Synthetic studies on the salicylihalamides: Macrolactone formation via ring closing metathesis versus macrolactonization

Article abstract of DOI:10.1016/S0040-4039(00)01420-9

Two routes to the unusual 12-membered unsaturated benzolactone of the highly cytotoxic marine metabolites the salicylihalamides are presented. The first involves an RCM step to construct the C9-C10 alkene bond and this provided the model macrolactones 9 and 10 in a ratio of 77:23, respectively. An alternative route involved a Stille coupling to construct the C8-C9 bond followed by a macrolactonization to give the lactones 9 and 10 in a ratio of 96:4. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)01420-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 8569–8572
Synthetic studies on the salicylihalamides: macrolactone
formation via ring closing metathesis versus
macrolactonization
John T. Feutrill,a Georgina A. Holloway,a Ferdows Hilli,a Helmut M. Hu¨gelb and
Mark A. Rizzacasaa,*
aSchool of Chemistry, The University of Melbourne, Parkville, Victoria 3010, Australia
bDepartment of Applied Chemistry, RMIT University, Plenty Road, Bundoora, Victoria 3083, Australia
Received 29 April 2000; accepted 22 August 2000
Abstract
Two routes to the unusual 12-membered unsaturated benzolactone of the highly cytotoxic marine
metabolites the salicylihalamides are presented. The first involves an RCM step to construct the C9ꢀC10
alkene bond and this provided the model macrolactones 9 and 10 in a ratio of 77:23, respectively. An
alternative route involved a Stille coupling to construct the C8ꢀC9 bond followed by a macrolactonization
to give the lactones 9 and 10 in a ratio of 96:4. © 2000 Elsevier Science Ltd. All rights reserved.
Marine organisms are a source of a large number of secondary metabolites that have a range
of biological activities.1 Marine sponges in particular, supply compounds with highly varied
molecular architecture and pharmacological properties.2 Recently, a pair of compounds named
salicylihalamides A (1) and B (2) (Fig. 1) were isolated from a sponge of the genus Haliclona
collected from waters around Rottnest island off the coast of Western Australia.3 These
compounds were identified as novel highly cytotoxic macrolides which possess a new 12-mem-
Figure 1.
* Corresponding author.
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)01420-9

8570
bered unsaturated benzolactone ring system as well as an unusual enamide sidechain4 and differ
only in the geometry about the C17ꢀC18 enamide double bond. Testing of salicylihalamide A (1)
in the USA National Cancer Institute (NCI) 60-cell line human tumor screen gave a pattern of
differential toxicity which did not correlate with the profiles of any known antitumor com-
pounds in the NCI standard database.3 These results suggest that compound 1 has a novel
mechanism of action and would make an interesting synthetic target for the potential develop-
ment of a new class of antitumor compound.
As part of a program directed towards the synthesis of Australian marine sponge metabolites5
we have targeted the salicylihalamides and decided to compare two different approaches to the
novel 12-membered unsaturated lactone system (Scheme 1). The first (path A) involves the
construction of the macrolactone by formation of the C9ꢀC10 alkene bond via ring-closing-
metathesis (RCM).6,7 The RCM approach to macrolactones has been extensively developed by
Fu¨rstner who has reported that a properly positioned coordinating group such as an ester is
needed for effective ring closure to occur.8 This protocol was recently applied in the total
synthesis of the macrolide (+)-lasiodiplodin in which the key step involved RCM to form an
intermediate which represented a truncated salicylihalamide.9
Scheme 1.
One possible problem with the RCM methodology is that the stereoselectivity is often low and
difficult to predict.6 We therefore elected to also examine an alternative route (path B) which
involves an intermolecular palladium-catalyzed Stille coupling10 between a vinyl stannane and
benzylic bromide11 to form the C8ꢀC9 sigma bond followed by macrolactonization to provide
the salicylihalamide ring system (Scheme 1). This route may provide the lactone with greater
stereocontrol in a more convergent fashion.
Our comparison study of the two approaches began with the synthesis of a model system
which does not possess the substituents at C3 and C15 (Scheme 2). Asymmetric
crotylmetallation12 of aldehyde 3 and subsequent silylation of the adduct13 provided the known
alkene 414 in good yield. Hydroboration with 9-BBN followed by oxidation gave aldehyde 5,
which upon one carbon Wittig extension and monodesilylation with HF·pyridine in THF
buffered with pyridine15 gave the alcohol 6.16 The methodology developed by Fu¨stner8,9 was then
utilized to provide the RCM precursor 8. Thus, esterification of salicylic acid with alcohol 6
under Mitsunobu conditions17 gave ester 7 which was transformed into the corresponding
triflate. Stille coupling of the triflate with allyltributylstannane mediated by Pd2(dba)3 in the
presence of TFP18 gave the RCM substrate 8 in fair yield. Treatment of diene with Grubbs
catalyst in boiling CH2Cl2 then gave the two macrocycles 919 and 10 in a ratio of 77:23,
respectively, which were separated by preparative HPLC (normal phase, 2.5% EtOAc/petrol

8571
eluent). The stereochemistry of the major unsaturated macrolactone 9 was determined to be E
by homonuclear decoupling experiments (JH9ꢀH10=15.0 Hz).
Scheme 2. Reagents and conditions: (a) (+)-Ipc2B-(E)-crotyl then H2O2/NaHCO3, 2 h; (b) TBSCl, imidazole, DMF,
16 h; (c) 9-BBN then H2O2/NaHCO3, rt, 1 h; (d) Dess–Martin reagent, CH2Cl2, rt, 1 h; (e) Ph3PꢁCH2, THF, 16 h
(71%); (f) HF·pyridine/pyridine, THF, rt, 3 h; (g) salicylic acid, DEAD, Ph3P, Et2O, rt, 16 h; (h) Tf2O, pyridine,
CH2Cl2, 1.5 h; (i) allyltributylstannane, Pd2(dba)3, TFP, LiCl, NMP, 36 h; (j) RuCl2(ꢁCHPh)(PCy3)2, CH2Cl2, reflux,
16 h
The Stille coupling macrolactonization approach to the macrolactone 9 is shown in Scheme 3.
Alkene 4, utilized in the RCM study, was treated with ozone and NaBH4 to yield the alcohol
11,20 which on tosylation and acetylide anion displacement afforded alkyne 12. Selective
deprotection of the primary TBS group and subsequent radical hydrostannylation proceeded
smoothly to give the stannane 13 in good yield. The Stille coupling11 between stannane 13 and
methyl 2-bromomethylbenzoate was best effected under conditions reported by Farina18 to give
the E alkene 14 (E:Z selectivity>95:5) in excellent yield. The use of other catalysts such as
Pd(MeCN)2Cl2 or Pd(Ph3P)4 resulted in poorer E:Z ratios and yields. Hydrolysis of the methyl
ester 14 then gave the seco acid 15 which underwent lactonization using the Mitsunobu
protocol17 to provide macrolactones 9 and 10 in 64% yield in a 96:4 ratio. Some dimer21 was
formed in competition with the desired macrolactone and dilution experiments did not improve
the yield. An attempt at macrolactonization using the Yamaguchi protocol failed.22
Scheme 3. Reagents and conditions: (a) O3, CH2Cl2MeOH, −78°C, NaBH4, 20 min; (b) TsCl, pyridine, DMAP,
CH2Cl2, rt, 16 h; (b) HCꢁCLi·EDA, DMSO, rt, 18 h; (d) HF·pyridine, pyridine, THF, rt, 3 h; (e) Bu3SnH, AIBN,
benzene reflux, 2 h; (f) methyl 2-bromomethylbenzoate, Pd2(dba)3, TFP, NMP, rt, 24 h; (g) LiOH, THF/H2O/MeOH,
rt, 16 h; (h) Ph3P, DEAD, benzene 0.04 M, rt, 16 h
In conclusion, the unusual 12-membered benzolactone ring system of the salicylihalamides has
been synthesized by two different routes. The stereoselectivity for Stille macrolactonization

8572
approach was far higher than that for the RCM route. In addition, a higher overall yield of pure
9 from the common intermediate 4 was obtained for the macrolactonization route versus the
metathesis sequence (both eight steps, 21% versus 17%). Work towards the introduction of the
interesting C15 alkenamide sidechain is underway and will be reported in due course.
Acknowledgements
We thank the Australian Research Council for financial support.
References
1. Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 1–6.
2. Faulkner, D. J. Nat. Prod. Rep. 2000, 17, 7–55. Faulkner, D. J. Nat. Prod. Rep. 1999, 16, 155–198.
3. Erickson, K. L.; Beutler, J. A.; Cardellina, I. J. H.; Boyd, M. R. J. Org. Chem. 1997, 62, 8188–8192.
4. For an elegant synthesis of the alkenamide sidechain of salicylihalamide A see: Snider, B. B.; Song, F. Org. Lett.
2000, 2, 407–408.
5. Czuba, I. R.; Rizzacasa, M. A. J. Chem. Soc., Chem. Commun. 1999, 1419–1420.
6. Grubbs, R. H.; Miller, S.; Fu, G. C. Acc. Chem. Res. 1995, 28, 446–452.
7. Schuster, M.; Blechert, S. Angew. Chem., Int. Ed. Engl. 1997, 36, 2037–2056.
8. Fu¨rstner, A.; Langemann, K. J. Org. Chem. 1996, 61, 3942–3943.
9. Fu¨rstner, A.; Kindler, N. Tetrahedron Lett. 1996, 37, 7005–7008. Fu¨rstner, A.; Seidel, G.; Kindler, N.
Tetrahedron 1999, 55, 8125–8230.
10. (a) Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524. (b) Farina, V.; Krishnamurthy, V.; Scott, W. J.
In Organic Reactions; Paquette, L. A., Ed.; J. Wiley and Sons: New York, 1997; Vol. 50, pp. 1.
11. Milstein, D.; Stille, J. K. J. Am. Chem. Soc. 1979, 101, 4992–4998.
12. Brown, H. C.; Blat, K. S. J. Am. Chem. Soc. 1986, 108, 293–294.
13. Nicolaou, K. C.; Piscopio, A. D.; Bertinato, P.; Chakraborty, T. K.; Minowa, N.; Koide, K. Chem. Eur. J. 1995,
1, 318–333.
14. White, J. D.; Hong, J.; Robarge, L. A. J. Org. Chem. 1999, 64, 6206–6216.
15. Evans, D. A.; Gage, J. R.; Leighton, J. L. J. Am. Chem. Soc. 1992, 114, 9434–9453.
1
16. New compounds were characterized by H and 13C NMR, IR and [h]D.
17. Mitsunobu, O. Synthesis 1981, 1–28.
18. Farina, V.; Krishnan, B. J. Am. Chem. Soc. 1991, 113, 9585–9595.
19. Data for macrolactone 9: [h] −17.6 (c 0.6, CHCl3): Rf 0.63 (5% EtOAc/petrol); IR (film) wmax 1729, 1463, 1380,
1
1268, 1129, 1102, 1077, 1053 cm−1; H NMR l −0.01 (s, 3H), 0.06 (s, 3H), 0.88 (s, 9H), 0.89 (d, J=6.6 Hz, 3H),
1.24–1.43 (m, 1H), 1.75–1.96 (m, 2H), 2.04–2.26 (m, 2H), 3.35 (dd, J=3.3, 16.0 Hz, 1H), 3.78 (dd, J=6.6, 16.0
Hz), 3.86 (ddd, J=2.1, 2.2, 9.3 Hz, 1H), 4.21 (ddd, J=1.5, 11.1, 11.1 Hz, 1H), 4.57 (ddd, J=3.3, 3.3, 11.1 Hz,
1H), 5.31 (m, 1H), 5.43 (ddd, J=3.3, 6.6, 15.0 Hz, 1H), 7.18–7.24 (m, 2H), 7.34 (ddd, J=1.5, 7.5, 7.8 Hz), 7.43
(dd, J=1.5, 7.8 Hz); 13C NMR l −4.64, −4.60, 14.1, 18.0, 25.8, 30.8, 36.6, 37.4, 37.9, 62.9, 71.1, 126.1, 127.8,
129.5, 130.27, 130.32, 131.5, 133.7, 139.8, 169.8. HRMS (ESI) calcd for C22H34NaO3Si [M+Na+]: 397.2175.
Found: 397.2188.
20. Ali, S. M.; Georg, G. I. Tetrahedron Lett. 1997, 38, 1703–1706.
21. Seebach, D.; Searing, B.; Kalinowski, H.; Lubosch, W.; Renger, B. Angew. Chem., Int. Ed. Engl. 1977, 16,
264–265. Gerlach, H.; Oertle, K.; Thalmann, A. Helv. Chim. Acta 1977, 60, 860–865.
22. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
.