Total synthesis of macrosphelide A by way of palladium-catalyzed carbonylative esterification

Article abstract of DOI:10.1016/j.tetlet.2003.09.186

We achieved the total synthesis of macrosphelide A, as part of a combinatorial library of its analogues. The key intermediate, the seco-acid derivative, was prepared from the corresponding vinyl iodide using sequential carbonylative esterification.

Full text of DOI:10.1016/j.tetlet.2003.09.186

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 8857–8859
Total synthesis of macrosphelide A by way of
palladium-catalyzed carbonylative esterification
Shin-ichi Kusaka, Suguru Dohi, Takayuki Doi and Takashi Takahashi*
Department of Applied Chemistry, Tokyo Institute of Technology, 2-12-1, Ookayama, Meguro, Tokyo 152-8552, Japan
Received 31 July 2003; revised 3 September 2003; accepted 22 September 2003
Abstract—We achieved the total synthesis of macrosphelide A, as part of a combinatorial library of its analogues. The key
intermediate, the seco-acid derivative, was prepared from the corresponding vinyl iodide using sequential carbonylative
esterification.
© 2003 Elsevier Ltd. All rights reserved.
Macrosphelide A–L are a family of compounds isolated
from two different culture medium of Macrospaeropsis
sp. FO-5050 and/or pericania byssoides by the Omura1
and Numata2 groups. Macrosphelides are 16-membered
macrolides including three ester linkages consisting of
one b-hydroxybutyric acid and two 5-hydroxy-2-
hexenoic acid units and strongly inhibit the adhesion of
human leukemia HL-60 cells to human-umbilical-vein
endothelial cell (HUVEC) in dose-dependent fashion.1–4
In order to prepare a variety of their analogues, a
simple synthetic method is required.3,5–7 As a part of
the synthesis of a macrosphelide library, we wish to
report the total synthesis macrosphelide A via sequen-
tial carbonylative esterification.
through macrolactonization of seco-acid derivative 2.
Compound 2 can be prepared from 3 and 46c by
applying alkoxycarbonylation8,9 as the key reaction.
Since palladium-catalyzed carbonylative esterification
of vinyl halides can be regarded as the synthetic equiv-
alent of the formation of an a,b-unsaturated ester, we
designed the vinyl iodide 3 as a masked activated ester
for this synthesis which can be repeatedly utilized in the
formation of remaining two ester linkages in 1.
The (E)-vinyl iodide 3 was prepared from commercially
available methyl (S)-lactate 5, which was converted into
the ynone 6 in three steps. Chelate-controlled reduction
with dimethylaluminium chloride10 provided the ery-
thro-alcohol
7 with the required stereochemistry
An outline of the synthetic strategy is described in
Scheme 1. The target molecule 1 would be synthesized
(>95%). Deprotection of the TMS group and subsequent
protection as the methoxyethoxymethyl ether gave
Scheme 1. Retrosynthetic analysis of macrosphelide A (1). MEM=methoxyethoxymethyl, TBS=tert-butyldimethylsilyl, Tce=
2,2,2-trichloroethyl.
Keywords: macrolactone; palladium catalyst; carbonylation; natural product synthesis.
* Corresponding author. Tel.: +81-3-5734-2120; fax: +81-3-5734-2884; e-mail: ttak@apc.titech.ac.jp
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2003.09.186

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S. Kusaka et al. / Tetrahedron Letters 44 (2003) 8857–8859
Desilylation of 10 produced alcohol 11 in 82% yield.
Palladium-catalyzed carbonylative esterification of 11
was accomplished under the above conditions except
using excess amount of vinyl iodide 3 (5 equiv) to
provide 12 in 78% yield. Deprotection of the TBS and
Tce groups furnished the key intermediate 13 (49%).
Macrolactonization of 13 under various conditions (i.e.
Yamaguchi,13a Keck,13b and Mitsunobu13c method)
yielded recovered starting material or the undesired
12-membered lactone that was formed via b-elimination
Scheme 2. Synthesis of (E)-vinyl iodide 3. (a) TBSCl, imida-
zole, CH2Cl2, rt, 6 h; (b) Me(OMe)NH·HCl, i-PrMgCl, THF,
0°C, 30 min; (c) trimethylsilyl acetylene, BuLi, THF, −78°C,
30 min; (d) Me2AlCl, Bu3SnH, CH2Cl2, −78°C, 1 h; (e)
MEMCl, i-Pr2NEt, rt, 1.5 h; (f) K2CO3, MeOH–H2O, rt, 24
h; (g) PdCl2(PPh3)2, Bu3SnH, THF, 0°C, 30 min; (h) NIS,
THF, 0°C to rt, 10 min.
alkyne 8. Treatment of 8 with tributyltinhydride in the
presence of a catalytic amount PdCl2(PPh3)2 afforded
the vinyl stannane11 which was converted to the corre-
sponding vinyl iodide with N-iodosuccinimide to afford
vinyl iodide 3 in 55% overall yield (Scheme 2).
Protection of methyl (S)-3-hydroxybutyrate 9 as its
TBS ether, transformation of the methyl ester to the
2,2,2-trichloroester, followed by desilylation generated
the second building block 4. With the desired vinyl
iodide 3 and alcohol 4 in hand, we next focused our
attention to the palladium-catalyzed carbonylative
esterification. The alkoxy carbonylation between 3 and
4 under the standard reaction conditions (Pd(PPh3)4,
CO 30 atm, NEt3, DMAP, DMF) provided moderate
conversion and produced the homo dimer of 3 and the
a,b-unsaturated carboxylic acid as a b-elimination
product via the desired ester 10 (Entry 1). Conse-
quently, the carbonylation reaction was extensively
optimized and the results are summarized in Table 1.
The best result was obtained using PdCl2(MeCN)2, as a
palladium catalyst, giving the desired ester 10 as the
sole product in 87% yield (Entry 6).12
Scheme 3. Total synthesis of macrosphelide A (1) by car-
bonylation and macrolactonization. (a) TBSCl, imidazole,
CH2Cl2, rt, 3 h; (b) 1 M NaOH in MeOH, rt, 12 h; (c)
2,2,2-trichloroethanol, DIC, DMAP, CH2Cl2, rt, 5 h; (d)
HF·pyridine, CH3CN, rt, 12 h; (e) TBAF, AcOH, CH2Cl2, rt,
24 h; (f) CO(30 atm), PdCl2(MeCN)2, Et3N, DMAP, DMF,
rt, 12 h; (g) AcOH–H2O–THF (1:1:3), rt, 48 h; (h) Zn dust,
NH4OAc, THF–H2O (3:1), rt, 2 h; (i) 2,2%-dipyridyl disulfide,
PPh3, toluene, rt, 1 h; AgOTf, rt, 30 min; (j) TFA, CH2Cl2. 6
h, rt; DIC=N,N-diisopropylcarbodiimide, DMAP=4-(di-
methylamino)pyridine, DMF=N,N-dimethylformamide, Tf=
trifluoromethanesulfonyl, TFA=trifluoroacetic acid.
Table 1. Palladium-catalyzed carbonylation between vinyl iodide 3 and alcohol 4a
Entry
Catalyst
3:4
DMAP (equiv.)
Temp. (°C)
Yield of 10b (%)
1
2
3
4
5
6
7
Pd(PPh3)4
Pd(PPh3)4
1:3
1:3
1:3
1:3
1:3
1:3
3:1
1.0
None
1.0
1.0
1.0
60
60
60
60
rt
57
0
PdCl2(PPh3)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
PdCl2(MeCN)2
60
72
81
87
37
0.1
0.1
rt
rt
a Reaction was performed on a 0.5 mmol scale in DMF using 10 mol% Pd-catalyst in the presence of triethylamine for 6 h under 30 atm of carbon
monoxide.
b Isolated yield after silica-gel column chromatography

S. Kusaka et al. / Tetrahedron Letters 44 (2003) 8857–8859
8859
of b-alkoxyester followed by cyclization. The
Mukaiyama–Corey method14 (2,2%-dipyridyl disulfide,
PPh3), provided the desired lactone 14, however in
disappointingly low yield. Extensive optimization of the
Mukaiyama method increased the yield of the desired
lactone 14 up to 40%. Addition of Ag-salt was crucial
to activate the pyridinium thioester intermediate.14
Finally, deprotection of the MEM group with TFA in
CH2Cl2 furnished 1 in 92% yield. The synthetic 1
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1
exhibited H and 13C NMR spectral data as well as
optical rotation identical to those published for the
natural product1b (Scheme 3).
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In summary, the total synthesis of macrosphelide A has
been achieved with a highly convergent and efficient
strategy. Further refinement of the synthetic scheme
toward the synthesis of combinatorial library of its
analogues will be reported.
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Acknowledgements
This work was supported by a Grant-In-Aid from the
Ministry of Education, Culture, Sports, Science and
Technology, Japan (No. 14103013). We also thank
Professors Satoshi Omura and Toshiaki Sunazuka
(Kitasato University, Japan) for fruitful discussion.
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To a solution of vinyl iodide (0.50 mmol) and alcohol
(1.50 mmol) in DMF (5.0 ml) was added Et3N (0.55
mmol), DMAP (0.05 mmol), and PdCl2(MeCN)2 (0.05
mmol) under an argon. The vessel was placed in an
autoclave, which was purged with CO three times before
applying a pressure of 30 atm. After stirring at room
temperature for 6 h, the catalyst was deposited through a
short florisil plug. The filtrate was partitioned between
EtOAc and 1 M HCl. The organic layer was washed with
saturated aqueous NaHCO3 and brine, dried over
MgSO4, and concentrated in vacuo. Column chromatog-
raphy on silica gel afforded the product.
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