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82 Chemistry and Biology of Beta-Lactams
R
1
R
R
1
O
O
3
O
R'
Br
P
Ph
R
O
R2
R1
R'
https://t.me/med1917
Arndtsen et al. demonstrated a one-pot palladium-catalyzed synthesis of 3-amido-β-lactams (Scheme
20
3.10).
3.2.5.2 Enolate-Imine Condensation
Gilman and Speeter investigated a reaction of zinc enolate with imines to give β-lactams. Later, various other metal enolates were employed in enolate-imine reaction for diastereoselective preparation of
β-lactams (Scheme 3.11).
21, 22
3.2.5.3 Staudinger Reaction
Staudinger cycloaddition was used for the rst synthesis of a β-lactam in 19071 by the reaction of ketene
and imine.23 In general, acid chlorides or activated carboxylic acids were used in the presence of a base
(Scheme 3.12).
3.2.5.4 Staudinger Reaction: Chiral Synthesis of β-Lactams
The synthesis of enantiopure β-lactams is crucial because of their biological activities. In general, asymmetry is induced using either optically active ketenes or chiral imines. Chiral imines can be obtained
from chiral aldehydes or amines.
Optically active imines derived from chiral aldehydes and achiral amines were used extensively
for Staudinger reaction. The N,O-protected aldimines were crucial starting materials for this purpose
(Scheme 3.13). Many new β-lactams with excellent diastereoselectivity were obtained.
24–26
N
2
H
SCHEME 3.10 Synthesis of β-Lactams by Palladium-Catalyzed Reaction.
SCHEME 3.11 Synthesis of β-Lactams by Enolates-Imines Method.
.
+
COOEt
R''
R'
O
3
R
+
COOEt
+
Cl
Ph
R1
+
CO
N
PMP
N
R2
Pd
R''
N
2
H
O
R
2
R
N
N
R
O
R
N
1
R
PM
R
N
SCHEME 3.12 Synthesis of β-Lactams by Cycloaddition Reaction.
83Polycyclic Beta-Lactams
R' = Ph
Boc
NR
NR
OTIPS
O
OTIPS
O
OTIPS
e
https://t.me/med1917
Boc
N
O
R'
SCHEME 3.13 Asymmetric Synthesis of β-Lactams.
O
R'
FIGURE 3.5 Chiral Imines used for the Synthesis of β-Lactams.
NSiMe
SCHEME 3.14 Synthesis of Stereospecic Trans β-Lactams.
Phth
O
OR'
( )
NR
3
n
OR''
Phth
HH
NR
R' = H
H H
N
R'
NR
NH
O
O
O
Phth =
OMe
O
O
Phth
NR
H H
N
O
O
O
O
O
O
+
NH
O
O
O
SCHEME 3.15 Synthesis of Chiral β-Lactams Using Chiral Imines.
In some examples, α,β-epoxyimines, α-oxy-aldehyde-derived imines, and sugar-derived imines were
27, 28
used .
Formation of the cis-isomer was predominant regardless of the conditions of the experiments.
Panunzio and co-workers showed the preparation reported of trans-isomer by reacting phthalimide
acetyl chloride with N-trimethylsilyl imines (Scheme 3.14).
3.2.5.5 Chiral Imines Obtained from Carbohydrates
Carbohydrates have received attention in the preparation of drugs and natural products.30 These are also
used in the asymmetric synthesis of β-lactams.
We demonstrated the use of optically active Schiff base prepared from carbohydrates in the cycloaddi-
31–33
tion.
These chiral imines were employed for the asymmetric preparation of β-lactams.
continued interests on carbohydrates as synthetic precursors for cyclizations and as activating groups, we
also showed several tellurium-based reactions and their applications.
A chiral Schiff base and a methoxy-ketene produced a cis-isomer. This compound was converted into
6-epi-lincosamide using a number of steps (Scheme 3.15).
O
O
N
H
Bn
NBn
Bn
OO
N
O
O
O
O
OMe
29
40–51
O
O
O
O
O
2
OM
34–39
Due to our
84 Chemistry and Biology of Beta-Lactams
OH
CH
2
A
r
Ms
PMP
OBn
OH
CH
H
C
CHO
(+)-thienamycin
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The reaction of benzyloxy ketene with the imine gave cis-β-lactam with full diastereoselectivity.
Synthesis of (-)-polyoxamic acid, a nonnatural form of natural (+)-polyoxamic acid, was performed
(Scheme 3.16).
52
An enantiospecic preparation of α-hydroxy-β-lactams using imines obtained from D-glyceraldehyde
following microwave method was reported
53–55
(Scheme 3.17).
The use of D-erythrose-derived Schiff bases was demonstrated for the preparation of 2,3-dideoxy-D-
mannonic acids (Scheme 3.18).
56
A β-amino ester was prepared from the (R)-glyceraldehyde acetonide. This on cyclization with dipyri-
dyl disulde and triphenylphosphine produced 3-unsubstituted β-lactam. This compound was then converted into (+)-thienamycin (Scheme 3.19).
57
The Schiff base derived from L-(-)-glyceraldehyde and 2,4-dimethoxybenzylamine on reaction with
phthalimide acetyl chloride produced the 3-phthalimido β-lactam. This is a key molecule for the preparation of carumonam antibiotics (Scheme 3.20).
58
A treatment of the imine obtained from L-(-)-glyceraldehyde and benzylamine with oxazolidinone
derivative gave cis-β-lactams (Scheme 3.21).
59
The β-amino acid on ring closure produced β-lactam. This was converted into (+)-thienamycin
(Scheme 3.22).
Ph
2
60
O
O
BnOCH
N
O
COCl
2
N
Et
3
OCH
Ph
2
O
O
O
HH
N
CH
Ph
O
OH
COOH
O
O
NH
OH
2
SCHEME 3.16 Synthesis of Polyoxamic Acid.
OO
N
SCHEME 3.17 Synthesis of Optically Active β-Lactams.
O
+
O
SCHEME 3.18 Synthesis of β-Lactams Using Sugar Imines.
3
3
O
O
SCHEME 3.19 Synthesis of Thienamycin Intermediates.
CH2PhOCH2COCl
MW
Et
N,
3
OBn
OBn
OBn
N
HO
NH
O
2
OCH
MsO
COOCH
O
O
N
Ar
HH
OH
OH
N
R
2
HH
N
PMP
-(PyS)
O
O
N
Pd/C,
2
4
MW
NH
HCO
Ar
OBn
OBn
CF
H
2
O
NH
COOCH
3
HH
Ph
2
O
O
PPh
3
3
CH3CN
HH
HO
O
H
N
3
O
O
R = COOH, PO3H
H
DM
DMB = 2,4-dimethoxybenzyl
carumonam AMA 1080
2
O
Bn
O
Ph
D-glucos
OH
2
(+)-thienamycin
H
CHO
NHCbz
HNH
H
H
CONH
D-Glucos
OR
1
6-epi thienamycin
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B
OO
+
N
O
N
O
CH2COCl
Et3N
DCM, 0 °C
2h
H H
Phth
N
DMB
O
Phth = -phthalimido
SCHEME 3.20 Synthesis of Carumonam Antibiotics Intermediates.
85Polycyclic Beta-Lactams
S
NH
OO
2
N
N
HH
CONH CH2OCONH
N
SO3H
O
O
CH2COOH
OO
N
O
Ph
N
Cl
O
+
R'
O
R' =
SCHEME 3.21 Stereospecic Synthesis of β-Lactams Using Chiral Imines.
OH
H H
e
HOOC
CO2Bzl
NH2.HCl
H H
CO2Bzl
N
O H
SCHEME 3.22 Synthesis of Optically Active Thienamycin.
OHH
HO
OHH
CH2OH
p-ClPhSO2O
OH
COOBn
H
O
H
NH
CbzNH
O
HH
R''
N
Bn
O
O
N
H
CO2Bn
H
OSO2PhCl-p
R'
+
O
,
R'' =
OH
HH
N
O
N
O
clavamine Ro 22-5417
HH
R''
N
O
COOH
O
Bn
S
H
NH
2
CO
2
SCHEME 3.23 Synthesis of Clavamine.
e
SCHEME 3.24 Synthesis of Optical Isomer of Thienamycin.
An amino alcohol on coupling with 4-acetyloxy-N-unsubstiuted β-lactam gave a mixture of β-lactams.
The main isomer was converted to the clavamine (Scheme 3.23).
The amide was cyclized with potassium tert-butoxide to afford bicyclic β-lactam. This compound was
transformed into 6-epi thienamycin (Scheme 3.24).
Me
MeO2SO
2
O
O
OMe
Me
H
O
N
H
H
62
OH
61
H H
NHR
CO2R
S
2
N
O
86 Chemistry and Biology of Beta-Lactams
D-
COOH
OBn
n
O
R'
O
R'
e
A
AcO
H
I
O
O
COCl
Ph
1
O
Ph
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glucosamine
SCHEME 3.25 Synthesis of Optically Active Thienamycin.
OAc
cO
SCHEME 3.26 Synthesis of the Side Chain of Taxol.
1
R
N
O
O
OAc
O
O
SCHEME 3.27 Non-stereospecic Synthesis of β-Lactams.
Ph
N
H
ROCH2COCl
N
Et
3
H
H
RO
N
RO
NH
HH
OBn
OHH
Ph
HH
O
HH
2
RO
+
O
N
I
1
R
H
NH
O
Ph
N
O
+
Ph
RO
OBn
CH2OB
OH
NH
2
OR
HH
O
O
OM
O
O
N
I
1
R
1
O
O
N
SCHEME 3.28 Synthesis of Optical Isomers of β-Lactams.
R
+
Et
DCM
N,
3
N
Ph
>96%
ee
Ph
O
O
HH
N
O
1
R
N
Ph
O
HH
N
+
Ph
O
R
N
The β-amino acid was converted to N-unsubstituted β-lactam in the presence of condensing agents.
This was used for the preparation of (+)-thienamycin (Scheme 3.25).
63
Optically active imine derived from 2,3,4,6-tetra-O-acetyl-β-D-galactosamine was used for the prepa-
ration of β-lactams as a diastereomeric mixture (Scheme 3.26). The α-isomer was converted to β-amino
ester, which was employed for the preparation of the side chain of taxol.
64
Imine obtained from D-glucose was used for the preparation of β-lactams.65 This method produced a
50:50 diastereomeric mixture of the products (Scheme 3.27).
3.2.5.6 Optically Active Ketenes
As stated before, Staudinger cycloaddition was used with either chiral ketenes and chiral Schiff bases or
achiral ketenes and chiral Schiff bases.
The cycloaddition of ketenes obtained from optically active oxazolidinyl acid chlorides with achiral
66
68, 69
67
imines produced β-lactams with a high enantiomeric excess (Scheme 3.28).
Phenanthridine gave exclusively trans-β-lactam with chiral ketene (Scheme 3.29).
A stereoselective route for the preparation of β-lactam using chiral heterocycles derived from L-(+)-
tartaric acid, (S)-glutamic acid, and (S)-serine was reported (Scheme 3.30).
87Polycyclic Beta-Lactams
O
O
OMe
O
OM
O
Ph
Ph
Ph
Ph
de >95%
https://t.me/med1917
O
O
N
Ph
SCHEME 3.29 Stereospecic Synthesis of Congested β-Lactams.
+
N
Cl
Et
3
OMe
MeO
OMe
MeO
O
N
O
O
OMOM
N
O
O
N
O
Ph
N
Ph
OMOM
Ph
N
O
O
N
CH2CO2H
N
CH2CO2H
O
N
CH2CO2H
OMOM
OMOM
N,
N
DCM
Ph
Ph
MeO
+
+
+
O
Ph
HH
N
N
O
O
N
Ph
O
N
O
N
O
O
N
O
O
Ph
OM
Ph
N
Ph
OMOM
Ph
N
Ph
SCHEME 3.30 Synthesis of β-Lactams from Heterocycles.
SCHEME 3.31 Asymmetric Induction in β-Lactam Synthesis.
Cooper et al. employed an oxazolidinone derivative and obtained >95% diastereoselectivity in the
synthesis of β-lactam (Scheme 3.31).
Tri-O-acetyl-D-glucal-derived chiral acid was used for the diastereoselective preparation of β-lactams.
The sugar group was cleaved by treatment with acid to generate 3-hydroxy-β-lactam (Scheme 3.32).
Shinkre et al. used ephedrine-derived acid with diverse imines in the presence of triphosgene for the
synthesis of cis-β-lactams. Ephedrine was removed following acid treatment (Scheme 3.33).
3.2.5.7 Optically Active Amines
Chiral Staudinger reaction using Schiff bases derived from achiral aldehydes and chiral amines gives
β-lactam with weak stereoselectivity.
Me
N
O
COCl
O
Ph
+
70
N
PMP
Me
O
H H
N
O
N
O
PMP
71
72
88 Chemistry and Biology of Beta-Lactams
A
Ph
AcO
H
PMP
R
O
R1
R2
Ph
O
N
Ph
COOBn
OR
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OAc
O
cO
AcO
OAc
O
O
COOH
OAc
O
Ph
N
O
SCHEME 3.32 Synthesis of Optically Active β-Lactams.
Ph
N
O
O
+
COOH
R1
N
R*O
R2
HH
R1
N
O R2
R*O
+
O R2
SCHEME 3.33 Synthesis of β-Lactams from Ephedrine Derivative.
PhthN
S
N
S
O
O
O
O
HH
N
O
AcO
R1
HH
N
O
O
O
O
HH
OH
N
O R2
Ph
S
S
O
R1
N
PMP
+
HH
OH
N
O
SCHEME 3.34 Synthesis of Chiral β-Lactams from Carbohydrate Derivative.
3
+
O Cl
SCHEME 3.35 Synthesis of β-Lactams from Amino Acid Derivative.
Asymmetric Staudinger method using Schiff base obtained from D-glucosamine73 and cinnamalde-
hyde gave cis-β-lactam (Scheme 3.34).
D-Threonine was employed for the preparation of β-lactam. The bulkiness of the substituents con-
trolled the diastereoselectivity (Scheme 3.35).
A chiral imine75 derived from (1S, 2S)-2-amino-1-phenyl-1,3-propanediol was used in the cycloaddi-
tion reaction. The hydroxyl functionality dictated the stereoselectivity (Scheme 3.36).
N
COOBn
CH
O
3
OR
Ph
3
OR
+
CH
N
N
Et
3
N
HH
3
O
N
HH
3
O
74
N
COOBn
Ph
CH
3
89Polycyclic Beta-Lactams
Ph
R
O
Ph
OR
3
Ph
Ph
R
O
O
3
https://t.me/med1917
HH
N
1
O
SCHEME 3.36 Hydoxy-Controlled Stereoselective Synthesis of β-Lactams.
SCHEME 3.37 Asymmetric Induction in β-Lactam Synthesis.
OR
PhR
O
N
O
O
+
Cl
1
PhthNCH2COCl
N
Et
3
RCH=N
+
C
H
2
R
Catalyst (A)=
R
R
CO2CH
NTs
N
2
PhthN
3
R
N
3
Fe
Ph
N
1
N
Et
3
-
R1R
OR
O
+
O
1
R
R
+
Catalyst*
2
B
PhthN
N R
O
NTs
R
2
HH
O
HH
O
R
N
N
1
O
R
CO2CH
Ph
Ph
SCHEME 3.38 Synthesis of β-Lactams Through Catalytic Method.
3.2.5.8 Stereochemistry Differentiation
A signicant level of asymmetric induction was seen in the Staudinger reaction between the EvansSjogren’s ketene and imines derived from chiral amino acid esters76 (Scheme 3.37).
3.2.5.9 Catalytic Chiral Staudinger Cycloaddition
Hodous and Fu77 identied enantioselective preparation of β-lactams mediated by an optically active
nucleophile (A). This chiral catalyst (A) was efcient in the cycloaddition method of diverse ketenes with
a variety of imines (Scheme 3.38). The reaction proceeded through the intermediate (B), and a similar
observation was noted by Lectka.
3.3 Current Development in the Chiral Preparation of β-Lactams
A reaction of oxazolidone with N-benzylimines was known. This reaction gave cycloadducts with high
asymmetric induction. Metal-mediated reduction afforded the homochiral β-lactam (Scheme 3.39). The
reactions of acid chloride with aldimine were conducted. The azetidinone was puried by crystallization. The one-step deprotection made this cycloaddition highly competitive (Scheme 3.39).
Evans et al.79 published an enantiospecic preparation of the carbacephalosporin using cis-β-lactam.
A dissolving metal reduction was used for three chemical reactions: to remove oxazolidone, to reduce the
anisole ring, and to debenzylate the azetidinone nitrogen.
78
90 Chemistry and Biology of Beta-Lactams
Ph
R1H
R
2
1
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Ph
O
O
R
N
N
O
R
O
O
N
ClO
SCHEME 3.39 Synthesis of β-Lactams from Oxazolidone.
Et
N R
N
3
2
Ph
O
O
H H
1
R
N
O
+
N
2
The carbamate salt used in this reaction was decomposed at pH 7, and the amino azetidinone was
protected with t-butyl pyrocarbonate. It was realized that the carbacephem system can be constructed
through a rhodium-catalyzed carbene insertion method. Following diazo transfer and titanium-catalyzed
transesterication, benzyl ester was prepared. The rhodium-catalyzed carbene insertion was performed.
The 3-hydroxy carbacephem was trapped. From the triate, a variety of C3- and C7-substituted carbacephalosporins were prepared. The nal product was obtained by removing the benzyl ester and the
p-nitrobenzyl group. The zwitterionic compound was isolated (Scheme 3.40).
An enantiospecic synthesis of carbacephalosporins was performed by Evans et al.80 The transformation of the aldol adduct to PS-5 was illustrated (Scheme 3.48). A removal of the auxiliary to give the
hydroxamic acid was achieved. The unprotected hydroxyl group was essential for the transamination
reaction. The synthesis of azetidinone was conducted through a methanesulfonylation and a subsequent
base-induced process. A few subsequent reactions on azetidinone resulted in carbapenem 155 (Scheme
79
3.41).
The synthesis of thienamycin using N-C4 intramolecular cyclization reaction was investigated by
Evans et al.81 The conversion of an intermediate to the thienamycin precursor utilized a series of reactions (Scheme 3.42). Transamination was performed to afford the trans-N-methyl azetidinone. A metal
reduction effected N-O bond cleavage. The synthesis was nally done by the cleavage of the alkene and
by the treatment with diazomethane (Scheme 3.42).
Evans et al.82 reported that the Schiff bases obtained from α,β-epoxyaldehydes were useful starting materials in the ketene-imine reaction. This process afforded 3-amino-4-alkylazetidinones (Scheme
3.43). Notably, formation of only cis-isomers was observed.
An enantioselective method to 3,4-cis-β-lactam based on the norephedrine-derived oxazolidines was
reported by Gennari et al.83 The procedure was initiated with unsaturated aldehyde obtained from norephedrine enantiomer. The aldehyde on reaction with potassium hypochlorite gave an epoxy acid (Scheme
3.44). The epoxy acid was then reacted with Me2CuLi to give anti-α-methyl-β-hydroxy acid. The acid
was reacted with N-hydroxybenzotriazole/DDC/methoxyamine hydrochloride to give the hydroxamate.
The optically active oxazoline was removed, and the product was cyclized to cis-azetidinone. The cis-
conguration was assigned by the coupling constant value. Dithiolane was hydrolyzed to give aldehyde
and reduced to alcohol. The alcohol was rearranged to γ-lactone (Scheme 3.44). A metal reduction of
alcohol was employed to afford the cis-β-lactam.
Asymmetric alkylation of an azetidin-2-one at C3 with methyl iodide and allyl bromide was reported
by Ojima et al.84 The electrophiles reacted from the opposite face of the styryl functionality to give the
product (Scheme 3.45). The 3-methyl-β-lactam was used as the starting compound for the preparation of
an optically active acid and an alcohol (Scheme 3.45).
Ojima et al.85 also investigated the action of optically active lithium ester enolates with imines, and
this reaction afforded β-lactams (Scheme 3.46).
Ikota et al.69 used tartarimide compound for the synthesis of β-lactams. A few optically active acids on
cycloaddition generated optically active β-lactams (Scheme 3.47).
Staudinger cycloaddition of a carbohydrate ketene and an imine produced cis-3-hydroxy-β-lactam
as demonstrated by Balogh et al.71 Carbohydrates with a group at the anomeric center worked well as a
ketene (Scheme 3.48).
Miller et al.86 identied acyl thiazolidinones as equivalent to activated esters. The hydroxy
alkene was reacted with O-t-butyldiphenylsilylhydroxylamine to produce hydroxamate.
MeO
Anhydride,
RHN
2
carbamate
https://t.me/med1917
Boc
DCM
N,
3
Et
DMAP,
H H
RHN
OMe
NH
O
91Polycyclic Beta-Lactams
ACN,
DCM,
base
2
Anisole,
,
NO
3
3
cysteamine,
P-nitrobenzyl
2
OR
N
O
O
NH
H H
O
BocHN
CH
of
Hunig's
AlCl
SR
Bn
2
CO
N
H H
H
N
O
O
PhO
DCM,
base
Anisole
MeO
O
O
O
O
Metal Reduction
H H
N
reduction
olefin
H H
N
Ph
N
Ph
TFA,
Phenoxyacetic
anhydride,
Hunig's
3
CF
H H
BocHN
4
base
anhydride,,
2
Triflic
Hunig's
H H
BocHN
N
N
2
OSO
O
OH
O
Bn
CO
Bn
2
CO
2
2
NH
S
Bn
CO
N
H H
H
N
O
O
PhO
OMe
O
O
Bn
NH
H H
O
O
BocHN
OAc
Rh
OMe
Bn
N
NH
O
H H
O
SCHEME 3.40 Synthesis of Carbacephalsporin.
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