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Файл:Ординатура / Хирургия / Библиотека им академика М.И. Перельмана / Книга_5671_Библиотеки_им_академика_М_И_Перельмана
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151Efavirenz
Cl
O
3
(1R,2S)-N-pyrrolidinylnorephedrine
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H
N
O
NH
2
X X'
O
OH
Cl
CF
3
O
O
C(CH3)
3
CF
3
C(CH3)
3
NH
NH
Cl
CF
O
3
Cl
O
CF
3
OCH2CH
Cyclopropylacetylene is formed from cyclopropyl methyl ketone.
O
NH
2
O
Cl
CF
3
O
Cl C(CH3)
NH
3
2
Cl
3
CH
Extended Discussion
(1R,2S)- N- Pyrrolidinylnorephedrine is the preferred ligand for the enantioselective addition of the Grignard reagent to the
ketone. Draw the structures of a retrosynthetic analysis of this ligand. Include the structures of the retrosynthetic analysis
of any organic starting material(s) from petrochemical or biochemical raw materials.
HO
Ph
N
CH
3
E152
H
2
OH
O
NC
Ph
Ph H
Route A
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Eflornithine
Anti- infective Medicines/Antiprotozoal Medicines/Antitrypanosomal Medicines/African Trypanosomiasis
A difluoromethyl group is often introduced by reaction of chlorodifluoromethane (HCFC-
N
2
H2N CHF
Discussion. Eflornithine is a 1 : 1mixture of (R)- and (S)- enantiomers. The carboxylic acid is released in the final step by
hydrolysis of the ester. The amine at C5 is formed by hydrogenation of the nitrile. The amine at C2 is released by hydrolysis
of the benzaldehyde imine. The N- protected α- amino ester is alkylated by reaction with chlorodifluoromethane (HCFC-
22). The N- protected α- amino ester is alkylated by reaction with acrylonitrile (Michael Addition). The N- protected
α- amino ester is formed from glycine ethyl ester and benzaldehyde. Benzophenone is used in place of benzaldehyde in the
parallel sequence in alternative Route B.
22) with a nucleophile.
O
H2N
H2N CH F
NC NC
H2N CH F
O
OCH2CH
N
CHClF
2
O
2
3
OH
2
OCH2CH
3
NC
N
Ph
O
H2N
OCH2CH
H2N CHF
Ph
3
O
O
N CH F
O
OCH2CH
2
OCH2CH
2
NH
2
O
3
3
OCH2CH
3
In Route C, the carboxylic acid is released in the final step by hydrolysis of the ester. Both amines are released by hydrolysis of the benzaldehyde imines. The N- protected α- amino ester is alkylated by reaction with fluoroform (HFC- 23). The
N- protected α- amino ester is formed from - ornithine methyl ester and benzaldehyde. - Ornithine methyl ester is formed
from - ornithine (Fischer Esterification). - Ornithine is produced by microbial fermentation. This may be the only
example of a racemic drug manufactured from a single enantiomer starting material!
Emtricitabine 153
Ph H
Route C
NH
F
O
HO
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H2N
H2N
O
OH
H2N CHF
NPh
N CHF
Ph
NH
2
O
OCH
3
2
O
OCH
3
2
O
H2N
H2N CH F
NPh
Ph
H2N
L-ornithine
N
NH
O
OCH
3
2
O
OCH
3
CHF
3
O
OH
2
CH
OH
3
Extended Discussion
List the pros and cons for Routes A, B, and C. Is one route preferred?
Emtricitabine
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Integrase Inhibitors
2
N
O
S
N
Discussion. The primary alcohol of emtricitabine is formed by reduction of the ()- menthyl ester in the final step. (How
is ()- menthol separated from emtricitabine?) The rings are joined by nucleophilic displacement of the acetate from the
(5R)- acetoxy- 1,3- oxathiolane- (2R)- carboxylate by N1 of the essential medicine flucytosine (5- fluorocytosine) (Silyl–
Hilbert–Johnson Reaction). (The desired product, with both oxathiolane ring substituents cis, and the trans- side product
are both formed. What is the highest ratio of cis- product to trans- side product? What reaction conditions are associated
with the highest ratio of cis- product to trans- side product?) The acetate is formed from the alcohol and acetyl chloride.
A chiral auxiliary can be used to control the stereochemical outcome of a reaction
which forms a nearby chiral carbon. A chiral auxiliary strategy for creating a chiral
carbon is cost- effective when the auxiliary is inexpensive and when the auxiliary
can be recovered after the chiral carbon is formed.
E154
HO
NH
3
3
O
CH
CH
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(How is (1R- ()- menthyl (5R)- acetoxy- 1,3- oxathiolane- (2R)- carboxylate separated from the mixture of stereoisomers
produced?) The (5R)- hydroxy- 1,3- oxathiolane- (2R)- carboxylate is formed by the condensation of (1R)- ()- menthyl glyoxalate hydrate with 1,4- dithiane- 2,5- diol.
2
N
F
CH
NH
2
N
F
CH
3
O
O
S
N
O
O
S
O
CH
CH
3
3
O
O
25
CH
S
CH
3
O
Cl
3
O
CH
3
3
OH
CH
CH
NH
2
F
N
CH
O
3
N
O
O
CH
3
CH
3
N
H
flucytosine
O
S
O
CH
3
O
3
HO
S
O
OH
O
S
OH
OH
CH
(1R)- ()- Menthyl glyoxalate hydrate is formed by ozololysis of ()- dimenthyl fumarate. The fumarate diester is formed
from maleic anhydride and ()- menthol.
CH
3
O
OH
O
OH
CH
3
3
CH
CH
3
CH
3
O
3
OO
CH
CH
3
O
CH
3
3
CH
3
O
CH
3
O
O
O
CH
CH
3
CH
3
CH
3
OH
3
CH
3
CH
3
O O
O
3
(-)- me nthol
Enalapril 155
CH
O
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Extended Discussion
The key C-N bond formation in the synthesis of emtricitabine can be accomplished using other leaving groups. Select
one alternative leaving group. What is the highest ratio of cis- product to trans- product and what reaction conditions are
associated with the highest ratio?
Enalapril
Cardiovascular Medicines/Medicines Used in Heart Failure
CH2O
3
O
H
N
CH
O
N
3
OH
An amide linkage between two α- amino acids in a peptide is often
formed by converting one α(NCA) then using the NCA to N-
amino acid.
α-
amino acid to an N- carboxyanhydride
acylate nitrogen of the other
Discussion. Enalapril is manufactured from the amino acids - alanine and - proline by two routes. In Route A, the
amide is formed in the final step by reaction of the N- carboxyanhydride with - proline. - Proline is produced by fermentation. The N- carboxyanhydride is formed from the α- amino acid (S,S)- N- (1- ethoxycarbonyl- 3- phenylpropyl)alanine.
(List the reagents and conditions used to make this NCA.) (S,S)-N- (1- ethoxycarbonyl- 3- phenylpropyl)alanine is separated
from the (R,S)- diastereomer by crystallization. The mixture of (S,S)- and (R,S)- diastereomers is formed by hydrogenation
of the (S,S)- and (R,S)- diastereomers of N- (1- ethoxycarbonyl- 3- oxo- 3- phenylpropyl) alanine. The (S,S)- and (R,S)-
diastereomers of N- (1- ethoxycarbonyl- 3- oxo- 3- phenylpropyl)alanine are formed by conjugate addition of
- alanine to ethyl 3- benzoylacrylate. (What is the highest SS to RS ratio reported for the conjugate addition? What
conditions are associated with this high ratio?) Ethyl 3- benzoylacrylate is formed from glyoxylic acid, acetophenone, and
ethanol (Aldol Condensation).
E156
CH
O
CH
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3CH2
3CH2
O
O
H
N
O
CH
O
N
3
OH
CH3CH2O
O
O
CH
O
3
N
HO
N
O
H
L-proline
O
H
N
O
S,S
CH
O
OH
3
CH3CH2O
O
H
N
O
OH
CH
3
S,Sand R,S
O
3CH2
O
3
OH
H
O
O
CH3CH2O
O
H
N
O
O
OH
O
CH
3
CH3CH2O
H2N
CH
3
L-alanine
OH
HO
O
CH
CH
In Route B, the (S,S,S)- diastereomer is separated from the mixture of (S,S,S)- and (R,S,S)- diastereomers in the final step
by crystallization of the maleate salt. Both diastereomers are formed in the reductive amination of ethyl
2- oxo- 4- phenylbutanoate with the dipeptide - ala- - pro. (What is the highest SSS to RSS ratio reported for the reductive
amination? What conditions are associated with this high ratio?) The amide in dipeptide - ala- - pro is formed by reaction
of - alanine N- carboxyanhydride with - proline. - Alanine N- carboxyanhydride is formed from - alanine. (List the reagents and conditions used to make this NCA.)
157Enalapril
CH
O
O
CH
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3CH2
3CH2
O
H
N
O
CH
O
N
3
OH
CH3CH2O
S,S,S
O
H
N
O
N
CH
3
S,S,S and R,S,S
OH
HO
O
O
O
H2N
CH
O
O
OH
O
L-proline
N
3
O
L-ala-L-pro
HN
N
H
O
CH
3
L-ala NCA
O
N
H
O
2
CH
OH
3
L-alanine
Ethyl 2- oxo- 4- phenylbutanoate is formed by addition of 2- phenylethylmagnesium bromide to diethyl oxalate (Grignard
Reaction
). (Draw the structures of two side products formed in this reaction. How is ethyl 2- oxo- 4- phenylbutanoate sepa-
rated from these side products?) The Grignard reagent is formed from (2- bromoethyl)benzene.
MgBr
3
Br
O
O
OCH2CH
CH3CH3O
OCH2CH
3
O
O
Extended Discussion
List the pros and cons for both routes. Is one route preferred?
E158
OH
H
O
O
O
OBn
MMTr
OBn
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Entecavir
Anti- infective Medicines/Antiviral Medicines/Antihepatitis Medicines/Medicines for Hepatitis B/Nucleoside/
Nucleotide Reverse Transcriptase Inhibitors
A nucleoside analog is often formed by displacement of a leaving group on the
HN
N
sugar by nitrogen of the heterocycle. Oxygenalcohols, and carboxylic acids. The leaving group is usually geminal to another oxygen atom, allylic, or is the oxygen of an epoxide.
N
2
HO
N
N
Discussion. The alcohols are released in the final step by cleavage of the benzyl ethers. Cleavage of benzyl and
4- monomethoxytrityl (MMTr) protecting groups reveals the guanine. The alkene is formed by reaction of the cyclopentanone with a reagent produced from dibromomethane, zinc, and tetrahydrofuran (Nysted Reagent). The cyclopentanone
is formed by oxidation of the secondary alcohol. The purine amino group is protected by reaction with 4- monomethoxytrityl
chloride prior to the alcohol oxidation. The secondary alcohol and C-N bond joining the two rings form in the key step by
ring- opening of the α- face epoxide by N9 of 2- amino- 6- (benzyloxy)purine.
based leaving groups include water,
CH2Br
H2N
HO
HN
BnO
OH
OBn
N
N
N
MMTr
N
O
OBn
N
NH
N
2
H2N
BnO
HN
N
N
H
N
N
H
HN
N
OBn
N
N
2
N
OBn
OBn
N
OBn
BnO
OH
N
N
N
N
MMTrHN
MMTrCl
O
N
BnO
N
BnO
N
OBn
OBn
NH2N
OBn
N
N
N
N
OH
The benzyl ether of 2- amino- 6- (benzyloxy)purine is formed by displacement of chloride by benzyl alcohol.
H
Bn
H
X
Pg
X
Pg, Pg' = hydroxyl protecting groups
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2- Amino- 6- chloropurine is formed from guanine.
159Entecavir
OBn
N
N
2
N
N
N
H
N
H2N
Cl
N
BnOH
N
N
H
H2N
HN
O
N
guanine
N
N
H
On the epoxide reaction partner, the α- face benzyl ether is formed by O- alkylation of the alcohol (Williamson Ether
Synthesis
). The α- face epoxide is formed epoxidation of the alkene. The α- face alcohol is formed by hydroborationoxidation of the 5- benzyloxymethyl- 1,3- cyclopentadiene. The 5- substituted- 1,3- cyclopentadiene is formed from cyclopentadiene and benzyl chloromethyl ether.
O
O
Bn
BnO
O
OH
BnBr
BnO
O
OH
BnO
BnOCH2Cl
Extended Discussion
Draw the structures of a retrosynthetic analysis of one alternative route to entecavir via displacement of an allylic oxygen
leaving group. Include the structures of the retrosynthetic analysis of any organic starting material(s) from petrochemical
or biochemical raw materials.
N
N
2
'O
N
OPg
N
N
H2N
Pg'O
N
N
OPg
N
N
H
OR
E160
OH
3
OH
3
HO
HO
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Ephedrine
Anesthetics, Preoperative Medicines and Medical Gases/Local Anesthetics
In a molecule with two adjacent chiral carbons, one chiral carbon is often
used to direct the formation of the second.
CH
H
N
CH
3
Discussion. Ephedrine is an alkaloid isolated from plants of the genus Ephedra (Ephedra equisetina, Ephedra
vulgaris
). Ephedrine is also manufactured by both semisynthetic and synthetic routes. In the preferred semisynthetic route,
ephedrine is formed in a single step from (R)- 1- hydroxy- 1- phenylacetone (also known as (R)- phenylacetylcarbinol) and
methylamine by reductive amination. (R)- 1- Hydroxy- 1- phenylacetone is produced from benzaldehyde by fermentation.
OH
CH
OH
H
N
CH
3
3
CH
2
O
3
O
H
CH3NH
Extended Discussion
Draw the structures of the retrosynthetic analysis of one synthetic route to ephedrine. Include the structures of the
retrosynthetic analysis of any organic starting material(s) from petrochemical or biochemical raw materials.
Epinephrine
Antiallergics and Medicines Used in Anaphylaxis
Cardiovascular Medicines/Antiarrhythmic Medicines
Opthalmological Preparations/Mydriatics
Medicines Acting on the Respiratory Tract/Antiasthmatic and Medicines for Chronic Obstructive Pulmonary Disease
H
N
CH
Discussion. Epinephrine is produced from 2- chloro- 3′,4′- dihydroxyacetophenone by three routes. In Route A, the
(R)- alcohol is formed by asymmetric hydrogenation of the ketone. The α- aminoketone is formed by chloride displacement
by methylamine.
A secondary benzylic alcohol is often formed by hydrogenation of a
ketone.
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