Total synthesis and cytotoxic activity of dechlorogreensporones A and D

Article abstract of DOI:10.1016/j.tet.2018.07.025

The first and convergent total syntheses of polyketide natural products dechlorogreensporones A and D have been accomplished in 17 longest linear steps with 2.8% and 5.4% overall yields, respectively, starting from known methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate and commercially available R-(+)-propylene oxide and 1,2-epoxy-5-hexene. Our synthesis exploited key Mitsunobu esterification and (E)-selective ring-closing metathesis (RCM) to assemble the macrocycles as well as a Jacobsen hydrolytic kinetic resolution to install the stereogenic centers. Both synthetic compounds were found to display significant cytotoxic activity against seven human cancer cell lines with the IC₅₀ ranges of 6.66–17.25 μM.

Full text of DOI:10.1016/j.tet.2018.07.025

Tetrahedron xxx (2018) 1e9
Contents lists available at ScienceDirect
Tetrahedron
journal homepage: www.elsevier.com/locate/tet
Total synthesis and cytotoxic activity of dechlorogreensporones A and
D
a
b
b
a
Laksamee Jeanmard , Panata Iawsipo , Jiraporn Panprasert , Vatcharin Rukachaisirikul ,
a, *
Kwanruthai Tadpetch
a
Department of Chemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Prince of Songkla University, Hat Yai, Songkhla 90112,
Thailand
Department of Biochemistry and Center of Excellence for Innovation in Chemistry, Faculty of Science, Burapha University, Chonburi 20131, Thailand
b
a r t i c l e i n f o
a b s t r a c t
Article history:
Received 5 June 2018
Received in revised form
The first and convergent total syntheses of polyketide natural products dechlorogreensporones A and D
have been accomplished in 17 longest linear steps with 2.8% and 5.4% overall yields, respectively, starting
from known methyl 2-(2-formyl-3,5-dihydroxyphenyl)acetate and commercially available R-(þ)-pro-
pylene oxide and 1,2-epoxy-5-hexene. Our synthesis exploited key Mitsunobu esterification and (E)-
selective ring-closing metathesis (RCM) to assemble the macrocycles as well as a Jacobsen hydrolytic
kinetic resolution to install the stereogenic centers. Both synthetic compounds were found to display
9
July 2018
Accepted 11 July 2018
Available online xxx
significant cytotoxic activity against seven human cancer cell lines with the IC50 ranges of 6.66e17.25
mM.
Keywords:
©
2018 Elsevier Ltd. All rights reserved.
Dechlorogreensporone A
Dechlorogreensporone D
Resorcylic acid lactone
Total synthesis
Cytotoxic activity
1
. Introduction
Pd-catalyzed cross coupling/elimination [7a,b,d,e], substitution by
dithiane anion [7c] and nucleophilic addition to Weinreb amide
(acylation) [7f-i].
The well-known 14-membered
b
-resorcylic acid lactones (RALs)
are a group of fungal polyketide metabolites that possess a multi-
tude of biological and pharmacological activities [1]. A subclass of
Dechlorogreensporones A (5) and D (6) are new 14-membered
-RALs, which were isolated, along with other 12 new RALs from
b
RALs are those containing an
positions, which are derivatives of radicicol [2]. The major examples
of this subclass of RALs are the pochonins [3] and the monocillins
a
,
b
-unsaturated ketone at the 8e10
a culture of a freshwater fungus Halenospora sp. by Oberlies and co-
workers in 2014 (Fig. 3) [8]. Compounds 5 and 6 are radicicol an-
alogues possessing a methoxy group at the 16-position, which
[
4] (Fig. 1). This group of metabolites has been shown to exhibit
represent rare examples of RALs containing b-resorcylic acid
various interesting biological activities e.g. antiviral activity against
Herpes Simplex Virus 1 (HSV 1) [3a], antifungal activity (against
Mucorflavas IFO 9560) [5], HSP-90 inhibitory activity [6], and latent
HIV-1 reactivation activity [3c]. In consequence of their diverse and
promising biological properties and structural features, this class of
macrolides has been synthetic targets for many synthetic organic
research groups worldwide [7]. Precedented strategies to construct
the macrocyclic cores of RALs possessing similar core skeleton
mainly relied on esterification reaction [7] and ring-closing
metathesis [7c,f-k] (Fig. 2). Other key bond formations included
monomethyl ethers. Dechlorogreensporones A and D have the
same planar structure which includes a stereogenic center at the 2-
position. However, the minor structural difference is that 5 contains
a keto group at the 5-position, whereas 6 bears an alcohol stereo-
genic center. In addition, dechlorogreensporone A (5) is structurally
very similar to the previously reported natural product crypto-
sporiopsin A [9]. The absolute configuration of the C-2 asymmetric
carbon in macrolactones 5 and 6 and other co-metabolites was
proposed by the isolation group to be S by the evidence of X-ray
diffraction analysis of the bromobenzoyl derivative of one of the
metabolites in the series. The absolute configuration of the C-5 in 6
and co-metabolites containing C-5 alcohol stereogenic center was
assigned to be S via a Mosher's ester method. Interestingly, the
assigned C-2 absolute configuration of 5 and 6 and other analogues
*
Corresponding author.
E-mail address: kwanruthai.t@psu.ac.th (K. Tadpetch).
https://doi.org/10.1016/j.tet.2018.07.025
040-4020/© 2018 Elsevier Ltd. All rights reserved.
0
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2018), https://doi.org/10.1016/j.tet.2018.07.025
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L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
Fig. 1. Structures of radicicol and selected examples of its analogues.
intermediate, the alcohol stereogenic center at the 5-position in 6
posed a challenge to the synthesis. Thus, we employed two
different routes for the synthesis of the requisite alcohol fragments
in conjunction with protecting group manipulation. The diene RCM
precursor 9 (for 5) or 10 (for 6) would be assembled by Mitsunobu
esterification between the common benzoic acid intermediate 11
and chiral alcohol intermediate 12 or 13. The common benzoic acid
intermediate 11 would be elaborated from the known phenol 14
using our previously described approach. The requisite chiral
alcohol 12 for the synthesis of 5 would be obtained from R-
(
þ)-propylene oxide (15) via double allylation, whereas enan-
tioenriched alcohol 13 would be prepared from 1,2-epoxy-5-
hexene (16) using Jacobsen hydrolytic kinetic resolution to
construct both chiral centers [10].
Fig. 2. Key bond formation strategies in previous syntheses of radicicol and its
analogues.
Synthesis of benzoic acid 11 which was required as a Mitsunobu
coupling partner for syntheses of both 5 and 6 commenced with
selective protection of known phenol 14 [11] with 4-
methoxybenzyl ether (PMB) group [12] to afford PMB ether 17 in
in the series is opposite to that of cryptosporiopsin A, which was
assigned by analogy to the known RAL pochonin D. Dechlor-
ogreensporones A and D were tested for cytotoxic activities against
two human cancer cell lines and were found to exhibit cytotoxicity
against the MDA-MB-435 (melanoma) cancer cell line with IC50
8
2% yield. Subsequent methylation of the remaining phenol moiety
with iodomethane and K CO in DMF furnished methyl ether 18 in
4% yield. Following our previously established sequence [7k],
2
3
9
benzaldehyde 18 was further elaborated to the requisite benzoic
acid 11 in 10 steps and 31% overall yield (Scheme 2).
values of 14.1 and 11.2
toxicity against the HT-29 (colon) cancer cell line with IC50 values of
20 and 25.4 M, respectively. Due to promising biological activ-
mM, respectively. They also exhibited cyto-
Synthesis of alcohol 12 required for the synthesis of 5 was
achieved in a concise sequence of 6 steps as illustrated in Scheme 3.
Regioselective ring opening of commercially available R-(þ)-pro-
pylene oxide (16) (>99% ee) by allylmagnesium bromide in the
presence of catalytic CuI provided the corresponding chiral sec-
ondary alcohol [13], which was instantaneously protected with
TBDPS group to afford TBDPS ether 19 in 78% yield over 2 steps.
Subsequent epoxidation of alkene 19 with m-CPBA afforded
racemic epoxide 20, which was then subjected to another regio-
selective ring opening by allylmagnesium bromide to give racemic
alcohol 21 in 89% yield [14]. Protection of the secondary alcohol of
>
m
ities of this subclass of RALs and our ongoing program for anti-
cancer drug discovery, our research group has been focusing on a
synthetic program of selected compounds of this class. Herein, we
report the first total synthesis of both 5 and 6 as well as evaluation
of their cytotoxic activity against seven human cancer cell lines.
2
. Results and discussion
Our retrosynthetic approach toward dechlorogreensporones A
(5) and D (6) would utilize similar disconnection strategy to
21 with ethoxymethyl (EOM) group provided EOM ether, which
Mohapatra and Thirupathi's [7j] and our previous report [7k] via
ring-closing metathesis (RCM) as a key macrocyclization protocol
and to concomitantly establish the (E) geometry of C8eC9 olefin.
We would also rely on the Mitsunobu esterification to construct the
ester functional group of the diene RCM precursor (Scheme 1).
Although the targets 5 and 6 only differ by the functional groups at
the 5-position and could be ideally synthesized from the same
after TBDPS deprotection with TBAF furnished the desired chiral
alcohol 12 in 95% yield. The absolute configuration of the alcohol
stereogenic center was confirmed to be R based on Mosher ester
analysis.
Having successfully synthesized both key fragments 11 and 12,
we continued to complete the synthesis of dechlorogreensporone A
(
(
Scheme 4). Benzoic acid 11 was subjected to esterification with
R)-alcohol 12 under Mitsunobu conditions using diisopropyl azo-
3
dicarboxylate (DIAD) and PPh in toluene at room temperature to
smoothly furnish the ester RCM diene precursor 9 in 72% yield. This
step was expected to provide the correct stereochemistry of the C-2
stereogenic center. With diene 9 in hand, the stage was then set for
the key ring-closing metathesis. We and the Mohapatra group have
previously demonstrated that the second-generation Grubbs cata-
lyst is a remarkable RCM catalyst for this type of substrate [7j,k].
However, in this case the second-generation Grubbs catalyst
proved to be less reactive and led to incomplete consumption of the
starting diene. To our delight, RCM of 9 using 10 mol% of second-
Fig. 3. Structures of dechlorogreensporones A (5) and D (6).
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L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
3
Scheme 1. Retrosynthesis of dechlorogreensporones A (5) and D (6).
Scheme 2. Synthesis of the common benzoic acid intermediate 11.
Scheme 3. Synthesis of alcohol 12.
generation Hoveyda-Grubbs catalyst in toluene at high dilution
was removal of both EOM protecting groups of 7 using 4 M HCl in
THF at ambient temperature to furnish diol 22 in 57% yield as, again,
a mixture of diastereomers. Both hydroxyl groups of 22 were then
simultaneously oxidized using a large excess Dess-Martin period-
ꢀ
(
5 mM) at 85 C proceeded to completion within 3.5 h to afford
RCM products 7 in 59% yield as an inseparable mixture of di-
astereomers. No attempts were made to separate these diastereo-
meric products because they would eventually be transformed into
the same diketo product via oxidation in the penultimate step. It
should be noted that the geometry of the resulting olefin at C8eC9
could not be determined by NMR spectroscopy at this stage. We
then carried this diastereomeric mixture on to the next step, which
2 2
inane in CH Cl to furnish diketone 23 in 62% yield. The geometry of
the C8eC9 olefin of the macrocyclic products from RCM could then
be verified to be (E) in this step on the basis of the coupling constant
of 15.6 Hz between H-8 and H-9. Finally, following Mohapatra's
protocol [7j], treatment of 23 with 1 M titanium tetrachloride in
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2018), https://doi.org/10.1016/j.tet.2018.07.025
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L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
Scheme 4. Completion of the synthesis of dechlorogreensporone A (5).
ꢀ
CH
2
Cl
2
at 0 C furnished dechlorogreensporone A (5) in 79% yield.
(R,R)-Co(III)(salen)(OAc) catalyst afforded (S)-diol 24 in 46% yield
and 98% ee [10]. The enantiomeric excess of 24 was determined by
chiral HPLC on the corresponding monobenzoate. Next, protection
of diol 24 using 2,2-dimethoxypropane in the presence of p-tol-
uenesulfonic acid gave the corresponding acetonide in 75% yield
based on the recovered diol 24 [15]. Subsequent epoxidation with
m-CPBA furnished racemic epoxide rac-25 in 72% yield [16].
Racemic epoxide 25 was then subjected to second hydrolytic ki-
netic resolution using (R,R)-Co(III)(salen)(OAc) as a catalyst to give
(R)-epoxide 25 in 42% yield [16,17]. Regioselective ring-opening of
epoxide 25 by allylmagnesium bromide in the presence of catalytic
CuI yielded chiral alcohol 26 in 88% yield and 98% de (determined
on the monobenzoate derivative by chiral HPLC). The absolute
configuration of the newly generated alcohol stereogenic center
was confirmed to be S based on Mosher ester analysis. We chose a
PMB protecting group for this chiral alcohol for the purpose of
1
13
The H and C NMR spectroscopic and HRMS data of synthetic 5
were nearly identical to those reported for natural 5 (see
Supplementary data). Additionally, the specific rotation of synthetic
2
6.4
5
([
a
]
D
¼ þ66.02 (c 0.10, MeOH)) was in excellent agreement with
20
the reported value for natural 5 ([
a]
D
¼ þ56.0 (c 0.10, MeOH)) [8].
Our synthesis thus confirmed the absolute configuration of the
natural product dechlorogreensporone A assigned by Oberlies and
co-workers.
The synthesis of chiral alcohol 13 required for the synthesis of 6
is outlined in Scheme 5. Although we could in theory use the
epoxide intermediate 20 for the synthesis of the desired chiral
epoxide, the Jacobsen hydrolytic kinetic resolution of 20 was un-
successful. Thus, we had to revise the synthesis of chiral alcohol 13
using a different starting material. Hydrolytic kinetic resolution of
commercially available 1,2-epoxy-5-hexene (16) using Jacobsen's
Scheme 5. Synthesis of chiral alcohol 13.
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2018), https://doi.org/10.1016/j.tet.2018.07.025
(

L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
5
global deprotection in the final step. (S)-Alcohol 26 on protection
using excess of both PMBCl and KI gave the corresponding PMB
ether in 88% yield. The next task was to convert to the protected
diol moiety to the chiral secondary alcohol which was accom-
plished in 3 steps. Removal of the acetonide protecting group with
by the Oberlies group. The spectroscopic and analytical properties
1
13
of 6 and 31 ( H and C NMR, and HRMS) were identical to those of
reported for the natural products 6 and 31 (see Supplementary
data). The specific rotation of synthetic 6 was observed as
2
6.8
[a
]
D
¼ þ64.60 (c 0.27, MeOH), which was in accordance with that
20
7
0% AcOH smoothly gave diol 27 in 91% yield. Diol 27 on further
monotosylation employing TsCl and Et N in the presence of cata-
lytic DMAP in CH Cl , followed by reduction using LiAlH in THF
of natural 6 ([
a
]
D
¼ þ116.0 (c 0.27, MeOH)), yet in a lower
3
magnitude [8]. In addition, the specific rotation of synthetic 31 was
obtained as [
identical to the reported value for natural 31 ([
MeOH)) [8].
27.3
2
2
4
a
]
D
¼ ꢁ38.48 (c 0.11, MeOH), which was nearly
20
yielded the requisite (R)-alcohol 13 in 85% yield [17]. The absolute
configuration of the alcohol stereogenic center was confirmed to be
R via Mosher ester analysis.
a]
D
¼ ꢁ31.0 (c 0.11,
Synthetic compounds 5 and 6 were assessed for their cytotoxic
activity by MTT assay against seven human cancer cell lines
including two breast adenocarcinoma (MDA-MB-231 and MCF-7),
one colorectal carcinoma (HCT116), one hepatoma (HepG2) and
three cervical carcinoma (C33A, HeLa and SiHa) cells as well as one
monkey kidney non-cancerous (Vero) cell line (Table 1) [18]. It was
observed that both compounds could inhibit the proliferation of all
With the requisite chiral alcohol 13 in hand, completion of the
synthesis of dechlorogreensporone D (6) was achieved via the same
synthetic approach as that of 5 (Scheme 6). Mitsunobu coupling of
benzoic acid 11 and (R)-alcohol 13 under the same conditions
previously described smoothly gave ester diene 10 in 83% yield.
Ring-closing metathesis of diene 10 using second-generation
ꢀ
Hoveyda-Grubbs catalyst (10 mol%) in toluene (5 mM) at 85 C
cancer cell lines with the IC50 ranges of 6.94e17.25
mM for com-
furnished macrocyclic product 8 in 72% yield as an inseparable
mixture of diastereomers. The slightly higher yield of the RCM of 10
compared to 9 was ascribed to the better compatibility of the PMB
protecting group under these RCM conditions. Similar to previous
observation, the geometry of the newly formed C8eC9 olefin could
be determined at a later stage of the synthesis. We proceeded to
remove the EOM protecting group using 4 M HCl solution in THF at
room temperature for 4 h to give 29 in 53% yield based on recovered
starting EOM ether. Careful monitoring must be done in this step to
prevent overdeprotection of the PMB groups. At this stage, the trans
geometry of the double bond of 29 was confirmed based on the
coupling constant (15.3 Hz) between H-8 and H-9. Oxidation of
allylic alcohol 29 was achieved using excess 2-iodoxybenzoic acid
pound 5 and 6.66e11.84 M for compound 6, although in a signif-
m
icantly lower extent compared to a standard drug doxorubicin.
Interestingly, however, both 5 and 6 showed more potent cytotoxic
activity than a standard drug cisplatin against five cancer cell lines
(MDA-MB-231, MCF-7, HCT116, HepG2 and SiHa) tested. Our results
also revealed that dechlorogreensporone D (6) showed higher
antiproliferative effect against most cancer cell lines tested than the
Table 1
Cytotoxic activity of synthetic 5 and 6 against seven cancer cell lines and Vero cells.
cell lines
cytotoxicity, IC50 (mM)
5
6
cisplatin
doxorubicin
(
IBX) in a mixture of toluene and DMSO to afford macrocyclic enone
MDA-MB-231
MCF-7
HCT116
HepG2
C33A
HeLa
SiHa
Vero
9.28 ± 0.13
17.25 ± 0.71
7.53 ± 0.13
13.81 ± 0.27
10.06 ± 0.53
15.5 ± 0
6.97 ± 1.73
11.84 ± 0.05
6.97 ± 0.05
7.88 ± 0.88
10.41 ± 0.13
7.88 ± 1.06
6.66 ± 1.02
10.13 ± 0.88
25.25
35.5
35
0.51
0.29
0.81
0.65
0.19
0.16
0.18
>1
3
0 in 74% yield. Finally, both PMB protecting groups of 30 were
ꢀ
removed using 6 equivalents of 1 M TiCl
4
in CH
2
Cl
2
at 0 C to deliver
26
the requisite dechlorogreensporone D (6) in 49% yield along with
unexpected analogue dechlorogreensporone F (31) in 48% yield.
Byproduct 31 was a proposed artifact from a facile intramolecular
cycloetherification of the parent 6 during the purification process
4.72
8.98
12.18
17.75
6.94 ± 1.06
46.00 ± 3.18
Scheme 6. Completion of the synthesis of dechlorogreensporone D (6).
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6
L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
2
4.6
ketone analogue 5. This observation was consistent with the report
by the Oberlies group [8]. Nevertheless, 5 was approximately 5-fold
less cytotoxic to Vero cells compared to 6.
72%): R
f
¼ 0.63 (40% EtOAc/hexanes); [
H NMR (300 MHz, CDCl
7.34 (d, J ¼ 8.4 Hz, 2H), 6.91 (d,
J ¼ 8.4 Hz, 2H), 6.49 (s, 1H), 6.40 (s, 1H), 5.81 (ddt, J ¼ 17.1, 10.2,
a
]
D
¼ þ0.47 (c 0.50, CHCl
3
);
1
3
) d
6
.6 Hz, 1H), 5.70 (ddd, J ¼ 17.1, 9.9, 7.2 Hz, 1H), 5.21e5.12 (m, 3H),
3
. Conclusion
5.04e4.93 (m, 4H), 4.69 (s, 2H), 4.61 (d, J ¼ 6.6 Hz, 1H), 4.49 (d,
J ¼ 6.6 Hz, 1H), 4.29e4.23 (m, 1H), 3.81 (s, 3H), 3.75 (s, 3H),
3.65e3.58 (m, 3H), 3.32 (qd, J ¼ 6.9, 2.1 Hz, 2H), 2.95e2.73 (m, 2H),
2.16e2.07 (m, 2H), 1.70e1.57 (m, 6H), 1.36e1.30 (m, 3H), 1.12 (td,
In conclusion, the first and convergent total syntheses of dech-
lorogreensporones A (5) and D (6) have been accomplished via a
longest linear sequence of 17 steps in 2.8% and 5.4% overall yields,
respectively, from known phenol 14 and commercially available R-
13
J ¼ 6.9, 2.1 Hz, 3H), 1.05 (t, J ¼ 7.2 Hz, 3H); C NMR (75 MHz, CDCl
3
)
d
167.7, 160.0, 159.5, 157.9, 138.5, 138.3, 138.2, 137.8, 129.2, 128.6,
(
þ)-propylene oxide and 1,2-epoxy-5-hexene. Our approach
117.9, 117.2, 117.1, 114.6, 114.0, 108.2, 97.8, 93.9, 92.3, 77.4, 77.3, 76.7,
76.5, 72.0, 71.7, 69.9, 63.3, 63.0, 55.7, 55.3, 39.7, 33.7, 33.6, 31.8, 31.5,
30.2, 30.1, 29.9, 29.8, 29.5, 29.4, 29.3, 21.9, 21.7, 20.2, 20.1, 15.1, 14.9;
exploited key Mitsunobu esterification and ring-closing metathesis
to assemble the macrocycles and construct the (E)-olefin. Jacobsen
hydrolytic kinetic resolution was also utilized to install the C-2 and
C-5 stereogenic centers. Our syntheses verified the absolute ste-
reochemistry of the natural products proposed by the Oberlies
group. Synthetic compounds 5 and 6 were found to display sig-
nificant cytotoxic activity against seven human cancer cell lines
ꢁ1
IR (thin film) 2977, 2935, 1717, 1517, 1250, 1159, 1107 cm ; HRMS
(MALDI-TOF) m/z calcd for C35
637.3341.
H50NaO
9
(M þ Na)þ 637.3347, found
4.3. RCM of 9 to afford macrolactones 7
with the IC50 ranges of 6.66e17.25 mM. In addition, dechlor-
ogreensporone D (6) showed more potent antiproliferative activity
compared to dechlorogreensprone A (5), although 5 was approxi-
mately 5-fold less cytotoxic to Vero cells compared to 6.
A solution of diene 9 (131.5 mg, 0.214 mmol) in toluene (42 mL,
5 mM) was degassed with Ar for 10 min and second-generation
Hoveyda Grubbs catalyst (13.4 mg, 0.021 mmol, 10 mol%) was
ꢀ
added. The reaction mixture was heated at 85 C for 3.5 h, which
4
. Experimental
the starting diene was completely consumed as judged by TLC.
Solvent was then removed under reduced pressure. Purification of
the crude residue by column chromatography (10e15% EtOAc/
hexanes) yielded a mixture of macrolactone products 7 as a light
4.1. General
All reactions were performed under argon or nitrogen atmo-
yellow oil (74.2 mg, 59%):
R
f
¼ 0.50 (40% EtOAc/hexanes);
2
5.3
1
sphere in oven- or flamed-dried glassware unless otherwise noted.
Solvents were used as received from suppliers or distilled prior to
use using standard procedures. All other reagents were obtained
from commercial sources and used without further purification.
[
a
]
D
¼ ꢁ5.26 (c 0.50, CHCl
3
); H NMR (300 MHz, CDCl 7.35 (d,
3
) d
J ¼ 8.4 Hz, 2H), 6.91 (dd, J ¼ 8.4, 2.7 Hz, 2H), 6.81e6.58 (m, 1H), 6.41
(s, 1H), 5.66e5.54 (m, 1H), 5.29e5.04 (m, 2H), 4.98 (s, 2H),
4.75e4.58 (m, 4H), 4.29e4.17 (m, 1H), 3.80 (s, 3H), 3.77 (d,
J ¼ 2.1 Hz, 3H), 3.72e3.45 (m, 5H), 3.24e2.75 (m, 2H), 2.30e1.42 (m,
®
Column chromatography was performed on SiliaFlash G60 Silica
13
(
60e200
mm, Silicycle) or Silica gel 60 (0.063e0.200 mm, Merck).
8H), 1.34 (t, J ¼ 6.6 Hz, 3H), 1.30e1.14 (m, 6H); C NMR (75 MHz,
Thin-layer chromatography (TLC) was performed on Silica gel 60
3
CDCl ) d 168.0, 167.9, 167.8, 160.3, 159.9, 159.5, 158.3, 158.2, 157.8,
1
13
F
254 (Merck). H, C and 2D NMR spectroscopic data were recorded
157.7, 138.6, 138.4, 138.1, 137.9, 137.4, 136.7, 134.8, 134.6, 133.8, 130.7,
129.3, 129.2, 129.1, 129.0,128.8,128.6,128.4,118.1, 114.1, 114.0, 109.3,
108.4, 107.1, 107.0, 98.1, 98.0, 97.8, 94.2, 94.0, 93.8, 93.5, 93.0, 92.4,
91.9, 91.7, 91.4, 79.3, 78.2, 77.9, 76.0, 75.5, 74.3, 73.0, 72.3, 70.9, 69.9,
69.8, 63.4, 63.3, 63.2, 63.1, 62.8, 55.9, 55.8, 55.3, 39.2, 38.9, 38.2,
37.2, 33.2, 32.8, 32.6, 32.1, 32.0, 31.1, 30.9, 30.5, 29.1, 28.8, 28.3, 27.8,
23.7, 21.9, 21.7, 20.7, 20.2, 20.1, 15.2, 15.1, 14.8; IR (thin film) 2971,
1
on a 300 MHz Bruker FTNMR UltraShield spectrometer. H NMR
spectra are reported in ppm on the scale and referenced to the
d
internal tetramethylsilane. The data are presented as follows:
chemical shift, multiplicity (s ¼ singlet, d ¼ doublet, t ¼ triplet,
q ¼ quartet,
quint ¼ quintet,
sext ¼ sextet,
m ¼ multiplet,
br ¼ broad, app ¼ apparent), coupling constant(s) in hertz (Hz), and
ꢁ
1
integration. Infrared (IR) spectra were recorded on a Perkin Elmer
2932, 1718, 1603, 1458, 1252, 1159 cm ; HRMS (MALDI-TOF) m/z
7
83 FTS165 FT-IR spectrometer. High-resolution mass spectra were
calcd for C33
H
46NaO
9
(M þ Na)þ 609.3034, found 609.3036.
obtained on a liquid chromatograph-mass spectrometer (2690, LCT,
Waters, Micromass) and on a SpiralTOF™ MALDI TOF Mass Spec-
trometer Revolutionary (Scientific and Technological Research
Equipment Centre; STREC, Chulalongkorn University). The optical
rotations were recorded on a JASCO P-2000 polarimeter. Melting
points were measured using an Electrothermal IA9300 melting
point apparatus and are uncorrected. Enantiopurity was deter-
mined using HPLC on an Agilent series 1200 equipped with a diode
4.4. Removal of EOM protecting groups of 7 to give diol 22
To a solution of EOM ether 7 (49.5 mg, 0.084 mmol) in THF
(4.2 mL) at rt was added 2.4 mL of 4 M HCl. The mixture was stirred
at rt overnight, then which was quenched with saturated aqueous
NaHCO (5 mL) and diluted with EtOAc (5 mL). The organic layer
3
was separated and the aqueous layer was extracted with EtOAc
®
array UV detector using either CHIRALCEL OD-H column (15 cm)
(4 ꢂ 5 mL). The combined organic layers were washed with brine,
®
or CHIRALPAK AS-H column (15 cm) and a guard column (1 cm).
2 4
dried with anhydrous Na SO and concentrated in vacuo. Purifica-
tion of the crude residue by column chromatography (40% EtOAc/
4
.2. Synthesis of diene RCM precursor 9
hexanes) yielded diol 22 as a light yellow oil (22.5 mg, 57%):
2
5.1
1
R
f
¼ 0.34 (80% EtOAc/hexanes); [
a
]
D
¼ ꢁ24.43 (c 0.50, CHCl
3
); H
To a solution of benzoic acid 11 (245.3 mg, 0.59 mmol, 1.0 equiv)
NMR (300 MHz, CDCl
3
)
d
7.34 (d, J ¼ 8.4 Hz, 2H), 6.91 (dd, J ¼ 8.4,
and (R)-alcohol 12 (122.3 mg, 0.57 mmol) in 5.9 mL of toluene at
room temperature were added PPh (314.9 mg, 1.20 mmol, 2.0
equiv), followed by diisopropyl azodicarboxylate (40% in toluene,
.58 mL, 1.18 mmol, 2.0 equiv). The resultant yellow mixture was
1.8 Hz, 2H), 6.75e6.52 (m, 1H), 6.43e6.40 (m, 1H), 5.60e5.51 (m,
1H), 5.38e5.02 (m, 2H), 4.98e4.97 (m, 2H), 4.46e4.34 (m, 1H),
3.81e3.75 (m, 6H), 3.72e3.57 (m, 1H), 3.21e2.74 (m, 2H), 2.17e1.54
(m, 8H), 1.36 (d, J ¼ 6.0 Hz, 3H); C NMR (75 MHz, CDCl
3
1
3
0
3
) d 168.4,
stirred at rt overnight before being concentrated in vacuo. Purifi-
cation of the crude residue by column chromatography (5e10%
EtOAc/hexanes) yielded ester diene 9 as a light yellow oil (259.1 mg,
167.9, 160.8, 160.3, 159.7, 158.9, 138.5, 138.0, 133.4, 133.0, 132.6,
132.2, 132.0, 131.6, 129.7, 129.5, 128.8, 128.6, 127.5, 118.1, 117.8, 114.2,
109.2, 108.4, 107.2, 106.9, 98.5, 98.1, 73.9, 73.8, 73.6, 73.2, 73.1, 72.9,
Please cite this article in press as: L. Jeanmard, et al., Total synthesis and cytotoxic activity of dechlorogreensporones A and D, Tetrahedron
2018), https://doi.org/10.1016/j.tet.2018.07.025
(

L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
7
7
3
2
0.3, 70.1, 70.0, 69.8, 67.7, 67.5, 56.1, 55.5, 41.7, 41.4, 39.1, 38.5, 36.6,
6.4, 35.5, 35.3, 34.5, 32.2, 31.9, 30.7, 30.6, 29.4, 29.1, 28.5, 27.9, 21.1,
0.9, 20.4, 20.3; IR (thin film) 3447, 2933, 2858, 1700, 1603, 1251,
EtOAc/hexanes) yielded ester diene 10 as a light yellow oil
25.5
(297.8 mg, 83%): R
f
¼ 0.55 (40% EtOAc/hexanes); [
a
]
D
¼ ꢁ2.40 (c
1
0.50, CHCl
3
); H NMR (300 MHz, CDCl
3
) d
7.36 (d, J ¼ 8.7 Hz, 2H),
ꢁ1
1161 cm
;
HRMS (MALDI-TOF) m/z calcd for
C
27
H34NaO
7
7.26 (d, J ¼ 8.7 Hz, 2H), 6.92 (d, J ¼ 8.7 Hz, 2H), 6.87 (d, J ¼ 8.7 Hz,
þ
(
M þ Na) 493.2202, found 493.2211.
2H), 6.49 (s, 1H), 6.39 (s, 1H), 5.81 (ddt, J ¼ 17.1, 10.2, 6.3 Hz, 1H),
5
.69 (ddd, J ¼ 17.4, 9.9, 7.2 Hz,1H), 5.20e5.18 (m, 3H), 5.03e4.92 (m,
4.5. Oxidation of diol 22 to give diketone 23
4H), 4.61 (d, J ¼ 6.9 Hz, 1H), 4.45 (d, J ¼ 6.9 Hz, 1H), 4.43 (s, 2H),
4.29e4.22 (m, 1H) 3.82 (s, 3H), 3.80 (s, 3H), 3.74 (s, 3H), 3.46e3.42
To a solution of macrolactone diol 22 (112.2 mg, 0.24 mmol) in
(m, 1H), 3.33 (qd, J ¼ 7.2, 3.0 Hz, 2H), 2.95e2.75 (m, 2H), 2.16e2.07
ꢀ
CH
(
2
Cl
2
(10 mL) at 0 C was added Dess-Martin periodinane
(m, 2H), 1.78e1.60 (m, 6H), 1.34e1.31 (m, 3H), 1.05 (t, J ¼ 7.2 Hz,
13
808.8 mg, 1.90 mmol, 8.0 equiv). The reaction mixture was stirred
3
3H); C NMR (75 MHz, CDCl ) d 167.7, 160.0, 159.6, 159.1, 158.0,
ꢀ
from 0 C to room temperature for 4 h. The reaction mixture was
138.7, 138.3, 138.2, 137.8, 131.1, 129.3, 129.2, 128.7, 118.0, 117.0, 114.5,
114.1, 113.8, 108.4, 97.9, 92.4, 77.5, 77.4, 77.3, 71.7, 70.4, 69.9, 63.0,
55.8, 55.3, 39.7, 33.2, 31.5, 29.6, 29.4, 20.2, 20.1, 14.9; IR (thin film)
quenched with saturated aqueous NaHCO
with CH Cl (10 mL). The organic layer was separated and the
aqueous layer was extracted with CH Cl
(3 ꢂ 10 mL). The com-
bined organic layers were washed with brine, dried with anhydrous
Na SO and concentrated in vacuo. Purification of the crude residue
by column chromatography (20e40% EtOAc/hexanes) provided
diketone 23 as a light yellow oil (66.2 mg, 62%): R
¼ 0.21 (40%
); H NMR (300 MHz,
7.35 (d, J ¼ 8.7 Hz, 2H), 6.92 (d, J ¼ 8.7 Hz, 2H), 6.78 (dt,
J ¼ 15.6, 6.3 Hz, 1H), 6.55 (d, J ¼ 1.8 Hz, 1H), 6.43 (d, J ¼ 1.8 Hz, 1H),
.05 (d, J ¼ 15.6 Hz, 1H), 5.18 (m, 1H), 4.98 (d, J ¼ 2.4 Hz, 1H), 4.32 (d,
J ¼ 14.1 Hz, 1H), 3.82 (s, 3H), 3.75 (s, 3H), 3.36 (d, J ¼ 14.1 Hz, 1H),
.73e2.38 (m, 6H), 2.07e1.97 (m, 1H), 1.82e1.68 (m, 1H), 1.37 (d,
3
(15 mL) and diluted
2
2
ꢁ1
2
2
2933, 2862, 1716,1516,1250, 1159, 1034 cm ; HRMS (ESI) m/z calcd
for C40
H
52NaO
9
(M þ Na)þ 699.3509, found 699.3533.
2
4
4.8. RCM of 10 to afford macrolactones 8
f
2
5.3
1
EtOAc/hexanes); [
CDCl
a
]
D
¼ þ2.80 (c 0.50, CHCl
3
To a solution of diene 10 (41.7 mg, 0.061 mmol) in toluene
(12.3 mL, 5 mM) was degassed with Ar for 10 min and second-
generation Hoveyda Grubbs catalyst (3.9 mg, 0.006 mmol, 10 mol
3
) d
ꢀ
6
%) was added. The reaction mixture was heated at 85 C for 4 h, at
which the starting diene was completely consumed as judged by
TLC. Solvent was then removed under reduced pressure. Purifica-
tion of the crude residue by column chromatography (10% EtOAc/
hexanes) yielded a mixture of macrolactone products 8 as a light
2
1
3
J ¼ 6.3 Hz, 3H); C NMR (75 MHz, CDCl
59.7, 159.1, 146.1, 135.2, 130.6, 129.4, 128.4, 116.8, 114.1, 107.9, 99.0,
1.1, 70.0, 56.0, 55.3, 44.2, 40.5, 39.1, 28.6, 28.3, 20.3; IR (thin film)
3
) d 209.5, 196.7, 167.9, 160.9,
1
7
3
yellow oil (28.8 mg, 72%):
R
f
¼ 0.48 (40% EtOAc/hexanes);
); H NMR (300 MHz, CDCl 7.34 (d,
J ¼ 8.4 Hz, 4H), 7.26e7.21 (m, 4H), 6.92e6.86 (m, 8H), 6.79 (s, 1H),
.59 (s, 1H), 6.39 (s, 2H), 5.66e5.46 (m, 2H), 5.36e5.13 (m, 2H),
ꢁ1
24.7
1
011, 2933, 2853, 1701, 1605, 1252, 1161 cm ; HRMS (MALDI-TOF)
m/z calcd for C27
[a
]
D
¼ ꢁ2.53 (c 0.50, CHCl
3
3
) d
H
30NaO
7
(M þ Na)þ 489.1884, found 489.1884.
6
4
.6. Deprotection of PMB group of 23 to furnish
5.13e4.90 (m, 6H), 4.76e4.71 (m, 2H), 4.68e4.60 (m, 2H),
4.53e4.46 (m, 2H), 4.38e4.25 (m, 4H), 3.79 (s, 6H), 3.74e3.62 (m,
dechlorogreensporone A (5)
8H), 3.62e3.47 (m, 2H), 3.46e3.21 (m, 2H), 3.21e3.07 (m, 1H),
To a solution of macrolactone 23 (66.2 mg, 0.14 mmol) in 15 mL
3.01e2.95 (m, 2H), 2.85e2.64 (m, 1H), 2.51e1.41 (m, 16H),
ꢀ
13
of CH
2
Cl
2
at 0 C was added TiCl
4
(1.0 M solution in CH
2
Cl
2
, 450
mL,
1.40e1.29 (m, 6H), 1.25e1.18 (m, 6H); C NMR (75 MHz, CDCl
3
)
0
.140 mmol, 3.2 equiv). The brick orange cloudy mixture was stirred
d 168.1, 167.9, 160.4, 159.9, 159.6, 159.2, 158.3, 138.6, 138.1, 134.8,
ꢀ
from 0 C to room temperature for 30 min, which was then
quenched with saturated aqueous NaHCO (20 mL) and the orange
color dissipated. The organic layer was separated and the aqueous
layer was extracted with CH Cl
(3 ꢂ 15 mL). The combined organic
layers were washed with brine, dried with anhydrous Na SO and
131.0, 129.3, 129.2, 128.7, 128.5, 118.2, 118.0, 114.0, 113.9, 109.2, 107.1,
98.0, 97.8, 93.1, 91.5, 77.4, 76.1, 76.0, 74.8, 70.8, 70.5, 70.2, 70.0, 63.4,
63.2, 55.9, 55.3, 39.9, 37.3, 31.5, 31.4, 30.7, 30.5, 28.8, 28.3, 28.2, 21.9,
21.7, 20.3, 20.2, 15.2; IR (thin film) 2933, 2875, 1716, 1603, 1516,
3
2
2
ꢁ
1
2
4
1250, 1160 cm ; HRMS (MALDI-TOF) m/z calcd for C38
H48NaO
9
concentrated in vacuo. The crude residue was purified by column
chromatography (30e40% EtOAc/hexanes) to give dechlor-
(M þ Na)þ 671.3191, found 671.3157.
ogreensporone A (5) as a light yellow solid (38.4 mg, 79%): R
f
¼ 0.37
4.9. Removal of EOM protecting group of 8 to give allylic alcohol 29
ꢀ
26.4
(
60% EtOAc/hexanes); mp 142.9e146.4 C; [
a
]
D
¼ þ66.02 (c 0.10,
1
MeOH); H NMR (300 MHz, CDCl
3
)
d
6.82e6.75 (m, 1H), 6.43 (d,
To a solution of EOM ether 8 (148.8 mg, 0.23 mmol) in THF
(11 mL) at rt was added 6.5 mL of 4 M HCl. The mixture was stirred
at rt for 4 h, which was then quenched with saturated aqueous
NaHCO (15 mL) and diluted with EtOAc (10 mL). The organic layer
3
was separated and the aqueous layer was extracted with EtOAc
J ¼ 2.1 Hz, 1H), 6.30 (d, J ¼ 2.1 Hz, 1H), 6.05 (d, J ¼ 15.6 Hz, 1H),
.21e5.16 (m, 1H), 4.29 (d, J ¼ 14.1 Hz, 1H), 3.72 (s, 3H), 3.35 (d,
J ¼ 14.1 Hz, 1H), 2.73e2.40 (m, 6H), 2.19e1.96 (m, 1H), 1.84e1.72 (m,
5
1
3
2
1
4
1
H), 1.37 (d, J ¼ 6.0 Hz, 3H); C NMR (75 MHz, CDCl
68.4, 159.6, 159.1, 147.5, 134.9, 130.6, 115.7, 109.8, 98.9, 71.4, 56.0,
4.1, 40.6, 39.4, 28.7, 28.4, 20.5; IR (thin film) 3367, 2930, 2855,
3
)
d
210.1, 198.6,
(3 ꢂ 20 mL). The combined organic layers were washed with brine,
2 4
dried with anhydrous Na SO and concentrated in vacuo. Purifica-
ꢁ
1
699, 1610, 1458, 1273 cm ; HRMS (MALDI-TOF) m/z calcd for
tion of the crude residue by column chromatography (10e20%
EtOAc/hexanes) yielded the desired allylic alcohol 29 as a light
yellow oil (34.2 mg, 25%, 53% based on 78.5 mg of recovered 8):
þ
C
19
H
22NaO
6
(M þ Na) 369.1314, found 369.1322.
2
5.1
1
4.7. Synthesis of diene RCM precursor 10
R
f
¼ 0.27 (40% EtOAc/hexanes); [
a
]
D
¼ ꢁ17.33 (c 0.50, CHCl
3
); H
NMR (300 MHz, CDCl
3
) d
7.34 (d, J ¼ 8.4 Hz, 4H), 7.27e7.21 (m, 4H),
To a solution of benzoic acid 11 (272.5 mg, 0.65 mmol, 1.2 equiv)
6.93e6.87 (m, 8H), 6.72 (s, 1H), 6.53 (s, 1H), 6.42e6.40 (m, 2H),
5.59e5.50 (m, 2H), 5.36 (dd, J ¼ 15.3, 3.6 Hz, 1H), 5.26 (dd, J ¼ 15.3,
8.4 Hz, 1H), 4.99 (s, 2H), 4.97 (s, 2H), 4.55e4.48 (m, 2H), 4.36e4.29
(m, 4H), 3.81 (s, 12H), 3.75 (s, 3H), 3.74 (s, 3H), 3.38e3.33 (m, 2H),
3.15 (dd, J ¼ 14.4, 3.6 Hz, 1H), 3.03e2.94 (m, 2H), 2.81 (dd, J ¼ 12.9,
and (R)-alcohol 13 (148.1 mg, 0.53 mmol) in 6 mL of toluene at
room temperature were added PPh (351.9 mg, 1.34 mmol, 2.5
equiv), followed by diisopropyl azodicarboxylate (40% in toluene,
.66 mL, 1.34 mmol, 2.5 equiv). The resultant yellow mixture was
3
0
13
stirred at rt overnight before being concentrated in vacuo. Purifi-
cation of the crude residue by column chromatography (5e10%
9.6 Hz, 1H), 2.14e1.71 (m, 16H), 1.42e1.26 (m, 6H); C NMR
3
(75 MHz, CDCl ) d 168.0,167.9, 160.5,160.1, 159.6, 159.2,158.7, 158.6,
Please cite this article in press as: L. Jeanmard, et al., Total synthesis and cytotoxic activity of dechlorogreensporones A and D, Tetrahedron
2018), https://doi.org/10.1016/j.tet.2018.07.025
(

8
L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
1
38.2, 137.7, 132.9, 132.0, 131.6, 131.0, 129.4, 128.6, 128.5, 127.9, 118.1,
J ¼ 17.1 Hz, 1H), 3.89e3.79 (m, 1H), 3.73 (s, 3H), 2.65 (dd, J ¼ 13.8,
3.9 Hz, 1H), 2.56 (dd, J ¼ 13.8, 8.1 Hz, 1H), 2.02e1.43 (m, 8H), 1.31 (d,
1
7
2
17.9, 114.1, 114.0, 113.9, 108.7, 106.9, 98.2, 98.0, 75.3, 75.1, 73.3, 73.0,
13
0.5, 70.3, 69.9, 69.8, 55.9, 55.3, 55.3, 41.4, 38.6, 31.5, 30.7, 30.6,
J ¼ 6.6 Hz, 3H); C NMR (75 MHz, CDCl
3
) d 208.6, 167.9,159.0,158.4,
8.5, 28.4, 28.0, 27.8, 20.2; IR (thin film) 3447, 2933, 2860, 1701,
133.8, 116.5, 109.4, 98.5, 79.3, 76.0, 72.6, 55.8, 49.1, 47.8, 33.5, 32.9,
ꢁ
þ
1
1605, 1249, 1161 cm
;
HRMS (MALDI-TOF) m/z calcd for
31.2, 30.4, 20.8; IR (thin film) 3366, 2927, 2855, 1716, 1608, 1458,
ꢁ1
C
35
H
42NaO
8
(M þ Na) 613.2772, found 613.2753.
1269 cm
(
19 6
; HRMS (MALDI-TOF) m/z calcd for C H24NaO
M þ Na)þ 371.1471, found 371.1464.
4.10. Oxidation of allylic alcohol 29 to give ketone 30
4.12. Cytotoxicity assay
To a solution of 29 (75.0 mg, 0.127 mmol) in 3 mL of DMSO:to-
luene (1:1) was added IBX (178.1 mg, 0.636 mmol, 5.0 equiv). The
reaction mixture was stirred at room temperature for 2 h before
being added IBX (106.9 mg, 0.382 mmol, 3.0 equiv), and stirred at
room temperature for 1 h. The reaction mixture was quenched with
H O (3 mL), and diluted with EtOAc (3 mL). The mixture was filtered
2
through a pad of Celite and washed with EtOAc. The organic layer
was separated and the aqueous layer was extracted with EtOAc
Cytotoxic activity of synthetic 5 and 6 were evaluated against
seven human cancer cell lines including two breast adenocarci-
noma (MDA-MB-231 and MCF-7), one colorectal carcinoma
(HCT116), one hepatoma (HepG2) and three cervical carcinoma
(C33A, HeLa and SiHa) cells as well as one monkey kidney non-
cancerous (Vero) cell line by MTT assay using the general procedure
previously described [18]. Cancer cells were exposed to various
(
3 ꢂ 5 mL). The combined organic layers were washed with brine,
concentrations of compounds 5 and 6 (0e25
mM; 0.2% (v/v) DMSO).
dried with anhydrous Na SO and concentrated in vacuo. Purifica-
2
4
Vero cells were exposed to 0e50 M of 5 and 6. Each experiment
m
tion of the crude residue by column chromatography (20% EtOAc/
hexanes) provided ketone 30 as a white solid (55.4 mg, 74%):
was performed in triplicate and was repeated three times. Data was
expressed as IC50values (the concentration needed for 50% cell
growth inhibition) relative to the untreated cells (0.2% (v/v) DMSO)
(means ± SD). Cisplatin (0e50 mM) and doxorubicin (0e1 mM)
(Pfizer, Australia) were used as positive controls.
ꢀ
24.5
R
f
¼ 0.48 (40% EtOAc/hexanes); mp 141.3e144.5 C; [
a
]
D
¼ þ10.6
1
(c 0.50, CHCl
3
); H NMR (300 MHz, CDCl
3
)
d
7.34 (d, J ¼ 8.4 Hz, 2H),
7
2
.23 (d, J ¼ 8.4 Hz, 2H), 6.91 (d, J ¼ 8.4 Hz, 2H), 6.89 (d, J ¼ 8.4 Hz,
H), 6.72 (dt, J ¼ 15.6, 7.8 Hz, 1H), 6.47 (s, 1H), 6.45 (s, 1H), 6.07 (d,
J ¼ 15.6 Hz, 1H), 4.96 (s, 2H), 4.90e4.85 (m, 1H), 4.51 (d, J ¼ 11.1 Hz,
Acknowledgements
1
3
(
H), 4.32 (d, J ¼ 11.1 Hz, 1H), 4.27 (d, J ¼ 15.6 Hz, 1H), 3.81 (s, 6H),
.76 (s, 3H), 3.45 (d, J ¼ 15.6 Hz, 1H), 3.37e3.31 (m, 1H), 2.29e2.22
This work was financially supported by the Thailand Research
Fund (Grant No. TRG5880272). We also acknowledge partial sup-
port from the Center of Excellence for Innovation in Chemistry
(PERCH-CIC), Office of the Higher Education Commission, Ministry
of Education (OHEC). Additional support is generously provided by
the Graduate School, Prince of Songkla University and the Devel-
opment and Promotion of Science and Technology Talents Project
1
3
m, 2H), 1.82e1.35 (m, 6H), 1.29 (d, J ¼ 6.0 Hz, 3H); C NMR
(
75 MHz, CDCl
3
)
d
197.0, 167.7, 160.9, 159.6, 159.4, 159.3, 147.6, 135.8,
1
7
2
30.6, 129.5, 129.4, 129.2, 128.3, 116.8, 114.1, 113.9, 107.8, 98.9, 75.0,
0.5, 70.0, 56.0, 55.3, 45.7, 30.8, 30.4, 28.7, 27.9, 20.2; IR (thin film)
ꢁ1
926, 2856, 1700, 1521, 1251, 1162, 1034 cm ; HRMS (MALDI-TOF)
m/z calcd for C35
H40NaO
8
(M þ Na)þ 611.2621, found 611.2640.
(DPST) for L. Jeanmard. Ms.Aticha Thiraporn, Mr.Pongsit Vijitphan
4.11. Deprotection of PMB groups of 30 to furnish
and Ms.Trichada Ratthachag are gratefully acknowledged for their
experimental assistance.
dechlorogreensporone D (6)
A solution of macrolactone 30 (55.4 mg, 0.094 mmol) in 9.5 mL
Appendix A. Supplementary data
ꢀ
of CH
2
Cl
2
at 0 C was added 1.0 M TiCl
4
(565
m
L, 0.565 mmol, 6.0
ꢀ
equiv). The brick orange cloudy mixture was stirred from 0 C to
room temperature for 30 min, which was then quenched with
Supplementary data related to this article can be found at
https://doi.org/10.1016/j.tet.2018.07.025.
3
saturated aqueous NaHCO (10 mL). The organic layer was sepa-
rated and the aqueous layer was extracted with EtOAc (3 ꢂ 10 mL).
References
The combined organic layers were washed with brine, dried with
anhydrous Na
2
SO
4
and concentrated in vacuo. The crude residue
[1] (a) N. Winssinger, S. Barleunga, Chem. Commun. 43 (2007) 22e36;
(
b) S. Barluenga, P.-Y. Dakas, M. Boulifa, E. Moulin, N.C.R. Winssinger, Chimie
1 (2008) 1306e1317.
2] P. Delmotte, J. Delmotte-Plaquee, Nature 171 (1953) 344.
was purified by column chromatography (20e30% EtOAc/hexanes)
to yield dechlorogreensporone D (6) as a light yellow solid (16.1 mg,
1
[
4
4
9%) and dechlorogreensporone F (31) as a light yellow oil (15.6 mg,
8%).
[3] (a) V. Hellwig, A. Mayer-Bartschmid, H. Müller, G. Grief, G. Kleymann,
W. Zitzmann, H.V. Tichy, M. Stadler, J. Nat. Prod. 66 (2003) 829e837;
(b) H. Shinonaga, Y. Kawamura, A. Ikeda, M. Aoki, N. Sakai, N. Fujimoto,
Dechlorogreensporone D (6). 16.1 mg, 49%; R
f
¼ 0.23 (60% EtOAc/
1
A. Kawashima, Tetrahedron 65 (2009) 13446e13453;
(c) E.J. Mejia, S.T. Loveridge, G. Stepan, A. Tsai, G.S. Jones, T. Barnes, K.N. White,
M. Dra ꢀs kovic, K. Tenney, M. Tsiang, R. Geleziunas, T. Cihlar, N. Pagratis, Y. Tian,
ꢀ
26.8
hexanes); mp 182.7e185.8 C; [
NMR (300 MHz, DMSO‑d
a
]
D
¼ þ64.60 (c 0.27, MeOH); H
6
) d
10.0 (br s, 1H), 6.68 (dt, J ¼ 15.9, 7.5 Hz,
H. Yu, P. Crews, J. Nat. Prod. 77 (2014) 618e624.
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766e773.
1
1
3
H), 6.39 (s, 1H), 6.29 (s, 1H), 5.98 (d, J ¼ 15.9 Hz, 1H), 4.94e4.87 (m,
[
H), 4.54 (br s, 1H), 4.06 (d, J ¼ 15.9 Hz, 1H), 3.72e3.62 (m, 4H),
.42e3.36 (m, 1H), 2.20e2.08 (m, 2H), 1.79e1.40 (m, 5H), 1.23 (d,
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L.M. Neckers, Cell Stress Chaperones 3 (1998) 100e108;
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(b) M. Lampilas, R. Lett, Tetrahedron Lett. 33 (1992) 777e780;
13
J ¼ 5.7 Hz, 3H), 1.19e1.10 (m, 1H); C NMR (75 MHz, DMSO‑d
6
)
d
196.0, 167.3, 159.8, 159.2, 148.3, 135.6, 128.5, 114.2, 109.7, 98.5,
9.4, 66.2, 55.9, 44.6, 34.6, 30.3, 29.2, 28.3, 20.2; IR (thin film) 3446,
6
2
ꢁ
1
926, 2857, 1695, 1685, 1523, 1089 cm ; HRMS (MALDI-TOF) m/z
(c) R.M. Garbaccio, S.J. Stachel, D.K. Baeschlin, S.J. Danishefsky, J. Am. Chem.
þ
calcd for C19
H
24NaO
6
(M þ Na) 371.1471, found 371.1478.
Soc. 123 (2001) 10903e10908;
(d) I. Tichkowsky, R. Lett, Tetrahedron Lett. 43 (2002) 3997e4001;
(e) I. Tichkowsky, R. Lett, Tetrahedron Lett. 43 (2002) 4003e4007;
Dechlorogreensporone F (31). 15.6 mg, 48%; R
f
¼ 0.33 (60% EtOAc/
2
7.3
1
hexanes); [
CDCl
6.32 (d, J ¼ 1.8 Hz, 1H), 6.24 (d, J ¼ 1.8 Hz, 1H), 5.28e5.25
m, 1H), 4.22e4.14 (m, 1H), 4.01 (d, J ¼ 17.1 Hz, 1H), 3.92 (d,
a
]
D
¼ ꢁ38.48 (c 0.11, MeOH); H NMR (300 MHz,
(
(
f) S. Barluenga, P. Lopez, E. Moulin, N. Winssinger, Angew. Chem. Int. Ed. 43
2004) 3467e3470;
3
) d
(
(g) E. Moulin, V. Zoete, S. Barluenga, M. Karplus, N. Winssinger, J. Am. Chem.
Please cite this article in press as: L. Jeanmard, et al., Total synthesis and cytotoxic activity of dechlorogreensporones A and D, Tetrahedron
2018), https://doi.org/10.1016/j.tet.2018.07.025
(

L. Jeanmard et al. / Tetrahedron xxx (2018) 1e9
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Please cite this article in press as: L. Jeanmard, et al., Total synthesis and cytotoxic activity of dechlorogreensporones A and D, Tetrahedron
2018), https://doi.org/10.1016/j.tet.2018.07.025
(