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Cholesterol total synthesis in
chemistry Chemistry is the scientific study of the properties and behavior of matter. It is a physical science within the natural sciences that studies the chemical elements that make up matter and chemical compound, compounds made of atoms, molecules a ...
describes the
total synthesis Total synthesis, a specialized area within organic chemistry, focuses on constructing complex organic compounds, especially those found in nature, using laboratory methods. It often involves synthesizing natural products from basic, commercially ...
of the complex
biomolecule A biomolecule or biological molecule is loosely defined as a molecule produced by a living organism and essential to one or more typically biological processes. Biomolecules include large macromolecules such as proteins, carbohydrates, lipids ...
cholesterol Cholesterol is the principal sterol of all higher animals, distributed in body Tissue (biology), tissues, especially the brain and spinal cord, and in Animal fat, animal fats and oils. Cholesterol is biosynthesis, biosynthesized by all anima ...
and is considered a great scientific achievement. The research group of Robert Robinson with John Cornforth (
Oxford University The University of Oxford is a collegiate research university in Oxford, England. There is evidence of teaching as early as 1096, making it the oldest university in the English-speaking world and the second-oldest continuously operating u ...
) published their synthesis in 1951 and that of Robert Burns Woodward with Franz Sondheimer (
Harvard University Harvard University is a Private university, private Ivy League research university in Cambridge, Massachusetts, United States. Founded in 1636 and named for its first benefactor, the History of the Puritans in North America, Puritan clergyma ...
) in 1952. 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 Cortisone is a pregnene (21-carbon) steroid hormone. It is a naturally-occurring corticosteroid metabolite that is also used as a pharmaceutical prodrug. Cortisol is converted by the action of the enzyme corticosteroid 11-beta-dehydrogenase ...
were produced from natural resources but expensive. Chemical companies Merck & Co. and
Monsanto The Monsanto Company () was an American agrochemical and agricultural biotechnology corporation founded in 1901 and headquartered in Creve Coeur, Missouri. Monsanto's best-known product is Roundup, a glyphosate-based herbicide, developed ...
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, the enantiomer of natural cholesterol was reported in 1996 by Rychnovsky and Mickus, in 2002 by Jiang & Covey and again in 2008 by Rychnovsky and Belani.


The molecule

Cholesterol is a tetracyclic
alcohol Alcohol may refer to: Common uses * Alcohol (chemistry), a class of compounds * Ethanol, one of several alcohols, commonly known as alcohol in everyday life ** Alcohol (drug), intoxicant found in alcoholic beverages ** Alcoholic beverage, an alco ...
and a type of
sterol A sterol is any organic compound with a Skeletal formula, skeleton closely related to Cholestanol, cholestan-3-ol. The simplest sterol is gonan-3-ol, which has a formula of , and is derived from that of gonane by replacement of a hydrogen atom on ...
. Added to the sterol frame with the alcohol group at position 3 are 2
methyl In organic chemistry, a methyl group is an alkyl derived from methane, containing one carbon atom bonded to three hydrogen atoms, having chemical formula (whereas normal methane has the formula ). In formulas, the group is often abbreviated as ...
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 In organic chemistry, an alkene, or olefin, is a hydrocarbon containing a carbon–carbon double bond. The double bond may be internal or at the terminal position. Terminal alkenes are also known as Alpha-olefin, α-olefins. The Internationa ...
group. The total number of
stereocenter In stereochemistry, a stereocenter of a molecule is an atom (center), axis or plane that is the focus of stereoisomerism; that is, when having at least three different groups bound to the stereocenter, interchanging any two different groups cr ...
s is 8. The unnatural cholesterol molecule that has also been synthesized is called ent-cholesterol.


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 formal synthesis was proof that these intermediates could be linked to each other via chemical synthesis. Starting point for the Robinson synthesis was 1,6-dihydroxynaphthalene 1 that was converted in about 20 steps into the then already known androsterone 4. Ruzicka had already demonstrated in 1938 that androsterone could be converted into
androstenedione Androstenedione, or 4-androstenedione (abbreviated as A4 or Δ4-dione), also known as androst-4-ene-3,17-dione, is an endogenous weak androgen steroid hormone and intermediate in the biosynthesis of estrone and of testosterone from dehydroe ...
5 and Robinson demonstrated its conversion to
dehydroepiandrosterone Dehydroepiandrosterone (DHEA), also known as androstenolone, is an endogenous steroid hormone precursor. It is one of the most abundant circulating steroids in humans. DHEA is produced in the adrenal glands, the gonads, and the brain. It funct ...
6 (note the
epimer In stereochemistry, an epimer is one of a pair of diastereomers. The two epimers have opposite configuration at only one stereogenic center out of at least two. All other stereogenic centers in the molecules are the same in each. Epimerization is t ...
ized hydroxyl group) also already a known compound. Conversion of 6 to
pregnenolone Pregnenolone (P5), or pregn-5-en-3β-ol-20-one, is an endogenous steroid and precursor/metabolic intermediate in the biosynthesis of most of the steroid hormones, including the progestogens, androgens, estrogens, glucocorticoids, and mineraloc ...
7 and then to
allopregnanolone Allopregnanolone is a natural product, naturally occurring neurosteroid which is made in the body from the hormone progesterone. As a medication, allopregnanolone is referred to as brexanolone, sold under the brand name Zulresso, and used to t ...
8 allowed the addition of the tail group as the acetate in 9 and then conversion to
cholestanol 5β-Coprostanol (5β-cholestan-3β-ol) is a 27-carbon stanol formed from the net reductive metabolism of cholesterol (cholest-5en-3β-ol) in the gut of most higher animals and birds. This compound has frequently been used as a biomarker for ...
10. The conversion of cholestanol to cholesterol was already demonstrated by oxidation of the ketone,
bromination In chemistry, halogenation is a chemical reaction which introduces one or more halogens into a chemical compound. Halide-containing compounds are pervasive, making this type of transformation important, e.g. in the production of polymers, drugs ...
to the bromoketone and elimination to the enone. The conversion of cholestenone into cholesterol by the method of Dauben and Eastham (1950) ''ON THE CONVERSION OF CHOLESTENONE TO CHOLESTEROL'' William G. Dauben, Jerome F. Eastham J. Am. Chem. Soc., 1950, 72 (5), p. 2305 consisted of reduction of the enol acetate (
lithium aluminium hydride Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula or . It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthe ...
) and fractionation with
digitonin Digitonin is a steroidal saponin (saraponin) obtained from the foxglove plant ''Digitalis purpurea''. Its aglycone is digitogenin, a spirostan steroid. It has been investigated as a detergent, as it effectively water-solubilizes lipids. As such, ...
for the isolation of the correct isomer.


Woodward synthesis

Starting point for the Woodward synthesis was the
hydroquinone Hydroquinone, also known as benzene-1,4-diol or quinol, is an aromatic organic compound that is a type of phenol, a derivative of benzene, having the chemical formula C6H4(OH)2. It has two hydroxyl groups bonded to a benzene ring in a ''para' ...
1 that was converted to cis-bicycle 2 in a Diels-Alder reaction with
butadiene 1,3-Butadiene () is the organic compound with the formula CH2=CH-CH=CH2. It is a colorless gas that is easily condensed to a liquid. It is important industrially as a precursor to synthetic rubber. The molecule can be viewed as the union of two ...
. Conversion to the desired
trans isomer Trans- is a Latin prefix meaning "across", "beyond", or "on the other side of". Used alone, trans may refer to: Sociology * Trans, a sociological term which may refer to: ** Transgender, people who identify themselves with a gender that dif ...
5 was accomplished by synthesis of the sodium enolate salt 4 (
benzene Benzene is an Organic compound, organic chemical compound with the Chemical formula#Molecular formula, molecular formula C6H6. The benzene molecule is composed of six carbon atoms joined in a planar hexagonal Ring (chemistry), ring with one hyd ...
, sodium hydride) followed by acidification. Reduction (
lithium aluminium hydride Lithium aluminium hydride, commonly abbreviated to LAH, is an inorganic compound with the chemical formula or . It is a white solid, discovered by Finholt, Bond and Schlesinger in 1947. This compound is used as a reducing agent in organic synthe ...
) then gave
diol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting gro ...
6, a
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
( HCl/water) gave ketol 7, deoxygenation of its acetate by elemental
zinc Zinc is a chemical element; it has symbol Zn and atomic number 30. It is a slightly brittle metal at room temperature and has a shiny-greyish appearance when oxidation is removed. It is the first element in group 12 (IIB) of the periodic tabl ...
gave enone 8, formylation ( ethyl formate) gave
enol In organic chemistry, enols are a type of functional group or intermediate in organic chemistry containing a group with the formula (R = many substituents). The term ''enol'' is an abbreviation of ''alkenol'', a portmanteau deriving from "-ene ...
9,
Michael Michael may refer to: People * Michael (given name), a given name * he He ..., a given name * Michael (surname), including a list of people with the surname Michael Given name * Michael (bishop elect)">Michael (surname)">he He ..., a given nam ...
ethyl vinyl ketone addition ( potassium t-butoxide/ t-butanol) gave dione 11 which on reaction with KOH in dioxane gave tricycle 12 in an aldol condensation with elimination of the formyl group. In the next series of steps oxidation (
osmium tetroxide Osmium tetroxide (also osmium(VIII) oxide) is the chemical compound with the formula OsO4. The compound is noteworthy for its many uses, despite its toxicity and the rarity of osmium. It also has a number of unusual properties, one being that the ...
) gave diol 13,
protection Protection is any measure taken to guard something against damage caused by outside forces. Protection can be provided to physical objects, including organisms, to systems, and to intangible things like civil and political rights. Although ...
(
acetone Acetone (2-propanone or dimethyl ketone) is an organic compound with the chemical formula, formula . It is the simplest and smallest ketone (). It is a colorless, highly Volatile organic compound, volatile, and flammable liquid with a charact ...
/
copper sulfate Copper sulfate may refer to: * Copper(II) sulfate, CuSO4, a common, greenish blue compound used as a fungicide and herbicide * Copper(I) sulfate, Cu2SO4, an unstable white solid which is uncommonly used {{chemistry index Copper compounds ...
) gave acetonide 14,
hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...
( palladium-strontium carbonate) gave 15, formylation ( ethyl formate) gave enol 16 which protected as the
enamine An enamine is an unsaturated compound derived by the condensation of an aldehyde or ketone with a secondary amine. Enamines are versatile intermediates. The word "enamine" is derived from the affix ''en''-, used as the suffix of alkene, and the r ...
17 ( ''N''-methylaniline/
methanol Methanol (also called methyl alcohol and wood spirit, amongst other names) is an organic chemical compound and the simplest aliphatic Alcohol (chemistry), alcohol, with the chemical formula (a methyl group linked to a hydroxyl group, often ab ...
) gave via the potassium anion 18,
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
19 by reaction with cyanoethylene using
triton B Benzyltrimethylammonium hydroxide, also known as Triton B or trimethylbenzylammonium hydroxide, is a quaternary ammonium salt that functions as an organic base. It is usually handled as a solution in water or methanol. The compound is colourless ...
as the base. Acid 19 was converted to
lactone Lactones are cyclic carboxylic esters. They are derived from the corresponding hydroxycarboxylic acids by esterification. They can be saturated or unsaturated. Lactones are formed by lactonization, the intramolecular esterification of the corresp ...
20 using
acetic anhydride Acetic anhydride, or ethanoic anhydride, is the chemical compound with the chemical formula, formula . Commonly abbreviated , it is one the simplest organic acid anhydride, anhydrides of a carboxylic acid and is widely used in the production of c ...
and
sodium acetate Sodium acetate, CH3COONa, also abbreviated Sodium, NaOxygen, OAcetyl, Ac, is the sodium Salt (chemistry), salt of acetic acid. This salt is colorless, deliquescent, and hygroscopy, hygroscopic. Applications Biotechnological Sodium acetate is u ...
. Subsequent Fujimoto-Belleau reaction with
methylmagnesium chloride Methylmagnesium chloride is an organometallic compound with the general formula . This highly flammable, colorless, and moisture sensitive compound is the simplest Grignard reagent and is commercially available, usually as a solution in tetrahydro ...
gave tetracyclic
ketone In organic chemistry, a ketone is an organic compound with the structure , where R and R' can be a variety of carbon-containing substituents. Ketones contain a carbonyl group (a carbon-oxygen double bond C=O). The simplest ketone is acetone ( ...
21. Treatment with
periodic acid Periodic acid ( ) is an oxoacid of iodine. It can exist in two forms: orthoperiodic acid, with the chemical formula , and metaperiodic acid, which has the formula . Periodic acids are colourless crystals. Periodic acid features iodine in the hig ...
(dioxane) and piperidine acetate (benzene) gave
aldehyde In organic chemistry, an aldehyde () (lat. ''al''cohol ''dehyd''rogenatum, dehydrogenated alcohol) is an organic compound containing a functional group with the structure . The functional group itself (without the "R" side chain) can be referred ...
24 through
diol A diol is a chemical compound containing two hydroxyl groups ( groups). An aliphatic diol may also be called a glycol. This pairing of functional groups is pervasive, and many subcategories have been identified. They are used as protecting gro ...
22 (oxidation) and dialdehyde 23 (aldol condensation). Sodium dichromate oxidation gave
carboxylic acid In organic chemistry, a carboxylic acid is an organic acid that contains a carboxyl group () attached to an Substituent, R-group. The general formula of a carboxylic acid is often written as or , sometimes as with R referring to an organyl ...
25,
Diazomethane Diazomethane is an organic chemical compound with the formula CH2N2, discovered by German chemist Hans von Pechmann in 1894. It is the simplest diazo compound. In the pure form at room temperature, it is an extremely sensitive explosive yellow ga ...
treatment gave methyl ester 26 and
sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula (sometimes written as ). It is a white crystalline solid, usually encountered as an aqueous basic solution. Sodi ...
the allyl alcohol 27.
Chiral resolution Chiral resolution, or enantiomeric resolution, is a process in stereochemistry for the separation of racemic mixture into their enantiomers. It is an important tool in the production of optically active compounds, including drugs. Another term wit ...
of this
racemic In chemistry, a racemic mixture or racemate () is a mixture that has equal amounts (50:50) of left- and right-handed enantiomers of a chiral molecule or salt. Racemic mixtures are rare in nature, but many compounds are produced industrially as r ...
compound with
digitonin Digitonin is a steroidal saponin (saraponin) obtained from the foxglove plant ''Digitalis purpurea''. Its aglycone is digitogenin, a spirostan steroid. It has been investigated as a detergent, as it effectively water-solubilizes lipids. As such, ...
produced chiral 28 and on
Oppenauer oxidation Oppenauer oxidation, named after , is a gentle method for selectively oxidizing secondary alcohols to ketones. The reaction is the opposite Meerwein–Ponndorf–Verley reduction. The alcohol is oxidized with aluminium isopropoxide in excess ...
chiral 29.
Hydrogenation Hydrogenation is a chemical reaction between molecular hydrogen (H2) and another compound or element, usually in the presence of a catalyst such as nickel, palladium or platinum. The process is commonly employed to redox, reduce or Saturated ...
(
Adams' catalyst Adams Pearmain, also called Adam's Parmane, is a cultivar of apple. It was introduced to the Royal Horticultural Society, Horticultural Society of London in 1826 by Robert Adams, under the name Norfolk Pippin. The fruit is large, varying from t ...
) gave alcohol 30,
chromic acid Chromic acid is a chemical compound with the chemical formula . It is also a jargon for a solution formed by the addition of sulfuric acid to aqueous solutions of dichromate. It consists at least in part of chromium trioxide. The term "chromic ...
oxidation gave ketone 31,
sodium borohydride Sodium borohydride, also known as sodium tetrahydridoborate and sodium tetrahydroborate, is an inorganic compound with the formula (sometimes written as ). It is a white crystalline solid, usually encountered as an aqueous basic solution. Sodi ...
reduction stereoselectively gave alcohol 32,
hydrolysis Hydrolysis (; ) is any chemical reaction in which a molecule of water breaks one or more chemical bonds. The term is used broadly for substitution reaction, substitution, elimination reaction, elimination, and solvation reactions in which water ...
followed by acylation gave acetate 33,
thionyl chloride Thionyl chloride is an inorganic compound with the chemical formula . It is a moderately Volatility (chemistry), volatile, colourless liquid with an unpleasant acrid odour. Thionyl chloride is primarily used as a Halogenation, chlorinating reagen ...
treatment gave
acyl chloride In organic chemistry, an acyl chloride (or acid chloride) is an organic compound with the functional group . Their formula is usually written , where R is a side chain. They are reactive derivatives of carboxylic acids (). A specific example o ...
34 and methyl cadmium the ketone 35. In the final stages reaction of 35 with isohexylmagnesium bromide 36 gave diol 37,
acetic acid Acetic acid , systematically named ethanoic acid , is an acidic, colourless liquid and organic compound with the chemical formula (also written as , , or ). Vinegar is at least 4% acetic acid by volume, making acetic acid the main compone ...
treatment gave
dehydration In physiology, dehydration is a lack of total body water that disrupts metabolic processes. It occurs when free water loss exceeds intake, often resulting from excessive sweating, health conditions, or inadequate consumption of water. Mild deh ...
and then hydrogenation gave acetate 38. Hydrolysis of this ester gave
cholestanol 5β-Coprostanol (5β-cholestan-3β-ol) is a 27-carbon stanol formed from the net reductive metabolism of cholesterol (cholest-5en-3β-ol) in the gut of most higher animals and birds. This compound has frequently been used as a biomarker for ...
39. The route from cholestanol to cholesterol was already known (see: Robinson synthesis).


External links


Woodward Cholesterol Synthesis @ SynArchive.com


References

{{Reflist Total synthesis