A simple asymmetric organocatalytic approach to optically active cyclohexenones

Article abstract of DOI:10.1039/b611366d

Optically active 2,5-disubstituted-cyclohexen-2-one derivatives have been prepared in a one-pot process consisting of five reaction steps: an organocatalytic asymmetric conjugated addition of β-ketoesters to α,β-unsaturated aldehydes that proceeds in aque

Full text of DOI:10.1039/b611366d

View Article Online / Journal Homepage / Table of Contents for this issue
COMMUNICATION
www.rsc.org/chemcomm | ChemComm
A simple asymmetric organocatalytic approach to optically active
cyclohexenones{
Armando Carlone, Mauro Marigo, Chris North, Aitor Landa and Karl Anker Jørgensen*
Received (in Cambridge, UK) 8th August 2006, Accepted 18th September 2006
First published as an Advance Article on the web 5th October 2006
DOI: 10.1039/b611366d
Optically active 2,5-disubstituted-cyclohexen-2-one derivatives
have been prepared in a one-pot process consisting of five
reaction steps: an organocatalytic asymmetric conjugated
addition of b-ketoesters to a,b-unsaturated aldehydes that
proceeds in aqueous solutions or under solvent-free conditions
has been implemented in a multi-step process.
Organocatalysis1 has in the last few years gained considerable
Scheme 1 One-pot organocatalytic asymmetric synthesis of cyclohex-2-
enone derivatives.
attention in chemistry, because the use of metal-free catalysts
rather than organometallic complexes for the formation of
optically active molecules has several potential advantages. For
instance, the organocatalytic approach might become valuable in
the preparation of life science products such as pharmaceutical
compounds which do not tolerate metal contamination.
Furthermore, organocatalysis is often associated with mild and
simple reaction conditions that are appealing because of the easy
handling, cost and safety issues. Unfortunately, the advantages
have sometimes been tempered by the use of large excesses of
solvent and/or reagent and catalyst, and by long reaction times. To
overcome these limitations, recently serious efforts have been
dedicated, not only to develop new organocatalytic transforma-
tions, but also to select more appealing reaction conditions. For
example, the use of water/aqueous solutions2 as an environmen-
tally friendly solvent has naturally received special attention.3
Here we wish to report a new series of asymmetric organoca-
talytic transformations that focus on the preparation of important
optically active molecules and on the green chemistry principles.4
We thought it would be important to design a new catalytic
process that could be easily incorporated into the synthesis of
complex chiral structures in ‘‘one simple, safe, environmentally
acceptable, and resource-effective operation that proceeds quickly
and in high yield’’.5
functionalization of readily available compounds from the chiral
pool, such as carvone, pulegone or piperitone. Optical purity and
low cost starting materials are advantages of the latter strategy;
however, this has as the obvious limitation, the lack of flexibility
deriving from the necessity of planning the synthesis of any desired
product using only a limited number of different starting materials.
Our goal is to develop a practical, efficient and flexible method
to access a broad range of optically active cyclohex-2-enone
derivatives. The optimization of our synthesis started with the
extension of the asymmetric Michael reactions of a,b-unsaturated
aldehydes to different b-ketoesters as nucleophiles9,10 but focusing
the screening process only on environmentally friendly reaction
conditions (Table 1).
Table 1 Organocatalytic Michael addition of tert-butyl-3-oxo-butyric
ester 1a with a,b-unsaturated aldehydes 2a
In this context, we have developed a one-pot (5 step) asymmetric
synthesis of the important optically active cyclohex-2-enone
derivatives, based on organocatalysis and which gives H2O and
CO2 as major by-products, along with isobutene (Scheme 1).
Chiral cyclohex-2-enones are versatile building blocks for the
synthesis of a large number of natural occurring products and
other important compounds for the life science industry.6 They can
be prepared by kinetic resolution,7 or by more articulated multi-
step synthesis,8 but a well exploited approach is based on the
Entry Solvent
R
Yield (%)b,c Ee (%)d
1
H2O
AcOH (0.5 M)
NaHCO3 (0.5 M)
Ph – 5a
Ph – 5a
Ph – 5a
97
89
94
95
68
93
96
94
84
90
93
2e
3e
4
,10
88
aq. NaCl (sea water) Ph – 5a
5
6
5% EtOH (beer)f
—
Ph – 5a
Ph – 5a
Me – 5b
Et – 5c
98
90
g
7
8
9
H2O
H2O
H2O
82
95
n-Bu – 5d
71
a
Danish National Research Foundation: Center for Catalysis,
Department of Chemistry, Aarhus University, DK 8000, Aarhus C,
Denmark. E-mail: kaj@chem.au.dk; Fax: +(45) 8619 6199;
Tel: +(45) 8942 3910
All reactions were performed on a 0.25 mmol scale using 0.5 mL
of solvent. Product isolated by flash chromatography. 1 : 1–6 : 1
b
c
d
dr were obtained. Determined by chiral HPLC or GC after
e
derivatization (see ESI). Reaction time: 16 h. Carlsberg Hof.
Neat reaction conditions.
f
g
{ Electronic supplementary information (ESI) available: Experimental
procedures and characterizations. See DOI: 10.1039/b611366d
4928 | Chem. Commun., 2006, 4928–4930
This journal is ß The Royal Society of Chemistry 2006

View Article Online
Table 2 One-pot organocatalytic asymmetric synthesis of 3a–ia
The tert-butyl-3-oxo-butyric ester 1a reacted smoothly with
cinnamaldehyde 2a in distilled H2O using 2-[bis(3,5-bistrifluoro-
methyl-phenyl)trimethylsilanyl-oxymethyl]pyrrolidine
4 as the
catalyst3d,9a,b,9d,11 (Table 1, entry 1). In solvents, such as
AcOH(aq), sea water and ca. 5% EtOH (beer) (entries 2, 4, 5)
high yields and enantioselectivities were also obtained, while
somewhat surprisingly, the reaction gave low yield when
performed using a basic water solution (entry 3). This iminium-
ion catalyzed Michael reaction is very effective and good yields
(71–97%) and enantioselectivities, 84–94% ee of the Michael
adducts 5a–d can generally be obtained using H2O as solvent at
room temperature (entries 1, 7–9). It is important to highlight that
the use of H2O as solvent in processes catalyzed by secondary
amines often imposes the use of a large excess of the organic
reagents to force the reaction to completion3a but in this
transformation, using 4 as the catalyst, only a slight excess of
cinnamaldehyde 2a is required to achieve very high yields. A closer
look at the reaction reveals that the chosen reagents and the
catalyst ‘‘cluster together’’ in H2O and the reaction probably
occurs in the organic phase constituted by the a,b-unsaturated
aldehyde, the b-ketoester and the newly formed product.3b,c In
fact, under solvent-free conditions product 5a was also obtained
with 90% yield and 94% ee (Table 1, entry 6). The same results can
also obtained with 5 mol% of catalyst.
Entry
R1
R2
Product
Yield (%)b
Ee (%)c
1
2
3
4
5
6
7
8
9
a
H
H
H
H
H
H
H
Me
Et
Me
Et
i-Pr
n-Bu
Ph
p-F-Ph
m-Me-Ph
Et
3a
3b
3c
3d
3e
3f
3g
3h
3i
93
98
56
69
80
94
96
92
94
95
94
91
89
63 (81)d
65
72
82
(74)d
Et
The b-ketoester 1 (0.25 mmol) was added to a mixture of catalyst 4
(0.025 mmol, 10 mol%) and a,b-unsaturated aldehyde 2 (0.37 mmol)
and after 5–16 h toluene (1 mL) and p-TSA (0.05 mmol, 20 mol%)
b
were added. The product was isolated after 16 h at 80 uC. Product
isolated by flash chromatography. Determined by chiral HPLC or
c
d
GC. The yield in brackets refers to the two-pot process involving
the isolation of the Michael adduct.
a,b-unsaturated aldehydes with aromatic substituents and both
electronic withdrawing and donating groups are tolerated leading
to products with excellent stereoselectivity (entries 5–7). The one-
pot organocatalytic asymmetric reaction can also be used for the
formation of more complex products by modifying the structure of
the b-ketoester. The very interesting 2,5-disubstituted cyclohex-2-
enones 3h and 3i were synthesized in 74–82% yield and 89–91% ee
with the same simple procedure (entries 8, 9).
The tert-butyl ester group was essential for the integration of the
Michael reaction into our synthetic strategy. Under the chosen
conditions, the addition of p-TSA12 as the second organocatalyst
leads directly to the formation of the chiral cyclohex-2-enones 3.
The Brønsted acid is capable of catalyzing the hydrolysis of the
tert-butyl ester, the decarboxylation of the newly formed
b-ketoacid 6, and finally p-TSA also catalyzes the aldol reaction
of 7, and the elimination reaction of 8. The combination of
organocatalysts 2-[bis(3,5-bistrifluoromethyl-phenyl)trimethylsila-
nyloxymethyl]pyrrolidine 4 and p-TSA constitutes a catalytic
system which leads to the one-pot five reaction step synthesis of the
optically active cyclohex-2-enones 3 (Scheme 2).
The optically active products obtained from this solvent-free
Michael reaction are also excellent starting materials for the
preparation of other biologically active compounds such as
optically active piperidines (Scheme 3).14
The five step synthesis of the benzyl protected piperidine 9 was
achieved with a limited number of manual operations. In this case,
the Michael addition between tert-butyl-3-oxo-butyric ester and
cinnamaldehyde was followed by the addition of TFA and
CH2Cl2. The crude mixture of 7, obtained after aqueous workup,
was directly subjected to double reductive amination and the cis-2-
methyl-4-phenyl-piperidine15 derivative 9 was isolated as one
diastereomer with 94% ee and in 46% overall yield.
The carefully designed five step and one-pot reaction for the
formation of the optically active cyclohex-2-enones derivatives
proceed in excellent yield and with remarkable enantioselectivities
(Table 2).
Our model substrate tert-butyl-3-oxo-butyric ester 1a works
perfectly well with different b-alkyl substituted a,b-unsaturated
aldehydes, and with the exception of 2-butenal, the enantioselec-
tivity of the products are in the range of 92–96% ee (Table 2,
entries 1–4). It should be noted that the reaction works well for
In summary, we have reported the first organocatalytic
asymmetric conjugated addition of b-ketoesters to a,b-unsaturated
aldehydes that proceeds in aqueous solutions or under solvent-free
Scheme 3 Synthesis of (2S,4S)-1-benzyl-2-methyl-4-phenylpiperidine.
Reagents: (a) 4 (10 mol%), neat, rt; (b) 50% TFA in CH2Cl2, rt, 1 h; (c)
benzyl amine (1.5 equiv.), NaBH3CN, MeOH, rt, 20 h.
Scheme 2 Mechanism of the one-pot organocatalytic asymmetric
synthesis of optically active cyclohex-2-enone derivatives.13
This journal is ß The Royal Society of Chemistry 2006
Chem. Commun., 2006, 4928–4930 | 4929

View Article Online
recent examples, see also: (c) M. Miyashita and M. Saino, Science,
2004, 305, 495; (d) P. S. Baran, J. M. Ritcher and D. W. Lin, Angew.
Chem., Int. Ed., 2005, 44, 609; (e) A. Goeke, D. Mertl and G. Brunner,
Angew. Chem., Int. Ed., 2005, 44, 99; (f) R. Lakshmi, T. D. Bateman
and M. C. McIntosh, J. Org. Chem., 2005, 70, 5313; (g) P. J. Mohr and
R. L. Halcomb, J. Am. Chem. Soc., 2003, 125, 1712.
conditions. The potential of this reaction has been demonstrated
by its easy and efficient incorporation in the synthesis of important
optically active molecules and by the great substrate generality. In
particular, the preparation of optically active 2,5-disubstituted-
cyclohex-2-enone derivatives was achieved in very high yield and
enantiomeric excess, in a simple one-pot procedure. The value of
this ‘‘green’’ process is further enhanced by having isobutene, H2O
and CO2 as the sole by-products.{
This work was made possible by a grant from The Danish
National Research Foundation. AL thanks Eusko Jaurlaritza/
Gobierno Vasco for financial support (postdoctoral fellowship)
and CN thanks EU: HMPT-CT-2001-00317 for financial support.
7 R. Naasz, L. A. Arnold, A. J. Minnaard and B. L. Feringa, Angew.
Chem., Int. Ed., 2001, 40, 927.
8 (a) G. Sarakinos and E. J. Corey, Org. Lett., 1999, 1, 811; (b)
G. P.-J. Hareau, M. Koiwa, S. Hikichi and F. Sato, J. Am. Chem. Soc.,
1999, 121, 3604; (c) T. Hanazawa, M. Koiwa, G. P.-J. Hareau and
F. Sato, Tetrahedron Lett., 2000, 41, 2659; (d) G. P.-J. Hareau-Vittini,
S. Hikichi and F. Sato, Angew. Chem., Int. Ed., 1998, 37, 2099; (e)
S. Hikichi, G. P.-J. Hareau and F. Sato, Tetrahedron Lett., 1997, 38,
8229.
9 For recent examples of organocatalyzed additions to a,b-unsaturated
aldehydes, see: (a) M. Marigo, S. Bertelsen, A. Landa and
K. A. Jørgensen, J. Am. Chem. Soc., 2006, 128, 5475; (b) S. Brandau,
A. Landa, J. Franze´n, M. Marigo and K. A. Jørgensen, Angew. Chem.,
Int. Ed., 2006, 45, 4305; (c) R. K. Kunz and D. W. C. MacMillan, J. Am.
Chem. Soc., 2005, 127, 3240; (d) M. Marigo, T. Schulte, J. Franze´n and
K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 15710; (e) Y. Huang,
A. M. Walji, C. H. Larsen and D. W. C. MacMillan, J. Am. Chem.
Soc., 2005, 127, 15051; (f) J. W. Yang, M. T. Hechavarria Fonseca and
B. List, J. Am. Chem. Soc., 2005, 127, 15036; (g) M. Marigo, J. Franze´n,
T. B. Poulsen, W. Zhuang and K. A. Jørgensen, J. Am. Chem. Soc.,
2005, 127, 6964; (h) S. G. Ouellet, J. B. Tuttle and D. W. MacMillan,
J. Am. Chem. Soc., 2005, 127, 32; (i) J. Woon, M. T.
Hechavarria Fonseca and B. List, Angew. Chem., Int. Ed., 2004, 43,
6660; (j) J. F. Austin, S.-G. Kim, C. J. Sinz, W.-J. Xiao and
D. W. C. MacMillan, Proc. Natl. Acad. Sci. U. S. A., 2004, 15, 5482;
(k) S. P. Brown, N. C. Goodwin and D. W. C. MacMillan, J. Am.
Chem. Soc., 2003, 125, 1192; (l) N. A. Paras and D. W. C. MacMillan,
J. Am. Chem. Soc., 2002, 124, 7894; S. Mayer and B. List, Angew.
Chem., Int. Ed., 2006, 45, 4193.
10 For organocatalyzed addition of b-ketoesters to enones see: (a)
N. Halland, P. S. Aburel and K. A. Jørgensen, Angew. Chem., Int.
Ed., 2003, 42, 661; (b) C. E. T. Mitchell, S. E. Brenner, J. Garcia-
Fortanet and S. V. Ley, Org. Biomol. Chem., 2006, 4, 2039 and
references therein.
11 For application of 4 in enamine catalyzed reaction, see: (a) J. Fra´nzen,
M. Marigo, D. Fielenbach, T. C. Wabnitz, A. Kjærsgaard and
K. A. Jørgensen, J. Am. Chem. Soc., 2005, 127, 18296; (b) M. Marigo,
D. Fielenbach, A. Braunton, A. Kjærsgaard and K. A. Jørgensen,
Angew. Chem., Int. Ed., 2005, 44, 3703; (c) M. Marigo, T. C. Wabnitz,
D. Fielenbach and K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44,
794. See also: (d) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji,
Angew. Chem., Int. Ed., 2005, 44, 4212; (e) Y. Chi and S. H. Gellman,
J. Am. Chem. Soc., 2006, 128, 6804.
References
{ General procedure for the Michael addition: 15.0 mg (0.025 mmol,
0.1 equiv.) of 4 was added to the a,b-unsaturated aldehyde
(0.37 mmol, 1.5 equiv.) 2 followed by the addition of the b-ketoester
(0.25 mmol, 1.0 equiv.) 1 under neat conditions or using water as solvent.
The product can be isolated by flash chromatography. General procedure
for the preparation of the cyclohex-2-enone derivatives 3: 15.0 mg
(0.025 mmol, 0.1 equiv.) of 4 was added to the a,b-unsaturated aldehyde
(0.37 mmol, 1.5 equiv.) 2 followed by the addition of the b-ketoester
(0.25 mmol, 1.0 equiv.) 1. After 5–16 h toluene (1 mL) and p-TSA
(0.05 mmol, 0.2 equiv.) were added and the reaction mixture was kept at
80 uC for 16 h. The product can be isolated by flash chromatography.
1 For reviews on organocatalysis see e.g.: (a) P. I. Dalko and L. Moisan,
Angew. Chem., Int. Ed., 2004, 43, 5138; (b) Acc. Chem. Res., 2004, 37,
special issue on organocatalysis; (c) A. Berkessel and H. Gro¨ger,
Asymmetric Organocatalysis, Wiley-VCH, Weinheim, 2005; (d) J. Seayad
and B. List, Org. Biomol. Chem., 2005, 3, 719; (e) B. List, Chem.
Commun., 2006, 819; (f) M. Marigo and K. A. Jørgensen, Chem.
Commun., 2006, 2001.
2 For reviews see e.g.: (a) U. M. Lindstrom, Chem. Rev., 2002, 102, 2751;
(b) C.-J. Li, Chem. Rev., 2005, 105, 3095; (c) R. A. Sheldon, Green
Chem., 2005, 7, 267; (d) S. Kobayashi, Adv. Synth. Catal., 2002, 344,
219.
3 (a) Y. Hayashi, S. Aratake, T. Okano, J. Takahashi, T. Sumiya and
M. Shoji, Angew. Chem., Int. Ed., 2006, 45, 5527; (b) S. Luo, X. Mi,
S. Liu, H. Xu and J.-P. Cheng, Chem. Commun., 2006, 3687; (c)
N. Mase, Y. Nakai, N. Ohara, H. Yoda, K. Takabe, F. Tanaka and
C. F. Barbas, III, J. Am. Chem. Soc., 2006, 128, 734; (d) Y. Hayashi,
T. Sumiya, J. Takahashi, H. Gotoh, T. Urushima and M. Shoji, Angew.
Chem., Int. Ed., 2006, 45, 958; (e) N. Mase, K. Watanabe, H. Yoda,
K. Takabe, F. Tanaka and C. F. Barbas, III, J. Am. Chem. Soc., 2006,
128, 4966; (f) W. Zhuang, M. Marigo and K. A. Jørgensen, Org.
Biomol. Chem., 2005, 3, 3883.
12 p-TSA: p-toluenesulfonic acid.
13 Our studies revealed that the overall transformation can also proceed
through the alternative aldol–elimination–hydrolysis–decarboxylation
sequence.
14 (a) A. D. Elbein and R. Molyneux, in Alkaloids; Chemical and Biological
Perspectives, ed. S. W. Pelletier, John Wiley & Sons, New York, 1987,
vol. 57, p. 1. For the synthesis of cis-2,4-disubstituted piperidines, see
e.g.: (b) M. S. Taylor, D. W. Zalatan, A. M. Lerchner and E.
N. Jacobsen, J. Am. Chem. Soc., 2005, 127, 1313; (c) M. P. Dwyer, J.
E. Lamar and A. I. Meyers, Tetrahedron Lett., 1999, 40, 8965.
15 For the determination of relative configuration see ESI.
4 (a) P. T. Anastas and J. C. Warner, Green Chemistry: Theory and
Practice, Oxford University Press, Oxford, 1998; (b) J. H. Clark, Green
Chem., 1999, 1, 1.
5 (a) T. Y. Zhang, Chem. Rev., 2006, 106, 2583; (b) P. A. Wender,
S. T. Handy and D. L. Wright, Chem. Ind., 1997, 765.
6 See e.g.: (a) T.-L. Ho, Enantioselective Synthesis: Natural Products
Synthesis from Chiral Terpenes, Wiley, New York, 1992; (b) A. J. H.
Klunder, J. Zhu and B. Zwanenburg, Chem. Rev., 1999, 99, 1163. For
4930 | Chem. Commun., 2006, 4928–4930
This journal is ß The Royal Society of Chemistry 2006