Enantioselective synthesis of aurisides A and B, cytotoxic macrolide glycosides of marine origin

Article abstract of DOI:10.1016/j.tet.2006.05.077

The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent approach. The C1-C9 segment 4 was prepared from (R)-pantolactone, and the C10-C17 segment 14 was synthesized from (R)-glycidyl trityl

Full text of DOI:10.1016/j.tet.2006.05.077

Tetrahedron 62 (2006) 7687–7698
Enantioselective synthesis of aurisides A and B, cytotoxic
macrolide glycosides of marine origin
Kiyotake Suenaga,a,y Hiroshi Hoshino,a Takanori Yoshii,a Kazunori Mori,a Hiroki Sone,b
Yuhki Bessho,b Akira Sakakura,a Ichiro Hayakawa,a Kiyoyuki Yamadab and Hideo Kigoshia,
*
aDepartment of Chemistry, University of Tsukuba, 1-1-1 Tennoudai, Tsukuba, Ibaraki 305-8571, Japan
bGraduate School of Sciences, Nagoya University, Chikusa, Nagoya 464-8602, Japan
Received 24 March 2006; revised 22 May 2006; accepted 29 May 2006
Available online 21 June 2006
Abstract—The enantioselective synthesis of aurisides A and B, macrolide glycosides of marine origin, was achieved by a convergent
approach. The C1–C9 segment 4 was prepared from (R)-pantolactone, and the C10–C17 segment 14 was synthesized from (R)-glycidyl
trityl ether. The Nozaki–Hiyama–Kishi reaction between 4 and 14 and subsequent reactions gave seco acid 10, which was converted into the
aglycon (3) of aurisides by construction of the 14-membered lactone and bromine-substituted conjugated diene. The glycosylation reaction
of the aglycon provided aurisides A and B.
Ó 2006 Elsevier Ltd. All rights reserved.
1. Introduction
The sea hare Dolabella auricularia (Aplysiidae) is known to
be a rich source of cytotoxic and/or antitumor peptides and
other unique metabolites.1,2 Aurisides A (1) and B (2) are
macrolide glycosides isolated from Japanese sea hare D.
auricularia, which exhibit cytotoxicity against HeLa S3 cells
with IC50 values of 0.17 and 1.2 mg mLꢀ1, respectively.3
The main structural features of aurisides are a bromine-
substituted conjugated diene, a 14-membered lactone, and
a cyclic hemiacetal. The biological activity and structural
novelty of aurisides prompted us to initiate the investigation
toward the synthesis of 1 and 2. We had achieved the synthe-
sis of aglycon (3) of aurisides,4 and synthetic studies of
aurisides have been carried out by a few groups.5 Recently,
2. Results and discussions
total synthesis of 1 and 2 were achieved by Paterson and
co-workers.6 Several natural products structurally related to
The outline of our previous synthesis of the aglycon of auri-
1 and 2 have been isolated,7 and studies have been made on
sides is shown in Scheme 1. There are some serious problems
in this route: (1) the macrolactonization of seco acid 5
synthesis of these compounds.8 We describe herein enantio-
required vigorous conditions because of steric hindrance of
trityl group and led to elimination of methanol to give lac-
tones 6a and 6b; (2) re-formation of the cyclic hemiacetal
and construction of the bromine-substituted conjugated
diene proceeded only in poor yields. Therefore, we began
reinvestigating more efficient routes. The second-generation
strategy is illustrated in Scheme 2. We planned to construct
the cyclic structure of aurisides by the macrolactonization
of seco acid 11 or 12. We expected that macrolactonization
of 11 or 12 provided lactone 9 or 10 without elimination of
methanol under milder conditions than the previous synthe-
sis, because the steric hindrance around 13-hydroxyl group
selective synthesis of aurisides A (1) and B (2) according to
a convergent synthetic methodology with some improvement
of our previous synthesis of their aglycon (3).4
* Corresponding author. Tel./fax: +81 29 853 4313; e-mail: kigoshi@chem.
tsukuba.ac.jp
Present address: Department of Chemistry, Faculty of Science and Tech-
y
nology, Keio University, 3-14-1 Hiyoshi, Kohoku, Yokohama, Kanagawa
223-8522, Japan.
0040–4020/$ - see front matter Ó 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2006.05.077

7688
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
Scheme 1. Outline of the previous synthesis of aglycon (3) of aurisides.
Scheme 2. The second generation strategy for synthesis of aurisides A (1) and B (2).
in 11 and 12 are much smaller than that in 5. The seco acid 11
could be synthesized from C1–C9 segment 4 and C10–C16
segment 13 by Nozaki–Hiyama–Kishi reaction as a key
step. The seco acid 12 might be obtained from 4 and C10–
C17 segment 14, which possesses a conjugated enyne group,
a precursor of the bromine-substituted conjugated diene.
The glycosylation of 3 with fluorosugars 7 and 8 under the
Mukaiyama protocol9 could provide aurisides A (1) and B
(2), respectively, inthesamewayasPatersonandco-workers.6
deprotection11 of the dithioacetal moiety in 16 gave ketone
17 (77%). Stereoselective reduction of 17 with tetramethyl-
ammonium triacetoxyborohydride12 afforded anti-1,3-diol
18a (86%) along with syn-1,3-diol 18b (7%). anti-1,3-Diol
18a was transformed into acetonide 19 (97%), the stereo-
chemistry of which was confirmed to be anti bythe 13C chem-
ical shifts of two acetonide methyls (dC 24.6 and 24.2).13
Oxidative cleavage of the vinyl group in 19 gave aldehyde
20 (96%), rhodium-catalyzed Reformatsky-type reaction14
of which with methyl 2-bromopropionate provided a dia-
stereomeric mixture of b-hydroxy esters 21 (88%).15 Swern
oxidation of 21 afforded b-keto ester 22 as an inseparable
1:1 mixture of diastereomers concerning the secondary
methyl group (88%). Acid treatment of 22 in methanol led
to cyclic methyl acetal 23 (96%), the secondary hydroxyl
The synthesis of C1–C9 segment 4 started from commer-
cially available (R)-pantolactone (Scheme 3). (R)-Pantolac-
tone was converted into epoxide 15 by a four-step sequence
of reactions.10 Alkylation of the carbanion generated from
2-allyldithiane with 15 afforded alcohol 16 (92%). Careful
Scheme 3. (a) 2-Allyldithiane, BuLi, THF–hexane, ꢀ78 ꢁC/ꢀ30 ꢁC, 92%; (b) (CF3CO2)2IPh, MeOH, 0 ꢁC; H2O, AcOH, THF, rt, 77%; (c) Me4NBH(OAc)3,
AcOH, MeCN, ꢀ30 ꢁC, 86%; (d) (MeO)2CMe2, CSA, acetone, rt, 97%; (e) OsO4, NMO, acetone–tBuOH, rt; NaIO4, H2O, rt, 96%; (f) methyl 2-bromopropio-
nate, Et2Zn, RhCl(PPh3)3, THF, 0 ꢁC, 88%; (g) DMSO, (COCl)2, CH2Cl2, ꢀ78 ꢁC; Et3N, ꢀ78 ꢁC/0 ꢁC, 88%; (h) CH(OMe)3, PPTS, MeOH, 50 ꢁC, 96%;
(i) TBDPSCl, imidazole, 0 ꢁC, 100%; (j) H2, 20% Pd(OH)2–C, dioxane, rt, 96%; (k) DMSO, SO3$pyridine, Et3N, rt, 95%.

K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
7689
group of which was silylated to give silyl ether 24 (100%).
Cleavage of the benzyl group in 24 afforded alcohol 25
(96%), which was oxidized to provide C1–C9 segment 4
(95%).
diastereomers concerning the allylic hydroxyl group
(Scheme 5). Hydrolysis of the methyl ester and silyl groups
in 34 afforded seco acid 11 (69%) along with ester 35
(19%). The macrolactonization of 11 was accomplished by
the Yamaguchi method19 to give lactone 9 (29%) without
elimination of methanol in contrast to that of 5. To improve
the yield of macrolactonization, we tried macrolactonization
by an alternative method. Coupling reaction between C1–C9
segment 4 and ent-13, prepared from (S)-trityl glycidyl ether,
gave seco acid C13-epi-11. Macrolactonization of C13-epi-
11 under Mitsunobu condition20 provided lactone 9, how-
ever, the yield was not improved (<30%). Treatment of 9
with formic acid in ether to remove the trityl group afforded
not desired alcohol but a complex mixture. Therefore,
another synthetic route was investigated.
The synthesis of C10–C16 and C10–C17 segments, 13 and
14, began with an alkylation reaction of lithium acetylide
with (R)-glycidyl trityl ether to afford acetylene 26 in 97%
yield (Scheme 4). Carbometallation of 26 followed by treat-
ment with iodine gave vinyl iodide 27,16 accompanied by
cleavage of the trityl group (50%). Protection of the primary
hydroxyl group in 27 followed by silylation of the secondary
hydroxyl group afforded silyl ether 28 (92%), which was con-
verted into primary alcohol 29 (99%). Oxidation of 29 gave
aldehyde 30 (95%), the Wittig reaction of which with
MeO2CCH]PBu317 provided conjugated ester 31 as a sole
product (92%). Reduction of 31 afforded alcohol 32 (86%),
the hydroxyl group of which was tritylated to give C10–
C16 segment 13 (89%). Wittig olefination reaction of alde-
hyde 30 with TMS–C^CCH2PPh3Br and BuLi provided
C10–C17 segment 14 (57%) along with cis-isomer 33 (9%).
Scheme 5. (a) 0.6% NiCl2–CrCl2, DMSO, rt, 90%; (b) LiOH, H2O, MeOH,
THF, (11) 69%, (35) 19%; (c) 2,4,6-trichlorobenzoyl chloride, Et3N, THF,
i
i
rt; DMAP, toluene, 80 ꢁC, 29%; (d) PrO2CN]NCO2 Pr, PPh3, toluene,
0 ꢁC/rt, <30%; (e) HCO2H, ether, rt.
Coupling reaction between C1–C9 segment 4 and C10–C17
segment 14 gave a diastereomeric mixture of alcohol 36 in
81% yield (Scheme 6). The trimethylsilyl and triethylsilyl
groups in 36 were removed to give acetylene 37 (98%), hy-
drostannation of which afforded vinylstannane 38 (81%),21
which was contaminated by (16Z)-isomer. The minor
(16Z)-isomer could be separated by HPLC at a later stage
in the synthesis. Treatment of 38 with NBS gave bromodiene
39 (98%), which was hydrolyzed under basic conditions to
provide seco acid 12 (63%). The macrolactonization of 12
under Yamaguchi condition afforded lactone 10 (57%),
which was treated with aqueous acid to give hemiacetal 40
Scheme 4. (a) LiC^CH$NH2(CH2)2NH2, THF–DMSO, rt, 97%; (b)
Cp2ZrCl2, Me3Al, CH2Cl2, rt; I2, THF, rt, 50%; (c) PivCl, pyridine,
0 ꢁC/rt; TESCl, rt, 92%; (d) DIBAL, CH2Cl2, ꢀ78 ꢁC, 99%; (e) Dess–
Martin periodinane, CH2Cl2, pyridine, rt, 95%; (f) MeO2CCH]PBu3,
benzoic acid, toluene, 90 ꢁC, 92%; (g) DIBAL, THF–hexane, ꢀ78 ꢁC,
86%; (h) TrCl, Et3N, DMAP, CH2Cl2, rt, 89%; (i) TMS–C^CCH2PPh3Br,
BuLi, THF, (14) 57%, (33) 9%.
Coupling reaction between C1–C9 segment 4 and C10–C16
segment 13 was effected by means of Nozaki–Hiyama–Kishi
reaction18 to give alcohol 34 in 90% yield as a 2:1 mixture of
Scheme 6. (a) 0.5% NiCl2–CrCl2, DMSO, rt, 81%; (b) Bu4NF, AcOH, THF, 0 ꢁC, 98%; (c) Bu3SnH, AIBN, THF, 70 ꢁC, 81%; (d) NBS, THF, 0 ꢁC, 98%; (e)
NaOH, H2O, MeOH, THF, 63%; (f) 2,4,6-trichlorobenzoyl chloride, Et3N, THF, rt; DMAP, toluene, reflux, 57%; (g) H2O, AcOH, acetone, rt, 86%; (h) Dess–
˚
Martin periodinane, CH2Cl2, pyridine, rt, (41a) 27%, (41b) 21%; (i) Bu4NF, AcOH, THF, rt, 90% from 41a, 96% from 41b; (j) 7, SnCl2, AgClO4, MS 4A, Et2O,
ꢁ
ꢁ
ꢁ
˚
0 C/rt; (k) HF$pyridine, THF, 0 C/rt, 42% in two steps; (l) 8, SnCl2, AgClO4, MS 4A, Et2O, 0 C/rt, 68%.

7690
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
(86%). The oxidation of allylic hydroxyl group in 40 gave
a separable1:1 mixture of conjugated enones, which was sep-
arated by HPLC to afford pure 41a and 41b. The minor (16Z)-
isomer could be completely removed at this stage. The
stereochemistry of 41a and 41b was determined by NOESY.
Removal of the silyl group in 41a gave the aglycon (3) of
aurisides A and B (90%). Under the same condition, enone
41b was converted into 3 with epimerization at C2 (96%).
The glycosylation reaction of 3 with fluorosugar 7 followed
by desilylation afforded auriside A (1) (42%).6 Similarly,
the reaction between 3 and 8 gave auriside B (2) (68%).6 Syn-
thetic aurisides A (1) and B (2) were found to be identical to
natural 1 and 2 in all respects, respectively, including the
spectroscopic (UV, IR, 1H NMR, MS, and [a]D) and chroma-
tographic properties.
4.1.1. Alcohol 16. To a stirred solution of 2-allyldithiane
(5.03 g, 31.4 mmol) in dry THF (50 mL) cooled at ꢀ78 ꢁC
was added a 1.6 M solution of n-BuLi in hexane (18.4 mL,
29.5 mmol) dropwise. The reaction mixture was stirred at
ꢀ20 ꢁC for 1.5 h. After cooling to ꢀ78 ꢁC, a solution of ep-
oxide 15 (4.05 g, 19.6 mmol) in THF (3 mL, 2ꢂ2 mL rinse)
was added dropwise, and the mixture was kept at ꢀ30 ꢁC for
2 h. The reaction was quenched with water (100 mL), and
the mixture was extracted with Et2O (2ꢂ100 mL). The com-
bined extracts were washed with brine (100 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (200 g, hexane–
ether 5:1) to give 16 (6.60 g, 92%) as a colorless oil: TLC,
Rf 0.39 (hexane–ether 2:1); [a]2D5 +25.9 (c 1.02, CHCl3);
1
IR (neat) 3490, 2960, 2860, 1640, 1100 cmꢀ1; H NMR
(270 MHz, CDCl3) d 7.36–7.26 (m, 5H), 5.94 (m, 1H),
5.15 (d, J¼17.0 Hz, 1H), 5.14 (d, J¼10.3 Hz, 1H), 4.53 (d,
J¼12.2 Hz, 1H), 4.51 (d, J¼12.2 Hz, 1H), 3.89 (dd,
J¼6.9, 3.6 Hz, 1H), 3.39 (d, J¼8.9 Hz, 1H), 3.30 (d,
J¼8.9 Hz, 1H), 2.95–2.70 (m, 6H), 2.08 (m, 2H), 2.04–
1.88 (m, 2H), 1.60 (br s, 1H), 0.96 (s, 3H), 0.94 (s, 3H);
13C NMR (67.8 MHz, CDCl3) d 138.0, 133.0, 128.2,
127.4, 127.3, 118.3, 78.4, 74.1, 73.4, 51.9, 43.6, 40.3,
39.0, 26.4, 26.1, 24.9, 22.6, 20.1; HRMS (ESI) calcd for
C20H30NaO2S2 (M+Na)+ 389.1585, found 389.1604.
3. Conclusion
In conclusion, enantioselective synthesis of aurisides A (1)
and B (2) was achieved from (R)-pantolactone in 26 steps
(1.4% overall yield) and 25 steps (2.3% overall yield), re-
spectively. In comparison with the previous synthesis of
the aglycon 3 of aurisides A (1) and B (2) reported as a com-
munication4 in 1998 (0.021% overall yield), the synthetic
procedures of 3 have been much improved as regards overall
yield (3.3%).
4.1.2. Ketone 17. To a stirred solution of alcohol 16 (2.80 g,
7.64 mmol) in MeOH cooled at 0 ꢁC was added [bis(trifluoro-
acetoxy)iodo]benzene (3.33 g, 7.74 mmol). The reaction
mixture was stirred at 0 ꢁC for 45 min and diluted with ether
(100 mL), saturated aqueous NaHCO3 (60 mL), and 5%
aqueous Na2S2O3 (60 mL). The organic layer was separated,
and the aqueous layer was extracted with ether (100 mL,
50 mL). The combined extracts were washed with saturated
aqueous NaHCO3 (70 mL) and brine (30 mL), dried
(Na2SO4), and concentrated. The residual oil was dissolved
in THF (15 mL), H2O (5 mL), and acetic acid (15 mL), and
the solution was stirred at room temperature for 15 min. The
reaction mixture was cooled at 0 ꢁC, neutralized with satu-
rated aqueous NaHCO3 (225 mL), and extracted with ether
(2ꢂ200 mL, 100 mL). The combined extracts were washed
with H2O (100 mL) and brine (100 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (200 g, hexane–ether 10:1/
5:1) to give 17 (1.63 g, 77%) as a colorless oil: TLC, Rf
0.36 (hexane–ether 1:1); [a]2D3 +45.5 (c 0.98, CHCl3); IR
(neat) 3480, 3030, 2960, 2870, 1710, 1640, 1100 cmꢀ1; 1H
NMR (270 MHz, CDCl3) d 7.38–7.28 (m, 5H), 5.92 (ddt,
J¼17.0, 10.3, 6.9 Hz, 1H), 5.17 (d, J¼10.3 Hz, 1H), 5.13
(d, J¼17.0 Hz, 1H), 4.52 (d, J¼12.5 Hz, 1H), 4.48 (d,
J¼12.5 Hz, 1H), 4.02 (dd, J¼8.6, 4.0 Hz, 1H), 3.35 (d,
J¼8.9 Hz, 1H), 3.30 (d, J¼8.9 Hz, 1H), 3.23 (d, J¼6.9 Hz,
2H), 2.57 (dd, J¼16.0, 8.6 Hz, 1H), 2.50 (dd, J¼16.0,
4.0 Hz, 1H), 1.64 (br s, 1H), 0.93 (s, 3H), 0.89 (s, 3H); 13C
NMR (67.8 MHz, CDCl3) d 209.1, 137.8, 130.2, 128.2,
127.6, 127.5, 118.8, 78.5, 73.6, 73.4, 48.5, 44.3, 38.1,
22.2, 19.9; HRMS (ESI) calcd for C17H24NaO3 (M+Na)+
299.1623, found 299.1650.
4. Experimental
4.1. General
Optical rotations were measured with a JASCO DIP-370
polarimeter or a JASCO DIP-1000 polarimeter. H NMR
1
spectra were recorded on a JEOL JNM-EX270 (270 MHz),
a Bruker AVANCE-400M (400 MHz), or a Bruker AVANCE
500 (500 MHz) instrument. Chemical shifts are reported in
parts per million from internal standards [tetramethylsilane
(0.00 ppm) for CDCl3 and C6D5H (7.16 ppm) for C6D6]
and J values are in hertz. 13C NMR spectra were recorded
on a JEOL JNM-EX270 (67.8 MHz) or a Bruker AVANCE
500 (125 MHz) instrument. Chemical shifts are reported in
parts per million from the solvent peak (77.0 ppm for
CDCl3, 128.0 ppm for C6D6). IR spectra were recorded on
a JASCO FT/IR-300 instrument. FAB mass spectra were
recorded on a JEOL SX-102 instrument. ESI mass spectra
were recorded on a QStar/Pulsar i spectrometer (Applied
Biosystems). Both TLC analysis and preparative TLC
were conducted on E. Merck precoated silica gel 60 F254
(0.25 mm layer thickness). Fuji Silysia silica gel BW-820
MH and FL-60D were used for column chromatography un-
less otherwise noted. Organic solvents for moisture-sensitive
reactions were distilled from the following drying agents:
THF and ether (Na–benzophenone ketyl), benzene and tolu-
ene (Na), acetonitrile and triethylamine (calcium hydride),
DMSO (calcium hydride under reduced pressure), CH2Cl2
(P2O5), acetone (anhydrous K2CO3), and MeOH (Mg). All
moisture-sensitive reactions were performed under an atmo-
sphere of nitrogen, and the starting materials were azeotropi-
cally dried with benzene before use. All new compounds
were determined to be >95% pure by 1H NMR unless other-
wise noted.
4.1.3. anti-1,3-Diol 18a and syn-1,3-diol 18b. To a stirred
solution of tetramethylammonium triacetoxyborohydride
(3.14 g, 11.9 mmol) in acetonitrile (10 mL) and acetic acid
(10 mL) cooled at ꢀ40 ꢁC was added a solution of ketone

K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
7691
17 (745 mg, 2.70 mmol) in acetonitrile (1.5 mL, 3ꢂ0.4 mL
rinse). The reaction mixture was stirred at ꢀ40 ꢁC, kept at
ꢀ30 ꢁC for 12 h, dilutedwith saturated aqueousNa/K tartrate
(35 mL), stirred at room temperature for 50 min, and ex-
tracted with CH2Cl2 (3ꢂ60 mL). The combined extracts
were washed with saturated aqueous NaHCO3 (70 mL), and
the aqueous layer was extracted with CH2Cl2 (100 mL). The
organic extracts were combined, dried (Na2SO4), and con-
centrated. The residual oil was purified by column chromato-
graphy on silica gel (FL-60D, 100 g, hexane–EtOAc 4:1) to
give 18a (644 mg, 86%) and syn-1,3-diol 18b (56 mg, 7%)
as a colorless oil. Compound 18a: TLC, Rf 0.39 (hexane–
EtOAc 2:1); [a]2D3 +26.5 (c 1.32, CHCl3); IR (neat) 3430,
tert-butyl alcohol (2.8 mL, 0.22 mmol). After being stirred
at room temperature for 2 h, a 0.4 M aqueous sodium period-
ate (34 mL, 13 mmol) was added. The reaction mixture was
stirred at room temperature for 30 min and extracted with
EtOAc (3ꢂ50 mL). The combined extracts were washed
with saturated aqueous Na2S2O3 (50 mL) and brine
(50 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel
(50 g, hexane–EtOAc 5:1) to give20 (1.53 g, 96%) as a color-
less oil: TLC, Rf 0.71 (hexane–EtOAc 2:1); [a]2D2 +24.2 (c
1.03, CHCl3); IR (neat) 2980, 2870, 1730, 1380, 1220,
1
1100 cmꢀ1; H NMR (270 MHz, CDCl3) d 9.75 (dd, J¼
2.6, 1.7 Hz, 1H), 7.35–7.26 (m, 5H), 4.51 (d, J¼12.2 Hz,
1H), 4.44 (d, J¼12.2 Hz, 1H), 4.25 (dddd, J¼9.9, 8.3, 5.9,
4.6 Hz, 1H), 3.83 (dd, J¼9.9, 6.6 Hz, 1H), 3.30 (d,
J¼8.6 Hz, 1H), 3.16 (d, J¼8.6 Hz, 1H), 2.60 (ddd, J¼16.5,
8.3, 2.6 Hz, 1H), 2.46 (ddd, J¼16.5, 4.6, 1.7 Hz, 1H), 1.89
(ddd, J¼12.5, 9.9, 5.9 Hz, 1H), 1.42 (ddd, J¼12.5, 9.9,
6.6 Hz, 1H), 1.32 (s, 3H), 1.29 (s, 3H), 0.91 (s, 3H), 0.86
(s, 3H); 13C NMR (67.8 MHz, CDCl3) d 200.9, 138.7,
128.9, 128.1, 127.2, 100.6, 76.3, 73.2, 69.2, 62.6, 49.2,
37.7, 32.8, 24.7, 24.0, 20.6, 19.8; HRMS (FAB) calcd for
C19H28NaO4 (M+Na)+ 343.1886, found 343.1857.
1
3030, 2960, 2870, 1640, 1100 cmꢀ1; H NMR (270 MHz,
CDCl3) d 7.38–7.28 (m, 5H), 5.83 (ddt, J¼17.0, 10.3,
6.8 Hz, 1H), 5.12 (d, J¼17.0 Hz, 1H), 5.10 (d, J¼10.3 Hz,
1H), 4.54 (d, J¼12.0 Hz, 1H), 4.48 (d, J¼12.0 Hz, 1H),
3.98 (m, 1H), 3.83 (ddd, J¼9.1, 3.8, 3.8 Hz, 1H), 3.60 (d,
J¼3.8 Hz, 1H), 3.40 (d, J¼8.9 Hz, 1H), 3.33 (d, J¼8.9 Hz,
1H), 2.60 (d, J¼5.1 Hz, 1H), 2.30 (dd, J¼6.8, 6.8 Hz, 2H),
1.62–1.48 (m, 2H), 0.92 (s, 3H), 0.90 (s, 3H); 13C NMR
(67.8 MHz, CDCl3) d 137.5, 135.0, 128.1, 127.4, 127.2,
117.0, 79.5, 74.6, 73.4, 67.9, 41.8, 38.0, 36.9, 22.5, 19.6;
HRMS (ESI) calcd for C17H26NaO3 (M+Na)+ 301.1780,
found 301.1782. Compound 18b: Rf 0.48 (hexane–EtOAc
4.1.6. b-Hydroxy ester 21. To a stirred solution of
RhCl(PPh3)3 (15.0 mg, 0.0160 mmol) in THF (4 mL) at
0 ꢁC were added methyl 2-bromopropionate (0.045 mL,
0.40 mmol), a solution of aldehyde 20 (99.1 mg, 0.310
mmol) in THF (1.0 mL, 3ꢂ0.3 mL rinse), and a 1.0 M hex-
ane solution of Et2Zn (0.91 mL). The mixture was stirred at
0 ꢁC for 20 min, and 2-bromopropionate (0.020 mL,
0.18 mmol) was added to the mixture. After being stirred
at 0 ꢁC for 15 min, saturated aqueous NaHCO3 (10 mL)
was added. The reaction mixture was filtered through Flori-
sil, and the filtrate was extracted with EtOAc (20 mL). The
combined extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (7 g, hexane–
EtOAc 3:1) to give 21 (107 mg, 88%) as a colorless oil:
TLC, Rf 0.47 (hexane–EtOAc 3:1); IR (neat) 3500, 2990,
1
2:1); H NMR (270 MHz, CDCl3) d 7.38–7.28 (m, 5H),
5.85 (ddt, J¼17.0, 10.3, 6.9 Hz, 1H), 5.10 (d, J¼17.0 Hz,
1H), 5.08 (d, J¼10.3 Hz, 1H), 4.53 (d, J¼13.5 Hz, 1H),
4.48 (d, J¼13.5 Hz, 1H), 4.12 (br s, 1H), 4.07–3.85 (m,
2H), 3.72 (br s, 1H), 3.39 (d, J¼8.9 Hz, 1H), 3.29 (d,
J¼8.9 Hz, 1H), 2.25 (m, 2H), 1.60 (m, 1H), 1.41 (m, 1H),
0.91 (s, 3H), 0.90 (s, 3H).
4.1.4. Acetonide 19. To a stirred solution of anti-1,3-diol 18a
(482 mg, 1.73 mmol) in acetone (6 mL) were added 2,2-
dimetoxypropane (2.9 mL, 24 mmol) and (ꢃ)-camphor-
sulfonic acid (23.4 mg, 0.101 mmol). The reaction mixture
was stirred at room temperature for 19 h, diluted with satu-
rated aqueous NaHCO3 (10 mL), and extracted with ether
(3ꢂ25 mL). The combined extracts were washed with brine
(10 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (26 g,
hexane–ether 25:1/10:1/2:1/1:2) to give 19 (540 mg,
97%) as a colorless oil: TLC, Rf 0.82 (hexane–EtOAc 5:1);
[a]2D4 +29.8 (c 0.97, CHCl3); IR (neat) 2980, 2880, 1220,
2860, 1740, 1220, 1100 cmꢀ1
;
1H NMR (270 MHz,
CDCl3) d 7.37–7.26 (m, 5H), 4.50 (d, J¼12.3 Hz, 1H),
4.44 (d, J¼12.3 Hz, 1H), 4.22–3.90 (m, 2H), 3.85–3.75
(m, 1H), 3.71 (s, 1.5H), 3.67 (s, 1.5H), 3.29 (d, J¼8.6 Hz,
0.5H), 3.28 (d, J¼8.6 Hz, 0.5H), 3.15 (d, J¼8.6 Hz, 0.5H),
3.14 (d, J¼8.6 Hz, 0.5H), 3.13 (d, J¼6.2 Hz, 0.5H), 3.06
(d, J¼4.3 Hz, 0.5H), 2.60–2.48 (m, 1H), 1.88–1.35 (m,
4H), 1.34 (s, 1.5H), 1.32 (s, 1.5H), 1.29 (s, 3H), 1.21 (d,
J¼7.1 Hz, 1.5H), 1.19 (d, J¼7.1 Hz, 0.75H), 1.15 (d,
J¼7.1 Hz, 0.75H), 0.89 (s, 3H), 0.85 (s, 3H); 13C NMR
(67.8 MHz, CDCl3) d 176.1, 176.0, 175.4, 175.3, 138.73,
138.67, 128.9, 128.09, 128.07, 128.05, 127.19, 127.17,
127.14, 125.1, 100.6, 100.41, 100.37, 76.4, 76.3, 73.2,
70.3, 69.4, 69.2, 68.7, 68.19, 68.12, 64.5, 64.3, 51.72,
51.67, 45.7, 45.5, 39.8, 39.5, 39.14, 39.09, 37.7, 37.6,
33.30, 33.23, 32.77, 32.72, 24.9, 24.7, 24.14, 24.09, 20.62,
20.59, 20.56, 19.7, 13.1, 12.1, 11.6; HRMS (ESI) calcd for
C23H36NaO6 (M+Na)+ 431.2410, found 431.2396.
1
1100 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.36–7.28 (m,
5H), 5.80 (ddt, J¼17.0, 10.3, 6.8 Hz, 1H), 5.09 (d, J¼
17.0 Hz, 1H), 5.03 (d, J¼10.3 Hz, 1H), 4.51 (d, J¼12.2 Hz,
1H), 4.45 (d, J¼12.2 Hz, 1H), 3.79 (dd, J¼10.3, 6.2 Hz,
1H), 3.75 (m, 1H), 3.29 (d, J¼8.4 Hz, 1H), 3.17 (d,
J¼8.4 Hz, 1H), 2.30 (ddd, J¼14.3, 6.8, 6.8 Hz, 1H), 2.18
(ddd, J¼14.3, 6.8, 6.8 Hz, 1H), 1.77 (ddd, J¼12.3, 10.3,
5.9 Hz, 1H), 1.40 (ddd, J¼12.3, 9.7, 6.2 Hz, 1H), 1.30 (s,
6H), 0.90 (s, 3H), 0.86 (s, 3H); 13C NMR (67.8 MHz,
CDCl3) d 138.9, 134.7, 128.2, 127.3, 127.2, 116.5, 100.2,
76.5, 73.2, 69.4, 66.7, 40.2, 37.6, 32.6, 24.6, 24.2, 20.5,
19.7; HRMS (ESI) calcd for C20H30NaO3 (M+Na)+
341.2093, found 341.2081.
4.1.5. Aldehyde 20. To a stirred solution of acetonide 19
(1.58 g, 4.97 mmol) in acetone (48 mL) and H2O (16 mL)
4.1.7. b-Keto ester 22. To a stirred solution of oxalyl chlo-
ride (0.047 mL, 0.54 mmol) in CH2Cl2 (1.5 mL) cooled at
ꢀ78 ꢁC was added a 3.6 M solution of DMSO in CH2Cl2
(0.35 mL, 1.3 mmol) dropwise. The resulting solution was
were
8.70 mmol) and a 0.078 M solution of osmium tetroxide in
added
N-methylmorpholine-N-oxide
(1.02 g,

7692
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
stirred at ꢀ78 ꢁC for 5 min, and a solution of b-hydroxy ester
21 (198 mg, 0.485 mmol) in CH2Cl2 (1 mL, 0.5 mL rinse)
was added dropwise. The mixture was stirred at ꢀ78 ꢁC for
15 min, and triethylamine (0.20 mL, 1.43 mmol) was added.
The resulting mixture was stirred at ꢀ78 ꢁC for 5 min,
warmed to 0 ꢁC, and stirred for 10 min. The mixture was di-
luted with H2O (3 mL) and extracted with ether (3ꢂ10 mL).
The combined extracts were washed with brine (3 mL), dried
(Na2SO4), and concentrated. The residual oil was purified by
column chromatography on silica gel (4 g, hexane–EtOAc
20:1/10:1/5:1) to give 22 (173 mg, 88%) as a colorless
oil: TLC, Rf 0.57 (hexane–EtOAc 3:1); IR (neat) 2990,
3.86 mmol) in DMF (2.5 mL) was added tert-butyldiphenyl-
silyl chloride (0.46 mL, 1.8 mmol). The mixture was stirred
at 0 ꢁC for 2 h, diluted with 5% aqueous NaHCO3 (30 mL),
and extracted with EtOAc (3ꢂ20 mL). The combined ex-
tracts were washed with brine (15 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (46 g, hexane–EtOAc 8:1) to
give 24 (739 mg, 100%) as a colorless oil: TLC, Rf 0.64
(hexane–EtOAc 3:1); IR (neat) 2960, 2860, 1740, 1110,
1
700 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.74–7.60 (m,
4H), 7.43–7.21 (m, 11H), 4.40 (d, J¼12.4 Hz, 1H), 4.35 (d,
J¼12.4 Hz, 1H), 4.22–4.05 (m, 1H), 3.63 (s, 1.5H), 3.62 (s,
1.5H), 3.49 (s, 1.5H), 3.33–3.25 (m, 2H), 3.06–3.00 (m, 1H),
2.97 (s, 1.5H), 2.93 (q, J¼7.3 Hz, 1H), 2.13–1.09 (m, 4H),
1.16 (d, J¼7.3 Hz, 1.5H), 1.05 (s, 9H), 1.01 (d, J¼7.3 Hz,
1.5H), 0.79 (s, 1.5H), 0.77 (s, 1.5H), 0.74 (s, 1.5H), 0.73
(s, 1.5H); 13C NMR (67.8 MHz, CDCl3) d 174.1, 173.2,
138.64, 138.56, 135.7, 134.7, 134.4, 134.3, 129.3, 128.1,
127.6, 127.37, 127.35, 127.2, 127.1, 101.3, 101.2, 77.2,
73.1, 72.3, 71.9, 67.2, 51.6, 51.4, 47.2, 46.9, 44.9, 43.4,
38.1, 38.0, 37.5, 34.5, 34.4, 27.09, 27.08, 26.6, 21.3, 21.1,
20.5, 20.2, 19.2, 14.3, 13.2, 11.6; HRMS (ESI) calcd for
C37H50NaO6Si (M+Na)+ 641.3274, found 641.3250.
1
2860, 1750, 1720, 1220, 1100 cmꢀ1; H NMR (270 MHz,
CDCl3) d 7.33–7.26 (m, 5H), 4.50 (d, J¼12.3 Hz, 1H), 4.44
(d, J¼12.3 Hz, 1H), 4.19 (m, 1H), 3.83–3.76 (m, 1H), 3.72
(s, 3H), 3.59 (q, J¼7.1 Hz, 0.5H), 3.58 (q, J¼7.1 Hz,
0.5H), 3.29 (d, J¼8.6 Hz, 1H), 3.15 (d, J¼8.6 Hz, 1H),
2.80 (dd, J¼16.2, 7.9 Hz, 1H), 2.57 (dd, J¼16.2, 5.1 Hz,
1H), 1.89 (m, 1H), 1.41–1.31 (m, 1H), 1.34 (d, J¼7.1 Hz,
1.5H), 1.32 (d, J¼7.1 Hz, 1.5H), 1.28 (s, 1.5H), 1.27 (s,
1.5H), 1.26 (s, 3H), 0.89 (s, 3H), 0.85 (s, 3H); 13C NMR
(67.8 MHz, CDCl3) d 203.7, 170.8, 138.8, 128.14, 128.12,
127.25, 127.21, 127.20, 100.6, 100.4, 76.4, 73.2, 69.3,
69.2, 63.8, 63.6, 53.3, 53.1, 52.4, 47.7, 47.3, 37.7, 32.8,
24.6, 24.1, 20.6, 19.75, 19.72, 12.7, 12.5; HRMS (ESI) calcd
for C23H34NaO6 (M+Na)+ 429.2253, found 429.2262.
4.1.10. Alcohol 25. A mixture of silyl ether 24 (66 mg,
0.13 mmol) and 20% Pd(OH)2 on carbon (26 mg) in dioxane
(3 mL) was stirred under a hydrogen atmosphere at room
temperature for 2 h. The mixture was filtered through
a pad of Celite, and the residue was washed with EtOAc.
The filtrate and the washings were combined and concen-
trated. The residual oil was purified by column chromato-
graphy on silica gel (4 g, hexane–EtOAc 5:1/3:1) to give
25 (52 mg, 96%) as a colorless oil: TLC, Rf 0.57 (hexane–
EtOAc 2:1); IR (neat) 3540, 2960, 2860, 1740, 1110,
4.1.8. Cyclic methyl acetal 23. To a stirred solution of
b-keto ester 22 (1.20 g, 10.3 mmol) in methanol (30 mL)
were added trimethyl orthoformate (4.7 mL, 43 mmol)
and pyridinium p-toluenesulfonate (71.6 mg, 0.29 mmol).
The mixture was stirred at room temperature for 1 h, diluted
with saturated aqueous NaHCO3 (35 mL), and extracted
with ether (4ꢂ50 mL). The combined extracts were washed
with H2O and brine (30 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified by column chromato-
graphy on silica gel (40 g, hexane–EtOAc 3:1/2:1/
1:1) to give 23 (785 mg, 96%) as a colorless oil: TLC, Rf
0.24 (hexane–EtOAc 2:1); IR (neat) 3450, 2950, 2870,
1
1040, 700 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.68–7.64
(m, 4H), 7.42–7.33 (m, 6H), 4.07 (m, 1H), 3.69 (s, 1.5H),
3.65 (s, 1.5H), 3.44–3.18 (m, 3H), 3.09 (s, 1.5H), 3.03 (s,
1.5H), 2.95 (q, J¼7.3 Hz, 1H), 2.08–1.86 (m, 1H), 1.72–
0.80 (m, 3H), 1.17 (d, J¼7.3 Hz, 1.5H), 1.06 (s, 9H), 1.03
(d, J¼7.3 Hz, 1.5H), 0.79 (s, 1.5H), 0.76 (s, 1.5H), 0.74 (s,
3H). A signal due to one proton (OH) was not observed;
13C NMR (67.8 MHz, CDCl3) d 174.0, 173.3, 136.1,
135.0, 134.9, 134.6, 129.9, 127.9, 102.3, 102.0, 78.3, 76.5,
72.1, 71.5, 67.2, 67.1, 52.3, 52.2, 48.2, 47.6, 45.6, 43.9,
39.0, 38.4, 38.1, 38.0, 35.4, 35.3, 27.51, 27.49, 23.1, 22.5,
20.0, 19.7, 19.6, 13.4, 11.8; HRMS (ESI) calcd for
C30H44NaO6Si (M+Na)+ 551.2805, found 551.2822.
1740, 1100, 1030 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d 7.39–7.26 (m, 5H), 4.51 (d, J¼12.2 Hz, 0.5H), 4.50 (d,
J¼12.2 Hz, 0.5H), 4.43 (d, J¼12.2 Hz, 0.5H), 4.42 (d,
J¼12.2 Hz, 0.5H), 4.08 (m, 1H), 3.67 (s, 1.5H), 3.63 (s,
1.5H), 3.58 (dd, J¼11.9, 1.6 Hz, 0.5H), 3.57 (dd, J¼11.9,
1.6 Hz, 0.5H), 3.49 (s, 1.5H), 3.40 (d, J¼8.6 Hz, 0.5H),
3.38 (d, J¼8.6 Hz, 0.5H), 3.17 (d, J¼8.6 Hz, 0.5H), 3.14
(d, J¼8.6 Hz, 0.5H), 3.10 (s, 1.5H), 3.07 (q, J¼7.2 Hz,
0.5H), 3.02 (q, J¼6.9 Hz, 0.5H), 2.10 (ddd, J¼12.2, 4.6,
1.6 Hz, 0.5H), 2.00 (ddd, J¼12.2, 4.8, 1.6 Hz, 0.5H),
1.94–1.81 (m, 1H), 1.74 (dd, J¼12.2, 11.2 Hz, 0.5H),
1.40 (dd, J¼12.2, 10.8 Hz, 0.5H), 1.27–1.06 (m, 1H),
1.21 (d, J¼6.9 Hz, 1.5H), 1.11 (d, J¼7.2 Hz, 1.5H), 0.95
(s, 1.5H), 0.93 (s, 1.5H), 0.89 (s, 3H). A signal due to
one proton (OH) was not observed; 13C NMR (67.8 MHz,
CDCl3) d 174.0, 173.2, 138.54, 138.47, 128.1, 127.2,
127.1, 101.3, 101.2, 73.1, 73.0, 72.5, 72.1, 65.4, 65.1,
51.7, 51.5, 47.3, 47.0, 44.8, 43.4, 38.3, 38.1, 38.0, 37.4,
34.0, 33.9, 21.4, 21.2, 20.4, 20.2, 13.2, 11.6; HRMS
(ESI) calcd for C21H32NaO6 (M+Na)+ 403.2097, found
403.2118.
4.1.11. C1–C9 segment 4. To a stirred solution of alcohol 25
(79 mg, 0.11 mmol) in DMSO (4.3 mL) were added triethyl-
amine (0.42 mL, 3.0 mmol) and sulfur trioxide pyridine
complex (153 mg, 0.961 mmol). The mixture was stirred
at room temperature for 1 h, diluted with saturated aqueous
NaHCO3 (15 mL), and extracted with EtOAc (3ꢂ15 mL).
The combined extracts were washed with brine (15 mL),
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (4 g,
hexane–EtOAc 9:1) to give 4 (75 mg, 95%) as a colorless
oil: TLC, Rf 0.63 (hexane–EtOAc 3:1); IR (neat) 2950,
1
2860, 1740, 1110, 700 cmꢀ1; H NMR (270 MHz, CDCl3)
d 9.49 (s, 0.5H), 9.47 (s, 0.5H), 7.68–7.64 (m, 4H), 7.42–
7.33 (m, 6H), 4.09 (m, 1H), 3.65 (s, 1.5H), 3.63 (s, 1.5H),
3.44 (dd, J¼12.4, 2.1 Hz, 0.5H), 3.39 (dd, J¼12.2, 2.1 Hz,
4.1.9. Silyl ether 24. To a stirred solution of cyclic methyl
acetal 23 (445 mg, 1.17 mmol) and imidazole (263 mg,

K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
7693
0.5H), 3.07 (s, 1.5H), 2.97 (s, 1.5H), 2.95 (q, J¼7.6 Hz,
0.5H), 2.90 (q, J¼7.6 Hz, 0.5H), 2.05–1.12 (m, 4H), 1.15
(d, J¼7.6 Hz, 1.5H), 1.05 (s, 9H), 1.01 (d, J¼7.6 Hz,
1.5H), 0.99 (s, 1.5H), 0.94 (s, 1.5H), 0.87 (s, 1.5H), 0.85
(s, 1.5H); 13C NMR (67.8 MHz, CDCl3) d 205.3, 205.0,
173.8, 172.8, 135.62, 135.61, 134.39, 134.36, 134.1,
134.0, 129.51, 129.49, 129.48, 127.4, 101.7, 101.6, 73.1,
72.5, 66.49, 66.42, 51.7, 51.6, 48.9, 48.7, 47.5, 47.2, 44.6,
43.1, 38.1, 37.4, 34.35, 34.32, 27.0, 19.2, 19.0, 18.9,
16.65, 16.60, 13.1, 11.5; HRMS (ESI) calcd for
C37H50NaO6Si (M+Na)+ 549.2648, found 549.2648.
(d, J¼3.4 Hz, 1H), 1.90 (d, J¼1.3 Hz, 3H), 1.86 (t, J¼
6.4 Hz, 1H); 13C NMR (67.8 MHz, CDCl3) d 143.9, 77.7,
69.6, 66.0, 42.9, 24.2; HRMS (ESI) calcd for C6H11INaO2
(M+Na)+ 264.9701, found 264.9696.
4.1.14. Silyl ether 28. To a stirred solution of vinyl iodide 27
(5.05 g, 20.9 mmol) in pyridine (42 mL) cooled at 0 ꢁC was
added pivaloyl chloride (2.59 mL, 21.1 mmol). The mixture
was stirred at 0 ꢁC for 30 min, and triethylsilyl chloride
(3.6 mL, 22 mmol) was added. The mixture was stirred at
room temperature for 30 min, diluted with H2O (50 mL),
and extracted with hexane (3ꢂ50 mL). The combined
extracts were washed with brine (30 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (50 g, hexane–ether 50:1/
10:1) to give 28 (8.44 g, 92%) as a colorless oil: TLC, Rf
0.65 (hexane–ether 9:1); [a]2D6 +9.1 (c 0.88, CHCl3); IR
(neat) 2960, 2870, 1730, 1460, 1280, 1150, 1000,
4.1.12. Acetylene 26. To a stirred solution of 90% lithium
acetylide ethylenediamine complex (16.2 g, 158 mmol) in
DMSO (90 mL) kept at 20 ꢁC was added a solution of (R)-
glycidyl trityl ether (25.0 g, 79.0 mmol) in THF (25 mL,
3 mL rinse) over 30 min. The mixture was stirred at room
temperature for 30 min, cooled to 0 ꢁC, dilutedwith saturated
aqueous NH4Cl (50 mL) and H2O (20 mL), and extracted
with ether (3ꢂ70 mL). The combined extracts were washed
with brine (70 mL), dried (Na2SO4), and concentrated. The
residual oil was purified by column chromatography on silica
gel (100 g, hexane–EtOAc 8:1) to give 26 (26.2 g, 97%) as
a colorless oil: TLC, Rf 0.49 (hexane–EtOAc 3:1); [a]D24
ꢀ3.1 (c 1.11, CHCl3); IR (neat) 3300, 3060, 2920, 1490,
740 cmꢀ1 1H NMR (270 MHz, CDCl3) d 5.97 (s, 1H),
;
4.01–3.86 (m, 3H), 2.43 (dd, J¼13.8, 5.1 Hz, 1H), 2.36
(dd, J¼13.8, 5.9 Hz, 1H), 1.86 (s, 3H), 1.20 (s, 9H), 0.95 (t,
J¼7.6 Hz, 9H), 0.56 (q, J¼7.6 Hz, 6H); 13C NMR
(67.8 MHz, CDCl3) d 178.1, 143.8, 77.9, 68.2, 67.4,
44.8, 38.8, 27.3, 24.5, 6.9, 5.0; HRMS (ESI) calcd for
C17H33INaO3Si (M+Na)+ 463.1141, found 463.1116.
1
1450, 1070, 760, 710 cmꢀ1; H NMR (270 MHz, CDCl3)
d 7.48–7.20 (m, 15H), 3.92 (m, 1H), 3.27 (dd, J¼9.2,
4.6 Hz, 1H), 3.22 (dd, J¼9.2, 5.9 Hz, 1H), 2.49 (ddd,
J¼11.9, 5.9, 2.6 Hz, 1H), 2.43 (ddd, J¼11.9, 5.9, 2.3 Hz,
1H), 2.36 (d, J¼5.3 Hz, 1H), 1.96 (dd, J¼2.6, 2.3 Hz, 1H);
13C NMR (67.8 MHz, CDCl3) d 143.5, 128.5, 127.7, 126.9,
86.7, 80.3, 70.5, 69.1, 66.0, 23.9; HRMS (ESI) calcd for
C24H22NaO2 (M+Na)+ 365.1517, found 365.1494.
4.1.15. Alcohol 29. To a stirred solution of silyl ether 28
(540 mg, 1.23 mmol) in CH2Cl2 (5 mL) cooled at ꢀ78 ꢁC
was added a 0.95 M solution of diisobutylaluminum hydride
(2.9 mL, 2.7 mmol). The mixture was stirred at ꢀ78 ꢁC for
1 h, and the reaction was quenched by addition of methanol
(1 mL). The mixture was warmed to room temperature, di-
luted with saturated aqueous Na/K tartrate (40 mL), and
stirred for 15 min. The organic layer was separated, and the
aqueous layer was extracted with EtOAc (3ꢂ20 mL). The
combined extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (20 g, hexane–
EtOAc 9:1) to give 29 (433 mg, 99%) as a colorless oil:
TLC, Rf 0.45 (benzene–acetonitrile 9:1); [a]2D2 ꢀ0.47 (c
1.14, CHCl3); IR (neat) 3450, 2950, 2870, 1240, 1110,
4.1.13. Vinyl iodide 27. A 2.0 M solution of trimethylalumi-
num in toluene (0.50 mL, 1.0 mmol) was added to a stirred
suspension of zirconocene dichloride (57 mg, 0.19 mmol)
in CH2Cl2 (1.0 mL). After being stirred at room temperature
for 15 min, a solution of acetylene 26 (99 mg, 0.29 mmol) in
CH2Cl2 (0.5 mL, 0.3 mL rinse) was added, and the resulting
mixture was stirred at room temperature for 24 h. A solution
of iodine (104 mg, 0.41 mmol) in THF (0.4 mL) was added,
and the mixture was stirred at room temperature for 50 min.
After the mixture was cooled to 0 ꢁC, the reaction was
quenched by addition of sodium fluoride (0.2 g) and THF–
H2O (5:1, 6 mL), and the mixture was stirred at room temper-
ature for 15 min. After addition of magnesium sulfate (0.5 g),
the mixturewas further stirred for 15 min and filtered through
a pad of Celite, and the residue was washed with EtOAc. The
filtrate and the washings were combined and concentrated.
The residual oil was dissolved in ether (10 mL), and the solu-
tion was washed with saturated aqueous Na2S2O3 (3 mL).
The aqueous layer was extracted with EtOAc (3ꢂ5 mL).
The organic layers were combined, washed with brine
(5 mL), dried (Na2SO4), and concentrated. The residual oil
was purified by column chromatography on silica gel (FL-
60D, 8 g, benzene–acetonitrile 4:1/3:1) to give 27 (35 mg,
50%) as a colorless oil: TLC, Rf 0.55 (benzene–acetonitrile
1:1); [a]2D6 +8.7 (c 0.96, CHCl3); IR (neat) 3370, 2930,
1
1000, 740 cmꢀ1; H NMR (270 MHz, CDCl3) d 5.98 (m,
1H), 3.86 (m, 1H), 3.54 (dd, J¼11.1, 3.8 Hz, 1H), 3.42 (dd,
J¼11.1, 3.8 Hz, 1H), 2.45 (ddd, J¼12.7, 6.5, 1.1 Hz, 1H),
2.38 (ddd, J¼12.7, 5.8, 1.1 Hz, 1H), 1.86 (d, J¼1.1 Hz,
3H), 1.76 (br s, 1H), 0.96 (t, J¼7.6 Hz, 9H), 0.61 (q,
J¼7.6 Hz, 6H); 13C NMR (67.8 MHz, CDCl3) d 144.0,
77.9, 70.6, 65.9, 44.0, 24.5, 6.9, 5.1; HRMS (ESI) calcd for
C12H25INaO2Si (M+Na)+ 379.0566, found 379.0578.
4.1.16. Aldehyde 30. To a stirred solution of alcohol 29
(1.45 g, 4.07 mmol) in CH2Cl2 (41 mL) were added pyridine
(4.5 mL, 57 mmol) and Dess–Martin periodinane (5.17 g,
12.2 mmol). The mixture was stirred at room temperature
for 1.5 h, diluted with saturated aqueous Na2S2O3 (50 mL)
and saturated aqueous NaHCO3 (50 mL), and stirred for
15 min. The organic layer was separated, and the aqueous
layer was extracted with EtOAc (3ꢂ70 mL). The organic
layers were combined, washed with brine (50 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (30 g, hexane–
EtOAc 9:1) to give 30 (1.37 g, 95%) as a colorless oil:
TLC, Rf 0.48 (hexane–ether 3:1); [a]2D2 +45.6 (c 1.01,
1270, 1090, 1040 cmꢀ1 1H NMR (270 MHz, CDCl3)
;
d 6.06 (m, 1H), 3.87 (m, 1H), 3.67 (ddd, J¼11.1, 6.4, 3.4 Hz,
1H), 3.47 (ddd, J¼11.1, 6.4, 5.4 Hz, 1H), 2.42 (ddd, J¼13.8,
7.9, 1.1 Hz, 1H), 2.35 (ddd, J¼13.8, 5.9, 1.1 Hz, 1H), 2.02

7694
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
CHCl3); IR (neat) 2950, 2870, 1730, 1120, 1010, 740 cmꢀ1
;
aqueous Na/K tartrate (5 mL), and stirred for 15 min. The
organic layer was separated, and the aqueous layer was
extracted with ether (3ꢂ5 mL). The combined extracts
werewashed with brine (5 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified by column chromato-
graphy on silica gel (4 g, hexane–EtOAc 20:1/10:1/
7:1) to give 32 (66 mg, 86%) as a colorless oil: TLC, Rf
1H NMR (270 MHz, CDCl3) d 9.60 (d, J¼1.8 Hz, 1H), 6.03
(m, 1H), 4.05 (ddd, J¼7.6, 4.9, 1.8 Hz, 1H), 2.53 (ddd,
J¼13.8, 4.9, 0.8 Hz, 1H), 2.47 (ddd, J¼13.8, 7.6, 0.8 Hz,
1H), 1.87 (d, J¼1.1 Hz, 3H), 0.95 (t, J¼7.6 Hz, 9H), 0.60
(q, J¼7.6 Hz, 6H); HRMS (ESI) calcd for C12H23INaO2Si
(M+Na)+ 377.0410, found 377.0381.
1
0.37 (hexane–EtOAc 3:1); [a]2D2 +6.5 (c 1.07, CHCl3); H
4.1.17. C10–C17 segment 14. To a stirred solution of (3-
trimethylsilyl-2-propynyl)triphenylphosphonium bromide
(228 mg, 0.50 mmol) in THF (2.5 mL) cooled at ꢀ78 ꢁC
was added a 1.6 M solution of BuLi in hexane (0.28 mL,
0.45 mmol). After being stirred at ꢀ78 ꢁC for 30 min, a solu-
tion of aldehyde 30 (148 mg, 0.42 mmol) in THF (3 mL,
2ꢂ1 mL rinse) was added. The mixture was stirred at
ꢀ78 ꢁC for 3 h, warmed to room temperature, diluted with
H2O, and extracted with hexane (3ꢂ5 mL). The combined
extracts were washed with brine (7 mL), dried (Na2SO4),
and concentrated. The residual oil was purified by column
chromatography on silica gel (FL-60D, 8 g, hexane–benzene
15:1) to give 14 (105 mg, 57%) and its cis-isomer 33 (17 mg,
9%) as a colorless oil. Compound 14: TLC, Rf 0.45 (hexane–
benzene 5:1); [a]2D0 +13.2 (c 0.33, CHCl3); IR (neat) 2960,
NMR (270 MHz, CDCl3) d 5.93 (q, J¼0.8 Hz, 1H), 5.78
(ddt, J¼15.6, 0.7, 5.1 Hz, 1H), 5.65 (ddt, J¼15.6, 5.7,
0.8 Hz, 1H), 4.24 (m, 1H), 4.13 (dd, J¼5.1, 0.8 Hz, 2H),
2.43 (dd, J¼13.2, 7.3 Hz, 1H), 2.33 (dd, J¼13.2, 5.4 Hz,
1H), 1.85 (d, J¼0.8 Hz, 3H), 1.40 (br s, 1H), 0.94 (t,
J¼7.6 Hz, 9H), 0.57 (q, J¼7.6 Hz, 6H).
4.1.20. C10–C16 segment 13. To a stirred solution of alco-
hol 32 (55 mg, 0.14 mmol) in CH2Cl2 (0.5 mL) were added
triethylamine (0.06 mL, 0.4 mmol), 4-(dimethylamino)pyri-
dine (3.3 mg, 0.027 mmol), and trityl chloride (69.7 mg,
0.250 mmol), and the mixture was stirred at room tempera-
ture for 16 h. The mixture was diluted with saturated aqueous
NaHCO3 (1 mL) and extracted with ether (3ꢂ1 mL). The
combined extracts were washed with brine (1 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (4 g, hexane–EtOAc
50:1) to give 13 (80 mg, 89%) as a colorless oil: TLC, Rf 0.73
(hexane–EtOAc 3:1); [a]2D2 +9.7 (c 1.08, CHCl3); 1H NMR
(270 MHz, CDCl3) d 7.48–7.20 (m, 15H), 5.95 (s, 1H),
5.83 (dd, J¼15.7, 5.9 Hz, 1H), 5.69 (dt, J¼15.7, 4.6 Hz,
1H), 4.26 (m, 1H), 3.57 (d, J¼4.6 Hz, 2H), 2.45 (dd,
J¼13.2, 7.3 Hz, 1H), 2.36 (dd, J¼13.2, 5.1 Hz, 1H), 1.88
(s, 3H), 0.96 (t, J¼7.6 Hz, 9H), 0.60 (q, J¼7.6 Hz, 6H).
1
2880, 2150, 1250, 1080, 1010, 840, 740 cmꢀ1; H NMR
(270 MHz, CDCl3) d 6.13 (dd, J¼15.7, 5.4 Hz, 1H), 5.97
(s, 1H), 5.70 (dd, J¼15.7, 1.6 Hz, 1H), 4.26 (m, 1H), 2.49
(dd, J¼13.5, 6.8 Hz, 1H), 2.32 (dd, J¼13.5, 5.4 Hz, 1H),
1.85 (s, 3H), 0.94 (t, J¼7.6 Hz, 9H), 0.57 (q, J¼7.6 Hz,
6H), 0.19 (s, 9H); HRMS (ESI) calcd for C18H33INaOSi2
(M+Na)+ 471.1013, found 471.1012. Compound 33: TLC,
Rf 0.40 (hexane–benzene 5:1); 1H NMR (270 MHz,
CDCl3) d 5.94 (s, 1H), 5.86 (dd, J¼10.8, 8.6 Hz, 1H), 5.47
(dd, J¼10.8, 0.8 Hz, 1H), 4.80 (m, 1H), 2.46 (dd, J¼13.5,
7.3 Hz, 1H), 2.33 (dd, J¼13.5, 4.3 Hz, 1H), 1.89 (s, 3H),
0.94 (t, J¼7.6 Hz, 9H), 0.57 (q, J¼7.6 Hz, 6H), 0.20 (s, 9H).
4.1.21. Alcohol 34. To a stirred solution of C1–C9 segment 4
(43 mg, 0.082 mmol) and C10–C16 segment 13 (225 mg,
0.36 mmol) in DMSO (1.5 mL) were added nickel chloride
(0.6 mg, 0.0047 mmol) and chromium(II) chloride
(203 mg, 1.65 mmol). The mixture was stirred at room tem-
perature for 4 days, diluted with saturated aqueous NH4Cl
(4 mL), and extracted with ether (3ꢂ7 mL). The organic
layers were combined, washed with brine (5 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (8 g, hexane–EtOAc
50:1/10:1/6:1) to give a diastereomeric mixture of 34
(77 mg, 90%) as a colorless oil: TLC, Rf 0.50 (hexane–
4.1.18. Conjugated ester 31. To a stirred solution of alde-
hyde 30 (129 mg, 0.364 mmol) in toluene (4.5 mL) heated
at 90 ꢁC were added benzoic acid (8.6 mg, 0.069 mmol)
and 1 M solution of (methoxycarbonylmethylene)tributyl-
phosphorane in toluene (0.70 mL, 0.70 mmol). The mixture
was stirred at 90 ꢁC for 15 min, diluted with saturated aque-
ous NH4Cl (4 mL), and extracted with ether (3ꢂ4 mL). The
combined extracts were washed with saturated aqueous
NaHCO3 (4 mL) and brine (4 mL), dried (Na2SO4), and con-
centrated. The residual oil was purified by column chromato-
graphy on silica gel (5 g, hexane–ether 50:1/15:1) to give
31 (138 mg, 92%) as a colorless oil: TLC, Rf 0.51 (hexane–
ether 3:1); [a]D22 +12.0 (c 1.05, CHCl3); 1H NMR
(270 MHz, CDCl3) d 6.89 (dd, J¼15.7, 4.9 Hz, 1H), 6.00
(dd, J¼15.7, 1.6 Hz, 1H), 5.98 (m, 1H), 4.40 (dddd, J¼7.6,
4.9, 4.9, 1.6 Hz, 1H), 3.75 (s, 3H), 2.44 (ddd, J¼13.8, 7.6,
1.1 Hz, 1H), 2.38 (ddd, J¼13.8, 4.9, 0.8 Hz, 1H), 1.87 (d,
J¼1.4 Hz, 3H), 0.94 (t, J¼7.6 Hz, 9H), 0.58 (q, J¼7.6 Hz,
6H).
1
EtOAc 3:1); H NMR (270 MHz, CDCl3) d 7.68–7.64 (m,
4H), 7.42–7.16 (m, 21H), 5.80 (dd, J¼15.4, 5.9 Hz, 1H),
5.65 (dt, J¼15.4, 4.9 Hz, 1H), 5.21 (m, 1H), 4.36–4.20 (m,
1.5H), 4.15–4.00 (m, 1.5H), 3.64 (s, 3H), 3.60–3.50 (m,
2H), 3.30 (m, 1H), 3.11 (s, 0.5H), 3.09 (s, 1H), 3.06 (s,
0.5H), 3.03 (s, 1H), 2.94 (m, 1H), 2.40–1.10 (m, 6H), 1.68
(s, 2H), 1.62 (s, 1H), 1.17 (m, 1.5H), 1.06 (s, 9H), 1.05–
0.93 (m, 10.5H), 0.76 (s, 3H), 0.67–0.56 (m, 9H). A signal
due to one proton (OH) was not observed.
4.1.22. Seco acid 11. To a stirred solution of alcohol 34
(27 mg, 0.026 mmol) in THF (0.6 mL) and MeOH
(0.3 mL) was added a 2 M aqueous NaOH (0.1 mL). The
mixture was stirred at 40 ꢁC for 29 h, acidified with 1 M
aqueous HCl, and extracted with ether (4ꢂ5 mL). The com-
bined extracts were dried (Na2SO4) and concentrated to give
a oil, which was purified by column chromatography on
silica gel (FL-60D, 3 g, hexane–EtOAc 3:1/2:1/1:1) to
4.1.19. Alcohol 32. To a stirred solution of conjugated ester
31 (80 mg, 0.20 mmol) in THF (3 mL) cooled at ꢀ78 ꢁC was
added 0.93 M solution of diisobutylaluminum hydride in
hexane (0.86 mL, 0.80 mmol). The mixture was stirred at
ꢀ78 ꢁC for 25 min, and the reaction was quenched by addi-
tion of methanol (0.1 mL). The mixture was warmed to
room temperature, diluted with ether (3 mL) and saturated

K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
7695
give 11 (16 mg, 69%) and ester 35 (5 mg, 19%) as a colorless
oil. Compound 11: TLC, Rf 0.17–0.39 (hexane–EtOAc 1:1);
1H NMR (270 MHz, CDCl3) d 7.68–7.64 (m, 4H), 7.46–7.19
(m, 21H), 5.88–5.73 (m, 2H), 5.32 (m, 1H), 4.41 (m, 1H),
4.25 (m, 1H), 4.12 (m, 1H), 3.67–3.56 (m, 2H), 3.35 (m,
1H), 3.04 (s, 3H), 2.91 (m, 1H), 2.30–1.10 (m, 6H), 1.72
(s, 2H), 1.67 (s, 1H), 1.17 (m, 1.5H), 1.06 (s, 9H), 0.96–
0.81 (m, 4.5H), 0.67 (s, 0.5H), 0.60 (s, 1.5H), 0.55 (s, 1H).
Signals due to three protons (COOH, OH) were not ob-
served; MS (FAB) m/z 942 (M+2NaꢀH)+. Compound 35:
TLC, Rf 0.55–0.71 (hexane–EtOAc 1:1); 7.70–7.64 (m,
4H), 7.46–7.19 (m, 21H), 5.88–5.73 (m, 2H), 5.21 (m,
1H), 4.40–4.20 (m, 2H), 4.09 (m, 1H), 3.66 (s, 3H), 3.67–
3.56 (m, 2H), 3.33 (m, 1H), 3.08 (s, 1H), 3.04 (s, 2H),
2.95 (m, 1H), 2.35–1.12 (m, 6H), 1.71 (s, 3H), 1.20 (m,
1.5H), 1.06 (s, 9H), 1.04 (m, 1.5H), 0.96 (m, 3H), 0.63 (m,
3H). A signal due to one proton (OH) was not observed.
EtOAc 18:1/7:1) to give a diastereomeric mixture of 36
(92.2 mg, 81%) as a colorless oil: TLC, Rf 0.60 (hexane–
EtOAc 3:1); IR (neat) 3520, 2960, 2880, 2140, 1740, 1250,
1
1080, 840, 740, 700 cmꢀ1; H NMR (270 MHz, CDCl3)
d 7.69–7.62 (m, 4H), 7.45–7.32 (m, 6H), 6.14 (dd, J¼15.9,
5.4 Hz, 1H), 5.63 (d, J¼15.9 Hz, 1H), 5.20 (m, 1H), 4.36–
4.02 (m, 3H), 3.69 (s, 1.5H), 3.65 (s, 1.5H), 3.45–3.31 (m,
1H), 3.10 (s, 1.5H), 3.05 (s, 1.5H), 2.95 (m, 1H), 2.35–1.12
(m, 6H), 1.67 (s, 3H), 1.17 (m, 1.5H), 1.06 (s, 9H), 1.02–
0.80 (m, 13.5H), 0.63–0.53 (m, 9H), 0.18 (s, 9H). A signal
due to one proton (OH) was not observed; HRMS (ESI) calcd
for C48H76NaO7Si3 (M+Na)+ 871.4797, found 874.4799.
4.1.26. Acetylene 37. To a stirred solution of alcohol 36
(70.0 mg, 0.824 mmol) in THF (2.7 mL) cooled at 0 ꢁC
was added a solution of tetrabutylammonium fluoride
(Bu4NF) and acetic acid (0.70 mL, 0.7 mmol for Bu4NF
and 0.6 mmol for acetic acid) prepared from a 1.0 M solution
of Bu4NF in THF (0.90 mL) and acetic acid (0.050 mL). The
mixture was stirred at 0 ꢁC for 4 h, diluted with brine
(15 mL), and extracted with EtOAc (3ꢂ15 mL). The com-
bined extracts were dried (Na2SO4) and concentrated. The re-
sidual oil was purified by column chromatography on silica
gel (2 g, hexane–EtOAc 2:1) to give 37 (53.4 mg, 98%) as
a colorless oil: TLC, Rf 0.45 (hexane–benzene 5:1); IR
(neat) 3300, 2960, 2860, 1740, 1210, 1110, 1040, 760,
4.1.23. Lactone 9. A solution of triethylamine and 2,4,6-tri-
chlorobenzoyl chloride in THF (0.25 mL, 0.054 mmol for
Et3N and 0.016 mmol for 2,4,6-Cl3C6H2COCl), prepared
from triethylamine (0.18 mL), 2,4,6-trichlorobenzoyl chlo-
ride (0.06 mL), and THF (6 mL), was added to seco acid
11 (11 mg, 0.012 mmol). The mixture was stirred at room
temperature for 2.5 h and diluted with toluene (22 mL) to
give a solution of mixed anhydride, which was added to a so-
lution of 4-(dimethylamino)pyridine (14 mg, 0.12 mmol) in
toluene (1.5 mL) warmed at 80 ꢁC over 1 h. The mixture was
stirred at 80 ꢁC for 30 min, cooled to room temperature, and
washed with brine (10 mL). The aqueous layer was extracted
with ether (2ꢂ5 mL), and the organic layers were combined,
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (0.3 g,
hexane–EtOAc 10:1/7:1/5:1) to give 9 (3.1 mg, 29%)
as a colorless oil: TLC, Rf 0.50, 0.57, 0.64 (hexane–EtOAc
1
700 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.69–7.64 (m,
4H), 7.46–7.31 (m, 6H), 6.23 (dd, J¼15.9, 5.1 Hz, 1H),
5.73 (d, J¼15.9 Hz, 1H), 5.31 (d, J¼9.2 Hz, 1H), 4.38–
4.03 (m, 3H), 3.68 (s, 1.5H), 3.66 (s, 1.5H), 3.40–3.31 (m,
1H), 3.08 (s, 1.5H), 3.04 (s, 1.5H), 2.95 (m, 1H), 2.86 (s,
1H), 2.35–1.12 (m, 6H), 1.69 (s, 3H), 1.17 (m, 1.5H), 1.06
(s, 9H), 1.02–0.80 (m, 4.5H), 0.65 (s, 1.5H), 0.62 (s, 1.5H).
Signals due to two protons (OH) were not observed; 13C
NMR (67.8 MHz, CDCl3) d 173.5, 145.9, 135.7, 134.7,
134.6, 134.1, 133.5, 129.49, 129.47, 127.43, 127.41, 102.2,
79.0, 77.2, 76.2, 75.6, 69.9, 66.5, 65.9, 61.1, 51.8, 47.3,
40.5, 30.4, 29.8, 29.1, 27.3, 27.0, 21.7, 19.19, 19.17, 17.2,
15.4, 13.8, 11.5, 11.3, 9.6; HRMS (ESI) calcd for
C39H54NaO7Si (M+Na)+ 685.3536, found 685.3547.
1
3:1); H NMR (270 MHz, CDCl3) d 7.68–7.64 (m, 4H),
7.46–7.19 (m, 21H), 5.86–5.73 (m, 2H), 5.67–5.25 (m,
2H), 4.44–4.04 (m, 2H), 3.61 (m, 2H), 3.04 (s, 1.5H), 3.01
(m, 1H), 2.85 (s, 1.5H), 2.72 (m, 1H), 2.30–1.10 (m, 6H),
1.72 (m, 3H), 1.17 (m, 3H), 1.06 (s, 9H), 0.90–0.75 (m,
6H). A signal due to one proton (OH) was not observed;
MS (FAB) m/z 901 (M+Na)+.
4.1.27. Vinylstannane 38. To a stirred solution of acetylene
37 (193 mg, 0.291 mmol) in THF (9.7 mL) were added tri-
butyltin hydride (0.094 mL, 0.035 mmol) and 2,20-azobisiso-
butyronitrile (10.6 mg, 0.0646 mmol). The mixture was
stirred at 70 ꢁC for 2 h, cooled to room temperature, and con-
centrated. The residual oil was purified by column chromato-
graphy on silica gel (5 g, hexane–EtOAc 5:1/2:1) to give
38 (225 mg, 81%) as a colorless oil: TLC, Rf 0.50 (hexane–
EtOAc 2:1); IR (neat) 3460, 2930, 2860, 1740, 1200, 1110,
4.1.24. C13-epi-Seco acid 11. TLC, Rf 0.17–0.39 (hexane–
EtOAc 1:1); H NMR (270 MHz, CDCl3) d 7.68–7.64 (m,
1
4H), 7.46–7.19 (m, 21H), 5.88–5.73 (m, 2H), 5.33 (m,
1H), 4.43 (m, 1H), 4.26 (m, 1H), 4.08 (m, 1H), 3.60 (m,
2H), 3.30 (m, 1H), 3.04 (m, 3H), 2.91 (m, 1H), 2.30–1.10
(m, 6H), 1.73 (s, 2H), 1.70 (s, 1H), 1.15 (m, 1.5H), 1.06 (s,
9H), 1.04 (m, 1.5H), 0.90 (m, 3H), 0.58 (m, 3H). Signals
due to three protons (COOH, OH) were not observed; MS
(FAB) m/z 942 (M+2NaꢀH)+.
1
1040, 700 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.69–7.64
(m, 4H), 7.46–7.21 (m, 6H), 6.49 (dd, J¼18.6, 10.0 Hz,
1H), 6.23 (d, J¼18.6 Hz, 1H), 6.18 (dd, J¼15.1, 10.0 Hz,
1H), 5.64 (dd, J¼15.1, 6.2 Hz, 1H), 5.31 (d, J¼9.2 Hz,
1H), 4.38–4.03 (m, 3H), 3.68 (s, 1.5H), 3.65 (s, 1.5H),
3.39–3.26 (m, 1H), 3.08 (s, 1.5H), 3.04 (s, 1.5H), 2.95 (m,
1H), 2.35–1.80 (m, 4H), 1.72–0.80 (m, 38H), 1.06 (s, 9H),
0.64 (s, 1.5H), 0.61 (s, 1.5H). Signals due to two protons
(OH) were not observed; HRMS (ESI) calcd for
C51H82NaO7Si120Sn (M+Na)+ 977.4761, found 977.4725.
4.1.25. Alcohol 36. To a stirred solution of C1–C9 segment 4
(71.3 mg, 0.135 mmol) and C10–C17 segment 14 (519 mg,
1.16 mmol) in DMSO (2.7 mL) were added nickel chloride
(1.7 mg, 0.013 mmol) and chromium(II) chloride (314 mg,
2.55 mmol). The mixture was stirred at room temperature
for 5 days, diluted with saturated aqueous NH4Cl (10 mL),
and extracted with EtOAc (3ꢂ10 mL). The organic layers
were combined, washed with brine (10 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (10 g, hexane–
4.1.28. Bromodiene 39. To a stirred solution of vinyl-
stannane 38 (128 mg, 0.134 mmol) in THF (4.5 mL) cooled

7696
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
at 0 ꢁC was added N-bromosuccinimide (34.0 mg,
0.197 mmol). The mixture was stirred at 0 ꢁC for 30 min,
diluted with 10% aqueous Na2S2O3 (10 mL), and extracted
with EtOAc (3ꢂ10 mL). The combined extracts were
washed with brine (5 mL), dried (Na2SO4), and concen-
trated. The residual oil was purified by column chromato-
graphy on silica gel (3 g, hexane–EtOAc 3:2) to give 39
(97.7 mg, 98%) as a colorless oil: TLC, Rf 0.50 (hexane–
EtOAc 1:1); IR (neat) 3460, 2930, 2860, 1740, 1210,
J¼13.5 Hz, 0.5H), 6.09 (m, 1H), 5.80–5.58 (m, 2H), 5.43
(m, 1H), 4.05–3.85 (m, 2H), 3.09 (m, 1.5H), 3.01 (m, 1H),
2.86 (m, 1.5H), 2.74 (m, 1H), 2.17–1.00 (m, 6H), 1.65 (m,
3H), 1.26 (m, 3H), 1.05 (s, 9H), 0.93–0.80 (m, 6H). A signal
due to one proton (OH) was not observed; HRMS (ESI) calcd
for C38H5179BrNaO6Si (M+Na)+ 733.2536, found 733.2544.
4.1.31. Hemiacetal 40. A solution of lactone 10 (22.4 mg,
0.0315 mmol) in acetone (0.4 mL), H2O (0.2 mL), and acetic
acid (0.8 mL) was stirred at room temperature for 30 min.
The mixture was concentrated and purified by column chro-
matography on silica gel (FL-60D, 1 g, hexane–EtOAc 7:1)
to give 40 (19.0 mg, 86%) as a colorless oil: TLC, Rf 0.34,
0.44 (hexane–EtOAc 3:1); IR (neat) 3440, 2960, 2860,
1
1110, 1040, 760, 700 cmꢀ1; H NMR (270 MHz, CDCl3)
d 7.68–7.64 (m, 4H), 7.45–7.31 (m, 6H), 6.69 (dd, J¼13.5,
10.3 Hz, 1H), 6.31 (d, J¼13.5 Hz, 1H), 6.18 (dd, J¼15.1,
10.3 Hz, 1H), 5.73 (dd, J¼15.1, 5.4 Hz, 1H), 5.31 (d,
J¼8.9 Hz, 1H), 4.38–4.03 (m, 3H), 3.69 (s, 1.5H), 3.65 (s,
1.5H), 3.39–3.30 (m, 1H), 3.08 (s, 1.5H), 3.04 (s, 1.5H),
2.95 (m, 1H), 2.31–1.12 (m, 6H), 1.70 (s, 3H), 1.17 (m,
1.5H), 1.06 (s, 9H), 1.02–0.80 (m, 4.5H), 0.64 (s, 1.5H),
0.61 (s, 1.5H). Signals due to two protons (OH) were not ob-
served; HRMS (ESI) calcd for C39H5579BrNaO7Si (M+Na)+
765.2798, found 765.2793.
1
1700, 1190, 1110, 1040, 980, 760, 700 cmꢀ1; H NMR
(270 MHz, CDCl3) d 7.68–7.64 (m, 4H), 7.45–7.31 (m,
6H), 6.69 (dd, J¼13.5, 10.8 Hz, 1H), 6.37 (d, J¼13.5 Hz,
1H), 6.15 (dd, J¼14.9, 10.8 Hz, 1H), 5.78–5.29 (m, 3H),
5.41 (d, J¼2.2 Hz, 0.5H), 4.30–4.15 (m, 1.5H), 4.23 (d,
J¼2.2 Hz, 0.5H), 3.86 (m, 0.5H), 3.75 (d, J¼8.9 Hz, 0.5H),
3.36 (d, J¼8.9 Hz, 0.5H), 2.51 (m, 1H), 2.30–1.00 (m, 6H),
1.69 (s, 1.5H), 1.68 (s, 1.5H), 1.26 (m, 3H), 1.06 (s, 9H),
0.87 (m, 3H), 0.76 (m, 3H). A signal due to one proton
(OH) was not observed; 13C NMR (125 MHz, CDCl3)
d 176.8, 174.4, 173.7, 141.8, 136.9, 136.6, 136.3, 135.7,
134.5, 134.3, 134.0, 133.5, 133.3, 132.7, 132.6, 131.8,
130.0, 129.6, 128.9, 128.6, 128.5, 128.0, 127.5, 110.3,
110.2, 98.2, 97.71, 97.66, 94.7, 74.3, 73.9, 72.0, 71.9,
71.60, 71.55, 71.4, 71.1, 67.2, 67.1, 67.0, 50.1, 48.7, 48.1,
47.5, 47.4, 46.4, 41.3, 41.2, 41.0, 40.8, 40.4, 40.0, 38.9,
38.8, 35.3, 34.9, 34.8, 34.4, 29.7, 27.0, 25.2, 25.0, 24.4,
24.1, 22.7, 22.5, 19.3, 19.1, 15.7, 14.1, 13.6, 12.6, 11.5,
11.2, 11.1; HRMS (ESI) calcd for C37H4979BrNaO6Si
(M+Na)+ 719.2379, found 719.2370.
4.1.29. Seco acid 12. To a stirred solution of bromodiene 39
(66.2 mg, 0.089 mmol) in THF (1.2 mL) and MeOH
(0.6 mL) was added a 2 M aqueous NaOH (0.2 mL). The
mixture was stirred at 40 ꢁC for 23 h, acidified with 1 M
aqueous HCl, and extracted with EtOAc (4ꢂ5 mL). The
combined extracts were dried (Na2SO4) and concentrated
to give a oil, which was purified by column chromatography
on silica gel (FL-60D, 2 g, hexane–EtOAc 5:1/3:1/1:1)
to give 12 (40.8 mg, 63%) as a colorless oil: TLC, Rf 0.08–
0.39 (hexane–EtOAc 1:1); IR (neat) 3440, 2930, 2860, 1710,
1220, 1110, 1040, 980, 760, 700 cmꢀ1; 1H NMR (270 MHz,
CDCl3) d 7.68–7.64 (m, 4H), 7.45–7.31 (m, 6H), 6.69 (dd,
J¼13.5, 10.3 Hz, 1H), 6.30 (d, J¼13.5 Hz, 1H), 6.18 (dd,
J¼15.1, 10.3 Hz, 1H), 5.73 (dd, J¼15.1, 5.7 Hz, 1H), 5.31
(d, J¼8.6 Hz, 1H), 4.48–4.03 (m, 3H), 3.49–3.30 (m, 1H),
3.06 (s, 1.5H), 3.04 (s, 1.5H), 2.95 (m, 1H), 2.31–1.12 (m,
6H), 1.70 (s, 3H), 1.17 (m, 1.5H), 1.06 (s, 9H), 1.02–0.80 (m,
4.5H), 0.67 (s, 1.5H), 0.58 (s, 1.5H). Signals due to three pro-
tons (COOH, OH) were not observed; HRMS (ESI) calcd for
C38H5379BrNaO7Si (M+Na)+ 751.2642, found 751.2612.
4.1.32. Enones 41a and 41b. To a stirred solution of hemi-
acetal 40 (19.0 mg, 0.027 mmol) in CH2Cl2 (0.6 mL) were
added pyridine (0.05 mL) and Dess–Martin periodinane
(38.3 mg, 0.090 mmol). The mixture was stirred at room
temperature for 1 h, diluted with saturated aqueous
Na2S2O3 (5 mL), stirred for 15 min, and extracted with ether
(3ꢂ5 mL). The combined organic layers were washed with
brine (3 mL), dried (Na2SO4), and concentrated. The residual
oil was purified by column chromatography on silica gel (FL-
60D, 1 g, hexane–EtOAc 9:1) to give a mixture of enones 41a
and 41b (17.4 mg, 92%). The mixture of enones (43.9 mg)
were purified by HPLC [Develosil ODS-HG-5 (f 4.6ꢂ
250 mm), 95% MeOH, flow rate 5 mL minꢀ1, detection at
254 nm] to give crude enone 41a (17.8 mg, tR¼47 min)
and pure 41b (13.0 mg, tR¼38 min, 27%) as a colorless oil.
The crude enone 41a was further purified by PLC
(200ꢂ200ꢂ0.25 mm, two plates, hexane–ether 3:1) to give
pure enone 41a (10.2 mg, 21%) as a colorless oil. Compound
41a: TLC, Rf 0.33 (hexane–ether 3:1); [a]2D0 +18.6 (c 0.196,
CHCl3); IR (neat) 3448, 1705, 1682, 1423, 1176, 1110,
4.1.30. Lactone 10. A solution of triethylamine and 2,4,6-
trichlorobenzoyl chloride in THF (0.47 mL, 0.082 mmol
for Et3N and 0.023 mmol for 2,4,6-Cl3C6H2COCl), prepared
from triethylamine (0.15 mL), 2,4,6-trichlorobenzoyl chlo-
ride (0.05 mL), and THF (6 mL), was added to seco acid
12 (15.3 mg, 0.0210 mmol). The mixture was stirred at
room temperature for 2 h and diluted with toluene (35 mL)
to give a solution of mixed anhydride, which was added
to a solution of 4-(dimethylamino)pyridine (26.0 mg,
0.210 mmol) in refluxing toluene (7 mL) over 2 h. The mix-
ture was heated at reflux for 30 min, cooled to room temper-
ature, and washed with brine (10 mL). The aqueous layer
was extracted with EtOAc (2ꢂ15 mL), and the organic
layers were combined, dried (Na2SO4), and concentrated.
The residual oil was purified by column chromatography
on silica gel (FL-60D, 1 g, hexane–EtOAc 8:1) to give 10
(8.5 mg, 57%) as a colorless oil: TLC, Rf 0.34, 0.40, 0.50
(hexane–EtOAc 3:1); IR (neat) 3510, 2930, 2860, 1730,
1
980 cmꢀ1; H NMR (270 MHz, CDCl3) d 7.68–7.63 (m,
4H), 7.45–7.33 (m, 6H), 6.70 (dd, J¼13.5, 10.8 Hz, 1H),
6.40 (d, J¼13.5 Hz, 1H), 6.23 (s, 1H), 6.18 (dd, J¼15.0,
10.8 Hz, 1H), 5.72 (dd, J¼15.0, 6.5 Hz, 1H), 5.66 (m, 1H),
4.32 (d, J¼2.7 Hz, 1H), 4.17 (m, 1H), 3.45 (dd, J¼11.9,
2.2 Hz, 1H), 2.56 (q, J¼7.2 Hz, 1H), 2.30–2.23 (m, 2H),
2.06 (s, 3H), 2.03 (dd, J¼11.9, 3.2 Hz, 1H), 1.30–1.15 (m,
3H), 1.19 (s, 3H), 1.07 (d, J¼7.2 Hz, 3H), 1.07 (s, 9H),
1180, 1110, 1040, 760, 700 cmꢀ1 1H NMR (270 MHz,
;
CDCl3) d 7.68–7.64 (m, 4H), 7.45–7.31 (m, 6H), 6.70 (dd,
J¼13.5, 10.0 Hz, 1H), 6.34 (d, J¼13.5 Hz, 0.5H), 6.33 (d,

K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
7697
0.80 (s, 3H); 13C NMR (67.8 MHz, CDCl3) d 204.6, 175.9,
147.7, 136.0, 135.6, 134.2, 134.1, 131.3, 129.6, 129.1,
127.5, 126.1, 110.6, 98.2, 74.1, 71.0, 66.7, 49.0, 47.9, 47.6,
41.3, 34.6, 27.1, 21.2, 19.3, 19.2, 18.7, 12.5; HRMS (FAB)
calcd for C37H4779BrNaO6Si (M+Na)+ 717.2223, found
717.2234. Compound 41b: TLC, Rf 0.28 (hexane–ether
3:1); [a]2D1 +11.4 (c 0.214, CHCl3); IR (neat) 3437, 1697,
dried (Na2SO4), and concentrated. The residual oil was
purified by column chromatography on silica gel (FL-60D,
2 g, hexane–EtOAc 5:1) to give TBS ether of auriside A
(1.9 mg) as a colorless oil.
To a stirred solution of TBS ether of auriside A (0.9 mg) in
THF (0.06 mL) cooled at 0 ꢁC was added HF$pyridine com-
plex (0.013 mL). The mixture was stirred at room tempera-
ture for 18 h, diluted with saturated aqueous NaHCO3
(2 mL), and extracted with EtOAc (3ꢂ10 mL). The com-
bined extracts were washed with brine (10 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (FL-60D, 1 g, hex-
ane–EtOAc 1:3) followed by HPLC [Develosil ODS-HG-5
(f 4.6ꢂ250 mm), 75% MeOH, flow rate 5 mL minꢀ1, detec-
tion at 215 nm] to give auriside A (1) (0.8 mg, 42% in two
steps) as a colorless oil: TLC, Rf 0.20 (hexane–EtOAc
1
1427, 1261, 1169, 1107, 980 cmꢀ1; H NMR (270 MHz,
CDCl3) d 7.69–7.63 (m, 4H), 7.46–7.33 (m, 6H), 6.70 (dd,
J¼13.5, 10.8 Hz, 1H), 6.40 (d, J¼13.5 Hz, 1H), 6.21 (s,
1H), 6.18 (dd, J¼14.0, 10.8 Hz, 1H), 5.78–5.67 (m, 2H),
5.11 (d, J¼2.7 Hz, 1H), 4.28 (m, 1H), 3.44 (dd, J¼11.9,
2.2 Hz, 1H), 2.56 (q, J¼7.0 Hz, 1H), 2.31–2.24 (m, 2H),
2.05 (s, 3H), 1.86 (dd, J¼11.6, 3.0 Hz, 1H), 1.64–1.50 (m,
2H), 1.27 (m, 1H), 1.25 (d, J¼7.0 Hz, 3H), 1.20 (s, 3H),
1.07 (s, 9H), 0.79 (s, 3H); 13C NMR (67.8 MHz, CDCl3)
d 204.9, 173.3, 147.3, 136.0, 135.6, 135.6, 134.3, 134.1,
131.3, 129.6, 129.6, 129.1, 127.5, 126.3, 110.1, 98.4, 73.8,
71.2, 66.8, 49.3, 48.6, 47.3, 40.8, 34.3, 27.1, 21.1, 19.2,
18.4, 11.4; HRMS (FAB) calcd for C37H4779BrNaO6Si
(M+Na)+ 717.2223, found 717.2200.
1
1:4); [a]2D3 ꢀ31 (c 0.040, MeOH); H NMR (500 MHz,
C6D6) d 6.40 (dd, J¼13.5, 10.9 Hz, 1H), 6.35 (s, 1H), 5.91
(d, J¼13.5 Hz, 1H), 5.63 (dd, J¼15.4, 10.9 Hz, 1H), 5.56
(m, 1H), 5.34 (d, J¼1.5 Hz, 1H), 5.18 (dd, J¼15.4, 6.5 Hz,
1H), 5.04 (d, J¼2.0 Hz, 1H), 4.93 (d, J¼2.5 Hz, 1H), 4.30
(dd, J¼9.5, 3.1 Hz, 1H), 4.26 (m, 1H), 4.24 (dd, J¼9.5,
3.7 Hz, 1H), 4.09 (dq, J¼9.5, 6.2 Hz, 1H), 3.94 (dd,
J¼11.8, 2.0 Hz, 1H), 3.90 (dq, J¼9.5, 6.2 Hz, 1H), 3.68
(dd, J¼3.1, 2.0 Hz, 1H), 3.56 (dd, J¼3.7, 1.5 Hz, 1H),
3.49 (s, 3H), 3.46 (t, J¼9.5 Hz, 1H), 3.31 (s, 3H), 3.26 (s,
3H), 3.16 (t, J¼9.5 Hz, 1H), 3.07 (s, 3H), 2.48 (q,
J¼7.2 Hz, 1H), 2.33 (dd, J¼11.8, 4.4 Hz, 1H), 2.30 (s,
3H), 2.18 (m, 1H), 1.97 (t, J¼12.1 Hz, 1H), 1.82 (m, 1H),
1.81 (m, 1H), 1.43 (d, J¼6.2 Hz, 1H), 1.35 (d, J¼6.2 Hz,
1H), 1.24 (q, J¼11.8 Hz, 1H), 1.14 (s, 3H), 1.05 (s, 3H),
1.03 (td, J¼11.8, 2.5 Hz, 1H), 0.97 (d, J¼7.2 Hz, 1H); 13C
NMR (125 MHz, C6D6) d 203.3, 176.4, 147.5, 136.5,
131.7, 129.2, 126.4, 110.8, 98.6, 98.5, 96.3, 84.4, 83.3,
81.6, 81.5, 79.5, 74.6, 72.1, 71.3, 71.1, 69.1, 68.3, 60.8,
60.7, 58.8, 57.9, 49.3, 48.1, 47.5, 39.8, 31.5, 21.6, 19.5,
18.6, 18.4, 18.1, 12.4; MS (FAB) m/z 827 (M+Na)+.
4.1.33. Aglycon 3. To a stirred solution of a diastereomeric
mixture of enone 41a (2.2 mg, 0.0032 mmol) in THF
(0.5 mL) was added a solution of tetrabutylammonium fluo-
ride (Bu4NF) and acetic acid (0.19 mL, 0.18 mmol for
Bu4NF and 0.19 mmol for acetic acid) prepared from
a 1.0 M solution of Bu4NF in THF (0.85 mL) and acetic
acid (0.050 mL). The mixture was stirred at room tem-
perature for 20 h, diluted with brine (5 mL), and extracted
with ether (3ꢂ4 mL). The combined extracts were dried
(Na2SO4) and concentrated. The residual oil was purified
by column chromatography on silica gel (FL-60D, 0.3 g, tol-
uene–acetone 9:1) to give 3 (1.3 mg, 90%) as a colorless oil.
Using the same procedure as described above, 3 (1.7 mg,
96%) was obtained from 41b (2.7 mg, 0.022 mmol). Com-
pound 3: TLC, Rf 0.35 (benzene–acetone 5:1), 0.37 (hex-
ane–EtOAc 3:1); [a]3D1 +6.7 (c 0.045, MeOH); IR (neat)
3450, 2970, 2860, 1710, 1680, 1610, 1200, 1180, 980,
1
760 cmꢀ1; H NMR (400 MHz, C6D6) d 6.40 (dd, J¼13.7,
4.1.35. Auriside B (2). To a stirred suspension of stannous
chloride (3.1 mg, 0.017 mmol), silver perchlorate (3.4 mg,
10.8 Hz, 1H), 6.32 (d, J¼1.0 Hz, 1H), 5.91 (d, J¼13.7 Hz,
1H), 5.65 (dd, J¼15.1, 10.8 Hz, 1H), 5.57 (m, 1H), 5.19
(dd, J¼15.1, 6.3 Hz, 1H), 4.82 (d, J¼3.0 Hz, 1H), 3.94 (m,
1H), 3.87 (dd, J¼11.8, 2.0 Hz, 1H), 2.47 (q, J¼7.3 Hz,
1H), 2.29 (d, J¼1.0 Hz, 1H), 1.99 (m, 1H), 1.97 (dd,
J¼13.2, 11.7 Hz, 1H), 1.82 (dd, J¼13.2, 2.5 Hz, 1H), 1.53
(m, 1H), 1.14 (s, 3H), 1.08 (s, 3H), 1.07 (m, 1H), 0.98 (d,
J¼7.3 Hz, 3H), 0.81 (dt, J¼3.0, 11.2 Hz, 1H). A signal
due to one proton (5-OH) was not observed; 13C NMR
(125 MHz, CDCl3) d 204.7, 176.1, 148.2, 136.1, 131.3,
129.3, 126.1, 110.8, 98.3, 74.3, 71.1, 64.9, 49.1, 47.8,
47.6, 41.1, 34.3, 21.3, 19.3, 18.6, 12.5; HRMS (ESI) calcd
for C21H2979BrNaO6 (M+Na)+ 479.1045, found 479.1041.
ꢁ
˚
0.017 mmol), and MS 4A (45 mg) in ether (0.2 mL) at 0 C
was added a solution of aglycon 3 (2.3 mg, 0.0050 mmol)
and fluorosugar 8 (5.4 mg, 0.023 mmol) in ether (0.9 mL,
2ꢂ0.05 mL rinse). The mixture was stirred at room temper-
ature for 2 h, diluted with saturated aqueous NaHCO3
(5 mL), and extracted with EtOAc (3ꢂ15 mL). The com-
bined extracts were washed with brine (15 mL), dried
(Na2SO4), and concentrated. The residual oil was purified
by column chromatography on silica gel (FL-60D, 1 g, hex-
ane–EtOAc 1:2) followed by HPLC [Develosil ODS-HG-5
(f 4.6ꢂ250 mm), 55% MeCN, flow rate 5 mL minꢀ1, detec-
tion at 215 nm] to give auriside B (2) (2.3 mg, 68%) as a col-
orless oil: Rf 0.30 (hexane–EtOAc 1:2); [a]1D9 ꢀ27 (c 0.080,
1
4.1.34. Auriside A (1). To a stirred suspension of stannous
chloride (3.1 mg, 0.017 mmol), silver perchlorate (3.3 mg,
MeOH); H NMR (500 MHz, C6D6) d 6.40 (dd, J¼13.5,
10.8 Hz, 1H), 6.35 (s, 1H), 5.91 (d, J¼13.5 Hz, 1H), 5.63
(dd, J¼15.3, 10.8 Hz, 1H), 5.57 (m, 1H), 5.54 (dd, J¼9.5,
3.2 Hz, 1H), 5.20 (dd, J¼15.3, 6.6 Hz, 1H), 5.04 (d,
J¼2.0 Hz, 1H), 4.94 (d, J¼1.9 Hz, 1H), 4.25 (m, 1H), 3.99
(dq, J¼9.5, 6.2 Hz, 1H), 3.94 (dd, J¼11.8, 1.9 Hz, 1H),
3.82 (dd, J¼3.2, 2.0 Hz, 1H), 3.73 (br s, 2H), 3.52 (t,
J¼9.5 Hz, 1H), 3.36 (s, 3H), 3.22 (s, 3H), 2.49 (q,
J¼7.2 Hz, 1H), 2.30 (s, 3H), 2.27 (dd, J¼11.8, 4.4 Hz,
˚
0.016 mmol), and MS 4A (43 mg) in ether (0.2 mL) at
0 ꢁC was added a solution of aglycon 3 (2.2 mg,
0.0048 mmol) and fluorosugar 7 (9.9 mg, 0.021 mmol) in
ether (0.1 mL, 3ꢂ0.05 mL rinse). The mixture was stirred
at room temperature for 24 h, diluted with saturated aqueous
NaHCO3 (3 mL), and extracted with EtOAc (3ꢂ10 mL).
The combined extracts were washed with brine (10 mL),

7698
K. Suenaga et al. / Tetrahedron 62 (2006) 7687–7698
5566; (d) Zampella, A.; D’Auria, M. V.; Minale, L.; Debitus,
C.; Roussakis, C. J. Am. Chem. Soc. 1996, 118, 11085–
11088; (e) Zampella, A.; D’Auria, M. V.; Minale, L.;
Debitus, C. Tetrahedron 1997, 53, 3243–3248; (f) Klein, D.;
Braekman, J. C.; Daloze, D.; Hoffmann, L.; Demoulin, V.
J. Nat. Prod. 1997, 60, 1057–1059; (g) Luesch, H.; Yoshida,
W. Y.; Harrigan, G. G.; Doom, J. P.; Moore, R. E.; Paul, V. J.
J. Nat. Prod. 2002, 65, 1945–1948; (h) Pettit, G. R.; Xu,
J.-P.; Doubek, D. L.; Chapuis, J.-C.; Schmidt, J. M. J. Nat.
Prod. 2004, 67, 1252–1255.
1H), 1.97 (t, J¼12.2 Hz, 1H), 1.80 (m, 1H), 1.80 (m, 1H),
1.37 (d, J¼6.2 Hz, 1H), 1.23 (q, J¼11.8 Hz, 1H), 1.16 (s,
3H), 1.06 (s, 3H), 0.97 (d, J¼7.2 Hz, 1H),0.96 (dt, J¼11.8,
1.9 Hz, 1H); 13C NMR (125 MHz, C6D6) d 203.5, 176.5,
155.7, 147.4, 136.5, 131.7, 129.2, 126.4, 110.8, 98.5, 96.3,
81.4, 79.9, 75.0, 74.6, 71.3, 68.6, 60.4, 58.7, 49.3, 48.0,
47.4, 39.6, 31.4, 21.6, 19.4, 18.6, 18.1, 12.4; MS (FAB) m/z
696 (M+Na)+.
8. (a) Smith, A. B. III; Chen, S. S.-Y.; Nelson, F. C.; Reichert,
J. M.; Salvatore, B. A. J. Am. Chem. Soc. 1995, 117, 12013–
12014; (b) Fujiwara, K.; Murai, A.; Y.-Yamashita, M.;
Yasumoto, T. J. Am. Chem. Soc. 1998, 120, 10770–10771; (c)
Paquette, L. A.; Barriault, L.; Pissarnitski, D. J. Am. Chem.
Soc. 1999, 121, 4542–4543; (d) Evans, D. A.; Hu, E.; Burch,
J. D.; Jaeschke, G. J. Am. Chem. Soc. 2002, 124, 5654–5655;
(e) Trost, B. M.; Gunzner, J. L.; Dirat, O.; Rhee, Y. H. J. Am.
Chem. Soc. 2002, 124, 10396–10415; (f) Paterson, I.; Davies,
R. D. M.; Heimann, A. C.; Marquez, R.; Meyer, A. Org. Lett.
2003, 5, 4477–4480.
Acknowledgements
This study was supported in part by the 21st Century COE
program and Grants-in-Aid for Scientific Research from
Ministry of Education, Culture, Sports, Science and Tech-
nology, Suntory Institute for Bioorganic Research, Yamada
Science Foundation, Astellas Foundation for Research on
Medicinal Resources, the Naito Foundation, Shorai Founda-
tion for Science and Technology, University of Tsukuba Re-
search Projects, and Wako Pure Chemical Industries, Ltd.
We are grateful to Daiso Co., Ltd for donation of chiral trityl
glycidyl ether. The IR spectra and optical rotations were re-
corded at Chemical Analysis Center, University of Tsukuba.
9. Mukaiyama, T.; Murai, Y.; Shoda, S. Chem. Lett. 1981,
431–432.
ꢀ
10. Lavallee, P.; Ruel, R.; Grenier, L.; Bissonnette, M. Tetrahedron
Lett. 1986, 27, 679–682.
References and notes
11. Stork, G.; Zhao, K. Tetrahedron Lett. 1989, 30, 287–290.
12. Evans, D. A.; Chapman, K. T.; Carreira, E. M. J. Am. Chem.
Soc. 1988, 110, 3560–3578.
13. (a) Rychnovsky, S. D.; Skalitzky, D. J. Tetrahedron Lett. 1990,
31, 945–948; (b) Evans, D. A.; Rieger, D. L. Tetrahedron Lett.
1990, 31, 7099–7100; (c) Rychnovsky, S. D.; Rogers, B.; Yang,
G. J. Org. Chem. 1993, 58, 3511–3515.
1. Pettit, G. R. Progress in the Chemistry of Organic Natural
Products; Herz, W., Kirby, G. W., Moore, R. E., Steglich, W.,
Tamm, Ch., Eds.; Springer: Wien, 1997; Vol. 70, pp 1–79.
2. (a) Yamada, K.; Kigoshi, H. Bull. Chem. Soc. Jpn. 1997, 70,
1479; (b) Yamada, K.; Ojika, M.; Kigoshi, H.; Suenaga, K.
Drugs from the Sea; Fusetani, N., Ed.; S. Karger AG: Basel,
2000; pp 59–73.
14. Kanai, K.; Wakabayashi, H.; Honda, T. Org. Lett. 2000, 2,
2549–2551.
15. The aldol reaction between aldehyde 20 and methyl propionate
previously reported4 was not reproducible.
3. Sone, H.; Kigoshi, H.; Yamada, K. J. Org. Chem. 1996, 61,
8956–8960.
16. Negishi, E.; Van Horn, D. E.; Yoshida, T. J. Am. Chem. Soc.
1985, 107, 6639–6647.
4. Sone, H.; Suenaga, K.; Bessho, Y.; Kondo, T.; Kigoshi, H.;
Yamada, K. Chem. Lett. 1998, 85–86.
17. Harcken, C.; Martin, S. F. Org. Lett. 2001, 3, 3591–3593.
18. (a) Takai, K.; Kimura, K.; Kuroda, T.; Hiyama, T.; Nozaki, H.
Tetrahedron Lett. 1983, 24, 5281–5284; (b) Jin, H.; Uenishi, J.;
Christ, W. J.; Kishi, Y. J. Am. Chem. Soc. 1986, 108, 5644–
5646.
5. (a) Rios, M.-Y.; Velazquez, F.; Olivo, H. F. Tetrahedron 2003,
59, 6531–6537; (b) Romero-Ortega, M.; Colby, D. A.; Olivo,
H. F. Tetrahedron Lett. 2002, 43, 6439–6441; (c)
Vakalopoulos, A.; Smits, R.; Hoffmann, H.; Martin, R. Eur. J.
Org. Chem. 2002, 1538–1545.
19. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi, M.
Bull. Chem. Soc. Jpn. 1979, 52, 1989–1993.
6. Paterson, I.; Florence, G. I.; Heimann, A. C.; Mackay, A. C.
Angew. Chem., Int. Ed. 2005, 44, 1130–1133.
20. (a) Mitsunobu, O. Synthesis 1981, 1–28; (b) Hughes, D. L.;
Reamer, R. A.; Bergan, J. J.; Grabowski, E. J. J. Am. Chem.
Soc. 1988, 110, 6487–6491.
21. Tolstikov, G. A.; Miftakhov, M. S.; Danilova, N. A.; Velder,
Y. L. Synthesis 1986, 496–499.
7. (a) Barchi, J. J., Jr.; Moore, R. E.; Patterson, G. M. L. J. Am.
Chem. Soc. 1984, 106, 8193–8197; (b) Y.-Yamashita, M.;
Haddock, R. L.; Yasumoto, T. J. Am. Chem. Soc. 1993, 115,
1147–1148; (c) Y.-Yamashita, M.; Seki, T.; Paul, V. J.;
Naoki, H.; Yasumoto, T. Tetrahedron Lett. 1995, 36, 5563–