Total Synthesis of (+)-Sieboldine A

Abstract

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 IC₅₀ 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 N-hydroxyazacyclononane ring last by the coupling of a tethered hydroxylamine with a five-membered lactol or derivative.⁴ The cis-hydrindanone core 3 was seen arising from a pinacol-terminated cyclization cascade.^5,6

Scheme 1.

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_N2´ 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 LiAlH₄ 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 CeCl₃·2LiCl, 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.

Scheme 2^a.

^a (a) MeMgBr, CuBr·SMe₂, THF:SMe₂ (4:1), −20 °C; (b) KI, I₂, NaHCO₃, THF, H₂O (93% over 2 steps); (c) LiAlH₄, THF, reflux (83%); (d) TESCl, 2,6-lutidine, CH₂Cl₂, −78 °C (98%); (e) Dess–Martin periodinane, CH₂Cl₂ (97%); (f) i. (E)-PhOCH₂CH=CI(CH₂)₃OTBDPS (9), s-BuLi, THF, −78 °C ii. CeCl₃·2LiCl, THF, −78 °C iii. 8, THF, −78 °C (90%); (g) TESOTf, 2,6-lutidine, CH₂Cl₂, 0 °C (90%); (h) Swern oxidation (86%); (i) N₂=C(COMe)PO(OMe)₂, K₂CO₃, MeOH, 23 °C (90%); (j) 10 mol % (t-Bu)₂P(o-biphenyl)AuCl, 5 mol % AgSbF₆, 1.1 equiv i-PrOH, CH₂Cl₂ (78%)

Orchestrating an efficient cyclization-pinacol sequence to deliver a cis-hydrindanone intermediate proved challenging. In early experiments, we discovered that standard Prins-pinacol reactions⁵ of the dimethyl acetal analog of 10 [CH(OMe)₂ in place of CH₂OTES] yielded the corresponding cis-hydrindanone¹² in <45% yield. 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 CH₂Cl₂ to the cationic gold(I) catalyst described by Kirsch^6b produced cis-hydrindanone 12 in 78% yield as a single stereoisomer.

The sequence that we developed after much experimentation for elaborating hydrindanone 12 to (+)-sieboldine A (1) is summarized in Scheme 3. Cleavage of the exomethylene group of 12 with ozone, followed by base-promoted elimination of phenoxide provided enone 13. A europium(III)-catalyzed cyclocondensation of this intermediate with ethyl vinyl ether¹⁵ gave tricyclic dihydropyran 14 in 65% overall yield from precursor 12. After establishing that the C13 carbonyl group would require protection during the cyclization to form the N-hydroxyazacyclononane ring,¹⁶ ketone 14 was reduced with DIBALH to provide axial alcohol 15. Facial selective oxidation of this intermediate with dimethyldioxirane (DMDO), followed by exposure of the crude product to BF₃·OEt₂ and EtSH gave rise to thioglycoside 16 in 53% overall yield from 14.

Scheme 3^a.

^a Reagents: ; (a) i. O₃, MeOH/CH₂Cl₂, −78 °C ii. Me₂S, −78→23 °C iii. DBU, MeCN, 0 °C (75%); (b) 10 mol % Eu(fod)₃, ethyl vinyl ether, 23 °C (86%); (c) DIBALH, CH₂Cl₂, −78 °C; (d) i. DMDO, CH₂Cl₂, 0 °C ii. BF₃·OEt₂, EtSH, CH₂Cl₂, 0 °C (53% from 14); (e) TBAF, THF, 23 °C (91%); (f) NsNH–OMOM (17), PPh₃, DEAD, C₆H₆, 5 °C (88%); (g) PhSH, K₂CO₃, DMF (95%); (h) DMTST, DTBMP, 4Å MS, MeCN, −20 °C (51%); (i) 10 mol % TPAP, NMO, 4Å MS, CH₂Cl₂, 23 °C (88%); (j) Me₂BBr, CH₂Cl₂, 0 °C (67%).

The final N-hydroxyazacyclononane ring was fashioned as follows. Removal of the TBDPS group from intermediate 16,¹⁷ Mitsunobu coupling¹⁸ of the resulting primary alcohol with N-Ns-O-MOM hydroxylamine (17), and removal of the Ns-group under conventional conditions,¹⁹ afforded the O-(methoxy)methyl (MOM)-protected hydroxylamine cyclization precursor 18. Exposure of 18 to dimethyl(methylthio)sulfonium triflate (DMTST)²⁰ in the presence of 2,6-di-tert-butyl-4-methylpyridine (DTBMP) at −20 °C in acetonitrile provided pentacyclic product 19 in 51% yield.²¹ Reintroduction of the C13 carbonyl group by TPAP (Pr₄N⁺RuO₄⁻)-catalyzed oxidation proved uneventful.²² The MOM protecting group was removed from the diketone product by reaction with an excess of Me₂BBr in CH₂Cl₂ at 0 °C to deliver (+)-sieboldine A (1) in 67% yield. Synthetic sieboldine A (1), [α]²³ _D +141 (c 0.4, MeOH), exhibited ¹H and ¹³C 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. Our construction of the cis-hydrindanone intermediate using Au(I)-catalyzed activation of an alkyne to promote a cyclization-pinacol sequence,⁶ rather than Lewis acid-activation of an acetal,⁵ illustrates the potential advantages in demanding contexts of this mild catalytic procedure. Of particular note was the surprisingly efficient cyclization to form the unprecedented N-hydroxyazacyclononane ring from a thioglycoside precursor.