Syntheses of two cytotoxic polyunsaturated pyrrole metabolites of the marine sponge Mycale micracanthoxea

Article abstract of DOI:10.1016/j.tetlet.2004.02.024

Starting from eicosapentaenoic acid (EPA) the marine, naturally occurring, pyrrole derivatives, mycalazol 5 and mycalazal 2 have been synthesized. The Stille coupling reaction is a key step in the syntheses.

Full text of DOI:10.1016/j.tetlet.2004.02.024

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 2809–2811
Syntheses of two cytotoxic polyunsaturated pyrrole metabolites of
the marine sponge Mycale micracanthoxea
Trond Vidar Hansena,* and Lars Skattebølb
aSchool of Pharmacy, Department of Medicinal Chemistry, University of Oslo, PO Box 1185, Blindern, N-0316, Oslo, Norway
bDepartment of Chemistry, University of Oslo, PO Box 1033, Blindern, N-0315, Oslo, Norway
Received 5 December 2003; revised 23 January 2004; accepted 6 February 2004
Abstract—Starting from eicosapentaenoic acid (EPA) the marine, naturally occurring, pyrrole derivatives, mycalazol 5 and
mycalazal 2 have been synthesized. The Stille coupling reaction is a key step in the syntheses.
ꢀ 2004 Elsevier Ltd. All rights reserved.
Marine organisms have proved to be an abundant source
of biologically interesting secondary metabolites.1;2 In
EPA. Hence we decided on a synthetic strategy for both
compounds in which one of the fragments contains all
the double bonds and the other an appropriate pyrrole
entity. For compound 3, a five carbon chain extension of
EPA leads to the acid 5, as one of the fragments. The
other fragment is the known stannylpyrrole 6,9 and we
anticipated that a Stille coupling would combine the two
fragments affording the target molecule after reduction.
A similar strategy has been used successfully by Nabbs
and Abell for the synthesis of some of the saturated
mycalazols.10
3
ꢀ
1997 Salva and co-workers identified fourteen struc-
turally related 2,5-disubstituted pyrroles from the
northeastern Atlantic sponge Mycale micracanthoxea.
The compounds exhibit interesting cytotoxic activity
towards several cancer cell lines. The characteristic
structural feature of the compounds is a C-16 or longer
carbon chain attached to the 5-position of the pyrrole
ring. Some of them contain several methylene inter-
rupted Z-double bonds in the side chain. As part of an
ongoing effort on the synthesis and biological testing of
derivatives of eicosapentaenoic acid (1, EPA) and
docosahexaenoic acid (2, DHA)4–8 the present paper
describes the first syntheses of two of the polyunsatura-
ted pyrroles: mycalazol 5 (3) and mycalazal 2 (4) (Fig. 1).
The acid 5 was prepared as outlined in Scheme 1.
Reduction of EPA with LAH in ether furnished the
known alcohol 7,11 which was converted to the thioether
8 with (PhS)2 and Bu3P.12 Oxidation of the sulfide with
oxone in aqueous MeOH at 0 ꢁC afforded the sulfone 9
(53% overall yield from EPA). Reaction of the a-sulfon-
yl carbanion, formed from 9 with LDA at )78 ꢁC, with
methyl 5-bromovalerate furnished the ester 10. The
phenylsulfonyl group was removed with sodium amal-
gam in the usual way,13 and the resulting ester 11 was
hydrolyzed with LiOH in aqueous MeOH to the acid 514
(34% yield from 9). The acid 5 was converted to the acid
chloride 12 with (COCl)2 in CH2Cl2 and the subsequent
Stille coupling with the organotin derivative 6 furnished
the pyrrole 13 in 81% yield (Scheme 2).14 The synthesis
was concluded by chemoselective reduction of the for-
myl group with Zn(BH4)2 in ether at 0 ꢁC affording the
target molecule 3 (76% yield) with spectral data in
agreement with those reported for mycalazol 5.3
The compounds 3 and 4 contain the same number of
methylene interrupted double bonds as those present in
Figure 1.
Keywords: Pyrroles; Synthesis; Stille coupling.
* Corresponding author. Tel.: +47-2285-7450; fax: +47-2285-5947;
e-mail: t.v.hansen@farmasi.uio.no
It seemed obvious to transform the mycalazol 3 into
the corresponding mycalazal derivative
4
using
0040-4039/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.02.024

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T. V. Hansen, L. Skattebøl / Tetrahedron Letters 45 (2004) 2809–2811
Scheme 1. Reagents and conditions: (i) LiAIH4, ether, D; (ii) (PhS)2, Bu3P, THF; (iii) KHSO5, MeOH, 0 ꢁC; (iv) (a) LDA, THF, )78 ꢁC, (b) methyl
5-bromovalerate, THF; (v) (a) Na(Hg), Na2HPO4, MeOH, )20 ꢁC, (b) LiOH, H2O, MeOH.
Scheme 2. Reagents and conditions: (i) (COCl)2, CH2Cl2; (ii) 6, Pd(PPh3)4 (10%), THF, D; (iii) Zn(BH4)2, THF, 0–25 ꢁC; (iv) (a) NaCN, CH2Cl2,
(b) MnO2, MeOH; (v) 14, Pd(PPh3)4 (10%), THF, D; (vi) TsNHNH2, MeOH, (b) NaB(CN)H3, MeOH; (vii) DIBAL-H, )78 ꢁC, THF.
ꢀ
3. Ortega, M. J.; Zubia, E.; Carballo, J. L.; Salva, J.
chemoselective reactions. However, some initial experi-
ments were unsatisfactory, and we chose to prepare 4 by
a similar route to that described above, viz. reaction of
the stannylpyrrole 14 with the acid chloride 12 under
Stille conditions, as outlined in Scheme 1. Transforma-
tion of the aldehyde function of 6 into a methyl carb-
oxylate group using the one-pot cyanohydrin procedure
reported by Corey et al.15 provided the organotin
derivative 14 in 86% yield.14 It underwent Stille coupling
with the acid chloride 12 to give the pyrrole 1514 (74%
yield), the carbonyl function of which was transformed
to a methylene group by reduction of the corresponding
tosylhydrazone with NaB(CN)H3. The ester thus
obtained was finally reduced by DIBAL-H in THF to
give 4 in 46% yield, which exhibited spectral data in
agreement with those reported for mycalazal 2.3
Tetrahedron 1997, 53, 331–340.
4. Holmeide, A. K.; Skattebøl, L.; Sydnes, M. J. Chem. Soc.,
Perkin. Trans. 1 2001, 1942–1946.
5. Flock, S.; Lundquist, M.; Skattebøl, L. Acta Chem. Scand.
1999, 53, 436–445.
6. Holmeide, A. K.; Skattebøl, L. J. Chem. Soc., Perkin.
Trans. 1 2001, 2271–2276.
7. Flock, S.; Skattebøl, L. J. Chem. Soc., Perkin. Trans. 1
2000, 3071–3076.
8. Holmeide, A. K.; Skattebøl, L. Tetrahedron 2003, 59,
7157–7162.
9. Denat, F.; Gaspard-Iloughmane, H.; Dubac, J. J. Orga-
nomet. Chem. 1992, 423, 173–182.
10. Nabbs, B. K.; Abell, A. D. Bioorg. Med. Chem. Lett. 1999,
9, 505–508.
ꢀ
11. Kuklev, D. V.; Popkov, A. A.; Kasyanov, S. P.; Akulin,
V. N.; Bezuglov, V. V. Bioorg. Khim. 1996, 22, 219–222.
12. Nakagawa, I.; Hata, T. Tetrahedron Lett. 1975, 1409–
1412.
13. Trost, B. M.; Arndt, H. C.; Strege, P. E.; Verhoeven, T. R.
Tetrahedron Lett. 1976, 3477–3478.
14. Spectral data of selected compounds: (all-Z)-
10,13,16,19,22-pentacosapentaenoic acid 5: pale yellow
oil; IR (film) 3300–3560, 1712 cmꢀ1; 1H NMR (300 MHz):
d 0.94 (t, J 7.5 Hz, 3H), 1.20–1.90 (m, 10H), 2.00–2.06 (m,
4H), 2.26 (t, J 7 Hz, 2H), 2.65–2.85 (m, 10H), 5.24–5.40
(m, 10H), 11.72 (br s, 1H); 13C NMR (75 MHz): d 14.13
(CH3), 22.74, 25.20, 25.44 (3 · CH2), 25.62 (3 · CH2),
26.15, 26.34, 26.42, 27.15, 28.52, 28.64, 32.43, (7 · CH2),
126.23, 128.41, 128.56, 128.61, 128.67, 128.73, 129.24,
129.31, 129.68, 129.79 (10 · CH), 176.31 (C); HRMS calcd
In conclusion, the syntheses of the naturally occurring
pyrrole derivatives 3 and 4 confirmed the assigned
structures and provided sufficient material for biological
testing.
References and notes
1. Rinehart, K. L.; Tachibana, K. J. Nat. Prod. 1995, 58,
344–358.
2. Faulkner, D. J. Nat. Prod. Rep. 2002, 19, 1–48.

T. V. Hansen, L. Skattebøl / Tetrahedron Letters 45 (2004) 2809–2811
2811
for C25H40O2 (Mþ): 372.3028, found 372.3019; 5-((all-Z)-
10,13,16,19,22-pentacosapentaenyl)pyrrole-2-carboxalde-
(75 MHz): d 10.25 (3 · CH2), 13.58 (3 · CH3), 27.41
(3 · CH2), 29.09 (3 · CH2), 52.33 (CH3), 120.91 (CH),
122.13 (CH), 136.41, 141.81, 177.81 (3 · C); Methyl 5-((all-
Z)-10,13, 16,19,22-pentacosapentaenoyl)pyrrole-2-carbox-
hyde 13: colourless oil; IR (film) 1700, 1680 cmꢀ1 1H
;
NMR (300 MHz): d 0.97 (t, J 7.5 Hz, 3H), 1.22–1.70 (m,
12H), 2.00–2.14 (m, 4H), 2.48 (t, J 7.2 Hz, 2H), 2.84–2.95
(m, 8H), 5.29–5.41 (m, 10H), 6.86 (dd, J 2.5, 3.6 Hz, 1H),
6.92 (dd, J 2.5, 3.6 Hz, 1H), 9.68 (s, 1H), 9.91 (br s, 1H);
13C NMR (75 MHz): d 14.21 (CH3), 20.64, 25.54, 27.39,
27.92, (4 · CH2), 29.31 (3 · CH2), 29.54 (3 · CH2), 29.66
(2 · CH2), 109.12 (CH), 122.28 (CH), 127.11, 127.51,
127.88, 128.12, 128.44, 128.78 (6 · CH), 130.12, 132.13,
132.51 (6 · CH), 135.24, 180.72, 191.20 (3 · C); HRMS
calcd for C30H45NO2 (Mþ): 449.3294, found 449.3270;
Methyl 5-tributylstannylpyrrole-2-carboxylate 14: pale
yellow oil; IR (film) 3288, 1709 cmꢀ1; 0.88 (m, 9H), 1.18–
1.70 (m, 18H), 3.82 (s, 3H), 6.33 (dd, J 2.5, 3.6 Hz, 1H),
6.96 (dd, J 2.5 Hz, 3.6 Hz, 1H) 9.88 (br s, 1H); 13C NMR
ylate 15: colourless oil, IR (film) 1690, 1722 cmꢀ1 1H
;
NMR (300 MHz): d 0.95 (t, J 7.5 Hz, 3H), 1.24–1.70 (m,
12H), 2.05–2.10 (m, 4H), 2.65 (t, J 7.2 Hz, 2H), 2.80–2.94
(m, 8H), 3.67 (s, 3H), 5.25–5.38 (m, 10H), 6.88 (dd, J 2.8,
3.8 Hz, 1H), 6.92 (dd, J 2.8, 3.8 Hz, 1H), 9.90 (br s, 1H);
13C NMR (75 MHz): d 14.26 (CH3), 20.53, 22.06, 25.51,
(3 · CH2), 25.58, (6 · CH2), 25.60, 25.62, 38.51 (4 · CH2),
52.08 (CH3), 115.32, 119.56, 126.98, 127.84, 127.85,
127.97, 128.04, 128.05, 128.23, 128.26, 128.30, 132.02,
(12 · CH), 134.67, 135.24, 178.03, 180.74 (4 · C); HRMS
calcd for C31H45NO2 (Mþ): 479.3399, found 479.3381.
15. Corey, E. J.; Gilman, N. W.; Ganem, B. E. J. Am. Chem.
Soc. 1968, 90, 5616–5617.