An efficient synthesis of lamellarin alkaloids: Synthesis of lamellarin G trimethyl ether

Article abstract of DOI:10.1016/S0040-4039(00)02222-X

A general and efficient synthesis of lamellarin alkaloids is described. The synthesis involves the formation of the core pyrrolo[2,1-a]isoquinoline, followed by the formation of the lactone ring.

Full text of DOI:10.1016/S0040-4039(00)02222-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 1205–1208
An efficient synthesis of lamellarin alkaloids: synthesis of
lamellarin G trimethyl ether
Somsak Ruchirawata,b,c,* and Thumnoon Mutarapata
aChulabhorn Research Institute, Vipavadee Rangsit Highway, Bangkok 10210, Thailand
bDepartment of Chemistry, Mahidol University, Rama 6 Road, Bangkok 10400, Thailand
cProgramme on Research and Development of Synthetic Drugs,
Institute of Science and Technology for Research and Development, Mahidol University, Salaya Campus, Thailand
Received 30 November 2000; accepted 4 December 2000
Abstract—A general and efficient synthesis of lamellarin alkaloids is described. The synthesis involves the formation of the core
pyrrolo[2,1-a]isoquinoline, followed by the formation of the lactone ring. © 2001 Published by Elsevier Science Ltd.
Lamellarins are a group of marine natural products
which were isolated from the prosobranch mollusc
Lamellaria sp and the ascidians.1 The first four lamel-
larins were isolated by Faulkner et al. in 1985 and
named lamellarins A, B, C, D. The structure of lamel-
larin A was determined by X-ray crystallographic analy-
sis and the structures of the remaining compounds
were derived from spectroscopic data.2 At present 35
lamellarins have so far been isolated and identified.2,3
Some of these lamellarins and related compounds
exhibit interesting biological activities4 including cell
division inhibition, cytotoxicity and immunomodula-
tory activity and the recently discovered multidrug-
resistant (MDR) reversal5 and HIV-1 integrase
inhibition.6 Due to this impressive array of biological
activity profiles, ever increasing elegant synthetic routes
Figure 1.
Keywords: lamellarin alkaloid.
* Corresponding author. Fax: 66 2 574 0616 or 66 2 247 1222; e-mail: somsak@tubtim.cri.or.th
0040-4039/01/$ - see front matter © 2001 Published by Elsevier Science Ltd.
PII: S0040-4039(00)02222-X

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S. Ruchirawat, T. Mutarapat / Tetrahedron Letters 42 (2001) 1205–1208
Scheme 1. Reagents and conditions: (i) K2CO3, CH3CN, reflux (3a, 63%; 3b, 63%); (ii) DMF, POCl3, rt (4a, 80%; 4b, 82%); (iii)
KOH, EtOH, reflux (5a, 77%; 5b, 81%); (iv) MnO2, CH2Cl2, rt (7a, 54%; 7b, 20% and 8, 37%); (v) Pd(OAc)2, PPh3, K2CO3, DMF,
PhBr, 120°C, 12 h (7a, 80%; 7b, 80%).
have been developed for the synthesis of lamellarins7 and
related 3,4-diaryl pyrrole derivatives,8 notably by Steglich
and Banwell. The core skeleton of these lamellarins A can
be viewed as the fusion of the pyrrolo[2,1-a]isoquinoline
withthelactoneunit. Ourretrosyntheticanalysisasshown
in Fig. 1 involves the lactonization of the appropriate
pyrrolo[2,1-a]isoquinoline derivative B. Pyrrolo[2,1-
a]isoquinoline C can be synthesized from the reaction of
3,4-dihydroisoquinoline with a phenacyl bromide deriva-
tive.
purification by preparative thin layer chromatography.
We found that manganese dioxide in dichloromethane
could be used to oxidize the phenolic aldehyde 5a to the
corresponding lamellarin derivative 7a in 54% yield,
presumably via the hemiacetal intermediate 6a.
The above approach has also been applied to the synthesis
of lamellarin G trimethyl ether as shown in series b of
Scheme 1. The first three steps used in the synthesis
proceeded well as planned. The condensation of 3,4-dihy-
droisoquinoline 1 with the phenacyl bromide derivative
2b9 gave the corresponding pyrrolo[2,1-a]isoquinoline 3b
in 63% yield. The introduction of the formyl group and
the removal of mesyloxy protecting group could be
accomplished in 82 and 81% yield, respectively. However,
the oxidation of compound 5b with manganese dioxide
gave lamellarin G trimethyl ether 7b in disappointing yield
(20%). The byproduct was found to be the quinone
derivative 8 formed by the preferred oxidation of the
electron rich phenolic ring.
In practice, the condensation of 3,4-dihydropapaverine
hydrochloride 1 with o-mesyloxyphenacyl bromide 2a9 in
the presence of potassium carbonate in acetonitrile gave
the expected mesyloxy pyrrolo[2,1-a]isoquinoline ana-
logue 3a in 63% yield. The reaction presumably involves
the intramolecular reaction of the derived enamine from
the isoquinolinium salt and the ketone as found in the
Knorr pyrrole synthesis.10 The introduction of the formyl
group on the pyrrole ring was accomplished by the
Vilsmeier reaction.11 The reaction was carried out using
dimethylformamide in phosphorus oxychloride as a
formylating agent at room temperature. The expected
product 4a was obtained in 85% yield after purification
by preparative thin layer chromatography. The mesyl
protecting group in the derived aldehyde intermediate was
easily removed by heating with potassium hydroxide in
ethanol. The phenol 5a was produced in 77% yield after

S. Ruchirawat, T. Mutarapat / Tetrahedron Letters 42 (2001) 1205–1208
1207
(c) Boger, D. L.; Soenen, D. R.; Boyce, C. W.; Hedrick,
M. P.; Jin, Q. J. Org. Chem. 2000, 65, 2479–2483.
7. Lamellarin G trimethyl ether: Heim, A.; Terpin, A.;
Steglich, W. Angew. Chem., Int. Ed. Engl. 1997, 36,
155–156. Lamellarin K: Banwell, M. G.; Flynn, B. L.;
Hockless, D. C. R. Chem. Commun. 1997, 2259–2260.
Lamellarin D and H: Ishibashi, F.; Miyazaki, Y.; Iwao,
M. Tetrahedron 1997, 53, 5951–5962. Banwell, M. G.;
Flynn, B. L.; Hockless, D. C. R.; Longmore, R. W.; Rae,
A. D. Aust. J. Chem. 1998, 52, 755–765. Lamellarin L:
Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J.
2000, 6, 1147–1152.
Scheme 2. Reagents and conditions: Series a. (i) MeSO2Cl,
Et3N, CH2Cl2 (97%); (ii) BnN+Me3Br3−, CH2Cl2 (2a, 81%):
Series b. (i) MeSO2Cl, Et3N, CH2Cl2 (97%); (ii) BnN+Me3Br3−,
CH2Cl2 (2b, 83%).
8. Lukianol A and lamellarin O dimethyl ether: Fu¨rstner,
A.; Weintritt, H.; Hupperts, A. J. Org. Chem. 1995, 60,
6637–6641. Lamellarin O and Q, lukianol A: Banwell, M.
G.; Flynn, B. L.; Hamel, E.; Hockless, D. C. R. Chem.
After some experimentation, we found that the above
conversion could be conveniently carried out by oxida-
tion with bromobenzene, palladium acetate and
triphenylphosphine using DMF as the solvent and
potassium carbonate as the base in the reaction.12 The
product 7b was formed in 80% yield. The physical and
spectroscopic data of the product 7b are in good agree-
ment with that reported for lamellarin G trimethyl
ether.7 Tetrakis(triphenylphosphine)palladium(0) could
be used in place of palladium acetate and the reaction
proceeded in the same yield. The oxidation of unsubsti-
tuted analogue 5a with the above system also gave the
required lactone 7a in 80% yield.
Commun. 1997, 207–208. Storniamide
A
nona-
methyl ether: Ebel, H.; Terpin, A.; Steglich, W. Tetra-
hedron Lett. 1998, 39, 9165–9166. Polycitrin A: Terpin,
A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51, 9941–
9946. Lukianol A: Gupton, J. T.; Krumpe, K. E.; Burn-
ham, B. S.; Webb, T. M.; Shuford, J. S.; Sikorski, J. A.
Tetrahedron 1999, 55, 14515–14522. Liu, J.-H.; Yang,
Q.-C.; Mak, T. C. W.; Wong, H. N. C. J. Org. Chem.
2000, 65, 3587–3595. Liu, J.-H.; Chan, H.-W.; Wong, H.
N. C. J. Org. Chem. 2000, 65, 3274–3283. Polycitone B:
Rudi, A.; Evan, T.; Aknin, M.; Kashman, Y. J. Nat.
Prod. 2000, 63, 832–833. Polycitrin B: Beccalli, E. M.;
Clerici, F.; Marchesini, A. Tetrahedron 2000, 56, 2699–
2702.
9. The starting phenacyl bromides 2a and 2b could be
prepared from the acetophenone derivatives 9a and 9b as
shown in Scheme 2. The mesylate protecting group could
be introduced by the reaction of the phenolic compounds
with methanesulfonyl chloride using triethylamine as a
base.13 The bromination of the acetophenone could be
carried out by using an equimolar quantity of benzyl-
trimethylammonium tribromide.14
10. (a) Casagrande, C.; Invernizzi, A.; Ferrini, R.; Ferrari, G.
G. J. Med. Chem. 1968, 11, 765–770; (b) Alberola, A.;
Ortega, A. G.; Sadaba, M. L.; Sanudo, C. Tetrahedron
1999, 55, 6555–6566.
Acknowledgements
We acknowledge the financial contribution from the
Thailand Research Fund (TRF) for the generous sup-
port of the research program. We also acknowledge the
facilities in the Department of Chemistry provided by
the PERCH program.
References
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Chem. Soc. 1985, 107, 5492–5495.
3. Davis, R. H.; Carroll, A. R.; Pierens, G. K.; Quinn, R. J.
J. Nat. Prod. 1999, 62, 419–424 and references cited
therein.
4. Biological activities: Lamellarins I–N: Carroll, A. R.;
Bowden, B. F.; Coll, J. C. Aust. J. Chem. 1993, 46,
489–501. Lamellarins T–X: Reddy, R. M. V.; Faulkner,
D. J.; Venkateswarlu, Y.; Rao, M. R. Tetrahedron 1997,
53, 3457–3466.
5. Reddy, R. M. V.; Rao, M. R.; Rhodes, D.; Hansen, M.
S. T.; Rubins, K.; Bushmen, F. D.; Venkateswarlu, Y.;
Faulkner, D. J. J. Med. Chem. 1999, 42, 1901–1907.
6. (a) Quesada, A. R.; Garcia Gravalos, M. D.; Fernandez
Puentes, J. L. Br. J. Cancer 1996, 74, 677–682; PCT int.
Appl., WO 9701336 A1 970116 (Chem. Abstr. 1996, 126,
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Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54–62;
13. Bates, R. W.; Rama-Davi, T. Synlett 1995, 1151–1152.
14. Kajigaeshi, S.; Kakinami, T.; Okamoto, T.; Fujisaki, S.
Bull. Chem. Soc. Jpn. 1987, 60, 1159–1160. All com-
pounds have been fully characterized. Spectroscopic data
of some selected compounds. 2-(3%%,4%%-Dimethoxy-2%%-me-
syloxyphenyl)-1-(3%,4%-dimethoxyphenyl)-8,9-dimethoxy-
5,6-dihydropyrrolo[2,1-a]isoquinoline (3b) mp (MeOH):
186–187°C; FTIR (CHCl3): wmax 3027, 2938, 2839, 1539,
1465, 1365, 1259, 1205 cm−1 1H NMR (300 MHz,
;
CDCl3): l 2.86 (s, 3H, OSO2CH3), 3.08 (t, 2H, J=6.5
Hz, CH2CH2N), 4.13 (t, 2H, J=6.5 Hz, CH2CH2N),
3.41, 3.48, 3.72, 3.88, 3.89, 3.90 (6s, 18H, C-9, C-21, C-8,
C-13, C-20 and C-14, 6×OCH3), 6.53 (s, 1H, C-10ArH),
6.72 (s, 1H, C-7ArH), 6.74 (s, 1H, C-19ArH), 6.82 (dd,
1H, J=8.0 and 1.6 Hz, C-16ArH), 6.84 (d, 1H, J=8.0
Hz, C-15ArH), 6.87 (d, 1H, J=1.6 Hz, C-12ArH), 6.89

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S. Ruchirawat, T. Mutarapat / Tetrahedron Letters 42 (2001) 1205–1208
(s, 1H, C-22ArH), 6.99 (s, 1H, C-3ArH). 13C NMR (75
(m, 2H, CH2CH2N), 4.51 (m, 1H, CH2CHHN), 4.95 (m,
1H, CH2CHHN), 3.35, 3.60, 3.68, 3.85, 3.89, 3.90 (6s,
18H, C-9, C-21, C-8, C-20, C-13 and C-14, 6×OCH3), 6.57
(s, 1H, C-10ArH), 6.76 (s, 2H, C-19, C-22ArH), 6.82 (m,
3H, C-12, C-15, C-16ArH), 6.87 (s, 1H, C-7ArH), 9.45 (s,
1H, C-23CHO). 13C NMR (75 MHz, CDCl3) l 180.2,
149.0 (2×C), 148.9, 148.0, 147.3, 147.2, 140.2, 133.8,
132.4, 126.8, 126.7, 125.7, 122.9, 122.3, 119.6, 118.0,
114.7, 114.0, 111.0, 110.7, 109.1, 106.5, 56.1, 55.9 (3×C),
55.8, 55.2, 42.3, 38.4, 28.7. MS: 623 (M+, 20.55), 528
(100.0), 516 (18.48), 485 (9.73), 470 (6.23), 454 (3.81), 440
(3.73), 410 (3.57), 272 (35.41), 264 (61.22), 243 (38.99).
Anal. calcd for C32H33NO10S: C, 61.61; H, 5.34; N, 2.25.
Found: C, 61.56; H, 5.28; N, 2.01.
MHz, CDCl3): l 148.9, 147.8, 147.4, 147.2, 147.1, 147.0,
139.9, 128.8, 125.9, 124.0, 123.0, 121.8, 121.0, 120.0,
119.2, 117.8, 114.1, 113.7, 112.3, 111.1, 107.4, 106.9, 56.1,
56.0, 55.9 (2×C), 55.6, 55.2, 44.8, 38.0, 29.4. MS: 595
(M+, 44.78), 516 (100.0), 499 (11.61), 485 (29.25), 470
(10.22), 442 (6.65), 426 (5.39), 410 (5.53), 243 (28.77).
Anal. calcd for C31H33NO9S: C, 62.49; H, 5.59; N, 2.35.
Found: C, 62.46; H, 5.71; N, 2.07. 3-Formyl-2-(3%%,4%%-
dimethoxy-2%%-mesyloxyphenyl)-1-(3%,4%-dimethoxyphenyl)-
8,9-dimethoxy-5,6-dihydropyrrolo[2,1-a]isoquinoline (4b)
mp (MeOH): 192–193°C; FTIR (CHCl3): wmax 3026, 2939,
1
2839, 1643, 1531, 1483, 1465, 1426, 1263 cm−1; H NMR
(300 MHz, CDCl3): l 2.89 (s, 3H, OSO2CH3), 3.00–3.20
.
.