Synthetic studies of tedanolide. 4. Stereoselective and efficient synthesis of the C13-C23 part

Article abstract of DOI:10.1055/s-1999-2730

The C13-C23 part (5) of tedanolide (1) war, synthesized starting from enantiomeric methyl (R)- and (S)-3-hydroxy-2-methylpropionates (8) via coupling between the C13-C17 aldehyde (6) and the C18-C21 iodoalkene (7).

Full text of DOI:10.1055/s-1999-2730

780
LETTER
Synthetic Studies of Tedanolide. 4. Stereoselective and Efficient Synthesis of
the C13-C23 Part
Tomohiro Matsushima,a Bao-Zhong Zheng,b Hiroshi Maeda,b Noriyuki Nakajima,c Jun-ichi Uenishib,
Osamu Yonemitsu*b
Faculty of Pharmaceutical Sciences, Hokkaido University,a Sapporo 060-0812, Department of Chemistry, Okayama University of Science,b
Okayama 700-0005, and Biotechnology Research Center, Toyama Prefectural University,c Kosugi, Toyama 939-0398, Japan
Fax: 81-86-256-8460; E-mail: yonemit@high.ous.ac.jp
Received 8 March 1999
23
Abstract: The C13-C23 part (5) of tedanolide (1) was synthesized
23
22
DMP
O
22
starting from enantiomeric methyl (R)- and (S)-3-hydroxy-2-meth-
ylpropionates (8) via coupling between the C13-C17 aldehyde (6)
and the C18-C21 iodoalkene (7).
O
1
O
5
20
O
1
OMe
3
O
5
18
17
20
3
O
18
7
O
OMOM
O
Key words: macrolide, cytotoxic activity, aldol reaction, benzyl
protecting group
O
7
MOMO
OMOM
17
OH
O
8
13
O
HO
R
13
OH
15
8
15
11
10
O
11
10
O
DMP
Tedanolide (1); R=OH
13-Deoxytedanolide (2); R=H
3
Tedanolide (1) is a potent cytotoxic macrolide isolated
from a Caribbean sponge, Tedania ignis, by Schmitz et al.
in 1984, and its structure was elucidated by X-ray analy-
sis.1a Its related compound 13-deoxytedanolide (2), isolat-
ed later from a Japanese marine sponge, Mycale
adhaerens, showed more potent cytotoxicity against P388
murine leukemia cells.1b This significant biological activ-
ity, along with unusual structural features, four labile al-
dol units, an a-epoxy alcohol, and an 18-membered
lactone constructed with the C16 primary (not the usual
secondary) hydroxy group, has prompted considerable
synthetic interest.2
DMP
DMP
O
O
1
O
3
O
5
OMOM
7
O
O
OMOM
17
HO
11
15
13
9
21
19
MOMO
23
OH
4
Figure 1 DMP: 3,4-(MeO)2C6H3-
MOM: MeOCH2-
Scheme 1 outlines the synthesis plan. The C13-C23 part
(5) would be synthesized by coupling between the C13-
C17 (6) and C18-C21 (7) fragments, which were obtained
from enantiomeric (R) and (S)-methyl 3-hydroxy-2-meth-
ylpropionates (R- and S-8), respectively.
Recently, we reported the synthesis of the 18-membered
lactone (3), a key intermediate to 1, via highly efficient
lactonization of the corresponding seco-acid (4), which
was designed with the aid of molecular mechanics (MM)
calculations, and synthesized via condensation of the C1-
C7, C8-C11, C13-C17, and C18-C21 fragments, although
the procedure required considerable improvement.2a
DMPM
O
O
OMOM
13
H
15
17
19
21
23
The selective protection strategy of different hydroxy
groups usually plays a key role in the successful synthesis
of polyol-containing compounds, and a variety of selec-
tive protecting groups such as silyl ethers and benzyl
ethers has been reported.3 Among the benzyl ethers, 4-
methoxybenzyl (MPM) and 3,4-dimethoxybenzyl
(DMPM) ethers4 were highlighted, because they can be
selectively cleaved5 or converted with a neighboring hy-
droxy group to a benzylidene acetal,6 which on regiose-
lective reductive opening7 gives an MPM or DMPM
ether.
OH
5
DMPMO
O
I
+
21 OTBDPS
13
15
TBDPSO
17 H
OTBS
19
6
7
O
O
MeO 19
MeO
OH
17
21 OH
15
(R)-8
(S)-8
The advantage of this MPM methodology was demon-
strated in the recent synthesis of the C1-C12 part of 1.2c In
this paper, we report a stereoselective and practical syn-
thesis of the C13-C23 part (5), almost a half molecular of
4, achieved successfully again, by taking advantage of the
DMPM protecting group.
Scheme 1 DMPM: 3,4-(MeO)2C6H3CH2-
Synlett 1999, No. 6, 780–782 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthetic Studies of Tedanolide
781
The synthesis of 6 from (R)-8 is shown in Scheme 2. (R)- Coupling of 6 and 710 was next carefully examined. Ex-
8 was first converted to the alkene (9), a common synthet- cess (1.5 equiv) 7 was first lithiated with tert-BuLi and al-
ic intermediate to the C1-C12 part, by using the procedure lowed to react with 6 at –78 ~ –30 °C. The coupling
described in our previous report.2c Oxidative cleavage of proceeded smoothly to give 18 as a 7.5 : 1 mixture of C17-
the double bond of 9 gave the aldehyde (10), which was isomers, but unfortunately the major product was the un-
then reduced with LiBH4, and protection of the resulting desired Cram adduct (18b). All attempts to selectively get
hydroxy group as a tert-butyldimethylsilyl (TBS) ether the desired chelation- controlled adduct (18a) by the addi-
gave 11. Regioselective reductive cleavage of the ben- tion of MgBr2OEt2 and ZnCl2 were unsuccessful. In order
zylidene acetal of 11 with DIBAH7 gave the primary alco- to convert the C17 configuration, selective reduction of
hol (12) in 54% yield, albeit accompanied with a by- the corresponding ketone (19), readily available by Dess-
product with loss of the TBS group in 30% yield. Subse- Martin oxidation11 of 18, was examined. However, reduc-
quent Swern oxidation of 12 completed the synthesis of 6. tion with LiAlH4 gave a 1 : 2 mixture (82%) of the desired
18a and the diol (21) deprotecting the TBS group, and
hence 19 was firstly subjected to selective deprotection of
DMP
DMP
the TBS group. Treatment of 19 with PPTS gave the ketol
(20) in 99% yield. Subsequent reduction of 20 with
Zn(BH4)212 proceeded with complete stereoselectivity due
to b-chelation of zinc with the C16 carbinol to give the de-
sired 21 as a single product in 96% yield. The C17 config-
uration was confirmed by NOE studies of the
corresponding 3,4-dimethoxybenzylidene acetal (22),
which was obtained by protection of the primary hydroxy
group of 21 with a pivaloyl group followed by oxidation
with DDQ.6 Protection of the diol of 21 by acetylation and
removal of the two TBDPS groups gave a new diol (23),
which was then treated with DDQ to selectively protect
the C13 hydroxy group as a benzylidene acetal6 and the al-
cohol (24) was isolated in excellent yield. Dess-Martin
oxidation of the C21 hydroxy group of 24 and subsequent
Wittig reaction with ethyltriphenyl-phosphonium bro-
mide and tert-BuOK led to the (Z)-alkene (25) with excel-
lent selectivity (15 : 1). Deprotection of the diacetyl
groups of 25 with LiAlH4 gave the diol (26). Protection of
the primary alcohol of 26 as a TBS ether and the second-
ary alcohol as a methoxymethyl (MOM) ether formed 27.
Selective cleavage of the benzylidene acetal of 27 with
DIBAH provided the alcohol (28), which was finally sub-
jected to Dess-Martin oxidation to achieve the synthesis
of the title compound (5). Coupling of 5 with the C1-C12
part, followed by macrolactonization to the lactone (3)
will be reported soon.
O
O
ref. 2c
O
O
i
(R)-8
TBDPSO
TBDPSO
8 steps
CHO
9
10
DMP
O
DMPMO
TBDPSO 13
15
O
ii
iii
iv
6
17 OH
OTBS
TBDPSO
OTBS
12
11
Scheme 2 i. a) OsO4, NMO, acetone-H2O (3 : 1), rt, 95%; b) NaIO4,
THF-H2O (1 : 1), rt, 100%. ii, a) LiBH4, Et2O, rt, 93%; b) TBSCl, imi-
dazole, CH2Cl2, rt, 100%. iii. DIBAH, CH2Cl2, -20°C, 54%. iv. DM-
SO, (COCl)2, CH2Cl2, Et3N, 98%.
A shorter and efficient synthesis of 6 was accomplished
by using Evans’ asymmetric aldol reaction.8 Thus, treat-
ment of (R)-13 with titanium enolate of the Evans auxilia-
ry (14)8a gave the desired syn adduct (15) in high
diastereoselectivity (>95% d.e.). Reduction of 15 with
9
LiBH4 and protection of the resulting diol as a DMPM
acetal gave 16, which was transformed to 6 in the usual
manner as described above.
O
O
N
O
O
ref. 2c
H
OTBDPS
(R)-8
14
References and Notes
3 steps
(R)-13
i
(1) a) Schmitz, F. J.; Gunasekera, S. P.; Yalamanchili, G.;
Hossain, M. B.; van der Helm, D. J. Am. Chem. Soc. 1984,
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Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi, J.;
DMP
O
OH
O
O
O
TBDPSO
N
O
ii
TBDPSO
15
16
DMPMO
iv
iii
6
TBDPSO
Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308. d) Liu, J.-
F.; Abiko, A.; Pei, Z.; Buske, D. C.; Masamune, S.
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P.; Hearn, B. R. Tetrahedron Lett. 1998, 39, 9361.
OTBS
17
Scheme 3 i. TiCl4, i-Pr2EtN, CH2Cl2, -76~0°C, 70%. ii, a) LiBH4,
cat. H2O, Et2O-THF, 87%; b) DMPCH(OMe)2, CSA, CH2Cl2, rt,
99%. iii, a) DIBAH, toluene, -30°C; b) TBSCl, imidazole, CH2Cl2,
0°C, 92%, in two-steps. iv, a) OsO4, NMO, acetone-H2O (3 : 1), rt;
b) NaIO4, THF-H2O (1 : 1), rt, 90%, in two-steps.
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Synlett 1999, No. 6, 780–782 ISSN 0936-5214 © Thieme Stuttgart · New York

782
T. Matsushima et al.
LETTER
DMPMO
O
R1
17
OTBS
DMPMO
13
R2
TBDPSO
OTBDPS
TBDPSO
OTBDPS
21
i
15
ii
19
iii
+
6
7
OTBS
18a : 19b= 1 : 7.5
19
18a : R1 = H, R2 = OH
18b : R1 = OH, R2 = H
DMPMO
OAc
DMPMO
OH
OH
DMPMO
O
HO
OH
TBDPSO
OTBDPS
TBDPSO
OTBDPS
iv
v
OAc
OH
20
21
23
DMP
DMP
O
DMP
O
DMP
O
O
O
OAc
O
OAc
O
OH
O
OMOM
vii
vi
viii
ix
OH
OAc
OAc
OH
OTBS
24
27
25
26
DMP
DMPM
O
O
O
OMOM
x
xi
5
TBDPSO
OTBDPS
HO 13
15
17
21
19
23
OPiv
22
OTBS
28
Scheme 4 i. tert-BuLi, Et2O, -78 ~ -30°C, 85%. ii. Dess-Martin reagent, pyridine, CH2Cl2, 0°C, 91%. iii. PPTS, EtOH, 50°C, 99%. iv.
Zn(BH4)2, Et2O, 0°C, 96%. v, a) Ac2O, Et3N, DMAP, CH2Cl2, rt, 96%; b) n-Bu4NF, AcOH, THF, rt, 100%. vi. DDQ, CH2Cl2, -10°C, 93%. vii,
a) Dess-Martin reagent, pyridine, CH2Cl2, 0°C, 92%; b) Ph3PCH2CH3Br, tert-BuOK, THF, rt. viii. LiAlH4, Et2O, rt, 74%, in two steps. ix, a)
TBSCl, imidazole, CH2Cl2, rt, 86%; b) MOMCl, i-Pr2EtN, CH2Cl2, rt, 100%. x. DIBAH, CH2Cl2, -50°C, 70%. xi. Dess-Martin reagent, pyridine,
CH2Cl2, rt, 100%.
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(10) The enantiomer of 7 was synthesized.2c
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Article Identifier:
1437-2096,E;1999,0,06,0780,0782,ftx,en;Y03699ST.pdf
Synlett 1999, No. 6, 780–782 ISSN 0936-5214 © Thieme Stuttgart · New York