(-)-Cytisine: Access to a stereochemically defined and functionally flexible piperidine scaffold

Article abstract of DOI:10.1039/c8ob01456f

N-Benzyl cytisine undergoes an efficient C(6)-N(7) cleavage via directed C(6) lithiation, borylation and oxidation to provide a "privileged" heterocyclic core unit comprising a highly functionalised, cis-3,5-disubstituted piperidine in enantiomerically pure form. The potential offered by this unit as a means to explore chemical space has been evaluated and methods have been defined (and illustrated) that allow for selective manipulation of N(1), C(3′), and the pyridone N. The pyridone core can also be diversified via bromination (at C(3′′) and C(5′′)) which is complementary to direct C-H activation based on Ir-catalyzed borylation to provide access to C(4′′). The use of a boronate-based 1,2-migration as an alternative trigger to mediate C(6)-N(7) cleavage of cytisine was evaluated but failed. However, the stability of the intermediate boronate opens a new pathway for the elaboration of cytisine itself using both Matteson homologation and Zweifel olefination.

Full text of DOI:10.1039/c8ob01456f

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DOI: 10.1039/C8OB01456F
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ARTICLE
(–)-Cytisine: Access to a Stereochemically Defined and
Functionally Flexible Piperidine Scaffold
Received 00th January
Worawat Niwetmarin, Hugo Rego Campello, Hazel A. Sparkes, Varinder K. Aggarwal and Timothy
Gallagher*
20xx,Received 00th January 20xx,
Accepted 00th January 20xx
DOI: 10.1039/x0xx00000x
N-Benzyl cytisine undergoes an efficient C(6)-N(7) cleavage via directed C(6) lithiation, borylation and oxidation to provide
a “privileged” heterocyclic core unit comprising a highly functionalised, cis-3,5-disubstituted piperidine in enantiomerically
pure form. The potential offered by this unit as a means to explore chemical space has been evaluated and methods have
been defined (and illustrated) that allow for selective manipulation of N(1), C(3’), and the pyridone N. The pyridone core
can also be diversified via bromination (at C(3’’) and C(5’’)) which is complementary to direct C-H activation based on Ir-
catalyzed borylation to provide access to C(4’’). The use of a boronate-based 1,2-migration as an alternative trigger to
mediate C(6)-N(7) cleavage of cytisine was evaluated but failed. However, the stability of the intermediate boronate opens
a new pathway for the elaboration of cytisine itself using both Matteson homologation and Zweifel olefination.
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structural diversity available is well exemplified by Schwarz’s
-santonin.5 Here, both the natural product
Introduction
work on α
readily available variant
1
and a
2
(available from 1 by acid-catalysed
Contemporary “small molecule” drug discovery relies on a
variety of strategies to both identify and develop “hits” into
leads and then drug candidates. Clearly, the ability to define
and explore novel “chemical space” plays a key role in terms of
generating (and then protecting to enable further exploitation)
intellectual property.1 For many years natural products
provided a valued entry to enable structural variation but
pharmaceutical industry interest in this area has, at points,
waned in favor of, for example, combinatorial chemistry and
related approaches as the preferred means by which to
rearrangement) provided analogues of both of these related
O
O
R
O
H
R
R
O
O
H
O
R
R
H
1-O-Acetylbritannilactone: 24 analogues4a
Maslinic acid: 264 analogues4b
achieve molecular diversity.2
However, the enormous
structural variation associated with natural products has,
regardless, continued to provide a source of inspiration (and a
guide) that has led to the development of, for example,
diversity-oriented and “chemical genetics” approaches to lead
discovery.3
Natural products, which are often available in enantiomerically
pure form and may contain multiply stereogenic centers, do
provide one important starting point for a diversity-oriented
approach to drug discovery. Several natural products or core
components
of
natural
products,
such
as
1-O-acetylbritannilactone4a and maslinic acid4b have found
application in this area (Scheme 1).
scaffolds that were explored as inhibitors of 5-lipoxygenase.
Scheme 1 Top: Example of natural products providing a
Taking this further, an ability to harness further the reactivity
of a readily available natural product to widen the reach of the
functionalised core scaffold.
-santonin
Bottom: derivatisation of
α
1.
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The role of “privileged scaffolds” serves as a further focus in was achieved as shown in Scheme 2 by C(6)-lithiation (via
8)
this area, with many being based on or incorporating a and (in situ) silylation of (–)-N-methylcytisine (caulophylline)
7
heterocyclic core. Of these, piperidines are especially widely followed by C-Si
distributed and are found in a large number of bioactive and sequence demonstrated the underlying concept by liberating
important pharmaceutical compounds.6
Our work has the piperidine moiety (highlighted in blue) and provided a
focussed on developing new and stereochemically-defined direct entry to the related lupin piperidine alkaloid (+)-
heterocyclic scaffolds based, in part, on nitrogen-based natural kuraramine 11 in 18% overall yield from (-)-7 14
products that incorporate piperidine moieties.7 These include
coerulescine , which led to the development of a range of
stereochemically-defined spirocyclic bis(azacycles), such as the
piperidine and the pyrrolidine-containing units Each
and 5 8
→ C-O oxidation followed by reduction. This
.
3
4
.
of these spirocyclic scaffolds (within which the individuals
enantiomers are accessible) offers three discrete
functionalisation sites:
two secondary but readily
differentiated amines (blue and purple), and a primary alcohol
(red), all of which are distributed across a spatially distinctive
spirocyclic core.
Scheme 2. Top: C(6) Lithiation triggering N(3)
→
C(6) acyl
Bottom: C(6) Oxidative
; a biomimetic synthesis
migration (Rouden et al13).
functionalisation of N-methylcytisine
7
of (+)-kuraramine 11 (Gallagher et al14).
We have, more recently, aimed to extend this chemistry by
evaluating the opportunity to “release” a stereochemically
complex and functionally-flexible piperidine core unit from a
readily accessible precursor; this is related to but distinctive
from the concept outlined in Scheme 1. Our initial focus for
this has been the development of the chemistry based on (–)-
However, this initial solution involved the use of a silyl
electrophile which necessitated a stoichiometric amount of a
mercury-based oxidant to achieve the key Fleming-Tamao
oxidative cleavage (9→ hemiaminal 10; overall 26% from 7);
alternatives to Hg(II) were evaluated but failed (see below).
This issue alone, notwithstanding the modest yields, presents a
clear block to any more general use of this approach to access
a versatile heterocyclic (piperidine) scaffold or in a fragment-
based approach to drug discovery. Given the goal of exploiting
an ability to fragment cytisine, alongside the recognised
importance of the piperidine scaffold within medicinal
chemistry and a consequential ability to access efficiently
differentiated and enantiomerically-pure piperidine-based
libraries, this key synthetic obstacle had to be addressed.
cytisine 6, a readily accessible lupin alkaloid from Laburnum
anagyroides,9 and the results of this work are summarised in
this paper.
(-)-Cytisine, which is
a partial agonist of the nicotinic
acetylcholine receptor (the high affinity nicotine binding site in
brain), is marketed (as Tabex®) within Eastern and Central
Europe for smoking cessation.10,11 While that specific nicotinic
profile may not be required (or desired), we recognised that
cytisine
6 offered a readily available starting point from which
In this paper, we describe a much more user-friendly solution
to the cleavage of the C(6)-N(7) bond of cytisine shown in
Scheme 2, which also offers access to the piperidine core with
flexibility around the secondary amine protecting group.
Further, the chemistry we have now developed avoids any
heavy metals and is significantly more efficient and scalable.
We have not explicitly focussed on a specific medicinal
chemistry target, rather we have aimed to exemplify how the
piperidine core can be both accessed and manipulated at
various sites to provide access to a wide range of functional
variants. The scope of this chemistry is outlined, in terms of
to construct a series of structurally diverse libraries if, for
example, the piperidine unit (coded blue) could be “released”
from within the tricyclic heterocyclic core of
6.
Cytisine 6 has already inspired a diversity-oriented synthesis
approach to novel inhibitors of Bcl-2 and there has been
extensive studies associated with the substitution of cytisine
itself, driven largely by attempts to develop novel nicotinic
ligands.12 Of particular relevance to the work described here
are the studies of Rouden and co-workers on the site-specific
lithiation of N-acylated cytisines; this is illustrated by an N to C
acyl transfer to functionalise at C(6) (Scheme 2).13 We had
reasoned that using an appropriate electrophile,
functionalisation of C(6) would allow for cleavage of the
C(6)-N(7) link, and release of an intact piperidine unit. This
the sites that become accessible, by general structure
A and
the issues around accessing each of these sites serves as the
focus of this paper. The positions immediately accessible for
derivatisation include two differentiated nitrogen centres (N(1)
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NMe
N
NMe
and N(1’’) in the piperidine and the pyridone moieties
respectively); an ability to manipulate the C(3′) methylene
unit; further functionalisation of the pyridone moiety via either
electrophilic bromination (which occurs predominantly at
C(3″)) or, and of more utility and novelty, Ir-catalysed C-H
activation which selectively targets C(4″).
NMe
LDA (0.1-0.5 M)
Me2PhSiCl (2-5 equiv.)
O
O
O
N
N
TMEDA (0-1 equiv.)
THF, -78°C to r.t.
10
E
9
E
(E=Me2PhSi)
7
12
up to 90%
up to 13%
O
This program has been driven in part by an increased
O
N
N
MeN
13
up to 17%
N
Me
Scheme 3. Optimization of C(6) lithiation. Variables evaluated
were substrate concentration, equivalents of LDA and
Me2PhSiCl, and presence of TMEDA (key to a high yield of
Details are available in the Supplementary Information.
9)
Although we did observe yields of
9 of up to 90%, 83%
reflected the yield obtained when competing lithiation (and
trapping) at C(10) was suppressed. The latter led to a C(10)
silylation adduct 12 (and this was exacerbated in the absence
of TMEDA) and we also observed a (known)13b dimerization
product 13 (Scheme 3).
awareness of the power and potential within medicinal
chemistry associated with cost effective in silico assessment of
ligands against protein targets of interest. Indeed, the goal
would be to enable a full evaluation of the “effectiveness” of a
ligand or family of ligands prior to embarking on an expensive
program of chemical synthesis and evaluation by biological
assay.15 As the dependability of these in silico methods
increases so will their value as a reliable predictive tool. This
would then enable the routine application of in silico
prioritization of putative ligands as an early step in lead
selection. It is likely that this, in turn, will lead to a rebalancing
of the current reliance on existing library collections (i.e.
physical samples) towards evaluating synthetic methodologies
that offer opportunities to access as-yet-unexplored ligands.16
Those methodologies must, necessarily, encompass versatile,
While LDA provided cleanly lithiation at C(6), Rouden observed
C(10) (as well as competing C(9)) metalation and (in situ)
silylation of N-methylcytisine
7 when a particularly bulky base
(LiTMP) was used. We did see some level of C(10) lithiation
with LDA and an analogous metalation (cf 12) within a simple
pyridone (i.e. at C(4), pyridone numbering) has been reported
by Katritzky.17 We evaluated N-Boc cytisine as a substrate for
C(6) metalation but analysis of the crude reaction mixture
(following reaction with LDA and silylation) indicated
substitution at C(2) and/or (C(4) had occurred which is
associated with Boc-directed metalation.18
drug-like scaffolds such as A.
Use of N-benzyl cytisine 14 was more attractive both for
downstream manipulations and because we did not observe
competitive metalation (as 12) or dimer formation (as 13).
Although Rouden has examined lithiation of 14, in our hands
and using a more synthetically useful aryl-based chlorosilane
(Me2PhSiCl), TMEDA (1 equiv.) did have an impact in terms of
reaction efficiency and in particular suppressed a small
amount of competing lithiation at C(10); 15 was isolated in
84% yield free of competing side products, with the mass
balance accounted for by recovered 14 (Scheme 4).
Results and discussion
To improve the efficiency of the fragmentation of cytisine, we
have explored the chemistry illustrated in Scheme 2 in a
number of ways: (i) the conditions for C(6) lithiation must
avoid metalation at other sites, see below. (ii) the variation of
the N(3) substituent that is possible; this was N-methyl earlier
but this is less attractive for downstream synthetic utility. (iii)
the choice of electrophile (ideally employed in situ during the
deprotonation step) used to trap the C(6) lithiated species (i.e.
8) in order facilitate C(6)-N(7) cleavage. (iv) the conditions
needed to achieve that critical transformation that also avoid
heavy metals such as Hg(II).
Revisiting C(6) lithiation of N-substituted cytisines.
Scheme 4. C(6) Lithiation and silylation of N-benzylcytisine 14
.
The original conditions used to lithiate N-methycytisine
7
Options around electrophilic component to facilitate C(6)-N(7)
cleavage
(which was trapped with Me2PhSiCl to give 9) had proceeded
.
in 48% yield. Relatively straightforward variation of some of
the basic reaction parameters allowed us to optimise this basic
Our original conditions for fragmentation of the cytisine
transformation to 83% in favour of C(6) lithiation and trapping. tricycle to generate the piperidine unit associated with
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kuraramine 11 involved silylation and Fleming-Tamao Elaboration of the piperidine scaffold; identification of
oxidation (using peracid and stoichiometric Hg(OAc)2) followed protecting group arrays that enable selective site
by a reductive ring opening of hemiaminal 10 (Scheme 2). manipulation.
Closer inspection of this process indicated two competing
reactions: desilylation of
9 to regenerate 7 and (ii) possible Heterocyclic scaffolds, such as 11 and 18, offer significant
competing N-oxidation of the tertiary (N(3)) amine was potential with the N-Bn residue in particular cleavable under a
suggested by MS analysis. These oxidation conditions were variety of different reaction conditions. Consequently, the
modified to give a small increase in yield of 11 (from 38% to majority of the remainder of this paper is focused on
47% from 8) by using a combination of H2O2 and peracetic acid developing the potential of the N-benzyl piperidine 18 as the
(rather than peracetic acid alone) but this transformation still basis of a flexible heterocyclic core structure. Our aim here is
required Hg(OAc)2. All attempts, however, to achieve the to demonstrate how the periphery of 18 can be functionalised
conversion of
HBF4, then H2O2; KH, tBuOOH then TBAF, thereby avoiding fragment-based drug discovery strategy, for the reasons
mercury salts, failed. This forced consideration of an articulated above. We have explored chemistry around four
electrophile that would offer an alternative cleavage specific sites illustrated in general scaffold : via the piperidine
mechanism. Lithiation followed by halogenation at C(6) was nitrogen (N(1)), at C(3′) (in 18, a primary alcohol), and in three
evaluated using a variety of halogen sources (Br2, I2 N- areas of the pyridone moiety, at C(3″) and C(4″) and across the
bromosuccinimide, BrCCl2CCl2Br, CBr4 proved unproductive. lactam unit (N(1″) and C=O). The latter is especially important
9 to 10 by other means e.g. KBr, AcOOH/AcOH; in ways that would make this unit well suited to a general
A
,
)
However, diphenyl disulfide (not shown, but see to protect (deactivate) when pursuing functionalization of C(3′)
Supplementary Information) and boron-based electrophiles (see below). Given the array of functional groups present
were effective in situ traps for the C(6) lithio intermediate within 18, we have determined methods for differentiating at
derived from
7
(Scheme 5). In the boron series, further these different sites. One consequence is that a series of
and protecting group arrays have been assessed and this is
optimisation using both N-methyl and N-benzylcytisine
7
14 respectively led to (OiPr)Bpin as the electrophile of choice, illustrated in Scheme 6.
and adducts 16 and 17 were obtained in 93 and 89% yields Selective N- and O-Boc protection in combination with O-
respectively. While boronate esters 16 and 17 were relatively silylation provided a comprehensive set of options, which has
tolerant of chromatography, further purification was allowed us to generate a number of differentially protected
unnecessary. Direct oxidation of the crude boronates (using variants 19-24; this includes the fully deprotected variant 22
.
NaBO3) followed by reduction (NaBH4) gave the piperidine Additionally, the structure of the N,O-bis-Boc protected
core structures, (+)-kuraramine 11 and the synthetically more alcohol 20 was solved by X-ray crystallographic analysis (see
flexible N-benzyl variant 18 in 32% and 52% overall yields Supplementary Information). The pyridone lactam underwent
(from
7
and 14) respectively.
O-acylation in the presence of an excess of Boc2O, a protecting
group array that is then cleavable under basic/nucleophilic
conditions, see below. Further, the ability to manipulate
selectively the pyridone nitrogen N(1″) is illustrated by
N-methylation of 24 to give adduct 25
.
Elaboration at C(3’); variation of C(3’) oxidation level.
That there is a requirement to protect/deprotect easily the
pyridone moiety is exemplified attempts to derivatise the C(3′)
primary alcohol (Scheme 7). Reaction of N-Boc piperidine 19
with phthalimide under Mitsunobu conditions in an attempt to
access the 3’ amino variant led cleanly (and in essentially
Scheme 5. C(6) borylation and ring cleavage. ‡
quantitative yield) to N-Boc cytisine 25
.
In summary, cytisine
N-benzyl variants
6
is easily derivatised to the N-methyl and
Of course, cis-disubstituted piperidine 19 is well set up to
undergo intramolecular alkylation, a possibility that was both
recognized and exploited elegantly in one of the very early
syntheses of cytisine carried out 60 years ago by van Tamelen
and Baran,19a,b and subsequently used in related contexts by
others.19c-e
7
and 14, each of which provides efficient
access to the corresponding enantiomerically pure cis-3,5-
disubstituted piperidines 11 and 18 respectively. The results
reported here serve to improve significantly the synthesis of
(+)-kuraramine 11 from N-methylcytisine and avoid heavy
metal oxidants to mediate the key C(6)-N(7) bond cleavage.
Use of a boron-based electrophile, and specifically (OiPr)Bpin
to trap the C(6) lithiated intermediate, was applicable to both
the N-methyl and N-benzyl series.
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4"
3"
OH
i. H2, Pd(OH)2
1"
3'
O
N
ii Boc2O (1-2.4 equiv.)
Na2CO3
H
i. H2, Pd(OH)2
ii Boc2O, DMAP, Et3N
i. H2, Pd/carbon, MeOH
ii. HCl in MeOH
1
18
N
Bn
70%
50%
OH
OH
OBoc
OH
O
N
H
BocO
N
BocO
N
O
N
H
21
22
19
N
20 (x-ray)
Boc2O (2.4 equiv.)
75%
N
Boc
N
N
Cl
Boc
Boc
H2
Boc2O (1 equiv.)
75%
TBDMSCl, Et3N
97%
OTBDMS
OTBDMS
NH3,H2O
90%
BocO
N
O
N
R
N
N
23
24 R=H
Boc
Boc
MeI,Cs2CO3
70%
25 R=Me
Scheme 6. Selective protection of piperidine, hydroxyl and pyridone moieties associated with 18
.
In addition, the scope of the C(3′) amino substituent can be
extended using aldehyde 29 derived from 20 using Swern
oxidation.
Aldehyde 29 was not routinely isolated (to minimize any risk of
epimerization) but used directly for reductive amination or
further oxidation (see below). Reductive amination using
nucleophilic amines was generally accompanied by O-Boc
cleavage under the reaction conditions (see 30a and 30b), and
where (as in the case of an α-amino ester) this does not occur,
O-Boc cleavage is then readily achieved using aqueous
ammonia (leading to 30c). The latter is a generally applicable
deprotection method20 and is illustrated further below.
Alcohol 20 is also readily converted to the corresponding
carboxylic acid 31 in excellent overall yield and acid 31 offers
access to a representative library of C(3′) derivatives (Scheme
9).
Scheme 7.
We attempted to circumvent this issue via double mesylation
of 19 to generate intermediate 27 (not isolated, but
assignment of a double mesylate was based on MS). However,
cyclisation still occured with 26 the only product observed on
exposure of 27 to azide or phthalate. Clearly, the O-mesylate
is labile in the presence of a good nucleophile but O-Boc
protection solves this issue. Using intermediate 20, activation
and phthalimide displacement at C(3′) followed by imide
cleavage provided the C(3′) amino derivative 28 (Scheme 8).
Here, hydrazine also cleaves the O-Boc residue liberating the
pyridone unit, but this is presumed to occur after nucleophilic
displacement at C(3’).
Again, the pyridone unit is unmasked by O-Boc cleavage under
nucleophilic conditions without disruption of other
functionality to provide pyridones 32a-c. In addition, global
deprotection of 31 is readily achieved to give the heterocyclic
β
-amino acid 33
Acid 33 is related to (S)-nipecotic acid (the parent piperidine-
based -amino acid), where 5-aryl substituted nipecotic acid
.
β
derivatives have attracted medicinal chemistry interest.21 We
had recognized a risk associated with C(3) epimerization of e.g.
aldehyde 29. For that reason we secured the X-ray crystal
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and versatile intermediate, followed by a representative
reductive amination leading to the bis(piperidine) 34 (Scheme
10). This does, however, serve to show that protection
elsewhere is not necessary in order to access N(1).
Scheme 10. Reductive amination at N(1).
Regioselective functionalisation of the pyridone moiety;
electrophilic bromination and Ir-catalyzed borylation.
The remaining region of the piperidine scaffold that was of
interest is associated with the pyridone unit. Electrophilic
halogenation of pyridones is well-established and leads
predominately to 3-substitution, with the 5-halo isomer as
(usually) the minor product. Using N-bromosuccinimide, this
pattern was observed with pyridone 19 (Scheme 11).
structure of acid 31 (see Supplementary Information), which
confirmed both the (intact) cis-configuration and the presence
of the O-Boc protected pyridine moiety.
Bromides 35 and 36 are readily separated (and easily
differential by 1H NMR) and provide an obvious and very useful
handle at C(3″) and C(5″).§ Access to C(4″) is also achievable
using Ir-catalyzed borylation, as has been reported recently.22
In our hands, however, NH pyridones (e.g. 19) are not viable
substrates for this C-H activation method. N-Alkyl pyridones
Scheme 8. Successful displacement at C(3’). Yields of 30a-c are
from alcohol 20
.
(e.g.
7) are, though, generally reactive and with O-Boc
protected pyridines (i.e. 23) highly selective borylation at C(4’’)
is observed.
The scope and potential of this chemistry is illustrated in
Scheme 11, and this includes two representative
transformations of the intermediate boronate esters: Suzuki
coupling of adduct 37, followed by O-Boc cleavage (using basic
ammonia) gave 38
;
Cu-mediated bromination and
deprotection of adduct 39a gave 40, offering a reactant that
complements the corresponding Bpin esters. It is useful to
note that the low yield of 40 reflects the instability in solution
of the intermediate bromide prior to O-Boc cleavage but this
transformation has not been optimized.
The chemistry outlined above serves to demonstrate the
ability to manipulate the piperidine scaffold aligned to general
structure A. This scaffold can be manipulated in a variety of
distinct locations, using different transformations, and the only
major requirement is the engagement of a suitable protecting
group array that is primarily associated with moderating the
reactivity of the pyridone unit. That moderation, largely based
on N- and O-(Boc) protection, is readily achieved. Thus, we
believe that the ready availability of (-)-cytisine and the
efficiency with which the piperidine core unit can be revealed
and then differentially manipulated makes this a potentially
Scheme 9. Ester/amide library based on carboxylic acid 31
;
global deprotection to provide acid 33
.
Elaboration at N(1).
The final target site for substitution on this piperidine scaffold
was at N(1). This can be carried out in a number of ways, and
we have simply illustrated the accessibility of this key position
by N-debenzylation of 18 to give 22 (Scheme 6) as an isolable
attractive starting point for
approach.
a fragment-based discovery
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3J=7.5 Hz
3J=9.5 Hz
H
H
H
Br
Br
H
5''
3''
OH
OH
OH
O
N
O
N
H
O
N
H
NBS
THF
H
19
N
36 23%
N
35 52%
N
Boc
Boc
Boc
Ph
Bpin
N
4''
OTBDMS
i PhBr, Pd(PPh3)4
[Ir(COD)OMe]2
BocO
N
O
N
H
BocO
R2
R2
K2CO3, DMF
ii NH4OH, MeOH
dtbpy, B2pin2
THF, reflux
R2
37
38
23
N
42% overall
Boc
91%
Bpin
Bpin
N
Bpin
OAc
CO2t-Bu
CO2Me
BocO
N
BocO
N
BocO
Br
N
39a 77%
39b 77%
39c 91%
N
N
Boc
Boc
Boc
i CuBr2, MeOH, air
ii NH4OH, MeOH
OAc
O
N
H
16%
40
N
Boc
Scheme 11. Pyridone functionalisation.
Enhancing the complexity of (-)-cytisine via C(6) lithiation; However, all attempts to achieve 1,2-migration using a range
Matteson homologation and Zweifel olefination.
of Lewis acids failed. Given that Bpin esters are sterically
demanding, we also evaluated Et3B as a less demanding
A key aspect of a fragment-based approach must be an ability electrophile. Again, “ate” formation (analogous to 41
)
to increase rapidly molecular complexity. We have also occurred (as judged by 11B NMR) but no migration products
explored additional avenues to address that issue where the could be detected.
goal has been to identify methods to introduce additional (and The most plausible explanation for these outcomes is that the
novel) complexity to the cytisine-based (tricyclic) precursor pyridone N is not a sufficiently good leaving group to drive the
prior to any fragmentation and further functionalisation. migration step. However, an appreciation of the stability of
While these reactions do not contribute to extending the the pyridone moiety with respect to a 1,2-migration provided
scope of the piperidine scaffold discussed earlier, they do an opportunity to assess to other “ate”-based chemistries
provide access to novel cytisine variants that can be available using boronate ester 17
considered as alternative scaffold configurations and Boronate 17 undergoes efficient Matteson homologation24 to
progenitors. give boronate 42 in 89% yield. Oxidation of 42 provided
.
Of particular relevance here was the potential associated with primary alcohol 43 and the structure of the corresponding 4-
trapping a C(6) lithiated cytisine (see Scheme 2, intermediate nitrobenzoate 44 confirmed the configuration at C(6) (see
8
) with a secondary boronate ester (e.g. EtBpin). Our goal Supplementary Information). A detailed 1H NMR analysis of 44
here had been to trigger a 1,2-migration sequence that would was also carried (see Supplementary Information) which aided
also serve to fragment the tricycle of cytisine and in the assignment of adduct 46 (see below). Zweifel
simultaneously create an addition stereocenter(*) at a key olefination25 also involves generation of a stable borate
position on the periphery. The concept, which draws on intermediate and using boronate 17 proceeds very efficiently.
previous work done within the Aggarwal group,23 is illustrated Using a modified procedure developed in the Aggarwal
in Scheme 12.
group,25c exposure of 17 to vinyl Grignard (and this likely
Using N-benzyl cytisine 14, lithiation and trapping with EtBpin generates the triethenyl borate intermediate 45), followed by
appeared to generate the requisite borate intermediate 41 exposure to I2 in methanol gave the C(6) ethenyl adduct 46 in
based on 11B NMR which showed a signal at 6.3 ppm. 94% yield (Scheme 12). The configuration at C(6) was
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confirmed by NOESY experiments (using 44 for comparison) We thank Achieve Life Sciences and Allychem Co. Ltd. for
and details of these studies are also available in the generous gifts of (‒)-cytisine and bis(pinacolato)diboron
Supplementary Information
respectively, and financial support from the Development and
Promotion of Science and Technology (DPST) Thailand, the
University of Bristol and EPSRC (EP/N024117/1) is
acknowledged.
NBn
O
Et
1,2-migration
i LDA
6
*
N
14
O
N
H
X
ii EtBpin
Bpin
N
X=Bpin
X=OH
Bn
Et
[O]
Notes and references
41
11B NMR= 6.3 ppm
‡ When we applied a more conventional oxidation protocol
(NaOH, H2O2) to the N-methyl boronate ester 16, we only
observed decomposition.
§ It is noteworthy that the corresponding O-Boc protected
variant 23 was unreactive under these same conditions.
NBn
N
NBn
NBn
BrCH2Cl (3 equiv.)
BuLi (2.5 equiv.)
O
H2O2
NaOH
86%
overall
O
O
N
N
MTBE
-78 °C to r.t.
Bpin
RO
pinB
(89% by NMR)
1
For leading discussions associated with small molecule drug
discovery linked to “chemical space” and privileged scaffolds,
see: (a) R. W. DeSimone, K. S. Currie, S. A. Mitchell, J. W. Darrow
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17
42
43 R=H
PNBCl
DMAP
32%
MgBr
NBn
44 R=PNB
(x-ray)
NBn
O
O
I2, MeOH
N
N
94%
overall
B
45
46
Scheme 12. Top: Attempt to couple 1,2-migration with tricycle
cleavage. Bottom: C(6) alkenylation of N-benzyl cytisine 14
.
2
For recent overviews of the role (and pitfalls e.g. PAINS2n) of
natural products within a drug discovery context and related
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Conclusions
In summary, C(6) metalation of N-alkyl cytisine derivatives
provides a direct and versatile method of functionalization
that allows for ring fragmentation to provide a synthetically
flexible, enantiomerically pure piperidine based heterocyclic
scaffold. Given the privileged nature of the piperidine ring
within medicinal chemistry, we suggest that this is an
attractive unit for the development of more complex
heterocyclic ligands within the context of a fragment-based
approach to drug discovery.
functionalised piperidine scaffold has been exemplified using
the N-benzylated variant 18 Critically it is possible to
The potential of this
.
differentiate all key elements and, using C-H activation, to
provide an additional functional handle within the pyridone
unit. Attempts to induce a B-based 1,2-migration as a means
to increase the molecular complexity within the piperidone
scaffold failed, however, the relative stability of the key
intermediate (identified by
a lack of reactivity) can be
exploited. Derivatives such as 43 and 46 that arise from this
offer new opportunities for modification of the established
nicotinic ligand profile of cytisine and studies in this area are
underway.
Conflicts of interest
There are no conflicts to declare.
3
For overviews of diversity-oriented synthesis approaches, see:
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43, 46-58; (b) M. D. Burke, E. M. Berger and S. L. Schreiber, J.
Am. Chem. Soc., 2004, 126, 14095-14104; (c) W. Galloway and
Acknowledgements
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Graphical Abstract
Cytisine undergoes ready fragmentation to provide a highly flexible (and “privileged”) piperidine
scaffold capable of exploring a diversity of chemical space.