Multicomponent asymmetric reactions mediated by proline lithium salt

Article abstract of DOI:10.1039/b924158b

The multicomponent reaction between proline lithium salt, 2-cyclohexen-1-one and aliphatic aldehydes affords the 4-alkylidene-2- cyclohexen-1-ones, which are interesting fragrances, and bicyclic amino acids that bear four additional stereocenters, obtaine

Full text of DOI:10.1039/b924158b

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Organic &
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Volume 8 | Number 5 | 7 March 2010 | Pages 929–1220
ISSN 1477-0520
PERSPECTIVE
COMMUNICATION
Elemér Fogassy et al.
Marco Bella et al.
Separation of non-racemic mixtures of
Multicomponent asymmetric reactions enantiomers: an essential part of optical
mediated by proline lithium salt
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www.rsc.org/obc | Organic & Biomolecular Chemistry
Multicomponent asymmetric reactions mediated by proline lithium salt†
Polyssena Renzi, Jacob Overgaard‡ and Marco Bella*
Received 18th November 2009, Accepted 21st December 2009
First published as an Advance Article on the web 13th January 2010
DOI: 10.1039/b924158b
The multicomponent reaction between proline lithium salt,
2-cyclohexen-1-one and aliphatic aldehydes affords the 4-
alkylidene-2-cyclohexen-1-ones, which are interesting fra-
grances, and bicyclic amino acids that bear four additional
stereocenters, obtained as single stereoisomer.
Organic synthesis has witnessed a major revolution since the year
2000 when two landmark papers, reporting on the discovery of
the proline-catalyzed intermolecular aldol reaction authored by
List, Barbas and Lerner,1 and on the first organocatalyzed high
enantioselective Diels–Alder reaction disclosed by MacMillan
and co-workers,2 opened a new horizon for asymmetric catalyzed
transformations. Since then, the growing interest of the scientific
community has been witnessed by the exponential increase of
publications in this field, and new privileged structures, such
Scheme 1 Addition of arylacetaldehydes 1 to 2-cyclohexen-1-one 2
mediated by SAOc.
as Jørgensen–Hayashi trimethylsilyl prolinol3 or Yamamoto–Ley
tetrazole4 have shown excellent efficacy in a multitude of asym-
metric transformations, including those where complex molecular
frameworks are accessed and several stereocenters are cast at
once.5
of aldehydes is employed, such as the aryl acetaldehydes 1; the
usage of aliphatic acetaldehydes 7 leads to a completely different
reaction pathway, and these intriguing results of our investigation
are presented here.
A recurring feature in the catalysts employed in these processes
can be identified: the presence of a secondary amine together with
a source of protons, within the same molecule, such as in proline
or in the combination of TMS diarylprolinol and MacMillan
imidazolidinone6 catalyst with organic acids.7 Examples where
the catalytic system is instead a combination of secondary
amines, such as proline and base, are seldom encountered. It
should be noted that in 1996 Yamaguchi had already shown
the synthetic potential of alkaline metal salts of proline in the
asymmetric conjugate addition of malonates8 and nitroalkanes9
to cyclic enones. In 2000 Hanessian optimized the addition of
nitroalkanes to enones exploiting a combination of proline and
amines.10 We recently proved that the combination of proline 4
or 2,2-dimethyl-4-carboxyl thiazolidine 6 with Cinchona alkaloids
such as 5a, b shows a strong synergistic effect in the reaction
affording compounds 3. These elaborated molecular frameworks
bear four asymmetric carbons and are obtained with excellent
stereochemical control. We defined this particular kind of catalysis
SAOc, or Synergic Asymmetric Organocatalysis (Scheme 1).11
Notably, the cycloadducts 3 are generated only if a particular class
When 1 eq of 2-cyclohexen-1-one 2 is reacted in toluene with
1 eq of proline 4 and an aldehyde such as isovaleraldehyde 7a or
capronaldehyde 7b, consumption of the a,b-unsaturated reactant
is observed within one or two days. Water is added and the reaction
mixture is then extracted with ethyl acetate; evaporation and pu-
rification (Flash Chromatography) of the organic phase affords the
cyclohexenone derivatives 8, together with the autocondensation
product of the aldehyde and dimerization product 9 derived from
2-cyclohexen-1-one 2 (Scheme 2).
Dipartimento di Chimica, Universita`” Sapienza” di Roma, and Istituto di
Chimica Biomolecolare del CNR, P.le Aldo Moro 5, 00185, Roma, Italy.
E-mail: marco.bella@uniroma1.it
† Electronic supplementary information (ESI) available: Spectral data and
experimental procedures for the preparation and isolation of compounds
8a–d and 10a–e. CCDC reference number 752699. For ESI and crystallo-
graphic data in CIF or other electronic format see DOI: 10.1039/b924158b
‡ To whom correspondence regarding X-ray should be addressed. De-
partment of Chemistry, Aarhus Universitet, Langelandsgade 140, 8000 C
Aarhus, Denmark; E-mail: jacobo@chem.au.dk
Scheme 2 Synthesis of 4-alkylidene-2-cyclohexen-1-ones 8.
Albeit in moderate yield, the formation of the 2-cyclohexen-1-
one derivatives 8 represents, to the best of our knowledge, the first
example of dienamine catalysis12 where an a,b-unsaturated ketone
980 | Org. Biomol. Chem., 2010, 8, 980–983
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Table 1 Cascade three-component reaction for the synthesis of bicyclic
adducts 10
is employed instead of an aldehyde. Compounds 8a–d, which are
formed as a mixture of geometric isomers, are unknown in the
literature, and they present an intense and characteristic scent.13
The 4-alkylidene-2-cyclohexen-1-one moiety is a recurring feature
in several fragrances and natural substances, such as in the aroma
of tobacco and honey.14 The cyclohexenone dimer 9, which has
already been prepared by us15 with 92% ee by chiral PTC,16 is the
major product if no aldehyde is added.
The mass balance of the crude reaction after aqueous workup, in
no case accounted for the initial amount of 2-cyclohexen-1-one 2,
suggesting the formation of a water-soluble adduct derived from 2.
To the crude reaction mixture was added DCM avoiding aqueous
workup. The mixture was then filtered in order to remove any
unreacted salt of proline, over a pad of celite, the solvent removed
in vacuo and crude product directly purified by FC. The 1H-NMR
spectra of a fraction eluted by methanol : ethyl acetate in the ratio
1 : 10 showed the presence of i) the aliphatic chains derived from
aldehydes 7a, b, ii) the cyclohexenone ring and iii) the proline
moiety. The material isolated was a thick yellow oil, which could
be purified either by dissolving most of it into D2O when the
reaction is performed with aldehyde 7a or by crystallization from
ethanol in the case of aldehyde 7b affording a white solid, which
13C-NMR spectra clearly indicated in both cases the presence of
only a single diastereoisomer.17
Entrya
Aldehyde, R
Time, days
Yield, b%
1c
2
3
4
5
7b, n-Bu
7b, n-Bu
7a, i-Pr
7e, n-Octyl
7f, Bn
2
2
4
5
3
10a, 22 (12)d
10a, 37 (21)d
10b, 32(20)e
10c, 38 (22)d
10d, 35 (21)d
a Reactions performed on 1 g of 2-cyclohexen-1-one 2 (10.4 mmol),
20.8 mmol of aldehyde 7 (2 eq) and 1.26 g of proline 4-lithuim salt
(10.4 mmol, 1 eq) in 20 mL of solvent. b Isolated yield after chromato-
graphic purification. c Toluene as the solvent. d Yield after crystallization.
e Purified by extraction in water, see SI for details.†
with excellent control of their absolute configuration. A possible
mechanism, which can rationalize the formation of reaction
products 8 and 10, is presented in Scheme 3. A “classic” catalytic
cycle operates when 2-cyclohexen-1-one 2 and proline 4 lithium
salt react to give iminium ion I which is in equilibrium with
enamine II. This vinylogous enamine II then condenses with
aldehydes 7 to give, through iminium ion III, the cyclohexenone
derivatives 8 and releases the organocatalyst, which initiates a new
catalytic cycle (reaction path 1).
In order to elucidate the structure of this compound, a
single crystal X-ray analysis was performed, which indicated the
formation of the three component adduct 10a (Fig. 1), where the
original stereocenter of proline 4 had been able to control the
configuration of four additional carbon atoms.18,19
Proline 4 lithium salt is consumed via the concurrent reaction
path 2: its enamine V, formed with aldehydes 7, deprotonates the
2-cyclohexen-1-one 2 giving rise to the formation of an activate
diene. The cycloaddition reaction occurs then through transition
state VI to trap in an irreversible manner the organocatalyst into
the bicyclic adducts 10.
The different stability of the conjugated enamine Va derived
from aryl acetaldehydes 1 (Fig. 2) with respect to the ones formed
from alkyl acetaldehydes 7 (Vb, R = alkyl) is probably involved
in the different kind of products observed when the two classes of
aldehydes are reacted with 2-cyclohexen-1-one 2.
Fig. 1 ORTEP drawing of compound 10a showing 50% thermal
ellipsoids.20
Several attempts were performed in order to optimize the
reaction yield; chloroform employed as the solvent rather than
toluene favored the formation of the aminoacid 10 over the
cyclohexenenone derivative 8, together with an improvement in
the yield, which, however, remained not high (Table 1, entry 1
and 2). The reaction was then tested on more aldehydes (Table 1,
entries 3–5) and the bicyclic adduct 10 was isolated in all cases.21
We cannot rule out the formation of more stereoisomers of
compounds 10, however, neither in the crude material obtained
after chromatography nor after crystallization, can any of these
diastereoisomers can be detected.
In any case, it should be noted that i) the reaction can be
performed on gram scale, ii) the bicyclic systems 10, which are
obtained as single stereoisomers, can be purified to a high degree
and iii) in this process three different substrates are combined,
forming two new carbon-carbon bonds and four new stereocenters
Fig. 2 Conjugated and non-conjugated enamine Va, b.
In the organocatalyzed reactions by proline and derivatives
generally the catalyst loading is significantly high (up to 30%);
investigations have been conducted in order to identify the byprod-
ucts arising from the organocatalyst responsible for such high
loading. We believe that similar processes to the cycloadditions of
enamines as described in Scheme 3 with the formation of water
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Scheme 3 Proposed mechanism for the formation of cyclohexenone derivative 8 and the cycloaddition reaction leading to bicycles 10.
soluble adducts could account for material loss also in several
other reactions.22
reactions employing these and other catalysts see: A. Michrowska and
B. List, Nat. Chem., 2009, 1, 225; (c) M. Rueping, A. Kuenkel, F. Tato
and J. W. Bats, Angew. Chem., Int. Ed., 2009, 48, 3699; (d) D. Enders,
C. Wang and J. W. Bats, Angew. Chem., Int. Ed., 2008, 47, 7539; (e) J.
Zhou and B. List, J. Am. Chem. Soc., 2007, 129, 7498; (f) E. Reyes, H.
Jiang, A. Milelli, P. Elsner, R. G. Hazell and K. A. Jørgensen, Angew.
Chem., Int. Ed., 2007, 46, 9202; (g) D. Enders, M. R. M. Huettl, C.
Grondal and G. Raabe, Nature, 2006, 441, 861; (h) Y. Huang, A. M.
Walji, C. H. Larsen, C. and D. W. C. MacMillan, J. Am. Chem. Soc.,
2005, 127, 15051.
6 G. Lelais and D. W. C. MacMillan, Aldrichim. Acta, 2008, 1, 3.
7 See as examples: (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.
8 M. Yamaguchi, T. Shiraishi and M. Hirama, J. Org. Chem., 1996, 61,
3520.
9 (a) M. Yamaguchi, Y. Igarashi, R. S. Reddy, T. Shiraishi and M.
Hirama, Tetrahedron, 1997, 53, 11223; (b) M. Yamaguchi, T. Shiraishi,
Y. Igarashi and M. Hirama, Tetrahedron Lett., 1994, 35, 8233.
10 (a) S. Hanessian and V. Pham, Org. Lett., 2000, 2, 2975; (b) S. Hanessian,
Z. Shao and J. S. Warrier, Org. Lett., 2006, 8, 4787.
11 M. Bella, D. M. Scarpino Schietroma, P. P. Cusella, T. Gasperi and V.
Visca, Chem. Commun., 2009, 597.
In conclusion, in this paper we present two new reaction types:
i) the organocatalytic vinylogous aldol condensation to afford 4-
alkylidene 1-cyclohexen-2-one derivatives 8, which are analogues
of well known odorous molecules and interesting fragrances, and
ii) the three component reaction of 2-cyclohexen-1-one 2, proline
4 lithium salt and aldehydes 7 to access the aminoacid derivatives
10 bearing four additional stereocenters as a single stereoisomer.
While the products are obtained in moderate yields, it should
be noted that complex molecular frameworks are prepared in a
single step on multigram quantities, employing inexpensive and
commercially available reactants.
Acknowledgements
Authors are grateful to Mr Pier Paolo Cusella who performed
important preliminary experiments. Financial support to this
work has been given by Universita` “Sapienza” di Roma and by
Royal Society of Chemistry Research Bursary. Authors are grateful
to Dr Philip Kraft, Givaudan, Schweiz AG for the evaluation of
compound 8a as a fragrance.
12 S. Bertelsen, M. Marigo, S. Brandes, P. Dine´r and K. A. Jørgensen,
J. Am. Chem. Soc., 2006, 128, 12973.
13 The technical description of this fragrance is: “floral rosy-green,
verbena-type odor with some allylic-sweaty aspects as well as a slight
lemongrass character. The main rosy character is in the direction of
geranil with a slight inflection of lily of the valley”.
14 For the synthesis of related natural substances see: N. Ito, T. Etoh, H.
Hagiwara and M. Kato, J. Chem. Soc., Perkin Trans. 1, 1997, 1571.
15 R. Ceccarelli, S. Insogna and M. Bella, Org. Biomol. Chem., 2006, 4,
4281.
16 Dimer 9 can be obtained in 55% yield and up to 76% ee; the excess
aliphatic aldehyde gives rise to autocondensation products.
17 If the reaction is mediated by a racemic lithium salt of proline, a
compound whose spectral data are identical to 10b is obtained, with the
exception of the optical rotation value, which is zero; alkaline salts of
proline are known to be configurationally stable under basic conditions;
see as an example ref. 4 and 5.
Notes and references
1 (a) B. List, R. A. Lerner and C. F. Barbas, III, J. Am. Chem. Soc., 2000,
122, 2395; (b) B. List and W. Notz, J. Am. Chem. Soc., 2000, 122, 7386.
2 K. A. Ahrendt, C. J. Borths and D. W. C. MacMillan, J. Am. Chem.
Soc., 2000, 122, 4243.
3 (a) C. Palomo and A. Mielgo, Chem.–Asian J., 2008, 3, 922; (b) C.
Palomo and A. Mielgo, Angew. Chem., Int. Ed., 2006, 45, 7876.
4 (a) D. A. Longbottom, V. Franckevicˇius, S. Kumarn, A. J. Oelke, V.
Wascholowski and S. V. Ley, Aldrichim. Acta, 2008, 1, 3.
5 Review: (a) D. Enders, C. Grondal and M. R. M. Huettl, Angew. Chem.,
Int. Ed., 2007, 46, 1570; (b) For recent examples of organocascade
18 In 1996 the non-stereoselective cycloaddition of enamines derived from
secondary amines and aromatic aldehydes, and 2-cyclohexen-1-one was
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reported. These adducts have been prepared as analogues of cocaine: S.
Javanmard, H. M. Deutsch, D. M. Collard and M. M. Schweri, J. Med.
Chem., 1996, 42, 4836.
21 Despite extensive optimization work, we were unable to increase the
yield of products 10; among the attempts performed, employing several
equivalents of proline 4 lithium salt or the addition of aldehydes 7 in
a portion wise manner did not lead to significant improvement of this
process.
22 For a discussion of the byproducts arising from proline when used
as the catalysts see: N. Zotova, A. Franzke, A. Armstrong and D. G.
Blackmond, J. Am. Chem. Soc., 2007, 129, 15100 and references cited
therein.
19 Enantioselective cycloaddition between imines and 2-cyclohexen-1-one
derivatives: (a) M. Rueping and C. Azap, Angew. Chem., Int. Ed., 2006,
45, 7832; (b) H. Sunden, I. Ibrahem, L. Eriksson and A. Cordova,
Angew. Chem., Int. Ed., 2005, 44, 4877.
20 The solvent molecule has been omitted for clarity. CCDC-number:
752699.
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