Transcript Modified Nucleosides

Nucleoside Mimics
Medicinal Chemistry and
Nucleic Acids
New Targets for the Rational
Design of Molecules Showing
Antitumor or Antiviral Activities
Nucleoside Mimics
• Modified nucleosides are useful
therapeutic
agents
used
as
antitumor, antiviral and antibiotic
agents.
• They continue to attract attention
since many of them do not fully
discriminate between normal and
tumor cells.
• Moreover, resistance is observed
during the course of treatment
Natural Nucleosides
O
NH2
N
N
HO
Me
N
N
OH
O
H
H
H
OH
H
H
Thymidine
2'-Deoxyadenosine
NH2
O
N
N
HO
N
NH
N
NH2
N
OH
O
HO
O
H
O
HO
O
H
NH
N
O
H
H
2'-Deoxyguanosine
H
OH
H
H
2'-Deoxycytidine
Natural Nucleosides
NH2
N
N
HO
O
NH
N
N
N
HO
O
H
OH
O
H
OH
H
Adenosine
OH
OH
N
N
HO
NH2
NH
N
N
NH2
N
HO
O
OH
H
Uridine
O
H
O
O
OH
H
Guanosine
H
OH
H
OH
Cytidine
O
DNA
In all cells, DNA is the support of the genetic information.
It has no functional role in the cell such as: catalysis,
architecture, metabolism. These roles are ascribed to
proteins.
However, DNA disposes of the information necessary to allow
the construction of proteins. This is accomplished in two
steps:
1) DNA is first transcribed into RNA; then
2) RNA is translated into proteins.
Moreover, DNA is a replicative bio-molecule.
Prokaryotic and eukaryotic cells
Schematic representation
DNA structure
Phosphate groups (phosphodiesters),
act as bridges linking the 3'-O of one
ribose unit the 5'-O of the next ribose
unit. This creates a backbone structure
of alternating phosphate - ribose phosphate - ribose, etc.
When the structure has -OH attached
to C-2', this is ribonucleic acid
(RNA). Deoxyribonucleic acid, DNA,
uses 2'-deoxyribose so the 2'-OH
groups are absent, but otherwise the
backbone structure is identical.
Bases are linked to C-1' of each ribose
forming nucleosides, and the unique
properties of a particular RNA or DNA
molecule are determined by the
sequence of bases.
By convention, the chain starts at the end
with an unattached 5'-group (the 5'-end)
and runs towards the end with an
unattached 3'-group, the 3'-end. By
unattached, we mean no more nucleotide
units beyond this point, and the actual
ends may either be plain -OH groups as
shown for the 3'-end, or carry a single
phosphate ester as shown for the 5'-end.
The DNA doubled stranded structure is in the form
of a double helix
The base pairs are seen
as horizontal stacked
structures within the
helix
with
their
‘surfaces’ visible in the
major (broad) and
minor (narrow) grooves
Mechanism of DNA polymerisation
DNA Transcription
Protein synthesis
Nucleoside synthesis
Vorbrüggen Method (Silyl-Hilbert-Johnson)
OTMS
OTMS
N
N
+
TMSO
+
R1X
N
O
TMSX
N
R1
BzO
O
X
X= Halide or Acetyl
R1X
BzO
OBz
Lewis Acid (SnCl4 ,TMS-Triflate..)
Solvent: ClCH2CH2Cl, Acetonitrile
Heterocyclic base
+
BzO
BzO
O
O
O
O
+
BzO
O
BzO
O
Stereochemistry
Control of the stereochemistry at the
anomeric center
Nucleoside synthesis (Vorbrüggen)
Mechanism
OTMS
N
Si
OSO2CF3
CF3SO3-
SiO
O
BzO
BzO
O O
O
O
O
BzO
N
+
BzO
O
OTMS
N
O
BzO
N
O
BzO
OBz
O
Enzymatic synthesis of nucleosides
In some cases it might be advantageous to apply enzymatic syntheses.
At present two basic strategies are employed:
Deoxynucleosides
HO
O
NT
C
HO
O
B
HO
HO
B
C
Nucleoside 2’-deoxyribosyltransferase (NT) catalyzes the transfer of the
deoxyribosyl moiety from a deoxynucleoside to any nucleoside base.
This enzyme is found in Lactobacilli and related microorganisms which
need deoxynucleosides for growth.
Enzymatic synthesis of nucleosides
HO
O
HO
B1
PNPase
B1
PNPase
O
HO
(OH)
HPO42-
HO
(OH)
B2
HO
OPO32-
O
HO
B2
HPO42-
PNPase = Purine and Pyrimidine phosphorylase
This protocol needs to combine two enzymes, a purine and a pyrimidine
phosphorylase with (or without) the isolation of the (deoxy)ribose-1phosphate.
(OH)
Nucleoside Analogues
in Anti-Viral
Chemotherapy
Replication of DNA and RNA Viruses
DNA viruses:
use their T Kinase and their DNA pol
use cell RNA pol II
RNA viruses:
Two cases
- virions use their own RNA replicase
- retroviruses use their reverse transcriptase to
synthesize complementary DNA which integrates
the cellular genome, but use cellular kinases
Antiviral Nucleoside Analogues
It has proven to be more practical to modify the ribose part of the molecule,
that serves as the substrate for kinases and polymerases required for
nucleotide biosynthesis and chain elongation.
Note that if a nucleotide analogue does not have a hydroxyl group at the 3’
position, it cannot form a 3’ to 5’ phosphate bond with another nucleotide, and
this effectively terminates nucleic acid replication.
Nucleoside analogues might be expected to be effective against most, if not all
forms of viruses. Unfortunately, only relatively few viral kinases have specific
activity toward individual nucleoside analogues, so they are useful against
only limited types of viruses (narrow antiviral spectrum of activity).
Antiviral Nucleoside Analogues: RNA viruses
O
Me
Me
HN
HO
O
O
NH2
O
N
HN
N
HO
O
O
N
HO
O
O
N
N3
Azidothymidine (AZT)
Statuvidine (d4T)
O
Zalcitabine (ddC)
NH2
R
Me
N
NH
N
O
O
N
OH
O
O
Telbivudine
OH
S
R= H Lamivudine (3TC)
R= F Emtricitabine
OH
O
N
HO
N
O
Didanosine (ddI)
N
NH
N
O
HN
N
HO
Abacavir
N
N
N
NH2
CH2 N
HO
HO
Entecavir
NH
N
NH2
Antiviral Nucleoside Analogues: DNA viruses
O
NH2
O
I
HN
HO
O
O
CF3
HN
N
HO
O
O
N
N
N
HO
O
N
OH
OH
OH
Idoxuridine
N
Araadenosine (AraA)
Trifluridine
O
N
NH2
N
HO
O
(Toxic)
HO
Ribavirin
OH
Anti-Viral Chemotherapy
Thymidine Kinase
Viral or cellular
thymidine kinase
adds first
phosphate
Thymidine
Thymidine triphosphate
Cellular kinases add
two more
phosphates to form
TTP
PO4 PO4 PO4
Anti-Viral Chemotherapy
Why does Herpes simplex code for its own
thymidine kinase?
Although
purine/pyrimidine
nucleosides
are
present in the cell, levels of phosphorylated
nucleosides are low.
Herpes simplex own thymidine kinase allows virus
to grow in cells that are not making DNA
Interestingly, such deoxynucleoside kinase is
NON-SPECIFIC
Anti-Viral Chemotherapy
Herpes thymidine kinase will phosphorylate any
deoxynucleoside including drugs – as a result of its
necessary non-specificity
Nucleoside analog may be given in non-phosphorylated form
• Gets drugs across membrane
• Allows selectivity as only infected cell has enzyme to
phosphorylate the drug
ACG P P P
Anti-Viral Chemotherapy
Need for activation restricts drug to:
• Viruses such as HSV that code for own thymidine
kinase
• Virus such as cytomegalovirus and Epstein-Barr
virus that induce cells to overproduce their own
thymidine kinase
• In either case it is the VIRUS-INFECTED cell
that activates the drug
General pharmacology of antiviral nucleoside
analogues
Absorption: Most nucleosides are adequately absorbed after oral administration.
Circulating concentrations of some drugs have been improved by formulation of
prodrugs, which are readily absorbed and then metabolized to release the active
nucleoside form of the drug.
Duration of action: The half-life of the nucleoside analogues is generally fairly short,
in the range of two to three hours. Thus, multiple daily doses are required to maintain
useful concentrations. However, once phosphorylated within the cells, the nucleotides
persist for much longer periods of time.
Adverse reactions: Much of the toxicity of nucleoside analogues is directly related to
the degree to which these compounds serve as substrates for human kinases and
polymerases. Some of the early antiviral agents were characterized by extreme
toxicity, and are currently used only topically (e.g., idoxuridine or vidarabine for
ocular Herpes infections).
Nucleoside Analogues
in Anticancer
Chemotherapy
Nucleoside analogues in cancer
treatment
Cytotoxic nucleoside analogues are antimetabolites which interfere with nucleic acids
synthesis:
- incorporation in DNA, RNA
- modification of the metabolism (catabolism) of physiological nucleosides
Conditions:
- their transport might be mediated by membrane transporter (cell penetration)
- within the cells they need to be transformed in active phosphate derivatives
Pyrimidine nucleoside analogues
NH2
O
F
N
HN
N
H
O
NH2
O
O
HO
N
N
O
O
HO
OH
F
HO
Fluorouracil (FU)
HO
Aracytidine (AraC)
O
NH
NH2
N
N
F
Gemcitabine
NH2
O(C5H11)
N
N
F
N
O
O
HO
O
Me O
N
O
N
OH
O
O
HO
HO
N
OH
HO
OH
Capecetabine
Azacytidine
Troxocitabine
Pyrimidine nucleoside analogues
NH2
N
N
O
O
OH
HO
Ara-C is used in treatment of acute leukemias & lymphoma.
Inside the cell, the rate limiting step in cellular anabolism
is its conversion to ara-CMP by dCK. The catabolism results
from rapid deamination by cytidine deaminase (CDD) to
the non-toxic ara-uridine. Ara-CMP can also be dephosphorylated by cytoplasmic 5’-nucleotidase (5’-NT)
HO
1-b-D-arabinosyl cytosine (ara-C)
Gemcitabine displays an activity against solid tumours (pancreas, breast, lung cancers).
It is one the best known substrate of dCK and it also inhibits CDD as well as
ribonucleotide reductase.
NH2
N
Troxocitabine, a nucleoside analogue with an unatural
b-L-configuration has anti tumour activity. It is resistant
to CDD and is transformed in triphosphate by dCK. It
does not inhibit ribonucleotide reductase.
O
N
O
OH
O
(-)-2'-deoxy-3'-oxacytidine (Troxacitabine)
Pyrimidine nucleoside analogues
Fluoropyrimidine nucleosides
O
F
HN
O
N
O
F
HO
HN
O
O
N
H
5-Fluorouracil
H
H
OH
H
H
H
5-Fluorodeoxyuridine
The nucleobase 5-FU and the
nucleoside 5-FdU have activity in
patients with various cancers.
These agents are metabolically
activated into 5’-mono, 5’-di and 5’triphosphates.
Among the biochemical effects, direct
inhibition of TS by 5-FdUMP is the
best characterized.
TS
catalyses
the
reductive
methylation of dUMP into dTMP in
the presence of 5,10-methylene
tetrahydrofolate.
TS is blocked after binding with 5-FdUMP in a stable ternary complex with
5,10-methylene tetrahydrofolate depleting the steady state pool of thymidine
nucleotides.
Pyrimidine nucleoside analogues
Fluoropyrimidine nucleosides
O
NH2
F
F
NH
N
N
Me
Me
H
H
H
OH
OH
2',5'-dideoxy-5-fluorocytidine
O
O
O
H
Capecitabine
N
O
H
H
OH
OH
H
H
2',5'-dideoxy-5-fluorouridine
New oral fluoropyrimidine nucleosides achieve higher levels of 5-FU in
tumours than in normal tissues. This is the case of capecitabine which is
metabolized into 5’-deoxy-5-FdC and 5’-deoxy-5-FdU. 5-FU is generated
secondarily by thymidine phosphorylase (TP) which is more expressed in
tumour cells than in normal cells.
Purine nucleoside analogues
NH2
N
N
N
N
X
O
RO
R = X = H; 9- b-D-arabinosyl adenosine (ara-A)
OH
R = H, X = F; 9- b-D-arabinosyl -2-fluoroadenosine
(F-ara-A)
HO
R = PO 3H2, X = F; fludarabine
NH2
N
N
Note: F-ara-A is administered as its 5’-phosphate
for solubility, it is dephosphorylated by serum
phosphatase before transport into the cell.
N
N
Cl
O
9-b-D-arabinosyl 2-chlorodeoxyadenosine (2-CdA, cladribine)
HO
HO
Purine nucleoside analogues
HO
OMe
N
N
S
N
N
H
N
NH
NH
N
HO
O
N
N
HO
N
O
OH
N
NH2
HO
Thio-G
Pentostatine = Coformycin
HO
Nelarabine
NH2
Purine nucleoside analogues
The initial step in the activation process of the nucleoside analogues is dCK 5’phosphorylation which competes with the dephosphorylation activity of the
cytosolic-5NT. Thus, the net accumulation of triphosphates depends on the relative
activities of dCK and 5NT. Once incorporated, nucleoside analogues cause
termination of chain elongation mediated by DNA polymerases.
DNA replication might also be impaired by inhibition of ribonucleotide
reductase decreasing the pool of dNTPs available for DNA synthesis.
In the case 2-CdA both the inhibition of ADA and of S-adenosylhomocycteine
hydrolase (SAHH) are responsible for the cytotoxicity. Alterated methylation
reactions inhibit nucleotide synthesis and cellular proliferation.
Moreover, incorporation of nucleoside analogues by the repair machinery can lead to
the accumulation of DNA strand breaks, inducing apoptosis mediated by both p53dependent or p53-independent pathways.
Enzymes involved in the metabolism of
nucleoside analogues :Anabolism & catabolism
dCK: deoxycytidine kinase (5’-phosphorylation)
5’-NT : 5’-nucleotidase (5’-dephosphorylation)
CDD : cytidine deaminase (transformation of cytidine into uridine)
RR : ribonucleotide reductase (ribonucleotide ––> 2’-deoxynucleotide)
TS : thymidilate synthase (dUMP ––> TMP)
DPD : dihydropyrimidine dehydrogenase (5,6-double bond)
TP : thymidine phosphorylase (cleavage of the glycosidic bond)
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines,
Fused heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’-substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Palladium-mediated substitution at C-5 pyrimidine position
O
HN
AcO
O
OTf
H
O N
O
AcO OAc
HN
R
Pd(PPh3)4,10%, CuI, 20%,
Et3N 1.2 Eq./DMF
AcO
O N
O
AcO OAc
O
H
O N
O
HO
O
I
HN
HO
O
I
O
CO2R
HN
O N
O
HO
O N
O
HO
HO
HO
R
HN
R
Sonogashira
HN
R
Heck
HO
O N
O
HO
CO2R
Synthesis of C-6 substituted pyrimidines
O
O
HN
O
HN
N
O
MOMO
O
LDA
Bu3SnCl
O
O
O
HN
N
SnBu3
MOMO
O
O
(Pd)
CuI
DMF
N
O
MOMO
Stille
Tetrahedron 1993, 49, 2553
O
O
O
G=
Ph
SiMe3
O
G
Synthesis of Bicycliclic Nucleosides (BCNA)
R
O
I
HN
O
O
N
HO
O
HN
R
O
HO
R
O
N
O
O
HO
Pd(PPh3)4, CuI
iPr2EtN, DMF, rt
N
HO
O
HO
Et3N/MeOH, CuI, 
N
HO
Anti VZV (varicella-zoster virus)
J. Med. Chem. 1999, 42, 4479
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Synthesis of 2',3'-Dideoxynucleosides and
2’,3'-Didehydro-2',3’- dideoxynucleosides
O
O
HN
HO
O
O
HN
N
HO
HO
O
O
O
HN
N
HO
O
O
OH
Uridine U
d4U
ddU
N
Synthesis of 2',3'-Dideoxyuridine
O
O
HN
HN
HO
O
O
N
p-TsOH
HO
O
O
HN
N
OH
Ac2O
AcO
CH(OMe)3
HO
O
O
O
H
OMe
O
O
N
> 120°C
Eastwood reaction
Aust. J. Chem. 1964, 17, 1392
O
O
HN
HN
H2
aq NaOH
Pd/C
AcO
O
O
N
HO
O
O
N
The procedure is
ineffective to prepare
ddC or ddA
J. Org. Chem 1988, 53, 5170
Synthesis of d4T and ddA
Me
HN
HO
O
O
HO
O
O
O
HN
O
Br
N
OAc
OH
Mattock's Bromide
J. Chem. Soc. 1964, 4840
Me
RO
O
O
N
Me
HN
Zn/Cu
RO
O
O
N
AcO
Br
R= Ac or Ac-isoBu
The procedure is
ineffective to prepare
ddC or ddA
J. Org. Chem. 1989, 54, 4780
O
O
X
HO
OH
X
Me
O
Me
O
O
X
O
HO
OAc
O
HO
O
J. Chem. Soc. 1964, 1918
O
X
O
O
Me
O
O
Me
HO
OH
O
H
O
O
O
O
Me
O
OH
Me
O
AcO
O
O
X-
J. Am. Chem. Soc. 1973, 95, 4016
X
Synthesis of d4B and ddB with B= A, CAc and GIbu
NH2
O
O
HN
N
N
N
NH
N
N
H
N
H
N
N
H
B
O
B
CS2, CH3I
N
O
Base
OH
O
RO
S
S
H3CS
B
Bu3SnH
RO
RO
HO
O
R'= H
NHCOC3H7
R'
O
Yield : 85-95%
G 50-55%
SCH3
O
H2, Pd/C
R= TBDMS
B
O
(EtO)3P
RO
Minor product
O
O
S
B
B
CH3
N
P
N
CH3
O
O
RO
H2, Pd/C
RO
J. Org. Chem. 1989, 54, 2217
Corey-Winter reaction
B
O
RO
N
HO
OH
B
S
N
B
O
N
N
RO
(EtO)3P
O
O
S
CH3
N
P
N
CH3
O
RO
Y= 50%
Tet. Lett. 1982, 1979
Corey-Winter reaction
P(OEt)3
HO
OH
O
O
O
-
O
O
O
+
S
S
P(OEt)3
+
S=P(OEt)3
J. Am. Chem. Soc. 1963, 85, 2677
Synthesis of 2',3'-Didehydro-2',3'-dideoxynucleosides
O
R
HN
O
1) (PhO)2C=O
O
HO
N
O
N
2) DMTCl, pyr
HO
O
O
O
R'TeTeR'
O
DMTO
OH
R
N
NaBH4, EtOH
DMTO
HO
R'= Me, Ph
R= H, Me
R
HN
EtO
H
N
O
TeR'
H
HO
Na BH3
O
HN
I2,H2O, Pyr
O
DMTO
HO
O
R
R
HN
N
- PhTeO2H
O
DMTO
O
Te
Ph
O
O
N
O
R
HN
O
HO
N
O
J. Org. Chem. 2008, 73, 3725
Synthesis of AZT from mannitol
CHO
O
D-mannitol
PPh3=CH2CO2Et
MeOH
CO2Et
O
O
O
O
TBMSCl
Imidazole, DMF
TBMSO
Ac2O, Py
O
LiN3,THF, TBMSO
AcOH, H2O
O
OAc
TMSO
O
HCl dil.
O
TBMSO
O
HO
N
N3
O
TBMSO
O
O
O
N3
O
Me
HN
N3
TMSTf, DCE,
(b mixture)
Tetrahedron Lett. 1988, 29, 5349
OH
DiBAL, CH2Cl2
-78°C
N3
OTMS
Me
N
O
TBMSO
N
HO
nBu4NF
THF
Me
HN
O
O
N3
N
AZT
C-4' Substituted nucleosides
O
Me
HN
HO
N3
HO
O
O
O
O
Me
HN
N
HO
O
O
HN
N
NC
HO
Potent anti-HIV agents
Me
HO
Me
HO
O
O
N
C-4' Substituted Nucleosides
O
O
Me
Me
HN
O
O
O
Me
HN
N
O
O
CH2Cl2
O
-30 °C
TBDMSO
O
O
HN
SiMe3
N
HO
SnCl4 (3 eq.)
CH2Cl2, -30 °C
TBDMSO
O
O
N
O
TBDMSO
Me
TMSCN
HN
Org. Lett. 2003, 5, 1399
HO
NC
TBDMSO
O
O
N
C-4' Substituted Nucleosides
NHCOtBu
NHCOtBu
N
N
O
N
N
O
N
N
O
O
CH2Cl2
TBDMSO
OTBDMS
N
N
O
SnCl4 (3 eq.)
CH2Cl2, -30 °C
-30 °C
TBDMSO
SiMe3
OTBDMS
NHCOtBu
N
N
HO
TBDMSO
N
N
O
Org. Lett. 2003, 5, 1399
OTBDMS
C-4' Substituted Nucleosides
BnO
BnO
O
O
O
HO
BnO
O
Swern
O
BnO
O
O
BnO
O
Br2C
CBr4 PPh3
CH2Cl2
1) nBuLi, THF
O
O
2) Et3SiCl
BnO
O
HN
BnO
BnO
O
O
Et3SiC
O
BnO
O
HC
CH2Cl2, reflux
BnO
O
OAc
BnO
Thymine, HDMS
N
O
HC
OAc
BnO
OAc
J. Med. Chem. 2000, 43, 4516
Locked Nucleic Acids
O
O
OH
O
O
O
H
H
O
H
O
H
OBn
H
OBn
O
HO
BnO
Bpg
O
H
H
OBn
OAc
AcO
O
H
H
OBn
OH
H
BnO
Bpg
O
H
OBn
H
OAc
Bpg
OBn
OBn
O
H
H
OBn
OAc
BnO
Bpg
O
H
H
OBn
OH
HO
AcO
B
HO
O
H
TsO
O
H
O
O
O
H
HO
O
BnO
O
O
H
H
O
O
O
O
O
BnO
BnO
HO
O
H
O
OH
Tetrahedron 1998, 54, 3607
Ethylene Nucleic Acids
BnO
HO
H
H
OBn
O
HO
H
H
OBn
O
HO
O
BnO
BnO
O
O
O
H
H
OBn
O
O
H
H
OBn
O
H2C
O
O
O
O
O
Me
Me
Me
HN
BnO
O
O
HN
HN
O
H
H
O
BnO
OAc
O
BnO
O
OAc
OBn
N
H
H
OBn
OAc
N
O
BnO
O
O
H
H
OBn
OH
N
H
H
OBn
OH
AcO
AcO
HO
O
O
Me
Me
HN
HN
O
BnO
TsO
N
O
O
HO
N
O
H
H
H
H
OBn
O
OH
O
Bioorg. Med. Chem. Lett. 2002, 12, 73
Heterocyclic Analogues
O
EtO
HO
OMe
OMe
Br
EtO
HO
OMe
OMe
O
Dowex 50W-8H
BzCl/Pyridine
OMe
BzO
O
BzO
B
O
Inactive against HIV
Tet. Lett. 1981, 32, 271
Heterocyclic Analogues
TsO
TsO
O
O 1% HOAc/MeOH
OH
OMe
OMe
- TsOH
O
OH
OMe MeO
O
OH
OMe
B
MeO
TsCl/Pyridine
OTs
O
1) NaN3
2) H2, Pd/C
HO
O
B= A (iso ddA)
B = A anti-HIV activity in the range of ddA
Tet. Lett. 1989, 30, 6259
Heterocyclic Analogues
O
O
OBz
O
O
O
O
NaIO4
OH
OH
OH
O
HO
NaBH4
OH
OBz
OH
O
RO
O
O
OBz
R = SiR3
OH
O
RO
O
OH
O
O
RO
NaIO4/RuO2
O
O
OH RO
Pb(OAc)4
O
OAc
O
HO
O
Tet. Lett. 1991, 32, 3791
B
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’-substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Pseudonucleoside (C-Nucleoside)
O
O
HN
O
N
Synthase
O
HO
Uridine
HN
HO
OH
NH
OH
O
CONH2
NH
N
O
O
HO
HO
O
O
HO
O
O
HO
Pseudouridine
NH
O
HO
OH
Showdomycin
O
HO
HO
S
O
OH
Oxazinomycin
HO
OH
Thiazofurin
Synthesis of Pseudouridine
BnO
O
N
+
O
BnO
N
N
HO
OBn
HO
O
O
H
N
O
O
NH
O
NaBH4
O
O
HO
O
O
OBn
N
O
N
OH
Li
O
OBn
OBn
O
AcO
N
H
N
NH
O
HO
H+
H2 Pd-C
O
O
HO
O
OH
Pseudouridine
Major isomer
(low yield)
J. Org. Chem. 1968, 33, 140
Stereocontrolled synthesis of C-nucleosides
R
N
O
O
R'O
Li
+
O
Heterocycle
Heterocycle
R'O
N
O
O
R
OH
O
R = Prot. Group
R' = TBDPSi
O
NaBH4
R
H
N
N
OH
OH
O
Heterocycle
R'O
O
OH
Mixture S/R
O
R'O
O
OH
Major
J. Org. Chem. 2002, 67, 3724
Stereocontrolled synthesis of C-nucleosides
R
H
N
N
OH
OH
O
Heterocycle
R'O
O
O
Heterocycle
R'O
O
OH
OH
Intramolecular Mitsunobu cyclisation
H
R
N
N
Heterocycle
Heterocycle
O
O
R'O
R'O
O
O
R = Prot. Group
R' = TBDPSi
Deprotection
O
O
J. Org. Chem. 2002, 67, 3724
Synthesis of Showdomycin
O
CHO
BnO
NaCN
H2O2
BnO
CO2Me
CONH2
O
O
CHOH
BnO
MeOH, H+
CHOH
BnO
OBn
BnO
BnO
OBn
OBn
H
N
O
CO2Me
O
O
BnO
O
O
Ph3P=CHCONH2
BnO
CHCl3
Swern
BnO
BnO
OBn
O
BCl3 , CH2Cl2, -78°C
OBn
H
N
O
O
HO
J. Org. Chem. 1973, 38, 1841
Showdomycine
HO
OH
Synthesis of Thiazofurin
COOEt
NH2
O
CN
O
H2S liq.
BzO
C=S
O
Br
BzO
DMAP
BzO
MeCN
OBz
BzO
S
OBz
COOEt
S
O
N
BzO
(42%)
BzO
NH3, MeOH
CONH2
O
N
HO
OBz
HO
S
COOEt
O
OH
Thiazofurin
N
BzO
(22%)
BzO
OBz
J. Med. Chem. 1977, 20, 256
Synthesis of Thiazofurin
CONH2
S
O
CN
HS
BzO
BzO
NH2
O
Benzene
BzO
OBz
CONH2
O
HS
O
S
CN
BzO
NH2
CONH2
O
N
BzO
O
S
N
BzO
O
O
CONH2
O
1) TFA MeOH
2) NH3, MeOH
MnO2
Benzene
MeOH:TEA
O
O
MnO2
N
BzO
MeOH:TEA
OBz
CONH2
S
CONH2
O
N
HO
HO
OH
J. Org. Chem. 2000, 65, 5849
Synthesis of a Pyrazine C-Nucleoside
O
OH
TBDMSO
O
(MeO)2P
O
COOMe
TBDMSO
COOMe
O
NHZ
COOMe H , Pd-C
2
TBDMSO
O
NHZ
O
O
b-Isomer
O
NHZ
OH
O
NH2
O
COOMe
TBDMSO
O
O
NH3, MeOH
NH2
O
CONH2
TBDMSO
O
O
Helv. Chim. Acta, 2004, 87, 1299
Synthesis of a Pyrazine C-Nucleoside
CN
H3 C
NH
NH2
O
O
CONH2
TBDMSO
O
MeCHO, HCN
O
CONH2
TBDMSO
O
NO2C6H4SCl
O
CH3
H3C
CN
S
LDA, THF
N
NO2 O
CONH2
TBDMSO
O
NH
TBDMSO
O
O
O
NH2
N
O
O
Helv. Chim. Acta, 2004, 87, 1299
Pd-Mediated Synthesis of C-Nucleosides
H
N
O
O
I
+
HO
HN
O
t-Bu(Ph)2SiO
Pd(OAC)2
O
O
t-Bu(Ph)2SiO
H
N
O
NH
HO
O
Na+
O
NH
-
HB(OAc)3 HO
O
O
NH
HO
As(Ph)3
N
H
H
N
F-
O
O
O
HO
J. Org. Chem., 1992, 57, 4690
Pd-Mediated Synthesis of C-Nucleosides
O
O
O
TBDMSO
OH
TBDMSO
DIBAH
Et2O, -70 °C
TBDMSO
MesCl, Et3N,
CH2Cl2
TBDMSO
O
O
TBDMSO
TBDMSO
HO
(Bu)4NF, THF
TBDMSO
J. Org. Chem., 2007 72, 6797
Pd-Mediated Synthesis of C-Nucleosides
N
Cl
I
O
O
+
Cl
HO
HO
N
Pd(OAC)2, As(Ph)3
Ag2CO3, CHCl3, 60 °C
TBDMSO
b-anomer 65%
TBDMSO
Cl
Cl
N
N
O
Et3N-3HF,
HO
THF
O
NaBH(OAc)3,
MeCN, AcOH
O
HO
HO
J. Org. Chem., 2007 72, 6797
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Cyclopentane carbocyclic nucleosides
NH2
NH2
N
N
N
N
N
N
HO
OH
O
N
HO
O
HN
N
NH
N
OH
Neplanocin A
Aristeromycin
N
N
HO
HO
HO
N
N
NH2
N
N
N
HO
NH2
CH2 N
HO
HO
Carbovir
Abacavir
Entecavir
NH
N
NH2
Important Synthons
O
O
O
HO
O
O
OR
RO
HO
O
Synthesis of Hydroxylated Cyclopentenones
O
HO
OH
OH
HO
O
HO
OMe
O
O
O
O
PCC,PhH
O
OMe
O
D-Ribose
O
O
OMe
O
(MeO)2POCH2Li
O
O
O
HO
HO
OH
OH
O
HO
O
OMe
O
O
O
O
OMe
O
O
O
O
O
O
D-Xylose
Tetrahedron Lett. 1990, 31, 1509
Synthesis of Hydroxylated Cyclopentanes
O
O
O
(CH3)3COCH3, t-BuOK,
sec-BuLi, THF, -78°C
RO
RO
AcO
RO
HO
O
O PdCl2(MeCN)2,
O
O
O
OAc
O
Benzoquinone,THF
R= t-Bu
SePh
O
RO
O
RO
O
RO
RO
OH
O
O
O
O
O
O
O
O
(t-BuOCH2)2CuLi,
t-BuOMe, THF,-30°C
O
OR
HO
O
O
O
J. Med. Chem. 2001, 44, 3985
O
Synthesis of Hydroxylated Cyclopentanes
O
HO
O
O
BnO
O
O
BnO
O
D-Ribose
O
O
BnO
O
O
O
O
O
BnO
O
t-BuOK, DMSO,
100°C,92%
OH
O
O
O
BnO
OTBDPS
H
O
O
O
O
O
O
CH2
CH2
BnO
CH2
BnO
OTBDPS
O
O
Tetrahedron Asym. 2005, 16, 425
CH2
BnO
O
OH
OH
O
O
RO
O
O
O
Grubbs
O
Synthesis of Carbocyclic Nucleosides
(Enzymatic resolution)
+
Singlet O2
Ac2O/Pyridine
OAc
AcO
Thiourea
Lipase: PPL
HO
O
NH
+
O
MeSO2CN
OH
NHAc
OAc
O
OMe
NHAc
PLE
OBn
NaH/ THF
BnOCH2Cl
BH
2
BnO
HO
BH3
J. Chem. Soc., Perkin Trans. 1988, 552
OBn
Synthesis of Aristeromycin
AcO
H
+/-
O2N
H
HO
OAc
H
H
MeNO2, CH2Cl2
(PPh3)4Pd, rt
OAc
H
EtOC(O)Cl, pyr
+
OAc
H
EtO(O)CO
H
OAc
H
N3
H
O2N
H
H
1) OsO4, Et3N->O, -10 °C
2) Acetone, H+
NaN3, THF/H2O
(PPh3)4Pd, 50 °C
N3
H
O2N
O
O
NH2
1) KMnO4, MeOH, 0 °C
2) NaBH4, (Me)2CHOH
Nef reaction
N
N3
H
HO
H
O
N
O
N
N
HO
HO
OH
J. Org. Chem. 1996, 61, 3616
Nef Reaction
The conversion of nitro compounds into carbonyls is known as
the Nef Reaction.
Mechanism
Nitroalkanes are relatively strong carbon acids, and
deprotonation leads to the nitronate salt. The hydrolysis of this
intermediate must take place in strong acid, to prevent the
formation of side products such as oximes or hydroxynitroso
compounds:
Synthesis of Aristeromycin
Cl
N
HO
H
+
OAc
H
N
HO
H
+
H
Cl
N
N
N
EtO(O)CO
EtOC(O)Cl, pyr
H
N
H
Cl
N
MeNO2, CH2Cl2
(PPh3)4Pd, rt
N
N
N
O 2N
H
H
J. Org. Chem. 1996, 61, 3616
N
N
Synthesis of Aristeromycin
PdLn
NO2
OEt
O
O
+PdL
-CH NO
2
2
O-
EtO
n
+PdL
n
O
EtOH
CH3NO2
+PdL
n
EtO-
EtO
CO2
O
PdLn
O
J. Org. Chem. 1996, 61, 3616
Synthesis of Aristeromycin
N
Me H
AcO
O
AcO
H
HO
O
H
AcO
H
O
O
AcO
H
H
H
+/-
AcO
H
N
N
OsO4, Et3N->O
NHBz
O
H
N
N
AdBz, CsNa, (PPh3)4Pd,
DMF
N
O
NHBz
NHBz
N
N
AcO
N
H
N
N
N
+
OH
HO
N
H
+ O
NH2
COOH
N
HO
OH
N
N
HO
HO
OH
Biorg. Med. Chem.Lett. 1997, 7, 247
Dihydroxylation of 4-Aryl-1-azido-2-cyclopentene
RO
H
NR2
OsO4
RO
H
N3
Ar
H
N
+
H
OsO4
HO
OH
HO
H
RO
N
N3
Ar
+
HO
OH
OH
H
N3
HO
OH
Ar
(PhO)2P(=O)N3
H
Ar
OH
NH2
N
ArMgX
CuCN cat.
H
AcO
OH
N
N
N
HO
HO
OH
J. Org. Chem. 2004, 69, 655
Dihydroxylation of 4-Aryl-1-azido-2-cyclopentene
N
O
N
Ar = 2-Furyl
H
N3
Ar
OsO4, MNO
H
X
X
H
N3
H
N3
HO
OH
Ar
MeCN/THF/t-BuOH/H2O
(4:2:1:1), 0 °C, (14/1), 72%
H
HO
+
Ar
OH
NH2
H
N3
O
O
O
1)RuCl3,3H2O
NaIO4, then CH2N2
2) LiAlH4
H
NH2
N
N
HO
N
O
O
N
HO
HO
OH
J. Org. Chem. 2004, 69, 655
Synthesis of 5'-Methylaristeromycin
H Me
O
O
MgBr
O
O
O
R= H
TBS
O
CuBr.Me2S, LiCl,
TMSCl, HMPA, THF, -20 °C
OR
O
HO
OR
O
1) DIBAL, CH2Cl2, -78 °C
2) TBSOTf, 2,6-lutidine, -78 °C
O
(R)MeCBS, diethylaniline borane, toluene
Cl
N
H Me
AcO
Ph Ph
H
O
N B
OH
O
N
AcO
NH2
N
N
H Me
N
O
H Me
N
N
N
HO
O
O
O
HO
OH
Me
(R)MeCBS
J. Org. Chem. 2006, 71, 8641
Synthesis of L-Carbocyclic Ribonucleosides
O
(t-BuOCH2)2CuLi
O
O
t-BuOMe/THF -30°C
O
O
O
O
O
O
O
(CF3SO2)O
Pyridine, 0 °C
O
5% Pd/C H2
O
140 °C
O
H2N
O
LiN3, DMF
RO
HO
-78 °C
N3
O
O
DIBAL-H, CH2Cl2
O
rt
O
O
R= CF3SO2
C
OH
A
OH
T
OH
U
HO
HO
OH
HO
OH
HO
OH
OH
OH
J. Org. Chem. 1999, 64, 4173
Synthesis of L-Carbocyclic Ribonucleosides
Cl
Cl
H2N
O
O
NHCHO
N
N
N
N
NH
N
O
N
O
O
O
O
(EtO)2CHCO2Me,
120-130 °C
O
O
Cl
Cl
N
H2N
N
NH
O
O
NH2
N
O
J. Org. Chem. 1999, 64, 4173
H2N
N
NH
1) HCl/MeOH
2) p-ClC6H4N2Cl, rt
3) Zn/AcOH, H2O/EtOH
70°C
O
O
N
HN
HO
OH
H2N
N
N
OH
1) CH(OEt)3, HCl
2) 2N HCl, reflux
HO
OH
Synthesis of Methanocarbocyclic Nucleosides
SePh
PhSeCl/NaN3
BnO
RO
NaIO4
N3
BnO
RO
R= TBDPS
P(Ph)3
RO
O
NH2
O
O
O
BnO
N3
BnO
O
BnO
RO
N
O
BnO
Et3N.HF
RO
HO
N
O
Et2Zn/CH2I2
O
BnO
N
BnO
O
NH2NH2
HO
NH2
HO
J. Org. Chem. 1997, 62, 4870
Synthesis of Methanocarbocyclic Nucleosides
O
BnO
O
NH2
HN
Dioxane, 
HN
EtO
HO
O
O
BnO
OMe
NH
OMe
HO
O
H2SO4
BnO
HO
H
N
N
O
O
Pd/C
HCOOH
HO
H
N
O
N
HO
J. Org. Chem. 1997, 62, 4870
Synthesis of Methanocarbocyclic Nucleosides
SePh
AgCF3CO2/PhSeCl
BnO
O
BnO
DMSO
CF3
O
BnO
NaIO4
SePh
5%KOH
MeOH/H2O
BnO
OH
P(Ph)3/DEAD
BnO
BnO
BnO
OCOPh
PhCOOH
Benzene
OH
EtOH
BnO
BnO
BnO
BnO
K2CO3/MeOH
OH
BnO
Et2Zn/CH2I2
CH2Cl2
BnO
OH
BnO
Hev. Chim. Acta. 1999, 82, 2119
Synthesis of (-)-Neplanocin A
O
RO
O
O
O
RO
O
O
O
RO
O
O
O
P(OMe)2
O
RO
N
Na
K2CO3
18-crown-6
O
O
O
N
N
RO
1) NaBH4/CeCl3
2) MesCl
CrO3, Pyridine
O
O
O
NH2
N
N
N
N
N
HO
O
J. Org. Chem. 1988, 53, 5709
O
P(OMe)2
RO
Cl
N
N
O
OMes
Cl
N
O
NaOMe, MeOH
LiCH2P(O)(OCH3)2
O O
OH
OH O
P(OMe)2 RO
1) NH3, MeOH
2) for R= Bn
BCl3/CH2Cl2
HO
OH
N
Synthesis of (-)-Neplanocin C
Cl
N
N
BnO
O
O
Cl
Cl
N
N
N
N
BnO
AcOH, 50 °C
HO
OH
N
N
N
N
BnO
m-CPBA, CH2Cl2
O
HO
N
BnO
NH3, MeOH, 70 °C
N
N
HO
O
+
Isomer
NH2
N
N
N
OH
NH2
N
N
N
N
O
H2, 10% Pd/C, MeOH, 3 atm.
HO
OH
HO
OH
Tetrahedron 2000, 56, 4639
Synthesis of (-)-Neplanocin F
O
BnO
O
O
BnO
BnO
BnO
OBn
OBn
O
O
O
BnO
O
1) NaBH4/CeCl3
2) BnBr, 50% NaH,
DMF, 0 °C
O
O
OBn
O
H
O
DIBAL, -78 °C
OMe
60% AcOH, 50 °C
N
OBn +
O
OH
N
H
N
N
DEAD, PPh3,THF, rt
MeO
Cl
BnO
N
N
NH2
N
HO
OH
N
N
N
1) NH3, MeOH
2) BCl3/CH2Cl2
BnO
OH
Cl
BnO
HC(OMe)3, CAN,
CH2Cl2, 0 °C
HO
N
N
HO
OH
Tetrahedron 2002, 58, 3129
Synthesis of (-)-Neplanocin A
O
RO
OH
OH OTBDMS
RO
O
RO
OTBDMS
(Me)3SiCH(Li)N2
O
O
R= C(Ph)3
:
RO
O
1) LiAlH4, Et2O
2) TBDMSCl,
imidazole, DMF
OTBDMS
O
O
(COCl)2, DMSO
then Et3N, CH2Cl2
O
THF, O °C
OTBDMS RO
RO
OH
O
O
Bu4NF, THF
O
1) PDC, CH2Cl2
2) LiAlH4, THF
O
O
O
NH2
N
Adenine
DEAD, Ph3P, THF
N
HO
N
N
HCl, MeOH
HO
OH
Tet. Lett. 1995, 36, 1537
Synthesis of Methanocarbanucleoside
OH OTBDPS
BnO
O
O
CH2 OH
BnO
1) (COCl)2, DMSO
then Et3N, CH2Cl2
2) PPh3CH3Br, nBuLi
THF
3) TBAF, MeCN
CH2 CH2
BnO
O
1) (COCl)2, DMSO
then Et3N, CH2Cl2
2) Vinylmagnesium
bromide, THF, -78 °C
O
OH
BnO
Grubbs Catalyst
OH
O
CH2Cl2
O
O
O
O
BnO
MnO2, CHCl3
O
O
NH2
N
BnO
OH
1) NaBH4, CeCl3
2) CH2I2, Zn
O
N
HO
O
HO
OH
N
N
1) PDC, CH2Cl2
2) LiAlH4, THF
Org. Lett. 2001, 4, 597
Synthesis of Entecavir
O
Na+
_
BnO
BnO
1) BnOCH2Cl, THF, -65 to -78°C
2) Diisoprpylcampheylborane, THF,
-65 to -78°C
3) aq. NaOH H2O2
HO
OBn
OBn
N
N
H
N
N
N
1) VO(acac)2, t-BuOOH, CH2Cl2 BnO
2) BnBr, NaH, Bu4NI, DMF
OH
NH2
BnO
N
OBn
N
N
N
NH2
OH
N
N
N
BnO
LiH, DMF, 125°C
BnO
BnO
(+)--pinene
Biorg. Med. Chem. Lett. 1997, 7, 127
NHMMT
Ring Closure Methathesis (RCM)
Initiation:
Catalytic cycle:
Ring Closure Methathesis (RCM)
Synthesis of Entecavir
OBn
N
OH
N
OBn
N
N
N
NH-MMT
BnO
Dess-Martin reagent
t-BuOH, CH2Cl2
O
N
N
N
NH-MMT
BnO
BnO
BnO
O
OBn
N
CH2
N
Nysted reagent
TiCl4, THF
BnO
N
N
CH2
N
NH-MMT
N
NH
N
HO
Aldrichemica Acta 1993, 26, 14
BnO
Biorg. Med. Chem. Lett. 1997, 7, 127
1) aq. HCl, THF, MeOH, 55°C
2)BCl3, CH2Cl2
HO
Entecavir
NH2
Dess-Martin Reagent
Dess, D.B.; Martin, J.C. J. Am. Chem. Soc. 1991, 113, 7277-7287
The Dess-Martin Reagent is a very mild oxidant for the conversion of primary
alcohols to aldehydes. There is very little over-oxidation to the carboxylic acid. As the
reagent is non-acidic (unlike the Cr-based reagents) acid-labile functional groups are
not affected by it.
Methylenation reagents
Aldrichemica Acta 1993, 26, 14
Wittig reaction (Phosphoranes, Phosphonates, Phosphonium salts....).
It is limited to aldehydes and ketones with minimal steric hindrance that does not readily enolize
H2
C
TheTebbe reaction
Me
Al
Ti
Cl
J. Am. Chem. Soc. 1978, 100, 3611
Synthesis 1991, 1, 165
Me
Tebbe reagent
The Zirconium-promoted methylenationtion
The Nysted reaction
Zn
Cl
Zn
Br
Zn
O
Br
Zr
Cl
Nysted reagent
Nysted reagent (30% excess)
+ TiCl4, then reflux inTHF
Zirconocene dichloride + Zn + CH2Br2 in THF
allows the rapid methylenation of aldehydes, ketones
and enones at rt in high yield
Synthesis of Entecavir
H
NMe2
O
O
O
2 steps
O
O
2 steps
O
O
HO
O
AcOAc, 120°C
O
O
O
O
O
O
O
O
O
O
O
O
OH
OH
(MeO)2POCN2COMe,
K2CO3/MeOH, rt
Synth. Commun. 1989, 19, 561
OTBS OTBS
m-CPBA,
CH2Cl2, rt
OTBS OTBS
Tetrahedron 2003, 59, 9013
Synthesis of Entecavir
Gilbert reagent
Bestmann modification
Tetrahedron 2003, 59, 9013
Synthesis of Entecavir
O
Cp2TiCl
OH
OTBS
PivO
HO
OTBS OTBS
J. Am. Chem. Soc. 1994, 116, 986
Synlett. 2000, 1357
TBSO
1) PivCl, Pyridine, DMAP TBSO
2) 80% aq. HOAc, rt
Cl
+
N
N
H
O
N
N
N
NH2
Mitsunobu procedure
CH2 N
NH
N
NH2
Entecavir
HO
HO
Tetrahedron 2003, 59, 9013
Synthesis of (-)-Carbovir
O
O
NH
O OH
NH
NH2
+
1)HCl, H2O, reflux
2) MeOH, HCl
3) Ac2O, pyr, CH2Cl2
O OMe
NHAc
(+)
(-)
HO
CaBH4, THF, ultra
sound
HO
NHAc
NH2
HCl, H2O, reflux
O
N
HO
N
NH
N
NH2
J. Chem. Soc., Chem. Commun. 1990, 1120
Synthesis of (-)-Carbovir
OTMS
O(Si)
O
O(Si)
1) LDA
2) TMSCl
THF
OAc
N
N
H
O(Si)
9-BBN, THF
TMS
N
NH2
N
Pd(PPh3)4
LiH, DMF
HO
N
O
N
Bu4NF, MeCN
HO
N
NH
N
TMS
O
N
+
OH
O(Si)
Pd(OAc)2
MeCN
O
O(Si)
O
NH2
Tetrahedron Lett. 1992,33, 1085
N
N
NH2
Synthesis of 4--Alkylcarbovir Derivatives
R= Me,Bn,
C10H21
O
R= Me,Bn,
C9H19
CO2Me
O
O
(R,R)-cycloheptane
-1,2-diol, TsOH
CO2Me
O
10% HCl,
MeOH
N
TBDPSO
OH
I
R
N
OH
O
N
N
DEAD, PPh3
R
HO
N
TBDPSO
N
NH2
DBU
1) DHP
2) LiAlH4
3) TBDSiCl
4) Pyr/TsOH
Cl
NH2
CO2Me
R
1) PdCl2(MeCN)2
Benzoquinone
2)K2CO3, MeOH
N
R
O
I2,Et3N
R
N
N
O
OAc
CO2Me MeO2C
1) NaBH4, CeCl3
2) Ac2O, Pyr.
Cl
N
H
R
R
CO2Me
R
OH
CO2Me
LDA, RI
O
O
O
CO2Me
NH
N
NH2
R
1) TBAF
2) 1N NaOH
Chem. Pharm. Bull. 1999, 47, 1256
1,2-Disubstituted Carbocyclic Ribonucleosides
O
N
C NSO2Cl
-
SO2Cl
N
SO2Cl
ClO2S
O
N
O
O
+
O
NH
1) CSI, Et2O, -60 °C, Na2SO3
aq NaOH
2) aq HCl (37%), rt
3) HCl/MeOH
NH2
OH HN
H2N
LiBH4, THF
NH2
Cl
N
N
N
Cl
HO
CH(EtO)3,aq HCl, rt
N
+
Cl
Cl
H2 N
OH
CO2CH3
N
N
NH2
N
N
N
HO
N
N
N
aq NH4OH
Chem. Pharm. Bull. 2006, 54, 1418
1,2-Disubstituted Carbocyclic Ribonucleosides
Cl
Cl
Cl
N
Cl
N
OH
NH2
+
N
NH2
OH HN
N
OH HN
Zn, AcOH,
H2O, EtOH
N
N
N
NH2
N
OH HN
N
NH2 HO
CH(EtO)3,
aq HCl, rt
Chem. Pharm. Bull. 2006, 54, 1418
N
N
N
N
NH2
O
Cl
N
N
N
N
Cl
H2N
Cl
Cl
NH2
HO
N
aq NaOH
Marginal activity against HIV
NH
N
NH2
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Thionucleosides
B
HO
S
B
HO
B
HO
S
HO
S
S
OH
B
HO
O
HO
HO
HO
B
B
S
O
S
Thionucleosides
OTs
O
OBz
PhC(O)S- K+
OMe DMF
OBz
Ac2O, AcOH
O
OBz
AcO
OAc
OMe H2SO4
OBz
BzS
OBz
Arabinose
+
B
S
OH
O
OMs
O
OBz
OAc
OBz
BzS
Major
B
HO
OBz
S
Minor
B
S
O
S
OH
HO
OMs
+
HO
S
OH
OH
B
OH
b = 3:2
B
HO
S
O
B
HO
HO
S
OH
J. Org. Chem. 1968, 33, 189
Thionucleosides
RO
Hg(OAc)2, AcOH
S
p-TolO
SBn
OR
OR
p-TolO
RO
OR
O
N
R'(CH=CH2)SnMe3
or (CH2=CH2)4Sn
(PPh3)4Pd, HMPA
R=p-Tol
RO
B
HN
HN
O
S
b =2:1
O
R'
I
HN
S
RO
OAc
O
O
S
TMSOTf, MeCN
S
N
OR
HO
O
S
N
OH
4'-S-EtdU
IC50 2-5 M against HSV-2,
BVDU : IC50 10 M
J. Med. Chem. 1996, 39, 789
Thionucleosides
BnO
S
S
1) BBr3, CH2Cl2 TBDMSO
1) Hg(OAc)2
SBn
SBn
AcOH, rt
2) NH3/MeOH, rt
2) TBDMSCl, Pyr
TBDMSO
BnO
MesCl, DMAP,
TBDMSO
CH2Cl2, rt
S
DMAP, DMF
t-Bu2Si
O
O
S
O
t-Bu2Si
O
R
HN
Bu3SnH (3 equiv)
Et3B (1 equiv)
Bz, O2, rt
O
Y: 88% (R= H)
62% (R= Me)
SePh
O
t-Bu2Si
O
S
O
O
R
HN
N
PhSeCl
bis-O-TMS-pyrimidine
MeCN
O
TBDMSO
OH
TBDMSO
S
O
t-Bu2Si(OTf)2,
S
TBDMSO
Me
HN
N
HO
O
S
HO
N
Anti herpes
Tetrahedron Lett. 1998, 39, 3713
Thionucleosides
O
RO
OMe
RO
OR
1) 4N HCl, dioxane, 100 °C
RO
2) NaBH4, MeOH
OH
OH
RO
OH
OR
RO
OTBDMS
OR
RO
R= Bn
p-nitrobenzoic acid,
DIAD, PPh3,THF
RO
RO
OTBDMS
RO
OH
RO
OR
RO
S
OH
Op-NO2Bz
OR
1) MesCl, Pyr
2) Na2S, DMF,
100 °C
RO
OR
O
S
S
O
HO
TIPDS
BCl3, CH2Cl2, -90 °C
HO
O3, CH2Cl2, -78 °C
OH
O
ODMBz
2,4-dimethoxybenzoyl
S
O
TIPDS
O
ODMBz
R/S > 16/1
J. Am. Chem. Soc. 2000, 122, 7233
Thionucleosides
O
S
O
H
H
S
H
TIPDS
S
H
O
O
H
OTMS H
TIPDS
O
ODMBz
O
S
O
H
O
S
O
H
O
H
H
H
TIPDS
O
ODMBz
S
O
TIPDS
J. Am. Chem. Soc. 2000, 122, 7233
ODMBz
S
H
O
TIPDS
ODMBz
O
ODMBz
OTMS
H
TIPDS
O
TIPDS
TMSOTf
H
H
H
O
ODMBz
Thionucleosides
O
OTMS
HN
N
S
TMSO
O
O
TMSOTf
ODMBz
H
BzO
TMSO
OAc
ODMBz
O
HN
N
BzO
H
H
TIPDS
O
OTMS
S
N
S
H
H
TIPDS
O
O
N
O
N
N
S
TMSOTf
OBz
BzO
H
+
H
BzO
H
BzO
BzO
J. Am. Chem. Soc. 2000, 122, 7233
S
OBz
O
H
N
OBz
NH
O
Thionucleosides
1)
2) BnCl
D-Xylose
OBn
BnO
H+/MeOH
1) 6M, HCl
O
OMe 2) LiBH
4
BnO
OH
OH
BnO
BnO
1) MesCl
2) Na2S.9H2O
S
BnO
1) mcpba
2) Ac2O
OBn
N
BnO
S
OBn
BnO
O
TMSOTf
OBn
Me
BnO
O
S
N
HO
BCl3
HO
BnO
OBn
O
S
O
Me
HN
OTMS
Me
TMSO N
OAc
O
HN
OBn
N
HO
+
20%
OH
Me
HN
O
S
N
20%
HO
OH
Bioorg. Med. Chem. Lett. 1998, 8, 889
Synthesis of Lamivudine (3TC)
S
HO
OH
HO2CCHO
S
O
HO2C
O
HO2C
OH
S
S
t-BuOMe, 
+/-
O
O
S
2) (-)-menthol, Py,
2,2,4,4trimethylpentane
N
N
TMSO
+/- 1) COClDMF
NH2
N(TMS)2
O
OAc
O
N
O
N
O
OAc
O
TMSI, CH2Cl2
S
(16%)
NH2
NaBH4,
EtOH
N
O
O
HO
Tet. Lett. 2005, 46, 8535
S
N
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Fluoro Nucleosides
N(Bz)2
NH2
N
N
HO
N
N
O
OH
N
N
BzO
OH
O
N(Bz)2
N
N
N
BzO
NO2
N
N
N
F
O
OBz OBz
OBz OBz
NH2
BzCl, Pyridine, 65°C, 4h
N
TBAN, TFAA, CH2Cl2, O°C to rt, 14h
N
TBAF, THF, DMF, rt, 1h
NH3, MeOH, rt, 24h
HO
N
N
O
OH
OH
Synthesis 2006, 2993
F
Fluoro Nucleosides
O
BzO
OAc
O
BzO
O
+
HBr
BzO
O
BzO
OBz
DAST
Ph
O
BzO
OBz
OBz
H 2O
BzO
O
BzO
O
BzO
Br
OH
O
BzO
B
HBr/HOAc
BzO
F
BzO
F
BzO
F
Fluorination
Et
HO
+
R1
F2S
Et
R2
F3S
N
O
Et
Diethylaminosulfur
trifluoride (DAST)
R1
R2
(CH3OCH2CH2)2NSF3 (BAST)
Bis(2-methoxyethyl)aminosulfur trifluoride
BAST is thermally more stable than DAST
N
Et
+ HF
F
R1
R2
Fluorothionucleosides
SO2Cl2
Imidazole
CH2Cl2
O
O
O
O
O
O
O
N
O
O
O
O
O
O
HO
O
KF,
2-MeOCH2CH2OH
reflux
O
O
F
SO2
N
1) 2M HCl/THF BzO
2) BzCl, Py/CH2Cl2
1) MsCl/Pyr
2) NaOMe/MeOH
O
O
HO
F
O
S
F
O
O
O
O
O
Ac2O, KOAc,
AcOH reflux
F
AcO
O
AcS
F
O
O
O
Thiourea/MeOH
reflux
O
1) 90%TFA
2) NaIO4/Meoh/H2O
3) HCl/MeOH relux
4) BzCl/pyr.
S
OMe
BzO
BzO
J. Org. Chem. 1999, 64, 7912
F
Fluorothionucleosides
H2SO4, Ac2O,
AcOH
S
OMe
BzO
BzO
BzO
B
BzO
BzO
S
BzO
F
Br
F
BzO
1) aq. NH4OH/MeOH
2)Separation
S
B
HO
F
H
S
OAc
BzO
F
S
HBr, AcOH
CH2Cl2
S
+
HO
F
B
HO
HO
J. Org. Chem. 1999, 64, 7912
F
4’-Fluoronucleosides
OAc
BzO
O
B
Nucleobase
F
X
BzO
O
BzO
O
F
OBz OBz BSTFA
TMSOTf
MeCN
X = OAc
35-54%
(30%)
OBz OBz
O
OBz OBz
1) NBS, h
F
X = 5-FU
(28%)
BzO
2) BF3.OEt2, AgF
HN
O
O
N
F
OBz OBz
Org. Lett. 2007, 9, 5007
Gemcitabine
O
O
+ Zn
O
F
O
O
RO
OH
RO
OR
F
F
C F
DIBA-H
MesCl,
Et3N, CH2Cl2
OMs
O
C F
OR
F
OR
F
NH2
R= TBDMS
RO
OH
O
C F
C F
F
HO
O
O
F
C(O)OEt
HO
Dowex 50
O
F
C(O)OEt
CHO
HO
O
O
BrF2CC(O)OEt
N
tris-TMSCyt
HO
O
O
N
F
OH
F
J. Org. Chem. 1988, 53, 2406
A prodrug of gemcitabine
O
NH2
N
N
O
O
HO
F
Me
Cl
O2N
O
OH
F
O
Cl
N
1) HMDS, (NH4)2SO4, dioxane, 
2) AOCCl, N-methylimidazole,
CH2Cl2, rt
3) Et3N, MeOH, rt
N
O
O
HO
O
F
N-MeImidazole,
py, rt
O
P
Me
N Cl HOBT, py,
THF, rt
(CH2)4
OH
O
HN
Cl
Cl
(CH2)4
O
Me N
P
Pd(PPh3)4, PhSO2Na
THF/H2O, rt
O
O2N
OH
O
OBt
N
P
N Cl
(CH2)4
O
NH2
Me
N
Cl
N
O
HN
F
O
O
O
P
O
N OBt
(CH2)4
N
O
O
F
OH
F
F
OH
F
J. Med. Chem. 2007, 50, 3743
Synthesis of Nucleoside Mimics
•Heterocyclic Modifications: Pyrimidines, Purines, Fused
heterocycles
•Ribose (deoxyribose) Modifications: 2’-deoxy, 3’-deoxy, 4’substitution, 4’-cyclisation, heterocyclic ribose….
•C-Nucleosides (Pseudonucleosides)
•Carbanucleosides
•Thionucleosides
•Fluoronucleosides
•Complex nucleosides
Complex Nucleoside Antibiotics
H
N
O
O
H2N
CO2H
O
OH O
O
OH
NH2
Polyoxin J
N
N
H
HO
OH
H
N
O
HO
CO2H
O
CH3 O
OH
NH2
NH2
Nikkomycin B
N
H
HO
CO2H
O
CH3 O
OH
O
N
OH
H
N
O
HO
O
N
CHO
Nikkomycin Bx
N
H
HO
OH
Chem. Rev. 1995, 95, 1859
Complex Nucleoside Antibiotics
RHN
O
H
N
O
CONH2
O
O
O
N
Capuramycin
O
HO
OH
OH
MeO
O
GlO
O
OH
O
RHN
HO
H
N
N
O
OH
MeO
OH
Tunicamycin V
H
N
O
O
OH
O
HO2C
O
N
Octosyl acid A
OH
Chem. Rev. 1995, 95, 1859
Complex Nucleoside Antibiotics
NH2
N
O
H2N
H
H2N
HO
HO2C
N
N
Sinefungin
N
OH
NH2
N
H
H
HO2C
HO
O
N
O
O
OH H
OH
N
N
Herbicidin
OH
Chem. Rev. 1995, 95, 1859
Complex Nucleoside Antibiotics
NH2
N
HO2C
N
O
H2N
N
H
H2N
HO
Sinefungin
N
OH
NH2
N
O
H2N
N
S+
HO2C
Me
HO
OH
N
N
S-Adenosylmethionine
Synthesis of Sinefungin
BocHN
MeO2C
NC
BocHN
O
O
EtO
P
EtO
O
+
MeO2C
O
Mg(OMe)2, MeOH
I
A
O
O
NC
A
BocHN
Mg/MeOH
A
O
CO2Me
O
CO2Me
A
O
O
O
O
O
CO2Me
NH2
N
A
O
BocHN
H
BocHN
C
30% H2O2
DMSO
PhI(OCOCF3)2
DMF/H2O
MeO2C
NH2
BocHN
BocHN
O
O
O
NC
O
ANBz2 CN
OEt
P
OEt
+
O
O
O
O
H 2N
O
HO2C
H
H 2N
HO
N
N
N
OH
J. Am. Chem. Soc. 1983, 105, 7638
Synthesis of Sinefungin
EtO2C
OMe EtO2C
O
O
OMe
O
OMe
O
N
O
O
O
O
OMe
O
CbzHN
Xc H
O
O
CbzN
OMe
O
O
O
CbzN Bn
BocHN
(PhO)2P(O)N3, Et3N
MePh, 114 °C then
BnOH
OMe
H
O
O
EtO2C
O
CbzN Bn
EtO2C
O
OMe
O
NAc O
H
O
Asymmetric
hydrogenation
ANHBz
NH2
H
AcO
BocHN
OAc
HO2C
N
O N
H2N
J. Org. Chem. 1996, 61, 6175
O
Bn
H
H
O
EtO2C
O
H
H2N
HO
OH
N
N
Synthesis of Malayamycin A
H
N
O
H2N
MeO
O
NH
NH
O
O
O
OH
OMe
O
Malayamycin A
O
O
O
O
HO
HO
O
OH
N
OMe
N
N
OMe
OH
OH
O
O
O
OMe
OMe
O
DEAD, PPh3
N
N
OMe
OMe
O
O
+
MeO
OMe
Li
N
O
O
Org. Lett. 2003, 5, 4277
Synthesis of Malayamycin A
N
O
OMe
O
O
Si
N
O
O
OMe
Si
Si
O
O
OMe
N
OMe
N
O
OMe
OPMB
1 N HCl, dioxane
OPMB
N
OH
O
N
O
O
N
O
OMe
N
OMe
OH
Si
OMe
1) (COCl)2, DMSO,
i-Pr2NEt, CH2Cl2
2) Ph3PCH3Br,
NaHMDS, THF
HO
OMe
OPMB
Org. Lett. 2003, 5, 4277
Synthesis of Malayamycin A
OMe
N
OMe
N
N
N
O
HO
O
OMe
O
OPMB
1)NBS, H2O, THF
2) NaOH, THF
3)NaN3, MeOCH2CH2OH
Br
O
HO
O
N
N
OPMB
O
N
N
O
O
OPMB
N
O
OMe
OPMB
N
N3
Dess-Martin periodinane, CH2Cl2
O
HO
OMe
OMe
N
N3
OMe
OMe
OPMB
OMe
N
O
O
RMC
OPMB
N
OMe
N
OMe
OMe
OMe
O
O
O
OMe
OPMB
Org. Lett. 2003, 5, 4277
Synthesis of Malayamycin A
N
OMe
N
N
N3
O
OMe
O
O
N
N
N3
O
MeO
OPMB
OMe
O
N
N3
O
OMe
MeO
OPMB
OMe
O
OMe
OPiv
1)NaBH4, MeOH
2) NaH, MeI, DMF
3) DDQ, H2O, CH2Cl2
4) PivCl, DMAP, NEt3, Pyr
HN
O
NH
N3
O
O
MeO
TMSCl, NaI,
MeCN
O
H2N
HN
NH
NH
O
O
MeO
O
OPiv
1) PMe3, H2O, THF
2) Trichloroacetylisocyanate,
CH2Cl2
3) MeNH2,MeOH, H2O
O
O
OH
Org. Lett. 2003, 5, 4277