[moggen]

Hi,

currently studying for an exam in our introductory course in organic chemistry and stumbled across an old exam-question which I'm having trouble figuring out. It's a synthesis of artificial amino acids with terminal trifluoromethyl groups where you're asked to specify certain reagents aswell as determinating the products of some steps.

The products C-G I managed to figure out however A, B and R1 is bothering me. Going backwards B should ofcourse be either an aldehyde or a primary alcohol however I can't determine the use of HBr in the reaction. Is it possibly a cleavage of an ether yielding the primary alchohol? If so, what would be the proper reagent R1 to get this ether?

/Marcus

[MissPhosgene]

They could be doing a peterson olefination with the appropriate acetal or ether. The diastereomers resulting from the initial reaction at the carbonyl should be separable. Acidic conditions would give the E-alkene and aldehyde or alcohol which can be oxidized to the acid.

[movies]

I have an idea of what A and B are (or could be), but I agree that is definitely the more challenging part of the question.  I think the HBr is probably serving two functions: causing elimination to form the trisubstituted alkene and probably cleaving a protecting group to reveal an alcohol (as you suggested).  Think about what sort of reagent R¹ would have to be for this to be the case (probably easiest to work backwards).

I doubt it is actually a Peterson olefination, but that is an interesting idea as well and it might be just as effective.

Would you mind posting your thoughts on C–G at some point as well?  It could be a good problem for other people on the board to consider.

[Doc Oc]

I would have guessed a Horner-Wadsworth-Emmons olefination to attach the ester and then a saponification, but then neither the HBr nor the Jones oxidation steps make any sense.  I confess I looked on SciFinder and it came up with those results as well, so I'm stumped now.  I'll definitely be checking back for new ideas/insights.

[MissPhosgene]

How about add ethyl magnesium bromide, dehydrate with HBr, CrO3 regioselective allylic oxidation.  Doesn't fit with the E-olefin (isomers as a result of the grignard), assuming that's the exclusive product of dehydration.

[nj_bartel]

could you run a wittig with the correct acetal, then HBr removing the acetal to yield the aldehyde?

[movies]

How about add ethyl magnesium bromide, dehydrate with HBr, CrO3 regioselective allylic oxidation.  Doesn't fit with the E-olefin (isomers as a result of the grignard), assuming that's the exclusive product of dehydration.

Pretty close to what I was thinking, but regioselectivity in the oxidation is probably not going to happen.  Think about introducing the oxygenation as part of the Grignard reagent.

The HWE/Wittig ideas are good ones too, it just doesn't seem to fit with the HBr step though.  Certainly I would think that would be a reasonable proposal if you weren't given the reagents.

[Doc Oc]

could you run a wittig with the correct acetal, then HBr removing the acetal to yield the aldehyde?

That would be my next guess since obviously it's not an ester being attached.  Just don't know why you'd use an acetal rather than the ester, but maybe this question is based on older chemistry?

[moggen]

Thanks for the advice, will try to apply them tomorrow and see if I can come up with something of value. Regarding the date of the reaction it was published in  (J. Med. Chem.1964, 7, 369) according to the question. Unfortunately we can only access SciFinder from our uni-library however I wasn't in range or I would've looked it up.

[MissPhosgene]

Thanks for the advice, will try to apply them tomorrow and see if I can come up with something of value. Regarding the date of the reaction it was published in  (J. Med. Chem.1964, 7, 369) according to the question. Unfortunately we can only access SciFinder from our uni-library however I wasn't in range or I would've looked it up.

They don't show or provide experimental details on A or B. Can't back track very far because my school doesn't have subscriptions to the listed journals. SciFinder yielded nothing.

[nj_bartel]

could you run a wittig with the correct acetal, then HBr removing the acetal to yield the aldehyde?

That would be my next guess since obviously it's not an ester being attached.  Just don't know why you'd use an acetal rather than the ester, but maybe this question is based on older chemistry?

I was just guessing at compatibility with forming the wittig intermediate / lack of side reactions.  Are esters wittig compatible?

[OC pro]

R1 could be a Phosphonium compound like Ph3PCHCH2OMe (pre-formed ylene) which upon reaction with the highly reactive trifluoromethylketone affords the allyl ether After ether cleavage with HBr one would obtain the allyl alcohol. Jones oxidation of this allylic alcohol gives the acid.

The rest C to G is much easier...

[MissPhosgene]

could you run a wittig with the correct acetal, then HBr removing the acetal to yield the aldehyde?

That would be my next guess since obviously it's not an ester being attached.  Just don't know why you'd use an acetal rather than the ester, but maybe this question is based on older chemistry?

I was just guessing at compatibility with forming the wittig intermediate / lack of side reactions.  Are esters wittig compatible?

Yes, they are compatible with esters. triphenyl phosphonium ylides, HWE, ..

[dunno260]

My thought was it was just a Wittig reagent with a MOM protected ether or some such acid labile group (TBS, TIPS, TBDPS.  Though you would have to run the reaction under Schlosser conditions to get the Z-alkene using the Wittig reagent.  That trifluoroacetone should be a very hot electrophile which would make a Julia-Kocienski olefination a possibility as well (with the correct acid labile protecting group).

[movies]

The alkene geometry isn't really important since it gets reduced later on anyway.