Total Synthesis of epi-Trichosetin

Article abstract of DOI:10.1021/acs.joc.8b02450

The natural 3-decalinoyltetramic acid epi-trichosetin was synthesized in ten steps starting from (R)-(+)-citronellal using an intramolecular Diels-Alder reaction and a Lacey-Dieckmann cyclization as the key steps. The use of a 2-nitrobenzyl protecting group resulted in an efficient synthetic endgame. The natural product was obtained in 4.1% overall yield.

Full text of DOI:10.1021/acs.joc.8b02450

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Article
Total Synthesis of epi-Trichosetin
Ulrich Kauhl, Lars Andernach, and Till Opatz
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.8b02450 • Publication Date (Web): 19 Nov 2018
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Total Synthesis of epi-Trichosetin
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Ulrich Kauhl, Lars Andernach, and Till Opatz*
Address: Institute of Organic Chemistry, University of Mainz, Duesbergweg 10–14, D-55128 Mainz,
Germany
Email: opatz@uni-mainz.de
GRAPHICAL ABSTRACT
ABSTRACT
The natural 3-decalinoyltetramic acid epi-trichosetin was synthesized in ten steps starting
from (R)-(+)-citronellal using an intramolecular Diels-Alder reaction and a Lacey-Dieckmann
cyclization as the key steps. The use of a 2-nitrobenzyl protecting group resulted in an
efficient synthetic endgame. The natural product was obtained in 4.1% overall yield.
INTRODUCTION
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-Acyltetramic acids represent a large and truly remarkable class of natural products. Being
produced by bacteria and fungi, they have been found to possess a variety of biological
activities ranging, including antibacterial, phytotoxic, fungicidal and anti-malarial effects. As
a consequence, they have been the subject of investigation not only in academic but also in
industrial settings and virtually all major companies became at some point interested in their
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pharmacological properties. As an example, equisetin (1), the first discovered member of the
1
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-decalinoyltetramic acids, not only exhibits antibacterial effects but also acts as a HIV-1
integrase inhibitor (Figure 1). For the structurally related (–)-hymenosetin (2), both fungicidal
2
and antibacterial activities against various strains including S. aureus have been reported. In
2
013, epi-trichosetin (4) was isolated by Inokoshi et al. from a culture of the plant pathogenic
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mold fungus Fusarium oxysporum. This 3-decalinoyltetramic acid possesses the same
decalin system as equisetin but a D- instead of an L-serine-derived side chain in the tetramic
acid moiety and the ring nitrogen is not methylated. Like its C-5’-epimer trichosetin (3), it
acts as an inhibitor of undecaprenyl phyrophosphate (UPP) synthase and is active against both
4
Gram-positive and -negative bacteria. The acyltetramic acid “warhead” with its largely
enolized tris-β-keto-motif is thought to be mainly responsible for the observed biological
effects of this compound class. So far, three different modes of action have been determined.5
First, the tetramic acids can act as ionophores by shuttling di- or trivalent metal ions through
biological membranes, which may explain at least part of the observed antibacterial effects.5b
On the other hand, the negatively charged 3-acyltetramate moiety is thought to mimic a
phosphate residue, which could explain the observed effective kinase or phosphatase
6
inhibitory effects. The chelating 3-acyltetramate motif is also responsible for the fact that
some representatives can bind via a metal ion to specific binding sites of their target
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molecules, such as cyclopiazonic acid to the calcium transporter SERCA. As can be seen
from the different biological effects of structurally closely related members of the 3-
decalinoyltetramic acid class, the configuration of both the decalin part and of the amino acid-
derived tetramic acid side chain play important roles. For the determination of the absolute
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configuration of the C2- and C5’-stereocenters of the natural 3-decalinoyltetramic acids, their
ECD characteristics (Cotton effect) at ~235 nm and ~275 nm are generally used.3
To determine the relative configuration of threonine-derived side chains as in (–)-hymenosetin
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(2), Halecker et al. successfully applied a HSQC-NMR-based method developed by
Matsumori et al.2,8 For comparison of the ECD-characteristics, the data of equisetin,
trichosetin and epi-trichosetin have been used so far. In contrast, the assignment of the
configuration of trichosetin (3) was made based on the comparison of the optical rotation of
the isolated natural product with that of equisetin and was not confirmed by total synthesis.4a
Due to the aforementioned chelating effects as well as other influences, a comparison of
optical rotations of tetramic acids is error-prone.4a,5a The absolute configuration of equisetin
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(
1) was however independently confirmed by several total syntheses. Still there are
contradictory statements in the literature regarding the influence of the C5’-stereocenter of
equisetin on its ECD spectra.3,10 To unequivocally confirm the utility of the ECD
characteristics used so far for the structure elucidation of 3-decalinoyltetramic acids, a total
synthesis of epi-trichosetin (4) is required.
Figure 1. Structures of equisetin (1), (–)-hymenosetin (2), 5’,6’-epi-hymenosetin (epi-2), trichosetin
(3) and epi-trichosetin (4).
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RESULTS AND DISCUSSION
For the total synthesis of 4, the decalin system was synthesized according to procedures of
Theodorakis, Gao and Ley et al. starting from (+)-citronellal (5), which was converted by SeO
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a-c,11
catalyzed allylic oxidation (Riley-Oxidation) into allylic alcohol 6 in 52% yield (Scheme 1).
Due
to problems with the regioselective Wittig reaction of the corresponsing dialdehyde employed by
Theodorakis, the route via 6 proved beneficial in our hands.
Scheme 1. Synthesis of the trans-decalin ring system starting from (+)-citronellal
Phosphonium bromide 7 was obtained in a yield of 84% from commercial (E,E)-hexa-2,4-dienol after
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b
bromination with PBr
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and reaction with PPh . Subsequent Wittig olefination of aldehyde 6 afforded
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the desired tetraene alcohol 8 in 56% yield and moderate stereoselectivity (3:2 E/Z). Oxidation with
DMP gave the corresponding aldehyde (isomeric mixture), which was converted into the all-trans
isomer by irradiation with a 500 W incandescent lamp in dichloromethane in the presence of 5 mol%
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9b,12
I
2
.
By adding BF
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·Et
2
O at –78 °C, an intramolecular Diels-Alder reaction (IMDA) was initiated to
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give the trans-decalin carbaldehyde 9 in 69% yield and high diastereoselectivity (9:1 as judged by H
NMR spectroscopy, the configuration of the minor product was not elucidated). Along the same lines
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as our earlier apporoach to (–)-hymenosetin, a Reformatsky reaction and subsequent IBX oxidation
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converted aldehyde 9 into β-keto ester 10, which was saponified to β-keto acid 11 (Scheme 2).
Scheme 2. Synthesis of epi-trichosetin (4)
Due to the known difficulties in the Lacey-Dieckmann cyclization of derivatives with a free NH
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moiety, the use of the 2-nitrobenzyl (2-NB) protecting group was evaluated, which can be cleaved
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photochemically in a single step. Therefore, β-keto acid 11 was coupled to O-TBDMS- and N-2-
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nitrobenzyl-protected (R)-serine 12 using Steglich conditions. The required amino acid building
block 12 was obtained after TBDMS protection of (R)-serine methyl ester with TBDMSCl and
imidazole, followed by a reductive amination with ortho-nitrobenzaldehyde in the presence of
NaCNBH . The Lacey-Dieckmann cyclization was promoted with tBuOK in tBuOH to produce
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tetramic acid 14 in 85% yield after acidic workup. The 2-nitrobenzyl-protecting group was removed
by irradiation with UV light (350 nm) in acetonitrile for 15 min to give the silyl protected tetramic
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acid 15 in 72% yield. Desilylation with 48% HF in acetonitrile finally led to epi-trichosetin (4) in
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9% yield (4.1% overall from (+)-citronellal).
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The C NMR data are consistent with the literature values of epi-trichosetin (Table 1) but due to the
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minute chemical shift differences between trichosetin (3) and its epimer 4, further analytical data
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should be used for the assessment. The optical rotation of the synthetic compound 4 ([α]
D
= –248;
2
2
c = 0.1; MeOH) agrees with the value reported for epi-trichosetin (([α]
D
= –233; c = 0.1; MeOH) and
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clearly deviates from that reported for its C-5’-epimer trichosetin ([α]
D
= –413; c = 0.1; MeOH).
These values should however be handled with great care since large discrepancies can result from
slight changes in temperature, pH, and metal content of the sample. The ECD spectrum of the
synthetic compound is in perfect accordance with literature data and with those of the 5’,6’-epimer of
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hymenosetin, which bears the same (2S,5’R)-configuration (Figure 2). This supports the suitability of
the ECD characteristics used so far for the assignment of the C-2 and C-5’ stereocenters of 3-
decalinoyl tetramic acids.
Table 1. 13C NMR shifts (CDCl
, 150.9 MHz), specific optical rotation and Cotton effects of synthetic epi-
3
trichosetin (4) and literature values of natural trichosetin (3) and epi-trichosetin (4).3 13C NMR shifts were
assigned based on HSQC and HMBC correlations.
synth. epi-trichosetin (4)
epi-trichosetin (4)
trichosetin (3)
assignment
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3
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δ C
δ C
δ C
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4
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00.7
200.8
49.3
200.6
49.0
C-1
9.1
C-2
4.0
14.1
13.9
C-2-Me
C-3
5.1
45.2
45.0
26.4
30.1
126.8
130.2
38.7
126.6
130.0
38.5
C-4
C-5
38.6
C-6
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2.2
42.5
42.1
33.4
C-7
3.6
33.7
22.7
C-8
2.6
22.4
C-8-Me
C-9
5.8
35.9
35.6
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28.3
C-10
C-11
C-13
C-14
C-15
C-2'
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40.2
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27.2
8.1
131.0
127.2
18.1
130.8
127.2
17.9
79.4
00.2
91.1
1.7
179.5
100.3
191.1
61.8
179.1
99.9
C-3'
190.6
62.2
C-4'
C-5'
3.1
63.2
62.9
C-6'
2
6
α
D
(c = 0.1, MeOH)
–248 °
–233 °
–413 °
CD (MeOH): λ in nm (Mol.
CD)
2
38 (0.23)
76 (–4.2)
238 (0.17)
272 (–5.5)
230 (–4.6)
277 (–8.2)
2
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Figure 2. ECD spectrum of synthetic epi-trichosetin (4, 0.05 mg/mL in MeOH).
In addition, we recorded VCD spectra of epi-trichosetin (4) which proved to be very helpful for the
distinction of different stereoisomers of 3-decalinoyltetramic acids in the case of hymenosetin (2) and
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its 5’,6’-epimer epi-2. Figure 3 compares the VCD spectra of 4, 2 and epi-2 and illustrates the higher
information content of the VCD versus the ECD technique, with the ECD spectra of 4 and epi-2 being
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highly similar. Thus, the VCD technique might facilitate the stereochemical analysis of different
tetramic acid derivatives.
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Figure 3. VCD spectra of epi-trichosetin (4), (–)-hymenosetin (2) and 5’,6’-epi-hymenosetin (epi-2).
CONCLUSION
In summary, the 3-decalinoyltetramic acid epi-trichosetin (4) was synthesized for the first time in ten
linear steps from (+)-citronellal using the photocleavable 2-nitrobenzyl protecting group for the
intermediate protection of the NH moiety to allow the Lacey-Dieckmann cyclization. The proposed
absolute configuration of this natural product was thus confirmed, as was the general applicability of
the ECD characteristics for the stereochemical analysis of 3-acyltetramic acids. As can be seen from
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the similarity of the C-NMR shifts of 3 and 4 and the known issues with the optical rotation,
chiroptical methods such as ECD and VCD spectroscopy are required for an unequivocal
configurational assignment.
EXPERIMENTAL SECTION
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General Procedures. All reagents were purchased in reagent grade quality and used without further
purification unless otherwise noted. All reactions involving air or moisture sensitive reagents or
intermediates were performed under an inert atmosphere of argon in glassware that was oven dried.
Reaction temperatures refer to the temperature of the particular cooling/heating bath. Reactions at
elevated temperatures were performed using oil baths for heat transfer. The photochemical reactions
using UV-A radiation were carried out in a photoreactor with 16 lamps (8 W, λ = 350 nm) arranged
cylindrically around a magnetic stirrer. Chromatography was performed using flash chromatography
with the indicated solvent system on 35-70 µm silica gel unless otherwise noted. Alternatively, the
purifications were performed on an automatic Flash Purification System with an integrated diode array
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detector. H NMR and C NMR spectra were recorded on a 300 MHz, 400 MHz or 600 MHz
spectrometer. Chemical shifts were referenced to the residual/deuterated solvent (e.g., for CDCl , δ=
.26 ppm and 77.16 ppm for H and C NMR, respectively) and reported in parts per million (ppm, δ)
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1
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relative to tetramethyl silane (TMS, δ = 0.00 ppm). Coupling constants (J) are reported in Hz and the
splitting abbreviations used were: s, singlet; d, doublet; t, triplet; m, multiplet; br, broad. Reactions
were monitored by thin layer chromatography (TLC) carried out on silica gel plates using an aqueous
solution of KMnO
4
(1%) and NaHCO (2%) and heat as developing agent. Specific reactions were
3
monitored by LC-MS on a system with a binary pump and integrated diode array detector coupled to
an LC/MSD-ion trap-mass-spectrometer. Ionization was achieved by an electrospray-ionization source
(ESI). High-resolution masses were recorded on an ESI/QTOF-Instrument and a suitable external
calibrant. Infrared spectra were recorded as FT-IR spectra using a diamond ATR unit and are reported
-
1
in terms of frequency of absorption (ν, cm ). ECD spectra were recorded on a ECD spectrometer in a
.00 mm quartz cuvette at 21 °C and at a scan rate of 20 nm/min (3 repetitions) over a wavelength
range of 180–400 nm. VCD spectra were recorded using a polarization modulation accessory attached
1
–
1
to a FT-IR spectrometer equipped with one photoelastic modulator optimized for 1400 cm . An
–
1
–1
accumulation time of 360 minutes, a spectral range of 1800–800 cm , a resolution of 4 cm , a 100
µm path length BaF sample cell and a concentration of 0.22 mol/L in CDCl were used for all
2
3
measurements. The spectra were baseline corrected by subtraction of a solvent spectrum recorded with
the same parameters. Tetrahydrofuran, benzene, toluene and diethyl ether were distilled under inert
gas from sodium and benzophenone, dichloromethane from P
2
O
5
and tBuOH from CaH .
2
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9
(2E,4E)-Hexa-2,4-dien-1-yl(triphenyl)phosphonium bromide (7).
9
b,11
Using the method of Theodorakis et al.,
(10 mL), and added dropwise at –8 °C to a solution of (2E,4E)-hexadien-1-ol (10.00 g, 102 mmol,
1.00 eq.) in DCM (20 mL). After stirring for 20 min, the solution was diluted with Et O (100 mL) and
washed with cold 5% NaHCO (50 mL) and brine. The aqueous layer was extracted with Et O (3x 50
mL), and the combined organic layers were dried over Na SO and evaporated. The residue was
dissolved in toluene (160 mL), and PPh (26.68 g, 102 mmol, 1.11 eq.) was added. After stirring for 72
PBr
3
(9.39 g, 34.6 mmol, 0.34 eq.) was dissolved in DCM
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
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5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
3
2
2
4
3
h at rt, the product was collected by filtration, washed with toluene and dried under reduced pressure.
Phosphonium bromide 7 was obtained as a beige solid (36.16 g, 84%): m.p..: 158–160 °C (lit. 159–
9b
–1
1
1
61 °C) ; IR (ATR) n (cm ) = 3054, 3018, 2991, 1437, 1112, 996, 738, 723, 691; H NMR, COSY
(
400 MHz, CDCl ) δ (ppm) = 7.84 – 7.73 (m, 9H, Ar-H2/6, Ar-H4), 7.68 – 7.62 (m, 6H, Ar-H3/5),
3
6
.33 (ddd, J = 15.5, 10.4, 5.3 Hz, 1H, H-3), 5.88 (ddt, J = 15.3, 10.4, 1.7 Hz, 1H, H-4), 5.63 (dqd, J =
5.3, 6.7, 2.7 Hz, 1H, H-5), 5.33 – 5.21 (m, 1H, H-2), 4.72 (dd, J = 15.4, 7.5 Hz, 2H, H-1), 1.66 (ddd,
1
1
3
1
J = 6.9, 3.0, 1.5 Hz, 3H, H-6); C{ H} NMR, HSQC, HMBC (100.6 MHz, CDCl
3
) δ (ppm) = 140.7
(d, JC,P = 13.6 Hz, C-3), 135.1 (d, JC,P = 2.9 Hz, Ar-C4), 133.9 (d, JC,P = 9.8 Hz, Ar-C2/6), 132.7 (d,
JC,P = 4.6 Hz, C-5), 130.4 (d, JC,P = 12.5 Hz, Ar-C3/5), 130.0 (d, JC,P = 5.1 Hz, C-4), 118.1 (d, JC,P
=
8
6
5.5 Hz, Ar-C1), 113.2 (d, JC,P = 11.2 Hz, C-2), 28.2 (d, JC,P = 49.4 Hz, C-1), 18.2 (d, JC,P = 1.5 Hz, C-
+
9b,11
); MS (ESI): m/z (%) = 343.2 (100) [M – Br] . The data are in accordance with the literature.
(2E,6R,8E,10E,12E)-2,6-Dimethyltetradeca-2,8,10,12-tetraenal.
9
c
Using the method of Gao et al. , alcohol 8 (808 mg, 3.45 mmol, 1.00 eq.) was dissolved in DCM (20
mL) and added dropwise to a suspension of DMP (95%, 2.19 g, 5.17 mmol, 1.50 eq.) in DCM (8 mL).
After stirring for 10 min, water (93 µL) was added and stirred or an additional 10 min before the
solution was evaporated. The residue was dissolved in EtOAc (40 mL) and stirred vigorously together
with sat. NaHCO
3
/ 10% Na
2
S
2
O
3
(20 mL) for 15 min. The aqueous layer was extracted with EtOAc
(3x 25 mL), brine (1x 25
(2x 25 mL), and the combined organic layers were washed with sat. NaHCO
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6
mL) and dried over Na
2
SO
4
. Evaporation gave the crude product as yellow oil (798 mg), which was
–1
used directly for the next step: R
f
= 0.48 (Pent/Et
2
O, 3:1); IR (ATR) n (cm ) = 2956, 2929, 2873,
31
1
1720, 1684, 1640, 1456, 1378, 1245, 992; [α]
D
= –15.6 (c 0.3, CHCl
3
); H NMR, COSY (400 MHz,
CDCl ) δ (ppm) = 9.38 (s, 1H, CHO), 6.46 (ddt, J = 7.3, 5.9, 1.4 Hz, 1H, H-3), 6.21 – 5.99 (m, 4H, H-
3
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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8
9
0
1
2
3
4
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9
0
8–H-13), 5.72 – 5.54 (m, 2H, H-8–H-13), 2.43 – 2.27 (m, 2H, H-4), 2.15 – 2.05 (m, 1H, H-7a), 1.98
(dt, J = 14.2, 7.2 Hz, 1H, H-7b), 1.75 (d, J = 6.2 Hz, 3H, H-14), 1.74 (s, 3H, C-2-Me), 1.63 – 1.48 (m,
1
3
1
2
H, H-5a, H-6), 1.36 – 1.20 (m, 1H, H-5b), 0.92 (dd, J = 6.6, 3.0 Hz, 3H, C-6-Me); C{ H} NMR,
) δ (ppm) = 195.5 (C-1), 155.1 (C-3), 139.4 (C-2), 132.28, 132.07,
31.81, 131.30, 130.41, 129.34 (C-8–C-13), 40.3 (C-7), 35.1 (C-5), 33.2 (C-6), 26.8 (C-4), 19.5 (C-6-
HSQC, HMBC (100.6 MHz, CDCl
3
1
+
Me), 18.4 (C-14), 9.3 (C-2-Me); MS (ESI): m/z (%) = 233.1 (100) [M + H] . Data are in accordance
9
c
with the literature.
O-[tert-Butyl(dimethyl)silyl]-D-serine methyl ester.
16
Using the method of Novachek et al. , D-serine hydrochloride methyl ester (1.00 g, 6.43 mmol, 1.00
eq.) and imidazole (1.31 g, 19.3 mmol, 3.00 eq.) were dissolved in DCM (20 mL). TBDMSCl (1.16 g,
7.70 mmol, 1.20 eq.) was added, and the solution was stirred overnight at rt. The solvent was
evaporated, and the residue was partitioned between water (10 mL) and ethyl acetate (10 mL). The
aqueous layer was extracted with ethyl acetate (3x 10 mL), and the combined organic layers were
dried over Na
2
SO and evaporated. The residue was purified by flash column chromatography (100%
4
ethyl acetate) to give the TBDMS-protected amino acid as colourless liquid (755 mg, 3.23 mmol,
–
1
5
0%): R
1680, 1464, 1256, 1111, 837, 778; [α]
δ (ppm) = 3.90 (dd, J = 9.7, 4.5 Hz, 1H, H-3a), 3.79 (dd, J = 9.7, 3.8 Hz, 1H, H-3b), 3.71 (s, 3H,
COOMe), 3.51 (pseudo-t, J = 4.1 Hz, 1H), 1.70 (s, br, 2H, NH), 0.86 (s, 9H, C(CH ), 0.03 (s, 3H, Si-
) δ (ppm) = 174.7 (C-1), 65.5
), –5.4 (SiMe), –5.5 (SiMe). The data
f
= 0.21 (silica gel, EtOAc/cyclohexane, 9:1); IR (ATR) n (cm ) = 2954, 2929, 2857, 1746,
3
1
1
D
= +7.3 (c 0.15; CHCl
3
); H NMR, COSY (400 MHz, CDCl )
3
)
3 3
1
3
Me), 0.02 (s, 3H, Si-Me); C NMR, HSQC, HMBC (100.6 MHz, CDCl
3
(C-3), 56.6 (C-2), 52.1 (COOMe), 25.9 (C(CH ), 18.3 (C(CH
3
)
3
)
3 3
1
6
are in accordance to the literature.
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(
1S,2R,4aS,6R,8aR)-1,6-Dimethyl-2-[(1E)-prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-
carbaldehyde (9).
9b,c,11,17
Using the method of Theodorakis, Burke and Gao et al.
a solution of I (7.3 mg, 0.03 mmol,
2
0
.05 eq.) in DCM (5 mL) was added dropwise to a solution of the unsaturated aldehyde (133 mg, 0.57
mmol, 1.00 eq.) in DCM (25 mL). After irradiation with a 500 W incandescent lamp (visible light), the
reaction mixture was cooled to –78 °C, and BF ·Et O (243 mg, 1.72 mmol, 3.00 eq.) was added
slowly. After stirring at this temperature for 10 min, sat. Na /sat. NaHCO (1:1, 10 mL) was
added and the reaction mixture was allowed to warm to rt under vigorous stirring. The aqueous layer
was extracted with DCM (3x10 mL). The combined organic layers were dried over Na SO and
evaporated. Purification by flash column chromatography (PE 9.5/0.5 Et O) gave aldehyde 9 (93 mg,
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
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6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
3
2
2
S
2
O
3
3
2
4
2
–
1
7
0%) as colorless oil: R
f
= 0.54 (Pent/Et
2
O, 9.5:0.5); IR (ATR) n (cm ) = 3017, 2948, 2916, 2856,
3
1
1
1
724, 1455, 1374, 974, 725; [α]
D
= –253.9 (c 1.00, CHCl
3
); H NMR, COSY (300 MHz, CDCl
3
)
δ (ppm) = 9.47 (s, 1H, H-1), 5.53 – 5.33 (m, 4H, H-5, H-1‘, H-2‘, H-4), 2.57 – 2.49 (m, 1H, H-3), 1.89
–
–
3
1.69 (m, 3H, H-7a, H-11, H-9a), 1.66 (d, J = 4.8 Hz, 4H, H-3‘, H-6), 1.53 – 1.43 (m, 1H, H-8), 1.40
1.33 (m, 1H, H-10a), 1.16 – 1.03 (m, 2H, H-10b, H-9b), 1.00 (s, 3H, C2-Me), 0.92 (d, J = 6.6 Hz,
1
3
1
H, C8-Me), 0.90 – 0.81 (m, 1H, H-7b); C{ H} NMR, HSQC, HMBC (75 MHz, CDCl )
3
δ (ppm) = 209.1 (C-1), 131.0 (C-5), 129.6 (C-1‘), 128.6 (C-2‘), 126.9 (C-4), 50.4 (C-2), 49.2 (C-3),
41.8 (C-7), 38.9 (C-6), 37.4 (C-11), 35.5 (C-9), 33.3 (C-8), 27.2 (C-10), 22.6 (C8-Me), 18.1 (C-3‘),
+
13.9 (C2-Me); MS (ESI): m/z (%) = 233.2 (100) [M + H] . The data are in accordance with the
9
b,11
literature.
Ethyl
3-{(1S,2R,4aS,6R,8aR)-1,6-dimethyl-2-[(1E)-prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-
octahydronaphthalen-1-yl}-3-oxopropanoate (10).
9
b,11
Using the method of Theodorakis et al. , ethyl 2-bromoacetate (835 mg, 5.00 mmol, 3.00 eq.) was
added dropwise to a suspension of activated zinc dust (545 mg, 8.33 mmol, 3.00 eq.) in benzene (3
mL) and refluxed for 5 min. The reaction mixture was diluted with further benzene (6 mL), and a
solution of 9 (387 mg, 1.67 mmol, 1.00 eq.) in benzene (4 mL) was slowly added. After refluxing for
3
0 min, the reaction mixture was allowed to cool to room temperature, acidified with 1 n HCl (25
mL), and extracted with EtOAc (4x 30 mL). The combined organic layers were washed with NaHCO
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5
6
(
35 mL) and brine, dried over Na
IBX (933 mg, 3.33 mmol, 2.00 eq.) was added, and the reaction mixture was heated to 80 °C for 15
min. After cooling to rt, the reaction was quenched with water (35 mL) and Et O (50 mL) was added.
After vigorous stirring for 10 min, the reaction mixture was filtered and the aqueous phase extracted
with Et O (4 x 35 mL). The combined organic layers were washed with 10% NaOH (2 x 35 mL) and
brine (1 x 35 mL), dried over Na SO and evaporated. After purification by silica gel column
chromatography (PE/Et O, 5% Et O), the product was obtained as clear, colorless oil (284 mg, 54%)
2
SO
4
, and evaporated. The residue was resolved in DMSO (7 mL),
2
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
2
2
4
2
2
along with the the β-hydroxy intermediate (120 mg, 22%) which was again oxidized by IBX. β-
Ketoester 10 was achieved in a total yield of 329 mg (62%). NMR shows a mixture of keto/enol
–
1
tautomers: R
310, 1135, 1036, 732; [α]
δ (ppm) = 12.43 (s, 0.01H, enol-OH), 12.41 (s, 0.06H, enol-OH), 5.45 – 5.31 (m, 3H, H-5, H-4, H-2‘),
.12 (ddq, J = 15.0, 9.2, 1.6 Hz, 1H, H-1‘), 5.06 (s, 0.06H, C=CH-COOEt, enol), 4.20–4.10 (m, 2H,
CH CH ), 3.48 (d, J = 15.8 Hz, 1H, CO-CH -COOEt a), 3.31 (d, J = 15.8 Hz, 1H, CO-CH -COOEt a),
.25 (d, J = 15.7 Hz, 0.06H, CO-CH -COOEt b rotamer), 2.59 – 2.48 (m, 1H, H-3), 2.21 (dtd, J = 6.6,
.6, 1.6 Hz, 0.06H, H-3), 1.82 – 1.66 (m, 4H, H-7a, H-9a, H-10a, H-11), 1.65 – 1.61 (m, 1H, H-6),
.60 (dd, J = 6.4, 1.6 Hz, 3H, H-3‘), 1.51 – 1.39 (m, 1H, H-8), 1.24 (t, J = 7.1 Hz, 3H, CH CH ), 1.16
f
= 0.31 (Pent/Et O, 9:1); IR (ATR) n (cm ) = 3016, 2947, 2915, 1745, 1708, 1455, 1377,
2
3
1
1
1
D
= –159.8 (c 0.25, CHCl
3
); H NMR, COSY (400 MHz, CDCl )
3
5
2
3
2
2
3
3
1
2
2
3
(s, 3H, C2-Me), 1.11 – 1.02 (m, 1H, H-9b), 1.07 (s, 0.18H, C2-Me enol), 0.97 – 0.91 (m, 1H, H-10b),
1
3
1
0.88 (d, J = 6.5 Hz, 3H, C8-Me), 0.87 – 0.79 (m, 1H, H-7b); C{ H} NMR, HSQC, HMBC
(100.6 MHz, CDCl ) δ (ppm) = 205.7 (C-1), 183.7 (C-1 enol), 167.9 (COOEt), 130.7 (H-5), 130.5 (H-
1‘), 127.1 (H-2‘), 126.4 (H-4), 89.0 (C=CH-COOEt enol), 61.1 (CH CH ), 53.5 (C-2), 49.6 (C-3), 46.6
(CO-CH -COOEt), 45.9 (C-2 enol), 42.0 (C-7), 39.7 (C-6), 38.4 (C-11), 35.6 (C-9), 33.5 (C-8), 27.3
(C-10), 22.6 (C8-Me), 17.9 (C-3‘), 1709 (C2-Me), 14.3 (CH
3
2
3
2
2
CH
3
); MS (ESI): m/z (%) = 341.4 (100)
+
+
9b,11
[M + Na] , 319.5 (39) [M + H] . The data are in accordance to the literature.
3
-Oxo-3-{(1S,2R,4aS,6R,8aR)-1,6-dimethyl-2-[(1E)-prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-
octahydronaphthalen-1-yl}propanoic acid (11).
A solution of NaOH (60 mg, 1.49 mmol, 1.80 eq.) in H O (1 mL) was added dropwise to a solution of
2
ester 10 (275 mg, 0.83 mmol, 1.00 eq.) in EtOH (14 mL). After stirring for 18 h at rt, the mixture was
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9
acidified carefully with 1 N HCl (pH 1–2) under cooling with an ice bath and extracted with EtOAc
(
3x 10 mL). The combined organic phases were washed with brine and dried over Na
2
SO . The
4
solvent was removed under reduced pressure to give 11 as colorless solid (264 mg, 98%), which was
directly used for the next step.
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
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1
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8
9
0
O-[tert-Butyl(dimethyl)silyl]-N-(2-nitrobenzyl)-D-serine methyl ester (12).
p-Nitrobenzaldehyde (427 mg, 2.83 mmol, 1.10 eq.) and acetic acid (308 mg, 5.14 mmol, 2.00 eq.)
were added to a solution of O-TBDMS-protected D-serine methyl ester (600 mg, 2.57 mmol, 1.00 eq.)
in methanol (15 mL). After stirring for 30 min at rt, NaCNBH
3
(95%, 255 mg, 3.86 mmol, 1.5 eq.) was
(650 mg, 7.71 mmol, 3.00 eq.)
added, and the solution was stirred for an additional 18 h at rt. NaHCO
3
was added, and the solvent was evaporated. The residue was partitioned between water (20 mL) and
DCM (40 mL), and the aqueous layer was extracted with DCM (2x 20 mL). The combined organic
layers were dried over Na
2
SO and evaporated. Purification by flash column chromatography
4
(cyclohexane/EtOAc, 5% EtOAc) gave the protected amino acid 12 as pale yellow liquid (918 mg,
–
1
2
.49 mmol, 97%): R
742, 1528, 1463, 1359, 1254, 1109, 837; [α]
) δ (ppm) = 7.91 (dd, J = 8.1, 1.3 Hz, 1H, Ar-H-3), 7.65 (dd, J = 7.5, 1.4 Hz, 1H, Ar-H-6), 7.55
(td, J = 7.5, 1.3 Hz, 1H, Ar-H-5), 7.39 (ddd, J = 8.1, 7.5, 1.4 Hz, 1H, Ar-H-4), 4.19 (d, J = 14.9 Hz,
1H, CH Ar), 4.00 (d, J = 14.9 Hz, 1H, CH Ar), 3.86 (dd, J = 9.8, 4.7 Hz, 1H, H-3a), 3.79 (dd, J = 9.8,
4.7 Hz, 1H, H-3b), 3.69 (s, 3H, COOMe), 3.36 (t, J = 4.7 Hz, 1H, H-2), 2.44 (s, 1H, NH), 0.84 (s, 9H,
f
= 0.26 (cyclohexane/EtOAc, 9.5:0.5); IR (ATR) n (cm ) = 2953, 2930, 2857,
2
5
1
1
D
= +2.4 (c 1.0; CHCl ); H NMR, COSY (400 MHz,
3
CDCl
3
2
2
1
3
1
C(CH
CDCl
(C-4-Ar), 124.8 (C-3-Ar), 64.7 (C-3), 62.9 (C-2), 51.9 (COOMe), 49.0 (CH
(C(CH
HRMS (ESI-QTOF) m/z: [M + H] Calcd for C17
3
)
3
), 0.01 (s, 3H, Si-Me), 0.00 (s, 3H, Si-Me); C{ H} NMR, HSQC, HMBC (100.6 MHz,
3
) δ (ppm) = 173.5 (C-1), 149.2 (C-2-Ar), 135.5 (C-1Ar), 133.2 (C-5-Ar), 130.9 (C-6-Ar), 128.0
2
Ar), 25.8 (C(CH ) ), 18.3
3
3
+
3
)
3
), –5.4 (SiMe), –5.51 (SiMe); MS (ESI): m/z (%) = 369.2 (100) [M + H] ;
+
H
29
N
2
O
5
Si 369.1846; Found 369.1849.
(2E,6R,8E,10E,12E)-2,6-Dimethyltetradeca-2,8,10,12-tetraen-1-ol (8).
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Phosphonium bromide 7 (10.04 g, 23.50 mmol, 1.00 eq.) was suspended in THF (100 mL), and sec-
BuLi (33.6 mL, 1.4 M in cyclohexane, 23.49 mmol, 2.00 eq.) was added dropwise at –78 °C. After
stirring for 10 min at this temperature, a solution of aldehyde 6 (4.05 g, 23.79 mmol, 1.00 eq.) in THF
(
60 mL) was added slowly. The mixture was allowed to warm to rt and stirred for 48 h. After addition
of sat. NH Cl (30 mL), the aqueous phase was extracted with n-pentane/Et O (40 mL, 3:1). The
combined organic phases were dried over Na SO and evaporated. Purification flash column
chromatography (PE/Et O, 0% to 40% Et O, automatic flash purification system) gave 8 (3.14 g,
3.40 mmol, 56%) as a pale yellow oil, which was an inseparable mixture of E/Z isomers (E/Z, 3:2): R
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
4
2
2
4
2
2
1
f
–
1
31
=
0.17 (Pent/Et
2
O, 3:1); IR (ATR) n (cm ) = 3322, 3013, 2956, 2913, 1454, 1377, 993; [α]
D
= –13.3
1
(
c 0.3, CHCl
3
); H NMR, COSY (400 MHz, CDCl ) δ (ppm) = 6.42 – 6.31 (m, 0.4H), 6.22 – 5.97 (m,
3
4.6H, H-9 – H-13 E/Z), 5.76 – 5.57 (m, 1H, H-8 E), 5.43 – 5.33 (m, 1.4H, H-3 E/Z, H-8 Z), 3.99 (s,
2H, H-1 E/Z), 2.23 – 2.12 (m, 1H), 2.12 – 1.99 (m, 3H), 1.94 (ddd, J = 12.7, 7.7, 6.7 Hz, 1H), 1.78 (d,
J = 6.4 Hz, 1H, H-14 E or Z), 1.75 (d, J = 6.3 Hz, 2H, H-14 E or Z), 1.66 (t, J = 1.3 Hz, 3H, C-2-Me
E/Z), 1.59 – 1.46 (m, 1H, H-6 E/Z), 1.45 – 1.33 (m, 1H, H-5a E/Z), 1.25 – 1.13 (m, 1H, H-5b E/Z),
1
3
1
0
.90 (d, J = 6.7 Hz, 1H, C-6-Me Z), 0.88 (d, J = 6.7 Hz, 2H, C-6-Me E); C{ H} NMR, HSQC,
HMBC (100.6 MHz, CDCl ) δ (ppm) = 134.7, 134.7 (C-2 E/Z), 132.96, 132.84 (C-8 E), 132.07,
31.92, 131.90, 130.97, 130.67, 130.46 (C-8 Z), 129.74, 129.72, 129.07, 126.72 (C-3 E/Z), 126.02,
3
1
69.22 (C-1 E/Z), 40.40 (C-7 E), 36.45, 36.39 (C-5 E/Z), 35.13 (C-7 Z), 33.33 (C-6 Z), 33.09 (C-6 E),
25.38, 25.32 (C-4 E/Z), 19.66 (C-6-Me E), 19.61 (C-6-Me Z), 18.48, 18.44 (C-14 E/Z), 13.80 (C-2-Me
+
+
E/Z); MS (ESI): m/z (%) = 217.1 (100) [M – H O + H] ; 235.1 (11) [M + H] ; The data are in
2
9
c
accordance to the literature.
O-[tert-Butyl(dimethyl)silyl]-N-(3-{(1S,2R,4aS,6R,8aR)-1,6-dimethyl-2-[(1E)-prop-1-en-1-yl]-
1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl}-3-oxopropanoyl)-N-(2-nitrobenzyl)-D-serine methyl ester
(
13).
A solution of DCC (132 mg, 0.64 mmol, 1.01 eq.) and DMAP (4 mg, 0.03 mmol, 0.05 eq.) in DCM
0.8 mL) was added dropwise to a solution of β-keto acid 11 (184 mg, 0.63 mmol, 1.00 eq.) and amino
(
acid 12 (233 mg, 0.63 mmol, 1.00 eq.) in DCM (1.3 mL). After stirring for 10 h at rt, the solution was
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filtered and evaporated. The residue was resolved in acetone to remove remaining urea by filtration,
and the filtrate was evaporated. After purification by reversed phase chromatography (MeCN/H
2
O, 5%
–
5
95% MeCN, automatic flash purification system), 13 was obtained as colorless lyophilizate (222 mg,
5%). NMR spectra show a mixture of rotameres and keto-enol tautomers: R = 0.35 (silica gel,
f
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
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3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
–1
CH/EtOAc, 8:2); IR (ATR) n (cm ) = 3016, 2951, 2857, 1746, 1658, 1528, 1455, 1253, 1118, 838;
3
1
1
[
α]
OH), 8.12 (dd, J = 8.2, 1.1 Hz, 1H, Ar-H3 enol), 8.10 (dd, J = 8.1, 1.1 Hz, 1H, Ar-H3 R1), 8.07 (dd, J
8.2, 1.1 Hz, 1H, Ar-H3 R2), 7.96 (d, J = 7.6 Hz, 1H, Ar-H6 R1), 7.80 (d, J = 7.8 Hz, 1H, Ar-H6
enol), 7.72 (dd, J = 8.0, 1.3 Hz, 1H, Ar-H6 R2), 7.70 (td, J = 7.6, 1.3 Hz, 1H, Ar-H5 R1), 7.63 (td, J =
.6, 1.3 Hz, 1H, Ar-H5 enol), 7.59 (td, J = 7.7, 1.3 Hz, 1H, Ar-H-5 R2), 7.50 – 7.47 (m, 1H, Ar-H3
R1), 7.47 – 7.41 (m, 1H, Ar-H3 enol), 7.35 (t, J = 7.5 Hz, 1H, Ar-H3 R2), 5.47 – 5.01 (m, 17H, H-4,
H-5, H-1‘, H-2‘, Ar-CH R1, Ar-CH enol, Ar-CH a R2), 4.97 (d, J = 18.2 Hz, 1H, Ar-CH b R2),
.94 – 4.92 (m, 1H, C-2‘‘ enol), 4.71 (s, 1H, C=CH-CONR enol), 4.55 (dd, J = 6.3, 4.0 Hz, 1H, C-2‘‘
R2), 4.47 (dd, J = 7.0, 3.3 Hz, 1H, C-2‘‘ R1), 4.25 – 4.20 (m, 1H, C-3‘‘ a enol), 4.20 – 4.17 (m, 2H, C-
D
= –74.5 (c 1.00, CHCl
3
); H NMR, COSY (600 MHz, CDCl
3
) δ (ppm) = 14.43 (s, 1H, enol-
=
7
2
2
2
2
4
2
3
‘‘ a R1 & R2), 4.04 – 3.98 (m, 3H, C-3‘‘ b), 3.76 (s, 3H, COOMe enol), 3.71 (s, 3H, COOMe R2),
.66 (s, 3H, COOMe R1), 3.64 (d, J = 16.5, 1H, CO-CH -CONR a R1), 3.62 (d, J = 16.4, 1H, CO-
-CONR b R2), 3.15 (d, J = 16.5 Hz, 1H, CO-
b R1), 2.60 (dd, J = 9.4, 5.0 Hz, 1H, H-3 R2), 2.44 (dd, J = 9.2, 5.2 Hz, 1H, H-3 R1),
3
2
2
CH
2
2
-CONR
2
2
a R2), 3.33 (d, J = 16.4 Hz, 1H, CO-CH
2
2
CH
-CONR
2.29 – 2.27 (m, 1H, H-3 enol), 1.84 – 1.65 (m, 16H, H-6, H-7a, H-9a, H-10a, H-11 R1 & enol), 1.65 –
1.57 (m, 4H, H-3‘, H-11 R2), 1.55 (dd, J = 6.4, 1.6 Hz, 3H, H-3‘), 1.53 – 1.44 (m, 2H, 2xH-8), 1.38
(dd, J = 6.4, 1.6 Hz, 3H, H-3‘), 1.37 – 1.33 (m, 2H, 1xH-8, 1xH-10b) 1.23 (s, 3H, C-2-Me R2), 1.12
(s, 3H, C-2-Me R1), 1.10 – 1.03 (m 2H, 2x H-9b), 0.93 – 0.87 (m, 13H, H-8-Me R1 & enol, C-2-Me
enol, 2xH-10b, 2x H-7b), 0.83–0.81 (m, 3H, C8-Me R2), 0.81 (s, 9H, C(CH
C(CH ), 0.76 – 0.74 (m, 1H, 1x H-7b), 0.50–0.46 (m, 1H, 1x H-9b), 0.02 (s, 3H, SiMe), –0.04 (s, 3H,
SiMe), –0.06 (s, 3H, SiMe), –0.07 (s, 3H, SiMe), –0.12 (s, 3H, SiMe), –0.13 (s, 3H, SiMe);
3
3
) ), 0.77 (s, 18H, 2x
)
3 3
1
3
1
C{ H} NMR, HSQC, HMBC (150.1 MHz, CDCl
C-1 enol), 173.9 (C=CH-CONR enol), 169.9 (COOMe enol), 169.8 (CONR
R1), 169.4 (COOMe R2), 168.7 (CONR R2), 147.8 (Ar-C2 R1), 147.44 (Ar-C2 R2), 147.39 (Ar-C2
3
) δ (ppm) = 208.1 (C-1 R2), 206.5 (C-1 R1), 183.9
(
2
2
R1), 169.5 (COOMe
2
enol), 136.7, 134.51 (Ar-C1 R2), 134.48 (Ar-C1 enol), 134.1 (Ar-C5 R1), 133.79 (Ar-C5 R2), 133.76
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(
Ar-C5 enol), 131.89, 130.86, 130.84, 130.67, 130.66, 130.10, 129.39 (Ar-C6 R1), 129.1 (Ar-C6
enol), 128.7 (Ar-C6 R2), 128.6 (Ar-C4 R1), 128.2 (Ar-C4 enol), 127.35, 127.31, 127.30 (Ar-C4 R2),
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26.85, 126.53, 126.46, 126.41, 125.51, 125.45 (Ar-C3 enol), 125.40 (Ar-C3 R1), 125.0 (Ar-C3 R2),
7.2 (C=CH-CONR enol), 62.9 (C-2‘‘ R2), 62.5 (C-3‘‘ enol), 62.2 (C-3‘‘ R2), 62.1 (C-3‘‘ R1), 61.0
8
2
0
1
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4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
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0
(
C-2‘‘ R1), 60.0 (C-2‘‘ enol), 53.9 (C-2 R2), 53.7 (C-2 R1), 52.6 (COOMe enol), 52.4 (COOMe R2),
2.3 (COOMe R1), 50.8 (C-3 enol), 50.7 (Ar-CH R1), 49.9 (Ar-CH enol), 49.8 (C-3 R2), 49.2 (C-3
R1), 46.7 (CO-CH -CON R2), 46.5 (Ar-CH R2), 46.1 (C-2 enol), 45.2 (CO-CH -CON R1), 42.0,
9.87, 39.85 (C-11), 39.8, 38.6, 38.5 (C-6), 35.61, 35.57 (C-9), 33.50, 33.48, 33.33 (C-8), 27.34,
7.23, 27.19 (C-10), 25.82, 25.72, 25.68 (C(CH ), 22.62, 22.51 (C-8-Me), 18.1, 18.0 (C(CH ), 17.8
5
2
2
2
2
2
3
2
3
)
3
)
3 3
(C-3‘), 17.2 (C2-Me R2), 17.0 (C2-Me R1), 16.9 (C-2-Me enol), –5.65, –5.71, –5.78, –5.84 (Si-Me);
+
+
+
MS (ESI) m/z: 641.7 (100) [M + H] , 663.4 (16) [M + Na] ; HRMS (ESI-QTOF) m/z: [M + H] Calcd
SiNa 663.3436; Found 663.3435.
for C35
H
52
N
2
O
7
(3Z,5R)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[{(1S,2R,4aS,6R,8aR)-1,6-dimethyl-2-[(1E)-
prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl}(hydroxy)methyliden]-1-(2-
nitrobenzyl)pyrrolidin-2,4-dione (14).
KOtBu (34 mg, 0.31 mmol, 1.20 eq.) was added to a solution of 13 (164 mg, 0.26 mmol, 1.00 eq.) in
tBuOH (1.4 mL). After stirring for 20 min at rt, the mixture was partitioned between sat. NH
mL) and EtOAc (5 mL). The aqueous layer was extracted with EtOAc (3x 10 mL), and the combined
organic layers were washed with brine (15 mL). The solution was dried over Na SO and evaporated.
Purification by flash column chromatography (n-pentane/Et O, 7:3) gave tetramic acid 14 as yellow
oil (132 mg, 0.217 mmol, 85%). NMR data show a mixture of different enols: R = 0.35 (silica gel,
4
Cl (3
2
4
2
f
–
1
Pent/Et
2
O, 6:4); IR (ATR) n (cm ) = 3017, 2950, 2858, 1696, 1566, 1528, 1470, 1341, 1114, 837;
2
5
1
[α]
D
= –101.6 (c 2.00, CHCl
3
); H NMR, COSY (600 MHz, CDCl
3
) δ (ppm) = 16.05 (s, 0.4H, C1-
OH), 8.10 (dd, J = 8.2, 1.3 Hz, 1H, Ar-H3 Z-enol major), 8.04 (dd, J = 8.2, 1.3 Hz, 0.5H, Ar-H3 E-
enol minor), 7.64 – 7.60 (m, 1H, Ar-H5 Z), 7.57 (td, J = 7.6, 1.3 Hz, 0.5H, Ar-H5 E), 7.49 – 7.39 (m,
3
H, Ar-H4 Z & E, Ar-H6 Z & E), 5.47 – 5.30 (m, 4.5H, H5 E & Z, H4 E & Z, H-2‘ E & Z), 5.27 (d, J
17.4, 1H, Ar-CH a Z), 5.24 – 5.14 (m, 1.5H, H-1‘ E & Z), 5.09 (d, J = 17.3 Hz, 0.5H, Ar-CH a E),
.98 (d, J = 17.4 Hz, 1H, Ar-CH b E), 4.00 – 3.88 (m, 4H,
=
2
2
4
2
b Z), 4.93 (d, J = 17.3 Hz, 0.5H, Ar-CH
2
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H-6’ E & Z, H-5’ E), 3.76 (s br, 1H, H-5’ Z), 3.71 – 3.66 (m, 1H, H-3 Z), 3.36 – 3.28 (m, 0.5H, H-3
E), 2.00 – 1.91 (m, 1.5H, H-10ª E & Z), 1.89 – 1.79 (m, 3H, H-7a E & Z, H-11 E & Z), 1.79 – 1.73 (m,
1
.5H, H-9a E & Z), 1.72 – 1.66 (m, 1.5H, H-6 E & Z), 1.61 – 1.55 (m, 4.5H, H-3’ E & Z), 1.55 – 1.48
m, 6H, C2-Me E & Z, H-8 E & Z), 1.16 – 0.99 (m, 3H, H-9b E & Z, H-10b E & Z), 0.92 (d, J = 6.6
Hz, 4.5H, C8-Me E & Z), 0.90 – 0.86 (m, 1.5H, H-7b E & Z), 0.79 (s, 9H, C(CH Z), 0.78 (s, 4.5H,
C(CH E), 0.00 (s, 3H, SiMe Z), -0.04 (s, 3H, 2x SiMe E), -0.04 (s, 3H SiMe Z); C{ H} NMR,
HSQC, HMBC (150.9 MHz, CDCl ) δ (ppm) = 203.5 (C-1 Z), 198.6 (C-1 E), 196.1 (C-4’ E), 189.1
C-4’ Z), 177.8 (C-2’ Z), 167.9 (C-2’ E), 148.2 (Ar-C2 E), 148.1 (Ar-C2 Z), 133.9 (Ar-C5 Z), 133.7
(
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
)
3 3
13
1
)
3 3
3
(
(
(
Ar-C5 E), 132.6 (Ar-C1 Z), 131.4 (C-1’’ E), 131.2 (C-1’’ Z), 130.3 (C-5 E), 130.0 (C-5 Z), 129.2
Ar-C6 E), 128.95 (Ar-C6 Z), 128.5 (Ar-C4 Z), 128.3 (Ar-C4 E), 127.6 (C-2’’ E), 127.0 (C-2’’ Z),
126.9 (C-4 Z), 126.4 (C-4 E), 125.5 (Ar-C3 Z), 125.2 (Ar-C3 E), 107.1 (C-3’ E), 100.5 (C-3’ Z), 66.6
(
C-5’ Z), 63.7 (C-5’ E), 61.8 (C-6’ Z), 60.3 (C-6’ E), 50.1 (C-2 Z), 48.9 (C-2 E), 45.5 (C-3 Z), 44.9
C-3 E), 42.5 (C-7 E), 42.3 (C-7 Z), 40.2 (C-11 Z), 39.8 (C-11 E), 38.9 (C-6 E), 38.5 (C-6 Z), 35.9 (C-
(
9
E), 35.8 (C-9 Z), 33.67, 33.64 (C-8 E/Z), 28.4 (C-10 Z), 28.1 (C-10 E), 25.9 (C(CH
C(CH E), 22.7 (C8-Me E & Z), 18.3 (C-3’’’ E), 18.2 (C(CH E & Z), 18.1 (C-3’’’ Z), 14.7 (C2-
Me Z), 14.1 (C2-Me E), –5.46 (SiMe), –5.55 (SiMe), –5.57 (SiMe), –5.7 (SiMe); MS (ESI): m/z (%) =
3
) Z), 25.7
3
(
3
)
3
)
3 3
+
+
+
6
09.7 (100) [M + H] , 631.4 (13) [M + Na] ; HRMS (ESI-QTOF) m/z: [M + H] Calcd for
C
34
H
49
N
2
O
6
Si 609.3360; Found 609.3350.
(3Z,5R)-5-({[tert-Butyl(dimethyl)silyl]oxy}methyl)-3-[{(1S,2R,4aS,6R,8aR)-1,6-dimethyl-2-[(1E)-
prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-octahydronaphthalen-1-yl}(hydroxy)methyliden]pyrrolidin-2,4-
dione (15).
A solution of tetramic acid 14 (31.0 mg, 50.9 µmol) in MeCN (3 mL) was irradiated for 15 min at rt,
using a photoreactor with 350 nm-UV-A lamps. Water (1–2 mL) was added, and the solution was
stirred for 12 h. The solvent was removed by lyophilization, and the residue was purified by reversed
phase chromatography (H
2
O/MeCN, 5–95%, automatic flash purification system). Compound 15 was
= 0.19 (silica gel,
cyclohexane/EtOAc, 8:2); IR (ATR) n (cm ) = 3250, 2945, 2950, 1858, 1660, 1572, 1456, 1362,
obtained as colorless lyophilisate (17.4 mg, 36.7 µmol, 72%): R
f
–
1
31
1
1
256, 1124, 838, 779; [α]
D
= –225 (c 0.20, CHCl
3
); H NMR, COSY (600 MHz, CDCl ) δ (ppm) =
3
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6
.08 (br s, 1H, NH), 5.44 – 5.36 (m, 2H, H-4, H-5), 5.21 (br s, 1H, H-14), 5.18 (br s, 1H, H-13), 4.00
(
br s, 1H, H-6'a), 3.90 (br s, 1H, H-5'), 3.53 (br s, 1H, H-6'b), 3.32 (br s, 1H, H-3), 1.96 (br s, 1H, H-
0a), 1.88 – 1.78 (m, 2H, H-6, H-7a), 1.78 – 1.72 (m, 1H, H-9a), 1.70 – 1.63 (m, 1H, H-11), 1.54 (d, J
5.2 Hz, 3H, H-15), 1.48 (br s, 4H, C2-Me, H-8), 1.15 – 1.01 (m, 2H, H-10b, H-9b), 0.92 (d, J = 6.5
Hz, 3H, C8-Me), 0.88 (s, 10H, C(CH , H-7b), 0.07 (s, 3H, Si-Me), 0.07 (s, 3H, Si-Me);
C{ H} NMR, HSQC, HMBC (150.9 MHz, CDCl ) δ (ppm) = 200.2 (C-1), 189.7 (C-4’), 179.0 (C-
’), 131.1 (C-13), 130.1 (C-5), 127.1 (C-14), 126.7 (C-4), 100.5 (C-3’), 64.1 (C-6’), 63.0 (C-5’), 49.0
C-2), 45.0 (C-3), 42.4 (C-7), 40.1 (C-11), 38.7 (C-6), 35.8 (C-9), 33.6 (C-8), 28.4 (C-10), 26.0
C(CH ), 22.6 (C-8-Me), 18.4 (C(CH ), 18.1 (C-15), 14.0 (C-2-Me), 2.1 (Si-Me), –5.3 (Si-Me); MS
ESI): m/z (%) = 474.6 (100) [M + H] , 496.4 (13) [M + Na] ; HRMS (ESI-QTOF) m/z: [M + H]
Si 474.3040; Found 474.3030.
1
=
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
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0
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0
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9
0
1
2
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6
7
8
9
0
)
3 3
13
1
3
2
(
(
(
3
)
3
)
3 3
+
+
+
Calcd for C27
H44NO
4
(
3Z,5R)-3-[{(1S,2R,4aS,6R,8aR)-1,6-Dimethyl-2-[(1E)-prop-1-en-1-yl]-1,2,4a,5,6,7,8,8a-
octahydronaphthalen-1-yl}(hydroxy)methyliden]-5-(hydroxymethyl)pyrrolidin-2,4-dione
epi-trichosetin, 4).
HF (190 μL, 3.83 mmol, 191 eq., 48% in water) was added to a solution of silyl ether 15 (9.5 mg,
0.0 µmol, 1.00 eq.) in MeCN (400 μL). After stirring for 10 min at room temperature, NaHCO (327
(
2
3
mg, 3.89 mmol, 194 eq.), dissolved in a small amount of water, was added. EtOAc (8 mL) was added,
and the aqueous layer was extracted with EtOAc (2x 8 mL). The combined organic layers were
washed with brine (5 mL), dried over Na
phase flash chromatography (H O/MeCN, automatic flash purification system) to give epi-trichosetin
7.2 mg, 20.0 µmol, 99%) as a colorless lyophilizate: R
2
SO and evaporated. The residue was subjected to reversed
4
2
(
f
= 0.15 (silica gel, EtOAc/MeOH, 9:1);
–
1
31
IR (ATR) n (cm ) = 3299 br, 3017, 2946, 2920, 2853, 1657, 1566, 1455, 1378, 976; [α]
D
= –248 (c
2
2
1
0.10, MeOH); ECD (MeOH) = 238 nm (0.23 deg×cm /dmol), 276 nm (–4.2 deg×cm /dmol); H NMR,
COSY (600 MHz, CDCl
J = 12.7, 6.6 Hz, 1H, H-14), 5.16 (br s, 1H, C-13), 3.94 (br s, 1H, H-5’), 3.92 – 3.86 (m, 1H, H-6’a),
.81 (dd, J = 11.2, 5.8 Hz, 1H, H-6’b), 3.39 (br s, 1H, H-3), 1.95 (s, 1H, H-10a), 1.87 – 1.79 (m, 2H,
H-6, H-7a), 1.78 – 1.73 (m, 1H, H-9a), 1.68 (br s, 1H, H-11), 1.53 (d, J = 6.0 Hz, 3H, H-15), 1.52 –
3
) δ (ppm) = 6.06 (br s, 1H, NH), 5.39 (d, J = 4.6 Hz, 2H, H-4, H-5), 5.25 (dt,
3
1.49 (m, 1H, H-8), 1.48 (s, 3H, C-2-Me), 1.17 – 1.01 (m, 2H, H-9b, H-10b), 0.92 (d, J = 6.7 Hz, 3H,
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3
1
H-8-Me), 0.90 – 0.86 (m, 1H, H-7b); C{ H} NMR, HSQC, HMBC (150.9 MHz, CDCl
00.7 (C-1), 191.1 (C-4’), 179.4 (C-2’), 130.9 (C-13), 130.1 (C-5), 127.2 (C-14), 126.7 (C-4), 100.2
C-3’), 63.1 (C-6’), 61.7 (C-5’), 49.1 (C-2), 45.1 (C-3), 42.4 (C-7), 40.1 (C-11), 38.6 (C-6), 35.8 (C-
), 33.6 (C-8), 28.5 (C-10), 22.6 (C-8-Me), 18.1 (C-15), 14.0 (C-2-Me); MS (ESI): m/z (%) = 360.5
3
) δ (ppm) =
2
(
9
1
1
1
1
1
1
1
1
1
1
2
2
2
2
2
2
2
2
2
2
3
3
3
3
3
3
3
3
3
3
4
4
4
4
4
4
4
4
4
4
5
5
5
5
5
5
5
5
5
5
6
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
1
2
3
4
5
6
7
8
9
0
+
+
+
(
100) [M + H] ; 382.3 (53.2) [M + Na] , 342.9 (6) [M – H
2
O + H] ; HRMS (ESI-QTOF) m/z: [M +
+
3
H] Calcd for C21
H
30NO 360.2175; Found 360.2170. The data are in accordance to the literature.
4
ASSOCIATED CONTENT
Supporting Information
The Supporting Information is available free of charge on the internet.
1
13
H and C NMR spectra of all novel compounds, overlay of VCD spectra of 2, epi-2 and 4, IR spectra
of 2, epi-2 and 4 and overlay of IR spectra of 2, epi-2 and 4.
AUTHOR INFORMATION
Corresponding Author
*E-mail: opatz@uni-mainz.de
Notes
The authors declare no competing financial interest.
ACKNOWLEDGEMENTS
This work was supported by the Rhineland-Palatinate Center for Natural Product Research. The
authors thank Professor Pol Besenius (Mainz) for granting access to his ECD spectrometer.
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