Lewis Acid Mediated Cyclizations: Diastereoselective Synthesis of Six- to Eight-Membered Substituted Cyclic Ethers

Article abstract of DOI:10.1055/s-0036-1589054

Cyclic ethers are widely abundant in natural products. Cyclic ether templates are also utilized in drug design and medicinal chemistry. Although the synthetic processes for this class of compounds have been studied extensively with respect to five- and six-membered rings, medium-sized cyclic ethers are synthetically more challenging due to a variety of factors. Herein, we report our results on the Lewis acid catalyzed synthesis of medium-sized cyclic ethers in a diastereoselective manner..

Full text of DOI:10.1055/s-0036-1589054

SYNTHESIS
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
© Georg Thieme Verlag Stuttgart · New York
2017, 49, 4229–4246
special topic
4229
en
A. K. Ghosh et al.
Special Topic
Synthesis
Lewis Acid Mediated Cyclizations: Diastereoselective Synthesis of
Six- to Eight-Membered Substituted Cyclic Ethers
Me
Arun K. Ghosh*a,b
Anthony J. Tomainea
Kelsey E. Cantwella
+
R1
R1
O
O
R
H
R
a Department of Chemistry, Purdue University, 560 Oval Drive,
West Lafayette, IN, 47907, USA
R1
O
n = 2
R
H
H
Me
b Department of Medicinal Chemistry, Purdue University, 575 W
Stadium Ave, West Lafayette, IN, 47907, USA
akghosh@purdue.edu
O
R1
R1
n = 2
O
(
)
n
n = 1
OH
R1
R
O
R1
O
H
R
Published as part of the Special Topic Modern Cyclization Strategies
in Synthesis
R1
n = 3
O
R1
O
R
Received: 19.04.2017
Accepted after revision: 22.05.2017
Published online: 25.07.2017
their application in synthesis.2,19,20 In general, five- and six-
membered cyclic ethers are widely prevalent in natural
products and a number of general synthetic strategies have
been reported for their construction.21–23 For six-membered
ether ring cycles, particularly for substituted tetrahydropy-
rans, hetero-Diels–Alder reactions,24 Prins cyclizations,25
Petasis–Ferrier rearrangements,26 and domino Michael/cy-
clization reactions27 have been extensively utilized to con-
struct multiple stereocenters. Interestingly, the synthesis of
substituted medium-sized cyclic ethers, particularly seven-,
eight-, and nine-membered rings, is vastly unexplored due
to increased enthalpic and entropic penalties contributing
DOI: 10.1055/s-0036-1589054; Art ID: ss-2017-c0259-st
Abstract Cyclic ethers are widely abundant in natural products. Cyclic
ether templates are also utilized in drug design and medicinal chemis-
try. Although the synthetic processes for this class of compounds have
been studied extensively with respect to five- and six-membered rings,
medium-sized cyclic ethers are synthetically more challenging due to a
variety of factors. Herein, we report our results on the Lewis acid cata-
lyzed synthesis of medium-sized cyclic ethers in a diastereoselective
manner.
Key words cyclization, cyclic ethers, diastereoselectivity, Lewis acids,
oxacycles, oxepanes, oxocenes, polycycles
Br
Functionalized cyclic ethers are structural features of a
variety of bioactive natural products.1,2 There are numerous
six- to nine-membered cyclic ethers embedded in a variety
of natural products. These include polyether antibiotics,3
macrolide antibiotics,4 C-glycosides,5 C-nucleotides,6 ma-
rine toxins,7,8 lauroxanes,9 and annonaceous acetogenins.10
Many marine polycyclic ethers, like brevetoxins, ciguatox-
ins, and maitotoxin, possess unique six-, seven-, and eight-
membered fused cyclic ether ring systems. Numerous syn-
thetic methods were developed for the construction of
these fused polyethers.11,12 Cyclic ether subunits have also
been utilized in drug discovery and medicinal chemistry.
We have designed a range of cyclic-ether-derived templates
and scaffolds in the context of our nonpeptide enzyme in-
hibitor research.13,14 A few representative examples of cy-
clic-ether-containing natural products, isolaurepan (1),15
laurencin (2),16 HIV-1 protease inhibitor 3,17 and prostacy-
clin derivative 4,18 are shown in Figure 1. Over the years,
considerable interest and research efforts have been devot-
ed toward the synthesis of various polyether ring sizes and
H
H
O
H
O
H
AcO
Laurencin (2)
Isolaurepan (1)
OMe
OH
H
N
H
O
H
N
S
O
O
O
H
O
Ph
O
HIV-1 protease inhibitor 3
CO2H
O
O
HO
OH
Prostacyclin derivative 4
Figure 1 Structures of oxacyclic bioactive molecules
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4230
A. K. Ghosh et al.
Special Topic
Synthesis
PtCl2 (0.5 mol%)
AgOTf (1 mol%)
toluene, 100 °C
H
+
Me
O
Me
O
6a
6b
trans
cis
O
77% yield (dr 92:8)
In(OTf)3 (10 mol%)
CH2Cl2, 0 ºC
Me
OH
5a
+
H
O
O
Me
O
Me
O
O
O
7a
7b
trans
cis
63% yield (dr 99:1)
Scheme 1 Synthesis of tetrahydropyrans by Hosomi29 and Loh30 and their co-workers
to medium-size-ring formation.28 Herein, we describe our
work on the Lewis acid catalyzed synthesis of substituted
medium-sized cyclic ether ring systems.
9a with high diastereoselectivity. Similarly, the reaction of
alkenol 8 with benzyloxyacetaldehyde afforded trans-tetra-
hydropyran 10a in a highly diastereoselective manner
(most results indicated >20:1 dr).
As part of our continuing interest in the synthesis of cy-
clic ethers, we developed a number of synthetic methodolo-
gies to construct these subunits. As represented in Scheme
1, Hosomi and co-workers reported the PtCl2 (0.5 mol%)
and AgOTf (1 mol%) catalyzed reaction of alkenol 5a and
benzaldehyde to achieve a diastereoselective synthesis of
trans-2,3-disubstituted tetrahydropyran derivative 6a.29
Loh and co-workers showed that the In(OTf)3-catalyzed re-
action of alkenol 5a and furfural provided a trans-2,3,6-tri-
substituted tetrahydropyran ring via an oxonium–ene-type
reaction, to provide 7a.30 The reaction proceeded with an
olefin migration followed by Prins-type cyclization. On the
basis of these previous results, we subsequently developed
an inexpensive catalytic system to promote the synthesis of
substituted tetrahydropyran rings with high diastereoselec-
tivity and good yields.31
We have carried out this reaction with an optically ac-
tive phenyl-substituted alkenol and showed that the result-
ing optically active tetrahydropyran derivative was ob-
tained without erosion of optical purity.31 This indicates
that the reaction does not involve a [3,3]-sigmatropic rear-
rangement pathway.32 We then attempted an FeCl3-cata-
lyzed reaction with cis-alkenol 11 and p-nitrobenzalde-
hyde. As shown in Scheme 3, this resulted in a tandem Prins
and Friedel–Crafts cascade cyclization, leading to polycyclic
fused hexahydro-1H-benzo[f]isochromene derivative 12 in
excellent yield (81%) and diastereoselectivity (dr >20:1).
Subsequently, we found that this cascade reaction can be
carried out efficiently using inexpensive FeCl3 as the cata-
lyst (10 to 15 mol%) in the presence of 4 Å molecular sieves
in CH2Cl2.33 Thus, cis-alkenol 11 provided cis-fused hexahy-
dro-2H-benzo[f]isochromene derivative 12 in high yield
and excellent diastereoselectivity (Scheme 3). Similarly, the
reaction of trans-alkenol 13 provided trans-ring-fused
product 14 in high diastereoselectivity. Further, the reac-
tion of secondary alkenol 15 with benzaldehyde afforded
the highly functionalized tetrahydropyran derivative 16 in
excellent yield and diastereoselectivity.
As shown in Scheme 2, the reaction of alkenol 8 and
benzaldehyde in the presence of a catalytic amount of
Cu(OTf)2 (15 mol%) and cis-1,2-bis(diphenylphosphino)eth-
ylene (15 mol%) provided trans-tetrahydropyran derivative
H
O
We have expanded the scope of the Cu(OTf)2- and bis-
phosphine-catalyzed reactions to a variety of substituted
alkenols and aldehydes, to provide highly functionalized
tetrahydropyran derivatives in good to excellent yields and
generally with excellent diastereoselectivity (dr >20:1).31
During the course of these olefin migration and Prins cy-
clization studies, we observed that the reaction of methyl-
substituted alkenol 5a and aromatic aldehydes afforded
substituted tetrahydropyran derivatives as the only isolated
product. However, as shown in Scheme 4, although the re-
action of substituted alkenol 5a and benzyloxyacetaldehyde
in the presence of Cu(OTf)2 (15 mol%) and bisphosphine (15
+
O
O
9a
9b
cis
trans
Ph2P
PPh2
(15 mol%)
92% yield (dr > 20:1)
Cu(OTf)2
(15 mol%)
CH2Cl2, reflux
OH
8
+
H
OBn
OBn
O
O
OBn
O
10a
10b
trans
cis
92% yield (dr > 20:1)
Scheme 2 Tetrahydropyran synthesis by Ghosh and Nicponski31
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4231
A. K. Ghosh et al.
Special Topic
Synthesis
rahydro-2H-oxocene 20, was obtained as a minor product
in 11% isolated yield. The stereochemical outcome for the
formation of tetrahydropyran derivative 19 can be rational-
ized based on the Zimmerman–Traxler32 transition-state
models 17a and 17b (Scheme 4). Olefin migration followed
by cyclization could proceed through favored transition
state 17b, leading to product 19. For the formation of the
eight-membered oxocene derivative, minor product 20, we
presume a direct nucleophilic attack by the olefin onto the
oxocarbenium ion 18a. The resulting carbenium ion may be
stabilized through an alternative oxocarbenium ion 18b,
which upon proton elimination forms the minor oxocene
product 20. To further expand the scope of this reaction to
form medium-sized ring systems, we then investigated oth-
er Lewis acid catalyzed reactions to improve the ratio of
oxocene product over tetrahydropyran derivatives.
Kobayashi and co-workers have demonstrated the utility of
Sc(OTf)3 as an efficient Lewis acid in the Diels–Alder reac-
tion.34 Recently, Sc(OTf)3 has been employed in a variety of
carbon–carbon and carbon–heteroatom bond-forming re-
actions.35
NO2
FeCl3
H
O
(10 mol%)
HO
H
CH2Cl2
reflux
11
H
12 (81% yield, dr > 20:1)
O
NO2
NO2
H
H
O
FeCl3
(10 mol%)
14 (89% yield, dr > 20:1)
CH2Cl2, reflux
OH
H
R
H
O
H
13 R = H
15 R = Ph
O
16
(94% yield,
dr > 20:1)
Scheme 3 Polycyclic ring formations by Ghosh and co-workers33
H
Table 1 Sc(OTf)3- and p-TSA-Catalyzed Cyclizationa
+
O
Me
OH
OBn
O
5a
H
+
PPh2
PPh2
Me
OH
5a
Cu(OTf)2,
(15 mol%)
NO2
Sc(OTf)3 and p-TSA
0 °C to 23 °C, 12 h
Me
δ+
δ+
O
H
R
Me
H
+
O
BnO
Me
Me
O
O
H
Me
NO2
NO2
18a
(disfavored)
17a
21
22a
R = CH2OBn
H
H
Entry
Solvent
Ratio (21/22a) Yield (%)b
O
Me
1c
2
CH2Cl2
CH2Cl2
71:29d
90:10
74:26
9:91
N/A
43
δ+
R
Bn
O
δ+
O
Me
18b
Me
3
toluene
MeCN
THF
54
H
(favored)
17b
4
27
5
N/A
N/A
37
6
CH2Cl2–MeCN, 1:1
CH2Cl2–MeCN, 1:1
CH2Cl2–MeCN, 1:1
CH2Cl2–MeCN, 1:1
17:83
17:83
64:36
29:71
Me
+
7c
8e
9f
33
Me
O
20 (11%)
O
Me
42
BnO
BnO
27
19 (55%)
a Reaction conditions: 5a (1 equiv), p-nitrobenzaldehyde (1 equiv), Sc(OTf)3
(10 mol%), p-TSA (30 mol%), 0.05 M solution; N/A = not applicable.
b Isolated yield of combined products.
Scheme 4 Formation of oxocene product as a minor isomer, with ben-
zyloxyacetaldehyde
c No p-TSA was used.
d No purification done; starting material remained after 48 h.
e Sc(OTf)3 (20 mol%) used.
f p-TSA (10 mol%) used.
mol%) provided the desired tetrahydropyran derivative 19
as the major product in 55% yield as a single diastereomer,
in this reaction an eight-membered cyclic ether, 3,4,7,8-tet-
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4232
A. K. Ghosh et al.
Special Topic
Synthesis
We first explored the cyclization reaction of alkenol 5a
with p-nitrobenzaldehyde in the presence of a catalytic
amount of Sc(OTf)3 and p-toluenesulfonic acid (p-TSA). The
results are shown in Table 1. The reaction performed in the
presence of Sc(OTf)3 (10 mol%), without p-TSA, in CH2Cl2 at
0 °C to 23 °C for 12 hours provided only a small amount of
substituted oxocene derivative 22a (entry 1). We then in-
vestigated this cyclization in the presence of a combination
of p-TSA (30 mol%) and Sc(OTf)3 (10 mol%). Similar condi-
tions were utilized by Yadav and co-workers for a Prins cy-
clization.36 These reactions were carried out in CH2Cl2 and
toluene, to provide tetrahydropyran derivative 21 as the
major product (entries 2 and 3). In MeCN, the reaction pro-
vided oxocene 22a as the major product (22a/21 10:1);
however, the yield of the combined products was only 27%
(entry 4). When the reaction was carried out in a mixture
(1:1) of MeCN and CH2Cl2, oxocene derivative 22a was ob-
tained as the major product (22a/21 5:1) and the combined
yield improved to 37% (entry 6). The cyclization reaction
performed in CH2Cl2–MeCN with Sc(OTf)3 (10 mol%) in the
absence of Brønsted acid provided a similar product ratio,
but the combined yield was slightly lower (entry 7). Inter-
Table 2 Sc(OTf)3-Catalyzed Reactions: Selected Substrate Scopea
Sc(OTf)3
O
(10 mol%)
+
+
H
R
R
Me
OH
p-TSA
Me
O
R
O
5a
(30 mol%)
Me
Entry
R
Productb
Yield (%)c
Me
+
Me
O
1
p-F-m-NO2C6H3
O
32
Me
F
F
22b
23
NO2
NO2
50:50
Me
+
2
p-BrC6H4
16
23
19
9
Me
O
O
Me
Br
Br
24
19
22c
100:0
Me
OBn
+
OBn
3
CH2OBn
Me
O
O
Me
20
40:60
Me
+
4d
p-MeOC6H4
Me
O
O
22d
Me
OMe
OMe
25
100:0
Me
+
5
(CH2)2Ph
Me
O
O
Me
26
22e
100:0
a Reaction conditions: as per entry 6, Table 1.
b Ratio of pyran/oxocene is given.
c Yield of combined products.
d Aldehyde (2 equiv) used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4233
A. K. Ghosh et al.
Special Topic
Synthesis
estingly, increasing the Sc(OTf)3 to 20 mol% improved the
reaction yield, but decreased the oxocene to tetrahydropy-
ran ratio significantly (entry 8). Also, reducing p-TSA to 10
mol% resulted in a decreased combined yield, with oxocene
22a being obtained as the major product (2.4:1, entry 9).
We then investigated the substrate scope of this cycliza-
tion using Sc(OTf)3 (10 mol%) and p-TSA (30 mol%) in a mix-
ture (1:1) of MeCN and CH2Cl2. The results are summarized
in Table 2. With p-fluoro-m-nitrobenzaldehyde, the reac-
tion provided a 1:1 mixture of tetrahydropyran derivative
23 and oxocene 22b in 32% yield (entry 1). The reaction
with p-bromobenzaldehyde provided tetrahydropyran de-
rivative 24 exclusively. Reaction with benzyloxyacetalde-
hyde afforded a 60:40 mixture of oxocene 20 and tetrahy-
dropyran derivative 19 in 23% yield (entry 3). Reaction of p-
methoxybenzaldehyde or 3-phenylpropionaldehyde pro-
vided the respective tetrahydropyran derivatives, 25 and
26, exclusively (entries 4 and 5).
We have also investigated the effect of lanthanide(III)
triflates to improve the product ratio in favor of the oxo-
cene. In particular, we examined dysprosium(III) triflate
[Dy(OTf)3] for this cyclization reaction. Dy(OTf)3 is com-
mercially available, inexpensive, and less toxic and much
less sensitive to moisture than Sc(OTf)3.37 Dy(OTf)3 has
been utilized as a Lewis acid in a variety of Lewis acid cata-
lyzed carbon–carbon bond-forming reactions.38 In an effort
to assess the scope and utility of Dy(OTf)3 over Sc(OTf)3, we
initially carried out the cyclization of 6-methylhept-6-en-
2-ol (5a) with p-nitrobenzaldehyde in a mixture (1:1) of
MeCN and CH2Cl2 in the presence of p-TSA (30 mol%), and
the results are summarized in Table 3. The use of Dy(OTf)3
(10 mol%) alone, without p-TSA, did not provide any appre-
ciable yield of oxocene product (entry 1). The use of p-TSA
(30 mol%) in combination with Dy(OTf)3 (10 mol%) afforded
oxocene product 22a as the only isolated product, in 26%
yield (entry 2). The use of camphorsulfonic acid (CSA, 30
mol%) in place of p-TSA showed comparable results (entry
3). The use of 2 equivalents of aldehyde resulted in the re-
tention of oxocene product 22a as the major product
(77:23), with an improved combined yield of 70% (entry 4).
Further reactions with 20 mol% and 30 mol% of Dy(OTf)3
and 2 equivalents of aldehyde in the presence of p-TSA (30
mol%) did not result in an improved product ratio in favor of
22a; furthermore, the overall combined yields were also re-
duced (entries 5 and 6).
The substrate scope for the Dy(OTf)3-catalyzed reac-
tions is summarized in Table 4. The reaction proceeded best
when the aromatic aldehyde contained electron-withdraw-
ing substituents. With p-fluoro-m-nitrobenzaldehyde, oxo-
cene product 22b and tetrahydropyran 23 were obtained in
a nearly 1:1 ratio, in 46% combined yield (entry 1). The re-
action with p-bromobenzaldehyde provided only 6% yield
of the combined products (entry 2). The cyclization reac-
tion with p-methoxybenzaldehyde also provided a very
poor yield, in this case with no oxocene product (entry 4).
The reaction with benzyloxyacetaldehyde afforded oxocene
Table 3 Dy(OTf)3- and p-TSA-Catalyzed Cyclizationa
O
H
+
Me
OH
5a
NO2
Dy(OTf)3 and p-TSA
0 °C to 23 °C, 12 h
Me
+
Me
O
O
Me
NO2
NO2
21
22a
Entry
Conditions
Ratio (21/22a)
Yield (%)b
1c
2
Dy(OTf)3 (10 mol%)
N/A
N/A
26
22
70
55
52
Dy(OTf)3 (10 mol%) and p-TSA (30 mol%)
Dy(OTf)3 (10 mol%) and CSA (30 mol%)
Dy(OTf)3 (10 mol%) and p-TSA (30 mol%)
Dy(OTf)3 (20 mol%) and p-TSA (30 mol%)
Dy(OTf)3 (30 mol%) and p-TSA (30 mol%)
0:100
0:100
23:77
41:59
47:53
3
4d
5d
6d
a Reaction conditions: 5a (1 equiv), p-nitrobenzaldehyde (1 equiv), Dy(OTf)3 (10 mol%), p-TSA (30 mol%), 0.05 M solution; N/A = not applicable.
b Yield of combined products.
c Only starting materials remained after 48 h.
d Aldehyde (2 equiv) used.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4234
A. K. Ghosh et al.
Special Topic
Synthesis
product 20 as the major product (20/19 2:1); however, the
reaction yield was very low (entry 3). The reaction of m-
tolualdehyde gave oxocene product 22f and tetrahydropy-
ran derivative 27 in a 1:1 ratio, with a combined yield of
only 7% (entry 5).
Aiming to form the oxocene core as the major product,
we further explored other Lewis acids. Overman and co-
workers reported a BF3·OEt2-catalyzed intramolecular Prins
reaction, during the synthesis of (+)-laurencin.39 As shown
in Scheme 5, the BF3·OEt2-catalyzed cyclization of vinyl sul-
fide 28 afforded oxocene derivative 29 in 57% yield. In this
reaction, the corresponding tetrahydropyran derivative 30
was obtained in 4% yield.
Based upon this result, we elected to investigate
BF3·OEt2 as catalyst in our cyclization of 5a and p-nitro-
benzaldehyde.40 The results are summarized in Table 5. The
reaction of alkenol 5a and p-nitrobenzaldehyde in the pres-
ence of 3 equivalents of BF3·OEt2 in t-BuOMe at 0 °C resulted
in the formation of oxocene derivative 22a and a new exo-
olefin derivative 31a in a 76:24 ratio and 33% combined
Table 4 Dy(OTf)3-Catalyzed Reactions: Substrate Scopea
Me
Dy(OTf)3
O
(10 mol%)
+
+
H
R1
p-TSA
(30 mol%)
R1
Me
OH
Me
O
R1
O
5a
Me
Me
Entry
R1
Productb
Yield (%)c
+
Me
O
1
p-F-m-NO2C6H3
O
46
Me
F
F
22b
23
NO2
NO2
45:55
Me
+
2
3
4
p-BrC6H4
6
6
5
Me
O
O
Me
Br
Br
24
22c
86:14
Me
OBn
+
CH2OBn
OBn
Me
O
O
20
19
Me
33:66
Me
+
p-MeOC6H4
Me
O
O
Me
OMe
OMe
25
22d
100:0
Me
Me
+
Me
5
m-MeC6H4
7
Me
O
O
Me
27
22f
50:50
a Reaction conditions: as per entry 2, Table 3.
b Ratio of pyran/oxocene is given.
c Yield of combined products.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4235
A. K. Ghosh et al.
Special Topic
Synthesis
Table 5 TMSOTf- and BF3·OEt2-Catalyzed Cyclizationa
OMe
O
SPh
O
O
O
H
+
28
Me
OH
5a
NO2
BF3•OEt2 (2 equiv)
0.05 M, t-BuOMe
–78 to –40 ºC, 7 h
BF3•OEt2 or TMSOTf
0 °C, 1 h
Me
SPh
PhS
+
+
Me
O
O
Me
O
Me
O
Me
22a (endo)
NO2
NO2
29
30
4% yield
31a (exo)
O
O
57% yield
O
O
Entry Solvent
Lewis acid Equivb Ratio
(22a/31a)c
Yield
(%)d
Scheme 5 Oxocene synthesis by Overman and co-workers39
1e
2e
3e
4e
5
t-BuOMe
CH2Cl2
BF3·OEt2
BF3·OEt2
BF3·OEt2
BF3·OEt2
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
TMSOTf
3.0
0.1
0.2
0.4
1.0
1.0
1.0
1.0
1.0
1.0
76:24
98:2
98:2
98:2
88:12
95:5
81:19
98:2
98:2
98:2
33
14
38
21
46
60
58
73
68
68
CH2Cl2
CH2Cl2
yield (entry 1). Interestingly, in this reaction we were not
able to identify the six-membered Prins cyclization product
21 by 1H NMR analysis of the crude product. In an effort to
improve the yield of endo-oxocene product 22a, we exam-
ined reactions in CH2Cl2 with decreased amounts of
BF3·OEt2 (entries 2–4). The use of 0.2 equivalents of BF3·OEt2
in CH2Cl2 provided the best results with an endo/exo-olefin
oxocene ratio of 98:2 and a modest yield of 38% (entry 3).40
In 2011, Cho and co-workers reported TMSOTf-catalyzed
Prins-type cyclization, leading to oxepane derivatives.41 We
therefore explored TMSOTf-catalyzed reactions, aiming to
improve the yield of oxocene product 22a. Reaction of alke-
nol 5a and p-nitrobenzaldehyde with 1 equivalent of
TMSOTf in t-BuOMe at 0 °C resulted in the improvement of
yield and endo/exo-olefin oxocene product ratio over the
BF3·OEt2-catalyzed reaction (entries 1 and 5). A further sur-
vey of solvents showed that the cyclization reaction in THF
with 1 equivalent of TMSOTf was optimum (entries 6–10).
The substrate scope of the TMSOTf-catalyzed reaction
with a number of alkenols was examined, with a variety of
substituted aromatic aldehydes, 3-phenylpropionaldehyde,
and benzyloxyacetaldehyde. The results are shown in Table
6, where the structure of the major endo-olefin oxocene
product is given for each entry, along with the ratio of
t-BuOMe
Et2O
6e
7
DME
8
THF
9
CH2Cl2–THF, 1:1
CH2Cl2–THF, 3:1
10
a Reaction conditions: 5a (1 equiv), p-nitrobenzaldehyde (1.2 equiv), 0.1 M
solution, molecular sieves (60 mg).
b Equivalents of Lewis acid.
c Ratio of endo/exo-olefin.
d Yield of combined products.
e No molecular sieves were used.
its exo-isomer 31k in a 91:9 ratio (entry 6). o-Nitrobenzal-
dehyde also provided a 58% yield of cyclization products
with good endo-olefin selectivity (entry 7). Reactions with
moderately electron-deficient aldehydes, such as p-fluoro-,
p-(trifluoromethyl)-, and p-chlorobenzaldehyde, gave the
corresponding endo-olefin oxocenes as the major product;
however, yields were moderate (entries 8–10). Reactions of
alkenol 5a with 3-phenylpropionaldehyde and benzyloxy-
acetaldehyde also provided the endo-olefin oxocenes as the
major product (entries 11 and 12), but with a substantial
reduction in yields compared to electron-deficient aromatic
aldehydes. Unfortunately, moderately electron-donating m-
tolualdehyde provided a very low yield of cyclization prod-
uct (entry 13). Similarly, 2-naphthaldehyde provided only
16% yield of oxocene products (entry 14). Finally, the reac-
tion of alkenol 5a with p-fluoro-m-nitrobenzaldehyde gave
41% yield of oxocene products with an endo/exo-olefin ratio
of 91:9 (entry 15).
1
endo/exo-olefin isomer as determined by H NMR analysis.
We first examined the compatibility of alkyl substituents
on the alkenol substrate in reactions with p-nitrobenzalde-
hyde (entries 2–5); the TMSOTf-catalyzed conditions pro-
vided consistently good to excellent yields of endo-olefin
products with excellent endo-olefin selectivity.
Next, we tested a variety of aldehyde substrates using
alkenol 5a (R = Me) as the starting material. m-Nitrobenzal-
dehyde provided a 65% yield of endo-olefin product 22k and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4236
A. K. Ghosh et al.
Special Topic
Synthesis
Table 6 TMSOTf-Catalyzed Reactions: Substrate Scopea
Table 6 (continued)
Entry
R1
R
Productb,c
Yield (%)d
H
+
Me
R1
O
5a–d, 8
OH
R
NO2
7
Me
Me
Me
Me
o-NO2C6H4
58
TMSOTf
0 °C, 1 h
MS
O
Me
22l/31l, 97:3
Me
+
Me
R1
R1
O
O
20, 22
8
9
p-FC6H4
20
R
R
O
31
Me
F
Entry
R
R1
Productb,c
Yield (%)d
22m/31m, 90:10
Me
Me
p-F3CC6H4
37
1
Me
p-NO2C6H4
73
O
O
Me
Me
CF3
NO2
22n/31n, 92:8
22a/31a, 98:2
Me
Me
10
p-ClC6H4
18
2
H
p-NO2C6H4
70
O
O
H
Me
Cl
NO2
22o/31o, 93:7
22g/31g, 90:10
Me
Me
3
4
Et
p-NO2C6H4
87
62
11
12
13
Me
Me
Me
(CH2)2Ph
35
24
8
O
O
Me
NO2
22h/31h, 90:10
22e/31e, 94:6
Me
Me
i-Pr
p-NO2C6H4
O
CH2OBn
O
NO2
O
Me
22i/31i, 91:9
20/19, 98:2
Me
Me
5
Ph
p-NO2C6H4
39
O
m-MeC6H4
O
NO2
Me
Me
22j/31j, 91:9
22f/31f, 92:8
Me
6
Me
m-NO2C6H4
65
O
Me
NO2
22k/31k, 91:9
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4237
A. K. Ghosh et al.
Special Topic
Synthesis
Table 6 (continued)
Me
Entry
R
R1
Productb,c
Yield (%)d
+
Me
O
O
Me
Me
22k
31k
NO2
NO2
14
Me
2-Naph
16
O
O3, CH2Cl2–MeOH (1:1)
Me2S, –78 °C, 12 h
Me
O
O
O
22p/31p, 94:6
H
Me
Me
+
O
O
Me
Me
32
33
15
Me
p-F-m-NO2C6H3
41
O
NO2
NO2
Me
F
1. Separation by chromatography
2. Ph3P=CH2, THF
NO2
22b/31b, 91:9
a Reaction conditions: as per entry 8, Table 5.
b The endo/exo-olefin ratio was determined by 1H NMR analysis.
c endo-Oxocene dr >20:1, as determined by 1H NMR analysis.
d Isolated yield of combined products.
O
Me
31k
In general, these endo/exo-isomer pairs are difficult to
separate by silica gel chromatography. To provide conclu-
sive structural evidence, we have carried out ozonolytic
cleavage of the mixture of 22k/31k isomers, as shown in
Scheme 6. The resulting products 32 and 33 were separated
by silica gel chromatography. Wittig olefination of ketone
33 afforded the exo-olefin product 31k which showed iden-
tical 1H NMR and 13C NMR data corresponding to the minor
product formed during the TMSOTf-catalyzed cyclization
NO2
Scheme 6 Preparation of exo-oxacyclic isomer 31k
ate as the substrate provided a 23% yield of oxepine 41 (en-
try 7), displaying the potential for further modifications ex-
ternal to the oxepine framework.
Further assignment of the relative stereochemistry was
carried out using 1H NMR NOESY experiments on com-
pound 35 (Figure 2). The depicted conformation is based on
the observed strong NOESY correlations. Thus, the strong
NOESY correlation between HE and HD supports the cis ste-
reochemical assignment between the methyl and aromatic
substituents. The additional NOESY correlations between
HC–HI, HI–HK, and HH–HJ support the conformation shown.
1
(Table 6, entry 6). H NMR NOESY experiments were used
for assignment of the stereochemistry of the oxocene prod-
ucts. Further support of the structural assignment was ob-
tained by determination of the X-ray crystal structure of
the corresponding sulfonamide derivative of the major oxo-
cene product 22a.40
In efforts to expand our cyclic ether synthetic method,
seven-membered oxepines have been synthesized. Using 5-
methylhex-5-en-2-ol (34), TMSOTf, 4 Å molecular sieves,
and a variety of aldehydes, oxepines were synthesized with
high diastereoselectivity (dr >20:1), with an unidentified
minor isomer. The results are summarized in Table 7. The
presence of one electron-withdrawing substituent on the
aromatic aldehyde (entries 1 and 2) resulted in moderate
yields of the corresponding oxepine products 35 and 36.
The reaction with 3-phenylpropionaldehyde gave oxepine
product 37 in moderate yield (entry 3), while the use of
benzyloxyacetaldehyde led to a decreased yield of product
38 (entry 4). Similarly, electron-deficient p-fluoro-m-nitro-
benzaldehyde produced oxepine 39 in only 28% yield (entry
5). Interestingly, an aldehyde with both an electron-donat-
ing and an electron-withdrawing substituent (entry 6) gave
a moderate yield (48%) of oxepine 40. Finally, ethyl glyoxyl-
HC
HJ
HI
HH
HG
O
HF
HK
NO2
HE
HD
HB
HA
Me
O
Me
35
NO2
Figure 2 NOE correlations of oxepine derivative 35
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4238
A. K. Ghosh et al.
Special Topic
Synthesis
Table 7 Preliminary Oxepine Synthesesa
The cis stereochemical outcome can be rationalized
based on the transition-state models shown in Scheme 7.
Steric clash, as seen in structure 42b, is likely the driving
force which favors the cis outcome over the trans outcome.
Successive cyclization, followed by proton elimination,
yields the cis-product 43a; formation of the trans-product
43b was not observed by 1H NMR analysis.
Me
O
TMSOTf
Me
+
R
O
H
R
Me
OH
34
Entry
R
Product
Yield (%)
O
Me
Me
+
H
R
OH
34
1
p-NO2C6H4
36
O
TMSOTf
Me
NO2
35
δ+
δ+
Me
Me
H
Me
Me
O
Me
O
Ar
H
H
H
Ar
2
m-NO2C6H4
49
NO2
42b
Favored
42a
Disfavored
O
Me
Me
Me
36
Me
Ar
Ar
O
O
Me
Me
3
4
(CH2)2Ph
49
27
43a
43b
O
Me
Scheme 7 Transition-state analysis for the oxepine products
37
Me
In addition to the seven-membered oxepine syntheses,
we were able to construct seven-membered oxepanes using
7-methyloct-7-en-2-ol (44) as the substrate. After con-
structing 44, we then subjected it to reaction conditions
which included TMSOTf, 4 Å molecular sieves, and nitro-
benzaldehydes. For this reaction, it was necessary to in-
crease the amount of TMSOTf to 1.2 equivalents, relative to
44. As summarized in Table 8, the reaction with p-nitro-
benzaldehyde yielded oxepane 45 in 14% yield (entry 1),
while m-nitrobenzaldehyde as the substrate gave oxepane
46 in 29% yield (entry 2). The diastereomers shown were
isolated from a reaction mixture with compounds that have
not been fully analyzed.
CH2OBn
O
O
Me
38
Me
5
p-F-m-NO2C6H3
28
NO2
F
O
Me
39
Me
The oxepane outcome is a similar result to that observed
with our Cu(OTf)2–bisphosphine ligand protocol. It was
suspected that the olefin migrates to the internal position,
subsequently cyclizing to form the oxepane core. We tested
our hypothesis by first subjecting 7-methyloct-7-en-2-ol
(44) to TMSOTf in THF with 4 Å molecular sieves at 0 °C.
These conditions provided 47 in 93% yield (Scheme 8). Sub-
sequently, product 47 was subjected to the Prins-type cy-
clization conditions with p-nitrobenzaldehyde, and indeed
gave oxepane 45 in 42% yield. Based upon this, the isomeri-
zation seems to occur first, under the reaction conditions to
form 47 in situ, followed by cyclization and proton elimina-
tion to give the oxepane scaffold.
NO2
6
7
p-MeO-m-NO2C6H3
48
23
O
Me
OMe
40
Me
CO2Et
O
O
Me
O
41
a Reaction conditions: 34 (1 equiv), aldehyde (1.2 equiv), TMSOTf (1 equiv),
0.1 M solution, 0 °C, molecular sieves (40 mg).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4239
A. K. Ghosh et al.
Special Topic
Synthesis
Table 8 Synthesis of Oxepane Derivativesa
OH
O
TMSOTf
Me
Entry
1
H
+
R
44
O
Me
R
R
Product
Yield (%)
p-NO2C6H4
14
O
Me
NO2
45
NO2
2
m-NO2C6H4
29
O
Me
46
a Reaction conditions: 44 (1 equiv), aldehyde (1.2 equiv), TMSOTf (1.2
equiv), 0.1 M solution, 0 °C, molecular sieves (40 mg).
Me
Me
TMSOTf
Me
Me
Me
THF, MS, 0 °C
93%
Scheme 9 X-ray crystal structure determination of 48 (white = hydro-
gen, black = carbon, red = oxygen, blue = nitrogen, yellow = sulfur,
brown = bromine)
OH
OH
44
47
Scheme 8 TMSOTf-catalyzed isomerization of alkenol 44
HM
HJ
HD
HD
To determine the X-ray crystal structure, oxepane deriv-
ative 45 was first subjected to reduction conditions using
zinc dust and acetic acid, as shown in Scheme 9. The result-
ing aniline derivative was then reacted with p-bromoben-
zenesulfonyl chloride to yield sulfonamide 48. This com-
pound was then recrystallized from CH2Cl2/MeOH at 23 °C
to yield white needles. The single-crystal X-ray analysis
supports the cis stereochemical assignment shown.41
Further assignment of the relative stereochemistry was
carried out using 1H NMR NOESY experiments on com-
pound 45 (Figure 3). The depicted conformation is based on
the X-ray crystal structure of 48. The observed strong
NOESY correlation between HE and HC supports the cis ste-
reochemical assignment between the methyl and aromatic
substituents of 45. Additional NOESY correlations between
HC–HK, HE–HK, and HF–HK support the notion of all substitu-
ents on the oxepane core having a cis relationship. The ob-
served NOESY correlations between HM–HJ and HM–HL fur-
ther support the cis relationship.
HG
H
HL
HI
HF
HH
Me
K O
NO2
HA
HB
HC
HE
O
Me
NO2
45
Figure 3 NOE correlations of oxepane derivative 45
tion, steric hindrance is likely the driving force which favors
the cis stereochemistry (50a), as seen with the oxepine sys-
tems.
The cis stereochemical outcome can be rationalized
based on the transition-state models shown in Scheme 10.
The transition-state structures 49a and 49b are based on
the X-ray crystal structure of 48 and the positive charge
distribution is based upon the results of our isomerization
studies. After the olefin has migrated to the internal posi-
In summary, medium-sized cyclic ethers are subunits of
numerous biologically active molecules; however, the di-
rect synthesis of these subunits is limited. Over the years,
we have investigated a variety of catalytic methods for the
synthesis of functionalized cyclic ethers with high diastere-
oselectivity and yields. In particular, a mild Cu(OTf)2 and
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4240
A. K. Ghosh et al.
Special Topic
Synthesis
(SiliCycle; 60 Å, 250 μm thickness, F-254 indicator). All solvent sys-
tems are given as volume/volume ratios. Flash chromatography was
performed using 230–400 mesh, 60 Å pore diameter silica gel (SiliCycle).
Preparative HPLC was performed on all compounds where impurities
remained after flash column chromatography. The system used was
comprised of an Agilent 1100 series dual-piston pump, YMC-Pack ODS-A
column (250 × 20 mm i.d.), variable wavelength detector, and Agilent
1260 series fraction collector. The mobile phase was HPLC-grade
MeCN at 10 mL/min and the hardware was controlled by ChemStation
software. 1H and 13C NMR spectra were recorded at room temperature
on a Bruker AV-500 spectrometer, using a CryoProbe. Chemical shifts
(δ values) are reported in parts per million, and are referenced to the
CDCl3 residual solvent peak (7.26 ppm). Data are reported as: δ value
(multiplicity, J value, integration), where s = singlet, d = doublet,
t = triplet, q = quartet, p = quintet, h = hextet, and m = multiplet. Mass
spectrometry experiments were performed under EI/CI, ESI+, or APCI
conditions (Hewlett Packard Engine, Agilent 1290, 6320 LCMS,
Thermofisher LTQ). The ratios of eight- to six-membered-ring com-
pounds were determined by 1H NMR analysis.
O
Me
Me
+
H
R
OH
44
TMSOTf
Me
δ+
δ+
Me
O
O
Ar
H
H
H
H
Ar
Favored
Disfavored
49b
49a
Ar
Ar
O
O
Me
Me
50a
50b
Scheme 10 Transition-state analysis for the oxepane products
Substituted Cyclic Ethers; General Procedure
To a 10-mL round-bottomed flask with a stir bar and activated molec-
ular sieves, under argon, was added THF (0.2 M) and aldehyde (1.2
equiv). The flask was cooled to 0 °C for 10 min, after which TMSOTf
(1.0 or 1.2 equiv) was added dropwise. After stirring for 5 min, a
chilled solution (–78 °C) of 6-methylhept-6-en-2-ol (5a) or 5-methyl-
hex-5-en-2-ol (34) (50 mg, 1.0 equiv) in THF (0.2 M) was added drop-
wise over 5 min. The reaction was monitored by TLC (EtOAc–hexanes,
5:95) until completion. The reaction was then quenched with sat.
NaHCO3 and the mixture was extracted with EtOAc (3 ×). Then,
Na2SO4 was added to the combined organic layers, which were then
filtered, concentrated, and purified by column chromatography
(EtOAc–hexanes, 5:95) to yield the cyclic ether products.
bisphosphine complex provided access to substituted tetra-
hydropyran rings through an olefin migration, followed by
Prins-type cyclization. Interestingly, this reaction protocol
with benzyloxyacetaldehyde provided the tetrahydropyran
derivative as the major product and an eight-membered
oxocene derivative as the minor product. We subsequently
investigated a number of other Lewis acid catalyzed condi-
tions, including Sc(OTf)3 and Dy(OTf)3 in the presence of a
catalytic amount of Brønsted acid. As it turned out, with 6-
methylhept-6-en-2-ol and p-nitrobenzaldehyde, Sc(OTf)3
(10 mol%) and p-TSA (30 mol%) in a mixture of CH2Cl2 and
MeCN resulted in the oxocene product as the major product
over the tetrahydropyran derivative, as a 83:17 mixture.
However, the yield of the combined products was 37%. Our
optimization efforts with Dy(OTf)3 also provided similar re-
sults. We subsequently developed a TMSOTf-catalyzed
Prins-type cyclization for the synthesis of a variety of sub-
stituted oxocene derivatives with 1-alkyl-5-methylhexen-
ols and aromatic aldehydes. This protocol is also suitable for
the synthesis of seven-membered cyclic ethers with excel-
lent diastereoselectivity and good yields. Further studies,
particularly on the subject of substrate scopes and applica-
tion, are currently underway in our laboratory.
(Z)-2,6-Dimethyl-8-(p-nitrophenyl)-3,4,7,8-tetrahydro-2H-oxo-
cine (22a)
Following the general procedure, activated molecular sieves (60 mg),
p-nitrobenzaldehyde (71 mg, 0.47 mmol, 1.2 equiv) in THF (2.4 mL,
0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-
en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22a
as a clear, pale yellow oil; yield: 74 mg (73%); 98:2 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 8.18 (d, J = 8.7 Hz, 2 H), 7.54 (d, J = 8.8
Hz, 2 H), 5.58–5.49 (m, 1 H), 4.45 (d, J = 9.1 Hz, 1 H), 3.77–3.66 (m, 1
H), 2.71 (dd, J = 13.9, 9.5 Hz, 1 H), 2.55–2.44 (m, 1 H), 2.14 (dd, J =
14.0, 1.8 Hz, 1 H), 2.04–1.96 (m, 1 H), 1.78 (s, 3 H), 1.75–1.67 (m, 1 H),
1.63–1.54 (m, 1 H), 1.14 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.78, 146.81, 134.37, 126.63,
126.05, 123.42, 80.34, 76.07, 42.47, 38.18, 25.30, 24.42, 22.3.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C15H20NO3: 262.1443; found:
262.1440.
All reagents were purchased from Sigma-Aldrich, Fisher-Acros,
Oakwood Chemical, or Alfa-Aesar. Liquid reagents were distilled and
solid reagents were solvated in EtOAc, followed by washes with sat.
NaHCO3, drying over Na2SO4, and finally removal of the solvent in vac-
uo. Methyltriphenylphosphonium bromide was dried by heating at
150 °C under reduced pressure overnight. The following reaction sol-
vents were distilled prior to use: CH2Cl2 and toluene from CaH2; Et2O
and THF from Na/benzophenone. MeCN and DME were dried over ac-
tivated 4 Å molecular sieves. All reactions were performed at 0 °C un-
der an argon atmosphere in oven-dried glassware. TLC analysis was
run using glass-backed thin-layer silica gel chromatography plates
(Z)-6-Methyl-8-(p-nitrophenyl)-3,4,7,8-tetrahydro-2H-oxocine
(22g)
Following the general procedure, activated molecular sieves (60 mg),
p-nitrobenzaldehyde (80 mg, 0.53 mmol, 1.2 equiv) in THF (2.64 mL,
0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-methylhex-5-
en-1-ol (50 mg, 0.44 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22g
as a clear, pale yellow oil; yield: 76 mg (70%); 90:10 (endo/exo).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4241
A. K. Ghosh et al.
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 8.19 (d, J = 8.8 Hz, 2 H), 7.53 (d, J = 8.7
Hz, 2 H), 5.53 (ddt, J = 9.7, 6.8, 1.5 Hz, 1 H), 4.47 (dd, J = 9.3, 2.0 Hz, 1
H), 4.04 (ddd, J = 12.0, 5.0, 2.1 Hz, 1 H), 3.52 (dt, J = 11.9, 3.3 Hz, 1 H),
2.69 (dd, J = 14.0, 9.3 Hz, 1 H), 2.49–2.38 (m, 1 H), 2.17 (dd, J = 14.0,
2.1 Hz, 1 H), 2.11–1.95 (m, 2 H), 1.77 (s, 3 H), 1.54–1.44 (m, 1 H).
13C NMR (125 MHz, CDCl3): δ = 151.29, 134.52, 126.63, 125.60,
123.49, 81.30, 69.30, 41.78, 31.07, 25.04, 24.07.
phenylhex-5-en-1-ol (50 mg, 0.26 mmol, 1.0 equiv) in THF (1.3 mL,
0.2 M) gave 22j as a clear, pale yellow oil; yield: 33 mg (39%); 91:9
(endo/exo).
1H NMR (500 MHz, CDCl3): δ = 8.20 (d, J = 8.8 Hz, 2 H), 7.59 (d, J = 8.2
Hz, 2 H), 7.32–7.22 (m, 3 H), 7.24–7.15 (m, 2 H), 5.64 (ddt, J = 9.9, 6.8,
1.5 Hz, 1 H), 4.66 (dd, J = 11.3, 4.0 Hz, 1 H), 4.55 (dd, J = 9.7, 1.6 Hz, 1
H), 2.85 (dd, J = 14.0, 9.7 Hz, 1 H), 2.73–2.60 (m, 1 H), 2.18 (dd, J =
14.0, 1.7 Hz, 1 H), 2.17–2.09 (m, 1 H), 2.00–1.88 (m, 2 H), 1.87 (d, J =
1.5 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.29, 146.89, 144.22, 134.88,
128.18, 126.80, 126.59, 125.83, 125.22, 123.49, 81.22, 81.00, 42.99,
38.85, 25.43, 24.58.
LRMS (EI/CI)+: m/z [M + H]+ = 324.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C20H22NO3: 324.1594; found:
LRMS (EI/CI)+: m/z [M + H]+ = 248.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C14H18NO3: 248.1281; found:
248.1281.
(Z)-2-Ethyl-6-methyl-8-(p-nitrophenyl)-3,4,7,8-tetrahydro-2H-
oxocine (22h)
Following the general procedure, activated molecular sieves (60 mg),
p-nitrobenzaldehyde (63 mg, 0.42 mmol, 1.2 equiv) in THF (2.1 mL,
0.2 M), TMSOTf (0.06 mL, 0.35 mmol, 1.0 equiv), and 7-methyloct-7-
en-3-ol (50 mg, 0.35 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22h
as a clear, pale yellow oil; yield: 85 mg (87%); 90:10 (endo/exo).
324.1595.
(Z)-2,6-Dimethyl-8-(m-nitrophenyl)-3,4,7,8-tetrahydro-2H-oxo-
cine (22k)
1H NMR (500 MHz, CDCl3): δ = 8.19 (d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.4
Hz, 2 H), 5.52 (ddt, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.39 (dd, J = 9.6, 1.6 Hz, 1
H), 3.48–3.39 (m, 1 H), 2.73 (dd, J = 14.1, 9.6 Hz, 1 H), 2.57–2.45 (m, 1
H), 2.09 (dd, J = 14.0, 1.7 Hz, 1 H), 2.04–1.96 (m, 1 H), 1.79 (s, 3 H),
1.70 (dddd, J = 14.4, 11.1, 5.1, 3.4 Hz, 1 H), 1.63–1.53 (m, 1 H), 1.47–
1.38 (m, 2 H), 0.81 (t, J = 7.4 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.63, 146.83, 134.34, 126.59,
126.08, 123.44, 81.77, 81.57, 42.80, 36.31, 29.80, 25.31, 24.26, 10.49.
LRMS (EI/CI)+: m/z [M + H]+ = 276.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C16H22NO3: 276.1594; found:
Following the general procedure, activated molecular sieves (100 mg),
m-nitrobenzaldehyde (0.51 g, 3.4 mmol, 1.2 equiv) in THF (17 mL, 0.2
M), TMSOTf (0.51 mL, 2.8 mmol, 1.0 equiv), and 6-methylhept-6-en-
2-ol (0.36 g, 2.8 mmol, 1.0 equiv) in THF (14 mL, 0.2 M) gave 22k as a
clear, pale yellow oil; yield: 476 mg (65%); 91:9 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 8.25 (t, J = 2.0 Hz, 1 H), 8.10 (ddd, J =
8.2, 2.4, 1.1 Hz, 1 H), 7.71 (ddt, J = 7.7, 1.7, 0.8 Hz, 1 H), 7.49 (t, J = 7.9
Hz, 1 H), 5.52 (ddt, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.45 (dd, J = 9.6, 1.6 Hz, 1
H), 3.73 (dtt, J = 12.6, 6.3, 3.1 Hz, 1 H), 2.75 (dd, J = 14.0, 9.6 Hz, 1 H),
2.57–2.46 (m, 1 H), 2.15 (dd, J = 14.0, 1.7 Hz, 1 H), 2.04–1.96 (m, 1 H),
1.80 (dd, J = 0.6, 0.6 Hz, 3 H), 1.76–1.66 (m, 1 H), 1.63–1.51 (m, 1 H),
1.15 (d, J = 6.3 Hz, 3 H).
276.1596.
13C NMR (125 MHz, CDCl3): δ = 148.18, 146.57, 134.42, 132.11,
129.01, 125.99, 121.88, 120.98, 80.12, 76.01, 42.44, 38.12, 25.33,
24.38, 22.34.
LRMS (EI/CI)+: m/z [M + H]+ = 262.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C15H20NO3: 262.1438; found:
(Z)-2-Isopropyl-6-methyl-8-(p-nitrophenyl)-3,4,7,8-tetrahydro-
2H-oxocine (22i)
Following the general procedure, activated molecular sieves (60 mg),
p-nitrobenzaldehyde (21 mg, 0.13 mmol, 1.2 equiv) in THF (0.7 mL,
0.2 M), TMSOTf (0.02 mL, 0.12 mmol, 1.0 equiv), and 2,7-dimethyloct-
7-en-3-ol (18 mg, 0.12 mmol, 1.0 equiv) in THF (0.58 mL, 0.2 M) gave
22i as a clear, pale yellow oil; yield: 21 mg (62%); 91:9 (endo/exo).
262.1429.
1H NMR (500 MHz, CDCl3): δ = 8.19 (d, J = 8.8 Hz, 2 H), 7.55 (d, J = 8.2
Hz, 2 H), 5.51 (ddt, J = 9.9, 6.6, 1.5 Hz, 1 H), 4.35 (d, J = 8.6 Hz, 1 H),
3.26 (ddd, J = 11.4, 6.1, 3.6 Hz, 1 H), 2.72 (dd, J = 14.0, 9.5 Hz, 1 H),
2.60–2.43 (m, 1 H), 2.06 (dd, J = 14.0, 1.7 Hz, 1 H), 2.04–1.96 (m, 1 H),
1.80 (s, 3 H), 1.74 (dddd, J = 13.6, 11.4, 5.0, 3.4 Hz, 1 H), 1.65–1.56 (m,
2 H), 0.82 (dd, J = 6.7, 1.6 Hz, 6 H).
13C NMR (125 MHz, CDCl3): δ = 151.68, 146.81, 134.35, 126.54,
126.14, 123.44, 85.16, 81.93, 43.09, 34.15, 33.51, 25.35, 24.27, 19.27,
18.22.
(Z)-2,6-Dimethyl-8-(o-nitrophenyl)-3,4,7,8-tetrahydro-2H-oxo-
cine (22l)
Following the general procedure, activated molecular sieves (60 mg),
o-nitrobenzaldehyde (71 mg, 0.47 mmol, 1.2 equiv) in THF (2.4 mL,
0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-
en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22l
as a clear, colorless oil; yield: 59 mg (58%); 97:3 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.92 (dd, J = 8.2, 1.2 Hz, 1 H), 7.87 (dd,
J = 7.9, 1.2 Hz, 1 H), 7.61 (td, J = 7.8, 1.2 Hz, 1 H), 7.41–7.36 (m, 1 H),
5.50 (ddt, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.94 (d, J = 9.2 Hz, 1 H), 3.75–3.66
(m, 1 H), 2.68 (dd, J = 13.8, 9.2 Hz, 1 H), 2.60–2.48 (m, 1 H), 2.15 (dd,
J = 13.8, 1.4 Hz, 1 H), 2.03–1.95 (m, 1 H), 1.87 (s, 3 H), 1.69 (dddd, J =
14.0, 11.2, 5.3, 2.9 Hz, 1 H), 1.61–1.50 (m, 1 H), 1.08 (d, J = 6.3 Hz, 3 H).
LRMS (EI/CI)+: m/z [M + H]+ = 290.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C17H24NO3: 290.1751; found:
290.1749.
13C NMR (125 MHz, CDCl3): δ = 146.67, 140.07, 135.40, 133.27,
128.55, 127.49, 125.45, 124.08, 76.91, 76.02, 42.39, 38.29, 24.77,
24.31, 22.14.
LRMS (EI/CI)+: m/z [M + H]+ = 262.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C15H20NO3: 262.1438; found:
(Z)-6-Methyl-8-(p-nitrophenyl)-2-phenyl-3,4,7,8-tetrahydro-2H-
oxocine (22j)
Following the general procedure, activated molecular sieves (60 mg),
p-nitrobenzaldehyde (47 mg, 0.312 mmol, 1.2 equiv) in THF (1.56 mL,
0.2 M), TMSOTf (0.045 mL, 0.26 mmol, 1.0 equiv), and 5-methyl-1-
262.1428.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4242
A. K. Ghosh et al.
Special Topic
Synthesis
(Z)-8-(p-Fluorophenyl)-2,6-dimethyl-3,4,7,8-tetrahydro-2H-oxo-
(Z)-2,6-Dimethyl-8-phenethyl-3,4,7,8-tetrahydro-2H-oxocine
cine (22m)
(22e)
Following the general procedure, activated molecular sieves (60 mg),
p-fluorobenzaldehyde (0.05 mL, 0.47 mmol, 1.2 equiv) in THF (2.4 mL,
0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-
en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave
22m as a clear, colorless oil; yield: 18 mg (20%); 90:10 (endo/exo).
Following the general procedure, activated molecular sieves (50 mg),
3-phenylpropionaldehyde (0.06 mL, 0.47 mmol, 1.2 equiv) in THF (2.4
mL, 0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methyl-
hept-6-en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M)
gave 22e as a clear, colorless oil; yield: 33 mg (35%); 94:6 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.38–7.30 (m, 2 H), 7.04–6.96 (m, 2 H),
5.49 (ddt, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.33 (d, J = 9.6 Hz, 1 H), 3.75–3.64
(m, 1 H), 2.77 (dd, J = 13.9, 9.8 Hz, 1 H), 2.58–2.46 (m, 1 H), 2.11 (dd,
J = 13.9, 1.6 Hz, 1 H), 2.02–1.93 (m, 1 H), 1.78 (s, 3 H), 1.73–1.63 (m, 1
H), 1.59–1.48 (m, 1 H), 1.14 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 161.79 (d, J = 244.3 Hz), 140.24,
135.12, 127.50 (d, J = 7.9 Hz), 125.43, 114.89 (d, J = 21.1 Hz), 80.66,
75.72, 42.18, 38.21, 25.38, 24.37, 22.38.
19F NMR (471 MHz, CDCl3): δ = –117.40 to –117.51 (m).
LRMS (EI/CI)+: m/z [M]+ = 234.
HRMS (ESI+): m/z [M + H]+ calcd for C15H20FO: 235.1498; found:
1H NMR (500 MHz, CDCl3): δ = 7.31–7.26 (m, 2 H), 7.23–7.15 (m, 3 H),
5.40 (dddd, J = 8.2, 6.7, 3.0, 1.5 Hz, 1 H), 3.56–3.47 (m, 1 H), 3.28 (tdd,
J = 9.5, 3.4, 1.5 Hz, 1 H), 2.89 (ddd, J = 15.0, 10.1, 5.3 Hz, 1 H), 2.63
(ddd, J = 13.8, 10.0, 6.3 Hz, 1 H), 2.52–2.39 (m, 2 H), 1.96–1.82 (m, 3
H), 1.78–1.73 (m, 3 H), 1.72–1.58 (m, 2 H), 1.57–1.46 (m, 1 H), 1.15 (d,
J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 142.51, 135.64, 128.48, 128.30,
125.64, 124.68, 79.78, 75.07, 40.81, 39.07, 38.09, 32.95, 25.55, 24.28,
22.06.
LRMS (EI/CI)+: m/z [M]+ = 244.
HRMS (ESI+): m/z [M + H]+ calcd for C17H25O: 245.1906; found:
245.1898.
235.1494.
(Z)-8-((Benzyloxy)methyl)-2,6-dimethyl-3,4,7,8-tetrahydro-2H-
oxocine (20)
(Z)-2,6-Dimethyl-8-(p-(trifluoromethyl)phenyl)-3,4,7,8-tetrahy-
dro-2H-oxocine (22n)
Following the general procedure, activated molecular sieves (30 mg),
benzyloxyacetaldehyde (0.033 mL, 0.23 mmol, 1.2 equiv) in THF (1.2
mL, 0.2 M), TMSOTf (0.036 mL, 0.2 mmol, 1.0 equiv), and 6-methyl-
hept-6-en-2-ol (25 mg, 0.2 mmol, 1.0 equiv) in THF (1.0 mL, 0.2 M)
gave 20 as a clear, colorless oil; yield: 12 mg (24%); endo-isomer, with
trace amounts of an unidentified minor isomer.
Following the general procedure, activated molecular sieves (60 mg),
p-(trifluoromethyl)benzaldehyde (0.06 mL, 0.47 mmol, 1.2 equiv) in
THF (2.4 mL, 0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-
methylhept-6-en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL,
0.2 M) gave 22n as a clear, colorless oil; yield: 41 mg (37%); 92:8
(endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.38–7.31 (m, 4 H), 7.31–7.27 (m, 1 H),
5.42 (ddt, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.61 (d, J = 12.0 Hz, 1 H), 4.56 (d, J =
12.0 Hz, 1 H), 3.59–3.46 (m, 3 H), 3.40 (tt, J = 8.6, 4.8 Hz, 1 H), 2.50–
2.38 (m, 2 H), 1.97 (d, J = 14.0 Hz, 1 H), 1.94–1.87 (m, 1 H), 1.77 (s, 3
H), 1.65–1.56 (m, 1 H), 1.53–1.45 (m, 1 H), 1.13 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 138.54, 135.31, 128.30, 127.59,
127.47, 124.98, 79.18, 75.52, 74.03, 73.29, 38.12, 36.99, 25.38, 24.27,
22.21.
1H NMR (500 MHz, CDCl3): δ = 7.58 (d, J = 8.2 Hz, 2 H), 7.49 (d, J = 8.1
Hz, 2 H), 5.51 (ddt, J = 10.3, 7.0, 1.8 Hz, 1 H), 4.40 (d, J = 9.5 Hz, 1 H),
3.77–3.64 (m, 1 H), 2.75 (dd, J = 13.9, 9.7 Hz, 1 H), 2.58–2.47 (m, 1 H),
2.13 (dd, J = 13.9, 1.7 Hz, 1 H), 2.04–1.93 (m, 1 H), 1.79 (s, 3 H), 1.75–
1.65 (m, 1 H), 1.62–1.49 (m, 1 H), 1.14 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 148.38, 134.81, 129.04 (q, J = 32.3 Hz),
126.16, 125.70, 125.09 (q, J = 3.5 Hz), 124.25 (q, J = 272.0 Hz), 80.72,
75.90, 42.44, 38.22, 25.33, 24.39, 22.35.
HRMS (ESI+): m/z [M + Na]+ calcd for C17H24O2Na: 283.1674; found:
283.1667.
19F NMR (471 MHz, CDCl3): δ = –63.55.
HRMS (ESI+): m/z [M + H]+ calcd for C16H20F3O: 285.1466; found:
285.1460.
(Z)-2,6-Dimethyl-8-(m-tolyl)-3,4,7,8-tetrahydro-2H-oxocine (22f)
Following the general procedure, activated molecular sieves (60 mg),
m-tolualdehyde (0.05 mL, 0.47 mmol, 1.2 equiv) in THF (2.4 mL, 0.2
M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-en-
2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22f as
a clear, colorless oil; yield: 7 mg (8%); 92:8 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.24–7.14 (m, 3 H), 7.07–7.03 (m, 1 H),
5.47 (ddt, J = 9.8, 6.6, 1.5 Hz, 1 H), 4.31 (d, J = 9.7 Hz, 1 H), 3.75–3.64
(m, 1 H), 2.82 (dd, J = 13.9, 10.0 Hz, 1 H), 2.62–2.49 (m, 1 H), 2.36 (s, 3
H), 2.10 (dd, J = 13.9, 1.4 Hz, 1 H), 2.01–1.93 (m, 1 H), 1.84–1.75 (m, 3
H), 1.69 (dddd, J = 14.1, 11.3, 5.2, 3.1 Hz, 1 H), 1.59–1.49 (m, 1 H), 1.14
(d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 144.39, 137.77, 135.51, 128.08,
127.66, 126.57, 125.15, 123.03, 81.59, 75.67, 42.29, 38.28, 25.36,
24.32, 22.35, 21.51.
HRMS (ESI+): m/z [M + H]+ calcd for C16H23O: 231.1749; found:
231.1741.
(Z)-8-(p-Chlorophenyl)-2,6-dimethyl-3,4,7,8-tetrahydro-2H-oxo-
cine (22o)
Following the general procedure, activated molecular sieves (50 mg),
p-chlorobenzaldehyde (66 mg, 0.47 mmol, 1.2 equiv) in THF (2.4 mL,
0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-
en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22o
as a clear, colorless oil; yield: 18 mg (18%); 93:7 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.34–7.27 (m, 4 H), 5.49 (ddt, J = 9.9,
6.7, 1.5 Hz, 1 H), 4.32 (dd, J = 9.7, 1.1 Hz, 1 H), 3.75–3.63 (m, 1 H), 2.74
(dd, J = 13.9, 9.7 Hz, 1 H), 2.57–2.45 (m, 1 H), 2.10 (dd, J = 13.9, 1.6 Hz,
1 H), 2.02–1.93 (m, 1 H), 1.78 (s, 3 H), 1.72–1.64 (m, 1 H), 1.60–1.49
(m, 1 H), 1.13 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 142.95, 134.99, 132.49, 128.23,
127.29, 125.50, 80.62, 75.78, 42.24, 38.20, 25.35, 24.36, 22.36.
LRMS (EI/CI)+: m/z [M]+ = 250.
HRMS (ESI+): m/z [M + H]+ calcd for C15H20ClO: 251.1203; found:
251.1199.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4243
A. K. Ghosh et al.
Special Topic
Synthesis
(Z)-2,6-Dimethyl-8-(2-naphthyl)-3,4,7,8-tetrahydro-2H-oxocine
(22p)
1H NMR (500 MHz, CDCl3): δ = 9.79 (s, 1 H), 8.21 (s, 1 H), 8.12 (dd, J =
8.1, 2.0 Hz, 1 H), 7.66 (d, J = 7.6 Hz, 1 H), 7.51 (t, J = 7.9 Hz, 1 H), 4.97
(dd, J = 8.8, 3.9 Hz, 1 H), 3.57 (h, J = 6.1 Hz, 1 H), 2.98 (dd, J = 17.0, 8.8
Hz, 1 H), 2.60–2.39 (m, 3 H), 2.17 (s, 3 H), 1.90–1.77 (m, 2 H), 0.94 (d,
J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 205.44, 202.44, 148.42, 145.38,
132.46, 129.47, 122.65, 121.23, 74.96, 74.48, 51.81, 39.59, 31.01,
28.15, 20.69.
Following the general procedure, activated molecular sieves (60 mg),
2-naphthaldehyde (73 mg, 0.47 mmol, 1.2 equiv) in THF (2.4 mL, 0.2
M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-methylhept-6-en-
2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M) gave 22p as
a clear, colorless oil; yield: 16 mg (16%); 94:6 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 7.88–7.76 (m, 4 H), 7.53–7.40 (m, 3 H),
5.52 (ddq, J = 9.9, 6.7, 1.5 Hz, 1 H), 4.51 (d, J = 9.5 Hz, 1 H), 3.82–3.72
(m, 1 H), 2.89 (dd, J = 13.9, 9.7 Hz, 1 H), 2.66–2.55 (m, 1 H), 2.24 (dd,
J = 13.9, 1.6 Hz, 1 H), 2.05–1.97 (m, 1 H), 1.86–1.79 (m, 3 H), 1.79–1.69
(m, 1 H), 1.63–1.55 (m, 1 H), 1.18 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 141.86, 135.39, 133.31, 132.61,
128.01, 127.79, 127.56, 125.88, 125.50, 125.35, 124.79, 124.02, 81.56,
75.88, 42.24, 38.31, 25.41, 24.42, 22.42.
LRMS (EI/CI)+: m/z [M]+ = 266.
HRMS (ESI+): m/z [M + H]+ calcd for C19H23O: 267.1749; found:
HRMS (ESI+): m/z [M + Na]+ calcd for C15H19NO5Na: 316.1161; found:
316.1149.
Compound 33
Yield: 0.013 g (59%, based on 31k).
1H NMR (500 MHz, CDCl3): δ = 8.30 (s, 1 H), 8.14 (dd, J = 8.2, 1.3 Hz, 1
H), 7.69 (d, J = 7.7 Hz, 1 H), 7.52 (t, J = 7.9 Hz, 1 H), 4.82 (dd, J = 10.8,
2.4 Hz, 1 H), 3.59–3.50 (m, 1 H), 3.12 (t, J = 11.1 Hz, 1 H), 2.68 (ddd, J =
13.7, 7.2, 2.0 Hz, 1 H), 2.57 (dd, J = 11.4, 2.5 Hz, 1 H), 2.46–2.32 (m, 2
H), 1.87 (dddd, J = 14.2, 9.9, 4.5, 2.3 Hz, 1 H), 1.79–1.71 (m, 1 H), 1.69–
1.61 (m, 1 H), 1.18 (d, J = 6.1 Hz, 3 H).
267.1742.
(Z)-8-(p-Fluoro-m-nitrophenyl)-2,6-dimethyl-3,4,7,8-tetrahydro-
2H-oxocine (22b)
13C NMR (125 MHz, CDCl3): δ = 213.94, 148.38, 144.52, 131.78,
129.35, 122.52, 120.78, 80.00, 75.73, 51.07, 44.06, 36.27, 22.38, 21.01.
HRMS (ESI+): m/z [M + Na]+ calcd for C14H17NO4Na: 286.1056; found:
286.1050.
Following the general procedure, activated molecular sieves (60 mg),
p-fluoro-m-nitrobenzaldehyde (79 mg, 0.47 mmol, 1.2 equiv) in THF
(2.4 mL, 0.2 M), TMSOTf (0.07 mL, 0.39 mmol, 1.0 equiv), and 6-meth-
ylhept-6-en-2-ol (50 mg, 0.39 mmol, 1.0 equiv) in THF (2.0 mL, 0.2 M)
gave 22b as a clear, colorless oil; yield: 45 mg (41%); 91:9 (endo/exo).
1H NMR (500 MHz, CDCl3): δ = 8.07 (dd, J = 7.2, 2.2 Hz, 1 H), 7.64 (ddd,
J = 8.6, 4.2, 2.3 Hz, 1 H), 7.23 (dd, J = 10.6, 8.6 Hz, 1 H), 5.52 (ddt, J =
9.8, 6.7, 1.5 Hz, 1 H), 4.39 (d, J = 9.4 Hz, 1 H), 3.75–3.66 (m, 1 H), 2.70
(dd, J = 13.9, 9.6 Hz, 1 H), 2.53–2.43 (m, 1 H), 2.12 (dd, J = 14.0, 1.7 Hz,
1 H), 2.03–1.95 (m, 1 H), 1.79 (s, 3 H), 1.74–1.65 (m, 1 H), 1.62–1.51
(m, 1 H), 1.14 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 154.31 (d, J = 263.7 Hz), 141.66 (d, J =
4.3 Hz), 134.17, 132.92 (d, J = 8.5 Hz), 126.12, 123.37, 118.01, 117.85,
79.39, 76.07, 42.38, 38.04, 25.32, 24.36, 22.32.
19F NMR (471 MHz, CDCl3): δ = –121.82 (ddd, J = 10.9, 7.1, 4.5 Hz).
LRMS (EI/CI)+: m/z [M]+ = 279.
8-Methyl-4-methylene-2-(m-nitrophenyl)oxocane (31k)
To a 5-mL round-bottomed flask with a stir bar, under argon, contain-
ing anhyd methyltriphenylphosphonium bromide (46 mg, 0.12 mmol,
2.5 equiv) and anhyd THF (1 mL, 0.12 M) at 0 °C was added 1.6 M n-
BuLi (0.08 mL, 0.13 mmol, 2.6 equiv). After 5 min, the red-orange re-
action mixture was cooled to –78 °C and cannulated over 2 min into a
mixture of 33 (13.5 mg, 0.05 mmol, 1 equiv) and THF (0.5 mL, 0.1 M)
in a dry 5-mL round-bottomed flask with a stir bar, under argon. The
reaction was gradually warmed to 0 °C and, after stirring for 5 h at
0 °C, salts had formed and the reaction mixture was quenched with
H2O. The organic and aqueous layers were then separated, after which
the aqueous layer was extracted with EtOAc (3 ×). The organic layers
were then combined, dried over Na2SO4, and concentrated. After puri-
fication by column chromatography (EtOAc–hexanes, 5:95), 31k was
isolated as a clear, colorless oil; yield: 7 mg (52%).
HRMS (EI/CI)+: m/z [M + H]+ calcd for C15H19FNO3: 280.1343; found:
280.1356.
1H NMR (500 MHz, CDCl3): δ = 8.26 (s, 1 H), 8.11 (dd, J = 8.2, 1.3 Hz, 1
H), 7.72 (d, J = 7.7 Hz, 1 H), 7.50 (t, J = 7.9 Hz, 1 H), 4.95 (s, 1 H), 4.91 (s,
1 H), 4.62 (dd, J = 10.5, 2.7 Hz, 1 H), 3.98–3.89 (m, 1 H), 2.59 (dd, J =
13.4, 2.6 Hz, 1 H), 2.47–2.30 (m, 3 H), 2.14–2.01 (m, 1 H), 1.82–1.72
(m, 1 H), 1.64–1.55 (m, 2 H), 1.17 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 148.82, 148.24, 146.29, 132.02,
129.08, 122.00, 120.92, 113.71, 81.73, 75.55, 45.47, 35.57, 35.12,
23.38, 22.13.
4-(1-(m-Nitrophenyl)-3-oxobutoxy)pentanal (32) and 8-Methyl-2-
(m-nitrophenyl)oxocan-4-one (33)
To a 10-mL round-bottomed flask with a stir bar and a 9:1 mixture of
22k/31k (0.226 g, 0.86 mmol, 1 equiv) was added CH2Cl2–MeOH (1:1,
5 mL). The reaction solution was then cooled to –78 °C and ozone
was bubbled through the solution. Once the reaction mixture was sat-
urated with ozone, the solution turned blue, whereupon oxygen was
bubbled through the solution to quench the excess ozone. Once the
solution was no longer blue, Me2S (630 μL, 8.64 mmol, 10 equiv) was
added directly to the reaction flask. This solution was then allowed to
stir overnight and warm to room temperature. The solvent was then
removed in vacuo and the remainder directly transferred to a column,
where the products were eluted with EtOAc–hexanes (20:80), giving
32 and 33 as clear, pale yellow oils.
LRMS (EI/CI)+: m/z [M + H]+ = 262.
HRMS (EI/CI)+: m/z [M + H]+ calcd for C15H20NO3: 262.1438; found:
262.1441.
4,7-Dimethyl-2-(p-nitrophenyl)-2,3,6,7-tetrahydrooxepine (35)
Following the general procedure, activated molecular sieves (40 mg),
p-nitrobenzaldehyde (80 mg, 0.52 mmol, 1.2 equiv) in THF (2.6 mL,
0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-methylhex-5-
en-2-ol (50 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M) gave 35
as a clear, pale yellow oil; yield: 39 mg (36%).
Compound 32
Yield: 0.22 g (96%, based on 22k).
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4244
A. K. Ghosh et al.
Special Topic
Synthesis
1H NMR (500 MHz, CDCl3): δ = 8.17 (d, J = 8.7 Hz, 2 H), 7.54 (d, J = 8.7
Hz, 2 H), 5.62 (d, J = 7.6 Hz, 1 H), 4.60 (d, J = 10.1 Hz, 1 H), 3.74 (dq, J =
12.5, 6.2 Hz, 1 H), 2.65 (dd, J = 15.9, 10.4 Hz, 1 H), 2.43–2.30 (m, 1 H),
2.27–2.11 (m, 2 H), 1.78 (s, 3 H), 1.24 (d, J = 6.3 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.51, 146.86, 137.33, 126.54,
124.29, 123.45, 79.46, 76.40, 45.02, 37.90, 26.61, 23.13.
13C NMR (125 MHz, CDCl3): δ = 138.46, 137.90, 128.32, 127.68,
127.51, 123.41, 77.45, 76.09, 73.78, 73.29, 39.47, 37.89, 26.63, 23.14.
LRMS (APCI)+: m/z [M + H]+ = 247.
HRMS (ESI+): m/z [M + Na]+ calcd for C16H22O2Na: 269.1518; found:
269.1513.
LRMS (ESI+): m/z [M + H]+ = 248.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO3: 248.1287; found:
2-(p-Fluoro-m-nitrophenyl)-4,7-dimethyl-2,3,6,7-tetrahydroo-
xepine (39)
248.1282.
Following the general procedure, activated molecular sieves (40 mg),
p-fluoro-m-nitrobenzaldehyde (91 mg, 0.53 mmol, 1.2 equiv) in THF
(2.6 mL, 0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-meth-
ylhex-5-en-2-ol (51 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M)
gave 39 as a clear, colorless oil; yield: 33 mg (28%).
1H NMR (500 MHz, CDCl3): δ = 8.07 (dd, J = 7.2, 2.3 Hz, 1 H), 7.64 (ddd,
J = 8.6, 4.3, 2.3 Hz, 1 H), 7.23 (dd, J = 10.6, 8.6 Hz, 1 H), 5.65–5.59 (m, 1
H), 4.58–4.52 (m, 1 H), 3.77–3.68 (m, 1 H), 2.71–2.61 (m, 1 H), 2.39–
2.29 (m, 1 H), 2.23–2.12 (m, 2 H), 1.78 (s, 3 H), 1.24 (d, J = 6.2 Hz, 3 H).
4,7-Dimethyl-2-(m-nitrophenyl)-2,3,6,7-tetrahydrooxepine (36)
Following the general procedure, activated molecular sieves (40 mg),
m-nitrobenzaldehyde (81 mg, 0.52 mmol, 1.2 equiv) in THF (2.6 mL,
0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-methylhex-5-
en-2-ol (51 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M) gave 36
as a clear, pale yellow oil; yield: 53 mg (49%).
1H NMR (500 MHz, CDCl3): δ = 8.25 (s, 1 H), 8.10 (dd, J = 8.1, 1.9 Hz, 1
H), 7.71 (d, J = 8.1 Hz, 1 H), 7.49 (t, J = 7.9 Hz, 1 H), 5.63 (d, J = 7.6 Hz, 1
H), 4.60 (d, J = 10.2 Hz, 1 H), 3.80–3.68 (m, 1 H), 2.70 (dd, J = 15.8, 10.4
Hz, 1 H), 2.42–2.30 (m, 1 H), 2.27–2.10 (m, 2 H), 1.79 (s, 3 H), 1.25 (d,
J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 148.20, 146.36, 137.36, 132.02,
129.07, 124.35, 121.99, 120.95, 79.29, 76.51, 45.01, 37.91, 26.64,
23.18.
LRMS (ESI+): m/z [M + H]+ = 248.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO3: 248.1287; found:
13C NMR (125 MHz, CDCl3): δ = 154.37 (d, J = 263.6 Hz), 141.47 (d, J =
4.2 Hz), 137.11, 132.85 (d, J = 8.4 Hz), 124.45, 123.38, 118.07, 117.90,
78.58, 76.53, 44.93, 37.86, 26.63, 23.14.
LRMS (CI)+: m/z [M + H]+ = 266.
2-(p-Methoxy-m-nitrophenyl)-4,7-dimethyl-2,3,6,7-tetrahydroo-
xepine (40)
Following the general procedure, activated molecular sieves (40 mg),
p-methoxy-m-nitrobenzaldehyde (96 mg, 0.53 mmol, 1.2 equiv) in
THF (2.6 mL, 0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-
methylhex-5-en-2-ol (51 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL,
0.2 M) gave 40 as a clear, yellow oil; yield: 57 mg (48%).
1H NMR (500 MHz, CDCl3): δ = 7.87 (d, J = 2.2 Hz, 1 H), 7.56 (dd, J = 8.7,
2.2 Hz, 1 H), 7.04 (d, J = 8.7 Hz, 1 H), 5.63–5.58 (m, 1 H), 4.52–4.47 (m,
1 H), 3.95 (s, 3 H), 3.75–3.67 (m, 1 H), 2.72–2.64 (m, 1 H), 2.38–2.28
(m, 1 H), 2.22–2.10 (m, 2 H), 1.78 (s, 3 H), 1.22 (d, J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 151.87, 139.27, 137.40, 137.02,
131.59, 124.24, 123.20, 113.27, 78.82, 76.45, 56.61, 44.83, 37.91,
26.65, 23.19.
LRMS (APCI)+: m/z [M + H]+ = 278.
HRMS (ESI+): m/z [M + H]+ calcd for C15H20NO4: 278.1393; found:
248.1282.
4,7-Dimethyl-2-phenethyl-2,3,6,7-tetrahydrooxepine (37)
Following the general procedure, activated molecular sieves (40 mg),
3-phenylpropionaldehyde (0.06 mL, 0.52 mmol, 1.2 equiv) in THF (2.6
mL, 0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-methyl-
hex-5-en-2-ol (50 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M)
gave 37 as a clear, colorless oil; yield: 49 mg (49%).
1H NMR (500 MHz, CDCl3): δ = 7.34–7.24 (m, 2 H), 7.24–7.13 (m, 3 H),
5.48 (d, J = 7.3 Hz, 1 H), 3.61–3.41 (m, 1 H), 3.34 (dt, J = 9.3, 3.6 Hz, 1
H), 2.81 (ddd, J = 13.9, 8.9, 5.2 Hz, 1 H), 2.75–2.62 (m, 1 H), 2.50–2.38
(m, 1 H), 2.30–2.16 (m, 1 H), 2.07 (dd, J = 15.7, 7.9 Hz, 1 H), 1.98–1.80
(m, 2 H), 1.77–1.61 (m, 4 H), 1.23 (d, J = 6.3 Hz, 3 H).
278.1384.
13C NMR (125 MHz, CDCl3): δ = 142.42, 138.09, 128.55, 128.26,
125.60, 123.26, 77.47, 76.09, 43.26, 38.77, 38.03, 32.36, 26.79, 23.06.
LRMS (APCI)+: m/z [M + H]+ = 231.
HRMS (ESI+): m/z [M + H]+ calcd for C16H23O: 231.1749; found:
231.1745.
Ethyl 4,7-Dimethyl-2,3,6,7-tetrahydrooxepine-2-carboxylate (41)
Following the general procedure, activated molecular sieves (40 mg),
ethyl glyoxylate (0.05 mL, 0.53 mmol, 1.2 equiv, in toluene) in THF
(2.6 mL, 0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-meth-
ylhex-5-en-2-ol (51 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M)
gave 41 as a clear, colorless oil; yield: 20 mg (23%).
1H NMR (500 MHz, CDCl3): δ = 5.57–5.51 (m, 1 H), 4.26–4.18 (m, 2 H),
4.10 (dd, J = 10.2, 1.6 Hz, 1 H), 3.71–3.61 (m, 1 H), 2.70–2.58 (m, 1 H),
2.38–2.27 (m, 2 H), 2.12–2.04 (m, 1 H), 1.77 (d, J = 1.4 Hz, 3 H), 1.29 (t,
J = 7.1 Hz, 3 H), 1.25 (d, J = 6.3 Hz, 3 H).
2-((Benzyloxy)methyl)-4,7-dimethyl-2,3,6,7-tetrahydrooxepine
(38)
Following the general procedure, activated molecular sieves (40 mg),
benzyloxyacetaldehyde (0.08 mL, 0.53 mmol, 1.2 equiv) in THF (2.6
mL, 0.2 M), TMSOTf (0.08 mL, 0.44 mmol, 1.0 equiv), and 5-methyl-
hex-5-en-2-ol (51 mg, 0.44 mmol, 1.0 equiv) in THF (2.2 mL, 0.2 M)
gave 38 as a clear, colorless oil; yield: 29 mg (27%).
13C NMR (125 MHz, CDCl3): δ = 171.75, 136.80, 124.11, 77.92, 76.31,
60.95, 39.25, 37.61, 26.44, 22.87, 14.20.
1H NMR (500 MHz, CDCl3): δ = 7.35 (d, J = 4.6 Hz, 3 H), 7.31–7.25 (m, 2
H), 5.53–5.47 (m, 1 H), 4.62–4.52 (m, 2 H), 3.68–3.61 (m, 1 H), 3.61–
3.55 (m, 1 H), 3.52–3.47 (m, 1 H), 3.37 (dd, J = 9.7, 5.9 Hz, 1 H), 2.42–
2.32 (m, 1 H), 2.28–2.17 (m, 1 H), 2.14–2.01 (m, 2 H), 1.74 (s, 3 H),
1.19 (d, J = 6.3 Hz, 3 H).
LRMS (APCI)+: m/z [M + H]+ = 199.
HRMS (ESI+): m/z [M + Na]+ calcd for C11H18O3Na: 221.1154; found:
221.1149.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4245
A. K. Ghosh et al.
Special Topic
Synthesis
7-Methyl-2-(p-nitrophenyl)-3-(prop-1-en-2-yl)oxepane (45)
The combined organic layer was then dried with Na2SO4, filtered, con-
centrated, and purified by column chromatography (EtOAc–hexanes,
20:80) to give 4-(7-methyl-3-(prop-1-en-2-yl)oxepan-2-yl)aniline as
a pale yellow oil; yield: 41 mg (70%).
1H NMR (500 MHz, CDCl3): δ = 7.10 (d, J = 8.1 Hz, 2 H), 6.60 (d, J = 8.3
Hz, 2 H), 4.73 (d, J = 5.4 Hz, 1 H), 4.57 (s, 1 H), 4.54 (s, 1 H), 3.72–3.62
(m, 1 H), 3.54 (s, 2 H), 2.81 (dt, J = 10.2, 5.5 Hz, 1 H), 1.93–1.71 (m, 4
H), 1.67–1.45 (m, 2 H), 1.39 (s, 3 H), 1.25 (d, J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 147.31, 144.45, 132.88, 127.10,
114.44, 112.48, 81.88, 77.87, 52.42, 40.17, 30.73, 24.81, 23.09, 20.68.
LRMS (ESI+): m/z [M + H]+ = 246.
HRMS (ESI+): m/z [M + H]+ calcd for C14H18NO: 246.1858; found:
To a 25-mL round-bottomed flask with a stir bar and activated molec-
ular sieves (50 mg), under argon, were added THF (10.6 mL, 0.2 M)
and p-nitrobenzaldehyde (320 mg, 2.11 mmol, 1.2 equiv). The flask
was cooled to 0 °C for 10 min, after which TMSOTf (0.380 mL, 2.11
mmol, 1.2 equiv) was added dropwise. After stirring for 5 min, a
chilled solution (–78 °C) of 7-methyloct-7-en-2-ol (0.251 g, 1.76
mmol, 1.0 equiv) in THF (8.80 mL, 0.2 M) was added dropwise over 5
min. The reaction was slowly warmed to room temperature and mon-
itored by TLC (EtOAc–hexanes, 5:95) until completion. After 3 h, the
reaction was quenched with sat. NaHCO3 and the mixture was ex-
tracted with EtOAc (3 ×). Then, Na2SO4 was added to the combined or-
ganic layers, which were then filtered, concentrated, and purified by
column chromatography (EtOAc–hexanes, 5:95) to give 45 as a clear,
pale yellow oil; yield: 67 mg (14%).
1H NMR (500 MHz, CDCl3): δ = 8.12 (d, J = 8.8 Hz, 2 H), 7.47 (d, J = 8.5
Hz, 2 H), 4.89 (d, J = 5.3 Hz, 1 H), 4.54 (s, 1 H), 4.50 (s, 1 H), 3.72–3.59
(m, 1 H), 2.89 (dt, J = 9.6, 6.1 Hz, 1 H), 2.01–1.83 (m, 3 H), 1.82–1.62
(m, 2 H), 1.61–1.48 (m, 1 H), 1.42 (s, 3 H), 1.30 (d, J = 6.2 Hz, 3 H).
13C NMR (125 MHz, CDCl3): δ = 150.68, 146.39, 145.86, 126.77,
122.74, 113.63, 81.76, 79.68, 52.42, 40.31, 31.37, 24.07, 22.86, 20.53.
246.1852.
To a 5-mL round-bottomed flask with a stir bar containing the above
aniline (41 mg, 0.17 mmol, 1.0 equiv) was added CH2Cl2 (1.7 mL, 0.1
M) and Et3-N (0.07 mL, 0.51 mmol, 3 equiv), followed by the addition
of p-bromobenzenesulfonyl chloride (0.13 g, 0.51 mmol, 3 equiv). The
reaction mixture was then stirred for 12 h at room temperature.
Then, H2O was added to the reaction mixture. The resulting mixture
was then extracted with CH2Cl2, dried over Na2SO4, and concentrated.
The crude mixture was then purified by column chromatography
(EtOAc–hexanes, 20:80) to give 48 as a white solid; yield: 40 mg
(35%); mp 162–164 °C.
1H NMR (500 MHz, CDCl3): δ = 7.74 (d, J = 8.5 Hz, 4 H), 7.67 (d, J = 8.4
Hz, 4 H), 7.31 (d, J = 8.2 Hz, 2 H), 6.89 (d, J = 8.1 Hz, 2 H), 4.84 (d, J = 5.3
Hz, 1 H), 4.54 (s, 2 H), 3.73–3.59 (m, 1 H), 2.84 (dt, J = 10.1, 5.4 Hz, 1
H), 1.97–1.83 (m, 3 H), 1.76 (q, J = 11.2 Hz, 1 H), 1.71–1.59 (m, 1 H),
1.59–1.46 (m, 1 H), 1.39 (s, 3 H), 1.27 (d, J = 6.0 Hz, 3 H).
LRMS (APCI)+: m/z [M + H]+ = 276.
7-Methyl-2-(m-nitrophenyl)-3-(prop-1-en-2-yl)oxepane (46)
To a 10-mL round-bottomed flask with a stir bar and activated molec-
ular sieves (40 mg), under argon, were added THF (2.1 mL, 0.2 M) and
m-nitrobenzaldehyde (63 mg, 0.42 mmol, 1.2 equiv). The flask was
cooled to 0 °C for 10 min, after which TMSOTf (0.07 mL, 0.42 mmol,
1.2 equiv) was added dropwise. After stirring for 5 min, a chilled solu-
tion (–78 °C) of 7-methyloct-7-en-2-ol (51 mg, 0.35 mmol, 1.0 equiv)
in THF (1.8 mL, 0.2 M) was added dropwise over 5 min. The reaction
was slowly warmed to room temperature and monitored by TLC
(EtOAc–hexanes, 5:95) until completion. After 4 h, the reaction was
quenched with sat. NaHCO3 and the mixture was extracted with
EtOAc (3 ×). Then, Na2SO4 was added to the combined organic layers,
which were then filtered, concentrated, and purified by column chro-
matography (EtOAc–hexanes, 5:95) to give 46 as a clear, pale yellow
oil; yield: 23 mg (24%).
13C NMR (125 MHz, CDCl3): δ = 146.30, 145.67, 138.20, 132.27,
131.36, 130.36, 130.03, 129.36, 127.12, 113.18, 81.69, 78.92, 52.61,
40.23, 30.93, 24.44, 22.93, 20.63.
LRMS (APCI)+: m/z [M + H]+ = 682.
HRMS (ESI+): m/z [M + Na]+ calcd for C28H29Br2NO5S2Na: 703.9752;
found: 703.9736.
Funding Information
1H NMR (500 MHz, CDCl3): δ = 8.19 (s, 1 H), 8.04 (d, J = 8.0 Hz, 1 H),
7.63 (d, J = 7.7 Hz, 1 H), 7.42 (t, J = 7.9 Hz, 1 H), 4.89 (d, J = 5.3 Hz, 1 H),
4.56 (s, 1 H), 4.51 (s, 1 H), 3.71–3.61 (m, 1 H), 2.90 (dt, J = 9.7, 5.9 Hz, 1
H), 1.97–1.85 (m, 3 H), 1.82–1.73 (m, 2 H), 1.67 (dd, J = 13.3, 11.8 Hz, 1
H), 1.42 (s, 3 H), 1.31 (d, J = 6.2 Hz, 3 H).
The National Institutes of Health.
N
oaitn
a
l
n
Itsu
i
te
of
G
e
n
era
l
M
e
dcai
l
Secinces
G(
M
5
3
3
8
6)
Acknowledgment
13C NMR (125 MHz, CDCl3): δ = 147.84, 145.95, 145.03, 132.23,
128.25, 121.27, 121.15, 113.72, 81.37, 79.49, 52.28, 40.25, 31.16,
24.17, 22.91, 20.59.
Financial support by the National Institutes of Health is gratefully ac-
knowledged. We also thank Dr. Margherita Brindisi and Ms Anne
Veitschegger (Purdue University) for helpful discussions.
LRMS (ESI+): m/z [M + H]+ = 276.
Supporting Information
4-Bromo-N-((4-bromophenyl)sulfonyl)-N-(4-(7-methyl-3-(prop-
1-en-2-yl)oxepan-2-yl)phenyl)benzenesulfonamide (48)
Supporting information for this article is available online at
To a 10-mL round-bottomed flask with a stir bar and 45 (67 mg, 0.24
mmol, 1.0 equiv) was added CH2Cl2 (2.4 mL, 0.1 M). The flask was
cooled to 0 °C for 10 min, after which AcOH (0.14 mL, 2.4 mmol, 10
equiv) was added dropwise, followed by activated Zn dust (0.11 g, 1.7
mmol, 7 equiv). The reaction was allowed to warm to room tempera-
ture and was monitored by TLC (EtOAc–hexanes, 20:80) until comple-
tion. After 30 min, the reaction mixture was filtered through Celite
and stirred overnight in sat. NaHCO3. The biphasic solution was then
transferred to a separatory funnel, where the organic layer was re-
moved and the aqueous layer was back-extracted with CH2Cl2 (3 ×).
https://doi.org /10.1055/s-0036-1589054.
S
u
p
p
o
nrtogI
f
rmoaitn
S
u
p
p
ortiInfogrmoaitn
References
(1) Martín, T.; Padrón, J. I.; Martín, V. S. Synlett 2014, 25, 12.
(2) Hernández-Torres, G.; Mateo, J.; Colobert, F.; Urbano, A.;
Carreño, M. C. ChemistrySelect 2016, 1, 4101.
(3) Rutkowski, J.; Brzezinski, B. BioMed Res. Int. 2013, 2013, 162513.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246

4246
A. K. Ghosh et al.
Special Topic
Synthesis
(4) Zhou, Z.-F.; Menna, M.; Cai, Y.-S.; Guo, Y.-W. Chem. Rev. 2015,
115, 1543.
(24) Eschenbrenner-Lux, V.; Kumar, K.; Waldmann, H. Angew. Chem.
Int. Ed. 2014, 53, 11146.
(5) Stambasky, J.; Hocek, M.; Kocovsky, P. Chem. Rev. 2009, 109,
6729.
(6) Bililign, T.; Griffith, B. R.; Thorson, J. S. Nat. Prod. Rep. 2005, 22,
742.
(7) Murata, M.; Yasumoto, T. Nat. Prod. Rep. 2000, 17, 293.
(8) Hotta, K.; Chen, X.; Paton, R. S.; Minami, A.; Li, H.; Swaminathan,
K.; Mathews, T. I.; Watanabe, K.; Oikawas, H.; Houk, K. N.; Kim,
C.-Y. Nature 2012, 483, 355.
(9) Wang, B.-G.; Gloer, J. B.; Ji, N.-Y.; Zhao, J.-C. Chem. Rev. 2013,
113, 3632.
(10) McLaughlin, J. L. J. Nat. Prod. 2008, 71, 1311.
(11) Nakata, T. Chem. Soc. Rev. 2010, 39, 1955.
(12) Nakata, T. Chem. Rev. 2005, 105, 4314.
(13) Ghosh, A. K.; Anderson, D. D. Future Med. Chem. 2011, 3, 1181.
(14) Ghosh, A. K.; Anderson, D. D.; Weber, I. T.; Mitsuya, H. Angew.
Chem. Int. Ed. 2012, 51, 1778.
(25) Pastor, I. M.; Yus, M. Curr. Org. Chem. 2007, 11, 925.
(26) Smith, A. B. III.; Fox, R. J.; Razler, T. M. Acc. Chem. Res. 2008, 41,
675.
(27) Clavier, H.; Pellissier, H. Adv. Synth. Catal. 2012, 354, 3347.
(28) Illuminati, G.; Mandolini, L. Acc. Chem. Res. 1981, 14, 95.
(29) Katsukiyo, M.; Horiike, M.; Inoue, G.; Ichikawa, J.; Hosomi, A.
Chem. Lett. 2008, 37, 270.
(30) Loh, T.-P.; Hu, Q.-Y.; Tan, K.-T.; Cheng, H.-S. Org. Lett. 2001, 3,
2669.
(31) Ghosh, A. K.; Nicponski, D. R. Org. Lett. 2011, 13, 4328.
(32) Zimmerman, H. E.; Traxler, M. D. J. Am. Chem. Soc. 1957, 79,
1920.
(33) Ghosh, A. K.; Keys, C.; Veitschegger, A. M. Tetrahedron Lett.
2014, 55, 4251.
(34) Kobayashi, S.; Hachiya, I.; Araki, M.; Ishitani, H. Tetrahedron Lett.
1993, 34, 3755.
(15) Fukuzawa, A.; Masamune, T. Tetrahedron Lett. 1981, 22, 4081.
(16) Cameron, A. F.; Cheung, K. K.; Ferguson, G.; Monteath Robertson, J.
Chem. Commun. 1965, 638.
(35) Banerjee, B. ARKIVOC 2017, (i), 1.
(36) Yadav, J. S.; Reddy, B. V. S.; Sekhar, K. C.; Geetha, V. Tetrahedron
Lett. 2001, 42, 4405.
(17) Ghosh, A. K.; Chapsal, B. D.; Baldridge, A.; Steffey, M. P.; Walters,
D. E.; Koh, Y.; Amano, M.; Mitsuya, H. J. Med. Chem. 2011, 54,
622.
(18) Sugimoto, I.; Kambe, T.; Okino, T.; Obitsu, T.; Ohta, N.;
Nishiyama, T.; Kinoshita, A.; Fujimoto, T.; Egashira, H.; Yamane,
S.; Shuto, S.; Tani, K.; Maruyama, T. ACS Med. Chem. Lett. 2017, 8,
107.
(37) Alaniz, J.; Palmer, L. Angew. Chem. Int. Ed. 2011, 50, 7167.
(38) Veits, G. K.; Alaniz, J. R. D. Tetrahedron 2012, 68, 2015.
(39) Bratz, M.; Bullock, W. H.; Overman, L. E.; Takemoto, T. J. Am.
Chem. Soc. 1995, 117, 5958.
(40) Ghosh, A. K.; Tomaine, A. J.; Cantwell, K. E. Org. Lett. 2016, 18,
396.
(41) Ullapu, P. R.; Kim, Y. S.; Lee, J. K.; Pae, A. N.; Kim, Y.; Min, S.-J.;
Cho, Y. S. Chem. Asian J. 2011, 6, 2092.
(42) Complete crystallographic data for 48, in CIF format, have been
deposited with The Cambridge Crystallographic Data Centre.
CCDC 1543753 contains the supplementary crystallographic
data for this paper. The data can be obtained free of charge from
(19) Kleinke, A. S.; Webb, D.; Jamison, T. F. Tetrahedron 2012, 68,
6999.
(20) Rainier, J. D. In Metathesis in Natural Product Synthesis: Strate-
gies, Substrates, and Catalysts; Cossy, J.; Arseniyadis, S.; Meyer,
C., Eds.; Wiley-VCH: Weinheim, 2010, 87–127.
(21) Morris, J. C.; Phillips, A. J. Nat. Prod. Rep. 2011, 28, 269.
(22) Clark, J. S. Chem. Commun. 2006, 3571.
(23) Ghosh, A. K.; Kass, J.; Nicponski, D. R.; Keyes, C. Synthesis 2012,
44, 3579.
The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synthesis 2017, 49, 4229–4246