Synthesis of (+)-Epoxydon, (–)-Phyllostine, (–)-RKTS 33, and (–)-Parasitenone Featuring Selective Sulfonylation and Oxirane Ring Closure of Aldol Cyclization Products

Article abstract of DOI:10.1002/ejoc.202000486

Two new synthetic approaches to anhydrogabosines are developed from the polyoxygenated aldol cyclization intermediates, bearing different O-protecting groups, which were transformed to various gabosine-type cyclitols. Selective sulfonylation on the required hydroxyl group of the intermediates and the subsequent oxirane ring closure are employed as the key steps in both approaches, by which (+)-epoxydon, (–)-phyllostine, (–)-RKTS 33, and (–)-parasitenone were synthesized from δ-d-gluconolactone.

Full text of DOI:10.1002/ejoc.202000486

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of (+)-epoxydon, (–)-phyllostine, (–)-RKTS 33 and (–)-
parasitenone featuring selective sulfonylation and oxirane ring
closure of aldol cyclization products
Authors: Feng Shui, Junhao Jia, Xing Yang, Qin Zhou, Yimin Jiang,
and Xiaochuan Chen
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000486
Link to VoR: https://doi.org/10.1002/ejoc.202000486
0
1/2020

European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
Synthesis of (+)-epoxydon, (–)-phyllostine, (–)-RKTS 33 and (–)-
parasitenone featuring selective sulfonylation and oxirane ring
closure of aldol cyclization products
[
a]
[a]
[a]
[a]
[a]
[a]
Feng Shui, Junhao Jia, Xing Yang, Qin Zhou, Yimin Jiang and Xiaochuan Chen*
[
a]
F. Shui, J. Jia, X. Yang, Q. Zhou, Y. Jiang, Prof. Dr. X. Chen
Key Laboratory of Green Chemistry & Technology of Ministry of Education,
College of Chemistry, Sichuan University, Chengdu 610064, PR China.
E-mail: chenxc@scu.edu.cn
http://chem.scu.edu.cn/
Supporting information for this article is given via a link at the end of the document.((Please delete this text if not appropriate))
.
3
a,6
Abstract: Two new synthetic approaches to anhydrogabosines are
developed from the polyoxygenated aldol-cyclization intermediates
bearing different O-protecting groups, which was transformed to
various gabosine-type cyclitols previously. Selective sulfonylation on
the required hydroxyl group of the intermediates and the subsequent
oxirane ring closure are employed as the key steps in both
approaches, by which (+)-epoxydon, (–)-phyllostine, (–)-RKTS 33
and (–)-parasitenone were synthesized from δ-D-gluconolactone.
seed growth inhibition, potato microtuber inducing effect,
7
the interleukin-1 receptor antagonism, radical scavenging
3
c
8
activity, phytotoxic and insecticidal activity. Moreover,
some synthetic anhydrogabosines also present interesting
and promising biological activities. RKTS-33 (5) show
inhibitory
activity
toward
apoptosis, whereas parasitenone (
inhibitor and therefore
inflammatory and anticancer agent (Figure 1).
death
receptor-mediated
9
6
) is a nuclear factor-κB
a
potent candidate as anti-
1
0
The anhydrogabosines and their derivatives have
attracted much synthetic attention due to their structural
diversity and their wide ranging biological activity, and
considerable elegant routes have been devised towards
Introduction
1
Anhydrogabosines, such as epoxydon (
1
) and phyllostine
1
,2,11
(
2
), belong to a class of naturally occurring cyclohexane
their synthesis.
In general, anhydrogabosines were
2
epoxides. Although they present a similar polyoxygenated
methyl cyclohexane framework to gabosines, the epoxide
functionality in anhydrogabosines distinguish them from the
latter. Formally, the two types of compounds should be
converted into each other by hydrolysis of the epoxide
functionality and intramolecular etherification of the vicinal
diol group. These natural anhydrogabosines have displayed
various important bioactivities, including antibiotic,
synthesized mainly starting from benzoquinone and
1
0,12
13
cyclohexenone derivatives,
as well as iodobenzene.
Thus, enzyme-mediated and chemical-catalytic asymmetric
reactions were employed to achieve the enantioselective
version. Undoubtedly the strategies based on chiral pool
materials should provide alternative access to optical active
anhydrogabosines. However only Maycock group reported
the syntheses of (+)-epoformin, (+)-epiepoformin, and (-)-
3
4
5
14
antifungal, algicidal, antitumor, β-1,3-glucan inhibition,
theobroxide from (-)-quinic acid. As cheap chiral sources,
carbohydrates have not employed to the synthesis of
anhydrogabosines yet.
For the past several years we have been engaged in
synthesis of bioactive natural products using commercial
1
5
carbohydrates.
synthetic strategy to the gabosine-type C7 carbasugars
featuring the employment of aldol condensation precursor
prepared from δ-D-gluconolactone ), by which the
Recently, we developed
a
general
7
(
8
syntheses of thirteen natural gabosine-type compounds,
including the first synthesis of gabosines P, Q and L, were
1
6
achieved. As part of a continuing studies on exploitation of
this strategy, we herein describe the enantioselective
synthesis of several anhydrogabosines from the common
intermediate
7 (Scheme 1).
Figure.1 Several examples of anhydrogabosines.
1
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European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
Scheme 1 Diversity-oriented strategy for the syntheses of gabosines and anhydrogabosines via the common intermediate
7
de-TBS product was observed. Thus, selective 1,2-reduction of
1
8
enone 11 under Luche reduction conditions afforded β-hydroxy
isomer 12b as the major product (75% yield), together with a
small amount of α-alcohol 12a that had been transformed to
Results and Discussion
1
6b
several gabosines in our previous work. The hydroxyl group in
2b was protected with Ac O to give acetate 13. Gratifyingly, the
According to our methods diketone precursor 7 with three types
of hydroxyl protecting groups is readily prepared from δ-D-
1
2
1
6
silyl group in cyclohexene 13 could be removed smoothly with
TBAF to give alcohol 14 due to reduction of the ketone group.
The resulting hydroxyl group in 14 was activated as mesylate 15
for the subsequent oxirane ring closure. The acetonide
gluconolactone in high overall yield. Upon treatment of 7 with
pyrrolidine and AcOH the desired aldol cyclization proceeded
smoothly with exclusive chemoselectivity to produce a 7:1
mixture of diastereoisomeric alcohols 9a and 9b respectively.
1
7
2
protecting group was then removed with CuCl in MeCN to
Both 9a and 9b could be dehydrated with Burgess reagent to
give the target α,β-unsaturated ketone 11. In the light of our
vision, the TBS protected hydroxy group would be sulfonated to
provide a good leaving group for the ring closure to epoxide.
However, the treatment of cyclic enone 11 with TBAF/AcOH or
HF/pyridine only led to complete decomposition, and no target
afford diol 16. 2-Hydroxyl sulfonate 16 was treated with DBU to
afford the desirable epoxide 17 smoothly via an intramolecular
N
S 2 reaction (Scheme 2).
Scheme 2 Preparation of epoxide 17 from diketone 7. Reagents and conditions: (a) pyrrolidine, AcOH, toluene, rt, 76% for 9a, 11% for 9b; (b) Burgess reagent,
o
o
o
THF, 45 C, 95%; (c) NaBH
4
, CeCl
3
·7H
2
O, MeOH,0o C,21% for 12a, 75% for 12b; (d) Ac
2
O, Et
3
N, DMAP, CH
2
Cl
2
, rt, 97 %; (e) TBAF, THF, 0 C, 92%; (f) MsCl,
Et N, DMAP, CH Cl , rt, 93%; (g) CuCl
3
2
2
2
, CH
3
CN, 0 C, 94%; (h) DBU, CH
2
Cl
2
, rt, 88%.
2
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European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
With the epoxide 17 in hand, we focused on its transformation to
several anhydrogabosines (Scheme 3). Thus, oxidation of allyl
alcohol 17 with Dess−Martin periodinane afforded enone 18, in
which the PMB ether protecting group was removed with DDQ to
give alcohol 19. Finally, acetate 19 was converted to (+)-
epoxydon by cleavage of the acetyl group. Up to date, only one
asymmetric synthesis of (+)-epoxydon was reported by the
Mehta group by employing enzymatic kinetic resolution as a key
less than three steps in comparison with the former route.
Furthermore, chemoselective and stereoselective reduction
of dione 21 with NaBH(OAc)
PMB group produce (−)-parasitenone (
two steps. it would be reasonable that preferential access
of NaBH(OAc) to the carbonyl group from the side
3
followed by removal of the
6
) in 71% yield over
3
opposite to the oxirane ring gives cis-epoxy alcohol
19
intermediate. On the other hand, following Ryu’s
2
step. On the other hand, deprotection of acetyl group in acetate
7 with K CO leading to diol 20, which was oxidized to
1
procedure,
coordination-controlled reduction of (−)-
1
2
3
phyllostine with DIBAL-H exhibited inverse stereoselectivity
to generate (−)-RKTS 33 with 68% yield through the
complexation of the aluminium with the epoxide oxygen and
primary hydroxyl group.
corresponding dione 21 by treatment with 2.2 eq. PIDA in 85%
yield for two steps. The PMB ether bond in 21 was cleaved to
afford (−)-phyllostine. When the amount of PIDA was reduced to
1.0 equivalent in the oxidation, monoketone 22 was obtained via
the selective oxidation of the less steric hydroxyl group in 20
with 94% overall yield from 17. TFA-mediated removal of PMB
group in 22 furnished (−)-RKTS 33.
O
O
OH
O
OTs
O
a
HO
b
HO
c
9a
OAc
OAc
PMBO
O
PMBO
O
b
c
O
O
(+)-epoxydon
23
24
HO
OH
O
O
O
PMBO
O
O
19
18
OTs
O
HO
PMBO
d
HO
O
e
HO
O
a
OH
d
e
O
PMBO
OH
PMBO
O
O
OH
1
7
25
26
27
PMBO
O
PMBO
OH
O
2
0
21
g
f
f
h, i
O
(-)-parasitenone
O
(-)-phyllostine
PMBO
O
2
1
O
h
(-)-RKTS 33
g
PMBO
OH
j
(-)-phyllostine
(-)-RKTS 33
22
Scheme 4 Synthesis of (-)-phyllostine, (-)-parasitenone and (-)-RKTS 33 from
Scheme 3 Synthesis of (+)-epoxydon, (-)-phyllostine and (-)-RKTS 33
from 17 Reagents and conditions: (a) Dess−Martin periodinane,
NaHCO , CH Cl , rt, 94%; (b) DDQ, phosphate buffer (PH≈7.21), CH Cl
C, 89%; (c) K , MeOH, 0 C; (e) 2.2
eq. PhI(OAc) , TEMPO, CH , rt, 85% from 17; (f) CH Cl :TFA:H O =
00:20:1, rt, 70%; (g) 1.0 eq. PhI(OAc) , TEMPO, CH Cl , rt, 94% from
; (h) CH Cl :TFA:H O = 100:20:1, rt, 87%.
o
9
a. Reagents and conditions: (a) TBAF, THF, 0 C, 92%; (b) TsCl, Et
3
N, 1-
, 0 C, 87%; (d)
2
, rt, 63% (80% based on recovered 25); (e) IBX, DMSO, rt; (f)
.
o
methylimidazole, toluene, rt, 85%; (c) p-TsOH·H
DBU, CH Cl
Burgess reagent, THF, 0 C, 66% for two steps; (g) CH
2 2 2
O, CH Cl
3
2
2
2
2
,
o
o
o
2
0
2
CO
3
, MeOH, 0 C, 58%; (d) K
Cl
2
CO
3
o
2
Cl
Cl
00:20:1, rt, 71% for two steps; (j) DIBAL-H, THF, ‒78 C, 68%.
2
:TFA:H
2
O
=
=
2
2
2
2
2
2
o
1
1
00:20:1, rt, 70%; (h) NaBH(OAc)
3
,
MeOH, 45 C; (i) CH
2
2
:TFA:H O
2
1
7
2
2
2
o
1
2
2
2
To further improve the overall synthetic efficiency of
the strategy, an alternative route was launched
subsequently (Scheme 4). Deprotection of the TBS group in
cyclization product 9a with TBAF gave alcohol 23. Selective
Conclusion
In summary, we have developed two new routes to
anhydrogabosines as extension part of a general gabosines
synthesis strategy featuring aldol-cyclization of common
3
tosylation of the secondary alcohol in 23 with TsCl-Et N-
DMAP proceeded sluggishly. The target sulfonate 24 was
obtained in low yield even after a long span, together with
nearly half of material 23, which was difficult to separate
from 24. Gratifyingly, a full conversion of 23 was achieved
diketone precursor
7. In the polyoxygented cyclization
product 9 with different O-protecting groups, the required
2
0
hydroxyl group can be selectively sulfonylated by control of
deprotection to achieve construction of oxirane ring. By the
approaches, (+)-epoxydon, (−)-phyllostine, (−)-RKTS 33
and (−)-parasitenone were synthesized from δ-D-
gluconolactone. Further exploitation of this useful strategy
in the syntheses of the other anhydrogabosines and
gabosines, as well as their analogues is in progress.
by Tanabe's method to give tosylate 24 in 85% yield. After
cleavage of the isopropylidene blocking group, the
treatment of the resulting 2-hydroxy p-toluenesulfonate 25
with DBU permitted oxirane ring closure, leading to epoxide
26. The secondary hydroxy group in diol 26 was selectively
oxidized with IBX to ketone 27, in which dehydration of the
tertiary alcohol group with Burgess reagent furnished
known enone 21 in 66% yield for two steps. Therefore, this
new synthesis of (−)-phyllostine via 23 was achieved with
Experimental Section
3
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European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
Flash chromatography was performed using silica gel (200–300
mesh). Reactions were monitored by thin layer chromatogramhy
(15 mL) and extracted with EtOAc (3 × 15mL), dried over anhydrous
Na
2 4
SO and concentrated. The residue was purified by silica gel
(TLC). Visualization was achieved under a UV lamp (254 nm), IR
column chromatography (petroleum ether/EtOAc, 6:1) to give 11
2
5
spectra were recorded on a commercial spectrophotometer. Optical
T
(523 mg, 95%) as a slight yellow oil. [α]
D
3
–25.1 (c 0.90, CHCl ); IR
rotations were reported as follows: [α]
1
D
(c g per 100 mL, in
(neat) vmax 2988, 2932, 2889, 2856, 1689, 1615, 1586, 1514, 1466,
13
solvent).
H
and
C
NMR were recorded on commercial
1379, 1299, 1250, 1148, 1106, 1068, 1037, 967, 928, 890, 842, 781,
-
1 1
instruments (400 MHz) with TMS as the internal standard and were
calibrated using residual undertreated solvent as an internal
3
675 cm ; H NMR (400 MHz, CDCl ) δ 7.29 – 7.24 (m, 2H), 6.91 –
6.86 (m, 2H), 6.11 (q, J = 2.0 Hz, 1H), 4.55 (d, J = 11.6 Hz, 1H),
4.51 (d, J = 11.6 Hz, 1H), 4.33 – 4.28 (m, 3H), 4.16 (d, J = 10.8 Hz,
1H), 3.81 (s, 3H), 3.80 (m, 1H), 1.47 (s, 3H), 1.44 (s, 3H), 0.94 (s,
1
: H NMR = 7.26, C NMR = 77.16; CD
13
reference (CDCl
1
3
3 3
COCD :
13
H NMR = 2.05, C NMR = 29.84; C
1
SO: H NMR = 2.50,
13
D
2 6
C
1
3
NMR = 39.52). Coupling constants (J) are reported in Hertz (Hz).
HRMS spectra were recorded by using a commercial apparatus and
methanol or dichloromethane was used to dissolve the sample.
All air sensitive manipulations were carried out under a dry
3
9H), 0.19 (s, 3H), 0.13 (s, 3H); C NMR (100 MHz, CDCl ) δ 197.4,
159.6, 157.7, 129.7, 129.5, 123.1, 114.1, 112.6, 82.5, 78.3, 75.8,
73.0, 67.0, 55.4, 26.9, 26.6, 25.9, 18.8, –4.4, –5.1; HRMS (ESI)
+
Si [M + Na] 471.2179; Found 471.2180.
calcd for C24
H
36NaO
6
argon. Solvents for reaction were distilled prior to use: CH
2 2
Cl and
PhCH from CaH , tetrahydrofuran (THF) from Na, and other
3
2
Compounds 12a and 12b
reagents were obtained from commercial suppliers unless
otherwise stated. Drying of organic extracts during the work-up of
To a solution of 11 (238 mg, 0.531 mmol) in MeOH (10.6 mL) was
o
O (237 mg, 0.637 mmol) at 0 C. After stirring at 0
added CeCl ·7H
3
2
o
reactions was performed over anhydrous Na SO
2
4
.
4
C for 30 min, NaBH (40 mg, 1.062 mmol) was added. The
reaction was stirred at 0 °C for 10 min, quenched with saturated
NH Cl, evaporated under reduced pressure and purified by flash
Compounds 9a and 9b
4
To a solution of
7
(1.58 g, 3.39 mmol) in toluene (35 mL) was added
column chromatography (petroleum ether/EtOAc, 4:1) on silica gel
pyrrolidine (0.3 mL, 3.56 mmol) and AcOH (0.2 mL, 3.56 mmol) at
room temperature under argon. After stirring for 18 h, the reaction
mixture was concentrated under reduced pressure and purified by
flash column chromatography (petroleum ether/EtOAc, 8:1) on silica
gel to afford 9a (1.20 g, 76%) and 9b (0.17 g, 11%).
to give 12a (48 mg, 21%) and 12b (172 mg, 75%).
25
12a: a colorless oil; [α]
D
3
+21.4 (c 0.28, CHCl ); IR (neat) vmax 3528,
2931, 2857, 1613, 1513, 1465, 1377, 1296, 1249, 1169, 1088, 841,
-1 1
3
781 cm ; H NMR (400 MHz, CDCl ) δ 7.27 (m, 2H), 6.89 – 6.85 (m,
2H), 5.78 (dd, J = 4.0, 2.4Hz, 1H), 4.51 (d, J = 11.2 Hz, 1H), 4.47 (d,
J = 11.2 Hz, 1H), 4.33 (t, J = 4.6 Hz, 1H), 4.19 (dd, J = 13.4, 1.4 Hz,
2
5
9
3
1
a: a colorless oil; [α]
D
3
+4.3 (c 0.94, CHCl ); IR (neat) vmax 3478,
455, 2932, 2857, 1733, 1612, 1514, 1466, 1376, 1296, 1249, 1176, 1H), 4.05 (d, J = 13.6 Hz, 1H), 4.01 (dd, J = 8.0, 1.2 Hz, 1H), 3.95
-1
1
116, 1024, 1002, 948, 841, 781, 666 cm ; H NMR (400 MHz,
) δ 7.26 – 7.21 (m, 2H), 6.91 – 6.85 (m, 2H), 4.51 (d, J = 12.0
Hz, 1H), 4.48 (d, J = 12.0 Hz, 1H), 4.26 (d, J = 10.8 Hz, 1H), 4.08
dd, J = 11.0, 9.4 Hz, 1H), 3.94 (d, J = 9.6 Hz, 1H), 3.81 (s, 3H),
.45 (d, J = 9.0 Hz, 1H), 3.39 (d, J = 9.0 Hz, 1H), 2.58 (s, 2H), 2.33
s, 1H), 1.49 (s, 3H), 1.45 (s, 3H), 0.92 (s, 9H), 0.14 (s, 3H), 0.06 (s,
(dd, J = 10.8, 5.6 Hz, 1H), 3.80 (s, 3H), 3.73 (dd, J = 10.8, 8.4 Hz,
CDCl
3
1H), 3.27 (s, 1H), 1.43 (s, 3H), 1.41 (s, 3H), 0.93 (s, 9H), 0.17 (s,
13
3
3H), 0.16 (s, 3H); C NMR (100 MHz, CDCl ) δ 159.3, 137.8, 130.4,
(
129.5, 123.2, 113.9, 112.1, 78.3, 77.0, 72.5, 71.3, 69.0, 68.3, 55.4,
3
27.0, 26.8, 25.9, 18.4, –4.3, –4.9; HRMS (ESI) calcd for
+
Si [M + Na] 473.2335; Found 473.2338.
25
(
C
24
H
38NaO
6
1
3
3
1
2
H); C NMR (100 MHz, CDCl ) δ 204.6, 159.6, 129.8, 129.5,
3
12b: a colorless oil; [α]
D
3
–12.1 (c 0.34, CHCl ); IR (neat) vmax 3443,
14.0, 111.9, 79.2, 77.7, 77.4, 73.3, 73.0, 70.9, 55.4, 46.9, 27.4,
2931, 2856, 1613, 1514, 1465, 1376, 1301, 1249, 1174, 1097, 841,
1
-1
6.7, 25.9, 18.8, –4.6, –5.1; HRMS (ESI) calcd for C24
H38NaO
7
Si
3
781, 668 cm ; H NMR (400 MHz, CDCl ) δ 7.29 – 7.26 (m, 2H),
+
M + Na] 489.2284; Found 489.2287.
[
6.90 – 6.84 (m, 2H), 5.58 (s, 1H), 4.51 (d, J = 11.6 Hz, 1H), 4.47 (d,
J = 11.6 Hz, 1H), 4.29 (s, 1H), 4.20 – 4.12 (m, 2H), 4.05 (d, J = 14.4
2
5
9
2
1
b: a colorless oil; [α]
D
3
+20.0 (c 0.10, CHCl ); IR (neat) vmax 3455,
930, 2857, 1734, 1661, 1612, 1514, 1472, 1464, 1371, 1302, 1250, Hz, 1H), 3.93 (dd, J = 10.6, 6.2 Hz, 1H), 3.80 (s, 3H), 3.51 (dd, J =
-1
1
177, 1099, 1036, 1007, 839, 779, 671 cm ; H NMR (400 MHz,
) δ 7.23 – 7.18 (m, 2H), 6.90 – 6.85 (m, 2H), 4.50 (d, J = 11.6
Hz, 1H), 4.46 (d, J = 11.6 Hz, 1H), 4.28 (d, J = 10.8 Hz, 1H), 4.11 (d, 136.2, 130.4, 129.5, 124.1, 113.9, 111.4, 80.3, 77.9, 77.7, 76.7,
10.8, 8.8 Hz, 1H), 2.01 (d, J = 5.2 Hz, 1H), 1.42 (s, 3H), 1.40 (s, 3H),
13
CDCl
3
3
0.92 (s, 9H), 0.14 (s, 6H); C NMR (100 MHz, CDCl ) δ 159.3,
J = 10.0 Hz, 1H), 3.81 (s, 3H), 3.73 – 3.61 (m, 2H), 3.40 (d, J = 9.1
72.4, 67.9, 55.4, 26.9, 26.7, 26.0, 18.4, –4.2, –4.7; HRMS (ESI)
+
Si [M + Na] 473.2335; Found 473.2336.
Hz, 1H), 3.14 (s, 1H), 2.98 (d, J = 15.4 Hz, 1H), 2.43 (d, J = 15.4 Hz, calcd for C24
H38NaO
6
1
3
1
2
H), 1.49 (s, 3H), 1.39 (s, 3H), 0.92 (s, 9H), 0.15 (s, 3H), 0.06 (s,
13
H); C NMR (100 MHz, CDCl ) δ 203.5, 159.6, 129.5, 129.4,
3
Compound 13
To a solution of 12b (1.21 g, 2.68 mmol) in CH
added Et N (3.73 mL, 26.8 mmol), 4-dimethyl-aminopyridine (32.7
mg, 0.268 mmol) and Ac O (2.54 mL, 26.87 mmol) at room
temperature under argon. The reaction mixture was stirred at room
temperature for 4 h, then quenched with saturated NaHCO (30 mL)
and extracted with CH Cl (3 × 30 mL). The combined organic
layers were dried over anhydrous Na SO and concentrated in
14.1, 112.1, 100.1, 80.8, 79.0, 77.2, 73.6, 70.7, 69.8, 55.4, 49.3,
2 2
Cl (26.8 mL) were
7.2, 26.6, 25.84, 19.00, –4.6, –5.1; HRMS (ESI) calcd for
+
Si [M + Na] 489.2284; Found 489.2285.
3
C
24
H38NaO
7
2
Compound 11
3
To a solution of
9
(573 mg, 1.23 mmol) in THF (12 mL) was added
2
2
freshly prepared Burgess reagent (944 mg, 3.69 mmol) at room
temperature under argon. Then the reaction mixture was stirred
2
4
vacuo. The residue was purified by flash column chromatography
o
heavily at 45 C for 30 min. The reaction was quenched with water
(petroleum ether/EtOAc, 8:1) to afford 13 (1.28 g, 97%) as a
4
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European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
2
5
colorless oil. [α]
D
−95.6 (c 0.88, CHCl
3
); IR (neat) vmax 2935, 2856,
CuCl ·2H
2
2
O (75 mg, 0.44 mmol) was added to the solution of 15
o
CN (4.4 mL) at 0 C. The violently
1
7
6
4
6
746, 1614, 1514, 1371, 1298, 1232, 1176, 1099, 1024, 964, 850,
1
87, 517 cm ; H NMR (400 MHz, CD
(101 mg, 0.22 mmol) in CH
3
-1
COCD ) δ 7.28 (m, 2H),
3 3
stirred mixture was kept at same temperature for 10 min. The
reaction was quenched with saturated NaHCO (5 mL). The mixture
was filtered and the filtrate was extracted with EtOAc (3 × 5 mL).
Then the organic phase was dried over anhydrous Na SO and
.93 – 6.88 (m, 2H), 5.49 (dd, J = 3.3, 1.9 Hz, 1H), 5.35 (m, 1H),
.48 (d, J = 2.5 Hz, 2H), 4.28 (d, J = 8.5 Hz, 1H), 4.20 (dd, J = 10.8,
.4 Hz, 1H), 4.11 (dd, J = 14.3, 1.6 Hz, 1H), 4.02 (dd, J = 14.3, 1.6
3
2
4
Hz, 1H), 3.79 (s, 3H), 3.56 (dd, J = 10.8, 8.5 Hz, 1H), 2.05 (s, 3H),
.42 (s, 3H), 1.39 (s, 3H), 0.89 (s, 9H), 0.13 (s, 3H) , 0.12 (s, 3H);
concentrated. The residue was purified by silica gel column
1
chromatography (petroleum ether/EtOAc, 1:1) to afford diol 16 (65
25
13
C NMR (100 MHz, CDCl ) (100 MHz, CD COCD ) δ 170.7, 160.4,
3 3 3
mg, 94%) as a colorless oil. [α]
D
3
−80.9 (c 0.38, CHCl ); IR (neat)
139.3, 131.4, 130.4, 120.6, 114.6, 112.1, 81.5, 79.7, 77.0, 75.5,
vmax 3495, 2929, 2360, 1741, 1612, 1514, 1348, 1242, 1174, 1029,
-
1 1
7
3.0, 68.2, 55.6, 27.1, 26.2, 21.2, 18.9, -4.0, -4.6; HRMS (ESI)
+
Si [M + H] 493.2616; Found 493.2613.
958, 837, 530 cm ; H NMR (400 MHz, CDCl
2H), 6.88 (d, J = 8.6 Hz, 2H), 5.59 (d, J = 8.0 Hz 1H), 5.53 (s, 1H),
.73 (dd, J = 10.8, 8.1 Hz, 1H), 4.45 (dd, J = 11.4, 5.6 Hz, 2H), 4.35
(s, 1H), 4.17 (d, J = 13.4 Hz, 1H), 4.01 (d, J = 13.4 Hz, 1H), 3.83 (m,
3
) δ 7.24 (d, J = 8.6 Hz,
calcd for C26
41
H O
7
4
Compound 14
13
To a solution of 13 (452 mg, 0.917 mmol) in THF (1.83 mL) was
o
added TBAF (1M in THF, 1.38 mL, 1.38 mmol) at 0 C. The
4H), 3.44 (d, J = 4.2 Hz, 2H), 3.11 (s, 3H), 2.11 (s, 3H). C NMR
(100 MHz, CDCl ) δ 170.6, 159.6, 138.4, 129.7, 129.5, 121.9, 114.1,
3
o
resulting mixture was stirred for 4.5 h at 0 C before saturated
81.5, 73.9, 73.1, 72.7, 71.5, 69.7, 55.4, 38.9, 21.1. HRMS (ESI)
+
S [M + H] 417.1214; Found 417.1212.
NH Cl (3 mL) was added. The aqueous phase was extracted with
4
calcd for C18
H O
25 9
EtOAc (3 × 5 mL). After the organic layer was concentrated under
reduced pressure, the residue was purified by flash
chromatography (petroleum ether/EtOAc, 2:1) to afford 14 (319 mg,
Compound 17
To a solution of 16 (1.48 g, 3.56 mmol) in CH
added DBU (1 mL, 7.11 mmol) at room temperature. The reaction
458, 2987, 2929, 2850, 2360, 1738, 1612, 1514, 1456, 1375, 1234, mixture was stirred for 4 h before quenched by a solution of
2
2
Cl (35.6 mL) was
2
5
9
3
1
7
1
4
2
8
2%) as a colorless oil. [
]
D
3
–55.0 (c 0.73, CHCl ); IR (neat) vmax
-1
1
171, 1080, 1033, 972 cm ; H NMR (400 MHz, CD
COCD ) δ
3 3
saturated aqueous NaHCO
35 mL). The combined organic layers were dried over anhydrous
Na SO and concentrated in vacuo. The residue was purified by
column chromatography (petroleum ether/EtOAc, 1:1) to afford
3 2 2
(30 mL) and extracted with CH Cl (3 ×
.32 – 7.27 (m, 2H), 6.94 – 6.89 (m, 2H), 5.52 (dt, J = 4.5, 1.9 Hz,
H), 5.37 (dq, J = 5.9, 3.3, 2.7 Hz, 1H), 4.82 (d, J = 4.4 Hz, 1H),
.49 (d, J = 2.1 Hz, 2H), 4.25 (d, J = 8.5 Hz, 1H), 4.19 – 4.09 (m,
H), 4.04 (dd, J = 14, 1.2 Hz, 1H), 3.79 (s, 3H), 3.59 (dd, J = 10.9,
2
4
25
compound 17 (1.00 g, 88%) as a colorless oil. [α]
D
−61.2 (c 0.36,
13
.5 Hz, 1H), 2.05 (s, 3H), 1.41 (s, 3H), 1.39 (s, 3H); C NMR (100
COCD
14.4, 111.9, 81.4, 79.5, 79.2, 76.8, 74.0, 72.78, 68.0, 55.5, 26.9,
CHCl ); IR (neat) vmax 3452, 2922, 2854, 2358, 1734, 1612, 1514,
3
-1 1
MHz, CD
3
3
) δ 206.3, 171.0, 160.2, 139.3, 131.2, 130.2, 120.4, 1456, 1369, 1240, 1172, 1028, 925, 829 cm ; H NMR (400 MHz,
1
2
CDCl ) δ 7.24 (d, J = 8.6 Hz, 2H), 6.88 (d,J= 8.6 Hz, 2H), 5.75 (d, J
3
+
[M + Na] 401.1571;
6.8, 21.0; HRMS (ESI) calcd for C20
H26NaO
7
= 1.2 Hz, 1H), 5.50 (s, 1H), 4.53 (s, 1H), 4.46 (s, 2H), 4.09 (d, J =
11.4 Hz, 1H), 4.02 (d, J = 11.4 Hz, 1H), 3.81 (s, 3H), 3.56 (dt, J =
Found 401.1573.
4.1, 2.1 Hz, 1H), 3.47 (dd, J = 4.0, 1.7 Hz, 1H), 3.10 (d, J = 3.3 Hz,
13
Compound 15
3
1H), 2.14 (s, 3H). C NMR (100 MHz, CDCl ) δ 170.7, 159.6, 136.0,
To a solution of 14 (217 mg, 0.573 mmol) in CH Cl
2
2
(11.5 mL) were
129.7, 129.4, 122.0, 114.1, 73.6, 72.7, 67.5, 64.7, 55.4, 54.0, 51.1,
+
[M + Na] 343.1152; Found
added Et N (0.86 mL, 6.19 mmol), 4-dimethylamino-pyridine (7.0
3
21.1; HRMS (ESI) calcd for C17
H20NaO
6
mg, 0.057 mmol) and MsCl (0.27 mL, 3.44mmol) successively at 0
o
C. The reaction mixture was stirred at room temperature for 15 h,
343.1154.
then it was quenched with saturated NaHCO
with CH Cl (3 × 15 mL). The combined organic layers were dried
over anhydrous Na SO and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (petroleum
3
(15 mL) and extracted
Compound 18
2
2
To a solution of 17 (650 mg, 2.03 mmol) in CH
added Dess−Martin periodinane (947 mg, 2.23 mmol) and sat.
NaHCO (188 mg, 2.23 mmol) at room temperature under argon.
2 2
Cl (40.6 mL) was
2
4
3
2
5
ether/EtOAc, 2:1) to afford 15 (244 mg, 93%) as a yellow oil. [
]
D
The reaction mixture was stirred at this temperature for 1 h, then it
was quenched with a solution of isopropyl alcohol (0.1 mL),
−
49.0 (c 0.40, CHCl
514, 1365, 1228, 1174, 1068, 1026, 962, 842, 524 cm ; H NMR
COCD ) δ 7.29 (d, J = 8.7 Hz, 2H), 6.94 – 6.88 (m,
3
); IR (neat) vmax 2926, 2854, 2360, 1745, 1612,
-1 1
1
Na
40 mL). The combined organic layers were dried over anhydrous
Na SO and concentrated in vacuo. The residue was purified by
column chromatography (petroleum ether/EtOAc, 1:1) to afford 18
2 2 3 2 2 2
S O (30 mL) and H O (30 mL) and extracted with CH Cl (3 ×
(
400 MHz, CD
3
3
2
H), 5.61 (m, 1H), 5.52 (dt, J = 4.5, 1.9 Hz, 1H), 5.10 (dd, J = 11.2,
.3 Hz, 1H), 4.54 (m, 1H), 4.50 (dd, J = 14.4, 2.8 Hz, 2H), 4.15 (dq,
2
4
6
25
J = 14.5, 1.8 Hz, 1H), 4.06 (dq, J = 14.5, 1.8 Hz, 1H), 3.86 (dd, J =
(607 mg, 94%) as a slight yellow oil. [
]
D
3
+17.2 (c 0.42, CHCl ); IR
1
3
1
7
1.2, 8.6 Hz, 1H), 3.79 (s, 3H), 3.17 (s, 3H), 2.84 (s, 3H), 1.47 (s,
(neat) νmax 2928, 2860, 1745, 1687, 1612, 1513, 1374, 1301, 1029,
-1
13
1
H), 1.44 (s, 3H); C NMR (100 MHz, CD
COCD ) δ 170.5, 160.4,
3 3
3
869, 824 cm ; H NMR (400 MHz, CDCl ) δ 7.27 – 7.22 (m, 2H),
39.5, 131.2, 130.4, 119.8, 114.6, 113.3, 82.4, 79.3, 78.8, 76.9,
6.91 – 6.84 (m, 2H), 6.46 (m, 1H), 5.81 (m, 1H), 4.48 (s, 2H), 4.21
(dt, J = 14.5, 2.0 Hz, 1H), 4.07 (dt, J = 14.5, 2.0 Hz, 1H), 3.87 (dt, J
= 4.0, 2.7 Hz, 1H), 3.80 (s, 3H), 3.49 (d, J = 4.1 Hz, 1H), 2.20 (s,
5.6, 73.0, 67.8, 39.0, 27.0, 26.8, 20.9; HRMS (ESI) calcd for
+
S [M + H] 457.1527; Found 457.1522.
C
21 29
H O
9
13
3
H); C NMR (100 MHz, CDCl
3
) δ 192.3, 170.4, 159.4, 136.3,
Compound 16
134.4, 129.7, 129.6, 113.9, 72.9, 66.8, 65.3, 55.4, 52.8, 51.4, 21.0.
5
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
+
[M + Na] 341.0996; Found
HRMS (ESI) calcd for C17H18NaO
6
NMR (400 MHz, CDCl
3
) δ 7.25 (d, J = 9.0 Hz, 2H), 6.89 (d, J = 9.0
341.0995.
Hz, 2H), 6.72 (q, J = 2.1 Hz, 1H), 4.53 (s, 2H), 4.37 (dd, J = 17.6,
.3 Hz, 1H), 4.17 (dd, J = 17.6, 2.3 Hz, 1H), 3.81 (s, 3H), 3.81 –
2
1
3
Compound 19
To a stirred solution of 18 (113 mg, 0.355 mmol) in CH
3
3.78 (m, 2H); C NMR (100 MHz, CDCl ) δ 191.6, 191.3, 159.6,
Cl
2 2
(17.7 mL) 146.7, 131.5, 129.6, 129.2, 114.1, 73.1, 65.0, 55.4, 54.1; HRMS
+
and phosphate buffer (pH = 7.2, 1.77 mL) was added DDQ (242 mg, (ESI) calcd for C15
.065 mmol) at 0 °C. Then the resulting mixture was stirred for 3 h
at 0 °C. The separated organic layer was washed with saturated
NaHCO and saturated Na (1:1), water and brine successively. To a solution of 21 (23 mg, 0.084 mmol) in CH
H
14NaO
5
[M + Na] 297.0733; Found 297.0735.
1
(–)-Phyllostine (2)
3
2 2
S O
3
2
2
Cl (8.4 mL) were
The organic layer was concentrated by rotary evaporation under
reduced pressure. The residue was purified by flash
chromatography (petroleum ether/EtOAc, 1:1) to afford 19 (63 mg,
added TFA (1.7 mL) and H O (84 μL) at room temperature. The
2
reaction mixture was stirred at room temperature for 10 min. The
solution was concentrated under reduced pressure. The residue
2
5
8
9%) as a colorless oil. [
454, 2925, 1744, 1685, 1373, 1230, 1026, 867, 540, 489 cm ; H
) δ 6.41 (tt, J = 2.6, 1.5 Hz, 1H), 5.82 (m, 1H), EtOH); lit: [
.38 (dd, J = 14.6, 5.9 Hz, 1H), 4.21 (dd, J= 14.6, 5.9 Hz, 1H), 3.89 2854, 1686, 1440, 1359 cm ; H NMR (400 MHz, CDCl
dt, J = 4.0, 2.7 Hz, 1H), 3.50 (d, J = 4.0 Hz, 1H), 2.22 (d, J = 6.5 Hz, J = 4.1, 2.0 Hz, 1H), 4.58 (dd, J = 17.6, 1.9 Hz, 1H), 4.40 (dd, J =
]
D
+147.9 (c 0.30, CHCl
3
); IR (neat) νmax
was purified by flash chromatography (petroleum ether/EtOAc, 2:1)
-1
1
25
D
3
to yield
2
(9.1 mg, 70%) as a colorless oil. [
]
−101.7 (c 0.06,
31
12e
NMR (400 MHz, CDCl
3
]
D
-100.4 (c 0.62, EtOH); IR (neat) νmax 3440, 2925,
-1 1
4
3
) δ 6.69 (dd,
(
13
13
1
H), 2.20 (s, 3H); C NMR (100 MHz, CDCl ) δ 193.3, 170.4, 136.4, 17.6, 1.9 Hz, 1H), 3.86 – 3.81 (m, 2H), 1.94 (d, J = 5.2 Hz, 1H);
3
C
1
36.2, 66.7, 60.4, 52.9, 51.5, 21.0; HRMS (ESI) calcd for
+
[M + Na] 221.0420; Found 221.0423.
NMR (100 MHz, CDCl ) δ 192.1, 191.3, 148.1, 131.3, 59.5, 54.2;
3
+
Na [M + Na] 177.0158; Found
C
9
H
10NaO
5
HRMS (ESI) calcd for C
7
H
6
O
4
177.0161.
(
+)-Epoxydon (1)
To a solution of 19 (66 mg, 0.33 mmol) in MeOH (3.3 mL) was
added K CO (12 mg, 0.087 mmol) at 0 °C. The resulting mixture
was stirred for 10 min before saturated NH Cl (5 mL) added, and
extracted with EtOAc (3 × 5 mL). The combined organic layers were
dried over anhydrous Na SO and concentrated in vacuo. The
residue was purified by column chromatography (petroleum
Compound 22
To a solution of 17 (156 mg, 0.49 mmol) in MeOH (5 mL) at 0 °C,
was added K CO (17 mg, 0.12 mmol). The mixture was stirred for
10 min before saturated NH Cl (5 mL) was added, and extracted
with EtOAc (3 × 5 mL). The combined organic layers were dried
over anhydrous Na SO and concentrated in vacuo, the residue
2
3
4
2
3
4
2
4
2
4
ether/EtOAc, 1:2) to afford (+)-epoxydon (
1
) (30 mg, 58%) as a
26
was purified by flash chromatography (petroleum ether/EtOAc, 1:2)
25
D
colorless oil. [
]
+81.6 (c 0.10, MeOH); lit: [
]
D
+71.6 (c 0.3,
on silica gel to afford intermediate 20. The resulting 20 was
4e
MeOH); IR (neat) νmax 3351, 2925, 2855, 1679, 1456, 1240, 1027,
2 2
dissolved in CH Cl (4.5 mL), and TEMPO (7.0 mg, 0.049 mmol)
-
1 1
9
2
1
=
4
6
1
03, 866 cm ; H NMR (400 MHz, DMSO-d
6
) δ 6.39 (dddd, J = 2.7,
and PhI(OAc) (158 mg, 0.49 mmol) were sequentially added at
2
.6, 2.2, 2.1 Hz, 1H), 5.79 (d, J = 6.2 Hz, 1H), 5.01 (t, J = 5.5 Hz,
H), 4.70 (m, 1H), 4.07 (ddt, J = 15.3, 5.6, 2.0 Hz, 1H), 3.96 (ddt, J
15.3, 5.6, 2.0 Hz, 1H), 3.76 (dt, J = 4.2, 2.7 Hz, 1H), 3.40 (d, J =
room temperature under argon. The mixture was stirred at room
temperature for 14 h, then it was quenched with saturated aqueous
NaHCO
3
(5 mL) and extracted with CH
2
Cl
2
(3 × 5 mL). The
SO and
13
.2 Hz, 1H); C NMR (100 MHz, DMSO-d
6
) δ 194.0, 141.4, 133.8,
+
combined organic layers were dried over anhydrous Na
2
4
3.7, 57.4, 54.0, 52.9; HRMS (ESI) calcd for C
7 8
H
NaO
4
[M + Na]
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 1:2) to afford
79.0315; Found 179.0312.
25
22
(127 mg, 94%) as a colorless oil. [
]
D
3
–221.3 (c 0.46, CHCl );
-
1
Compound 21
To a solution of 17 (128 mg, 0.40 mmol) in MeOH (4 mL) at 0 °C
was added K CO (14 mg, 0.10 mmol). The mixture was stirred for
0 min before saturated NH Cl (5 mL) was added, and extracted
with EtOAc (3 × 5 mL). The combined organic layers were dried
over anhydrous Na SO and concentrated in vacuo, the residue
IR (neat) νmax 3246, 2943, 2513, 1715, 1558, 1442, 1349,1026 cm ;
1
3
H NMR (400 MHz, CDCl ) δ 7.24 (d, J = 8.7 Hz, 2H), 6.89 (d, J =
2
3
8.7 Hz, 2H), 5.96 (d, J = 1.6 Hz, 1H), 4.66 (d, J = 5.5 Hz, 1H), 4.49
(s, 2H), 4.25 (dd, J = 14.0, 1.3 Hz, 1H), 4.15 (dd, J = 14.0, 1.3 Hz,
1H), 3.81 (s, 3H), 3.78 (dd, J = 3.6, 1.3 Hz, 1H), 3.44 (ddd, J = 3.5,
1
4
13
2
4
1.6, 1.0 Hz, 1H), 3.34 (d, J = 5.6 Hz, 1H); C NMR (100 MHz,
was purified by flash chromatography (petroleum ether/EtOAc, 1:2)
CDCl ) δ 193.6, 159.8, 154.2, 129.7, 128.9, 122.9, 114.2, 73.2, 71.4,
3
+
on silica gel to afford intermediate 20. The resulting 20 was
5
64.4, 56.6, 55.4, 52.9; HRMS (ESI) calcd for C15H16NaO [M + Na]
2 2
dissolved in CH Cl (4 mL), and TEMPO (5.7 mg, 0.04 mmol) and
299.0890; Found 299.0891.
PhI(OAc) (283 mg, 0.88 mmol) were sequentially added at room
2
temperature under argon. The mixture was stirred at room
temperature for 14 h, then it was quenched with saturated aqueous
(–)-RKTS 33 (5)
To a stirred solution of 22 (11 mg, 0.040 mmol) in CH
2 2
Cl (4 mL)
NaHCO
3
(5 mL) and extracted with CH Cl
2
2
(3 × 5 mL). The
SO and
was added TFA (0.8 mL) and H O (40 μL) at room temperature.
2
combined organic layers were dried over anhydrous Na
2
4
The solution was stirred at room temperature for 10 min. The
reaction mixture was concentrated by rotary evaporation under
reduced pressure. The residue was purified by flash
concentrated in vacuo. The residue was purified by column
chromatography on silica gel (petroleum ether/EtOAc, 1:1) to afford
2
5
2
1
(86 mg, 85%) as a colorless oil. [
]
D
−109.4 (c 0.88, CHCl ); IR
3
chromatography (petroleum ether/EtOAc, 1:2) to yield
25
5
(5.4 mg,
25
-1
1
(
neat) νmax 3255, 2938, 2354, 1715, 1557, 1438, 1354 cm ;
H
87%) as a colorless oil. [
]
D
–287.3 (c 0.08, EtOH); lit: [
]
D
-
6
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.202000486
FULL PAPER
1
2h
2
1
1
1
1
6
1
75.7 (c 0.33, EtOH);
IR (neat) νmax 3240, 2927, 1726, 1445,
(petroleum ether/EtOAc, 1:2) to give compound 25 (472 mg, 88%)
25
-1
1
279 cm ; H NMR (400 MHz, CD COCD ) δ 6.00 (d, J = 1.8 Hz,
3
3
as a colorless oil. [
]
D
3
+1.26 (c 0.76, CHCl ); IR (neat) νmax 3475,
H), 4.56 (s, 1H), 4.49 (1/2ABq, J = 17.2 Hz, 1H), 4.24 (1/2ABq, J =
7.2 Hz, 1H), 3.78 (dd, J = 3.6, 1.5 Hz, 1H), 3.35 (ddd, J = 3.6, 1.8,
2924, 2865, 1745, 1608, 1514, 1463, 1363, 1248, 1175, 1095, 994,
-1 1
3
846, 758, 675, 526 cm ; H NMR (400 MHz, CDCl ) δ 7.82 (d, J =
13
.0 Hz, 1H); C NMR (100 MHz, CD COCD
3
3
) δ 194.0, 161.2, 120.0, 8.3 Hz, 2H), 7.27 (d, J = 8.3 Hz, 2H), 7.17 (d, J = 8.7 Hz, 2H), 6.82
+
3.6, 62.6, 57.7, 53.5; HRMS (ESI) calcd for C
7 8
H
NaO
4
[M + Na]
(d, J = 8.7 Hz, 2H), 5.15 (d, J = 9.7 Hz, 1H), 4.40 (d, J = 20.4 Hz,
11.6 Hz, 2H), 4.10 (d, J = 9.3 Hz, 1H), 4.01 (t, J = 9.5 Hz, 1H), 3.76
79.0315; Found 179.0310.
(s, 3H), 3.53 (d, J = 9.2 Hz, 1H), 3.31 (d, J = 9.2 Hz, 1H), 2.67 (d, J
1
3
Compound 23
= 14.7 Hz, 1H), 2.50 (d, J = 14.7 Hz, 1H), 2.39 (s, 3H); C NMR
(100 MHz, CDCl ) δ 197.9, 159.4, 145.2, 133.4, 129.8, 129.6, 128.3,
To a solution of 9a (1.45 g, 3.10 mmol) in THF (20.6 mL) was
o
added TBAF (1M in THF, 4.65 mL, 4.65 mmol) at 0 C. The
o
resulting mixture was stirred for 5 h at 0 C before saturated NH
3
114.0, 84.3, 73.9, 73.2, 72.8, 55.4, 45.6, 21.8; HRMS (ESI) calcd
+
S [M + Na] 489.1190; Found 489.1192.
4
Cl
for C22H26NaO
9
(
30 mL) and EtOAc (30 mL) were added. The phases were
separated and the aqueous phase was extracted with EtOAc (3 ×
0 mL). After the organic layer was concentrated under reduced
pressure, the residue was purified by flash chromatography
Compound 26
2 2
To a solution of compound 25 (325 mg, 0.70 mmol) in CH Cl (70
3
mL) was added DBU (97.5 µL, 0.70 mmol) at room temperature.
The reaction mixture was stirred for 1.5 h. After completion of the
(petroleum ether/EtOAc, 1:1) yielding 23 (0.92 g, 92%) as a yellow
2
5
oil. [
]
D
–19.3 (c 0.30, CHCl
3
); IR (neat) νmax 3463, 2987, 2930,
reaction, it was quenched with saturated aqueous NaHCO
and the aqueous phase extracted with CH Cl (3 × 70 mL). The
combined organic layers were dried over anhydrous Na SO and
3
(70 mL),
1
725, 1612, 1586, 1513, 1456, 1375, 1301, 1246,1175, 1085, 962,
1
99, 779, 735, 703 cm ; H NMR (400 MHz, CD
2
2
-1
8
COCD ) δ 7.29
3 3
2
4
(
dd, J = 9.1, 2.3 Hz, 2H), 6.94 – 6.86 (dd, J = 9.1, 2.3 Hz, 2H), 4.52
d, J = 2.3 Hz, 2H), 4.37 (dd, J = 10.8, 3.6 Hz, 1H), 4.29 (s, 1H),
concentrated in vacuo. The residue was purified by column
chromatography (petroleum ether/EtOAc, 1:2) to afford compound
(
2
5
4
.23 (d, J = 3.9 Hz, 1H), 4.16 (d, J = 9.4 Hz, 1H), 3.99 (dd, J = 10.8,
.5 Hz, 1H), 3.78 (s, 3H), 3.60 (d, J = 9.2 Hz, 1H), 3.40 (d, J = 9.2
26 (129 mg, 63%) as a slight yellow oil. [α]
D
3
–8.9 (c 0.56, CHCl );
9
IR (neat) νmax 3471, 2924, 2860, 1721, 1611, 1514, 1463, 1248,
-1 1
3
Hz, 1H), 2.91 (d, J = 15.6 Hz, 1H), 2.49 (d, J = 15.6 Hz, 1H), 1.45 (s, 1177, 1076, 849, 541 cm ; H NMR (400 MHz, CDCl ) δ 7.21 (d, J
1
3
3
1
4
3
H), 1.38 (s, 3H); C NMR (100 MHz, CD
3
COCD ) δ 207.8, 160.2,
3
= 8.6 Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 4.52 – 4.43 (d, J = 14
Hz,11.6 Hz, 2H), 4.16 (d, J = 4.2 Hz, 1H), 3.81 (s, 3H), 3.47 (d, J =
9.2 Hz, 1H), 3.45 (d, J = 3.6 Hz, 1H), 3.35 (d, J = 9.2 Hz, 1H), 3.31
(s, 1H), 3.24 (s, 1H), 2.61 (d, J = 14.2 Hz, 1H), 2.30 (d, J = 14.2 Hz,
31.1, 129.9, 114.4, 112.0, 78.9, 78.4, 78.3, 73.6, 73.5, 71.9, 55.5,
+
7.5, 27.5, 26.9; HRMS (ESI) calcd for C18
7
H24NaO [M + Na]
75.1414; Found 375.1422.
13
1
3
H); C NMR (100 MHz, CDCl ) δ 203.2, 159.8, 129.7, 129.0,
Compound 24
114.2, 76.6, 75.5, 73.7, 68.6, 60.3, 55.4, 55.0, 40.6; HRMS (ESI)
+
[M + Na] 317.0996; Found 317.0997.
TsCl (194 mg, 0.78 mmol) in toluene (0.52 mL) was added to a
calcd for C15
H
18NaO
6
solution of 23 (184 mg, 0.52 mmol), N-methylimidazole (NMI) (62
uL, 0.78 mmol), and Et N (109 uL, 0.78 mmol) in toluene (0.52 mL)
3
Preparation of 21 from 26
at room temperature under argon. The mixture was stirred at the
same temperature for 1 h. Water was added to the mixture, and
extracted with EtOAc (3 × 5 mL). After the organic layer was
concentrated under reduced pressure, the residue was purified by
flash chromatography (petroleum ether/EtOAc, 1:2) yielding 24 (237
To a solution of 26 (63 mg, 0.22 mmol) in DMSO (2.2 mL) was
added the IBX (120 mg, 0.44 mmol) at room temperature. The
resulting mixture was stirred at room temperature for 3.5 h. The
mixture was diluted with H
10 mL). The combined organic layers were dried over anhydrous
Na SO and concentrated in vacuo. The residue was purified by
2
O (15 mL) and extracted with EtOAc (3 ×
25
mg, 85%) as a colorless oil. [
]
D
+17.5 (c 0.58, CHCl ); IR (neat)
3
2
4
ν
4
2
max 3248, 2942, 2057, 1717, 1559, 1440, 1352, 1176, 834, 619,
flash chromatography (petroleum ether/EtOAc, 2:1) on silica gel to
afford intermediate 27. The resulting 27 was dissolved in THF (8.8
mL), and freshly prepared Burgess reagent (157 mg, 0.66 mmol)
was added at room temperature. Then the reaction mixture was
heated at 45 °C for 10 min, extracted with EtOAc (3 × 10 mL), dried
-
1
1
87 cm ; H NMR (400 MHz, CD
3 3
COCD ) δ 7.84 (d, J = 8.0 Hz,
H), 7.43 (d, J = 8.0 Hz, 2H), 7.28 (dd, J = 9.0, 2.3 Hz, 2H), 6.90
(
dd, J = 9.0, 2.3 Hz, 2H), 5.48 (d, J = 11.1 Hz, 1H), 4.50 (t, J = 3.2
Hz, 2H), 4.46 (m, 1H), 4.31 (d, J = 9.5 Hz, 1H), 4.15 (dd, J = 11.1,
.5 Hz, 1H), 3.79 (s, 3H), 3.58 (d, J = 9.2 Hz, 1H), 3.39 (d, J = 9.2
Hz, 1H), 2.98 (d, J = 15.7 Hz, 1H), 2.87 (s, 1H), 2.45 (s, 3H), 1.36 (s, by silica gel column chromatography (petroleum ether/EtOAc, 1:2)
9
2 4
over anhydrous Na SO and concentrated. The residue was purified
1
3
3
1
7
H), 1.31 (s, 3H); C NMR (100 MHz, CD
3
COCD ) δ 199.4, 160.2,
3
to give 21 (40 mg, 66%) as a colorless oil.
45.5, 135.5, 131.1, 130.3, 130.0, 129.0, 114.5, 112.6, 84.3, 78.6,
5.3, 73.5, 73.3, 71.5, 55.5, 48.5, 27.2, 26.8, 21.5; HRMS (ESI)
+
S [M + Na] 529.1503; Found 529.1500.
(−)-Parasitenone (6)
calcd for C25
H
30NaO
9
To a solution of 21 (20 mg, 0.073 mmol) in MeOH (3.7 mL) was
added NaBH(OAc)
3
(17 mg, 0.080 mmol) at 0 °C. The reaction
Compound 25
To a solution of 24 (583 mg, 1.15 mmol) in MeOH (23 mL) was
added p-TsOH·H O (33 mg, 0.17 mmol) at room temperature. After
mixture was stirred at 0 °C for 10 min, quenched with saturated
NH
were dried over anhydrous Na
residue was dissolved in CH
4
Cl, and extracted with CH
2
Cl
2
. The combined organic layers
and concentrated in vacuo. The
2
2
SO
4
stirring for 5 h, the reaction mixture was concentrated under
reduced pressure and purified by flash column chromatography
2 2
Cl (6.8 mL), and TFA (1.4 mL) and
2
H O (68 μL) were added at room temperature. The resulting mixture
7
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European Journal of Organic Chemistry
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Chem. 1971, 35, 105-110; c) S. Sakamura, H. Niki, Y. Obata, R.
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was stirred at room temperature for 10 min. The reaction was
concentrated by rotary evaporation under reduced pressure. The
residue was purified by flash chromatogramphy (petroleum
ether/EtOAc, 1:2) to yield
6
(8.1 mg, 71%) as a slight yellow oil. []
D
Vishwakarma, S. Riyaz-Ul-Hassan, B. Ali Shah, J. Nat. Prod. 2013
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25
25
12h
–
113.6 (c 0.20, EtOH); lit: [
]
D
-115.4 (c 0.39, EtOH);
IR
1
76, 194-199; e) M. J. Jo, S. J. Bae, B. W. Son, C. Y. Kim, G. D. Kim,
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-1
(neat) νmax 3466, 2926, 2855, 1729, 1683, 1385, 1261 cm ;
H
6
NMR (400 MHz, DMSO-d ) δ 5.86 (d, J = 7.5 Hz, 1H), 5.82 (t, J =
1397−1403; g) G. D. Anaya-Eugenio, T. Ali, L. H. Rakotondraibe, E.
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4
.4, 2.8 Hz, 1H), 3.38 (dd, J = 4.1, 2.3 Hz, 1H); C NMR (100 MHz,
DMSO-d ) δ 193.6, 163.0, 117.2, 64.6, 60.4, 55.3, 53.2; HRMS (ESI)
calcd for C
6
a) H. Nagasawa, A. Suzuki, S. Tamura, Agric. Biol. Chem. 1978, 42,
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8 4
H NaO [M + Na] 179.0315; Found 179.0312.
Preparation of (–)-RKTS 33 from (–)-phyllostine
To a solution of 2 (15 mg, 0.097 mmol) in CH Cl (2.0 mL) was added
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,
2
2
́
DIBAL-H (1.5 M in toluene, 0.13 mL, 0.19 mmol) dropwise at -78 °C
under argon. After 30 min, saturated sodium potassium tartrate (3 mL)
1
7
.
M. S. Kuo, D. A.Yurek, S. A. Mizsak, V. P. Marshall, W. F. Liggett, J.
was added and the mixture was diluted with CH
mixture was warmed to room temperature and stirred until the layers
were separated. The aqueous layer was extracted with CH Cl (3 × 5
mL). The combined organic layers were dried over anhydrous Na SO
2 2
Cl (3 mL). The reaction
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2
4
and concentrated. The residue was purified by flash chromatography on
silica gel (petroleum ether/EtOAc, 1:2) to yield 5 (10.2 mg, 68%) as a
colorless oil.
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This work was supported by grants from the National
Natural Science Foundation of China (21172153), the
Sichuan Science and Technology Program (2019YJ0032)
and ‘‘the Fundamental Research Funds for the Central
Universities”. We thank the Comprehensive Training
Platform of Specialized Laboratory, College of Chemistry,
Sichuan University, for spectral data measurement.
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European Journal of Organic Chemistry
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Entry for the Table of Contents
Anhydrogabosine synthesis
Four anhydrogabosines, (+)-epoxydon, (–)-phyllostine, (–)-RKTS 33 and (–)-parasitenone, are synthesized from δ-D-gluconolactone
via two new approaches, which both feature selective sulfonylation and oxirane ring closure on the polyoxygenated aldol cyclization
products.
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