New building blocks for peptide and depsipeptide synthesis: Hexafluoroacetone protected L-homoisoserine and D,L-homoisocysteine derivatives

Article abstract of DOI:10.1016/S0040-4039(02)02712-0

Efficient syntheses of L-homoisoserine and D,L-homoisocysteine derivatives starting from L-malic and D,L-thiomalic acid using hexafluoroacetone as protecting and activating agent are described. The new compounds are interesting building blocks for the pre

Full text of DOI:10.1016/S0040-4039(02)02712-0

TETRAHEDRON
LETTERS
Pergamon
Tetrahedron Letters 44 (2003) 1059–1062
New building blocks for peptide and depsipeptide synthesis:
hexafluoroacetone protected -homoisoserine and
-homoisocysteine derivativesꢀ
L
D L
,
Ga´bor Radics,a Raul Pires,a Beate Koksch,a Salah M. El-Kousyb and Klaus Burgera,*
aDepartment of Organic Chemistry, University of Leipzig, Johannisallee 29, D-04103 Leipzig, Germany
bFaculty of Science, Minufiya University, Shebin El-Kom, Egypt
Received 12 November 2002; revised 27 November 2002; accepted 28 November 2002
Dedicated to Professor Dr. Lothar Beyer on the occasion of his 65th birthday
Abstract—Efficient syntheses of L-homoisoserine and D,L-homoisocysteine derivatives starting from L-malic and D,L-thiomalic
acid using hexafluoroacetone as protecting and activating agent are described. The new compounds are interesting building blocks
for the preparation of non-natural peptides and depsipeptides as well as for the construction of new GABA derivatives. © 2003
Elsevier Science Ltd. All rights reserved.
Homoisoserine (2-hydroxy-4-aminobutyric acid) is a
constituent of numerous antibiotics, like arbekacin,2
amikacin3 and butirosin.4 Furthermore, it was identified
as subunit of phytosiderophores, e.g. in distichonic,
avenic and mugineic acid. Phytosiderophores are
responsible for iron up-take and iron-transport in
plants like wheat and oats.5 Homoisoserine acts as
inhibitor for GABA up-take and exhibits antitumor
activity.6 Therefore, numerous syntheses have been
developed, starting from 4-amino-2-oxobutyric acid,7
Z-b-alanine,6 isoxazolidin-5-carboxylate,8 malic acid
dicarboxylates14 and their thioanalogues.15 The synthe-
ses of
-isoserine16 and -isocysteine17 represent the
first examples of the application of this new synthetic
approach to multifunctional a-hydroxy and a-mercapto
acids. We now report on the synthesis of L-homoisoser-
L
D,L
ine and
D,L-homoisocysteine derivatives and their
incorporation into peptidomimetics using hexa-
fluoroacetone as protecting and activating agent.
a-Hydroxy and a-mercapto acids react with hexa-
fluoroacetone in dimethyl sulfoxide at room tempera-
ture to give 2,2-bis(trifluoromethyl)-1,3-dioxolan-4-ones
(3)18 and 2,2-bis(trifluoromethyl)-1,3-oxathiolan-5-ones
(4),15 in excellent yields (85–90%). In one step, protec-
tion of the a-hydroxy and the a-mercapto as well as the
adjacent carboxy group can be achieved. Concomi-
tantly, the a-carboxy group is activated toward nucle-
amide,9
pyrrolidone.11
L
-2,4-diamino-butyric
acid,10
and
2-
In contrast, homoisocysteine (2-mercapto-4-aminobu-
tyric acid) has not been found in nature, to the best of
our knowledge. Although, the first publication on
homoisocysteine appeared already in 1963,12 there is no
information available about its chemistry.
ophiles and can be regioselectively functionalized.14
A
variety of functional groups in the side-chain are toler-
ated, e.g. an v-carboxy group remains unaffected and
can be selectively activated and derivatized in a consec-
utive step. On heating with an excess of thionyl chloride
compounds 3 and 4 are converted into acid chlorides 5
and 6 in high yields (80–85%). Compounds 5 and 6 are
dielectrophiles, and the v-function is more reactive than
the a one (Scheme 1).
Recently, we demonstrated that a new protection/acti-
vation concept, developed for regioselective functional-
ization of multifunctional a-amino acids like aspartic
acid,13 can also be applied to a-hydroxy-a,v-
Keywords: L-homoisoserine; D,L-homoisocysteine; GABA derivatives;
Compounds 5 and 6 exhibit the typical reaction pattern
of acid chlorides. Diazoketones 7 and 8 are formed in
very good yields (90%) on treatment with an excess of
peptide modification; Wolff rearrangement; Curtius rearrangement.
ꢀ Part 3. For part 2 see Ref. 1
* Corresponding author. Fax: (49) 341 9736599.
0040-4039/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0040-4039(02)02712-0

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G. Radics et al. / Tetrahedron Letters 44 (2003) 1059–1062
Scheme 1. Reagents and conditions: (a) HFA/DMSO/rt; (b) SOCl2/reflux/4 h; (c) >2 equiv. CH2N2/Et2O/−78°C to rt/12 h; (d)
tBuOH/reflux/PhCO2Ag/X=O: 10 min, X=S: 2 h; (e) SOCl2/reflux/4 h; (f) 1.1 equiv. TMS–N3/toluene/80–90°C/24 h; (g) 1.1
equiv. ROH/CHCl3/reflux/12 h.
diazomethane (>2 equiv.:1 equiv. is necessary for trap-
ping the HCl formed during the reaction), which can be
easily purified by column chromatography (eluent:
DCM). Wolff rearrangement19 was accomplished on
heating of compounds 7 and 8 in dry tert-butanol in
the presence of catalytic amounts of silver benzoate.
The ketene formed first is trapped by tert-butanol. The
tert-butyl esters (9, 10) are directly transformed into
acid chlorides (11, 12) on heating with thionyl chloride.
Alternatively, chain elongation can be achieved, how-
ever in lower yields, via Photo–Wolff rearrangement in
aqueous dioxane to give the corresponding a-hydroxy
and a-mercapto glutaric acid derivatives, which are
directly subjected to treatment with thionyl chloride to
form acid chlorides 11 and 12, which can be purified by
distillation in vacuo. For the introduction of the g-
amino group, acyl azides are synthesized on reaction
with trimethylsilyl azide, which are subjected to a Cur-
tius rearrangement20 to give the isocyanates 13 and 14
on heating. Compounds 13 and 14 are dielectrophiles.
As expected, the isocyanate moiety is the more reactive
center towards nucleophiles. This strategy offers an
elegant and efficient route for regioselective functional-
ization of trifunctional compounds with a minimum of
steps.
Introduction of orthogonal protection groups can be
accomplished on heating isocyanates 13 and 14 with
alcohols. Treatment with tert-butanol, benzyl alcohol
and 9-fluorenylmethanol provides access to N-Boc-,
N-Z- and N-Fmoc-protected 4-amino-2-hydroxybu-
tyric acid and 4-amino-2-mercaptobutyric acid deriva-
tives (15, 16), which represent -XH-protected (X=O, S)
and carboxy group activated species. They are stabile
compounds and can be stored for months in a fridge on
exclusion of moisture (Scheme 2).
Compounds 15 and 16 are ready for direct application
in peptide synthesis. On reaction with amino acid
derivatives (a-amino acid, b-amino acid and g-amino
acid esters, amides and hydrazides) dipeptides of type
17,19 and azapeptides of type 21,22 become readily
accessible. They represent a class of dipeptide deriva-
tives which are interesting per se, since they are GABA
derivatives. Furthermore, they represent new building
blocks for peptide and depsipeptide modification.
Remarkably, peptide bond formation and deblocking
of the a-functionality occur in one-step. The reaction
sequence is suitable for the generation of libraries of
peptidomimetics.
3-Hydroxy-2-pyrrolidinones 18 can be isolated as minor
by-products (up to 10%) of the aminolytic ring opening
of 15a–c. They are the result of a base-induced
intramolecular cyclocondensation reaction. The
thioderivatives should be handled under inert gas atmo-
Recently, we demonstrated that a homologue of 13-
(5S)-2,2-bis(trifluoromethyl)-4-oxo-1,3-dioxolan-5-yl]-
methyl isocyanate16 is an excellent reagent for photo-
affinity labeling experiments.21

G. Radics et al. / Tetrahedron Letters 44 (2003) 1059–1062
1061
Scheme 2. Reagents and conditions: (h) 1.2 equiv. HCl×H-Phe-OR2/DMF/1.2 equiv. NMM/12 h; (i) 1.2 equiv. H2NNHCO2R3/
DMF/12 h.
sphere to avoid oxidation of the mercapto group. Com-
pounds containing the mercapto or mercaptoacyl moi-
ety often exhibit strong inhibitory effects on
metal-containing enzymes (metallozymes),22 similar to
hydroxamic acids.23
2. Kondo, S.; Tamura, A.; Gomi, S.; Ikeda, Y.; Takeuchi,
T.; Mitsuhashi, S. J. Antibiot. 1993, 46, 310–315.
3. (a) Kawaguchi, H.; Naito, T. In Chronicles of Drug
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4. Woo, P. W. K.; Dion, H.; Bartz, Q. R. Tetrahedron Lett.
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5. Shioiri, T.; Hamada, Y.; Matsuura, F. Tetrahedron 1995,
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area of current research.25 This is mainly due to the
ability of these amino acids to modify the geometry of
the peptide backbone,25d providing proteolytic resis-
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In the case of L-malic acid we proved that all steps of
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On further applications of hexafluoroacetone-protected
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amino acids in peptide, depsipeptide and glycopeptide
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14. Burger, K.; Windeisen, E.; Heistracher, E.; Lange, T.;
Abdel Aleem, H. Monatsh. Chem. 2002, 133, 41–58.
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Bisson, W.; Duchateau, L. H. L.; Maes, I. C. M.;
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Acknowledgements
The authors are grateful to DFG (Bu 277/21-1) and to
FCI for financial support. S.M.E thanks DFG for a
grant.
16. (a) Burger, K.; Windeisen, E.; Pires, R. J. Org. Chem.
1995, 60, 7641–7645; (b) Pires, R.; Burger, K. Synthesis
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17. Pires, R.; Burger, K. Tetrahedron Lett. 1996, 8159–8160.
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