Enantioselective total syntheses and absolute configuration of JBIR-02 and Mer-A2026B

Article abstract of DOI:10.1021/ol303502a

The first total syntheses of the piericidin related natural products Mer-A2026B and JBIR-02 are reported. Key features of the synthetic approach involve an Ir-catalyzed one-pot C-H activation/oxidation procedure for the preparation of the hydroxypyridine, a vinylogous Mukaiyama aldol reaction, and a final Negishi cross-coupling of an advanced pyridine derivative with an allylic side chain precursor. In addition, the absolute configuration of Mer-A2026B (9R,10R) and JBIR-02 (9R,10R) was established.

Full text of DOI:10.1021/ol303502a

ORGANIC
LETTERS
2013
Vol. 15, No. 3
670–673
Enantioselective Total Syntheses and
Absolute Configuration of JBIR-02 and
Mer-A2026B
Johannes Hoecker and Karl Gademann*
Department of Chemistry, University of Basel, St. Johanns-Ring 19, 4056 Basel,
Switzerland
karl.gademann@unibas.ch
Received December 21, 2012
ABSTRACT
The first total syntheses of the piericidin related natural products Mer-A2026B and JBIR-02 are reported. Key features of the synthetic approach
involve an Ir-catalyzed one-pot CꢀH activation/oxidation procedure for the preparation of the hydroxypyridine, a vinylogous Mukaiyama aldol
reaction, and a final Negishi cross-coupling of an advanced pyridine derivative with an allylic side chain precursor. In addition, the absolute
configuration of Mer-A2026B (9R,10R) and JBIR-02 (9R,10R) was established.
The piericidin class of natural products has been known
as potent inhibitors of the complex I electron transport
for decades, and several studies have highlighted the
structural similarity of these natural products to ubiqui-
none (coenzyme Q), a cofactor in NADH dehydrogenase
mediated electron transport.1 Inparticular, the dimethoxy-
pyridone core has served as a central structural argument
corroborating these observations.2 Surprisingly, members
of the piericidin family devoid of this dimethoxy motif
have received much less attention. Compounds such as
JBIR-023 and Mer-A2026B4 lack the 40-oxygenation of the
piericidins but otherwise share many of their structural
features regarding the pyridone core and the polyene side
chain (Figure 1). Interestingly, JBIR-02 was reported as an
inhibitor of nucleocytoplasmic transport,3 which is appeal-
ing as these pyridones would constitute a new lead struc-
ture for inhibitors of this important biological process.5f
We have investigated this phenomenon in the context of
our studies on the anguinomycins, where we could identify
structural features responsible for biological activity.5a,b
In addition, JBIR-02 and Mer-A2026B share structural
similarity to the neuritogenic pyridone polyenes such as
militarinone D or torrubiellone C recently investigated in
our group.5cꢀe
(1) Nelson, D. L.; Cox, M. M. Lehninger Principles of Biochemistry;
Worth: New York, 2000; Chapter 19.
(2) Total synthesis of piericidin A1: (a) Schnermann, M. J.; Boger,
D. L. J. Am. Chem. Soc. 2005, 127, 15704–15705. (b) Schnermann, M. J.;
Romero, F. A.; Hwang, I.; Nakamura-Ogiso, E.; Yagi, T.; Boger, D. L.
J. Am. Chem. Soc. 2006, 128, 11799–11807. (c) Lipshutz, B. H.; Amorelli,
B. J. Am. Chem. Soc. 2009, 131, 1396–1397. (d) Kikuchi, R.; Fujii, M.;
Akita, H. Tetrahedron: Asymmetry 2009, 20, 1975–1983. (e) Total
synthesis of 7-demethylpiericidin A1: Phillips, A. J.; Keaton, K. A.
J. Am. Chem. Soc. 2006, 128, 408–409.
(3) Ueda, J.; Togashi, T.; Matukura, S.; Nagai, A.; Nakashima, T.;
Komaki, H.; Anzai, K.; Harayama, S.; Doi, T.; Takahashi, T.; Natsume,
T.; Kisu, Y.; Goshima, N.; Nomura, N.; Takagi, M.; Shin-ya, K.
J. Antibiot. 2007, 60, 459–462.
(4) (a) Kominato, K.; Watanabe, Y.; Hirano, S.-I.; Kioka, T.;
Terasawa, T.; Yoshioka, T.; Okamura, K.; Tone, H. J. Antibiot. 1995,
48, 103–105. (b) Hirano, S.; Watanabe, Y.; Kaichiro, K.; Agata, N.;
Hara, Y.; Shibamoto, N.; Yoshioka, T.; Kioka, T.; Iguchi, H.; Shirai,
M.; Tone, H.; Okamoto, R. European Patent EP0491281A1, 1991.
€
(5) (a) Bonazzi, S.; Guttinger, S.; Zemp, I.; Kutay, U.; Gademann, K.
Angew. Chem., Int. Ed. 2007, 46, 8707–8710. (b) Bonazzi, S.; Eidam, O.;
Guttinger, S.; Wach, J.-Y.; Zemp, I.; Kutay, U.; Gademann, K. J. Am.
€
Chem. Soc. 2010, 132, 1432–1442. (c) Review: Jessen, H. J.; Gademann,
K. Nat. Prod. Rep. 2010, 27, 1168–1185. (d) Jessen, H. J.; Schumacher,
A.; Shaw, T.; Pfaltz, A.; Gademann, K. Angew. Chem., Int. Ed. 2011, 50,
4222–4226. (e) Jessen, H. J.; Schumacher, A.; Schmid, F.; Pfaltz, A.;
Gademann, K. Org. Lett. 2011, 13, 4368–4370. (f) Review: Gademann,
K. Curr. Drug Targets 2011, 12, 1574–1580.
r
10.1021/ol303502a
Published on Web 01/18/2013
2013 American Chemical Society

unsuccessful. Selective O-SEM protection to direct the
aromatic functionalization in the next steps was accom-
plished using SEMCl. The correct substitution pattern at
the heteroaromatic ring was installed by sequential two-fold
Li halogen exchange using n-BuLi in THF at ꢀ78 °C: (1)
trapping of the stabilized C20-lithiated aryl species with MeI
(for C20 substitution) followed by (2) protonation with
MeOH (for the C40 position) completed the target fragment
6 with the correct substitution pattern in 67% yield over two
steps. Apparently, the donor capacity of the neighboring
bromine is higher than the stabilizing effect of the methoxy
group. This strategy was found to be superior to ortho-
metalation, in which even bulky non-nucleophilic bases
such as LDA or LiTMP resulted in nucleophilic substitution
of the bromo substituent and could not be suppressed by
varying the reaction conditions.
The polyene side chain synthesis was addressed next.
As the configuration of both target compounds was un-
known, we assumed the same absolute configuration as
established for piericidin A1. The preparation of the side
chain started with a vinylogous Mukaiyama aldol reaction
developed by Kobayashi and co-workers.7 Treatment of
N,O-silyl ketene acetal 7 and bromoacrylate 98 provided
the desired hydroxyl imide 10 via a TiCl4 mediated CꢀC
bond forming reaction with exclusive formation of one
diastereomer (1H NMR > 50:1) in 91% yield (12 mmol
scale). The absolute configuration at C9 and C10 was
established by the X-ray crystal structure analysis of the
aldol product 10 (Scheme 2).
Figure 1. Structures of Piericidin A1, JBIR-02, 1 (R = C4H7),
and Mer-A2026B, 2 (R = CH3).
The combination of structural features with the reported
mechanism of action for these compounds leads to the
hypothesisthatsmall variationsonthe pyridonecorecould
result in a large variation of selectivity for biological tar-
gets.5 As there are, to the best of our knowledge, no
published reports on compounds lacking the 40-methoxy
group, we wanted to develop synthetic access to JBIR-02
and Mer-A2026B, which should also allow for the assign-
ment of the unknown absolute and relative configuration
of the two stereogenic centers of these compounds. In this
communication, we report the total synthesis and absolute
configuration of JBIR-02 and Mer-A2026B.
Scheme 1. Synthesis of the Heteroaromatic Intermediate 6
(Positions Labeled 20 and 40 Refer to the Piericidin
Nomenclature)
Scheme 2. Kobayashi’s Vinylogous Mukaiyama Aldol Reac-
tion7a
The total synthesis started with the preparation of
the protected bromopyridinol 6 in five steps, as shown
in Scheme 1. Commercially available 2-bromo-6-methox-
ypyridine was converted to pyridinol 3 in 79% yield by a
CꢀH activation reaction using 2 mol % of [Ir(COD)OMe]2,
4 mol % of 4,40-di-tert-butyl-2,20-bipyridine (dtbpy), and
pinacolborane (pinBH) in hexane at room temperature,
followed by oxidation of the crude boronic acid inter-
mediate with oxone in THF.6 Subsequent treatment with
N-bromosuccinimide (NBS) afforded tribromopyridinol 4
in 92% yield, as attempts to selectively monofunctionalize
C20 with different electrophilic bromination reagents were
Silylation of hydroxyl imide 10 with TBSOTf in the
presence of 2,6-lutidine in CH2Cl2 at ꢀ78 °C, followed by
the removal of the chiral auxiliary in a two-step process via
reduction with NaBH4 and oxidation of the allylic alcohol
with activated MnO2, afforded aldehyde 11 in 87% over
(7) (a) Shirokawa, S.; Kamiyama, M.; Nakamura, T.; Okada, M.;
Nakazaki, A.; Hosokawa, S.; Kobayashi, S. J. Am. Chem. Soc. 2004,
126, 13604–13605. (b) Paterson, I.; Kan, S. B. J.; Gibson, L. J. Org. Lett.
2010, 12, 3724–3726.
(8) Murakami, Y.; Nakano, M.; Shimofusa, T.; Furuichi, N.;
Katsumura, S. Org. Biomol. Chem. 2005, 3, 1372–1374.
(6) CꢀH activation: (a) Ishiyama, T.; Nobuta, Y.; Hartwig, J. F.;
Miyaura, N. Chem. Commun. 2003, 2924–2925. (b) Maleczka, R. E., Jr.;
Shi, F.; Holmes, D.; Smith, M. R., III. J. Am. Chem. Soc. 2003, 125,
7792–7793.
Org. Lett., Vol. 15, No. 3, 2013
671

Scheme 3. Synthesis of the Polyene Side Chain
three steps. Elongation to the unsaturated ester 12 was
achieved by a HornerꢀWadsworthꢀEmmons (HWE)
reaction applying a protocol developed by Masamune
and Roush to avoid partial epimerization at C9.9 When
the scope of this strategy was expanded, this transformation
allows, in principle, the introduction of different residues at
C5ꢀas for example CH3 present in natural piericidinsꢀby
changing the phosphonate coupling partner.
ratio of 5:1 as its E- and Z-isomers. Both isomers could be
separated for both 17a and 17b by preparative HPLC with
hexane/iPrOH (99.5:0.5) as solvent.
Scheme 4. Possible Mechanism for the Isomerization during
Allylic Substitution with Stannane 16
Cross-coupling of vinyl bromide 12 under Stille condi-
tions (Pd(PtBu3)2 (10 mol %), LiCl, NMP, 80 °C) with
stannane 13, derived from commercially available (E)-2-
bromo-2-butene by lithiation and quenching with Bu3SnCl,
afforded tetraene 14a in very good yield. Under these condi-
tions, isomerization of the terminal methyl group could be
avoided (see Supporting Information).
The vinylogous Mukaiyama aldol reaction with the
more complex substrate (2E,4E)-2,4-dimethylhexa-2,-
4-dienal 8 (Scheme 2) as coupling partner targeting the
identical side chain was found to be unsuccessful under
the previously described conditions. This finding could be
explained by the extended conjugation, transforming the
dienal in a rather unreactive coupling partner toward nu-
cleophilic attack.10 Using the opportunity to transform 12
by transition metal catalysis into a number of natural
piericidins (Scheme 3), the vinylbromide was elongated at
C12 by Suzuki coupling (Pd(PPh3)4 (5mol%),CH3B(OH)2,
Cs2CO3, dioxane, H2O, 65 °C) to triene 14b in 69% yield.
DIBAH reduction of esters 14 followed by acetylation
produced the allylic acetates 15 as precursors for the first
allylic substitution(90% for 15a and 95% for 15b, over two
steps). To remove traces of AcOH, which led to signifi-
cantly reduced yields, Ac2O was filtered through a small
column of Al2O3 before use. Next, allylic substitution
using Pd(dba)2, LiCl, DIPEA, and hydroxystannane 1611
at 45 °C for 3 h delivered 17a (90%) and 17b (77%) in a
Interestingly, the isomerization could be observed at the
olefinic linkage between C7 and C8. A reasonable mechan-
ism for the isomerization is shown in Scheme 4. Upon
treatment with Pd catalyst and formation of the Pd-allyl
complex, isomerization of this complex along the chain is
likely to occur. Due to the allylic strain of the adjacent
methyl groups, this complex could isomerize to the ther-
modynamically more stable Z-olefin and react further with
stannane 16 to afford (7Z)-17. This ratio could not be
improved by exploring different reaction parameters such
as catalyst, reaction time, and temperature. Next, (7E)-
allylic alcohols 17a/b were transformed to their corre-
sponding carbonates 18a/b (CH3OCOCl, Et3N at 0 °C),
thereby generating a suitable leaving group for the sub-
sequent allylic substitution.
(9) Blanchette, M.; Choy, W.; Davis, J. T.; Essenfeld, A. P.;
Masamune, S.; Roush, W. R.; Sakai, T. Tetrahedron Lett. 1984, 25,
2183–2186.
The crucial connection of both moieties, the 4-hydroxy-
pyridine core and the fully elaborated polyene chain, was
realized after extensive experimentation on the Negishi
cross-coupling reaction and proved to be mild enough to
(10) (a) Bock, M.; Dehn, R.; Kirschning, A. Angew. Chem., Int. Ed.
2008, 47, 9134–9137. (b) Nakamura, Y.; Kiyota, H.; Baker, B. J.;
Kuwahara, S. Synlett 2005, 635–636.
(11) Betzer, J.-F.; Delaloge, F.; Muller, B.; Pancrazi, A.; Prunet, J.
J. Org. Chem. 1997, 62, 7768–7780.
672
Org. Lett., Vol. 15, No. 3, 2013

Scheme 5. Completion of the Synthesis of JBIR-02 and Mer-A2026B
avoid isomerization or decomposition.12 The protected
Br-pyridinol 6 was lithiated using n-BuLi in THF at
ꢀ78 °C. After 10 min, ZnCl2 was added and the resulting
mixture was allowed to warm to room temperature over 1 h
to form a relatively stable 2-pyridylzinc reagent13 which was
exposed to a freshly prepared mixture of carbonate 18 and
5 mol % of Pd(PPh3)4 and warmed to 50 °C for 3 h to
provide 19a (69% over two steps) and 19b (65%) without
detectable isomerization (Scheme 5). The Negishi condi-
tions proved superior to Sn-based cross-coupling, in which
significant isomerization was observed.2e Final deprotec-
tion was achieved by treatment with TBAF at elevated
temperatures (70 °C, THF) to produce JBIR-02 (1, 82%)
and Mer-A2026B (2, 93%) in good yield.
The comparison of spectra of natural and synthetic
samples was carried out next, to confirm the reported
structures and to assign the absolute configuration. The
spectroscopic data of synthetic Mer-A2026B (2) were
found to be identical in all respects (1H, 13C NMR, UV
spectra, and optical rotation: [R]D =ꢀ1.1 (c= 0.11, MeOH)
lit. [R]D = ꢀ1.07 (c = 0.36, MeOH)) to those reported in the
literature for the natural product.14 For JBIR-02, confir-
mation of the structure proved to be more complex.
At first, several key signals of the aromatic core in the 1H
NMR spectra displayed different chemical shifts when
compared to the reported data of the natural product.
Therefore, a synthetic sample of JBIR-02 was compared to
a natural one by NMR under the same conditions (solvent,
NMR tube, and concentration), and the identity of spectra
could be observed.15 The final proof of identical constitu-
tion of synthetic and natural samples of JBIR-02 was
established by co-injection of both samples and analysis
by UHPLC.14 Apparently, the amount of water and/or
the amount of acid in the CDCl3 solution can lead to the
observation of tautomerism and, therefore, drastically
different spectra. Interestingly, the pyridone form of these
piericidin analogues has rarely been observed (see also the
work of Boger and co-workers2a,b). The optical rotation
([R]D = ꢀ11.1 (c = 0.21, MeOH)) matched its literature
value ([R]D = ꢀ13.0 (c = 0.88, MeOH)) and thereby estab-
lished the absolute configuration of 1.
In conclusion, the first total syntheses of piercidin
derivatives Mer-A2026B and JBIR-02 (longest linear se-
quence 12 steps, overall yield 28% for 1 and 20% for 2)
were developed, and the absolute configuration could be
established as (9R,10R). Salient features of this efficient
and convergent synthetic route are (1) a highly diastereo-
selective KobayashiꢀMukaiyama aldol reaction, (2) a
CꢀH activation reaction in combination withanoxidation
protocol for the preparation of the highly functionalized
pyridine moiety, and (3) a final Negishi cross-coupling
reaction without isomerization of the labile side chain.
Furthermore, this strategy opens up the stage for the
synthesis of a number of piericidins by simply changing
the coupling partner for the HWE reaction (C5 analogues)
or the organometallic species for the cross-coupling reac-
tion (C12 functionalization). Studies targeting these deri-
vatives are underway in our laboratories.
Acknowledgment. Financial support by the Swiss Na-
tional Science Foundation (200021_144028 and PE002-
117136/1) is gratefully acknowledged. We thank Dr. M.
€
Neuburger for X-ray analysis, and Dr. D. Haussinger and
(12) Negishi, E.; Liu, F. Handbook of Organopalladium Chemistry for
Organic Synthesis; Negishi, E., Ed.; Wiley: New York, 2002; pp 551ꢀ589.
(13) Selected 2-pyridylzinc reagents: (a) Luzung, M. R.; Patel, J. S.;
Yin, J. J. Org. Chem. 2010, 75, 8330–8332. (b) Klosterman, J. K.;
Linden, A.; Siegel, J. S. Org. Biomol. Chem. 2008, 6, 2755–2764. (c)
H. Gsellinger (all University of Basel) for NMR analysis
support. Further, we sincerely thank Prof. Dr. K. Shin-ya
and Dr. M. Izumikawa (bothAIST Japan) for measuring a
sample of synthetic 1, sending us an authentic sample of
natural 1, and helpful discussions.
€
Kiehne, U.; Bunzen, J.; Staats, H.; Lutzen, A. Synthesis 2007, 1061–
1069. (d) Sammakia, T.; Stangeland, E. L.; Whitcomb, M. C. Org. Lett.
ꢀ
2002, 4, 2385–2388. (e) Mongin, F.; Trecourt, F.; Mongin, O.;
ꢀ
Queguiner, G. Tetrahedron 2002, 58, 309–314. (f) Savage, S. A.; Smith,
Supporting Information Available. Detailed experimen-
tal procedures, full characterization, and copies of all
spectra. This material is available free of charge via the
Internet at http://pubs.acs.org.
A. P.; Fraser, C. L. J. Org. Chem. 1998, 63, 10048–10051.
(14) See Supporting Information for details.
(15) The identity of natural and synthetic JBIR-02 was confirmed by
1H, 13C NMR, and UHPLC measurements by Dr. Izumikawa in the
laboratories of Prof. Dr. Shin-ya (National Institute of Advanced
Industrial Science and Technology (AIST)) and later in our laboratories
by 1H and 13C NMR spectroscopy.
The authors declare no competing financial interest.
Org. Lett., Vol. 15, No. 3, 2013
673