A formal synthesis of iridoid 9-deoxygelsemide

Article abstract of DOI:10.1002/cjoc.201201039

A formal total synthesis of iridoid 9-deoxygelsemide has been accomplished. Our approach features the use of (S)-carvone as starting material, Favorskii rearrangement to construct the functionalized cyclopentane core, Chugeav elimination to introduce the

Full text of DOI:10.1002/cjoc.201201039

COMMUNICATION
DOI: 10.1002/cjoc.201201039
A Formal Synthesis of Iridoid 9-Deoxygelsemide†
Yang Liu and Gang Zhao*
Key Laboratory of Synthetic Chemistry of Natural Substances, Shanghai Institute of Organic Chemistry,
Chinese Academy of Sciences, Shanghai 200032, China
A formal total synthesis of iridoid 9-deoxygelsemide has been accomplished. Our approach features the use of
(S)-carvone as starting material, Favorskii rearrangement to construct the functionalized cyclopentane core,
Chugeav elimination to introduce the endocyclic double bond, and the ring-opening reaction of epoxide to build the
second five-membered ring.
Keywords iridoid, 9-deoxygelsemide, Favorskii rearrangement, Chugeav elimination
Introduction
Scheme 1 Retrosynthetic analysis of 9-deoxygelsemide (1)
O
The iridoid 9-deoxygelsemide (1) was firstly isolated
from the plant Gelsemium elegans Benth. in 1994.[1] It
was one of the ancient folkloric medicines stored in the
Shosoin imperial repository in Japan. 9-Deoxygel-
semide has been a challenging target for chemical syn-
thesis since its isolation. It has five continuous stereo-
centers on the cyclopentane ring and a cis-α-1,2-di-
oxygenated moiety at C-6 and C-7, which is unique in
iridoid structures, occurring only in three other related
iridoids 2－4 (Figure 1).[2,3] To date, only the Vidari’s
group has completed the total synthesis of this molecule
as well as determination of its absolute configuration.[4]
Herein, we report a formal enantioselective total syn-
thesis of 9-deoxygelsemide.
OH
H
O
H
ref.4
O
HO
O
O
H
OH
H
9-deoxygelsemide (1)
6
OPG
OPG
MeOOC
MeOOC
O
7
8
OPG
MeOOC
Chugeav
elimination
O
OH
11
O
9
H
4
6
3
OPG
O
Favorskii
rearrangement
HO
9
7
O
1
H
10
9-deoxygelsemide (1)
OR
(S)-carvone (11)
10
O
O
COOH
HO
H
O
O
H
H
synthetic plan is based on three key synthetic transfor-
mations including Favoskii rearrangement, Chugaev
elimination and ring-opening of epoxide 7. We envi-
sioned that epoxide 7, which might be generated from
alkene 8, could be converted into the target compound 6
through a ring-opening reaction with carboxylic group.
Ultilizing Chugaev elimination reaction, the alkene 8
could be obtained from alcohol 9, which is in turn
available from alkene 10 by an oxidation and deprotec-
tion sequence. Alkene 10 would be synthesized from
HO
HO
O
O
O
O
HO
HO
R
2
3
4 R = OH; 5 R = H
Figure 1 Structures of 9-deoxygelsemide (1) and plant iridoids
(2－5) of the same family.
Results and Discussion
As illustrated retrosynthetically in Scheme 1, our
*
E-mail: zhaog@mail.sioc.ac.cn; Tel.: 0086-021-54925182; Fax: 0086-021-64166128
Received October 23, 2012; accepted December 31, 2012; published online January 8, 2013.
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/cjoc.201201039 or from the author.
Dedicated to the Memory of Professor Weishan Zhou.
†
18
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 18—22

A Formal Synthesis of Iridoid 9-Deoxygelsemide
Scheme 3 Synthesis of the intermediate 21
commercially-available (S)-carvone by several trans-
formations including Favorskii rearrangement.
OPMB
.
O
OPMB
K2OsO4 2H2O, NMO
The synthesis commenced with commercially-
available (S)-carvone, essentially following the same
synthetic route originally described by Lee and cowork-
ers from (R)-carvone.[5] A sequence of epoxidation,[6]
chlorination[7] and protection of the OH functionality
afforded the cyclohexanone 13 (Scheme 2). We chose
tert-butyldimethylsilyl as the protecting group, and the
subsequent Favorskii ring-contraction proceeded suc-
cessfully to deliver functionalized cyclopentane unit 14
in excellent diastereoselectivity (dr＞19∶1). Reduction
of 14 with LiAlH4 and protection of the hydroxyl group
as its p-methoxybenzyl ether produced compound 16,
which includes the requisite stereocenters at C5, C8 and
C9.
then NaIO4, acetone/H2O, r.t.
85%
OTBS
OTBS
17
16
OTf
OPMB
Pd(OAc)2, Ph3P,
n-Bu3SnH, THF, r.t.
LHMDS, -78 oC, THF,
3 h, then PhNTf2
88%
85%
OTBS
18
OPMB
.
BH3 SMe2, THF, then
H2O2, NaOH
OPMB
HO
55%
Scheme 2 Construction of the cyclopentane core
OTBS
OTBS
19
1) 30 % H2O2, NaOH, MeOH, 0 oC;
2) LiCl, TFA, THF, 0 oC;
20
O
O
Cl
OPMB
(98%, over two steps)
PDC, MeOH, DMF, r.t.
73%
HO
MeOOC
(S)-carvone (11)
12
OTBS
21
TBSOTf,
2,6-lutidine,
DCM, r.t.
O
MeONa,
MeOH/Et2O, 0 oC
COOMe
Cl
TBAF in THF gave product 22 in only 20% yield along
with mostly the recovered starting material. Considering
the steric hindrance of the substrate, we tried an acidic
conditions (HF/MeCN).[8] To our delight, the reaction
could proceed smoothly to provide the desired secon-
dary alcohol 22 in 65% yield (Scheme 4). Next step
would be the regioselective elimination of the hydroxyl
group of 22. A variety of conditions were attempted,
such as POCl3/py,[9] Martin sulfurane[10] and Burgess
dehydrant,[11] but all of them gave a mixtures of regio-
isomers, which could not be separated by column chro-
matography. Finally, we solved the problem by using
the condition of Chugaev elimination,[12] deprotonation
of secondary alcohol 22 with NaH, and the following
addition of CS2 and MeI gave xanthate 23, which was
dissolved in o-xylene and heated to reflux overnight to
give compound 24 as a single product in 69% yield over
two steps. Notably, the regiospecific formation of al-
kene 24 was consistent with the established mechanism
of the Chugeav reaction. The reaction proceeded
through a six-membered ring transition state involving a
cis-β-hydrogen atom of alcohol moiety and the thione
sulfur atom of the xanthate.[13] The β-hydrogen atom
and the xanthate group must be coplanar in the cyclic
transition state. So the trans-β-hydrogen atom at C8
could not be involved in the reaction, only the cis-β-
hydrogen atom of alcohol moiety at C6 was eliminated
in Chugaev reaction.
(88%)
(99%)
TBSO
OTBS
OPMB
14
13
OH
LAH, THF
(92%)
PMBCl, NaH,
TBAI, THF
(96%)
OTBS
OTBS
15
16
With 16 in hand, we next turned to the conversion of
the 2-propenyl group. Firstly, the alkene 16 was dihy-
droxylated with K2OsO4/NMO in acetone/H2O, and
then treated with an excess of NaIO4, which delivered
ketone 17 in 85% yield (Scheme 3). Ketone 17 was de-
protonated with LHMDS (1.2 equiv.) in THF at −78 ℃
for 3 h, and then trapped by PhNTf2 (1.2 equiv.) to pro-
duce trifluoromethanesulfonate 18. To our delight, the
hydrogenolysis of 18 could be carried out under mild
conditions with Pd(OAc)2 (0.05 equiv.), Ph3P (1.3
equiv.), and n-Bu3SnH (1.3 equiv.) in THF at room
temperature. Next, hydroboration of compound 19 with
BH3•SMe2, followed by oxidation with H2O2/NaOH,
gave product 20 in moderate yield as a single regioi-
somer. Sequentially, subjection of alcohol 20 to the
Cr-mediated oxidation conditions [PDC (5.0 equiv.),
MeOH (10 equiv.), DMF, r.t.] yielded ester 21.
Now we were in a position to introduce the double
bond between C6 and C7. The deprotection of com-
pound 21 would be our first task. Treating 21 with
So far, compared with the target molecule 1, only
one stereocenter at C7 was different. Considering the
steric hindrance of the substrate, two steps involving
Chin. J. Chem. 2013, 31, 18—22
© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
www.cjc.wiley-vch.de
19

Liu & Zhao
COMMUNICATION
Scheme 4 Introduction of the endocyclic double bond by
Scheme 5 Stereoselective synthesis of the key intermediate 6
Chugeav elimination
OPMB
OPMB
+
m-CPBA, NaHCO3,
DCM, r.t.
OPMB
OPMB
MeOOC
MeOOC
(84%)
MeOOC
MeOOC
HF, MeCN
(25:26 = 2:1)
O
65%
24
26
OTBS
21
OH
22
OPMB
OPMB
LiOH, THF/H2O,
then 1 mol/L HCl
H
NaH, THF, 0 oC,
30 min, then CS2
2 h, then MeI, r.t.
OPMB
MeOOC
O
O
(62%)
o-xylene, reflux
MeOOC
O
H
OH
92%
75%
25
OC(S)SMe
27
23
OPMB
1) DMP, NaHCO3, DCM, r.t.;
2) NaBH4, MeOH, 0 oC
SMe
H
OPMB
O
O
MeOOC
S
O
(80%)
H
H
OH
PMBO
H
28
MeOOC
24
OH
H
H
H
O
CAN, MeCN/H2O
OH
O
(98%, combined yield)
O
+
oxidation and reduction were employed for the inver-
sion of the configuration of C7. Firstly compound 27
was subjected to DMP/NaHCO3 in DCM. After com-
pletion of the reaction, the crude product was then
treated with NaBH4 in a mixed solvent of THF and
MeOH, and the desired compound 28 was obtained in
80% yield after column chromatography over two steps.
The cleavage of PMB protecting group produced 6 and
O
OH
H
OH
29
6
(6:29 = 6:1)
(cm−1). Optical rotations were measured on JASCO
P-1030 polarimeter operating at the sodium D line with
a 100 mm path cell, and reported as follows: [α]DT
(concentration/(g/100 mL), solvent).
1
29,[14] with a ratio of 6∶1. Their H and 13C NMR
spectral are in agreement with those reported by
Vidari.[4] Since compound 6 has been converted into
9-deoxygelsemide in five steps, our synthetic route thus
constitutes a formal total synthesis of (−)-9-deoxygel-
semide.
2-((1S,2S,3R,4S)-4-(tert-Butyldimethylsilyloxy)-2-
((4-methoxybenzloxy)methyl)-3-methylcyclopentyl)-
ethanol (20) A solution of BH3•SMe2 (17.0 mL of a
2.0 mol/L solution in THF, 34.0 mmol) was added
dropwise at r.t. to a solution of 19 (8.87 g, 22.7 mmol)
in anhydrous THF (80 mL). The mixture was stirred at
r.t. for 10 h, then NaOH solution (20 mL, 3.0 mol/L in
water) and H2O2 (20 mL, 30% in water) was added
carefully, followed by stirring for 3 h. The reaction
mixture was diluted with water (50 mL), and extracted
with EA (50 mL×3). The combined organic layer was
washed with brine and dried over anhydrous Na2SO4.
After concentration under vacuum, the crude product
was purified by flash column chromatography (PE/EA
＝4∶1, V/V) to give the product 20 (4.88 g, 55%) as a
Conclusions
In summary, starting from the known compound
(S)-carvone, we have achieved the synthesis of the ad-
vanced intermediate 6 in 17 steps with an overall yield
of 3.9%, which constitutes a formal total synthesis of
(−)-9-deoxygelsemide.
Experimental
20
α
[ ]
1
Unless otherwise indicated, all reactions were car-
ried out under an argon atmosphere in oven-dried
glassware with magnetic stirring. Anhydrous THF was
distilled from sodium and benzophenone. Anhydrous
DCM was distilled from CaH2. Column chromatograph
colorless oil.
44.5 (c 1.05, CHCl3); H NMR (400
MHz, CDCl3) δ: D7.25 (d, J＝8.4 Hz, 2H), 6.87 (d, J＝
8.4 Hz, 2H), 4.42 (dd, J＝11.6, 16.0 Hz, 2H), 4.02 (t,
J＝4.0 Hz, 1H), 3.80 (s, 3H), 3.70－3.64 (m, 1H), 3.60
－3.54 (m, 1H), 3.43－3.37 (m, 2H), 2.41－2.33 (m,
1H), 2.07－1.99 (m, 1H), 1.90－1.81 (m, 1H), 1.76－
1.73 (m, 1H), 1.66－1.60 (m, 1H), 1.43－1.37 (m, 1H),
0.94 (d, J＝6.8 Hz, 3H), 0.87 (s, 9H), 0.02 (s, 6H); 13C
NMR (100 MHz, CDCl3) δ: 159.3, 130.7, 129.4, 113.9,
75.3, 72.9, 70.7, 62.9, 55.4, 46.1, 42.3, 34.8, 33.9, 26.0,
18.3, 14.3, −4.5, −4.8; IR (film) ν: 3412, 2955, 2850,
1
was performed on silica gel (300－400 mesh). All H
NMR (400 MHz), 13C NMR (100 MHz) spectra were
recorded on a Bruker-AMX 400 spectrometer in CDCl3
or CD3OD, with tetramethylsilane as an internal stan-
dard. Infrared spectra were recorded on a Shimadazu
IR-440 spectrophotometer and reported as wavenumber
20
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© 2013 SIOC, CAS, Shanghai, & WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim
Chin. J. Chem. 2013, 31, 18—22

A Formal Synthesis of Iridoid 9-Deoxygelsemide
1713, 1514, 1036, 774 cm−1; MS (ESI) m/z: 431.2 [M＋
Na]＋; HRMS calcd for C23H40NaO4Si 431.2588, found
431.2591.
1.5 mmol) was added in portions to a solution of 22 (63
mg, 0.20 mmol) in anhydrous THF (5.0 mL) at 0 ℃. 30
min later, CS2 (0.10 mL, 1.65 mmol) was added to the
reaction mixture, followed by stirring for another 2 h,
and then MeI (0.10 mL, 1.61 mmol) was added to the
mixture, followed by stirring for 10 h. The reaction was
quenched with saturated NH4Cl solution and diluted
with water. The mixture was extracted with EA (5 mL
×3). The combined organic layer was washed with
brine and dried over anhydrous Na2SO4. After concen-
tration under vacuum, the crude product was purified by
flash column chromatography (PE/EA＝20∶1, V/V) to
Methyl 2-((1R,2S,3R,4S)-4-(tert-butyldimethylsil-
yloxy)-2-((4-methoxybenzyloxy)methyl)-3-methylcy-
clopentyl)acetate (21) PDC (8.12 g, 21.6 mmol) and
anhydrous MeOH (1.2 mL, 30.8 mmol) was added to a
solution of alcohol 20 (1.26 g, 3.08 mmol) in DMF (100
mL) at r.t. The mixture was stirred vigorously for 10 h,
and then quenched with water (100 mL). The mixture
was extracted with EA (50 mL×3). The combined or-
ganic layer was washed with brine and dried over anhy-
drous Na2SO4. After concentration under vacuum, the
crude product was purified by flash column chromatog-
raphy (PE/EA＝20∶1, V/V) to give the product 21 (987
give the product 23 (60 mg, 75%) as a colorless oil.
20
[ ]D
α
37.3 (c 1.17, CHCl3); 1H NMR (400 MHz, CDCl3)
δ: 7.24 (d, J＝8.8 Hz, 2H), 6.87 (d, J＝8.8 Hz, 2H),
5.94－5.92 (m, 1H), 4.40 (dd, J＝11.6, 21.6 Hz, 2H),
3.81 (s, 3H), 3.62 (s, 3H), 3.46－3.36 (m, 2H), 2.83－
2.77 (m, 1H), 2.61 (dd, J＝6.8, 16.0 Hz, 1H), 2.54 (s,
3H), 2.26 (dd, J＝9.2, 16.0 Hz, 1H), 2.18－2.12 (m,
3H), 1.77－1.70 (m, 1H), 1.01 (d, J＝6.8 Hz, 3H); 13C
NMR (100 MHz, CDCl3) δ: 215.6, 173.8, 159.4, 130.5,
129.3, 113.9, 88.0, 73.0, 69.4, 55.4, 51.6, 46.7, 40.6,
38.6, 35.7, 34.9, 18.9, 13.8; IR (film) ν: 2960, 2856,
1735, 1248, 1053, 821 cm−1; MS (ESI) m/z: 435.2 [M＋
Na]＋; HRMS calcd for C20H28NaO5S2 435.1270, found
435.1271.
mg, 73%) as a colorless oil.
α
20 40.3 (c 0.90, CHCl3);
[ ]D
1H NMR (400 MHz, CDCl3) δ: 7.30 (d, J＝8.4 Hz, 2H),
6.87 (d, J＝8.4 Hz, 2H), 4.38 (dd, J＝11.6, 21.2 Hz,
2H), 4.02 (t, J＝3.2 Hz, 1H), 3.80 (s, 3H), 3.61 (s, 3H),
3.39 (dd, J＝4.4, 9.6 Hz, 1H), 3.33 (t, J＝8.8 Hz, 1H),
2.83－2.77 (m, 1H), 2.62 (dd, J＝6.0, 15.2 Hz, 1H),
2.18 (dd, J＝9.6, 15.2 Hz, 1H), 2.09－2.02 (m, 1H),
1.80 (dd, J＝7.2, 13.2 Hz, 1H), 1.72－1.68 (m, 1H),
1.45－1.39 (m, 1H), 0.93 (d, J＝6.8 Hz, 3H), 0.87 (s,
9H), 0.02 (s, 3H), 0.02 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ: 174.4, 159.3, 130.8, 129.3, 113.9, 75.4, 72.9,
70.2, 55.4, 51.4, 45.3, 42.1, 41.9, 36.0, 34.6, 26.0, 18.3,
14.1, −4.5, −4.8; IR (film) ν: 2950, 2856, 1736, 1249,
1036 cm−1; MS (ESI) m/z: 561.2 [M＋Na]＋; HRMS
calcd for C24H37F3NaO6SSi 561.1924, found 561.1950.
Methyl 2-((1R,2S,3R,4S)-4-hydroxy-2-((4-meth-
oxybenzyloxy)methyl)-3-methylcyclopentyl)acetate
(22) HF (2 mL, 40% in water) was added to a solution
of ester 21 (1.52 g, 3.49 mmol) in MeCN (20 mL). The
mixture was stirred at r.t. for 10 h and diluted with wa-
ter (20 mL). The mixture was extracted with EA (20 mL
×3). The combined organic layer was washed with
saturated NaHCO3 solution, brine and dried over anhy-
drous Na2SO4. After concentration under vacuum, the
crude product was purified by flash column chromatog-
raphy (PE/EA＝3∶1, V/V) to give the product 22 (735
Methyl 2-((1S,4S,5R)-5-((4-methoxybenzyloxy)-
methyl)-4-methylcyclopent-2-enyl)acetate (24)
A
solution of 23 (72 mg, 0.18 mmol) in o-xylene (5 mL)
was heated to reflux overnight. The solvent was evapo-
rated under vacuum. The crude product was purified by
flash column chromatography (PE/EA＝25∶1, V/V) to
give the product 24 (49 mg, 92%) as a colorless oil.
20
[ ]
α
153.6 (c 0.99, CHCl3); 1H NMR (400 MHz,
CDDCl3) δ: 7.25 (d, J＝8.4 Hz, 2H), 6.87 (d, J＝8.4 Hz,
2H), 5.69－5.66 (m, 1H), 5.61－5.59 (m, 1H), 4.46－
4.38 (m, 2H), 3.80 (s, 3H), 3.63 (s, 3H), 3.50－3.41 (m,
2H), 3.25－3.20 (m, 1H), 2.55 (dd, J＝5.6, 15.2 Hz,
2H), 2.47－2.43 (m, 1H), 2.17－2.09 (m, 2H), 1.05 (d,
J＝7.2 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ: 173.8,
159.3, 136.8, 132.9 130.7, 129.4, 113.9, 72.9, 69.7, 55.4,
51.5, 48.8, 43.1, 41.7, 35.0, 19.8; IR (film) ν: 2952,
mg, 65%) as a colorless oil.
α
20 34.1 (c 1.12, CHCl3);
[ ]D
1H NMR (400 MHz, CDCl3) δ: 7.24 (d, J＝8.8 Hz, 2H),
6.87 (d, J＝8.8 Hz, 2H), 4.39 (dd, J＝11.6, 22.4 Hz,
2H), 4.10 (s, 1H), 3.80 (s, 3H), 3.62 (s, 3H), 3.43－3.34
(m, 2H), 2.86－2.80 (m, 1H), 2.62 (dd, J＝9.2, 15.6 Hz,
1H), 2.22 (dd, J＝9.2, 15.6 Hz, 1H), 2.09－2.03 (m,
1H), 1.91 (dd, J＝1.2, 7.2 Hz, 1H), 1.88－1.79 (m, 1H),
1.58－1.52 (m, 1H), 1.29 (br, 1H), 1.01 (d, J＝6.8 Hz,
3H); 13C NMR (100 MHz, CDCl3) δ: 174.0, 159.2,
130.6, 129.2, 113.8, 75.0, 72.7, 69.8, 55.3, 51.4, 45.2,
41.4, 41.2, 35.8, 34.6, 13.2; IR (film) ν: 3503, 2953,
2871, 1734, 1508, 1248, 821 cm−1; MS (ESI) m/z: 345.1
[M＋Na]＋; HRMS calcd for C18H26NaO5 345.1673,
found 345.1675.
2867, 1734, 1508, 1248, 1088, 821 cm−1; MS (ESI) m/z:
＋
327.2 [M ＋ Na] ; HRMS (MALDI) calcd for
C18H24O4Na 327.1567, found 327.1570.
Epoxides 25 and 26 m-CPBA (587 mg, 77%, 2.62
mmol) and NaHCO3 (331 mg, 3.94 mmol) were added
to a solution of 24 (400 mg, 1.31 mmol) in DCM (15
mL). The mixture was stirred at r.t. for 5 h and
quenched with saturated Na2SO3 solution. The mixture
was extracted with DCM (10 mL×3). The combined
organic layer was washed with brine and dried over an-
hydrous Na2SO4. After concentration under vacuum, the
crude product was purified by flash column chromatog-
raphy (PE/EA＝3∶1, V/V) to give the product 25 and
26 (351 mg, 84% combined yield) as a colorless oil.
(3aR,4R,5R,6R,6aR)-6-Hydroxy-4-((4-methoxyben-
zyloxy)methyl)-5-methylhexahydro-2H-cyclopenta-
2-((1R,2S,3R,4S)-2-((4-Methoxybenzyloxy)meth-
yl)-3-mthyl-4-(methylthiocarbonothioyloxy)cyclo-
pentyl)acetate (23) NaH (60 mg, 40% in mineral oil,
Chin. J. Chem. 2013, 31, 18—22
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21

Liu & Zhao
COMMUNICATION
[b]furan-2-one (27) LiOH•H2O (23 mg, 0.55 mmol)
was added to a solution of the mixture of 25 and 26 (118
mg, 0.37 mmol) in THF/H2O (2.0 mL/2.0 mL). The
mixture was stirred at r.t. for 10 h, followed by addition
of HCl solution (2.0 mL, 1 mol/L in water), and stirred
for another 3 h. The mixture was diluted with water and
extracted with EA (5 mL×3). The combined organic
layer was washed brine and dried over anhydrous
Na2SO4. After concentration under vacuum, the crude
product was purified by flash column chromatography
(PE/EA＝1∶1, V/V) to give the product 27 (70 mg,
MeCN (4.0 mL) and H2O (1.0 mL). The mixture was
stirred at r.t. overnight. After concentration under vac-
uum, the crude product was purified by flash column
chromatography (DCM/MeOH＝10∶1, V/V) to give
the mixture 6 and 29 (75 mg, 98%) as a colorless oil. 1H
NMR (400 MHz, CD3OD) δ: 4.84－4.82 (m, 1H), 4.28
(dd, J＝4.0, 11.2 Hz, 1H)*, 4.11 (dd, J＝4.8, 11.2 Hz)*,
3.92 (dd, J＝4.4, 4.8 Hz, 1H)*, 3.75 (dd, J＝4.0, 11.2
Hz, 1H), 3.56－3.49 (m, 2H), 3.32－3.31 (m, 1H), 3.06
－2.99 (m, 1H), 2.75－2.74 (m, 1H)*, 2.58－2.55 (m,
1H)*, 2.46 (dd, J＝8.0, 15.2 Hz, 1H)*, 2.71－2.69 (m,
2H), 1.90－1.89 (m, 2H)*, 1.78－1.70 (m, 1H), 1.64－
1.54 (m, 1H), 1.11 (d, J＝6.0 Hz, 3H)*, 1.06 (d, J＝6.4
Hz, 3H); 13C NMR (100 MHz, CD3OD) δ: 180.5,
177.8*, 86.2, 81.1*, 80.4, 75.0*, 69.8*, 61.2, 46.8,
42.3*, 39.9*, 39.1, 38.1, 36.7*, 30.7, 29.5*, 16.5*, 15.7;
MS(ESI) m/z: 209.1 [M＋ Na] ＋ ; HRMS calcd for
C9H14NaO4 209.0784, found 209.0789.
20
1
62%) as a colorless oil.
α
26.0 (c 1.0, CHCl3); H
[ ]
NMR (400 MHz, CDCl3) δ:D7.35 (d, J＝8.8 Hz, 2H),
6.88 (d, J＝8.8 Hz, 2H), 4.71 (d, J＝11.6 Hz, 1H), 4.42
(dd, J＝11.6, 26.8 Hz, 2H), 4.12 (d, J＝3.6 Hz, 1H),
3.81 (s, 3H), 3.54 (dd, J＝3.6, 9.6 Hz, 1H), 3.33 (t, J＝
9.2 Hz, 1H), 3.21－3.13 (m, 1H), 2.63－2.50 (m, 2H),
2.32－2.24 (m, 1H), 1.91－1.86 (m, 1H), 1.73 (br, 1H),
1.01 (d, J＝6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ:
177.8, 159.5, 130.2, 129.5, 114.1, 88.6, 77.9, 73.2, 68.6,
55.5, 44.4, 38.8, 37.5, 29.7, 11.6; IR (film) ν: 3448,
2932, 2874, 1773, 1611, 1247, 1027, 816 cm−1; MS(ESI)
m/z: 329.2 [M＋Na]＋; HRMS calcd for C17H22NaO5
329.1359, found 329.1365.
*signals of the minor product 29.
Acknowledgement
This work is financially supported by National Basic
Research Program of China (973 Program,
2010CB833200), the National Natural Science Founda-
tion of China (No. 21032006), Shanghai Natural Sci-
ence Council (11XD1406400).
(3aR,4R,5R,6S,6aR)-6-Hydroxy-4-((4-methoxy-
benzyloxy)methyl)-5-methylhexahydro-2H-cyclopen-
ta[b]furan-2-one (28) DMP (245 mg, 0.58 mmol) and
NaHCO3 (60 mg, 0.69 mmol) were added to a solution
of 27 (70 mg, 0.23 mmol) in DCM (5.0 mL). The mix-
ture was stirred at r.t. for 5 h and quenched with satu-
rated Na2SO3 solution. The mixture was diluted with
water and extracted with DCM (5 mL×3). The com-
bined organic layer was washed with brine and dried
over anhydrous Na2SO4. After concentration under
vacuum, the crude product was dissolved in MeOH (2.5
mL) and THF (2.5 mL). NaBH4 (13 mg, 0.35 mmol)
was added to the solution, followed by stirring at 0 ℃
for 30 min. The mixture was diluted with water and ex-
tracted with EA (5 mL×3). The combined organic layer
was washed with brine and dried over anhydrous
Na2SO4. After concentration under vacuum, the crude
product was purified by flash column chromatography
(PE/EA＝1∶1, V/V) to give the product 28 (56 mg,
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20
[ ]
1
80%) as a colorless oil.
α
1.33 (c 1.07, CHCl3); H
NMR (400 MHz, CDCl3) δD: 7.23 (d, J＝8.4 Hz, 2H),
6.89 (d, J＝8.4 Hz, 2H), 4.83 (t, J＝6.0 Hz, 1H), 4.41
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1,63－1.53 (m, 1H), 1.06 (d, J＝6.4 Hz, 3H); 13C NMR
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83.9, 80.0, 73.2, 68.1, 55.5, 44.0, 39.2, 36.8, 30.0, 15.5;
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Compound 6 and 29 CAN (560 mg, 1.02 mmol)
was added to the solution of 28 (125 mg, 0.41 mmol) in
(Zhao, X.)
22
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