compound3

Katalin Sagi (extra credit) Katalin: This is a nice, workable, and straight forward synthesis. While it would probably be effective the way you have it written, you may get a higher yield if you reverse the order of the simmons-smith reaction and the williamson ether synthesis. Having the double bond there will activate the bromide toward sn2 substitution, because it is an allylic halide. Bruce Bondurant

Assigned to: Shaun Alvarado, Alex Kravetz

Current Attempt: 1) Formation of the lithium enolate 2) aldol condensation 3) reduction 4) halogenation via Tosyl Ester intermediate 5) SN2 via sodium methoxide 6) cyclopropane ring formation via Zinc Coupled catalyst

This looks like it will work. I think you have a unique and clever synthesis route. Bruce Bondurant​

First attempt:

Proceeds via the following: 1) protection of the aldehyde via acetylation 2) formation of the grignard reagent 3) combination of grignard reagent with acetone under ether 4) deprotection of the aldehyde and protonation of the alkoxide via a weak acid 5) E1 elimination via alcohol dehydration reacted to completion via removal of water 6) reduction of the aldehyde to an alcohol via NaBH4 7) halogenation via TsOH and NaBr 8) SN2 substitution via sodium methoxide 9) cyclopropanation via the Simmons-Smith.

Shaun and Alex: This is really an ingeneous synthesis. It almost completely makes sense, and makes good use of the reactions that you are familiar with. There is one verry subtil issue with the third step, grignard reaction. There is something called the beta oxygen effect. If you make a grignard one carbon away from an ether or acetal, It will tend to eliminate the alkene in an E2 type reaction. This is because alkoxide is less basic than carbanion. Look at Enamines in WADE chapter 22. Also addition of a cyanide followed by hydrolysis, then formation of the ester and finally methyl grignard may by a way arround it. Since you are converting the aldehyde to an alcohol anyway, you may consider the malonic ester synthesis, also in Chapter 22 to be a better route. Over all, this is a good synthetic strategy though. Bruce Bondurant

Second Attempt: 1) Aldol condensation of acetone and acetyl-aldehyde. 2) reduction of the aldehyde via NaBH4 3) Synthesis continues at step 7 of the original.

You would probably want to completely convert the aldehyde to the enolate by treatment with LDA, or better yet convert it to the enamine by treatment with pyrrolidine. Also consider the alkyne chemistry that I mentioned today. The conditions that cleave the borate ester and tautomerize the resulting enol would probably also dehydrate the alcohol and form the double bond. Bruce Bondurant