First total synthesis of natural aplyolides C and E, ichthyotoxic macrolides isolated from the skin of the marine mollusc Aplysia depilans

Article abstract of DOI:10.1016/S0957-4166(02)00575-X

A convergent pathway is described for the synthesis of the marine macrolides aplyolides C 4 and E 5. The key fragment 8 was prepared stereoselectively by Sharpless asymmetric dihydroxylation of eneyne 13.

Full text of DOI:10.1016/S0957-4166(02)00575-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 13 (2002) 2071–2073
First total synthesis of natural aplyolides C and E, ichthyotoxic
macrolides isolated from the skin of the marine mollusc Aplysia
depilans†
Tonino Caruso and Aldo Spinella*
Dipartimento di Chimica, Universita` di Salerno, Via S. Allende, 84081 Baronissi (Salerno), Italy
Received 22 July 2002; accepted 18 September 2002
Abstract—A convergent pathway is described for the synthesis of the marine macrolides aplyolides C 4 and E 5. The key fragment
8 was prepared stereoselectively by Sharpless asymmetric dihydroxylation of eneyne 13. © 2002 Elsevier Science Ltd. All rights
reserved.
Many macrocyclic compounds derived from natural
sources contain a lactone moiety in their structure.
These compounds have been the object of many studies
as a result of their remarkable biological properties.
Typical sources of macrolides are terrestrial organisms
but recently several members of this family have been
isolated from marine invertebrates.1,2 Aplysia depilans is
an opisthobranch mollusc scarcely predated despite its
significant size and its slow motion. Early studies on the
defensive strategy of this mollusc showed that some
compounds of dietary origin are stored in particular
glands and ejected when the marine organism is
molested.3 However, recently an investigation on sec-
ondary metabolites contained on the skin of A. depilans
has allowed the detection of some macrolides, aply-
olides A–E 1–5, whose ichthyotoxic activity together
with the particular location indicates that they play a
defensive role.4
and for aplyolides B 2 and D 3.7 Herein, we disclose a
synthetic strategy for the first enantioselective prepara-
tion of aplyolides C 4, and E 5.
Aplyolides 4 and 5 are macrolides containing three
unconjugated double bonds and differ from each other
by the size of the macrocycle, being, respectively, a 17-
and 16-membered lactone. (15S,16S)-15,16-Dihydroxy-
octadecyl-(6Z,9Z,12Z)-trienoic acid 6 is the common
seco-acid precursor of both macrolactones 4 and 5.
Consequently, retrosynthetic analysis of 6 offers a gen-
eral synthetic strategy suitable for the preparation of
both 4 and 5. A convergent route towards triyne 7,
which was envisaged as precursor of triene 6, was
devised through a simple disconnection of the two
bonds, as illustrated in Scheme 1.
We envisaged the introduction of the 15S,16S stereo-
chemistry by Sharpless asymmetric dihydroxylation
(AD) of an appropriate eneyne. The assembly of the
fragments 8, 9, 10 was planned by using an improved
methodology for the coupling of copper acetylide and
propargylic halides.
In order to evaluate their pharmacological and biologi-
cal activities, synthetic efforts have recently allowed
preparation of adequate quantities of some of these
compounds. In particular, synthetic approaches have
been developed for the preparation of aplyolide A 15,6
* Corresponding author.
† Dedicated to the memory of Professor G. Sodano.
0957-4166/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00575-X

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T. Caruso, A. Spinella / Tetrahedron: Asymmetry 13 (2002) 2071–2073
Scheme 1. Retrosynthetic analysis of 4 and 5.
The coupling of propargyl bromide 17 and the copper
acetylide derived from 8, in the presence of CuI and
Cs2CO3, gave an 88% yield of compound 7. Triene 6
was obtained by partial hydrogenation13,14 (Pd/BaSO4,
quinoline, 90% yield) of 7, followed by alkaline hydrol-
ysis using LiOH (Scheme 4).
The synthesis began with the coupling of trans-1-
bromo-2-pentene 11 and trimethylsilylacetylene 12,
which was conducted using a procedure recently
improved during the synthesis of aplyolides B and D.7
This reaction gave eneyne 13 (60% yield) together with
the isomeric compound 14. Sharpless enantioselective
dihydroxylation,8 using commercial AD-mix-a reagent,
provided the expected diol 15 in excellent yield (95%)
and good enantiomeric excess (85%).9,10
Finally, aplyolides C 4 and E 5 were obtained in a 1.7:1
ratio in 80% yield, by macrolactonization of dihydroxy
acid 6 using the Yamaguchi methodology.15 Purifica-
tion of the obtained mixture (silica gel, Et2O–petroleum
ether, 9:1) allowed the isolation of aplyolide C 4 and E
5 whose spectroscopic data (1H, 13C NMR, IR and MS)
were in complete agreement with those of the natural
products. The values of [h]D measured for synthetic
aplyolides C and E were in accordance to those
reported for the natural products confirming the abso-
lute stereochemistry assigned.16
Finally, compound 811 was prepared, in 99% yield, by
removal of the silyl group using TBAF (Scheme 2). The
planned synthetic scheme required, at this point, two
consecutive coupling reactions between a propargylic
halide and an acetylide. Recently, this reaction has been
the subject of several investigations and an improved
methodology involving copper acetylide, generated with
Cs2CO3 in the presence of CuI, was recently proposed
during our synthesis of aplyolide A 1.6 We applied this
methodology to our synthesis of aplyolides C and E
(Scheme 3) obtaining 1612 by coupling of 9 and 10 in
90% yield. Primary alcohol 16 was then converted into
bromide 17 by treatment with CBr4 and Ph3P (90%
yield).
In conclusion, we have accomplished the first total
synthesis of potent ichthyotoxic macrolides aplyolides
C 4 and E 5. The convergent approach uses a Sharpless
asymmetric dihydroxylation and an efficient methodol-
ogy for coupling alkynes with propargylic halides in
key steps.
Scheme 2. Reagents and conditions: (a) Cs2CO3, CuI, NaI, DMF, 20 h, 60% of 13 and 30% of 14; (b) AD-mix-a, t-BuOH–H2O
(1:1), CH3SO2NH2, 0°C, 5 h, 95%, e.e. 85%; (c) TBAF, THF dry, 30 min, 99%.
Scheme 3. Reagents and conditions: (a) Cs2CO3, CuI, NaI, DMF, 20 h, 90%; (b) CBr4, PPh3 dry, CH2Cl2 dry, 0°C, 1 h, 90%.

T. Caruso, A. Spinella / Tetrahedron: Asymmetry 13 (2002) 2071–2073
2073
Scheme 4. Reagents and conditions: (a) Cs2CO3, CuI, NaI, DMF, 20 h, 88%; (b) H2, Pd/BaSO4, quinoline, MeOH, 1 h, 90%; (c)
LiOH (3N), 1,2-DME, 30 min, 99%; (d) 2,4,6-TBCl, THF dry, 3 h; 4-DMAP, toluene dry, 20 h, 50% of 4 and 30% of 5.
An investigation into the biological activity of these
aplyolides is now in progress and the results will be
given in due course.
11. Compound 8: [h]1D5=−1.3 (c 5.2, CHCl3); 1H NMR
(400 MHz, CDCl3) l 3.65 (1H, ddd, J=6.5 Hz, J=5.6
Hz, J=4.2 Hz); 3.54 (1H, ddd, J=8.2 Hz, J=4.7 Hz,
J=4.2 Hz); 2.50 (1H, ddd, J=17.0 Hz, J=5.6 Hz, J=
2.7 Hz); 2.46 (1H, ddd, J=17.0 Hz, J=6.5 Hz, J=2.7
Hz); 2.06 (1H, t, J=2.7 Hz), 1.55 (2H, m); 1.0 (3H, t,
J=7.5 Hz). 13C NMR (100 MHz, CDCl3) l 80.7 (s);
74.3 (d); 71.7 (d); 70.6 (d); 26.3 (t); 23.9 (t); 9.9 (q).
Anal. calcd for C7H12O2: C, 65.60; H, 9.44. Found C,
65.43; H, 9.63%.
Acknowledgements
This research was in part assisted financially by the
MURST (PRIN ‘Chimica dei Composti Organici di
Interesse Biologico’).
12. Compound 16: 1H NMR (400 MHz, CDCl3) l 4.26
(2H, t, J=2.1 Hz); 3.67 (3H, s); 3.17 (2H, tt, J=2.1
Hz, J=2.4 Hz); 2.34 (2H, t, J=7.5 Hz); 2.19 (2H, tt,
J=7.5 Hz, J=2.4 Hz); 1.75 (2H, m); 1.56 (2H, m). 13C
NMR (100 MHz, CDCl3) l 174.1 (s); 80.2 (s); 78.8 (s);
78.5 (s); 73.9 (s); 51.5 (q); 50.8 (t); 33.4 (t); 27.8 (t);
23.9 (t); 18.2 (t); 9.6 (t). MS m/z: 208, 147, 131, 115,
91, 77.
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in accordance with those reported for the natural prod-
ucts (lit.4 4, [h]D25=−26.7; c=0.7; CHCl3 and 5 [h]2D5=
+46.3; c=0.3; CHCl3).