First total synthesis of the marine alkaloids purpurone and ningalin C

Article abstract of DOI:10.1016/S0040-4039(00)01614-2

Purpurone is obtained from 3-(3,4-dimethoxyphenyl)pyruvic acid, 2-(4-methoxyphenyl)ethylamine and 2',2',2'-trichloroethyl 2-bromo-2-(3,4-dimethoxyphenyl)acetate in seven steps with an overall yield of 11%. Ningalin C is synthesized from 1-[2-(3,4-dimethox

Full text of DOI:10.1016/S0040-4039(00)01614-2

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 9477–9481
First total synthesis of the marine alkaloids purpurone and
ningalin C†
Christian Peschko and Wolfgang Steglich*
Department Chemie der Ludwig-Maximilians-Universita¨t, Butenandtstraße 5-13, Haus F, D-81377 Munich, Germany
Received 20 July 2000; revised 14 September 2000; accepted 18 September 2000
Abstract
Purpurone is obtained from 3-(3,4-dimethoxyphenyl)pyruvic acid, 2-(4-methoxyphenyl)ethylamine and
2%,2%,2%-trichloroethyl 2-bromo-2-(3,4-dimethoxyphenyl)acetate in seven steps with an overall yield of 11%.
Ningalin
C is synthesized from 1-[2-(3,4-dimethoxyphenyl)ethyl]-3,4-bis-(3,4-dimethoxyphenyl)-1H-
pyrrole and methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate in five steps with a total yield of 19%. © 2000
Published by Elsevier Science Ltd.
Keywords: purpurone; ningalins; marine natural products; ACL inhibitors; pyrrole alkaloids.
In 1993 Chan, Faulkner and co-workers1 reported the isolation and structural elucidation of
the marine alkaloid purpurone (1) from an Indopacific sponge of the genus Iotrochota. In the
course of the bioassay-guided fractionation of the extracts, purpurone was identified as a potent
ATP-citrate lyase (ACL) inhibitor2 (IC50=25 mg/mL). The compound probably represents the
aglycon of more complex sugar or protein conjugates as it is liberated only after acidic
hydrolysis. Later, an hydroxy derivative of 1, ningalin D (2), was discovered by Kang and
Fenical3 in an unidentified ascidian of the genus Didemnum together with three biogenetically
related analogues including ningalin C (3).
* Corresponding author. Fax: (+49) 89-2180-7756; e-mail: wos@cup.uni-muenchen.de
†
Dedicated to Professor Harry H. Wasserman on the occasion of his 80th birthday.
0040-4039/00/$ - see front matter © 2000 Published by Elsevier Science Ltd.
PII: S0040-4039(00)01614-2

9478
Retrobiosynthetic analysis suggests that purpurone (1) is built-up from five aromatic amino
acid residues4 (Scheme 1). The core unit is the N-substituted 3,4-diarylpyrrole-2,5-dicarboxylic
acid 5, which could be formed by oxidative dimerization of aryl pyruvic acid 4 followed by
condensation of the resulting 1,4-diketone with tyramine 6.4 Attachment of two further
molecules of 4 to the pyrrole ring in 5 would yield an intermediate, from which the purpurone
system can be derived by decarboxylation and subsequent cyclization. In this paper we describe
the syntheses of purpurone (1) and ningalin C (3) according to this proposal, a strategy which
has already been successfully applied to the total syntheses of other marine pyrrole alkaloids
like polycitrin A,5 lamellarin G trimethyl ether,4 lamellarin L6 and storniamide A nonamethyl
ether.7
Scheme 1. Retrobiosynthetic analysis of purpurone (1)
Our highly convergent total synthesis of purpurone (1) started with the one pot formation4 of
pyrrole–dicarboxylic acid 8 by oxidative dimerization of two molecules of 3-(3,4-dimethoxy-
phenyl)pyruvic acid (7) and subsequent condensation with 2-(4-methoxyphenyl)ethylamine
(Scheme 2). Decarboxylation by treatment with trifluoroacetic acid8 afforded pyrrole 9 in almost
quantitative yield. The twofold Friedel–Crafts alkylation was accomplished by heating 9 with

9479
Scheme 2. Reagents and conditions: (a) i) n-BuLi (2 equiv.), THF, −78°C; ii) I2 (0.5 equiv.), −78 to 25°C; iii)
,
2-(4-methoxyphenyl)-ethylamine (3 equiv.), 4 A molecular sieves, 18 h; (b) TFA (15 equiv.), CHCl3, reflux, 10 h; (c)
14 (2.5 equiv.), acidic Al2O3 (40 equiv.), CHCl3, reflux, 10 h; (d) Zn dust (50 equiv.), aq. NH4OAc (1N, 4 equiv.),
THF, 25°C, 1.5 h; (e) Ac2O, KOAc (2.6 equiv.), reflux, 1.25 h; (f) 5% aq. NaOH, air, MeOH, 55°C, 0.5 h; (g) BBr3
(10 equiv.), cyclohexene (20 equiv.), CH2Cl2, −78°C
bromoester 149 in chloroform in the presence of acidic alumina (40 equiv.). The key compound
10 was thereby obtained in 57% yield.10 Cleavage of the ester groups under mild conditions with
Zn/aqueous NH4OAc in THF11 furnished the crude diacid 11 in 89% yield, which on heating
with Ac2O/KOAc12 was regioselectively cyclized to the diacetate 12 (63% yield). Conversion of
12 to purpurone nonamethyl ether (13)13 was achieved by saponification with aqueous sodium
hydroxide in methanol under exposure to air in 66% yield. The synthesis was completed by
cleavage of the O-methyl groups with an excess of boron tribromide14 in dichloromethane under
addition of cyclohexene as bromine scavenger.15 Purpurone (1) was thereby obtained as an
amorphous deep purple solid in 11% overall yield. Its spectroscopic data (UV, NMR, MS)
agreed with those reported for the natural product.1

9480
For the total synthesis of ningalin C (3), pyrrole 9a16 was monoalkylated by Rh(II)acetate
catalyzed insertion of the carbene17 generated from methyl 2-diazo-2-(3,4-dimethoxyphenyl)-
acetate18 (Scheme 3). Saponification of ester 15 and subsequent intramolecular Friedel–Crafts
acylation12 of crude acid 16 furnished the trifluoroacetate 17. Formation of both the conjugated
and the amide carbonyl groups of the ningalin C skeleton 18 was achieved in one step (25%
from 16) by simply subjecting the acylated phenol 17 to aqueous sodium hydroxide/methanol
under exposure to air. The deep orange-colored permethyl ningalin C (18)13 was converted to the
natural product by methyl ether cleavage using boron tribromide in dichloromethane14 to
1
furnish 3 in a total yield of 19% from 9a. The spectral data (IR, UV–vis, MS, H, 13C NMR)
correspond to those given for the natural product.3
Scheme 3. Reagents and conditions: (a) Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate (1.5 equiv.), cat. [Rh(OAc)2]2,
CH2Cl2, 25°C, 2.5 h; (b) 5% aq. NaOH, EtOH, reflux, 1 h; (c) TFAA, KO2CCF3 (1.1 equiv.), CH2Cl2, 45°C, 4 h; (d)
10% aq. NaOH, MeOH, 25°C, 18 h; (e) BBr3 (13 equiv.), CH2Cl2, −78 to 25°C, 18 h
Acknowledgements
We thank the Deutsche Forschungsgemeinschaft for financial support of this work.
References
1. Chan, G. W.; Francis, T.; Thureen, D. R.; Offen, P. H.; Pierce, N. J.; Westley, J. W.; Johnson, R. K.; Faulkner,
D. J. J. Org. Chem. 1993, 58, 2544–2546.
2. Berkhout, T. A.; Havekes, L. M.; Pearce, N. J.; Groot, P. H. E. Biochem. J. 1990, 272, 181–186.
3. Kang, H.; Fenical, W. J. Org. Chem. 1997, 62, 3254–3262.
4. Heim, A.; Terpin, A.; Steglich, W. Angew. Chem. 1997, 109, 158–159; Angew. Chem., Int. Ed. Engl. 1997, 36,
155–156.
5. Terpin, A.; Polborn, K.; Steglich, W. Tetrahedron 1995, 51, 9941–9946.
6. Peschko, C.; Winklhofer, C.; Steglich, W. Chem. Eur. J. 2000, 6, 1147–1152.
7. Ebel, H.; Terpin, A.; Steglich, W. Tetrahedron Lett. 1998, 39, 9165–9166.
8. Boger, D. L.; Boyce, C. W.; Labroli, M. A.; Sehon, C. A.; Jin, Q. J. Am. Chem. Soc. 1999, 121, 54–62.
9. Preparation of 14: (a) (3,4-dimethoxyphenyl)acetic acid, DCC (1.1 equiv.), DMAP (0.1 equiv.), 2,2,2-
trichloroethanol (2.5 equiv.), CH2Cl2, 25°C, 15 h; (b) CCl4, NBS (1.05 equiv.), cat. AIBN, hw, 35°C, 1 h.
10. The NMR spectra indicate a mixture of stereoisomers.

9481
11. (a) Jou, G.; Gonza´lez, I.; Albericio, F.; Lloyd-Williams, P.; Giralt, E. J. Org. Chem. 1997, 62, 354–366; (b) Just,
G.; Grozinger, K. Synthesis 1976, 457–458.
12. Boger, D. L.; Han, N.; Tarby, C. M.; Boyce, C. W.; Cai, H.; Jin, Q.; Kitos, P. A. J. Org. Chem. 1996, 61,
4894–4912.
13. Selected spectroscopic data: 13: UV (MeOH): umax (m)=226 (25 834), 283 (16 935), 498 nm (11 202). IR (KBr):
1
v˜=1713 (m), 1618 (m), 1588 (s), 1558 (m), 1513 (s), 1464 (m), 1270 (s), 1027 cm−1 (m). H NMR (CDCl3, 300
MHz): l 7.84 (s, 2H), 7.68 (s, 2H), 6.96 (dd, J=8.7, 1.8 Hz, 2H), 6.95 (d, J=1.8 Hz, 2H), 6.90 (d, J=8.7 Hz,
2H), 6.50 (d, J=8.7 Hz, 2H), 6.43 (d, J=8.7 Hz, 2H), 4.02 (s, 6H), 3.91 (s, 6H), 3.90 (s, 6H), 3.88 (s, 6H), 3.53
(s, 3H), 3.03 (t, J=7.2 Hz, 2H), 2.27 (t, J=7.2 Hz, 2H). 13C NMR (CDCl3, 75 MHz): l 182.99 (CꢀO), 158.14,
154.37, 151.12, 151.03, 149.06, 148.66, 131.15, 129.62 (CH), 129.37, 126.30, 125.42, 124.10, 123.73 (CH), 117.31,
114.24 (CH), 113.29 (CH), 110.89 (CH), 109.81 (CH), 108.65 (CH), 56.51 (CH3), 56.21 (CH3), 55.97 (CH3), 55.88
(CH3), 54.92 (CH3), 46.85 (CH2), 33.48 (CH2). EIMS (170°C): m/z (rel. intensity)=823 (100) [M+], 702 (47), 690
(30), 689 (30), 658 (17). HREIMS calcd for C49H45NO11 [M+] 823.2958, found 823.2955. 18: UV (MeOH): umax
(m)=203 (54 833), 282 (13 514), 343 nm (8866). IR (KBr): v˜=1706 (s), 1626 (s), 1593 (s), 1515 (s), 1264 (s), 1235
1
(s), 1142 (s), 1027 cm−1 (s). H NMR (CDCl3, 300 MHz): l 7.62 (s, 1H), 7.17 (dd, J=8.2, 2 Hz, 1H), 7.05 (d,
J=1.9 Hz, 1H), 7.02 (d, J=8.2 Hz, 1H), 6.99–6.68 (br, 3H), 6.97 (s, 1H), 6.68 (d, J=8.2 Hz, 1H), 6.39 (dd, J=8,
2 Hz, 1H), 6.29 (d, J=2 Hz, 1H), 3.95 (s, 6H), 3.94 (s, 3H), 3.92 (s, 3H), 3.90 (s, 3H), 3.88–3.81 (br, 2H), 3.80
(s, 3H), 3.76 (s, 3H), 3.53 (s, 3H), 2.52 (t, J=8.1 Hz, 2H). 13C NMR (CDCl3, 75 MHz): l 183.59 (CꢀO), 170.81
(CꢀO), 152.06, 150.68, 150.24, 149.36, 149.26, 148.79, 148.61, 147.63, 147.13, 134.31, 130.48, 130.31, 124.98,
124.48, 123.81, 123.71 (CH), 123.13, 122.91 (CH), 120.75 (CH), 118.92, 114.24 (CH), 112.69 (CH), 111.71 (CH),
111.36 (CH), 111.20 (CH), 110.87 (CH), 109.38 (CH), 107.76 (CH), 56.08 (CH3), 56.07 (CH3), 56.06 (CH3), 56.00
(CH3), 55.91 (CH3), 55.86 (CH3), 55.72 (CH3), 55.67 (CH3), 43.14 (CH2), 34.85 (CH2). EIMS (170°C): m/z (rel.
intensity)=693 (24) [M+], 542 (24), 529 (100). HREIMS calcd for C40H39NO10 [M+] 693.2581, found 693.2579.
14. (a) McOmie, J. F. W.; Watts, M. L.; West, D. E. Tetrahedron 1968, 24, 2289–2292; (b) Vickery, E. H.; Pahler,
L. F.; Eisenbraun, E. J. J. Org. Chem. 1979, 44, 4444–4446.
15. Utilization of excess BBr3 without the addition of cyclohexene resulted in partial mono-bromination of 1 at the
4-hydroxybenzene unit. 1 and its bromo derivative were easily separated by RP-18-HPLC (solvents: A:
CH3CN/H2O 1:9+0.1% TFA, B: CH3CN. Gradient: 100% A to 100% B within 50 min. Retention times: 1: 21
min, bromo derivative: 22 min).
16. The synthesis of 9a followed the procedure described for 9 with homoveratrylamine instead of 2-(4-
methoxyphenyl)ethylamine.
17. (a) Maryanoff, B. E. J. Org. Chem. 1982, 47, 3000–3002; (b) Padwa, A.; Wisnieff, T. J.; Walsh, E. J. J. Org.
Chem. 1989, 54, 299–308; (c) Adams, J.; Spero, D. M. Tetrahedron 1991, 47, 1765–1808.
18. Methyl 2-diazo-2-(3,4-dimethoxyphenyl)acetate was obtained in 62% yield by stirring methyl 2-(3,4-
dimethoxyphenyl)acetate with 4-toluenesulfonyl azide (1 equiv.) and DBU (1 equiv.) in CH3CN for 15 h at
ambient temperature.
.