Toward the Total Synthesis of Scabrosins: Synthesis of a Desulfur-scabrosin Skeleton and Its Stereoisomers

Article abstract of DOI:10.1021/acs.joc.9b00015

The enantioselective synthesis of a desulfur-scabrosin skeleton was reported. The synthesis began from 3-(hydroxymethyl)phenol, and key steps include asymmetric nucleophilic epoxidation, a Mitsunobu reaction using a sulfonamide as the nucleophile, the con

Full text of DOI:10.1021/acs.joc.9b00015

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Note
Towards the Total Synthesis of Scabrosins: Synthesis
of Desulfur-scabrosins Skeleton and Its Stereoisomers
Yuyin Liu, Zhipeng Wang, Sreenivas Banne, Jian Guo, and Yun He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00015 • Publication Date (Web): 22 Mar 2019
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Towards the Total Synthesis of Scabrosins: Synthesis
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of Desulfur-scabrosins Skeleton and Its Stereoisomers
9
Yuyin Liu, Zhi-Peng Wang, Sreenivas Banne, Jian Guo,* and Yun He*
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Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P.R. China.
E-mail: jian.guo@cqu.edu.cn; yun.he@cqu.edu.cn
O
O
O
O
H
H
H
N
O
OH
R2
O
N
N
S
R1
S
HO
N
O
O
HO
H
H
H
O
O
O
OH
O
R1 = CH3, or C3H7; R2 = CH3, C3H7, or C5H11
scabrosins
Abstract: The enantioselective synthesis of desulfur-scabrosins skeleton was reported. The
synthesis began from 3-(hydroxymethyl)phenol and key steps include asymmetric nucleophilic
epoxidation, Mitsunobu reaction using a sulfonamide as the nucleophile, the construction of
pyrrolidine ring by intramolecular nucleophilic substitution and inversion of configuration through
base-induced keto-enol isomerization. Additionally, two isomers of the carbon skeleton were also
obtained via an alternative ring-closing strategy.
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The epidithiodiketopiperazine natural products (ETPs) are a large family of fungal metabolites,
and more than 100 ETPs belonging to nearly twenty distinct subgroups have been isolated.1 Due to
their unique structures and potent biological activities, they have attracted considerable interests
from synthetic chemists and pharmacologists.2 However, relatively few total syntheses of ETPs
have succeeded despite decades of efforts. The scarcity of these compounds has hampered their
further profiling and applications.
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Scabrosins, a special subgroup of ETPs (Figure 1, 1-5), were initially isolated in 19783 and their
final structures were revised on the basis of 2D NMR and X-ray structural analysis in 1999.4 They
are the sole subgroup of ETPs isolated from lichens and the sole subgroup among all natural ETPs
possessing the epoxy groups. Different members of scabrosins possess the same core carbon
skeleton and different side chains. This skeleton contains two C2 symmetrical functionalized epoxy
cyclohexenes with five distinct stereogenic centers. They exhibited not only potent cytotoxic
activity in vitro (compound 2 against murine leukemia P388: IC50 = 16 nM; human breast MCF7:
IC50 = 1 nM), but also significant antineoplastic activity in vivo.5 Although scabrosins have been
known for decades and shown attractive prospects as anticancer agents, their total synthesis has yet
to be reported. The main challenge lies in the construction of dense-functionality core skeleton with
sensitive epoxy groups, and the introduction of the epidisulfide. Some efforts have been directed
toward the efficient construction of the multi-functionality and multi-stereocenter carbon skeletons,6
but just several simplified skeletons have been finished in those work, such as the structures of 66a
and 76b (Figure 1). As part of our efforts to study biologically active natural and designed products,7
we report the progress of our synthetic efforts towards scabrosins, which have culminated
enantioselective synthesis of the carbon skeleton of scabrosins with all functional groups except the
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disulfide bridge.
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O
R1
R2
O
H
O
1
2
-CH3
-CH3
-CH3
O
N
R2
S
-C3H7
S
R1
N
O
O
3
4
-C3H7 -C3H7
-CH3 -C5H11
-C3H7 -C5H11
H
O
9
O
1-5
Scabrosins
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O
O
H
H
N
H
OH
OAc
BnO
N
N
N
OBn
HO
AcO
H
H
H
O
O
6
7
Figure 1. Scabrosins and reported simplified core skeleton.
Scheme 1. Retrosynthetic analysis.
Scabrosins
Sulfenylation
O
O
1
H
N
H
3
2
OR3
CO2Me
4
5
N
6
NH
H
R3O
9
R3O
7
8
H
H
O
O
O
8
9
Strategy I
Strategy II
CO2Me
NHBoc
Br
CO2Me
NSO2Ph
TIPSO
O
TBSO
H
O
O
10
14
Br
O
OTBS
OH
I
CO2Me
NHBoc
CO2Me
TBSO
TIPSO
+
+
O
PhO2SHN
O
O
16
11
12
15
OMe
Br
HO
OH
17
OH
13
As shown in the retrosynthetic analysis (Scheme 1), the symmetrical carbon skeleton 8 could be
disconnected to monomer 9, which we plan to synthesize by first constructing the epoxycyclohexene
moiety and then building the fused pyrrolidine ring. In respect of constructing the epoxycyclohexene
moiety, it was expected an early- stage enantioselective installation of epoxy group could well direct
the stereochemistry of following reactions. The ring-closing step of the pyrrolidine moiety could be
realized by the formation of the C9-N bond through reductive amination (Strategy I) or the
formation of the C2-C3 bond through intramolecular nucleophilic substitution (Strategy II). In
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Strategy I, compound 10 could be prepared by Negishi cross-coupling between iodide 11 derived
from L-serine methyl ester and epoxycyclohexene 12, which could be prepared from commercially
available phenol 13. Alternatively, according to Strategy II, compound 14 could be prepared by the
Mitsunobu reaction between glycine derivatives 15 and epoxycyclohexene 16, which could be
derived from 3-(hydroxymethyl)phenol 17 through several steps including hypervalent iodine-
mediated dearomatization, asymmetric nucleophilic epoxidation, etc.
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The attempted synthesis of monomer 9 was initiated according to Strategy I. Epoxyketone 18 was
enantioselectively prepared from 3-bromo-4-methoxyphenol (13),8 and then reduced with Super-
Hydride to afford a syn-epoxyquinol followed by protection with TBS group to furnish silyl ether
12 (Scheme 2). Iodide 119 was transformed to organozinc reagent under Zn/1,2-
dibromoethane/TMSCl conditions, which reacted with 12 in the presence of Pd2(dba)3 in DMF10 to
provide the desired Negishi cross-coupling product 19. Selective deprotection of the cyclic ketal in
the presence of TBS group in 19 led to epoxy enone 10. Removal of Boc in 10 using TFA and
subsequent reductive amination produced monomer 9a exclusively. To our surprise and
disappointment, the configuration of the newly formed chiral center at C9 was not the desired as
determined by extensive NOE analysis. Huge efforts were made to establish the correct
stereochemistry at C9 by using various reducing reagents and conditions, but all gave the 9a and
the desired 9a’ was not isolated. Since all substituted groups in 20 face the same direction, it might
be the collective steric hindrance that forced the reducing reagents to approach the imine from the
undesired face exclusively.
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Scheme 2. Synthesis of monomer 9a.
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9
LiEt3BH
CO2Me
I
THF, -78 °C
98%
O
O
O
O
O
O
Br
Br
MeO2C
BocHN
11
1. Zn,
NHBoc
O
O
O
TBSCl
Imid, DMF
2. CuBr·SMe2,
Pd2(dba)3,
P(o-tol)3, 67%
O
OTBS
OTBS
19
18
12
10
11
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O
CO2Me
MeO2C
BocHN
clay K10
90%
TFA
O
N
TBSO
OTBS
O
10
20
1
H
H
NaBH(OAc)3
AcOH
2
CO2Me
H
4
3
5
2 steps
71%
6
9
NH
TBSO
8
H
7
O
9a
NOE correlation
Energy minimization model
20
of
by Chem3D
H
H
CO2Me
H
NH
TBSO
H
O
9a'
Since all efforts failed, we sought for an alternative strategy to access 9, in which the C9-N bond
with the correct stereochemistry at C9 could be first constructed, and then pyrrolidine ring could be
synthesized by forming the C2-C3 bond (Strategy II, Scheme 1). As shown in Scheme 3, the
alternative synthesis of 9 commenced with constructing epoxycyclohexene intermediate 16 starting
from commercially available phenol 17. The primary hydroxyl group in 17 was protected with TBS
group, followed by PhI(OAc)2-mediated dearomatization to afford dimethylketal 22.
.
Transketalization of 22 with 1,3-propanediol using BF3 Et2O as catalyst provided 1,3-dioxane 23,
which was a good substrate for the next step, tartrate-mediated asymmetric nucleophilic epoxidation
developed by Porco et al.11 Under a condition similar to Porco’s, epoxy ketone 24 was produced in
69% yield and 91% ee. It was proved that the stereochemistry of following reactions could well
controlled by the new-installed epoxy group in 24. Reduction of 24 with Super-Hydride followed
by TIPS protection of the resulting secondary hydroxyl group afforded the protected syn-epoxy
cyclohexenone derivative 25 as a single diastereomer. Deprotection of ketal in 25 under the
condition of Clay K10/DCM proceeded smoothly, leading to ketone 26. Reduction of the carbonyl
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in 26 gave epoxycyclohexene alcohol 16. Mitsunobu reaction between 16 and 15 led to amino
epoxide 27, which proceeded through SN2 mechanism and would construct the desired absolute
configuration of the carbon that corresponds to the C9 in 9. Selective deprotection of the TBS group
in 27 quantitatively and subsequent bromination of the resulting primary hydroxyl group led to the
ring-closing precursor 14. We then systematically examined the annulation conditions and found
that bases and solvents had profound influences on the cyclization reaction (Table 1). Neither
acetonitrile nor tetrahydrofuran was a suitable solvent for this reaction (entries1-3).
Dimethylformamide performed best (entries 4-6) and resulted in monomer 28 in the yield of 70%
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o
when used in combination with KHMDS at -60 C. However, NOE studies suggested that the
configuration at C2 was opposite to that of the natural scabrosins. This could be easily understood,
as the conformation of enolate ion 14’ is more stable than that of 14’’ during cyclization process,
which resulted in 28, but not 28’ (Figure 2). Though 28 has the opposite configurations at C2, we
speculated its configuration could be reversed through base-induced keto-enol isomerization at the
later stage.
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Scheme 3. Synthesis of monomer 28.
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Imidazole
TBSCl
DMF
O
O
PhI(AcO)2
MeOH
HO
TBSO
TBSO
65%
86%
OH
17
OH
21
O
22
9
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Ph3COOH
NaHMDS
L-DIPT
1) LiBH(Et)3
THF, -78 ºC
OH OH
O
O
O
O
BF3.Et2O
TBSO
TBSO
O
2) Imidazole
TIPSCl
90%, 2 steps
69%
DME
69%
O
O
23
24
O
TBSO
OH
O
O
O
LiBH(Et)3
THF, -78 ºC
TBSO
Clay K10
DCM
O
O
TBSO
89%
88%
OTIPS
26
OTIPS
OTIPS
25
16
Br
TBSO
CO2Me
PhO2SHN
15
CO2Me
CO2Me
1) CH3CN/
0.1 N HCl
PPh3, DIAD
TIPSO
NSO2Ph
TIPSO
NSO2Ph
2) MsCl, Et3N,
H
H
91%
LiBr
O
O
H
91%, 2 steps
14
27
H
CO2Me
H
KHMDS
DMF, -60 ºC
NSO2Ph
TIPSO
70%
H
O
NOE correlation
28
Table 1. Optimization of Cyclization Conditions.a
Br
CO2Me
H
CO2Me
NSO2Ph
TIPSO
NSO2Ph
TIPSO
H
H
O
O
14
28
Entry Conditions
Yield [%]b
no reaction
20%
1
2
3
4
5
6
CH3CN, DBU, 0 oC
THF, KHMDS, -78 oC
THF, KHMDS, -40 to 0 oC decomposed
DMF, K2CO3, r.t.c
DMF, Cs2CO3, r.t.
DMF, KHMDS, -60 oC
40%
47%
70%
aAll reactions were carried out on a 0.2 mmol scale in
8.0 mL solvent for 6 h. bIsolated yields. cOver 24 h.
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H
-O
H
OMe
H
Br
H
Br
OMe
N
N
R
O-
R
14''
14'
7
8
CO2Me
H
CO2Me
H
9
NSO2Ph
NSO2Ph
TIPSO
TIPSO
H
H
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O
O
28
28'
Figure 2. Cyclization pathways for 14.
With key monomers 9a and 28 in hand, dimerization to form the carbon skeleton of scabrosins
was explored. Firstly, saponification of the ester 9a with lithium hydroxide afforded crude
carboxylic acid 9a’’, which was directly dimerized to produce 8a in 67% under the classic amide
coupling condition
(HATU/DIPEA). Similarly, deprotection of benzenesulfonyl group in
monomer 28 under the condition of Mg/MeOH/ultrasound, followed by saponification afforded
crude carboxylic acid 9b’, which was again directly dimerized to give 8b in the yield of 85% under
the same amide coupling condition. The absolute configuration of 8b was unequivocally confirmed
by single-crystal X-ray analysis (Scheme 4).12 It has been proved that the dimer was too sensitive
to survive under base conditions, even in the presence of TBAF. For the successful deprotection of
silyl group in 8b, the condition of TBAF coordinated with AcOH was applied, which led to desulfur-
scabrosins skeleton stereoisomer 8b’ in nearly quantitative yield. After the further screening of
conditions, it was found that 8b was stable under the condition of NaOMe/MeOH, and as expected
could be transformed into the thermodynamically more stable product 8c with the reversed
configuration at C2 and C2’ through base-induced keto-enol isomerization, which was verified by
NOE correlation analysis. Finally, desilylation of 8c under the same condition as above resulted in
the desulfur-scabrosins skeleton 8c’. Then stereoselective installation of the disulfide bridge was
explored. We attempted to use bis(pyridine)-silver(I) permanganate as the oxidant to introduce
dihydroxyl which would be transferred to the disulfide bridge under strong acid conditions or K. C.
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Nicolaou’s method which used NaHMDS, KHMDS or LiHMDS as bases and S8 as sulfur
resource.13 Unfortunately, all efforts resulted in decomposition of 8c or 8c’.
8
9
In conclusion, we have accomplished the enantioselective synthesis of the desulfur-scabrosins
skeleton . It was proved that an enantioselective installation of the epoxy group at early stage could
control the stereochemistry well during the synthesis of epoxycyclohexene moiety. Pyrrolidine
moiety could be constructed effectively by the formation of the C2-C3 bond using intramolecular
nucleophilic substitution reaction, during which the undesired configuration of C2 was finally
revised after dimerization through base-induced keto-enol isomerization. Also, two desulfur-
scabrosins skeleton isomers were obtained via another pyrrolidine ring-closing strategy. Although
it was a pity that the final introduction of the disulfide bridge was unsuccessful because of the
sensitivity of the skeleton to both base and oxdizing conditions, the results presented here was
helpful in devising a next-generation synthetic strategy of scabrosins and also for syntheses of other
ETPs.
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Scheme 4. Deprotection and dimerization.
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I:
7
8
9
CO2Me
H
CO2H
H
HATU
DIPEA
LiOH
NH
NH
TBSO
TBSO
OTBS
2 steps
67%
H2O/THF
H
H
O
O
10
11
12
13
14
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22
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9a
9a''
O
H
O
H
N
N
TBSO
H
H
O
O
8a
II:
Mg
CO2Me
H
CO2Me
MeOH
Ultrasonic
H
LiOH
NSO2Ph
NH
TIPSO
TIPSO
85%
H2O/THF
H
H
O
O
28
9b
O
CO2H
H
O
H
H
OR
HATU
DIPEA
N
NH
TIPSO
N
H
2 steps, 85%
RO
H
H
O
O
9b'
O
8b
8b'
, R = TIPS
TBAF, AcOH
quant.
, R = OH
O
O
H
H
H
N
H
O
Py2AgMnO4
then H2S;
or KHMDS, S8
OR
NaOMe,
MeOH
N
RO
H
H
X
Scabrosins 1-5
H
90%
H
O
8c
TBAF, AcOH
80%
, R = TIPS
8c'
, R = H
NOE correlation
8b
ORTEP of
EXPERIMENTAL SECTION
General Information
All reactions were carried out under a nitrogen atmosphere with a dry solvent under anhydrous
conditions unless otherwise noted. Tetrahydrofuran (THF) and ethylene glycol dimethyl ether
(DME) were dried and distilled from sodium. Toluene, N, N-dimethylformamide (DMF) and
methylene chloride (DCM) were distilled from calcium hydride and stored under a nitrogen
atmosphere. Methanol (MeOH) was distilled from magnesium and stored under a nitrogen
atmosphere. Reagents were purchased at the highest commercial quality and used without further
purification unless otherwise stated. CDCl3 (+0.03% TMS) was used and purchased from
Cambridge Isotope Laboratories, Inc. Reactions were monitored by analytical thin-layer
chromatography (TLC) on Merck silica gel 60 F254 plates (0.25 mm), visualized by ultraviolet light
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and/ or by staining with cerium ammonium nitrate. 1H NMR spectra were obtained on an Agilent
400MR DD2 spectrometer at ambient temperature. Data were reported as follows: chemical shift
on the δ scale using residual proton solvent as internal standard [δ 7.26 (CDCl3)], multiplicity (br =
broad, s = singlet, d = doublet, t = triplet, q = quartet, m = multiplet), integration, and coupling
constant(s) in Hertz. 13C NMR spectra were obtained with proton decoupling on an Agilent 400MR
DD2 (100 MHz) spectrometer and were reported in ppm with residual solvent for internal standard
[δ 77 (CDCl3)]. The MS spectra were acquired on a 7 Tesla SolariX FT-ICR MS(Bruker Daltonics,
Bremen, Germany) with an ESI source. Melting point was determined by WRS-2A digital melting
point Apparatus. IR spectra were recorded on a Bruker 100 FT-IR spectrometer and are reported in
terms of frequency of absorption (cm–1). The oil bath is the heat source for reactions that require
heating. The yields refer to chromatographically and spectroscopically (1H and 13C NMR) pure
material. Energy-minimization of compound 20 was calculated using ChemBio3D (MM2) until the
root mean square became smaller than 0.001 kcal/mol/Å. Abbreviations: TBS = t-butyldimethylsilyl,
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TIPS
=
triisopropylsilyl, DIPEA
=
N,N-diisopropylethylamine, HATU
=
1-
[Bis(dimethylamino)methylene]-1H-1,2,3-triazolo[4,5-b] pyridinium 3-oxide hexafluoro-
phosphate, EtOAc = ethyl acetate, L-DIPT = diisopropyl-L-tartarte.
Preparation of Organozinc Reagent for Negishi-Coupling Reaction. Zinc powder (7.0 g, 107.02
mmol, 12.0 equiv) was added to dry DMF (8.0 mL) under nitrogen atmosphere and 1,2-
dibromoethane (507.6 mg, 2.7 mmol, 0.3 equiv) was added slowly via syringe. The mixture was
stirred at 60 oC for 30 min and then cooled to room temperature. Trimethyl chlorosilane (58.6 mg,
0.54 mmol, 0.06 equiv) was injected to the suspension and stirred for 30 min at room temperature.
Methyl (R)-2-((tert-butoxycarbonyl) amino)-3-iodopropanoate 11 (3.0 g, 8.99 mmol, 2.6 equiv)
dissolved in 5.0 mL dry DMF was dropped to the above mixture and stirred for another 4 h at room
temperature to afford the “solution of organozinc reagent”, which was directly used for the next
Negishi-Coupling reaction.
Methyl
(S)-2-((tert-butoxycarbonyl)amino)-3-((1S,5S,6R)-5-((tert-butyldimethylsilyl)oxy)-7-
oxaspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]dioxan]-3-en-3-yl)propanoate (19). To a solution of ketal
12 (1.3 g, 3.44 mmol, 1.0 equiv) in 10.0 mL DMF was added copper(I) bromide-dimethyl Sulfide
(72.0 mg, 0.34 mmol, 0.1 equiv), tris(dibenzylideneacetone) dipalladium(0) (634.0 mg, 0.69 mmol,
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0.2 equiv), and tris(2-methylphenyl) phosphine (1.3 g, 4.15 mmol, 1.2 equiv). Then the solution of
organozinc reagent was dropped to the above solution slowly at 50 oC within 1 h and the resulting
solution was stirred for another 11 h at the same temperature. The reaction mixture was then
quenched with saturated aqueous NH4Cl and extracted with EtOAc (three times). The combined
organic layers were washed with brine, dried over anhydrous sodium sulfate and filtered. The filtrate
was concentrated. The resulting residue was purified by flash chromatography (silica gel, petroleum
ether:EtOAc, 5:1 to 2:1) to give the compound 19 as a colorless oil (1.2 g, 67%). 19: Rf = 0.25 (silica
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gel, petroleum ether:EtOAc, 2:1); [α]D = +68.5 (c = 0.19, CHCl3); IR (film) Vmax: 3691, 2957,
2933, 1746, 1715, 1512, 1366, 1170, 1121,1071, 1001866 cm-1, 1H NMR (400 MHz, CDCl3) δ 5.34
(s, 2H), 4.58 (s, 1H), 4.33-4.23 (m, 3H), 4.06-3.98 (m, 3H), 3.72 (s, 3H), 3.42 (m, 1H), 2.63-2.55
(m, 2H), 2.26-2.14 (m, 1H), 1.50 (d, J = 13.2 Hz, 1H) 1.42 (s, 9H), 0.91 (s, 9H), 0.12 (s, 6H) ppm;
13C{1H} NMR (100 MHz, CDCl3,) δ 173.0, 155.4, 132.2, 129.1, 93.4, 79.5, 65.7, 61.2, 60.7, 54.3,
53.4, 52.0, 48.4, 31.4,28.3, 25.8, 24.6, 18.2, -4.6 ppm; HRMS (ESI): calcd for C24H41NO8SiNa+
[M+Na+] 522.2494, found 522.2490.
Methyl (S)-2-((tert-butoxycarbonyl)amino)-3-((1S,5S,6R)-5-((tert-butyldimethylsilyl)oxy)-2-oxo-
7-oxabicyclo[4.1.0]hept-3-en-3-yl)propanoate (10). To a solution of ketal 19 (100.0 mg, 0.20 mmol)
in DCM (5.0 mL) was added clay K10 (300.0 mg). The reaction mixture was stirred for 12 h at
room temperature and was filtered through a pad of Celite. The filtrate was concentrated in vacuum
and then purified by flash column chromatography (silica gel, petroleum ether:EtOAc, 5:1 to 2:1)
to give α,β-unsaturated ketone 10 as a white solid (80.0 mg, 90%). 10: m.p. 56-58 oC; Rf = 0.5 (silica
gel, petroleum ether:EtOAc,2;1 ); [α]D25 = -23.2 (c = 0.11, CHCl3); IR (film) Vmax: 3681, 2930, 2857,
1715, 1505, 1364, 1167, 1110 ; 1H NMR (400 MHz, CDCl3) δ 6.23 (s, 1H), 5.20 (d, J c= 7.1 Hz,
1H), 4.76 (s, 1H), 4.32 (d, J = 6.1 Hz, 1H), 3.74 (s, 3H), 3.66 (d, J = 3.3 Hz, 1H), 3.42 (d, J = 4.0
Hz, 1H), 2.72 (dd, J = 13.7, 4.7 Hz, 1H), 2.55 (dd, J = 13.8, 7.8 Hz, 1H), 1.42 (s, 9H), 0.95 (s, 9H),
0.18 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 194.0, 172.1, 155.0, 144.8, 130.6, 79.9, 66.2,
54.0, 53.1, 52.9, 52.4, 32.0, 28.3, 25.7, 18.2, -4.6 ppm; HRMS(ESI): calcd for C21H35NO7SiNa+
[M+Na+] 464.2075, found 464.2073.
Methyl
(1aR,2S,5S,6aR,6bR)-2-((tert-butyldimethylsilyl)oxy)-1a,4,5,6,6a,6b-hexahydro-2H-
oxireno[2,3-g]indole-5-carboxylate (9a). The α,β-unsaturated ketone 10 (57.0 mg, 0.13 mmol, 1.0
equiv) was dissolved in TFA/DCM (V/V = 0.4 mL/5.0 mL) at 0 oC and stirred at that temperature
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for 30 min. Then the reaction was quenched with saturated NaHCO3 solution and extracted by DCM
three times. The combined organic layers were washed with brine, dried over anhydrous Na2SO4
and filtered. The organic solvent was removed under vacuum. The resulting residue was dissolved
in dry DCM and NaBH(OAc)3 (54.7 mg, 0.26 mmol, 2.0 equiv) and acetic acid (15.5 mg, 0.26
mmol, 2.0 equiv) were added to the mixture at room temperature. The resulting mixture was stirred
for 3 h and then quenched by saturated NaHCO3 solution, extracted with DCM three times. The
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The
solvent was concentrated in vacuum and the resulting residue was purified by flash chromatography
(silica gel, petroleum ether:EtOAc, 3:1 to1:1) to give product 9a as a brown oil (30.0 mg, 71%). 9a:
Rf = 0.2 (silica gel, petroleum ether:EtOAc, 1:1); [α]D25 = 110.8 (c = 0.09, CHCl3); IR (film) Vmax:
3708, 3681, 3074, 2956, 2929, 2857, 1739, 1547, 1085, 1254, 875 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.22 (d, J = 1.9 Hz, 1H), 4.63 (s, 1H), 3.89-3.85 (m, 1H), 3.74 (s, 3H), 3.59-3.55 (m, 2H), 3.40
(dt, J = 4.2, 2.1 Hz, 1H), 2.84-2.78 (m, 1H), 2.52 (dd, J = 16.7, 7.8 Hz, 1H), 1.96 (s, 1H), 0.93 (s,
9H), 0.14 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 172.9, 136.0, 119.2, 67.7, 58.6, 58.1.
55.3, 52.3, 50.5, 35.0, 25.9, 18.3, -4.6 ppm; HRMS (ESI): calcd for C16H27NO4SiNa+ [M+Na+]
348.1602, found 348.1604.
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(2R,4aS,6aS,9R,11aS,13aS)-2,9-di((tert-butyldimethylsilyl)oxy) 2,3,4,4a,6a,7,9,10,11,11a,13a,14-
dodecahydro-6H,13H-dioxireno[1,2-a:4,5-a']diindole-6,13-dione (8a). A solution of lithium
hydroxide monohydrate (2.6 mg, 0.06 mmol, 2.0 equiv) in distilled water (1.5 mL) was added
dropwise to a solution of compound 9a (10.0 mg, 0.03 mmol) in THF (1.5 mL). After stirring at
room temperature for 30 min, the reaction was quenched with pH = 2.5 acidic buffer (preparing by
acidifying a 10% NaH2PO4 aqueous solution by KHSO4 until pH reaches 2.5). The solution was
extracted with EtOAc five times. The filtrate was concentrated in vacuum to get the crude product
9a’’ as a white solid, which was directly used without further purification. To a solution of 9a’’ in
dry DMF (5.0 mL) were added HATU (46.7 mg, 0.123 mmol, 4.0 equiv), DIPEA (16.0 mg, 0.123
mmol, 4.0 equiv) under nitrogen atmosphere at room temperature. After stirring at room temperature
for 3 h, the solvent was removed under reduced pressure and the residue was purified by flash
column chromatography (silica gel, petroleum ether:EtOAc, 3:1 to 1:1 ) to give the dimer as a white
solid (6 mg, 67%). 8a: m.p. 48-50 oC; Rf = 0.5 (silica gel, EtOAc,); [α]D25 = 123.8 (c = 0.1, CHCl3);
IR (film) Vmax: 3797,3731, 2926, 1752, 1517, 1089 cm-1; 1H NMR (400 MHz, CDCl3) δ 5.39 (d, J
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= 1.7 Hz, 1H), 4.61 (s, 1H), 4.41 (dd, J = 4.4, 1.6 Hz, 1H), 4.31 (s, 1H), 4.30-4.25 (m, 1H), 3.35-
3.33 (m, 1H), 3.26-3.20 (m, 1H), 2.91-2.84 (m, 1H), 0.92 (s, 9H), 0.13 (s, 6H) ppm; 13C{1H} NMR
(100 MHz, CDCl3) δ 167.6, 130.5, 123.0 67.6, 59.1, 58.7, 54.3, 48.4, 29.3, 25.8, 18.2, -4.7 ppm;
HRMS (ESI): calcd for C30H46N2O6Si2Na+ [M+Na+] 609.2787, found 609.2780.
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3-(((tert-Butyldimethylsilyl)oxy)methyl)phenol (21). To a stirred solution of 3-hydroxybenzyl
alcohol 17 (18.6 g, 149.83 mmol, 1.0 equiv) and imidazole (13.26 g, 194.78 mmol, 1.3 equiv) in
anhydrous DMF (130.0 mL) was added TBSCl (23.7 g, 157.32 mmol, dissolved in 30.0 mL DMF,
1.05 equiv) dropwise at 0 oC. The resulting mixture was stirred under nitrogen atmosphere at room
temperature for 30 min. The mixture was quenched with H2O and extracted with EtOAc. The
combined organic layers were washed with brine (50.0 mL), dried over anhydrous Na2SO4 and
filtered. The organic solvent was removed under vacuum. The resulting residue was purified by
flash chromatography (silica gel, petroleum ether:EtOAc, 10:1 to 5:1) to give phenol 21 as a brown
oil (30.6 g, 86%). 21: Rf = 0.3 (silica gel, petroleum ether:EtOAc, 10:1); IR (film) Vmax: 3473, 2955,
2857,1636, 837, 778 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.19 (t, J = 7.8 Hz, 1H), 6.86 (d, J = 7.6
Hz, 1H), 6.83 (s, 1H), 6.70 (dd, J = 8.0, 2.2 Hz, 1H), 4.91 (s, 1H), 4.70 (s, 2H), 0.94 (s, 9H), 0.10
(s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 155.7, 143.0, 129.4, 118.3, 114.0, 113.1, 64.8,
26.0, 18.5, -5.2 ppm; HRMS (ESI): calcd for C13H22O2SiNa+ [M+Na+] 261.1281, found 261.1272.
3-(((tert-Butyldimethylsilyl)oxy)methyl)-4,4-dimethoxycyclohexa-2,5-dien-1-one (22). To
a
suspension of iodobenzene diacetate (5.4 g, 16.76 mmol, 2.0 equiv) in 50.0 mL MeOH was added
a solution of phenol 21 (2.0 g, 8.38 mmol, 1.0 equiv) dissolved in 30.0 mL MeOH dropwise at 0 oC.
The mixture was stirred for 40 min at that temperature and then quenched with saturated aqueous
NaHCO3 and extracted with EtOAc three times. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4. The dried organic solution was filtered and the filtrate was
concentrated. The resulting residue was purified by flash chromatography (silica gel, petroleum
ether:EtOAc, 10:1 to 5:1) to afford the ketal 22 as a brown oil (1.6 g, 65%). 22: Rf = 0.3 (silica gel,
petroleum ether:EtOAc, 8:1); IR (film) Vmax: 2954, 2857, 1680, 1638, 1618, 1144, 1062, 839, 621
cm-1; 1H NMR (400 MHz, CDCl3) δ 6.71 (d, J = 10.3 Hz, 1H), 6.51 (q, J = 2.1 Hz, 1H), 6.37 (dd, J
= 10.3, 2.2 Hz, 1H), 4.37 (d, J = 2.1 Hz, 2H), 3.20 (s, 6H), 0.88 (s, 9H), 0.05 (s, 6H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 185.0, 158.2, 143.0, 132.4, 126.0, 95.2, 59.4, 51.0, 25.8, 18.2, -5.6 ppm;
HRMS (ESI): calcd for C15H26O4SiNa+ [M+Na+] 321.1493, found 321.1486.
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7-(((tert-Butyldimethylsilyl)oxy)methyl)-1,5-dioxaspiro[5.5]undeca-7,10-dien-9-one (23). To a
solution of ketal 22 (30.0 g, 100.52 mmol, 1.0 equiv) and propan-1,3-diol (30.6 g, 402.07 mmol,
4.0 equiv) in anhydrous DME (804.0 mL) was added boron trifluoride ethyl ether (12.8 mL, 105.54
mmol, 1.05 equiv) dropwise at 0 oC. The resulting mixture was stirred under nitrogen atmosphere
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at 0 C for 30 min. The resulting mixture was quenched with saturated aqueous NaHCO3 and
extracted with EtOAc three times. The combined organic layers were washed with brine, dried over
anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the resulting
residue was purified by flash chromatography (silica gel, petroleum ether:EtOAc, 10:1 to 5:1) to
o
afford ketone 23 as a faint yellow solid (21.5 g, 69%). 23: m.p. 69-71 C; Rf = 0.25 (silica gel,
petroleum ether:EtOAc, 10:1); IR (film) Vmax: 2955, 2930, 2884, 2857, 1682, 1643, 1619, 1113,
1036, 988, 839 cm-1 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 10.4 Hz, 1H), 6.35 (q, J = 2.1 Hz,
;
1H), 6.21 (dd, J = 10.6, 2.1 Hz, 1H), 4.58 (d, J = 2.2 Hz, 2H), 4.20 (td, J = 12.7, 2.4 Hz, 2H), 3.98-
3.94 (m, 2H), 2.26-2.13 (m, 1H), 1.52 (d, J = 13.6 Hz, 1H), 0.92 (s, 9H), 0.09 (s, 6H) ppm; 13C{1H}
NMR (100 MHz, CDCl3) δ 185.1, 159.5, 137.6, 128.3, 123.0, 90.3, 60.9, 59.5, 25.8, 24.9, 18.3, -5.5
ppm; HRMS (ESI): calcd for C16H26O4SiNa+ [M+Na+] 333.1493, found 333.1482.
(1S,6R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-7-oxaspiro[bicyclo[4.1.0]heptane-2,2'-[1,3]
dioxan]-3-en-5-one (24). A solution of Ph3COOH (17.8 g, 64.42 mmol, dissolved in 159.0 mL dry
toluene, 5.0 equiv) was added to a round flask with molecular sieve (4 Å, powder) at nitrogen
atmosphere and stirred for 15 min at room temperature. NaHMDS (2 N, 51.54 mmol, 25.8 mL, 4.0
equiv) was dropped into the above mixture slowly and was stirred for 25 min at room temperature.
L-DIPT (6.0 g, 25.76 mmol, 2.0 equiv) in 16 mL dry toluene was added to the reaction mixture. The
reaction mixture was stirred for another 25 min, then cooled to -78 oC, and ketone 23 (4.0 g, 12.88
mmol, dissolved in 15 mL dry toluene, 1.0 equiv) was dropped to the mixture slowly. The solution
was stirred at -55 oC for 48 h. The reaction was quenched with saturated aqueous NH4Cl solution
and extracted with EtOAc three times. The combined organic layers were washed with brine, dried
over anhydrous Na2SO4 and filtered. The solvent was removed under reduced pressure and the
resulting residue was purified by flash chromatography (silica gel, petroleum ether:acetone, 10:1 to
5:1) to give epoxide 24 as colorless oil product ( 2.87 g, 69%, 91% ee). 24: Rf = 0.5 (silica gel,
petroleum ether:acetone, 5:1); [α]D25 = +138.7 (c = 0.08, CHCl3); IR (film) Vmax: 2955, 2930, 2885,
2857, 1686, 1143, 1131, 1103, 840, 779 cm-1, 1H NMR (400 MHz, CDCl3) δ 6.13 (q, J = 2.1 Hz,
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1H), 4.45 (dd, J = 4.4, 2.1 Hz, 2H), 4.41 (d, J = 4.1 Hz, 1H), 4.36-4.28 (m, 2H), 4.08-3.99 (m, 2H),
3.48 (dd, J = 4.0, 2.1 Hz, 1H), 2.20-2.15 (m, 1H), 1.58 (d, J = 13.6 Hz, 1H), 0.89 (s, 9H), 0.06 (s,
6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 192.3, 157.9, 120.4, 93.1, 61.0, 60.8, 59.6, 53.0,
50.7, 25.8, 24.6, 18.2, -5.5 ppm; HRMS (ESI): calcd for C16H26O5SiNa+ [M+Na+] 349.1442, found
349.1429.
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tert-Butyldimethyl(((1S,5S,6R)-5-((triisopropylsilyl)oxy)-7-oxaspiro[bicyclo[4.1.0]heptane-2,2'-
[1,3]dioxan]-3-en-3-yl)methoxy)silane (25). Lithium triethylborohydride (22.0 mL, 1 N, 22.0 mmol,
1.2 equiv) was added to the solution of epoxide 24 (6.0 g, 18.37 mmol, 1.0 equiv) in dry THF (184.0
o
mL) dropwise at -78 C. The resulting mixture was stirred under nitrogen atmosphere at that
temperature for 30 min and then was quenched with saturated aqueous NH4Cl and extracted with
EtOAc. The combined organic layers were washed with brine, dried over anhydrous Na2SO4 and
filtered. The solvent was removed under reduced pressure and the resulting residue was directly
used for next step. The crude product and imidazole (5.0 g, 73.51 mmol, 4.0 equiv) were dissolved
in anhydrous DMF (90.0 mL). TIPSCl (4.6 g, 23.89 mmol, 1.3 equiv) was added to the above
o
solution at 50 C. The resulting mixture was stirred overnight under nitrogen atmosphere at that
temperature and then was quenched with saturated aqueous NH4Cl and extracted with EtOAc. The
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The
solvent was removed under reduced pressure and the residue was purified by flash column
chromatography (silica gel, petroleum ether:EtOAc, 10:1) to give the white solid 25 (8.0 g, 2 steps
90%). 25: m.p. 71-73 oC; Rf = 0.2 (silica gel, petroleum ether:EtOAc, 10:1); [α]D25 = +26.9 (c = 0.07,
CHCl3); IR (film) Vmax: 2948, 2866, 1688, 1129, 1102, 997, 838 cm-1, 1H NMR (400 MHz, CDCl3)
δ 5.72 (s, 1H), 4.73 (s, 1H), 4.29-4.22 (m, 4H), 4.07 (d, J = 4.2 Hz, 1H), 3.99-3.96 (m, 2H), 3.51 (s,
1H), 2.11 (ddd, J = 23.0, 15.3, 8.9 Hz, 1H), 1.50 (d, J = 13.2 Hz, 1H), 1.10 (s, 18H), 1.08 (s, 3H),
0.91 (d, J = 7.6 Hz, 9H), 0.05 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 136.0, 123.1, 94.0,
65.8, 61.1, 60.4, 59.5, 54.7, 48.6, 25.9, 24.9, 18.2, 18.0, 12.3, -5.5 ppm; HRMS (ESI): calcd for
C25H48O5Si2Na+ [M+Na+] 507.2933, found 507.2910.
(1S,5S,6R)-3-(((tert-Butyldimethylsilyl)oxy)methyl)-5-((triisopropylsilyl)oxy)-7-oxabicyclo [4.1.
0]hept-3-en-2-one (26). To a solution of compound 25 (100.0 mg, 0.21 mmol) in DCM (5.0 mL)
was added clay K10 (300.0 mg). The resulting mixture was stirred for 12 h at room temperature and
then the solution was filtered through a pad of Celite. The filtrate was concentrated in vacuum and
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then purified by flash column chromatography (silica gel, petroleum ether:EtOAc, 20:1 to 10:1) to
give α,β-unsaturated ketone 26 as a colorless oil (86.0 mg, 88%). 26: Rf = 0.5 (silica gel, petroleum
ether:EtOAc, 10:1); [α]D25 = +38 (c = 0.05, CHCl3); IR (film) Vmax: 2929, 2866, 1684, 1618, 1324,
1112, 920 cm-1; 1H NMR (400 MHz, CDCl3) δ 6.56-6.54 (m, 1H), 4.91-4.90 (m, 1H), 4.46-4.41 (m,
1H), 4.18 (dt, J = 15.8, 2.0 Hz, 1H), 3.75 (dd, J = 6.6, 2.8 Hz, 1H), 3.40 (d, J = 4.0 Hz, 1H), 1.13
(s, 18 H), 1.12 (s, 3 H), 0.90 (s, 9H), 0.06 (d, J = 2.2 Hz, 6H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 193.3, 139.8, 134.2, 66.2, 59.2, 54.1, 53.2, 25.8, 18.1, 18.0, 12.2, -5.6 ppm; HRMS (ESI):
calcd for C22H42O4Si2Na+ [M+Na+] 449.2514, found 449.2501.
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(1R,2R,5S,6R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((triisopropylsilyl)oxy)-7-oxabicyclo
[4.1.0]hept-3-en-2-ol (16). To a solution of α,β-unsaturated ketone 26 (9.0 g, 20.94 mmol, 1.0 equiv)
in anhydrous THF (105.0 mL) was added lithium triethylborohydride (25.1 mL, 1 N in THF, 25.13
mmol, 1.2 equiv) dropwise at -78 oC. The resulting mixture was stirred under nitrogen atmosphere
at that temperature for 30 min and then was quenched with saturated aqueous NaHCO3 and extracted
with EtOAc three times. The combined organic layers were washed with brine, dried over anhydrous
Na2SO4 and filtered. The solvent was removed under vacuum and the resulting residue was purified
by flash chromatography (silica gel, petroleum ether:EtOAc, 10:1 to 8:1) to give alcohol 16 as a
25
white solid (8.0 g, 89%). 16: m.p. 59-61 oC; Rf = 0.4 (silica gel, petroleum ether:EtOAc, 6:1); [α]D
= +4.5 (c = 0.07, CHCl3); IR (film) Vmax: 3551, 3476, 3414, 2945, 2866, 1618, 1159, 837 cm-1; 1H
NMR (400 MHz, CDCl3) δ 5.53 (s, 1H), 4.64 (d, J = 1.3 Hz, 1H,), 4.39 (d, J = 9.3 Hz, 1H), 4.29 (d,
J = 13.6 Hz, 1H), 4.20 (d, J = 13.6 Hz, 1H), 3.54 (s, 2H), 2.38 (d, J = 9.6 Hz, 1H), 1.11 (s, 18H),
1.09 (s, 3H) 0.90 (s, 9H), 0.07 (s, 6H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 135.7, 122.8, 66.1,
65.7, 63.6, 55.6, 54.8, 25.8, 18.2, 18.0, 12.3, -5.5 ppm; HRMS (ESI): calcd for C22H44O4Si2Na+
[M+Na+] 451.2670, found 451.2658.
Methyl N-((1R,2S,5S,6R)-3-(((tert-butyldimethylsilyl)oxy)methyl)-5-((triisopropylsilyl)oxy)-7-
oxabicyclo[4.1.0]hept-3-en-2-yl)-N-(phenylsulfonyl)glycinate (27). To a solution of alcohol 16
(142.0 mg, 0.33 mmol, 1.0 equiv), compound 15 (91.7 mg, 0.40 mmol, 1.2 equiv) and triphenyl
phosphine (130.0 mg, 0.49 mmol, 1.5 equiv) in anhydrous THF (6.6 mL) was added DIAD (100.0
mg, 0.49 mmol, 1.5 equiv) dropwise at 0 oC. The resulting mixture was stirred for 40 min at room
temperature. The mixture was quenched by water and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was
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concentrated in vacuum and the resulting residue was purified by flash chromatography (silica gel,
petroleum ether:EtOAc, 15:1 to 5:1) to give product 27 as a white solid (192.0 mg, 91%). 27: m.p.
66-67; Rf = 0.5 (silica gel, petroleum ether:EtOAc, 5:1); [α]D25 = +36.2 (c = 0.06, CHCl3); IR (film)
Vmax: 3553, 3477, 3414, 1759, 1637, 1618, 618 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.94 (d, J = 7.5
Hz, 2H), 7.64-7.60 (m, 1H), 7.54 (t, J = 7.5 Hz, 2H), 5.78 (s, 1H), 4.60 (s, 1H), 4.45 (s, 1H), 3.90
(q, J = 17.9 Hz, 2H), 3.66 (s, 3H), 3.58 (d, J = 14.9 Hz, 1H), 3.49 (d, J = 14.8 Hz, 1H), 3.34 (d, J =
8.4 Hz, 2H), 1.08 (s, 18H), 1.06 (s, 3H), 0.83 (s, 9H), -0.07 (s, 6H) ppm; 13C{1H} NMR (100 MHz,
CDCl3) δ 169.8, 139.8, 133.2, 131.0, 129.1, 127.6, 125.8, 65.8, 62.1, 54.6, 52.4, 52.3, 52.0, 44.9,
25.7, 18.1, 18.0, 12.2, -5.6 ppm; HRMS (ESI): calcd for C31H53NO7SSi2Na+ [M+Na+] 662.2979,
found 662.2974.
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Methyl N-((1R,2S,5S,6R)-3-(bromomethyl)-5-((triisopropylsilyl)oxy)-7-oxabicyclo[4.1.0]hept-3-
en-2-yl)-N-(phenylsulfonyl)glycinate (14). Compound 27 (503.0 mg, 0.79 mmol) was dissolved in
CH3CN/0.1 N HCl (33.0 mL, V/V= 30.0 mL/3.0 mL) and stirred for 6 h at room temperature. The
resulting mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The
combined organic layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The
organic solvent was removed under vacuum. The resulting residue was directly used without further
purification. To a solution of above crude product and triethylamine (397.6 mg, 3.93 mmol, 5.0
equiv) in anhydrous THF (6.0 mL) was added methane sulfonyl chloride (270.0 mg, 2.36 mmol, 3.0
equiv) at -20 oC and stirred for 30 min at this temperature. Lithium bromide (682.6 mg, 7.86 mmol,
o
10.0 equiv) was added to the reaction mixture and stirred for another 4 h at 0 C. The resulting
mixture was quenched with saturated aqueous NaHCO3 and extracted with EtOAc. The combined
organic layers were washed with brine, dried over sodium sulfate and filtered. The filtrate was
concentrated and the resulting residue was purified by flash chromatography (silica gel, petroleum
ether:EtOAc, 5:1 to 2:1) to give 14 as a white solid (462.6 mg, 91%). 14: m.p. 91-93 oC; Rf = 0.25
(silica gel, petroleum ether:EtOAc, 3:1); [α]D25 = +48.3 (c = 0.06, CHCl3); IR (film) Vmax: 2927,
2865, 1756, 1637, 1618, 1161, 1092, 687 cm-1; 1H NMR (400 MHz, CDCl3) δ 7.99 (d, J = 7.6 Hz,
2H), 7.64 (t, J = 7.3 Hz, 1H), 7.56 (t, J = 7.5 Hz, 2H), 5.76 (s, 1H), 4.82 (s, 1H), 4.61 (s, 1H), 4.02
(d, J = 18.1 Hz, 1H), 3.84 (d, J = 18.1 Hz, 1H), 3.67 (s, 3H), 3.60 (q, J = 10.7 Hz, 2H), 3.36 (s, 1H),
3.31 (s, 1H), 1.09 (s, 18H), 1.08 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 169.9, 139.5,
133.4, 132.5, 129.3, 127.7, 65.8, 54.0, 52.4, 52.1, 51.8, 45.4, 32.6, 18.0, 12.3 ppm; HRMS (ESI):
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calcd for C25H38BrNO6SSiNa+ [M+Na+] 610.1263, found 610.1265.
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Methyl (1aR,2S,5R,6aS,6bR)-6-(phenylsulfonyl)-2-((triisopropylsilyl)oxy)-1a,4,5,6,6a,6b-hex-
ahydro-2H-oxireno[2,3-g]indole-5-carboxylate (28). To a solution of compound 14 (318.0 mg,
0.54 mmol, 1.0 equiv) in anhydrous DMF (30 mL) was added KHMDS (1.1 mL, 1N, 1.1 mmol,
1.2 equiv) dropwise at -60 oC. The mixture was stirred at the temperature for 1 h and then was
quenched with saturated aqueous NH4Cl and extracted with EtOAc. The combined organic layers
were washed with brine, dried over anhydrous Na2SO4 and filtered. The solvent was removed
under reduced pressure and the residue was purified by flash column chromatography (silica gel,
petroleum ether:EtOAc, 10:1 to 3:1 ) to get the product 28 as a white solid (193.0 mg, 70%). 28:
m.p. 35-37 oC; Rf = 0.4 (silica gel, petroleum ether:EtOAc, 3:1); [α]D25 = -52.6 (c = 0.08, CHCl3);
IR (film) Vmax: 2945, 2892, 2866, 1758, 1356, 1205, 1171, 720, 603 cm-1; 1H NMR (400 MHz,
CDCl3) δ 7.92 (d, J = 7.9 Hz, 2H), 7.66 (t, J = 7.2 Hz, 1H), 7.57 (t, J = 7.5 Hz, 2H), 5.49 (s, 1H),
4.69 (s, 1H), 4.39 (d, J = 9.8 Hz, 1H), 4.12 (s, 1H), 3.82 (s, 1H), 3.73 (s, 3H), 3.43 (s, 1H), 2.38 (d,
J = 14.0 Hz, 1H), 2.27-2.21 (m, 1H), 1.09 (m, 21H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ
171.0, 136.0, 134.6, 133.6, 129.5, 127.9, 122.2, 64.2, 60.4, 58.2, 56.5, 54.0, 52.7, 34.7, 18.0, 12.3
ppm; HRMS (ESI): calcd for C25H37NO6SSiNa+ [M+Na+] 530.2003, found 530.2000.
Methyl (1aR,2S,5R,6aS,6bR)-2-((triisopropylsilyl)oxy)-1a,4,5,6,6a,6b-hexahydro-2H-oxireno [2,
3-g]indole-5-carboxylate (9b). To a solution of compound 28 (266.0 mg, 0.52 mmol, 1.0 equiv) in
anhydrous MeOH (30 mL) was added magnesium powder (127.0 mg, 5.24 mmol, 15.0 equiv) at
nitrogen atmosphere. The mixture was sonicated at room temperature for 40 min. Then the reaction
was quenched with saturated NH4Cl solution and extracted with EtOAc. The combined organic
layers were washed with brine, dried over anhydrous Na2SO4 and filtered. The filtrate was
concentrated and the residue was purified by flash column chromatography (silica gel, petroleum
ether:EtOAc, 2:1 to 1:1) to compound 9b as a colorless oil (164.0 mg, 85%). 9b: Rf = 0.3 (silica gel,
petroleum ether:EtOAc, 1:1); [α]D25 = +46.5 oC (c = 0.07, CHCl3); IR (film) Vmax: 3473, 3416, 2944,
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2892, 2866, 1741, 1637, 1619, 1090, 898, 883, 683 cm-1, H NMR (400 MHz, CDCl3) δ 5.37 (s,
1H), 4.70 (s, 1H), 3.97 (dd, J = 10.6, 4.6 Hz, 1H), 3.73 (s, 3H), 3.63 (s, 1H), 3.55 (d, J = 3.3 Hz,
1H), 3.41 (t, J = 3.6 Hz, 1H), 2.88-2.82 (m, 1H), 2.46 (dd, J = 15.6, 4.5 Hz, 1H), 2.19 (s, 1H), 1.10
(s, 18H), 1.09 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 174.1, 138.7, 118.1, 65.3, 57.0,
56.5, 55.3, 54.3, 52.3, 34.2, 18.0, 12.4 ppm; HRMS (ESI): calcd for C19H33NO4SiNa+ [M+Na+]
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390.2071, found 390.2056.
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(2R,4aR,6aR,9R,11aR,13aR)-2,9-di((triisopropylsilyl)oxy)-2,3,4,4a,6a,7,9,10,11,11a,13a,14-
dodecahydro-6H,13H-dioxireno[1,2-a:4,5-a']diindole-6,13-dione. (8b). To a solution of compound
9b (30.0 mg, 81.62 µmol, 1.0 equiv) in THF (1.4 mL) was added a solution of lithium hydroxide
(6.8 mg, 163.24 µmol, 2.0 equiv) in distilled water (1.4 mL). After stirring at room temperature for
15 min, the reaction was quenched with pH = 2.5 acidic buffer (preparing by acidifying a 10%
NaH2PO4 aqueous solution by KHSO4 until pH reached 2.5) till the pH reached about 6. The solution
was extracted with EtOAc for five times, dried over anhydrous Na2SO4 and filtered. The filtrate was
concentrated in vacuum to get the crude product 9b’, which was used for next reaction directly
without further purification. To a solution of crude product 9b’, HATU (124.0 mg, 326.47 µmol,
4.0 equiv) in dry DMF (3 mL) under nitrogen atmosphere was added DIPEA (42.0 mg, 326.47
µmol, 4.0 equiv). After stirring at room temperature for 3 h, the solvent was removed under reduced
pressure and the residue was purified by flash column chromatography (silica gel, petroleum
ether:EtOAc, 3:1 to 1:1 ) to give dimer 8b as a white solid (23.3 mg, 85%). 8b: m.p. 160-162 oC; Rf
= 0.5 (silica gel, petroleum ether:EtOAc, 1:1); [α]D25 = -44.4(c = 0.06, CHCl3); IR (film) Vmax: 3236,
2943, 2866, 1685, 1666, 1637, 1618, 1404, 1085, 1051, 882, 618 cm-1; 1H NMR (400 MHz, CDCl3)
δ 5.54 (s, 1H), 4.85 (d, J = 3.5 Hz, 1H), 4.67 (s, 1H), 4.29 (dd, J = 11.1, 2.9 Hz, 1H), 4.23 (s, 1H),
3.40 (t, J = 3.2 Hz, 1H), 3.15 (dd, J = 15.7, 2.7 Hz, 1H), 2.82-2.75 (m, 1H), 1.10 (s, 18H), 1.09 (s,
3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 166.7, 134.5, 121.2, 64.7, 59.5, 56.3, 54.7, 53.6,
29.1, 18.0, 12.3 ppm; HRMS (ESI): calcd for C36H58N2O6Si2Na+ [M+Na+] 693.3726, found
693.3739.
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(2R,4aR,6aR,9R,11aR,13aR)-2,9-dihydroxy-2,3,4,4a,6a,7,9,10,11,11a,13a,14-dodecahydro-
6H,13H-dioxireno[1,2-a:4,5-a']diindole-6,13-dione (8b’). Acetic acid (8.0 mg, 134.12 µmol, 3.0
equiv) was added dropwise to the solution of dimer 8b (30.0 mg, 44.70 µmol, 1.0 equiv) in THF (3
mL) at room temperature and then TBAF (35.0 mg, 1 N in THF, 134.12 µmol, 3.0 equiv) was added.
The reaction was stirred at room temperature for 1.5 h. The cation exchange resin (about 200 mg)
was added into the solution and stirred for another 1 h. The mixture was filtered and the filtrate was
concentrated under reduced pressure. The residue was purified by flash column chromatography
(silica gel, EtOAc:methanol, 1:0 to 10:1) to give diol as a wax solid (16.0 mg, 100%). 8b’: Rf = 0.3
(silica gel, EtOAc:methanol, 10:1); [α]D25 = -7.3 (c = 0.06, CHCl3); IR (film) Vmax: 3444, 1632, 1422,
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1025, 679, 543 cm-1; H NMR (400 MHz, CDCl3) δ 5.67-5.66 (m, 1H), 4.92 (d, J = 3.5 Hz, 1H),
4.47 (s, 1H), 4.31 (dd, J = 11.1, 3.3 Hz, 1H), 4.17 (s, 1H), 3.52 (t, J = 3.5 Hz, 1H), 3.19 (dd, J =
16.0, 3.2 Hz, 1H), 2.85-2.78 (m, 1H), 1.93 (d, 1H); ppm 13C{1H} NMR (100 MHz, CDCl3) δ 166.9,
135.6, 121.1, 63.0, 59.5, 56.2, 55.6, 54.3, 29.0 ppm; HRMS (ESI): calcd for C18H18N2O6Na+
[M+Na+] 381.1057, found 381.1045.
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(2R,4aR,6aS,9R,11aR,13aS)-2,9-di((triisopropylsilyl)oxy)-2,3,4,4a,6a,7,9,10,11,11a,13a,14-
dodecahydro-6H,13H-dioxireno[1,2-a:4,5-a']diindole-6,13-dione (8c). The dimer 8b (50 mg, 74.51
µmmol, 1.0 equiv) was dissolved in dry methanol (10 mL), and then sodium methoxide (45.0 µL,
30 wt% in methanol, 3.0 equiv) was injected into the solvent. The reaction was finished after stirred
for about 4h at room temperature and was quenched with saturated NH4Cl solution. The methanol
was removed under reduced pressure. The resulting solid was dissolved using EtOAc and water.
The mixture was extracted with EtOAc three times. The combined organic layers were washed with
brine, dried over anhydrous Na2SO4 and filtered. The filtrate was concentrated and the residue was
purified by flash column chromatography (silica gel, petroleum ether:EtOAc, 1:4 to 1:2 ) to give 8c
as a white solid (45.0 mg, 90%). 8c: m.p. 160-162 oC; Rf = 0.4 (silica gel, petroleum ether:EtOAc,
1:2); [α]D25 = -45.2 (c = 0.47, CHCl3); IR (film) Vmax, 3693, 2949, 2868, 1677, 1089, 882,682 cm-
1; 1H NMR (400 MHz, CDCl3) δ 5.69 (s, 1H), 4.71 (s, 1H), 4.39 (s, 1H), 4.29 (dd, J = 10.3, 6.9 Hz,
1H), 4.19 (d, J = 3.3 Hz, 1H), 3.38 (t, J = 3.5 Hz, 1H), 2.87-2.81 (m, 1H), 2.75 (dd, J = 14.0, 6.8
Hz, 1H), 1.12 (s, 18H), 1.10 (s, 3H) ppm; 13C{1H} NMR (100 MHz, CDCl3) δ 166.4, 135.2, 122.1,
64.4, 60.8, 55.7, 54.9, 53.8, 33.6, 18.0, 12.4 ppm; HRMS (ESI): calcd for C36H58N2O6Si2Na+
[M+Na+] 693.3726, found 693.3726.
(2R,4aR,6aS,9R,11aR,13aS)-2,9-dihydroxy-2,3,4,4a,6a,7,9,10,11,11a,13a,14-dodecahydro-
6H,13H-dioxireno[1,2-a:4,5-a']diindole-6,13-dione (8c’). Acetic acid (4 mg, 62.59 µmol, 3.0 equiv)
was added dropwise to the solution of dimer 8c (14 mg, 20.86 µmol, 1.0 equiv) in THF (2 mL) at
room temperature and then TBAF (62.59 µmol, 1 N in THF, 3.0 equiv) was added. After stirring at
room temperature for 3 h the solvent was removed under reduced pressure directly and the residue
was purified by flash column chromatography (silica gel, EtOAc:methanol, 1:0 to 10:1 ) to give diol
o
8c’ as a white solid (6.0 mg, 80%). 8c’: m.p. 258-260 C; Rf = 0.2 (silica gel, EtOAc:methanol,
10:1); [α]D25 = -76.9 (c = 0.23, DMSO); IR (film) Vmax; 3723, 3694,2955, 1738, 1521, 1462, 1018
1
cm-1, H NMR (400 MHz, DMSO) δ 5.66 (s, 1H), 5.02 (d, J = 7.1 Hz, 1H), 4.48 – 4.41 (m, 2H),
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4.19 (s, 1H), 3.94 (d, J = 3.5 Hz, 1H), 2.66-2.64 (m, , 2H); 13C{1H} NMR (100 MHz, DMSO) δ
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166.4, 135.2, 121.9, 61.9, 60.0, 55.9, 54.3, 53.3, 32.9 ppm; HRMS (ESI): calcd for C18H17N2O6 [M-
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H]- 357.1092, found 357.1095.
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Acknowledgements
We are grateful for the financial support from the National Natural Science Foundation of China
(Nos. 21572027, 21372267 and 81741169), the Fundamental Reasearch Funds for the Central
Universities: 2018CDYXYX0027. We would also like to thank Analytical and Testing Center of
Chongqing University for X-ray single crystal structural analyses.
Supporting Information:
This material is available free of charge via the Internet at http://pubs.acs.org.
1H and 13C NMR spectra of new compounds and X-ray Crystallographic Data.
REFERENCES
[1] For reviews of the chemistry and biology of ETP natural products, see: (a) Welch, T. R.;
Williams, R. M. Epidithiodioxopiperazines. Occurrence, Synthesis and Biogenesis. Nat. Prod.
Rep. 2014, 31, 1376-1404; (b) Iwasa, E.; Hamashima, Y.; Sodeoka, M.
Epipolythiodiketopiperazine Alkaloids: Total Syntheses and Biological Activities. Isr. J. Chem.
2011, 51, 420-433; (c) Borthwick, A. D. 2,5-Diketopiperazines: Synthesis, Reactions,
Medicinal Chemistry, and Bioactive Natural Products. Chem. Rev. 2012, 112, 3641-3716 (d)
Jiang, C.-S; Guo, Y.-W. Epipolythiodioxopiperazines from Fungi: Chemistry and Bioactivities.
Mini-Rev. Med. Chem. 2011, 11, 728-745. (e) Patron, N. J.; Waller, R. F.; Cozijnsen, A. J.;
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Straney, D. C.; Gardiner, D. M.; Nierman, W. C.; Howlett, B. J. Origin and Distribution of
Epipolythiodioxopiperazine (ETP) Gene Clusters in Filamentous Ascomycetes. BMC Evol.
Biol. 2007, 7, 174-188; (f) Waring, P.; Eichner, R. D.; Müllbacher, A. The Chemistry and
Biology of the Immunomodulating Agent Gliotoxin and Related Epipolythiodioxopiperazines.
Med. Res. Rev. 1988, 8, 499-524.
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43
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46
47
48
49
50
51
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53
54
55
56
57
58
59
60
[2] (a) Kim, J.; Movassaghi, M. Biogenetically-Inspired Total Synthesis of
Epidithiodiketopiperazines and Related Alkaloids. Acc. Chem. Res. 2015, 48, 1159-1171. (b)
Wang, H.; Regan, C. J.; Codelli, J. A.; Romanato, P.; Puchlopek-Dermenci, A. A.; Reisman,
S. E. Enantioselective Synthesis of (−)-Acetylapoaranotin. Org. Lett. 2017, 19, 1698-1701. (c)
Kurogi, T.; Okaya, S.; Fujiwara, H.; Okano, K; Tokuyama, H. Total Synthesis of (+) ‐
MPC1001B. Angew. Chem., Int. Ed. 2016, 55, 283-287. (d) Fujishiro, S.; Dodo, K.; Iwasa, E.;
Teng, Y.; Sohtome, Y.; Hamashima, Y.; Ito, A.; Yoshida, M.; Sodeoka, M.
Epidithiodiketopiperazine as a Pharmacophore for Protein Lysine Methyltransferase G9a
Inhibitors: Reducing Cytotoxicity by Structural Simplification. Bioorg. Med. Chem. Lett. 2013,
23, 733-736. (e) Dubey, R.; Levin, M. D.; Szabo, L. Z.; Laszlo, C. F.; Kushal, S.; Singh, J. B.;
Oh, P.; Schnitzer, J. E.; Olenyuk, B. Z. Suppression of Tumor Growth by Designed Dimeric
Epidithiodiketopiperazine Targeting Hypoxia-Inducible Transcription Factor Complex. J. Am.
Chem. Soc. 2013, 135, 4537-4549. (f) Tokuyama, H.; Yamada, K.; Fujiwara, H.; Sakata, J.;
Okano, K.; Sappan, M.; Isaka, M. Structural Determination of (−)-SCH 64874 and
Hirsutellomycin by Semisynthesis. J. Org. Chem. 2017, 82, 353-371.
[3] Begg, W. R.; Elix, J. A.; Jones, A. J. Nonacyclic Amides from Lchens of the Genus
Xanthoparmelia. Tetrahedron Lett. 1978, 19, 1047-1050.
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Page 24 of 26
1
2
3
4
5
6
7
8
9
[4] Ernst-Russell, M. A. Elix, J. A.; Chai, C. L. L.; Hockless, D. C. R.; Hurne, A. M.; Waring, P.
Structure Revision and Cytotoxic Activity of the Scabrosin Esters, Epidithiopiperazinediones
from the Lichen Xanthoparmelia Scabrosa. Aust. J. Chem. 1999, 52, 279-283.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
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40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[5] Williams, D. E.; Bombuwala, K.; Lobkovsky, E.; de Silva, E. D.; Karunatne, V.; Allen, T. M.;
Clardy, J.; Andersen, R. J. Ambewelamides A and B, Antineoplastic Epidithiapiperazinediones
Isolated from the Lichen Usnea sp. Tetrahedron Lett. 1998, 39, 9579-9582.
[6] (a) Zipfel, H. F.; Carreira, E. M. An Efficient Synthesis Strategy to the Core Structure of 6–5–
6–5–6-Membered Epipolythiodiketopiperazines. Org. Lett. 2014, 16, 2854-2857. (b)
Middleton, M. D.; Peppers, B. P.; Diver, S. T. Studies Directed toward the Synthesis of the
Scabrosins: Validation of a Tandem Enyne Metathesis Approach. Tetrahedron 2006, 62,
10528-10540. (c) Sun, F.; Metz, P. Synthesis and Application of an Enantiomerically Pure
Triflate Analogue of Microbially Derived 3-Halo-cis-1,2-dihydrocatechol Acetonides. Synlett
2013, 24, 457-460. (d) Zipfel, H. F.; Carreira, E. M. A Unified Strategy to 6–5–6–5–6‐
Membered Epipolythiodiketopiperazines: Studies towards the Total Synthesis of Scabrosin
Diacetate and Haematocin. Chem. Eur. J. 2015, 21, 12475-12480.
[7] (a) Lin, Z.; Xu, X.; Zhao, S.; Yang, X.; Guo, J.; Zhang, Q.; Jing, C.; Chen, S.; He, Y. Total
Synthesis and Antimicrobial Evaluation of Natural Albomycins against Clinical Pathogens.
Nat. Commun. 2018, 9, 3445-3452. (b) Banne, S.; Reddy, D. P.; Li, W.; Wang, C.; Guo, J.; He,
Y. A Unified Modular Synthetic Strategy for Dictyodendrins F, H, I, and G. Org. Lett. 2017,
19, 4996-4999. (c) Liu, Q.; Hu, P.; He, Y. Asymmetric Total Synthesis of Nannocystin A. J.
Org. Chem. 2017, 82, 9217-9222. (d) Reddy, D. P.; Zhang, N.; Yu, Z.; Wang, Z.; He, Y. Total
Synthesis of Kanamienamide. J. Org. Chem. 2017, 82, 11262-11268. (e) Qi, N.; Allu, S. R.;
ACS Paragon Plus Environment

Page 25 of 26
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1
2
3
4
5
6
7
8
9
Liu, Q.; Guo, J.; He, Y. Asymmetric Total Syntheses of Aetheramides and Their Stereoisomers:
Stereochemical Assignment of Aetheramides. Org. Lett. 2016, 18, 4718-4721. (f) Qi, N.; Wang,
Z.; Allu, S. R.; Liu, Q.; Guo, J.; He, Y. Total Syntheses of Anti-HIV Cyclodepsipeptides
Aetheramides A and B. J. Org. Chem. 2016, 81, 12466-12471. (g) Xu, B.; Yu, Z. M.; Xiang,
S. C.; Li, Y. S.; Zhang, S. L.; He, Y. Rational Design of Mitochondria-Targeted Pyruvate
Dehydrogenase Kinase 1 Inhibitors with Improved Selectivity and Antiproliferative Activity.
Eur. J. Med. Chem. 2018, 155, 275-284; h) Zhang, N.; Yu, Z. M.; Yang, X. H.; Zhou, Y.; Tang,
Q.; Hu, P.; Wang, J.; Zhang, S. L.; Wang, M. W.; He, Y. Difuran-Substituted Quinoxalines as
a Novel Class of PI3Kα H1047R Mutant Inhibitors: Synthesis, Biological Evaluation and
Structure-Activity Relationship. Eur. J. Med. Chem. 2018, 157, 37-49; i) Zhang, N.; Yu, Z.
M.; Yang, X. H.; Zhou, Y.; Wang, J.; Zhang, S. L.; Wang, M. W.; He, Y. Design, Synthesis,
Biological Evaluation and Structure-Activity Relationship of Sophoridine Derivatives bearing
Pyrrole or Indole Scaffold as Potential Antitumor Agents. Eur. J. Med. Chem. 2018, 157, 665-
682.
10
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17
18
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22
23
24
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42
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44
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50
51
52
53
54
55
56
57
58
59
60
[8] Lei, X.; Johnson, R. P.; Porco, J. A., Jr., Total Synthesis of the Ubiquitin‐Activating Enzyme
Inhibitor (+)‐Panepophenanthrin. Angew. Chem., Int. Ed. 2003, 42, 3913-3917.
[9] Fenster, E.; Fehl, C.; Aubé, J. Use of a Tandem Prins/Friedel–Crafts Reaction in the
Construction of the Indeno-Tetrahydropyridine Core of the Haouamine Alkaloids: Formal
Synthesis of (−)-Haouamine A. Org. Lett. 2011, 13, 2614-2617.
[10] Espejo, V. R.; Rainier, J. D. Total Synthesis of Kapakahine E and F. Org. Lett. 2010, 12, 2154-
2157.
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9
[11] Li, C.; Johnson, R. P.; Porco, J. A., Jr. Total Synthesis of the Quinone Epoxide Dimer (+)-
Torreyanic Acid: Application of a Biomimetic Oxidation/Electrocyclization/Diels−Alder
Dimerization Cascade. J. Am. Chem. Soc. 2003, 125, 5095-5106.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
[12] CCDC number for 13n: 1485461.
[13] a) Kim, J.; Ashenhurst, J. A.; Movassaghi, M. Total Synthesis of (+)-11,11'-Dideoxyverticillin
A. Science 2009, 324, 238-241; b) Nicolaou, K. C.; Giguere, D.; Totokotsopoulos S., Sun, Y.-P.
A Practical Sulfenylation of 2,5‐Diketopiperazines. Angew. Chem. Int. Ed. 2012, 51, 728-
732.
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