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. Author manuscript; available in PMC: 2012 Jun 1.
Published in final edited form as: J Am Chem Soc. 2009 Feb 4;131(4):1396–1397. doi: 10.1021/ja809542r

Total Synthesis of Piericidin A1. Application of a Modified Negishi Carboalumination-Nickel-Catalyzed Cross-Coupling

Bruce H Lipshutz 1,*, Benjamin Amorelli 1
PMCID: PMC3365511  NIHMSID: NIHMS91536  PMID: 19138148

Abstract

A total synthesis of the mitochondrial complex I inhibitor piericidin A1 is described. It features a unique strategy for the key disconnection, highlighting a modified Negishi carboalumination/Ni-catalyzed cross-coupling on a polyenyne precursor.

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 dehydrogenase) 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

graphic file with name nihms91536f4.jpg

Our approach to a practical synthesis of piericidin A15 highlights a modified Negishi carboalumination followed by 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 chlorides 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, generated in situ via a modified carboalumination,6 to the chloromethylated pyridinol 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 generates the eight carbon vicinal hydroxymethyl side chain framework.

Scheme 1.

Scheme 1

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Retrosynthetic Analysis of Piericidin A1

The chloromethyl pyridinol 4 was prepared in seven steps from the N-p-methoxybenzyl-cis-3-aminotiglate 5 (Scheme 2; see SI). Acylation with methoxyacetyl chloride generated the cis-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-aminotiglate. Treatment of 7 with TFA while heating in a sealed reaction flask followed by selective O-silylation gave 2-pyridone 9. The heterobenzylic chloride coupling partner 4 was ultimately obtained from an alkylative aromatization (CH3I, Ag2CO3) followed by ortho-benzylic chlorination with t-butyllithium/hexachloroethane.

Scheme 2.

Scheme 2

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Preparation of Chloromethylated Picoline 4

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 hydroxymethyl 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, 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 to separate from the desired nonpolar alkyne. Hydrozirconation-iodination of enyne 15 with in situ prepared Schwartz’ reagent followed by I2 quench gave the vinyl iodide 16.13 The use of Schwartz’ 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 proteodesilylation was conducted at 0 °C.

Scheme 3.

Scheme 3

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Preparation of Alkyne Coupling Partner 18, and Completion of the Synthesis of Piericidin A1

The crucial carboalumination of terminal alkyne 18 was effected with catalytic Cp2ZrCl2, trimethylaluminum, and isobutylaluminoxane6 in DCM. Once complete, the Ni(0) catalyst was added at −50 °C followed by the heterobenzylic chloride 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 on 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 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 joins two of the most complex partners reported to date using this technology in natural products total synthesis.

Supplementary Material

1_si_001

Acknowledgement

Financial support provided by the NIH (GM 40287) is warmly acknowledged.

Footnotes

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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Associated Data

This section collects any data citations, data availability statements, or supplementary materials included in this article.

Supplementary Materials

1_si_001
NIHMS91536-supplement-1_si_001.pdf (2.5MB, pdf)

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