Controlling the formation of 1 out of 64 stereoisomers using organocatalysis

Article abstract of DOI:10.1039/b806418k

The formation of 1 out of 64 stereoisomers, i.e. controlling the creation of 6 stereocenters, of important optically active bicyclo[3.3.1]non-2-ene compounds, has been achieved using organocatalysis; the reaction proceeds with excellent stereocontrol and

Full text of DOI:10.1039/b806418k

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Controlling the formation of 1 out of 64 stereoisomers using
organocatalysisw
Søren Bertelsen, Rasmus L. Johansen and Karl Anker Jørgensen*
Received (in Cambridge, UK) 15th April 2008, Accepted 12th May 2008
First published as an Advance Article on the web 9th June 2008
DOI: 10.1039/b806418k
The formation of 1 out of 64 stereoisomers, i.e. controlling the
creation of 6 stereocenters, of important optically active bicy-
clo[3.3.1]non-2-ene compounds, has been achieved using orga-
nocatalysis; the reaction proceeds with excellent stereocontrol
and can be carried out with the generation of enantiopure
products using chromatography-free procedures.
Scheme 1 Organocatalytic asymmetric two-component reaction lead-
ing to bicyclo[3.3.1]non-2-enes.
Recently, organocatalysis has proven to be a powerful strategy
for the stereoselective synthesis of highly valuable building
blocks, being complementary to the established methods using
metals or enzymes.1 The organocatalysts are readily available
small organic molecules, which are easily synthesized or
purchased and are tolerant of a great variety of benign
reaction conditions.1
recurrent target in total synthesis of highly important bio-
molecules,4 while the racemic analogues5 have shown antitu-
mor activity.6
The proposed mechanism for the formation of the 6 stereo-
centers in the optically active bicyclo[3.3.1]non-2-ene products
4 is outlined in Scheme 2. The chiral organocatalyst 3 acts by
first activating the a,b-unsaturated aldehyde 1 via an iminium
ion intermediate A shown to the left in the scheme. This allows
for a nucleophilic attack by one of the methylene carbon
atoms of the tricarbonyl compound 2 at the b-carbon atom
in A, generating the first 2 stereocenters. A cyclization initiated
by the second activated methylene of the tricarbonyl com-
pound leads to intermediate B. It is likely, yet unclear, that the
cyclization is preceded by hydrolysis of the catalyst. Inter-
mediate B can undergo a stereoselective conjugate addition by
another molecule of tricarbonyl compound 2 leading to the
formation of C. The diastereocontrol of this second addition is
probably governed by the stereocenter bearing R in the second
catalytic cycle to the right in Scheme 2. A final ring closure
reaction, between the last free activated methylene and the
central ketone leads to the highly functionalized product D
(with 7 stereocenters), which is in tautomeric equilibrium with
the more stable enol form 4, by reason of strong intramole-
cular hydrogen bonding. The piperidine might act as a catalyst
for several of the reaction steps in the second part of the
reaction course.
In the field of synthesis of complex molecules with one or
multiple stereocenters, the asymmetric catalytic strategy, using
e.g. organocatalysis, has shown promising results towards the
simultaneous synthesis of several stereocenters in easy multi-
component, domino or cascade procedures,2 a task that was
traditionally considered elusive. Examples are now available
for the formation of six-membered ring systems having several
stereocenters as in e.g. the substituted cyclohexenes developed
by Enders et al. using a three-component domino reaction,2d
or Hayashi et al.’s Michael–Henry reaction sequence for the
formation of optically active cyclohexane derivatives.2f Re-
cently, we have shown the development of a one-pot asym-
metric reaction with the formation of five stereocenters by an
intermolecular two-component reaction of a,b-unsaturated
aldehydes with a dinitroalkane, leading in this particular case
to the formation of highly substituted optically active cyclo-
hexanols.3,9
In the present work we will show the development of a new
organocatalytic asymmetric cascade reaction by demonstrat-
ing that two simple molecules, an a,b-unsaturated aldehyde
and a tricarbonyl compound, react in a one-pot reaction to
selectively form 4 new carbon–carbon bonds, providing 6 new
stereocenters, and thereby 1 out of 64 possible (26) stereo-
isomers with excellent diastereo- and enantioselectivity
(Scheme 1). The optically active products formed, bicy-
clo[3.3.1]non-2-enes, have a number of important applications
and properties. The carbon skeleton in these compounds is a
A series of experiments were performed to develop the
optimal reaction conditions for the formation of the optically
active bicyclo[3.3.1]non-2-ene products. The optimization in-
vestigations gave the following standard reaction conditions:
dimethyl 3-oxapentanedioate 2 (0.50 mmol) was added at
room temperature to a stirred solution of (S)-(À)-a,a-diphe-
nyl-2-pyrrolidinemethanol trimethylsilyl ether7
3 (0.025
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
w Electronic supplementary information (ESI) available: Full experi-
mental details. CCDC 682910 and 687505. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/
b806418k
mmol), benzoic acid (0.025 mmol) and the a,b-unsaturated
aldehyde 1 (0.25 mmol) in toluene (125 mL). After complete
consumption of the a,b-unsaturated aldehyde, as monitored
by 1H NMR spectroscopy, MeOH (1.0 mL) and piperidine
(0.05 mmol) were added and the reaction was stirred at 40 1C
until full consumption of 2 (as indicated by TLC). Table 1
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Scheme 2 Proposed organocatalytic cycles for the formation of 1 out of 64 stereoisomers by one-pot organocatalytic cascade reaction of an
a,b-unsaturated aldehyde with a tricarbonyl compound.
shows the results obtained for the reaction of a number of
different a,b-unsaturated aldehydes 1 with dimethyl 3-oxapen-
tanedioate 2 in the presence of 3 (10 mol%) and piperidine
(20 mol%) as the catalysts (Scheme 3).
reaction. For the simple aliphatic a,b-unsaturated aldehydes
(entries 1–3), the optically active products 4a–4c are formed in
good yields, after the multiple reaction steps, and for the two
former products, only one diastereoisomer could be detected
and both with more than 94% ee. For the optically active
bicyclo[3.3.1]non-2-enes having an ester or olefin as R, 4d and
4e, respectively, excellent results are also obtained (entries 4,
5). The product diversity can be expanded to also include
aromatic and heteroaromatic substituents as shown for 4f–4i.
The aromatic compounds, both unsubstituted, and para- and
ortho-substituted phenyls (entries 6–9), gave excellent yields
with up to 93% isolated yield, one diastereoisomer and up to
96% ee. The presence of a heteroaromatic substituent, such as
furyl, 4h, led to an 86% yield, 94 : 6 dr and 90% ee.
Table 1 Organocatalytic asymmetric cascade reaction of different
a,b-unsaturated aldehydes with dimethyl 3-oxapentanedioate
Entry
R
Yield (%)
Dra
Eeb (%)
1
2
3
4
5
6
7
8
9
Et
i-Pr
n-C7H15
EtO2C
(Z)-3-Hexenyl
Ph
p-MeOPh
2-Furyl
o-BrPh
4a
4b
4c
4d
4e
4f
4g
4h
4i
48
65
69
38
51
70
93
86
86
499 : 1
499 : 1
88 : 12
499 : 1
94 : 6
499 : 1
92 : 8
94 : 6
94
96
95
89
94
93
91
90
96
Scheme 3 Reaction of different a,b-unsaturated aldehydes 1 with
dimethyl 3-oxapentanedioate 2 in the presence of 3 (10 mol%) and
piperidine (20 mol%) as the catalysts.
As it appears from Table 1, various a,b-unsaturated alde-
hydes have successfully been subjected to the reaction condi-
tions giving
a
broad range of optically active
499 : 1
bicyclo[3.3.1]non-2-enes 4. Aliphatics (linear and branched,
including heteroatoms and olefins), aromatics, heteroaro-
matics and esters are all well tolerated as substituents in the
a
b
Dr measured by 1H NMR spectroscopy. Ee measured by HPLC
using a Daicel Chiralpak AD column.
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This work was made possible by a grant from The Danish
National Research Foundation and OChemSchool. Thanks
are expressed to Dr Jacob Overgaard for the X-ray analysis.
Notes and references
1. For recent reviews on organocatalysis see e.g.: (a) P. L. Dalko and
L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138; (b) A. Berkessel and
H. Groger, Asymmetric Organocatalysis, VCH, Weinheim, Germany,
2004; (c) Acc. Chem. Res., 2004, 37(8), special issue on organocatalysis;
(d) J. Seayed and B. List, Org. Biomol. Chem., 2005, 3, 719; (e) B. List
and J.-W. Yang, Science, 2006, 313, 1584; (f) B. List, Chem. Commun.,
2006, 819; (g) M. J. Gaunt, C. C. C. Johansson, A. McNally and
N. C. Vo, Drug Discovery Today, 2007, 2, 8; (h) P. I. Dalko,
Enantioselective Organocatalysis, Wiley-VCH, Weinheim, 2007;
(i) Chem. Rev., 2007, 107(12), special issue on organocatalysis.
2. For recent reviews on organocatalytic cascade and related reactions
see e.g.: (a) D. Enders, C. Grondal and M. R. M. Huttl, Angew.
Chem., Int. Ed., 2007, 46, 1570; (b) G. Guillena, D. J. Ramon and
M. Yus, Tetrahedron: Asymmetry, 2007, 18, 693; (c) D. J. Ramon
and M. Yus, Angew. Chem., Int. Ed., 2005, 44, 1602. See also e.g.:
(d) D. Enders, M. R. M. Huttl, C. Grondal and G. Raabe, Nature,
2006, 441, 861(e) D. Enders, M. R. M. Huttl, J. Runsink, C. Raabe
and B. Wendt, Angew. Chem., Int. Ed., 2007, 46, 467(f) Y. Hayashi,
T. Okano, S. Aratake and D. Hazelard, Angew. Chem., Int. Ed.,
2007, 46, 4922(g) H. Y. Kim, A. E. Lurain, P. Garcia-Garcia,
P. J. Carroll and P. J. Walsh, J. Am. Chem. Soc., 2005, 127,
13138(h) N. Halland, P. S. Aburel and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2004, 43, 1272.
3. E. Reyes, H. Jiang, A. Milelli, P. Elsner, R. G. Hazell and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2007, 46, 9202.
4. (a) R. Takagi, Y. Miwa, T. Nerio, Y. Inoue, S. Matsumura and
K. Ohkata, Org. Biomol. Chem., 2007, 5, 286; (b) J. Qi and
J. A. Porco, Jr, J. Am. Chem. Soc., 2007, 129, 12682.
5. (a) J. K. F. Geirsson, J. F. Johannesdottir and S. Jonsdottir, Synlett,
1993, 133; (b) J. K. F. Geirsson and J. F. Johannesdottir, J. Org.
Chem., 1996, 61, 7320; (c) K. Aoyagi, H. Nakamura and
Y. A. Yamamoto, J. Org. Chem., 1999, 64, 4148; (d) J. K.
F. Geirsson and E. G. Eiriksdottir, Synlett, 2001, 664; (e) J. K.
F. Geirsson, L. Arnadottir and S. Jonsson, Tetrahedron, 2004, 60, 9149.
6. J. K. F. Geirsson, S. Jonsson and J. Valgeirsson, Bioorg. Med.
Chem., 2004, 12, 5563.
Fig. 1 X-Ray structure of (1R,4R,5S,6S,7R,9S)-tetramethyl 7-(2-
bromophenyl)-3,5-dihydroxybicyclo[3.3.1]non-2-ene-2,4,6,9-tetracar-
boxylate 4i. Colour coding: white: hydrogen; grey: carbon; red:
oxygen; green: bromine. Some hydrogen atoms are omitted for clarity.
This new organocatalytic reaction can easily be scaled up to
gram scale and isolation of the optically active bicyclo[3.3.1]-
non-2-enes 4 was performed using chromatography-free pro-
cedures by crystallizing the product after finishing the
reaction. Using this procedure, product 4a was isolated in 3
g quantity (44% yield, compared to 48% on the mg scale) and
as an enantiopure compound; i.e. dr 499 : 1 and 499% ee.
The other products could also be isolated as enantiopure
compounds after recrystallization.
The optically active bicyclo[3.3.1]non-2-enes having
6
stereocenters are set up for the introduction of 2 additional
stereocenters in the ring systems and e.g. initial hydrogenation
studies of the enol in 4a shows promising results and is
currently under investigation.
The absolute configuration of tetramethyl 7-(2-bromophenyl)-
3,5-dihydroxybicyclo[3.3.1]non-2-ene-2,4,6,9-tetracarboxylate 4i,
was unambiguously established as (1R,4R,5S,6S,7R,9S) by
X-ray crystallographic analysis (Fig. 1).8
7. For design and introduction of this catalytic system see: e.g.:
(a) M. Marigo, T. C. Wabnitz, D. Fielenbach and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 794. See also:
(b) M. Marigo, D. Fielenbach, A. Braunton, A. Kjærsgaard and
K. A. Jørgensen, Angew. Chem., Int. Ed., 2005, 44, 3703;
(c) Y. Hayashi, H. Gotoh, T. Hayashi and M. Shoji, Angew. Chem.,
Int. Ed., 2005, 44, 4212; (d) J. Franzen, M. Marigo, D. Fielenbach,
T. C. Wabnitz, A. Kjærsgaard and K. A. Jørgensen, J. Am. Chem.
Soc., 2005, 127, 18296; (e) C. Palomo and A. Mielgo, Angew.
Chem., Int. Ed., 2006, 45, 7876.
8. Crystal data for [4i]w: C23H25BrO10, M = 540.06, orthorhombic,
space group P21212 (no. 112), a = 15.9364(7) A, b = 15.936(0) A,
c = 18.6763(10) A, V = 4743.2(3) A3, T = 293 K, Z = 8, Dc =
1.516 g cmÀ3, m(Mo Ka, l = 0.71073 A) = 1.789 mmÀ1, 16 280
reflections collected, 5229 unique [Rint = 0.0296], which were
used in all calculations. Refinement on F2, final R(F) = 0.044,
wR(F2) = 0.0808.
Organocatalysis has been taken to a new level, allowing the
selective formation of 4 new carbon–carbon bonds, providing
6 new stereocenters, one of which is quaternary, leading to the
controlled synthesis of 1 out of 64 possible stereoisomers by
mixing two simple molecules, an a,b-unsaturated aldehyde
and a tricarbonyl compound. The products generated, opti-
cally active bicyclo[3.3.1]non-2-enes, are formed in high yield,
and with excellent diastereo- and enantiocontrol and perform-
ing the reaction on the gram scale leads to optically pure
products. The optically active bicyclo[3.3.1]non-2-enes are
bicyclic carbon skeletons which are precursors for important
biomolecules with antitumor activity.
9. Note added in proof: O. Penon, A. Carlone, A. Mazzanti,
M. Locatelli, L. Sambri, G. Bartoli and P. Melchiorre, Chem.–Eur.
J., 2008, 14, 4788.
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This journal is The Royal Society of Chemistry 2008
3018 | Chem. Commun., 2008, 3016–3018