Total Synthesis of Luminmycin A, a Cryptic Natural Product from Photorhabdus Luminescens

Article abstract of DOI:10.1002/ejoc.201900460

Luminmycin A, a natural proteasome inhibitor transcripted by a silent gene cluster from Photorhabdus luminescens, belongs to the compound family of the syrbactins and is structurally closely related to the glidobactins. Key step for the synthesis of the 12-membered cyclopeptide ring is an intramolecular Horner–Wadsworth–Emmons reaction, while the double unsaturated fatty acid side chain can be obtained via phosphane-catalyzed isomerization of a corresponding acetylenic fatty acid ester.

Full text of DOI:10.1002/ejoc.201900460

A Journal of
Accepted Article
Title: Total synthesis of luminmycin A, a cryptic natural product from
Photorhabdus luminescens
Authors: Phil Servatius, Tanja Stach, and Uli Kazmaier
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the VoR from the journal website shown below when it is published
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201900460
Link to VoR: http://dx.doi.org/10.1002/ejoc.201900460
Supported by

European Journal of Organic Chemistry
10.1002/ejoc.201900460
FULL PAPER
DOI: 10.1002/ejoc.200((will be filled in by the editorial staff))
Total synthesis of luminmycin A, a cryptic natural product from Photorhabdus lu-
minescens
†
†
a
Phil Servatius , Tanja Stach , and Uli Kazmaier*
Keywords: Glidobactin / Isomerization / Luminmycin / Proteasome inhibitor / Syrbactin
Luminmycin A, a natural proteasome inhibitor transcripted by a si-
lent gene cluster from Photorhabdus luminescens, belongs to the
compound family of the syrbactins and is structurally closely related
to the glidobactins. Key step for the synthesis of the 12-membered
cyclopeptide ring is an intramolecular Horner-Wadsworth-Emmons
reaction, while the double unsaturated fatty acid side chain can be
obtained via phosphine-catalyzed isomerization of a correspond-
ing acetylenic fatty acid ester.
(© WILEY-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Ger-
many, 2015)
Introduction
The compound class of syrbactins consists of more selective in-
hibitors.[9] Discovered independently, the natural product families of
[
10]
[11]
[12]
Proteasomes are ubiquitously found within the cytosol of all
eukaryotes and archaes and are responsible for the degradation of
damaged or excess proteins.[1] The target protein first undergoes
ubiquitylation through the action of ubiquitin ligases, followed by a
nucleophilic attack of a N-terminal threonine residue of the protea-
some, resulting in cleavage of peptidic bonds.[2] Proteasomal
degradation is an essential step during the cell cycle and is involved
in regulation of gene expression and other cellular functions.[3] Thus,
inhibition of this process has severe effects on cell viability since
interrupted degradation of damaged proteins acts as a signal for
apoptosis, and therefore, the proteasome presents an interesting
syringolin, glidobactin and cepafungin have common struc-
tural features. A central 12-membered ring system with a crucial Mi-
chael acceptor is complemented by exocyclic amino acids and, in
some cases, fatty acid residues. The Michael system is responsible
for irreversible proteasome inhibition since the adduct formed by
nucleophilic attack of threonine is stable under physiological condi-
[
9b]
tions. Recently, Müller and co-workers were able to express silent
megasynthetase gene clusters from Photorhabdus luminescens in
heterologous hosts and elucidated the biochemical pathway of a new
[
13]
class of syrbactins, the luminmycins. Luminmycin A was identi-
fied as one of the metabolites transcripted by the silent gene cluster
and evinced structural similarity to the known proteasome inhibitor
glidobactin A (figure 2).
[
4]
target for the treatment of e.g. neurodegenerative diseases or
[
5]
cancer. Many proteasome inhibitors have been discovered in
[
6]
recent years. Currently, three inhibitors are approved for clinical
use for the treatment of multiple myeloma.[7] The peptide derived
structures of bortezomib, ixazomib and carfilzomib (figure 1)
possess electrophilic centers to interact with proteasome’s threonine
residue through nucleophilic addition. However, they show poor
selectivity towards the proteasome since their electrophilic sites are
prone to react with numerous endogenous compounds.[8]
Figure 1: Approved proteasome inhibitor carfilzomib.
Figure 2: Natural occuring syrbactins.


[
a] Dr. P. Servatius, Dr. T. Stach, Prof. Dr. U. Kazmaier
Organic Chemistry, Saarland University
Further luminmycins were detected in the culture broth and
[
14]
P.O. Box 151150, 66041 Saarbrücken (Germany)
Fax: +49-681-302-2409
E-mail: u.kazmaier@mx.uni-saarland.de
upon infection of crickets with P. asymbiotica. While the linear
structures of luminmycin B and C were speculated to be biosynthetic
precursors, luminmycin D was identified as potential proteasome
Homepage: http://www.uni-saarland.de/lehrstuhl/kazmaier.html
inhibitor. Luminmycin A and D differ only in the fatty acid moiety,

Supporting information for this article is available on the WWW un-
der http://dx.doi.org/
[11b, c]
as seen for glidobactin A-G.
Both natural products possess
striking biological activities against a series of human cancer cell
lines, including colon carcinoma (HCT-116, 91.8 nM)
[
13b]
†
: both authors contributed equally to the present work
and
1
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European Journal of Organic Chemistry
10.1002/ejoc.201900460
pancreatic cancer (18 nM).[14] Interestingly, no synthetic approach
towards the luminmycins has been accomplished yet, although the
comparable syringolins[5c, 15] and glidobactins are well described
in literature. Our longstanding interest in the synthesis of
biologically active peptides and natural products[17] emphasized the
development of a synthetic protocol towards this promising
compound class. The key challenge is definitely the macrocyc-
lization towards the 12-membered ring system, including a trans
double bond. However, several methods to accomplish this goal
have been developed, especially for the synthesis of the syringolins,
and should in principle be applicable to the synthesis of luminmycin
[16]
[
5c,15]
A.
Most obvious is the ring closure via macrolactamization, an
approach which was used by several groups, but in general gave only
[
5c,15b,16b]
moderate yields.
Kaiser et al. reported a ring closing
metathesis to generate the ,-double bond of syringolin A,[5c] and
Pirrung used an intramolecular Horner-Wadsworth-Emmons
reaction, to generate the ,-double bond of the unsaturated -amino
[
15a,c,f]
acid.
Ichikawa finally used an Ugi reaction to generate the
stereogenic center of the unsaturated lysine in a highly stereo-
selective ring closing four componetn reaction.[15d,g,h] Construction
of the dienic fatty acid moiety should be achieved through
phosphine-catalyzed isomerization of the corresponding propargylic
[
18]
acid ester.
Results and Discussion
The initial step towards luminmycin A was the synthesis of a
glidobamine-analogue macrocycle. Therefore, a similar approach as
reported by Pirrung et al. for the synthesis of syringolin analogues
[
15c]
was used.
Coupling of N-protected lysine with L-alaninol af-
forded dipeptide 1 in quantitative yield (scheme 1). Hydrogenative
cleavage of the Cbz-group and coupling of amine 2 with the N-hy-
droxysuccinimid (NHS) ester of phosphonoacetate (3) gave cycliza-
tion precursor 4 in good yield. Oxidation of the alcohol in 4 to the
corresponding aldehyde with Dess-Martin periodinane[19] and ole-
fination under HWE conditions using a protocol developed by
Schauer and Helquist[20] afforded macrocycle 5 in 50 % yield after
optimization. This was the most critical step throughout the synthe-
sis. The yields varied and a by-product, resulting from aldol conden-
sation, was detected frequently in the reaction mixture, but could
never be isolated in pure form. In addition, varying amounts of sep-
arable cyclodimer were obtained. Boc-deprotection afforded the
glidobamine-analogue 6 in quantitative yield. In order to attach the
exocyclic threonine residue, fully protected threonine 7 had to be
used in the coupling reaction, while complex mixtures were obtained
if only N-protected Boc-Thr-OH was used instead. Global deprotec-
tion of both the Boc- and TBS-group in 8 was achieved in meth-
anolic HCl solution and glidobactamine-analogue 9 was obtained in
quantitative yield.
Scheme 1: Synthesis of glidobactamine-analogue 9.
Next, the double unsaturated fatty acid moiety had to be synthe-
sized and attached to 9. As outlined above, phosphine-catalyzed
isomerization of the corresponding acetylenic acid ester should give
rise to the desired diene.[18] Deprotonation of 1-undecyne and addi-
tion of CO
2
afforded unsaturated acid 10 in quantitative yield
(
scheme 2). To facilitate both, the isomerization and coupling with
[
18]
9
1
5
, activation of 10 as Pfp-ester was performed. The active ester
1 was isomerized using 5 mol% triphenylphosphine in toluene at
0 °C overnight. Unfortunately, all attempts to couple the activated
dienic acid with 9 failed. This drawback called for another strategy
to access the natural product. Consequently, active ester 12 was re-
acted with threonine methyl ester to give compound 13 in acceptable
yield. Saponification of the methyl ester in 13 occurred readily and
the carboxylic acid 14 was reacted with glidobamine-analogue 6.
Luminmycin A was obtained after column chromatography as a sin-
gle diastereomer.
Scheme 2: Phosphine-catalyzed isomerization and total synthesis of lu-
minmycin A.
2
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European Journal of Organic Chemistry
10.1002/ejoc.201900460
Poor solubility of 6 and azlactone formation after activation of
4 limited the yield of this final coupling step. However, the azlac-
combined organic phases were washed with sat. NaHCO
and dried over Na SO . The crude product 1 (2.18 g, 4.99 mmol,
quant.) was obtained as a colourless oil and was used without further
purification. R (1) = 0.07 (silica, CH Cl : MeOH 95:5). HPLC
Reprosil, n-hexane:iPrOH 70:30, 1 mL/min, 20 °C): t (1) = 16.4
). H NMR (400 MHz, CDCl ):
δ = 1.15 (d, J = 6.9 Hz, 3 H), 1.39 (m, 2 H), 1.43 (s, 9 H), 1.51 (tt, J
6.8, 6.8 Hz, 2 H), 1.63 (m, 1 H), 1.80 (m, 1 H), 3.17 (dt, J = 6.2,
.2 Hz, 2 H), 3.45 (dd, J = 11.1, 5.8 Hz, 1 H), 3.66 (dd, J = 11.2, 3.5
3
solution
1
2
4
tone could easily be separated by reversed phase column chroma-
tography. The spectra of luminmycin A were in accordance to pre-
viously reported data and confirmed the elucidated structure of the
f
2
2
(
R
ퟐퟎ
1
[
1]
min. [휶]푫 = –21.4 (c = 1.0, CHCl
3
3
natural product.
=
6
Conclusions
Hz, 1 H), 3.94–4.08 (m, 2 H), 5.05 (m, 1 H), 5.09 (m, 2 H), 5.34 (br
s, 1 H), 6.34 (d, J = 7.6 Hz, 1 H), 7.28–7.38 (m, 5 H) ppm. The signal
of OH wasn’t observed in the H NMR spectrum. C NMR (100
A straightforward and short synthesis of the natural proteasome
inhibitor luminmycin A was developed. The challenging macrocyc-
lization was accomplished with acceptable yield after optimization.
Phosphine-catalyzed isomerization of an activated acetylenic acid
proceeded readily and gave the desired dienic fatty acid. However,
coupling of this substrate with a glidobactamine analogue proved to
be a non-trivial issue. This setback could be overcome by coupling
of the fatty acid with threonine and following assembly into the nat-
ural scaffold. Further applications of this isomerization protocol are
currently under investigation. Furthermore, the outlined synthesis of
luminmycin A should provide access to luminmycin D as well as
derivatives thereof through alteration of the fatty acids incorporated.
1
13
MHz, CDCl ): δ = 16.8, 22.4, 28.3, 29.5, 31.7, 40.2, 47.6, 54.7, 66.3,
3
66.7, 80.2, 128.0, 128.1, 128.5, 136.5, 156.0, 156.9, 172.3 ppm.
+
+
HRMS (CI) calcd. for C22
438.2603.
36 3
H N O [M + H] : 438.2599, found
tert-Butyl ((S)-6-amino-1-(((S)-1-hydroxypropan-2-yl)amino)-1-
oxohexan-2-yl)carbamate (2): A solution of 1 (875 mg, 2.00
mmol) in MeOH (10 mL) was treated with Pd on charcoal (88 mg,
1
2
0 w% Pd) and was hydrogenated overnight under atmospheric H -
pressure. The reaction mixture was filtrated through a pad of celite,
and the filtrate was concentrated in vacuo. Amine 2 (607 mg, 2.00
2
0
mmol, quant.) was obtained as a colorless resin. [훼] = –12.3 (c =
퐷
1
1
.0, CHCl
H), 1.40 (m, 2 H), 1.42 (s, 9 H), 1.48 (m, 2 H), 1.62 (m, 1 H), 1.78
m, 1 H), 2.48–2.82 (br s, 3 H), 2.70 (t, J = 6.3 Hz, 2 H), 3.45 (dd, J
3 3
). H NMR (400 MHz, CDCl ): δ = 1.16 (d, J = 6.8 Hz, 3
Experimental Section
(
General remarks: All air- or moisture-sensitive reactions were
carried out in dried glassware (> 100 °C) under an atmosphere of
nitrogen or argon. THF was distilled over Na/benzophenone prior to
use. EtOAc and petroleum ether (PE) were distilled prior to use. Re-
actions were monitored by analytical TLC, which was performed on
precoated silica gel on TLC PET-foils by Sigma-Aldrich. Visualiza-
=
2
11.2, 5.1 Hz, 1 H), 3.64 (dd, J = 11.0, 3.5 Hz, 1 H), 3.96–4.13 (m,
1
3
H), 5.39 (d, J = 5.3 Hz, 1 H), 6.58 (d, J = 6.8 Hz, 1 H) ppm.
): δ = 16.9, 22.4, 28.3, 31.9, 32.3, 41.1, 47.5,
4.4, 65.6, 79.9, 155.7, 172.1 ppm. HRMS (CI) calcd. for
C
NMR (100 MHz, CDCl
5
C
3
+
+
14 30 3 4
H N O [M + H] : 304.2231, found 304.2250.
4
tion was accomplished with UV-light (254 nm), KMnO solution or
Ce(IV) solution. The products were purified by flash chromatog-
tert-Butyl ((S)-6-(2-(diethoxyphosphoryl)acetamido)-1-(((S)-1-
hydroxypropan-2-yl)amino)-1-oxohexan-2-yl)carbamate (4): To
raphy on silica gel columns (Macherey-Nagel 60, 0.063–0.2 mm) or
a solution of 2 (293 mg, 966 µmol) in CH
2 2
Cl (10 mL) was added a
®
by automated flash chromatography (Grace Reveleris , Teledyne
solution of 2,5-dioxopyrrolidin-1-yl 2-(diethoxyphosphoryl)acetate
Isco RediSep R
f
silica cartridges or Kinesis silica C-18 cartridges).
[1]
3
2 2
(318 mg, 1.08 mmol) in CH Cl (10 mL) at 0 °C. The reaction
Melting points were determined with a melting point apparatus IA
was allowed to warm to room temperature overnight and concen-
trated in vacuo. The crude product was purified by column chroma-
1
13
9
100 by Electrothermal and are uncorrected. H and C NMR spec-
1
tra were recorded with a Bruker AV II 400 [400 MHz ( H), 100 MHz
tography (silica, CH
351 mg, 729 µmol, 75 %) as a colorless resin. R
CH Cl :MeOH 90:10).HPLC (Reprosil, n-hexane:iPrOH 70:30,1
mL/min,20 °C): t
2
Cl
2
:MeOH 100:0, gradient 90:10) to obtain 4
1
3
1
13
(
C)] or a Bruker AV 500 [500 MHz, ( H), 125 MHz ( C)] spec-
trometer in CDCl unless otherwise specified. NMR spectra were
evaluated using NMR Processor from ACD. Chemical shifts are re-
ported in ppm relative to Si(CH and the solvent residual peak was
used as the internal standard. Multiplicities are reported as br s
(
f
(4) = 0.22 (silica,
3
2
2
20
R
(4) = 19.4 min (> 99 %). [훼]퐷 = –9.3 (c = 1.0,
). H NMR (400 MHz, CDCl ): δ = 1.15 (d, J = 6.9 Hz, 3 H),
.32 (t, J = 7.1 Hz, 6 H), 1.39 (m, 2 H), 1.41 (s, 9 H), 1.52 (m, 2 H),
.63 (m, 1 H), 1.77 (m, 1 H), 2.84 (d, J = 20.9 Hz, 2 H), 3.25 (dt, J
5.9, 5.9 Hz, 2 H), 3.45 (dd, J = 11.1, 5.9 Hz, 1 H), 3.66 (dd, J =
1.2, 3.5 Hz, 1 H), 3.99–4.07 (m, 2 H), 4.12 (qd, J = 7.1, 3.0 Hz, 4
H), 5.46 (d, J = 7.7 Hz, 1 H), 6.69 (d, J = 7.6 Hz, 1 H), 7.01 (t, J =
3
)
4
1
CHCl
3
3
1
1
=
(broad signal), s (singlet), d (doublet), t (triplet), q (quartet) and m
(multiplet). High resolution mass spectra were recorded with a Fin-
nigan MAT 95 spectrometer using the CI technique. Gas chromatog-
raphy was performed on a Shimadzu (GC-2010, autoinjector AOC-
1
2
0i, mass detector GCMS-QP2010, CI technique) with a FS-Su-
1
5
.5 Hz, 1 H) ppm. The signal of OH wasn’t observed in the H NMR
preme-5ms capillary column (25 m x 0.25 mm) and nitrogen as car-
rier gas. HPLC analyses were performed on a Merck Hitachi D-7000
with a Diode Array detector L-7455. Optical rotations were meas-
ured with a Perkin-Elmer polarimeter (Model 341) in a thermostated
13
spectrum. C NMR (100 MHz, CDCl
3
): δ = 16.3 (d, J = 5.9 Hz),
6.8, 22.4, 28.3, 28.6, 32.2, 35.1 (d, J = 131 Hz), 39.1, 47.5, 54.5,
2.8 (d, J = 6.6 Hz), 62.9 (d, J = 6.6 Hz), 65.9, 79.8, 155.7, 164.1,
1
6
1
4
+
+
72.1 ppm. HRMS (CI) calcd. for C20
82.2626, found 482.2650.
41 3 6
H N O P [M + H] :
(20 °C ± 1 °C) cuvette. The radiation source used was a sodium va-
por lamp (λ = 589 nm). The concentrations are given in g/100 ml.
tert-Butyl ((5S,8S,E)-5-methyl-2,7-dioxo-1,6-diazacyclododec-3-
en-8-yl)carbamate (5):
Oxidation: Compound 4 (478 mg, 993 µmol) was dissolved in dry
Benzyl tert-butyl ((S)-6-(((S)-1-hydroxypropan-2-yl)amino)-6-
oxohexane-1,5-diyl)dicarbamate (1): To a solution of Boc-(L)-
Lys(Cbz)-OH (1.90 g, 4.99 mmol) in dry THF (50 mL) were added
N-methylmorpholine (0.61 mL, 561 mg, 5.55 mmol) and isobutyl
chloroformate (0.72 mL, 754 mg, 5.52 mmol) dropwise at –20 °C.
After stirring for 10 min at this temperature, a solution of (L)-alani-
nol (387 µL, 375 mg, 4.99 mmol) in dry THF (10 mL) was added
dropwise, and the reaction was allowed to warm to room tempera-
ture overnight. For workup, the reaction was filtrated, and the resi-
due was washed with diethyl ether and ethyl acetate. The filtrate was
concentrated in vacuo and the residue was dissolved in ethyl acetate.
HCl solution (1 M) was added and the layers were separated. The
aqueous phase was extracted three times with ethyl acetate, and the
CH
589 mg, 1.39 mmol) at room temperature. The reaction was stirred
for 45 min and diluted with ethyl acetate (10 mL). A mixture of sat.
NaHCO and 2 % Na SO (1:1) was added and the reaction was
2 2
Cl (5.0 mL) and treated carefully with Dess Martin periodinane
(
3
2
3
stirred for 5 min until the organic phase became clear. The layers
were separated, and the aqueous phase was extracted two times with
ethyl acetate. The combined organic phases were concentrated in
vacuo, filtrated in order to remove the insoluble by-products and
dried over Na
purification.
2 4
SO . The crude aldehyde was used without further
3
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900460
Macrolactamization: To a suspension of Zn(OTf)
2
(1.14 g, 3.14
(2S,3R)-2-Amino-3-hydroxy-N-((5S,8S,E)-5-methyl-2,7-dioxo-
1,6-diazacyclododec-3-en-8-yl)butanamide hydrochloride (9):
To a solution of 8 (22.2 mg, 41.1 µmol) in MeOH (1.0 mL) was
added acetyl chloride (28.4 µL, 31.2 mg, 397 µmol) at 0 °C. The
reaction was stirred for 3.5 h at this temperature and was then con-
centrated in vacuo. The crude hydrochloride 9 (14.9 mg, 41.1 µmol,
quant.) was obtained as an off-white solid after lyophilization, mp
mmol) in dry THF (500 mL) were added TMEDA (502 µL, 389 mg,
.14mmol) and NEt (547 µL, 397 mg, 4.17 mmol) at room temper-
3
3
ature. The reaction mixture was stirred for 15 min at this temperature
before a solution of the crude aldehyde (470 mg, 980 µmol) in dry
THF (20 mL) was added dropwise over 14 h. The reaction was
stirred for further two days and concentrated in vacuo to approxi-
mately 10 mL. Ethyl acetate (40 mL) was added and the organic
125 °C (decomposition). R
f
(9) = 0.03 (silica, CH
2
Cl
2
: MeOH 90:10).
20
1
phase was washed with water, KHSO
sequently. The organic layer was dried over Na
trated in vacuo. The crude product was purified by reversed phase
column chromatography (silica C-18, H O:MeCN gradient) to ob-
tain macrocycle 5 (160 mg, 492 µmol, 50 %) as an off-white solid
after lyophilisation, mp: 230 °C (decomposition). R (5) = 0.25 (sil-
ica, CH Cl
mL/min, 20 °C): t
4
solution (1 M) and brine sub-
[훼] = –21.4 (c = 0.5, MeOH). H NMR (400 MHz, MeOH-d
4
): δ
퐷
2
SO and concen-
4
= 1.15 (m, 1 H), 1.31 (d, J = 6.4 Hz, 3 H), 1.34 (d, J = 7.1 Hz, 3 H),
1.44 – 1.60 (m, 2 H), 1.70 (m, 1 H), 1.87 (m, 1 H), 2.21 (m, 1 H),
3.19 (d, J = 15.5 Hz, 1 H), 3.58 (dd, J = 13.2, 13.2 Hz, 1 H), 3.81 (d,
J = 6.5 Hz, 1 H), 4.01 (ddq, J = 6.4, 6.4, 6.4 Hz, 1 H), 4.57 (dq, J =
6.1, 6.1 Hz, 1 H), 4.68 (m, 1 H), 6.44 (d, J = 15.5 Hz, 1 H), 7.11 (dd,
2
f
2
2
:MeOH 90:10). HPLC (Reprosil, n-hexane: iPrOH 70:30, J = 15.5, 4.8 Hz, 1 H) ppm. The signals of OH and NH weren’t ob-
2
퐷
0
1
13
1
0
1
1
R
(5) = 36.0 min (> 99 %). [훼] = –35.2 (c =
4
served in the H NMR spectrum. C NMR (100 MHz, MeOH-d ):
1
.5, MeOH). H NMR (400 MHz, MeOH-d
4
): δ = 1.12 (m, 1 H),
δ = 19.0, 20.2, 30.9, 31.0, 40.3, 47.8, 54.2, 60.1, 67.7, 118.8, 151.2,
.32 (d, J = 7.1 Hz, 3 H), 1.39–1.52 (m, 2 H), 1.44 (s, 9 H), 1.65 (m,
H), 1.80 (m, 1 H), 2.09 (m, 1 H), 3.11 (d, J = 15.5 Hz, 1 H), 3.49
168.3, 172.7 ppm. The signal of one carbonyl group was not ob-
1
3
served in the C NMR spectrum. HRMS (CI) calcd. for
+
+
(m, 1 H), 4.36 (m, 1 H), 4.56 (m, 1 H), 6.37 (d, J = 15.5 Hz, 1 H),
C
15
H
27
N
4
O
4
[M + H] : 327.2027, found 327.2032.
7
.00 (dd, J = 15.4, 4.7 Hz, 1 H) ppm. The signals of NH weren’t
1
13
Pentafluorophenyl dodec-2-ynoate (11): A solution of 1-undecyne
observed in the H NMR spectrum. C NMR (100 MHz, MeOH-
d
1
(
767 mg, 5.04 mmol) in dry THF (25 mL) was cooled to –78 °C
before n-BuLi (2.0 mL, 5.0 mmol, 2.5 M in hexane) was added drop-
wise. The reaction was stirred for 10 min before gaseous CO was
4
): δ = 18.8, 18.8, 28.8, 31.4, 31.6, 39.9, 47.7, 54.7, 80.8) 119.5,
+
28 3 4
49.6, 157.5, 169.9, 173.7 ppm. HRMS (CI) calcd. for C16H N O
+
2
[
M + H] : 326.2074, found 326.2075.
bubbled through the solution for 5 min. Afterwards, the reaction was
allowed to warm to room temperature quickly. The reaction mixture
was concentrated in vacuo, and the residue was dissolved in diethyl
(
5S,8S,E)-8-Amino-5-methyl-1,6-diazacyclododec-3-ene-2,7-di-
one hydrochloride (6): A solution of 5 (31.8 mg, 97.7 µmol) in di-
oxane (0.50 mL) was treated with HCl solution (0.50 mL, 2.00 mmol, ether. HCl solution (1 M) was added, and the layers were separated.
M in dioxane) at room temperature for 90 min. Afterwards, the The aqueous phase was extracted three times with diethyl ether, the
reaction mixture was concentrated in vacuo and the crude product 6 combined organic phases were dried over Na SO and concentrated
25.6 mg, 97.7 mmol, quant.) was obtained as an off-white solid af- in vacuo. The crude acid (981 mg, 5.00 mmol) was dissolved in dry
CH Cl (20 mL) before pentafluorophenol (1.06 g, 5.76 mmol) and
4
2
4
(
1
ter lyophilisation. H NMR (400 MHz, MeOH-d
.36 (d, J = 7.1 Hz, 3 H), 1.43–1.55 (m, 2 H), 1.72 (m, 1 H), 1.94
m, 1 H), 2.36 (m, 1 H), 3.18 (dt, J = 15.4, 3.4 Hz, 1 H), 3.59 (dd, J
13.3, 13.3 Hz, 1 H), 4.19 (m, 1 H), 4.62 (dq, J = 6.3, 6.3 Hz, 1 H),
.41 (d, J = 15.4 Hz, 1 H), 7.09 (dd, J = 15.5, 4.8 Hz, 1 H) ppm. The
4
): δ = 1.15 (m, 1 H),
2
2
1
(
=
6
EDC·HCl (1.06 g, 5.53 mmol) were added subsequently at 0 °C. The
reaction was stirred for 2 h at this temperature and concentrated in
vacuo. Purification by column chromatography (silica, petroleum
ether) afforded 11 (1.48 g, 4.08 mmol, 82 %) as a colorless oil. R
f
(11) = 0.66 (silica, petroleum ether:ethyl acetate 90:10). GC/MS
1
13
signals of NH weren’t observed in the H NMR spectrum. C NMR
100 MHz, MeOH-d ): δ = 18.1, 18.6, 29.8, 30.8, 39.9, 47.9, 53.9,
19.2, 150.4, 169.7, 169.9 ppm.
(
4
(Supreme DB5, column flow 1.25 mL/min, injector 250 °C; 60 °C
1
(2 min), 200 °C (5 °C/min), 220 °C (20 °C/min), 5 min): t
R
(11) =
): δ = 0.89
t, J = 6.8 Hz, 3 H), 1.22–1.37 (m, 10 H), 1.44 (m, 2 H), 1.65 (tt, J =
1
2
(
7
8.76 min (> 99 %, m/z 363). H NMR (400 MHz, CDCl
3
tert-Butyl ((2S,3R)-3-((tert-butyldimethylsilyl)oxy)-1-(((5S,8S,E)
5-methyl-2,7-dioxo-1,6-diazacyclododec-3-en-8-yl)amino)-1-
-
13
.4, 7.4 Hz, 2 H), 2.44 (t, J = 7.2 Hz, 2 H) ppm. C NMR (100 MHz,
CDCl
5.9, 148.8 ppm. The four aromatic signals weren’t observed in the
20 5 2
C NMR spectrum. HRMS (CI) calcd. for C18H F O [M + H] :
oxobutan-2-yl)carbamate (8): To a solution of N-(tert-butoxycar-
bonyl)-O-(tert-butyldimethylsilyl)-(L)-threonine (37.0 mg, 111
3
): δ = 14.1, 18.9, 22.6, 27.2, 28.8, 29.0, 29.2, 29.3, 31.8, 70.7,
9
µmol) and 6 (25.6 mmol, 97.7 µmol) in dry CH
2
Cl
2
(1.0 mL) and
13
+
+
dry MeOH (0.25 mL) were added HOBt (16.5 mg, 122 µmol),
EDC·HCl (21.8 mg, 114 µmol) and DIPEA (18.8 µL, 13.9 mg, 108
µmol) subsequently at 0 °C. The reaction was allowed to warm to
3
63.1378, found 363.1398.
Pentafluorophenyl (2E,4E)-dodeca-2,4-dienoate (12): Penta-
fluorophenylester 11 (374 mg, 1.032 mmol) was dissolved in tolu-
ene (5.0 mL), treated with triphenylphosphine (14.9 mg, 56.8 µmol)
and heated to 50 °C overnight (16 h). The reaction mixture was con-
centrated in vacuo, and the crude product was purified by column
chromatography (silica, petroleum ether:ethyl acetate 98:2). The
room temperature overnight and was then diluted with CH
2 2
Cl . HCl
solution (1 M) was added and the layers were separated. The aque-
ous phase was extracted three times with CH
organic layers were washed with sat. NaHCO
over Na SO
CH Cl
3.6 µmol, 45 %) as an off-white solid after lyophilisation. R
.02 (silica, CH Cl :MeOH 95:5). HPLC (Reprosil, n-hexane:iPrOH
0:30, 1 mL/min, 20 °C): t
): δ = 0.04 (s, 3 H), 0.08 (s, 3 H), 0.86 (s, 9 H), 1.12 (d,
J = 6.2 Hz, 3 H), 1.22–1.40 (m, 3 H), 1.30 (d, J = 7.0 Hz, 3 H), 1.46
s, 9 H), 1.66 (m, 1 H), 1.92 (m, 1 H), 2.04 (m, 1 H), 3.12 (m, 1 H),
.42 (m, 1 H), 4.09 (d, J = 7.7 Hz, 1 H), 4.46 (qd, J = 5.5, 5.5 Hz, 1
H), 4.68 (m, 1 H), 4.86 (m, 1 H), 5.25 (d, J = 8.2 Hz, 1 H), 6.07 (t, J
2
Cl
2
, and the combined
3
solution and dried
2
4
. Purification by column chromatography (silica,
2
2
:MeOH 100:0, gradient 95:5) afforded compound 8 (23.6 mg, isomerized compound 12 (308 mg, 850 µmol, 82 %) was obtained
(8) = as a colourless oil. R (12) = 0.38 (silica, petroleum ether:ethyl ace-
4
0
7
f
f
2
2
tate 98:2). GC/MS (Supreme DB5, column flow 1.25 mL/min, in-
jector 250 °C; 60 °C (2 min), 200 °C (5 °C/min), 220 °C (20 °C/min),
1
R
(8) = 23.0 min (> 99 %). H NMR (400
1
MHz, CDCl
3
5 min): t
CDCl
2 H), 2.23 (dt, J = 6.7, 6.7 Hz, 2 H), 5.99 (d, J = 15.3 Hz, 1 H), 6.24–
6.35 (m, 2 H, 8-H), 7.52 (dd, J = 15.3, 10.1 Hz, 1 H) ppm. C NMR
(100 MHz, CDCl ): δ = 14.1, 22.6, 28.5, 29.1, 29.1, 31.8, 33.2, 115.0,
R
(12) = 30.73 min (> 99 %, m/z 363). H NMR (400 MHz,
3
): δ = 0.89 (t, J = 6.8 Hz, 3 H), 1.22–1.36 (m, 8 H), 1.45 (m,
(
3
1
3
3
=
1
7.1 Hz, 1 H), 6.34 (d, J = 15.4 Hz, 1 H), 7.07 (dd, J = 15.3, 4.6 Hz,
128.0, 148.6, 149.9, 162.8 ppm. The four aromatic signals weren’t
1
3
13
H), 7.22 (d, J = 7.0 Hz, 1 H), 7.68 (d, J = 6.1 Hz, 1 H) ppm.
): δ = –5.0, –4.5, 17.7, 17.9, 18.7, 19.8, 25.7,
8.3, 30.3, 31.0, 39.1, 46.0, 52.6, 59.9, 68.2, 80.4, 117.9, 147.9,
56.0, 167.5, 170.0, 170.3 ppm. HRMS (CI) calcd. for
C
observed in the C NMR spectrum. HRMS (CI) calcd. for
+
+
NMR (100 MHz, CDCl
2
1
C
3
18 20 5 2
C H F O [M + H] : 363.1378, found 363.1395.
Methyl ((2E,4E)-dodeca-2,4-dienoyl)-(L)-threoninate (13): To a
solution of pentafluorophenylester 12 (145 mg, 400 µmol) in dry
CH Cl (4.0 mL) was added DIPEA (143 µL, 106 mg, 820 µmol) at
2 2
+
+
26 48 4 6
H N O Si [M + H] : 540.3338, found 540.3359.
room temperature. Afterwards, HCl·H-(L)-Thr-OMe (74.0 mg, 436
4
This article is protected by copyright. All rights reserved.

European Journal of Organic Chemistry
10.1002/ejoc.201900460
µmol) was added and the reaction was stirred for 3 days. For workup, 18.3, 19.6, 22.0, 28.3, 28.5, 28.5, 29.6, 30.1, 31.2, 32.2, 37.9, 45.6,
the reaction was concentrated in vacuo. The residue was redissolved
in diethyl ether and HCl solution (1 M) was added. The layers were
separated, and the aqueous phase was extracted three times with di-
ethyl ether. The combined organic layers were washed with sat. Na-
51.5, 58.0, 66.5, 118.4, 122.9, 128.5, 139.8, 142.1, 146.7, 165.5,
+
41 4 4
165.8, 169.4, 170.5 ppm. HRMS (CI) calcd. for C25H N O [M –
+
2 4
C H O + H] : 461.3122, found 461.3132.
3 2 4
HCO solution and dried over Na SO . The crude prouct was puri-
fied by column chromatography (silica, petroleum ether:ethyl ace-
tate 70:30) to obtain 13 (82.3 mg, 264 µmol, 66 %) as an off-white
Supporting Information (see footnote on the first page of this arti-
cle): Copies of NMR spectra of all compounds.
solid, mp 113 °C. R
f
(13) = 0.17 (silica, petroleum ether:ethyl acetate
5
0:50). HPLC (Reprosil, n-hexane:iPrOH 80:20, 1 mL/min, 20 °C):
Acknowledgement
20
1
t
R
(13) = 18.7 min (> 99 %). [훼] = –3.7 (c = 0.5, CHCl
3
). H NMR
): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.22 (d, J = 6.4 Hz,
H), 1.17–1.34 (m, 8 H), 1.41 (tt, J = 6.8, 6.8 Hz, 2 H), 2.15 (dt, J
7.1, 6.7 Hz, 2 H), 2.30 (br s, 1 H), 3.77 (s, 3 H), 4.36 (qd, J = 6.4,
퐷
(400 MHz, CDCl
3
Financial support by the Saarland University and the DFG is grate-
fully acknowledged. P.S. and T.S. thank the Fonds der Chemischen
Industrie for providing them with PhD scholarships.
3
=
2
.5 Hz, 1 H), 4.70 (dd, J = 8.9, 2.5 Hz, 1 H), 5.87 (d, J = 15.0 Hz, 1
H), 6.06–6.18 (m, 2 H), 6.35 (d, J = 8.8 Hz, 1 H), 7.23 (dd, J = 15.0,
___________
1
3
9
2
1
3
.8 Hz, 1 H) ppm. C NMR (100 MHz, CDCl
8.7, 29.1, 31.8, 33.0, 52.6, 57.2, 68.2, 120.7, 128.1, 142.6, 144.2,
66.8, 171.7 ppm. HRMS (CI) calcd. for C17
11.2097, found 311.2085.
3
): δ = 14.1, 19.9, 22.6,
[
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4
+
+
4
H29NO [M + H] :
4
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(
(2E,4E)-Dodeca-2,4-dienoyl)-L-threonine (14): A solution of 13
(60.7 mg, 195 µmol) in dioxane (2.0 mL) was cooled to 0 °C and
2
treated with a LiOH solution (244 µL, 244 µmol, 1.0 M in H O).
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solution (1 M) was added, and the layers were separated. The aque-
ous phase was extracted three times with diethyl ether, and the com-
4
9, 9346-9367.
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bined organic layers were dried over Na
2
SO
4
. The crude product 14
(56.3 mg, 189 µmol, 97 %) was used without further purification
f
after lyophilisation. mp 97 °C. R (14) = 0.03 (silica, petroleum
ether:ethyl acetate 50:50). [훼] = –23.2 (c = 0.5, CHCl
2
0
1
3
). H NMR
): δ = 0.88 (t, J = 6.8 Hz, 3 H), 1.21 (d, J = 6.4 Hz,
H), 1.17–1.34 (m, 9 H), 1.40 (m, 2 H, 6-H), 2.14 (dt, J = 6.6, 6.6
퐷
(400 MHz, CDCl
3
[
3
7
58; b) A. Rentsch, D. Landsberg, T. Brodmann, L. Bulow, A.
Hz, 2 H), 4.47 (qd, J = 6.3, 1.9 Hz, 1 H), 4.63 (dd, J = 8.3, 2.0 Hz, 1
H), 5.92 (d, J = 15.0 Hz, 1 H), 6.06–6.18 (m, 2 H), 6.71 (br s, 1 H),
6
NMR (100 MHz, CDCl
3
K. Girbig, M. Kalesse, Angew. Chem. Int. Ed. 2013, 52, 5450-
5488.
.98 (d, J = 8.3 Hz, 1 H), 7.23 (dd, J = 15.1, 9.7 Hz, 1 H) ppm. 13
C
[7] a) J. Adams, M. Kauffman, Cancer Investig. 2004, 22, 304-
3
): δ = 14.1, 19.2, 22.6, 28.8, 29.1, 29.2, 31.8,
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11; b) R. A. Kyle, S. V. Rajkumar, New Engl. J. Med. 2004,
3.1, 57.7, 67.6, 120.3, 128.1, 143.3, 144.9, 168.2, 173.5 ppm.
+
+
351, 1860-1873; c) A. K. Stewart, S. V. Rajkumar, M. A.
Dimopoulos, T. Masszi, I. Spicka, A. Oriol, R. Hajek, L.
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4
HRMS (CI) calcd. for C16H28NO [M + H] : 298.2013, found
2
98.2025.
Luminmycin A: To a solution of 6 (25.6 mg, 97.7 mmol) and 14
(
32.0 mg, 108 µmol) in dry CH Cl (1.0 mL) were added HOBt (16.7
mg, 109 µmol), EDC·HCl (22.5 mg, 117 µmol) and DIPEA (18 µL,
3.3 mg, 103 µmol) subsequently at 0 °C. The reaction was allowed
to warm to room temperature within 4.5 h. The reaction was diluted
with CH Cl and HCl solution (1 M) was added. The layers were
separated, and the aqueous phase was extracted three times with
CH Cl . The combined organic layers were washed with sat. Na-
HCO solution and dried over Na SO . The crude product was puri-
fied by reversed phase column chromatography (silica C-18,
O:MeCN 90:10, gradient 10:90) to afford luminmycin A (12.8 mg,
2
2
1
2
2
2
2
3
2
4
H
2
2
1
5.4 µmol, 26 %) as an off-white solid after lyophilisation, mp
95 °C (decomposition). In addition, a separable by-product (10.2
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mg, 39.0 µmol, 36 %) was obtained, which appeared to be an azlac-
tone formed by the threonine residue after activation. R (luminmy-
cin A) = 0.13 (silica, CH Cl :MeOH 90:10). HPLC (Reprosil, n-
hexane:iPrOH 50:50, 1 mL/min, 20 °C): t (luminmycin A) = 21.2
min. [훼]2 = –15.4 (c = 0.36, MeOH). H NMR (500 MHz, DMSO-
d
3
1
2
4
6
f
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2
2
R
0
1
퐷
6
): δ = 0.86 (t, J = 7.1 Hz, 3 H), 0.93 (m, 1 H), 1.02 (d, J = 6.6 Hz,
H), 1.20 (d, J = 6.9 Hz, 3 H), 1.18–1.29 (m, 10 H), 1.38 (m, 2 H),
.44 (m, 1 H), 1.68 (m, 1 H), 2.05 (m, 1 H), 2.13 (dt, J = 7.3, 6.9 Hz,
H), 2.95 (m, 1 H), 3.27 (m, 1 H), 3.99 (m, 1 H), 4.32 (dd, J = 8.5,
.1 Hz, 1 H), 4.40 (m, 1 H), 4.51 (m, 1 H), 4.93 (d, J = 5.0 Hz, 1 H),
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J = 15.5, 10.7 Hz, 1 H), 6.23 (d, J = 15.5 Hz, 1 H), 6.78 (dd, J = 15.3,
.6 Hz, 1 H), 7.00 (dd, J = 15.1, 10.7 Hz, 1 H), 7.35 (t, J = 6.3 Hz, 1
H), 7.63 (d, J = 7.3 Hz, 1 H), 8.01 (d, J = 8.5 Hz, 1 H), 8.46 (d, J =
.9 Hz, 1 H) ppm. 13C NMR (125 MHz, DMSO-d
): δ = 13.9, 17.1,
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This article is protected by copyright. All rights reserved.

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European Journal of Organic Chemistry
10.1002/ejoc.201900460
Entry for the Table of Contents
Natural Product Synthesis
Phil Servatius, Tanja Stach and Uli
Kazmaier
Page No. – Page No.
Total synthesis of luminmycin A, a cryp-
tic natural product from Photorhabdus
luminescens
Luminmycin A, a natural proteasome in-
hibitor has been synthesized for the first
time. Key steps are an intramolecular
Horner-Wadsworth-Emmons reaction
3
and a PPh -catalyzed isomerization of a
Keywords: Glidobactin / Isomerization /
Luminmycin / Proteasome inhibitor /
Syrbactin
acetylenic fatty acid ester, giving access
to the double unsaturated fatty acid side
chain.
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