Novel azetidinones for carbapenems and fragmentation in the allylamine precursor analogue

Article abstract of DOI:10.1016/j.mencom.2018.03.005

(2R,3R)-N-(3-Methoxy-2,3-dioxopropyl)-N-(4-methoxy-phenyl)-2,3-epoxybutanamide on treatment with strong bases (LDA, LHMDS) gives 3-[(1R)-1-hydroxyethyl]azetidin-2-one derivative, while the N-(3-methoxy-2-methylidene-3-oxo-propyl) analogue undergoes fragme

Full text of DOI:10.1016/j.mencom.2018.03.005

Mendeleev
Communications
Mendeleev Commun., 2018, 28, 131–132
Novel azetidinones for carbapenems and fragmentation
in the allylamine precursor analogue
Natalya K. Selezneva, Zuleykha R. Valiullina, Lidiya S. Khasanova,
Fanuza A. Gimalova, Raisa Z. Biglova and Mansur S. Miftakhov*
Ufa Institute of Chemistry, Russian Academy of Sciences, 450054 Ufa, Russian Federation. E-mail: bioreg@anrb.ru
DOI: 10.1016/j.mencom.2018.03.005
O
(2R,3R)-N-(3-Methoxy-2,3-dioxopropyl)-N-(4-methoxy-
phenyl)-2,3-epoxybutanamide on treatment with strong bases
(LDA, LHMDS) gives 3-[(1R)-1-hydroxyethyl]azetidin-2-one
derivative, while the N-(3-methoxy-2-methylidene-3-oxo-
propyl) analogue undergoes fragmentation.
X
Me
O
Me
O
H
LDA or
LDA or
HO
Me
H
LiHMDS
LiHMDS
H
CO2Me
CO2Me
X = O
X = CH2
C
C
N
N
N
O
O
Ar
Ar
Ar
O
Ar = 4-MeOC6H4
Antibiotics of the carbapenem series (Meropenem, Ertapenem,
Biapenem, Orapenem, Tebipenem, etc.) belong to much-in-demand
antimicrobial agents.1,2 Properly functionalized key azetidinone
blocks, such as compounds 1 and 2, are widely used in the
synthesis of carbapenem antibiotics.3
whose stereochemistry matches that of the side hydroxyethyl
moieties in azetidinones 1 and 2 (cf. ref. 5).
The syntheses of compounds 3–5, we reasoned, can be started
from bromo hydroxy acid 66 (Scheme 1). It was first converted
into amide 7 and then into epoxide 8. Attempts to N-alkylate
epoxy amide 10 with active bromides 97 or 108 were unsuccessful.
At the same time, the reaction of bromo hydroxy amide 7 with
compound 9 smoothly occurred under phase transfer conditions
TBSO
Me
TBSO
Me
Me
HO
O
H
H
H
H
H
H
N
OAc
Me
CO2Me
CO2Me
1
to afford product 11. Its H NMR spectrum contained a double
NH
NH
1:1 set of rotamer signals (cf. ref. 9).
O
O
O
Ar
2
1
At the next stage, a-keto ester 12, a precursor for intra-
molecular cyclization, was obtained by ozonolytic cleavage of the
double bond in compound 11 (Scheme 2). The intramolecular
cyclization of compound 12 was carried out in THF at –30°C by
treatment with 1.5 equiv. LiHMDS to afford azetidinone 3 whose
subsequent Baeyer–Villiger oxidation gave the target derivative 4.
The 1H NMR spectrum of 3 demonstrates characteristic coupling
constants of H(2) and H(3) of the azetidinone ring whose small
values of 2.2 Hz indicate trans-orientation of the substituents.9
3
HO
Me
HO
CH2
O
H
H
H
H
O
Me
CO2Me
CO2Me
N
N
O
Ar
O
Ar
5
4
TBS = ButMe2Si
Ar = 4-MeOC6H4
Within the approaches to carbapenems that we are developing,
we planned to obtain similar new azetidinones 3–5 from l-threonine
using a version of intramolecular ‘epoxide-enolate’ cyclization.4
Threonine contains 3R-chiral center with b-oriented hydroxy group
Me
O
3'
i
ii
2'
3
11
2
CO2Me
HO
60%
72%
O
N
Ar
O
Me
OH
OH
O
12
Br
Br
i
ii
HO
1''
O
O
Me
Me
H
H
H
H
1''
O
iii
CO2H
C(O)NHAr
O
NHAr
2
2
Me
CO2Me
Me
3'
2'
3'
2'
CO2Me
6
7
8
4'
4'
N
N
Me
O
Ar
O
Ar
ii, 9
ii, 9 or 10
O
3
4
Ar = 4-MeOC6H4
N-alkylation
products
CO2Me
CH2
O
N
Scheme 2 Reagents and conditions: i, O3, CH2Cl2, –78°C, then Me2S;
ii, LiHMDS, THF, –40 to –10°C; iii, mCPBA, CH2Cl2.
Ar
11
The approaches to compound 5 included an attempt to generate
a carbaninon from 11 by treatment with bases (LDA, NaHMDS
or LiHMDS). However, in all cases epoxy amide 8 was obtained
as the fragmentation product (Scheme 3) in 49–60% yields. Note
that a similar ‘deallylation’of molecule 11 to give 8 was observed
upon Ru-catalyzed oxidation (RuCl3–K2OsO4–NaIO4).
Ar = 4-MeOC6H4
CH2
O
Br
Br
MeO2C
MeO2C
9
10
Scheme 1 Reagents and conditions: i, 4-MeOC6H4NH2, DMAP, DCC,
CH2Cl2, 0°C; ii, 50% NaOH, Bu4NI (cat.), CH2Cl2, ~20°C.
© 2018 Mendeleev Communications. Published by ELSEVIER B.V.
on behalf of the N. D. Zelinsky Institute of Organic Chemistry of the
Russian Academy of Sciences.
– 131 –

Mendeleev Commun., 2018, 28, 131–132
Me
Online Supplementary Materials
O
Supplementary data associated with this article (synthetic
procedures and characteristics of products) can be found in the
online version at doi: 10.1016/j.mencom.2018.03.005.
N(SiMe3)2
NaHMDS, THF
Na+
11
–40 °C to room
temperature
O
N
Ar
CO2Me
A
References
Me
O
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Scheme 3
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This study was supported by the Russian Science Foundation
(project no. 15-13-00039).
Received: 2nd June 2017; Com. 17/5266
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