Total synthesis of piericidin A1 and B1

Article abstract of DOI:10.1021/ja055041f

The first total syntheses of piericidin A1 and B1 are disclosed and unambiguously establish the relative and absolute stereochemistry of the natural products by an approach that will facilitate the synthesis of a series of analogues. Central to the approach is an inverse electron demand Diels-Alder reaction of a N-sulfonyl-1-aza-1,3-butadiene with tetramethoxyethene followed by Lewis acid-promoted aromatization used to assemble the functionalized pyridine core. Additional key elements in the convergent approach include the use of an anti-aldol reaction to install the C9 and C10 relative and absolute stereochemistry, a modified Julia olefination for formation of the C5-C6 trans double bond with convergent assemblage of the side chain, and a penultimate heterobenzylic Stille cross-coupling reaction of the pyridyl core with the fully elaborated side chain. Copyright

Full text of DOI:10.1021/ja055041f

Published on Web 10/22/2005
Total Synthesis of Piericidin A1 and B1
Martin J. Schnermann and Dale L. Boger*
Department of Chemistry and The Skaggs Institute for Chemical Biology, The Scripps Research Institute, 10550
North Torrey Pines Road, La Jolla, California 92037
Received July 26, 2005; E-mail: boger@scripps.edu
Scheme 1. Synthesis of the Pyridine Core
The piericidins are an important class of biologically active
natural products isolated from Streptomyces mobaraensis and S.
pactam of which piericidin A1 (1) is the prototypical member.1
Piericidin A1 is one of the most potent inhibitors of the mitochon-
drial electron transport chain protein NADH-ubiquinone reductase
(complex I, Ki ) 0.6-1.0 nM) defined to date and has contributed
extensively to the elucidation of the enzyme properties.1 It has been
suggested that the 4-hydroxypyridine of 1 (as the pyridone tautomer)
mimics the quinone of ubiquinone (coenzyme Q, 3) with the side
chain of 1 mimicking the prenyl chain, and this apparent structural
relationship was confirmed through their competitive binding
against complex I.2-4
such electron-deficient N-sulfonylazadienes substituted with an
additional C2 electron-withdrawing substituent,12a,b the Diels-Alder
reaction of 7 with the electron-rich dienophile 5 was found to
proceed at or near room temperature, even though 5 is tetrasub-
stituted and sterically demanding. Efforts to induce aromatization
of 8 under a variety of basic conditions were not successful, whereas
the use of the Lewis acid BF3‚OEt2 cleanly affected this transfor-
mation (CH2Cl2, 0 °C, 1 h, 88%). Reduction of the ethyl ester 9
with DIBAL (CH2Cl2, 0 °C, 1 h, 92%) followed by protection of
the resulting alcohol 10 as its TIPS ether provided 11 (TIPSCl,
imidazole, DMF, 25 °C, 18 h, 95%). It was envisioned that directed
lithiation of the remaining site on the pyridine ring followed by a
borylation/oxidation sequence would permit incorporation of the
remaining oxygen substituent at C4′.15 Thus, treatment of 11 with
excess base followed by trimethylborate (5 equiv of BuLi, 6 equiv
of B(OMe)3, -78 °C, 1 h, 88%) and oxidative cleavage of the
resulting aryl boronate ester unexpectedly provided the C-silylated
species 12, resulting from both the desired C4′ hydroxylation and
a competitive reverse Brook rearrangement of the benzylic TIPS
ether under the strongly basic conditions.16 The use of fewer
equivalents of base results in the migrated, non-oxidized product,
and the use of alternative silyl ether protecting groups (TBS and
TBPDS) or the free alcohol 10 itself resulted in lower yields of
the diol 13. The deprotection of 12 proceeded cleanly and,
interestingly, through the O-silylated intermediate S116 (Bu4NF,
THF, 30 min, 25 °C, 80%) resulting from a Brook rearrangement,
to give 13 (Bu4NF, THF, 36 h, 25 °C, 96% overall). Conversion
of 13 to the heterobenzylic bromide 14 (CBr4, PPh3, CH2Cl2,
25 °C, 84%) provided a surprisingly stable partner for the Stille
cross-coupling.
Despite an array of additional important biological activity, no
total synthesis of a member of this now large class of natural
products has been disclosed. In efforts directed at this family, the
preparation of the fully elaborated pyridine ring system substituted
with simplified side chains has been reported,5 as well as an
asymmetric synthesis of the C6-C13 segment of the side chain
bearing the most recent stereochemical assignment (9R,10R).6
Notably, the originally assigned absolute stereochemistry7 of the
side chain substituents of 1 has been challenged, reassigned, and
remained to be determined.8,9
Herein we detail the first total synthesis of piericidin A1 and
B1 by an approach that establishes the absolute stereochemistry of
the natural products and will facilitate the synthesis of a series of
key analogues. Central to the approach is an inverse electron
demand Diels-Alder reaction between a N-sulfonyl-1-aza-1,3-
butadiene10 and tetramethoxyethene11 followed by Lewis acid-
promoted aromatization used to assemble the functionalized pyridine
core.12 Additional key elements in the convergent approach include
the use of an asymmetric anti-aldol reaction to install the C9 and
C10 relative and absolute stereochemistry, a modified Julia olefi-
nation for formation of the C5-C6 trans double bond with
convergent assemblage of the side chain, and a penultimate
heterobenzylic Stille cross-coupling reaction of the pyridyl core
with the fully elaborated side chain.
The key N-sulfonyl-1-aza-1,3-butadiene 7 was accessed through
a two-step sequence initiated by oxime formation of the ketone 413
(NH2OH-HCl, EtOH, 25 °C, 18 h, 96%) (Scheme 1). Treatment
of the oxime 6 with Et3N and methylsulfinyl chloride led to
formation of the O-methanesulfinate and in situ homolytic rear-
rangement to give sulfonylimine 7 (CH3SOCl, Et3N, CH2Cl2, 0 °C,
20 min).14 Treatment of 7 with tetramethoxyethene11 (5, 18 h,
toluene, 50 °C, 64% for two steps from 6) smoothly afforded the
[4 + 2] cycloadduct 8. Characteristic of the unusual reactivity of
Synthesis of the side chain C2-C5 segment consisted of the
preparation of the vinyl iodide 17 appropriately substituted for
Julia-Kocienski olefination17 coupling with the C6-C13 side chain
aldehyde 21, accessible from the known alcohol 20.6 This was
accomplished through the reaction of alcohol 1518 with 1-phenyl-
1H-tetrazole-5-thiol (PTSH) under Mitsunobu conditions (DEAD,
9
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J. AM. CHEM. SOC. 2005, 127, 15704-15705
10.1021/ja055041f CCC: $30.25 © 2005 American Chemical Society

C O M M U N I C A T I O N S
a larger optical rotation value, was also conducted.23 Thus, selective
protection of the pyridine hydroxyl of 1 as its pivolate ester 25
(PivCl, HSO4NBu4, aqueous 5 N NaOH-CH2Cl2, 25 °C, 92%),
followed by O-methylation of the secondary alcohol 25 (NaH, MeI,
DMF, 25 °C, 1 h, 78%), and finally pivolate hydrolysis of 26 (t-
BuONa, MeOH, 60 °C, 3 h, 88%) provided 2. Synthetic piericidin
B1 proved to be identical in all respects with properties reported
Scheme 2. Synthesis of 17
25
for natural 2, including its optical rotation ([R]D -7.3 (c 0.2,
Scheme 3. Synthesis of Piericidin A1 and B1
18
MeOH) vs lit23 [R]D -6.5 (c 3.2, MeOH)), thereby further
confirming the absolute configuration assignment for 1 and 2.
Throughout these studies and the handling of 1, 2, 12, 13, 14,
and 24, only the 4-hydroxypyridine tautomer, and not the 4-pyridone
tautomer, was observed even in protic solvents. Provocatively, this
suggests that the ability of 1 to bind and inhibit NADH-ubiquinone
reductase (complex I) may result from mimicry of reduced
coenzyme Q (hydroquinone) and rather than 3 itself. The synthesis
of a series of analogues based on the natural products are underway
and will probe such questions.
Acknowledgment. We gratefully acknowledge the financial
support of the National Institutes of Health (CA 42056), and the
Skaggs Institute for Chemical Biology. M.J.S. is a Skaggs Fellow.
Supporting Information Available: Full experimental details. This
material is available free of charge via the Internet at http://pubs.acs.org.
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3). A modified Julia coupling between 17 and 21 cleanly provided
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employed by Fu,21 and LiCl as an additive to achieve good
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25
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and magnitude of the reported optical rotation for 1 ([R]D +1.8
25
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