A unified approach for the stereoselective total synthesis of pyridone alkaloids and their neuritogenic activity

Article abstract of DOI:10.1002/anie.201007671

Unus pro omnibus: The development of compounds inducing neurite outgrowth might constitute a valuable approach for the non-invasive medical treatment of neurodegenerative diseases. With the aid of a bifunctional building block, the total syntheses of a gr

Full text of DOI:10.1002/anie.201007671

Communications
DOI: 10.1002/anie.201007671
Natural Product Synthesis
AUnified Approach for the Stereoselective Total Synthesis of Pyridone
Alkaloids and Their Neuritogenic Activity**
Henning Jacob Jessen, Andreas Schumacher, Travis Shaw, Andreas Pfaltz, and Karl Gademann*
The enhancement of cognitive function, memory, and learn-
ing in healthy human subjects by application of chemical
compounds is becoming more prevalent in our knowledge-
focused society.[1] The use of such compounds also constitutes
a promising approach to address the deleterious effects of
neurodegenerative diseases.[2] In the search for novel lead
structures traditional medicine is an important resource. For
instance in China, entomopathogenic fungi such as Cordyceps
and their extracts have been used for centuries to strengthen
the immune system and improve cognitive function.[3] Many
of these fungi contain pyridone alkaloids, for example,
pretenellin B (1), tenellin (2), and bassianin (4).[4] A few
years ago Hamburger and co-workers disclosed the structures
of additional representatives isolated from the entomopatho-
genic fungi Paecilomyces farinosus and Paecilomyces milita-
ris: the farinosones A (5) and B (6) as well as militarinone D
(9).[5,6] Farinosone A (5) induces and enhances neurite out-
growth in the PC-12 cell line, which would be in line with the
postulated positive effects on learning and cognition. How-
ever, it remains unclear, whether pyridone alkaloids—in
particular (pre)-tenellin B, (pre)-bassianin, and militarin-
one D—generally display neuritogenic activity. To address
this question, a unified synthetic approach towards the total
synthesis of this family of natural products would be desirable
and would also provide access to putative natural products
such as pyridones 3, 7, and 8.
Herein, we report a modular approach for the stereose-
lective total synthesis of the pyridone alkaloids pretenellin B
(1), farinosone A (5), militarinone D (9), and the unknown
precursor prebassianin B (3), as well as their respective
enantiomers. In addition, we were able to assign the
previously unknown absolute configuration of the natural
products and evaluate their neuritogenic activity.
Since pyridone alkaloids generally feature structural
differences in both the polyene chain and in the oxidation
pattern of the ring system, a flexible route is required to
introduce substituents onto the pyridone core. The aromatic
group could be attached by a cross-coupling reaction and the
polyene side chain could be introduced by a Horner–Wads-
worth–Emmons (HWE) reaction[7] on a densely functional-
ized pyridone b-ketophosphonate, which should allow for
high yields of the desired E isomers. To our knowledge, such
an approach has never been applied in the numerous reported
total syntheses of pyridone alkaloids, as surprisingly few
pyridone core functionalizations have been reported in this
context.[6]
The synthesis of the target natural products started with
the preparation of the pyridone core 12[8] on a 10 g scale from
ethyl cyanoacetate (11, Scheme 1). Selective bromination of
12 with NBS gave bromopyridone 13, which crystallized from
toluene/ethyl acetate. The initial plan was to conduct cross-
coupling reactions at this stage, but the reactivity of bromo-
pyridone 13 proved to be too low regardless of the different
reagents, catalysts, additives, temperatures, and solvents
employed. This pyridone might inactivate the catalyst by
complexation, and we therefore blocked the amide function-
ality with different protecting groups. The 2-trimethylsilyl-
ethoxymethyl group (SEM) was the most effective protecting
group, although problems concerning N- and O-selectivity[9]
were encountered that could not be solved by using different
solvents and bases. However, the obtained (ca. 1:1) mixtures
were amenable to Suzuki–Miyaura cross-coupling[10] and gave
the para-methoxybenzyl(PMB)-protected pyridones in 95%
[*] Dr. H. J. Jessen, A. Schumacher, T. Shaw,[+] Prof. Dr. A. Pfaltz,
Prof. Dr. K. Gademann
Department Chemie, Universitꢀt Basel
4056 Basel (Switzerland)
Fax: (+41)61-267-1103
E-mail: karl.gademann@unibas.ch
Homepage: http://www.chemie.unibas.ch/~gademann
[+] Current address: Department of Chemistry
Princeton University, Princeton, NJ 08544 (USA)
[**] K.G. is a European Young Investigator (EURYI). We gratefully
acknowledge financial support from the DFG (project JE 572/1-1)
and the SNF (PE002-117136/1). We thank Prof. Hamburger for
providing the PC-12 cell line and discussions, Dr. Neuburger for X-
ray analyses, and Dr. Hꢀussinger for NMR analyses.
Supporting information for this article is available on the WWW
under http://dx.doi.org/10.1002/anie.201007671.
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Angew. Chem. Int. Ed. 2011, 50, 4222 –4226

of the high volatility of the corresponding aldehydes after
oxidation with TEMPO/PhI(OAc)2, a HWE reaction under
Masamune–Roush conditions[12a] was carried out directly
after aqueous workup. Unfortunately, these conditions led
to partial racemization (e.r. 83:17),[12b–d] which was also the
case when lithium hexafluoroisopropoxide[13] or barium
hydroxide[14] were employed. Further optimization supported
by GC analysis on a chiral stationary phase revealed TPAP/
NMO[15] as a suitable oxidant, followed by condensation with
the less basic Wittig reagent at 358C (completely E-selective,
e.r. 97:3).[16] After reduction with DIBAH followed by
oxidation with activated MnO2, aldehyde 18 was obtained in
85% yield (two steps). This aldehyde was not only the starting
material for the synthesis of pretenellin B (1) but also useful
in obtaining the homologous aldehyde 19 for the synthesis of
prebassianin B (3). In this case, the HWE reaction under
Masamune–Roush conditions gave selectively the homolo-
gous E-configured ester without racemization. Reduction and
oxidation resulted in dienal 19. Repetition of this sequence
resulted in the C2-homologated aldehyde 20, with high E-
selectivity and no observed racemization. This trienal 20 was
required for the preparation of farinosone A (5). As the final
steps proceeded in only moderate yield, an alternative
sequence was explored: a Takai reaction[17] (E/Z 4:1) was
followed by a Stille coupling,[18] and subsequent oxidation
directly yielded trienal 20. At this stage, the minor Z isomer
was removed by flash chromatography. In summary, the
described protocols provided the required series of R- and S-
configured all-E unsaturated aldehydes efficiently and ste-
reoselectively.
Scheme 1. a) CH3C(OCH3)3, reflux; b) DMF/dimethyl acetal, reflux;
c) aq AcOH, reflux, 41%, 3 steps; d) NBS, NH4NO3, CH3CN, reflux,
90%; e) SEM-Cl, Et3N, CH2Cl2, 08C; f) [Pd(PPh3)4], K2CO3, (4-[{4-
methoxybenzyl}oxy]phenyl)boronic acid, DME/H2O/DMF, 608C; g) for
N-SEM pyridone: TBAF, THF, 608C, 95%, 3 steps; for O-SEM pyridine:
TFA, 95%, 3 steps; h) MeP(O)(OR)2, nBuLi, À788C, THF, quant.
Abbreviations: AcOH=acetic acid, DME=1,2-dimethoxyethane,
DMF=dimethylformamide, NBS=N-bromosuccinimide, PMB=para-
methoxybenzyl, SEM-Cl=(trimethylsilyl)ethoxymethyl chloride, TBAF=
tetrabutylammonium fluoride, TFA=trifluoroacetic acid.
yield, which were then readily separated. In both cases,
subsequent removal of the SEM group gave phenylpyridone
14, which was quantitatively transformed on a gram scale into
the corresponding b-ketophosphonates 15a/b by using three
equivalents of lithiated methyl phosphonate (X-ray crystal
structure analysis in the Supporting Information).
The syntheses of the different aldehydes for the HWE
reactions are summarized in Scheme 2. The stereogenic
center of the R-configured aldehydes was established in
high diastereomeric excess (> 50:1) by stereoselective enolate
alkylation according to a procedure published by Myers
et al.[11] Reductive cleavage of the auxiliary with lithium
amidotrihydridoborate released (R)-2-methyl-1-butanol (16)
in 79% yield (two steps) with e.r. > 98:2, whereas (S)-2-
methyl-1-butanol (ent-16) is commercially available. Because
The synthesis of militarinone D (9) required aldehyde 23,
which was obtained by diastereoselective hydrogenation
under catalyst control (Scheme 3). The reliable generation
Scheme 3. a) 2 mol% [Ir(L1)cod]BArF , 50 bar H2, 78C, CH2Cl2, 4 h;
4
b) DIBAH, CH2Cl2, À788C; c) TPAP, NMO, CH2Cl2, 08C; d) ethyl 2-
(triphenylphosphoranylidene)propanoate, CH2Cl2, 358C; e) MnO2,
CH2Cl2; f) methyl 2-(diethoxyphosphoryl)acetate, LiCl, DBU, CH3CN,
08C. Abbreviations: ArF =3,5-bis(trifluoromethyl)phenyl, cod=cyclo-
octadiene.
of 1,3-syn-methyl arrays can be achieved by repeated
stereoselective enolate alkylations according to Myers.[11]
Other interesting approaches have been published, for
example, by the research groups of Breit,[19a] Feringa/Min-
naard,[19b] Negishi,[19c] and Burgess.[16c] As a streamlined
alternative, the iridium-catalyzed diastereoselective hydro-
genation of intermediate ester 17 under catalyst con-
Scheme 2. a) TPAP, NMO, CH2Cl2, 08C; b) ethyl 2-(triphenylphosphor-
anylidene)propanoate, CH2Cl2, 358C; c) DIBAH, CH2Cl2, À788C;
d) MnO2, CH2Cl2; e) methyl 2-(diethoxyphosphoryl)acetate, LiCl, DBU,
CH3CN, 08C; f) CrCl2, CHI3, 08C; g) (E)-3-(tributylstannyl)prop-2-en-1-
ol, [Pd(CH3CN)2Cl2], N-methyl-2-pyrrolidinone. Abbreviations:
DIBAH=diisobutylaluminum hydride, NMO=N-methylmorpholine
N-oxide, TPAP=tetrapropylammonium perruthenate.
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Communications
trol[16c,d,19d] would directly confer the syn or anti configuration
synthetic compounds were not separable by either standard
flash chromatography or by HPLC on a RP-18 column.
Gratifyingly, the E/Z isomers showed pronounced differences
in their retention times in HPLC on amyolse- or cellulose-
derived chiral stationary phases. HPLC separations were
conducted on a semipreparative scale with the UV detector
switched off, as otherwise again isomerization occurred. After
removal of the PMB group, the corresponding synthetic
natural products were isolated in multi-milligram quantities
with high enantiomeric purity and all-E configuration.
In addition to the natural products, their enantiomers (and
some additional Z isomers) were also isolated in relevant
amounts and evaluated in neurite outgrowth assays. The
absolute configuration of the natural products was deter-
mined by comparison of optical rotation values. In the case of
militarinone D (9), the synthetic product was mixed with an
authentic sample and analyzed by NMR spectroscopy.[20] The
absolute configuration of militarinone D (9) was established
as R,R and the absolute configuration of pretenellin B (1) and
farinosone A (5) was established as R. As pretenellin B (1)
was shown to be the direct precursor in the biosynthesis of
tenellin (2), the R configuration would also be expected for 2,
and most likely also for natural bassianin (4) and farinosone B
(6). In this context, the N-oxidation[21] of rac-pretenellin B (1)
has been described in the literature[22] and was identified as
the last step in the biosynthesis in a CYP-dependent
oxidation.[23]
of the two methyl groups in a single step. After extensive
screening (see the Supporting Information) of different
oxazoline- and pyridine-derived N,P ligands,[19e] we found
that the NeoPHOX ligand L1 can be used to generate the syn-
dimethyl configuration under optimized conditions in good
diastereoselectivity (> 99% conversion, d.r. = 12.4:1.0). Fur-
ther enrichment of the diastereomeric mixture to d.r. > 50:1
(after reduction to alcohol 21) was feasible with standard flash
chromatography.[19c]
The coupling of phosphonates 15a and 15b with the
corresponding aldehydes was addressed next. Diethylphos-
phonate 15b generally gave better E/Z ratios; however, this
derivative was not reactive enough to couple with the a-
branched aldehydes 18 and 22. In these cases, dimethyl-
phosphonate 15a was utilized as an efficient substitute
(Scheme 4). The phosphonates were prone to a range of
All compounds were evaluated in a standardized assay in
PC-12 cells[24] (rat pheochromocytoma) to assess their neu-
ritogenic potential. To this end, cells were grown on collagen-
coated 24-well plates and incubated for 2 days with the
compounds (c = 20 mm) in “Dulbeccoꢀs modified Eagle
medium” (DMEM), then fixed, stained with Giemsa, and
examined under a microscope. The ratio of differentiated cells
(at least one neurite with a length equal to one cell diameter)
to total cells per area was determined (Figure 1). In control
experiments, the effect of DMSO (0.1%) and nerve growth
factor (NGF 7S, 10 ngmLÀ1) was measured on each plate. At
Scheme 4. a) LiOH, H2O/THF; b) LiI, pyridinium chloride, THF, micro-
wave irradiation, 608C, 4 h; c) 2.5% TFA in CH2Cl2, 5 min.
side reactions, and careful optimization of the reaction
parameters provided conditions under which the formation
of by-products was almost completely suppressed. Finally,
2 equivalents of LiOH in a degassed THF/water (5:1) mixture
under exclusion of light and with a 1:1.2 ratio of phosphonate
to aldehyde furnished the protected natural products after 1–
4 days with yields ranging from 51 to 84% and in good
selectivities (E/Z 10:1 to 20:1). The subsequent cleavage of
the protecting groups generated additional problems; despite
the lability of the methyl ether, which was readily cleaved by
heating in the presence of 10 equivalents of sodium chloride,
we always observed partial isomerization of the a,b double
bond of the polyene system (6:1 in the case of pretenellin B,
2.5:1 in the case of farinosone A). The best ratios were
obtained by deprotection with freshly crystallized LiI in
degassed THF in the presence of pyridinium hydrochloride
under microwave irradiation. The E/Z mixtures of the
Figure 1. Neuritogenic activity of the pyridones in the PC-12 assay. All
values were determined at c=20 mm. Nerve growth factor (NGF)
control: 10 ngmLÀ1. DMSO control: 0.1%. Incubation period 2 days.
Number of counted cells >500. Error bars denote SEM.
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were evaluated for each compound.
The data obtained (Figure 1) reveal the general neurito-
genic activity of pyridone alkaloids in the PC-12 cell model.
Only little influence on the activity appears to arise from the
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pharmacophore. Furthermore, this study constitutes the first
report on the neuritogenic activity of pretenellin B (1) and
militarinone D (9), as well as the putative natural products
prebassianin B (3) and HJJ-510 (7). This general activity
might render 2-pyridones valuable lead structures for the
development of modulators of neurite outgrowth. In addition,
N-oxidation would lead to the corresponding hydroxamic
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chains on pyridones to access natural products with even
more structural diversity (e.g. the synthesis of ilicicolin H[26]).
In summary, we have reported a modular assembly for the
efficient stereoselective total synthesis of a whole family of
sensitive polyene pyridone natural products. Notable steps in
this convergent route include: 1) functionalization of a
densely substituted pyridone core structure by cross-coupling
reactions, 2) assembly of the polyenes under modified HWE
conditions, and 3) diastereoselective synthesis of the syn-
dimethyl array in 21 by iridium-catalyzed, stereoselective
hydrogenation. Furthermore, we were able to show that these
pyridone polyenes display general neuritogenic activity in the
PC-12 cell model. Detailed studies on the mechanism of
action of these natural products and the consequences of
these results on the stimulation of cognitive processes will be
carried out in our laboratories.
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Received: December 7, 2010
Published online: March 29, 2011
Keywords: farinosone A · militarinone D · neurite outgrowth ·
.
neurochemistry · pyridone alkaloids
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