Synthesis of the C1-C11 segment of tedanolide via vinylogous Mukaiyama aldol reaction

Article abstract of DOI:10.1055/s-2002-35582

The successful construction of complex natural products depends to a large extent on how efficiently key intermediates can be generated. Here we report our efforts towards the first total synthesis of tedanolide (1), employing Evans' aldol methodology in combination with a vinylogous Mukaiyama aldol reaction (VMAR) and Sharpless' asymmetric dihydroxylation. This protocol allows for rapid access to its numerous chiral centers.

Full text of DOI:10.1055/s-2002-35582

LETTER
2007
Synthesis of the C1–C11 Segment of Tedanolide via Vinylogous Mukaiyama
Aldol Reaction
Synthesis
o
of the
C
1-C
1
r
1 Segme
m
nt of Tedanolide a Hassfeld, Markus Kalesse*
Institut für Chemie der Freien Universität Berlin, Fachbereich Organische Chemie, Takustrasse 3, 14195 Berlin, Germany
Fax +49(30)83855644; E-mail: Kalesse@chemie.fu-berlin.de
Received 3 September 2002
the fact that the three ketone carbonyl groups in the natu-
Abstract: The successful construction of complex natural products
ral product are sensitive to retro-aldol processes. We
therefore decided to carry them through the synthesis as
protected alcohols, which could be liberated and oxidized
depends to a large extent on how efficiently key intermediates can
be generated. Here we report our efforts towards the first total syn-
thesis of tedanolide (1), employing Evans’ aldol methodology in
combination with a vinylogous Mukaiyama aldol reaction (VMAR) at a later stage. With theses prerequisites in mind we gen-
and Sharpless’ asymmetric dihydroxylation. This protocol allows
for rapid access to its numerous chiral centers.
erated the C1–C11 segment as the all syn-polyketide in
which the C5-ketone was the TES-protected alcohol.
Key words: aldol reactions, Mukaiyama, natural products, dihy-
droxylations, stereoselective synthesis
OH
O
OH
5
7
1
3
Tedanolide (1) and 13-deoxytedanolide (2) are two potent
marine natural products that were isolated and whose
structure was elucidated by Schmitz et al.1 and Fusetani et
al.,2 respectively (Figure 1). Due to their challenging
structure in combination with their promising anti-tumor
activity, a variety of fragment syntheses have been put
forward.3
O
15
O
OMe O
9
13
19
17
11
21
O
OH
R
O
1
2
R = OH Tedanolide
R = H 13-Deoxytedanolide
Our retrosynthetic analysis (Scheme 1) dissected tedano-
lide between C12 and C13. In synthetic direction, this
coupling could be performed by an aldol reaction. An el-
egant analysis of aldol reactions of such methyl ketones
has been reported by Roush et al. who demonstrated that
both the -methyl group of the methyl ketone and the ste-
reochemistry of the aldehyde direct the stereochemical
outcome of the reaction towards the Felkin product.3e,4
Another obvious problem in a total synthesis of 1 and 2 is
Figure 1 Tedanolide and 13-deoxytedanolide.
Fueled by our work on the synthesis of ratjadone,5 we fo-
cused on the vinylogous Mukaiyama aldol reaction as a
method for the rapid access to aldol segments. The use of
silyl ketene acetal 12 substitutes the sequence of a propi-
onate aldol reaction followed by Wittig olefination and
circumvents functional group manipulations. In earlier
aldol
O
OMe O
OTBS
O
OH
O
OTBS
1
HO
13
1
7
9
11
15
17
19
21
3
5
12
OTBS
OH
3
TES
OMe
O
O
OTBS
O
O
OH OTBS
OPMB
MeO
MeO
OTBS
4
5
Scheme 1 Retrosynthetic analysis of tedanolide.
Synlett 2002, No. 12, Print: 02 12 2002.
Art Id.1437-2096,E;2002,0,12,2007,2010,ftx,en;G25602ST.pdf.
© Georg Thieme Verlag Stuttgart · New York
ISSN 0936-5214

2008
J. Hassfeld, M. Kalesse
LETTER
studies from our group, the use of a sterically demanding When aldehyde 11 was reacted with 2 equivalents of
Lewis acid such as tris(pentafluorophenyl)borane (TPPB) ketene acetal 12 using 0.6 equivalents of tris(pentafluoro-
was shown to be essential for achieving high syn-selectiv- phenyl)borane (TPPB) at –78 °C in CH2Cl2/diethyl ether
ity and Felkin control (Scheme 2).6
(9:1), two products, 14a and 14b were isolated
(Scheme 3). Studies from Hoffmann et al.7 have shown
that the 13C chemical shift for the methyl groups in the all
syn stereotriad is significantly high-field shifted ( <10
ppm) compared to structures with at least one anti rela-
tionship ( >10 ppm). This analysis requires a hydrogen
bond between the two adjacent oxygen functionalities.
These bis-TBS ethers (14a and 14b) were therefore con-
verted to mono-TBS protected ethers 15a and 15b by se-
lective deprotection at the C7 hydroxy group. This was
The synthesis started from enantiomerically pure PMB-
protected methyl-hydroxyisobutyrate (6) that was con-
verted to aldehyde
7 under standard conditions
(Scheme 2). Wittig-olefination generated the , -unsatur-
ated ester in 95% yield. DIBALH reduction followed by
oxidation with MnO2 furnished aldehyde 8 in 88% yield
over two steps. The remaining propionate subunit of alde-
hyde 11 was introduced by an Evans aldol reaction, which
was followed by transamination and TBS-protection
(77% yield over two steps). The Weinreb amide (10) was
directly reduced to aldehyde 11 by the aid of DIBALH.
This sets the stage for the pivotal vinylogous Mukaiyama
aldol reaction.
achieved by using HF·pyridine in pyridine/THF. The 13
C
NMR spectrum showed the signal for the C6 methyl
groups at -values of 9.51 ppm and 9.14 ppm for the major
(15a) and minor isomer (15b), respectively, thus indicat-
ing the all-syn stereochemistry in both cases (Felkin con-
trol, Scheme 3).
O
OPMB
O
OPMB
O
OPMB
a, b
c - e
MeO
8
6
7
f
O
OH
OPMB
O
O
O
OTBS
OPMB
g, h
MeO
N
N
Bn
10
9
i
O
OH OTBS
OPMB
O
OTBS
OPMB
j
MeO
OTBS
MeO
11
13
12
Scheme 2 Synthesis of 13. Reagents and conditions: a) DIBALH, CH2Cl2, 93%; b) Dess–Martin-periodinane, CH2Cl2, 90%;
c) Ph3P=C(CO2Et)Me, CH2Cl2, 95%; d) DIBALH, CH2Cl2, 90%; e) MnO2, CH2Cl2, 98%; f) (R)-4-benzyl-3-propionyl-2-oxazolidinone,
(n-Bu)2BOTf, NEt3, CH2Cl2, 82%; g) AlMe3, N,O-dimethyl-hydroxylamine hydrochloride, CH2Cl2; h) TBSOTf, 2,6-lutidine, CH2Cl2,
77% over 2 steps; i) DIBALH, THF, 89%; j) tris(pentafluorophenyl)borane (TPPB), ketene acetal 12, isopropyl alcohol, Et2O, 62%.
O
TBSO
OR
OPMB
4
5
6
Felkin-product
MeO
14a : R = TBS
15a : R = H
O
OTBS
OPMB
b
b
a
O
TBSO
OR
OPMB
OTBS
4
6
MeO
5
MeO
Felkin-product
11
12
14b : R = TBS
15b : R = H
14a : 14b = 2:1 = C4/C5 syn:anti
Scheme 3 Reagents and conditions: a) 12 (2 equiv), TPPB (0.6 equiv), CH2Cl2/Et2O (9:1), –78 °C, r.t, 2 h, 72%; b) HF·pyridine, THF/pyridine
(1:1), r.t., 30 h, 56%.
Synlett 2002, No. 12, 2007–2010 ISSN 0936-5214 © Thieme Stuttgart · New York

LETTER
Synthesis of the C1-C11 Segment of Tedanolide
2009
TES
O
OH OTBS
OPMB
O
OH
O
OTBS
OPMB
a, b
MeO
MeO
OH
13
16
c, d
TES
TES
OTBS
O
OMe O
OTBS
O
O
OMe O
OPMB
MeO
TBSO
MeO
TBSO
4
17
Scheme 4 Reagents and conditions: Synthesis of 16: a) TESOTf, 2,6-lutidine, CH2Cl2, 93%; b) AD-mix- , t-BuOH-H2O, 88% (94% de);
c) TBSCl, imidazole, DMF, 91%; d) MeOTf, 2,6-di-t-butylpyridine, CHCl3, 60%.
Chem. Pharm. Bull. 1998, 46, 1335. (c) Liu, J.-F.; Abiko,
In optimization studies for this pivotal reaction, when al-
dehyde 11 was treated with 2 equivalents of ketene acetal
12 using 1 equivalent of TPPB and 1 equivalent of isopro-
panol in diethyl ether, only aldol product 13 was isolated.
(Scheme 2).8 As before, its stereochemistry was assigned
unambiguously using 13C NMR data. A stoichiometric
amount of alcohol is necessary in order to trap reactive sil-
icon species liberated in the course of the reaction. It is
known that these R3Si+ species can catalyze aldol reac-
tions albeit with little or no stereocontrol. Failure to
quench them leads to the formation of isomer 14b. Inter-
estingly, use of BF3 OEt2 as sterically less demanding
Lewis acid exclusively alkylates the ketene acetal at the -
position.
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.
(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.
Continuing with the synthesis of tedanolide, the newly
generated secondary alcohol was TES-protected and sub-
sequent Sharpless dihydroxylation to 16 stereoselectively
established the remaining stereocenters of the all-syn
polyketide fragment (Scheme 4).3b,f The alcohol at C2
could be selectively protected as TBS-ether and the re-
maining hydroxyl group at C3 was transformed into the
methyl ether 17 using MeOTf and di-tert-butylpyridine
for the O-alkylation. These transformations completed the
synthesis of the C1–C11 segment in which 6 chiral centers
were selectively generated in 14 steps and 9.6% overall
yield. Additionally, the hydroxyl groups have been differ-
entially protected thus allowing for selective removal fol-
lowed by functional group transformations in the
endgame of the synthesis. Progress on the total synthesis
will be reported in due course.
(4) Roush, W. R.; Bannister, T. D.; Wendt, M. D.; Jablonowski,
J. A.; Scheidt, K. A. J. Org. Chem. 2002, 67, 4275.
(5) (a) Christmann, M.; Bhatt, U.; Quitschalle, M.; Claus, E.;
Kalesse, M. Angew. Chem. Int. Ed. 2000, 39, 4364; Angew.
Chem. 2000, 112, 4535. (b) Christmann, M.; Bhatt, U.;
Quitschalle, M.; Claus, E.; Kalesse, M. J. Org. Chem. 2001,
66, 1885.
(6) (a) Christmann, M.; Kalesse, M. Tetrahedron Lett. 2001, 42,
1269. (b) Hassfeld, J.; Christmann, M.; Kalesse, M. Org.
Lett. 2001, 3, 3561. (c) Hassfeld, J.; Kalesse, M.
Tetrahedron Lett. 2002, 43, 5093.
(7) Hoffmann, R. W.; Weidmann, U. Chem. Ber. 1985, 118,
3980.
References
(1) Tedanolide was isolated from Tedanis 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.
(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.
(8) Aldehyde 11 (92 mg, 0.218 mmol) dissolved in diethyl ether
(2 mL) was cooled to –78 °C under an argon atmosphere.
Tris(pentafluorophenyl)borane (110 mg, 0.217 mmol) was
added and a mixture of ketene acetal 12 (100 mg, 0.438
mmol) and isopropyl alcohol (17 L, 0.24 mmol) dissolved
Synlett 2002, No. 12, 2007–2010 ISSN 0936-5214 © Thieme Stuttgart · New York

2010
J. Hassfeld, M. Kalesse
LETTER
in diethyl ether (1 mL) was added via syringe pump over 6
h. An additional equivalent of ketene acetal 12 (100 mg,
0.438 mmol) was added in diethyl ether (1 mL) over 4 h.
After complete addition, the reaction was quenched by sat.
aq NaHCO3 (2 mL), slowly warmed to r.t. and stirred
overnight. Water (3 mL) was added and the mixture was
extracted with ether (2 15 mL). The organic layer was
separated, dried with MgSO4 and evaporated in vacuo. Flash
column chromatography using petroleum ether/ethyl acetate
(4:1) as eluent afforded 13 (73 mg, 62%) as a colorless oil.
1H NMR (400 MHz, CDCl3): = 7.21 (d, J = 8.78 Hz, 2 H),
6.85 (d, J = 8.78 Hz, 2 H), 6.70 (dd, J = 15.69, 9.29 Hz,
1 H), 5.80 (dd, J = 15.69, 0.75 Hz, 1 H), 5.16 (d, J = 9.54
Hz, 1 H), 4.38 (s, 2 H), 3.87 (d, J = 7.44 Hz, 1 H), 3.77 (s,
3 H), 3.70 (s, 3 H), 3.28 (dd, J = 8.90, 5.90 Hz, 1 H), 3.28–
3.24 (m, 1 H), 3.18 (dd, J = 8.90, 8.03 Hz, 1 H), 2.77–2.66
(m, 1 H), 2.44–2.36 (m, 2 H), 1.59–1.51 (m, 1 H), 1.53 (d,
J = 1.25 Hz, 3 H), 0.97 (d, J = 6.52 Hz, 3 H), 0.90 (d,
J = 6.77 Hz, 3 H), 0.85 (d, J = 6.90 Hz, 3 H), 0.85 (s, 9 H),
0.02 (s, 3 H), –0.05 (s, 3 H); 13C NMR (100 MHz, CDCl3):
= 166.9, 159.2, 151.0, 136.2, 130.8, 130.3, 129.2, 120.7,
113.8, 82.4, 75.1, 72.7, 55.2, 51.4, 40.8, 39.7, 32.5, 26.9,
25.9, 18.1, 17.1, 16.7, 11.9, 8.1, –4.4, –5.1; HRMS calcd for
C30H50O6Si: 534.3377. Found: 534.3371.
Synlett 2002, No. 12, 2007–2010 ISSN 0936-5214 © Thieme Stuttgart · New York