Question

In a series of seven steps, (S)-malic acid is converted to the bromoepoxide shown on the right in \(50 \%\) overall yield. This synthesis is enantioselective-of the stereoisomers possible for the bromoepoxide, only one is formed. In thinking about the chemistry of these steps, you will want to review the use of dihydropyran as an - OH protecting group (Section 16.7D) and the use of the \(p\)-toluenesulfonyl chloride to convert the \(-\mathrm{OH}\), a poor leaving group, into a tosylate, a good leaving group (Section 10.5D). (a) Propose structural formulas for intermediates \(\mathrm{A}\) through \(\mathrm{F}\) and specify the configuration at each chiral center. (b) What is the configuration of the chiral center in the bromoepoxide? How do you account for the stereoselectivity of this seven-step conversion?

Short answer

Question: Propose structural formulas for the intermediates A through F and the final bromoepoxide for the given step-by-step solution. Determine the configuration of the chiral center in the bromoepoxide and explain the stereoselectivity of the seven-step conversion. Answer: Intermediate A is (S)-2-(2,2-dihydro-2H-pyran-2-yloxy)butanedioic acid, which forms when the hydroxy group of (S)-malic acid is protected by a THP group. Intermediate B is (S)-2-(2,2-dihydro-2H-pyran-2-yloxy)-4-(4-methylbenzenesulfonyloxy)butanoic acid, with a tosyl group attached to the remaining hydroxy group in intermediate A. Intermediate C is (S)-2-(2,2-dihydro-2H-pyran-2-yloxy)-1,2-epoxybutane-1-sulfonic acid, which forms due to the epoxidation reaction with the tosylate leaving group. Intermediate D is (S)-2-hydroxy-1,2-epoxy-4-(2,2-dihydro-2H-pyran-2-yloxy)butane, with the hydroxy group restored after the removal of the THP protecting group. Intermediate E is (S)-2-hydroxy-4-(2-bromo-1,2-dihydro-2H-pyran-2-yloxy)butan-1,2-diol with a bromonium ion and a positive charge formed due to the bromination reaction of the epoxide. Intermediate F is (S)-2-bromo-1,2,4-trihydroxy-butane-4-(2,2-dihydro-2H-pyran-2-yloxy)butane, in which a hydroxy group is added to one side of the bromine atom after the nucleophilic attack by water. The final bromoepoxide product is (S)-2-bromo-3,4-epoxybutanol, formed by an intramolecular nucleophilic substitution that forms the new epoxide ring and eliminates the bromide ion. The configuration of the chiral center in the bromoepoxide is S. The stereoselectivity of the seven-step conversion is attributed to the specific arrangements of the reactants and intermediates, which allow for controlled preservation or alteration of the stereochemistry, resulting in the formation of the desired enantiomer.

Step-by-step solution

Protecting the Hydroxy Group

In the first step, the hydroxy group of (S)-malic acid is protected using dihydropyran. The reaction between the hydroxy group and dihydropyran forms a tetrahydropyranyl (THP) ether, which serves as a protecting group for the hydroxy group. Therefore, intermediate A is formed by the addition of a THP group to the hydroxy group of (S)-malic acid.

Converting OH to a Good Leaving Group

Since hydroxy groups are poor leaving groups, we need to convert it into a good leaving group. In this case, we can use p-toluenesulfonyl chloride (TsCl) to convert the hydroxy group into a tosylate group. Intermediate B is then formed by attaching the tosyl group to the remaining hydroxy group in intermediate A.

Formation of the Epoxide

Now that we have a good leaving group (tosylate), the next step is to form an epoxide. An epoxidation reaction will occur, with the breaking of the tosylate bond and the formation of an epoxide. Intermediate C is the resulting compound with the epoxide ring.

Deprotection of the THP Ether

With the epoxide formation complete, we need to remove the THP protecting group. This is done through hydrolysis, which breaks the THP ether and restores the hydroxy group. Intermediate D is the resulting compound with the hydroxy group and the epoxide ring intact.

Formation of the Bromonium Ion

In this step, a bromination reaction occurs in which a bromine atom attacks the epoxide ring. A bromonium ion is formed by opening the epoxide ring and the attachment of the bromine atom. Intermediate E is the resulting compound with the bromonium ion and a positive charge.

Nucleophilic Attack by Water

Next, a nucleophilic attack by water occurs where the water acts as a nucleophile and attacks the positively charged center of the bromonium ion. The attack breaks the bromonium ion, resulting in intermediate F, in which a hydroxy group is added to one side of the bromine atom.

Formation of the Bromoepoxide

In the final step, an intramolecular nucleophilic substitution takes place where the hydroxy group formed in the previous step attacks the adjacent carbon. This forms a new ether or epoxide ring while eliminating the bromide ion. The final product is a bromoepoxide with the desired chirality and configuration.

Answer for part (b)

The configuration of the chiral center in the bromoepoxide is S, as the synthesis proceeds with complete diastereoselectivity. The stereoselectivity in this seven-step conversion can be attributed to the specific arrangement of the reactants and intermediates. In each step, the configurations are preserved or altered in a controlled manner, favoring the formation of the desired stereoisomer. Such tactic stereochemistry control ensures that only one enantiomer is formed as the final product.

Key concepts

Enantioselective Synthesis

Enantioselective synthesis refers to a method in organic chemistry that leads to the formation of a specific enantiomer of a chiral product. Chirality, a key concept here, means that the molecule can exist in two mirror-image forms that cannot be superimposed on each other, much like our left and right hands.

Enantioselectivity is crucial because different enantiomers can have vastly different biological activities and properties. For example, one enantiomer might be therapeutic while another could be harmful. The (S)-malic acid conversion to bromoepoxide mentioned in the exercise is an excellent illustration of enantioselective synthesis—only the desired S-enantiomer of bromoepoxide is formed.

This stereoselective outcome can be achieved through the use of chiral auxiliaries, catalysts, or reagents, which help to promote the reaction down a pathway that favors the formation of one enantiomer over the other.

Protecting Groups in Organic Synthesis

In organic synthesis, sensitive functional groups often need to be 'protected' to prevent them from reacting under conditions where we want to modify other parts of the molecule. A protecting group can be added to a functional group to modify its reactivity.

In the step-by-step solution, dihydropyran is used as a protecting group for an alcohol (hydroxy group) of (S)-malic acid to create a THP ether. This intermediate protects the hydroxy group during subsequent reactions. The use of protecting groups is like putting a cap on a bottle—the contents are kept safe until the cap is intentionally removed. Later in the synthesis, the protecting group is removed (deprotected) to restore the original functionality of the molecule.

Protecting groups are essential for the strategic planning of complex organic syntheses, as they allow chemists to 'mask' functional groups temporarily and then 'unmask' them when needed.

Nucleophilic Substitution Reactions

Nucleophilic substitution is a fundamental type of reaction in organic chemistry, often abbreviated as SN1 or SN2 (Substitution Nucleophilic Unimolecular or Bimolecular, respectively).

In such reactions, a nucleophile, which is a electron-rich species, attacks an electrophile, typically a carbon atom attached to a good leaving group. During the conversion of (S)-malic acid to bromoepoxide, p-toluenesulfonyl chloride (TsCl) is used to transform an alcohol into a tosylate, thereby converting a poor leaving group into a good one. This change facilitates the nucleophilic attack, leading to the formation of the desired substitution product. For example, in step 7, a hydroxy group acts as a nucleophile and performs an intramolecular attack to form the bromoepoxide.

Epoxidation Reaction

An epoxidation reaction involves the formation of an epoxide, a three-membered cyclic ether, typically from an alkene or an alkyne. In synthesis pathways, epoxidation is a crucial step for introducing an oxygen atom in a highly strained ring structure, which can then be further manipulated.

The formation of the epoxide in the provided solution occurs as an intermediate step. Converting the tosylate into an epoxide increases the molecule's reactivity, making it suitable for further reaction steps like opening the epoxide ring or forming a bromoepoxide, as with the given problem. Epoxidation is often achieved using specific reagents such as peroxy acids, which transfer an oxygen atom to the substrate.

Stereochemistry

Stereochemistry is concerned with the spatial arrangement of atoms in molecules and how this arrangement affects the physical and chemical properties of those compounds. Stereochemistry is particularly important when dealing with chiral substances, which have molecules that are non-superimposable on their mirror images.

The stereochemistry of a molecule can determine its reactivity, the direction in which it will interact with other chiral molecules, and importantly, biological activity. In the conversion to bromoepoxide, care is taken at each step to ensure that the desired stereochemistry is preserved or correctly altered, enabling the selective formation of the targeted enantiomer.

Chirality in Organic Compounds

Chirality in organic compounds is a property that occurs due to the presence of an asymmetrical carbon atom, known as a chiral center, which is bonded to four different groups. This property leads to the existence of two enantiomers for every chiral molecule.

Chirality is of significant interest in organic chemistry because each enantiomer of a chiral compound can exhibit different behavior in chiral environments, such as biological systems. Understanding how to control and predict the formation of specific enantiomers is vital for the synthesis of pharmaceuticals, agrochemicals, and other chiral substances. The mention of the specific configuration at the chiral center in the exercise highlights the importance of chirality and enantioselectivity in such syntheses.