Asymmetric total synthesis of (?)-perforanoid A

Article abstract of DOI:10.1016/j.tet.2017.03.072

Asymmetric total synthesis of (?)-perforanoid A, a novel limonoid isolated from the leaves of Harrisonia perforata, has been achieved. The key features of our total synthesis include the Rh-catalyzed intramolecular Pauson–Khand reaction of an allene and an alkene, the Pd-catalyzed lactonization of an allylic alcohol with a vinyl ether, and the enantioselective alkenylation of 3-furaldehyde.

Full text of DOI:10.1016/j.tet.2017.03.072

Accepted Manuscript
Asymmetric total synthesis of (-)-perforanoid A
Chao Lv, Qian Tu, Jianxian Gong, Xiaojiang Hao, Zhen Yang
PII:
S0040-4020(17)30329-0
10.1016/j.tet.2017.03.072
TET 28578
DOI:
Reference:
To appear in: Tetrahedron
Received Date: 30 January 2017
Revised Date: 24 March 2017
Accepted Date: 26 March 2017
Please cite this article as: Lv C, Tu Q, Gong J, Hao X, Yang Z, Asymmetric total synthesis of (-)-
perforanoid A, Tetrahedron (2017), doi: 10.1016/j.tet.2017.03.072.
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ACCEPTED MANUSCRIPT
Graphic abstract
O
O
O
OtBu
Pd(OAc)2
OH
O
O
O
58%
OtBu
+
Rh[(CO2Cl]2, CO 85%
O
O
O
O
O
CHO
H
H
O
O
H
O
H
H
1
2
O
2
H
O
O
O
Perforanoid A (1)

ACCEPTED MANUSCRIPT
Graphical Abstract
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Asymmetric Total Synthesis of (-)-Perforanoid
A
Leave this area blank for abstract info.
Chao Lv,b Qian Tu,a Jianxian Gong, a, Xiaojiang Hao b, and Zhen Yang a,
aLaboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University
Shenzhen Graduate School, Shenzhen, 518055, China
bState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany,
Chinese Academy of Sciences, Kunming, 650204, China

1
ACCEPTED MANUSCRIPT
Tetrahedron
journal homepage: www.elsevier.com
Asymmetric Total Synthesis of (-)-Perforanoid A
Chao Lv,b Qian Tu, a Jianxian Gong, a, Xiaojiang Hao b, and Zhen Yang a,
a Laboratory of Chemical Genomics, School of Chemical Biology and Biotechnology, Peking University Shenzhen Graduate School, Shenzhen, 518055, China
bState Key Laboratory of Phytochemistry and Plant Resources in West China, Kunming Institute of Botany, Chinese Academy of Sciences, Kunming, 650204
,China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Asymmetric total synthesis of (−)-perforanoid A, a novel limonoid isolated from the leaves of
Harrisonia perforata, has been achieved. The key features of our total synthesis include the
Rh-catalyzed intramolecular Pauson–Khand reaction of an allene and an alkene, the
Pd-catalyzed lactonization of an allylic alcohol with a vinyl ether, and the enantioselective
alkenylation of 3-furaldehyde.
Available online
2009 Elsevier Ltd. All rights reserved
.
Keywords:
(-)-Perforanoid A
Lemonoids
Asymmetric total synthesis
Rhodium catalyzed
Intramolecular Pauson-Khand
Corresponding authors. E-mail addresses: gongjx@pku.edu.cn (J. Gong), haoxj@mail.kib.ac.cn (X. Hao), zyang@pku.edu.cn (Z. Yang)

ACCEPTED MANUSCRIPT
2
____________________________________________________
1. Introduction
_
The synthesis of natural products with interesting biological
activity but low abundance in natural sources remains an
important area of research in chemistry, chemical biology, and
drug discovery.1 In this context, the limonoids represent an
important family of natural products that exhibit structural
diversity and a broad spectrum of biological activities.2 They
have applications in agriculture and medicine as a result of
their anti-feedent,2 anti-multi-drug resistance (MDR) bacteria,3
antimalarial,4 anti-cancer,5 and anti-leukemia6 properties.
While isolating the limonoids from species of the
Meliaceae and Simaroubaceae families in southern China, we
isolated a group of ring-demolished imonoids, featuring a
polycyclic lactone fragment (1–3 in Figure 1)7. Perforanoid A
(1), which is a novel type of limonoid, was isolated from the
dried leaves of Harrisonia perforata (Blanco) Merr. of the
Simaroubaceae family and is characterized by its fused
bicyclic γ-lactone subunit. Structurally, perforanoid A consists
of five rings, which contain six stereogenic centers; among
these is an all-carbon quaternary chiral center (C13). The
structural novelty of this compound and its cytotoxic activity
against tumor cell lines (HEL, K562, CB3) render perforanoid
A a compelling target for total synthesis..
From a synthetic point of view, we sought to design a
unified strategy to enable the total synthesis of perforanoid A,
and anticipated that the developed chemistry could also be
used to synthesize other limonoids, such as haperforin G (2)
and harrpemoid B (3). In a previous paper,8 we presented our
concise strategy for the construction of perforanoid A (1)
using a Pauson–Khand reaction as a key step. This strategy
enabled the total synthesis of perforanoid A to be achieved in
10 linear steps. In this full paper, we describe the details of our
efforts that led to the asymmetric total synthesis of
(−)-perforanoid A, which paves the way for the total synthesis
of the other liminoid family members.
Scheme 1. Retrosynthetic analysis for perforanoid A.
O
O
O
CHO
O
10
O
H
O
C
H
O
D
+
O
O
H
H
B
H
H
2
1
O
O
5
4
O
Michael
reaction
IMPK
reaction
Perforanoid A (1)
O
O
O
O
O
MeO
O
7
6
____________________________________________________
3. Model study
To explore the synthetic feasibility of the proposed IMPK
reaction, compound 8, which bears the BCD ring system of
perforanoid A (1), was chosen as a synthetic model. Scheme 2
illustrates our retrosynthetic analysis of 8. We envisaged that 8
could be assembled from enyne 9 by an IMPK reaction
followed by a decarboxylation.11 In 2010, Waser’s group
reported the ethynylation of keto, cyano, and nitro esters using
Waser’s
reagent
([(trimethylsilyl)ethynyl]-1,2-benziodoxol-3(1H)-one,
TMS-EBX). We envisioned that enyne 9 could be accessed
from diester 10 by sequential Michael addition,12
intramolecular lactonization, and Waser’s ethynylation.13 Ester
10 could in turn be prepared from ketone 11 and dimethyl
malonate in a Knoevenagel reaction.14
_____________________________________________________
____________________________________________________
Scheme 2. Retrosynthetic analysis for model compound 8.
Fig. 1. Representitive liminoids from Harrisonia perforate.
_____________________________________________________
2. Retrosynthetic analylisis
Retrosynthetically, perforanoid A (1) can be divided into
two major pieces, 4 (right fragment) and 5 (left fragment),
which could be combined in an aldol condensation. Right
ketoester fragment 4, which contains the BCD tricyclic core of
perforanoid A (1) could in turn be constructed from enyne 6 in
an intramolecular Pauson–Khand (IMPK) reaction, a powerful
instrument used in the total synthesis of complex natural
products.9 The γ-lactone side chain (A ring) in left fragment 5
could be generated from known optically pure butenolide 7
through a Michael reaction.10
_____________________________________________________
Scheme 3 illustrates the synthesis of key intermediate 9.
The synthesis commenced with a TiCl4-mediated Knoevenagel

ACCEPTED MANUSCRIPT
3
reaction of ketone 11 with dimethyl malonate in THF to afford
α,β-unsaturated ester 10 in 74% yield. With compound 10 in
hand, we then adopted two protocols for the synthesis of
lactone 14. Substrate 10 was converted to corresponding
lactone 12 by treatment with HCl in MeOH, followed by
reaction with but-3-enylmagnesium bromide in the presence of
CuI and BF3•Et2O to give 14 in 71% yield as a pair of
diastereoisomers in a ratio of 3/2. Alternatively, product 14
could also be prepared by reaction of 10 with
but-3-enylmagnesium bromide in the presence of CuI and
BF3•Et2O to give diester 13, which was then treated with
K2CO3 to afford lactone 14 in 44% yield in two steps as a pair
of diastereoisomers in a ratio of 3/2. It is worth mentioning
that BF3•Et2O was more effective than other Lewis acids (such
as TiCl4, TMSCl, and AlCl3) as an additive in the Michael
reaction, and that in the absence of a Lewis acid, the addition
product was not observed.[12]
NR
6
7
Benzene
PhMe
-
reflux
110
110
110
110
NMO
15a (19.6%)+15b (5.4%)
15a (10%)+15b (5%)
15a (21.4%)+15b(8.6%)
trace
TMAMO
Me2S
8
PhMe
9
PhMe
TMTU
10
PhMe
a Isolated yield.
With substrates 9 and 9a in hand, we began to investigate
the Pauson–Khand reactions. Initially, we carried out the
reaction in the presence of a stoichiometric amount of
Co2(CO)8 in toluene at 80 °C, and expected products 15a and
15b were obtained in yields of 5.7% and 4.3%, respectively
(Table 1, entry 1). To improve the yields, we performed the
reaction at a higher temperature, and the yields increased to
16.8% and 11.2%, respectively (entry 3). We also attempted to
improve the outcome by changing the reaction solvent from
toluene to THF, acetonitrile, and benzene; however, none of
these solvents gave the expected products (entries 4–6). The
structure of 15a was confirmed by NOESY experiments, and
that of 15b was confirmed by X-ray crystallographic analysis.
Thus, the relative stereochemistry of 15a was in agreement
with that of the natural product perforanoid A (1).
To further improve the yield, we next added additives to the
annulation. However, no significant improvement was
observed when Me2S, N-methylmorpholine-N-oxide (NMO),
trimethylamine-N-oxide (TMANO), or tetramethyl thiourea
(TMTU) (entries 7–10) were added.15
We reasoned that the quaternary carbon center in the
substrate might provide steric hindrance that could interfere
with the desired annulation. We therefore decided to remove
the ester group from its quaternary center. To this end, we
treated lactone 9 with LiCl in the presence of water in DMF at
130 °C. To our surprise, expected enyne 17 was not obtained;
however, allene 16 was obtained in 78% yield. Thus, under
similar conditions, 9a was also converted to 16 (Scheme 4).
_____________________________________________________
_____________________________________________________
HCl
MeOH
CO2Me
O
MeO2C
CO2Me
CO2Me
OAc
MeO2C
O
OAc
TiCl4, Py, THF
74%
73%
O
11
10
12
MgBr
MgBr
71%
dr 3:2
62%
CuI, BF3 Et2O
CuI, BF3 Et2O
TMS
O
I
O
MeO2C
CO2Me
OAc
K2CO3
71%
O
Waser's reagent
MeO2C
dr 3:2
O
14
13
Waser's reagrnt
TBAF
(44% for
O
+
O
9
34% for 9a)
O
O
MeO
O
MeO
O
9
9a
Scheme 3. Synthesis of key intermediate 9.
_____________________________________________________
We then worked on the synthesis of compounds 9 and 9a.
To this end, lactone 14 was directly reacted as a pair of
diastereisomers with Waser’s reagent in the presence of
tetrabutylammonium fluoride (TBAF), and resultant enynes 9
and 9a could be separated by flash chromatography on silica
gel to give 9 and 9a in 44% and 34% yield, respectively.
_____________________________________________________
Scheme 4. Synthesis of model compound 8.
Table 1. Optimization results of the Pauson-Khand reaction.
entry solvents additive
T(°C)
resultsa
1
2
3
4
5
PhMe
PhMe
PhMe
THF
-
-
-
-
-
80
95
15a (5.7%)+15b (4.3%)
15a (14.1%)+15b (10.9%)
_____________________________________________________
110
15a (16.8%)+16b (11.2%)
In 2006, Mukai and co-workers reported rhodium-catalyzed
Pauson–Khand reactions of allenenes for the formation of
bicyclo[4.3.0]non-1(9)-en-8-ones,16 and applied the method in
the total synthesis of sesquiterpene-based natural products.16b
Inspired by this chemistry, we attempted to adopt this protocol
reflux
reflux
NR
NR
CH3CN

ACCEPTED MANUSCRIPT
4
for the formation of enone 8 from allene 16. When we treated
allene 16 with [Rh(CO)(dppp)Cl]2 (5 mol%) in refluxing
toluene under a balloon pressure of CO, enone 8, which has
the desired stereochemistry at C9, was formed in 50% yield as
a single isomer,16b and its stereochemistry was confirmed by
X-ray crystallographic analysis. To further improve the yield,
we tested other rhodium catalysts, such as [Rh(CO)2Cl]2,
[Rh(CO)(dppp)Cl]2, [Rh(CO)(dppe)Cl]2, and found that enone
8 could be obtained in 73% yield when [RhCl(cod)]2 was used
as the catalyst in refluxing toluene under a balloon pressure of
CO.
dimethyl malonate 24 proceeded to afford 25 in 44% yield in
two steps. It is worth mentioning that TMSCl was effective as
a Lewis acid additive in the Michael reaction, but other Lewis
acids (such as BF3•Et2O, TiCl4, and AlCl3) failed to give the
desired product.12
4. First-Generation for the synthesis of right fragment
_____________________________________________________
Having established a way to construct the BCD tricyclic
ring system of perforanoid A (1), we decided to apply it to the
synthesis of the right fragment (BCDE ring system) of 1.
As illustrated in Scheme 5, enone motif 4 was expected to
be obtained from the Rh-catalyzed IMPK reaction of allenene
18, which, in turn, could be prepared from α,β-unsaturated
ester 19 through Michael addition, alkynylation, and
decarboxylation. The relative stereochemistry of the methyl
group and the furyl ring in 4 could be controlled by the
chirality of the furyl ring, to make the nucleophile approach
the α,β-unsaturated ester from the back of the furyl ring. Thus,
our retrosynthetic analysis leads back to the formation of
α,β-unsaturated ester 19, which, in turn, is expected to be
formed through a Knoevenagel reaction of ketone 20 followed
by intramolecular lactonization.
Scheme 6. Synthesis of 27.
O
O
O
(90%)
MgCl
a)
c) Hg(OTf)2, TMU, H2O
(90%)
b) Ac2O, Et3N
DMAP (91%)
OAc
CHO
OAc
22
O
21
20
d)
MeO2C
CO2Me
TiCl4 (83%)
O
O
O
g) Waser's
e)
MgBr
reagent
TBAF (90%)
CuI,TMSCl
(54%)
h) LiCl, H2O
(51%)
O
O
f) K2CO3
(81%)
OAc
CO2Me
MeO2C
25
MeO2C
O
O
26
23
i) [Rh(CO)2Cl]2 (5 mol%)
PhMe, CO, reflux (74%)
acidic
or basic
_____________________________________________________
O
O
Scheme 5. First-generation retrosynthetic analysis of right
fragment.
17
O
H
O
O
O
O
H
O
MeO2C
Rh-catalyzed
PK reaction
27
19
O
ORTEP of 27
O
H
O
O
_____________________________________________________
H
O
O
18
To complete the synthesis of 27, ester 25 was first reacted
with Waser’s reagent in the presence of TBAF, and the
resultant enyne was then subjected to decarboxylation by
treatment with LiCl–H2O in DMF at 130 °C to give allenene
26 in 46% overall yield. Thus, under the optimized IMPK
reaction conditions, allenene 26 was treated with [RhCl(CO)2]2
(5 mol%) under a balloon pressure of CO at 120 °C in toluene
to give enone 27 in 74% yield as a single isomer. However,
X-ray crystallographic analysis revealed that the
stereochemistry at C17 in enone 27 was opposite to the desired
stereochemistry. To account for this observation, we built a
Felkin–Ahn model,17 which indicated that the nucleophile
approached the α,β-unsaturated double bond in ester 23 from
the less hindered side. As a result, ester 24 was generated as
the major product (Scheme 7).
4
O
O
Knoevenagel
condensation
O
intramolecular
lactonization
OAc
MeO2C
O
20
19
O
_____________________________________________________
Scheme shows our synthesis of compound 27.
6
Commercially available furan-3-carbaldehyde 21 was reacted
with ethynylmagnesium chloride to generate the alcohol,
which was then converted into acetate 22 in 82% yield in two
steps. Further treatment of 22 with H2O in the presence of a
catalytic amount of Hg(OTf)2-TMU afforded ketone 20, which
in turn underwent a TiCl4-mediated condensation to give 23 in
75% yield in two steps.
With 23 in hand, we then proceeded to prepare lactone 19
through an intramolecular lactonization. Initially, we treated
23 with various acids or bases; however, lactone 19 was not
formed, presumably because of the double bond in substrate
23 which prevented the lactonization. We therefore treated
ester 23 with but-3-enylmagnesium bromide in the presence of
CuI-TMSCl, and the expected lactonization of resultant
_____________________________________________________
Scheme 7. Felkin-Ahn model to rationalize the stereochemical
outcome.

ACCEPTED MANUSCRIPT
5
O
OAc
CO2Me
H
OAc
CO2Me
H
Me
17
13
Me
OAc
CO2Me
CO2Me
MeO2C CO2Me
O
23
O
24
_____________________________________________________
Although this synthetic route failed to afford right fragment
4, the Rh-catalyzed IMPK reaction for the stereoselective
formation of 27 from allenene 26 might provide a concise
route to the core structure of perforanoid A (1).
We then attempted to develop a strategy to invert the
stereochemistry at C17. To this end, substrate 24 was
subjected to decarboxylation by reaction with LiCl–H2O in
DMF at 130 °C, and resultant monoester 28 was reduced with
LiAlH4 to give diol 29 in 48% overall yield.
_____________________________________________________
Scheme 8. Synthesis of diol 32.
_____________________________________________________
Further oxidation of inseparable diol 32 with
TEMPO-DAIB afforded lactones 34 and 33 as separable
diastereoisomers19 in 37% and 30% yields, respectively. By
1
comparing the H NMR spectra of 33 and 34 with lactone 25,
we confirmed that 33 was our desired lactone. Thus, the
enolate obtained after treatment of lactone 33 with lithium
hexamethyldisilazide (LiHMDS) was reacted with methyl
carbonochloridate to give ester 35 in 93% yield as a pair of
diastereoisomers in
a
ratio of 1.2:1. The pair of
diastereoisomers of 35 was further reacted without separation
with Waser’s reagent in the presence of TBAF, followed by
decarboxylation with LiCl–H2O to afford allene 18 through
intermediate 17 in 68% overall yield. [RhCl(CO)2]2-catalyzed
(5 mol%) reaction of allene 18 with CO at 120 °C in toluene
gave enone (±)-4 in 83% yield. In this way, we successfully
constructed desired right fragment (±)-4 of perforanoid A in
15 steps (Scheme 9).
_____________________________________________________
To invert the C17 stereogenic center, diol 29 was first
treated with Ac2O/Et3N, and resultant monoacetate 30 was
then oxidized with DMP to afford ketone 31 in 73% yield for
the last two steps. However, attempts with various reducing
agents, including NaBH4, LiAlH4, Me4NBH4, Zn(BH4)2,
5. Second-Generation for the synthesis of right fragment
LiHBEt3,
NaBH4/CeCl3•7H2O,
diastereoselective reduction of ketone 31 were unsuccessful.
Li(OtBu)3AlH,
and
Bu4NBH4,
LiBH4, to
NaBH4/CaCl2,
achieve the
Having established a strategy for the racemic synthesis of
the right fragment of perforanoid A (1), we next aimed to
determine an asymmetric strategy with a Rh-catalyzed IMPK
reaction as the key step. To achieve this goal, we needed to
The best result was obtained when LiAlH4 was used as the
reductant, and gave diol 3218 in 95% yield with
a
diastereoselectivity ratio of 1.3:1 (Scheme 8).
_____________________________________________________
find
a method for the asymmetric synthesis of key
intermediate 37 (Scheme 10), which would ensure that we
could construct the right fragment of perforanoid A (1) in an
asymmetric fashion according to the chemistry presented
above.
Scheme 9. Synthesis of ( )-4.
±
_____________________________________________________
Scheme 10. Second-generation retrosynthetic analysis of right
fragment.

ACCEPTED MANUSCRIPT
6
_____________________________________________________
Scheme 10 illustrates the retrosynthetic analysis for our
second generation, asymmetric synthesis of intermediate 4.
Accordingly, we expected intermediate 4 to be derived from
cyclic acetal 36 through intermediate 18, and cyclic acetal 36
was in turn expected to be generated from chiral allylic
alcohol 37 by a Pd-catalyzed Oshima–Utimoto reaction.20
Scheme 11 illustrates our asymmetric synthesis of right
fragment 4. The synthesis began with the asymmetric
construction of allylic alcohol 37 in an asymmetric allylation
in the presence of 1-[(S)-phenyl{[(1′S)-1′-phenylethyl]methyl-
amino}-methyl]-2-naphthol.21 When furan-3-carbaldehyde 19
was reacted with 2-butenyl methyl zinc [derived from the
reaction of 2-butyne, dicyclohexylborane (Cy2BH), and
Me2Zn]22 in the presence of tertiary aminonaphthol, desired
allylic alcohol 37 was isolated in 80% yield with 90% ee.
Acetal 36 was furnished by adopting Morken’s protocal in a
Pd-catalyzed Oshima–Utimoto reaction from allylic alcohol
37. In this reaction, treatment of 37 with Pd(OAc)2 in the
presence of benzoquinone and AcOH in CH3CN gave acetal
36 in 58% yield as anomers with a dr value of 1:1, and
diastereoisomers at the C13 quaternary center in a ratio of
20:1, in favor of the desired isomer. The reaction proceeded
through a stereoselective carbopalladation of the tethered
alkene via a chair-like transition state to afford a cyclic acetal
bearing a defined quaternary carbon stereocenter. This cyclic
acetal then underwent a β-hydride elimination to deliver the
furan acetal product as well as palladium(0), which required
reoxidation to continue the catalytic cycle.20
Scheme 11. Asymmetric synthesis of (-)-4.
_____________________________________________________
To prepare lactone (−)-33, we intended to develop a
synthetic protocol containing sequential iodination,
metal-catalyzed cross-coupling,23-24 and Jones oxidation
reactions. To this end, acetal 36 was treated with ZrCp2Cl2 and
LiAlH(OtBu)3, and then quenched with I2 to give iodide 38 in
85% yield. The ligation of iodide 38 with an olefin was
achieved in a nickel-catalyzed coupling reaction developed by
Molander and co-workers,25 and the resultant product was then
subjected to
a
Jones oxidation to give expected
γ
-butyrolactone (−)-33 in 45% yield over two steps. Treatment
of (−)-33 with LiHMDS and reaction of the resultant enolate
with methyl carbonochloridate, followed by acetylation by
treatment with Waser’s reagent gave enyne 6 in 88% yield as a
pair of diastereoisomers at the newly generated stereogenic
center at C14. Thus, treatment of enyne 6 with LiCl–H2O in
DMF at 130 °C, followed by an optimized Rh-catalyzed IMPK
reaction8 of resultant allenene (−)-18 gave (−)-4 in 68%
overall yield as a single isomer. The relative stereochemistry
of 4 was confirmed by X-ray crystallographic analysis.
_____________________________________________________
6. Synthesis of left fragment
Having constructed the right fragment of 1, we turned our
attention to the synthesis of left fragments 5a and 5b; Scheme
12 lists the synthetic details. We attempted to prepare
intermediate 39 using a Cu-mediated Michael reaction of
known optically pure compound 7. To this end, furanone 7
was reacted with a Grignard reagent in the presence of
(phenylthio)copper (PhSCu) to give lactones 39a and 39b in
60% combined yield as a pair of diastereoisomers at C10 with
a dr ratio of 3:2. PhSCu was essential for the success of the
desired reaction; other cuprite reagents, including CuI, CuCl,
and CuBr2•Me2S, with or without Lewis acids, did not furnish
expected products 39a and 39b. Both diastereosiomers (39a
and 39b) were then treated with ozone, followed by reaction
with NaBH4 to give alcohols 40a and 40b in 85% yield.
_____________________________________________________
Scheme 12. Asymmetric synthesis of 5a/5b.

ACCEPTED MANUSCRIPT
7
HO
a.
PhSCu
Me
b. O3
CH2Cl2
MeOH
10
10
H
H
MgCl
O
O
O
O
then NaBH4
(85%)
O
(60% with
dr 3:2
at C-10)
O
40a/40b
7
39a/39b
c.TBDPSCl, Imid.
CH2Cl2 (90%)
TBDPSO
TBDPSO
N
TBDPSO
10
O
10
10
d. Me3Al
e. DMP
NaHCO3
Me2NH HCl
H
H
H
N
O
43a/43b
O
0 °C to rt
O
O HO
42a/42b
(53% for 42a
and 32% for 42b)
41a/41b
f. MeMgCl, then 1M HCl
(75% for 44a and 77% for 44b)
Scheme 13. Synthesis of mosher’s esters 46ar/46as and
46br/46bs.
TBDPSO
O
_____________________________________________________
O
10
10
g. TBAF
H
H
To complete the total synthesis, enone (-)-4 was treated with
h. DMP
(68% for 5a
and 66% for 5b)
°
O
LDA in THF at -78 C; the resulting enolate underwent an
O
O
aldol reaction with aldehyde 5a to give an alcohol, which was
then dehydrated by treatment with Burgess reagent29 to give
perforanoid A (1) in 33% (51% brsm) overall yield (Scheme
14). Under identical conditions, 10-epi perforanoid A (47) was
44a/44b
5a/5b
_____________________________________________________
Alcohols 40a and 40b were protected as the silyl ethers
using TBDPSCl in the presence of imidazole to furnish 41a
and 41b in 90% yield. To separate the diastereoisomers, 41a
and 41b were treated with the hydrochloride salt of
dimethylamine in the presence of trimethylaluminum to afford
hydroxyamides 42a and 42b as separable products in 53% and
32% yields, respectively.26 Because one of the objectives of
our asymmetric total synthesis of perforanoid A was to
confirm the stereochemical assignment at C10, we needed to
convert 42a and 42b into left fragments 5a and 5b, and react
them both with right fragment (−)-4 to afford the
corresponding aldol condensation products. One of these
condensation products should match the natural product with
the desired stereochemistry at C10.
1
obtained in 36% (53% brsm) overall yield. The H and 13C
NMR spectra and specific rotation of the synthesized
perforanoid A were in agreement with those of natural
perforanoid A (synthetic perforanoid A: [α]2D2 = -183.5 (c =
0.18, MeOH); natural perforanoid A: ([α]2D2 = -199.2 (c = 0.09,
MeOH)). Our results show that the structure of perforanoid A
is 1, and compound 47 was assigned as 10-epi perforanoid A.
_____________________________________________________
Scheme 14. Completion of the total synthesis.
Oxidation of 42a with DMP in the presence of NaHCO3 in
CH2Cl2, and treatment of resulting ketone 43a with MeMgCl
followed by an acid-mediated intramolecular lactonization27
afforded lactone 44a in 75% overall yield. Under similar
conditions, lactone 44b was obtained in 77% yield from
alcohol 42b. Finally, treatment of 44a with TBAF to remove
the silyl protection group and oxidation of the obtained
primary alcohol gave corresponding aldehyde 5a in 68% yield
over two steps. Alcohol 44b was converted to aldehyde 5b in
66% yield by following the same procedure. Notably, DMP
oxidation was effective for the preparation of aldehydes 5a
and 5b without epimerization.
_____________________________________________________
8. Conclusion
7. Completion of total synthesis
In summary, we have achieved a concise total synthesis of
limonoid perforanoid A (1) in 10 steps by developing a unified
synthetic strategy. The key features of our approach include
the chiral tertiary aminonaphthol-mediated enantioselective
alkenylation of aldehydes for the asymmetric synthesis of
allylic alcohol 37, Pd-catalyzed coupling of 37 with a vinyl
To establish the absolute stereochemistry at C10 in 5a and
5b, 45a, and 45b were converted into corresponding Mosher
esters 46ar/46as and 46br/46bs (Scheme 13). The absolute
stereochemistry at C10 in 5a and 5b was determined to be S
and R, respectively, by comparison of the H NMR and 19F
1
NMR spectra.28
ether to form the
γ-lactone ring with stereoselective
_____________________________________________________
construction of the C13 all-carbon quaternary center, and a
Rh-catalyzed Pauson–Khand reaction to form the polycyclic
cyclopentenone ring system in perforanoid A. The developed
chemistry may be modified to facilitate the total synthesis of
other limonoid natural products.

ACCEPTED MANUSCRIPT
8
28.3, 20.7, 17.5; HRMS (ESI) (M+Na)+ calcd for
C15H15O5Na+: 301.1046, found: 301.1045.
Experimental section
8.1. Synthesis of Compound (±)-33 and (±)-34
:
8.3. Synthesis of Compound )-6
(±
To a solution of diol 32 (113 mg, 0.5 mmol) in dry
CH2Cl2 (3 mL) was added TEMPO
To a solution of ester 35 (134 mg, 0.48 mmol, 1.0 equiv.) in
dry THF (3 mL) was added Waser’s reagent (332 mg, 0.96
mmol, 2.0 equiv.) at -78 °C, and the resultant mixture was
stirred at the same temperature for 5 min. To this solution was
added TBAF (1M in THF, 0.96 mL, 0.96 mmol, 2.0 equiv.) at
-78 °C in a drop-wise manner, and the resultant mixture was
stirred first at -78 °C for 1 h, and then at room temperature for
9 h. The reaction was quenched with brine (10 mL), and the
mixture was extracted by EA, then the combined organic
extracts were dried over Na2SO4. The solvent was removed
under vacuum, the residue was purified by a flash column
chromatography (hexane/EA = 20/1) on silica gel to give
enyne 6 (128 mg, yield 85%) as colorless oil.
(2,2,6,6-tetramethylpiperidinooxy, 23.4 mg, 0.15 mmol, 0.3
equiv.), and the resultant mixture was stirred at room
temperature for 5 min. To this solution was added DAIB
(Iodobenzene diacetate, 209.3 mg, 6.5 mmol, 1.3 equiv.), and
the mixture was then stirred at room temperature for 12 h. The
reaction was quenched by addition of a saturated solution of
NH4Cl (10 mL), and the mixture was extracted with EA (5 ×
10 mL), the combined organic extract was dried over
anhydrous Na2SO4. After removal of the solvent under
vacuum, the residue was purified by a flash column
chromatography (hexane/EA = 30/1) on silica gel to give
lactones 33 (40.5 mg, 37% yield) and 34 (33.5 mg, 30% yield)
as colorless oil.
1
(±)-6: H NMR (400 MHz, CDCl3) δ 7.61 – 7.39 (m, 2H),
(±)-33: IR (neat, ν cm-1): 2936, 1781, 1503, 1460, 1164,
1029, 875, 800, 602; 1H NMR (400 MHz, CDCl3) δ 7.43 (s,
1H), 7.42 (s, 1H), 6.34 (t, J = 1.3 Hz, 1H), 5.80 (ddt, J = 16.8,
10.2, 6.5 Hz, 1H), 5.13 (s, 1H), 5.09 – 4.94 (m, 2H), 2.54 (d, J
= 16.9 Hz, 1H), 2.41 (d, J = 16.9 Hz, 1H), 2.16 (dtdd, J = 13.6,
7.3, 4.5, 3.1 Hz, 1H), 2.10 – 1.93 (m, 1H), 1.65 – 1.52 (m,
2H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 175.7,
143.5, 140.0, 137.5, 120.3, 115.4, 108.8, 83.3, 43.8, 42.2,
37.7, 29.1, 20.0; HRMS (ESI) (M+Na)+ calcd for
C13H16O3Na+: 243.0992, found: 243.0992.
6.48 – 6.23 (m, 1H), 5.88 – 5.59 (m, 1H), 5.44 and 5.37 (2s,
1H), 5.01 (dddd, J = 13.4, 10.2, 2.8, 1.5 Hz, 2H), 3.89 and
3.86 (2s, 3H), 2.72 and 2.69 (2s, 1H), 2.49 – 2.35 (m, 0.6H),
2.26 – 2.02 (m, 2H), 1.92 (ddd, J = 14.0, 11.5, 6.5 Hz, 0.4H),
1.57 – 1.42 (m, 2H), 1.11 and 0.95 (2s, 3H); 13C NMR (100
MHz, CDCl3) δ 169.7, 168.6, 166.4, 166.2, 143.7, 141.1,
140.9, 137.7, 137.6, 118.9, 118.6, 115.3, 115.2, 109.4, 109.3,
82.2, 81.5, 77.9, 77.9, 76.0, 74.5, 61.5, 59.3, 53.9, 53.5, 52.0,
51.7, 34.7, 34.5, 27.7, 27.6, 18.3, 16.7; HRMS (ESI) (M+Na)+
calcd for C17H18O5Na+: 325.1046, found: 325.1046.
(±)-34: IR (thin film, ν cm-1): 2936, 1781, 1164, 1029,
1
8.4. Synthesis of Compound (±)-18
874, 800; H NMR (400 MHz, CDCl3) δ 7.44 (t, J = 1.7 Hz,
1H), 7.43 – 7.40 (m, 1H), 6.32 (dd, J = 1.7, 0.7 Hz, 1H), 5.67
(ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.13 (s, 1H), 5.02 – 4.80 (m,
2H), 2.60 (d, J = 17.1 Hz, 1H), 2.38 (dd, J = 17.1, 0.6 Hz, 1H),
2.10 – 1.81 (m, 2H), 1.43 – 1.04 (m, 5H); 13C NMR (100
MHz, CDCl3) δ 175.9, 143.8, 140.1, 137.8, 120.5, 115.1,
108.8, 84.7, 43.4, 41.0, 34.3, 28.7, 23.3; HRMS (ESI)
(M+Na)+ calcd for C13H16O3Na+: 243.0992, found: 243.0998.
To a solution of enyne 6 (0.228 g, 0.76 mmol, 1.0 equiv)
in DMF (4 mL) was sequentially added H2O (28 ꢀL, 0.76
mmol, 2.0 equiv) and LiCl (96 mg, 2.28 mmol, 3.0 equiv), and
the resultant mixture was degased with N2 for 6 times. The
reaction mixture was stirred at room temperature for 5 min,
and then transferred to a preheated oil bath at 110 °C for 2 h.
After cooling to room temperature, then reaction mixture was
quenched by addition of water (10 mL), and the mixture was
extracted with Et2O, and the combined organic extracts were
dried over anhydrous Na2SO4. After removal of the solvent
under vacuum, the residue was purified by a flash column
chromatography (hexane/EA :30/1) on silica gel to give allene
(±)-18 (95 mg, 51%) as wax.
8.2. Synthesis of Compound (±)-35
:
To a solution of lactone 33 (2.83 g, 12.83 mmol) in dry
THF (60 mL) was added LiHMDS (32.1 mL, 32.1 mmol, 2.5
equiv) at -78 °C in a drop-wise manner, and the resultant
mixture was stirred at the same temperature for 2 h. To this
solution was added ClCO2Me (2.42 g, 25.66 mmol, 2.0 equiv)
at -78 °C in a drop-wise manner, and the resultant mixture was
first stirred at the same temperature for 1 h, and then at room
temperature for 11 h. The reaction was quenched by addition
of a saturated solution of NH4Cl (100 mL), and the mixture
was extracted with EA (5 × 100 mL), and finally dried over
anhydrous Na2SO4. The solvent was removed under vacuum,
(±)-18: IR (neat,
ν
cm-1): 3439, 2929, 1971, 1759, 1641,
1329, 1140, 1025, 874, 783, 601;1H NMR (400 MHz, CDCl3)
δ 7.46 (d, J = 0.7 Hz, 1H), 7.45 (t, J = 1.7 Hz, 1H), 6.36 (d, J =
0.9 Hz, 1H), 5.64 (ddt, J = 16.9, 10.2, 6.5 Hz, 1H), 5.55 – 5.37
(m, 2H), 5.18 (s, 1H), 4.90 (ddd, J = 8.6, 3.3, 1.6 Hz, 2H),
2.07 – 1.82 (m, 2H), 1.45 (ddd, J = 13.7, 11.9, 4.8 Hz, 1H),
1.31 (s, 3H), 1.22 (ddd, J = 13.7, 11.9, 5.1 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 208.7, 169.0, 143.9, 140.2, 137.7, 119.6,
114.9, 108.6, 103.5, 83.8, 83.5, 46.4, 34.8, 27.9, 21.7; HRMS
(ESI) (M+Na)+ calcd for C15H16O3Na+: 267.0992, found:
267.0990.
and the residue was purified by
a
flash column
chromatography (hexane/EA = 30/1) on silica gel to give
lactone(±)- 35 (3.32 gꢀyield 93%, dr 1.2:1) as colorless oil.
1
(±)-35: H NMR (500 MHz, CDCl3) δ 7.52 – 7.36 (m,
2H), 6.36 (dd, J = 8.6, 0.8 Hz, 1H), 5.86 – 5.60 (m, 1H), 5.52
and 5.18 (2s, 1H), 5.11 – 4.94 (m, 2H), 3.79 and 3.78(2s, 3H),
3.65 and 3.42 (2s, 2H), 2.09 (dddd, J = 20.3, 15.6, 10.5, 3.7
Hz, 2H), 1.68 (dd, J = 10.1, 6.8 Hz, 1H), 1.55 (dddd, J = 17.7,
13.9, 10.3, 6.4 Hz, 1H), 0.97 and 0.92 (2s, 3H), 0.92; 13C
NMR (125 MHz, CDCl3) δ 171.3, 167.4, 167.1, 143.6, 140.7,
140.5, 137.4, 137.2, 119.3, 119.2, 115.6, 115.3, 109.1, 109.1,
82.4, 81.5, 58.7, 55.9, 52.8, 52.5, 48.1, 47.7, 37.2, 33.4, 28.6,
8.5. Synthesis of Compound (±)-4
To a solution of allene (±)-18 (49 mg, 0.2 mmol) in dry
toluene (20 mL) was added [Rh(CO)2Cl]2 (3.9 mg, 5 mol%) at
room temperature, the resultant mixture was degased with N2
and CO for 6 times, respectively, and the resultant mixture

ACCEPTED MANUSCRIPT
9
was stirred at 120 °C under CO atmosphere for 3 h. After
cooling to room temperature, the mixture was concentrated
under vacuum, and the residue was purified by a flash column
chromatography (hexane/EA = 1/1) on silica gel to give enone
(±)-4 (45 mg, yield 83%) as white solid.
filtrate was concentrated under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/EA =
1000/1 to 50/1) to give acetal 36 (957 mg, 58%, colorless oil)
as a mixture of diastereoisomers (dr = 1:1).
36: IR (thin film,
ν
cm-1): 2975, 2870, 1640, 1502, 1391,
1
(±)-4: IR (neat,
ν
cm-1): 3440, 2929, 1768, 1705, 1625,
1365, 1162, 1034, 922, 764; H NMR (400 MHz, CDCl3) δ
7.39 – 7.32 (m, 2H) , 6.35 and 6.27 (2 s, 1H), 5.95 – 5.83 (m,
1H), 5.53 and 5.45 (t, J = 5.4 Hz and dd, J = 6.4, 2.8 Hz, 1H),
5.09 – 4.99 (m, 2H), 4.85 and 4.66 (2s, 1H), 2.21, 2.09 – 1.97
and 1.80 (dd, J = 13.1, 6.4 Hz, m and dd, J = 13.1, 2.8 Hz, 2H),
1.27 and 1.26 (2 s, 9H), 0.99 and 0.85 (2s, 3H); 13C NMR (100
MHz, CDCl3) δ 144.4, 143.0, 142.4, 142.3, 140.0, 139.5,
124.2, 122.7, 113.9, 113.1, 109.8, 109.2, 98.1, 97.6, 82.2, 79.2,
74.2, 74.2, 48.5, 48.3, 46.9, 46.4, 29.0, 28.9, 19.8, 19.0;
HRMS (ESI) (M+Na)+ calcd for C15H22O3Na+: 273.1461,
found: 273.1461.
1
1461, 1274, 1134, 1002, 793; H NMR (400 MHz, CDCl3) δ
7.46 (s, 1H), 7.41 (s, 1H), 6.30 (s, 1H), 6.12 (s, 1H), 5.15 (s,
1H), 3.70 (s, 1H), 2.73 (dd, J = 11.8, 5.6 Hz, 1H), 2.64 (dd, J =
18.8, 6.5 Hz, 1H), 2.16 – 2.06 (m, 1H), 2.06 – 1.88 (m, 2H),
1.81 (d, J = 12.8 Hz, 1H), 1.32 (ddd, J = 26.3, 13.3, 3.0 Hz,
1H), 0.95 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 207.2, 173.1,
173.0, 144.2, 140.1, 133.6, 120.9, 108.6, 83.2, 49.5, 46.6, 41.7,
39.2, 34.3, 29.8, 19.5; HRMS (ESI) (M+H)+ calcd for
+
C16H17O4 : 273.1121, found: 273.1127.
8.6. Synthesis of Compound 37
8.8. Synthesis of Compound 38
To a solution of dicyclohexylborane (1.42 g, 8.0 mmol, 2.0
equiv.) in toluene (5 mL) was added 2-butyne (0.63 mL, 8.0
mmol, 2.0 equiv.) in one portion, and the resultant mixture
was first stirred at room temperature for 1 h, and then cooled
to -78 °C. To this solution was added a solution of
dimethylzinc (8 mL, 8.0 mmol, 1 M in toluene, 2.0 equiv.) at
-78 °C slowly, and the resultant mixture was then stirred at the
same temperature for 1 h. To this solution was added a
solution of ligand A (212 mg, 0.6 mmol, 0.15 equiv.) in
toluene (8 mL), and the resultant mixture was then gradually
warmed up to -30 °C during 30 min with stirring. To this
solution was added aldehyde 19 (346 ꢀL, 4.0 mmol, 1.0
equiv.) slowly, and the resultant mixture was stirred at -30 °C
for 12 h. The reaction mixture was quenched by slowly
addition of water (10 mL), and the mixture was extracted with
To a solution of alkene 36 (1.5 g, 6.0 mmol, 1.0 equiv.)
and ZrCp2Cl2 (2.63 g, 9.0 mmol, 1.5 equiv.) in THF (15 mL)
was added a solution of LiAlH(OtBu)3 (9.0 mL, 9.0 mmol, 1
M in THF, 1.5 equiv.) at room temperature. The resulting
mixture was then stirred at room temperature for 2 h. To this
solution was added a solution of iodine (3.0 g, 12.0 mmol, 2.0
equiv) in THF (10 mL) in a drop-wise manner, and the
resultant mixture was then stirred at room temperature for 3 h.
The mixture was quenched by addition of a solution of HCl
(1M, 20.0 mL) carefully, and the resultant mixture was
extracted with Et2O (3 × 50 mL). The combined organic
extract was washed successively with saturated aqueous
Na2SO3 solution (2 × 20 mL) and brine (2 × 30 mL), and dried
over Na2SO4. The solvent was removed under vacuum, and the
residue was purified by a flash chromatography on silica gel
(shield from light) (hexane/EA : 50/1) to give the iodoalkane
EA (3
× 20 mL), and the combined extracts were washed
with brine, and dried over Na2SO4. The solvent was removed
under vacuum,[1] and the residue was purified by a flash
chromatography on silica gel (hexane/EA : 20/1 to 10/1) to
give product 37 (486 mg, 80%, 90% ee) as bright oil.
38 (1.93 g, 85%, colorless oil) as
diastereoisomers (dr = 2.2:1).
a
mixture of
1
38: H NMR (400 MHz, CDCl3) δ 7.47 – 7.32 (m, 2H),
6.40 (d, J = 1.1 Hz, 0.32H), 6.34 (d, J = 1.0 Hz, 0.69H), 5.50
(dd, J = 5.9, 4.5 Hz, 0.62H), 5.44 (dd, J = 6.3, 2.9 Hz, 0.32H),
4.71 (s, 0.71H), 4.55 (s, 0.34H), 3.20 (dddd, J = 12.2, 9.2, 5.4,
3.4 Hz, 1H), 3.10 (dddd, J = 12.4, 9.3, 7.1, 5.4 Hz, 1H), 2.20 –
1.96 (m, 3H), 1.85 – 1.77 (m, 1H), 1.27 (s, 3H), 1.25 (s, 6H),
0.90 (s, 1H), 0.75 (s, 2H); 13C NMR (100 MHz, CDCl3) δ
142.8, 142.7, 140.3, 139.9, 124.1, 122.5, 110.0, 109.4, 97.8,
97.1, 82.5, 79.6, 74.3, 47.3, 46.5, 46.4, 45.4, 45.3, 43.9, 29.0,
20.0, 20.2, 20.2, 0.1; HRMS (ESI) (M+Na)+ calcd for
C15H23IO3Na+: 401.0584, found: 401.0582. It should be noted
that the iodoalkane 14 was unstable.
37: [α]2D2 = -10.4, (c = 0.35, MeOH); IR (thin film,
ν
cm-1):
1
3365, 2920, 1502, 1445, 1380, 1158, 1023, 875, 787, 758; H
NMR (500 MHz, CDCl3) δ 7.34 (s, 2H), 6.27 (s, 1H), 5.62 (q,
J = 6.7 Hz, 1H), 5.04 (s, 1H), 2.20 (brs, 1H), 1.63 (d, J = 6.7
Hz, 3H), 1.56 (s, 3H); 13C NMR (125 MHz, CDCl3) δ 142.9,
139.4, 137.1, 127.6, 121.0, 109.0, 73.0, 13.0, 11.5; HRMS
(ESI) (M+H-H2O)+ calcd for C9H11O: 135.0804, found:
135.0806.
8.7. Synthesis of Compound 36
To a solution of alcohol 37 (1.0 g, 6.6 mmol, 1.0 equiv)
in acetonitrile (8 mL) was sequentially added t-butyl vinyl
ether (3.5 mL, 26.4 mmol, 4.0 equiv.), benzoquinone (2.1 g,
19.8 mmol, 3.0 equiv.), palladium (II) acetate (157 mg, 0.7
mmol, 0.1 equiv.) and glacial acetic acid (0.38 mL, 6.7 mmol,
1.1 equiv.), and the resultant mixture was stirred at room
temperature for 20 h. To this solution was added pyridine (1.2
mL, 14.5 mmol, 2.2 equiv.) followed by addition of a solution
of hexane and Et2O (3/1, v/v, 100 mL). The reaction mixture
was filtered off through a pad of Celite, and the pad was then
rinsed with a second portion of hexane and Et2O (3/1, v/v, 100
mL). The filtrate was concentrated under vacuum and the
residue was suspended in hexane, and the suspension was then
filtered off through a Buchner funnel to remove more
benzoquinone, which was then washed with hexane. The
8.9. Synthesis of Compound (-)-33
To a flame-dried flask with a stirring bar was added
bathophenanthroline (33 mg, 0.1 mmol, 10 mol %), potassium
vinyltrifluoroborate (148 mg, 1.1 mmol, 1.1 equiv.) and
compound 38 (378 mg, 1.0 mmol, 1.0 equiv.), and the flask
was then moved into a glove box. To this flask was added
NiBr2•glyme (31 mg, 0.1 mmol, 10 mol %) and NaHMDS
(550 mg, 3.0 mmol, 3 equiv), and the flask was took out from
the glove box. To this flask was added a mixture of dry
cyclopentyl methyl ether (CPME, 2 mL) and t-BuOH (2 mL)
via syringe, and the resultant mixture was degased with N2 for
8 times then stirred at room temperature for 0.5 h, and the
mixture was stirred at 60 °C, the reaction was monitored by

ACCEPTED MANUSCRIPT
10
TLC until the compound 38 was consumed off. After
completion, the reaction was worked up by filtration of the
reaction mixture through a silica pad, which was then washed
thoroughly with CH2Cl2 (3 × 20 mL) and EA (3 × 20 mL).[2]
The filtrate was concentrated under vacuum, and the residue
was purified by a flash column chromatography on silica gel
(hexane/EA : 500/1 to 50/1) to afford alkene 38a (167 mg,
60%, as colorless oil) as a mixture of diastereoisomers (dr =
3:1).
temperature slowly. Then additional 3.0 equiv of TBAF
solution was added in a drop-wise manner at 0 °C then stirred
for 30 min. The mixture quenched with brine (50 mL), and
extracted with Et2O (3 × 100 mL). The combined extract was
washed with brine (3 × 50 mL) and dried over Na2SO4. The
solvent was removed under vacuum, and the residue was
purified by a flash column chromatography on silica gel
(hexane/EA = 30/1) to give alkyne 6 (611 mg, 88%) as
colorless oil.
38a: IR (thin film,
ν cm-1): 2974, 2933, 1641, 1501,
8.11. Synthesis of Compound (-)-18
1458, 1391, 1197, 1162, 1010, 764; 1H NMR (400 MHz,
CDCl3) δ 7.50 – 7.30 (m, 2H), 6.42 (d, J = 1.0 Hz, 0.26 H),
6.35 (s, 0.79H), 5.93 – 5.73 (m, 1H), 5.59 – 5.48 (m, 0.77H),
5.45 (dd, J = 6.3, 3.0 Hz, 0.28H), 5.09 – 4.89 (m, 2H), 4.73 (s,
0.84H), 4.57 (s, 0.27H), 2.19 – 1.97 (m, 3H), 1.91 – 1.75 (m,
1H), 1.59 – 1.39 (m, 2H), 1.27 (d, J = 6.5 Hz, 9H), 0.90 (s,
1H), 0.76 (s, 2H); 13C NMR (100 MHz, CDCl3) δ 142.6,
142.5, 140.3, 139.8, 139.0, 138.9, 124.9, 123.1, 114.5, 114.4,
110.2, 109.6, 98.1, 97.4, 83.2, 80.6, 74.1, 47.4, 46.0, 45.3,
44.1, 39.5 37.9, 29.8, 29.6, 29.1, 29.0, 21.0, 20.8; HRMS
(ESI) (M+Na)+ calcd for C17H26O3Na+: 301.1774, found:
301.1770.
To a solution of acetal 38a (350 mg, 1.26 mmol, 1.0
equiv) in acetone (10 mL) was added Jones reagent (4.2 mL,
5.0 mmol, 1.2 M, 4.0 equiv) at 0 °C, and the resultant reaction
mixture was first stirred at 0 °C for 1 h, and then at room
temperature for 2 h. The reaction mixture was worked up by
addition of a saturated solution of NaHCO3 slowly until the
pH of the mixture reached 7. The reaction mixture was filtered
through a pad of Celite, and then rinsed with EA (50 mL). The
filtrate was concentrated under vacuum, and the residue was
extracted with EA (3 × 50 mL). The combined extracts were
washed with brine (3 × 50 mL), dried over Na2SO4. The
solvent was removed under vacuum, and the residue was
purified by a flash chromatography on silica gel (hexane/EA :
30/1) to deliver the lactone (-)-33(208 mg, 75% yield) as
colorless oil.
To a solution of alkyne 6 (151 mg, 0.5 mmol, 1.0 equiv.)
in a mixed solvent of DMF (2.5 mL) and H2O (45 ꢀL, 2.5
mmol, 5.0 equiv.) was added LiCl (105 mg, 2.5 mmol, 5.0
equiv.) at room temperature, and the mixture was degased
with N2 for 8 times, and the resultant mixture was first stirred
at the same temperature for 5 min, and then transferred to a
preheated bath oil at 130 °C for 2 h with stirring. After cooling
to room temperature, the reaction mixture was quenched with
a saturated solution of NH4Cl (5 mL), and then diluted with
H2O (30 mL). The mixture was extracted with Et2O (3 × 100
mL), and the combined extracts were dried over Na2SO4. The
solvent was removed under vacuum, and the residue was
purified by a flash column chromatography (hexane/EA :
30/1) on silica gel to give the allene compound (-)-18 (98 mg,
80%) as wax.
(-)18: [α]2D2 = -18.4 (c = 0.56, CHCl3); IR (neat,
ν
cm-1):
3439, 2929, 1971, 1759, 1641, 1329, 1140, 1025, 874, 783,
601; 1H NMR (400 MHz, CDCl3) δ 7.48 – 7.36 (m, 2H), 6.30
(s, 1H), 5.79 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.52 – 5.40 (m,
2H), 5.25 (s, 1H), 5.09 – 4.94 (m, 2H), 2.23 – 2.04 (m, 2H),
1.78 – 1.70 (m, 2H), 0.97 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 208.8, 169.1, 143.7, 140.2, 137.4, 121.5, 115.2,
108.7, 103.4, 83.6, 81.4, 46.3, 39.3, 28.4, 22.0; HRMS (ESI)
(M+Na)+ calcd for C15H17O3Na+: 267.0992, found: 267.0990.
8.12. Synthesis of Compound (-)-4
(-)-33: [α]2D2 = -24.7 (c = 0.5, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.43 (s, 1H), 7.42 (s, 1H), 6.34 (t, J = 1.3 Hz, 1H),
5.80 (ddt, J = 16.8, 10.2, 6.5 Hz, 1H), 5.13 (s, 1H), 5.09 – 4.94
(m, 2H), 2.54 (d, J = 16.9 Hz, 1H), 2.41 (d, J = 16.9 Hz, 1H),
2.16 (dtdd, J = 13.6, 7.3, 4.5, 3.1 Hz, 1H), 2.10 – 1.93 (m, 1H),
1.65 – 1.52 (m, 2H), 0.88 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 175.7, 143.5, 140.0, 137.5, 120.3, 115.4, 108.8, 83.3,
43.8, 42.2, 37.7, 29.1, 20.0; HRMS (ESI) (M+Na)+ calcd for
C13H16O3Na+: 243.0992, found: 243.0992.
To a solution of the allene (-)-18 (49 mg, 0.2 mmol, 1.0
equiv.) in dry toluene (25 mL, 0.008M) was added
[Rh(CO)2Cl]2 (5.4 mg, 0.014, 7 mol %), and the resultant
mixture was degased with N2 for 8 times and with CO for 8
times, the mixture was then stirred at 120 °C for 3 h under CO
atmosphere.[3] After the reaction was completed, the solvent
was removed under vacuum, and the residue was purified by a
flash column chromatography (hexane/EA : 1/1) on silica gel
to obtain (-)-4 (46 mg, 85%) as colorless crystal.
(-)-4: [α]2D2 = -155.3 (c = 0.35, CHCl3); IR (neat,
ν
cm-1):
8.10. Synthesis of Compound
6
3440, 2929, 1768, 1705, 1625, 1461, 1274, 1134, 1002, 793;
1H NMR (400 MHz, CDCl3) δ 7.46 (s, 1H), 7.41 (s, 1H), 6.30
(s, 1H), 6.12 (s, 1H), 5.15 (s, 1H), 3.70 (s, 1H), 2.73 (dd, J =
11.8, 5.6 Hz, 1H), 2.64 (dd, J = 18.8, 6.5 Hz, 1H), 2.16 – 2.06
(m, 1H), 2.06 – 1.88 (m, 2H), 1.81 (d, J = 12.8 Hz, 1H), 1.32
(ddd, J = 26.3, 13.3, 3.0 Hz, 1H), 0.95 (s, 3H); 13C NMR (100
MHz, CDCl3) δ 207.2, 173.1, 173.0, 144.2, 140.1, 133.6,
120.9, 108.6, 83.2, 49.5, 46.6, 41.7, 39.2, 34.3, 29.8, 19.5;
To a solution of lactone (-)-33 (506 mg, 2.3 mmol, 1.0
equiv.) in dry THF (15 mL) was added LiHMDS (5.8 mL, 5.8
mmol, 1.0 M in THF, 2.5 equiv.) at -78 °C, and the mixture
was stirred -78 °C for 2 h. To this solution was added
ClCO2Me (0.35 mL, 4.6 mmol, 2.0 equiv.) at -78 °C, and the
mixture was stirred at the same temperature for 12 h, and at
the end of the reaction, the reaction temperature of the mixture
was warmed to room temperature. To this solution, Waser’s
reagent (C) (1.6 g, 4.6 mmol, 2.0 equiv.) was added at -78 °C,
and the resultant mixture was then stirred for 5 min. To this
solution was added a solution of TBAF (11.5 mL, 11.5 mmol,
1 M in THF, 5.0 equiv.) at -78 °C in a drop-wise manner, the
mixture was then stirred at the same temperature for another
10 h, during which time the temperature was return to room
+
HRMS (ESI) (M+H)+ calcd for C16H17O4 : 273.1121, found:
273.1127.
8.13. Synthesis of perforanoid A (1)
To a solution of (-)-4 (9.8 mg, 0.036 mmol, 1.0 equiv.) in
THF (1 mL) was LDA (55 ꢀL, 0.11 mmol, 2 M in THF, 3.0
equiv.) in a drop-wise manner at -78 °C, and the resultant

ACCEPTED MANUSCRIPT
11
mixture was then stirred the same temperature for 2 h, during
this time the temperature was warmed to c. To this solution
was added a solution of aldehyde 5a (30.6 mg, 0.18 mmol, 5.0
equiv.) in THF (1 mL) slowly, and and the resultant mixture
was stirred at -78 °C for 10 h, during which time the
temperature was warmed to room temperature. The reaction
mixture was quenched by addition of a saturated solution of
NH4Cl in a drop-wise manner, and the water phase was
extracted with EA (6 × 20 mL) and CH2Cl2 (3× 20 mL). The
combined extracts were washed with brine, and dried over
Na2SO4. The solvent was removed under vacuum, and the
residue was used in next step without further purification.
To a solution of the alcohol in dry toluene (3 mL) was
added Burgess reagent (42.9 mg, 0.18 mmol, 5.0 equiv.), and
the resultant mixture was stirred at 70 °C for 2 h. After cooling
to the room temperature, the reaction mixture was quenched
with brine, extracted with EA, and finally dried over Na2SO4.
The solvent was removed under vacuum, and the residue was
purified by a silica gel column chromatography on silica gel
(hexane/EA : 5/1 to 1/1) to give perforanoid A(1) (5.1 mg,
33%, 51% brsm, white solid) and 3.4 mg recovery of
compound (-)-4. 1: Rf = 0.3 (silica, hexane/EA : 1/1); [α]2D2 =
47: IR (thin film,
ν
cm-1): 2972, 1772, 1696, 1654,
1
1620, 1459, 1271, 1127, 986, 874, 734, 602; H NMR (400
MHz, CDCl3) δ 7.50 (t, J = 1.7 Hz, 1H), 7.45 (d, J = 0.6 Hz,
1H), 6.53 (dd, J = 10.0, 1.5 Hz, 1H), 6.33 (s, 2H), 5.20 (s, 1H),
3.73 (s, 1H), 3.23 (dd, J = 12.3, 5.1 Hz, 1H), 2.71 (dd, J = 16.3,
7.2 Hz, 1H), 2.56 (td, J = 9.7, 6.9 Hz, 1H), 2.45 – 2.29 (m, 3H),
2.05 (td, J = 13.7, 3.2 Hz, 1H), 1.88 (dd, J = 14.2, 1.7 Hz, 1H),
1.47 (s, 3H), 1.45 – 1.30 (m, 2H), 1.23 (s, 3H), 1.10 (d, J = 6.8
Hz, 3H), 0.98 (s, 3H). 13C NMR (100 MHz, CDCl3) δ 194.1,
174.4, 173.1, 166.7, 144.4, 140.2, 138.8, 136.7, 134.3, 120.7,
108.6, 86.3, 83.2, 51.6, 49.7, 46.9, 41.2, 34.6, 34.2, 34.2, 28.9,
28.1, 22.5, 19.8, 19.5. HRMS (ESI) (M+Na)+ calcd for
C25H28O6Na+: 447.1778, found: 447.1781.
Acknowledgments
We thank the National Science Foundation of China (Grant
Nos.21372016,21572009 and 21402002), Guangdong Natural
Science Foundation (Grant Nos.2014A030312004 and
2016A030306011), Shenzhen Basic Research Program (Grant
-183.5 (c = 0.18, MeOH). IR (thin film,
ν
cm-1): 2926, 1736,
Nos.
ZDSYS20140509094114168,
JCYJ20150629144231017,
1
JSGG20140717102922014,
1662, 1236, 1155, 1035, 904, 873, 742; H NMR (400 MHz,
CDCl3) δ 7.48 (dd, J = 11.1, 9.4 Hz, 2H), 6.44 – 6.27 (m, 3H),
5.19 (s, 1H), 3.73 (s, 1H), 3.23 (dd, J = 12.3, 5.3 Hz, 1H), 2.58
– 2.41 (m, 2H), 2.33 – 2.15 (m, 3H), 2.08 (td, J = 13.9, 3.2 Hz,
1H), 1.86 (dd, J = 14.1, 1.5 Hz, 1H), 1.55 (s, 3H), 1.49 – 1.41
(m, 1H), 1.35 (s, 3H), 1.15 (d, J = 6.6 Hz, 3H), 0.96 (s, 3H);
13C NMR (100 MHz, CDCl3) δ 194.2, 174.0, 173.0, 166.6,
144.4, 140.2, 137.9, 136.6, 134.5, 120.7, 108.6, 85.9, 83.3,
50.7, 49.7, 46.7, 41.9 35.2, 34.5, 34.1, 29.4 28.0 21.9,
19.7,19.4; RMS(ESI) (M+Na)+ calcd for C25H28O6Na+:
447.1778, found: 447.1776.
JCYJ20160226105337556 and JCYJ20160330095629781),
and the Shenzhen Municipal Development and Reform
Commission (Disciplinary Development Program for
Chemical Biology) for financial support.
Appendix A. Supplementary data
Supplementary data related to this article can be found at??
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