Synthetic studies towards the total synthesis of tedanolide: Formation of the C(13)-C(23) fragment

Article abstract of DOI:10.1016/S0040-4039(01)00401-4

The C(13)-C(23) subunit of tedanolide was obtained using a boron-mediated aldol reaction as the key step to control the C₁₆ and C₁₇ stereocenters.

Full text of DOI:10.1016/S0040-4039(01)00401-4

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 3223–3226
Synthetic studies towards the total synthesis of tedanolide:
formation of the C(13)–C(23) fragment
Teck-Peng Loh* and Li-Chun Feng
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543, Singapore
Received 8 January 2001; revised 2 March 2001; accepted 8 March 2001
Abstract—The C(13)–C(23) subunit of tedanolide was obtained using a boron-mediated aldol reaction as the key step to control
the C16 and C17 stereocenters. © 2001 Elsevier Science Ltd. All rights reserved.
Tedanolide, an antitumor agent, was isolated from a
prevalent Caribbean sponge Tedania ignis by Schmitz
and co-workers1 in 1984 and its structure was eluci-
dated by means of X-ray analysis.1 This antitumor
macrolide features four labile aldol units, a side chain
containing an a-epoxy alcohol, an 18-membered lac-
tone and the crowded contiguous chiral centers from
C16 to C19, thus making the construction of this
molecule one of the most difficult and challenging tasks
for organic chemists. Tedanolide is highly cytotoxic,1
exhibiting ED50 values of 250 pg/mL in KB cell lines
and 16 pg/mL in PS cell lines. It also shows in vivo
antitumor activity,2 increasing the lifespan of mice
implanted with lymphocytic leukemia cells (23% at 1.56
mg/kg). In view of its intricate architecture and biologi-
cal activity, tedanolide has attracted extensive synthetic
studies.3–13 However, to date, there is still no reported
total synthesis of this molecule. In this article, we
present an efficient and stereoselective construction of
fragment C(13)–C(23).
Our retrosynthetic analysis of tedanolide 1 is outlined
in Fig. 1. Disconnection at the C29 lactone and between
C12 and C13 produces subunits 2 C(13)–C(23) and 3
C(1)–C(12). The key step in our synthetic plan involves
a boron-mediated aldol reaction developed by Paterson
and co-workers14 to construct fragment 2 with the
desired stereochemistry.
Our synthesis commences with the preparation of
ketone 5. Ketone 5 was prepared from the readily
available chiral aldehyde I15 (Scheme 1). Aldol reaction
of I with methyl acetate followed by DIBAL-H reduc-
tion provided alcohol 8 in 90% yield as a 55:45 mixture
of two isomers. Selective protection of the primary
alcohol with TBDMSCl in the presence of pyridine
afforded 9 as a mixture of two isomers.16 Finally, the
target ketone 5 was obtained through Dess–Martin
periodinane oxidation, amounting to 72% total yield
over four steps.
OH
OR
1
O
OH
O
+
OR"
OTBS
16 13
23
1
23
O
OMe O
12
OH OMe OR'
29
17
OPMB
13
16
17
O
12
O
OH OH
O
2
OH
O
OH O
R = TBS, R' = PMB
R" = TBDPS
Tedanolide 1
TBSO
+
3
TBDPSO
CHO
OPMB
4
5
O
Figure 1.
* Corresponding author.
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)00401-4

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T.-P. Loh, L.-C. Feng / Tetrahedron Letters 42 (2001) 3223–3226
Aldehyde 4 was synthesized from the commercially
available (S)-methyl 3-hydroxy-2-methylpropionate as
reported in the literature.14 With the two requisite
fragments 4 and 5 in hand, we attempted the boron-medi-
ated aldol reaction using Paterson’s conditions.14
As expected, the reaction proceeded smoothly and
the aldol product was obtained in 95% yield as a mix-
ture of two separable isomers (major:minor=85:15)
(Scheme 2).
Further elaboration of fragment C(13)–C(23) com-
menced with selective removal of TBDPS from acetonide
12 (Scheme 4). In the presence of 10% NaOH/MeOH,18
after refluxing for 8 h, only two-thirds of 12 was
transformed into alcohol 14. Prolonging the reaction
time was found to result in cleavage of the TBS group.
The alcohol 14 obtained was oxidized by Dess–Martin
periodinane to aldehyde 15. A Wittig reaction of 15 with
unstablized CH3CHꢀPPh3 afforded 16 as a single isomer
in 93% yield. To remove the acetonide group of 16,
we first tried a 1:1 mixture of 1 M HCl and THF at
room temperature, but unfortunately, the reaction
did not proceed and allowed only the recovery
of the starting material. So we turned to Zn-
(NO3)2·6H2O which has been used to selectively
cleave an acetonide group.19 Fortunately, the reaction
proceeded cleanly but with incomplete conversion of
starting material. Efforts to raise the conversion yield by
means of prolonging the reaction time failed due to the
cleavage of the TBS group. After removal of ace-
In order to determine the relative stereochemistry of the
major product, 10 was first selectively reduced to syn diol
11 as a >20:1 diastereomeric mixture using Et2BOMe/
NaBH4,17 which was then converted into acetonide 12 as
well as the p-methoxybenzylidene acetal 13. The configu-
rations at C16 and C17 were confirmed by NOESY studies
of p-methoxybenzylidene acetal 13 and J value analysis
of acetonide 12 (Scheme 3). This result is also in
accordance to the predicted stereochemistry based on the
transition state proposed by Paterson.14
1) CH3CO2Me, LDA
THF, -78 oC
OH
TBDMSCl, pyridine
OPMB
OPMB
OHC
0 oC, 76 % over three steps
2) DIBAL-H, Et2O, 0 oC
I
OH
8
90 % over two steps
TBSO
TBSO
Dess-Martin periodinane
OPMB
CH2Cl2, 0 oC, 95 %
OPMB
OH
O
9
5
Scheme 1.
TBSO
TBDPSO
TBDPSO
OPMB
OPMB
1) (c-hex)2BCl, Et3N
Et2O, 5, -78 oC to 0 oC
TBSO
+
CHO
OH O
(major)
10
OPMB
TBDPSO
+
2) 4, -78 oC to -20 oC
TBSO
O
95%
4
5
OH O
minor
Scheme 2.
TBSO
17
OH
TBSO
Et2BOMe, NaBH4
16
TBDPSO
OPMB
TBDPSO
OPMB
THF/MeOH
-78 oC, 80%
O
OH OH
11
10
Me2C(OMe)2, PPTS
CH2Cl2, 0 oC to r.t.
100 %
H
H
80%
DDQ, CH2Cl2
H
H
O
H
PMP
PMPO
H
H
O
4
3
J1,2 = 10.44 Hz
J2,3 = 10.44 Hz
H
3
4
Me
O
2
O
13
1
TBSO
12
H
NOESY
Scheme 3.

T.-P. Loh, L.-C. Feng / Tetrahedron Letters 42 (2001) 3223–3226
3225
TBSO
TBSO
Dess-Martin
10% NaOH/MeOH
HO
OPMB
TBDPSO
OPMB
reflux,
Pyridine/CH2Cl2,
72% (isolated yield)
85% (based on recovered
starting material)
0 oC, 85%
O
O
O
O
12
14
16
TBSO
TBSO
1) BrPPh3CH2CH3, n-BuLi
THF, -78 oC to 0 oC.
Zn(NO3)2.6H2O
CH3CN, 50 oC
OPMB
OPMB
OHC
2) THF, -78 oC to r.t.
93%
O
O
O
O
42% (isolated yield)
15
75% (based on
recovered starting
material)
TBSO
TBSO
O
MCPBA, NaHCO3
OPMB
OPMB
CH2Cl2, -78 oC to -30 oC
54%
OH OH
OH OH
17
2
Scheme 4.
tonide, the diol 17 was treated with MCPBA in the
presence of NaHCO3 with CH2Cl2 as solvent. To our
surprise, the epoxide product 2 was obtained in 54%
isolated yield as a single isomer along with some
unidentified by-products. The stereochemistry of the
epoxide 2 was assigned on the basis of NOESY studies
of the intramolecular epoxide opened product 18.20
7. Matrushima, T.; Mori, M.; Zheng, B. Z.; Maeda, H.;
Nakajima, N.; Uenishi, J.; Yonemitsu, O. Chem. Phar.
Bull. 1999, 47, 308.
8. Zheng, B. Z.; Maeda, H.; Mori, M.; Kusaka, S.; Yone-
mitsu, O.; Matsushima, T.; Nakajima, N.; Uenishi, J.
Chem. Phar. Bull. 1999, 47, 1288.
9. Matsushima, T.; Zheng, B. Z.; Maeda, H.; Nakajima,
N.; Uenishi, J.; Yonemitsu, O. Synlett 1999, 780.
10. Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
11. Smith, A. B.; Lodise, S. Papers, 218th National Meet-
ing of the American Chemical Society, New Orleans,
LA, Aug. 22–26, 1999; American Chemical Society:
Washington, DC, 1999; p. 549. Org. Lett. 1999, 1, 1249.
12. Jung, M. E.; Marquez, R. Org. Lett. 2000, 2, 1669.
13. Jung, M. E.; Lee, C. P. Tetrahedron Lett. 2000, 41,
9719.
In conclusion, we have completed the construction of
the C(13)–C(23) subunit 2. Key features include the
boron-promoted aldol reaction to control the configu-
rations at C16 and C17 of tedanolide and hydroxy-
directed epoxidation. The synthesis is highly convergent
and practical. Assembly of subunit 3 and its combina-
tion with subunit 2 are in progress.
14. Paterson, I.; Tillyer, R. D. J. Org. Chem. 1993, 58,
4182. Data for compound 2: colorless oil, Rf 0.58 (n-
Acknowledgements
hexane/EtOAc, 2:1); [h]3D1 +36 (c 0.9, CHCl3); H NMR
1
(300 MHz, CDCl3) l (ppm): −0. 02 (d, J=4.5 Hz, 6H),
0.86 (s, 9H), 0.98 (d, J=7.0 Hz, 3H), 1.12 (d, J=6.3
Hz, 3H), 1.28 (s, 3H), 1.62 (d, J=7.0 Hz, 3H), 1.84–
1.76 (m, 1H), 2.04–1.97 (m, 1H), 2.56–2.35 (m, 1H),
2.87 (d, J=9.1 Hz, 1H), 3.46–3.48 (m, 2H), 3.55–3.62
(m, 2H), 3.64 (d, J=8.0 Hz, 1H), 3.80 (s, 3H), 3.87 (br,
1H), 4.00 (dd, J=2.4, 8.0 Hz, 1H), 4.43 (s, 2H), 5.31–
5.23 (m, 1H), 5.53–5.43 (m, 1H), 6.86 (d, J=8.7 Hz,
2H), 7.23 (d, J=8.7 Hz, 2H); 13C NMR (75 MHz,
CDCl3) l (ppm): 159.2, 130.7, 130.4, 129.2, 124.5,
113.8, 76.9, 74.5, 73.4, 73.0, 66.5, 64.1, 61.7, 55.3, 44.8,
36.0, 31.7, 25.8, 18.8, 18.0, 13.2, 12.7, 10.6, −5.2, −5.5;
HRMS (ESI) calcd for C29H50NaO6Si [M+Na+]:
545.3282. Found: 545.3274; IR (neat) cm−1: 3417, 3008,
2959, 2938, 2884, 2852, 1614, 1582, 1512, 1453, 1243,
1092, 828.
This work was financially supported by grants from the
National University of Singapore.
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