Organocatalytic cascade reactions: Diversity-oriented synthesis for the construction of hydroisoquinoline scaffolds

Article abstract of DOI:10.1039/c4cc01231c

The organocatalytic enantioselective synthesis of highly functionalized hydroisoquinolines by trienamine-mediated [4+2]-cycloaddition/nucleophilic ring-closing reaction cascade sequence of cyanoacrylamides with 2,4-dienals is presented. The corresponding cycloadducts are formed in high yields and excellent stereoselectivities. Moreover, a series of transformations demonstrate the synthetic application of the obtained hydroisoquinolines. the Partner Organisations 2014.

Full text of DOI:10.1039/c4cc01231c

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Organocatalytic cascade reactions: diversity-
oriented synthesis for the construction of
hydroisoquinoline scaffolds†
Cite this: Chem. Commun., 2014,
50, 6035
Received 17th February 2014,
Accepted 22nd April 2014
Clarisa Villegas Gomez, David Cruz Cruz, Rasmus Mose and Karl Anker Jørgensen*
´
DOI: 10.1039/c4cc01231c
www.rsc.org/chemcomm
The organocatalytic enantioselective synthesis of highly functionalized Wender, Martin and Shea independently developed methodologies
hydroisoquinolines by trienamine-mediated [4+2]-cycloaddition/ for the construction of functionalized hydroisoquinoline scaffolds
nucleophilic ring-closing reaction cascade sequence of cyano- as key DE-ring precursors by the Diels–Alder cycloaddition/
acrylamides with 2,4-dienals is presented. The corresponding cyclo- Cope rearrangement,5 intramolecular Diels–Alder cycloaddition of
adducts are formed in high yields and excellent stereoselectivities. azatrienes2a,6 and N-vinylimidates.7 In all these cases, the desired
Moreover, a series of transformations demonstrate the synthetic precursors were obtained after more than three steps and without
application of the obtained hydroisoquinolines.
control of absolute configuration.
Diversity-oriented synthesis (DOS) has provided efficient
Privileged molecular structures, small molecules and backbones of methodologies for the preparation of small molecules. Thus,
more complex natural architectures, have become central topics libraries of compounds with a wide range of physical and
for synthetic chemists because such molecules usually exhibit biological properties have been prepared, including drugs, drug
important biological-activity, properties associated to its structural candidates and precursors for more complex structures.8 Given
connectivity and shape in a three-dimensional environment.1
that the screening of small molecules has helped to identify
As privileged structures, hydroisoquinoline scaffolds are new classes of biologically active molecules, DOS is still a
interesting synthetic targets because they have been demonstrated challenge for an efficient generation of libraries.
to be precursors for important compounds, such as yohimboid
In terms of diversity, organocatalysis has played an important
alkaloids, of which reserpine,2 deserpidine3 and yohimbines4 are role due to the way in which both small and complex molecules
among the most important targets (Fig. 1). Particularly, reserpine are prepared.9 The recent development of new organocatalytic
which shows pharmacological activity as a nervous-system depres- activations involving dienamines,10 vinylogous-iminium-ions11
sant and has been applied as a medicinal agent for the treatment of and trienamines12 offers new tools for DOS.
hypertension and mental disorders has received considerable
Trienamine activation is an efficient HOMO-raising strategy
attention.2b Driven by both total and formal syntheses of reserpine, in organocatalysis for both simple and cascade asymmetric
transformations. In the following we will apply the trienamine
activation to provide an efficient methodology to access the
privileged hydroisoquinoline structures through DOS. The strategy
for the asymmetric synthesis of highly functionalized hydroisoqui-
nolines is based on an organocatalytic Diels–Alder/nucleophilic
ring-closing reaction cascade sequence.
As part of the strategy, we hypothesized that cyanoacrylamides
might be good dienophiles13 to react with an activated trienamine
system. The two electron-withdrawing groups attached to the double
bond in the cyanoacrylamides will ensure a good reactivity toward
the [4+2]-cycloaddition, while it is expected that the planarity of
Fig. 1 Hydroisoquinoline scaffold occurring in natural products.
the molecule will provide a correct endo–exo selection. Finally,
once the catalytic cycloaddition proceeds, a nucleophilic ring-
closing reaction can take place between the nitrogen atom of
Center for Catalysis, Department of Chemistry, Aarhus University, 8000 Aarhus C,
Denmark. E-mail: kaj@chem.au.dk
† Electronic supplementary information (ESI) available: Reactions conditions
the amide and the aldehyde to obtain the corresponding
hydroisoquinolines in a cascade fashion (Scheme 1).
and spectra. CCDC 984677. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c4cc01231c
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Scheme 1 Proposed reaction pathway for the organocatalytic cascade
reaction providing optically active hydroisoquinoline scaffolds.
In order to prove the feasibility of the hypothesis, we chose
to study the cascade sequence between (E)-5-methylhexa-2,4-
dienal 1a and cyanoacrylamide 2a as a model reaction (Table 1).
In a first approach, in presence of 20 mol% of the TMS-protected
prolinol catalyst 3a and p-nitrobenzoic acid ( p-NBA), the desired
product 4a was observed only with 20% of conversion after 24 h
in CDCl3 (entry 1). By changing the solvent to THF or 1,4-dioxane
the conversion was enhanced to be 50% and 60%, respectively
(entries 2 and 3). Finally when the reaction was performed at
70 1C in 1,4-dioxane, full conversion, excellent diastereomeric
ratio and promising enantiomeric excess of product 4a were
observed after 20 h (entry 4). However, only a moderate enantio-
selectivity of 70% ee of 4a was obtained.
Table 1 Screening of the reaction conditions for the [4+2]-cycloaddition/
nucleophilic ring-closing reaction of (E)-5-methylhexa-2,4-dienal 1a and
cyanoacrylamide 2a
Entry
3
Solvent T [1C] t [h]
drc
eed [%] Conv.c/yield [%]
1a
3a CDCl3
3a THF
rt
rt
rt
24
24
24
nd
nd
nd
nd
nd
nd
70
46
84
20/nd
50/nd
60/nd
2a
Scheme 2 Scope of the [4+2]-cycloaddition/nucleophilic ring-closing
reactions for the formation of optically active hydroisoquinoline scaffolds.
Reaction conditions: 1 (0.2 mmol), 2 (0.1 mmol), 3g (0.02 mmol) and
p-NBA (0.02 mmol) in 0.5 mL of 1,4-dioxane. The reported yields are for
the major diastereoisomer only. The dr values were determined by 1H NMR
spectroscopy on the crude mixture. The ee values (major diastereoisomer)
were determined by chiral ultraperformance convergence chromato-
3a
3a Dioxane
3a Dioxane
3b Dioxane
3c Dioxane
3d Dioxane
3e Dioxane
3f Dioxane
3g Dioxane
3g Dioxane
4b
70
70
70
70
70
70
70
70
20 90 : 10
20 90 : 10
20 90 : 10
495/50
495/24
495/40
495/46
495/43
495/49
495/53
495/80
5b
6b
7b
20 90 : 10 À63
8b
20 90 : 10
20 90 : 10
20 90 : 10
20 90 : 10
85
89
95
95
9b
a
graphy (UPC2). dr was not determined.
10b
11a
a
Reactions were performed with 1a (0.2 mmol), 2a (0.1 mmol),
b
of the screening study, that small amounts of the aldehyde were
degraded at 70 1C, we switched the equivalents of the reactants
to be two for the aldehyde and one for the cyanoacrylamides to
obtain 80% yield of 4a (entry 11).
3 (0.02 mmol) and p-NBA (0.02 mmol) in solvent (0.5 mL). 1a
(0.1 mmol) and 2a (0.2 mmol). Determined by 1H NMR spectroscopy
c
d
on the crude reaction mixture. Determined by chiral ultraperfor-
mance convergence chromatography (UPC2).
With the optimal conditions established, our attention was
In attempts to improve the enantioselectivity of the reaction, addressed towards the scope of the reaction with various
several silyl-protected prolinol catalysts 3 were tested. Interestingly, dienals 1 and different cyanoacrylamides 2 (Scheme 2).
the screening showed that the enantioselectivity is very dependent
Pleasingly, a variety of substitution patterns were well-tolerated
on the sterics of the substituent in the silyl-protecting group. This for the dienals 1 and cyanoacrylamides 2. Both electron-withdrawing
sterics-dependence provided the Ph3Si-protected prolinol 3g as the and electron-donating substituents on the aromatic ring of
best catalyst giving the hydroisoquinoline 4a in 53% yield and the cyanoacrylamides 2 lead to excellent enantioselectivities
95% ee (entry 10). Finally, as it was observed at the beginning (91–96% ee) and very good yields and diastereoselectivities of
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the hydroisoquinoline scaffolds 4b–g were obtained. Heteroaromatic Finally, a stereoselective epoxidation at the double bond was
substituents as well as fused aromatic rings in 2 were also compa- achieved, leading to the highly functionalized compound 8 with
tible with the methodology and afforded the corresponding products six stereocenters (Scheme 3, eqn IV).
4h–j with high levels of stereocontrol (93–97% ee and 90 : 10 dr) and
In summary, an organocatalytic cascade reaction mediated
very good yields. Alkyl group in the cyanoacrylamide resulted in less trienamine [4+2]-cycloaddition/nucleophilic ring-closing sequence
reactivity and reduced stereoselectivity, probably due to a loss in the has been developed. The reaction between diversely substituted
planarity of the molecule as obtained for product 4k.
cyanoacrylamides and 2,4-dienals to generate multifunctionalized
Next, a variety of dienals 1, acting as trienamine precursors, hydroisoquinolines proceeded efficiently. The highly steric Ph3Si-
were evaluated for this asymmetric Diels–Alder/nucleophilic protecting group at the catalyst was decisive to reach high enantio-
ring-closing reaction. Delightfully, good yields and excellent selectivities. The synthetic application of the obtained cycloadducts
stereoselectivities were also observed for the dienal precursors. was demonstrated. The stereochemistry at C-3 could be modulated
It was found that alkyl and aryl substituents at g- and d-positions depending on the work-up of the reaction mixture. A reduction and
can be attached to the dienal and the corresponding products oxidation at the same position could also be achieved efficiently.
4l–q were obtained in up to 78% yield, 495: 5 dr and up to 98% Finally, a stereoselective epoxidation led to multifunctional hydro-
ee. Interestingly, the highest diastereomeric ratios were observed isoquinolines with up to six stereocenters.
when alkyl or aryl substituents at C-4 of 1 are present (4m,n).
This work was made possible by grants from Aarhus University
Tri- and tetracyclic products could also be prepared (4o,r). and Carlsberg Foundation. The authors thank Dr Jacob Overgaard
Slightly lower yields were observed; however, the excellent enantio- and Espen Eikeland for performing the X-ray analysis.
selectivities were maintained.
The absolute configuration of the hydroisoquinoline 4b
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6038 | Chem. Commun., 2014, 50, 6035--6038
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