Catalytic enantioselective total synthesis of (-)-pyridovericin

Article abstract of DOI:10.1055/s-0033-1340868

The first enantioselective catalytic total synthesis of (-)-pyridovericin is reported. The key steps involve a modified HWE reaction under aqueous conditions and an asymmetric iridium-catalyzed hydrogenation. This resulted in a highly modular and stereoselective approach that delivered the target natural product in high yield and stereoselectivity. Georg Thieme Verlag Stuttgart New York.

Full text of DOI:10.1055/s-0033-1340868

864▌
FEATURE ARTICLE
feature article
Catalytic Enantioselective Total Synthesis of (–)-Pyridovericin
Total Synthesis of (–)-Pyridovericin
Fabian Schmid, Maurizio Bernasconi, Henning J. Jessen,1 Andreas Pfaltz, Karl Gademann*
University of Basel, Department of Chemistry, St. Johanns-Ring 19, 4056 Basel, Switzerland
Fax +41(61)2671144; E-mail: karl.gademannn@unibas.ch
Received: 17.12.2013; Accepted after revision: 06.02.2014
5-(4-hydroxyphenyl) substituent. In addition to these
structural features, pyridovericin (1)5 and torrubiellone C
(2)2a have a hydroxymethylene substituent in their side
chain. Several methodologies, relying on chiral auxilia-
Abstract: The first enantioselective catalytic total synthesis of
(–)-pyridovericin is reported. The key steps involve a modified
HWE reaction under aqueous conditions and an asymmetric iridi-
um-catalyzed hydrogenation. This resulted in a highly modular and
stereoselective approach that delivered the target natural product in ries, chiral starting materials, or enzymatic reactions, have
high yield and stereoselectivity.
been reported for the synthesis of this (hydroxymeth-
yl)ethyl stereogenic center.6 We have addressed this chal-
Key words: pyridovericin, total synthesis, natural products, hydro-
genation, asymmetric catalysis
lenge in the synthesis of torrubiellone C (2) by developing
a protocol for the asymmetric hydrogenation of silyl-
protected 2-(hydroxymethyl)acrylates, culminating in the
enantioselective synthesis of torrubiellone C (2).7
Introduction
Intrigued by the recently published findings on the poten-
tial use of pyridovericin (1) as an antiallergenic lead struc-
ture,8 we wanted to apply our asymmetric hydrogenation
strategy towards the total synthesis of this compound.
Two research groups have previously reported their ef-
forts towards this goal: Baldwin and co-workers pub-
lished a route to racemic material10 and a conceptually
new quasiracemic approach was reported by Curran and
co-workers.6c However, the latter approach was plagued
by racemization along the synthetic route, and final mate-
rial with only 15–25% ee, depending on the analysis
method, was obtained.6c We envisaged avoiding a de-
crease in the enantiopurity of the intermediates and final
products by an iridium-catalyzed asymmetric hydrogena-
tion approach, the results of which are reported here.
Entomopathogenic fungi and their extracts, containing
pyridone alkaloids, show a wide range of biological
activity2 and they have even found commercial applica-
tions, for example as a food supplement in the form of
dried Ophiocordyceps sinensis, or as microbial pest con-
trol agents in the case of Beauveria bassiana.3 Evaluation
of these fungal extracts led to the isolation and identifica-
tion of several pyridone polyene natural products, such as
pyridovericin (1), torrubiellone C (2), militarinone D (3),
and farinosone A (4) (Figure 1); the latter three have re-
cently been synthesized in our laboratories.4
HO
OH
O
Me
n
R1
N
H
O
R2
Results and Discussion
n = 1, R1 = Me, R2 = OH: pyridovericin (1)
n = 2, R1 = H, R2 = OH: torrubiellone C (2)
The synthesis started with the enantioselective hydroge-
nation of the known silyl-protected β-hydroxy ester 57 us-
ing 1 mol% of the iridium catalyst9 (Scheme 1).
HO
OH
O
We have previously reported7 that this hydrogenation can
result in enantiomeric purity of up to 95:5 er, but we were
not able to consistently reproduce these results. With a
new batch of catalyst, we were only able to achieve 94:6
er in screening conditions (80 μmol of substrate), which
decreased to 92:8 er on a 0.5-mmol substrate scale. The li-
gand was determined to be optically pure (>99:1 er) by
HPLC on chiral phases, and also the configuration of ole-
fin was determined to be >99% E by GC-MS. The workup
of the final catalyst–ligand complexation reaction can be
delicate, and we therefore suspect that the catalyst itself
might contain impurities, although we were not able to ob-
serve any by our standard analytical methods.
R2
X=
Me
nR1
Me
Me
N
H
O
n = 2, R1 = Me, R2 = X: militarinone D (3)
n = 3, R1 = Me, R2 = Me: farinosone A (4)
Figure 1 Pyridone alkaloid natural products
These compounds all feature a central 4-hydroxy-2-pyri-
done ring decorated with a 3-acylpolyene side chain and a
Nevertheless, the obtained (S)-configured ester 6 (99%,
92:8 er) was reduced with diisopropylaluminum hydride
to give the aldehyde in 82% yield. Since the aldehyde was
SYNTHESIS 2014, 46, 0864–0870
Advanced online publication: 27.02.2014
DOI: 10.1055/s-0033-1340868; Art ID: SS-2013-T0814-FA
© Georg Thieme Verlag Stuttgart · New York
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X

FEATURE ARTICLE
Total Synthesis of (–)-Pyridovericin
865
Biographical Sketches█
Fabian Schmid (1988) was of truncated pyridone natu- studies, culminating in the
born and raised in Basel, ral products in the group of total synthesis of (–)-pyri-
where he obtained his B.Sc. Prof. Karl Gademann, grad- dovericin, and is now in-
degree in 2009. He then uating in 2011. He contin- volved in
a new total
started his master thesis on ued this work on pyridone synthesis project.
the neuritogenic properties alkaloids during his Ph.D.
Maurizio Bernasconi was nia, Berkeley under the su- Prof. Andreas Pfaltz at the
born in 1985 in Mendrisio, pervision of Prof. F. D. University of Basel, where
Switzerland. He obtained Toste. In 2009 he moved to he is conducting his doctoral
his B.Sc. and M.Sc. degrees Basel (Switzerland) for an studies focused on the iridi-
in chemistry from the ETH internship in the medicinal um-catalyzed asymmetric
Zürich, during the latter car- chemistry laboratories of hydrogenation of new sub-
rying out a research project Hoffmann-La Roche before strate classes.
at the University of Califor- joining the laboratory of
Henning Jacob Jessen EPFL and University of Ba- habilitation (Liebig Stipend,
(1978) obtained his Ph.D. sel, Switzerland. In this re- SNF Ambizione Fellow) in
from the University of Ham- search project he developed the group of Prof. Jay Siegel
burg, Germany, working on synthetic approaches to- and Prof. John Robinson.
pronucleotides in the group wards pyridone alkaloids His current research is
of Prof. Chris Meier. From and studied these natural focused on the chemical bi-
2008–2011 he worked as a products in phenotypic as- ology of densely phosphor-
postdoctoral fellow (DFG says. In 2011 he moved to ylated natural products.
Stipend) in the group of the University of Zürich,
Prof. Karl Gademann at the Switzerland, beginning his
Andreas Pfaltz (born 1948) Professor of Organic Chem- search focuses on catalytic
obtained a Ph.D. degree istry at the University of methods for organic synthe-
from ETH Zürich under the Basel and from 1995–1998 sis, with special emphasis
direction
of
Albert director at the Max-Planck- on asymmetric catalysis.
Eschenmoser in 1978. After Institut für Kohlenfor- His contributions have been
postdoctoral research with schung in Mülheim an der recognized with a number of
Gilbert Stork at Columbia Ruhr. In 1999, he returned awards, including the Pre-
University he returned to to the University of Basel to log Medal from ETH, the
ETH for his Habilitation. his current position as Pro- Noyori Prize, and the
From 1990–1995 he was fessor of Chemistry. His re- Yamada–Koga Prize.
Karl Gademann (born the EPFL Lausanne, and Ruzicka Medal, and the
1972) was educated at ETH since 2010, he has been pro- Liebig Lectureship of the
Zürich and Harvard Univer- fessor at the University of GDCh. He was awarded the
sity (Ph.D. with Prof. Dr. Basel. He has had over nine- European Young Investiga-
Dieter Seebach, postdoctor- ty publications, holds two tor grant related to natural
al studies with Prof. Dr. Eric patents, and received sever- product synthesis research.
N. Jacobsen, Habilitation al awards including the No- His research interests in-
associated with Prof. Dr. vartis Early Career Award, clude the synthesis and
Erick M. Carreira). His first the National Latsis Prize, chemical biology of natural
faculty appointment was at Lilly Lecture Award, the products.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 864–870

866
F. Schmid et al.
FEATURE ARTICLE
Initial experiments on the olefination of protected alde-
hyde 8 (1.8 equiv) with phosphonate 11 (1.0 equiv) under
our modified Horner–Wadsworth–Emmons13 (HWE)
conditions (LiOH 2.0 equiv, THF–H2O, 4:1, 1.5 d) gave
low yields (<30%) accompanied by formation of β-keto
phosphonate analogues to 13, supposedly through a
Knoevenagel-type process.14 We therefore decided to
screen other reaction conditions, which would also give us
insight into the role of different additives and hopefully
increase yield. The results of this qualitative ultra perfor-
mance liquid chromatography–mass spectrometry
(UPLC-MS) screening on the test substrate 10 are summa-
rized in Table 1.
O
O
a)
b), c)
MeO
Me
MeO
Me
OTBDPS
OTBDPS
5
6
O
O
d), e)
H
Me
f)
EtO
Me
Me
Me
OR
OTBDPS
R = TBDPS 8
R = H 9
7
L =
Ph
N
Comparing the product formation under the conditions in
Table 1 entries 1 and 2 revealed that upon addition of wa-
ter in presence of DBU the product distribution did not
change considerably, as both products were observed. Un-
der Masamune–Roush conditions15 (entry 3), the forma-
tion of the Knoevenagel product 13 was not observed, and
a solvent mixture of tetrahydrofuran–water (4:1) in the
presence of lithium chloride accelerated formation of the
HWE product 12 (entry 4), which might be attributed to a
solubility effect. Screening conditions in entries 5 and 6
further attested to these observations, as using lithium hy-
droxide as a base and internal Li+ source in the presence
of water led to almost quantitative product formation
while preventing side product formation. It should also be
noted that under the conditions in entry 1, the Knoevena-
gel product 13 was not observed 24 hours after addition of
lithium hydroxide (1 equiv) and a few drops of water, sug-
gesting it might be hydrolyzed under basic aqueous con-
ditions.
O
Ph2P
Scheme
1
Reagents and conditions: (a) [Ir(L)(cod)]{B[3,5-
(CF3)2C6H3]4} (1 mol%), H2 (50 bar), CH2Cl2, 0 °C, 16 h, 99%, 92:8
er; (b) DIBAL-H (1.15 equiv), CH2Cl2, –78 °C, 1 h, 82%; (c) ethyl 2-
(triphenylphosphoranylidene)propanoate (2.0 equiv), CH2Cl2, reflux,
48 h, 95%; E/Z >30:1; (d) DIBAL-H (3.0 equiv), THF, –78 °C to r.t.,
2 h, 88%; (e) TPAP (2.5 mol%), NMO (1.5 equiv), CH2Cl2, r.t., 1 h,
99%; (f) TBAF (1.0 equiv), THF, r.t., 2 h, 95%.
prone to decomposition, it was immediately olefinated in
a Wittig reaction11 and the unsaturated ester 7 was ob-
tained (95%, 91:9 er) with complete E-selectivity. A re-
duction–oxidation sequence (DIBAL-H; TPAP, NMO,12
87% over 2 steps) gave the protected α,β-unsaturated al-
dehyde 8 (89:11 er) and cleared the way for the assembly
of the polyene side chain and the known methyl phospho-
nate 11.4
Table 1 Optimization of the Conditions of the HWE Reaction Using UPLC-MS Screening
PMBO
PMBO
conditions
OMe
O
OMe
O
O
O
PO(OMe)2
+
Me
H
Me
R
Me
Me
Me
Me
N
H
O
N
H
10 (rac)
11
R = H HWE product (12)
R = PO(OMe)2 Knoevenagel product (13)
Entry
Conditionsa
Conversion (%)
HWE product 12
Knoevenagel product 13
1
2
3
4
5
6
DBU (1.2 equiv), THF
DBU (1.2 equiv), THF–H2O (4:1)
DBU (1.2 equiv), LiCl (2 equiv), THF
<50
<50
<50
>50
<50
>50
<50
<50
b
–
b
DBU (1.2 equiv), LiCl (2 equiv), THF–H2O (4:1)
LiOH (1.2 equiv), THF
–
traces
b
LiOH (1.2 equiv), THF–H2O (4:1)
–
a Conditions: 10 (1 equiv), 11 (1 equiv), r.t. under exclusion of light.
b Not observed.
Synthesis 2014, 46, 864–870
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of (–)-Pyridovericin
867
Taking into account these findings, we then chose to opt UPLC-MS screening also revealed that basic aqueous
for the free alcohol 9, obtained by deprotection of 8 conditions in the presence of Li+ were the optimal condi-
(TBAF 1 equiv, r.t., 2 h, 95%). UPLC-MS monitoring of tions for the second key step, the HWE reaction merging
the subsequent HWE reaction revealed that a prolonged the two building blocks. Under these conditions, product
reaction time (6 d) was necessary to give the three-fold formation was considerably accelerated and no Knoeve-
substituted pyridone 14 in 77% yield as the all-E isomer nagel product 13 was observed. After two deprotection
after flash chromatography (Scheme 2). Surprisingly, steps, synthetic pyridovericin was obtained that could be
NMR analysis of the crude reaction after workup did not purified by fractionated crystallization. We are currently
indicate the presence of the Z-isomer. According to our trying to expand our knowledge of the reported biological
experience, these HWE reactions usually tend to give in- activity of pyridovericin8 and pyridone alkaloids in gener-
separable E/Z mixtures even under optimized conditions.
al.
Reactions involving air or moisture sensitive reagents or intermedi-
ates were performed under an argon atmosphere in flame-dried
glassware. Concentration under reduced pressure was performed by
rotary evaporation at 40 °C, unless specified otherwise. Yields refer
to purified, dried, and spectroscopically pure compounds. Reagents
were purchased from Sigma-Aldrich and used without further puri-
fication unless stated otherwise. Technical grade solvents were dis-
tilled before use for workup and chromatography. Solvents used for
chemical transformations were either puriss. quality or dried by fil-
tration through activated alumina under argon or N2 (H2O content
<10 ppm, Karl–Fischer titration) in a PureSolve MD 5 solvent puri-
fication system and then stored under argon over activated molecu-
lar sieves. TLC was performed on Merck silica gel 60 F254 plates
(0.25-mm thickness) precoated with fluorescent indicator. The de-
veloped plates were examined under UV light and stained with
KMnO4 followed by heating. Flash chromatography was performed
using silica gel 60 (230–240 mesh) from Fluka at 0.3–0.5 bar pres-
sure. Reactions under microwave irradiation were performed in a
Biotage Initiator+ microwave synthesizer. 1H and 13C NMR spectra
were recorded either using Bruker Avance 400 MHz, Bruker
Avance DRX 500 MHz, or Bruker DRX 600 MHz spectrometers at
r.t.; spectra were calibrated relative to the solvent residual proton
chemical shift and the solvent residual carbon chemical shift.16 Op-
tical rotations [α]D were measured at the Na D line (1-mL cell, 1-dm
path length, Jasco P-2000 digital polarimeter, 25 °C); concentration
c in g/100 mL in the indicated solvent. IR spectra were recorded us-
ing a Varian 800 FT-IR ATR spectrophotometer. HRMS-ESI data
was recorded by the Mass spectrometric Service of the University
of Bern on a Sciex QSTAR Pulsar mass spectrometer using electro-
spray ionization. UPLC-MS analysis was performed on an Agilent
1290 Infinity LC system with an Eclipse plus C18 (1.8 μm, 50 × 2.1
mm) column and an Agilent Technologies 6130 Quadrupol mass
spectrometer using ESI-API. The solvents used were MeCN–0.1%
TFA (solvent A) and H2O–1% MeCN–0.1% TFA (solvent B); gra-
dient: 0.0–0.4 min 95% B; 0.4–3.0 min 95% B to 95% A; 3.0–4.0
min 95% A at a flow rate of 1 mL/min. Semi-preparative RP-HPLC
was performed on a Thermo Scientific Ultimate 3000 system using
a Phenomenex Gemini 10μ C18 110A (150 × 10.0 mm) column
eluting with gradients of MeCN in H2O at a flow rate of 5 mL/min.
Enantiomeric ratios (er) were determined by chiral HPLC on a
PMBO
O
OMe
O
O
PO(OMe)2
H
Me
OH
+
Me
N
H
11
9
a)
R2O
OR1
O
Me
OH
Me
N
H
O
R1 = Me, R2 = PMB 14
R1 = H, R2 = H 1
b)
Scheme 2 Reagents and conditions: (a) 9 (1.2 equiv), LiOH (2.0
equiv), THF–H2O (4:1), light exclusion, r.t., 6 d, 77%, E/Z >30:1; (b)
1. LiI (4 equiv), Py·HCl (6.0 equiv), 71%; ii. TFA (5% in CH2Cl2),
83%, E/Z >30:1, 93:7 er.
With the coupling product 14 in hand, the total synthesis
was completed by an established4,7 two-step deprotection
sequence. The 4-methoxy group was cleaved in the pres-
ence of lithium iodide hydrate (4.0 equiv) and pyridine
hydrochloride (6.0 equiv) under microwave heating (60
°C) in tetrahydrofuran in 71% yield. The obtained crude
E/Z mixture (>5:1) was then stirred in trifluoroacetic acid
(5% v/v in CH2Cl2) for 30 minutes, which gave after puri-
fication fully deprotected pyridovericin (1) in 83% yield
(E/Z >6:1). A cascade of fractionated crystallizations
from dichloromethane–methanol and pentane gave an an-
alytical sample of pyridovericin with E/Z >30:1 and 93:7
er ratios determined by HPLC analysis, supporting that no
racemization occurred in our reaction sequence. The ana- Shimadzu Class-VP Version 5.0 system with a SCL-10A system
controller, LC-10AD pump system, SIL-10AD auto injector, CTO-
10AC column oven, DGU-14A degasser and SPD-M10A diode ar-
ray- or UV/VIS detector at 20 °C with the stated solvent gradients
and columns.
lytical data of the synthetic material were found to be
identical in all respects in comparison with the published
values,5 and the previously assigned6c R-configuration of
naturally occurring pyridovericin (1) was corroborated by
Methyl (S)-2-[(tert-Butyldiphenylsiloxy)methyl]butanoate (6)
A high pressure steel autoclave (Premex Reactor AG; Lengnau,
Switzerland; Model HPM-005) with a dry glass insert and a mag-
netic stirrer bar was charged with methyl (E)-2-[(tert-butyldimeth-
ylsiloxy)methyl]but-2-enoate (5, 184 mg, 500 μmol, 1.0 equiv) and
anhyd CH2Cl2 (2.5 mL) and then the catalyst [Ir(L)(cod)]{B[3,5-
(CF3)2C6H3]4} (1 mol%) was added. The autoclave was closed and
attached to a high-pressure hydrogen line and purged with H2. The
autoclave was sealed under 50 bar of H2 pressure and the mixture
was stirred at 900 rpm for 16 h at r.t. The H2 was released, the solu-
the measured optical rotation.
Conclusion
In summary, we have achieved the enantioselective total
synthesis of the natural R-enantiomer of pyridovericin (1)
with 93:7 er that did not erode during the synthesis.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 864–870

868
F. Schmid et al.
FEATURE ARTICLE
tion was concentrated in a stream of N2, diluted with hexane–MTBE
(4:1, 1 mL), and passed through a short plug of silica gel in a Pasteur
pipette, and the filtrate was concentrated in a stream of N2 to give
the pure 6 (184 mg, 500 μmol, quant.; 93:7 er). Analytical data are
in full agreement with previously reported values,7 except for in-
verted optical rotation of [α]D25 +102 (c 0.89, CHCl3);
vigorously until two clear layers were observed (~2 h), and these
were then separated. The aqueous layer was extracted with Et2O
(2 × 20 mL) and the combined organic layers were dried (Na2SO4),
filtered, and the solvents removed in vacuo. Flash chromatography
(pentane–Et2O 4:1) gave the title alcohol (249 mg, 621 μmol, 88%;
E/Z >30:1; 89:11 er) as a colorless oil; Rf = 0.30 (pentane–Et2O
4:1); [α]D25 –24.6 (c 1.1, CHCl3); 89:11 er [HPLC (Chiralcel AD-H
column, hexane–i-PrOH, 99:1, flow rate 0.6 mL/min, UV 206 nm):
tR = 15.3 (major), 17.3 (minor)].
93:7 er [HPLC (Chiralcel OD-H column, hexane–i-PrOH, 99:1,
flow rate 0.5 mL/min, UV 230 nm): tR = 8.11 (minor), 9.10 min
(major)].
FT-IR (neat): 3324 (br), 2958, 2930, 2857, 1389, 1427, 1111, 1007,
702 cm–1.
(S)-2-[(tert-Butyldiphenylsiloxy)methyl]butanal
To a –78 °C cold solution of ester 6 (370 mg, 1.04 mmol, 1.0 equiv)
in anhyd CH2Cl2 (4 mL) was added 1 M DIBAL-H in CH2Cl2 (1.15
mL, 1.15 mmol, 1.1 equiv) portionwise (100 μL every 5 min); the
solution was precooled by allowing it to run down the wall of the
flask. This mixture was then stirred at –78 °C for 1 h and then
quenched by slow addition of a mixture of MeOH–CH2Cl2 (1:1, 2
mL); the solution was precooled by running down the wall of the
flask. The mixture was diluted with Et2O (20 mL) and then quickly
poured into sat. aq sodium potassium tartrate soln (20 mL). The re-
sulting gray slurry was stirred vigorously until two clear layers were
observed (~1 h), and these were then separated. The aqueous layer
was extracted with Et2O (2 × 20 mL) and the combined organic lay-
ers were dried (Na2SO4), filtered, and the solvents removed in vac-
uo. Flash chromatography (pentane–Et2O, 15:1) gave the title
aldehyde (289 mg, 849 μmol, 82%) as a colorless oil. Analytical
data are in full agreement with previously reported values,7 except
for the inverted optical rotation of [α]D25 +16.7 (c 0.83, CHCl3).
1H NMR (400 MHz, CDCl3): δ = 7.69–7.64 (m, 4 H), 7.45–7.35 (m,
6 H), 5.13 (dq, J = 9.8, 1.1 Hz, 1 H), 3.98 (d, J = 5.9 Hz, 2 H), 3.60–
3.50 (m, 2 H), 2.48–2.37 (m, 1 H), 1.71–1.58 (m, 1 H), 1.62 (d,
J = 1.1 Hz, 3 H), 1.27–1.15 (m, 2 H), 1.05 (s, 9 H), 0.84 (t,
J = 7.4 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 136.4, 135.8, 134.2, 129.7, 128.0,
127.7, 69.1, 67.2, 42.3, 27.0, 24.7, 19.4, 14.3, 11.8.
HRMS (ESI): m/z [M + H]+ calcd for C24H35O2Si: 383.2401; found:
383.2401.
(R,E)-4-(Hydroxymethyl)-2-methylhex-2-enal (9)
To a solution of (R,E)-4-[(tert-butyldiphenylsiloxy)methyl]-2-
methylhex-2-en-1-ol (160 mg, 397 μmol, 1.0 equiv) in anhyd
CH2Cl2 (3 mL) was added powdered molecular sieves (50 mg, 4 Å,
stored at 120 °C) and NMO (70.0 mg, 596 μmol, 1.5 equiv). To this
slurry, TPAP (3.5 mg, 10.0 μmol, 0.025 equiv) was added and the
resulting black suspension was stirred for 1 h at r.t.; TLC indicated
complete consumption of the starting material. The crude mixture
was filtered over a plug of silica, which was further washed with
CH2Cl2 (70 mL). The solvents were removed in vacuo to give the
protected aldehyde 8 as a yellow oil (155 mg, 397 μmol, 99%),
which was used without further purification in the next step;
Rf = 0.45 (pentane–Et2O, 10:1).
Ethyl (R,E)-4-[(tert-Butyldiphenylsiloxy)methyl]-2-methylhex-
2-enoate (7)
To a solution of (S)-2-[(tert-butyldiphenylsiloxy)methyl]butanal
(257 mg, 753 μmol, 1.0 equiv) in anhyd CH2Cl2 (3 mL) was added
ethyl 2-(triphenylphosphoranylidene)propanoate (409 mg, 1.13
mmol, 1.5 equiv) in one portion. The resulting yellow solution was
heated to reflux and the consumption of the aldehyde was followed
1
by H NMR; after 24 h a further portion of the phosphorane (136
1H NMR (500 MHz, CDCl3): δ = 9.37 (s, 1 H), 7.64–7.60 (m, 4 H),
7.46–7.35 (m, 6 H), 6.27 (dq, J = 10.2, 1.3 Hz, 1 H), 3.70 (dd,
J = 10.0, 5.3 Hz, 1 H), 3.62 (dd, J = 10.0, 6.6 Hz, 1 H), 2.73 (dddt,
J = 10.2, 9.0, 6.4, 5.2 Hz, 1 H), 1.72 (d, J = 1.3 Hz, 3 H), 1.71–1.62
(m, 1 H), 1.41–1.31 (m, 1 H), 1.03 (s, 9 H), 0.84 (t, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 195.5, 156.7, 135.6, 135.5, 129.8,
127.7, 66.1, 43.7, 26.8, 24.0, 11.7, 9.7.
mg, 376 μmol, 0.5 equiv) was added. After complete consumption
of the aldehyde (48 h), the solvent was removed in vacuo and the
crude slurry was directly subjected to flash chromatography (pen-
tane–Et2O, 25:1) to afford ester 7 (304 mg, 715 μmol, 95%; E/Z
>30:1; 91:9 er) as a colorless oil; Rf = 0.33 (pentane–Et2O, 15:1);
[α]D25 +6.27 (c 0.93, CHCl3); 91:9 er [HPLC (Chiralpak IC column,
hexane–i-PrOH, 99:1, flow rate 0.5 mL/min, UV 206 nm): tR = 11.1
(minor), 11.5 min (major)].
To a solution of the crude aldehyde 8 (179 mg, 447 μmol 1.0 equiv)
in anhyd THF (3 mL) was added 1 M TBAF in THF (450 μL, 450
μmol 1.0 equiv) and the resulting dark yellow solution was stirred
at r.t.; after 2 h, UPLC-MS indicated complete consumption of the
starting material. The mixture was poured into sat. aq NH4Cl (10
mL) and extracted with Et2O (5 × 10 mL). The combined organic
layers were dried (Na2SO4), filtered, and the solvents removed in
vacuo. Flash chromatography (pentane–Et2O, 1:10) gave the depro-
tected aldehyde 9 (60.3 mg, 424 μmol, 95%, E/Z >30:1) as a color-
FT-IR (neat): 2962, 2933, 2859, 1710, 1463, 1388, 1229, 1107, 741,
702 cm–1.
1H NMR (500 MHz, CDCl3): δ = 7.66–7.63 (m, 4 H, CHAr), 7.45–
7.35 (m, 6 H), 6.59 (dq, J = 10.3, 1.3 Hz, 1 H), 4.28–4.14 (m, 2 H),
3.63–3.53 (m, 2 H), 2.60–2.50 (m, 1 H), 1.81 (d, J = 1.4 Hz, 3 H),
1.72–1.63 (m, 1 H), 1.35–1.25 (m, 1 H), 1.29 (t, J = 7.1 Hz, 3 H),
1.03 (s, 9 H), 0.84 (t, J = 7.5 Hz, 3 H).
13C NMR (126 MHz, CDCl3): δ = 168.4, 143.9, 135.8, 133.8, 129.8,
129.2, 127.8, 66.4, 60.6, 43.5, 26.9, 24.2, 19.4, 14.5, 13.1, 11.9.
25
less oil; [α]D –26.6 (c 0.90, CHCl3); Rf = 0.45 (pentane–Et2O,
1:10).
FT-IR (neat): 3363 (br), 2962, 2931, 2876, 2361, 2335, 1685, 1042,
766 cm–1.
1H NMR (400 MHz, CDCl3): δ = 9.45 (s, 1 H), 6.32 (dq, J = 10.1,
1.3 Hz, 1 H), 3.75–3.60 (m, 2 H), 2.84–2.71 (m, 1 H), 1.80 (d,
J = 1.4 Hz, 3 H), 1.72–1.62 (m, 1 H), 1.46–1.34 (m, 1 H), 0.91 (t,
J = 7.5 Hz, 3 H).
13C NMR (101 MHz, CDCl3): δ = 195.3, 155.5, 141.4, 65.6, 43.9,
24.1, 11.8, 10.0.
HRMS (ESI): m/z [M + H]+ calcd for C8H15O2: 143.1067; found:
143.1066.
HRMS (ESI): m/z [M + Na]+ calcd for C26H36O3NaSi: 447.2326;
found: 447.2319.
(R,E)-4-[(tert-Butyldiphenylsiloxy)methyl]-2-methylhex-2-en-
1-ol
To a –78 °C cold solution of ester 7 (300 mg, 706 μmol, 1.0 equiv)
in anhyd THF (3 mL) was added dropwise 1 M DIBAL-H in hexane
(2.12 mL, 2.12 mmol, 3 equiv). The solution was stirred for 20 min
at –78 °C, 30 min at 0 °C, and finally 1 h at r.t., after which TLC
indicated complete consumption of the starting material. The reac-
tion was quenched by dropwise addition of MeOH (2 mL), diluted
with Et2O (20 mL), and then quickly poured onto sat. aq sodium po-
tassium tartrate soln (20 mL). The resulting gray slurry was stirred
Synthesis 2014, 46, 864–870
© Georg Thieme Verlag Stuttgart · New York

FEATURE ARTICLE
Total Synthesis of (–)-Pyridovericin
869
3-[(R,2E,4E)-6-(Hydroxymethyl)-4-methylocta-2,4-dienoyl]-4-
methoxy-5-[4-(4-methoxybenzyloxy)phenyl]pyridin-2(1H)-one
(14)
93:7 er [HPLC (Chiralcel IC column, hexane–i-PrOH, 70:30, flow
rate 1.0 mL/min, UV 206 nm): tR = 8.3 (minor), 9.2 min (major)].
FT-IR (neat): 3287 (br), 2960, 2929, 2360, 2341, 1648, 1610, 1518,
1460, 1263, 1215, 1037, 985, 835, 769 cm–1.
To a suspension of the aldehyde 9 (36.0 mg, 253 μmol, 1.2 equiv)
and the phosphonate 114 (103 mg, 211 μmol, 1.0 equiv) in THF–
H2O (4:1, 1 mL) was added LiOH·H2O (17.7 mg, 422 μmol, 2.0
equiv). A yellow solution formed immediately, which was stirred
under exclusion of light at r.t. and monitored by UPLC-MS. After 6
d, the dark orange mixture was poured into sat. aq NH4Cl (10 mL)
and extracted with EtOAc (4 × 10 mL). The combined organic lay-
ers were dried (Na2SO4), filtered, and the solvents removed in
vacuo. Flash chromatography (CH2Cl2–MeOH, 20:1) gave the pyr-
idopolyene 14 (82.0 mg, 162 μmol, 77%, E/Z >30:1) as a yellow oil;
Rf = 0.30 (CH2Cl2–MeOH, 20:1).
1H NMR (500 MHz, DMSO-d6): δ = 17.56 (s, 1 H), 11.62 (s, 1 H),
9.48 (s, 1 H), 7.99 (d, J = 14.9 Hz, 1 H), 7.55 (s, 1 H), 7.51 (d,
J = 15.6 Hz, 1 H), 7.30–7.24 (m, 2 H), 6.81–6.75 (m, 2 H), 5.94 (d,
J = 9.6 Hz, 1 H), 4.59 (t, J = 5.4 Hz, 1 H), 3.41–3.30 (m, 2 H), 2.57–
2.49 (m, 1 H), 1.85 (s, 3 H), 1.65–1.54 (m, 1 H), 1.28–1.17 (m, 1 H),
0.82 (t, J = 7.5 Hz, 3 H).
13C NMR (151 MHz, DMSO-d6): δ = 193.7, 176.9, 161.8, 156.7,
149.4, 147.5, 140.7, 134.5, 130.1, 123.5, 123.1, 115.0, 112.8, 106.0,
64.0, 43.6, 24.0, 12.8, 11.7.
FT-IR (neat): 3400 (br), 2934, 2358, 1634, 1611, 1512, 1237, 1033,
830, 733 cm–1.
HRMS (ESI): m/z [M + H]+ calcd for C21H24O5N: 370.1649; found:
370.1647.
1H NMR (500 MHz, CDCl3): δ = 12.91 (br s, 1 H), 7.40–7.35 (m, 3
H), 7.32–7.27 (m, 2 H), 7.22 (d, J = 15.8 Hz, 1 H), 7.01–6.97 (m, 2
H), 6.95–6.91 (m, 2 H), 6.50 (d, J = 15.8 Hz, 1 H), 5.74 (d, J = 10.1
Hz, 1 H), 5.01 (s, 2 H), 3.82 (s, 3 H), 3.64–3.59 (m, 1 H), 3.61 (s, 3
H), 3.52–3.46 (m, 1 H), 2.68–2.58 (m, 1 H), 1.89 (d, J = 1.0 Hz, 3
H), 1.59–1.52 (m, 1 H), 1.32–1.22 (m, 1 H), 0.86 (t, J = 7.5 Hz, 3
H).
13C NMR (126 MHz, CDCl3): δ = 194.2, 168.4, 165.6, 164.4, 159.7,
158.7, 150.6, 145.4, 145.2, 136.0, 135.2, 130.0, 129.4, 129.3, 126.9,
126.4, 114.8, 113.9, 69.8, 68.8, 60.7, 55.2, 43.9, 24.2, 13.0, 11.6.
UV: λmax (MeCN–H2O, 60:40) = 206, 249, 338 nm.
Dimethyl {(2Z,4E,6E)-1-[4-Methoxy-5-[4-(4-methoxybenzyl-
oxy)phenyl]-2-oxo-1,2-dihydropyridin-3-yl]-6,8-dimethyl-1-
oxodeca-2,4,6-trien-2-yl}phosphonate (13)
The phosphonate 114 (9.5 mg, 20 μmol, 1.0 equiv) and aldehyde 10
(5.7 mg, 19.5 μmol, 1.0 equiv) were suspended in anhyd THF (0.3
mL) and 1 drop of DBU was added. The suspension was stirred for
24 h at r.t. under exclusion of light, poured into sat. aq NH4Cl (2
mL), extracted with CH2Cl2 (5 × 3 mL), dried (Na2SO4), filtered,
and evaporated. The crude yellow oil was purified by flash chroma-
tography (CH2Cl2–MeOH, 20:1) to give the HWE product (4.0 mg,
7.8 μmol, 40%) and the crude Knoevenagel product. This was fur-
ther purified by semipreparative HPLC (95% MeCN to 100% H2O
in 25 min) to give the desired Knoevenagel product (4.0 mg, 6.4
μmol, 30%) as a mixture of 4 E/Z isomers. NMR data is given for
the major all-E isomer. Most 1H shifts were assigned from 2D-NMR
spectra (see the Supporting Information). The signal of the carbon
atom at the C3 position of the pyridone could not be detected.
HRMS (ESI): m/z [M + H]+ calcd for C30H34O6N: 504.2381; found:
504.2377.
(–)-Pyridovericin (1)
A suspension of the pyridopolyene 14 (74 mg, 147 μmol, 1.0 equiv),
LiI·3H2O (111 mg, 589 μmol mol, 4.0 equiv) and pyridine hydro-
chloride (102 mg, 883 μmol, 6.0 equiv) in degassed (freeze/thaw)
THF (4 mL) was heated to 60 °C for 4 h in a microwave reactor. The
yellow suspension was poured into brine (5 mL) and then extracted
with CH2Cl2 (3 × 7 mL). The combined organic layers were dried
(Na2SO4), filtered, and the solvents removed in vacuo. Flash chro-
matography (CH2Cl2–MeOH, 20:1) gave the crude demethylated
Rf = 0.15 (CH2Cl2–MeOH 20:1).
FT-IR (neat): 2957, 2853, 2361, 1589, 1643, 1513, 1462, 1387,
1292, 1243, 1177, 1030, 791, 649 cm–1.
1
pyridone (51 mg, 104 μmol, 71%, E/Z >5:1) as a yellow oil. H
1H NMR (600 MHz, CDCl3): δ = 12.62 (br s, 1 H), 7.62 (dd,
J = 14.7, 11.6 Hz, 1 H), 7.37 (d, J = 8.4 Hz, 2 H), 7.29 (d, J = 8.9
Hz, 2 H), 7.27 (s, 1 H), 7.27 (dd, J = 33.0,11.6 Hz, 1 H), 6.99 (d,
J = 8.6 Hz, 2 H), 6.77 (d, J = 14.7 Hz, 1 H), 6.39 (d, J = 8.5 Hz, 2
H), 5.67 (d, J = 9.7 Hz, 1 H), 5.01 (s, 2 H), 3.83 (d. J = 2.8 Hz, 6 H),
3.74 (s, 3 H), 3.58 (s, 3 H), 2.50–2.39 (m, 1 H), 1.87 (s, 3 H), 1.44–
1.35 (m, 1 H), 1.33–1.22 (m, 1 H), 0.96 (d, J = 6.4 Hz, 3 H), 0.82 (t,
J = 7.40 Hz, 3 H).
13C NMR (151 MHz, CDCl3): δ = 193.0, 168.2, 165.0, 163.6, 162.2,
160.7, 159.5, 158.5, 154.8, 149.7, 134.9, 133.7, 130.0, 129.2, 128.9,
123.2, 117.0, 114.9, 114.0, 69.8, 60.4, 54.3, 52.8, 35.0, 29.8, 20.1,
12.7, 11.9.
NMR data is given for the E isomer; Rf = 0.40 (CH2Cl2–MeOH,
15:1).
1H NMR (400 MHz, CDCl3): δ = 11.59 (s, 1 H), 7.98 (d, J = 15.4
Hz, 1 H), 7.62 (d, J = 15.4 Hz, 1 H), 7.44–7.33 (m, 5 H), 7.07–6.98
(m, 2 H), 6.98–6.89 (m, 2 H), 5.82 (d, J = 10.0 Hz, 1 H), 5.01 (s, 2
H), 3.82 (s, 3 H), 3.71–3.60 (m, 1 H), 3.56–3.45 (m, 1 H), 2.75–2.60
(m, 1 H), 1.94 (s, 3 H), 1.63–1.53 (m, 1 H), 1.34–1.24 (m, 1 H), 0.88
(t, J = 7.4 Hz, 3 H).
The crude pyridone (16 mg, 33 μmol, 1.0 equiv) was suspended in
CH2Cl2 (2 mL) and TFA (100 μL, 5% v/v final concentration) was
added dropwise. The formed yellow solution was stirred at r.t. for
30 min, after which TLC indicated complete consumption of the
starting material. The crude solution was poured into sat. aq
NaHCO3 (5 mL) and extracted with CH2Cl2–MeOH–EtOAc (6:1:1,
5 × 10 mL), after which the aqueous layer appeared to be colorless.
The combined yellow organic layers were dried (Na2SO4), filtered,
and the solvents removed in vacuo. Flash chromatography
(CH2Cl2–MeOH, 20:1) gave (–)-pyridovericin (1) (10 mg, 27 μmol,
83%, E/Z >6:1) as a yellow oil. Fractional crystallization was
achieved by dissolving the crude material in MeOH–CH2Cl2 (1:9,
300 μL) and dropwise addition of pentane (1.2 mL) while swirling
vigorously. The yellow suspension was stored at 5 °C for 10 min,
centrifuged and the supernatant removed carefully with a syringe.
After 5 repetitions of the process, this gave an analytical sample of
1 (3 mg) as an amorphous yellow solid; E/Z >30:1; 93:7 er;
Rf = 0.17 (CH2Cl2–MeOH, 15:1); [α]D25 –10.8 (c 0.16, MeOH);
31P NMR (243 MHz, CDCl3): δ = 17.1.
HRMS (ESI): m/z [M + H]+ calcd for C34H41O8NP: 622.2564;
found: 622.2565.
Acknowledgment
We thank PD. Dr. Daniel Häussinger and Heiko Gsellinger for
NMR measurements and helpful discussions. We acknowledge the
Swiss National Science Foundation (SNF) (200021-144028) for
support.
Supporting Information for this article is available online at
http://www.thieme-connect.com/ejournals/toc/synthesis. Included
are 1H and 13C NMR spectra and HPLC traces.SnugIoipfn
rioatmtrSufpnogrmIpintart
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 864–870

870
F. Schmid et al.
FEATURE ARTICLE
10, 449. (h) Yadav, J. S.; Nanda, S.; Bashkar Rao, A.
Tetrahedron: Asymmetry 2001, 12, 3223. (i) Panek, J. S.;
Jain, N. F. J. Org. Chem. 2001, 66, 2747.
References
(1) Present address: University of Zürich, Institute of Organic
Chemistry, Winterthurerstrasse 190, 8057 Zürich,
Switzerland.
(2) (a) Review: Jessen, H. J.; Gademann, K. Nat. Prod. Rep.
2010, 27, 1168. (b) Schmidt, K.; Riese, U.; Li, Z.;
Hamburger, M. J. Nat. Prod. 2003, 66, 378. (c) Isaka, M.;
Chinthanom, P.; Supothina, S.; Tobwor, P.; Hywel-Jones, N.
L. J. Nat. Prod. 2010, 73, 2057. (d) Schmidt, K.; Günther,
W.; Stoyanova, S.; Schubert, B.; Li, Z.; Hamburger, M. Org.
Lett. 2002, 4, 197.
(7) (a) Jessen, H. J.; Schumacher, A.; Schmid, F.; Pfaltz, A.;
Gademann, K. Org. Lett. 2011, 13, 4368. (b) For a recent
synthesis of the torrubiellone B congener, see: Ding, F.;
William, R.; Leow, M. L.; Chai, H.; Fong, J. Z. M.; Liu, X.-
W. Org. Lett. 2014, 16, 26.
(8) de Souza Santos, M.; Andrioli, W. J.; de Morais Del Lama,
M. P. F.; Bastos, J. K.; Nanayakkara, N. P. D.; Naal, R. M.
Z. G. Int. Immunopharmacol. 2013, 1.
(9) Ganic, A. Ph.D. Thesis; University of Basel: Switzerland,
2013, ISBN 978–3-8439-0952-5.
(3) Scholte, E.-J.; Knols, B. G. J.; Samson, R. A.; Takken, W.
J. Insect Sci. 2004, 19, 1.
(10) Baldwin, J. E.; Adlington, R. M.; Conte, A.; Irlapati, N. R.;
Marquez, R.; Pritchard, G. J. Org. Lett. 2002, 4, 2125.
(11) Wittig, G.; Schöllkopf, U. Chem. Ber. 1954, 87, 1318.
(12) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P.
Synthesis 1994, 639.
(13) (a) Wadsworth, W. S.; Emmons, W. D. J. Am. Chem. Soc.
1961, 83, 1733. (b) Horner, L.; Hoffmann, H.; Wippel, H. G.
Chem. Ber. 1958, 91, 61.
(14) Knoevenagel, E. Chem. Ber. 1898, 31, 2596.
(15) Blanchette, M. A.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett.
1984, 25, 2183.
(16) Fulmer, G. R.; Miller, A. J. M.; Sherden, N. H.; Gottlieb, H.
E.; Nudelman, A.; Stoltz, B. M.; Bercaw, J. E.; Goldberg, K.
I. Organometallics 2010, 29, 2176.
(4) Jessen, H. J.; Schumacher, A.; Shaw, T.; Pfaltz, A.;
Gademann, K. Angew. Chem. Int. Ed. 2011, 50, 4222.
(5) Takahashi, S.; Ucha, K.; Kakinuma, N.; Hashimoto, R.;
Yanagisawa, T.; Nakawaga, A. J. Antibiot. 1988, 51, 1051.
(6) (a) Senanayake, C. H.; Larsen, R. D.; Bill, T. J.; Liu, J.;
Corley, E. G.; Reider, P. J. Synlett 1994, 199. (b) Loubinoux,
B.; Viriot-Chauveau, C.; Sinnes, J. L. Tetrahedron Lett.
1992, 33, 2145. (c) Zhang, Q.; Rivkin, A.; Curran, D. P.
J. Am. Chem. Soc. 2002, 124, 5774. (d) Xie, X.-G.; Wu, X.-
W.; Lee, H.-K.; Peng, X.-S.; Wong, H. N. C. Chem. Eur. J.
2010, 16, 6933. (e) Katsumata, A.; Setsu, F.; Tokunaga, Y.;
Fukumoto, K. J. Org. Chem. 1996, 61, 677.
(f) Wullschleger, C. W.; Gertsch, J.; Altmann, K.-H. Org.
Lett. 2010, 12, 1120. (g) Izquierdo, I.; Plaza, M. T.;
Rodriguez, M.; Tamayo, J. Tetrahedron: Asymmetry 1999,
Synthesis 2014, 46, 864–870
© Georg Thieme Verlag Stuttgart · New York