Spirocycles as Rigidified sp3-Rich Scaffolds for a Fragment Collection

Article abstract of DOI:10.1021/acs.orglett.9b01499

Novel divergent methodology to access sp³-rich spirocyclic fragments is reported. First, a robust modular synthesis of bis-alkene amino ester building blocks was developed. Three different carbocycles and six heterocycles were then constructed

Full text of DOI:10.1021/acs.orglett.9b01499

Letter
Cite This: Org. Lett. XXXX, XXX, XXX−XXX
pubs.acs.org/OrgLett
3
Spirocycles as Rigidified sp ‑Rich Scaffolds for a Fragment Collection
Attila Sveiczer, Andrew J. P. North, Natalia Mateu,* Sarah L. Kidd, Hannah F. Sore,
and David R. Spring*
Department of Chemistry, University of Cambridge, Lensfield Road, Cambridge, CB2 1EW, U.K.
*
S Supporting Information
3
ABSTRACT: Novel divergent methodology to access sp -rich spirocy-
clic fragments is reported. First, a robust modular synthesis of bis-alkene
amino ester building blocks was developed. Three different carbocycles
and six heterocycles were then constructed to assemble eight spirocycles.
Importantly, strategic exit vectors were incorporated within each scaffold
to aid fragment growth and were elaborated via chemical modifications.
Finally, computational methods demonstrate higher levels of rigidity,
three-dimensionality, and structural diversity of the library compared to a
commercial collection.
ince the rise of fragment-based drug discovery (FBDD)
over two decades ago this strategy has proven particularly
can be later elaborated to afford highly potent lead
3
−7
S
compounds.
effective, producing numerous clinical candidates and two
Within this paradigm the generation of a suitable screening
library is paramount. However, despite the undoubted success
of FBDD, within recent years organic synthesis has been
identified as a significant bottleneck within this process, owing
to the overrepresentation of predominantly “flat” (hetero)-
aromatic fragments lacking three-dimensionality as well as
synthetically tractable exit vectors that could be utilized in
1
2
FDA-approved drugs, Vemurafenib and Venetoclax (Figure
A). The success of this approach can be linked to two main
1
benefits. First, due to the considerably fewer number of
possible fragment-sized molecules, the chemical space coverage
of a relatively small fragment library is exceedingly more
efficient than that of a vast high-throughput screening (HTS)
library. Second, fragment hits possess fewer but nonetheless
high-quality binding interactions with the protein target, which
4
,5,8
rapid structure−activity relationship (SAR) studies.
While
complexity of fragments remains under debate within the
9
,10
literature,
importantly, more three-dimensional (3D) frag-
ments displaying exit vectors increase the potential for
multidirectional fragment growth and the ability to identify
leads for challenging targets such as protein−protein
8
,11
interactions.
Thus, recent efforts from within the synthetic
community have focused on the development of novel
12−15
strategies to access 3D fragments.
Spirocyclic motifs remain an important bioactive substruc-
1
6−18
ture appearing within several natural products
approved drugs
and FDA-
(Figure 1B). Importantly, as a direct result
of their architecture, these small molecules often provide
19,20
21
several advantages. First, the spiranic center generates an
inherently 3D structure that gives rise to higher levels of
complexity, a feature which has been linked to improved
10,22,23
clinical success.
Moreover, the conformationally re-
stricted nature of spirocycles can reduce both the conforma-
tional entropy penalty of target binding and the number of
possible conformations (distinct 3D shapes) that a molecule
can adopt leading to higher potency and selectivity,
24,25
respectively.
However, despite their utility, these motifs
remain underrepresented in fragment screening collections.
Indeed, very few compounds within the ChemBridge spiro-
26,27
Figure 1. (A) Two FBDD-derived FDA-approved drugs: Venetoclax
and Vemurafenib. (B) Examples of spirocyclic natural products
cycle library meet the size criteria of FBDD,
while only
(
(
Griseofulvin and Histrionicotoxin) and FDA-approved drugs
Spironolactone and Irbesartan).
Received: April 29, 2019
©
XXXX American Chemical Society
A
DOI: 10.1021/acs.orglett.9b01499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
three spirocycles feature within the Maybridge core fragment
collection. Thus, there is an urgent need for spirocyclic
fragments and calls from within the field have encouraged the
ing various reagents. Reaction with cyanogen bromide formed
amino oxazoline 6 whereas ethyl benzimidate hydrochloride
gave the phenyl-substituted oxazoline 7. The two morpholi-
nones 8 and 9 were constructed by the chemoselective
alkylation/acylation with chloroacetyl chloride and phenyl
bromoacetate respectively (Scheme 2).
25
development of novel strategies to access such motifs.
3
While strategies to access spirocycles within sp -rich
screening libraries have been reported, they either do not
28−30
solely seek to construct spirocycles
or focus on more
3
1
32
complex bis- and bridged- spirocycles. In addition, these
compounds often lie outside the requirements for FBDD.
Thus, we envisaged that a novel approach to access diverse
spirocyclic fragments containing a polar heterocycle and a
lipophilic carbocycle could give rise to a valuable library
complementing already existing screening collections. To
achieve this, our efforts were directed at utilizing α,α-
disubstituted amino acid derivatives as building blocks,
providing the potential to exploit the functional handles to
generate fragment-like spirocyclic scaffolds. The incorporation
of the two alkene handles enabled the carbocycle formation via
ring-closing metathesis (RCM), forming an essential alkene
exit vector, allowing us to alter the properties of this portion of
the fragments. In addition, the amino and ester functionalities
were installed to enable diverse heterocycle formations,
increasing the possible polar interactions and the overall
water solubility of the fragments. Accordingly, rapid access to
varied scaffolds and the potential to exploit the exit vectors for
fragment growth and merging to aid hit-to-lead development
was envisioned.
Scheme 2. Synthesis of Different Core Heterocycles and
Carbocycles
a
First, the building blocks were prepared through the double
alkylation of the glycine Schiff base 1 to form building blocks
3
a−c (Scheme 1). Despite similar procedures having been
Scheme 1. Synthesis of the Building Blocks
a
Reaction conditions: (a) (i) Boc O, THF, 85%; (ii) Grubbs II,
2
CH Cl , 81%; (iii) LiBH , THF, 89%; (b) tBuOK, THF, 90%; (c)
2
2
4
HCl, dioxane; then BrCN, Et N, EtOH, 58%; (d) HCl, dioxane; then
3
ethyl benzimidate hydrochloride, Et N, DCE, 57%; (e) (i) HCl,
3
dioxane; then chloroacetyl chloride, Et N, CH Cl , 57%; (ii) tBuOK,
3
2
2
tBuOH, 99%; (f) HCl, dioxane; then phenyl bromoacetate, iPr NEt,
2
MeCN, 43%; (g) (i) ethyl malonyl chloride, Et N, CH Cl , 73−81%;
3
2
2
(
ii) tBuOK, THF; then aq. HCl, THF, 86−92%; (h) Grubbs II,
a
CH Cl , 69−99%.
Reaction conditions: (i) tBuOK, THF; (ii) tBuOK, THF; (iii) HCl,
THF/H O; then Na CO . Overall yields 3a: 67% (steps i and ii the
2
2
2
2
3
same, steps i−iii in one pot); 3b: 61% (steps i−iii in one pot); 3c:
Building block 3b could also be acylated with ethyl malonyl
chloride, and then the base-mediated cyclization onto the ester
group followed by the acid-catalyzed decarboxylative hydrol-
ysis yielded the tetramic acid intermediate 10b. Formation of
the carbocycle ring in an RCM gave 12 in a good yield. To
exemplify the potential to expand the cyclohexene ring,
spirocycles also featuring the five- and seven-membered
carbocycles were also synthesized from 3a and 3c, respectively
(Scheme 2). Importantly, all the spirocycles were synthesized
in no more than five steps from the building blocks.
3
1% (steps i−iii done stepwise).
3
3−36
reported before,
herein we describe the straightforward
racemic synthesis of α-quaternary amino esters with two
different alkyl chains bearing terminal alkenes (3b,c). A brief
33
optimization of the related literature procedure allowed us to
form 3c in a simple stepwise process. Further optimization of
the analogous route, however, resulted in the development of a
one-pot procedure removing the chromatographic steps to
access 3b on large-scale in an improved 61% yield. This
approach also enabled the formation of 3a.
Although racemic compounds were sought for our fragment
library, the ability to produce optically pure isomers e.g. for
SAR studies was also crucial. Thus, a second asymmetric route
to the desired building blocks was devised utilizing the well-
precedented stereoselective alkylation of iminolactones derived
Subsequently, investigations into the formation of the
different heterocycles were pursued using the racemic amino
ester building block 3b. First, the amine was Boc-protected to
allow the cyclohexene formation in an RCM, followed by the
37,38
from phenylglycinol.
In this case, only one diastereomer of
reduction of the ester to the hydroxymethyl group by LiBH to
the aminolactone (R)-15 was observed, which was successively
deprotected to form the optically pure building block (R)-3d.
As proof of concept, the single R-enantiomer of 12, with the
spiro[4,5] scaffold, was also synthesized (Scheme 3).
With eight fragment scaffolds in hand, it was next crucial to
demonstrate the utility of the exit vectors installed within the
4
afford the key intermediate 4 in good yield. Intramolecular
base-mediated pairing between the alcohol and Boc groups
could then be achieved forming the oxazolidone moiety in 5.
The removal of the Boc protecting group under acidic
conditions could be followed by pairing reactions incorporat-
B
DOI: 10.1021/acs.orglett.9b01499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
a
Scheme 3. Enantioselective Synthesis of (R)-12
Scheme 5. Double Bond Modification and PMB
Deprotection
a
a
Reaction conditions: (a) allyl bromide, Zn, DMF, 68%; (b) (i)
SOCl , MeOH; (ii) Pb(OAc) , MeOH/CH Cl ; then HCl, H O, 92%
2
4
2
2
2
over 2 steps; (c) (i) ethyl malonyl chloride, Et N, CH Cl , 46%; (ii)
3
2
2
tBuOK, THF; then aq. HCl, THF, 92%; (iii) Grubbs II, CH Cl , 97%.
2
2
molecules. Thus, N-alkylation of the oxazolidone (16), O-
alkylation (17), and cross-coupling of the tetramic acid (18)
were demonstrated. In addition, a modified heterocycle with an
alcohol functionality (19) and two with new double bonds (20
and 21) were synthesized, incorporating new exit vectors to
the resultant molecules (Scheme 4).
a
Scheme 4. Heterocycle Modification
a
R = PMB unless specified otherwise. All products are racemic.
Reaction conditions (combined yields with ratios a/b are given): (a)
Fe(acac) , tBuOH, air, 47%, 1.9:1; (b) OsO , NMO, citric acid, H O/
2
4
2
THF, 99%, 2.5:1; (c) TMSCF , NaI, THF, 62%, 20:1; (d) TsNClNa·
3
3
H O, PhNMe Br , 4 Å MS, 70%, 1.4:1; (e) R = H, mCPBA,
2 3 3
NaHCO , CH Cl , 52%, 8:1; (f) PhNMe Br , CH Cl , 96%, 18:1; (g)
3
2
2
3
3
2
2
CAN, MeCN/H O, 96% (R = H in product).
2
Table 1. Physicochemical Properties of Fragment Libraries
Compared to the Ideal Range
a
Reaction conditions: (a) PMBCl, NaH, DMF, 96%; (b) KHMDS,
EtBr, THF, 54%; (c) (i) Tf O, Et N, CH Cl , 59%; (ii) PMPB(OH) ,
2
3
2
2
2
Pd(PPh ) , Na CO , H O/THF, 73%; (d) NaBH , MeOH, 23%; (e)
3
4
2
3
2
4
TFAA, Et N, CH Cl ; then KHCO , MeOH, 30%; (f) Pb(OAc) ,
3
2
2
3
4
MeCN, 92%.
Finally, to exhibit the versatility of the double bond as an
exit vector, modifications such as Wacker oxidation (22a,b),
dihydroxylation (23a,b), difluoro-cyclopropanation (24a,b),
aziridination (25a,b), epoxidation (26a,b), and dibromination
a
MW = molecular weight (Da), HBD = number of hydrogen-bond
donors, HBA = number of hydrogen-bond acceptors, SlogP =
partition coefficient, RBC = rotatable bond count, TPSA = topological
polar surface area (Å ). Protecting groups virtually removed from
(27a,b) were explored (Scheme 5). Initial attempts of the
epoxidation of 5, however, proved challenging with respect to
the isolation and purification of 26a,b. Thus, a PMB group was
installed (16) indeed proving to be compatible with several
reaction conditions generating the diversified fragments in
good to excellent yields. Removal of the PMB protecting group
was also exemplified by the treatment of compound 27a with
CAN to generate the unprotected modified spirocycle 28.
The physicochemical properties of our library consisting of
b
2
c
our library. Maybridge core fragment collection of 1000 fragments.
d
26,27
Guidelines set by Astex Pharmaceuticals.
Information.
See Supporting
3
Strikingly, our library also displayed far superior sp -content
3
3
with an average fraction of sp atoms (Fsp ) of 0.52, which also
translates into a much lower fraction of aromatic atoms (Faro)
of 0.16. Moreover, the average number of chiral centers (1.6)
is also considerably higher, resulting in greater stereochemical
diversity achieved by the spirocyclic fragments.
2
8 different nonprotected spirocyclic molecules were then
calculated and compared to the commercially available
Maybridge core fragment library using the widely accepted
guidelines from within the field (Table 1).
26,27
This revealed
the spirocyclic library adheres well to the guidelines and was
additionally predicted to be significantly less lipophilic (SlogP
of 0.9 versus 1.8) and more rigid (rotatable bond count of 0.2
versus 2.0) than the Maybridge core fragment collection.
In order to qualitatively assess the shape diversity in our
library, a principal moments of inertia (PMI) analysis was
carried out. Our library was then compared to the whole
Maybridge core fragment collection of 1000 fragments and a
C
DOI: 10.1021/acs.orglett.9b01499
Org. Lett. XXXX, XXX, XXX−XXX

Organic Letters
Letter
Figure 2. PMI plots for the visual representation of shape diversity. Each corner of the plot represents a unique shape (rod-, disk-, and sphere-like
11
features). The dashed line represents the boundary of “flat land”. Our virtual deprotected library of 28 spirocycles (blue) is compared to 1000
fragments (red, left) and the 147 best-matched fragments based on heavy and heteroatom count (red, right) from the Maybridge collection. The
a
3
3
table on the right summarizes the physicochemical properties used to describe the 3D properties of the two libraries. Fsp = fraction of sp atoms,
Far = fraction of aromatic atoms, chiral = number of chiral centers, npr = normalized PMI ratio, Fflat = fraction of molecules lying below the “flat
11
b
c
land line” . Virtual deprotected library. 147 best-matched fragments from the Maybridge collection. See Supporting Information.
representative subset consisting of the 147 best-matched
compounds based on heavy atoms (Figure 2). Both plots
show that the Maybridge fragments tend to aggregate to the
left-hand edge (rod- and disc-like features) or the “flat land”,
whereas our spirocyclic fragments are more evenly distributed.
Analysis showed that more than 70% of the whole Maybridge
collection and 75% of the best formula match subset fall within
Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax: +44
1223 336033.
AUTHOR INFORMATION
■
Corresponding Authors
*
*
E-mail: spring@ch.cam.ac.uk.
E-mail: nm462@ch.cam.ac.uk.
11
“
flat land” (defined as npr1 + npr2 ≤ 1.1). On the other
hand, no spirocyclic fragment in our library was found below
ORCID
the “flat land” criteria, suggesting more 3D molecules.
David R. Spring: 0000-0001-7355-2824
Notes
In conclusion, we have developed a robust, scalable, and
modular route to racemic α,α-disubstituted amino ester
building blocks including an adapted stereoselective alkylation
protocol to access the optically pure intermediate. These were
utilized in the efficient construction of eight novel spirocyclic
scaffolds comprising pharmacophore heterocycles and variable
carbocycles. All core scaffolds display an array of 3D exit
vectors demonstrated by a number of chemical modifications
to both the hetero- and carbocycles. Together with the
enantioselective synthesis, rapid SAR studies and binding
pocket exploration by fragment growth could therefore be
envisioned. Finally, the computational predictions revealed
optimal physicochemical properties, higher rigidity increased
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
A.S. acknowledges support from the Walters family and Selwyn
College, University of Cambridge. A.J.P.N., H.F.S., and D.R.S.
acknowledge support from the Engineering and Physical
Sciences Research Council (EP/P020291/1). N.M.S. thanks
the EU for a Marie Curie Fellowship (2013-IEF-626191).
S.L.K. thanks AstraZeneca for funding. D.R.S. acknowledges
support from the Royal Society (Wolfson Research Merit
Award). The Spring lab acknowledges general lab support from
the ERC, EPSRC, BBSRC, MRC, and Royal Society. The
authors would like to thanks Dr. Andrew Bond (Department of
Chemistry, University of Cambridge) for carrying out the
single-crystal crystallography for the project.
3
D properties, shape, and stereochemical diversity compared
to a commercial fragment library.
ASSOCIATED CONTENT
Supporting Information
■
*
S
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.or-
glett.9b01499.
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