Organic Process Research & Development 2005, 9, 757−763
A Scalable Synthesis of L-Leucine-N-carboxyanhydride
N. M. B. Smeets, P. L. J. van der Weide, J. Meuldijk, J. A. J. M. Vekemans, and L. A. Hulshof*
‡
†
‡
†
,†
EindhoVen UniVersity of Technology, Laboratory of Macromolecular and Organic Chemistry and Department of
Chemical Engineering and Chemistry, P.O. Box 513, 5600 MB EindhoVen, The Netherlands
Abstract:
Due to its relevance in the synthesis of well-defined oligopep-
tides, the L-leucine-N-carboxyanhydride (leucine-NCA) synthesis
was selected for fine chemical scale-up with a scope on
application on larger scales. The heterogeneous gas-solid-
liquid nature of the leucine-NCA synthesis implied a mass
transfer limited reaction rate towards phosgenation and was
investigated on bench scale. Upon scale increase, the liquid-
gas mass transport of HCl is drastically reduced, retarding the
reaction and consequently rendering the process unsuitable for
scale-up. Addition of an HCl scavenger such as (+)-limonene
prevented side reactions thus allowing a cost reduction, a
considerably faster reaction, and minimization of the amount
of phosgene source used. The modified leucine-NCA synthesis
has successfully been made scalable, maintaining high product
The formation of R-amino acid-NCA is accompanied by
that of two molecules of HCl. HCl is reported to be a
contaminant and an initiator of numerous side reactions.8
Alternative R-amino acid-NCA synthetic routes have been
reported to circumvent the usage of HCl forming acylation
9
10
agents. Nagai et al. applied di-tert-butyltricarbonate, which
resulted in low yields after long reaction times. R-Amino
acid-NCAs have also been successfully synthesized using a
3
purity on a 1.0 dm scale.
1
1
prebiotic synthetic route, but the required process design
is not suitable for fine chemical scale-up.
Introduction
Earlier scale-up of the R-amino acid-NCA synthesis was
found to result in a significant decrease in purity of the crude
NCA, with a concomitant reduction in the ease of (re)-
R-Amino acid-N-carboxyanhydrides (R-amino acid-
NCAs) are commonly synthesized for their ring opening
polymerization properties, giving access to well-defined
synthetic oligomeric amino acids. With specific interest in
oligo-L-leucines (OLLs), these oligomeric amino acids find
their application in the assembly of highly ordered nano-
12
crystallization and prolongation of the reaction time when
13
compared to small-scale experiments. A high purity of the
R-amino acid-NCA monomer is a prerequisite for successful
application in ring opening polymerizations leading to
peptides. In these ring opening polymerizations a variety of
1
structures and as synzyme catalysts in the Juli a´ -Colonna
epoxidation.2
14
nucleophilic bases can be used as initiator. The average
The synthesis of R-amino acid-NCAs was first reported
chain length of the peptides is governed by the initiator-
NCA molar ratio.
3
early in the 20th century by Leuchs. NCAs were prepared
by heating the corresponding N-alkoxycarbonyl R-amino acid
chlorides, a synthetic route which was about four decades
but later replaced by the direct synthesis from the unprotected
Impurities, like unreacted amino acid, containing free
amine functions, arbitrarily alter the initiator-NCA molar
ratio resulting in a poorly defined peptide. Due to its
relevance in the Juli a´ -Colonna epoxidation catalyst syn-
thesis, L-leucine 1 was selected as the R-amino acid of choice.
Diphosgene was used as a phosgene source throughout this
study.
4
amino acid with an excess of phosgene gas. Addition of
gaseous phosgene was later replaced by a safer procedure
5
using a standard solution of phosgene in benzene. The
6
application of trichloromethyl chloroformate (diphosgene)
7
and bis(trichloromethyl)carbonate (triphosgene) inhibited
Involvement of three phases, with possible corresponding
mass transfer interfacial limitations, adds to the complexity
side reactions that were due to the large excess of gaseous
phosgene, see Scheme 1.
(8) Iwakura, Y.; Uno, K.; Kang, S. J. Org. Chem. 1965, 30, 1158.
*
Author for correspondence. E-mail: L.A.Hulshof@tue.nl.
Laboratory of Macromolecular and Organic Chemistry.
Department of Chemical Engineering and Chemistry.
(9) Nagai, A.; Sato, D.; Ishikawa, J.; Ochiai, B.; Kudo, H.; Endo, T.
Macromolecules 2004, 37, 2332.
(10) Dean, C. S.; Tarbell, D. S.; Friederang, A. W. J. Org. Chem. 1970, 35, 5,
3393.
†
‡
(
1) Senet, J.-P. G. Chimica Oggi 2004, 22, 24.
(
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S.; Masana, J.; Vega, J. C. Angew. Chem., Int. Ed. Engl. 1980, 19, 929. (c)
Juli a´ , S.; Guixer, J.; Masana, J.; Rocas, J.; Colonna, S.; Annuziata, R.;
Molinari, H. J. Chem. Soc., Perkin Trans. 1 1982, 1317.
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(13) Gerlach, A.; Geller, T. AdV. Synth. Catal. 2004, 346, 1247.
(14) Kricheldorf, H. R. R-Aminoacid-N-carboxyanhydrides and related hetero-
cycles; Springer-Verlag: New York, 1987.
(
(
(
(
(
4) Farthing, A. C. J. Chem. Soc. 1950, 3213.
5) Fuller, W. D.; Verlander, M. S.; Goodman, M. Biopolymers 1976, 15, 1869.
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