Total synthesis of piericidin A1. application of a modified negishi carboalumination-nickel-catalyzed cross-coupling

Full text of DOI:10.1021/ja809542r

Published on Web 01/12/2009
Total Synthesis of Piericidin A1. Application of a Modified Negishi
Carboalumination-Nickel-Catalyzed Cross-Coupling
Bruce H. Lipshutz* and Benjamin Amorelli
Department of Chemistry and Biochemistry, UniVersity of California, Santa Barbara, California 93106
Received December 11, 2008; E-mail: lipshutz@chem.ucsb.edu
Piericidin A1 (1) is a metabolite of Streptomyces mobaraensis
and S. pactum. It is a potent inhibitor of complex I (Ki ) 0.6-1.0
µm)1 in the mitochondrial electron transport chain sequence, where
protein NADH:ubiquinone oxidoreductase (or NADH dehydroge-
nase) is responsible for the oxidation of NADH to NAD+ using
coenzyme Q10 (ubiquinone, 2) as the hydride acceptor. Coenzyme
Q10 (2) has also been reported to act as a potent endogenous
antioxidant for the treatment of cancer and the relief of side effects
caused by some cancer therapies.2 Analogues of coenzyme Q10 have
been shown to suppress cancer growth directly,3 and therefore the
competitive binding of piericidin A1 against complex I implicates
its biological potential making it an attractive synthetic target.4
The protected chloromethyl pyridinol 4 was prepared in seven
steps from the N-p-methoxybenzyl-3-aminotiglate 5 (Scheme 2; see
Supporting Information, SI). Acylation with methoxyacetyl chloride
generated methoxyacetamido aminotiglate 6, which underwent base
promoted Dieckmann cyclization8 to the corresponding 2-pyridone
7. Attempted cyclizations with hexamethyldisilazane bases gave
very low yields of the desired pyridone (7) at the expense of
isomerization to the E-isomer of 6. Treatment of 7 with TFA while
heating in a sealed reaction flask followed by selective O-silylation
gave 2-pyridone 9. The heterocyclic chloride coupling partner 4
was obtained ultimately from an alkylative aromatization (CH3I,
Ag2CO3) followed by ortho-methyl chlorination with tert-butyl-
lithium/hexachloroethane.
Scheme 2. Preparation of Chloromethylated Picoline 4
Our approach to a practical synthesis of piericidin A15 highlights
a modified Negishi carboalumination followed by a Ni-catalyzed
cross-coupling strategy recently introduced. This powerful strategy
allows for couplings of benzylic chlorides and in situ generated
vinylalanes, arrived at via stereoselective carboalumination of
terminal alkynes.6,7 Within the context of natural products total
synthesis, however, the tolerance of multifunctionalized terminal
alkynes had yet to be investigated. Moreover, notwithstanding the
efficiency with which quinones and benzylic/heterobenzylic chlo-
rides can be coupled to vinylalanes, piericidin A1 also features a
fully fashioned, pentasubstituted pyridyl heterocyclic core.
Retrosynthetically, the key disconnection (Scheme 1) features a
penultimate one-pot Ni-catalyzed coupling of vinylalane 3, gener-
ated in situ via a modified carboalumination,6 to the chloromethy-
lated pyridine 4. The skipped enyne is anticipated by a propargyl
selective (over allenyl) coupling of a corresponding vinyl iodide
and TMS-propyne. A vinylogous Mukaiyama aldol reaction gener-
ates the eight carbon vicinal methyl/hydroxyl side chain framework.
The required acetylenic side chain precursor was assembled from
an initial TiCl4-promoted remote 1,6,7-asymmetric vinylogous
Mukaiyama aldol reaction between D-valine derived N,O-silyl
ketene acetal 119 and tiglic aldehyde. This coupling provided the
vicinal methyl/hydroxyl imide 12 in reasonable yield (Scheme 3).10
Silylation with TBSCl in DMF, followed by removal of the chiral
auxiliary with DIBAL in THF at -78 °C, gave enal 14. The
alternative two-step process via reduction to the corresponding
allylic alcohol (NaBH4, THF, H2O) followed by oxidation (MnO2,
CH2Cl2, 88% overall) to 14 was employed in larger scale reactions
due to the expected better stability profile for the allylic alcohol
on storage relative to that of enal 14. Direct Takai homologation11
to vinyl iodide 16 consistently gave a mixture of the desired trans-
iodide and an inseparable homologated trans-olefinic coproduct.
Therefore, a two-step procedure was developed. Alkynylation of
14 with the Bestmann-Ohira diazophosphonate12 gave reproducibly
moderate yields of enyne 15 regardless of variations in the addition
of reagent or reaction temperature. The mass balance, however,
Scheme 1. Restrosynthetic Analysis of Piericidin Al
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1396 J. AM. CHEM. SOC. 2009, 131, 1396–1397
10.1021/ja809542r CCC: $40.75
2009 American Chemical Society

C O M M U N I C A T I O N S
Scheme 3. Preparation of Alkyne Coupling Partner 18 and Completion of the Synthesis of Piericidin Al
was recovered as starting material. Attempts to apply the typical
Corey-Fuchs and TMS-diazomethane promoted alkynylations were
also unsuccessful, as each protocol gave products that were difficult
toseparatefromthedesirednonpolaralkyne.Hydrozirconation-iodination
of enyne 15 with in situ prepared Schwartz’s reagent followed by
I2 quench gave the vinyl iodide 16.13 The use of Schwartz’s reagent
was far superior to attempts at preparing vinyl iodide 16 with
Bu3SnH/(PPh3)2PdCl2.14 Propargyl coupling15 of 16 with TMS-
propyne gave unstable skipped enyne 17, which was converted
immediately with K2CO3 in MeOH to the desired terminal acetylene
18, accompanied by the corresponding vinyl allene 19. The extent
of isomerization to allene 19 in the presence of excess K2CO3 at rt
was minimized when protiodesilylation was conducted at 0 °C.
The crucial carboalumination of terminal alkyne 18 was effected
with catalytic Cp2ZrCl2, trimethylaluminum, and isobutylalumi-
noxane6 in DCM. Once complete, the Ni(0) catalyst was added at
-50 °C followed by the coupling partner 4, after which the reaction
was warmed to 0 °C. Without isolation, subsequent removal of the
silyl protecting groups (TBAF, THF, 50 °C) afforded piericidin
A1 in 58% yield from alkyne 18. Comparison of spectral data of
this material to that published,5 including superimposable 1H NMR
spectra16 as well as a 13C NMR, HRMS, and specific rotation,
confirm the assignment of our synthetic material as piericidin A1.
In summary, piericidin A1 (1) has been synthesized in a total of
18 steps from commercial material. The route involves a longest
linear sequence of 11 steps (9 pots) from the N,O-silyl ketene acetal
11, which overall compares very favorably with the previous
synthesis of 1.5 A carboalumination/Ni-catalyzed cross-coupling
applied to two complex partners highlights the potential of this
technology in natural products total synthesis.
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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Acknowledgment. Financial support provided by the NIH (GM
40287) is warmly acknowledged.
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