Protecting-Group-Free Total Synthesis of (-)-Lycopodine via Phosphoric Acid Promoted Alkyne Aza-Prins Cyclization

Article abstract of DOI:10.1021/acs.orglett.6b02072

A protecting-group-free route for the total synthesis of (-)-lycopodine was demonstrated in only 8 steps from Wade's fawcettimine enone (12 steps from commercial availiable (R)-(+)-pulegone). The key core of this alkaloid was constructed through a phosphoric acid promoted and highly stereocontrolled alkyne aza-Prins cyclization reaction, synchronously establishing the bridged B-ring and the C13 quaternary stereocenter. Importantly, the synthesis further features a new efficient approach for the preparation of other lycopodine-type alkaloids.

Full text of DOI:10.1021/acs.orglett.6b02072

Letter
pubs.acs.org/OrgLett
Protecting-Group-Free Total Synthesis of (−)-Lycopodine via
Phosphoric Acid Promoted Alkyne Aza-Prins Cyclization
Donghui Ma,† Zhuliang Zhong,† Zaimin Liu,† Mingjie Zhang,† Shiyan Xu,† Dengyu Xu,†
Dengpeng Song,† Xingang Xie,† and Xuegong She*,†,‡
†State Key Laboratory of Applied Organic Chemistry, College of Chemistry and Chemical Engineering, Lanzhou University, 222
TianShui South Road, Lanzhou 730000, China
‡Collaborative Innovation Center of Chemical Science and Engineering (Tianjin), Tianjin 300071, China
S
* Supporting Information
ABSTRACT: A protecting-group-free route for the total synthesis of
(−)-lycopodine was demonstrated in only 8 steps from Wade’s
fawcettimine enone (12 steps from commercial availiable (R)-
(+)-pulegone). The key core of this alkaloid was constructed through
a phosphoric acid promoted and highly stereocontrolled alkyne aza-Prins
cyclization reaction, synchronously establishing the bridged B-ring and
the C13 quaternary stereocenter. Importantly, the synthesis further
features a new efficient approach for the preparation of other lycopodine-
type alkaloids.
he Lycopodium alkaloids are a skeletally diverse and
structurally complex family of natural products, compris-
ing approximately 300 known compounds which are divided
into four groups: lycopodine group, lycodine group, fawcetti-
mine group, and phlegmarine group.1 Several representatives of
the lycopodine group are shown in Figure 1, such as lycopodine
treatment of skin disorders and analgesia. Later studies found
that the intricate polycyclic scaffold in the lycopodium alkaloids
possess various important biological properties, such as
antipyretic and anticholinesterase activities.1l,9
T
Because of their fascinating polycyclic architectures and
diverse biological activities, these alkaloids have attracted
significant synthetic interest for several decades, and to date,
16 groups reported the syntheses on them.10−13 For lycopodine
synthesis, racemic lycopodine was first achieved by Stork11a,b
and Ayer11c in 1968. Afterward, elegant total syntheses of this
natural product were completed by Heathcock,11d,e Schu-
mann,11f Wenkert,11g Kraus,11h,i Grieco,11j and Carter,11k,l
respectively. In addition, several formal syntheses were also
reported by Kim,11m,n Padwa,11o and Mori.11p Notably, the only
asymmetric synthesis of lycopodine (1) was achieved by
Carter11k,l in 2008. As for clavolonine, Wenkert11g reported its
racemic synthesis in 1984, and recently Evans,12a Breit,12b and
Fujikoka12c achieved its asymmetric synthesis. Because of their
similar skeletal structure, the highly efficient synthesis of
lycopodine would pave the way for the synthesis of other
lycopodine-type alkaloids. Herein, we describe an enantiose-
lective synthesis of 1 without any protecting-group manipu-
lations. The key step is an aza-Prins cyclization of alkyne and
enamide moiety, synchronously establishing the bridged B-ring
and the C13 quaternary stereocenter.
Figure 1. Lycopodine, dihydrolycopodine, and structurally related
Lycopodium alkaloids.
(1),2 dihydrolycopodine (2),3 clavolonine (3),4 lycodoline
(4),5 10-hydroxylycopodine (5),6 and 7-hydroxylycopodine
(6).7 Among them, lycopodine (1) is the archetypal member of
this family which possesses the classic tetracyclic core skeleton.
Lycopodine was originally isolated from Lycopodium compla-
We undertook a retrosynthetic analysis of (−)-lycopodine, as
shown in Scheme 1. The target molecule 1 could be accessed
from a tetracycle intermediate 7 via a final-stage functional
group interconversion, in which (−)-dihydrolycopodine (2)
natum L. by Bodeker in 1881,2,8 and its natural congener
̈
dihydrolycopodine (2) was discovered in 1942 by Manske and
Marion.3,8a,b These alkaloids have been widely used in
traditional Chinese medicine and homeopathic therapies; for
example, lycopodine (1) is a Chinese folk medicine for the
Received: July 15, 2016
© XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.6b02072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 1. Retrosynthetic Analysis of (−)-Lycopodine
Scheme 2. Synthesis of the Alkyne-enamide 9
a
Reagents and conditions: (a) In (power), propargyl bromide,
TMSCl, THF, dark, rt, 32 h; (b) HCONH2, 170 °C, 3 h; (c)
allylamine or homoallylamine, AcOH, toluene, 130 °C, 3 h.
Table 1. Alkyne Aza-Prins Cyclization of Alkyne-enamide 9
could be synthesized simultaneously. The A-ring of lycopodine
lactam 7 would be constructed via an aldol/elimination/
hydrogenation sequence from a pivotal tricyclic ketone 8, in
which a terminal olefin was accordingly devised as the
equivalent of the aldehyde. For the formation of ketone 8, a
key aza-Prins cyclization was designed to construct the B-ring
from alkyne-enamide 9. However, to the best of our knowledge,
the alkyne-enamide aza-Prins reaction is still undeveloped in
establishing bridge-like rings.14 Combined with the large steric
hindrance of the C13-position and the presence of a terminal
olefin which generally could involve a Prins reaction or
rearrangement, this crucial cyclization would be the major
challenge in our designed route. Subsequently, the C-ring of 9
could be constructed from alkyne-ketone 10 via a one-pot
amidation and coinstantaneous cyclization. As for the
preparation of 10, it could be in turn obtained from Wade’s
fawcettimine enone 11 and propargyl bromide by a classical
Michael addition. Wade’s fawcettimine enone 11 is easily
accessible from cheap (R)-(+)-pulegone through a four-step
transformation based on the reference of Dake’s fawcettimine
synthesis.15
On the basis of the above analysis, we first investigated the
synthesis of the basic building block 9 (Scheme 2). Readily
available and optically pure ketone 11 was used as the starting
material.15 Michael addition of propargylindium reagent to
Wade’s fawcettimine enone 11 gave 10 as a 1:1 mixture of
inseparable diastereomers in 63% yield.16,17 Next, model
substrate 9c was chosen to test the key aza-Prins cyclization.
After heating alkyne 10 in formamide at 170 °C for 3 h, alkyne-
enamide 9c was successfully obtained in 70% yield via a one-
pot amidation and cyclization.18 Gratifyingly, enamide 9a/b
were also smoothly generated under acetic acid at 130 °C with
an excellent yield.19 It is noteworthy that the B-ring of the
natural product has been constructed efficiently and enamide
9a/9b contain all the requisite skeletal atoms for lycopodine
(1).
a
b
entry substrate
solvent (volume ratio)
t/h product yield/%
1
2
3
4
5
6
7
9c
9c
9c
9c
9c
9c
9c
THF/6 M HCl (aq), 1:1
THF/6 M H2SO4 (aq), 1:1
THF/HCO2H/H2O, 2:1:1
THF/TFA/H2O, 2:1:1
THF/85% H3PO4 (aq), 1:1
HCO2H/H2O, 1:1
12
12
22
22
36
66
21
8c
8c
8c
8c
8c
8c
8c
23
46
/
c
c
/
84
/
c
d
HCO2H/85% H3PO4 (aq),
1:1
96
e
f
8
9
9a
9b
HCO2H/85% H3PO4 (aq),
1:1
19
18
8a
8b
99
90
HCO2H/85% H3PO4 (aq),
1:1
a
Reaction conditions: alkyne-enamide 9c (R = H, 12 mg, 0.0591
mmol) in solvent (1 mL), rt, air. Isolated yields. Most of starting
material was recovered. Alkyne-enamide 9c (70 mg, 0.345 mmol) in
solvent (4 mL). Alkyne-enamide 9a (R = allyl, 241 mg, 1.016 mmol)
in solvent (3 mL). Alkyne-enamide 9b (R = homoallyl, 249 mg, 0.969
mmol) in solvent (3 mL).
b
c
d
e
f
With alkyne-enamide 9 in hand, our next challenge was to
construct B-ring of (−)-lycopodine with an alkyne aza-Prins
reaction. As we envisioned in Table 1, enamide 9 was
protonated to give N-acyliminium ion 12, which was captured
by intramolecular alkyne in a 6-exo-trig fashion to further
provide alkene cation 13, and then the unstable intermediate 13
quickly reacted with water to generate the enol 14, which then
further isomerized into the tricyclic product 8. Based on the
above analysis of reaction process, a Brønsted acid and an
B
DOI: 10.1021/acs.orglett.6b02072
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
aqueous−organic solvent would be necessary in this cyclization.
A series of Brønsted acids were tested for aza-Prins cyclization,
and the results are summarized in Table 1. 8c was afforded in
low or moderate yield with hydrochloric acid or sulfuric acid
with most of starting material decomposed (entries 1 and 2).
Therefore, we turned our attention to some weaker acids, such
as formic acid, trifluoroacetic acid, and phosphoric acid (entries
3−6). While formic acid and trifluoroacetic acid failed to
promote this reaction, we were pleased to find that by using
85% H3PO4, 8c was finally obtained in 84% yield with a little
remaining starting material 9c. We further noticed that, when
9c was treated with 85% phosphoric acid in formic acid,
tricyclic ketone 8c was obtained as the sole product in almost
quantitative yield (entry 7). The structure of 8c was
subsequently confirmed by X-ray crystallographic analysis.20
This highly selective reaction may be attributed to a
stereoselective enamine protonation, which was sterically
guided by the axial propargylic group at C7 (see TS of Table
1).21
Encouraged by the positive result of the aza-Prins cyclization,
we immediately applied the optimized reaction conditions to
N-allyl 9a and N-homoallyl 9b. The substituted amide 9a/b
might accelerate the protonation of enamine and then enhance
the alkyne aza-Prins reaction. As we predicated, the Prins
reactions on 9a/b are very clean under the previous conditions,
giving the corresponding tricyclic ketone 8a and 8b in 99% and
90% yield, respectively (Table 1, entries 8 and 9). The absolute
configuration of ketone 8a was also unambiguously determined
by single-crystal X-ray crystallography.22 The terminal alkenyl
group, which often could participate in a carbocation reaction,
remained untouched under the aza-Prins conditions, probably
because of a more favored geometry to attack the imine by the
alkyne (6-exo-trig) rather than the alkene (n = 1,5-endo-trig,
disfavored; n = 2, 6-endo-trig) group.
Scheme 3. Completion of the Synthesis of (−)-Lycopodine
a
Reagents and conditions: (a) Pd(MeCN)2Cl2 (10 mol %), CuCl (10
mol %), HMPA, O2, (CH2Cl)2, rt, 43 h; (b) O3, DCM, −78 °C, 15
min; then PPh3, rt, 12 h; (c) pTsOH (50 mol %), benzene, reflux, 30
h; (d) 10% Pd/C, H2, EtOAc, rt, 6 h; (e) LiAlH4, THF/Et2O (1:1),
reflux, 6 h; (f) Jones reagent (2.7 M), acetone, 0 °C, 10 min.
acid promoted alkyne aza-Prins cyclization. Finally, the
exclusion of the protecting group from the overall synthetic
design will improve the synthesis efficiency. Further applica-
tions of this strategy described herein toward the synthesis of
other lycopodine-type alkaloids are currently under inves-
tigation and will be reported in due course.
ASSOCIATED CONTENT
* Supporting Information
■
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.6b02072.
Having solved the key aza-Prins cyclization, we then turned
to finish the total synthesis of (−)-lycopodine (1) and
(−)-dihydrolycopodine (2). Palladium-catalyzed anti-Markov-
nikov oxidation23 of lactam-ketone 8a proceeded smoothly to
provide a 68% yield of the required keto aldehyde 15 which can
be also readily prepared by ozonolysis of the terminal alkene
from 8b in 72% yield (Scheme 3). Next, our attention was
focused toward construction of the remaining piperidine ring
via a tandem intramelocular aldol/elimination reaction. After
screening various common acids and bases for this cyclization,
we found 50% p-TsOH could realize the last cyclization and
generate α,β-enone 16 in 57% yield. It should be noted that the
yield and reaction rate of this step dropped significantly with a
lesser amount of p-TsOH. A highly stereoselective hydro-
genation of this enone led to lycopodine lactam 7 in a nearly
quantitative yield, and its absolute configuration was also
ascertained by X-ray crystallographic analysis.22 Finally,
reduction of lactam 7 under LiAlH4 yielded (−)-dihydro-
lycopodine (2) in 94% yield, which matched nicely with the
reported spectrum data.24a−c Then, (−)-dihydrolycopodine (2)
was converted into (−)-lycopodine (1) using Jones’ oxidizing
reagent. The physical and spectral properties, including optical
rotation of our synthetic 1, were also in good agreement with
the published data.11i,k,24a,d
X-ray crystallographic data for 8c (CIF)
X-ray crystallographic data for 8a (CIF)
X-ray crystallographic data for 7 (CIF)
Detailed experimental procedures and full spectrosco-
picdata for all new compounds (PDF)
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: shexg@lzu.edu.cn.
Notes
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
Financial support from IRT_15R28, the National Science
Foundation of China (21125207, 21372103, 21472079, and
21572088) and SRFDP (20130211110018) is gratefully
acknowledged. We also thank Dr. Xiaolei Wang (The Scripps
Research Institute) for helpful discussions.
REFERENCES
■
In summary, we have completed the enantioselective total
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fawcettimine enone (12 steps from commercially availiable
(R)-(+)-pulegone). In addition, the bridged quaternary stereo-
center at C13 was successfully constructed via the phosphoric
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DOI: 10.1021/acs.orglett.6b02072
Org. Lett. XXXX, XXX, XXX−XXX

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