dormouse (Member)
04-19-00 19:30
No 122826
      new routes from ET to LSD -pHas3d  Bookmark   


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Author  Topic:   new routes from ET to LSD 
pHas3d
PimpBee   posted 02-12-2000 03:29 PM           
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Ok,
Didnt want to bring the "other" of topic, so I started this to hopefully stimulate discussion on new routes, and possibly find some interesting journal articles.
Ok, so we all know ET's classic Shulgin route
et->lysergic acid hydrate->LSD freebase->LSD tartrate

Now, Even sticking to the same route, there is obvious room for improvement.

K.C. Nicolaou and Slappy both suggested new chems for step #2 but provided no refs(hint, wink, please, please, please). Slappy was suggesting DCC, then KC was touting HATU, HBTU, BOP and other salt coupling reagents. Bright Star! So what is this interesting "The Alkaloids" publication?

KC and Slappy, I(and im betting the Hive) would like to hear more. And Im betting that step #1 could be improved upon as well.

What about different salts? Anyone experiment with sulfate or hydrochloride salts?

I asked for it Drone!

pHas3d


 
KCN
Hive Bee   posted 02-15-2000 01:59 AM           
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No, I didnít forget you pHas3d. I just had to take a peek at a book here and there and get my shit together so I could give a complete answer without sticking my foot in my mouth. So, here are a few representative examples(from ďThe Practice of Peptide SynthesisĒ ?) of the use of different coupling reagents, some comments by me, and a proposed procedure for the use of each reagent in the coupling of diethylamine and LSA.
Note that in many of these examples the amide products do not contain a basic nitrogen and can be washed with acid solutions. This is not an option with LSD due to the fact that it contains a tertiary amine, so that places a significant constraint on the workup procedures and reagents that can be used. In particular, you canít use EDAC, which is otherwise the easiest carbodiimide coupling reagent (same class as DCC) to use. Also note that I will not specify the particular solvent or amine base to use in my proposed procedures, as these parameters are pretty flexible and generally not very critical(there may be exeptions!) to the success of the rxn. Generally, good solvents for these rxns are
fairly dry, polar aprotic, non-ketone solvents such as DCM, chloroform, EtOAc, DMF, ACN, NMP, THF, DME, dimethoxymethane, DMA, toluene, etc. The same principle pretty much applies to the selection of an amine base. In appropriate situations, diethylamine itself can be used, and in others a tertiary amine base is required. Since you canít really use acid washes to get rid of the base, I will generally suggest removal of the base by vacuum distillation. As such, it is probably advisable to use fairly volatile bases. Trimethylamine (b.p. 3C), N,N-dimethylethylamine (b.p. 37C), N-methyl-N,N-diethylamine (b.p. 66C), triethylamine (b.p. 89C), N-methylmorpholine (b.p. 116C), and diisopropylethylamine (b.p. 127C) will probably all get the job done with varying ease of removal. Also, Shulgin indicates that he isolates LSA hydrate after hydrolyzing ET. This shouldnít really be used directly in any of the following rxns. Rather, the water of crystalization should be removed by azeotroping with toluene or dissolving the hydrate and drying the solution with MgSO4, Na2SO4, or Mol. Sieves.

Coupling with BOP-Reagent

Example:

A solution of tert-butyloxycarbonyl threonine (2.19g, 10mmol) (the carboxylic acid) and phenylalanine methyl ester hydrochloride (2.16g, 10mmol) (amine hydrochloride) in 150mL ACN is stirred at RT while the BOP-reagent (4.42g, 10mmol) is added, followed by the addition of triethylamine (2.2g, 2.8mL, 20mmol). The rxn is stirred at RT for 1.5hr. 100mL of a saturated NaCl solution is added and the product extracted with EtOAc 3x. The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the dipeptide (3.74g, 98%).

Comments:

Should be very high-yielding and mild in terms of rxn conditions. BOP-reagent is not the most common chemical and therefore may present some problems in terms of aquisition,
but it is most definitely not associated with bad kids who do drugs. I would suggest trying around with companies that specialize in peptide synthesis reagents, because not to many people would carry this. Commercial BOP-reagent is expensive.

Proposed LSD synthesis procedure:

1eq. LSA is dissolved in a suitable solvent(must be fairly dry) at RT, 1.05 eq BOP-reagent is added. 2eq. of diethylamine is added and the rxn is stirred at RT until it goes to completion(15min-2hr). The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and saturated NaHCO3(or NH4OH). The layers were separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated
NaCl, dried over MgSO4, filtered and concentrated in vacuo to remove the solvent and excess diethylamine. The crude LSD, which should be fairly pure, is then further purified by chromatography and converted to the tartrate salt.

Coupling with HBTU/HATU

Example:

The carboxyl-component (10mmol), the amine component (10.4mmol), and triethylamine (20 mmol) are dissolved in ACN (20mL) and
HBTU/HATU (10.4mmol) is added to the solution. After 15-30min the rxn is complete. 100-200mL of a saturated NaCl solution is then added and the product extracted with EtOAc 3x. The combined organics are washed with 2N HCl, H2O, 5% NaHCO3, and then H2O. The organics are dried over MgSO4, filtered, and concentrated in vacuo to give the amide (90-100% yield).

Comments:

Should be very high-yielding and mild in terms of rxn conditions. Similar chemically and in terms of aquisition problems as BOP-reagent, but HBTU/HATU is actually relatively easy to make yourself if you have access to the required chemicals and have pretty good lab skills. To make it, you need oxalyl chloride, teramethylurea, toluene, ether, chloroform, ammonium hexafluorophosphate(or NH4BF4), DCM, HOBt, and triethylamine. Like BOP-reagent, itís pretty expensive if you buy it. We use a lot of HATU in the lab I work in and we make it ourselves due to the high cost of buying it. Iíve never been suckered into whipping up a batch of it, but the people who have made it in the past are nothing special as chemists. I can provide refs for preparing it if you want.

Proposed LSD synthesis procedure:

1eq. LSA is dissolved in a suitable solvent(must be fairly dry) at RT, 1.05 eq HBTU/HATU is added. 2eq. of diethylamine is added and the rxn is stirred at RT until it goes to completion(15min-2hr). The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and saturated NaHCO3(or NH4OH). The layers were separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to remove the solvent and excess diethylamine. The crude LSD, which should be fairly pure, is then further purified by chromatography and converted to the tartrate salt.


Coupling with DCC in the presence of 1-hydroxybenzotriazole (HOBt)

Example:

Phenylalanine methyl ester hydrochloride (21.6g, 100mmol) (amine hydrochloride), HOBt monohydrate (15.3g, 100mmol), tert-butyloxycarbonyl leucine (23.1g, 100mmol) (carboxylic acid) and N-methylmorpholine (100mmol) are dissolved in dry THF (32mL, I think this is a typo) and cooled to 0C in an ice/water bath. To the stirring solution was added DCC (21.6g, 105mmol). The rxn was stirred for 1hr at 0C and an additional hour
at RT. The N,N-dicyclohexylurea (DCU) which precipitated out was removed by filtration and the solvent evaporated in vacuo. A mixture of EtOAc (500mL) and a saturated solution of NaCO3 in water (250mL) is added to the residue and the layers were separated. The organics were washed with 10% citric acid, satíd NaCO3, water, dried over Na2SO4, filtered and evaporated to dryness in vacuo. The residue is triturated w/ hexanes, filtered, washed with hexanes and dried. The crude dipeptide (34.4g, 88%) was purified by chromatography on an alumina column to give 30.0g (76.5%) of the pure compound.

Comments:

Mild rxn conditions, yields should be good. Longer rxn times than with BOP/HBTU/HATU. DCC is a very common chemical and is cheap and much more avaliable than BOP/HBTU/HATU. The acid reacts with DCC to give a sort of mixed anhydride which is very reactive. If the rxn is carried out without HOBt or HOSu, the alpha carbon of the acid is very prone to racemization/epimerization. With HOBt or
HOSu, the mixed anhydride is immediately attacked by the N-hydroxy alcohol to give the
OBt/OSu ester, which is still very reactive towards amines, but not very prone towards
epimerization. As such, it is often common practice to prepare the OBt/OSu ester in situ
and then treat it with the amine, rather than adding everything at once as in the example. HOBt and HOSu can be removed by washing with weak base.

The main problem I have with DCC-based methods is the removal of the DCU byproduct.
Although most of the DCU crashes out of solution due to the fact that it is pretty insoluble in damn near everyting and can then be filtered off, some of it always hangs around with you product and must be removed by chromatography or recrystalization(usually from toluene). It may be that the DCU is easily removed in the purification/tartrate salt formation, but keep the fact that it may be hanging around in mind if you get a >100% yield by weight or have shit crystalize out on you at strange times. If you are going to run a column anyway, no sweat, use it and donít worry about it. Most of my negative feelings
towards DCC are due to times at work where I had to run a column on something to get rid of the DCU when I really didnít want to run yet another fucking column.

Another thing to keep in mind is that DCC is an irritant and a sensitizer, meaning that you can build up a serious sensitivity and have adverse reactions to tiny amounts of the stuff if you donít take appropriate precautions.

Proposed LSD synthesis procedure:

1eq. LSA is dissolved in a suitable solvent(must be fairly dry) and 1.05 eq HOBT is added. The solution is cooled to 0C and 1.05 eq. of DCC is added. The rxn is stirred at 0C for 30min. 1.05eq. of diethylamine is added and the rxn is stirred at 0C for 30min, and allowed to warm to room temp and is stirred until the rxn goes to completion(0-24hr). The rxn is cooled in the freezer to precipitate out the maximum amount of DCU. The precipitated DCU is filtered and washed with solvent. The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and
saturated NaHCO3(or NH4OH). The layers are separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated NaCl, dried over MgSO4, filtered and concentrated in vacuo to remove the solvent and excess diethylamine. The crude LSD, is then further purified by chromatography and converted to the tartrate salt.

Coupling with DCC in the presence of N-hydroxysuccinimide (HOSu)

Example:

Pht-Phe-Val-Gln-Trp-Leu-OH hemihydrate (8.35g 10mmol) (carboxylic acid), Met-Asn-Thr(tBu)-OtBu (4.78g, 10mmol) (amine freebase), and N-hydroxysuccinimide (1.15g, 10mmol) are dissolved in 67mL DMF. The solution is cooled to -10C during the addition of DCC (2.06g, 10mmol). After 2hr at -10C and 48hr at -3C, the DCU was filtered and 330mL water was added. The solid precipitate was filtered, washed w/ satíd NaCO3, washed w/ water, and dried over P2O5 in vacuo. The crude product (12.1g, 93.5%) was recrystalized from H2O/EtOH to give 9.7g (75%) of the pure product.

Comments:

Same as with HOBt

Proposed LSD synthesis procedure:

Same as with HOBt, just substitute HOSu for HOBt.

Coupling with the use of a mixed carbonic acid anhydride

Example:

A solution of glycine ethyl ester hydrochloride (1.40g, 10mmol) (amine hydrochloride) in DMF (20mL) is prepared and treated with triethylamine (1.01g, 1.4mL, 10mmol). A solution of Z-Gly-Phe-OH (3.56g, 10 mmol) (carboxylic acid) in dry THF (50mL) is cooled to -15C and treated with N-methylmorpholine (1.01g, 1.1mL,10mmol). Isobutyl chloroformate (1.37g, 1.32mL, 10mmol) is added and the rxn was stirred at -15C for 15min, after which the solution of glycine ethyl ester prepared earlier was added. The rxn was allowed to warm to RT and stirred for 30min. The precipitated amine salts were removed by filtration and rinsed with THF. The combined filtrate and washings were evaporated in vacuo and the residue partitioned between 150mL EtOAc and 50mL H2O.
The organic phase was separated, washed w/ 5% KHSO4 (50mL), washed w/ 5% HCl (50mL), water (50mL), dried over Na2SO4, filtered and evaporated to dryness in vacuo to give 4.0g (91%) of the desired product.

Comments:

This procedure actually works quite well in my experience using it to prepare diazomethylketones. It involves the use of an acid chloride, so obviously anhydrous conditions are required. Chloroformates(you can use other ones, isobutyl chloroformate is merely the most commonly used, there is little difference in reactivity between different componds of this type) tend to be kind of squirrely when you try to store them due to the fact that they are very water-sensitive and evolve CO2 when they decompose and CO2/HCl when exposed to water. As such, they are usually shipped with a small amount of chloroformate in a big bottle (100mL in a 500mL bottle) to guard against pressure build-up and subsequent breakage. Store them in the freezer and open the bottle BEFORE it warms to RT.

Proposed LSD synthesis procedure:

1eq. LSA is dissolved in a suitable solvent(must be very dry, DCM, chloroform, and THF
are best) and 1.15 eq of a tertiary amine is added. The solution is cooled to -20C and 1.10 eq. of isobutyl chloroformate is added. The rxn is stirred at -20C for 20min. 1.1eq. of diethylamine is added and the rxn is stirred at 0C for 30min, and allowed to warm to room temp and is stirred until the rxn goes to completion(0-1hr). The rxn is quenched with 10 eq. MeOH. The solvent is removed under vacuum and the residue partitioned between EtOAc(or other suitable solvent) and saturated NaHCO3(or NH4OH). The layers were separated and the organics were washed with NaHCO3(or NH4OH), H2O, saturated
NaCl, dried over MgSO4, filtered and concentrated in vacuo to remove the solvent and excess tertiary amine and diethylamine. The crude LSD, is then further purified by
chromatography and converted to the tartrate salt.

Hope that helps. There really are 101 ways to make amides from carboxylic acids and amines, so the previous suggestions should in no way be construed to be the end-all-be-all of ďmodernĒ LSA->LSD syntheses. However, all of these methods have been used by me in the course of the synthesis of different, non-LSD molecules and have proved their worth to me as highly useful techniques, so I have no qualms about suggesting them to others. Feel free to ask for clarification on any of the above.


Strontium
Hive Bee   posted 02-15-2000 02:52 PM           
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What can I say KCN. You bring tears of pure joy in my eyes
Strontium


pHas3d
PimpBee   posted 02-15-2000 09:54 PM           
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Bravo! Bravo!
Slappy? Rev?

gettin' his learn on,
pHas3d


rev drone
Hive Bee   posted 02-16-2000 06:49 AM           
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KCN,
Wow, that is quite an impressive bit of work! Do you have ref's for all of this stuff?

Phas3d,

I'll dig out and submit what I have, but much of it will be redundant in light of KCN's contribution. E-mail me.

------------------
-the good reverend drone

Ipsa scientia potestas est


 
KCN
Hive Bee   posted 02-16-2000 11:02 AM           
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Thanks for the kind words guys.  As for refs, all of those examples are from the same book. The exact name and author escape me right now, but I'll find out and post it, along with some other related material. All of this stuff relates to work I do, so I already have most of the material and don't really have to dig around in the library for it.
 
Methamphibian man
Hive Bee   posted 02-16-2000 01:09 PM           
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Symptoms of ergot poisioning: Flushing

vomiting

headache

Burning sensation in arms and legs

Dialation of the pupils
Ergot poisioning is not a fun experience. I would like to take this oppertunity to tell you all to be very careful around ergot. You can get sick even by touching it, as well as all the other routes of ingestion.

bee safe, bees


 
Slappy
PimpBee   posted 02-22-2000 04:45 AM           
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Phas3d,
I must apologize for my tardiness. I have been sooo busy lately and have been neglecting my beloved Hive. I don't know where I put all of my ref's on amide formation, but I will try and compile some info and post it asap.


Bright Star
Hive Bee   posted 02-22-2000 01:36 PM           
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Like KCN said, there are hundreds of ways to turn an acid to an amine. But, not to detract from the list, a nice bit o' work.
What of the LSA?

That is the hard one, and that is the 'limiting reagent'.