Exceedingly Concise and Elegant Synthesis of (+)-Paniculatine, (-)-Magellanine, and (+)-Magellaninone

Article abstract of DOI:10.1021/acs.orglett.5b01975

Starting from inexpensive (+)-pulegone as the chiral building block, a highly convergent synthesis of the unusual diquinane-based structures of (+)-paniculatine (1), (-)-magellanine (2), and (+)-magellaninone (3), has been achieved. This approach is based upon a tandem acylation-alkylation of ketoester 8 and palladium-catalyzed olefin insertion, oxidation, and hydrogenation for construction of the tetracyclic framework. This exceedingly concise strategy, requiring only 12-14 steps, is the shortest to date.

Full text of DOI:10.1021/acs.orglett.5b01975

Letter
pubs.acs.org/OrgLett
Exceedingly Concise and Elegant Synthesis of (+)-Paniculatine,
(
−)-Magellanine, and (+)-Magellaninone
Kuo-Wei Lin, Bakthavachalam Ananthan, Sheng-Fang Tseng, and Tu-Hsin Yan*
Department of Chemistry, National Chung Hsing University, Taichung 402, Taiwan R.O.C
*
S Supporting Information
ABSTRACT: Starting from inexpensive (+)-pulegone as the chiral building block, a
highly convergent synthesis of the unusual diquinane-based structures of
(
+)-paniculatine (1), (−)-magellanine (2), and (+)-magellaninone (3), has been
achieved. This approach is based upon a tandem acylation−alkylation of ketoester 8
and palladium-catalyzed olefin insertion, oxidation, and hydrogenation for
construction of the tetracyclic framework. This exceedingly concise strategy,
requiring only 12−14 steps, is the shortest to date.
he Lycopodium alkaloids are a family of skeletally diverse
natural products that have continued to attract much
the background, the development of exceedingly concise and
convergent synthetic strategies to the three Lycopodium
alkaloids (+)-paniculatine, (−)-magellanine, and (+)-magella-
ninone remains an attractive challenge.
T
synthetic interest due to their polycyclic architecture and useful
1
biological activity. The unusual diquinane-based structure of
2a
2b
(
+)-paniculatine (1), (−)-magellanine (2), and (+)-magel-
Herein, we report a new synthetic strategy that leads from an
2
c
8
laninone (3), which are unique members of Lycopodium
alkaloids, represents a challenging vehicle to explore the
development of efficient methodology for the stereocontrolled
construction of the complete diquinane-based tetracyclic
framework and the direct installation of the five to seven
stereogenic centers of these ring systems. Several synthetic
approaches toward construction of the requisite tetracyclic
skeleton have been reported. In 1993, enantioselective total
syntheses of both (−)-magellanine and (+)-magellaninone via a
inexpensive (R)-(+)-pulegone-derived enone 9 to the
diketocarbamate 4, a convenient precursor to (+)-paniculatine,
(−)-magellanine, and (+)-magellaninone.
Scheme 1 outlines, in retrosynthetic format, our overall plan
for construction of the required tetracyclic diketocarbamate 4
from (R)-(+)-pulegone. We envisioned the diketocarbamate 4
to be derived from the Pd-catalyzed intramolecular olefin
insertion of keto−enol triflate 5, whose connection to bicyclic
diketone 6 could be recognized through standard functional
group manipulations. The origins of 6 were then traced to
ketoester 8 through tandem intramolecular acylation/inter-
molecular alkylation. Finally, ketoester 8 was expected to arise
from enone 9 through a conjugate addition of a functionalized
zinc−copper reagent.
Prins−pinacol rearrangement was successfully completed over
3
2
5−26 steps by Overman. In the same year, a 20-step racemic
synthesis of magellanine and magellaninone based upon
Michael−Michael addition was accomplished by Paquette et
al. In addition, the first 26-step asymmetric synthesis of
+)-paniculatine from (R)-(+)-pulegone was achieved by Sha et
4
According to the synthetic blueprint, the synthesis of 8 began
from chiral enone 9 (Scheme 2). Thus, 1,4-addition of zinc
(
al. in 1999 via a novel application of tandem radical cyclization
5
homoenolate to enone 9 under copper-catalyzed conditions
to produce the angularly fused tricyclic skeleton. In 2002, a 16-
9
(
CuBr·SMe /TMSCl/HMPA) led smoothly to the desired
step synthesis of (±)-magellanine by Liao demonstrated the
value of the oxa-di-π-methane rearrangement for construction
2
ketoester 8 in 85% yield with complete stereocontrol. To
incorporate the B and D rings into 8, with concomitant
stereocontrolled construction of the quaternary center,
application of a base-promoted intramolecular cyclization and
an intermolecular alkylation with the ketoester 8 were
attempted. Gratifyingly, exposure of 8 to t-BuOK in THF at
6
of the linear triquinane framework. By employing the Pauson−
Khand reaction of an enyne for the construction of the
bicycle[4.3.0] framework, asymmetric syntheses of (+)-pan-
iculatine, (−)-magellanine, and (+)-magellaninone in 43−45
steps from diethyl L-tartrate were demonstrated by the group of
7
a
0
°C for 1 h followed by the addition of DBU and 3-
Mukai in 2007. Very recently, Yang and co-workers reported
the use of site-specific and stereoselective aldol cyclization in
the collective total synthesis of tetracyclic diquinane Lycopo-
Received: July 10, 2015
7b
dium alkaloids in 25−28 steps from (R)-(+)-pulegone. Given
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.5b01975
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 1. Retrosynthetic analysis of (+) - paniculatine,
stereochemical outcome of this tandem conjugate addition/
alkylation sequence was achieved as anticipated on steric
grounds. The next object was the forging of the final
carbocyclic C ring within the skeleton of 6. To accomplish
this goal, an intramolecular Heck was envisaged. Incorporation
(−)-magellanine, and (+)-magellaninone
of the final C ring was initiated by chemoselective ketalization
+
(
HOCH CH OH/H ), which produced a single diastereomeric
2
2
keto ketal 10 in 79% yield. Conversion of 10 into its enol
triflate (LiHMDS/PhNTf ) and removal of the dioxolane
2
group (80% HOAc) could be accomplished in one pot to give
keto−enol triflate 5 in 93% yield. The critical Pd-promoted
intramolecular olefin insertion was effected by exposing 5 to
0
.09 equiv of Pd(OAc) and 0.26 equiv of PPh in CH CN/
2 3 3
NEt and gave the tetracyclic dienone 11 in 82% yield. With
3
dienone 11 in hand, we began to investigate the challenging
chemoselective oxidation of the diene with concomitant
stereocontrolled construction of the tertiary center. Through
an extensive screening of reaction conditions, we found that the
desired enediketone 12 could be generated in 55% yield by the
treatment of dienone 11 with PdCl /CuCl/O in DMF/H O/
2
2
2
11
THF at 40 °C for 84 h. Subsequent hydrogenation of the
alkene that remained with H (5 atm)/10% Pd/C in EtOH
2
provided the desired diketocarbamate 4 in 86% yield. The
configuration of this saturated diketocarbamate 4 was
confirmed by single-crystal X-ray analysis (see the Supporting
Information). This overall sequence has allowed diketocarba-
mate 4 to be prepared in enantiopure fashion in 39% overall
yield from 5. A more convenient operation took keto−enol
triflate 5 through the three-step without purification of any
intermediates to deliver the diketocarbamate 4 in 44% overall
yield, which is identical to what was obtained when each step
began with purified material.
Scheme 2. Synthesis of Diketocarbamate 4
The ready accessibility to 4 by the preceding protocol has set
the stage for completion of the synthesis of (+)-paniculatine
(
1) (Scheme 3). Thus, chemoselective silylation of one of the
two ketones in 4 with TBSCl/NaH in THF at 0−25 °C
provided the desired silyl enol ether 13 in 92% yield. After
careful optimization of the reduction conditions, we were
pleased to find that treatment of 13 with L-Selectride in THF at
−
78 to +25 °C for 8 h, followed by addition of DIBAL-H at 0
C and stirring for 1 h and then addition of 2 N HCl and
stirring for 1 h, afforded an 85% yield of (+)-paniculatine (1),
°
25
[α] = +77.38 (c 0.88, CHCl ), whose physical properties are
D 3
6
identical to those reported earlier, and its structure was
secured by single-crystal X-ray analysis. The excellent
diastereocontrolled introduction of the last stereogenic center
on the A ring with >13:1 diastereoselectivity is noteworthy.
The synthetic route described above makes use of novel
approaches to the construction of the tetracyclic framework and
for the introduction of seven stereogenic centers. The
asymmetric synthesis requires 12 steps from commercially
available (+)-pulegone to give (+)-paniculatine in ∼8.2%
overall yield.
This convergent sequence offers an exceedingly concise and
elegant approach to the tetracyclic framework of this family of
alkaloids which share a common diquinane core. To
demonstrate the versatility of this convergent strategy, we
were able to access both (−)-magellanine (2) and (+)-ma-
gellaninone (3). All that now remained to reach these targets
was the functionalization of the A and B rings. Fortunately,
exposing 4 to L-Selectride in THF at −78 °C for 6 h cleanly
effected the desired chemoselective reduction of the less
hindered ketone in 4 to give ketocarbamate 14 in 96% yield
1
0
pyridinemethanol-derived allyl bromide 7, and heating at
reflux for 1 h smoothly and cleanly effected the desired
cyclization and alkylation to afford the desired bicyclic diketone
in 86% yield. The quaternary carbon center was correctly
6
installed by this remarkable transformation. The desired
B
DOI: 10.1021/acs.orglett.5b01975
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Scheme 3. Synthesis of (+)-paniculatine 1, (−)-magellanine
ASSOCIATED CONTENT
Supporting Information
■
2
, and (+)-magellaninone 3
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.5b01975.
Experimental procedures and characterization data for
1
13
all reactions and products, including H and C NMR
spectra (PDF)
X-ray data for compound 1 (CIF)
X-ray data for compound 4 (CIF)
X-ray data for compound 14 (CIF)
AUTHOR INFORMATION
Corresponding Author
■
*
E-mail: thyan@mail.nchu.edu.tw.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
We thank the National Science Council of Taiwan R.O.C. for
generous financial support.
■
REFERENCES
■
(
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spectral properties are in full agreement with those of the
(
3
−5
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(+)-pulegone as an inexpensive chiral starting material. The
asymmetric synthesis is the shortest to date. The most striking
maneuver in this synthesis is the construction of tetracycle 4 by
combining three-component coupling and palladium-mediated
olefin reactions. This efficient and flexible entry should offer
opportunities for the construction of many other polycycle
analogues for chemical biology investigations.
(
2
(
1
C
DOI: 10.1021/acs.orglett.5b01975
Org. Lett. XXXX, XXX, XXX−XXX