Dynamic kinetic asymmetric domino oxa-michael/carbocyclization by combination of transition-metal and amine catalysis: Catalytic enantioselective synthesis of dihydrofurans

Article abstract of DOI:10.1002/chem.201001992

Into the pot: A one-pot highly chemo- and enantioselective catalytic domino oxa-Michael/carbocyclization between α,β-unsaturated aldehydes and propargylic alcohols is presented. This dynamic kinetic transformation requires a combination of transition-meta

Full text of DOI:10.1002/chem.201001992

DOI: 10.1002/chem.201001992
Dynamic Kinetic Asymmetric Domino Oxa-Michael/Carbocyclization by
Combination of Transition-Metal and Amine Catalysis:
Catalytic Enantioselective Synthesis of Dihydrofurans
Shuangzheng Lin,[a] Gui-Ling Zhao,*[a, b] Luca Deiana,[a, b] Junliang Sun,[b, c]
Qiong Zhang,[d] Hans Leijonmarck,[a, b] and Armando Cꢀrdova*[a, b, e]
À
Domino reactions can give access to multiple C C and
hydes and ketones has grown tremendously during the last
decade and significantly contributed to the research field of
asymmetric catalysis.[7]
À
C hetero atom bonds in one-pot and allow for the chemical
synthesis of demanding organic structures.[1] This improves
parameters such as atom economy[2] and allows for the de-
velopment of green chemistry.[3] Transition-metal catalysis is
an important research field of homogeneous catalysis.[4] In
À
In 2006, we disclosed that C C bond formation could be
achieved by transition-metal catalysis combined with amine
catalysis, involving enamine activation of an aldehyde or a
ketone.[8] This gives access to chemical reactivity that is only
possible by metal and amine co-catalysis.[9–11] For example,
co-catalytic systems based on this concept to achieve carbo-
cyclization have been reported.[9e,f] However, with respect to
the development of domino reactions there are very few re-
ports on the employment of amine and metal co-catalyzed
transformations.[9e,12] In this context, we developed a catalyt-
ic dynamic kinetic asymmetric transformation (DYKAT) be-
tween enals and propargylated carbon acids involving a
transition state in which both the metal and chiral amine are
simultaneously present.[12] Furans are common heterocyclic
substructures and can be found in several natural products
(e.g., lignans, mycotoxines, polyether antibiotics, spiroketals,
and amino acids) that have biological activities.[13] They are
also versatile building blocks in organic synthesis.[14] Based
on our previous research experience[15] and the importance
of the furan structural motif,[13,14] we became intrigued in
the challenge of developing a one-pot, catalytic, domino
oxa-Michael/carbocyclization between a,b-unsaturated alde-
hydes 1 and propargyl alcohol (2a) by combination of tran-
sition-metal and amine catalysis (Scheme 1). However, there
are only a few reports on the amine-catalyzed enantioselec-
tive conjugate addition (ECA) of oxygen-based nucleophiles
to enals.[16] For example, the addition of aliphatic primary al-
cohols (e.g., ethanol) gives racemic oxa-Michael products in
low yields.[16c] Thus, the equilibrium of the amine-catalyzed
conjugate addition of 2a to an enal 1 would not be towards
formation of the oxa-Michael product 3 (Scheme 1). Howev-
er, we envisioned that a DYKAT involving a metal and
chiral amine co-catalyzed carbocyclization would push the
À
this context, metal-mediated C H bond functionalization is
a powerful tool in the development of methods for the as-
sembly of complex organic molecules.[5] In particular, metal-
catalyzed carbocyclizations give access to versatile and
useful molecular structures.[6] On the other hand, organic
catalysis involving enamine and iminium activation of alde-
[a] Dr. S. Lin, Dr. G.-L. Zhao, L. Deiana, Dr. H. Leijonmarck,
Prof. Dr. A. Cꢀrdova
Department of Organic Chemistry
The Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
Fax : (+46)8-154908
E-mail: acordova@organ.su.se
armando.cordova@miun.se
zhaogl@organ.su.se
[b] Dr. G.-L. Zhao, L. Deiana, Prof. Dr. J. Sun, Dr. H. Leijonmarck,
Prof. Dr. A. Cꢀrdova
Berzelii Center EXSELENT on Porous Materials
The Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
[c] Prof. Dr. J. Sun
Department of Structural Chemistry
The Arrhenius Laboratory, Stockholm University
106 91 Stockholm (Sweden)
[d] Dr. Q. Zhang
Department of Theoretical Chemistry, School of Biotechnology
Royal Institute of Technology, Roslagstullsbacken 15
10691 Stockholm (Sweden)
[e] Prof. Dr. A. Cꢀrdova
Department of Natural Sciences, Engineering and Mathematics
Mid Sweden University, 851 70 Sundsvall (Sweden)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.201001992.
À
equilibrium towards C O bond formation by making the
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Chem. Eur. J. 2010, 16, 13930 – 13934

COMMUNICATION
Table 1. Initial investigation for the oxa-Michael/carbocyclization be-
tween 1a and 2a.[a]
Scheme 1. Combined amine- and transition-metal-catalyzed oxa-Michael/
carbocyclization between enals 1 and 2a.
Amine Metal salt
Solvent
T
t
Yield e.r.
[8C] [h] [%][b] [%][c]
1
2
3
4
5a
–
–
CHCl3
CHCl3
CHCl3
CH3CN RT
toluene RT
RT
RT
RT
44
44
44
44 28
65 10
41 17
–
–
–
–
–
–
97:3
96:4
94:6
95:5
95.5:4.5
94:6
PdCl2
PdCl2
Pd
oxa-Michael reaction irreversible. The bulky group of the
amine would also allow for a faster carbocyclization with
oxa-Michael intermediate 3 over ent-3 to form furan 4 due
to less steric interactions in the transition state (Scheme 1).
Herein, we describe a highly enantioselective dynamic ki-
netic domino oxa-Michael/carbocyclization between a,b-un-
saturated aldehydes 1 and propargylic alcohols 2 by the in-
terconnected catalytic cycles of PdCl2 and readily available
chiral amines to afford dihydrofurans 4 (up to 99.5:0.5 e.r.).
We began to investigate the ability of Pd salts and com-
plexes to catalyze the oxa-Michael/carbocyclization transfor-
mation between enal 1a and 2a (Table 1). The oxa-Michael
product 3a or dihydrofuran 4 were not formed in the ab-
sence of chiral amine (entry 2). The same reaction with only
chiral amine 5a did not afford 4 and only trace amount of
3a (entry 1). The reaction with a Pd salt and a tertiary
DBU
5a
5a
5a
5a
5a
5a
G
5
Au
G
6[d]
7
A
ZnCl2
AgNTf2
PdCl2
toluene RT
66
9
8
toluene RT 120 12
CH3CN RT 140 12
89 12
9[e]
10[d,e] 5a
A
98:2
11[e]
12[e]
13[e]
14[e]
15[e]
16[e]
17[e]
18[e]
5a
5a
5a
5a
5a
5b
5c
5d
PdCl2
PdCl2
PdCl2
CH2Cl2 RT
16 39
18 65
15 62
15 21
15 72
20 77
96 77
19 75
93:7
96.5:3.5
95:5
94:6
96:4
96.5:3.5
95.5:4.5
95.5:4.5
CHCl3
THF
THF
CHCl3
CHCl3
CHCl3
CHCl3
RT
RT
RT
4
Pd
N
PdCl2
PdCl2
PdCl2
PdCl2
4
4
4
[a] Experimental conditions: A mixture of 2a (0.375 mmol) and metal
salt or complex (5 mol%) in solvent (0.5 mL) was stirred for 5 min. Next,
aldehyde 2a (0.25 mmol) and chiral amine 5 (20 mol%) were added and
the reaction was stirred at RT or 48C for the time shown in the table.
[b] Isolated yield of aldehyde 4a after silica gel column chromatography.
[c] Determined by chiral-phase HPLC analysis. [d] 5 mol% CuOTf and
20 mol% PPh3 were used. [e] 20 mol% benzoic acid was added.
amine such as 1,8-diazabicycloACTHNUTRGNEUGN[5.4.0]undec-7-ene (DBU) did
not render any product (entry 3). Thus, we began investigat-
ing the ability of a transition metal in combination with a
chiral amine to catalyze the asymmetric domino reaction be-
tween 1a and 2a. The main results are shown in Table 1.
To our delight, we found that chiral amines and in partic-
ular protected diarylprolinol derivatives such as 5[17] cata-
lyzed the reaction with excellent chemoselectivity and high
enantioselectivity to form the corresponding hydrofuran 4a
as the only product (Table 1). Several metal salts were inves-
tigated and we found that AuI, CuI, ZnII, AgI, Pd0, and PdII
were able to co-catalyze the reaction in combination with 5
with high chemo- and enantioselectivity (entries 4–10).
However, the corresponding product 4a was isolated in low
yields. The influence of solvent and the employment of an
acid additive were also investigated (entries 10–18).[18] For
example, 4a was isolated in 65% yield and 96.5:3.5 e.r.
when PdCl2 and 5a were employed as the co-catalysts and
benzoic acid was used as the additive in CHCl3 (entry 12).
The yield improved when the reaction temperature was de-
creased (entries 15–18). Increasing the bulk of the chiral pyr-
rolidine catalysts 5 as compared to 5a in combination with
PdCl2 slightly improved the yield of 4a (entries 16–18). For
example, the combination of PdCl2 and amine 5b co-cata-
lyzed the cascade reaction with the highest enantioselectivi-
ty and gave dihydrofuran 4a in 77% yield and a 96.5:3.5 e.r.
(entry 16). With these results in hand, we decided to investi-
gate the combined transition metal- and amine-catalyzed
oxa-Michael/carbocyclization by using chiral pyrrolidine 5b
and PdCl2 as the catalysts, benzoic acid as the additive and
CHCl3 as the solvent (Table 2).
Under the optimized reaction conditions, the a,b-unsatu-
rated aldehydes bearing electron-withdrawing groups afford-
ed the corresponding products 4a–e and 4i in high yields
and 95.5:4.5–99.5:0.5 e.r. (entries 1–5 and 9). In some cases,
changing the solvent to THF improved the efficiency and
enantioselectivity (entries 4–9). The co-catalyzed cascade re-
actions with a,b-unsaturated aldehydes 1 without an elec-
tron-withdrawing group gave the corresponding nearly enan-
tiopure dihydrofurans 4 (99.5:0.5 e.r., entries 6–8). The reac-
tion was also highly enantioselective with aliphatic enals as
acceptors (entry 10).
We also investigated the domino reaction using secondary
and tertiary propargylic alcohols 2 (Scheme 2). In all cases,
the chiral amine 5b and PdCl2 co-catalyzed the asymmetric
formation of dihydrofurans 4 with high enantioselectivity.
Chem. Eur. J. 2010, 16, 13930 – 13934
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A. Cꢀrdova, G.-L. Zhao et al.
Table 2. The combined metal- and chiral amine-catalyzed domino oxa-
Secondary alcohol 2c with a bulky iPr group and tertiary al-
cohol 2d reacted slower than the secondary alcohol 2b and
the primary alcohol 2a. The relative stereochemistry of 4k
and 4l was established by NOE experiments of 4l, which
confirmed the relative configuration of the p-nitrophenyl
and iPr groups to be anti. Initial experiments, with a propar-
gylic alcohol with an internal alkyne as the substrate,
formed the corresponding product 4n in 27% conversion
after 17 h.
The dihydrofurans 4 were readily converted to the corre-
sponding alcohols 6 by reduction with NaBH4 in MeOH and
oxidation with NaClO2 afforded the corresponding acids 7
in high yields (see Supporting Information). Highly diaste-
reoselective epoxidaton of alcohols 6h with m-CPBA pro-
vided the corresponding epoxide 8h in high yield with
>20:1 d.r. [Eq. (1].
Michael/carbocyclization between enals 1 and 2a.[a]
R
Product
Solvent
t
Yield
[%][b]
e.r.
[h]
[%][c]
1
2
4a
4b
CHCl3
CHCl3
20
77
75
96.5:3.5
95.5:4.5
18
18
23
3
4c
4d
CHCl3
THF
75
67
96:4
4[d,f]
99.5:0.5
5[d]
4e
4 f
4g
4h
THF
THF
THF
THF
50
96
63
97.5:2.5
99.5:0.5
99.5:0.5
99.5:0.5
6[d,e]
7[d–f]
8[d]
57
144
40
51 (91)[g]
72
9[d]
4i
4j
THF
THF
48
70
70
40
98:2
This type of epoxide scaffold is synthetically useful and is
present in natural products such as verrucosidin. Moreover,
epoxide opening gives the scaffold of the related mycotoxins
(e.g., citreovindin).[13p,q] X-ray analysis of the crystalline
product 6e[19] established the absolute configuration at C2 to
be (R) (Figure 1).
10[h,j]
95.5:4.5
[a] Experimental conditions: A mixture of 2 (0.375 mmol) and PdCl2
(5 mol%) in CHCl3 or THF (0.5 mL) was stirred for 5 min. Next, alde-
hyde 2 (0.25 mmol), amine 6 (20 mol%) and benzoic acid (20 mol%)
were added and the reaction was stirred at 48C for the time shown in the
table. [b] Isolated yield of the corresponding product 4 after silica gel
column chromatography. [c] Determined by chiral-phase HPLC analysis.
[d] Reaction volume was 0.25 mL and 0.75 mmol propargyl alcohol 2a
was used. [e] Reaction was run at RT. [f] 10 mol% PdCl2. [g] Yield based
on recovered starting material. [h] 2.5 mmol of propargyl alcohol 2a was
used. [i] e.r. determined by chiral-phase GC analysis.
Figure 1. ORTEP picture of compound 6e.
Based on the established absolute configuration and our
experimental results, we propose the following mechanism
for the reaction pathway (Scheme 3).
The proposed mechanism is a formal DYKAT and the re-
action starts by formation of iminium intermediate I.[12a,20]
Next, oxa-Michael addition of 2a to I renders chiral enam-
ine intermediates II and IIa. Hydrolysis of II and IIa can
give 3; however, retro-Michael reaction and racemization is
favored and gives back the starting materials 1 and 2a.
Next, stereoselective Re-facial oxidative cycloaddition, ac-
cording to the mechanism proposed by Trost for enyne cy-
cloisomerization, of the less sterically hindered chiral enam-
ine III as compared to IIIa affords bicyclic PdIV intermediate
IV.[6c] However, the possible alternative Lewis acid activa-
Scheme 2. Co-catalyzed asymmetric synthesis of dihydrofurans 4. [a] E.r.
of the minor diastereoisomer. [b] Reaction run in THF.
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Asymmetric Catalysis
COMMUNICATION
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Scheme 3. Proposed reaction mechanism.
tion of the alkyne by PdII and simultaneous intermolecular
nucleophilic attack by the chiral enamine VII cannot be
completely ruled out. b-Elimination and protonation of pal-
ladium gives iminium intermediate V. Subsequent reductive
elimination releases PdII, which can now take part in its cat-
alytic cycle again, and renders iminium intermediate VI. Hy-
drolysis of VI releases the chiral amine catalyst and affords
the dihydrofuran product 4 after isomerization. Thus, the si-
multaneous co-operative catalysis of the chiral amine and
metal is essential to achieve product formation.
In summary, we have developed an unprecedented highly
enantioselective domino oxa-Michael/carbocyclization be-
tween propargyl alcohols and enals by combination of asym-
metric amine and transition-metal catalysis. The DYKAT
gives access to valuable dihydrofurans in good to high yields
with e.r. of up to 99.5:0.5. The development and expansion
of the concept of one-pot combinations of transition metal
and amine catalysis to other metals and reactants is current-
ly ongoing in our group. Further results will be communicat-
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Acknowledgements
We gratefully acknowledge the Swedish National Research council and
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).
Keywords: asymmetric catalysis
reactions · furans · palladium
· co-catalysis · domino
Chem. Eur. J. 2010, 16, 13930 – 13934
ꢁ 2010 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemeurj.org
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Received: July 14, 2010
Published online: November 16, 2010
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