Uploaded January 2023 | Updated September 2026, 2 weeks ago
A classical disconnection approach for a retrosynthesis of this molecule with a benzyl protecting group on a base-sensitive aldol product.
More retrosynthesis videos available at this playlist:
youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1
Retrosynthetic analysis identifies disconnection of the benzyl ether as a protecting group for the hydroxyl group of an aldol product. A Williamson ether synthesis is not possible to form this C-O bond due to a risk of retro-aldol fragmentation under strongly basic conditions. A more mild trichloroacetimidate reagent (TCA) can be used to benzylate under mild acidic conditions instead.
The next disconnection will come from identifying a 1,3-difunctional relationship (1,3-diX) which is best formed by enolate chemistry using an aldol reaction. The lithium enolate formed by reaction of ethyl acetate with LDA is appropriate for this transformation.
The aldehyde required for this aldol reaction also has a 1,3-difunctional relationship between the aldehyde carbonyl and an alkene. To use enolate chemistry and aldol reactions again, a functional group interconversion must be used. The alkene can be formed by elimination reaction from an alcohol. An E2 elimination reaction can be done by first converting the hydroxyl group into a tosylate leaving group, and then treating the tosylate species with a non-nucleophilic base such as potassium tert-butoxide (KOtBu).
The final intermediate in the retrosynthesis can also be disconnected by aldol chemistry back to isobutyraldehyde. Isobutyraldehyde will be treated with a reversible base to cause the aldol self-reaction between the enolate and the aldehyde forms of this molecule, as nucleophile and electrophile, respectively.
#organicchemistry #retrosynthesis #chemistry
A classical disconnection approach for a retrosynthesis of this molecule with a benzyl protecting group on a base-sensitive aldol product.
More retrosynthesis videos available at this playlist:
youtube.com/playlist?list=PLavaRHHaRimVhyZD79H8g08cfhxrZMcB1
Retrosynthetic analysis identifies disconnection of the benzyl ether as a protecting group for the hydroxyl group of an aldol product. A Williamson ether synthesis is not possible to form this C-O bond due to a risk of retro-aldol fragmentation under strongly basic conditions. A more mild trichloroacetimidate reagent (TCA) can be used to benzylate under mild acidic conditions instead.
The next disconnection will come from identifying a 1,3-difunctional relationship (1,3-diX) which is best formed by enolate chemistry using an aldol reaction. The lithium enolate formed by reaction of ethyl acetate with LDA is appropriate for this transformation.
The aldehyde required for this aldol reaction also has a 1,3-difunctional relationship between the aldehyde carbonyl and an alkene. To use enolate chemistry and aldol reactions again, a functional group interconversion must be used. The alkene can be formed by elimination reaction from an alcohol. An E2 elimination reaction can be done by first converting the hydroxyl group into a tosylate leaving group, and then treating the tosylate species with a non-nucleophilic base such as potassium tert-butoxide (KOtBu).
The final intermediate in the retrosynthesis can also be disconnected by aldol chemistry back to isobutyraldehyde. Isobutyraldehyde will be treated with a reversible base to cause the aldol self-reaction between the enolate and the aldehyde forms of this molecule, as nucleophile and electrophile, respectively.
#organicchemistry #retrosynthesis #chemistry
