Synthesis of Simplified Tedanolide Analogues-Connecting Tedanolide to Myriaporone and Gephyronic Acid

Full text of DOI:10.1002/cmdc.201100576

MED
DOI: 10.1002/cmdc.201100576
Synthesis of Simplified Tedanolide Analogues—Connecting Tedanolide to
Myriaporone and Gephyronic Acid
Nina Diaz,[a] Arun Naini,[a] Yazh Muthukumar,[b] Florenz Sasse,[b] and Markus Kalesse*[a, c]
(+)-Tedanolide (1) was isolated from the Caribbean sponge
Tedania ignis by Schmitz et al. in 1984,[1] and this natural prod-
uct was found to be cytotoxic against KB and PS tumor cell
lines in the picomolar range. Importantly, compound 1 was
shown to increase significantly the lifespan of mice implanted
with lymphocytic leukaemia.[1] A congener of 1, (+)-13-deoxy-
tedanolide (2), was discovered later by Fusetani et al.[2] from
Mycale adhaerens, and it exhibited similar biological activity in
inhibiting the growth of P388 tumors.[2] Furthermore, the isola-
tion of additional metabolites, namely tedanolide C (3) and the
candidaspongiolides (4) was reported by Ireland[3] and
McKee.[4] Ten years after tedanolide (1) was discovered, Rine-
hart isolated the myriaporones from Myriapora truncate.[5]
It was proposed that myriaporones 1 (6) and 2 (11) are artifi-
cial derivatives obtained through the isolation and purification
steps used to obtain myriaporones 3/4 (8/9). Myriaporones 3/4
exist in dynamic equilibrium between the cyclic hemiketal and
the open-chain isomer. The promising biological activity (IC50 =
100 ngmLꢀ1 against L-1210 murine leukemia cells) as well as
the similarities of their structure to the C10 to C23 portion of
tedanolide (1) suggest that the myriaporones are in fact natu-
rally occurring analogues. The myriaporones would then share
the same mode of action as tedanolide, and their simpler
structure renders them more attractive as drug candidates and
serves as a starting point for more readily available potential
lead compounds.
Recently, a study established that like tedanolide (1), myria-
porones 3/4 (8/9) are potent protein synthesis inhibitors selec-
tive for eukaryotes.[6] A similar natural product, gephyronic acid
(10), was isolated from the cultivation broth of Archangium ge-
phyra (strain Ar 3895).[7a] Initial biological analysis revealed se-
lective inhibition of eukaryotic protein synthesis along with
a nanomolar cytostatic effect against a range of mammalian
cell lines. For example, compound 10 exhibits an IC50 value of
10 ngmLꢀ1 against human cervix carcinoma (HeLa) and human
myelogenous leukemia (K-562) cell lines. These similar struc-
tures prompted us to initiate a program to identify simplified
analogues along the lines of our synthesis of the southern
[a] Dr. N. Diaz, A. Naini, Prof. Dr. M. Kalesse
hemisphere of tedanolide (1).
As a consequence of the biological profiles (Table 1) and
Leibniz Universitꢀt Hannover, Institut fꢁr Organische Chemie
Schneiderberg 1B, 30167 Hannover (Germany)
E-mail: Markus.Kalesse@oci.uni-hannover.de
challenging structures, natural products 1 and 2 have initiated
a variety of synthetic studies.[7–10] Thus far, several research
[b] Y. Muthukumar, Dr. F. Sasse
groups have investigated the construction of fragments, and
the total synthesis of 1 and 2 has been completed by Smith,[8]
Roush[9] and Kalesse.[10] More recently, Laschat[7a] and Taylor[7b]
reported the structure elucidation and synthesis of gephyronic
acid (10). Consequently, we initiated a synthesis program to
identify simplified tedanolides as potential lead compounds for
drug development.
Department of Chemical Biology, Helmholtz Center for Infection Research
Inhoffenstr. 7, 38124 Braunschweig (Germany)
[c] Prof. Dr. M. Kalesse
Department of Medicinal Chemistry
Helmholtz Center for Infection Research
Inhoffenstr. 7, 38124 Braunschweig (Germany)
Supporting information for this article is available on the WWW under
http://dx.doi.org/10.1002/cmdc.201100576.
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Table 1. Biological activity of tedanolide (1) and desepoxytedanolide (7).
Compd
Cell line
IC50[a] [nmolmLꢀ1
]
1
1
1
1
1
7
KB-3-1 (cervix carcinoma)
KB-V1 (mdr KB)
SW-480 (colon cancer)
Primary human fibroblasts
L-929 mouse fibroblasts
L-929 mouse fibroblasts
0.33
1.64
0.082
0.15
0.082
0.89
[a] Growth inhibitory effects in the given cell lines were measured after
five days of incubation using an MTT assay.
Scheme 2. Synthesis of epoxide analogues. Reagents and conditions:
a) Et2Zn, CH2I2, CH2Cl2, ꢀ108C!RT, 96%; b) Pyridine, HF–pyridine, THF, 40%;
c) CAN, CH3OH/H2O, 08C!RT, 9 h, 26%.
The starting point of our synthetic endeavors was intermedi-
ate 12 that serves as a pivotal building block during our total
synthesis of tedanolide. Our rational was to incorporate the ap-
propriate functionalities to substitute for the missing elements
of the macrocyclic lactone. In particular, those were an acetate
group at the primary hydroxy group to compensate for the
lactone moiety, and the p-methoxybenzyl (PMB) group, which
should participate in hydrophobic interactions comparable to
the eastern part of tedanolide. Additionally, we planned to
probe whether the epoxide would add to the biological activi-
ty. Along this line, the first obvious derivatives were com-
pounds 13–15. These compounds were obtained by removal
of the tert-butyldimethylsilyl (TBS) protecting group, subse-
quent acylation of the primary alcohol, and finally Henbest ep-
oxidation (Scheme 1).
Scheme 3. Synthesis of derivatives 20 and 21. Reagents and conditions:
a) Ac2O, Et3N, DMAP, CH2Cl2, RT, 2.5 h, 62%; b) m-CPBA, NaHCO3, CH2Cl2,
ꢀ788C!ꢀ408C, 16 h, 41%; c) pyridine, HF–pyridine, THF, 08C, 30 min, 73%;
d) pyridine, HF–pyridine, THF, 63%.
When these derivatives were subjected to biological evalua-
tion, it became apparent that acylation at the primary hydroxy
group would led to simplified analogues, with IC50 values of
approximately 7 mgmLꢀ1. Remarkably, acylation at the secon-
dary hydroxy group decreases the biological activity compared
with compound 14. Introduction of the epoxide moiety does
not significantly alter the activity. However, cyclopropanation
and epoxidation does reduce the biological activity for deriva-
tives that do not exhibit acetylation of the primary hydroxy
group (Table 2). Active compound 15 was checked for inhibito-
ry effects on protein synthesis in an in vitro translation assay
but was found to be inactive.
Scheme 1. Synthesis of derivatives 13, 14 and 15. Reagents and conditions:
a) Pyridine, HF–pyridine, THF, 95%; b) AcCl, DIPEA, CH2Cl2, 80%; c) m-CPBA,
NaHCO3, CH2Cl2, 44%.
Analogues that exhibit the conformational restriction of ep-
oxides but lack the capability to form hydrogen bonding inter-
actions were derived through cyclopropanation of intermedi-
ate 12 and removal of the TBS and PMB groups, respectively
(Scheme 2).
In conclusion, these first data on simplified tedanolides
show that these biologically active compounds are approxi-
mately one order of magnitude less active than desirable for
promising drug candidates. However, these data show that the
decoration, namely the incorporation of acetyl groups, has
a more pronounced effect on the biological activity of these
derivatives, while epoxidation has only a little contribution, if
at all, to the overall activity. While this might not be true of
the parent compound, tedanolide, for the simplified analogues
this might be pivotal in order to obtain compounds with activ-
ities in the low nanomolar range. These first biological evalua-
tions also showed that simplified analogues can potentially
Finally, the derivatives positioning the acetyl group at the
secondary alcohol instead of the primary hydroxy group and
having the epoxide incorporated without any acetyl group
present are outlined in Scheme 3. These transformations in-
volved acetylation of intermediate 12, and its subsequent TBS
deprotection or epoxidation followed by TBS removal, respec-
tively (Scheme 3).
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tion was quenched by addition to saturated aq NaHCO3, the layers
Table 2. Biological activity of tedanolide, desepoxytedanolide and simpli-
were separated, and the aqueous layer was extracted with EtOAc
(3ꢁ15 mL). The combined organic layers were dried (Na2SO4), fil-
tered and concentrated. Purification by column chromatography
(PE/EtOAc, 3:1) afforded compound 13 as colorless oil (58 mg,
95%): [a]2D3 = +11.0 (c=1.5 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.19 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.37–5.31 (m,
1H), 5.30 (dd, J=4.9, 4.0 Hz, 1H), 5.23–5.14 (m, 1H), 4.41 (d, J=
11.5 Hz, 1H), 4.38 (d, J=11.5 Hz, 1H), 4.26 (d, J=8.6 Hz, 1H), 3.79
(s, 3H), 3.65–3.55 (m, 2H), 3.49 (dd, J=8.7, 4.5 Hz, 1H), 3.41–3.31
(m, 1H), 3.19–3.09 (m, 2H), 2.55 (br s, 2H), 1.66 (d, J=1.3 Hz, 3H),
1.62 (dd, J=6.8, 1.7 Hz, 3H), 1.01 (d, J=3.3 Hz, 3H), 1.00 ppm (d,
J=3.1 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=218.1, 159.6, 134.8,
133.9, 132.8, 129.6, 129.3, 122.3, 114.0, 76.9, 73.4, 72.9, 62.5, 57.9,
55.4, 47.7, 30.6, 21.4, 13.1, 12.9, 11.5 ppm; HRMS-ESI: m/z [M+Na]+
calcd for C23H34O5Na: 413.5028, found 413.1573.
fied analogues in mammalian cell lines.[a]
Structure
Compd
IC50[a] [mmolmLꢀ1
]
KB-3-1
L-929
Tedanolide (1)
Desepoxytedanolide (7)
0.00033
n.d.
0.000082
0.00089
13
14
15
17
18
20
21
23
41
25
16
(2R,3S,4E,6S,7Z)-3-Hydroxy-2-((R)-3-((4-methoxybenzyl)oxy)-2-
methylpropanoyl)-4,6-dimethylnona-4,7-dien-1-yl acetate (14): A
solution of compound 13 (57 mg, 0.14 mmol) in CH2Cl2 (7 mL) was
cooled to ꢀ788C and treated with DIPEA (46 mL, 0.26 mmol) and
acetyl chloride (12.2 mL, 0.17 mmol). The mixture was stirred for 1 h
and again DIPEA (46 mL, 0.26 mmol) and acetyl chloride (12.2 mL,
0.17 mmol) were added and stirred for 5 h at ꢀ788C, and then at
ꢀ508C for 16 h. Water (10 mL) and saturated aq NaHCO3 (10 mL)
were added. The mixture was allowed to warm to RT, the layers
were separated, and the aqueous layer was extracted with CH2Cl2
(3ꢁ5 mL). The organic layers are combined, dried (Na2SO4), filtered
and concentrated. Purification by column chromatography on silica
gel (PE/EtOAc, 3:1) gave compound 14 as colorless oil (45 mg,
80%): [a]2D3 = +13.2 (c=1.0 in CHCl3); 1H NMR (400 MHz, CDCl3):
d=7.21 (d, J=8.7 Hz, 2H), 6.86 (d, J=8.7 Hz, 2H), 5.34 (dqd, J=
10.7, 6.7, 0.9 Hz, 1H), 5.27 (d, J=9.0 Hz, 1H), 5.18 (ddq, J=10.8,
9.2, 1.7 Hz, 1H), 4.44 (d, J=11.8 Hz, 1H), 4.40 (d, J=11.7 Hz, 1H),
4.19 (d, J=8.5 Hz, 1H), 4.03 (qd, J=11.3, 6.8 Hz, 1H), 3.79 (s, 3H),
3.64 (dd, J=9.1, 7.8 Hz, 1H), 3.41–3.30 (m, 2H), 3.27 (td, J=8.3,
5.4 Hz, 1H), 3.09–2.98 (m, 1H), 2.58 (br s, 1H), 1.91 (s, 3H), 1.67 (d,
J=1.3 Hz, 3H), 1.62 (dd, J=6.8, 1.7 Hz, 3H), 1.05 (d, J=7.0 Hz, 3H),
1.03 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=214.3,
170.6, 159.4, 134.6, 134.1, 132.5, 129.8, 129.4, 122.5, 113.9, 76.8,
73.1, 71.6, 62.9, 55.4, 53.6, 47.1, 30.5, 21.3, 20.8, 13.2, 13.1,
11.4 ppm; HRMS-ESI: m/z [M+Na]+ calcd for C25H36O6Na: 455.5395,
found 455.3230.
20
17
20
49
>140
>100
46
>140
>100
46
[a] Growth inhibitory effect in KB-3-1 cervix carcinoma cells and L-929
mouse fibroblasts were measured after five days of incubation using an
MTT assay. n.d.=not determined.
(2R,4R)-2-((S)-Hydroxy((2R,3R)-2-methyl-3-((S,Z)-pent-3-en-2-yl)-
oxiran-2-yl)methyl)-5-((4-methoxybenzyl)oxy)-4-methyl-3-oxo-
pentyl acetate (15): A solution of 14 (14 mg, 0.03 mmol) in CH2Cl2
(0.6 mL) at ꢀ788C was treated with NaHCO3 (9.5 mg, 0.113 mmol)
and m-CPBA (5.6 mg, 0.03 mmol). The reaction was stirred for 1 h
at ꢀ788C, warmed to ꢀ408C and stirred for 16 h at this tempera-
ture. Saturated aq NaHCO3 (2 mL) and CH2Cl2 (3 mL) were added,
and the reaction was warmed to RT. The layers was separated, and
the aqueous layer was extracted with CH2Cl2 (2ꢁ3 mL). The com-
bined organic layers were dried (Na2SO4), filtered and concentrated
in vacuo. Purification by column chromatography (PE/EtOAc, 6:1)
open up a therapeutic window and help identifying new tar-
gets even though the mode of action might be different than
for the other members of this family, which act through inhibi-
tion of translation. Remarkably, compounds 13 and 17 already
exhibit selectivity towards tumor cells. This unexpected result
will potentially provide access to a new target and provides
a promising starting point for further optimization.
afforded compound 15 as a colorless oil (6.5 mg, 44%): [a]D23
=
1
Experimental Section
+4.5 (c=0.35 in MeOH); H NMR (400 MHz, [D6]benzene): d=7.19
(d, J=8.7 Hz, 2H), 6.80 (d, J=8.7 Hz, 2H), 5.49–5.38 (m, 1H), 5.20–
5.10 (m, 1H), 4.37 (dd, J=11.0, 4.9 Hz, 1H), 4.27 (s, 2H), 4.22 (dd,
J=10.9, 8.8 Hz, 1H), 3.66 (dd, J=9.1,7.4 Hz, 1H), 3.47 (dd, J=8.8,
4.6 Hz, 1H), 3.40–3.34 (m, 1H), 3.29 (s, 3H), 3.12–3.02 (m, 1H),
2.55–2.51 (m, 1H), 2.50 (s, 1H), 2.41–2.31 (m, 1H), 1.58 (s, 3H), 1.43
(dd, J=6.9, 1.8 Hz, 3H), 1.31 (s, 3H), 1.17 (d, J=6.9 Hz, 3H),
1.08 ppm (d, J=6.6 Hz, 3H); 13C NMR (100 MHz, [D6]benzene): d=
Chemistry
(2R,4R,5S,6E,8S,9Z)-5-Hydroxy-4-(hydroxymethyl)-1-((4-methoxy-
benzyl)oxy)-2,6,8-trimethylundeca-6,9-dien-3-one (13): A solution
of 12 (78 mg, 0.15 mmol) in THF (8 mL) was treated dropwise at
08C with pyridine (8.1 mL, 0.1 mol) and then HF–pyridine (5.26 mL,
70%). The mixture was warmed to RT and stirred for 4 h. The reac-
ChemMedChem 2012, 7, 771 – 775
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212.5, 169.9, 159.8, 130.8, 130.5, 129.5, 124.9, 114.1, 76.5, 73.1, 71.9,
66.4, 62.9, 62.3, 54.7, 52.8, 48.4. 31.6, 20.3, 18.7, 13.3, 13.3,
12.0 ppm; HRMS-ESI: m/z [M+Na]+ calcd for C26H36O7Na:
471.5389, found 471.2265.
arated, and the aqueous phase was extracted with EtOAc (3ꢁ
2 mL). The combined organic extracts were dried (Na2SO4), filtered
and concentrated in vacuo. Purification by column chromatogra-
phy (PE/EtOAc, 3:1!1:1) provided triol 18 as a colorless oil (2 mg,
7.0 mmol, 26%): [a]2D3 = +7.6 (c=0.5 in CHCl3); 1H NMR (400 MHz,
CDCl3): d=5.41 (m, 2H), 3.88 (d, J=5.5 Hz, 2H), 3.80 (dd, J=5.5 Hz,
2H), 3.55 (br s, 1H), 3.35–3.30 (m, 1H), 3.10–3.02 (m, 2H), 1.61 (d,
J=5.1 Hz, 3H), 2.16–2.10 (m, 1H), 1.94 (br s, 1H), 1.28 (s, 3H), 1.11
(d, J=6.1 Hz, 3H), 1.04 (d, J=6.8 Hz, 3H), 0.94–0.85 (m, 1H), 0.79–
0.73 (m, 1H), 0.52 ppm (dd, J=9.2, 4.4 Hz, 1H); 13C NMR (100 MHz,
CDCl3): d=207.7, 136.0, 121.9, 79.7, 65.4, 61.7, 55.2, 51.0, 32.1, 29.7,
24.7, 21.4, 16.4, 13.8, 13.2, 12.5 ppm; HRMS-ESI: m/z [M+Na]+
calcd for C16H28O4Na: 307.1885, found: 307.1883.
(1S,2R,4R)-2-(((tert-Butyldimethylsilyl)oxy)methyl)-1-hydroxy-5-
((4-methoxybenzyl)oxy)-4-methyl-1-((1S,2R)-1-methyl-2-((S,Z)-
pent-3-en-2-yl)cyclopropyl)pentan-3-one (16): A solution of allyl-
alcohol 12 (30 mg, 0.06 mmol) in CH2Cl2 (0.6 mL) was cooled to
ꢀ108C and treated slowly with Et2Zn (0.3 mL, 0.3 mmol, 1m in
hexane) and CH2I2 (24 mL, 0.3 mmol). After the addition was com-
pleted, the mixture was stirred for 2.5 h at RT. The reaction was
stopped by the addition of saturated aq NH4Cl (0.3 mL). The organ-
ic layer was diluted with methyl tert-butyl ether (2.5 mL) and treat-
ed with 10% aq HCl (0.3 mL), then washed consecutively with satu-
rated aq Na2SO3 (0.3 mL), saturated aq NaHCO3 (1 mL) and brine
(1 mL). The organic phase was dried (MgSO4), filtered and concen-
trated in vacuo. Purification by column chromatography (petrole-
um ether (PE)/EtOAc, 8:1) provided 16 as a colorless oil (30.4 mg,
(2R,4R,5S,6E,8S,9Z)-4-(((tert-Butyldimethylsilyl)oxy)methyl)-1-((4-
methoxybenzyl)oxy)-2,6,8-Trimethyl-3-oxoundeca-6,9-dien-5-yl
acetate (19): A solution of alcohol 12 (14.6 mg, 0.029 mmol) in
CH2Cl2 (1 mL) was cooled to 08C and treated slowly with Et3N
(24 mL, 0.17 mmol) and acetic acid anhydride (8.2 mL, 0.87 mmol).
DMAP (0.37 mg, 0.003 mmol) was then added, and the reaction
was stirred for 2.5 h. The reaction was quenched with saturated aq
NaHCO3 (1 mL), and the aqueous layer was extracted with CH2Cl2
(3ꢁ1 mL). The combined organic layers were dried (Na2SO4), fil-
tered and concentrated in vacuo. Purification by column chroma-
tography (PE/EtOAc, 2:1) provided compound 19 as a colorless oil
(10.0 mg, 0.018 mmol, 62%): [a]2D3 = +15.6 (c=1.0 in CHCl3);
1H NMR (400 MHz, CDCl3): d=7.24 (d, J=8.5 Hz, 2H), 6.85 (d, J=
8.5 Hz, 2H), 5.38 (dd, J=8.5 Hz, 1H), 5.30 (ddq, J=13.7, 7.5, 2.0 Hz,
1H), 5.22 (d, J=10.2 Hz, 1H), 5.19 (ddq, J=10.6, 9.2, 1.7 Hz, 1H),
4.44 (d, J=11.3 Hz, 1H), 4.40 (d, J=11.6 Hz, 1H), 3.8 (s, 3H), 3.70
(dd, J=9.2, 5.12 Hz, 1H), 3.61 (dd, J=9.1, 6.5 Hz, 1H) 3.42 (dd, J=
9.9, 4.8 Hz, 1H), 3.35–3.28 (m, 3H), 2.98–2.92 (m, 1H), 1.91 (s, 3H),
1.83 (s, 3H), 1.14 (d, J=6.8 Hz, 3H), 1.63 (d, J=1.0 Hz, 3H), 1.60
(dd, J=6.8, 1.7 Hz, 3H), 1.00 (d, J=6.8 Hz, 3H), 0.83 (s, 9H), ꢀ0.04
(s, 3H), 0.05 ppm (s, 3H); 13C NMR (100 MHz, CDCl3): d=212.9,
169.2, 159.3, 136.2, 134.7, 130.6, 129.4, 128.8, 122.2, 114.0, 78.1,
73.0, 70.5, 62.8, 55.4, 54.3, 48.3, 30.6, 26.0, 21.2, 21.1, 18.4, 13.5,
13.1, 11.6, ꢀ5.5, ꢀ5.7 ppm; HRMS-ESI: m/z [M+Na]+ calcd for
C31H50O6SiNa: 569.8004, found: 569.8001.
1
0.058 mmol, 96%): [a]2D3 = +9.2 (c=1.0, CHCl3); H NMR (400 MHz,
CDCl3): d=7.22 (d, J=8.5 Hz, 2H), 6.86 (d, J=8.5 Hz, 2H), 5.39–5.27
(m, 2H), 4.44 (d, J=11.6 Hz, 1H), 4.39 (d, J=11.6 Hz, 1H), 3.84 (dd,
J=9.9, 5.1 Hz, 1H), 3.79 (s, 3H), 3.75–3.66 (m, 2H), 3.35 (dd, J=8.9,
6.8 Hz, 1H), 3.24 (m, 1H), 3.05–2.99 (m, 1H), 2.87 (d, J=8.8 Hz, 1H),
2.08–2.04 (m, 1H), 1.58 (dd, J=6.1, 1.4 Hz, 3H), 1.13 (d, J=7.2 Hz,
3H), 1.06 (s, 3H), 1.03 (d, J=6.8 Hz, 3H), 0.84 (s, 9H), 0.60–0.54 (m,
1H), 0.51 (dd, J=8.8, 13.3 Hz, 2H), ꢀ0.01 (s, 3H), ꢀ0.01 ppm (s,
3H); 13C NMR (100 MHz, CDCl3): d=215.9, 159.4, 136.3, 130.2, 129.5
121.8, 113.9, 78.5, 73.0, 71.5, 62.2, 57.8, 55.4, 47.1, 32.2, 29.6, 26.0,
24.7, 21.5, 18.3, 16.8, 13.8, 13.1, 12.7, ꢀ5.3, ꢀ5.4 ppm; HRMS-ESI:
m/z [M+Na]+ calcd for C30H50O5SiNa: 541.3325, found: 541.3330.
(1S,2R,4R)-1-Hydroxy-2-(hydroxymethyl)-5-((4-methoxybenzyl)-
oxy)-4-methyl-1-((1S,2R)-1-methyl-2-((S,Z)-pent-3-en-2-yl)cyclo-
propyl)pentan-3-one (17): A solution of 16 (15 mg, 0.029 mmol) in
THF (1.5 mL) was cooled to 08C and treated slowly with pyridine
(1.5 mL, 0.018 mol) and HF–pyridine (0.95 mL, 70%). The reaction
was stirred for 15 min at 08C, then transferred to an EtOAc/buffer
(pH 7) mixture (2 mL). The slurry was stirred for 5 min and the
layers were separated. The aqueous layer was extracted with
EtOAc (3ꢁ2 mL), and the combined organic layers were dried
(Na2SO4), filtered and concentrated in vacuo. Purification by
column chromatography (PE/EtOAc, 2:1) provided cyclopropane 17
as a colorless oil (4.6 mg, 0.011 mmol, 40%): [a]2D3 = +12.6 (c=0.5
in CHCl3); 1H NMR (400 MHz, CDCl3): d=7.19 (d, J=8.5 Hz, 2H),
6.87 (d, J=8.5 Hz, 2H), 5.42–5.32 (m, 2H), 4.43 (d, J=11.6 Hz, H),
4.39 (d, J=11.6 Hz, 1H), 3.91–3.82 (m, 2H), 3.79 (s, 3H), 3.65 (dd,
J=11.8 Hz, 2H), 3.50 (dd, J=8.8, 4.4 Hz, 1H), 3.20–3.16 (m, 1H),
3.13–3.10 (m, 1H), 3.10 (m, 1H), 2.13–2.04 (m, 2H), 1.58 (dd, J=6.1,
1.4 Hz, 3H), 1.57 (s, 3H), 1.05 (d, J=5.8 Hz, 3H), 1.02 (d, J=6.8 Hz,
3H), 0.79–0.72 (m, 1H), 0.52 (dd, J=8.8, 13.6 Hz, 1H), 0.02 ppm
(dd, J=7.2, 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3): d=218.8,
159.5, 136.1, 129.6, 129.4, 121.6, 114.0, 78.7, 73.3, 72.7, 61.3, 57.8,
55.4, 47.6, 32.2, 29.5, 24.3, 21.4, 16.6, 13.2, 13.0, 12.5 ppm; HRMS-
ESI: m/z [M+Na]+ calcd for C24H36O5Na: 427.2460, found:
427.2462.
(1S,2R,4R)-1-Hydroxy-2-(hydroxymethyl)-5-((4-methoxybenzyl)-
oxy)-4-methyl-1-((2R,3R)-2-methyl-3-((S,Z)-pent-3-en-2-yl)oxiran-
2-yl)pentan-3-one (20): A solution of allylalcohol 12 (53.4 mg,
0.11 mmol) in CH2Cl2 (1.9 mL) was cooled to ꢀ788C and treated
with NaHCO3 (32 mg, 0.38 mmol) and m-CPBA (18 mg, 0.11 mmol).
The reaction was stirred at ꢀ408C for 16 h, quenched with saturat-
ed aq NaHCO3 (3 mL) and warmed to RT. The layers were separat-
ed, and the aqueous layer was extracted with CH2Cl2 (2ꢁ1.5 mL).
The combined organic layers were dried (Na2SO4), filtered and con-
centrated in vacuo. Purification by column chromatography (PE/
EtOAc, 6:1) gave the intermediate as a yellow oil (22.5 mg,
0.05 mmol, 41%): [a]D23 = +21.8 (c=1.03 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.23 (d, J=8.9 Hz, 2H), 6.86 (d, J=8.5 Hz,
2H), 5.50 (ddq, J=10.8, 6.8, 0.6 Hz, 1H), 5.23 (ddq, J=10.8, 10.3,
1.6 Hz, 1H), 4.44 (d, J=11.6 Hz, 1H), 4.41 (d, J=11.6 Hz, 1H), 3.79
(s, 3H,), 3.73 (dd, J=9.4, 5.5 Hz, 1H), 3.71 (dd, J=9.2, 5.5 Hz, 1H),
3.64 (dd, J=9.9, 5.5 Hz, 1H), 3.45 (dd, J=8.2, 4.4 Hz, 1H), 3.36 (dd,
J=9.2, 7.2 Hz, 1H), 3.17 (dd, J=8.7, 5.3 Hz, 1H), 3.04 (d, J=4.8 Hz,
1H), 2.91 (d, J=9.2 Hz, 1H), 2.41 (m, 1H), 1.65 (dd, J=6.8, 1.7 Hz,
3H), 1.31 (s, 3H), 1.16 (d, J=7.2 Hz, 3H), 1.13 (d, J=6.8 Hz, 3H),
0.84 (s, 9H), ꢀ0.01 (s, 3H), ꢀ0.02 ppm (s, 3H); 13C NMR (100 MHz,
CDCl3): d=214.7, 159.2, 130.5, 130.0, 129.6, 124.6, 113.7, 75.2, 72.8,
71.1, 66.2, 63.0, 61.6, 55.8, 55.2, 47.8, 31.4, 25.8, 18.7, 18.6, 13.4,
(1S,2R,4R)-1,5-Dihydroxy-2-(hydroxymethyl)-4-methyl-1-((1S,2R)-
1-methyl-2-((S,Z)-pent-3-en-2-yl)cyclopropyl)pentan-3-one (18): A
solution of cyclopropane 17 (13.5 mg, 0.026 mmol) in MeOH/water
(2:1, 1.5 mL) was cooled to 08C and treated with ammonium ceriu-
m(IV) nitrate (31 mg, 0.056 mmol) to give an orange solution. The
reaction was stirred for 3 h at 08C, and the treated with an addi-
tional aliquot of ammonium cerium(IV) nitrate (14.3 mg,
0.026 mmol). The reaction was stirred for 16 h. The layers were sep-
774
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ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
ChemMedChem 2012, 7, 771 – 775

MED
13.2, 12.1, ꢀ5.6, ꢀ5.7 ppm; HRMS-ESI: m/z [M+Na]+ calcd for
gift from Dr. Karl-Heinz Thierauch (Bayer-Schering Pharma AG,
C29H48O6NaSi: 543.3118, found: 543.3123.
Berlin, Germany). Antiproliferative activities were measured in 96-
well plates. Serial dilutions of inhibitor (60 mL) were incubated with
suspended cells (120 mL, 50000 cellsmLꢀ1; two replicates). After
five days, the metabolic activity in each well was determined using
A solution of epoxide (18.4 mg, 0.035 mmol) in THF (1.8 mL) was
cooled to 08C and treated slowly with pyridine (1.84 mL, 0.22 mol)
and HF–pyridine (1.2 mL, 70%). The reaction was stirred at 08C for
30 min, and then transferred to a mixture of EtOAc/buffer (pH 7)
solution (2 mL) and stirred for 5 min. The layers were separated,
and the aqueous layer was extracted with EtOAc (3ꢁ2 mL). The
combined organic layers were dried (Na2SO4), filtered and concen-
trated in vacuo. Purification by column chromatography (PE/EtOAc,
a
3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium
bromide
(MTT) assay.
Acknowledgements
4:1!2:1) provided epoxide 19 as
a colorless oil (10.4 mg,
0.025 mmol, 73%): [a]2D3 = +9.2 (c=1.0 in CHCl3); 1H NMR
(400 MHz, CDCl3): d=7.19 (d, J=8.8 Hz, 2H), 6.87 (d, J=8.5 Hz, H),
5.51 (ddq, J=10.6, 6.8, 2.4 Hz, 1H), 5.26 (ddq, J=10.2, 8.8, 1.7 Hz,
1H), 4.42 (d, J=11.6 Hz, 1H), 4.38 (d, J=11.6 Hz, 1H), 3.80 (s, 3H),
3.74 (dd, J=11.3, 3.4 Hz, 1H), 3.68–3.62 (m, 2H), 3.55–3.50 (m, 2H),
3.17 (m, 1H), 3.03 (m, 1H), 2.76 (d, J=9.2 Hz, 1H), 2.46–2.39 (m,
1H), 1.63 (dd, J=6.8, 1.7 Hz, 3H), 1.31 (s, 3H), 1.12 (d, J=6.5 Hz,
3H), 1.03 ppm (d, J=6.8 Hz, 3H); 13C NMR (100 MHz, CDCl3): d=
217.3, 159.4, 130.3, 129.5, 129.3, 124.6, 113.9, 76.1, 73.2, 72.7, 66.6,
62.7, 60.9, 56.5, 55.3, 47.8, 31.4, 18.6, 14.1, 13.3, 12.7 ppm; HRMS-
ESI: m/z [M+Na]+ calcd for C23H34O6Na: 429.2252, found:
429.2254. 6.9
We thank Bettina Hinkelmann (Helmholtz Centre for Infection Re-
search, Braunschweig Germany) for technical assistance with the
biological assays. This work was supported by the German Re-
search Foundation (DFG) (KA 913/17-1).
Keywords: gephyronic acid
·
myriaporones
·
natural
products · ribosomes · tedanolide
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1
9.2 mmol, 89%): [a]2D3 = +11.9 (c=0.4 in CHCl3); H NMR (400 MHz,
CDCl3): d=7.18 (d, J=8.5 Hz, 2H), 6.85 (d, J=8.5 Hz, 2H), 5.45 (d,
J=8.8 Hz, 1H), 5.35 (d, J=10.5 Hz, 1H), 5.31 (ddq, J=13.3, 6.5,
4.4 Hz, 1H), 5.16, (ddq, J=10.6, 8.8, 1.7 Hz, 1H), 4.41 (d, J=11.6 Hz,
1H), 4.37 (d, J=11.6 Hz, 1H), 3.80 (s, 3H), 3.62 (dd, J=12.0, 6.5 Hz,
1H), 3.51 (dd, J=11.6, 7.5 Hz, 1H), 3.47 (dd, J=8.8, 4.1 Hz, 1H),
3.38–3.29 (m, 2H), 3.17–3.12 (m, 1H), 2.83–2.79 (m, 1H), 1.93 (s,
3H), 1.63 (d, J=0.9 Hz, 3H), 1.62 (dd, J=6.8, 1.7 Hz, 3H), 1.01 (d,
J=6.8 Hz, 3H), 1.00 ppm (d, J=7.2 Hz, 3H); 13C NMR (100 MHz,
CDCl3): d=215.4, 169.2, 160.7, 136.9, 134.5, 129.6, 129.4, 128.7,
122.4, 114.0, 78.0, 73.5, 72.8, 62.1, 56.4, 55.4, 48.2, 30.6, 21.2, 21.2,
13.1, 12.7, 11.6 ppm; HRMS-ESI: m/z [M+Na]+ calcd for
C25H36O6Na: 455.5395, found: 455.5397.
Biology
The in vitro translation assay was carried out with Flexi rabbit retic-
ulocyte lysate (Promega). In brief, rabbit reticulocyte lysate (20 mL)
was mixed with amino acid mixture minus leucine and amino acid
mixture minus methionine (0.5 mL), KCl (1 mL), RNasin ribonuclease
inhibitor (0.5 mL), luciferase mRNA (0.5 mL), water (10 mL) and 15 to
a final concentration of 15 mgmLꢀ1. The mixture was incubated at
308C for 90 min. Then an aliquot of reaction mixture (5 mL) was
mixed with luciferase assay buffer (10 mL), and the luminescence
was measured using a plate reader. The results were compared to
control wells in which MeOH was used instead of compound 15.
Cell lines were obtained from the German Collection of Microor-
ganisms and Cell Cultures (DSMZ, Braunschweig, Germany). Pri-
mary human fibroblasts isolated from foreskin were a generous
Received: December 6, 2011
Published online on March 1, 2012
ChemMedChem 2012, 7, 771 – 775
ꢀ 2012 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.chemmedchem.org
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