Highly enantioselective organocascade intermolecular iminium/enamine Michael addition on enals

Article abstract of DOI:10.1039/c1cc11967b

An unprecedented intermolecular iminium/enamine Michael addition on enals has been developed by taking advantage of the high reactivity of vinyl sulfones. This powerful organocascade allows for the rapid construction of attractive synthons in high enantioselectivities (typically 99% ee).

Full text of DOI:10.1039/c1cc11967b

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COMMUNICATION
Highly enantioselective organocascade intermolecular iminium/enamine
Michael addition on enalsw
Adrien Quintard and Alexandre Alexakis*
Received 7th April 2011, Accepted 27th April 2011
DOI: 10.1039/c1cc11967b
An unprecedented intermolecular iminium/enamine Michael
addition on enals has been developed by taking advantage of
the high reactivity of vinyl sulfones. This powerful organocascade
allows for the rapid construction of attractive synthons in high
enantioselectivities (typically 99% ee).
Multicomponent catalytic cascade reactions such as organo-
cascades, mimicking the efficiency of biocatalytic processes,
have recently appeared as methods of choice for the rapid
construction of complex molecular structures.1 These reactions
are highly attractive given the industrial requirements for
environmentally friendly reactions limiting the overall waste
and time consuming operations. Among these multicomponent
processes, aminocatalysis, unique because of its ability to
promote multiple activation modes using a single catalyst,
has come out to be a method of choice as soon as carbonyl
groups are involved.2 Notably, the combination of iminium/
Scheme 1 Hypothesis and limiting issues for the development of an
iminium/enamine Michael addition through an olefin.
enamine catalysis on enals affords acyclic a,b-chiral aldehydes
that are essential building blocks for natural products synthesis.
problematic aspect: the iminium addition adduct should react
faster with the electrophile before a possible retro-Michael
addition (the entering iminium nucleophile acting as a leaving
group); retro-addition that would considerably reduce the
overall selectivity/efficiency of the process. Given the usual
low reactivity of most Michael acceptors in enamine catalysis,
this reversibility of the iminium step seems detrimental for the
development of the proposed process. Other crucial point:
Michael acceptors should selectively react with the intermediate
aldehyde and not with the starting enal by dienamine catalysis
or with the iminium nucleophile. Consequently, the control of
the kinetics of the different pathways is the key for the
development of the expected cascade reactions.
In our ongoing research for the rapid construction of such
challenging molecules, we were surprised by the lack of general
approach for the generation of acyclic a,b-chiral aldehydes
containing an alkyl group in the a-position.3 Indeed, even
though many organocascade iminium/enamine processes are
able to perform an enamine C–C bond trapping in an intra-
molecular way, most of the corresponding acyclic methods
only afford C-heteroatom bond formation.1,4
The lack of organocascade process creating this essential
backbone by C–C bond forming reactions arises from several
critical issues associated with the reactivity of most carbon
bond forming electrophiles notably Michael acceptors. This
challenging reaction was unsolved until now due to all the
inherent problems of aminocatalyzed Michael additions
depicted in Scheme 1.5
Finally, we recently disclosed the important observation that if
two sterically different groups are present in the b-position
of an aldehyde there were conflicting interactions between the
incoming Michael acceptor, the substrate and the catalyst leading
to decrease in both reactivity and enantioselectivities (substrate
vs. catalyst control).6 This particular behaviour could render such
reaction, where bulky groups are entered in the b-position, even
harder to perform and to control.
To obtain
a powerful nucleophile—carbon addition
through an olefin via iminium–enamine organocascade, one
must first solve the compatibility issues between both steps
(solvent, co-catalyst, reactant, turnover. . .). Probably the most
Department of Organic Chemistry, University of Geneva,
Quai Ernest Ansermet, 30, 1211, Geneva 4, Switzerland.
E-mail: alexandre.alexakis@unige.ch; Tel: +41 (0)22 379 65 22
w Electronic supplementary information (ESI) available: Full experi-
mental details. See DOI: 10.1039/c1cc11967b
Vinyl sulfones introduced recently in our group for enamine
catalysis present several interesting key features.7 Compared
to most Michael acceptors, they appear to be highly reactive in
many different conditions (1–2 hour reactions) using only a
c
7212 Chem. Commun., 2011, 47, 7212–7214
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the fact that reduced temperature disfavours the kinetic
differences between productive and unproductive pathways.
To fully explore this remarkable transformation, we
continued investigating the scope by testing the hydroxy-
alkylation to a small family of enals (Table 1). Different linear
chains from methyl to C7H15 could be used in this process
without any influence on the overall selectivity of the reaction
(58–61% yield, 9 : 1 to 11,5 : 1 dr, 99% ee). When increasing
the steric requirement of the R functionality with an iPr, a
dramatic loss in reactivity was observed leading to an inseparable
mixture of products while cinnamaldehyde did not react at all.
Despite the creation of 1,3 diols, we screened a variety of
diverse nucleophiles that would render this approach even
more attractive. As a general trend the organocascade tolerated a
wide variety of heteroatoms or carbon nucleophiles. These
nucleophiles can be divided into three groups. First of all,
triazole 5 and Angelica lactone 7 did react in the APY
catalyzed process leading efficiently to the cascade product
in perfect enantioselectivities (98–99% ee, Scheme 3).10
Remarkably, the product of addition of Angelica lactone
containing three contiguous stereocenters one being tetra
substituted was obtained almost as a single diastereoisomer
(eqn (2)).
Scheme 2 Catalysts screening for the hydro-alkylation of enals.
slight excess of aldehyde (1.1 eq). In addition, this sulfonyl
group can easily be used as a formal alkyl chain in further
transformations rendering it highly useful for its future
application in total synthesis or in Diversity Oriented Synthesis.8
We thus postulated that the exceptional reactivity of bis-vinyl
sulfone 1 would allow us to overcome the problem associated
with other Michael acceptors. The transient aldehyde should
react irreversibly and rapidly under kinetic control with the
sulfone avoiding any detrimental epimerization. Herein we
describe an unprecedented organocascade intermolecular
iminium/enamine Michael addition through an olefin leading
to the synthesis of highly attractive synthons for further
synthetic applications.
The second class of nucleophiles consists of thiol and
nitrogen nucleophiles that failed to react using APY
(Scheme 4).11 Indeed, under these conditions, the only product
observed was the one arising from the addition of the iminium
nucleophile to the vinyl sulfone. This indicates that APY does
not catalyze the required iminium reaction. Fortunately,
turning to diphenyl prolinol silyl ether 5a and adding the
electrophile after a short iminium reaction time, the efficiency
To validate our hypothesis we first focused our attention on
the hydro-alkylation of pentenal 2a using benzaldoxime 3 as
nucleophile (Scheme 2).9 This reaction would lead to highly
attractive chiral 1,3 diols. Gratifyingly, performing the domino
reaction (all the reactant/catalyst added all at once), the
expected cascade product was obtained in moderate to good
yields depending on the catalyst (MacMillan imidazolidinone
was the only catalyst inefficient here). The best result was
obtained using only 10 mol% of aminal pyrrolidine (APY)
with a good 61% yield together with good stereoselectivities
(9/1 dr, 99% ee).7c,7h This demonstrates the high potential of
APY for organocascade reactions where both iminium and
enamine catalysis are involved. The observed high yield,
perfect enantioselectivity and short reaction time confirm
our initial hypothesis of global reaction rate acceleration by
the entering electrophile. Decreasing the temperature to 0 1C
slightly reduced the yield (52% yield) while not increasing the
stereoselectivities (result not shown). This is probably due to
Scheme 3 Organocascade triazole-alkylation and double alkylation
Table 1 Scope of the hydro-alkylation of enals
of enals.
Entry
R
Yielda (%)
dr (anti/syn)b
eec (%)
1
2
3
4
Me
Et
nC7H15
iPr
4b : 58
4a : 61
4c : 58
4d : 30d
9/1
9/1
11,5/1
nd
99
99
99
nd
a
b
Yield of the isolated product. Determined by 1H NMR analysis on
c
the crude material. Determined by chiral Supercritical Fluid
d
Chromatography for the major diastereoisomer. NMR yield
1
determined by H NMR.
Scheme 4 Organocascade sulfa-alkylation and amino-alkylation.
Chem. Commun., 2011, 47, 7212–7214 7213
c
This journal is The Royal Society of Chemistry 2011

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2011, 47, 3828; (c) S.-K. Xiang, B. Zhang, L.-H. Zhang, Y. Cui and
N. Jiao, Chem. Commun., 2011, 47, 5007.
4 Intermolecular iminium/enamine cascade reactions on enals:
(a) Y. Huang, A. M. Walji, C. H. Larsen and D. W. C. MacMillan,
J. Am. Chem. Soc., 2005, 127, 15051; (b) M. Marigo, T. Schulte,
J. Franzen and K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 15710;
(c) J. Yang, W. M. T. Hechavarria Fonseca and B. List, J. Am. Chem.
Soc., 2005, 127, 15036; (d) H. Jiang, J. B. Nielsen, M. Nielsen and
K. A. Jørgensen, Chem.–Eur. J., 2007, 13, 9068; (e) P. Galzerano,
F. Pesciaioli, A. Mazzanti, G. Bartoli and P. Melchiorre, Angew.
Chem., Int. Ed., 2009, 48, 7892; (f) B. Simmons, A. M. Walji and
D. W. C. MacMillan, Angew. Chem., Int. Ed., 2009, 48, 4349;
(g) C. Appayee and S. E. Brenner-Moyer, Org. Lett., 2010, 12, 3356.
5 Selected reviews on aminocatalyzed 1,4 addition: (a) S. Sulzer-Mosse
and A. Alexakis, Chem. Commun., 2007, 3123; (b) D. Almasi,
D. A. Alonso and C. Najera, Tetrahedron: Asymmetry, 2007, 18,
299; (c) S. B. Tsogoeva, Eur. J. Org. Chem., 2007, 1701; (d) D.
Roca-Lopez, D. Sadaba, I. Delso, R. P. Herrera, T. Tejero and
P. Merino, Tetrahedron: Asymmetry, 2010, 21, 2561.
Scheme 5 Class 3 nucleophiles: no organocascade.
of the organocascade was recovered. Good to excellent
enantioselectivities (95–99% ee) were obtained in this process
giving rise to highly valuable synthons such as 12e, a 1,3 amino
alcohol that should be applied as a precursor of indolizidine.12
Finally, several carbon nucleophiles failed to give organo-
cascade products and are classified in class 3 (Scheme 5).13
They all have the same particularity of giving slow conversion
in the iminium catalysis. This can explain the bad results
observed in organocascade. Indeed, if the iminium reaction
is rather slow, it is possible that the retro-Michael occurs faster
than the electrophilic trapping. This reduces the amount of
enamine present in the mixture and increases potential side
reactions. Furthermore, increasing the steric hindrance notably
with compounds 13a–13e probably slows down the enamine
reaction.
6 A. Quintard, A. Alexakis and C. Mazet, Angew. Chem., Int. Ed.,
2011, 50, 2354.
7 (a) S. Mosse and A. Alexakis, Org. Lett., 2005, 7, 4361; (b) Q. Zhu
and Y. Lu, Org. Lett., 2008, 10, 4803; (c) A. Quintard,
C. Bournaud and A. Alexakis, Chem.–Eur. J., 2008, 14, 7504;
(d) Q. Zhu, L. Cheng and Y. Lu, Chem. Commun., 2008, 6315;
(e) A. Landa, M. Maestro, C. Masdeu, A. Puente, S. Vera,
M. Oiarbide and C. Palomo, Chem.–Eur. J., 2009, 15, 1562;
(f) A. Quintard and A. Alexakis, Chem.–Eur. J., 2009, 15, 11109;
(g) S. Sulzer-Mosse, A. Alexakis, J. Mareda, G. Bollot,
G. Bernardinelli and Y. Filinchuk, Chem.–Eur. J., 2009, 15,
3204; (h) A. Quintard, S. Belot, E. Marchal and A. Alexakis,
Eur. J. Org. Chem., 2010, 927; (i) A. Quintard and A. Alexakis,
Chem. Commun., 2010, 46, 4085; (j) Q. Zhu and Y. Lu, Chem.
Commun., 2010, 46, 2235; (k) A. Quintard and A. Alexakis, Adv.
Synth. Catal., 2010, 352, 1856; (l) C. Bournaud, E. Marchal,
A. Quintard, S. Sulzer-Mosse and A. Alexakis, Tetrahedron:
Asymmetry, 2010, 21, 1666; (m) J. Xiao, Y.-L. Liu and
T.-P. Loh, Synlett, 2010, 2029; (n) P. J. Chua, B. Tan, L. Yang,
X. Zeng, D. Zhu and G. Zhong, Chem. Commun., 2010, 46, 7611;
(o) S. A. Moteki, S. Xu, S. Arimitsu and K. Maruoka, J. Am.
Chem. Soc., 2010, 132, 17074; (p) A. Quintard and A. Alexakis,
Org. Biomol. Chem., 2011, 9, 1407; (q) J. Xiao, Y.-P. Lu, Y.-L. Liu,
P.-S. Wong and T.-P. Loh, Org. Lett., 2011, 13, 876.
8 Recent reviews on the use of sulfones in organocatalysis:
(a) M. Nielsen, C. B. Jacobsen, N. Holub, M. W. Paixao and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2010, 49, 2668;
(b) Q. Zhu and Y. Lu, Aust. J. Chem., 2009, 62, 951; (c) A.-N. R.
Alba, X. Companyo and R. Rios, Chem. Soc. Rev., 2010, 39, 2018.
9 (a) S. Bertelsen, P. Diner, R. L. Johansen and K. A. Jørgensen,
J. Am. Chem. Soc., 2007, 129, 1536; (b) N. R. Andersen,
S. G. Hansen, S. Bertelsen and K. A. Jørgensen, Adv. Synth.
Catal., 2009, 351, 3193.
This hypothesis of fast retro-Michael compared to electro-
philic trapping was confirmed when performing a two-pot
reaction with compounds 13b–13d. Even though the electro-
phile was added after isolation of the transient aldehyde, an
unidentified mixture of compounds was obtained, probably
arising from initial retro-iminium and subsequent product
decompositions. The importance of the kinetic stability of
the transient iminium adduct was further confirmed when
performing the enamine trapping with racemic iminium
adducts derived from Angelica lactone where a resolution of
the aldehyde was observed.14
In conclusion we have developed an unprecedented inter-
molecular iminium/enamine Michael addition on enals taking
advantage of the high reactivity of vinyl sulfones. This powerful
organocascade allows for the rapid construction of highly
attractive synthons in high enantioselectivities (typically
99% ee). The described study has allowed for a clear under-
standing of both reactivity and selectivity issues. We are
convinced that it will find further applications in total synthesis
and in the development of other organocascade reactions.
Notes and references
10 For the iminium catalyzed addition of triazole: (a) P. Diner,
M. Nielsen, M. Marigo and K. A. Jørgensen, Angew. Chem., Int.
Ed., 2007, 46, 1983; For the iminium catalyzed addition of
Angelica lactone: (b) A. Quintard, A. Lefranc and A. Alexakis,
Org. Lett., 2011, 13, 1540.
1 For selected review on organocascade reactions see:
(a) A. M. Walji and D. W. C. MacMillan, Synlett, 2007, 1477;
(b) D. Enders, C. Grondal and M. R. M. Huttl, Angew. Chem., Int.
Ed., 2007, 46, 1570; (c) G. Guillena, D. J. Ramon and M. Yus,
Tetrahedron: Asymmetry, 2007, 18, 693; (d) C. Grondal, M. Jeanty
and D. Enders, Nat. Chem., 2010, 2, 167.
2 Selected reviews on aminocatalysis: (a) S. Bertelsen and
K. A. Jørgensen, Chem. Soc. Rev., 2009, 38, 2178; (b) D. W. C.
MacMillan, Nature, 2008, 455, 304; (c) P. Melchiorre, M. Marigo,
A. Carlone and G. Bartoli, Angew. Chem., Int. Ed., 2008, 47, 6138;
(d) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH,
Weinheim, 2007; (e) A. Erkkilae, I. Majander and P. M. Pihko,
Chem. Rev., 2007, 107, 5416.
11 For the iminium catalyzed addition of thiol: ref. 4(b); for the
iminium catalyzed addition of 11: (a) Y. K. Chen, M. Yoshida and
D. W. C. MacMillan, J. Am. Chem. Soc., 2006, 128, 9328.
12 X. Pu and D. Ma, J. Org. Chem., 2003, 68, 4400.
13 For pioneering iminium addition of 13a: (a) A. Landa, A. Puente,
J. I. Santos, S. Vera, M. Oiarbide and C. Palomo, Chem.–Eur. J.,
2009, 15, 11954; 13b: (b) J. L. Garcia Ruano, V. Marcos and
J. Aleman, Chem. Commun., 2009, 4435; (c) A.-N. Alba,
X. Companyo, A. Moyano and R. Rios, Chem.–Eur. J., 2009,
15, 11095; 13e: (d) J. F. Austin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2002, 124, 1172; 13f: (e) N. Halland, R. G. Hazell and
K. A. Jørgensen, J. Org. Chem., 2002, 67, 8331. The addition of 13c
and 13d was precedently unreported in the literature.
3 For recently appeared examples without incorporation of hetero-
atoms (without potential leaving groups) see: (a) Y. Chi,
S. T. Scroggins and J. M. J. Frechet, J. Am. Chem. Soc., 2008,
130, 6322; (b) M. Rueping, K. L. Haack, W. Ieawsuwan,
H. Sunden, M. Blanco and F. R. Schoepke, Chem. Commun.,
14 See ESIw for details.
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7214 Chem. Commun., 2011, 47, 7212–7214
This journal is The Royal Society of Chemistry 2011