Synthesis of biologically active natural products by [3?+?2] cycloaddition of non-stabilized azomethine ylides (AMY): Concepts and realizations

Article abstract of DOI:10.1016/j.tetlet.2017.01.036

Non-stabilized azomethine ylides (AMY) which are represented as a zwitterionic form of a C[sbnd]N[sbnd]C unit having four electrons in three parallel atomic π orbitals perpendicular to the plane of the dipole, undergoes 1,3-dipolar cycloaddition to produc

Full text of DOI:10.1016/j.tetlet.2017.01.036

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Synthesis of biologically active natural products by [3+2] cycloaddition of non-
stabilized azomethine ylides (AMY): Concepts and realizations
Ganesh pandey, Debasis Dey, Sandip Kumar Tiwari
PII:
S0040-4039(17)30058-8
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http://dx.doi.org/10.1016/j.tetlet.2017.01.036
TETL 48539
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Tetrahedron Letters
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Please cite this article as: pandey, G., Dey, D., Kumar Tiwari, S., Synthesis of biologically active natural products
by [3+2] cycloaddition of non-stabilized azomethine ylides (AMY): Concepts and realizations, Tetrahedron
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Tetrahedron Letters
Synthesis of biologically active natural products by [3+2] cycloaddition of non-stabilized
azomethine ylides (AMY): Concepts and realizations
Ganesh pandey, Debasis Dey, Sandip Kumar Tiwari
Molecular Synthesis Laboratory, Centre of Bio-Medical Research (CBMR), Sanjay Gandhi Postgraduate Institute of Medical Science Campus Raebareli Road Lucknow-
226014 (India)
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Available online
Non-stabilised azomethine ylides (AMY) which are represented as a zwitterionic form of a C-N-
C unit having four electrons in three parallel atomic π orbitals perpendicular to the plane of the
dipole, undergoes 1,3-dipolar cycloaddition to produce isolated as well as fused pyrrolidine ring
system
stereoselectively.
Various
new
structural
entities
related
to
x-
Keywords:
Azomethine ylide
Claisen rearrangement
Diels-Alder reaction
[3+2]-cycloaddition reaction
Enantioselective catalysis
azatricyclo[m.n.0.0a,b]alkanes are constructed by the intramolecular 1,3-dipolar cycloaddition
of nonstabilized cyclic azomethine ylides. The ylide is generated by the sequential double
desilylation of N-alkyl α, α’-bis(trimethylsilyl)cyclic amines using Ag(I)F as a one-electron
oxidant. Various alkaloids such as (±)-pancracine, (±)-brunsvigine, (±)-maritidine, (±)-crinine, (-
)-vincodifformine and (+)-aspidospermidine have been synthesized employing AMY
cycloaddition strategy.
1. Introduction
activated olefin to generate fused or isolated pyrrolidine 4
scaffolds, respectively9a,b,11 as shown in Scheme 1.
Isolated as well as fused pyrrolidine rings are common
scaffolds found in vast number of biologically active alkaloids,1
therefore, their construction in an efficient manner has attracted
attention of a large number of synthetic organic chemists.
Although, there are many approaches known to construct
substituted pyrrolidine rings in regio- and stereo-selective
manner,2,3 [3+2]-cycloaddition reaction of azomethine ylides
(AMY) with a suitable olefins is the most reliable and attractive
approach.4 Azomethine ylides5 are represented by a zwitterionic
structure with a C-N-C unit having four electrons in three parallel
atomic π orbitals perpendicular to the plane of the dipole which
reacts with another π system (olefins) involving a total of six π
electrons [π4s + π2s] and is considered to proceed through a
thermally allowed6 concerted process, though, non-concerted
possibility is also suggested.7 A detailed account on the
mechanistic discussion of AMY and its cycloaddition could be
found in literature.8 Our group has developed9 an innovative
concept to generate non-stabilized AMY 3 via one electron
oxidation of N, N’-dialkylsilylamines 1 either by photoredox
catalysis9a or by using Ag(I)F as one electron oxidant.9b
Mechanistically, this reaction was rationalized considering
sequential desilylation10 from the amine radical cation 2, thus,
generated after one electron oxidation of corresponding amine.
Scheme 1: Pyrrolidine ring generation through 1,3 dipolar
cycloaddition.
This strategy was utilized to construct indolizidine and
pyrrolizidine skeletons by [3+2]-cycloaddition9b of corresponding
AMY 6, generated by the sequential desilylation of 5, with ethyl
acrylate 7. The cycloaddition provided two regeoisomeric
pyrrolizidines 8 and 9 in 17:3 ratios. Since the isolation of pure
diastereomers was difficult, the mixture was reduced by LAH to
The resultant AMY reacts inter-or intra-molecularly with an
———
 E-mail: gp.pandey@cbmr.res.in

2
Tetrahedron
produce corresponding alcohols which upon derivatization with
bicyclic products (27 and 29) in excellent yields and
benzoyl chloride were separated to obtain pure diastereomers [10
(major) and 11 (Minor)]. The stereochemical assignments were
suggested on the basis of spectral comparison12 after their
conversion to alkaloids (±)-trachelanthamidine (11a) and (±)-
isoretronecenol (12a). A similar sequence from 8b provided a
short synthesis of indolizidine natural products, 1-aza-7-
(hydroxyl)-bicyclo[4:3:0] nonane13a (11b) and (±)-tashiromine
(12b)13b as shown in Scheme 2.
selectivity.11e (Scheme 5)
Scheme 5: Fused pyrrolidine ring generation through
intramolecular 1,3-dipolar cycloaddition
Driven by these successes, synthesis of some important
biologically active natural products were taken up to establish the
efficacy this strategy
Scheme 2: Natural product synthesis through AMY
2. APPLICATION IN NATURAL PRODUCT SYNTHESIS
Furthermore, generation of cyclic AMYs11 of the type 15 from
14 and their trapping with suitable dipolarophiles 16 was utilized
to construct x-azabicylo[m.2.1]alkanes (17 and 18) ring system
with good exo/endo selectivity14 as shown in Scheme 3.
Amaryllidaceae class15 of alkaloids are known to display wide
range of biological activities16,17 such as antitumor, antiviral,
acetylcholinesterase (AChE) inhibitory, immunostimulatory,
antimalarial, anxiolytic, antidepressive, anticonvulsive and weak
hypotensive activity. Since majority of these alkaloids possesses
fused pyrrolidine ring system, synthesis of some these natural
products were selected to establish the efficacy this strategy.18,19
Figure 1: Pyrrolidine ring containing Amaryllidaceae and
Aspidosperma alkaloids.
Scheme 3: Synthesis of x-azabicylo[m.2.1]alkanes
This strategy was extended for the synthesis of epibatidine11c
(25), an entirely new class of analgesic alkaloid which possesses
7-azabicyclo [2.2.1] heptane skeleton to which
a 5-(2-
chloropyridinyl) substituent is attached in exo-orientation.
(Scheme-4)
Therefore, we synthesized some of these natural products
utilizing 1,3-dipolar cycloaddition of corresponding non-
stabilized AMY generated through the concept delineated above.
At first, construction of alkaloids having pentacyclic 5,11-
methanomorphanthridine scaffold, encompassing alkaloids of
amaryllidaceae subclass such as [(±)-pancracine (30), (±)-
brunsvigine (31) (±)-montanine (32), and (±)-coccinine (33),]
which are associated with a variety of biological activities
(Figure 1)20 were initiated. We accomplished the synthesis of
some of these alkaloids by [3+2]-cycloaddition of AMY 43.
While designing the synthetic route for 30-31, it was envisioned
that intramolecular endo attack (A) of AMY 43 on the “re”
face of the α,β-unsaturated carbonyl moiety would be
energetically more
Scheme 4: Synthesis of Epibatidine.
Optically pure (-)-24 was also synthesized11c by carrying out
cycloaddition of 15 using chiral dipolarophile which produced
corresponding cycloadducts in 9:1 diastereomeric mixture. As a
part of further exploration of this reaction, substrates 26 and 28
on AMY generation and cycloaddition gave corresponding

carbon Wittig olefination27 produced 53 which on reduction with
DIBAL-H and re-oxidation under Swern oxidation condition28
gave 54. Reaction of 54 with vinyl magnesium bromide followed
by acetate protection of free –OH group produced 55 as a mixture
of two diastereomers. Ring closing metathesis (RCM)29 using
Grubb’s second-generation30 catalyst with 55.HCl salt in DCM
produced corresponding cyclized products 56:57 in 1:2.5 ratio.
The major diastereomer 57 was subjected to dihydroxylation
followed by isopropylidine protection to generate 58. After –O-
acetate deprotection followed by mesylation, it was refluxed with
DBU for 2 days in toluene to give 59. Finally, the synthesis of 31
was completed after acetonide deprotection by passing HCl (gas)
in its methanolic solution. (Scheme 9)
Scheme 6: Retrosynthetic planning for alkaloids.
favored than exo-attack (B) due to steric repulsion. Such a
cycloaddition was also expected to fulfill all the stereochemical
requirements of 42 in a single step without using a starting
material with fixed stereocenters. (Scheme 6)
Scheme 9: Stereoselective synthesis of racemic brunsvigine.
Scheme 7: Synthesis of AMY precursor.
Maritidine (34), another important member of Amaryllidaceae
alkaloids, isolated from Pancratium maritimum, Pancratium
tortuosum, and Zephyranthes genera, is one of the first alkaloid
to possess a 5,10b-ethanophenanthridine nucleus containing
dimethoxy rather than methylenedioxy substituents at C-8 and C-
9 positions of the crinine skeleton31 (Figure 1). These alkaloids
display structural complexities due to the presence of adjacent
quaternary and tertiary carbon stereocenters with a fused
pyrrolidine ring. Proper stereospecific installation of substituents
has been the key challenge to the synthesis of these types of
alkaloids.
While envisaging a novel route32 towards the synthesis of 34
via oxomaritidine (60), we constructed C1–C2 double bond by
the cyclo-aldolization/ condensation of corresponding
methylester 61. After serious evaluation of 61, it was convincing
enough to evaluate an intramolecular [3 + 2]-cycloaddition of a
non- stabilized AMY 62 with tethered geminally disubstituted
dipolarophile for the formation of both C4a–C10b and C11–C12
bonds in one step which would also generate required
stereocenters of 61 in a single step. The corresponding AMY was
generated in situ from the corresponding α,α'-bis(trimethylsilyl-
methyl) alkyl amine 63 using Ag(I)F as one electron oxidant.
(Scheme 10)
The cycloaddition precursor 44 was prepared (60 % yield) by
the Heck coupling21 of 47 with the methyl vinyl ketone (MVK, 8
equiv.). Synthesis of 47 was achieved in 81 % yield by the N-
alkylation of 45 with benzyl iodide (46) in refluxing CH3CN in
the presence of activated K2CO3 followed by simple benzoylation
of the primary hydroxyl group. The bis-silylated secondary
amine 45 was synthesized easily from 3-propan-1-ol following
literature protocol.22 (Scheme 7)
Cycloaddtion of 44 in acetonitrile in the presence of Ag(I)F as
one electron oxidant produced 48 smoothly in 56% yield which
on debenzoylation with LiOH/MeOH gave 49. Interestingly, the
important C12 stereocenter epimerized during this reaction.
Conversion of free –OH moiety to mesylate followed by
intramolecular cyclization under kinetic control23 using KHMDS
furnished 50. The resultant 50 was converted to enol triflate by
enolisation using LDA followed by Commin’s reagent24 which
on treatment with palladium (0) gave 51 in excellent yield. (±)-
Pancracene (30) was synthesized from this intermediate by
following known procedure.25 (Scheme 8)
Scheme 8: Formal synthesis of (±)-pancracine.
Relatively different synthetic sequence was adopted for the
synthesis of (±)-brunsvigine (31) from 52, formed by the
cycloaddition of corresponding AMY precursor.26 Acetal moiety
deprotection of 52 by oxalic acid/THF-H2O followed by one-
Scheme 10: Retrosynthetic analysis of Maritidine.

4
Tetrahedron
The requisite precursor 63 was synthesized by the simple
transformation of commercially available veratryl alcohol and
methyl vinyl ketone.33
Scheme 12: Synthesis of oxo-Maritidine and Maritidine
After accomplishing the total synthesis of 34, our focus was
shifted towards synthesizing the (±)-crinine (35) because of its
structural complexities and pronounced biological activities36.
Subsequent study has also shown this molecule to be highly
selective in inducing apoptosis against tumor cells at low
concentration.37 Furthermore, this alkaloid is also shown to
possess immune-stimulant, antitumor and antiviral activities.36
The only structural difference between 35 and 34 is the presence
of methylene dioxy group at aromatic ring instead of dimethoxy.
Therefore, entire synthetic sequence was carried out identically35
except starting with appropriately substituted starting material 68.
(Scheme 13)
Scheme 11: Rationale for regio- and stereoselectivity.
Regio- as well as stereoselectivity issues, the two important
aspects of this cycloaddition protocol, were critically scrutinized
at the planning stage. The origin of the 5,10b-
ethanophenanthridine regiochemistry during cycloaddition was
envisioned on the basis of the change in the lowest unoccupied
molecular orbital (LUMO) energy of the dipolarophile owing to
its conjugation with the aromatic ring and ester moiety present on
the same carbon. The cycloaddition reaction of 63 was visualized
to generate the vicinal quaternary and tertiary carbon
stereocenters in one step with the orientation of substituents in
the dipole deciding the stereochemical outcome at C4a position.
For illustration, it was envisioned that the alkyl ketal moiety in
AMY 64 may experience severe stereoelectronic congestion with
the tethered aromatic ring flanked between the dipole and the
dipolarophile as shown in transition State-I (TS-I) (Scheme 11)
resulting in the epimeric epi-4a-66. On the other hand, TS-II, in
which the alkyl ketal side chain of AMY 65 and the aromatic ring
are distantly away from each other, would generate the desired
C4a stereochemistry 66. Thus, it was anticipated that substrate-
controlled stereo- electronic effect would favor during
cycloaddition of 63 and reinforce the stereochemical outcome in
the tricyclic skeleton with suitable stereochemical disposition of
the substituents required for assembling of the C-ring of the
target alkaloid.
Scheme 13: Synthesis of crinine alkaloid.
Structurally intricate and bio-enriched Aspidosperma
alkaloids38 such as 38 and 39 constitute a unique class having
pentacyclic[6.5.6.6.5] ABCDE ring frameworks with contiguous
cis-stereocenters at C-7, C-21 and C-20 (all carbon quaternary) as
a common skeletal feature (Figure 1). Some members of this
class of alkaloid [vincristine, vinblastine] are well known drugs
for cancer chemotherapy39 whereas other members like
vincadifformine (cytotoxic),40 tabersonine (pronounced inhibitory
effect against SK-BR-3 human cancer cell lines, better than
cisplatin),41 and jerantinine-E (stronger in vitro cytotoxicity
against human KB cells, IC50 < 1 μg/mL)42 are known to be
pharmacologically important alkaloids.
The basic pentacyclic framework of 38, common to most of
these pharmacologically active alkaloids, has been an attractive
synthetic target for the showcasing of any new synthetic
methodologies. Therefore, development of an efficient strategy
for the construction of 38 still invites great interest. One of the
most exploited approaches for the construction of this pentacyclic
alkaloid in racemic43 as well as in enantioselective44 form has
been the indolization of the 6a-ethyloctahydro-1H-pyrrolo-
[3,2,1-ij]quinolin-9(2H)-one (tricyclic core 73).45 Therefore, from
a synthetic point of view, how to expeditiously establish such a
privileged core 73 with the crucial C-20 all-carbon quaternary
stereocenter is an important issue in developing asymmetric
synthesis of 38 and structurally related bisindole alkaloids.
The above hypothesis was corroborated by isolating 66 (56%)
as a single diastereomer by the cycloaddition of AMY, generated
from 63 by the treatment with Ag(I)F in dichloromethane at
ambient temperature and inert atmosphere. Cycloadduct 66 was
easily transformed to oxomaritidine (60) by following a series of
simple transformations such as LAH reduction, Swern
oxidation34 to generate 67 followed by careful deketalization
using p-TSA and intramolecular aldol reaction. Oxomaritidine
(60) was transformed to maritidine (34) by following the
literature procedure.35 (Scheme 12)

Scheme 16: Synthesis of aspidospermidine.
Scheme 14: Retrosynthetic analysis of Aspidospermidine.
Since structural framework 73 embodies a fused pyrrolidine
framework (E-ring) and all-carbon quaternary stereocenter at C-3
position of D-ring (a piperidine ring), a strategy was designed to
construct C-ring with the required ketone functionality
encompassing these two rings. Since, a strategy of creating all
carbon quaternary stereocenter (both enantiomers) at C-3 position
of cyclic amides using Johnson-Claisen rearrangement was
available46 and an obvious choice of intramolecular [3 + 2]
cycloaddition of AMY 74 was proposed for the construction of
fused pyrrolidine moiety, the reasonable retrosynthetic strategy
looked simple (Scheme 14) for the synthesis of
aspidospermidine.
However, this compound failed to generate azomethine ylide,
therefore, it was manipulated to 85 via TMSCN addition
followed by PPTS treatment. Oxidation of 85 by Dess-Martin
reagent produced 75. It was visualized that 75 on treatment with
a Lewis acid will lead to the generation of iminium ion by the
opening of the aminal ring which subsequently would undergo
desilylation to give azomethine ylide 74. Intramolecuclar [3 + 2]
cycloaddition of this ylide with a tethered dipolarophile produced
(−)-40 in stereospecific manner presumably involving
nonstabilized azomethine ylide 74 as the intermediate.2,48 This
important intermediate was converted to aspidospermidine (38)
via Fischer indolization.49 (Scheme 16)
Acknowledgments
Authors are grateful to all those who contributed in this field
from the group. We are also thankful to Department of Science
and Technology, New Delhi for their generous support in the
form of J. C. Bose Fellowship to one of us.
References and notes
Scheme 15: Synthesis of AMY precursor for
Aspidospermidine.
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Tetrahedron
8
Highlights
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Developed non-stabilized AMY via one electron oxidation of N,N’-dialkylsilylamines
Synthesized indolizidine and pyrrolizidine frameworks by [3+2]-cycloaddition of AMY
Synthesis of epibatidine alkaloid having 7-azabicyclo [2.2.1] heptane skeleton
Synthesis of (±)-pancracine, (±)-brunsvigine, maritidine, crinine
Synthesis of (-)-vincodifformine and (+)-aspidospermidine

Graphical abstract
Synthesis of biologically active natural products by [3+2] cycloaddition of non-stabilized
azomethine ylides (AMY): Concepts and realizations
Ganesh Pandey*, Debasis Dey, Sandip Kumar Tiwari