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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5594_Библиотеки_им_академика_М_И_Перельмана
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252 Chemistry and Biology of Beta-Lactams
R
O
R
1
= Me
3
R
1
i) Sm
3
Ar
Cl
1
MeO2C
3
MeO
OMe
https://t.me/med1917
1
O
H H
HN
O
O
n
(CH2)
NH
2
i), ii)
Z NHPh
NH
O
Z = Ph; R =H, CO
Z
N
Ph
H2N
H
H
O
HN
R
n
(CH2)
H
2
n = 0, 2
i) Et3N; ii) H2, Pd/C.
SCHEME 8.23 Synthesis of cyclic peptides.
O
R
O
R
NH
O
2
NHH
Ph
i)
H
Z NHPh
HNNH
1
R
NH
O
3
HN
R
H2N
2
R
O
Z
NH
O
Ph
NH
NHH
Z
i)
H
Z NHPh
H
H
O
2
R
N
O
H
O
R
O
HNNH
NH
1
O
Z = Ph; R
3
R
O
NH
2
R
1
= R2= R
3
3
1
R
N
2
R
O
R
i)
HO
O
1
R
ii)
N
2
R
R2HN
MeO
1
R
OH
R
O
R2HN
iii)
3
O
R
O
I2, R3CHO, THF/HMPA; ii) NaOMe/MeOH; iii) HCl.
SCHEME 8.24 Synthesis of α-aminomethyl-γ-butyrolactones.
N
O
Ar
i) NaCN/CH
2
i)
1
OH
Ar
2
N
Ar
SCHEME 8.25 Preparation of piperidines through ring-opening reaction of β-lactams.
H H
N
O
i) TFA/CH
O
Ph
OH
O
MeO
i)
O
H H
N
H
OH
OH
Ph
HOH2C
BnHN
O
O
SCHEME 8.26 Conversion of optically active β-lactams to ve-membered lactones.
253Beta-Lactams as Synthons for Diverse Heterocycles
4
O
Ar
1
HO
2
O
O
1
O
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2
NO
2
i) In/NH
SCHEME 8.27 Preparation of oxazines through ring-opening reaction of β-lactams.
O
O
O
HBnH
O
O
N
O
i) NaOCl, KBr, TEMPO; ii) (S) H
SCHEME 8.28 Preparation of α-aminofuranuronic acids.
i)
Ar
Cl/EtOH
O
O
NCH(R)CO2Bn.
O
H
N
1
R
i) R2NH2.
N
O
i)
1
O
O
O
H
N
O
O
O
O
Bn
i)
O
N
H
ii)
BnO2C
O
H
O
NHR
NHR
2
O
Ar
2
NHAr
R
O
N
H
NH
Bn
O
O
O
O
O
SCHEME 8.29 Synthesis of α-amino acid derivatives.
8.3.2 C2–C3 Bond Cleavage
Many synthetic strategies for the synthesis of α-amino acids exploiting the C2–C3 bond ssion in
β-lactam skeleton were available.
α-Aminofuranuronic acid derivatives were synthesized from β-lactam by tempo-induced cycloexpan-
sion to afford the N-carboxy anhydride (Scheme 8.28).27 Subsequent amide coupling by (S)-Leu-OBn or
(S)-Phe-OBn produced the desired peptides in excellent yields.
A simple strategy29 to have access to α-amino acid derivatives was reported by Alcaide et al. It involved
the reaction of azetidine-2,3-diones with primary amines to afford the α-amino acid derivatives (Scheme
8.29). The amines were able to break the reactive 1,3-diketo system.
The mechanism showed a nucleophilic addition of the amine to the azetidine-2,3-dione carbonyl
group to form an intermediate carbinolamine. This intermediate underwent an intramolecular nucleophilic attack by the -NH2 group to produce bicyclic aziridine intermediate. It was interesting to note that
the nucleophilic reaction proceeded in the absence of any catalysts. This reacted through two pathways
to give N-formyl-amide. An intermediate was formed via N1–C2 bond ssion reaction or by a direct
decomposition process. Subsequently, loss of carbon monoxide furnished the desired α-amino acids in
good yields (Scheme 8.30). The intermediate was transformed to the product rapidly.
A similar preparation of optically active α-amino acids starting from chiral trans-azido β-lactams was
known.28 Tempo-induced ring expansion of 3-keto-β-lactams gave the N-carboxy anhydrides, which,
upon treatment with trimethylsilyl chloride in methanol, produced the α-amino esters (Scheme 8.31). The
anhydride ring that was formed can be degraded rapidly by this reaction. Oxidation of the keto system
was, therefore, a crucial reaction for this synthesis.
254 Chemistry and Biology of Beta-Lactams
O
O
1
R
H
N
O
n
iii) TMSCl, MeOH.
1
2
2
MeO
R
2
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H
3
R
R2NH
2
N
1
R
R2HN
H
OH
3
R
N
1
O
R
3
H
R
O
NHR
NHR
2
2
HO
1
SCHEME 8.30 Mechanism for the synthesis of α-amino acid derivatives.
R
3
i)
N
Bn
O
i) a) H
, Pd-C; b) tBuOCl; c) DBU; d) oxalic acid; ii) TEMPO;
2
R
O
ii)
O
N
Bn
O
O
SCHEME 8.31 Preparation of α-amino acid derivatives.
N
PMP
i) SnCl
X
R
i)
1
O
O
.
MeO
O
NR
OH
-CO
N
R
Bn
X
N
PMP
H
3
R
N
1
R
H
O
iii)
O
H
O
2
MeO2C
R
HNN
3
O
H
R
HN R
N
2
R
3
1
R
R
NHB
R
R
SCHEME 8.32 Preparation of oxazine or pyrazine-2,3-dione derivatives.
8.3.3 C3–C4 Bond Cleavage
A synthetic method30 toward the preparation of dihydrooxazines or pyrazinediones using tin(II) chloride-promoted C3–C4 bond cleavage with a rearrangement of dimethoxy-2-azetidinones was developed
(Scheme 8.32). This was possible and assisted due to the presence of two methoxy groups at the C3 center
in the ring system.
Two possible pathways were advanced realizing the function and property of tin chloride as an acid
reagent. A coordination of tin was involved due to its Lewis acid nature, and this triggered the subsequent
facile rearrangement process (Scheme 8.33).
Path A dictated a coordination of tin to the reactive group at C3 position, which increased the labile
character of the C3–C4 bond spontaneously. This process was helpful enormously to cleave the C3–C4
bond. This was highly possible because of the immediate stabilization of the carbocation intermediate
assisted by the ketal group through electronic effects. Subsequently, ring closure and hydrolysis of these
intermediates were feasible. In path B, the dimethoxy-substituted compound underwent a di-coordination with the reactive ketal group. This coordination was helpful, and then a six-electron rearrangement
of the intermediate was obvious, and this produced the nal product without any trouble.
A conversion of oxoazetidine carbaldehyde to γ-lactam was accomplished through sulfuric acid-catalyzed rearrangement, breaking the C3–C4 bond. Strong acid was able to activate the carbonyl group.
This was a facile process because of the activation exerted by the aldehyde group located at the C4 center
of the substrate (Scheme 8.34).
31
MeO
MeO
1
2
PMP
Me
Me
Me
PMP
Me
Me
Me
O
Me
Me
Me
O
R
1
3
3
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255Beta-Lactams as Synthons for Diverse Heterocycles
X
Me
Me
N
PMP
1
R
2
R
X
O
O
R
R
N
PMP
O
O
O
2
R
X
SnCl
1
R
N
O
PMP
path
L
Sn
n
2
B
2
path
R
N
PMP
A
SnL
2
X
SnL
n
1
R
MeO
MeO
O
n
1
X
R
2
R
N
-
L
Sn
n
SnCl
MeO
MeO
O
SCHEME 8.33 Mechanism for the formation of dihydro-1,4-oxazines or pyrazine-2,3-diones.
Me Me
CHO
N
PMP
O
i)
O
H
N
PMP
i) H2SO4.
SCHEME 8.34 Synthesis of γ-lactam.
O
N
PMP
O
Me
Me
Me
OH
N
PMP
O
O
Me
Me
N
OH
H
Me
SCHEME 8.35 Mechanism for the formation of γ-lactam.
O
Me
O
H
N
PMP
2
R
1
3
R
R
N
i) R3SnH, AIBN.
SCHEME 8.36 Preparation of tetrahydropyridines.
In principle, the process proceeded through a protonation to the carbonyl group, forming an intermediate (Scheme 8.35), which had undergone a C3–C4 bond breakage. At the nal stage of the process, a
1,2-hydride shift followed by a deprotonation occurred in the facile formation of the heterocycles.
A facile synthesis of tetrahydropyridines was performed using enyne-β-lactams by tributyltin hydride.
Clearly, this was a radical-induced reaction. Mechanistically, the stannyl radical was added to the triple
bond to form the vinyl radical. The acidic character of the alkyne bond was higher than that of the alkenyl bond. So, a preferential reaction took place at the triple bond (Scheme 8.36).
2
R
1
3
i)
R
Sn
3
R
O
R
N
SnR
3
2
R
3
R
O
R
N
R
N
O
3
R
N
1
O
SnR
3
2
R
R
1
SnR
3
R
N
O
3
1
2
R
R
SnR
2
R
3
SnR
32
256 Chemistry and Biology of Beta-Lactams
R
2
R
2
3
i) toluene, reflux.
Me
Ph
Me
Ph
H
Cbz
R
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The generated alkynyl tin radical underwent a 5-exo ring closure to form the carbapenem-like radical
or 6-endo ring closure to the bicyclic radical. Both pathways were possible. The C3–C4 bond cleavage
followed by radical quenching proceeded to form tetrahydropyridine. Interestingly, the carbapenemrelated radical intermediate was capable to rearrange to give bicyclic radical also. This reaction was
unique as almost all radical-mediated pathways were noted here.
An effective pericyclic reaction33 toward the synthesis of tetrahydroazocinones from dialkenyl β-lactam
was reported (Scheme 8.37). This was conducted under thermal conditions with functionalized alkenes.
A novel thermal [3, 3]-sigmatropic rearrangement was used in the stereospecic formation of the eightmembered lactam (Scheme 8.38). Synthesis of both optical isomers of the eight-membered rings was
possible by this method. The formation of optical isomers with two different substrates was interesting.
A novel synthesis of diazabicyclo[4,3,0]nonanes from suitably functionalized spiro-β-lactams was
performed via C3–C4 bond ssion by palladium-induced hydrogenation (Scheme 8.39).34 The removal
of the Cbz group, a retro-Mannich process involving ring scission of the β-lactam nucleus, followed by
hydrogenation of the imine functional group took place. The secondary amine on nucleophilic addition
2
R
1
N
3
R
O
i)
1
R
N
3
R
O
R
R
1
N
R
O
SCHEME 8.37 Preparation of tetrahydroazocinones.
Ph
toluene
O
H
Me
H
N H
R
Ph
H
Me
H
O
H
Ph
H
N
R
Ph
SCHEME 8.38 Cope rearrangement toward tetrahydroazocinones.
N
O
i)
N
R
O
H
-Cbz
2
O
N
N
H
R
O
toluene
O
N
O
Me
S
N
O
R
Ph
Me
H
Ph
Me
R
N
O
R
Me
N
i) H2, Pd/C.
N
H
R
2
O
H
2
N
R
N
N
O
SCHEME 8.39 Synthesis of 1,4-diazabicyclo[4,3,0]nonanes.
257Beta-Lactams as Synthons for Diverse Heterocycles
Ph
Ph
i) NaH, DMF.
O
n
n
2
PMP
n
R
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to the aldehyde group produced the bicyclic enamine, which on hydrogenation afforded the diazabicyclononane. In this reaction, the use of hydrogenation was demonstrated efciently.
8.3.4 C4–N1 Bond Cleavage
Sodium hydride-induced conversion of 4-benzoyl-2-azetidinone to γ-lactam was accomplsihed.35 A number of reactions were possible with this substrate under the conditions of the experiments. Specically, a
carbanion formation at the active center, C4–N1 bond breakage, and O-benzylation took place to furnish
the γ-lactam (Scheme 8.40).
The reduction of the carbonyl group in the β-lactam was achieved by a novel reducing agent. Selective
reduction of this group was considered problematic by many reagents. Acetal azetidines were prepared
via monochloroalane reduction of cyclic acetal or thioacetal β-lactams.36 A treatment with AlEt2Cl, a
moderately strong acid, produced pyrrolidine derivatives through a rearrangement reaction (Scheme
8.41).
Mechanistically, the product formation was successfully explained. A coordination of nitrogen lone
pair with the aluminum reagent made the C4–N1 bond weak leading to a ring cleavage. This process
generated an unstable zwitterionic system. The ve-membered acetal on rearrangement created a new
carbocation. This positively charged species was intramolecularly trapped by nitrogen, resulting in the
production of the nal molecule (Scheme 8.42).
HPhPh
O
Ph
N
PMP
O
i)
O
N
PMP
Ph
OBn
i)
Ph
Ph
O
SCHEME 8.40 Synthesis of benzyloxy triphenyl γ-lactam.
X
1
R
i) AlH
SCHEME 8.41 Synthesis of bicyclic pyrrolidine derivatives.
SCHEME 8.42 Mechanism for the formation of bicyclic pyrrolidine derivatives.
X
1
N
PMP
X
N
PMP
Cl, Et2O; ii) AlEt2Cl.
n
X
AlEt
Cl
2
O
Ph
N
PMP
1
i)
1
R
N
PMP
R
n
X
X
Al
Ph
O
X
N
PMP
Ph
Ph
O
N
PMP
n
X
R
ii)
X
N
PMP
X
Al
1
Ph
Br
1
R
X
X
N
PMP
n
1
R
X
X
N
258 Chemistry and Biology of Beta-Lactams
Cl
1
R
1
e
R
HO
1
O OH
i) tBuOK; ii) TFA.
https://t.me/med1917
A route37 toward the preparation of new aziridines from 3,3-dichloroazetidines involving C4–N1 bond
cleavage was developed (Scheme 8.43). The mechanism of the process was intriguing. Monochloroalane
reduction of β-lactam afforded the azetidine selectively. The azetidine eliminated hydrochloric acid
through a base-induced process to yield enamine, which produced a methoxy intermediate upon methanol addition. The elimination of chloride by the lone pair of nitrogen using a base-induced process helped
to form the bicyclic aziridinium intermediate, which on ring opening yielded aziridine derivatives in
good yields.
Glutarimides were synthesized by the reaction of hydroxyphenyl-azetidine-2-ones with tert-butyl
methyl malonate in the presence of potassium tert-butoxide.38 The phenoxide anion formed due to
the reaction by the base followed a concomitant C4–N1 bond cleavage to give the quinoid derivative.
Subsequently, a facile 1,6-nucleophilic attack by the malonate anion and then a nucleophilic trapping
produced the glutarimides in good yield (Scheme 8.44).
Isochromans were prepared39 by the treatment of suitably substituted enyne-β-lactam mesylates with
DBU. This transformation was explained by a C4–N1 β-lactam bond breakage through a base-induced
reaction followed by an intramolecular Diels–Alder reaction. The isomerization to an aromatic ring in
the isochroman was the driving force behind the reaction (Scheme 8.45).
A reaction between cis-formyl-β-lactam and 2-(trimethylsilyl)thiazole (TMST) produced the
α-hydroxy acid along with the expected β-lactam in minor quantities.40 The production of the α-hydroxy
acid was rationalized by considering the formation of alkoxide on a 1,2-migration of hydride along with
concomitant C4–N1 bond ssion of β-lactam (Scheme 8.46). The alkoxide had no other choice in this
reaction rather than the migration of a hydride ion.
The ring expansion of cis-4-arylimino-methyl-azetidin-2-ones to arylimino-pyrrolidin-2-ones was
catalyzed by tetrabutylammonium cyanide. The mechanism involved a cyanide attack upon the imine
group resulting in the formation of the cyano carbanion. The formation of a negatively charged enamino
nitrile through ring opening was possible. This unstable species was then tautomerized to the relatively
R
Cl
MeO OMe
N
R
N
2
R
2
R
O
OMe
2
H
N
1
R
1
R
N
Cl
ii)
1
R
OMe
2
R
R
NaOM
MeOH
1
R
O
N
2
R
O
NaOMe
MeOH
N
MeO
+
t
BuO2C
Cl
Cl
N
2
R
1
R
NaOMe
MeOH
2
R
C
2
i)
ii)
O
Cl
N
2
R
O
i) AlH2Cl, Et2O; ii) NaOMe.
SCHEME 8.43 Synthesis of aziridine derivatives.
O
2
H H
N
1
R
i)
Cl
OH
SCHEME 8.44 Synthesis of glutarimides.
259Beta-Lactams as Synthons for Diverse Heterocycles
R
1
O
n
z
TMSO
O
Ar
TMST
HH
R
2
O
R
R
3
R
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H H
OMs
2
R
i)
N
PMP
O
B
H H
N
PMP
i) DBU, benzene.
1
R
2
R
O
O
SCHEME 8.45 Synthesis of isochromans.
MeO
CHO
N
Ar
O
O
MeO
Thz
H
N
i)
PMPHN
NHPMP
i) TMST.
R
MeO
O
O
2
NHAr
O
1
[4+2]
R
cycloaddition
O
H
Thz
1
R
2
R
PMPHN
+
O
O
H
MeO
N
O
Thz = thiazole
isomerizatio
R
R
Th
Ar
1
2
SCHEME 8.46 Synthesis of α-hydroxy acids.
2
R
O
N
O
3
NR
1
R
i)
3
O
NR
N
1
R
i)TBACN.
CN
NC
2
O
O
SCHEME 8.47 Preparation of 5-arylimino-pyrrolidin-2-ones.
stable imino nitrile (Scheme 8.47). A nucleophilic attack by the nitrogen with the imine group created
the heterocyclic product.
H
3
NR
N
1
R
36
A similar ring enlargement reaction was reported during the conversion of N-benzyl-4-phenyl-2-
NC
2
R
O
N
O
3
NHR
1
R
H
2
R
O
O
NR
3
2
R
O
CN
N
1
O
NR
N
1
azetidinones to γ-lactams via C4–N1 bond cleavage of β-lactams by a base-catalyzed process.41 The
formation of a resonance stabilized benzylic carbanion, and its subsequent rearrangement into an iminic
carbanion through C4–N1 bond cleavage was involved. This underwent a Michael type 5-endo ring
closure to form the γ-lactams (Scheme 8.48). The high reactivity of the -N-benzyl group was responsible
for the success of this reaction.
260 Chemistry and Biology of Beta-Lactams
O
R
i) a) Lawesson's
ii) DP
Ph
Ph
R
1
R
2
i) LDA, THF.
https://t.me/med1917
2
1
R
R
Ph
N
O
LDA
2
1
R
Ph
N
O
Li
SCHEME 8.48 Synthesis of densely substituted γ-lactams.
Ph
Ph
i)
O
N
H
2
1
R
Ph
R
Li
O
Ph
N
EtS
Ph
O
DPP
Ph
O
Ph
N
Ph
O
1
i)
R
1
R
NH
2
R
SEt
+
N
2
R
O
Ph
Ph
1
R
SEt
Ph
N
2
R
ii)
Ph
1
R
N
SEt
2
R
SEt
2
R
1
R
N
O
2
R
1
R
O
P, MeCN.
reagent; b) EtOBF4;
SCHEME 8.49 Synthesis of highly functionalized 7-azabicyclo[4.2.1]nonene.
Ph
Ph
1
R
N
SEt
2
The 4-vinyl-substituted β-lactams were converted into vinyl-thioxo analogues using Lawesson’s
reagent. A subsequent reaction of vinyl derivative (thioether) with diphenylcyclopropenone (DPP)
resulted in the formation of 7-azabicyclo[4.2.1]-nonene in good yield.42 The pathway involved the reaction of 4-vinyl-2-thioxo analogues with DPP to give azabicyclo[3.2.0]-heptane. This stereochemical
nature favored the [3,3]-sigmatropic shift to form the nal bridged product (Scheme 8.49).
2-(Haloalkyl)-azetidines obtained from the reduction of substituted β-lactams were employed for the synthesis of 3,4-cis-disubstituted-pyrrolidines and piperidines.43 The nitrogen participated in an intramolecular
nucleophilic reaction to expel the halide. This process created the azetidinium intermediate. Ring opening of
bicyclic azetidinium intermediates by diverse nucleophiles (hydroxide, cyanide, azide, and halide) resulted
in the formation of various substituted pyrrolidine and piperidine heterocycles (Scheme 8.50).
8.3.5 Cleavage of Two Bonds in the β-Lactams
A conversion of N-arylidene or alkylidene-amino-2-azetidinones to vinyl ethers was conducted with
high degree of stereoselectivity by ozone and reduction.44 A reaction of the starting compound with
261Beta-Lactams as Synthons for Diverse Heterocycles
Nu
R
i) Al
R
2
i) a)
3
https://t.me/med1917
2
R
O
O
2
R
O
O
Cl
N
1
R
Br
N
1
R
H2Cl; ii) MeCN; iii) NaOH.
2
R
i)
O
2
R
i)
O
Cl
or
ii)
iii)
N
1
R
2
R
O
N
Cl
Br
ii)
N
1
R
2
R
O
Br
SCHEME 8.50 Preparation of 3,4-cis-disubstituted pyrrolidines and piperidines.
3
R
O
1
R
H
i)
N
N
O
4
R
2
R
O
R1R
H
+
R
3
R
H
1
R
H
N
1
4
CH2OH
2
O
N
1
R
Br
2
R
O
N
1
R
O
3
2
R
3
R
O
1
R
O
H
N
N
O
4
-
R
CH2OH
O
4
R
O
path
path
H
O3; b) NaBH4, MeOH.
2
R
3
R
O
1
R
H
N
N
O
A
O
B
R
3
R
2
O
1
R
O
O
-
N
N
2
R
H
O
R1R
-
CO
2
3
R
2
R
N
O
2
1
R
O
O
SCHEME 8.51 Synthesis of vinyl ethers.
ozone followed by a sodium borohydride reduction produced the product in good yield (Scheme 8.51).
The functional group connected to the –N of the β-lactam ring was suitable for a reaction with ozone.
An electrophilic addition of ozone to the exocyclic imine double bond created the ozonide. Reduction
of the ozonide by sodium borohydride eliminated primary alcohol and formed heterocycle, which upon
releases of nitrogen formed the zwitterion. This then underwent carbon dioxide elimination to give the
olen. In another route, ozonide produced N-nitroso-β-lactam, which on rearrangement produced the
heterocycle.
Another example following this method involved a double-bond cleavage45 during the synthesis of
olen from azetidine. The azetidine was prepared from the chloroalane reduction of β-lactam ring. An
initial coordination of the nitrogen electron pair to the aluminum made the C–N bond unstable, and this
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