Synthetic studies on apoptolidin: Synthesis of the C1-C21 macrolide fragment

Article abstract of DOI:10.1016/S0040-4039(01)01948-7

The stereoselective and convergent synthesis of the C1-C21 macrocyclic segment (2) of the apoptosis inducing macrolide antibiotic, apoptolidin (1), is described.

Full text of DOI:10.1016/S0040-4039(01)01948-7

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 8873–8876
Synthetic studies on apoptolidin: synthesis of the C1–C21
macrolide fragment
Kazunobu Toshima,* Tsuyoshi Arita, Koji Kato, Daisuke Tanaka and Shuichi Matsumura
Department of Applied Chemistry, Faculty of Science and Technology, Keio University, 3-14-1 Hiyoshi, Kohoku-ku,
Yokohama 223-8522, Japan
Received 13 September 2001; revised 9 October 2001; accepted 12 October 2001
Abstract—The stereoselective and convergent synthesis of the C1–C21 macrocyclic segment (2) of the apoptosis inducing
macrolide antibiotic, apoptolidin (1), is described. © 2001 Elsevier Science Ltd. All rights reserved.
Novel drugs that can selectively sensitize cancer cells to
apoptosis induction are very useful for treating certain
cancers. Apoptolidin (1), isolated in 1997 by Seto and
Hayakawa,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-workers
identified the mitochondrial F0F1-ATPase as one possi-
ble target to explain this biological action.2 The relative
and absolute configuration of 1 has been established by
extensive NMR analysis and degradation studies.3
Apoptolidin (1) possesses a novel molecular structure
OH
Me Me
HO
O
O
MeO
Me
Me
Me
O
OH Me
O
OH
H
MeO
HO
O
OMe
O
Me
O
Me
OH
Me
Me
O
OH
O
OMe
Apoptolidin (1)
HO Me
Me Me
HO
I
Me Me
Me
12
TIPSO
Me
OTBS
MeO
Me
OH
21
O
+
Me
OH Me
11
1
O
n-Bu3Sn
O
O
Me
1
O
MeO
O
Me
OH
21
3
Me
4
O
Me
Me
2
Figure 1.
Keywords: apoptolidin; apoptosis; macrolide; macrocyclization.
* Corresponding author. Tel./fax: +81 45 566 1576; e-mail: toshima@applc.keio.ac.jp
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01948-7

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K. Toshima et al. / Tetrahedron Letters 42 (2001) 8873–8876
primary alcohol 10 was subjected to Swern oxidation
and then Wittig reaction employing Ph3PꢀC(Me)CO2Et
in toluene to furnish only the desired trans-olefin 12 via
11 in 96% overall yield. Subsequent reduction of the
ethyl ester in 12 utilizing DIBAL-H followed by oxida-
tion of the resulting allyl alcohol 13 employing MnO2
gave the a,b-unsaturated aldehyde 14 in 93% overall
yield. Repeating the elongation of 14 by Wittig reaction
(Ph3PꢀC(Me)CO2Et), reduction (DIBAL-H) and oxida-
tion (MnO2) afforded the all-trans diene aldehyde 17 in
94% overall yield. Subsequent Horner–Wadsworth–
Emmons olefination employing (Et2O)2(O)PCH-
(Me)CO2Et and n-BuLi in THF provided only the
desired all-trans triene 18 in 99% yield. It was found
that Wittig reaction employing Ph3PꢀC(Me)CO2Et gave
which consists of a complex aglycon and two sugar
units. The aglycon is constructed of a 20-membered
macrocyclic lactone containing independent conjugated
triene and diene systems and a side chain at C19
containing a six-membered cyclic hemiacetal. A b-
oleandrosyl-a- -olivomycose disaccharide is located at
C27, while a novel sugar, 6-deoxy-4-O-methyl-a- -glu-
D-
L
L
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, elegant synthetic studies
on 1 have independently been announced by Koert’s,4a
Nicolaou’s5 and Sulikowski’s6 groups, and the synthesis
of apoptolidinone,4b the aglycon of apoptolidin, has
very recently been reported by Koert and co-workers.
Herein we now disclose the stereoselective and conver-
gent synthesis of the C1–C21 macrocyclic core (2) of 1,
which makes use of the key synthetic intermediates, the
C1–C11 (3) and the C12–C21 (4) segments (Fig. 1).
a
small amount of the cis-isomer. Pd0-catalyzed
hydrostannylation (n-Bu3SnH, cat. PdCl2(PPh3)2)8 pro-
ceeded regio- and stereoselectively to furnish the desired
trans-vinyl tributyltin 19 in 92% yield. In the final
transformation, hydrolysis of the ethyl ester in 19 under
basic conditions (LiOH, 1,4-dioxane) yielded the car-
boxylic acid 3 in 79% yield.
The synthesis of the vinyl tributyltinated carboxylic
acid 3 corresponding to the C1–C11 segment of 1 is
summarized in Scheme 1. Reaction of the aldehyde 5,
which was readily prepared from methyl (R)-3-
hydroxy-2-methylpropionate by Terashima’s method,7
and the trimethylsilylacetylene 6 activated by n-BuLi in
THF at −78°C proceeded stereoselectively to afford the
desired Cram-adduct 7 in 60% yield in a Cram:anti-
Cram ratio of 2:1. The deprotection of the trimethylsil-
yl group in 7 under basic conditions using K2CO3 in
MeOH gave 8 in 99% yield. The secondary alcohol 8
was protected with the triisopropylsilyl (TIPS) group
and then the trityl group was selectively deprotected
under mild acidic conditions using CSA to give the
primary alcohol 10 via 9 in 78% overall yield. The
The construction of the vinyl iodidenated secondary
alcohol 4 corresponding to the C12–C21 segment of 1
from diethyl
L-tartrate is depicted in Scheme 2. The
primary alcohol 20, which was easily obtained from
diethyl
L
-tartrate by Somfai’s procedure in four steps,9
was subjected to Dess–Martin oxidation10 and then
Wittig reaction employing Ph3PꢀCH2 to furnish the
olefin 22 via 21 in 60% overall yield. Hydroboration of
22 utilizing dicyclohexylborane proceeded effectively to
give the alcohol 23 in 88% yield after the subsequent
oxidative work-up. Dess–Martin oxidation10 of the
resulting alcohol 23 yielded the aldehyde 24 in quantita-
TMS
Me
Me
Me
Me
Me
CHO
6
b
c
e
HO
OTr
HO
OTr
TIPSO
OR
OTr
TIPSO
OHC
a
5
TMS
8
9: R=Tr
10: R=H
11
d
7
f
Me
Me
Me
Me Me
Me
Me
Me
Me
TIPSO
TIPSO
TIPSO
TIPSO
m
l
n
i
R
3
R
Me
Me
Me
n-Bu3Sn
CO2Et
Me
CO2Et
12: R=CO2Et
13: R=CH2OH
14: R=CHO
15: R=CO2Et
16: R=CH2OH
17: R=CHO
g
h
j
19
18
k
Scheme 1. Reagents and conditions: (a) n-BuLi, THF, −78°C, 13 h, 60%; (b) K2CO3, MeOH, 25°C, 2 h, 99%; (c) TIPSOTf, Py,
0°C, 1 h, 90%; (d) CSA, MeOH–CH2Cl2, 30°C, 40 min, 87%; (e) (COCl)2, DMSO, Et3N, CH2Cl2, −78°C, 20 min; (f)
Ph3PꢀC(Me)CO2Et, PhMe, 110°C, 13 h, 96% (E/Z=100/0) from 10; (g) DIBAL-H, PhMe, −78°C, 30 min, 98%; (h) MnO2,
CH2Cl2, 25°C, 1 h, 95%; (i) Ph3PꢀC(Me)CO2Et, PhMe, 110°C, 14 h, 99% (E/Z=97/3); (j) DIBAL-H, PhMe, −78°C, 1 h, 97%;
(k) MnO2, CH2Cl2, 25°C, 30 min, 98%; (l) (EtO)2(O)PCH(Me)CO2Et, n-BuLi, THF, 0°C, 13 h, 99% (E/Z=100/0); (m) n-Bu3SnH,
cat. PdCl2(PPh3)2, PhMe, 0°C, 45 min, 92%; (n) LiOH (aq.), 1,4-dioxane, 80°C, 10 h, 79%.

K. Toshima et al. / Tetrahedron Letters 42 (2001) 8873–8876
8875
OMPM
OMPM
OMPM
HO
OMPM
OHC
OMPM
HO
OHC
b
c
d
a
O
O
O
O
O
O
O
O
O
O
Me
Me
Me
Me
Me
Me
Me
22
Me
23
Me
24
Me
21
20
OTBS
25
e
n-Bu3Sn
I
R
OTBS
MeO
RO
OTBS
MeO
Me
l
OTBS
OTBS
OMPM
OMPM
g
OMPM
k
i
OMPM
4
MeO
RO
O
O
O
O
O
Me
O
O
O
Me
Me
Me
Me
Me
Me
Me
32
26: R=H
30: R=H
31: R=Me
28: R=H
j
h
f
27: R=Me
29: R=Ts
Scheme 2. Reagents and conditions: (a) Dess–Martin periodinane, Py, 25°C, 1 h, 73%; (b) Ph3PꢀCH2, PhH, 25°C, 2.5 h, 81%; (c)
(c-Hex)2BH, THF, 25°C, 1 h, 88%; (d) Dess–Martin periodinane, 25°C, 1 h, 99%; (e) MgBr2·Et2O, CH2Cl2, −20°C, 14 h, 83%;
(f) MeOTf, 2,6-di-tert-butylpyridine, 25°C, 10 h, 90%; (g) (c-Hex)2BH, THF, 25°C, 1 h, 89%; (h) TsCl, Et3N, TMEDA, MeCN,
0°C, 1 h, 95%; (i) LiCꢁCH, DMSO, 25°C, 30 min, 86%; (j) MeI, n-BuLi, THF, 25°C, 1 h, 96%; (k) Cp2ZrHCl, NIS, THF, 0°C,
15 min, 80%; (l) DDQ, CH2Cl2–H2O, 25°C, 18 h, 99%.
tive yield. At this stage, it was found that the addition
of the allylstannane 2511 to 24 in the presence of
MgBr2·OEt2 in CH2Cl2 at −20°C proceeded with high
stereoselectivity consistent with b-chelation control to
give a 92:8 mixture of the desired alcohol 26 and the
diastereomer in 91% combined yield. Methylation of the
hydroxy group in 26 using MeOTf and 2,6-di-tert-
butylpyridine furnished 27 whose terminal olefin under-
went hydroboration employing dicyclohexylborane to
provide the alcohol 28 in 80% overall yield. It was found
that methylation using MeI and NaH in DMF caused the
migration of the silyl group in 26. Tosylation of the
alcohol 28 yielded the tosylate 29 which was subjected
to the reaction with lithium acetylide in DMSO to give
the acetylene 30 via 29 in 82% overall yield. After
methylation of the terminal alkyne in 30 using MeI and
n-BuLi, the resulting 31 was treated with Cp2ZrHCl and
NIS in THF12 to afford only the trisubstituted trans-vinyl
iodide 32 in 77% overall yield as the sole isolated product.
Finally, selective deprotection of the MPM group in 32
using DDQ13 afforded the secondary alcohol 4 in quan-
titative yield.
With both key intermediates 3 and 4 in hand, the
synthesis of the C1–C21 macrocyclic lactone (2) was
addressed (Scheme 3). The esterification of the carboxylic
acid 3 and the secondary alcohol 4 was best effected by
the Yamaguchi method14 to give the ester 33 in 89% yield.
Unfortunately, the macrocyclizations of the fully pro-
tected 33 by intramolecular Stille coupling under several
conditions failed. After many attempts, we finally found
that the macrocyclization of 34, which was obtained by
TBAF-mediated deprotection of two silyl groups in 33
in 67% yield, was realized by intramolecular Stille
coupling15 using a catalytic amount of PdCl2(MeCN)2 in
the presence of Ph2PO2NBu416 and LiCl in DMF at 25°C
for 3 h to furnish the desired 20-membered lactone 2 in
30% yield as the only isolated product.17
Me Me
TIPSO
Me Me
HO
Me
Me
n-Bu3Sn
O
n-Bu3Sn
O
b
c
a
HO Me
TBSO Me
2
+
3
4
O
O
MeO
Me O
MeO
I
I
Me
O
O
O
Me
Me
Me
Me
33
34
Scheme 3. Reagents and conditions: (a) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, 4-DMAP, PhMe, 25°C, 16 h, 89%; (b) TBAF,
THF, 25°C, 12 h, 67%; (c) cat. PdCl2(MeCN)2, Ph2PO2NBu4, LiCl, DMF, 25°C, 3 h, 30%.

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K. Toshima et al. / Tetrahedron Letters 42 (2001) 8873–8876
In conclusion, we have demonstrated, for the first time,
the stereoselective and convergent synthesis of the
apoptolidin macrocyclic core by the macrocyclization
using the intramolecular Stille coupling reaction.
5. Nicolaou, K. C.; Li, Y.; Weyershausen, B.; Wei, H.
Chem. Commun. 2000, 307.
6. Sulikowski, G. A.; Lee, W.-M.; Jin, B.; Wu, B. Org. Lett.
2000, 2, 1439.
7. Kawabata, T.; Kimura, Y.; Ito, Y.; Terashima, S. Tetra-
hedron Lett. 1986, 27, 6241.
Acknowledgements
8. Zhang, H. X.; Guibe, F.; Balavoine, G. J. Org. Chem.
1990, 55, 1857.
9. Somfai, P.; Olsson, R. Tetrahedron Lett. 1993, 34, 6645.
10. Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 24, 4155.
11. Keck, G. E.; Abbott, D. E.; Wiley, M. R. Tetrahedron
Lett. 1987, 28, 139.
We thank Dr. T. Jyojima and Mr. M. Fujii for their
early contribution to this study.
12. (a) Wailes, P. C.; Weigold, H.; Bell, A. P. J. Organomet.
Chem. 1971, 27, 373; (b) Hart, D. W.; Blackburn, T. F.;
Schwartz, J. J. Am. Chem. Soc. 1975, 97, 679.
13. Oikawa, Y.; Yoshioka, T.; Yonemitsu, O. Tetrahedron
Lett. 1982, 23, 885.
References
1. Kim, J. W.; Adachi, H.; Shin-ya, K.; Hayakawa, Y.;
Seto, H. J. Antibiot. 1997, 50, 628.
2. (a) Salomon, A. R.; Voehringer, D. W.; Herzenberg, L.
A.; Khosla, C. Chem. Biol. 2001, 8, 71; (b) Salomon, A.
R.; Zhang, H.; Seto, H.; Khosla, C. Org. Lett. 2001, 3,
57.
3. Hayakawa, Y.; Kim, J. W.; Adachi, H.; Shin-ya, K.;
Fujita, K.; Seto, H. J. Am. Chem. Soc. 1998, 120, 3524.
4. (a) Schuppan, J.; Ziemer, B.; Koert, U. Tetrahedron Lett.
2000, 41, 621; (b) Schuppan, J.; Wehlan, H.; Keiper, S.;
Koert, U. Angew. Chem., Int. Ed. 2001, 40, 2063.
14. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.;
Yamaguchi, M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.
15. Stille, J. K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
16. Srogl, J.; Allred, G. D.; Liebeskind, L. S. J. Am. Chem.
Soc. 1997, 119, 12376.
17. In contrast to Nicolaou’s5 and Koert’s4b observations, an
alternative route towards this macrocycle, including a
macrolactonization using several methods, was less effec-
tive than the present macrocyclization.