Synthetic studies on apoptolidin: Synthesis of the C12-C28 fragment via a highly stereoselective aldol reaction

Article abstract of DOI:10.1016/j.tetlet.2004.09.177

The stereoselective and convergent synthesis of the C12-C28 segment 2 of the apoptosis inducing macrolide antibiotic, apoptolidin (1), is described. The synthesis involves a highly stereoselective tin(II)-mediated aldol reaction between the C17-C22 ethyl

Full text of DOI:10.1016/j.tetlet.2004.09.177

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 8849–8853
Synthetic studies on apoptolidin: synthesis of the
C12–C28 fragment via a highly stereoselective aldol reaction
Kazuyuki Abe, Koji Kato, Tadamasa Arai, Mohammad Abdur Rahim, Israt Sultana,
Shuichi Matsumura and Kazunobu Toshima*
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi,
Kohoku-ku, Yokohama 223-8522, Japan
Received 25 August 2004; revised 28 September 2004; accepted 30 September 2004
Available online 14 October 2004
Abstract—The stereoselective and convergent synthesis of the C12–C28 segment 2 of the apoptosis inducingmacrolide antibiotic,
apoptolidin (1), is described. The synthesis involves a highly stereoselective tin(II)-mediated aldol reaction between the C17–C22
ethyl ketone 3 and the C23–C28 aldehyde 4 as the key step.
Ó 2004 Elsevier Ltd. All rights reserved.
Apoptolidin (1), discovered in 1997 by Seto and co-
workers,1 possesses impressive biological properties.
Thus, 1 induces apoptotic cell death in rat glia cells
transformed with the adenovirus E1A oncogene, but
not in normal glia cells. Recently, Khosla and co-work-
ers identified the mitochondrial F0F1–ATPase as one
possible target to explain this biological action.2 In a re-
cent test of 37,000 compounds against the National
Cancer Instituteꢀs 60 human cancer cell line panel, 1
was found to be amongthe top 0.1% of the most selec-
tive cytotoxic agents.3 The relative and absolute config-
uration of 1 has been established by extensive NMR
analysis and degradation studies.4 Apoptolidin (1) pos-
sesses a novel molecular structure, which consists of a
complex aglycon and two sugar units, and is distin-
guished by a total of 25 stereocenters and five geometri-
cal sites. The aglycon is constructed of a 20-membered
macrocyclic lactone containingindependent conjugated
triene and diene systems and a side chain at C19 con-
taininga six-membered cyclic hemiacetal. A b-D-ole-
androsyl-a-L-olivomycose disaccharide is located at
C27, while a novel sugar, 6-deoxy-4-O-methyl-a-L-glu-
cose is attached at C9. Because of its important biolog-
ical activity and novel molecular architecture,
apoptolidin (1) has been deemed a prime target for total
synthesis. In this context, besides our own studies,5 ele-
gant synthetic studies on 1 have been announced by
Nicolaou and co-workers,6 Koert and co-workers,7 Suli-
kowski et al.,8a Fuchs and co-workers,9 Loh and co-
workers,10 and Paquette and Taylar11 groups, and two
total syntheses of apoptolidin have been reported by
Nicolaou and co-workers6b–e and Koert and co-work-
ers.7c In addition, Wender and co-workers12 and
Sulikowski and co-workers8b groups reported semisyn-
thetic studies on analogs of 1. Herein we now disclose
the stereoselective and convergent synthesis of the
C12–C28 fragment 2 of 1 via a highly stereoselective
aldol reaction, which makes use of the key synthetic
intermediates, the C17–C22 segment 3 and the C23–
C28 segment 4 (Fig. 1).
The synthesis of the ethyl ketone 3 correspondingto the
C17–C22 segment of 1 is summarized in Scheme 1. The
olefin 6 was readily obtained from dimethyl L-tartrate
(5) usingthe procedures reported by Kibayashi and
co-workers13 and Chen and Marx.14 Hydroboration of
6 employingdicyclohexylborane smoothly proceeded
to afford the primary alcohol 7 in 85% yield after the
subsequent oxidative work-up. Protection of 7 with ben-
zyl group, followed by deprotection of the TBS group,
gave the alcohol 9 via 8 in 94% overall yield. Dess–Mar-
tin oxidation15 of 9 and subsequent Grignard reaction of
the resultingaldehyde 10 usingEtMgCl yielded the sec-
ondary alcohol 11 in 60% overall yield. Finally, 11 was
oxidized usingDess–Martin periodinane to give the de-
sired ethyl ketone 3 in 75% yield.
Keywords: Apoptolidin; Macrolide; Antibiotic; Apoptosis; Aldol
reaction.
*
Correspondingauthor. Tel./fax: +81 45 566 1576; e-mail: toshima@
applc.keio.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.09.177

8850
K. Abe et al. / Tetrahedron Letters 45 (2004) 8849–8853
Me Me
OH
HO
O
O
MeO
Me
Me
Me
O
OH Me
12
O
28
OH
H
MeO
HO
O
OMe
O
Me
23
OH
O
Me
OH
Me
Me
O
O
OMe
Apoptolidin (1)
HO Me
Me
22
O
Me
O
Me
I
O
O
28
O
H
Me
Me
O
28
23
OHC
Me
TBSO
OMe
OTBS
BnO
+
12
OMe
OTBS
23
17
Me
OMe
Me
MPMO
O
Me
Me
OTBS
2
4
3
Figure 1. Molecular structure of apoptolidin (1) and retrosynthesis of the C12–C28 portion.
TBSO
TBSO
HO
MeO2C
MeO2C
OH
OH
O
O
6
O
O
O
O
Me
Me
Me
Me
Me
Me
d
a
b
RO
BnO
7: R=H
9
5
c
8: R=Bn
e
O
OH
g
Me
f
O
O
O
O
Me
Me
Me
Me
3
BnO
BnO
11
10
Scheme 1. Reagents and conditions: (a) Refs. 13,14; (b) (c-Hex)2BH, THF, 25°C, 1h then H2O2, 25°C, 1h, 85%; (c) BnBr, NaH, DMF, 25°C, 1h; (d)
TBAF, THF, 0°C, 3h, 94% from 7; (e) Dess–Martin periodinane, Py, CH2Cl2, 25°C, 18h; (f) EtMgCl, THF, 25°C, 0.5h, 60% from 9; (g) Dess–
Martin periodinane, Py, CH2Cl2, 25°C, 3h, 75%.
The construction of the aldehyde 4 correspondingto the
C23–C28 segment of 1 is depicted in Scheme 2. The p-
methoxybenzylidene acetal 13 prepared from D-malic
With both key intermediates 3 and 4 in hand, the synthe-
sis of the C12–C28 segment 2 via an aldol reaction was
addressed as shown in Scheme 3. In the aldol reaction
using 3 and 4, we expected that if the Z-enolate of 3
was selectively formed and reacted with the aldehyde 4
via a six-membered transition state as depicted in Figure
2, the desired anti Felkin aldol adduct could be predomi-
nantly obtained due to the steric effect, namely, the
gauche–gauche pentane interaction.21 Based on this
mechanistic consideration, we examined many aldol
reactions of 3 and 4 usingLDA, LiHMDS, n-Bu2BOTf,
PhBCl2, TiCl4, and Sn(OTf)2, with or without a base
such as Et3N or DIPEA under several conditions.22
Amongthem, we finally found that the aldol reaction
of 2.0equiv of 3 and 1.0equiv of 4 using2.6equiv of
Sn(OTf)2 in the presence of 3.0equiv of DIPEA23 in
CH2Cl2 at À78 to 0°C for 4h effectively and stereoselecti-
vely proceeded to give the desired aldol 23 in 80% yield
with very high stereoselectivity (80:8:5:0 diastereoselecti-
vity). Deprotection of the p-methoxybenzyl group along
with the TBS group using DDQ in MeOH–CH2Cl2 led to
16
acid (12) usingthe methods by Hanessian et al.
and
17
´
Herradon et al. was chosen as the startingmaterial.
After methylation of the primary alcohol in 13, DIBAL
reduction of the resulting 14 proceeded selectively
(>10:1 regioselectivity) to give the secondary alcohol
158 in 87% overall yield. Protection of the secondary
alcohol of 15 with TBS group, followed by deprotection
of the p-methoxybenzyl group utilizing DDQ,18 fur-
nished the primary alcohol 17 via 16 in 92% overall
yield. Swern oxidation of 17 gave the aldehyde 18, which
was subjected to Evans aldol reaction usingthe oxazo-
lidinone 1919 in the presence of n-Bu2BOTf and Et3N
in CH2Cl2 at 0°C to selectively give the desired aldol
20 in 93% overall yield (>95:5 diastereoselectivity). Con-
version of 20 into the Weinreb amide 21,20 followed by
protection with p-methoxybenzyl group, afforded 22 in
45% overall yield. Finally, DIBAL reduction of 22 at
À78°C furnished the desired aldehyde 4 in 60% yield.

K. Abe et al. / Tetrahedron Letters 45 (2004) 8849–8853
OR
8851
OMe
CO2H
OH
12
c
f
a
OMe
OTBS
18
HO2C
OR1 OR2
O
O
O
15: R1=MPM, R2=H
MP
13: R=H
14: R=Me
d
16: R1=MPM, R2=TBS
17: R1=H, R2=TBS
b
O
e
O
N
g
Me
Bn
O
19
O
Me Me
N
h
O
j
Me
4
MeO
OMe
N
OMe
O
OR OTBS
21: R=H
22: R=MPM
Bn
O
OH OTBS
i
20
Scheme 2. Reagents and conditions: (a) Refs. 16,17; (b) MeI, NaH, DMF, 25°C, 2h, 94%; (c) DIBAL, PhMe, À78°C, 6h, 93% (>10:1); (d) TBSCl,
imidazole, CH2Cl2, 35°C, 18h; (e) DDQ, CH2Cl2–H2O, 25°C, 2h, 92% from 15; (f) (COCl)2, DMSO, Et3N, CH2Cl2, À78°C, 20min; (g) n-Bu2BOTf,
Et3N, CH2Cl2, 0°C, 2h, 93% (>95:5) form 18; (h) MeONHMeHCl, AlMe3, CH2Cl2, 25°C, 16h, 93%; (i) MPMOC(@NH)CCl3, CSA, CH2Cl2, 35°C,
48h, 48%; (j) DIBAL, PhMe, À78°C, 2h, 60%.
Me
Me
Me Me
23
Me
O
Me
O
OMe H
O
b
a
O
O
+
3
4
OMe
OTBS
MPM
OMe
22
BnO
O
OH O
BnO
OR
Me
Me
d
OR
24: R=H
23
c
25: R=Ac
26: R=TBS
e
OTBS
Me
Me
Me
Me
O
Me
O
n-Bu3Sn
Me
O
OMe H
O
OMe H
O
OMe H
O
O
O
O
29
TBSO
OMe
OTBS
f
OMe
OTBS
OMe
O
HO
OTBS
g
Me
Me
OTBS
Me
Me
OTBS
27
Me
Me
OR
OTBS
28
30: R=H
h
31: R=Me
i
Me
O
Me
O
Me
Me
OMe H
OMe H
O
O
O
O
k
m
TBSO
OMe
OTBS
TBSO
OMe
2
OTBS
Me
RO
Me
Me
OTBS
Me
OMe
OMe
R
OTBS
32: R=H
33: R=Ts
34: R=H
j
l
35: R=Me
Scheme 3. Reagents and conditions: (a) Sn(OTf)2, DIPEA, À78 to 0°C, 4h, 80% (80:8:5:0); (b) DDQ, MeOH, CH2Cl2, 25°C, 24h, 74%; (c) Ac2O,
Py, 0°C, 1h, 85%; (d) TBSOTf, Py, 0°C, 1.5h, 91%; (e) H2, Pd–C, EtOH, 25°C, 2h, 89%; (f) Dess–Martin periodinane, Py, CH2Cl2, 25°C, 5h, 81%;
(g) MgBr2OEt2, CH2Cl2, À20°C, 12h, 86% (89:11); (h) MeOTf, 2,6-DTBP, 60°C, 18h, 74%; (i) (c-Hex)2BH, THF, 0°C, 2h then H2O2, 25°C, 1h,
84%; (j) TsCl, Et3N, TMEDA, MeCN, 0°C, 1h, 99%; (k) LiC + CH, DMSO, 25°C, 12h, 55%; (l) MeI, n-BuLi, THF, 25°C, 1.5h, 96%; (m)
Cp2ZrHCl, THF, 25°C, 1.5h then NIS, À25°C, 0.5h, 53%.
the acetal formation to give 24 in 74% yield. At this
stage, we first confirmed the configurations of the newly
generated stereocenters at C22 and C23 by the aldol
reaction. Thus, 24 was acetylated to produce the diace-
tate 25, in which NOEs were observed between the
C23 and C25 protons and between the C23 proton
and C22 methyl group as indicated in Figure 3. These re-
sults clearly indicated that the configurations at C22 and
C23 possessed the desired stereochemistry. For the syn-
thesis of 2, the diol 24 was protected with TBS groups to

8852
K. Abe et al. / Tetrahedron Letters 45 (2004) 8849–8853
R1
anti Felkin
Felkin
R2
Me Me
23
R1
O
Me Me
23
M
O
M
>>
O
22
22
O
R2
O
OH
O
OH
favored
disfavored
M=metal
=Me
R1=segment of 3
R2=segment of 4
Figure 2. Mechanistic aspect of aldol reaction between 3 and 4.
9%
to the JSPS Postdoctoral Fellowship for Foreign
Researchers and Grant-in-Aid for JSPS Fellows from
Japan Society for the Promotion of Science.
MeO
H
7%
Me
R1=
OMe
H
R2
R1
25
O
OAc
Me
23
AcO
Me
Me
O
25
References and notes
R2=
O
BnO
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Figure 3. NOE studies of 25.
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lysis to afford the primary alcohol 27 in 81% overall
yield. From the alcohol 27 to 2, we successfully applied
our previously developed procedure5 to elongate the
C12–C16 portion. Thus, Dess–Martin oxidation of 27
yielded the aldehyde 28 in 81% yield. Addition of the
allylstannane 2924 to 28 in the presence of MgBr2ÆOEt2
proceeded with stereoselectivity consistent with b-chela-
tion control to give a 89:11 mixture of the desired alco-
hol 30 and the diastereomer in 97% combined yield.
Methylation of 30 usingMeOTf and 2,6-di- tert-butylpy-
ridine (2,6-DTBP) furnished 31 whose terminal olefin
underwent hydroboration employingdicyclohexylbo-
rane, followed by oxidation to provide the primary alco-
hol 32 in 62% overall yield. Tosylation of the alcohol 32
yielded the tosylate 33, which was subjected to a reac-
tion with lithium acetylide in DMSO, to give the acetyl-
ene 34 in 54% overall yield. After methylation of the
terminal alkyne in 34 usingMeI and n-BuLi, the result-
ing 35 was treated with Cp2ZrHCl and N-iodosucci-
nimide (NIS)25 in THF to afford the tri-substituted
trans vinyl iodide 2 in 51% overall yield as the sole iso-
lated product.
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In conclusion, we have demonstrated the stereoselective
and convergent synthesis of the suitably functionalized
and protected C12–C28 segment of apoptolidin contain-
inga total of 10 stereocenters and one geometrical site
10. Chng, S.-S.; Xu, J.; Loh, T.-P. Tetrahedron Lett. 2003, 44,
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via
a highly stereoselective tin(II)-mediated aldol
reaction.26
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Acknowledgements
This research was supported in part by Grant-in-Aid for
the 21st Century COE program ꢁKEIO Life Conjugate
Chemistryꢀ from the Ministry of Education, Culture,
Sports, Science, and Technology, Japan. M.A.R. thanks
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K. Abe et al. / Tetrahedron Letters 45 (2004) 8849–8853
8853
´
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(2H, dt, J = 10.8 and 7.2), 3.56–3.68 (2H, m), 4.07 (1H, d,
J = 8.0), 4.14 (1H, ddd, J = 8.0, 8.0 and 4.2), 4.48 (2H, s),
7.26–7.36 (5H, m). Compound 4: d 0.07 (3H, s), 0.08 (3H,
s), 0.89 (9H, s), 1.11 (3H, d, J = 7.0), 1.58 (1H, ddd,
J = 14.2, 9.6, and 3.2), 1.77 (1H, ddd, J = 14.2, 9.2, and
3.0), 2.67 (1H, dq, J = 3.0 and 7.0), 3.24–3.32 (2H, m),
3.32 (3H, s), 3.80 (3H, s), 3.96–4.09 (2H, m), 4.42 and 4.50
(each 1H, ABq, J = 11.0), 6.86 (2H, d, J = 8.4), 7.23 (2H,
d, J = 8.4), 9.81 (1H, s). Compound 23: d 0.07 (3H, s), 0.08
(3H, s), 0.81 (3H, d, J = 7.0), 0.89 (9H, s), 1.08 (3H, d,
J = 7.0), 1.41 (3H, s), 1.43 (3H, s), 1.60 (1H, ddd, J = 14.2,
9.6, and 2.8), 1.77 (1H, ddd, J = 14.2, 9.4, and 3.0), 1.86–
2.00 (1H, m), 2.00–2.21 (2H, m), 3.08 (1H, br q, J = 7.0),
3.24–3.30 (2H, m), 3.30 (3H, s), 3.53–3.69 (2H, m), 3.78
(3H, s), 3.84–3.92 (2H, m), 3.92–4.03 (1H, m), 4.16–4.27
(3H, m), 4.40 and 4.63 (each 1H, ABq, J = 11.0), 4.47 (2H,
s), 6.84 (2H, d, J = 8.4), 7.23 (2H, d, J = 8.4), 7.25–7.32
(5H, m). Compound 2: d 0.03 (3H, s), 0.06 (3H, s), 0.07
(3H, s), 0.08 (6H, s), 0.10 (3H, s), 0.85 (3H, d, J = 7.0),
0.88 (9H, s), 0.89 (18H, s), 1.10 (3H, d, J = 7.0), 1.36 (3H,
s), 1.42 (3H, s), 1.40–1.50 (2H, m), 1.52–1.60 (1H, m),
1.60–1.74 (3H, m), 1.81 (1H, ddd, J = 13.6, 10.0, and 6.2),
1.90–2.26 (3H, m), 2.36 (3H, s), 3.22–3.42 (3H, m), 3.27
(3H, s), 3.33 (3H, s), 3.34 (3H, s), 3.74 (1H, dd, J = 10.0
and 4.6), 3.76–3.84 (1H, m), 3.84–3.96 (3H, m), 4.18 (1H,
ddd, J = 10.0, 7.0, and 2.0), 6.14 (1H, br tq, J = 7.6 and
1.0).
´
17. Herradon, B.; Cueto, S.; Morcuende, A.; Valverde, S.
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26. Selected 1H NMR (300MHz, CDCl3): (d, SiMe4; J Hz)
data for 3, 4, 23, and 2. Compound 3: d 1.03 (3H, t,
J = 7.2), 1.41 (3H, s), 1.43 (3H, s), 1.87–2.00 (1H, m),
2.02–2.15 (1H, m), 2.60 (2H, dt, J = 10.8 and 7.2), 2.67