NPTEL Chemistry Principles of Organic Synthesis

Lecture 36
12.1 Reserpine

MeO

A
B

N 2
H H

C
3

N
D
15

H
MeO2C

20

16

H
O

19

OMe
O

OMe
OMe

Reserpine

OMe

It is found, with other alkaloids, in the roots of the plant genus Rauwolfia and used in the
treatment of some mental disorders as well as for the reduction of hypertension.
This lecture will focus on the Woodward total synthesis of reserpine (R. B. Woodward et
al. J. Am. Chem. Soc. 1956, 78, 2023; Tetrahedron 1958, 2, 1).

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NPTEL Chemistry Principles of Organic Synthesis

12.1.1 Retrosynthetic Analysis

The strategy was based on building five contiguous stereocentres into a decalin derivative
that could be opened to a monocyclic compound to form ring E (Scheme 1).

MeO

CHO
C
B
N
N
H H
D
H
MeO2C

NH2
N
H

MeO

MeO2C
MeO2C

E
OAc
OMe

E
O

Ar

OMe

O
H
+

H
CO2Me MeO2C

Scheme 1. Retrosynthetic Analysis

12.1.2 Total Synthesis

The Diels-Alder reaction can lead to the ring junction having cis stereochemistry
and the carboxyl group lie on the same side as the rings with respect to the ring
junction (i) (Scheme 2). This step fixes the stereochemistry at C15, C16 and C20 of
reserpine.

NaBH4 reduction of the less hindered of the two carbonyl groups of 2 can
provide 3 (ii). The epoxidation of the isolated double bond with mCPBA at the
less hindered side can afford 4 (iii) that could undergo dehydration to give the
lactone 5 (iv).

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DielsAlder

NPTEL Chemistry Principles of Organic Synthesis

O
[4+ 2]

NaBH4

heat
i

reduction
ii

+
CO2H

O
1

OH
H

OH
H

CO2H

PhCO3H
H

CO2H

epoxidation
iii

H
O 4 CO2H

Ac2O-NaOAc

iv
O

O
MeO -MeOH
OMe

-H2O

vii

Al(O Pr)3

vi

O
O

H
5

O
Br
HO

OMe

O
9

11

10 O
NH2

OHC

N
H

MeO

MeO2C

xiii

NaBH4

N
H
MeO2C
MeO2C

..
N
H

OAc
OMe

Cl+
N
O
O PCl2

ii. CH2N2

OMe
CO2Me
12

xii

POCl3

N
H

H
MeO2C
15

OAc

i. HIO4

N
H

xiv

OH
H

HO

OMe
CO2Me
13

MeO

i. CH2N2
ii. Ac2O/pyridine

OMe iii. OsO

4
CO2H
xi

OAc

14

OH

Zn-AcOH

ix

OMe

Br

CrO3

MeO

CO

NBS
H2SO4

viii

MeO

OH

O
8

xv
OAc

OMe

MeO
MeO
OAc
OMe
CO2Me

16

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H
+
N
..
N
H O
Cl2OP
H
MeO2C
17

N+

N
H
H

-POCl2OH
OAc

OMe

H
MeO2C
18

OAc
OMe

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NPTEL Chemistry Principles of Organic Synthesis

MeO

MeO

MeO
N

N
H H

DCC

lactone formation

H
MeO2C

OH

xvi
OAc

OMe

OMe

20

NaBH4

N
H H

H+
xvii

H
HO2C

xviii

21 OMe

OH-

N
H H

19

epimerization
xix

BuCOOH

MeO
MeO

MeO

MeO
NaOMe/MeOH

N
H H

xx

MeO
acylation

N
H H

ONa

MeO2C

22

23

OMe

COCl

xxi

OMe
MeO

MeO
N

N
H H

N
H H
MeOH/CHCl3 (3:1)
(+)-CSA

H
O

OMe
O

MeO2C
OMe

(-)-Reserpine

OMe

H
O

OMe
O

MeO2C
OMe

(+)-Reserpine

OMe
OMe

OMe
Scheme 2. Total Synthesis

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NPTEL Chemistry Principles of Organic Synthesis

Meerwein-Ponndorf-Verley reduction of 5 could convert the keto group into

hydroxyl that can displace on the carbonyl of the six membered lactone ring,
giving a five membered lactone, and the hydroxyl group so released can open the
epoxide ring to afford 6 (Scheme 3).
O-

H
O
O-

CO
H

O
O-

OH

Scheme 3

Dehydration of 6 can give -unsaturated carbonyl compound 7 that could undergo

conjugate addition at the less hindered -side with methoxide to give 8 (vi and vii).
NBS in acid could approach -side of 8 to give a brominium ion that could be opened
by water to give the biaxial bromo-alcohol 9 (viii) that could undergo mild oxidation
to afford 10 (ix).
Zn in AcOH can bring the reductive opening of both the lactone and the strained ether
of 10 to give 11 (x) (Scheme 4).
-

Zn:

2H+
O

CO2-

CO2H

O
O
Zn:

O-

H+

OH

Br
Scheme 4

Esterification of the carboxyl group using diazomethane, acetylation of the alcohol

group using Ac2O and dihydroxylation of the double bond can give 12 (xi) that could
undergo oxidative cleavage followed by esterification of the new carboxyl group with
diazomethane to give 13 (xii).

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NPTEL Chemistry Principles of Organic Synthesis

Schiff base formation of 13 with 6-methoxytryptamine can give 14 that could be

converted into 15 by NaBH4 reduction of the imine double bond (xiii and xiv).
Treatment of 15 with POCl3 can bring ring closure as in the Bischler-Napieralski
synthesis of isoquinoline, providing an imminium salt 18 via 16 and 17 (xv), which
could be reduced using NaBH4 to give 19 (xvi).
Base hydrolysis of 19 can give 20 having free OH and COOH groups that could be
joined to give a lactone 21 using DCC (xvii and xviii). Epimerization of the less
stable 21 using t-butyric acid can give the required more stable 22 that could be
converted into (+)-reserpine by opening of the lactone with MeOH followed by
acylation using 3,4,5-trimethoxybenzoyl chloride. The (+)-reserpine could be
resolved using CSA in a 3:1 mixture of MeOH and CHCl3.

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NPTEL Chemistry Principles of Organic Synthesis

Problems
A. Complete the following reactions.
O

CO2H

CO2H

PhCO3H

1.

CN
2.

CN

O
CH2N2

3.
N
H

CO2Me

N
Me

O
4.

Ph

N
H

CH2N2
H

CO2Me

OMe
Ph

Me

CN
5.
N
H

B.

+ CH2O + Me2NH

H
MeI

N
H

Explain the stereochemical principles of Diels-Alder reaction.

Text Books
R. O. C. Norman, J. M. Coxon, Principles of Organic Synthesis, CRC Press, London,
2009.
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996.

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NPTEL Chemistry Principles of Organic Synthesis

Lecture 37
12.2 Penicillin V
O
PhO

HN

Me

Me
H CO2K
Penicillin V
N

Penicillins are produced from the mould Penicillium notatum, different strains produce
different penicillins. They owe their importance to their powerful effect on various
pathogenic organisms. This lecture will present Sheehan total synthesis of penicillin V (J.
Am. Chem. Soc. 1959, 81, 3089).

12.2.1 Retrosynthetic Analysis

The synthetic strategy employed by Sheehan for penicillin synthesis is shown in Scheme
1.
O
R

O
PhO

X
Ring formation

+
HN

N
O

Me
Me
CO2H

HN

HO2C HN

Lactamization
Penicillin V

Me
Me
CO2H

H2N

+
CO2H RO C
2

NH2
CHO

Scheme 1

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NPTEL Chemistry Principles of Organic Synthesis

12.2.2 Total Synthesis

[Link]. Synthesis of (+)-Penicillamine
Scheme 2 shows the synthesis of (+)-penicillamine from (+)-valine.
O
CO2H

ClCH2COCl

NH2

HO2C

O
N
H
1

(+-)-Valine

Ac2O

Cl

HO2C
O

ii

H2S

iii
2

HO2C
HO2C

H2O
iv

SH

HCl, pyridine

N
H

NH2
SH

(+)-Penicillamine

Scheme 2. Synthesis of Penicillamine

N-Acylation of (+)-valine with -chloroacetyl chloride gives 1 (i) that undergoes

dehydrative cyclization with acetic anhydride to provide 2 (ii) by the elimination of
HCl followed by a proton shift (Scheme 3).

HO2C

HO2C

O
N
H
1

Cl

OH
N

Cl

Ac2O
-H2O

O
-HCl

O
N

O
O

N
2

Cl

Scheme 3

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O
N

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NPTEL Chemistry Principles of Organic Synthesis

The azlactone 2 can be cleaved by H2S and the resulting thiol could cyclize via
Michael-type addition to the -unsaturated acid to give thiazoline 3 (iii) (Scheme 4)
that could be opened in boiling water to afford 4 (iv). The N-acyl group of 4 could be
removed by acid hydrolysis to yield (+)-penicillamine (v) that could be resolved using
brucine to give the optically pure (+)-penicillamine.
O

HO2C

O
O

H2S:

OH

..
HS

S
3

2
Scheme 4

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NPTEL Chemistry Principles of Organic Synthesis

[Link] Synthesis of PenicillinV

Scheme 5 describes the total synthesis of penicillin
V.
H CO H
2
HCO2Et-NH2-

ClCH2CO2CMe3
N
K+
5

Me3CO2C

ii

Me3CO2C
6

Cl H3N
N2H4

Me3CO2C

H
HN

HCl
iv

H CO2H

Cl

PhO
O

PhO

CHO

Me3CO2C

S
H
HN
8 H CO H
2

HCl/CH2Cl2

H
HN
H CO2H

vi

HN
HO2C

H
HN
11 H CO2H

O
HN

KOH
HO2C
vii

PhO

10

O
PhO

O
HN

Et3N
v

Me3CO2C

iii

O
-

NH3+Cl-

HS

PhO
H

H
HN
12
H CO2K

HN

DCC

S
DCC =

viii

N C N

H CO2K
Penicillin V

Scheme 5. Total Synthesis

Nucleophilic substitution of 5 with t-butyl chloroacetate gives 6 (Gabriels synthesis,

i) that undergoes cross Claisen condensation with ethyl formate to afford 7 (ii).

The intermediate 7 with penicillamine hydrochloride at room temperature in sodium

acetate buffer affords 8 as a mixture of four diastereomers via Schiff base formation
followed by cyclization with the imine double bond (Scheme 6). However, the
required 8 could be separated from the mixture of diastereomers.

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NPTEL Chemistry Principles of Organic Synthesis

H CO H
2
O
HS
O
Me3O2C

N
7

Me3CO2C

O
CHO

NH2

-H2O

HS

O
Me3CO2C

N
H CO2H

O
S

H
HN
H CO2H

Scheme 6

The removal of the phthalimido group from 8 could be accomplished using

hydrazine to afford 9 as a salt in the presence of HCl in acetic acid (iv).

Acylation of the amino group of 9 in the presence of triethyl amine can give 10 (v)
that could be converted into 11 by acid hydrolysis of t-butyl ester in
dichloromethane at 0 oC (vi).

The intermediate 11 in the presence of KOH can give the potassium salt (vii) that
could be cyclized using DCC to give the potassium penicillinate (viii). Penicillin V
can be extracted after acidification with phosphoric acid which crystallizes from
aqueous solution at pH 6.8.

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NPTEL Chemistry Principles of Organic Synthesis

Problems
A. How will you synthesize the following compounds?

OH
O
Camphor

Menthol

B. Predict the major products for the following reactions.

CO2H
1.

ClCH2COCl, Ac2O

NH2

Ph

OH
DCC

2.
CH2Cl2

3.

NH2 +

DCC

HO2C

CH2Cl2
O
i. NaN3, AcOH
4.
ii. PPh3

5.

NH

CO2Me

LiClO4

NaH
6.
O

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NPTEL Chemistry Principles of Organic Synthesis

Text Books
R. O. C. Norman, J. M. Coxon, Principles of Organic Synthesis, CRC Press, London,
2009.
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996.

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NPTEL Chemistry Principles of Organic Synthesis

Lecture 38
12.3 Prostaglandins E2 and F2a
Prostaglandins are a series of closely related hormones that are derivatives of prostanoic
acid:

1
CO2H

10
Prostanoic acid

19

Parent skeleton of the prostaglandin family

Prostaglandins are present in many mammalian tissues at very low concentrations and
exhibit potent effects on various types of smooth muscle. They are of considerable
medical interest for the control of hypertension.
Prostaglandins E2 (PGE2) and F2a (PGF2) are two of the six primary prostaglandins. The
E series have a -hydroxy ketone structure in the ring and differ in the degree of
unsaturation in the side-chain, while F series have a -hydroxy group in the ring and
likewise differ in the extent of unsaturation in the side-chains.

OH
CO2H

HO

H OH
PGE2

CO2H

HO

H OH
PGF2

This lecture presents E. J. Coreys approach for the synthesis of PGE2 and PGF2a (J. Am.
Chem. Soc. 1969, 91, 5675; ibid 1971, 93, 1489; ibid 1972, 94, 8616).

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NPTEL Chemistry Principles of Organic Synthesis

12.3.1 Retrosynthetic Analysis of PGF2a

Scheme 1 outlines the general features of Coreys strategy for PGF2a synthesis.
CO2-

Ph2P
+

Wittig reaction

OH

OH
CO2H

HO

H OH

Horner-Wadsworth
Emmons Reaction

THPO

H OTHP

THPO

PGF2

O
RO

HO

Iodolactonization
O

PO(OMe)2
Me

+
I
O

OR

O
AcO

RO

OR

AcO

HO

RO

RO

Cl

CN

+
O

Cl
CN
Scheme 1

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NPTEL Chemistry Principles of Organic Synthesis

12.3.2 Total Synthesis

Scheme 2 presents the synthesis of PGE2 and PGF2a.

Thallium(I) cyclopentadiene 1, prepared from cyclopentadiene with TlSO4 and KOH

in water, could be alkylated using benzyl chloromethyl ether, which has the
advantage that subsequent debenzylation can be more easily accomplished
(i).

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NPTEL Chemistry Principles of Organic Synthesis

Ph
_

Cl

Tl+

mCPBA
O

Ph

Ph

Ph
ii
3 O

NaHCO3
CH2Cl2
iii

4
O
O

O
Ph
NaOH, H2O

O
CO2H KI3, NaHCO3

CO2
iv

OH

i. Ac2O, Pyridine

O ii. Bu3SnH, AIBN,

PhH, heat
AcO
7
vi
Ph

H2O
HO

O
O

O
CrO3 .2Py

H2-Pd/C
OH

vii
AcO

CHO NaH, DME, RT

ix

AcO

P(OMe)2
O

CH2Cl2
viii

AcO

i. K2CO3, MeOH
ii. DHP, TsOH,
CH2Cl2

O
Zn(BH4)2, DME

DIBAL-H, PhCH3,
-60 oC

xii

xi

x
11

10

9
O

AcO

THPO

H OH

H OTHP
12

DHP =
O

OH
O

CO2Na

PPh3
DMSO

HO
CO2H

xiii
THPO

THPO
13

H OTHP
i. H2Cr2O7, PhH/H2O
ii. AcOH, H2O, 37 oC

H OTHP
14

xiv

O
CO2H

HO

H OH
PGF2a

xv

AcOH, H2O, 37 oC

HO
CO2H

HO

H OH
PGE2

Scheme 2

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Ph

NPTEL Chemistry Principles of Organic Synthesis

The copper(II)-catalyzed [4:2] cycloaddition of 2 with 2-chloroacrylonitrile can give

15 that could be hydrolyzed using KOH in DMSO to afford 3 (Scheme 3) (ii).
Cl
O
H

CN

Ph

KOH,
Ph
H2O/DMSO

Ph

Cl

Cu(BF4)2, 0 oC

CN
15

Scheme 3

Baeyer-Villiger oxidation of the ketone 3 can give lactone 4 resulting from migration
of secondary carbon in preference to the primary carbon (iii).

The lactone 4 can be hydrolyzed with aqueous NaOH and the free acid 5 could be
obtained by neutralization with CO2 (iv). The latter could be iodolactonized with KI3
to afford 6 having five asymmetric centres (v).

Acetylation of the OH group employing acetic anhydride as an acylating agent

followed by deiodination using tributyltin hydride (Bu3SnH) in the presence of
radical initiator AIBN can give 7 (vi) that could be debenzylated by hydrogenolysis
to afford 8 (vii).

The PDC promoted alcohol oxidation of 8 can give the aldehydes 9 (viii) that could
undergo Wadsworth-Emmons reaction with the anion of dimethyl 2-oxoheptyl
phosphonate to give 10 (ix).

The Zn(BH4)2 mediated reduction of the carbonyl group of the side-chain can yield
11 (x). The protection of OH groups of 11 can be readily accomplished with DHP in
the presence of TsOH to afford 12 (xi).

The selective reduction of 11 to lactol 12 using DIBAL-H (xii) followed by Wittig

reaction on the masked aldehydes in DMSO with the phosphorus ylide can afford 13
(xiii).

The resultant prostanoid material 13 could be converted into prostaglandins E2 by

oxidation of the unprotected hydroxyl group followed by aqueous acidic hydrolysis
(xv), whilest the aqueous acid hydrolysis of 13 could afford F2(xiv).

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NPTEL Chemistry Principles of Organic Synthesis

Problems

A.

Outline synthetic route for oleic acid.

B.

Complete the following.

O
1.

MCPBA

KBrO3

2.

CO2H H2SO4

Cs2CO3
3.
OH PhCH2Br
Br
O
4.

N
H

i. PPh3
CF2CF3

CHN2
5.

ii. base

Cu(II)

Text Books
R. O. C. Norman, J. M. Coxon, Principles of Organic Synthesis, CRC Press, London,
2009.
K. C. Nicolaou, E. J. Sorensen, Classics in Total Synthesis, VCH, Weinheim, 1996.

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NPTEL Chemistry Principles of Organic Synthesis

Lecture 39
12.4 Ibogamine

N
N
H
Ibogamine

Ibogamine is an alkaloid in the oboga family that has the clinically important antitumor
alkaloid vinblastine. Hence, efficient synthetic approaches for the construction of the
family of compounds have been stimulated. This section focuses on a short,
stereocontrolled synthesis of ibogamine (B. M. Trost et al., J. Am. Chem. Soc. 1978, 100,
3930).

12.4.1 Retrosynthetic Analysis

Scheme 1 outlines the common featurs of Trosts strategy for ibogamine synthesis:
H
N

H
N
Electrophilic
Substitution

-Allyl
Substitution

N
N
H
Ibogamine

N
AcO

NH Reduction
AcO

N
H
Condensation
NH2
CHO

OAc
+

CHO

AcO
[4+2]

+
N
H

Scheme 1

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NPTEL Chemistry Principles of Organic Synthesis

12.4.2 Synthesis of Ibogamine

The synthesis of ibogamine could be accomplished in five steps employing Diels-Alder
reaction as key step to control the stereochemistry (Scheme 2).
H
N
NH2

OAc

CHO

CHO

N
H

AcO
BF3OEt
[4+2]

Toluene, MeSO4
-10 oC ii

H
N

B. M. Trost et al., J. Am. Chem. Soc. 1978, 100, 3930.

NH
Pd(PPh3)4

AcO

iii

NaBH4, MeOH

AcO

N
o

CH3CN, 70 C
iv
4

N
H

AgBF4, CH3CN, 1 h
PdCl2(CH3CN)2, RT
NaBH4
v

N
N
H
Ibogamine

Scheme 2

The Diels-Alder reaction of diene 1 with acrolein could afford the six-membered
ring 2 having all the three substituents cis (i). Although, it is immaterial for the
acetoxy group, the cis relationship between the ethyl and aldehydes groups is
required to obtain the right stereochemistry of the target molecule.

The Schiff base formation of 2 with tryptamine can give 3 (ii) that could be
readily reduced using NaBH4 to afford 4 (iii).

The intermediate 4 may undergo reaction with Pd(0) to give -allylic complex
with a loss of acetate ion, that could react with the nucleophilic nitrogen atom of
the amino group to afford 5 (iv).

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NPTEL Chemistry Principles of Organic Synthesis

The PdCl2 effected electrophilic substitution of the indole ring can give metal salt
complex (Scheme 3) that could be reduced using NaBH4 to afford the target
molecule (v). The presence of silver ion increases the reactivity of the process.
M

N
M

N
H

N
H

M = silver-palladium salt complex or partially ionized palladium salt

Scheme 3

Problems
Complete the following with major products.
NMe2
i. KCN, DMF
1.

ii. LiAlH4, THF

N
H

heat

2.

OTMS
3.

NO2
N
CO2Et

i. heat, ii. HCl. THF

+
NMe2

O
heat

N
4.
S

MgBr

5.
NO2

NH4Cl

Me

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NPTEL Chemistry Principles of Organic Synthesis

Text Book
R. O. C. Norman and J. M. Coxon, Principles of Organic Synthesis, CRC Press, London,
2009.

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NPTEL Chemistry Principles of Organic Synthesis

Lecture 40
12.5 Synthesis of Adenosine Triphosphate (ATP)
NH2
N

OH OH OH
HO
O
O
O
P
P
P
O
O
O

O
HO

N
N

OH

Adenosine Triphosphate (ATP)

ATP, in conjunction with its diphosphate, ADP, acts as a reversible phosphorylating

couple and energy store. For example, it is concerned with the supply of energy for
muscular contraction.

NH2
HO

OH OH
O
O
P
P
O
O

O
HO

N
N

OH

Adenosine Diphosphate (ADP)

Synthesis of -Chloro-2,3,5-Triacetyl-D-Ribofuranose
The synthesis of -chloro-2,3,5-triacetyl-D-ribofurance from D-ribose could be
accomplished in five steps (Scheme 1).

The selective reaction of the primary OH group of D-ribose with triphenylmethyl

chloride ensures the sugar to adopt the furanose ring 1 system (i) that could be
transformed into 3 via 2 by acetylation (ii) followed by removel of the
triphenylmethyl group of using hydrogenation (iii).

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NPTEL Chemistry Principles of Organic Synthesis

Acetylation (iv) followed by SN2 reaction at the carbon next to the ring oxygen of
4 using HCl (v) give the target molecule.
CHO
OH
OH
OH
OH
D-Ribose

H
H
H

Ph3CCl
i

CHO
OH
OH
OH
OCPh3

H
H
H

Ph3C

O
Ac2O

O
OH
OH

HO

Ph3C

ii

OAc
OAc

AcO

2
iii

AcO

AcO

Cl

A. R. Todd et al, J
Chem. Soc. 1947,
1052.

O
AcO

HCl, Et2O
OAc

OAc
OAc

AcO

Ac2O

H2, Pd

HO

iv

OAc
OAc

AcO
3

4
-Chloro-2,3,5-Triacetyl-D-Ribofuranose
Scheme 1

Synthesis of denosine
Uric acid could also be converted into adenosine in five steps (Scheme 2).
NH2

AcO

N
HO
HN

POCl3

N
N

Cl
OH

HN

uric acid

H2N

Cl

OH

NH3
Cl

N
H

ii

AcO

AcO

iv
NH2
A. R. Todd et al., J.
Chem. Soc. 1948, 967.

N
HO
O

HO
H2, Pd/BaSO4

Hydrolysis
NH2
N

Cl
O

v
HO

OH

HO

OH
9

adenosine
Scheme 2

Uric acid could be converted into 6 by reaction with POCl3 (i) that could undergo
nuleophilic substitution selectively at 6-position with NH3 to afford 7 (ii).

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Cl

OAc

N
N

OAc
iii

Cl

Cl

AcO
N

Cl

Cl

Page 26 of 30

Cl

NPTEL Chemistry Principles of Organic Synthesis

Reaction of 7 with the chloro-furanoside gives 8, presumably as a result of the

formation of an acetoxonium ion followed by an SN2 reaction (iii) (Scheme 3).

AcO
O
AcO

Cl

N
H
H

AcO
O
O

AcO

AcO
O
AcO

OAc

Scheme 3

Hydrolysis of the acetyl groups of 8 (iv) followed by hydrogenolysis of the C-Cl

bonds of 9 (v) gives the target adenosine.

Synthesis of ATP
The synthesis of ATP can be accomplished in eight steps form the above synthesized
adenosine (Scheme 4).

The 2- and 3-hydroxyl groups of the furanose ring of adenosine could be protected
by the formation of ketal to afford ketal 10 (i).

Phosphorylation of 10 could be effected to give 11 at a low temperature and the

removal of HCl can be performed using pyridine as a solvent (ii).

Mild acid hydrolysis of 11 leads to the formation of 12 by removal of the one of

benzyl groups along with the isopropylidene group (iii). After removal of the acid as
barium sulfate, the product could be dissolved in alkali and precipitated as its silver
salt.

Phosphorylation of 12 in anhydrous CH3COOH can give 13 (iv) that could be

selectively debenzylated with N-methylmorpholine to afford 14 (v).

Treatment of 14 with AgNO3 can give 15 (vi) that could be phosphorylated in a

mixture of CH3CN and PhOH to afford 16 (vii).

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Page 27 of 30

NPTEL Chemistry Principles of Organic Synthesis

The four benzyl groups of 16 could be removed by hydrogenolysis and the target
product, ATP, can be precipitated as its barium salt, liberated with sulfuric acid, and
isolated as its acridinium salt (viii).
Ph

NH2
N
HO
O
HO

HO
Acetone, H+

Ph
ClPO(OCH2Ph)2

adenosine

NH2

O
+
Ag-O
O
P
O

Ph

O
P
O

ClPO(OCH2Ph)2

O
P
O

O
HO

N
N

OH

13
Ph

NH2

Ph
N

O
O
P
O

O
O
P
O

iv

O
-

11
NH2

Ph

HO OH
12
Ph

10
Ph

AgNO3
iii

O
O
P
O

Ph

0.1 N-H2SO4

ii

OH

NH2

AgNO3

N
N

Ag+ O

vi

O
P
O

NH2

Ph
O
O
P
O

N
O

Ph
Me

N+

HO

HO

OH

OH

15

14

NH2
Ph Ph
ClPO(OCH2Ph)2
vii

Ph

NH2

Ph

O
O O
O
O
O
O
P
P
P
O
O
O

N
O

N H2, Pd
N

HO

OH OH OH
O
O
O
P
P
P
O
O
O

N
O

viii
ATP

HO

OH

HO OH
16
A. D. Todd et al., J. Chem. Soc. 1947, 648; 1949, 582.
Scheme 4

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Page 28 of 30

N
N

NPTEL Chemistry Principles of Organic Synthesis

Preparation of Dibenzyl Chlorophosphonate

The chlorination of dibenzyl phosphate can give the phosphorylating agent, dibenzyl
chlorophosphonate, in carbon tetrachloride (Scheme 5).
2PhCH2OH +

H3PO3

HPO(OCH2Ph)2

Cl2
ClPO(OCH2Ph)2

Scheme 5

Problems
A. Provide synthetic routes for ADP and AMP.

NH2
NH2
OH OH
HO
O
O
P
P
O
O

N
O

N
N

OH
O
HO
P
O

N
O
HO

HO

OH

Adenosine Diphosphate (ADP)

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N
N

OH

Adenosine Monophosphate (AMP)

Page 29 of 30

NPTEL Chemistry Principles of Organic Synthesis

B. Complete the following reactions.

OH

Ph3CCl

1.

OH
OH

Ru(II)/O2

2.

OH

Pd/CaCO3/Pb

3.

CH2OH

H2

NaBH4, CeCl3

I
4.
O
O

Zn, TiCl4

5.

CH2Br2

SnMe3

Text Books
R. O. C. Norman, J. M. Coxon, Principles of Organic Synthesis, CRC Press, London,
2009.
J. Clayden, N. Greeves, S. Warren, P. Wothers, Organic Chemistry, Oxford University
Press, New York, 2001.

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Page 30 of 30