Combined heterogeneous metal/chiral amine: Multiple relay catalysis for versatile eco-friendly synthesis

Article abstract of DOI:10.1002/anie.201310216

Herein is described a versatile and broad synergistic strategy for expansion of chemical space and the synthesis of valuable molecules (e.g. carbocycles and heterocycles), with up to three quaternary stereocenters, in a highly enantioselective fashion from simple alcohols (31 examples, 95:5 to >99.5:0.5 e.r.) using integrated heterogeneous metal/chiral amine multiple relay catalysis and air/O₂ as the terminal oxidant. A novel highly 1,4-selective heterogeneous metal/amine co-catalyzed hydrogenation of enals was also added to the relay catalysis sequences. Relay switch: A versatile strategy for expansion of chemical space and the synthesis of valuable molecules, having up to three quaternary stereocenters, in a highly enantioselective fashion from simple alcohols is described. The method employs integrated heterogeneous metal/chiral amine multiple relay catalysis and air/O₂ as the terminal oxidant.

Full text of DOI:10.1002/anie.201310216

Angewandte
Chemie
DOI: 10.1002/anie.201310216
Synthetic Methods
Combined Heterogeneous Metal/Chiral Amine: Multiple Relay
Catalysis for Versatile Eco-Friendly Synthesis**
Luca Deiana, Yan Jiang, Carlos Palo-Nieto, Samson Afewerki, Celia A. Incerti-Pradillos,
Oscar Verho, Cheuk-Wai Tai, Eric V. Johnston,* and Armando Cꢀrdova*
Abstract: Herein is described a versatile and broad synergistic
strategy for expansion of chemical space and the synthesis of
valuable molecules (e.g. carbocycles and heterocycles), with up
to three quaternary stereocenters, in a highly enantioselective
fashion from simple alcohols (31 examples, 95:5 to > 99.5:0.5
e.r.) using integrated heterogeneous metal/chiral amine multi-
ple relay catalysis and air/O2 as the terminal oxidant. A novel
highly 1,4-selective heterogeneous metal/amine co-catalyzed
hydrogenation of enals was also added to the relay catalysis
sequences.
heterogeneous, or biphasic reaction conditions, then such
adversities could be circumvented.[5] The development of
increasingly tolerant and robust catalytic systems would bring
practical laboratory chemistry closer to the platonic ideal of
nature by mediating several transformations in a single
reaction event under green chemistry parameters.[3c,6]
In recent years, the development of asymmetric relay
catalysis (ARC), which combines homogeneous metal and
organic catalysts,[4,7] has attracted considerable attention as
a means to new transformations which cannot be achieved
using the catalysts individually. An important expansion to
this multicatalysis approach would be the inclusion of
heterogeneous catalysis since it would allow reactivity not
possible using homogeneous organometallic catalysts (e.g.
both oxidation and reduction cascade reactions), as well as
simple separation and recycling of the expensive and non-
environmentally friendly transition metals.[5b,c,8] Thus, we
reasoned that merging the powerful paradigms of heteroge-
neous metal catalysis with organocatalysis and applying it in
ARC transformations would produce a carefully designed
chiral molecule of particular stereochemistry after a single
purification in an operationally simple, efficient, and green
manner (Scheme 1). Here the asymmetric construction of
quaternary stereocenters is a challenging task in organic
I
n practice, organic synthesis operates through stepwise
processes where isolation and purification of key intermedi-
ates are often required for success in further transforma-
tions.[1] This process is in contrast to that of nature, where
well-organized multienzymatic systems within cells accom-
plish efficient and selective one-pot tandem catalyzed trans-
formations of simple precursors into complex molecules.[2]
While each discipline of catalysis (i.e., metal catalysis, metal-
free catalysis, and biocatalysis) has its own advantages,
limitations, and range of applications, the combination of
catalytic paradigms to better match biosynthesis are often
limited by compatibility problems such as cross-reactivity or
mutual inactivation.[3,4] If it were possible to compartmen-
talize the catalytic species, such as performing catalysis in
sequential steps or by site-isolation through immobilization,
[*] Dr. L. Deiana, Dr. Y. Jiang, Dr. C. Palo-Nieto, Dr. O. Verho,
Dr. E. V. Johnston, Prof. A. Cꢀrdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
E-mail: eric@organ.su.se
armando.cordova@miun.se
acordova@organ.su.se
Dr. C.-W. Tai
Department of Materials and Environmental Chemistry
The Arrhenius Laboratory, Stockholm University
10691 Stockholm (Sweden)
S. Afewerki, C. A. Incerti-Pradillos, Prof. A. Cꢀrdova
Department of Natural Sciences
Holmgatan 10, 85170 Sundsvall (Sweden)
[**] We gratefully acknowledge financial support from the European
Union, Mid Sweden University, and Swedish National Research
Council. The Berzelii Center EXSELENT is financially supported by
VR and the Swedish Governmental Agency for Innovation Systems
(VINNOVA). The Knut and Alice Wallenberg Foundation is
acknowledged for an equipment grant for the electron microscopy
facilities at Stockholm University.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201310216.
Scheme 1. Combined heterogeneous-transition-metal/chiral amine
relay catalysis.
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synthesis.[9] The foundation of this strategy
lies in the ability of a heterogeneous metal
catalyst to take part in multiple cascade
sequences co-directed by tandem interac-
tions with small chiral amine catalysts and
substrate additives.
Palladium is arguably one of the most
powerful and versatile transition-metal
catalysts which can be immobilized on
various heterogeneous supports and be
used for a variety of organic transforma-
tions.[10] We recently disclosed asymmetric
carbocyclizations implementing a hetero-
geneous palladium catalyst with a simple
chiral amine co-catalyst.[11] The success in
this endeavor prompted us to design the
proposed multicatalysis relay strategy
using a palladium nanocatalyst, where the
initial transformation would be the selec-
tive aerobic oxidation of alcohols to alde-
hydes (Scheme 1; level 1). Next, these
aldehydes could be further transformed
by an organic catalyst into a plethora of
molecules, thus unleashing the full poten-
tial of aminocatalytic transformations
(Scheme 1; level 2).[12] However, such con-
trol of the reaction outcome would require
strict stipulations. Relay transformations
are only possible if the palladium nano-
catalyst does not impede or get inhibited
prior to or during the subsequent reaction.
Furthermore, if the heterogeneous metal
Scheme 2. Examples of co-catalytic relay catalysis at level 2. Boc=tert-butoxycarbonyl,
Cbz=benzyloxycarbonyl, TBS=tert-butyldimethylsilyl, TMS=trimethylsilyl, Ts=4-toluenesul-
fonyl.
catalyst was used in a subsequent synergistic step with the
metal-free catalyst, the relay sequence would be perpetuated
(level 2). The product from this approach could take part in
further relay catalysis sequences as described, thus increasing
the complexity and versatility of the strategy (Scheme 1;
level 3). Thus, as the catalytic relay sequence continues,
a higher level would be reached and importantly the hetero-
geneous metal catalyst could be recycled after the target
molecule is synthesized. Herein we demonstrate a versatile
strategy for the synthesis of valuable molecules (up to three
quaternary stereocenters) through expansion of chemical
space in a highly selective fashion (up to > 99.5:0.5 e.r., 1,4-
specific hydrogenation) from simple alcohols using a combi-
nation of heterogeneous transition-metal and chiral amine
catalysts (Scheme 1).
We began our investigations by designing ARC for the
level 2 as disclosed in Scheme 1, since it in principle should be
possible to apply and implement it for a broad range of
aminocatalytic transformations. Thus, several new ARC
reactions were developed after extensive efforts using the
Pd0-AmP-MCF-catalyzed aerobic oxidation[10e] of alcohols (1)
combined with one-pot cascade transformations using the
chiral amine 4[13] as a catalyst (Scheme 2). For example, the
aziridine 3a[14] and d-amino olefin (E)-6b,[15] which is rapidly
converted into (S)-cocaine in one-pot, were assembled in an
asymmetric fashion in high overall yields and e.r. values
(Scheme 2a,b). The application of parallel aerobic oxidations
in sequence with asymmetric multicomponent transforma-
tions was also investigated. Thus, the chiral pyrrolidine 7a
(19:1 d.r. and 97:3 e.r.),[16] which has a quaternary a-
stereocenter, was synthesized from 1a by an aerobic oxida-
tion/one-pot three-component cycloaddition catalytic relay
using a three-catalyst system (Scheme 2c). The one-pot three-
component ARC synthesis of the advanced key intermediate
8d,[17] which is employed in the total synthesis of several
secologanine tryptamine alkaloids, was also successful
(Scheme 2d). The above results demonstrate that heteroge-
neous-palladium-catalyzed aerobic oxidation of the alcohols
1 can be performed in tandem with a large variety of
aminocatalytic reactions with carbonyl compounds in one pot
without inhibiting the catalytic actions of the amine catalysts.
Next, a catalytic enantioselective aerobic oxidation/Michael/
carbocyclization relay sequence was examined using air/O2 as
the terminal oxidants (Scheme 1; level 2). This cascade trans-
formation starts with the aerobic oxidation of the allylic
alcohol 1 through Pd0-AmP-MCF catalysis and is followed by
the Pd/4-co-catalyzed dynamic carbocyclization transforma-
tion between the in situ generated enal 2 and either the
propargylic cyanoacetate 9a, propargyl isoindolinone 9b, or
propargyl alcohol 9c (Scheme 3). The multicatalytic ARC
sequences were highly enantioselective, thus providing the
corresponding cyclopentenes 10[18] and spirocyclic oxindoles
11,[19] each bearing a quaternary stereocenter, as well as the
chiral dihydrofurans 12[20] in high yields and e.r. values
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Scheme 4. Examples of combined transition-metal/chiral amine relay
catalysis (level 3).
Scheme 3. Co-catalytic enantioselective aerobic oxidation/Michael/car-
bocyclization relay sequence (level 2). [a] Benzoic acid (20 mol%) was
added. [b] Air, p-xylene.
complexity and construction of vicinal quaternary sterocen-
ters by extending the relay protocol to level 3. A novel
aerobic oxidation/Michael/carbocyclization/azirdination cat-
alytic relay sequence was developed (Scheme 4a). Notably,
we found that to obtain the desired polysubstituted chiral
azirdines 13 (up to 97:3 d.r. and > 98.5:1.5 e.r.), bearing three
quaternary stereocenters, ent-4 had to be added as a co-
catalyst. If only the chiral amine 4 was used as the co-catalyst,
the ARC sequence stopped exclusively at the formation of the
cyclopentene 10a. Thus, in the last step of this ARC trans-
formation 4 was racemic, however, only ent-4 was catalytically
active.
(95.5:4.5–99.5:0.5 e.r.). The transformation also exhibited
a broad scope in that the allylic alcohols 1 with both electron-
rich, electron-deficient, aliphatic, and heteroaromatic sub-
stituents were tolerated as starting materials. In comparison,
the same relay sequence using homogeneous [Pd(PPh3)4] as
the co-catalyst is narrower in substrate scope and less
efficient.[21]
After probing level 2 of the combined heterogeneous
metal/chiral amine ARC concept (Scheme 1), we embarked
on the possibility of reaching a higher degree of molecular
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An interesting aspect of utilizing a versatile heteroge-
neous nanocatalyst based on palladium is that it can be used
both for aerobic oxidation and hydrogenation reactions. In
this context, we envisioned an aerobic oxidation/Michael/
carbocyclization/reduction cascade using molecular oxygen as
the green oxidant for the first step, and molecular hydrogen as
the reducing agent for the last step of the catalytic relay
sequence (Scheme 4b). Notably, this would be the first
example with simple H2 instead of the Hantzsch pyridine
ester for use in amine-catalyzed stereoselective hydrogena-
tions of enals.[22] The development of this one-pot ARC
transformation was successful and the hydrogenation was 1,4-
regiospecific and highly enantioselective, thus exclusively the
providing polysubstituted cyclopentanes 14, which contain
a quaternary all-carbon stereocenter, from enals 1 in good
yields and with up to greater than 99.5:0.5 e.r. Subsequent
reduction of 14 with NaBH4 and NaCNBH3 provided the
cyclopentanes 15 and 16a, respectively. The catalytic cascade
relay sequence was also successful for the synthesis of the
spirocyclic oxoindoles 17 (up to > 99.5:0.5 e.r.), having
a quaternary stereocenter, and subsequent reduction gave
the corresponding alcohol 18b in high yields (92% yield,
Scheme 4c). Notably, the synergistic heterogeneous metal/
chiral amine co-catalysis both accelerated the hydrogenation
of the enal with hydrogen gas, as well as slightly improved the
e.r. values of 14 (up to > 99.5:0.5) and 17 (up to > 99.5:0.5) as
compared to their intermediates 10 and 11, respectively. In
fact, the hydrogenation of 10m without the chiral amine 4
present gave trace amounts of the product 15m after 72 h.
Crucial to the practical value of this multicatalytic sequence is
the ability to reuse the heterogeneous catalyst over multiple
cycles, in order to justify its use over homogeneous counter-
parts. Thus, we investigated the possibility of recycling the
palladium nanocatalyst after level 2 and level 3 (see the
Supporting Information). Both relay sequences displayed
excellent recyclability in terms of yield and stereoselectivity.
It is noteworthy that no leaching of the metal catalyst was
observed.
In summary, we have developed a unique concept for the
synthesis of small organic molecules of varying complexity,
and it is based on combined heterogeneous transition-metal/
chiral amine relay catalysis. Starting from simple alcohols,
valuable molecules are assembled with high chemo-, regio-,
diastereo-, and enantioselectivity by catalytic multiple relay
sequences without the need for toxic oxidants and numerous
purification steps. Thus, the eco-friendly concept presented
includes advantages such as the significant reduction of
solvents needed for chromatography, use of molecular
oxygen/air as the oxidant, hydrogen gas for 1,4-selective
hydrogenations, and recyclability of the heterogeneous tran-
sition-metal catalyst. Notably, the disclosed model is not only
possible to apply as a direct entry to today’s know-how in
chiral amine catalysis or combined homogeneous transition-
metal/amine catalysis with carbonyl compounds, but as
demonstrated here, allows the creation of novel transforma-
tions.
Keywords: alcohols · heterogeneous catalysis ·
homogeneous catalysis · hydrogenation · oxidation
.
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