New Azetidinone Building Block for Carbapenems

Article abstract of DOI:10.1134/S1070428019030187

A new versatile building block for the synthesis of carbapenems, (3S,4R)-3-{(R)-1-[tert-butyl-(dimethyl)silyloxy]ethyl}-4-[(2RS)-5-(4-methoxybenzyloxy)pent-3-yn-2-yl]azetidin-2-one, has been obtained by zinc-promoted alkylation of (3R,4R)-(+)-3-{(R)-1-[te

Full text of DOI:10.1134/S1070428019030187

ISSN 1070-4280, Russian Journal of Organic Chemistry, 2019, Vol. 55, No. 3, pp. 377–380. © Pleiades Publishing, Ltd., 2019.
Russian Text © The Author(s), 2019, published in Zhurnal Organicheskoi Khimii, 2019, Vol. 55, No. 3, pp. 438–441.
SHORT
COMMUNICATIONS
New Azetidinone Building Block for Carbapenems
L. S. Khasanovaa, Z. R. Valiullinaa, A. M. Galeevaa, V. A. Egorova, and F. A. Gimalovaa*
a Ufa Institute of Chemistry, Ufa Federal Research Center, Russian Academy of Sciences,
pr. Oktyabrya 71, Ufa, 450054 Bashkortostan, Russia
*e-mail: fangim@anrb.ru
Received May 23, 2018; revised June 6, 2018; accepted November 27, 2018
Abstract—A new versatile building block for the synthesis of carbapenems, (3S,4R)-3-{(R)-1-[tert-butyl-
(dimethyl)silyloxy]ethyl}-4-[(2RS)-5-(4-methoxybenzyloxy)pent-3-yn-2-yl]azetidin-2-one, has been obtained
by zinc-promoted alkylation of (3R,4R)-(+)-3-{(R)-1-[tert-butyl(dimethyl)silyloxy]ethyl}-2-oxoazetidin-4-yl
acetate with 1-[(4-bromopent-2-yn-1-yloxy)methyl]-4-methoxybenzene.
Keywords: carbapenems, β-lactams, azetidinone, propargyl alcohol, acetaldehyde, building block.
DOI: 10.1134/S1070428019030187
Carbapenems remain among the best β-lactam anti-
biotics used in the treatment of infectious diseases
[1, 2]. The basic bicyclic core of carbapenems 1 is
shown in Scheme 1; a number of synthetic approaches
to particular carbapenems have been proposed [3–7],
including those implemented on an industrial scale
[7–10].
Herein we describe the synthesis of azetidine build-
ing block 2 for the development of a new approach to
carbapenems 1 via intramolecular N,C-cyclization to
precursors like 3, followed by appending a required
side chain. It is seen that structure 2 contains all
functionalities necessary for intramolecular N,C-cy-
clization and “workpieces” for building up side-chain
substituents.
replaced by bromine, and bromide 6 reacted with
azetidinone 7 [11, 12] in the presence of zinc. We thus
isolated 56% of azetidinone 2 as a 3:2 mixture of dia-
1
stereoisomers at the 4-CH chiral center. The H NMR
spectrum of 2 showed signals of the 4-H proton as
doublets of doublets at δ 3.62 and 3.71 ppm with
a coupling constant J4,3 of 1.9 Hz, which indicated
trans arrangement of 4-H and 3-H [13].
Building block 2 was used to test versions of
intramolecular N,C-cyclization in order to obtain bi-
cyclic carbapenem precursors like 3. For this purpose,
azetidinone 2 was converted into N-bromo derivative 8
by treatment with N-bromosuccinimide. However,
attempts to effect 5-endo-dig radical cyclization of 8
by the action of tributyltin hydride were unsuccessful.
Studies of other ways to accomplish intramolecular
cyclization of 2 are now in progress in our laboratory.
Scheme 2 outlines the synthesis of 2. The starting
material was propargyl alcohol whose hydroxy group
was protected by etherification with 4-methoxybenzyl
alcohol. Ether 4 was converted to lithium derivative
which was brought into condensation with acetalde-
hyde to obtain alcohol 5. The hydroxy group in 5 was
Thus, we have demonstrated the possibility of
substitution of the acetoxy group in azetidinone 7 by
secondary propargyl bromide 6 despite its tendency to
isomerize into allene structure.
Scheme 1.
Me
NH
Me
Me
HO
Me
TBSO
Me
TBSO
Me
H
N
1
H
N
3
H
H
H
SR
OPMB
O
O
O
COOH
CH2OPMB
2
TBS = t-BuMe2Si; PMB = 4-MeOC6H4CH2.
377

KHASANOVA et al.
378
Scheme 2.
4-MeOC6H4CH2OH
CH2Cl2, Amberlyst
(1) BuLi, THF, –78°C
(2) MeCHO, –78°C
OPMB
HO
OH
OPMB
HC
HC
Me
4
5
OPMB
CBr4, PPh3, MeCN room temp.
Br
Me
6
Me
H
TBSO
Me
TBSO
Me
H
H
OAc
6, Zn, THF, reflux
NH
NH
OPMB
O
O
7
2
Me
H
TBSO
(n-Bu)3SnH
AIBN, PhH, ∆
H
4''
1''
NBS, CH2Cl2
1'
3
3
2
4
Me
N
OPMB
O
Br
8
PMB = 4-MeOC6H4CH2.
1-[(4-Bromopent-2-yn-1-yloxy)methyl]-
4-methoxybenzene (6). Carbon tetrabromide, 0.62 g
(1.90 mmol), was added in portions to a solution of
0.38 g (1.70 mmol) of compound 5 and 0.50 g
(1.90 mmol) of triphenylphosphine in 10 mL of anhy-
drous acetonitrile under stirring at room temperature.
The mixture was stirred for 12 h at room temperature,
the solvent was evaporated, and the product was
isolated from the residue by column chromatography
on silica gel (ethyl acetate–petroleum ether, 1:4). Yield
0.31 g (61%), oily material, Rf 0.43 (petroleum ether–
5-(4-Methoxybenzyloxy)pent-3-yn-2-ol (5). A so-
lution of 0.5 g (2.8 mmol) of compound 4 in 10 mL
of anhydrous THF was cooled to –78°C, 3.2 mL
(3.4 mmol) of a 1.1 M solution of butyllithium in
hexane was added with stirring, and the mixture was
stirred for 35–40 min at that temperature. A solution of
0.19 mL (3.4 mmol) of acetaldehyde in 5 mL of THF
was then added dropwise, and the mixture was stirred
for 1 h at –78°C and quenched by adding 3–4 mL of
a saturated aqueous solution of ammonium chloride.
Tetrahydrofuran was distilled off, the residue was
extracted with methylene chloride (3 ×10 mL), the
combined extracts were dried over MgSO4 and
evaporated, and the residue was purified by column
chromatography on silica gel. Yield 0.30 g (40%),
colorless oil, Rf 0.59 (petroleum ether–ethyl acetate,
1
ethyl acetate, 4:1). H NMR spectrum (500 MHz,
CDCl3), δ, ppm: 1.93 d (3H, CH3, J = 6.9 Hz), 3.81 s
(3H, OCH3), 4.19 d (2H, OCH2, J = 1.7 Hz), 4.56 s
(2H, OCH2), 4.68 m (1H, CHBr), 6.89 d (2H, Harom
,
J = 8.6 Hz), 7.29 d (2H, Harom, J = 8.5 Hz). 13C NMR
spectrum (125 MHz, CDCl3), δC, ppm: 27.30 (CH3),
30.89 (CHBr), 55.26 (OCH3), 56.90 (OCH2), 71.27
(OCH2), 82.25 and 86.41 (C2′, C3′), 113.83 (Carom),
129.24 (Carom), 129.64 (Carom), 159.40 (Carom). Found,
%: C 55.53; H 5.12; Br 28.48. C13H15BrO2. Calculated,
%: C 55.14; H 5.34; Br 28.22.
1
2:1). H NMR spectrum (CDCl3, 500 MHz), δ, ppm:
1.47 d (3H, CH3, J = 6.6 Hz), 2.04 br.s (1H, OH),
3.80 s (3H, OCH3), 4.16 d (2H, OCH2, J = 1.2 Hz),
4.52 s (2H, OCH2), 4.59 m (1H, OCH), 6.89 d (2H,
Harom, J = 8.6 Hz), 7.28 d (2H, Harom, J = 8.6 Hz).
13C NMR spectrum (CDCl3, 125 MHz), δC, ppm: 24.34
(CH3), 55.26 (OCH3), 56.96 (OCH2), 58.29 (C2), 71.26
(OCH2), 79.91 and 88.39 (C3, C4), 118.80 (Carom),
129.33 (Carom), 129.75 (Carom), 159.34 (Carom). Mass
spectrum, m/z (Irel, %): 238 [M + H2O]+ (33), 121
[CH2C6H4OCH3]+ (100).
(3S,4R)-3-{(R)-1-[tert-Butyl(dimethyl)silyloxy]-
ethyl}-4-[5-(4-methoxybenzyloxy)pent-3-yn-2-yl]-
azetidin-2-one (2). A mixture of 0.12 g (0.42 mmol) of
azetidinone 7, 0.35 g (1.20 mmol) of bromide 6, and
0.19 g (2.9 mmol) of zinc in 10 mL of anhydrous THF
RUSSIAN JOURNAL OF ORGANIC CHEMISTRY Vol. 55 No. 3 2019

NEW AZETIDINONE BUILDING BLOCK FOR CARBAPENEMS
379
was refluxed for 30 min (until compound 6 disap-
peared according to the TLC data). The mixture was
filtered, the filtrate was evaporated, and the residue
was purified by column chromatography on silica gel
(petroleum ether–ethyl acetate, 4:1). Yield 0.11 g
(56%), colorless oil, Rf 0.54 (petroleum ether–ethyl
acetate, 4:1), diastereoisomer mixture at a ratio of 3:2
(according to the 1H NMR data). IR spectrum, ν, cm–1:
3244, 2955, 2931, 2856, 1734, 1613, 1514, 1444,
1374, 1360, 1303, 1249, 1174, 1143, 1095, 1078,
(6H, SiCH3), 0.88 s (9H, t-Bu), 1.22 d (3H, J = 6.2 Hz,
CH3), 1.27 d (3H, CH3, J = 7.4 Hz), 2.83 m (1H,
1″-H), 3.28 m (1H, 3-H), 3.96 m (1H, 4-H), 3.79 s
(3H, OCH3), 4.11 s (2H, OCH2), 4.19 m (1H, 1′-H),
4.49 s (2H, OCH2), 6.86 d (2H, Harom, J = 7.8 Hz),
7.26 d (2H, Harom, J = 8.0 Hz).
The IR spectra were recorded from thin films on
1
a Shimadzu IR Prestige-21 spectrometer. The H and
13C NMR spectra were measured on Bruker AM-300
(300.13 and 75.47 MHz, respectively) and Bruker
Avance-500 spectrometers (500.13 and 125.77 MHz)
using tetramethylsilane as internal standard. The mass
spectra were obtained on a Shimadzu LCMS-2010EV
instrument (syringe injection of a solution in chloro-
form–acetonitrile; eluent acetonitrile–water, 95:5, flow
rate 0.1 mL/min; positive ion detection; needle voltage
4.5 kV; interface capillary voltage 5 V, temperature
250°C). The elemental compositions were determined
with a Euro EA-2000 CHNS analyzer. The progress of
reactions was monitored by TLC on Sorbfil plates
(Russia); spots were visualized by treatment with a so-
lution of 4-methoxybenzaldehyde in ethanol acidified
with sulfuric acid, followed by heating at 120–150°C.
The products were isolated by column chromatography
on silica gel using 30–60 g of the sorbent per gram of
substrate.
1
1036, 1011, 988, 959, 834, 812, 777, 726. H NMR
spectrum (500 MHz, CDCl3), δ, ppm: major isomer:
0.12 s (6H, SiCH3), 0.94 s (9H, t-Bu), 1.29 d (3H, CH3,
J = 7.4 Hz), 1.30 d (3H, CH3, J = 6.1 Hz), 2.69 q (1H,
1″-H, J = 7.1 Hz), 2.89 d.d (1H, 3-H, J = 3.5, 1.4 Hz),
3.62 d.d (1H, 4-H, J = 7.5, 1.9 Hz), 3.85 s (3H, OCH3),
4.18 d (2H, OCH2, J = 1.8 Hz), 4.23 q (1H, 1′-H, J =
5.5 Hz), 4.56 s (2H, OCH2), 6.20 s (1H, NH), 6.94 d
(2H, Harom, J = 8.7 Hz), 7.33 d (2H, Harom, J = 8.5 Hz);
minor isomer: 0.13 s (6H, SiCH3), 0.94 s (9H, t-Bu),
1.28 d (3H, CH3, J = 7.4 Hz), 1.30 d (3H, CH3, J =
6.1 Hz), 2.81 q (1H, 1″-H, J = 6.7 Hz), 3.04 m (1H,
3-H), 3.71 d.d (1H, 4-H, J = 6.3, 1.9 Hz), 3.85 s (3H,
OCH3), 4.16 d (2H, OCH2, J = 1.8 Hz), 4.28 d.d (1H,
1′-H, J = 3.9, 6.3 Hz), 4.55 s (2H, OCH2), 6.19 s (1H,
NH), 6.93 d (2H, Harom, J = 8.9 Hz), 7.33 d (2H, Harom
,
J = 8.5 Hz). 13C NMR spectrum (500 MHz, CDCl3),
δC, ppm: major isomer: –4.35 (SiCH3), 17.79 (CH3),
17.90 (Me3CSi), 22.81 (CH3), 25.73 [C(CH3)3], 31.21
(C1″), 54.59 (C3), 55.22 (OCH3), 57.08 (OCH2), 62.12
(C4), 65.32 (C1′), 71.20 (OCH2), 78.44 and 86.79 (C2″,
C3″), 113.77 (Co), 129.44 (Ci), 129.68 (Cm), 159.30
(Cp), 168.11 (C=O); minor isomer: –4.99 (SiCH3),
17.73 (CH3), 17.90 (Me3CSi), 22.88 (CH3), 25.73
[C(CH3)3], 30.43 (C1″), 55.22 (OCH3), 53.61 (C3),
57.08 (OCH2), 62.92 (C4), 64.73 (C1′), 71.13 (OCH2),
78.62 and 86.59 (C2″, C3″), 113.80 (Co), 129.38 (Ci),
129.70 (Cm), 159.30 (Cp), 168.72 (C=O). Mass
spectrum, m/z (Irel, %): 432 (100) [M + H]+, 312 (21)
[M + H – CHC6H4OCH3]+, 241 (29), 121 (71)
[CH2C6H4OCH3]+.
ACKNOWLEDGMENTS
The spectral and analytical data were obtained
using the equipment of the Chemistry Joint Center
(Ufa Institute of Chemistry, Russian Academy of
Sciences).
FUNDING
This study was performed under financial support
by the Russian Science Foundation (project no. 15-13-
00039-P).
CONFLICT OF INTERESTS
The authors declare the absence of conflict of
interests.
(3S,4R)-1-Bromo-3-{(R)-1-[tert-butyl(dimethyl)-
silyloxy]ethyl}-4-[5-(4-methoxybenzyloxy)pent-3-
yn-2-yl]azetidin-2-one (8). N-Bromosuccinimide,
32 mg (0.18 mmol), was added to a solution of 50 mg
(0.12 mmol) of compound 2 in 10 mL of anhydrous
methylene chloride, and the mixture was stirred until
the initial compound disappeared (TLC). The solvent
was evaporated, and the residue was purified by flash
chromatography on silica gel (petroleum ether–ethyl
acetate, 4:1). Yield 45.5 mg (77%), colorless oil.
1H NMR spectrum (300 MHz, CDCl3) δ, ppm: 0.08 s
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