A Combinatorial Synthesis of a Macrosphelide Library Utilizing a Palladium-Catalyzed Carbonylation on a Polymer Support

Article abstract of DOI:10.1002/anie.200352229

Supported total synthesis: The combinatorial synthesis of a 122-membered macrosphelide library including macrosphelides A, C, E, and F (see picture) has been achieved based on a unique strategy for a three-component coupling utilizing a palladium-catalyzed chemoselective carbonylation and an unprecedented macrolactonization on a polymer support.

Full text of DOI:10.1002/anie.200352229

Communications
drug discovery and recently for the
construction of important chemical
probes for use in the fields of chem-
ical genetics, genomics, and proteo-
mics.[1–3] Therefore, it is necessary to
develop strategies for the high-speed
synthesis of natural-product libraries
that are more efficient than those
traditionally used for the synthesis of
a single final product.[4,5]
Figure 1. 1a: X=H,
Y=OH; 1b: X=Y=O.
Macrosphelides A (1a) and B (1b, Figure 1), isolated
from the culture medium of Macrospaeropsis sp. FO-5050 by
the Omura group,[6] strongly inhibit the adhesion of human
leukemia HL-60 cells to human-umbilical-vein endothelial
cells (HUVEC) in a dose-dependent fashion.[7] They have
received much attention as a lead compound for the develop-
ment of new anti-cancer drugs and although the total
A Macrosphelide Library
syntheses of macrosphelides have been reported,[8–11]
a
A Combinatorial Synthesis of a Macrosphelide
strategy for the high-speed synthesis of a variety of these
analogues is still required. Herein we report a highly
convergent synthesis of a library of macrosphelide analogues
on a solid support by utilizing a palladium-catalyzed chemo-
selective carbonylation of vinyl halides.
In considering an efficient strategy for the combinatorial
synthesis of macrosphelide analogues 2, we chose a solid-
phase synthesis utilizing the three synthetic building blocks A,
B, and C as illustrated in Scheme 1. The process involves:
1) attachment of the secondary alcohol in block A to a
Library Utilizing a Palladium-Catalyzed
Carbonylation on a Polymer Support**
Takashi Takahashi,* Shin-ichi Kusaka, Takayuki Doi,
¯
Toshiaki Sunazuka, and Satoshi Omura
The combinatorial synthesis of natural products is being
developed to explore the analogues of lead compounds for
Scheme 1. Strategy for a combinatorial synthesis of macrosphelide analogues 2.
polymer-support, 2) esterification with block B, 3) chemo-
[*] Prof. Dr. T. Takahashi, S.-i. Kusaka, Prof. Dr. T. Doi
Department of Applied Chemistry
Tokyo Institute of Technology
selective carbonylation[12] of the vinyl iodide in unit A with
alcohol C containing a vinyl bromide moiety, 4) carbonylative
macrolactonization[13] of the polymer-supported 3 by exploit-
ing the rather less reactive vinyl bromide unit, and 5) cleavage
from the polymer-support. We planned a 128-member natural
product-like library, consisting of blocks A (four), B (four),
and C (eight) summarized in Figure 2.
2-12-1 Ookayama, Meguro, Tokyo 152-8552 (Japan)
Fax: (+81)3-5734-2884
E-mail: ttak@apc.titech.ac.jp
¯
Prof. Dr. T. Sunazuka, Prof. Dr. S. Omura
The Kitasato Institute for Life Science, and
School of Pharmaceutical Science,
The preparation of the building blocks including the
various diastereomers of (E)-vinyl halides for blocks A and C
is shown in Scheme 2. Commercially available methyl (S)-
lactate 4 was converted into ynone (S)-5 in three steps. The
ynone 5 is a key intermediate to prepare a variety of vinyl
halides. Chelation-controlled reduction of 5 with Me2AlCl/
Bu3SnH provided 6 (> 95% selectivity),[14] while Felkin–Ahn
Kitasato University and The Kitasato Institute
Shirokane, Minatoku, Tokyo 108-8641 (Japan)
[**] This work was supported by a Grant-in-Aid from the Ministry of
Education, Culture, Sports, Science and Technology, Japan
(No. 14103013).
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
5230
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/anie.200352229
Angew. Chem. Int. Ed. 2003, 42, 5230 –5234

Angewandte
Chemie
Scheme 2. Preparation of the vinyl halides, the blocks A and C:
a) TBSCl, imidazole, CH2Cl2, RT, 6 h; b) Me(OMe)NH·HCl, iPrMgCl,
THF, 08C, 30 min; c) trimethylsilylacethylene, BuLi, ꢀ788C, THF, 2 h;
d) Me2AlCl, Bu3SnH, CH2Cl2, ꢀ788C, 3 h; e) l-selectride, THF, ꢀ788C,
1 h; f) Sc(OTf)3, CH(OMe)3, ethylene glycol, CH3CN, RT!608C, 24 h;
g) EVE, CSA, CH2Cl2, RT, 6 h; h) 5% KOH in MeOH, RT, 30 min;
i) PPTS, MeOH, RT, 3 h; j) [PdCl2(PPh3)2], Bu3SnH, THF, 08C, 1 h;
k) NIS, THF, 08C, 30 min; l) MEMCl, iPr2NEt, RT, 24 h; m) NBS, THF,
RT, 30 min; n) TBAF, THF, RT, 6 h; o) DIBAL-H, CH2Cl2, ꢀ788C,
30 min; p) SO3·Py, Et3N, CH2Cl2, RT, 2 h; q) CBr4, P P 3h, THF, 08C, 1 h;
r) BuLi, THF, ꢀ788C, 1 h; s) [PdCl2(MeCN)2], PCy3, Bu3SnH, THF, 08C,
2 h. TBSCl=chlorodimethyl-1,1-dimethylethyl silane, TMS=trimethylsi-
lane, Tf=trifluoromethanesulfonate, EVE=ethyl vinyl ether, CSA=
camphorsulfonic acid, PPTS=pyridinium p-toluenesulfonate, NIS=N-
iodosuccinimide, MEM=methoxyethoxymethyl, NBS=N-bromosucci-
nimide, TBAF=tetrabutylammonium fluoride, DIBAL-H=bis(2-methyl-
propyl)aluminium hydride, Py=pyridine.
Figure 2. The building blocks A, B, and C for the synthesis of a combi-
natorial library of macrosphelide analogues 2.
type reduction with l-selectride yielded 7 (> 95% selectiv-
ity).[15] Acetal formation of 5 with ethylene glycol afforded 8.
After removal of TMS, the alkyne was converted into the
desired (E)-vinyl halides A1 and A2 and C1–C3 by regiose-
lective hydrostannylation (cat. [PdCl2(PPh3)2]/Bu3SnH),[16]
followed by either iodination with NIS or bromination with
NBS. Their enantiomers A3 and A4 and C5–C7 were
prepared from methyl (R)-lactate 4 by the same method.
The vinyl bromides C4 and C8 were prepared from methyl
(S)- and (R)-3-hydroxybutyrates 9, respectively, through the
regioselective hydrostannylation of 10 (cat. [PdCl2(MeCN)2]/
PCy3/Bu3SnH), followed by bromination.
released the desired macrosphelide 1a in 68% purity.
Purification by preparative HPLC provided 1a in 38%
overall yield from 11 (7 steps). The synthetic 1a exhibited
1H and 13C NMR spectral data as well as optical rotation
identical to those published for the natural product.[6b,24]
On the basis of the above solid-phase strategy, we
constructed a macrosphelide combinatorial library utilizing
radiofrequency encoded combinatorial (REC) chemistry by a
split-and-pool method (Scheme 4).[4,25] The 128 microreactors
each containing 30 mg of PS-DHP resin 11 were encoded and
split into four flasks. After attachment of block A (A1–A4) to
the resin, the microreactors were pooled together for washing
and drying. After deprotection of the TBS group, the
microreactors were decoded and split, followed by esterifica-
tion with block B (B1–B4)[18] in separate flasks. The micro-
reactors were subsequently pooled for washing and drying.
The microreactors were again decoded and split, followed by
palladium-catalyzed carbonylative esterification of vinyl
iodides with block C (C1–C8) in separate autoclaves. The
microreactors were again pooled for washing and drying.
A solid-phase synthesis of 1a was initially investigated
(Scheme 3). The block A1 was attached to a PS-DHP resin 11
(0.96 mmolgꢀ1 PS = polystyrene, DHP = dihydropyran[17]
using PPTS. Selective deprotection of the TBS group with
TBAF and esterification of the polymer-supported alcohol 13
with acid B2[18] provided 14. Palladium-catalyzed carbon-
ylation of the vinyl iodide 14 with alcohol C1 was carried
out.[19] The reaction proceeded at room temperature under
30 atm of carbon monoxide utilizing [PdCl2(MeCN)2] as a
catalyst.[20,21] The product 15 was cleaved from the resin (0.1m
TsOH/MeOH, THF; Ts = 4-methylphenylsulfonyl) and its
purity was determined to be 71% by HPLC analysis. The
vinyl bromide moiety remained intact under the above
reaction conditions. The 4-methoxyphenylmethyl (MPM)
group in 15 was removed with DDQ to afford polymer-
supported cyclization precursor 16.[22] The palladium-cata-
lyzed carbonylation of 16 was achieved at 808C utilizing
[Pd2(dba)3]/dppf to provide macrolactone 17.[23] Finally, treat-
ment of 17 with 4n HCl in dioxane at room temperature
Angew. Chem. Int. Ed. 2003, 42, 5230 –5234
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ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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Communications
Scheme 4. A combinatorial synthesis of macrosphelide analogues 2
utilizing a split-and-pool method: Reagents and conditions a)–g) are
the same as shown in Scheme 3.
After removal of the MPM group, the palladium-catalyzed
carbonylative macrolactonization of vinyl bromides was
performed. Finally, the microreactors were decoded and
treated with acid in parallel for removal of the MPM group
and cleavage from the polymer support to afford crude 2.
Purification by preparative HPLC (silica gel) provided
122 macrosphelide analogues 2 (0.2–1.5mg) from 128 trials,
isolated in good purities (Table 1).[26,27]
We have demonstrated the combinatorial synthesis of a
natural product-like library based on macrosphelide. The
combinatorial synthesis of a 122-member macrosphelide
library including macrosphelides A, C, E, and F has been
achieved based on a unique strategy for a three-component
coupling utilizing a palladium-catalyzed chemoselective car-
bonylation and an unprecedented macrolactonization on a
polymer support.
Scheme 3. Solid-phase synthesis of macrosphelide A (1a): a) PPTS
(0.05m), CH2Cl2, RT, 24 h; b) TBAF (0.3m), THF, RT, 24 h; c) DIC
(0.1m), DMAP(0.001 m), CH2Cl2, RT, 24 h; d) [PdCl2(MeCN)2] (0.03m),
CO (30 atm), NEt3 (0.2m), DMAP(0.03 m), DMF, RT, 12 h; e) DDQ
(0.3m), aq.NaHCO3 (0.3m), CH2Cl2:H2O (1:1), RT, 5 h; f) [Pd2(dba)3]/
dppf (0.03m), CO (30 atm), NEt3 (0.2m), DMAP(0.03 m), DMF, 808C,
12 h; g) 4n HCl in dioxane, RT, 5 h; TBS=dimethyl-1,1-dimethylethyl
silane, DIC=diisopropylcarbodiimide, DMAP=(4-dimethylamino)pyri-
dine, DDQ=2,3-dichloro-5,6-dicyano-1,4-benzoquinone, dba=dibenzy-
lideneacetone, dppf=bis(diphenylphosphanyl)ferrocene.
Received: June 26, 2003 [Z52229]
Keywords: chemoselectivity · combinatorial chemistry ·
.
macrosphelides · palladium · solid-phase synthesis
Table 1: A combinatorial library of macrosphelide analogues 2.
Entry
A
B
C
Yield [mg][a]
Purity [%][b]
Rt [min][c]
Entry
A
B
C
Yield [mg][a]
Purity [%][b]
Rt [min][c]
1[d]
2
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
1.2
1.1
0.3
1.1
0.6
<0.1
0.5
0.3
0.5
1.3
1.3
0.8
0.5
0.5
1.3
0.3
0.8
0.7
0.7
0.6
0.3
<0.1
0.4
0.2
1.2
1.6
0.1
80
99
99
81
72
–
5.78
5.43
7.01
6.83
5.52
–
65
66
67
68
69
70
71
72
73
74
75
76
77
78
79
80
81
82
83
84
85
86
87
88
89
90
91
3
3
3
3
3
3
3
3
3
3
3
3
3
2
3
3
3
3
3
3
3
3
3
3
3
3
3
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
0.9
1.5
0.9
0.7
1.1
0.2
0.6
0.5
0.5
1.4
0.5
1.0
1.0
<0.1
0.9
0.5
0.6
1.6
0.5
1.7
1.2
0.5
0.7
0.4
1.2
1.5
0.8
99
98
95
97
97
78
96
88
88
65
77
86
91
–
95
82
99
95
73
88
81
82
84
59
99
94
70
5.67
5.79
7.10
6.94
5.97
5.43
7.16
7.14
5.61
5.31
6.89
6.74
5.70
–
7.02
6.82
5.99
5.81
7.22
7.05
6.11
5.90
7.34
7.19
5.64
5.55
6.98
3
4[e]
5
6
7
8
83
91
99
99
93
96
91
99
98
97
90
73
78
94
80
–
6.89
6.73
6.06
5.44
7.18
7.14
5.59
5.87
7.10
6.93
5.76
5.34
7.02
6.94
5.64
–
9[f]
10
11
12[g]
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
85
95
98
84
54
6.98
6.78
6.20
5.91
7.35
5232
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www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5230 –5234

Angewandte
Chemie
Table 1: (Continued)
Entry
A
B
C
Yield [mg][a]
Purity [%][b]
Rt [min][c]
Entry
A
B
C
Yield [mg][a]
Purity [%][b]
Rt [min][c]
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
61
62
63
64
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
2
4
4
4
4
4
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1.1
0.9
0.4
0.5
0.5
1.2
1.0
0.2
1.9
0.5
0.2
1.4
0.7
0.1
<0.1
0.4
1.5
0.1
0.5
0.4
0.3
0.6
0.7
0.7
1.8
0.2
0.4
0.2
0.3
0.6
0.8
0.5
0.5
0.2
<0.1
0.5
0.3
40
80
82
91
85
96
97
74
66
95
84
83
69
94
–
99
97
99
75
89
93
89
99
80
92
93
95
84
90
98
95
94
93
81
–
7.20
5.98
5.81
7.22
5.72
5.78
5.61
7.12
6.86
5.74
5.40
7.02
6.92
5.61
–
6.81
6.71
5.60
5.35
6.87
6.64
5.81
5.52
6.93
6.78
5.74
5.35
7.00
6.78
5.81
5.52
7.00
6.80
5.65
–
92
93
94
95
96
97
98
99
3
3
3
3
3
4
4
4
4
4
4
3
4
4
3
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
4
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1
2
3
4
5
6
7
8
1.6
0.3
<0.1
0.6
0.2
0.8
1.3
0.1
0.9
1.0
0.9
0.6
0.4
0.8
1.5
0.5
1.3
0.8
<0.1
0.6
0.2
0.6
1.1
1.1
1.5
0.6
0.5
0.4
0.4
0.3
1.5
0.2
1.5
0.5
0.2
0.2
0.2
88
94
–
6.79
5.76
–
80
91
93
95
96
94
95
60
84
69
99
86
82
72
84
–
92
81
96
98
88
88
80
66
91
97
90
99
81
64
50
71
70
94
7.02
6.93
5.60
5.37
6.87
6.65
5.60
5.16
6.81
6.67
5.75
5.31
6.98
6.93
5.69
–
7.12
6.85
5.74
5.35
6.92
6.79
5.72
5.61
6.99
6.79
5.74
5.34
7.00
6.79
5.74
5.53
6.92
6.77
100
101
102
103
104
105
106
107
108
109
110
111
112
113
114
115
116
117
118
119
120
121
122
123
124
125
126
127
128
91
91
6.92
6.78
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hexane at 7.0 mLminꢀ1 flow rate). [b] Purity was determined by reverse-phase HPLC with peak area (UV) at 214 nm. LC/MS were obtained on an
AppliedBioSystems Mariner TK3500 Biospectrometry Workstation (ESI-TOF) mass spectrometery and Hewlett-Packard Series 1100 (GL Science Inc.
Inertsil ODS-3, 3 mm, 4.6ꢀ75 mm with a linear gradient of 10% acetonitrile containing 0.1% formic acid/water containing 0.1% formic acid to 100%
acetonitrile containing 0.1% formic acid over 9 min at 1.0 mLminꢀ1 flow rate). [c] Retention time. Positive ion electrospray MS data, [M+H]+ were
recorded. [d] Macrosphelide E. [e] Macrosphelide F. [f] Macrosphelide A. [g] Macrosphelide C.
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5233

Communications
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catalyzed carbonylation of the vinyl bromide proceeded at 808C
using triphenylphosphane, dppf, or [(tBu)3PH]BF4 as a ligand.
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[23] The dimerized product was not obtained (16: ca. 0.6 mmolgꢀ1
loading). Under the cyclization conditions, elimination of the b-
acyloxy ester moiety was not observed.
[24] The spectral data are given in the Supporting Information.
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[26] LC/MS spectra of the 122 products gave the corresponding
[M+H]+ data and the structures of 15compounds randomly
selected were determined by 1H NMR spectra. The acetal of the
ethylene glycol moiety in C3 and C7 was intact under the
cleavage conditions.
[27] No other isomer was detected in LC/MS. However, as a referee
pointed out, there is some uncertainty about the structure of the
new lactones by the possibility of complete transesterification
under acid cleavage conditions.
5234
ꢀ 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.angewandte.org
Angew. Chem. Int. Ed. 2003, 42, 5230 –5234