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                           New routes from ET to LSD
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pHas3d:

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

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KCN:

No, I didn’t 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 can’t 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 can’t 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 shouldn’t 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, it’s 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. I’ve 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, sat’d 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 don’t 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 didn’t 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 don’t 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/ sat’d 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 “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.

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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.

Encyclopedia of Reagents for Organic Synthesis, 1995, vol. 3, 1731

JOC 1989, 54, 1922-1927

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 0 deg C. 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.

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aminator:

Interesting pepetide synthses proposals. But what about the old fashioned
methods, like the Pcl5 or Pcl3 + COOH+ = POH3 + COCl + dialkylamine =
dialkylamide + hcl, shit simple. I heard that phosphorous halides are rough on
those ergoline molecules though are they? can you actually remove the water of
crystalization by the simple use of a drying agent, mama always told me it took
2mm Hg vacum and a lot af heat i`d like to see where you found that gold nugget
if you could kindly reference it please. And why chromatogragh? maleic acid and
recrystalization is a viable way to purify,i suppose it depends on the
impurities present. I`ll refrence that procedure for you: J.O.C., 24, 368 or
C.A., 57, 5979. as an added bonus, the acid serves as a free radical scavenger
preventing the oxidation of the molecule the equivalance point is 5.32 i think.

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