Stereoselective synthesis of (+)-IKD-8344

Article abstract of DOI:10.1016/j.tet.2007.07.005

Total synthesis of IKD-8344 was accomplished via stepwise cyclodimerization of the monomeric seco acid under Yamaguchi conditions. In the synthesis of the monomeric seco acid, Wittig olefination reaction was employed for an efficient bond formation at C7-C8. The threo-trans oxolane unit for the rings a and c was prepared via intramolecular Williamson ether synthesis of the hydroxyl mesylate prepared via asymmetric aldol reaction. Radical cyclization of a β-alkoxymethacrylate intermediate furnished the threo-cis oxolane unit for the b ring fragment.

Full text of DOI:10.1016/j.tet.2007.07.005

Tetrahedron 63 (2007) 9784–9801
Stereoselective synthesis of (D)-IKD-8344
Woo Han Kim, Sung Kil Hong, Sang Min Lim, Min-Ae Ju, Soon Kyu Jung,
*
Yong Wook Kim, Jae Hoon Jung, Min Sang Kwon and Eun Lee
Department of Chemistry, College of Natural Sciences, Seoul National University NS60, Seoul 151-747, Republic of Korea
Received 8 June 2007; revised 3 July 2007; accepted 3 July 2007
Available online 10 July 2007
Abstract—Total synthesis of IKD-8344 was accomplished via stepwise cyclodimerization of the monomeric seco acid under Yamaguchi
conditions. In the synthesis of the monomeric seco acid, Wittig olefination reaction was employed for an efficient bond formation at C7–
C8. The threo-trans oxolane unit for the rings a and c was prepared via intramolecular Williamson ether synthesis of the hydroxyl mesylate
prepared via asymmetric aldol reaction. Radical cyclization of a b-alkoxymethacrylate intermediate furnished the threo-cis oxolane unit for
the b ring fragment.
Ó 2007 Elsevier Ltd. All rights reserved.
1. Introduction
In the retrosynthetic analysis, synthesis of 1 would be accom-
plished via dimerization of the monomeric seco acid A,
which may be prepared by coupling of the fragments B and
D. The fragment B may be obtained via radical cyclization
of the b-alkoxymethacrylate derivative C, which incorpo-
rates the threo-cis ring b element. The intermediate C should
be accessible from the fragment D (Scheme 1). A successful
total synthesis of 1 would then require development of a
reliable and efficient route to the threo-trans fragment D,
which serves as a precursor for both rings a and c.
In 1992, Minami and co-workers reported a novel 28-mem-
bered ring macrodiolide1 antibiotic IKD-8344 (1) from an
unidentified alkalophilic Actinomycete, strain No. 8344,
which exhibits potent anthelmintic activity against Trichi-
nella spiralis and strong cytotoxicity against L5178Y mouse
leukemia cells with IC50 of 0.54 ng mLꢀ1 2a
They also re-
.
ported X-ray crystal structure of 1 in 1994, which enabled
full stereochemical assignment of this intriguing natural pro-
duct.2b More recently, it was also isolated from Streptomyces
sp. A6792 and selective antifungal activities against the
mycelial form of Candida albicans were noted.3 The unique
bioactivity profile of the molecule makes it an attractive
target for synthetic investigations.
O
3
O
CO2H
threo
trans
c
O
O
O
O
O
O
IKD-8344 (1) is a dimer of a monomeric seco acid A. The
monomeric seco acid A contains three methyl branches and
three oxolane units: a threo (C2–C3)-trans (C3–C6) array
(ring c) is connected to a threo (C9–C10)-cis (C10–C13)
arrangement (ring b), which is flanked by another threo
(C16–C17)-trans (C17–C20) unit (ring a). Efficient and
stereoselective construction of these structural units is the
prerequisite to a successful total synthesis of 1, and Fuchs
and co-workers reported in 2000 a viable solution to this
problem starting from Jacobsen catalytic epoxidation of cy-
cloheptadienyl sulfones.4 More serious problems are encoun-
tered at the assemblage stage; it is difficult to couple these
units and the difficulty therein is manifested by the absence
of reports on the total synthesis of 1 in the literature prior
to our communication in 2006.5 In this paper, we describe a
full account of our efforts in the successful synthesis of 1.
O
O
O
O
O
10
threo
cis
b
O
OR'
threo
trans
17
1
a
O
O
A
O
O
O
RO
Y
O
O
OR'
OR'
O
B
OR"
D
O
RO
C
X
* Corresponding author. Tel.: +82 2 880 6646; fax: +82 2 889 1568; e-mail:
eunlee@snu.ac.kr
Scheme 1. Retrosynthetic analysis.
0040–4020/$ - see front matter Ó 2007 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2007.07.005

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9785
syn-anti
anti-anti
2. Results and discussion
OMs
OMs
O
O
R
S
Efficacy of the known6 and new procedures was examined in
search of an efficient synthesis of the fragment D, and satis-
factory results were obtained following the protocol involv-
ing asymmetric aldol reaction and intramolecular hydroxyl
substitution. In practice, aldol reaction of aldehyde 37 with
the boron enolate of the chiral imide 28 yielded the imide
aldol 4. Lithium borohydride reduction of 4 and selective
TBDPS protection of the primary hydroxyl group of the
diol product afforded the secondary alcohol 5. The threo-
trans oxolane derivative 6 was obtained via mesylation of
the hydroxyl group in 5, acetonide deprotection, and treat-
ment with sodium hexamethyldisilazide. The push toward
1 started in earnest at this point as a reliable supply of the
fragment D was realized following the above reaction
sequence. The primary mesylate 7 prepared from 6 was
converted into aldehyde 8 via TBDPS deprotection and
PCC oxidation (Scheme 2).
8
OH
OH
9
10
1.5 eq.
1.5 eq.
2.0 eq.
2.0 eq. TiCl4
1.1 eq. In
95% (4:1)
~ (1:1.5)
DCM, -78 °C
SiMe3
Br
THF-H2O (1:1), r.t.
toluene, -78 °C
O
B
O
60% (1:2)
CO2i-Pr
CO2i-Pr
Scheme 3. Allylation studies.
tosylation of the primary hydroxyl group of 13, reaction
with the dimethyl acetal 14,12 and iodide substitution. Radi-
cal cyclization13 of b-alkoxymethacrylate 15 proceeded
smoothly to produce selectively (10:1) the threo-cis oxolane
product 16 in good yield14 (Scheme 4).
Ph
Ph
Bu2BOTf
TEA
O
O
1) LAH
9
O
O
N
O
N
2) NaHMDS, BnBr
59%
-40 ~ 0 °C;
OBn
3, -78 °C
84%
O
11
O
OH
4
O
O
2
1) O3; Ph3P
O
2) CH2CHCH2SnBu3
1) LiBH4
O
MgBr2.Et2O
94%
.
H
2) TBDPSCl
imidazole
88%
3
O
1) O3;
O
HO
O
Ph3P
1) MsCl, TEA
2) CSA
OH
O
OH OBn
OBn
13
2) NaBH4
97%
O
O
HO
12 (>20:1 favored)
3) NaHMDS
66%
TBDPSO
TBDPSO
TBDPSO
OH
1) p-TsCl, TEA
2) 14, PPTS
3) NaI
6
5
OMe
MeO2C
MsCl, TEA
98%
74%
OMe
14
O
O
Bu3SnH, Et3B
OMs
OMs
MeO2C
O
O
toluene, -78 °C
91%
H
OBn
1) TBAF
I
2) PCC
78%
15
O
8
7
O
O
MeO2C
Scheme 2. Synthesis of the fragment D.
OBn
16 (10:1 favored)
Next, conditions for stereoselective allylation reactions were
explored. For preparation of the anti-anti homoallylic alco-
hol 9, introduction of the (15R) configuration was required,
and this was problematic.9 For example, Roush allylation
using allyl boronate prepared from isopropyl (S,S)-tartrate
yielded a mixture of the products favoring (1:2) the wrong
isomer 10. Little stereoselectivity materialized when allyl
bromide and indium were employed. Finally, reaction of 8
with allyltrimethylsilane in the presence of titanium chloride
led to a 4:1 mixture of the homoallylic alcohols favoring the
correct isomer 9 (Scheme 3).
Scheme 4. Synthesis of the fragment B.
With fragments B and D in hand, ways were explored for the
efficient coupling of these fragments at C7–C8. First, the
dithiane derivative 17 was prepared from ester 16 in three
steps, and it was allowed to react with mesylate 7 after
exposure to t-BuLi at ꢀ78 ꢁC. The reaction did not proceed.
Triflate 18 and iodide 19 decomposed under the same
reaction conditions. There was little evidence of deuterium
exchange when a sample of 17 was allowed to react with
t-BuLi at ꢀ78 ꢁC, and then with D2O, which suggested
that the desired lithiation of 17 did not occur at low tem-
perature (Scheme 5). When a sample of 17 was allowed
to react with n-BuLi at room temperature15 and then with
mesylate 7, the coupling reaction did not proceed. Instead,
a low yield of an olefinic product was obtained, which was
the product of benzyl alcohol elimination from 17. Benzyl-
oxy elimination upon lithiation has already been reported
in literature.15,16
At this point, the mesyloxy group in 9 was removed via LAH
reduction,10 and the homoallylic ether 11 was obtained after
benzyl protection. Ozonolysis of 11 providedthe correspond-
ing aldehyde, which was converted stereoselectively into the
homoallylic alcohol 12 by reaction with allyltributylstannane
in the presence of magnesium bromide etherate.11 Sodium
borohydride reduction of the aldehyde obtained from 12
via ozonolysis provided diol 13. Iodide 15 was obtained via

9786
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
16
1) LiBH4
2) D-M periodinane
3) HSCH2CH2CH2SH, LiBF4
75%
n-BuLi
(Decomposition)
(No reaction)
HMPA
22
21
THF
-20 °C
or 23
7
(No reaction)
t-BuLi
1) MeONa
(Decomposition)
or 18
THF
O
O
S
2) TIPSOTf, 2,6-lutidine, DMAP
3) CSA
(Decomposition)
(No reaction)
or 19
or D2O
HMPA
-78 °C
O
S
OBn
OTf
4) p-TsCl, TEA
MeO2C
TBSO
17
4
5) DBU
OMs
4
6) TBAF
7) MsCl, TEA
24%
I2
I
22
Tf2O
Ph3P
O
O
O
6
base
90%
imidazole
94%
TBDPSO
TBDPSO
23
18
19
Scheme 7. Attempted model dithiane lithiation and epoxide alkylation
reactions.
Scheme 5. Attempted dithiane coupling reactions of the fragments B and D.
For more detailed studies on lithiation, the model dithiane 20
was prepared from 6 via benzylation, TBDPS deprotection,
oxidation, and dithiane formation. As in the case of 17, there
was little evidence of deuterium exchange for 20 when it was
allowed to react with t-BuLi at ꢀ78 ꢁC, and then with D2O.
The situation changed when the corresponding PMB ether
21 was employed;17 a reasonable degree (58%) of deuterium
exchange was noted upon sequential exposure to t-BuLi at
ꢀ78 ꢁC and then D2O. Unfortunately, the lithiated sample
of 21 did not react with triflate 18 (Scheme 6).
O
MeO
O
OBn
24
1) DIBAL
2) TMSCN, ZnI2
63%
(No reaction)
(No reaction)
19
LiHMDS
O
TMSO
or 26
THF
CN
OBn
-78 °C
25
Epoxides were considered to be viable partners in these
coupling reactions as the desired reaction product would
be obtained via epoxide alkylation followed by intramole-
cular hydroxyl substitution. The candidate epoxide 22 was
prepared from aldol 4, but the mesyloxy elimination in 22
was the only reaction observed from the reaction between
the lithiated sample of 21 and epoxide 22. The reaction
with epoxide 23 was also fruitless (Scheme 7). From these
reaction results, it was concluded that dithiane alkylation
is untenable for coupling reactions of substrates like 17,
20, and 21 due to steric reasons.
1) MsCl, TEA
2) CSA
O
5
3) TsCl, TEA
4) DBU
TBDPSO
OMs
26
44%
Scheme 8. Attempted model cyanohydrin TMS ether alkylation reactions.
SO2Ph
1) I2, Ph3P
O
imidazole
LDA, THF
(Epimerization)
6
2) NaSO2Ph
77%
TBDPSO
-78 °C;
octanal
27
The cyanohydrin derivative 25 was prepared from (+)-
methyl 8-epi-nonactate benzyl ether (24)18 for further model
studies. Unfortunately, the lithiated sample of 25 reacted
with neither iodide 19 nor epoxide 26 prepared from aceto-
nide alcohol 5 (Scheme 8). It was concluded that cyano-
hydrin derivatives like 25 also suffer from fatal steric
hindrance problems in the proposed coupling reactions.
Scheme 9. Attempted model Julia coupling reaction of the fragment D.
octanal upon lithiation, and the partial epimerization was the
only reaction observed (Scheme 9).
Reaction of the alternative sulfone 28, prepared from the B
fragment 16, yielded more promising results. After lithia-
tion, it reacted with iodide 19, and the desired product 29
was obtained in 43% yield. Unfortunately, the usual lithia-
tion–oxidation protocol using oxaziridine 30 did not pro-
ceed, and it was not possible to obtain the desired ketone
product. Little evidence of deuterium exchange for 29 was
noted when it was allowed to react with n-BuLi, and then
with D2O, which implied that there were fundamental prob-
lems in the lithiation step (Scheme 10).
Next, the sulfone derivative 27 was prepared from alcohol 6
for potential use in the coupling reaction. It did not react with
6
1) BnBr, NaHMDS or PMBCl, NaHMDS, TBAI
2) TBAF
3) SO pyr, TEA, DMSO
.
3
4) HSCH2CH2CH2SH, LiBF4
D2O
20
(No reaction)
OR
t-BuLi
THF, HMPA
-78 °C
O
S
After considerable exploration, it was found that the crucial
coupling at C7–C8 was possible employing Wittig olefina-
tion reaction. Aldehyde 31 was prepared from the primary
alcohol 6. Ester 16 was converted into the corresponding
phosphonium salt via lithium borohydride reduction, iodide
substitution, and reaction with triphenylphosphine, and the
ylide obtained from the phosphonium salt reacted with
58% D
S
D2O
21
or 18
(Decomposition)
20 (R=Bn) 66%
21 (R=PMB) 41%
Scheme 6. Attempted model dithiane lithiation and triflate alkylation
reactions.

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9787
1) LiBH4
O
O
O
O
O
2) I2, Ph3P, imidazole
TBDPSO2C
16
3) NaSO2Ph
86%
PhO2S
OBn
O
34
OH
28
n-BuLi, THF, HMPA; 19
43% (s.m. 36%)
1) TBDPSCl, imidazole, DMAP
2) H2, Pd(OH)2/C
88%
O
O
33
O
H2, Pd/C, MeOH, r.t. 1 h
93%
SO2Ph
29
OBn
TBDPSO
O
O
O
O
(No reaction)
n-BuLi
30
HO2C
Ph
N
SO2Tol
or D2O
THF
O
35
OH
(No reaction)
30
-40 °C
Scheme 10. Attempted sulfone alkylation and oxidation reactions of the
fragments B and D.
CDIC
O
O
Cs2CO3;
O
O
DMAP
28%
O
aldehyde 31 in good yield to produce olefin 32. A mixture of
epoxides was obtained from 32 via oxidation with m-CPBA.
Reaction of the mixture with excess lithium aluminum
hydride produced diol products resulting from concomitant
TBDPS deprotection. Dess–Martin oxidation of the diol
mixture, and sodium chlorite oxidation of the aldehyde func-
tionality provided regioselectively (w12:1) the correct keto
carboxlylic acid 33. Use of DIBAL as the reducing agent
eventually produced the alternative ketone as the major
product (Scheme 11).
O
(s.m. 59%)
36
Scheme 12. Synthesis of the monomeric seco acid and attempted
cyclodimerization.
33
Cl3PhCOCl, TEA;
34, DMAP
92%
O
1) HCl
SO pyr
.
3
O
O
O
2) H2
TEA
H
Pd(OH)2/C
86%
6
DMSO
89%
TBDPSO
O
O
O
31
O
O
O
O
O
O
O
O
1) LiBH4
O
O
O
O
O
O
2) I2, Ph3P
imidazole
O
O
TBDPSO
16
3) Ph3P
OBn
4) n-BuLi, THF
-78 °C; 31
86%
32
OH
OBn
1) m-CPBA
2) LAH
CO2H
CO2TBDPS
3) D-M periodinane
4) NaClO2, NaH2PO4
70%
O
O
37
38
Cl3PhCOCl, TEA, DMAP
toluene, reflux
65%
O
O
O
HO2C
O
OBn
1
33 (12:1 favored)
Scheme 13. Synthesis of IKD-8344.
Scheme 11. Wittig coupling reactions of the fragments B and D.
The secondary alcohol 34 was obtained from 33 via TBDPS
protection and hydrogenolysis. The monomeric seco acid 35
was prepared via hydrogenolysis. The direct macrodiolide
formation of the monomeric seco acid 35 did not proceed.
A relatively low yield of the macrolide product 36 was
obtained in the presence of 2-chloro-1,3-dimethylimidazol-
inium chloride (CDIC) and Cs2CO319 (Scheme 12).
Efficacy of the ring-forming olefin metathesis reaction was
investigated for the crucial C7–C8 coupling in the synthe-
sis of the monomeric seco acid. The unsaturated carboxylic
acid 39 was prepared from aldehyde 31 in four steps, and
the keto alcohol 40 was obtained from the B fragment
16. Coupling reaction of 39 and 40 proceeded efficiently
under Yamaguchi conditions and the resulting keto ester
was converted into the silyl enol ether 41. In the presence
of the second generation Grubbs–Hoveyda catalyst,22
no trace of the product resulting from olefin-silyl enol
ether ring-forming metathesis reaction23 was found in the
reaction mixture. The low-yield products from the reac-
tion were tentatively identified as the tail–tail dimers
(Scheme 14).
Coupling reaction of 33 and 34 proceeded efficiently under
standard Yamaguchi conditions to afford ester 37. The
dimeric seco acid 38 was obtained efficiently via TBDPS
deprotection and hydrogenolysis. IKD-8344 (1)20 was
finally obtained upon lactonization of 38 under modified
Yamaguchi conditions21 (Scheme 13).

9788
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
31
16
1) LiBH4
Unless otherwise specified, all reactions were conducted un-
-
1) Ph3P+CH3Br , n-BuLi
der a slight positive pressure of dry nitrogen. The usual
work-up refers to washing the quenched reaction mixture
with brine, drying the organic extracts over anhydrous
MgSO4, and evaporating under reduced pressure using a
rotary evaporator.
2) D-M periodinane
3) MeMgI
2) TBAF
3) D-M periodinane
4) NaClO2, NaH2PO4
39%
4) D-M periodinane
5) H2, Pd/C
70%
O
O
O
HO
All solvents used in the reactions were dried under nitrogen
atmosphere. THF was distilled from Na-benzophenone and
CH2Cl2 was distilled from P2O5. Benzene was washed
with concd H2SO4, distilled from Na-benzophenone, and
O
O
OH
39
40
1) Cl3PhCOCl, TEA;
40, DMAP
2) TBSCl, KHMDS
86%
N
N
Mes
Mes
Cl
˚
stored over 4 A molecular sieves. Et2O was distilled from
LAH. CH3CN was distilled from CaH2 and stored over
Ru
O
Cl
˚
4 A molecular sieves. Pyridine and TEA was distilled over
˚
KOH and stored over 4 A molecular sieves.
42
0.2 eq. 42
O
O
(Dimerization)
(tail-tail)
benzene, reflux
25%
O
4.1.1. Alcohol 5. n-Bu2BOTf (1.0 M in CH2Cl2, 10.7 mL)
was added to a solution of imide 2 (3.25 g, 13.9 mmol) in
CH2Cl2 (14 mL) at ꢀ40 ꢁC, followed within 1 min by
TEA (1.78 mL, 12.7 mmol). The reaction mixture was
allowed to warm to 0 ꢁC and stirred for 30 min at this tem-
perature. Upon cooling to ꢀ78 ꢁC, a solution of aldehyde
3 (1.47 g, 9.29 mmol) in CH2Cl2 (5 mL) was introduced
over 3 min. The reaction mixture was stirred for 1 h at
ꢀ78 ꢁC, warmed to 0 ꢁC over 15 min, and stirred at 0 ꢁC
for 3.5 h. The reaction was quenched by addition of water
(10 mL). The reaction mixture was extracted with CH2Cl2
(15 mLꢂ3) and the organic extracts were washed with satu-
rated NH4Cl solution (15 mL) and brine (15 mL), dried over
MgSO4, filtered, and concentrated. The boron containing
compounds in the residue was azeotroped off a few times
with CH3OH. Purification of the residue by flash column
chromatography (Hex–EtOAc, 3:1) yielded aldol 4 (3.05 g,
84%). Rf 0.25 (Hex–EtOAc, 3:1). 1H NMR (300 MHz,
CDCl3): d 7.45–7.30 (m, 5H), 5.70 (d, 1H, J¼7.2 Hz),
4.85–4.76 (m, 1H), 4.13–4.03 (m, 2H), 4.01–3.95 (m, 1H),
3.84–3.79 (m, 1H), 3.56–3.51 (m, 1H), 3.21 (d, 1H,
J¼3.1 Hz), 1.88–1.49 (m, 4H), 1.42 (s, 3H), 1.36 (s, 3H),
1.25 (d, 3H, J¼6.9 Hz), 0.89 (d, 3H, J¼6.5 Hz). 13C NMR
(75 MHz, CDCl3): d 176.7, 152.5, 133.0, 128.64, 128.55,
125.4, 108.6, 78.7, 75.9, 71.3, 69.2, 54.6, 42.4, 30.3, 30.0,
26.8, 25.6, 14.2, 10.4. MS m/z (CI, relative intensity): 392
(M++1, 10), 334 (100), 234 (39), 178 (28), 101 (45).
HRMS (CI) calcd for C21H30O6N (M++1) 392.2073, found
392.2075. [a]2D8 ꢀ3.2 (c 3.74, CHCl3).
OTBS
O
O
41
Scheme 14. Attempted synthesis of the seco acid unit via ring-forming
metathesis reaction.
3. Conclusions
In the present synthesis, radical cyclization of a b-alkoxyme-
thacrylate intermediate furnished the threo-cis oxolane unit.
The threo-trans oxolane unit was prepared via intramolecu-
lar Williamson ether synthesis of the hydroxyl mesylate
prepared via asymmetric aldol reaction. The crucial C7–C8
bond formation was accomplished via Wittig olefination,
epoxidation, regioselective reduction by lithium aluminum
hydride, and Dess–Martin oxidation. The present synthesis
presents another example of application of b-alkoxymeth-
acrylate radical cyclization reactions for stereoselective con-
struction of complex oxacyclic natural products.
4. Experimental
4.1. General
1H and 13C NMR spectra were obtained on the 300, 400, 500,
and 600 MHz spectrometer. Chemical shift values were
recorded as parts per million relative to tetramethylsilane
as an internal standard unless otherwise indicated, and cou-
pling constants as hertz. Mass spectra were recorded using
electron impact (EI), chemical ionization (CI), and fast
atom bombardment (FAB) method. Significant fragments
are reported as m/z (relative intensity). Optical rotation
data were obtained on a automatic polarimeter.
LiBH4 (2.0 M in THF, 8.9 mL) was added to a suspension of
aldol 4 (3.50 g, 8.94 mmol) in Et2O (89 mL) at 0 ꢁC and the
reaction mixture was allowed to warm to room temperature.
After 30 min, the reaction was quenched by addition of
saturated NH4Cl solution (50 mL). The reaction mixture
was extracted with EtOAc (50 mLꢂ2) and the organic ex-
tracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography
(Hex–EtOAc, 1:1) gave the corresponding diol. Rf 0.20
(Hex–EtOAc, 1:1).
The progress of reaction was checked on TLC plates, and the
spots were visualized under 254 nm UV light and/or charring
after dipping the TLC plate into vanillin solution (9.0 g of
vanillin and 1.5 mL of concentrated sulfuric acid in 300 mL
of methanol), KMnO4 solution (3 g of KMnO4, 20 g of
K2CO3, and 5 mL of 5% NaOH solution in 300 mL of water),
or phosphomolybdic acid solution (250 mg phosphomolyb-
dic acid in 50 mL ethanol). Column chromatography was
performed on silica gel using hexane–EtOAc (v/v). The
solvents were simple distilled unless otherwise noted.
Imidazole (0.910 g, 13.4 mmol) and TBDPSCl (2.74 mL,
10.7 mmol) were added to a solution of the diol in CH2Cl2
(30 mL) at room temperature. After 1 h, the reaction was
quenched by addition of saturated NH4Cl solution
(20 mL). The reaction mixture was extracted with CH2Cl2
(20 mLꢂ3), and the organic extracts were washed with brine

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9789
(20 mL), dried over MgSO4, filtered, and concentrated. Pu-
rification of the residue by flash column chromatography
(Hex–EtOAc, 1:1) provided alcohol 5 (3.59 g, 88% for two
steps). Rf 0.72 (Hex–EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): d 7.68–7.65 (m, 4H), 7.47–7.37 (m, 6H), 4.14–
4.03 (m, 2H), 3.90–3.83 (m, 1H), 3.75 and 3.67 (ABX,
2H, JAB¼10.0 Hz, JAX¼4.1 Hz, JBX¼6.0 Hz), 3.60–3.51
(m, 1H), 2.95 (d, 1H, J¼4.0 Hz), 1.85–1.74 (m, 2H), 1.68–
1.45 (m, 3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.06 (s, 9H), 0.92
(d, 3H, J¼7.1 Hz). 13C NMR (75 MHz, CDCl3): d 135.6,
135.5, 132.8, 129.9, 129.8, 127.8, 108.8, 76.4, 74.1, 69.6,
68.5, 39.3, 30.7, 30.6, 27.0, 26.8, 25.8, 19.1, 10.4. IR
(neat): nmax¼3500, 3070, 3048, 2931, 2859, 1471, 1427,
C25H39O6SiS (M++1) 495.2236, found 495.2230. [a]2D3
+1.9 (c 0.65, CHCl3).
NaHMDS (1.0 M in THF, 1.4 mL) was added to a solution of
the diol (0.34 g, 0.69 mmol) in THF (7 mL) at 0 ꢁC. The re-
action mixture was allowed to warm to room temperature.
After 2 h, the reaction was quenched by addition of saturated
NH4Cl solution (5 mL). The reaction mixture was extracted
with Et2O (5 mLꢂ2) and the organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
2:1) gave alcohol 6 (0.22 g, 80%). Rf 0.52 (Hex–EtOAc,
1
2:1). H NMR (300 MHz, CDCl3): d 7.70–7.69 (m, 4H),
1369, 1216, 1157, 1110, 1066, 823, 703, 613, 505 cmꢀ1
.
7.45–7.36 (m, 6H), 4.06–3.98 (m, 1H), 3.95–3.90 (m, 1H),
3.77–3.67 (m, 2H), 3.59 and 3.46 (ABX, 2H, JAB¼11.4 Hz,
JAX¼2.9 Hz, JBX¼6.3 Hz), 2.03–1.54 (m, 5H), 1.07 (s, 9H),
0.97 (d, 3H, J¼6.8 Hz). 13C NMR (75 MHz, CDCl3):
d 135.6, 133.9, 129.5, 127.6, 80.3, 79.0, 66.1, 65.1, 40.8,
29.8, 27.6, 26.9, 19.4, 13.1. IR (neat): nmax¼3444, 3070,
3048, 2929, 1471, 1427, 1390, 1361, 1187, 1112, 823,
701, 613 cmꢀ1. MS m/z (CI, relative intensity): 399
(M++1, 33), 341 (53), 321 (45), 303 (44), 291 (24), 243
(100), 95 (54). HRMS (CI) calcd for C24H35O3Si (M++1)
399.2355, found 399.2353. [a]2D3 +6.2 (c 0.35, CHCl3).
MS m/z (CI, relative intensity): 457 (M++1, 38), 399 (29),
341 (100), 321 (36), 303 (28), 269 (15), 263 (39), 243
(49), 199 (49). HRMS (CI) calcd for C27H41O4Si (M++1)
457.2774, found 457.2773. [a]2D3 +9.1 (c 0.53, CHCl3).
4.1.2. Alcohol 6. TEA (1.12 mL, 8.03 mmol) and MsCl
(0.540 mL, 6.89 mmol) were added to a solution of alcohol
5 (2.62 g, 5.74 mmol) in CH2Cl2 (12 mL) at 0 ꢁC, and then
the reaction mixture was allowed to warm to room tempera-
ture. The reaction mixture was stirred for 1 h, and the reac-
tion was quenched by addition of saturated NH4Cl solution
(6 mL). The reaction mixture was extracted with CH2Cl2
(10 mLꢂ3), and the organic extracts were washed with brine
(10 mL), dried over MgSO4, and concentrated. Purification
of the residue by flash column chromatography (Hex–
EtOAc, 2:1) provided the corresponding mesylate (3.01 g,
98%). Rf 0.53 (Hex–EtOAc, 2:1). 1H NMR (300 MHz,
CDCl3): d 7.67–7.62 (m, 4H), 7.46–7.25 (m, 6H), 5.00–
4.94 (m, 1H), 4.07–4.00 (m, 2H), 3.61–3.51 (m, 3H), 2.94
(s, 3H), 1.96–1.80 (m, 3H), 1.62–1.59 (m, 2H), 1.40 (s, 3H),
1.35 (s, 3H), 1.07 (s, 9H), 0.91 (d, 3H, J¼6.9 Hz). 13C
NMR (75 MHz, CDCl3): d 135.53, 135.49, 133.3, 133.2,
129.8, 127.7, 108.8, 83.6, 75.6, 69.2, 64.8, 38.8, 38.3,
4.1.3. Mesylate 7. TEA (0.160 mL, 1.16 mmol) and MsCl
(0.078 mL, 0.99 mmol) were added to a solution of alcohol
6 (0.33 g, 0.83 mmol) in CH2Cl2 (2 mL) at 0 ꢁC and the re-
action mixture was allowed to warm to room temperature.
The reaction mixture was stirred for 1 h, and the reaction
was quenched by addition of saturated NH4Cl solution
(2 mL). The reaction mixture was extracted with CH2Cl2
(5 mLꢂ3). The organic extracts were washed with brine
(5 mL), dried over MgSO4, filtered, and concentrated. Puri-
fication of the residue by flash column chromatography
(Hex–EtOAc, 2:1) gave mesylate 7 (0.387 g, 98%). Rf 0.53
1
(Hex–EtOAc, 2:1). H NMR (300 MHz, CDCl3): d 7.68–
29.7, 28.9, 26.9, 26.8, 25.6, 19.1, 10.9. IR (neat): nmax
¼
7.64 (m, 4H), 7.44–7.32 (m, 6H), 4.20–4.14 (m, 3H),
3.92–3.90 (m, 1H), 3.69 and 3.63 (ABX, 2H, JAB¼9.8 Hz,
JAX¼4.4 Hz, JBX¼6.0 Hz), 2.90 (s, 3H), 2.02–1.97 (m,
2H), 1.81–1.62 (m, 3H), 1.05 (s, 9H), 0.96 (d, 3H,
J¼6.8 Hz). 13C NMR (75 MHz, CDCl3): d 135.64, 135.63,
133.8, 129.6, 127.6, 80.9, 76.1, 72.0, 66.1, 40.8, 37.6,
29.5, 28.1, 26.9, 19.4, 13.1. IR (neat): nmax¼2931, 2867,
2827, 1359, 1176, 1112, 958, 823, 742, 703, 615,
505 cmꢀ1. MS m/z (CI, relative intensity): 477 (M++1, 63),
419 (92), 399 (48), 381 (39), 277 (42), 125 (86), 95 (100).
HRMS (CI) calcd for C25H37O5SiS (M++1) 477.2131, found
477.2134. [a]2D3 +1.9 (c 2.88, CHCl3).
3072, 3046, 2987, 2956, 2933, 2857, 1471, 1427, 1359,
1176, 1112, 908, 742, 703, 615, 505 cmꢀ1. MS m/z (FAB, rela-
tive intensity): 535 (M++1, 4), 323 (18), 303 (14), 277 (56),
269 (14), 239 (19), 217 (22), 199 (41), 183 (24), 135 (100),
125 (61). HRMS (FAB) calcd for C28H43O6SiS (M++1)
535.2549, found 535.2546. [a]2D3 ꢀ11.5 (c 0.39, CHCl3).
CSA (59.9 mg, 0.260 mmol) was added to a solution of the
mesylate (2.76 g, 5.16 mmol) in CH3OH (52 mL) at room
temperature. After stirring for 2 h, the reaction was
quenched by addition of TEA (0.036 mL) and the reaction
mixture was concentrated. Purification of the residue by
flash column chromatography (EtOAc) afforded the corre-
4.1.4. Aldehyde 8. TBAF (1.0 M in THF, 2.9 mL) was added
to a solution of mesylate 7 (1.3 g, 2.7 mmol) in THF (27 mL)
at room temperature and the reaction mixture was stirred for
2 h. After evaporation of the solvent, the residue was purified
by flash column chromatography (EtOAc) to give the corre-
sponding primary alcohol (0.60 g, 95%). Rf 0.53 (EtOAc).
1H NMR (300 MHz, CDCl3): d 4.35–4.15 (m, 3H), 3.87–
3.75 (m, 1H), 3.61–3.56 (m, 2H), 3.06 (s, 3H), 3.03–2.99
(m, 1H), 2.21–2.02 (m, 2H), 1.82–1.16 (m, 3H), 0.83 (d,
3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 85.1, 76.4,
71.1, 67.9, 40.6, 37.6, 31.1, 27.3, 13.3. IR (neat):
nmax¼3419, 3018, 2967, 2935, 2884, 1351, 1174, 1087,
954, 528 cmꢀ1. MS m/z (CI, relative intensity): 239
1
sponding diol (2.14 g, 84%). Rf 0.55 (EtOAc). H NMR
(300 MHz, CDCl3): d 7.69–7.62 (m, 4H), 7.46–7.37 (m,
6H), 5.02–4.97 (m, 1H), 3.70–3.58 (m, 4H), 3.46–3.44 (m,
1H), 2.94 (s, 3H), 2.85 (s, 2H), 1.95–1.85 (m, 3H), 1.51–
1.46 (m, 2H), 1.07 (s, 9H), 0.91 (d, 3H, J¼6.9 Hz). 13C
NMR (75 MHz, CDCl3): d 135.59, 135.55, 133.4, 133.3,
129.8, 127.8, 127.6, 83.7, 71.7, 66.6, 64.9, 38.8, 38.3,
29.7, 28.6, 26.9, 19.2, 10.8. IR (neat): nmax¼3390, 3072,
2931, 2857, 1471, 1427, 1390, 1336, 1172, 1112, 908,
823, 740, 615, 505 cmꢀ1. MS m/z (CI, relative intensity):
495 (M++1, 0.6), 377 (8), 257 (15), 239 (31), 199 (100),
179 (79), 137 (14), 75 (35). HRMS (CI) calcd for

9790
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
(M++1, 87), 221 (100), 179 (38), 125 (57), 107 (42), 83 (30).
HRMS (CI) calcd for C9H19O5S (M++1) 239.0953, found
239.0953. [a]2D4 +0.5 (c 1.08, CHCl3).
NaHMDS (1.0 M in THF, 0.49 mL), BnBr (0.060 mL,
0.49 mmol) were added to a solution of the homoallylic
alcohol 9A (75 mg, 0.41 mmol) in THF–DMF (5:1,
5.8 mL) at 0 ꢁC and the reaction mixture was allowed to
warm to room temperature. After 2 h, the reaction was
quenched by addition of 2 N HCl (2 mL). The reaction mix-
ture was extracted with Et2O (10 mLꢂ2). The organic
extracts were washed with brine (10 mLꢂ3), dried over
MgSO4, filtered, and concentrated. Purification of the resi-
due by flash column chromatography (Hex–EtOAc, 8:1)
gave benzyl ether 11 (0.10 g, 90%). Rf 0.56 (Hex–EtOAc,
A solution of the alcohol (0.940 g, 3.94 mmol) in CH2Cl2
(10 mL) was added to a stirred solution of PCC (1.70 g,
˚
7.89 mmol) and 4 A molecular sieve (1.70 g) in CH2Cl2
(40 mL) at room temperature. After stirring for 2 h, the reac-
tion mixture was diluted with hexane (50 mL) and filtered
through a short pad of silica gel. Concentration of the filtrate
and purification of the residue by flash column chromato-
graphy (Hex–EtOAc, 1:2) gave aldehyde 8 (0.764 g, 82%).
1
8:1). H NMR (300 MHz, CDCl3): d 7.34–7.27 (m, 5H),
1
Rf 0.47 (Hex–EtOAc, 1:2). H NMR (300 MHz, CDCl3):
5.98–5.87 (m, 1H), 5.13–5.02 (m, 2H), 4.53–4.50 (ABq,
2H, JAB¼11.7 Hz), 4.07–4.01 (m, 1H), 3.97–3.89 (m, 1H),
3.67–3.62 (m, 1H), 2.38–2.23 (m, 2H), 2.07–1.88 (m, 3H),
1.61–1.39 (m, 2H), 1.20 (d, 3H, J¼6.0 Hz), 0.85 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 139.1, 136.1,
128.2, 127.6, 127.3, 116.3, 80.1, 79.5, 74.7, 71.3, 40.4,
34.3, 33.9, 30.1, 21.4, 10.2. IR (neat): nmax¼3066, 3029,
2967, 2933, 1641, 1496, 1454, 1376, 1070, 1027, 910,
734, 696 cmꢀ1. MS m/z (CI, relative intensity): 275
(M++1, 42), 233 (55), 167 (22), 125 (15), 91 (49), 85
(100). HRMS (CI) calcd for C18H27O2 (M++1) 275.2011,
found 275.2016. [a]2D6 ꢀ8.9 (c 0.83, CHCl3).
d 9.73 (d, 1H, J¼2.4 Hz), 4.35–4.25 (m, 1H), 4.22–4.10
(m, 3H), 3.06 (s, 3H), 2.54–2.44 (m, 1H), 2.17–2.09 (m,
2H), 1.77–1.58 (m, 2H), 1.07 (d, 3H, J¼3.4 Hz). 13C NMR
(75 MHz, CDCl3): d 203.6, 79.8, 76.6, 71.3, 51.2, 37.6,
30.0, 27.4, 10.3. IR (neat): nmax¼2969, 2938, 2728, 1725,
1353, 1174, 954, 821, 528 cmꢀ1. [a]D24 +26.8 (c 1.16,
CHCl3).
4.1.5. Homoallylic alcohols 9 and 10. TiCl4 (1.0 M in
CH2Cl2, 1.4 mL) was added to a solution of aldehyde 8
(0.17 g, 0.72 mmol) in CH2Cl2 (36 mL) at ꢀ78 ꢁC under
N2. After 15 min, allyltrimethylsilane (0.17 mL, 1.1 mmol)
was added to the solution, and the resulting solution was
stirred for 30 min at ꢀ78 ꢁC. The reaction was quenched
by addition of saturated NaHCO3 solution (20 mL). The
reaction mixture was extracted with CH2Cl2 (30 mLꢂ3),
and the organic extracts were dried over MgSO4, filtered,
and concentrated. Purification of the residue by flash column
chromatography (Hex–EtOAc, 1:1) gave a mixture (4:1) of
the homoallylic alcohols 9 and 10. Rf 0.34 (Hex–EtOAc,
1:1).
O3 was introduced to a stirred solution of the benzyl ether
11 (183 mg, 0.670 mmol) in CH2Cl2 (7 mL) over a period
of 10 min at ꢀ78 ꢁC. Following the addition of PPh3
(525 mg, 2.00 mmol), the reaction mixture was allowed to
warm to room temperature. After stirring for 3 h, the solvent
was evaporated and the residue was purified by flash column
chromatography (Hex–EtOAc, 4:1) to give the correspond-
ing aldehyde (179 mg, 97%). Rf 0.31 (Hex–EtOAc, 4:1).
MgBr2$Et2O (751 mg, 2.91 mmol) and allyltributylstan-
nane (0.450 mL, 1.45 mmol) were added to a solution of
the aldehyde (268 mg, 0.970 mmol) in CH2Cl2 (5 mL) at
room temperature. After 1 h, the reaction was quenched
by addition of 2 N HCl (3 mL). The reaction mixture
was extracted with CH2Cl2 (5 mLꢂ3), dried over
MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
4:1) gave the homoallylic alcohol 12 (300 mg, 97%). Rf
0.19 (Hex–EtOAc, 4:1). 1H NMR (300 MHz, CDCl3):
d 7.35–7.27 (m, 5H), 5.92–5.78 (m, 1H), 5.09 (dd, 2H,
J¼13.6, 6.5 Hz), 4.56 and 4.49 (ABq, 2H, JAB¼11.4 Hz),
4.13–4.03 (m, 1H), 3.99–3.93 (m, 1H), 3.90–3.78 (m, 2H),
2.92 (d, 1H, J¼4.2 Hz), 2.27–2.23 (m, 2H), 2.11–1.96 (m,
3H), 1.70–1.38 (m, 4H), 1.19 (d, 3H, J¼6.1 Hz), 0.84 (d,
3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 138.6,
135.2, 128.4, 127.8, 127.6, 117.3, 79.7, 77.8, 74.9, 71.1,
69.1, 42.2, 40.1, 35.6, 33.8, 31.0, 21.4, 10.0. IR (neat):
nmax¼3419, 3066, 3029, 2967, 2929, 1454, 1376, 1068,
1027, 997, 734, 698 cmꢀ1. MS m/z (CI, relative intensity):
319 (M++1, 38), 301 (10), 277 (10), 233 (10), 211 (29),
193 (15), 169 (19), 107 (18), 91 (28), 85 (100). HRMS
(CI) calcd for C20H31O3 (M++1) 319.2273, found
319.2276. [a]2D5 +28.6 (c 0.87, CHCl3).
4.1.6. Homoallylic alcohol 12. A mixture of the homoallylic
alcohols 9 and 10 (0.730 g, 2.62 mmol) in Et2O (10 mL) was
added dropwise to a suspension of LAH (498 mg,
13.1 mmol) in Et2O (26 mL) at 0 ꢁC. The reaction mixture
was stirred for 2 h at room temperature. The reaction was
quenched by addition of water (2 mL) and 15% aqueous
NaOH solution (0.5 mL). Filtration, concentration, and puri-
fication of the residue by flash column chromatography
(Hex–EtOAc, 2:1) gave the homoallylic alcohols 9A
(0.319 g, 66%) and 10A (0.077 g, 16%). Compound 9A: Rf
0.70 (Hex–EtOAc, 2:1). 1H NMR (300 MHz, CDCl3):
d 6.02–5.88 (m, 1H), 5.09 (dd, 2H, J¼7.6, 13.2 Hz), 4.76
(s, 1H), 4.15–4.07 (m, 1H), 3.90–3.82 (m, 1H), 3.66–3.60
(m, 1H), 2.41–2.63 (m, 1H), 2.18–2.09 (m, 2H), 2.04–1.95
(m, 1H), 1.66–1.34 (m, 3H), 1.20 (d, 3H, J¼6.0 Hz), 0.75
(d, 3H, J¼6.8 Hz). 13C NMR (75 MHz, CDCl3): d 135.3,
116.6, 84.5, 75.6, 75.5, 43.4, 38.7, 33.4, 32.5, 21.0, 12.6.
IR (neat): nmax¼3465, 3073, 2969, 2931, 1639, 1459,
1432, 1378, 1083, 1000, 908, 873 cmꢀ1. MS m/z (CI, relative
intensity): 185 (M++1, 3), 177 (12), 167 (49), 149 (100), 113
(43), 85 (11). HRMS (CI) calcd for C11H21O2 (M++1)
185.1541, found 185.1541. [a]2D6 ꢀ27.6 (c 0.65, CHCl3).
Compound 10A: Rf 0.61 (Hex–EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): d 5.96–5.87 (m, 1H), 5.15–5.06 (m,
2H), 4.15–4.08 (m, 1H), 4.01–3.94 (m, 1H), 3.81–3.76 (m,
1H), 3.19 (d, 1H, J¼6.8 Hz), 2.28–2.21 (m, 2H), 2.08–
2.00 (m, 2H), 1.76–1.60 (m, 2H), 1.52–1.42 (m, 1H), 1.21
(d, 3H, J¼6.1 Hz), 0.87 (d, 3H, J¼7.1 Hz).
4.1.7. Iodide 15. O3 was introduced to a stirred solution
of the homoallylic alcohol 12 (867 mg, 2.72 mmol) in
CH2Cl2 (54 mL) over a period of 15 min at ꢀ78 ꢁC. Follow-
ing addition of PPh3 (2.14 g, 8.17 mmol), the reaction

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9791
mixture was allowed to warm to room temperature. After
stirring for 3 h, concentration of the solvent gave the crude
aldehyde. Rf 0.47 (Hex–EtOAc, 1:1).
d 7.74 (d, 2H, J¼8.2 Hz), 7.38–7.08 (m, 8H), 4.52 and
4.28 (ABq, 2H, JAB¼11.1 Hz), 4.24–4.15 (m, 1H), 4.13–
3.99 (m, 3H), 3.83–3.79 (m, 1H), 3.70–3.62 (m, 1H), 3.65
(s, 3H), 2.41 (s, 3H), 2.06–1.90 (m, 5H), 1.74–1.70 (m,
1H), 1.64 (s, 3H), 1.59–1.39 (m, 3H), 1.16 (d, 3H,
J¼6.1 Hz), 0.80 (d, 3H, J¼6.9 Hz). 13C NMR (75 MHz,
CDCl3): d 169.1, 157.2, 144.8, 138.5, 132.6, 129.8, 128.3,
127.8, 127.7, 127.5, 105.5, 79.6, 78.2, 75.2, 74.5, 70.4,
66.3, 51.0, 39.1, 34.8, 34.7, 33.7, 31.7, 21.5, 21.2, 9.6, 9.0.
IR (neat): nmax¼3064, 3031, 2965, 2923, 2867, 1704,
1644, 1598, 1454, 1361, 1294, 1178, 1122 cmꢀ1. [a]D26
+43.4 (c 3.46, CHCl3).
NaBH4 (124 mg, 3.27 mmol) was added slowly to a solution
of the crude aldehyde in CH3OH (27 mL) at 0 ꢁC and the
reaction mixture was allowed to warm to room temperature.
After 30 min, the reaction mixture was diluted with Et2O
(30 mL). The reaction was quenched by addition of saturated
NH4Cl solution (30 mL). The reaction mixture was extracted
with EtOAc (40 mLꢂ3). The organic extracts were washed
with brine (80 mL) and dried over MgSO4, filtered, and
concentrated. Purification of the residue by flash column
chromatography (EtOAc) afforded diol 13 (851 mg, 97%
for two steps). Rf 0.5 (EtOAc). 1H NMR (300 MHz,
CDCl3): d 7.38–7.28 (m, 5H), 4.57 and 4.48 (ABq, 2H,
JAB¼11.3 Hz), 4.15–4.03 (m, 2H), 4.00–3.94 (m, 1H),
3.85–3.75 (m, 3H), 3.57 (d, 1H, J¼4.0 Hz), 2.93 (t, 1H,
J¼5.4 Hz), 2.13–2.00 (m, 3H), 1.82–1.37 (m, 6H), 1.19 (d,
3H, J¼6.1 Hz), 0.85 (d, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3): d 138.4, 132.1, 128.4, 127.8, 127.6,
79.8, 77.4, 75.0, 71.0, 70.4, 61.8, 40.0, 38.7, 36.3, 33.7,
31.2, 21.3, 9.9. IR (neat): nmax¼3390, 3062, 3029, 2965,
2935, 2875, 1666, 1646, 1496, 1454, 1438, 1378, 1120,
1027 cmꢀ1. MS m/z (CI, relative intensity): 323 (M++1,
44), 305 (14), 279 (26), 215 (36), 197 (44), 107 (28), 85
(100). HRMS (CI) calcd for C19H31O4 (M++1) 323.2222,
found 323.2223. [a]2D7 +15.9 (c 4.46, CHCl3).
NaI (69 mg, 0.46 mmol) was added to a solution of the
b-alkoxymethacrylate derivative (0.10 g, 0.18 mmol) in
acetone (5 mL) at room temperature, and then the solution
was heated under reflux for 2 h. The reaction mixture was
washed with brine (5 mL). The reaction mixture was
extracted with Et2O (10 mLꢂ3). The organic extracts were
dried over MgSO4, filtered, and concentrated. Purification
of the residue by flash column chromatography (Hex–
EtOAc, 4:1) gave iodide 15 (87 mg, 90%). Rf 0.41 (Hex–
EtOAc, 4:1). 1H NMR (300 MHz, CDCl3): d 7.37–7.25
(m, 6H), 4.54 and 4.33 (ABq, 2H, JAB¼11.3 Hz), 4.24–
4.16 (m, 1H), 4.08–4.00 (m, 1H), 3.86 (dt, 1H, J¼10.6,
2.9 Hz), 3.73–3.61 (m, 1H), 3.65 (s, 3H), 3.25–3.07 (m,
2H), 2.19–1.98 (m, 3H), 1.84–1.79 (m, 1H), 1.75 (d, 3H,
J¼0.4 Hz), 1.66–1.37 (m, 3H), 1.17 (d, 3H, J¼6.1 Hz),
0.83 (d, 3H, J¼7.0 Hz). 13C NMR (75 MHz, CDCl3):
d 169.3, 157.6, 138.6, 128.4, 127.9, 127.6, 105.5, 82.0,
79.8, 75.5, 74.7, 70.7, 51.1, 39.8, 39.3, 34.6, 33.8, 31.7,
21.4, 9.8, 9.3.
TEA (0.740 mL, 5.28 mmol) and p-TsCl (755 mg,
3.96 mmol) were added to a solution of the diol (851 mg,
2.64 mmol) in CH2Cl2 (3 mL). The reaction mixture was
stirred at 0 ꢁC for 14 h, the resulting solution was diluted
with CH2Cl2 (5 mL), and poured into saturated NH4Cl
solution (4 mL). The reaction mixture was extracted with
CH2Cl2 (5 mLꢂ2), and the organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
1:1) gave the corresponding tosylate (1.16 g, 92%). Rf 0.5
4.1.8. Ester 16. n-Bu3SnH (0.018 mL, 0.070 mmol) and
Et3B (1.0 M in hexane, 0.088 mL) were added to a solution
of iodide 15 (31 mg, 0.058 mmol) in toluene (6 mL) at
ꢀ78 ꢁC. The resulting solution was stirred for 1 h under
air at ꢀ78 ꢁC. Concentration and purification of the residue
by flash column chromatography (Hex–EtOAc, 4:1) fur-
nished ester 16 (22 mg, 91%). Rf 0.31 (Hex–EtOAc, 4:1).
1H NMR (300 MHz, CDCl3): d 7.33–7.24 (m, 5H), 4.53
and 4.47 (ABq, 2H, JAB¼11.3 Hz), 4.08–3.99 (m, 3H),
3.86–3.78 (m, 2H), 3.69 (s, 3H), 2.60–2.55 (m, 1H), 2.05–
1.90 (m, 6H), 1.70–1.39 (m, 5H), 1.19 (d, 3H, J¼6.0 Hz),
1.11 (d, 3H, J¼7.0 Hz), 0.82 (d, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3): d 175.5, 139.2, 128.2, 127.7, 127.2,
80.0, 79.6, 77.9, 77.2, 74.6, 71.6, 51.6, 45.2, 40.6, 36.5,
33.9, 31.6, 30.7, 28.4, 21.4, 13.1, 10.0. IR (neat):
nmax¼3029, 2967, 2877, 1739, 1455, 1376, 1197, 1068,
736, 698 cmꢀ1. MS m/z (CI, relative intensity): 405
(M++1, 81), 297 (100), 295 (28), 279 (11), 213 (63), 183
(31), 157 (42), 91 (23). HRMS (CI) calcd for C24H37O5
(M++1) 405.2641, found 405.2641. [a]2D7 +14.0 (c 1.16,
CHCl3).
1
(Hex–EtOAc, 1:1). H NMR (300 MHz, CDCl3): d 7.78
(d, 2H, J¼8.3 Hz), 7.37–7.26 (m, 6H), 4.54 and 4.42
(ABq, 2H, JAB¼11.4 Hz), 4.23–4.15 (m, 2H), 4.10–4.04
(m, 1H), 3.94–3.88 (m, 2H), 3.78–3.70 (m, 1H), 3.03 (s,
1H), 2.43 (s, 3H), 2.10–1.97 (m, 3H), 1.86–1.68 (m, 2H),
1.64–1.37 (m, 4H), 1.18 (d, 3H, J¼6.1 Hz), 0.82 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 144.6, 138.4,
133.1, 129.8, 128.4, 127.9, 127.8, 127.7, 79.7, 77.3, 74.9,
70.8, 68.1, 66.0, 39.9, 36.5, 35.8, 33.7, 31.3, 21.6, 21.3,
10.0. IR (neat): nmax¼3419, 3031, 2965, 2929, 2875, 1598,
1454, 1359, 1176, 1068, 960, 917 cmꢀ1. MS m/z (CI, relative
intensity): 477 (M++1, 44), 369 (11), 351 (11), 215 (12), 197
(23), 101 (11), 91 (63), 85 (100). HRMS (CI) calcd for
C26H37O6S (M++1) 477.2311, found 477.2310. [a]2D7 +9.1
(c 1.10, CHCl3).
Methyl 3,3-dimethoxy-2-methylpropionate (14, 48 mg,
0.29 mmol) was added to a solution of the tosylate (28 mg,
0.060 mmol) and PPTS (3.0 mg, 0.010 mmol) in benzene
(1 mL). The reaction mixture was heated under reflux for
2 h. After removal of the solvent, purification of the residue
by flash column chromatography (Hex–EtOAc, 2:1) af-
forded the b-alkoxymethacrylate derivative (30 mg, 89%).
4.1.9. Dithiane 17. LiBH4 (2.0 M in THF, 0.050 mL) was
added to a solution of ester 16 (19 mg, 0.050 mmol) in
Et2O (1 mL) at 0 ꢁC and the reaction mixture was allowed
to warm to room temperature. After 2 h, the reaction was
quenched by addition of saturated NH4Cl solution (1 mL).
The reaction mixture was extracted with Et2O (2 mLꢂ4)
and the organic extracts were dried over MgSO4, filtered,
and concentrated. Purification of the residue by flash column
1
Rf 0.45 (Hex–EtOAc, 2:1). H NMR (300 MHz, CDCl3):

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W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
chromatography (Hex–EtOAc, 1:1) gave the corresponding
alcohol (18 mg, 100%). Rf 0.52 (Hex–EtOAc, 1:1). 1H
NMR (300 MHz, CDCl3): d 7.34–7.23 (m, 5H), 4.57
and 4.45 (ABq, 2H, JAB¼11.4 Hz), 4.10–4.01 (m, 2H),
3.93–3.87 (m, 1H), 3.81–3.73 (m, 1H), 3.66–3.45 (m, 4H),
2.04–1.92 (m, 5H), 1.73–1.39 (m, 7H), 1.20 (d, 3H,
J¼6.1 Hz), 0.83–0.79 (m, 6H). 13C NMR (75 MHz,
CDCl3): d 139.1, 128.2, 127.8, 127.3, 85.3, 79.7, 77.6,
77.3, 74.6, 71.5, 68.5, 41.3, 40.2, 36.0, 33.8, 30.95, 30.92,
30.6, 21.3, 13.9, 9.9. IR (neat): nmax¼3444, 3064, 3029,
MS m/z (CI, relative intensity): 377 (M++1, 100), 269 (35),
185 (33), 129 (18), 107 (11), 91 (15), 85 (41). HRMS (CI)
calcd for C23H37O4 (M++1) 377.2692, found 377.2693.
[a]2D7 +39.4 (c 2.56, CHCl3).
was allowed to warm to 0 ꢁC and filtered. The filtrate was
washed with 1 N HCl (2 mL) and brine (2 mL). The organic
phase was dried over MgSO4, filtered, and concentrated. The
resulting residue was purified immediately by flash column
chromatography (Hex–EtOAc, 10:1) to afford the triflate
18 (78 mg, 90%). Rf 0.50 (Hex–EtOAc, 10:1).
4.1.11. Iodide 19. PPh3 (88 mg, 0.34 mmol), imidazole
(45 mg, 0.67 mmol), and I2 (85 mg, 0.34 mmol) were added
to a solution of alcohol 6 (89 mg, 0.22 mmol) in THF (2 mL)
at 0 ꢁC and the reaction mixture was allowed to warm to
room temperature. After 1 h, the reaction mixture was di-
luted with Et2O (4 mL) and poured into saturated Na2S2O3
solution (2 mL), and the reaction mixture was extracted
with Et2O (3 mLꢂ3). The organic extracts were dried over
MgSO4, filtered, and concentrated. Purification of the resi-
due by flash column chromatography (Hex–EtOAc, 12:1)
gave iodide 19 (101 mg, 94%). Rf 0.68 (Hex–EtOAc,
2964, 2875, 1455, 1376, 1070, 894, 863, 734, 698 cmꢀ1
.
Dess–Martin periodinane (676 mg, 1.59 mmol) was added
to a solution of the alcohol (400 mg, 1.06 mmol) in
CH2Cl2 (70 mL). The reaction mixture was stirred at room
temperature for 1 h and the reaction was quenched by addi-
tion of saturated Na2S2O3 solution (50 mL). The reaction
mixture was extracted with CH2Cl2 (40 mLꢂ3). The organic
extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography
(Hex–EtOAc, 2:1) gave the corresponding aldehyde
(394 mg, 99%). Rf 0.66 (Hex–EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): d 9.83 (d, 1H, J¼1.9 Hz), 7.34–7.26
(m, 5H), 4.47 and 4.56 (ABq, 2H, JAB¼11.4 Hz), 4.14–
4.11 (m, 1H), 4.08–4.01 (m, 1H), 3.96–3.90 (m, 2H),
3.78–3.73 (m, 1H), 2.52–2.42 (m, 1H), 2.03–1.95 (m, 6H),
1.73–1.51 (m, 4H), 1.49–1.39 (m, 1H), 1.17 (d, 3H,
J¼6.1 Hz), 1.05 (d, 3H, J¼7.0 Hz), 0.83 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 205.3, 139.2,
128.2, 127.7, 127.3, 79.8, 79.6, 77.5, 77.1, 74.6, 71.6,
51.8, 40.4, 36.3, 33.9, 31.3, 31.1, 29.6, 21.4, 10.4, 10.0. IR
(neat): nmax¼3087, 3062, 3030, 2966, 2933, 2871, 2725,
1726, 1496, 1456, 1377, 1070, 893, 737, 698 cmꢀ1. [a]D29
ꢀ6.0 (c 0.45, CHCl3).
1
12:1). H NMR (300 MHz, CDCl3): d 7.71–7.66 (m, 4H),
7.45–7.36 (m, 6H), 4.06–3.99 (m, 2H), 3.68–3.66 (m, 2H),
3.26 and 3.14 (ABX, 2H, JAB¼9.7 Hz, JAX¼4.5 Hz,
JBX¼7.7 Hz), 2.22–2.10 (m, 1H), 2.05–1.94 (m, 1H),
1.81–1.58 (m, 3H), 0.95 (s, 9H), 0.94 (d, 3H, J¼6.8 Hz).
4.1.12. Attempted coupling reaction of dithiane 17 with
triflate 18. t-BuLi (1.7 M in pentane, 0.019 mL) and
HMPA (0.010 mL) were added sequentially to a solution
of dithiane 17 (10 mg, 0.022 mmol) in THF (0.10 mL) at
ꢀ78 ꢁC. After 5 min, a solution of triflate 18 (17 mg,
0.032 mmol) in THF (0.10 mL) was added to the solution
at ꢀ78 ꢁC. The reaction mixture was allowed to warm to
ꢀ50 ꢁC. After 1 h, TLC analysis indicated that triflate 18
decomposed.
4.1.13. Attempted coupling reaction of dithiane 17 with
iodide 19. t-BuLi (1.7 M in pentane, 0.025 mL) and
HMPA (0.010 mL) were added sequentially to a solution
of dithiane 17 (10 mg, 0.022 mmol) in THF (0.10 mL) at
ꢀ78 ꢁC. After 5 min, a solution of iodide 19 (16 mg,
0.032 mmol) in THF (0.10 mL) was added to the solution
at ꢀ78 ꢁC. The reaction mixture was allowed to warm to
ꢀ50 ꢁC. After 1 h, TLC analysis indicated that iodide 19
decomposed.
A mixture of the aldehyde (25 mg, 0.070 mmol), 1,3-pro-
panedithiol (0.010 mL, 0.10 mmol), and LiBF4 (0.63 mg,
0.0070 mmol) in CH3CN (0.1 mL) was stirred at room tem-
perature. After completion of the reaction, as indicated by
TLC, the reaction mixture was diluted with water (0.5 mL)
and extracted with CH2Cl2 (2 mLꢂ2). The organic extracts
were dried over Na2SO4, filtered, and concentrated. The
resulting residue was purified by column chromatography
(Hex–EtOAc, 4:1) to afford dithiane 17 (25 mg, 81%).
4.1.14. Attempted deuterium exchange reaction of di-
thiane 17. t-BuLi (1.7 M in pentane, 0.013 mL) and
HMPA (0.010 mL) were added sequentially to a solution
of dithiane 17 (8.7 mg, 0.019 mmol) in THF (0.10 mL) at
ꢀ78 ꢁC. After 5 min, the reaction was quenched by addition
of D2O. 1H NMR analysis indicated that deuterium
exchange did not proceed at all.
1
Rf 0.64 (Hex–EtOAc, 4:1). H NMR (300 MHz, CDCl3):
d 7.38–7.23 (m, 5H), 4.63 (d, 1H, J¼3.2 Hz), 4.56 and
4.52 (ABq, 2H, JAB¼11.3 Hz), 4.13–4.03 (m, 2H), 3.92–
3.80 (m, 3H), 3.05–2.80 (m, 4H), 2.13–1.78 (m, 9H),
1.77–1.26 (m, 5H), 1.20 (d, 3H, J¼6.1 Hz), 1.03 (d, 3H,
J¼7.0 Hz), 0.84 (d, 3H, J¼7.0 Hz). 13C NMR (75 MHz,
CDCl3): d 139.3, 128.2, 127.7, 127.3, 79.6, 79.4, 78.1,
74.6, 71.7, 52.6, 44.7, 40.6, 36.6, 33.9, 31.7, 31.3, 30.7,
30.6, 29.5, 26.5, 21.5, 12.6, 10.0.
4.1.15. Dithiane 20. NaHMDS (1.0 M in THF, 2.0 mL),
BnBr (0.24 mL, 2.0 mmol) were added to a solution of
alcohol 6 (0.63 g, 1.6 mmol) in DMF (7 mL) at 0 ꢁC and
the reaction mixture was allowed to warm to room tempera-
ture. After 2 h, the reaction was quenched by addition of
2 N HCl (5 mL). The reaction mixture was extracted with
CH2Cl2 (10 mLꢂ3). The organic extracts were washed
with brine (5 mL), dried over MgSO4, filtered, and concen-
trated. Purification of the residue by flash column chromato-
graphy (Hex–EtOAc, 4:1) gave the corresponding benzyl
4.1.10. Triflate 18. Triflic anhydride (0.030 mL, 0.20 mmol)
was added dropwise to a solution of alcohol 6 (65 mg,
0.16 mmol) and 2,6-di-tert-butyl-4-methylpyridine (50 mg,
0.24 mmol) in CH2Cl2 (6 mL) at ꢀ78 ꢁC. After 15 min,
the mixture was diluted with ether (3 mL) and the mixture
1
ether (0.70 g, 91%). Rf 0.67 (Hex–EtOAc, 4:1). H NMR

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9793
(300 MHz, CDCl3): d 7.68–7.65 (m, 4H), 7.42–7.18 (m,
11H), 4.57 and 4.53 (ABq, 2H, JAB¼12.3 Hz), 4.15–4.05
(m, 1H), 3.96–3.89 (m, 1H), 3.72 and 3.65 (ABX, 2H,
JAB¼9.8 Hz, JAX¼4.7 Hz, JBX¼6.1 Hz), 2.02–1.80 (m,
3H), 1.71–1.57 (m, 2H), 1.05 (s, 9H), 0.93 (d, 3H, J¼6.8 Hz).
reaction mixture was allowed to warm to room temperature.
After 2 h, the reaction was quenched by addition of 2 N HCl
(5 mL). The reaction mixture was extracted with CH2Cl2
(10 mLꢂ3). The organic extracts were washed with brine
(5 mL), dried over MgSO4, filtered, and concentrated. Puri-
fication of the residue by flash column chromatography
(Hex–EtOAc, 4:1) gave the corresponding PMB ether
(0.14 g, 67%). Rf 0.56 (Hex–EtOAc, 4:1). 1H NMR
(300 MHz, CDCl3): d 7.69–7.65 (m, 4H), 7.42–7.23 (m,
6H), 7.24 (d, 2H, J¼7.6 Hz), 6.85 (d, 2H, J¼7.7 Hz), 4.51
and 4.46 (ABq, 2H, JAB¼11.8 Hz), 4.11–4.08 (m, 1H),
3.94–3.92 (m, 1H), 3.79 (s, 3H), 3.70 and 3.65 (ABX, 2H,
JAB¼9.3 Hz, JAX¼4.5 Hz, JBX¼6.2 Hz), 3.43–3.36 (m,
2H), 1.96–1.83 (m, 3H), 1.63–1.56 (m, 2H), 1.04 (s, 9H),
0.93 (d, 3H, J¼6.8 Hz).
TBAF (1.0 M in THF, 0.46 mL) was added to a solution of
the benzyl ether (0.15 g, 0.31 mmol) in THF (10 mL) at
room temperature and the reaction mixture was stirred for
12 h. After evaporation of the solvent, the residue was puri-
fied by flash column chromatography (Hex–EtOAc, 1:1) to
give the corresponding alcohol (0.60 g, 92%). Rf 0.25
1
(Hex–EtOAc, 1:1). H NMR (300 MHz, CDCl3): d 7.38–
7.25 (m, 5H), 4.60 (s, 2H), 4.27–4.19 (m, 1H), 3.81 (td,
1H, J¼8.7, 5.9 Hz), 3.66–3.51 (m, 3H), 3.48 (d, 2H,
J¼5.0 Hz), 2.14–1.97 (m, 2H), 1.79–1.54 (m, 3H), 0.80 (d,
3H, J¼6.9 Hz).
TBAF (1.0 M in THF, 0.42 mL) was added to a solution of
the PMB ether (0.14 g, 0.29 mmol) in THF (10 mL) at
room temperature and the reaction mixture was stirred for
12 h. After evaporation of the solvent, the residue was puri-
fied by flash column chromatography (Hex–EtOAc, 1:2) to
give the corresponding alcohol (72 mg, 93%). Rf 0.41
TEA (0.290 mL, 2.07 mmol) and SO3$pyridine (198 mg,
1.24 mmol) were added to a solution of the alcohol
(165 mg, 0.659 mmol) in DMSO–CH2Cl2 (1:1, 2.60 mL) at
room temperature. The reaction mixture was stirred for
30 min, and the reaction was quenched by addition of satu-
rated NH4Cl solution (5 mL). The reaction mixture was ex-
tracted with CH2Cl2 (10 mLꢂ3). The organic extracts were
dried over MgSO4, filtered, and concentrated. Purification
of the residue by flash column chromatography (Hex–EtOAc,
2:1) gave the corresponding aldehyde (150 mg, 92%). Rf 0.68
(Hex–EtOAc, 2:1). 1H NMR (300 MHz, CDCl3): d 9.79 (d,
1H, J¼2.3 Hz), 7.38–7.22 (m, 5H), 4.59 and 4.57 (ABq,
2H, JAB¼12.3 Hz), 4.28–4.20 (m, 1H), 4.14 (td, 1H, J¼8.0,
5.8 Hz), 3.47 (d, 2H, J¼4.9 Hz), 2.56–2.45 (m, 1H), 2.12–
1.97 (m, 2H), 1.79–1.61 (m, 2H), 1.06 (d, 3H, J¼7.0 Hz).
1
(Hex–EtOAc, 1:2). H NMR (300 MHz, CDCl3): d 7.26
(d, 2H, J¼8.5 Hz), 6.88 (d, 2H, J¼8.6 Hz), 4.49 (s, 2H),
4.22–4.18 (m, 1H), 3.83–3.76 (m, 4H), 3.66–3.54 (m, 3H),
3.44 (d, 2H, J¼4.9 Hz), 2.11–1.97 (m, 2H), 1.76–1.59 (m,
3H), 0.79 (d, 3H, J¼6.9 Hz).
TEA (0.180 mL, 1.28 mmol) and SO3$pyridine (123 mg,
0.770 mmol) were added to a solution of the alcohol
(72.0 mg, 0.260 mmol) in DMSO–CH2Cl2 (1:1, 1.00 mL)
at room temperature. The reaction mixture was stirred for
30 min, and the reaction was quenched by addition of satu-
rated NH4Cl solution (5 mL). The reaction mixture was ex-
tracted with CH2Cl2 (10 mLꢂ3). The organic extracts were
dried over MgSO4, filtered, and concentrated. Purification of
the residue by flash column chromatography (Hex–EtOAc,
2:1) gave the corresponding aldehyde (56.0 mg, 78%). Rf
0.51 (Hex–EtOAc, 2:1).
A mixture of the aldehyde (53 mg, 0.21 mmol), 1,3-pro-
panedithiol (0.030 mL, 0.26 mmol), and LiBF4 (2.0 mg,
0.020 mmol) in CH3CN (0.21 mL) was stirred at room tem-
perature. After completion of the reaction, as indicated by
TLC, the reaction mixture was diluted with water (1 mL)
and extracted with CH2Cl2 (3 mLꢂ2). The organic extracts
were dried over Na2SO4, filtered, and concentrated. The
resulting residue was purified by column chromatography
(Hex–EtOAc, 4:1) to afford dithiane 20 (62 mg, 86%). Rf
0.61 (Hex–EtOAc, 4:1). 1H NMR (300 MHz, CDCl3):
d 7.38–7.28 (m, 5H), 4.66–4.56 (m, 3H), 4.23–4.15 (m,
1H), 4.03 (td, 1H, J¼8.7, 5.4 Hz), 3.51 and 3.44 (ABX,
2H, JAB¼10.1 Hz, JAX¼6.0 Hz, JBX¼4.5 Hz), 3.06–2.80
(m, 4H), 2.16–1.76 (m, 5H), 1.72–1.47 (m, 2H), 1.02 (d,
3H, J¼7.0 Hz).
A mixture of the aldehyde (72 mg, 0.26 mmol), 1,3-pro-
panedithiol (0.040 mL, 0.39 mmol), and LiBF4 (2.4 mg,
0.030 mmol) in CH3CN (0.3 mL) was stirred at room tem-
perature. After completion of the reaction, as indicated by
TLC, the reaction mixture was diluted with water (1 mL)
and extracted with CH2Cl2 (3 mLꢂ2). The organic extracts
were dried over Na2SO4, filtered, and concentrated. The
resulting residue was purified by column chromatography
(Hex–EtOAc, 4:1) to afford dithiane 21 (80 mg, 84%). Rf
0.61 (Hex–EtOAc, 4:1). 1H NMR (300 MHz, CDCl3):
d 7.29 (d, 2H, J¼8.6 Hz), 6.88 (d, 2H, J¼8.6 Hz), 4.60 (d,
1H, J¼3.1 Hz), 4.56 and 4.52 (ABq, 2H, JAB¼11.8 Hz),
4.22–4.12 (m, 1H), 4.03 (td, 1H, J¼8.7, 5.4 Hz), 3.81 (s,
3H), 3.48 and 3.40 (ABX, 2H, JAB¼10.1 Hz, JAX¼6.0 Hz,
JBX¼4.6 Hz), 3.06–2.79 (m, 4H), 2.15–1.81 (m, 5H),
1.69–1.41 (m, 2H), 1.01 (d, 3H, J¼7.0 Hz).
4.1.16. Attempted deuterium exchange reaction of di-
thiane 20. t-BuLi (1.7 M in pentane, 0.047 mL) and
HMPA (0.032 mL) were added sequentially to a solution
of dithiane 20 (18 mg, 0.053 mmol) in THF (1 mL) at
ꢀ78 ꢁC. After 20 min, the reaction mixture was allowed to
warm to ꢀ20 ꢁC and stirred for 2.5 h. The reaction was
quenched by addition of D2O. 1H NMR analysis confirmed
that deuterium exchange reaction did not proceed at all.
4.1.18. Deuterium exchange reaction of dithiane 21.
t-BuLi (1.7 M in pentane, 0.067 mL) and HMPA (0.040 mL)
were added sequentially to a solution of dithiane 21
(28 mg, 0.076 mmol) in THF (1 mL) at ꢀ78 ꢁC. After
4.1.17. Dithiane 21. NaHMDS (1.0 M in THF, 0.50 mL),
PMBCl (0.080 mL, 0.62 mmol), and TBAI (15 mg,
0.040 mmol) were added to a solution of alcohol 6 (0.17 g,
0.41 mmol) in THF–DMF (5:1, 6.0 mL) at 0 ꢁC and the
1
5 min, the reaction was quenched by addition of D2O. H
NMR analysis confirmed 58% deuterium exchange.

9794
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
4.1.19. Attempted coupling reaction of dithiane 21 with
triflate 18. t-BuLi (1.7 M in pentane, 0.040 mL) and
HMPA (0.043 mL) were added sequentially to a solution
of dithiane 21 (23 mg, 0.062 mmol) in THF (1 mL) at
ꢀ78 ꢁC. After 20 min, the reaction mixture was allowed to
warm to ꢀ20 ꢁC and stirred for 2 h. A solution of triflate
18 (40 mg, 0.075 mmol) in THF (0.5 mL) was added to
the solution at ꢀ78 ꢁC. The reaction mixture was allowed
to warm to ꢀ50 ꢁC. After 2 h, TLC analysis indicated that
triflate 18 decomposed.
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
3:1) gave the corresponding tosylate (440 mg, 72%). Rf
0.47 (Hex–EtOAc, 3:1). 1H NMR (300 MHz, CDCl3):
d 7.79 (d, 2H, J¼8.3 Hz), 7.36 (d, 2H, J¼8.0 Hz), 4.20 (td,
1H, J¼4.4, 7.7 Hz), 4.00 (dd, 1H, J¼9.6, 3.0 Hz), 3.91–
3.73 (m, 2H), 3.65 (s, 3H), 2.52 (qd, 1H, J¼6.9, 4.5 Hz),
2.45 (s, 3H), 2.26 (d, 1H, J¼4.1 Hz), 1.70–1.28 (m, 4H),
1.13 (d, 3H, J¼7.0 Hz), 1.02 (s, 21H).
DBU (0.060 mL, 0.41 mmol) was added to a solution of the
tosylate (0.10 g, 0.19 mmol) in THF (6 mL) and the reaction
mixture was stirred at room temperature for 2 h. After evap-
oration of the solvent, the residue was subjected to flash
column chromatography (Hex–EtOAc, 8:1) to give the cor-
responding epoxide (54 mg, 81%). Rf 0.43 (Hex–EtOAc,
4.1.20. Epoxide 22. A solution of Na (129 mg, 5.60 mmol)
in CH3OH (10 mL) was added dropwise to a solution of the
aldol imide 4 (2.00 g, 5.10 mmol) in CH3OH (10 mL) at
0 ꢁC. After 10 min, the reaction was quenched by addition
of saturated NH4Cl solution (10 mL). The reaction mixture
was extracted with CH2Cl2 (10 mLꢂ2) and the resulting
extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography
(Hex–EtOAc, 1:1) gave the corresponding hydroxy methyl
1
8:1). H NMR (300 MHz, CDCl3): d 4.28 (td, 1H, J¼4.5,
7.8 Hz), 3.67 (s, 3H), 2.94–2.88 (m, 1H), 2.76 (t, 1H,
J¼4.1 Hz), 2.55 (qd, 1H, J¼7.0, 4.1 Hz), 2.48–2.46 (m,
1H), 1.84–1.41 (m, 4H), 1.16 (d, 3H, J¼7.0 Hz), 1.05 (s,
21H).
1
ester (850 mg, 68%). Rf 0.47 (Hex–EtOAc, 1:1). H NMR
(300 MHz, CDCl3): d 4.14–4.03 (m, 2H), 3.96–3.76 (m,
1H), 3.71 (s, 3H), 3.53 (t, 1H, J¼7.1 Hz), 2.77 (d, 1H,
J¼4.7 Hz), 2.56 (qd, 1H, J¼7.2, 3.8 Hz), 1.85–1.70 (m,
1H), 1.68–1.44 (m, 3H), 1.41 (s, 3H), 1.36 (s, 3H), 1.21 (d,
3H, J¼7.2 Hz).
TBAF (1.0 M in THF, 0.85 mL) was added to a solution of
the epoxide (0.23 g, 0.65 mmol) in THF (10 mL) at room
temperature and the reaction mixture was stirred for 12 h.
After evaporation of the solvent, the residue was purified
by flash column chromatography (Hex–EtOAc, 1:1) to
give the corresponding alcohol (0.12 g, 95%). Rf 0.20
2,6-Lutidine (2.00 mL, 17.3 mmol), DMAP (2.10 g,
17.3 mmol), and TIPSOTf (2.80 mL, 10.4 mmol) were
added sequentially to a solution of the hydroxyl methyl ester
(850 mg, 3.45 mmol) in CH2Cl2 (10 mL) at room tempera-
ture. After 12 h, the reaction was quenched by addition of
saturated NH4Cl solution (10 mL). The reaction mixture
was extracted with CH2Cl2 (10 mLꢂ3). The organic extracts
were washed with brine (10 mL), dried over MgSO4, fil-
tered, and concentrated. The resulting residue was purified
by flash column chromatography (Hex–EtOAc, 6:1) to
give the corresponding TIPS derivative (1.30 g, 94%). Rf
0.57 (Hex–EtOAc, 6:1). 1H NMR (300 MHz, CDCl3):
d 4.37–4.25 (m, 1H), 4.14–4.01 (m, 2H), 3.66 (s, 3H),
3.55–3.41 (m, 1H), 2.56 (qd, 1H, J¼7.0, 4.0 Hz), 1.77–
1.65 (m, 1H), 1.64–1.40 (m, 3H), 1.40 (s, 3H), 1.35 (s,
3H), 1.15 (d, 3H, J¼7.0 Hz), 1.04 (s, 21H).
1
(Hex–EtOAc, 1:1). H NMR (300 MHz, CDCl3): d 3.97–
3.90 (m, 1H), 3.72 (s, 3H), 2.99–2.93 (m, 1H), 2.78 (t, 1H,
J¼4.2 Hz), 2.70 (d, 1H, J¼4.7 Hz), 2.62–2.50 (m, 2H),
1.98–1.87 (m, 1H), 1.64–1.39 (m, 3H), 1.21 (d, 3H,
J¼7.2 Hz).
TEA (0.12 mL, 0.87 mmol) and MsCl (0.080 mL,
0.75 mmol) were added to a solution of the alcohol
(0.12 g, 0.62 mmol) in CH2Cl2 (10 mL) at 0 ꢁC and the reac-
tion mixture was allowed to warm to room temperature.
The reaction mixture was stirred for 1 h, and the reaction
was quenched by addition of saturated NH4Cl solution
(10 mL). The reaction mixture was extracted with CH2Cl2
(10 mLꢂ3). The organic extracts were washed with brine
(5 mL), dried over MgSO4, filtered, and concentrated. Puri-
fication of the residue by flash column chromatography
(Hex–EtOAc, 1:1) gave epoxide 22 (0.14 g, 85%). Rf 0.25
CSA (6.9 mg, 0.030 mmol) was added to a solution of the
TIPS derivative (0.240 g, 0.060 mmol) in CH3OH (10 mL)
at room temperature. After stirring for 2 h, the reaction
was quenched by addition of TEA (1 mL) and the reaction
mixture was concentrated. Purification of the residue by
flash column chromatography (Hex–EtOAc, 1:1) afforded
the corresponding diol (0.170 g, 80%). Rf 0.27 (Hex–EtOAc,
1
(Hex–EtOAc, 1:1). H NMR (300 MHz, CDCl3): d 5.05–
5.01 (m, 1H), 3.73 (s, 3H), 3.04 (s, 3H), 2.96–2.93 (m,
1H), 2.82–2.77 (m, 2H), 2.53–2.51 (m, 1H), 1.98–1.87 (m,
3H), 1.50–1.44 (m, 1H), 1.26 (d, 3H, J¼7.1 Hz).
4.1.21. Epoxide 23. Imidazole (1.22 g, 0.0180 mol) and
TBSCl (2.50 g, 0.0170 mol) were added to a solution of
10-undecen-1-ol (2.35 g, 0.0140 mol) in CH2Cl2 (50 mL)
at room temperature. After 1 h, the reaction was quenched
by addition of saturated NH4Cl solution (15 mL). The reac-
tion mixture was extracted with CH2Cl2 (15 mLꢂ3). The
organic extracts were washed with brine (10 mL), dried
over MgSO4, and concentrated to give the crude TBS ether.
Rf 0.80 (Hex–EtOAc, 6:1).
1
1:1). H NMR (300 MHz, CDCl3): d 4.28–4.23 (m, 1H),
3.69–3.64 (m, 1H), 3.47–3.41 (m, 1H), 2.63–2.55 (m, 1H),
2.34 (br s, 1H), 1.95 (br s, 1H), 1.83–1.54 (m, 2H), 1.48–
1.38 (m, 2H), 1.16 (d, 3H, J¼7.0 Hz), 1.05 (s, 21H).
TEA (0.250 mL, 1.78 mmol) and p-TsCl (270 mg,
1.42 mmol) were added to a solution of the diol (430 mg,
1.19 mmol) in CH2Cl2 (1.19 mL). The reaction mixture
was stirred at 0 ꢁC for 14 h, and the resulting solution was
diluted with CH2Cl2 (2 mL) and poured into saturated
NH4Cl solution (2 mL). The reaction mixture was extracted
with CH2Cl2 (3 mLꢂ2), and the organic extracts were dried
m-CPBA (4.76 g, 0.0170 mol) was added to a solution of the
crude TBS ether obtained above in CH2Cl2 (30 mL) at room
temperature. After 1 h, the reaction mixture was washed

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9795
with saturated NaHCO3 solution (15 mL). The organic
layer was dried over MgSO4, filtered, and concentrated. Pu-
rification of the residue by flash column chromatography
(Hex–EtOAc, 6:1) afforded epoxide 23 (3.50 g, 84% for
(5 mL). The reaction mixture was stirred at 0 ꢁC for 14 h,
the resulting solution was diluted with CH2Cl2 (5 mL) and
poured into saturated NH4Cl solution (7 mL). The reaction
mixture was extracted with CH2Cl2 (10 mLꢂ2), and the
organic extracts were dried over MgSO4, filtered, and con-
centrated. Purification of the residue by flash column
chromatography (Hex–EtOAc, 1:1) gave the corresponding
tosylate (530 mg, 65%). Rf 0.63 (Hex–EtOAc, 1:1).
1
two steps) Rf 0.61 (Hex–EtOAc, 6:1). H NMR (300 MHz,
CDCl3): d 3.59 (t, 2H, J¼6.6 Hz), 2.93–2.87 (m, 1H),
2.76–2.73 (m, 1H), 2.47–2.44 (m, 1H), 1.56–1.38 (m, 6H),
1.38–1.09 (m, 11H), 0.88 (s, 9H), 0.04 (s, 6H).
4.1.22. Attempted coupling reaction of dithiane 21 with
epoxide 22. n-BuLi (2.5 M in hexane, 0.026 mL) and
HMPA (0.038 mL) were added sequentially to a solution
of dithiane 21 (20 mg, 0.054 mmol) in THF (1 mL) at
ꢀ78 ꢁC. After 20 min, the reaction mixture was allowed to
warm to ꢀ20 ꢁC and stirred for 2 h. A solution of epoxide
22 (17 mg, 0.065 mmol) in THF (0.5 mL) was added to
the solution at ꢀ78 ꢁC. The reaction mixture was allowed
to warm to ꢀ20 ꢁC. After 2 h, the reaction was quenched
by addition of saturated NH4Cl solution (5 mL). The reac-
tion mixture was extracted with Et2O (5 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and con-
centrated. Purification of the residue by flash column chro-
matography (Hex–EtOAc, 2:1) gave only a trace amount
of mesyloxy elimination product. Rf 0.25 (Hex–EtOAc, 2:1).
DBU (0.260 mL, 1.72 mmol) was added to a solution of the
tosylate (530 mg, 0.820 mmol) in THF (40 mL) and the re-
action mixture was stirred at room temperature for 2 h. After
evaporation of the solvent, the residue was subjected to flash
column chromatography (Hex–EtOAc, 4:1) to give epoxide
26 (295 mg, 73%). Rf 0.31 (Hex–EtOAc, 4:1).
4.1.26. Attempted coupling reaction of 25/250 with iodide
19. LiHMDS (1.0 M in THF, 0.058 mL) was added dropwise
to a solution of the mixture of 25 and 250 in THF (2 mL) at
ꢀ78 ꢁC. After 40 min, a solution of iodide 19 (80 mg,
0.16 mmol) in THF (1 mL) was added to the solution and
the reaction mixture was allowed to warm to 0 ꢁC over
2 h. The reaction mixture was stirred at 0 ꢁC for 1 h and at
room temperature for 1 h. TLC analysis indicated that the
coupling reaction did not proceed at all.
4.1.23. Attempted coupling reaction of dithiane 21 with
epoxide 23. n-BuLi (2.5 M in hexane, 0.050 mL) and
HMPA (0.072 mL) were added sequentially to a solution
of dithiane 21 (38 mg, 0.103 mmol) in THF (1 mL) at
ꢀ20 ꢁC. After 1.5 h, a solution of epoxide 23 (59 mg,
0.124 mmol) in THF (0.5 mL) was added to the solution
at 0 ꢁC and the reaction mixture was stirred for 2 h. TLC
analysis indicated that the coupling reaction did not proceed
at all.
4.1.27. Attempted coupling reaction of 25/250 with epox-
ide 26. LiHMDS (1.0 M in THF, 0.032 mL) was added drop-
wise to a solution of the mixture of 25 and 250 in THF (1 mL)
at ꢀ78 ꢁC. After 40 min, a solution of epoxide 26 (21 mg,
0.044 mmol) in THF (1 mL) was added to the solution and
the reaction mixture was allowed to warm to 0 ꢁC over
2 h. The reaction mixture was stirred at 0 ꢁC for 1 h and at
room temperature for 1 h. TLC analysis indicated that the
coupling reaction did not proceed at all.
4.1.24. Cyanohydrin derivatives 25 and 250. DIBAL
(1.0 M in toluene, 0.13 mL) was added to a solution of ester
24 (39 mg, 0.13 mmol) in CH2Cl2 (2 mL) at ꢀ78 ꢁC. After
30 min, the reaction was quenched by addition of CH3OH
(0.4 mL) at ꢀ78 ꢁC and the reaction mixture was diluted
with EtOAc (5 mL). Saturated sodium potassium tartrate
(5 mL) was added to the mixture at 0 ꢁC. The reaction mix-
ture was stirred at room temperature for 2 h, and extracted
with EtOAc (5 mLꢂ3). The extracts were dried over
MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
2:1) gave the corresponding aldehyde (30 mg, 85%). Rf
0.65 (Hex–EtOAc, 2:1).
4.1.28. Sulfone 27. NaSO2Ph (944 mg, 5.75 mmol) was
added to a solution of iodide 19 (585 mg, 1.15 mmol) in
DMF (6 mL) at room temperature. After stirring at 50 ꢁC
for 1 day, the reaction mixture was diluted with EtOAc
(6 mL), and washed with water (10 mLꢂ2) and brine
(10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated. Purification of the resi-
due by flash column chromatography (Hex–EtOAc, 4:1)
gave sulfone 27 (490 mg, 82%). Rf 0.32 (Hex–EtOAc,
4:1). 1H NMR (300 MHz, CDCl3): d 7.82 (d, 2H,
J¼14.5 Hz), 7.81–7.64 (m, 4H), 7.43–7.40 (m, 6H), 7.36–
7.28 (m, 3H), 4.30 (m, 1H), 3.64 (m, 1H), 3.54 and 3.18
(ABX, 2H, JAB¼24.0 Hz, JAX¼9.1 Hz, JBX¼11.3 Hz),
3.35 (m, 2H), 2.18–2.12 (m, 1H), 1.93–1.85 (m, 1H),
1.69–1.59 (m, 3H), 1.02 (s, 9H), 0.86 (d, 3H, J¼6.8 Hz).
TMSCN (0.010 mL, 0.090 mmol) and ZnI2 (3.0 mg,
0.010 mmol) were added to a solution of the aldehyde
(20 mg, 0.070 mmol) in CH2Cl2 (2 mL) at room tempera-
ture. After 8 h, the reaction was quenched by addition of sat-
urated NaHCO3 solution and the reaction mixture was
extracted with CH2Cl2 (5 mLꢂ3). The extracts were dried
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–EtOAc,
4:1) gave a mixture of cyanohydrin derivatives 25 and 250
(20 mg, 74%). Rf 0.60 (Hex–EtOAc, 4:1).
4.1.29. Sulfone 28. PPh3 (0.15 g, 0.57 mmol), imidazole
(78 mg, 1.2 mmol), and I2 (0.15 g, 0.57 mmol) were added
to a solution of the alcohol obtained from 16 (0.14 g,
0.38 mmol) in THF (0.8 mL) at 0 ꢁC and the reaction mix-
ture was allowed to warm to room temperature. After 1 h,
the reaction mixture was diluted with Et2O (2 mL) and
poured into saturated Na2S2O3 solution (2 mL), and the
reaction mixture was extracted with Et2O (3 mLꢂ3). The
organic extracts were dried over MgSO4, filtered, and
concentrated. Purification of the residue by flash column
chromatography (Hex–EtOAc, 8:1) gave the corresponding
4.1.25. Epoxide 26. TEA (0.360 mL, 2.56 mmol) and p-
TsCl (366 mg, 1.92 mmol) were added to a solution of the
diol obtained from 4 (634 mg, 1.28 mmol) in CH2Cl2

9796
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
1
iodide (0.18 g, 99%). Rf 0.44 (Hex–EtOAc, 8:1). H NMR
(300 MHz, CDCl3): d 7.38–7.26 (m, 5H), 4.58 and 4.52
(ABq, 2H, JAB¼11.3 Hz), 4.13–4.04 (m, 2H), 3.97–3.92
(m, 1H), 3.80–3.77 (m, 1H), 3.57–3.54 (m, 1H), 3.47–3.38
(m, 2H), 2.05–1.94 (m, 5H), 1.64–1.50 (m, 5H), 1.48–1.38 (m,
2H), 1.20 (d, 3H, J¼6.1 Hz), 0.95 (d, 3H, J¼6.6 Hz), 0.83(d,
3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 139.2, 128.2,
127.7, 127.2, 81.9, 79.7, 77.5, 76.6, 74.5, 71.7, 40.6, 40.5,
36.4, 33.8, 31.7, 31.0, 29.2, 21.5, 17.5, 16.0, 10.0.
(300 MHz, CDCl3): d 9.61 (d, 1H, J¼1.9 Hz), 7.71–7.66
(m, 4H), 7.43–7.34 (m, 6H), 4.23–4.18 (m, 1H), 4.04–3.96
(m, 1H), 3.78–3.69 (m, 2H), 2.19–2.07 (m, 1H), 1.99–1.78
(m, 3H), 1.66–1.52 (m, 1H), 1.07 (s, 9H), 0.98 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 203.1, 135.5,
133.8, 133.7, 129.5, 127.5, 82.4, 82.0, 65.8, 40.5, 28.9,
27.3, 26.8, 19.3, 13.1. IR (neat): nmax¼3070, 3048, 2960,
2931, 2857, 1733, 1471, 1427, 1390, 1112, 1070, 823,
703, 505 cmꢀ1. [a]D28 ꢀ7.2 (c 1.90, CHCl3).
NaSO2Ph (133 mg, 0.810 mmol) was added to a solution of
the iodide (79.0 mg, 0.160 mmol) in DMF (2 mL) at room
temperature. After stirring for 6 h at room temperature, the
reaction mixture was diluted with EtOAc (2 mL), washed
with brine (2 mL), and dried over Na2SO4. Filtration, con-
centration, and purification of the residue by flash column
chromatography (Hex–EtOAc, 2:1) furnished sulfone 28
(74.0 mg, 91%). Rf 0.42 (Hex–EtOAc, 2:1).
4.1.34. Olefin 32. PPh3 (275 mg, 1.05 mmol) was added to
a solution of the iodide obtained from 16 (340 mg,
0.700 mmol) in CH3CN (7 mL). The resulting solution
was heated under reflux for 14 h. The reaction mixture was
diluted with CH3CN (7 mL) and washed with hexane
(10 mLꢂ10). Evaporation of the solvent afforded the corre-
sponding phosphonium salt (487 mg, 93%) as a white solid.
1H NMR (300 MHz, CDCl3): d 7.95–7.89 (m, 6H), 7.81–
7.77 (m, 3H), 7.74–7.68 (m, 6H), 7.34–7.30 (m, 5H), 4.56
and 4.42 (ABq, 2H, JAB¼11.5 Hz), 4.02–3.87 (m, 3H),
3.76–3.70 (m, 4H), 2.08–1.98 (m, 6H), 1.69–1.60 (m, 3H),
1.51–1.06 (m, 3H), 0.94 (d, 3H, J¼6.0 Hz), 0.83 (d, 3H,
J¼6.9 Hz), 0.74 (d, 3H, J¼6.7 Hz). [a]2D7 +50.9 (c 0.39,
CHCl3).
4.1.30. Sulfones 29/290. n-BuLi (2.5 M in hexane, 0.05 mL,
0.12 mmol) was added dropwise to a solution of sulfone 28
(56 mg, 0.11 mmol) in THF (0.6 mL) at ꢀ40 ꢁC and the
slurry was stirred for 20 min. The mixture was warmed to
room temperature and stirred for 10 min. The mixture was
cooled to ꢀ40 ꢁC. HMPA (0.20 mL) was added followed
by a solution of iodide 19 in THF (0.9 mL). The mixture
was stirred at ꢀ40 ꢁC for 1 h and then at room temperature
for 1 h. The reaction was quenched by addition of saturated
NH4Cl solution (3 mL) and the reaction mixture was ex-
tracted with EtOAc (4 mLꢂ3). The organic extracts were
dried over MgSO4, and purified by flash chromatography
(Hex–EtOAc, 4:1) to give the mixture of sulfones 29 and
290 (42 mg, 43%). Rf 0.31 (Hex–EtOAc, 4:1).
n-BuLi (2.5 M in hexane, 0.48 mL) was added dropwise to
a solution of the phosphonium salt (600 mg, 0.800 mmol)
in THF (4 mL) at ꢀ78 ꢁC. The resulting orange solution
was stirred at ꢀ78 ꢁC for 30 min. A solution of aldehyde
31 (381 mg, 0.960 mmol) in THF (4 mL) was added drop-
wise to the solution at ꢀ78 ꢁC. After 1 h, the mixture was
allowed to warm to room temperature and stirred for 1 h.
The reaction was quenched by addition of acetone (0.8 mL)
and water (16 mL), and the reaction mixture was extracted
with Et2O (20 mLꢂ3). The organic extracts were dried
over MgSO4, filtered, and concentrated. Purification of the
residue by flash column chromatography (Hex–Acetone,
4:1) gave olefin 32 (557 mg, 94%). Rf 0.66 (Hex–Acetone,
4.1.31. Attempted oxidation of 29/290. n-BuLi (2.5 M in
hexane, 0.0060 mL) was added to a solution of the mixture
of 29 and 290 (9.0 mg, 0.010 mmol) in THF (0.1 mL) at
ꢀ40 ꢁC. After 1 h, a solution of oxaziridine 30 (5.6 mg,
0.020 mmol) in THF (0.1 mL) was added to the solution at
ꢀ40 ꢁC. The reaction mixture was allowed to warm to
0 ꢁC over 1 h. TLC analysis indicated that the oxidation
reaction did not proceed at all.
1
4:1). H NMR (300 MHz, CDCl3): d 7.69–7.66 (m, 4H),
7.39–7.22 (m, 11H), 5.49–5.33 (m, 2H), 4.67–4.60 (m,
1H), 4.55 and 4.49 (ABq, 2H, JAB¼11.4 Hz), 4.07–3.94
(m, 3H), 3.88–3.84 (m, 1H), 3.82–3.73 (m, 2H), 3.66–3.60
(m, 2H), 2.65–2.57 (m, 1H), 2.07–1.92 (m, 7H), 1.87–1.67
(m, 3H), 1.63–1.45 (m, 5H), 1.44–1.38 (m, 1H), 1.17 (d,
3H, J¼6.0 Hz), 1.05 (s, 9H), 0.99 (d, 3H, J¼6.7 Hz), 0.94
(d, 3H, J¼6.8 Hz), 0.83 (d, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3): d 139.3, 135.60, 135.57, 134.2, 133.9,
131.3, 129.38, 129.36, 128.1, 127.6, 127.5, 127.2, 82.5,
80.2, 79.6, 78.0, 76.7, 74.7, 74.6, 71.5, 66.4, 40.9, 40.7,
36.9, 36.4, 33.9, 33.7, 31.8, 30.8, 29.9, 28.2, 26.9, 21.5,
19.3, 17.1, 12.9, 10.0. IR (neat): nmax¼3066, 2962, 2931,
4.1.32. Attempted deuterium exchange reaction of 29/290.
n-BuLi (2.5 M in hexane, 0.016 mL) was added to a solution
of the mixture of 29 and 290 (10 mg, 0.020 mmol) in THF
(0.1 mL) at ꢀ40 ꢁC. The reaction mixture was stirred for
1 h and HMPA (0.010 mL) was added to the mixture. After
2 h, the reaction was quenched by addition of D2O. 1H NMR
analysis confirmed that deuterium exchange reaction did not
proceed at all.
2861, 1457, 1428, 1375, 1108, 1058, 740, 701, 505 cmꢀ1
.
4.1.33. Aldehyde 31. TEA (1.58 mL, 11.4 mmol) and
SO3$pyridine (1.09 g, 6.80 mmol) were added to a solution
of alcohol 6 (905 mg, 2.27 mmol) in DMSO–CH2Cl2 (1:1,
4.50 mL) at room temperature. The reaction mixture was
stirred for 30 min, and the reaction was quenched by
addition of saturated NH4Cl solution (3 mL). The reaction
mixture was extracted with CH2Cl2 (5 mLꢂ3). The organic
extracts were washed with brine (5 mL), dried over MgSO4,
filtered, and concentrated. Purification of the residue by flash
column chromatography (Hex–EtOAc, 2:1) gave aldehyde
MS m/z (FAB, relative intensity): 739 (M++1, 3), 307 (19),
282 (19), 154 (100), 137 (64), 107 (31). HRMS (FAB) calcd
for C47H67O5Si (M++1) 739.4758, found 739.4760. [a]2D7
+18.9 (c 5.15, CHCl3).
4.1.35. Keto carboxylic acid 33. m-CPBA (327 mg,
1.46 mmol) was added to a solution of olefin 32 (540 mg,
0.730 mmol) in CH2Cl2 (8 mL) at 0 ꢁC. After 3 h, the reac-
tion mixture was washed with saturated NaHCO3 solution
(5 mLꢂ2). The organic layer was dried over MgSO4, fil-
tered, and concentrated. Purification of the residue by flash
1
31 (801 mg, 89%). Rf 0.69 (Hex–EtOAc, 2:1). H NMR

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9797
column chromatography (Hex–EtOAc, 3:1) afforded a mix-
ture of epoxides 32A (238 mg, 43%) and 32A0 (230 mg,
42%). Epoxide 32A: Rf 0.41 (Hex–EtOAc, 3:1). H NMR
a solution of the keto aldehyde (24 mg, 0.050 mmol) in t-
BuOH (3.1 mL) and 2-methyl-2-butene (1.5 mL). The reac-
tion mixture was stirred for 1 h at room temperature and then
an additional equivalent of NaClO2 and NaH2PO4 in water
was added to the solution. After 1 h, the reaction mixture
was concentrated and the residue was dissolved in Et2O
(3 mL) and water (1 mL). The solution was acidified (pH
2) by addition of 2 N HCl solution. The aqueous layer was
extracted with Et2O (3 mLꢂ3) and the organic extracts
were dried over MgSO4. Filtration, concentration, and puri-
fication of the residue by flash column chromatography
(Hex–EtOAc, 1:1) gave keto carboxylic acid 33 (25 mg,
99%). Rf 0.1 (Hex–EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): d 7.33–7.24 (m, 5H), 4.54 and 4.43 (ABq, 2H,
JAB¼11.4 Hz), 4.47–4.38 (m, 1H), 4.15–4.00 (m, 3H),
3.88–3.78 (m, 3H), 3.09–2.98 (m, 1H), 2.70–2.56 (m, 2H),
2.51–2.41 (m, 1H), 2.25–1.88 (m, 8H), 1.70–1.39 (m, 8H),
1.20 (d, 3H, J¼6.1 Hz), 1.13 (d, 3H, J¼7.0 Hz), 1.00 (d,
3H, J¼6.9 Hz), 0.83 (d, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3): d 211.8, 177.4, 139.2, 128.2, 127.6,
127.3, 80.8, 79.74, 79.66, 77.8, 75.4, 74.7, 71.6, 52.2,
48.1, 44.6, 40.4, 36.3, 33.8, 32.1, 31.3, 30.7, 30.2, 29.4,
21.3, 12.9, 12.8, 9.9. IR (neat): nmax¼3066, 3027, 2969,
1
(300 MHz, CDCl3): d 7.68–7.64 (m, 4H), 7.43–7.25 (m,
11H), 4.56 and 4.52 (ABq, 2H, JAB¼11.4 Hz), 4.10–4.02
(m, 2H), 3.96–3.87 (m, 3H), 3.85–3.67 (m, 2H), 3.65–3.61
(m, 2H), 2.93 (dd, 1H, J¼9.2, 4.2 Hz), 2.77 (dd, 1H,
J¼8.2, 4.2 Hz), 2.17–2.13 (m, 1H), 2.03–1.67 (m, 10H),
1.64–1.57 (m, 5H), 1.43–1.34 (m, 1H), 1.14 (d, 3H,
J¼6.1 Hz), 1.05 (s, 9H), 0.97 (d, 3H, J¼6.3 Hz), 0.95 (d,
3H, J¼6.4 Hz), 0.83 (d, 3H, J¼6.9 Hz). 13C NMR
(75 MHz, CDCl3): d 139.4, 135.60, 135.57, 134.1, 134.0,
129.5, 129.4, 128.2, 127.7, 127.5, 127.2, 81.6, 81.1, 79.6,
78.1, 76.7, 75.8, 74.6, 71.7, 66.2, 58.8, 57.1, 41.1, 40.7,
36.5, 36.4, 34.0, 31.9, 31.3, 30.8, 29.7, 27.7, 26.9, 21.5,
19.4, 13.1, 12.7, 10.0. [a]2D8 +15.5 (c 1.90, CHCl3). Epoxide
32A0: Rf 0.36 (Hex–EtOAc, 3:1). 1H NMR (300 MHz,
CDCl3): d 7.71–7.65 (m, 4H), 7.40–7.22 (m, 11H), 4.56
and 4.46 (ABq, 2H, JAB¼11.5 Hz), 4.10–3.93 (m, 3H),
3.87–3.62 (m, 5H), 3.57–3.52 (m, 1H), 2.95 (dd, 1H,
J¼7.8, 4.2 Hz), 2.82 (dd, 1H, J¼9.4, 4.2 Hz), 2.17–2.11
(m, 1H), 2.03–1.72 (m, 9H), 1.71–1.35 (m, 7H), 1.17 (d,
3H, J¼6.1 Hz), 1.04 (s, 12H), 0.94 (d, 3H, J¼6.8 Hz),
0.83 (d, 3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3):
d 139.2, 135.7, 135.6, 134.1, 134.0, 129.4, 128.2, 127.7,
127.6, 127.3, 81.3, 80.5, 79.6, 78.1, 77.8, 77.2, 74.7, 71.5,
66.3, 60.7, 60.0, 40.7, 40.6, 37.4, 36.1, 34.0, 31.5, 30.8,
29.4, 29.3, 29.1, 26.9, 21.5, 19.4, 14.1, 12.9, 9.9. [a]D27
+15.2 (c 0.85, CHCl3).
2938, 2877, 1733, 1712, 1455, 1376, 1193, 1068 cmꢀ1
.
MS m/z (FAB, relative intensity): 531 (M++1, 20), 339 (7),
283 (4), 209 (9), 143 (22), 125 (23), 85 (100). HRMS
(FAB) calcd for C31H47O7 (M++1) 531.3322, found
531.3328. [a]2D4 +9.7 (c 0.60, CHCl3).
4.1.36. The monomeric seco acid 35. Keto carboxylic acid
33 (26 mg, 0.048 mmol) was dissolved in MeOH (1 mL) and
palladium on activated carbon (10% w/w, 100 mg) was
added. The reaction mixture was stirred under hydrogen
atmosphere for 1 h and then filtered through a filter paper.
After solvent evaporation, flash column chromatography
(EtOAc) yielded the monomeric seco acid 35 (20 mg,
93%). Rf 0.20 (EtOAc). 1H NMR (300 MHz, CDCl3):
d 4.48–4.41 (m, 1H), 4.12–4.00 (m, 3H), 3.96–3.90 (m, 2H),
3.78–3.72 (m, 1H), 3.04–2.96 (m, 1H), 2.71–2.55 (m, 2H),
2.50–2.42 (m, 1H), 2.28–1.90 (m, 6H), 1.75–1.39 (m, 9H),
1.22 (d, 3H, J¼6.0 Hz), 1.15 (d, 3H, J¼7.0 Hz), 1.01 (d, 3H,
J¼6.9 Hz), 0.76 (d, 3H, J¼6.8 Hz). 13C NMR (75 MHz,
CDCl3): d 211.6, 177.646, 83.9, 80.5, 79.8, 76.6, 75.5, 75.3,
73.2, 52.3, 47.7, 44.7, 44.3, 40.1, 33.4, 32.08, 32.05, 31.1,
30.1, 29.2, 21.0, 13.0, 12.7, 12.5.
A solution of the mixture of 32A and 32A0 (300 mg,
0.400 mmol) in Et2O (1.3 mL) was added dropwise to a sus-
pension of LAH (90.0 mg, 2.38 mmol) in Et2O (3 mL) at
0 ꢁC. After 12 h, the reaction was quenched by addition of
water (3.6 mL) and 15% aqueous NaOH solution (0.9 mL).
Drying the organic layer over MgSO4, filtration, and concen-
tration gave a crude mixture of diols 32B and 32B0.
Dess–Martin periodinane (84 mg, 0.20 mmol) was added to
a solution of 32B/32B0 (34 mg, 0.07 mmol) in CH2Cl2
(4.4 mL). The reaction mixture was stirred at room temper-
ature for 1 h and the reaction was quenched by addition of
saturated Na2S2O3 solution (3 mL). The reaction mixture
was extracted with CH2Cl2 (4 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. Purifica-
tion of the residue by flash column chromatography (Hex–
EtOAc, 1:1) gave the corresponding keto aldehyde (30 mg,
88%). Rf 0.5 (Hex–EtOAc, 1:1). 1H NMR (300 MHz,
CDCl3): d 9.72 (d, 1H, J¼2.3 Hz), 7.38–7.21 (m, 5H),
4.53 and 4.44 (ABq, 2H, JAB¼11.3 Hz), 4.48–4.38 (m, 1H),
4.10–3.96 (m, 3H), 3.91–3.68 (m, 3H), 2.97–2.90 (m, 1H),
2.71–2.62 (m, 2H), 2.48–2.38 (m, 1H), 2.24–1.90 (m, 8H),
1.68–1.36 (m, 7H), 1.18 (d, 3H, J¼6.1 Hz), 1.02 (d, 3H,
J¼6.9 Hz), 1.00 (d, 3H, J¼6.8 Hz), 0.82 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 211.8, 204.4,
139.2, 128.2, 127.6, 127.3, 80.8, 79.7, 79.1, 77.8, 76.9,
75.3, 74.6, 71.7, 52.1, 51.5, 48.4, 40.5, 36.4, 33.9, 31.8,
31.3, 30.8, 30.4, 29.4, 21.5, 12.8, 10.2, 10.0. IR (neat):
nmax¼3089, 3066, 3029, 2967, 2935, 1714, 1455, 1375,
1070, 892 cmꢀ1. [a]D27 +16.2 (c 0.65, CHCl3).
4.1.37. Secondary alcohol 34. Imidazole (52 mg,
0.77 mmol), TBDPSCl (0.10 mL, 0.45 mmol), and DMAP
(7.0 mg, 0.060 mmol) were added to a solution of keto car-
boxylic acid 33 (60 mg, 0.11 mmol) in CH2Cl2 (4 mL) at
room temperature. The reaction mixture was stirred for 2 h.
After evaporation of the solvent, flash column chromato-
graphy (Hex–EtOAc, 3:1) gave the corresponding TBDPS
ester (80 mg, 95%). Rf (Hex–EtOAc, 3:1). 1H NMR
(300 MHz, CDCl3): d 7.69 (d, 4H, J¼7.3 Hz), 7.54–7.23 (m,
11H), 4.53 and 4.44 (ABq, 2H, JAB¼11.3 Hz), 4.48–4.39
(m, 1H), 4.31–4.23 (m, 1H), 4.08–4.00 (m, 2H), 3.92–3.74
(m, 3H), 2.97–2.91 (m, 1H), 2.79–2.59 (m, 3H), 2.21–2.15
(m, 1H), 2.06–1.86 (m, 6H), 1.70–1.37 (m, 8H), 1.17 (d,
6H, J¼6.0 Hz), 0.93 (s, 9H), 0.97 (d, 3H, J¼6.9 Hz), 0.82
(d, 3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 211.8,
173.6, 139.1, 135.2, 131.96, 131.90, 129.9, 129.8, 128.2,
127.61, 127.59, 127.2, 80.5, 80.0, 79.6, 77.8, 75.2, 74.6,
A solution of NaClO2 (2.7 mg, 0.030 mmol) and NaH2PO4
(3.6 mg, 0.030 mmol) in water (0.15 mL) was added to

9798
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
71.6, 52.1, 48.1, 47.0, 40.5, 36.4, 33.9, 32.1, 31.3, 30.8,
29.22, 29.17, 26.8, 21.5, 19.1, 13.0, 12.8, 10.0.
quenched by addition of TEA (0.16 mL) and the reaction
mixture was concentrated. Purification of the residue
by flash column chromatography (EtOAc) gave the corre-
sponding acid (25 mg, 92%). Rf 0.4 (EtOAc). 1H NMR
(300 MHz, CDCl3): d 7.33–7.31 (m, 5H), 5.25–5.22 (m,
1H), 4.52 and 4.44 (ABq, 2H, JAB¼11.3 Hz), 4.45–4.31
(m, 2H), 4.17–4.02 (m, 5H), 3.92–3.75 (m, 6H), 3.04–3.00
(m, 1H), 2.84–2.80 (m, 1H), 2.66–2.58 (m, 4H), 2.54–2.47
(m, 2H), 2.23–2.13 (m, 3H), 2.01–1.94 (m, 13H), 1.79–
1.76 (m, 2H), 1.72–1.40 (m, 13H), 1.20 (d, 3H, J¼5.9 Hz),
1.18 (d, 3H, J¼5.9 Hz), 1.14 (d, 3H, J¼
7.0 Hz), 1.07 (d, 3H, J¼7.0 Hz), 1.00 (d, 3H, J¼6.0 Hz),
0.98 (d, 3H, J¼6.4 Hz), 0.82 (d, 3H, J¼6.6 Hz), 0.80 (d,
3H, J¼6.7 Hz). 13C NMR (75 MHz, CDCl3): d 211.8,
173.9, 139.1, 128.2, 127.7, 127.3, 80.6, 80.4, 79.7, 79.4,
77.8, 77.2, 75.4, 75.1, 74.8, 74.6, 73.0, 71.6, 65.8, 52.2,
52.1, 47.9, 47.7, 45.5, 44.6, 40.9, 40.5, 36.3, 36.0, 33.9,
33.8, 32.1, 32.0, 31.4, 31.1, 30.8, 30.6, 30.0, 29.3, 29.1,
21.4, 21.2, 15.2, 12.9, 12.73, 12.67, 10.5, 10.0. IR (neat):
nmax¼2967, 2877, 1731, 1712, 1457, 1376, 1189, 1070,
889, 736, 698 cmꢀ1. MS m/z (FAB, relative intensity): 953
(M++1, 4), 423 (10), 307 (28), 289 (14), 154 (100), 136
(65), 91 (30). HRMS (FAB) calcd for C55H85O13 (M++1)
953.5990, found 953.6002. [a]2D6 +6.3 (c 0.6, CHCl3).
The TBDPS ester (80 mg, 0.10 mmol) was dissolved in
EtOAc (5 mL) and palladium hydroxide on activated carbon
(20% w/w, 35 mg) was added. The reaction mixture was
stirred under hydrogen atmosphere for 1 h and then filtered
through a filter paper. After solvent evaporation, flash col-
umn chromatography (Hex–EtOAc, 3:1) yielded the second-
ary alcohol 34 (63 mg, 93%). Rf 0.28 (Hex–EtOAc, 3:1). 1H
NMR (300 MHz, CDCl3): d 7.69 (d, 4H, J¼6.8 Hz), 7.42–
7.27 (m, 6H), 4.74 (s, 1H), 4.47–4.39 (m, 1H), 4.34–
4.22 (m, 1H), 4.19–4.01 (m, 2H), 3.97–3.78 (m, 2H),
3.72–3.66 (m, 1H), 2.93–2.85 (m, 1H), 2.75–2.56 (m, 3H),
2.20–1.96 (m, 6H), 1.73–1.37 (m, 9H), 1.20–1.17 (m, 6H),
1.10 (s, 9H), 0.98 (d, 3H, J¼6.9 Hz), 0.73 (d, 3H,
J¼6.7 Hz). 13C NMR (75 MHz, CDCl3): d 211.5, 173.6,
135.2, 131.95, 131.89, 129.87, 129.84, 127.60, 127.57,
84.1, 80.4, 80.0, 76.8, 75.4, 75.1, 73.5, 52.4, 47.6, 47.0,
44.4, 40.5, 33.4, 32.2, 32.1, 31.3, 29.3, 29.1, 26.8, 21.1,
19.1, 13.0, 12.8, 12.6. IR (neat): nmax¼3462, 3072, 3049,
2966, 2933, 2881, 2862, 1728, 1462, 1429, 1377, 1254,
1190, 1115, 1068, 742, 700 cmꢀ1. [a]D23 ꢀ4.8(c 0.55, CHCl3).
4.1.38. Ester 37. To a mixture of the keto carboxylic acid 33
(33 mg, 0.062 mmol) and TEA (0.0220 mL, 0.155 mmol) in
THF (2.5 mL) was added 2,4,6-trichlorobenzoyl chloride
(0.016 mL, 0.105 mmol). The reaction mixture was stirred
for 2 h at room temperature. The white precipitate that had
formed was removed by filtration under N2 via cannula
transfer to a glass pipette equipped with a septum and
a plug of glass wool. The THF filtrate was evaporated by
a stream of N2. The residue was diluted with benzene
(3 mL) and DMAP (23 mg, 0.186 mmol) was added. To
this mixture was added the secondary alcohol 34 (55 mg,
0.081 mmol) in benzene (1 mL). The reaction mixture was
stirred for 2 h at room temperature and the reaction was
quenched by addition of saturated NH4Cl solution (3 mL).
The reaction mixture was extracted with CH2Cl2
(10 mLꢂ3). The organic extracts were dried over MgSO4,
filtered, and concentrated. Purification of the residue by flash
column chromatography (Hex–EtOAc, 1:1) gave ester 37
(68 mg, 92%). Rf 0.63 (Hex–EtOAc, 1:1). 1H NMR
(300 MHz, CDCl3): d 7.69 (d, 4H, J¼6.6 Hz), 7.42–7.26
(m, 10H), 5.19–5.16 (m, 1H), 4.53 and 4.44 (ABq, 2H,
JAB¼11.3 Hz), 4.45–4.33 (m, 2H), 4.30–4.23 (m, 1H),
4.15–4.04 (m, 4H), 3.90–3.75 (m, 6H), 2.89–2.80 (m, 2H),
2.72–2.49 (m, 6H), 2.18–2.04 (m, 2H), 1.99–1.81 (m,
13H), 1.70–1.28 (m, 15H), 1.19–1.16 (m, 9H), 1.09 (s,
9H), 1.09–1.05 (m, 3H), 1.00 (d, 3H, J¼6.9 Hz), 0.95 (d,
3H, J¼6.9 Hz), 0.82 (d, 3H, J¼7.0 Hz), 0.80 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 211.7, 211.6,
173.7, 173.6, 139.2, 135.2, 131.9, 129.9, 128.2, 127.63,
127.60, 127.3, 80.5, 80.1, 79.7, 79.6, 79.3, 77.8, 75.2,
75.1, 74.7, 74.6, 71.6, 52.1, 48.1, 47.8, 47.1, 45.5, 41.0,
40.5, 36.3, 36.1, 33.9, 32.2, 32.1, 31.4, 31.1, 30.8, 30.1,
29.3, 29.1, 26.8, 21.5, 21.3, 19.2, 13.0, 12.8, 10.6, 10.0.
[a]2D2 +5.0 (c 0.16, CHCl3).
The carboxylic acid (10 mg, 0.010 mmol) was dissolved in
EtOAc (1 mL) and palladium hydroxide on activated carbon
(20% w/w, 22 mg) was added. The reaction mixture was
stirred under hydrogen atmosphere for 1 h and then filtered
through a filter paper. After solvent evaporation, flash
column chromatography (EtOAc) yielded the dimeric seco
acid 38 (8.4 mg, 93%). Rf 0.2 (EtOAc). MS m/z (FAB, rela-
tive intensity): 863 (M++1, 9), 423 (24), 339 (11), 227 (7),
209 (18), 154 (32), 136 (26), 85 (100), 69 (19). HRMS
(FAB) calcd for C48H79O13 (M++1) 863.5520, found
863.5516.
The dimeric seco acid 38 (15 mg, 0.017 mmol) was dis-
solved in toluene (113 mL). TEA (0.15 mL, 1.04 mmol),
2,4,6-trichlorobenzoyl chloride (0.11 mL, 0.70 mmol), and
DMAP (42 mg, 0.35 mmol) were added to the solution at
room temperature, and then the solution was heated under
reflux for 4 h. The reaction was quenched by addition of
saturated NH4Cl solution (100 mL) and the reaction mixture
was extracted with CH2Cl2 (150 mLꢂ3). The organic
extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography
(Hex–EtOAc, 2:1) gave IKD-8344 (1, 9.5 mg, 65%). Rf 0.28
1
(Hex–EtOAc, 2:1). H NMR (400 MHz, CDCl3): d 5.32–
5.28 (m, 2H), 4.38–4.31 (m, 2H), 4.15–4.01 (m, 4H),
3.96–3.87 (m, 4H), 3.82–3.76 (m, 2H), 2.95–2.83 (m, 4H),
2.46–2.26 (m, 6H), 2.19–2.13 (m, 2H), 2.03–1.90 (m, 9H),
1.81–1.73 (m, 3H), 1.68–1.59 (m, 5H), 1.51–1.38 (m, 9H),
1.18 (d, 6H, J¼6.0 Hz), 1.09 (d, 6H, J¼7.4 Hz), 1.00 (d,
6H, J¼7.3 Hz), 0.83 (d, 6H, J¼7.5 Hz). 13C NMR
(100 MHz, CDCl3): d 212.0, 175.1, 80.5, 80.0, 79.5, 75.2,
74.9, 74.8, 72.2, 53.4, 45.6, 45.6, 41.1, 36.2, 33.9, 32.1,
30.9, 30.7, 29.6, 29.4, 21.2, 14.4, 13.7, 10.9. MS m/z
(FAB, relative intensity): 867 (M++Na, 58), 883 (45),
845 (14), 423 (12), 307 (22), 289 (11), 209 (43), 154
(83), 85 (100). HRMS (FAB) calcd for C48H76O12Na
(M++Na) 867.5235, found 867.5239. [a]1D5 +39.7 (c 0.25,
CHCl3).
4.1.39. IKD-8344 (1). Concd HCl (0.090 mL) was added to
a solution of ester 37 (34 mg, 0.028 mmol) in CH3OH
(3 mL) at 0 ꢁC, and the reaction mixture was allowed to
warm to room temperature. After 3 h, the reaction was

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9799
4.1.40. Keto alcohol 40. MeMgI (3.0 M in Et2O, 0.24 mL)
was added dropwise to a solution of the aldehyde obtained
from 16 (90 mg, 0.24 mmol) in THF (0.5 mL) at ꢀ78 ꢁC.
The reaction mixture was stirred at ꢀ78 ꢁC for 1 h and the
reaction was quenched by addition of saturated NH4Cl solu-
tion (8 mL). The reaction mixture was extracted with Et2O
(5 mLꢂ3). The organic extracts were dried over MgSO4, fil-
tered, and concentrated. Purification of the residue by flash
column chromatography (Hex–EtOAc, 2:1) gave a mixture
of alcohols. Rf 0.50 (Hex–EtOAc, 2:1).
was allowed to warm to room temperature and stirred for
1 h. The reaction was quenched by addition of acetone
(4 mL) and water (80 mL), and the reaction mixture was ex-
tracted with Et2O (50 mLꢂ3). The organic extracts were
dried over MgSO4, filtered, and concentrated. Purification
of the residue by flash column chromatography (Hex–
Et2O, 8:1) gave the corresponding olefin (0.91 g, 61%). Rf
0.56 (Hex–Et2O, 8:1). 1H NMR (300 MHz, CDCl3):
d 7.70–7.66 (m, 4H), 7.43–7.34 (m, 6H), 5.88–5.77 (m,
1H), 5.20 (d, 1H, J¼17.1 Hz), 5.05 (d, 1H, J¼10.3 Hz),
4.34–4.26 (m, 1H), 4.02–3.94 (m, 1H), 3.75–3.63 (m, 2H),
2.09–2.01 (m, 1H), 2.00–1.93 (m, 1H), 1.90–1.79 (m, 1H),
1.66–1.54 (m, 2H), 1.05 (s, 9H), 0.95 (d, 3H, J¼6.8 Hz).
13C NMR (75 MHz, CDCl3): d 139.7, 135.6, 134.0, 133.9,
129.44, 129.40, 127.53, 127.52, 114.6, 80.3, 79.7, 66.2,
40.8, 32.7, 29.5, 26.9, 19.3, 12.9. IR (neat): nmax¼3070,
3051, 2962, 2931, 2858, 1469, 1427, 1111, 1057, 702,
505 cmꢀ1. MS m/z (CI, relative intensity): 395 (M++1, 44),
337 (53), 317 (100), 303 (34), 209 (16), 199 (11), 121
(81), 107 (28). HRMS (CI) calcd for C25H35O2Si (M++1)
395.2406, found 395.2409. [a]2D5 +5.6 (c 0.36, CHCl3).
Dess–Martin periodinane (153 mg, 0.361 mmol) was added
to a solution of the mixture of the alcohols in CH2Cl2
(16 mL). The reaction mixture was stirred at room tempera-
ture for 1 h and the reaction was quenched by addition of
saturated Na2S2O3 solution (10 mL). The reaction mixture
was extracted with CH2Cl2 (15 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. Purifica-
tion of the residue by flash column chromatography (Hex–
EtOAc, 2:1) gave the corresponding ketone (68.0 mg, 73%
for two steps). Rf 0.56 (Hex–EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): d 7.33–7.25 (m, 5H), 4.45 and 4.54
(ABq, 2H, JAB¼11.4 Hz), 4.06–4.00 (m, 2H), 3.94–3.84
(m, 2H), 3.82–3.76 (m, 1H), 2.67–2.57 (m, 1H), 2.24 (s,
3H), 2.01–1.97 (m, 5H), 1.66–1.55 (m, 5H), 1.49–1.36 (m,
1H), 1.17 (d, 3H, J¼6.0 Hz), 1.01 (d, 3H, J¼6.9 Hz), 0.82
(d, 3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 212.3,
139.2, 128.2, 127.7, 127.3, 80.9, 79.7, 77.4, 76.7, 74.5,
71.6, 52.5, 40.5, 36.3, 33.9, 31.3, 31.0, 30.4, 29.5, 21.4,
12.9, 9.9. IR (neat): nmax¼3091, 3064, 3030, 2968, 2937,
TBAF (1.0 M in THF, 3.5 mL) was added to a solution of the
olefin (0.91 g, 2.3 mmol) in THF (23 mL) at room tempera-
ture and the reaction mixture was stirred for 2 h. After evap-
oration of the solvent, the residue was purified by flash
column chromatography (Hex–EtOAc, 4:1) to give the cor-
responding alcohol (0.36 g, 99%). Rf 0.22 (Hex–EtOAc,
1
4:1). H NMR (300 MHz, CDCl3): d 5.88–5.77 (m, 1H),
5.22 (d, 1H, J¼17.1 Hz), 5.08 (d, 1H, J¼10.3 Hz), 4.47–
4.40 (m, 1H), 3.88–3.81 (m, 1H), 3.67–3.59 (m, 3H),
2.17–2.02 (m, 2H), 1.80–1.71 (m, 1H), 1.70–1.56 (m, 2H),
0.80 (d, 3H, J¼6.9 Hz). 13C NMR (75 MHz, CDCl3):
d 138.8, 115.1, 85.5, 80.1, 68.7, 40.7, 32.0, 31.7, 13.3. IR
(neat): nmax¼3402, 3070, 2958, 2931, 2858, 1466, 1427,
1111, 1034, 872, 706, 505 cmꢀ1. [a]D25 ꢀ0.9 (c 0.75, CHCl3).
2877, 1712, 1456, 1375, 1358, 1090, 1072, 737, 698 cmꢀ1
.
MS m/z (CI, relative intensity): 389 (M++1, 100), 281 (53),
197 (22), 167 (17), 141 (17), 85 (53). HRMS (CI) calcd
for C24H37O4 (M++1) 389.2692, found 389.2689. [a]2D6
+11.0 (c 0.26, CHCl3).
The ketone (196 mg, 0.504 mmol) was dissolved in CH3OH
(9 mL) and palladium on activated carbon (10% w/w,
268 mg) was added. The reaction mixture was stirred under
hydrogen atmosphere for 4 h and then filtered through a filter
paper. After solvent evaporation, flash column chromato-
graphy (Hex–EtOAc, 2:1) yielded the keto alcohol 40
(147 mg, 98%). Rf 0.22 (Hex–EtOAc, 2:1). 1H NMR
(300 MHz, CDCl3): d 4.71 (s, 1H), 4.13–4.08 (m, 2H),
3.99–3.84 (m, 2H), 3.76–3.70 (m, 1H), 2.62–2.55 (m, 1H),
2.20 (s, 3H), 2.16–2.08 (m, 1H), 2.03–1.99 (m, 3H), 1.77–
1.70 (m, 1H), 1.66–1.35 (m, 6H), 1.20 (d, 3H, J¼6.0 Hz),
1.03 (d, 3H, J¼6.9 Hz), 0.76 (d, 3H, J¼6.7 Hz). 13C NMR
(75 MHz, CDCl3): d 211.6, 84.0, 80.5, 76.8, 75.4, 73.4,
52.8, 44.4, 40.4, 33.4, 32.2, 31.3, 29.2, 29.1, 21.1, 12.8,
12.5. IR (neat): nmax¼3458, 2968, 2933, 2877, 1712, 1460,
1444, 1377, 1356, 1095, 1066, 876, 820 cmꢀ1. MS m/z
(CI, relative intensity): 299 (M++1, 100), 281 (20), 227
(11), 197 (8), 185 (11), 141 (14), 85 (43). HRMS (CI) calcd
for C17H31O4 (M++1) 299.2222, found 299.2222. [a]2D6 ꢀ3.7
(c 0.25, CHCl3).
Dess–Martin periodinane (1.16 g, 2.75 mmol) was added to
a solution of the alcohol (358 mg, 2.29 mmol) in CH2Cl2
(150 mL). The reaction mixture was stirred at room temper-
ature for 1.5 h and the reaction was quenched by addition of
saturated Na2S2O3 solution (80 mL). The reaction mixture
was extracted with CH2Cl2 (50 mLꢂ3). The organic extracts
were dried over MgSO4, filtered, and concentrated. Purifica-
tion of the residue by flash column chromatography (Hex–
EtOAc, 4:1) gave the corresponding aldehyde (291 mg,
82%). Rf 0.51 (Hex–EtOAc, 4:1). 1H NMR (300 MHz,
CDCl3): d 9.79 (d, 1H, J¼2.1 Hz), 5.88–5.77 (m, 1H),
5.23 (d, 1H, J¼17.1 Hz), 5.10 (d, 1H, J¼10.3 Hz), 4.46–
4.41 (m, 1H), 4.21–4.14 (m, 1H), 2.54–2.45 (m, 1H),
2.17–2.08 (m, 2H), 1.72–1.63 (m, 2H), 1.07 (d, 3H,
J¼6.9 Hz). 13C NMR (75 MHz, CDCl3): d 204.3, 138.8,
115.2, 80.2, 79.4, 51.5, 32.0, 30.2, 10.3.
A solution of NaClO2 (111 mg, 1.23 mmol) and NaH2PO4
(147 mg, 1.23 mmol) in water (5.50 mL) was added to a
solution of the aldehyde (291 mg, 1.89 mmol) in t-BuOH
(110 mL) and 2-methyl-2-butene (55.0 mL). The reaction
mixture was stirred for 1 h at room temperature and then
an additional equivalent of NaClO2 and NaH2PO4 in water
was added to the solution. After 1 h, the reaction mixture
was concentrated and the residue was dissolved in Et2O
(80 mL) and water (50 mL). The solution was acidified
4.1.41. Acid 39. n-BuLi (2.5 M in hexane, 1.6 mL) was
added dropwise to a solution of MePPh3Br (1.4 g,
4.0 mmol) in THF (20 mL) at ꢀ78 ꢁC. The resulting orange
solution was stirred at ꢀ78 ꢁC for 30 min. A solution of
aldehyde 31 (1.6 g, 4.0 mmol) in THF (20 mL) was added
dropwise to the solution at ꢀ78 ꢁC. After 1 h, the mixture

9800
W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
(pH 2) by addition of 2 N HCl solution. The aqueous layer
was extracted with Et2O (50 mLꢂ3) and the organic extracts
were dried over MgSO4. Filtration, concentration, and puri-
fication of the residue by flash column chromatography
(CHCl3–MeOH, 5:1) gave acid 39 (255 mg, 79%). Rf 0.19
(CHCl3–MeOH, 5:1). 1H NMR (300 MHz, CDCl3):
d 5.88–5.77 (m, 1H), 5.24 (d, 1H, J¼17.1 Hz), 5.09 (d,
1H, J¼10.3 Hz), 4.50–4.34 (m, 1H), 4.24–4.11 (m, 1H),
2.62–2.53 (m, 1H), 2.17–2.06 (m, 2H), 1.76–1.60 (m, 2H),
1.17 (d, 3H, J¼7.1 Hz). 13C NMR (75 MHz, CDCl3):
d 179.8, 138.6, 115.4, 80.3, 80.0, 44.9, 32.2, 29.6, 13.0. IR
(neat): nmax¼3084, 2978, 2941, 2883, 2636, 1712, 1462,
1425, 1227, 1057, 928, 889, 854 cmꢀ1. MS m/z (CI, relative
intensity): 171 (M++1, 37), 153 (93), 125 (14), 101 (38), 97
(100), 83 (15), 59 (37). HRMS (CI) calcd for C9H15O3
(M++1) 171.1021, found 171.1022. [a]2D6 +15.3 (c 0.44,
CHCl3).
by column chromatography (Hex–EtOAc, 4:1) on neutral
alumina to afford the TBS enol ether 41 (34 mg, 93%). Rf
0.50 (Hex–EtOAc, 4:1). 1H NMR (300 MHz, CDCl3):
d 5.85–5.74 (m, 1H), 5.25–5.16 (m, 2H), 5.03 (d, 1H,
J¼10.3 Hz), 4.41–4.35 (m, 1H), 4.24–4.16 (m, 1H), 4.13–
4.00 (m, 3H), 3.93–3.79 (m, 3H), 2.58–2.53 (m, 1H),
2.35–2.29 (m, 1H), 2.09–1.93 (m, 9H), 1.79–1.56 (m, 3H),
1.46–1.37 (m, 3H), 1.17 (d, 3H, J¼6.0 Hz), 1.11 (d, 3H,
J¼7.0 Hz), 0.95 (d, 3H, J¼6.9 Hz), 0.91 (s, 9H), 0.83 (d,
3H, J¼6.9 Hz), 0.16 (d, 6H, J¼4.4 Hz). 13C NMR
(75 MHz, CDCl3): d 174.0, 161.2, 139.2, 130.9, 128.8,
114.7, 89.1, 80.2, 79.9, 79.3, 74.7, 73.6, 45.6, 44.7, 41.0,
36.3, 33.9, 32.5, 31.8, 29.8, 29.2, 27.7, 27.4, 25.7, 21.3,
19.1, 18.1, 13.2, 13.0, 10.7, ꢀ4.7, ꢀ4.8.
4.1.43. Attempted ring-forming metathesis reaction of
the silyl enol ether 41. A suspension of catalyst 42
˚
(6.0 mg, 0.0090 mmol) and 4 A molecular sieves (0.40 g)
4.1.42. Silyl enol ether 41. To a mixture of acid 39 (30 mg,
0.174 mmol) and TEA (0.0620 mL, 0.442 mmol) in THF
(5 mL) was added 2,4,6-trichlorobenzoyl chloride
(0.0460 mL, 0.295 mmol). The reaction mixture was stirred
for 2 h at room temperature. The white precipitate that had
formed was removed by filtration under N2 via cannula
transfer to a glass pipette equipped with a septum and
a plug of glass wool. The THF filtrate was evaporated by
a stream of N2. The residue was diluted with benzene
(4 mL) and DMAP (49 mg, 0.402 mmol) was added. To
this mixture was added alcohol 40 (40.0 mg, 0.134 mmol)
in benzene (3 mL). The reaction mixture was stirred for
2 h at room temperature and the reaction was quenched by
addition of saturated NH4Cl solution (4 mL). The reaction
mixture was extracted with CH2Cl2 (8 mLꢂ3). The organic
extracts were dried over MgSO4, filtered, and concentrated.
Purification of the residue by flash column chromatography
(Hex–EtOAc, 2:1) gave the corresponding ester (55 mg,
92%). Rf 0.47 (Hex–EtOAc, 2:1). 1H NMR (300 MHz,
CDCl3): d 5.86–5.74 (m, 1H), 5.28–5.23 (m, 1H), 5.19 (d,
1H, J¼17.1 Hz), 5.04 (d, 1H, J¼10.3 Hz), 4.42–4.35 (m,
1H), 4.22–4.15 (m, 1H), 4.13–4.02 (m, 1H), 3.88–3.80 (m,
3H), 2.64–2.50 (m, 2H), 2.23 (s, 3H), 2.14–1.88 (m, 8H),
1.85–1.80 (m, 1H), 1.71–1.35 (m, 6H), 1.18 (d, 3H,
J¼6.0 Hz), 1.10 (d, 3H, J¼7.0 Hz), 1.00 (d, 3H,
J¼6.9 Hz), 0.83 (d, 3H, J¼6.9 Hz). 13C NMR (75 MHz,
CDCl3): d 212.1, 173.9, 139.2, 114.6, 80.5, 80.3, 79.9,
79.4, 76.5, 74.6, 73.1, 52.5, 45.6, 41.0, 36.2, 33.8, 32.4,
31.1, 29.9, 29.6, 29.3, 29.2, 21.3, 13.0, 12.8, 10.6. IR
(neat): nmax¼2970, 2933, 2877, 1732, 1714, 1460, 1377,
1356, 1254, 1190, 1057, 951, 891 cmꢀ1. MS m/z (CI, relative
intensity): 451 (M++1, 47), 379 (19), 281 (100), 197 (27),
141 (14), 85 (37). HRMS (CI) calcd for C26H43O6 (M++1)
451.3059, found 451.3058. [a]2D8 +5.4 (c 1.15, CHCl3).
in benzene (8 mL) was heated under reflux. A solution of
the silyl enol ether 41 (25 mg, 0.044 mmol) in benzene
(2 mL) was added slowly to the suspension over 30 min.
After 30 min, the reaction mixture was allowed to cool to
room temperature and the solvent was removed. Purification
of the residue by flash column chromatography (Hex–
EtOAc, 4:1) provided the starting material 41 (9.9 mg,
40%) and a product tentatively assigned as the tail–tail dimer
(12 mg, 25%). Rf 0.19 (Hex–EtOAc, 4:1). 1H NMR
(300 MHz, CDCl3): d 5.58–5.66 (m, 2H), 5.24–5.19 (m,
2H), 4.37 (br s, 2H), 4.25–4.18 (m, 2H), 4.13–4.06 (m,
2H), 4.06 (s, 2H), 4.01 (s, 2H), 3.93–3.80 (m, 6H), 2.60–
2.55 (m, 2H), 2.34–2.30 (m, 2H), 2.05–1.87 (m, 18H),
1.78–1.52 (m, 8H), 1.47–1.37 (m, 4H), 1.17 (d, 6H,
J¼6.0 Hz), 1.10 (d, 6H, J¼7.0 Hz), 0.96 (d, 6H, J¼
6.9 Hz), 0.92 (s, 18H), 0.83 (d, 6H, J¼6.9 Hz), 0.16 (d,
12H, J¼4.2 Hz).
Acknowledgements
This work was supported by a grant from the Center for Bio-
active Molecular Hybrids (Yonsei University and KOSEF),
and a grant from MarineBio21, Ministry of Maritime Affairs
and Fisheries, Korea. BK21 graduate fellowship grants to
W.H.K., S.K.H., S.M.L., S.K.J., Y.W.K., and J.H.J. are
gratefully acknowledged.
Supplementary data
Supplementary data associated with this article can be found
in the online version, at doi:10.1016/j.tet.2007.07.005.
KHMDS (0.50 M in toluene, 0.20 mL) was added to a
solution of TBSCl (50 mg, 0.33 mmol) in THF (1 mL) at
ꢀ78 ꢁC. To the resulting mixture was added dropwise a solu-
tion of the ester (30 mg, 0.070 mmol) in THF (1 mL) at
ꢀ78 ꢁC over 30 min. After stirring for 1 h at ꢀ78 ꢁC, TEA
(0.050 mL, 0.33 mmol) was added followed by saturated
NaHCO3 solution (3 mL). The reaction mixture was stirred
at 23 ꢁC for 20 min and extracted with petroleum ether
(5 mLꢂ3). The organic extracts were dried over Na2SO4, fil-
tered, and concentrated. The resulting residue was purified
References and notes
1. For a recent review on total syntheses of oxacyclic macro-
diolides, see: Kang, E. J.; Lee, E. Chem. Rev. 2005, 105,
4348–4378.
2. (a) Minami, Y.; Yoshida, K.; Azuma, R.; Nishii, M.; Inagaki, J.;
Nohara, F. Tetrahedron Lett. 1992, 33, 7373–7376; (b) Ishida,
T.; In, Y.; Nishii, M.; Minami, Y. Chem. Lett. 1994, 23,
1321–1322.

W. H. Kim et al. / Tetrahedron 63 (2007) 9784–9801
9801
3. Hwang, E. I.; Yun, B. S.; Yeo, W. H.; Lee, S. H.; Moon, J. S.;
Kim, Y. K.; Lim, S. J.; Kim, S. U. J. Microbiol. Biotechnol.
2005, 15, 909–912.
4. Jiang, W.; Lantrip, D. A.; Fuchs, P. L. Org. Lett. 2000,2, 2181–2184.
5. Kim, W. H.; Hong, S. K.; Lim, S. M.; Ju, M.-A.; Jung, S. K.;
Kim, Y. W.; Jung, J. H.; Kwon, M. S.; Lee, E. Angew. Chem.,
Int. Ed. 2006, 45, 7072–7075.
6. For example, there is a report on the asymmetric titanium
aldol reactions involving cyclic oxocarbenium ion derived
from (S)-glutamic acid, but we were not able to reproduce
the results: Pilli, R. A.; Riatto, V. B.; Vencato, I. Org. Lett.
2000, 2, 53–56.
7. For an example of the use of this known aldehyde, see: Smith,
A. B., III; Kim, D.-S. J. Org. Chem. 2006, 71, 2547–2557.
8. For an example of asymmetric aldol reactions, see: Evans,
D. A.; Kaldor, S. W.; Jones, T. K.; Clardy, J.; Stout, T. J.
J. Am. Chem. Soc. 1990, 112, 7001–7031.
J. M.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Kwak, H. S.;
Park, J. H.; Lee, E.; Hong, C. Y.; Jeong, S.; Jeon, K.; Park,
J. H. J. Org. Chem. 2003, 68, 8080–8087; (c) Jeong, E. J.;
Kang, E. J.; Sung, L. T.; Hong, S. K.; Lee, E. J. Am. Chem.
Soc. 2002, 124, 14655–14662; (d) Lee, E.; Choi, S. J.; Kim,
H.; Han, H. O.; Kim, Y. K.; Min, S. J.; Son, S. H.; Lim,
S. M.; Jang, W. S. Angew. Chem., Int. Ed. 2002, 41, 176–178.
14. Lee, E.; Choi, S. J. Org. Lett. 1999, 1, 1127–1128.
15. For examples for room temperature metallation of 2-
substituted 1,3-dithiane derivatives, see: Ide, M.; Nakata, M.
Bull. Chem. Soc. Jpn. 1999, 72, 2491–2499.
16. (a) Matsushita, M.; Nagaoka, Y.; Hioki, H.; Fukuyama, Y.;
Kodama, M. Chem. Lett. 1996, 25, 1039–1040; (b) De
Brabander, J.; Vanhessche, K.; Vandewalle, M. Tetrahedron
Lett. 1991, 32, 2821–2824.
17. For profitable use of PMB ethers in place of benzyl ethers, see
the Ref. 15.
9. See the following reference for detailed discussions: Evans,
D. A.; Allison, B. D.; Yang, M. G.; Masse, C. E. J. Am.
Chem. Soc. 2001, 123, 10840–10852.
10. It was best to keep the mesyloxy group until this point as the
volatility problem arose when mesyloxy group was removed
at an earlier stage.
11. For use of magnesium bromide etherate in allylstannane reac-
tion, see: Lee, E.; Jeong, E. J.; Kang, E. J.; Sung, L. T.; Hong,
S. K. J. Am. Chem. Soc. 2001, 123, 10131–10132.
12. Walkup, R. D.; Obeyesekere, N. U. Synthesis 1987, 607–611.
13. For recent examples of b-alkoxyacrylate and b-alkoxymeth-
acrylate radical cyclization, see: (a) Kang, E. J.; Cho, E. J.;
Ji, M. K.; Lee, Y. E.; Shin, D. M.; Choi, S. Y.; Chung, Y. K.;
Kim, J.-S.; Kim, H.-J.; Lee, S.-G.; Lah, M. S.; Lee, E.
J. Org. Chem. 2005, 70, 6321–6329; (b) Song, H. Y.; Joo,
18. Kim, W. H.; Jung, J. H.; Sung, L. T.; Lim, S. M.; Lee, E. Org.
Lett. 2005, 7, 1085–1087.
19. For an example of the successful macrodiolide formation under
similar conditions, see: F€urstner, A.; Mlynarski, J.; Albert, M.
J. Am. Chem. Soc. 2002, 124, 10274–10275.
20. The spectral data of the synthetic sample were identical with
those of the natural product.
21. For use of the modified Yamaguchi conditions, see: Evans,
D. A.; Ng, H. P.; Rieger, D. L. J. Am. Chem. Soc. 1993, 115,
11446–11459.
22. Garber, S. B.; Kingsbury, J. S.; Gray, B. L.; Hoveyda, A. H.
J. Am. Chem. Soc. 2000, 122, 8168–8179.
23. (a) Okada, A.; Ohshima, T.; Shibasaki, M. Tetrahedron Lett.
2001, 42, 8023–8027; (b) Aggarwal, V. K.; Daly, A. M.
Chem. Commun. 2002, 2490–2491.