Preliminary feasibility studies on total synthesis of the unusual marine bryozoan alkaloids chartellamide A and B

Article abstract of DOI:10.1016/S0040-4039(03)00876-1

A strategy for synthesis of the chartellamide marine alkaloids has been tested in a model, leading to the polycyclic ring system of the natural product, but which unfortunately does not provide the requisite C-9,20 relative stereochemistry.

Full text of DOI:10.1016/S0040-4039(03)00876-1

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 4141–4143
Preliminary feasibility studies on total synthesis of the unusual
marine bryozoan alkaloids chartellamide A and B
Joanne L. Pinder and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 6 March 2003; accepted 19 March 2003
Abstract—A strategy for synthesis of the chartellamide marine alkaloids has been tested in a model, leading to the polycyclic ring
system of the natural product, but which unfortunately does not provide the requisite C-9,20 relative stereochemistry. © 2003
Elsevier Science Ltd. All rights reserved.
Chartellines A (1), B (2), and C (3) are members of a
small group of about a dozen highly halogenated
indole–imidazole alkaloids containing a b-lactam which
are produced by the marine bryozoan Chartella
papyracea collected in the North Sea.1a–c Two biogenet-
ically-related alkaloids containing b-lactam rings are
chartellamides A (4) and B (5), produced by the same
organism.1d In addition, several congeneric alkaloids
exist where the b-lactam has been rearranged to a
g-lactam, such as in securamines A (6), B (7), C (8), and
D (9).1e,f The alkaloids in this class are all most likely
derived in Nature from tryptophan, histidine, and one
isoprene unit. These complex metabolites have very
challenging structures from a synthetic viewpoint since
they incorporate a number of unprecedented functional
group arrays. We are currently attempting to develop
strategies for total synthesis of both the chartellines and
chartellamides and in this communication describe
some of our initial feasibility studies towards the latter
metabolites. To our knowledge the only previous syn-
thetic work in this area is our report on studies leading
to synthesis of the chartellines 1–3.2
Initial studies were aimed at both developing the chem-
istry to construct the unique ring system of the marine
metabolites 4 and 5, and to investigate important stereo-
chemical issues related to the synthetic strategy. We
have been exploring an approach to synthesis of the
chartellamides outlined retrosynthetically in Scheme 1.
Thus, one might simplify 4 by breaking the indicated
bonds to afford a structure 10 bearing an a,b-unsatu-
rated ester-containing sidechain at the quaternary cen-
ter C-9. The C-9 allyl group in structure 11 could
potentially serve as a precursor to this unsaturated ester
functionality via the application of a Grubbs olefin
cross metathesis with methacrylate.3 The plan was to
generate an equivalent of bis-imine 12 and to then
introduce the b-lactam and allyl groups with the requi-
site chartellamide C-9,20 stereochemistry to produce 11.
In addition, for simplicity we have chosen at the outset
to investigate a model system where the imidazole
moiety of alkaloids 4 and 5 has been replaced by a
benzene ring.
Thus, known isatin ketal 134 was converted to the
N-Boc derivative 14 and subsequently combined with
2-lithio styrene to afford adduct 15 in high yield
Keywords: Staudinger cycloadditions; azetidinones; imines; alkaloids;
marine metabolites.
* Corresponding author.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)00876-1

4142
J. L. Pinder, S. M. Weinreb / Tetrahedron Letters 44 (2003) 4141–4143
(Scheme 2). This intermediate was then O-methylated
to form methoxy olefin 16, which was cleanly hydrobo-
rated, producing primary alcohol 17. A Mitsunobu
reaction of alcohol 17 served to generate ketal azide 18
which could be hydrolyzed to the corresponding keto
azide, and then cyclized to the desired seven-membered
ring imine 19 by treatment with triphenylphosphine.5
With the key imine 19 in hand, we next investigated
construction of the chartellamide b-lactam system via a
Staudinger reaction.6 The cycloaddition of cyclic imine
19 with chloroketene, generated in situ from
chloroacetyl chloride and triethylamine, proved to be
Scheme 3.
Scheme 1.
Figure 1. Chem-3D structure of a-chloro-b-lactam 21.
quite sluggish. After some experimentation, it was
found that slow addition of a large excess (10 equiv.) of
chloroacetyl chloride to a solution of imine 19 in reflux-
ing benzene containing 10 equiv. of triethylamine
afforded the desired chloro b-lactam 21 along with
oxazine 227 in a 2:1 ratio in 85% combined yield
(Scheme 3). Since this is only a model system, no
serious attempt was made here to fully optimize the
Staudinger cycloaddition for the b-lactam.8 Com-
pounds 21 and 22 were not chromatographically sepa-
rable, but the b-lactam could be obtained sufficiently
pure for use in the next step by fractional crystalliza-
tion. Both adducts 21 and 22 were obtained as single
stereoisomers whose complete stereostructures were
established to be as shown by X-ray crystallography.9.10
A Chem-3D representation of the crystal structure of
21 is depicted in Figure 1.
Scheme 2.

J. L. Pinder, S. M. Weinreb / Tetrahedron Letters 44 (2003) 4141–4143
4143
It seems likely that imine 19 reacts with chloroketene to
Acknowledgements
initially produce a zwitterion 20,11 which for steric
reasons probably closes slowly to b-lactam 21. This
intermediate likely has a long enough lifetime that it
reacts with excess chloroketene or chloroacetyl chloride
leading to oxazine 22.7 Interestingly, reaction of imine
19 with 10 equiv. of chloroacetyl chloride and 5 equiv.
of triethylamine leads exclusively to oxazine 22, sug-
gesting that the condensation with zwitterion 20
involves the acid chloride rather than the ketene.
We are grateful to the National Science Foundation
(CHE-0102402) for financial support of this research.
References
1. (a) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.; Larsen,
C.; Anthoni, U. J. Am. Chem. Soc. 1985, 107, 4542; (b)
Anthoni, U.; Chevolot, L.; Larsen, C.; Nielsen, P. H.;
Christophersen, C. J. Org. Chem. 1987, 52, 4709; (c)
Nielsen, P. H.; Anthoni, U.; Christophersen, C. Acta
Chem. Scand. 1988, B42, 489; (d) Anthoni, U.; Bock, K.;
Chevolot, L.; Larsen, C.; Nielsen, P. H.; Christophersen,
C. J. Org. Chem. 1987, 52, 5638; (e) Rahbaek, L.;
Anthoni, U.; Christophersen, C.; Nielsen, P. H.; Petersen,
B. O. J. Org. Chem. 1996, 61, 887; (f) Rahbaek, L.;
Christophersen, C. J. Nat. Prod. 1997, 60, 175.
2. (a) Lin, X.; Weinreb, S. M. Tetrahedron Lett. 2001, 42,
2631; (b) Lin, X. Ph.D. Thesis, The Pennsylvania State
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3. Chatterjee, A. K.; Morgan, J. P.; Scholl, M.; Grubbs, R.
H. J. Am. Chem. Soc. 2000, 122, 3783.
4. Wenkert, E.; Hudlicky, T. Synth. Commun. 1977, 7,
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5. Lambert, P. H.; Vaultier, M.; Carrie, R. J. J. Chem. Soc.,
Chem. Commun. 1982, 1224.
6. For reviews of the Staudinger reaction, see: Palomo, C.;
Aizpurua, J. M.; Ganboa, I.; Oiarbide, M. Eur. J. Org.
Chem. 1999, 3223 and references cited therein.
7. For formation of related by-products in Staudinger reac-
tions, see: Sohar, P.; Stajer, G.; Pelczer, I.; Szabo, A. E.;
Szunyog, J.; Bernath, G. Tetrahedron 1985, 41, 1721;
Afonso, A.; Rosenblum, S. B.; Puar, M. S.; McPhail, A.
T. Tetrahedron Lett. 1998, 39, 7431.
8. The reaction of imine 19 with ketene generated from
acetyl chloride/NEt3 does not produce a b-lactam. More-
over, reaction of 19 with dichloroketene from
dichloroacetyl chloride gives an unstable product tenta-
tively assigned structure A, but none of the desired
b-lactam.
We next turned to introduction of an allyl group at C-9
of our system. It was found that treatment of com-
pound 21 with boron trifluoride etherate leads to imine
23 (Scheme 4). This imine can be isolated if desired, but
it is preferable to simply generate it in situ and add
allylmagnesium bromide, leading to a single stereoiso-
meric alkylation product 24. The structure of this com-
pound was firmly secured by X-ray crystallography.9,10
Although we were pleased that this reaction was indeed
stereoselective, unfortunately the product 24 has the
incorrect C-9,20 relative stereochemistry for the chartell-
amides. We believe imine 23 exists in a conformation
where the ethylene bridge of the seven-membered ring
blocks the a-face of the molecule. Such a conformation
is probably similar to the one that can be seen in the
X-ray structure of precursor 21 (Fig. 1). In an attempt
to explore whether removal of the chlorine might possi-
bly change the situation, a-chloro-b-lactam 21 was
reduced with Raney nickel to b-lactam 25. Allylation of
this compound as was done for 21 led to a single
product 26 which still has the incorrect configuration.
The structure of b-lactam 26 was confirmed by inter-
conversion with chloro b-lactam 24 by dechlorination
with samarium iodide.
In conclusion, although the strategy outlined here
allows for efficient construction of the polycyclic ring
system of the chartellamides, it does not appear to be
amenable to setting the requisite C-9,20 stereochemistry
of the alkaloids. We are presently using what was
learned here in devising alternative strategies to solve
this stereochemical problem.
9. We are grateful to Dr. Hemant Yennawar for X-ray
analyses.
10. X-ray data has been deposited with the Cambridge Crys-
tallographic Data Centre (21: CCDC 204598; 22: CCDC
204739; 24: CCDC 204740).
11. See: Venturini, A.; Gonzalez, J. J. Org. Chem. 2002, 67,
9089 and references cited therein.
Scheme 4.