Convergent total synthesis of lamellarin K

Article abstract of DOI:10.1039/a705874h

The azomethine ylide derived from dihydroisoquinolinium salt 24 undergoes an intramolecular [3 + 2] cycloaddition reaction to give pyrrole 25 which upon de-isopropylation affords the marine alkaloid lamellarin K 4.

Full text of DOI:10.1039/a705874h

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Convergent total synthesis of lamellarin K†
Martin Banwell,*‡ Bernard Flynn* and David Hockless
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
The azomethine ylide derived from dihydroisoquinolinium
salt 24 undergoes an intramolecular [3 + 2] cycloaddition
reaction to give pyrrole 25 which upon de-isopropylation
affords the marine alkaloid lamellarin K 4.
frameworks are unknown) only two studies directed towards the
total synthesis of these marine natural products appear to have
been reported to date.§ Thus, very recently Steglich7 described
a biomimetic synthesis of lamellarin G trimethyl ether, while
Ishibashi et al.8 have completed total syntheses of lamellarins D
and H. These reports prompt us to disclose a quite different and
highly convergent method for the synthesis of the title
compound 4 and the parent ring-system 7.
In 1985 Faulkner and his colleagues reported1 the isolation of
four members of a new class of marine natural product which
they had obtained from a Lamellaria sp. of marine prosobranch
mollusc collected in the waters off Palau. These compounds
were called lamellarins A–D and through a combination of
spectroscopic and X-ray crystallographic studies were shown to
be highly oxygenated derivatives of 14-phenyl-6H-
[1]benzopyrano[4A,3A:4,5]pyrrolo[2,1-a]isoquinolin-6-one or
its 8,9-dihydro analogue. Thus, lamellarin D possesses structure
1 while congener C has structure 2. Subsequently, Fenical2
isolated further members of this type of compound (lamellarins
E–H) from the Indian Ocean marine ascidian Didemnum
chartaceum. More recently Bowden3 reported obtaining la-
mellarins I–N from a Pacific ascidian Didemnum sp. collected
off the north east coast of Australia, while Urban and Capon4
have isolated lamellarin S from the same species.§ In 1997,
Faulkner described5 the isolation of nine new alkaloids of the
lamellarin class, including the first examples of lamellarin
sulfates, from an unidentified ascidian found in the Arabian
Sea.
O
N
O
8
9
7
The pivotal step in our approach to the lamellarin ring
systems involves construction of the central pyrrole moiety via
an intramolecular [3 + 2] cycloaddition of an isoquinoline-based
azomethine ylide to a suitably tethered tolan,9 a hitherto
unproven process. The reaction sequence leading to the parent
framework (Scheme 1) starts with Sonogashira cross-cou-
pling10 of phenylacetylene 8 and o-iodophenyl acetate 911 to
give, after hydrolysis of the initial coupling product 1011 (99%),
o-hydroxytolan 11.11 This last compound was subjected to
dicyclohexylcarbodiimide (DCC)-promoted coupling with
a-bromoacetic acid and the resulting ester 12 (91% from 10)
treated with isoquinoline to give the isoquinolinium salt 13.
Compound 13 was immediately reacted with Et3N so as to
generate the associated azomethine ylide which underwent
intramolecular cycloaddition to the tethered triple bond upon
heating. The resulting mixture of dihydropyrrole-type products
thereby obtained was subjected to oxidation with 2,3-dichloro-
5,6-dicyano-1,4-benzoquinone (DDQ). In this manner, the
target compound 7 (92% from 12, mp 313–315 °C) was
obtained and its structure established by single-crystal X-ray
analysis.∑
OR3
OR2
R2O
R1O
OMe
OMe
OH
OH
1
14
O
6
O
13
MeO
R1O
MeO
HO
N
N
O
O
8
8
10
9
9
X
2 X = OMe, R1 = R3 = Me, R2= H
3 X = OMe, R1 = R2 = R3 = Me
4 X = OH, R1 = R3 = Me, R2 = H
5 X = R1 = R3 = H, R2 = Me
1 R1 = H, R2 = Me
6 R1 = Me, R2 = H
The highly convergent nature of the reaction sequence
outlined here would suggest that this approach could be readily
+
I
A number of the lamellarins exhibit highly interesting
biological properties. For example, at concentrations of 19 mg
ml21, compound 1 caused a 78% inhibition of cell division in a
fertilised sea urchin assay while congener 2 caused 15%
inhibition.1 Lamellarins I 3, K 4 and L 5 all showed comparable
and significant cytotoxicity against P388 and A549 cell lines in
AcO
i
8
9
iv
v, vi
7
culture (IC50
≈
0.25 mg ml21 against each cell line).3
Lamellarins K and L also exhibited moderate immuno-
modulatory activity (LcV:MLR 147 and 98, respectively).3 In
the NCl 60 cell-line panel, lamellarin N 6 showed some
selectivity toward melanoma cell lines SK-MEL-5 (LC50 1.87
3 1027 m) and UACC-62 (LC50 9.88 3 1026 m).5 Perhaps most
significantly, very recent work at Pharma Mar S. A.6 has raised
the possibility that certain of the lamellarins, especially
lamellarin K, may be highly effective in the treatment of multi-
drug resistant tumours.
O
RO
O
10 R = Ac
11 R = H
12 R = BrCH2CO
N
ii
+
–
Br
iii
13
Scheme 1 Reagents and conditions: i, Pd(PPh3)4 (1 mol%), CuI (2 mol%),
Et3N, 18 °C, 4 h; ii, K2CO3 (1.5 equiv.), MeOH, 18 °C, 0.25 h; iii,
BrCH2COBr (1 equiv.), DMAP (5 mol%), DCC (1.05 equiv.), CH2Cl2,
18 °C, 3 h; iv, isoquinoline (1 equiv.), THF, 18 °C, 6 h; v, Et3N (1 equiv),
THF, 66 °C, 4 h; vi, DDQ (1 equiv.), CH2Cl2, 18 °C, then silica gel
chromatography
Despite the intriguing biological properties and the un-
precedented structures of lamellarins A–N and S–X (the parent
Chem. Commun., 1997
2259

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OMe
OR
MeO
RO
DCC-mediated condensation of this last compound with
a-iodoacetic acid then provided ester 23 (97%, mp 127–128 °C)
which was reacted with 3,4-dihydro-6,7-dimethoxy-5-isopro-
poxyisoquinoline (readily available by standard methods) to
give salt 24. This last compound was not isolated but
immediately treated with Hu¨nig’s base. The resulting mixture
was heated at reflux in 1,2-dichloroethane and in this manner
cycloaddition (followed by in situ aromatisation) took place to
give lamellarin K triisopropyl ether 25 (81% from 23, mp
244–245 °C). Treatment of this last compound with 3.6 mol
equiv. of AlCl3 in CH2Cl2 at 18 °C resulted in three-fold de-
isopropylation and formation of the target compound 4 (96%,
X
H
X
+
OHC
14 X = O, R = H
15 X = O, R = Pri
16 X = CBr2, R = Pri
17 X = R = H
i
ii
18 X = H, R = Pri
19 X = I, R = Pri
ii
iii
16, 19
iv
MeO
PriO
OMe
OPri
1
mp 230–232 °C) which was identical, by H and 13C NMR
spectroscopy, with an authentic sample.
We thank the Institute of Advanced Studies for financial
support including the provision of a post-doctoral Research
Fellowship to B. L. F. Associate Professor B. Bowden (James
Cook University of North Queensland) is thanked for providing
spectral data on lamellarin K.
X
20 X = CHO
21 X = OCHO
22 X = OH
v
vi
vii
23 X = OCOCH2I
viii
Footnotes and References
MeO
OMe
OPri
† The work described herein is the subject of a patent application (AIPO
Patent Office Provisional Application No. PO6565, May 2nd, 1997).
‡ E-mail: mgb@rsc.anu.edu.au
PriO
§ A series of structurally simpler lamellarins (O–R) have been isolated by
Capon from a southern Australian marine sponge Dendrilla cactos (see
work cited in ref. 4). Certain members of this simpler class of lamellarins
have been the subject of synthetic studies (see M. G. Banwell, B. L. Flynn,
E. Hamel and D. C. R. Hockless, Chem. Commun., 1997, 207 and references
cited therein) but the strategies used are quite different from those reported
here.
MeO
MeO
PriO
O
O
+
N
I –
24
viii
∑ Crystal data for 7: C25H15NO2, M = 361.40, T = 296(1) K, orthorhombic,
space group Pnma, a = 23.441(2), b = 6.804(4), c = 11.175(4) Å,
OMe
PriO
OMe
OPri
U
F(000)
=
1782(2) Å3, Dc (Z
752, m(MoKa)
correction; 2381 unique data (2qmax
R = 0.065, wR = 0.049, GOF = 2.88. CCDC 182/606.
=
4)
0.80 cm21, semi-empirical absorption
55.0°), 661 with I 2s(I);
=
1.347
g
cm23
,
=
=
=
>
ix
4
O
MeO
1 R. J. Andersen, D. J. Faulkner, H. Cun-heng, G. D. Van Duyne and
J. Clardy, J. Am. Chem. Soc., 1985, 107, 5492.
N
O
2 N. Lindquist, W. Fenical, G. D. Van Duyne and J. Clardy, J. Org.
Chem., 1988, 53, 4570.
3 A. R. Carroll, B. F. Bowden and J. C. Coll, Aust. J. Chem., 1993, 46,
489.
MeO
OPri
25
Scheme 2 Reagents and conditions: i, PriBr (1.2 equiv.), K2CO3 (3.5
equiv.), DMF, 18 °C, 19 h; ii, CBr4 (2 equiv.), Zn (2 equiv.), PPh3 (2 equiv.),
0 to 18 °C, 22 h, then 0 °C, 15, 18 °C, 1 h; iii, AgOCOCF3 (1.1 equiv.), I2
(1.1 equiv.), CHCl3, reflux, 7 h; iv, 16, BunLi (2.05 equiv.), THF, 278 °C,
0.83 h then ZnCl2 (1.1 equiv.), 278 to 18 °C, 1 h then 19 (0.95 equiv.),
Pd(PPh3)4 (ca. 2 mol%), 18 °C, 4 h; v, MCPBA (1.5 equiv.), KHCO3 (3
equiv.), CH2Cl2, 18 °C, 1 h; vi, NH3 in MeOH (sat.), 18 °C, 1 h; vii,
ICH2CO2H (1.05 equiv.), DCC (1.05 equiv.), DMAP (5 mol%), CH2Cl2,
18 °C, 3 h; viii, 3,4-dihydro-6,7-dimethoxy-5-isopropoxyisoquinoline (1.1
equiv.), ClCH2CH2Cl, 18 °C, 7 h, then Hu¨nig’s base (1.0 equiv.), 83 °C, 32
h; ix, AlCl3 (3.6 equiv.), CH2Cl2, 18 °C, 2 h
4 S. Urban and R. J. Capon, Aust. J. Chem., 1996, 49, 711.
5 M. Venkata Rami Reddy, D. J. Faulkner, Y. Venkateswarlu and
M. Rama Rao, Tetrahedron, 1997, 53, 3457.
6 A. R. Quesada, M. D. Garc´ıa Gra´valos and J. L. Ferna´ndez Puentes, Br.
J. Cancer, 1996, 74, 677; J. L. Ferna´ndez Puentes, D. Garc´ıa Gra´valos
and A. Quesada, PCT Int. Appl., WO 9701336 (Chem. Abstr., 1996,
126, 166 474).
7 A. Heim, A. Terpin and W. Steglich, Angew. Chem., 1997, 109, 158;
Angew. Chem., Int. Ed. Engl., 1997, 36, 155.
8 F. Ishibashi, Y. Miyazaki and M. Iwao, Tetrahedron, 1997, 53, 5951.
9 For reviews on azomethine ylide chemistry see: R. Grigg, Chem. Soc.
Rev., 1987, 16, 89; O. Tsuge and S.Kanemasa, Adv. Heterocycl. Chem.,
1989, 45, 232; A. Padwa, in Comprehensive Organic Synthesis, Vol. 4,
ed. B. M. Trost and I. Fleming, Pergamon, New York, 1991, pp. 1085–
1089; P. A. Wade, in Comprehensive Organic Synthesis, Vol. 4, ed.
B.M. Trost and I. Fleming, Pergamon, New York, 1991, pp. 1134–
1141.
10 For a review see K. Sonogashira, in Comprehensive Organic Synthesis,
Vol. 3, ed. B. M. Trost and I. Fleming, Pergamon, New York, 1991,
pp. 521–549.
11 A. Arcadi, S. Cacchi, M. D. Rosario, G. Fabrizi and F.Marinelli, J. Org.
Chem., 1996, 61, 9280.
12 M. F. Comber and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1991,
2783.
13 T. Sala and M. V. Sargent, J. Chem. Soc., Perkin Trans. 1, 1979,
2593.
14 E. J. Corey and P. L. Fuchs, Tetrahedron Lett., 1972, 3769.
15 H. Ishii, I.-S. Chen and T. Ishikawa, J. Chem. Soc., Perkin Trans. 1,
1987, 671.
adapted to the preparation of lamellarins A–N and S–X as well
as many analogues thereof. Certainly, compounds in the
8,9-dihydroseries would seem to be readily accessible as
evidenced by our synthesis of lamellarin K 4 (Scheme 2). Thus,
the isopropyl ether 1512 (100%), prepared from vanillin 14
under standard conditions,13 was subjected to a Corey–Fuchs
gem-dibromomethylenation reaction14 thereby affording sty-
rene 16 (100%, mp 36–38 °C). This latter compound was treated
with BunLi and the lithium acetylide so formed was trans-
metallated using zinc(ii) chloride. Palladium-mediated cross-
coupling of the resulting alkynylzinc chloride with aryl iodide
19 (mp 75–76 °C) (obtained in 93% yield by iodination of the
isopropyl ether 1815 of isovanillin 17 using AgOCOCF3–I2)
then gave tolan 20 (84%, mp 121–122 °C) which was subjected
to a Baeyer–Villiger reaction using MCPBA as oxidant. The
resulting formate ester 21 was readily hydrolysed to the
corresponding phenol 22 (92% from 20, mp 130–131 °C).
Received in Cambridge, UK, 12th August 1997; 7/05874H
2260
Chem. Commun., 1997