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102 Chemistry and Biology of Beta-Lactams
Bn
OH
1
OH
K
OsO
2NH2
PMP
https://t.me/med1917
H H
O
N
O
SCHEME 3.70 Chiral Synthesis of β-Lactams.
Bn
R
1
CH3SO
2
K
Fe(CN)
3
(OH)
2
Ligand
OH
N
Ph
+
RN
PMP
O
OH
R
NH
O
Ph
H
SO
4
2
PMP
4
6
LDA
ZnCl
BnO
2
O
H H
1
R
+
N
OH
Bn
R
NH
PMP
R
NH
PMP
R
NH
OCH
O
3
LHMDS
BnO
O
O
O
R PMP
H H
N
N
Bn
PMP
PMP
O
OH
R
R
R
NH
NH
O
O
SCHEME 3.71 Synthesis of β-Lactams by Enolate Method.
of adducts was prepared using DABCO as the amine catalyst. This gave a mixture of the products. A
different reaction was conducted with an external optically active catalyst. Following this concept, the
dihydroxylation was investigated using (DHQ)2PHAL and (DHQD)2PHAL catalyst (Scheme 3.70).
Vicario et al.
107
studied the reaction of lithium enolate of propionamide with a Schiff base in the
presence of LiCl. The reaction proceeded with LDA/ZnCl2. The amides were hydrolyzed/esteried,
and α-methyl-β-amino acids were obtained (Scheme 3.71). At the end, β-aminoesters were cyclized to
β-lactams by base-catalyzed conditions.
An enantio- and diastereoselective condensation with achiral esters and imines was reported
by Magriotis et al.
108
This work was conducted by Corey et al. to explore chiral organoboron Lewis
acid (Scheme 3.72). A cyclization of β-amino acid ester with Grignard reagent produced disubstituted
β-lactams. The cycloaddition of the lithium enolate of a propanoate with imine and a ligand afforded
β-lactam in good enantiomeric excess.
109
Fu et al.
chiral bis (azaferrocene) ligand was used for catalytic enantioselective Kinugasa reaction to prepare
synthesized β-lactams reacting copper acetylide with nitrone. A new C2-symmetric planar-
β-lactams (Scheme 3.73).
Mata et al.
110
showed a solid-phase method for the chiral synthesis of disubstituted β-lactams using
cycloaddition method. Resin linker was employed as the solid support. A few chiral aldehydes were
employed for the preparation of β-lactams with substituents at C4. Some of these are intermediates
for the preparation of carbacephems and isooxacephems. Resin-supported glycine with (S)-(tertbutyldiphenylsilanyloxy) phenylacetaldehyde was applied for the asymmetric method. Staudinger cycloaddition of aldimine with phenoxyacetyl chloride gave β-lactam (Scheme 3.74).
A single-electron transfer process to a radical functionalization using titanocene monochloride
(Cp2TiCl) for epoxide ring cleavage was identied by Grande et al.
111
(Scheme 3.75). This was an effec-
tive method to synthesize bicyclic β-lactams. Chiral D-glucosamine was employed to synthesize azetidin-2-ones for bicyclic β-lactams. The reductive opening of an epoxide with Cp2TiCl was useful for
103Polycyclic Beta-Lactams
CF
O
S-t-Bu
R
R R
2
1
Me
H
*
O O
https://t.me/med1917
CF
Ph
N
O
3
S
O
CF
2
2
R
N
1
H
Me
Me
S-t-Bu
N
Et
3
O
HR
3
Me Me
O O
H
Ph Ph
Me
LDA,
Me
N
2
toluene
PMP
H Ph
3
CF
3
t-
BuMgCl,
Ph
S
O
N
B
2
Br
Et
2
SCHEME 3.72 Synthesis of β-Lactams Using Chiral Organoboranes.
+
R2H
N
O
1
R
CuCl
2
Me
O-BR
MeO
N
2
*
2
t-
Bu
S-
O
PMP
Ph
N
1
R
CH=NR
O
HH
Me
2
R
O
HHN
1
R
H
Me
N
R
O
Me
Me
Me
R
N
Fe
Me
Me
Me
Me
SCHEME 3.73 Synthesis of β-Lactams Using Chiral Ligands.
N
2
O O
1
R
O
*
1
R
N
O O
TFA in
CH
DCM
2N2
10%
*
1
2
R
R
N
O
or
O O
Me
Me
Fe
N
R
2
*
N
O O
1
R
2
R
2
R
CH2COCl
Et
R
N
3
*
1
R
O
N
O
SCHEME 3.74 Synthesis of β-Lactams Using Solid Support.
104 Chemistry and Biology of Beta-Lactams
Me
O
OTi
v
Ph
MeO
Ph
R
HO
MeO
Ph
Me
Sg
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a rapid access to functionalized tricyclic β-lactams. These tribactams were starting materials for the
preparation of carbacephem antibiotics.
Some epoxides employing the styryl group in β -lactams were prepared (Scheme 3.76). For example,
cis-2-azetidinones were reacted with PhI (CF3-CO2)2, and a mixture of hemiketals was obtained.
Grande et al.
112
identied a TiCp2Cl-induced ring opening through single electron transfer reaction
of epoxy-monobactams. A cyclization and 1,4 addition of benzyl radical gave a conjugated γ-lactone.
The available cis-2-azetidinones were used to synthesize the epoxides. A deprotection of dithioacetal
functionality with [bis(triuoroacetoxy)iodo] benzene produced the aldehydes. Wittig reaction on the
aldehydes gave conjugated alkenes. The selective epoxidation of the alkene with m-CPBA afforded a
series of epoxides. Ozonolysis of epoxides proceeded to epoxyaldehydes (Scheme 3.77).
Alcaide et al.
113
synthesized alkenyl-4-oxoazetidine-2-carbaldehydes. The diolenic compounds in
ring-closing metathesis method produced 2-azetidinone-tethered imines. Depending on the size of the
ring, the target needed alkene group. Bis-β-lactams were synthesized through a two-step method. A
O
O
O
Ph
O
N
O
Cp
2
O
TiCl
MeO
Ph
N
O
R
O
O
MeO
+
H
O
3
O
SCHEME 3.75 Synthesis of β-Lactams Related to Tribactams.
MeO
N
O
HO
O
O
m
N
R
O
-CPBA
CH(SEt)
H
O
MeO
CO
PhI(CF
2
N
O
/NaHCO3/CH3CN/H2O.
2)2
3
H
O
Ph
R
O
SCHEME 3.76 Synthesis of β-Lactams: Precursors for Diverse Antibiotics.
N
CH(SEt)
O
O
O
O
2
H
O
PhI(CF
Ph
P=CH-CO
3
CO
2)2
3
Me
2
MeO
O
Ph
N
CO
Me
2
Sg
Ph
N
O
R
m
-CPBA
OH
O
Ph
PDC
MeO
R
MeO
O
MeO
N
O
OH
N
3
O
R
H
CO
2
Ph
N
O
O
Ph
O
CO
2
Sg
PhI(CF
MeO
N
O
CHO
Sg
SCHEME 3.77 Synthesis of β-Lactams by Single Electron Transfer.
Ph
Me
O
S
,
2
CO
2)2
3
3
H
Ph
O
N
CHO
Sg
H
MeO
X
O
Ph
O
N
CHO
MeO
O
105Polycyclic Beta-Lactams
X
R
3
Me
O
TBDMSO
OTBDMS
O OBu-t
(5R)
https://t.me/med1917
ketene-imine annulation produced the diene bis-β-lactam. Following an identical method, bis-β-lactam
was obtained (Scheme 3.78).
Some dienes were investigated for ring-closing metathesis to prepare tricyclic β-lactams with two
bridgehead nitrogen atoms. For this purpose, ruthenium-based catalyst Cl2 (Cy3P)2Ru=CHPh was chosen. Treatment of dienes with Grubbs catalyst did not produce the desired tricycles. The cause of this
failure was not established. A weak reactivity of the structures and the ring strain was responsible for
this failure. However, it was found that dienic compounds required drastic conditions for a ring closure.
A high temperature and a “cis”-like conformation were required for cyclization. Toluene gave the best
yields of tricyclic β-lactams with medium-sized rings. A reaction of dienes with the ruthenium catalyst
Cl2(Cy3P)2Ru=CHPh resulted in the production of the tricycles (Scheme 3.78).
Hart et al.
114
identied a route for the preparation of carbapenem using an intramolecular cyclization
method. A Mukaiyama reagent was tested for this purpose (Scheme 3.79). This carbapenem has 5R
conguration at the C5 position. However, the preparation of a carbapenem derived from L-serine may
produce the other isomer with S absolute stereochemistry.
Annunziata et al.
115
demonstrated the preparation of trans-β-lactam. No report on the preparation of
enantiomeric thrombin inhibitor is known. Therefore, it is crucial to prepare both enantiomeric forms
of thrombin inhibitor. An oxidation afforded aldehyde (Scheme 3.80), and the stereocenter at C4 was
epimerized to the stable trans-β-lactam.
Almqvist et al.
116
disclosed the preparation of bicyclic β-lactam methyl esters by reacting acyl
Meldrum’s acids and thiazoline methyl ester. Esters were reduced to the aldehydes (Scheme 3.81).
3
H H
R
4
R
CO
2
NH
N
2
R
=
NCH(R
4
R
Me
CO
2
NH
N
2
R
OPhO
n
MeO2C
1
R
O
+
O
O
R
H H
MeO2C
H H
1
O
O
N
N
3
H H
1
R
O
O
4
H H
O
)CO
X
N
2
R
H
4A
Me
2
CHOMeO
N
R
NCH(R4)CO
2
Molecular
PhOCH
N
Et
3
CO
AgOAc/Et
Me
2
Sieves
NH
2
n
COCl
2
Me
2
N
3
MeO
H H
MeO
N
O
SCHEME 3.78 Synthesis of Chiral Bis β-Lactams.
O
-tBuO
SCHEME 3.79 Synthesis of Carbapenem β-Lactams.
OPhO
N
n
Grubs's
carbene
N
MeO
H H
Cl
TfO
COOH
N
H
MeCN, DIEA
OPhO
N
n
H
(R)
(S)
N
O
N
(R)
106 Chemistry and Biology of Beta-Lactams
PMPO
OH
H H
PMP
O
NaIO
O
S
CHO
R
3
CO
R
1
Cl
O
Me
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,
2CH2
4
AcOEt/water
CO
O-(CH
2CH2
O)n-CH
2CH2
PMPO
O
O
O
MeO-(H
H H
2CH2
-
BrBu
N
-
BrBu
PMP
CO)n-H
+
N
3
+
N
3
OH
SCHEME 3.80 Synthesis of β-Lactam Thrombin Inhibitor.
Me
CO
R
OH
N
H
2
R
O
O
OO
O
SCHEME 3.81 Synthesis of Optically Active β-Lactams.
CHO
N
O
+
N
Br
Bu
3
+
N
BuBr
+
N
BuBr
PTC
PMP
-
-
-
PMPO
H H
CH
N
O
R
S
N
Me
CO
2
DIBAL-H
O
S
N
O
3
R
NH
O
2
NH
2
ClCH2COCl
1
R
CO
2
Ar-CHO
NaBH
CH3OCH2Cl
3
R
4
HN
Cl
R
CO
R
ClCH
3
N
2
CO
R
R
2
2
2
1
COCl
1
R
2
Base
Ph
O
3
R
N
H
N
R
O
2
1.
2.
3
R
CO
N
R
O
2
Me
CO
2
TFA
H-L-Phe-OMe/BOP
1
R
2
+
R
O
R
N
O
SCHEME 3.82 Synthesis of β-Lactams Using Chiral Amines.
The stereoselectivity because of memory of chirality is dependent on the substituents of the starting
N-chloroacetyl amino acid derivative as shown by Muñiz et al.
directing element. The chloroacetyl derivative was prepared by the reaction of chloroacetyl chloride with
117
The amino acid side chain was the main
a substituted compound. This compound was prepared by reductive amination of α-amino esters with an
aldehyde. The enantiomeric pair was prepared using coupling with α-amino esters (Scheme 3.82).
Nyitrai et al.
118
used a 3-unsubstituted β-lactam in the investigation. The reaction of N-unsubstituted
β-lactams with benzyl-2,3-dioxobutyrate was conducted, and the adducts were converted to oxo-disubstituted-azetidin-1-yl acetoacetates. In another method, an intermolecular carbene insertion was followed into the β-lactam N-H group. The cyclizations were performed with triethylamine in chloroform.
The dioxobutyrate route provided better results than the carbene insertion method (Scheme 3.83).
Ph
O
3
N
CO
2
H
N
R
2
3
1
R
CO
2
R
2
107Polycyclic Beta-Lactams
O
R
OZ
Et
SOCl
OZ
X
O
2
X
Me
Bn
Me
https://t.me/med1917
N,
(OAc)
2
2
4
2
1
R
OZ
3
Zn/AcOH
Rh
NH
2
1
R
R
N
O
O
OOO
Ph
OCH
2
SCHEME 3.83 Synthesis of β-Lactams by Carbene Insertion.
Y
Base
O
C
X H
N
R H
Ph
OO
O
N
O
N
Ph
O
OH
OR
O
NR1R
O
X
2
1
R
N
Et
3
R
N
O
O
OR
O
O
N
2
2
NR1R
O
N
RX
Me
N
N
OMe
Et
Et
BnO
N
O
N
Me
R
SCHEME 3.84 Synthesis of β-Lactams Using Hydrazones.
N
N
Me
H
R
BnO
Bn
O
H
OBnO
O
OH
N
O
Bn
O
N
Cl
i-Pr
2
I
EtN
Me
N
O
N
O
R
N
Bn
SCHEME 3.85 Synthesis of β-Lactams Using Dialkylhydrazones.
Lassaletta et al.
119
found that formaldehyde compounds act as monomeric methanimines in reaction
with functionalized ketenes. It was shown that the stability of aliphatic N,N-dialkylhydrazones is crucial
for the preparation of 3-alkoxy-4 (aryl)-azetidin-2-ones and of the isoserines (Scheme 3.84).
Lassaletta et al.
tion of 3-amino-4alkylazetidin-2-ones. A few hydrazones containing C2-symmetric 2,5-dimethylpyrro-
119
showed cycloaddition of N,N-dialkylhydrazones to α-aminoketenes for the prepara-
lidine were used as the auxiliary. N-benzyloxycarbonyl-N-benzyl-glycine was employed as aminoketene
equivalent and 2-chloro-N-methyl pyridinium iodine as the promoter (Scheme 3.85).
Staudinger reaction between chiral acid chloride and N-benzyl-N-[1E)-phenylmethylene]amine was
investigated by Thiruvazhi et al.
120
(Scheme 3.86). The formation of four diastereomers was observed.
The structures of the products were not conrmed. The NMR data was difcult to analyze by the presence of rotamers due to the N-Cbz group. Therefore, the Cbz group was eliminated to give pyrrolidine.
108 Chemistry and Biology of Beta-Lactams
R
MsO
Ph
Bn
Ph
O
Cyclohexyl
R
R
R
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K
CO
Bn
2
K
CO
2
3
N
MsO
N
Cbz
N
Cbz
O
O
N Bn
Ph
O
1
N
Cbz
O
Cl
E-PhCH=NBn
N
Et
3
SCHEME 3.86 Synthesis of β-Lactams Using Chiral Amino Ketenes.
A
A,
A,
HN
A:
A:
O
O
O
O
O
A
A
A
NaH,
BrCH
NaOH
THF
COOEt,
2
Me
OH
O
O
N
O
O
O
O
O
A
A
A
A
3
Mukaiyama
Et
N
Cbz
3
N
Cbz
N
Ph
O
O
R
Ph
N
N Bn
N
H
10%
Bn
H
10%
reagent,
2
Pd/C
2
Pd/C
A
O
Ph
N
N
H
O
O
N Bn
N
H
A
A
A
O
O
O
H H
O
N
O
N
O
SCHEME 3.87 Synthesis of β-Lactams Obtained from Functionalized Mannitol.
SCHEME 3.88 Synthesis of β-Lactams from Ferrocene Derivatives.
The structure was found to be correct by X-ray crystal structure. Importantly, using K2CO3/MeOH,
dihydropyrrole isomer was obtained. Alkene was deprotected to produce proline-derived product.
The structure of the nal product was correct as conrmed by converting it to proline-derived compound by an elimination of methanesulfonic acid, hydrogenation, and removal of the Cbz protecting
group (Scheme 3.86).
Jun et al.
carboxylic acids and imines to produce β-lactams.
Two chiral compounds obtained from D-mannitol were alkylated with ethyl bromoacetate, followed
121
showed that Mukaiyama reagent is a powerful activating agent for the cycloaddition of
up by an ester hydrolysis to obtain acids (Scheme 3.87). The bicyclic acids on reaction with imines
afforded the desired β-lactams.
Bonini et al.
nylimines (Scheme 3.88).
122
showed the preparation of 4-ferrocenyl-β-lactams starting from planar chiral ferroce-
109Polycyclic Beta-Lactams
1
HATU, DIPEA, NMP,
O-
OH
https://t.me/med1917
1
s
R
CO
2
Cl
N
O
Base
N
O
CO
1
R
2
O
R
CO
2
N
OMe
CO
t
Bu
2
O
O
N
O
O
OH
SCHEME 3.89 Synthesis of β-Lactams Using Phase Transfer Catalysts.
SCHEME 3.90 Synthesis of β-Lactams Using Chiral Ketene.
H
N
DCBB
O
3
O
NA[B-H(OAC)
OO
N
Boc
COOH
(2,6-dichlorobenzyl)tyrosine
ester
mehtyl
hydrochloride
N
O
O
OMe
OMe
H
N
DCBB
]
3
N
O
O
O
DEAD
PPh
THF
,
OO
3
DCBB
N
N
O
H
CO
O
O
SCHEME 3.91 Synthesis of Chiral Spirocyclic β-Lactams.
3
Bonache et al.
acid-derived β-lactams. A base-catalyzed cyclization in the presence of the cinchonidine compounds
(-) TADDOL and (-)-BINOL was conducted. This was the rst evidence for TADDOL as an additive to
improve the memory of chirality in β-lactam research (Scheme 3.89).
Rosa et al.
124
lactams (Scheme 3.90).
DCBB
H
THF,
LiOH,
O
123
showed the use of various phase-transfer catalysts in the preparation of the amino
82%
0,
2
O
N
N
O
O
O
HO
OClCl
DCBB:
showed a reaction of amino acid, imine, and Mukaiyama reagent to give the spiro-β-
110 Chemistry and Biology of Beta-Lactams
H
Me
Ph
O
Ph
Ph
3
https://t.me/med1917
OH
H H
CO
3
O
H H
H
CO
3
O
N
PMP
N
OH
PMP
Me
Me
Toluene, 220
Toluene, 220
0
C
0
C
H H
O
H H
O
OH
N
PMP
Me
OH
N
PMP
O
H H
N
N
PhPh
Ph
OH
R
H
Ph
+
N
O
CO
3
O
SCHEME 3.92 Synthesis of Polycyclic Chiral β-Lactams.
+
SCHEME 3.93 Synthesis of Optically Active β-Lactams Using Nitrones.
Bittermann et al.
N
O
125
showed the preparation of chiral spirocyclic compound using L-proline. The sterically crowded amino acid was treated with HATU and coupled with glycine methyl ester, to give the
peptide. Ozonolysis of the double-bond group and reduction with borohydride produced the hydroxy-
Me
N
HPh
Ph
Toluene,
N
O
metal salt
TOX
Et
0
220
C
N
O
N
O
N
H
CO
3
OH
H H
H
methyl compound. The β-lactam was obtained by an intramolecular process with DEAD (Scheme 3.91).
Alcaide et al.
126
demonstrated cyclization of the enallene by heating a solution in toluene at 220°C
in a tube. The thermolysis produced the tricyclic lactam, which has a cyclobutane system. Some other
enallenes also underwent thermal cyclization to strained tricycles. The regioselectivity of the reaction
was not changed by the substitution pattern in the allene system. The ring closure of the allene was slow
but proceeded with identical regioselectivity. Substitution in enallenes was altered in order to force the
selectivity to the six-membered ring formation. But the thermal method gave tricycles, which have a
seven-membered ring. No compounds with exocyclic methylene were obtained (Scheme 3.92).
Tang et al.
127
studied the reaction of phenylacetylene with nitrone using TOX following asymmetric
Kinugasa method. This method showed the synthesis of β-lactams with good diastereo- and enantioselectivity. The Cu(II) salt used in this study was proved to be efcient (Scheme 3.93).
Buttero et al.
128
showed the reaction of the glycine methylester or L-alanine methylester with cinna-
maldehyde to imines. Staudinger reaction of these imines and phenoxyketene produced cis-β-lactams.
111Polycyclic Beta-Lactams
Ph
Ph
R
Bn
O
NaH
Ph
Cl
O
https://t.me/med1917
Ph
N
R
PhO
Ph
Me
CO
2
Ph
Cl
N
O
R
NH-NHPh
CCl
O
PhO
O
Ph
P
,
4
3
Ph
H
H
N
N
N
Ph
O
NH-NHPh
PhOCH2COCl
N
Et
3
PhO
N
Me
CO
2
R
O
N
O
R
SCHEME 3.94 Chiral Synthesis of β-Lactams Using Amino Acids.
O
O
H H
NaBH
H
4
N
Cl
BnO
O
H H
OH
N
Cl
NaOH
DMSO
Ag
PhO
CO
2
O
BnO
Ph
(COCl)
N
COOH
R
PhO
3
N
O
R
PhNHNH
Ph
N Ph
N
2
2
H H
O
N
O
O
O
H H
O
NaBH
H
4
N
PhO
H H
N
O
OH
NaH
DMSO
Cl
PhO
H H
O
SCHEME 3.95 Asymmetric Synthesis of Bicyclic β-Lactams By Base-Induced Method.
A series of reactions were conducted to obtain enantiopure products. These included ester hydrolysis,
activation of the acid, triphenylphosphine treatment, and heating with silver carbonate (Scheme 3.94).
The synthesis of new bicyclic β-lactam was reported by Kimpe et al.
129
4-Formyl-1-haloalkyl-β-lactams
are the useful starting materials. These were reacted with NaBH4 to obtain 4-hydroxymethyl-β-lactam. A
deprotonation of the alcohols and addition of DMSO produced bicyclic β-lactams (Scheme 3.95).
Guiry et al.
130
described Kinugasa reaction using CuCl and bis(azaferrocene) ligands to synthesize
cis-β-lactam. Tang applied trisoxazoline ligand in the reaction of diphenylnitrone and phenylacetylene
with a Cu (II) compound (Scheme 3.96).
Shaikh et al.
131
showed the use of isosorbide for asymmetric preparation of β-lactams. Isosorbide was
converted to an iodoalcohol, which was converted to an epoxide. The epoxide gave diol which on oxidative reaction gave dimethyl-tetra-hydrofuro dioxole-4-carbaldehyde. The aldehyde afforded Schiff’s
bases. The cycloaddition of imines with ketene gave excellent cis-selectivity (Scheme 3.97).
The application of isosorbide for the asymmetric synthesis of β-lactams was demonstrated by Shaikh
131
et al.
A low diastereoselectivity was observed with the endo-ketene. The endo-acid was made from
isosorbide (Scheme 3.98). The asymmetric reaction of the chiral bicyclic acid with achiral imine produced a mixture of two cis-β-lactams.
Banik et al.25 demonstrated synthesis of trans-β-lactams from a chiral ketene. Importantly, these chi-
ral trans-β-lactams demonstrated anticancer activity.
had effects on the biological activities.
148 –159
132–147
The dipole moment values of the compounds
N
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