Architecturally diverse heterocycle formation by N-acyliminium ion initiated cyclization

Article abstract of DOI:10.1016/S0040-4039(03)01190-0

Enaminoesters containing a tethered indole or aryl moiety on the amine react with substituted maleic anhydrides or acryloyl chlorides to provide pyrrolinone or dihydropyridone products, respectively. The indole-tethered dihydropyridones can be induced to undergo a one-pot cyclization whereas, the indole-tethered pyrrolinone intermediates are readily cyclized with HCl. The aryl-tethered pyrrolinones or dihydropyridones can be isolated and subsequently induced to cyclize with triflic acid. This methodology culminates in the synthesis of erythrane-like and other natural products that are readily amenable to combinatorial library production.

Full text of DOI:10.1016/S0040-4039(03)01190-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6527–6531
Architecturally diverse heterocycle formation by N-acyliminium
ion initiated cyclization
Matthew M. Abelman,* Jeffrey K. Curtis and Donald R. James
Signature Bioscience Inc. 1240 South 47th St., Richmond, CA 94804, USA
Received 9 April 2003; revised 6 May 2003; accepted 7 May 2003
Dedicated to Professor Larry Overman on occasion of his 60th birthday
Abstract—Enaminoesters containing a tethered indole or aryl moiety on the amine react with substituted maleic anhydrides or
acryloyl chlorides to provide pyrrolinone or dihydropyridone products, respectively. The indole-tethered dihydropyridones can be
induced to undergo a one-pot cyclization whereas, the indole-tethered pyrrolinone intermediates are readily cyclized with HCl.
The aryl-tethered pyrrolinones or dihydropyridones can be isolated and subsequently induced to cyclize with triflic acid. This
methodology culminates in the synthesis of erythrane-like and other natural products that are readily amenable to combinatorial
library production.
© 2003 Elsevier Ltd. All rights reserved.
The desire for structurally diverse, natural product-like
scaffolds to populate large sets of structurally complex
molecules prompted us to explore various cyclization
reactions which afford the desired degree of product
complexity and functional diversity.1 The N-
acyliminium ion cyclization protocol to prepare alka-
loid natural products has been utilized with great effect
over the past 30 years to this end.2 Recently, Padwa3a,b
developed a general procedure for heterocycle synthesis
by using a Pummerer induced thionium ion to initiate
the intermediacy of an N-acyliminium ion for subse-
quent olefin or aryl termination. Katzenellenbogen3c
and Kirkpatrick3d also utilized N-acyliminium ions in
the synthesis of diverse hexahydrobenzoisoquinolines.
pyridone with a new cyclic b-enamino ester (Fig. 1;
Table 1).
At this stage, the indolylethylpyridones prepared from
any of the three acryloyl chlorides (methallyl, crotonyl
and acryloyl) proceed onward (50–60°C, 3 h) to tetra-
cycle formation via the intermediacy of an N-
acyliminium ion catalyzed by the HCl released from the
reaction, (Fig. 2; example 1, Table 1). The use of
methallyl and crotonyl chloride provides substituted
pyridones with an a or b methyl, respectively. These
substituents induced complete 1,3 and 1,2-relative
asymmetric induction, respectively, on the resulting
dihydropyridone ring during the final cyclization, pre-
sumably due to a preference for pseudo-equatorial
alignment of the substituents prior to protonation and
Using an N-acyliminium ion as a key intermediate in a
multistep cyclization sequence, we have developed a
simple two or three-step procedure to natural product-
like heterocyclic scaffolds and templates. At the outset
we prepared b-enamino ethyl esters of tryptamine,
homovalerylamine,
2,5-dimethoxyphenethylamine,
phenethylamine and 2-thienylphenethylamine as the
principal starting materials by condensation with ethyl
acetoacetate.
The combination of the b-enamino ester with an acryl-
oyl chloride results in an aza-annulation4 forming a
Keywords: indoles; N-acyliminium ion; erythrane; tryptamine; Pictet–
Spengler.
* Corresponding author. Tel.: 510-323-1021; fax: 510-323-1002;
e-mail: mabelman@signaturebio.com
Figure 1. Proposed stepwise mechanism with indole tethered
pyridones.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01190-0

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M. M. Abelman et al. / Tetrahedron Letters 44 (2003) 6527–6531
Table 1. Tryptamine b-enamino ethyl esters as precursors for N-acyliminium ion cyclizationsa
ridone bearing an acetic acid residue, (Fig. 3; examples
11 and 13, Table 2).
These structures, likewise, undergo the N-acyliminium
ion induced cyclizations. The foregoing reactions
demonstrate the one-pot formation of three stereospe-
cific centers along the newly formed piperidinone or
pyrrolidinone backbone of the final tetracycle. Enam-
ino ester 8, when subjected to acryloyl chloride, pro-
vided two tetracycles, 9 and 10, in a 1:1 ratio.
The lack of stereoselectivity in the ring formation
implies that an asymmetric center external to the dihy-
dropyridone ring does not induce any facial selectivity
during the protonation giving the N-acyliminium ion
intermediate. The pyrrolinones and dihydropyridones
with a-acetic acid side chains and tethered indoles
require the addition of dry HCl (ꢀ1.5 equiv. from 4 M
HCl in dioxane, 70°C, 3 h) to accomplish ring closure
of the initial anhydride–enamine adduct since there is
no liberated HCl present as is the case with the acryloyl
chloride additions.
Figure 2. N-Acyliminium ion induced cyclization.
formation of the N-acyliminium ion. The protonation
will ultimately take place from the least hindered face
of the enamino ester providing an axial ester, so as to
minimize interaction with the iminium methyl sub-
stituent (the relative configuration was determined
through analysis of the 2-D 1H COSY and 2-D
NOESY experiments at 400 MHz).
Dihydropyridones or pyrrolinones with methoxy substi-
tuted aryl rings require the aid of triflic acid (TfOH, 1
equiv.) in 1,2-dichloroethane or dioxane (ꢀ50°C, 1 h)
to effect ring closure (Table 3).
The original b-enamino ester substrates can, on the
other hand, be combined with maleic, citraconic or
itaconic anhydride to form a pyrrolinone or dihydropy-

M. M. Abelman et al. / Tetrahedron Letters 44 (2003) 6527–6531
6529
thrane skeleton does not epimerize the a center next to
the amide carbonyl.
Enaminoester 28 undergoes clean aza-annulation to the
dihydropyridone using acryloyl chloride (easily fol-
lowed by thin-layer chromatography). After 1 h at
room temperature, an equivalent of triflic acid is added
and the mixture warmed to 45°C for 1 h. This provides
30 in 65% yield as a 4:1 (a/b) mixture. Similar condi-
tions for enaminoester 31 gave compound 33 as 3:1
(a/b) mixture. These examples show that a basic one-
pot sequence can be utilized in the preparation of these
heterocycles if one uses the acryloyl chloride aza-annu-
lation with an aryl tether.
Figure 3. Anhydride addition to b-enamine.
In summation, we have developed a unique and general
N-acyliminium ion methodology to prepare natural
product-like substrates for diverse combinatorial
libraries. We are continuing to explore this protocol by
looking at other ring systems and ring sizes, by using
more elaborate b-ketoesters to prepare the b-enam-
inoesters and exploring Lewis acids by which to con-
duct these cyclizations enantiospecifically.
It is not clear why compounds with tethered phenyl
groups require a stronger protonator like triflic acid to
initiate the formation of the N-acyliminium ion as
opposed to the indole series, which favors the use of
HCl to the same end. Quinolizinones 185 and 21
demonstrate that two and three contiguous asymmetric
centers, respectively, can be prepared quickly,
analogous to the indolo substrates 2 and 3 of Table 1.
Example 24 shows that only the syn ring juncture is
obtained upon cyclization in accord with previous
work.6 Enaminoester 25 can be utilized in the forma-
tion of an erythrinane-like class of alkaloids. Reaction
of the b-enaminoester with maleic anhydride results in
the stereospecific formation7 of indolizine 26 with the
acetic acid side chain cis to the tertiary carboethoxy-
group in excellent yield. Final cyclization to the ery-
Acknowledgements
We would like to thank Betty Fitzgerald for her exper-
tise in obtaining COSY, NOESY, IR and LCMS spec-
tra. We would also like to thank Richard Gless and
Paul Baures for critical and insightful commentary on
this manuscript.
Table 2. Cyclic anhydrides as the acylation componenta

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Table 3. b-Aryl phenethyl amino-enamino ethyl esters as precursors for N-acyliminium ion cyclizationa
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