Tricyclic alkaloid core structures assembled by a cyclotrimerizationcoupled intramolecular nucleophilic substitution reaction

Article abstract of DOI:10.1021/ol100177u

Chemical Equation Presented A facile approach to tricyclic alkaloid core structures was developed by sequencing a pyrldine-forming [2 + 2 + 2] cyclotrimerization reaction with an intramolecular nucleophilic substitution. This methodology enabled the facile assembly of the spiroindolinone framework of citrinadins A and B, and cyclopiamine B.

Full text of DOI:10.1021/ol100177u

ORGANIC
LETTERS
2010
Vol. 12, No. 6
1288-1291
Tricyclic Alkaloid Core Structures
Assembled by a Cyclotrimerization-
Coupled Intramolecular Nucleophilic
Substitution Reaction
Andrew L. McIver and Alexander Deiters*
North Carolina State UniVersity, Department of Chemistry,
Raleigh, North Carolina 27695-8204
alex_deiters@ncsu.edu
Received January 24, 2010
ABSTRACT
A facile approach to tricyclic alkaloid core structures was developed by sequencing a pyridine-forming [2 + 2 + 2] cyclotrimerization reaction
with an intramolecular nucleophilic substitution. This methodology enabled the facile assembly of the spiroindolinone framework of citrinadins
A and B, and cyclopiamine B.
Tricyclic alkaloid structures are present in a wide range of
natural products, many of which have important biological
activity. Figure 1 shows six examples of these types of
natural products with the central tricyclic alkaloid core
highlighted in red. The citrinadins A (1) and B (2) are
recently isolated marine derived pentacyclic spiroindolinone
alkaloids containing a dodecahydrocyclopenta[b]quinolizine
core.1,2 They both exhibit important cytotoxic activities
against various cancer cell lines with IC50’s in the low
micromolar range.1,2 No total synthesis of 1 or 2 has been
reported to date, but one stereoselective approach to the
spirooxindole A,B,C-ring system in seven steps has been
accomplished recently.3 Cyclopiamine B (3) is another fungal
spiroindolinone alkaloid4,5 containing six rings including a
central tricyclic decahydro-1H-cyclopenta[f]indolizine struc-
ture. The biological function of 3 is unknown, and no total
synthesis of 3 has been reported.
Other notable natural products containing similar tricyclic
alkaloid structures are veraflorizine (4), a steroidal cevanine
alkaloid6 that has also not been synthesized, roserine (5), a
pyrrolophenanthridinium alkaloid7 that has been synthesized
once,8 and xylopinine (6), a protoberberine alkaloid, which
is part of a large group of isoquinoline alkaloids that have
attracted considerable synthetic interest due to their diverse
biological activities.9
Building onto our recent applications of microwave-
mediated [2 + 2 + 2] cyclotrimerization reactions in the
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10.1021/ol100177u  2010 American Chemical Society
Published on Web 02/23/2010

the nitrile 9 tethered to a leaving group X would deliver the
intermediate fused pyridine 10 (Scheme 1). A tandem
intramolecular SN2 reaction would directly form the tricyclic
pyridinium compounds 11, which could subsequently be
reduced, e.g., with NaBH4, to give the tricyclic structures
12. This reaction sequence could provide the alkaloid core
structures found in the natural products in Figure 1 in as
little as two steps.
Scheme 1. [2 + 2 + 2] Cyclotrimerization Reaction Coupled
with an Intramolecular SN2 Reaction Enables the Rapid
Assembly of Tricyclic Pyridinium Ions 11 and a Subsequent
Reduction Delivers the Alkaloid Core Structures 12a
Figure 1. Selected natural products with tricyclic alkaloid core
structures shown in red.
synthesis of alkaloids,10,11 we are reporting the sequencing
of a cyclotrimerization with an intramolecular pyridinium
formation via a nucleophilic substitution to rapidly access a
variety of tricyclic alkaloid structures; including the ones
present in the natural products shown in Figure 1. Moreover,
we are reporting the synthesis of the pentacyclic spiroin-
dolinone core of citrinadin A (1), citrinadin B (2), and
cyclopiamine B (3).
The classical [2 + 2 + 2] cyclotrimerization reaction
toward pyridines involves the reaction of two alkynes and a
nitrile.12-14 In order to avoid chemoselectivity issues in the
cyclotrimerization step, the two alkynes are often tethered
together, leading to the synthesis of fused pyridine rings.12-16
These cyclotrimerization reactions are typically conducted
under cobalt catalysis.12-17 Recently, it was discovered by
others18-22 and us23,24 that microwave irradiation25-27
greatly enhances the rates and yields of [2 + 2 + 2]
cyclotrimerization reactions. In the case of Co-catalyzed
reactions, reaction times are reduced from days to minutes
without the necessity of catalyst activation through additives
or light irradiation.
a X ) Br, I, OSO2CH3; m, n g 1.
The investigation of this approach commenced with
commercially available 1,6-heptadiyne (7) or 1,7-octadiyne
(8) by reacting each with either 4-bromobutyronitrile (13)
or the corresponding cyano mesylate 1428 to directly produce
the tricyclic pyridinium structures 15-18 (Scheme 2). The
tricyclic molecules 15-18 were obtained in 22-45% yield
(40 min). Increasing the reaction times to 1 h or increasing
the amount of the nitrile 13 or 14 to >10 equiv did not afford
improved yields.
Scheme 2. Tandem [2 + 2 + 2]
Cyclotrimerization-Substitution Reactions Delivering the
Pyridinium Compounds 15-18 with Bromide and Mesylate
Counterions
We speculated that a [2 + 2 + 2] cyclotrimerization
reaction of the commercially available diynes 7 and 8 with
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We suspected that the modest yields for 15-18 were
caused by decomposition of the pyridinium salts due to
their strong absorption of microwave irradiation based on
their ionic nature25-27 leading to localized heating in the
microwave reactor. Additionally, the intermolecular reaction
of the pyridine intermediate 10 with an excess alkyl bromide
.
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Org. Lett., Vol. 12, No. 6, 2010
1289

13 or mesylate 14 could potentially lead to a competing side
reaction. In order to solve this problem, we employed a two-
step cyclotrimerization-substitution process. Here, the diynes
7 and 8 underwent a smooth cyclotrimerization reaction using
the CpCo(CO)2 catalyst in toluene under microwave irradia-
tion (300 W) for 40 min with the known cyano alcohols 19
and 20.28 This afforded the fused bicyclic pyridine rings
21-24, bearing an ε-hydroxyalkyl chain (Scheme 3), in
ester in 94% yield, followed by a reaction with CuCN30
delivering the nitrile 33 in 85% yield. The nitrile 33 was
reacted in a Co-catalyzed cyclotrimerization reaction with
the two diynes 7 and 8 in toluene under microwave
irradiation (300 W) for 40 min to give the pyridines 34 and
35 in 93% and 86% yield, respectively (Scheme 4). This
Scheme 4. Three-step Cyclotrimerization-Substitution Reaction
to form the Tetracyclic Pyridinium Compounds 38-39 Followed
by Reduction to 40-41
Scheme 3. Two-Step [2 + 2 + 2]
Cyclotrimerization-Substitution Reaction Followed by
Reduction to the Indolizines and Quinolizines 29-32
was followed by a LiAlH4 reduction of the esters 34 and 35
to the alcohols 36 and 37. The pyridinium formation was
conducted under the previously developed cyclization condi-
tions using MsCl and polymer bound piperidine to afford
the tricyclic compounds 38 and 39 in near-quantitative yields.
Reduction of 38 and 39 with NaBH4 delivered the tetracyclic
molecules 40 and 41 in quantitative yield (Scheme 4).
89-95% yield. The hydroxy group was then converted into
a mesylate in situ using MsCl and polymer-bound piperidine
as the base, thus obviating purification and affording clean
products 25-28 in almost quantitative yield. The overall
yield for formation of the tricyclic pyridinium compounds
25-28 from the diynes 7-8 was greater than 80%, making
this two-step reaction favorable over the tandem one-step
reaction depicted in Scheme 2. The reduction of the
pyridinium rings was accomplished using NaBH429 (Scheme
3) to afford the amines 29-32 that display the tricyclic motif
found in the natural products 1-6 (Figure 1). The remaining
double bond represents a valuable handle for potential further
functionalization toward the installation of the substituents
present in citrinadin A and B (1 and 2), and cyclopiamine B
(3).
The developed route shown in Scheme 3 was applied to
the synthesis of the core structure of citrinadins A (1) and B
(2) and cyclopiamine B (3). The synthesis commenced with
the known ester 42 (Scheme 5A).31 Reduction of the nitro
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Weinheim, 2006.
In order to demonstrate the generality of the developed
approach, another reaction sequence was performed that
would lead to the core structure of xylopinine (6). The nitrile
33 was synthesized starting from commercially available
2-iodophenylacetic acid, which was converted to the methyl
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Eur. J. Med. Chem. 2001, 36, 303–311.
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1290
Org. Lett., Vol. 12, No. 6, 2010

CpCo(CO)2 under microwave irradiation (300 W, 90 min).
This delivered the pyridines 45 and 46 in 42% and 41% yield,
respectively. In addition, 57% and 50% of the starting
material 44 was recovered, but extending reaction times led
to unidentified by-products. Gratifyingly, both compounds
were obtained as single regioisomers, since the bulky
trimethylsilyl (TMS) group on 44 directs the formation of
the desired pyridine regioisomer.34-36 However, the sterically
demanding TMS group also leads to the moderate cyclotri-
merization yields, as previously observed.34,37-39 As ex-
pected, the cyclotrimerization reaction with the terminal
diyne 51 delivered the pyridine 52 in a much higher yield
of 83% (Scheme 5B). The majority of the TMS moiety was
removed from the cyclotrimerization product of 44 under
the cyclotrimerization microwave conditions, and any re-
maining silyl groups were cleaved by a subsequent treatment
with potassium fluoride under microwave irradiation (300
W, 2 min) to give the desired products 45 and 46. The
substitution and reduction sequence following Scheme 3 was
then employed by treating the alcohols 45 and 46 with MsCl
in the presence of polymer-bound piperidine to produce the
pyridinium compounds 47 and 48 in excellent yields.
Reduction with NaBH4 completed the pentacyclic spiroin-
dolinone framework 49 of citrinadin A (1) and B (2) in 72%
yield and the alkaloid core structure 50 of cyclopiamine B
(3) in 82% yield. The overall yield of the assembly of 49
and 50 from the common diyne 44 was 30% and 28%,
respectively.
Scheme 5. (A) Synthesis of Racemic 49 and 50, the Core
Structures of Citrinadin A (1) and B (2), as Well as
Cyclopiamine B (3).a (B) Reaction of the Terminal Diyne 51
Produced the Pyridine 52 in Good Yield
In summary, we developed an expedient route to tricyclic
alkaloid core structures by conducting a microwave-mediated
[2 + 2 + 2] cyclotrimerization/intramolecular nucleophilic
substitution/reduction sequence. This methodology was
demonstrated to deliver several tricylic frameworks in good
to excellent yield. These represent the core structures in a
variety of natural alkaloids with important biological activi-
ties.
a brsm ) based on recovered starting material.
Acknowledgment. Financial support from the National
Science Foundation (CAREER Award 0846756 to A.D.) is
acknowledged.
group with zinc and ammonium chloride31,32 followed by a
Mitsunobu reaction33 with methanol produced the known
methoxy oxindole 43 in 60% yield over both steps. Treatment
of 43 with 3-bromo-1-trimethylsilyl-1-propyne and NaH
generated the diyne 44 in 65% yield, which set the stage for
the [2 + 2 + 2] cyclotrimerization reaction. The cyclotri-
merization reaction was accomplished by reacting the diyne
44 with 4-hydroxypentanenitrile (20, n ) 2) for the citrinadin
A (1) and B (2) core and with 4-hydroxybutanenitrile (19, n
) 1) for the cyclopiamine B (3) core in the presence of
Supporting Information Available: Detailed experimen-
tal procedures, analytical data, and copies of NMR spectra.
This material is available free of charge via the Internet at
http://pubs.acs.org.
OL100177U
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