Synthesis and evaluation of lasonolide a analogues

Article abstract of DOI:10.1016/j.bmcl.2004.01.088

Homolasonolide A and 10-desmethyllasonolide A are biologically less active than lasonolide A. The ethyl ester analogue of lasonolide A exhibited higher activity than the parent compound in some biological test.

Full text of DOI:10.1016/j.bmcl.2004.01.088

Bioorganic & Medicinal Chemistry Letters 14 (2004) 1905–1908
Synthesis and evaluation of lasonolide A analogues
Jung Min Joo, Hyo Shin Kwak, Jin Hyun Park, Ho Young Song and Eun Lee*
School of Chemistry and Molecular Engineering, Seoul National University, Seoul 151-747, South Korea
Received 16 December 2003; revised 27 January 2004; accepted 28 January 2004
Abstract—Homolasonolide A and 10-desmethyllasonolide A are biologically less active than lasonolide A. The ethyl ester analogue
of lasonolide A exhibited higher activity than the parent compound in some biological test.
# 2004 Elsevier Ltd. All rights reserved.
The structure of lasonolide A originally put forward1
was in error, and the correct structure turned out to be
the (17E,25Z)-isomer.2 In addition, the (À)-enantiomer
(1) was found to be much more active than the (+)-
enantiomer providing compelling evidence that (À)-
lasonolide A is the natural product.3,4 In view of the
high cytotoxicity against some tumor cell lines,1 we were
interested to prepare analogues of 1 for screening tests.
Homolasonolide A (2) was our first candidate, because
synthesis of this homologue requires omission of several
steps from the original scheme for 1. 10-Desmethyl-
lasonolide A (3) was also an interesting candidate,
because it incorporated minimum perturbation of the
original structure. We were also interested to test ester
analogues 4 and 5 as they would yield information on
the side chain requirements (Fig. 1).
Acetonide protection of the known diol 64 and sub-
sequent debenzylation and oxidation provided the alde-
hyde 7. Kocienski–Julia reaction5 of the sulfone 8 and
the aldehyde 7 proceeded smoothly, and the product
(E)-olefin was converted into a second sulfone 10 via
TBDPS-deprotection, Mitsunobu-type substitution of
the hydroxy group with the sulfide 9, and selective oxi-
dation (Scheme 1). Reaction of the known aldehyde 114
with 10 accomplished the crucial connection of the two
components by forming another trans double bond, and
the product was converted into the macrolide 13 via
acetonide-deprotection, selective TBS-protection of the
primary hydroxy group, esterification with the acid 12,
* Corresponding author. Tel.: +82-2-880-6646; fax: +82-2-889-1568;
e-mail: eunlee@snu.ac.kr
Figure 1. Lasonolide A and analogues.
0960-894X/$ - see front matter # 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.bmcl.2004.01.088

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J. M. Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1905–1908
prepared from 18 via reaction with ethyl propiolate,
TBS-deprotection, and bromide substitution. Radical
cyclization of 19 in the presence of tris(trimethylsilyl)-
silane and AIBN in hot benzene proceeded smoothly to
yield the tetrahydropyran 20.7 Debenzylation via
hydrogenolysis, TBS-protection of the hydroxy groups,
lithium borohydride reduction of the ester functionality,
and oxidation provided the corresponding aldehyde,
which was converted into the vinyl iodide 21 via Takai
protocol.8 Selective TBS-deprotection, oxidation, and
olefination under Still–Gennari conditions9 provided
the corresponding (Z)-enoate, which was converted into
the enal 22 via reduction and oxidation (Scheme 3).
Kocienski–Julia reaction of the aldehyde 22 with the
known sulfone 234 provided a new triene, which was
converted into the macrolide 24 via a 4-step sequence as
employed in the preparation of 13. The macrolide alde-
hyde 25 was prepared following the known reaction
protocol, and 3 was finally obtained from 25 via Wittig
reaction and TBS-deprotection (Scheme 4).
Scheme 1. (a) Me2C(OMe)2, CSA, acetone; (b) H2, Pd(OH)2/C,
ꢀ
.
MeOH; (c) SO3 pyridine, TEA, DMSO–DCM (1:1), 0 C; (d) 8,
LiHMDS, DMF–HMPA (4:1), À35 ꢀC; 7, À35 ꢀC–rt; (e) TBAF, THF;
(f) 9, DIAD, Ph3P, THF, 0 ꢀC; (g) (NH4)6Mo7O24, H2O2, EtOH, 0 ꢀC–
rt.
and intramolecular Stille coupling reaction. Selective
reduction of the pivaloate group and oxidation pro-
vided the macrolide aldehyde 14, which was converted
into 2 via reaction with the ylide from the phosphonium
salt 154 and global TBS-deprotection (Scheme 2).
Synthesis of the ester analogues 4/5 utilized the known
acetal lactone 26,4 which was reacted with ethanol and
n-dodecanol to yield the primary alcohols 27/28 after
TBS-protection and -deprotection. The phosphonium
salts 29/30 obtained from 27/28 were employed in the
Synthesis of 10-desmethyllasonolide A (3) was initiated
by conversion of the known ester 164 into the enone 17
via vinyl Grignard reaction of the corresponding Wein-
rebamide. Syn reduction6 of the enone 17, benzylidene
acetal formation, regioselective DIBAL reduction, clea-
vage of the double bond, sodium borohydride reduc-
tion, and TBS-protection of the primary hydroxy group
led to the intermediate 18. The b-alkoxyacrylate 19 was
.
Scheme 3. (a) MeNH(OMe) HCl, Me3Al, THF; (b) H2CCHMgBr,
THF; (c) Et3B, NaBH4, THF–MeOH (4:1), À78 ꢀC; (d) PhCH(OMe)2,
CSA, DCM; (e) DIBAL, DCM; (f) OsO4, NMO, acetone–H2O (3:1);
NaIO4; (g) NaBH4, EtOH, 0 ꢀC; (h) TBSCl, imidazole, DCM, 0 ꢀC; (i)
HCCCO2Et, NMM, MeCN; (j) HCl, MeOH, 0 ꢀC; (k) CBr4, Ph3P,
pyridine, DCM; (l) (TMS)3SiH, AIBN, benzene, reflux; (m) H2, Pd/C,
MeOH; (n) TBSOTf, 2,6-lutidine, DCM; (o) LiBH4, ether; (p)
Scheme 2. (a) 10, LiHMDS, THF, À78 ꢀC; 11, À78 ꢀC–rt; (b) CSA,
(HOCH2)2, MeOH; (c) TBSCl, imidazole, DCM; (d) 12, DIC, DMAP,
DCM; (e) Pd2dba3, DIPEA, Ph2PO2NBu4, DMF; (f) LiEt3BH, THF,
ꢀ
.
SO3 pyridine, TEA, DMSO–DCM (1:1), 0 C; (q) CrCl2, CHI3, dioxane–
.
ꢀ
ꢀ
.
À78 C, (s.m. 35%); (g) SO3 pyridine, TEA, DMSO–DCM (1:1), 0 C;
THF (6:1); (r) CSA, MeOH; (s) SO3 pyridine, TEA, DMSO–DCM
(1:1), 0 ꢀC; (t) MeO2C(Me)CHPO(OCH2CF3)2, KHMDS, 18-c-6,
ꢀ
ꢀ
.
(h) 15, KHMDS, THF, À78 C; 14, À78 C–rt; (i) HF pyridine, pyri-
dine, THF.
THF, À78 ꢀC; (u) DIBAL, DCM, À78 ꢀC; (v) MnO2, DCM.

J. M. Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1905–1908
1907
Table 1. GI50 (mM) values for lasonolide A and analogues against
selected cell lines
Compd
A549
HCT-116
NCI-H460
1
2
3
4
5
0.015
0.800
0.100
0.007
0.390
0.003
1.800
0.045
0.100
0.190
<0.003
1.000
0.065
0.015
0.170
cytotoxicity against the three cell lines than expected.
The bioactivity of the n-dodecanyl ester 5 was low, but
the cytotoxicity of the ethyl ester 4 against the A549 cell
line was actually higher than that of 1 (Table 1).
Acknowledgements
The authors thank the Ministry of Science and Tech-
nology, Republic of Korea, and KISTEP for a National
Research Laboratory grant (1999). Brain Korea 21
graduate fellowship grants to H. S. Kwak and J. H.
Park are gratefully acknowledged. The authors also
thank Dr. ShinWu Jeong, and Mr. Ji Hyun Park of LG
Life Science/R&D for the biological assay.
Scheme 4. (a) LiHMDS, THF, À78 ꢀC; 22, À78 ꢀC–rt; (b) CSA,
(HOCH2)2, MeOH, (s.m. 25%); (c) TBSCl, imidazole, DCM; (d) 12,
DIC, DMAP, DCM; (e) Pd2dba3, DIPEA, Ph2PO2NBu4, DMF;
ꢀ
.
(f) LiEt3BH, THF, À78 C, (s.m. 9%); (g) SO3 pyridine, TEA, DMSO–
DCM (1:1), 0 ꢀC; (h) 15, KHMDS, THF, À78 ꢀC; 25, À78 ꢀC–rt;
.
(i) HF pyridine, pyridine, THF.
References and notes
1. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell,
O. J. J. Am. Chem. Soc. 1994, 116, 6015.
2. Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-
K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384.
3. Lee, E.; Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D. S.;
Jung, C. K.; Hong, C. Y.; Jeong, S.; Jeon, K. Bioorg.
Med. Chem. Lett. 2002, 12, 3519.
4. Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D.-S.; Jung,
C.-K.; Kwak, H. S.; Park, J. H.; Lee, E.; Hong, C. Y.;
Jeong, S.; Jeon, K.; Park, J. H. J. Org. Chem. 2003, 68,
8080.
5. Blakemore, P. R.; Cole, W. J.; Kocienski, P. J.; Morley,
A. Synlett 1998, 26.
6. Chen, K.-M.; Gunderson, K. G.; Hardtmann, G. E.;
Prasad, K.; Repic, O.; Shapiro, M. J. Chem. Lett. 1987,
1923.
7. (a) For selected examples of b-alkoxyacrylate radical
cyclizations, see: Lee, E.; Choi, S. J.; Kim, H.; Han, H. O.;
Kim, Y. K.; Min, S. J.; Son, S. H.; Lim, S. M.; Jang, W. S.
Angew. Chem., Int. Ed. Engl. 2002, 41, 176. (b) Jeong,
E. J.; Kang, E. J.; Sung, L. T.; Hong, S. K.; Lee, E. J. Am.
Chem. Soc. 2002, 124, 14655. (c) For further references,
see: Lee, E. In Radicals in Organic Synthesis, Vol. 2:
Applications; Renaud, P., Sibi, M. P., Eds.; Wiley-VCH:
Weinheim, 2001; p 303.
Scheme 5. (a) NaHMDS, EtOH, 0 ꢀC or n-C12H25OH, NaHMDS,
.
THF; (b) TBSCl, imidazole, DMAP, DCM; (c) HF pyridine, pyridine,
THF, 0 ꢀC; (d) Ph3P, I2, imidazole, THF; (e) Ph3P, MeCN, reflux;
ꢀ
ꢀ
.
(f) 29 or 30, KHMDS, THF, À78 C; 31, –78 C–rt; (g) HF pyridine,
pyridine, THF.
8. Takai, K.; Nitta, K.; Utimoto, K. J. Am. Chem. Soc.
1986, 108, 7408.
9. Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
10. Experimental details are given in the ref 3.
13C NMR (75.5 MHz, CDCl3) and optical rotation data
for the analogues:
reaction with the known macrolide aldehyde 31 to yield
the ester analogues 4/5 (Scheme 5).
The samples prepared were subjected to cytotoxicity
test.10 Homolasonolide A (2) displayed much lower
activity than that of lasonolide A (1). It appears that the
position of the hydroxy functionality at C39 is quite
important for the bioactivity. Surprisingly, 10-des-
methyllasonolide A (3) also exhibited relatively low
2: d 174.0, 167.4, 146.3, 143.8, 143.7, 138.7, 134.6, 131.4,
129.5, 129.4, 129.3, 128.8, 125.9, 124.6, 120.0, 112.4, 80.7,
77.2, 74.7, 72.7, 70.8, 70.3, 68.9, 67.6, 58.5, 39.4, 39.0,
38.4, 37.9, 37.8, 36.7, 34.3, 33.6, 32.6, 31.1, 27.8, 27.6,
22.5, 21.0, 17.0, 11.4; [a]2D4 À8.6 (c 0.38, CDCl3).

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J. M. Joo et al. / Bioorg. Med. Chem. Lett. 14 (2004) 1905–1908
3: d 174.0, 168.5, 148.4, 145.1, 143.7, 138.5, 134.4, 130.9,
33.7, 33.7, 32.5, 28.0, 21.1, 15.2, 14.2, 11.4; [a]1D3 À72.0 (c
129.7, 129.1, 128.9, 128.8, 127.9, 125.2, 118.2, 112.4, 77.8,
77.2, 74.4, 71.3, 70.3, 67.6, 66.8, 65.6, 64.5, 41.3, 38.9,
38.3, 38.2, 36.6, 34.8, 33.4, 32.5, 31.0, 28.0, 27.7, 22.5,
20.8, 15.2; [a]1D8 À25.2 (c 0.41, CDCl3).
0.30, CDCl3).
5: d 174.4, 168.6, 148.4, 145.1, 138.9, 134.2, 130.8, 129.7,
129.1, 129.0, 128.9, 125.1, 124.5, 118.3, 78.0, 77.2, 74.7,
72.4, 70.7, 70.2, 68.9, 65.6, 41.2, 38.5, 38.3, 35.0, 33.8,
33.7, 32.5, 31.9, 29.6, 29.6, 29.5, 29.3, 29.2, 28.6, 28.0,
25.8, 22.7, 21.1, 15.2, 14.1, 11.4; [a]2D0 À33.2 (c 0.39,
CDCl3).
4: d 174.3, 168.6, 148.4, 145.1, 139.0, 134.3, 130.8, 129.7,
129.1, 129.0, 128.9, 125.1, 124.5, 118.2, 77.9, 77.2, 74.6,
72.4, 70.7, 70.2, 68.9, 65.6, 61.5, 41.2, 38.5, 38.3, 35.0,