Synthesis of the C13-C23 segment of tedanolide

Article abstract of DOI:10.1055/s-2005-862391

The synthesis of the C13-C23 segment of tedanolide is described making use of orthogonal protecting groups in the construction of the carbon skeleton and for the selective liberation of hydroxyl groups in the endgame of the total synthesis.

Full text of DOI:10.1055/s-2005-862391

LETTER
655
Synthesis of the C13-C23 Segment of Tedanolide
Synthesis of the
C
1
u
3-C23 Fragm
n
ent of
T
eda
n
nolide ar Ehrlich, Markus Kalesse*
Universität Hannover, Institut für Organische Chemie, Schneiderberg 1B, 30167 Hannover, Germany
Fax +49(511)7623011; E-mail: Markus.Kalesse@oci.uni-hannover.de
Received 3 December 2004
OH
Abstract: The synthesis of the C13-C23 segment of tedanolide is
described making use of orthogonal protecting groups in the con-
5
O
OH
1
struction of the carbon skeleton and for the selective liberation of
hydroxyl groups in the endgame of the total synthesis.
O
OMe O
23
17
12
Key words: tedanolide, natural product, aldol, protecting groups
O
OH
O
R
O
R = OH, tedanolide 1
R = H, 13-deoxytedanolide 2
Tedanolide1 (1) and 13-deoxytedanolide (2) are poly-
ketide natural products that were isolated from marine
sources by Schmitz1 and Fusetani2, respectively
(Figure 1). Their promising anti-tumor activity in combi-
nation with their limited availability prompted several
research groups to investigate the synthetic access to these
natural products.3 The challenging structure has focused
the retro-synthetic analyses to certain pivotal disconnec-
tion in such as the aldol coupling between the C1-C12 and
the C13-C23 segment. Inspired by the fundamental contri-
butions of Roush et al. on this transformation, we also
chose the aldol connection to join both hemispheres of
the molecule. In contrast to the Roush approach we de-
cided to establish a C14-C15-syn configuration in the
aldehyde segment, which requires a challenging Felkin-
controlled aldol coupling. Recently, Smith et al. published
the first total synthesis of 13-deoxytedanolide (2),4 while
the total synthesis of tedanolide still remains to be accom-
plished.
PMB
TES
OTBS
O
1
OMe O
O
O
O
OTBS
13
HO
17
12
OTBS
23
OR
3
R = MEM,
SEM,
4
5
6
Felkin opposing
MOM,
Figure 1 Retrosynthetic disconnection of tedanolide (1)
using p-TsOH followed by a sequence of Dess–Martin
oxidation, olefination and reduction furnished allylic al-
cohol 12.
Next we performed a MnO2 oxidation of the allylic alco-
hol 12 and used the so-derived aldehyde for an aldol reac-
tion with ethyl acetate. DIBALH reduction followed by
protection of the primary alcohol as the TBS ether provid-
ed compound 14 that could be used in the aldol coupling
with aldehyde 15, also derived from the Roche ester 7.
Based on the contributions from Roush et al. and Smith et
al. we decided to perform the epoxidation as one of the lat-
est steps in the synthesis. Additionally, we envisioned to
protect the hydroxyl groups at C17 as the TBS ether and
at C15 as PMB ether, respectively. In order to find the op-
timal protecting group for the primary alcohol we estab-
lished a route that could be used for introducing either the
MOM, MEM or SEM protecting groups. The correct
choice of this protecting group seems to be one of the piv-
otal steps since it would have to tolerate the preceding
transformations and should be removed under mild condi-
tions prior to the macro lactonization.
1. Dess–Martin
1. TrCl, Et3N
CH2Cl2, r.t.
TrO
OH
OH
O
CH2Cl2, 0 °C, 81%
2. Ph3PCH2CH3+Br –
BuLi, THF, –78 °C
then r.t., 89%
OMe
2. LiAlH4, THF
40 °C, 93%,
2 steps
8
7
1. p-TsOH,
EtO2C
PPh3
TrO
1.
MeOH/CH2Cl2,
78%
11
O
2. Dess–Martin,
CH2Cl2, 0 °C
2. DIBALH, THF,
–78 °C, 65% 3 steps
We started from the Roche ester (7) by protecting with the
acid labile trityl protecting group. Reduction with LiAlH4
and subsequent Dess–Martin Oxidation provided the
aldehyde which in turn was subjected to a Wittig olefina-
tion to establish the desired Z-configured double bond
(Z/E = 93:7) (Scheme 1). Removal of the trityl group
9
10
Z/E = 93:7
OH
12
E/Z > 95:5
SYNLETT 2005, No. 4, pp 0655–0657
Advanced online publication: 22.02.2005
0
4.
0
3.
2
0
0
5
Scheme 1 Synthesis of allylic alcohol 12
DOI: 10.1055/s-2005-862391; Art ID: G44504ST
© Georg Thieme Verlag Stuttgart · New York

656
G. Ehrlich, M. Kalesse
LETTER
PMP
O
Dess–Martin oxidation and transformation to the bis-cy-
clohexyl boron enolate was accomplished prior to the
anti-selective aldol reaction with aldehyde 15. We could
isolate the desired anti-aldol product from a 2:1 mixture
of the Felkin and anti-Felkin product, respectively
(Scheme 2).
DDQ, MS
CH2Cl2,
0 °C, 83%
PMBO
OH
O
O
O
OTBS
OTBS
16
17
In the end game of the synthesis we finally had to establish
the appropriate positioning of protecting groups and had
to set the desired configuration at C17.
PMP
O
1. HF/pyridine
THF, pyridine, r.t.
O
OH
OH
NaH, THF, MEMCl
0 °C, 71%
2. Zn(BH4)2, Et2O,
–78 °C, 82%
18
OH
O
OH
dr > 95:5
1. MnO2, Et2O, 90%
EtO
PMP
1. TBSOTf,
CH2Cl2,
0 °C, 76%
2. CH3COOEt,
LDA, THF, –78 °C
86%
PMB
13
OH
O
OTBS
O
O
OH
12
2. DIBALH,
toluene,
–16 °C, 67%
TBSO
OH
OMEM
OMEM
19
20
1. Dess–Martin
CH2Cl2, 0 °C
1. DIBALH, THF
–78 °C, 93%
PMB
14
TPAP/NMO
quant.
2. Cy2BCl, Et3N
–78 °C, then –5 °C,
2. TBSCl, imidazole,
CH2Cl2, 90%
O
O
OTBS
16 h, then
PMBO
O
–78 °C to –25 °C,
16 h, 70%
OMEM
21
PMBO
OH
O
15
Scheme 3 Synthesis of the C13-C23 segment of tedanolide (1)
OTBS
Felkin:anti-Felkin = 2:1
16
Chem. Pharm. Bull. 1998, 46, 1335. (c) Liu, J.-F.; Abiko,
A.; Pei, Z.; Buske, D. C.; Masamune, S. Tetrahedron Lett.
1998, 39, 1873. (d) Taylor, R. E.; Ciavarri, J. P.; Hearn, B.
R. Tetrahedron Lett. 1998, 39, 9361. (e) Roush, W. R.;
Lane, G. C. Org. Lett. 1999, 1, 95. (f) Matsushima, T.;
Mori, M.; Zheng, B.-Z.; Maeda, H.; Nakajima, N.; Uenishi,
J.; Yonemitsu, O. Chem. Pharm. Bull. 1999, 47, 308.
(g) Jung, M. E.; Karama, U.; Marquez, R. J. Org. Chem.
1999, 64, 663. (h) Matsushima, T.; Zheng, B.-Z.; Maeda,
H.; Nakajima, N.; Uenishi, J.; Yonemitsu, O. Synlett 1999,
780. (i) Smith, A. B. III; Lodise, S. A. Org. Lett. 1999, 1,
1249. (j) Zheng, B.-Z.; Maeda, H.; Mori, M.; Kusaka, S.-i.;
Yonemitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J.
Chem. Pharm. Bull. 1999, 47, 1288. (k) Jung, M. E.;
Marquez, R. Tetrahedron Lett. 1999, 40, 3129.
Scheme 2 Synthesis of ketone 16
Therefore the PMB group was oxidized with DDQ in the
absence of water to provide PMP acetal 17. Liberation of
the primary hydroxyl with HF–pyridine allowed chelation
controlled reduction of the keton with Zn(BH4)2 accord-
ing to the work published by Yonemitsu.3h At this stage a
variety of different protecting groups could be introduced.
The 2-methoxyethoxymethyl protecting group was intro-
duced by deprotonation with NaH and subsequent treat-
ment with MEMCl. Finally, reductive acetal cleavage
with DIBALH followed by TPAP oxidation furnished al-
dehyde 215 for the aldol coupling with the western hemi-
sphere of tedanolide (Scheme 3). The remaining aldol
step and macrolactonization procedure towards the total
synthesis of tedanolide will be reported in due course.
(l) Matsushima, T.; Nakajima, N.; Zheng, B.-Z.; Yonemitsu,
O. Chem. Pharm. Bull. 2000, 48, 855. (m) Zheng, B.-Z.;
Yamauchi, M.; Dei, H.; Kusaka, S.-I.; Matsui, K.;
Yonemitsu, O. Tetrahedron Lett. 2000, 41, 6441.
(n) Zheng, B.-Z.; Yamauchi, H.; Dei, H.; Yonemitsu, O.
Chem. Pharm. Bull. 2000, 48, 1761. (o) Jung, M. E.;
Marquez, R. Org. Lett. 2000, 2, 1669. (p) Jung, M. E.; Lee,
C. P. Org. Lett. 2001, 3, 333. (q) Loh, T.-P.; Feng, L.-C.
Tetrahedron Lett. 2001, 42, 6001. (r) Loh, T.-P.; Feng, L.-
C. Tetrahedron Lett. 2001, 42, 3223. (s) Matsui, K.; Zheng,
B.-Z.; Kusaka, S.-I.; Kuroda, M.; Yoshimoto, K.; Yamada,
H.; Yonemitsu, O. Eur. J. Org. Chem. 2001, 3615.
(t) Hearn, B. R.; Ciavarri, J. P.; Taylor, R. E. Org. Lett. 2002,
4, 2953.
References
(1) Tedanolide was isolated from Tedania ignis: Schmitz, F. J.;
Gunasekera, S. P.; Yalamanchili, G.; Hossain, M. B.; van der
Helm, D. J. Am. Chem. Soc. 1984, 106, 7251.
(2) 13-Deoxytedanolide was isolated from Mycale adhaerens:
Fusetani, N.; Sugawara, T.; Matsunaga, S.; Hirota, H. J. Org.
Chem. 1991, 56, 4971.
(4) (a) Smith, A. B. III; Adams, C. M.; Barbosa, S. A. L.;
Degnan, P. J. Am. Chem. Soc. 2003, 125, 350. (b) Smith, A.
B. III; Adams, C. M.; Barbosa, S. A. L.; Degnan, P. Proc.
Natl. Acad. Sci. U.S.A. 2004, 101, 12042.
(3) (a) Matsushima, T.; Horita, K.; Nakajima, N.; Yonemitsu, O.
Tetrahedron Lett. 1996, 37, 385. (b) Matsushima, T.; Mori,
M.; Nakajima, N.; Maeda, H.; Uenishi, J.; Yonemitsu, O.
Synlett 2005, No. 4, 655–657 © Thieme Stuttgart · New York

LETTER
Synthesis of the C13-C23 Fragment of Tedanolide
657
(5) Spectroscopic analysis for 20:
13C NMR (100 MHz, CDCl3): d = 159.1 (s), 135.0 (d), 133.8
(s), 132.1 (d), 130.9 (s), 129.2 (d, 2 C), 121.8 (d), 113.7 (d,
2 C), 95.9 (t), 79.5 (d), 77.5 (d), 71.8 (t), 67.7 (t), 66.8 (t),
66.1 (t), 59.0 (q), 55.2 (q), 44.1 (d), 37.7 (d), 30.3 (d), 25.9
(q, 3 C), 21.0 (q), 18.1 (s), 13.0 (q), 12.9 (q), 12.2 (q), –4.3
(q), –5.1 (q).
1H NMR (400 MHz, CDCl3): d = 7.23 (d, J = 8.0 Hz, 2 H),
6.88 (d, J = 8.5 Hz, 2 H), 5.30 (dq, J = 10.9 Hz, J = 6.6 Hz,
1 H), 5.25–5.21 (m, 2 H), 4.59 (s, 2 H), 4.55 (d, J = 11.2 Hz,
1 H), 4.36 (d, J = 11.2 Hz, 1 H), 4.12 (m, 1 H), 3.78 (s, 3 H),
3.77–3.73 (m, 1 H), 3.68–3.56 (m, 4 H), 3.49 (t, J = 4.6 Hz,
2 H), 3.47–3.42 (m, 1 H), 3.40–3.35 (m, 1 H), 3.34 (s, 3 H),
3.31 (dd, J = 9.7 Hz, J = 6.6 Hz, 1 H), 2.40 (br s, 1 H), 2.37–
2.30 (m, 1 H), 2.13–2.03 (m, 1 H), 1.63–1.58 (m, 6 H), 0.97
(d, J = 6.8 Hz, 3 H), 0.95 (d, J = 7.0 Hz, 3 H), 0.83 (s, 9 H),
–0.02 (s, 3 H), –0.07 (s, 3 H) ppm.
HRMS (LC-MS, ESI): m/z calcd for C33H58O7SiNa+:
617.3850; found: 617.3864.
IR: 3455 (br), 3010 (w), 2956 (s), 2928 (s), 2888 (s), 2858
(s), 1613 (w), 1514 (m), 1463 (w), 1363 (w), 1301 (w), 1248
(s), 1174 (w), 1040 (ss), 837 (m), 776 (m), 740 (m) cm–1.
[a]D25 +21.9 (c 1.04, CHCl3).
Synlett 2005, No. 4, 655–657 © Thieme Stuttgart · New York