Добавил:
Sekretar
kiopkiopkiop18@yandex.ru
t.me/Prokururor I Вовсе не секретарь, но почту проверяю
Опубликованный материал нарушает ваши авторские права? Сообщите нам.
Вуз:
Предмет:
Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5594_Библиотеки_им_академика_М_И_Перельмана
.pdf
202 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
SCHEME 6.16 Reagents and condition: a) Fmoc-L-Phe-OH, DIPCDI/DMAP/DMF; b) i) Pip, DMF; ii) Ns-Cl, Py, DMF;
c) i) Pip, DMF; ii) MeOC6H4CHO, (MeO)3CH; iii) NaBH3CN, (MeO)3CH; d) propylene oxide, ClCH2COCl; e) BTPP or
BEMP; f) Bzl-Br, MTBD; g) HS(CH2)2OH, DBU; h) BTPP; i) TFA/H2O.
SCHEME 6.17 Synthesis of different types of imines. Adapted with permission from Singh R et al. (1999). .
203Solid Support-Mediated Beta-Lactam Synthesis
https://t.me/med1917
SCHEME 6.18 Reaction of imines in which solid parts were bound with the carbonyl system. Adapted with permission
from Singh R et al. (1999).
TABLE 6.1
Yields and Purity from the Staudinger Reaction and Subsequent Steps
Source: Adapted with permission from Singh R et al. (1999).
204 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
have been used in the production of imines. The only heterocyclic amines that posed a problem were
those that were electron decient. As an example of how imines are formed in the context of this study,
four amines are used as examples. This communication illustrates that the carbamate formation step is
equally consistent with the use of either primary or secondary amines; however, only data on the use
of 3-amines are presented here. Accordingly, under the same conditions, 3,4,5-trimethoxybenzylamine,
aminomethylcyclopropane, and tetrahydrofurfurylamine have been observed to react.
A study reporting an efcient, stereoselective solid-phase synthesis of beta-lactams using Mukaiyama
salt for the Staudinger reaction has been published.
107
6.2.3 Synthesis of Beta-Lactams by Three-Component Reactions
Researches have reported that C-glycosyl-beta-lactams can be synthesized stereoselectively by a threecomponent Staudinger reaction (Scheme 6.19).36 The formation of chiral C-glycosylamines in CH2Cl2
was achieved by mixing the appropriate compounds
108, 109
with an excess of p-methoxybenzylamine. A
resin-supported sulfonyl chloride treatment was used to remove the unreacted amine from the reaction.
Therefore, solid support was not used as a component for this reaction. But the importance of this solid
support was established in this reaction. An acetoxy ketene was generated in situ and reacted with chiral
C-glycosylimines to produce C-glycosyl-beta-lactams as a result. By treating the excess ketene with
nucleophilic aminomethylated resin, excess ketene was removed from the mixture.
6.2.4 Synthesis of Beta-Lactams by Solid-Phase Reagents as Catalysts
It was demonstrated that by using a column asymmetric catalysis assembly, a catalytic asymmetric reaction process involving solid-phase reagents and catalysts was possible for the synthesis of beta-lactams
(Scheme 6.20).
110, 111
Through the use of SPOS (Scheme 6.21), a number of optically active 1,3,4,4-tetra-substituted beta-
lactams were synthesized and evaluated for their antitumor activity.
112
Several enantiopures as well as
derivatives of these molecules were prepared, and their in vitro activity was evaluated. The results of
preliminary experiments indicated that the (3S,4 S)-4- benzy l-1-p -meth oxybe nzyl- 3-met hyl-4 -meth oxyca
rbony l derivatives prepared from the amino acid Phe, as well as the Tyr analog, show anticancer activity comparable to that of doxorubicin against HT 29 cell lines. The authors have also prepared different derivatives of tetra-substituted beta-lactams as well as conducted SAR studies on these derivatives.
SCHEME 6.19 Reagents and condition: a) i) R1NH2, 4 Å MS, CH2Cl2, then B; ii) Et3N, R2OCH2COCl, 12 hours, then C.
SCHEME 6.20 The synthesis of beta-lactams using an asymmetric column catalysis method.
https://t.me/med1917
205Solid Support-Mediated Beta-Lactam Synthesis
SCHEME 6.21 Reagents and condition: a) i) 20% piperidine in DMF; ii) R1CHO, TMOF; iii) NaBH3CN, 1% AcOH,
TMOF; b) Cl3CCN, PPh3, propylene oxide; c) BTPP, DMF; d) TFA/H2O.
According to the results of this study, it has been concluded that the stereochemistry (3S,4S) and aromatic hydrocarbon-type substitution at C4α position are crucial for the activity.
There was a report that described the chiral synthesis of (3S,4S)-1,3,4,4-tetrasubstituted beta-lactams from amino acids using the SPS strategy (Scheme 6.22).
Staudinger reaction, which provides the beta-lactam products that were wanted. A facile cyclization of
chiral N-2-chloro alkanoyl amino acid derivatives is achieved by base-catalyzed cyclization without
the aid of any external chiral auxiliary or catalyst. The enantioselectivity of the reaction is determined
solely by the conguration of the 2-chloro alkanoyl substituent that is used. It is important to note that the
method can be applied equally well to any amino acid precursor linked to the resin, allowing preparation
of a large number of derivatives for high-throughput screening (HTS).
113
This is an excellent example of a non-
206 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
SCHEME 6.22 Reagents and condition: a) (S)-2- Cl(CH3)CHCOOH, Cl3CCN/PPh3P/THF, propylene oxide; b) BEMP,
BTTP, DMF; d) TFA/H2O.
FIGURE 6.4 Beta-lactam antibiotics with aryl glycine at the nitrogen of the ring.
6.2.5 Synthesis of β-Lactams from Unnatural Resin-Bound Amino Acids
A number of beta-lactam antibiotics, including amoxicillin, cephalexin, nocardicins, etc., have aryl glycine moieties
114, 115
incorporated into the C3 of the beta-lactam ring of the antibiotic (Figure 6.4). A
simple method for the rapid generation of libraries of cis-beta-lactam derivatives with unnatural amino
acids (such as aryl glycine derivatives) linked at the C3 of the azetidinone moiety has been demon-
116
strated
(Scheme 6.23).
As an initial step in the preparation of beta-lactam, excess of an acid chloride derived from Fmocprotected sarcosine was added to an in situ-synthesized resin-bound imine in a traditional manner. A
resin-bound compound was obtained by treating lactam with 30% piperidine in DCM and then treating it with glyoxylic acid and phenyl boronic acid in the multicomponent Petasis reaction.
117
Previously
reported solvent mixtures of DCM:HFIP (9:1) failed to yield satisfactory results due to competing hydrolysis of the resin-bound beta-lactam moiety, which caused undesirable results.
118
During this SP reaction,
it was determined that the optimum conditions would be the treatment of the resin-bound beta-lactam
with nine equivalents of glyoxylic acid and boronic acid at room temperature for 73 hours. As a result
of varying the substitution pattern in glyoxylic acid and boronic acid, several analogs were prepared
(Scheme 6.23). There was always a 3,4-cis-stereochemistry present in all of the products. There was a
wide variation in stereochemistry of the new alpha carbon associated with the substituent at C3, ranging
from 2:1 to 10:1, with the exception of one case, in which the product was solely one isomer. There has
been a general consensus on the mechanism for the Petasis reaction,
119, 120
and it is shown in Scheme 6.24.
It is well known that trans-3-alkyl-substituted beta-lactams inhibit the absorption of cholesterol
(Figure 6.5). As a matter of fact, accumulation of cholesterol in the blood serum plays a major role in
the development of coronary artery disease, one of the major life-threatening diseases of present time.
There are several trans-3-alkyl beta-lactams that have been well known as antihypercholesterolemic
agents, such as SCH48461
121
and SCH58235,
122
with the latter being approved by the US Food and Drug
207Solid Support-Mediated Beta-Lactam Synthesis
https://t.me/med1917
SCHEME 6.23 Reagents and condition: a) 30% piperidine in DMF; b) R1CHO, 1% AcOH in DMF; c) Et3N, CH2Cl2; d)
PhB(OH )2, CH2Cl2; e) 10% TFA in CH2Cl2.
SCHEME 6.24 Mechanism of Petasis reaction.
FIGURE 6.5 Examples of cholesterol absorption inhibitors (CAI)
208 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
Administration
124
et al.,
123
since 2002. Using the stereoselective synthesis approach developed by Delpiccolo
a library of trans-3-alkyl substituted beta-lactams has been synthesized in a stereoselective
manner.
Figure 6.5 Examples of cholesterol absorption inhibitors (CAIs).
A resin-bound imine was prepared using Fmoc-Gly-Wang resin and p-anisaldehyde by the authors. It
has been found, however, that the Staudinger reaction using the resin-bound imine with excess 5-phenyl
valeroyl chloride and triethyl amine (15 and 20 moles each, respectively) failed to yield the desired betalactam. In place of this, an oxazinone derivative, which was identied as a free ester, was obtained in a
yield of 40% (Scheme 6.25). In this case, it became evident that the unexpected product was formed as
a result of the formation of acyl ketene, which underwent a Diels–Alder-type reaction with the imine to
give the six-membered cyclic compound (Scheme 6.26).
After a number of unsuccessful attempts, it was nally able to synthesize the desired beta-lactam by
reuxing in toluene (12 hours) resin-bound imines with four and eight equivalents of acid chloride and
triethyl amine, respectively (Scheme 6.27). There are several reasons for the exclusive trans-stereochemistry of this molecule, including the bulky substituents at C3 of the beta-lactam ring and the lack
of electron-donating groups in the ketene part, which favor the isomerization of the intermediate prior to
SCHEME 6.25 Reagents and condition: a) Ph(CH2)4COCl, Et3N; b) i) 10% TFA in CH2Cl2; ii) CH2N2.
SCHEME 6.26 Description of ketene-imine mechanism.
SCHEME 6.27 Reagents and condition: a) R2CH2COCl, Et3N; b) i) 10% TFA; ii) CH2N2.
209Solid Support-Mediated Beta-Lactam Synthesis
https://t.me/med1917
SCHEME 6.28 Mechanism of the cycloaddition.
SCHEME 6.29 Reagents and condition: a) R2CH2COCl, Et3N or R2CH2COCl, Mukaiyama reagent, Et3N; b) 10% TFA.
SCHEME 6.30 Reagents and condition: a) Fmoc-NHOH, DIPEA; b) piperidine, DMF; c) (L)-Cbz-Ser-OH or (L)-Cbz-
Thr-OH, DMTMM, DIPEA, NMP; d) DEAD, PPh3, THF; e) SmI2, 0.1M in THF; f) 5% TFA in DCM.
ring closure (Scheme 6.28). It was also shown that substituents at the imine part do not inuence the nal
outcome of the stereochemistry. The in situ production of ketenes from glycine derivatives (using triethyl
amine) was sufcient, while the activation of aliphatic acid chlorides required the use of Mukaiyama
reagent (Scheme 6.27 and 6.29). This (Scheme 6.28) illustrates a model of the probable mechanism for
forming the trans-beta-lactam.
There are also several other trans-beta-lactam analogs that have been synthesized with varying substituents in all three possible positions of the ring (Scheme 6.29).
6.2.6 Synthesis of Beta-Lactams by Hydroxamate Approach
A new method for preparing beta-lactams on solid phase was developed by Meloni and Taddei
lizing the Miller hydroxamate approach in combination with the solid-phase method (Scheme 6.30).
125, 126
127
by uti-
128
210 Chemistry and Biology of Beta-Lactams
https://t.me/med1917
SCHEME 6.31 Reagents and condition: a) i) LiHMDS, THF; ii) R2CH=NPh; iii) H2O; b) 5% TFA; c) THF/DMF (5:2).
In this instance, the tethered complex was formed by rst coupling O-trityl-linked-hydroxylamine
129
to either L-Cbz-serine or L-Cbz-threonine. Following the cyclization of the compound in THF using
freshly distilled DEAD and PPh3, it was possible to obtain solid-bound beta-lactams. There were two
approaches that were used to remove the products from the resin.
6.2.7 Synthesis of Beta-Lactams Using Triazene Support
It has been demonstrated that beta-lactams can be synthesized in solid phase by using ester enolate-imine
condensation (Scheme 6.31).
T1-triazene linker,
131
130
As a result of the treatment with LiHMDS of the compound attached to
the ester enolate resulting from this treatment was condensed with various imines
in order to produce resin-bound beta-lactams. Following cleavage of the products from the resin with
5% TFA in CH2Cl2, diazonium salt was obtained which was heated at 60°C in THF/DMF to yield
beta-lactams.
It has been reported that a solid-phase synthesis of monocyclic beta-lactam derivatives could be
achieved.
132
Studies have been conducted in liquid phase concerning the solid-phase synthesis of monocyclic beta-lactams via enolate-ester condensation routes using triazene esters as model compounds in
order to study the liquid-phase synthesis of monocyclic beta-lactams. An ester was attached to benzylamine resin through a triazene linker containing their respective diazonium salts in order to form the
linker. In order to produce polymer-bound beta-lactams in different substitution patterns, immobilized
ester-enolates were reacted with various imines and imine precursors. As a result of the non-traceable
cleavage of the triazene linker, beta-lactams are obtained.
6.2.8 Solid-Supported Sulfonyl-Assisted Synthesis of Beta-Lactams
The [2+2] cycloaddition of chlorosulfonyl isocyanate (CSI) with vinyl ethers on solid phase to form
beta-lactam, which is then converted into oxacephanes by intramolecular cyclization, was shown to be
effective (Scheme 6.32).
133
By sulfonylating the compound with p-pivaloyloxybenzenesulfonyl chloride,
211Solid Support-Mediated Beta-Lactam Synthesis
https://t.me/med1917
SCHEME 6.32 Reagents and condition: a) PivOC6H4SO2Cl, Py, DMAP; b) Na/MeOH; c) Wang resin, DEAD, TPP; d) i)
CSI, Na2CO3; ii) Red-Al; e) BEMP or DBU.
SCHEME 6.33 Reagents and condition: a) BuLi; b) i) CSI, Na2CO3; ii) Red-Al; c) BEMP.
3-O-propenyl ether is obtained. As a result of removing the pivaloyl group by Na in MeOH, followed
by the attachment of the resultant phenol to the Wang resin by the Mitsunobu reaction procedure,
the vinyl ether is obtained. The reaction between CSI and vinyl ether resulted in the formation of betalactam, which was then subjected to intramolecular cyclization/cleavage in the presence of BEMP or
DBU in order to yield oxacephems and oxetane.
There has been a report from the same group
ethers bound to the Merrield,
6.34). In order to attach the vinyl ether to the Merrield resin, the Musicki and Wadlanski procedure has
been used.
140
It was found that [2+2] cycloadditions between CSI and resin-bound vinyl ethers, followed
by a cyclization/cleavage protocol, resulted in cephams and oxetane (Scheme 6.33).
The beta-lactam is synthesized by attaching vinyl ether to the NCPS resin followed by [2+2] cycloaddition. As a result of the treatment of beta-lactam with TBAI, mixtures of iodides were obtained.
As a result of cyclization of iodides under standard phase-transfer conditions, cephams were produced
(Scheme 6.34).
137
M P P,
138
or NCPS
136
that suggests the [2+2] cycloaddition of CSI and vinyl
139
resins using alkylsulfonyl linkers (Scheme6.33–
134, 135
Соседние файлы в папке Библиотека им академика М.И. Перельмана