A short diastereoselective synthesis of orthogonally protected diaminosuccinic acid derivatives

Article abstract of DOI:10.1021/jo049371e

Homogeneous, Rh-catalyzed hydrogenation of heteromeric olefinic glycine dimers presents an efficient route to diastereomerically pure, orthogonally protected diaminosuccinic acid derivatives depending on the double bond geometry of the starting material.

Full text of DOI:10.1021/jo049371e

acid derivatives7 include oxidative dimerization with the
possible use of chiral esters for asymmetric induction,8
Pd-catalyzed R-alkylation,9 and chiral pool derived elec-
trophilic amination of aspartic acid enolates.10 However,
these methods often need special protecting groups or,
as in the latter case, require different syntheses for each
diastereomer. Herein, we report an efficient method for
the preparation of racemic diastereomerically pure,
orthogonally protected diaminosuccinic acids starting
from easily accessible olefinic glycine dimers.11
A Sh or t Dia ster eoselective Syn th esis of
Or th ogon a lly P r otected Dia m in osu ccin ic
Acid Der iva tives
Kirsten Zeitler and Wolfgang Steglich*
Department Chemie, Ludwig-Maximilians-Universita¨t
Mu¨nchen, Butenandtstr. 5-13 (Haus F),
D-81377 Mu¨nchen, Germany
We envisaged a cis-selective hydrogenation of olefinic
glycine dimers to provide either the syn- or anti-isomers
of the diamino dicarboxylic acids, depending on the
double bond geometry. Catalytic hydrogenation of dehy-
droamino acids is one of the most efficient methods for
the enantioselective preparation of R-12 and â-amino13
acids. In our case, however, the strong deactivation14 of
the tetrasubstituted double bond15 had to be overcome,
and additionally, the hydrogenation should be stereose-
lective16 and compatible with N-carbamate protecting
groups17 to facilitate later deprotection of the products.
To study and optimize the reaction conditions, we chose
the symmetrical N-Boc-glycinate dimer 1 as an example.
The Z- and E-isomers of 1 are easily accessible,11 and the
wos@cup.uni-muenchen.de
Received April 15, 2004
Abstr a ct: Homogeneous, Rh-catalyzed hydrogenation of
heteromeric olefinic glycine dimers presents an efficient
route to diastereomerically pure, orthogonally protected
diaminosuccinic acid derivatives depending on the double
bond geometry of the starting material. The products were
obtained as racemates.
R,â-Diamino acids constitute a structural element in
several antibiotics, such as capreomycins, antrimycin,
and lavendomycin.1 A variety of different routes have
been reported for the synthesis2 of R,â-diamino propanoic
and R,â-diamino butanoic acids, highlighting the great
interest in these vicinal diamine components.3 In addi-
tion, natural and synthetic diamino dicarboxylic acids
play an important role as cross-linking elements and may
be used for stabilization of peptide secondary structures
and the introduction of conformational constraints. To
date, most synthetic efforts have concentrated on diami-
nopimelic acid, an essential component of bacterial
peptidoglycan cell walls,4 and diaminosuberic acid, a
dicarba analogue of cystine.5 However, it has also been
shown that shorter connections can be advantageous for
biological activity.6 Major approaches to diaminosuccinic
(6) Bhatnagar, P. K.; Agner, E. K.; Alberts, D.; Arbo, B. E.; Callahan,
J . F.; Cuthbertson, A. S.; Engelsen, S. J .; Fjerdingstad, H.; Hartmann,
M.; Heerding, D.; Hiebl, J .; Huffman, W. F.; Hysben, M.; King, A. G.;
Kremminger, P.; Kwon, C.; LoCastro, S.; Løvhaug, D.; Pelus, L. M.;
Petteway, S.; Takata, J . S. J . Med. Chem. 1996, 39, 3814-3819.
(7) Diaminosuccinic acid (3-aminoaspartic acid)7a,c,d has been isolated
from Streptomyces rimosus ((+)-(S,S)-diastereomer).7b Several studies
support its possible use as ligand for aspartate-dependent enzymes
that might be of interest for tumor therapy:7e (a) Ozaki, Y.; Iwasaki,
T.; Miyoshi, M.; Matsumoto, K. J . Org. Chem. 1979, 44, 1714-1716.
(b) Hochstein, F. A. J . Org. Chem. 1959, 24, 679-680. (c) McKennis,
H.; Yard, A. S. J . Org. Chem. 1958, 23, 980-982. (d) Biernat, J . F.
Rocz. Chem. 1971, 45, 2081-2087. (e) Chang, P. K.; Sciarini, L. J .;
Handschumacher, R. E. J . Med. Chem. 1973, 16, 1277-1280.
(8) Alvarez-Ibarra, C.; Csa´ky¨, A. G.; Colmenero, B.; Quiroga, M. L.
J . Org. Chem. 1997, 62, 2478-2482.
(9) Chen, Y.; Yudin, A. K. Tetrahedron Lett. 2003, 44, 4865-4868.
(10) (a) Fernandez-Megia, E.; Paz, M. M.; Sardina, F. J . J . Org.
Chem. 1994, 59, 7643-7652. (b) Riemer, C.; Bayer, T.; Kessler, H.
Peptides 1998, 25th European Peptide Symposium; Bajusz, S., Hudecz,
F., Eds.; Akade´miai Kiado´: Budapest, 1999; pp 690-691.
(11) Schumann, S.; Zeitler, K.; J a¨ger, M.; Polborn, K.; Steglich, W.
Tetrahedron 2000, 56, 4187-4195.
(1) For comprehensive overviews of biologically active R,â-diamino
acids, see: (a) Luo, Y.; Blaskovich, M. A.; Lajoie, G. A. J . Org. Chem.
1999, 64, 6106-6111. (b) Dunn, P. J .; Ha¨ner, R.; Rapoport, H. J . Org.
Chem. 1990, 55, 5017-5025 and references therein.
(2) Most methodologies rely on stepwise preparations, often starting
from chiral pool precursors. Recently, some new catalytic approaches
such as olefinic diamination2a-c or Mannich reaction of imines with
glycine derivatives2d have been developed: (a) Mun˜iz, K.; Nieger, B.
Synlett 2003, 211-214. (b) Pei, W.; Timmons, C.; Xu, X.; Wei, H.-X.;
Li, G. Org. Biomol. Chem. 2003, 1, 2919-2921. (c) Wei, H.-X.; Kim, S.
H.; Li, G. J . Org. Chem. 2003, 67, 4777-4781. (d) Bernardi, L.; Gothelf,
A. S.; Hazell, R. G.; J ørgensen, K. A. J . Org. Chem. 2003, 68, 2583-
2591. A summary of different synthetic methods and related literature
can be found in ref 1a and (e) Ambroise, L.; Dumez, E.; Szeki, A.;
J ackson, R. F. W. Synthesis 2002, 2296-2308. (f) Viso, A.; de la
Pradilla, R. F.; Lo´pez-Rodr´ıguez, M. L.; Garc´ıa, A.; Flores, A.; Alonso,
M. J . Org. Chem. 2004, 69, 1542-1547.
(12) (a) Ager, D. J . Curr. Opin. Drug Discov. Devel. 2002, 5, 892-
905. (b) Blaser, H.-U.; Malan, C.; Pugin, B.; Spindler, F.; Steiner, H.;
Studer, M. Adv. Synth. Catal. 2003, 345, 103-151. (c) Burk, M. J .;
Bienewald, F. In Transition Metals in Organic Synthesis; Beller, M.,
Bolm, C., Eds.; Wiley-VCH: Weinheim, 1998; Vol. 2, pp 13-24 and
references therein.
(13) As a consequence of the increasing interest in â-amino acids,13a
several examples have been described; for a recent review, see ref 13b
and references therein: (a) Gademann, K.; Hintermann, T.; Schreiber,
J . V. Curr. Med. Chem. 1999, 6, 905-925. (b) Drexler, H.-J .; You, J .;
Zhang, S.; Fischer, C.; Baumann, W.; Spannenberg, A.; Heller, D. Org.
Process Res. Dev. 2003, 7, 355-361.
(14) Only few examples for the hydrogenation of diamino dehy-
droamino acid derivatives are known: (a) McGarrity, J .; Spindler, F.;
Fuchs, R.; Eyer, M. European Patent EP-A 624 587A2, 1995; Chem.
Abstr. 1995, 122, P81369q. (b) Kuwano, R.; Okuda, S.; Ito, Y.
Tetrahedron: Asymmetry 1998, 9, 2773-2775. (c) Robinson, A. R.; Lim,
C. Y.; He, L.; Ma, P.; Li, H.-Y. J . Org. Chem. 2001, 66, 4141-4147. (d)
Robinson, A. J .; Stanislawski, P.; Mulholland, D.; He, L.; Li, H.-Y. J .
Org. Chem. 2001, 66, 4148-4152.
(3) (a) Lucet, D.; Le Gall, T.; Mioskowski, C. Angew. Chem., Int. Ed.
1998, 37, 2580-2627. (b) De Clercq, P. J . Chem. Rev. 1997, 97, 1755-
1792 and references therein.
(4) (a) Cox, R. J .; Sutherland, A.; Vederas, J . C. Bioorg. Med. Chem.
2000, 8, 843-871. (b) Gao, Y.; Lane-Bell, P.; Vederas, J . C. J . Org.
Chem. 1998, 63, 2133-2143. (c) Roberts, J . L.; Chan, C. Tetrahedron
Lett. 2002, 43, 7679-7682 and references therein.
(5) (a) Williams, R. M.; Liu, J . J . Org. Chem. 1998, 63, 2130-2132.
(b) Nutt, R. F.; Strachan, R. G.; Veber, D. F.; Holly, F. W. J . Org. Chem.
1980, 45, 3078-3080. (c) Collier, P. N.; Campbell, A. D.; Patel, I.;
Raynham, T. M.; Taylor, R. J . K. J . Org. Chem. 2002, 67, 1802-1815
and references therein.
(15) Hydrogenation of tetrasubstituted double bonds remains chal-
lenging; for some selected examples, see: (a) Burk, M. J .; Gross, M.
F.; Martinez, J . P. J . Am. Chem. Soc. 1995, 117, 9375-9376. (b) Burk,
M. J .; Gross, M. F.; Harper, G. P.; Kalberg, C. S.; Lee, J . R.; Martinez,
J . P. Pure Appl. Chem 1996, 68, 37-44.
10.1021/jo049371e CCC: $27.50 © 2004 American Chemical Society
Published on Web 07/30/2004
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J . Org. Chem. 2004, 69, 6134-6136

TABLE 1. Con d ition s for Hyd r ogen a tion of Dim er 1
entry
catalysta/reagent
PtO2
Pd/C
N2H2
Mg/ultrasound
Pd(PPh3)4/Bu3SnH
Et3SiH/TFA
solvent
T [°C]
p [bar]
resultb
1c
2
3
MeOH
MeOH
CH2Cl2
MeOH
THF
rt
85
rt
rt
rt
rt
60
rt
50
80
80
5
85
27% conv; 2 anti/syn; isomerized 1
36% conv; 2 anti/syn ) 2:1
4
5
6c
7c
8
TFA
Rh(PPh3)3Cl
MeOH
MeOH
toluene
toluene
toluene
1
5
70
90
90
[Rh(COD)Cl]2; dppe
[Rh(COD)Cl]2; dppf
[Rh(COD)Cl]2; dppf
[Rh(COD)Cl]2; dppf
29% conv; 2 anti/syn ) 5:1
55% (anti)-2
9
10
92% (anti)-2
90% (syn)-2
11d
a
b
10 mol % catalyst was used; entries 3-6 represent non-catalytic reaction conditions. Ratio of anti/syn-isomers determined by
integration of baseline separated methyl ester singlets in the 1H NMR spectra. c Instead of Boc-protected dimer (Z)-1, the corresponding
benzoyl derivative was used. (E)-1 was used as substrate.
d
spectroscopic data of both diastereomers of the resulting
diamino dicarboxylic acid derivative 2 are known from
the literature.10a,18 Disappointingly, all of our attempts
(see Table 1; entries 1-8) to achieve the hydrogenation
with different heterogeneous and homogeneous catalyst
systems either failed or provided diastereomeric mixtures
with only low conversions.
SCHEME 1. Ster eosp ecific Hyd r ogen a tion of th e
cis Dip ep tid e Dim er (Z)-3
Hydrogenation of (Z)-1 with H2/PtO2 under mild condi-
tions yielded just 27% of a diastereomeric mixture (entry
1). On raising temperature and H2 pressure and using
Pd/C as a catalyst (entry 2), a 2:1 mixture of anti- and
syn-isomers was obtained.19 First attempts with Rh-
catalyzed homogeneous hydrogenations (entry 8) showed
similar problems. However, on introducing the more
stable 1,1′-bis(diphenylphosphino)ferrocene (dppf) cata-
lyst system, the expected diastereomer (anti)-2 could be
obtained exclusively (entry 9); further optimization by
increasing the temperature and H2 pressure led to full
conversion and afforded (anti)-2 in 92% (entry 10) and
(syn)-2 in 90% yield (entry 11).
dipeptide dimer (Z)-3 (see Scheme 1) was used. It yielded
a single diastereomer, (anti)-4, thus proving the ste-
reospecifity of the hydrogenation.20
Further studies addressed the selection of suitable
orthogonal protecting groups,21 which had to be compat-
ible with the reagents used for dimer synthesis (SO2Cl2)
as well as the hydrogenation conditions. Moreover, they
should allow a simple separation of the E- and Z-olefinic
dimers to facilitate the access to the E-substrate. All of
these prerequisites are met with the heteromeric diami-
nosuccinic acid derivative 5 shown in Figure 1, whichs-
hould permit the selective removal of all four protecting
groups.22
To study the influence of adjacent chiral centers on the
stereochemical outcome of the reaction, the terminal
(16) In many cases the E- and Z-isomers show differences in respect
to selectivity and conversion: (a) You, J .; Drexler, H.-J .; Zhang, S.;
Fischer, C.; Heller, D. Angew. Chem., Int. Ed. 2003, 42, 913-916. For
cases in which only one enantiomer was obtained from an E/Z mixture,
see: (b) Lee, S.; Zhang, Y. J . Org. Lett. 2002, 4, 2429-2431. (c) Tang,
W.; Zhang, X. Org. Lett. 2002, 4, 4159-4161 and references therein.
(17) Most procedures have been developed for N-acyl protecting
groups. Recently, successful approaches for N-carbamate-protected
dehydroamino acids have been reported: (a) Evans, D. A.; Michael, F.
E.; Tedrow, J . S.; Campos, K. R. J . Am. Chem. Soc. 2003, 125, 3534-
3543. (b) Burk, M. J . Acc. Chem. Res. 2000, 33, 363-372. (c) Kuwano,
R.; Ito, Y. J . Org. Chem. 1999, 64, 1232-1237. (d) See ref 12c. (e)
Almena Perea, J . J .; Lotz, M.; Knochel, P. Tetrahedron: Asymmetry
1999, 10, 375-384.
(19) The low stereoselectivity might be due to isomerization pro-
cesses on the catalyst’s surface promoted by the long reaction times:
King, A. O.; Larsen, R. D. In Handbook of Organopalladium Chemistry
for Organic Synthesis; Negishi, E., Ed.; Wiley-VCH: Weinheim, 1998;
Vol. 2, chapter VII.2, pp 13-24. This assumption is supported by the
isolation of isomerized starting material (entry 1).
(20) Because of the symmetry of starting material (Z)-3 syn addition
of dihydrogen (as known from the model systems) at both sides of the
double bond furnishes the same nonracemic diastereomer (anti)-4.
(21) (a) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis; Wiley: New York, 1999. (b) Clarke, P. A.; Martin, W. H. C.
Annu. Rep. Prog. Chem., Sect. B 2003, 99, 84-103.
(18) Both syn- and anti-(meso) diastereomers 2 show slight but
distinct differences in their 1H and 13C NMR spectra. Their stereo-
chemical assignment was established by Sardina et al. by the analysis
of NOE effects and coupling constants of their cyclic urea derivatives.10a
J . Org. Chem, Vol. 69, No. 18, 2004 6135

SCHEME 3. Ster eosp ecific Hyd r ogen a tion of
Or th ogon a lly P r otected Dim er s (Z)-8 a n d (E)-8
F IGURE 1. Orthogonally protected diaminosuccinic acid
derivative 5 with possible conditions for deprotection.
SCHEME 2. Syn th esis of Or th ogon a lly P r otected
cis Dip ep tid e Dim er (Z)-8
short and flexible route to diastereopure diaminosuccinic
acid derivatives in racemic form. An extension of this
reaction to the synthesis of optically pure compounds
should be possible by using asymmetric hydrogenation
conditions or chiral ester groups.
The diastereoselective synthesis of 5 started from two
different R-(ethylthio)glycine precursors,23 6 and 7, that
were cross-coupled to (Z)-8 in 61% yield (Scheme 2).
Isomerization of the central double bond under basic
conditions afforded the trans-isomer (E)-824 (Scheme 3).
Hydrogenation of each isomer produced the racemic
diaminosuccinic acid derivatives (anti)-5 and (syn)-5,
respectively, in good yield.
Exp er im en ta l Section
Gen er a l P r oced u r e for Hom ogen eou s Hyd r ogen a tion of
Glycin a te Dim er s. For the hydrogenation of 0.15 mmol of a
glycinate dimer, a solution of 10 mol % of the respective Rh-
complex in 5 mL of absolute and degassed toluene was prepared.
After addition of 2 equiv of a suitable phosphine ligand (dppf,
etc.) (based on Rh-complex), the mixture was stirred for 30 min
at room temperature and then transferred via cannula to the
hydrogenation flask containing the glycinate dimer (c ) 0.4
mmol/mL) under an argon atmosphere. After three cycles of
evacuation and H2 refilling, the hydrogenation was conducted
at the H2 pressure and temperature given in Table 1. Upon
complete conversion (TLC) the reaction mixture was concen-
trated in vacuo. To remove catalyst remains, the residue was
purified by column chromatography on silica gel.
In conclusion, hydrogenation of olefinic glycine dimers
and their corresponding peptide derivatives provides a
(22) Several methods are known for deprotection of tert-butyl esters
in the presence of Boc groups22a,b and vice versa.22c Selective cleavage
of Cbz-protection is achievable via Pd-catalyzed hydrogenation; how-
ever, homogeneous hydrogenation leaves the Cbz group untouched.22d
(a) Marcantoni, E.; Massaccesi, M.; Torregiani, E.; Bartoli, G.; Bosco,
M.; Sambri, L. J . Org. Chem. 2001, 66, 4430-4432. (b) Wu, Y.;
Limburg, D. C.; Wilkinson, D. E.; Vaal, M. J .; Hamilton, G. S.
Tetrahedron Lett. 2000, 41, 2847-2849. (c) Gibson, F. S.; Bergmeier,
S. C.; Rapoport, H. J . Org. Chem. 1994, 59, 3216-3218. (d) Kreuzfeld,
H.-J .; Do¨bler, C.; Krause, H. W.; Facklam, C. Tetrahedron: Asymmetry
1993, 4, 2047-2051.
(23) For a general procedure for peptide dimerization see Supporting
Information and ref 11.
(24) After reaching an approximately 1:1 ratio of Z- and E-isomers,
the reaction is terminated; non-converted Z-starting material can be
recovered and reused.
Ack n ow led gm en t. We thank the Fonds der Che-
mischen Industrie for generous support.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails and spectroscopic and analytical data. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O049371E
6136 J . Org. Chem., Vol. 69, No. 18, 2004