Synthesis of 2-Azabicyclo[m.n.0]–Alkanes and Their Application towards the Synthesis of Strychnos and Stemona Classes of Alkaloids

Article abstract of DOI:10.1002/ejoc.202000507

2-Azabicyclo[m.n.0]alkane ring systems, the conceptual precursors towards the synthesis of Strychnos and Stemona classes of alkaloids, were synthesized from tert-butyl 2-(phenylsulfonyl)-7-aza-bicyclo[2.2.1]hept-2-ene-7-carboxylate by alkyl Grignard reaction and intramolecular cyclisation of the in situ generated ring opening product 2. The synthesized cis-hexahydroindole 3 and cis-octahydro-benzo[b]azepine 5 scaffolds were utilized to construct the advanced intermediates 25 and 35, respectively, towards the synthesis of the corresponding Strychnos and Stemona classes of alkaloids.

Full text of DOI:10.1002/ejoc.202000507

European Journal of Organic Chemistry
Accepted Article
Accepted Article
Title: Synthesis of 2-Azabicyclo[m.n.0]alkanes and Their Application
Towards the Synthesis of Strychnos and Stemona Class of
Alkaloids
Authors: Binoy Majumder and Ganesh Pandey
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.202000507
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01/2020

10.1002/ejoc.202000507
European Journal of Organic Chemistry
COMMUNICATION
Synthesis of 2-Azabicyclo[m.n.0]alkanes and Their Application
Towards the Synthesis of Strychnos and Stemona Classes of
Alkaloids.
Binoy Majumder[a],[b] and Ganesh Pandey*[a]
[a]
B.Majumder, Prof. Dr. G. Pandey
Department of Chemistry
Institute of Science, Banaras Hindu University
Varanasi, 221005, Uttar Pradesh, India
E-mail: ganesh.pandey1@bhu.ac.in
http://www.bhu.ac.in/science/chemistry/
[b]
B. Majumder
Division of Organic Chemistry
National Chemical Laboratory, CSIR
Pune, 411008, India
Supporting information for this article is given via a link at the end of the document.
Abstract: 2-Azabicyclo[m.n.0]alkane ring systems, the conceptual
precursors towards the synthesis of Strychnos and Stemona classes
of alkaloids are synthesized from tert-butyl 2-(phenylsulfonyl)-7-aza-
bicyclo[2.2.1]hept-2-ene-7-carboxylate by alkyl Grignard reaction
and intramolecular cyclisation of the insitu generated ring opening
product 2.The synthesized cis-hexahydroindole 3 and cis-octahydro-
benzo[b]azepine 5 scaffolds have been utilized to construct the
advanced intermediates 25 and 35 respectively,towards the
synthesis of corresponding Strychnos and Stemona classes of
alkaloids.
Visualizing an appropriate precursor for easily accessing a
common molecular scaffold of either a natural product or
analogues is an important approach in natural products
synthesis1. In this context, we envisioned cis-2-alkyl
cyclohexenylamine (1) as an ideal precursor for stereoselective
construction of cis-2-azabicyclo[m.n.0]alkane (3,
4 and 5)
scaffolds and their further diversification towards various classes
of biologically active natural products as depicted in Fig. 1. Our
long-standing research interest in the area of synthesizing
naturally occurring, structurally complex and biologically active
alkaloids kindled our interest to develop a unified strategy to
synthesize these alkaloids.2,3 Careful literature survey revealed
that the synthesis of 1 and its exploration in natural product
synthesis is not yet known. The presence of an internal Michael
acceptor at 3,4-position of this molecule attracted our attention
towards synthesizing this scaffold owing to its easy
transformation to other useful functionalities, easily amenable for
application in the synthesis of various classes of alkaloids.
We visualized that the synthesis of scaffold 1 could be achieved
by nucleophilic ring opening of 14 with appropriate Grignard
reagents, functional group transformations followed by
cyclization. For this purpose, (±)-14 was prepared (overall yield
64%) via [4+2] cycloaddition of N-Boc-pyrrole and
ethynylsulphonyl benzene followed by chemoselective reduction
of electron rich olefinic double bond4(see supporting information).
Figure 1. Structures of the most abundant 2-azabicyclo[m.n.0]alkane ring
system (m ═ 3,4,5 and n ═ 4.) related to the both natural products synthesis
and drug discovery.
It was further surmised that Grignard reaction to this highly
strained bicyclic framework 14 would be facially selective and
would provide corresponding cis-1,2-disubstituted cyclohexe-
nylamine ring template
manipulation.
1 amenable for more synthetic
Towards this premise, we commenced our synthetic study with
(±)-14 to validate our proposed hypothesis. Vinyl Grignard
addition to 14 in the presence of CuCN (0.6 equiv.) resulted in
the formation of 15 which on hydroboration with 0.5 (M) 9-BBN
(1.5 equiv.) followed by treatment with MsCl/Et3N delivered
corresponding cyclized product 3 (overall yield 19%, 36% brsm)
as shown in Scheme 1. Alternatively, scaffold 3 was also
obtained in much improved yield (overall yield 84%) following a
reaction sequence which includes initial ring opening of (±)-14
with allyl magnesium Grignard, oxidative cleavage (OsO4/NaIO4)
of terminal olefin followed by reductive amination
1
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10.1002/ejoc.202000507
European Journal of Organic Chemistry
COMMUNICATION
(NaBH3CN/CH3COOH). This result encouraged us further to
construct scaffold 4 and 5 from common intermediate14 as
shown in Scheme 1.
strategies. Moreover, to the best of our knowledge, devising a
new and general strategy in a stereoselective fashion for the
construction of cis-decahydro-[1H]-benzo[b]azepine ring system
(5), except Beckmann rearrangement7f, is not yet known.
After establishing that scaffolds 3, 4 and 5 can be easily
accessed in multi-gram scale from common bicyclic scaffold 14,
we set our goal to explore their applications in the synthesis of
some of the alkaloidsas shown in Fig.1. In this communication,
we report a new synthetic route for the synthesis of 25, a
functionalized aza-[6,5,6]-tricyclic skeleton,which can be utilized
in the total synthesis of Strychnos class of alkaloids8 such as
dehydrotubifoline (6), tubifoline (7),tubifolidine (27)9 and 35
towards the synthesis of (±)-stenine (11) and (±)-
tuberostemonine (12).
Scheme 1. Synthetic routes for the construction of cis-2-azabicyclic scaffolds
To synthesize scaffold 4, precursor 17 was first transformed to
corresponding 19 (yield 71%, 90% on brsm) through the similar
hydroboration condition as described above . However, further
attempt of cyclizing 19 using the usual condition (MsCl/Et3N)
failed to provide 4 even at elevated temperature and gave only
corresponding mesylated product which on N-Boc deprotection
(TMSCl/NaI) followed by stirring at room temperature in
presence of Cs2CO3 (2 equiv.) and N-Boc-reprotection gave 4 in
51% overall yield (overall yield 33%, 42% brsm from 14).
Similarly, scaffold 5 (overall yield 33%) was prepared by the
Grignard (derived from A1) addition to 14 (81% yield),
chemoselective deprotection of -OTBS [0.8 (N) HCl] followed by
cyclization sequence as used in case of 19.
It may be worth highlighting that few approaches are known for
the construction of functionalized hexahydro-1H-indole5 and
corresponding octahydro-1H-indole (3) ring systems6 involving
transition-metal or noble metal catalyzed cyclization of dienes
with amino-functionalities. Other methodologies include
hydrogenation of commercially available (S)-indoline-2-
carboxylic acid,6a tandem Friedel-Crafts intramolecular
macrocyclization of non-activated tethered alkenes or alkynes
with N-acyloxyiminium ion6b and organocatalyzed Michael
addition followed by a tandem Robinson-aza-Michael double
cyclization process5f. Similarly, construction of scaffold 4 have
involved intramolecular aldol cyclization of a tetrasubstituted
piperidine derivative,7afree radical/anionic cyclization of
cyclohex-2-enylamine,7btandem ene-yne-ene ring closing
metathesis of L-alanine derived an acyclic precursor followed by
a stereoselective hydrogenation of the resulting diene7c and ring
opening-ring closing metathesis (ROM, RCM) of 2-
azabicyclo[2.2.2]octene.7dOther strategies involve aza-[4+2]
Scheme 2. Synthesis of aza-[6,5,6]-tricyclic core 25.
Initially, we focused our attention to synthesize scaffold 26 from
precursor 3 following the steps as shown in scheme 2.
Dihydroxylation of 3, using OsO4 (6 mol%)in presence of citric
acid10and subsequent removal of the phenylsulphonyl group
provided corresponding α-hydroxy ketone 22 in 88% yield which
was transformed to 23 via elimination of the corresponding
11
mesylate using Li2CO3 as a base. After N-Boc deprotection, it
was N-alkylated with A2 (see supporting information)8ato obtain
24.12Lithiation of 24 using t-BuLi in presence of CuBr2.SMe2
failed to undergo intra-molecular 1,4-conjugate addition.13Our
another attempt involving Ni(COD)2 mediated cyclisation14 was
also remained unsuccessful. However, to our gratification, 24
under reductive Heck reaction condition provided 25 with an
endocyclic double bond in good yield (overall yield 48% from 23)
instead of desired 26.15At this stage, we became confident that
successful construction of (±)-25 and its further elaboration
would lead to some of the Strychnos class of the alkaloids.
Simultaneously, we had also started to diversify 5 towards the
total synthesis of both (±)-11 and (±)-12, a class of Stemona
alkaloids, which were isolated from the roots of Stemona
species,16used for the treatments of respiratory ailments along
with insecticidal, anthelmintic and various neurochemical
effects.17In particular, stenine B displays inhibitory activities on
cycloaddition
of
acylnitroso
compound
followed
by
intramolecular aldol condensation.7eHowever, stereoselectivities
remains a major concern associated with some of these
2
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10.1002/ejoc.202000507
European Journal of Organic Chemistry
COMMUNICATION
AChE (IC50=19.8±1.2μM) whereas 12 has promising neurotropic
activity (ChAT enzyme inhibitor)17d and displays activity in
reversing multidrug resistance in chronic myelogenous leukemia
cells K562/ADR.17eThe unique structural features with
remarkable bioactivity has attracted the attention of many
synthetic organic chemists18 and owing this reason, we initially
directed our attempt towards the synthesis (±)-11 exploiting
scaffold 5. Allylic oxidation of 519withPDC/TBHP20gave28 in 65-
70% yield. Stereoselective α-alkylation of 28 using ethyl
iodoacetate as an eletrophile and LiHMDS as a base gave 29 as
a single diastereomer whose stereochemistry was established
by observing NOE correlation between the C9a-H (δ = 4.77
ppm) and C2-H (δ = 2.66 ppm). Subsequent, desulphonylation
of 29 using Al/Hg delivered 30 in 86% isolated yield.21At this
stage, we proceeded to achieve the synthesis of 32 by
stereoselective conjugate addition using Gilman reagent
(Et2CuLi) in presence of TMSCl,22followed by in situ α -
hydroxylation of corresponding enolate using Davis oxaziridine.
However, this attempt remained unsuccessful probably due to
the steric hindrance. Therefore, we progressed stepwise and
first carried out 1,4-conjugate addition using EtMgBr/CuI (RCu¯
type)23c in presence of LiBr and isolated corresponding 31 in
81% yield.23Davis oxaziridine mediated hydroxylation of 31 in
presence LDA, successfully provided 32 in 77% yield as a single
diastereomer.24
Scheme 3. Synthesis of fully substituted cyclohexane ring C (33).
At this stage, to construct crucial butenolide ring with C-13
methyl substitution, we utilized an intramolecular aldol reaction
of 33 (prepared by treating 32 with Ac2O in presence of dry
pyridine) using KHMDS as a base and gave 35 probably in situ
elimination of -OAc group from intermediate 34. As we have
made significant progress using optically pure 1425, compound
35 was not fully characterized here because of insufficient
quantity, but HRMS confirmed its formation.
After successful elaboration of 3 to 25 and 5 into 35, we
became confident that our conceptual approach of synthesizing
alkaloids as shown in Fig 1 by exploiting molecular scaffold 2
would succeed, we stopped further research using (±)-14 and
began with optically pure1425 and results will be published as full
paper soon.
In summary, an effective synthetic route has been developed
for the syntheses of cis-hexahydroindole (3), cis-
octahydroquinoline (4) and cis-octahydrobenzo[b]azepine (5)
Figure 2: Observed key NOESY correlations of the intermediate
30 and 32.
The relative stereochemistry of 32 was fully established by
NOE correlation between C11-H (δ = 3.50 ppm), C9-H (δ =
2.22 ppm) and C9a-H (δ = 2.60 ppm) (Fig. 2).
scaffolds embedded with
a
versatile functionality (vinyl
sulphone) for further functionalization. The pivotal CDE ring
system 25 is set up from 3 for further elaboration toward the total
synthesis of Strychnos alkaloids. Similarly,
a
highly
stereoselective and flexible synthetic route toward the synthesis
of Stemona alkaloids utilizing the cis-octahydrobenzo[b]azepine
scaffold 5 have been established. Future research is continuing
using optically pure 14.
Acknowledgements
G.P. thanks to SERB, New Delhi for financial support (J.C. Bose
Fellowship). B.M. thanks to CSIR, New Delhi for award of a
research fellowship.
3
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10.1002/ejoc.202000507
European Journal of Organic Chemistry
COMMUNICATION
[16] F.-P.Wanga, Q.-H. Chen, Natural Product Communications2014,9, 1809 –
1822.
Keywords:cis-2-alkyl cyclohexenyl amines• Michael addition•
Grignard reagents•Strychnosalkaloids•Stemona alkaloids
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Entry for The Table of Contents
Key Topic: 2-Azabicyclo[m.n.0]alkane ring systems
Synthesis of 2-Azabicyclo[m.n.0]alkanes and Their Application Towards the Synthesis of Strychnos and Stemona Classes
of Alkaloids.
I
From an common precursor to three 2-azabicyclic ring systems– This is a first report on the synthesis of cis-hexahydroindole,
cis-octahydroquinoline and cis-octahydrobenzo[b]azepine scaffolds using a common synthetic route and a common precursor. The
scaffolds further have been used to diversify into more advanced scaffolds towards the synthesis of Strychnos and Stemona class of
alkaloids.
5
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