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_5429_Библиотеки_им_академика_М_И_Перельмана
.pdf
Latanoprost 231
PP
THPO
HO
O
https://t.me/medicina_free
Discussion. In one preferred route, latanoprost is formed in nine steps from PPB- Corey Lactone. In the final step, the ester
is formed by alkylation of the carboxylate with 2pyranyl (THP) ether. The C5–C6 alkene is formed by reaction of the C6 aldehyde with the ylid from (4enylphosphonium bromide (Wittig Reaction). The aldehyde is formed in situ by ring-
iodopropane. The C15 alcohol is released by hydrolysis of the tetrahydro-
carboxybutyl)triph-
opening of the lactol. The lactol is
formed by reduction of the lactone. The C11 alcohol is also released during the lactone reduction or by hydrolysis of the
4-
phenylbenzoyl (PPB) ester after the reduction.
O
(CH3)2CHI
OH
HO
CH
5
6
9
3
O
CH
HO
3
HO
HO
11
O
14
15
13
HO
O
OH
THPO
O
HO
HO
HO
OH
O
Ph3P
Br
THPO
O
OH
BO
The C13–C14 alkene is reduced. The C15 alcohol is protected as the THP ether. The C15 alcohol is formed by reduction of
the ketone. The C13–C14 alkene is formed by reaction of the aldehyde with a phosphonate ester (H orner–Wadsworth–
Emmons Reaction). The aldehyde is formed by oxidation of the C13 alcohol of PPB- Corey Lactone.
L232
PPBO
O
O
PPBO
PPBO
PPB-Corey Lactone
Ph
https://t.me/medicina_free
O
THPO
O
O
O
HO
O
O
H
CH3O
CH3O
P
O
O
O
PPBO
THPO
O
O
PPBO
O
O
O
OH
O
PPBO
(4- Carboxybutyl)triphenylphosphonium bromide is formed from 5- bromopentanoic acid (5- bromovaleric acid).
Bromovaleric acid is formed from δ- valerolactone.
5-
P OH
3
Br
O
PPh
3
Br OH
O
O
O
Latanoprost 233
CH
CH
X=Br,I
CH
CH
O
https://t.me/medicina_free
The phosphonate ester, dimethyl (2- oxo- 4- phenylbutyl)phosphonate, is formed from the α- iodoketone and trimethyl phos-
phite (Michaelis–Arbuzov Reaction). The α-
bromoketone is formed by bromination of 4- phenyl- 2- butanone.
The α-
iodoketone is formed from the α- bromoketone (Finkelstein Reaction).
O
3
P
O
3
O O
O
P(OCH3)
X
3
CH
3
O
The condensation of dimethyl methylphosphonate with ethyl 3- phenylpropanoate is an alternative route to dimethyl
(2-
oxo- 4- phenylbutyl)phosphonate. (List the pros and cons for both routes to the phosphonate ester. Is one route
preferred?)
O
3
P
O
3
O
O
CH3O
P
CH3O
CH
CH3CH2O
3
O
PPB- Corey Lactone is manufactured in ten steps from cyclopentadiene. The C13 alcohol is released by hydrogenolysis of the
benzyl ether. The C10 iodide is removed by reduction. The C11 alcohol is protected as an ester by reaction with 4chloride (PPB-
Cl). 4- Phenylbenzoyl chloride is formed from 4- phenylbenzoic acid. The lactone is formed by iodolactonization
phenylbenzoyl
from the C6 carboxylic acid and C9–C10 alkene. The C6 carboxylic acid and C11 alcohol are formed by hydrolysis of the lactone.
The lactone is formed by oxidation of the ketone (Baeyer–Villiger Oxidation). The ketone is formed by oxidative decarboxyla-
tion of the carboxylic acid. The carboxylic acid is released by ester hydrolysis. (How is the chiral auxiliary -
pantolactone recovered and recycled?) The bicyclo[2.2.1]heptane ring is formed by cycloaddition of the cyclopentadiene and the acrylate ester
(Diels–Alder Cycloaddition). (Draw the structures of the two diastereoisomers formed by endo- cycloaddition. What is the
diastereoselectivity of the cycloaddition?) 5-
[(Benzyloxy)methyl]cyclopentadiene is formed by alkylation of cyclopentadiene
with benzyl chloromethyl ether. The acrylate ester is formed from the alcohol (- pantolactone) and acryloyl chloride. Acryloyl
chloride is formed from acrylic acid. (Draw the structure of one alternative alcohol used as the chiral auxiliary in the synthesis
of a Corey Lactone.)
L234
O
O
O
I
Ph
https://t.me/medicina_free
PPBO
HO
CH2O
O
9
10
11
O
PPBCl
6
13
OH
O
OCH2Ph
HO
PPBOH
PhCH2O
PPBO
OCH2Ph
O
I
OCH2Ph
PhCH2O
OH
O
PPB
O
OCH2Ph
O
PhCH2O
O
O
OCH2Ph
O
PhCH2OCH2Cl
OHO
O
CH
OR*O
O
O
O
3
CH
3
HO
CH
3
(R)-pantolactone
CH
Cl
O
O
O
3
OH
O
Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to latanoprost that does not use a Corey
Lactone. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical or
biochemical raw materials.
Ledipasvir
3
OCH
CH
3
OCH
CH
https://t.me/medicina_free
Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis C/Other Antivirals
3
Ledipasvir 235
CH
3
N
3
O
HN
O
NH
F F
N
N
H
O
O
N
NH
CH
N
CH
3
CH3O
A 2,5- disubstituted imidazole is formed by reaction of an α- acyloxyketone with ammonium acetate. Four C–N bonds
of the imidazole ring are formed in the reaction.
Discussion. The amide bonds are formed in the final step by reaction of the amines with N- (methoxycarbonyl)- - valine
(Moc-
- valine). The amines are both released by hydrolysis of the N- tert- butoxycarbonyl (Boc) carbamate.
3
CH
3
N
3
O
HN
O
NH
N
F
F
N
H
O
O
N
CH3O
NH
CH
N
CH
3
N
H
NH
N
N
NH
Boc
F F
F
OCH
3
NHO
HO
CH
3
N
H
N
N
H
F
N
Boc
O
CH
3
N
N
H
L236
Boc
3
https://t.me/medicina_free
A biaryl C–C bond is formed from the arylboronate ester and the bromofluorene (Suzuki–Miyaura Coupling).
N
Boc Boc
NH
N
F
F
N
N
N
H
F F
N
N
NH
N
Br
N
H
O
B
O
CH
CH
3
Boc
N
The aryl boronate ester is formed from bis(neopentyl glycolato)diboron and the 6- bromobenzimidazole. The benzimidazole ring is formed by ring4-
bromo- 1,2- diaminobenzene with the carboxylic acid. 1,2-diamino-4-bromobenzene is formed by bromination of
ortho-
phenylenediamine.
closure of an α- aminoanilide. A mixture of two α- aminoanilides is formed by reaction of
N
Boc
N
Boc
N
Boc
H
N
O
N
H
N
O
H2N
H
N
O
H2N
B
O
Br
Br
CH
CH
3
3
N
Boc
CH
CH
3
3
O
N
Boc
O
O
OH
O
B
B
O
H2N
H2N Br
H
N
N
CH
3
CH
3
HO
HO
H2N
H2N
Br
CH
CH
3
3
Ledipasvir 237
3
CH
F F
Br
Br
Br
https://t.me/medicina_free
The carboxylic acid is formed by ester hydrolysis. The secondary amine is protected as the Boc- carbamate. The secondary amine
is released by hydrogenolysis of the NCycloaddition of the imine formed from (R)1,3-
cyclopentadiene forms the azabicyclo[2.2.1]heptene (aza- Diels–Alder Cycloaddition).
benzyl tertiary amine and the alkene on the azabicyclo[2.2.1]heptene ring is reduced.
α- methylbenzylamine and methyl glyoxalate methyl hemiacetal with
OH
N
Boc
N
3
O
OCH
3
O
Ph N
Ph
CH
N
Boc
3
OCH
3
O
OCH
3
O
Ph
CH3O
N
H
(Boc)2O
CH
3
NH
OH
OCH
O
2
OCH
3
O
The imidazole ring of the 2- bromofluorene used in the aryl–aryl coupling is formed by reaction of the α - acyloxyketone
with ammonium acetate. The α-
acyloxyketone is formed from the α- chloroketone by chloride displacement by the car-
boxylate salt.
N
N
H
Boc
N
F F
F F
Boc
O
O
Cl
O
N
O
Boc
N
KO
O
L238
F F
Br
https://t.me/medicina_free
The α- chloroketone is formed by reaction of 2- chloro- N- methoxy- N- methylacetamide (a Weinreb Amide) with a Grignard rea-
gent. The amide is formed from chloroacetyl chloride and N,O-
dimethylhydroxylamine. The Grignard reagent is formed from the
iodofluorene by a metal exchange with isopropylmagnesium chloride. Isopropylmagnesium chloride is formed from
chloropropane. 2- Bromo- 9,9- difluoro- 7- iodofluorene is formed by iodination and then fluorination of 2- bromofluorene.
2-
N
OCH
3
CH
O
Cl
CH
3
NH
3
3
MgCl
I
CH
OCH
3
CH
3
3
Br
Cl
Cl
CH
3
O
F
F
Br
F F
Br
MgX
Br
CH
I
O
Cl
Cl
The carboxylate salt is formed from the carboxylic acid, (S)- 5- (tert- butoxycarbonyl)- 5- azaspiro[2.4]heptane- 6- carboxylic acid. The
enantiomer is obtained by resolution. The racemic carboxylic acid is formed by ester hydrolysis. The pyrrolidine ring is formed
(S)by N-
and C- alkylation of N- ( tert- butoxycarbonyl)glycine ethyl ester. The dialkylating agent (X=leaving group) is formed from
bis(hydroxymethyl)cyclopropane. (Which leaving group is preferred?)
1,1-
Boc
N
KO
HO
O
Boc
N
CH3CH2O
O
Boc
O
CH3CH2O
N
HO
NHBoc
O
X
X
O
HO
Boc
N
OH
Extended Discussion
Draw the structures of the retrosynthetic analysis of an alternative route to (S)- 5- (tert- butoxycarbonyl)- 5- azaspiro[2.4]heptane- 6carboxylic acid that does not utilize 1,1- bis(hydroxymethyl)cyclopropane. Include the structures of the retrosynthetic analysis of any
organic starting material(s) from petrochemical or biochemical raw materials. List the pros and cons for both routes and select one
route as the preferred route.
Leuprorelin 239
pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHCHCH
23
HO
α
pGlu-His-Trp-Ser-Tyr-D-Leu-Leu-Arg-Pro-NHCH2CH
pG
2CH3
https://t.me/medicina_free
Leuprorelin
Hormones and Antihormones
A polypeptide is often constructed from the constituent amino
acids by forming the amide bonds. The amide bonds are
formed via a solidpeptide synthesis, or a hybrid approach using both solidand solution-
Discussion. To simplify polypeptide synthetic schemes, the amino acids are represented by acronyms and are assumed to
be in the Polypeptide amino acid sequences are drawn with the CN-
terminal amino acid (amino group) on the left. (Create a Table of the acronyms used in the analysis. Draw the structure
configuration. Protecting groups used in construction of the polypeptide are also represented by acronyms.
terminal amino acid (carboxylic acid) on the right and the
associated with each acronym.)
phase peptide synthesis, a solution- phase
phase
phase methods.
O
OH
NH
2
L-tyrosine
H-Tyr-OH
Hofα-NHOHofCOOH
CH
CH
CH
3
3
3
O
protecting group
for
Fmoc-Tyr(tBu)-OCH
-amino
O
OCH
HN
O
O
protecting group
off the peptide chain
3
3
Construction of leuprorelin by solid- phase peptide synthesis, by solution- phase peptide synthesis, and by the hybrid
approach are all described in patents. In a preferred hybrid approach, the final step is a global deprotection of the five functional groups which are off the peptide chain. The final amide bond is formed between the carboxylic acid of a protected
pentapeptide and the amine of a protected tetrapeptide.
3
pGlu-His(Trt)-Trp(Boc)-Ser(t Bu)-Ty r( tB u)-D-Leu-Leu-Arg(pbf)-Pro-NHCH2CH
3
lu-His(Trt)-Trp(Boc)-Ser(tBu)-Tyr(tB u)-OHH-D-Leu-Leu-Arg (pbf)-Pro-NHCH
The protected tetrapeptide is constructed from two dipeptides by solution- phase peptide synthesis. Dipeptide Fmoc- - LeuH- Leu- OH is formed by reaction of the carboxylic acid of Fmoc- - Leu- OH with the amino group of leucine (H- Leu- OH).
Dipeptide Fmoc- Arg(pbf)- Pro- NHCH
amine of proline N- ethylamide (H- Pro- NHCH
is formed by reaction of the carboxylic acid of F moc- Arg(pbf )- OH with the
2CH3
). The terminal amine of this dipeptide is released by Fmoc- deprotection.
2CH3
L240
Fm
Fm
H-D- Le u-Leu-Arg(pbf) -P ro-NHCH2CH
3
pG
pG
er
Fm
Fmoc-Tyr(tBu)-OH Cl-Polymer
pGlu-His(Trt)-Trp(Boc)-Ser(t Bu)-Tyr(tBu)-OH
https://t.me/medicina_free
The central amide bond of the tetrapeptide is formed by reaction of the two dipeptides. The terminal amine of the tetrapeptide is released by Fmoc-
deprotection.
3
Fmoc-D -L eu-Leu-Arg(pbf)-Pro-NHCH2CH
oc-D -Leu-Leu-OHH-Arg(pbf )-Pro- NHCH2CH
oc-D -Leu-OHH-Leu-OHFmo c-Arg(pbf)-Pro -N HCH2CH
Fmoc-Arg(pbf)- OH H-Pro-NHCH2CH
3
3
3
The protected pentapeptide is constructed by solid- phase peptide synthesis. Starting with the polymer and the C- terminal amino
acid, the peptide chain is constructed rightride to form an ester link to the polymer. The amino group is released by Fmoction of this amino group with the carboxylic acid of the next Fmocformation are repeated three times to produce the polymer-
to- left. The carboxylate of the Fmoc- protected C- terminal amino acid displaces chlo-
deprotection. An amide bond is formed by reac-
protected amino acid. Fmoc- deprotection and amide bond
bound pentapeptide. The carboxylic acid is released when the penta-
peptide is released from the resin.
lu-His(Trt)-Trp(Boc)-Ser(t Bu)-Tyr(tBu)-O-P olymer
lu-OHH-His(Trt)-Trp(Bo c)-Ser(tBu)-Tyr(tBu)-O-Polymer
Fmoc-His(Trt)-Trp(Bo c)-Ser(tBu)-Tyr(tBu)-O-Polym
oc-H is(Trt)-OH H-Trp(Boc)-Ser(t Bu)-Tyr(tBu)-O-Polymer
Fmoc-Trp(Boc)-Ser(tB u)-Tyr(t Bu)-O-Polymer
Fmoc-Trp(Boc)-OH H- Ser(tBu)-Tyr(tBu)-O-Polymer
Fmoc-Ser(tBu)-Tyr(tBu)-O-Polymer
Fmoc-Ser(tBu)-OH H-Tyr(tBu)-O-Polymer
Fmoc-Tyr(tBu)-O-Polymer
Соседние файлы в папке Библиотека им академика М.И. Перельмана