A Two-Step Synthesis of 2-Spiropiperidines

Article abstract of DOI:10.1002/chem.201702467

A general two-step synthesis of 2-spiropiperidines has been developed. δ-Amino-β-ketoesters can be reacted with cyclic ketones to generate 2-spiropiperidines in good to excellent yields. The 2-spiropiperidines formed occupy an under-explored region of 3D-chemical space and are novel scaffolds for use in drug discovery programs. These 2-spiropiperidines can be further functionalised to generate small highly sp³-rich structures, which exhibit an excellent likeness to lead-molecules in drug discovery.

Full text of DOI:10.1002/chem.201702467

A Journal of
Accepted Article
Title: A Two-Step Synthesis of 2-Spiropiperidines
Authors: Samuel D Griggs, Nathan Thompson, Daniel T Tape, Marie
Fabre, and Paul A. Clarke
This manuscript has been accepted after peer review and appears as an
Accepted Article online prior to editing, proofing, and formal publication
of the final Version of Record (VoR). This work is currently citable by
using the Digital Object Identifier (DOI) given below. The VoR will be
published online in Early View as soon as possible and may be different
to this Accepted Article as a result of editing. Readers should obtain
the VoR from the journal website shown below when it is published
to ensure accuracy of information. The authors are responsible for the
content of this Accepted Article.
To be cited as: Chem. Eur. J. 10.1002/chem.201702467
Link to VoR: http://dx.doi.org/10.1002/chem.201702467
Supported by

10.1002/chem.201702467
Chemistry - A European Journal
COMMUNICATION
A Two-Step Synthesis of 2-Spiropiperidines
Samuel D. Griggs,[a] Nathan Thompson,[a] Daniel T. Tape,[b] Marie Fabre,[a] and Paul A. Clarke*[a]
Abstract: A general two-step synthesis of 2-spiropiperidines has
been developed. -Amino--ketoesters can be reacted with cyclic
ketones to generate 2-spiropiperidines in good to excellent yields.
The 2-spiropiperidines formed occupy an under-explored region of
3D-chemical space and are novel scaffolds for use in drug discovery
programs. These 2-spiropiperidines can be further functionalized to
generate small highly sp3-rich structures which exhibit an excellent
likeness to lead-molecules in drug discovery.
rich area of chemical space as assessed by PMI analysis and
have a good “lead-likeness” as assessed by LLAMA.
Traditional drug discovery programs rely on the identification
and synthesis of small molecule leads which can be elaborated
into potential drug candidates. Recently it has been recognized
that
a
very large proportion of these molecules are
comparatively two-dimensional structures containing a high
proportion of sp and sp2-hybridised carbons,[1] and hence, there
has been a drive to develop new routes to access the relatively
under-explored sp3-rich area of chemical space.[2] Consequently,
several tools have been developed to assess the degree of 3-
dimensionality of small molecules, these include Principle
Moments of Inertia (PMI) analysis,[3] Plane of Best Fit analysis[4]
and, more recently, Lead Likeness And Molecular Analysis
(LLAMA).[5] There is a growing consensus that out of all the sp3-
rich structural types spirocyclic molecules hold a privileged
position,[6] as they are conformationally well defined which
allows the functionality on the spirocycle to be elaborated in
well-defined directions.[7],[8] Furthermore, we identified that a
highly desirable, yet under represented subset of spirocyclic
systems is the 2-spiropiperidine unit. While routes for the
synthesis of spirocyclic oxetanes[9] and other 4-membered
rings,[10] indolenines[11] and ethers[12],[13] have been developed,
and the advent of SnAP and SLAP reagents has led to the facile
synthesis of spirocyclic morpholines, piperazines and
piperidines,[14],[15] there are limited methods for the synthesis of
2-spiropiperidines,[16] with the vast majority of spiropiperidines
being spirofused at either the 3- or 4-positions.[16]
Scheme 1. The aza-Maitland-Japp reaction
Initial studies focused on adapting the one-pot aza-Maitland-
Japp synthesis of highly functionalized piperidines from diketene,
N-tosyl imines and aldehydes (Scheme 1a).[18b] However, we
were unable to extend this reaction to the synthesis of 2-
spiropiperidines, as the N-tosyl group was either eliminated in
the Mannich-like step or it inhibited the cyclisation step when
ketones were used. These problems were overcome by the use
of N-Boc imines and the Weiler dianion[19] (Scheme 1b). We
rationalized that the Boc group would still increase the
electrophilicity of the azamethine carbon, as the tosyl group had,
and that it could easily be removed before cyclisation. Known
aryl N-Boc imines were prepared from the corresponding aryl
aldehydes via the procedure of Lam.[20] However, the other N-
Boc imines used were relatively unstable and so were generated
in situ from the N-Boc sulfone precursor 1 (Figure 1). N-Boc
sulfone precursors 1 were treated with the Weiler dianion and
the resultant N-Boc--amino--ketoesters
2 were isolated.
In this paper we report a general, expedient and operationally
simple two-step route for the synthesis of 2-spiropiperidines,
which builds on our extensive expertise in the development of
the Maitland-Japp[17] and aza-Maitland-Japp reactions[18]
(Scheme 1). The 2-spiropiperidines synthesized occupy the sp3-
Removal of the N-Boc group was achieved by treatment with
HCl in dioxane and the -amino--ketoester·HCl salt was
“cracked” in the presence of a ketone 3 with NaHCO3, which
promoted cyclisation and yielded 2-spiropiperidines 4 (Figure 1).
N-Boc sulfone precursors 1a-j derived from a range of medicinal
chemistry relevant aldehydes were prepared, including 3-pyridyl
1g, 4-methyl thiazole 1h, N-methyl-4-pyrazole 1i and 4-
cyanophenyl 4j from the GSK aldehyde library.[21] Acetone and a
selection of cyclic (4-6 membered ring) ketones containing O, S
or N-heteroatoms all reacted smoothly with the -amino--
ketoester to give the desired piperidines 4a-s. The two-step
procedure is easy to carry out and robust as is demonstrated by
the synthesis of 2-spiropiperidine 4h on a 1.5 g scale. The
piperidines existed as a mixture of diastereomeric methyl esters,
with the relative stereochemistry shown predominating, and
there was no evidence of the diastereomers interconverting
during chromatographic purification. Interestingly, in the major
[a]
[b]
Mr. S. D. Griggs, Mr. N. Thompson, Miss M. Fabre, Dr. P. A. Clarke,
Department of Chemistry,
University of York,
Heslington, York, UK, YO10 5DD.
E-mail: paul.clarke@york.ac.uk
Dr. D. T. Tape,
Flexible Discovery Unit,
GlaxoSmithKline Medicines Research Centre,
Gunnels Wood Road, Stevenage, UK, SG1 2NY.
Supporting information for this article is given via a link at the end of
the document.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702467
Chemistry - A European Journal
COMMUNICATION
diastereomer the methyl ester is axial, presumably to alleviate a
destabilizing steric interaction with the protons on the adjacent
spiro-ring (Figure 2).
2-Spiropiperidines 4a-s were subjected to PMI analysis to
determine their degree of 3-dimensionality. As can be seen in
Figure 3, almost all of the spirocycles 4a-4s reside in the under-
explored area of chemical space, making these molecules more
3-dimensional than 75% of the structures in the comparison
library of 35,270 lead-like molecules from the ZINC database.[22]
Figure 2. X-ray crystal structure of 4j with thermal ellipsoids shown at 50%
CCDC Number 1549997.
Figure 3. PMI plot of 4a-4s (orange) and 5a-11 (purple) on a library of 35,270
‘lead-like’ molecules out of the 6,053,287 molecules from the ZINC
database[22] (blue). This lead-like set has 250≤mw≤350, clogP ≤3.5, number of
rotatable bonds ≤7 and an overall charge of 0 or +1 at physiological pH. 75%
of the population of this library lies to the left of the line.
With a procedure in place for the synthesis of a range of
substituted 2-spiropiperidines, we wished to demonstrate the
versatility of the scaffold by carrying out
a series of
transformations, which would enable them to be converted into
lead-like structures. To this end the transformations investigated
were the reduction of the ketone carbonyl with NaBH4 which
generated alcohols 5a-d, and the conversion of the ester to an
amide 6a-c (Figure 4). Amides 6a-c were formed directly from
the esters following the amidation procedure of Woodward.[23] Of
particular note is the formation of propargyl amide 6a, which
installed the functionality required for the spirocyclic scaffold to
Figure 1. 2-Spiropiperidine scaffolds. Spirocyclisation reactions were run on
100 mg scale with the exceptions of 2e, 2g and 2h which were synthesised on
5 g scale and 4h which was synthesised on 1.5 g scale. The ratio of
diastereomers was determined by 1H NMR of the crude reaction mixture.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702467
Chemistry - A European Journal
COMMUNICATION
participate in azide-alkyne “Click” chemistry.[24] Tertiary amine 7a
was formed by reaction of 5c with Ag2O and MeI in 50% yield.
The removal of the ester group by LiOH in THF/H2O promoted
decarboxylation and yielded 8a-c, reductive amination of the
ketone function with propargyl amine and NaBH(OAc)3 gave 9a,
Wittig methylenation of the carbonyl generated 10a, and
epoxidation of carbonyl through sulfoxonium ylide addition,
generated a tri-spirocyclic system 11a (Figure 4).
LLAMA score if the molecule has >1 aromatic rings or functional
groups which are deemed too reactive to be present in a lead
molecule. As can be seen 6a-c, 8-11a all have low LLAMA
values (≤3) indicating that these molecules are highly lead-like.
Molecules 5a-d and 7a have LLAMA values of ≥5 showing that
they are less lead-like. Further analysis of these values and
structures, indicated that these high LLAMA scores are due to
the presence of the ester functionality which carries a significant
penalty (+5) due to its reactivity. However, as we have shown
the ester group can be removed or converted to an amide these
molecules still have significant potential as lead precursors.
In summary, we have developed a simple and robust procedure
for the synthesis of novel 2-spiropiperidine scaffolds, which
occupy the under-explored region of sp3-rich chemical space.
The properties of these molecules in terms of new defined
vectors for functionalization make these molecules highly
desirable in drug discovery programs. Further functionalization
of these scaffolds generated molecules which are highly lead-
like, as assessed by LLAMA. As such we believe this work will
be of great interest to synthetic and computational chemists
involved in drug discovery programmes.
Acknowledgements
We thank the Department of Chemisty, University of York,
GlaxoSmithKline (SDG) and the ERASMUS+ program (MF) for
financial support and Dr. Adrian Whitwood for X-ray analysis.
Conflict of Interest
The authors declare no conflict of interest.
Keywords: spirocyclic • piperidine • scaffolds • Maitland-Japp •
medicinal chemistry
[1]
[2]
a) F. Lovering, J. Bikker, C. Humblet, J. Med. Chem. 2009, 52, 6752-
6756; b) F. Lovering, Med. Chem. Commun. 2013, 4, 515-519.
For over views see: a) C. J. O’Connor, H. S. G. Beckmann, D. R.
Spring, Chem. Soc. Rev. 2012, 41, 4444-4456; b) A. Karawajczyk, F.
Giordanetto, J. Benningshof, D. Hamza, T. Kalliokoski, K. Pouwer, R.
Morgentin, A. Nelson, G. Muller, A. Piechot, D. Tzalis, Drug Discov.
Today 2015, 11, 1310-1316; c) J. Meyers, M. Carter, N. Y. Mok, N.
Brown, Future Med. Chem. 2016, 8, 1753-1767.
[3]
[4]
[5]
W. H. B. Sauer, M. K. Schwarz, J. Chem. Inf. Comput. Sci. 2003, 43,
987-1003.
N. C. Firth, N. Brown, J. Blagg, J. Chem. Inf. Model. 2012, 52, 2516-
2525.
I. Colomer, C. J. Empson, P. Craven, Z. Owen, R. G. Doveston, I.
Churcher, S. P. Marsden, A. Nelson, Chem. Commun. 2016, 52, 7209-
7212.
[6]
F. Voss, S. Schunk, H. Steinhagen, RSC Drug Discovery Series 2016,
50, Privileged Scaffolds in Medicinal Chemistry: Design, Synthesis,
Evaluation, 439-458, Ed. S. Bräse.
Figure 4. Functionalization of 2-spiropiperidines
The lead-likeness of all of these structures was assessed using
the LLAMA protocol[5] (Figure 4). LLAMA assigns a lead-likeness
value to molecules, where the lower the value, the more lead-
like the molecule is. Penalties are applied to a molecule’s
[7]
[8]
Y. Zheng, C. M. Tice, S. B. Singh, Bioorg. Med. Chem. Lett. 2014, 24,
3673-3682.
G. Müller, T. Berkenbosch, J. C. J. Benningshof, D. Stumpfe, J.
Bajorath, Chem. Eur. J. 2017, 23, 703-710.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702467
Chemistry - A European Journal
COMMUNICATION
[9]
a) G. Wuitschik, M. Rogers-Evans, A. Buckl, M. Bernasconi, M. Märki,
T. Godel, H. Fischer, B. Wagner, I. Parrilla, F. Schuler, J. Schneider, A.
Alker, W. B. Schweizer, K. Müller, E. M. Carreira, Angew. Chem. Int.
Ed. 2008, 47, 4512-4515; b) M. Gurry, P. McArdle, F. Aldabbagh,
Molecules, 2015, 20, 13864-13874.
[10] E. M. Carreira, T. C. Fessard, Chem. Rev. 2014, 114, 8257-8322.
[11] a) M. J. James, P. O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew.
Chem. Int. Ed. 2016, 55, 9671-9675. b) A. K. Clarke, M. J. James, P.
O’Brien, R. J. K. Taylor, W. P. Unsworth, Angew. Chem. Int. Ed. 2016,
55, 13798-13802; c) M. J. James, P. O’Brien, R. J. K. Taylor, W. P.
Unsworth, Chem. Eur. J. 2016, 22, 2856-2881. d) S. J. Chambers, G.
Coulthard, W. P. Unsworth, P. O’Brien, R. J. K. Taylor, Chem. Eur. J.
2016, 22, 6496-6500.
[12] T. Xu, N. A. Savage, G. Dong, Angew. Chem. Int. Ed. 2014, 53, 1891-
1895.
[13] K. Adams, A. K. Ball, J. Birkett, L. Brown; B. Chappell, D. M. Gill, P. K.
T. Lo, N. J. Patmore, C. R. Rice, J. Ryan, P. Raubo, J. B. Sweeney,
Nature Chem. 2017, 9, 396-401.
[14] a) W.-Y. Siau, J. W. Bode, J. Am. Chem. Soc. 2014, 136, 17726-17729;
b) K. Geoghegan, J. W. Bode, Org. Lett. 2015, 17, 1934-1937; c) S.- Y.
Hsieh, J. W. Bode, Org. Lett. 2016, 18, 2098-2101.
[15] For an over view see: C.-V. T. Vo, J. W. Bode, J. Org. Chem. 2014, 79,
2809-2815.
[16] Y. Troin, M. E. Sinibaldi, Targets in Heterocyclic Systems: Chemistry
and Properties, Italian Chemical Socciety (Rome), 2009, 13, 120-146.
[17] a) P. A. Clarke, K. Ermanis, Curr. Org. Chem. 2013, 17, 2025-2037; b)
P. A. Clarke, P. B. Sellars, N. M. Nasir, Org. Biomol. Chem. 2015, 13,
4743-4750; c) P. A. Clarke, N. M. Nasir, P. B. Sellars, A. M. Peter, C. A.
Lawson, J. L. Burroughs, Org. Biomol. Chem. 2016, 14, 6840-6852.
[18] P. A. Clarke, A. V. Zaytzev, A. C. Whitwood, Tetrahedron Lett. 2007,
48, 5209-5212; b) P. A. Clarke, A. V. Zaytsev, T. W. Morgan, A. C.
Whitwood, C. Wilson, Org. Lett. 2008, 10, 2877-2880; c) P. A. Clarke,
A. V. Zaytsev, A. C. Whitwood, Synthesis 2008, 3530-3532.
[19] S. N. Huckin, L. Weiler, Tetrahedron Lett. 1971, 50, 4835-4838.
[20] D. Best, S. Kujawa, H. W. Lam, J. Am. Chem. Soc. 2012, 134, 18193-
18196.
[21] For GSK compounds for lead oriented synthesis, contact
free.buildingblocks@gsk.com
[22] J. J. Irwin, T. Sterling, M. M. Mysinger, E. S. Bolstad, R. G. Coleman, J.
Chem. Inf. Model. 2012, 52, 1757–1768.
[23] N. Dubois, D. Glynn, T. McInally, B. Rhodes, S. Woodward, D. J. Irvine,
C. Dodds, Tetrahedron 2013, 69, 9890-9897.
[24] a) V. V. Rostovtsev, L. G. Green, V. V. Fokin, K. B. Sharpless, Angew.
Chem. Int. Ed., 2002, 41, 2596-2599; b) F. Himo, T. Lovell, R. Hilgraf, V.
V. Rostovtsev, L. Noodleman, K. B. Sharpless, V. V. Fokin, J. Am.
Chem. Soc. 2005, 127, 210-216.
This article is protected by copyright. All rights reserved.

10.1002/chem.201702467
Chemistry - A European Journal
COMMUNICATION
Entry for the Table of Contents (Please choose one layout)
Layout 1:
COMMUNICATION
Spiro-tastic! 2-Spiropiperidines are
readily synthesised in good to
excellent yields via a two-step
procedure. These molecules
Samuel D. Griggs, Nathan Thompson,
Daniel T. Tape, Marie Fabre and Paul.
A. Clarke*
Page No. – Page No.
constitute novel 3D-scaffolds for use
in drug discovery programs,
occupying an under-populated region
of chemical space. The 2-
A Two-Step Synthesis of 2-
Spiropiperidines
spiropiperidines formed can be readily
modified into lead-like molecules.
This article is protected by copyright. All rights reserved.