Stereoselective total synthesis of the natural (+)-lasonolide A

Article abstract of DOI:10.1055/s-2004-822340

The natural (+)-lasonolide A (1), an anti-tumor agent, has been synthesized via thermodynamic benzylidene formation at the C₂₂ quaternary chiral center, use of a disulfone equivalent for elongation of the C ₁₅-C₁₇ three-carbon chain as well as introduction of the two trans olefins at C₁₅ and C₁₇, iodocyclization for the upper THP, Michael addition for the bottom THP, and intramolecular Horner-Emmons olefination for the 20-membered macrolactone.

Full text of DOI:10.1055/s-2004-822340

1102
FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
Stereoselective
u
Total Synth
n
esis of the
N
g
atural
(
+)-Lasonoli
H
de
A
o Kang,*a Suk Youn Kang,a Hyeong-wook Choi,a Chul Min Kim,a Hyuk-Sang Jun,a Joo-Hack Younb
a
Center for Molecular Design and Synthesis, Department of Chemistry, School of Molecular Science (BK21), Korea Advanced Institute
of Science and Technology, Daejeon 305-701, Korea
Fax +82(42)8692810; E-mail: shkang@kaist.ac.kr
b
Department of Chemical Engineering, Sun Moon University, Asan Si, Chung-Nam 336-840, Korea
Received 5 January 2004
of 7 was conceived to be derived from an asymmetric al-
lylation of the known alkene 8.
Abstract: The natural (+)-lasonolide A (1), an anti-tumor agent,
has been synthesized via thermodynamic benzylidene formation at
the C22 quaternary chiral center, use of a disulfone equivalent for
elongation of the C15–C17 three-carbon chain as well as introduction
of the two trans olefins at C15 and C17, iodocyclization for the upper
THP, Michael addition for the bottom THP, and intramolecular
Horner–Emmons olefination for the 20-membered macrolactone.
The synthesis commenced with Swern oxidation6 of the
known alcohol 97 followed by the asymmetric allylation
with allylboronate 10r8 to afford the homoallylic alcohol
6 in 86% yield and 78% ee (Scheme 2). It was necessary
to differentiate between the two alkoxymethyl groups of 6
in the next stage. It was hoped that thermodynamic forma-
tion of benzylidene from 6 would favor 11 rather than 12,
due to the hydrogen-bonding between the axial primary
hydroxyl group and the two ring oxygens. To determine
the optimal procedure benzaldehyde was reacted with 6
Key words: asymmetric synthesis, diastereomeric differentiation,
macrocyclization, natural products, total synthesis
In 1994, McConnel et al. identified lasonolide A from the
shallow water Caribbean marine sponge, Forcepia sp.,
during the search for new anti-tumor agents from marine
resources.1 Lasonolide A exhibits anti-neoplastic activity
by antagonizing the in vitro proliferation of A-549 human
lung carcinoma cells as well as cell adhesion in a cell as-
say for the detection of signal-transduction agents.2 Its rel-
ative stereochemistry was originally proposed incorrectly
by extensive spectroscopic studies, and later revised as
shown in 1, with the stereochemistry of the C28 hydroxyl
group and the absolute configuration, based on synthetic
studies.3,4 Lasonolide A is a novel 20-membered macro-
lactone, which comprises two cis-2,6-disubstituted tet-
rahydorpyrans, nine chiral centers including a quaternary
center, and seven olefinic double bonds composed of one
terminal, two cis and four trans olefins. The intriguing
structural and biological features of the natural product at-
tracted us to its total synthesis. In this paper, we present an
efficient asymmetric total synthesis of the natural product
(+)-lasonolide A (1).
O
15
28
O
O
17
25
35
22
14
HO
21
HO
O
O
O
2
4
OH
1
TBSO
O
O
OH
TBSO
O
(EtO)2OP
O
O
O
OTBS
OTBS
2
6
Following the retrosynthetic analysis of 1, introduction of
the double bonds at C2 and C25 was planned by an in-
tramolecular Horner–Emmons olefination and a Wittig
reaction, respectively (Scheme 1). The appositely func-
tionalized intermediate 2 could be prepared by the Julia–
Kocieński sulfone-coupling protocol5 of sulfone 3 and al-
dehyde 4. Formation of the two tetrahydropyranyl rings
was envisaged as iodocyclization of d-hydroxyalkene 5
for 3 and by intramolecular Michael addition of 7 for 4.
While the quaternary center in 5 was proposed to be in-
stalled by thermodynamic differentiation of the two
alkoxymethyl groups of 6, the homoallylic alkoxy group
TBSO
TBSO
O
OH
SO2
N
S
OH
O
O
Ph
3
5
+
OHC
EtOOC
OBn
H
O
OH
O
OBn
OTIPS
OTBS
OTBS
SYNTHESIS 2004, No. 7, pp 1102–1114
Advanced online publication: 15.04.2004
x
x
.
x
x
.2
0
0
4
8
4
7
DOI: 10.1055/s-2004-822340; Art ID: F00304SS
© Georg Thieme Verlag Stuttgart · New York
Scheme 1 Retrosynthetic analysis

FEATURE ARTICLE
Biographical Sketches
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1103
Sung Ho Kang was born in in Korea. His major re- moted cyclization as one of
1949 in Sancheong, Korea. search projects at the Insti- the key features. He has es-
He studied chemistry at tute were new process tablished
stereoselective
Seoul National University, development of pyrethroid synthesis of syn- and anti-b-
where he earned his BSc insecticides and develop- amino alcohols by utilizing
(1972) and his MSc (1977) ment of new insecticides. In electrophile-promoted cy-
degrees. He moved to the 1985 he took a faculty posi- clization of allylic and ho-
University of Texas at Aus- tion in the Department of moallylic trichloroacetim-
tin in 1977, and worked on Chemistry at the Korea In- idates. The developed pro-
the total synthesis of terpe- stitute of Technology, tocol has been applied to the
noids such as zizanol and which was merged with Ko- total synthesis of various
quadrone containing bicyc- rea Advanced Institute of physiologically
valuable
lo[3.2.11,5]octane skeleton Science and Technology natural products such as in-
and received his PhD in (KAIST). The merged Insti- dolizidine and pyrrolizidine
1982 under the supervision tute was named as the latter alkaloids, (+)-furanomycin,
of Prof. S. Monti. He then one (KAIST). He has been a (+)-lactacystin,
sphin-
joined the group of Prof. Y. full professor since 1992. gosines, and so forth. Re-
Kishi at Harvard University His research interests in- cently his group has
as a postdoctoral fellow and clude total synthesis of natu- succeeded in developing
was involved in the total ral products and develop- asymmetric catalysts for
synthesis of palytoxin. Dur- ment of asymmetric reac- enantioselective mercurio-
ing 1984–1985, he was tions. In most of his natural cyclization and iodocycliza-
hired as a principal scientist product syntheses, he has tion.
at Lucky Research Institute employed electrophile-pro-
Suk Youn Kang was born BSc (1998). Then he was and received a PhD degree
in 1975 in Seoul, Korea. He admitted to the Department (2004) under the supervi-
graduated from the Depart- of Chemistry at the Gradu- sion of Prof. S. H. Kang.
ment of Chemistry at Yon- ate School of KAIST. He
sei University receiving a gained a MSc degree (2000)
Hyeong-wook Choi was FR901483, N-acetylneur- asymmetric Nozaki–Hiya-
born in 1972 in Sacheon, aminic acid, and (+)-lasono- ma–Kishi reaction. Since
Korea. He received his BSc lide A. Then he joined the 2002, he has been employed
(1994), MSc (1996), and group of Prof Y. Kishi at as a senior scientist at the
PhD (2000) at KAIST under Harvard University as a Chemical Development De-
the guidance of Prof. S. H. postdoctoral fellow. He partment of LG Life Scienc-
Kang. His PhD thesis was worked on the total synthe- es, Ltd.
on the total synthesis of nat- sis of halichondrin B and the
ural products such as development of a catalytic
Chul Min Kim was born in under the guidance of Prof. hired as a senior research
1970 in Busan, Korea. He S. H. Kang. He was subse- scientist at LG Life Scienc-
graduated from Chemistry quently awarded a KOSEF es. Since 2003, he is a prin-
Department at KAIST, and fellowship and carried out cipal research scientist at
obtained his BSc (1993), his postdoctoral work on the Crystalgenomics Inc. His
MSc (1995), and PhD de- synthesis of serotonin N- current research interest is
grees (1999) working on the acetyltransferase inhibitor the design and synthesis of
total synthesis of (+)-lano- with Prof. P. A. Cole at the new concept antibiotics and
mycin, the side chain of tax- Johns Hopkins Medical phosphodiesterase 4 inhibi-
ol, and (+)-lasonolide A School. In 2001, he was tors.
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1104
S. H. Kang et al.
FEATURE ARTICLE
under various acidic conditions. While a 1:1 mixture of
the desired benzylidene 11 and its diastereomeric acetal
12 was obtained in 80% yield in the presence of 3 mol%
of p-TsOH in toluene at room temperature, the best result
was attained using 4 equivalents of CF3COOH in toluene
at –20 to 0 °C to give a 5:1 mixture of 11 and 12 in 72%
yield along with 24% of the other diastereomers 13. After
chromatographic separation, the undesired diastereomers
were resubmitted to the established reaction conditions to
produce 11 in a total yield of 82%. The stereochemistry of
11 was determined by measuring the NOE enhancements
between C4 hydrogen and C5 methyl group. The remain-
ing primary hydroxyl group of 11 was subjected to Swern
oxidation and a second asymmetric allylation with 10s to
furnish another homoallylic alcohol 5 in 77% yield and
91% enhanced ee. It was found that the cyclic acetal pro-
tecting group of 5 was beneficial in the formation of the
upper tetrahydropyran (THP) ring. Iodocyclization of 5
was carried out using I2 in the presence of K2CO3 at –30
to –20 °C to give rise to a 24–27:1 mixture of cis-2,6-di-
substituted THP 15 and the corresponding trans isomer in
95% combined yield. In the case of 14 compared with 5,
the products were formed in an isomeric ratio of 12:1 and
88% yield. The 2,6-cis-relationship of 15 was deduced by
the NOE enhancements between C2 hydrogen and C6 hy-
drogen. After converting 15 into the benzoate 16 in 1-me-
thyl-2-pyrrolidinone (NMP), the benzoate was ozonized,
reduced with NaBH4, and then deprotected by hydro-
genolysis rather than inefficient acidic hydrolysis to pro-
vide triol 17 in 83% overall yield. The two primary and
one secondary hydroxyl groups of 17 were differently si-
lylated with TBSCl and TESOTf, respectively, and then
the benzoate group of the resultant silyl ether 18 was re-
moved to supply alcohol 19 in 85% overall yield, which
was oxidized to aldehyde 20 by Dess–Martin periodi-
nane.9
To complete the synthesis of the upper THP subunit 3,
sulfone sulfide 24 was designed as a novel building block
to install the three-carbon fragment at C18, and the two
trans olefinic double bonds at C15 and C17. 1,3-Pro-
panediol 21 was exposed to tetrazolethiol 22 under Mit-
sunobu conditions using DEAD10 and subsequently
oxidized by buffered heptamolybdate11 to procure the cor-
responding sulfone alcohol in 67% overall yield
(Scheme 3). Another Mistunobu reaction of the sulfone
alcohol with benzothiazolethiol 23 afforded the proposed
sulfone sulfide 24 in 90% yield. The coupling reaction be-
tween 20 and 24 was attained most efficiently by adding
KHMDS dropwise to the mixture in DME to give a readi-
ly separable 31:1 mixture of the desired trans-alkene and
cis isomer in 98% combined yield. The trans-olefinic sul-
Scheme 2 Reagents and conditions: a) (COCl)2, DMSO, CH2Cl2,
–78 °C, then Et3N, –78 to 0 °C; b) 10r, 4 Å MS, PhMe, –78 °C to r.t.,
then 2 N NaOH, 0 °C, 86% (for steps a, b); c) PhCHO (3 equiv),
CF3CO2H (4 equiv), PhMe, –20 to 0 °C, 82% (after 2 cycles); d) 10s,
4 Å MS, PhMe, –78 °C to r.t., then 2 N NaOH, 0 °C, 77% (for steps
a, d); e) I2, K2CO3, MeCN, –30 to –20 °C, 91%; f) NaOBz, NMP,
100 °C, 97%; g) O3, NaHCO3, MeOH, –78 °C, then NaBH4, –78 to
0 °C, 96%; h) H2, 10% Pd/C, HOAc, MeOH, r.t., 89%; i) TBSCl, imi-
dazole, DMF, 0 °C, 95%; j) TESOTf, 2,6-lutidine, CH2Cl2, 0 °C,
98%; k) K2CO3, MeOH, r.t., 91%; l) Dess–Martin periodinane, pyri-
dine, CH2Cl2, r.t.
fide was oxidized to sulfone 25 in 94% yield under the in the presence of TBS groups, all the silyl groups of 25
were stripped off under acidic conditions, and consecu-
tively the primary hydroxyl groups of the resulting triol 26
were protected chemoselectively with TBSCl to produce
the upper subunit 3 in 94% yield.
aforementioned conditions. It is worth mentioning that the
buffered heptamolybdate for sulfide oxidation was supe-
rior to the plain oxidant or MCPBA in terms of chemical
yield and reaction time. In addition, the TES group was
partially desilylated in the absence of phosphate buffer.
Since it was difficult to remove the TES group exclusively
To secure the bottom THP subunit 4, the known alcohol
812 was protected as p-methoxybenzyl (PMB) ether, oxi-
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1105
OP
OH OPMB
OBn
Ph
N
b,c
a-c
HO
N
S
OBn
N
SO2
S
N
OH
N
8 : P = H
28
a
24
21
27 : P = PMB
b,d
d,e
Ph
N
EtOOC
OBn
N
N
P1
N
S
O
SH
SH
P1O
O
SO2
O
EtOOC
OBn
g
N
22
OTIPS
OP2
P1O
OP2
29 : P1 = PMB, P2 = H
30 : P1 = PMB, P2 = TIPS
7 : P1 = H, P2 = TIPS
31 : P1 = H, P2 = TBS
N
32
25 : P1 = TBS, P2 = TES
26 : P1,P2 = H
e
f
f
S
g
h,i
23
3
: P1 = TBS, P2 = H
Scheme 3 Reagents and conditions: a) 22, DEAD, Ph3P, THF, 0 °C,
81%; b) (NH4)6Mo7O24·4H2O, H2O2, phosphate buffer (pH 7.6), THF,
EtOH, r.t., 83%; c) 23, DEAD, Ph3P, THF, 0 °C, 90%; d) 20,
KHMDS, DME, –70 °C to r.t., 95% (from 19); e) H2O2, phosphate
buffer (pH 7.6), (NH4)6Mo7O24·4H2O, THF, EtOH, r.t., 94%; f) p-
TsOH·H2O, MeOH, r.t., 98%; g) TBSCl, imidazole, DMF, r.t., 96%.
OHC
O
OBn
TBSO
O
EtO2C
OTIPS
OTBS
33
4
j
dativley cleaved with OsO4–NaIO4,13 and allylated using
Brown’s allylborane14 in sequence to furnish homoallylic
alcohol 28 in 72% overall yield without appreciable
amounts of diastereomers (Scheme 4). Another oxidative
cleavage of 28 followed by olefination with (phosphora-
nylidene)acetate generated a separable 24:1 mixture of
trans- and cis-conjugated esters in 91% yield, the trans
isomer 29 of which was silylated with TIPSOTf and then
deprotected with DDQ15 to give rise to d-hydroxyalkene 7
in 85% yield. The best cyclization of TIPS ether 7 was
achieved with NaH at low temperature to provide cis-2,6-
disubstituted THP 32 exclusively in 81% yield. Curiously,
cyclization of TBS ether 31 barely proceeded at tempera-
tures lower than –10 °C and supplied a 4–10:1 mixture of
2,6-disubstituted THP in favor of the cis isomer in 65–
75% combined yield at –5 to 0 °C. After DIBAL reduc-
tion of 32 to aldehyde, it was olefinated with phophonoac-
etate in the presence of NaH to procure conjugated ester
33 in 89% yield. The ester was reduced with DIBAL and
debenzylated by dissolving metal reduction to afford diol
35 in 79% yield. The allylic hydroxyl group was regiose-
lectively protected using TBSCl and NaH to give the de-
sired TBS ether 36 in 84% yield along with 3% of the
other diastereomeric TBS ether and 11% of recovered 35.
Swern oxidation of 36, and the subsequent olefination by
Still and Gennari’s protocol16 using trifluoroethyl phos-
phonate and KHMDS in the presence of 18-crown-6 pro-
duced 79% of cis-conjugated ester 37 and 12% of the
trans isomer. Since it turned out that TIPS-protected la-
sonolide A was demasked with extensive decomposition
in the final step of our synthesis under various desilylation
conditions, the TIPS group of 37 was switched with TBS
group in 98% yield by a sequence of desilylation and si-
lylation. The resulting ester 38 was reduced with DIBAL
to furnish aldehyde 4 in 78% yield along with 11% of
starting ester.
q
MeOOC
O
O
OP2
m,n
P1O
OTIPS
OTBS
OP
34 : P1 = H, P2 = Bn
35 : P1 = H, P2 = H
36 : P1 = TBS, P2 = H
k
l
37 : P = TIPS
38 : P = TBS
o,p
Scheme 4 Reagents and conditions: a) NaH, PMBCl, n-Bu4NI,
DMF, THF, r.t., 97%; b) OsO4, NaIO4, H2O, THF, r.t.; c)
(–)-Ipc2BCH2CH=CH2, Et2O, –78 °C, then 3 N NaOH, H2O2, r.t.,
74% (for steps b, c); d) Ph3P=CHCOOEt, PhH, reflux, 87% (for b, d);
e) TIPSOTf, 2,6-lutidine, CH2Cl2, 0 °C, 98%; f) DDQ, H2O, CH2Cl2,
r.t., 87%; g) NaH, THF, –78 to –20 °C, 81%; h) DIBAL, CH2Cl2,
–78 °C; i) EtOOCCH2PO(OEt)2, NaH, THF, –78 °C, 89% (for steps
h, i) j) DIBAL, CH2Cl2, –78 °C, 91%; k) Li, NH3 (liq.), THF, –78 °C,
87%; l) NaH, TBSCl, THF, 0 °C, 94% (based on 11% of recoverd
sm); m) (COCl)2, DMSO, CH2Cl2, –78 °C, then Et3N, –78 to 0 °C; n)
KHMDS, 18-crown-6, MeOOCCH(Me)PO(OCH2CF3)2, THF,
–78 °C, 79% (for steps m, n); o) TBAF, THF, r.t., 99%; p) TBSOTf,
2,6-lutidine, CH2Cl2, 0 °C, 99%; q) DIBAL, CH2Cl2, –78 °C, 88%
(based on 11% of recovered sm).
With access to the two key subunits 3 and 4 completed,
they were coupled by dropwise addition of LiHMDS to
the mixture to give rise to a >20:1 mixture of trans-alkene
39 and its cis isomer at the newly formed double bond in
a total yield of 86%. Since macrolactonization proved
abortive with trans,trans-2,4-dienyl carboxylic acid con-
taining a hydroxyl group at C21 prepared from 39, 39 was
esterified to phosphonate 2 in 94% yield with phospho-
noacetic acid17 in the presence of DCC and DMAP. Thus
a Horner–Emmons olefination could then be applied to
form the macrolactone. Treatment of 2 with PPTS result-
ed in deprotection of the two sterically less hindered TBS
groups in 91% yield. After allylic oxidation of the gener-
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1106
S. H. Kang et al.
FEATURE ARTICLE
ated diol 40 with MnO2, the most effective macrolacton-
ization was realized by heating the resultant conjugated
aldehyde at 70–80 °C with K2CO3 in the presence of 18-
crown-618 under high dilution conditions (1 mg of alde-
hyde/mL) to procure macrolactone 41 in 71% overall
yield. While 12% of 41 was obtained with i-Pr2NEt and
LiCl in MeCN at 70–80 °C, use of KHMDS in the pres-
ence of 18-crown-6 at 0 °C supplied 41 in 45% yield. Al-
cohol 41 was oxidized to aldehyde 42 with Dess–Martin
periodinane for Wittig olefination with the C26–C35 side
chain. For preparation of the side chain moiety, the known
acetonide 4319 and alcohol 4420 were coupled under acidic
conditions in 85% yield. The resulting ester 45 was si-
lylated with TESOTf and then heated with Ph3P to give
phosphonium salt 47 in 89% overall yield. Wittig olefina-
tion of 42 and 47 could be accomplished most efficiently
by adding KHMDS to the mixture to furnish the protected
lasonolide A 48 in 86% yield from 41, in which an appre-
ciable amount of the corresponding trans-isomer could
not be found. Although desilylation of 48 was unsuccess-
ful with TBAF, TAS-F, HF, p-TsOH and so forth, it was
accomplished using pyridinum fluoride21 in a 1:1 mixture
of pyridine and THF to produce lasonolide A 1 in 87%
yield, all the physical and spectroscopic data of which
matched those reported in the literature.1,3
PO
O
a
+
3
4
TBSO
OR
PO
O
OTBS
O
O
39 : R = H, P = TBS
b
c
Br
2 : R = COCH2PO(OEt)2
P = TBS
O
43
40 : R = COCH2PO(OEt)2
P = H
+
OH
d,e
44
O
g
R
TBSO
O
OP
O
O
O
Br
O
OTBS
41 : R = CH2OH
42 : R = CHO
f
45 : P = H
h
46 : P = TES
i
OTES
O
We have established a highly enantioselective total syn-
thesis of the natural (+)-lasonolide A from the known al-
cohol 8 through 26 steps (7.2% overall yield) and from the
known alcohol 9 through 25 steps (10.8% overall yield).
The synthetic sequence culminated in the diastereomeric
differentiation of the two alkoxymethyl groups in 6, de-
velopment of sulfone sulfide 24 as the C15–C17 three-car-
bon surrogate and the intramolecular Horner–Emmons
macrocyclization.
42
+
PPh3Br
O
47
j
O
O
O
OP1
P2O
O
O
O
NMR spectra were obtained on a Bruker AVANCE 400 spectrom-
eter (400 MHz for 1H NMR, 100 MHz for 13C NMR) and measured
in CDCl3, C6D6, or CD3OD. Chemical shifts were recorded in ppm
relative to internal standard CDCl3, C6D6, or CD3OD, and coupling
constants are reported in Hz. The high resolution mass spectra were
recorded on a VG Autospec Ultima spectrometer or a JMS-HX110/
110A Flight Resolution Tandem Mass spectrometer. Optical rota-
tions were collected on a JASCO P-1020 polarimeter. All reactions
were carried out in oven-dried glassware under a N2 atmosphere.
All solvents were distilled from the indicated drying reagents right
before use: Et2O and THF (Na, benzophenone), CH2Cl2 (P2O5), and
MeCN (CaH2). The normal work-up included extraction with Et2O,
drying over Na2SO4 and evaporation of volatile materials in vacuo.
Purifications by column chromatography were performed using
Merck silica gel 60 (230–400 mesh).
OP2
48 : P1 = TES, P2 = TBS
1 : P1,P2 = H
k
Scheme 5 Reagents and conditions: a) LiHMDS, DME, –70 °C to
r.t., 82%; b) HOOCCH2PO(OEt)2, DCC, DMAP, CH2Cl2, r.t., 94%;
c) PPTS, MeOH, r.t., 91%; d) MnO2, EtOAc, r.t.; e) K2CO3, 18-
crown-6, PhMe, 70 –80 °C, 71% (for steps d, e); f) Dess–Martin pe-
riodinane, pyridine, CH2Cl2, r.t.; g) p-TsOH·H2O, PhMe, r.t., 85%; h)
TESOTf, 2,6-lutidine, CH2Cl2, 0 °C, 99%; i) Ph3P, MeCN, reflux,
89%; j) KHMDS, THF, –60 °C, 86% (for steps f, j); k) HF·py, pyridi-
ne, THF, r.t., 87%.
Roush’s allylboronate 10r (0.5 M in toluene, 15 mL) was injected
at –78 °C. The reaction mixture was stirred at –78 °C for 5 h,
warmed up to r.t. over 5 h, and then filtered through celite with Et2O
(50 mL). Aqueous 2 N NaOH (10 mL) was added to the filtrate, and
the mixture was stirred at 0 °C for 6 h. Normal work-up followed by
column chromatography (Et2O–hexane 1:2) yielded homoallylic al-
cohol 6 (1.08 g, 86% for 2 steps).
[a]D17 +141.1 (c 1.8, C6H6).
1H NMR (400 MHz, C6D6): d = 5.72–5.65 (1 H, m), 5.00 (1 H, m),
4.97 (1 H, d, J = 1.2 Hz), 3.96 (1 H, dd, J = 11.5, 1.3 Hz), 3.66 (1
(1S)-1-(2,2,5-Trimethyl-1,3-dioxan-5-yl)but-3-en-1-ol (6)
To a solution of (COCl)2 (1.1 mL, 12.48 mmol) in CH2Cl2 (20 mL)
was added DMSO (1.77 mL, 25.0 mmol) dropwise at –78 °C. The
mixture was stirred at –78 °C for 10 min, and then alcohol 9 (1 g,
6.24 mmol) in CH2Cl2 (5 mL) was injected slowly. The reaction
temperature was maintained at –78 °C for 30 min, then Et3N (5.2
mL, 37.4 mmol) was added at –78 °C, and the mixture warmed up
to 0 °C. The reaction was quenched with water (5 mL) and the nor-
mal work-up gave the crude aldehyde. To a mixture of the aldehyde
and 4 Å molecular sieve (500 mg) in toluene (30 mL), (R,R)-
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1107
H, d, J = 12.4 Hz), 3.63 (1 H, dd, J = 11.8, 1.4 Hz), 3.47 (1 H, d,
J = 11.5 Hz), 3.31 (1 H, d, J = 11.7 Hz), 2.07–1.89 (2 H, m), 1.38
(3 H, s), 1.35 (3 H, s), 0.77 (3 H, s). 13C NMR (100 MHz, C6D6): d
= 136.44, 117.62, 97.97, 71.64, 66.92, 66.85, 37.15, 36.37, 24.96,
23.02, 15.42.
presence of K2CO3 (192 mg, 1.38 mmol) at –30 to –20 °C. The re-
sultant mixture was stirred in this temperature range for 1 h. The
reaction was quenched with aqueous 10% Na2S2O3 (20 mL) at
–20 °C, and stirred in an ice bath for 20 min. Normal work-up fol-
lowed by column chromatography (EtOAc–hexane 1:15) yielded
the desired THP 15 (273 mg, 91%) along with the trans isomer (10
mg).
HRMS (EI): m/z calcd for C11H20O3: 200.1412; found: 200.1445.
{(2R,4S,5S)-4-Allyl-5-methyl-2-phenyl-1,3-dioxan-5-yl}metha-
nol (11)
[a]D14 +171.4 (c 1.01, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.50–7.47 (2 H, m), 7.40–7.34 (3
H, m), 6.08–5.97 (1 H, m), 5.50 (1 H, s), 5.12 (1 H, dd, J = 17.2, 1.5
Hz), 5.06 (1 H, dd, J = 10.2, 1.3 Hz), 4.33 (1 H, dd, J = 9.7, 3.1 Hz),
4.04 (1 H, d, J = 12.2 Hz), 3.85 (1 H, t, J = 2.9 Hz), 3.76 (1 H, m),
3.52 (1 H, d, J = 12.2 Hz), 3.23 (1 H, dd, J = 10.3, 4.3 Hz), 3.16 (1
H, dd, J = 10.4, 6.7 Hz), 2.31–2.16 (2 H, m), 1.87–1.74 (2 H, m),
0.82 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 138.15, 136.04, 129.09, 128.34,
126.17, 116.13, 101.98, 79.94, 75.72, 73.08, 71.61, 34.76, 33.94,
33.48, 14.47, 10.20.
To a solution of alcohol 6 (200 mg, 1.0 mmol) and PhCHO (0.3 mL,
3.0 mmol) in toluene (10 mL) was added CF3CO2H (0.3 mL, 4.0
mmol) at –20 °C. The mixture was stirred at –20 2 °C for 20 min,
and then between –20 °C and 0 °C for 2 h. The reaction was
quenched with 2 N aqueous NaOH (5 mL) at 0 °C. Normal work-up
followed by column chromatography (EtOAc–hexane 1:4) yielded
the desired benzylidene 11 (149 mg, 60%) along with 12 (30 mg,
12%) and 13 (59 mg, 24%). A mixture of 12 (30 mg) and 13 (59 mg)
was re-subjected to the aforementioned reaction conditions to give
11 (54 mg, 61%); the total combined yield was 82%.
[a]D16 –575.5 (c 0.8, C6H6).
HRMS (EI): m/z calcd for C18H23IO3: 414.0692; found: 414.0669.
1H NMR (400 MHz, C6D6): d = 7.65–7.62 (2 H, m), 7.21–7.09 (3 H,
m), 5.92 (1 H, m), 5.32 (1 H, s), 5.09–5.03 (2 H, m), 4.11 (1 H, d,
J = 11.3 Hz), 3.93 (1 H, d, J = 10.4 Hz), 3.38 (2 H, dd, J = 10.2, 2.8
Hz), 3.09 (1 H, d, J = 11.3 Hz), 2.21–2.11 (2 H, m), 1.38 (1 H, br
s), 0.49 (3 H, s).
13C NMR (100 MHz, C6D6): d = 139.44, 136.27, 128.75, 127.89,
126.52, 116.36, 101.86, 84.92, 73.58, 63.25, 37.18, 33.91, 16.65.
(2R,4aR,5R,7R)-5-Allyl-4a-methyl-2-phenyltetrahydropyra-
no[4,3-d][1,3]dioxan-7-ylmethyl Benzoate (16)
Iodide 15 (273 mg, 0.66 mmol) and sodium benzoate (950 mg, 6.6
mmol) in NMP (2 mL) were heated at 100 °C for 6 h. After quench-
ing the reaction with water (2 mL), normal work-up and column
chromatography (EtOAc–hexane 1:10) yielded the desired ben-
zoate 16 (261 mg, 97%).
HRMS (EI): m/z calcd for C15H20O3: 248.1412; found: 248.1436.
[a]D14 +140.9 (c 0.94, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.05 (2 H, dd, J = 8.2, 1.1 Hz),
7.54–7.42 (3 H, m), 7.38–7.35 (5 H, m), 6.00–5.91 (1 H, m), 5.53 (1
H, s), 5.14–5.09 (1 H, m), 5.03–4.99 (1 H, m), 4.39–4.35 (3 H, m),
4.35–4.18 (1 H, m), 4.05 (1 H, d, J = 12.2 Hz), 3.91 (1 H, t, J = 3.0
Hz), 3.53 (1 H, J = 12.2 Hz), 2.32–2.26 (1 H, m), 2.23–2.15 (1 H,
m), 1.97–1.88 (1 H, m), 1.76 (1 H, dt, J = 13.9, 2.7 Hz), 0.85 (3 H,
s).
13C NMR (100 MHz, CDCl3): d = 166.41, 138.20, 136.05, 132.88,
130.20, 129.66, 129.10, 128.36, 128.27, 126.21, 116.03, 102.03,
79.68, 75.33, 73.30, 70.69, 67.18, 34.97, 33.38, 30.16, 14.47.
(1R)-1-[(2R,4S,5R)-4-Allyl-5-methyl-2-phenyl-1,3-dioxan-5-
yl]but-3-en-1-ol (5)
To a solution of (COCl)2 (0.45 mL, 5.15 mmol) in CH2Cl2 (15 mL)
was added DMSO (0.73 mL, 10.31 mmol) dropwise at –78 °C. Af-
ter stirring at –78 °C for 10 min, alcohol 9 (640 mg, 2.58 mmol) in
CH2Cl2 (5 mL) was injected slowly. The resulting mixture was
stirred at –78 °C for 30 min, and then Et3N (2.14 mL, 15.46 mmol)
was introduced. The mixture warmed to 0 °C over 30 min. The re-
action solution was quenched with water (5 mL), and the normal
work-up gave the crude aldehyde. To a mixture of the aldehyde and
4 Å MS (200 mg) in toluene (20 mL) was injected (S,S)-Roush’s al-
lylboronate 10s (0.5 M in toluene, 6.2 mL) dropwise at –78 °C, and
the reaction mixture was stirred at –78 °C for 5 h. The mixture
warmed to r.t. over 5 h, then filtered through celite, and the filtrate
was washed with Et2O (30 mL). Aqueous 2 N NaOH (7 mL) was
added to the filtrate and the mixture was stirred at 0 °C for 6 h. Nor-
mal work-up followed by column chromatography (EtOAc–hex-
ane, 1:2) yielded homoallylic alcohol 5 (665 mg, 77% for 2 steps).
HRMS (EI): m/z calcd for C25H28O5: 408.4868; found, 408.4701.
(2R,4S,5S,6R)-4-Hydroxy-6-(2-hydroxyethyl)-5-hydroxymeth-
yl-5-methyltetrahydropyran-2-ylmethyl Benzoate (17)
Benzoate 16 (322 mg, 0.79 mmol) in the presence of NaHCO3 (66
mg, 1.58 mmol) in MeOH (20 mL) was treated with O3 at –78 °C
until the starting material disappeared by TLC. After addition of
Me2S (4 mL) at –78 °C, the reaction mixture was stirred at 0 °C for
30 min to produce the aldehyde. NaBH4 (90 mg, 2.37 mmol) was
added, and then the reaction solution was stirred at 0 °C for 30 min.
The reaction was quenched with sat. aqueous NH4Cl (8 mL) at 0 °C
for 10 min. Normal work-up followed by column chromatography
(EtOAc–hexane 1:2) gave rise to the desired alcohol (313 mg,
96%).
[a]D15 –502.3 (c 1.03, C6H6).
1H NMR (400 MHz, C6D6): d = 7.63–7.60 (2 H, m), 7.20–7.10 (3 H,
m), 6.08–5.97 (1 H, m), 5.63–5.53 (1 H, m), 5.36 (1 H, s), 5.16–5.11
(1 H, ddd, J = 17.2, 3.5, 1.6 Hz), 5.09–5.05 (1 H, ddt, J = 10.2, 2.1,
1.2 Hz), 4.98–4.90 (2 H, m), 4.17 (1 H, d, J = 11.8 Hz), 3.91 (1 H,
dt, J = 10.8, 2.7 Hz), 3.45 (1 H, dd, J = 10.2, 2.7 Hz), 3.13 (1 H, d,
J = 11.8 Hz), 2.75–2.68 (1 H, m), 2.55–2.47 (1 H, m), 2.44–2.37 (1
H, m), 2.28–2.20 (1 H, m), 1.41 (1 H, br s), 0.63 (3 H, s).
13C NMR (100 MHz, C6D6): d = 139.50, 136.89, 136.47, 128.71,
127.89, 126.54, 118.19, 116.19, 102.03, 86.49, 73.52, 70.35, 39.14,
38.77, 35.06, 16.45.
[a]D16 +167.0 (c 0.84, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.04 (2 H, dd, J = 8.0, 1.0 Hz),
7.54–7.44 (3 H, m), 7.43–7.34 (5 H, m), 5.53 (1 H, s), 4.57 (1 H, dd,
J = 9.6, 4.0 Hz), 4.44 (1 H, dd, J = 11.6, 2.9 Hz), 4.31–4.24 (1 H,
m), 4.16 (1 H, dd, J = 11.6, 7.7 Hz), 3.95 (1 H, d, J = 12.2 Hz),
3.94–3.87 (2 H, m), 3.81 (1 H, dt, J = 11.0, 4.3 Hz), 3.54 (1 H, d,
J = 12.3 Hz), 1.91 (1 H, ddd, J = 14.1, 11.8, 3.1 Hz), 1.79 (1 H, t,
J = 2.6 Hz), 1.77–1.70 (2 H, m), 0.86 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 166.43, 138.00, 133.07, 129.80,
129.66, 129.16, 128.42, 128.38, 126.13, 101.98, 79.07, 77.44,
73.14, 70.92, 67.07, 62.72, 34.84, 30.41, 29.73, 14.57.
HRMS (EI): m/z calcd for C18H24O3: 288.1725; found: 288.1701.
(2R,4aR,5R,7R)-5-Allyl-7-iodomethyl-4a-methyl-2-phenyltet-
rahydropyrano[4,3-d][1,3]dioxane (15)
I2 (916 mg, 3.6 mmol) in CH3CN (13 mL) was added dropwise over
4 h to benzylidene 5 (200 mg, 0.7 mmol) in CH3CN (20 mL) in the
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1108
S. H. Kang et al.
FEATURE ARTICLE
HRMS (EI): m/z calcd for C24H28O6: 412.1886; found: 412.1908.
13C NMR (100 MHz, CDCl3): d = 72.69, 71.81, 70.75, 66.38, 66.28,
60.03, 42.04, 33.40, 31.66, 26.01, 25.93, 18.36, 18.25, 14.61, 6.99,
5.08, –5.32, –5.35, –5.39, –5.54.
To the prepared alcohol (210 mg, 0.51 mmol) in MeOH (10 mL)
and HOAc (4 drops) was added 10% Pd/C (20 mg). The reaction
flask was briefly evacuated and filled with hydrogen gas twice. Af-
ter 3 h under an atmospheric pressure of hydrogen gas using a bal-
loon at r.t., the mixture was filtered through a short silica gel column
with MeOH. After evaporation of the volatile materials in vacuo,
the resulting residue was purified by column chromatography (10%
MeOH–CH2Cl2) to furnish triol 17 (147 mg, 89%).
HRMS (EI): m/z calcd for C28H62O5Si3: 562.3905; found: 562.3942.
2-[3-(1-Phenyl-1H-tetrazole-5-sulfonyl)propylsulfanyl]benzo-
thiazole (24)
To a mixture of 1,3-propanediol 21 (300 mg, 3.3 mmol), 1-phenyl-
1H-tetrazole-5-thiol 22 (588 mg, 3.3 mmol) and Ph3P (866 mg, 3.3
mmol) in THF (20 mL) was added DEAD (0.52 mL, 3.3 mmol)
dropwise at 0 °C over 30 min. After 20 min, the reaction mixture
was quenched with H2O (5 mL). Normal work-up with EtOAc fol-
lowed by column chromatography (EtOAc–hexane 1:1) yielded tet-
razole sulfide (631 mg, 81%).
1H NMR (400 MHz, CDCl3): d = 7.55–7.51 (5 H, m), 3.74 (2 H, t,
J = 5.6 Hz), 3.50 (2 H, t, J = 6.8 Hz), 3.11 (1 H, br s, OH), 2.08–
2.01 (2 H, m).
[a]D16 +141.4 (c 0.9, CHCl3).
1H NMR (400 MHz, CDCl3): d = 8.03 (2 H, dd, J = 6.2, 1.0 Hz),
7.55–7.50 (1 H, m), 7.41 (2 H, t, J = 7.4 Hz), 4.37 (1 H, d, J = 8.4
Hz), 4.29–4.18 (3 H, m), 3.95 (1 H, t, J = 2.7 Hz), 3.79 (2 H, t,
J = 5.2 Hz), 3.62–3.55 (2 H, m), 2.11–2.00 (1 H, m), 1.81–1.77 (2
H, m), 1.59–1.54 (1 H, m), 0.77 (3 H, s).
13C NMR (100 MHz, CDCl3): d = 166.60, 133.08, 129.62, 128.41,
74.60, 74.28, 70.34, 69.57, 67.31, 61.41, 39.99, 32.15, 30.90, 15.22.
13C NMR (100 MHz, CDCl3): d = 154.97, 133.45, 130.19, 129.76,
123.80, 59.59, 32.44, 29.90.
HRMS (EI): m/z calcd for C17H24O6: 324.1573; found: 324.1501.
H2O2 (30% in H2O, 5.0 mL) and phosphate buffer (0.1 M, pH 7.6,
0.5 mL) were added to (NH4)6Mo7O24·4H2O (3.7 g, 3.0 mmol) at r.t.
to get a homogeneous solution, which was injected dropwise at r.t.
into a mixture of the tetrazole sulfide (631 mg, 2.67 mmol) in THF
(3 mL) and EtOH (12 mL). After the starting material had disap-
peared by TLC, normal work-up followed by column chromatogra-
phy (EtOAc–hexane 1:1) generated sulfone alcohol (594 mg, 83%).
1H NMR (400 MHz, CDCl3): d = 7.69–7.66 (2 H, m), 7.62–7.58 (3
H, m), 3.89 (2 H, dd, J = 7.5, 6.8 Hz), 3.81 (2 H, t, J = 5.8 Hz),
2.25–2.18 (2 H, m).
(2R,4S,5R,6R)-6-[2-(tert-Butyldimethylsilanyloxy)-ethyl]-5-
(tert-butyldimethylsilanyloxymethyl)-5-methyl-4-triethylsila-
nyloxytetrahydropyran-2-ylmethyl Benzoate (18)
Triol 17 (147 mg, 0.45 mmol) in DMF (2 mL) reacted with TBSCl
(81 mg, 0.54 mmol) in the presence of imidazole (62 mg, 0.91
mmol) at 0 °C. After the reaction mixture was stirred for 3 h, it was
quenched with H2O (2 mL). Normal work-up and column chroma-
tography (EtOAc–hexane 1:10) yielded disilyl ether (236 mg,
95%). TESOTf (0.12 mL, 0.52 mmol) was added slowly to the di-
silyl ether (236 mg, 0.43 mmol) in CH2Cl2 (5 mL) in the presence
of 2,6-lutidine (0.2 mL, 1.72 mmol) at 0 °C, and then the mixture
was stirred at 0 °C for 30 min. The reaction was quenched with sat.
aqueous NH4Cl (5 mL). Normal work-up followed by column chro-
matography (EtOAc–hexane 1:20) gave the desired trisilyl ether 18
(281 mg, 98%).
1H NMR (400 MHz, CDCl3): d = 8.04 (2 H, dd, J = 6.2, 1.0 Hz),
7.56–7.51 (1 H, m), 7.43–7.38 (2 H, m), 4.31–4.22 (2 H, m), 4.12–
4.06 (1 H, m), 3.88 (1 H, t, J = 2.8 Hz), 3.83 (1 H, dd, J = 10.7, 1.3
Hz), 3.70 (1 H, dd, J = 4.8, 1.9 Hz), 3.68 (1 H, d, J = 4.4 Hz), 3.50
(1 H, d, J = 9.5 Hz), 3.31 (1 H, d, J = 9.5 Hz), 1.77–1.73 (1 H, m),
1.62–1.56 (1 H, m), 1.48–1.44 (2 H, m), 0.94 (9 H, t, J = 8.0 Hz),
0.88 (9 H, s), 0.86 (9 H, s), 0.58 (6 H, q, J = 8.0 Hz), 0.01 (6 H, d,
J = 2.6 Hz), –0.01 (6 H, d, J = 3.0 Hz).
13C NMR (100 MHz, CDCl3): d = 153.52, 132.96, 131.51, 129.73,
125.08, 59.92, 53.17, 25.38.
To a mixture of the sulfone alcohol (594 mg, 2.21 mmol), 2-mercap-
tobenzothiazole 23 (418 mg, 2.5 mmol) and Ph3P (656 mg, 2.5
mmol) in THF (20 mL) was added DEAD (0.4 mL, 2.5 mmol) drop-
wise at 0 °C. The resulting solution was stirred at 0 °C for 20 min,
and then quenched with H2O (5 mL). Normal work-up followed by
column chromatography (EtOAc–hexane 1:10 → 1:5) afforded sul-
fone sulfide 24 (830 mg, 90%).
1H NMR (400 MHz, CDCl3): d = 7.86–7.72 (2 H, m), 7.66–7.64 (2
H, m), 7.58–7.56 (3 H, m), 7.41–7.23 (2 H, m), 3.96 (2 H, dd,
J = 7.6, 5.7 Hz), 3.55 (2 H, t, J = 6.9 Hz), 2.59–2.51 (2 H, m).
13C NMR (100 MHz, CDCl3): d = 165.16, 153.27, 152.71, 135.14,
132.88, 131.49, 129.71, 126.19, 125.00, 124.56, 121.57, 121.04,
54.54, 31.14, 22.63.
13C NMR (100 MHz, CDCl3): d = 166.47, 132.85, 130.31, 129.62,
128.28, 72.73, 70.52, 69.66, 67.72, 66.29, 60.03, 41.93, 33.28,
32.36, 26.01, 25.92, 18.34, 18.26, 14.78, 7.00, 5.09, –5.32, –5.37,
–5.43, –5.53.
HRMS (EI): m/z calcd for C17H15N5O2S3: 417.0388; found:
417.0337.
HRMS (EI): m/z calcd for C35H66O6Si3: 666.4167; found: 666.4098.
2-{4-[(2R,4S,5S,6R)-6-[2-(tert-Butyldimethylsilanyloxy)ethyl]-
5-(tert-butyldimethylsilanyloxymethyl)-5-methyl-4-triethylsila-
nyloxytetrahydropyran-2-yl]-(3E)-butene-1-sulfonyl}benzothi-
azole (25)
{(2R,4S,5R,6R)-[2-(tert-Butyldimethylsilanyloxy)ethyl]-5-(tert-
butyldimethylsilanyloxymethyl)-5-methyl-4-triethylsilanyl-
oxytetrahydropyran-2-yl}methanol (19)
Benzoate 18 (281 mg, 0.42 mmol) in MeOH (3 mL) was treated
with K2CO3 (5 mg, 0.04 mmol) at r.t. for 4.5 h. After quenching the
reaction with sat. aqueous NH4Cl (2 mL), normal work-up followed
by column chromatography (EtOAc–hexane 1:7) produced alcohol
19 (215 mg, 91%).
Alcohol 19 (298 mg, 0.53 mmol) in CH2Cl2 (10 mL) and pyridine
(1 mL) was treated with Dess–Martin periodinane (400 mg, 1.06
mmol) at r.t. for 30 min. EtOAc (10 mL) was added to the reaction
mixture, which was filtered through a short silica gel column
(EtOAc). After evaporation of the volatile materials, the resulting
aldehyde 20 and sulfone sulfide 24 (440 mg, 1.05 mmol) were dis-
solved in DME (10 mL). The mixture was cooled to –70 °C, and
KHMDS (0.5 M in PhMe, 2.65 mL, 1.33 mmol) was injected slowly
at that temperature. The reaction mixture was stirred at –70 °C for
1 h, and then warmed to r.t. over 4 h. After quenching the reaction
with sat. aqueous NH4Cl (10 mL), normal work-up and column
[a]D17 +102.1 (c 1.1, CHCl3).
1H NMR (400 MHz, CDCl3): d = 3.86–3.81 (3 H, m), 3.67 (2 H, dd,
J = 7.9, 4.4 Hz), 3.58 (1 H, dd, J = 11.4, 3.1 Hz), 3.48 (1 H, d,
J = 9.3 Hz), 3.44 (1 H, dd, J = 11.4, 6.9 Hz), 3.31 (1 H, d, J = 9.6
Hz), 1.73–1.66 (2 H, m), 1.47 (1 H, m), 1.24 (1 H, m), 0.93 (9 H, t,
J = 8.0 Hz), 0.87 (9 H, s), 0.86 (9 H, s), 0.85 (3 H, s), 0.57 (6 H, q,
J = 8.0 Hz), 0.02 (6 H, d, J = 2.5 Hz), 0.01 (6 H, d, J = 3.5 Hz).
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1109
chromatography (EtOAc–hexane 1:20) furnished trans-olefinic
sulfide (379 mg, 95%) along with the cis isomer (12 mg).
[a]D16 +35.3 (c 1.0, CHCl3).
13C NMR (100 MHz, CDCl3): d = 165.65, 152.74, 134.33, 128.04,
127.67, 125.52, 125.20, 122.33, 77.21, 74.50, 71.64, 70.63, 70.03,
60.07, 54.13, 39.74, 35.52, 32.10, 26.03, 25.97, 25.73, 25.39, 18.44,
17.95, 15.43, –5.25, –5.39, –5.74, –5.88.
HRMS (FAB): m/z calcd for C32H56NO6S2Si2 (M+ + 1): 670.3088;
found: 670.3068.
1H NMR (400 MHz, CDCl3): d = 7.86 (1 H, d, J = 8.2 Hz), 7.74 (1
H, d, J = 7.6 Hz), 7.40 (1 H, dt, J = 7.2, 1.1 Hz), 7.28 (1 H, dt,
J = 6.9, 1.1 Hz), 5.69 (1 H, dt, J = 15.6, 6.4 Hz), 5.61 (1 H, dd,
J = 15.6, 5.6 Hz), 4.23–4.19 (1 H, m), 3.92–3.81 (2 H, m), 3.78–
3.65 (2 H, m), 3.51 (1 H, d, J = 9.5 Hz), 3.40 (2 H, t, J = 7.4 Hz),
3.30 (1 H, d, J = 9.5 Hz), 2.58 (1 H, d, J = 6.8 Hz), 2.54 (1 H, d,
J = 6.8 Hz), 1.74–1.63 (2 H, m), 1.50–1.41 (2 H, m), 0.95 (9 H, t,
J = 8.1 Hz), 0.89 (18 H, s), 0.87 (3 H, s), 0.59 (6 H, q, J = 8.1 Hz),
0.04 (6 H, d, J = 4.0 Hz), 0.02 (6 H, d, J = 3.7 Hz).
13C NMR (100 MHz, CDCl3): d = 166.98, 153.31, 135.18, 133.90,
127.77, 125.98, 124.12, 121.46, 120.90, 77.20, 72.48, 71.80, 70.85,
66.37, 59.92, 41.69, 36.09, 33.23, 32.99, 32.15, 26.02, 25.97, 18.37,
18.30, 14.80, 7.00, 6.96, 5.10, 5.03, –5.30, –5.32, –5.40, –5.53.
(4R,5S,6R)-7-Benzyloxy-6-(4-methoxybenzyloxy)-5-methyl-
hept-1-en-4-ol (28)
To alcohol 8 (2.1 g, 10.18 mmol) and PMBCl (2.22 mL, 15.27
mmol) in THF (30 mL) were added NaH (60% in mineral oil, 450
mg, 11.2 mmol) and n-Bu4NI (20 mg, 0.05 mmol) at 0 °C in se-
quence. Then, the reaction temperature was raised to r.t., and main-
tained at this temperature for 9 h. The reaction was quenched with
sat. aqueous NH4Cl (10 mL) at 0 °C. Normal work-up followed by
column chromatography (EtOAc–hexane 1:10) afforded PMB ether
27 (3.22 g, 97%).
HRMS (FAB): m/z calcd for C38H70NO4S2Si3 (M+ + 1): 752.4054;
found: 752.4098.
[a]D25 +49.3 (c 0.90, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.33–7.30 (3 H, m), 7.28–7.24 (4
H, m), 6.85–6.82 (2 H, m), 5.83–5.74 (1 H, m), 5.00 (1 H, dt,
J = 17.2, 1.6 Hz), 4.97 (1 H, m), 4.64 (1 H, d, J = 11.2 Hz), 4.51 (2
H, s), 4.50 (1 H, d, J = 11.2 Hz), 3.78 (3 H, s), 3.59 (1 H, dd,
J = 10.2, 3.7 Hz), 3.52 (1 H, dd, J = 10.2, 3.7 Hz), 3.44 (1 H, m),
2.51–2.42 (1 H, m), 1.03 (3 H, d, J = 6.8 Hz).
13C NMR (100 MHz, CDCl3): d = 159.04, 140.99, 138.48, 131.07,
129.36, 128.31, 127.56, 127.48, 114.46, 113.65, 81.47, 73.30,
72.42, 71.57, 55.26, 39.98, 15.57.
To (NH4)6Mo7O24·4 H2O (1.25 g, 1.01 mmol) were added H2O2
(30% in H2O, 1.7 mL) and phosphate buffer (0.1 M, pH 7.6, 0.7 mL)
at r.t. in sequence to give a homogeneous solution. The prepared
heptamolybdate solution was injected dropwise to the trans-olefinic
sulfide (379 mg, 0.5 mmol) in a mixture of THF (2 mL) and EtOH
(8 mL) at r.t. After 2 h, normal work-up followed by column chro-
matography (EtOAc–hexane 1:10) yielded sulfone 25 (371 mg,
94%).
[a]D17 = +29.9 (c 0.90, CHCl3).
HRMS (EI): m/z calcd for C21H26O3: 326.1882; found: 326.1903.
1H NMR (400 MHz, CDCl3): d = 8.25–8.21 (1 H, m), 8.03–8.00 (1
H, m), 7.67–7.56 (2 H, m), 5.56–5.49 (2 H, m), 4.14 (1 H, dt,
J = 11.7, 1.5 Hz), 3.82–3.78 (2 H, m), 3.70–3.63 (2 H, m), 3.62–
3.55 (2 H, m), 3.48 (1 H, d, J = 9.6 Hz), 3.28 (1 H, d, J = 9.5 Hz),
1.62–1.53 (2 H, m), 1.44–1.32 (2 H, m), 1.26–1.21 (2 H, m), 0.92 (9
H, t, J = 7.9 Hz), 0.86 (9 H, s), 0.86 (9 H, s), 0.80 (3 H, s), 0.55 (6
H, q, J = 7.8 Hz), 0.00 (6 H, d, J = 0.9 Hz), –0.01 (6 H, d, J = 3.7
Hz).
13C NMR (100 MHz, CDCl3): d = 165.66, 152.74, 136.80, 134.66,
128.04, 127.67, 125.51, 125.06, 122.33, 72.54, 71.39, 70.75, 66.31,
59.86, 54.10, 41.66, 35.94, 33.20, 26.01, 25.95, 25.33, 18.36, 18.28,
14.75, 6.99, 5.08, –5.31, –5.33, –5.41, –5.54.
The olefin 27 (1.5 g, 4.6 mmol) in a mixture of THF (20 mL) and
H2O (4 mL) was treated with NaIO4 (3.9 g, 18.4 mmol) and OsO4
(20 mg, 0.08 mmol) at r.t. for 4 h. After quenching the reaction with
sat. aqueous Na2S2O3 (10 mL), normal work-up (EtOAc) provided
aldehyde. To a stirred solution of (+)-B-methoxydiisopinocamphe-
nylborane (1.96 g, 6.2 mmol) in Et2O (20 mL) was added allylmag-
nesium bromide (1.0 M in Et2O, 6.2 mL, 6.2 mmol) dropwise at
–78 °C. The resulting mixture was allowed to warm to r.t., stirred at
that temperature for 1 h, and then cooled to –78 °C. The aldehyde in
Et2O (20 mL) was added dropwise, and stirred at –78 °C for 5 h. The
mixture was warmed to 0 °C, quenched with MeOH (2.5 mL) at
0 °C, and subsequently 2 N NaOH (2.5 mL) and 30% aqueous H2O2
(2 mL) were introduced carefully in sequence at r.t. After stirring
the exothermic solution for 6 h, normal work-up and column chro-
matography purification (EtOAc– hexane 1:5) gave homoallylic al-
cohol 28 (1.7 g, 74%).
HRMS (FAB): m/z calcd for C38H70NO6S2Si3 (M+ + 1): 784.3952,
found: 784.3893.
(2R,3S,4S,6R)-6-[4-(Benzothiazole-2-sulfonyl)-(E)-butenyl]-2-
[2-(tert-butyldimethylsilanyloxy)ethyl]-3-(tert-butyldimethylsi-
lanyloxymethyl)-3-methyltetrahydropyran-4-ol (3)
[a]D25 +35.6 (c 1.45, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.35–7.29 (5 H, m), 7.24–7.21 (2
H, m), 6.86–6.83 (2 H, m), 5.83–5.73 (1 H, m), 5.11–5.03 (2 H, m),
4.66 (1 H, d, J = 11.2 Hz), 4.53 (2 H, s), 4.48 (1 H, d, J = 11.2 Hz),
3.87–3.83 (1 H, m), 3.78 (3 H, s), 3.74–3.70 (1 H, m), 3.68 (1 H, dd,
J = 9.8, 4.7 Hz), 3.55 (1 H, dd, J = 9.8, 4.7 Hz), 2.31–2.24 (1 H, m),
2.16–2.09 (1 H, m), 1.84–1.77 (1 H, m), 0.90 (3 H, d, J = 7.1 Hz).
13C NMR (100 MHz, CDCl3): d = 159.22, 137.87, 135.55, 130.25,
129.47, 128.43, 127.75, 127.70, 116.95, 113.81, 81.80, 73.48,
73.06, 71.97, 71.10, 55.23, 39.30, 38.72, 6.84.
Sulfone 25 (371 mg, 0.47 mmol) reacted with p-TsOH·H2O (3 mg,
0.016 mmol) in MeOH (5 mL) at r.t. for 2 h. After removal of all the
volatile materials in vacuo, the residue was dissolved in DMF (1
mL). Imidazole (160 mg, 2.35 mmol) and TBSCl (71 mg, 1.03
mmol) were added to the resulting solution at 0 °C, and stirred at
0 °C for 10 min and then at r.t. for 30 min. After quenching the si-
lylation with water, normal work-up followed by column chroma-
tography (EtOAc–hexane 1:5) yielded sulfone alcohol 3 (298 mg,
94%).
[a]D17 +30.1 (c 0.94, CHCl3).
HRMS (EI): m/z calcd for C23H30O4: 370.2144; found: 370.2232.
1H NMR (400 MHz, CDCl3): d = 8.22 (1 H, m), 8.01 (1 H, m), 7.67–
7.57 (2 H, m), 5.58 (2 H, m), 4.22 (1 H, dt, J = 10.2, 4.1 Hz), 4.07
(1 H, dd, J = 10.4, 2.3 Hz), 3.84 (1 H, t, J = 2.8 Hz), 3.71 (2 H, m),
3.63 (1 H, d, J = 10.4 Hz), 3.58 (1 H, d, J = 10.4 Hz), 3.55 (2 H, dd,
J = 8.4, 3.6 Hz), 2.61 (2 H, m), 1.54 (4 H, m), 0.89 (9 H, s), 0.87 (9
H, s), 0.71 (3 H, s), 0.08 (6 H, d, J = 3.9 Hz), 0.02 (6 H, d, J = 3.0
Hz).
Ethyl (5R,6R,7R)-8-Benzyloxy-7-hydroxy-6-methyl-5-triisopro-
pylsilanyloxy-(2E)-octenoate (7)
To a solution of olefin 28 (780 mg, 2.11 mmol) and NaIO4 (900 mg,
4.20 mmol) in a mixture of THF (30 mL) and H2O (6 mL) was add-
ed OsO4 (5 mg, 0.02 mmol) at 0 °C. Then, the reaction temperature
was raised to r.t., and maintained at the temperature for 6 h. After
quenching the reaction with sat. aqueous Na2S2O3 (10 mL), normal
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1110
S. H. Kang et al.
FEATURE ARTICLE
work-up with EtOAc furnished aldehyde. A mixture of the aldehyde
and ethyl (triphenylphosphoranylidene)acetate (882 mg, 2.53
mmol) in benzene (20 mL) was heated at 80–90 °C for 3 h, and sub-
sequently cooled to r.t. The solution was concentrated in vacuo, and
the residue was purified by column chromatography (EtOAc–
hexane 1:2) to afford trans-conjugated ester 29 (812 mg, 87%, 2
steps) along with the cis isomer (33 mg, 4%).
Ethyl [(2S,4R,5R,6R)-6-Benzyloxymethyl-5-methyl-4-triisopro-
pylsilanyloxytetrahydropyran-2-yl]acetate (32)
Conjugated ester 7 (303 mg, 0.63 mmol) dissolved in THF (5 mL)
was treated with NaH (60% in mineral oil, 50 mg, 1.25 mmol) at
–78 °C. The reaction temperature was raised from –78 to –30 °C
over 30 min and then maintained at –30 °C to –20 °C for 3 h. After
quenching the reaction with sat. aqueous NH4Cl (5 mL), normal
work-up followed by column chromatography (EtOAc–
hexane 1:15) yielded cis-2,6-disubstituted THP 32 (245 mg, 81%)
as the sole stereoisomer.
[a]D29 +34.5 (c 0.94, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.37–7.27 (5 H, m), 7.20 (2 H, d,
J = 8.6 Hz), 6.92 (1 H, dt, J = 15.7, 7.4 Hz), 6.84 (2 H, d, J = 8.6
Hz), 5.85 (1 H, d, J = 15.7 Hz), 4.65 (1 H, d, J = 11.2 Hz), 4.53 (2
H, s), 4.45 (1 H, d, J = 11.2 Hz), 4.16 (2 H, q, J = 7.1 Hz), 3.94 (1
H, ddd, J = 7.8, 5.8, 1.6 Hz), 3.78 (3 H, s), 3.72–3.64 (2 H, m), 3.52
(1 H, dd, J = 9.7, 4.8 Hz), 2.45–2.37 (1 H, m), 2.26–2.17 (1 H, m),
1.78–1.72 (1 H, m), 1.26 (3 H, t, J = 7.1 Hz), 0.89 (3 H, d, J = 7.1
Hz).
[a]D27 –11.7 (c 1.06, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.32–7.22 (5 H, m), 4.60 (1 H, d,
J = 12.2 Hz), 4.47 (1 H, d, J = 12.2 Hz), 4.24 (2 H, m), 4.10 (2 H,
q, J = 7.2 Hz), 3.90 (1 H, m), 3.49 (1 H, dd, J = 10.4, 7.3 Hz), 3.37
(1 H, dd, J = 10.4, 5.1 Hz), 2.58 (1 H, dd, J = 14.6, 6.8 Hz), 2.35 (1
H, dd, J = 14.6, 6.7 Hz), 1.72 (1 H, m), 1.57 (2 H, m), 1.21 (3 H, t,
J = 7.2 Hz), 1.07–0.97 (21 H, m), 0.81 (3 H, d, J = 7.1 Hz).
13C NMR (100 MHz, CDCl3): d = 171.07, 138.63, 128.27, 127.52,
127.39, 73.40, 73.07, 71.32, 70.89, 69.25, 60.33, 41.63, 36.89,
34.45, 18.09, 17.72, 17.69, 14.18, 12.29, 12.25, 10.97.
13C NMR (100 MHz, CDCl3): d = 166.42, 159.33, 145.85, 137.69,
130.04, 129.55, 128.50, 127.87, 127.79, 123.24, 113.90, 81.60,
73.59, 72.49, 71.96, 70.77, 60.20, 55.27, 39.21, 37.61, 14.27, 6.76.
HRMS (EI): m/z calcd for C26H34O6: 442.2355, found: 442.2302.
HRMS (EI): m/z calcd for C27H46O5Si: 478.3115; found: 478.3087.
To a stirred solution of alcohol 29 (782 mg, 1.77 mmol) and 2,6-lu-
tidine (0.62 mL, 5.30 mmol) in CH2Cl2 (10 mL) was added
TIPSOTf (0.52 mL, 1.95 mmol) dropwise at 0 °C. The reaction was
maintained at that temperature for 3 h. After quenching with sat.
aqueous NH4Cl (5 mL), normal work-up and column chromatogra-
phy (EtOAc–hexane 1:10) produced silyl ether 30 (1.04 g, 98%).
4-[(2R,4R,5R,6R)-6-Benzyloxymethyl-5-methyl-4-triisopropyl-
silanyloxytetrahydropyran-2-yl]-(2E)-buten-1-ol (34)
Ester 32 (880 mg, 1.84 mmol) in CH2Cl2 (10 mL) reacted with
DIBAL (1.5 M in toluene, 1.84 mL, 2.76 mmol) at –78 °C. The re-
action solution was stirred for 10 min at –78 °C, and then MeOH (2
mL) was injected dropwise. To the solution were added sat. Roch-
elle salt (potassium sodium tartrate tetrahydrate, 5 mL) and EtOAc
(10 mL) at r.t., and it was stirred until the mixture became homoge-
neous. Normal work-up with EtOAc furnished aldehyde. Triethyl
phosphonoacetate (454 mg, 2.03 mmol) was treated with NaH (60%
in mineral oil, 80 mg, 2.03 mmol) in THF (15 mL) at 0 °C for 10
min. The mixture was cooled to –78 °C, and maintained at that tem-
perature for 10 min. To the reaction mixture was introduced the al-
dehyde in THF (5 mL) dropwise at –78 °C over 5 min, and the
mixture was stirred at –78 °C for 20 min. After quenching the mix-
ture with sat. aq NH4Cl (5 mL), normal work-up and column chro-
matography (EtOAc–hexane 1:10) produced conjugated trans-ester
33 (826 mg, 89%) along with the cis isomer (36 mg, 4%).
[a]D29 +21.5 (c 0.7, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.34–7.25 (5 H, m), 7.22 (2 H, d,
J = 8.6 Hz), 6.90 (1 H, dt, J = 15.7, 7.4 Hz), 6.83 (2 H, d, J = 8.6
Hz), 5.83 (1 H, d, J = 15.7 Hz), 4.66 (1 H, d, J = 11.2 Hz), 4.53 (1
H, d, J = 12.2 Hz), 4.49 (1 H, d, J = 12.2 Hz), 4.44 (1 H, d, J = 11.3
Hz), 4.15 (2 H, q, J = 7.2 Hz), 3.94 (1 H, dd, J = 10.1, 5.9 Hz), 3.78
(3 H, s), 3.70 (1 H, dt, J = 9.9, 5.0 Hz), 3.58 (1 H, d, J = 4.7 Hz),
3.57 (1 H, d, J = 3.3 Hz), 2.48–2.35 (1 H, m), 2.33–2.24 (1 H, m),
1.88–1.81 (1 H, m), 1.24 (3 H, t, J = 7.2 Hz), 1.01–0.93 (21 H, m),
0.89 (3 H, d, J = 6.3 Hz).
13C NMR (100 MHz, CDCl3): d = 166.30, 145.96, 138.44, 131.07,
129.38, 128.32, 127.61, 127.50, 123.22, 113.65, 77.74, 73.28,
73.00, 71.94, 71.59, 60.12, 55.26, 40.14, 37.51, 18.25, 18.21, 14.26,
12.95, 10.05.
[a]D23 –9.8 (c 0.79, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.32–7.22 (5 H, m), 6.97 (1 H, dt,
J = 15.7, 7.2 Hz), 5.87 (1 H, dt, J = 15.7, 1.3 Hz), 4.62 (1 H, d,
J = 12.3 Hz), 4.49 (1 H, d, J = 12.3 Hz), 4.23–4.19 (1 H, m), 4.15
(2 H, q, J = 7.1 Hz), 3.99–3.92 (1 H, m), 3.89 (1 H, dd, J = 5.5, 2.7
Hz), 3.51 (1 H, dd, J = 10.3, 7.4 Hz), 3.38 (1 H, dd, J = 10.3, 4.8
Hz), 2.45–2.37 (1 H, m), 2.34–2.27 (1 H, m), 1.72–1.66 (1 H, m),
1.58–1.50 (2 H, m), 1.46–1.42 (1 H, m), 1.24 (3 H, t, J = 7.1 Hz),
1.06–1.00 (21 H, m), 0.80 (3 H, d, J = 7.2 Hz).
HRMS (EI): m/z calcd for C35H54O6Si: 598.3690; found: 598.3851.
The silyl ether 30 (1.04 g, 1.73 mmol) in a mixture of CH2Cl2 (10
mL) and H2O (1 mL) was treated with DDQ (590 mg, 2.60 mmol)
at 0 °C, and then the reaction temperature was raised to r.t. After 3
h, Et2O (20 mL) and H2O (10 mL) were added to the reaction mix-
ture. Normal work-up followed by column chromatography (Et2O–
hexane 1:2) yielded conjugated ester 7 (721 mg, 87%).
[a]D21 +22.8 (c 1.05, CHCl3).
13C NMR (100 MHz, CDCl3): d = 166.43, 145.35, 138.60, 128.29,
127.51, 127.40, 123.22, 73.41, 73.17, 71.48, 70.93, 60.12, 38.69,
36.99, 34.52, 18.10, 14.25, 12.23, 11.04.
1H NMR (400 MHz, CDCl3): d = 7.35–7.24 (5 H, m), 6.89–6.84 (1
H, m), 5.84 (1 H, dt, J = 15.6, 1.4 Hz), 4.53 (2 H, dd, J = 17.4, 12.0
Hz), 4.17 (2 H, q, J = 7.2 Hz), 4.05–3.92 (2 H, m), 3.48–3.40 (2 H,
m), 2.64 (1 H, br s), 2.55–2.41 (2 H, m), 1.71–1.64 (1 H, m), 1.26
(3 H, t, J = 7.2 Hz), 1.03 (18 H, s), 1.02–0.95 (3 H, m), 0.92 (3 H,
d, J = 7.0 Hz).
13C NMR (100 MHz, CDCl3): d = 166.24, 145.09, 138.01, 128.41,
127.76, 127.72, 123.48, 75.14, 73.31, 72.86, 71.58, 60.23, 39.41,
37.43, 18.17, 18.12, 14.24, 13.02, 8.02.
HRMS (EI): m/z calcd for C29H48O5Si: 504.3271; found: 504.3281.
The ester 33 (420 mg, 0.83 mmol) in CH2Cl2 (10 mL) reacted with
DIBAL (1.5 M in toluene, 1.4 mL, 2.1 mmol) at –78 °C for 10 min.
MeOH (2 mL) was added to the reaction mixture, and then the so-
lution warmed to r.t. After addition of a sat. solution of Rochelle salt
(5 mL) and EtOAc (10 mL), the mixture was stirred at r.t. until the
solution became homogeneous. Normal work-up with EtOAc fol-
lowed by column chromatography (EtOAc–hexane 1:4) yielded al-
lylic alcohol 34 (350 mg, 91%).
HRMS (EI): m/z calcd for C27H46O5Si: 478.3115; found: 478.3167.
[a]D24 –7.4 (c 0.98, CHCl3).
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1111
1H NMR (400 MHz, CDCl3): d = 7.33–7.24 (5 H, m), 5.72–5.69 (2
H, m), 4.63 (1 H, d, J = 12.3 Hz), 4.49 (1 H, d, J = 12.3 Hz), 4.22–
4.20 (1 H, m), 4.06 (2 H, d, J = 4.3 Hz), 3.91–3.82 (2 H, m), 3.52 (1
H, dd, J = 10.3, 7.6 Hz), 3.39 (1 H, dd, J = 10.3, 4.8 Hz), 2.34–2.27
(1 H, m), 2.18–2.12 (1 H, m), 1.72–1.63 (1 H, m), 1.58 (1 H, br s),
1.52 (1 H, dd, J = 11.0, 2.6 Hz), 1.46 (1 H, dt, J = 13.6, 2.4 Hz),
1.08–1.00 (21 H, m), 0.81 (3 H, d, J = 4.1 Hz).
13C NMR (100 MHz, CDCl3): d = 138.57, 131.15, 129.13, 128.27,
127.48, 127.41, 73.28, 73.10, 71.80, 71.59, 71.03, 63.69, 38.77,
37.09, 34.40, 18.08, 12.21, 11.05.
dropwise. The mixture was stirred at –78 °C for 10 min, and alcohol
36 (280 mg, 0.58 mmol) in CH2Cl2 (3 mL) was introduced slowly.
After 40 min at –78 °C, Et3N (0.48 mL, 3.48 mmol) was injected.
The reaction mixture was stirred at –78 °C for 10 min and then at
0 °C for 20 min. Normal work-up gave the crude aldehyde, which
was used without further purification. A solution of methyl 2-[bis-
O-(2,2,2,-trifluoroethyl)phosphono]propionate (162 mg, 0.70
mmol) and 18-crown-6 (770 mg, 2.9 mmol, recrystallized in
CH3CN) in THF (10 mL) was treated with KHMDS (0.5 M in tolu-
ene, 1.4 mL, 0.70 mmol) at –78 °C, and maintained at –78 °C for 20
min. Then, the aldehyde in THF (2 mL) was added, and the resulting
mixture was stirred at –78 °C for 3 h. After quenching the reaction
with sat. aqueous NH4Cl (3 mL), normal work-up followed by col-
umn chromatography (EtOAc–hexane 1:20) yielded cis-conjugated
ester 37 (254 mg, 79%) along with the trans isomer (39 mg, 12%).
HRMS (EI): m/z calcd for C27H46O4Si: 462.3165, found: 462.3323.
4-[(2R,4R,5R,6R)-6-Hydroxymethyl-5-methyl-4-triisopropylsi-
lanyloxytetrahydropyran-2-yl]-(2E)-buten-1-ol (35)
NH3 (ca. 10 mL) was collected at –78 °C in a two-neck round-bot-
tomed flask containing THF (1 mL). Pieces of lithium metal (40 mg,
5.76 mmol) were placed in the solution at –78 °C, and then the so-
lution was stirred vigorously until it became dark blue in color. Ben-
zyl ether 34 (450 mg, 0.97 mmol) in THF (3 mL) was injected into
the mixture dropwise. After 20 min, the reaction was quenched with
a mixture of t-BuOH (1 mL) and THF (1 mL), and the resulting so-
lution was left until most of the NH3 had evaporated. Addition of
sat. aqueous NH4Cl (5 mL) followed by normal work-up and col-
umn chromatopgraphy yielded alcohol 35 (314 mg, 87%).
[a]D11 –21.4 (c 1.05, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.88 (1 H, dd, J = 7.7, 1.3 Hz),
5.66–5.51 (2 H, m), 5.10 (1 H, dd, J = 7.8, 1.4 Hz), 4.10 (2 H, d,
J = 4.4 Hz), 3.91 (1 H, m), 3.84 (1 H, m), 3.69 (3 H, s), 2.26 (1 H,
m), 2.15 (1 H, m), 1.90 (3 H, s), 1.89–1.87 (1 H, m), 1.55–1.49 (2
H, m), 1.23–0.99 (21 H, m), 0.90 (9 H, s), 0.89 (3 H, d, J = 4.1 Hz),
0.04 (6 H, s).
13C NMR (100 MHz, CDCl3): d = 167.92, 140.85, 131.57, 127.24,
126.78, 72.36, 71.38, 71.17, 63.89, 51.38, 39.31, 38.91, 33.75,
25.97, 20.72, 18.40, 18.14, 18.10, 18.06, 12.28, 11.66, –5.15.
25
[a]D –9.4 (c 0.98, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.72–5.69 (2 H, m), 4.08 (2 H, d,
J = 2.3 Hz), 4.04 (1 H, dt, J = 9.1, 2.9 Hz), 3.89–3.80 (2 H, m), 3.65
(1 H, dd, J = 11.3, 9.2 Hz), 3.43 (1 H, dd, J = 11.3, 3.3 Hz), 2.32–
2.24 (1 H, m), 2.19–2.12 (1 H, m), 1.65–1.61 (1 H, m), 1.53 (1 H,
dd, J = 11.1, 2.5 Hz), 1.49–1.44 (1 H, m), 1.07–0.99 (21 H, m), 0.82
(3 H, d, J = 7.2 Hz).
HRMS (EI): m/z calcd for C30H58O5Si2: 554.3823; found: 554.3843.
(3Z)-{(2S,3R,4R,6R)-4-(tert-Butyldimethylsilanyloxy)-6-[4-(tert-
butyldimethylsilanyloxy)-(2E)-butenyl]-3-methyltetrahydropy-
ran-2-yl}-2-methylpropenal (4)
To a stirred solution of 37 (355 mg, 0.64 mmol) in THF (5 mL) was
added TBAF (1.0 M in THF, 1.4 mL, 1.4 mmol) at 0 °C, and the re-
sultant solution was allowed to warm to r.t. The reaction mixture
was quenched with H2O (5 mL). Normal work-up followed by col-
umn chromatography (EtOAc–hexane 2/1) yielded diol (180 mg,
99%). The diol (180 mg, 0.63 mmol) reacted with TBSOTf (0.32
mL, 1.39 mmol) and 2,6-lutidine (0.29 mL, 2.52 mmol) in CH2Cl2
(5 mL) at 0 °C for 30 min, and then quenched with sat. aqueous
NH4Cl (5 mL). Normal work-up followed by column chromatogra-
phy (EtOAc–hexane 1:20) yielded disilyl ether 38 (321 mg, 99%).
13C NMR (100 MHz, CDCl3): d = 131.34, 128.96, 75.06, 71.81,
71.09, 64.51, 63.67, 38.76, 37.06, 34.55, 18.09, 12.23, 11.45.
HRMS (EI): m/z calcd for C20H40O4Si: 372.2696; found: 372.2823.
{(2R,3R,4R,6R)-6-[4-(tert-Butyldimethylsilanyloxy)-(2E)-bute-
nyl]-3-methyl-4-triisopropylsilanyloxytetrahydropyran-2-
yl}methanol (36)
To diol 35 (230 mg, 0.62 mmol) in THF (7 mL) was added NaH
(60% in mineral oil, 37 mg, 0.93 mmol) at 0 °C. After 30 min at
0 °C, TBSCl (140mg, 0.93 mmol) was injected. The resulting mix-
ture was stirred at 0 °C for 30 min, allowed to warm to r.t., and
quenched with sat. aqueous NH4Cl (5 mL). Normal work-up fol-
lowed by column chromatography (EtOAc–hexane 3:20) provided
disilyl ether 36 (254 mg, 84%) along with the starting 35 (25 mg,
11%) and the diasteromeric disilyl ether (7 mg, 2%).
[a]D10 –25.4 (c 1.2, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.87 (1 H, dd, J = 7.8, 1.4 Hz),
5.64–5.56 (2 H, m), 5.08–5.06 (1 H, m), 4.10 (2 H, d, J = 4.6 Hz),
3.84–3.77 (2 H, m), 3.69 (3 H, s), 2.28–2.24 (1 H, m), 2.15–2.11 (1
H, m), 1.90 (3 H, s), 1.80–1.77 (1 H, m), 1.58–1.48 (1 H, m), 1.35–
1.30 (1 H, m), 0.90 (9 H, s), 0.88 (9 H, s), 0.86 (3 H, d, J = 8.9 Hz),
0.04 (6 H, d, J = 6.8 Hz), 0.02 (6 H, d, J = 5.8 Hz).
13C NMR (100 MHz, CDCl3): d = 167.82, 141.43, 131.47, 131.47,
126.92, 126.81, 77.19, 72.45, 71.35, 71.00, 63.87, 51.37, 39.10,
38.89, 33.63, 25.95, 25.85, 20.61, 18.38, 18.11, 11.57, –4.85, –4.99,
–5.14, –5.15.
[a]D10 –10.4 (c 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): d = 5.67–5.55 (2 H, m), 4.10 (2 H, d,
J = 4.7 Hz), 4.05–4.00 (1 H, m), 3.87–3.85 (1 H, m), 3.85–3.79 (1
H, m), 3.63 (1 H, dd, J = 11.3, 9.3 Hz), 3.41 (1 H, dd, J = 11.3, 3.2
Hz), 2.31–2.23 (1 H, m), 2.16–2.09 (1 H, m), 1.89 (1 H, br s), 1.62–
1.55 (1 H, m), 1.54–1.46 (2 H, m), 1.43–1.32 (1 H, m), 1.05–0.93
(21 H, m), 0.88 (9 H, s), 0.82 (3 H, d, J = 7.2 Hz), 0.04 (6 H, s).
13C NMR (100 MHz, CDCl3): d = 131.61, 126.72, 74.96, 71.94,
71.09, 64.51, 63.80, 38.83, 37.05, 34.50, 25.95, 18.39, 18.09, 17.71,
12.21, 11.44, –5.16.
HRMS (EI): m/z calcd for C27H52O5Si2: 512.3353; found: 512.3332.
The conjugated ester 38 (321 mg, 0.62 mmol) reacted with DIBAL
(1.5 M in toluene, 0.4 mL, 0.6 mmol) in CH2Cl2 (10 mL) at –78 °C
for 30 min. After quenching the reaction with MeOH (1 mL), a sat.
solution of Rochelle salt (5 mL) and EtOAc (10 mL) were added at
r.t., and the resulting mixture was stirred until it became homoge-
neous. Normal work-up followed by column chromatography
(EtOAc–hexane 1:20→ 1:15) provided aldehyde 4 (236 mg, 78%)
along with the starting 38 (35 mg, 11%).
1H NMR (400 MHz, CDCl3): d = 10.15 (1 H, s), 6.40 (1 H, dd,
J = 7.4, 1.4 Hz), 5.64–5.57 (2 H, m), 5.25 (1 H, d, J = 6.7 Hz), 4.11
(2 H, d, J = 4.2 Hz), 3.87–3.83 (2 H, m), 2.25 (1 H, m), 2.16 (1 H,
HRMS (EI): m/z calcd for C26H54O4Si2: 486.3561; found: 486.3544.
Methyl (Z)-3-{(2S,3R,4R,6R)-6-[4-(tert-Butyldimethylsilanyl-
oxy)-(2E)-butenyl]-3-methyl-4-triisopropylsilanyloxytetrahy-
dropyran-2-yl}-2-methylacrylate (37)
A solution of (COCl)2 (0.10 mL, 1.16 mmol) in CH2Cl2 (5 mL) was
cooled to –78 °C, and then DMSO (0.16 mL, 2.32 mmol) was added
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1112
S. H. Kang et al.
FEATURE ARTICLE
m), 1.78 (3 H, s), 1.63–1.54 (2 H, m), 1.39 (1 H, m), 0.91 (3 H, d,
J = 7.2 Hz), 0.88 (9 H, s), 0.87 (9 H, s), 0.04 (6 H, d, J = 3.0 Hz),
0.02 (6 H, s).
13C NMR (100 MHz, CDCl3): d = 192.18, 147.60, 135.90, 131.82,
126.42, 72.15, 70.77, 70.60, 63.78, 41.50, 38.77, 33.38, 25.96,
25.76, 18.40, 17.98, 16.39, 11.05, –4.86, –4.94, –5.14, –5.15.
(1S,9R,11R,12R,13R,21R,23R,24R)-11-(tert-Butyldimethylsilan-
yloxy)-24-(tert-butyldimethylsilanyloxymethyl)-23-(2-hydroxy-
ethyl)-12,15,24-trimethyl-2,22,26-trioxatricyclo[19.3.1.19,13]-
(4E,6E,14Z,16E,19E)-hexacosapentaen-3-one (41)
Phosphonate 2 (92 mg, 0.082 mmol) reacted with PPTS (4 mg,
0.016 mmol) in MeOH (4 mL) at r.t. for 18 h. NaHCO3 (20 mg) was
added to the resulting solution, and stirred for 10 min. The solution
was concentrated in vacuo followed by column chromatography
(EtOAc–hexane 2:1) to yield diol 40 (64 mg, 91%).
trans-Alkene 39
After dissolving sulfone 3 (90 mg, 0.13 mmol) and aldehyde 4 (84
mg, 0.17 mmol) in DME (5 mL) at r.t., LiHMDS (1.0 M in THF,
0.39 mL, 0.39 mmol) was added dropwise to the mixture at –70 °C.
The resulting solution was stirred at –75 to –70 °C for 1 h, warmed
to r.t. over 5 h, and then quenched with sat. aqueous NH4Cl (5 mL).
Normal work-up followed by column chromatography (EtOAc–
hexane 1:15) yielded trans-alkene 39 (103 mg, 82%) along with the
cis isomer (5 mg).
[a]D7 +40.1 (c 0.91, CH3OH).
1H NMR (400 MHz, CD3OD): d = 6.28 (1 H, d, J = 15.4 Hz), 5.64–
5.54 (4 H, m), 5.38 (1 H, dd, J = 15.5, 5.8 Hz), 5.19 (1 H, d, J = 7.7
Hz), 4.91 (1 H, s), 4.10–4.01 (5 H, m), 3.89 (2 H, d, J = 4.7 Hz),
3.79 (1 H, m), 3.75–3.73 (2 H, m), 3.57–3.55 (2 H, m), 3.43 (1 H, d,
J = 9.4 Hz), 3.26 (1 H, d, J = 9.3 Hz), 3.08 (1 H, dd, J = 21.9, 14.6
Hz), 2.88 (1 H, dd, J = 21.8, 14.6 Hz), 2.75 (2 H, m), 2.14–2.04 (1
H, m), 2.04–2.01 (1 H, m), 1.71 (3 H, s), 1.61 (2 H, dd, J = 6.9, 2.8
Hz), 1.52–1.42 (5 H, m), 1.32–1.16 (8 H, m), 0.91 (3 H, s), 0.85 (9
H, s), 0.82–0.78 (5 H, m), 0.77 (9 H, s), –0.02 (6 H, d, J = 1.8 Hz),
–0.08 (6 H, d, J = 12.2 Hz).
13C NMR (100 MHz, CD3OD): d = 165.94, 165.87, 133.52, 132.72,
132.49, 130.93, 130.27, 129.59, 129.44, 120.07, 75.33, 75.12,
73.90, 73.82, 72.49, 72.29, 66.86, 64.12, 63.63, 60.13, 41.92, 41.63,
39.96, 37.20, 35.45, 34.90, 34.12, 33.87, 33.42, 26.47, 26.33, 20.61,
19.01, 18.97, 16.82, 16.77, 16.71, 15.70, 11.35, 7.10, 5.64, –4.62,
–4.74, –5.44, –5.56.
[a]D4 +43.7 (c 0.98, CHCl3).
1H NMR (400 MHz, CDCl3): d = 6.36 (1 H, d, J = 15.4 Hz), 5.75–
5.49 (4 H, m), 5.47 (1 H, dd, J = 15.4, 5.9 Hz), 5.29 (1 H, d, J = 8.0
Hz), 4.90 (1 H, d, J = 8.1 Hz), 4.34 (1 H, br s), 4.25 (1 H, m), 4.10
(2 H, m), 3.87 (1 H, m), 3.85–3.78 (2 H, m), 3.73 (2 H, dd, J = 7.4,
5.4 Hz), 3.63 (1 H, d, J = 10.4 Hz), 3.53 (1 H, d, J = 10.4 Hz), 2.79
(2 H, m), 2.27 (1 H, m), 2.14 (1 H, m), 1.79 (3 H, s), 1.70–1.60 (2
H, m), 1.57–1.47 (5 H, m), 1.34 (1 H, d, J = 13.8 Hz), 0.90 (9 H, s),
0.89 (9 H, s), 0.87 (9 H, s), 0.87 (9 H, s), 0.86 (3 H, d, J = 7.1 Hz),
0.75 (3 H, s), 0.07 (6 H, d, J = 3.2 Hz), 0.03 (6 H, s), 0.03 (6 H, d,
J = 1.5 Hz), 0.01 (6 H, d, J = 2.3 Hz).
13C NMR (100 MHz, CDCl3): d = 132.25, 131.50, 131.42, 129.66,
129.14, 128.54, 128.14, 126.95, 77.20, 74.61, 72.33, 71.98, 70.94,
70.90, 70.58, 70.60, 63.90, 60.08, 40.49, 39.80, 38.98, 36.37, 35.66,
33.63, 32.12, 26.03, 25.96, 25.82, 25.73, 20.42, 18.42, 18.38, 18.01,
17.95, 15.49, 11.12, –4.82, –4.97, –5.12, –5.27, –5.41, –5.75, –5.88.
HRMS (FAB): m/z calcd for C45H84O11PSi2 (M+ + 1): 887.5290;
found: 887.5846.
Allylic alcohol 40 (75 mg, 0.085 mmol) in EtOAc (5 mL) was treat-
ed with MnO2 (37 mg, 0.425 mmol) at r.t. for 3 h. After filtration of
the mixture through a short silica gel column, which was washed
with EtOAc, evaporation of the volatile materials in vacuo yielded
the crude aldehyde, which was used without further purification.
HRMS (FAB): m/z calcd for C51H101O7Si4 (M+ + 1): 937.6624;
found: 937.6677.
1H NMR (400 MHz, CD3OD): d = 9.44 (1 H, d, J = 8.0 Hz), 7.01 (1
H, dt, J = 15.6, 7.0 Hz), 6.37 (1 H, d, J = 15.5 Hz), 6.16–6.10 (1 H,
m), 5.73–5.63 (2 H, m), 5.46 (1 H, dd, J = 15.6, 5.8 Hz), 5.28 (1 H,
d, J = 7.7 Hz), 5.01 (1 H, br s), 4.91 (1 H, d, J = 7.7 Hz), 4.17–4.10
(6 H, m), 4.00–3.96 (1 H, m), 3.92 (1 H, m), 3.84 (1 H, dd, J = 8.7,
3.9 Hz), 3.67–3.62 (2 H, m), 3.52 (1 H, d, J = 9.4 Hz), 3.35 (1 H, d,
J = 9.4 Hz), 3.30–3.27 (2 H, m), 3.16 (1 H, dd, J = 22.0, 14.7 Hz),
2.99 (1 H, dd, J = 22.0, 14.7 Hz), 2.81 (2 H, t, J = 6.8 Hz), 2.47 (2
H, t, J = 6.7 Hz), 1.80 (3 H, s), 1.72–1.69 (2 H, m), 1.68–1.62 (1 H,
m), 1.56–1.52 (4 H, m), 1.43–1.38 (1 H, m), 1.35–1.28 (8H, m),
1.00 (3 H, s), 0.94 (9 H, d, J = 2.8 Hz), 0.91 (3 H, s), 0.89 (3 H, d,
J = 2.7 Hz), 0.86 (9 H, d, J = 2.6 Hz), 0.08 (6 H, d, J = 1.8 Hz),
0.01 (6 H, d, J = 12.1 Hz).
Phosphonate 2
Diethyl phosphonoacetic acid (36 mg, 0.18 mmol) in EtOAc (2 mL)
was treated with DCC (46 mg, 0.22 mmol) and DMAP (27 mg, 0.22
mmol) at r.t. A solution of alcohol 39 (70 mg, 0.075 mmol) in
EtOAc (2 mL) was added slowly, and then the reaction mixture was
stirred at r.t. for 3 h. After filtering the mixture through silica gel
(EtOAc), the solution was concentrated and column chromatogra-
phy (EtOAc–hexane 1:5) yielded phosphonate 2 (75 mg, 90%).
[a]D6 +74.4 (c 0.94, MeOH).
1H NMR (400 MHz, CD3OD): d = 6.39 (1 H, d, J = 15.4 Hz), 5.73–
5.63 (3 H, m), 5.59 (1 H, dt, J = 15.4, 4.8 Hz), 5.47 (1 H, dd,
J = 15.5, 5.7 Hz), 5.30 (1 H, d, J = 7.8 Hz), 5.01 (1 H, s), 4.91 (1 H,
d, J = 7.8 Hz), 4.20–4.12 (7 H, m), 3.90–3.81 (3 H, m), 3.78–3.69
(2 H, m), 3.49 (1 H, d, J = 9.5 Hz), 3.39 (1 H, d, J = 9.5 Hz), 3.05
(2 H, m), 2.83 (2 H, br s), 2.27–2.21 (1 H, m), 2.16–2.08 (1 H, m),
1.82 (3 H, s), 1.72 (2 H, m), 1.62–1.47 (4 H, m), 1.41 (1 H, d,
J = 13.7 Hz), 1.33 (3 H, t, J = 7.1 Hz), 1.32 (3 H, t, J = 7.2 Hz),
1.01 (3 H, s), 0.96 (9 H, s), 0.92 (9 H, s), 0.91 (9 H, s), 0.90 (3 H, d,
J = 4.0 Hz), 0.88 (9 H, s), 0.08 (6 H, d, J = 3.3 Hz), 0.07 (6 H, s),
0.06 (6 H, s), 0.03 (6 H, d, J = 12.0 Hz).
13C NMR (100 MHz, CD3OD): d = 165.85, 165.82, 133.40, 132.69,
132.39, 130.92, 130.22, 129.63, 129.50, 128.02, 75.34, 74.66,
73.85, 72.53, 72.28, 67.04, 64.83, 64.24, 64.17, 64.10, 60.92, 41.94,
41.54, 39.83, 37.22, 35.53, 34.82, 34.29, 34.19, 33.49, 26.59, 26.54,
26.47, 26.37, 20.66, 19.28, 19.21, 19.04, 18.99, 16.83, 15.64, 11.42,
–4.54, –4.67, –4.86, –4.88, –4.94, –5.07, –5.42, –5.51.
The resulting aldehyde (75 mg, 0.085 mmol) was heated at 70–
80 °C in the presence of K2CO3 (59 mg, 0.42 mmol) and 18-crown-
6 (112 mg, 0.42 mmol, recrystallized in CH3CN) in toluene (75 mL)
for 7 h, and then cooled to r.t. The mixture was filtered through sil-
ica gel, washed with EtOAc, and then the solution was concentrated
in vacuo. Column chromatography (EtOAc–hexane 1:5) of the res-
idue yielded macrolactone 41 (44 mg, 71%).
[a]D7 +36.1 (c 0.83, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.14 (1 H, dd, J = 15.4, 10.6 Hz),
6.49 (1 H, d, J = 15.8 Hz), 6.23 (1 H, dd, J = 15.2, 10.6 Hz), 6.10
(1 H, ddd, J = 15.3, 8.2, 4.9 Hz), 5.77 (1 H, dt, J = 15.9, 7.1 Hz),
5.72 (1 H, d, J = 15.4 Hz), 5.49 (1 H, ddd, J = 14.9, 9.9, 3.8 Hz),
5.45–5.36 (2 H, m), 5.04 (1 H, s), 4.75 (1 H, dd, J = 9.4, 2.1 Hz),
4.28 (1 H, m), 4.01–3.95 (2 H, m), 3.85–3.73 (3 H, m), 3.43 (1 H, d,
J = 9.7 Hz), 3.35 (1 H, d, J = 9.7 Hz), 2.83 (1 H, m), 2.67 (1 H, m),
2.30 (2 H, m), 1.86–1.74 (3 H, m), 1.78 (3 H, s), 1.73–1.56 (3 H, m),
1.53–1.46 (2 H, m), 1.38–1.33 (2 H, m), 1.03 (3 H, s), 0.99 (3 H, d,
HRMS (FAB): m/z calcd for C57H112O11PSi4 (M+ + 1): 1115.7019;
found: 1115.7023.
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

FEATURE ARTICLE
Stereoselective Total Synthesis of the Natural (+)-Lasonolide A
1113
J = 7.1 Hz), 0.91 (9 H, s), 0.88–0.87 (1 H, m), 0.83 (9 H, s), 0.05 (6
H, d, J = 9.4 Hz), 0.04 (6 H, d, J = 1.9 Hz).
Hz), 5.72 (1 H, d, J = 15.4 Hz), 5.53–5.37 (3 H, m), 4.98 (1 H, s),
4.76 (1 H, dd, J = 9.3, 2.0 Hz), 4.38 (1 H, dd, J = 9.9, 2.5 Hz), 4.29
(1 H, t, J = 9.2 Hz), 4.00–3.95 (1 H, m), 3.84 (1 H, d, J = 2.5 Hz),
3.43 (2 H, dd, J = 14.9, 10.2 Hz), 2.91–2.80 (1 H, m), 2.75–2.62 (2
H, m), 2.52 (1 H, ddd, J = 16.6, 9.9, 2.5 Hz), 2.35–2.28 (2 H, m),
1.83–1.80 (1 H, m), 1.81 (3 H, s), 1.61–1.54 (1 H, m), 1.39–1.34 (1
H, m), 1.02 (3 H, s), 0.98 (3 H, d, J = 7.1 Hz), 0.91 (9 H, s), 0.84 (9
H, s), 0.04 (6 H, d, J = 9.4 Hz), –0.03 (6 H, d, J = 2.6 Hz).
13C NMR (100 MHz, CDCl3): d = 166.70, 145.62, 143.50, 138.19,
135.48, 129.34, 128.99, 128.45, 128.31, 125.13, 120.14, 80.92,
77.20, 73.49, 73.40, 73.00, 71.16, 68.88, 66.16, 62.74, 40.44, 39.42,
38.60, 34.80, 34.00, 33.67, 32.11, 25.87, 25.79, 21.03, 18.12, 15.13,
11.44, –4.84, –5.77, –5.80.
HRMS (FAB): m/z calcd for C41H71O7Si2 (M+ + 1): 731.4738;
found: 731.4734.
The prepared aldehyde 42 and phosphonium salt 47 (180 mg, 0.26
mmol) were dissolved in THF (2 mL) at r.t., and then cooled to
–60 °C. KHMDS (0.5 M in toluene, 0.5 mL, 0.25 mmol) was added,
and then the mixture was stirred at –60 5 °C for 1 h. After quench-
ing the reaction with sat. aqueous NH4Cl (1 mL), normal work-up
and column chromatography (EtOAc–hexane 1:15) yielded the pro-
tected lasonolide A 48 (36 mg, 86% from alcohol 41).
{(3S)-3-[2-(3-Methylbutyl)allyloxycarbonyl]-3-triethylsilany-
loxypropyl}triphenylphosphonium Bromide (47)
Acetonide 43 (312 mg, 1.50 mmol) and alcohol 44 (260 mg, 2.02
mmol) in benzene (20 mL) were treated with p-TsOH·H2O (60 mg,
0.30 mmol) at r.t. for 6 h. The reaction was quenched with NaHCO3
(100 mg), and then the mixture was filtered through a short silica gel
column (Et2O, 30 mL). Evaporation of the volatile materials in vac-
uo followed by column chromatography (EtOAc–hexane 1:10)
yielded ester 45 (353 mg, 80%).
1H NMR (400 MHz, CDCl3): d = 5.00 (1 H, s), 4.96 (1 H, s), 4.63
(2 H, dd, J = 17.5, 13.0 Hz), 4.37 (1 H, dd, J = 8.7, 3.7 Hz), 3.60–
3.49 (2 H, m), 2.36–2.30 (1 H, m), 2.18–2.11 (1 H, m), 2.04 (2 H, t,
J = 7.8 Hz), 1,57–1.49 (1 H, m), 1.37–1.29 (2 H, m), 0.88 (6 H, d,
J = 6.6 Hz).
[a]D11 +74.1 (c 0.93, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.13 (1 H, dd, J = 15.4 Hz, 10.6
Hz), 6.48 (1 H, d, J = 15.8 Hz), 6.21 (1 H, dd, J = 15.3, 10.8 Hz),
6.09 (1 H, ddd, J = 15.2, 8.5, 4.6 Hz), 5.78 (1 H, m), 5.71 (1 H, d,
J = 15.5 Hz), 5.64 (1 H, m), 5.49–5.38 (4 H, m), 5.07 (1 H, s), 5.00
(1 H, s), 4.91 (1 H, s), 4.73 (1 H, dd, J = 9.3, 1.8 Hz), 4.53 (2 H, s),
4.25 (2 H, dt, J = 21.6, 6.2 Hz), 4.19 (1 H, m), 3.95 (1 H, m), 3.84
(1 H, d, J = 2.4 Hz), 3.66 (1 H, dd, J = 8.0, 1.8 Hz), 3.45 (1 H, d,
J = 9.6 Hz), 3.27(1 H, d, J = 9.6 Hz), 2.84 (1 H, m), 2.67 (1 H, m),
2.52–2.41 (2 H, m), 2.33–2.22 (3 H, m), 2.15–2.08 (1 H, m), 2.04 (2
H, dd, J = 8.3, 7.6 Hz), 1.79 (3 H, s), 1.77–1.69 (2 H, m), 1.62–1.48
(2 H, m), 1.39–1.26 (3 H, m), 1.01 (3 H, s), 0.98 (3 H, d, J = 7.1 Hz),
0.93 (9 H, t, J = 7.9 Hz), 0.91 (9 H, s), 0.88 (6 H, d, J = 6.7 Hz),
0.84 (9 H, s), 0.60 (6 H, q, J = 7.9 Hz), 0.04 (6 H, d, J = 8.9 Hz),
–0.04 (6 H, d, J = 5.7 Hz).
13C NMR (100 MHz, CDCl3): d = 172.88, 166.83, 145.45, 144.07,
143.21, 138.21, 134.49, 130.40, 129.41, 129.28, 129.19, 129.02,
125.04, 124.77, 120.35, 112.15, 79.21, 77.19, 73.69, 73.03, 71.90,
71.20, 68.91, 67.03, 66.11, 40.66, 39.44, 38.62, 36.61, 34.82, 34.20,
33.73, 33.64, 31.06, 28.62, 27.76, 25.86, 25.83, 22.49, 21.02, 18.16,
18.10, 15.08, 11.43, 6.71, 4.61, –4.85, –5.74, –5.77.
13C NMR (100 MHz, CDCl3): d = 174.26, 143.39, 112.97, 68.42,
68.34, 37.11, 36.63, 31.00, 28.68, 27.72, 22.45.
HRMS (EI): m/z calcd for C12H21BrO3: 292.0674, found: 292.0677.
To a stirred solution of the alcohol 45 (353 mg, 1.20 mmol) and 2,6-
lutidine (0.4 mL, 3.60 mmol) in CH2Cl2 (5 mL) was added TESOTf
(0.3 mL, 1.30 mmol) dropwise at 0 °C. After 30 min at 0 °C, the si-
lylation was quenched with sat. aqueous NH4Cl (3 mL). Normal
work-up and column chromatography (Et2O–hexane 1:15) yielded
bromide 46 (491 mg).
1H NMR (400 MHz, CDCl3): d = 5.00 (1 H, d, J = 0.9 Hz), 4.94 (1
H, d, J = 0.9 Hz), 4.56 (2 H, s), 4.42 (1 H, dd, J = 7.7, 4.7 Hz),
3.52–3.48 (2 H, m), 2.29–2.20 (2 H, m), 2.06–2.01 (2 H, m), 1.55–
1.52 (1 H, m), 1.39–1.30 (2 H, m), 0.95 (9 H, t, J = 7.8 Hz), 0.88 (6
H, d, J = 6.6 Hz), 0.64 (6 H, q, J = 7.8 Hz).
HRMS (FAB): m/z calcd for C59H103O9Si3 (M+ + 1): 1039.6910;
found: 1039.6915.
13C NMR (100 MHz, CDCl3): d = 172.82, 143.88, 112.55, 69.85,
67.39, 37.94, 36.63, 31.07, 29.21, 27.77, 22.47, 6.71, 4.61.
Lasonolide A (1)
Pyridine (0.5 mL) and HF·pyridine (0.5 mL) were mixed in a
polypropylene vessel at 0 °C. The prepared solution was added
dropwise to 48 (34 mg, 0.03 mmol) in a mixture of pyridine (1.0
mL) and THF (1.0 mL) at 0 °C. The reaction mixture warmed to r.t.,
and then was stirred for 40 h. After quenching with sat. aqueous
NaHCO3 at 0 °C carefully, normal work-up (EtOAc) followed by
columnchromatography(EtOAc–hexane 1:2→ 1:1)yieldedlasono-
lide A 1 (20 mg, 87%).
HRMS (EI): calcd for C18H35BrO3Si: 406.1539, found: 406.1439.
The bromide 46 (491 mg, 1.21 mmol) was heated at 100 °C in the
presence of Ph3P (630 mg, 2.4 mmol) in CH3CN (20 mL) for 25 h,
and then cooled to r.t. The solution was concentrated in vacuo and
column chromatography of the residue (5% MeOH in CH2Cl2, and
then 10% MeOH in CH2Cl2) yielded phosphonium salt 47 (807 mg,
88%).
1H NMR (400 MHz, CD3OD): d = 7.92–7.75 (15 H, m), 5.01 (1 H,
s), 4.96 (1 H, s), 4.68 (1 H, d, J = 12.8 Hz), 4.57 (1 H, d, J = 12.8
Hz), 4.55 (1 H, t, J = 4.9 Hz), 3.51–3.33 (2 H, m), 2.11–2.03 (4 H,
m), 1.51 (1 H, m), 1.33 (2 H, m), 0.93 (9 H, t, J = 8.0 Hz), 0.88 (6
H, d, J = 6.6 Hz), 0.64 (6 H, q, J = 8.0 Hz).
[a]D10 +24.2 (c 0.20, CHCl3).
1H NMR (400 MHz, CDCl3): d = 7.22 (1 H, dd, J = 15.3, 10.8 Hz),
6.57 (1 H, d, J = 15.7 Hz), 6.24 (1 H, dd, J = 15.2, 10.9 Hz), 6.13
(1 H, dt, J = 15.3, 6.1 Hz), 5.81 (1 H, dt, J = 15.8, 7.2 Hz), 5.69 (1
H, d, J = 15.3 Hz), 5.71–5.62 (1 H, m), 5.52–5.44 (3 H, m), 5.44 (1
H, d, J = 9.3 Hz), 5.01 (1 H, s), 4.95 (1 H, s), 4.95 (1 H, s), 4.79 (1
H, dd, J = 9.2, 2.1 Hz), 4.60 (2 H, s), 4.36–4.25 (1 H, m), 4.23 (1 H,
dd, J = 7.0, 4.6 Hz), 4.12–3.93 (1 H, m), 3.54 (1 H, dd, J = 10.0, 2.0
Hz), 3.38 (1 H, d, J = 11.4 Hz), 3.32 (1 H, d, J = 11.4 Hz), 2.86 (1
H, dd, J = 12.7, 7.1 Hz), 2.77–2.65 (1 H, m), 2.53–2.46 (2 H, m),
2.36–2.30 (2 H, m), 2.23–2.15 (1 H, m), 2.04 (3 H, t, J = 7.7 Hz),
1.90–1.82 (1 H, m), 1.80 (3 H, s), 1.70–1.59 (3 H, m), 1,55–1.52 (2
H, m), 1.41 (1 H, m), 1.35–1.31 (2 H, m), 1.05 (3 H, s), 1.04 (3 H,
d, J = 7.1 Hz), 0.88 (6 H, d, J = 6.6 Hz).
Protected Lasonolide A (48)
Alcohol 41 (30 mg, 0.041 mmol) in CH2Cl2 (3 mL) and pyridine
(0.6 mL) was treated with Dess–Martin periodinane (30 mg, 0.08
mmol) at r.t. for 30 min. EtOAc (5 mL) was added to the reaction
mixture, which was then filtered through a short silica gel column
(EtOAc) to give the crude aldehyde which was used in the next step
without further purification.
1H NMR (400 MHz, CDCl3): d = 9.79, (1 H, s), 7.19 (1 H, dd,
J = 15.4, 10.6 Hz), 6.49 (1 H, d, J = 15.8 Hz), 6.24 (1 H, dd,
J = 15.0, 10.4 Hz), 6.17–6.09 (1 H, m), 5.77 (1 H, dt, J = 15.0, 7.1
13C NMR (100 MHz, CDCl3): d = 174.00, 168.55, 148.35, 145.10,
143.76, 138.96, 134.25, 130.90, 129.69, 129.12, 129.04, 128.91,
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York

1114
S. H. Kang et al.
FEATURE ARTICLE
(6) (a) Mancuso, A. J.; Swern, D. Synthesis 1981, 165.
(b) Tidwell, T. T. Org. React. 1990, 39, 297.
(7) Gash, V. W. J. Org. Chem. 1972, 37, 2197.
(8) Roush, W. R.; Walts, A. E.; Hoong, L. K. J. Am. Chem. Soc.
1985, 107, 8186.
125.15, 124.55, 118.30, 112.45, 77.90, 77.21, 74.65, 72.45, 70.75,
70.27, 68.89, 67.65, 65.65, 41.24, 38.50, 38.03, 36.63, 35.00, 33.77,
33.66, 32.55, 31.02, 28.01, 27.73, 22.48, 15.20, 11.40.
HRMS (FAB): m/z calcd for C41H61O9 (M+ + 1): 697.4316; found:
697.4317.
(9) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113, 7727.
(10) Mitsunobu, O. Synthesis 1981, 1.
(11) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am.
Chem. Soc. 1999, 121, 4924.
(12) Nicolaou, K. C.; Patron, A. P.; Ajito, K.; Richter, P. K.;
Khatuya, H.; Bertinato, P.; Miller, R. A.; Tomaszewski, M.
J. Chem.–Eur. J. 1996, 2, 847.
Acknowledgment
This work was supported by a grant from the Korea Research Foun-
dation (KRF-2002-070-C00058).
(13) Pappo, R.; Allen, D. S. Jr.; Lemieux, R. U.; Johnson, W. S.
J. Org. Chem. 1956, 21, 478.
References
(14) (a) Brown, H. C.; Jadhav, P. K. J. Am. Chem. Soc. 1983, 105,
2092. (b) Brown, H. C.; Jadhav, P. K.; Bhat, K. S.; Perumal,
T. J. Org. Chem. 1986, 51, 432.
(15) (a) Horita, K.; Yoshioka, T.; Tanaka, T.; Yonemitsu, O.
Tetrahedron 1986, 42, 3021. (b) Tanaka, T.; Oikawa, Y.;
Hamada, T.; Yonemistu, O. Tetrahedron Lett. 1986, 27,
3651.
(16) Still, W. C.; Gennari, C. Tetrahedron Lett. 1983, 24, 4405.
(17) (a) Cooke, M. P. Jr.; Biciunas, K. P. Synthesis 1981, 283.
(b) White, J. D.; Hanselmann, R. J.; Randy, W.; Porter, W.
J.; Ohda, Y.; Tiller, T.; Wang, S. J. Org. Chem. 2001, 66,
5217.
(18) (a) Nicolaou, K. C.; Seitz, S. P.; Pavia, M. R. J. Am. Chem.
Soc. 1982, 104, 2030. (b) Morin-Fox, M. L.; Lipton, M. L.
Tetrahedron Lett. 1993, 34, 7899.
(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. 1991, 44, 93.
(3) (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. (b) 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.
(4) For other synthetic approaches see: (a) Gurjar, M. K.;
Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996, 37, 8617.
(b) Nowakowski, M.; Hoffmann, H. M. R. Tetrahedron Lett.
1997, 38, 1001. (c) Gurjar, M. K.; Chakrabarti, A.; Rao, B.
V.; Kumar, P. Tetrahedron Lett. 1997, 38, 6885. (d) Beck,
H.; Hoffmann, H. M. R. Eur. J. Org. Chem. 1999, 2991.
(e) Kang, S. H.; Choi, H.-W.; Kim, C. M.; Jun, H.-S.; Kang,
S. Y.; Jeong, J. W.; Youn, J.-H. Tetrahedron Lett. 2003, 44,
6817.
(19) Kim, H.-O.; Lum, C.; Lee, M. S. Tetrahedron Lett. 1997, 38,
4935.
(20) Fleming, I.; Paterson, I.; Pearce, A. J. Chem. Soc., Perkin
Trans. 1 1981, 25.
(5) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Lorne, R.; Ruel,
O. Bull. Soc. Chim. Fr. 1993, 130, 856. (b) Blakemore, P.
R.; Cole, W. J.; Kocieński, P. J.; Morley, A. Synlett 1998, 26.
(21) Wipf, P.; Kim, H. J. Org. Chem. 1993, 58, 5592.
Synthesis 2004, No. 7, 1102–1114 © Thieme Stuttgart · New York