A synthetic approach to the communesins

Article abstract of DOI:10.1055/s-2008-1078251

A synthetic approach to the communesin family of indole alkaoids has been investigated, with a cascade reaction sequence involving formation of a transient 1-alkoxycarbonyl-imidazole intermediate and subsequent addition onto an indole as the key step. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2008-1078251

LETTER
2093
A Synthetic Approach to the Communesins
Synthetic
o
A
pproach to
n
Communesin
a
s
than H. George, Robert M. Adlington*
Chemistry Research Laboratory, University of Oxford, 12 Mansfield Road, Oxford OX1 3TA, UK
Fax +44(1865)275632; E-mail: robert.adlington@chem.ox.ac.uk
Received 30 May 2008
Dedicated to Professor Jack E. Baldwin in celebration of his 70th birthday
double bond as the dienophile. This idea has been exam-
ined by Stoltz4a and Funk,4b,c but without formation of the
key vicinal quaternary centres of the communesins. Our
approach was to synthesise a substituted 1,3-benzoxazin-
2-one 4 that could undergo a precedented8 thermal [4+2]
cycloreversion with loss of carbon dioxide to generate an
aza-ortho-xylylene 5 that would be set up for an intramo-
lecular [4+2] cycloaddition onto the N(1)-methyl indole,
generating one of the aminal units and the adjacent quater-
nary centres in one step to give 6 (Scheme 1). Such a cas-
cade reaction sequence would result in a rapid build up of
functionality and provide a platform for synthetic endeav-
ours towards the communesins. This scheme is a modifi-
cation of an earlier biomimetic proposal for synthesis of
the communesins made by Prof. J. E. Baldwin.
Abstract: A synthetic approach to the communesin family of
indole alkaoids has been investigated, with a cascade reaction se-
quence involving formation of a transient 1-alkoxycarbonyl-
imidazole intermediate and subsequent addition onto an indole as
the key step.
Key words: alkaloids, indoles, cascade reactions, heterocycles,
communesins
The communesins are a family of structurally complex in-
dole alkaloids found in marine strains of Penicillium sp.
(Figure 1). Communesins A and B were first isolated by
Numata in 1993,1a since when seven more congeners have
been reported.1 Communesin B is the most biologically
active member of the family, exhibiting a moderate cyto-
toxic effect on P-388 leukemia cells with ED50 = 0.45 mg/
mL. The heptacyclic framework of the communesins con-
tains several synthetically challenging features, most no-
tably two adjacent quaternary stereocentres and two
aminal groups. The biosynthesis of the communesin alka-
loids has been suggested to result from oxidative dimeri-
sation of two tryptamine moieties.2 The communesins
have attracted considerable synthetic interest over the past
five years, with the first synthesis of a member of the com-
munesin family, communesin F, recently achieved by
Qin.3 Several model studies have also been undertaken.4
The structurally related indole alkaloid perophoramidine,
containing two amidine units and halogenated phenyl
rings, was characterised by Ireland in 2002.5 This natural
product was synthesised by Funk,6a and a synthesis of de-
haloperophoramidine was completed by Ranier.6b
PG
N
PG
N
O
O
R1
R1
O
HO
CDI
N
HN
R2
N
O
N
R2
Me
Me
3
4
– CO2
PG
PG
N
N
O
O
hetero
Diels–Alder
reaction
R1
R1
An interesting approach to the core of the communesins is
to instigate a hetero Diels–Alder reaction between an aza-
ortho-xylylene7 as the diene and an indole carbon–carbon
N
N
R2
N
N
R2
H
Me
Me
5
6
O
O
Scheme 1 Planned formation of the communesin core
N
N
O
O
N
N
In order to investigate this idea, tryptamine 7 was reacted
with N-Boc-isatin in THF at room temperature to give ke-
tone 8 (Scheme 2). Treatment of this compound with al-
lylmagnesium bromide gave tertiary alcohol 9, which was
converted into the 1,3-benzoxazin-2-one 10 by reaction
with 1,1¢-carbonyldiimidazole (CDI) in THF. Removal of
the N-Boc protecting group of 9 with TFA in CH2Cl2 gave
amino alcohol 11, which was reacted with CDI to give
1,3-benzoxazin-2-one 12.
NH
H
NH
H
N
N
Me
Me
communesin B (2)
communesin A (1)
Figure 1 Communesins A and B
SYNLETT 2008, No. 14, pp 2093–2096
Advanced online publication: 05.08.2008
2
2
.0
8
.2
0
0
8
DOI: 10.1055/s-2008-1078251; Art ID: D18108ST
© Georg Thieme Verlag Stuttgart · New York

2094
J. H. George, R. M. Adlington
LETTER
Bn
N
Bn
O
N
O
NHBn
a
a
O
HO
8
N
HN
Boc
N
HN
Boc
N
Me
Me
Me
7
13
8
b
b
Bn
N
Bn
N
Bn
O
O
Bn
N
N
O
O
c
c
HO
O
N
N
N
N
N
Me
HN
Boc
H
H
H
N
O
N
Me
Boc
Me
Me
Boc
10
9
14
17
+
Bn
d
N
O
Bn
N
Bn
He
Bn
O
Hd
O
N
O
Hc
Hb
Ha
N
N
N
N
HN
Boc
Me
Hf
O
c
HO
H2N
Hg
N
O
N
15
+
N
N
H
Me
H
Me
N
12
11
Bn
N
O
NOE studies of 17
Scheme 2 Reagents and conditions: (a) N-Boc-isatin, THF, r.t., 18
h, 81%; (b) allylmagnesium bromide, THF, r.t., 2 h, 73%; (c) CDI,
THF, 60 °C, 2 h, 83% (for 10), 88% (for 12); (d) TFA, CH2Cl2, r.t., 1
h, 93%.
N
N
Me
Boc
16
Scheme 3 Reagents and conditions: (a) vinylmagnesium bromide,
THF, 0 °C, 1 h, warm to r.t., 1 h, 89%; (b) CDI, CH2Cl2, 40 °C, 48 h,
36% (14), 42% (15), 10% (16); (c) TFA, CH2Cl2, r.t., 2 h, 79%.
However, heating compounds 10 and 12 up to tempera-
tures of 220 °C failed to generate the desired aza-ortho-
xylylene intermediates and no hetero Diels–Alder adducts
were observed, with the cyclic carbamate structures re-
maining intact under these conditions. Reaction of 9 with
CDI at room temperature gave an isolable, but unstable in
solution, 1-alkoxycarbonylimidazole with initial addition
of CDI to the tertiary alcohol having occurred.
istry. This analysis was later confirmed by single-crystal
X-ray crystallography.9
The products 14–16 can be rationalised by either of two
related mechanisms as outlined in Scheme 4. Firstly, it
can be considered that initial formation of the activated
carbamate intermediate 18 is followed by loss of carbon
dioxide and an imidazole anion to form the stabilised al-
lylic carbocation 19a. Intramolecular attack of the indole
to the carbocation centre would give a spirocyclic indole-
nium ion, which could be attacked by the neighbouring
NHBoc group to furnish 14. The byproduct 15 might be
formed by intermolecular attack of an imidazole anion at
the CH2 terminus of the allyl cation 19a, while 16 could
be formed via intramolecular attack by the NHBoc group
at the same site. Formation of carbocationic intermediates
by decarboxylation of such 1-alkoxycarbonylimidazoles
has been postulated in the formation of imidazoles from
primary and secondary alcohols by reaction with CDI.10
In contrast, substitution of a vinyl group for the allyl
group gave very different reactivity. Reaction of amino al-
cohol 13 (formed by addition of vinylmagnesium bromide
to ketone 8) with CDI in CH2Cl2 at 40 °C gave pentacyclic
aminal 14 in 36% yield, alongside allylic imidazole 15
(42%) and dihydroquinoline 17 (10%, Scheme 3). Com-
pound 14 contains five of the seven rings of the commu-
nesins, with the vicinal quaternary centres and one of the
aminal functional groups being formed in one step. The
deprotected aminal group of 17 showed characteristic
chemical shifts of d = 4.59 and 82.9 ppm in the 1H NMR
and 13C NMR spectra, respectively. The NOE studies on
17 showed strong NOE interactions between Ha and Hb/
Hc and between Hf and Hg, but the absence of any NOEs
between Hf and Ha/Hb or Hd/He indicated that the six-
membered lactam had been formed with syn stereochem-
Alternatively, the products of the reaction can be ex-
plained by invoking a genuine aza-ortho-xylylene inter-
mediate 19b. This reactive species could undergo either
[4+2] cycloaddition onto the indole C=C to give 14, or a
Synlett 2008, No. 14, 2093–2096 © Thieme Stuttgart · New York

LETTER
Synthetic Approach to Communesins
2095
Bn
Bn
N
O
N
O
O
HO
CDI
O
N
CH2Cl2
N
HN
N
HN
Boc
N
Me
Me
Boc
13
14
15
18
– CO2, – imidazole–
Bn
N
O
Bn
N
O
N
N
+
H
+
Me
Boc
N
HN
Bn
N
O
Me
Boc
19a
– H+
Bn
N
N
HN
Boc
Me
N
O
N
+
Bn
N
O
N
Me
N
Boc
19b
N
N
Me
Boc
16
Scheme 4 Proposed mechanism for CDI-mediated cyclization of indole 13
6p-electrocyclic reaction involving the vinyl group to aldehyde, to give a diamine 24. Oxidative cleavage of the
give dihydroquinoline 16. Attack by imidazole onto the terminal alkene could then allow formation of the second
terminal alkene could give allylic imidazole 15.
aminal moiety to give 25 and complete the synthesis of the
core structure of the communesins.
Although the pentacyclic compound 14 was formed in rel-
atively modest yield, the rapid assembly of two new rings In conclusion, a short synthetic route to the core of the
and two vicinal quaternary centres adjacent to an aminal communesins has been developed. The key step is a CDI-
group render it practical in terms of a synthetic approach mediated cascade reaction in which a proposed transient
to the communesins. The desired product 14 is signifi- 1-alkoxycarbonylimidazole intermediate fragments to
cantly less polar than the byproducts and could be readily give either a stabilised allylic carbocation or an aza-ortho-
purified by flash chromatography on silica gel.
xylylene species, which undergoes intramolecular reac-
tion with an indole carbon–carbon double bond in either
an ionic two-step or [4+2] cycloaddition process. In this
manner two adjacent all-carbon quaternary centres and an
aminal group are formed in one step. The product of this
cascade reaction has been elaborated to a compound,
which should allow synthesis of the second aminal group
of the communesins in a few steps.
In order for N-benzyl lactam 14 to be elaborated towards
communesin the lactam C–N bond would need to be
cleaved as the relative stereochemistry of the lactam ring
junction is opposite to that found in the communesins. To
activate the lactam to nucleophilic attack, the benzyl
group was removed under Birch reduction conditions and
replaced by a tosyl group to give N-tosyl lactam 20 in 80%
yield over two steps (Scheme 5). Reduction of this com-
pound with LiAlH4 furnished amino alcohol 21 in 95%
yield, while treatment with DIBAL-H in CH2Cl2 gave
hemiaminal 22 in 62% yield as a 1:1 mixture of epimers.
Acknowledgment
We thank F. Hoffmann-La Roche Ltd, Basel, Switzerland for post-
doctoral funding to J.G. and we thank Dr Michael Jones for assi-
stance with the X-ray crystallographic studies.
A Wittig reaction between aldehyde equivalent 22 and
Ph3P=CHOMe gave enol ether 23 in 67% yield as a single
alkene stereoisomer. A coupling constant of 6.4 Hz be-
tween the newly formed vinylic protons of enol ether 23
indicated that the Z-isomer had been formed. It is now in-
tended that enol ether 23 could undergo acid-catalysed hy-
drolysis, followed by reductive amination of the resultant
Synlett 2008, No. 14, 2093–2096 © Thieme Stuttgart · New York

2096
J. H. George, R. M. Adlington
LETTER
Bn
Ts
N
References and Notes
N
O
O
(1) (a) Numata, A.; Takahashi, C.; Ito, Y.; Takada, T.; Kawai,
K.; Usami, Y.; Matsumura, E.; Imachi, M.; Ito, T.;
Hasegawa, T. Tetrahedron Lett. 1993, 34, 2355.
(b) Jadulco, R.; Edrada, R. A.; Ebel, R.; Berg, A.;
Schaumann, K.; Wray, V.; Steube, K.; Proksch, P. J. Nat.
Prod. 2004, 67, 78. (c) Hayashi, H.; Matsumoto, H.;
Akiyama, K. Biosci., Biotechnol., Biochem. 2004, 68, 753.
(d) Dalsgaard, P. W.; Blunt, J. W.; Munro, M. H. G.;
Frisvad, J. C.; Christophersen, C. J. Nat. Prod. 2005, 68,
258.
a, b
N
N
N
N
H
H
Me
Boc
Me
Boc
20
14
c
d
Ts
N
OH
TsHN
OH
(2) Wigley, L. J.; Mantle, P. G.; Perry, D. A. Phytochemistry
2006, 67, 561.
(3) (a) Yang, J.; Wu, H.; Shen, L.; Qin, Y. J. Am. Chem. Soc.
2007, 129, 13794. (b) Yang, J.; Song, H.; Xiao, X.; Wang,
J.; Qin, Y. Org. Lett. 2006, 8, 2187.
N
N
N
N
H
H
Me
Boc
Me
Boc
22
21
(4) (a) May, J. A.; Zeidan, R. K.; Stoltz, B. M. Tetrahedron.
Lett. 2003, 44, 1203. (b) Crawley, S. L.; Funk, R. L. Org.
Lett. 2003, 5, 3169. (c) Crawley, S. L.; Funk, R. L. Org.
Lett. 2006, 8, 3995. (d) Seo, J. H.; Artman, G. D. III.;
Weinreb, S. M. J. Org. Chem. 2006, 71, 8891.
e
MeO
NHR
TsHN
TsHN
(5) Verbitski, S. M.; Mayne, C. L.; Davis, R. A.; Concepcion, G.
P.; Ireland, C. M. J. Org. Chem. 2002, 67, 7124.
(6) (a) Fuchs, J. R.; Funk, R. L. J. Am. Chem. Soc. 2004, 126,
5068. (b) Sabahi, A.; Novikov, A.; Ranier, J. D. Angew.
Chem. Int. Ed. 2006, 45, 4317.
N
N
H
N
N
H
Me
Boc
Me
Boc
23
24
(7) Wojciechowski, K. Eur. J. Org. Chem. 2001, 3587.
(8) (a) Bowen, R. D.; Davies, D. E.; Fishwick, C. W. G.;
Glasbey, T. O.; Noyce, S. J.; Storr, R. C. Tetrahedron Lett.
1982, 23, 4501. (b) Hodgetts, I.; Noyce, S. J.; Storr, R. C.
Tetrahedron Lett. 1984, 25, 545. (c) Fishwick, C. W. G.;
Storr, R. C.; Manley, P. W. J. Chem. Soc., Chem. Commun.
1984, 1304. (d) Consonni, R.; Croce, P. D.; Ferraccioli, R.;
La Rosa, C. J. Chem. Soc., Perkin Trans. 1 1996, 1809.
(9) Crystal structure obtained for compound 20. CCDC 689636
contains the supplementary crystallographic data for this
paper. These data can be obtained free of charge from The
Cambridge Crystallographic Data Centre via
R
Ts
N
H
N
N
N
H
Me
Boc
25
www.ccdc.cam.ac.uk/data_request/cif.
(10) Njar, V. C. O. Synthesis 2000, 2019.
Scheme 5 Reagents and conditions: (a) Na, liq. NH3, THF, –78 °C,
20 min; (b) TsCl, LHMDS, THF, 0 °C, 1 h, 80% over 2 steps; (c)
LiAlH4, THF, r.t., 30 min, 95%; (d) DIBAL-H, CH2Cl2, r.t., 30 min,
62%; (e) Ph3P(Cl)CH2OMe, NaHMDS, THF, 0 °C, 30 min, 67%.
Synlett 2008, No. 14, 2093–2096 © Thieme Stuttgart · New York