Crossed intramolecular rauhut-currier-type reactions via dienamine activation

Article abstract of DOI:10.1021/ol901614t

The intramolecular Rauhut-Currier reaction creates a carbon-carbon bond between two tethered Michael acceptors. Previous asymmetric versions have relied on 1,4-additions of chiral nucleophilic catalysts. Herein, we Investigate a novel strategy that involves the formation of electron rich dienamines as key Intermediates. Our methodology provides an efficient entry to the iridoid framework.

Full text of DOI:10.1021/ol901614t

ORGANIC
LETTERS
2009
Vol. 11, No. 18
4116-4119
Crossed Intramolecular
Rauhut-Currier-Type Reactions via
Dienamine Activation
Eugenia Marque´s-Lo´pez, Raquel P. Herrera, Timo Marks, Wiebke C. Jacobs,
Daniel Ko¨nning, Renata M. de Figueiredo, and Mathias Christmann*
TU Dortmund UniVersity, Otto-Hahn-Str. 6, D-44227 Dortmund, Germany
mathias.christmann@tu-dortmund.de
Received July 14, 2009
ABSTRACT
The intramolecular Rauhut-Currier reaction creates a carbon-carbon bond between two tethered Michael acceptors. Previous asymmetric
versions have relied on 1,4-additions of chiral nucleophilic catalysts. Herein, we investigate a novel strategy that involves the formation of
electron rich dienamines as key intermediates. Our methodology provides an efficient entry to the iridoid framework.
The use of functionalized chiral scaffolds as switches for
biological signaling pathways has spurred the development
Scheme 1
.
Activation of R,ꢀ-Unsaturated Aldehydes with
Different Nucleophilic Catalysts
of new reactions for their rapid assembly by means of
asymmetric synthesis.1 In this context, organocatalysis2
complements existing transition metal-based catalysis al-
lowing for the enantioselective synthesis of densely func-
tionalized hetero- and carbocyclic motifs with often orthogo-
nal chemoselectivity.3
While R,ꢀ-unsaturated aldehydes4 1 are traditionally used
as a1/a3-synthons (Scheme 1), organocatalysis has added new
value to this important structural class. In addition to the
(1) (a) Carreira, E. M.; Kvaerno, L. Classics in StereoselectiVe Synthesis:
Wiley-VCH: Weinheim, 2008. (b) Asymmetric Synthesis: The Essentials;
Christmann, M., Bra¨se, S., Eds.; Wiley-VCH: Weinheim, 2007.
(2) (a) Berkessel, A.; Gro¨ger, H. Asymmetric Organocatalysis; Wiley-
VCH: Weinheim, 2005. (b) Erkkila¨, A.; Majander, I.; Pihko, P. M. Chem.
ReV. 2007, 107, 5416. (c) Mukherjee, S.; Yang, J. W.; Hoffmann, S.; List,
B. Chem. ReV. 2007, 107, 5471. (d) de Figueiredo, R. M.; Christmann, M.
Eur. J. Org. Chem. 2007, 2575. (e) Dondoni, A.; Massi, A. Angew. Chem.,
Int. Ed. 2008, 47, 2. (f) Melchiorre, P.; Marigo, M.; Carlone, A.; Bartoli,
G. Angew. Chem., Int. Ed. 2008, 47, 6138. (g) Mielgo, A.; Palomo, C.
Chem. Asian J. 2008, 3, 922. (h) Bertelsen, S.; Jørgensen, K. A. Chem.
Soc. ReV. 2009, 38, 2178.
long-known 1,4-addition of nucleophilic catalysts (1 f 2)
such as tertiary phosphines, 1,2-additions have recently
allowed for new chemoselective transformations. N-Hetero-
cyclic carbenes have converted 1 into homoenolate equiva-
lents5 3 and secondary amines have been shown to convert
(3) Shenvi, R. A.; O’Malley, D. P.; Baran, P. S. Acc. Chem. Res. 2009,
42, 530.
(4) Escher, I.; Glorius, F. Sci. Synth. 2007, 25, 733.
10.1021/ol901614t CCC: $40.75
Published on Web 08/12/2009
 2009 American Chemical Society

1 into electron-rich dienamines6 5 via iminium ion 4, a key
intermediate in iminium ion catalysis.7
pharmacological activities.18 We started our investigations
using compound 6a as the test substrate in order to explore
the viability of an enantioselective cyclization to give
cyclopentene 7a. An initial screening of catalysts I-V in
the absence of any additives revealed catalyst IV to be best
in terms of both reactivity and enantioselectivity (Table 1,
entries 1-5).
The intramolecular Rauhut-Currier (RC) reaction8 gener-
ates chiral cycloalkenes from acyclic precursors bearing two
tethered Michael acceptors. Surprisingly, a transannular
version of this reaction by Moore9 preceded thorough
investigations of Krische10 and Roush11 of intramolecular
RC reactions using alkyl phosphines as catalyst. In 2007,
Miller12 and shortly after Gladysz13 reported enantioselective
intramolecular RC reactions of bis(enones). While Miller
used cysteine derivatives as catalyst, Gladysz employed
phosphines associated with a chiral rhenium complex.
Recently, Scheidt14 made progress in the intermolecular RC
reaction using silyloxyallenes. There is also evidence for the
involvement of RC-type processes in biosynthesis of iri-
dodials.15
Table 1. Catalyst and Solvent Screeninga
Our previous work6h in the area of dienamine catalysis
was concerned with the d4-reactivity of R,ꢀ-unsaturated
aldehydes (1 f 5). Herein, we report the potential of 5 as a
d2-synthon in a mechanistically distinct RC-type reaction.
Since the Jørgensen-Hayashi catalyst (IV) is specific toward
aldehydes, selective activation over other Michael acceptors
such as R,ꢀ-unsaturated ketones might be attainable. More
importantly, this mode of activation should allow the
activation of ꢀ-disubstituted alkenes, thereby providing an
entry into the iridoid class16,17 of natural products, found
widely in plants and insects which possess important
entry catalyst additive solvent time (h) yieldb (%) eec (%)
1
2
3
4
I
II
III
IV
V
IV
IV
IV
IV
IV
IV
VI
VII
IV
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
72
72
72
72
72
3
24
28
28
3
22
n.d.
6
79
-
60
32
57
41
29
32
57
58
58
53
63
88
94
89
93
44
93
87
91
76
54
91
5
(5) (a) Burstein, C.; Glorius, F. Angew. Chem., Int. Ed. 2004, 43, 6205.
(b) Sohn, S. S.; Rosen, E. L.; Bode, J. W. J. Am. Chem. Soc. 2004, 126,
14370. (c) Phillips, E. M.; Wadamoto, M.; Chan, A.; Scheidt, K. A. Angew.
Chem., Int. Ed. 2007, 46, 3107.
6
AcOH CH2Cl2
AcOH CH2Cl2
AcOH PhMe
AcOH MeCN
AcOH CHCl3
AcOH CH2Cl2
AcOH CH2Cl2
AcOH CH2Cl2
AcOH CH2Cl2
7d
8
(6) (a) Chen, S.-H.; Hong, B.-C.; Su, C.-F.; Sarshar, S. Tetrahedron
Lett. 2005, 46, 8899. (b) Bench, B. J.; Liu, C.; Evett, C. R.; Watanabe,
C. M. H. J. Org. Chem. 2006, 71, 9458. (c) Bertelsen, S.; Marigo, M.;
Brandes, S.; Diner, P.; Jørgensen, K. A. J. Am. Chem. Soc. 2006, 128, 12973.
(d) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.; Liao, J.-H. Org. Lett. 2006, 8,
2217. (e) Utsumi, N.; Zhang, H.; Tanaka, F.; Barbas, C. F., III. Angew.
Chem., Int. Ed. 2007, 46, 1878. (f) Hong, B.-C.; Wu, M.-F.; Tseng, H.-C.;
Huang, G.-F.; Su, C.-F.; Liao, J.-H. J. Org. Chem. 2007, 72, 8459. (g)
Hong, B.-C.; Tseng, H.-C.; Chen, S.-H. Tetrahedron 2007, 63, 2840. (h)
de Figueiredo, R. M.; Fro¨hlich, R.; Christmann, M. Angew. Chem., Int.
Ed. 2008, 47, 1450. (i) Han, B.; He, Z.-Q.; Li, J.-L.; Li, R.; Jiang, K.; Liu,
T.-Y.; Chen, Y.-C. Angew. Chem., Int. Ed. 2009, 48, 5474. (j) Hong, B.-
C.; Nimje, R. Y.; Liao, J.-H. Org. Biomol. Chem. 2009, 7, 3095.
(7) Ahrendt, K. A.; Borths, C. J.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2000, 122, 4243.
9
10
11e
12e
13e
14e,f
4
4
4
5
a Experimental conditions: to a solution of aldehyde 6a (0.19 mmol)
and additive (26 mol %) in 0.5 mL of solvent, 26 mol % of catalyst I-VII
in 1 mL of solvent was added at room temperature. The product was purified
by flash chromatography. b Yield of isolated product. c Determined by HPLC
methods. d Reaction was carried out at +5 °C. e Slow addition (5-10 min)
of aldehyde 6a in CH2Cl2 (1.0 mL) to a solution of the catalyst (20 mol %)
and the additive (20 mol %) in CH2Cl2 (0.5 mL). f 0.36 mmol scale.
(8) (a) Rauhut, M. M.; Currier, H. US Patent 3,074,999, 1963. For an
excellent review, see: (b) Aroyan, C. E.; Dermenci, A.; Miller, S. J
Tetrahedron 2009, 65, 4069.
(9) Erguden, J. K.; Moore, H. W. Org. Lett. 1999, 1, 375.
(10) Wang, L.-C.; Luis, A. L.; Agapiou, K.; Jang, H.-Y.; Krische, M. J.
J. Am. Chem. Soc. 2002, 124, 2402.
The use of acetic acid as an additive led to a considerable
increase in the reaction rate without impairing the enanti-
oselectivity (entry 6). Lowering the temperature to 5 °C
improved the enantioselectivity at the expense of reactivity
and yield (entry 7). Switching solvents to toluene or
acetonitrile (entries 8 and 9) again had a negative influence
on the reactivity whereas the use of chloroform gave
comparable results (entry 10). Slow addition of the substrate
to a solution of the catalyst IV was the key to lowering the
(11) (a) Frank, S. A.; Mergott, D. J.; Roush, W. R. J. Am. Chem. Soc.
2002, 124, 2404. (b) Thalji, R. K.; Roush, W. R. J. Am. Chem. Soc. 2005,
127, 16778.
(12) Aroyan, C. E.; Miller, S. J. J. Am. Chem. Soc. 2007, 129, 256.
(13) Seidel, F.; Gladysz, J. A. Synlett 2007, 986.
(14) Reynolds, T. E.; Binkley, M. S.; Scheidt, K. A. Org. Lett. 2008,
10, 2449.
(15) Lorenz, M.; Boland, W.; Dettner, K. Angew. Chem., Int. Ed. 1993,
32, 912.
(16) Unelius performed formal [4 + 2]-cycloadditions with 8-oxocitral
and stoichiometric amounts of chiral secondary amines leading to iridoids:
Santangelo, E. M.; Liblikas, I.; Mudalige, A.; To¨rnroos, K. W.; Norrby,
(18) (a) Pasteels, J. M.; Rowell-Rahier, M.; Braekman, J.-C.; Daloze,
D. Biochem. Syst. Ecol. 1984, 12, 395. (b) Boros, C. A.; Stermitz, F. R. J.
Nat. Prod. 1990, 53, 1055. (c) Boros, C. A.; Stermitz, R. R. J. Nat. Prod.
1991, 54, 1173. (d) Dawson, G. W.; Pickett, J. A.; Smiley, W. M. Bioorg.
Med. Chem. 1996, 4, 351.
P.-O.; Unelius, C. R. Eur. J. Org. Chem. 2008, 5915
.
(17) (a) Tundis, R.; Loizzo, M. R.; Menichini, F.; Statti, G. A.;
Menichini, F. Mini-ReV. Med. Chem. 2008, 8, 399. (b) Nangia, A.; Prasuna,
G.; Rao, B. Tetrahedron 1997, 53, 14507
Org. Lett., Vol. 11, No. 18, 2009
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catalyst loading down to 20 mol %, which was accompanied
by a slight increase in the asymmetric induction (entry 11).
However, employing catalysts VI and VII in this manner
offered no improvements (entries 12 and 13). Finally, at 0.36
mmol scale we were able to increase the yield to 63% and
91% ee (entry 14). In order to evaluate the scope of this
new cyclization, various aldehydes (6b-h) were allowed to
react under the optimized conditions. The desired iridoid
aldehydes (7b-h) were obtained in good yields and enan-
tioselectivities up to 96% ee as shown in Table 2.
Electron-withdrawing groups in the aromatic ring increase
the reaction rate (entries 2-4), whereas the electron-donating
4-methoxy substituent reduced the reaction rate significantly
(entry 5). Other Michael acceptors such as nitroalkenes can
be employed but the reaction proceeds with somewhat lower
enantioselectivity (entry 6). The presence of a methyl group
in the ꢀ-position of the aldehyde was crucial to the
enantioselectivity and the reaction rate. We speculate that
the methyl substituent renders the dienamine more nucleo-
philic and lowers the relative energy of the required
3Z-configuration (vide infra). In order to determine the
stereochemical outcome of the cyclization, single crystals
were obtained from 7e, and the absolute configuration was
determined to be R (Figure 1).
Table 2. Substrate Scopea
Figure 1. X-ray crystal structure of (R)-7e.
To further demonstrate the utility of our methodology, we
identified (+)-rotundial (7h, entry 7), a powerful mosquito
repellent from Vitex rotundifolia,19 as target molecule for
the application of an asymmetric RC-type cyclization. The
precursor dialdehyde 6h was obtained in five steps from
geranyl acetate. The yield of the cyclization step (36%, 86%
ee) was hampered by the sensitivity of rotundial to degrada-
tion.20 The overall yield (25%) compares favorably with
previous syntheses,21 and the sign of the optical rotation was
in agreement with the assumed (R)-configuration.
Based on our previous experience, we propose the fol-
lowing catalytic cycle which is in agreement with our
observations although further experiments will be necessary
to support this working hypothesis (Scheme 2).
The first step is the condensation of the substrate 6a with
the catalyst IV to form an iminium ion 8.22 Jørgensen has
shown using NMR studies that the iminium ion exists in an
equilibrium with the electron-rich dienamine 9.23 Previous
work has focused on its reactivity as d4-synthon. In this
instance, we were able to exploit the d2-reactivity with the
aid of sterics. It is conceivable that acetic acid assists in the
formation of the carbon-carbon bond by activating the
acceptor. In our model system, the tentative intermediate is
(19) Watanabe, K.; Takada, Y.; Matsuo, N.; Nishimura, H. Biosci.
Biotech. Biochem. 1996, 59, 1979.
a Experimental conditions: to a solution of IV·AcOH (20 mol %) in
CH2Cl2 (1 mL) was slowly added (5-10 min) a solution of aldehydes 6b-h
(0.36 mmol) in CH2Cl2 (2 mL) at room temperature. The products (7b-h)
were isolated by flash chromatography. b Isolated yield. c Determined by
HPLC methods. d After one recrystallization.
(20) Another possible explanation is capture of the catalyst as described
by Unelius (ref 16).
(21) For the first synthesis of (R)- and (S)-rotundial, see: Takikawa, H.;
Yamazaki, Y.; Mori, K. Eur. J. Org. Chem. 1998, 229.
(22) (a) Seebach, D.; Grosˇelj, U.; Badine, D. M.; Schweizer, W. B.;
Beck, A. K. HelV. Chim. Acta 2008, 91, 1999. (b) Grosˇelj, U.; Schweizer,
W. B.; Ebert, M.-O.; Seebach, D. HelV. Chim. Acta 2009, 92, 1.
(23) For theoretical discussions concerning dienamine intermediates, see
ref 6d and: Duarte, F. J. S.; Cabrita, E. J.; Frenking, G.; Santos, A. G.
Chem.sEur. J. 2009, 15, 1734.
The electronic environment at the acceptor strongly
influences the reaction rate and the enantioselectivity.
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Org. Lett., Vol. 11, No. 18, 2009

Scheme 2. Proposed Reaction Mechanism
cis-10.24 Hydrolysis of the iminium ion would lead to
compound cis-11.25 However, it should be noted that each
step in the catalytic cycle is reversible and proton abstraction
(10 f 12) and reprotonation (12 f 10) could easily lead to
trans-10. Presumably, hydrolysis of 10 is slow; therefore,
protonation of 12 in the γ-position leads to iminium ion 13,
which upon hydrolysis releases 7a to regenerate the catalyst.
In summary, we have developed an enantioselective
organocatalytic RC-type cyclization of R,ꢀ-unsaturated al-
dehydes catalyzed by the commercially available Jørgensen-
Hayashi catalyst IV. The iridoid products, cyclopentene
derivatives bearing a tetra-substituted olefin, were obtained
in moderate to good yields and with good enantioselectivity.
Due to the unprecedented mode of activation in RC-processes
(1,2- vs 1,4-activation), complementary chemoselectivity can
be achieved. The extremely simple operational procedure and
the synthetic versatility of the products render this new
approach highly appealing for the synthesis of optically active
iriods, such as (+)-rotundial.
Acknowledgment. Financial support was provided by the
DFG (SPP1179), the Fonds der Chemischen Industrie
(Dozentenstipendium to M. C.), the Alexander von Humboldt
Foundation (fellowship to E. M.-L.) and the Arago´n I+D
Foundation and the Spanish Ministry of Science and In-
novation (Programa Nacional de Movilidad de Recursos
Humanos del Plan Nacional de I-D+I 2008-2011) and CSIC
(PIE 200880I260) (R. P. H.). We thank Dr. Pablo J. Sanz
Miguel (TU Dortmund University) for X-ray structure
analysis.
Supporting Information Available: Experimental pro-
cedures, NMR spectra, and characterization of all new
compounds. This material is available free of charge via the
Internet at http://pubs.acs.org
(24) The possibility of the enone to adopt an s-cis conformation and
participate in a formal [4 + 2]-process leading to Unelius-type intermediates
followed by hydrolytic cleavage of the catalyst cannot be ruled out
completely.
(25) EZ-Isomerization of the enol moiety of 10 could lead to an
intramolecular attack of the iminium ion and to a dead end in the catalytic
cycle .
OL901614T
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