Total synthesis of leustroducsin B via a convergent route

Article abstract of DOI:10.1016/j.tetlet.2007.03.152

Total synthesis of leustroducsin B was achieved via a convergent route, which includes Julia coupling reaction of segment A with segment B followed by Stille coupling reaction of segment C.

Full text of DOI:10.1016/j.tetlet.2007.03.152

Tetrahedron Letters 48 (2007) 3829–3833
Total synthesis of leustroducsin B via a convergent route
Kazuyuki Miyashita,a,b Tomoyuki Tsunemi,a Takafumi Hosokawa,a Masahiro Ikejiria
and Takeshi Imanishia,*
aGraduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamadaoka, Suita, Osaka 565-0871, Japan
bFaculty of Pharmacy, Osaka Ohtani University, 3-11-1 Nishikiori-Kita, Tondabayashi, Osaka 584-8540, Japan
Received 27 February 2007; revised 22 March 2007; accepted 28 March 2007
Available online 2 April 2007
Abstract—Total synthesis of leustroducsin B was achieved via a convergent route, which includes Julia coupling reaction of segment
A with segment B followed by Stille coupling reaction of segment C.
Ó 2007 Elsevier Ltd. All rights reserved.
Leustroducsins, isolated from the culture broth of Strep-
tomyces platensis SANK 60191 by Sankyo’s groups in
1993,1 are known to show a variety of biological activi-
ties. For example, leustroducsin B (1) shows induction
of a colony-stimulating factor via NF-jB activation
and thrombopoiesis.2 Although a number of inhibitors
against serine/threonine protein phosphatases (PPs 1
and 2A) have been isolated,3 a structurally related
natural product, fostriecin, is known to show the most
specific inhibitory activity toward PP 2A.4 It is also
known that a hydrated analog of leustroducsin B, leus-
troducsin H, has potent PP 2A inhibitory activity,5
which may have a relation to the biological activity,
and is of great interest from a viewpoint of structure–
activity relationship. These facts make this type of natu-
ral products an attractive synthetic target,6 and several
successful syntheses of fostriecin including ours have
been reported to date.7,8 However, only a limited num-
ber of syntheses of leustroducsin-type compounds hav-
ing aminoethyl and ethyl substituents at C-8 and C-4,
respectively,9 were reported: leustroducsin B (1) by
Fukuyama’s group in 200310 and phoslactomycin B by
Kobayashi’s group in 2006.11
synthetic strategy for these natural products, which is
highly convergent and versatile for the synthesis of their
analogs as well, and, as a first step, we have already syn-
thesized fostriecin successfully.8 Herein, we describe the
total synthesis of leustroducsin B (1) (Fig. 1).
Based on our strategy for fostriecin, we divided a leus-
troducsin molecule into three segments A, B, and C,
as shown in Figure 2. Taking account of the synthesis
of various analogs, such as hybrid analogs with fostrie-
cin, we selected aldehyde-based reactions and Pd(0)-cat-
alyzed reactions as a coupling reaction between each
segment.8 Segment A (2), a precursor of an ethyl substi-
tuted d-lactone structure, was planned to be synthesized
O
OH
O
P
8
4
HO
OH
O
O
OH
OR
H2N
leustroducsin B (1): R =
4
O
Taking account of application to studies of chemical
biology and medicinal chemistry, particularly focusing
on the PP inhibitory activity, we planned a cognate
leustroducsin H: R = H
O
OH
O
P
HO
OH
OH
O
O
OH
fostriecin
Keywords: Leustroducsin B; Total synthesis; Convergent route;
Proteinphosphatase inhibitor.
*
Corresponding author. Tel.: +81 6 6879 8200; fax: +81 6 6879
8204; e-mail: imanishi@phs.osaka-u.ac.jp
Figure 1. Structures of leustroducsins B, H and fostriecin.
0040-4039/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2007.03.152

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K. Miyashita et al. / Tetrahedron Letters 48 (2007) 3829–3833
Phospholylation
O
OH
O
via cyclic phosphate
P
HO
OH
O
O
OH
Leustroducsin B (1)
OR
H2N
Julia coupling
Stille coupling
Wittig
O
OTBS
OMPM
O O
S
N
Bu3Sn
Ph3P CHI
BzO
MPMO
S
MPMO
+
OR
O
TBDPSO
Segment A (2)
Segment B (3)
Segment C (4)
Sharpless asymmetric
dihyroxylation
OTBS
OMPM
HO2C
10
OMPM
OH
+
BzO
TBDPSO
O
Et2Al
5
6
8
Asymmetric
DA reaction
Sharpless asymmetric
epoxidation
O
O
OH
CO2H
9
HO2C
OH
O
N
7
Bn
11
Figure 2. Synthetic strategy for leustroducsin B.
by a combination of Sharpless asymmetric epoxida-
tion12 and an epoxide cleavage reaction employing an
organometallic reagent as key steps. A sulfone func-
tional group was also allowed to be introduced at a suit-
able position for Julia coupling reaction13 with segment
B (3). Segment B (3), having an oxyethyl substituent and
sequential stereogenic centers, was expected to be syn-
thesized from (R)-malic acid (9) employing a combina-
tion of Wittig reaction and Sharpless asymmetric
dihydroxylation.14 A cyclohexane structure of segment
C (4) was planned to be synthesized by asymmetric
Diels–Alder reaction, and a diene moiety was expected
to be constructed by a Pd(0)-catalyzed coupling reac-
tion.15 According to the strategy, we have synthesized
leustroducsin B (1) as follows.
OMPM
12
a
OH
OH
O
b
8
5
OMPM
d
e
MPMO
O
OR2
O
OR1
13: R1 = R2 = H
4-(MeO)C6H4
c
15
14: R1, R2
=
4-(MeO)C6H4
f
N
Synthesis of segment A (2) is shown in Scheme 1. Opti-
cally active epoxide 5 prepared by Sharpless asymmetric
epoxidation of trans-2-pentenol (8) was treated with an
alkynylaluminum reagent prepared from 12, giving 13
as a main product. After protection of a diol moiety
of 13 with an anisylidene group, partial reduction of
an alkyne moiety10,16 of 14 and regioselective reductive
cleavage of the anisylidene group of the resultant olefin
15 afforded primary alcohol 16, which was transformed
into Julia reagent 2 as follows. Treatment of 16 with
2-mercaptobenzothiazole under Mitsunobu conditions17
afforded sulfide 17, which was oxidized to give the
desired segment A (2).
OH
X
MPMO
MPMO
MPMO
S
MPMO
16
17: X = S
g
2: X = SO2
Scheme 1. Synthesis of segment A. Reagents and conditions: (a)
Ti(OPri)4, L-(+)-DIPT, TBHP, MS4A, CH2Cl2, ꢀ20 °C, overnight,
82% (95% ee); (b) 12, n-BuLi, then Et2AlCl, 5, toluene, ꢀ20 °C to rt,
4 h, 39% (regioisomer: 15%); (c) p-anisaldehyde dimethylacetal, PPTS,
CH2Cl2, rt, 2 h, 60%; (d) Zn, BrCH2CH2Br, LiCuBr2, EtOH, reflux,
22 h; (e) DIBAlH, CH2Cl2, ꢀ100 °C, 2 h, 62% from 14; (f) 2-
mercaptobenzothiazole, DEAD, Ph3P, THF, rt, 2 h, 98%; (g) 30%
H2O2, (NH4)6Mo7O24Æ4H2O, EtOH, rt, 2 days, 82%.
Segment B (3) was synthesized as shown in Scheme 2.
Alcohol 18, which was easily obtainable from (R)-malic
acid (9) according to literature procedures,8,18 was oxi-
dized and treated in situ with Wittig reagent 19 having
a c-lactone structure, affording 20. After reduction of
20 with DIBAlH, the resultant primary hydroxyl group
of 21 was protected with a TBDPS group to give 22. An
aldehyde group of 22 was converted to a benzoyloxy
group according to a usual procedure, then two stereo-

K. Miyashita et al. / Tetrahedron Letters 48 (2007) 3829–3833
3831
O
O
O
O
O
O
O
HO2C
a
b
b
a
O
O
O
N
O
N
9
HO
O
O
Bn
Bn
18
20
PPh3
19
O
11
28
10
Br
g
O
e, f
O
c
O
Br
O
O
c
OHC
e, f
X
O
BzO
TBDPSO
OH
RO
29: X = I
31
d
21: R = H
22: R = TBDPS
23
30: X = H
d
Bu3Sn
HO2C
anti
4
h
34
i
OH
O
33: R = H
4: R =
Bu3Sn
O
g
h
BzO
32
OR
OH
OH
4
TBDPSO
O
24
Scheme 3. Synthesis of segment C. Reagents and conditions: (a) 1,3-
butadiene, Et2AlCl, galvinoxyl, CH2Cl2, ꢀ15 °C, overnight, 63%; (b)
30% H2O2, LiOH, THF–H2O (5:1), rt, 5 h, 67% (94% ee); (c) KI, I2,
NaHCO3, CH2Cl2–H2O (1:2), rt, 24 h; (d) (TMS)3SiH, AIBN,
benzene, reflux, 3 h, 76% from 10; (e) DIBAlH, toluene, ꢀ78 °C, 1 h;
(f) Br2CHP+Ph3ÆBrꢀ, t-BuOK, 1,4-dioxane, 70 °C, 30 min, 71% from
30; (g) n-BuLi, THF, then Bu3SnCl, ꢀ78 °C to 0 °C, 3 h; (h) CpZrHCl,
THF, rt, 2 h, 52% from 31; (i) 34 (94% ee), EDC-MeI, DMAP, Et3N,
CH2Cl2, rt, 24 h, 84%.
25: R1, R2
26: R1 = R2 = H
=
i
j
O
OR1
OR2
BzO
TBDPSO
27: R1 = H, R2 = MPM
3: R1 = TBS, R2 = MPM
O
k
Scheme 2. Synthesis of segment B. Reagents and conditions: (a) see
Refs. 8,16; (b) DMSO, (COCl)2, Et3N, CH2Cl2, ꢀ78 °C to 0 °C,
30 min, then 19, rt, 2 h, 83%; (c) DIBAlH, toluene, ꢀ78 °C, 20 min; (d)
TBDPSCl, imidazole, DMF, rt, 30 min, 49% from 20; (e) NaBH4,
CeCl3Æ7H2O, MeOH, ꢀ78 °C, 15 min; (f) BzCl, Et3N, CH2Cl2, 0 °C,
1 h, 88% from 22; (g) (DHQD)2PHAL, K2OsO2(OH)4, K3Fe(CN)6,
K2CO3, MeSO2NH2, t-BuOH–H2O (2:1), rt, overnight, 91% (anti-
isomer only); (h) 2,2-dimethoxypropane, p-TsOHÆH2O, rt, 20 min; (i)
Zn(NO3)2Æ6H2O, MeCN, 50 °C, 3 h, 93% from 24; (j) n-Bu2SnO,
toluene, reflux, 12 h, then MPMCl, n-Bu4NI, reflux, 1.5 h, 76%; (k)
TBSOTf, 2,6-lutidine, CH2Cl2, rt, 15 min, quant.
Segment B (3) was coupled with segment A (2) at first
because of the expectable labile property of the diene
moiety and versatility of the acyl side-chain in segment
C. Removal of the benzoyl group of 3 followed by oxi-
dation of the terminal hydroxyl group gave aldehyde 35.
Julia coupling reaction of 35 with 3 employing NaH-
MDS as a base afforded a coupling product 36 in 49%
yield, but unexpected epimerization at C-5 took place
simultaneously, to result in the formation of a ca. 1:1
diastereomeric mixture.22 On the contrary, when
LiHMDS was used as a base, no epimerization was
observed to give a diastereomerically pure 36, although
yield of product 36 was rather low.23 All MPM groups
of 36 were removed by oxidative treatment, and TEM-
PO oxidation of the resultant triol 37 afforded lac-
tone–aldehyde 38, which was iodomethylenated by
Wittig reaction, affording cis-olefin 39, stereoselectively.
As the next step, the hydroxyethyl group of 39 was
converted to an aminoethyl group before coupling with
segment C (4) as follows. After removal of the silyl
protecting groups of 39, the resultant secondary hydro-
xyl group at C-11 was selectively reprotected with a TBS
group, affording 41. Then the hydroxyl group of 41 was
replaced with an azido group, yielding azide 42, which
was reduced and protected with an Alloc group to give
43. Acidic treatment of 43 removed both TBS and ace-
tonide groups to give 44, Stille coupling of which with
segment C (4) afforded 45 having the whole skeleton
of leustroducsin B. After selective protection of the hy-
droxyl group at C-11 with a TBS group, introduction
of the phosphate group to the C-9 hydroxyl group
of 46 was achieved by partial hydrolysis of cyclic
genic centers at C-8 and C-9 were introduced to 23 by
Sharpless asymmetric dihydroxylation, giving diol 24.
Bisacetonide formation and regioselective removal of
the terminal acetonide group of 25 by treatment with
zinc nitrate gave diol 26. After selective protection of a
primary hydroxyl group of 26 with an MPM group
via cyclic stannane, the residual secondary hydroxyl
group of 27 was protected with a TBS group to afford
segment B (3).
Segment C (4) was synthesized as shown in Scheme 3.
Optically active cyclohexenecarboxylic acid 10 was syn-
thesized by asymmetric Diels–Alder reaction employing
optically active oxazolidinone 1119 as a starting material
to give diastereomerically pure 28. After hydrolysis, iodo-
lactonization20 and reduction with a silane afforded
lactone 30, which was reduced with DIBAlH and subse-
quently treated with Wittig reagent to give dibromide
31. A dibromoethylene moiety of 31 was transformed
into a stannylethylene structure via alkynylstannane 32
by treatment with a base and hydrozirconylation, giving
33, which was esterified with optically active carboxylic
acid 3421 to give segment C (4).

3832
K. Miyashita et al. / Tetrahedron Letters 48 (2007) 3829–3833
O
OTBS
CHO
O
OTBS
OMPM
O
OTBS
OR
c
e
a, b
f
5
3
OHC
O
O
RO RO
O
O
O
TBDPSO
TBDPSO
TBDPSO
38
35
36: R = MPM
d
37: R = H
OR2
O
OTBS
OH OH
O
j
m
l
I
I
I
O
O
O
O
O
O
11
OH
O
O
R1O
X
AllocHN
39: R1 = TBDPS, R2 = TBS
42: X = N3
44
g
k
43: X = NHAlloc
40: R1 = R2 = H
h, i
41: R1 = H, R2 = TBS
O-Et3N+H
O
P
O
O
P
o
p
OH OR
O
OTBS
O
O
O
O
O
O
OH
OH
O
O
O
4
4
AllocHN
AllocHN
AllocHN
O
O
48
47
q, r
45: R = H
n
46: R = TBS
leustroducsin B (1)
Scheme 4. Synthesis of leustroducsin. Reagents and conditions: (a) K2CO3, MeOH, rt, 4 h, 81% from 27; (b) TPAP, NMO, MS4A, CH2Cl2, 2 h, rt,
95%; (c) segment A (2), LiHMDS, THF then 35, ꢀ78 °C to ꢀ20 °C, 1 h, 14%; (d) DDQ, wet CH2Cl2, rt, 1 h, 79%; (e) TEMPO, DAIB, CH2Cl2, rt,
1.5 h; (f) ICH2P+Ph3ÆIꢀ, NaHMDS, HMPA, THF, ꢀ100 °C to 0 °C, 30 min, 59% (Z:E = 4.3:1) from 37; (g) TBAF, AcOH, THF, rt, overnight, 64%;
(h) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ78 °C, 1 h; (i) p-TsOHÆH2O, THF–MeOH (1:3), 0 °C, 1 h, 81% from 40; (j) Ph3P, DPPA, DEAD, THF, rt, 1 h;
(k) Ph3P, H2O, THF, rt, 20 h, then pyridine, AllocCl, rt, 20 min, 74% from 41; (l) MeOH–concd HCl (20:1), rt, overnight; (m) segment C (4),
PdCl2(MeCN)2, DMF, rt, 1.5 h, 61% from 43; (n) TBSOTf, 2,6-lutidine, CH2Cl2, ꢀ78 °C, 30 min, 76%; (o) POCl3, pyridine, then allyl alcohol, 0 °C,
2 h; (p) CF3CH2OH–H2O–Et3N (20:1:1), rt, 1 h, 87% from 46;23 (q) HF, pyridine, MeCN, rt, 8 h; (r) Pd(PPh3)4, Ph3P, HCO2NH4, 50 °C, 7 h, 49%
from 48.
phosphate 47, producing the desired phosphate 48 as a
main product.24 Eventually, removal of all protecting
groups of 48 afforded leustroducsin B (1), the physi-
cal properties (1H NMR and [a]D value) of which
were identical to those of the authentic sample25
(Scheme 4).
ducsin B. A part of this work was supported by a Grant-
in-Aid from the JSPS.
References and notes
1. (a) Kohama, T.; Enokita, R.; Okazaki, T.; Miyaoka, H.;
Torikata, A.; Inukai, M.; Kaneko, I.; Kagasaki, T.;
Sakaida, Y.; Satoh, A.; Shiraishi, A. J. Antibiot. 1993,
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3. Recent review: Colby, D. A.; Chamberlin, A. R. Mini-Rev.
Med. Chem. 2006, 6, 657.
In summary, although there still remain some problems
to be resolved, we have successfully achieved the total
synthesis of leustroducsin B via a convergent route
involving a coupling of three segments A, B, and C,
which is compatible with our previous total synthesis
of fostriecin. The present synthesis proved the versatility
and wide applicability of our strategy to the synthesis of
various analogs, including hybrid analogs of fostriecin
and leustroducsins, which, hence, would open a door
for the studies of chemical biology and medicinal chem-
istry focusing on PPs.
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Acknowledgments
We thank Dr. Kousei Shimada (Sankyo Co., Ltd.) and
Professor Tohru Fukuyama (The University of Tokyo)
for their kind gift of spectral data for authentic leustro-

K. Miyashita et al. / Tetrahedron Letters 48 (2007) 3829–3833
3833
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preparation of the optically active cyclohexenecarboxylic
acid 10 were reported, we utilized the optically active
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56, 3285.
20. Linde, R. G., II.; Egbertson, M.; Coleman, R. S.; Jones,
A. B.; Danishefsky, S. J. J. Org. Chem. 1990, 55, 2771.
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Co., Ltd.
22. To the best of our knowledge, a similar epimerization was
reported on the reaction of a sulfone derivative having a
tetrahydrofuran ring: Evans, D. A.; Rajapakse, H. A.;
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23. An olefinic by-product, which was produced by elimina-
tion of the neighboring MPM group, was obtained in 32%
yield. Further optimization of this coupling reaction
including utilization of other reactions is in progress,
details of which would be described in a full article.
24. A mixture of the hydrated products, C-9 phosphate 48,
C-8 phosphate 49 and cyclic phosphodiester 50, was
obtained in 87% yield from 46, and the ratio was ca.
71:22:7, respectively. The mixture was employed for the
next reaction without separation.
7. (a) Boger, D. L.; Ichikawa, S.; Zhong, W. J. Am. Chem.
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O-Et3N+H
OH
10. Shimada, K.; Kaburagi, Y.; Fukuyama, T. J. Am. Chem.
Soc. 2003, 125, 4048.
P
O
O
11. Wang, Y.-G.; Takeyama, R.; Kobayashi, Y. Angew.
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45, 3320.
12. (a) Pfenninger, A. Synthesis 1986, 89; (b) Katsuki, T.;
Martin, V. S. Org. React. 1996, 48, 1–299.
O
P
48
+
+
AllocHN
O
O
O
O-Et3N+H
AllocHN
50
49
13. Recent review: Blakemore, P. R. J. Chem. Soc., Perkin
Trans. 1 2002, 2563.
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4808; . Angew. Chem., Int. Ed. 2004, 43, 4704.
25. The final product 1 was purified at first by preparative
TLC with MeOH, then by reversed phase silica gel (C18)
column chromatography with H2O–MeCN (40:1–1:2) as
1
eluant, and showed the following spectral data. H NMR
(CD3OD): d 7.09 (dd, J = 10, 5 Hz, 1H), 6.33–6.24 (m,
2H), 6.07 (dd, J = 16, 6 Hz, 1H), 6.02 (dd, J = 10, 1 Hz,
1H), 5.95 (d, J = 16 Hz, 1H), 5.46 (br t, J = 8 Hz, 1H),
5.31 (br t, J = 9 Hz, 1H), 5.10 (dd, J = 6, 4 Hz, 1H), 4.95
(br t, J = 8 Hz, 1H), 4.76–4.69 (m, 1H), 4.29 (td, J = 10,
3 Hz, 1H), 3.11–2.97 (m, 2H), 2.67–2.54 (m, 2H), 2.28 (t,
J = 7 Hz, 2H), 2.25–2.15 (m, 1H), 1.96–1.81 (m, 4H),
1.74–1.24 (m, 15H), 1.19–1.03 (m, 3H), 0.96 (t, J =
8 Hz, 3H), 0.88 (t, J = 7 Hz, 3H), 0.86 (d, J = 6 Hz, 3H).
16. Aerssens, M. H. P.; Van der Heiden, R.; Heus, M.;
Brandsma, L. Synth. Commun. 1990, 20, 3421.
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´
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25
½aꢁD +98.8 (c 0.0500, MeOH) [lit.10 [a]D +99.3 (c 0.0500,
18. Mori, K.; Takigawa, T.; Matsuo, T. Tetrahedron 1979, 35,
MeOH)].
933.