Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene-Embedding Linear and Angular Polycycles

Article abstract of DOI:10.1002/anie.201501894

A direct aminocatalytic synthesis has been developed for the chemo-, regio-, diastereo-, and enantioselective construction of densely substituted polycyclic carbaldehydes containing fused cyclohexadiene rings. The chemistry utilizes, for the first time, remotely enolizable π-extended allylidenemalononitriles as electron-rich 1,3-diene precursors in a direct eliminative [4+2] cycloaddition with both aromatic and aliphatic α,β-unsaturated aldehydes. The generality of the process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-, and 6,5,6-fused ring systems, as well as biorelevant steroid-like 6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism for the key [4+2] addition is proposed as a domino bis-vinylogous Michael/Michael/retro-Michael reaction cascade. The utility of the malononitrile moiety as traceless activating group of the dicyano nucleophilic substrates is demonstrated.

Full text of DOI:10.1002/anie.201501894

Angewandte
Chemie
International Edition: DOI: 10.1002/anie.201501894
German Edition: DOI: 10.1002/ange.201501894
Organocatalysis
Organocatalytic, Asymmetric Eliminative [4+2] Cycloaddition of
Allylidene Malononitriles with Enals: Rapid Entry to Cyclohexadiene-
Embedding Linear and Angular Polycycles**
Nicoletta Brindani, Gloria Rassu,* Luca DellꢀAmico, Vincenzo Zambrano, Luigi Pinna,
Claudio Curti, Andrea Sartori, Lucia Battistini, Giovanni Casiraghi, Giorgio Pelosi,
Daniela Greco, and Franca Zanardi*
Abstract: A direct aminocatalytic synthesis has been devel-
oped for the chemo-, regio-, diastereo-, and enantioselective
construction of densely substituted polycyclic carbaldehydes
containing fused cyclohexadiene rings. The chemistry utilizes,
for the first time, remotely enolizable p-extended allylidene-
malononitriles as electron-rich 1,3-diene precursors in a direct
eliminative [4+2] cycloaddition with both aromatic and
aliphatic a,b-unsaturated aldehydes. The generality of the
process is demonstrated by approaching 6,6-, 5,6-, 7,6-, 6,6,6-,
and 6,5,6-fused ring systems, as well as biorelevant steroid-like
6,6,6,6,5- and 6,6,6,5,6-rings. A stepwise reaction mechanism
for the key [4+2] addition is proposed as a domino bis-
vinylogous Michael/Michael/retro-Michael reaction cascade.
The utility of the malononitrile moiety as traceless activating
group of the dicyano nucleophilic substrates is demonstrated.
tion reaction is, no doubt, an effective and rapid avenue to
access six-membered rings, a route that nature has admirably
pursued and chemists have diligently imitated.[3] Since the
advent of modern organocatalysis at the turn of the 21st
century, amine-triggered reactions have been at the center of
an explosive growth, and culminated in the implementation of
myriad of high-impact organic transformations, including
efficient and creative organocatalytic [4+2] cycloadditions.[4]
Figure 1 (top) shows a possible retrosynthesis of the fused
S
ix-membered carbocycles, as well as five- and seven-
membered rings, are common motifs in nature and they can
be found in many terpenoid, polyketide, and shikimate-
derived monocyclic and polycyclic molecular architectures.[1,2]
The synchronous or stepwise Diels–Alder [4+2] cycloaddi-
[*] Dr. N. Brindani, Dr. L. Dell’Amico, Dr. C. Curti, Dr. A. Sartori,
Prof. Dr. L. Battistini, Prof. Dr. G. Casiraghi, Dr. D. Greco,
Prof. Dr. F. Zanardi
Dipartimento di Farmacia, Universitꢀ degli Studi di Parma
Parco Area delle Scienze 27A, 43124 Parma (Italy)
E-mail: franca.zanardi@unipr.it
Figure 1. Retrosynthetic analysis of the prototypical cyclohexadiene-
containing structures A (top) and the allylidene malononitrile-based
strategy to access them (bottom, this work).
Dr. N. Brindani
Dipartimento di Scienze degli Alimenti
Universitꢀ degli Studi di Parma, Parma (Italy)
cyclic structure A, with an embedded cyclohexadiene motif,
into two elements, B and C, with B (a g-enolizable a,b-
unsaturated carbonyl) acting as the diene precursor and the C
(an enolizable or non-enolizable enal) serving as the dien-
ophile. Direct [4+2] cycloaddition between B and C to give A
seems short and facile. However it is not, especially when the
reactivity of the two carbonyl groups is similar. Several
challenges are indeed associated with such a cross-cyclizative
strategy, with the control of chemoselectivity being a stringent
issue. To avoid the competition of alternate reaction path-
ways, such as self-condensations or reversal in the addition,
one should distinguish a priori which is the diene component
and which is the dienophile, so that the process can proceed
cleanly and productively.
Dr. G. Rassu, Dr. V. Zambrano
Istituto di Chimica Biomolecolare
Consiglio Nazionale delle Ricerche
Traversa La Crucca 3, 07100 Li Punti Sassari (Italy)
E-mail: gloria.rassu@icb.cnr.it
Dr. L. Dell’Amico
Institute of Chemical Research of Catalonia, Tarragona (Spain)
Dr. L. Pinna
Dipartimento di Chimica e Farmacia
Universitꢀ degli Studi di Sassari, Sassari (Italy)
Prof. Dr. G. Pelosi
Dipartimento di Chimica
Universitꢀ degli Studi di Parma, Parma (Italy)
[**] Financial support provided by the Universitꢀ degli Studi di Parma is
gratefully acknowledged.
Even with these challenges, direct, intermolecular [4+2]
cycloadditions merging two a,b-unsaturated carbonyls have
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201501894.
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Table 1: Scope of the direct amine-catalyzed vinylogous asymmetric
[4+2] cycloaddition varying the donor component.[a–d]
been achieved with success, notably in the dienamine- or
trienamine-triggered catalytic modalities, where maximum
selectivity was attained when the reactivity of the two
reaction partners was properly differentiated.[5–8] Despite
these achievements, a truly viable and general approach to
chemo- and stereoselectively merging two similarly reactive
a,b-unsaturated carbonyls remains elusive. Hence, we
became interested in designing a reliable organocatalytic
strategy which could impart precise assignment of the roles
between the reaction components, and would subsequentially
react in a chemoselective, asymmetric aminocatalytic cycle to
produce a single product.
Following this ideal, we planned to temporarily alter the
carbonyl reactivity of one a,b-unsaturated component (e.g.,
B) with a malononitrile handle by a Knoevenagel reaction
(Figure 1, bottom), a modification that would arguably render
the deprotonation at its remote e-position much easier than
that of the other participant (e.g., C). Thus, the formed doubly
unsaturated malononitrile D, a surrogate of B, would
decidedly work as a nucleophilically activated diene (D’),
with the second partner playing the role of the dienophile,
thereby largely avoiding any selectivity concern. Once the
cycloadduct E formed, release of the amine catalyst along
with the malononitrile handle would deliver the targeted
polycyclic skeleton A.[9,10] The high competence of this
approach was herein demonstrated by targeting several
carbo- and hetero-polycycles, all featuring a fused cyclo-
hexadiene carbaldehyde framework. The utility of the
dicyano moiety was also demonstrated by direct one-pot
executions, where the present malononitrile-based procedure
was compared to the traditional carbonyl cross-coupling
reaction.
[a] Additional reaction conditions: 1a (0.25 mmol, 1.0 equiv), 2a
(1.8 equiv), [1a]0 =0.2m, in air. [b] Yields refer to the isolated products 3.
Yield of 3 obtained on a 5ꢁ scale is reported within parentheses.
[c] Diastereomeric ratio (d.r.) determined by 1H NMR analysis of the
crude reaction mixture. [d] Enantiomeric excess (ee) determined by
HPLC analysis using a chiral stationary phase. pBrBz=p-bromoben-
zoyl.[14]
substitutions were examined. Gratifyingly, the monocyclic
and bicyclic substrates 1a–f and 1g–j, respectively, easily
reacted with 2a under the established reaction conditions to
deliver the expected naphthalene- or phenanthrene-type
carbaldehydes 3aa–fa and 3ga–ja, respectively, in moderate
to good yields upon isolation, and with outstanding levels of
chemo-, diastereo-, and enantiocontrol.[13] In particular, it was
pleasing that the dicyano substrate 1 f, embodying a ring with
three enolizable sites (e-, h-, and h’-positions), solely reacted
at the e-site, thus furnishing the adduct 3 fa with complete
regio- and stereocontrol. Variously substituted aromatic,
heteroaromatic, and aliphatic a,b-unsaturated aldehydes,
beyond 2a, participated in this [4+2] coupling, and these
included the o-, m-, and p-substituted aromatic aldehydes 2b–
h, aliphatic 2-pentenal (2i), 4-methyl-2-pentenal (2j), 2,4-
heptadienal (2k), as well as the furanyl derivative 2m
(Table 2). By using either 1a, 1 f, or 1g, a variety of fused
multicyclic carbaldehyde scaffolds were constructed in fairly
good yields and with outstanding levels of diastereo- and
enantioselectivity. As an exception, the b,b-disubstituted 3-
methyl-2-butenal 2l did not provide the desired cyclohexa-
diene 3al, even when forced experimental conditions were
applied.
At the outset of our study we synthesized the cyclo-
hexanone-derived allylidene malononitrile 1a and screened
its capability in a [4+2] cycloaddition with cinnamaldehyde
(2a; Figure 2 and Table 1) under the catalysis of several chiral
Figure 2. Structures of the pro-diene dicyano substrates 1 of this
study.
secondary amines. After extensive optimization studies (see
the Supporting Information for details), it was found that
treatment of 1a and 2a (1.0:1.8 mol ratio) with the l-prolinol
TMS-ether C1[11] (20 mol%) and Et3N (20 mol%) in CH2Cl2
at room temperature gave the expected naphthalene-type
carbaldehyde 3aa[12] in 79% yield, greater than 20:1 d.r., and
greater than 99% ee.
After having optimized reaction conditions for the
eliminative [4+2] cycloaddition, the scope of the method-
ology was evaluated. First, various carbocyclic and hetero-
cyclic allylidene malononitriles with diverse ring features and
The relative and absolute configuration of the products 3
was assigned as shown in Tables 1 and 2 on the basis of a X-ray
crystallographic analysis of the p-bromobenzoate ester 4
derived from 3ga (see Table 1 and Figure S1 in the Supporting
Information).[14,15]
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Table 2: Scope of the direct amine-catalyzed vinylogous asymmetric
[4+2] cycloaddition varying the acceptor component.[a]
Scheme 1. The amine-catalyzed vinylogous [4+2] cycloaddition as
applied to steroid-based allylidene malononitriles.
expansion, although at a slightly lesser extent than the 17a-
methyltestosterone progenitor (see Figure S2).
One-pot reactions based on in situ formation of the
allylidene malononitriles were performed, and involved the
concomitant addition of the donor aldehyde component (11
or 12), 2a, stoichiometric or even substoichiometric malono-
nitrile, as well as the C1/Et3N catalyst system (Scheme 2).
Remarkably, in the presence of 100 mol% of the malononi-
trile activator the reactions performed well [Eqs. (1) and (3)
in Scheme 2], thus giving rise to the expected products 3aa
and 3ga quite efficiently and stereoselectively, almost in line
with the previously disclosed two-step experiments. When
substoichiometric malononitrile was used (20 mol%), the
reaction gave product 3aa in 41% yield [Eq. (5) in Scheme 2]
after a much longer reaction time (19 days), and is indicative
of slow malononitrile recycle. In contrast, control experi-
ments with no malononitrile [Eqs. (2) and (4) in Scheme 2]
gave inferior results, thus testifying to the cardinal role of the
malononitrile handle in the cycloadditive processes.[16]
A plausible mechanistic scenario for these formal [4+2]
eliminative cycloadditions is shown in Figure 3, using sub-
strates 1a and 2a for illustrative purposes. First, interaction of
2a with C1 is likely to form the chiral iminium species I, which
can undergo a bis-vinylogous Michael addition[17] with the
activated nitrile anion II (from remote deprotonation of 1a)
to give the adduct III. A favorable Coulombic interaction
between the nitrile anion within II and the iminium ion I
could be invoked,[18] thus accounting for a stabilized endo-
Diels–Alder-like approach. A second intramolecular Michael
addition can then occur to give the cycloadduct IV, which
liberates the prolinol ether catalyst upon hydrolysis and
eliminates one mole of malononitrile (by retro-Michael
reaction), thus finally delivering 3aa as the sole product.
Overall, the reaction can be viewed as a stepwise domino
process involving a bis-vinylogous Michael/Michael/retro-
Michael organocascade.[19]
[a] For details, see footnotes [a–d] in Table 1. [b] Compound 3ak 14:1 d.r.
[c] The ee values for 3ai, 3aj, and 3ak were determined for the
corresponding thiosemicarbazone derivatives (see the Supporting
Information for details).
To further demonstrate the general applicability of this
[4+2] eliminative cycloaddition in more challenging scenar-
ios, three tetracyclic steroid-based dicyano substrates (5–7),
respectively derived from commercially available 17a-meth-
yltestosterone, 3-keto-4-cholestenone, and estrone, were used
(Scheme 1). By slightly modifying the above optimized
standard reaction conditions (30 mol% catalyst loading,
408C reaction temperature) the reactions with 2a were
productive and clean and returned the expected ring-A or
ring-D-modified steroidal carbaldehydes 8, 9, and 10 as the
sole detectable isomers in excellent yields. Detailed one- and
two-dimensional NMR analyses confirmed the respective
stereo-structures as shown, in line with the previously
disclosed results with naphthalene and phenanthrene deriv-
atives. As expected, changing ent-C1 (R) for C1 (S) produced
trans-configured isomers 8’, 9’, and 10’ with complete reversal
of the catalyst-induced chirality.
Interestingly, the modified methyltestosterone 8 did not
show any cell toxicity and retained biological activity in a cell
proliferation assay. It stimulated human smooth muscle cell
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remotely enolizable alkyl groups. Additional results will be
disclosed in due course.
Keywords: asymmetric catalysis · carbocycles · cycloaddition ·
organocatalysis · synthetic methods
[1] a) Dictionary of Natural Products, Chapmann&Hall, London,
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[2] K. J. Hale, Org. Lett. 2013, 15, 3181.
[3] a) Y. Hayashi in Cycloaddition Reactions in Organic Synthesis
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[4] Comprehensive Enantioselective Organocatalysis, Vol. 1 – 3 (Ed.:
P. I. Dalko), Wiley-VCH, Weinheim, 2013.
[5] For proline-promoted and/or prolinol silyl ether-catalyzed
intermolecular self- and cross-annulations of enals, see: a) B. J.
Bench, C. Liu, C. R. Evett, C. M. H. Watanabe, J. Org. Chem.
2006, 71, 9458; b) B.-C. Hong, M.-F. Wu, H.-C. Tseng, G.-F.
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Med. Chem. 2008, 16, 7573.
Scheme 2. One-pot malononitrile-driven [4+2] annulations on mono-
cyclic and bicyclic aldehydes 11 and 12, respectively, and comparison
to control experiments.
[6] For amine-catalyzed intramolecular annulations of a,b-unsatu-
rated dialdehydes, see: R. M. de Figueiredo, R. Frçhlich, M.
Christmann, Angew. Chem. Int. Ed. 2008, 47, 1450; Angew.
Chem. 2008, 120, 1472.
[7] For prolinol silyl ether catalyzed intermolecular [4+2] cyclo-
additions between a,b-unsaturated aldehydes and ketones
en route to steroid compounds, see: K. S. Halskov, B. S. Don-
slund, S. Barfꢀsser, K. A. Jørgensen, Angew. Chem. Int. Ed.
2014, 53, 4137; Angew. Chem. 2014, 126, 4221.
[8] For an example of intermolecular asymmetric [4+2] cycloaddi-
tion reaction of enones, see: D. Yang, L. Wang, F. Han, D. Zhao,
R. Wang, Chem. Eur. J. 2014, 20, 8584.
[9] For the use of a,a’-dicyanoalkenes and a,a’-dicyanodienes as
vinylogous carbon pronucleophiles, see: a) T.-Y. Liu, H.-L. Cui,
J. Long, B.-J. Li, Y. Wu, L.-S. Ding, Y.-C. Chen, J. Am. Chem.
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2009, 4479; c) L. DellꢁAmico, G. Rassu, V. Zambrano, A. Sartori,
C. Curti, L. Battistini, G. Pelosi, G. Casiraghi, F. Zanardi, J. Am.
Chem. Soc. 2014, 136, 11107.
Figure 3. Proposed reaction mechanism for the formal eliminative
[4+2] cycloaddition of this study.
[10] For examples of eliminative Michael/Michael/retro-Michael
domino reactions, see: a) J.-W. Xie, W. Chen, R. Li, M. Zeng,
W. Du, L. Yue, Y.-C. Chen, Y. Wu, J. Zhu, J.-G. Deng, Angew.
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Jiang, B. Tan, C. F. Barbas III, Angew. Chem. Int. Ed. 2013, 52,
9261; Angew. Chem. 2013, 125, 9431.
In summary, we have developed the chemo-, diastereo-,
and enantioselective [4+2] eliminative cycloaddition of
extended monocyclic and polycyclic allylidene malononitriles
with aromatic and aliphatic enals. The process enables the
formation of linear and angular polycycles embedding a cyclo-
hexadiene carbaldehyde frame with uniformly high levels of
trans-diastereo- and enantioselectivity, even in the case of
complex multicyclic steroidal substrates. The proliferative
activity of one testosterone-based product towards human
smooth muscle cells illustrates the potential of this steroid-
transforming technique in a medicinally relevant context. We
believe that this catalytic, malononitrile-driven asymmetric
strategy may enable further application in structural diversi-
fication of other allylidene carbo- and heterocyles bearing
[11] For key references on the use of diphenylprolinol silyl ether
catalyst, see: a) M. Marigo, T. C. Wabnitz, D. Fielenbach, K. A.
Jørgensen, Angew. Chem. Int. Ed. 2005, 44, 794; Angew. Chem.
2005, 117, 804; b) Y. Hayashi, H. Gotoh, T. Hayashi, M. Shoji,
Angew. Chem. Int. Ed. 2005, 44, 4212; Angew. Chem. 2005, 117,
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Gotoh, S. Tsuzuki, T. Uchimaru, D. Seebach, Chem. Eur. J. 2014,
20, 17077.
[12] While the 13C and 1H NMR spectra of 3aa in our hands are
identical to those reported (Ref. [5b]), the optical rotation is
D
rather different in absolute value (½aꢀ22¼ꢁ936.0 (c = 0.1 in
4
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D
CHCl3, > 99% ee); ½aꢀ22¼ꢁ475.9 (c = 9.0 in CHCl3, 98% ee).[5b]
see for example: V. P. R. Gajulapalli, P. Vinayagam, V. Kesavan,
RCS Adv. 2015, 5, 7370.
Note that the absolute configuration of the product reported in
Ref. [5b] was not assigned.
[13] In few instances (e.g. compounds 3da, 3ea, 3ia), scant degra-
dation and/or epimerization occurred during chromatographic
purification.
[14] CCDC 1047357 (4) contains the supplementary crystallographic
data for this paper. These data can be obtained free of charge
from The Cambridge Crystallographic Data Centre via www.
ccdc.cam.ac.uk/data_request/cif.
[15] The result is consistent with the stereochemical outcome
observed in other reactions in which the catalyst C1 has been
used with a,b-unsaturated aldehydes under iminium ion activa-
tion. See, for example: K. L. Jensen, G. Dickmeiss, H. Jiang, Ł.
Albrecht, K. A. Jørgensen, Acc. Chem. Res. 2012, 45, 248. See
also ref. [11c].
[17] For leading references, see: a) G. Casiraghi, L. Battistini, C.
Curti, G. Rassu, F. Zanardi, Chem. Rev. 2011, 111, 3076; b) C.
Schneider, F. Abels, Org. Biomol. Chem. 2014, 12, 3531.
[18] For similar Coulombic interactions see, for example: L. DellꢁA-
mico, Ł. Albrecht, T. Naicker, P. H. Poulsen, K. A. Jørgensen, J.
Am. Chem. Soc. 2013, 135, 8063.
[19] For selected reviews on organocatalytic domino/cascade reac-
tions, see: a) D. Enders, C. Grondal, M. R. M. Hꢀttl, Angew.
Chem. Int. Ed. 2007, 46, 1570; Angew. Chem. 2007, 119, 1590;
b) C. Grondal, M. Jeanty, D. Enders, Nat. Chem. 2010, 2, 167;
c) H. Pellissier, Chem. Rev. 2013, 113, 442; d) C. M. R. Volla, I.
Atodiresei, M. Rueping, Chem. Rev. 2014, 114, 2390.
Received: February 27, 2015
Revised: March 31, 2015
Published online: && &&, &&&&
[16] For the use of malononitrile as stoichiometric reagent for in situ
activation of acceptor components in multicomponent reactions,
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Communications
Organocatalysis
N. Brindani, G. Rassu,* L. Dell’Amico,
V. Zambrano, L. Pinna, C. Curti, A. Sartori,
L. Battistini, G. Casiraghi, G. Pelosi,
D. Greco, F. Zanardi*
&&&& — &&&&
Organocatalytic, Asymmetric Eliminative
[4+2] Cycloaddition of Allylidene
Malononitriles with Enals: Rapid Entry to
Cyclohexadiene-Embedding Linear and
Angular Polycycles
Without a trace: The covalent activation
of a,b-unsaturated aldehydes with malo-
nonitrile produced remotely enolizable p-
extended allylidene malononitriles. Their
amine-catalyzed eliminative [4+2] cyclo-
addition to aromatic and aliphatic enals
enabled the construction of cyclohexa-
diene-containing polycycles with out-
standing diastereo- and enantioselectiv-
ities. The essential role of the malononi-
trile handle as a traceless activating
moiety was demonstrated.
6
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