Question

A step in a synthesis of \(\mathrm{PGE}_{1}\) (prostaglandin \(\mathrm{E}_{1}\), alprostadil) is the reaction of a trisubstituted cyclohexene with bromine to form a bromolactone. Propose a mechanism for formation of this bromolactone and account for the observed stereochemistry of each substituent on the cyclohexane ring. Alprostadil is used as a temporary therapy for infants born with congenital heart defects that restrict pulmonary blood flow. It brings about dilation of the ductus arteriosus, which in turn increases blood flow in the lungs and blood oxygenation.

Short answer

Answer: The stereochemistry of each substituent is determined by the oxygen nucleophile's attack on the carbon bonded to the bromonium ion, causing an inversion of configuration at this carbon. The bromine atom retains its original configuration, while the two-carbon chain substituent has an opposite configuration compared to its initial stereochemistry. Oxygen's role in this mechanism is to act as a nucleophile, forming a new bond with the attacked carbon and leading to the formation of the bromolactone.

Step-by-step solution

1. Identify the starting trisubstituted cyclohexene

To start the mechanism, we first have to know the trisubstituted cyclohexene molecule necessary for the synthesis of PGE1. In this case, the trisubstituted cyclohexene has a double bond, an oxygen substituent, and a two-carbon chain substituent.

2. Perform bromination of the starting molecule

The next step is to add bromine to the trisubstituted cyclohexene molecule. This is done through a bromination reaction. In this reaction, the bromine will attack the double bond, forming a bromonium ion (a three-membered ring containing a positively charged bromine). The other bromine ion will remain as Br-. At this point, the molecule has the bromonium ion and a negatively charged bromine ion.

3. Formation of bromolactone with explanation of its stereochemistry

Now that we have the bromonium ion formed, the oxygen substituent on the cyclohexene will act as a nucleophile, which will attack the carbon atom bonded to the bromonium ion (the same carbon as the double bond was). This forms a new bond between the oxygen and the carbon, leading to the formation of the bromolactone. In this step, the stereochemistry of this reaction is determined. As the oxygen attacks from the backside of the molecule (opposite to the bromonium ion), it will result in an inversion of configuration at the attacked carbon, and the bromine will retain its original stereochemistry.

4. Explain the stereochemistry of each substituent on the cyclohexane ring

The stereochemistry of each substituent on the cyclohexane ring is determined by the attack of the oxygen nucleophile and the inversion of configuration at the attacked carbon. The attacking oxygen will cause the bromine atom to remain in its original configuration (its initial stereochemistry in the bromonium ion). Meanwhile, the oxygen's attack will generate an inversion of configuration at the attacked carbon, making the two-carbon chain substituent have an opposite configuration compared to its initial stereochemistry. The orientation of the oxygen substituent itself does not change during the reaction. Thus, by analyzing the stereochemistry of the substituents, we can see how the bromolactone is formed with its specific stereochemical configuration.

Key concepts

Bromolactone Formation Mechanism

Understanding the formation of bromolactones in organic synthesis often involves a reaction known as halolactonization. In the case study question, the trisubstituted cyclohexene undergoes a transformation into a bromolactone as part of the prostaglandin E1 (PGE1) synthesis.

The halolactonization mechanism begins with the addition of elemental bromine to the double bond of the cyclohexene. As a result, a transient bromonium intermediate forms, characterized by its positively charged bromine atom and strained three-membered ring structure. This intermediate is highly susceptible to nucleophilic attack.

Following the bromonium ion formation, the adjacent oxygen substituent, present as a part of another functional group, attacks the more substituted carbon of the bromonium ion. This nucleophilic attack occurs from the back side, leading to the ring closure and the subsequent formation of a bromolactone.

Key Steps in Bromolactone Formation:

• Electrophilic addition of bromine to the double bond forms the bromonium ion.
• The oxygen substituent attacks from the opposite side, opening the bromonium ring and creating a new carbon-oxygen bond.
• As a consequence, a cyclic lactone structure is established with the bromine atom attached to the ring, now known as bromolactone.

Stereochemistry in Organic Reactions

Stereochemistry plays a critical role in the outcome of organic reactions and is particularly important within the context of prostaglandin synthesis, which often requires high stereochemical control. The stereochemistry of a substituent refers to its spatial orientation in three-dimensional space and can significantly influence the biological activity of a molecule.

In the above reaction, the stereochemistry of the bromolactone is determined by the way the oxygen nucleophile attacks the bromonium ion. As the oxygen performs a backside attack (which is a characteristic feature of the S_N2 mechanism), it forces the molecule to undergo inversion of configuration at the carbon atom to which it bonds. This results in the bromine remaining on the opposite face of the molecule relative to the newly formed lactone.

Considerations in Stereochemistry:

• Inversion of configuration typically happens during an S_N2 reaction, which is what stems from the oxygen's nucleophilic attack on the cyclohexene.
• The configuration of other substituents on the ring is dictated by the original stereochemistry and the mechanism of attack by the nucleophile.
• Understanding how these substitutions take place is essential for predicting the biological activity of the final product.

Prostaglandin Synthesis

The synthesis of prostaglandins such as PGE1 is of great interest due to their significant role in mediating physiological responses, including the regulation of inflammation, blood flow, and smooth muscle activity. The synthesis of prostaglandins often involves intricate steps requiring precise control over stereochemistry.

In the synthesis of PGE1 (alprostadil), the bromolactone formation is a pivotal step as it builds the lactone ring, which is a characteristic structural feature of many prostaglandins.

Stages in Prostaglandin Synthesis:

• Building the core carbon framework that contains the necessary functional groups.
• Introducing unsaturation, like the double bonds present in the prostaglandin structure.
• Forming the lactone ring through reactions such as the one discussed in the bromolactone mechanism.
• Final adjustments for the specific side chains and stereochemistry to yield the active prostaglandin molecule.

Alprostadil's ability to dilate blood vessels is leveraged in lifesaving treatments for infants with congenital heart defects, showcasing the profound impact that synthetic organic chemistry has in the development of therapeutic agents.