Enantioselective total synthesis of aigialomycin D

Article abstract of DOI:10.1016/j.tetasy.2006.03.027

An efficient, convergent approach for the total synthesis of aigialomycin D 1 is described. Key features of the synthetic strategy include (a) a Sharpless asymmetric epoxidation reaction and selective opening of a 2,3-epoxy alcohol to elaborate the two hy

Full text of DOI:10.1016/j.tetasy.2006.03.027

Tetrahedron: Asymmetry 17 (2006) 1066–1073
Enantioselective total synthesis of aigialomycin D
Jiangping Lu,a Junying Ma,a Xingang Xie,a Bo Chen,a Xuegong Shea,b, and Xinfu Pan
a,
*
*
aDepartment of Chemistry, State Key Laboratory of Applied Organic Chemistry, Lanzhou University, Lanzhou 730000, PR China
bState Key Laboratory of Synthesis and Selective Oxidation, Lanzhou Institute of Chemical Physics, Chinese Academy of Sciences,
Lanzhou 730000, PR China
Received 8 February 2006; accepted 24 March 2006
Available online 6 May 2006
Abstract—An efficient, convergent approach for the total synthesis of aigialomycin D 1 is described. Key features of the synthetic
strategy include (a) a Sharpless asymmetric epoxidation reaction and selective opening of a 2,3-epoxy alcohol to elaborate the
two hydroxy-bearing stereogenic centers at the C50 and C60 positions; (b) a Kocienski modified Julia protocol to construct the two
E-configured double bonds; and (c) Yamaguchi macrolactonization to acccess the 14-membered macrocyclic ring.
ꢀ 2006 Elsevier Ltd. All rights reserved.
1. Introduction
Yamaguchi macrolactonization of 2, which in turn could
be obtained by Kocienski modified Julia coupling of alde-
hyde 4 with sulfone 3. Aldehyde 4 could be disconnected
between C10 and C20 to give aldehyde 6 and sulfone 5.
Sulfones 3 and 5 could be obtained from commercially
available (S)-butane-1,3-diol 7 and 2,3-epoxy alcohol 8,4
respectively.
The resorcinylic macrolides, a novel family of naturally
occurring homologous macrolides, are usually bacterial
metabolites with unique chemical structures and potent
biological activities (antitumor, antibiotic, and antimalar-
ial).1 These attractive biological properties of the structur-
ally related macrolactones render them desirable for the
total syntheses and serve as excellent scaffolds for the develop-
ment and validation of new synthetic methodologies.2
2. Results and discussion
Aigialomycin D, a new 14-membered resorcyclic macro-
lide, which was isolated from the mangrove fungus, Aigia-
lus parvus BCC 5311,3 has been shown to possess potent
antimalarial activity (IC50 value of 6.6 lg/mL against
Plasmodium falciparum K1) and antitumor activity (IC50
value of 3.0 lg/mL against KB cells).3 The total synthesis
of aigialomycin D has been previously reported by Dani-
shefsky.2f,g In his approach, all the stereogenic centers were
derived from chiral pool starting materials. Herein, we
report the enantioselective total synthesis of aigialomycin
D utilizing a Sharpless asymmetric epoxidation reaction
as the source of chirality from the commercially available
starting material propargyl alcohol.
Our starting point for sulfone 5 was commercially available
propargyl alcohol 9 (Scheme 2). Thus, alkylation of 9 with
1-((3-iodopropoxy)methyl)benzene gave propargylic alco-
hol 10 in 95% yield; this was converted into (E)-allylic alco-
hol 11 in 96% yield by LiAlH4 reduction.5 Treatment of 11
with Ti(O-iPr)4 and TBHP in the presence of (ꢀ)-DIPT
ligand under Sharpless AE conditions6 afforded the epoxy
alcohol 84 in 89% yield with excellent (91% ee) selectivity.
The titanium-assisted regioselective opening of 2,3-epoxy
alcohol 8 with PhCO2H gave 12 in 75% yield,7 which was
further converted into triol 13 by treatment with EtMgBr.8
The primary hydroxyl group of 13 was protected as its
pivaloyl derivative and the two secondary hydroxyl groups
were engaged in an isopropylidene linkage (see 15). Com-
pound 15 was easily converted into alcohol 162f,g in excel-
The retrosynthetic analysis is outlined in Scheme 1. We
envisioned that aigialomycin D would be derived from a
lent yield by
a standard hydrogenation procedure.
Mitsunobu reaction of 16 with 1-phenyl-1H-tetrazole-5-
thiol followed by oxidation of the resultant sulfide fur-
nished sulfone 5 in good yield over two steps.9
*
Corresponding authors. Tel.: +86 931 891 2407; fax: +86 931 891 2582
(X.S.); e-mail: shexg@lzu.edu.cn
0957-4166/$ - see front matter ꢀ 2006 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2006.03.027

J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
1067
OH
5
O
OMOM
COOH
OH
3
O
10'
8'
1
1'
HO
MOMO
O
5'
OH
OH
O
2'
2
aigialomycin D (1)
TBSO
OMOM
Br
H
O
O
O
OH
N
N
+
S
O
O
3
HO
N
MOMO
N
7
4
Ph
OPiv
OMOM
O
Br
+
OH
O
BnO
N
N
O
N
N
O
MOMO
S
O
O
H
8
5
6
Ph
Scheme 1. Retrosynthetic analysis of aigialomycin D 1.
c
a
OH
b
BnO
BnO
OR2
OH
OH
OH
9
10
11
OPiv
O
g
OH
d
BnO
RO
BnO
O
OR1
O
12. R1 = Bz, R2 = H;
13. R1 = H, R2 = H;
14. R1 = H, R2 = Piv.
8
e
15. R = Bn;
16. R = H.
OPiv
O
h
N
N
f
N
i,j
N
S
O
O
Ph
O
5
Scheme 2. Reagents and conditions: (a) BnOCH2CH2CH2I, BuLi, HMPA, ꢀ78 ꢁC, 8 h, 70%; (b) LiAlH4, THF, reflux, 1 h, 96%; (c) Ti(O-iPr)4, TBHP,
(ꢀ)-DIPT, cat. CaH2, CH2Cl2, ꢀ25 ꢁC, 12 h, 89%; (d) Ti(O-iPr)4, PhCO2H, CH2Cl2, rt, 15 min, 75%; (e) EtMgBr, ether, rt, 1 h, 95%; (f) PivCl, Et3N,
DMAP, CH2Cl2, rt, 10 h, 88%; (g) 2-methoxypropene, PPTS, CH2Cl2, rt, 5 h, 95%; (h) 10% Pd/C, H2, EtOH, rt, 4 h, 95%; (i) 1-phenyl-1H-tetrazole-5-
thiol, DIAD, PPh3, THF, 0 ꢁC to rt, 1 h; (j) m-CPBA, NaHCO3, rt, CH2Cl2, 12 h, 81% for two steps.
Aldehyde 6 was readily prepared from alcohol 17 in two
steps (Scheme 3): regioselective aromatic bromination with
NBS and oxidation with PCC.
1-phenyl-1H-tetrazole-5-thiol, followed by oxidation of
the resultant sulfide, furnished sulfone 3 in good yield over
two steps.9
OR2
N
OMOM
OMOM
Br
OMOM
Br
N
OTBS
OH
a
d,e
N
R1O
a
b
N
Ph
S
HO
O
O
OH
19. R1 = Bz, R2 = H;
OH
O
3
7
MOMO
MOMO
MOMO
b
20. R1 = Bz, R2 = TBS;
21. R1 = H, R2 = TBS
c
6
17
18
H
Scheme 3. Reagents and conditions: (a) NBS, CHCl3, rt, 30 min, 98%; (b)
PCC, NaOAc, CH2Cl2, rt, 4 h, 85%.
Scheme 4. Reagents and conditions: (a) BzCl, Et3N, DMAP, CH2Cl2, rt,
10 h, 80%; (b) TBSCl, C3H4N2 (imidazole), DMF, rt, 5 h, 95%; (c)
DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 1 h, 95%; (d) 1-phenyl-1H-tetrazole-5-thiol,
DIAD, PPh3, THF, 0 ꢁC to rt, 1 h; (e) m-CPBA, NaHCO3, CH2Cl2, rt,
12 h, 83% for two steps.
The synthesis of sulfone 3 started from commercially avail-
able (S)-butane-1,3-diol 7 (Scheme 4). Selective protection
of the primary hydroxyl group of 7 with BzCl and protec-
tion of the secondary hydroxyl group with TBSCl, followed
by reductive removal of the benzoate moiety with DIBAL-
H, provided alcohol 21. Mitsunobu reaction of 21 with
Having completed the synthesis of the key fragments 3, 5,
and 6, we needed to couple the three fragments in sequence
and carry out subsequent macrolactonization. First, the

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J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
OMOM
Br
OMOM
Br
OR
O
H
O
O
O
c
a
d
5 + 6
MOMO
MOMO
O
4
22. R = Piv;
b
23. R = H.
MOMO
R1O
R2
MOMO
O
OH
O
O
g
O
h
MOMO
O
MOMO
HO
O
O
24. R1 = TBS, R2 = Br;
25. R1 = H, R2 = Br;
2. R1 = H, R2 = COOH
OH
26
e
O
OH
aigialomycin D 1
f
Scheme 5. Reagents and conditions: (a) KHMDS, DME, ꢀ60 ꢁC to rt, 3 h, 68%; (b) DIBAL-H, CH2Cl2, ꢀ78 ꢁC, 1 h, 96%; (c) Dess–Martin periodinane,
CH2Cl2, rt, 2 h, 85%; (d) 3, KHDMS, DME, ꢀ60 ꢁC to rt, 3 h, 58%, (e) TBAF, THF, rt, 8 h, 95%, (f) n-BuLi, CO2, THF, ꢀ78 ꢁC to rt, 2 h, 83%; (g) 2,4,6-
trichlorobenzoylchloride, Et3N, THF, rt, 2 h, then DMAP, toluene, reflux, 36 h, 51%; (h) 0.5 M HCl, H2O/MeOH, rt, 2 d, 70%.
addition of aldehyde 6 to the potassium salt of sulfone 5 in
DME (Scheme 5) provided (E)-ene 22 in 68% yield with
good stereoselectivity (E/Z = 95/5).9,10 Reductive removal
of the pivaloate moiety with DIBAL-H gave 23 in 96%
yield, which was oxidized to the corresponding aldehyde
4 under Dess–Martin conditions,11 then subsequently
treated with the potassium salt of sulfone 3 in DME under
conventional Julia–Kocienski conditions9,10 to afford com-
pound 24 with moderate stereoselectivity (E/Z = 83/17).
Removal of the TBS group in 24 with TBAF and carboxyl-
ation with n-BuLi and CO2 afforded acid 2. Finally,
macrolactonization of 2 under Yamaguchi conditions12
produced macrocyclic lactone 26,2f,g which on subsequent
cleavage of the protecting groups2f,g afforded target
molecule 1. The physical and spectroscopic data of 1 were
identical with those reported.2f,g,3
dried by standard methods prior to use. All commercially
available reagents were used without further purification
unless otherwise noted. Column chromatography was per-
formed on silica gel (200–300 mesh). Optical rotations were
measured on a Perkin–Elmer model 341 polarimeter. Infra-
red spectra were recorded on a Nicolet NEXUS 670 FT-IR
spectrometer. 1H NMR and 13C NMR spectra were
recorded on Varian Mercury-300 (300 MHz) or Bruker
AM-400 (400 MHz) spectrometers. Chemical shifts are
reported as d values relative to internal chloroform (d
1
7.26 for H and 77.0 for 13C).
4.2. 6-(Benzyloxy)hex-2-yn-1-ol 10
To a solution of propargyl alcohol 9 (168 mg, 3.0 mmol) in
THF (3 mL) was added n-BuLi (2.0 M in petroleum ether,
3.0 mL, 6.0 mmol) at ꢀ78 ꢁC. The white suspension was
warmed up to 0 ꢁC and stirred for 30 min before adding
HMPA (1.5 mL) at ꢀ50 ꢁC. Thirty minutes later, 1-((3-iodo-
propoxy)methyl)benzene (830 mg, 3.0 mmol) in THF
(1 mL) was added via a cannula and the mixture was
warmed up to rt (8 h) before being quenched with saturated
aqueous NH4Cl solution, and extracted with EtOAc
(50 mL · 3). The organic layers were combined, washed
with saturated aqueous NaCl solution, and dried with
anhydrous Na2SO4, filtered, and concentrated under re-
duced pressure vacuum. The residue was purified on a silica
gel column using petroleum ether/ethyl acetate (5/1) as the
3. Conclusion
In conclusion, we have achieved the enantioselective total
synthesis of aigialomycin D with inexpensive commercially
available starting materials. Notable features of this
approach include a Sharpless asymmetric epoxidation
reaction and selective opening of a 2,3-epoxy alcohol to
elaborate the two hydroxy-bearing stereogenic centers at
the C50 and C60 position; application of the Kocienski
modified Julia protocol to construct the two E-configured
double bonds, and Yamaguchi macrolactonization to
access the 14-membered macrocyclic ring. Further applica-
tion of this methodology to the syntheses of other
compounds of this family is currently underway in our
laboratory.
1
eluent to afford 10 as a colorless oil (428 mg, 70%). H
NMR (300 MHz, CDCl3) d 1.77–1.86 (m, 2H), 2.34 (t,
2H, J = 7.2 Hz), 3.10 (t, 1H, J = 5.7 Hz), 3.56 (t, 2H,
J = 6.3 Hz), 4.17 (d, 2H, J = 5.7 Hz), 4.51 (s, 2H), 7.27–
7.35 (m, 5H). 13C NMR (75 MHz, CDCl3): d 15.3, 28.4,
50.6, 68.4, 72.6, 78.7, 84.9, 127.4, 128.1, 138.0. HRMS
(ESI) calcd for C13H16O2Na+ [M+Na]+ 227.1052, found
227.1047, D = ꢀ2.2 ppm.
4. Experimental
4.1. General
4.3. (E)-6-(Benzyloxy)hex-2-en-1-ol 11
Oxygen- and moisture-sensitive reactions were carried out
under an argon atmosphere. Solvents were purified and
To a suspension of LiAlH4 (80 mg, 2.1 mmol) in THF
(10 mL) was added a solution of 10 (428 mg, 2.1 mmol)

J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
1069
in THF (5 mL) dropwise. After the reaction mixture was
stirred for 2 h at reflux, water was added. The resulting
mixture was filtered through a short pad of Celite and
washed with EtOAc (100 mL · 3), and the filtrate was dried
over Na2SO4. The solvent was removed and the residue
purified on a silica gel column using petroleum ether/ethyl
acetate (5/1) as the eluent to afford 11 as a colorless oil
idue was purified on a silica gel column using petroleum
ether/ethyl acetate (2/1) as the eluent to afford 12 as a col-
20
1
orless oil (463 mg, 75%). ½aꢁ ¼ ꢀ19 (c 1.45, CHCl3). H
NMR (300 MHz, CDCl3) dD1.68–1.81 (m, 2H), 1.87–1.95
(m, 2H), 3.50 (m, 3H), 3.56–3.60 (m, 1H), 3.66–3.70
(m, 1H), 3.82–3.88 (m, 2H), 4.48 (s, 2H), 5.16 (m, 1H),
7.26–7.33 (m, 5H), 7.41 (t, 2H, J = 7.5 Hz), 7.54 (t, 1H,
J = 7.5 Hz), 8.04 (d, 2H, J = 8.4 Hz). 13C NMR
(75 MHz, CDCl3): d 25.3, 27.1, 62.7, 69.7, 72.6, 72.7,
74.4, 127.4, 127.5, 128.1, 128.2, 129.5, 133.0, 138.1, 166.5.
HRMS (ESI) calcd for C20H24O5Na+ [M+Na]+ 367.1517,
found 367.1522, D = 1.5 ppm.
1
(415 mg, 96%). H NMR (300 MHz, CDCl3) d 1.71 (m,
2H), 2.05 (b, 1H), 2.14 (m, 2H), 3.48 (t, 2H, J = 6.6 Hz),
4.04 (d, 2H, J = 4.2 Hz), 4.50 (s, 2H), 5.64 (m, 2H), 7.27–
7.35 (m, 5H). 13C NMR (75 MHz, CDCl3): d 28.6, 28.9,
63.1, 69.4, 72.6, 127.3, 127.4, 128.1, 129.4, 131.8, 138.3.
HRMS (ESI) calcd for C13H16O2Na+ [M+Na]+ 229.1202,
found 229.1206, D = 1.7 ppm.
4.6. Triol 13
4.4. ((2R,3R)-3-(3-(Benzyloxy)propyl)oxiran-2-yl)methanol
8
To a solution of 6.0 equiv of EtMgBr, previously formed,
was added 12 (688 mg, 2.0 mmol) in 2 mL THF and the
reaction mixture was stirred for 2 h before being quenched
with saturated aqueous NH4Cl solution, and extracted
with EtOAc (50 mL · 3). The organic layers were com-
bined and dried with anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
˚
To a suspension of 4-A molecular sieves (1.5 g) and CaH2
(84 mg, 2.0 mmol) in 30 mL CH2Cl2 were added (ꢀ)-diiso-
propyl tartarate (0.25 mL, 1.2 mmol), Ti(O-iPr)4 (0.30 mL,
1.0 mmol), and tBuOOH (3.3 M in CH2Cl2, 5.15 mL,
17.0 mmol) sequentially at ꢀ25 ꢁC. The reaction mixture
was stirred for 30 min before 11 (2.06 g, 10 mmol) was
added. The reaction mixture was then stored overnight
(12 h) in the freezer at ꢀ25 ꢁC without stirring. The reac-
tion was then warmed to ꢀ20 ꢁC and quenched by the
addition of 10% NaOH/saturated aqueous NaCl
(4.0 mL). Upon further warming to ꢀ10 ꢁC, the reaction
was diluted with Et2O (100 mL), treated with MgSO4
(4.0 g) and Celite (1.0 g), and stirred for an additional
15 min. The reaction mixture was then allowed to settle
for 1 h before filtration through Celite using Et2O and con-
centrated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
acetate (1/2) as the eluent to afford 13 as a colorless oil
20
(456 mg, 95%). ½aꢁD ¼ ꢀ8 (c 1.50, CHCl3). 1H NMR
(300 MHz, CDCl3) d 1.44–1.49 (m, 1H), 1.61–1.68 (m,
2H), 1.77–1.80 (m, 1H), 3.46–3.51 (m, 3H), 3.64 (m, 3H),
3.89 (m, 1H), 4.10 (m, 2H), 4.72 (s, 2H), 7.24–7.34 (m,
5H). 13C NMR (75 MHz, CDCl3): d 26.3, 30.0, 63.2,
70.3, 73.0, 74.2, 127.6, 127.7, 128.4, 137.9. HRMS (ESI)
calcd for C13H20O4H+ [M+H]+ 241.1434, found
241.1429, D = 2.1 ppm.
4.7. Pivalate 14
acetate (3/1) as the eluent to afford 8 as a colorless oil
To a solution of triol 13 (456 mg, 1.9 mmol), DMAP
(49 mg, 0.4 mmol), and Et3N (0.57 mL, 4.0 mmol) in
20 mL CH2Cl2 was added PivCl (123 lL, 2.0 mmol) at
0 ꢁC. The reaction mixture was warmed to rt overnight
(10 h) before being quenched with saturated aqueous NaH-
CO3 solution, and extracted with EtOAc (50 mL · 3). The
organic layers were combined and dried with anhydrous
Na2SO4, filtered, and concentrated under reduced pressure
vacuum. The residue was purified on a silica gel column
20
(1.98 g, 89%). ½aꢁD ¼ þ28 (c 1.50, CHCl3); lit.4 (ent-8)
1
[a]D = ꢀ29. H NMR (300 MHz, CDCl3) d 1.60–1.79 (m,
4H), 2.74 (b, 1H), 2.86–2.89 (m, 1H), 2.91–2.96 (m, 1H),
3.48–3.56 (m, 3H), 3.80 (dd, 1H, J = 2.4, 12.6 Hz), 4.49
(s, 2H), 7.25–7.34 (m, 5H). 13C NMR (75 MHz, CDCl3):
d 25.9, 28.3, 55.6, 58.5, 61.6, 69.5, 72.7, 127.5, 128.2,
138.2. HRMS (ESI) calcd for C13H18O3H+ [M+H]+
223.1330, found 223.1334, D = 1.7 ppm. For the measure-
ment of enantiomeric excess, compound 8 was converted
into its benzoate. The enantiomeric purity of the benzoate
was estimated to be 91% by chiral HPLC (Chiralcel OD
from Daicel Chemical Industries, Ltd, 15% iPrOH in hex-
ane, 254 nm, 1 mL/min).
using petroleum ether/ethyl acetate (1/1) as the eluent to
20
afford 14 as a colorless oil (542 mg, 88%). ½aꢁD ¼ ꢀ20 (c
1.25, CHCl3). 1H NMR (300 MHz, CDCl3) d 1.20 (s,
9H), 1.52 (m, 1H), 1.71–1.81 (m, 3H), 2.89 (d, 1H,
J = 4.8 Hz), 3.39 (d, 1H, J = 4.5 Hz), 3.51 (m, 2H), 3.61
(m, 1H), 3.70–3.73 (m, 1H), 4.20–4.23 (m, 2H), 7.27–7.33
(m, 5H). 13C NMR (75 MHz, CDCl3): d 26.2, 27.1, 29.7,
38.8, 65.6, 70.3, 72.0, 72.9, 73.0, 127.6, 128.3, 137.8,
179.1. HRMS (ESI) calcd for C18H28O5Na+ [M+Na]+
347.1830, found 347.1829, D = ꢀ0.3 ppm.
4.5. (2R,3S)-6-(Benzyloxy)-1,2-dihydroxyhexan-3yl
benzoate 12
To a solution of PhCO2H (262 mg, 2.15 mmol) and
8 (398 mg, 1.79 mmol) in CH2Cl2 (10 mL) was added
Ti(O-iPr)4 (0.64 mL, 2.15 mmol), and the reaction mixture
was stirred for 15 min before ether (50 mL) and 5% H2SO4
(6.4 mL) were added. The two-phase mixture was stirred
vigorously until two clear layers formed, which were ex-
tracted with EtOAc (50 mL · 3). The organic layers were
combined and dried over anhydrous Na2SO4, filtered,
and concentrated under reduced pressure vacuum. The res-
4.8. ((4R,5S)-5-(3-(Benzyloxy)propyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl pivalate 15
To a solution of pivalate 14 (542 mg, 1.67 mmol), and
PPTS (25 mg, 0.1 mmol) in 10 mL CH2Cl2 was added 2-
methoxypropene (0.49 mL, 4.0 mmol), and the reaction
mixture was stirred for 5 h before being quenched with sat-

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J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
urated aqueous NaHCO3 solution, and extracted with
EtOAc (30 mL · 3). The organic layers were combined
and dried with anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
were combined and dried with anhydrous Na2SO4,
filtered, and concentrated under reduced pressure vacuum.
The residue was purified on a silica gel column using
petroleum ether/ethyl acetate (4/1) as the eluent to afford
15
5 as a colorless oil (1.13 g, 81%). ½aꢁD ¼ ꢀ8 (c 1.25,
1
acetate (20/1) as the eluent to afford 15 as a colorless oil
CHCl3). H NMR (300 MHz, CDCl3) d 1.17 (s, 9H), 1.31
20
(577 mg, 95%). ½aꢁD ¼ þ13 (c 1.25, CHCl3). 1H NMR
(s, 3H), 1.41 (s, 3H), 1.68–1.80 (m, 2H), 2.01–2.22
(m, 2H), 3.70–3.92 (m, 2H), 4.04 (d, 2H, J = 6.0 Hz),
4.13–4.26 (m, 2H), 7.54–7.61 (m, 3H), 7.66 (m, 2H).
13C NMR (75 MHz, CDCl3): d 19.8, 25.2, 26.9, 27.4,
27.8, 38.4, 55.3, 62.3, 74.8, 76.2, 108.4, 124.9, 129.4,
131.2, 132.8, 153.1, 177.7. HRMS (ESI) calcd for
(300 MHz, CDCl3) d 1.20 (s, 9H), 1.33 (s, 3H), 1.43 (s,
3H), 1.63–1.72 (m, 3H), 1.81–1.87 (m, 1H), 3.46–3.55 (m,
2H), 4.08 (dd, 2H, J = 0.9, 2.6 Hz), 4.13–4.23 (m, 2H),
4.50 (s, 2H), 7.26–7.33 (m, 5H). 13C NMR (75 MHz,
CDCl3): d 25.5, 25.9, 26.8, 27.1, 28.1, 38.6, 62.9, 69.7,
72.8, 75.2, 76.9, 108.2, 127.4, 127.5, 128.3, 138.4, 178.1.
HRMS (ESI) calcd for C21H32O5Na+ [M+Na]+ 387.2142,
found 387.2146, D = 1.1 ppm. For the measurement of
the enantiomeric excess, the enantiomeric purity of com-
pound 15 was estimated to be 91% by chiral HPLC (Chiral-
cel OD from Daicel Chemical Industries, Ltd, 5% iPrOH in
hexane, 254 nm, 0.8 mL/min).
C21H30N4O6SNH [M+NH4]+ 484.2224, found 484.2219,
þ
4
D = 1.0 ppm.
4.11. (2-Bromo-3,5-bis(methoxymethoxy)phenyl)methanol
18
To a solution of (3,5-bis(methoxymethoxy)phenyl)metha-
nol 17 (500 mg, 2.2 mmol) in CHCl3 (10 mL) was added
NBS (392 mg, 2.2 mmol) portionwise at ambient tempera-
ture. The reaction mixture was stirred for 30 min before
being quenched with saturated aqueous NaHCO3 solution
and aqueous Na2S2O3, and extracted with CHCl3
(25 mL · 3). The organic layers were combined and dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure vacuum. The residue was purified on a sil-
ica gel column using petroleum ether/ethyl acetate (5/1) as
the eluent to afford 18 as a white solid (664 mg, 98%). Mp:
4.9. ((4R,5S)-5-(3-Hydroxypropyl)-2,2-dimethyl-1,3-
dioxolan-4-yl)methyl pivalate 16
A suspension of benzyl ether 15 (728 mg, 2.0 mmol) and
Pd/C (10%, 20 mg) in 5 mL EtOH was flushed with H2
and then stirred vigorously under balloon pressure. The
reaction mixture was stirred for 6 h before being filtered
through a Celite pad, which had been moistened with
EtOH and Et3N. The resulting filtrate was concentrated
under reduced pressure vacuum. The residue was purified
on a silica gel column using petroleum ether/ethyl acetate
1
60–61 ꢁC. H NMR (300 MHz, CDCl3) d 2.84 (br s, 1H),
3.43 (s, 3H), 3.48 (s, 3H), 4.65 (s, 2H), 5.13 (s, 2H), 5.20
(s, 2H), 6.76 (d, 1H, J = 2.7 Hz), 6.88 (d, 1H,
J = 2.7 Hz). 13C NMR (75 MHz, CDCl3): d 56.0, 56.3,
94.3, 95.0, 103.8, 104.3, 108.8, 141.9, 154.1, 157.1. Calcd
for C11H15BrO5H+ [M+H]+ 307.0180, found 307.0183,
D = 1.0 ppm.
(8/1) as the eluent to afford 16 as a colorless oil (521 mg,
15
95%). ½aꢁD ¼ þ77 (c 0.9, CHCl3); [lit.2f,g +82.4 (c 0.07,
CHCl3)]. 1H NMR (300 MHz, CDCl3) d 1.19 (s, 9H),
1.33 (s, 3H), 1.43 (s, 3H), 1.57–1.75 (m, 4H), 2.15 (b,
1H), 3.64–3.68 (m, 2H), 4.05–4.09 (m, 2H), 4.16–4.25 (m,
2H). 13C NMR (75 MHz, CDCl3): d 25.5, 25.8, 27.1,
28.0, 29.9, 38.7, 62.3, 62.8, 75.3, 77.0, 108.3, 178.2. HRMS
(ESI) calcd for C14H26O5Na+ [M+Na]+ 297.1670, found
297.1665, D = ꢀ1.8 ppm.
4.12. 2-Bromo-3,5-bis(methoxymethoxy)benzaldehyde 6
To a solution of 18 (308 mg, 1.0 mmol) in 10 mL CH2Cl2
was added NaHCO3 (126 mg, 1.5 mmol), and then PCC
(323 mg, 1.5 mmol) at 0 ꢁC. After being stirred for 4 h,
the reaction mixture was filtered through a short Celite
pad and washed with EtOAc, the filtrate was concentrated
under reduced pressure. The residue was purified on a silica
gel column using petroleum ether/ethyl acetate (5/1) as the
eluent to afford 6 as a white solid (260 mg, 85%). Mp:
80–81 ꢁC. 1H NMR (300 MHz, CDCl3) d 3.45 (s, 3H),
3.51 (s, 3H), 5.17 (s, 2H), 5.25 (s, 2H), 7.07 (d, 1H,
J = 2.7 Hz), 7.24 (d, 1H, J = 2.7 Hz), 10.36 (s, 1H). 13C
NMR (75 MHz, CDCl3): d 56.2, 56.5, 94.4, 95.2, 108.8,
110.3, 110.4, 134.7, 154.9, 157.2, 191.6. Calcd for
C11H13BrO5Na+ [M+Na]+ 326.9841, found 326.9832,
D = ꢀ2.8 ppm.
4.10. ((4R,5S)-5-(3-(1-Phenyl-1H-tetrazol-5-ylsulfonyl)-
propyl)-2,2-dimethyl-1,3-dioxolan-4-yl)methyl pivalate 5
To a solution of 16 (822 mg, 3.0 mmol), PPh3 (944 mg,
3.6 mmol), and 1-phenyl-1H-tetrazole-5-thiol (642 mg,
3.6 mmol) in THF (20 mL) was added a solution of DIAD
(94%, 0.76 mL, 3.6 mmol) in THF (5 mL) dropwise. The
reaction mixture was stirred for 2 h before being quenched
with saturated NaCl solution, and extracted with EtOAc
(60 mL · 3). The organic layers were combined and dried
with anhydrous Na2SO4, filtered, and concentrated under
reduced pressure vacuum. The residue was purified on a
silica gel column using petroleum ether/ethyl acetate (4/1)
as the eluent to afford the corresponding sulfide.
4.13. (S)-3-Hydroxybutyl benzoate 19
To a solution of the sulfide obtained above in CH2Cl2
(30 mL) was added NaHCO3 (554 mg, 6.6 mmol), and then
m-CPBA (95%, 1.14 g, 6.6 mmol) at 0 ꢁC. The reaction
mixture was stirred at ambient temperature for 12 h before
being quenched with saturated Na2S2O3 solution and
extracted with EtOAc (60 mL · 3). The organic layers
To a solution of (S)-butane-1,3-diol 7 (906 mg, 10 mmol),
DMAP (244 mg, 2 mmol), and Et3N (2.8 mL, 20 mmol)
in CH2Cl2 (20 mL) was added BzCl (1.2 mL, 10.3 mmol)
at 0 ꢁC. The reaction mixture was warmed to rt overnight
(10 h) before being quenched with saturated aqueous

J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
1071
NaHCO3 solution and extracted with EtOAc (50 mL · 3).
The organic layers were combined and dried with anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure vacuum. The residue was purified on a silica gel
4.16. Sulfone 3
To a solution of 21 (800 mg, 3.9 mmol), PPh3 (1.2 g,
4.6 mmol), and 1-phenyl-1H-tetrazole-5-thiol (0.8 g,
4.5 mmol) in 10 mL THF was added a solution of DIAD
(94%, 1 mL, 4.5 mmol) in THF dropwise. The reaction
mixture was stirred for 2 h before being quenched with sat-
urated aqueous NaHCO3 solution, and extracted with
EtOAc (50 mL · 3). The organic layers were combined
and dried over anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
acetate (15/1) as the eluent to afford the corresponding
sulfide.
column using petroleum ether/ethyl acetate (8/1) as the elu-
14
ent to afford 19 as a colorless oil (1.55 g, 80%). ½aꢁD ¼ þ25
1
(c 2.00, CHCl3). H NMR (300 MHz, CDCl3) d 1.26 (d,
3H, J = 6.6 Hz), 1.79–1.98 (m, 2H), 2.36 (b, 1H), 3.94–
4.00 (m, 1H), 4.33–4.41 (m, 1H), 4.55–4.63 (m, 1H), 7.43
(t, 2H, J = 7.5 Hz), 7.56 (t, 1H, J = 7.5 Hz), 8.02 (d, 2H,
J = 7.5 Hz). 13C NMR (75 MHz, CDCl3): d 23.5, 38.1,
62.1, 64.7, 128.3, 129.5, 130.0, 133.0, 166.9. Calcd for
C11H14O3Na+ [M+Na]+ 217.0841, found 217.0849,
D = 3.6 ppm.
4.14. tert-Butyldimethyl silyl ether 20
To a solution of the sulfide obtained above in CH2Cl2
(15 mL) was added NaHCO3 (0.7 g, 8.3 mmol), and then
m-CPBA (1.4 g, 8.3 mmol) at 0 ꢁC. The reaction mixture
was stirred at ambient temperature for 12 h before being
quenched with saturated aqueous Na2S2O3 solution, and
extracted with EtOAc (50 mL · 3). The organic layers were
combined and dried with anhydrous Na2SO4, filtered, and
concentrated under reduced pressure vacuum. The residue
was purified on a silica gel column using petroleum ether/
To a solution of benzoate 19 (1.55 g, 8.0 mmol) and imid-
azole (1.36 g, 20 mmol) in DMF (5 mL) was added TBSCl
(1.44 g, 9.6 mmol) at 0 ꢁC. The reaction mixture was
warmed to rt overnight (10 h) before being quenched with
saturated aqueous NH4Cl solution, and extracted with
EtOAc (50 mL · 3). The organic layers were combined
and dried with anhydrous Na2SO4, filtered, and concen-
trated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
ethyl acetate (20/1) as the eluent to afford 3 as a colorless
15
oil (1.3 g, 83%). ½aꢁD ¼ 12 (c 1.50, CHCl3). 1H NMR
acetate (30/1) as the eluent to afford 20 as a colorless oil
(300 MHz, CDCl3) d 0.07 (s, 6H), 0.89 (s, 9H), 1.20 (d,
3H, J = 5.7 Hz), 1.95–2.15 (m, 2H), 3.72–3.91 (m, 2H),
4.01–4.07 (m, 1H), 7.56–7.63 (m, 3H), 7.67–7.71 (m, 2H).
13C NMR (75 MHz, CDCl3): d ꢀ4.9, ꢀ4.4, 17.9, 23.4,
25.7, 31.3, 52.7, 66.2, 125.0, 129.7, 131.4, 133.0, 153.4.
Calcd for C17H28N4O3SiSH+ [M+H]+ 397.1724, found
397.1721, D = 0.8 ppm.
14
(2.34 g, 95%). ½aꢁD ¼ þ33 (c 2.05, CHCl3). 1H NMR
(300 MHz, CDCl3) d 0.05 (s, 3H), 0.06 (s, 3H), 0.89 (s,
9H), 1.21 (d, 3H, J = 6.0 Hz), 1.82–1.92 (m, 2H), 4.01–
4.07 (m, 1H), 4.34–4.45 (m, 2H), 7.41–7.46 (m, 2H),
7.53–7.59 (m, 1H), 8.04 (9d, 2H, J = 8.4 Hz). 13C NMR
(75 MHz, CDCl3): d ꢀ5.0, ꢀ4.4, 18.0, 24.1, 25.8, 38.4,
62.1, 65.2, 128.3, 129.5, 130.4, 132.8, 166.6. Calcd for
C17H28O3SiNa+ [M+Na]+ 331.1701, found 331.1705,
D = 1.2 ppm.
4.17. ((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(methoxymeth-
oxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-4-yl)-
methyl pivalate 22
4.15. Alcohol 21
To a solution of 5 (466 mg, 1.0 mmol) in DME (3 mL) was
added KHMDS (0.89 M in DME, 1.2 mL, 1.1 mmol) at
ꢀ60 ꢁC. The resultant yellow solution was stirred for
30 min before 6 (306 mg, 1.0 mmol) in DME (2 mL) was
introduced via a cannula. The reaction mixture was stirred
for 1 h at ꢀ60 ꢁC, warmed to rt, and stirred for an addi-
tional 2 h before being quenched with saturated aqueous
NaCl solution, and extracted with EtOAc (30 mL · 3).
The organic layers were combined and dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure vacuum. The residue was purified on a silica gel
column using petroleum ether/chloroform/acetone (12/1/
To a solution of tert-butyldimethyl silyl ether 20 (2.34 g,
7.6 mmol) in CH2Cl2 (20 mL) was added DIBAL-H (1 M
in hexane, 8.4 mL, 8.4 mmol) dropwise at ꢀ78 ꢁC. The
reaction mixture was stirred for 30 min before being
quenched with MeOH and saturated aqueous potassium
sodium tartarate solution. The two-phase mixture was stir-
red vigorously and extracted with EtOAc (50 mL · 3). The
organic layers were combined and dried over anhydrous
Na2SO4, at room temperature, and diluted with ether
(150 mL). The organic layer was separated and washed
with saturated aqueous NaCl solution (3 · 25 mL). After
drying over anhydrous Na2SO4, concentration of the resi-
due in vacuo, filtration, and concentration under reduced
pressure vacuum, the residue was purified on a silica gel
1
1) as the eluent to afford the Z isomer [15 mg, 2.8%, H
NMR (300 MHz, CDCl3) d 5.73 (ddd, 1H, J = 7.2, 11.4,
3.6 Hz), 6.46 (d, 1H, J = 11.4 Hz)] and the E isomer 22
14
column using petroleum ether/ethyl acetate (8/1) as the elu-
as a colorless oil (371 mg, 68%) ½aꢁD ¼ þ11 (c 1.20,
14
1
ent to afford 21 as a colorless oil (1.47 g, 95%). ½aꢁD ¼ þ25
CHCl3). H NMR (300 MHz, CDCl3) d 1.20 (s, 9H), 1.35
1
(c 2.00, CHCl3). H NMR (300 MHz, CDCl3) d 0.06 (s,
(s, 3H), 1.45 (s, 3H), 1.66–1.77 (m, 2H), 2.29–2.50 (m,
2H), 3.46 (s, 3H), 3.50 (s, 3H), 4.09 (d, 2H, J = 4.8 Hz),
4.23 (m, 2H), 5.14 (s, 2H), 5.21 (s, 2H), 6.13 (ddd, 1H,
J = 7.2, 15.9, 1.2 Hz), 6.74 (d, 1H, J = 3.0 Hz), 6.77 (d,
1H, J = 15.9 Hz), 6.86 (d, 1H, J = 3.0 Hz). 13C NMR
(75 MHz, CDCl3): d 25.6, 27.1, 28.1, 28.4, 29.8, 38.7,
56.1, 56.4, 62.8, 75.1, 76.2, 94.5, 95.1, 103.7, 106.3, 107.3,
6H), 0.86 (s, 9H), 1.16 (d, 3H, J = 6.3 Hz), 1.58–1.65 (m,
1H), 1.69–1.75 (m, 1H), 2.82 (b, 1H), 3.64–3.71 (m, 1H),
3.75–3.81 (m, 1H), 4.04–4.10 (m, 1H). 13C NMR
(75 MHz, CDCl3): d ꢀ5.0, ꢀ4.4, 17.9, 23.4, 25.7, 40.4,
60.3, 68.2. Calcd for C10H24O2SiNa+ [M+Na]+ 227.1443,
found 227.1445, D = 0.9 ppm.

1072
J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
108.3, 129.7, 133.0, 139.2, 154.4, 156.9, 178.1. Calcd for
stirred for 30 min before aldehyde 4 in DME (2 mL) was
introduced via a cannula. The reaction mixture was stirred
for 30 min at ꢀ60 ꢁC, warmed to rt, and stirred for an addi-
tional 2 h before being quenched with saturated aqueous
NaCl solution, and extracted with EtOAc (10 mL · 3).
The organic layers were combined and dried over anhy-
drous Na2SO4, filtered, and concentrated under reduced
pressure. The residue was purified on a silica gel column
using dichloromethane/acetone (50/1) as the eluent to
C25H37BrO8NH [M+NH4]+ 562.2010, found 562.2014,
þ
4
D = 0.7 ppm.
4.18. Compound 23
To a solution of pivalate 22 (120 mg, 0.22 mmol) in CH2Cl2
(20 mL) was added DIBAL-H (1 M in hexane, 0.23 mL,
0.23 mmol) dropwise at ꢀ78 ꢁC. The reaction mixture
was stirred for 30 min before being quenched with MeOH
and saturated aqueous potassium sodium tartarate solu-
tion. The two-phase mixture was stirred vigorously for
30 min and extracted with EtOAc (30 mL · 3). The organic
layers were combined and dried over anhydrous Na2SO4,
filtered, and concentrated under reduced pressure vacuum.
The residue was purified on a silica gel column using petro-
leum ether/ethyl acetate (2/1) as the eluent to afford 23 as a
1
afford the Z isomer [12.7 mg, 12%, H NMR (300 MHz,
CDCl3) 5.47 (dd, 1H, J = 8.7, 10.5 Hz), 5.67–5.74 (m,
1H). Calcd for C30H49BrO7SiNH4 [M+NH4]+ 646.2769,
þ
found 646.2755, D = ꢀ2.2 ppm] and the E isomer 24 as a
14
colorless oil (62.3 mg, 58%) ½aꢁD ¼ ꢀ17 (c 1.00, CHCl3).
1H NMR (300 MHz, CDCl3) d 0.04 (s, 6H), 0.87 (s, 9H),
1.12 (d, 3H, J = 6.0 Hz), 1.36 (s, 3H), 1.49 (s, 3H), 1.55–
1.61 (m, 1H), 1.66–1.72 (m, 1H), 2.21 (t, 2H, J = 6.6 Hz),
2.27–2.42 (m, 2H), 3.47 (s, 3H), 3.51 (m, 3H), 3.83–3.89
(m, 1H), 4.10–4.20 (m, 1H), 4.50 (m, 1H), 5.15 (s, 2H),
5.21 (s, 2H), 5.49 (dd, 1H, J = 9.3, 15.0 Hz), 5.70–5.78
(m, 1H), 6.09–6.18 (m, 1H), 6.75 (d, 1H, J = 2.7 Hz),
6.77 (d, 1H, J = 15.0 Hz), 6.87 (d, 1H, J = 2.7 Hz). 13C
NMR (75 MHz, CDCl3): d ꢀ4.8, ꢀ4.6, 18.1, 23.4, 25.7,
25.8, 28.3, 29.6, 30.1, 42.6, 56.1, 56.4, 68.2, 77.5, 79.5,
94.5, 95.1, 103.7, 106.3, 107.3, 107.9, 127.9, 129.4, 132.2,
14
1
colorless oil (96 mg, 95%). ½aꢁD ¼ þ13 (c 2.00, CHCl3). H
NMR (300 MHz, CDCl3) d 1.36 (s, 3H), 1.47 (s, 3H), 1.60–
1.68 (m, 1H), 1.71–1.80 (m, 1H), 2.16 (t, 1H, J = 6.0 Hz),
2.27–2.34 (m, 1H), 2.40–2.47 (m, 1H), 3.46 (s, 3H), 3.49
(s, 1H), 3.56 (m, 2H), 4.09–4.25 (m, 2H), 5.14 (s, 2H),
5.20 (s, 2H), 6.13 (ddd 1H, J = 7.2, 15.9, 1.2 Hz), 6.74 (d,
1H, J = 3.0 Hz), 6.77 (d, 1H, J = 17.4 Hz), 6.86 (d, 1H,
J = 3.0 Hz). 13C NMR (75 MHz, CDCl3): d 25.5, 28.1,
28.4, 30.0, 56.0, 56.3, 61.7, 76.0, 77.7, 94.4, 95.0, 103.7,
106.2, 107.2, 108.1, 129.7, 133.0, 139.1, 154.4, 156.9. Calcd
þ
133.4, 139.3, 154.4, 156.9. Calcd for C30H49BrO7SiNH4
[M+NH4]+ 646.2769, found 646.2775, D = 0.9 ppm.
þ
for C20H29BrO7NH4
[M+NH4]+ 478.1435, found
478.1431, D = 0.8 ppm.
4.21. Alcohol 25
4.19. Aldehyde 4
To a solution of 24 (45 mg, 0.072 mmol) in THF (2 mL)
was added TBAF (28 mg, 0.11 mmol). The reaction mix-
ture was stirred for 8 h before being quenched with satu-
rated aqueous NaCl solution, and extracted with EtOAc
(15 mL · 3). The organic layers were combined and dried
over anhydrous Na2SO4, filtered, and concentrated under
reduced pressure vacuum. The residue was purified on a sil-
To a solution of 23 (92 mg, 0.2 mmol) in CH2Cl2 (5 mL)
was added NaHCO3 (25 mg, 0.3 mmol), and Dess–Martin
periodinane (127 mg, 0.30 mmol) in turn at 0 ꢁC. After
being stirred for 4 h, the reaction mixture was then diluted
with saturated NaHCO3 (aq) (2 mL), saturated Na2S2O3
(aq) (2 mL) and stirred for an additional 30 min. The mix-
ture was extracted with CH2Cl2 and the organic layers were
combined, dried over anhydrous Na2SO4, filtered, and con-
centrated under reduced pressure vacuum. The residue was
purified on a silica gel column using petroleum ether/ethyl
ica gel column using ethyl acetate as the eluent to afford 25
15
as a colorless oil (35.2 mg, 95%). ½aꢁD ¼ ꢀ3 (c 0.85,
CHCl3). 1H NMR (300 MHz, CDCl3) d 1.15 (d, 3H,
J = 6.0 Hz), 1.33 (s, 3H), 1.45 (s, 3H), 2.12–2.39 (m, 4H),
3.43 (s, 3H), 3.47 (s, 3H), 3.78–3.84 (m, 1H), 4.11–
4.18 (m, 1H), 4.51 (m, 1H), 5.12 (s, 2H), 5.18 (s, 2H),
5.49–5.76 (m, 2H), 6.05–6.15 (m, 1H), 6.71 (d, 1H,
J = 2.7 Hz), 6.73 (d, 1H, J = 15.9 Hz), 6.84 (d, 1H,
J = 2.7 Hz). 13C NMR (75 MHz, CDCl3): d 22.8, 25.5,
28.2, 29.5, 29.9, 42.0, 55.9, 56.2, 67.0, 77.3, 79.2, 94.3,
95.0, 103.6, 106.2, 107.1, 107.9, 129.0, 129.4, 131.1, 133.2,
acetate (4/1) as the eluent to afford 4 as a colorless oil
14
(78 mg, 85%). ½aꢁD ¼ þ3 (c 2.25, CHCl3). 1H NMR
(300 MHz, CDCl3) d 1.41 (s, 3H), 1.60 (s, 3H), 1.66–1.77
(m, 2H), 2.33–2.46 (m, 2H), 3.46 (s, 3H), 3.50 (s, 3H),
4.27 (dd, 1H, J = 7.2, 3.6 Hz), 4.38 (m, 1H), 5.14 (s, 2H),
5.21 (s, 2H), 6.09 (m, 1H), 6.75 (d, 1H, J = 3.0 Hz), 6.78
(d, 1H, J = 15.3 Hz), 6.86 (d, 1H, J = 3.0 Hz), 9.66 (d,
1H, J = 3.6 Hz). 13C NMR (75 MHz, CDCl3): d 25.3,
27.6, 29.0, 29.7, 56.1, 56.4, 77.6, 81.8, 94.5, 95.1, 103.8,
106.3, 107.3, 110.5, 130.1, 132.3, 139.1, 154.4, 156.9,
202.3. Calcd for C20H27BrO7H+ [M+H]+ 459.1013, found
459.1016, D = 0.7 ppm.
þ
139.1, 154.3, 156.8. Calcd for C24H35BrO7NH4
[M+NH4]+ 532.1904, found 532.1910, D = 1.1 ppm.
4.22. Acid 2
To a solution of alcohol 25 (35.0 mg, 0.068 mmol) obtained
above in THF (2 mL) was added n-BuLi (2.0 M in petro-
leum ether, 79 lL, 0.16 mmol) at ꢀ78 ꢁC. The resultant
yellow solution was stirred for 30 min before addition of
solid dry ice. The reaction mixture was allowed to warm
up to room temperature over 2 h after which time water
was added. The aqueous layer was acidified with 1 M
HCl to pH 2–3 and then extracted with EtOAc (15 mL ·
3). The combined organic extracts were washed with a
4.20. ((S,4E)-5-((4R,5S)-5-((E)-4-(2-Bromo-3,5-bis(meth-
oxymethoxy)phenyl)but-3-enyl)-2,2-dimethyl-1,3-dioxolan-
4-yl)pent-4-en-2-yloxy)(tert-butyl)dimethylsilane 24
To a solution of sulfone 3 (67 mg, 0.17 mmol) in 10 mL
DME was added KHMDS (0.89 M in DME, 0.20 mL,
0.19 mmol) at ꢀ60 ꢁC. The resultant yellow solution was

J. Lu et al. / Tetrahedron: Asymmetry 17 (2006) 1066–1073
1073
saturated NaCl solution, dried over anhydrous Na2SO4,
and the solvent was evaporated in vacuo. The residue
was purified on a silica gel column using ethyl acetate as
6.53 (d, 1H, J = 2.7), 7.16 (d, 1H, J = 15.9), 9.17 (br s,
1H), 11.68 (s, 1H). 13C NMR (100 MHz, acetone-d6): d
19.1, 28.0, 28.6, 38.0, 73.0, 73.2, 76.4, 102.4, 104.4, 107.8,
125.5, 130.7, 133.6, 135.7, 144.3, 163.1, 165.6, 172.1. Calcd
for C18H22O6Na+ [M+H]+ 357.1309, found 357.1310,
D = 0.3 ppm.
the eluent to afford 2 as a colorless oil (27.3 mg, 79%).
15
½aꢁD ¼ ꢀ20 (c 1.00, acetone). 1H NMR (300 MHz,
acetone-d6) d 1.13 (d, 3H, J = 6.0 Hz), 1.29 (s, 3H), 1.40
(s, 3H), 1.48–1.67 (m, 2H), 2.19–2.35 (m, 4H), 3.36 (s,
3H), 3.40 (s, 3H), 3.78–3.83 (m, 1H), 4.11–4.19 (m, 1H),
4.49 (m, 1H), 5.18 (s, 2H), 5.22 (2,H), 5.47–5.55 (m, 1H),
5.66–5.81 (m, 1H), 6.25–6.39 (m, 1H), 6.53 (d, 1H,
J = 15.9 Hz), 6.72 (s, 1H), 6.91 (s, 1H). 13C NMR
(75 MHz, acetone-d6): d 23.4, 25.9, 28.6, 30.7, 30.9, 42.8,
56.2, 56.3, 67.4, 78.2, 80.1, 94.9, 95.4, 103.2, 105.9, 108.2,
108.3, 127.7, 129.7, 131.9, 133.8, 137.5, 155.7, 159.1,
170.3. Calcd for C25H36O9Na+ [M+Na]+ 503.2252, found
503.2269, D = 1.4 ppm.
Acknowledgments
We are grateful for the generous financial support by the
Special Doctorial Program Funds of the Ministry of Edu-
cation of China (20040730008), NSFC (QT program, No.
20572037), the key grant project of Chinese Ministry of
Education (No. 105169) and Gansu Science Foundation
(3ZS051-A25-004).
4.23. Macrolactone 26
References
To a solution of acid 2 (27.3 mg, 0.057 mmol) in THF
(1 mL) were added Et3N (31 lL, 0.22 mmol) and trichloro-
benzoyl chloride (10 lL, 0.06 mmol). The reaction mixture
was stirred for 2 h and then diluted with 100 mL anhydrous
toluene. The toluene solution was added dropwise (5 mL/
h) to a toluene solution (150 mL) of 4-DMAP (53 mg,
0.43 mmol) heated at reflux. After continued heating for
36 h, the reaction mixture was diluted with EtOAc, washed
with aqueous CuSO4, dried over anhydrous Na2SO4, and
the solvent evaporated in vacuo. The residue was purified
on a silica gel column using petroleum ether/ethyl acetate
1. (a) Delmotte, P.; Delmotte-Plaquee, J. Nature 1953, 171, 344;
(b) Ellestad, G. A.; Lovell, F. M.; Perkinson, N. A.;
Hargreaves, R. T.; McGahren, W. J. J. Org. Chem. 1978,
43, 2339; (c) Ayer, W. A.; Lee, S. P.; Tsuneda, A.; Hiratsuka,
Y. Can. J. Microb. 1980, 26, 766; (d) Ayer, W. A.; Pena-
Rodriguez, L. Phytochemistry 1987, 26, 1353; (e) Sugawara,
F.; Kim, K. W.; Kobayashi, K.; Uzawa, J.; Yoshida, S.;
Murofushi, N.; Takahashi, N.; Strobel, G. A. Phytochemistry
1992, 31, 1987; (f) Sharma, S. V.; Agatsuma, T.; Nakano, H.
Oncogene 1998, 16, 2639; (g) Yamamoto, K.; Garbaccio, R.
M.; Stachel, S. J.; Solit, D. B.; Chiosis, G.; Rosen, N.;
Danshefsky, S. J. Angew. Chem., Int. Ed. 2003, 42, 1280.
2. (a) Hitchcock, S. A.; Pattenden, G. Tetrahedron Lett. 1990,
(4/1) as the eluent to afford 26 as a colorless oil (17 mg,
15
51%). ½aꢁD ¼ ꢀ120 (c 1.00 CHCl3); [lit.2f,g = ꢀ123.8
´
31, 3641; (b) Solladie, G.; Maestro, M. C.; Rubio, A.;
(c 0.08, CHCl3)]. 1H NMR (400 MHz, CDCl3) d 1.36
(s, 3H), 1.37 (d, 3H, J = 6.4 Hz), 1.47 (s, 3H), 1.49–
1.55 (m, 1H), 1.79–1.85 (m, 1H), 2.05–2.12 (m, 1H),
2.30–2.33 (m, 1H), 2.45–2.53 (m, 2H), 3.45–3.48 (m, 6H),
4.18–4.21 (m, 1H), 4.57 (dd, 1H, J = 5.2, 9.6 Hz), 5.11–
5.21 (m, 4H), 5.32–5.35 (m, 1H), 5.60 (dd, 1H, J = 15.2,
9.6 Hz), 5.70–5.76 (m, 1H), 6.14–6.17 (m, 1H), 6.23 (d,
1H, J = 15.6 Hz), 6.69 (d, 1H, J = 1.6 Hz), 6.81 (s, 1H).
13C NMR (100 MHz, CDCl3): d 21.1, 25.8, 28.5, 28.7,
29.0, 39.5, 56.0, 56.1, 71.6, 77.2, 80.1, 94.3, 94.6, 102.6,
104.8, 108.3, 117.9, 128.4, 129.3, 131.9, 132.3, 136.8,
155.1, 158.9, 167.3. Calcd for C25H34O8H+ [M+H]+
463.2326, found 463.2321, D = 1.1 ppm.
Pedregal, C.; Carreno, M. C.; Ruano, J. L. G. J. Org. Chem.
1991, 56, 2317; (c) Furstner, A.; Thiel, O. R.; Kindler, N.;
Bartkowska, B. J. Org. Chem. 2000, 65, 7990; (d) Garbaccio,
R. M.; Stachel, S. J.; Baeschlin, D. K.; Danishefsky, S. J. J.
Am. Chem. Soc. 2001, 123, 10903; (e) Yang, Z.-Q.; Dani-
shefsky, S. J. J. Am. Chem. Soc. 2003, 125, 9602; (f) Geng,
X.-D.; Danishefsky, S. J. Org. Lett. 2004, 6, 413; (g) Yang,
Z.-Q.; Geng, X.; Solit, D.; Pratilas, C. A.; Rosen, N.;
Danishefsky, S. J. J. Am. Chem. Soc. 2004, 126, 7881.
3. Isaka, M.; Suyarnsestakorn, C.; Tanticharoen, M.; Kong-
saeree, P.; Thebtaranonth, Y. J. Org. Chem. 2002, 67, 1561.
4. The synthesis of ent-8 was described. Kermadec, K.; Pru-
dhomme, M. Tetrahedron Lett. 1993, 34, 2757.
5. Tjijs, L.; Waanders, P. P.; Stokkingreef, E. H. M.; Zwaned-
burg, B. Recl. Trav. Chim. Pays-Bas 1986, 105, 332.
6. (a) Katsuki, T.; Sharpless, K. B. J. Am. Chem. Soc. 1980, 102,
5974; (b) Wang, Z.-M.; Zhou, W.-S.; Lin, G.-Q. Tetrahedron
Lett. 1985, 26, 6221.
7. Caron, M.; Sharpless, K. B. J. Org. Chem. 1985, 50, 1560.
8. Watanabe, Y.; Fujimoto, T.; Ozaki, S. J. Chem. Soc., Chem.
Commun. 1992, 681.
4.24. Aigialomycin D 1
According to the literature,2f,g aigialomycin D 1 was
obtained as a white solid (9 mg, 70%). Mp: 84–86 ꢁC.
15
½aꢁD ¼ ꢀ21 (c 0.43, MeOH). IR (KBr) mmax 3338, 1640,
1603, 1318, 1262, 1167, 1013, 968 cmꢀ1
.
1H NMR
9. Blakemore, P. R.; Cole, W. J.; Kocienshi, P. J.; Morley, A.
Synlett 1998, 26.
(300 MHz, acetone-d6) d 1.39 (d, 3H, J = 6.3 Hz), 1.56–
1.62 (m, 1H), 2.13–2.18 (m, 1H), 2.31–2.35 (m, 2H),
2.41–2.46 (m, 1H), 2.53–2.61 (m, 1H), 3.63 (br, 2H), 3.83
(br d, 1H, J = 4.2 Hz), 4.36 (br, 1H), 5.41–5.46 (m, 1H),
5.69 (dd, 1H, J = 5.4, 15.5 Hz), 5.84–5.94 (m, 1H), 6.10
(ddd, 1H, J = 5.4, 15.9, 5.7 Hz), 6.28 (d, 1H, J = 2.7),
10. Blakemore, P. R. J. Chem. Soc., Perkin Trans. 1 2002, 2563.
11. (a) Dess, D. B.; Martin, J. C. J. Am. Chem. Soc. 1991, 113,
7277; (b) Ireland, R. E.; Liu, L. J. Org. Chem. 1993, 58, 2899.
12. Inanaga, J.; Hirata, K.; Saeki, H.; Katsuki, T.; Yamaguchi,
M. Bull. Chem. Soc. Jpn. 1979, 52, 1989.