Synthetic studies on palau'amine. Construction of the cyclopentane core via an asymmetric 1,3-dipolar cycloaddition

Article abstract of DOI:10.1016/j.tetlet.2010.10.037

The cyclopentane core of palau'amine has been constructed in optically pure form through the use of an asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.

Full text of DOI:10.1016/j.tetlet.2010.10.037

Tetrahedron Letters 51 (2010) 6557–6559
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Tetrahedron Letters
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Synthetic studies on palau’amine. Construction of the cyclopentane core via
an asymmetric 1,3-dipolar cycloaddition
Kosuke Namba a, Makoto Inai a, Uta Sundermeier a, Thomas J. Greshock a, Robert M. Williams a,b,
⇑
a Department of Chemistry, Colorado State University, 1301 Center Avenue, Fort Collins, CO 80523, USA
b University of Colorado Cancer Center, Aurora, CO 80045, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The cyclopentane core of palau’amine has been constructed in optically pure form through the use of an
asymmetric azomethine ylid [1,3]-dipolar cycloaddition reaction.
Ó 2010 Elsevier Ltd. All rights reserved.
Received 9 September 2010
Revised 5 October 2010
Accepted 6 October 2010
Available online 14 October 2010
Keywords:
Amino acid
Dipolar cycloaddition
Spiro-guanidine
Palau’amine is a dauntingly complex hexacyclic bis-guanidine
antibiotic obtained from the sponge Stylotella agminata that dis-
plays potent cytotoxic and immunosuppressive activities
(Fig. 1).1a,b This substance has attracted considerable attention
from the synthetic community2 and a recent, brilliant total synthe-
sis of racemic palau’amine by the Baran laboratory is particularly
noteworthy.3 The relative stereochemistry of palau’amine was re-
cently revised independently by Quinn4 and Köck5 to the stereo-
structure depicted in Figure 1 and turned out to be a fortuitous
stereochemical array for the approach described herein. The re-
lated alkaloids, the styloguanidines, were isolated from the marine
sponge Stylotella aurantium and have been shown to be inhibitors
of chitinase, an important enzyme in the molting of crustaceans.6
The axinellamines, isolated from the marine sponge Axinella sp.,
display moderate bactericidal activity against Helicobacter pylori.7
All of these substances share a structurally related cyclopentane
core and thus far, only the Baran laboratory has been successful in
total synthesis efforts in this family of alkaloids.8,9 The relative ste-
reochemistry of the cyclopentane core of palau’amine and the
styloguanidines is the same while the axinellamines dispose the
aminomethyl substituent adjacent to the chlorine atom in an
anti-relationship.
density of functionality and stereochemistry and provides perhaps
an extreme test of suitable synthetic methodologies. While the
landmark accomplishment by Baran and co-workers on the first to-
tal synthesis of palau’amine represents an important milestone in
the chemistry of this fascinating family of alkaloids, the asymmet-
ric synthesis of palau’amine remains an important synthetic
objective.
3
2
5
O
O
N
N
1
15
N
H
H
6
N
10
HN
HN
13
9
7
N
N
12
H2N
H2N
H2N
H2N
N
N
16
NH2
NH2
18
20
22
N
N
H
Cl
Cl
H
OH
palau'amine
(new, revised stereochemistry)
OH
palau'amine
(original stereostructure)
R2
NH
OR
H
N
O
Cl
O
R1
HN
N
H
H
H
HN
N
Br
N
H
HN
NH
It should be noted that the absolute stereochemistry of these
natural products has not been rigorously assigned, although based
on CD similarities with monobromophakellin hydrochloride, Sche-
uer and co-workers, have postulated the absolute stereostructure
shown.1 All of these agents represent an unusually challenging
N
HN
HN
Br
Br
OH
NH
H2N
H2N
N
NH2
O
HN
N
H
Cl
OH
Br
R1 = R2 = H, styloguanidine
R = H, axinellamine A
R = Me, axinellamine C
R1 = Br, R2 = H, 3-bromostyloguanidine
R1 = Br, R2 = Br, 2,3-dibromostyloguanidine
⇑
Corresponding author. Tel.: +1 970 491 6747; fax: +1 970 491 3944.
E-mail address: rmw@lamar.colostate.edu (R.M. Williams).
Figure 1. Structures of palau’amine and congeners.
0040-4039/$ - see front matter Ó 2010 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2010.10.037

6558
K. Namba et al. / Tetrahedron Letters 51 (2010) 6557–6559
O
tetramethyl guanidine in acetonitrile at room temperature to give
Boc
N
exclusively, the 1,2-anti product. Reduction of the ketone gave diol
11 which was subjected to extensive 1H NMR NOE experiments to
secure the relative stereochemistry of this substance. The relative
stereochemistry of the vicinal hydroxymethyl and nitromethyl
substituents in 11 are set with the correct relative stereochemistry
as per the newly reassigned stereochemistry of palau’amine.
Cyclopentane 11 embodies the stereochemistry and relevant
functionality to constitute a viable intermediate for the asymmet-
ric synthesis of palau’amine and congeners. Efforts to complete an
asymmetric total synthesis of palau’amine from cyclopentane 11
are currently under investigation in these laboratories.
Cl
O
O
Boc
N
Ph
Ph
TFA
NaHMDS
Ph
Ph
CH2Cl2
rt, 2 h
THF
O
O
O
°
-78 C, 1h
2
1
O
H
(CHO)n
Ph
N
O
N
O
Ph
Ph
dioxane
Δ, 4 h
O
Ph
O
O
68% (3 steps)
3
A
1. H2, PdCl2
LiAlH4, THF
N
Acknowledgments
Ph
Ph
N
2. Boc2O
Δ, 2h
Ph
HO
OH
OH
O
O
61% (3 steps)
O
We are grateful to the National Institutes of Health (GM068011)
for financial support. We also acknowledge fellowship support
from the JSPS (to K.N.) and the Uehara Foundation (to M.I.).
Ph
N
5
4
IBX, NMO
RuCl3, NaIO4
O
t-BocN
DMSO
rt, 24 h
80%
MeCN, CCl4
H2O, rt, 18 h
81%
Supplementary data
OH
Ot-Boc
O
Boc
OBoc
Supplementary data (complete experimental details and spec-
troscopic characterization of all new compounds) associated with
this article can be found, in the online version, at doi:10.1016/
j.tetlet.2010.10.037.
7
6
aq HCHO
n-Bu3P
OH
LiOH
O
O
N
Boc
N
Boc
THF, rt, 6 h
MeOH, rt, 0.5 h
75% (2 steps)
O
O
OBoc
OBoc
8
9
References and notes
MeOOC
BocHN
MeOOC
NO2
OH
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1. MeNO2, TMG
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MeCN, rt, 6 h
2. NaBH4, THF
MeOH, rt, 1 h
92% (2 steps)
BocHN
O
OH
OBoc
OBoc
11
10
Scheme 1. Asymmetric synthesis of cyclopentane 11.
We have devised an efficient, stereocontrolled entry to the
highly functionalized cyclopentane core of palau’amine by an
asymmetric intramolecular azomethine ylide dipolar cycloaddi-
tion10,11 as the key step and report these preliminary studies here-
in (Scheme 1).
Our synthesis commences with the enolate acylation of com-
mercially available oxazinone 111 to provide 2 (relative stereo-
chemistry unassigned and inconsequential). Removal of the t-Boc
group furnishes aminoketone 3 which was condensed with formal-
dehyde to generate the incipient azomethine ylid (A) that pro-
duced tricyclic intramolecular cycloaddition product 4 as a single
diastereomer in 63% overall yield for the three steps. The intrinsic
facial bias of this intramolecular cycloaddition remains unclear and
constitutes the subject of ongoing studies.
This substance was reduced with LiAlH4 to triol 5, followed by
catalytic hydrogenation and t-Boc-protection to give 6 in 61% over-
all yield from 4. Ruthenium-mediated oxidation cleanly afforded
ketoamide 7 in 81% yield that was converted into the unsaturated
ketone by exposure to IBX and N-methylmorpholine N-oxide in
DMSO delivering enone 8 in 80% yield.12
Stereoselective installation of the two one-carbon arms to en-
one 8 was accomplished in two stages beginning with a Morita–
Baylis–Hillman type of hydroxymethylation that deployed aque-
ous formaldehyde and tri-N-butyl phosphine providing 9 in good
yield.13 Methanolic lithium hydroxide treatment of 9 gave the
monocyclic methyl ester 10 in 75% overall yield from 9. For the
second stage, enone 10 was then treated with nitromethane and
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6559
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a-amino acids. (a)
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a-
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A., Ed.; Vol. 1, JAI Press: 1995; pp 45–94.; (c) Burnett, C.; Williams, R. M.
Strategies and Tactics in Organic Synthesis, 2008; Vol. 7, Chapter 8, pp 268–
327.
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103, 811–892.