Asymmetric Total Synthesis of (-)-Pavidolide B via a Thiyl-Radical-Mediated [3 + 2] Annulation Reaction

Article abstract of DOI:10.1021/acs.joc.9b02230

The development of an efficient strategy for the asymmetric total synthesis of the bioactive marine natural product (-)-pavidolide B is described in detail. The development process and detours leading to the key thiyl-radical-mediated [3 + 2] annulation reaction, which constructed the central C ring with four contiguous stereogenic centers in one step, are depicted. Subsequently, the seven-membered D ring is constructed via a ring-closing metathesis reaction followed by a Rh(III)-catalyzed isomerization. This strategy enables the total synthesis of (-)-pavidolide B in the longest linear sequence of 10 steps.

Full text of DOI:10.1021/acs.joc.9b02230

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Article
Asymmetric Total Synthesis of (–)-Pavidolide B via
a Thiyl-Radical-Mediated [3+2] Annulation Reaction
Pengpeng Zhang, Yuan-He Li, Zhiming Yan, Jianxian Gong, and Zhen Yang
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b02230 • Publication Date (Web): 21 Nov 2019
Downloaded from pubs.acs.org on November 23, 2019
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The Journal of Organic Chemistry
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Asymmetric Total Synthesis of (–)-Pavidolide B via a
Thiyl-Radical-Mediated [3+2] Annulation Reaction
†
,‡
†
,† ,
,†,‡,
§
§
Pengpeng Zhang, Yuanhe Li , Zhiming Yan, Jianxian Gong,* and Zhen Yang,*
†Key Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen
Graduate School, Shenzhen 518055, China
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‡State Key Laboratory of Bioorganic Chemistry and Molecular Engineering of Ministry of Education and Beijing National
Laboratory for Molecular Science (BNLMS), College of Chemistry and the Peking University, Beijing 100871, China
§Laboratory for Marine Drugs and Bioproducts of Qingdao National Laboratory for Marine Science and Technology,
Qingdao 266237, China
RECEIVED DATE
Me
Me
Me
EtO
O
O
O
H
Me
Me
Me
5
PhSH, [Ir]
p-toluidine
4
5
11
EtO
EtO
D
4
11
A
H
C
C
Me
Me
Me
Me
Me
Me
H
H
blue LEDs
MeCN
O
EtO
MeO2C
14
H
B
MeO2C
O
O
O
O
O
O
dr > 20:1
pavidolide B
10 LLS
Mild visible-light conditions
Fully functionalized five-membered ring C
Two C-C bonds, two rings and four stereocenters
16% overall yield
300 mg synthesized
ABSTRACT: The development of an efficient strategy for the asymmetric total synthesis of the
bioactive marine natural product (–)-pavidolide B is described in detail. The development process and
detours leading to the key thiyl-radical-mediated [3+2] annulation reaction, which constructed the
central C ring with 4 contiguous stereogenic centers in one step, is depicted. Subsequently, the seven-
membered D ring is constructed via a ring-closing metathesis reaction followed by a Rh(III)-catalyzed
isomerization. This strategy enables the total synthesis of (–)-pavidolide B in a longest linear sequence
of 10 steps.
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INTRODUCTION
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The cembranoid family is one of the largest and most diverse marine metabolite families. To
date, hundreds of cembrane-based derivatives have been isolated from marine soft corals, particularly
of the genera Sinularia and Sarcophyton.1 In 2012, a structurally diverse set of cembranoids, namely,
pavidolides A–E (Figure 1), were isolated from the marine soft coral Sinularia pavida.2 A preliminary
biological study with a panel of tumor cell lines indicated that tetracyclic diterpenoid (–)-pavidolide B
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(1) shows selective inhibition against human promyelocytic leukemia cell line HL-60 (IC50 = 2.7
μ
g/mL).2 Structurally, (–)-pavidolide B (1) possesses an unprecedented highly rigid 6,5,7-tricarbocyclic
core, which includes a fully functionalized five-membered C-ring, seven contiguous stereocenters, and
a quaternary bridgehead carbon center. The stereocontrolled construction of such a highly functionalized
five-membered ring system with five contiguous stereogenic centers is the primary synthetic challenge
for the total synthesis of this natural product. Herein, we describe our efforts to develop a concise strategy
for the asymmetric total synthesis of (–)-pavidolide B (1),3a which was enabled by a thiyl-radical-
mediated intramolecular [3+2] annulation reaction of a vinylcyclopropane (VCP) under visible-light
irradiation. More recently, Ding and coworkers also realized the total synthesis of (–)-pavidolide B by
constructing the 6,5,7-tricarbocyclic core through a pinacol rearrangement3b and ring contraction
strategy3c respectively.
Me
Me
O
8
O
CO2Me
19
Me
H
3
Me
O
11
C
1
H
Me
Me
H
12
O
14
O
Me
20
O
Me
1
pavidolide B ( )
pavidolide A
CO2Me
Me
Me
Me
Me
OH
OH
O
O
Me
Me
H
H
H
Me
O
Me
HO
Me
HO
H
H
Me
Me
Me
Me
pavidolide D
Me
pavidolide E
pavidolide C
Figure 1. Structures of pavidolides A–E.
RESULTS AND DISCUSSION
Retrosynthetic Analysis of Pavidolide B (1)
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Given the concise and powerful features of the [3+2] annulation reaction of VCPs4 with alkenes
for the stereoselective construction of highly substituted cyclopentanoids, we envisaged applying this
reaction as the key disconnection strategy for the stereoselective construction of the 5-membered ring
core of pavidolide B (1). To get the correct stereochemistry at C4 and C13, the VCP part needs to
approach the enone from the top side, which is, however, hindered by the isopropyl group. To overcome
the steric effect of iPr group, the intermolecular [3+2] annulation reaction was designed as an
intramolecular reaction with an ester linker, where the stereochemistry of C14 controls the
stereoselectivity at C4 and C13.
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Scheme 1. Retrosynthetic Analysis of Pavidolide B (1)
RCM &
C=C migration
[3+2] annulation
Me
Ni-catalyzed
coupling Reaction
Me
Me
O
H
O
Me
O
H
Me
Me
H
5
RO
O
4
C
11
Me
Me
H
14
Me
Me
Me
13
H
O
H
EtO2C
H
O
O
O
Me
O
O
O
A
1
pavidolide B ( )
2
O
O
Me
Me
O
Me
4
Me
OH Me
Me
RO
Me
Me
3
6
(+)-carvone ( )
13
Me
5
14
11
+
O
CO2Et
EtO2C
O
Br
EtO2C CO2H
CO2Et
B
4
Mitsunobu Reaction
OR
+
Me
O
asymmetric
cyclopropanation
C
Me
H
5
Scheme 1 illustrates our retrosynthetic analysis. We envisioned that 1 could be made from
compound 2 via a ring-closing metathesis (RCM) reaction5 followed by a double-bond migration
reaction6. The compound 2, in turn, could be assembled via a Ni-catalyzed cross-coupling reaction7 of
an aldehyde derived from compound A. We expected that compound A bearing the core structure of the
five-membered ring could be generated directly from its corresponding VCP-tethered cyclohexanone
(B) through an intramolecular [3+2] annulation reaction described above. The correct stereochemistry
of C14 in substrate B could be made easily from alcohol 6 and acid C via a Mitsunobu reaction.
Enantiopure alcohol 6 could then be prepared stereoselectively from (+)-carvone (3), whereas acid C
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could be prepared from bromide 4 and aldehyde 5 via a reported protocol for organocatalyzed
asymmetric cyclopropanation8.
6
7
Model Study of the [3+2] Annulation Reaction
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With this proposed route in mind, we first conducted a model study to test the key reaction by
using 7 as a simplified substrate, which can be easily prepared in one step from known compounds9 (see
Supporting Information for details). In the beginning, we attempted Pd-catalyzed [3+2] cycloaddition
reaction4b,4e,10 with Pd(0) and various phosphine ligands (Table 1). When P(n-Bu)3 and dppf (1,1'-
bis(diphenylphosphino)ferrocene) were used as ligands, no desired product was observed (entries 1–2).
When dppe (1,2-bis(diphenylphosphino)ethane) ligand was used, a small amount of desired product 8
was detected (entry 3); however, most of the substrate decomposed, which may be due to the
coordination of Pd to the enone double bond followed by cleavage of the C–O bond. Lowering the
temperature prevented the decomposition of the starting material but no desired product was formed
(entry 4). To promote the selective coordination of Pd to the VCP double bond over the enone double
bond and probably reducing substrate decomposition, more hindered Trost ligand10 was used, but no
reaction occurred (entry 5).
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Table 1. Model Study of [3+2] the Annulation Reaction
O
Me
Me
O
Me
Me
Me
Me
conditions
11
H
O
O
MeO2C
CO2Me
O
O
11
7
8
8
ORTEP of
entry
conditions
temp
resulta
no reaction
decomposed
traceb
1
2
3
4
5
6
Pd2(dba)3·CHCl3, P(n-Bu)3, DCM
Pd2(dba)3·CHCl3, dppf, DCM
Pd2(dba)3·CHCl3, dppe, DCM
Pd2(dba)3·CHCl3, dppe, DCM
20 °C to reflux
30 °C
30 °C
10 °C
no reaction
no reaction
30%
Pd2(dba)3·CHCl3, Trost ligandc, DCM
PhSH, ABVNd, toluene
30 °C
80 °C
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8
PhSSPh, AIBN, sunlamp, toluene
PhSH, AIBN, toluene
50 °C
80 °C
23%
47%e
6
7
8
9
aIsolated yield; bReagents and conditions: 7 (0.5 mmol), solvent (0.05 M for substrate), catalyst (5 mol%), ligand (10 mol%),
h; cTrost ligand
under
a
nitrogen atmosphere for
3
=
(1R,2R)-(+)-1,2-diaminocyclohexane-N,N'-bis(2'-
diphenylphosphinobenzoyl); dAVBN = 2,2'-Azobis (2,4 dimethylvaleronitrile); eSlow addition of the mixture of PhSH (1.2
equiv) and AIBN (0.3 equiv) in toluene to the substrate.
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Facing the difficulty with Pd catalyzed cyclization methods, we turned our attention to thiyl-
radical mediated reactions. Fortunately, treating substrate 7 with PhSH and ABVN,11 we successfully
obtained the desired product 8 with 30% yield (entry 6). The relative stereochemistry of newly formed
4 stereocenters was confirmed to be consistent with that in natural product 1 by X-ray crystallography.
Modification of the procedure12 by slow addition of the mixture of PhSH and AIBN in toluene to the
solution of the substrate at 80 °C increased the yield of product 8 to 47% (entry 8). Subsequently, product
8 underwent Krapcho decarboxylation13 smoothly at 120 °C to give compound 9 in 77% yield (Scheme
2), which indicate the applicability of those reactions in total synthesis of pavidolide B.
To avoid the need of following high-temperature decarboxylation reaction, we investigated
whether the mono-ester substrate could also work in this [3+2] annulation reaction. Mono-ester 10 was
synthesized from simple starting materials14. However, under the similar reaction conditions (Scheme
2), only trace amounts of desired product 9 were detected, and further optimization of the reaction
conditions did not give better results. This poor yield may due to the decomposition of the highly reactive
radical intermediate from 10 without stabilization of the diester.
Scheme 2. Synthesis of Compound 9a
O
O
Me
Me
O
Me
Me
Me
Me
Me
Me
Me
a) LiCl, 120 oC
b) PhSH, AIBN
H
H
80 oC
DMSO, H2O
(77%)
H
MeO2C
O
toluene
O
O
O
O
O
8
9
10
aReagents and conditions: (a) LiCl (5.0 equiv), H2O (10.0 equiv), DMSO, 120 °C, 5 h, 77%; (b) PhSH (1.2 equiv), AIBN
(0.3 equiv), toluene, 80 °C, trace.
Preparation of Asymmetric Precursors
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The success of the model study with substrate 7 provided a basis for testing the viability of our
designed approach for the synthesis of 1. Our total synthesis began with the preparation of two
enantiopure fragments, 13 and 6 as shown in Scheme 3. The preparation of enantiopure alcohol 6
commenced from commercially available (+)-carvone (3), which was subjected to enone allylic
hydroxylation catalyzed by a copper-aluminum mixed oxide15 in the presence of oxygen in ethanol to
give alcohol 11 in 42% yield, followed by selective hydrogenation with Wilkinson’s catalyst16 to
selectively remove the terminal double bond in excellent yield.
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Scheme 3. Asymmetric Synthesis of Alcohol 6 and Acid 13a
O
O
O
a) Cu-Al Ox
b) RhCl(PPh3)3
(5 mol%),
Me
Me
Me
air, t-BuOK
Me
EtOH
(42%)
H2 (1 atm)
toluene, rt
(95%)
OH Me
11
OH Me
Me
3
6
(+)-carvone ( )
c)
Ph
Ph
CO2Et
d) CH(OEt)3
ethylene glycol
PTSA, CH2Cl2
N
OTMS
H
(20 mol%)
Br
CO2Et
4
EtO2C CO2H
EtO2C CO2Et
F
12
12
5
11
O
+
e) Me4NOH
i-PrOH/H2O
(65% in 2 steps)
Et3N, CHCl3
(R)
Me
(R)
Me
CHO
rt
CHO
O
Me
12
13
dr = 1:1
(79%)
5
dr = 11:1
ee = 88%
aReagents and conditions: (a) Cu–Al Ox (84 mg per mmol of carvone 3), air, t-BuOK (0.5 equiv), EtOH, rt, 36 h, 42%; (b)
RhCl(PPh3)3 (5 mol%), H2 (1 atm), toluene, rt, 14 h, 95%; (c) (S)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine F (20
mol%), 5 (1.2 equiv), Et3N (1.0 equiv), CHCl3, rt, 6 h, 79%; (d) CH(OEt)3 (1.5 equiv), ethylene glycol (2.0 equiv), PTSA
(0.1 equiv), CH2Cl2, rt, 2 h; (e) Me4NOH (1.1 equiv), i-PrOH/H2O = 10:1, rt, 12 h, 65% for two steps.
Aldehyde 12 was synthesized in 79% yield by following a reported protocol8, and then protected
with ethylene glycol in the presence of PTSA and CH(OEt)3 in CH2Cl2. The hydrolysis of the ethyl-ester
with Me4NOH in a mixed solvent of i-PrOH and H2O afforded mono-acids 13 in 80% overall yield as a
pair of diastereomers at C12 (13a:13b = 1:1). As the C12 stereogenic centre will be rebuilt in the
following [3+2] annulation reaction, we envisioned that this lack of diastereoselectivity would not affect
the asymmetric total synthesis of our final target.
The control of C5 stereochemistry in the [3+2] Annulation Reaction
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To verify our hypothesis, acids 13a (the stereochemistry of C12 was determined by the NOE-
NMR analysis of its reduced derivative 13a', see Supporting Information for details)19 and 13b were
separated and subjected to a typical Mitsunobu reaction20 with alcohol 6 in the presence of diethyl
azodicarboxylate (DEAD) and PPh3 in THF, respectively, providing 14a in 87% yield and 14b in 84%
yield (Scheme 4). Then the [3+2] annulation reaction was performed under the same conditions of model
study by treating 14a or 14b with thiophenol and AIBN at 80 °C. However, both reactions occurred
slowly in low yields. When we performed the reactions at a higher temperature of 120 °C, both 14a and
14b gave the same tricyclic product (15) in similar yields and diastereoselectivities (dr = 5:1). These
results confirmed that the lack of diastereoselectivity at C12 in precursors would not affect the following
[3+2] annulation reaction. Unfortunately, further X-ray crystallographic analysis of the major product
15 showed that the stereochemistry of C5 (R) was opposite to that of the natural product pavidolide B
(1).
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Scheme 4. [3+2] Annulation of Ethylene-Glycol-Protected C11-(R) Precursor 14
O
Me
Me
O
(R)
(a) PPh3
DEAD
(b) PhSH
AIBN
14
Me
Me
EtO2C CO2H
5
O
O
2
4
(S)
12
C
12
11
O
O
11
(R)
H
Me
Me
toluene
120 oC
(37%)
O
6
, THF
5
Me
14
EtO2C
EtO2C
O
(87%)
O
11
O
O
13a
(R)
5
O
15
(dr = 5:1)
14a
Me
HO
EtO2C
H
NOE
O
H
(S)
Me
O
O
13a'
15
ORTEP of
Me
Me
14
Me
O
(a) PPh3
DEAD
(b) PhSH
AIBN
(R)
EtO2C CO2H
5
O
O
2
O
O
Me
O
4
12
(R)
C
12
6
toluene
120 oC
(36%)
, THF
(84%)
11
11
(R)
EtO2C
H
Me
Me
O
5
11
Me
14
EtO2C
(R)
O
5
O
O
O
13b
15
(dr = 5:1)
14b
Me
aReagents and conditions: (a) PPh3 (2.0 equiv), DEAD (2.0 equiv), 6 (1.1 equiv), THF, 0 °C to rt, overnight; (b) PhSH (1.2
equiv), AIBN (0.3 equiv), toluene, 120 °C, 6 h.
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As shown in figure 2, compared with the stereoselectivity exhibited in the model study (product
8), radical cyclization with substrate 14 gave compound 15 as product, where the C5 stereochemistry
is inverted. We reasoned that the product might preferably form with the substitution on C5 anti to that
of C11. Although a thermodynamic analysis doesn’t guarantee the corresponding kinetic preference, we
do believe that similar interaction exists in the stereoselectivity-determining transition state. To gain
confidence in this analysis, computational studies were carried out at DSD-PBEP86-D3/def2-
TZVP//PBE0/def2-SV(P) level with SMD solvation in MeCN to evaluate the thermodynamic preference
of C5, C11 diastereomers. For products derived from compound 14, the undesired C5-(R) configuration
B is thermodynamically favored by 4.1 kJ/mol. On the contrary, if the stereogenic centre at C11 is
inverted (compound 14’), compound C with an (anti,syn)-configuration would be the
thermodynamically favored one over the (syn,anti)-product D by 6.2 kJ/mol. Based on conformational
search, in the most stable conformation of product D, the acetal group is forced to occupy the out-of-
plain carbon of the cyclopentane ring to minimize the steric interaction of the acetal group with the
lactone and alkenyl chain. According to the RDG analysis, this will increase the strain of the tricyclic
skeleton itself, causing the alkenyl chain to occupy the axial position of the cyclopentane envelope
conformation which sterically contacts the other part of the tricyclic skeleton. In product C, steric
repulsion between the alkenyl chain and the cis-methyl group positively contributes to the overall free
energy, albeit to a lesser extent. Thus, we decided to prepare the C11-(S) substrate and see whether it
would give the desired stereochemistry at C5. With this strategy, however, the stereochemistry of C11
will be opposite to that of the natural product, but we reasoned that C11, adjacent to a carbonyl group,
could be epimerized later.
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O
O
Me
Me
Me
Me
Me
Me
O
O
H
O
H
H
14
O
H
Me
Me
Me
(S)
(R)
RS
RS
5
O
O
11
O
O
Me
Me
Me
O
11
H
H
O
Me
Me
EtO2C
MeO2C
O
11
CO2Me
O
O
EtO2C
(R)
O
O
5
O
O
O
11
7
8
1
pavidolide B ( )
14
15
Me
O
O
O
O
Me
Me
O
Me
Me
Me
Me
O
H
O
H
O
O
H
(R)
(R)
Me
Me
Me
Me
(S)
(S)
O
O
5
O
O
5
O
O
5
O
O
5
O
+
+
11
11
11
11
H
Me
Me
Me
Me
Me
Me
MeO2C
MeO2C
O
O
MeO2C
MeO2C
MeO2C
MeO2C
11
11
O
O
O
O
Me
Me
(R)
(S)
O
O
O
O
O
O
A
B
C
D
14'
+5.7 kJ/mol
+1.7 kJ/mol
0 kJ/mol
+6.2 kJ/mol
Me 14
Me
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19
20
21
22
23
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45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
RDG analysis of C
RDG analysis of D
Figure 2. Different diastereoselectivity in model and real system, calculated thermodynamic
preference and RDG analysis for product with inversed stereochemistry at C11 .
C11-(S) substrate 17 was prepared by similar procedures using (R)-2-
(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine G as catalyst (Scheme 5). Meanwhile, dimethyl 2-
bromomalonate 16 was chosen instead of diethyl 2-bromomalonate to guarantee milder conditions for
the later decarboxylation13b. After screening of a series of protecting groups18, aldehyde 17 was protected
with a diethoxyl group in the presence of PTSA and CH(OEt)3 in CH2Cl2. This protecting group has an
enhanced steric effect that could ensure higher diastereoselectivity at C5 in the following [3+2]
annulation reaction. After similar hydrolysis and Mitsunobu reaction sequences, precursor 19 was
prepared as a pair of diastereomers (dr = 1.5:1) at C12. Then, this mixture was treated with thiophenol
and AIBN at 120 °C to undergo the [3+2] annulation reaction. Fortunately, tricyclic product 20 was
isolated in 35% yield as a single diastereomer, in which stereochemistry of C5 was consistent with
pavidolide B (1). This clean control of all the relative stereochemistries in the C ring of 20 and the
installation of the C4 quaternary carbon ultimately provided a concise access to pavidolide B (1).3a
Scheme 5. [3+2] Annulation Reaction of C11-(S) Substrate 19a
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2
Ph
a)
O
Ph
OTMS
3
4
5
6
7
8
9
CO2Me
N
CO2H
Me
H
MeO2C
Me
O
H
b) CH(OEt)3
PTSAH2O
MeO2C
Me
H
OEt
OEt
12
5
(20 mol%)
G
(S)
(S)
Br
MeO2C
c) Me4NOH
i-PrOH/H2O
Et3N, CHCl3
0 oC
CO2Me
17
dr = 11:1
ee = 95%
dr = 1.5:1
18
(80% in 2 steps)
(79%)
16
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
d) PPh3
DEAD
, THF
(74%)
O
6
O
O
Me
Me
Me
Me
SPh
Me
Me
Me
O
H
O
Me
Me
Me
e) PhSH
AIBN
5
6
EtO
EtO
5
11
O
O
O
13
12
H
120 oC
toluene
(35%)
MeO2C
(s)
EtO
EtO
OEt
Me
OEt
Me
Me
12
MeO2C
O
MeO2C
OEt
O
MeO2C
Me
(S)
OEt
O
O
dr > 20:1
20
19
dr = 1.5:1
19''
19'
Me
PhS
Me
aReagents and conditions: (a) (R)-2-(diphenyl((trimethylsilyl)oxy)methyl)pyrrolidine G (20 mol%), 5 (1.2 equiv), Et3N (1.0
equiv), CHCl3, 0 °C, 6 h, 79%; (b) CH(OEt)3 (1.5 equiv), PTSA (0.1 equiv), CH2Cl2, rt, 2 h; (c) Me4NOH (1.1 equiv), i-
PrOH/H2O = 10:1, rt, 12 h, 80% in two steps; (d) PPh3 (2.0 equiv), DEAD (2.0 equiv), 6 (1.1 equiv), THF, 0 °C to 45 °C,
overnight, 74%; (e) PhSH (1.2 equiv), AIBN (0.3 equiv), toluene, 120 °C, 35%.
Optimization of the [3+2] Annulation Reaction Conditions
With the success of the key [3+2] annulation reaction for the stereoselective formation of the
tricyclic core of 1. We tried to vary the conditions to thermally generate the thiyl radical12, involving the
treatment of 19 with a mixture of PhSH (1.5 equiv) and AIBN (0.3 equiv) in degassed toluene at various
temperatures. We found that substrate 19 was completely consumed at 60 °C after 9 h, but only a trace
amount of the desired product 20 was detected (Table 2, entry 1). When the reaction was conducted at
120 °C for 3 h, the desired product 20 was isolated in 35% yield, along with decomposition of the
substrate (entry 4).
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Table 2. Thermal Conditions Screening for the [3+2] Annulation Reaction
4
5
6
7
8
9
Me
O
O
H
Me
Me
Me
4
5
conditions
5
EtO
EtO
MeO2C
4
11
EtO
EtO
11
Me
Me
13
13
(S)
Me
(S)
O
MeO2C
O
Me
20
dr > 20:1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
O
O
19
entry
conditionsa
PhSH, AIBN
PhSH, AIBN
PhSH, AIBN
PhSH, AIBN
solvent
toluene
toluene
toluene
toluene
temp (°C) time (h) yield (%)b
1
2
3
4
60
80
9
6
3
3
trace
32
100
31
120
35
a Reaction conditions: 19 (0.5 mmol) in toluene (20 mL), slow addition of PhSH (1.5 equiv) and AIBN (0.3 equiv) in toluene
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
(10 mL); b Isolated yield.
To gain insight into this highly stereospecific annulation reaction, we carried out DFT calculation
at DSD-PBEP86-D3/def2-TZVP//PBE0-D3/def2-SV(P) level with SMD solvation in MeCN for the
pathways from 19 to 20. 21a-f As shown in Figure 3, the calculation indicates that the rate-determining
step is the 5-exo conjugate addition of intermediate IM2 (19’, Scheme 5) forming IM3 (19’’, Scheme
5). The activation Gibbs free energy is 72.3 kJ/mol from (12S)-19, and 59.6 kJ/mol from (12R)-19 (for
all possible pathways, see Supporting Information). Similar to what’s predicted by the thermodynamic
data, with (11S)-19 as the substrate, product 20 is favored over 5-epi-20 in all pathways. This preference
is inverted when (11R)-19 was used as the substrate, shown in the right part of Figure 3. The substrate
dependence of stereoselectivity in this reaction demonstrated that C5 stereocenter is controlled by the
C11 acetal group during the cyclization process.
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100
72.3
TS3
B
A
37.6
4
5
6
7
8
9
50.7
48.6
TS1
40.7
TS2
26.9
IM2
26.5
IM1
B
42.2
A
11-epi
7.9
-10.2
A
29.3
B
TS4
0.0
(12S)-19
0.0
11-epi
IM3
0
A
-17.4
IM3
B
A
11-epi
-25.1
-47.1
-31.3
TS4
TS5
O
O
-37.5
B
IM4
O
Me
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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29
30
31
32
33
34
35
36
37
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40
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45
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Me
IM4
iPr
O
5-epi-20
-127.2
-100
iPr
O
OEt
OEt
O
MeO2C
-134.6
20
(S)
MeO2C
11
5
(S)
OEt
5
11
Me
OEt
PhS
Me
19
IM2
(12S)-
Me
Me
SPh
Me
SPh
SPh
SPh
SPh
Me
Me
Me
Me
EtO
EtO
O
H
O
O
O
O
H
O
H
Me
Me
Me
Me
Me
5
5
5
5
EtO
EtO
EtO
5
EtO
H
H
H
O
11
11
11
11
11
(R)
(R)
iPr
iPr
iPr
iPr
iPr
iPr
EtO
MeO2C
EtO
EtO
(EtO)2HC
MeO2C
EtO
MeO2C
MeO2C
MeO2C
MeO2C
O
O
O
O
O
O
O
O
O
O
O
IM3
IM4 A
IM4 B
20
11-epi-IM4 A
11-epi-IM4 B
Figure 3. DFT calculation of PhS· initiated cyclization reaction from (12S)-19 and 11-epi-19
Besides the rate-determining step and the origin of diastereoselectivity, the computational study
shown in Figure 3 also indicates that the cyclization process, once initiated, requires less than 75 kJ/mol
of activation Gibbs free energy, which means the cyclization could occur rapidly at room temperature.
Thus, combined with the fact that the VCP moiety in the substrate is thermally unstable,22 we next
attempted to optimize this reaction by room temperature radical initiation methods. We first tested
irradiation with UV light23 (entries 1-6, Table 3). The desired annulation proceeded smoothly when the
reaction was performed in the presence of PhSSPh and AIBN under UV-light irradiation in toluene at
25 °C for 5 h (entry 1), giving product 20 in 32% yield. According to Feldman’s work24, the addition of
AlMe3 as a Lewis acid could promote this reaction and, to our delight, the yield of 20 was improved to
40%–48% with a shorter reaction time (entry 2). However, the yield of 20 was variable when using this
approach, as AlMe3 is sensitive to moisture and its quality is difficult to control. The screen of other
Lewis acids, such as Zn(OTf)2, Sc(OTf)2, and Ti(Oi-Pr)4, failed to promote this reaction. Solvent
screening showed that toluene was the best solvent. Even the reaction gave similar yield (47%) in
cyclohexane, the yield declined in a larger scale due to the lower solubility in cyclohexane. When we
tested BPO as an initiator25 (entry 5), the desired product 20 was generated in only 20% yield.
Interestingly, when a higher-power UV light (500 W) was used (entry 6), the yield of 20 dropped to
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35%. We recognized that high-energy UV irradiation may lead to some side reactions, which could
potentially be minimized by using lower-energy visible-light irradiation.
4
5
6
7
8
9
Table 3. Optimization for UV-initiated [3+2] Annulation Reaction at Room Temperature
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
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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
Me
O
O
Me
Me
Me
4
5
conditions
5
EtO
EtO
MeO2C
4
11
EtO
EtO
11
Me
Me
13
13
H
(S)
Me
(S)
O
MeO2C
O
Me
20
dr > 20:1
O
O
19
entry
conditions
solvent
additive time (h) yield (%)a
1
2
3
4
5
6
PhSSPh, AIBN, UV (250 W)
PhSSPh, AIBN, UV (250 W)
PhSSPh, AIBN, UV (250 W)
Toluene
toluene
MeCN
5
3
6
3
5
3
32
40–48b
37
AlMe3
AlMe3
PhSSPh, AIBN, UV (250 W) cyclohexane AlMe3
47c
PhSSPh, BPO, UV (250 W)
PhSSPh, AIBN, UV (500 W)
toluene
toluene
AlMe3
AlMe3
20
35
aIsolated yield; bReaction conditions: 19 (0.5 mmol), AlMe3 (1.0 equiv), PhSSPh (1.2 equiv),
AIBN (0.5 equiv), toluene (30 mL), UV (250 W) irradiation. cthe yield dropped in larger scale
due to the poor solubility.
Recently, the couplings of thiols and alkenes were realized by using transition-metal catalysts26
or organic photocatalysts27 under visible-light irradiation28, representing state-of-the-art chemical
transformations promoted by low-cost energy. Motivated by this recent progress, we applied similar
conditions to our thiyl-radical-mediated [3+2] annulation reaction (Table 4). To this end, several
commercially available photoredox catalysts29 were screened (entries 1–3). Under irradiation of low-
energy blue light-emitting diodes (LEDs), when Ir(dF(CF3)ppy)2(dtbbpy)PF6 (0.5 mol%) was selected
as the catalyst, desired product 20 was obtained in 50% yield. In contrast, when alkyl thiols, such as
benzyl mercaptan and methyl thioglycolate (entries 4 and 5) were used as the thiyl-radical source, the
yield of 20 declined, probably because of the higher bond dissociation energy (BDE) of S–H bonds in
alkyl thiols than that of PhSH12c.
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18
19
20
21
22
23
24
25
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Table 4. Screening of Visible-Light Irradiation Conditions
4
5
6
7
8
9
Me
O
F
F
tBu
PF6
O
Me
Me
O
Me
5
4
N
N
5
conditions
N
EtO
EtO
MeO2C
4
EtO
EtO
11
11
F3C
F
Me
Me
Ir
13
13
H
(S)
(S)
Me
Me
N
tBu
O
MeO2C
O
F
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
CF3
O
20
Ir(dF(CF3)ppy)2(dtbbpy)PF6
19
dr > 20:1
entry
conditions
PhSH, Ru(bpy)3Cl2, p-toluidine
time (h) yield (%)a
1
2
3
4
5
4
4
2
5
2
30
47
50b
23
25
PhSH, Ir(ppy)2(dtbbpy)PF6, p-toluidine
PhSH, Ir(dF(CF3)ppy)2(dtbbpy)PF6, p-toluidine
benzyl mercaptan, Ir(dF(CF3)ppy)2(dtbbpy)PF6, p-toluidine
methyl 2-mercaptoacetate, Ir(dF(CF3)ppy)2(dtbbpy)PF6, p-toluidine
aIsolated yield; bReaction conditions: 19 (0.5 mmol), PhSH (1.1 equiv), p-toluidine (0.5 equiv),
Ir(dF(CF3)ppy)2(dtbbpy)PF6 (0.5 mol%), MeCN (30 mL), 25 °C, 2 h.
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Building the Tetracyclic Core
Table 5. Screening of Krapcho Decarboxylation Reaction Conditions
Me
Me
Me
O
O
O
Me
Me
Me
H
O
conditions
H
O
EtO
EtO
(S)
(S)
(R)
H
H
H
11
11
11
Me
Me
Me
Me
Me
Me
H
H
MeO2C
H
H
H
O
O
O
O
O
O
21a
ORTEP of
20
21a
21b
entry
conditions
temp (°C)
120
time (h)
yield of 21a (%)a
ratio (21a:21b)
1
2
3
4
5
6
LiCl, DMAc, H2O
LiCl, DMSO, H2O
LiCl, DMAc, H2O
LiI, DMAc, H2O
NaI, DMAc, H2O
NaI, DMF, H2O
12
12
6
<10
<10
20
-
120
-
160
1.3:1
1.3:1
1.6:1
1.5:1
160
6
28
160
4.5
4.5
38b
32
160
aYield of isolated product; bReagents and conditions: NaI (5.0 equiv), H2O (10.0 equiv), DMAc, 160 °C, 4.5 h.
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To remove the extra C12 carboxylic ester needed for the [3+2] cyclization reaction, compound
20 was treated under Krapcho decarboxylation reaction conditions.13 Various halogen salts, such as LiCl,
NaCl, LiBr, LiI, and NaI, were tested in different solvents at high temperatures. Interestingly, we found
that the deprotection of the aldehyde occurred simultaneously to give aldehyde 21a in low yields (Table
5, entries 1–3). The stereochemistry of product 21a was assigned by X-ray crystallography. After careful
examination of the other messy byproducts, we found that aldehyde 21b was formed at the same time
(entry 3), in which all seven contiguous stereocenters are the same as those in the target molecule 1.
However, attempts to drive further epimerization of 21a to 21b under several basic or acidic conditions
led to a mixture of diastereomers, with a ratio of 21a:21b = 1:1.5 (see Supporting Information for
details). These results indicate that equilibrium may exist between 21a and 21b.
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 6. Building the Tetracyclic Skeleton 23a from aldehyde 21aa
Me
Me
a)
Me
c) Grubbs II
O
O
O
Me
Me
Ni(acac)2
Et2Zn, THF
Me
H
O
O
H
H
(S)
H
Me
Me
(S)
H
Me
Me
(S)
Me
DCM
45 oC
(85%)
b) DMP, NaHCO3
DCM
(94% in 2 steps)
O
H
H
H
O
H
O
O
Me
O
O
O
21a
22a
23a
aReagents and conditions: (a) Ni(acac)2 (20 mol%), isoprene (4.0 equiv), Et2Zn (2.4 equiv), THF, rt, 4 h; (b) NaHCO3 (5.0
equiv), Dess−Martin periodinane (1.2 equiv), CH2Cl2, rt, 4 h, 94% in two steps; (c) Grubbs II catalyst (2 mol%), CH2Cl2,
reflux, 6 h, 85%.
With key intermediates 21a and 21b in hand, we focused on constructing the seven-membered
ring D of 1. We adopted the Ni-catalyzed reductive coupling reaction of aldehydes with 1,3-dienes
developed by Tamaru and co-workers7 to install the alkene side chain. When aldehyde 21a was coupled
with isoprene in the presence of Ni(acac)2 and Et2Zn in THF at room temperature for 2 h, the expected
homoallylic product was obtained in almost quantitative yield. Then DMP oxidation of this product
without purification gave diene 22a in 94% yield over two steps (Scheme 6). Then, the intramolecular
RCM reaction5 of diene 22a was explored with several catalysts. The Grubbs II catalyst gave the best
result, with an 85% annulation yield for product 23a, thus completing the tetracyclic skeleton of 1.3a
Final trip to pavidolide B (1)
Scheme 7. Hydrogenation and Oxidation Sequencea
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5
6
7
8
Me
Me
Me
O
H
O
O
H
Me
Me
Me
a) Pd/C, H2
H
Me
Me
Me
Me
Me
Me
MeOH
36 h
O
O
O
H
H
H
O
O
O
(81%)
O
O
O
23a
24a
25a
9
aReagents and conditions: (a) Pd/C (20 wt%), H2 (1 atm), MeOH, 36 h, 81%.
10
11
12
13
14
To build the enone moiety, we first tried a hydrogenation and oxidation sequence, proposing the
less hindered carbonyl group on 7-membered ring may be more prone to be activated. As shown in
Scheme 7, hydrogenation of the C-C double bond of 23a in the presence of Pd/C in a hydrogen
atmosphere (1 atm) provided product 24a in 81% yield. Unfortunately, several methods to build the
enone moiety30 were investigated, including Saegusa oxidation,31 selenylation,32 IBX oxidation,33 and
Stahl’s palladium-catalyzed dehydrogenation,34 but these conditions failed to generate desired product
25a, resulting in decomposition or no reaction.
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
Scheme 8. Realizing the Total Synthesis of Pavidolide B (1) through Double-Bond Migrationa
Me
Me
O
Me
Me
a)
O
O
H
Me
Ni(acac)2
Et2Zn, THF
Me
O
H
O
H
O
c) Grubbs II
H
11
Me
H
Me
Me
Me
DCM
45 oC
(86%)
b) DMP, NaHCO3
DCM
(90% in 2 steps)
H
H
H
O
H
O
H
Me
H
O
O
Me
O
O
21b
22b
23b
d) RhCl3•3H2O
sealed tube
(85%)
O
EtOH, 100 oC
Me
H
Me
H
Me
Me
H
O
H
O
O
ORTEP of pavidolide B
1
pavidolide B ( )
aReagents and conditions: (a) Ni(acac)2 (20 mol%), isoprene (4.0 equiv), Et2Zn (2.4 equiv), THF, rt, 4 h; (b) NaHCO3 (5.0
equiv), Dess−Martin periodinane (1.2 equiv), CH2Cl2, rt, 4 h, 90% in two steps; (c) Grubbs II catalyst (2 mol%), CH2Cl2,
reflux, 6 h, 86%; (d) RhCl3·3H2O (20 mol%), EtOH, 100 °C, sealed tube, 5 h, 85%.
As an alternative, we thought that double-bond migration6 of the α,β-unsaturated enone to the
more stable α,β-unsaturated enone would be a more efficient and direct strategy. We tested this idea by
using C11-(S) aldehyde 21b as substrate, with all seven contiguous stereocenters the same as those in
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pavidolide B (1). Following a similar procedure, tetracyclic compound 23b was prepared from 21b
smoothly in three steps (Scheme 8). After screening various olefin isomerization catalysts6, 35, including
Ru, Rh, and Pd catalysts, we were glad to find that when 23b was treated with RhCl3·3H2O (20 mol%)
in absolute ethanol at 100 °C in a sealed-tube for 5 h35a, the target molecular 1 was generated in 85%
yield ([α]26 D = -146, c = 0.42 in MeOH). The structure of the synthesized product was unambiguously
confirmed by X-ray crystallography to match that of the isolated (–)-pavidolide B (1).
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Optimization of Synthetic Route
Scheme 9. Revised Synthetic Routea
Me
Me
Me
O
O
O
H
b) 120 oC
Me
Me
a) Me4NOH
iPrOH / H2O
H
O
EtO
EtO
EtO
EtO
(S)
(S)
toluene, 4 h
(S)
H
H
Me
Me
Me
Me
Me
Me
then HCl
MeO2C
HO2C
H
O
O
O
(90%
in 2 steps)
O
O
O
20
26
21a
c) Ni(acac)2
Et2Zn
d) DMP, NaHCO3
DCM
(94% in 2 steps)
300 mg scale
Me
Me
Me
O
f) RhCl33H2O
e) Grubbs II
DCM, reflux
Me
O
H
O
H
Me
O
Me
O
H
100 oC
H
O
(S)
H
Me
Me
EtOH/DCM
Sealed tube
(95%)
(85%)
Me
Me
Me
O
H
H
O H
200 mg scale
H
H
O
O
Me
O
O
50 mg scale
1
23a
pavidolide B ( )
22a
aReagents and conditions: (a) Me4NOH (1.1 equiv), i-PrOH/H2O = 10:1, rt, 12 h; then toluene, 120 °C, 4 h; (b) HCl (2.0 M),
THF, rt, 2 h, 90%; (c) (Ni(acac)2 (20 mol%), isoprene (4.0 equiv), Et2Zn (2.4 equiv), THF, rt, 4 h; (d) NaHCO3 (5.0 equiv),
Dess−Martin periodinane (1.2 equiv), CH2Cl2, rt, 4 h, 90% in two steps; (e) Grubbs II catalyst (20 mol%), CH2Cl2, reflux, 6
h, 86%; (f) RhCl3·3H2O (20 mol%), EtOH/CH2Cl2 = 6:1, 100 °C, sealed tube, 5 h, 95%.
After successfully realizing the total synthesis of 1, we attempted to improve the efficiency of
this synthetic route (Scheme 9). To improve the yield of the decarboxylation reaction, the methyl ester
of compound 20 was selectively hydrolyzed by treatment with Me4NOH in a mixed solvent of i-PrOH
and H2O at room temperature. Without purification, the resultant acid 26 was subjected to
decarboxylation36 by heating at 120 °C in toluene and then deprotection with HCl solution (3 N) in situ
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to furnish 21a in 90% yield over two steps. Following the same procedure, 21a was transformed into
tetracyclic 23a on the scale of hundreds of milligrams. When 23a was treated with RhCl3·3H2O (20
mol%) in ethanol (with a small amount of CH2Cl2 as a cosolvent) at 100 °C for 5 h, to our delight,
epimerization of C11 occurred simultaneously with double-bond migration to give natural product 1 in
95% yield. Thus, the entire synthetic route was shortened to 10 linear steps and the overall yield was
improved to 16%. Finally, 300 mg of pavidolide B (1) was synthesized for further bioactivity studies.
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CONCLUSIONS
In summary, the asymmetric total synthesis of (–)-pavidolide B (1) was realized in 10 steps in
16% overall yield. In this work, a thiyl-radical-mediated [3+2] annulation reaction under visible-light
irradiation conditions was used for the concise construction of a highly substituted cyclopentane core
structure, with two C–C bonds, two rings, and four stereocenters, including one quaternary all-carbon
center, formed in one step. The four newly formed stereocenters were cleanly controlled through the
logical design of the substrate. This cascade radical reaction provides a powerful strategy for the
construction of highly substituted five-membered rings under mild conditions with good functional-
group tolerance, which may have broad potential applications in organic synthesis.
EXPERIMENTAL SECTION
General Experimental Information. Unless otherwise mentioned, all reactions were carried out under
an argon atmosphere in oven-dried glassware with dry solvents. An oil bath was used as the heating
source for the reactions that require heating. Reagents were purchased at the highest commercial quality
and used without further purification, unless otherwise stated. Solvents purification was conducted
according to Purification of Laboratory Chemicals (Peerrin, D. D.; Armarego, W. L. and Perrins, D. R.,
Pergamon Press: Oxford, 1980). Reactions were monitored by thin-layer chromatography (TLC) carried
out on 0.25 mm Tsingdao silica gel plates (GF-254) and visualized under UV light at 254 nm. Staining
was performed with an ethanolic solution of phosphomolybdic acid (PMA) and cerium sulfate, or by
oxidative staining with an aqueous basic potassium permanganate (KMnO4) solution and subsequent
heating. Tsingdao silica gel (60, particle size 0.040-0.063 mm) was used for flash column
chromatography. NMR spectra were recorded on either a Brüker Advance 400 MHz or Brüker Advance
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500 MHz NMR spectrometer. All 1H-NMR data are reported in δ units, parts per million (ppm), and all
1
13C-NMR data were obtained with H decoupling unless otherwise stated. They were calibrated using
5
residual undeuterated solvent as an internal reference (CDCl3: 1H NMR = 7.26 ppm, 13C NMR = 77.2
ppm; Acetone-d6: 1H NMR = 2.05 ppm, 13C NMR = 206.3 ppm; DMSO-d6: 1H NMR =2.50 ppm, 13C
NMR = 40.0 ppm). The following abbreviations were used to explain the multiplicities: s = singlet, d =
doublet, t = triplet, q = quartet, m = multiplet, br = broad. IR spectra were recorded on an IR Prestige-
21 FTIR spectrometer with a KBr disc. Melting points (m.p.) are uncorrected and were recorded on a
SGWX-4B apparatus. High resolution mass spectrometric (HRMS) data were recorded on a Brüker
Apex IV RTMS instrument and a VG Auto Spec-3000 spectrometer using quadrupole analyzer,
respectively. CD spectrum was measured using the Applied Photophysics Chirascan with a 150W Xe
lamp (165 nm – 900 nm). Optical rotation values were recorded on a Rudolph Research Analytical
Autopol I polarimeter (Rudolph Research Co.).
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4,4,5a-trimethyl-6-vinyloctahydroindeno[7,1-bc]furan-1,5-dione (9):
A flame dried round-bottom flask containing a solution of 7 (300 mg, 1.0 mmol, 1.0 equiv, see
Supporting Information for details) in toluene (20 mL) under N2 was heated to 80 °C in an oil bath. Then
a mixture solution of PhSH (150 μL, 1.5 mmol, 1.5 equiv) and AIBN (50 mg, 0.3 mmol, 0.3 equiv) in
toluene (10 mL) was added dropwise by syringe pump over 5 h at 80 °C. The reaction mixture was
stirred at the same temperature for an additional 30 min. After cooling to ambient temperature, the
solvent was removed under vacuum and the residue was purified by a flash column chromatography on
silica gel (hexane/EtOAc = 10:1) to give the desired product 8 (141 mg, 47%) as a crystalline solid.
Compound 8: Rf = 0.50 (silica gel, hexane/EtOAc = 4:1, KMnO4); m.p.: 106.2–107.5 oC; IR (thin film,
ν cm-1): 3000, 2961, 2918, 2850, 1772, 1759, 1377, 1250, 1243, 1054, 800; HRMS (ESI): m/z calcd for
+
C17H23O5 [M+H]+: 307.1540; found: 307.1532. 1H NMR (400 MHz, CDCl3) δ = 5.82 – 5.74 (m, 1H),
5.17 – 5.14 (m, 1H), 5.08 (td, J = 9.2, 7.0 Hz, 1H), 5.02 – 4.98 (m, 1H), 3.81 (s, 3H), 3.25 (d, J = 9.3
Hz, 1H), 2.65 – 2.58 (m, 2H), 2.50 – 2.39 (m, 1H), 2.33 (dd, J = 14.5, 7.0 Hz, 1H), 2.04 (dd, J = 14.5,
9.2 Hz, 1H), 1.18 (s, 3H), 1.15 – 1.08 (m, 3H), 1.05 (s, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ =
213.0, 175.0, 169.9, 133.8, 117.8, 74.6, 61.3, 55.8, 54.6, 53.5, 50.1, 42.4, 39.1, 36.4, 25.9, 25.0, 20.3
ppm.
To a stirred solution of 8 (100 mg, 0.33 mmol, 1.0 equiv) in DMSO (10 mL) was added LiCl (138 mg,
3.3 mmol, 10.0 equiv) and H2O (0.3 mL, 16.5 mmol, 50.0 equiv), and the resultant reaction mixture was
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then heated to 120 oC in an oil bath, and stirred for 5 h. After cooling to ambient temperature, the mixture
was extracted with Et2O (5 x 30 mL). The combined extracts were dried over Na2SO4, filtered and
concentrated under vacuum. The residue was purified by a flash column chromatography on silica gel
(hexane/EtOAc = 6:1) to give the desired product 9 (66 mg, 77%) as a viscous oil. Compound 9: Rf =
0.45 (silica gel, hexane/EtOAc = 4:1, KMnO4); IR (thin film, ν cm-1): 2961, 2929, 2854, 1765, 1661,
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+
1472, 1243, 1018; HRMS (ESI): m/z calcd for C15H20NaO3 [M+Na]+: 271.1305; found: 271.1305. 1H
NMR (400 MHz, CDCl3) δ = 5.76 (ddd, J = 17.1, 10.5, 6.4 Hz, 1H), 5.13 (dt, J = 10.5, 1.3 Hz, 1H), 4.97
(M, 2H), 3.30 (td, J = 10.3, 1.7 Hz, 1H), 3.07 (t, J = 9.9 Hz, 1H), 2.70 – 2.55 (m, 1H), 2.38 – 2.21 (m,
2H), 2.19 – 2.09 (m, 1H), 2.05 – 2.00 (m, 1H), 1.18 (s, 3H), 1.12 (s, 3H), 1.04 (s, 3H) ppm. C{1H}
13
NMR (100 MHz, CDCl3) δ = 213.9, 179.3, 134.4, 117.5, 75.0, 56.3, 50.2, 48.6, 44.0, 42.4, 39.4, 33.2,
25.9, 25.0, 20.2 ppm.
(2R,3R)-2-(1,3-dioxolan-2-yl)-1-(ethoxycarbonyl)-3-((E)-prop-1-en-1-yl)cyclopropane-1-
carboxylic acid (13):
Compound 12 was prepared by following known procedures8 in 79% yield as a colorless oil, which is
an inseparable 11:1 mixture of diastereomers. (For the determination of enantiomeric excess of 12, see
Supporting Information.) To a stirred solution of aldehyde 12 (2.84 g, 11.2 mmol, 1.0 equiv) in dry DCM
(100 mL) was added triethyl orthoformate (2.23 mL, 13.4 mmol, 1.2 equiv), ethylene glycol (1.14 mL,
22.4 mmol, 2.0 equiv) and PTSA•H2O (213 mg, 1.12 mmol, 0.1 equiv) at 0 oC. The reaction mixture
was stirred at room temperature for 2 h. After completion, the mixture was quenched with saturated
aqueous NaHCO3 (30 mL) and extracted with DCM (3 × 50 mL). The combined organic layers were
washed with saturated aqueous NaHCO3 (20 mL), brine (20 mL) and dried over Na2SO4, filtered and
concentrated under vacuum. The residue can be used directly for the next step without further
purification.
To a solution of the residue in i-PrOH/H2O = 50 mL/5 mL, tetramethylammonium hydroxide (5.5 mL,
25% w/w solution in H2O, 12.0 mmol, 1.1 equiv) was added at room temperature. The reaction mixture
was heated to 40 oC in an oil bath and stirred for 12 h. After completion, the solution was extracted with
DCM (2 × 20 mL). The organic phase was discarded and the water phase was acidified with 2 N aq. HCl
at 0 oC to pH = 2, and extracted with DCM (3 × 50 mL). The combined organic layer were dried over
Na2SO4. The solvent was removed under vacuum to give acid 13 (1.97 g, 65% yield in two steps) as a
colorless oil, which is a 1:1 mixture of diastereomers, and can be separated by flash column
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chromatography (PE:EA = 2:1) to afford 13a and 13b. Compound 13a: Rf = 0.40 (silica gel,
hexane/EtOAc = 1:1, PMA). [α]25 D = + 2.4 (c = 0.5, CHCl3); IR (thin film, ν cm-1): 2974, 2925, 2857,
+
1726, 1713, 1453, 1374, 1292, 1211, 1113, 966; HRMS (ESI): m/z calcd for C13H18NaO6 [M+Na]+:
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293.0996; found: 293.0998. 1H NMR (400 MHz, CDCl3) δ = 5.86 – 5.77 (m, 1H), 5.37 – 5.31 (m, 1H),
4.88 (d, J = 6.7 Hz, 1H), 4.29 – 4.24 (m, 2H), 4.01 – 3.98 (m, 2H), 3.90 – 3.81 (m, 2H), 2.83 (t, J = 8.3
Hz, 1H), 2.43 (dd, J = 8.1, 6.7 Hz, 1H), 1.68 (dd, J = 6.5, 1.5 Hz, 3H), 1.29 (t, J = 7.1 Hz, 3H) ppm.13C
NMR (100 MHz, CDCl3) δ = 170.6, 169.4, 131.6, 123.7, 102.4, 65.1, 65.0, 62.4, 37.9, 36.7, 35.7, 17.9,
13.8 ppm. Compound 13b: Rf = 0.30 (silica gel, hexane/EtOAc = 1:1, PMA). [α]25 D = - 6.4 (c = 0.5,
CHCl3); IR (thin film, ν cm-1): 2964, 2922, 2853, 1722, 1445, 1374, 1266, 1096, 1022, 800; HRMS
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+
(ESI): m/z calcd for C13H18NaO6 [M+Na]+: 293.0996; found: 293.0998. 1H NMR (400 MHz, CDCl3)
δ = 5.88 – 5.79 (m, 1H), 5.34 – 5.24 (m, 1H), 5.09 (d, J = 7.0 Hz, 1H), 4.35 – 4.18 (m, 2H), 4.05 – 3.98
(m, 2H), 3.92 – 3.83 (m, 2H), 2.95 (t, J = 8.3 Hz, 1H), 2.48 – 2.44 (m, 1H), 1.68 (dd, J = 6.6, 1.5 Hz,
13
3H), 1.29 (t, J = 7.1 Hz, 3H) ppm. C{1H} NMR (100 MHz, CDCl3) δ = 170.7, 169.6, 132.2, 123.9,
101.8, 65.1, 65.1, 62.6, 37.8, 37.6, 37.0, 18.0, 14.0 ppm.
1-ethyl 1-((1R,6S)-6-isopropyl-3-methyl-4-oxocyclohex-2-en-1-yl) (1R,2R,3R)-2-(1,3-dioxolan-
2-yl)-3-((E)-prop-1-en-1-yl)cyclopropane-1,1-dicarboxylate (14a) and 1-ethyl 1-((1R,6S)-6-
isopropyl-3-methyl-4-oxocyclohex-2-en-1-yl) (1S,2R,3R)-2-(1,3-dioxolan-2-yl)-3-((E)-prop-1-en-1-
yl)cyclopropane-1,1-dicarboxylate (14b):
To a solution of 13a (576 mg, 2.1 mmol, 1.0 equiv), alcohol 6 (430 mg, 2.56 mmol, 1.2 equiv) and PPh3
(1.9 g, 4.2 mmol, 2.0 equiv) in THF, was added DEAD (0.66 mL, 4.2 mmol, 2.0 equiv) dropwise at 0
oC. Then the reaction mixture was warmed to room temperature and stirred overnight. The reaction was
quenched by the addition of a saturated aqueous NH4Cl (10 mL), and extracted with Et2O (4 × 10 mL).
The combined organic layers were washed with brine (5 mL), dried over Na2SO4, filtered and
concentrated under vacuum. The residue was purified by flash column chromatography on silica gel
(hexane/ethyl acetate = 20:1) to give 14a (767 mg, 87% yield) as a colorless oil. Compound 14a: Rf =
0.60 (silica gel, hexane/EtOAc = 4:1, UV & PMA). [α]25 D = + 261 (c = 0.6, CHCl3); IR (thin film, ν
cm-1): 2964, 2925, 1724, 1683, 1459, 1370, 1285, 1204, 1110, 1051, 907; HRMS (ESI): m/z calcd for
+
C23H32NaO7 [M+Na]+: 443.2040; found: 443.2041; 1H NMR (400 MHz, CDCl3) δ = 6.86 – 6.78 (m,
1H), 5.81 – 5.71 (m, 1H), 5.41 (dd, J = 5.7, 2.9 Hz, 1H), 5.10 – 5.01 (m, 1H), 4.65 (d, J = 6.9 Hz, 1H),
4.20 – 4.02 (m, 2H), 4.00 – 3.93 (m, 2H), 3.85 – 3.73 (m, 2H), 2.69 (t, J = 8.0 Hz, 1H), 2.58 (dd, J =
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16.9, 3.3 Hz, 1H), 2.34 (dd, J = 16.9, 12.8 Hz, 1H), 2.27 – 2.19 (m, 1H), 1.77 (d, J = 1.6 Hz, 3H), 1.75
–1.70 (m, 1H), 1.60 (dd, J = 6.6, 1.4 Hz, 3H), 1.24 – 1.17 (m, 1H), 1.10 (t, J = 7.1 Hz, 3H), 0.86 (dd, J
= 13.2, 6.6 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 199.3, 166.9, 166.4, 138.9, 138.6, 130.8,
124.0, 102.2, 67.7, 65.1, 65.0, 61.7, 44.5, 39.3, 37.6, 33.6, 32.0, 28.2, 20.2, 19.8, 17.9, 15.4, 13.8 ppm.
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Compound 14b was prepared through the same procedure from 13b in 84% yield as a colorless oil.
Compound 14b: Rf = 0.70 (silica gel, hexane/EtOAc = 4:1, UV & PMA). [α]25 D = + 40 (c = 1.0,
CHCl3); IR (thin film, ν cm-1): 2965, 2926, 1727, 1684, 1459, 1371, 1286, 1205, 1110, 1051, 908; HRMS
+
(ESI): m/z calcd for C23H32NaO7 [M+Na]+: 443.2040; found: 443.2041; 1H NMR (400 MHz, CDCl3)
δ = 6.89 (dd, J = 5.8, 1.2 Hz, 1H), 5.81 – 5.72 (m, 1H), 5.43 – 5.42 (m, 1H), 5.15 – 5.06(m, 1H), 4.64
(d, J = 6.5 Hz, 1H), 4.14 – 4.04 (m, 2H), 4.00 – 3.93 (m, 2H), 3.85 – 3.72 (m, 2H), 2.68 – 2.59 (m, 2H),
2.41 – 2.29 (m, 1H), 2.27 (t, J = 7.1 Hz, 1H), 1.80 (s, 3H), 1.64 – 1.62 (m, 3H), 1.29 – 1.20 (m, 1H),
1.11 (t, J = 7.1 Hz, 3H), 0.92 (d, J = 6.1 Hz, 6H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 199.5,
166.9, 166.6, 138.8, 138.7, 130.8, 123.7, 102.3, 68.1, 65.1, 64.9, 61.6, 44.8, 39.1, 37.6, 33.8, 31.7, 28.1,
20.3, 20.0, 17.9, 15.5, 14.0 ppm.
ethyl (2aR,2a1R,3R,4R,4aR,7S,7aR)-3-(1,3-dioxolan-2-yl)-7-isopropyl-4a-methyl-2,5-dioxo-4-((E)-
prop-1-en-1-yl)octahydroindeno[7,1-bc]furan-2a(2H)-carboxylate (15):
A flame dried three-necked round-bottom flask containing solution of mixture 14 (100 mg, 0.25 mmol,
1.0 equiv) in toluene (20 mL) was heated to 120 °C in an oil bath under N2. Then a solution of PhSH
(31 μL, 0.3 mmol, 1.2 equiv) and AIBN (50 mg, 0.3 mmol, 0.3 equiv) in toluene (10 mL) was added
dropwise by syringe pump over 5 h at 120 °C. The reaction mixture was stirred at the same temperature
for an additional 30 min. After cooling to ambient temperature, the solvent was removed under vacuum
and the residue was purified by a flash column chromatography on silica gel (hexane/EtOAc = 10:1) to
give the desired product 15 (37 mg, 37%, dr = 5:1) as a crystalline solid. Compound 15 (major): Rf =
0.40 (silica gel, hexane/EtOAc = 4:1, KMnO4). m.p.: 146.1-148.2 °C. [α]25 D = + 18 (c = 1.0, CHCl3);
IR (thin film, ν cm-1): 2968, 2916, 2850, 1774, 1733, 1710, 1022; HRMS (ESI): m/z calcd for
+
1
C23H32NaO7 [M+Na]+: 443.2040; found: 443.2041; H NMR (400 MHz, CDCl3) δ = 5.95 – 5.86 (m,
1H), 5.46 – 5.36 (m, 1H), 5.24 (d, J = 5.1 Hz, 1H), 4.87 (d, J = 6.9 Hz, 1H), 4.30 – 4.21 (m, 2H), 4.00 –
3.92 (m, 2H), 3.88 – 3.73 (m, 2H), 3.23 (d, J = 6.8 Hz, 1H), 2.68 – 2.54 (m, 2H), 2.44 (dd, J = 11.9, 9.5
Hz, 1H), 2.17 – 1.99 (m, 2H), 1.78 (dd, J = 11.3, 4.6 Hz, 1H), 1.69 (dd, J = 6.4, 1.6 Hz, 3H), 1.36 – 1.25
(m, 6H), 1.03 (d, J = 6.6 Hz, 3H), 0.95 (d, J = 6.7 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ =
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212.0, 174.0, 168.7, 128.8, 127.5, 104.0, 75.0, 65.3, 64.3, 62.5, 62.4, 58.9, 57.3, 55.7, 52.4, 43.4, 38.2,
30.4, 23.0, 20.6, 20.4, 17.8, 13.9 ppm.
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General procedure of [3+2] annulation under visible light irradiation conditions.
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To a stirred solution of compound 193a (110 mg, 0.25 mmol, 1.0 equiv) and p-toluidine (13.4 mg, 0.12
mmol, 0.5 equiv), Ir(dF(CF3)ppy)2(dtbbpy)PF6 (0.5 mol %) in dry MeCN (15 mL) under argon
atmosphere was added a solution of aryl or alkyl thiols (0.27 mmol, 1.1 equiv) in dry MeCN (5 mL)
dropwise. The reaction mixture was stirred at room temperature at a distance of approximately 3 cm
from blue LED strips (λmax = 465 nm, 0.5m, 11.52W/m). Upon completion of the reaction, the solution
was washed with aq. NaOH solution (10%, 5 mL) to remove unreacted thiol. The aqueous layers were
extracted with Et2O (4 × 10 mL), and the combined organic layers were washed with brine (5 mL), and
dried over Na2SO4, filtered, and concentrated under vacuum. The residue was purified by flash column
chromatography on silica gel (hexane/EtOAc = 10:1) to give the desired product 20 as a colorless oil.
The yields are shown in the table 4. Compound 20: Rf = 0.40 (silica gel, hexane/EtOAc = 4:1, KMnO4);
[α]25 D = - 48 (c = 0.5, CHCl3); IR (thin film, ν cm-1): 2965, 2922, 1781, 1748, 1733, 1683, 1260, 1065,
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1011, 771; HRMS (ESI): m/z calcd for C24H36NaO7 [M+Na]+: 459.2353; found: 459.2353. H NMR
(400 MHz, CDCl3) δ = 5.30 – 5.10 (m, 2H), 4.80 (s, 1H), 4.78 (s, 1H), 3.86 – 3.76 (m, 4H), 3.67 (dq, J
= 14.1, 7.0 Hz, 2H), 3.45 (dq, J = 14.2, 7.1 Hz, 1H), 3.12 (dd, J = 12.6, 8.1 Hz, 1H), 2.81 (d, J = 6.6 Hz,
1H), 2.59 (t, J = 14.3 Hz, 1H), 2.41 – 2.30 (m, 2H), 1.92 – 1.77 (m, 1H), 1.65 (dd, J = 6.1, 1.1 Hz, 3H),
1.63 – 1.60 (m, 1H), 1.15 – 1.09 (m, 9H), 1.02 (d, J = 6.7 Hz, 3H), 0.98 (d, J = 6.7 Hz, 3H) ppm. 13C{1H}
NMR (100 MHz, CDCl3) δ = 208.9, 173.0, 170.5, 128.2, 127.0, 104.1, 76.4, 65.3, 64.8, 63.8, 58.5, 56.0,
53.6, 53.2, 52.7, 45.8, 35.0, 30.2, 29.9, 20.7, 20.5, 18.1, 15.4, 15.3 ppm.
(2aR,2a1S,3S,4S,4aR,7S,7aR)-7-isopropyl-4a-methyl-2,5-dioxo-4-((E)-prop-1-en-1-
yl)decahydroindeno[7,1-bc]furan-3-carbaldehyde (21a) and (2aR,2a1S,3R,4S,4aR,7S,7aR)-7-
isopropyl-4a-methyl-2,5-dioxo-4-((E)-prop-1-en-1-yl)decahydroindeno[7,1-bc]furan-3-
carbaldehyde (21b):
To a solution of compound 20 (218 mg, 0.5 mmol, 1.0 equiv) in DMAc (5.0 ml) and H2O (0.05 mL, 2.5
mmol, 5.0 equiv) was added NaI (375 mg, 2.5 mmol, 5.0 equiv). Then the sealed tube was heated to 160
oC in oil bath and stirred for 12 hours under N2. After completion, the mixture was diluted with 20 mL
Et2O and washed with H2O (5 ×10 mL). The combined organic layers were washed with brine (10 mL)
and dried over anhydrous Na2SO4, filtered, and concentrated. The residue was purified by a flash column
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chromatography on silica gel (hexane/EtOAc = 6:1) to give the aldehyde 21a (58 mg, 38% yield) as a
colorless crystal and aldehyde 21b (36 mg, 24% yield) as a white solid.
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Optimized procedure: To a solution of 20 (0.87 g, 2.0 mmol, 1.0 equiv) in i-PrOH (20 mL) and H2O (2
mL) was added Me4NOH (25% w/w solution in H2O, 0.84 mL, 2.2 mmol, 1.1 equiv) at room
temperature. The reaction mixture was stirred for 12 h at room temperature. After completion, the
solution was acidified by the slow addition of 2 N aq. HCl solution at 0 oC until pH = 2. The aqueous
layer was extracted with DCM (3 × 20 mL). The combined organic layers were dried over anhydrous
Na2SO4, filtered, and concentrated under vacuum. The residue was dissolved in toluene and heated to
120 °C for 4 h under N2. After cooling to room temperature, THF (5 mL) and 2 N aq. HCl solution (2
mL) was added to the solution and stirred for 2 h. After completion, the mixture was quenched with a
saturated solution of NaHCO3 (10 mL) and extracted with EtOAc (3 × 20 mL). The combined organic
layers were washed with saturated aqueous NaHCO3 (10 mL), brine (10 mL) and dried over anhydrous
Na2SO4, filtered, and concentrated. The residue was purified by a flash column chromatography on silica
gel (hexane/EtOAc = 6:1) to give the aldehyde 21a (0.54 g, 90% yield in 2 steps) as a colorless crystal.
Compound 21a: Rf = 0.35 (silica gel, hexane/EtOAc = 2:1, PMA); [α]25 D = - 65 (c = 0.5, CHCl3); m.p.:
138.9–140.2 oC; IR (thin film, ν cm-1): 2993, 2917, 2851, 1762, 1726, 1693, 1276, 1204; HRMS (ESI):
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m/z calcd for C18H25O4 [M+H]+: 305.1747; found: 305.1748. 1H NMR (500 MHz, Acetone) δ = 9.76
(d, J = 2.9 Hz, 1H), 5.48 – 5.39 (m, 1H), 5.25 – 5.14 (m, 1H), 5.06 (d, J = 6.7 Hz, 1H), 3.88 (t, J = 8.1
Hz, 1H), 3.15 – 3.03 (m, 2H), 2.99 (dd, J = 12.1, 7.5 Hz, 1H), 2.73 (t, J = 14.3 Hz, 1H), 2.27 (dd, J =
14.5, 1.9 Hz, 1H), 1.92 – 1.85 (m, 1H), 1.84 – 1.76 (m, 1H), 1.61 (d, J = 6.3 Hz, 3H), 1.04 (s, 3H), 1.03
(d, J = 6.7 Hz, 3H), 1.00 (d, J = 6.6 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, Acetone) δ = 210.1, 201.6,
177.4, 130.1, 127.2, 79.7, 56.4, 56.0, 53.6, 50.8, 49.9, 46.7, 35.6, 31.2, 21.2, 21.0, 20.7, 18.4 ppm.
Compound 21b: Rf = 0.6 (silica gel, hexane/EtOAc = 2:1, PMA). [α]25 D = 86 (c = 0.5, CHCl3); m.p.:
87.4–93.0 oC; IR (thin film, ν cm-1): 2995, 2918, 2853, 1765, 1727, 1695, 1207; HRMS (ESI): m/z calcd
+
for C18H25O4 [M+H]+: 305.1747; found: 305.1748; 1H NMR (400 MHz, Acetone) δ = 9.63 (d, J = 0.4
Hz, 1H), 5.76 – 5.61 (m, 1H), 5.26 – 5.13 (m, 2H), 3.93 (dd, J = 10.5, 6.2 Hz, 1H), 3.61 (dd, J = 10.9,
7.2 Hz, 1H), 3.30 (dd, J = 10.5, 7.4 Hz, 1H), 3.04 (dd, J = 12.1, 5.4 Hz, 1H), 2.72 – 2.62 (m, 1H), 2.24
– 2.12 (m, 2H), 1.75 – 1.67 (m, 1H), 1.65 (dd, J = 6.5, 1.6 Hz, 3H), 1.11 (s, 3H), 1.05 (d, J = 6.7 Hz,
3H), 0.98 (d, J = 6.7 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, Acetone) δ = 211.3, 199.0, 177.8, 130.4,
125.7, 76.0, 57.8, 56.4, 51.6, 50.3, 43.5, 42.7, 35.9, 30.4, 20.3, 19.8, 19.6, 17.0 ppm.
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(2aR,2a1S,3R,4S,4aR,7S,7aR)-7-isopropyl-4a-methyl-3-(3-methylpent-4-enoyl)-4-((E)-prop-1-en-
1-yl)octahydroindeno[7,1-bc]furan-2,5-dione (22b):
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To a flame-dried flask under N2 containing Ni(acac)2 (51.4 mg, 0.2 mmol, 0.2 equiv) was introduced a
solution of aldehyde 21b (304 mg, 1.0 mmol 1.0 equiv) in THF (10 mL) and isoprene (0.4 mL, 4.0
mmol, 4.0 equiv) via syringe at room temperature. Then Et2Zn (1 M in hexane, 2.4 mL, 2.4 mmol, 2.4
equiv) was added dropwise at 0 oC.[6] The mixture was stirred at room temperature for 4 h, during which
the reaction was monitored by TLC. After dilution with ethyl acetate (10 mL), the mixture was washed
successively with aq. HCl solution (1N, 10 mL), saturated aqueous NaHCO3 (10 mL), brine (10 mL)
and dried over Na2SO4 and concentrated under vacuum. The residual oil was used directly for the next
step without further purification. To a solution of this crude alcohol in DCM (10 mL) was added
NaHCO3 (0.42 g, 5.0 mmol, 5.0 equiv) and Dess-Martin periodinane (2.54 g, 6.0 mmol, 1.2 equiv) at 0
oC. The reaction mixture was stirred for 4 h at room temperature. After completion, the solvent was
removed under vacuum, and the residue was purified by flash column chromatography on silica gel
(hexane/ethyl acetate = 6:1) to give compound 22b (332 mg, 94% yield for 2 steps) as a viscous oil.
Compound 22b: Rf = 0.50 (silica gel, hexane/EtOAc = 2:1, PMA); [α]25 D = - 110 (c = 0.5, CHCl3);
IR (thin film, ν cm-1): 2961, 2930, 2880, 2853, 1771, 1710, 1372, 1120; HRMS (ESI): m/z calcd for
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C23H32NaO4 [M+Na]+: 395.2193; found: 395.2197; H NMR (500 MHz, CDCl3) δ = 5.80 – 5.69 (m,
1H), 5.62 – 5.51 (m, 1H), 5.05 – 4.90 (m, 4H), 4.04 (dd, J = 10.8, 7.4 Hz, 1H), 3.58 (dd, J = 11.0, 6.9
Hz, 1H), 3.15 – 3.01 (m, 2H), 2.75 – 2.62 (m, 2H), 2.49 (dd, J = 17.2, 4.9 Hz, 1H), 2.35 – 2.18 (m, 2H),
2.02 – 1.93 (m, 1H), 1.84 – 1.73 (m, 1H), 1.63 (d, J = 5.4 Hz, 3H), 1.09 (s, 3H), 1.05 (d, J = 6.6 Hz, 3H),
0.97 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H) ppm. 13C{1H} NMR (125 MHz, CDCl3) δ = 212.4,
204.9, 178.2, 142.9, 131.0, 125.1, 113.0, 75.7, 57.8, 57.5, 53.5, 49.9, 49.4, 45.0, 42.9, 36.3, 32.5, 30.3,
22.0, 20.7, 20.4, 19.7, 17.8 ppm.
(2aR,2a1S,3S,5aR,5bS,10aR,10bR)-3-isopropyl-5a,8-dimethyl-2a,2a1,3,4,5a,5b,8,9,10a,10b-
decahydro-1H-cyclohepta[2,3]indeno[7,1-bc]furan-1,5,10-trione (23b):
To an N2-purged flask containing Grubbs II catalyst (100 mg, 0.12 mmol, 0.2 equiv) was introduced a
solution of 22b (220 mg, 0.6 mmol) in DCM via syringe. The solution was refluxed for 6 h. After
completion, the solvent was removed under vacuum, and the residue was purified by flash column
chromatography on silica gel (hexane/ethyl acetate = 8:1) to give 23b (170 mg, 86% yield) as colorless
viscous oil. Compound 23b: Rf = 0.5 (silica gel, hexane/EtOAc = 2:1, PMA); IR (thin film, ν cm-1):
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2961, 2922, 1765, 1695, 1168; HRMS (ESI): m/z calcd for C20H26NaO4 [M+Na]+: 353.1723; found:
353.1723; 1H NMR (400 MHz, CDCl3) δ = 5.64 – 5.60 (m, 1H), 5.34 (dt, J = 11.5, 2.5 Hz, 1H), 4.93 (d,
J = 6.7 Hz, 1H), 4.05 (d, J = 8.5 Hz, 1H), 3.80 (d, J = 8.9 Hz, 1H), 3.09 – 2.99 (m, 1H), 2.98 – 2.88 (m,
2H), 2.61 (dd, J = 18.7, 3.6 Hz, 1H), 2.54 – 2.33 (m, 3H), 1.88 – 1.78 (m, 1H), 1.74 – 1.66 (m, 1H), 1.09
(d, J = 7.0 Hz, 3H), 1.03 (d, J = 6.6 Hz, 3H), 0.97 (d, J = 6.7 Hz, 3H), 0.88 (s, 3H) ppm. 13C{1H} NMR
(100 MHz, CDCl3) δ = 211.0, 209.6, 179.4, 137.7, 125.3, 77.9, 56.6, 54.9, 53.1, 51.4, 49.2, 47.6, 45.5,
34.7, 30.0, 27.1, 21.5, 21.5, 20.5, 20.2 ppm.
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(2aR,2a1S,3S,5aR,5bS,10aS,10bR)-3-isopropyl-5a,8-dimethyldodecahydro-1H-
cyclohepta[2,3]indeno[7,1-bc]furan-1,5,10-trione (24a):
To a Ar-purged flask containing Pd/C catalyst (12 mg, 20 wt%) was introduced a solution of 23a3a (57.5
mg, 0.17 mmol, 1.0 equiv) in MeOH via syringe. The solution was bubbled with H2 balloon and was
stirred for 36 h under H2 atmosphere. After completion, the solvent was removed under vacuum, and the
residue was purified by flash column chromatography on silica gel (hexane/ethyl acetate = 8:1) to give
24a (45 mg, 85% yield) as a viscous oil. Compound 24a: Rf = 0.45 (silica gel, hexane/EtOAc = 2:1,
PMA); [α]26 D = - 142 (c = 0.5, CHCl3); IR (thin film, ν cm-1): 2961, 2922, 2854, 1765, 1700, 1462,
1221, 1162, 1009; HRMS (ESI): m/z calcd for C20H26NaO4 [M+Na]+: 355.1880; found: 355.1877; 1H
+
NMR (400 MHz, CDCl3) δ = 4.86 (dd, J = 4.8, 1.6 Hz, 1H), 3.70 (dd, J = 8.3, 6.9 Hz, 1H), 2.86 (dd, J
= 13.0, 2.2 Hz, 1H), 2.79 – 2.61 (m, 3H), 2.59 – 2.52 (m, 1H), 2.39 – 2.34 (m, 1H), 2.24 – 2.16 (m, 1H),
1.91 – 1.78 (m, 2H), 1.78 – 1.66 (m, 2H), 1.65 – 1.52 (m, 1H), 1.06 – 1.00 (m, 6H), 0.99 (d, J = 6.7 Hz,
3H), 0.87 (d, J = 7.4 Hz, 3H) ppm. 13C{1H} NMR (100 MHz, CDCl3) δ = 210.6, 176.9, 77.8, 57.7, 54.3,
51.3, 50.7, 50.2, 47.8, 46.0, 35.5, 34.7, 29.9, 29.6, 28.3, 22.6, 20.5, 20.2, 19.4, 17.2 ppm.
Rh(III)-catalyzed double bond migration
To a flame-dried microwave vial equipped with a magnetic stir bar was charged with RhCl3•3H2O (8.0
mg, 0.03 mmol, 0.2 equiv), capped with a rubber septum, and evacuated and backfilled with N2 three
times. Then a solution of compound 23b (50.0 mg, 0.15 mmol, 1.0 equiv) in ethanol (3 mL) and DCM
(0.5 mL) was added to the vial. The vial was heated to 100 oC in an oil bath for 5 h. After completion,
the solvent was removed under vacuum, and the residue was purified by flash column chromatography
on silica gel (hexane/ethyl acetate = 6:1) to give Pavidolide B (1) (42.5 mg, 85% yield) as colorless
crystals. Pavidolide B (1): Rf = 0.40 (silica gel, hexane/EtOAc = 2:1, UV); [α]25 D = -146 (c = 0.42,
MeOH); mp : 179.6–180.9 oC; IR (thin film, ν cm-1): 2960, 2924, 1764, 1707, 1695, 1195, 1170; HRMS
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(ESI): m/z calcd for C20H26NaO4 [M+Na]+: 353.1723; found: 353.1723; 1H NMR (400 MHz, DMSO)
δ = 5.90 (s, 1H), 4.98 (d, J = 6.9 Hz, 1H), 3.71 (d, J = 9.0, 1H), 3.41 (d, J = 9.4 Hz, 1H), 2.96 (dd, J =
9.0, 6.8 Hz, 1H), 2.59 – 2.52 (m, 1H), 2.50 – 2.43 (m, 2H) 2.33 (dd, J = 17.8, 6.2 Hz, 1H), 2.17 (dd, J =
15.2, 2.5 Hz, 1H), 1.97 (s, 3H), 1.94 – 1.82 (m, 1H), 1.72 – 1.63 (m, 2H), 1.32 (dd, J = 24.7, 12.5 Hz,
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1H), 0.98 (d, J = 6.7 Hz, 3H), 0.93 (d, J = 6.7 Hz, 3H), 0.81 (s, 3H) ppm; C{1H} NMR (100 MHz,
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DMSO) δ = 211.5, 199.2, 179.9, 164.4, 128.3, 78.1, 59.2, 54.4, 53.8, 48.1, 46.8, 44.2, 34.7, 33.7, 30.2,
27.7, 26.3, 20.7, 20.7, 20.4 ppm.
ASSOCIATED CONTENT
Supporting Information. Additional experiments, NMR spectra, computational data, X-ray
crystallography data and CIF files are available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
gongjx@pku.edu.cn
zyang@pku.edu.cn
ORCID
Zhen Yang: 0000-0001-8036-934X
Jianxian Gong: 0000-0003-4331-0976
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENT
This work was supported by National Science Foundation of China (Grant Nos. 21632002, 21572009,
and U1606403), Guangdong Natural Science Foundation (Grant No. 2016A030306011), Shenzhen
Basic Research Program (Grant Nos. JCYJ20170818090044432, JCYJ20160226105337556 and
GRCK2017042414425972), and Qingdao National Laboratory for Marine Science and Technology
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(Nos. 2015ASKJ02 and LMDBKF201703). The hardware for the computational study was supported
by the high-performance computing platform of Peking University (PKU-HPC)
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REFERENCES
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(4)
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radical-mediated ring expansion and related annulations. Chem. Rev. 1993, 93, 2091–2115. For
transition metal-catalyzed annulation between activated VCPs and electron-deficient alkenes,
see: (b) Shimizu, I.; Ohashi, Y.; Tsuji, J. Palladium-catalyzed [3+2] cycloaddition reaction of
vinylcyclopropanes with α,β-unsaturated esters or ketones. Tetrahedron Lett. 1985, 26, 3825–
3828. (c) Jiao, L.; Yu, Z.-X. Vinylcyclopropane derivatives in transition-metal-catalyzed
cycloadditions for the synthesis of carbocyclic compounds. J. Org. Chem. 2013, 78, 6842–6848.
For recent applications of VCP [3+2] annulations in natural product synthesis, see: (d) Zhang,
H.; Curran, D. P. A short total synthesis of (±)-epimeloscine and (±)-meloscine enabled by a
cascade radical annulation of a divinylcyclopropane. J. Am. Chem. Soc. 2011, 133, 10376–10378.
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