Silver carboxylate promoted lactonization: A general method applicable to prepare medium and large-sized lactones without high dilution or slow addition

Article abstract of DOI:10.1016/j.tet.2013.07.064

Efficient and applicable approach to macrolactonizations, with ready availability of starting materials and simple operation, remains a challenging task for the organic community. We developed a 'freshman-can-do' protocol to medium- and large-sized lactones, not depending on high-dilution or slow addition techniques. Application of this method for the synthesis of natural lactones or potentially pharmaceutical compounds might be useful for organic chemists and pharmacists.

Full text of DOI:10.1016/j.tet.2013.07.064

Tetrahedron 69 (2013) 8386e8391
Contents lists available at SciVerse ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Silver carboxylate promoted lactonization: a general method
applicable to prepare medium and large-sized lactones without high
dilution or slow addition
*
Le Liu, Shimin Xu, Hongwei Zhou
Department of Chemistry, Zhejiang University (Campus Xixi), Hangzhou 310028, People’s Republic of China
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 10 June 2013
Received in revised form 12 July 2013
Accepted 18 July 2013
Available online 26 July 2013
Efficient and applicable approach to macrolactonizations, with ready availability of starting materials and
simple operation, remains a challenging task for the organic community. We developed a ‘freshman-can-
do’ protocol to medium- and large-sized lactones, not depending on high-dilution or slow addition
techniques. Application of this method for the synthesis of natural lactones or potentially pharmaceutical
compounds might be useful for organic chemists and pharmacists.
Ó 2013 Elsevier Ltd. All rights reserved.
Keywords:
Macrolactonizations
Medium-sized lactones
Large-sized lactones
Silver carboxylate
Phoracantholide I
1. Introduction
ready availability of starting materials and simple operation, remains
a challenging task for the organic community.12
Medium-sized (7- to 11-membered) and large-sized (12-mem-
bered and larger) lactones are important structural motifs in a wide
range of biologically active natural products.1,2 In the last decades,
there are a variety of numerous methods widely used for macro-
lactonization: (i) the CoreyeNicolaou S-pyridyl ester lactonization
method;3 (ii) the Masamune thiol ester activation method;4 (iii) the
Mukaiyama onium salt method;5 (iv) the Yamaguchi mixed-
anhydride method;6 (v) the KeckeSteglich DCC/DMAP$HCl activa-
tion method;7 (vi) the Mitsunobu alcohol activation method;8 and
(vii) the Shiina benzoic anhydride method.9
2. Results and discussion
2.1. Reaction examination
During our research, we tried to examine the reactivity of silver
carboxylate with sulfide and prepare a particular substratedsilver
2-(3-(phenylthio)propoxy)benzoate (1). We heated 1 in DMF at
100 ꢀC for 24 h and isolated 3,4-dihydrobenzo[b][1,5]dioxocin-
6(2H)-one (2) in 3% yield with a 78% recovery (Scheme 1).
However, the above macrolactonizations, via the ring closure
from
u-hydroxycarboxylic acids, would encounter trouble in the
cases of polyhydroxycarboxylic acids; and as reported in the refer-
ences, numerous protections for other hydroxyl groups have to be
introduced before macrolactonization.10 Actually, the poly-
hydroxylactones are very common in the chemical synthesis of nat-
ural and unnatural useful compounds11 and the complexity and
diversity of the pretreatment for protection increase with the num-
ber of hydroxyl groups, which offers a more exquisite task for organic
chemists bent on the conscientious construction of precursors. Thus,
the efficient and applicable approach to macrolactonizations, with
Scheme 1.
It was envisaged that the interaction of silveresulfur might favor
the lactonization because the control experiment showed that
potassium 2-(3-(phenylthio)propoxy)benzoate, the analog of 1,
* Corresponding author. Fax: þ86 571 8892 0271; e-mail address: zhouhw@
zju.edu.cn (H. Zhou).
0040-4020/$ e see front matter Ó 2013 Elsevier Ltd. All rights reserved.
http://dx.doi.org/10.1016/j.tet.2013.07.064

L. Liu et al. / Tetrahedron 69 (2013) 8386e8391
8387
Table 2
could not give 2 even in trace yield under the similar conditions.
Synthesis of 7- to 11-membered lactonesa,b
Considering that the phenylthio group is a poor leaving group, we
speculated that the bromides, with a good leaving group, strong
silverebromine interaction, easy availability, and acceptable sta-
bility, might be a suitable choice. Reasonably, we hypothesized
silver 2-(3-bromopropoxy)benzoate as the substrate. Because the
synthesis of silver 2-(3-bromopropoxy)benzoate is not well docu-
mented, we managed to directly use 2-(3-bromopropoxy)benzoic
acid and treated it with KHCO3/AgNO3 in DMF at 60 ꢀC to conduct
macrolactonization reaction. After work up, expected product 2
was isolated in 27% yield. Notably, control experiment showed that
the absence of AgNO3 could only afford 2 in 3% yield, showing an
obvious silver salt effect (Scheme 2).
Scheme 2.
Encouraged by this result, we optimized the reaction by testing
various silver salts and examining the solvent effect. DMSO and
CH3CN were the suitable solvent and AgBF4 could give the highest
yield. Notably, further study showed only slight concentration and
temperature effects (Table 1).
Table 1
Examination of silver salt and solvent effectsa,b
Entry
Agþ
Solvent
Temp (ꢀC)
Time (h)
Concn (M)
Yield (%)
1
2
3
4
5
6
7
8
AgNO3
AgNO3
AgNO3
AgNO3
AgOTf
AgOTf
AgOTf
AgOTf
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
DMF
CH3CN
DMA
DMSO
DMF
CH3CN
DMA
DMSO
DMF
CH3CN
DMA
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
DMSO
80
80
80
60
80
80
80
60
80
80
80
60
40
rt
8
10
8
12
6
8
8
10
7
10
8
14
26
42
14
14
14
14
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.02
0.01
0.1
27
38
32
44
33
40
35
37
42
50
43
56
53
55
58
56
54
50
a
Method A: bromocarboxylic acid (0.5 mmol), KHCO3 (1.5 mmol), AgBF4
(1.0 mmol) in acetonitrile (10 mL) at 80 ꢀC. Method B: bromocarboxylic acid
(0.5 mmol), KHCO3 (1.5 mmol), AgBF4 (1.0 mmol) in DMSO (10 mL) at 60 ꢀC.
9
b
Isolated yields.
10
11
12
13
14
15
16
17
18
synthesis of 12- to 18-membered lactones and obtained the ex-
pected products in good yields (Table 3).
60
60
60
60
We prepared 2-(2-bromo-N-(2-hydroxyethyl)acetamido)ben-
zoic acid as the substrate for testing the influence of hydroxyl group
in the substrate on the macrolactonization and obtained 1-(2-
hydroxyethyl)benzo[e][1,4]oxazepine-2,5(1H,3H)-dione (3m) in
excellent yield, demonstrating that the reaction is compatible with
hydroxycarboxylic acids (Scheme 3).
0.2
a
All reactions were conducted on a 0.5 mmol scale and monitored by TLC.
Isolated yields.
b
2.2. Substrate scope
2.3. Mechanism
With this result in hand, we firstly examined the application of
the reaction in the synthesis of medium-sized lactones and ob-
tained 7- to 11-membered lactones in satisfactory yields (Table 2).
Then our attention was diverted to the large-sized lactones. As
a promising expansion, we directly applied the protocol in the
For the mechanism of the reaction, we observed that the con-
centration of substrate could only influence the results slightly
(entries 14e18, Table 1), reminding that the silver salt might pro-
mote the reaction through a more complicated way than the simple
activation to the CeBr bond. Generally, the activation to the CeBr

8388
L. Liu et al. / Tetrahedron 69 (2013) 8386e8391
SN2 process unless under high elution conditions.13 We have added
2 equiv of potassium acetate to the reaction mixture to trap the
bromide activated by silver salt; however, we did not isolate the
Table 3
Synthesis of 12- to 18-membered lactonesa,b
expected
u-acetoxycarboxylic acid (Scheme 4).
Scheme 4. Control experiment of macrolactonization versus intermolecular nucleo-
philic substitution.
We proposed a plausible pathway as shown in Scheme 3. The
electrophilic silver of carboxylic acid silver gets close to the bro-
mine atom and forms a silverebromine interaction, which might be
thought of as a ‘silver-finding-bromine’ process and overcome the
negative entropic change.14 The carbonyl oxygen atom attacks the
u-carbon atom intramolecularly, via a six-membered transition
state, to finish the ring closure (Scheme 5).
Scheme 5. Proposed mechanism.
Phoracantholide I, isolated from the metasternal gland secretion
of the common eucalypt longicorn, Phoracantha semipunctata, is
a representative medium sized lactone.15 The acyclic precursor of
phoracantholide I before cyclization, with a long backbone, would
have a high degree of conformational flexibility and transannular
strain as the prevalent in ring closure. We managed a short and
simple route to phoracantholide I via the macrolactonization of 9-
bromodecanoic acid (Scheme 6).
a
Method A: bromocarboxylic acid (0.5 mmol), KHCO3 (1.5 mmol), AgBF4
3. Conclusion
(1.0 mmol) in acetonitrile (10 mL) at 80 ꢀC. Method B: bromocarboxylic acid
(0.5 mmol), KHCO3 (1.5 mmol), AgBF4 (1.0 mmol) in DMSO (10 mL) at 60 ꢀC.
b
The cyclization of
u-bromocarboxylic acid is one of the oldest
Isolated yields.
methods available for the preparation of medium-sized lactones,16
and high-dilution conditions (10ꢁ4 M) are required to avoid un-
desired intermolecular reaction between the substrates.13 Addition
of silver salt changes the reaction mechanism and makes the oper-
ation extremely convenient. This type of reaction presented here, as
a result of ‘freshman-can-do’ operation, might be interesting for
synthetic chemists and application of this efficient method for the
synthesis of potentially pharmaceutical compounds also might be
useful for pharmacists.
Scheme 3. Control experiment of the influence of hydroxyl group.
4. Experimental section
4.1. Instrumentation
bond would increase the rate of both intramolecular nucleophilic
substitution (macrolactonization) and intermolecular nucleophilic
substitution, which would show an obvious concentration effect.
Illuminati and co-workers demonstrated that the formation of an
eight-membered ring is difficult to compete with intermolecular
All 1H NMR and 13C NMR spectra were measured in CDCl3 or
DMSO and recorded on Bruker Avance-400 spectrometer or Bruker

L. Liu et al. / Tetrahedron 69 (2013) 8386e8391
8389
Scheme 6. Short synthesis of phoracantholide I.
Avance-500 spectrometer. Chemical shifts are expressed in parts
per million (ppm) and J values are given in hertz (Hz). IR spectra
were run on a Bruker vector 22 spectrometer. EIMS were de-
termined with an HP5989B mass spectrometer.
J¼7.6 Hz, 1H), 7.64 (t, J¼15.2 Hz, 1H), 7.28 (t, J¼15.2 Hz, 1H), 7.18 (d,
J¼8.4 Hz,1H), 4.67 (s, 2H); 13C NMR (100 MHz, DMSO)
d 169.0, 168.2,
138.2,134.7,133.2,124.7,121.2,121.0, 67.4; IR (neat) 2250, 2124,1699,
1652, 1513, 1394, 1052, 1025, 1005, 822, 759 cmꢁ1; HRMS (TOF) calcd
for C9H7NO3 177.0426, found 177.0428.
4.2. General procedures
4.3.5. 2H-Benzo[e][1,4]dioxepin-5(3H)-one (3d).19 Yield (method
B): 58 mg, 70%; 1H NMR (400 MHz, CDCl3)
d
7.88 (dd, J¼9.6, 1.6 Hz,
7.12 (t, J¼15.2 Hz, 1H), 7.02 (d, J¼8.4 Hz,
1H), 4.50 (m, 4H); 13C NMR (100 MHz, CDCl3)
169.2, 154.6, 134.9,
4.2.1. General procedure A. To a solution of bromodecanoic acid
(0.5 mmol) in acetonitrile (10 mL) was added potassium bi-
carbonate (150 mg, 1.5 mmol). After stirred for 30 min, AgBF4
(194 mg, 1 mmol) was charged and the reaction mixture was
allowed to warm to 80 ꢀC. Upon to completion, the reaction mixture
was diluted with 50 mL of water and extracted with ethyl ether
(3ꢂ20 mL). The extract was washed with water (2ꢂ20 mL) and
dried with anhydrous Na2SO4. After evaporation, chromatography
on silica gel (hexane/ethyl acetate 5:1) of the reaction mixture
afforded desired product.
1H), 7.52e7.48 (m, 1H),
d
d
133.5,122.6,121.0,119.2, 70.8, 65.5; IR (neat) 2945,1703,1603,1294,
1114, 1020, 880, 753 cmꢁ1; HRMS (TOF) calcd for C9H803 164.0473,
found 164.0475.
4.3.6. 1-Methylbenzo[e][1,4]oxazepine-2,5(1H,3H)-dione
(3e).18
7.89 (dd,
Yield (method A): 86 mg, 90%; 1H NMR (400 MHz, CDCl3)
d
J¼9.2, 6.4 Hz, 1H), 7.66 (t, J¼14.4 Hz, 1H), 7.36 (t, J¼15.2 Hz,1H), 7.26
(d, J¼8.4 Hz,1H), 4.67 (s, 2H), 3.43 (s, 3H); 13C NMR (100 MHz, CDCl3)
d
168.0, 167.2, 141.1, 134.0, 132.4, 125.9, 123.3, 120.8, 67.1, 34.7; IR
4.2.2. General procedure B. To a solution of bromodecanoic acid
(0.5 mmol) in dimethyl sulfoxide (10 mL) was added potassium
bicarbonate (150 mg, 1.5 mmol). After stirring for 30 min, AgBF4
(194 mg, 1 mmol) was charged and the reaction mixture was
allowed to warm to 60 ꢀC. Upon to completion, the reaction mixture
was diluted with 50 mL of water and extracted with ethyl ether
(3ꢂ20 mL). The extract was washed with water (2ꢂ20 mL) and
dried with anhydrous Na2SO4. After evaporation, chromatography
on silica gel (hexane/ethyl acetate 5:1) of the reaction mixture
afforded desired product.
(neat) 2921,1724,1674,1455,1376,1143,1109, 760, 704 cmꢁ1; HRMS
(TOF) calcd for C10H9NO3 191.0582, found 191.0585.
4.3.7. 4-Methyl-1-tosyl-3,4-dihydro-1H-benzo[c][1,5]oxazocin-
6(2H)-one (3f). Amorphous solid; yield (method B): 147 mg, 85%;
1H NMR (400 MHz, CDCl3)
d 7.62e7.57 (m, 3H), 7.50e7.44 (m, 2H),
7.27 (d, J¼8.0 Hz, 2H), 7.13 (dd, J¼6.4, 2.0 Hz,1H), 4.40e4.31 (m, 2H),
3.20e3.13 (m, 1H), 2.43 (s, 3H), 2.29e2.18 (m, 1H), 1.66 (d,
J¼15.3 Hz, 1H), 1.31 (d, J¼6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d
168.4, 143.8, 137.9, 136.6, 134.3, 132.6, 130.1, 129.7, 129.6, 129.5,
127.5, 49.6, 37.0, 23.2, 21.5; IR (neat) 2929, 1715, 1598, 1451, 1344,
1291, 1161, 1078, 734, 688 cmꢁ1; HRMS (TOF) calcd for C18H19NO4S
345.1035, found 345.1039.
4.3. Characterization data
4.3.1. 3,4-Dihydrobenzo[b][1,5]dioxocin-6(2H)-one
(2). Yield
d 7.51 (d,
(method B): 51 mg, 56%; 1H NMR (400 MHz, CDCl3)
4.3.8. 1-Tosyl-3,4-dihydro-1H-benzo[c][1,5]oxazocin-6(2H)-one
J¼7.6 Hz, 1H), 7.40 (t, J¼14.4 Hz, 1H), 7.04 (t, J¼14.8 Hz, 1H), 6.96 (d,
(3g). Solid, mp: 55e58 ꢀC; yield (method B): 86 mg, 52%; 1H NMR
J¼8.4 Hz, 1H), 4.34 (t, J¼8.0 Hz, 1H), 4.30 (t, J¼8.0 Hz, 1H), 2.27e1.98
(m, 2H); 13C NMR (100 MHz, CDCl3)
d 171.3,157.4,133.0,132.9,121.8,
119.5, 116.7, 64.7, 30.9; IR (neat) 2919, 1707, 1603, 1483, 1441, 1290,
1158, 1123, 1038, 966, 752 cmꢁ1; HRMS (TOF) calcd for C10H10O3
178.0630, found 178.0628.
(400 MHz, CDCl3)
J¼6.8 Hz, 2H), 7.07 (d, J¼7.2 Hz, 1H), 4.23e4.20 (m, 2H), 3.75 (s, 2H),
2.43 (s, 3H), 2.07e2.05 (m, 2H); 13C NMR (100 MHz, CDCl3)
169.0,
d
7.63e7.58 (m, 3H), 7.48 (t, J¼6.8 Hz, 2H), 7.28 (d,
d
143.9, 138.0, 136.6, 133.6, 132.7, 130.4, 129.7, 129.6, 127.5, 68.0, 49.8,
30.5, 21.5; IR (neat) 2922, 1710, 1597, 1449, 1339, 1287, 1158, 1115,
1084, 742, 681 cmꢁ1; HRMS (TOF) calcd for C17H17NO4S 331.0878,
found 331.0879.
4.3.2. 3-Methyloxepan-2-one (3a).17 Yield (method A): 32 mg, 50%;
1H NMR (400 MHz, CDCl3)
d 4.31e4.19 (m, 2H), 2.76e2.69 (m, 1H),
1.99e1.92 (m, 2H), 1.78e1.58 (m, 3H), 1.56e1.45 (m, 1H), 1.20 (d,
J¼6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3)
d 178.1, 68.3, 37.3, 31.9,
4.3.9. 1-Tosyl-2,3,4,5-tetrahydrobenzo[c][1,5]oxazonin-7(1H)-one
(3h). Amorphous solid; yield (method B): 71 mg, 41%; 1H NMR
28.8, 28.3, 18.4.
(400 MHz, CDCl3)
(d, J¼8.0 Hz, 2H), 4.28 (t, J¼12.0 Hz, 2H), 3.75 (br, 2H), 2.41 (s, 3H),
1.99e1.76 (m, 4H); 13C NMR (100 MHz, CDCl3)
168.2, 143.5, 140.5,
d
7.60 (t, J¼12.0 Hz, 3H), 7.44e7.33 (m, 3H), 7.25
4.3.3. 1-Tosyl-2,3-dihydrobenzo[e][1,4]oxazepin-5(1H)-one
Solid, mp: 45e48 ꢀC; yield (method A): 146 mg, 92%; 1H NMR
(400 MHz, CDCl3)
7.65 (d, J¼2.8 Hz, 2H), 7.59 (d, J¼7.6 Hz, 1H),
7.52e7.43 (m, 1H), 7.40 (d, J¼8.0 Hz, 2H), 7.22 (d, J¼8.0 Hz, 2H),
4.18e3.92 (m, 4H), 2.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
168.2,
(3b).
d
137.2, 133.1, 131.5, 129.8, 129.3, 128.6, 128.1, 127.8, 67.3, 54.5, 27.2,
d
26.3, 21.5; IR (neat) 2961, 1739, 1347, 1264, 1160, 732, 701, 617 cmꢁ1
HRMS (TOF) calcd for C18H19NO4S 345.1035, found 345.1029.
;
d
144.3, 134.7, 134.0, 133.7, 132.2, 131.3, 129.8, 129.6, 129.2, 127.1, 64.4,
50.2, 21.5; IR (neat) 2927, 1710, 1598, 1451, 1344, 1294, 1161, 1075,
730; HRMS (TOF) calcd for C16H15NO4S 317.0722, found 317.0724.
4.3.10. 4,5-Dihydro-2H-benzo[b][1,5]dioxonin-7(3H)-one (3i). Gum;
yield (method B): 60 mg, 62%; 1H NMR (400 MHz, CDCl3)
7.59 (dd,
d
J¼8.8, 6.0 Hz, 1H), 7.42e7.38 (m, 1H), 7.13 (t, J¼15.2 Hz, 1H), 7.08 (d,
4.3.4. Benzo[e][1,4]oxazepine-2,5(1H,3H)-dione (3c).18 Yield (method
J¼8.0 Hz, 1H), 4.50 (t, J¼8.0 Hz, 2H), 4.14 (t, J¼¼8.0 Hz, 2H),
2.00e1.93 (m, 4H); 13C NMR (100 MHz, CDCl3)
d 168.9, 160.1, 132.6,
A): 50 mg, 56%; 1H NMR (400 MHz, DMSO)
d 10.82 (s, 1H), 7.82 (d,

8390
L. Liu et al. / Tetrahedron 69 (2013) 8386e8391
129.4, 126.1, 123.5, 122.2, 66.9, 28.5, 27.3; IR (neat) 2954, 1721, 1457,
1295, 1241, 1121, 971, 766 cmꢁ1; HRMS (TOF) calcd for C11H12O3
192.0786, found 192.0788.
A): 150 mg, 70%; 1H NMR (400 MHz, CDCl3)
d 7.93e7.91 (m, 1H),
7.45 (d, J¼12.0 Hz, 2H), 7.37e7.35 (m, 2H), 7.23 (d, J¼8.0 Hz, 2H),
6.74e6.71 (m, 1H), 4.40e4.35 (m, 2H), 3.83 (br, 1H), 3.22 (br, 1H),
2.41 (s, 3H), 1.87 (s, 1H), 1.66e1.57 (m, 2H), 1.40e1.19 (m, 13H); 13
C
4.3.11. 4,5-Dihydro-1H-benzo[g][1,5]dioxonine-1,7(3H)-dione (3j).
NMR (100 MHz, CDCl3) d 167.6, 143.1, 137.4, 135.0, 133.7, 131.7, 131.4,
Gum; yield (method B): 67 mg, 65%; 1H NMR (400 MHz, CDCl3)
129.3, 127.6, 127.5, 127.2, 65.8, 49.4, 27.0, 25.9, 25.8, 25.2, 24.2, 24.1,
23.9, 23.3, 21.4; IR (neat) 2929, 1714, 1451, 1347, 1291, 1180, 732,
661 cmꢁ1; HRMS (TOF) calcd for C24H31NO4S 429.1974, found
429.1960.
d
7.77e7.74 (m, 2H), 7.59e7.57 (m, 2H), 4.66 (t, J¼12.0 Hz, 4H),
2.09e2.04 (m, 2H); 13C NMR (100 MHz, CDCl3)
d
168.6, 133.9, 131.4,
128.4, 66.2, 23.7; IR (neat) 2964, 1724, 1270, 1121, 1031, 998, 748,
689 cmꢁ1; HRMS (TOF) calcd for C11H10O4 206.0579, found
206.0580.
4.3.19. 3,4,5,6,7,8,9,10,11,12-Decahydrobenzo[c][1,6]dioxacyclohex-
adecine-1,14-dione (4e). Amorphous solid; yield (method B):
4.3.12. 3,4,5,6-Tetrahydrobenzo[c][1,6]dioxecine-1,8-dione
Amorphous solid; yield (method B): 75 mg, 68%; 1H NMR
(400 MHz, CDCl3) 7.75e7.73 (m, 2H), 7.57e7.55 (m, 2H), 4.40 (s,
4H), 2.00e1.95 (m, 4H); 13C NMR (100 MHz, CDCl3)
167.9, 132.9,
131.3, 128.6, 65.6, 26.5; IR (neat) 2961, 1721, 1275, 1122, 952,
737 cmꢁ1; HRMS (TOF) calcd for C12H12O4 220.0736, found
220.0736.
(3k).
107 mg, 65%; 1H NMR (400 MHz, CDCl3)
d
7.75e7.73 (m, 2H),
7.54e7.52 (m, 2H), 4.41 (t, J¼10.8 Hz, 4H), 1.77e1.73 (m, 4H), 1.36 (s,
12H); 13C NMR (100 MHz, CDCl3)
167.6, 132.3, 130.8, 128.7, 64.2,
d
d
d
28.0, 26.4, 25.4, 24.1;IR (neat)2929, 2857,1721,1460,1264,1119,1071,
742 cmꢁ1; HRMS (TOF) calcd for C18H24O4 328.0947, found 328.0950.
4.3.20. 5-Tosyl-6,7,8,9,16,17,18,19-octahydrodibenzo[b,k][1,4,9,13]tri-
oxaazacycloheptadecin-21(5H)-one (4f). Solid, mp: 56e59 ꢀC; yield
4.3.13. 4,5,6,7-Tetrahydro-1H-benzo[c][1,6]dioxacycloundecine-
(method B): 183 mg, 72%; 1H NMR (400 MHz, CDCl3)
d 7.93 (dd,
1,9(3H)-dione (3l). Amorphous solid; yield (method B): 78 mg, 67%;
J¼9.2, 4.4 Hz, 1H), 7.44 (d, J¼8.0 Hz, 2H), 7.40e7.34 (m, 2H), 7.22 (d,
J¼8.0 Hz, 2H), 6.93e6.88 (m, 4H), 6.74e6.72 (m, 1H), 4.43 (s, 2H),
4.04 (t, J¼8.8 Hz, 2H), 3.96 (s, 2H), 3.87 (br, 1H), 3.44 (br,1H), 2.41 (s,
3H), 1.98 (s, 4H), 1.69 (s, 2H), 1.58 (s, 2H); 13C NMR (100 MHz, CDCl3)
1H NMR (400 MHz, CDCl3)
d
7.78 (dd, J¼9.2, 2.4 Hz, 2H), 7.57 (dd,
J¼8.8, 2.4 Hz, 2H), 4.45 (t, J¼12.0 Hz, 4H), 1.96e1.90 (m, 4H),
1.73e1.66 (m, 2H); 13C NMR (100 MHz, CDCl3)
168.1, 131.9, 131.2,
d
129.5, 65.6, 25.5, 24.5; IR (neat) 2934, 2859, 1710, 1281, 1123, 1042,
908, 740 cmꢁ1; HRMS (TOF) calcd for C13H14O4 234.0892, found
234.0894.
d 167.6, 150.1, 148.8, 143.1, 138.4, 135.4, 133.9, 131.7, 131.6, 129.3,
127.8,127.6,121.9,121.0,115.7,113.8, 69.8, 68.5, 65.3, 52.0, 27.0, 26.6,
26.4, 25.5, 21.4; IR (neat) 3062, 2922, 1713, 1595, 1502, 1382, 1346,
1252, 1161, 1058, 732, 622 cmꢁ1; HRMS (TOF) calcd for C28H31NO6S
509.1872, found 509.1878.
4.3.14. 1-(2-Hydroxyethyl)benzo[e][1,4]oxazepine-2,5(1H,3H)-dione
(3m). Amorphous solid; yield (method B): 101 mg, 92%; 1H NMR
(400 MHz, CDCl3)
d
7.87 (d, J¼6.8 Hz, 1H), 7.65 (t, J¼15.6 Hz, 1H),
4.3.21. 6,7,8,9,18,19,20,21-Octahydrodibenzo[b,k][1,4,9,14]tetraox-
7.51 (d, J¼8.0 Hz, 1H), 7.38 (t, J¼15.2 Hz, 1H), 4.66 (s, 2H), 4.07 (s,
acyclooctadecine-11,16-dione (4g). Solid, mp: 62e65 ꢀC; yield
2H), 3.95 (t, J¼10.0 Hz, 2H), 2.34 (s, 1H); 13C NMR (101 MHz, CDCl3)
(method B): 157 mg, 82%; 1H NMR (400 MHz, CDCl3)
d 7.75e7.72 (m,
d
168.0, 167.4, 140.6, 134.1, 132.3, 126.5, 124.1, 122.6, 67.4, 60.4, 51.3;
2H), 7.55e7.52 (m, 2H), 6.91e6.85 (m, 4H), 4.45 (t, J¼6.4 Hz, 4H), 4.04
IR (neat) 2926, 1725,1676, 1459, 1396, 1261, 1223, 1112, 1017, 982,
790, 706 cmꢁ1; HRMS (TOF) calcd for C11H11NO4 221.0688, found
221.0690.
(t, J¼10.8 Hz, 4H), 2.03e1.98 (m, 4H), 1.94e1.89 (m, 4H); 13C NMR
(100 MHz, CDCl3) d 167.7, 148.7, 132.3, 130.9, 129.0, 120.8, 112.7, 68.1,
65.9, 26.1, 25.7; IR (neat) 2952, 1719, 1504, 1251, 1123, 1071, 1040,
735 cmꢁ1; HRMS (TOF) calcd for C22H24O6 384.1573, found 384.1580.
4.3.15. 3,4,5,6,7,8-Hexahydrobenzo[c][1,6]dioxacyclododecine-1,10-
dione (4a). Amorphous solid; Yield (method B): 96 mg, 77%; 1H
4.3.22. Phoracantholide I (6).15b Yield (method B): 34 mg, 40%; 1H
NMR (400 MHz, CDCl3)
d
7.75e7.72 (m, 2H), 7.55e7.52 (m, 2H), 4.41
NMR (400 MHz, CDCl3)
d
5.09e5.04 (m, 1H), 2.36 (t, J¼14.8 Hz, 2H),
(t, J¼8.0 Hz, 4H), 1.86e1.80 (m, 4H), 1.60e1.57 (m, 4H); 13C NMR
1.64e1.54 (m, 4H), 1.35 (d, J¼6.4 Hz, 3H), 1.33 (s, 4H), 1.26 (s, 2H),
0.90e0.83 (m, 2H); HRMS (TOF) calcd for C10H18O2 170.1307, found
170.1309.
(100 MHz, CDCl3)
d 167.9, 131.7, 130.9, 129.1, 66.1, 25.5, 24.2; IR
(neat) 2954, 1717, 1278, 1244, 1073, 1040, 743, 648 cmꢁ1; HRMS
(TOF) calcd for C14H16O4 248.1049, found 248.1049.
Acknowledgements
4.3.16. 4,5,6,7,8,9-Hexahydro-1H-benzo[c][1,6]dioxacyclotridecine-
1,11(3H)-dione (4b). Amorphous solid; yield (method B): 105 mg,
Financial support from Natural Science Foundation of China (no.
20972134) is greatly appreciated.
80%; 1H NMR (400 MHz, CDCl3)
d 7.71e7.69 (m, 2H), 7.54e7.52 (m,
2H), 4.44 (t, J¼8.0 Hz, 4H), 1.82e1.80 (m, 4H), 1.53 (s, 6H); 13C NMR
(100 MHz, CDCl3)
d 167.9, 132.4, 130.7, 128.9, 65.5, 26.6, 25.3, 24.9;
Supplementary data
IR (neat) 2923, 1721, 1281, 1124, 1072, 741 cmꢁ1; HRMS (TOF) calcd
for C15H18O4 262.1205, found 262.1201.
Supplementary data associated with this article can be found in
the online version, at http://dx.doi.org/10.1016/j.tet.2013.07.064.
4.3.17. 6,7,16,17-Tetrahydrodibenzo[e,l][1,4,7,10]tetraoxacyclote-
tradecine-9,14-dione (4c). Amorphous solid; yield (method B):
References and notes
123 mg, 75%; 1H NMR (400 MHz, CDCl3)
d 7.75e7.73 (m, 2H),
7.54e7.52 (m, 2H), 6.94e6.88 (m, 4H), 4.68 (t, J¼8.4 Hz, 4H), 4.30 (t,
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