Transcript YS_Synthesis of dl-Progesterone

Synthesis of dl-Progesterone
by William S. Johnson
JACS 1971, 93, 4332
Ye-Geun Song
April 3rd, 2012
CHEM635
William S. Johnson
February 24, 1913 - August 19, 1995
• He did his undergraduate studies at Amherst
College.
• He finished his doctoral work with Prof. Louis
Fieser at Harvard University in 1939 and did
postdoctoral work at Harvard with Prof. R. P.
• He began his independent academic career at
the University of Wisconsin in 1940.
– A full professor in 1946
– Elected to the Board of Editors of Organic
Synthesis in 1948
– Elected to the National Acadamny of
Sciences in 1958
• Moved to Stanford in 1960.
• He did important research in the artificial
production of steroids and was awarded the
National Medal of Science in 1987.
What is Progesterone?
• Progesterone is a C-21 steroid hormone involved in
menstrual cycle, pregancy, and embryogenesis of
mammals and is the major naturally occuring human
progestogen.
• Progesterone is commonly manufactured from the
Dioscorea (a family of yam), which produces large
amounts of a steroid called diosgenin that can be
converted into progesterone.
• Like other steroids, progesterone consists of four
interconnected cyclic hydrocarbons with ketone and
oxygenated functional groups, as well as two methyl
branches.
Why are we interested in making it?
• Progesterone can be used as a part of hormone
replacement therapy in women who have passed
menopause to treat symptoms of menopause and
reduce the risk of developing certain hormone
related diseases.
• Estrogen is often used in the therapy but can also
cause abnormal thickening of the lining of the
uterus and increase the risk of developing uterine
cancer. Progesterone helps to prevent this
thickening and decreases the risk of the cancer.
• Progesterone is also used to bring on menstruation
in women who should have normal periods by
replacing the natural progesterone that some
women are missing.
A Big Picture of Johnson’s Synthesis
11 was produced by a convergent
synthesis:
The key step is a stereoselective
Wittig condensation of the
aldehyde 4 with the ylide 7 to
produce diketal 8.
(Scheme 1) The Synthesis of Aldehyde 4
(Scheme 2) The Synthesis of Ylide 7
(Continued)
Finkelstein Rxn:
The classic Finkelstein reaction involves the conversion of an alkyl chloride or an
alkyl bromide to an alkyl iodide by the addition of NaI in acetone.
Because NaI is soluble in acetone and NaCl and NaBr are not, the
equilibrium is shifted by the precipitation of the insoluble salt.
Example:
CH3CH2Br (acetone) + NaI (acetone) → CH3CH2I (acetone) + NaBr (s)
(Scheme 3) The Synthesis of Progesterone 14
Conclusion
• Acetylenic bond participating in an olefinic
cyclization to produce trans-fused five
membered ring in one step
• Simple starting materials