Synthesis of 23-, 25-, 27-, and 29-Membered (Z)-Selective Unsaturated and Saturated Macrocyclic Lactones from 16- and 17-Membered Macrocyclic Lactones and Bromoalcohols by Wittig Reaction, Yamaguchi Macrolactonization, and Photoinduced Decarboxylative Radical Macrolactonization

Article abstract of DOI:10.1021/acs.joc.9b00870

A new strategy for the synthesis of 23-, 25-, 27-, and 29-membered (Z)-selective unsaturated and saturated macrocyclic lactones from commercially available 16- and 17-membered macrocyclic lactones and bromoalcohols by Wittig reaction, Yamaguchi macrolactonization, and photoinduced decarboxylative radical macrolactonization is described. The position of the unsaturated part in the macrocyclic lactones can be controlled by changing the number of carbons in the starting materials. This protocol can provide facile access to the desired large-ring (Z)-selective unsaturated and saturated macrocyclic lactones from simple starting materials.

Full text of DOI:10.1021/acs.joc.9b00870

Article
pubs.acs.org/joc
Cite This: J. Org. Chem. XXXX, XXX, XXX−XXX
Synthesis of 23‑, 25‑, 27‑, and 29-Membered (Z)-Selective
Unsaturated and Saturated Macrocyclic Lactones from 16- and 17-
Membered Macrocyclic Lactones and Bromoalcohols by Wittig
Reaction, Yamaguchi Macrolactonization, and Photoinduced
Decarboxylative Radical Macrolactonization
Tomoya Iwasaki,† Yuka Tajimi,† Kenta Kameda,† Callum Kingwell,‡,§ William Wcislo,§
Kazuyuki Osaka,† Mugen Yamawaki,† Toshio Morita,† and Yasuharu Yoshimi*,†
†Department of Applied Chemistry and Biotechnology, Graduate School of Engineering, University of Fukui, 3-9-1 Bunkyo, Fukui
910-8507, Japan
‡Department of Neurobiology and Behavior, Cornell University, Ithaca, New York 14853, United States
§Smithsonian Tropical Research Institute, Luis Clement Avenue, Building 401 Tupper, Balboa Ancon, Panama 0843-03092,
Republic of Panama
S
* Supporting Information
ABSTRACT: A new strategy for the synthesis of 23-, 25-, 27-,
and 29-membered (Z)-selective unsaturated and saturated
macrocyclic lactones from commercially available 16- and 17-
membered macrocyclic lactones and bromoalcohols by Wittig
reaction, Yamaguchi macrolactonization, and photoinduced
decarboxylative radical macrolactonization is described. The
position of the unsaturated part in the macrocyclic lactones
can be controlled by changing the number of carbons in the
starting materials. This protocol can provide facile access to
the desired large-ring (Z)-selective unsaturated and saturated
macrocyclic lactones from simple starting materials.
unsaturated carbonyl group leads to the formation of an α-
carbonyl radical, which subsequently participates in back-
electron transfer with the radical anion of DCB to yield
macrocyclic lactones after protonation. This photoreaction has
been proven to allow for a two-carbon ring expansion of
macrocyclic lactones. Fortunately, the obtained macrocyclic
lactones (18-, 20-, 22-, and 24-membered macrocyclic
lactones) in the photoreaction have been identified as
candidate pheromones involved in communicating reproduc-
tive dominance in the bee family Halictidae. To enable
experimental bioassays testing the function of these putative
pheromones, the synthesis of 23-, 25-, 27-, and 29-membered
macrocyclic lactones 3−6 is desirable. This motivation
encouraged us to design a new synthetic strategy for these
macrocyclic lactones from commercially available 16- and 17-
membered macrocyclic lactones 1, 2 and bromoalcohols 9 by
means of Wittig reaction, Yamaguchi macrolactonization, and
photoinduced decarboxylative radical macrolactonization
(Scheme 1c). Carboxylic acids containing a (Z)-alkene and a
hydroxy group (7) or an acyloxy group (8) are key
INTRODUCTION
■
Macrocyclic lactones contain cyclic esters with a large-sized
(more than 12-membered) ring. These lactones are found in a
variety of natural products such as exaltolide 1 (16-membered
macrocyclic lactone) and cyclohexadecanolide 2 (17-mem-
bered macrocyclic lactone), which are used in perfumes, and
synthetic pharmaceuticals such as erythromycin and clari-
thromycin, which have strong antibacterial and antitumor
activities (Scheme 1a).1 Therefore, a number of efficient
synthetic routes to macrocyclic lactones have been developed
based on transition-metal-catalyzed ring-closing metathesis,2
Horner−Wadsworth−Emmons reaction,3 Yamaguchi macro-
lactonization,4 Shiina macrolactonization,5 and intramolecular
radical cyclization using azobisisobutyronitrile and Bu3SnH.6
We recently reported a radical cyclization of carboxylic acids
bearing electron-deficient alkenes via photoinduced decarbox-
ylation7 under mild photoredox catalyst conditions for the
formation of macrocyclic lactones in high yields (Scheme 1b).8
The radical cation of phenanthrene (Phen) photogenerated
through photoinduced electron transfer between the excited
state of Phen and 1,4-dicyanobenzene (DCB) can oxidize the
carboxylate ion to produce the alkyl radical via decarbox-
ylation. Cyclization of the resulting radical to an α,β-
Received: March 28, 2019
Published: May 28, 2019
© XXXX American Chemical Society
A
DOI: 10.1021/acs.joc.9b00870
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Scheme 1. (a) Examples of Macrocyclic Lactones, (b) Photoinduced Decarboxylative Radical Macrolactonization of Carboxylic
Acid Bearing Electron-Deficient Alkene (Previous Work), and (c) Strategy Developed in This Work
intermediates in our synthetic route, and they are prepared by
the Wittig reaction of phosphonium bromide derived from 9
and aldehydes derived from 1 or 2. The results of this effort,
which led to the development of a new route to large-ring-
saturated and (Z)-selective unsaturated macrocyclic lactones,
are described below.
tion from 16-membered macrocyclic lactone 1 (C = 15) and 7-
bromoheptanol 9a (C = 7). Protection of the hydroxy group of
9a by acetylation and refluxing with PPh3 yielded the
corresponding phosphonium bromide 10a as the Wittig
reaction precursor (96 and 99%) (Scheme 2; these two steps
Scheme 2. Preparation of 10a from 9a
RESULTS AND DISCUSSION
■
Synthesis of 23-, 25-, 27-, and 29-Membered Macro-
cyclic Lactones 3−6 from 16-Membered Macrocyclic
Lactone 1 and Bromoalcohols 9a and 9b. Initially, 23-
membered macrocyclic lactone 3 (C = 22: carbon number in
macrocyclic lactones, bromoalcohols, and acryloyl group) was
synthesized by Wittig reaction and Yamaguchi macrolactoniza-
B
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Article
were illustrated by I). Hydrolysis of 1 with KOH, followed by
esterification with CH3I, afforded a methyl ester (92%), which
was converted into the corresponding aldehyde 11a (92%) by
pyridinium dichromate (PDC) oxidation (Scheme 3; these
lactones was employed by transition-metal-catalyzed ring-
closing metathesis,2 leading to the formation of (E) and (Z)
mixtures; however, (Z)-unsaturated macrocyclic lactone was
exclusively obtained by this protocol. Reduction of 12a by Pd−
C and H2 provided saturated 23-membered macrocyclic
lactone 3 in a slightly lower yield (78%) because this saturated
lactone was slightly volatile (Scheme 4; these two steps were
illustrated by IV). On the other hand, a similar reduction of the
larger-sized unsaturated macrocyclic lactones such as 12b−d
yielded almost quantitative yields of saturated macrocyclic
lactones 4−6. Before Yamaguchi macrolactonization, a similar
reduction of unsaturated carboxylic acid 7a by Pd−C and H2
gave an insoluble saturated carboxylic acid, which was not used
in further synthesis. These results indicated that the presence
of the (Z)-alkene unit in 7a is essential for promoting the
macrolactonization and increasing the solubility of the
carboxylic acid. Thus, (Z)-selective unsaturated and saturated
23-membered macrocyclic lactones 12a and 3 (C = 22) were
prepared by Wittig reaction and Yamaguchi macrolactoniza-
tion from 1 and 9a (C = 15 + 7).
Next, to synthesize 25-membered macrocyclic lactone 4 (C
= 24), photoinduced decarboxylative radical macrolactoniza-
tion was employed because this protocol can facilitate a two-
carbon ring expansion (C = 3 (addition of acryloyl group) − 1
(decarboxylation) = 2) of macrocyclic lactones (Scheme 5). In
our previous report,8 we mentioned that the addition of an
acryloyl group to carboxylic acids bearing a hydroxy group,
such as 7a, required three steps, leading to the loss of time and
a decrease in the total yield. The improved one-pot method is
shown in Scheme 5. Addition of 3 equiv of acryloyl chloride to
7a led to the formation of an intermediate bearing both an
acrylic ester and an acid anhydride, and subsequent hydrolysis
with 3 M HCl in one pot exclusively yielded carboxylic acid 8a
bearing an acrylic ester. Photoreaction of an aqueous (aq)
acetonitrile solution (CH3CN/H2O = 9:1, v/v) containing
Phen (20 mM), DCB (20 mM), carboxylic acid 8a (1 mM),
and NaOH (1 mM) with irradiation by a 100 W high-pressure
mercury lamp equipped with a Pyrex filter (>280 nm) under
an argon atmosphere for 6 h at room temperature afforded
(Z)-selective unsaturated 25-membered macrocyclic lactone
12b in 81% yield. The (Z)-alkene unit in 8a could promote
radical macrocyclization via photoinduced decarboxylation. A
similar reduction of 12b by Pd−C and H2 provided saturated
Scheme 3. Preparation of 11a from 1
three steps were illustrated by II). Sequential Wittig reaction of
10a with 11a and hydrolysis in one pot selectively afforded
(Z)-alkene 7a bearing carboxy and hydroxy groups in
moderate yield (54%), which may be due to the low solubility
of the corresponding (E)-alkene (Scheme 4; this sequential
Scheme 4. Preparation of 3 from 10a and 11a by Wittig
Reaction and Yamaguchi Macrolactonization
reaction was illustrated by III). Yamaguchi macrolactonization
of 7a proceeded smoothly to afford (Z)-selective unsaturated
23-membered macrocyclic lactone 12a (79%), probably
because the (Z)-alkene unit in 7a assisted this macro-
cyclization. In general, the synthesis of unsaturated macrocyclic
Scheme 5. Preparation of 4 from 7a by Photoinduced Decarboxylative Radical Macrolactonization
C
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Scheme 6. Preparation of 5 and 6 from 1 and 9b
Scheme 7. Preparation of 3 and 4 from 2 and 9c
25-membered macrocyclic lactone 4 in high yield (97%,
Scheme 5; these four steps including the photoreaction were
illustrated by V). Thus, two-carbon elongated macrocyclic
lactone 4 (C = 24) was also prepared from 7a by photoinduced
decarboxylative radical macrolactonization (C = 15 + 7 + 2).
To synthesize 27- and 29-membered macrocyclic lactones
(C = 26 and 28) from 1 (C = 15), 11-bromoundecanol 9b (C
= 11) was used as a starting material (Scheme 6). Similar
repetition of reaction sequences (I + III) between 9b and 11a
(C = 15) yielded the corresponding carboxylic acid 7b.
Yamaguchi macrolactonization and reduction IV of 7b led to
the formation of (Z)-selective unsaturated and saturated 27-
membered macrocyclic lactones 12c and 5 (C = 15 + 11),
while the addition of acryloyl group and photoreaction V of 7b
provided (Z)-selective unsaturated and saturated 29-mem-
bered macrocyclic lactones 12d and 6 (C = 15 + 11 + 2).
These results show that changing the number of carbons in the
starting bromoalcohol 9 can help us control the size of the
macrocyclic lactones.
Synthesis of 23- and 25-Membered Macrocyclic
Lactones 3 and 4 from 17-Membered Macrocyclic
Lactone 2 and 6-Bromohexanol 9c. Finally, we attempted
to synthesize 23- and 25-membered macrocyclic lactones 3 and
4 from the 17-membered macrocyclic lactone 2 (C = 16) and
6-bromohexanol 9c (C = 6) as starting materials (Scheme 7).
The use of macrocyclic lactones and bromoalcohols with
different carbon numbers helped us alter the position of the
(Z)-alkene part in the unsaturated macrocyclic lactones. A
similar repetition (I + II + III) sequence of 2 and 9c through
the formation of 10c and 11b produced the corresponding
carboxylic acid 7c, which had the unsaturated part at a different
position. Moreover, subjecting carboxylic acids 7c and 8c to
conditions IV or V provided the respective 23- and 25-
membered (Z)-selective unsaturated macrocyclic lactones 12e
and 12f having the (Z)-alkene part at different positions, and a
similar reduction of 12e and 12f afforded saturated macro-
cyclic lactones 3 and 4 (C = 16 + 6 and 16 + 6 + 2). Thus, the
use of macrocyclic lactones with different carbon numbers (C
D
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13C{1H} NMR (125 MHz, CDCl3) δ 171.1, 64.3, 33.7, 32.6, 28.4,
27.8, 25.1, 21.0.
= 15 or 16) and bromoalcohols (C = 6 or 7) as the starting
materials allowed us to prepare 23-membered macrocyclic
lactone 3 (C = 15 + 7 or 16 + 6) and 25-membered
macrocyclic lactone 4 (C = 15 + 7 + 2 or 16 + 6 + 2) via the
formation of unsaturated macrocyclic lactones 12 with the (Z)-
alkene unit at different positions.
7-Bromoheptyl acetate (1.52 g, 6.41 mmol) and PPh3 (1.2 equiv,
2.03 g, 7.74 mmol) in anhydrous CH3CN were refluxed for 48 h
under an argon atmosphere. The mixture was evaporated, and then
Et2O was added to the residue and filtered. The filtrate was washed
with Et2O several times and dried in vacuo to afford 7-O-acetyl
pentyltriphenylphosphonium bromide 10a as a yellow oil in a
quantitative yield (3.21 g, 6.41 mmol, quant.). A similar procedure
using 11-bromoundecanyl acetate (0.100 g, 0.341 mmol) and 6-
bromohexyl acetate (1.21 g, 5.42 mmol) gave the corresponding
phosphonium bromides 10b (0.183 g, 0.330 mmol, 97%) and 10c
(2.74 g, 5.42 mmol, quant.), respectively.
CONCLUSIONS
■
We proposed a new strategy for the synthesis of 23-, 25-, 27-,
and 29-membered (Z)-selective unsaturated and saturated
macrocyclic lactones from 16- and 17-membered macrocyclic
lactones and bromoalcohols. The (Z)-alkene unit in 7 and 8
promoted the macrolactonization and increased the solubility
of the substrates. The use of macrocyclic lactones and
bromoalcohols with different carbon numbers as the starting
materials in our protocol helped in changing the ring size of
the macrocyclic lactones and the (Z)-alkene position. The role
of these macrocyclic lactones in the chemical communication
systems of species in the Sweat Bee family Halictidae is
currently being investigated.
7-O-Acetyl Pentyltriphenylphosphonium Bromide (10a). Yellow
1
oil; IR (neat, cm−1) 2934, 2858, 1731, 1437, 1243, 1113; H NMR
(300 MHz, CDCl3) δ 7.90−7.69 (m, 15H), 3.99 (t, J = 6.7 Hz, 2H),
3.79−3.88 (br, 2H), 2.02 (s, 3H), 1.66−1.54 (m, 4H), 1.27 (m 6H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.5, 135.2, 133.9, 133.8,
130.7, 130.7, 118.9, 118.2, 64.6, 30.5, 30.4, 29.0, 28.6, 25.7, 23.1, 22.9,
22.8, 22.7, 21.3; high-resolution mass spectrometry (HRMS) (FAB)
calcd for (M − Br)+ C27H32O2P: 419.2134, found: 419.2154.
11-O-Acetyl Undecanyltriphenylphosphonium Bromide (10b).
1
Yellow oil; IR (neat, cm−1) 2929, 2853, 1733, 1438, 1114; H NMR
(500 MHz, CDCl3) δ 7.87−7.73 (m, 15H), 4.04 (t, J = 6.6 Hz, 2H),
3.74 (br, 2H), 2.05 (s, 3H), 1.67−1.53 (m, 4H), 1.26 (m, 14H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.4, 135.1, 133.8, 133.7,
130.6, 130.5, 118.7, 118.1, 64.7, 30.6, 30.5, 29.5, 29.3, 29.2, 28.6, 25.9,
23.0, 22.7, 22.6, 21.1; HRMS (FAB) calcd for (M − Br)+ C31H40O2P:
475.2760, found: 475.2743.
EXPERIMENTAL SECTION
■
General Information. All reagents and solvents were used as
received from commercial suppliers. IR spectra were recorded on a
Fourier transform infrared spectrometer. 1H NMR spectra were
recorded in CDCl3 containing tetramethylsilane as an internal
standard and were acquired on either a 300 or 500 MHz
spectrometer. 13C{1H} NMR spectra were acquired on a 125 MHz
spectrometer. High-resolution mass spectra were obtained using a
double-focusing magnetic sector mass spectrometer coupled with fast
atom bombardment (FAB). The light source was a Riko UV-100HA
high-pressure (100 W) mercury arc, and Pyrex vessels (18 mm × 180
mm) were directly attached to the light source (λ > 280 nm, Phen
mainly absorbed at 313 nm light). Column chromatography was
performed on Wakogel C-300, particle size 45−75 μm.
6-O-Acetyl Hexyltriphenylphosphonium Bromide (10c). Yellow
1
oil; IR (neat, cm−1) 2934, 2862, 1731, 1437, 1114; H NMR (300
MHz, CDCl3) δ 7.89−7.69 (m, 15H), 3.99 (t, J = 6.5 Hz, 2H), 3.82
(br, 2H), 2.02 (s, 3H), 1.72−1.55 (m, 4H), 1.36−1.32 (m, 4H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.2, 135.1, 135.0, 133.7,
133.6, 130.6, 130.5, 118.7, 118.0, 64.3, 30.1, 30.0, 28.2, 25.7, 22.9,
22.7, 22.6, 22.5, 21.1; HRMS (FAB) calcd for (M − Br)+ C26H30O2P:
405.1978, found: 405.1996.
Preparation of Aldehydes 11a and 11b from 1 and 2 (II). 16-
Membered macrocyclic lactone 1 (4.81 g, 20 mmol) was added to a
solution of KOH (1.68 g, 30 mmol) in EtOH (80 mL), and the
mixture was refluxed for 2 h. The resulting mixture was evaporated,
and then Et2O was added to the residue and filtered. The filtrate was
dried in vacuo to afford the ring-opened potassium carboxylate as a
white solid in a quantitative yield (5.91 g, quant.), as reported by us
previously.8 Also, the similar hydrolysis of 17-membered macrocyclic
lactone 2 (1.62 g, 6.37 mmol) gave the corresponding potassium
carboxylate in a quantitative yield (2.03 g, quant.).
The potassium carboxylate derived from 1 (5.91 g, 20 mmol),
CH3I (1.2 equiv, 1.49 mL, 24 mmol), and K2CO3 (1 equiv, 5.91 g, 20
mmol) in anhydrous dimethyl sulfoxide (80 mL) was stirred
overnight at 50 °C, and then water was added. The product was
extracted with Et2O, dried over Na2SO4, and concentrated under
reduced pressure. Purification by column chromatography on silica gel
using hexane/EtOAc = 25:1−1:1 as the eluent gave methyl 15-
hydroxypentadecanoate as a white solid in 92% yield (4.98 g, 18.4
mmol). Similar methylation of the potassium carboxylate derived
from 2 (2.00 g, 6.44 mmol) yielded methyl 16-hydroxyhexadecanoate
(1.22 g, 4.25 mmol, 66%).
Methyl 15-Hydroxypentadecanoate. White solid; m.p. 53−54 °C;
IR (KBr, cm−1) 3370, 2920, 2850, 1741; 1H NMR (300 MHz,
CDCl3) δ 3.67−3.64 (m, 5H), 2.31 (t, J = 7.5 Hz, 2H), 1.63−1.55
(m, 4H), 1.26−1.21 (m, 20H); 13C{1H} NMR (125 MHz, CDCl3) δ
174.5, 62.9, 51.5, 34.1, 32.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.8,
25.0; HRMS (FAB) calcd for (M + H)+ C16H33O3: 273.2424, found:
273.2427.
Procedure for Synthesis of 23-, 25-, 27-, and 29-Membered
Macrocyclic Lactones 3−6 by Reaction of 1 or 2 with 9.
Preparation of Phosphonium Bromides 10a−c from 9a−c (I).
Acetyl chloride (1.5 equiv, 0.72 mL, 10.1 mmol) in anhydrous
CH2Cl2 (1 mL) was added dropwise to a solution of 7-
bromoheptanol 9a (1.30 g, 6.66 mmol) and N,N-diisopropylethyl-
amine (DIPEA) (3.3 mL) in anhydrous CH2Cl2 (33 mL) at 0 °C.
The mixture was stirred overnight at room temperature, then
quenched by 1 M HCl, and extracted with CHCl3. The combined
organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The crude product was purified by silica gel
column chromatography using hexane/EtOAc = 5:1 as the eluent to
yield 7-bromoheptyl acetate as a colorless liquid (1.52 g, 6.39 mmol,
96%). A similar acetylation using 9b (1.00 g, 3.98 mmol) and 9c (1.23
g, 6.79 mmol) yielded 11-bromoundecanyl acetate (1.05 g, 3.58
mmol, 90%) and 6-bromohexyl acetate (1.44 g, 6.45 mmol, 95%),
respectively.
7-Bromoheptyl Acetate. Colorless oil, 1H NMR (300 MHz,
CDCl3) δ 4.06 (t, J = 6.7 Hz, 2H), 3.41 (t, J = 6.8 Hz, 2H), 2.05 (s,
3H), 1.91−1.82 (m, 2H), 1.68−1.59 (m, 2H), 1.50−1.35 (m, 6H);
13C{1H} NMR (125 MHz, CDCl3) δ 171.0, 64.3, 33.7, 32.5, 28.3,
28.2, 27.8, 25.5, 20.8.
11-Bromoundecanyl Acetate. (Using hexane/EtOAc = 10:1 as the
1
eluent), colorless oil, H NMR (300 MHz, CDCl3) δ 4.05 (t, J = 6.7
Hz, 2H), 3.41 (t, J = 6.9 Hz, 2H), 2.04 (s, 3H), 1.90−1.80 (m, 2H),
1.65−1.57 (m, 2H), 1.45−1.28 (m, 14H); 13C{1H} NMR (125 MHz,
CDCl3) δ 171.2, 64.7, 34.1, 32.9, 29.5, 29.5, 29.4, 29.3, 28.8, 28.6,
28.2, 25.9, 21.1.
Methyl 16-Hydroxyhexadecanoate. White solid; m.p. 57−58 °C,
IR (KBr, cm−1) 3427, 2923, 2850, 1740; 1H NMR (300 MHz,
CDCl3) δ 3.68−3.64 (m, 5H), 2.30 (t, J = 7.6 Hz, 2H), 1.62−1.54
(m, 4H), 1.26−1.21 (m, 22H); 13C{1H} NMR (125 MHz, CDCl3) δ
6-Bromohexyl Acetate. Colorless oil, 1H NMR (300 MHz,
CDCl3) δ 4.07 (t, J = 6.6 Hz, 2H), 3.43 (t, J = 6.8 Hz, 2H), 2.06
(s, 3H), 1.93−1.84 (m, 2H), 1.71−1.61 (m, 2H), 1.54−1.36 (m, 4H);
E
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174.5, 63.0, 51.5, 34.2, 32.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.2, 25.8,
25.0; HRMS (FAB) calcd for (M + H)+ C17H35O3: 287.2581, found:
287.2570.
Yamaguchi Macrolactonization of 7a−c for Preparation of 12a,
12c, and 12e and Reduction of 12a, 12c, and 12e for Preparation
of 3 and 5 (IV). A solution of 22-hydroxy-15-(Z)-docosenoic acid 7a
(0.0200 g, 0.0564 mmol), 2,4,6-trichlorobenzoyl chloride (10 equiv,
0.138 g, 0.0882 mL, 0.564 mmol), and DIPEA (12 equiv, 0.115 mL,
0.660 mmol) in anhydrous toluene (22 mL) was added dropwise to a
solution of 4-dimethylaminopyridine (25 equiv, 0.190 g, 1.39 mmol)
in anhydrous toluene (177 mL) under an argon atmosphere. The
mixture was stirred for 2 h at room temperature and quenched by
saturated aq NH4Cl. The aqueous layer was extracted with EtOAc and
washed with brine. The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The crude
product was purified by silica gel column chromatography using
hexane/chloroform = 3:1 as the eluent to yield unsaturated 23-
membered macrocyclic lactone 12a as a colorless oil (0.0151 g,
0.0446 mmol, 79%). Similar Yamaguchi macrolactonization of 7b
(0.0600 g, 0.169 mmol) and 7c (0.0233 g, 0.0629 mmol) yielded 12c
(0.0618 g, 0.150 mmol, 89%) and 12e (0.0176 g, 0.0522 mmol, 83%),
respectively.
Methyl 15-hydroxypentadecanoate (0.600 g, 2.20 mmol) was
added to a solution of PDC (1.5 equiv, 1.24 g, 3.30 mmol) in
anhydrous CH2Cl2 (10 mL) under an argon atmosphere. The mixture
was stirred overnight at room temperature, filtered through celite, and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography using hexane/EtOAc = 10:1 as
the eluent to yield aldehyde 11a as a white solid (0.547 g, 2.02 mmol,
92%). Similar PDC oxidation of methyl 16-hydroxyhexadecanoate
(1.16 g, 4.05 mmol) gave aldehyde 11b (0.916 g, 3.24 mmol, 80%).
Methyl 15-Formylpentadecanoate 11a. White solid; m.p. 43−44
°C; IR (KBr, cm−1) 2913, 2853, 1741; 1H NMR (500 MHz, CDCl3)
δ 9.74 (s, 1H), 3.65 (s, 3H), 2.40 (t, J = 7.4 Hz, 2H), 2.28 (t, J = 7.4
Hz, 2H), 1.61−1.58 (m, 4H), 1.28−1.20 (m, 18H); 13C{1H} NMR
(125 MHz, CDCl3) δ 203.0, 174.4, 51.5, 43.9, 34.1, 29.6, 29.5, 29.4,
29.3, 29.2, 29.1, 25.0, 22.1; HRMS (FAB) calcd for (M + H)+
C16H31O3: 271.2268, found: 271.2269.
Methyl 16-Formylhexadecanoate 11b. White solid; m.p. 43−44
°C; IR (KBr, cm−1) 2918, 2850, 1723; 1H NMR (500 MHz, CDCl3)
δ 9.77 (s, 1H), 3.67 (s, 3H), 2.42 (t, J = 7.4 Hz, 2H), 2.30 (t, J = 7.7
Hz, 2H), 1.62−1.58 (m, 4H), 1.30−1.20 (m, 22H); 13C{1H} NMR
(125 MHz, CDCl3) δ 203.0, 174.4, 51.5, 43.9, 34.1, 29.6, 29.5, 29.4,
29.3, 29.2, 29.1, 25.0, 22.1; HRMS (FAB) calcd for (M + H)+
C17H33O3: 285.2424, found: 285.2413.
15-(Z)-Cyclodocosenolide 12a. Colorless oil; IR (neat, cm−1)
2925, 2852, 1736; 1H NMR (300 MHz, CDCl3) δ 5.35 (m, 2H), 4.09
(t, J = 6.3 Hz, 2H), 2.32 (t, J = 6.9 Hz, 2H), 2.03 (m, 4H), 1.64−1.60
(m, 4H), 1.35−1.27 (m, 26H); 13C{1H} NMR (125 MHz, CDCl3) δ
174.1, 130.2, 129.9, 64.4, 34.5, 29.7, 29.1, 29.0, 28.9, 28.8, 28.7, 28.6,
28.5, 28.4, 28.3, 28.2, 27.1, 26.6, 26.3, 26.2, 24.9; HRMS (FAB) calcd
for (M + H)+ C22H41O2: 337.3101, found: 337.3100.
15-(Z)-Cyclohexacosenolide 12c. White solid; m.p. 52−53 °C; IR
(KBr, cm−1) 2911, 2850, 1727; 1H NMR (500 MHz, CDCl3) δ 5.35−
5.34 (m, 2H), 4.09 (t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.9 Hz, 2H), 2.02
(m, 4H), 1.62 (t, J = 6.6 Hz, 4H), 1.35−1.26 (m, 34H); 13C{1H}
NMR (125 MHz, CDCl3) δ 174.2, 130.3, 129.7, 64.8, 34.6, 29.6, 29.0,
28.8, 28.7, 28.6, 28.5, 28.4, 28.3, 28.2, 26.6, 25.9, 25.0; HRMS (FAB)
calcd for (M + H)+ C26H49O2: 393.3727, found: 393.3746.
Wittig Reactions of 10a−c with 11a and 11b for Preparation of
7a−c (III). Lithium hexamethyldisilazide (1.3 M, 1 equiv, 3.90 mL,
5.07 mmol) in tetrahydrofuran (THF) was slowly added to a solution
of 7-O-acetyl pentyltriphenylphosphonium bromide 10a (2.51 g, 5.03
mmol) in anhydrous THF (44 mL) under an argon atmosphere at
−78 °C. Aldehyde 11a (1 equiv, 1.36 g, 5.04 mmol) in anhydrous
THF (44 mL) was also added dropwise to the mixture at −78 °C,
stirred for 30 min at −78 °C, and further stirred for 2 h at room
temperature. A solution of LiOH (7.59 g, 320 mmol) in H2O (88
mL) and MeOH (88 mL) was added to the resulting mixture and
stirred overnight at 50 °C. The aqueous layer was acidified (1 M HCl)
to pH 2−3, extracted with Et2O, and washed with brine. The
combined organic layers were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The crude product was purified
by silica gel column chromatography using hexane/EtOAc = 4:1−3:1
as the eluent to yield carboxylic acid 7a (0.968 g, 2.72 mmol, 54%) as
a white solid. Similar Wittig reactions of 10b (0.400 g, 0.720 mmol)
with 11a (0.198 g, 0.715 mmol) and 10c (0.190 g, 0.391 mmol) with
11b (0.110 g, 0.387 mmol) produced 7b (0.186 g, 0.465 mmol, 65%)
and 7c (0.0706 g, 0.201 mmol, 52%), respectively.
22-Hydroxy-15-(Z)-docosenoic Acid (7a). White solid; m.p. 53−
54 °C; IR (KBr, cm−1) 3358, 2916, 2850, 1691; 1H NMR (500 MHz,
CDCl3) δ 5.38−5.31 (m, 2H), 3.63 (t, J = 6.6 Hz, 2H), 2.33 (t, J = 7.4
Hz, 2H), 2.01 (m, 4H), 1.64−1.55 (m, 4H), 1.33−1.26 (m, 26H);
13C{1H} NMR (125 MHz, CDCl3) δ 179.5, 130.1, 129.7, 62.9, 34.2,
32.5, 29.8, 29.7, 29.6, 29.5, 29.4, 29.3, 29.1, 27.3, 27.2, 25.7, 24.8;
HRMS (FAB) calcd for (M + H)+ C22H43O3: 355.3207, found:
355.3201.
16-(Z)-Cyclodocosenolide 12e. Colorless oil; IR (neat, cm−1)
2925, 2854, 1737; 1H NMR (500 MHz, CDCl3) δ 5.35 (m, 2H), 4.09
(t, J = 6.0 Hz, 2H), 2.31 (t, J = 6.9 Hz, 2H), 2.02 (t, J = 6.0 Hz, 4H),
1.63 (m, 4H), 1.26 (m, 26H); 13C{1H} NMR (125 MHz, CDCl3) δ
174.1, 130.0, 129.9, 64.2, 34.5, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0,
28.7, 28.5, 28.4, 26.9, 26.5, 26.0, 25.0; HRMS (FAB) calcd for (M +
H)+ C22H41O2: 337.3101, found: 337.3132.
Unsaturated lactone 12a (0.0271 g, 0.0803 mmol) was added to a
solution of 10% Pd/C (0.00830 g) in MeOH (8.3 mL) and purged
with H2. The mixture was stirred overnight, filtered through celite,
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography using hexane/chloro-
form = 1:1 as the eluent to yield cyclodocosanolide 3 as a colorless oil
(0.0212 g, 0.0626 mmol, 78%). Similar reduction of 12c (0.0265 g,
0.0714 mmol) and 12e (0.0146 g, 0.0371 mmol) yielded cyclo-
hexacosanolide 5 (0.0259 g, 0.0692 mmol, 97%) and 3 (0.0126 g,
0.0319 mmol, 86%), respectively.
Cyclodocosanolide 3. Colorless oil; IR (neat, cm−1) 2925, 2854,
1
1738; H NMR (500 MHz, CDCl3) δ 3.83 (t, J = 6.0 Hz, 2H), 2.04
(t, J = 7.2 Hz, 2H), 1.38−1.34 (m, 4H), 1.02 (m, 34H); 13C{1H}
NMR (125 MHz, CDCl3) δ 174.2, 64.4, 34.7, 29.1, 29.0, 28.9, 28.8,
28.7, 28.6, 28.3, 28.2, 28.1, 28.0, 27.8, 27.7, 26.1, 25.2; HRMS (FAB)
calcd for (M + H)+ C22H43O2: 339.3258, found: 339.3283.
26-Hydroxy-15-(Z)-hexacosenoic Acid (7b). White solid; m.p.
1
63−64 °C; IR (KBr, cm−1) 3387, 2917, 2848, 1698; H NMR (500
MHz, CDCl3) δ 5.32 (m, 2H), 3.65 (t, J = 6.6 Hz, 2H), 2.34 (t, J =
7.4 Hz, 2H), 2.01 (m, 4H), 1.66−1.54 (m, 4H), 1.33−1.26 (m, 34H);
13C{1H} NMR (125 MHz, CDCl3) δ 179.3, 129.9, 129.8, 63.1, 34.0,
32.7, 32.6, 29.8, 29.7, 29.6, 29.59, 29.5, 29.4, 29.3, 29.2, 29.1, 27.2,
25.7, 24.7; HRMS (FAB) calcd for (M + H)+ C26H51O3: 411.3833,
found: 411.3834.
Cyclohexacosanolide 5. White solid; m.p. 29−30 °C; IR (KBr,
cm−1) 2925, 2853, 1739; 1H NMR (300 MHz, CDCl3) δ 4.09 (t, J =
6.2 Hz, 2H), 2.31 (t, J = 7.2 Hz, 2H), 1.64−1.60 (m, 4H), 1.28 (m,
42H); 13C{1H} NMR (125 MHz, CDCl3) δ 173.9, 64.2, 34.4, 29.1,
29.0, 28.9, 28.8 28.7, 28.6, 28.5, 28.4, 28.3, 28.2, 25.8, 24.9; HRMS
(FAB) calcd for (M + H)+ C26H51O2: 395.3884, found: 395.3881.
Addition of Acryloyl Group to 7a−c for Preparation of 8a−c (V).
Acryloyl chloride (3 equiv, 0.823 mL, 1.02 mmol) was added
dropwise to a solution of 22-hydroxy-15-(Z)-docosenoic acid 7a
(0.120 g, 0.338 mmol) and DIPEA (0.26 mL) in anhydrous
dimethylformamide (2.6 mL) at 0 °C under an argon atmosphere.
The mixture was stirred for 2 h at room temperature, followed by the
addition of 3 M HCl at 0 °C, and stirred for 12 h at 50 °C. The
mixture was extracted with hexane/EtOAc = 4:1, dried over Na2SO4,
22-Hydroxy-16-(Z)-docosenoic Acid (7c). White solid; m.p. 55−56
1
°C; IR (KBr, cm−1) 3444, 2917, 2850, 1696; H NMR (500 MHz,
CDCl3) δ 5.35 (m, 2H), 3.65 (t, J = 6.6 Hz, 2H), 2.34 (t, J = 7.4 Hz,
2H), 2.02 (m, 4H), 1.64−1.57 (m, 4H), 1.33−1.26 (m, 26H);
13C{1H} NMR (125 MHz, CDCl3) δ 179.5, 130.3, 129.6, 63.1, 34.1,
32.7, 29.8, 29.7, 29.6, 29.6, 29.5, 29.4, 29.3, 29.2, 29.1, 29.0, 27.3,
27.2, 25.5, 24.8; HRMS (FAB) calcd for (M + H)+ C22H43O3:
355.3207, found: 355.3201.
F
DOI: 10.1021/acs.joc.9b00870
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Article
and concentrated under reduced pressure. The crude product was
purified by silica gel column chromatography using chloroform/
EtOAc = 8:1 as the eluent to yield 8a as a colorless oil (0.114 g, 0.281
mmol, 83%). Similar addition of the acryloyl group to 7b (0.139 g,
0.338 mmol) and 7c (0.120 g, 0.338 mmol) gave 8b (0.112 g, 0.338
mmol, 81%) and 8c (0.101 g, 0.301 mmol, 89%), respectively.
22-Acryloxy-15-(Z)-docosenoic Acid (8a). Colorless oil; IR (neat,
28.8, 28.7, 28.6, 28.5, 28.4, 27.9, 25.4, 25.1; HRMS (FAB) calcd for
(M + H)+ C24H45O2: 365.3414, found: 365.3401.
The abovementioned reduction of unsaturated lactones 12b
(0.0265 g, 0.0725 mmol), 12d (0.0259 g, 0.0615 mmol), and 12f
(0.0146 g, 0.0400 mmol) with Pd−C and H2 gave saturated lactones
4 (0.0251 g, 0.0703 mmol, 97% from 12b) (0.0126 g, 0.0344 mmol,
86% from 12f) and 6 (0.0255 g, 0.0602 mmol, 98%), respectively.
Cyclotetracosanolide 4. Colorless oil; IR (neat, cm−1) 2925, 2855,
1
cm−1) 2918, 2850, 1725, 1696; H NMR (300 MHz, CDCl3) δ 6.41
1
1737; H NMR (500 MHz, CDCl3) δ 4.09 (t, J = 5.4 Hz, 2H), 2.31
(dd, J = 17.2, 1.5 Hz, 1H), 6.12 (dd, J = 17.2, 10.4 Hz, 1H), 5.82 (dd,
J = 10.4, 1.5 Hz, 1H), 5.37−5.33 (m, 2H), 4.15 (t, J = 6.7 Hz, 2H),
2.35 (t, J = 7.5 Hz, 2H), 2.01 (m, 4H), 1.67−1.61 (m, 4H), 1.35−
1.26 (m, 26H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.2, 166.4,
130.5, 130.1, 129.6, 128.6, 64.7, 33.9, 29.8, 29.7, 29.6, 29.4, 29.3, 29.2,
29.1, 28.9, 28.6, 27.2, 27.1, 25.8, 24.7; HRMS (FAB) calcd for (M +
H)+ C25H45O4: 409.3312, found: 409.3300.
26-Acryloxy-15-(Z)-hexacosenoic Acid (8b). Colorless oil; IR
(neat, cm−1) 2919, 2850, 1721, 1694; 1H NMR (500 MHz, CDCl3) δ
6.40 (dd, J = 17.2, 1.5 Hz, 1H), 6.12 (dd, J = 17.2, 10.3 Hz, 1H), 5.82
(dd, J = 10.3, 1.5 Hz, 1H), 5.35 (t, J = 4.6 Hz, 2H), 4.15 (t, J = 6.9
Hz, 2H), 2.35 (t, J = 7.4 Hz, 2H), 2.01 (m, 4H), 1.69−1.60 (m, 4H),
1.35−1.26 (m, 34H); 13C{1H} NMR (125 MHz, CDCl3) δ 179.4,
166.4, 130.5, 129.9, 129.9, 128.6, 64.8, 33.9, 29.8, 29.7, 29.6, 29.5,
29.4, 29.3, 29.2, 29.1, 28.6, 27.2, 25.9, 24.7; HRMS (FAB) calcd for
(M + H)+ C29H53O4: 465.3938, found: 465.3948.
(t, J = 8.0 Hz, 2H), 1.70−1.59 (m, 4H), 1.41−1.15 (m, 38H);
13C{1H} NMR (125 MHz, CDCl3) δ 174.1, 64.4, 34.6, 29.3, 29.2,
29.1, 29.0, 28.9, 28.8, 28.7, 28.6, 28.4, 28.3, 28.2, 28.1, 26.1, 25.14;
HRMS (FAB) calcd for (M + H)+ C24H47O2: 367.3571, found:
367.3557.
Cyclooctacosanolide 6. White solid; m.p. 34−35 °C; IR (KBr,
cm−1) 2922, 2853, 1736; 1H NMR (500 MHz, CDCl3) δ 4.08 (t, J =
6.3 Hz, 2H), 2.31 (t, J = 7.4 Hz, 2H), 1.70−1.59 (m, 4H), 1.40−1.14
(m, 46H); 13C{1H} NMR (125 MHz, CDCl3) δ 174.2, 64.5, 34.6,
29.4, 29.3, 29.2, 29.1, 29.0, 28.9, 28.8, 28.7, 26.1, 25.14; HRMS
(FAB) calcd for (M + H)+ C28H55O2: 423.4197, found: 423.4178.
ASSOCIATED CONTENT
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.9b00870.
■
S
22-Acrolyoxy-16-(Z)-docosenoic Acid (8c). Colorless oil; IR (neat,
1
cm−1) 2917, 2849, 1725, 1701; H NMR (500 MHz, CDCl3) δ 6.40
1H and 13C NMR spectra of 7-bromoheptyl acetate; H
1
(dd, J = 17.2, 1.5 Hz, 1H), 6.12 (dd, J = 17.2, 10.3 Hz, 1H), 5.82 (dd,
J = 10.3, 1.5 Hz, 1H), 5.36 (t, J = 7.2 Hz, 2H), 4.15 (t, J = 6.9 Hz,
2H), 2.35 (t, J = 7.4 Hz, 2H), 2.04−1.99 (m, 4H), 1.68−1.61 (m,
4H), 1.39−1.25 (m, 26H); 13C{1H} NMR (125 MHz, CDCl3) δ
180.1, 166.5, 130.6, 130.4, 129.4, 128.7, 64.8, 34.2, 29.8, 29.7, 29.6,
29.5, 29.4, 29.3, 29.2, 28.6, 27.3, 27.1, 26.0, 25.7, 24.8; HRMS (FAB)
calcd for (M + H)+ C25H45O4: 409.3312, found: 409.3316.
Photoinduced Decarboxylative Radical Macrolactonization of
8a−c for Preparation of 12b, 12d, and 12f and Reduction of 12b,
12d, and 12f for Preparation of 4 and 6 (V). An aqueous solution
(CH3CN 171 mL, H2O 19 mL) of 22-acryloxy-15-(Z)-docosenoic
acid 8a (0.0792 g, 0.170 mmol, 1 mM), NaOH (0.0068 g, 0.170
mmol, 1 mM), Phen (0.610 g, 3.42 mmol, 20 mM), and DCB (0.440
g, 3.42 mmol, 20 mM) in Pyrex vessels (18 mm × 180 mm) was
purged with argon for 10 min. The mixture was irradiated with a 100
W high-pressure mercury lamp for 6 h. Then, the solvent was
concentrated under reduced pressure. The product was purified by
silica gel column chromatography using hexane/EtOAc = 1:0−30:1 as
the eluent to obtain unsaturated macrocyclic lactone 12b as a
colorless oil (0.0523 g, 0.124 mmol, 73%). Similar photoreactions of
8b (0.0792 g, 0.170 mmol) and 8c (0.0803 g, 0.197 mmol) yielded
the corresponding unsaturated lactones 12d (0.0523 g, 0.124 mmol,
73%) and 12f (0.0503 g, 0.119 mmol, 60%), respectively.
and 13C NMR spectra of 10a, 11a, 7a, 12a, 3, 8a, 12b, 4,
11-bromoundecanyl acetate, 10b, 7b, 12c, 5, 8b, 12d, 6,
11b, 6-bromohexyl acetate, 10c, 7c, 12e, 8c, 12f (PDF)
AUTHOR INFORMATION
Corresponding Author
*E-mail: yyoshimi@u-fukui.ac.jp.
■
ORCID
Yasuharu Yoshimi: 0000-0003-0768-417X
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was partially supported by the Japan Society for the
Promotion of Science (JSPS), Grant-in-Aid no. 17K05779, for
scientific research. Also, funding from the Smithsonian
Tropical Research Institute’s Research Opportunity Fund
supported this research.
15-(Z)-Cyclotetracosanolide 12b. Colorless oil; IR (neat, cm−1)
2925, 2853, 1731; 1H NMR (300 MHz, CDCl3) δ 5.36 (m, 2H), 4.08
(t, J = 6.4 Hz, 2H), 2.31 (t, J = 7.1 Hz, 2H), 2.05−1.99 (m, 4H),
1.63−1.57 (m, 4H), 1.34−1.27 (m, 30H); 13C{1H} NMR (125 MHz,
CDCl3) δ 174.2, 130.6, 130.5, 64.5, 34.6, 32.5, 32.1, 29.8, 29.6, 29.0,
28.9, 28.8, 28.7, 28.6, 27.8, 26.1, 25.0; HRMS (FAB) calcd for (M +
H)+ C24H45O2: 365.3414, found: 365.3412.
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