Total synthesis of (+)-sieboldine A

Article abstract of DOI:10.1021/ja103666n

The first total synthesis of (+)-sieboldine A was completed in 20 steps from readily available (3aS,6aR)-3,3a,4,6a-tetrahydro-2H-cyclopenta[b]furan-2- one (5). Key steps are as follows: (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).

Full text of DOI:10.1021/ja103666n

Published on Web 05/19/2010
Total Synthesis of (+)-Sieboldine A
Stephen M. Canham, David J. France,† and Larry E. Overman*
Department of Chemistry, 1102 Natural Sciences II, UniVersity of California, IrVine, California 92697-2025
Received April 29, 2010; E-mail: leoverma@uci.edu
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 embed-
ded in a bicyclo[5.2.1]decane-N,O-acetal. To our knowledge, these
functional group arrays were previously unknown not only in natural
products but also 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-hydroxyazacy-
clononane 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
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 analogue 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 tem-
perature in CH2Cl2 to the cationic gold(I) catalyst described by
Kirsch6b produced cis-hydrindanone 12 in 78% yield as a single
stereoisomer.
Scheme 2a
Scheme 1
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 perio-
dinane, CH2Cl2 (97%); (f) i. (E)-PhOCH2CHdCI(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) N2dC(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%).
The enantiomerically pure cis-hydrindanone intermediate 12 was
assembled in 10 steps from readily available tetrahydrocyclopent-
a[b]furan-2-one 5 (>99:1 er) (Scheme 2).7 Methylcuprate-promoted
SN2′ alkylation 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
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
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.
† Current address: WestCHEM Department of Chemistry, University of Glasgow,
Glasgow, United Kingdom, G12 8QQ.
9
7876 J. AM. CHEM. SOC. 2010, 132, 7876–7877
10.1021/ja103666n  2010 American Chemical Society

C O M M U N I C A T I O N S
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.
Acknowledgment. The NIH Neurological Disorders and Stroke
Institute (NS-12389) supported this research. Synthetic assistance
from Mr. Brian Leo´n is gratefully acknowledged. NMR and mass
spectra were obtained at UC Irvine using instrumentation acquired
with the assistance of NSF and NIH Shared Instrumentation grants.
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 conditions19 afforded the O-(methoxy)methyl (MOM)-
protected hydroxylamine cyclization precursor 18. Exposure of 18
to dimethyl(methylthio)sulfonium triflate (DMTST)20 in the pres-
ence 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
Supporting Information Available: Experimental details and copies
of 1H and 13C NMR spectra of new compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
References
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(1) in 67% yield. Synthetic sieboldine A (1), [R]23 +141 (c 0.4,
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MeOH), exhibited 1H and 13C NMR spectra indistinguishable from
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(alkoxyamino)propyl side chain condenses with the ketone to form a
carbinolamine or tetracyclic nitrone during the final cyclization step.
(17) Introduction of the side chain as a protected alcohol allowed various N-
and O-protected hydroxylamine functionalities to be incorporated at this
point. This diversification proved important, as defining the optimal nature
of the hydroxylamine nucleophile for the final cyclization reaction required
significant experimentation. For example, 1,2-oxazacyclodecane formation
was observed under alternative cyclization conditions when the hydroxy-
lamine oxygen was unprotected.
a Reagents: (a) i. O3, MeOH/CH2Cl2, -78 °C ii. Me2S, -78f23 °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, 4 Å MS, MeCN, -20 °C
(51%); (i) 10 mol % TPAP, NMO, 4 Å MS, CH2Cl2, 23 °C (88%); (j)
Me2BBr, CH2Cl2, 0 °C (67%).
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(21) Activation of 18 with mercury or silver salts, tris(4-bromophenyl)ammo-
niumyl hexachloroantimonate, or benzenesulfenyl triflate provided the
cyclized product 19 in low yields (0-28%).
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 inter-
mediate 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.
(22) Ley, S. V.; Norman, J.; Griffith, W. P.; Marsden, S. P. Synthesis 1994,
639–666.
(23) The reported optical rotation for natural (+)-sieboldine A is [R]D +139
(c 0.3, MeOH).1 A sample of natural sieboldine A is apparently no longer
available.
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