Toward Palau'amine: Hg(OTf)2-Catalyzed synthesis of the cyclopentane core

Article abstract of DOI:10.1002/chem.200900622

An efficient synthesis of the cyclopentane core of palau'amine by the application of a highly efficient novel Hg(OTf)₂-catalyzed cyclization reaction was reported. The synthesis started with a Morita-Baylis Hillman reaction of the two commercia

Full text of DOI:10.1002/chem.200900622

DOI: 10.1002/chem.200900622
Toward Palau’amine: Hg
ACHTUNGERTN(NUNG OTf)2-Catalyzed Synthesis of the
Cyclopentane Core
Kosuke Namba,*[a] Yukari Kaihara,[b] Hirofumi Yamamoto,[b] Hiroshi Imagawa,[b]
Keiji Tanino,[a] Robert M. Williams,[c] and Mugio Nishizawa*[b]
The pyrrole–imidazole alkaloids, which comprise a large
family of natural products, have received a great deal of at-
tention due to their potent biological activities and tremen-
dous structural diversity.[1] Palau’amine (1) was originally
isolated from a sponge, Stylotella agminata, in 1993 by Sche-
uer as a novel class of the pyrrole–imidazole alkaloid.[2]
Since the initial disclosure of its proposed structure (1a),
palau’amine (1; Figure 1) has been an attractive synthetic
target because of its intriguing molecular architecture and
significant biological properties such as antifungal, antitu-
mor, and immunosuppressive activities. However, according
to several groups, the originally proposed structure 1a was
recently revised as 1b, which instead possesses the indicated
the trans-D/E ring junction and the b-chlorine substitu-
and the first total synthesis of the related natural products
axinellamines A/B (2)[6a,b] and massadine/massadine chlori-
de[6c] was recently accomplished. However, a total synthesis
of palau’amine itself has not yet been reported. Efficient
construction of the complex cyclopentane core with the cor-
rect stereochemistry at each carbon center, including a qua-
ternary carbon center, is definitely one of the most difficult
synthetic challenges of the synthesis of palau’amine. Herein,
we describe an efficient synthesis of the cyclopentane core
of palau’amine by the application of a highly efficient novel
Hg
ACHTUNGTRENNUNG
laboratory.[7] In 2008, the Hg
AHCTUNGTRENNUNG
tion method was extended to the alkene cyclization reac-
tions of allylic alcohols and vinyl methyl ethers which, after
cyclization, undergo a smooth proto-demercuration to give
ACHTUNGTRENNUNG
ent.[3,5e,g] The noteworthy structural features of palau’amine
include: two guanidine moieties, a fused polycyclic system
with a spiro cycle, a fully substituted complex cyclopentane
ring, and eight contiguous stereogenic centers including a ni-
trogen-substituted quaternary carbon center.
the cyclized products and the regenerated the Hg
ACHTUNGRTENN(UNG OTf)2 cat-
alyst.[8] For instance, the Hg
AHCTUNGTRENNUNG
N-tosylanilino allylic alcohol 3 provided 2-vinylindolines 4
in high yield (Scheme 1).[8b] Thus, the cyclization of cyclo-
pentylidene alcohol 5 could potentially give 6, simultaneous-
ly constructing a quaternary carbon center that corresponds
to the C16 of palau’amine. However, the alternative cycliza-
tion mode of amide 5 is also possible, which gives the O-cy-
clized product 7 in preference to the N-cyclized product 6.
Indeed, we confirmed that this was the case. Conventionally,
N-selective cyclization of amide has been achieved by the
cumbersome substrate modifications, addition of strong
Not surprisingly, many attempts to synthesize palau’amine
and related natural products have been reported so far,[4,5]
[a] Dr. K. Namba, Prof. Dr. K. Tanino
Division of Chemistry, Hokkaido University
Kita-ku, Sapporo 060-0810 (Japan)
Fax : (+81)11-706-2703
E-mail: namba@mail.sci.hokudai.ac.jp
[b] Y. Kaihara, Dr. H. Yamamoto, Dr. H. Imagawa,
Prof. Dr. M. Nishizawa
Faculty of Pharmaceutical Science
Tokushima Bunri University, Yamashiro-cho
Tokushima 770-8514 (Japan)
Fax : (+81)88-602-8446
E-mail: mugi@ph.bunri-u.ac.jp
[c] Prof. Dr. R. M. Williams
Department of Chemistry, Colorado State University
Fort Collins, CO 80523 (USA)
and the University of Colorado
Cancer Center Aurora, CO 80045 (USA)
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/chem.200900622.
Figure 1. Structure of palau’amine (original and revised structures) and
axinellamines (2).
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COMMUNICATION
Lewis acids and/or strong base, or the formation of an N-
radical.[9] Moreover, the catalytic cyclization method, which
simultaneously creates a quaternary carbon center, has not
yet been established. Therefore, we designed an acyl tosyl-
hydrazide 8 as a simple substitute of the primary amides 5
for the Hg
ACHTUNGTRENNUNG
prepared by the HgAHCTUNGTRENNUNG
serve as an excellent precursor for the cyclopentane core 10.
Introduction of the two CH2-N side chains to lactam 9 fin-
ishes the construction of 10 (Scheme 1).
Scheme 2. Synthesis of hydrazide 18.
Treatment of 18 with 2 mol% of HgACTHNUTRGNEUNG(OTf)2 in nitrome-
thane at room temperature smoothly afforded 19a and 19b
in 84% yield as a separable 1:2 diastereomeric mixture
(Scheme 3). The lactone 20 was not detected. Stereochemi-
cal outcome at the ring junction was completely controlled
to be cis regardless of the stereochemistry of the secondary
alcohol at C17. The structures of 19a and 19b were unam-
biguously confirmed by an X-ray diffraction study and NOE
studies (see the Supporting Information).[14] We thus estab-
Scheme 1. HgACHTUNGTRENNUNG(OTf)2-catalyzed cyclization of allylic alcohol and synthetic
design of palau’amine cyclopentane core 10.
lished an efficient HgACHTGUNTERNNU(G OTf)2-catalyzed protocol of N-selec-
tive cyclizations of N-acyl compounds, which is difficult to
achieve using the conventional combinations of substrates
and methods.[15]
Our synthesis started with a Morita-Baylis–Hillman reac-
tion of the two commercially available compounds, 2-cyclo-
pentene-1-one (11) and (tert-butyldimethylsilyloxy)acetalde-
hyde, to afford 12 in 70% yield (Scheme 2). Compound 12
was subsequently converted to a 1:2 diastereomeric mixture
of the acetates 14 by a sequential operation of acetylation, a
Luche reduction,[10] and a TBS protection. Without separa-
tion, the diastereomeric mixture of the acetates 14 was sub-
jected to an Ireland–Claisen rearrangement.[11,12] After the
treatment of 14 with LHMDS/TBSCl/HMPA in THF at
À788C, refluxing in toluene induced the desired Ireland–
Claisen rearrangement to afford the cyclopentylidene car-
boxylic acid 16 via 15 in good yield. The double bond geom-
etry of 16 was determined to be Z by the NOE experiment
of its amide derivative. Next, we attempted to prepare an
acyl tosylhydrazide by the coupling of 16 with N-tosylhydra-
zide by the combined action of EDCI and DMAP in di-
chloromethane. Surprisingly, the nitrogen atom masked with
a tosyl group participated in the condensation to give a 1:2
diastereomeric mixture of 17 in 68% overall yield after four
steps from 14. Presumably, the nucleophilicity of the more
basic primary amine was attenuated due to the protonation
by the HCl derived from an EDCI-HCl salt.[13] The TBS
groups were then cleaved under mild acidic conditions to
give diol 18 (Scheme 2).
Scheme 3. HgACHTNUTRGNE(UNG OTf)2-catalyzed allyl alcohol cyclization of acylhydrazide.
Having prepared a sufficient amount of the N-cyclized
product 19, we attempted to complete the construction of
the cyclopentane core of palau’amine. SO3·pyridine oxida-
tion of the mixture of 19a and 19b gave the ketone 21 in
quantitative yield.[16] Direct oxidation of 21 to enone 23
using IBX[17] or selenium dioxide was not successful. Neither
was oxidation of 21 via its enolate using selenium halide,
sulfinimidoyl chloride,[18] or NBS. Although the preparation
of the silyl enol ether was initially difficult, a combination of
TMSI and hexamethyldisilazane in dichloromethane was
later found to give trimethylsilyl enolether 22 in quantitative
yield.[19,20] Saegusa–Ito oxidation of 22 provided enone 23 in
good yield.[21] A Morita-Baylis–Hillman reaction of 23 with
formaldehyde gave alcohol 24 in excellent yield. Subsequent
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K. Namba, M. Nishizawa et al.
1,4-addition of nitromethane in the presence of a catalytic
amount of 1,1,3,3-tetramethylguanidine (TMG) afforded the
desired 1,4-adduct 25.[22] We found that 25 was readily un-
derwent dehydration during column chromatography purifi-
cation to give the exomethylene product. Therefore, the
crude 25 was directly subjected to reduction with NaBH4 to
give 26. The stereochemistry of 26 was confirmed to be as
we planned for our palau’amine synthesis by an NOE ex-
periment. Finally, the primary alcohol of 26 was converted
to azide 27, which is the targeted cyclopentane core inter-
mediate of palau’amine. The structure of 27 was unequivo-
cally established by an X-ray diffraction study (Scheme 4
and the Supporting Information).[23]
Experimental Section
Experimental details, full data, 1H and 13C NMR spectra of each inter-
mediate from 11 to 27, and data of X-ray analysis are available in the
Supporting Information.
Acknowledgements
This work was supported by Grants-in-Aid for Scientific Research from
the Ministry of Education, Culture, Sports, Science, and Technology of
Japanese Government, MEXT. HAITEKU, 2003–2007, and the Global
COE Program (Project No. B01: Catalysis as the Basis for Innovation in
Materials Science). We acknowledge financial support from the National
Institutes of Health (NIH Grant GM068011 to R.M.W. and K.N., Colora-
do State University). K.N. is grateful to Astellas Co., Inc. and JSPS, for a
Research Fund for Young Scientists.
Keywords: alkaloids
palau’amine
· cyclization · natural products ·
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Palau’amine
COMMUNICATION
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[23] CCDC 713396 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[14] CCDC 711310 contains the supplementary crystallographic data for
this paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via www.ccdc.cam.ac.uk/
data_request/cif
[15] The Hg
G
Received: March 9, 2009
only lactone ii, and lactam iii was not detected at all under a variety
Published online: June 2, 2009
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