A Unified Synthetic Approach to Optically Pure Curvularin-Type Metabolites

Article abstract of DOI:10.1021/acs.joc.9b00776

A unified and concise approach to the synthesis of nine curvularin-type metabolites and two analogues has been developed with few steps and high yields. Among them, sumalactones A-D were synthesized for the first time. The key steps in this approach inclu

Full text of DOI:10.1021/acs.joc.9b00776

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Article
A Unified Synthetic Approach to Optically Pure Curvularin-type Metabolites
Srinivasa Rao Allu, Sreenivas Banne, Jia Jiang, Na Qi, Jian Guo, and Yun He
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.9b00776 • Publication Date (Web): 14 May 2019
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A Unified Synthetic Approach to Optically Pure
Curvularin-type Metabolites
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Srinivasa Rao Allu,†,‡ Sreenivas Banne,†,‡ Jia Jiang,‡ Na Qi,*,§,‡ Jian Guo,*,‡ and Yun He*,‡
‡Chongqing Key Laboratory of Natural Product Synthesis and Drug Research, School of
Pharmaceutical Sciences, Chongqing University, Chongqing 401331, P. R. China.
§Biomedicine and Health Engineering Laboratory, College of Bioengineering, Chongqing University,
Chongqing 401331, P. R. China.
Abstract Graphic
Esterification
O
OR
F-C acylation
O
O
R
MeO
OH
HO

Cross-Metathesis
HO
n
O
RCM
OMe
O
O
OH
Oxa-Michael
OH
O
F-C acylation
Curvularin, dehydrocurvularin,
sumalactones A-D, two analogues
xestodecalactone A
nine natural curvularin-type
metabolites, 15%-39% in 5-10 steps
Curvulone B
Curvulone C
Abstract: A unified and concise approach to the synthesis of nine curvularin-type
metabolites and two analogues has been developed with few steps and high yields.
Among them, sumalactones A–D were synthesized for the first time. The key steps in this
approach included esterification, Friedel-Crafts acylation and ring-closing metathesis (or
cross-methathesis).
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INTRODUCTION
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Curvularin-type metabolites, featuring a macrolide core fused to a resorcinol aromatic
ring, are produced by a variety of fungi sources, such as Curvularia, Penicillium,
Alternaria, et al.1 These compounds exhibit diverse biological activities including
anti-inflammatory activities, cytotoxicity against human cancer cell lines, antifungal
activities, etc.1 The interesting structures and potential biological activities of curvularins
have attracted ever-growing researching interests.1,2
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O
O
O
O
O
O
O
O
HO
OH
HO
HO
HO
OH
OH O
OH O
OH O
OH O
1
2
3
4
Sumalactone B ( )
Curvularin ( )
Dehydrocurvularin ( )
Sumalactone A ( )
OH
OH
O
O
O
O
O
O
O
O
HO
OH
HO
HO
HO
HO
OH O
OH O
OH O
OH O
5
6
Sumalactone D ( )
7
8
Sumalactone C ( )
O
OMe
O
OH
O
O
HO
HO
HO
OH O
O
OH O
O
OH O
9
10
Curvulone B (
11
Curvulone C ( )
Xestodecalactone A ( )
)
Figure 1. Structures of curvularin-type metabolites and analogues.
Among the curvularin-type metabolites, there are some representatives with unique
structures and excellent biological activities (Figure 1). Curvularin (1), the first
discovered 12-membered macrolide with a sole chiral center coupled with a resorcinol
aromatic ring,3 exhibited potent anti-inflammatory activity through inhibiting the
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pro-inflammatory enzymes iNOS (inducible nitric-oxide synthase) and COX-2
(cyclooxygenase-2).2c,4 Meanwhile, curvularin had little influence on the constitutive
human eNOS (endothelial nitric-oxide synthase) promoter, so it showed little cytotoxic
effects to normal cells.5 Dehydrocurvularin (2), the α,β-unsaturated derivative of
curvularin,6 exhibited much better inhibitory activity of nitric-oxide production than the
well-known NOS (nitric-oxide synthase) inhibitor L-NMMA (NG-methyl-L-arginine
acetate salt).7 Moreover, both curvularin (1) and dehydrocurvularin (2) also exhibited
significant antifungal and anti-tumor activities.8 Sumalactones A–D (3–6), were newly
isolated from the Fungus Penicillium Sumatrense, among which sumalactones C and D
bear a rare 11-membered macrolide skeleton.7 Xestodecalactone A (9), discovered from
the Fungus Penicillium cf. montanense, is a representative 10-membered curvularin-type
macrolides.9 Curvulone B (10) and C (11) featured with a cis-disubstituted
tetrahydropyran ring are newly reported ring-opened forms of the 12-membered
curvularin-type macrolides.2c,10
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To further explore their pharmaceutical activities, a number of strategies were
disclosed to synthesize the curvularin-type metabolites using various reactions as the key
steps., such as Friedel-Crafts acylation,11 Diels-Alder cycloaddition,12 aryne
acyl-alkylation,13 umpolung Pd-catalyzed α-arylation,14 et al. Among these strategies,
ring-closing-metathesis (RCM) approaches were advantageous in simple operation and
easily available starting materials, and could be applied to the synthesis of unsaturated
curvularin-type metabolites, such as dehydrocurvularin (2). However, the reported
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synthetic routes were with either long linear steps, low-efficient steps, or failed in the
final deprotection steps.15 Moreover, no unified synthetic strategy suitable for these
curvularins with different skeletons has been developed.
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Scheme 1. Retrosynthetic Analysis of Curvularin-type Metabolites and Analogues
1–11
O
O
R
O
O
R
n
O
O
R



HO
MeO
MeO
Hydrogenation
n
n
RCM
OMe O
OH
Curvularin ( ),
Sumalactones A-D ( - ),
Analogues and
Xestodecalactone A ( )
O
OMe O
12
13
1
(
2
Providing dehydrocurvularin
after removing protecting groups
and without hydrogenation)
O
3 6
Friedel-Crafts
acylation
7
8
,
Cl
Cl
9
14
O
OMe
O
O
R
HO
R


O
MeO
OH
MeO
n
n
MeO
Cl
Cl
O
14
16
OMe
OMe
O
OMe
18
Friedel-Crafts
acylation
Esterification
17
15
TBSO

Cross-
Metathesis
3
O
OR
19
HO
O
OMe

MeO
Oxa-Michael
O
O

OH

O
OTBS
OMe
10
11
Curvulone B (
Curvulone C (
)
)
20
Herein we report a unified and concise RCM strategy with ingenious design of starting
materials, protecting groups and some important transformations. With this unified
strategy, nine natural curvularin-type metabolites (1–6 and 9–11) were efficiently
synthesized from the same starting material with high yields (15%–39%) in short linear
steps (5–10 steps). Two more analogues (7 and 8) with curvularin-type skeletons were
also obtained in the synthesis. Moreover, the synthesis of sumalactones A–D (3–6) was
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reported for the first time. In our synthetic routes, the structures of curvularins were
assembled with three starting materials, two of which are commercially available and the
left one could be synthesized and modified easily.
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Our retrosynthetic analysis of curvularin-type natural products and analogues 1–11 is
outlined in Scheme 1. All the final targets 1–11 could be derived from the same starting
material 2-(3,5-dimethoxyphenyl) acetic acid 17 which is commercially available. In the
previously reported RCM strategy for the synthesis towards curvularin-type
metabolite,15c the methyl groups on the resorcinol aromatic ring could not be removed
successfully to obtain the target, therefore benzyl groups were applied in subsequently
reported RCM strategies. However, considering the convenience in the synthesis of
unsaturated curvularins, we still chose methyl ether as protecting group after careful
preliminary experiments.16 The curvularin-type macrolides 1 and 3–9 could be prepared
via the hydrogenation and deprotection of unsaturated macrolides 12, which not only
were the synthetic precursors but also provided natural product dehydrocurvularin 2 after
direct deprotection. Unsaturated macrolides 12 could be constructed via the RCM
reactions of dienes 13,17 which could be prepared by Friedel-Crafts acylation from its
precursors 15. Esters 15 could be achieved by steglich esterification from the same
starting material 17 and different chiral alcohol fragments 16 containing the single
stereogenic center present in final targets 1–9. Natural products 10 and 11 with
cis-disubstituted tetrahydropyran rings are the ring-opening forms of macrolides. The
tetrahydropyran rings would be constructed via the combination of cross-metathesis and
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intramolecular oxa-Michael addition, which have been powerful tools to construct
tetrahydropyran rings and always gave excellent stereoselectivities.18 The desilylation
and subsequent oxa-Michael addition of compound 20 would lead to the final targets 10
and 11.18 Compound 20 could be assembled through the cross-metathesis of chiral TBS
ethers 19 and enone 18.17 The stereogenic center of 19 would finally present in the final
targets 10 and 11, and induce another stereogenic center generated. Enone 18 could be
prepared by Friedel-Crafts acylation11 from the starting material 17.
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RESULTS AND DISSCUSSION
The stereogenic centers of curvularin-type metabolites and analogues 1–11 were
mainly constructed through the introduction of chiral alcohol fragments, except that one
chiral center of curvulone B (10) and C (11) was separately built by thermodynamically
controlled oxa-Michael addition. Therefore, it was important to develop convenient and
rapid methods for the synthesis of alcohol fragments. For the synthesis of alcohol
fragments 16a and 16c, and TBS ethers 19a and 19b, different commercially available
chiral 2-methyloxiranes were chosen as starting materials. The synthesis of alcohol
fragments 16a and 16b started from the ring opening reaction of (S)-2-methyloxirane (21)
and (R)-2-methyloxirane (22) with 3-butenylmagnesium bromide 23 in the presence of
CuI respectively (Scheme 2).19a–b 16a could be used for the synthesis of curvularin (1)
and dehydrocurvularin (2). Compounds 16a and 16b could be further protected to
provide TBS ethers 19a and 19b for the synthesis of curvulone B (10) and curvulone C
(11).19c–d Following a similar procedure to the synthesis of 16a and 16b, alcohol fragment
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16c was prepared for the synthesis of xestodecalactone A (9).19e
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Scheme 2. Synthesis of Alcohol Fragments 16a and 16c, TBS Ethers 19a and 19b
8
9
OH
OH
OTBS
23
, CuI, THF
O
TBSCl, imidazole
DCM, rt, 2 h, 90%
-15 oC, 2 h, 86%
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11
12
13
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21
16a
16b
19a
OTBS
19b
23
O
, CuI, THF
TBSCl, imidazole
DCM, rt, 2 h, 93%
-15 oC, 2 h, 82%
22
OH
16c
O
24
, CuI, THF
MgBr
MgBr
24
-15 oC, 2 h, 87%
22
23
Scheme 3. Synthesis of Alcohol Fragments 16d–g
1) DIBAL-H
DCM, -78 oC, 2 h
30
1) , DIAD, PPh3
OH
O
OBn O
OBn OH
THF, rt, 12 h
OBn OH
BnBr, Ag2O
ether, 40 oC
12 h, 85%
29
2) , TiCl4
OEt
2) NaOH, MeOH
OEt
DCM, -78 oC, 1 h
/THF, 0 oC to rt, 12 h
90% over two steps
25
26
16d
16e
74% over two steps
1) DIBAL-H
DCM, -78 oC, 2 h
30
1) , DIAD, PPh3
OH
OBn
OBn
OBn
THF, rt, 12 h
BnBr, Ag2O
ether, 40 oC
12 h, 88%
OEt
OEt
23
2) , ether
2) NaOH, MeOH
/THF, 0 oC to rt, 12 h
O
O
OH
16f
OH
0 oC, 2 h
27
28
16g
80% over two steps
92% over two steps
NO2
Si
HOOC
29
30
The synthesis of alcohol fragment 16d started from commercially available ethyl
(S)-3-hydroxybutanoate 25 (Scheme 3), which was first protected with benzyl group to
obtain ester 26.20 Ester 26 was reduced into aldehyde and further underwent Reetz
o
allylation by treating with TiCl4 and allyltrimethylsilane 29 at -78 C to provide
secondary alcohol 16d in excellent yield.21a The preparation of alcohol fragments 16f
began with commercially available ethyl (S)-2-hydroxypropanoate 27.21b
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Benzyl-protected compound 27 was reduced into aldehyde and subjected to a
chelation-controlled Grignard reaction with 3-butenylmagnesium bromide 23 to afford
secondary alcohol 16f (Scheme 3).22 The resulting alcohol fragments 16d and 16f were
converted to their epimers 16e and 16g respectively by Mitsunobu reactions. Alcohol
fragments 16d–g were used for the synthesis of sumalctones A–D (3–6).
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The synthesis of curvularin-type metabolites and analogues 1–9 began with the
Steglich esterification of commercially available 2-(3,5-dimethoxyphenyl) acetic acid 17
and different alcohols 16a, 16c–g, which afforded esters 15a–f bearing one vinyl group
efficiently (Scheme 4). To introduce the acrolyl group, esters 15a–f were subjected to
Friedel-Crafts acylation with 3-chloropropanoyl chloride 14 and subsequent elimination
reactions under mild conditions to provide dienes 13a–f in good yields.18a The
introduction of acrolyl group was quite efficient under mild conditions, and worked for
various substrates. Next, the RCM reaction of dienes 13a–f using Grubbs’ II catalyst in
refluxing DCM furnished macrolide frames 12a–f with E-configuration (with 10, 11 or
12-membered ring respectively) in 80–85% yields. The Z-isomers were formed in very
small amount, which ensured the high efficiency of the total synthesis. In all the reported
RCM strategies for the synthesis of curvularins, the RCM reactions were carried out at
70–90 oC in toluene,15 while our RCM reactions took place in refluxing DCM. The lower
reaction temperature made the synthesis more convenient and practical.
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Scheme 4. Synthesis of Curvularin-type metabolites and Analogues 1–9
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7
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9
O
O
R
O
O
R
n
O
O
R
n



Grubbs' II
catalyst
MeO
MeO
MeO
n
16a 16c g
or
-
14
17
DCM, reflux
24 h
SnCl4, TEA
DCM, -40 oC
to rt
DCC, DMAP, DCM
0 oC to rt, 2 h
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11
12
13
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O
OMe
O
OMe
OMe
15a
15b
13a
13b
12a
12b
: S, n = 3, 88%
: R, n = 1, 92%
: S, n = 3, 60%
: R, n = 1, 62%
: S, n = 3, 80%
: R, n = 1, 85%
R = CH3
R =
12c
12d
: R, n = 1, 83%
: S, n = 1, 85%
13c
13d
: R, n = 1, 71%
: S, n = 1, 72%
15c
15d
: R, n = 1, 90%
: S, n = 1, 88%
OBn
15e
15f
13e
13f
12e
: R, n = 2
12f
: S, n = 2
OBn
: R, n = 2, 87%
: S, n = 2, 84%
: R, n = 2, 68%
: S, n = 2, 71%
R =
Pd/C, H2, EtOAc/MeOH, rt, 12 h
AlI3, Bu4NI, benzene, 0 oC, 0.5 h
AlI3, Bu4NI
benzene
0 oC, 0.5 h
O
O
O
O
O
O
O
O
HO
HO
OH
HO
OH
HO
OH
O
OH
O
OH
O
OH O
7
9
3
Xestodecalactone A ( )
61% over two steps
Sumalactone A ( )
49% over two steps
from
byproduct in the synthesis of
sumalactone A ( ) from
2
dehydrocurvularin ( )
12a
3
12c
64% from
Pd/C, H2,
12b
12c
from
16% over two steps
EtOAc/MeOH,
rt, 12 h
OH
OH
O
O
O
O
O
O
O
O
HO
OH
HO
HO
OH
OH
O
OH
O
OH
Sumalactone C ( )
62% over three steps
13e
O
OH
O
4
5
6
Sumalactone B ( )
66% over two steps
Sumalactone D ( )
45% over three steps
13f
from
1
Curvularin ( ), 95%
12d
from
from
O
O
HO
HO
OH
O
8
6
byproduct in the synthesis of sumalactone D ( )
13f
from
, 18% over three steps
Next, the deprotection of compound 12a was examined. After careful screening of
reaction conditions, the methyl groups in compound 12 could be removed with freshly
o
prepared AlI3 in benzene at 0 C in the presence of Bu4NI to provide dehydrocurvularin
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(2) in 64% yield.16 This is the first time to synthesize dehydrocurvularin (2) bearing an
acrolyl group vis the RCM strategy. The successful application of methyl ethers as
protecting groups greatly facilitated the synthesis of unsaturated curvularins.
Dehydrocurvularin (2) was further hydrogenated to afford curvularin (1). Compounds
12b–f were hydrogenated and further deprotected to provide sumalactones A–D (3–6),
analogue 7, analogue 8 and xestodecalactone (9). Analogues 7 and 8 were the
immigration products of sumalactone A (3) and D (6).23 The analytical data of
synthesized curvularin (1),3 dehydrocurvularin (2),6 sumalctones A-D (3–6)7 and
xestodecalactone (9)9 was in full agreement with the reported values of these natural
products.
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The synthesis of curvulone B (10) and C (11) is outlined in Scheme 5. Protection with
methyl groups followed by a similar Friedel-Crafts acylation to that in Scheme 4, acid 17
was transformed into enone 18, which was subjected to cross-metathesis with TBS ethers
19a–b to yield compounds 20a–b. Following a similar oxa-Michael addition reported by
Bates,18a precursors 20a–b were transformed into 31a–b with cis-disubstituted
tetrahydropyran rings exclusively in 91–94% yield under mild conditions with
Amberlyst-15 in methanol. Removal of the corresponding protecting groups in 31a–b,
curvulone B (10) and C (11) were obtained in good yields. The structures of curvulone B
(10) and C (11) were confirmed by comparing with the reported analytical data of the
natural products.2c,10
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Scheme 5. Synthesis of Curvulone B (10) and Curvulone C (11)
6
7
8
9
O
OMe
O
OMe
O
OMe
1) SOCl2, MeOH
MeO
Amberlyst 15
MeOH, rt, 12 h
MeO
MeO
0 oC to rt, 12 h
19a 19b
or
17
11

O
Grubbs' II
catalyst,
DCM, reflux,
24 h
14
2) , SnCl4, TEA
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16
17
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19
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DCM, -40 oC to rt
O
O
OMe
15

OMe

O
OMe
OTBS
18
20a
20b
31a
31b
: R, 85%
: S, 80%
: 11R,15R, 91%
: 11S,15S, 94%
67% over two steps
AlI3, Bu4NI
benzene
0 oC, 0.5 h
LiOH
THF/MeOH
O
OH
O
OH
O
OMe
AlI3, Bu4NI
benzene
0 oC, 0.5 h
1
3
HO
MeO
HO
11S
11R
8
O
O
O
O
O
O
OH
OMe
OH
15R
15S
11
32
10
)
Curvulone C (
61%
)
Curvulone B (
31a
31b
80% from
66% from
CONCLUSION
In summary, we have developed a unified RCM approach to nine natural
curvularin-type metabolites from the same starting material with 15–39% overall yield in
5–10 linear steps. The synthesis of sumalactones A-D was achieved for the first time. In
this synthesis, we also obtained two analogues with the curvularin-type skeleton. This
synthetic strategy features high efficiency and broad application for the synthesis of
different curvularins. The starting materials are easily available and reaction conditions
are mild. This approach would greatly accelerate further structure-activity relationship
studies of curvularins. The synthesis of more curvularin-type analogues and their
biological evaluations are underway.
EXPERIMENTAL SECTION
General information. Unless otherwise noted, all reactions were carried out in
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oven-dried glassware under nitrogen atmosphere. All solvents were dried by standard
techniques and distilled prior to use. Reactions were monitored by analytical thin-layer
chromatography (TLC) on Merck silica gel 60 F254 plates (0.25 mm), visualized by
ultraviolet light and/or by staining with ceric ammonium molybdate or potassium
permanganate. 1H NMR spectra were obtained on an Agilent 400NMR or 600NMR DD2
spectrometer at ambient temperature. Data were reported as follows: chemical shift on
the δ scale using residual proton solvent as internal standard [δ 7.26 (CDCl3), 2.05
(Acetone-d6), 3.31 (CD3OD)], multiplicity (br = broad, s = singlet, d = doublet, t = triplet,
q = quartet, m = multiplet), integration, and coupling constant(s) in hertz. 13C NMR
spectra were obtained with proton decoupling on an Agilent 400MR or 600MR DD2 (100
MHz or 150 MHz) spectrometer and were reported in ppm with residual solvent for
internal standard [δ 77.16 (CDCl3), 29.84 (Accetone-d6), 49.00 (CD3OD)]. High
resolution mass spectra were obtained on a 7 Tesla SolariX FT-ICR MS (Bruker Daltonics,
Bremen, Germany) with an ESI source. Optical rotations were measured with a Rudolph
polarimeter.
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Synthesis of Curvularin (1). Palladium on charcoal (10 wt%, 8.0 mg) was added to a
solution of dehydrocurvularin (2) (8.0 mg, 27.0 μmol, 1.0 equiv) in methanol/EtOAc
(1/1). The suspension was stirred under hydrogen for 12 h. The solution was filtered
through a short plug of silica (EtOAc), and the solvent was removed in vacuo and
purified with silica gel column chromatography (PE: EtOAc, 10:1, Rf = 0.5) to afford
curvularin (1) (7.5 mg, 95%) as colorless oil. 1H NMR (600 MHz, Acetone-d6) δ 9.12 (s,
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1H), 8.68 (s, 1H), 6.39 (d, J = 2.2 Hz, 1H), 6.35 (d, J = 2.2 Hz, 1H), 4.94–4.89 (m, 1H),
3.77 (d, J = 10.3 Hz, 1H), 3.71 (d, J = 15.7 Hz, 1H), 3.07–3.14 (m, 1H), 2.81–2.81 (m,
1H), 1.78–1.72 (m, 1H), 1.64–1.58 (m, 1H), 1.55–1.51 (m, 1H), 1.48–1.40 (m, 3H),
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13
1.35–1.23 (m, 2H), 1.12 (d, J = 6.3 Hz, 3H); C{1H} NMR (150 MHz, Acetone-d6) δ
205.8, 170.1, 159.2, 157.4, 136.0, 120.4, 111.3, 101.7, 71.7, 43.1, 38.8, 32.0, 26.6, 23.7,
22.6, 19.7; [α]D27: -23.4 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for
+
C16H21O5 293.1384; Found 293.1394.
Synthesis of Dehydrocurvularin (2). I2 (4.0 mg, 1.6 mmol, 26.0 equiv) was added to a
mixture of Al powder (30.0 mg, 1.1 mmol, 18.0 equiv) in dry benzene (3.0 mL). The
o
mixture was heated at refluxing (color changed) for 0.5 h and cooled to 0 C, then
compound 12a (20.0 mg, 62.0 μmol, 1.0 equiv) and Bu4NI (2.7 mg, 7.5 μmol, 0.12 equiv)
o
in benzene (2.0 mL) were added. The reaction mixture was stirred for 15 min at 0 C,
o
then the reaction was quenched with 2 N HCl (5.0 mL) at 0 C, and the mixture was
extracted with EtOAc (10.0 mL × 3). The combined organic layers were washed with sat.
NaHCO3 (3.0 mL) and brine (5.0 mL), then dried over anhydrous Na2SO4 and
concentrated in vacuo. The residue was purified with silica gel column chromatography
(PE:EtOAc, 3:7, Rf = 0.5) to afford dehydrocurvularin (2) (11.6 mg, 64%) as colorless oil.
1H NMR (600 MHz, Acetone-d6) δ 6.78 (d, J = 15.4 Hz, 1H), 6.61–6.54 (m, 1H), 6.36 (d,
J = 2.0 Hz, 1H), 6.30 (d, J = 2.2 Hz, 1H), 4.76–4.70 (m, 1H), 4.08 (d, J = 17.7 Hz, 1H),
3.61 (d, J = 17.7 Hz, 1H), 2.46–2.39 (m, 1H), 2.38–2.31 (m, 1H), 2.02–1.95 (m, 1H),
1.88–1.81 (m, 1H), 1.68–1.60 (m, 2H), 1.19 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (150
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MHz, Acetone-d6) δ 196.3, 170.9, 165.1, 162.1, 148.7, 138.5, 131.6, 114.7, 112.8, 102.0,
71.9, 42.8, 33.8, 32.2, 24.0, 19.4; [α]D27: -51.3 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z:
8
9
+
[M+H]+ Calcd for C16H19O5 291.1227; Found 291.1233.
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Synthesis of Sumalactone A (3) and 7. Palladium on charcoal (10 wt.%, 15.0 mg) was
added to a solution of compound 12c (20.0 mg, 47.0 μmol, 1.0 equiv) in methanol/EtOAc
(1/1). The suspension was stirred under hydrogen for 12 h. The solution was filtered
through a short plug of silica (EtOAc), and the solvent was removed in vacuo. This
yielded a crude compound of saturated lactone with protecting groups. The crude
compound was used for next reaction without further purification.
I2 (310.0 mg, 1.2 mmol, 26.0 equiv) was added to a mixture of Al powder (23.0 mg,
0.85 mmol, 18.0 equiv) in dry benzene (3 mL). The mixture was heated at refluxing
o
(color changed) for 0.5 h and cooled to 0 C, then Bu4NI (2.0 mg, 5.3 μmol) and the
crude compound gotten in the first step in benzene (2.0 mL) were added. The reaction
mixture was stirred for 15 min at 0 oC, then the reaction was quenched with 2 N HCl (5.0
o
mL) at 0 C, and the mixture was extracted with EtOAc (10.0 mL × 3). The combined
organic layers were washed with sat. NaHCO3 (3.0 mL) and brine (5.0 mL), then dried
over Na2SO4 and concentrated in vacuo. The residue was purified with silica gel column
chromatography (PE:EtOAc, 1:4, Rf = 0.4) to afford sumalactone A (3) (7.1 mg, 49%
over two steps) as colorless oil. Compound 7 formed through the ester migration of
sumalactone A (3) (2.3 mg, 16% over two steps) as colorless oil. Sumalactone A (3): 1H
NMR (600 MHz, CD3OD) δ 6.22 (s, 1H), 6.12 (s, 1H), 4.96–4.87 (m, 1H), 3.96 (d, J =
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18.2 Hz, 1H), 3.74–3.62 (m, 1H), 3.45 (d, J = 18.2 Hz, 1H), 3.11–3.01 (m, 1H),
6
7
2.77–2.65 (m, 1H), 1.99–1.92 (m, 1H), 1.91–1.83 (m, 2H), 1.74–1.66 (m, 1H), 1.54–1.42
8
9
13
(m, 2H), 1.13 (s, 3H); C{1H} NMR (150 MHz, CD3OD) δ 211.5, 171.8, 161.0, 158.8,
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136.3, 122.7, 110.6, 102.4, 76.3, 65.6, 46.7, 45.3, 41.4, 35.5, 23.9, 23.4; [α]D27: -117.1 (c
+
0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C16H20NaO6 331.1152;
Found 331.1144.
Compound 7: 1H NMR (600 MHz, CD3OD) δ 6.24 (s, 1H), 6.18 (s, 1H), 5.09–5.01 (m,
1H), 4.06 (d, J = 14.3 Hz, 1H), 3.66 (s, 1H), 3.52 (d, J = 15.9 Hz, 1H), 3.41 (s, 1H),
2.66–2.58 (m, 1H), 1.83–1.75 (m, 1H), 1.74–1.65 (m, 2H), 1.63–1.55 (m, 1H), 1.42–1.32
13
(m, 2H), 1.13 (s, 3H); C{1H} NMR (150 MHz, CD3OD) δ 209.2, 172.4, 161.5, 160.1,
137.6, 120.4, 112.2, 102.8, 69.5, 68.6, 44.5, 40.8, 34.7, 21.8, 21.0; [α]D27: -117.1 (c 0.1,
+
MeOH); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C16H20NaO6 331.1152; Found
331.1147.
Synthesis of Sumalactone B (4). Prepared according to the synthesis of sumalactone A
(3) from compound 12d (20.0 mg, 47.0 μmol, 1.0 equiv) to afford sumalactone B (4) (9.6
mg, 66% over two steps) as pale yellow oil. 1H NMR (600 MHz, CD3OD) δ 6.24 (d, J =
1.7 Hz, 1H), 6.12 (d, J = 1.5 Hz, 1H), 4.92–4.86 (m, 1H), 3.97 (d, J = 18.3 Hz, 1H),
3.66–3.62 (m, 1H), 3.48 (d, J = 18.4 Hz, 1H), 3.05 (ddd, J = 15.5, 10.6, 2.2 Hz, 1H),
2.72–2.67 (m, 1H), 1.93–1.81 (m, 3H), 1.56 (ddd, J = 14.2, 8.0, 3.8 Hz, 1H), 1.50–1.43
13
(m, 2H), 1.08 (d, J = 6.3 Hz, 3H); C{1H} NMR (150 MHz, CD3OD) δ 211.5, 172.7,
161.1, 158.9, 136.3, 122.6, 110.7, 102.5, 76.3, 65.1, 46.7, 45.9, 41.3, 36.3, 23.6, 23.5;
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+
[α]D27: +81.7 (c 0,1 MeOH); HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for C16H21O6
6
7
309.1333; Found 309.1325.
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9
Synthesis of Sumalactone C (5). Diene 13e (20.0 mg, 44.0 μmol, 1.0 equiv) was
dissolved in dry DCM (30.0 mL), and Grubbs’ II catalyst (8.0 mg, 8.0 μmol, 0.2 equiv)
was added, and the reaction mixture was heated to 45 °C for 12 h. The solvent was
removed in vacuo to get crude compound. Crude compound 12e was used to next step
without purification. Prepared according to the synthesis of sumalactone A (3) from
crude compound 12e to afford sumalactone C (5) (8.5 mg, 62% over three steps) as
colorless oil. 1H NMR (600 MHz, CD3OD) δ 6.24 (d, J = 2.1 Hz, 1H), 6.15 (d, J = 1.9 Hz,
1H), 4.74 (ddd, J = 10.4, 4.9, 3.3 Hz, 1H), 4.13 (d, J = 17.1 Hz, 1H), 3.65–3.60 (m, 1H),
3.46 (d, J = 17.1 Hz, 1H), 3.16 (ddd, J = 17.2, 11.6, 3.0 Hz, 1H), 2.86 (ddd, J = 17.4, 5.9,
3.3 Hz, 1H), 1.92–1.85 (m, 1H), 1.78–1.71 (m, 1H), 1.70–1.61 (m, 1H), 1.50–1.41 (m,
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13
2H), 1.26–1.18 (m, 1H), 0.97 (d, J = 6.4 Hz, 3H); C{1H} NMR (150 MHz, CD3OD) δ
209.9, 172.4, 160.8, 158.8, 136.3, 122.0, 111.5, 102.6, 79.8, 69.4, 41.7, 41.1, 26.1, 23.9,
22.0, 18.7; [α]D27: -44.2 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for
+
C16H21O6 309.1333; Found 309.1325.
Synthesis of Sumalactone D (6) and 8. Prepared according to the synthesis of
sumalactone C (5) from compound 13f (20.0 mg, 44.0 μmol, 1.0 equiv) to afford
sumalactone D (6) (6.1 mg, 45% over three steps) as pale yellow oil. Compound 8
formed through the ester migration of sumalactone D (6) (2.5 mg, 18% over three steps)
as colorless oil. Sumalactone D (6): 1H NMR (600 MHz, CD3OD) δ 6.23 (d, J = 2.1 Hz,
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1H), 6.16 (d, J = 2.0 Hz, 1H), 4.79–4.75 (m, 1H), 4.10 (d, J = 17.1 Hz, 1H), 3.61 (q, J =
6.3 Hz, 1H), 3.49 (d, J = 17.1 Hz, 1H), 3.19 (ddd, J = 17.4, 11.6, 3.2 Hz, 1H), 2.85 (ddd,
J = 17.4, 6.0, 3.3 Hz, 1H), 1.91–1.84 (m, 1H), 1.71–1.60 (m, 2H), 1.51–1.43 (m, 2H),
1.25–1.19 (m, 1H), 1.01 (d, J = 6.5 Hz, 3H); 13C{1H} NMR (150 MHz, CD3OD) δ 209.9,
172.6, 160.9, 158.8, 136.4, 122.1, 111.7, 102.7, 80.0, 69.3, 41.8, 41.2, 26.4, 23.9, 22.2,
19.0; [α]D27: +29.4 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for
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13
14
15
16
17
18
19
20
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22
23
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+
C16H21O6 309.1333; Found 309.1327.
Compound 8: 1H NMR (400 MHz, CD3OD) δ 6.27 (d, J = 2.1 Hz, 1H), 6.19 (d, J = 1.6
Hz, 1H), 4.95–4.87 (m, 1H), 4.01 (d, J = 16.0 Hz, 1H), 3.64–3.57 (m, 2H), 3.16–3.06 (m,
1H), 2.86–2.76 (m, 1H), 1.96–1.87 (m, 1H), 1.64–1.54 (m, 1H), 1.45–1.37 (m, 2H),
1.36–1.29 (m, 2H), 1.09 (d, J = 6.6 Hz, 3H); 13C{1H} NMR (100 MHz, CD3OD) δ 206.3,
170.8, 160.4, 159.6, 137.0, 118.5, 111.4, 101.6, 72.3, 68.6, 42.7, 40.5, 29.0, 22.9, 21.5,
12.2; [α]D27: +33.1 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for
+
C16H21O6 309.1333; Found 309.1325.
Synthesis of Xestodecalactone A (9). Prepared according to the synthesis of
sumalactone A (3) from compound 12b (15.0 mg, 51.0 μmol, 1.0 equiv) to afford
1
xestodecalactone A (9) (8.2 mg, 61% over two steps) as pale yellow oil. H NMR (600
MHz, CD3OD) δ 6.29 (d, J = 2.0 Hz, 1H), 6.16 (d, J = 1.7 Hz, 1H), 4.76–4.69 (m, 1H),
4.01 (d, J = 18.3 Hz, 1H), 3.48 (d, J = 18.4 Hz, 1H), 3.10–3.02 (m, 1H), 2.77 (dd, J =
15.4, 7.6 Hz, 1H), 1.98–1.81 (m, 3H), 1.56–1.46 (m, 1H), 1.18 (d, J = 6.2 Hz, 3H);
13C{1H} NMR (150 MHz, CD3OD) δ 210.6, 170.9, 159.9, 157.8, 135.1, 121.8, 109.6,
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101.5, 74.7, 45.9, 40.2, 36.9, 22.9, 20.1; [α]D27: +68.1 (c 0.1, MeOH); HRMS
6
7
+
(ESI-FT-ICR) m/z: [M+Na]+ Calcd for C14H16NaO5 287.0890; Found 287.0881.
8
9
Synthesis of Curvulone B (10). Prepared according to the synthesis of
dehydrocurvularin (2) from compound 31a (15.0 mg, 42.0 μmol, 1.0 equiv) to afford
curvulone B (10) (9.0 mg, 66%) as pale yellow oil. 1H NMR (600 MHz, CDCl3) δ 9.74 (s,
1H), 6.80 (s, 1H), 6.24 (d, J = 2.2 Hz, 1H), 6.18 (d, J = 2.2 Hz, 1H), 4.10 (t, J = 10.6 Hz,
1H), 3.87 (d, J = 16.6 Hz, 1H), 3.70 (s, 3H), 3.56–3.48 (m, 2H), 3.29 (dd, J = 14.4, 10.0
Hz, 1H), 2.55 (dd, J = 14.3, 3.1 Hz, 1H), 1.85–1.80 (m, 1H), 1.64 (d, J = 12.5 Hz, 1H),
1.60–1.52 (m, 2H), 1.41–1.36 (m, 1H), 1.25–1.20 (m, 1H), 1.14 (d, J = 6.2 Hz, 3H);
13C{1H} NMR (150 MHz, CDCl3) δ 204.3, 172.8, 159.9, 159.5, 135.7, 120.4, 112.0,
104.0, 77.8, 74.9, 52.2, 49.1, 39.9, 32.7, 30.8, 23.1, 21.5; [α]D27:-17.2 (c 0.1, MeOH);
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+
HRMS (ESI-FT-ICR) m/z: [M+H]+ Calcd for C17H23O6 323.1489; Found 323.1480.
Synthesis of Curvulone C (11). Prepared according to the synthesis of
dehydrocurvularin (2) from compound 32 (15.0 mg, 44.0 μmol, 1.0 equiv) to afford
1
curvulone C (11) (8.4 mg, 61%) as colorless oil. H NMR (600 MHz, CDCl3) δ 6.47 (s,
1H), 6.34 (s, 1H), 4.16 (d, J = 9.4 Hz, 1H), 3.64–3.48 (m, 3H), 3.43–3.35 (m, 1H), 2.61
(d, J = 13.3 Hz, 1H), 1.87 (d, J = 12.8 Hz, 1H), 1.69 (d, J = 12.4 Hz, 1H), 1.62–1.58 (m,
3H), 1.48–1.44 (m, 1H), 1.19 (d, J = 5.8 6.5 Hz, 3H); 13C{1H} NMR (150 MHz, CDCl3)
δ 207.1, 161.4, 160.4, 135.9, 120.4, 111.7, 104.9, 78.6, 75.3, 48.6, 41.9, 32.6, 30.6, 29.7,
23.0, 21.4; [α]D27: +16.1 (c 0.1, MeOH); HRMS (ESI-FT-ICR) m/z: [M-H]– Calcd for
-
C16H19O6 307.1187; Found 307.1176.
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(S,E)-11,13-Dimethoxy-4-methyl-4,5,6,7-tetrahydro-1H-benzo[d][1]oxacyclododecine
-2,10-dione (12a). Diene 13a (100.0 mg, 0.3 mmol, 1.0 equiv) was dissolved in dry DCM
(50.0 mL), and Grubbs’ II catalyst (49.0 mg, 57.0 μmol, 0.2 equiv) was added, and the
reaction mixture was heated to 45 °C for 12 h. The solvent was removed in vacuo.
Purified with silica gel column chromatography (PE:EtOAc, 7:3, Rf = 0.5) and yielded
compound 12a (73.0 mg, 80%) as brown oil. 1H NMR (400 MHz, CDCl3) δ 6.50–6.36 (m,
3H), 6.24 (d, J = 15.8 Hz, 1H), 4.92–4.82 (m, 1H), 3.80 (s, 3H), 3.72 (s, 3H), 3.35 (s, 2H),
2.33–2.29 (m, 1H), 2.21–2.11 (m, 1H), 1.89–1.85 (m, 1H), 1.82–1.73 (m, 1H), 1.51–1.37
(m, 2H), 1.14 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 198.4, 170.5,
160.9, 157.5, 156.5, 133.2, 132.8, 122.5, 106.5, 97.8, 72.9, 55.8, 55.4, 39.5, 34.2, 34.1,
24.4, 20.2; [α]D27: -21.6 (c 1.4, CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for
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+
C18H22NaO5 341.1359; Found 341.1361.
(R,E)-9,11-Dimethoxy-4-methyl-4,5-dihydro-1H-benzo[d]oxecine-2,8-dione
(12b).
Prepared according to the synthesis of compound 12a from compound 13b (60.0 mg, 0.2
mmol, 1.0 equiv) to afford compound 12b (46.0 mg, 85%) as colorless oil. 1H NMR (400
MHz, CDCl3) δ 6.96 (d, J = 12.3 Hz, 1H), 6.39 (s, 1H), 6.30 (s, 1H), 5.93–8.84 (m, 1H),
5.19–5.08 (m, 1H), 3.96 (d, J = 17.1 Hz, 1H), 3.82 (s, 3H), 3.82 (s, 3H), 3.60 (d, J = 17.2
Hz, 1H), 3.10–3.01 (m, 1H), 2.19–2.06 (m, 1H), 1.14 (d, J = 6.7 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 199.9, 169.7, 161.6, 158.4, 136.9, 135.4, 131.3, 122.6, 108.4, 97.3,
69.5, 55.7, 55.4, 41.1, 29.9, 17.9; [α]D27: +11.1 (c 1.6, CHCl3); HRMS (ESI-FT-ICR) m/z:
+
[M+H]+ Calcd for C16H19O5 291.1227; Found 291.1223.
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(R,E)-4-((S)-2-(Benzyloxy)propyl)-9,11-dimethoxy-4,5-dihydro-1H-benzo[d]oxecine-2,
8-dione (12c). Prepared according to the synthesis of compound 12a from compound 13c
(100.0 mg, 0.2 mmol, 1.0 equiv) to afford compound 12c (77.0 mg, 83%) as colorless oil.
1H NMR (400 MHz, CDCl3) δ 7.35–7.23 (m, 5H), 6.95 (d, J = 12.3 Hz, 1H), 6.39 (s, 1H),
6.28 (s, 1H), 5.87–5.78 (m, 1H), 5.21–5.12 (m, 1H), 4.50 (d, J = 11.7 Hz, 1H), 4.34 (d, J
= 11.7 Hz, 1H), 3.95 (d, J = 17.1 Hz, 1H), 3.81 (d, J = 5.3 Hz, 6H), 3.57 (d, J = 17.2 Hz,
1H), 3.51–3.42 (m, 1H), 3.06–2.96 (m, 1H), 2.15–2.06 (m, 1H), 1.91–1.83 (m, 1H),
1.58–1.50 (m, 1H), 1.17 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.9,
169.7, 161.6, 158.4, 138.5, 137.0, 135.3, 131.2, 128.3, 127.6, 127.5, 122.6, 108.5, 97.2,
71.6, 70.9, 70.1, 55.7, 55.4, 41.0, 38.6, 28.4, 19.3; [α]D27: -16.7 (c 0.9, CHCl3); HRMS
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+
(ESI-FT-ICR) m/z: [M+Na]+ Calcd for C25H28NaO6 447.1778; Found 447.1769.
(S,E)-4-((S)-2-(Benzyloxy)propyl)-9,11-dimethoxy-4,5-dihydro-1H-benzo[d]oxecine-2,
8-dione (12d). Prepared according to the synthesis of compound 12a from compound 13d
(100.0 mg, 0.2 mmol, 1.0 equiv) to afford compound 12d (79.0 mg, 85%) as brown oil;
1H NMR (400 MHz, CDCl3) δ 7.33–7.29 (m, 5H), 6.90 (d, J = 12.2 Hz, 1H), 6.38 (s, 1H),
6.28 (s, 1H), 5.91–5.83 (m, 1H), 5.33 (dd, J = 9.6, 3.7 Hz, 1H), 4.50 (d, J = 11.1 Hz, 1H),
4.33 (d, J = 11.1 Hz, 1H), 3.92 (d, J = 16.9 Hz, 1H), 3.81 (s, 6H), 3.57 (d, J = 16.9 Hz,
1H), 3.44–3.37 (m, 1H), 3.07–2.98 (m, 1H), 2.17–2.11 (m, 1H), 1.66–1.54 (m, 2H), 1.12
(d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 199.9, 169.8, 161.5, 158.4,
138.4, 136.8, 135.4, 131.6, 128.3, 128.1, 127.5, 108.4, 97.2, 71.0, 70.8, 70.6, 55.7, 55.4,
41.0, 39.7, 29.2, 19.6; [α]D27: +22.7 (c 1.1, CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+
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+
Calcd for C25H28NaO6 447.1778; Found 447.1767.
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(S)-Hept-6-en-2-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13a). A solution of
SnCl4 (121.0 μL, 1.0 mmol, 1.2 equiv) in DCM (1 mL) was added to a solution of 3-
chloropropionyl chloride 14 (98.0 μL, 1.0 mmol, 1.2 equiv) in dry DCM (25.0 mL) at -78
oC. A solution of compound 15a (250.0 mg, 0.9 mmol, 1.0 equiv) in DCM (15.0 mL),
was added dropwise to the mixture at -78 oC over 30 min. The mixture was stirred at -40
oC overnight under nitrogen. Triethylamine (0.6 mL, 4.3 mmol) was added and the
mixture was allowed to warm to room temperature. The reaction mixture was quenched
with sat. NH4Cl. The aqueous layer was extracted with DCM (10.0 mL × 2). The
combined organic layers were washed with brine, dried over anhydrous Na2SO4,
concentrated and purified with silica gel column chromatography (PE: EtOAc, 10:1, Rf =
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0.4) to afford the title compound 13a (178.0 mg, 60%) as colorless oil. H NMR (400
MHz, CDCl3) δ 6.62 (dd, J = 17.4, 10.3 Hz, 1H), 6.36 (d, J = 4.7 Hz, 2H), 6.03 (d, J =
17.2 Hz, 1H), 5.76–5.71 (m, 1H), 5.72–5.64 (m, 1H), 4.98–4.84 (m, 2H), 4.81 (dd, J =
12.4, 6.2 Hz, 1H), 3.75 (s, 3H), 3.70 (s, 3H), 3.53 (s, 2H), 2.02–1.90 (m, 2H), 1.56–1.46
(m, 1H), 1.45–1.37 (m, 1H), 1.35–1.22 (m, 2H), 1.12 (d, J = 6.3 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 195.5, 170.6, 161.6, 159.1, 138.4, 138.0, 135.4, 128.3, 122.1, 114.6,
107.7, 97.4, 71.3, 55.6, 55.3, 38.9, 35.2, 33.4, 24.5, 19.8; [α]D27: -15.7 (c 1.0, CHCl3);
+
HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C20H26NaO5 369.1672; Found 369.1678.
(R)-Pent-4-en-2-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13b). Prepared
according to the synthesis of compound 13a from compound 15b (100.0 mg, 0.4 mmol,
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1.0 equiv) to afford compound 13b (74.0 mg, 62%) as colorless oil. 1H NMR (400 MHz,
CDCl3) δ 6.67 (dd, J = 17.3, 10.4 Hz, 1H), 6.39 (s, 2H), 6.08 (d, J = 17.3 Hz, 1H), 5.80 (d,
J = 10.3 Hz, 1H), 5.75–5.62 (m, 1H), 5.09–4.96 (m, 2H), 4.95–4.84 (m, 1H), 3.80 (s, 3H),
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3.75 (s, 3H), 3.57 (s, 2H), 2.36–2.14 (m, 2H), 1.17 (d, J = 6.2 Hz, 3H); C{1H} NMR
(100 MHz, CDCl3) δ 195.8, 170.6, 161.6, 159.1, 138.0, 135.3, 133.6, 128.6, 122.1, 117.7,
107.7, 97.5, 70.7, 55.7, 55.4, 40.1, 38.9, 19.4; [α]D27: +18.1 (c 1.0, CHCl3); HRMS
(ESI-FT-ICR) m/z: [M+Na]+ Calcd for C18H22NaO5 341.1359; Found 341.1350.
+
(4R,6S)-6-(Benzyloxy)hept-1-en-4-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13c).
Prepared according to the synthesis of compound 13a from compound 15c (150.0 mg, 0.4
1
mmol, 1.0 equiv) to afford compound 13c (120.0 mg, 71%) as colorless oil. H NMR
(400 MHz, CDCl3) δ 7.38–7.20 (m, 5H), 6.67 (dd, J = 17.4, 10.3 Hz, 1H), 6.38 (d, J = 0.9
Hz, 2H), 6.09 (dd, J = 17.3, 1.2 Hz, 1H), 5.77 (dd, J = 10.4, 1.1 Hz, 1H), 5.73–5.65 (m,
1H), 5.05–4.97 (m, 3H), 4.50 (d, J = 11.7 Hz, 1H), 4.38 (d, J = 11.7 Hz, 1H), 3.79 (s, 3H),
3.75 (s, 3H), 3.59–3.50 (m, 3H), 2.31–2.22 (m, 2H), 1.99–1.90 (m, 1H), 1.65–1.55 (m,
1H), 1.18 (d, J = 6.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 195.4, 170.5, 161.6,
13
159.2, 138.8, 138.0, 135.4, 133.4, 128.3, 128.3, 127.6, 127.4, 122.2, 117.9, 107.9, 97.5,
71.9, 71.3, 70.2, 55.7, 55.4, 40.4, 38.9, 38.8, 19.5; [α]D27: -39.3 (c 1.0, CHCl3); HRMS
(ESI-FT-ICR) m/z: [M+Na]+ Calcd for C27H32NaO6 475.2091; Found 475.2081.
+
(4S,6S)-6-(Benzyloxy)hept-1-en-4-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13d).
Prepared according to the synthesis of compound 13a from compound 15d (250.0 mg,
0.6 mmol, 1.0 equiv) to afford compound 13d (204.0 mg, 72%) as colorless oil. 1H NMR
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(400 MHz, CDCl3) δ 7.31–7.21 (m, 5H), 6.66 (dd, J = 17.3, 10.3 Hz, 1H), 6.39 (s, 2H),
6.07 (dd, J = 17.3, 0.7 Hz, 1H), 5.77–5.66 (m, 2H), 5.22–5.14 (m, 1H), 5.01 (d, J = 12.6
Hz, 2H), 4.47 (d, J = 11.2 Hz, 1H), 4.31 (d, J = 11.2 Hz, 1H), 3.78 (s, 3H), 3.76 (s, 3H),
3.57 (d, J = 4.1 Hz, 2H), 3.53–3.47 (m, 1H), 2.34–2.22 (m, 2H), 1.75–1.66 (m, 1H),
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1.62–1.56 (m, 1H) 1.16 (d, J = 6.1 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 195.5,
170.5, 161.6, 159.2, 138.7, 138.1, 135.5, 133.5, 128.3, 128.0, 127.4, 122.2, 117.7, 107.8,
97.5, 71.4, 71.0, 70.9, 55.7, 55.4, 41.4, 39.2, 38.8, 19.9; [α]D27: +11.2 (c 1.1, CHCl3);
+
HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C27H32NaO6 475.2091; Found 475.2085.
(2S,3R)-2-(Benzyloxy)hept-6-en-3-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13e).
Prepared according to the synthesis of compound 13a from compound 15e (100.0 mg, 0.3
mmol, 1.0 equiv) to afford compound 13e (77.0 mg, 68%) as colorless oil. 1H NMR (400
MHz, CDCl3) δ 7.34–7.22 (m, 5H), 6.67 (dd, J = 17.4, 10.3 Hz, 1H), 6.42 (s, 1H), 6.38 (s,
1H), 6.08 (d, J = 17.3 Hz, 1H), 5.80–5.71 (m, 2H), 5.01–4.92 (m, 3H), 4.48 (q, J = 11.8
Hz, 2H), 3.77 (s, 3H), 3.74 (s, 3H), 3.63 (d, J = 7.2 Hz, 2H), 3.60–3.54 (m, 1H),
2.13–1.92 (m, 2H), 1.70–1.64 (m, 2H), 1.13 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 195.5, 170.7, 161.6, 159.2, 138.6, 138.0, 137.8, 135.4, 128.5, 128.3,
127.6, 127.4, 122.2, 115.0, 107.7, 97.6, 75.8, 75.6, 71.1, 55.6, 55.4, 38.9, 29.7, 28.7, 15.8;
+
[α]D27: -26.1 (c 1.6, CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C27H32NaO6
475.2091; Found 475.2087.
(2S,3S)-2-(Benzyloxy)hept-6-en-3-yl 2-(2-acryloyl-3,5-dimethoxyphenyl)acetate (13f).
Prepared according to the synthesis of compound 13a from compound 15f (100.0 mg, 0.3
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mmol, 1.0 equiv) to afford compound 13f (80.0 mg, 71%) as colorless oil. 1H NMR (400
MHz, CDCl3) δ 7.35–7.19 (m, 5H), 6.66 (dd, J = 17.4, 10.3 Hz, 1H), 6.39 (s, 2H),
6.11–6.03 (m, 1H), 5.76–5.63 (m, 2H), 5.22–5.14 (m, 1H), 5.00 (d, J = 12.9 Hz, 2H),
4.47 (d, J = 11.2 Hz, 1H), 4.31 (d, J = 11.2 Hz, 1H), 3.79 (s, 3H), 3.76 (s, 3H), 3.56 (d, J
= 4.1 Hz, 2H), 3.54–3.48 (m, 1H), 2.36–2.21 (m, 2H), 1.72–1.58 (m, 2H), 1.16 (d, J = 6.1
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Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ 195.5, 170.5, 161.6, 159.2, 138.7, 138.1,
135.5, 133.5, 128.3, 128.0, 127.4, 122.2, 117.7, 107.8, 97.5, 71.4, 71.0, 70.9, 55.7, 55.4,
41.4, 39.2, 38.8, 19.9; [α]D27: +17.9 (c 1.1, CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+
+
Calcd for C27H32NaO6 475.2091; Found 475.2087.
(S)-Hept-6-en-2-yl 2-(3,5-dimethoxyphenyl)acetate (15a). To
a
solution of
2-(3,5-dimethoxyphenyl) acetic acid 17 (200.0 mg, 1.0 mmol, 1.0 equiv) and compound
16a (128.0 mg, 1.1 mmol, 1.1 equiv) in DCM (20.0 mL), were added DCC (315.0 mg,
1.5 mmol, 1.5 equiv) and DMAP (25.0 mg, 0.2 mmol, 0.2 equiv) at room temperature.
The reaction was stirred at room temperature for 2 h. After completion, the mixture was
concentrated and purified with silica gel column chromatography (PE:EtOAc, 10:1, Rf =
1
0.5) to afford compound 15a (262.0 mg, 88%) as colorless oil. H NMR (400 MHz,
CDCl3) δ 6.44 (d, J = 1.8 Hz, 2H), 6.36 (s, 1H), 5.81–5.68 (m, 1H), 5.04–4.90 (m, 3H),
3.77 (s, 6H), 3.52 (s, 2H), 2.01 (q, J = 7.1 Hz, 2H), 1.64–1.53 (m, 1H), 1.53–1.45 (m, 1H),
1.41–1.30 (m, 2H), 1.20 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 171.0,
27
160.8, 138.4, 136.4, 114.7, 107.2, 99.2, 71.4, 55.3, 42.0, 35.3, 33.4, 24.5, 19.9; [α]D
:
+
-6.3 (c 0.6, CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C17H24NaO4
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315.1567; Found 315.1559.
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(R)-Pent-4-en-2-yl 2-(3,5-dimethoxyphenyl)acetate (15b). Prepared according to the
synthesis of compound 15a from compound 17 (100.0 mg, 0.5 mmol, 1.0 equiv) and
compound 16c (48.0 mg, 0.55 mmol, 1.1 equiv) to afford compound 15b (124.0 mg, 92%)
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as colorless oil. H NMR (400 MHz, CDCl3) δ 6.42 (d, J = 1.9 Hz, 2H), 6.35 (s, 1H),
5.76–5.64 (m, 1H), 5.09–5.00 (m, 2H), 4.99–4.90 (m, 1H), 3.76 (s, 6H), 3.52 (s, 2H),
2.37–2.20 (m, 2H), 1.21 (d, J = 6.3 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3) δ 170.8,
160.8, 136.3, 133.5, 117.7, 107.3, 99.2, 70.6, 55.3, 41.9, 40.2, 19.4; [α]D27: +12.4 (c 1.1,
+
CHCl3); HRMS (ESI-FT-ICR) m/z: [M+Na]+ Calcd for C15H20NaO4 287.1253; Found
287.1258.
(4R,6S)-6-(Benzyloxy)hept-1-en-4-yl 2-(3,5-dimethoxyphenyl)acetate (15c). Prepared
according to the synthesis of compound 15a from compound 17 (150.0 mg, 0.8 mmol,
1.0 equiv) and compound 16e (185.0 mg, 0.8 mmol, 1.0 equiv) to afford compound 15c
(274.0 mg, 90%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.37–7.22 (m, 5H), 6.41
(s, 2H), 6.35 (s, 1H), 5.74–5.62 (m, 1H), 5.09–4.95 (m, 3H), 4.47 (d, J = 11.6 Hz, 1H),
4.34 (d, J = 11.6 Hz, 1H), 3.75 (s, 6H), 3.50–3.39 (m, 3H), 2.36–2.21 (m, 2H), 2.01–1.91
(m, 1H), 1.67–1.56 (m, 1H), 1.17 (d, J = 6.1 Hz, 3H); 13C{1H} NMR (100 MHz, CDCl3)
δ 170.8, 160.8, 138.7, 136.2, 133.3, 128.3, 127.6, 127.4, 117.9, 107.3, 99.1, 71.9, 71.3,
70.2, 55.3, 42.0, 40.5, 38.9, 19.5; [α]D27: -39.3 (c 1.0, CHCl3); HRMS (ESI-FT-ICR) m/z:
+
[M+Na]+ Calcd for C24H30NaO5 421.1985; Found 421.1977.
(4S,6S)-6-(Benzyloxy)hept-1-en-4-yl 2-(3,5-dimethoxyphenyl)acetate (15d). Prepared
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according to the synthesis of compound 15a from compound 17 (100.0 mg, 0.5 mmol,
1.0 equiv) and compound 16d (123.0 mg, 0.55 mmol, 1.1 equiv) to afford compound 15d
(178.0 mg, 88%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.35–7.21 (m, 5H), 6.42
(s, 2H), 6.35 (s, 1H), 5.77–5.64 (m, 1H), 5.27–5.16 (m, 1H), 5.01 (d, J = 12.9 Hz, 2H),
4.42 (d, J = 11.2 Hz, 1H), 4.19 (d, J = 11.2 Hz, 1H), 3.74 (s, 6H), 3.47 (s, 2H), 3.44–3.38
(m, 1H), 2.38–2.22 (m, 2H), 1.77–1.56 (m, 2H), 1.14 (d, J = 6.1 Hz, 3H); 13C{1H} NMR
(100 MHz, CDCl3) δ 170.7, 160.8, 138.6, 136.3, 133.4, 128.3, 127.9, 127.5, 117.8, 107.3,
99.2, 71.3, 70.9, 70.8, 55.3, 42.1, 41.4, 39.2, 19.8; [α]D27: +19.7 (c 1.4, CHCl3); HRMS
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(ESI-FT-ICR) m/z: [M-H]- Calcd for C24H29O5 397.2020; Found 397.2019.
(2S,3R)-2-(Benzyloxy)hept-6-en-3-yl 2-(3,5-dimethoxyphenyl)acetate (15e). Prepared
according to the synthesis of compound 15a from compound 17 (100.0 mg, 0.5 mmol,
1.0 equiv) and compound 16g (123.0 mg, 0.55 mmol, 1.1 equiv) to afford compound 15e
(176.0 mg, 87%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.39–7.18 (m, 5H), 6.45
(d, J = 1.8 Hz, 2H), 6.33 (d, J = 19.1 Hz, 1H), 5.83–5.69 (m, 1H), 5.09–4.89 (m, 3H),
4.51 (d, J = 11.8 Hz, 1H), 4.44 (d, J = 11.8 Hz, 1H), 3.74 (s, 6H), 3.63–3.49 (m, 3H),
2.09–1.93 (m, 2H), 1.79–1.64 (m, 2H), 1.14 (d, J = 6.4 Hz, 3H); 13C{1H} NMR (100
MHz, CDCl3) δ 170.9, 160.8, 138.5, 137.7, 136.2, 128.3, 127.6, 127.5, 115.1, 107.3, 99.3,
75.7, 75.5, 71.1, 55.3, 42.0, 29.8, 28.7, 15.7; [α]D27: -8.4 (c 2.1, CHCl3); HRMS
+
(ESI-FT-ICR) m/z: [M+Na]+ Calcd for C24H30NaO5 421.1985; Found 421.1973.
(2S,3S)-2-(Benzyloxy)hept-6-en-3-yl 2-(3,5-dimethoxyphenyl)acetate (15f). Prepared
according to the synthesis of compound 15a from compound 17 (100.0 mg, 0.5 mmol,
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1.0 equiv) and compound 16f (123.0 mg, 0.55 mmol, 1.1 equiv) to afford compound 15f
(170.0 mg, 84%) as colorless oil. 1H NMR (400 MHz, CDCl3) δ 7.38–7.27 (m, 5H), 6.43
(d, J = 13.8 Hz, 2H), 6.36 (s, 1H), 5.78–5.70 (m, 1H), 5.01–4.92 (m, 3H), 4.58 (d, J =
12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 3.77 (s, 6H), 3.62–3.53 (m, 3H), 2.03–1.90 (m,
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2H), 1.77–1.68 (m, 2H), 1.11 (d, J = 6.3 Hz, 3H); C{1H} NMR (100 MHz, CDCl3) δ
171.0, 160.8, 138.5, 137.7, 136.1, 128.3, 127.6, 115.0, 107.3, 99.3, 75.5, 74.6, 71.0, 55.3,
41.8, 32.2, 29.7, 28.7, 15.2; [α]D27: +22.3 (c 1.4, CHCl3); HRMS (ESI-FT-ICR) m/z:
+
[M+Na]+ Calcd for C24H30NaO5 421.1985; Found 421.1973.
(S)-Hept-6-en-2-ol (16a).19a A solution of CuI (327.0 mg, 1.7 mmol, 0.1 equiv) in dry
THF (10.0 mL) under argon was cooled -20 oC and then compound 23 (1 M in THF, 25.8
mL, 25.8 mmol, 1.5 equiv) was added at the same temperature. Finally,
(S)-2-methyloxirane 21 (1.0 g, 17.2 mmol, 1.0 equiv) in dry THF (10.0 mL) was added
o
dropwise at the same temperature. The reaction mixture was stirred at -20 C for 2 h.
After completion, the reaction mixture was quenched with sat. NH4Cl and extracted with
EtOAc (20.0 mL × 3). The combined organic layers were washed with brine, dried over
anhydrous Na2SO4, concentrated and purified with silica gel column chromatography
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(PE:EtOAc, 10:1, Rf = 0.2) to afford compound 16a (1.7 g, 86%) as colorless oil. H
NMR (400 MHz, CDCl3) δ 5.87–5.64 (m, 1H), 4.58–4.94 (m 2H), 3.83–3.68 (m, 1H),
2.03 (dd, J = 13.3, 6.6 Hz, 2H), 1.55–1.32 (m, 4H), 1.15 (d, J = 6.2 Hz, 3H).
(R)-Hept-6-en-2-ol (16b).19b Prepared according to the synthesis of 16a from
(R)-2-methyloxirane 22 (0.5 g, 8.6 mmol, 1.0 equiv) and compound 23 (1 M in THF, 12.9
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mL, 12.9 mmol, 1.5 equiv) to afford compound 16b (0.8 g, 82%) as colorless oil. H
NMR (400 MHz, CDCl3) δ 5.88–5.68 (m, 1H), 4.58–4.94 (m 2H), 3.81–3.68 (m, 1H),
2.07–1.93 (m, 2H), 1.51–1.30 (m, 4H), 1.14 (d, J = 6.2 Hz, 3H).
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(R)-Pent-4-en-2-ol (16c).19e Prepared according to the synthesis of 16a from
(R)-2-methyloxirane 22 (0.5 g, 8.6 mmol, 1.0 equiv) and compound 24 (1 M in THF, 12.9
mL, 12.9 mmol, 1.5 equiv) to afford compound 16c (645.0 mg, 87%) as colorless oil. 1H
NMR (400 MHz, CDCl3) δ 5.87–5.65 (m, 1H), 5.19–4.93 (m, 2H), 3.86–3.72 (m, 1H),
2.25–2.07 (m, 2H), 1.13 (d, J = 6.1 Hz, 3H).
(4S,6S)-6-(Benzyloxy) hept-1-en-4-ol (16d).21a To a solution of compound 26 (1.3 g,
5.9 mmol, 1.0 equiv) in dry DCM (15 mL), was added DIBAL-H (1 M in toluene, 6.5 mL,
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6.4 mmol, 1.1 equiv) at -78 C. After being stirred at -78 C for 2 h, the reaction was
quenched with sat. sodium potassium tartrate (15.0 mL) at the same temperature, and
then warmed to room temperature and stirred for another 1 h. The mixture was extracted
with DCM (15.0 mL × 3). The combined organic layers were washed with brine, dried
over anhydrous Na2SO4, and concentrated to get crude aldehyde product.
To a solution of the above crude aldehyde product in DCM (10.0 mL), was added
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TiCl4 (1 M in DCM, 6.4 mL, 6.4 mmol, 1.1 equiv) at -78 C. After the mixture was
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stirred at -78 C for 15 min, allyltrimethylsilane 29 was added. After being stirred at -78
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oC for 1 h, the reaction was quenched with sat. NaHCO3 (10.0 mL) at -78 C, and then
stirred at room temperature for another 1 h. The reaction mixture was extracted with
DCM (15.0 mL × 3). The combined organic layers were washed with brine, dried over
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colorless oil. H NMR (400 MHz, CDCl3) δ 7.37–7.22 (m, 5H), 5.90–5.76 (m, 1H),
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5.15–5.04 (m, 2H), 4.62 (d, J = 11.6 Hz, 1H), 4.48–4.40 (m, 1H), 4.01–3.93 (m, 1H),
3.87 (dq, J = 11.7, 5.9 Hz, 1H), 2.51 (s, 1H), 2.22 (t, J = 6.7 Hz, 2H), 1.65 (dd, J = 12.9,
7.6 Hz, 2H), 1.25 (d, J = 6.2 Hz, 3H).
(4R,6S)-6-(Benzyloxy)hept-1-en-4-ol (16e). To a solution of compound 16d (650.0
mg, 2.9 mmol, 1.0 equiv) in dry THF (10.0 mL), were added compound 30 (986.0 mg,
5.9 mmol, 2.0 equiv) and Ph3P (2.7 g, 10.3 mmol, 3.5 equiv) at room temperature. The
solution of DIAD (1.9 g, 9.8 mmol, 3.3 equiv) in THF was added dropwise to the
reaction at room temperature. The reaction was stirred at room temperature for 12 h.
After quenching with H2O (20.0 mL), the mixture was extracted with EtOAc (20.0 mL ×
3). The combined organic layers were washed with brine, dried over anhydrous Na2SO4
and concentrated to afford crude ester compound.
To a solution of above crude ester compound in THF/H2O (3/1, 10.0 mL), was added
NaOH (348.0 mg, 8.7 mmol, 3.0 equiv) at room temperature. The mixture was stirred for
12 h at room temperature. The reaction was concentrated and extracted with EtOAc (20.0
mL × 3). The organic layers were washed with brine, dried over anhydrous Na2SO4,
concentrated and purified with silica gel column chromatography (PE:EtOAc, 3:1, Rf =
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0.2) to afford compound 16e (584.0 mg, 90% over two steps) as colorless oil. H NMR
(400 MHz, CDCl3) δ 7.38–7.22 (m, 5H), 5.90–5.75 (m, 1H), 5.09 (d, J = 8.5 Hz, 1H),
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