Question

A synthesis of the alkaloid morphine was completed by Gates and Tschudi in 1952 by way of the following key intermediates starting from naphthalene. Show the reagents, conditions, and important reaction intermediates that you expect would be successful in achieving each of the indicated transformations, noting that more than one synthetic step may be required between each key compound and considering carefully the order in which the operations should be carried out. Indicate those reactions which might be expected to give mixture of stereo- or position-isomers.

Short answer

To synthesize morphine from naphthalene, follow these steps: 1. Formation of 1-tetralone: Use CrO3, Ac2O, NaBH4, and PCC as reagents in sequence. 2. α-Bromination of 1-tetralone: Use NBS and a radical initiator like AIBN. 3. Grignard reaction with brominated 1-tetralone: Use MeMgBr to add a methyl group. 4. Formation of 6,7-dimethoxy-1-tetralone: React the tertiary alcohol with POCl3. 5. Robinson annulation and Fischer indole synthesis: Perform Robinson annulation with ethyl vinyl ketone (EVK) and Fischer indole synthesis using HCl and Zn-Hg reduction. 6. Double bond and ethoxycarbonylation: Use SeO2 in dioxane and react with diethyl carbonate (EtOCO2Et) and TEA. 7. Formation of enamine, isomerization, and cyclization: Employ NaH, ethylamine, concentrated HCl, ethyl chloroformate (EtOC(O)Cl), and sodium ethoxide (NaOEt). 8. Deprotection of PMB groups: Utilize cerium(III) chloride (CeCl3). 9. Final steps to synthesize morphine: Treat with p-toluenesulfonic acid (p-TSA) in methanol (MeOH) and react with ammonia (NH3) and hydrogen (H2) under pressure.

Step-by-step solution

Formation of 1-tetralone

To form 1-tetralone from naphthalene, we first perform an oxidation with chromium trioxide (CrO3) and acetic anhydride (Ac2O) to form 1-naphthaldehyde. Next, perform a reduction with sodium borohydride (NaBH4) to form the corresponding alcohol, followed by oxidation with pyridinium chlorochromate (PCC) to form 1-tetralone. Step 2: Perform α-bromination

α-Bromination of 1-tetralone

To perform α-bromination, treat 1-tetralone with N-bromosuccinimide (NBS) in the presence of a radical initiator like AIBN. This will selectively form the α-brominated 1-tetralone. Step 3: Perform Grignard reaction

Grignard reaction with brominated 1-tetralone

Treat the α-brominated 1-tetralone with methylmagnesium bromide (MeMgBr) to perform a Grignard reaction. This will add a methyl group at the α-position of the ketone, forming a tertiary alcohol as a result. Step 4: Perform ring closure

Formation of 6,7-dimethoxy-1-tetralone

To form the ring, the tertiary alcohol is reacted with phosphorus oxychloride (POCl3). This forms a phosphite intermediate, which rearranges to form the desired ring-closed product, 6,7-dimethoxy-1-tetralone. Step 5: Robinson annulation

Robinson annulation and Fischer indole synthesis

Firstly, perform a Robinson annulation using ethyl vinyl ketone (EVK). This will involve aldol condensation followed by an intramolecular Michael addition. This gives us an intermediate with an indole ring that we will convert to an indoline using the Fischer indole synthesis by treating the compound with hydrochloric acid (HCl) and then reduction by zinc amalgam (Zn-Hg). Step 6: Re-formation of the double bond

Double bond and ethoxycarbonylation

To re-form the double bond, treat the compound with selenium dioxide (SeO2) in the presence of dioxane. Then, perform an ethoxycarbonylation with diethyl carbonate (EtOCO2Et) and TEA (triethylamine) to create the necessary ethoxycarbonyl group. Step 7: Form the enamine

Formation of enamine, isomerization, and cyclization

Treat the compound with sodium hydride (NaH) and ethylamine to form the enamine. Then, perform an isomerization by treating the enamine with concentrated hydrochloric acid (HCl). Finally, perform a cyclization reaction using ethyl chloroformate (EtOC(O)Cl) and sodium ethoxide (NaOEt) to form the intermediate before the final steps of morphine synthesis. Step 8: Perform deprotection

Deprotection of PMB groups

Treat the intermediate with cerium(III) chloride (CeCl3) to remove the PMB protecting groups on the morphine skeleton. This will give us the penultimate morphine intermediate. Step 9: Final steps

Final steps to synthesize morphine

Treat the penultimate intermediate with p-toluenesulfonic acid (p-TSA) in methanol (MeOH) to perform a rearrangement and generate the morphine structure. Then, treat the compound with ammonia (NH3) and hydrogen (H2) under pressure to perform a reductive amination and generate the final morphine product.

Key concepts

Alkaloid Synthesis

Alkaloid synthesis refers to the process of creating alkaloids, which are naturally occurring compounds often found in plants and known for their pharmacological effects. These compounds frequently contain basic nitrogen atoms and are classified by their common nitrogenous precursor or their biosynthesis. In a laboratory setting, alkaloids can be synthesized through a series of chemical reactions starting with simple organic molecules.

For example, the synthesis of morphine, a well-known alkaloid used for pain relief, involves multiple steps designed to introduce complexity and specificity into the molecular structure. This encompasses oxidation, reduction, and reactions that introduce nitrogen or modify its existing functional groups. During the Gates and Tschudi synthesis of morphine, various intermediates are strategically shaped to eventually form the complex structure of morphine. Techniques such as protecting group strategies are often employed to prevent certain functional groups from reacting until the desired step, ensuring accurate structural development and isomer control.

Grignard Reaction

The Grignard reaction is an organometallic chemical reaction in which alkyl, vinyl, or aryl-magnesium halides (Grignard reagents) add to a carbonyl group in an aldehyde or ketone. This reaction forms a secondary or tertiary alcohol, respectively, after treatment with water or another proton source.

In the context of morphine synthesis, a Grignard reagent is used to add a carbon chain to the α-brominated 1-tetralone, a key intermediate. The Grignard reagent, prepared from an alkyl or aryl halide and magnesium, is a strong nucleophile and attacks the electrophilic carbon in the carbonyl group of the α-brominated 1-tetralone. This forms an alcohol upon subsequent work-up. Proper handling and anhydrous conditions are crucial, as Grignard reagents are highly reactive with water. The Grignard reaction is pivotal in increasing the carbon count and contributing to the complex architecture of the morphine molecule.

Robinson Annulation

Robinson annulation is a classic organic chemistry reaction that combines an aldol condensation with a Michael addition to form ring structures, specifically six-membered carbocycles. This reaction sequence is powerful for creating dense, complex molecular architectures from simpler starting materials.

Within the pathway to synthesize morphine, the Robinson annulation is performed to construct a key ring system integral to the morphine framework. The initial aldol condensation adds a new carbon-carbon bond, whereas the subsequent Michael addition closes the ring. This multi-step process serves to expand the molecular complexity and is particularly useful in alkaloid synthesis for constructing the steroidal and polycyclic backbones found in many alkaloid structures. The conditions of the reaction are carefully controlled to avoid undesired side products and to favor the formation of the desired isomers.

Fischer Indole Synthesis

Fischer indole synthesis is a chemical reaction that produces indoles, which are structural motifs present in numerous natural products and pharmaceuticals, from phenylhydrazines and ketones or aldehydes. The reaction involves heating the reactants in the presence of an acid catalyst.

For the conversion of certain intermediates into indoline, a component of the morphine structure, the Fischer indole synthesis is employed. The method involves acid-catalyzed rearrangement, which helps construct the indole from a hydrazone intermediate that would be derived from an earlier step involving a ketone precursor. Following the formation of indoline, further synthetic transformations will elaborate the scaffold towards the morphine core. This synthesis is crucial for crafting the heterocyclic structure that is central to the biological activity of many alkaloids. The Fischer indole synthesis illustrates the elegance of utilizing functional group interconversions to build complex, nitrogen-containing heterocycles.