Cholesterol total synthesis

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Cholesterol
Cholesterol space-filling model

Cholesterol total synthesis in

Oxford University) published their synthesis in 1951 [2] and that of Robert Burns Woodward with Franz Sondheimer (Harvard University) in 1952.[3] Both groups competed for the first publication since 1950 with Robinson having started in 1932 and Woodward in 1949. According to historian Greg Mulheirn the Robinson effort was hampered by his micromanagement style of leadership and the Woodward effort was greatly facilitated by his good relationships with chemical industry. Around 1949 steroids like cortisone were produced from natural resources but expensive. Chemical companies Merck & Co. and Monsanto
saw commercial opportunities for steroid synthesis and not only funded Woodward but also provided him with large quantities of certain chemical intermediates from pilot plants. Hard work also helped the Woodward effort: one of the intermediate compounds was named Christmasterone as it was synthesized on Christmas Day 1950 by Sondheimer.

Other cholesterol schemes have also been developed: racemic cholesterol was synthesized in 1966 by W.S. Johnson,[4] the enantiomer of natural cholesterol was reported in 1996 by Rychnovsky and Mickus,[5] in 2002 by Jiang & Covey [6] and again in 2008 by Rychnovsky and Belani.[7]

The molecule

Cholesterol is a tetracyclic

methyl groups at carbon positions 10 and 13 and a 2-isooctyl group at position 17. The molecule is unsaturated at position 5,6 with an alkene group. The total number of stereocenters
is 8. The unnatural cholesterol molecule that has also been synthesized is called ent-cholesterol. Cholesterol overview

Robinson synthesis

The Robinson synthesis is an example of a so-called relay synthesis. As many of the chemical intermediates (all steroids) were already known and available from natural resources all that was needed for a

cholestanol
10.

Cholesterol Robinson synthesis
Cholesterol Robinson synthesis

The conversion of cholestanol to cholesterol was already demonstrated by oxidation of the ketone,

enone
.

Cholestenone - cholesterol synthesis Ruzicka
Cholestenone - cholesterol synthesis Ruzicka

The conversion of cholestenone into cholesterol by the method of Dauben and Eastham (1950) [10] consisted of reduction of the enol acetate (lithium aluminium hydride) and fractionation with digitonin for the isolation of the correct isomer.

Woodward synthesis

Starting point for the Woodward synthesis was the

triton B
as the base.

Cholesterol synthesis Woodward 1
Cholesterol synthesis Woodward 1

Acid 19 was converted to

racemic compound with digitonin produced chiral 28 and on Oppenauer oxidation chiral 29. Hydrogenation (Adams' catalyst) gave alcohol 30, chromic acid oxidation gave ketone 31, sodium borohydride reduction stereoselectively gave alcohol 32, hydrolysis followed by acylation gave acetate 33, thionyl chloride treatment gave acyl chloride 34 and methyl cadmium
the ketone 35.

Cholesterol synthesis Woodward 2
Cholesterol synthesis Woodward 2

In the final stages reaction of 35 with isohexylmagnesium bromide 36 gave diol 37,

cholestanol
39. The route from cholestanol to cholesterol was already known (see: Robinson synthesis).

Cholesterol synthesis Woodward 3
Cholesterol synthesis Woodward 3

External links

References

  1. ^ Cardwell, H. M. E., Cornforth, J. W., Duff, S. R., Holtermann, H ,Robinson, Robert, Chemistry & Industry, 1951, 389-90
  2. ^ Kuwada and Nakamura (1938) J. Pharm. Soc. Jpn 58, 235
  3. ^ ON THE CONVERSION OF CHOLESTENONE TO CHOLESTEROL William G. Dauben, Jerome F. Eastham J. Am. Chem. Soc., 1950, 72 (5), p. 2305