A stereoselective synthesis of the C15-C25 subunit of (+)-lasonolide A

Article abstract of DOI:10.1016/S0040-4039(03)01748-9

The C₁₅-C₂₅ upper THP segment 2 of (+)-lasonolide A has been synthesized efficiently via diastereomeric differentiation, iodocyclization and Julia-Kocieński's sulfone olefination to install its quaternary chiral center, cis-2,6-disubstituted THP and trans-olefin, respectively.

Full text of DOI:10.1016/S0040-4039(03)01748-9

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 6817–6819
A stereoselective synthesis of the C15–C25 subunit of
(+)-lasonolide A
Sung Ho Kang,a,* Hyeong-wook Choi,a Cheol Min Kim,a Hyuk-Sang Jun,a Suk Youn Kang,a
Joon Won Jeonga and Joo-Hack Younb
aDepartment of Chemistry, Center for Molecular Design and Synthesis, School of Molecular Science (BK21), Korea Advanced
Institute of Science and Technology, Daejeon 305-701, Republic of Korea
bDepartment of Chemical Engineering, Sun Moon University Asan Si, Chung-Nam 336-840, Republic of Korea
Received 28 June 2003; revised 15 July 2003; accepted 16 July 2003
Abstract—The C15–C25 upper THP segment 2 of (+)-lasonolide A has been synthesized efficiently via diastereomeric differentia-
tion, iodocyclization and Julia–Kocien´ski’s sulfone olefination to install its quaternary chiral center, cis-2,6-disubstituted THP and
trans-olefin, respectively.
© 2003 Elsevier Ltd. All rights reserved.
In conjunction with discovering new antitumor agents
from marine organisms, lasonolide A was isolated from
the shallow water Carribean marine sponge, Forcepia
sp., by McConnell et al.1 It displays potent in vitro
cytotoxic activity against A-549 human lung carcinoma
cells and inhibition of cell adhesion in a cell assay for
searching signal transduction agents.2 Although the rel-
ative stereochemistry of lasonolide A was proposed by
extensive spectroscopic studies, it was recently revised,
and the undetermined C28 hydroxy group and the abso-
lute configuration were suggested as 1 by synthetic
studies.3 The attractive structural and biological fea-
tures of lasonolide A directed us to be involved in its
total synthesis. In this paper, we report an enantioselec-
tive synthesis of the C15–C25 fragment comprising four
stereogenic centers with a quaternary carbon center and
one trans-olefinic double bond.4
asymmetric center of 3 was planned to be established
by diastereomeric differentiation of the two alkoxy-
methyl groups of 4.
Based on the retrosynthetic analysis toward 1, the
C15–C25 segment was chosen as our immediate synthetic
target, which was appositely functionalized to build the
C14 trans-double bond by sulfone chemistry and the C25
cis-double bond by Wittig reaction (Scheme 1). We
envisaged that the THP ring of 2 could be formed by
iodocyclization of d-hydroxyalkene 3 and its double
bond by another sulfone protocol. The quaternary
* Corresponding author. Tel.:+ 82-42-869-2825; fax: +82-42-869-2810;
e-mail: shkang@kaist.ac.kr
Scheme 1. Retrosynthetic analysis.
0040-4039/$ - see front matter © 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/S0040-4039(03)01748-9

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S. H. Kang et al. / Tetrahedron Letters 44 (2003) 6817–6819
The known alcohol 55 was sequentially subjected to
Swern oxidation6 and asymmetric allylation using allyl-
boronate 6s7 to afford homoallyl alcohol 4 in 78% ee
and 79% overall yield (Scheme 2). To differentiate the
two alkoxymethyl groups of 4, it was treated with
benzaldehyde in the presence of 3 mol% of p-TsOH to
give rise to a 1:1 mixture of the desired benzylidene 7
and its diastereomer 8 in 80% combined yield along
with 14% of the other diastereomers 9. After two more
resubmission of 8 and 9 to benzylidene formation, 7
was obtained in 76% combined yield, the stereochem-
istry of which was corroborated by observing the NOE
enhancements between the C4 hydrogen and the C5
methyl group. Another Swern oxidation and asymmet-
ric allylation using allylboronate 6r furnished alcohol
10 in 91% increased ee and 77% yield. Its protecting
groups were adjusted by p-methoxybenzylation, acidic
hydrolysis of the benzylidene group and silylation in
sequence to give d-hydroxyalkene 3 in 83% overall
yield. Stereoselective formation of tetrahydropyranyl
ring was attained by iodocyclization8 of 3 to produce a
12:1 inseparable mixture of cis- and trans-2,6-disubsti-
tuted THP derivatives. After converting the mixture
into benzoates by sodium benzoate in 1-methyl-2-
pyrrolidinone (NMP), the desired benzoate 11 was sep-
arated in 79% overall yield, and its cis-stereochemistry
was manifested by NOE enhancements between C2
hydrogen and C6 hydrogen, and the coupling constants
(J2H,3H=10.1 and 2.5 Hz, J3H,4H=2.6 and 2.6 Hz).
With access to the right THP part 11 secure, the left
three carbon equivalent 13 was prepared in 56% overall
yield by Mitsunobu reaction of 1,3-propanediol using
1-phenyl-1H-tetrazole-5-thiol9 followed by MCPBA
oxidation and silylation (Scheme 3). The olefinic double
bond of 11 was oxidatively cleaved, the generated alde-
hyde was protected as acetal using 2,2-dimethyl-1,3-
propanediol and the benzoate group was hydrolyzed to
provide alcohol 12 in 92% overall yield. After Swern
oxidation of 12, the resulting aldehyde was olefinated
with sulfone 13 using KHMDS to afford an inseparable
mixture of alkenes. Desilylation of the alkenes gave a
9:1 separable mixture of trans-alkene 14 and cis-isomer
in 80% combined overall yield. Alcohol 14 was trans-
formed into sulfide under Mitsunobu conditions using
2-mercaptobenzothiazole10 and oxidized to sulfone with
Scheme 3. Reagents and conditions: (a) OsO4, NaIO4, MeOH,
H2O, THF, 0°C; (b) HOCH2C(Me)2CH2OH, p-TsOH, PhMe,
80°C; (c) K2CO3, MeOH, rt; (d) 1-phenyl-1H-tetrazole-5-
thiol, DEAD, Ph3P, THF, 0°C; (e) MCPBA, NaHCO3,
CH2Cl2, 0°C to rt; (f) TESCl, DMAP, Et3N, CH2Cl2, 0°C; (g)
Swern oxidation; (h) KHMDS, DME, −60°C to rt; (i) PPTS,
THF, MeOH, 0°C; (j) 2-mercaptobenzothiazole, DEAD,
Ph3P, THF, 0°C; (k) 30% H2O2, (NH4)6Mo7O24·4H2O, THF,
EtOH, rt.
Scheme 2. Reagents and conditions: (a) Swern oxidation; (b)
,
6s, 4 A MS, PhMe, −78°C to rt; 2N NaOH, 0°C; (c) PhCHO,
,
p-TsOH, PhMe, rt; (d) 6r, 4 A MS, PhMe, −78°C to rt; 2N
NaOH, 0°C; (e) p-MeOC6H4CH2Cl, KH, n-Bu4NI, THF, 0°C
to rt; (f) p-TsOH, MeOH, rt; (g) TIPSCl, DMAP, Et3N,
CH2Cl2, rt; (h) I2, K2CO3, MeCN, −25 to −15°C; (i)
PhCOONa, NMP, 100°C.

S. H. Kang et al. / Tetrahedron Letters 44 (2003) 6817–6819
6819
heptamolybdate to produce the C15–C25 upper THP
subunit 211 in 71% overall yield along with 13% of
corresponding sulfoxide, which could be reoxidized to
sulfone 2 in 81% yield.
1997, 38, 1001; (d) Gurjar, M. K.; Kumar, P.; Rao, B. V.
Tetrahedron Lett. 1996, 37, 8617.
5. Gash, V. W. J. Org. Chem. 1972, 37, 2197.
6. (a) Tidwell, T. T. Org. React. 1990, 39, 297; (b) Mancuso,
A. J.; Swern, D. Synthesis 1981, 165.
In summary, a stereocontrolled synthesis of the C15–C25
fragment 2 of (+)-lasonolide A has been developed via
diastereomeric differentiation for the C22 quaternary
stereogenic center, asymmetric allylation for the C21
and C23 asymmetric centers, and iodocyclization for the
C19 chiral center.
7. Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem.
Soc. 1985, 107, 8186.
8. (a) Cardillo, G.; Orena, M. Tetrahedron 1990, 46, 3321;
(b) Boivin, T. L. Tetrahedron 1987, 43, 3009; (c) Bartlett,
P. A. In Asymmetric Synthesis; Morrison, J. D., Ed.;
Academic Press: London, 1984; Vol. 3, p. 411.
9. Blackmore, P. R.; Cole, W. J.; Kocien´ski, P. J.; Morley,
A. Synlett 1998, 1, 26.
10. (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.;
Ruel, O. Bull. Soc. Chim. Fr. 1993, 130, 856; (b) Baudin,
J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Bull. Soc. Chim.
Fr. 1993, 130, 336.
Acknowledgements
This work was supported by Korea Research Founda-
tion Grant (KRF-2002-070-C00058).
1
11. Spectral data of 2: H NMR (400 MHz, CDCl3) d 8.20
(1H, dd, J=8.5, 1.0 Hz), 7.99 (1H, dd, J=8.1, 0.6 Hz),
7.62–7.56 (2H, m), 7.19 (2H, d, J=8.5 Hz), 6.82 (2H, d,
J=8.5 Hz), 5.57–5.55 (2H, m), 4.55–4.52 (1H, m), 4.42
(1H, d, J=11.1 Hz), 4.35 (1H, d, J=11.1 Hz), 4.10 (1H,
dt, J=11.8, 2.7 Hz), 3.78 (3H, s), 3.79–3.72 (1H, m), 3.73
(1H, d, J=9.1 Hz), 3.61–3.58 (2H, m), 3.54–3.51 (3H, m),
3.42–3.35 (3H, m), 2.64–2.59 (2H, m), 1.67–1.57 (3H, m),
1.46–1.39 (1H, m), 1.13 (3H, s), 1.06–0.99 (21H, m), 0.90
(3H, s), 0.67 (3H, s); 13C NMR (100 MHz, CDCl3) d
165.7, 158.9, 152.7, 136.7, 134.5, 131.3, 128.9, 128.0,
127.6, 125.4, 125.0, 122.3, 113.5, 100.0, 77.2, 76.8, 72.6,
71.6, 70.9, 66.3, 55.2, 54.1, 41.9, 35.9, 30.9, 30.1, 25.3,
23.0, 21.8, 18.1, 15.2, 12.0.
References
1. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell,
O. J. J. Am. Chem. Soc. 1994, 116, 6015.
2. Longley, R. E.; Harmody, D. J. Antibiot. 1994, 44, 93.
3. Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung,
C.-K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384.
4. (a) Beck, H.; Hoffmann, H. M. R. Eur. J. Org. Chem.
1999, 2991; (b) Gurjar, M. K.; Chakrabarti, A.; Rao, B.
V.; Kumar, P. Tetrahedron Lett. 1997, 38, 6885; (c)
Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett.