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LSD Synthesis using Peptide Coupling Reagents

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pHas3d:

Ok, so we all know the classic Shulgin route:

Ergotamine Tartrate → Lysergic Acid Hydrate → LSD freebase → LSD Tartrate

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

KCN and Slappy both suggested new chems for step #2 but provided no refs. Slappy was suggesting DCC, then KCN was touting HATU, HBTU, BOP and other salt coupling reagents.



KCN:

No, I didnt 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 The Practice of Peptide Synthesis) 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 cant 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 cant 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 shouldnt 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 MeCN (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, its 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. Ive 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 NaHCO3 in water (250mL) is added to the residue and the layers were separated. The organics were washed with 10% citric acid, satd NaHCO3, 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 dont 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 didnt 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 dont 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 0°C and 1.05 eq. of DCC is added. The rxn is stirred at 0°C 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/ satd NaHCO3, 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 -15°C 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 -15°C 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 modern 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.



Rev Drone:

Phas3d, Sorry for the tardiness; I've been carrying it around with me for a couple days, but today has been the first time I've had an opportunity to submit my meager selection.

The gist of the procedure is roughly: under an inert atmosphere, in flame-dried glassware, 1 molar equivalent of the acid, dissolved in DCM, is treated with a 10% excess of DCC at 0C. The amine, dissolved in DCM, is added, and the reaction is monitored by TLC. Upon completion, the reaction mixture is quenched with a smidge of AcOH or H2O to decompose unreacted DCC.



Abbreviations for various coupling reagents

HBTU
2-(1H-benzo-triazole-1-yl)-1,1,3,3-tetramethyluronium
HOBt
N-hydroxybenzotriazole
HOSu
H-Hydroxysuccinimide
BOP
Benzotriazolyl N-oxytrisdimethylaminophosphonium hexafluorophosphate
DCC
Diclohexylcarbodiimide
HBTU
2-(1H-benzo-triazol-1-yl)-1,1,3,3-tetramethyluronium Hexafluorophosphate