Org Prep Daily

October 11, 2006

(S)-4-(benzyloxycarbonylamino)-3-hydroxybutyric acid

Filed under: procedures — milkshake @ 7:20 pm

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(S)-4-hydroxypyrrolidin-2-one 4.99g (49.35mmol, Aldrich) and lithium hydroxide monohydrate 8.40g (200mmol, Aldrich) was dissolved in water 100mL. The mixture was stirred in a closed 0.5L flask at 40C for 24 hours. [The progress of hydrolysis was conveniently monitored by NMR, by diluting a small react. mix sample directly with D2O and taking  the proton spectra] . The reaction mixture was diluted with THF 160mL and water 100mL, cooled on ice bath and saturated with a stream of CO2 gas [generated in a separate flask from dry ice] at 5-10C for 20 min. Solid Cbz-OSu 11.714g (47mmol, Aldrich) was added in single portion followed by additional THF 40mL (to wash the funnel). The mixture was stirred at 5-10C for 30 min and then at 10-20C for 2h30min. The reaction mixture was acidified with conc. HCl 18mL (CO2 evolution!) and concentrated on rotavap down to about 80mL of total volume. The resulting slurry was placed into fridge (+5C) overnight. The precipitated crude product (9.30g) was collected by filtration, rinsed with a small volume of ice-cold water and dried on highvac. The supernatants were concentrated down to aprox 40mL volume, extracted twice with ethyl acetate (2x150mL), the extracts were washed with brine (100mL) , combined, dried (MgSO4) and evaporated. The residue (3.5g) was re-crystallized from a ethyl acetate -benzene 1:4 mixture to produce additional 1.40g of crude product. The combined two fractions of crude product (9.30g +1.40g) were re-dissolved in refluxing ethyl acetate 40mL. With heating, the mixture was carefully diluted with benzene 160mL, inoculated and allowed to crystallize at RT for 8 hours. The supernatants were decanted from the crystallized pure product, the crystalls (6.92g) were suspended in a mixture EtOAc-benzene 1:4 (40mL), collected by filtration, washed with EtOAc-benzene 1:1 (2x20mL) and dried on highvac. A second pure crop (1.741g) crystallized from the supernatants in a fridge over weekend (+5C, 2 days). The combined Y=8.661g(72.5%) of a white crystalline solid

1H(6-6, DMSO, 400MHz): 12.073(br s, 1H), 7.357(m, 5H), 7.243(t, 5.8Hz, 1H), 5.020(s, 2H), 4.923(br s, 1H), 3.883(br s, 1H), 3.006(m, 2H), 2.383(dd,15.2Hz, 4.0Hz, 1H), 2.149(dd, 15.2Hz, 8.7Hz, 1H); LC/MS (+ESI): 254 

Acid-promoted hydrolysis of the starting lactam (6M HCl, reflux) proceeded with a partial decomposition and extensive racemisation. The racemisation possibly takes place by OH beta-elimination/water addition; 4-aminocrotonic acid was identified as a major side-product. By contrast, LiOH-hydrolysis at 40C does not produce any measurable racemisation, as confirmed by 1H-NMR spectra of diasteremeric ureas, from (S)-N,N-dimethy-4-amino-3-hydroxybutyramide hydrochloride  (synthesized from the Cbz-protectd aminoacid) with opticaly-pure PhCHMeNCO 

8 Comments »

  1. I’m about to run my first column on 100g of material. It’s pretty polar stuff (10/90 iPOH-Hex works well). Any suggestions?

    Comment by Movin'on up — October 12, 2006 @ 2:01 am

  2. “Acid-promoted hydrolysis of the starting LACTAME…”

    Comment by petr — October 12, 2006 @ 8:47 am

  3. re # 1,

    Yeah, recrystallize or distill… at that scale the old fashioned methods of purification are really useful.

    If you really want a column (I assume silly-ca), then you must load the silica with at least a 1% IPA/Hexane solvent. At that scale, you want to avoid any heating of the silica, so pretreating with IPA eliminates (ar at least greatly reduces) the risk of silica heating due to sharp polarity increases.

    You may also want to break your stuff up into 4-5 smaller batches.

    Comment by milo — October 12, 2006 @ 11:40 am

  4. Any reason for running the CBZ protection under a CO2 atmosphere? Is it just an inert atmosphere or I am missing something?

    Comment by Canadian Chromatographer — October 12, 2006 @ 11:51 am

  5. Petr – thank you, I corrected the typo.

    The reason for bubbling CO2 into the reaction was to buffer it – I got over 3 equivalents of LiOH left in there after the reaction. I did not want to have a background hydrolysis problem due to the hydroxide – and bicarbonate is a good base for the reaction, it is not likely to eat the CbzOSu.

    Comment by milkshake — October 12, 2006 @ 11:57 am

  6. Milkshake,

    That is a really slick way to buffer a solution, I never would have thought of that…

    Comment by milo — October 12, 2006 @ 1:32 pm

  7. I seem to recall that many amines form reversable adducts with CO2. Don’t they use solid supported amines to trap CO2 on the space shuttle?

    Comment by Atompusher — October 13, 2006 @ 11:26 am

  8. They do – you often see it as a white solid around mouth of an old bottle, it mostly happens with reactive primary amines. Apollo space program used LiOH. Polyamines would work, it is possible. I know the polyamine resins were considered for big powerplant-scale CO2 sequestation (because the reaction is reversible and the polymer could be re-activated by heating).

    I would not worry much about these adducts with aminoacids, especialy in aqueous solutions.

    Comment by milkshake — October 13, 2006 @ 12:21 pm


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