Diversity-orientated synthesis of macrocyclic heterocycles using a double SNAr approach

Article abstract of DOI:10.1039/d1ob00612f

An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK) was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisation enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropisomers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).

Full text of DOI:10.1039/d1ob00612f

Organic &
Biomolecular Chemistry
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Diversity-orientated synthesis of macrocyclic
heterocycles using a double SNAr approach†
Cite this: Org. Biomol. Chem., 2021,
19, 6274
Piotr Raubo, * Rodrigo J. Carbajo, William McCoull,
Morgan Thomas
Joanna Raubo and
An efficient macrocyclisation approach based on the double aromatic nucleophilic substitution (SNACK)
was developed. This methodology allows a facile incorporation of heterocyclic motifs into macrocyclic
rings and rapid synthesis of a significant number of structurally diverse macrocycles. SNACK macrocyclisa-
tion enables preparation of stable diastereoisomers of conformationally restricted macrocycles (atropi-
somers). Practical application of SNACK macrocyclisation in a drug discovery project was exemplified by
the identification of high affinity macrocyclic binders of B-cell lymphoma 6 (BCL6).
Received 30th March 2021,
Accepted 25th June 2021
DOI: 10.1039/d1ob00612f
rsc.li/obc
lating the function of biological systems into their bioactive
conformation. This can significantly increase potency through
Introduction
Macrocycles, a class of compounds containing a ring system maximising polar intermolecular interactions such as hydro-
consisting of 12 or more atoms, are gaining increasing attention gen bonding, minimising entropic cost and improving selecti-
within the scientific community. For example, one of the recent vity against other biological targets.6,7
issues of Chemical Reviews has been solely devoted to this
At AstraZeneca, we successfully employed the macrocyclisa-
important chemotype.1 From a drug design and development tion approach to lock “acyclic” small molecules into a bioactive
perspective, macrocycles occupy a distinctive chemical and prop- conformation, enriching the population of a desired bioactive
erty space residing between small molecules and biologics with form and, as a result, significantly improving affinity and
molecular weights ranging from 400 to 1500 Da.2 Despite often selectivity in a number of oncology projects such as, for
being outside Lipinski’s rule of 5, macrocycles can demonstrate example, MCL1,8 BCL69 and MTH1.10
drug-like properties, for example enhanced cell permeability
Despite all the recent advances, macrocycles are still con-
associated with their cyclic conformation and internalisation of sidered a relatively underexploited structural class due to their
polarity can be observed.3 Indeed, many naturally occurring or complex structure and relatively low synthetic tractability. The
synthetic macrocyclic compounds were developed into success- macrocyclisation step often requires high dilution to favour
ful therapeutics, for example: powerful antibiotics, immunosup- the macrocyclisation pathway over formation of unwanted
pressants, antiviral and anticancer agents (Fig. 1).4
intermolecular oligo- and polymerisation side-products.7,11
With the increasing complexity of biological targets macro- Solid-phase synthesis has been also employed as an alternative
cyclic molecules provide a promising starting point to modu- strategy to achieve pseudo-high dilution conditions for macro-
late challenging targets and interrupt biological pathways. cyclisation reactions.12 In reality, the competition between
Macrocyclic rings provide a compromise between structural cyclisation and polymerisation can lead to complex mixtures
preorganization and sufficient flexibility to fit to a target and reduced overall synthetic efficiency. In the past, as macro-
surface and maximise binding interactions. Thus facilitate cyclic molecules often reside outside Lipinski’s rule of 5, they
modulation of “difficult” targets that contain large, shallow may have been considered as less attractive targets in drug
and featureless binding sites such as, for example, protein– design and candidates for screening library enhancement
protein interactions (PPI).5 Therefore, macrocycles may be con- initiatives. This combined with potentially demanding syn-
sidered as attractive prospective candidates for drug discovery thesis may have led to under-representation of macrocyclic
and chemical biology. A macrocyclisation strategy has been structures in screening collections of pharmaceutical compa-
often used to lock acyclic ligands capable of selectively modu- nies.13 The macrocyclic ring can be constructed in a number
of ways, using an range of chemical reactions. These strategies
were extensively reviewed in literature6b,14 with a special focus
Medicinal Chemistry, Research and Early Development, Oncology R&D, AstraZeneca,
on diversity generating library designs.2b,13,15 However, there is
Cambridge, UK. E-mail: piotr.raubo@astrazeneca.com
still a limited number of methods which allow the introduc-
†Electronic supplementary information (ESI) available. See DOI: 10.1039/
tion of diversity within the macrocyclisation step itself. These
d1ob00612f
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Fig. 1 Selected examples of macrocyclic drugs.
methods are frequently based on multicomponent reactions
such as Ugi or Passerini16 or SN2 17 and sometimes on SNAr
Results and discussion
processes.12b,18 Heterocyclic ring systems are often essential At the outset, to test the possibility of the one-step macrocycli-
elements of many pharmaceuticals and play a significant role sation, we prepared a model di-nucleophile N1 (Scheme 2).
in controlling molecular properties such as the electronic dis- Boc 3-(R)-hydroxypyrrolidine (1) first was O-alkylated with 1,4-
tribution, rigidity and three dimensionality as well as modulat- dibromobutane under phase transfer conditions to afford the
ing physicochemical properties such as lipophilicity, solubility bromide 2, which subsequently was used in the second
and metabolic stability.19 Heterocyclic ring systems are also O-alkylation with 1 to provide the protected bis-pyrrolidine 3.
frequently important components of bioactive natural and syn- Pleasingly, after N-Boc deprotection, N1 underwent dual SNAr
thetic macrocycles.14b,15c,20 Therefore, we were interested in with 2,4,6-trichloropyrimidine (H1) to afford the expected
developing a novel, efficient, robust and high yielding method 15-membered macrocycle M1 in 30% yield. The putative side
that allowed an expeditious construction of macrocyclic product 4 and other higher oligomers were also detected by
scaffolds to support our medicinal chemistry programs and to LCMS, but were not isolated.
expand the AstraZeneca internal screening collection with
Encouraged by these initial results, N1 was reacted with a
novel diverse macrocyclic compounds. We aimed for the range of heterocyclic di-electrophiles H2–H10 to obtain a
method to be easily adoptable for automated, parallel syn- variety of 15-membered macrocycles M2–M10 in a single step,
thesis of large arrays of diverse macrocycles. Aromatic nucleo- however, in low isolated yields (Table 1). Emac index is a useful
philic substitution (SNAr) is one of the most widely used reac- descriptor of macrocyclisation efficiency, which takes into
tion in pharmaceutical industry.21 However, SNAr appears to account both the chemical yield of the reaction and the con-
be rarely used in the preparation of the synthetic macro- centration at which the macrocyclisation is performed.22 This
cycles.18 From our standpoint, the double aromatic nucleophi- index allows comparison of a large number of literature macro-
lic substitution reaction between pre-assembled, masked di- cyclisation reactions and enables identification of the most
nucleophiles (N) with corresponding heteroaromatic di-electro- efficient methods. For our unoptimised one step SNACK
philes (H) should allow introduction of an element of diversity macrocyclisation reaction Emac index was in the low to
at the macrocyclisation step, thus facilitating rapid assembly medium range (Emac 4.2–6.5). One of the limitations of the
of diverse macrocyclic scaffolds (M), ideally in a simple one- one step process is an inadequate control of regioselectivity of
pot process (Scheme 1). In this double SNAr attack (SNACK)9a the macrocyclisation, when unsymmetrical reagents are used.
approach the di-nucleophile and di-halo-heterocycle should be A difference in nucleophilicity of both amine centres and dis-
easily varied. Importantly, we could also take advantage of the similar reactivity of both electrophilic position of the hetero-
availability of a large set of commercial halogenated hetero- cycle is required to avoid formation of isomeric mixtures. For
cyclic building blocks (∼90 000, SciFinder), thus comfortably example, the more nucleophilic pyrrolidine N2 exclusively dis-
achieving the required structural diversification within the set placed the more reactive chlorine at the 7-position of 5,7-
of constructed macrocyclic rings.
dichloropyrazolo[1,5-a]pyrimidine-3-carbonitrile
(H11,
Table 1). The subsequent SNAr at the 5-position with the mor-
pholine gave an expected macrocycle M11 as a single isomer.
N2 was prepared in 3 steps from the 2-hydroxymethyl mor-
pholine 5 as shown in Scheme 3.
To expand the scope of SNACK macrocyclisation, we sought
to minimise formation of oligomeric side products and
achieve better control of regioselectivity by developing a 3-step
procedure. We assumed that using monoprotected di-nucleo-
philes (e.g. N-Boc) should direct the first aromatic nucleophilic
Scheme 1 Double SNAr attack (SNACK) approach.
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Scheme 2 (a) 1,4-Dibromobutane, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 86%; (b) 1, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 80%; (c) HCl, 1,4-dioxane, EtOH,
rt, 99%; (d) 2, iPr2EtN, n-BuOH, rt-120 °C (<35%).
attack to the more reactive centre of the heterocycle. After sub- addition. Excess of one of the reagents, or incomplete first
sequent release of the second nucleophile, the second aro- nucleophilic substitution, generally leads to formation of side
matic nucleophilic substitution would take place to form the products at the second nucleophilic addition step. Secondly,
expected macrocycle M (Scheme 4).
variation in relative reactivity of both the nucleophile and elec-
To test this concept, we prepared the orthogonally protected trophile required careful monitoring to ensure complete con-
di-pyrrolidine 9 (Scheme 5). Selective mono-deprotection of versions for the first SNAr. For more electron rich heterocycles
the N-Cbz group in 9 afforded the mono-N-Boc-protected bis- higher reaction temperature or/and longer reaction time was
pyrrolidine N3 in good overall yield. In the next step, N3 was required to achieve acceptable conversion of both nucleophilic
set to react with 2,4,5-trichloro-pyrimidine (H8) in iso-propanol substitutions. This sometimes led to more complex reaction
at 80 °C. After completion, the reaction mixture was acidified profiles and, in consequence, lower overall yields. For example,
with excess of methanesulfonic acid and the resulting mixture for M17, the first reaction of our SNACK sequence progressed
was heated until full N-Boc deprotection. After basification cleanly, albeit very slowly (90 h at 100 °C). However, after the
with Hunig’s base and dilution, the reaction mixture was sub- deprotection, the second nucleophilic substitution was much
sequently heated within the microwave reactor to provide the slower and by-products were observed, providing M17 in only
expected macrocycle M8, pleasingly, in good isolated yield 17% isolated yield. In the attempt to make the macrocycle
(73%, for a 3 step sequence). Furthermore, we used N3 in M18, the aniline N4 did not react with H9 at the first step of
several more macrocyclisations with other heterocyclic coup- the sequence at all. However, H9 reacted with the more nucleo-
ling partners (H9–H11) to obtain corresponding 15-membered philic pyrrolidine N3 to give M9, albeit in 32% yield.
macrocyclic compounds M9–M13. This procedure significantly Furthermore, SNACK macrocyclisation between N4 and H14
improved isolated yields over the one-step experiments (e.g. and H15 provided the corresponding 17- and 16-membered
73% vs. 31% for M8 and 55% vs. 12% for M10, Table 2).
macrocycles M19 and M20 in moderate yields. For very elec-
To demonstrate the scope of our SNACK approach, a set of tron deficient and reactive heterocycles such as the triazine
diverse masked di-nucleophiles was prepared using well estab- H16, iso-propanol was replaced with dichloromethane to avoid
lished chemistry. The aniline base di-nucleophiles N4 and N5 side reactions with protic solvent. Trifluoroacetic acid was then
were synthesised as drawn in Scheme 6. (R)-N-Boc-3-hydroxy- used for the N-Boc deprotection and M21 was obtained in 38%
proline (1) was allylated with (E)-1,4-dibromobut-2-ene to form yield. In our standard macrocyclisation conditions, the 2,5-
the allyl bromide 10, which in turn, was used to O-allylate the dichloropyrimidine H17 reacted with the aniline N4 to allow
corresponding 3-nitro- and 2-nitrophenol to afford meta- and incorporation of the pyrimidine ring into the macrocycle ring
ortho-substituted nitrobenzenes 11 and 12 in excellent isolated in M22. Furthermore, the reaction between N4 and the
yields (98% and 95%, respectively). Finally, the nitro group in 4-fluoro-substituted H18 or the 4-chloro-substituted H19 pro-
11 and 12 was reduced to provide the anilines N4 and N5.
vided corresponding macrocycles M23 and M24 in modest iso-
The aniline N4 was set to react in our 3-step SNACK macro- lated yields (45–52%). However, the attempt to make M25 from
cyclisation with a range of di-chloro-heterocycles (H1, H8, H9, the corresponding 4,6-dichloro-5-(difluoromethyl)pyrimidine
H11–H22, Table 2). The reaction between N4 and 2,4,5-tri- was unsuccessful. The first nucleophilic substitution worked
chloropyrimidine (H8) provided the expected macrocycle M14 very well, as did the amine deprotection. Disappointingly, the
in excellent yield. Similarly, macrocyclisation of N4 with H1 macrocyclisation step failed to provide the required difluoro-
and H11 proceeded smoothly affording corresponding macro- methyl analogue M25 due to instability of the macrocyclic
cyclic structures M15 and M16 in 78% and 86% yield, respect- product. An isomeric ortho-substituted aniline N5 (prepared as
ively. In the case of M16 a mixture of 3 possible isomers was shown in Scheme 6) worked well in our SNACK macrocyclisa-
obtained in a ratio ∼5 : 2 : 2 with M16 being the major isomer. tion. The reaction of N5 with heterocyclic partners such as H8,
There are several practical aspects that must be considered to H14, H19 delivered the corresponding macrocycles M26, M27
achieve good overall yields for this SNACK macrocyclisation. and M28 in high overall yields (79%, 76%, 69%, respectively).
Firstly, purity of the di-halo heterocycles is important, because In the case of M28, we observed formation of 2 isomeric pro-
of the impact on stoichiometry of the first nucleophilic ducts at the final macrocyclisation step. The isomer ratio was
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Table 1 One step macrocyclisation
Di-nucleophile
Heterocycle
Di-halo-heterocycle
Macrocycle
Structure
Yield (%)
30
Ring size
Emac
N1
H1
M1
15
5.4
N1
H2
M2
35
15
6.2
N1
N1
N1
N1
N1
H3
H4
H5
H6
H7
M3
M4
M5
M6
M7
26
21
22
16
16
15
15
15
15
15
5.3
5.0
5.0
4.6
4.6
N1
N1
H8
H9
M8
M9
31
27
15
15
6.1
5.9
N1
N2
H10
H11
M10
M11
12
26
15
15
4.2
6.0
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Scheme 3 (a) 1,4-Dibromobutane, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 94%; (b) 1, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 73%; (c) HCl, 1,4-dioxane, EtOH,
rt, quant.
Scheme 4 Three-step SNACK macrocyclisation.
Scheme 5 (a) 1,4-Dibromobutane, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 76%; (b) H2, Pd/C, THF–H2O, rt, 99%; (c) H8, iPrOH, iPr2EtN, 80 °C; then
MsOH, iPrOH, 80 °C; then iPr2EtN, iPrOH, 120 °C, 73%.
improving with longer reaction time and, after completion, strain and/or lower nucleophilicity of the piperidine nitrogen in
this sequence gave a 17 : 1 mixture of 2 isomeric macrocycles comparison to the corresponding pyrrolidine. Interestingly, the
M28 in 69% overall isolated yield. To explore the scope of prolinol N10 bearing the conformationally more defined unsa-
SNACK macrocyclisation further, O,O-butylene linked pyrroli- turated linker was significantly more efficient in SNACK macro-
dines N6, N7 and N8 were prepared in a 3-step sequence from cyclisation (Emac 6.8) when compared to the saturated chain
the commercial chiral building blocks (13, 14 and 15, respect- linked N8. N10 was quickly assembled as depicted in Scheme 8
ively) in excellent overall yields (Scheme 7).
Similarly, the analogous piperidine N9 was synthesised. 16-membered macrocycle M35 in excellent yield (81%).
The macrocyclisations performed using N6 and the hetero- In order to evaluate the scope of macrocyclisation, more
and allowed to react with the di-electrophile H11 to provide a
cycles H8 and H11 were comparably efficient to the reactions precursors were quickly prepared. Both the amide linked
of alkene N4 giving the expected macrocycles M29 and M30 in aniline N11 and N12 were easily made from the commercially
high yields (64% and 81%, respectively, Table 2). SNACK available carboxylic acid 25 and corresponding amines 26 and
macrocyclisation between N7 and H18 proved to be more slug- 28 (Scheme 9).
gish leading to lower efficiency (Emac 5.1) and, as a result, low
Furthermore, the one-pot double aromatic nucleophilic
chemical yield (M31, 25%). Similarly, the reaction between a substitutions with 2,4,5-trichloropyrimidine allowed swift
more sterically hindered prolinol N8 and H8 was significantly assembly of the pyrimidine linked primary amines N13 and
less efficient (M32, 30%, Emac 5.5). While the piperidine N9 N14 as shown in Scheme 10.
underwent smooth macrocyclisation with H11 to give M33 in
Two isomeric morpholines N15 and N16 were prepared
72% yield, the second nucleophilic substitution at the 6-posi- from 6 using standard procedures (Scheme 11).
tion of 5-aza-quinazoline H14 was very slow even at 150 °C and
The spirocyclic masked di-nucleophile N11 smoothly
thus low yielding (M34, 9%). This may be due to higher ring reacted with the heterocyclic reagents H8 and H11 forming
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Table 2 One-pot three-step macrocyclisation
Di-nucleophile
Heterocycle
Di-halo-heterocycle
Macrocycle
Structure
Yield (%)
73
Ring size
Emac
N3
H8
M8
15
6.5
N3
H9
M9
32
15
5.5
N3
N3
H10
H11
M10
M12
55
44
15
15
6.1
5.9
N3
N4
N4
N4
H12
H8
M13
M14
M15
M16
42
86
78
86a
15
16
16
16
6.1
6.8
6.7
6.8
H11
H1
N4
H13
M17
17
16
4.7
N4
N4
H9
M18
M19
0
NA
17
NA
6.0
H14
50
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Table 2 (Contd.)
Di-nucleophile
Heterocycle
Di-halo-heterocycle
Macrocycle
Structure
Yield (%)
55
Ring size
16
Emac
N4
H15
M20
6.2
N4
N4
H16
H17
M21
M22
38b
42
16
16
6.0
5.9
N4
H18
M23
52
16
6.2
N4
N4
N5
H19
H20
H8
M24
M25
M26
45
0
16
NA
15
6.0
NA
6.7
79
N5
N5
H14
H19
M27
M28
77
16
15
6.6
6.5
69c
N6
N6
H8
M29
M30
64
81
16
16
6.4
6.8
H11
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Table 2 (Contd.)
Di-nucleophile
Heterocycle
Di-halo-heterocycle
Macrocycle
Structure
Yield (%)
25
Ring size
Emac
N7
H18
M31
16
5.1
N8
H8
M32
M33
M34
M35
30
72
9
16
16
17
16
5.5
6.5
3.9
6.8
N9
H11
H14
H11
N9
N10
81
N11
N11
H8
M36
M37
68
73
17
17
6.5
6.6
H11
N12
N12
N13
H8
M38
M39
M40
53
32
76
18
18
17
6.2
5.5
6.6
H21
H11
N14
N14
H14
H21
M41
M42
44
31
19
18
5.9
5.4
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Table 2 (Contd.)
Di-nucleophile
Heterocycle
Di-halo-heterocycle
Macrocycle
Structure
Yield (%)
20d
Ring size
18
Emac
N14
H22
M43
NA
N15
H8
M44
51
15
6.3
General procedure: Di-halo-heterocycle (H, 0.18 mmol) was added to a stirred solution of mono-N-Boc protected diamine (N-Boc, 0.18 mmol) and
DIPEA (0.05 mL, 0.29 mmol) in iPrOH (2 mL). The reaction mixture was stirred at 20–80 °Ca until completion. Methanesulfonic acid (0.1 mL,
1.54 mmol) was added and mixture was stirred at 60–80 °Ca until completion. The mixture was diluted with iPrOH (15 mL) and further DIPEA
(0.6 mL, 3.44 mmol) was added. The mixture was stirred at 20–150 °Ca and cooled to rt. The mixture was concentrated in vacuo and purified by
reverse phase HPLC to afford M. (a) Microwave reactor was used to heat the reaction vessel when necessary. a Total yield for 3 possible regioisomers.
b For this reactive heterocycle the sequence was carried out stepwise: the first step was performed in dichloromethane, then the Boc group
removed with trifluoroacetic acid in dichloromethane and the macrocyclisation step was performed in iso-propanol at room temperature.
c 17 : 1 mixture of 2 diastereoisomers. d Overall isolated yield for 4-step one-pot procedure.
Scheme 6 (a) (E)-1,4-Dibromobut-2-ene, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 78%; (b) 3-nitrophenol, K2CO3, DMF, 80 °C, 98% or 2-nitrophenol,
K2CO3, DMF, 80 °C, 95%; (c) Fe, NH4Cl, 2-MeTHF, H2O, 60 °C, for N4 quant., for N5 91%.
Scheme 7 (a) 1,4-Dibromobutane, n-Bu4HSO4 cat, PhMe, NaOHaq, rt; for 16 88%; for 17 93%; for 18 82%; (b) 3-nitrophenol or 3-bromo-5-nitro-
phenol, Cs2CO3, DMF, 80 °C; for 19 82%; for 20 81%;9b for 21 quant.; for 22 92%; (c) HCOONH4, Pd/C, EtOH, 80 °C; for N6 quant.; for N8 95%; for
N9 96%; (d) Fe, NH4Cl, 2-MeTHF, H2O, 75 °C, for N7 94%.9b
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Scheme 8 (a) (E)-1,4-Dibromobut-2-ene, n-Bu4HSO4 cat, PhMe, NaOHaq, rt, 65%;9b (b) 3-nitrophenol, K2CO3, DMF, 80 °C, 95%; (c) Fe, NH4Cl,
2-MeTHF, H2O, 60 °C, 91%.
Scheme 9 (a) HATU, iPr2EtN, DMF, rt, 78% for 27, 81% for 29; (b) HCOONH4, Pd/C, EtOH, 80 °C, quant. both for N11 and N12.
Scheme 10 (a) 30, iPr2EtN, i-PrOH, 80 °C; then 31 120 °C, 75%; (b) 26, iPr2EtN, i-PrOH, 80 °C; then 31 120 °C, 61%.
corresponding spirocyclic macrocycles M36 and M37 in good nucleophilic substitutions (the SNACK macrocyclisation fol-
overall yields (68% and 73%, respectively). The macrocyclisa- lowed by a displacement of the remaining C6 fluorine with pyr-
tion step between the primary amine in N12 and the hetero- rolidine) delivered the grossly substituted macrocyclic pyrimi-
cyclic partners H8 and H21 was less efficient. In this case, dine M43. A less nucleophilic morpholine N15 required pro-
expected macrocycles M38 and M39 were isolated in modest to longed heating (65 h) at 150 °C to achieve acceptable conver-
low yields (53% and 32%, respectively). Compounds contain- sion of the macrocyclisation step, but despite such harsh con-
ing two heterocyclic units incorporated into the larger macro- ditions the required macrocycle M44 was isolated in a
cyclic ring, such as M40, M41 and M42, where rapidly respectable 51% yield.
assembled from the corresponding amines (N13 and N14) and
For M28 we observed the formation of two isomeric macro-
relevant heterocyclic partners H11, H14 and H21 in two simple cyclic products at the macrocyclisation step. In this experiment
separate steps involving four SNAr reactions. As previously, the isomer ratio was improving with reaction time. We hypoth-
macrocyclisation with the pyrazolopyrimidine H11 proved to esised that this was due to the presence of the chloro substitu-
be efficient for the 17-membered M40 (yield 76%). However, in ent at the 5-position of the pyrimidine ring, which in the pres-
the case of the 5-azaquinazoline H14, formation of the ence of the ortho-substituted aniline motif can create a steric
19-membered macrocyclic ring in M41 was less effective (44% clash between the chlorine and the ether oxygen, thus restrict-
yield). As previously found, the SNACK macrocyclisation with ing conformational changes of the macrocyclic ring (Fig. 1).
5-cyano-1,6-dichloropyrimidine (H21) was less successful Restricted ring interconversion can lead to formation of a new
affording the 18-membered macrocycle M42 in 31% yield only. chiral centre, similar to the formation of chiral atropisomers
The SNACK procedure employing heterocyclic reagents in rotationally restricted biaryls.23 In the presence of an
bearing three leaving groups can easily expand structural diver- another chiral centre (as in the pyrrolidine M28) two distinc-
sity of prepared macrocycles. In the case of 5-chloro-2,4,6-tri- tive diastereoisomers may be observed. Thus we postulated
fluoropyrimidine (H22) and N14 three subsequent one-pot that in SNACK macrocyclisations involving heterocyclic
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Scheme 11 (a) 3-Nitrophenol or 2-nitrophenol, Cs2CO3, DMA, 80 °C, 47% for 32, 34% for 33; (b) HCOONH4, Pd/C, EtOH, 80 °C, 100% for N15,
100% for N16; N17 prepared as described.9b
reagents with a substituent residing between two electrophilic cyclic R2 (35) the ring interconversion should still be fairly fast
sites formation of a new chiral centre could be plausible.
at room temperature. Thus 35 can be considered as an achiral
In the case of reaction between both a symmetrical diamine molecule. By increasing the molecular volume of R2, or alterna-
and a symmetrical dihalo-heterocycle, an achiral macrocycle tively decreasing size of the macrocyclic ring, interconversion
34 will form, independently of the size of the R2 substituent in 36 may become more restricted making this molecule
(Scheme 12). In the case, when R2 relatively is small (e.g. H or chiral. Thus, 36 should exist in two enantiomeric forms 37 and
F), then macrocyclic ring interconversion can easily occur. 38. Similarly, when an unsymmetrical diamine motif is linked
When R2 in 34 is larger the ring interconversion may be to a symmetrically substituted pyrimidine with a relatively
restricted, but 34 has a plane of symmetry and is superimposa- small endo-cyclic R2 (39) the ring interconversion should be
ble on its mirror image. The situation should change when fast at room temperature. Thus, 39 should be considered as
one or both fragments (diamine and heterocycle) of the macro- achiral. In turn, increasing R2 size can block ring interconver-
cycle become unsymmetrical. For example, in the case of com- sion in 40, thus making this macrocycle chiral. Again, it
bination of a symmetrical diamine unit and an unsymmetri- should be possible to separate the racemic 40 into two enan-
cally substituted pyridazine ring. With a relatively small endo- tiomers 41 and 42. Incorporation of another stereo-defined
Scheme 12 Formation of a new chiral centre during SNACK macrocyclisations.
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chiral centre (R4 in 43) into the diamine should allow for- each isomer. The experimentally derived constraint sets for
mation of 2 distinctive diastereoisomeric macrocycles 44 and each rotamer (in the form of distances) were combined alter-
45. We assumed that this was the case with observation of two natively with the two sets of conformers using the MSpin soft-
isomeric products in M28. Under the reaction conditions ware. It was found that the NMR data for Isomer 1 agreed best
(120 °C) the initial kinetic macrocycle underwent slow equili- with structure M45-1 below, and Isomer 2 with structure M45-
bration to enrich the mixture with the most stable thermo- 2 (Fig. 3). The NOEs from the CH proton in the pyrrolidine
dynamic diastereoisomer. Interestingly, only one isomer was ring were key to differentiate between these isomers. For M45-
detected for the isomeric macrocycle M24. We hypothesised 2 the pyrrolidine C3–H, a NOE with the aromatic H pointing
that in M24 the negative steric interaction between the chlor- inwards and with both protons in the double bond is
ine atom and the ether oxygen was removed by moving the observed, whilst for the same C3–H in the diastereoisomer
ether substituent from the ortho to meta position of the phenyl M45-1 only the NOE with one of the double bond protons is
ring (Fig. 2). With the inner cavity of the macrocyclic ring detected and no NOE is observed with the aromatic CH.
potentially being large enough to accommodate the chlorine
Likewise, ethyl 4,6-dichloropyrimidine-5-carboxylate (H23)
atom the energy barrier would be greatly reduced allowing rela- reacted with N4 to form a ∼2 : 1 mixture of two stable macro-
tively free interconversion of the macrocyclic ring. This would cycles M46-1 and M46-2, although in low yield. A similar result
eliminate the effect of planar chirality and a single isomer can was obtained when N6 was coupled with H21 to give a mixture
be anticipated. Similarly, only one isomer was observed for of M47-1 and M47-2 (ratio ∼3 : 1). On the contrary, high chemi-
some other macrocycles bearing endo-cyclic substituents. This cal yields (>77%) were achieved in reactions between ortho-sub-
was the case for both 16-membered rings in M23 and M31 stituted anilines N5 or N15 and 5-cyano-4,6-dichloro-pyrimi-
(Rendo = F) as well as for the 18-membered macrocycle H42 dine (H21). Two pairs of 15-membered macrocycles M48-1/
(Rendo = CN).
M48-2 and M49-1/M49-2 were obtained in equal amount.
To check if stable macrocyclic diastereoisomers can be Similarly, macrocyclisation of N16 with H21 was very efficient
formed, we investigated the reaction between the amine N4 providing a 3 : 1 mixture of 15-membered diastereoisomeric
and 5-cyano-4,6-dichloro-pyrimidine (H21). We were pleased to macrocycles M50-1 and M50-2 in high 81% yield. Contrary,
find that SNACK macrocyclisation between the amine N4 and SNACK macrocyclisation between H21 and the ethylene linked
5-cyano-4,6-dichloro-pyrimidine (H21) led to formation of a di-nucleophile N17 9b was sluggish delivering a 3 : 1 mixture of
∼2 : 1 mixture of 2 isomers in 37% yield. Both isomers were isomeric M51-1 and M51-2 in only 18% yield. The reaction
successfully separated using preparative reverse-phase HPLC between N13 and H21 gave a 1.1 : 1 mixture of 17-membered
to afford two stable diastereoisomeric compounds M45-1 and macrocycles M52-1 and M52-2. Both isomers were successfully
M45-2 (Table 3). No isomer interconversion (epimerisation) separated using achiral SFC. However, gradual erosion of dia-
was observed at room temperature. To determine the structural stereoisomeric purity of collected fractions was observed in
identity of each diastereoisomer we used a complementary solution at room temperature measured by LCMS. Attempts to
NMR and computational approach. NOE data was collected for isolate separated isomers M52-1 and M52-2 from SFC fractions
the rotamers using 2D ROESY experiments and the interproton lead to equilibration. As shown in Fig. 4 the major isomer
distances were extracted from the intensities of the cross M52-1 easily equilibrated to the 1.1 : 1 mixture of diastereo-
peaks. The conformational landscape of the diastereoisomers isomers within 4 days at rt.
was explored independently of the NMR using low mode mole-
Increasing the size of the substituent at the 4-position of
cular dynamics methods resulting in a set of conformers for the pyrimidine (switching from CN in H21 to CO2Et in H23)
Fig. 2 Restricted interconversion of the macrocyclic ring in M28.
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Table 3 Formation of atropisomers during SNACK macrocyclisation
Di-nucleophile
Heterocycle No
R2
Macrocycle No
Isomer 1
Isomer 2
Ring size
16
Yield (%)
37
Isomer ratio 1 : 2
N4
H21
CN
M45-1
M45-2
2 : 1
N4
H23
CO2Et
M46-1
M46-2
16
14
2 : 1
N6
N5
H21
H21
CN
CN
M47-1
M47-2
16
15
26
80
3 : 1
1 : 1
M48-1
M48-2
N15
N16
N17
H21
H21
H21
CN
CN
CN
M49-1
M49-2
15
16
14
77
81
18
1 : 1
3 : 1
3 : 1
M50-1
M50-2
M51-1
M51-2
N13
N13
H21
H23
CN
M52-1
M52-2
17
17
36
46
1 : 1.1
2 : 3
CO2Et
M53-1
M53-2
blocked interconversion of the macrocyclic ring and the pair of Synthesis of BCL6 inhibitors
stable diastereoisomeric macrocycles M53-1 and M53-2 was
obtained. Similar atropisomerism due to restricted bond This SNACK macrocyclisation approach was particularly valu-
rotation in macrocycles has aslo been observed and reported able in the discovery and evaluation of high affinity binders of
by others.24
macrocyclic B-cell lymphoma 6 (BCL6).9a,b BCL6 is a transcrip-
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Fig. 3 Conformational analysis (in solution) for diastereoisomers M45-1 and M45-2.
N18 and corresponding heterocycles H2, H10, H22, H24 or
H27 afforded expected macrocycles (M54, M58, M59 or M61,
respectively), alongside of regioisomeric macrocycles (M54a,
M58a, M59a or M61a). In the case of M54, M58, M59, for-
mation of the regioisomeric products was attributed to
reduced regioselectivity of the first nucleophilic aromatic sub-
stitution between the 4- vs. 2-position of the pyrimidine ring in
H2, H10 or H22. Isomeric M61 and M61a formed as a result of
the competitive reactivity of both remaining electrophilic
centres in the final macrocyclisation step. Removal of Cbz-pro-
tection in M54–M61 with 33% hydrobromic acid in acetic acid
followed by reductive amination with formaldehyde yielded
the N-methylated piperazine derivatives M62–M69. Subsequent
displacement of the fluorine in M67 with dimethylamine
smoothly afforded the macrocycle M70 in quantitative yield.
We tested these macrocycles (M62–M70) and the known
reference BCL6 inhibitior FX1 25 in both biochemical and cell-
based assays for BCL6 activity (Table 4).9a A derivative M62
that is unsubstituted at the 5- and 6-position of pyrimidine dis-
Fig. 4 Equilibration of major isomer M52-1 to
diastereomers.
a
mixture of
tional repressor required for germinal centre formation and played low-micromolar affinity to BCL6 and encouraging
maintenance during the humoral immune response. activity in the cell reporter assay. 26-Fold improvement in
Inhibition of the protein-protein interaction (PPI) between binding affinity was observed for the 5-fluoro-pyridimine M63
BCL6 and corepressors has been implicated as a therapeutic as well as 5-fold increase in cell potency. Further improvement
target in diffuse large B-cell lymphoma (DLBCL) cancers. Thus in both BCL6 affinity and cell potency was seen for the
potent and selective BCL6 inhibitors were highly attractive 5-chloro-pyridimine M64 (BCL6 FRET IC50 30 nM). Larger sub-
targets. To design small molecule high affinity ligands, we stituents at the 5-position such as bromine (M65) and cyano
used a macrocyclisation strategy to improve binding affinity of (M66) were less tolerated and led to lower BCL6 affinity (3-fold
our initial “acyclic” leads by increasing the proportion of con- and 8-fold, respectively). Interestingly, despite lower binding
formers close to the bioactive conformation. SNACK macrocy- affinity, M66 was equipotent to M64 in the cell reporter assay.
clisation greatly facilitated access to diverse macrocyclic frame- An additional fluorine at the 6-position of pyrimidine in M67
works and allowed rapid exploration of structure–activity further increased BCL6 affinity in comparison to 5-chloro-pyri-
relationship (SAR) of macrocyclic BCL6 inhibitors. BCL6– dimine M64 (BCL6 FRET IC50 9 nM) as well as cell potency
ligand complex crystal structures revealed a close proximity (BCL6 cell IC50 720 nM). The 5,6-difluoro-pyrimidine M68 was
between the central heteroaromatic ring of the ligand and the 10-fold less active in the FRET assay than M67. Larger substitu-
protein backbone, thus indicatating a relatively tight space to ents at the 6-position reduced activity. 6-Chloro-5-fluoro-pyri-
accommodate substitution. To evaluate the effect of the substi- midine M69 was only slightly less active than M68. However,
tution of the central heteroaromatic ring on binding to the larger substituents such as 6-dimethylamino in M70 led to a
BTB domain homodimer a set of pyrimidine based macro- significant drop in activity. Opportunistically, we also tested
cycles (M62–M70) was prepared starting from the aniline N18 selected N-Cbz-protected piperazine intermediates M56, M57
as drawn in Scheme 13. SNACK macrocyclisation with differ- and M60. Despite showing encouraging binding to BCL6 these
ently substituted halo-pyrimidines delivered corresponding compounds were inactive in the cell-based assay. A drop-off
Cbz-protected macrocyclic piperazines (M54–M61) in good from FRET affinity to cell potency is to be expected since the
yields (38–78%). It’s worth noting, that the reaction between FRET assay is a biochemical assay measuring affinity to BCL6
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Scheme 13 (a) N18,9b heterocycle (H), iPr2EtN, iPrOH, 20–80 °C; (b) MsOH, iPrOH, 60–80 °C; (c) iPr2EtN, iPrOH, 120–150 °C; 57% for M54 and 3%
for M54a, 49% for M55, 66% for M56, 63% for M57, 24% for M58 and 14% for M58a, 76% for M59 and M59a, 78% for M60, 43% for M61 and 11% for
M61a (overall yield for 3 steps) (d) 33% HBr, AcOH, rt; (e) CH2Oaq, NaCNBH3, MeOH; 62% for M62, 80% for M63, 85% for M64, 85% for M65, 60% for
M66, 65% for M67, 60% for M68, 81% for M69 (overall yield for 2 steps); (f) Me2NH, THF, rt, quant.; N24 prepared as described.9b
Table 4 SAR of macrocyclic inhibitors of BCL6
Macrocycle
SNACK yield (%)
BCL6 inhibitor
BCL6 FRET IC50 (μM) SDa
BCL6 cell IC50 (μM) SDa
log D7.4
M54; M54a
M55
M56
60b
49
66
M62
M63
M64
M65
M66
M67 9a
M68
M69
M70
FX1 25
3.4 2.7
0.13 0.1
0.029 0.028
0.23 0.09
0.24 0.06
0.009 0.002
0.096 0.04
0.17 0.13
5.1d
17 9.6c
2.4 0.4
1.4 0.08
2.3 1.0
1.4 0.15
0.72 0.17
2.9 0.9
2.1 0.9
15d
2.5
2.5
3.0
3.3
2.4
3.5
3.2
3.6
3.2e
2.2
M57
63
M58; M58a
M59; M59a
M60
M61; M61a
n/a
38b
76b
78
53b
n/a
n/a
n/a
49
>30
a IC50 values are mean values of >3 independent experiments unless otherwise stated, SD = standard deviation; for the assay protocols see ref. 9a
and b. b Combined yield for both macrocyclic regioisomers. c n = 2. d n = 1. e Calculated log D7.4
.
in competition with a truncated form of the co-repressor
peptide SMRT-2 whereas in the cell assay full length versions
Conclusions
of any of the BCL6 binding co-repressor peptides will be In summary, a diversity-orientated, efficient macrocyclisation
present and competing for binding to BCL6. All N-methyl- approach based on the double aromatic nucleophilic substi-
piperazines M62–M70 resided in an acceptable lipophilicity tution (SNACK) was developed. This methodology benefited
space (log D7.4 < 3.6).
from a large set of diverse commercially available heterocyclic
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reagents and allowed a facile incorporation of heterocyclic tem-
plates into macrocyclic rings. Using our SNACK macrocyclisa-
tion procedure a significant number of structurally diverse
macrocycles were prepared to support AstraZeneca internal
medicinal chemistry projects. The SNACK reaction enables syn-
thesis of stable diastereoisomers and enantiomers of confor-
mationally restricted macrocycles (atropisomers). The structural
identity of the pair of selected diastereoisomers was confirmed
by complementary NMR studies and computational methods.
SNACK macrocyclisation was particularly valuable in the identi-
fication of high affinity binders of B-cell lymphoma 6 with the
macrocycle M67 displaying low-nanomolar affinity to BCL6.
8 (a) J. W. Johannes, S. Bates, C. Beigie, M. A. Belmonte,
J. Breen, S. Cao, P. A. Centrella, M. A. Clark, W. J. Cuozzo,
C. E. Dumelin, A. D. Ferguson, S. Habeshian,
D. Hargreaves, C. Joubran, S. Kazmirski, A. D. Keefe,
M. L. Lamb, H. Lan, Y. Li, H. Ma, S. Mlynarski,
M. J. Packer, P. B. Rawlins, D. W. Robbins, H. Shen,
E. A. Sigel, H. H. Soutter, N. Su, D. M. Troast, H. Wang,
K. F. Wickson, C. Wu, Y. Zhang, Q. Zhao, X. Zheng and
A. W. Hird, ACS Med. Chem. Lett., 2017, 8, 239;
(b) A. Y. S. Balazs, R. J. Carbajo, N. L. Davies, Y. Dong,
A. W. Hird, J. W. Johannes, M. L. Lamb, W. McCoull,
P. Raubo, G. R. Robb, M. J. Packer and E. Chiarparin,
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P. Barton, M. Box, J. Burgess, K. Byth, Q. Cao, C. Chuaqui,
R. J. Carbajo, T. Cheung, E. Code, A. D. Ferguson, S. Fillery,
N. O. Fuller, E. Gangl, N. Gao, M. Grist, D. Hargreaves,
M. R. Howard, J. Hu, P. D. Kemmitt, J. E. Nelson,
N. O’Connell, D. B. Prince, P. Raubo, P. B. Rawlins,
G. R. Robb, J. Shi, M. J. Waring, D. Whittaker, M. Wylot
and X. Zhu, J. Med. Chem., 2017, 60, 4386; (b) W. McCoull,
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R. J. Carbajo, E. Code, S. Cowan, P. R. Davey,
A. D. Ferguson, S. Fillery, N. O. Fuller, N. Gao,
D. Hargreaves, M. R. Howard, J. Hu, A. Kawatkar,
P. D. Kemmitt, E. Leo, M. D. Molina, N. O’Connell,
P. Petteruti, T. Rasmusson, P. Raubo, P. B. Rawlins,
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Conflicts of interest
There are no conflicts to declare.
Acknowledgements
The authors would like to thank Eva Lenz, Dan Rhodes, Emma
Gates, Paul Davies, David Longmire, Neil Summer and
Matthew Sanders for providing analytical support, and Erin
Code and Erica Banks for generating biological data.
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