Synthesis of pyrrolo-isoquinolines related to the lamellarins using silver-catalyzed cycloisomerization/dipolar cycloaddition

Article abstract of DOI:10.1021/ja072737v

Synthesis of pyrrolo-isoquinolines related to the lamellarin alkaloids employing silver-catalyzed cycloisomerization-dipolar cycloaddition of alkynyl N-benzylidene glycinates is described. Mechanistic studies revealed Ag(I)-catalyzed cycloisomerization to an azomethine ylide as a key step for formation of angular pyrrolo-isoquinolines. Copyright

Full text of DOI:10.1021/ja072737v

Published on Web 06/01/2007
Synthesis of Pyrrolo-isoquinolines Related to the Lamellarins Using
Silver-Catalyzed Cycloisomerization/Dipolar Cycloaddition
Shun Su and John A. Porco, Jr.*
Department of Chemistry and Center for Chemical Methodology and Library DeVelopment (CMLD-BU),
Boston UniVersity, Boston, Massachusetts 02215
Received April 19, 2007; E-mail: porco@bu.edu
The lamellarin alkaloids are a family of novel marine natural
products containing a highly substituted pyrrolo-isoquinoline core.1
Lamellarin D 1 (Figure 1a) is a potent inhibitor of human
topoisomerase I2 and was recently shown to act on mitochondria
to induce apoptosis.3 Another member of the family, lamellarin
R-20-sulfate 2, displays selective inhibition against HIV-1 integrase
in vitro.4,5 We have considered development of methodology for
rapid access to angular, pyrrolo-isoquinoline core structures6 related
to the lamellarins7 using variants of the cycloisomerization of
alkynyl imines8 involving dipolar cycloaddition of derived azo-
methine ylides.9 In this approach, treatment of alkynyl imines 3
Figure 1.
with alkynophilic metal catalysts should afford azomethine ylides
4 which may undergo dipolar cycloaddition in the presence of
dipolarophiles. Subsequent aromatization may lead to the formation
of pyrrole frameworks 5 (Figure 1b).
To identify suitable conditions for the proposed metal-catalyzed
domino cycloisomerization/dipolar-cycloaddition process, reaction
screening10 involving alkynyl N-benzylidene glycinate 6, dimethyl
acetylene dicarboxylate (DMAD) 7, and a series of alkynophilic
metals was carried out in DCE using DIEA as base (50 °C).11
Figure 2. Reaction screening.
Fortunately, a number of catalysts including the Au, Ag, and Cu
salts shown in Figure 2 and Pd(OAc)2 were able to facilitate the
transformation. AgOTf and AgSbF6 provided the best results in
comparison to other metals investigated and were effective in
catalytic quantities (10 mol %). Control experiments in the absence
of metal salts led to decomposition ruling out the possibility of
spontaneous formation of 8 under thermal conditions.12
To improve the efficiency of the cycloisomerization/dipolar-
cycloaddition process, further optimization was carried out using
imine 6, DMAD 7, and AgOTf (10 mol %). Parameters including
solvents, bases, reaction temperature, and inclusion of external
oxidants (e.g., DDQ, MnO2) were investigated. Reactions conducted
at 60 °C under ambient conditions in toluene using 2,6-di-tert-butyl-
Figure 3. Proposed reaction pathway.
4-methylpyridine (DTBMP) as base in the absence of oxidants
afforded optimal results. Using this condition, select dipolarophiles
were reacted with a number of alkynyl imines to generate diverse
pyrrolo-isoquinolinone structures 8 and 24-37 (Table 1). Silver-
mediated pyrrolo-isoquinoline formation was found to be workable
with ortho alkynyl imines 9-17 bearing aryl, cyclopropane,
propargyl ether, trimethylsilyl, terminal alkyne, and enyne func-
tionality, as well as substrates with electron withdrawing and
donating substituents on the aromatic backbone (entries 2, 5, and
7-9). In addition to DMAD, alkynes 19-23 were also investigated
to provide lamellarin-type structures with unsymmetrical substit-
uents on the pyrrolo-isoquinoline core. Reactions involving alkynes
19-23 typically afforded the desired products with lower yield
compared to those using DMAD owing to diminished reactivity.
The addition of Lewis acids13 to further activate the dipolarophiles
led to only marginal improvement in reaction yields. Cycloisomer-
ization/dipolar-cycloaddition was generally found to be highly
regioselective, providing 33-34 and 36-37 as single regioiso-
mers.11 However, reaction involving alkynoate 21 produced 35 as
a 1.3:1 mixture of regioisomers14 and a desilylation product derived
from 37 was observed when using alkyne 23 as dipolarophile. Thus
far, alkynes lacking electron withdrawing groups have not been
workable as dipolarophiles.
To probe possible reaction pathways for the cycloisomerization/
dipolar-cycloaddition, we conducted a series of NMR experiments.
Treatment of substrate 6 with AgOTf, DMAD, and DTBMP
(toluene-d8, room temperature, 6 min) afforded dihydropyrrole 41,
presumably via dihydropyrrole 40 (Figure 3). The structure of
intermediate 41 was determined by extensive 2-D NMR experi-
ments.11,15 Subsequent thermolysis of a solution of 41 at 60 °C
under aerobic conditions led to the formation of 8. Additional
experiments were conducted to rule out a dipolar-cycloaddition/
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10.1021/ja072737v CCC: $37.00 © 2007 American Chemical Society

C O M M U N I C A T I O N S
Table 1. Reaction Scopea
also led to the formation of 41. The available mechanistic data
supports initial cycloisomerization of 6 to isoquinolinium species
38.8e Subsequent proton transfer and regeneration of Ag (I) affords
azomethine ylide 39, which may be followed by dipolar cyclo-
addition to dihydropyrrole 40. Isomerization and final oxidation
affords pyrrolo-isoquinoline 8.
In summary, we have developed an efficient synthesis of pyrrolo-
isoquinolines related to the lamellarin natural products involving
domino cycloisomerization/dipolar-cycloaddition of readily avail-
able alkynyl N-benzylidene glycinates. Mechanistic studies revealed
Ag(I)-catalyzed cycloisomerization to an azomethine ylide as a key
step for formation of pyrrolo-isoquinoline structures. Further studies,
including applications toward the syntheses of the lamellarin
alkaloids, are currently in progress and will be reported in due
course.
Acknowledgment. Financial support from the NIH-NIGMS
CMLD initiative (Grant P50 GM067041) and Merck Research
Laboratories is gratefully acknowledged. We thank Dr. Emil
Lobkovsky (Cornell University) for X-ray crystal structure analyses
and Dr. Aaron B. Beeler and Ms. Ji Qi (Boston University) for
experimental assistance.
Supporting Information Available: Experimental procedures and
characterization data for all new compounds. X-ray crystal structure
coordinates and files in CIF format. This material is available free of
charge via the Internet at http://pubs.acs.org.
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a Yields based on the corresponding alkynyl benzylaldehydes.11 b R5 )
Me, for entries 7 and 10, R5 ) tBu. c Yb(OTf)3 (5 mol %) was added. d 16%
of a desilylation product was also isolated.
cycloisomerization pathway. Reaction of des-alkyne substrate 6a
under conditions employed for formation of 8 led to recovered
starting material. In the absence of DMAD, treatment of 6 with
AgOTf and DTBMP (toluene-d8, room temperature) led to the
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