Facile synthesis of the trans-fused azabicyclo[3.3.0]octane core of the palau'amines and the tricyclic core of the axinellamines from a common intermediate

Article abstract of DOI:10.1021/ol801289b

(Chemical Equation Presented) A facile synthesis of the trans-fused azabicyclo[3.3.0]octane core of palau'amine and related pyrrole-imidazole alkaloids is described. Following γ-lactam cleavage with concomitant epimerization at C12 of a previously reported tricycle, a facile intramolecular Mitsunobu reaction delivered the fully functionalized tricyclic core common to several members of the oroidin-derived alkaloids including palau'amine. An alternative cyclization of a related intermediate provides the tricyclic aza-angular triquinane core of the axinellamines.

Full text of DOI:10.1021/ol801289b

ORGANIC
LETTERS
2008
Vol. 10, No. 17
3685-3688
Facile Synthesis of the Trans-Fused
Azabicyclo[3.3.0]octane Core of the
Palau’amines and the Tricyclic Core of
the Axinellamines from a Common
Intermediate
Manuel A. Zancanella and Daniel Romo*
Department of Chemistry, Texas A&M UniVersity, P.O. Box 30012,
College Station, Texas 77842-3012
romo@mail.chem.tamu.edu
Received June 8, 2008
ABSTRACT
A facile synthesis of the trans-fused azabicyclo[3.3.0]octane core of palau’amine and related pyrrole-imidazole alkaloids is described. Following
γ-lactam cleavage with concomitant epimerization at C12 of a previously reported tricycle, a facile intramolecular Mitsunobu reaction delivered
the fully functionalized tricyclic core common to several members of the oroidin-derived alkaloids including palau’amine. An alternative cyclization
of a related intermediate provides the tricyclic “aza-angular triquinane” core of the axinellamines.
The pyrrole-imidazole family of marine alkaloids features a
variety of structurally diverse and complex natural products,
e.g. 1-4.1 Because of their intriguing molecular architecture
and, in some cases, enticing biological activities, these natural
products have attracted much synthetic interest. While a
racemic synthesis of axinellamine A and B was recently
described,2 other dimeric bis-guanidine alkaloids in this
family, e.g. palau’amine, have not been synthesized despite
the efforts of several groups.3 The synthetic challenge of a
number of these dimeric pyrrole-imidazole alkaloids was
seemingly made more daunting after several recent inde-
pendent reports revealed that the common, azabicyclo[3.3.0]-
(3) For recent advances toward oroidin alkaloids not cited in ref 1 see:
(a) Sivappa, R.; Hernandez, N. M.; He, Y.; Lovely, C. J. Org. Lett. 2007,
9, 3861–3864. (b) Lanman, B. A.; Overman, L. E.; Paulini, R.; White, N. S.
J. Am. Chem. Soc. 2007, 129, 12896. (c) O’Malley, D. P.; Li, K.; Maue,
M.; Zografos, A. L.; Baran, P. S. J. Am. Chem. Soc. 2007, 129, 4762. (d)
Tan, X.; Chen, C. Angew. Chem., Int. Ed. 2006, 45, 4345. (e) Wang, S.;
Dilley, A. S.; Poullennec, K. G.; Romo, D. Tetrahedron 2006, 62, 7155.
(f) Garrido-Hernandez, H.; Nakadai, M.; Vimolratana, M.; Li, Q.; Doun-
doulakis, T.; Harran, P. G. Angew. Chem., Int. Ed. 2005, 44, 765.
(1) For recent reviews on this family of natural products, see: (a)
Hoffman, H.; Lindel, T. Synthesis 2003, 12, 1753. (b) Jacquot, D. E. N.;
Lindel, T. Curr. Org. Chem. 2005, 9, 1551.
(2) O’Malley, D. P.; Yamaguchi, J.; Young, I. S.; Seiple, I. B.; Baran,
P. S. Angew. Chem., Int. Ed. 2008, 47, 3581.
10.1021/ol801289b CCC: $40.75
Published on Web 08/12/2008
2008 American Chemical Society

octane moiety was in fact trans-fused4 and not cis-fused as
originally reported (Figure 1).5
oxidative cyclization that provided the first enantioselective
synthesis of (+)-phakellin starting from L-prolinol (Figure
2a).9 We envisioned the application of such phakellin
Figure 2. (a) Enantioselective synthesis of (+)-phakellin (Tces )
2,2,2-trichloroethoxysulfonyl) via an oxidative cyclization of a Tces-
guanidine 5. (b) Proposed application of this phakellin annulation
strategy to palau’amine synthesis from aminoalcohol 6.
annulation strategies to an eventual synthesis of palau’amine,
which encompasses this substructure (Figure 2b).
Figure 1. Structures of the palau’amines (1), konbu’acidins (2),
and styloguanidines (3). The common trans-azabicyclo[3.3.0]octane
core is highlighted in red. Structure of the axinellamines (4). The
tricyclic carbon core synthesized in this work is highlighted in green
(vide infra).
Building on early biosynthetic proposals of Kinnel and
Scheuer5 and subsequently Al Mourabit and Potier,10 we
previously described concise entries to the spirocyclic
chlorocyclopentane 7 via a sequential Diels-Alder/oxidation/
chlorination/ring contraction process.11 Herein, we describe
an entry into the trans-azabicyclo[3.3.0]octane core (e.g., 6,
Figure 2b) of palau’amine and related pyrrole-imidazole
marine alkaloids by a facile Mitsunobu process. In addition,
a synthesis of the tricyclic carbon core of the axinellamines
from the same intermediate is described.
Although trans-bicyclo[3.3.0]octane systems are known
and several strategies for their synthesis have been reported,6
analogous systems containing a nitrogen atom are rare.7 This
bicyclic structure is even more scarce in the context of natural
products.4c As described by Baran and Ko¨ck, of the >2000
known bicyclo[3.3.0]octane structures, only 10 feature a trans
junction, and even more significantly, only a single crystal
structureoutofthe121reportedcontaininganazabicyclo[3.3.0]octane
moiety is trans-fused. Furthermore, calculations suggest that
a cis-fused system is significantly (∼27 kJ/mol) favored
energetically over the trans-fused counterpart.8
We began our studies toward the trans-azabicyclo[3.3.0]
core of palau’amine from anti-substituted cyclopentyl ester
8, obtained from known tricyclic γ-lactam 7a11a by selective
deprotection followed by simultaneous ring cleavage/epimer-
ization of alcohol 7b with freshly prepared sodium meth-
oxide.12 The inversion of stereochemistry at C12 was
confirmed by X-ray crystallographic analysis of the p-
bromobenzoate derivative 9 (Scheme 1). The single-crystal
X-ray structure of ester 9 verifies the all-trans-stereochem-
istry of the cyclopentane and also the relative stereochemistry
of the spiro quaternary carbon, which is now common to
various members of this alkaloid family.
In our ongoing synthetic investigations of the pyrrole-
imidazole alkaloids, we recently described an unusual
(4) (a) Buchanan, M. S.; Carroll, R.; Quinn, R. J. Tetrahedron Lett. 2007,
48, 4573. (b) Buchanan, M. S.; Carroll, R.; Addepalli, R.; Avery, V. M.;
Hooper, J. N. A.; Quinn, R. J. J. Org. Chem. 2007, 72, 2309. (c) Grube,
A.; Ko¨ck, M. Angew. Chem., Int. Ed. 2007, 46, 2320. (d) Kobayashi, H.;
Kitamura, K.; Nagai, K.; Nakao, Y.; Fusetani, N.; van Soest, R. W. M.;
Matsunaga, S. Tetrahedron Lett. 2007, 48, 2127.
(5) (a) Kinnel, R. B.; Gehrken, H-P.; Swali, R.; Skoropowski, G.;
Scheuer, P. J. J. Org. Chem. 1998, 63, 3281. (b) Kinnel, R. B.; Gehrken,
H-P.; Scheuer, P. J. J. Am. Chem. Soc. 1993, 115, 3376.
In preparation for cyclization to the trans-azabicyclo[3.3.0]
core of palau’amine, the primary alcohol of ester 8 was
protected and then reduction of the methyl ester gave amino
(6) (a) Grieco, P. A.; Brandes, E. B.; McCann, S.; Clark, J. D. J. Org.
Chem. 1989, 54, 5849. (b) Grieco, P. A.; Clark, J. D.; Jagoe, C. T. J. Am.
Chem. Soc. 1991, 113, 5488. (c) Keese, R. Angew. Chem., Int. Ed. 1992,
31, 344, and references cited therein. (d) J-Gregoire, B.; Brosse, N.; Ianelli,
S.; Nardelli, M.; Caubere, P. J. Org. Chem. 1993, 58, 4572. (e) Paquette,
L. A.; Morwick, T. M. J. Am. Chem. Soc. 1997, 119, 1230. (f) Paquette,
L. A.; Hamme, A. T.; Kuo, L. H.; Doyon, J.; Kreuzholz, R. J. Am. Chem.
Soc. 1997, 119, 1242. (g) Molander, G. A.; Nichols, P. J.; Noll, B. C. J.
Org. Chem. 1998, 63, 2292.
(8) Ko¨ck, M.; Grube, A.; Seiple, I. B.; Baran, P. S. Angew. Chem., Int.
Ed. 2007, 46, 6586.
(9) Wang, S.; Romo, D. Angew. Chem., Int. Ed. 2008, 47, 1284.
(10) Al Mourabit, A.; Potier, P. Eur. J. Org. Chem. 2001, 237.
(11) (a) Dransfield, P. J.; Dilley, A. S.; Wang, S.; Romo, D. Tetrahedron
2006, 62, 5223. (b) Dilley, A. S.; Romo, D. Org. Lett. 2001, 3, 1535.
(12) Full details of the extensive studies leading to optimization of this
ring cleavage/epimerization of ꢀ-lactam 7 to deliver ester 8 will be described
in a separate report.
(7) To the best of our knowledge Mori was the first to report the synthesis
of this system, see: Mori, M.; Saitoh, F.; Uesaka, N.; Okamura, K.; Date,
T. J. Org. Chem. 1994, 59, 4993.
3686
Org. Lett., Vol. 10, No. 17, 2008

Scheme 1
.
Simultaneous Ring Cleavage/C12 Epimerization of
Table 1. Coupling Constant Comparison between Common
γ-Lactam 7 and Structural Verification by X-ray Analysis
(Protecting Groups Are Removed for Clarity) of
p-Bromobenzoate Derivative 9
Tricyclic Core of palau’amine and trans-Azabicyclo[3.3.0]octane
12a
proton
palau’amineb mult (J)c
12 mult (J)c
dd (14.5. 10.0)
11
d (14.4)
12
dddd (14.6, 10.2, 9.0, 7.2) dddd (14.5, 11.0, 10.5, 6.5)
13R
13ꢀ
17
dd (10.2, 7.2)
t (10.2)
d (9.0)
dd (11.0, 6.5)
t (11.0)
d (10.5)
a Obtained in DMSO-d6. b Values from ref 14. c All J values are
expressed in Hz.
alcohol 11.13 For reasons indicated above, it was not clear
how facile the cyclization to the trans-fused system might
be; however, models indicated that a bis-envelope conforma-
tion was readily accessible in such an intermediate. Indeed,
intramolecular displacement of the activated alcohol by the
pendant sulfonamide under Mitsunobu conditions proceeded
efficiently at ambient temperature to generate the desired
trans-azabicyclooctane 12 in 74% yield (Scheme 2). Evi-
tricycle 12 also corroborate the relative stereochemistry and
the conformation of this rather rigid, spirotricyclic system
(Figure 3).
Scheme 2. Synthesis of trans-Azabicyclo[3.3.0]octane 12
Figure 3. Selected NOE correlations for spirocycle 12 (R1 ) TIPS,
R2 ) TBDPS) identified by 1D (single-headed arrows) and 2D
(double-headed arrows) NOE experiments.
Further studies were conducted to determine the relative
ease of cyclization to the trans-azabicyclo[3.3.0]octane core
in comparison to other potential modes of intramolecular ring
formation. In particular, we were interested in assessing the
competition between formation of an aziridine and the trans-
azabicyclo[3.3.0]octane when both modes of cyclization are
possible. When aminodiol 13, obtained by DIBAL reduction
of ester 8, was subjected to Mitsunobu conditions, nearly
equal amounts of aziridine 14 and tricycle 15 were obtained
(Scheme 3). The structure of tricycle 15 was verified by TIPS
deprotection of tricycle 12 obtained previously, which gave
the same compound. The structure of aziridine 14 was
correlated to a related aziridine 16, prepared by Mitsunobu
reaction of alcohol 8, by comparison of diagnostic signals
in the 1H NMR spectrum. It is noteworthy that this reaction
leading to the aziridine required an excess amount of reagents
and prolonged reaction time compared to formation of the
pyrrolidine 12.
dence for the stereochemistry of this bicyclic intermediate
was garnered by comparison of the coupling constants of
several key protons of pyrrolidine 12 with those reported
for palau’amine by Quinn14 (Table 1). The coupling constants
indeed correlate well further confirming the revised stereo-
chemistry of palau’amine, i.e. the trans-azabicyclo[3.3.0]-
octane core. In addition, selected NOE enhancements for
(13) Likely due to coordination of the aluminum reagent with the Lewis
basic sulfonamide, a mixture of the desired alcohol and corresponding
aldehyde was isolated after the first step. Treatment of the crude mixture
with NaBH4 enabled complete conversion to the desired alcohol.
(14) Buchanan, M. S.; Carroll, A. R.; Quinn, R. J. Tetrahedron Lett.
2007, 48, 4573.
We were also interested in studying the facility of a related
intramolecular cyclization from the same intermediate ester
Org. Lett., Vol. 10, No. 17, 2008
3687

(Scheme 4). A presumed overoxidation15 of the DMB group
to a benzoyl derivative 19 was observed; however, this
intermediate was not fully characterized given that it was
readily converted to the same carbinolamine 18 by basic
hydrolysis. Thus, intramolecular cyclization to the tricyclic,
“angular triquinane-type” core of the axinellamines (Figure
1, highlighted in green) is also quite facile.16
Scheme 3. Competition between Aziridine 14 and
Azabicyclo[3.3.0]octane 15 Formation and Structural
Correlations
In summary, we have described facile modes of intramo-
lecular cyclization from a common spiro hydantoin cyclo-
pentane intermediate that efficiently delivers the core sub-
structures of the palau’amines and the axinellamines. The
facility of these cyclizations is consistent with a proposed
biogenesis involving the synthesis of the various ring systems
found in these natural products from a common cyclopentane
intermediate. The relative configuration of the anti-chloro-
cyclopentane core has been verified crystallographically,
firmly establishing the relative stereochemistry, including the
spiro quaternary carbon. The tricyclic prolinol derivative 12
is a viable substrate for phakellin annulation employing our
previously described oxidative cyclization from prolinol9 and
results of these studies will be described in due course.
8, which can serve as a precursor to the axinellamines.
Following Dess-Martin oxidation of the primary alcohol,
exposure to ceric ammonium nitrate (CAN) not only
promoted the desired deprotection but also led to facile
intramolecular cyclization generating the stable carbinola-
mine 18 under the slightly acidic conditions of this process
Acknowledgment. This work was made possible by
funding from the NIH (GM 52964) and the Welch Founda-
tion (A-1280). We thank Dr. Joseph Reibenspies (TAMU)
for solving the X-ray crystal structure of benzoate 9.
Supporting Information Available: Experimental pro-
cedures and 1H and 13C NMR spectra for compounds 7b, 8,
10-12, 15, 16, and 18, crystal structure of 9, and two-
dimensional NMR spectra for 12. This material is available
free of charge via the Internet at http://pubs.acs.org.
Scheme 4
. Alternative Cyclization Mode of Cyclopentane 8
Leading to the Axinellamine Tricyclic Core
OL801289B
(15) For a related example of over-oxidation during PMB removal, see:
Ohfune, Y.; Demura, T.; Iwama, S.; Matsuda, H.; Namba, K.; Shimamoto,
K.; Shinada, T. Tetrahedron Lett. 2003, 44, 5431.
(16) While our work was in progress, Baran and co-workers also reported
the facility of this cyclization in the course of their studies leading to
axinellamine (see ref 2).
3688
Org. Lett., Vol. 10, No. 17, 2008