Divergent Synthesis of Marine Natural Products Siphonodictyal B, Corallidictyals C/D, and Liphagal Based on the Early Presence of an Aldehyde Group Instead of a Late-Stage Introduction

Article abstract of DOI:10.1021/acs.joc.8b00989

An iodine-promoted sunlight-induced olefin Z/E isomerization reaction together with a palladium-catalyzed direct cross-coupling reaction of a drimanal hydrazone and an iodobenzaldehyde, without touching the aromatic aldehyde group, facilitated a divergent and expeditious access to bioactive marine natural products siphonodictyal B, corallidictyals C/D, and liphagal based on the early presence of an aldehyde group instead of a late-stage introduction.

Full text of DOI:10.1021/acs.joc.8b00989

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Note
Divergent Synthesis of Marine Natural Products Siphonodictyal
B, Corallidictyals C/D and Liphagal Based on the Early Presence
of an Aldehyde Group Instead of a Late-Stage Introduction
Jun-Li Wang, Hui-Jing Li, and Yan-Chao Wu
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b00989 • Publication Date (Web): 05 Jun 2018
Downloaded from http://pubs.acs.org on June 5, 2018
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Divergent Synthesis of Marine Natural Products Siphonodictyal B,
Corallidictyals C/D and Liphagal Based on the Early Presence of an
Aldehyde Group Instead of a Late-Stage Introduction
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JunꢀLi Wang,† HuiꢀJing Li,† and YanꢀChao Wu*,†,‡
†School of Marine Science and Technology, Harbin Institute of Technology, Weihai 264209, China.
‡Beijing National Laboratory for Molecular Sciences, ICCAS, Beijing 100190, China.
CHO
CHO
NNHTs
iꢀPrO
OiꢀPr
OiꢀPr
iꢀPrO
iꢀPrO
OiꢀPr
Pd(PPh3)4 (cat.)
K2CO3, xylene,
120 °C, 10 h, 86%
OiꢀPr
I2, sunlight
H
+
hexane/Et2O (2:1)
rt, 2 h, 99%
OiꢀPr
H
H
Z/E = 53:47
E/Z > 99:1
siphonodictyal B
I
CHO
corallidictyals C/D
liphagal
OiꢀPr
1 or 2 steps
ABSTRACT
An iodineꢀpromoted sunlightꢀinduced olefin Z/E isomerization reaction together with a palladiumꢀcatalyzed direct crossꢀcoupling reaction
of a drimanal hydrazone and an iodobenzaldehyde, without touching the aromatic aldehyde group, facilitated a divergent and expeditious
access to bioactive marine natural products siphonodictyal B, corallidictyals C/D and liphagal based on the early presence of an aldehyde
group instead of a lateꢀstage introduction.
The aldehyde group is presented in numerous natural products. In recent decades, aldehydeꢀcontaining marine natural products have
attracted increasing attention due to their special chemical structures and intriguing biological activities.1 Antimicrobial natural product
siphonodictyal B (1, Figure 1) was isolated from the marine sponge Aka coralliphaga (also known as Siphonodictyon coralliphagum).2
Marine natural product liphagal (2), isolated by Andersen in 2006 from Aka coralliphaga,3 exhibits the special “liphagane” carbon skeleton.
Liphagal (2) has significant therapeutic potential in the treatment of autoimmune disorders, cancer, and cardiovascular diseases through
selectively attenuating human phosphoinositideꢀ3ꢀkinase α (PI3Kα) signaling.3,4 Corallidictyal C (3) and corallidictyal D (4), two marine
spirosesquiterpene products isolated from Aka coralliphaga, are potential protein kinase C inhibitors.5
HO
OH
HO
CHO
OH
CHO
OH
CHO
HO
HO
OH
OH
CHO
O
O
O
H
H
H
H
1: siphonodictyal B
2: liphagal
3: corallidictyal C
4: corallidictyal D
Figure 1. Marine natural products 1–4.
The importance of these marine natural products has served to stimulate the continual interest within the synthetic community.3,6ꢀ12 The
pioneering work on the synthesis of natural product liphagal (2) was completed by Andersen, who introduced the aromatic aldehyde
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functionality by treatment of the brominated liphagane precursor 5 (X = Br) with nꢀbutyl lithium in THF and subsequent reaction with
DMF (Scheme 1a).3,6b George7a and AlvarezꢀManzaneda7b independently reported an alternative total synthesis of liphagal (2) in 2010, in
which the aromatic aldehyde group was installed by direct lithiation of the liphagane precursor 5 (X = H) with nꢀbutyl lithium in the
presence of TMEDA followed by quenching with DMF (Scheme 1a). Afterwards, Stoltz,7c Katoh7d and Ferreira7e reported elegant total
syntheses of liphagal (2) respectively by direct introducing the aromatic aldehyde group to the liphagane precursor 5 (X = H) followed by
1–2 conventional steps (Scheme 1a). Chahboun and AlvarezꢀManzaneda reported the first total synthesis of corallidictyal D (4) by
installing spirodihydrobenzofuran 7 (X = H) with an aldehyde group followed by two conventional steps (Scheme 1b).8 Dethe introduced
the aromatic aldehyde functionality of corallidictyal D (4) by the oxidation of benzyl alcohol 5 (X = CH2OH) with IBX in acetonitrile
(Scheme 1b ).9 Recently, George10a and Katoh10c reported impressive total syntheses of siphonodictyal B (1) by introducing the aromatic
aldehyde group to the siphonodictyal B precursor 9 followed by removal of the alkyl ether protecting groups (Scheme 1c). Siphonodictyal
B (1) could be in turn converted to liphagal (2) 10a and corallidictyals C/D (3 and 4) 10b, respectively in one step (Scheme 1c). The aromatic
aldehyde moieties of these natural products were all introduced only after the constructions of their molecular skeletons were completed.
The ability to break this conception would make the natural product syntheses more convergent. However, the goal may be difficult to
achieve as the aromatic aldehyde group is a quite reactive functional group. Herein, we wish to report a direct crossꢀcoupling reaction of
drimanal hydrazone 11 and iodobenzaldehyde 12, which facilitated an expeditious synthesis of siphonodictyal B, corallidictyals C/D and
liphagal (Scheme 1d).
10
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a) Andersen3, 6b and Mehta's6a work (X = Br); George,7a Alvarezꢀ
Manzaneda,7b Stoltz,7c Katoh7d and Ferreira's7e work (X = H):
OR
OR
RO
RO
CHO
X
O
O
1) nꢀBuLi, THF
1ꢀ2 steps
liphagal (2)
2) DMF
H
H
5
6
b) AlvarezꢀManzaneda's8 work (X = H); Dethe's9 work (X = CH2OH):
RO
RO
OR
OR
CHO
2 steps
X
1) nꢀBuLi, THF
2) DMF (X = H)
O
O
corallidictyal D (4)
or 3) IBX, CH3CN
(X = CH2OH)
H
7
H
8
c) George10a, 10b and Katoh's10c work:
CHO
RO
OR
RO
OR
siphonodictyal B (1)
liphagal (2)
OR
OR
nꢀBuLi, THF
then DMF
1ꢀ2 steps
corallidictyals
C/D (3,4)
9
10
H
H
d) This work:
NNHTs
CHO
siphonodictyal B (1)
liphagal (2)
1) Pd(PPh3)4,
RO
OR
OR
K2CO3, xylene
10
+
corallidictyals
C/D (3,4)
2) I2, sunlight
I
H
11
12
Scheme 1. Syntheses of marine natural products 1–4.
Our retrosynthesis of marine natural products
1–
4
is outlined in Scheme 2. Liphagal (2), corallidictyal C (3) and corallidictyal D (4) were
thought to be synthesized from siphonodictyal B (
1
), which could be prepared from sesquiterpene aldehyde 10 by removal of the alkyl
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ether protecting groups. Intermediate 10 was planned to be assembled by the crossꢀcoupling reaction between drimanal hydrazone 11 and
iodobenzaldehyde 12. Compounds 11 and 12 were thought to be prepared from sclareolide (13) and 3,4ꢀdihydroxybenzaldehyde (14),
respectively (Scheme 2).
6
7
8
9
CHO
HO
OH
OH
liphagal (2)
10
11
12
13
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corallidictyal C (3)
corallidictyal D (4)
tandem
reaction
OR deprotection
reaction
H
siphonodictyal B (1)
O
O
NNHTs
CHO
RO
OR
OR
11
13
H
H
+
crossꢀcoupling
reaction
CHO
OHC
OH
OH
RO
I
OR
OR
H
10
12
14
Scheme 2. Retrosynthetic analysis.
Synthesis of drimanal hydrazone 11 is depicted in Scheme 3. The commercially available sclareolide (13) was converted to enol 16 in
four conventional steps with 80% overall yield.13 Ozonolysis of 16 followed by quenching with NaBH4 afforded 1,2ꢀdecalindiol 17 in 98%
yield. Rearrangement of 17 in the presence of BF3•Et2O provided drimanal 18 in 90% yield.11h WittigꢀHorner reaction14 of 18 with
Ph2P(O)CH2OCH3 gave allyl ether 19 in 75% yield, which underwent a hydrolysis with aqueous hydrochloric acid to give drimanal
aldehydes 20a and 20b in 18% and 72% yields, respectively. Condensation of 20b with
hydrazone 11 in 95% yield (Scheme 3).
pꢀtoluenesulfonyl hydrazide afforded drimanal
O
I
O
OH
OCHO
2 steps, 96%
ref 13a,b,d
2 steps, 83%
ref 13c,e
H
H
H
13
15
16
OH
O
O
BF3•Et2O
(2.0 equiv)
O3, CH2Cl2,
ꢀ78 oC, 20 min
OH
Ph2PCH2OMe
n-BuLi, ꢀ78 oC to rt,
then NaBH4, rt,
1 h, 98%
CH2Cl2, rt, 0.5 h
90%
THF, 1 h, 75%
H
H
17
18
O
O
OMe
NNHTs
p-TsNH2NH2
aq 2 M HCl
rt, 10 min
+
MeOH, rt, 5 h
95%
H
H
H
H
19
20a (18%) 20b (72%)
11
Scheme 3. Synthesis of drimanal hydrazone 11
.
Synthesis of iodobenzaldehyde 12a is shown in Scheme 4. Treatment of a DMF solution of 3,4ꢀdihydroxybenzaldehyde (14) with
2ꢀiodopropane and K2CO3 afforded ether 21 in 89% yield.15 Oxidation of aldehyde 21 with 30% H2O2 in the presence of sulfuric acid at
room temperature, and the concurrent transesterification reaction of the in situ generated ester with methanol were achieved in one pot to
give phenol 22 in 85% yield.15
ether 23 in 70% yield. Lithiation of 23 with
O
ꢀisopropylation of phenol 22 in the presence of tetrabutylammonium iodide (TBAI) furnished aromatic
n
ꢀbutyl lithium followed by quenching with DMF gave benzaldehyde 24, which underwent a
Bi(OTf)3ꢀcatalyzed electrophilic aromatic iodination to afford iodobenzaldehyde 12a in 78% yield (Scheme 4).
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OH
OiꢀPr
OiꢀPr
OiꢀPr
OH
OiꢀPr
i-PrI, K2CO3, DMF
30% H2O2, H2SO4
MeOH, rt, 7 h, 85%
70 oC, 12 h, 89%
6
7
8
9
CHO
CHO
OH
14
21
22
OiꢀPr
OiꢀPr
OiꢀPr
OiꢀPr
OiꢀPr
nꢀBuLi, THF, 0 oC, 1 h
i-PrI, TBAI, K2CO3, DMF
78 oC, 12 h, 70%
then DMF, 10 min, 80%
CHO
10
11
12
13
14
15
16
17
18
19
20
21
22
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OiꢀPr
23
24
OiꢀPr
OiꢀPr
NIS, Bi(OTf)3, MeCN
rt, overnight, 78%
I
CHO
OiꢀPr
12a
Scheme 4. Synthesis of iodobenzaldehyde 12a
.
Synthesis of siphonodictyal B (
aldehydes,16a−f ketones16g and esters16h is well known, which was even used for the synthesis of 8ꢀepipuupehedione,16d a natural product
stereoisomer with a molecular structure similar to that of siphonodictyal B ( ). Thus, how to suppress the competitive reaction of a
ꢀtosylhydrazone with the benzaldehyde moiety of an iodobenzaldehyde becomes a high priority for the highly selective crossꢀcoupling
1) and liphagal (2) is shown in Scheme 5. The facile reaction of Nꢀtosylhydrazones with aromatic
1
N
reaction of the Nꢀtosylhydrazone with the iodobenzene moiety of the iodobenzaldehyde. To the best of our knowledge, the crossꢀcoupling
reaction of drimanal hydrazones and iodobenzaldehyde derivatives with an intact preservation of aromatic aldehyde moieties is still a
challenge to date. This demanding task was carried out by us due to its synthetic importance as well as our curiosity about it.17 The direct
crossꢀcoupling reaction of drimanal hydrazone 11 and iodobenzaldehyde 12a, without touching the benzaldehyde moiety, has been
accomplished. Indeed, the treatment of 11 and 12a in the presence of Pd(PPh3)4 (10 mol%) and K2CO3 in xylene at 120 °C for 10 h
afforded vinyl benzaldehydes (ZE)-10a (Z/E
= 53:47) in 86% yield.18 The isopropyl ether protecting groups were used to shield the
benzaldehyde moiety of iodobenzaldehyde 12a from the attack of drimanal hydrazone 11. Decreasing yields were observed with primary
alkyl ether protecting groups in comparison to secondary alkyl ether protecting groups, indicating that the steric factor of the ether affects
the selective crossꢀcoupling reaction. For example, when methyl ether protecting groups were used instead of isopropyl ether protecting
groups, the reaction became relatively complex and the yield of the crossꢀcoupling product was decreased down to 72% yield (Z/E =
55:45).
CHO
iꢀPrO
iꢀPrO
OiꢀPr
NNHTs
+
OiꢀPr
OiꢀPr
OiꢀPr
Pd(PPh3)4 (10 mol %)
K2CO3, xylene, 120 °C
10 h, 86%
I
CHO
12a
CHO
H
H
11
(ZE)-10a
CHO
iꢀPrO
OiꢀPr
OiꢀPr
iꢀPrO
iꢀPrO
OiꢀPr
I2, sunlight
isomerization
hexane/Et2O (2:1)
rt, 2 h, 99%
I
I
H
H
25
26
OH
CHO
CHO
HO
iꢀPrO
OiꢀPr
OiꢀPr
HO
OH
OH
CHO
O
BCl3
1 step
CH2Cl2, 0 o
3 h, 76%
C
42%
ref 10a
H
H
H
(E)-10a
1
2
Scheme 5. Synthesis of siphonodictyal B (1) and liphagal (2).
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The conversion of alkene (Z)-10a to alkene (E)-10a was next investigated, and the representative results are summarized in the Table 1.
Irradiation of alkenes (ZE)-10a
hours afforded alkenes (ZE)-10a
thermodynamically more stable alkene (E)-10a (entry 1). With the addition of benzanthrone or (diacetoxyiodo)benzene (PIDA) to the
reaction system under similar reaction conditions, no obviously better results were obtained (entries 1 3). In contrast, when iodine (I2) was
(Z
/
E
= 53:47) under direct sunlight in a coꢀsolvent of hexane/Et2O (v/v, 2:1) at room temperature for 6
(Z/E = 49:51) in 99% yield, in which only small part of alkene (Z)-10a was converted to the
8
9
−
10
11
12
13
14
15
16
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used as a promoter, nearly all the alkene (Z/E)-10a was converted to the alkene (E)-10a within a shorter reaction time (entries 1 and 4). The
photoisomerization reaction of (Z)-10a to (E)-10a with a 150 W mercury lamp or a 200 W flood lamp was not as effective as that with
direct sunlight (entries 4−6). The olefin Z/E isomerization reaction did not take place at all in the dark (entry 7). Sunlight has a broad
spectrum, which might be essential for providing the required light wavelength for this transformation. A sunlight intensity of no less than
300 Lux was found to be enough for the smooth photoisomerization reaction. Thus, sunlight might have been already used consciously or
unconsciously for the iodineꢀpromoted olefin
Z
/
E
isomerization. 19 Further parameter optimization identified the coꢀsolvent of hexane/Et2O
(v/v, 2:1) as the most effective reaction media (entries 4 and 8
−13).
Table 1. Survey of Conditions for the Z/E Isomerization of Olefin 10a a
CHO
CHO
CHO
iꢀPrO
δH 6.18
H
OiꢀPr
OiꢀPr
iꢀPrO
iꢀPrO
OiꢀPr
iꢀPrO
iꢀPrO
OiꢀPr
δH 5.86
H
conditions
+
H
H
H
(ZE)-10a (Z/E = 53:47)
(Z)-10a
(E)-10a
time Z/E b
entry
promoter
light
solvent
ꢀꢀ
sunlight
sunlight
sunlight
sunlight
Hg lampc
hexane/Et2O (2:1) 6 h 49:51
hexane/Et2O (2:1) 6 h 46:54
hexane/Et2O (2:1) 6 h 47:53
1
2
3
4
5
benzanthrone
PIDA
I2
I2
hexane/Et2O (2:1) 2 h
1:99
hexane/Et2O (2:1) 6 h 25:72
I2
flood lampd hexane/Et2O (2:1) 6 h 45:55
6
I2
ꢀꢀ
hexane/Et2O (2:1) 6 h 53:47
7
I2
I2
I2
I2
I2
I2
sunlight
sunlight
sunlight
sunlight
sunlight
sunlight
benzene
hexane
THF
2 h 47:53
2 h 24:76
2 h 35:65
2 h 23:77
8
9
10
11
12
13
Et2O
hexane/Et2O (1:1) 2 h
hexane/Et2O (3:1) 2 h
6:94
3:97
aGeneral conditions: (ZE)-10a (1.0 equiv.,
hours, all yields were nearly 99%. bThe ratio of
Z/
E
= 53/47) and promoter (2.0 equiv.) in solvent (c = 0.04 M) at room temperature for 2 or 6
was detected by 1H NMR spectrum. c150 W. d200 W.
Z/E
According to the literature,19 a possible reaction mechanism is illustrated in Scheme 5. Iodine radical is easily formed from I2 under
direct sunlight. Attachment of an iodine radical to (ZE)-10a generated radical 25, which underwent an internal rotation to provide a
relatively less sterically hindered radical 26. Detachment of the iodine radical from 26 afforded (E)-10a. As the olefin
reaction did not take place in the dark (Table 1, entry 7), herein the potential reaction mechanism involved the formation of an iodonium
ion was not proposed. Removal of the isopropyl ether protecting groups of (E)-10a in the presence of BCl3 provided siphonodictyal B (
in 76% yield. Following George’s procedure,10a treatment of siphonodictyal B (
) with ꢀCPBA at 0 °C and subsequent reaction with TFA
Z/E isomerization
1
)
1
m
afforded liphagal (
2
) in 42% yield (Scheme 5). The spectroscopic and spectrometric data (1H NMR, 13C NMR, [α]D and HRMS) of the
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synthetic molecules are identical to those of natural siphonodictyal B and liphagal.2,3,6,7,10
As shown in Scheme 6, the treatment of siphonodictyal B (
oxacyclization conditions8 afforded the marine natural products corallidictyal C (
diastereomers in a ratio of 1:1.2, similar to the 1:1.5 ratio of corallidictyal C ( ) to corallidictyal D (
Chahboun and AlvarezꢀManzaneda,8 the above oxacyclization reaction took place through an intermediate carbocation 26 that was formed
from the tandem reaction of NIS, PPh3, one phenolic hydroxyl group, and the C9ꢀC15 double bond of siphonodictyal B ( , Scheme 6), in
which the phenolic hydroxyl group acted as a nucleophile and a proton donor simultaneously. Activated by the phosphoniun ion +PPh3I, the
phenolic hydroxyl group transferred the proton to the C15 and thus the ꢀnucleophilic attacks at the C9 position took place from either the
1
) with NIS and PPh3 in DCM under the Chahboun and AlvarezꢀManzaneda
) and corallidictyal D ( ) as an inseparable mixture of
) found in nature.5 As mentioned by
3
4
3
4
1
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
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O
αꢀface or the βꢀface produced the intermediate carbocation 28, which formed corallidictyal D (4) and corallidictyal C (3), respectively
(Scheme 6).
I
CHO
δ+
Ph3P
HO
OH
OH
CHO
δ+
O
OH
OH
H
IPPh3
H
1
27
O
H
NIS, PPh3
DCM, rt
76%
N
NIS
+
PPh3
O
HO
HO
HO
OH
CHO
OH
OH
CHO
PPh3
CHO
O
O
O
O
I
N
H
H
H
O
3
4
28
Scheme 6. Synthesis of corallidictyals C/D (
In summary, we described a palladiumꢀcatalyzed direct crossꢀcoupling reaction of an iodobenzaldehyde and a drimanal hydrazine,
without touching the aromatic aldehyde group, and an iodineꢀpromoted sunlightꢀinduced isomerization reaction of a sesquiterpene
3 and 4).
Z/E
alkene, which are employed to a convergent and concise synthesis of marine natural products siphonodictyal B, corallidictyals C/D and
liphagal from readily available and inexpensive starting materials. For the first time the aromatic aldehyde moieties of these marine natural
products were introduced before the constructions of their molecular skeletons, which could make the natural product synthesis more
convergent. Our work indicated that the concept of introducing an aromatic aldehyde group only at the late stage of the natural product
synthesis might be changeable.
Experimental
General experimental methods.
Common reagents and materials were purchased from commercial sources and were used without further purification. All
experiments were carried out under an argon atmosphere in flameꢀdried glassware using standard inert techniques for introducing
reagents and solvents unless otherwise noted. TLC plates were visualized by exposure to ultra violet light (UV). IR spectra were
recorded by using an Electrothemal Nicolet 380 spectrometer. Highꢀresolution mass spectra (HRMS) were recorded by using an
Electrothemal LTQꢀOrbitrap mass spectrometer. Melting points were measured by using a Gongyi Xꢀ5 microscopy digital
1
melting point apparatus and are uncorrected. H NMR and 13C NMR spectra were obtained by using a Bruker Avance III 400
MHz NMR spectrometer.
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Compound 15. To a solution of (+)ꢀsclareolide (13, 1.2 g, 4.8 mmol) in 40 mL of CH2Cl2 at −78 °C was added DIBALꢀH (1.5
M in toluene, 3.9 mL, 5.8 mmol) dropwise over 10 min by syringe along the wall of the flask. The resulting mixture was stirred
at −78 °C for 1 h, added slowly with a solution of aqueous hydrochloric acid (2 M, 50 mL), warmed up to room temperature, and
extracted with CH2Cl2 (3 × 50 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure to afford lactol (1.17 g, 97%) as a white solid that was used immediately in the next step.13c A solution of lactol
(1.2 g, 4.8 mmol) in 50 mL of benzene was treated with PIDA (2.2 g, 6.7 mmol, 1.4 equiv) and I2 (1.7 g, 5.8 mmol). The purple
reaction mixture was stirred at 70 °C with simultaneous irradiation using a 150ꢀwatt flood lamp for 1 h. The reaction mixture was
cooled down to room temperature, diluted with water, and extracted with EtOAc (3 × 30 mL). The organic layers were
combined, washed with saturated aqueous Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The
10
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15
16
17
18
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49
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residue was immediately diluted with anhydrous MeOH, swirled, and cooled in a −78
°C bath. The resulting white solid 15 (1.5
g, 86%) was collected via filtration: mp 54–56 °C; [α]ꢁꢀꢂ = −28 (
c
= 1 g/100 mL, CHCl3); HRMS m
/
z calcd for C16H28O2I
1
[M+H]+ 379.1128, found 379.1130; IR (film) νmax 2919, 2840, 1703, 1393, 1203, 1168, 1146, 1122, 911, 769 cmꢀ1; H NMR
(400 MHz, CDCl3)
δ
8.01 (s, 1H), 3.36 (d,
J
= 10.6 Hz, 1H), 3.11–3.14 (m, 1H), 2.56 (d,
J
= 12.2 Hz, 1H), 2.46 (s, 1H), 1.85–
= 12.3 Hz, 1H), 0.87 (s, 3H), 0.85 (s,
δ 160.2, 88.3, 62.1, 55.2, 41.5, 40.8, 39.6, 38.9, 33.2, 33.1, 21.4, 20.3, 19.7, 18.3,
1.90 (m, 2H), 1.70 (d,
3H), 0.78 (s, 3H); 13C NMR (100 MHz, CDCl3)
J
= 13.8 Hz, 1H), 1.46–1.62 (m, 5H), 1.18–1.41 (m, 4H), 1.05 (d,
J
14.8, ꢀ3.0.
Enol 16. A solution of compound 15 (1.5 g, 3.9 mmol) in anhydrous pyridine (20 mL) at room temperature was treated with
silver (I) fluoride (1.0 g, 84.0 mmol). The reaction flask was wrapped with aluminium foil to protect from light. The reaction
mixture was stirred at room temperature overnight, diluted with Et2O (50 mL), and filtered through a celite pad to remove the
dark grey solid. The filter cake was rinsed with Et2O (50 mL). The organic layers were combined, washed with saturated aqueous
NaHCO3 and saturated aqueous Na2S2O3 (v/v, 5:1, 50 mL), then washed with brine (150 mL), dried over Na2SO4, filtered, and
concentrated under reduced pressure to afford an unstable pale yellow syrup (0.95 g, 98%), which was used immediately in the
next step.13d A solution of the above compound (800 mg, 3.2 mmol) in 60 mL of MeOH was treated with K2CO3 (530 mg, 3.8
mmol) at 0 °C. The resulting mixture was warmed up to room temperature and stirred at this temperature for 2 h, extracted with
Et2O (3 × 40 mL), washed with H2O (100 mL), and backꢀextracted with Et2O (100 mL). The organic layers were combined,
dried over Na2SO4, filtered, and concentrated under reduced pressure to afford enol 16 (700 mg, 98%) as an ivoryꢀwhite
solid:13a,b [α]ꢀꢁꢂ = +9 (
c
= 0.97 g/100 mL, CHCl3); HRMS m
/
z calcd for C15H26ONa [M+Na]+ 245.1876, found 245.1880; IR
1
(film) νmax 3018, 2927, 2850, 1769, 1215, 1081, 1011, 914, 757, 668 cmꢀ1; H NMR (400 MHz, CDCl3)
δ
J
5.22 (s, 1H), 4.84 (s,
= 13.5 Hz, 1H), 1.09
1H), 2.01 (d,
(s, 3H), 1.98 (d,
39.8, 38.8, 33.6, 33.1, 30.4, 22.2, 21.5, 20.0, 18.9.
1,2ꢀDecalindiol 17. To a solution of enol 16 (200 mg, 0.90 mmol) in CH2Cl2 (2 mL) was bubbled with O3 at −78
J
= 9.7 Hz, 1H), 1.79 (d,
J = 12.7 Hz, 1H), 1.63–1.73 (m, 2H), 1.31–1.53 (m, 6H), 1.15 (d,
J
= 10.7 Hz, 1H), 0.87 (s, 6H), 0.85 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 166.3, 103.6, 73.1, 53.3, 43.9, 41.6,
°
C until the blue color
appeared. The resulting reaction mixture was bubbled with N2 for 10 min, added NaBH4 (68 mg, 1.8 mmol), warmed up to room
temperature and stirred at this temperature for 1 h, quenched with a solution of saturated aqueous NH4Cl (5 mL), and extracted with
CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under reduced pressure to afford
o
1,2ꢀdecalindiol 17 (198 mg, 98%) as a white solid: mp 102–104 C; [α]ꢁꢃꢂ = +1.3 (
c
= 1 g/100 mL, CHCl3); HRMS m/z calcd for
1
C14H26O2Na [M+Na]+ 249.1826, found 249.1825; IR (film) νmax 3347, 2925, 2852, 1079, 1062, 1030, 996, 979, 935, 912, 672 cm–1; H
NMR (400 MHz, CDCl3)
Hz, 1H), 1.21 (s, 3H), 1.13 (dd,
86.8, 73.9, 53.2, 41.8, 40.0, 39.3, 38.6, 33.1, 32.9, 22.2, 21.5, 19.8, 18.2, 13.6.
δ
3.12 (s, 1H), 2.25 (bs, 2H), 1.78–1.86 (m, 2H), 1.61 (d,
J = 13.3 Hz, 2H), 1.38–1.46 (m, 4H), 1.27 (d, J = 12.2
J
= 3.5, 13.5 Hz, 1H), 0.98 (d, δ
J
= 10.7 Hz, 1H), 0.87 (s, 6H), 0.81 (s, 3H); 13C NMR (100 MHz, CDCl3)
Drimanal 18. To a solution of 1,2ꢀdecalindiol 17 (50 mg, 0.22 mmol) in CH2Cl2 (1 mL), BF3•Et2O (58 ꢁL, 0.44 mmol) was added
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dropwise at 0 °C. The resulting mixture was warmed up to room temperature and stirred at this temperature for 30 min, diluted with brine
(5 mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 20:1) to give drimanal 18 (42
mg, 90%) as a colorless oil: [α]ꢁꢃꢂ = –23 (
c
0.44 g/100 mL, CHCl3); HRMS m/z calcd for C14H25O [M+H]+ 209.1900, found 209.1904; IR
1
(film) νmax 2928, 2868, 1706, 1459, 1389, 1133, 1081, 991 cm–1; H NMR (400 MHz, CDCl3)
δ
2.64–2.73 (m, 1H), 2.07–2.13 (m, 1H),
= 6.4 Hz,
216.8, 54.2, 48.8, 41.5, 39.9, 35.7, 34.2, 33.2, 33.0, 22.0, 21.3, 18.7, 18.1,
1.69–1.75 (m, 2H), 1.53–1.60 (m, 4H), 1.40 (d,
J = 13.5 Hz, 1H), 1.18–1.28 (m, 2H), 1.14 (s, 3H), 1.08–1.10 (m, 1H), 0.98 (d, J
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11
12
13
14
15
16
17
18
19
20
21
22
23
24
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60
3H), 0.93 (s, 3H), 0.88 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ
15.0.
Allyl ether 19. To a stirred suspension of (methoxymethyl)ꢀdiphenylphosphine oxide (24.6 mg, 0.1 mmol) in dry THF (2 mL) under N2
atmosphere was added a solution of ꢀBuLi (2.5 M in THF, 4.8 uL, 0.12 mmol) at –78 C. The resulting mixture was stirred at –78 C for
n
°
°
30 min, added drimanal 18 (25 mg, 0.12 mmol), warmed up to room temperature and stirred at this temperature for 1 h, quenched with
water (5 mL), and extracted with EtOAc (3 × 10 mL). The combined organic layers were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum ether/EtOAc = 30:1) to afford allyl
ether 19 (25 mg, 75%) as a colorless oil: Rf = 0.8 (Hexane/EtOAc = 30:1); HRMS m/z calcd for C16H29O [M+H]+ 237.2213, found
237.2216; IR (film) νmax 3417, 2928, 2867, 2844, 2359, 1652, 1459, 1372, 1233, 1148, 1052, 1024, 1003, 823, 759, 633, 621 cm–1; H
1
NMR (400 MHz, DMSOꢀd6
3H), 1.23 (s, 1H), 1.09 1.17 (m, 2H), 1.06 (s, 3H), 1.03 (d,
(100 MHz, DMSOꢀd6 138.0, 127.5, 59.3, 53.2, 41.7, 40.4, 38.6, 37.4, 33.3 (d), 31.0, 22.0, 21.7, 20.7, 19.6, 18.5.
)
δ
5.36 (s, 1H), 3.39 (s, 3H), 2.01 (d,
J
= 14.1 Hz, 1H), 1.76
–1.90 (m, 2H), 1.53–1.62 (m, 2H), 1.31–1.40 (m,
–
J
= 2.5 Hz, 1H), 0.89 (d,
J
= 6.4 Hz, 3H), 0.81 (s, 3H), 0.79 (s, 3H); 13C NMR
)
δ
Drimanal aldehydes 20a/20b. To the solution of allyl ether 19 (20.0 mg, 0.08 mmol) in CH2Cl2 (3 mL) under N2 atmosphere was added
aqueous HCl (2.0 M, 60 uL, 0.16 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 10 min,
quenched with saturated aqueous NaHCO3 (7 mL), and extracted with CH2Cl2 (3 × 10 mL). The combined organic layers were dried over
Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash chromatography on silica gel (petroleum
ether/EtOAc = 20:1) to give drimanal aldehydes 20a (3 mg, 18%) and 20b (13 mg, 72%) as a colorless oil: Data for 20b
(Hexane/EtOAc = 30:1); HRMS m/z calcd for C15H27O [M+H]+ 223.2056, found 223.2058; IR (film) νmax 2927, 2869, 2847, 2363, 1715,
1459, 1388, 908, 733 cm–1; 1H NMR (400 MHz, CDCl3)
9.69 (d, = 4.6 Hz, 1H), 1.98–2.08 (m, 1H), 1.72–1.86 (m, 2H) 1.45–1.54 (m,
, Rf = 0.6
δ
J
2H), 1.29–1.38 (m, 3H), 1.02–1.17 (m, 2H), 1.04 (s, 3H), 0.85–1.01 (m, 3H), 0.81 (s, 3H), 0.79 (s, 3H),0.73 (d,
(100 MHz, CDCl3) δ 207.9, 70.3, 54.1, 41.8, 40.2, 38.1, 35.4, 33.4, 33.2, 27.5, 21.8, 21.5, 20.6, 18.3, 15.9.
J
= 6.3 Hz, 3H); 13C NMR
Drimanal hydrazone 11. To a solution of drimanal aldehyde 20b (1.0 g, 4.5 mmol) in MeOH (20 mL) was added pꢀtoluenesulfonyl
hydrazide (1.1 g, 5.4 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 5 h, and concentrated
under reduced pressure. The crude product was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 3:1) to
afford drimanal hydrazone 11 a white solid (1.6 g, 95%): mp = 54–56 °C; Rf = 0.5 (Hexane/EtOAc = 3:1); HRMS m/z calcd for
C22H34N2NaO2S [M+Na]+ 413.2233, found 413.2237; IR (film)
669, 648 cm–1; 1H NMR (400 MHz, CDCl3)
8.34 (s, 1H), 7.80 (d,
(s, 3H), 1.75 (dd, = 12.9, 2.7 Hz, 1H), 1.60 (m, 1H), 1.40–1.53 (m, 3H), 1.04–1.32 (m, 7H), 0.84–0.94 (m, 4H), 0.79 (s, 3H), 0.76 (s, 3H),
ν
max 3197, 2925, 1598, 1456, 1368, 1323, 1166, 1093, 1019, 907, 812, 731,
δ
J
= 8.2 Hz, 2H), 7.25 (d, = 8.2 Hz, 2H), 6.99 (d, = 8.5 Hz, 1H), 2.38
J
J
J
0.74 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 155.5, 143.7, 135.0, 129.4, 127.9, 60.8, 54.0, 41.8, 39.7, 37.2, 35.7, 33.2, 33.0, 29.4, 26.8,
21.6, 21.4, 20.5, 18.3, 15.3.
Ether 21. To a solution of 14 (5.0 g, 36.2 mmol) in DMF (150 mL) was added sequentially K2CO3 (11.0 g, 79.7 mmol) and
2ꢀiodopropane (13.6 g, 79.7 mmol) at room temperature. The resulting reaction mixture was stirred at 70 °C for 12 h, cooled down to room
temperature, and diluted with EtOAc (50 mL) and water (100 mL). The organic layer was separated, and the aqueous layer was extracted
with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The
residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 6:1) to give ether 21 as a colorless oil (7.2 g,
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89%): Rf = 0. 5 (Hexane/EtOAc = 6:1); HRMS m/z calcd for C13H19O3 [M+H]+ 223.1329, found 223.1329; IR (film)
ν
max 2977, 2930, 1686,
9.75 (s,
= 6.2 Hz, 6H), 1.28 (d,
190.5, 154.6, 148.6, 129.7, 126.2, 115.8, 114.5, 72.1, 71.4, 21.8, 21.7.
1
1593, 1579, 1500, 1466, 1432, 1384, 1262, 1235, 1104, 1001, 987, 946, 909, 812, 929, 650 cm–1; H NMR (400 MHz, CDCl3)
δ
1H), 7.37 (s, 2H), 6.91 (d,
J
= 8.5 Hz, 1H), 4.56 (quint,
J
= 5.9 Hz, 1H), 4.45 (quint,
J
= 5.9 Hz, 1H), 1.31 (d,
J
J =
6.2 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ
Phenol 22. To a solution of aldehyde 21 (7.0 g, 31.5 mmol) in MeOH (100 mL) was added dropwise H2SO4 (98%, 2.6 g, 26.1 mmol) at
room temperature, and then added 30% H2O2 (25.2 mL, 242.5 mmol) in one portion. The resulting reaction mixture was stirred for at room
temperature 7 h, quenched with saturated aqueous NaHCO3 (20 mL), and extracted with EtOAc (3 × 50 mL). The combined organic
extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 3:1) to afford phenol 22 as a yellow oil (5.6 g, 85%): Rf = 0.3 (Hexane/EtOAc =
6:1); HRMS m/z calcd for C12H19O3 [M+H]+ 211.1329, found 211.1329; IR (film) νmax 3372, 2975, 2931, 1601, 1504, 1455, 1383, 1372,
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
1290, 1212, 1180, 994, 918, 847, 731 cm–1; 1H NMR (400 MHz, CDCl3)
8.6, 2.6 Hz, 1H), 5.91 (br, 1H), 4.39 (quint, = 6.0 Hz, 1H), 4.28 (quint,
CDCl3)
δ
J
6.77 (d,
J
= 8.6 Hz, 1H), 6.41 (d,
J = 2.6 Hz, 1H), 6.30 (dd, J =
J
= 6.1 Hz, 1H), 1.27 (d,
J
= 6.1 Hz, 12H); 13C NMR (100 MHz,
δ
151.5, 150.3, 141.6 (d), 121.0, 107.0, 104.5, 73.9, 71.2, 22.1, 21.9.
Aromatic ether 23. To a solution of 22 (5.0 g, 23.7 mmol) in DMF (100 mL) was added sequentially K2CO3 (3.6 g, 26.2 mmol),
2ꢀiodopropane (4.5 g, 26.2 mmol) and TBAI (0.7 g, 1.9 mmol) at room temperature. The resulting reaction mixture was stirred at 78 °C for
12 h, cooled down to room temperature, diluted with EtOAc (50 mL) and water (100 mL). The organic layer was separated, and the
aqueous layer was extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated
under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 12:1) to give
aromatic ether 23 as a colorless oil (4.2 g, 70%): Rf = 0.8 (Hexane/EtOAc = 12:1); HRMS m/z calcd for C15H25O3 [M+H]+ 253.1798, found
253.1796; IR (film)
732 cm–1; 1H NMR (400 MHz, CDCl3)
1H), 4.41 (quint, = 6.1 Hz, 1H), 4.29 (quint,
120.6, 107.4, 106.6, 73.3, 71.4, 70.3, 22.2, 22.1, 22.0.
Benzaldehyde 24. To a solution of aromatic ether 23 (4.0 g, 15.8 mmol) in anhydrous THF (50 mL) was added
ν
max 2975, 2930, 1605, 1584, 1500, 1466, 1382, 1371, 1334, 1298, 1257, 1215, 1181, 1163, 1111, 1005, 953, 908, 854,
6.82 (d, = 8.7 Hz, 1H), 6.49 (d, = 1.3 Hz, 1H), 6.39 (d, = 8.7 Hz, 1H), 4.47 (quint, = 6.1 Hz,
= 6.1 Hz, 1H), 1.28 153.2, 150.3, 142.6,
1.33 (m, 18H); 13C NMR (100 MHz, CDCl3)
δ
J
J
J
J
J
J
–
δ
n
ꢀBuLi (2.5 M in toluene,
31.6 mL, 79.0 mmol) at 0 °C, and stirred at this temperature for 1 h. The resulting reaction mixture was added DMF (11.6 g, 158 mmol)
dropwise, stirred at 0 °C for 10 min, quenched with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 × 50 mL). The
combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc = 6:1) to afford benzaldehyde 24 as a yellow oil (3.6 g, 80%): Rf = 0.5
(Hexane/EtOAc = 5:1); HRMS m/z calcd for C16H25O4 [M+H]+ 281.1747, found 281.1749; IR (film) νmax 2976, 2929, 2357, 1693, 1578,
1473, 1403, 1382, 1372, 1334, 1251, 1219, 1137, 1107, 1063, 910, 805, 732 cm–1; 1H NMR (400 MHz, CDCl3)
= 8.8 Hz, 1H), 6.61 (d, = 9.0 Hz, 1H), 4.62 (quint, = 6.1 Hz, 1H), 4.49 (quint, = 6.1 Hz, 1H), 4.42 (quint,
(m, 18H); 13C NMR (100 MHz, CDCl3)
δ
J
10.45 (s, 1H), 7.043 (d,
J
J
J
J
= 6.1 Hz, 1H), 1.25–1.36
δ
190.3, 154.2, 151.4, 144.9, 124.4, 122.3, 109.8, 76.3, 72.6, 72.1, 22.2, 22.1, 21.9.
Iodobenzaldehyde 12a. To a solution of benzaldehyde 24 (3.5 g, 12.5 mmol) in MeCN (60 mL) was added subsequently NIS (2.4 g,
13.7 mmol) and Bi(OTf)3 (1.6 g, 2.5 mmol) at 0 °C. The resulting reaction mixture was stirred at room temperature overnight, quenched
with saturated aqueous NH4Cl (50 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4,
filtered, and concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum
ether/EtOAc = 20:1) to give iodobenzaldehyde 12a as a yellow oil (3.74 g, 78%): Rf = 0.7 (Hexane/EtOAc = 6:1); HRMS m/z calcd for
C16H24IO4 [M+H]+ 407.0714, found 407.0718; IR (film) νmax 2976, 2930, 1693, 1551, 1450, 1399, 1382, 1371, 1332, 1285, 1237, 1215,
1175, 1101, 992, 909, 849, 815, 730, 648 cm–1; 1H NMR (400 MHz, CDCl3)
(quint, = 6.1 Hz, 1H), 4.38 (quint,
= 6.1 Hz, 1H), 1.24–1.38 (m, 18H); 13C NMR (100 MHz, CDCl3)
125.9, 86.3, 78.7, 76.6, 72.3, 22.2, 22.1, 22.0.
δ
10.32 (s, 1H), 7.49 (s, 1H), 4.63 (quint,
J = 6.1 Hz, 1H), 4.47
J
J
δ
189.8, 151.9, 151.3, 148.0, 131.1,
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Vinyl benzaldehydes (ZE)-10a. A mixture of drimanal hydrazone 11 (200 mg, 0.51 mmol), iodobenzaldehyde 12a (173 mg, 0.42 mmol),
K2CO3 (265 mg, 1.92 mmol) and Pd(PPh3)4 (49 mg, 0.04 mmol) in xylene (20 mL) was stirred at 120 °C under N2 atmosphere for 10 h. The
resulting reaction mixture was cooled down to room temperature, diluted with water (30 mL), and extracted with EtOAc (3 × 20 mL). The
combined organic extracts were dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash
column chromatography on silica gel (petroleum ether/EtOAc = 15:1) to afford a mixture of vinyl benzaldehydes (ZE)ꢀ10a as a colorless
liquid (177 mg, 86%).
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Vinyl benzaldehyde (E)-10a. To a solution of vinyl benzaldehydes (ZE)ꢀ10a (50 mg, 0.11 mmol) in a coꢀsolvent of hexane (2 mL) and
ethyl ether (1mL) was added iodine (28 mg, 0.11 mmol), and then stirred in sunlight under N2 atmosphere at room temperature for 2 h. The
resulting reaction mixture was diluted with water (30 mL), and extracted with EtOAc (3 × 10 mL). The combined organic extracts were
washed with Na2S2O3, dried over Na2SO4, filtered, and concentrated under reduced pressure. The residue was purified by flash column
chromatography on silica gel (petroleum ether/EtOAc = 15:1) to give vinyl benzaldehyde (E)
0.8 (Hexane/EtOAc = 10:1): HRMS m/z calcd for C31H49O4 [M+H]+ 485.3631, found 485.3636; IR (film) νmax 2971, 2926, 2869, 2358,
2341, 1696, 1564, 1456, 1380, 1332, 1252, 1224, 1137, 1104, 1027, 916, 733, 667 cm–1; 1H NMR (400 MHz, CDCl3)
10.43 (s, 1H), 6.89
(s, 1H), 6.19 (s, 1H), 4.58 (septet, = 6.2 Hz, 1H), 4.47 (septet, = 6.0 Hz, 1H), 4.31 (septet, = 6.2 Hz, 1H), 2.68– 2.60 (m, 1H), 1.81–
1.60 (m, 4H), 1.57–1.33 (m, 7H), 1.31 (d, = 6.1 Hz, 6H), 1.29 (d, = 6.0 Hz, 3H), 1.25 (d, = 6.1 Hz, 3H), 1.22 (d,
(d, = 6.1 Hz, 3H), 1.17 (s, 3H), 0.91 (s, 3H), 0.88 (s, 3H), 0.86 (d,
= 7.1 Hz, 3H); 13C NMR (100 MHz, CDCl3)
ꢀ10a as a colorless liquid (49 mg, 99%): Rf =
δ
J
J
J
J
J
J
J
= 6.2 Hz, 3H), 1.19
J
J
δ 191.2, 157.2, 150.8,
148.6, 146.0, 130.0, 125.8, 125.6, 115.1, 76.1, 75.6, 72.2, 50.4, 42.4, 41.0, 39.7, 33.9, 33.2, 32.8, 32.7, 22.4, 22.3, 22.2 (d), 22.1, 21.9 (d),
21.6, 20.3, 19.5.
Siphonodictyal B (1). To a solution of vinyl benzaldehyde (E)ꢀ10a (30 mg, 0.07 mmol) in CH2Cl2 (2 mL) at –78 °C was added BCl3
(423 uL, 0.43 mmol) dropwise over 5 min. The resulting reaction mixture was stirred at room temperature for 3 h, quenched with water (10
mL), and extracted with CH2Cl2 (3 × 5 mL). The combined organic extracts were dried over Na2SO4, filtered, and concentrated under
reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc = 5:1) to afford
siphonodictyal B (
1
) as a yellow solid (17 mg, 76%): Rf = 0.3 (Hexane/EtOAc = 5:1); [α]ꢁꢃꢂ = +28 (
c
= 1 g/100 mL, CHCl3); HRMS
m/z
calcd for C22H31O4 [M+H]+ 359.2217, found 359.2219; IR (film)
ν
max 3368, 2927, 2869, 1644, 1599, 1460, 1389, 1305, 1270, 907, 733 cm–
1; H NMR (400 MHz, CDCl3)
δ 11.47 (s, 1H), 10.31 (s, 1H), 6.84 (s, 1H), 5.92 (s, 1H), 5.43 (s, 1H), 5.13 (s, 1H), 2.61–2.56 (m, 1H),
1
1.83–1.74 (m, 3H), 1.60–1.46 (m, 5H), 1.27–1.17 (m, 3H), 1.18 (s, 3H), 0.91 (s, 3H), 0.89 (s, 3H), 0.77 (d, J = 7.0 Hz, 3H); 13C NMR (100
MHz, CDCl3)
21.1, 19.3.
δ 194.5, 165.7, 148.4, 147.5, 136.9, 123.6, 116.6, 109.3, 109.0, 52.3, 42.2, 41.8, 39.1, 34.7, 34.1, 33.9, 33.1, 22.5, 21.7, 21.2,
Liphagal (2). To a solution of siphonodictyal B (1, 50 mg, 0.14 mmol) and NaHCO3 (14 mg, 0.17 mmol) in CCl4 (5 mL) at 0 °C was
added ꢀCPBA (24 mg, 0.14 mmol) in one portion. The resulting reaction mixture was stirred at 0 °C for 1 h, added TFA (31.8 mg, 0.28
m
mmol) at 0 °C dropwise, allowed to warm up to room temperature and stirred at this temperature for 2 h, quenched with saturated aqueous
NaHCO3 (30 mL), and extracted with EtOAc (3 × 50 mL). The combined organic extracts were dried over Na2SO4, filtered, and
concentrated under reduced pressure. The residue was purified by flash column chromatography on silica gel (petroleum ether/EtOAc =
10:1) to give liphagal (
2
) as a yellow solid (21.0 mg, 42%): Rf = 0.6 (Hexane/EtOAc = 5:1); HRMS
m/
z
calcd for C22H29O4 [M+H]+
1
357.2066, found 357.2063; IR (film) νmax 3417, 2929, 2868, 1654, 1455, 1389, 1328, 1301, 1272, 906, 730 cm–1; H NMR (400 MHz,
CDCl3)
1.83–1.90 (m, 1H), 1.65–1.75 (m, 4H), 1.49–1.55 (m, 3H), 1.43 (d,
3H); 13C NMR (100 MHz, CDCl3)
192.7, 156.7, 148.2, 145.5, 139.6, 125.7, 120.5, 116.2, 106.5, 77.5, 77.2, 76.9, 53.9, 42.1, 40.5, 39.7,
δ
11.24 (s, 1H), 10.45 (s, 1H), 7.55 (s, 1H), 5.32 (s, 1H), 3.21 (sextet,
J = 7.0 Hz, 1H), 2.48–5.56 (m, 1H), 2.14–2.22 (m, 1H),
J
= 7.1 Hz, 3H), 1.34 (s, 3H), 1.26–1.28 (m, 1H), 0.98 (s, 3H), 0.94 (s,
δ
35.4, 35.0, 33.9, 33.5, 24.4, 22.2, 21.9, 20.4, 19.0.
Corallidictyal C (3) and corallidictyal D (4). To a solution of PPh3 (7.3 mg, 0.028 mmol) in CH2Cl2 (2 mL) was added NIS (6.3 mg,
0.028 mmol) at room temperature. The resulting reaction mixture was stirred at room temperature for 20 min, added dropwise a solution of
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(100 mg, 0.28 mmol) at 0 °C, stirred at room temperature for 1 h, and concentrated under reduced pressure. The residue was purified by
flash column chromatography on silica gel (petroleum ether/EtOAc = 10:1) to afford corallidictyals C/D ( and ) as a yellow solid (75 mg,
76%):
f = 0.5 (Hexane/EtOAc = 10:1); HRMS m/z calcd for C22H31O4 [M+H]+ 359.2217, found 359.2219; IR (film) νmax 3340, 2922, 2852,
1732, 1651, 1575, 1466 cm–1.
NMR of
: 1H NMR (400 MHz, DMSOꢀd6
Hz, 1H, ArCH2–), 2.85 (d, = 16.5 Hz, 1H, ArCH2–), 2.15–2.21 (m, 1H), 1.63–1.10 (m, 10H), 1.12 (s, 3H), 1.04 (dd,
Hz, 1H), 0.85 (s, 3H), 0.82 (s, 3H), 0.68 (d, 191.6, 155.0, 147.0, 137.3, 120.6, 117.1,
= 6.7 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6
106.05, 99.7, 47.0, 43.0, 41.2, 34.5, 33.13, 32.7, 30.5, 30.2, 29.0, 21.4, 20.8, 17.7, 14.8, 14.5; 1H NMR (400 MHz, CDCl3)
11.10 (s, 1H,
OH), 10.13 (s, 1H CHO), 6.96 (s, 1H), 5.05 (s, 1H, OH), 3.07 (d, = 16.3 Hz, 1H, ArCH2–), 2.88 (d, = 16.3 Hz, 1H, ArCH2–), 2.23–
2.29 (m, 1H), 0.99–1.70 (m, 10 H), 1.17 (s, 3H), 1.01 (dd, = 12.3 Hz, = 2.6 Hz, 1H), 0.88 (s, 3H), 0.86 (s, 3H), 0.74 (d, = 6.4 Hz, 3H);
192.87, 156.44, 146.09, 136.7, 119.3, 117.7, 105.6, 100.9, 48.0, 42.5, 35.0, 33.48, 33.2, 33.0, 31.2, 30.9,
3
4
R
3
)
δ
10.53 (s, 1H, OH), 10.08 (s, 1H, CHO), 8.67 (br s, 1H, OH), 6.94 (s, 1H), 3.05 (d,
J = 16.7
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
35
36
37
38
39
40
41
42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
J
J
= 12.2 Hz, J = 3.3
J
) δ
δ
，
J
J
J
J
J
13C NMR (100 MHz, CDCl3)
21.6, 21.2, 18.1, 15.2, 14.9.
δ
NMR of
Hz, 1H, ArCH2–), 2.71 (d,
(d,
= 6.7 Hz, 3H); 13C NMR (100 MHz, DMSOꢀd6
32.8, 32.7, 30.6, 30.5, 21.7, 20.8, 17.7, 15.6, 15.4; 1H NMR (400 MHz, CDCl3)
(s, 1H, OH), 3.15 (d, = 16.0 Hz, 1H, ArCH2–), 2.73 (d, = 16.0 Hz, 1H, ArCH2–), 1.74–1.81 (m, 1H), 0.99–1.70 (m, 10 H), 1.48 (dd,
12.5 Hz, = 3.8 Hz, 1H), 0.96 (s, 3H), 0.91 (s, 3H), 0.85 (s, 3H), 0.74 (d,
= 6.4 Hz, 3H); 13C NMR (100 MHz, CDCl3) δ 192.92, 156.9,
4
: 1H NMR (400 MHz, DMSOꢀd6
= 16.3 Hz, 1H, ArCH2–), 1.73–1.80 (m, 1H), 1.63–1.06 (m, 11H), 0.92 (s, 3H), 0.88 (s, 3H), 0.82 (s, 3H), 0.66
191.9, 155.6, 146.9, 137.3, 120.6, 116.7, 105.97, 98.1, 46.0, 41.9, 41.2, 36.3, 33.07,
11.09 (s, 1H, OH), 10.20 (s, 1H, CHO), 6.93 (s, 1H), 5.05
) δ 10.56 (s, 1H, OH), 10.14 (s, 1H, CHO), 8.68 (br s, 1H, OH), 6.90 (s, 1H), 3.09 (d, J = 16.4
J
J
) δ
δ
J
J
J =
J
J
146.1, 136.8, 119.3, 117.4, 105.6, 99.3, 46.7, 41.9, 41.6, 37.1, 33.50, 33.4, 31.27, 31.1, 29.7, 21.9, 21.3, 18.2, 16.2, 15.6.
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the ACS Publications website.
Copies of 1H NMR, 13C NMR spectra for all compounds spectra (PDF).
AUTHOR INFORMATION
Corresponding Author *
Eꢀmail: ycwu@iccas.ac.cn.
ACKNOWLEDGMENT
This project was funded by the National Natural Science Foundation of China (21672046, 21372054), and the Fundamental Research
Funds for the Central Univercities (HIT.NSRIF.201701).
Notes and references
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