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A full FAQ post has been written on meta.chem.SE, explaining the premise of synthesis golf and the 'rules'. Please take a look at this before answering (if you haven't already).


This fifth round of golf concerns the synthesis of (−)-α-(3,4-Dimethoxyphenethylaminomethyl)-4-hydroxy­benzyl­alcohol (denopamine), a synthetic drug indicated for use in the treatment of angina.

4-[(1R)-2-{[2-(3,4-dimethoxyphenyl)ethyl]amino}-1-hydroxyethyl]phenol

The challenge is to propose a route to denopamine. You may start with anything that has less than 10 carbons, but it must be available in the Sigma-Aldrich catalogue. A method should also be included to set the oxymethine stereocentre (no buying it!).

Given the relative simplicity of the target and the need for large quantities of the drug, consideration to step count and scalability should also be taken.

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  • $\begingroup$ Sorry (again) for this not being quite to schedule- the last few weeks of summer are always hectic. An easier target this time so hopefully easier to do on the back of an envelope to get more people involved. $\endgroup$ – NotEvans. Sep 9 '17 at 10:04
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    $\begingroup$ Given that this is the schedule, I’m really happy I got my plaunotol answer in before it was too late. $\endgroup$ – Jan Sep 9 '17 at 14:00
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OK, new route. Retrosynthesis:

retrosynthesis

Denopamine 1 can be made by a reductive amination between amine 2 and aldehyde 3 (either of the two reductive amination disconnections are fairly obvious choices).

The requisite amine 2 contains 10 carbons and so it becomes necessary to make it using some other means - in this case, reduction of a nitroolefin 4, which can itself be made via a nitroaldol reaction from 3,4-dimethoxybenzaldehyde 5 and nitromethane 6.

The chiral α-hydroxyketone 3 can probably be made in numerous ways. Earlier I proposed organoocatalytic oxygenation with PhNO, but another possibility is to have an addition of "formaldehyde anion" to 4-hydroxybenzaldehyde 7. Nitromethane 6 was chosen as the acyl anion equivalent, as the asymmetric Henry reaction is well-established methodology, e.g. by the Evans group (J. Am. Chem. Soc. 2003, 125 (42), 12692–12693).

The forward synthesis is fairly straightforward:

synthesis of amine 2

synthesis of ketone 3

reductive amination

5 steps from cheap starting materials, with longest linear sequence being 3 steps.

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    $\begingroup$ You might want to choose a different reduction for the nitrostyrene, in my experience LiAlH4 reduction is quite low-yuelding. Hydrogenation over Raney Ni in the presence of NH3 might be better $\endgroup$ – Waylander Sep 11 '17 at 7:32
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    $\begingroup$ I was going to post something similar, definitely hydrogenation for the nitromethane product. I was going to do a Jacobsen oxidation on 4-acetoxystyrene to give a chiral epoxide. Hydrolysed in last step. BTW, Ti chlorides are a pig to work up on scale. $\endgroup$ – Beerhunter Sep 17 '17 at 7:34
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Sorry for the mistake in the drawing, the synthesis does NOT start from stryene rather the 4-hydroxylated derivative 4-vinylphenol, it does not affect anything throughout the synthesis later on.

Denopamine Synthesis (Theoretical)

5 Steps Total -

Longest Linear Sequence of 5 -

(1) - Asymmetric Sharpless aminohydroxylation:

OsO4, Chloramine, tBuOH, heat, ligand

(2) - Azide synthesis via diazo transfer :

Imidazole-1-sulfonyl azide hydrochloride, CuSO4, K2CO3, MeOH

(3) - Deprotection (not shown)

(4) - Aziridination through nitrene

Ethylene, heat

(5) - Ring opening using aromatic

1,2-dimethoxybenzene

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    $\begingroup$ Sharpless aminohydroxylation puts a protecting group on N - the reagent is $\ce{TsNCl^-Na+}$ - so you need one more step to get rid of it. $\endgroup$ – orthocresol Sep 9 '17 at 12:05
  • $\begingroup$ That is fair, but alternatively I could do something like azidohydroxylation which is 2 steps in place of the aminohydroxylation + diazo transfer, I picked the latter due to the scalability aspect but disregarded the point you brought up, when I first thought of it. $\endgroup$ – AS_1000 Sep 9 '17 at 12:15
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A synthesis using Sharpless dihydroxylation for stereoinduction:

enter image description here

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