Enantioselective Total Synthesis of (+)-Sieboldine A

Article abstract of DOI:10.1021/acs.orglett.6b03416

The first total synthesis of (+)-sieboldine A was completed starting from 5-(p-methoxybenzyloxy)pentyne in 19 steps. The enantioselective Keck allylation provided the dienyne derivative, which was exposed to the Pauson-Khand conditions to afford the bicyclo[4.3.0]nonenone derivative with high stereoselectivity with an ee value of 93%. The following Ueno-Stork reaction formed the cis-hydrindane core with a quaternary carbon center. The late-stage Schmidt glycosylation led to the formation of the N-hydroxyazacyclononane ring.

Full text of DOI:10.1021/acs.orglett.6b03416

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Letter
pubs.acs.org/OrgLett
Enantioselective Total Synthesis of (+)-Sieboldine A
Mohammed K. Abd El-Gaber, Shigeo Yasuda, Eisuke Iida, and Chisato Mukai*
Division of Pharmaceutical Sciences, Graduate School of Medical Sciences, Kanazawa University, Kakuma-machi, Kanazawa 920-1192,
Japan
S
* Supporting Information
ABSTRACT: The first total synthesis of (+)-sieboldine A was completed starting from 5-(p-methoxybenzyloxy)pentyne in 19
steps. The enantioselective Keck allylation provided the dienyne derivative, which was exposed to the Pauson−Khand conditions
to afford the bicyclo[4.3.0]nonenone derivative with high stereoselectivity with an ee value of 93%. The following Ueno−Stork
reaction formed the cis-hydrindane core with a quaternary carbon center. The late-stage Schmidt glycosylation led to the
formation of the N-hydroxyazacyclononane ring.
he Lycopodium alkaloids consist of more than 200
structurally diverse natural products, which have attracted
subsequently extended their methodology to the synthesis of
these two optically active alkaloids in 2012.6b
Our retrosynthetic plan for the preparation of (+)-sieboldine
A (1) is presented in Scheme 1. The elaboration of the sensitive
T
significant interest from biogenetic and biological points of view
and provided challenging targets for their total synthesis.1,2
(+)-Sieboldine A (1) is a fawcettimine-type Lycopodium alkaloid
that was isolated from the club moss Lycopodium sieboldii along
with (+)-alopecuridine (2) by Kobayashi et al. in 2003 (Figure
1).3 (+)-Sieboldine A (1) has been found to inhibit
Scheme 1. Retrosynthetic Analysis of (+)-Sieboldine A
Figure 1. Structures of sieboldine A (1) and alopecuridine (2).
acetylcholinesterase (from the electric eel) with an IC50 value
of 2.0 μM. This value was comparable to that of ( )-huperzine
A4 and exhibited cytotoxicity against murine lymphoma L1210
cells with an IC50 value of 5.1 μg/mL.3
(+)-Sieboldine A (1) contains an unprecedented fused
tetracyclic skeleton consisting of (i) a cis-hydrindane ring system,
the distinctive structural feature of the fawcettimine-type
Lycopodium alkaloids, and (ii) an N-hydroxyazacyclononane
ring embedded in bicyclo[5.2.1]decane-N,O-acetal. This unusual
and unique skeleton with the unstable N,O-acetal moiety made 1
an important and attractive target molecule for its total synthesis.
Two groups have already succeeded in the total synthesis of
(+)-1. In 2010, the Overman group recorded the first total
synthesis of (+)-1 in 20 steps starting from the chiral
tetrahydrocyclopenta[b]furan-2-one using a gold(I)-catalyzed
pinacol-terminated 1,6-enyne cyclization for construction of the
cis-hydrindanone core.5 In the following year, Tu and co-workers
reported the first total synthesis of ( )-alopecuridine (2) and its
biomimetic transformation into ( )-16a according to Kobaya-
shi’s proposed biogenetic pathway.3 Tu and co-workers
N,O-acetal functionality of (+)-1 was planned to be formed
during the late stage of the synthesis via the intramolecular
displacement reaction of the lactol functionality of 3 by the O-
protected hydroxylamine residue.7 The spirolactol framework of
3 would be formed through oxidative cyclization of the diol 4.
Introduction of the nitrogen functionality could be achieved
through the hydroboration−oxidation of the allyl side chain of 5,
followed by the Mitsunobu coupling with the protected
hydroxylamine derivative. The cis-hydrindanone 5 with all-
carbon units required for 1 would be obtained by the consecutive
Received: November 16, 2016
© XXXX American Chemical Society
A
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Letter
bromoacetalization, Ueno−Stork cyclization, and Wittig olefi-
nation of 6. In our previous studies,8 we definitely showed that
the Pauson−Khand reaction (PKR) is a powerful and efficient
synthetic tool to assemble bicyclo[4.3.0] frameworks. Based on
our previous results, the PKR of the dienyne 7 would be expected
to stereoselectively produce 6. Thus, the highly enantioselective
preparation of 7, a substrate for the PKR, is mandatory. We
envisioned that the optically active 7 would be available by the
asymmetric allylation of aldehyde 8 with a suitable allyl
derivative.9
Scheme 3. Construction of the cis-Hydrindane Framework
with a Quarternary Carbon Center
The formylation of 5-(p-methoxybenzyloxy)pentyne10 under
conventional conditions11 gave the aldehyde 9 in 81% yield
(Scheme 2). The asymmetric allylation of aldehyde 9 is obviously
Scheme 2. Enantioselective Synthesis of the
Bicyclo[4.3.0]nonenone 13
oxidation of 17 with mCPBA occurred from the sterically less-
hindered α face, and the resulting acetoxy epoxide moiety was
hydrolyzed to give the α-hydroxy ketone derivative 18 in 96%
yield.21 The ketone derivative 18 was temporarily converted to
the trans-diol derivative 19 in 86% yield by the stereoselective K-
selectride reduction to avoid any side reactions during further
chemical elaboration.22 Compound 19 was treated with PPTS,
and the resulting hemiacetal was subsequently subjected to the
Wittig olefination with MePPh3Br to form the allyltriol (−)-20 in
55% yield.
Having established all the carbon units with the proper
stereochemistry, we focused on the introduction of the nitrogen
functionality and formation of the spirotetrahydrofuran ring
(Scheme 4). The two secondary hydroxyl groups of the triol
one of the crucial steps in our synthesis. Several allyl derivatives
and different asymmetric reaction conditions were evaluated to
optimize the allylation process in terms of the chemical yield and
enantiomeric excess (ee).12 As a result, the Keck asymmetric
allylation using the modified Ti(IV) catalyst described by
Maruoka et al.13 was found to be the most satisfactory one.
Indeed, the treatment of 9 with 2-((tributylstannyl)methyl)allyl
acetate14 using Maruoka’s conditions afforded the hydroxyenyne
(+)-10 in 80% yield with 93% ee.15 The TBS protection of 10
was followed by treatment with vinylmagnesium bromide to
furnish 12 in 85% yield from 10.16 A highly diastereoselective
PKR of 12 was realized under catalytic conditions using 20 mol %
of Co2(CO)8 and 20 mol % of tetramethylthiourea in toluene at
70 °C under 1 atm of CO17 to afford the indenone 13 and its
epimer 13′ in 96% yield in the ratio of 98:2.
Scheme 4. Introduction of the Nitrogen Functionality and
Formation of the Spirotetrahydrofuran Ring
Deprotection of the TBS group of 13 with TBAF provided 14,
which was recrystallized from EtOAc/hexanes to furnish the
optically pure (−)-14 (>99% ee; Scheme 3).18 The efficient
construction of the cis-hydrindane framework possessing the C15-
methyl group19 and the quaternary carbon center at the C12-
position19 was realized as follows. The hydrogenation of 14 in the
presence of Wilkinson’s catalyst proceeded in a highly chemo-
and stereoselective manner to form 15, having the C15-methyl
group with the desired stereochemistry in 98% yield. According
to the procedures developed during our previous investiga-
tions,8g,j the Ueno−Stork reaction was applied to 15 to produce
16 in 91% yield as a mixture of two diastereomers in the ratio of
3:1.20 Upon exposure to acetic anhydride in the presence of Et3N
and DMAP at 40 °C, 16 underwent regioselective enolization to
provide the vinyl acetate derivative 17 in 92% yield. The
derivative 20 were protected by the pivaloyl group to provide 21
in 71% yield, which was subjected to hydroboration with BH3·
SMe2, followed by oxidation using NaBO3 to afford 22 in 82%
yield.23 The Mitsunobu reaction of 22 with NsNH−OMOM
effected the introduction of the nitrogen atom to give 23 in 88%
yield.24 The PMB group of 23 was then removed with DDQ to
afford the diol 24 in 85% yield. The optimized oxidation
condition of 24 was required to exclusively obtain the spirolactol
25 in a satisfactory yield without overoxidation to the
corresponding lactone species. After testing different oxidation
B
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Letter
conditions, we found that the oxidation of the diol 24 with 1.5
equiv of IBX in THF/DMSO (1:1) at room temperature
provided a clean conversion to the spirolactol 25 in 83% yield.25
With the spirolactol 25 in hand, our efforts moved toward
constructing the azacyclononane ring and removing the nosyl,
pivaloyl, and MOM groups to complete the total synthesis of
(+)-sieboldine A (1) (Scheme 5). The denosylation of 25 with
Experimental procedures, characterization for new com-
pounds including NMR spectra and HPLC charts (PDF)
X-ray crystallographic data for 14 (CIF)
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: mukai@p.kanazawa-u.ac.jp.
ORCID
Scheme 5. Completion of the Total Synthesis of
(+)-Sieboldine A (1)
Chisato Mukai: 0000-0001-8621-1068
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
This work was financially supported by JSPS KAKENHI Grant
Nos. 15H02490 (C.M.) and 15K18826 (S.Y.), for which we are
thankful.
REFERENCES
■
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24
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In conclusion, we have completed the highly enantioselective
total synthesis of (+)-sieboldine A (1) from 5-(p-
methoxybenzyloxy)pentyne in 19 steps with a 1.9% overall
yield. The key features of this synthesis include (i)
enantioselective Keck allylation to form the optically active
enyne 10; (ii) PKR to build the bicyclo[4.3.0]nonenone
fragment 13 with a high diastereoselectivity; (iii) Ueno−Stork
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quaternary center; (iv) regioselective formation of the vinyl
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ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.orglett.6b03416.
C
DOI: 10.1021/acs.orglett.6b03416
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23
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D
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