Enantioselective construction of the C1-C16 segment of lasonolide A

Article abstract of DOI:10.1055/s-2003-40856

An efficient and enantiocontrolled synthesis of the C₁-C ₁₆ segment of lasonolide A has been accomplished starting from a readily available optically pure aldehyde.

Full text of DOI:10.1055/s-2003-40856

1500
LETTER
Enantioselective Construction of the C1-C16 Segment of Lasonolide A
E
nantioselective
a
Constructtion of 1
t
s
he
C
-C16 uSegment of
y
L
asonolide
A
a Deba, Fumika Yakushiji, Mitsuru Shindo, Kozo Shishido*
Institute for Medicinal Resources, University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Fax +81(88)6339575; E-mail: shishido@ph2.tokushima-u.ac.jp
Received 29 April 2003
As shown in Scheme 1, we envisaged that the target seg-
ment 2 would be prepared from the aldehyde 3, the C5-C12
segment, by sequential Z,E-diene and E,E-diene forma-
tions. The aldehyde 3 with the requisite four stereogenic
centers would be prepared by a diastereoselective intro-
duction of the C-1 unit at the C11 position of the lactone 4,
which could be obtained from the linear precursor 5. The
triol 5 would be derived from a chiral auxiliary-directed
diastereoselective aldol reaction4 of 6 with the optically
pure aldehyde 7.
Abstract: An efficient and enantiocontrolled synthesis of the C1-
C16 segment of lasonolide A has been accomplished starting from a
readily available optically pure aldehyde.
Key words: natural products, cytotoxic activity, asymmetric syn-
thesis, macrocycles, pyran
Lasonolide A (1)1 has been isolated from an extract of the
shallow water Caribbean marine sponge, Forcepia sp. by
McConnell. This compound was discovered to inhibit the
in vitro proliferation of A-549 human lung carcinoma
cells as well as cell adhesion in a newly developed whole
cell assay that detects signal transduction agents. The
promising biological profiles of this compound coupled
with its intriguing structural features inspired us to devel-
op an efficient strategy for the synthesis of this natural
product. Recently, Lee2 completed the first total synthesis
of lasonolide A, thereby correcting the structure proposed
by McConnell and establishing the absolute stereo-
chemistry, as shown below. However, in a recent
communication3 Lee indicated that the absolute structure
of 1 might be the enantiomeric one, based on its biological
activity. We report herein an efficient and enantiocon-
trolled synthesis of the C1-C16 segment of lasonolide A 2
with the unnatural configuration (Figure 1).
OTBS
2
5
12
H
O
OTBDPS
O
3
OTBS
O
OH OH OH
X
11
O
O
OTBDPS
5: X=chiral auxiliary
4
O
O
O
OHC
+
X
6
7
HO
Scheme 1 Retrosynthetic analysis.
Katsuki–Sharpless asymmetric epoxidation5 of 5-benzyl-
oxy-2-pentenol (8) gave the epoxy alcohol 9,6 which was
treated with Red-Al® to furnish the 1,3-diol.7 Acetonide
formation, reductive cleavage of the benzyl ether and
Dess–Martin oxidation8 provided the aldehyde 7 in good
overall yield. Aldol reaction of 7 with the N-propionyl
sultam 119 in the presence of dibutylboron triflate and
Hünig’s base gave the aldol product 12 diastereoselective-
ly in 82% yield. Acidic hydrolysis followed by selective
protection of the primary alcohol function of the resulting
triol 13 as the t-butyldiphenylsilyl (TBDPS) ether provid-
ed the diol 14. Hydrolytic removal of the chiral auxiliary
produced the carboxylic acid 15, which was treated imme-
diately with p-toluenesulfonic acid to furnish the lactone
16 in 82% yield for the two steps (Scheme 2).
O
1
O
O
OH
OH
O
O
16
O
lasonolide A (1)
TBSO
O
1
CO2Et
16
C1-C16 segment (2)
OPiv
After protection of the secondary hydroxyl group as the
t-butyldimethylsilyl (TBS) ether, benzyloxymethyl anion,
generated in situ from benzyloxymethyl tributylstan-
nane,10 was added to the C11-position to give the hemiac-
etal 18 as a single product. Now the stage was set for the
Figure 1
Synlett 2003, No. 10, Print: 05 08 2003.
Art Id.1437-2096,E;2003,0,10,1500,1502,ftx,en;U07903ST.pdf.
© Georg Thieme Verlag Stuttgart · New York

LETTER
Enantioselective Construction of the C1-C16 Segment of Lasonolide A
1501
desired 22 by NOESY experiments, as shown in
Scheme 3. After conversion of 22 into the aldehyde 24, it
was subjected to sequential Wittig reaction, reduction
with DIBALH and pivaloylation to give the C5-C16 seg-
ment 27. Desilylation followed by Dess–Martin oxidation
gave the aldehyde 29, which was exposed to vinylogous
Horner–Emmons olefination13 using triethyl 4-phos-
phonocrotonate to provide 2, the target C1-C16 segment
(Scheme 4).
O
a
BnO
b, c
OH
BnO
OH
8
9
O
O
d, e
O
O
OHC
BnO
10
7
O
OTBS
N
O
OH
O
O
S
f
11
OTBDPS
O
O
a
b
N
O
16
S
O
O
12
O
17
OTBS
O
OH OH OR
i
g, h
c
OTBDPS
N
O
HO
S
13: R=H
14: R=TBDPS
OH
O
O
OBn
H-
18
O
OH OH OR
j
OR
TBSO
HO
OTBDPS
+
O
O
O
15: R=TBDPS
16: R=TBDPS
OBn
Scheme 2 Reagents and Conditions a) D-(–)-diethyl tartrate, Ti(O-
i-Pr)4, t-BuOOH, 4Å MS, CH2Cl2, –23 °C, 91%; b) Red-Al®, Et2O,
–20 °C, 90%; c) Me2C(OMe)2, PPTS, 25 °C, 95%; d) Li, liq. NH3,
THF, 25 °C, 92%; e) Dess–Martin ox., CH2Cl2, 25 °C, 81%; f) n-
Bu2BOTf, i-Pr2NEt, CH2Cl2, –5 °C to –78 °C to –20 °C, 82%; g) Do-
wex, MeOH, H2O, reflux, 95%; h) t-BuPh2SiCl, imidazole, 4-DMAP,
CH2Cl2, 25 °C, 91%; i) LiOH·H2O, H2O2, THF, H2O, 25 °C; j)
TsOH·H2O, CH2Cl2, 25 °C, 85% (2 steps).
19
OTBS
OTBDPS
e
f
3
O
20: R=Bn
21: R=H
d
OR
OTBS
TBSO
H
OTBDPS
key construction of the fourth stereogenic center on the
hydropyran ring. Treatment of 18 with boron trifluoride
etherate and subsequent reduction with triethylsilane11
provided 20 in 84% yield as a single product. Although
the stereochemistry at the newly generated stereogenic
center could not be determined at this stage, it was de-
duced to be the desired S-configuration from a mechanis-
tic point of view.
H
OTBDPS
H
CO2Et
Me
O
H
Me
O
H
CO2Et
22
NOESY of 22
Scheme 3 Reagents and Conditions a) t-BuMe2SiOTf, 2,6-lutidine,
DMF, 25 °C, 90%; b) n-BuLi, n-Bu3SnCH2OBn, THF, –78 °C, 89%;
c) BF3·OEt2, Et3SiH, CH2Cl2, –78 °C to –30 °C, 84%; d) H2, Pd-C,
EtOH, 25 °C, 82%; e) Dess–Martin ox., CH2Cl2, 25 °C, 95%; f) (o-i-
PrC6H4O)2P(O)CHMeCO2Et, DBU, NaI, THF, –78 °C to 0 °C, 87%.
Thus, the oxonium intermediate, which can be generated
from 18 by acidic treatment, would assume the conforma-
tion 19 and should be attacked by hydride from the stereo-
electronically favorable b-face to provide 20 stereo-
selectively. Catalytic hydrogenolysis followed by Dess–
Martin oxidation of the resulting alcohol 21 gave the alde-
hyde 3 in good overall yield. The crucial Z-selective ole-
fination of 3 for the installation of the C12-C14 fragment
was realized by using the method of Ando.12 Treatment of
3 with ethyl 2-[di(o-isopropylphenyl)phosphono]propi-
onate in the presence of DBU and sodium iodide in THF
at low temperature produced 22 stereoselectively in 87%
yield. At this stage, the Z-geometry and the stereochemis-
tries on the pyran ring were established to be those of the
In summary, the enantioselective synthesis of the C1-C16
segment of lasonolide A has been achieved stereoselec-
tively. The synthesis involved several important steps;
e.g., an Oppolzer diastereoselective aldol reaction, diaste-
reoselective hydride reduction of the oxonium salt to form
the pyran ring with the desired stereogenic centers and a
highly selective construction of the C12-C13 Z-olefin unit.
Further efforts directed toward the total synthesis of
lasonolide A are in progress.
Synlett 2003, No. 10, 1500–1502 © Thieme Stuttgart · New York

1502
T. Deba et al.
LETTER
OTBS
Acknowledgment
We are grateful to Professor Eun Lee, Seoul National University,
for providing us with valuable comments. This work was financial-
ly supported by the Uehara Memorial Foundation and by a Grant-
in-Aid of Scientific Research (B) (No. 14370722) from the Japan
Society for the Promotion of Science.
c - e
a, b
22
O
R
OTBDPS
23: R=CH2OH
24: R=CHO
References
OTBS
O
OTBS
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f, g
h
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O
R
R
OTBDPS
OPiv
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26: R=CH2OH
27: R=OPiv
28: R=CH2OH
29: R=CHO
(6) Hirai, Y.; Chintani, M.; Yamazaki, T.; Momose, T. Chem.
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Scheme 4 Reagents and Conditions a) DIBALH, CH2Cl2, –78 °C,
99%; b) MnO2, CH2Cl2, benzene, 25 °C, 99%; c) Ph3PCHCO2Et, to-
luene, reflux, 83%; d) DIBALH, CH2Cl2, –78 °C, 81%; e) t-BuCOCl,
pyridine, 4-DMAP, CH2Cl2, 25 °C, 90%; f) TBAF, THF, CH2Cl2,
25 °C, 73%; g) Dess–Martin ox., CH2Cl2, 25 °C; h)
(EtO)2P(O)CH2CHCHCO2Et, LiOH·H2O, 4Å MS, THF, reflux, 74%
(2 steps).
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V. S.; Masamune, S. J. Org. Chem. 1982, 47, 1378.
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Synlett 2003, No. 10, 1500–1502 © Thieme Stuttgart · New York