Quaternary stereogenic carbon atoms in complex molecules by an asymmetric, organocatalytic, triple-cascade reaction

Article abstract of DOI:10.1002/chem.200800440

A study was conducted to prepare quaternary stereogenic carbon atoms in complex molecules by using an asymmetric, organocatalytic, and triple-cascade reaction. It was observed that an organocatalytic triple-cascade reaction can be used for direct and one-pot synthesis of tri- and tetra-substituted cyclohexene carbaldehydes with stereogenic carbon atoms. The study used synthetic cascade reaction to avoids time consuming and costly protection/de-protection, isolation procedures of intermediates is environmentally friendly, robust, and nontoxic organocatalysts. The study found that the chiral secondary amines can be used in cascade catalysis due possibility to integrate orthogonal activation modes of carbonyl compounds. The study can be used to prepare cyclohexene carbaldehydes with stereogenic carbon atoms with high diastereomeric and enantiomeric control.

Full text of DOI:10.1002/chem.200800440

DOI: 10.1002/chem.200800440
Quaternary Stereogenic Carbon Atoms in Complex Molecules by an
Asymmetric, Organocatalytic, Triple-Cascade Reaction
[b]
OriolPenon, Armando Carlone,[a] Andrea Mazzanti,[a] Manuela Locatelli,[a]
Letizia Sambri,[a] Giuseppe Bartoli,[a] and Paolo Melchiorre*[a]
The stereoselective construction of all-carbon quaternary
sterogenic centers in complex organic molecules is an ongo-
ing synthetic challenge.[1] This is due to the growing number
of biologically active natural products and pharmaceutical
agents that possess quaternary stereogenic carbons. Howev-
er, creating these complex fragments rapidly and selectively
is a difficult task, because of the inherent steric bias encoun-
À
tered in the C C bond-forming event. In this field, enantio-
selective cascade catalysis has been recognized as a new syn-
thetic solution to the stereoselective construction of molecu-
lar complexity.[2] This bio-inspired strategy is based upon the
combination of multiple asymmetric transformations in a
cascade sequence, providing rapid access to complex mole-
Scheme 1. Quaternary stereocenters through a triple organocascade.
cules containing multiple stereocenters from simple precur-
sors and in a single operation.
Here we report the development of an organocatalytic,[3]
triple-cascade reaction that allows the direct, one-pot syn-
thesis of tri- and tetra-substituted cyclohexene carbalde-
hydes 4 with three or four stereogenic carbon atoms, one of
which is quaternary by all-carbon substitution (Scheme 1).
This three-component domino strategy is based on an opera-
tionally trivial procedure that employs unmodified, cheap,
and commercially available starting materials and catalyst,
while achieving excellent levels of stereocontrol (up to 20:1
diastereomeric ratio (dr) and complete enantioselectivity).
Notably, the development of the first asymmetric conjugate
addition of aldehydes 1 to cyanoacrylates 2, a new class of
suitable Michael acceptors for enantioselective aminocataly-
sis, is at the heart of the presented triple organocascade.
Recently, the use of simple chiral organic molecules to
catalyze asymmetric domino reactions has represented an
additional step forward to the identification of a powerful
and reliable strategy for the stereoselective synthesis of
complex molecules.[4] In this approach, the synthetic benefits
inherent to cascade sequences—which avoids time consum-
ing and costly protection/deprotection as well as isolation
procedures of intermediates—is combined with the use of
environmentally friendly, robust, and nontoxic organocata-
lysts. In particular, chiral secondary amines have been suc-
cessfully used in cascade catalysis, because of the possibility
to integrate orthogonal activation modes of carbonyl com-
pounds (enamine and iminium ion catalysis)[5] into more
elaborate reaction sequences.[6,7]
Despite the impressive recent achievements in the field, a
general and efficient organocatalytic cascade reaction that
allows the direct preparation of complex fragments, contain-
ing all-carbon quaternary stereocenters, is still lacking.[8]
Toward this ambitious goal, we were inspired by the spectac-
ular example of an enantioselective, organocatalytic, triple-
cascade reaction recently reported by Enders and collea-
[a] Dr. A. Carlone, Dr. A. Mazzanti, Dr. M. Locatelli, Dr. L. Sambri,
Prof. G. Bartoli, Dr. P. Melchiorre
Dipartimento di Chimica Organica “A. Mangini”
Alma Mater Studiorum, Università di Bologna
Viale Risorgimento 4-40136 Bologna (Italy)
Fax : (+39)051-209-3654
E-mail: p.melchiorre@unibo.it
[b] O. Penon
Facultat de Farmàcia, Universitat de Barcelona
Avinguda Joan XXIII s/n, 08028 Barcelona (Spain)
Supporting information for this article is available on the WWW
under http://www.chemistry.org or from the author.
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Chem. Eur. J. 2008, 14, 4788 – 4791

COMMUNICATION
gues.[6] Exploiting the catalytic behavior of the chiral secon-
dary amine 5,[9] they realized an outstanding enamine–imini-
um–enamine sequential activation of aldehydes 1, nitroal-
kenes, and a,b-unsaturated aldehydes 3, affording cyclohex-
ene aldehydes with four stereocenters in essentially enantio-
pure form.[6a] We speculated that an adequate combination
of the reaction components, still including the aldehydic
partners 1 and 3 to preserve the catalytic machinery of this
efficient triple cascade sequence, might provide a rapid and
highly selective creation of quaternary stereocenters in com-
plex molecules.
As summarized in Table 1, the triple organocascade
proved successful for a range of aldehyde substituents, pro-
viding a facile and flexible access to highly functionalized
tri-substituted cyclohexenals 4a–e, with a quaternary stereo-
center, in almost enantiomerically pure form.
Table 1. Organocatalytic triple-cascade: a route toward quaternary ster-
eocenters.[a]
Central to the implementation of this strategy was the in-
dividuation of a suitable Michael acceptor 2 that must ad-
dress some specific issues. Initially, such reagent must inter-
cept the enamine intermediate, generated by catalyst con-
densation with aldehyde 1, much faster than the unsaturated
carbonyl compounds do (aldehyde 3 or the corresponding
activated iminium intermediate). The resulting conjugate
adduct A (Scheme 1) should constitute a prochiral carbon
nucleophile that can selectively engage in the iminium-cata-
lyzed conjugate addition to 3. The last step is an enamine-
promoted aldol reaction, in which the less hindered alde-
hyde acts as a nucleophile affording the intermediate B and,
after dehydration, the desired cyclohexene carbaldehydes 4.
Along these lines, we envisaged cyanoacrylate derivatives 2
as a potential candidate to address these concerns.
Entry
R1
R2
4
Yield [%][b]
dr[c]
ee [%][d]
1
Me
Me
Et
allyl
Me
Me
Ph
Ph
Ph
Ph
a
a
b
c
d
e
42
40
35
40
34
42
5.5:1
5.4:1
3.5:1
3:1
3.8:1
2.5:1
>99
>99
>99
>99
98
2[e]
3
4
5
6
pNO2-C6H4
Me
>99
[a] Reactions performed on a 0.4 mmol scale by using 2 equivalents of al-
dehyde 1, 1.2 equivalents of 2a, and 1 equivalent of enal 3. [b] Yield of
the isolated main diastereomer. The diastereomeric purity of the isolated
products 4 (de>99%) was determined by HPLC and 1H NMR analysis.
1
[c] Determined by H NMR analysis of the crude mixture. The minor dia-
stereomer was identified as the 1-epimer of 4. [d] The enantiomeric ex-
cesses were determined by HPLC analysis of the isolated products 4.
[e] (R)-5 was used as the catalyst, affording the opposite enantiomer of
compound ent-4a.
To assess the feasibility of such an asymmetric, organoca-
talytic, triple-cascade strategy, we focused on the use of
ethyl 2-cyanoacrylate (2a),[10] probing its ability to act as a
suitable Michael acceptor for enamine-catalyzed, enantiose-
lective, direct conjugate addition of aldehydes. Exposure of
propanal (1a) to 2a in the presence of diphenylprolinol silyl
ether 5 (10 mol%) in toluene (0.25m) resulted in a fast,
clean and highly selective (>95% enantiomeric excess (ee),
This three-component domino strategy can also be suc-
cessfully extended to the highly chemo-, diastereo-, and
enantioselective synthesis of tetra-substituted cyclohexene
carbaldehydes 7 (Table 2). The use of trans-a-cyanocinna-
1
determined by H NMR analysis in chiral medium, see Sup-
Table 2. Control of four stereocenters through an organocatalytic triple-
cascade reaction.[a]
porting Information) conjugate addition [Eq. (1)].
Entry
2
R1
R2
7
Yield [%][b]
dr[c]
2.6:1
2.2:1
2.3:1
ee [%][d]
These results, besides broadening the scope of enamine
catalysis, set conditions for the realization of the cascade se-
quence. Extensive optimization experiments revealed that
the presence of an acidic additive and the relative ratios of
the reagents were the crucial parameters to obtain high
levels of stereocontrol and reaction efficiency:[11] mixing al-
dehyde 1 (2 equiv), cyanoacrylate 2a (1.2 equiv), and unsa-
turated aldehyde 3 at room temperature in the presence of
the catalytic salt 5·oF-C6H4CO2H (10 mol%) in toluene, the
desired cyclohexene carbaldehyde 4 was obtained in good
diastereoselectivity and complete enantiocontrol after 48 h.
Importantly, the main diastereomer can be easily isolated
(diastereomeic excess (de) and ee up to 99%) by column
chromatography.
1
b
b
b
c
b
b
b
c
Me
Me
Et
Me
Me
Et
Ph
Ph
Ph
Ph
Me
Me
Me
Me
a
a
b
c
d
e
f
52
45
40
32
48
39
40
38
>99
>99
>99
>99
98
98
99
99
2[e]
3
4
5
6
7
2:1
>20:1
>20:1
>20:1
7.6:1
allyl
Me
8
g
[a] Reactions performed on a 0.4 mmol scale using 2 equivalents of alde-
hyde 1, 1.2 equivalents of 2 and 1 equivalent of enal 3. [b] Yield of the
isolated main diastereomer. The diastereomeric purity of the isolated
products 7 (de>99%) was determined by HPLC and 1H NMR analysis.
1
[c] Determined by H NMR analysis of the crude mixture. The minor dia-
stereomer was identified as the 1-epimer of 7. [d] The enantiomeric
excess was determined by HPLC analysis of the isolated products 7.
[e] Reaction carried out with 5 mol% of the catalyst 5.
Chem. Eur. J. 2008, 14, 4788 – 4791
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P. Melchiorre et al.
mates 2b,c[12] determines a fast and efficient triple organo-
cascade, leading to the desired products after 24 h reaction
time. Interestingly, aliphatic b-substituted enals induce an
higher stereocontrol, with diastereomeric ratio of up to 20:1.
The efficiency of the presented organocatalytic strategy
prompted us toward a more ambitious goal, the formation
of a complex structure with two all-carbon quaternary ste-
reocenters. Employing an a,a-disubstituted aldehyde, such
as 2-phenyl propanal (8), as a component of the triple orga-
nocascade led to the unexpected formation of cyclohexane
9, a highly functionalized molecule with five stereocenters
[Eq. (2)]. It is worth noting that this reaction allows the
highly enantioselective synthesis of just two diastereomers,
out of the 16 possible ones—compound 9 and its 5-epimer
(epi-9)—that can be separated by chromatography.[13]
The relative configuration of the tri- and tetra-substituted
cyclohexene carbaldehydes 4a and 7a and the cyclohexanes
9 and epi-9 was determined by NMR NOE analysis and X-
ray crystallography (see Supporting Information). Interest-
ingly, 4a and 7a have an opposite configuration at the C(1)
quaternary center, while the other stereogenic carbon
atoms, directly forged by the catalyst stereo-induction, have
the same configuration. The absolute configuration was as-
signed by means of TD-DFT calculations of the electronic
circular dichroism (ECD) spectra.[14] As shown in Figure 1,
the experimental ECD spectra match with the theoretical
data. The relative and absolute configurations are in agree-
ment with related aminocatalytic conjugate additions pro-
moted by catalyst 5.[6,9]
In summary, we have disclosed a novel organocatalytic
triple cascade that allows the stereoselective construction of
all-carbon quaternary sterogenic centers in complex organic
molecules. The method provides a flexible and direct access
to cyclohexene carbaldehydes with three or four stereogenic
carbon atoms with high diastereomeric and complete enan-
tiomeric control, and can be extended to the preparation of
enantiopure cyclohexanes with five chiral centers and two
quaternary carbons.[13] A full account of this new organocas-
cade strategy will be forthcoming.
Figure 1. Experimental (full trace) and calculated ECD spectra (dotted
trace) of the tri- and tetra-substituted cyclohexene carbaldehydes 4a
(top) and 7a (bottom).
After addition of the aldehyde 1 (0.8 mmol, 2 equiv), the solution was
stirred for 10 min at room temperature. Then the cyanoacrylate deriva-
tives 2 (0.48 mmol, 1.2 equiv) and a,b-unsaturated aldehyde 3 (0.4 mmol,
1 equiv) were sequentially added. After 24–48 h stirring, the crude reac-
tion mixture was diluted with DCM (2 mL) and flushed through a short
plug of silica, using DCM/Et2O 2:1 as the eluent. Solvent was removed in
vacuo, and the residue was purified by flash chromatography (FC) to
yield the desired products 4 or 7 as a single diastereomer in almost enan-
tiomerically pure form.
Acknowledgements
Workcarried out in the frameworkof the National Project “Stereosele-
zione in Sintesi Organica” supported by MIUR, Rome.
Keywords: asymmetric synthesis
· domino reactions ·
multicomponent reactions · organocatalysis · quaternary
stereocenters
ExperimentalSection
All the reactions were carried out in undistilled toluene without any pre-
cautions to exclude air. In an ordinary vial equipped with a Teflon-coated
stir bar, catalyst 5 (0.04 mmol, 13.0 mg, 10 mol%) and 2-fluorobenzoic
acid (0.04 mmol, 5.6 mg, 10 mol%) were dissolved in toluene (1.12 mL).
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Cascade Reactions
COMMUNICATION
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[10] It is impressive how, despite being the main component of one of
the most used superglue solution (Loctiteꢁ Super Attak, Henkel),
ethyl 2-cyanoacrylate 2a is compatible with organocatalytic reaction
conditions. This underscores, once again, the reliability and the syn-
thetic potential of asymmetric aminocatalysis.
[11] The use of different acidic (e.g., pNO2-C6H4CO2H) and basic addi-
tives (e.g., DABCO) resulted in considerably lower reaction rate
and worse diastereoselectivity.
[12] Efforts to use aliphatic cyanoacrylate derivatives in the triple orga-
nocascade resulted in very poor conversion.
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Received: March 11, 2008
Published online: April 15, 2008
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