Sciencemadness Discussion Board

Phenol coupling?

stygian - 29-2-2008 at 16:26

I was marveling at the biosynthetic route to morphine the otherday and I learned of what they called oxidative phenolic coupling, that converts the isoquinoline reticuline into the morphinan structure. I also noticed that in a certain morphinan synthesis written by one DopaMan, phosphoric acid was said to accomplish this same goal, though without introduction of pesky oxygen.
Quote:
This isoquinoline product is then converted, in one of several ways, to racemorphan (levorphanol+dextrorphan). Other methods may be discovered that work well, but this is probably the best method, as it methylates the compound at the same time as the reduction is going on: reduce the quinoline catalytically, in the presence of formaldehyde, by one of a number of acceptable methods (general catalytic reduction - many will work with a semi-complex, cyclic aryl-amine like this). Just be sure to remember to use formaldehyde! Otherwise, use another method.

Another, different, way of finishing the process is as follows: After the Raney nickel reduction, separate the product from the catalyst, purifying as previously outlined. Now, react your product with CH2O and hydrogen, or formic acid, resulting in 2-methyl substitution of the isoquinoline. Heat this with ten times its weight in phosphoric acid (specific gravity, 1.75) at 140-150 degrees Celsius for approximately 70 hours, or a bit longer.


Is this text implying that catalytic reduction with formaldehyde will accomplish the same coupling as the phosphoric acid treatment? What takes place that causes this/these methods to work? What might be some good reading material for understanding how these reactions work?

human biosynthesis of morphine

chemrox - 29-2-2008 at 19:01

Here are a couple of articles (maybe one at a time) on the topic. I want to look further into this and will read and then, perhaps, write. Meanwhile...

Attachment: biosyn M-1.pdf (428kB)
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another, citing, ref.

chemrox - 29-2-2008 at 19:03



Attachment: How human neuroblastoma cells make morphine.pdf (541kB)
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Sandmeyer - 29-2-2008 at 20:12

I fail to see the point with those papers... :(
Quote:
Originally posted by stygian

Is this text implying that catalytic reduction with formaldehyde will accomplish the same coupling as the phosphoric acid treatment? What takes place that causes this/these methods to work? What might be some good reading material for understanding how these reactions work?


Dopaman's "writeup" is (to me at least) impossible to concentrate on, I soon had to stop reading it. Anyways, the key step that you (and Dopaman) refer to is not phenolic coupling but a simple (yet beautiful) aromatic electrophilic substitution, i.e Friedel-Crafts alkylation, where the alkene (via cation) acts as an electrophile and a benzoid nucleus as nucleophile. The reaction is by now a classic for constructing morphinans and is named Grewe cyclization.

As usually on fridays I'm away from the literature, but a quick search on RCS page showed a free paper that might be of interest for this thread, I haven't read it but it looks cool at glance.

Morphine, the Proteus of organic molecules
http://www.rsc.org/delivery/_ArticleLinking/DisplayArticleFo...

Quick espacenet search provided Rices (exploiting Grewe cyclization as key step) patent: http://v3.espacenet.com/origdoc?DB=EPODOC&IDX=US4521601&...

One should search before asking esp considering a structure so well-studied as the classic morphine (and subsystems).

[Edited on 1-3-2008 by Sandmeyer]

LSD25 - 11-4-2008 at 16:30

Dopamans synthesis route appears to be less than complete and lacking in some detail.

There are three major reactions in the process that need to be dealt with, (1) the isoquinoline synthesis; (2) the reduction of the isoquinoline to the octahydroisoquinoline; and (3) the Grewe cyclization of the same.

There are several, minor problems to be dealt with along the way as well, namely the n-methylation of the substrate, the resolution and last but not least, the isolation of several of the intermediates along the way. Depending upon where you start, there is also the question as to whether or not you might want to protect the phenolic groups along the way, there are a few articles which deal with the problems you will run into in doing this.

Now, dopamans synthesis of levorphanol is interesting, and looking at his starting points maybe even possible - provided the initial isoquinoline could be formed. Now numerous studies have been done on this, particularly with the morphine precursors - reticuline (Rice, et al - remember this name).

This particular synthesis is fucking difficult to understand, the following folder contains some of the material you will probably require in order to make sense of it.

http://www.4shared.com/dir/2820972/b38f26c3/Codeine__Morphin...

Now there are several options - Konda, et al, deal with the coupling of l-dopa with the relevant glycidate to both laudanosine and reticuline with retention of stereochemistry. Rice deals with the preparation of reticuline in good yield from vanillin and isovanillin derivatives. There are the various Mg-mediated couplings of isoquinoline to benzylisoquinolines, etc.

Insofar as the oxidative coupling of reticuline to salutaridine, there are only really two option VOCl3 (Schwartz & Zoda) or TfOH.NH4F.HF (Rice). In relation to the morphinans the Japanese papers deal with two in particular, HBr & H3PO4 (85%- 60 hours).

The reduction is carried out with catalytic hydrogenation or birch reduction in ammonia as you will see.

By all means, read up. I'd love to discuss this shit.:D

Oh yeah, given the hassles reported with benzoxylation of l-dopa (see Konda, et al), they resorted to fries rearrangement of p-acetyl-tyrosine - with AlCl3 to the 4-hydroxy-3-acetyl-pehnylalanine - now there is a new and improved Fries rearrangement reported using aqueous MsOH.

PS Does anyone think that MsOH could be used instead of TfOH for morphine? What about instead of HBr/H3PO4 for the morphinans? What about MsCl instead of the PCl5/POCl3 for the isoquinoline synth's (it appears that ability to chlorinate is also required)?

[Edited on 11-4-2008 by LSD25]

Attachment: Fries.Rearrangement.MsOH.pdf (82kB)
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Sandmeyer - 11-4-2008 at 17:34

IMO the most practical total synthesis of morphine skeleton systems is still that of Rices, it is non-chromatographic and has an overall yield (to dihydrocodeinone that is) of about 30%, such an operation can be carried out in the kitchen provided there is enough of determination and skill. It does not need to be carried all the way to morphine, in fact it would be more desirable to stop at the intermediate stages, since these compounds are reported by junkies to be extremely euphoric (for those that like to zombify themselves), leaving even brown H in the dust.

LSD25 - 11-4-2008 at 21:18

Yeah, that really is beyond argument:

http://www.cpdd.vcu.edu/Media/Index/AwardSpeeches/RiceK_Eddy...

By Mr Rice himself:
Quote:
“The requirement for clean chemistry in a sequence such as this where intermediates are not isolated or purified is obvious and ultimately led to the formulation of Rice’s rule, which is well known to all that have worked in my group. It simply states the obvious: ‘If you don’t make impurities you don’t have to take them out of your product.’” http://tinyurl.com/4swydz


The thing is, the decision to use TfOH was, according to that discussion (in the googlebook result) serendipitious and might well be more than is required to affect cyclization. He was simply looking for something to do the job well, and by the looks of it simply put in the strongest acid on hand - he actually intended to heat the frig out of it if it didn't work.

By the way, have you seen Rice, et al's conversion of dihydrocodeine to dihydromorphine? It uses 30% HBr in AcOH - the method also covers the conversion of codeine to 8-bromodesoxymorphine which upon hydrogenation should give the dihydrodesoxymorphine-C/D (I'll attach it). Rhodium's site has a good article on the hydrogenation of codeine to dihydrocodeine (I think it deals with the synthesis of codeinone) in quantitive yields.

http://www.erowid.org/archive/rhodium/chemistry/hydrocodone....

Thus the idea is to hydrogenate codeine to dihydrocodeinone:

Quote:
Dihydrocodeine from Codeine

In a Parr hydrogenator jar, codeine (2.0g, 6.7 mmol) and 10% Pd/C (200mg) were combined in ethyl acetate (75ml). This mixture was hydrogenated at room temp at 37 psi for 2h. During this time, the hydrogen pressure dectreased to 34 psi within 30 min, was increased back to 37 psi, and thereafter remained constant for the duration of the reaction. The mixture was filtered through Celite, the filter cake washed with 2x10ml ethyl acetate, the resulting solution stripped of solvent using a rotary evaporator by high vacuum. The product foamed considerably upon initial application of high vacuum, so care was taken not to lose any product. Leaving the product on high vacuum overnight afforded a white, crunchy, crystalline solid (2.0g (99.3%), mp 113-4°C [lit. 112-3°C]).(From Rhodium's site, cited above)


Then to demethylate the product:
Quote:
(b) From Dihydrocodeine (10). Dihydrocodeine (10, 1.00
g, 3 mmol), obtained by catalytic reduction of codeine (7) with Pd/C in MeOH, was dissolved in a mixture of 5 mL of glacial acetic acid and 5 mL of 30% HBr in acetic acid. The mixture was treated as shown above for tetrahydrothebaine (1).* Compound 15.HBr (1.15 g) was obtained from 10 in 94% yield.

Dihydromorphine (8).1.1H2O. 6-Acetyldihydromorphine.
HBr (15.HBr, 39.00 g, 95 mmol) was dissolved in 10% NaOH
solution (200 mL) and refluxed under nitrogen for 30 min. The
aqueous solution was cooled and adjusted to pH 7 with 36%
hydrochloric acid (25 mL) and then made alkaline (pH 9-9.5) with NH4OH (2 mL). The crystals that formed were washed with
ice-water (60 mL) and dried in vacuo at 40 °C to give a creamcolored solid (8.1.1H2O, 26.36 g, 90%), mp 151-152 °C (lit.12 mp 155-157 °C). The combined filtrate was evaporated to 100 mL, and 1 mL of NH4OH was added to pH 9-9.5. A second crop crystallized and was washed with 10 mL of ice-water. The crystals were dried under reduced pressure at 40 °C to afford 1.91 g (6.6%), for a total yield of 97% (28.27 g).


The tetrahydrothebaine procedure cited in the above example is:
Quote:
The reaction mixture was stirred for 5 h at 100 °C at 20 psi (in a 1 L hydrogenation bottle, 2002 Ace Glass catalog no. 8648-157; using a #25 Teflon screw cap, Ace Glass catalog no. 5846-5). Crystalline material appeared in about 1 h. The mixture was cooled to room temperature, and ether (400 mL) was added. The reaction mixture was refrigerated overnight (5 °C). The mixture was filtered, and the crystals were washed with a mixture of ether and acetic acid (4:3, 210 mL) until a few drops of the wash solution diluted with an equal volume water gave a negative AgNO3 test, to afford 33.54 g (82%) of chromatographically and analytically pure 15.HBr. The filtrate was evaporated to a thick slurry and filtered, and the collected solid was washed with the mixture of ether and acetic acid (4:3, 21 mL) to afford 5.46 g (13%) of 15.HBr as a second crop (total yield 39.00 g, 95%). The salt was converted to free base 15 by heating with aqueous NaHCO3 and extracted with CHCl3. The free base was recrystallized from MeOH: mp 241 °C (lit.12 mp 245 °C)...


The end product is somewhat stronger than morphine (about 2x) and lasts almost twice as long.

[Edited on 11-4-2008 by LSD25]

Attachment: dihydromorphine.pdf (98kB)
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Sandmeyer - 11-4-2008 at 22:13

Quote:
Originally posted by LSD25

The thing is, the decision to use TfOH was, according to that discussion (in the googlebook result) serendipitious and might well be more than is required to affect cyclization. He was simply looking for something to do the job well, and by the looks of it simply put in the strongest acid on hand - he actually intended to heat the frig out of it if it didn't work.


Grewe cyclization dosen't require triflic acid, for example, an italian group* have used 80% H2SO4 to affect cyclization (at R.T), they've got a yield above 80%.


*: Passarella, D.; Consonni, A.; Giardini, A.; Lesma, G.; Silvani, A. Bioorg. Med. Chem. Lett. 2002, 12, 1981.

EDIT: http://grande.nal.usda.gov/ibids/index.php?mode2=detail&...

I'm sure there are more examples, but I'm away from the literature searching-tools.
Quote:
By the way, have you seen Rice, et al's conversion of dihydrocodeine to dihydromorphine? It uses 30% HBr in AcOH - the method also covers the conversion of codeine to 8-bromodesoxymorphine which upon hydrogenation should give the dihydrodesoxymorphine-C/D (I'll attach it). Rhodium's site has a good article on the hydrogenation of codeine to dihydrocodeine (I think it deals with the synthesis of codeinone) in quantitive yields.


No, I'm not interested in making opioids so details on ether cleavage and hydogenation of C=C bond in regard to morphine system dosen't interest me.

[Edited on 12-4-2008 by Sandmeyer]

LSD25 - 11-4-2008 at 22:39

OK, but the point is, that with the simplicity of the conversion of salutaridine to the two salutaridinols (NaBH4), and the cyclization of them to thebaine with 1N HCl, the Rice & Brossi synthesis of Reticuline from 4-methoxy-3-hydroxyphenylacetic acid and 3-methoxy-4hydroxyphenethylamine* makes this VERY interesting. This means that by hydrogenating the thebaine produced, then demethylating it with HBr/AcOH, one has made it to dihydromorphine in 85-90% yield (through the hydrogenation & demethylation).

* Although I suspect another paper deals with the Pictet-Spengler of this via the phenylacetaldehyde and the Russian paper above deals with making it from the acid and the phenethylamine with polyphosphoric acid) with POCl3 and the salutaridine from the reticuline via the use of a blocking group (via N-bromoacetamide).

[Edited on 11-4-2008 by LSD25]

Attachment: Bartonetal.Conversion.Salutaridine.Thebaine.pdf (1.9MB)
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