Stereoselective synthesis of both tetrahydropyran rings of the antitumor macrolide, (-)-lasonolide A

Article abstract of DOI:10.1021/jo202631e

Stereoselective syntheses of both functionalized tetrahydropyran subunits of (-)-lasonolide A are described. These tetrahydropyran rings were constructed using catalytic asymmetric hetero Diels-Alder reactions as the key steps. The C22 quaternary stereocenter present in the upper tetrahydropyran ring was constructed by a stereoselective alkylation, and the C9 hydroxy stereochemistry of the bottom tetrahydropyran was constructed by a stereoselective epoxidation followed by a regioselective epoxide opening reaction.

Full text of DOI:10.1021/jo202631e

Note
pubs.acs.org/joc
Stereoselective Synthesis of Both Tetrahydropyran Rings of the
Antitumor Macrolide, (−)-Lasonolide A
Arun K. Ghosh* and Guo-Bao Ren
Department of Chemistry and Department of Medicinal Chemistry, Purdue University, West Lafayette, Indiana 47907, United States
S
* Supporting Information
ABSTRACT: Stereoselective syntheses of both functionalized tetrahydropyran
subunits of (−)-lasonolide A are described. These tetrahydropyran rings were
constructed using catalytic asymmetric hetero Diels−Alder reactions as the key
steps. The C22 quaternary stereocenter present in the upper tetrahydropyran
ring was constructed by a stereoselective alkylation, and the C9 hydroxy
stereochemistry of the bottom tetrahydropyran was constructed by a
stereoselective epoxidation followed by a regioselective epoxide opening
reaction.
addition. The bicyclic isoxazoline led to the tetrahydropyran
asonolide A was isolated from the Caribbean marine
ring as well as the C22 quarternary stereocenter. However, the
route was long with over 20 steps, including a number of steps
with low yields. The bottom tetrahydropyran ring was
constructed using an asymmetric catalytic hetero Diels−Alder
reaction developed by Jacobsen and co-workers.8 However,
elaboration of the C9 hydroxy stereochemistry required ketone
reduction producing a mixture of diastereoisomers (1:2 minor
isomer being the desired isomer), separation, and then
recycling of the major isomer through an oxidation/reduction
sequence.5 Our retrosynthesis of lasonolide A is summarized in
Figure 1. Key macrolactone 2 will be prepared from acyclic
precursor 3, which we had previously constructed by a Julia−
Kocienski reaction,5,9 using sulfone 4 and aldehyde 5.5 We
further envisioned that both sulfone 4 and the aldehyde 5 could
be stereoselectively constructed using Jacobsen’s chromium-
catalyzed hetero Diels−Alder reactions as key steps.8
As shown in Scheme 1, the synthesis of silyloxy dienes for the
hetero Diels−Alder reaction commenced with the known
aldehyde 8.10 Methyl or ethylmagnesium bromide was added to
aldehyde 8 to afford the respective alcohol in 97 and 95%
yields, respectively. Parikh−Doering oxidation11 of the resulting
alcohols provided the corresponding ketones. Reaction of these
ketones with TMSOTf or TESOTf in the presence of
triethylamine provided silyl enol ethers 912 and 10 in 97 and
91% yields, respectively. Asymmetric hetero Diels−Alder
reactions of the silyl enol ethers 9 and 10 with benzylox-
yacetaldehyde 1213 in the presence of chiral Cr(III) catalyst 118
(7.5 to 10 mol %) afforded cycloadducts 6 and 7. The
enantiomeric excess of the cycloadducts 6 (91% ee) and 7
L
sponge, Forcepia sp., by McConnell and co-workers in
1994.1 Lasonolide A exhibited potent antitumor activity against
a range of cancer cell lines in the low nanomolar level. It has
shown IC50 values of 8.6 and 89 nM against A-549 human lung
carcinoma and Panc-1 human pancreatic carcinoma, respec-
tively.1 Furthermore, it showed cell adhesion in the EL-4.IL-2
cell line, which detects signal-transduction agents. Interestingly,
the mechanism of action of lasonolide A is still unknown. The
natural abundance of lasonolide is very limited. The scarce
supply and important biological properties of lasonolide A has
attracted much interest in the chemistry and biology of
lasonolide A. The structure of lasonolide A was initially
determined by extensive NMR studies. Subsequently, its
structure was revised through total synthesis,2 and biological
studies were reported by Lee and co-workers.3 Since then, two
more total syntheses and numerous synthetic studies on both
tetrahydropyran rings have been reported.4−6 We recently
reported an asymmetric total synthesis of lasonolide A.5
Utilizing this synthetic lasonolide A, we have investigated the
biological mechanism of action in collaboration with the
National Cancer Institute.7 Our studies revealed that lasonolide
A uniquely induces premature chromosome condensation,
which may lead to a new treatment of many disorders. In an
effort to further elucidate lasonolide A’s structure−activity
relationships as well as to identify its biological target, we
sought to improve the synthesis of both tetrahydropyran
subunits of lasonolide A. Herein, we report our studies leading
to a stereoselective synthesis of both highly substituted
tetrahydropyran rings using asymmetric hetero Diels−Alder
reactions as key steps.
Our previous route5 to the upper tetrahydopyran ring
utilized a diastereoselective intramolecular 1,3-dipolar cyclo-
Received: December 29, 2011
Published: February 10, 2012
© 2012 American Chemical Society
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Scheme 2. Synthesis of the Upper Tetrahydropyran Ring
Figure 1. Retrosynthetic analysis of lasonolide A.
Scheme 1. Synthesis of Dihydropyrans 6 and 7
was subjected to a Julia−Kocienski reaction.9 The requisite
sulfone 17 was readily prepared by a Mitsunobu reaction with
known alcohol 16,14 triphenylphosphine, diisopropylazodicar-
boxylate (DIAD), and phenyl tetrazole thiol. Reaction of the
sulfone 17 with KHMDS in a mixture (5:1) of DME and
HMPA followed by addition of the aldehyde provided the
corresponding trans-olefin as a major isomer (trans/cis = 10:1
1
by H NMR analysis) in 90% yield. Interestingly, trans/cis
selectivity was reduced when THF was used as the solvent
(75% yield, trans/cis = 5:1 by 1H NMR analysis). The resulting
trans sulfide was oxidized to the corresponding sulfone using
ammonium heptamolybdate15 as a catalyst in the presence of
hydrogen peroxide. Subsequent protecting-group manipulation
afforded the sulfone 4 in 10 steps from the hetero Diels−Alder
product 6.5
The synthesis of the bottom tetrahydropyran ring is shown in
Scheme 3. Hetero Diels−Alder product 7 was treated with
TBAF in the presence of acetic acid in THF to provide ketone
19 in 72% yield, over 2 steps. As described previously, selective
reduction5 of this ketone to the desired axial alcohol 21 was
very challenging. Direct reduction with a variety of hydride
reagents provided undesired alcohol 20 as the major isomer (dr
≥ 2:1). Conversion of the undesired alcohol 20 back to alcohol
21 using Swern oxidation followed by reduction did improve
the yield of 21. However, it required tedious separation, which
was not very convenient even during large scale preparation.
We therefore devised an alternative strategy to circumvent the
poor diastereoselectivity issue. Thus, ketone 19 was converted
to the corresponding enol triflate with NaHMDS and phenyl
triflimide.16 Palladium-catalyzed reduction17 of the resulting
enol triflate afforded alkene 22 in 75% yield over two steps.
Epoxidation of the resulting olefin with dimethyldioxirane
(93% ee) was determined by chiral HPLC. These silyl enol
ethers were then used as the key intermediates in the
construction of the two tetrahydropyran rings.
As shown in Scheme 2, for the construction of the top
tetrahydropyran ring, silyl ether 6 was treated with MeLi at −78
°C for 1 h. The resulting lithium enolate was reacted with ethyl
cyanoformate to provide the corresponding β-keto ester as a
mixture in 82% yield. The mixture was subjected to alkylation
with NaH and MeI to provide the desired methylation product
13 in 74% total yield (dr 6.6:1 by 1H NMR analysis). Exposure
of β-keto ester 13 to L-selectride in THF provided the
corresponding axial alcohol, which was subjected to LiAlH4
reduction in the same pot to afford diol 14 diastereoselectively
(ratio 10:1), and diastereomers were separated to provide 14 in
82% yield. Protection of the diol as an acetonide followed by
removal of the benzyl group using catalytic hydrogenation
afforded the alcohol 15 in 84% yield over 2 steps. Parikh−
Doering oxidation11 of 15 gave the precursor aldehyde, which
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Note
tive alkylation followed by diastereoselective reduction steps.
The C9 hydroxy group in the bottom tetrahydropyran ring was
introduced stereoselectively using selective epoxidation with
DMDO and reduction with DIBAL-H. Julia−Kocienski
reaction of the two subunits provided the advanced
intermediate 3 of our previous synthesis of lasonolide A. The
synthesis of 3 has been carried out in 12 linear steps (13.5%
overall yield from 8) and 25 overall steps. In comparison, our
previous synthesis of 3 was accomplished in 23 linear steps
(2.78% overall yield) and 38 overall steps.5 Overall, these routes
are amenable to the synthesis of structural analogues of
lasonolide A.
Scheme 3. Synthesis of the Bottom Tetrahydropyran Ring
EXPERIMENTAL SECTION
General experimental details are provided in the Supporting
Information.
■
(2-((2S,6S)-6-(Benzyloxymethyl)-4-(trimethylsilyloxy)-5,6-di-
hydro-2H-pyran-2-yl)ethoxy)(tert-butyl)dimethylsilane (6). A
mixture of enol ether 912 (1.05 g, 3.51 mmol), 12 (1.58 g, 10.5
mmol), and 4 Å molecular sieves (1.2 g) was treated with the
Jacobsen’s catalyst, 11 (123 mg, 0.26 mmol) at 23 °C for 24 h. The
reaction was diluted with EtOAc and filtered through a short pad of
Celite and eluted with EtOAc. The filtrate was collected and
concentrated in vacuo. The residue was purified quickly by a short
pad of silica gel (1% NEt3/5% EtOAc/hexanes) to afford enol ether 6
25
1
(1.12 g, 71%) as a yellow oil: [α]D −23.2 (c 0.6, CHCl3); H NMR
(400 MHz, CDCl3) δ 7.35−7.26 (m, 5H), 4.80 (s, 1H), 4.59 (ABq, JAB
= 12.3 Hz, 2H), 4.32−4.27 (m, 1H), 3.82−3.71 (m, 3H), 3.55 (dd, J =
10.3, 6.2 Hz, 1H), 3.49 (dd, J = 10.3, 4.2 Hz, 1H), 2.15−2.06 (m, 1H),
1.91 (m, 1H), 1.80−1.68 (m, 2H), 0.89 (s, 9H), 0.20 (s, 2H), 0.05 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 148.0, 138.3, 128.3, 127.6,
127.5, 106.6, 73.6, 73.3, 72.7, 71.2, 59.6, 39.4, 32.8, 25.9, 18.3, 0.2,
−5.4; FT-IR (film) 2955, 2928, 1668, 1098 cm−1; ESI-MS m/z 451.2
([M + H]+), 473.4 ([M + Na]+); ESI-HRMS calcd for C24H43O4Si2
([M + H]+) 451.2694, found 451.2708.
(2S,3S,6S)-Ethyl-6-((benzyloxy)methyl)-2-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-3-methyl-4-oxotetrahydro-2H-
pyran-3-carboxylate (13). To a solution of 6 (1.12 g, 2.49 mmol) in
dry THF (10 mL) was added MeLi (1.6 M in diethyl ether, 4.7 mL) at
−78 °C. The reaction was then kept at −20 °C for 1 h and then cooled
down to −78 °C. NCCO2Et (0.74 mL, 7.46 mmol) was added. The
mixture was warmed to 23 °C and quenched with water. The aqueous
layer was extracted with ethyl acetate. The combined organic phase
was washed with water and brine, dried over Na2SO4, and
concentrated. Silica gel chromatography (10% EtOAc/hexanes) of
the residue provided alkylated product (922 mg, 82%) as a yellow oil.
To a solution of the former oil (392 mg, 0.87 mmol) in dry THF (5
mL) was added NaH (42 mg, 60% in oil, 1.04 mmol) at 0 °C. After 30
min, MeI (494 mg, 3.48 mmol) was added. The reaction was kept at 0
°C for 1 h and then at 23 °C overnight. The reaction was quenched
with aq NH4Cl. The aqueous layer was extracted with ethyl acetate.
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated. Silica gel chromatography (10%
EtOAc/hexanes) of the residue afforded the desired isomer 13 (324
mg, 80%) as a colorless oil: [α]D25 45.2 (c 1.1, CHCl3); 1H NMR (400
MHz, CDCl3) δ 7.35−7.26 (m, 5H), 4.60 (ABq, JAB = 12.3 Hz, 2H),
4.27−4.23 (m, 1H), 4.20 (q, J = 6.8 Hz, 2H), 3.97−3.90 (m, 1H),
3.81−3.70 (m, 2H), 3.64−3.55 (m, 2H), 2.63 (dd, J = 12.1, 5.5 Hz,
1H), 2.32 (dd, J = 15.2, 2.8 Hz, 1H), 1.81−1.70 (m, 1H), 1.45−1.41
(m, 1H), 1.37 (s, 3H), 1.26 (t, J = 6.9 Hz, 3H), 0.89 (s, 9H), 0.05 (s,
6H); 13C NMR (100 MHz, CDCl3) δ 206.4, 170.6, 137.9, 128.4,
127.7, 127.5, 76.6, 76.1, 73.4, 71.9, 61.8, 61.2, 59.1, 39.8, 33.7, 25.8,
18.2, 14.3, 14.0, −5.4, −5.6; FT-IR (film) 2955, 2930, 2858, 1738,
1715, 1254 1103 cm−1; ESI-MS m/z 465.1 ([M + H]+), 487.1 ([M +
Na]+); ESI-HRMS calcd for C25H40O6SiNa ([M + Na]+) 487.2486,
found 487.2496.
(DMDO) afforded the desired epoxide in 69% yield as the
major isomer (5.3:1 ratio). Epoxidation presumably proceeded
from the top-side as shown in the stereochemical model 23.
The isomers were separated by silica gel chromatography.
DIBAL-H reduction of the major epoxide provided alcohol 21
as a single isomer in excellent yield. The observed epoxide ring-
opening selectivity is consistent with the expected diaxial
epoxide opening, in accordance with the Furst−Plattner rule.18
̈
Protection of the alcohol as a TBS ether followed by selective
deprotection of the primary TBS group with CSA in MeOH
provided the primary alcohol 24 in 89% yield. Parikh−Doering
oxidation of alcohol 24 followed by Horner−Wadsworth−
Emmons olefination of the resulting aldehyde furnished the
α,β-unsaturated ester 25 in 91% yield. This was converted to
alcohol 26 in a three step sequence involving (1) DIBAL-H
reduction, (2) protection of the resulting alcohol as a TBS
ether, and (3) selective removal of the benzyl group19 with Li in
liquid ammonia (70% yield, over three steps). Alcohol 26 was
converted to aldehyde 5 as described by us previously.5
Deprotonation of sulfone 4 using KHMDS in THF at −78 °C
followed by addition of aldehyde 5 afforded trans-olefin 3 as a
single isomer in 70% yield. This coupling product 3 was the key
intermediate of our previous synthesis of lasonolide A.5
In summary, we have accomplished a stereoselective
synthesis of both tetrahydropyran subunits of lasonolide A
using catalytic asymmetric hetero Diels−Alder reactions as key
steps. The C22 quaternary carbon stereocenter present in the
upper tetrahydropyran ring was installed using diastereoselec-
(2S,3R,4R,6S)-6-((Benzyloxy)methyl)-2-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-3-(hydroxymethyl)-3-methylte-
trahydro-2H-pyran-4-ol (14). To a solution of 13 (320 mg, 0.69
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Note
mmol) in dry THF (5 mL) was added L-selectride (1 M in THF, 2.07
mL) at −78 °C. The reaction was kept at −78 °C for 3 h. LiAlH4 (26
mg, 0.69 mmol) was then added, and the reaction was allowed to stir
at 0 °C for 2 h. The reaction was quenched slowly with aq NaOH (1
M, 2 mL) and aq 30% H2O2 (1 mL). The mixture was stirred at 0 °C
for another 1 h. The aqueous layers were extracted with ethyl acetate.
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated. Silica gel chromatography (40%
EtOAc/hexanes to 50% EtOAc/hexanes) of the residue afforded diol
14 (240 mg, 82%) as a colorless oil: [α]D 34.6 (c 0.70, CHCl3); H
NMR (400 MHz, CDCl3) δ 7.36−7.25 (m, 5H). 4.57 (s, 2H), 4.11 (d,
J = 6.8 Hz, 1H), 4.03 (m, 1H), 3.90 (s, 1H), 3.82−3.78 (m, 2H), 3.67
(d, J = 11.6 Hz, 1H), 3.55−3.46 (m, 3H), 1.80−1.63 (m, 2H), 1.61−
1.42 (m, 2H), 0.90 (s, 9H), 0.76 (s, 3H), 0.07 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 138.4, 128.3, 127.5, 127.4, 74.6, 73.21, 73.16, 71.6,
71.5, 69.7, 61.3, 39.9, 32.5, 26.0, 18.4, 15.1, −5.4; FT-IR (film) 3376,
2955, 2928, 1089 cm−1; ESI-MS m/z 425.2 ([M + H]+), 447.1 ([M +
Na]+); ESI-HRMS calcd for C23H40O5SiNa ([M + Na]+) 447.2543,
found 447.2539.
mmol) at −78 °C. After 30 min, a solution of above aldehyde (206 mg,
0.56 mmol) in dry DME (1 mL) was added. The reaction was kept at
−78 °C for 2 h and then quenched with aq NH4Cl. The layers were
separated, and the aqueous layers were extracted with ethyl acetate.
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated. Purification of the residue by flash
chromatography (15% EtOAc/hexanes) afforded the corresponding
25
olefin (290 mg, 91%) as a colorless oil: [α]D 24.9 (c 0.95, CHCl3);
1H NMR (400 MHz, CDCl3) δ 7.60−7.51 (m, 5H), 5.70−5.61 (m,
1H), 5.59−5.48 (m, 1H), 4.27−4.12 (m, 2H), 3.85−3.80 (m, 1H),
3.76−3.63 (m, 2H), 3.53−3.44 (m, 2H), 3.43−3.36 (m, 2H), 2.58−
2.49 (m, 2H), 1.73−1.62 (m, 2H), 1.52−1.46 (m, 2H), 1.42 (s, 3H),
1.39 (s, 3H), 0.90 (s, 9H), 0.72 (s, 3H), 0.06 (s, 6H); 13C NMR (100
MHz, CDCl3) δ 154.2, 133.9, 133.6, 130.0, 129.7, 127.4, 123.8, 98.4,
77.2, 71.9, 71.1, 66.0, 59.9, 34.2, 33.5, 32.8, 32.2, 31.8, 29.2, 25.9, 18.8,
18.2, 14.8, −5.35, −5.42; FT-IR (film) 2928, 1384, 836 cm−1; ESI-MS
m/z 575.2 ([M + H]+), 597.2 ([M + Na]+); ESI-HRMS calcd for
C29H46N4O4SSiNa ([M + Na]+) 597.2907, found 597.2904.
25
1
To a solution of above olefin (245 mg, 0.43 mmol) in EtOH (5
mL) and THF (2 mL) was added buffer (pH = 7.5, Na2HPO4−
NaH2PO4, 0.5 mL) followed by (NH4)6Mo7O24·7H2O (132 mg, 0.107
mmol) and aq H2O2 (30%, 0.5 mL) at 0 °C. The reaction was allowed
to stir at 23 °C for 2 h until another portion of (NH4)6Mo7O24·7H2O
(132 mg, 0.11 mmol) and aq H2O2 (30%, 0.5 mL) was added. The
mixture was stirred for 12 h and then carefully quenched with aq
Na2SO3. The mixture was extracted with ethyl acetate. The combined
extracts were washed with water and brine, dried over Na2SO4, and
concentrated.
((4aS,5S,7S,8aR)-5-(2-((tert-Butyldimethylsilyl)oxy)ethyl)-
2,2,4a-trimethylhexahydropyrano[4,3-d][1,3]dioxin-7-yl)-
methanol (15). To a solution of 14 (276 mg, 0.651 mmol) in dry
CH2Cl2 (5 mL) was added 2,2-dimethoxypropane (2 mL) followed by
PPTS (16.4 mg, 0.065 mmol). The reaction was kept at 23 °C for 10
h. The reaction was quenched with aq NaHCO3. The aqueous layers
were extracted with ethyl acetate. The combined organic phase was
washed with water and brine, dried over Na2SO4, and concentrated.
Silica gel chromatography (10% EtOAc/hexanes) of the residue
provided the acetonide derivative as a colorless oil (278 mg, 92%).
A mixture of the former colorless oil (295 mg, 0.64 mmol) and Pd−
C (20 wt %, 50% wet, 60 mg) in EtOAc (6 mL) was stirred at 23 °C
under H2 atmosphere for 10 h. The solid was filtered off and washed
with EtOAc twice. The combined organic phase was concentrated in
vacuo and purified by flash chromatography to afford alcohol 15 (217
The above residue was dissolved in THF (5 mL). HF·Py (0.16 mL,
4.27 mmol) was added. The reaction was allowed to stir at 23 °C for 4
h, and then it was quenched with aq NaHCO3. The mixture was
extracted with ethyl acetate. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated. Silica gel
chromatography (50% EtOAc/hexanes) of the residue afforded the
25
1
mg, 91%) as a colorless oil: [α]D 36.0 (c 1.05, CHCl3); H NMR
(400 MHz, CDCl3) δ 4.26 (d, J = 10.3 Hz, 1H), 3.89−3.80 (m, 2H),
3.77−3.70 (m, 2H), 3.65−3.54 (m, 1H), 3.54−3.45 (m, 2H), 3.46−
3.37 (m, 1H), 2.10−2.01 (br, 1H), 1.84−1.72 (m, 1H), 1.70−1.64 (m,
1H), 1.52−1.32 (m, 2H), 1.43 (s, 3H), 1.39 (s, 3H), 0.89 (s, 9H), 0.73
(s, 3H), 0.06 (s, 3H), 0.05 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
98.4, 72.3, 71.7, 71.3, 66.0, 65.9, 60.1, 34.5, 32.3, 29.24, 29.17, 25.9,
18.8, 18.2, 14.7, −5.36, −5.42; FT-IR (film) 3460, 2955, 1089 cm−1;
ESI-MS m/z 397.2 ([M + Na]+); ESI-HRMS calcd for C19H38O5SiNa
([M + Na]+) 397.2381, found 397.2387.
5
1
desired alcohol 18 (160 mg, 76% for 2 steps) as a colorless oil: H
NMR (400 MHz, CDCl3) δ 7.65−7.54 (m, 5H), 5.68−5.48 (m, 2H),
4.35 (t, J = 7.6 Hz, 1H), 4.27−4.24 (m, 1H), 3.84−3.69 (m, 5H), 3.50
(ABq, JAB = 12.5 Hz, 2H), 2.95 (br, 1H), 2.68−2.60 (m, 2H), 1.71−
1.64 (m, 3H), 1.50 (m, 1H), 1.41 (s, 3H), 1.39 (s, 3H), 0.75 (s, 3H).
TES-enol Ether (10). To a solution of 8 (1.9 g, 8.88 mmol) in dry
THF (40 mL) was added ethylmagnesium bromide (3 M in ether, 3.85
mL) at −20 °C. The reaction was kept at −20 °C for 2 h and then
quenched with aq NH4Cl. The mixture was extracted with ethyl
acetate. The combined extracts were washed with water and brine,
dried over Na2SO4, and concentrated. Silica gel chromatography (20%
EtOAc/hexanes) of the residue gave the desired alcohol (2.05 g, 95%)
as a colorless oil.
1-Phenyl-5-((3-((1-phenyl-1H-tetrazol-5-yl)sulfonyl)propyl)-
thio)-1H-tetrazole (17). To a solution of 16 (4.34 g, 16.19 mmol), 1-
phenyl-1H-tetrazole-5-thiol (3.33 g, 19 mmol), and Ph3P (7.86 g, 30
mmol) in dry CH2Cl2 (150 mL) was added DIAD (4.44 g, 22 mmol)
dropwise. The reaction was kept at 23 °C overnight. The solvent was
removed, and the residue was purified by silica gel chromatography to
To a solution of above alcohol (1.71 g, 7 mmol) in CH2Cl2/DMSO
(2:1, 45 mL) was added Et3N (9.75 mL, 70 mmol) followed by
SO3·Py (2.79 g, 17.5 mmol) at 0 °C. When the reaction was complete
as shown by TLC, it was quenched with aq NaHCO3. The mixture was
extracted with ethyl acetate. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated. Silica gel
chromatography (10% EtOAc/hexanes) of the residue gave the
desired ketone (1.61 g, 95%) as a yellow oil.
To a solution of the former ketone (2.63 g, 10.9 mmol) in diethyl
ether (15 mL) was added NEt3 (3.8 mL, 27.2 mmol) followed by
TESOTf (4.3 g, 16.3 mmol) at −78 °C. The reaction was kept at −78
°C for 30 min and at 0 °C for 1 h. The reaction was quenched with aq
NaHCO3. The mixture was extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na2SO4, and concentrated. Purification by flash chromatography (1%
NEt3/5% EtOAc/hexane) afforded TES-enol ether 10 (3.53 g, 91%)
as a colorless oil: 1H NMR (400 MHz, CDCl3) δ 5.90 (d, J = 15.4 Hz,
1H), 5.82−5.70 (m, 1H), 4.73 (q, J = 7.0 Hz, 1H), 3.64 (t, J = 6.8 Hz,
2H), 2.29 (q, J = 6.9 Hz, 2H), 1.64 (d, J = 7.0 Hz, 3H), 1.03−0.91 (m,
12H), 0.89 (s, 9H), 0.70 (q, J = 8.1, 5.9 Hz, 6H), 0.05 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 149.5, 130.4, 124.3, 107.4, 62.9, 35.8, 25.8,
18.2, 11.3, 6.7, 6.3, 5.4, −5.4; FT-IR (film) 2954, 1657, 1627, 1097
1
give the desired sulfide 17 as a white solid (5.26 g, 76%): H NMR
(400 MHz, CDCl3) δ 7.71−7.26 (m, 10H), 3.95 (t, J = 7.0 Hz, 2H),
3.60 (t, J = 6.9 Hz, 2H), 2.61 (m, 2H); 13C NMR (100 MHz, CDCl3)
δ 153.2, 153.1, 133.3, 132.8, 131.5, 130.3, 129.8, 129.7, 125.0, 123.8,
54.2, 31.0, 22.3; FT-IR (film) 1730, 1498, 1340 cm−1; ESI-MS m/z
429.1 ([M + H]+); ESI-HRMS calcd for C17H17O2N8S2 ([M + H]+)
429.0910, found 429.0925.
2-((4aS,5S,7S,8aR)-2,2,4a-Trimethyl-7-((E)-4-((1-Phenyl-1H-
tetrazol-5-yl)sulfonyl)but-1-en-1-yl)hexahydropyrano[4,3-d]-
[1,3]dioxin-5-yl)ethanol (18). To a solution of 15 (210 mg, 0.56
mmol) in CH2Cl2 (5 mL) and DMSO (2 mL) was added NEt3 (0.63
mL, 4.49 mmol) followed by SO3·Py (358 mg, 2.25 mmol) at 0 °C.
The reaction was kept at 0 °C for 2 h. The reaction was quenched with
aq NaHCO3. The aqueous layers were extracted with ethyl acetate.
The combined organic phase was washed with water and brine, dried
over Na2SO4, and concentrated. Purification of the residue by flash
chromatography (30% EtOAc/hexanes) afforded the desired aldehyde
(206 mg, 99%) as a colorless oil.
To a solution of 17 (960 mg, 2.25 mmol) in DME/HMPA (v/v, 10
mL/2 mL) was added KHMDS (0.5 M in toluene, 4.5 mL, 2.25
2562
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The Journal of Organic Chemistry
Note
cm−1; MS m/z 357.3 ([M + H]+); ESI-HRMS calcd for C19H41O2Si2
([M + H]+) 357.2640, found 357.2648.
1.33 (m, 1H), 0.88 (s, 9H), 0.83 (d, J = 6.9 Hz, 3H), 0.04 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 138.2, 128.3, 127.6, 127.5, 77.4, 73.3, 72.9,
70.8, 70.7, 59.4, 38.9, 36.1, 35.4, 25.9, 18.3, 4.8, −5.4; FT-IR (film)
3411, 2927, 1093 cm−1; MS m/z 417.3 ([M + Na]+); ESI-HRMS calcd
for C22H38O4SiNa ([M + Na]+) 417.2437, found 417.2437.
(2-((2S,5R,6S)-6-((Benzyloxy)methyl)-5-methyl-5,6-dihydro-
2H-pyran-2-yl)ethoxy)(tert-butyl)dimethylsilane (22). To a
solution of 19 (245 mg, 0.63 mmol) in dry THF (6.3 mL) was
added NaHMDS (1 M in THF, 0.94 mL) at −78 °C. The reaction was
kept at −78 °C for 1 h before a solution of PhNTf2 (290 mg, 0.81
mmol) in THF (1 mL) was added. The reaction was stirred at that
temperature for 30 min and then at 23 °C overnight. The reaction was
quenched with aq NH4Cl. The mixture was extracted with ethyl
acetate, and the combined extracts were washed with water and brine,
dried over Na2SO4, and concentrated. Purification of the residue by
passing through a short pad of silica gel (20% EtOAc/hexanes) gave
the crude enol triflate as a colorless oil.
(2-((2S,5S,6S)-6-(Benzyloxymethyl)-5-methyl-4-(triethylsily-
loxy)-5,6-dihydro-2H-pyran-2-yl)ethoxy)(tert-butyl)-
dimethylsilane (7). A mixture of the TES-enol ether 10 (3.4 g, 9.55
mmol), 12 (4.3 g, 28.7 mmol) and 4 Å molecular sieves (3.2 g) was
treated with Jacobsen’s catalyst, 11 (278 mg, 0.57 mmol) at 23 °C for
48 h. The reaction was diluted with EtOAc, filtered through a short
pad of Celite, and eluted with EtOAc. The combined filtrate was
concentrated in vacuo. The residue was purified with flash
chromatography (1% NEt3/5% EtOAc/hexane) to afford the desired
cycloadduct 7 as a colorless oil: [α]D25 +46.3 (c 0.8, CHCl3); 1H NMR
(300 MHz, CDCl3) δ 7.37−7.21 (m, 5H), 4.69 (m, 1H), 4.58 (ABq,
JAB = 12.0 Hz, 2H), 3.23 (t, J = 5.1 Hz, 1H), 3.90−3.63 (m, 3H), 3.58
(dd, J = 9.8, 6.9 Hz, 1H), 3.47 (dd, J = 9.8, 6.1 Hz, 1H), 2.10−1.98 (m,
1H), 1.80−1.68 (m, 2H), 0.99 (t, J = 3.8 Hz, 9H), 0.98 (d, J = 7.5 Hz,
3H), 0.91 (s, 9H), 0.68 (q, J = 7.9 Hz, 6H), 0.06 (s, 6H); 13C NMR
(75 MHz, CDCl3) δ 153.4, 138.2, 128.2, 127.6, 127.4, 104.1, 75.5,
73.3, 71.4, 70.4, 59.6, 39.4, 36.1, 25.9, 18.3, 11.9, 6.6, 4.9, −5.4; FT-IR
(film) 2935, 2955, 1664, 1089 cm−1; MS m/z 507.25 ([M + H]+);
ESI-HRMS calcd for C28H51O4Si2 ([M + H]+) 507.3320, found
507.3335.
To a solution of the former enol triflate, Pd(OAc)2 (7 mg, 0.03
mmol), PPh3 (16.4 mg, 0.06 mmol), and DIPEA (404 mg, 3.13 mmol)
in dry DMF (5 mL) was added HCO2H (86.3 mg, 1.88 mmol) at 23
°C. After addition, the reaction was allowed to stir at 65 °C for 1 h.
Then it was cooled to 23 °C, diluted with ether, washed with water
and brine, and dried over Na2SO4. Evaporation of solvent gave a
residue, which was chromatographed (20% EtOAc/hexanes) to afford
alkene 22 (176 mg, 75% over 2 steps) as a colorless oil: [α]D25 −46.7
( 2 S , 3 S , 6 S ) - 2 - ( ( B e n z y l o x y ) m e t h y l ) - 6 - ( 2 - ( ( t e r t -
butyldimethylsilyl)oxy)ethyl)-3-methyldihydro-2H-pyran-
4(3H)-one (19). To a solution of the former silyl enol ether 7 in dry
THF (100 mL) was added HOAc (1.1 mL, 19.1 mmol) followed by
TBAF (1 M in THF, 9.55 mL, 9.55 mmol) dropwise at 0 °C. The
reaction was allowed to stir at 0 °C for 2 h. The reaction was quenched
with aq NaHCO3. The mixture was extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na2SO4, and concentrated. Purification of the residue by flash
chromatography (10% EtOAc/hexanes) gave ketone 19 (2.69 g,
1
(c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.35−7.26 (m, 5H),
5.82−5.77 (m, 1H), 5.58 (d, J = 10.0 Hz, 1H), 4.62 and 4.52 (ABq, JAB
= 11.6 Hz, 2H), 4.29 (m, 1H), 3.89−3.82 (m, 1H), 3.80−3.71 (m,
2H), 3.55 (dd, J = 10.4, 6.8 Hz, 1H), 3.44 (dd, J = 10.1, 6.0 Hz, 1H),
2.12 (m, 1H), 1.80−1.69 (m, 2H), 0.90 (d, J = 7.2 Hz, 3H), 0.89 (s,
9H), 0.05 (s, 6H); 13C NMR (100 MHz, CDCl3) δ 138.4, 131.0,
129.3, 128.3, 127.6, 127.5, 75.1, 73.3, 72.4, 70.9, 59.5, 38.6, 30.8, 25.9,
18.3, 13.9, −5.4; FT-IR (film) 2928, 1255, 1089 cm−1; MS m/z 377.3
([M + H]+); ESI-HRMS calcd for C22H37O3Si ([M + H]+) 377.2512,
found 377.2509.
25
1
72%) as a colorless oil: [α]D +14.6 (c 1.07, CHCl3); H NMR (400
MHz, CDCl3) δ 7.32−7.27 (m, 5H), 4.59 and 4.50 (ABq, JAB = 11.7
Hz, 2H), 3.90−3.85 (m, 1H), 3.85−3.70 (m, 3H), 3.65 (dd, J = 9.6,
6.9 Hz, 1H), 3.49 (dd, J = 9.6, 6.2 Hz, 1H), 2.58−2.52 (m, 1H), 2.46
(dd, J = 13.0, 11.6 Hz, 1H), 2.28 (d, J = 15.1 Hz, 1H), 1.90−1.82 (m,
1H), 1.78−1.68 (m, 1H), 1.09 (d, J = 7.5 Hz, 3H), 0.89 (s, 9H), 0.05
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 210.8, 137.9, 128.3, 127.7,
127.6, 74.1, 73.3, 69.4, 58.8, 46.8, 44.5, 39.2, 25.9, 18.2, 10.8, −5.4,
−5.5; FT-IR (film) 2928, 1717, 1093 cm−1; ESI-MS m/z 393.2 ([M +
H]+), 415.1 ([M + Na]+); ESI-HRMS calcd for C22H36O4SiNa ([M +
Na]+) 415.2275, found 415.2282.
(2S,3R,4S,6S)-2-((Benzyloxy)methyl)-6-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-3-methyltetrahydro-2H-pyran-4-
ol (21). To a solution of 22 (40 mg, 0.11 mmol) in MeCN (1 mL)
and buffer (pH = 7.5, Na2HPO4−NaH2PO4, 1 mL) was added a
solution of DMDO in acetone (1.5 mL) at −15 °C slowly. The
reaction was allowed to stir at −15 °C for 20 min and then at 23 °C
for 4 h. The reaction was quenched with aq Na2SO3. The mixture was
extracted with ethyl acetate. The combined extracts were washed with
water and brine, dried over Na2SO4, and concentrated. Silica gel
chromatography (10% EtOAc/hexanes) of the residue gave the
epoxide (29 mg, 69%) as a colorless oil.
To a solution of the epoxide (26 mg 0.07 mmol) in dry THF (1
mL) was added DIBAL-H (1 M in CH2Cl2, 0.2 mL) slowly at −15 °C.
The reaction was allowed to stir at 0 to 23 °C for 2 h before it was
quenched with aq Rochelle's salt. EtOAc was added, and the reaction
was allowed to stir vigorously at 23 °C for another 2 h. The layers were
separated, and the aqueous phase was extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na2SO4, and concentrated. Silica gel afforded the desired alcohol 21
(26 mg, 99%) as a colorless oil.
2-((2S,4S,5S,6S)-6-((Benzyloxy)methyl)-4-((tert-
butyldimethylsilyl)oxy)-5-methyltetrahydro-2H-pyran-2-yl)-
ethanol (24). To a solution of 21 (1.38 g, 3.49 mmol) in dry CH2Cl2
(20 mL) was added 2,6-lutidine (747 mg, 6.98 mmol) followed by
TBSOTf (1.2 g, 4.53 mmol) at 0 °C. The reaction was kept at 0 °C for
1 h before it was quenched with aq NaHCO3. The layers were
separated, and the aqueous phase was extracted with CH2Cl2. The
combined extracts were dried over Na2SO4 and concentrated.
Purification of the residue by flash chromatography (5% EtOAc/
hexanes) afforded di-TBS-protected diol (1.72 g, 97%) as a colorless
oil.
(2S,3R,4R,6S)-2-((Benzyloxy)methyl)-6-(2-((tert-
butyldimethylsilyl)oxy)ethyl)-3-methyltetrahydro-2H-pyran-4-
ol (18) and (2S,3R,4S,6S)-2-((Benzyloxy)methyl)-6-(2-((tert-
butyl-dimethylsilyl)oxy)ethyl)-3-methyltetrahydro-2H-pyran-
4-ol (20). To a solution of 19 (2.7 g, 6.89 mmol) in dry CH2Cl2 (50
mL) was added DIBAL-H (1 M in CH2Cl2, 10.3 mL) dropwise at −78
°C. The reaction was kept at −78 °C for 2 h before it was quenched
with MeOH (1 mL). EtOAc and aq Rochelle's salt were added. The
reaction was stirred for 2 h and then extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na2SO4, and concentrated. The residue was purified by flash
chromatography (20% EtOAc/hexanes to 30% EtOAc/hexanes) to
25
afford alcohol 21 (810 mg, 30%) as a colorless oil: [α]D −12.6 (c
1
1.10, CHCl3); H NMR (400 MHz, CDCl3) δ 7.34−7.26 (m, 5H),
4.60 and 4.49 (ABq, JAB = 12.3 Hz, 2H), 4.13 (dt, J = 2.8, 6.9 Hz, 1H),
3.95−3.86 (m, 2H), 3.75−3.68 (m, 2H), 3.53 (dd, J = 9.6, 6.8 Hz,
1H), 3.39 (dd, J = 9.7, 6.1 Hz, 1H), 1.78−1.65 (m, 2H), 1.65−1.48
(m, 3H), 0.89 (s, 9H), 0.88 (d, J = 7.2 Hz, 3H), 0.04 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ 138.4, 128.3, 127.6, 127.5, 73.2, 72.7, 71.0,
70.5, 69.0, 59.5, 39.2, 36.5, 34.4, 25.9, 18.3, 10.9, −5.4; FT-IR (film)
3443, 2927, 1096 cm−1; MS m/z 395.2 ([M + H]+). 417.2 ([M +
Na]+); ESI-HRMS calcd for C22H38O4SiNa ([M + Na]+) 417.2437,
found 417.2440.
Undesired alcohol 20 (1.76 g, 65%) was obtained as a colorless oil:
25
1
To a solution of the former di-TBS ether (1.72 g, 3.39 mmol) in
MeOH (15 mL) and CH2Cl2 (15 mL) was added CSA (78.6 mg, 0.34
mmol) at 23 °C. After 2 h, the reaction was quenched with aq
NaHCO3. The aqueous phase was extracted with ethyl acetate. The
[α]D −6.7 (c 1.04, CHCl3); H NMR (400 MHz, CDCl3) δ 7.30−
7.26 (m, 5H), 4.59 and 4.48 (ABq, JAB = 12.0 Hz, 2H), 3.90 (m, 1H),
3.89−3.61 (m, 2H), 3.60−3.45 (m, 3H), 3.45 (m, 1H), 2.02−1.99 (m,
1H), 1.80−1.71 (m, 1H), 1.70−1.60 (m, 2H), 1.56 (br, 1H), 1.43−
2563
dx.doi.org/10.1021/jo202631e | J. Org. Chem. 2012, 77, 2559−2565

The Journal of Organic Chemistry
Note
combined organic layers were washed with water and brine, dried over
Na2SO4, and concentrated. Purification of the residue by flash
chromatography (20% EtOAc/hexanes) gave the primary alcohol 24
(1.18 g, 89%) as a colorless oil: [α]D25 +9.9 (c 1.05, CHCl3); 1H NMR
The layers were separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic phase was washed with water and
brine, dried over Na2SO4, and concentrated. Silica gel chromatography
(25% EtOAc/hexanes) of the residue gave alcohol 265 (283 mg, 81%)
as a colorless oil: 1H NMR (500 MHz, CDCl3) δ 5.54−5.66 (m, 2H),
4.12 (d, J = 4.4 Hz, 2H), 4.01 (dt, J = 9.0, 3.0 Hz, 1H), 3.74−3.82 (m,
2H), 3.64 and 3.41 (ABq, JAB = 11.0 Hz, 2H), 2.25 (m, 1H), 2.14 (m,
1H), 2.09 (br, 1H), 1.47−1.52 (m, 2H), 1.38 (m, 1H), 0.89 (s, 9 H),
0.88 (s, 9 H), 0.83 (d, J = 7.5 Hz, 3H), 0.05 (s, 6H), 0.02 (s, 6H); 13C
NMR (125 MHz, CDCl3) δ 135.2, 117.1, 75.4, 72.1, 71.4, 64.9, 40.8,
37.4, 34.7, 26.2, 18.4, 11.8, −4.5.
(400 MHz, CDCl3) δ 7.34−7.26 (m, 5H), 4.57 and 4.48 (ABq, JAB
=
12.3 Hz, 2H), 4.21 (m, 1H), 4.06 (m, 1H), 3.88−3.75 (m, 3H), 3.47
(dd, J = 9.6, 8.2 Hz, 1H), 3.36 (dd, J = 9.9, 3.5 Hz, 1H), 1.81−1.53 (m,
4H), 1.38−1.29 (m, 1H), 0.89 (s, 9H), 0.83 (d, J = 6.8 Hz, 3H), 0.04
(s, 6H); 13C NMR (100 MHz, CDCl3) δ 138.2, 128.4, 127.7, 127.5,
73.8, 73.3, 73.1, 70.6, 62.2, 37.4, 36.8, 34.7, 25.7, 18.0, 11.0, −5.0; ; FT-
IR (film) 3443, 2928, 1254, 1098 cm−1; ESI-MS m/z 395.1 ([M +
H]+), 417.2 ([M + Na]+); ESI-HRMS calcd for C22H39O4Si ([M +
H]+) 395.2612, found 395.2620.
ASSOCIATED CONTENT
■
(E)-Ethyl-4-((2S,4S,5S,6S)-6-((benzyloxy)methyl)-4-((tert-
butyldimethylsilyl)oxy)-5-methyltetrahydro-2H-pyran-2-yl)-
but-2-enoate (25). To a solution of 24 (1.15 g, 2.92 mmol) in
CH2Cl2/DMSO (2:1, 20 mL) was added Et3N (4 mL, 29.2 mmol)
followed by SO3·Py (1.16 g, 7.31 mmol) at 0 °C. When the reaction
was complete as shown by TLC, it was quenched with aq NaHCO3.
The aqueous phase was extracted with ethyl acetate. The combined
organic layers were washed with water and brine, dried over Na2SO4,
and concentrated. Purification of the residue by silica gel
chromatography (10% EtOAc/hexanes) gave the desired aldehyde
(1.14 g, 99%) as a colorless oil.
S
* Supporting Information
General experimental methods and H NMR and 13C NMR
1
spectra of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: akghosh@purdue.edu.
Notes
To a solution of triethyl phosphonoacetate (1.3 g, 5.82 mmol) in
dry THF (15 mL) was added NaH (60% in oil, 209 mg, 5.23 mmol)
portionwise at 0 °C. A solution of the aldehyde (1.14 g, 2.91 mmol) in
dry THF (5 mL) was then added slowly. The reaction was then stirred
at 0 °C for 2 h before it was quenched with aq NH4Cl. The layers were
separated, and the aqueous layer was extracted with ethyl acetate. The
combined extracts were washed with water and brine, dried over
Na2SO4, and concentrated. Silica gel chromatography (5% EtOAc/
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support for this work was provided by the National
Institutes of Health and Purdue University.
REFERENCES
25
■
hexanes) afforded ester 25 (1.22 g, 91%) as a colorless oil: [α]D
1
(1) Horton, P. A.; Koehn, F. E.; Longley, R. E.; McConnell, O. J. J.
Am. Chem. Soc. 1994, 116, 6015−6016.
+2.3(c 1.2, CHCl3); H NMR (400 MHz, CDCl3) δ 7.35−7.26 (m,
5H), 7.01 (dt, J = 15.8, 6.9 Hz, 1H), 5.88 (d, J = 15.7 Hz, 1H), 4.63
and 4.51 (ABq, JAB = 12.0 Hz, 2H), 4.21−4.14 (m, 1H), 4.16 (q, J =
6.8 Hz, 2H), 3.94 (m, 1H), 3.78 (m, 1H), 3.50 (dd, J = 10.3, 7.5 Hz,
1H), 3.38 (dd, J = 10.3, 4.1 Hz, 1H), 2.47−2.36 (m, 1H), 2.35−2.27
(m, 1H), 1.65−1.50 (m, 2H), 1.38−1.32 (m, 1H), 1.26 (t, J = 7.2 Hz,
3H), 0.89 (s, 9H), 0.82 (d, J = 6.8 Hz, 3H), 0.03 (s, 6H); 13C NMR
(100 MHz, CDCl3) δ 166.4, 145.4, 138.5, 128.3, 127.5, 127.4, 123.1,
73.3, 73.2, 71.5, 70.78, 70.75, 60.0, 38.6, 36.8, 34.4, 25.7, 18.0, 14.2,
10.9, −4.9; FT-IR (film) 2929, 1722, 1257, 1073 cm−1; ESI-MS m/z
485.2 ([M + Na]+); ESI-HRMS calcd for C26H42O5SiNa ([M + Na]+)
485.2699, found 485.2709.
(2) (a) Lee, E.; Song, H. Y.; Kang, J. W.; Kim, D.-S.; Jung, C.-K.; Joo,
J. M. J. Am. Chem. Soc. 2002, 124, 384−385. (b) Song, H. Y.; Joo, 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.
(3) (a) Kang, S. H.; Kang, S. Y.; Choi, H.; Kim, C. M.; Jun, H.; Youn,
J. Synthesis 2004, 7, 1102−1114. (b) Kang, S. H.; Kang, S. Y.; Kim, C.
M.; Choi, H.; Jun, H.; Lee, B. M.; Park, C. M.; Jeong, J. W. Angew.
Chem., Int. Ed. 2003, 42, 4779−4782.
(4) Yoshimura, T.; Yakushiji, F.; Kondo, S.; Wu, X.; Shindo, M.;
Shishido, K. Org. Lett. 2006, 8, 475−478.
((2S,3S,4S,6S)-4-((tert-Butyldimethylsilyl)oxy)-6-((E)-4-((tert-
butyldimethylsilyl)oxy)but-2-en-1-yl)-3-methyltetrahydro-2H-
pyran-2-yl)methanol (26). To a solution of 25 (1.22 g, 2.64 mmol)
in dry CH2Cl2 (10 mL) was added DIBAL-H (1 M in CH2Cl2, 7.93
mL) dropwise at −78 °C. The reaction was kept at −78 °C for 2 h,
before it was quenched with MeOH (1 mL). EtOAc and aq Rochelle's
salt were added. The layers were separated, and the aqueous layer was
extracted with ethyl acetate. The combined organic layers were washed
with water and brine, dried over Na2SO4, and concentrated.
Purification of the residue by flash chromatography (5% EtOAc/
hexanes) gave the desired alcohol (1 g, 90%) as a colorless oil.
To a solution of the former oil (1 g, 2.39 mmol) in dry CH2Cl2 (10
mL) was added Et3N (1 mL, 7.16 mmol) and DMAP (29.3 mg, 0.24
mmol) followed by TBSCl (540 mg, 3.58 mmol). The reaction was
kept at 23 °C overnight. The reaction was quenched with aq NaHCO3.
The layers were separated, and the aqueous layer was extracted with
ethyl acetate. The combined organic phase was washed with water and
brine, dried over Na2SO4, and concentrated. Purification of the residue
by flash chromatography (25% EtOAc/hexanes) afforded the di-TBS
ether (1.22 g, 96%) as a colorless oil.
(5) (a) Ghosh, A. K.; Gong, G. L. Org. Lett. 2007, 9, 1437−1440.
(b) Ghosh, A. K.; Gong, G. L. Chem.Asian J. 2008, 3, 1811−1823.
(6) (a) Gurjar, M. K.; Kumar, P.; Rao, B. V. Tetrahedron Lett. 1996,
37, 8617−8620. (b) Nowakowski, M.; Hoffmann, H. M. R.
Tetrahedron Lett. 1997, 38, 1001−1004. (c) Gurjar, M. K.;
Chakrabarti, A.; Rao, B. V.; Kumar, P. Tetrahedron Lett. 1997, 38,
6885−6888. (d) Misske, A. M.; Hoffmann, M. R. H. Chem.Eur. J.
2000, 6, 3313−3320. (e) Deba, T.; Yakushiji, F.; Shindo, M.; Shishido,
K. Synlett 2003, 10, 1500−1502. (f) Hart, D. J.; Patterson, S.; Unch, J.
P. Synlett 2003, 9, 1334−1338. (g) Yoshimura, T.; Bando, T.; Shindo,
M.; Shishido, K. Tetrahedron Lett. 2004, 45, 9241−9244. (h) Dalgard,
J. E.; Rychnovsky, S. D. Org. Lett. 2005, 7, 1589−1591. (i) Sawant, K.
B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2006, 47, 939−942.
(j) Sawant, K. B.; Ding, F.; Jennings, M. P. Tetrahedron Lett. 2007, 48,
5177−5180.
(7) Pommier, Y.; Zhang, Y.; Ghosh, A. K. U.S. Pat. Appl. Publ. 2010,
US 201000041619A12010218.
(8) (a) Dossetter, A. G.; Jamison, T. F.; Jacobsen, E. N. Angew.
Chem., Int. Ed. 1999, 38, 2398−2400. (b) Gademann, K.; Chavez, D.
E.; Jacobsen, E. N. Angew. Chem., Int. Ed. 2002, 41, 3059−3061.
(9) (a) Baudin, J. B.; Hareau, G.; Julia, S. A.; Ruel, O. Tetrahedron
Lett. 1991, 32, 1175−1178. (b) Blakemore, P. R.; Cole, W. J.;
Kocienski, P. J.; Morley, A. Synlett 1998, 1, 26−28.
A solution of Li (120 mg, 17.1 mmol) in liquid NH3 (60 mL) was
transferred dropwise to a solution of the di-TBS ether (400 mg, 0.75
mmol) and allyl ethylether (645 mg, 7.49 mmol) in dry THF (7 mL)
at −78 °C. The reaction was quenched with solid NH4Cl (1 g) at −78
°C and then gradually raised to 23 °C. Water and EtOAc were added.
(10) Caron, P.-Y.; Deslongchamps, P. Org. Lett. 2010, 12, 508−511.
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dx.doi.org/10.1021/jo202631e | J. Org. Chem. 2012, 77, 2559−2565

The Journal of Organic Chemistry
Note
(11) Parikh, J. R.; Doering, W. v. E. J. Am. Chem. Soc. 1967, 89,
5505−5507.
(12) Vijn, R. J.; Hiemstra, H.; Kok, J. J.; Knotter, M; Speckamp, W.
N. Tetrahedron 1987, 43, 5019−5030.
(13) Denmark, S. E.; Herbert, B. J. Org. Chem. 2000, 65, 2887−2896.
(14) Kang, S. H.; Kang, S. Y.; Choi, H.; Kim, C. M.; Jun, H.; Youn, J.
Synthesis 2004, 1102−1114.
(15) Williams, D. R.; Brooks, D. A.; Berliner, M. A. J. Am. Chem. Soc.
1999, 121, 4924−4925.
(16) For a similar reaction sequence for 4-ketotetrahydropyran 19 to
its endocyclic olefins as in 22, see: Liu, P.; Hong, S.; Weinreb, S. M. J.
Am. Chem. Soc. 2008, 130, 7562−7563.
(17) Cacchi, S.; Morera, E.; Ortar, G. Tetrahedron Lett. 1984, 25,
4821−4824. (b) Mori, M.; Nakanishi, M.; Kajishima, D.; Sato, S. J. Am.
Chem. Soc. 2003, 125, 9801−9807.
(18) (a) Furst, v. A.; Plattner, Pl. A. Helv. Chim. Acta 1949, 275−283.
̈
(b) Alt, G. H.; Barton, D. H. R. J. Chem. Soc. 1954, 4284−4294.
(19) Zakarian, A.; Batch, A.; Holton, R. A. J. Am. Chem. Soc. 2003,
125, 7822−7824.
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