This article is part of ChemTalk’s Organic Synthesis Series. These longer articles are designed to show how ideas and reactions from organic chemistry are put into practice in the synthesis of pharmaceuticals and other useful compounds.
Introduction
Progesterone is a key steroid hormone essential for regulating the menstrual cycle, maintaining pregnancy, and supporting overall health. Produced mainly in the ovaries, placenta, and adrenal glands, it prepares the uterine lining for implantation, prevents ovulation during pregnancy, and influences bone, brain, and immune function. However, its laboratory production faces challenges, including costly synthesis from plant-based precursors (e.g., wild yams), poor oral bioavailability, and complex manufacturing processes, leading to supply shortages and high costs. These limitations hinder access to progesterone-based therapies, despite their critical role in women’s health. Advances in biotechnology and drug delivery systems could help overcome these barriers, ensuring wider availability and more effective treatments.
Here we demonstrate the synthesis procedure for (±)-progesterone in a three-phase strategy starting from simple commercially available materials. The first phase begins with 2-methylfuran. This compound undergoes alkylation and cyclization to form a key spiroacetal intermediate that is converted to a phosphonium salt. In parallel, ethyl acetoacetate is transformed through alkylation, decarboxylation, and selective reduction to provide an aldehyde fragment. Wittig olefination then couples these fragments, followed by a series of cyclization reactions to build the steroid framework. This novel 15-step synthesis of progesterone from simple chemicals using classical reactions bypasses traditional plant-derived precursors. The approach demonstrates how strategic reaction sequencing can build complex steroid frameworks, offering a more sustainable and reliable production route for this essential hormone.
Progesterone Synthesis: Step 1
We achieve the regioselective C-5 alkylation of 2-methylfuran via deprotonation with n-BuLi, generating a stabilized α-furyllithium intermediate that undergoes an efficient SN2 reaction with 1,4-dibromobutane. The observed selectivity stems from enhanced kinetic acidity at the 5-position and thermodynamic stabilization of the organolithium species. This key step for the synthesis of progesterone avoids competing O-alkylation pathways.
The brominated furan undergoes acid-catalyzed cyclization with formaldehyde to form a bicyclic acetal, where p-toluenesulfonic acid promotes the transformation while hydroquinone prevents formaldehyde polymerization. The reaction proceeds efficiently thanks to the Dean-Stark apparatus, ensuring complete water removal and driving the equilibrium toward acetal formation.
Our brominated intermediate undergoes a Finkelstein reaction with sodium iodide in methyl ethyl ketone (MEK) to form the corresponding alkyl iodide. This halogen exchange proceeds via SN2 mechanism: the iodide ion displaces the bromide, forming the more reactive alkyl iodide. The Finkelstein reaction is essential because alkyl iodides are significantly more reactive than bromides in nucleophilic substitutions and eliminations. This enhanced reactivity is crucial for the subsequent phosphonium salt formation, as bromides react much more slowly with triphenylphosphine.
The final step for reactant 1 in progesterone synthesis involves treatment with triphenylphosphine in benzene to generate the corresponding triphenylphosphonium salt. This product serves as a Wittig reagent precursor for subsequent transformations.
Progesterone Synthesis: Step 2
The second part begins with ethyl 3-oxobutanoate (ethyl acetoacetate) undergoing alkylation with 1,3-dichloropropan-2-one using sodium ethoxide in ethanol. The sodium ethoxide deprotonates the active methylene group between the ketone and ester carbonyls, creating an enolate anion that attacks the primary chloride via an SN2 mechanism to form ethyl 2-(3-chloro-2-oxopropyl)-3-oxobutanoate. This alkylation is regioselective due to the increased acidity of the methylene protons adjacent to both electron-withdrawing groups. The alkylated product then undergoes elimination using potassium hydroxide in ethylene glycol, ethanol, water, and 2-methoxyethanol to yield 5-methylhex-4-yn-1-oic acid. This eliminative decarboxylation proceeds through a β-keto acid intermediate that spontaneously decarboxylates while the hydroxide promotes elimination of the chloride, forming the alkyne.
The carboxylic acid undergoes Fischer-Speier esterification using p-toluenesulfonic acid in dichloromethane/methanol over three steps to form methyl 5-methylhex-4-ynoate. This acid-catalyzed esterification proceeds through protonation of the carboxyl oxygen, nucleophilic attack by methanol, proton transfers, and water elimination. The mechanism follows the Protonation-Addition-Deprotonation-Protonation-Elimination-Deprotonation (PADPED) sequence. The use of Dean-Stark apparatus or azeotropic removal of water drives the equilibrium toward ester formation.
This method is chosen over other esterification approaches because it uses reagents with excellent functional group tolerance. Unlike acid chloride methods, it doesn’t generate corrosive HCl gas or require moisture-sensitive conditions. Compared to DCC coupling, it’s more economical and doesn’t produce difficult-to-remove urea byproducts.
The methyl ester undergoes selective reduction using Red-Al (sodium bis(2-methoxyethoxy)aluminum hydride) in benzene/THF to yield 5-methylhex-4-ynal. Red-Al coordinates to the carbonyl oxygen through its Lewis acidic aluminum center, followed by attack of hydride to the carbonyl carbon, forming a tetrahedral hemiacetal-aluminum complex. At the controlled low temperature, the reaction stops at the aldehyde oxidation state, preventing over-reduction to the primary alcohol. The bulky aluminum reagent and low temperature are crucial for achieving this selectivity.
Red-Al is superior to other reducing agents like DIBAL-H, LiAlH4, or NaBH4 for this transformation. LiAlH4 would over-reduce to the alcohol, while NaBH4 cannot reduce esters. DIBAL-H could work, but requires more precise temperature control and often gives variable results. Red-Al provides consistent, high-yielding reduction to aldehydes with excellent functional group tolerance, including compatibility with alkynes and alkenes.
The aldehyde undergoes nucleophilic addition with methylmagnesium bromide in THF, yielding 6-methylhept-5-yn-2-ol. The Grignard reagent acts as a carbanion equivalent, attacking the electrophilic aldehyde carbon to form a magnesium alkoxide intermediate. Aqueous workup protonates the alkoxide to give the secondary alcohol. Why do we conduct the reaction in THF? THF effectively solvates the magnesium cation, making the reagent more reactive and homogeneous.
Methylmagnesium bromide is preferred over organolithium reagents because it’s less basic and more chemoselective. The THF solvent ensures homogeneous reaction conditions and prevents aggregation of the organometallic species. The temperature control (-15°C to room temperature) balances reaction rate with stereochemical control.
A parallel route employs the Johnson-Claisen rearrangement using trimethyl orthoacetate and propionic acid under Dean-Stark conditions. This begins with transesterification between the ortho ester and an allylic alcohol precursor, followed by acid-catalyzed elimination of ethanol to form a ketene acetal intermediate. The ketene acetal then undergoes a -sigmatropic rearrangement to produce ethyl 3-(3-methylcyclohex-2-en-1-yl)propanoate. This rearrangement is stereospecific and proceeds through a chair-like transition state, providing excellent stereochemical control.
This rearrangement is particularly valuable because it simultaneously forms a C-C bond and establishes specific stereochemistry in a single step. The sigmatropic mechanism ensures predictable stereochemical outcomes, making it superior to multistep alkylation/cyclization sequences that might give stereochemical mixtures.
The ester from the Johnson-Claisen pathway then undergoes Red-Al reduction in benzene/THF, producing the corresponding aldehyde 3-(3-methylcyclohex-2-en-1-yl)propanal. This demonstrates the general applicability and reliability of the Red-Al methodology for ester-to-aldehyde reductions.
Progesterone Synthesis: Step 3
The synthesis proceeds with a Wittig reaction between the triphenyl[4-(6,10-dioxaspiro[4.5]decan-9-yl)butyl]phosphonium iodide (from Step 1) and 3-(3-methylcyclohex-2-en-1-yl)propanal (from Step 2) using phenyllithium in diethyl ether and THF. The phenyllithium deprotonates the phosphonium salt at the α-carbon, generating a red-colored phosphonium ylide (Wittig reagent). This ylide acts as a nucleophile, attacking the aldehyde carbonyl to form a four-membered oxaphosphetane intermediate (betaine). The oxaphosphetane undergoes syn-elimination to produce triphenylphosphine oxide and the desired alkene 9-[4-(3-methylcyclohex-2-en-1-yl)but-1-en-1-yl]-6,10-dioxaspiro[4.5]decane. The low temperature ensures (Z)-selectivity in the alkene formation, critical for the subsequent cyclization geometry.
The Wittig reaction is preferable over alternative alkene-forming methods (such as Peterson olefination or Julia-Kocienski olefination) because it provides excellent control over alkene geometry and tolerates the complex polyfunctional substrate. The use of phenyllithium rather than stronger bases like n-butyllithium prevents competing deprotonation reactions elsewhere in the molecule.
Next, we remove the spiroketal protecting groups using hydrochloric acid in water/methanol, revealing a dialdehyde intermediate. This acidic hydrolysis proceeds through protonation of the acetal oxygens, followed by water attack and C-O bond cleavage to regenerate the carbonyl groups. The mild conditions prevent decomposition of the sensitive alkene and cyclohexene functionalities while ensuring complete acetal cleavage.
The dialdehyde undergoes base-catalyzed intramolecular aldol condensation using sodium hydroxide in water/methanol in three steps to form a tetracyclic enone structure. The mechanism involves deprotonation of the α-hydrogen adjacent to one aldehyde by hydroxide, forming an enolate anion stabilized by resonance. This enolate acts as a nucleophile, attacking the carbonyl carbon of the second aldehyde intramolecularly to form a six-membered ring. The resulting β-hydroxy aldehyde (aldol) spontaneously dehydrates under the basic conditions to form the α,β-unsaturated ketone (enone), driven by the extended conjugation and aromatic stabilization.
The staged approach of acetal removal followed by aldol condensation allows for precise control of ring formation. Direct exposure to strongly basic conditions without prior acetal removal could lead to competing intermolecular reactions or decomposition of sensitive functionalities.
At room temperature, the enone undergoes nucleophilic addition with methyllithium in diethyl ether for two minutes. In doing so, we achieve 99% yield to install a tertiary alcohol at the 17-position. Methyllithium, being extremely nucleophilic and basic, attacks the carbonyl carbon with high efficiency. We perform the reaction in diethyl ether, rather than THF, to moderate the reactivity and prevent over-reaction or elimination. The brief reaction time (two minutes) indicates the organolithium reagents’ high reactivity toward ketones.
The tertiary alcohol undergoes acid-catalyzed cyclization using trifluoroacetic acid and ethylene carbonate in 1,2-dichloroethane at 0°C for three hours, yielding a pentacyclic steroid framework as an 83:17 mixture of diastereomers at C-17. Trifluoroacetic acid protonates the tertiary alcohol, yielding a tertiary carbocation that undergoes intramolecular electrophilic attack on the alkene. This attack results in formation of the D-ring of the steroid. The ethylene carbonate serves as a mild carbonic acid source, buffering the reaction and preventing over-acidification that could lead to rearrangements or decomposition. The 83:17 diastereoselectivity arises from the chair-like transition state preference during the cyclization, with the major isomer having the thermodynamically favored β-configuration at C-17.
The alkene undergoes ozonolysis followed by reductive workup with acetic acid and zinc in dichloromethane/methanol. Ozonolysis proceeds through formation of a primary ozonide, which rearranges to form a more stable secondary ozonide. The zinc/acetic acid reduction cleaves the ozonide reductively, preventing formation of hydrogen peroxide and ensuring clean conversion to the diketone. The low temperature prevents side reactions and maintains the integrity of the sensitive steroid framework.
The zinc/acetic acid reductive workup is preferred over other reducing agents, like dimethyl sulfide or triphenylphosphine. It provides cleaner product isolation and better functional group compatibility. The controlled temperature range prevents over-oxidation while ensuring complete ozonide cleavage.
The synthesis concludes with an intramolecular aldol condensation using potassium hydroxide in water/methanol yielding our end product, (±)-progesterone. This critical reaction forms the steroid’s A-ring through nucleophilic attack of the enolate (formed by deprotonation of the α-methyl ketone) on the adjacent ketone carbonyl. The resulting aldol intermediate dehydrates to form the characteristic α,β-unsaturated ketone of progesterone’s A-ring. The use of potassium hydroxide rather than sodium hydroxide provides better solubility in the methanol/water mixture, ensuring homogeneous reaction conditions. Performing the final aldol condensation at room temperature prevents epimerization at sensitive stereocenters, while allowing time to complete intramolecular cyclization. The water/methanol solvent system provides optimal solvation for both the substrate and the hydroxide base, ensuring efficient deprotonation and cyclization.
Conclusion
The convergent synthesis of progesterone presented here offers a robust and efficient route to this vital hormone, demonstrating how strategic cyclization, functionalization steps, and classical organic transformations aid in the synthesis of complex steroid frameworks from simple precursors. This approach not only overlooks traditional reliance on natural steroid sources but also provides a versatile platform for accessing structurally related compounds through analogous synthetic strategies. Beyond its well-established roles in reproductive health, progesterone continues to reveal therapeutic potential in neuroprotection, immunomodulation, and oncology. These are the main areas where scalable and modular synthetic routes could accelerate drug development. As synthetic methodologies advance, this work emphasizes the importance of progesterone as both a biological target and a foundation for steroid-based medicinal chemistry.
