sertraline

Sources: 1. Wade. 2. "Efficient Enantioselective Synthesis of Sertraline, A Potent Antidepressant, via a Novel Intramolecular Nucleophilic Addition to Imine" Organic Letters,Volume 1, No.2, April 1999, Pages 293-294. 3. "Indium Triflate Mediated Acetalization of Aldehydes and Ketones" Tetrahedron Letters, Volume 47, Issue 52, 25 December 2006, Pages 9317-9319. 4. "Lithium-Initiated Imide Formation. A Simple Method for N-Acylation of 2-Oxazolidinones and Bornane-2,10-Sultam" J. Org. Chem., 1995, 60 (7), pp 2271–2273.

Kerri- In the paper that I have, I didn't see any Diels-Alder reactions. I think I see a Wittig reaction and they seem to also use a poison catalyst. I'm still trying to sort through the 7 steps they use to find out what they all are.

We have found a synthesis that hints at Nucleophilic Addition to an imine that we are working through right now, will be posted asap.

The paper I have starts with 2-bromobenzaldehyde and converts it to arylmagnesium bromide. From there they reacted it with a cinnamic imide to get another imide which was then reduced to an alcohol. It was then treated with I2-PPh3-imidazole and hydrolysis with HCl giving an iodoaldehyde. The ring was then closed with t-BuLi in THF. This is just a blanket summary of the steps in my paper and this only gave one of the enantiomers. It sounds very similar to yours. I'll try to get the steps outlined in the paper drawn up and posted today. -Meaghan

This synthesis looks good. the iodine, imidazole and triphenyl phosphene appears to be a variation of the appel reaction, which is a gentle and effective way to replace an alcohol with a halogen. All the steps make sense, and you have a good explanation of them, indicating that you also understand what is going on in each reaction. I think that Sertraline is as good as made. Nice work, everyone! Bruce Bondurant Source 2 Meaghan: This is really an interesting synthesis. Part C is known as a Michael Addition, or vinylogous addition to an alpha beta unsaturated carbonyl. This example of it is unique for two reasons. First is that the nucleophile is a grignard reagent Usually these attack the carbonyl rather than the beta position as in this case. Second is that stereochemistry of the addition is directed by the cyclic carbamate / imide protecting group that acts as a chiral auxillery through the stereochemistry of the phenyl group. Nice find Bruce Bondurant

Creation of compound 4:

Part a: After this compound is created is then protected using Acetalization (Source 3). Acetalization is a reaction for protection carbonyl groups such as the one in compound 4: The carbonyl is treated with an alcohol or diol with a dehydrating agent in the presence of a catalytic amount of acid. In part a the alcohol used was MeOH, the dehydrating agent was (MeO)3CH and the catalytic acid was p-TsOH. The next portion of part A is coverting the Br to an arylmagnesium bromide. This is simply done using Mg and THF.

Kerri- In theory this would work and give the right regiochemistry. In practice, you will need to use a different formylating reagent, because the formyl chloride is unstable to carbon monoxide and HCl. Though it's not practical in the laboratory, HCl CO and AlCl3 will give the formylation under high pressure. Bruce Bondurant

Dr. Bondurant, Kerri, James and I all found the same paper to work from. Just thought I'd let you know. I don't want all the credit for the great find! Meaghan

Creation of compound 5 using Wittig.

Starting research failed to find anything about "Ho's" Procedure; however, eventually searching the author came up with source 4. My understanding of the paper is that using the anhydride of a starting acid is reacted with Pivalic acid ( (CH3)3CCOCl) and Oxazolidone in LiCl with Et3N as the base. Oxazolidones are normally used in the creation of Imines.. This procedure which I assume to be "Ho's Procedure" is taken exactly as written from source 4 for the use of synthesizing Sertraline. This procedure creates the cinnamic amide for the next portion of the synthesis, the Michael's reaction.

The cinnamic imine and the protected arylmagnesium bromide are reacted together in a Michael's reaction to create compound 8.

Compound 8 using Wade.



Now that you have seen some of the alpha carbon reactions, could you more easily get into this via the malonic ester synthesis followed by decarboxylation and dehydration of the resulting alcohol? I think this would give you the right oxidation state. the compound here is a ketone, what you really want is a carboxylic acid derivative. You could also, of course do the wittig with the triphenylphosphine derivative of methyl-2-chloro ethanoate. Meaghan