Synthesis of the polyketide segment of apratoxin A

Article abstract of DOI:10.1016/j.tetasy.2003.11.026

Apratoxin A 1 is a potent cytotoxic agent extracted from a marine cyanobacterium. We report the results of our synthetic approaches to the polyketide segment 3-OTBS-7-OPMB-2,5,8,8-tetramethylnonanoic acid 4, and the scope and limitations of these approach

Full text of DOI:10.1016/j.tetasy.2003.11.026

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 15 (2004) 355–363
Synthesis of the polyketide segment of apratoxin A
Zhengshuang Xu,a Zhiyong Chena and Tao Yea,b,
*
aDepartment of Chemistry, The University of Hong Kong, Pokfulam Road, Hong Kong
bOpen Laboratory of Chirotechnology of the Institute of Molecular Technology for Drug Discovery and Synthesis and Department of
Applied Biology and Chemical Technology, The Hong Kong Polytechnic University, Hung Hom, Kowloon, Hong Kong
Received 14 October 2003; accepted 20 November 2003
Abstract—Apratoxin A 1 is a potent cytotoxic agent extracted from a marine cyanobacterium. We report the results of our synthetic
approaches to the polyketide segment 3-OTBS-7-OPMB-2,5,8,8-tetramethylnonanoic acid 4, and the scope and limitations of these
approaches.
ꢀ 2003 Elsevier Ltd. All rights reserved.
1. Introduction
number of intriguing structural elements, including a
tert-butyl group as the starter unit of the polyketide
segment and a thiazoline ring attached to the beta car-
bon of an a,b-unsaturated amide.
Marine cyanobacteria, in particular those of the genus
Lyngbya, have provided abundant bioactive secondary
metabolites over the past two decades.1;2 During the
investigation of one particular Lyngbya sp. from Fin-
gerꢀs Reef, Apra Harbor, Guam, apratoxin A–C (Fig. 1)
were isolated by Moore and co-workers.3;4 Complete
structure assignment for apratoxin A 1 has resulted
from extensive NMR, molecular modelling, chiral
HPLC, and derivatization studies. Apratoxin A 1 dis-
plays potent in vitro cytotoxicity against KB and LoVo
cancer cell lines with IC50 values of 0.52 and 0.36 nM,
respectively. In contrast to most known potent anti-
cancer natural products, the cellular and molecular basis
of apratoxinsꢀ action is unknown at present.3 Apratoxin
A uniquely combines a tetrapeptide and a polyketide
portion within a macrolactone ring, which possesses a
Intrigued by the unusual molecular architecture, striking
biological profile, and limited availability of apratoxin
A, we recently undertook its total synthesis.5 Herein we
report the results of synthetic approaches to the poly-
ketide segment 4.
From a retrosynthetic perspective, the known propen-
sity of the stereogenic centers at, and adjacent to, the
thiazoline ring to undergo facile epimerization6;7 led us
to targets 2 and 3 as advanced intermediates. This will
make the synthetic strategy more convergent. In both of
these two synthetic plans, the targeted molecular 1 was
divided into two parts, the peptidic segment and the
polyketide segment. We have secured the key polyketide
3,7-dihydroxy-2,5,8,8- tetramethylnonanoic acid (Dtena)
as a partially protected intermediate 4 (Fig. 2), in our
quest for the synthesis of apratoxin A. The PMB
protected alcohol provides a means of attaching to the
proline residue in the peptidic portion of the molecule,
while the carboxylic acid could be incorporated into the
thioamide or thioester, which could then be further
converted into the thiazoline motif.8–17
S
Apratoxin A (1)
H
N
R1=CH3; R2=CH3
O
N
OH
O
O
O
N
Apratoxin B
R1=H; R2=CH3
O
O
R2
N
R1
O
N
Apratoxin C
R1=CH3; R2=H
Figure 1.
2. Results and discussion
The synthesis commenced with commercially available
starting materials, with our first generation synthesis of
* Corresponding author. Tel.: +852-27664173; fax: +852-22641912;
e-mail: bctaoye@inet.polyu.edu.hk
0957-4166/$ - see front matter ꢀ 2003 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2003.11.026

356
Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
O
O
OH
PMBO
O
O
N
ii, iii
i
H
H
O
6
S
5
S
7
H
N
H
N
iv
N
NH
Boc
OH
O
O
O
O
OFmoc
PMBO
O
O
O
PMBO
O
N
O
O
v
N
O
O
O
N
O
O
O
N
N
O
N
O
10
11
Ph
N
Ph
O
9
viii
vi
1
PMBO
PMBO
PMBO
PMBO
3
O
O
N
OH
13
vii
HO
O
+
S
H
O
O
O
HO
N
N
H
OTBS
OH
H
NH
Ph
O
O
O
N
12
O
O
O
O
O
O
N
PMBO
N
O
(EtO)2P
O
N
N
14
4
O
8
Ph
2
Scheme 1. Reagents and conditions: (i) ())-IPC2BOMe, allyl-magne-
sium bromide, then H2O2, Et3N, 60%; (ii) PMB-Br, NaH, THF, 95%;
(iii) (a) NMO, OsO4 (cat), methanesulfonamide, t-BuOH/H2O; (b)
NaIO4–silica gel, CH2Cl2, 90%; (iv) 8, KHMDS, THF/HMPA, then 7,
69%; (v) CH3MgBr, CuBr–DMS, DMS–THF, 92%; (vi) NaBH4,
THF–H2O, 67%; (vii) (COCl)2, DMSO, CH2Cl2, then DIPEA, 94%;
(viii) HN(CH3)OCH3, (CH3)3Al, CH2Cl2, )50 ꢁC 90% (with a ratio of
13:14 ¼ 1:1.7).
Figure 2. Retrosynthetic analysis of apratoxin A.
4 twice employing Brownꢀs asymmetric synthesis via
organoborane chemistry18–22 to build up the C2, C3, and
C7 stereogenic centers, with the C5 stereogenic center
being introduced by Hrubyꢀs asymmetric conjugate
addition protocol (Scheme 1).23;24
produce the Weinreb amide 13 cleanly, appearing to
attack the carbamate carbon to produce 14 instead. The
primary alcohol 11 was easily converted into the corre-
sponding aldehyde 12 under Swern conditions,36 and
thus setting the stage for the pivotal asymmetric crotyl-
ation (Scheme 2).
Thus, treatment of pivalaldehyde 5 at )100 ꢁC with the
chiral boron reagent derived from ())-B-(methoxy)-di-
isopinocampheylborane and allylmagnesium bromide
afforded the corresponding allylic alcohol 6 in 60% yield
and with excellent enantioselectivity (99% ee).19 This
was protected as its PMB ether by reaction with
p-methoxybenzyl bromide and sodium hydride. The
terminal alkene was then converted into the corre-
sponding aldehyde 7 by first treating the PMB ether of 6
with osmium tetroxide, N-methylmorpholine N-oxide
(NMO) and methanesulfonamide, and the resulting diol
was oxidatively cleaved with sodium periodate coated
on silica gel.25 The aldehyde 7 was obtained in 91% yield
over three steps.
PMBO
OH
PMBO
O
i
H
15
12
TBSO
ii
TBSO
PMBO
PMBO
OH
iii
O
Wadsworth–Emmons condensation26 of phosphonate
8,27 with aldehyde 7 provided trans-a,b-unsaturated
enimide as the sole stereoisomer, which simultaneously
homologated and introduced the chiral auxiliary
required for the asymmetric conjugate addition. The
oxazolidinone-derived chiral phosphonate 8 was in turn
16
4
Scheme 2. Reagents and conditions: (i) (+)-IPC2BOMe, trans-2-
butene, t-BuOK, n-BuLi, BF3–Et2O, 11, )100 ꢁC, then H2O2, Et3N,
THF, 53%; (ii) TBS-Cl, imid., DMF, 93%; (iii) (a) NMO, OsO4 (cat),
methanesulfonamide, t-BuOH/H2O; (b) NaIO4–silica gel, CH2Cl2; (c)
NaClO2, 2-methyl-2-butene, NaH2PO4, t-BuOH/H2O, 83% (three
steps).
prepared from
L
-phenylglycine.28–31 Treatment of eni-
mide precursor 9 with an excess of methylmagnesium
bromide and 1 equiv amount of copper(I) bromide–di-
methyl sulfide complex, led to the methylated adduct 10
in 92% yield, with excellent diastereoselectivity (>95%
de). The chiral auxiliary in 10 was then reductively
cleaved to furnish the alcohol 11 by use of sodium
borohydride.32;33 The usual procedure34;35 of treating the
imide 10 with N,O-dimethyl hydroxylamine failed to
Treatment of aldehyde 12 with the chiral boron reagent
derived from (E)-2-butene, n-butyllithium, potassium
tert-butoxide, and (+)-B-(methoxy)diisopinocampheyl
borane in the presence of boron trifluoride etherate gave
secondary alcohol 15 in 53% yield and with excellent
diastereoselectivity (>95% de).22 TBS protection of the

Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
357
secondary alcohol of 15, oxidative cleavage of the alkene
unit and further oxidation of the corresponding alde-
hyde under mild conditions by use of sodium chlorite37
furnished the key intermediate 4 (83% yield over three
steps).
conformer. As shown in Scheme 4, attack on the top
face of the most stable conformation 21 gives the chair-
like enolate ion 23, which would produce 19. The ste-
rically hindered tert-butyl group enhanced the selectivity
via formation of the most stable conformer 21 exclu-
sively.
Although successful, this route was not entirely satis-
factory, since it employed a chiral auxiliary during the
conjugate addition for the C5 stereogenic center, and
some of the obtained yields were poor for a multi-step
synthesis. An alternative method was sought, which
produced the C5 stereogenic center without the need of
an auxiliary/stoichiometric amount of reagent, and
provided a more viable way of producing 4 in gram
quantities. The second approach is outlined in Scheme 3.
O
O
H
Me
O
O
O
H
O
O
more stable
less stable
18
21
22
O
H
O
Me
O
O
O
H
OH
O
O
i
ii
chair-like enolate
19
23
6
17
18
iii
Scheme 4.
O
OH
O
O
iv
3. Conclusions
O
N
20
In summary, two alternative practical methods have
been developed for the synthesis of a fully elaborated
fragment related to the polyketide segment of the unique
anti-tumor natural product apratoxin A. Key steps in-
volve asymmetric allylation, crotylation, and asymmet-
ric conjugate additions. Both strategies are very efficient
and proceed with high levels of stereocontrol through-
out. Progress toward the total synthesis continues and
will be reported in due course.
v
19
PMBO
O
PMBO
O
vi
O
N
H
12
13
Scheme 3. Reagents and conditions: (i) CH2@CHCOCl, Et3N, THF,
92%; (ii) Grubbsꢀs cat, CH2Cl2, reflux, 88%; (iii) CuCN, MeLi, Et2O,
)78 ꢁC 86%; (iv) HN(CH3)OCH3, (CH3)3Al, CH2Cl2, )50 ꢁC 91%; (v)
NaH, PMBBr, TBAI, THF, 91%; (vi) DIBAL-H, CH2Cl2, )78 ꢁC
92%.
Alcohol 6 was reacted with acryloyl chloride to form
ester 17. Treatment of 17 in dichloromethane with
Grubbsꢀ catalyst effected the ring-closing metathesis
reaction38–53 to yield unsaturated lactone 18. This was
subjected to a conjugate addition with methyllithium
and copper(I) cyanide to provide the methyl-substituted
lactone 19 in 83% yield as the only detectable stereo-
isomer.54–57 Ring opening of the lactone 19 with N,O-
dimethyl hydroxylamine34;35 gave the corresponding
alcohol 20, which was converted into its PMB ether 13
in the presence of p-methoxybenzyl bromide, sodium
hydride, and tetra-n-butyl-ammonium iodide.58 Weinreb
amide 13 was readily converted into the corresponding
aldehyde 12 under reductive condition. The aldehyde 12
was then transformed into key compound 4 by the
previously described procedures.
4. Experimental
4.1. General experimental
All nonaqueous reactions were run under an inert
atmosphere (nitrogen or argon) with rigid exclusion of
moisture from reagents and all reaction vessels were
oven-dried. Solvents were distilled prior to use: THF
from Na/benzophenone, dichloromethane, DMF, tri-
ethylamine, and diisopropylethylamine from CaH.
NMR spectra were recorded on Bruker Advance DPX
300 MHz or AV400 MHz spectrometers. Chemical shifts
are reported in parts per million (ppm), relative to either
a tetramethylsilane internal standard or the signals due
to the solvent. Data are reported as follows: chemical
shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet, br ¼ broad), integration, and coupling
constants. Low- and high-resolution EI and FAB mass
spectra were obtained using a Finnigan MAT 95 mass
spectrometer, while ESI mass spectra were obtained
with Micromass Q-Tof-2TM spectrometer. IR spectra
were recorded neatly or as KBr disk on a Bio-Red FTS
165 Fourier transform spectrophotometer. Optical rota-
tions were recorded on a Perkin Elmer 343 Polarimeter.
A simple, yet compelling explanation for the stereo-
chemical outcome resulted from the mixed higher order
cyanocuprate-mediated conjugate addition of 18
involves the stereoelectronic effects.59 The kinetically
controlled conjugate addition to a conjugated enone
takes place preferentially by way of the chair-like eno-
late, which resulted from the more stable half-chair

358
Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
TLC was carried out using pre-coated sheets (Merck
silica gel 60-F250, 0.2 mm), which, after development,
were visualized at 254 nm, and/or staining in p-anisole,
ninhydrin, or phosphomolybdic acid solution followed
by heating. Flash column chromatography was
performed using the indicated solvents (with Rf ¼ 1.5–
2.0 for the desired component) on E. Merck silica gel 60
(230–400 mesh ASTM). Melting points were measured
on Carl Zeiss and were uncorrected.
mixture was filtered and the inorganic cake was washed
with ethyl acetate (150 mL). The combined filtrate was
dried over sodium sulfate. Removal of the solvent in
vacuo followed by chromatography on silica gel (ethyl
acetate–hexane ¼ 1:4) afforded aldehyde 7 (1.17 g, 90%)
1
as a clear oil. H NMR (400 MHz, CDCl3) d 9.84 (t,
1H, J ¼ 2:0 Hz), 7.25–7.26 (m, 2H), 7.23–7.24 (m, 2H),
4.52 (d, 1H, J ¼ 11:3 Hz), 4.48 (d, 1H, J ¼ 11:3 Hz),
3.79 (s, 3H), 3.64 (dd, 1H, J ¼ 4:6 Hz, 6.8 Hz), 2.62–
2.65 (m, 2H), 0.94 (s, 9H); 13C NMR (100 MHz,
CDCl3) d 202.07, 159.13, 130.60, 129.21, 113.71, 81.85,
73.48, 55.23, 45.84, 35.73, 26.11; IR (film): 2958.6,
4.2. (4S)-4-(para-Methoxy-benzyloxy)-5,5-dimethyl-1-
hexene
2837.1, 1724.2, 1612.4, 1514.0, 1247.9, 1080.1, 1035.7,
20
D
821.6 cmꢀ1; ½aꢁ ¼ )17.3 (c 3.3, CHCl3); ESI-HRMS
To the suspension of NaH (703 mg, 17.6 mmol, 60%
dispersion in mineral oil) in THF (10 mL) was added
homoallyl alcohol 6 (750 mg, 5.86 mmol) in THF (2 mL)
at 0 ꢁC. Ten minutes later, freshly prepared PMB-Br
(1.5 g, 7.6 mmol) in THF (2 mL) was added. The mixture
was then allowed to warm to room temperature and
stirred for 12 h. Cold water (5 mL) was carefully added
to quench the reaction; ethyl acetate (3 · 50 mL) was
used for extraction after volatiles were removed in
vacuo. The combined extractive organic layers were
washed with saturated aqueous NH4Cl (50 mL) and
brine (50 mL), dried over Na2SO4, and evaporated. The
residue, after chromatographic purification on silica gel
using ethyl acetate–hexane (5:95) as eluant, produced
the title compound (1.38 g, 95%) as a clear oil. 1H NMR
(300 MHz, CDCl3) d 7.23–7.28 (m, 2H), 6.83–6.87 (m,
2H), 5.90–5.99 (m, 1H), 5.00–5.13 (m, 2H), 4.58 (d, 1H,
J ¼ 10:5 Hz), 4.40 (d, 1H, J ¼ 10:7 Hz), 3.78 (s, 3H),
3.05 (dd, 1H, J ¼ 3:3 Hz, 8.4 Hz), 2.19–2.38 (m, 2H),
0.93 (s, 9H); 13C NMR (75 MHz, CDCl3) d 158.95,
137.46, 131.33, 129.09, 115.89, 113.58, 87.43, 73.94,
55.17, 36.00, 35.82, 26.39; IR (film): 2954.9, 2868.1,
calcd for C15H22NaO3 (M+23) 273.1467, found
273.1471.
4.4. (4S)-3-[(5S)-5-(4-Methoxy-benzyloxy)-6,6-dimethyl-
hept-2-enoyl]-4-phenyl-oxazolidin-2-one, 9
To a solution of the phosphonate 8 (2.88 g, 8.4 mmol) in
THF (65 mL) at )70 ꢁC was successively added
KHMDS (18.1 mL, 7.24 mmol, 0.4 M in toluene) and
HMPA (2.9 mL, 16.9 mmol). The mixture was brought
to room temperature and stirred for 45 min and then
cooled to )70 ꢁC again. Aldehyde 7 (1.51 g, 6 mmol) in
THF (20 mL) was added via a cannula. The reaction
mixture, after being stirred for 16 h, was quenched with
pH 7.0 phosphonate buffer (25 mL). Volatiles were
removed in vacuo and the residue was then extracted
with ethyl acetate (3 · 75 mL). The combined organic
layers were washed with saturated aqueous solution of
NH4Cl (50 mL) and brine (50 mL), dried over sodium
sulfate. Removal of the solvent in vacuo followed by
chromatography on silica gel, using ethyl acetate–hex-
ane (1:4) as eluant, afforded the title compound 9 (1.82 g,
69%) as a light yellow oil. 1H NMR (300 MHz, CDCl3) d
7.17–7.40 (m, 9H), 6.79–6.82 (m, 2H), 5.47 (dd, 1H,
J ¼ 4:0 Hz, 8.7 Hz), 4.67 (t, 1H, J ¼ 8:8 Hz), 4.43 (d,
1H, J ¼ 10:8 Hz), 4.37 (d, 1H, J ¼ 10:7 Hz), 4.23 (dd,
1H, J ¼ 4:1 Hz, 8.9 Hz), 3.77 (s, 3H), 3.12 (dd, 1H,
J ¼ 3:7 Hz, 8.2 Hz), 2.39–2.57 (m, 2H), 0.93 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 164.31, 158.96, 153.61,
150.32, 139.06, 130.68, 129.20, 129.09, 128.52, 125.75,
121.45, 113.60, 86.45, 73.90, 69.85, 57.62, 55.17, 36.10,
1513.7, 1247.9, 1081.4, 1038.5, 910.4, 820.9 cmꢀ1
½aꢁ ¼ )7.45 (c 15.2, CHCl3); EI-HRMS, calcd for
;
20
D
C16H24O2 248.1776, found 248.1770.
4.3. (3S)-3-(para-Methoxy-benzyloxy)-4,4-dimethyl-
pentanal, 7
To a solution of the above alkene (1.29 g, 5.2 mmol) in
t-BuOH–acetone–H2O (30 mL, 2:1:2), chilled with an
ice-water bath, was added successively NMO (2.82 mL,
10.4 mmol, 50 wt % in H2O), OsO4 (1.3 mL, 0.05 mmol,
10 mg/mL in H2O), and CH3SO2NH2 (496 mg,
5.2 mmol) with vigorous stirring. Then the mixture was
stirred at room temperature for 24 h. After being di-
luted with brine (15 mL), the reaction was quenched
with an excess of Na2SO3. After being stirred for an
additional 3 h, volatiles were removed under reduced
pressure and the reaction mixture was extracted with
ethyl acetate (3 · 75 mL). The combined organic layers
were washed with saturated aqueous solution of NH4Cl
(50 mL) and brine (50 mL), dried over Na2SO4, and
concentrated in vacuo to provide the corresponding
diol. To a solution of the diol in dichloromethane
(50 mL), a pre-coated NaIO4–SiO2 (17.7 g, 10.4 mmol,
1 mmol/1.7 g) was added and the suspension was then
stirred at room temperature for 30 min. The reaction
34.70, 26.26; IR (film): 2958, 2869, 1778, 1698, 1613,
20
D
EIMS calcd for C26H31NO4 437.2202, found 437.2197.
1513, 1248, 1197 cmꢀ1; ½aꢁ ¼ +22.1 (c 7.7, CHCl3); HR-
4.5. (4S)-3-[(3R,5S)-5-(4-Methoxy-benzyloxy)-3,6,6-tri-
methyl-heptanoyl]-4-phenyl-oxazolidin-2-one, 10
To a suspension of copper(I) bromide–dimethylsulfide
complex (1.62 g, 7.9 mmol) in THF–Me2S (30 mL, 1:1)
at )40 ꢁC was added slowly a solution of methyl mag-
nesium bromide (5.6 mL, 7.9 mmol, 1.4 M in Et2O). One
hour later, the yellow slurry was cooled to )78 ꢁC and 9
(1.38 g, 3.16 mmol) in THF (10 mL) was added dropwise
via a cannula. The reaction was maintained at )78 ꢁC
for 2 h, and then slowly warmed to room temperature
and stirred overnight. A saturated aqueous solution of

Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
359
NH4Cl (20 mL) was used to quench the reaction and
volatiles were removed in vacuo. The reaction mixture
was further extracted with ethyl acetate (3 · 75 mL). The
combined organic layers were washed with brine
(50 mL) and dried over Na2SO4. After concentration,
the residue was subjected to chromatography on silica
gel, eluting with ethyl acetate–hexane (1:4), to afford 10
(1.32 g, 92%) as a clear oil. De value (>95%) for this
before compound 10 (71.6 mg, 0.16 mmol) in DCM
(0.5 mL) was added slowly via a cannula. The reaction
mixture was then slowly warmed to room temperature
and stirred overnight. Saturated aqueous solution of
Rochelleꢀs salt (10 mL) was used to quench the reaction,
vigorous stirring was continued until the mixture
became clear (ca. 1.5 h). Ethyl acetate (3 · 25 mL) was
then used for extraction and the combined organic lay-
ers were washed with saturated aqueous solution of
NH4Cl (30 mL) and brine (30 mL), and dried over
Na2SO4. Removal of the solvent in vacuo followed by
chromatography on silica gel, using ethyl acetate–hex-
ane as eluant, provided compound 13 (3:7 eluant recipe)
(20 mg, 36%) as an oil and 14 (1:1 eluant recipe) (44 mg,
54%) as white needle-like crystal.
1
adduct was determined by NMR technicque. H NMR
(400 MHz, CDCl3) d 7.24–7.39 (m, 7H), 6.82–6.86 (m,
2H), 5.41 (dd, 1H, J ¼ 3:7 Hz, 8.7 Hz), 4.63 (t, 1H,
J ¼ 8:8 Hz), 4.49 (dd, 2H, J ¼ 10:7 Hz, 18.54 Hz), 4.22
(dd, 1H, J ¼ 3:7 Hz, 8.9 Hz), 3.77 (s, 3H), 3.04 (dd, 1H,
J ¼ 2:9 Hz, 8.5 Hz), 2.95 (dd, 1H, J ¼ 4:7 Hz, 10.6 Hz),
2.82 (dd, 1H, J ¼ 8:7 Hz, 16.53 Hz), 2.17–2.25 (m, 1H),
1.37–1.52 (m, 2H), 0.92 (d, 3H, J ¼ 6:7 Hz), 0.90 (s, 9H);
13C NMR (100 MHz, CDCl3) d 171.93, 158.83, 153.67,
139.12, 131.26, 129.09, 129.05, 128.53, 125.74, 113.56,
85.22, 73.96, 69.74, 57.51, 55.13, 41.53, 38.41, 36.09,
1
13 H NMR (300 MHz, CDCl3) d 7.30–7.33 (m, 2H),
6.85–6.88 (m, 2H), 4.60 (d, 1H, J ¼ 10:4 Hz), 4.50 (d,
1H, J ¼ 10:2 Hz), 3.79 (s, 3H), 3.68 (s, 3H), 3.20 (s, 3H),
3.08 (dd, 1H, J ¼ 3:3 Hz, 8.0 Hz), 2.49–2.53 (m, 1H),
2.21–2.33 (m, 2H), 1.48 (ddd, 2H, J ¼ 3:2 Hz, 8.0 Hz,
11.1 Hz), 1.02 (d, 3H, J ¼ 6:2 Hz), 0.94 (s, 9H); 13C
NMR (75 MHz, CDCl3) d 174.06, 158.93, 131.39,
129.17, 113.66, 85.63, 74.12, 61.16, 55.25, 39.03, 38.60,
36.16, 32.12, 27.65, 26.47, 21.60; IR (film): 2957.3,
27.27, 26.37, 21.22; IR (film): 2958, 2870, 1781, 1612,
20
D
for C27H35NO5 453.2515, found 453.2512.
1513 cmꢀ1; ½aꢁ ¼ +17.8 (c 3.1, CHCl3); EI-HRMS calcd
4.6. (5S,3S)-5-(4-Methoxy-benzyloxy)-3,6,6-trimethyl-
heptan-1-ol, 11
2869.7, 1660.2, 1514.1, 1463.0, 1385.3, 1248.9, 1173.9,
20
D
1072.7, 1036.8, 820.3, 749.8 cmꢀ1; ½aꢁ ¼ )29.6 (c 0.7,
To a solution of compound 10 (1.1 g, 2.4 mmol) in
THF–H2O (30 mL, 3:1) at 0 ꢁC NaBH4 (737 mg,
19.4 mmol) in cold water (2 mL) was added slowly. The
mixture was stirred for 24 h at room temperature before
being quenched carefully with 10% solution of citric acid
(30 mL) at 0 ꢁC THF was removed in vacuo and the
residue was extracted with ethyl acetate (4 · 30 mL). The
combined organic layers were washed with brine
(40 mL), dried over Na2SO4 and evaporated to leave an
oily residue, which was then purified by chromatogra-
phy on silica gel, using ethyl acetate–hexane (2:3) as
eluant, to provide alcohol 11 (479 mg, 67.0%) as an oil.
1H NMR (400 MHz, CDCl3) d 7.27–7.29 (m, 2H), 6.86–
6.89 (m, 2H), 4.54 (s, 2H), 3.80 (s, 3H), 3.70–3.75 (m,
1H), 3.60–3.66 (m, 1H), 3.12 (dd, 1H, J ¼ 4:9 Hz,
7.1 Hz), 1.71–1.83 (m, 2H), 1.39–1.42 (m, 2H), 1.26–1.32
(m, 1H), 1.20–1.22 (br, 1H), 0.96 (d, 3H, J ¼ 6:7 Hz),
0.94 (s, 9H); 13C NMR (75 MHz, CDCl3) d 158.92,
131.44, 129.02, 113.64, 85.42, 74.21, 61.03, 55.22, 39.28,
38.89, 36.12, 26.90, 26.46, 21.07; IR (film): 3377.3(br),
CHCl3); EI-HRMS calcd for C20H33NO4 351.2490,
found 351.2408.
1
14 H NMR (300 MHz, CDCl3) d 7.23–7.35 (m, 7H),
6.82–6.87 (m, 2H), 6.50 (d, 1H, J ¼ 7:8 Hz), 5.28–5.35
(m, 1H), 4.56 (dd, 2H, J ¼ 10:5 Hz, 16.2 Hz), 4.43 (dd,
1H, J ¼ 7:9 Hz, 11.5 Hz), 4.28 (dd, 1H, J ¼ 4:6 Hz,
11.5 Hz), 3.77 (s, 3H), 3.59 (s, 3H), 3.10 (s, 3H), 3.09–
3.12 (m, 1H), 2.43 (dd, 1H, J ¼ 5:4 Hz, 13.6 Hz), 2.16–
2.25 (m, 1H), 1.86–1.93 (m, 1H), 1.46–1.50 (m, 2H), 0.99
(d, 3H, J ¼ 6:7 Hz), 0.93 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 172.00, 158.94, 157.04, 138.32, 131.11, 129.11,
128.63, 127.76, 126.63, 113.68, 85.35, 74.17, 67.62,
61.48, 55.17, 53.00, 43.56, 37.96, 36.18, 35.40, 28.48,
26.45, 21.10; IR (film): 3261.4, 2954.7, 1733.9, 1710.7,
1637.5, 2552.6, 1512.1, 1245.9, 1170.7, 1039.6,
20
D
808.1 cmꢀ1; ½aꢁ ¼ +18.0 (c 0.1, CHCl3); mp: 146.1 ꢁC;
FAB HRMS calcd for C29H43N2O6 (M+1) 515.3121,
found 515.3129.
2954.7, 2869.9, 1613.2, 1513.9, 1248.9, 1109.7, 1037.9,
20
820.7, 771.7 cmꢀ1; ½aꢁ ¼ )30.7 (c 3.0, CHCl3); EI-
D
HRMS calcd for C18H30O3 294.2195, found 294.2191.
4.8. (3R,5S)-5-(4-Methoxy-benzyloxy)-3,6,6-trimethyl-
heptanal, 12
To a solution of (COCl)2 (314.1 lL, 3.6 mmol) in DCM
(7 mL) at )78 ꢁC was added DMSO (514 lL, 5.38 mmol)
in DCM (1.5 mL) via a cannula, the cloudy mixture was
stirred for 10 min before alcohol 11 (527 mg, 1.79 mmol)
in DCM (1.5 mL) was introduced. One hour later, DI-
PEA (1.5 mL, 10.76 mmol) was added slowly at )78 ꢁC
The reaction mixture was warmed to )60 ꢁC within 1 h
and quenched with a saturated aqueous solution of
NH4Cl. (10 mL). After that, the mixture was poured
into ethyl acetate (150 mL), layers were separated and
the organic phase was washed with water (30 mL) and
brine (30 mL). This solution, after being dried over
4.7. (3R,5S)-5-(4-Methoxy-benzyloxy)-3,6,6-trimethyl-
heptanoic acid methoxy-methyl-amide 13 and (3R,5S)-5-
(4-Methoxy-benzyloxy)-3,6,6-trimethyl-heptanoic acid
[(S)-2-methoxymethyl carbamyloxy-1-phenyl-ethyl]-
amide, 14
To
a
suspension of N,O-dimethylhydroxylamine
hydrochloride (31.2 mg, 0.32 mmol) in DCM (3 mL) at
)30 ꢁC was added (CH3)3)Al (160 lL, 0.32 mmol, 2.0 M
in hexane). The reaction mixture was brought to an ice-
water bath for 30 min and then cooled to )30 ꢁC again

360
Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
Na2SO4, was concentrated in vacuo. The resulting crude
product was subjected to chromatography on silica gel,
using ethyl acetate–hexane (1:4) as eluant, to give the
4.10. (3R,4S,6S,8S)-8-(4-Methoxy-benzyloxy)-3,6,9,9-
tetramethyl-4-(tert-butyldimethylsilanyloxy)-dec-1-en, 16
1
title aldehyde 12 (492 mg, 94%) as a clear oil. H NMR
To a solution of TBSCl (354 mg, 2.35 mmol) in DMF
(0.5 mL) at 0 ꢁC was added alcohol 15 (329 mg,
0.94 mmol) in DMF (0.5 mL), followed by addition of
imidazole (320 mg, 4.7 mmol) under argon. The mixture
was then stirred at room temperature for 16 h before it
was poured into ethyl acetate–benzene (150 mL, 3:1).
The mixture was washed sequentially with water
(50 mL), saturated aqueous solution of NH4Cl (50 mL),
and brine (50 mL). The organic solution was then dried
over sodium sulfate and evaporated in vacuo. The resi-
due was purified by chromatography on silica gel, using
ethyl acetate–hexane (1:9) for elution, to produce 16
(406 mg, 93%) as a clear oil. 1H NMR (400 MHz, CDCl3)
d 7.27–7.29 (m, 2H), 6.81–6.88 (m, 2H), 5.72–5.79 (m,
1H), 5.00–5.05 (m, 2H), 4.62 (d, 1H, J ¼ 10:9 Hz), 4.47
(d, 1H, J ¼ 10:9 Hz), 3.81 (s, 3H), 3.82 (td, 1H,
J ¼ 3:0 Hz, 9.5 Hz), 3.07 (dd, 1H, J ¼ 4:5 Hz, 6.4 Hz),
2.37–2.41 (m, 1H), 1.79–1.84 (m, 1H), 1.58–1.65 (m, 1H),
1.40–1.43 (m, 2H), 1.04 (d, 3H, J ¼ 6:9 Hz), 0.94 (d, 3H,
J ¼ 6:6 Hz), 0.92–0.94 (m, 1H), 0.92 (s, 9H), 0.88 (s, 9H),
0.08 (s, 3H), 0.05 (s, 3H); 13C NMR (75 MHz, CDCl3) d
158.82, 141.00, 131.70, 128.72, 114.37, 13.56, 85.53,
73.57, 73.00, 55.21, 43.92, 40.37, 38.89, 36.06, 26.62,
26.44, 25.94, 20.65, 18.12, 13.20, )4.27, )4.41; IR (film):
(300 MHz, CDCl3) d 9.68 (dd, 1H, J ¼ 1:8 Hz, 2.9 Hz),
7.25–7.29 (m, 2H), 6.84–6.89 (m, 2H), 4.57 (d, 1H,
J ¼ 10:8 Hz), 4.49 (d, 1H, J ¼ 10:9 Hz), 3.79 (s, 3H),
3.05 (dd, 1H, J ¼ 3:7 Hz, 8.0 Hz), 2.44–2.49 (m, 1H),
2.09–2.19 (m, 2H), 1.42–1.47 (m, 2H), 1.01 (d, 3H,
J ¼ 6:5 Hz), 0.94 (s, 9H); 13C NMR (75 MHz, CDCl3)
d 202.69, 159.06, 131.12, 129.12, 113.71, 85.22, 74.32,
55.20, 50.11, 38.70, 36.18, 26.44, 25.66, 21.52; IR (film):
2959.7, 2870.5, 1724.5, 1613.6, 1513.9, 1248.5, 1110.5,
1075.8, 1036.6, 821.2 cmꢀ1
20
½aꢁ ¼ )19.3 (c 8.30,
;
D
CHCl3); EI-HRMS calcd for C18H28O3 292.2038, found
292.2046.
4.9. (3R,4S,6S,8S)-8-(4-Methoxy-benzyloxy)-3,6,9,9-
tetramethyl-dec-1-en-4-ol, 15
To a solution of KOBut (301.3 mg, 2.69 mmol) in THF
(5 mL) in a three-neck round bottom flask equipped
with an argon inlet and a dry ice–acetone condenser was
added trans-2-butene (ca. 0.4 g) at )78 ꢁC, followed by
addition of n-BuLi (1.78 mL, 2.69 mmol, 1.51 M in
hexane). Upon the end of addition, the mixture was
moved to a )45 ꢁC cooling bath and kept there for
45 min. The resulting orange solution was again cooled
to )78 ꢁC and (+)-B-OMe(Ipc)2 (908 mg, 2.87 mmol) in
THF (2.5 mL) was added slowly along the inner sides of
the flask. One hour later, BF3ÆOEt2 (386 lL, 3.05 mmol)
was added and the mixture was brought to )100 ꢁC
when aldehyde 12 (524 mg, 1.8 mmol) in THF (3 mL)
was added to the flask within 30 min. The reaction
mixture was stirred at )78 ꢁC for further 12 h and then
quenched by addition of Et3N (2 mL) and H2O2 (2 mL,
50% solution). After being stirred at room temperature
for 3 h, the solution was diluted with brine (15 mL). The
volatiles were removed in vacuo and the residue was
then extracted with ethyl acetate (3 · 50 mL). The com-
bined organic layers were washed with water (30 mL)
and brine (30 mL), dried over Na2SO4 and evaporated
under reduced pressure. After concentration, the residue
was subjected to chromatography on silica gel, using
ethyl acetate–hexane (1:4) as eluant to afford 15 (329 mg,
53%) as an oil. De value (>95%) of the title compound
was determined by NMR technique. 1H NMR
(300 MHz, CDCl3) d 7.24–7.29 (m, 2H), 6.82–6.86 (m,
2H), 5.70–5.79 (m, 1H), 5.08–5.13 (m, 2H), 4.61 (d, 1H,
J ¼ 10:5 Hz), 4.49 (d, 1H, J ¼ 10:4 Hz), 3.77 (s, 3H),
3.71–3.78 (m, 1H), 3.48 (m, 1H), 3.10 (dd, 1H,
J ¼ 2:6 Hz, 9.1 Hz), 2.11–2.19 (m, 1H), 1.89–2.01 (m,
1H), 1.51–1.57 (m, 1H), 1.40–1.49 (m, 1H), 1.29–1.38
(m, 1H), 1.06–1.16 (m, 1H), 1.02 (d, 3H, J ¼ 6:8 Hz),
0.95 (d, 3H, J ¼ 6:6 Hz), 0.92 (s, 9H); 13C NMR
(75 MHz, CDCl3) d 158.89, 140.58, 131.61, 129.11,
116.17, 113.61, 85.19, 74.09, 72.26, 55.19, 45.18, 40.75,
39.75, 36.07, 26.59, 26.48, 20.88, 16.15; IR (film):
2956.0, 2864.9, 1513.9, 1248.7, 1111.3, 1041.9, 909.6,
20
835.2, 773.3 cmꢀ1; ½aꢁ ¼ +29.85 (c 2.1, CHCl3); EI-
D
HRMS calcd for C28H50SiO3 462.3529, found 462.3535.
4.11. (2S,3S,5S,7S)-3-(tert-Butyl-dimethyl-silanyloxy)-7-
(4-methoxy-benzyloxy)-2,5,8,8-tetramethyl-nonanoic
acid, 4
Alkene 16 (270 mg, 0.58 mmol) was dissolved in
t-BuOH–acetone–H2O (5 mL, 2:3:3) and chilled with ice-
water bath, NMO (315 mg, 1.17 mmol, 50 wt % in H2O),
followed by OsO4 (0.28 mL, 0.011 mmol, 10 mg/mL in
H2O) and CH3SO2NH2 (55.5 mg, 0.58 mmol), was added
to the above solution. After being vigorously stirred for
24 h at room temperature, the reaction was quenched
with Na2SO3 (440.7 mg, 3.498 mmol). The mixture was
stirred for further 3 h and then diluted with brine (5 mL).
Volatiles were removed in vacuo and the residue was
extracted with ethyl acetate (3 · 30 mL). The combined
organic layers, were washed with brine (30 mL), dried
over Na2SO4, and concentrated to provide the corre-
sponding diol (256 mg). To a solution of the diol in
dichloromethane (15 mL), a pre-coated NaIO4–SiO2
(2.2 g, 1.29 mmol, 1 mmol/1.7 g) was added and the re-
sulted suspension was then stirred at room temperature
for 20 min. The reaction mixture was filtered and the
inorganic cake was washed with ethyl acetate (150 mL).
The combined filtrates were dried over Na2SO4 and
concentrated to provide the crude aldehyde, which was
1
used in next step without further purification. H NMR
(300 MHz, CDCl3) d 9.73 (d, 1H, J ¼ 1:5 Hz), 7.25–7.26
(m, 2H), 6.83–6.86 (m, 2H), 4.56 (d, 1H, J ¼ 10:9 Hz),
4.47 (d, 1H, J ¼ 10:8 Hz), 4.20 (td, 1H, J ¼ 3:6 Hz,
9.0 Hz), 3.79 (s, 3H), 3.04 (dd, 1H, J ¼ 4:4 Hz, 6.6 Hz),
2.54–2.58 (m, 1H), 1.74–1.85 (m, 2H), 1.38–1.44 (m, 2H),
3480.4(br), 2961.5, 2868.8, 1612.9, 1513.9, 1248.3,
20
D
1086.2, 1037.4, 810.3, 702.3 cmꢀ1; ½aꢁ ¼ )60.4 (c 2.5,
CHCl3). EI-HRMS calcd for C22H36O3 348.2664, found
348.2658.

Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
361
1.22–1.30 (m, 1H), 1.15 (d, 3H, J ¼ 7:0 Hz), 0.99 (d, 3H,
4.13. (6S)-6-tert-Butyl-5,6-dihydro-pyran-2-one, 18
J ¼ 6:6 Hz), 0.91 (s, 9H), 0.86 (s, 9H), 0.09 (s, 3H), 0.07
(s, 3H); 13C NMR (75 MHz, CDCl3) d 204.21, 158.84,
131.49, 128.66, 113.59, 85.54, 73.63, 70.11, 55.23, 41.13,
40.13, 36.10, 29.67, 26.70, 26.41, 25.81, 20.68, 18.03,
8.99, )4.20, )4.63.
To a solution of compound 17 (400 mg, 2.2 mmol) in
DCM (60 mL, degassed) was introduced (PCy3)2Cl2
Ru ¼ CHPh (179 mg, 0.22 mmol) dissolved in DCM
(10 mL, degassed) at room temperature. The total vol-
ume of the reaction was then made up to 110 mL with
degassed DCM and the mixture was brought to reflux for
6 h. The solvent was removed by fractional distillation.
The residue was purified by chromatography on silica
gel, using ether–pentane (2:3) as eluant to give the title
lactone 18 (298 mg, 88%) as an oil. 1H NMR (300 MHz,
CDCl3) d 6.88–6.94 (m, 1H), 5.32–5.97 (m, 1H), 4.05 (dd,
1H, J ¼ 5:5 Hz, 10.8 Hz), 2.28–2.33 (m, 2H), 0.98 (s, 9H);
13C NMR (75 MHz, CDCl3) d 164.41, 145.65, 120.87,
85.18, 36.64, 25.18, 24.57; IR (film): 2961.9, 2920.9,
To a solution of the above aldehyde in t-BuOH–H2O
(3 mL, 2:1), 2-methyl-2-butene (0.2 mL) was added at
0 ꢁC. A solution of NaClO2 (140 mg, 1.55 mmol) in a
pH 4.5 buffer (1.5 mL, prepared from water and 1.0 M
NaH2PO4) was then added to the above aldehyde
solution. After being stirred at 0 ꢁC for 5 min, the reac-
tion mixture was stirred at room temperature for further
15 min and then diluted with brine (5 mL). The volatiles
were removed in vacuo and the residue was then
extracted with ethyl acetate (3 · 30 mL). The combined
organic phases were washed with brine (40 mL) and
dried over Na2SO4. Removal of the solvent in vacuo
followed by chromatography on silica gel, eluting with
ethyl acetate–hexane (3:7), to afford the title acid 4
2880.4, 1726.7, 1391.0, 1251.2, 1084.5, 1044.9, 1028.9,
20
D
calcd for C9H14O2 154.2063, found 154.2061.
816.9 cmꢀ1; ½aꢁ ¼ )115.2 (c 3.5, n-pentane); EI-HRMS
1
(250 mg, 89%) as an oil. H NMR (400 MHz, CDCl3) d
4.14. (4R,6S)-6-tert-Butyl-4-methyl-tetrahydro-pyran-2-
one, 19
8.50–9.01 (br, 1H), 7.26 (d, 2H, J ¼ 9:1 Hz), 6.84–6.87
(m, 2H), 4.59 (d, 1H, J ¼ 10:9 Hz), 4.47 (d, 1H,
J ¼ 11:0 Hz), 4.13–4.17 (m, 1H), 3.80 (s, 3H), 3.05 (dd,
1H, J ¼ 4:4 Hz, 6.5 Hz), 2.69–2.76 (m, 1H), 1.72–1.81
(m, 2H), 1.37–1.40 (m, 2H), 1.20 (d, 3H, J ¼ 7:1 Hz),
0.95–1.00 (m, 1H), 0.97 (d, 3H, J ¼ 6:5 Hz), 0.91 (s, 9H),
0.87 (s, 9H), 0.11 (s, 3H), 0.08 (s, 3H); 13C NMR
(75 MHz, CDCl3) d 178.57, 158.85, 131.54, 128.69,
113.61, 85.58, 73.63, 71.02, 55.26, 45.87, 40.13, 36.11,
29.68, 26.73, 26.43, 25.81, 20.71, 17.99, 11.00, )4.26,
)4.78; IR (film): 3000.0(br), 2954.9, 2929.5, 2856.6,
CuCN (183.5 mg, 2.16 mmol, dried under high vacuum
at 70 ꢁC for 12 h), was suspended in Et2O (6 mL) at
)78 ꢁC. To this suspension MeLi (3.3 mL, 4.32 mmol,
1.3 M in Et2O) was added. Five minutes later, the
reaction mixture was brought to an ice-water bath and
stirred for additional 20 min and was then re-cooled to
78 ꢁC again before unsaturated lactone 18 (280 mg,
1.8 mmol) in Et2O (4 mL) was added via a cannula. The
reaction was kept at )78 ꢁC or 20 min and warmed up to
)45 ꢁC within 30 min, then to )20 ꢁC within another
30 min. The reaction mixture was diluted with Et2O
(25 mL), followed by addition of 20% aqueous acetic
acid (20 mL). The above mixture was further stirred at
0 ꢁC for 2 h and the layers were separated. The aqueous
phase was extracted with Et2O (3 · 50 mL). The com-
bined organic layers were washed with saturated aque-
ous solution of NaHCO3 (30 mL), brine (30 mL) and
dried over Na2SO4. Removal of the solvent in
vacuo followed by chromatography on silica gel,
using Et2O–pentane (2:3) as eluant, to give the title
compound 19 (263 mg, 86%) as an oil. 1H NMR
(300 MHz, CDCl3) d 3.99 (dd, 1H, J ¼ 3:8 Hz, 11.8 Hz),
2.42–2.51 (m, 1H), 2.13–2.22 (m, 2H), 1.81 (ddd, 1H,
J ¼ 10:4 Hz, 11.8 Hz, 14.0 Hz), 1.51 (dddd, 1H,
J ¼ 0:6 Hz, 4.1 Hz, 4.1 Hz, 13.9 Hz), 1.10 (d, 3H,
J ¼ 6:6 Hz), 0.96 (s, 9H); 13C NMR (75 MHz, CDCl3) d
172.84, 83.49, 36.89, 33.72, 29.68, 25.11, 24.07, 20.99; IR
1709.1, 1514.2, 1463.7, 1249.1, 1111.8, 1041.8, 836.4,
20
D
calcd for C27H48SiO5 480.3271, found 480.3277.
775.1 cmꢀ1; ½aꢁ ¼ )20.5 (c 1.5, CHCl3); EI-HRMS
4.12. (S)-Acrylic acid 1-tert-butyl-but-3-enyl ester, 17
To a solution of homoallylic alcohol 6 (0.8 g, 6.25 mmol)
dissolved in Et2O (30 mL) at 0 ꢁC acryloyl chloride
(0.73 mL, 8.12 mmol) in Et2O (5 mL), followed by Et3N
(2.6 mL, 18.8 mmol) in Et2O (8 mL), were added suc-
cessively. The reaction mixture was then stirred at room
temperature for 12 h before it was poured into cold
water (30 mL) and extracted with diethyl ether
(3 · 30 mL). The combined organic layers were washed
with saturated aqueous solution of NaHCO3 (30 mL),
NH4Cl (30 mL) and brine (30 mL), dried over Na2SO4
and concentrated in vacuo. The residue was purified by
chromatography on silica gel, using diethyl ether–pen-
tane (1:4) as eluant, to produce the title ester 17 (1.05 g,
(film): 2960.3, 2880.4, 1743.1, 1367.2, 1285.1, 1241.5,
1073.5, 1002.6 cmꢀ1
20
½aꢁ ¼ +28.3 (c 3.2, Et2O);
1
92%) as an oil. H NMR (300 MHz, CDCl3) d 6.39 (dd,
;
D
1H, J ¼ 1:6 Hz, 15.3 Hz), 6.11 (dd, 1H, J ¼ 10:5 Hz,
17.49 Hz), 5.81 (dd, 1H, J ¼ 1:7 Hz, 10.4 Hz), 5.66–5.78
(m, 1H), 4.96–5.07 (m, 2H), 4.87 (dd, 1H, J ¼ 2:7 Hz,
1.0 Hz), 2.36–2.45 (m, 1H), 2.16–2.27 (m, 1H), 0.94 (s,
9H); 13C NMR (75 MHz, CDCl3) d 165.99, 135.08,
130.25, 128.79, 117.03, 79.84, 34.64, 34.59, 26.90; IR
(film): 2967.8, 2920.9, 2880.4, 1726.8, 1642.8, 1480.6,
EI-HRMS calcd for C10H18O2 170.1307, found
170.1313.
4.15. (3R,5S)-5-Hydroxy-3,6,6-trimethyl-heptanoic acid
methoxy-methyl-amide, 20
1405.1, 1367.1, 1295.5, 1270.6, 1191.1, 1045.3, 985.1,
To a solution of N,O-dimethylhydroxylamine hydro-
chloride (88 mg, 0.9 mmol) in DCM (2 mL) at )78 ꢁC
Al(CH3)3 (450 lL, 0.9 mmol, 2.0 M in hexane) was
20
D
HRMS calcd for C11H18O2 182.1307, found 182.1299.
914.9, 807.2 cmꢀ1; ½aꢁ ¼ +18.7 (c 7.0, n-pentane) EI-

362
Z. Xu et al. / Tetrahedron: Asymmetry 15 (2004) 355–363
added slowly. The solution was allowed to warm to
room temperature and stirred overnight. The reaction
vessel was chilled in ice-water bath and lactone 19
(51 mg, 0.3 mmol) in DCM (2 mL) was then added. The
reaction mixture was stirred for another 6 h at room
temperature before it was quenched at 0 ꢁC with
Rochelleꢀs salt (1.0 g, 3.6 mmol) in water (5 mL). After
the solution became clear (ca. 2 h), it was extracted with
ethyl acetate (3 · 30 mL). The combined organic layers
were washed with brine (30 mL), dried over Na2SO4,
and concentrated in vacuo. The resulting crude product
was purified by chromatography on silica gel, using
ethyl acetate–hexane (2:3) as eluant, to afford Weinreb
Acknowledgements
We thank the support from the Area of Excellence
Scheme (established under the University Grants Com-
mittee of the Hong Kong Special Administrative
Region), The University of Hong Kong and The Hong
Kong Polytechnic University (PolyU5285/02P, Project
G-T628).
References and notes
1
amide 20 (58 mg, 91%) as an oil. H NMR (300 MHz,
1. Burja, A. M.; Banaigs, B.; Abou-Mansour, E.; Burgess,
J. G.; Wright, P. C. Tetrahedron 2001, 57, 9347–9377.
2. Gerwick, W. H.; Tan, L. T.; Sitachitta, N. Nitrogen-
containing Metabolites from Marine Cyanobacteria. In
Alkaloids. 2001, p 184.
3. Luesch, H.; Yoshida, W. Y.; Moore, R. E.; Paul, V. J.;
Corbett, T. H. J. Am. Chem. Soc. 2001, 123, 5418–5423.
4. Luesch, H.; Yoshida, Y.; Moore, R. E.; Paul, V. J. Bioorg.
Med. Chem. 2002, 10, 1973–1978.
5. Xu, Z. S.; Chen, Z. Y.; Ye, T. Abstracts of Papers, 225th
ACS National Meeting, New Orleans, LA, United States,
March 23–27, 2003; American Chemical Society: Wash-
ington, DC, 2003; ORGN-415.
CDCl3) d 3.70 (s, 3H), 3.20 (s, 3H), 3.15 (dd, 1H,
J ¼ 2:8 Hz, 9.8 Hz), 2.80–3.00 (br, 1H), 2.25–2.51 (m,
3H), 1.38 (ddd, 2H, J ¼ 4:1 Hz, 9.7 Hz, 9.7 Hz), 1.04 (d,
3H, J ¼ 6:6 Hz), 0.89 (s, 9H); 13C NMR (75 MHz,
CDCl3) d 174.74, 76.36, 61.13, 39.41, 38.15, 34.66, 32.27,
26.29, 25.85, 22.23; IR (film): 3440.4(br), 2956.2, 2870.3,
1650.8, 1463.0, 1387.8, 1179.9, 1093.9, 1006.1,
20
D
calcd for C12H25NO3: 213.1729, found 213.1727.
987.5 cmꢀ1; ½aꢁ ¼ )22.9 (c 2.6, CHCl3); EI-HRMS
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