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Letter
Ugi Multicomponent Reaction Based Synthesis of Medium-Sized
Rings
Eman M. M. Abdelraheem,† Rudrakshula Madhavachary, Arianna Rossetti, Katarzyna Kurpiewska,
,‡,∥
†,∥
†
§
§
†
,†
Justyna Kalinowska-Tłusc
́
̈
ik, Shabnam Shaabani, and Alexander Domling*
†
‡
§
Department of Drug Design, University of Groningen, A. Deusinglaan 1, 9713 AV Groningen, The Netherlands
Chemistry Department, Faculty of Science, Sohag University, Sohag 82524, Egypt
Jagiellonian University, Faculty of Chemistry, Gronostajowa 2, 30-387 Krakow, Poland
*
S Supporting Information
ABSTRACT: An Ugi multicomponent reaction based two-
step strategy was applied to generate medium-sized rings. In
the first linear expansion phase, a series of diamines reacted
with cyclic anhydrides to produce different lengths of terminal
synthetic amino acids as the starting material for the second
phase. The Ugi-4-center 3-component reaction was utilized to
construct complex medium-sized rings (8−11) by the addition
of isocyanides and oxo components. This method features
mild conditions and a broad substrate scope.
edium-sized rings are molecules which contain between
8 and 11 ring atoms. Surprisingly, they are highly
1
,2
M
underrepresented in screening libraries and in general in the
synthetic organic chemistry world. Examples of bioactive
medium-sized cycles, however, exist and include taxol (8-
3
membered), griseoviridin (9-membered), crotalanian alkaloids
(
10-membered), and diplodialide natural products (11-
4
membered). As opposed to small rings or macrocycles5,
medium-sized rings are a challenging class of synthetic targets.
While small rings can often be closed based on favorable
enthalpy, macrocyclic ring closure needs a favorable entropic
component. Medium cycles, however, often show an
unfavorable entropy and enthalpy component, including Pitzer
ring strains and transannular interactions, for their ring closure
and thus are highly demanding synthetic targets. Different
synthetic methodologies have been applied for the ring closure
of medium-sized cycles, including ring-closing metathesis
Figure 1. Described macrocyclization strategy.
manifold of artificial macrocycles by a short sequence involving
an initial linear diversification, followed by an exponential
diversification step of macrocyclization using an Ugi and
8
,9
Passerini multicomponent reaction (MCR) .
6
We initially started our study by the synthesis of α-amino ω-
carboxylic acid by reacting symmetrical and unsymmetrical
cyclic anhydride with diamines followed by an Ugi reaction. We
reacted a total of nine cyclic anhydrides with five diamines
providing 11 amino acids of different linker length (Scheme 1).
For the synthesis of medium-sized ring compounds, we
focused on the small diamines, such as ethylene diamine,
propane diamine, butane diamine, and pentane diamine
derivatives (Scheme 1). The ring opening reaction of cyclic
anhydrides was carried out by slowly dropping anhydride to the
unprotected alkyl diamine solution in THF as an aprotic polar
solvent. This reaction proceeded under diluted conditions (0.1
M), on a 10 mmol scale, at room temperature, and the product
α-amino ω-carboxylic acid was isolated in good yields (59−
(
RCM), macro-lactonization, metal mediated C−C coupling
7
reactions, and ring expansion. However, these methods mostly
suffer from low yields and limited substrate scope. Therefore,
the discovery of general methodologies for the fast and efficient
construction of various medium rings in good yields and with
useful levels of diversity is of considerable importance. Our
design toward the synthesis of complex medium ring structures
is based on two simple but diverse reactions steps. Moreover, it
is based on commercially available starting materials. The first
step involves a ring opening reaction of cyclic carboxylic acid
anhydrides with unprotected diamines to afford α,ω-amino
acids. In the next step, α,ω-amino acids are used in an Ugi
reaction with oxo components and isocyanides to close
medium rings of 8−11 membered size (Figure 1). This method
closely follows our recently described strategy to create a
8
0%). Next, the macrocyclic ring closure was performed by Ugi
Received: October 3, 2017
©
XXXX American Chemical Society
A
Org. Lett. XXXX, XXX, XXX−XXX