First total synthesis of natural aplyolides B and D, ichthyotoxic macrolides isolated from the skin of the marine mollusk Aplysia depilans

Article abstract of DOI:10.1016/S0040-4039(02)00117-X

A convergent pathway is described for the synthesis of the marine macrolides aplyolides B (2) and D (3). Stereoselective preparation of a key fragment was achieved by Sharpless asymmetric dihydroxylation of eneyne 10.

Full text of DOI:10.1016/S0040-4039(02)00117-X

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 43 (2002) 1681–1683
First total synthesis of natural aplyolides B and D, ichthyotoxic
macrolides isolated from the skin of the marine mollusk
Aplysia depilans†
Aldo Spinella,* Tonino Caruso and Carmine Coluccini
Dipartimento di Chimica, Universita` di Salerno, Via S. Allende, 84081 Baronissi, Salerno, Italy
Received 21 December 2001; revised 10 January 2002; accepted 16 January 2002
Abstract—A convergent pathway is described for the synthesis of the marine macrolides aplyolides B (2) and D (3). Stereoselective
preparation of a key fragment was achieved by Sharpless asymmetric dihydroxylation of eneyne 10. © 2002 Elsevier Science Ltd.
All rights reserved.
Marine organisms have been proven to be a unique
source of novel and diverse bioactive compounds.1
Aplyolides, e.g. 1–3, are lactonized hydroxy fatty acids
recently isolated from the skin of the marine mollusk
Aplysia depilans, during a study on chemical aspects of
the ecology of marine organisms.2 These compounds
displayed potent ichthyotoxicity and are probably
involved in the defence strategy of the mollusc involv-
ing organic molecules (chemical defence).3 However,
aplyolides are intriguing synthetic targets also because
of their structure related to some others bioactive lac-
tonized fatty acids from marine source4 and their
preparation will provide enough material for an investi-
gation of their biological activities. Recently, two syn-
thetic routes have been reported for aplyolide A (1);5,6
in this communication we present the first stereocon-
trolled total synthesis of natural aplyolides B (2) and D
(3).
and C-16 of the same precursor, (S,S)-15,16-dihydroxy-
octadeca-9(Z),12(Z)-dienoic acid (4). A convergent way
for the synthesis of both 2 and 3 was planned starting
from easily available materials. Our retrosyntetic plan is
shown in Scheme 1. Dihydroxyacid 4 could be prepared
by diyne 5 which should be readily obtainable by
coupling the propargylic bromide
6 and methyl
decinoate (7). Compound 6 would be available after
Sharpless asymmetric dihydroxylation of an appropri-
ate eneine precursor.
The synthesis of 6 (Scheme 2) began with a coupling
reaction between trans 2-bromo-1-pentene (8) and
methyl propiolate (9). This reaction was carried out
using a recent methodology which forms in situ Cu(I)
alkynide as nucleofile.6,7 The reaction gave eneyne 10
(86% yield) together with a small amount (10%) of
isomeric compound 11. Sharpless enantioselective
dihydroxylation8 of compound 10, using commercial
AD-mix-a reagent, afforded diol 12 with good yield
(95%) and satisfactory enantiomeric excess (85%).9
Aplyolides B (2) and D (3) are macrolides characterized
by the presence of two not conjugated double bonds.
They derive from the cyclization respectively at C-15
O
O
15
HO
15
16
16
O
O
OH
O
O
Aplyolide A (1)
Aplyolide D (3)
Aplyolide B (2)
* Corresponding author.
† Dedicated to the memory of Professor G. Sodano.
0040-4039/02/$ - see front matter © 2002 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)00117-X

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A. Spinella et al. / Tetrahedron Letters 43 (2002) 1681–1683
OH
( or 3)
COOCH3
4
OH
OH
COOCH3
OH
5
OH
Br
COOCH3
OH
Scheme 1. Retrosynthetic analysis of 2 and 3.
O
O
O
OCH3
a
OCH3
Br
COOCH3
11
10
9
8
O
O
OH
O
x
OCH3
OCH3
c
b
d
10
O
OH
O
13
12
14 X= OH
X= Br
e
6
Scheme 2. Reagents and conditions: (a) Cs2CO3, CuI, NaI, DMF, 20 h, 86% of 10; (b) AD-mix-a, t-BuOH–H2O 1:1, CH3SO2NH2,
0°C, 20 h, 95%, e.e. 85%; (c) 2,2-DMP, PPTS, 24 h, 99%; (d) DIBAL, Et2O dry, 0°C, 3 h, 85%; (e) CBr4, PPh3 dry, CH2Cl2 dry,
0°C, 20 h, 85%.
Protection of diol 12 as an acetonide, followed by
reduction of the ester functionality with diisobutylalu-
minium hydride (DIBAL), furnished alcohol 14 (84%
two-step yield). The preparation of bromide 6 was
completed by treatment of 14 with CBr4 and Ph3P.
by treatment of pyridinium p-toluenesulfonate (PPTS) in
methanol. This allowed us to obtain 5 with a 85% yield.
Final conversion to aplyolides B and D was achieved
upon sequential partial hydrogenation11 (Pd/BaSO4,
quinoline, 95% yield) of 5, saponification (LiOH 3N,
1,2-DME) of the obtained ester 19 and lactonization of
dihydroxyacid 4 using the Yamaguchi protocol.12 This
last step furnished a mixture of macrolides 2 and 3 in
2.5:1 ratio with a yield of 70%. Purification of the
obtained mixture (silica gel, Et2O–petroleum ether 9:1)
allowed the isolation of aplyolide B (2) and D (3) whose
spectroscopic data (1H NMR, 13C NMR, IR and MS)
were in complete agreement with those of the natural
products.13 The value of [h]D measured for synthetic
aplyolides B ([h]D24=−18; c=0.7; CHCl3) and D ([h]2D4=
+24; c=0.2; CHCl3) were in accordance to those reported
for the natural products (lit.2 2 [h]D25=−43; c=0.2; CHCl3
and 3 [h]2D5=+28; c=0.1; CHCl3).
The synthesis of the required coupling partner 7 is
presented in Scheme 3. Preparation of methyl dec-9-
ynoate (7) started submitting 3-decinol (15) to a ‘zipper’
reaction using NaH and 1,3-diaminopropane (DAP).10
This reaction led to dec-9-yn-1-ol (16) which was oxi-
dized with Jones reagent and esterified with MeOH under
sulfuric acid catalysis. Union of alkyne 7 and propargyl
bromide 6 (Scheme 4) was achieved, once again, via an
improved methodology set-up during the synthesis of
aplyolide A.6 In fact, the use of Cs2CO3 as a base for the
preparation of Cu(I) alkynide allowed the preparation of
diyne 18 in 86% yield. Deprotection of 18 was performed
OH
a
b
COOR
OH
15
16
17 R=H
c
7 R=CH3
Scheme 3. Reagents and conditions: (a) NaH, 1,3-DAP, 70°C, 20 h, 95%; (b) CrO3, CH3COCH3, H2SO4, H2O, 1 h, 95%; (c)
CH3OH, H2SO4, 70°C, 20 h, 95%.

A. Spinella et al. / Tetrahedron Letters 43 (2002) 1681–1683
1683
MURST (PRIN ‘Chimica dei Composti Organici di
Interesse Biologico’).
O
COOCH3
a
6
+ 7
18
O
b
c
References
OH
COOCH3
COOCH3
1. Faulkner, D. J. Nat. Prod. Rep. 2001, 18, 1 and references
cited therein.
2. Spinella, A.; Zubia, E.; Martinez, E.; Ortea, J.; Cimino,
G. J. Org. Chem. 1997, 62, 5471.
3. Faulkner, D. J. In Ecological Roles of Marines Natural
Products; Paul, V. J., Ed. Chemical defenses of marine
molluscs. Cornell University Press: Ithaca, NY, 1992; p.
119.
5
OH
OH
OH
19 R=CH3
4 R=H
d
e
4. Gerwick, W. H. Chem. Rev. 1993, 93, 1807.
5. Vidar, T. V.; Stenstrom, Y. Tetrahedron: Asymmetry
2001, 12, 1407.
aplyolide B (2)
aplyolide D (3)
6. Spinella, A.; Caruso, T.; Martino, M.; Sessa, C. Synlett
Scheme 4. Reagents and conditions: (a) Cs2CO3, CuI, NaI,
DMF, 20 h, 86%; (b) PPTS, MeOH, 50°C, 10 h, 85%; (c) H2,
Pd/BaSO4, quinoline, MeOH, 3 h, 95%; (d) LiOH 3N, 1,2-
DME, 30 min, 99%; (e) 2,4,6-TBCl, THF dry, 3 h; 4-DMAP,
toluene dry, 20 h, 50% of 2 and 20% of 3.
2001, 1971.
7. Pivnistky, K. K.; Lapitskaya, M. A.; Vasijeva, L. L.
Synthesis 1993, 65.
8. Sharpless, K. B.; Amberg, W.; Bennani, Y. L.; Crispino,
G. A.; Hartung, J.; Joeng, K. S.; Kwong, H. L.;
Morikawa, K.; Wang, Z. M.; Xu, D.; Zhang, X.-L. J.
Org. Chem. 1992, 57, 2768.
9. When we submitted to Sharpless dihydroxylation also a
mixture of 10 and 11 in presence of methanesulfonamide
only 10 reacted while all alkene 11 was recovered at the
end of the reaction. The enantiomeric excess was calcu-
lated by analysis of the proton NMR spectra of the
Mosher esters obtained exposing diol 12 to (R)-a-
methoxy-a-trifluoromethylphenylacetyl chloride.
10. Macaulay, S. R. J. Org. Chem. 1980, 45, 734.
11. Cram, D. J.; Allinger, N. L. J. Am. Chem. Soc. 1956, 78,
2518.
In conclusion, a concise total synthesis of potent ichthy-
otoxic macrolides aplyolides B (2) and D (3) is presented.
The approach uses a Sharpless asymmetric dihydroxyla-
tion of the eneyne 10 to give the diol 12 and an efficient
methodology for coupling alkynes with propargylic
halides in key steps. This is also the first confirmation of
the absolute stereochemistry of aplyolides B and D.
An investigation on the biological activity of aplyolides
is now in progress and the results will be given in due
course.
12. Yamaguchi, M.; Inanaga, J.; Hirata, K.; Saeki, H.; Kat-
suki, T. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
13. All new compounds gave satisfactory spectral and analyt-
ical data. All yields are from material purified by column
chromatography.
Acknowledgements
This research was in part assisted financially by the