Synthesis of [6-6-6] ABE tricyclic ring analogues of methyllycaconitine

Article abstract of DOI:10.1016/j.cclet.2021.03.068

A new synthesis of the bridged [6-6-6] ABE tricyclic ring analogues of methyllycaconitine with the C-1 oxygenated substituents has been developed using an efficient aza-annulation of β-enamino ketone followed by a facile decarboxylation to form BE rings. Subsequent elaboration to form the A ring was achieved by a transannular acyl radical cyclization with concomitant equipment of the key C-1 oxygen functionality.

Full text of DOI:10.1016/j.cclet.2021.03.068

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CCLET-6264; No. of Pages 3
Chinese Chemical Letters xxx (xxxx) xxx–xxx
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Chinese Chemical Letters
journal homepage: www.elsevier.com/locate/cclet
Communication
Synthesis of [6-6-6] ABE tricyclic ring analogues of methyllycaconitine
Dan Xiaoa, Xin Zhaoa, Jiang Leia, Mengqian Zhua, Liang Xua,b,
*
a
Key Laboratory of Drug Targeting and Drug Delivery Systems of the Ministry of Education, West China School of Pharmacy, Sichuan University, Chengdu
610041, China
b
State Key Laboratory of Biotherapy, West China Hospital, West China Medical School, Sichuan University, Chengdu 610041, China
A R T I C L E I N F O
A B S T R A C T
Article history:
A new synthesis of the bridged [6-6-6] ABE tricyclic ring analogues of methyllycaconitine with the C-1
oxygenated substituents has been developed using an efficient aza-annulation of β-enamino ketone
followed by a facile decarboxylation to form BE rings. Subsequent elaboration to form the A ring was
achieved by a transannular acyl radical cyclization with concomitant equipment of the key C-1 oxygen
functionality.
Received 10 February 2021
Received in revised form 23 March 2021
Accepted 25 March 2021
Available online xxx
© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences.
Published by Elsevier B.V. All rights reserved.
Keywords:
C
19-Diterpenoid alkaloids
Methyllycaconitine
Aza-annulation
Decarboxylation
Acyl radical cyclization
C19-Diterpenoid alkaloids, mainly isolated from the genera
Aconitum and Delphinium, constitute a structurally diverse class of
natural products and have been shown a wide range of potent
physiological activities [1]. For example, methyllcaconitine (MLA)
(1) (Fig. 1), first discovered from Delphinium brownii by Manske in
1938 [2] and its whole stereochemical structure was correctly
lycoctonine (2) are essential for potent pharmacological activities
[7]. Several research groups [8], including our own [9], have
synthesized a variety of analogues of MLA including E, AE, BE, ABE,
AEF, ABDE, ABEF and ABDEF rings, some of which display
significant biological activities. Of particular interest to our group
is the [6-6-6] ABE tricyclic ring system of MLA due to the resembled
[6-7-6] ABE tricyclic analogue 5 (one of diastereomers) [10]
has been reported to exhibit high nAChR affinity binding
(IC50 = 478 nmol/L) which is amongst the highest reported to
date for small molecule analogues of MLA. Although Kraus and co-
workers have reported the preparation of [6-6-6] ABE tricyclic
analogue 8 [11] from a known spirocyclic diketone 6, no structure-
activity data was given and compounds with a key oxygenated
substitution at the C-1 position had not been included (Scheme 1).
It has been found that substitution at the C-1 has a considerable
effect on biological activity, so that compounds with a C-1 hydroxyl
group, e.g., grandiflorine, exhibits 100–1000 times less binding
efficiency for nAChR than MLA with a C-1 methoxy group [7b]. In
order to explore new area of structural alteration of MLA with the
aim to obtain more potent nAChRs antagonists, herein, we
described a new route for the synthesis of the [6-6-6] ABE tricyclic
determined by Pelletier in 1981 [3], is a representative C19
-
diterpenoid alkaloid and major toxic component found in at least
30 Delphinium species as well as in Consolida ambigua and
Inaularoyaleana [4]. The toxicity has been attributed to its ability to
act at the neuromuscular junction, inhibiting neurotransmission
and inducing paralysis [5], and it has been found to be a potent
inhibitor of the nicotinic acetylcholine receptor (nAChR) binding in
mammalian and insect neural membranes [5]. Among the α-7
subtype nAChR, MLA is one of the most effective small molecule
competitive antagonists reported so far. Researchers have
proposed that MLA or analogs could be potentially useful for
developing drug candidates for the treatment of neurological
conditions such as schizophrenia, Alzheimer’s disease and
epilepsy [6].
Structure activity relationship (SAR) studies on MLA (1) have
shown that the N-substituted anthranilate ester moiety and a
homocholine backbone corresponding to the piperidine E ring of
analogue 11 bearing
a key methoxy group at the position
corresponding to C-1 of MLA, utilizing an efficient aza-annulation
and a transannular acyl radical cyclization as the key steps
(Scheme 1).
The synthetic study commenced with the preparation
of the known N-alkyl substituted 3,4,5,6,7,8-hexahydro-2(1H)-
quinolinone 10 [12,13] as the precursor of BE rings (Scheme 2).
Although a principle method for preparation of this crucial type of
* Corresponding author at: Key Laboratory of Drug Targeting and Drug Delivery
Systems of the Ministry of Education, West China School of Pharmacy, Sichuan
University, Chengdu 610041, China.
E-mail address: liangxu@scu.edu.cn (L. Xu).
https://doi.org/10.1016/j.cclet.2021.03.068
1001-8417/© 2021 Chinese Chemical Society and Institute of Materia Medica, Chinese Academy of Medical Sciences. Published by Elsevier B.V. All rights reserved.
Please cite this article as: D. Xiao, X. Zhao, J. Lei et al., Synthesis of [6-6-6] ABE tricyclic ring analogues of methyllycaconitine, Chin. Chem. Lett.,
https://doi.org/10.1016/j.cclet.2021.03.068

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Chinese Chemical Letters xxx (xxxx) xxx–xxx
Fig. 1. Methyllycaconitine and lycoctonine.
Scheme 2. Synthesis of ABE ring analogues 18 and 19. Reagents and conditions: (a)
benzylamine or ethylamine, Et2O BF3, CHCl3, reflux, 12 h; then acrylylchloride, THF,
Á
reflux, 12 h, 95% for 12a, 94% for 12b; (b) KOH, EtOH/H2O (3:1, v/v), 50 ꢀC, 15 h; then
1 mol/L HCl, 50 ꢀC, 2 h, 85% for 10a; 84% for 10b; (c) LiHMDS, CH3OOCCl, THF, -78 ꢀC,
3 h, 80%; (d) acrolein, K2CO3, acetone, r.t., 12 h, 90%; (e) (i) 2-methyl-2-butene,
NaClO2, NaH2PO4, t-BuOH/H2O (3:1, v/v), 50 ꢀC, 3 h; (ii) Ph2Se2, n-Bu3P, DCM, 0 ꢀC,
Scheme 1. (a) Representative approaches to the ABE analogues of methylly-
caconitine; (b) an aza-annulation followed by acyl radical cyclization strategy in this
work.
1 h, 80% for two steps; (f) Bu3SnH, ACN, toluene, reflux, 3 h, 84%; (g) t-BuNH2
Á
BH3,
DCM, r.t., 2 h, 86%; (h) Ag2O, CH3I, sealed, 60 ꢀC, 24 h, 90%; (i) BH3
2 h, 85%.
Á
THF, THF, reflux,
ene-lacatams has been reported starting from cyclohexone and
acrylonitrile by Murahashi via a two-step sequence [13], poor yield
and using of noble metal catalyst (RuH2PPh3) under forcing
conditions (sealed tube, 120 ꢀC) limit its application in a scalable
synthesis. Other methodology [12] involving aza-annulation with
imines and various acrylate derivatives were restricted by lack of
alkene regioselectivity and poor yields that result from formation
of the imines from ketones. In this event, we present a new two-
step reaction to produce 10 involving a highly efficient aza-
annulation of a β-enamino ketone and an incidentally discovered
enamine tautomerization induced by a facile decarboxylation.
First, following the Stille’s aza-annulation protocol [14], reaction of
ethyl 2-cyclohexanonecarboxylate 9 with benzyl amine in the
90% yield. Pinnick oxidation [15] cleanly converted aldehyde into
crude acid, which without purification, was transformed into
selenoester 15 through a selenation [16] using a combination of
diphenyldiselenide and tributylphosphine in 80% yield over two
steps. Having selenoester 15 in hand, we examined the key
transannular radical cyclization [17] to construct the bridged
analogues of ABE rings. Treatment of compound 15 with tributyltin
hydride (1.5 equiv.) and 1,10-azobiscyclohexanecarbonitrile (ACN)
(0.2 equiv.) in toluene at reflux caused a transannular cyclization of
an intermediary acyl radical to give the desired azabicyclo [3.3.1]
compound 16 in
a completely stereoselective manner. The
stereochemistry of the radical addition could be confirmed with
NOE difference experiments showing through-space interactions
between the amino methine proton (H-17) and the adjacent
methylene (H-5a) (the NOE spectrum of 16, see Supporting
information). The exclusive formation of the trans-fused BE moiety
in the present cyclization might be due to the acyl radical
cyclization has ostensibly tended to be thermodynamically
controlled [17d].
Next, incorporation of the functionality on the ABE rings was
attempted. To our surprising, selective reduction of the ketone
group of 16 was unexpectedly difficult. Employment of standard
reductive reagents such as NaBH4, NaBH(OAc)3 or L-selectride
uniformly gave a mixture of unidentified products. After screening
a variety of other conditions, it was finally discovered that
treatment of ketone with tert-butylamine-borane complex [18] at
room temperature afforded the desired alcohol 17 as a single stereo
isomer. Methylation with methyl iodide in the presence of silver(I)
oxide [19] as soft base in THF at reflux proceeded cleanly to furnish
11 in 90% yield. Subsequent thorough hydride reduction of the
presence of the Et2O BF3 followed by exposure of resultant crude
Á
enamine to acryloyl chloride gave the 12a smoothly, with the
alkene exocyclic relative to the ring generated through annulation.
Then hydrolysis of the ester group of 12a provided the crude acid,
which without purification, was warmed at 50 ꢀC under acidic
conditions in one pot to effect a mild decarboxylation, delivering
the desired double bond shifting ene-lacatam 10a in 81% yield over
two steps. Pleasingly, replacement of benzyl amine to ethyl amine
in first step could achieve the almost the same yield of N-ethyl
substituted ene-lacatam 10b by executing the same two-step
reaction sequence.
With the BE-ring surrogate in place, the formation of bridged
A-ring moiety with oxygen functionality at C-1 was addressed next
by means of a pivotal intramolecular transannular cyclization via
an acyl radical strategy. Thus, treatment of 10a with ClCOOMe
in the presence of LiHMDS at -78 ꢀC provided the β-ketoester 13 in
80% yield. Michael addition of 13 to acrolein gave the adduct 14 in
2

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Chinese Chemical Letters xxx (xxxx) xxx–xxx
ester and lactam moieties of 17 with BH3 in THF [20] provided diol
18 in 85% yield. The stereochemistry of the OH group at C-1 of 17
was established as an α orientation on the basis of the observation
of the key NOESY relationship between H-1 and H-5β in 18 (the
NOE spectrum of 18, see Supporting information).
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In summary, the synthesis of the new [6-6-6] ABE tricyclic ring
analogues of MLA with C-1 oxygenated substituents has been
achieved. The improved two-step reaction sequence involving a
smooth aza-annulation of β-enamino ketone and the facile
decarboxylation under mild condition provided a highly efficient
and practical preparation of N-alkyl substituted ene-lactam as the
precursor of BE rings. The bridged A ring unit was constructed
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Supplementary material related to this article can be
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cclet.2021.03.068.
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