Stereoselective synthesis of the tricyclic core ABC-rings of nakadomarin and manzamine from a common intermediate

Article abstract of DOI:10.1016/S0040-4039(01)02301-2

Pauson-Khand cyclization of the enamide 9 proceeds in trifluoroethanol to give cyclopentenone 10, which on hydrogenation gives 11, having the core ABC-rings of nakadomarin 1.

Full text of DOI:10.1016/S0040-4039(01)02301-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 947–950
Stereoselective synthesis of the tricyclic core ABC-rings of
nakadomarin and manzamine from a common intermediate
Philip Magnus,* Mark R. Fielding, Charles Wells and Vince Lynch†
Department of Chemistry and Biochemistry, University of Texas at Austin, Austin, TX 78712, USA
Received 10 October 2001; revised 29 November 2001; accepted 3 December 2001
Abstract—Pauson–Khand cyclization of the enamide 9 proceeds in trifluoroethanol to give cyclopentenone 10, which on
hydrogenation gives 11, having the core ABC-rings of nakadomarin 1. © 2002 Elsevier Science Ltd. All rights reserved.
Manzamine A 1 was isolated in 1985 from a marine
sponge (Haliclona sp.) and inhibits the growth of P388
mouse leukemia cells (IC50 0.07 mg mL−1).1 The com-
plex structure of manzamine disguises its simple bio-
genetic connection to the so-called 3-alkylpiperidine
alkaloids.2 There are many different and complex struc-
tures derived from 3-alkylpiperidines, and ircinal 23 has
the most obvious structural connection to 1. There have
been many reports of approaches to the synthesis of
1 and 2 and without exception they all focus on
the azadecalin and attach the 5-, 8- and 13-membered
ring later.4a–p Recently, the Winkler5 and Martin6
groups have completed the total synthesis of 1 and 2
(Scheme 1).
The structure of nakadomarin A 3 has recently been
disclosed.7 It was isolated from an Amphimedon sponge
sp. (SS-264), and exhibited cytotoxicity against murine
lymphoma L1210 cells (IC50 1.3 mg mL−1), inhibitory
activity against cyclin dependent kinase 4 (IC50 9.9 mg
mL−1), and antimicrobial activity against a fungus and
a Gram-positive bacterium.
N
N
CHO
H
N
N
N
O
OH
OH
H
H
H
N
N
N
H
H
H
2, Ircinal A
3, Nakadomarin
1, Manzamine A
H
H
O
A
B
O
A
B
R1N
R1N
R1N
R1N
O
H
H
NR2
C
H
C
NR2
NR2
NR2
7
5
6
4
Scheme 1.
Keywords: nakadomarin; Pauson–Khand; enamide.
* Corresponding author.
† Author for inquiries concerning the X-ray data.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)02301-2

948
P. Magnus et al. / Tetrahedron Letters 43 (2002) 947–950
The tricyclic core structure of nakadomarin that com-
prises the ABC-rings 5 (manzamine lettering), in princi-
ple, can be constructed by an intramolecular
Pauson–Khand reaction of 7 to give 6, which on reduc-
tion of the cyclopentenone should give 5 (Scheme 1).
Furthermore, ring expansion of the B-ring in 5 would
result in the tricyclic core structure of manzamine,
namely 4. Thus, the intermediate 5 can serve as precur-
sor to both 1 and 3. The literature describing the many
facets of Pauson–Khand reactions is substantial,8 and
while both allylamines and propargylamines have been
successfully used as substrates,9 there are no examples
of enamines or enamides as substrates. The conversion
of 4 into 3 also creates a quaternary carbon atom as
part of the tricyclic angularly fused heterocycle.10,11
This is a particularly demanding test of the structural
latitude that the Pauson–Khand reaction can endure. It
should be noted that Shore has described the conver-
sion of 8 into 9 using standard Pauson–Khand reaction
conditions,12 but the corresponding conversion of 10
into 11 has not been reported (Eq. (1)).
house–Pagenkopf et al.16 conditions, where b,b,b-tri-
fluoroethanol is used as solvent, we were able to isolate
17 in 25% yield. This could be improved to 50–55%
yield if the reaction mixture was washed with aqueous
ethylenediaminetetraacetic acid (EDTA) in the work-
up.17,18 The yield of 17 was further increased by
employing the Sugihara procedure.19 Treatment of 16
with Co2(CO)8 (1.1 equiv.)/n-BuSMe (3.5 equiv.) in
1,2-dichloroethane at 83°C gave 17 in 63–69% yield.
1
While the IR, H and 13C NMR spectral data20 were in
agreement with the proposed structure for 17, confir-
mation of the structure was sort by X-ray crystallogra-
phy. Hydrogenation of 17 gave 18 (65%) and 19 (30%)
(Scheme 3). The assignment of stereochemistry for 18
was confirmed by removal of the Boc protecting group
and formation of the p-nitrophenylcarbamate deriva-
tive 20, which gave crystals suitable for X-ray crystal-
lography. Fig. 1 shows an ORTEP representation of 20
that indicates the correct relative stereochemistry of the
ABC-ring fusions (see 1). The stereoisomer 19 was
Pauson
Pauson
O
O
Khand
Khand
(1)
9 (35%)
8
10
11
Treatment of 1213 with LiN(SiMe3)2/THF at −78°C
followed by methyl chloroformate gave 13 (Scheme 2).
Reduction of 13 with diisobutylaluminum hydride in
THF at −78°C, followed by dehydration using quino-
linium camphor sulfonic acid (cat.) gave 14.14 Reduc-
tive amination of 14 with 1-amino-3-butyne
hydrochloride 14a15/Et3N/MeOH/NaBH4 at −5°C gave
the sec-amine 15. Attempted complexation of 15 with
Co2(CO)8 gave a complex intractable mixture, therefore
we masked the sec-amino group as its p-toluenesulfon-
amide derivative 16. Exposure of 16 to a wide variety of
conditions that have been used for Pauson–Khand
reactions gave either no reaction or decomposition to
complex mixtures that contained no detectable amounts
of the tricyclic adduct 17. However, using the Living-
characterized in the same way. Use of Pd/BaSO4/H2 or
Raney nickel did not change the ratio of 18 and 19 to
any significant extent.21
A variety of methods to ring expand the cyclopen-
tanone 18 into
a cyclohexanone derivative were
attempted without success, except the classical diazo-
alkane technology. Treatment of the acid stable
derivative 21 with ethyl diazoacetate/BF3·OEt2 resulted
in the formation of 22 (53%), which exists in the enol
form (l 12.2s for the hydrogen bonded -OH) (Scheme
4).
In summary, the Pauson–Khand reaction provides a
reasonably concise route to the nakadomarin and manz-
Scheme 2.

P. Magnus et al. / Tetrahedron Letters 43 (2002) 947–950
949
Scheme 3.
Scheme 4.
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Figure 1. View of 20 with heteroatoms labelled. Thermal
ellipsoids are scaled to 30% probability level. Hydrogen atoms
shown are drawn to an arbitary scale. The Ts and CO2-
C6H4NO2-p groups have been removed for clarity.
amine core structures. It is planned to investigate if the
stereoselectivity of the reduction of 17 can be improved.
Acknowledgements
The National Institutes of Health (GM 32718), Robert
A. Welch Foundation, Merck Research Laboratories
and Novartis are thanked for their support of this
research. Dr. Brian Pagenkopf is thanked for his advice
concerning Pauson–Khand reaction conditions.
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1
20. 17. IR (film) 2976, 1718, 1701, 1688 cm−1. H NMR (500
MHz, CDCl3) l 7.59 (2H, d, J=8 Hz), 7.30 (2H, d, J=8
Hz), 5.82 (1H, s), 4.05 (1H, m), 3.93 (1H, d, J=12.1 Hz),
3.78 (1H, m), 3.12 (1H, br q), 2.74 (1H, m), 2.39 (3H s),
2.37–2.28 (2H, m), 2.16 (1H, m), 1.95 (1H, m), 1.45 (9H,
s), 1.42 (2H, m). 13C NMR (125 MHz, CDCl3) l 202.0,
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.
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Hz), 7.44 (2H, d, J=8 Hz), 7.37 (2H, d, J=8 Hz), 4.63
(1H, s), 3.70 (4H, m), 2.69 (1H, dd, J=12.7 Hz, J=53.3
Hz), 2.46 (3H, s), 2.45–2.38 (2H, m), 2.17 (1H, d, J=20
Hz), 2.07 (1H m), 1.95 (1H, m), 1.67 (1H, m), 1.52 (2H,
m).
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