Practical Synthesis of Fluorinated Piperidine Analogues Based on the 2-Azaspiro[33]heptane Scaffold

Article abstract of DOI:10.1055/s-0035-1562113

The synthesis of a set of conformationally restricted fluorinated analogues of piperidine, based on a 2-azaspiro[3.3]heptane scaffold, is reported. Different pattern of fluorine substitution within the rigid skeleton make the analogues excellent candidate

Full text of DOI:10.1055/s-0035-1562113

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© Georg Thieme Verlag Stuttgart · New York
2016, 27, A–D
letter
A
A. V. Chernykh et al.
Letter
Synlett
Practical Synthesis of Fluorinated Piperidine Analogues Based on
the 2-Azaspiro[3.3]heptane Scaffold
Anton V. Chernykha,b
Anton N. Tkachenkob
Illia O. Feskovb,c
28% overall yield
5 steps
one-pot Wittig olefination
O
N
F
NH
Boc
F
Constantin G. Daniliucd
Nataliya A. Tolmachovab
Dmitriy M. Volochnyuka
Dmytro S. Radchenko*b,c
NH
analogues
F
F
O
or
H
F
N
Ts
NH
NH
a Institute of Organic Chemistry, National Academy of Sciences
of Ukraine, Murmanska St. 5, Kyiv 02660, Ukraine
b Enamine Ltd., Alexandra Matrosova Street 23, Kyiv 01103,
Ukraine
65%
38%
dmitry.radchenko@gmail.com
c Institute of High Technologies, Taras Shevchenko National
University of Kyiv, Volodymyrska 60, Kyiv 01601, Ukraine
d Westfälische Wilhelms-Universität Münster, Organisch-
Chemisches Institut, Corrensstrasse 40, 48149 Münster,
Germany
Received: 15.02.2016
Accepted after revision: 08.04.2016
Published online: 04.05.2016
ment for novelty and patentability have eventually led to an
increase in the interest toward conformationally restricted,
nonflattened, and nonaromatic building blocks.4–6 It is rea-
sonable to suggest that the availability of rigid, nonflat-
tened and at the same time fluorinated building blocks
would facilitate the drug discovery process, in particular,
lead optimization.
DOI: 10.1055/s-0035-1562113; Art ID: St-2016-b0109-l
Abstract The synthesis of a set of conformationally restricted fluori-
nated analogues of piperidine, based on a 2-azaspiro[3.3]heptane scaf-
fold, is reported. Different pattern of fluorine substitution within the
rigid skeleton make the analogues excellent candidates for use in drug
design. The overall simplicity of the experimental procedures and the
availability of inexpensive starting materials allow for multigram-scale
syntheses of the described compounds.
Fluorinated piperidines7,8 and their derivatives9,10 have
already attracted significant interest in the field of medici-
nal chemistry. Exchange of a fluorinated piperidine for the
piperidine fragment has been extensively exploited to im-
prove potency, bioavailability, and metabolic stability
during hit-to-lead optimization.11–16 Moreover, virtual ab-
sence of fluorine in living organisms allowed the use of flu-
orinated piperidine derivatives as a probe for metabolite
tracing using 19F NMR in cancer cells17 as well as in vivo PET
imaging.18
Azaspiro[3.3]heptane derivatives have been often con-
sidered as conformationally restricted analogues of piperi-
dine with unique properties.19 We have previously reported
the synthesis and structural analysis of several
spiro[3.3]heptane derivatives as aminocyclohexane ana-
logues.20,21 Herein, as a part of the strategy toward finding
nonflattened, fluorinated building blocks we describe the
synthesis of a set of 2-azaspiro[3.3]heptane-containing
piperidine analogues.
Key words piperidine analogues, fluorinated building blocks,
azaspiro[3.3]heptane, deoxofluorination, azetidine derivatives
Among different trends in drug design, the introduction
of fluorine-containing substituents proved to be one of the
most useful,1 and the use of nonaromatic, 3D-shaped build-
ing blocks is one of the most recent approaches.2 Improve-
ment in metabolic stability is the most prominent feature
of fluorinated building blocks. Other beneficial properties
associated with fluorination are increased solubility, per-
meability, potency, adjacent group pKa modulation, and
conformational control caused by a strong fluorine gauche
effect.3 Not surprisingly, fluorinated pharmaceuticals con-
stitute a significant part of marketed drugs and agrochemi-
cals. The use of rigid scaffolds in drug design also proved to
be beneficial, and initially this led to a wide propagation of
aromatic and heteroaromatic moieties among the drug can-
didates. Development of excellent methods for the synthe-
sis and coupling of aromatic building blocks further popu-
larize their use in medicinal chemistry. However, efforts to
minimize toxicity, often associated with the presence of ar-
omatic and heteroaromatic moieties, as well as the require-
Our general synthetic approach to the fluorinated 2-aza-
spiro[3.3]heptanes included preparation of corresponding
ketones bearing a protected amino group as the starting re-
agents. Although an analogue of ketone 3 bearing a di-
phenylmethyl protecting group was previously used for the
construction of the 5-oxo-2-azaspiro[3.3]heptane skele-
ton,22 we decided to employ the N-Boc-protected derivative
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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A. V. Chernykh et al.
Letter
Synlett
to avoid formation of possible byproducts during the re-
moval of the diphenylmethyl moiety by hydrogenolysis.
Other features of our synthesis of compound 3 are the use
of cheap starting materials and the one-pot procedure for
the Wittig olefination. We substituted commonly employed
and rather expensive cyclopropylsulfonium tetrafluorobo-
rate with the much cheaper (3-bromopropyl)triphenyl-
phosphonium bromide that allowed for upscaling the pro-
tocol to a multigram scale.23 The key transformation includ-
ed a one-pot assembly of the cyclopropane ring by the
intramolecular alkylation reaction, a formation of the cor-
responding ylide followed by the Wittig reaction. Subse-
quent epoxidation of the double bond in 2 and the rear-
rangement of the intermediate epoxide afforded 3 in 38%
yield (Scheme 1).
into mesylate 7; however, nucleophilic substitution with
the fluoride ion failed in our hands. Mesylate 7 proved to be
quite resistant to the nucleophilic substitution, probably
because of steric hindrance. Therefore, we switched to the
deoxofluorination reaction of alcohol 6 using Morf-DAST.
However, treatment of the alcohol with Morf-DAST led to
the formation of rearrangement product 9 as the main
product. No target compound 8 was observed in the crude
mixture. Rearrangement product 9 was purified by column
chromatography and characterized. The N-Boc protection
was removed with trifluoroacetic acid yielding amine 10.
The rearrangement of the alcohol 6 during the deoxo-
fluorination reaction could be explained by dissociation of
intermediate compound 11 with the formation of carbeni-
um ion 12 (Scheme 2). Apparently, due to steric hindrance,
the deoxofluorination reaction proceeded by an SN1 mecha-
nism rather than by SN2. Secondary carbocation 12 could
then undergo a reversible rearrangement to more stable
tertiary carbenium ion 13. Finally, addition of the fluoride
ion gave 3-fluoro-3-substituted azetidine 9.24,25 Notably, no
elimination product was detected. Previously, we observed
a similar rearrangement of spiro[3.3]heptane-derived ke-
tones and formation of the corresponding cyclopropanes in
small amounts.26
6, X = OH
N
Boc
11, X = OSF2NR2
X
– X
F–
N
Boc
N
Boc
N
Boc
F
12
13
9
Scheme 2 Possible rearrangement mechanism
Synthesis of amine 16 included deoxofluorination with
MorfDAST of N-tosyl-protected amino ketone 14,27,28 fol-
lowed by the tosyl group removal with sodium amalgam
(Scheme 3). Our synthesis of 19 also started with protected
amino ketone 14; its reduction with sodium borohydride
afforded amino alcohol derivative 17. The fluorine substitu-
ent was then introduced by a nucleophilic substitution re-
action via the corresponding mesylate. The moderate yield
of this reaction could be rationalized taking into account
that a significant amount of the corresponding alkene was
formed as a result of the elimination reaction. Deprotection
of the amino group in compound 18 finished the synthesis.
The structures of compounds 15 and 19 were confirmed by
X-ray analysis (Scheme 3).29 The overall yields (calculated
from ketone 14) were 65% and 38% for the hydrochlorides
16 and 19, respectively.
Scheme 1 Synthesis of compounds 5 and 10 and X-ray structure of 5.
Thermal ellipsoids are shown with 30% probability
Treatment of spirocyclic ketone 3 with Morf-DAST led to
a clean formation of difluoride 4. Removal of the N-Boc pro-
tection with trifluoroacetic acid gave desired compound 5
in 28% overall yield starting from commercially available
ketone 1. The structure of trifluoroacetate 5 was confirmed
by X-Ray analysis (Scheme 1). Initially, we considered com-
pound 3 as a starting material for the synthesis of both di-
fluoro- and monofluoro-substituted derivatives. Therefore,
we synthesized N-Boc amino alcohol 6 by reduction of 3
with sodium borohydride. The alcohol was easily converted
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D

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A. V. Chernykh et al.
Letter
Synlett
Scheme 3 Synthesis of amines 16 and 19 and their X-ray structures. Thermal ellipsoids are shown with 15% (15) and 30% (19) probability.
In conclusion, we reported a practical preparation of a
set of fluorine-substituted amines based on the 2-
azaspiro[3.3]heptane scaffold. The synthesized compounds
could be considered as conformationally restricted fluori-
nated piperidine analogues. We also modified the proce-
dure for the preparation of compound 3 using only easily
available and cheap starting materials, thus enabling pre-
parative scale synthesis of the reported amine. The synthe-
sized compounds are expected to find applications in the
field of medicinal chemistry and drug design.
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The authors acknowledge Enamine LTD for financial support and Dr.
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Supporting Information
Supporting information for this article is available online at
http://dx.doi.org/10.1055/s-0035-1562113.
S
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Primary Data
for this article are available online at http://www.thieme-con-
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be cited using the following DOI: 10.4125/pd0077th. PmriaryDatPmriaryDat104.1
2
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(23) tert-Butyl 3-Cyclopropylideneazetidine-1-carboxylate (2)
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to
a suspension of (3-bromopropyl)triphenylphosphonium
bromide (69.00 g, 148.70 mmol) in toluene (600 mL) under an
Ar atmosphere at –30 °C. The orange solution was stirred for 2 h
at room temperature, and then the solution of compound 1
(23.00 g, 134.35 mmol) in THF (100 mL) was slowly added drop-
wise to reaction mixture at –78 °C. The reaction mixture was
stirred at –78 °C for 1 h, slowly warmed up to room tempera-
ture overnight, refluxed for 3 h, and poured into cold sat. aq
NH4Cl. The mixture was extracted with EtOAc. The organic
phase was dried over Na2SO4, filtered, and evaporated. The
resulting solid was washed with hexanes–EtOAc (7:1, 3 × 100
mL), and the combined organic extracts were evaporated. The
residue was purified by column chromatography (hexanes–
EtOAc = 7:1); yield 13.90 g (71.19 mmol, 53%); white solid; mp
90–93 °C. TLC: Rf = 0.37 (hexanes–EtOAc = 7:1). 1H NMR (500
MHz, CDCl3): δ = 4.55–4.50 (m, 4 H), 1.44 (s, 9 H), 1.08–1.03 (m,
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(29) The CCDC numbers 1451977–1451979 for compounds 5, 15,
and 19 contain the supplementary crystallographic data for this
paper. The data can be obtained free of charge from The
Cambridge
Crystallographic
Data
Centre
via
www.ccdc.cam.ac.uk/getstructures.
© Georg Thieme Verlag Stuttgart · New York — Synlett 2016, 27, A–D