1,2-Dihydroisoquinolines as templates for cascade reactions to access isoquinoline alkaloid frameworks

Article abstract of DOI:10.1021/ol702176h

The synthesis of isoquinoline alkaloid frameworks has been achieved via a series of cascade reactions identified through reaction discovery utilizing 1,2-dihydroisoquinoline scaffolds.

Full text of DOI:10.1021/ol702176h

ORGANIC
LETTERS
2007
Vol. 9, No. 24
4983-4986
1,2-Dihydroisoquinolines as Templates
for Cascade Reactions To Access
Isoquinoline Alkaloid Frameworks
Shun Su and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library
DeVelopment (CMLD-BU), Boston UniVersity, 590 Commonwealth AVenue,
Boston, Massachusetts 02215
porco@bu.edu
Received September 4, 2007
ABSTRACT
The synthesis of isoquinoline alkaloid frameworks has been achieved via a series of cascade reactions identified through reaction discovery
utilizing 1,2-dihydroisoquinoline scaffolds.
Tetrahydroisoquinolines are found abundantly in Nature and
comprise the largest family of alkaloids.1 Their structural
novelty and diverse biological activities inspired us to
undertake preparation of tetrahydroisoquinoline-based small
molecule libraries.2,3 In an effort to identify novel reactions
leading to the production of highly functionalized, alkaloidal
structures, we considered 1,2-dihydroisoquinoline scaffolds
1 (Figure 1)2b,4,5 as templates for reaction discovery.6 As
discovery of a series of cascade reactions to produce novel
isoquinoline alkaloid frameworks from diverse 1,2-dihydro-
isoquinolines generated via cycloisomerization-addition of
alkynylacylimines.7
In order to efficiently access the requisite 1,2-dihydroiso-
quinoline scaffolds, we first evaluated cycloisomerization-
addition of alkynylacylimine 3 (Table 1) using select carbon
nucleophiles and alkynophilic transition metals.8 Reaction
screening led to the identification of AgSbF6 as the most
(1) Phillipson, J. D.; Roberts, M. F.; Zenk, M. H. The Chemistry and
Biology of Isoquinoline Alkaloids; Springer-Verlag: New York, 1985.
(2) For recent examples of isoquinoline-based chemical libraries, see:
(a) Gracias, V.; Moore, J. D.; Djuric, S. W. Tetrahedron Lett. 2004, 45,
417. (b) Taylor, S. J.; Taylor, A. M.; Schreiber, S. L. Angew. Chem., Int.
Ed. 2004, 43, 1681. (c) Pla, D.; Marchal, A.; Olsen, C. A.; Francesch, A.;
Cuevas, C.; Albericio, F.; Alvarez, M. J. Med. Chem. 2006, 49, 3257.
(3) For reviews concerning diversity-oriented synthesis (DOS), see: (a)
Schreiber, S. L. Science 2000, 287, 1964. (b) Burke, M. D.; Schreiber, S.
L. Angew. Chem., Int. Ed. 2004, 43, 46.
Figure 1. Synthesis of diverse isoquinoline alkaloid frameworks
using dihydroisoquinoline scaffolds.
(4) For reactions of enamines, see: Dyke, S. F. AdV. Heterocycl. Chem.
1972, 14, 279.
(5) For seminal work concerning preparation of polycyclic, alkaloid-
like libraries, see: (a) Gan, Z.; Reddy, P. T.; Quevillon, S.; Couve-Bonnaire,
S.; Arya, P. Angew. Chem., Int. Ed. 2005, 44, 1366. (b) Reayi, A.; Arya, P.
Curr. Opin. Chem. Biol. 2005, 9, 240.
(6) Beeler, A. B.; Su, S.; Singleton, C. A.; Porco, J. A., Jr. J. Am. Chem.
Soc. 2007, 129, 1413.
outlined in Figure 1, we anticipated that treatment of 1 with
electrophiles would lead to dihydroisoquinolinium intermedi-
ates 2 which could provide access to alkaloidal frameworks
after subsequent reaction processes. Herein, we report the
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and dimethyl malonate 10, silyl ketene acetals 12 and 13
were found to cleanly generate dihydroisoquinolines 20-
21. Notably, dihydroisoquinoline 21 mimics the skeleton of
the bisbenzylisoquinoline alkaloids.10 Furthermore, reaction
of alkynyl acylimine 8 and O-silylated dienolate 1411
provided dihydroisoquinoline 22 with complete γ selectiv-
ity.12
Table 1
We next evaluated a number of transformations of the
enecarbamate moiety of the 1,2-dihydroisoquinoline scaffolds.2b
Initial studies were focused on intramolecular condensation
of the ketone and enecarbamate of substrate 23 in an effort
to generate an aza-tricyclic framework (Scheme 1).13 After
Scheme 1
evaluation of Lewis acid promoters, we found that the
bridged, exocyclic enecarbamate 24 was formed in 84% yield
when scaffold 23 was treated with TMSOTf/N,N-diiso-
propylethylamine (DIEA) (CH2Cl2, -78 f -20 °C).14
Subsequent reaction of 24 with 4-methoxycinnamaldehyde
and TMSOTf unexpectedly provided diene 27, likely through
fragmentation of the intermediate dihydroisoquinolinium
species 25 and subsequent elimination of the derived
dihydroisoquinoline 26. After further reaction optimization,
a
Isolated yields based on alkynylacylimine. b 1.0 equiv of MgO was
added as base. c Reaction employing bis(2,4,6-trimethylpyridine)silver(I)
hexafluorophosphate (10 mol %) and t-BuOH (1.0 equiv); alkynylacylimine
and nucleophile were added via syringe pump simultaneously over 15 min.8
(7) For cycloisomerization of alkynyl imines and related derivatives,
see: (a) Huang, Q.; Larock, R. C. J. Org. Chem. 2003, 68, 980. (b) Dai,
G.; Larock, R. C. J. Org. Chem. 2003, 68, 920. (c) Ohtaka, M.; Nakamura,
H.; Yamamoto, Y. Tetrahedron Lett. 2004, 45, 7339. (d) Asao, N.; Yudha,
S.; Nogami, T.; Yamamoto, Y. Angew. Chem., Int. Ed. 2005, 44, 5526. (e)
Yanada, R.; Obika, S.; Kono, H.; Takemoto, Y. Angew. Chem., Int. Ed.
2006, 45, 3822. (f) Sromek, A. W.; Rheingold, A. L.; Wink, D. J.;
Gevorgyan, V. Synlett. 2006, 2325. (g) Obika, S.; Kono, H.; Yasui, Y.;
Yanada, R.; Takemoto, Y. J. Org. Chem. 2007, 72, 4462. (h) Su, S.; Porco,
J. A., Jr. J. Am. Chem. Soc. 2007, 129, 7744.
(8) See the Supporting Information for complete experimental details.
(9) Brunel, Y.; Rousseau, G. J. Org. Chem. 1996, 61, 5793.
(10) Curcumelli-Rodostamo, M. Alkaloids; Academic Press: New York,
1971; Vol. 13, p 303.
(11) Gaudemar, M.; Bellassoued, M. Tetrahedron Lett. 1989, 30, 2229.
(12) (a) Fleming, I.; Lee, T. V. Tetrahedron Lett. 1981, 22, 705. (b)
Denmark, S. E.; Heemstra, J. R., Jr. Synlett 2004, 2411.
(13) (a) Gupta, R. B.; Franck, R. W. J. Am. Chem. Soc. 1987, 109, 5393.
(b) Yadav, J. S.; Reddy, B. V. S.; Srinivas, M.; Sathaiah, K. Tetrahedron
Lett. 2005, 46, 3489.
effective catalyst for the transformation. Further reaction
optimization revealed that reactions conducted at 40 °C in
1,2-dichloroethane (DCE) (AgSbF6, 10 mol %) afforded
optimal results. Bis(2,4,6-trimethylpyridine)silver(I) hexa-
fluorophosphate9 was found to be superior to AgSbF6 when
employing silyl enol ether 11 as nucleophile. Using AgSbF6
and bis(2,4,6-trimethylpyridine)silver(I) hexafluorophosphate,
select nucleophiles were reacted with various alkynyl-
acylimines to generate a number of dihydroisoquinoline
scaffolds 15-22 (Table 1). Silver-mediated dihydroisoquino-
line formation was found to be workable with o-alkynyl-
acylimines 5-8 bearing enyne, propargyl ether, and cyclo-
propane functionality, as well as substrates with electron-
withdrawing and -donating substituents on the aromatic
backbone (cf. entries 2 and 4). In addition to â-keto esters 9
(14) For isomerization of bicyclic iminium ions to exocyclic enamines,
see: (a) Walker, G. N.; Alkalay, D. J. Org. Chem. 1967, 32, 2213. (b)
Quast, U.; Schneider, W. Liebigs Ann. Chem. 1982, 8, 1501.
4984
Org. Lett., Vol. 9, No. 24, 2007

a one-pot procedure was developed to generate 27-28 (69
and 62% yields, respectively) directly from 23 and aromatic
aldehydes.
Scheme 3
Based on the successful intramolecular condensation of
ketone-substituted dihydroisoquinoline 23, related reactions
of R,â-unsaturated ketone-containing substrate 22 (Table 1)
were investigated with the anticipation of forming a proto-
berberine alkaloid15 core structure (cf. karachine, inset,
Scheme 2). After investigation of various Lewis acids, the
Scheme 2
sequent NBS-mediated bromo-lactonization was conducted
and was found to selectively produce compound 36 as
determined by X-ray crystallography.8 In contrast, treatment
of 33 with dimethoxyacetal 37 and triflic acid (0.5 equiv)
afforded diene 38 as the major product along with a trace
amount of annulation product 35. The formation of 38 may
proceed through a similar pathway to that of 27 and 28
(Scheme 1) in which enecarbamate 33 first condenses at its
â-carbon with acetal 37.
Interestingly, treatment of 33 with 4-methoxy benzyl-
aldehyde, TMSOTf, and DIEA unexpectedly provided the
tetrasubstituted dihydroisoquinoline 39 (Scheme 4A). Ini-
Scheme 4
aza-tetracyclic structure 29 was generated from enone 22
using TMSOTf (CH2Cl2, 40 °C, 76%) via a tandem Michael
addition-Mannich reaction process likely involving inter-
mediates 30 and 31. The structure of 29 was confirmed by
X-ray crystal structure analysis.8 Interestingly, treatment of
22 with Eu(fod)3 under thermal conditions (200 °C, toluene,
microwave 300 W) led to the production of the formal hetero-
Diels-Alder product 32.16 Further studies revealed that
dihydropyran 32 could be converted to ketone 29 in the
presence of TMSOTf. However, transformation of 29 to 32
was not observed under various reaction conditions.
tially, we speculated that a Cannizzaro-type hydrogen-transfer
reduction of proposed intermediate 41 (Scheme 4B) may be
responsible for the formation of 39. However, a deuterium-
labeling experiment employing deuterated benzaldehyde
derivative 42 afforded the monodeuterated product 43 (1:1
dr), which led to the assumption that DIEA may serve as a
hydride donor19 required for the formation of alkylation
product 39. To further investigate the reaction pathway and
to improve reproducibility, various hydride sources and bases
were evaluated. It was ultimately determined that treatment
of 33 with TMSOTf, arylaldehyde, Et3SiH, and 2,6-di-tert-
butyl-4-methylpyridine (DTBMP) afforded tetrasubstituted
dihydroisoquinolines 39 and 40 in moderate yields. Using
this condition, tetracycle 35 (Scheme 3) was not observed.
In order to evaluate intermolecular condensation of the
enecarbamate moiety with electrophiles followed by further
annulation, the ester-substituted dihydroisoquinoline 33 was
condensed with electron-rich aromatic aldehydes and alde-
hyde equivalents using Lewis acids. For example, treatment
of 33 and piperonal 34 with Sc(OTf)3 and TFAA17 produced
the novel indenoisoquinoline18 35 (Scheme 3). To determine
the relative stereochemistry of 35, saponification and sub-
(15) (a) Blasko, G.; Murugesan, N.; Freyer, A. J.; Shamma, M.; Ansari,
A. A.; Atta, R. J. Am. Chem. Soc. 1982, 104, 2039. (b) Stevens, R. V.;
Pruitt, J. R. J. Chem. Soc., Chem. Commun. 1983, 23, 1425.
(16) For Eu(fod)3-catalyzed hetero-Diels-Alder cycloaddition of ene-
carbamates, see: Gaulon, C.; Dhal, R.; Chapin, T.; Maisonneuve, V.;
Dujardin, G. J. Org. Chem. 2004, 69, 4192.
(17) For synthesis of geminal acetates using Sc(OTf)3/TFAA, see:
Aggarwal, V. K.; Fonquerna, S.; Vennall, G. P. Synlett. 1998, 849.
(18) Nagarajan, M.; Morrell, A.; Ioanoviciu, A.; Antony, S.; Kohlhagen,
G.; Agama, K.; Hollingshead, M.; Pommier, Y.; Cushman, M. J. Med.
Chem. 2006, 49, 6283.
(19) (a) Schreiber, S. L. Tetrahedron Lett. 1980, 21, 1027. (b) Cheng,
Y.; Meth-Cohn, O.; Taylor, D. J. Chem. Soc., Perkin Trans. 1 1998, 7,
1257.
Org. Lett., Vol. 9, No. 24, 2007
4985

Based on these results, it is apparent that a common,
unsaturated iminium ion 4620 (Scheme 5) is likely responsible
Scheme 6
Scheme 5
derived anilide 52.8 Formation of 51 may be initiated by
facially selective condensation of 33 and an isobenzo-
furanylium species generated from phthaldialdehyde 47 and
TMSOTf.24 Subsequent generation of isobenzofuranylium
enecarbamate 49, followed by intramolecular cyclization,
affords dihydroisoquinolinium 50, which may undergo
further isomerization to dihydroisoquinoline 51.
In summary, 1,2-dihydroisoquinoline scaffolds obtained
via cycloisomerization of alkynylacylimines have been
utilized as templates for discovery of novel transformations
of the enecarbamate moiety. Using this approach, a number
of cascade reaction processes to access diverse isoquinoline
alkaloid frameworks have been identified including an aza-
tetracyclic structure via a tandem Michael-Mannich reaction
process and intermolecular condensation/annulations with
benzaldehydes and phthaldialdehyde to construct indenoiso-
quinolines and polycyclic isobenzofurans, respectively. Fur-
ther studies, including syntheses of tetrahydroisoquinoline
alkaloids based on adaptations of the methodology described
herein, are currently in progress and will be reported in due
course.
for the formation of products 35 and 39-40. In the absence
of hydride, intramolecular Friedel-Crafts cyclization21 leads
to indenoisoquinoline product 35 (route A). Alternatively,
conjugate hydride addition22 to iminium 46 affords dihydro-
isoquinolines 39-40 (route B). In order to understand the
stereochemical outcome leading to the production of 35, a
conformer search23 was conducted on the putative iminium
intermediate 46. The minimum energy conformer of 46
(Scheme 5) shows a boat conformation and a pseudoaxial
orientation of the ester substituent which minimizes peri
strain with the neighboring aryl hydrogen. As a result, the
subsequent Friedel-Crafts reaction generates 35 with the
methyl group at C2 position anti to the ester group at C4 as
revealed by X-ray crystal structure analysis of 36.8 Trans-
formations to prepare 35, and 38-40 thus illustrate access
to diverse frameworks using reagent-controlled diversity
generation.2b
As previously described, dihydroisoquinolinium intermedi-
ates generated from condensation of the dihydroisoquinoline
and suitable electrophiles may lead to the formation of
exocyclic enecarbamates (cf. 23 f 24, Scheme 1). Tandem
transformations utilizing this enecarbamate transposition
strategy were therefore investigated with bis-electrophiles
including phthaldialdehyde 47 (Scheme 6). Accordingly,
treatment of 33 and 47 with TMSOTf/DIEA (CH2Cl2, -78
f 0 °C) led to the production of the highly complex
isobenzofuran 51 (63%). The relative stereochemistry of 51
was determined by X-ray crystal structure analysis of the
Acknowledgment. Financial support from the NIGMS
CMLD initiative (P50 GM067041) and Merck Research
Laboratories is gratefully acknowledged. We thank Prof.
James Panek (Boston University) for helpful discussions and
Ms. Stephanie Chichetti (Boston University) for experimental
assistance. We thank CEM Corp. (Matthews, NC) for
assistance with microwave instrumentation.
Supporting Information Available: General experimen-
tal procedures, X-ray crystallographic data, and selected
NMR spectra. This material is available free of charge via
the Internet at http://pubs.acs.org.
(20) For a related unsaturated iminium ion, see: Rivas, L.; Quintero,
L.; Fourrey, L-L.; Benhida, R. Tetrahedron Lett. 2002, 43, 7639.
(21) For intramolecular Friedel-Crafts cyclization of dihydroisoquino-
linium ions, see: Diaz, J. L.; Miguel, M. L.; Lavilla, R. J. Org. Chem.
2004, 69, 3550.
OL702176H
(22) Ouellet, S. G.; Tuttle, J. B.; MacMillan, D. W. C. J. Am. Chem.
Soc. 2005, 127, 32.
(23) Low energy conformations were generated through a stochastic
conformational search using MOE (molecular operating environment).
(24) For generation of isobenzofurans from phthaldialdehyde, see:
Yasuda, M.; Fujibayashi, T.; Shibata, I.; Baba, A.; Matsuda, H.; Sonoda,
N. Chem. Lett. 1995, 3, 167.
4986
Org. Lett., Vol. 9, No. 24, 2007