Synthesis of Spirocyclic Pyrrolidines: Advanced Building Blocks for Drug Discovery

Article abstract of DOI:10.1002/chem.201702362

In the context of drug discovery, novel spirocyclic pyrrolidines have been synthesized in two steps from common three- to seven-membered-ring (hetero)alicyclic ketones. The key transformation is a reaction between an electron-deficient exocyclic alkene and an in situ generated N-benzyl azomethine ylide. The developed method has been used to synthesize the central diamine core of the known antibacterial agents Sitafloxacin and Olamufloxacin.

Full text of DOI:10.1002/chem.201702362

A Journal of
Accepted Article
Title: Synthesis of spirocyclic pyrrolidines: advanced building blocks for
drug discovery
Authors: Bohdan Chalyk, Maryna Butko, Oksana Yanshyna,
Konstantin Gavrilenko, Tetiana Druzhenko, and Pavel
Mykhailiuk
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To be cited as: Chem. Eur. J. 10.1002/chem.201702362
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Synthesis of spirocyclic pyrrolidines:
advanced building blocks for drug discovery
Bohdan A. Chalyk,1 Maryna V. Butko,1,2 Oksana O. Yanshyna,1,3 Konstantin S. Gavrilenko,1,4 Tetiana V.
Druzhenko,1,3 and Pavel K. Mykhailiuk5*
Abstract: Novel spirocyclic pyrrolidines were synthesized in two
steps from common 3- to 7-membered (hetero)alicyclic ketones. The
key transformation was the reaction between electron-deficient
exocyclic alkenes with in situ generated N-benzyl azomethine ylide.
The method was used to synthesize the central diamine core of the
known antibacterial agents - Sitafloxacin and Olamufloxacin.
In this context, recently our group, and Juhl with coworkers
independently developed rapid two-step approach to
a
spirocyclic pyrrolidines from four-membered aliphatic ketones.10
The key reaction was the [3+2]-cycloaddition of the azomethine
ylide - generated by treatment of azomethine ylide precursor 1
with LiF, - and the corresponding electron-deficient alkenes
(Scheme 1).11-13
Three and six-membered (hetero)aliphatic cyclic alkenes
were also used before, but very rare and not systematically. In
fact, cyclopropyl-containing substrates were mentioned in only
one patent,14 while six-membered (hetero)aliphatic received a bit
In this work therefore, we have
systematically elaborated a practical approach to spirocyclic
pyrrolidines from common 3- to 7-membered alicyclic ketones.
Introduction
Over the past years novel terms such as “Scaffold hopping,”1
“Escape the Flatland”2 and “Conformational restriction”3
appeared and already changed the drug discovery. In fact,
medicinal chemists have been already looking for novel
3D-shaped building blocks with high fraction of Fsp3-hybridized
more attention.10a,15,16
,5
carbons.4
In 2010, spirocyclic compounds were introduced as novel
building blocks for drug discovery.6 Moreover, at the moment,
they have been already playing an important role in medicinal
chemistry. Especially popular are the spirocyclic pyrrolidines
(Figure 1).7-9
Scheme 1. Approaches to spirocyclic pyrrolidines.
Results and Discussion
Reaction scope. Quite recently, we showed that alkene 2
(easily obtained by Horner-Wadsworth-Emmons reaction of
cyclobutanone) smoothly reacted with N-Bn azomethine ylide to
Figure 1. Drugs, bioactive compounds with spirocyclic pyrrolidines.
[]
1) Enamine Ltd., Chervonotkatska 78, Kyiv 02094, Ukraine
Homepage: www.enamine.net
2) Department of Chemical Technology, National technical
university of Ukraine "Igor Sikorsky Kyiv Polytechnic Institute",
Prosp. Peremohy 37, Kyiv 03056, Ukraine
3) Institute of High Technologies, Taras Shevchenko National
University of Kyiv, Volodymyrska 60, Kyiv 01601, Ukraine
4) ChemBioCenter, Taras Shevchenko National University of
Kyiv, Volodymyrska 64, Kyiv 01601, Ukraine
5) Department of Chemistry, Taras Shevchenko National
University of Kyiv, Volodymyrska 64, Kyiv 01601, Ukraine
E-mail: Pavel.Mykhailiuk@gmail.com
Supporting information for this article is given via a link at the
end of the document
Scheme 2. Synthesis of spirocyclic pyrrolidines 2a and 4a.
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give spirocyclic pyrrolidine 2a in 85% yield.10b For the generation
of the azomethine ylide, we treated reagent 1 with cat. LiF in
acetonitrile under heating (Scheme 2).11 Herein, we wanted to
expend this strategy towards other spirocycles. Surprisingly,
however, all attempts to react five-membered alkene 3 failed.
Only starting material was recovered from the reaction mixture.
Six-membered alkene 4, on the contrary, gave the desired
product 4a in 46% yield. These results correlated well with the
known activities of cycloalkanones: the carbonyl group of
cyclopentanone is less active towards nucleophiles than that of
cyclobutanone and cyclohexanone.17
Having a working procedure in hand, we next studied its scope.
(Table 1). In fact, all three- (5,6), four- (2, 7-10), five- (11-13),
six- (4, 14-20), and seven-membered (21) alkenes gave the
desired spirocyclic products in good to excellent yields. The
exception was cyclopentane-containing alkene 3. Interestingly to
note that heteroatoms (N, O, S) within the five-membered ring
activated the C=C double bond by negative inductive effect, and
it was enough to force the reaction to proceed. In fact, in strict
contrast to alkene 3, compounds 11-13 gave the desired
products 11a-13a in 29-53% yield.
3
11
12
13
3a
11a
12a
13a
0%
29%d
53%d
52%d
4
4a
46%
14
14a
31%10a
Table 1. Reaction scope.
15
16
17
18
19
15a
16a
17a
18a
19a
43%d
33%10a
53%
Alkene
Product
Yielda
5b
5a
85%
6b
6a
2a
46%
2
7
85%c
53%d
37%
7a
93%c
8
9
8a
9a
89%c
83%c
20
21
20a
21a
46%
39%d
10
10a
90%c
aReagent 1, LiF, CH3CN, 60 °C; bCyclopropanone ethyl-, TMS-ketale was used for the synthesis of
alkene; cdata were taken from Ref. 10; dmixture of two diastereomers.
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Products 11a-13a, 15a, 18a and 21a were obtained as 1/1
mixture of diastereomers. Among all 3- to 7-membered
substrates, the 4-membered ones were the most reactive. Other
alkenes also reacted but in low yields. All syntheses were
scalable: 20 g of product 4a was obtained in one run.
Synthesis of building blocks. Having developed a powerful
tool towards the spirocyclic structures, we wanted next to
synthesize several appropriately N-protected building blocks
ready for the direct use in drug discovery projects.
In fact, removal of the N-Bn group in pyrrolidine 5a by
hydrogenolysis over Pd/C (22), followed by N-Cbz protection
and subsequent basic hydrolysis of the ester group gave the
N-protected amino acid 23 (Scheme 3). Analogously, amino acid
25 was synthesized from compound 12a via the intermediate
acid 24. Reduction of nitrile 17a with LiAlH4 (26) followed by
N-Boc protection, and N-benzyl hydrogenolysis gave the
N-monoprotected spirocyclic diamine 27.
protection (29) and treatment with morpholinosulfur trifluoride
(morph-DAST) gave pyrrolidine 30. Acidic cleavage of N-Boc
group furnished the fluoromethyl pyrrolidine 31 (Scheme 4).18
Oxidation of alcohol 29 with Py*SO3, followed by treatment of
the intermediate aldehyde with morph-DAST gave compound 32.
Acidic cleavage of N-Boc group finalized the synthesis of
difluoromethylated pyrrolidine 33.
Synthesis of bioactive cores. We additionally developed a
novel synthetic approach to optically pure diamine (S)-35 – the
component of antibacterial drugs Sitafloxacin and Olamufloxacin
(Scheme 5).19 Racemic acid 23 was converted with Evans
oxazolidinone20 into diastereomeric amides 34a (X-Ray)21 and
34b that were separated chromatographically. Cleavage of the
chiral auxiliary in 34a gave acid (S)-23, followed by Curtius
rearrangement provided the aimed diamine (S)-35.
Scheme 3. Synthesis of amino acids 23 and 25, and N-Boc diamine 27.
Scheme 5. Novel synthesis of optically active diamine (S)-35.
Reduction of the ester group in 5a with LiAlH4, followed by
hydrogenolysis over Pd/C gave amino alcohol 28. N-Boc
Conclusions
We have elaborated a two-step approach to novel spirocyclic
pyrrolidines from common three- to seven-membered cyclic
(hetero)aliphatic ketones. The key reaction was
a [3+2]-
cycloaddition between electron-deficient alkenes and an in situ
generated N-benzyl azomethine ylide. The high practical
potential of the elaborated method was demonstrated by the
synthesis of diamine (S)-35: the central core of the known
antibacterial agents - Sitafloxacin and Olamufloxacin. Given the
simplicity and availability of all starting materials, and the rapid
two-step synthesis of the products, we believe that this efficient
method will find practical application very soon in drug discovery
within both academia and industry.
Experimental Section
Measured melting points are uncorrected. Solvents were purified
according to standard procedures. Column chromatography was
Scheme 4. Synthesis of fluorinated pyrrolidines 31 and 33.
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performed using Kieselgel Merck 60 (230-400 mesh) as the stationary
phase. 1H-, 19F-, 13C-NMR spectra were recorded on at 500 or 400 MHz,
376 MHz and 125 or 101 MHz respectively. Chemical shifts are reported
in ppm downfield from TMS (1H, 13C) or CFCl3 (19F) as internal standards.
Mass spectra were recorded on an LC-MS instrument with chemical
ionization (CI) or a GC-MS instrument with electron impact ionization (EI).
LC-MS data were acquired on Agilent 1200 HPLC system equipped with
DAD/ELSD/LCMS-6120 diodematrix and mass-selective detector,
column: Poroshell 120 SBC18, 4.6 mm × 30 mm. Eluent, A, acetonitrile–
water with 0.1% of FA (99: 1); B, water with 0.1% of FA. Optical rotations
were measured on polarimeter in methanol using 1 dm cell; optical
rotation values are given in 10-1 deg cm2 g-1; concentrations (M) are
given in mmol L-1, wavelength 589 nm at 20 ºC. The enantiomeric excess
and retention time (tR) was determined for major signal by HPLCs: Daicel
CHIRALPACK IA, 5 µm, 4.6 × 250 mm, Daicel CHIRALPACK IB, 5 µm,
4.6 × 250 mm, Daicel CHIRALPACK OJ-H, 5 µm, 4.6 × 250mm, Daicel
CHIRALPACK AS-H, 5µm, 4.6 × 250 mm chiral columns, injection
volume 0.1 µL, eluent (hexane: 2-propanol). Solid compounds were
recrystalized from acetonitrile unless other is specified.
Keywords: building blocks • drug discovery • pyrrolidine •
azomethine ylide • spirocycles
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Acknowledgements
Authors are very grateful to Dr. S. Shishkina for X-Ray studies,
to Prof. A. Tolmachev for financial support, and to Mrs I.
Sankova for the help with the preparation of the manuscript. to
Dr. O. Brusylovets, V. Alekseev, V. V. Skyba for purification by
chromatography. Dr. K. Nikitin is acknowledged for providing
acid 25. All chemicals were kindly provided by Enamine Ltd
(www.enamine.net).
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Spirocyclic pyrrolidines
B. A. Chalyk, M. V. Butko, O. O.
Yanshyna, K. S. Gavrilenko, T. V.
Druzhenko, P. K. Mykhailiuk*
Synthesis of spirocyclic pyrrolidines:
advanced building blocks for drug
discovery.
Text for Table of Contents
Novel spirocyclic pyrrolidines were synthesized in two steps from common 3- to 7-membered (hetero)alicyclic ketones. The key
transformation was the reaction between electron-deficient exocyclic alkenes with in situ generated N-benzyl azomethine ylide. The
method was used to synthesize the central diamine core of the known antibacterial agents - Sitafloxacin and Olamufloxacin.
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