An Efficient, General Asymmetric Synthesis of Carbocyclic Nucleosides: Application of an Asymmetric

1
An Efficient, General Asymmetric Synthesis of
Carbocyclic Nucleosides Application of an
Asymmetric Aldol/Ring-Closing Metathesis Strategy

• Michael T. Crimmins, Bryan W. King, William J.
  Zuercher, and Allison L Choy
• Venable and Kenane Laboratories of Chemistry, The
  University of North Carolina at Chapel Hill

Presentation by Simon Curtis 3/17/06
2
Background information on HIV

• HIV binds and enters host cell
• Virus sheds protein coat and releases genetic
  material in the form of RNA
• The RNA is then converted to DNA through reverse
  transcription (RT)
• The HIV DNA is then integrated into the host
  cells genetic material (DNA) in the nucleus
• The virus then produces new virus polyproteins
• The polyproteins are cut up and the pieces used
  to produce new virus particles that are released
  from the host cell to infect new cells
• HIV replication is the causative agent for
  acquired immune deficiency syndrome (AIDS)

Antiretroviral Therapy Investigational NRTIs
HIV clinical management Vol. 3 Medscope Inc. 1998
3
HIV Treatment options
Fusion Inhibitors prevent HIV from binding with
the host cells Integrase Inhibitors Interfere
with HIVs integrase enzyme so the HIV DNA
would be prevented entering the
nucleus Protease inhibitor Interfere with the
action of the portease enzyme preventing the
polyprotein from being cut up into usable pieces
Antiretroviral Therapy Investigational NRTIs
HIV clinical management Vol. 3 Medscope Inc. 1998
4
Reverse Transcriptase Inhibitor

• Drugs that interfere with the action of the HIVs
  reverse transcriptase preventing HIV genetic
  material from being used to make new virus
• Types of these
• nucleoside analogs
• nucleotide analogs
• non-nucleoside RT inhibitors

Antiretroviral Therapy Investigational NRTIs
HIV clinical management Vol. 3 Medscope Inc.
1998
5
What are nucleoside analogues?

• Mimic nucleotides
• Small differences that effect the function of the
  nucleotide no phosphate group and replacing
  oxygen in the sugar portion of the nucleoside
  with a methylene
• Works in two ways
• Preventing the addition of anymore nucleotides
  resulting in termination of the reverse
  transcription
• Preventing a secondary replication by not linking
  to a complimentary nuclotide
• Examples AZT(Retrovir), ddI(Videx), 3TC(Epivir),
  abacavir, and carbovir

www.niaid.nih.gov/factsheets/ hivinf.htm www.sfaf.
org/treatment
6
Studied Nucleoside analogues and corresponding
Nucleotide
Carbovir
Deoxyguanosine
Abacavir
http//www.ia.ucsb.edu/pa/display.aspx?pkey511
7
Synthesis of the Nucleoside Analogues
4-pentenoate
Crimmins, M.T. King, B. W. J.Org. Chem. 1996,
61,4192-4193
8
Synthesis of Nucleoside analogues
Acyl oxazolidinethione
crotonaldehyde
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
9
Synthesis of Nucleoside Analogues
Thione Removal Step
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
10
Synthesis of Nucleoside Analogues
Acetylation of the diol
Ac2O
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
11
Synthesis of Nucleoside Analogues
Nobel Prize Winning Grubbs Catalyst
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
12
Alternate possible protecting groups
diacetate
Cyclic carbonate
dicarbonate
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
13
Synthesis of Nucleoside Analogues
86
14
Deoxyguanosine2
Chloropurine acetate
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509. 2.http//www
.ia.ucsb.edu/pa/display.aspx?pkey511
14
Synthesis of Nucleoside Analogues
Abacavir
Carbovir
Ac
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
15
Nucleoside Analogues
These two analogues were synthesized using a
similar process
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
16
The effect of the extra Methyl group
97
3
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
17
Nucleoside analogues with 6-membered ring
Crimmins, M.T. King, B. W., Zuercher,W., Choy,
A. J.Org. Chem. 2000, 65, 8499-8509.
18
Application of the nucleoside analogues
Allow the Kinase enzymes to phosphorolate the
molecules The molecules can then be introduced
into the DNA strand Lacking the 3-prime OH so no
further nucleotides bind to them
Deoxyguanosine
Abcavir
Carbovir
Marquez, V., Lim,M., M. Med. Res, Rev. 1986,
6,1. DeClerq, E. Herdewijn, P. Biochem.
Pharmacol. 1983, 3583
19
Review of HIV
Antiretroviral Therapy Investigational NRTIs
HIV clinical management Vol. 3 Medscope Inc.
1998
20
Conclusion

• There are millions of people infected with HIV
  and AIDS and an estimated 3 million people die a
  year as a result of AIDS
• When treating HIV it is common for the virus to
  become resistant to certain drug therapies
• Highly active antirotroviral therapy or HAART has
  been developed and it means using a combination
  of treatments to more effectively suppress the
  virus and avoid drug resistance
• HAART has been credited with significantly
  reducing the number of AIDS deaths in the US and
  has allowed many people with HIV/AIDS to be much
  healthier and live a higher quality of life
• HAART is only possible when there are many
  different types of drugs available to treat
  patients, so the more nucleoside analogues (and
  other HIV drugs) that are synthesized the easier
  it will be to treat the virus

www.niaid.nih.gov/factssheets/hivinf.htm
21
THANK YOU

• Dr. Downey (who worked with Dr. Crimmins when he
  was at UNC)
• Dr. Gindhart

22
HAPPY ST. PATTYS DAY