Synergic asymmetric organocatalysis (SAOc) of Cinchona alkaloids and secondary amines in the synthesis of bicyclo[2.2.2]octan-2-ones

Article abstract of DOI:10.1039/b816550e

A synergistic effect between chiral secondary and tertiary amines gives access to bicyclo[2.2.2]octan-2-ones with up to 90% ee and >10: 1 dr. The Royal Society of Chemistry.

Full text of DOI:10.1039/b816550e

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Synergic asymmetric organocatalysis (SAOc) of Cinchona alkaloids and
secondary amines in the synthesis of bicyclo[2.2.2]octan-2-oneswz
Marco Bella,* Daniele M. Scarpino Schietroma, Pier Paolo Cusella, Tecla Gasperi
and Valerio Visca
Received (in Cambridge, UK) 22nd September 2008, Accepted 19th November 2008
First published as an Advance Article on the web 8th December 2008
DOI: 10.1039/b816550e
A synergistic effect between chiral secondary and tertiary
amines gives access to bicyclo[2.2.2]octan-2-ones with up to
90% ee and 410 : 1 dr.
With the renaissance of organocatalysis in the past few years,
several strategies to activate nucleophiles have been developed and
amid them stands functionalization of the aldehyde a-position.1
Fig. 1 Privileged catalysts in the enamine activation of aldehydes.
Among the common features of the privileged structures
(Fig. 1) employed as asymmetric catalysts,2 emerges (i) a second-
ary amine functional group, framed into a five membered ring
activating the aldehyde via the formation of a reactive enamine (in
structures I–IV) and (ii) a carboxylic acid or isostere group in I and
II. Catalysts such as III or IV, due to their increased steric bulk,
show reduced reaction rates with respect to I or II. Several authors
have reported the importance of an additional acid as co-catalyst
in order to significantly improve yields and conversion (HCl, TFA
or HClO4 are employed in the case of III and generally substituted
benzoic acids are employed with IV).3 A proton source, either
present in the molecule or externally added, is crucial to achieve
Scheme 1 Reaction between aldehydes 1a,b and enone 2 mediated by
elevated yields because it increases catalyst turnover, speeding up
the hydrolysis rate of the functionalized enamine.
I Li-salt as the catalyst. Y = 81% for 3a,b; 75% for 4a,b.
The reaction is a formal [4 + 2] cycloaddition;8 the two
In this work, we present a strategy in which aldehydes are
activated towards electrophilic attack by a secondary amine in
combination not with an acid, but instead with a base.4 Notably,
column chromatography. Concentration of the crude reaction
diastereoisomers could be easily and completely separated by
we demonstrate that by employing the Cinchona alkaloids, which
feature another privileged framework in asymmetric synthesis,5 the
50% yield as a racemate. This novel cascade reaction generates
mixture after aqueous workup affords white crystals of 3a in about
four stereocenters in a single operation.9 It is also worth noting that
reactivity is enhanced and a higher degree of stereocontrol is
achieved. This new type of catalysis is an example of synergic
asymmetric organocatalysis, (SAOc); synergy comes from the
it affords good yields even when a-substituted aldehyde 1b is
employed, generating an all C-substituted quaternary stereocenter.
Greek words syn, together, and ergon, work, and describes a
The use of a-substituted aldehydes like 1b in enamine catalysis is
situation where the outcome is greater than the sum of the parts.6
The transformation in which we have exploited this concept
is the formal cycloaddition of aldehydes to cyclic enones.
Adding phenylacetaldehyde 1a or hydratropaldehyde 1b
(1.1 eq.) to 2-cyclohexen-1-one 2 (1 eq.) in toluene saw no
reaction with or without stoichiometric catalysts I or II. Upon
the addition of I-Li salt,7 disappearance of the reagents was
observed within 24 h and two diastereoisomers, 3a,b and 4a,b,
were isolated in good yields (Scheme 1).
less common with respect to unsubstituted aldehydes such as 1a.10
Given the importance of this transformation, affording in a quick
and straightforward way the bicyclo[2.2.2]octan-2-one framework
that is present in numerous biologically interesting as well as
natural substances,11 and the lack of direct access to these mole-
cular architectures, we further investigated in order to develop an
efficient, stereoselective and catalytic reaction.
Upon addition of I-Li salt (Table 1, entry 3) a good yield of 4a
and 4b was achieved within 3 days, although, with low stereo-
control (ees = 23 and 33%). The addition of a tertiary amine
co-catalyst afforded similar results (entries 4 and 5). Quinine Q
(entry 6) gave a modest but significant increase in the enantio-
selection. After screening several commercially available as well as
synthesized Cinchona alkaloid derivatives,12,13 we found that
dihydrocupreine (desmethyldihydroquinine) DHCp increased
both the reaction rate and the enantioselectivity (entry 7).
The reaction stereoselection appears to be steered essen-
tially by the secondary amine. Using the dihydrocupreidine
Dipartimento di Chimica and Istituto di Chimica Biomolecolare del
`
CNR, Universita di Roma ‘‘Sapienza’’, P. le Aldo Moro 5,
00185 Roma, Italy. E-mail: marco.bella@uniroma1.it;
Fax: (+)39 06 490631
w The authors wish to dedicate this paper to Professor Giovanni
Piancatelli on the occasion of his 71st birthday.
z Electronic supplementary information (ESI) available: Characteri-
zation of new compounds and crystallographic data for 6a. CCDC
701756. For ESI and crystallographic data in CIF or other electronic
format see DOI: 10.1039/b816550e
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Table
Scheme 1): screening of the catalyst system (R = Me, H)
1
Catalytic enantioselective addition of 1a,b to
2
(see
reaction had low conversion but yield and ee were further
improved with the use of veratrol as the solvent (entry 20): 3a
could then be finally obtained as a single diastereoisomer with
87% ee (15 : 1 dr). About 60% of the original amount of
2-cyclohexen-1-one can be recovered while the aldehydes
employed underwent autocondensation reactions due the long
reaction time. In combination with thiazoline V, cupreines as
co-catalysts led to a faster reaction but with lower ees.
We then extended this methodology to some substituted
acetaldehydes (Table 2, entries 1–4) achieving ees of up to 90%.
Absolute and relative stereochemistry has been established via
single crystal X-ray analysis on 6a (entry 2, Table 2).z A possible
reaction mechanism is presented in Scheme 2: enamine activation
occurs via deprotonation by the additional tertiary amine base,
generating the reactive enamines 11a–f and 12a–f. Thiazoline V
and proline I give rise to the prevalent formation of opposite
enantiomeric products 4a and 3–8a, which is in agreement with
reversed conformation of enamine intermediates 9a–f and 10a–f.
The enamine derived from proline I generally attacks the electro-
phile from its most hindered Re face because of hydrogen
bonding;1,2 instead in this case the 2-cyclohexen-1-one 2 is
approached from the more accessible Si face.16 Magnification of
ees is rationalized assuming that a larger cation (protonated Q
instead of Li+) for deprotonated enamines 11a–f and 12a–f
enhances enamine Re face shielding. After the a-functionalization
the secondary amine catalysts I and V are released and unstable
aldehydes 11a–f undergo spontaneous intramolecular aldol reac-
tion to afford the bicyclo[2.2.2]octan-2-one system. Aromatic
solvents are necessary to achieve high ees suggesting that tight
ion pairing is crucial, as is similarly observed in Cinchona alkaloids
catalysis, to control the reaction stereoselection. Nearly racemic
products are obtained with the most common solvents for enamine
catalysis, such as DMSO, DMF, or with the addition of water.
To the best of our knowledge, the only enone successfully
reacting in the intermolecular Michael addition of aldehyde
enamines is the especially reactive methyl vinyl ketone;17 we
are unaware of other intermolecular additions of aldehydes to
2-cyclohexen-1-one 2 or other cyclic enones.18
Entrya
R
Catalysts
drb
ee (%)b
Yield (%)c
1
2
3
4
5
6
7
8
Me
Me
I
Q
—
—
—
—
—
—
82
76
72
75
85
83
80
75
Me I Li salt
1 : 1.3
1 : 1.5
1 : 1.4
1 : 1.5
1 : 1.6
1 : 1.8
1 : 2.3
23/33
20/30
21/31
33/44
64/64
66/60
ꢁ68/ꢁ72d
ꢁ51/ꢁ50d
Me I + Et3N
Me I + DBU
Me I + Q
Me I + DHCp
Me I + DHCpd
Me Ent-I + DHCp
Me Ent-I + DHCpd 1 : 2.2
Me Ent-I + DHCpd 1 : 3
Me II
Me II + Q
Me II + DHCp
H
H
H
H
H
H
9
10
11
12
13
14
15
16
17
18
19
20
ꢁ71/ꢁ80d,e 55
—
—
—
74
82
84
74
83
1 : 1.5
1 : 1.8
1 : 4
1 : 2.5
1 : 4
28/16
35/44
10/17
62/41
66/48
I Li salt
I + Q
I + DHCp
V Li Salt
V + Q
1 : 1.2
1 : 6
ꢁ62/ꢁ63d,f 23
Nd/ꢁ82d,f
22
V + Q
o1 : 10 —/ꢁ87d,f,g 41
a
Reactions performed with 0.5 mmol of 2 and 0.55 mmol of 1a,b in 1 mL
of toluene and catalyzed by 25 mol% I and 25 mol% Cinchona alkaloid;
reaction time 3 days. b dr (3,4b : 3,4a) and ee% (3,4a/3,4b) determined by
c
HPLC using a IC Chiralpack column. Isolated yield of pure material
after flash chromatography. d Negative ee indicates the prevalent forma-
e
tion of the enantiomer with opposite absolute configuration. Reaction
f
temperature 4 1C and reaction time 7 days. Reaction time 14 days.
Veratrol (1,2-dimethoxybenzene) as the solvent; reaction time 3.5 days.
g
Bicyclo[2.2.2]octan-2-one 3a was regioselectively oxidized to 14 as
depicted in Scheme 3; the corresponding lactone can be easily opened
in basic conditions to give densely functionalized cyclohexanes.
pseudoenantiomer DHCpd, comparable enantiomeric excess
was achieved (entry 8); inversion of the product’s absolute con-
figuration is observed instead when the proline I enantiomer is
used, again with a similar ee% value (entries 9 and 10). Lower
reaction temperatures led to the magnification of ees (entry 11).
Similar results were obtained with catalyst II: ees increased
when dihydrocupreine co-catalyst was used (entries 13 and 14).
When reacting phenylacetaldehyde 1a, good control of the
absolute stereochemistry of the less abundant diastereoisomer
3b was obtained, but achieving high ees on the major diastereo-
isomer proved challenging (entries 15–17).
Table 2 Examples of enantioselective addition of aldehydes 1c–f to 2
mediated by synergic organocatalytic combination of V and Q
Entrya Ar
Time/daysc drb
ee (%)b Yield (%)c
25
We then tested the 2,2-dimethyl thiazoline carboxylate V-Li salt
and we observed moderate ees, (above 60% for both diastereo-
isomers, entry 18) with no significant diastereoselection. Notably,
our synergic organocatalytic approach also led to the activation
of thiazoline catalyst V, which has not been used previously
in asymmetric organocatalysis,14,15 probably because of its
low reactivity. Quinine as co-catalyst not only increased the
enantioselectivity to 82% ee, but also induced the preferential
formation of one diastereoisomer (entry 19). In toluene the
1
2
3
4
4-Br-Ph, 5
4-Cl-Ph, 6
4-OMe-Ph, 7
2-Napththyl, 8
14
5
410 : 1 90
410 : 1 81
33
21
20
8
8
410 : 1 82
410 : 1 72
a
Reactions performed with 0.5 mmol of 2 and 0.55 mmol of 1c–f, with
b
1 mL of veratrol and catalyzed by 25 mol% V and Q. dr and ee%
c
determined by HPLC using IC Chiralpack column. Isolated yield of
pure material after FC.
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37(8), special issue on organocatalysis; (d) J. Seayad and B. List, Org.
Biomol. Chem., 2005, 3, 719; (e) B. List, Chem. Commun., 2006, 819;
(f) P. I. Dalko, Enantioselective Organocatalysis, Wiley-VCH,
Weinheim, 2007; (g) Chem. Rev., 2007, 107(12).
2 II: (a) D. A. Longbottom, V. Franckevicius, S. Kumarn,
A. J. Oelke, V. Wascholowski and S. V. Ley, Aldrichimica Acta,
2008, 41, 3; III: (b) C. Palomo and A. Mielgo, Angew. Chem., Int.
Ed., 2006, 45, 7876; IV: (c) G. Lelais and D. W. C. MacMillan,
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3 (a) S. Bertelsen, N. Halland, S. Bachmann, M. Marigo, A. Braunton
and K. A. Jørgensen, Chem. Commun., 2005, 4821; (b) T. J. Peelen,
Y. Chi and S. H. Gellman, J. Am. Chem. Soc., 2005, 127, 11598.
4 Achiral bases and proline: (a) B.-C. Hong, M.-F. Wu, H.-C. Tseng and
J.-H. Liao, Org. Lett., 2006, 8, 2217; for use of Cinchona alkaloids and
proline but with decreased ees (antagonist effect) see: (b) B.-C. Hong,
M.-F. Wu, H.-C. Tseng, G.-F. Huang, C.-F. Su and J.-H. Liao, J. Org.
Chem., 2007, 72, 8459; proline and amino acids in combination with
Cinchona alkaloid derived thiourea: (c) T. Mandal and C.-G. Zhao,
Angew. Chem., Int. Ed., 2008, 47, 7714.
5 (a) K. Kacprzak and J. Gawronski, Synthesis, 2001, 961; (b) ref. 1b;
(c) ref. 1g.
6 With no doubt several already published catalytic systems can be
included in this definition. Multifunctional catalysis occurs when two or
more functionalities covalently bound in the same molecule activate
both the electrophile and the nucleophile reagents; examples:
(a) M. Shibasaki, Chemtracts, 1999, 12, 979; (b) M. Shibasaki and
N. Yoshikawa, Chem. Rev., 2002, 102, 2187; (c) H. Li, Y. Wang,
L. Tang and L. Deng, J. Am. Chem. Soc., 2004, 126, 9906;
(d) B. Wang, F. Wu, Y. Wang, X. Liu and L. Deng, J. Am. Chem.
Soc., 2007, 129, 768.
7 Early use of prolinates: (a) M. Yamaguchi, T. Shiraishi and
M. Hirama, J. Org. Chem., 1996, 61, 3520; proline activation by
amines: (b) S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975; chiral
amines and proline: (c) T. Hongying, Z. Guofeng, Z. Zhenghong,
P. Gao, H. Liangnian and T. Chuchi, Eur. J. Org. Chem., 2008, 126.
8 Examples of formal organocatalytic cycloadditions: (a) Y. Yamamoto,
N. Momiyama and H. Yamamoto, J. Am. Chem. Soc., 2004, 126,
5962; (b) C.-L. Cao, X.-L. Sun, Y.-B. Kang and Y. Tang, Org. Lett.,
2007, 9, 4151; (c) ref. 4a–b.
Scheme 2 Proposed mechanism of the formal [4 + 2] cycloaddition
catalyzed by I or V and Q.
9 Organocatalytic cascade reactions with several stereocenters
formed at once: (a) D. Enders, M. R. M. Huttl, C. Grondal and
G. Raabe, Nature, 2006, 441, 861; (b) S. Bertelsen, R. L. Johansen
and K. A. Jørgensen, Chem. Commun., 2008, 3016; (c) X. Yu and
W. Wang, Org. Biomol. Chem., 2008, 6, 2037.
Scheme 3 Baeyer–Villiger oxidation of 3a.
10 Enamine mediated formation of quaternary stereocenters:
(a) N. S. Chowdari and C. F. Barbas III, Org. Lett., 2005, 7,
867; (b) S. Brandes, B. Niess, M. Bella, A. Prieto, J. Overgaard and
K. A. Jørgensen, Chem.–Eur. J., 2006, 12, 6039; (c) O. Penon,
A. Carlone, A. Mazzanti, M. Locatelli, L. Sambri, G. Bartoli and
P. Melchiorre, Chem.–Eur. J., 2008, 14, 4788; (d) D. Enders,
C. Wang and W. Bats, Angew. Chem., Int. Ed., 2008, 47, 7539.
11 S. Di Stefano, F. Leonelli, B. Garofano, L. Mandolini, R. Marini
Bettolo and L. M. Migneco, Org. Lett., 2002, 4, 2783 and ref. therein.
12 Covalently bound proline-cinchonine: J.-R. Chen, X.-L. An,
X.-Y. Zhu, X.-F. Wang and W.-J. Xiao, J. Org. Chem., 2008, 73, 6006.
13 Complete screening results will be reported in a full account;
cinchonine (R1 = H) gave lower ee; proline and Cinchona alkaloid
molar ratio in the range 1 : 2 to 2 : 1 gave no significant ee
variation. No synergic effect was observed when catalysts III or IV
were employed together with quinine or other Cinchona alkaloids.
14 Despite V insolubility in organic solvents, the mixture is homo-
geneous, indicating enamine formation between V and 1a–f.
15 5,5-Dimethyl thiazolidine 4-carboxylate, in the aldol reaction:
(a) K. Sakthivel, W. Notz, T. Bui and C. F. Barbas III, J. Am. Chem.
Soc., 2001, 123, 5260; thiazoline amide organocatalyst activated with
organic acids: (b) Y. Hayashi, H. Gotoh, T. Tamura, H. Yamaguchi,
R. Masui and M. Shoji, J. Am. Chem. Soc., 2005, 127, 16028.
16 This unusual attack by the Si face of enamine I is reported also
in ref. 4c.
In conclusion, to develop an asymmetric catalytic synthesis of
bicyclo[2.2.2]octan-2-ones we exploited the synergic beneficial
effect of two of the widely employed classes of organocatalysts,
the Cinchona alkaloids and cyclic secondary amines, achieving high
diastereoselection and up to 90% ee. Synergic asymmetric organo-
catalysis (SAOc) allowed the discovery and optimization of new
reactions, the extension of aldehyde enamine activation scope, and
exploitation of new catalysts such as V. Work is in progress in our
laboratory to extend this concept to other interesting reactions.
The authors thank Dr Jacob Overgaard, University of Aarhus,
for X-ray analysis of compound 3a, Prof. Francesco De Riccardis,
Universita di Salerno, for high field NMR spectra of 3a/3b,
Prof. Maria Antonietta Loreto for economical support and HPLC
analysis facilities and Prof. Pavel Kocovsky, University of
Glasgow, for valuable suggestions. The authors thank the late
Dr Andy Parkin, for preliminary X-ray analysis of compound 3a.
M.B. acknowledges financial support from a 2007/2008 RSC
research scholarship and ‘‘Finaziamento di Ateneo 2007’’.
17 (a) P. Melchiorre and K. A. Jørgensen, J. Org. Chem., 2003, 68, 4151;
(b) Y. Chi and S. H. Gellman, Org. Lett., 2005, 7, 4253; (c) ref. 3b.
18 (a) J. L. Vicario, D. Badia and L. Carrillo, Synthesis, 2007, 2065;
intramolecular example: (b) ref. 15b; (c) N. T. Vo, T. Ngoc, R. D.
M. Pace, F. O’Hara and M. J. Gaunt, J. Am. Chem. Soc., 2008, 130, 404.
Notes and references
1 (a) P. I. Dalko and L. Moisan, Angew. Chem., Int. Ed., 2004, 43, 5138;
(b) A. Berkessel and H. Groger, Asymmetric Organocatalysis,
Wiley-VCH, Weinheim, Germany, 2004; (c) Acc. Chem. Res., 2004,
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Chem. Commun., 2009, 597–599 | 599