Progress towards the total synthesis of tedanolide: An efficient assembly of the C1-C11 subunit

Article abstract of DOI:10.1016/S0040-4039(01)01169-8

The C₁-C₁₁ subunit of tedanolide was constructed using a boron-mediated syn aldol reaction as the key step to control the C₆ and C₇ stereocenters. Other features of this work include the asymmetric Sharpless dihydroxylation to incorporate the C₂, C₃ hydroxyl groups, selective protection of the hydroxyl group at C₂ as well as the usage of a tert-butyl ester to tolerate the attack of Grignard and enolate reagents.

Full text of DOI:10.1016/S0040-4039(01)01169-8

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 42 (2001) 6001–6005
Progress towards the total synthesis of tedanolide: an efficient
assembly of the C1–C11 subunit
Teck-Peng Loh* and Li-Chun Feng
Department of Chemistry, National University of Singapore, 3 Science Drive 3, Singapore 117543
Received 9 May 2001; revised 21 June 2001; accepted 28 June 2001
Abstract—The C1–C11 subunit of tedanolide was constructed using a boron-mediated syn aldol reaction as the key step to control
the C6 and C7 stereocenters. Other features of this work include the asymmetric Sharpless dihydroxylation to incorporate the C2,
C3 hydroxyl groups, selective protection of the hydroxyl group at C2 as well as the usage of a tert-butyl ester to tolerate the attack
of Grignard and enolate reagents. © 2001 Elsevier Science Ltd. All rights reserved.
Tedanolide was isolated from a prevalent Caribbean
sponge Tedania ignis by Schmitz and co-workers1 in
1984. As a member of the macrolide group, tedanolide
1 shows very good biological activity as well as a very
interesting chemical structure,1,2 which has initiated
extensive synthetic studies towards its total synthesis.3–
15 Recently, we have established an elegant and
efficient construction of the C13–C23 fragment of
tedanolide.3 In this article, we present our assembly of
the C1–C11 subunit 4 of tedanolide.
C4) as well as the control of the stereochemistry of the
C6, C7, C16 and C17 chiral centers. Retrosynthetically,
tedanolide can be disconnected into two subunits 2 and
3 via disconnection at the C29 lactone and the C12, C13
aldol unit, as outlined in Fig. 1. The subunit 2 was
envisioned to derive from the intermediate 4, which
could be obtained from the coupling between precur-
sors 5 and 6. Precursor 6 can be easily synthesized
according to the reported procedure.3,16 Our synthesis
focuses on the preparation of the precursor 5. As
shown in Fig. 2, the precursor 5 can be traced back to
the readily available aldehyde 9. The key features of
our strategy involve the syn–syn selective boron-medi-
ated aldol reaction, as developed by Paterson,17,18 to
As a synthetic target, tedanolide poses numerous chal-
lenges, including the assembly of two groups of
crowded contiguous chiral centers (C16 to C19 and C2 to
OH
OR
1
OTBS
23
5
3
7
O
OH
1
3
7
OR’’
5
O
4
2
6
9
2
4
6
8
23
17
O
OMe O
12
13
OPMB
8
29
17
+
OR’’ OMe OR’
16
O
10
9
11
13
OH OH
12
11
16
OH
10
O
3
O
OH
O
O
2
3
Tedanolide 1
TBSO
1
OR
11
7
5
O
OTBDPS
+
2
6
OTBDPS
4
t-BuO2C
10
8
OHC
9
t-BuO
OMe O
O
OMe O
5
6
4
Figure 1.
* Corresponding author. Fax: (65)-7791691; e-mail: chmlohtp@nus.edu.sg
0040-4039/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(01)01169-8

6002
T.-P. Loh, L.-C. Feng / Tetrahedron Letters 42 (2001) 6001–6005
OH
TBSO
t-BuO2C
TBSO
t-BuO2C
OPMB
t-BuO2C
CHO
OMe O
OH
OMe
15
5
8
OPMB
OPMB
t-BuO2C
OHC
9
7
Figure 2.
control the C6, C7 stereochemistry, the asymmetric
Sharpless dihydroxylation to incorporate the C2, C3
hydroxyl groups, selective protection of the hydroxyl
group at C2 as well as the use of a tert-butyl ester to
tolerate the attack of Grignard and enolate reagents.
The formation of acetal 11 confirmed the selective
protection of the hydroxyl group at C2.
Having successfully incorporated the C2 and C3 chiral
centers, we carried on with the synthesis of precursor 5
from 10, starting with the methyl protection of the
hydroxyl group. Due to the crowded environment
around the hydroxyl group, strong reaction conditions
(Ag2O, MeI, CH3CN, reflux) were employed. However,
this led to the cleavage of the TBDPS protecting group
and none of the desired product. In order to circumvent
this, TBDMS was introduced as a protecting group and
alternative methylation conditions25,26 were explored
(Scheme 3). From these conditions, AgOTf/MeI26 was
found to be more desirable, providing the expected
product 13 in 50% yield.
The synthesis of precursor 5 commenced with the
preparation of the conjugated tert-butyl ester 7, which
was easily obtained as a single isomer in 83% yield via
a Wittig reaction of aldehyde 9 with the stabilized
Wittig reagent t-BuO2CCHꢀPPh3.19–21 Next, Sharpless
asymmetric dihydroxylation using AD-mix-a was
explored to incorporate the C2, C3 hydroxyl groups
(Scheme 1).10,22,23
It can be seen from the results that the expected diol 8
was obtained in excellent yield with very good selectiv-
ity (86:14) when AD-mix-a was employed. The two
diastereoisomers can be easily separated by flash silica
gel column chromatography. The stereochemistry of
the desired syn dihydroxylation product was established
as shown in Scheme 2 by analysis of the coupling
constant between the protons H3 and H4 of the acetal
11 (a mixture of two isomers, ratio: 77:23), which was
prepared from diol 8 through selective protection of the
vicinal diol24 and acetal formation mediated by DDQ.
Further elaboration of precursor 5 began with the
removal of the PMB protecting group of the tert-butyl
ester 13 (Scheme 4). Treatment of 13 with DDQ (1.1
equiv.) provided the alcohol 14 cleanly in 85% yield.
Dess–Martin oxidation of alcohol 14 afforded aldehyde
15 in excellent yield (97%). Grignard reaction of alde-
hyde 15 with ethylmagnesium bromide was then suc-
cessfully carried out in Et2O at −78°C to give the
desired alcohol 16, which was subjected to another
-
+
n-BuLi, THF
-78 oC to r.t., 83%
t-BuO2CCH2PPh3Br
+
OPMB
OPMB
OH
t-BuO2C
OHC
9
7
OH
OH
AD-mix-α, t-BuOH/H2O
MeSO2NH2 0 oC to r.t.,89%
OPMB
OPMB
+
:
t-BuO2C
t-BuO2C
OH
8
8
6
14
4
Scheme 1.
TBDPSO
TBDPSO
HO
3
DDQ, CH2Cl
r.t., 93%
2t-BuO2C
TBDPSCl, AgNO3
THF/Pyridine, 0 oC
85%
3
OPMB
2
3
OPMB
t-BuO2C
2
t-BuO2C
2
O
O
OH
OH
MPM
10
11
8
J
3,4 = 2.1 Hz
Scheme 2.

T.-P. Loh, L.-C. Feng / Tetrahedron Letters 42 (2001) 6001–6005
6003
TBSO
t-BuO2C
TBSO
HO
reagent
conditions
OPMB
TBDMSCl, AgNO3
OPMB
OPMB
o
t-BuO2C
t-BuO2C
THF/Pyridine, 0 C
OMe
OH
12
85%
OH
13
8
1. Ag2O, MeI, CH3CN, reflux, 8 h 10% (yield)
2. Ag2O, MeI, DMF, r.t., 20 h 5% (yield)
3. AgOTf, MeI, CH2Cl2, 0 oC to r.t. 50% (yield)
2,6-di-tert-butyl-pyridine, 4 h
Scheme 3.
TBSO
TBSO
t-BuO2C
DDQ,CH2Cl2/H2O
r.t., 85%
Dess-Martin periodinane
OH
OPMB
CH2Cl2, 0 oC to r.t., 97%
t-BuO2C
OMe
OMe
14
13
TBSO
t-BuO2C
TBSO
t-BuO2C
TBSO
EtMgBr, Et 2O,
-78 oC to r.t.
77%
Dess-Martin periodinane
CH2Cl2, 0 oC to r.t., 95%
CHO
t-BuO2C
OMe O
OMe
15
OMe OH
5
16
Scheme 4.
Dess–Martin oxidation to furnish the ketone 5 in 19%
diastereomeric mixture using Et2BOMe/NaBH4,32
which was then converted into acetonide 4 as well as
lactone 20. The stereochemistries at C6 and C7 were
confirmed by NOESY studies of both lactone 20 and
acetonide 4 (Scheme 6). This result is also in accor-
dance with the predicted stereochemistry based on the
transition state proposed by Paterson (Scheme 5).33
overall yield (eight steps).
Since aldehyde 6 can be easily synthesized from the
commercially available (R)-methyl 3-hydroxy-2-methyl-
propionate as reported in the literature,3,16 we pro-
ceeded to effect CꢁC bond formation at C6, C7 via a
boron-promoted syn aldol reaction (Scheme 5).17,18,27–31
To our delight, in the presence of Bu2BOTf, the reac-
tion proceeded in 35% isolated yield (90% conversion
yield) and excellent diastereoselectivity (91:9), favoring
the desired C6, C7 syn product. In order to determine
the relative stereochemistry of the major product, 17
was first selectively reduced to the syn diol 19 as a >20:1
In summary, the assembly of the C1–C11 subunit of
tedanolide has been achieved using very few steps. The
C2 and C3 hydroxyl groups were incorporated using
Sharpless asymmetric dihydroxylation. The stereochem-
istry of the C6 and C7 stereocenters were established via
the Bu2BOTf-mediated syn selective aldol reaction.
TBSO
Bu2BOTf, Et3N, CH2Cl2
-78 oC to 0 oC, 35 %,
(conversion yield: 90%)
+
OTBDPS
t-BuO2C
OHC
OMe O
6
5
TBSO
TBSO
OTBDPS
OTBDPS
+
t-BuO2C
t-BuO2C
OMe O
18
OH
OMe O
17
OH
:
91
9
H
RS
RS
RS
RL
L
H
RCHO
R
-
+
B
RL
RL
R
O
L
re face attack
O
OBL2
O
OH
Scheme 5.

6004
T.-P. Loh, L.-C. Feng / Tetrahedron Letters 42 (2001) 6001–6005
TBSO
Et2BOMe, NaBH4,
THF/MeOH
-78 oC to 0 oC, 90%
TBSO
t-BuO2C
3
7
5
OTBDPS
7
OTBDPS
t-BuO2C
2
4
6
6
OMe OH OH
OMe O
17
OH
19
(MeO)2CMe2, PPTS
1M HCl/MeOH
r.t., 58%
2
2
H
3
TBSO
H
O
H3CO
OH
7
5
OTBDPS
4
5
t-BuO2C
6
H
2
H
OH
OMe O
O
HO
O
4
20
NOESY
H
CH3
H
5
o
CH3
H
o
7
6
CH3
NOESY
Scheme 6.
Besides, a tert-butyl ester was employed to tolerate the
attack of Grignard and enolate reagents. The assembly
of subunit 2 and its combination with subunit 3 are in
progress.
11. Roush, W. R.; Lane, G. C. Org. Lett. 1999, 1, 95.
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This work was financially supported by grants from the
National University of Singapore.
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(m, 6H, Ph), 5.24 (d, J=9.4 Hz, 1H, ꢀCH), 4.09 (d, J=8.0
Hz, 1H, CHOTBS), 4.08 (br, 1H, ꢀCCHO), 3.68 (dd,
J=1.4, 9.4 Hz, 1H, CHO), 3.46 (s, 3H, OMe), 3.47 (dd,
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