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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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Docetaxel 141
CH
Cl
HO
HO SH
SH
HO
3
CH
O
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3
N
CH
N
O
3
O
O
O
HO
ClO
Cl
Cl
Dimercaprol
Antidotes and Other Substances Used in Poisonings/Specific
Thiols are often formed by displacement of a leaving group (Cl, Br, I, OTs, OMs) by hydrogen sulfide anion.
O
O
CH
NH
Cl
3
O
Cl
O
O
OH
Cl
Cl
Discussion. Dimercaprol (also known as British anti- Lewisite) is a 1 : 1mixture of (R)- and (S)- enantiomers. The 1,2- dithiol
is formed from 2,3-
SH
dibromo- 1- propanol by bromide displacement with hydrogen sulfide.
Br
SH
HO Br
Docetaxel
Antineoplastics and Immunosuppressives/Cytotoxic and Adjuvant Medicines
3
CH
3
O
O
NH
HO
CH
3
CH
3
O
O
HO
OH
CH
O
3
CH
OH
CH
3
3
H
O
O
H
O
CH
O
A single- enantiomer molecule with multiple chiral carbons is often formed by modification of a natural product which has
most or all of the chiral carbons already
in place. Taxanes are often formed by
modification of 10- deacetylbaccatin III.
10- Deacetylbaccatin III is a diterpenoid
isolated from the leaves of the European
yew Taxus baccata.
D142
CH
3
O
3
CH
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Discussion. Docetaxel is semisynthetic. The final step is release of the secondary alcohols at C7 and C10 by cleavage of the
trichloroethyl carbonates. (List other alcohol protecting groups used in alternative routes to docetaxel. How are the C7 and
C10 alcohols released using the alternative protecting groups?) The alcohol at C2′ and carbamate NH at C3′ are released
from the oxazolidine.
3
CH
3
O
O
NH
3′
CH
2′
3
CH
O
O
HO
3
13
10
OH
CH
O
9
3
CH
OH
CH
3
7
3
H
O
O
H
O
CH
3
HO
O
O
CCl
O
CH
O
O
3
CH
CH
3
CH
3
O
O
NH
CH
3
CH
3
O
O
O
OH
3
O
O
CH
3
3
H
O
O
O CCl
H
O
CH
3
HO
O
O
OCH
CH
3
O
O
CH
3
3
O
3
O
NO
CH
3
CH
O
Ph
OH
O
CCl
3
O
O
O
CH
3
3
CH
3
H
O
O
O CCl
H
O
O
CH
3
O
The ester at C13 is formed from the carboxylic acid and the secondary alcohol. The C7 and C10 secondary alcohols of
10- deacetylbaccatin III (10- DAB) are protected as trichloroethyl carbonates (troc). 10- Deacetylbaccatin III is a diterpenoid
isolated from the leaves of the European yew T. baccata.
Docetaxel 143
3
CH
3
OCH
10-deacetylbaccatin III
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CH
3
O
CCl
3
O
O
O
CH
CH
O
CH
3
3
O
3
O
N
CH
O
3
CH
CH
O
Ph
OH
O
CH
3
3
3
H
O
O
O
O CCl
H
O
CH
O
3
O
CCl
3
O
O
CH
H
3
O
O
3
O CCl
H
O
O
CH
3
O
OCH
3
CH
3
3
O
3
O
N
O
Ph
OH
CH
HO
3
O
O
CH
O
3
O
CH
OH
O
O
3
O
CH
H
OH
3
H
O
O
CH
3
O
Cl O
CCl
HO
CH
CH
3
3
CH
3
HO
OH
O
O
The carboxylic acid used in formation of the C13 ester is formed by hydrolysis of the methyl ester. The oxazolidine is
formed from (2R,3S)- N- ( tert- butoxycarbonyl)- 3- phenylisoserine methyl ester and para- anisaldehyde. (List other aldehydes
and ketones used to form oxazolidines in alternative routes to d ocetaxel. How are the alcohol at C2′ and carbamate NH at
C3′ released from these alternative oxazolidines?) The carbamate is formed by reaction of (2R,3S)- 3- phenylisoserine methyl
ester with di- tert- butyl dicarbonate.
D144
OCH
OH
CH
OCH
3
OH
OH
3
3
Ph
Ph
Br
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3
CH
CH
CH
3
3
O
CH
CH
CH
3
3
3
O
NO
Ph
OH
O
3
O
NO
Ph
O
OCH
3
CH
CH
3
CH
3
3
O
3
OCH
NH
Ph OC H
3
O
3
HO
O
3
OCH
NH
O O
O
2
O
Ph OC H
O
3
3
CH
OCH
3
CH
3
CH
3
In one preferred route to (2R,3S)- 3- phenylisoserine methyl ester, the ester is formed from the amide. The (2R,3S)- and (2S,3R)-
3- phenylisoserine amides are separated by resolution. The β- amino alcohol is formed by ring- opening of the epoxide of methyl
cis-
3- phenylglycidate with ammonia. The amide is formed by the reaction of the methyl ester with ammonia in the same pot. The
epoxide is formed from the threotrans-
3- phenylglycidate by hydrogen bromide. Methyl trans- 3- phenylglycidate is formed by condensation of benzaldehyde and
methyl chloroacetate (Darzens Reaction). (Methyl ciscis-
side product is present in the crude methyl 3- phenylglycidate? What is the fate of this side product in the next step?)
NH
Ph
H H
Br
H
O
2
OCH
3
OH
OH
OCH
3
O
O
OH
OCH
3
H
bromohydrin. The threo- bromohydrin is formed by the ring- opening of the epoxide of methyl
3- phenylglycidate is a side product of this condensation. How much of the
H H
OH
Ph
NH
2
Ph H
O
H
O
H
Ph
H H
NH
2
Ph
O
O
NH
Ph
NH
2
2
OH
OCH
Ph
H
NH
3
H
2
O
NH
Ph
2
O
O
O
OCH
3
Ph H
Cl
H
O
H H
O
H
O
OCH
OCH
O
O
OCH
H
3
Dolutegravir 145
CH
CH
3
ONa
O
CH
CH
CH
O
OH
O
F
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Extended Discussion
Draw the structures of the retrosynthetic analysis of one alternative route to (2R,3S)- 3- phenylisoserine methyl ester utilizing a Sharpless Dihydroxylation. 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.
Docusate Sodium
Medicines for Pain and Palliative Care/Medicines for Other Common Symptoms in Palliative Care
O
O
3
CH
3
O
O
S O
3
CH
A sulfonic acid is often
formed by conjugate addition of sodium bisulfite to
an acrylate ester.
Discussion. The sulfonate of docusate (dioctylsulfosuccinate) is formed in the final step by sodium bisulfite addition to the
maleate diester. The maleate diester is formed by reaction of maleic anhydride with 2-
CH
3
3
O
CH
3
CH
3
3
O
O
S O
ONa
O
O
CH
3
ethyl- 1- hexanol.
CH
3
CH
3
Dolutegravir
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Integrase Inhibitors
3
N
O
N
H
O O
O
O
CH
3
CH
3
O
O
OH
O
In a molecule with two chiral carbons, one chiral carbon
O
F
H
N
is often used to direct the formation of the second.
D146
CH
O
OH
F
3
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Discussion. The hydroxyl group is protected through the entire sequence as the benzyl ether. The final step is hydrogenolysis of the benzyl ether. The 1,3-
oxazine ring is assembled from the aldehyde, ester, and (R)- 3- amino- 1- butanol. The formation of the new chiral carbon at C2 of the oxazine ring is directed by the chiral carbon from the amino alcohol. The aldehyde
is formed by hydrolysis of an acetal.
3
HO
CH
N
O
H
CH
3
N
O
H
3
NH
CH3O
2
O H
N
O
O OBn
OBn
N
N
O
H
N
O
O
H
N
O
O
H
N
O
FF
FF
FF
O OBn
CH3O
O
N
O
CH3O OCH
F
H
N
The amide is formed from the selective reaction of one of two esters with 2,4- difluorobenzylamine. (Why is this ester more reactive?
Was this difference in reactivity known prior to the synthesis of dolutegravir?) The pyridine- 2,5- dicarboxylate is formed by reaction of
the 4- oxo- 4H- pyran- 2,5- dicarboxylate with 2- aminoacetaldehyde dimethyl acetal. The 4- oxo- 4H- pyran- 2,5- dicarboxylate is formed by
condensation of the aminomethylene acetoacetate with dimethyl oxalate (mixed Claisen Condensation). The aminomethylene
acetoacetate is formed from methyl 4- benzyloxy- 3- oxobutanoate and dimethylformamide dimethyl acetal. The benzyl ether is formed
by displacement of chloride from methyl 4- chloro- 3- oxobutanoate by benzyl alcohol (Williamson Ether Synthesis).
Dopamine 147
CH
CH
O OBn
3
3
HO
HO
NH
2
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O OBn
O
3
N
O OCH
3
CH3O
CH3O OCH
N
CH
3
CH3O
NH
OCH
CH
2
3
3
O
H
N
O
O OBn
O
BnO
CH3O
O
FF
N
OCH
3
O
CH3O
OCH
3
FF
H2N
OCH
3
O
OBn
O
O
O
OCH
3
OCH
3
O
CH
3
O
O
BnOH
CH
O
OCH
3
Cl
OCH
3
ON
3
O
OCH
3
Extended Discussion
Sequences with the same disconnections but in a different order are often evaluated in the search for the optimal route to
a target molecule. Draw the structures of the retrosynthetic analysis of an alternative route to dolutegravir which forms the
amide with 2,4- difluorobenzylamine after formation of the 1,3- oxazine. List pros and cons for the two routes and select one
route as the preferred route.
Dopamine
Cardiovascular Medications/Medicines Used in Heart Failure
A primary alkanamine is often formed by catalytic hydrogenation of a nitrile.
Discussion. The hydroxyl groups are released by demethylation of the ethers in the final step. The primary amine is
formed by reduction of the nitrile. The nitrile is formed by displacement of chloride by cyanide. 3,4- Dimethoxybenzyl
chloride is formed by chloromethylation of veratrole.
D148
HO
NH
CH
CH
OH
O
CH
CH
2
OO
OH
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2
HO
O
3
O
3
CN
CH3O
CH3O
CH3O
CH3O
NaCN
CH2Cl CH3O
CH3O
veratrole
NH
2
H H
O
Extended Discussion
List the many challenges associated with the chloromethylation step. Discuss procedure details provided to address the
challenges.
Doxycycline
Anti- infective Medicines/Antibacterials/Other Antibacterials
CH
3
OH
H
3
H
N
H
3
Many tetracyclines are semisynthetic, they are formed by modification of the C and/or D rings of a tetracycline natural prod-
OH
uct (tetracycline, chlorotetracycline, oxytetracycline) or a
tetracycline produced by a mutant strain of Streptomyces aure-
demethyltetracycline, 7- chloro- 6- demethyltetracy
bromotetracycline).
OH
NH
ofaciens (6cline, 7-
Discussion. Doxycycline (H at the 6β- position) is produced in three steps from oxytetracycline (OH at the 6β- position). In
the final step, hydrogen at the 6(methacycline). Methacycline is formed by reduction of the αand the α-
chloroketone are formed in the dehydration of an α- chlorohemiacetal. The α- chlorohemiacetal is formed by the
position is introduced by hydrogenation of the 6- methylene group of 6- methylenetetracycline
chloroketone (α- chlorine at C11a). The 6- methylene group
reaction of oxytetracycline with a chlorinating agent.
149Doxycycline
CH
CH
CH
CH
2
oxytetracycline
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7
8
9
10
OH
OH O
CH
CH
CH
3
3
11
OH
3
OH
H
H
6
5a
CD
11a
O
H
5
4a
B
12a
12
OH
OH
3
N
4
OH
3
A
2
NH
2
1
OO
OH O
CH
2
H
OH
OH
3
H
OH
3
N
OH
NH
2
OO
methacycline
CH
3
OH
2
H
H
CH
3
N
CH
O
3
CH
3
OH
H
H
OH
NH
2
Cl
OH
OH O
CH
OO
3
O
CH
3
OH
H
N
H
Cl
OH
OH
CH
3
N
OH
NH
OO
OH
NH
2
OH
OH
O
OH
OO
Extended Discussion
Draw the structure of another 6- deoxytetracycline formed in a one- step hydrogenolysis of the 6β- hydroxyl group of
oxytetracycline.
150
H
O
Cl
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E
Efavirenz
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Non- nucleoside Reverse Transcriptase Inhibitors
Anti- infective Medicines/Antiviral Medicines/Antiretrovirals/Integrase Inhibitors
N
A tertiary alcohol is often formed by addition of an organometallic reagent RLi
or RMX (M = Mg, Zn, X = Cl, Br, I) to a ketone.
O
CF
3
Discussion. The carbamate is formed from the amino alcohol in the final step. (List all the known reagents for the carbamate
formation. Which reagent is preferred?) The tertiary alcohol is formed by enantioselective addition of the acetylide from cyclopropylacetylene to the ketone. (List the reagents used to form the metal acetylide and the associated yield of the tertiary alcohol.) The amine is released by hydrolysis of the pivalamide. The ketone is formed by ortholithiation of the N- (4- chlorophenyl)
pivalamide and capture of the aryllithium by ethyl trifluoroacetate. The pivalamide is formed from 4- chloroaniline and pivaloyl chloride.
Routes to Essential Medicines: A Workbook for Organic Synthesis, First Edition. Peter J. Harrington.
© 2022 John Wiley & Sons, Inc. Published 2022 by John Wiley & Sons, Inc.
Companion website: www.wiley.com/go/Harrington/routes_essential_medicine
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