Hydrogen bonding-promoted efficient Ru-catalyzed ring-closing metathesis of demanding homoallyl 2-(hydroxymethyl)acrylates

Article abstract of DOI:10.1039/c6ob02129h

An efficient hydrogen bonding-guided ring-closing metathesis (RCM) reaction of sterically demanding homoallyl 2-(hydroxymethyl)acrylates catalyzed by the Hoveyda-Grubbs 2nd generation catalyst was developed and the reaction mechanism was explored. Adding

Full text of DOI:10.1039/c6ob02129h

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Journal Name
ARTICLE
Hydrogen bonding-promoted efficient Ru-catalyzed ring-closing
metathesis of demanding homoallyl 2-(hydroxymethyl)acrylates
Received 00th January 20xx,
Accepted 00th January 20xx
Liang Feng,a,+ Yuehui Liu,a,+ Bo Hou,b,+ Zaifeng Yuan,a Fu-Chao Yu,a Tingbin Yan,a Qi Qin,a Ruigeng
Ji,a Ya-Min Li,a Yuehai Shena,* and Zhi-Li Zuob,*
DOI: 10.1039/x0xx00000x
An efficient hydrogen bonding-guided ring-closing metathesis (RCM) reaction of steric demanding homoallyl 2-
(hydroxymethyl)acrylates catalyzed by Hoveyda-Grubbs 2nd generation catalyst was developed and the reaction
mechanism was explored. Adding a substituent to the hydroxymethyl group in this scaffold results in a class of challenging
RCM substrates, although usable yields could be obtained. However, substrates bearing 1-oxygenated alkyl group on the
homoallylic carbon gave excellent RCM yields, providing a practical solution. Experimental and computational evidences
indicated an unusual directing effect of OH···Cl hydrogen bonding between the substrate and Ru catalyst, which guides Ru
to interact with the electron-deficient, more hindered acrylic C=C bond and thus triggers the RCM process.
www.rsc.org/
O
Introduction
c
c
O
OA OA
OH
O
5,6-Dihydro-
fungus-originated natural products (Figure 1).
this framework is also an important class of synthetic
α-pyrone (DHP) is a common motif in plant- or
O
OH
1,2
H
orono
e
lid
B
c
OA
Moreover,
O
om none
S
i
H
H
OH OH
O
3,4
HO
intermediates.
For the synthesis of DHPs, ring-closing
OH
Ph
metathesis (RCM) of the corresponding homoallyl acrylates is
currently the most popular choice,
approaches including ,β-elimination,
oxidization-cyclization, hetero Diels-Alder-oxidation, and
intramolecular Horner-Wadsworth-Emmons reaction
r c o one
t i tif li
S
2a,b,f-i
O
O
although other
lactonization,
O
O
2c,d
2e
H
α
c
OA
O
5
6
H
H
ano
e
With
lid
A
7
r
C
o a o one
t l tif li
are
yp
OH
O
available. Due to the electron-deficient nature of the acrylic
C=C bond and the coordination effect of the carbonyl group,
homoallyl acrylates are usually less reactive than electron-
richer substrates. Substituent(s) on the acrylic or homoallylic
O
O
O
O
O
O
Cl
OH
roas rone
OH
OH
O
ra ac one
Vib
OH
l
t
s
rone
Q
A
py
oro
hl h d
B
C
y
py
C=C bond further suppress the reactivity, resulting challenging
Fig. 1 Representative 5,6-dihydro-α-pyrone natural products.
7,8
systems.
In fact, the simplest DHP with a tetrasubstituted
-pyrone, is difficult to
double bond, 3,4-dimethyl-5,6-dihydro-
α
construct by RCM, thus has been used as a model target for
the evaluation of olefin metathesis catalysts and reaction
conditions. 9
a su a s
a a e ama s wor
M t
'
H t k
'
k
&
y
y
R
N
N
o
T l
o o
T l
o
R
O
O
In 2009, Matsuya group 2i reported an efficient protocol to
construct the trisubstituted olefin-containing DHP motif of
steroidal natural product sominone and its analogues (Scheme
1), using homoallyl 2-(hydroxymethyl)acrylate substrates and
Stewart-Grubbs catalyst (SG). A reaction using a similar
O
Cl
-
II
H
SG
G
/
O
u
R
Cl
o uene
t l
O
80 o
C
i
OH
r
P
-
e
i ld
52 88
%
O
y
OH
SG
s wor
Thi
k
R1
N
N
u
es
M
es
M
R1
R2
O
R2
O
Cl
-
II
H
G
O
R
a.Faculty of Life Science and Technology, Kunming University of Science and
Technology, Kunming 650500, China. E-mail: yuehaishen@gmail.com; Phone: +86
871 65920747.
R3
C
l
R3
o uene
t l
O
110 o
C
OH
a
i
r
P
b.State Key Laboratory of Phytochemistry and Plant Resources in West China,
Kunming Institute of Botany, Chinese Academy of Sciences, Kunming 650201,
China. E-mail: zuozhili@mail.kib.ac.cn.
O
H
1: ar
-
e
%
y
-
H
II
G
R
R1
l
/
lk l 43 60
i ld
,
y
y
:
-ox ena e
a
-
e
i ld
%
y
1
t d lk l 79 90
,
yg
y
Scheme
acrylates.
1
Ru-catalyzed RCM of homoallyl 2-(hydroxymethyl)
† These authors contributed equally to this work and share first authorship.
Electronic
Supplementary
Information
(ESI)
available.
See
DOI: 10.1039/x0xx00000x
This journal is © The Royal Society of Chemistry 20xx
J. Name., 2013, 00, 1-3 | 1
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Organic & Biomolecular Chemistry
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ARTICLE
Journal Name
Ph
Ph
R2
substrate and Hoveyda-Grubbs second generation catalyst
(HG-II) was also developed by Hatakeyama group in a study
-
-
R1
O
O
G II/HG II
View Article Online
O
B
O
O
O
10
mo
l
)
2
O
10
%
O
DOI: 10.1039/C6OB02129H
(
)
R3
or
+
R3
R1
o uene
t
R2
l
towards clutiolide synthesis. This method was later used in the
preparation of unnatural sominone and withanolide analogues
.
0 01 M
OR
2
3
OR
Ph
OH
80 110 oC
OH
a
-
1
1b
w
w
ro ec on: race ma n
ith OH
ou
t
ti
ro ec on: ma n
,
t
2
,
i
3
race
11a
11b
-
p
r
r
M
-
t
n-
d
-
MOM
,
p
o
r
o ec e
t
o
TBS
t
d
TBS
,
,
by Matsuya
and Waldmann
groups. In our efforts to
e- ro ec e
t
ti
2 t
3
ith t OH
i
t
p
p
develop metathesis methods potentially useful in total
synthesis of natural products, 4,12 we found that simply adding
a substituent (R3) into the hydroxymethyl of homoallyl 2-
(hydroxymethyl)acrylate scaffold severely retards the RCM
reactions (Scheme 1). Fortunately, introducing a 1-oxygenated
alkyl group (R1) at the homoallylic carbon could retrieve the
reactivity and give high yields with HG-II as the catalyst.
Surprisingly, our study on the reaction mechanism indicated
that the seemingly less reactive acrylic C=C bond is the starting
point of the RCM process effected by the hydrogen bonding
between the substrate and Ru catalyst. Herein we wish to
summarize our results.
Scheme 2 Preliminary screening.
reaction remained incomplete even with high catalyst
loadings. Raising the temperature to 110 oC was found
detrimental due to fast decomposition of G-II. In contrast,
o
although slow initiating HG-II gave slower reactions at 80 C
than G-II did, high conversions were observed at 110 oC.
Further optimization was thus focused on reactions with
HG-II using 1a and 1b (Tables 1). For substrate 1a, the reaction
o
at 80 C reached full conversion after stirring 24 hours (entry
o
1), while the reaction at 110 C was found faster and able to
give a higher yield in 15 hours (entry 2). The variation of
concentration in the range of 0.01 to 0.1 M had no significant
impact on the yields (entries 2-4); the reaction at 0.05 M gave
a slightly higher yield, thus was determined to be the optimal
concentration for substrate 1a. It is worth to note that DHP 2a
is of small molecular weight and highly polar, making its
separation from HG-II-derived ruthenium side products quite
difficult. Therefore, only moderate isolated yields were
obtained.
Results and discussion
Substrate and condition screening
Initially, we performed a preliminary study comparing
reactions of homoallyl 2-(hydroxymethyl)acrylates 1a and 1b
or their protected forms at 0.01 M concentrations in toluene in
the presence of G-II and HG-II (Scheme 2). Reactions for
compounds with hydroxy protections (TBS, Bn, MOM, Me)
In comparison, the concentration change had significant
impacts on the reaction of demanding substrate 1b. A quick
screening on concentrations with 10 mol% G-II loading
revealed that a better conversion (~40% by TLC) was achieved
at 0.005 M (entries 5-7), but adding more G-II portionwise
could only afford RCM product in low yields (entries 8 and 9).
On the other hand, the reactions with HG-II gave higher yields
(entries 10 and 11). To our delight, the reaction with higher
gave mainly self metathesis (SM) products 3. However, for
substrates with free hydroxy, although SM took place in the
early stage of the reactions, RCM became the main reaction
after prolonged stirring, proving the promoting effect of the
allylic hydroxy group in this system. 2i Importantly, the reaction
of substrate 1b were found very sluggish, presumably due to
the introduction of the phenethyl group in the acrylic moiety.
o
In terms of Ru catalysts, G-II performed best at 80 C, but the
Table 1 Screening of catalyst, temperature, and concentration for RCM of 1a and 1b a
Catalyst
(mol% x times)
HG-II (5 x 2)
HG-II (5 x 2)
HG-II (5 x 2)
HG-II (5 x 2)
G-II (10)
G-II (10)
G-II (20)
G-II (10 x 4)
G-II (5 x 6)
HG-II (5 x 4)
HG-II (4 x 6)
Temp.
(oC)
80
110
110
110
80
80
80
80
80
Conc.
(M)
0.01
0.01
0.05
Time
(h)
24
15
15
15
24
24
48
Conversion
(%) b
100
100
100
100
~20
~40
~10
49
RCM yield SM Yield
Entry Substrate Procedure
(%) c
50
57
60
58
--
(%) c
none
none
none
none
--
1 d
1a
1a
1a
1a
1b
1b
1b
1b
1b
1b
1b
A
A
A
A
B
B
B
A
A
C
C
2 d
3 d
4 d
0.1
0.01
5 e
6 e
0.005
0.002
0.005
0.005
0.005
0.005
--
--
--
--
7 e
8 d
72
110
48
30
42
60
48
12
13
11
12
9 d
60
92
69
10 d
11 d
110
110
96
a. Procedure A: the first portion of catalyst was added at r.t., and the rest portions were added at 12 h intervals, Procedure B: the catalyst
was added in one portion at r.t., Procedure C: the first portion of catalyst was added at r.t., the second portion was added after reacting for
30 min, and the rest portions were added at 12 h intervals; b. the conversion was estimated by TLC, or calculated based on recovered
starting material; c. isolated yield; d. the reaction was carried out at 0.25 mmol scale; e. the reaction was carried out at 0.05 mmol scale.
2 | J. Name., 2012, 00, 1-3
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Journal Name
initial loading (10 mol% HG-II in the first 30 min) afforded 60% products bearing an aromatic R1 group (2a
ARTICLE
,
2c
,
2d) were found
View Article Online
DOI: 10.1039/C6OB02129H
yield of RCM product, along with 11% yield of SM product and relatively easier to be purified than their aliphatic counterpart
8% recovery of 1b with 20 mol% HG-II in total (entry 10). The
(
2e, R1 = phenethyl) and thus gave higher isolated yields.
In contrast to substrates 1c-e, substrate 1f (R3 = 4-
trial to slightly lower the loading was found unsuccessful,
resulting in a decreased yield (48%) even with more catalyst bromophenyl) resembled 1b (R3 = phenethyl) in terms of the
used (entry 11).
reactivity. A moderate yield of 2f (43%) and incomplete
conversion was observed after reacted for 36 hours. Significant
amount of SM product (13%) was also obtained. This indicated
Substrate scope and application
that introducing a R3 group (1b
, 1f) indeed inhibits the RCM
With the optimal conditions in hand, the scope and
limitation of this reaction was then investigated (Table 2).
Substrates bearing various substituents were prepared using
Baylis-Hillman reaction, Barbier-type allylation or syn-
crotylation and esterification as the key steps. For substrates
reaction, and a small R2 group (1b, R2 = Me) has neglectable
impact on the reactivity.
Surprisingly however, further exploration on R1 group
revealed that compounds 1g-k, which contain 1-oxygenated
alkyl R1 groups in place of aromatic or aliphatic groups,
exhibited dramatically improved reactivity. Comparing with
sluggish 1b-type substrates, 1g-type substrates universally
delivered much higher yields (79-90% versus 43-60%). In
addition, the reactions consumed less HG-II (10-15 mol%
versus 15-20 mol%), and could reach full conversion within 15-
24 h. The structural feature related to this difference is
obviously the R1 groups. The results suggest that the 1-
oxygenated alkyl R1 groups could promote the RCM process.
The highly efficient RCM of 1g-type substrates not only
provides a practical access to structurally complex DHPs, which
could be otherwise difficult to construct due to R3-
introduction, but also opens the door for further
functionalization. For example, the C=C bond could be
hydrogenated to stereoselectively generate δ-valerolactone
derivatives with a new chiral carbon (Scheme 3). This method
is also potentially useful for the synthesis of natural products
like aspyrone and chlorohydroaspyrone B (Figure 1).
bearing a simple 2-(hydroxymethyl)acryl moiety (1a-type, 1c-e
,
R3 = H), the reactions were similar to that of substrate 1a. The
substrates were fully reacted in 15 hours with 10 mol% loading
of HG-II and only a trace of SM product was detected. DHP
Table 2 Substrate scope of HG-II-catalyzed RCM a,b
R1
1
O
R1
O
R2
O
-
HG II
110 o
C
o uene
,
O
3
5
R3
R2
R3
t l
OH
roce ure
A
d
/C
p
2
1
OH
a- e su s ra es
-
e su s ra es
1
t
b t
t
1b t
b t
t
yp
yp
Ph
R1
Ph
R1
R1
Ph 60
,
a
:
:
1
1
%
(
(
)
B
O
O
O
O
O
c
-
r
C6
H4
58%
6 %
,
)
p
O
1d R1
4
:
-
e
O
M Ph
,
)
-
p
r
p
B C H
(
6
4
R1
h
t
h l 51
y
e
1
:
n
e e
,
)
%
p
(
Ph
OH
60% 65%
O
H
u
x
A
R
5
%
2 15 h
,
,
OH
e
,
d
c
1f 4
3% 53%
,
1b
,
(
%
)
(
)
Mechanism study
u
x
3 36 h
,
A
R
5
u
x
4 48 h
,
,
C R
5
%
,
-
t
e su s ra es
b t
t
1
g
yp
To better understand this RCM system, several control
experiments were carried out (Scheme 4). First, homodimer
3a, which was synthesized from TBS-protected 1a by SM and
deprotection, was found able to convert to RCM product 2a
(equation 1) in the presence of HG-II, similar to a
O
OTBS
O
O
e
O
M
(
)
3
1h R3
C
:
u
x
Ph 83
R
5
3 24 h
,
,
%,
,
%
(
)
r
1i R3
7
9
,
)
C
O
:
-
u
x
B C H
R
5
%
3 24 h
,
%,
,
p
(
6
4
O
O
1
j
R3
h
th l
C R
:
ene
u
x
x
5% 3 24 h
,
90%
,
y
)
,
,
p
3: -
(
R3
r
u
5
%
1k
R
(
C R
%,
,
i P 88
2 15 h
,
,
)
Ph
OH
O
H
-
en
%
1
C R
t 1
4
,
86%
8 %
,
;
g
,
g
u
x
3 24 h
,
5
Ph
O
O
O
O
O
O
roce ure
:
.
s
or on o ca a s was a
e
a r. . e res or ons were a
e
P
a
d
A
t
t
i
t
t
t
t
t
h
t
t
i
p
0 05 M 1
f
l
y
dd d
dd d
,
,
p
)
2
-
mo
l
%
HG II 10
(
)
n erva s
t 12 h i t
l
1
( )
Ph
o uene
t l
110 o
C
roce ure
,
:
.
s
or on o ca a s was a
e
dd d
a r. .
n
or on was a
2 d
t
p
e
dd d
a
er
t
P
d
C
t
t
i
t
t
t
t
0 005 M 1
f
l
i
f
,
,
p
y
a
2
a
H
H
reac n or
ti
m n e res or ons were a
e
a
n erva s
3
f
30
i
th ti
t
dd d t 12 h i t
l
49
%
,
g
p
a. The reactions were carried out at 0.25 mmol scales; b. isolated
yields are listed, numbers in parentheses are yields based on
recovered starting material; c. 11% isolated yield of SM product; d.
isolated as p-nitrobenzoate; e. 13% isolated yield of SM product.
O
O
O
O
-
mo
l
%
HG II 10
(
)
2
( )
O
O
110 o
C
O
O
o uene
t l
,
61%
)
2
-
-
TBS
1
g
TBS
3
Ph
O
Ph
O
OTBS
Ph
OTBS
Ph
g
O
O
O
a
ve
iti
e
i ld
y
O
O
dd
.
O
1 MOMCl DIPEA
,
-
mo
l
%
HG II 10
O
O
O
O
(
)
t
3
( )
u
O
H
B
36%
32
o uene
t l
.
e
110 o
C
,
2 H2 Pd/C M OH
,
,
THF
%
a
2
OH
a
dditi
1
ve
H
MOM
OH
a
1
Ph
OH
v.
2
g
Ph
e u
4
i
q
(
)
Scheme 3 Synthesis of δ-valerolactone derivative.
Scheme 4 Control experiments.
This journal is © The Royal Society of Chemistry 20xx
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ARTICLE
Journal Name
View Article Online
DOI: 10.1039/C6OB02129H
T 1
S
T 2
S
T 3
S
T 4
S
a
P th
wa -
R
y
N
N
N
N
N
N
N
N
.
19 87
Cl
Cl
Cl
Cl
u
R
u
R
u
R
u
R
Cl
Cl
Cl
Cl
H
H
H
H
O
O
O
O
O
O
O
O
O
O
O
O
O
O
.
13 55
.
11 12
.
12 99
.
13 41
.
11 54
.
10 21
∆Ε
ca mo
l/
k
(
l
)
V
.
7 94
.
5 22
.
5 10
VI
.
3 21
.
2 48
.
2 96
O
O
.
2 01
R1
0 00
O
.
0 60
O
.
.
1 54
OH
-
.
0 75
VII
HO
I
R2
-
.
3 88
-
.
3 97
-
.
5 05
II
IV
III
T 1
S
T 2
S
T 3
S
T 4
S
N
N
N
N
N
N
N
N
Cl
Cl
Cl
Cl
R
u
R
u
R
u
R
u
H
H
O
O
Cl
Cl
Cl
Cl
H
H
O
O
O
O
O
O
O
O
O
O
O
O
Fig. 2 Computation results on RCM process started from the homoallylic end (pathway R).
T 1
S
T 2
S
T 3
S
T 4
S
a
P th
wa -
L
y
N
H
N
Cl
N
H
N
N
H
R
N
N
H
N
O
O
O
Cl
O
Cl
Cl
u
u
R
R
u
u
R
O
O
Cl
C
l
Cl
Cl
O
O
O
O
O
O
O
O
.
12 62
.
11 79
.
10 91
.
∆
Ε
9 70
ca mo
l/
k
(
l
)
.
10 26
.
8 75
.
6 99
.
.
6 67
6 67
.
5 46
.
5 11
.
4 41
V
L1
.
2 29
.
2 70
O
O
.
1 76
O
.
0 51
O
.
- .
0 0
1
0 00
- .
0 88
OH
VII
IV
VI
L2
HO
- .
2 71
I
- .
3 84
II
III
T 1
S
T 2
S
T 3
S
T 4
S
N
N
Cl
N
N
N
N
N
N
Cl
H
O
H
O
l
C
C
l
u
R
u
R
H
H
u
R
u
R
O
O
Cl
Cl
Cl
Cl
O
O
O
O
O
O
O
O
O
O
Fig. 3 Computation results on RCM process started from the acrylic end (pathway L).
4 | J. Name., 2012, 00, 1-3
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Page 5 of 10
Organic & Biomolecular Chemistry
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Journal Name
ARTICLE
R1
R2
es
Cl
O
O
O
SIM
transformation reported by D’Annibale et al. with homoallyl
methacrylate homodimer. This indicates that SM products
H
R1
View Article Online
O
O
O
9c
R3
u
R
DOI: 10.1039/C6OB02129H
R3
Cl
RS
u
R2
R
could serve as substrate reservoirs in the RCM reactions.
Second, upon TBS-protection of the hydroxy of 1g, a superior
RCM substrate, SM became the dominant pathway (equation
2), again demonstrating that the presence of an allylic hydroxy
is essential for the RCM reaction (compare with Scheme 1).
Third, the effects of adding hydrogen bond donor (tBuOH) and
acceptor (THF) were tested and reduced yields were obtained
(equation 3), suggesting that hydrogen bonding is involved in
the reaction.
The hydrogen bonding in this reaction is probably formed
between the allylic OH of the substrate and a chloride ligand in
Ru complex according to Forman’s 13 and Hoveyda’s 14 seminal
pioneer works. Therefore, a computation study was carried
out on OH···Cl hydrogen bond-participated reaction pathways
and provided some unexpected interpretations. At first glance,
it seems reasonable that Ru catalyst should interact with the
electron-rich and less hindered homoallyl C=C bond, as shown
experimentally that the reactions first produced significant
amounts of SM products, and the OH···Cl hydrogen bond
would then guide the Ru atom to react with the acryl C=C
Cl
OH
RL
ree
2
f
(
O
H
)
D
H
ove a s mo
e
l
H
d
'
d
y
R1
R1
R2
O
es
SIM
Cl
R2
R
O
O
1
1
O
H
u
R
o
mo mer
h
di
R3
Cl
u
A
e
ene
l
th
y
u
O
R
A
E
or
-
G
II
C
H
O
Cl
R3
R1
H
R2
R1
R1
O
O
O
e
ene
th l
y
R2
R2
O
O
R3
O
O
H
α
R3
O
Cl
α
u
R
'
H
OH
R3
B
ree
oc e
k
d O
1
H
)
1
l
(
H
)
f
O
(
or omo mer
di
h
Scheme 5 Proposed mechanism.
the formation of homoallyl end Ru carbene
E is energetically
favored (comparing Figures 2 and 3), but this pathway is
reversible and the homodimer could be consumed.
Alternatively, the homodimer could also form hydrogen bond
associate with complex
the RCM pathway. Importantly, the OH···Cl hydrogen bond in
associate serves to direct ruthenium species to coordinate
with the acrylic C=C bond, and also to activate ruthenium by
reducing its electron density. Intermediate is similar to
A and then be directly consumed by
bond. With model structure
I and HG-II, we calculated possible
B
RCM processes started from homoallylic (pathway R, Figures 2)
or acrylic C=C bond (pathway L, Figures 3) by density functional
theory (DFT) methods. The allylic OH could bind with the front
or back chloride ligand to give four pathways (R1/R2 and
L1/L2). Among them, pathways R2 and L2 have the lowest
overall energy requirements (67.50 kcal·mol-1 for R1, 42.60
kcal·mol-1 for R2, 68.65 kcal·mol-1 for L1, 30.51 kcal·mol-1 for
L2), respectively. Our calculation revealed that although the
metathesis between HG-II and the homoallylic C=C bond of
D
14
Hoveyda’s six-membered OH···Cl hydrogen bonding model
for ring-opening cross metathesis (ROCM) of allylic alcohols.
This model fits our results and previous observations well.
The presence of a R1 group could accelerate the ring-closing
step from
same as in cases of simple homoallyl acrylates. 9c On the other
hand, as the formation of hydrogen bonding associate
C to D due to favorable chain conformations, the
B
structure I is indeed easy to take place (Figure 2, R2, I to IV),
involves the rotation of the Cα-Cα bond, it is predictable that
’
the following ring-closing events (IV to VII) have high energy
barriers, thus resulting a high overall energy requirement
(42.60 kcal·mol-1) for pathway R2. In comparison, for pathway
L2 (Figure 3), the high energy barriers for the starting
this rotation will be severely hampered by introducing an alkyl
or aryl R3 group. For the promoting effects of 1-oxygenated
alkyl R1 group, a conformational analysis on intermediate
C
suggested that due to the dipole repulsion between the
oxygenated group and the ester moiety, the homoallyl
terminal olefin is likely to be positioned close to the Ru atom,
metathesis of the acrylic C=C bond (L2,
I to IV) are
compensated by the relatively low energy barriers of the ring-
closing conversions (IV to VII), significantly lowering the overall
energy requirement (30.51 kcal·mol-1). These unexpected
results demonstrated that the electron-deficient, more
hindered acrylic C=C bond is likely the starting point of the
RCM process as a result of OH···Cl hydrogen bonding.
thus dramatically accelerating the step from C to D.
Conclusion
Based on the above experiment and computation results,
In summary, an efficient Ru-catalyzed RCM reaction for
steric demanding homoallyl 2-(hydroxymethyl)acrylates was
developed and the reaction mechanism studied. The
introduction of an alkyl or aryl substituent to the
hydroxymethyl group of homoallyl 2-(hydroxymethyl)acrylates
results a class of challenging RCM substrates, which are not
able to completely converted under the optimal condition
although usable yields were afforded. Notably, installing a 1-
oxygenated alkyl group on the homoallylic carbon reverses this
trend and excellent yields were obtained for the
corresponding substrates. Experimental and computational
study on the mechanism confirmed that the RCM reaction is
promoted by OH···Cl hydrogen bonding between the substrate
we propose that the formation of lactone
unique hydrogen bonding-involved pathway (Scheme 5). At
first, the free alcohol form of diene substrate , presumably in
equilibrium with the intramolecular hydrogen bond-locked
form, associates the catalytic ruthenium species or HG-II
through OH···Cl hydrogen bonding to give rise to intermediate
, which then transforms to Ru carbene by releasing a
molecule of ethylene. Following the Chauvin mechanism, a
[2+2] cycloaddition produces ruthenacyclo-butane , which
then collapses to regenerate complex and give 5,6-dihydro-
α-pyrone . At the meantime, the self metathesis pathway
2 experiences a
1
A
B
C
D
A
2
competes with the hydrogen bonding-guided RCM event as
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Organic & Biomolecular Chemistry
Page 6 of 10
ARTICLE
Journal Name
and Ru catalyst, and unexpectedly revealed that the OH···Cl solution in toluene. The rest portions of HG-II (5% x n) were
View Article Online
hydrogen bond directs Ru catalytic species to interact with the added at 12 h intervals. The solventDwOIa: s10.r1e0m39o/Cv6eOdB0u2n12d9eHr
seemingly less reactive acrylic C=C bond and triggers the RCM reduced pressure. The residue was purified by silica gel column
process. Our results demonstrated the strong directing and chromatography using a gradient solvent system (petroleum
activating effect of OH···Cl hydrogen bonding in Ru-catalyzed ether/ethyl acetate 50:1 - 5:1) as the eluent repeatedly to give
olefin metathesis, suggesting its potential application in the the product.
design of advanced substrates.
3-(Hydroxymethyl)-6-phenyl-5,6-dihydro-2H-pyran-2-one
(2a). General Procedure A was used. Pale white wax. Yield: 60%. 1H-
NMR (400 MHz, CDCl3) δ 7.42-7.35 (m, 5H), 6.94-6.90 (m, 1H), 5.45
(dd, J = 11.5, 4.5 Hz, 1H), 4.43-4.33 (m, 2H), 2.78-2.60 (m, 2H), 2.54
(bs, 1H). 13C-NMR (100 MHz, CDCl3) δ 165.1, 140.0, 138.2, 131.9,
128.8, 128.7, 126.1, 79.4, 61.6, 31.7. HRMS (ESI) [M+Ma]+ calcd for
C12H12NaO3 227.0679, found 227.0681. IR (KBr) (cm-1) 3489, 3446,
2920, 1710, 1454, 1393, 1234, 1127, 1049, 702.
6-(4-Bromophenyl)-3-(hydroxymethyl)-5,6-dihydro-2H-pyran-
2-one (2c). General Procedure A was used. Colorless oil. Yield: 58%.
1H-NMR (400 MHz, CDCl3) δ 7.53 (d, J = 8.0 Hz, 2H), 7.28 (d, J = 8.0
Hz, 2H), 6.91 (bs, 1H), 5.41 (dd, J = 10.0, 6.0 Hz, 1H), 4.42-4.33 (m,
2H), 2.69-2.61 (m, 2H), 2.33 (bs, 1H). 13C-NMR (100 MHz, CDCl3) δ
164.8, 139.7, 137.2, 132.0, 131.9, 127.7, 122.7, 78.6, 61.5, 31.6.
HRMS (ESI) [M+Ma]+ calcd for C12H11BrNaO3 304.9784, found
304.9780. IR (KBr) (cm-1) 3421, 2926, 1712, 1491, 1379, 1235, 1128,
1047, 1011, 820.
Experimental section
Materials and methods
1H and 13C NMR spectra were obtained on a Bruker AM-
400MHz or DRX-500MHz spectrometer. Deuterated CDCl3 was
used as the solvent. Chemical shifts (δ) are expressed in ppm,
and coupling constants (J) are given in Hz. HRMs were
performed on an Agilent LC/MS TOF instrument. IR spectra
were recorded on a FT-IR Thermo Nicolet Avatar 360 using KBr
pellet. Values of optical rotation were recorded on a WZZ-2S
spectropolarimeter.
Chemicals were purchased from Adamas, J&K Scientific and
Sigma-Aldrich, and were used as received. Silica gel ZCX II (300-
400 mesh) was purchased from Qingdao Haiyang Chemicals.
Anhydrous solvents were prepared by standard methods.
Column chromatography was performed using silica gel
3-(Hydroxymethyl)-6-(4-methoxyphenyl)-5,6-dihydro-2H-py-
ran-2-one (2d). General Procedure A was used. Colorless oil. Yield:
1
64%. H-NMR (400 MHz, CDCl3) δ 7.33 (d, J = 8.5 Hz, 2H), 6.93 (m,
(200
‑300 mesh) with solvents distilled prior to use.
1H), 6.92 (d, J = 8.5 Hz, 2H), 5.39 (dd, J = 12.0, 4.0 Hz, 1H), 4.42-4.32
(m, 2H), 3.81 (s, 3H), 2.79-2.61 (m, 1H), 2.65-2.55 (m, 1H), 2.46 (bs,
1H). 13C-NMR (100 MHz, CDCl3) δ 165.3, 159.9, 140.1, 131.8, 130.2,
127.7, 114.1, 79.4, 61.7, 55.4, 31.6. HRMS (ESI) [M+Ma]+ calcd for
C13H14NaO4 257.0784, found 257.0787. IR (KBr) (cm-1) 3421, 2984,
1711, 1614, 1517, 1381, 1251, 1128, 1031, 832.
3-(Hydroxymethyl)-6-phenethyl-5,6-dihydro-2H-pyran-2-one
(2e). General Procedure A was used. Light yellow oil. Yield: 51%. 1H-
NMR (400 MHz, CDCl3) δ 7.33-7.26 (m, 2H), 7.23-7.17 (m, 3H), 6.81
(bs, 1H), 4.45-4.37 (m, 1H), 4.36-4.26 (m, 2H), 2.93-2.72 (m, 2H),
2.57 (bs, 1H), 2.43-2.33 (m, 2H), 2.20-2.08 (m, 1H), 2.00-1.89 (m,
1H). 13C-NMR (100 MHz, CDCl3) δ 165.5, 140.8, 140.1, 131.5, 128.6,
128.5, 126.2, 77.1, 61.7, 36.4, 31.0, 29.5. HRMS (ESI) [M+Ma]+ calcd
for C14H16NaO3 255.0992, found 255.0994. IR (KBr) (cm-1) 3425,
2932, 2867, 1709, 1454, 1396, 1225, 1134, 1050, 702.
General procedures for ring-closing metathesis
General procedure A. To a mixture of homoallyl 2-
(hydroxymethyl)acrylate (1 mmol) in anhydrous toluene (20
mL, c 0.05 M) was added the first portion of HG-II (5%) as a
o
solid. The mixture was stirred under nitrogen at 110 C. The
rest portions of HG-II (5% x n) were added at 12 h intervals
until the complete conversion of starting material was
detected. The solvent was removed under reduced pressure.
The residue was purified by silica gel column chromatography
using
a gradient solvent system (petroleum ether/ethyl
acetate 50:1 - 5:1) as the eluent repeatedly to give the
product.
In a few cases, the products were found difficult to be
purified, and was then converted to the corresponding p-
nitrobenzoates as following: The obtained impure 3-
(hydroxymethyl)-5,6-dihydro-2H-pyran-2-one was mixed with
triethylamine (3 equiv.) and 4-nitrobenzoyl chloride (2 equiv.)
in DCM. Upon a complete conversion was detected, the
mixture was diluted with DCM, washed with water and brine,
dried over anhydrous Mg2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by silica gel
column chromatography using a gradient solvent system
(petroleum ether/ethyl acetate 100:1 - 20:1) as the eluent to
give the product.
General procedure C. To a mixture of homoallyl 2-
(hydroxymethyl)acrylate (0.5 mmol) in anhydrous toluene (100
mL, c 0.005 M) was added the first portion of HG-II (5%) as a
solid. The mixture was stirred under nitrogen at 110 C. After
30 min, the second portion of HG-II (5%) was added as a
3-(1-Hydroxy-3-phenylpropyl)-5-methyl-6-phenyl-5,6-syn-di-
hydro-2H-pyran-2-one (2b). General Procedure
C was used.
Colorless oil. Yield: 60%. Mixture of stereoisomers. HRMS calcd for
C21H22NaO3 [M+Ma]+ 345.1461, found 345.1462. Two
diastereomers were obtained after repeated careful column
1
separation. Diastereomer 1: [α]2D5 = +39.7 (c 3.12, CHCl3). H-NMR
(500 MHz, CDCl3) δ 7.34-7.09 (m, 10H), 6.92 (d, J = 6.5 Hz, 1H), 5.37
(d, J = 3.5 Hz, 1H), 4.49 (t, J = 6.0 Hz, 1H), 2.83-2.76 (m, 1H), 2.74
(bs, 1H), 2.70-2.63 (m, 1H), 2.61-2.53 (m, 1H), 2.00-1.94 (m, 2H),
0.71 (d, J = 7.0 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 165.4, 145.6,
142.0, 137.1, 133.7, 128.9, 128.5, 126.2, 125.8, 81.2, 69.9, 37.7,
35.1, 32.4, 12.3. IR (KBr) (cm-1) 3423, 2962, 1710, 1634, 1449, 1324,
1
1167, 1045, 816. Diastereomer 2: [α]2D5 = +36.0 (c 1.62, CHCl3). H-
NMR (500 MHz, CDCl3) δ 7.36-7.09 (m, 10H), 6.85 (d, J = 6.3 Hz, 1H),
5.33 (d, J = 3.2 Hz, 1H), 4.29 (t, J = 6.0 Hz, 1H), 3.19 (bs, 1 H), 2.85-
2.75 (m, 1H), 2.69-2.60 (m, 1H), 2.59-2.51 (m, 1H), 2.07-1.94 (m,
o
6 | J. Name., 2012, 00, 1-3
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Page 7 of 10
Organic & Biomolecular Chemistry
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ARTICLE
2H), 0.72 (d, J = 7.1 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ 165.8, 1.91-1.81 (m, 1H), 1.72-1.63 (m, 1H), 1.62-1.54 (m, 2H), 1.06-1.01
View Article Online
13
146.9, 141.9, 137.0, 133.2, 128.9, 128.5, 126.4, 125.9, 81.2, 71.8, (m, 3H), 0.88 (bs, 9H), 0.04 (bs, 6H). C-NDMORI: 1(102.1503M9/HC6z,OCBD02C1l23)9Hδ
37.8, 35.3, 32.6, 12.1. IR (KBr) (cm-1) 3438, 2927, 2860, 1709, 1625, (165.50, 165.24), (148.30, 146.99), (141.23, 141.17), (133.61,
1406, 1266, 1159, 1050, 819.
133.49), (128.91, 128.96), (128.35, 128.19), (127.20, 126.84),
(79.52, 79.43), 77.86, 73.31, 71.90, 63.46, 57.31, (30.33, 30.20),
(4-Bromophenyl)(2-oxo-6-phenethyl-5,6-dihydro-2H-pyran-
3-yl)methyl 4-nitrobenzoate (PNB-2f). General Procedure A was 30.09, 27.12, 26.36, 25.23, 18.71, (11.94, 11.84), -4.89. HRMS calcd
used. Light yellow oil. Yield: 43%. Mixture of stereoisomers. 1H-NMR for C24H38NaO5Si [M+Ma]+ 457.2386, found 457.2380. IR (KBr) (cm-1)
(400 MHz, CDCl3) δ 8.32-8.27 (m, 2H), 8.24-8.19 (m, 2H), 7.54-7.48 3432, 2928, 1712, 1635, 1485, 1383, 1260, 1169, 1040, 818.
(m, 2H), 7.37-7.33 (m, 2H), 7.32-7.26 (m, 2H), 7.24-7.16 (m, 3H),
(5S,6R)-3-((4-bromophenyl)(hydroxy)methyl)-6-((S)-4-((tert-
6.94 (bs, 1H), 6.88 (bs, 0.5H), 6.76 (t, J = 4.0 Hz, 0.5H), 4.50-4.33 (m, butyldimethylsilyl)oxy)-1-methoxybutyl)-5-methyl-5,6-dihydro-2H-
1H), 2.92-2.82 (m, 1H), 2.81-2.69 (m, 1H), 2.49-2.40 (m, 2H), 2.19- pyran-2-one (2i). General Procedure C was used. Colorless oil. Yield:
1
2.08 (m, 1H), 1.99-1.89 (m, 1H). 13C-NMR (100 MHz, CDCl3) δ 79%. Mixture of stereoisomers. H-NMR (500 MHz, CDCl3) δ 7.53-
163.04, 162.77, 142.05, (140.68, 140.66), 139.40, (136.27, 136.16), 7.48 (m, 2H), 7.30-7.26 (m, 2H), 6.83 (d, J = 6.5 Hz, 0.5H), 6.72 (d, J =
(135.08, 135.02), 131.97, (130.91, 130.87), 129.19, 128.88, 128.60, 6.5 Hz, 0.5H), 5.59 (bs, 0.5H), 5.47 (bs, 0.5H), 4.25 (dd, J = 9.0, 3.0
(128.44, 128.42), 126.26, (123.71, 123.66), 73.34, 36.34, (30.95, Hz, 0.5H), 4.19 (dd, J = 9.0, 3.0 Hz, 0.5H), 3.70-3.60 (m, 2.5H), 3.52-
30.91), (29.71, 29.68), 29.50. HRMS (ESI) [M+K]+ calcd for 3.46 (m, 1H), 3.39 (s, 3H), 3.20 (s, 0.5H), 2.75-2.66 (m, 1H), 1.93-
C27H22BrKNO6 574.0262, found 574.0261. IR (KBr) (cm-1) 2956, 2925, 1.83 (m, 1H), 1.75-1.65 (m, 1H), 1.65-1.55 (m, 2H), 1.07 (d, J = 7.0
1730, 1528, 1346, 1266, 1099, 1013, 827.
(5S,6R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(1-hydroxy-
3-phenylpropyl)-5-methyl-5,6-dihydro-2H-pyran-2-one
Hz, 1.5H), 1.06 (d, J = 7.0 Hz, 1.5H), 0.91 (bs, 9H), 0.06 (bs, 6H). 13C-
NMR (125 MHz, CDCl3) δ (165.36, 165.12), (148.44, 147.20),
(2g). (140.38, 140.17), (133.33, 133.14), (132.03,131.99), (128.90,
General Procedure C was used. Colorless oil. Yield: 86%. Mixture of 128.52), (122.29, 122.14), (79.61, 79.51), 77.82, 72.94, 71.42, 63.42,
diastereomers. [α]2D5 = +54.5 (c 3.12, CHCl3). 1H-NMR (500 MHz, 57.31, (30.36, 30.22), 27.12, 26.34, 25.23, 18.70, (11.92, 11.81), -
CDCl3) δ 7.30-7.25 (m, 2H), 7.22-7.16 (m, 3H), 6.93 (dd, J = 6.5, 1.0 4.90. HRMS (ESI) [M+Ma]+ calcd for C24H37BrNaO5Si 535.1491, found
Hz, 0.6H), 6.84 (d, J = 6.5 Hz, 0.4H), 4.52-4.47 (m, 0.6H), 4.28 (bs, 535.1499. IR (KBr) (cm-1) 3445, 2921, 1716, 1639, 1488, 1394, 1293,
0.4H), 4.20-4.15 (m, 2H), 4.11-4.06 (m, 0.6H), 4.06-4.00 (m, 1.4H), 1160, 1046, 820.
3.14 (bs, 0.4H) 2.87-2.79 (m, 1H), 2.74-2.61 (m, 2.6H), 2.07-1.96 (m,
(5S,6R)-6-((S)-4-((tert-butyldimethylsilyl)oxy)-1-methoxybu-
2H), 1.39 (s, 3H), 1.35 (s, 3H), 1.10 (d, J = 7.0 Hz, 3H). 13C-NMR (125 tyl)-3-(1-hydroxy-3-phenylpropyl)-5-methyl-5,6-dihydro-2H-pyran-
MHz, CDCl3) δ (164.86, 164.46), (146.86, 145.47), (141.92, 141.86), 2-one (2j). General Procedure C was used. Colorless oil. Yield: 90%.
(133.66, 133.06), 128.85, 126.40, 110.22, (80.07, 80.01), (73.55, Mixture of stereoisomers. 1H-NMR (500 MHz, CDCl3) δ 7.33-7.28 (m,
73.48), 71.83, 69.70, (67.86, 67.82), 37.66, (32.47, 32.31), (30.26, 2H), 7.25-7.19 (m, 3 H), 6.94 (d, J = 6.5 Hz, 0.6H), 6.86 (d, J = 6.5 Hz,
30.14), 27.38, 25.49, (12.08, 11.95). HRMS (ESI) [M+Ma]+ calcd for 0.4H), 4.50 (t, J = 6.3 Hz, 0.6H), 4.31 (dd, J = 7.5, 5.0 Hz, 0.4H), 4.19
C20H26NaO5 369.1678, found 369.1688. IR (KBr) (cm-1) 3420, 2939, (dd, J = 9.0, 3.0 Hz, 0.6H), 4.16 (dd, J = 9.0, 3.0 Hz, 0.4H), 3.72-3.63
2861, 1719, 1632, 1457, 1378, 1256, 1088, 836.
(5R,6S)-6-((R)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-(1-hydroxy-3- (m, 1H), 2.12-1.97 (m, 2H), 1.95-1.86 (m, 1H), 1.77-1.69 (m, 1H),
phenylpropyl)-5-methyl-5,6-dihydro-2H-pyran-2-one (ent-2g). 1.67-1.59 (m, 2H), 1.06 (d, J = 7.0 Hz, 3H), 0.93 (bs, 9H), 0.09 (bs,
(m, 2H), 3.53-3.47 (m, 1H), 3.41 (s, 3H), 2.90-2.81 (m, 1H), 2.77-2.65
General Procedure C was used. Colorless oil. Yield: 84%. Mixture of 6H). 13C-NMR (125 MHz, CDCl3) δ (165.52, 165.18), 147.37, 146.00,
diastereomers. [α]2D5 = -64.6 (c 2.00, CHCl3). 1H-NMR (500 MHz, (142.00, 141.94), (133.49, 132.92), (128.88, 128.83), 126.34, (79.52,
CDCl3) δ 7.31-7.26 (m, 2H), 7.23-7.17 (m, 3H), 6.94 (dd, J = 6.5, 1.0 79.40), 77.88, 71.82, 69.81, 63.46, 57.28, (37.78, 37.71), (32.51,
Hz, 0.6H), 6.85 (d, J = 6.5 Hz, 0.4H), 4.53-4.48 (m, 0.6H), 4.29 (dd, J = 32.43), (30.23, 30.08), 27.14, 26.36, 25.25, 18.71, (12.04, 11.90), -
13.0, 7.0 Hz, 0.4H), 4.22-4.16 (m, 2H), 4.12-4.08 (m, 0.6H), 4.07-4.01 4.88. HR-MS (ESI) [M+Ma]+ calcd for C26H42NaO5Si 485.2699, found
(m, 1.4H), 3.12 (d, J = 7.5 Hz, 0.4H), 2.88-2.81 (m, 1H), 2.75-2.63 (m, 485.2706. IR (KBr) (cm-1) 3423, 2926, 1709, 1490, 1382, 1231, 1126,
2H), 2.59 (d, J = 3.5 Hz, 0.6H), 2.08-1.97 (m, 2H), 1.40 (s, 3H), 1.37 1010, 819.
(s, 3H), 1.11 (d, J = 7.0 Hz, 3H). 13C-NMR (125 MHz, CDCl3) δ (164.47,
(5S,6R)-6-((S)-4-((tert-butyldimethylsilyl)oxy)-1-methoxybu-
164.08), (146.48, 145.08), (141.49, 141.42), (133.19, 132.59), tyl)-3-(1-hydroxy-2-methylpropyl)-5-methyl-5,6-dihydro-2H-pyran-
(128.48, 128.45), 128.43, (126.00, 125.98), (109.81, 109.80), (79.64, 2-one (2k). General Procedure C was used. Colorless oil. Yield: 88%.
79.58), (73.12, 73.06), 71.50, 69.33, (67.44, 67.40), 37.23, (32.07, Mixture of stereoisomers. [α]2D5 = +41.4 (c 2.12 , CHCl3). 1H-NMR
31.92), (29.85, 29.73), 26.98, (25.09, 25.07), (11.68, 11.55). HRMS (500 MHz, CDCl3) δ 6.88 (bd, J = 6.5 Hz, 0.5H), 6.82 (d, J = 6.5 Hz,
calcd for C20H27O5 [M+H]+ 347.1853, found 347.1846. IR (KBr) (cm-1) 0.5H), 4.23-4.14 (m, 1H), 3.79 (bs, 0.5H), 3.68-3.58 (m, 2H), 3.50-
3442, 2923, 2852, 1711, 1622, 1386, 1259, 1169, 1012, 810.
(5S,6R)-6-((S)-4-((tert-butyldimethylsilyl)oxy)-1-methoxybu-
tyl)-3-(hydroxy(phenyl)methyl)-5-methyl-5,6-dihydro-2H-pyran-2-
3.44 (m, 1H), 3.38 (s, 3H), 3.23 (bs, 0.5H), 2.74-2.65 (m, 1H), 2.01-
1.92 (m, 1H), 1.92-1.83 (m, 1H), 1.74-1.66 (m, 1H), 1.64-1.56 (m,
2H), 1.06 (d, J = 7.0 Hz, 1.5 H), 1.04 (d, J = 7.0 Hz, 1.5 H), 0.99 (d, J =
one (2h). General Procedure C was used. Colorless oil. Yield: 83%. 7.0 Hz, 1.5 H), 0.91 (d, J = 7.0 Hz, 1.5 H), 0.89-0.87 (m, 10.5H), 0.81
Mixture of stereoisomers. [α]2D5 = +8.65 (c 4.38, CHCl3). 1H-NMR (500 (d, J = 7.0 Hz, 1.5H), 0.04 (s, 6H). 13C-NMR (125 MHz, CDCl3) δ
MHz, CDCl3) δ 7.39-7.32 (m, 4H), 7.31-7.26 (m, 1H), 6.83 (d, J = 6.5 (165.62, 164.77), (148.41, 146.76), (132.67, 131.81), 79.58, 79.33,
Hz, 0.7H), 6.67 (d, J = 6.5 Hz, 0.3H), 5.61 (s, 0.7H), 5.50 (s, 0.3H), 79.06, (77.96, 77.87), 75.95, 63.48, (57.36, 57.31), (33.19, 33.00),
4.24 (dd, J = 9.0, 3.5 Hz, 0.3H), 4.17 (dd, J = 9.0, 3.5 Hz, 0.7H), 3.66- (30.37, 30.15), 27.16, 26.34, 25.30, (20.25, 19.96), (18.70, 18.63),
3.56 (m, 2H), 3.49-3.44 (m, 1H), 3.37 (s, 3H), 2.72-2.63 (m, 1H), 17.75, (12.08, 11.88), -4.90. HRMS (ESI) [M+Ma]+ calcd for
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Organic & Biomolecular Chemistry
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Journal Name
C21H40NaO5Si 423.2543, found 423.2546. IR (KBr) (cm-1) 3433, 2963,
2925, 1710, 1641, 1451, 1385, 1261, 1093, 1029, 802.
1.
2.
a) J. A. Marco and M. Carda. Recent Advances in the Field of
Naturally Occuring 5,6-Dihydropyran-2-ones,ViewinArticNleaOtunlrinael
Lactones and Lactams: Synthesis, OcDcuOrIr:e1n0.c1e03a9n/Cd6OBiBo0lo21g2ic9aHl
Activity, ed. Tomasz Janecki, Wiley-VCH, Germany, 1st edn,
2013, p. 51; b) L. X. Chen, H. He and F. Qiu, Nat. Prod. Rep.,
2011, 28, 705; c) D. H. Zhang, X. D. Yang, J. S. Kang, H. D. Choi
and B. W. Son, J. Nat. Prod., 2008, 71, 1458; d) H. P. Chen, Z.
Z. Zhao, R. H. Yin, X. Yin, T. Feng, Z. H. Li, K. Wei and J. K. Liu,
Nat. Prod. Bioprospect., 2014, 4, 271.
Selective examples of total syntheses of 5,6-dihydro-α-pyrone
natural products: boronolide, a) P. Kumar and S. V. Naidu, J.
Org. Chem., 2006, 71, 3935; b) B. M. Trost and V. S. C. Yeh,
Org. Lett., 2002, 4, 3513; c) T. Honda, S. Horiuchi, H. Mizutani
and K. Kanai, J. Org. Chem., 1996, 61, 4944; d) M.
Chandrasekhar, K. L. Chandra and V. K. Singh, J. Org. Chem.,
2002, 68, 4039; e) S. G. Hu, T. S. Hu and Y. L. Wu, Org. Biomol.
Chem., 2004, 2, 2305; strictifolione, f) S. BouzBouz and J.
Cossy, Org. Lett., 2003, 5, 1995; g) S. Ghadigoanokar, M. R.
Koli, S. S. Gamre, M. K. Choudhary, S. Chattopadhyay and A.
Sharma, Tetrahedron Asymmetry, 2012, 23, 1093;
cryptolatifolione, h) L. F. T. Novaes, A. M. Sarotti and R. A. Pilli,
RSC Adv., 2015, 5, 53471; sominone, i) Y. Matsuya, Y.
Yamakawa, C. Tohda, K. Teshigawara, M. Yamada and H.
Nemoto, Org. Lett., 2009, 11, 3970.
a) W. Schmidt, T. M. Schulze, G. Brasse, E. Nagrodzka, M.
Maczka, J. Zettel, P. G. Jones, J. Grunenberg, M. Hilker, U.
Trauer-Kizilelma, U. Braun and S. Schulz, Angew. Chem. Int.
Ed., 2015, 54, 7698; b) A. G. Song, X. S. Zhang, X. X. Song, X. B.
Chen, C. G. Yu, H. Huang, H. Li and W. Wang, Angew. Chem.
Int. Ed., 2014, 53, 4940; c) X. Huang, L. Q. Song, G. L. Zhu and
B. Liu, Angew. Chem. Int. Ed., 2013, 52, 952; d) J. Y. Cha, J. T. S.
Yeoman and S. E. Reisman, J. Am. Chem. Soc., 2011, 133,
14964; e) Y. S. Park, C. I. Grove, M. Gonzalez-Lopez, S.
Urgaonkar, J. C. Fettinger and J. T. Shaw, Angew. Chem. Int.
Ed., 2011, 50, 3730.
Conversion of ring-closing metathesis products
(3S,5S,6R)-6-((S)-2,2-dimethyl-1,3-dioxolan-4-yl)-3-((R)-1-
(methoxymethoxy)-3-phenylpropyl)-5-methyltetrahydro-2H-
pyran-2-one (4). Compound 2g (100 mg, 0.289 mmol) was mixed
with chloromethyl methyl ether (45 μL, 47.1 mg, 2.0 equiv.) and
diisopropylethylamine (151 μL, 112 mg, 3 equiv.) in anhydrous DCM
(2 mL) at 0 oC, and then stirred at r.t. overnight. The reaction
mixture was diluted with DCM, washed with water, diluted
hydrochloric acid (1 N) and brine, dried over anhydrous MgSO4,
filtered, and concentrated under reduced pressure. The crude
MOM-ether was stirred with 10% Pd/C (30 mg) in ethyl acetate (5
ml) under a hydrogen balloon at r.t. Upon the full conversion was
detected by TLC, the reaction mixture was filtered through celite,
concentrated, and purified by silica gel column chromatography
(petroleum ether/ethyl acetate 10:1) to give compound 4 as a
colorless oil (96.3 mg, 85%, mixture of diastereomers). 1H-NMR
(500 MHz, CDCl3) δ 7.24-7.18 (m, 2H), 7.17-7.08 (m, 3H), 4.74 (d, J =
6.5 Hz, 0.5H), 4.69 (d, J = 7.0 Hz, 0.5H), 4.61 (d, J = 7.0 Hz, 0.5H),
4.58 (d, J = 6.5 Hz, 0.5H), 4.16-4.10 (m, 1H), 4.10-3.96 (m, 3H), 3.92-
3.86 (m, 1H), 3.35 (s, 1.5H), 3.31 (s, 1.5H), 2.95-2.88 (m, 0.5H), 2.80-
2.72 (m, 0.5H), 2.71-2.60 (m, 1H), 2.57-2.48 (m, 1H), 2.37-2.23 (m,
1.5H), 2.14-2.06 (m, 0.5H), 2.03-1.94 (m, 0.5H), 1.88-1.80 (m, 0.5H),
1.76-1.64 (m, 1.5H), 1.61-1.53 (m, 0.5H), 1.34 (bs, 3H), 1.28 (s,
1.5H), 1.27 (s, 1.5H), 0.96 (d, J = 7.0 Hz, 1.5H), 0.92 (d, J = 7.0 Hz,
1.5H). 13C-NMR (125 MHz, CDCl3) δ (172.75, 172.62), (141.90,
141.52), (128.49, 128.44), (128.38, 128.28), (126.04, 125.89),
(109.75, 109.71), (97.45, 97.40), (80.68, 80.09), 77.80, 76.55, (73.29,
73.21), 67.73, (55.97, 55.88), (42.00, 41.45), 34.34, 33.00, 32.42,
32.12, (27.82, 27.26), (26.98, 26.94), 26.81, 25.67, (25.25, 25.13),
(15.28, 15.11). HRMS (ESI) [M+Ma]+ calcd for C22H32NaO6 415.2097,
found 415.2105. IR (KBr) (cm-1) 3032, 2960, 2939, 1746, 1479, 1397,
1342, 1237, 1166, 1055, 926, 834.
3.
4.
5.
6.
7.
8.
Y. L. Ge, N. Z. Wang, F. C. Yu, Z. F. Yuan, K. J. Chang and Y. H.
Shen, J. Chem. Res., 2015, 39, 1.
Z. W. You, Z. X. Jiang, B. L. Wang and F. L. Qing, J. Org. Chem.,
2006, 71, 7261.
J.-Y. Wach, S. Güttinger, U. Kutay and K. Gademann, Bioorg.
Med. Chem. Lett. 2010, 20, 2843.
E. Fleury, G. Sorin, E. Prost, A. Pancrazi, F. Sautel, G. Massiot,
M.-I. Lannou and J. Ardisson, J. Org. Chem., 2013, 78, 855.
Selective examples for constructing 3- or 4-substituted 5,6-
dihydro-α-pyrones through RCM reactions and their synthetic
uses: α-substituted, a) E. Roulland, Angew. Chem. Int. Ed.,
2008, 47, 3762; b) J. Liu and J. K. De Brabander, J. Am. Chem.
Soc., 2009, 131, 12562; c) G. W. O'Neil and M. J. Black, Synlett,
2010, 107; d) A. Schwäblein and J. Martens, Eur. J. Org. Chem.,
2011, 4335; e) K. Fujioka, H. Yokoe, M. Yoshida and K.
Shishido, Org. Lett., 2012, 14, 244; f) M. Şardan, S. Sezer, A.
Günel, M. Akkaya and C. Tanyeli, Bioorg. Med. Chem. Lett.,
2012, 22, 5814; β-substituted, g) A. P. Green, A. T. L. Lee and
E. J. Thomas, Chem. Commun., 2011, 47, 7200; h) S.
Chandrasekhar and L. Sreelakshmi, Tetrahedron Lett., 2012,
53, 3233; i) C. M. Neuhaus, M. Liniger, M. Stieger and K.-H.
Altmann, Angew. Chem. Int. Ed., 2013, 52, 5866; j) A. D.
Wadsworth, D. P. Furkert and M. A. Brimble, J. Org. Chem.,
2014, 79, 11179.
a) J. M. Berlin, K. Campbell, T. Ritter, T. W. Funk, A. Chlenov
and R. H. Grubbs, Org. Lett., 2007, 9, 1339; b) I. C. Stewart, T.
Ung, A. A. Pletnev, J. M. Berlin, R. H. Grubbs and Y. Schrodi,
Org. Lett., 2007, 9, 1589; c) A. D’Annibale, L. Ciaralli, M.
Bassetti and C. Pasquini, J. Org. Chem., 2007, 72, 6067; d) D.
Rost, M. Porta, S. Gessler and S. Blechert, Tetrahedron Lett.,
2008, 49, 5968; e) T. Vorfalt, S. Leuthausser and H. Plenio,
Angew. Chem. Int. Ed., 2009, 48, 5191; f) C. Samojłowicz, E.
Borre, M. Mauduit and K. Grela, Adv. Synth. Catal., 2011, 353,
Computation study
The structures and the various conformations of relative
15
compounds were optimized at B3LYP level using the mixed basis
set, i.e., 6–31G (d) for nonmetals and SDD+f for metal atoms. Time-
dependent density functional theory (TDDFT) calculations of the
compounds were carried out to understand the low-lying electronic
transitions. All the computations were performed with the help of
Gaussian 09 program package. 16
Acknowledgements
We are grateful for the financial support from Kunming
University of Science and Technology (14078134), Yunnan
Natural Science Foundation (2010ZC016), Fund of Basic
Research Plan of Yunnan Provincial Science and Technology
Department (2014FA042) and Western Light Talent Culture
Project (to Z. L. Zuo).
9.
Notes and references
8 | J. Name., 2012, 00, 1-3
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Journal Name
1993.
ARTICLE
View Article Online
10. J. Ishihara, O. Tokuda, K. Shiraishi, Y. Nishino, K. Takahashi and
S. Hatakeyama, Heterocycles, 2010, 80, 1067.
DOI: 10.1039/C6OB02129H
11. a) K. Sugimoto, H. Hajima, Y. Hayashi, D. Minato, S. Terasaki,
C. Tohda and Y. Matsuya, Org. Lett., 2015, 17, 5910; b) J.
Švenda, M. Sheremet, L. Kremer, L. Maier, J. O. Bauer, C.
Strohmann, S. Ziegler, K. Kumar and H. Waldmann, Angew.
Chem. Int. Ed., 2015, 54, 5596.
12. a) X. G. Liu, Z. L. Yang, Y. M. Li, F. Yang, L. Feng, N. Z. Wang, D.
B. Ma, K. J. Chang and Y. H. Shen, Tetrahedron, 2014, 70,
9522; b) F. Yang, L. Feng, N. Z. Wang, X. G. Liu, J. Li and Y. H.
Shen, Tetrahedron, 2013, 69, 9463.
13. a) G. S. Forman, A. E. McConnell, R. P. Tooze, W. J. van
Rensburg, W. H. Meyer, M. M. Kirk, C. L. Dwyer and D. W.
Serfontein, Organometallics 2005, 24, 4528; b) G. S. Forman
and R. P. Tooze, J. Organomet. Chem., 2005, 690, 5863.
14. A. H. Hoveyda, P. J. Lombardi, R. V. O’Brien and A. R.
Zhugralin, J. Am. Chem. Soc., 2009, 131, 8378.
15. a) A. D. Becke, J. Chem. Phys., 1993, 98, 5648-5652; b) A. D.
Becke, J. Chem. Phys., 1988, 88, 2547-2553.
16. M. J. Frisch, G. W. Trucks, H. B. Schlegel, G. E. Scuseria, M. A.
Robb, J. R. Cheeseman, G. Scalmani, V. Barone, B. Mennucci,
G. A. Petersson, H. Nakatsuji, M. Caricato, X. Li, H. P.
Hratchian, A. Z. Izmaylov, J. Bloino, G. Zheng, Gaussian 09
(Revision B. 01), Gaussian, Wallingford, 2010.
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DOI: 10.1039/C6OB02129H
Graphical abstract
An efficient Ruꢀcatalyzed RCM of steric demanding homoallyl 2ꢀ(hydroxymethyl)acrylates was
developed. The unusual directing effect of OH···Cl hydrogen bonding was disclosed by experimental
and computational approaches.