Eremophilone, (–)-1a, is a constituent of a commercially available oil with anti-inflammatory and re — Organic Chemistry Chemistry Question
Synthesis of eremophilone
Eremophilone, (–)-1a, is a constituent of a commercially available oil with anti-inflammatory and relaxing properties, isolated from the Australian Eremophila mitchellii shrub (buddha wood). The synthesis of enantiomerically pure eremophilone is challenging due to the cis-configuration of the two methyl groups and the axial orientation of the isopropenyl group. The synthesis of the corresponding diastereomeric mixture 1 starts from ketone 2, which is reacted with ethane-1,2-diol under acidic conditions to provide compound A, followed by regioselective reduction with a borane–THF complex. Oxidative work-up of the borane intermediate yields substance B. Its mild oxidation gives product C, which is reacted stereoselectively in the next step with an appropriate λ5-alkylidenephosphane (ylide) D to furnish compound 3. Its reduction leads to substance E, which reacts with butyl vinyl ether in the presence of mercury acetate to afford compound 4. Heating of compound 4 results in its rearrangement to compound F, which, after deprotection, provides dioxo compound G. Final intramolecular aldolization using reagent H leads to bicyclic 5 as the key intermediate in the synthesis of eremophilone stereoisomeric mixture (1).
Draw the structures of the products and reagents A–H. [VISUAL]
Model Answer
A: Ketal of ketone 2 (formed by reaction of ketone 2 with ethane-1,2-diol under acidic conditions).
B: Primary alcohol formed by regioselective hydroboration-oxidation of the terminal double bond of A.
C: Aldehyde formed by mild oxidation of the primary alcohol B.
D: Ph3P=CHCOOMe (Wittig ylide).
3: Methyl ester ketal formed by stereoselective Wittig reaction of aldehyde C with ylide D.
E: Primary allylic alcohol ketal formed by reduction of methyl ester 3 with LiAlH4 and subsequent mild acid workup.
F: Rearranged aldehyde ketal formed by thermal Claisen rearrangement of allylic vinyl ether 4.
G: Dioxo compound (keto-aldehyde) formed by deprotection of the ketal group of F under acidic conditions.
H: NaOH or NaOMe (base to catalyze the subsequent intramolecular aldol condensation of G to bicyclic compound 5).
The key step in the synthesis is a thermal rearrangement of allylic vinyl ether 4, leading to compound F. For the reaction to proceed, compound 4 must adopt appropriate orientation I to allow for the subsequent sigmatropic transformation. Draw the required orientation of the allylic vinyl ether moiety I in compound 4 that enables the sigmatropic transformation. Use curved arrows to show the flow of electrons in the rearrangement step that provides compound F. What is the name of the rearrangement? Note: You do not have to draw 3D structures. [VISUAL]
Model Answer
This reaction is called the Claisen rearrangement.
Orientation I represents a six-membered chair-like conformation of the allylic vinyl ether moiety with curved arrows showing a [1]-sigmatropic rearrangement (one arrow shifting the double bond of the allyl group to form a new carbon-carbon bond, one arrow breaking the allylic C-O bond to form a carbonyl double bond, and one arrow shifting the vinyl double bond).
This rearrangement typically requires high temperatures, but this is not always an essential requirement. For example, allylic esters, e.g. ester 6, can also undergo this transformation by first treatment with a strong non-nucleophilic base such as lithium diisopropylamide (LDA) at −78 °C to give the corresponding enolate. Subsequent trapping of the enolate with chlorotrimethylsilane yields silyl enol ether J. When allowed to warm to room temperature, substance J undergoes spontaneous rearrangement to substituted silyl ester L through conformation K. Draw the structures of J and L and orientation K that enables the sigmatropic transformation to proceed. Use curved arrows to show the flow of electrons in the rearrangement step to compound L. Note: You do not have to draw 3D structures. [VISUAL]
Model Answer
J: Silyl ketene acetal (silyl enol ether) prepared by deprotonation of allylic ester 6 with LDA and subsequent trapping with TMSCl.
K: Chair-like transition state conformation of silyl ketene acetal J, with curved arrows showing the [1]-sigmatropic shift (Ireland-Claisen rearrangement).
L: Substituted silyl ester product (trimethylsilyl 2-methylpent-4-enoate derivative).