
The investigations began with the keto ester 1[12] which was
coupled with cinnamaldehyde 3a in the presence of a secondary
amine organocatalyst (cat. IIII). Proof of principle for the first
step was obtained using cat I (10 mol%) and 3a (1.5 equiv) in
MeOH at room temperature. This reaction afforded 4a with high
enantioselectivity (conv. 100%, 94% ee, cond. 1, Scheme 3).
Key to this success was the excellent regioselectivity with the
enone reacting exclusively at the -position. The increased
acidity of the  protons in substrate 1 seems to be essential,
since the application of exactly the same conditions to 2-
cyclopentenone 9 (Scheme 3) did not promote an analogous
reaction. Furthermore, the advantage of using a protic solvent
(cond. 1–3, MeOH being the best), was confirmed by the slow
reaction in either DCM or toluene (cond. 4, 5). This observation
is consistent with a recently published report; in which, evidence
was presented that the reaction between acidic carbon
nucleophiles and LUMO-lowered 2-enals is accelerated in protic
solvents.[13] With regard to the ee levels, cat II and III proved to
be more selective than cat I (cond. 7 & 8). Cat III was deemed to
be the optimal choice due to its enhanced reactivity compared to
cat II (cond. 8 vs cond. 7), probably a result of its more basic
nature.[13]
were included in the reaction conditions (50–55% yield, cond.
C–E). Following these observations, we reasoned that a Et3N-
anhydride combination might prove to be ideal. Thus, a
breakthrough was achieved when Et3N and either acetic
anhydride (Ac2O) or trifluoroacetic anhydride (TFAA) were
employed. Full details of this protocol, which furnished 6a in a
very good isolated yield considering the number of steps
involved (72% cond. F, 80% cond. G) and with high optical purity
(97% ee), are presented in the accompanying SI. The combined
optimum conditions for the single-pot synthesis of 6a from 1,
were, therefore, found to be 8G.
To explore the scope of the reaction, various ,-unsaturated
aldehydes of type 3 were tested with 2-cyclopentenone 1, under
the optimal conditions 8G (Scheme 4). Harnessing aryl-
substituted enals (3af), the reaction successfully delivered the
desired products 6af, regardless of the nature of the aryl-
substituent. All the reactions exhibited excellent regioselectivity
proceeding exclusively via the intermediate of type 4. Moreover,
all the reactions were performed as single synthetic operations
furnishing compounds of type 6 with high ee values (9697%)
and in good isolated yields (6582%). In contrast, however,
conditions 8G were not effective for the alkyl-substituted enal 3g.
Under conditions 8 (Scheme 3), the vinylogous Michael-addition
of substrate 1 to 3g was slow (conv. 15%, 14 h) and not very
regioselective (/' regioisomeric ratio = 5/1). Using conditions 1
(cat I instead of III) the regioisomeric ratio was the same;
however, full conversion was achieved after 14 h. Gratifyingly,
the regioselectivity could be enhanced (reaching 16/1) by
performing this reaction (1→4g) at 0 oC for 48 h. In this case, the
tandem reaction sequence (1 → 4g → 5g→6g) afforded the
desired compound 6g in an isolated yield of 50% and with ee =
91% (Scheme 4).
Now that optimized conditions for the first step (1→4a) had
been established, we could continue with an investigation of the
cyclization/dehydration step (4a → 6a). Experiments were
performed without isolating 4a (generated from 1 using cond. 8).
We found that the addition of Et3N (1.2 equiv) to a solution of 4a
in MeOH, promoted the nucleophilic addition of the ' carbon to
the aldehyde group (4a→5a) followed by dehydration (5a→6a),
ultimately, furnishing 6a, albeit in a rather low isolated yield
(28%, cond. A, Scheme 3). Attempting the same reaction, but
this time in DCM (cond. B), led to the formation of the compound
5a, exclusively. The results improved when either PTSA or TFA
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Scheme 4. Asymmetric synthesis of carbocycles of type 6. [a] Determined by
chiral HPLC analysis. [b] Isolated yields. [c] The reaction towards 4g was
performed using 15 mol% of cat I at 0 oC and 2 equiv of 3g, for 48 h.
An interesting observation emerged during the optimization
of the transformation of 4a to 5a (Scheme 3). Specifically, 5 h
after the addition of Et3N (0.5 equiv) to a solution of 4a in DCM,
the reaction yielded four diastereoisomers of compound 5a
(dr=1/1.3/1.4/3.5). This ratio changed significantly (to a dr for 5a
of 11/1) if 4a was subjected to Et3N (1.2 equiv) for 5 h (cond. B).
This latter result must arise from two different factors which lead
to the domination of the most favourable isomer; namely, it is a
consequence of a reversible intramolecular aldol, as well as, of
the epimerizability of '-position in 5 (Scheme 5). We were not
able to purify 5 due to its susceptibility to dehydration during
chromatography. However, it was envisaged that hydrogenation
of the olefin might deliver a more stable product, and, indeed,
direct hydrogenation of 5a (H2, PtO2) in EtOAc, afforded the
stable compound 7a (Scheme 5), bearing five stereocenters with
a high degree of diastereoselectivity (dr = 11/1, separable
diastereoisomers, ee = 96% for the major isomer). The overall
yield of this one-pot reaction sequence (1→7a), was 60%. A
number of different enals were tested in this multi-step
transformation and the results are shown in Scheme 5. All the
products of type 7 were afforded with high dr (10/111/1). Since
conditions could not be found to separate the enantiomers of 7
by chiral HPLC, the ee values were determined (9196%) after
reduction of pure compounds 7 with NaBH4 (Scheme 5, dr =
7.4/1 in all cases, the major diastereoisomer of 10 was isolated
in yields of 7077%). The absolute configuration was
unambiguously, confirmed via single-crystal X-ray analysis of
product 10a.[14] The overall yields for 1 → 7 (5067%) are
remarkably good when the dramatic enhancement in both the
3D-skeletal and the stereochemical complexity achieved through
this tandem reaction sequence is taken into account.
Scheme 5. Asymmetric synthesis of carbocycles of type 7. [a] Determined by
the 1H NMR of crude 7. [b] Determined by chiral HPLC analysis of compounds
10. [c] Isolated yields for the major diastereoisomer. [d] The first reaction of the
sequence was performed using 15 mol% of cat I at 0 oC and 2 equiv of 3g, for
48 h.
functionality. These bicyclic lactone motifs (11 and 12) are found
in a plethora of natural products.[16]
To further underscore the strong synthetic credentials of the
current methodology, we next sought to examine the application
of the protocol to 2-cyclohexenone 2[12] (Scheme 7). Attempts to
react substrate 2 with enal 3a under conditions 8 did not
succeed. Intriguingly, when Et3N (1 equiv) was added to a
solution of 2 in MeOH which contained enal 3a (1.5 equiv) and
cat III (20 mol%, Scheme 7), the vinylogous Michael addition
occurred with excellent regioselectivity furnishing 4a' (albeit with
moderate conversion of 70% after 24 h). Upon increasing the
amount of Et3N to 1.5 equiv, the reaction proceeded to
completion after 24 h. Moving forward to the cyclization-
dehydration step (4a'→8a), a combination of TFAA with Et3N in
DCM proved effective for the formation of the desired carbocycle
8a (72% yield). The isolated yield was further improved to 75%
using PTSA (1 equiv). These transformations were performed
without the purification of compound 4a' and furnished the
desired product 8a with an excellent ee (98%). By employing
similar conditions to the reactions of 2 with various aryl-
With the aim of illustrating the versatility of the ester handle,
the next part of the investigation looked at the reactions of
compounds of type 7 with bases. Initially, the keto-esters 7 were
treated with K2CO3 (1 equiv) in refluxing acetone. Under these
conditions, the presence of the hydroxyl group on the concave
face of 7 facilitated a retro-Claisen condensation,[15] affording
lactones 11 in very good isolated yields and with excellent
optical purity (11a, 11b, 11f, 11g, 8993% yield, >99% de,
9197% ee, Scheme 6). Moreover, when 7a was subjected to
K2CO3, followed by EtONa in refluxing EtOH, the bridged bicyclic
compound 12a (80% yield, >99% de, Scheme 6) was obtained.
This product had been derived via lactone 11a which then
underwent ethanolysis and lactone formation with the other ester
Scheme 6. Base-assisted controlled derivatization of compounds of type 7.
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[2]
Scheme 7. Asymmetric synthesis of carbocycles of type 8. [a] Determined by
chiral HPLC analysis. [b] Isolated yields.
[3]
[4]
a) H. Pellissier, Adv. Synth. Catal. 2012, 354, 237-294; b) P. Chauhan,
S. Mahajan, D. Enders, Acc. Chem. Rec. 2017, 50, 2809-2821.
For a review in vinylogous reactivity, see: a) G. Casiraghi, L. Battistini,
C. Curti, G. Rassu, F. Zanardi, Chem. Rev. 2011, 111, 3076-3154. For
reviews in asymmetric vinylogous Michael reactions, see: b) C.
Schneider, F. Abels, Org. Biomol. Chem. 2014, 12, 3531-3543; c) Y.
Yin, Z. Jiang, ChemCatChem 2017, 9, 4306-4318.
substituted enals (3b, 3df), the corresponding carbocyclic
compounds of type 8 were all synthesized with remarkably high
enantioselectivity (9899% ee) and in good isolated yields (50-
75%). For the alkyl-substituted enal 3g, the developed
conditions were ineffective.
[5]
For selected examples of organocatalysed [4+2] cycloaddition reactions
of cyclic 2-enones from ΄, position, see: a) Y. Yamamoto, N.
Momiyama, H. Yamamoto, J. Am. Chem. Soc. 2004, 126, 5962-5963;
b) H. Sundén, R. Rios, Y. Xu, L. Eriksson, A. Córdova, Adv. Synth.
Catal. 2007, 349, 2549-2555; c) D.-Q. Xu, A.-B. Xia, S.-P. Luo, J. Tang,
S. Zhang, J.-R. Jiang, Z.-Y. Xu, Angew. Chem. Int. Ed. 2009, 48, 3821-
3824; Angew. Chem. 2009, 121, 3879-3882; d) X. Feng, Z. Zhou, R.
Zhou, Q.-Q. Zhou, L. Dong, Y.-C. Chen, J. Am. Chem. Soc. 2012, 134,
19942-19947; e) R. Mose, M. E. Jensen, G. Preegel, K. A. Jørgensen,
Angew. Chem. Int. Ed. 2015, 54, 13630-13634; Angew. Chem. 2015,
127, 13834-13838.
In summary, we have introduced a straightforward synthetic
methodology for the asymmetric construction of important fused
carbocycles containing the privileged bicyclo[4,3,0]nonane or
bicyclo[4,4,0]decane framework, as well as, for certain key fused
and bridged lactones. This method oversees
a dramatic
increase in structural complexity both in terms of the
stereocentre density and the 3D skeletal framework. The
concept of an organocatalysed coupling of a LUMO-lowered
dielectrophile with an easily enolizable cyclic 2-enone through
two sequential vinylogous additions (first
a regioselective
[6]
[7]
a) G. Bencivenni, P. Galzerano, A. Mazzanti, G. Bartoli, P. Melchiorre,
Proc. Natl. Acad. Sci. USA 2010, 107, 20642-20647; b) D. Bastida, Y.
Liu, X. Tian, E. Escudero-Adán, P. Melchiorre, Org. Lett. 2013, 15, 220-
223; c) N. Di Iorio, P. Righi, A. Mazzanti, M. Mancinelli, A. Ciogli, G.
Bencivenni, J. Am. Chem. Soc. 2014, 136, 10250-10253.
vinylogous Michael addition from the position, then
a
vinylogous aldol from the ' position) to afford the [3+3]-
annulation product, has also been introduced for the first time.
All the actions were performed with
regioselectivity and with remarkable diastereo-
a
high degree of
and
X. Yin, Y. Zheng, X. Feng, K. Jiang, X.-Z. Wei, N. Gao, Y.-C. Chen,
Angew. Chem. Int. Ed. 2014, 53, 6245-6248; Angew. Chem. 2014, 126,
6359-6362.
enantioselectivity, in one-pot operations.
[8]
[9]
C. Zou, C. Zeng, Z. Liu, M. Lu, X. Sun, J. Ye, Angew. Chem. Int. Ed.
2016, 55, 14257-14261; Angew. Chem. 2016, 128, 14469-14473.
a) L. Dell’Amico, G. Rassu, V. Zambrano, A. Sartori, C. Curti, L.
Battistini, G. Pelosi, G. Casiraghi, F. Zanardi, J. Am. Chem. Soc. 2014,
136, 11107-11114; b) Q.-Z. Li, J. Gu, Y.-C. Chen, RSC Adv. 2014, 4,
37522-37525.
Acknowledgements
The research leading to these results has received funding from
the European Research Council under the European Union’s
Seventh Framework Programme (FP7/2007-2013)/ERC grant
agreement no. 277588. We thank the Greek General Secretariat
of Research and Technology for matching (reward) funds (KA:
4143). We also thank the Alexander S. Onassis Public Benefit
Foundation for the Ph.D. fellowship of Manolis Sofiadis (G ZM
063-1/2016-2017). We thank the ProFI (Proteomics Facility at
IMBB-FORTH) for performing all the HRMS analyses. We are
grateful to Prof. P. Trikalitis (University of Crete) for obtaining the
X-ray crystallographic data.
[10] For representative reviews on malononitrile activation of carbonyl
compounds, see: a) H.-L. Cui, Y.-C. Chen, Chem. Commun. 2009, 45,
4479-4486; b) L. Battistini, C. Curti, G. Rassu, A. Sartori, F. Zanardi,
Synthesis 2017, 49, 2297-2336.
[11] a) For kempane, see: G. D. Prestwich, Tetrahedron 1982, 38, 1911-
1919; b) For tundrenone, see: A. W. Puri, E. Mevers, T. R. Ramadhar,
D. Petras, D. Liu, J. Piel, P. C. Dorrestein, E. P. Greenberg, M. E.
Lidstrom, J. Clardy, J. Am. Chem. Soc. 2018, 140, 2002-2006; c) For
fawcettimine, see: K. Katakawa, A. Nozoe, N. Kogure, M. Kitajima, M.
Hosokawa, H. Takayama, J. Nat. Prod. 2007, 70, 1024-1028; d) For
paniculatine, see: L. A. Loyola, G. Morales, M. Castillo, Phytochemistry
1979, 18, 1721-1723; e) For mifepristone, see: J. R. Goldberg, M. G.
Plescia, G. D. Anastasio, Arch. Fam. Med. 1998, 7, 219-222.
Keywords: Vinylogous reactivity•[3+3]-annulations
[12] For its synthesis, see supporting information.
•organocatalysis•bicyclo[4,3,0]nonanes•bicyclo[4,4,0]decanes
[13] S. Duce, I. Alonso, A. M. Lamsabhi, E. Rodrigo, S. Morales, J. L. G.
Ruano, A. Poveda, P. Mauleón, M. B. Cid, ACS Catal. 2018, 8, 22-34.
[1]
For a review, see: a) Y. Hayashi, Chem. Sci. 2016, 7, 866-880. For
representative examples with organocatalysis, see: b) Y. Hayashi, S.
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[14] CCDC 1896370 contains the supplementary crystallographic data.
These data can be obtained free of charge from the Cambridge
Crystallographic Data Center via www.ccdc.cam.ac.uk/data_request/cif.
[15] For a recent review on retro-Claisen condensation, see: A. Ortega-
Martinez, C. Molina, C. Moreno-Cabrerizo, J. M. Sansano, C. Najera,
Eur. J. Org. Chem. 2018, 2394-2405.
Lett. 2018, 59, 4028-4030; b) D. Xu, B.-Y. Zhang, X.-L. Yang, Chem.
Biodivers. 2016, 13, 1422-1425; c) Y.-S. Wanga, R. Huang, Y. Li, W.-B.
Shang, F. Chen, H.-B. Zhang, J.-H. Yang, Phytochem. Lett. 2013, 6,
26-30; d) G. Xu, A.-J. Hou, Y.-T. Zheng, Y. Zhao, X.-L. Li, L.-Y. Peng,
Q.-S. Zhao, Org. Lett. 2007, 9, 291-293; e) T. J. Schmidt, H. M.
Schmidt, E. Müller, W. Peters, F. R. Fronczek, A. Truesdale, N. H.
Fischer, J. Nat. Prod. 1998, 61, 230-236.
[16] For representative examples see: a) Z.-X. Zhang, H.-H. Li, D.-J. Zhi, P.-
Q. Wu, Q.-L.Hu, Y.-F. Yu, Y. Zhao, C.-X. Yu, D.-Q. Fei, Tetrahedron
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Entry for the Table of Contents (Please choose one layout)
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Manolis Sofiadis, Dimitris Kalaitzakis,
John Sarris, Tamsyn Montagnon and
Georgios Vassilikogiannakis*
Page No. – Page No.
Vinylogous Reactivity of Cyclic 2-
Enones: Organocatalysed Aymmetric
Addition to Enals to Synthesize
Fused Carbocycles
Asymmetric and site selective annulations from the  and ΄ positions of cyclic 2-
enones with ,-unsaturated aldehydes have been developed. The
organocatalysed [3+3]-annulations proceeded with high levels of regio- diastereo-
and enantioselectivity affording a series of high value fused carbocycles. Further
elaboration gave key lactones (both bridged and fused).
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