Synthesis of aplyolide A, ichthyotoxic macrolide isolated from the skin of the marine mollusk Aplysia depilans

Article abstract of DOI:10.1055/s-2001-18749

A convergent pathway is described for the synthesis of (S)-aplyolide A (1) using ethyl (S)-lactate as chiral source. Key steps of the synthesis are two couplings between copper(I) alkynides and propargylic halides for the formation of skipped diyne systems and were performed with an improved procedure based on the use of cesium carbonate as base for alkynide preparation.

Full text of DOI:10.1055/s-2001-18749

LETTER
1971
Synthesis of Aplyolide A, Ichthyotoxic Macrolide Isolated from the Skin of the
Marine Mollusk Aplysia depilans
Synthesis of
A
plyo
l
lide
A
do Spinella,* Tonino Caruso, Marco Martino, Carmine Sessa
Dipartimento di Chimica, Università di Salerno, Via S. Allende, 84081 Baronissi (Salerno), Italy
Fax +39(89)965296; E-mail: spinella@unisa.it
Received 14 September 2001
Dedicated to the memory of Professor G. Sodano
O
Abstract: A convergent pathway is described for the synthesis of
(S)-aplyolide A (1) using ethyl (S)-lactate as chiral source. Key
steps of the synthesis are two couplings between copper(I)
alkynides and propargylic halides for the formation of skipped
diyne systems and were performed with an improved procedure
based on the use of cesium carbonate as base for alkynide prepara-
tion.
O
Aplyolide A (1)
Key word: aplyolide A, natural product, macrocycles, total synthe-
sis, alkynes
O
TBDMSO
CH3O
Aplyolide A (1) belongs to a group of lactonized hydroxy
fatty acids recently isolated from the skin of the marine
mollusk Aplysia depilans.1 These compounds are strongly
suspected to play a role as allomones in the chemical
defense2 of these mollusks because of both their ichthyo-
toxicity and their exclusive location on the external part of
the animal skin. Aplyolides should also possess other bio-
logical activities which might be of useful application in
medicine owing their structural similarities with other
bioactive compounds.3 However, these potential bioactiv-
ities are still undetected because the paucity of material
obtained from the natural source has precluded further in-
vestigation. We therefore have recently been engaged
with the development of a synthetic process which would
make these compounds readily available for biological
evaluation. Reported herein is a convergent and stereo-
controlled synthesis of (S)-aplyolide A (1).
2
O
TBDMSO
CH3O
Br
3
4
HO
HO
OEt
Cl
O
5
6
Scheme 1
Retrosynthetic analysis for 1 (Scheme 1) revealed that the
enetriyne 2 could be a good precursor for the Z,Z,Z,Z
skipped tetraene moiety of the hydroxy tetraunsaturated
droxy group, can provide the needed propargylic halide 3
for the second coupling required in order to obtain 2.
acid obtained after opening of the lactone. Further discon- (S)-(tert-Butyldimethylsilyloxy)-2-hepten-6-yne (4) was
nection of 2 gives two fragments 3 and 4 whose discon- synthesized by Wittig reaction of aldehyde 8 with phos-
nections lead to easily available starting materials. In fact, phonium salt 11 as outlined in Scheme 2. The first step
4 can be prepared from cheap chiral template ethyl (S)- was the protection of the ethyl (S)-lactate (6) with the t-
lactate (6) while 3 can be obtained by coupling an alkyne butyl-dimethylchlorosilane (TBDMS-Cl) to give 2-(tert-
with a propargylic halide such as chlorobutynol (5).4a butyl-dimethyl-silyloxy)-propionic acid ethyl ester 7.5
Central to the approach is the formation of skipped diynes Reduction of 7 with diisobutylaluminium hydride
by coupling of propargylic halides and alkynes. In this (DIBALH) in dichloromethane at –78 °C gave the alde-
frame, a bifunctional compound such as 5 is particularly hyde 8 in 88% yield [ [ ]22 –6.30 (c = 12.5, 95% etha-
D
useful4b because, in the first coupling, it leads to a product nol); lit.6 [ ]21 –6.13 (c = 1, 95% ethanol)]. But-3-ynyl-
D
which, after functional group transformation of the hy- triphenyl-phosphonium bromide (11)7 was prepared start-
ing from 3-butynol (9) in three steps: conversion into the
corresponding tosylate 10 which was subjected to reaction
with NaBr in order to obtain a bromide whose reaction
with PPh3 afforded 11 (62%, three steps yield). With the
two required reagents in hand, the Wittig reaction was car-
Synlett 2001, No. 12, 30 11 2001. Article Identifier:
1437-2096,E;2001,0,12,1971,1973,ftx,en;G15201ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

1972
A. Spinella et al.
LETTER
Table Skipped Diyne Formation by Coupling Reactions between
Copper(I) Alkynides and Propargylic Halides
RO
TBDMSO
b
O
OEt
O
Entry
Alkyne
Propargyl halide
Carbonate
K2CO3
Yield (%)
6 R=H
7 R=TBDMS
f
8
a
1
2
3
4
12
4
5
3
5
3
85
42
95
68
4
K2CO3
d,e
PPh3
12
4
Cs2CO3
Cs2CO3
R
Br
9 R=OH
c
11
10 R=OTs
Scheme 2 (a) TBDMS-Cl, imidazole, CH2Cl2, (100%). (b) DI-
BALH, CH2Cl2, –78 °C, (88%). (c) p-TsCl, pyridine, CH2Cl2, 0 °C,
(100%). (d) NaBr, CH3CN. (e) PPh3, CH3CN, 60 °C, (62% overall
from 9). (f) 11, n-BuLi, THF, 0 °C, then addn. 8 in THF, then 60 °C,
2 h (80%).
Finally, compound 215 upon careful semi-hydrogenation
over Lindlar catalyst16 gave the corresponding all cis tet-
raene 1417 (Scheme 3). After removal of the t-butyl-dime-
thylsilyl group with pyridine p-toluenesulfonate (PPTS),18
the hydroxy ester 15 obtained was subjected to hydrolysis
with LiOH19 affording the hydroxyacid 16. Finally, mac-
ried out affording the required Z alkene 48 as the sole rolactonization according to Yamaguchi’s procedure20
product in 80% yield.
gave aplyolide A (1) in 71% yield (Scheme 3).21
The following crucial steps of the planned synthesis were The [ ]25 value (–58.5; c = 0.2, CHCl3) and the other
D
two coupling reactions between a terminal alkyne and a spectral data (1H NMR, 13C NMR, IR and MS) of synthet-
propargylic halide for the preparation of 2. In fact, 13 ic 1 were in agreement with those of the natural product.1
(Scheme 3) was planned to derive from coupling of 12
and 5 while a second similar coupling was envisioned for
the formation of 2 by reaction of 4 and the propargylic
bromide 39 obtained from 13. It is well known that these
O
coupling reactions are generally complicated by some
5
H3CO
H3CO
side reactions when a Group I alkynide is used, while cop-
per(I) alkynides proved to give better results and several
methods have been proposed using preformed or in situ
generated copper(I) alkynides.10 Furthermore, in our case
the reaction must be performed under conditions highly
tolerant of a sensitive group such as the ester functional-
ity. Initially, we used the methodology described by Jef-
fery and co-workers11 in which a carbonate is used to
produce the alkynide under phase transfer conditions but
an unsatisfactory result was obtained for the coupling of
the alkyne 12 with chlorobutynol (5) (46% yield). There-
fore we turned to the procedure proposed by Lapitskaya et
al.12 in which K2CO3 is used as base and NaI is added in
order to convert the propargylic halide into the more reac-
tive iodide in the reaction mixture. However, the yields
obtained were quite acceptable (Table; entries 1 and 2)
only for the first coupling so a further improvement was
needed to make also the second coupling fully satisfacto-
ry.
12
a
O
R
13 R=OH
3 R=Br
b
O
c
TBDMSO
H3CO
2
d
O
OTBDMS
OH
H3CO
14
e
O
RO
We focused our attention on the kind of carbonate used as
base. In fact, it is well known that among the alkali metal
cations present in carbonates cesium plays a prominent
role in solving synthetic problems.13 Many reactions in
which a carbonate is used as base, take advantage of a “ce-
sium effect” mainly due to the higher solubility in organic
solvent14 and appropriate basicity of this carbonate. Ex-
perimental results showed the improvement that we ex-
pected making these reactions fully applicable to our
multistep synthesis devoted to the construction of the
skipped polyyne (Table; entries 3 and 4).
15 R=CH3
16 R=H
f
g
1
Scheme 3 (a) Cs2CO3, NaI, CuI, DMF, 20 h (95%). (b) CBr4, PPh3,
CH2Cl2, 0 °C (90%). (c) 4, Cs2CO3, NaI, CuI, DMF, 20 h (68%). (d)
1 Atm H2, Pd–CaCO3, (Lindlar), EtOH (54%). (e) PPTS, EtOH 95%
(100%). (f) LiOH, DME–H2O, (100%). (g) 2,4,6-trichlorobenzoyl
chloride, Et3N; 4-DMAP, toluene, reflux (71%).
Synlett 2001, No. 12, 1971–1973 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of Aplyolide A
1973
(10) (a) Brandsma, L. Preparative Acetylene Chemistry, 2nd ed.;
Elsevier: Amsterdam, 1998. (b) Furber, M. In
In conclusion, the stereo and enantioselective total synthe-
sis of aplyolide A (1) has been described which confirms
the S stereochemistry of the natural product.22 The starting
material, used as chiral source, is the relatively unexpen-
sive ethyl (S)-lactate. The synthesis is convergent and re-
quires only 10 steps from either 9 or 6. A particularly
valuable feature of the synthesis was the development and
the use of an improved methodology of coupling between
Cu(I) alkynide and propargylic halides. An investigation
on the biological activity of aplyolide A is now in progress
and the results will be given in due course.
Comprehensive Organic Functional Group
Transformations, Vol. 1; Katritzky, A. R.; Meth-Cohn, O.;
Rees, C. W., Eds.; Pergamon: London, 1995, Chap. 1.21,
1000.
(11) Jeffery, T.; Gueugnot, S.; Linstrumelle, G. Tetrahedron Lett.
1992, 33, 5757.
(12) Pivnistky, K. K.; Lapitskaya, M. A.; Vasijeva, L. L.
Synthesis 1993, 65.
(13) Flessner, T.; Doye, S. J. Prakt. Chem. 1999, 341, 186.
(14) Cella, J. A.; Bacon, S. W. J. Org. Chem. 1984, 49, 1122.
(15) Compound 2: [ ]22D = +12.0 (c = 1.17, CHCl3); FTIR
(cm–1): 1734. 1H NMR (400 MHz, CDCl3): = 5.47 (1 H,
bdd, J = 10.9, 7.5 Hz), 5.32 (1 H, dt, J = 10.9, 7.0 Hz), 4.58
(1 H, dq, J = 7.5, 6.2 Hz), 3.70 (3 H, s), 3.11 (4 H, m), 2.92
(2 H, bd, J = 7.0 Hz), 2.50 (4 H, m), 1.19 (3 H, d, J = 6.2 Hz),
0.91 (9 H, s), 0.05 (3 H, s), 0.04 (3 H, s). 13C NMR (100
MHz, CDCl3): = 172.4 (s), 136.7 (d), 122.3 (d), 78.6 (s),
78.4 (s), 74.7 (s, 2C), 74.6 (s), 74.0 (s), 64.9 (d), 51.7 (q),
33.3 (t), 25.8 (q, 3 C), 24.5 (q), 18.1 (s), 17.4 (t), 14.7 (t), 9.7
(t, 2 C), –5.0 (q), –5.2 (q). MS (EI) m/z (%) = 386 (3.8), 329
(5), 255 (4), 226 (9.5), 159 (67), 131 (83), 115 (100). Anal.
Calcd for C23H34O3Si: C, 71.46; H, 8.86. Found: C, 71.34; H,
8.68.
Acknowledgement
We gratefully acknowledge Prof. G. Sodano for his review of the
manuscript. This research was assisted financially by the MURST
(PRIN “Chimica dei Composti Organici di Interesse Biologico”).
References
(1) Spinella, A.; Zubia, E.; Martinez, E.; Ortea, J.; Cimino, G. J.
Org. Chem. 1997, 62, 5471.
(2) Faulkner, D. J. Chemical Defenses of Marine Molluscs, In
Ecological Roles of Marines Natural Products; Paul, V. J.,
Ed.; Cornell University Press: Ithaca, 1992, 119.
(3) Gerwick, W. H. Chem. Rev. 1993, 93, 1807.
(4) (a) Chlorobutynol was prepared by hydroxymethylation of
propargyl chloride using a procedure according to: Schaap,
A.; Brandsma, L.; Arens, J. L. Recl. Trav. Chim. Pays-Bas
1965, 84, 1200. (b) Durand, S.; Parrain, J. L.; Santelli, M.
Synthesis 1998, 1015.
(5) Coppola, G. M.; Schuster, H. F. -Hydroxy Acids in
Enantioselective Syntheses; VCH: Weinheim, 1997, Chap.
1, 1.
(6) Massad, S. K.; Hawkins, L. D.; Baker, D. C. J. Org. Chem.
1983, 48, 5180.
(16) Huang, W.; Pulaski, S. P.; Meinwald, J. J. Org. Chem. 1983,
48, 2270.
(17) Compound 14: [ ]22D = +23.0 (c = 1.3, CHCl3); FTIR
(cm–1): 1740. 1H NMR (400 MHz, CDCl3): = 5.43–5.34 (7
H, m), 5.26 (1 H, m), 4.63 (1 H, dq, J = 6.3, 7.2 Hz), 3.67 (3
H, s), 2.82 (6 H, m), 2.38 (4 H, m), 1.19 (3 H, d, J = 6.3Hz),
0.87 (9 H, s), 0.05 (3 H, s), 0.04 (3 H, s). 13C NMR (100
MHz, CDCl3): = 173.5 (s), 135.7 (d), 129.3 (d), 128.3 (d),
128.2 (d), 128.1 (d), 127.9 (d, 2 C), 125.8 (d), 65.1 (d), 51.6
(q), 34.0 (t), 25.9 (t), 25.8 (q, 3C), 25.6 (t), 25.5 (t), 24.8 (q),
22.8 (t), 18.2 (s), –4.5 (q), –4.7 (q). EIMS (EI): m/z (%) =
392(9)359(19), 335(100), 303(91), 261(15), 239(51),
206(58), 185(24), 131(72), 75(25), 57(19). Anal. Calcd for
C23H40O3Si: C, 70.35; H, 10.27. Found: C, 70.18; H, 10.47.
(18) Prakash, C.; Saleh, S.; Blair, I. A. Tetrahedron Lett. 1989,
30, 19.
(7) Dharanipragada, R.; Fodor, G. J. Chem. Soc., Perkin
Trans. 1 1986, 545.
(8) Compound 4: [ ]22D = +22.8 (c = 1.7, CHCl3); FTIR (cm–1):
3313, 1086. 1H NMR (400 MHz, CDCl3): = 5.50 (1 H, ddt,
J = 10.9 Hz, J = 7.6 Hz, J = 1.6 Hz), 5.33 (1 H, dt, J = 10.9
Hz, J = 7 Hz), 4.59 (1 H, dq, J = 7.6 Hz, J = 6.3 Hz), 2.96 (2
H, ddd, J = 7 Hz, J = 2.8 Hz, J = 1.6 Hz), 1.98 (1 H, t, J = 2.8
Hz), 1.20 (3 H, d, J = 6.3 Hz), 0.88 (9 H, s), 0.06 (3 H, s),
0.05 (3 H, s). 13C NMR (100 MHz, CDCl3): = 137.1 (d),
121.7 (d), 82.1 (s), 68.4 (d), 64.8 (d), 25.8 (q, 3 C), 24.4 (q),
18.1 (s), 17.1 (t), –4.6 (q), –4.8 (q). MS (EI): m/z (%) =
224(2), 223(4), 183(38), 167(11), 131(42), 93(27), 75(100),
57(49). Anal. Calcd for C13H24OSi: C, 69.58; H, 10.78.
Found: C, 69.63; H, 10.97.
(19) Yeola, S. N.; Saleh, S. A.; Brash, A. R.; Prakash, C.; Taber,
D. F.; Blair, I. A. J. Org. Chem. 1996, 61, 838.
(20) Yamaguchi, M.; Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki,
T. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
(21) Macrolactonization procedure: 2,4,6-Trichlorobenzoyl
chloride (0.28 mmol) was added to a mixture of 16 (0.28
mmol) and triethylamine (0.32 mmol) in dry THF (2.8 mL).
The mixture was stirred for 3 h at r.t. After removal by
filtration of triethylamine hydrochloride, the filtrate was
diluted with dry toluene (140 mL) and added dropwise to a
refluxing solution of 4-(dimethylamino)pyridine (DMAP)
(1.68 mmol) in toluene (28 mL) over a period of 2 h. After
refluxing for 12 h, the solution was cooled, diluted with
ether, then washed successively with 3 N HCl, water, sat. aq
NaHCO3 solution and water, dried (Na2SO4), filtered and
concentrated. Flash chromatography on silica gel (Et2O/
petroleum ether 2:98) provided 1 (49 mg, 71%).
(22) Vidar, T. V.; Stenstrom, Y. Tetrahedron: Asymmetry 2001,
12, 1407. During the submission of this manuscript we
learned of a recent independent synthesis of aplyolide A
which also confirms the stereo-chemistry of the natural
product. However, a commercial chiral template by far more
expensive than ethyl (S)-lactate was used in this synthesis.
(9) Compound 3: FTIR (cm–1): 1735. 1H NMR (400 MHz,
CDCl3): = 3.90 (2 H, t, J = 2.1 Hz), 3.70 (3 H, s), 3.19 (2
H, t, J = 2.1 Hz), 2.50–2.48 (4 H, m). 13C NMR (100 MHz,
CDCl3): = 172.2 (s), 81.5 (s), 79.1 (s), 75.3 (s), 73.7 (s),
51.6 (q), 33.1 (t), 14.6 (t), 14.4 (t), 9.9 (t). MS (EI): m/z (%)
= 244 (5.6), 242 (5.4), 229 (42), 227 (39), 213 (40), 211 (40),
185 (38), 183 (37), 171 (57), 169 (56), 163(100). Anal.
Calcd for C10H11BrO2: C, 49.41; H, 4.56. Found: C, 49.47;
H, 4.74.
Synlett 2001, No. 12, 1971–1973 ISSN 0936-5214 © Thieme Stuttgart · New York