Dynamic kinetic asymmetrie iransformation (DYKAT) by combined amine- And transition-metal-catalyzed enantioselective cvcloisomerization

Article abstract of DOI:10.1002/chem.200902818

The first examples of one-pot highly chemo- and enantioselective dynamic kinetic asymmetric transformations (DYKATs) involving ot,ss-unsaturated aldehydes and propargylated carbon acids are presented. These DYKATs, which proceed by a combination of catalytic iminium activation, enamine activation, and Pd-catalyzed enyne cycloisomerization, give access to functionalized cyclopentenes with up to 99% ee and can be used for the generation of all-carbon quaternary stereocenters.

Full text of DOI:10.1002/chem.200902818

FULL PAPER
DOI: 10.1002/chem.200902818
Dynamic Kinetic Asymmetric Transformation (DYKAT) by Combined
Amine- and Transition-Metal-Catalyzed Enantioselective Cycloisomerization
Gui-Ling Zhao,[a] Farman Ullah,[a] Luca Deiana,[a] Shuangzheng Lin,[a] Qiong Zhang,[c]
Junliang Sun,[b] Ismail Ibrahem,[a] Pawel Dziedzic,[a] and Armando Cꢀrdova*[a]
Abstract: The first examples of one-pot highly chemo- and enantioselective dy-
namic kinetic asymmetric transformations (DYKATs) involving a,b-unsaturated
aldehydes and propargylated carbon acids are presented. These DYKATs, which
proceed by a combination of catalytic iminium activation, enamine activation, and
Pd0-catalyzed enyne cycloisomerization, give access to functionalized cyclopen-
tenes with up to 99% ee and can be used for the generation of all-carbon quater-
nary stereocenters.
Keywords: asymmetric synthesis ·
cyclopentenes
· dynamic kinetic
transformation · organocatalysis ·
transition-metal catalysis
Introduction
In this context, the development of asymmetric dual cata-
lytic systems for cascade reactions is even more challenging.
Dual applications of metal-based and metal-free catalysis in
dynamic kinetic transformation (DYKAT) processes are
very few.[5] A DYKAT process overcomes the disadvantage
of the maximum 50% theoretical yield obtainable from a ki-
netic resolution. One example is the combination of metal-
and enzyme-based catalysis used by Bꢀckvall and co-work-
ers, which proceeds through de-epimerization of diastereo-
isomers (type III).[5a–b] To the best of our knowledge, no ex-
ample of dual metal-based catalysis and organocatalysis in-
volving epimerization of diastereoisomers through (reversi-
ble) destruction of both centers to yield two achiral inter-
mediates (type IV) has yet been reported.[5a,c,d] The
development of organocatalytic asymmetric one-pot cascade
and domino reactions based on (single or multiple) amine-
based organocatalysts is a rapidly growing research area.[6]
The key activation modes are: i) enamine activation[7] of car-
bonyl compounds, and ii) iminium activation[8] of a,b-unsatu-
rated carbonyl compounds. The combination of these activa-
tion modes has produced impressive results, with the forma-
tion of complex molecules from simple starting materials.
In parallel, the field of transition-metal-catalyzed cascade
sequences is continuing to grow and develop. One area in
particular is that of cascade reactions involving alkyne func-
tionality, in which transition metal ions are employed to pro-
vide the necessary activation to trigger the process.[9]
Cascade and domino reactions that involve the formation of
multiple carbon-carbon or carbon-heteroatom bonds in one-
pot fashion can be synthetically useful and allow the synthe-
sis of small molecules with complex molecular scaffolds.[1]
The advantages of domino reactions include important fac-
tors such as atom economy,[2] reduction of synthetic steps,
and minimization of solvents and waste.[3] Whereas several
elegant cascade sequences catalyzed by single chemical enti-
ties have been described,[1] far fewer reports on the use of
combinations of more than one compatible catalyst for reac-
tion sequences exist.[4]
[a] Dr. G.-L. Zhao, Dr. F. Ullah, L. Deiana, Dr. S. Lin, Dr. I. Ibrahem,
P. Dziedzic, Prof. Dr. A. Cꢁrdova
Department of Organic Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: acordova@organ.su.se
[b] Prof. Dr. J. Sun
Department of Structural Chemistry, The Arrhenius Laboratory
Stockholm University, 106 91 Stockholm (Sweden)
and Berzelii Center EXSELENT on Porous Materials
The Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
[c] Q. Zhang
Department of Theoretical Chemistry School of Biotechnology
Royal Institute of Technology, Roslagstullsbacken 15
10691 Stockholm (Sweden)
In 2006, we successfully developed a merged catalytic
dual system based on enamine activation and Pd0 catalysis
for the direct a-allylation of ketones and aldehydes.[10] In
the same research area,[11,12] Kirsch recently showed that en-
Supporting information for this article is available on the WWW
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amine activation of ketones could be combined with gold
catalysis to give racemic cyclopentenes.[11d] At almost the
same time, Dixon reported elegant cascade reactions be-
tween a,b-unsaturated ketones and propargylated carbon
acids based on a combination of achiral amine and cop-
per(I) catalysis.[11e] As a result of our research experience in
dual-catalysis and DYKATs, we became interested in the
challenging strategy of developing a process, based on a
combination of amine catalysis and transition metal catalysis
(Scheme 1), for highly enantioselective DYKATs between
a,b-unsaturated aldehydes and activated carbonyl com-
pounds such as propargylated carbon acids for the construc-
tion of complex stereodefined small molecules.
generate electrophilic species and allow for subsequent ste-
reoselective intramolecular cycloisomerization with the
chiral enamine intermediates IIa or IVa. If the rate of the
non-reversible oxidative cycloaddition were faster in the
case of IIa than in that of IVa, cycle 1 would be faster than
cycle 2 and the optically active cyclopentene derivatives 4
would be formed after protonolysis, subsequent hydrolysis
of the iminium intermediates III, and double bond isomeri-
zation. This would also regenerate the metal and amine cat-
alysts, so that the DYKAT could proceed.
Results and Discussion
À
The reaction design would enable multiple C C bond for-
mation by first allowing in situ generation of the catalytic
iminium intermediates I, derived from enals 2. These would
undergo nucleophilic conjugate attack by the alkyne-teth-
ered nucleophiles 1, followed by generation of chiral enam-
ine intermediates II (Scheme 1, cycle 1) or IV (cycle 2). No-
tably, this conjugate step is reversible and the corresponding
Michael adducts 3 and ent-3 are formed in equal amounts
(0% ee). Indeed, the chiral amine 5 catalyzed the metal-free
Michael reactions between nucleophiles 1 and enals 2 with
no enantioselectivity to form products 3 with 0% ee in
CH3CN at room temperature.[13] Next, catalytic activation of
the alkynyl functional groups by a metal complex would
Here we describe the first highly enantioselective dynamic
kinetic asymmetric transformations (DYKATs) based on a
one-pot combination of catalytic iminium activation, enam-
ine activation, and Pd0-catalyzed enyne cycloisomerization.
We initially treated dimethyl propargylmalonate (1a,
0.375 mmol) and cinnamaldehyde (2a, 0.25 mmol) in the
presence of a catalytic amount of [PdACHTNUTRGNE(UNG PPh3)4] (5 mol%) and
of chiral pyrrolidines (20 mol%) in MeOH or CH3CN
(0.6 mL) at room temperature (Table 1). To our delight, we
found that protected diarylprolinol derivatives such as 5[14]
catalyzed the reaction with excellent chemoselectivity and
high enantioselectivity to form the corresponding cyclopen-
Scheme 1. Combined transition-metal- and amine-catalyzed DYKAT.
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Dynamic Kinetic Asymmetric Transformation
FULL PAPER
Table 1. Combined palladium- and chiral amine-catalyzed asymmetric DYKAT.[a]
catalytic system of Pd0[15] and
pyrrolidine 5 was further opti-
mized in various solvents (en-
tries 8–12). The yields were im-
proved when the cascade reac-
tion was run in CHCl3,
ClCH2CH2Cl, or CH3CN (en-
tries 9, 11, and 12); compound
4a was isolated in 48% yield
(80% based on recovered 2a)
with 98% ee in CH3CN, for ex-
ample (entry 12). Running the
reaction at higher concentra-
tion increased the rate and
yield but slightly decreased the
enantioselectivity of the reac-
tion, with 4a being obtained
with 91% ee (entry 13). En-
couraged by these initial re-
sults, we decided to investigate
Entry
Metal salt
[Pd(PPh3)4]
AgOTf+PPh3
AgOTf+PPh3
Solvent
t [h]
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
G
MeOH
MeOH
MeOH
MeOH
MeOH
MeOH
CHCl3
46
22
94
120
192
16
<5
11
n.d.
82
[Au
[Cu(OTf)2]+PPh3
[Au(PPh3)Cl]+[Pd
[(PPh3)AuSbF6]
A
22[d]
–
0 g]
–
E
192
48
N
(PPh3)4]
–
–
26
45
29
42
–
–
96
94
97
98
98
U
48[h]
136
88
[Pd
[Pd
[Pd
[Pd
[Pd
[Pd
N
EtOH
CHCl3
9
combined
transition-metal-
10
11
12
13
14
15
16
17
CH2Cl2
ClCH2CH2Cl
CH3CN
CH3CN
CH3CN
CH3CN[i]
CH3CN
CH3CN
64
88
40
24
and amine-catalyzed DYKATs
for a set of simple enals 2
(Table 2).
The reactions proceeded
smoothly, giving the corre-
sponding cyclopentenes 4a–k
in moderate to high yields with
48 (80)[e]
53[f]
23[d]
0[i]
91[f]
0[g]
0[i]
<5[j]
92[k]
none
24
[Pd
[Pd
[Pd
(PPh3)4]
(PPh3)4]
(PPh3)4]
66[i]
72[j]
88[k]
N
26[j]
22[k]
ACHTUNGTRENNUNG
[a] Experimental conditions: a mixture of 1a (0.75 mmol) and PdACTHUNRTGNEUNG(PPh3)4 (5 mol%) in solvent (1.2 mL) was
stirred for 5 min. Next, aldehyde 2a (0.5 mmol) and amine 5 (20 mol%) were added and the reaction mixture
was stirred at room temperature for the time shown in the table. [b] Isolated yield of the corresponding alde-
hyde 4a after silica gel column chromatography. [c] Determined by chiral-phase HPLC analysis. [d] The Mi-
chael product 3a was formed. [e] Yield based on recovered starting material. [f] Reaction volume was 0.3 mL.
[g] The ee of Michael product 3a. [h] Reaction run at 708C. [i] Reaction run with chiral amine 5a. [j] Reaction
run with chiral amine 5b. [k] Reaction run with chiral amine 5c.
excellent
chemoselectivities
and high enantioselectivities
(93–99% ee). In some cases,
the starting material 1 was dif-
ficult to separate from the
product 4, and so these cyclo-
pentenes were chemoselective-
tene 4a as the only product together with remaining alde-
hyde 2a (Table 1).
ly reduced with NaBH4 in situ to afford the corresponding
alcohols 6 [Eq. (1)]. The opposite enantiomers were readily
assembled by employing ent-5 as the catalyst.
Other metal salts were also investigated and we found
that AgI was able to co-cata-
lyze the reaction together with
5 with high chemo- and enan-
tioselectivity (entries 2 and 3).
However, the reaction was
slower than those with Pd0 as
the co-catalyst and the corre-
sponding product was isolated
in low yield and with 82% ee
(entry 3). With Cu and Au salts as co-catalysts the reactions
did not afford 4a as a product under our reaction conditions
(entries 4–7). In the case in which AuACTHNUTRGENUG(N PPh)3Cl was em-
ployed as the co-catalyst, the corresponding Michael prod-
uct 3a was formed with 0% ee (entry 4). No products were
formed in the cases of entries 5 and 6, however, which is
possibly due to inhibition of the catalytic iminium species by
the metal complex. Indeed, the Michael product 3a was
formed with 0% ee even if the metal complex was not
added (entry 14). On the basis of on these findings, the co-
The development of methods for the formation of all-
carbon quaternary stereocenters is an important and diffi-
cult task in organic synthesis.[16] Notably, the combined
metal-catalyzed and organocatalyzed DYKAT was employed
for the formation of cyclopentenes 4 containing all-carbon
quaternary stereocenters (Table 3). The reactions between
1b and enals 2 thus gave the corresponding cyclopentenes
4l–o with good to excellent diastereoselectivities and high
enantioselectivities (entries 1–4). The relative stereochemis-
try of 4m was established by NOE experiments, which con-
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A. Cꢁrdova et al.
Table 2. Combined palladium- and amine-catalyzed DYKAT of enals 2.[a]
with an all-carbon quaternary
stereocenter as a single diaste-
reoisomer. We also performed
X-ray analysis of the oxime
9e[17] and assigned the absolute
configuration of acid 7i as R
with the aid of TD-DFT calcu-
lations of the electronic circu-
lar dichroism (ECD) spectra.[18]
The absolute configuration was
also established by X-ray anal-
ysis of acid 8e.[17] From this, we
propose the following mecha-
nism for the reaction pathway.
Two potential catalytic cycles
can thus operate in the reac-
tions between nucleophiles 1
and enals 2 (Scheme 1). In the
faster cycle, the major enantio-
Entry
1
R
R1
t [h]
Prod.
Yield [%][b]
48[d]
ee [%][c]
Me
40
4a
98
2
3
4
Me
Me
Me
44
24
46
4b
4c
4d
83
98
99
96
62[e]
70
5
6
7
8
Me
Me
Et
24
63
48
64
4e
4 f
4g
4h
66[e]
54[d,f]
77
97
99
98
98
mer product
4
is formed
(cycle 1) and in the slower
cycle the minor enantiomer
ent-4 is formed (cycle 2). The
initial Michael step, which pro-
ceeds through the iminium in-
termediate I, is dynamic and
reversible, leading to formation
of the Michael product 3 and
its mirror image ent-3 in equal
amounts (0% ee). In the case
of the DYKAT with nucleo-
phile 1b, the corresponding
Me
70[d]
9
Me
Me
16
72
4i
4j
86[e]
97
95
10
39[d,e]
11
Me
46
4k
63
93
Michael adduct
3 was first
formed in a 1:1 mixture with
0% ee. All four possible enan-
tiomers are therefore reversi-
bly formed and destroyed, to
afford the corresponding start-
ing 1b and enals 2 once more
by the retro-Michael process
[a] Experimental conditions: a mixture of 1 (0.75 mmol) and [PdACHTUNGTRNEG(UN PPh3)4] (5 mol%) in CH3CN (1.2 mL) was
stirred for 5 min. Next, aldehyde 2 (0.5 mmol) and amine 5 (20 mol%) were added and the reaction mixture
was stirred at room temperature for the time shown in the table. [b] Isolated yield of the corresponding prod-
uct 4 after silica gel column chromatography. [c] Determined by chiral-phase HPLC analysis. [d] The isolated
yield of corresponding alcohol 6 after in situ reduction of aldehyde 4 with excess NaBH4. [e] Reaction volume
was 0.3 mL. [f] Reaction volume was 0.6 mL.
firmed the relative configura-
tion between the neighboring
substituents.
The DYKAT reactions in-
volving non-terminal alkyne nu-
cleophiles are not limited to ter-
minal alkynes, as shown in the
synthesis of the pentenol 6o
[Eq. (2)] with 92% ee.
The aldehydes
4 are also
readily oxidized to the corre-
sponding more stable acids 7
[Eq. (3)]. It is noteworthy that
the highly chemoselective hy-
drolysis of the acid 7e with
two methyl ester groups gave
the corresponding diacid 8e
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Dynamic Kinetic Asymmetric Transformation
FULL PAPER
Table 3. Combined palladium- and amine-catalyzed DYKAT of enals 2.[a]
nium intermediate C gives the
aldehyde product 4 and regen-
erates the amine catalysts 5.
Performing the DYKAT in
CD3CN did not give the corre-
sponding deuterated product 4,
which indicates that the oxida-
tive cycloaddition to Pd0
(path B, Scheme 2) is predomi-
nant under our reaction condi-
tions.
Entry
1
R
t [h]
Prod.
Yield [%][b]
59
d.r.[c]
7:1
ee [%][d]
16
4l
95
2
3
4
15
16
16
4m
4n
4o
60
56
55
12:1
3:1
86
92
89
The Michael reactions be-
tween compounds 1 and 2, cat-
alyzed by the amines 5, give
7:1
the
racemic
products
3
(0% ee) under the conditions
employed in the DYKAT. Fur-
thermore, the co-catalyzed [by
amine 5 and Pd0] reaction be-
tween 1a and 2a gave the cor-
responding Michael adduct 3a
and the cyclopentene 4a in a
[a] Experimental conditions: a mixture of 1b (0.75 mmol) and PdACHTUNGTRNEG(UN PPh3)4 (5 mol%) in CH3CN (1.2 mL) was
stirred for 5 min. Next, aldehyde 2 (0.5 mmol) and amine 5 (20 mol%) were added and the reaction mixture
was stirred at room temperature for the time shown in the table. [b] Isolated yield of the corresponding prod-
uct 4 after silica gel column chromatography. [c] Determined by 1H NMR of the crude reaction mixture.
[d] Determined by chiral-phase HPLC or GC analysis.
(DYKAT, type IV).[5a] Next, because of the efficient shield-
ing of the Re-face (R=Ar) of the chiral enamine intermedi-
ate IIa by the bulky aryl groups of 5, a stereoselective Si-
facial intramolecular cycloisomerization between the enam-
ine and the metal-activated triple bond occurs instead of cy-
cloaddition of the enamine intermediate IV originating from
the slowly reacting enantiomer ent-3. This irreversible enan-
tioselective step, involving both the metal and the amine
catalysts, thus dictates the continuation of cycle 1 at a faster
rate over entrance to cycle 2. For the Pd0-catalyzed cycliza-
tion of enamine IIa we propose the following two initiation
mechanisms: either 1) oxidative addition of the solvent
(HX) to palladium(0) (path A, Scheme 2), or 2) a cycloaddi-
tion reaction (path B, Scheme 2).[19,20] Both paths in
Scheme 2 are also similar to the two paths proposed for the
palladium(0)-catalyzed cycloisomerizations of enynes.[20] In
accordance with this, the addition of solvent HY to Pd0
would give a PdII hydride species. This palladium (II) species
can add to the alkyne to form a vinylpalladium intermediate
(A). An insertion of the double bond into the palladium-
carbon bond would give intermediate B, which would subse-
quently undergo a b-elimination to give the iminium inter-
mediate C and—after hydrolysis and isomerization—prod-
uct 4 (Scheme 2, path A). In this step, the PdII hydride spe-
cies is regenerated and can again be coordinated to the en-
amine IIa, closing the catalytic cycle.
53:47 ratio with 0% and 94% ees, respectively, after 28 h. In
addition, the intramolecular reaction of the isolated racemic
product 3a in the presence of a combination of Pd0
(5 mol%) and 5 (20 mol%) in CH3CN gave the correspond-
ing cyclopentene 4a with 35% ee. We also performed the
exact same reaction as described (vide infra), but changed
the chiral amine 5 to a tertiary amine (such as N,N-diisopro-
pylethylamine, DIPEA). The racemic product 3a was thus
treated in the presence of Pd0 (5 mol%) and DIPEA
(20 mol%) in CH3CN. No formation of 4a was observed; in-
stead the retro-Michael reaction occurred, and after 48 h
cinnamaldehyde (2a) and 1a had been formed in significant
amounts. All of these experiments support the DYKAT
mechanism (Scheme 1). We also showed that the one-pot re-
action procedure is essential for achievement of excellent
enantioselectivity. Running the same reaction in a sequential
fashion, firstly by treating 1a with 2a in the presence of 5
(20 mol%) in MeOH, resulted after 22 h in the Michael
1
adduct 3a being formed, as determined by crude H NMR
analysis. Pd0 (5 mol%) was then added to the reaction mix-
ture. The reaction was then quenched after an additional
20 h and the cyclopentene 4a was isolated in 39% yield
with 74% ee. The one-pot combination of iminium-, enam-
ine- and Pd0-catalyzed enyne cycloisomerization is thus cru-
cial for achieving a highly enantioselective DYKAT. The
concentrations of substrates and products are completely
different in the sequential procedure and this will affect the
selectivity of the DYKAT process.
The cyclization of enamine IIa can also be explained by
an oxidative cycloaddition of the enyne to palladium(0),
forming the palladium(II) intermediate
D
(path B,
Scheme 2). b-Elimination and protonation of Pd would give
the iminium intermediate E and subsequent reductive hy-
dride elimination would afford the iminium intermediate C.
In this step, the Pd0 is regenerated and can perform the oxi-
dative cycloaddition with the enamine IIa again and close
the catalytic cycle. Hydrolysis and isomerization of the imi-
Conclusion
In summary, we have developed a simple and highly enan-
tioselective DYKAT procedure (of type IV) utilizing propar-
gylated carbon acids and enals with the aid of a one-pot
Chem. Eur. J. 2010, 16, 1585 – 1591
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A. Cꢁrdova et al.
Scheme 2.
Nicolaou, D. J. Edmonds, P. G. Bulger, Angew. Chem. 2006, 118,
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metal catalysis. Catalytic iminium activation, enamine acti-
vation, and transition-metal-catalyzed enyne cycloisomeriza-
tion can thus be efficiently merged for the development of
DYKATs and the formation of all-carbon quaternary stereo-
centers with high stereoselectivity. We are currently focusing
on the following topics: a) expansion of the concept of one-
pot combinations of transition metal and amine catalysis to
other metals and reactants, and b) development of catalytic
asymmetric reactions through the employment of simple
and inexpensive optically active amine catalysts and/or
chiral metal ligands. Preliminary results will be communicat-
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Acknowledgements
Professor Jan-E. Bꢀckvall is acknowledged for valuable discussions. We
gratefully acknowledge the Swedish National Research Council and the
Wenner-Gren-Foundation for financial support. The Berzelii Center EX-
SELENT is financially supported by VR and the Swedish Governmental
Agency for Innovation Systems (VINNOVA). We also thank Professor
Astrid Grꢀslund and Dr. Jesper Lind for time on the CD spectropolarim-
eter.
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ACHTUNGTRENNUNG(PPh3)4]
AHCTUNGTRENNUNG
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Received: October 13, 2009
Published online: December 28, 2009
Chem. Eur. J. 2010, 16, 1585 – 1591
ꢂ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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