Prostaglandins and prostaglandin intermediates. 25. Synthesis of PGF<sub>2α</sub> Intermediates by addition of 1‐metalated hept‐1‐ynes to a substituted cyclopentanecarbaldehyde bearing already the complete carboxylic side chain

Mahrwald, Rainer; Schick, H.; Vasil'eva, L. L.; Pivnitsky, K. K.; Weber, Gisela; Schwarz, S.

doi:10.1002/prac.19903320206

Cited by 8 publications

(4 citation statements)

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“…Efficient addition of the vinylcerium reagent generated from 13 to ketone 63 necessitated slowly warming the reaction mixture to room temperature overnight (Scheme ). Silylation of tertiary allylic alcohol product 64 , followed by Swern oxidation of the primary TES ether, , afforded aldehyde 65 in 77% yield over two steps. Exposure of aldehyde 65 to trimethylorthoformate and a catalytic amount of pyridinium p -toluenesulfonate (PPTS) provided the requisite alkenyl acetal Prins–pinacol precursor 66 bearing the C15 methyl group …”

Section: Resultsmentioning

confidence: 99%

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Canham

Overman

2012

J. Org. Chem.

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This article describes synthetic studies that culminated in the first total synthesis of the Lycopodium alkaloid sieboldine A. During this study a number of pinacol-terminated cationic cyclizations were examined to form the cis-hydrindanone core of sieboldine A. Of these, a mild Au(I)-promoted 1,6-enyne cyclization that was terminated by a semipinacol rearrangement proved to be most efficient. Fashioning the unprecedented N-hydroxyazacyclononane ring embedded within the bicyclo[5.2.1]decane-N,O-acetal moiety of sieboldine A was a formidable challenge. Ultimately, the enantioselective total synthesis of (+)-sieboldine A was completed by forming this ring in good yield by cyclization of a protected-hydroxylamine thioglycoside precursor.

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Section: Resultsmentioning

confidence: 99%

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Canham

Overman

2012

J. Org. Chem.

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“…As a result, we turned to the related pinacol-terminated 1,6-enyne cyclization reaction reported recently by Kirsch and Rhee 6. The cyclization precursor 11 was readily prepared in 77% overall yield from 10 by Swern oxidation of the primary silyl ether,13 followed by condensation of the resulting aldehyde with the Ohira–Bestmann reagent 14. Exposure of enyne 11 at room temperature in CH 2 Cl 2 to the cationic gold(I) catalyst described by Kirsch6b produced cis -hydrindanone 12 in 78% yield as a single stereoisomer.…”

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confidence: 99%

“…22 The MOM protecting group was removed from the diketone product by reaction with an excess of Me 2 BBr in CH 2 Cl 2 at 0 °C to deliver (+)-sieboldine A (1) in 67% yield. Synthetic sieboldine A (1), [R] 23 D +141 (c 0.4, MeOH), exhibited 1 H and 13 C NMR spectra indistinguishable from those reported for the natural isolate. 1,23 In summary, the first total synthesis of (+)-sieboldine A was accomplished in 20 steps from (3aS,6aR)-tetrahydrocyclopenta- [b]furan-2-one 5.…”

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Total Synthesis of (+)-Sieboldine A

Canham

Overman

2010

J. Am. Chem. Soc.

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The first total synthesis of (+)-sieboldine A was completed in 20 steps from readily available (3aS, 6aR)-3,3a,4,6-atetrahydro-2H-cyclopenta [b]furan-2-one (5). Key steps are: (a) a pinacol-terminated 1,6-enyne cyclization reaction to form the cis-hydrindanone core (11 → 12), (b) formation of the spiro tetrahydrofuran ring by stereoselective DMDO oxidation of tricyclic dihydropyran intermediate 15, and (c) formation of the unprecedented N-hydroxyazacyclononane ring by cyclization of a thioglycoside precursor (18 → 19).In 2003, Kobayashi and co-workers reported the isolation of (+)-sieboldine A (1) from the club moss Lycopodium sieboldii, securing its structure by 2D NMR and X-ray analysis. 1,2 Sieboldine A was reported to inhibit electric eel acetylcholinesterase with an IC 50 value comparable to the Lycopodium alkaloid (±)-huperzine A, 3 although it was the uniqueness of its structure, rather than its biological properties that provoked our interest in its synthesis. Sieboldine A contains an unprecedented N-hydroxyazacyclononane ring embedded in a bicyclo[5.2.1]decane-N,O-acetal. To our knowledge, these functional group arrays were not only previously unknown in natural products, but in the chemical literature as a whole. We report herein the first total synthesis of (+)-sieboldine A (1).Our retrosynthetic plan for preparing sieboldine A (1) is outlined in Scheme 1. The bicyclo [5.2.1]decane-N,O-acetal was expected to be sensitive, so we chose to fashion the Nhydroxyazacyclononane ring last by the coupling of a tethered hydroxylamine with a fivemembered lactol or derivative. 4 The cis-hydrindanone core 3 was seen arising from a pinacolterminated cyclization cascade. 5,6 The enantiomerically pure cis-hydrindanone intermediate 12 was assembled in ten steps from readily available tetrahydrocyclopenta[b]furan-2-one 5 (>99:1 er) (Scheme 2). 7 Methylcuprate-promoted S N 2´ anti-opening of 5 and iodolactonization, as described by Curran for the racemate, 8 provided hexahydrocyclopentafuranone 6 in 93% yield (Scheme 2). Slow addition of this intermediate to a slurry of LiAlH 4 in refluxing THF afforded diol 7. 9 Selective protection of the primary alcohol of 7, followed by Dess-Martin oxidation yielded (2S,4R)-cyclopentanone 8. Conversion of (E)-vinyl iodide 9 10,11 to the corresponding lithium reagent, addition of this species to a THF slurry of CeCl 3 ·2LiCl, and addition of cyclopentanone 8 (all at −78 °C) delivered a single allylic alcohol product in 90% yield. Silylation of this intermediate with triethylsilyl triflate (TESOTf) delivered bis(triethylsilyl)ether 10 in 59% overall yield from cyclopentafuranone 5. 6 The cyclization precursor 11 was readily prepared in 77% overall yield from 10 by Swern oxidation of the primary silyl ether, 13 followed by condensation of the resulting aldehyde with the Ohira-Bestmann reagent. 14 Exposure of enyne 11 at room temperature in CH 2 Cl 2 to the cationic gold(I) catalyst described by Kirsch 6b produced cis-hydrindanone 12 in 78% yield as a single stereoisomer.Th...

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Titanium in Organic Synthesis

Reetz

1994

Organometallics in Synthesis

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Prostaglandins and prostaglandin intermediates. 25. Synthesis of PGF_2α Intermediates by addition of 1‐metalated hept‐1‐ynes to a substituted cyclopentanecarbaldehyde bearing already the complete carboxylic side chain

Cited by 8 publications

References 10 publications

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Total Synthesis of (+)-Sieboldine A

Titanium in Organic Synthesis

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Prostaglandins and prostaglandin intermediates. 25. Synthesis of PGF2α Intermediates by addition of 1‐metalated hept‐1‐ynes to a substituted cyclopentanecarbaldehyde bearing already the complete carboxylic side chain

Cited by 8 publications

References 10 publications

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Total Synthesis of (+)-Sieboldine A: Evolution of a Pinacol-Terminated Cyclization Strategy

Total Synthesis of (+)-Sieboldine A

Titanium in Organic Synthesis

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Prostaglandins and prostaglandin intermediates. 25. Synthesis of PGF_2α Intermediates by addition of 1‐metalated hept‐1‐ynes to a substituted cyclopentanecarbaldehyde bearing already the complete carboxylic side chain