Stereo- and regiocontrolled synthesis of highly functionalized cyclopentanes with multiple chiral centers

Article abstract of DOI:10.1080/00397911.2020.1733612

The synthesis of some highly substituted three-dimensional cyclopentanes with multiple chiral centers and with high regiochemical and stereochemical diversity has been accomplished starting from cyclopentadiene-derived aminocyclopentenecarboxylic acids. The small-molecular design consisted of stereo- and regiocontrolled functionalization of the starting cyclopentene β- and γ-amino acids through oxirane formation/oxirane opening and afforded regio- and diastereoisomers of orthogonally protected aminocyclopentanecarboxylates.

Full text of DOI:10.1080/00397911.2020.1733612

Synthetic Communications
An International Journal for Rapid Communication of Synthetic Organic
Chemistry
ISSN: 0039-7911 (Print) 1532-2432 (Online) Journal homepage: https://www.tandfonline.com/loi/lsyc20
Stereo- and regiocontrolled synthesis of highly
functionalized cyclopentanes with multiple chiral
centers
Melinda Nonn, Adrienn Binder, Balázs Volk & Loránd Kiss
To cite this article: Melinda Nonn, Adrienn Binder, Balázs Volk & Loránd Kiss (2020): Stereo-
and regiocontrolled synthesis of highly functionalized cyclopentanes with multiple chiral centers,
Synthetic Communications, DOI: 10.1080/00397911.2020.1733612
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https://doi.org/10.1080/00397911.2020.1733612
Stereo- and regiocontrolled synthesis of highly
functionalized cyclopentanes with multiple chiral centers
a
d
a,b
Melinda Nonna,b,c, Adrienn Binder , Balazs Volk , and Lorand Kiss
ꢀ
ꢀ
aInstitute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary; Interdisciplinary
b
c
Excellence Centre, Institute of Pharmaceutical Chemistry, University of Szeged, Szeged, Hungary; MTA-
d
SZTE Stereochemistry Research Group, Hungarian Academy of Sciences, Szeged, Hungary; Directorate
of Drug Substance Development, Egis Pharmaceuticals Plc., Budapest, Hungary
ABSTRACT
ARTICLE HISTORY
Received 15 January 2020
The synthesis of some highly substituted three-dimensional cyclo-
pentanes with multiple chiral centers and with high regiochemical
and stereochemical diversity has been accomplished starting from
cyclopentadiene-derived aminocyclopentenecarboxylic acids. The
small-molecular design consisted of stereo- and regiocontrolled func-
tionalization of the starting cyclopentene b- and c-amino acids
through oxirane formation/oxirane opening and afforded regio- and
diastereoisomers of orthogonally protected aminocyclopentanecar-
boxylates.
KEYWORDS
Amino acids;
functionalization; selectivity;
stereocontrol; three-
dimensional molecules
GRAPHICAL ABSTRACT
Introduction
Trends in modern drug design and the concepts in drug development are changing in a
rapid manner. Highly functionalized elements and small-molecular entities are currently
regarded as promising scaffolds in medicinal research. Novel terms such as
“conformational restriction,”[1] “escape from flatland,”[2] or “scaffold hopping”[3] have
gained high relevance and application over the period of the last decade.
As a result of their special stereochemical arrangement, highly-functionalized three-
dimensional small molecules with multiple chiral centers and complex chemical diver-
sity are regarded as interesting elements in drug research. Pharmaceutical properties of
ꢀ
CONTACT Lorand Kiss
kiss.lorand@pharm.u-szeged.hu
Institute of Pharmaceutical Chemistry, University of
Szeged, Szeged, Hungary.
Supplemental data for this article can be accessed on the publisher’s website.
ß 2020 Taylor & Francis Group, LLC

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M. NONN ET AL.
Figure 1. Some representative drugs with highly functionalized amino acid structures.
a certain molecule are in strong relationship with its three-dimensional shape. The
introduction of a three-dimensional character into a compound library provides struc-
tural complexity and increased possibility for diversity. Consequently, selective synthetic
methodologies with regard to the cost, applicability, scalability or generalization toward
such elements containing sp3 hybridized carbon atoms are of interest in synthetic
organic and pharmaceutical chemistry.[4]
Diversity-oriented synthesis (DOS) with the scope of the synthesis of structurally
diverse, three-dimensional small-molecular entities has been applied as a common
approach to create molecular libraries. A number of strategies utilized in DOS with a
focus on selectivity and stereocontrol of various methods are known in the literature.
The main characteristics of these approaches are the use of readily available and easily
accessible cheap starting materials toward the formation of complex scaffolds with high
chemical and stereostructural diversity.[5]
Because the ring olefin bond provides a large number of possible chemical transfor-
mations, cyclic dienes of nearly planar structure with different ring sizes are considered,
readily available starting materials to the access of structurally diverse molecular entities.
Among many possible transformations, the ring olefin bond of cyclic dienes may fur-
nish valuable b-lactams[1a,b,6,7] or (1a,b) c-lactams,[8] which are known to be useful pre-
cursors for the synthesis of varied compounds such as amino acids, amino alcohols,
amino ketones, azido esters, hydroxylated amino esters, and fluorinated amino esters, all
possessing various functional moieties as well as stereochemical and structural diversity.
[1a,b,6]
Moreover, cyclic amino acids, as conformationally rigid molecules, are interesting
monomers as building blocks in the synthesis of various types of oligopeptides[1,9] and
cyclic amino acid structures (Figure 1 contains the structure of some representative
drugs with a cyclic amino acid core).[1a,b,10]
Results and discussion
The aim of the current work was to give an insight into the controlled synthesis of a
series of highly functionalized cyclopentane derivatives, possessing architectural com-
plexity with high regiochemical and stereochemical diversity starting from cyclopenta-
diene (Scheme 1).
Taking into consideration the high biological potential of the alicyclic b-[1,11] and
c-amino acid derivatives,[12] cyclopentadiene-derived bicyclic lactam derivatives ( )26
and ( )230 were selected as starting model compounds for this purpose.

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Scheme 1. Schematic designation of the current work for stereo- and regioselective functionalization
of the ring olefin bonds of cyclopentadiene to generate highly functionalized cyclopentane libraries.
The diversity-oriented synthetic concept was based on the consecutive functionalization
of the ring olefin bonds of cyclopentadiene. First, the synthesis of unsaturated bicyclic
b-lactam ( )26,[7] and c-lactam ( )230[8b] was carried out followed by selective
functionalization of their ring C–C double bond through epoxidation and oxirane
opening protocols.
Racemic unsaturated bicyclic b-lactam ( )26, derived by the addition of chlorosul-
fonyl isocyanate (CSI) to cyclopentadiene, was converted according to known meth-
ods.[7] The procedure included lactam ring-opening, esterification, N-Boc protection,
isomerization and diastereoselective epoxidation with m-chloroperbenzoic acid
(MCPBA) into bicyclic oxirane stereoisomers ( )210[13] and ( )213 involving NHBoc
hydrogen-bonding directing effect.[7] Next, both epoxide-fused N-Boc amino esters were
subject to oxirane opening with NaN3. As a result of electronic factors, azidolysis of
( )213 proceeded with full regioselectivity with the azide attack at C-4 position. In the
case of ( )210, in contrast, due to stereochemical reasons, a mixture of azido esters
( )211 and ( )212 was formed in 6:1 ratio.[13] Next, these N-Boc-protected azido
esters were subjected to catalytic reduction/N-Fmoc protection in one pot according to
a modified experimental protocol (see reference [7]). Namely, the N-Boc-protected azido
ester regio- and stereoisomers were transformed into the corresponding orthogonally
protected diamino ester derivatives with the NHBoc moieties in position C-2 and the
NHFmoc group introduced at C-4 (see products ( )214 and ( )216) and at C-3 (see
product ( )215) (Scheme 2). Utilizing Pd/C under H2 atmosphere and FmocOSu/
EtOAc at room temperature in the azide group reduction/amino protection step, instead
of using PhP3/THF/H2O and Et3N/FmocOSu, the formation of a complex reaction mix-
ture could be avoided.
The protocol of the incorporation of the N-protected amino groups onto the cyclo-
pentane skeleton was continued by changing the order of amino group protection
protocol. Thus, instead of a Boc-protection, cyclopentene amino acid ( )27 underwent
esterification and then subjected to N-Fmoc protection. Upon treatment with MCPBA,
Fmoc-protected amino ester ( )217 yielded oxirane derivative ( )218 possessing the

4
M. NONN ET AL.
Scheme 2. Earlier work and its further extension. Synthesis of highly functionalized cyclopentanes
( )214,[7] ( )215,[7] and ( )216.
three-membered ring with the carbamate and ester groups in a cis relative arrangement,
because of the hydrogen-bonding directing effect of the NHFmoc moiety. Analogously
to all-cis N-Boc-protected derivative ( )213, the azidolysis of Fmoc-protected derivative
( )218 took place regioselectively giving azido ester ( )219[7] with the azide moiety in
position 4. Next, compound ( )219 was subjected to one-pot azide reduction and N-
Boc protection in the presence of H2/Pd/C and Boc2O in EtOAc at room temperature
in 12 h. The process afforded orthogonally protected diamino ethyl cyclopentanecarbox-
ylate ( )220 in which the NHBoc group is connected to C-4, while the NHFmoc group
is in position 2 of the cyclopentane ring (Scheme 3). Interestingly, N-Fmoc deprotection
and double N-Boc protection also occurred in a prolonged reaction in 24 h providing
amino ester ( )221 (Scheme 3).
In continuation, the synthetic protocol to access novel highly functionalized
cyclopentane derivatives was investigated with trans counterpart ( )224 of the cis N-
Fmoc-protected cyclopentene amino ester ( )217. Compound ( )224 was synthesized
starting from N-Boc-protected trans-ethyl-2-aminocyclopentenecarboxylate ( )222 by

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Scheme 3. Synthesis of orthogonally protected amino acid derivatives ( )220 and ( )221.
Scheme 4. Synthesis of highly functionalized cyclopentanes ( )226, ( )227, ( )228, and ( )229.
N-Boc deprotection followed by N-Fmoc protection. Oxidation with MCPBA proceeded
with cis diastereoselectivity relative to the carbamate group, providing oxirane derivative
( )225. Similar to its N-Boc-protected counterpart ( )210, oxirane ring opening by
nucleophilic azide attack on ( )225 afforded two azido amino ester regioisomers
( )226 and ( )227 in a nearly 1:1 ratio (Scheme 4). These two azido amino esters,
which can also be regarded as orthogonally protected (N-Fmoc/N3) diamino carboxy-
lates, could be separated and isolated in moderate yields. Both azido esters (( )226 and
( )227) were readily converted in a one-pot catalytic hydrogenation/Boc-protection to
the corresponding NBoc/NFmoc-protected diamino esters ( )228 and ( )229 in good
yields (Scheme 4).
The investigation in view of increasing the number of stereo- and regioisomers of
orthogonally protected diamino carboxylic acid derivatives was continued with the
transformation of cyclopentene c-amino acid ( )231 derived from Vince-lactam

6
M. NONN ET AL.
Scheme 5. Synthesis of orthogonally protected amino acid derivatives ( )234 and ( )235.
( )230.[8] Esterification of ( )231,[14] N-Boc protection, epoxidation, and subsequent
oxirane opening led diastereoselectively and regioselectively across ( )233 to azido
amino esters ( )234 and ( )235 (2:1 ratio).[14a] After separation by column chroma-
tography, both azido esters were subjected to reduction and Fmoc protection according
to a modified version of the procedure described earlier (Scheme 2, H2/Pd/C,
FmocOSu, EtOAc). The protocol yielded the corresponding orthogonally protected (N-
Boc/N-Fmoc) diamino carboxylic acid esters ( )236 and ( )237 with a cyclopentane
skeleton (Scheme 5).
Next, we continued the synthetic venture for the preparation of novel orthogonally
protected amino ester isomers with a reverse protocol. Namely, first amino acid ( )231
underwent esterification and then the product was converted to N-Fmoc-protected
derivative ( )238. It was then subjected to epoxidation furnishing compound ( )239
in a stereoselective manner because of the H-bonding directing effect. Azidolysis of
( )239 proceeded smoothly, giving azido ester regioisomers ( )240 and ( )241
regarded as orthogonally protected (N-Fmoc/N3) diamino carboxylates. The products
formed approximately in a 1:1 ratio were then separated and isolated (Scheme 6).
It should be noted that the above-described azido esters (Schemes 2–5) could easily
be accessed in gram scale by applying the presented synthetic procedure.
Obviously, all orthogonally protected diaminocarboxylates with various amino-group
protecting systems (N3/NHBoc/NHFmoc) are precursors for access the azido amino
acids or azido amino esters. An illustrative synthetic description toward such derivatives
are presented on Scheme 7, when azido ester diastereoisomers ( )242 and ( )211 as
model starting compounds were subjected to deprotection procedures. Both azido esters

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7
Scheme 6. Synthesis of highly functionalized cyclopentanes ( )240 and ( )241.
Scheme 7. Synthesis of diamino-cyclopentanecarboxylic ethyl esters and acids ( )243 and ( )245
as well as ( )244 and ( )246.
were first subjected to acid-catalyzed hydrolysis in MeCN at 20 ꢀC giving the corre-
sponding amino esters ( )243 and ( )245. When azido esters ( )242 and ( )211
underwent hydrolysis under similar conditions but at reflux temperature, amino acid
stereoisomers ( )244 and ( )246 were formed in good yields (Scheme 7).
Conclusions and outlook
The synthesis of some highly functionalized, three-dimensional cyclopentanes with
multiple stereogenic centers has been achieved through regiochemical and stereo-
chemical diversity-oriented synthesis by starting from nearly planar cyclopentadiene.
The synthesis protocols involved the transformation of cyclopentadiene-derived
unsaturated bicyclic b- and c-lactams across their ring olefin bond with diastereose-
lective epoxidation followed by regioselective oxirane ring opening leading to various
orthogonally protected diamino carboxylic acid derivatives. Although the present
work is intended to afford an insight into the functionalization protocol in view of
the creation of multifunctionalized cyclopentanes, further extensions of this type of
functionalization approach toward various other systems and the synthesis of enan-
tiopure substances are currently being studied in our laboratory. Furthermore, add-
itional experiments are also investigated on related transformations to generate other

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M. NONN ET AL.
highly functionalized cycloalkane derivatives in order to enlarge the three-
dimensional, conformationally restricted, orthogonally protected cyclic amino acid
library. The synthesized polyfunctionalized alicyclic molecular entities rich in sp3 car-
bon atoms, as orthogonal diaminocarboxylates, might be interesting building blocks
in drug design projects.
Experimental part
General procedure for the epoxidation of cyclopentene amino esters
To a solution of amino ester (6 mmol) in CH2Cl2 (50 mL), MCPBA (1.5 equiv.) was
added in portions at 0 ꢀC.[13–14a] The mixture, after stirring at this temperature for 1 h
and further 5 h at room temperature, was diluted with CH2Cl2 (80 mL). The organic
layer was washed with a saturated aqueous solution of NaHCO3 (3 Â 35 mL). The com-
bined organic layers were next dried (Na2SO4) and concentrated under reduced pres-
sure. The crude product was purified by means of column chromatography on silica gel
(n-hexane/EtOAc).
General procedure for oxirane opening reaction with sodium azide
To a solution of epoxy amino ester (5 mmol) in EtOH (25 mL), NaN3 (1.5 equiv.), H2O
(1.5 mL), and NH4Cl (80 mg) were added and the mixture was stirred at reflux tempera-
[13–14a]
ture for 6 h.
The solvent was then evaporated under reduced pressure. The crude
mixture was taken up in EtOAc (25 mL) and washed with H2O (2 Â 15 mL). The com-
bined organic layers were dried (Na2SO4) and concentrated under reduced pressure.
The crude material was purified by column chromatography on silica gel (n-hex-
ane/EtOAc).
General procedure for N-Fmoc protection of amino esters
To a solution of azido ester (1 mmol) in EtOAc (20 mL), Pd/C (70 mg) and FmocOSu
(1.1 equiv.) were added and the mixture was stirred under H2 atmosphere at room tem-
perature for 12 h. Then the solids were filtered off through celite, the filtrate was con-
centrated and the crude product was purified by column chromatography on silica gel
(n-hexane/EtOAc).
General procedure for N-Boc protection of amino esters
To a solution of azido ester (1 mmol) in EtOAc (20 mL), Pd/C (70 mg) and Boc2O (1.1
equiv.) were added and the mixture was stirred under H2 atmosphere at room
temperature for 12 h. Then the solids were filtered off through celite, the filtrate was
concentrated and the crude product was purified by column chromatography on silica
gel (n-hexane/EtOAc).

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9
General procedure for the deprotection of amino esters
Method A: To a solution of amino ester (0.7 mmol) in MeCN (10 mL), 1 drop of 18%
aqueous HCl solution was added and the mixture was kept at reflux temperature for
8 h. Then it was concentrated and purified by trituration with MeOH/Et2O mixture.
Method B: To a solution of an amino ester (0.7 mmol) in MeCN (10 mL), 1 drop of
18% aqueous HCl solution was added and the mixture was stirred at room temperature
for 26 h. Then the reaction mixture was concentrated and purified by trituration with
MeOH/Et2O mixture.
Characterization and NMR data of the new compounds are found in Supporting
Information.
Funding
We are grateful to the Hungarian Research Foundation (NKFIH No K 119282) for financial sup-
port. The financial support of the GINOP-2.3.2-15-2016-00014 project is also acknowledged. This
research was supported by the EU-funded Hungarian [grant EFOP-3.6.1-16-2016-00008].
Ministry of Human Capacities, Hungary [grant 20391-3/2018/FEKUSTRAT] is also
acknowledged.
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