Synthesis of alkylphenols and alkylcatechols from the marine mollusc Haminoea callidegenita

Article abstract of DOI:10.1016/S0040-4039(00)00532-3

Alkylphenols 1-5, potential alarm pheromones of the marine mollusc Haminoea callidegenita, have been synthesized using a convergent approach centred on a Stille coupling reaction. (C) 2000 Elsevier Science Ltd.

Full text of DOI:10.1016/S0040-4039(00)00532-3

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 41 (2000) 3975–3978
Synthesis of alkylphenols and alkylcatechols from the marine
mollusc Haminoea callidegenita
Irene Izzo, Salvatore De Caro, Francesco De Riccardis ∗ and Aldo Spinella ∗
Dipartimento di Chimica, Università di Salerno, Via S. Allende, Baronissi-84081- Salerno, Italy
Received 31 January 2000; accepted 28 March 2000
Abstract
Alkylphenols 1–5, potential alarm pheromones of the marine mollusc Haminoea callidegenita, have been
synthesized using a convergent approach centred on a Stille coupling reaction. © 2000 Elsevier Science Ltd. All
rights reserved.
Keywords: Haminoea callidegenita; alkylphenols; pheromones; palladium catalysts.
Alkylphenols and alkylcatechols 1–5 are marine metabolites recently isolated from the cephalaspidean
mollusc Haminoea callidegenita.1 These molecules are particularly interesting because both their origin
and structure strongly suggest a potential role as semiochemicals. In fact, it has been shown that some
metabolites of Haminoea species, e.g. 6,2 are responsible for an alarm pheromone based defensive
behaviour. Furthermore, the compounds isolated from H. callidegenita are clearly structurally related to
navenone C (7), isolated from the Pacific cephalaspidean Navanax inermis, belonging to the first group
of chemically described alarm pheromones from a marine mollusc.3
Another aspect which makes these molecules intriguing synthetic targets is related to the interesting
biological activities exhibited by several alkylphenols and alkylcatechols (e.g. cytotoxic, antibacterial
and DNA strand scission activities).4 This prompted us to produce adequate quantities of compounds
1–5 in order to start a wide bioassay investigation.
∗
Corresponding authors. Tel: +39 089965373; fax: +39 089965296; e-mail: spinella@unisa.it (A. Spinella)
0040-4039/00/$ - see front matter © 2000 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(00)00532-3
tetl 16811

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In this paper we describe a synthesis of these molecules using a convergent route in which the key step
is the Stille coupling between the building blocks A and B.
Alkenyl iodides corresponding to block A were prepared starting from protected esters 105 and 11
derived from commercially available starting materials such as 4-hydroxydihydrocinnamic (8) and 3,4-
dihydroxydihydrocinnamic (9) acids. In particular, 10 was obtained from 4-hydroxydihydrocinnamic
acid after Fischer esterification (MeOH, H2SO4) followed by silylation with tert-butyldimethylsilyl
chloride (TBS-Cl) and 1,8-diazabicyclo[5.4.0]undec-7-ene (DBU).6 Acetal 11 was prepared by treating
the methyl ester, easily obtained from 3,4-dihydroxydihydrocinnamic acid (9), with 2,2-dimethoxy
propane.7
Our route to alkenyl iodides 14 and 15 is shown in Scheme 1. Ester 10 was reduced with LiAlH4 to
afford the alcohol 12 in quantitative yield. Oxidation of 12 with pyridinium dichromate (PDC)8 gave the
aldehyde 13. This was subjected to reaction with chromium(II) chloride and iodoform9 to afford a 90:10
mixture of E-alkenyl iodide 14 and its Z isomer (not shown).10 The application of the same procedure to
ester 11 gave alkenyl iodide 15 (41% overall yield from 9, E:Z ratio 90:10).11
Scheme 1. (a) 1.0 equiv of LiAlH4, THF, 0°C, 0.5 h 100%; (b) 1.3 equiv of PDC, 3 Å molecular sieves, CH2Cl2, rt, 1 h, 71%;
(c) 6.0 equiv. of CrCl2, 2 equiv. of CHI3, 1,4-dioxane:THF (6:1), 15°C, 24 h, 72%
The synthesis of the block B started with hydrostannylation12 of the THP protected 3-butyn-1-ol (16,
Scheme 2). This reaction afforded the tributylstannane 17 which, after treatment with iodine,13 gave
18 (80% yield, two steps). Enyne 19 was assembled from vinylic iodide 18 and tributyl(ethynyl)tin
using a (CH3CN)2PdCl2 catalyzed Stille coupling13 reaction (45% yield; E:Z ratio 95:5). The yield
of 19 was improved with a two step procedure involving a Sonogashira coupling14 of iodide 18 with
(trimethylsilyl)acetylene13 (81% yield) followed by removal of the silyl group with tetrabutylammonium
fluoride (TBAF, 72% yield; E:Z ratio 97:3).
Scheme 2. (a) 0.9 equiv of Bu3SnH, 0.02 equiv of AIBN, toluene, reflux, 4 h (b) 1.0 equiv of I2, CH2Cl2, 0.5 h, 80% (two steps);
(c) 0.07 equiv of (CH3CN)2PdCl2, 1.1 equiv of HCCSnBu3, 25°C, 0.5 h, DMF, 45%; (d) 2.0 equiv of HCCSiMe3, 0.07 equiv of
(CH3CN)2PdCl2, 0.3 equiv of CuI, 2.0 equiv of Et3N, 0°C, 1 h, 81%, (e) 2.0 equiv of TBAF, THF, rt, 0.5 h, 72%
With enyne 19 in hand, we tried the conventional hydrostannylation reaction12 with 2,2-
azobis(isobutyronitrile) (AIBN) as radical initiator. Unfortunately this reaction proved to be inefficient

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giving a low yield of 21. The enyne 19 was successfully metalated with the stannyl cuprate donor,
prepared in situ with CuCN, n-BuLi and Bu3SnH.15 The dienylstannane 2116 was thus obtained in
decent yield (60%) and good isomeric purity ((E,E)>97%, 1H NMR analysis).
Finally, alkenyl iodide 14, on coupling with stannane 21 using Stille’s conditions (Scheme 3), provided,
1
after careful column chromatography on silica gel, the isomerically enriched triene 22 (95% pure, H
NMR analysis).17,18 Deprotection of the THP group with pyridinium p-toluenesulfonate (PPTS) and
subsequent acetylation gave the silyl ether 23. Removal of tert-butyldimethylsilyl group with TBAF in
THF afforded target alkylphenol 2 in 15% overall yield from 8. Stronger deprotective conditions on 22
(PPTS, p-TsOH) afforded 24 which, after acetylation, gave 1 (8% overall yield from 8).
Scheme 3. (a) 0.05 equiv. of (CH3CN)2PdCl2, DMF, rt, 0.5 h, 53%; (b) 0.1 equiv. of PPTS, EtOH, 55°C, 7 h, 80%; (c) 4.0 equiv.
of Ac2O, 6.0 equiv. of pyridine, 0.02 equiv. of DMAP, CH2Cl2, rt, 2 h, 81%; (d) 0.3 equiv. of PPTS, 0.3 equiv. p-TsOH, EtOH,
55°C, 40%; (e) 2.0 equiv. of TBAF, THF, rt, 0.5 h, 95%; (f) 4.0 equiv. of Ac2O, 6.0 equiv. of pyridine, 0.02 equiv. of DMAP,
CH2Cl2, rt, 2 h, 80%
The synthesis of catechols 3–5 started from the palladium-catalyzed cross-coupling12 of the alkenyl-
iodide 15 with the stannane 21 (Scheme 4) to afford, after a careful purification, triene 25 (95% pure, 1H
NMR analysis).17,19 Exposure of 25 to aqueous acetic acid gave the monoacetylated catechol 26. Target
3 (12% overall yield from 9) was obtained after acetylation of 26. A 1:1 mixture of catechols 4 and 5
(9% overall yield from 9) was obtained by acetylating 26 using 0.8 equivalents of acetic anhydride.
Scheme 4. (a) 0.05 equiv. of (CH3CN)2PdCl2, DMF, rt, 3 h, 56%; (b) CH3COOH:H2O (8:2), 80°C, 16 h, 63%; (c) 4.0 equiv. of
Ac2O, 6.0 equiv. of pyridine, 0.02 equiv of DMAP, CH2Cl2, rt, 2 h, 84%; (d) 0.8 equiv. of Ac2O, 3.0 equiv. of pyridine, CH2Cl2,
rt, 2 h, 65%
Synthetic compounds 1–5 showed 1H and 13C NMR spectra identical to those reported for the natural
products.1 An investigation into the biological activities of these compounds is now in progress and the
results will be given in due course.
In conclusion, a straightforward synthetic route to alkylphenols 1, 2 and alkylcatechols 3–5 from
H. callidegenita has been developed in fair overall yields, starting from quite inexpensive dihydrocin-
namic acid derivatives 8 and 9, using a convergent approach centred on the Stille coupling reaction.

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Acknowledgements
This work has been supported by the MURST (PRIN ‘Chimica dei Composti Organici di Interesse
Biologico’).
References
1. Spinella, A.; Alvarez, L. A.; Cimino, G. Tetrahedron Lett. 1998, 39, 2005–2008.
2. Cimino, G.; Passeggio, A.; Sodano, G.; Spinella, A.; Villani, G. Experientia 1991, 47, 61–63.
3. (a) Sleeper, H. L.; Fenical, W. J. Am. Chem. Soc. 1977, 99, 2367–2368. (b) Fenical, W.; Sleeper, H. L.; Paul, V. J.; Stallard,
U. O.; Sun, H. H. Pure Appl. Chem. 1979, 51, 1865–1874. (c) Sleeper, H. L.; Paul, V. J.; Fenical, W. J. Chem. Ecol. 1980,
6, 57–70.
4. (a) Wasser, Ch.; Silva, F.; Rodriguez, E. Experientia 1990, 46, 500–502. (b) Singh, U. S.; Scannell, R. T.; An, H.; Carter,
B. J.; Hecht, S. M. J. Am. Chem. Soc. 1995, 117, 12691–12699 (c) Orjala, J.; Mian, P.; Rali, T.; Sticher O. J. Nat. Prod.
1998, 61, 939–941.
5. Satisfactory analytical data (1H and 13C NMR, EI-MS spectra, and elemental analyses) were obtained for all the new
compounds.
6. Aizpurua, J. M.; Palomo, C. Tetrahedron Lett. 1985, 26, 475–476.
7. Iwagami, H.; Nakazawa, M.; Yatagai, M.; Hijiya, T.; Honda, Y.; Naora, H.; Ohnuki, T.; Yukawa, T. Bull. Chem. Soc. Jpn.
1990, 63, 3073–3081.
8. Herscovici, J.; Antonakis, K. J. Chem. Soc., Chem. Commun. 1980, 561–562
9. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc. 1986, 108, 7408–7410; Evans, D.A.; Ng, H. P.; Tetrahedron Lett. 1993,
34, 2229–2232.
1
10. Configurational assignment of the (Z) and (E) isomers was based on the 400 MHz H NMR resonance of their vinylic
protons (E isomer: δ 6.01, d, J=14.3 Hz and 6.54, dt, J=14.3, 7.3 Hz; Z isomer: δ 6.21, m, and 7.07, d, J=8.2 Hz).
1
11. Configurational assignment of the (Z) and (E) isomers was based on the 400 MHz H NMR resonance of their vinylic
protons (E isomer:δ 6.03, d, J=14.4 Hz and 6.52, m; Z isomer: δ 6.22, m and 6.64, d, J=8.2 Hz).
12. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508–524 and references therein.
13. Stille, J. K.; Simpson, J. H. J. Am. Chem. Soc. 1987, 109, 2138–2152.
14. Robins, M. J.; Barr, P. J. J. Org. Chem. 1983, 48, 1854–1862.
15. Aksela, R.; Oehlschlager, A. C. Tetrahedron 1991, 47, 1163–1176.
16. Compound 21: 1H NMR (CDCl3, 400 MHz): δ 6.49 (1H, dd, J=18.0, 10.0 Hz), 6.12 (1H, dd, J=10.0, 15.2 Hz), 6.11 (1H,
d, J=18.0 Hz), 5.67 (1H, dt, J=15.2, 7.2 Hz), 4.60 (1H, t, J=4.3 Hz), 3.87 (1H, m), 3.77 (1H, m), 3.48 (1H, m), 3.46 (1H,
m), 2.39 (2H, dt, J=7.2, 6.8 Hz), 1.70–1.45 (12H, m), 1.30 (6H, m), 0.88 (15H, m); 13C NMR (CDCl3, 100 MHz): δ 146.9,
135.4, 131.7, 129.6, 98.8, 66.9, 62.3, 32.9, 30.7, 29.1 (×3), 27.2 (×3), 25.5, 19.6, 13.6 (×3), 9.5 (×3).
17. The stereochemistry of the triene moiety was deduced from the coupling constants of the higher field protons which were
carefully measured through 1H homodecoupling experiments and comparison of the 13C NMR values with literature data
(Wehrli, F. W.; Nishida, T. Progr. Chem. Org. Nat. Products 1979, 36, p. 128).
18. Compound 22: 1H NMR (CDCl3, 400 MHz): δ 7.02 (2H, bd, J=8.4 Hz), 6.74 (2H, bd, J=8.4 Hz), 6.17–6.04 (4H, m), 5.70
(1H, dt, J=14.1, 7.0 Hz), 5.68 (1H, dt, J=14.6, 7.2 Hz), 4.59 (1H, t, J=3.6 Hz), 3.86 (1H, m), 3.78 (1H, dt, J=9.7, 7.0 Hz),
3.48 (1H, m), 3.45 (1H, dt, J=9.7, 6.7 Hz), 2.63 (2H, t, J=8.3 Hz), 2.38 (4H, m), 1.85–1.50 (6H, m), 0.98 (9H, s), 0.18
(6H, s); 13C–NMR (CDCl3, 100 MHz): δ 153.7, 134.4, 133.7, 132.2, 131.3, 131.0, 130.9, 130.2, 129.2 (×2), 119.8 (×2),
98.8, 67.0, 62.3, 35.0, 34.8, 33.2, 30.7, 25.7 (×3), 25.5, 19.6, 18.2, –2.8 (×2).
19. Compound 25: 1H NMR (CDCl3, 400 MHz): δ 6.62 (1H, bd, J=8.0 Hz), 6.58 (1H, bd, J=8.0 Hz), 6.57 (1H, bs), 6.15–6.06
(4H, m), 5.74–5.65 (2H, m), 4.59 (1H, t, J=3.8 Hz), 3.86 (1H, m), 3.76 (1H, dt, J=9.7, 7.0 Hz), 3.51 (1H, m) 3.44 (1H, dt,
J=9.7, 6.7 Hz), 2.60 (2H, t, J=8.1 Hz), 2.38 (4H, m), 1.80–1.50 (6H, m), 1.65 (6H, s); 13C NMR (CDCl3, 100 MHz): δ
147.3, 145.5, 134.9, 133.5, 132.2, 131.2, 131.0, 130.8, 130.1, 120.4, 117.4, 108.6, 107.8, 98.7, 66.9, 62.2, 35.5, 34.9, 33.2,
30.6, 25.8 (×2), 25.4, 19.5.