Model studies on total synthesis of the chartellines, spirocyclic β-lactam alkaloids from a marine bryozoan

Article abstract of DOI:10.1016/S0040-4039(01)00270-2

A chartelline alkaloid model system containing a spirocyclic β-lactam moiety and α,β-unsaturated imine has been constructed from isatin using a Staudinger imine-ketene cycloaddition and an addition to an N-activated γ-lactam as key steps.

Full text of DOI:10.1016/S0040-4039(01)00270-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 2631–2633
Model studies on total synthesis of the chartellines, spirocyclic
b-lactam alkaloids from a marine bryozoan
Xichen Lin and Steven M. Weinreb*
Department of Chemistry, The Pennsylvania State University, University Park, PA 16802, USA
Received 30 January 2001; revised 12 February 2001; accepted 13 February 2001
Abstract—A chartelline alkaloid model system containing a spirocyclic b-lactam moiety and a,b-unsaturated imine has been
constructed from isatin using a Staudinger imine–ketene cycloaddition and an addition to an N-activated g-lactam as key steps.
© 2001 Elsevier Science Ltd. All rights reserved.
Chartellines A (1), B (2), C (3) and methoxydech-
lorochartelline A (4, possibly an artifact of isolation) are
members of a small group of highly halogenated indole–
imidazole alkaloids containing a b-lactam which are
produced by the marine bryozoan Chartella papyracea
and are collected in the North Sea.1a,b These unusual
natural products, whose structures and absolute configu-
ration were determined by a combination of spectral
methods and X-ray crystallography, also contain a rigid
ten-membered tub-shaped ring. Two biogenetically-
related alkaloids containing similar spiro b-lactam rings
are chartellamides A (5) and B (6), produced by the same
organism.1c,d These complex metabolites have very chal-
lenging structures from a synthetic point of view since
they incorporate a number of unique functional group
arrays. To our knowledge no synthetic work has been
reported in this area to date. We are currently attempting
to develop a strategy for total synthesis of the chartellines
and in this communication describe some of our prelim-
inary feasibility studies.
O
Br
O
O
Br
Cl
OMe
N
N
R
Br
N
N
N
N
N
R'
Br
Br
Br
Br
Br
N
N
O
Br
R
N
H
N
N
11
H
Me
Br
10
1 R, R' = Br (chartelline A)
2 R = Br, R' = H (chartelline B)
3 R, R' = H (chartelline C)
4 (methoxydechlorochartelline A)
5 R = H (chartellamide A)
6 R = Br (chartellamide B)
(TMS)3SiH
O
O
O
AIBN
PhMe
100 oC
93%
Bu
Cl
Cl
N
ClCH2COCl
N
N
N
Bu
Bu
Bu
NEt3, CH2Cl2
O
+
O
O
O
N
H
87% from
isatin
N
N
N
H
H
H
7
10
9
8
Scheme 1.
Keywords: Staudinger cycloadditions; azetidinones; imines; alkaloids; marine metabolites.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00270-2

2632
X. Lin, S. M. Weinreb / Tetrahedron Letters 42 (2001) 2631–2633
We have opted to construct the spirocyclic b-lactam
ring of these alkaloids via a Staudinger ketene–imine
cycloaddition.2,3 Thus imine 7, prepared from isatin
and n-butylamine, was found to undergo smooth
cycloaddition with chloroketene, generated in situ from
chloroacetyl chloride and triethylamine,3b to afford a
high yield of a mixture of stereoisomeric a-chloro b-lac-
tams 8 and 9 (3:1 ratio) (Scheme 1). Attempted dechlo-
rination of the mixture with zinc–HOAc4 proved
unsuccessful, and only the recovered starting material
was obtained. Free radical reduction of the mixture of
8/9 with tributyltin hydride5 did in fact lead to the
desired b-lactam 10, but it has proven more convenient
and efficient to conduct the dehalogenation with
tris(trimethylsilyl)silane.6 Attempting the cycloaddition
of imine 7 with the ketene itself, generated in situ from
acetyl chloride7 and gave b-lactam 10 but only in poor
yield.
A number of attempts were made to effect a Lindlar
reduction of alkyne 12b to produce Z-olefin 14, but in
general either starting material was recovered or the
undesired totally saturated product was obtained.
Hydroboration of 12b similarly failed. Alternatively,
vinylmagnesium bromide could be added to lactam 11b
to afford the requisite adduct 15a in high yield as an
inseparable 3:2 mixture of diastereomers. Similarly, Z-
1-lithiopropene (prepared from commercially available
Z-1-bromopropene and t-butyllithium) could be con-
verted to the corresponding Grignard reagent and then
added to N-Boc lactam 11b to produce adduct 15b,
again as an inseparable 3:2 mixture of diastereomers.
Subjection of these mixtures to TFA in an attempt to
remove the Boc group and dehydrate to form the
corresponding a,b-unsaturated imine led to complex
mixtures of products in which the b-lactam ring was
lost, presumably via rearrangement to a 5,5-ring sys-
tem. However, thermolysis of Boc compound 15a in
DMSO did indeed lead to the desired unsaturated imine
16, which proved to be very sensitive and decomposes
on silica gel chromatography.10 Unfortunately,
analogous thermolysis of the propenyl N-Boc com-
pound 15b led to a complex mixture of products rather
than the desired imine.
We next turned to introduction of a suitably functional-
ized carbon moiety into intermediate 10 intended to
become the chartelline C-10, 11 double bond. Initially
we tried to elaborate the molecule by converting the
g-lactam functionality of 10 to a reactive methyl imi-
date, triflate or iminyl chloride, but all of these attempts
failed. On the other hand, lactam 10 could be converted
in high yield to the N-tosyl lactam 11a (Scheme 2). We
were pleased to find that this tosylation provides suffi-
cient carbonyl activation that addition of lithio t-butyl-
acetylide to 11a is completely chemoselective, affording
the desired adduct 12a as a 1:1 mixture of diastereoiso-
mers. Similarly, the N-Boc lactam 11b, which could be
prepared from 10 in high yield, also undergoes clean
and selective t-butylacetylide addition to provide
adduct 12b (1:1 mixture of stereoisomers).8 Interest-
ingly, attempted trifluoroacetic acid-promoted cleavage
of the Boc group of 12b led to the vinylogous amide 13
via a Meyer–Schuster rearrangement.9
In conclusion, we have been able to successfully convert
isatin into a chartelline model system 16 containing the
spirocyclic b-lactam and a,b-unsaturated imine func-
tionality, two of the unique structural features found in
these natural products. It should be noted that we
anticipate that the rearrangement and instability prob-
lems encountered with these simple models should not
occur in the authentic chartelline system due to the
constraints of the rigid ten-membered ring. We are
currently investigating this chemistry in devising a strat-
egy for total synthesis of the chartelline alkaloids.
O
O
O
TFA, rt
N
TsCl, rt
N
CH2Cl2
76%
Bu
N
Bu
Bu
NaH, THF
Li
t-Bu
10
O
or
N
X
THF
(X = Boc)
N
X
OH
N
H
(Boc)2O
NEt3, DMAP
CH2Cl2, rt
-78 oC-rt
O
13
12a X = Ts (83%)
12b X = Boc (94%)
11a X = Ts (96%)
11b X = Boc (95%)
R
MgBr
THF
-78 oC
O
O
O
DMSO
170 oC
N Bu
N Bu
OH
N Bu
OH
R
R = H
90%
N
N
N
Boc
14
Boc
15a R = H (95%)
15b R = Me (78%)
16
Scheme 2.

X. Lin, S. M. Weinreb / Tetrahedron Letters 42 (2001) 2631–2633
1983, 2241.
2633
Acknowledgements
5. (a) Daum, S. J.; Hansen, P. E. Synth. Commun. 1981, 11,
1; (b) Santer, G.; Ongania, K.-H. Monat. Chem. 1994,
125, 71 and references cited therein.
We are grateful to the National Science Foundation
(CHE-97-32038) for financial support of this research.
6. Bandini, E.; Favi, G.; Martelli, G.; Panunzio, M.; Pier-
santi, G. Org. Lett. 2000, 2, 1077.
7. Rawat, T. R.; Srivasta, S. D. Ind. J. Chem. 1998, 37B, 91.
8. An example of the addition of an acetylide to an N-Boc
lactam exists: Padwa, A.; Dean, D. C.; Fairfax, D. J.; Xu,
S. L. J. Org. Chem. 1983, 58, 4646.
9. Cf.: (a) Omar, E. A.; Tu, C.; Wigal, C. T.; Braun, L. L.
J. Heterocycl. Chem. 1992, 29, 947; (b) Mamouni, A.;
Daich, A.; Decroix, B. Synth. Commun. 1998, 28, 1839.
For a review of the Meyer–Schuster rearrangement, see:
(c) Swaminathan, S.; Narayanan, K. V. Chem. Rev. 1971,
71, 429.
10. Formation of a,b-unsaturated imine 16: A solution of
Boc alkene 15a (25 mg, 0.067 mmol) in 1 mL of deuter-
ated DMSO was heated at 170°C for 0.5 h. The resulting
solution was used directly for NMR analysis without
purification of the imine. 1H NMR (360 MHz, DMSO-
d6): l 7.61 (d, J=7.7 Hz, 1H), 7.42–7.38 (m, 2H), 7.30–
7.26 (m, 1H), 6.79 (dd, J=18.1, 11.5 Hz, 1H), 6.27 (d,
J=18.1 Hz, 1H), 5.84 (d, J=11.5 Hz, 1H), 3.43 (d,
J=14.7 Hz, 1H), 3.29 (d, J=14.7 Hz, 1H), 3.10–3.05 (m,
2H), 1.18–0.96 (m, 4H), 0.75 (t, J=7.0 Hz, 3H); 13C
NMR (75 MHz, DMSO-d6): l 175.8, 165.5, 153.3, 135.5,
130.2, 128.8, 126.8, 125.0, 122.6, 121.2, 67.5, 46.6, 41.0,
29.1, 19.5, 13.2; HRMS (C16H18N2O) calcd 255.1497
(MH+). Found 255.1481.
References
1. (a) Chevolot, L.; Chevolot, A.-M.; Gajhede, M.; Larsen,
U.; Christophersen, C. J. Am. Chem. Soc. 1985, 107,
4542; (b) Anthoni, U.; Chevolot, L.; Larsen, C.; Nielson,
P. H.; Christophersen, C. J. Org. Chem. 1987, 52, 4709;
(c) Anthoni, U.; Bock, K.; Chevolot, L.; Larsen, C.;
Nielson, P. H.; Christophersen, C. J. Org. Chem. 1987,
52, 5638; (d) Some other biogenetically-related alkaloids
which are not b-lactams have been isolated: Rahbaek, L.;
Anthoni, U.; Christophersen, C.; Nielsen, P. H.; Petersen,
B. O. J. Org. Chem. 1996, 61, 887; Rahbaek, L.; Christo-
phersen, C. J. Nat. Prod. 1997, 60, 175.
2. 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.
3. For related Staudinger cycloadditions of isatin imines,
see: (a) Singh, G. S.; Mehrotra, K. N. Ind. J. Chem. 1985,
24B, 129; (b) Joshi, K. C.; Jain, R.; Sharma, V. J. Ind.
Chem. Soc. 1986, 430; (c) Skiles, J. W.; McNeil, D.
Tetrahedron Lett. 1990, 31, 7277; (d) Joshi, K. C.; Dan-
dia, A.; Bhagat, S. J. Fluorine Chem. 1990, 48, 169.
4. Steele, J.; Stoodley, R. J. J. Chem. Soc., Perkin Trans. 1
.
.