Chapter 24, Problem 24.39P

E. J. Corey’s 1964 total synthesis of α-caryophyllene (essence of cloves) solves a number of problems of construction of unusual-sized rings.

The first step uses an efficient photochemical [2 + 2] reaction. The desired stereochemistry and regiochemistry had been predicted based on model reactions.

1. (a) [2 + 2] Reactions are quite common in photochemical reactions. Would this reaction be predicted to occur in the ground state?

The next steps follow. Basic alumina is a chromatography support that will often act as a base catalyst.

1. (b) What is the mechanism of the first step?
2. (c) What is the mechanism of the second step?
3. (d) Look at later steps in the synthesis. Does the stereochemistry of the added carbomethoxy group matter?

The next steps are shown here.

1. (e) What is the structure of compound (A)?
2. (f) Give a mechanism for the formation of the cyclized product.

1. (g) Give a mechanism for the first step. Hint: Attack on the lactone carbonyl may be the first step.
2. (h) Give a structure for product (B).

The following two steps are next.

1. (i) Show the reactions of (B).
2. (j) Write a mechanism for the ring-opening reaction. Hint: Note the presence of an acidic proton and a good leaving group in the molecule.

The synthesis was completed by the following steps.

1. (k) What is (C)?
2. (l) What reagents would you use for these transformations?

Interpretation Introduction

Interpretation:

Whether the $[2+2]$ reaction will occur in ground state or not that has to be determined.

Concept introduction:

$[2+2]$ Reaction:

$[2+2]$ Photocycloaddition is the combination of an excited state enone with an alkene to produce cyclobutane.

Woodward-Hoffmann’s rule:

These are set of rules to determine the geometry and the feasibility of pericyclic reactions.  The rules are as follow,

In an open chain system containing $\text{4nπ}$ electrons, the orbital symmetry of HOMO is such that the bonding interaction between the ends must involve overlap between orbital envelopes on opposite faces of the system and this can only be achieved in conrotatory process.

In an open chain system containing $\left(\text{4n}\text{+}\text{2}\right)\text{π}$ electrons terminal bonding interaction within the ground state molecules requires the overlap between orbital envelopes on the same face of the system, attained only by disrotatory displacements.

For photochemical condition the electron of HOMO is excited to LUMO and hence the reversal of the terminal symmetry relationship occurs.

Explanation of Solution

According to Woodward Hoffmann’s rule ground state $[2+2]$ which is under thermal condition is forbidden.

Ground state it shows ${\text{π}}_{\text{2}}{}_{\text{s}}+{\text{π}}_{\text{2}}{}_{\text{s}}$ and no antarafacial electrons.  So it violates the formula.

Hence ground state reaction is forbidden.

Interpretation Introduction

Interpretation:

The mechanism of the given step has to be given.

Concept introduction:

Tautomerisation:

Tautomers are structural isomers of a compound that readily interconverts into each other.  The process of interconversion is called the tautomerisation and it involves simple proton transfer in intramolecular fashion.

One of the major examples of tautomerisation is keto–enol tautomerism.  The mechanism is as follows,

Among these keto and enol keto is more stable due to high bond energy of carbon oxygen double bond ($\text{799}\text{kJ}{\text{mol}}^{\text{-1}}$) than single bonded carbon oxygen energy ($\text{358}\text{kJ}{\text{mol}}^{\text{-1}}$) in enol.

Explanation of Solution

Here basic alumina acts as base and abstract the enolisable hydrogen from left side because thus the enol form is much more stabilised due to formation of more substituted alkene.

But again the enol form tautomarises to keto form as the bond energy of carbon double bonded oxygen is more than single bonded carbon and oxygen.  Thus the proton undergoes backside attack and so this product is formed.

The mechanism is as follows,

Interpretation Introduction

Interpretation:

The mechanism for the given step has to be given.

Concept introduction:

Acid-base reaction:

The species that donates proton or accepts lone pair of electrons are called acids and those who accepts proton or donates lone pair of electrons are called base.

$S_{N^2}$ Reaction:

The ${\text{S}}_{{\text{N}}^{\text{2}}}$ reaction is a type of nucleophilic substitution reaction where one bond is broken and one bond is formed simultaneously. Since the two reacting species are involved in the rate determining step hence it is bimolecular also.  The reaction passes through a five co-ordinated intermediate.  The mechanism is as follows,

Explanation of Solution

Here the reaction undergoes acid base reaction followed by ${\text{S}}_{{\text{N}}^{\text{2}}}$ reaction pathway.

Here $\text{NaH}$ acts as base and abstract the acidic hydrogen from right side (as the carbanion formed is secondary which is stable than the tertiary carbanion that could have formed from left side) and thus the carbanion formed undergoes ${\text{S}}_{{\text{N}}^{\text{2}}}$ with ${\text{(MeO)}}_{\text{2}}\text{C=O}$.  The nucleophile i.e. the carbanion attacks on the electron deficient carbonyl carbon and $-\text{OMe}$ being a good leaving group leaves

Then again this leaving group $-\text{OMe}$ acts as base and abstract the acidic hydrogen from right side as it is more acidic than left side hydrogen because of the electron withdrawing nature of both of the $\text{C=O}$ of carbonyl carbon and the ester.  Thus the carbanion formed can be stabilised by resonance with both the $\text{C=O}$.  Now again the carbanion acts as nucleophile and does normal ${\text{S}}_{{\text{N}}^{\text{2}}}$ attack on $\text{Me}-\text{I}$ and thus the product is formed.

The mechanism is as follows,

Interpretation Introduction

Interpretation:

Whether the stereochemistry of the added carbomethoxy group matters or not that has to be determined.

Concept introduction:

Steric hindrance:

Steric effects are non bondind interactions that influence the shape (conformation) and reactivity of the ions and molecules.  Steric effects complement electronic effects which usually dictate shape and reactivity.  Steric effects result from repulsive forces between overlapping electron clouds. 

Steric hindrance is the consequence of steric effects.  Steric hindrance is the slowing of chemical reactions due to steric bulk.

Explanation of Solution

From the later steps included in the reaction it can be concluded that the added carbomethoxy group’s stereochemistry matters as it is a bulky group and later on the reaction more bulkier rings are formed so it has to be properly oriented to the opposite side to avoid the steric hindrance.

Interpretation Introduction

Interpretation:

The structure of the compound A has to be given for the given reaction,

Concept introduction:

Nucleophilic addition reaction:

Nucleophilic addition reaction can be described as the addition reaction between the chemical compound that is electron deficient and having electron deficeint pi bonds with electron rich chemical compound known as nucleophile that results into disapperance of the pi bond amnd formation of new sigma bonds.

Addition of nucleophile to carbon heteroatom double or triple bonds shows variety as these bonds are polar due to high electrnegetive differences and hence the carbon atom carries a partial positive cahrge   thus the carbon atom becomes the electrophilic centre and becomes primary target for nucleophile and thus the reactions occurs is aclled 1,2-nucleophilic addition reaction.  The mechanism is as follows,

Organolithium compounds:

Organo lithium compounds are organometallic compounds containing carbon lithium bond.  These act as nucleophile and bases also because of the high electronegetive difference between carbon and lithium and the bond becomes polar.  Nucleophilic organolithium reagents can add to electrophilic carbonyl double bonds to form carbon-carbon bonds.  They react with ketone or aldehyde to give alcohol i.e. they mainly undergoes 1,2-nucleophilic addition reaction

Explanation of Solution

Here the Organolithium compound is used as nucleophile which will attack the carbonyl carbon that behaves as electrophile and reduce it to alcohol.  The oxygen lithium bond formed is more polar.  The reaction is as follows,

Thus the structure of compound A is,

Interpretation Introduction

Interpretation:

The mechanism for the cyclised product given the question has to be given.

Concept introduction:

Reduction of alkyne:

Treatment of an alkyne with ${\text{H}}_{\text{2}}$ in the presence of transition metal mostly palladium, platinum or nickel results in the addition of two moles of ${\text{H}}_{\text{2}}$ to the alkyne via the formation of alkene.  Catalytic reduction of an alkyne is done above room temperature and with moderate pressure with ${\text{H}}_{\text{2}}$ gas.

Oxidation by $Cr{O}_3$:

Chromic acid is used as oxidising agent.  It oxidises primary alcohol to acid and it oxidides seconadary alcohol to ketone in presence of acid.  The mechanism as follows,

Lactone formation:

Lactones are cyclic carboxylic esters  that are formed by intramolecular esterification of the corresponding hydroxycarboxylic acids which takes place spontaneously when th ering that is formed is five or six membered.  The reaction pathway is as follows,

Explanation of Solution

In this pathway of lactone formation 1^st the alkyne has been reduced to alkane… the reaction mechanism as follows,

In the 2^nd step the orthoester is oxidised to aldehyde which is further oxidised to acid with reaction with $Cr{O}_3$.  Here the aldehyde is oxidised as aldehyde shows more reactivity than secondary alcohol.  Final step lactone formation occurs.

Interpretation Introduction

Interpretation:

Mechanism for the given step has to be given,

Concept introduction:

Acid-base reaction:

The species that donates proton or accepts lone pair of electrons are called acids and those who accepts proton or donates lone pair of electrons are called base.

Explanation of Solution

The mechanism follows as,

Interpretation Introduction

Interpretation:

Structure of product B has to be given.

Concept introduction:

Decarboxylation reaction:

This is the reaction where carboxyl acid group is eliminated along with carbon dioxide.

Explanation of Solution

The reaction pathway follows as,

1^st the ester is hydrolysed to acid followed by decarboxylation.

Hence the product B is,

Interpretation Introduction

Interpretation:

The reactions of B for given condition has to be shown.

Concept introduction:

Reduction of ketone:

${\text{H}}_{\text{2}}\text{/Ni}$ reduces ketone to secondary alcohol.

$S_{N^2}$ Reaction:

The ${\text{S}}_{{\text{N}}^{\text{2}}}$ reaction is a type of nucleophilic substitution reaction where one bond is broken and one bond is formed simultaneously. Since the two reacting species are involved in the rate determining step hence it is bimolecular also.  The reaction passes through a five co-ordinated intermediate.  The mechanism is as follows,

Explanation of Solution

The reaction goes as,

1^st the ketone is reduced to alcohol which further undergoes ${\text{S}}_{{\text{N}}^{\text{2}}}$ with $\text{TsCl}$.

Interpretation Introduction

Interpretation:

Mechanism of the ring opening reaction has to be shown.

Concept introduction:

Acid-base reaction:

The species that donates proton or accepts lone pair of electrons are called acids and those who accepts proton or donates lone pair of electrons are called base.

Explanation of Solution

DMSO here acts as a strong base and takes up the acidic hydrogen from alcohol.  Thus to form strong carbon oxygen double bond the ring opens and $-\text{OTs}$ being a very good leaving group leaves easily forming a new carbon-carbon double bond.

Interpretation Introduction

Interpretation:

The structure of C has to be determined.

Concept introduction:

Tautomerisation:

Tautomers are structural isomers of a compound that readily interconverts into each other.  The process of interconversion is called the tautomerisation and it involves simple proton transfer in intramolecular fashion.

One of the major examples of tautomerisation is keto–enol tautomerism.  The mechanism is as follows,

Among these keto and enol keto is more stable due to high bond energy of carbon oxygen double bond ($\text{799}\text{kJ}{\text{mol}}^{\text{-1}}$) than single bonded carbon oxygen energy ($\text{358}\text{kJ}{\text{mol}}^{\text{-1}}$) in enol.

Explanation of Solution

Here basic alumina acts as base and abstract the enolisable hydrogen from left side because thus the enol form is much more stabilised due to formation of more substituted alkene.

But again the enol form tautomarises to keto form as the bond energy of carbon double bonded oxygen is more than single bonded carbon and oxygen.  Thus the proton undergoes backside attack and so this product is formed.

The mechanism is as follows,

Hence the product C is,

Interpretation Introduction

Interpretation:

The reagents required for the transition given in the question has to be determined.

Concept introduction:

Wittig reaction:

Wittig reaction is the reaction of an aldehyde or ketone with a triphenyl phosphonium ylide to give an alkene and triphenylphosphine oxide.  This is a step up reaction.

Explanation of Solution

The reaction as follows,

Thus the final product is obtained.