Diastereoselective synthesis of the 19-epi-C18-C25 segment of (-)-lasonolide a and an unusual inversion at C19

Article abstract of DOI:10.1016/j.tetlet.2004.10.071

Diastereoselective construction of the 19-epi-C₁₈-C₂₅ segment of (-)-lasonolide A was achieved using a 5-exo-trigonal mode of radical cyclization for the creation of the contiguous quaternary and tertiary stereogenic centers at C₂₂ and C₂₃ as the key reaction step. During the dehydration stage, it was found that an unusual inversion of configuration took place.

Full text of DOI:10.1016/j.tetlet.2004.10.071

Tetrahedron
Letters
Tetrahedron Letters 45 (2004) 9241–9244
Diastereoselective synthesis of the 19-epi-C18–C25 segment of
(À)-lasonolide A and an unusual inversion at C19
Tomoyuki Yoshimura, Toshikazu Bando, Mitsuru Shindo and Kozo Shishido*
Graduate School of Pharmaceutical Sciences, The University of Tokushima, 1-78 Sho-machi, Tokushima 770-8505, Japan
Received 13 September 2004; revised 29 September 2004; accepted 13 October 2004
Available online 28 October 2004
Abstract—Diastereoselective construction of the 19-epi-C18–C25 segment of (À)-lasonolide A was achieved using a 5-exo-trigonal
mode of radical cyclization for the creation of the contiguous quaternary and tertiary stereogenic centers at C22 and C23 as the
key reaction step. During the dehydration stage, it was found that an unusual inversion of configuration took place.
Ó 2004 Elsevier Ltd. All rights reserved.
HO
Lasonolide A, a polyketide-derived natural product
isolated from extracts of the Caribbean marine sponge
Forcepia sp. by McConnell and co-workers,1 was discov-
ered to inhibit the in vitro proliferation of A-549 human
lung carcinoma cell as well as cell adhesion in a newly-
developed whole cell assay that detects signal transduc-
tion agents. Because of its intriguing structural features,
interesting biological profile and limited availability,
lasonolide A is an attractive target for total synthesis.
To date, two total syntheses2,3 have been communicated
by Korean groups. In particular, Lee and co-workers2
revised the proposed structure and established the
absolute structure by their first total synthesis. We
attempted the synthesis of the C18–C25 segment (2) of
(À)-lasonolide A (1),4 the unnatural enantiomer, using
a 5-exo-trigonal mode of radical cyclization for the con-
struction of the crucial quaternary and tertiary stereo-
genic centers5 at C22 and C23 as the key reaction step.
Herein we report a diastereoselective construction of
the 19-epi-C18–C25 segment (3) of (À)-lasonolide A
and an unusual inversion at C19 during the dehydration
stage (Fig. 1).
O
O
O
1
O
O
22
25
CN
19
OH
25
18
OH
O
22
O
OH
O
2: C19 -S
3: C19 -R
18
O
(-)-lasonolide A (1)
Figure 1.
metal hydride, for example, tri-n-butyltin hydride, from
the opposite face of the C19 alkoxymethyl moiety to fur-
nish the (23R)-tetrahydropyran (4), which would be
transformed to the target molecule (2) via sequential
one-carbon elongation, oxidation of the carbon–silicon
bond and protection of the resulting 1,3-diol (Scheme 1).
Aldol condensation of 7,6 derived from (S)-malic acid,
with (S)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone in
the presence of dibutylboron triflate and Hunigꢀs base
gave the aldol product (8) diastereoselectively in 95%
yield. Acidic hydrolysis followed by selective protection
of the primary alcohol moiety of the resulting triol as the
t-butyldiphenylsilyl (TBDPS) ether provided the diol
(9). Hydrolytic removal of the chiral auxiliary produced
the carboxylic acid, which was treated with EDC,
HOBT, and triethylamine to provide the lactone (10)7
in 59% yield from 8. After protection of the secondary
hydroxyl group as the t-butyldimethylsilyl (TBS) ether,
the benzyloxymethyl anion,8 generated in situ from benz-
yloxymethyl(tributyl)stannane, was added to the C23
We envisaged constructing the C22 quaternary stereo-
genic center of the target segment (2) using a 5-exo-trigo-
nal mode of radical cyclization of the dihydropyran (6)
to give the radical intermediate (5) with the (22R) config-
uration. This radical species would abstract hydrogen of
Keywords: Polyketide; Lasonolide A; Radical cyclization; Inversion;
Tamao oxidation.
*
Corresponding author. Tel.: +81 88 633 7287; fax: +81 88 633
9575; e-mail: shishido@ph.tokushima-u.ac.jp
0040-4039/$ - see front matter Ó 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2004.10.071

9242
T. Yoshimura et al. / Tetrahedron Letters 45 (2004) 9241–9244
Si
O
Si
O
Si
O
O
O
22
19
OR'
OR'
OR'
CN
O
O
O
O
H
OR
OR
OR
OH
6
2
4
5
H-M
Scheme 1. Retrosynthetic analysis.
Et
Et
O
OH
Et
O
OH
O
O
ref. 6
a
b, c
Et
O
CO2H
O
HO2C
(S)-malic acid
CHO
N
O
8
7
Bn
H
OR2
O
OH OH
O
O
H
R2O
d, e
R1O
RO
N
O
Me
R1O
O
O
H
O
Bn
9: R=TBDPS
10: R1=TBDPS; R2=H
11: R1=TBDPS; R2=TBS
f
NOESY of 11
RO
O
OTBS
OTBS
OTBS
g
h
11
OH
OBn
RO
RO
OBn
H
Me
H
BnO
O
O
12: R=TBDPS
13: R=TBDPS
NOESY of 13
Scheme 2. Reagents and conditions: (a) (S)-3-(1-oxopropyl)-4-benzyl-2-oxazolidinone, n-Bu2OTf, i-Pr2NEt, CH2Cl2, 0°C, 1h, 95%; (b) DowexÒ, aq
MeOH, reflux, 12h; (c) t-BuPh2SiCl, imidazole, 4-DMAP, CH2Cl2, 0°C, 1.5h, 86% for the two steps; (d) LiOHÆH2O, 35% H2O2, H2O, THF, 0°C,
1.5h; (e) EDC, HOBT, Et3N, CH2Cl2, rt, 1.5h, 68% for the two steps; (f) TBSOTf, 2,6-lutidine, DMF, rt, 13h, 97%; (g) n-Bu3SnCH2OBn, n-BuLi,
THF, À78°C, 2h, 97%; (h) POCl3, pyridine, rt, 48h, 51%.
position of 11 to give the hemiacetal (12) as a single
product,9 which was exposed to dehydration conditions
using phosphorus oxychloride in pyridine at room tem-
perature. The simple dehydrated product could not be
obtained; however, surprisingly, the epimeric product
at C19 was generated in 51% yield. The structure was de-
duced by a NOESY spectrum, in which a distinct corre-
lation between the C19 and C21 methine protons was
observed (Scheme 2).
lactol (12) opens up to the hydroxy ketone (14) and
the C19 hydroxyl function is activated as the chlorophos-
phonate (15), which is then displaced by the carbonyl
oxygen in an intramolecular SN2-type reaction. This
process would invert C19 and give the oxonium interme-
diate (16), which would be converted to 13 with the 19R
configuration.
Although disappointing, this result did not deter us
from examining further transformations because, ulti-
mately, we were interested in the stereochemical out-
come of the radical cyclization for the construction of
contiguous quaternary and tertiary stereogenic centers.
Thus deprotection of the silyl ethers in 13 followed by
selective protection of the primary hydroxyl group as
TBDPS ether gave the alcohol (17), which was treated
with bromomethyldimethylchlorosilane and triethylam-
ine to provide 18, the substrate for the key radical reac-
tion, in 57% yield from 13. Treatment of 18 with a
catalytic tri-n-butyltin chloride, sodium cyanoborohy-
dride, and AIBN in refluxing t-butanol10 for 3h pro-
vided the bicyclic silyl ether (19) as a single product.
Since this compound was slightly unstable, it was imme-
diately exposed to Tamao oxidation conditions11 to pro-
duce the 1,3-diol (20) in 59% yield for the two steps. The
stereochemistry of the newly generated stereogenic cen-
ters (C22 and C23) was confirmed by NOESY experi-
ments on 22, which was prepared from 20 by
sequential acetonide formation, debenzylation, and p-
bromobenzoylation of 21. The exclusive formation of
As a plausible mechanistic explanation for the unusual
and interesting inversion at C19, we propose that inver-
sion takes place via an intramolecular SN2-type dis-
placement process, as shown in Scheme 3. Initially, the
OTBS
OTBS
POCl3
pyridine
O
Cl2OPO
RO
S
12
S
RO
OH
O
•
•
OBn
14
OBn
15
R=TBDPS
inversion
at C19
OTBS
TBSO
:Py
H
R
R
RO
n
RO
OBn
OB
O
O
+
13
16
Scheme 3. A plausible mechanism.

T. Yoshimura et al. / Tetrahedron Letters 45 (2004) 9241–9244
9243
19 could be explained by considering the intermediate
radical species 24, generated from 23 via a diastereose-
lective 5-exo-trigonal mode of radical cyclization, in
which, after inversion at the C19 stereogenic center, the
bottom face turned out to be more convex, and the
hydrogen abstraction took place from the a-face to yield
the (22R,23S)-isomer (19) (Scheme 4).
benzoate (27), as shown in Scheme 5. Finally, one car-
bon elongation of the aldehyde (26) was realized via
sequential NaBH4 reduction, triflate formation, and
cyanation to give the cyanide (3). The structure and rel-
ative configuration of 3 was firmly established by X-ray
crystallographic analysis12 (Fig. 2).
In summary, we have completed a diastereoselective
construction of the 19-epi-C18–C25 segment of (À)-laso-
nolide A using a 5-exo-trigonal mode of radical cycliza-
tion for the creation of the contiguous quaternary and
tertiary stereogenic centers at C22 and C23 as the key
reaction step. The synthetic route we developed here
would contribute to the synthesis of a variety of lasono-
lide A analogs. In addition, it should be emphasized that
an unusual and unprecedented inversion of configura-
tion was found during the dehydration leading to the
formation of the dihydropyran. A generalization of this
Although we obtained the (23S) isomer selectively, our
initial target was the (23R) isomer. Consequently, we
examined the epimerization at the C23 stereogenic cen-
ter. The alcohol 21 was oxidized with Dess–Martin rea-
gent to give the aldehyde (25), which was subjected to a
variety of epimerization conditions. After numerous at-
tempts, the use of DBU provided the best result. Thus,
treatment of 25 with DBU at 90°C for 0.5h provided
the epimerized product (26) in 46% yield. The structure
was determined by NOESY experiments on the p-bromo-
O
Si
OH OH
OR2
22
H
a, b
d
e
13
23
O
n
RO
OB
RO
OBn
R1O
OBn
O
O
H
17: R1=TBDPS, R2=H
18: R1=TBDPS, R2=Si(Me)2CH2Br
c
19: R=TBDPS
20: R=TBDPS
f - h
TBDPSO
Si
Si
O
RO
RO
O
O
O
O
O
O
RO
H
H
H
H
Me
23: R=TBDPS
Me
BnO
H
BnO
H
NOESY
H-M
24: R=TBDPS
21: R=H
22: R=p-Br-C6H4CO
Scheme 4. Reagents and conditions: (a) n-Bu4NF, THF, rt, 1h; (b) t-BuPh2SiCl, imidazole, 4-DMAP, CH2Cl2, rt, 2h, 66% for the two steps; (c)
bromomethyldimethylchlorosilane, Et3N, 4-DMAP, CH2Cl2, rt, 1h, 86%; (d) n-Bu3SnCl, NaBH3(CN), AIBN, t-BuOH, 100°C, 3h; (e) KHCO3,
H2O2, THF, MeOH, 90°C, 1.5h, 59% for the two steps; (f) Me2C(OMe)2, PPTS, CH2Cl2, reflux, 10h, 90%; (g) Li, liq. NH3, THF, À78°C, 20min,
77%; (h) p-Br–C6H4COCl, Et3N, H2Cl2, rt, 3.5h, 74%.
NOESY
TBDPSO
c, d
O
O
O
O
O
O
O
H
O
a
b
21
RO
RO
O
C
HO
CHO
Me
27: R=p-Br-C6H4CO
OR
25: R=TBDPS
26: R=TBDPS
e - g
O
O
O
25
CN
RO
18
3: R=TBDPS
Scheme 5. Reagents and conditions: (a) Dess–Martin periodinane, CH2Cl2, rt, 0°C, 85%; (b) DBU, 90°C, 0.5h, 46%; (c) NaBH4, MeOH, 0°C, 2h;
(d) p-Br–C6H4COCl, Et3N, CH2Cl2, rt, 2.5h, 70% for the two steps; (e) NaBH4, MeOH, 0°C, 2h, 97%; (f) Tf2O, pyridine, CH2Cl2, À78°C, 20min;
(g) KCN, 18-crown-6, DMSO, rt, 12h, 32% for the two steps.

9244
T. Yoshimura et al. / Tetrahedron Letters 45 (2004) 9241–9244
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. W.;
Jeon, K.; Park, J. H. J. Org. Chem. 2003, 68, 8080–8087.
3. (a) Kang, S. H.; Kang, S. Y.; Kim, C. M.; Choi, H. W.;
Jun, H. S.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew.
Chem., Int. Ed. 2003, 42, 4779–4782; (b) Kang, S. H.;
Kang, S. Y.; Choi, H. W.; Kim, C. M.; Jun, H. S.; Youn,
J. H. Synthesis 2004, 1102–1114.
4. During this synthetic study, it was revealed that (+)-
lasonolide A is the natural enantiomer by the total
synthesis of Lee and co-workers.2a However, they
reported2b that (À)-lasonolide A was found to be the
biologically active enantiomer and the optical rotation
data for natural lasonolide A in the original report1 is in
error. Therefore, the syntheses of (À)-lasonolide A and its
analogs would be of great significance.
Figure 2. ORTEP drawing of 3 (R = TBDPS).
interesting inversion will be made in our laboratories in
due course.
5. (a) Ohtsuka, M.; Takekawa, Y.; Shishido, K. Tetrahedron
Lett. 1998, 39, 5803–5806; (b) Yamamura, I.; Fujiwara,
Y.; Yamato, T.; Irie, O.; Shishido, K. Tetrahedron Lett.
1997, 38, 4121–4124; (c) Fujiwara, Y.; Yamato, T.; Bando,
T.; Shishido, K. Tetrahedron: Asymmetry 1997, 8, 2793–
2799.
Acknowledgements
We thank Professor Tadashi Nakata (Tokyo University
of Science) for providing us with the 1H NMR spectrum
of 10 and also thank Dr. Masahiko Bando (Otsuka
Pharmaceutical Co., Ltd) for X-ray analysis. This work
was supported financially by the Uehara Memorial
Foundation and by a Grant-in-Aid of Scientific Re-
search (B) (No 14370722) from the Japan Society for
the Promotion of Science. We also thank the Sasakawa
Scientific Research Grant from the Japan Science Soci-
ety for funding to T.Y.
6. Hanessian, S.; Ugolini, A.; Dube, D.; Glamyan, A. Can. J.
Chem. 1984, 62, 2146–2147.
7. Fukui, M.; Okamoto, S.; Sano, T.; Nakata, T.; Oishi, T.
Chem. Pharm. Bull. Jpn. 1990, 38, 2890–2892.
8. Still, W. C. J. Am. Chem. Soc. 1978, 100, 1481–1487.
9. The stereochemistry of 12 was confirmed by the NOE
experiment.
10. Stork, G.; Sher, P. M. J. Am. Chem. Soc. 1986, 108, 303–
304.
11. Tamao, K.; Nagata, K.; Ito, Y.; Maeda, K.; Shiro, M.
Synlett 1994, 257–259.
12. Crystal data of 3: C29H39NO4Si, M = 493.72, monoclinic,
References and notes
˚ ˚
1. Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell,
O. J. J. Am. Chem. Soc. 1994, 116, 6015–6016.
space group P21, a = 10.833(1)A, b = 9.862(2)A, c =
˚
3
˚
13.138(1)A, b = 91.039(9)°, V = 1403.4(4)A , Z = 2,
2. (a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D. S.; Jung, C.
K.; Joo, J. M. J. Am. Chem. Soc. 2002, 124, 384–385; (b)
Lee, E.; Song, H. Y.; Joo, J. M.; Kang, J. W.; Kim, D. S.;
Jung, C. K.; Hong, C. Y.; Jeong, S. W.; Jeon, K. Bioorg.
Med. Chem. Lett. 2002, 12, 3519–3520; (c) Song, H. Y.;
Dc = 1.168MgmÀ3, F(000) = 532, l(MoKa) = 1.160cmÀ1
.
The final R and wR were 0.037 and 0.042 for 316
parameters. The crystallographic data will be sent on
quoting the CCDC number, CCDC 249373 (e-mail;
deposit@ccdc.cam.ac.uk).