Enantioselective synthesis of diamino dicarboxylic acids

Article abstract of DOI:10.1021/jo982034j

The preparation of alkyl diamino dicarboxylic acids with high optical purity (100% ee, >98.5% de) and high yields based on asymmetric catalytic hydrogenation is described. The required prochiral precursors are prepared from dialdehydes and Z-, Boc-, and acetyl-protected phosphonoglycines. Aqueous solutions of glyoxal, succinic dialdehyde, and glutaric dialdehyde were used to prepare the diunsaturated precursors for 2,5-diaminoadipic acid (DAA), 2,7-diaminosuberic acid (DAS), and 2,8-diaminoazelaic acid (DAZ). Z- Protected dimethyl esters of DAA, DAS, and DAZ were obtained by hydrogenation of the corresponding prochiral starting materials with [(COD)Rh(S,S)- EtDuPHOS]OTf.

Full text of DOI:10.1021/jo982034j

J . Org. Chem. 1999, 64, 1947-1952
1947
En a n tioselective Syn th esis of Dia m in o Dica r boxylic Acid s
J ohann Hiebl,*,† Hermann Kollmann,‡ Franz Rovenszky,† and Karin Winkler§
Topcro Pharma Research GmbH, St. Peter Strasse 25, A-4020 Linz, Austria; Hafslund Nycomed
Pharma AG, St. Peter Strasse 25, A-4020 Linz, Austria; and Nycomed Austria AG,
St. Peter Strasse 25, A 4020 Linz, Austria
Received October 8, 1998
The preparation of alkyl diamino dicarboxylic acids with high optical purity (100% ee, >98.5% de)
and high yields based on asymmetric catalytic hydrogenation is described. The required prochiral
precursors are prepared from dialdehydes and Z-, Boc-, and acetyl-protected phosphonoglycines.
Aqueous solutions of glyoxal, succinic dialdehyde, and glutaric dialdehyde were used to prepare
the diunsaturated precursors for 2,5-diaminoadipic acid (DAA), 2,7-diaminosuberic acid (DAS), and
2,8-diaminoazelaic acid (DAZ). Z-Protected dimethyl esters of DAA, DAS, and DAZ were obtained
by hydrogenation of the corresponding prochiral starting materials with [(COD)Rh(S,S)-Et-
DuPHOS]OTf.
Sch em e 1. Im p or ta n t Mem ber s of
Dia m in od ica r boxylic Acid s
In tr od u ction
Diamino dicarboxylic acids1 or bis(amino acids) are
characterized by two glycine residues that are connected
by a spacer via the R-carbons. They contain two asym-
metric carbons, two chemically identical amino and
carboxylic groups. Cystine (1, proteinogenic amino acid,
see Scheme 1) and 2,5-diaminopimelic acid2 (2, DAP,
precursor of lysine) are the biologically most important
members of this interesting class of compounds.5-7 In
particular, the biological importance of DAP had stimu-
lated the synthesis of DAP isomers and analogues as
possible inhibitors of the enzymes involved in the DAP
biosynthetic pathway.8
The use of diamino dicarboxylic acid derivatives for
peptidomimetic drug design is becoming more common
place. Recently, members of this class have been used
as conformational constraints in order to mimic the
secondary structures of peptides, such as â-turns,9 and
to stabilize a helical conformation.10 Since they contain
two amino and two carboxylic groups, they are interesting
starting materials for the preparation of chemical librar-
ies using solid-phase chemistry. In addition, alkyne
bridged bis(amino acids) have been prepared in order to
investigate their nonlinear optical properties.11
Replacement of the chemically and metabolically labile
disulfide bridge in cystine 1 by an isosteric ethylene
spacer results in the unnatural 2,7-diaminosuberic acid
(4, DAS). This amino acid has been used successfully as
a substitute for cystine to prepare biologically active
peptide hormone analogues with improved chemical
stability, e.g. oxytocin12 and somatostatin analogues.13
Brandenburg and co-workers reported the replacement
of cystine even within a protein by incorporating diami-
nosuberic acid in insulin to give A7,B7-dicarbainsulin.14
Recently compound 615 (SK&F 107647, Scheme 2), a
nonapeptide with hematoregulatory activity, has dem-
onstrated significant protection in animal models of
bacterial, fungal, and viral diseases and bone marrow
* Present address of the corresponding author: J ohann Hiebl,
SmithKline Beecham Pharmaceuticals, Synthetic Chemistry, UW
2820, 709 Swedeland Road, King of Prussia, PA 19406. Tel: (610)-
270-5676, Fax: (610)-270-4829, e-mail: J ohann_Hiebl-1@sbphrd.com.
† Topcro Pharma Research GmbH.
‡ Hafslund Nycomed Pharma AG.
§ Nycomed Austria AG.
(1) Greenstein, J . P.; Winitz, M. Chemistry of the Amino Acids;
Wiley: New York, 1961; Vol. 3, pp 2501-2528.
(2) Diaminopimelic acid is found in bacteria and higher plants. It
is the precursor of lysine, which is formed via the diaminopimelic
pathway. Since mammals lack this biochemical transformation, inhibi-
tors of the diaminopimelic acid pathway could be potential antimicro-
bial agents.3 Clinical studies on FK-565, a peptide containing meso-
2,6-diaminopimelic acid, revealed that it exhibits strong antiviral
activity and remarkable antitumor potency.4
(3) Abbott, S. D.; Lane-Bell, P.; Sidhu, K. P. S.; Vederas, J . C. J .
Am. Chem. Soc. 1994, 116, 6513-6520; and references therein.
(4) Hoshi, A.; Castan˜er, J . Drugs Fut. 1994, 19, 243-247.
(5) Other naturally occurring sulfur-containing diamino dicarboxylic
acids: lanthionine and its 3-methyl homologue. They are found in
unusual bioactive polypeptides called “lanthibiotics”.6 Compared to the
metabolically labile disulfide bridge of cystine, the monosulfide bridge
of lanthionine provides an improvement in the stability toward
enzymatic degradation. Therefore lanthionines have been used as
peptidomimetic building blocks.6
(9) Review: Hanessian, S.; McNaughton-Smith, G.; Lombart, H.-
G.; Lubell, W. D. Tetrahedron 1997, 53, 12789-12854.
(10) Andrews, M. J . I.; Tabor, A. B. Tetrahedron Lett. 1997, 38,
3063-3066.
(11) Kayser, B.; Altman, J .; Beck, W. Tetrahedron 1997, 53, 2475-
2484.
(12) Keller, O. Doctoral Thesis, No. 5325 E.T.H. Zu¨rich, 1974.
(13) Nutt, R. F.; Veber, D. F.; Saperstein, R. J . Am. Chem. Soc. 1980,
102, 6539-6545.
(14) Videnov, G.; Bu¨ttner, K.; Casaretto, M.; Fo¨hles, J .; Gattner, H.-
G.; Stoev, S.; Brandenburg, D. Biol. Chem. Hoppe-Seyler 1990, 371,
1057-1066.
(6) Goodman, M.; Shao, H. Pure Appl. Chem. 1996, 68, 1303-1308.
(7) For diamino dicarboxylic acids with an aryl ether spacer: Rama
Rao, A. V.; Gurjar, M. K.; Rao, A. S. Chem. Rev. 1995, 95, 2135-2167.
(8) Gao, Y.; Lane-Bell, P.; Vederas, J . C. J . Org. Chem. 1998, 63,
2133-2143.
10.1021/jo982034j CCC: $18.00 © 1999 American Chemical Society
Published on Web 03/03/1999

1948 J . Org. Chem., Vol. 64, No. 6, 1999
Hiebl et al.
Sch em e 3. Retr osyn th etic An a lysis
Sch em e 2. Hem a tor egu la tor y Active P ep tid es
Con ta in in g Dia m in od ica r boxylic Acid s
The advantage of using the Kolbe electrolysis was that
it allowed the preparation of diaminosuberic acid bearing
the required protecting groups in just one step from the
appropriate N-protected R-carboxyl esters of glutamic
acid.20 While useful for the preparation of kilogram
quantities of 2,7-diaminosuberic acid, the Kolbe elec-
trolysis had its limitations. The main problems faced in
the scale-up process were the heat generated during the
electrolysis, which increased the amount of side products,
and the high costs for the chiral starting materials.
For further toxicological and clinical evaluation of
hematoregulary peptide 6, a scaleable synthetic route to
2,7-diaminosuberic acid became critical. A method al-
lowing the synthesis of 2,7-diaminosuberic acid with
>98% de from achiral starting materials which creates
the chiral centers in a catalytic fashion was considered
as the most economical approach.
Resu lts a n d Discu ssion
Scheme 3 shows our retrosynthetic analysis, which is
based on an enantioselective hydrogenation of a prochiral
2,7-diaminosuberic acid derivative. The starting materi-
als 9 and 12 for the prochiral intermediate are com-
mercially available.
transplantation.16 Compound 6 is the dicarba analogue
of the disulfide 7,17 which is the dimer of the hemoregu-
latory peptide, HP5b (Pyr-Glu-Asp-Cys-Lys) isolated by
Laerum and Paukovits from mature human leukocytes.18
The identification of these low molecular weight com-
pounds, 6 and 7, which display high biological activity,
represented a breakthrough in the field of hematopoiesis,
which is dominated by proteins, e.g. cytokines.19
The 2,7-L,L-diaminosuberic acid used for the structure-
activity relationship15 and toxicological studies of 6 was
synthesized by either Kolbe electrolysis20 or by alkylation
of a chiral bislactim ether (Scho¨llkopf technology).21 Other
synthetic routes published in the literature are based
on the alkylation of another chiral glycine template22
and on the template-promoted ring-closing olefin meta-
thesis.8,23-25
The Wittig-Horner reaction of Z-phosphonoglycine
methyl ester 926 with anhydrous butanedial27 in the
presence of tetramethylguanidine28 yielded the desired
dimethyl ester 13 (see Table 1) as a mixture of olefin
isomers (95:5). The major product could be isolated by a
single crystallization, if desired, and was determined to
contain the 2Z,6Z configuration by X-ray analysis.29 The
minor compound 14 (Scheme 4) was determined to be the
2E,6Z isomer by 1H and 13C NMR. Interestingly, mo-
nounsaturated compound 15 was identified as a major
side product. It is formed by reaction of butanedial with
just 1 equiv of phosphonoglycine 9 and was isolated as
the hydrate.
When the Wittig-Horner reaction was carried out with
the commercially available aqueous solution of butane-
dial (40%) in the presence of dichloromethane30 and
DBU,28 the desired product 13 was isolated in 76% yield.
In this case, the ratio between 13 (2Z,6Z) and 14 (2E,6Z)
(15) 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.
(16) Bhatnagar, P. K.; Alberts, D.; Callahan, J . F.; Heerding, D.;
Huffman, W. F.; King, A. G.; LoCastro, S.; Pelus, L. M.; Takata, J . S.
J . Am. Chem. Soc. 1996, 118, 12862-12863.
(23) Miller, S. J .; Blackwell, H. E.; Grubbs, R. H. J . Am. Chem. Soc.
1998, 118, 9606-9614.
(24) O’Leary, D. J .; Miller, S. J .; Grubbs, R. H. Tetrahedron Lett.
1998, 39, 1689-1690. We thank Profs. Grubbs and O’Leary for sending
a preprint of this work.
(17) Laerum, O. D.; Sletvold, O.; Bjerknes, R.; Eriksen, J . A.;
J ohansen, J . H.; Schanche, J . S.; Tverteraas, T.; Paukovits, W. R. Exp.
Hematol. 1988, 16, 274-280.
(25) Williams, R. M.; Liu, J . J . Org. Chem. 1998, 63, 2130-2132.
(26) Schmidt, U.; Lieberknecht, A.; Wild, J . Synthesis 1984, 53-
60.
(27) Falkstorp, J .; Raleigh, D.; Schniepp, L. E. J . Org. Chem. 1950,
15, 869-875.
(28) Schmidt, U.; Griesser, H.; Leitenberger, V.; Lieberknecht, A.;
Mangold, R.; Meyer, R.; Riedl, B. Synthesis 1992, 487-490.
(29) Klepp, K. O.; Hiebl, J .; Kollmann, H.; Rovenszky, F. Z. Natur-
forsch., in press.
(18) Paukovits, W. R.; Laerum, O. D. Hoppe-Seylers Z. Physiol.
Chem. 1984, 365, 303-311.
(19) Review: Hansen, F. Acta Oncol. 1995, 34, 453-468.
(20) Hiebl, J .; Blanka, M.; Guttman, A.; Kollmann, H.; Leitner, K.;
Mayrhofer, G.; Rovenszky, F.; Winkler, K. Tetrahedron 1998, 54, 2059-
2074.
(21) Kremminger, P.; Undheim, K. Tetrahedron 1997, 53, 6925-
6936.
(22) Williams, R. M.; Yuan, C. J . Org. Chem. 1992, 57, 6519-6527.
(30) Ciattini, P. G.; Morera, E.; Ortar, G. Synthesis 1988, 140-142.

Enantioselective Synthesis of Diamino Dicarboxylic Acids
J . Org. Chem., Vol. 64, No. 6, 1999 1949
Sch em e 4. Sid e P r od u cts
material prepared from Z-Glu-OMe by Kolbe electroly-
sis.20 None of the D,D-enantiomer 34 of 30 was detectable,
but a small amount (0.5%) of the meso-compound was
formed during the hydrogenation. Me-DuPHOS-Rh and
DIPAMP-Rh catalysts gave lower diastereomeric ex-
cesses, 97.0% de and 95% de, respectively (entries 3 and
4, Table 2). CHIRAPHOS-Rh catalyst (prepared in situ,
entry 5, Table 2) did not hydrogenate the bis-enamide
13 under the standard reaction conditions. Increasing the
H2 pressure to 500 psi at 60 °C was successful, but only
35.8% de was obtained. In addition, a small amount of
the D,D-enantiomer was formed under these conditions
resulting in 86.5% ee. Ru-BINAP gave only moderate
diastereoselectivity (70% de, entry 6, Table 2).
Based on these results, Et-DuPHOS was selected for
the large-scale synthesis of 2,7-diaminosuberic acid
derivative 30.38 In addition, Et-DuPHOS was used suc-
cessfully for the asymmetric hydrogenation of bis-ena-
mides 18 and 21 (see Table 1) yielding 2,5-diaminoadipic
acid 32 (97.2% de, entry 7, Table 2) and 2,8-diaminoa-
zelaic acid 33 (97.0% de, entry 8, Table 2) in 50% and
56% overall yield (two steps) from glyoxal or glutaralde-
hyde, respectively. In both cases optically pure com-
pounds (100% ee, 100% de by HPLC) could be obtained
by a single crystallization. These results were important
since derivatives of 2,5-diaminoadipic acid were not
available by dialkylation of Scho¨llkopf’s bislactim ether
with dibromoethane39 and the Kolbe electrolysis yielded
compound 32 in only 23% yield.20 Interestingly, an
analogue (8, see Scheme 2) of hematoregulatory peptide
6 containing 2,5-diaminoadipic acid 2 (DAA, see Scheme
1) instead of 2,7-diaminosuberic acid 4 was found to be
more active than 6.15
Con clu sion . Optically pure (100% ee, g 98.5% de by
HPLC) alkyl diamino dicarboxylic acids are prepared in
two steps from commercially available starting materials.
The key step is the asymmetric catalytic hydrogenation
(Et-DuPHOS-Rh) of the bis-enamides which are prepared
from the corresponding dialdehydes and N-protected
phosphonoglycine methyl esters. Because of the prochiral
nature of the precursors, both enantiomers of diamino
dicarboxylic acids containing the same configuration at
the two chiral centers are available from one starting
material.
To use the whole potential of diamino dicarboxylic acids
as new building blocks for combinatorial chemistry, or
as replacements for cystine in biologically active peptides,
orthogonal protected diamino dicarboxylic derivatives are
required. Methods to prepare selectively protected bis-
(amino acids) have been reported recently.8,9,22,24,25,39-44
Efforts to extend the methodology described in this paper
in the crude mixture was also determined to be 95:5. The
corresponding Boc- and acetyl-protected derivatives 16
and 17 were available in 60-78% yield from the corre-
sponding N-protected glycine derivatives 11 and 10.26
The successful preparation of prochiral precursors 13,
16, and 17 for diaminosuberic acid motivated us to
investigate the synthesis of diunsaturated analogues of
other diamino dicarboxylic acids. These results are sum-
marized in Table 1. High yields were obtained with
dialdehydes available as aqueous solutions (with n ) 0,
2, 3, see entries 1-3), with middle-sized carbon chain
dialdehydes (n ) 6, entry 4), longer carbon chain alde-
hydes (n ) 10, entry 5), and aromatic dialdehydes (iso-
and p-phthalaldehydes, entries 6 and 7). Interestingly,
none of the desired product was obtained from the
reaction of Z-phosphonoglycine
9
and o-phthal-
aldehyde.31 Analogues of aromatic compounds 27 and 28
(see Table 1) bearing different protecting groups have
been prepared using a Heck reaction as the key step.32
Interestingly, this method also failed to produce the
corresponding ortho-substituted derivatives.
The reaction of 15 with acetyl derivative 10 (entry 8,
Table 1) in anhydrous CH2Cl2 (DBU, molecular sieves)
yielded the unsymmetrical protected compound 29. This
result demonstrates the possibility to prepare precursors
of orthogonally protected diamino dicarboxylic acids with
this new methodology.
Asym m etr ic Hyd r ogen a tion . Having the prochiral
precursors 13, 16, and 17 in hand, we next identified the
best chiral catalyst33-36 for the transformation into opti-
cally pure protected 2,7-diaminosuberic acid. Because the
Z-protected 2,7-diaminosuberic acid (di-Z-DAS) 31 was
selected as most suitable starting material for the large
scale synthesis of hematoregulatory peptide 6,37 Z-
protected, unsaturated compound 13 was selected for this
investigation. The following standard set of parameters
was used for the screening: 3.5 g of 13 was dissolved in
200 mL of oxygen-free MeOH. The hydrogenation was
carried out with 100 mg of catalyst, 60 psi initial pressure
of H2, at ambient temperature for 18 h.
The results of this screening are shown in Table 2. Et-
DuPHOS-Rh catalyst gave the Z-protected 2,7-L,L-diami-
nosuberic acid 30 in high yield (85%) and high optical
purity (100% ee, 99.0% de by HPLC [see legend to Table
2], entry 1, Table 2). The product was identical with
(38) Using this new method, optically pure 2,7-diaminosuberic acid
derivative 30 was prepared on multikilogram scale in 75% isolated
yield with 100% ee and 98.5% de (chiral HPLC) from a technical
aqueous solution of succinic dialdehyde 12 (data not shown).
(39) Bold, G.; Allmendinger, T.; Herold, P.; Moesch, L.; Scha¨r, H.-
P.; Duthaler, R. O. Helv. Chim. Acta 1992, 75, 865-882, footnote on
page 868.
(40) Hiebl, J .; Kollmann, H.; Rovenszky, F.; Winkler, K. Bioorg. Med.
Chem. Lett. 1997, 7, 2963-2966.
(41) Nutt, R. F.; Strachan, R.; Veber, D.; Holly, F. J . J . Org. Chem.
1980, 45, 5, 3078-3080.
(42) Zakhariev, S.; Videnov, G.; Stoev, S.; Golovinsky, E.; Branden-
burg, D. Asymmetrical derivatives of diaminosuberic acid useful in
peptide synthesis. In Peptides 1988; J ung, G., Bayer, E., Eds.; De
Gruyter & Co.: Berlin, 1989; pp 307-309.
(43) Holcomb, R. C.; Schow, S.; Ayral-Kaloustian, S.; Powell, D.
Tetrahedron Lett. 1994, 35, 7005-7008.
(44) J urgens, A. R. Tetrahedron Lett. 1992, 33, 4727-4730.
(31) Hiebl, J .; Kollmann, H. Unpublished results.
(32) Carlstro¨m, A.-S.; Frejd, T. J . Org. Chem. 1991, 56, 1289-1293.
(33) Et-DuPHOS, Me-DuPHOS: Burk, M. J .; Feaster, J . E.; Nugent,
W. A.; Harlow, R. L. J . Am. Chem. Soc. 1993, 115, 10125-10138.
(34) DIPAMP: Knowles, W. S.; Sabacky, M. J .: Vineyard, B. D.;
Weinkauff, D. J . J . Am. Chem. Soc. 1975, 97, 2567-2568.
(35) CHIRAPHOS: Fryzuk, M. D.; Bosnich, B. J . Am. Chem. Soc.
1977, 99, 6262-6267.
(36) BINAP: Miyashita, A.; Takaya, H.; Souchi, T.; Noyori, R.
Tetrahedron 1984, 40, 1245-1253.
(37) Hiebl, J .; Alberts, D.; Banyard, A. F.; Baumgartner, H.; Bern-
wieser, I.; Bhatnagar, P. K.; Blanka, M.; Bodenteich, M.; Chen, T.;
Esch, P. M.; Kollmann, H.; Lantos, I.; Leitner, K.; Mayrhofer, G.; Patel,
R.; Rio, A.; Rovenszky, F.; Stevenson, D.; Tubman, K. D.; Undheim,
K.; Weihtrager, H.; Welz, W.; Winkler, K. J . Peptide Res., in press.

1950 J . Org. Chem., Vol. 64, No. 6, 1999
Hiebl et al.
Ta ble 1. P r och ir a l P r ecu r sor s of Dia m in od ica r boxylic Acid s
°C for 1 h and allowed to warm to room temperature with
stirring overnight.
to the preparation of orthogonally protected diamino
dicarboxylic acids are ongoing, and the results will be
reported in due course.
Workup for Z- or Ac-protected derivatives: The reaction
mixture was washed with 1 N HCl solution (15.0 mL) and with
brine (2 × 10 mL each) until neutral. The organic phase was
dried with Na2SO4 and filtered, and the filtrate was concen-
trated in vacuo to yield the crude product, which was purified
by crystallization or chromatography as outlined.
Workup for Boc-protected derivatives: The reaction was
washed first with a 5% KHSO4 solution and then with brine
(2 × 10 mL). The organic phase was separated, and the
aqueous phase was extracted with EtOAc (3 × 30 mL). The
organic phases were combined, dried with Na2SO4, and
filtered, and the filtrate was concentrated in vacuo to yield
the crude product, which was purified by crystallization or
chromatography as outlined.
Exp er im en ta l Section
Gen er a l. Common experimental procedures and instru-
mentation have been described previously.20 Z-Phosphonogly-
cine methyl ester 9 was purchased from Fluka. Octanedial and
dodecanedial were gifts from DSM Chemie Linz. The Rh-
DuPHOS catalysts were obtained from Chiroscience or Strem
Chemicals. Rh-DIPAMP catalyst was obtained from NSC-
Technologies. The CHIRAPHOS ligand was obtained from
Fluka.
Gen er a l Meth od for th e P r ep a r a tion of P r otected
Dien ea m id es. The corresponding N-protected phosphonogly-
cine methyl ester 9, 10, or 1126 (12.075 mmol) was dissolved
in dichloromethane (30 mL), DBN (1.45 mL, 12.075 mmol) was
added, and the mixture was stirred for 10 min at 10 °C. The
dialdehyde (5.84 mmol) was added slowly at a rate to keep
the temperature below 10 °C. The reaction was stirred at 5-10
(2Z,6Z)-2,7-Bis-(ben zyloxyca r bon yla m in o)-octa -2,6-d i-
en e-1,8-d ioic Acid Dim eth yl Ester (13). Compound 13 was
prepared from 9 and aqueous butanedial 12. Crystallization
1
from toluene gave 21.97 g (76.3%) of 13, mp 130-132 °C. H
NMR (400 MHz, CDCl3) δ 2.35 (m, 4 H), 3.75 (s, 6 H), 5.12 (s,

Enantioselective Synthesis of Diamino Dicarboxylic Acids
J . Org. Chem., Vol. 64, No. 6, 1999 1951
Ta ble 2. Hyd r ogen a tion of Un sa tu r a ted P r ecu r sor s Yield in g Dia m in od ica r boxylic Acid sa
entry
n
SMb
catalyst
prodc
L,L
meso
D,D
1
2
3
4
5
6
7
8
2
2
2
2
2
2
0
3
13
13
13
13
13
13
18
21
[(COD)Rh(S,S)-Et-DuPHOS]OTf
[(COD)Rh(R,R)-Et-DuPHOS]OTf
[(COD)Rh(S,S)-Me-DuPHOS]OTf
[(COD)Rh(R,R)-DIPAMP]BF4
[(COD)Rh(R,R)-CHIRAPHOS]OTfd
Ru-BINAP‚TEA dimere
30
34
30
30
30
30
32
33
99.5
-
98.5
97.5
4.7
85
98.5
98.7
0.5
0.3
1.5
2.5
30.6
15
-
99.7
-
-
64.7
na
-
[(COD)Rh(S,S)-Et-DuPHOS]OTf
[(COD)Rh(S,S)-Et-DuPHOS]OTf
1.5
1.3
-
a
All reactions were performed using the following standard set of parameters: 3.5 g of 13, 18, or 21 was dissolved in 200 mL oxygen-
free MeOH, 100 mg of catalyst, 60 psi initial pressure, ambient temperature, 18 h. The resulting crude material was analyzed by chiral
HPLC: Daicel Chiracel OJ -R, 50% 0.5 M NaClO4 buffer pH 6.5 with HClO4; 50% acetonitrile, flow rate: 1.0 mL/min; detection: UV-254
b
d
nm. SM ) starting material. c Prod. ) compound number of the major stereoisomer. This catalyst did not hydrogenate at 60 psi:
Results shown were obtained using 500 psi and 60 °C, overnight. e Because of impurities, the value for the D,D-form was not available
(na).
4 H), 6.46 (m, 2 H), 6.51 (m, 2 H), 7.25-7.35 (m, 10 H). 13C
NMR (100 MHz, CDCl3) δ 27.25, 52.44, 67.49, 126.50, 128.19,
128.27, 128.54, 134.57, 135.95, 154.10, 164.93. Anal. Calcd for
(2Z,4Z)-2,5-Bis(ben zyloxyca r bon yla m in o)h exa -2,4-d i-
en e-1,6-d ioic Acid Dim eth yl Ester (18). Compound 18 was
prepared from aqueous glyoxal and 9. The resulting crude
product was recrystallized from MeOH. Yield: 72%, mp 170-
C
26H28N2O8 (MW: 496.52): C, 62.90; H, 5.68; N, 5.64. Found:
1
C, 62.8; H, 5.5; N, 5.7.
175 °C. H NMR (400 MHz, CDCl3) δ 3.76 (s, 6 H), 5.16 (s, 4
H), 6.66 (s, 2 H), 7.08 (s, 2 H), 7.26-7.40 (m, 10 H). 13C NMR
(100 MHz, CDCl3) δ 52.86, 67.87, 123.13, 127.78, 128.37,
128.39, 128.56, 135.67, 153.63, 164.66. Anal. Calcd for
(2E,6Z)-2,7-Bis(ben zyloxycar bon ylam in o)octa-2,6-dien e-
1,8-d ioic Acid Dim eth yl Ester (14). Compound 14 contain-
ing one E configured double bond was isolated as an oil by
chromatography (silica gel, eluent: ethyl acetate/petroleum
ether ) 1/3) of the mother liquor of 13. The NMR signals are
doubled in comparison to 13. 1H NMR (400 MHz, CDCl3) δ
2.38 (q, 2 H, J ) 7.4 Hz), 2.70 (q, 2 H, J ) 7.4 Hz), 3.73 (s, 3
H), 3.77 (s, 3 H), 5.11 (s, 2 H), 5.13 (s, 2 H), 6.40 (br s, 1 H),
6.62 (t, 1 H), 6.71 (m, 1 H), 6.81 (br s, 1 H), 7.26-7.35 (m, 10
H). 13C NMR (100 MHz, CDCl3) δ 26.84, 28.36, 52.30, 67.00,
67.29, 125.35, 126.28, 128.08, 128.16, 128.23, 128.28, 128.48,
128.55, 129.35, 135.99, 136.09, 136.55, 153.76, 154.20, 164.11,
164.96. Anal. Calcd for C26H28N2O8 (MW: 496.52): C, 62.90;
H, 5.68; N, 5.64. Found: C, 62.7; H, 5.4; N, 5.6.
(2Z)-2-(Ben zyloxyca r bon yla m in o)-1-ca r boxyh ex-2-en -
6-a l Meth yl Ester Hyd r a te (15). Compound 15 was isolated
as an oil by chromatography (silica gel, eluent: ethyl acetate/
petroleum ether ) 1/3) of the mother liquor of 13. 1H NMR
(400 MHz, CDCl3) δ 1.78 (m, 1 H), 1.96 (m, 1 H), 1.78 (m, 1
H), 2.10-2.20 (m, 1 H), 2.28-2.40 (m, 1 H), 3.50 (s, 3 H), 5.12
(AB-system, 2 H, J ) 12.2 Hz), 6.45-6.58 (m, 3 H), 7.19 (s, 1
H), 7.25-7.38 (m, 10 H). 13C NMR (100 MHz, CDCl3) δ 18.42,
28.06, 51.93, 68.23, 122.96, 128.38, 128.43, 128.56, 129.45,
135.37, 153.45, 165.20. Anal. Calcd for C15H19NO6 (MW:
309.32): C, 58.25; H, 6.19; N, 4.53. Found: C, 58.0; H, 5.9; N,
4.3.
C
24H24N2O8 (MW: 468.46): C, 61.53; H, 5.16; N, 5.98. Found:
C, 61.1; H, 5.2; N, 5.9.
(2Z,4Z)-2, 5-Bis(ter t-bu tyloxya m in o)h exa -2,4-d ien e-1,6-
d ioic Acid Dim eth yl Ester (19). Compound 19 was prepared
from aqueous glyoxal and 11. Crystallization: MeOH. Yield:
1
65%. mp: 195-196 °C. H NMR(400 MHz, CDCl3) δ 1.40 (s,
18 H), 3.74 (s, 6 H), 6.38 (s, 2 H), 6.98 (s, 1 H). 13C NMR (100
MHz, CDCl3) δ 28.06, 52.67, 81.43, 122.53, 127.83, 152.66,
165.03. Anal. Calcd for C18H28N2O8(MW: 400.43): C, 53.99;
H, 7.05; N, 7.00. Found: C, 53.8; H, 6.9; N, 6.5.
(2Z,4Z)-2,5-Bis(a cet yla m in o)h exa -2,4-d ien e-1,6-d ioic
Acid Dim eth yl Ester (20). Compound 20 was prepared from
aqueous glyoxal and 10. During the addition of DBN, a
precipitate was formed. After 15 min, TLC (CHCl3/MeOH )
9/1) showed that all starting material was consumed. The
resulting precipitated product was filtered, washed on the frit
with water (10 mL) and methanol (2 × 5 mL), and dried.
1
Yield: 73%, mp: 274-277 °C. H NMR (400 MHz, d6-DMSO)
δ 1.98 (s, 6 H), 3.68 (s, 6 H), 6.72 (s, 2 H), 6.87 (s, 2 H). 13C
NMR (100 MHz, d6-DMSO) δ 21.76,51.60, 120.21, 130.38,
164.24, 168.42. Anal. Calcd for C12H16N2O6 (MW: 284.27): C,
50.70; H, 5.67; N, 9.85. Found: C, 50.6; H, 5.4; N, 9.4.
(2Z,7Z)-2,8-Bis(ben zyloxyca r bon yla m in o)n on a -2,7-d i-
en e-1,9-d ioic Acid Dim eth yl Ester (21). Compound 21 was
prepared from aqueous glutaraldehyde and 9. Yield: 78%;
mp: 243-247 °C. 1H NMR (400 MHz, CDCl3) δ 1.62 (m, 2 H),
2.22 (q, 4 H, J ) 7.4 Hz), 3.72 (s, 6 H), 5.11 (s, 4 H), 6.26 (br
s, 2 H), 6.58 (t, 2 H, J ) 7.4 Hz), 7.25-7.36 (m, 10 H). 13C
NMR (100 MHz, CDCl3) δ 26.80, 28.06, 52.36, 67.41, 128.16,
128.26, 128.55, 136.03, 137.10, 154.14, 164.96. Anal. Calcd for
(2Z,6Z)-2,7-Bis(ter t-b u t yloxyca r bon yla m in o)oct a -2,6-
d ien e-1,8-d ioic Acid Dim eth yl Ester (16). Compound 16
was prepared from 11 and aqueous butanedial 12. Crystal-
lization: toluene/ethyl acetate. Yield: 60%; mp 189-193 °C.
1H NMR (400 MHz, CDCl3) δ 1.45 (m, 18 H), 2.34 (m, 4 H),
3.76 (s, 6 H), 6.21 (m, 2 H), 6.45 (m, 2 H). 13C NMR (100 MHz,
CDCl3) δ 27.28, 28.22, 52.31, 80.62, 126.52, 133.88, 153.29,
165.26. Anal. Calcd for C20H32N2O8 (MW:428.48): C, 56.06; H,
7.53; N, 6.54. Found: C, 56.0; H, 7.4; N, 6.6.
C
27H30N2O8 (MW: 510.54): C, 63.52; H, 5.92; N, 5.49. Found:
C, 63.2; H, 5.7; N, 5.5.
2,7-Bis(a cetyla m in o)octa -2,6-d ien e-1,8-d ioic Acid Dim -
eth yl Ester (17). Compound 17 was prepared from 10 and
aqueous solution of butanedial 12. Yield: 78%. Crystalliza-
tion: MeOH; mp 243-247 °C. 1H NMR (400 MHz, CDCl3) δ
1.93 (m, 6 H), 2.20 (m, 4 H), 3.63 (s, 6 H), 6.29 (m, 2 H), 9.20
(m, 2 H). 13C NMR (100 MHz, CDCl3) δ 22.45, 26.06, 51.96,
128.03, 134.36, 164.87, 168.63. Anal. Calcd for C14H20N2O6
(MW: 312.32): C, 53.84; H, 6.45; N, 8.97. Found: C, 53.8; H,
6.4; N, 8.5.
1,4-Bis[2-(a cetyla m in o)-2-(m eth oxyca r bon yl)eth en yl]-
ben zen e (27). Compound 27 was prepared from p-phthalal-
dehyde and 10. The crude product was crystallized from
toluene to give 2 in 80% yield. mp: 275 °C (decomposition).
1H NMR (400 MHz, d6-DMSO) δ 1.99 (s, 6 H), 3.70 (s, 6 H),
7.16 (s, 2 H), 7.62 (s, 4 H), 9.51 (s, 2 H). 13C NMR (100 MHz,
d6-DMSO) δ 22.62, 52.48, 127.52, 130.38, 130.86, 134.76,
165.95, 170.08. Anal. Calcd for C18H20N2O6(MW: 360.37): C,
59.99; H, 5.59; N, 7.73. Found: C, 59.7; H, 5.5; N, 7.5.

1952 J . Org. Chem., Vol. 64, No. 6, 1999
Hiebl et al.
1,3-Bis[2-(ben zyloxyca r bon yla m in o)-2-(m eth oxyca r bo-
n yl)eth en yl]ben zen e (28). Compound 28 was prepared from
isophthalaldehyde and 9. The crude product was crystallized
from toluene to give 28 in 55% yield. mp: 153-155 °C. 1H
NMR (400 MHz, CDCl3) δ 3.79 (s, 6 H), 5.05 (s, 4 H), 6.30 (s,
2 H), 7.26-7.30 (m, 10 H), 7.40 (m. 2 H), 7.63 (s, 1 H). 13C
NMR (100 MHz, CDCl3) δ 52.66, 67.55, 124.86, 128.25, 128.50,
128.84, 130.41, 130.66, 130.80, 134.13, 135.89, 153.74, 165.50.
Anal. Calcd for C30H26N2O8 (MW: 542.54): C, 66.41; H, 4.83;
N, 5.16. Found: C, 66.3; H, 5.2; N, 5.1.
inactive material (1:2:1; oil) was prepared using Wilkinson
catalyst: retention time of L,L-isomer: 9.94 min; D,D-isomer:
9.24, meso-compound: 11.87 min. The crude material (2.02 g)
was dissolved in hot MeOH (10 mL) and allowed to crystallize
at +4 °C in the refrigerator overnight to give optically pure
32 (100% ee, 100% de by HPLC). Yield: 1.41 g (70%) of
colorless crystals. Melting point (111-112 °C) and optical
rotation ([R]20 ) +21.4; 5% in CHCl3) were identical with
D
material prepared by Kolbe electrolysis.20
(2S,8S)-2,8-Bis(ben zyloxyca r bon yla m in o)n on a n e-1,9-
d ioic Acid Dim eth yl Ester (33). The hydrogenation was
carried out as described for 30 using diene 21 as starting
material. Chiral analysis of the crude material by HPLC:
97.4% de (contains 1.3% meso-compound), 100% ee (no D,D-
compound detectable. Optically inactive material (1:2:1; mp
64-67 °C) was prepared using Wikinson catalyst: retention
time of L,L-isomer: 15.37 min; meso-compound: 13.67; D,D-
isomer: 13.18. The crude material (2.34 g) was dissolved in
hot MeOH (10 mL) and allowed to crystallize at +4 °C in the
refrigerator overnight to give optically pure 33 (100% ee, 100%
de by HPLC). Yield: 1.68 g (72.0%) colorless crystals; mp 76-
78 °C (MeOH); [R]20D ) +12.8 (5% CHCl3). 1H NMR (400 MHz,
CDCl3) δ 1.29 (br s, 6 H), 1.61 (br s, 2 H), 1.67 (br s, 2 H), 3.71
(s, 6 H), 4.33 (m, 2 H), 5.09 (s, 4 H), 5.24 (m, 2 H), 7.26-7.35
(m, 10 H). 13C NMR (400 MHz, CDCl3) δ 24.92, 28.63, 32.58,
52.31, 53.78, 67.01, 128.10, 128.18, 128.53, 136.29, 155.86,
172.93. Anal. Calcd for C27H34N2O8 (MW: 514.57): C, 63.02;
H, 6.66; N, 5.44. Found: C, 62.9; H, 6.6; N, 5.3.
(2Z,6Z)-2-(Acetyla m in o)-7-(ben zyloxyca r bon yla m in o)-
h exa -2,6-d ien e-1,8-d ioic Acid Dim eth yl Ester (29). Com-
pound 15 (5.09 g, 16.46 mmol) and 10 (3.94 g, 16.46 mmol)
were dissolved in dichloromethane (50 mL). Molecular sieves
(3 Å, 1 g) were added, and the reaction was stirred for 15 min.
Then DBN (1.97 mL, 16.46 mmol) was added via syringe, and
the reaction was stirred for 20 h. The reaction was washed
with diluted HCl solution (20 mL, 1 N) and water (3 × 50 mL).
The organic phase was dried with Na2SO4 and filtered, and
the filtrate was concentrated to give 5.22 g of crude product.
This was crystallized from methanol (35 mL) to yield 3.35 g
1
(50%) of 29. mp: 141-150 °C. H NMR (400 MHz, CDCl3) δ
2.07 (s, 3 H), 2.31 (m, 4 H), 3.73 and 3.76 (s, 3 H), 5.12 (s, 2
H), 6.45-6.58 (m, 3 H), 7.19 (s, 1 H), 7.25-7.38 (m, 10 H). 13
C
NMR (100 MHz, CDCl3) δ 23.28, 27.12, 27.51, 52.38, 52.41,
67.40, 126.07, 128.02, 128.08, 128.25, 128.53, 128.56, 135.06,
135.23, 135.89, 154.17, 164.90, 164.97, 168.56. Anal. Calcd for
C
20H24N2O7 (MW: 404.42): C, 59.39; H, 5.98; N, 6.93. Found:
C, 58.8; H, 6.1; N, 6.8.
Ack n ow led gm en t. We thank Drs. David Chaplin
and Nicholas B. J ohnson and Ms. Catherine Rippe´ of
Chirotech Technology Ltd., UK, for their assistance in
the process development of the Rh-Et-DuPHOS-medi-
ated hydrogenation and analytical method development
for the 2,7-diaminosuberic acid. We thank Dr. Harald
Baumgartner, J ohann Traxler, and Peter Eisenmann
(Topcro Pharma Research GmbH) for their contribution,
enabling the transfer of this synthetic route into the
pilot plant. We thank Dr. Michael A. McGuire (Smith-
Kline Beecham Pharmaceuticals, King of Prussia, PA)
for carrying out the hydrogenation with Rh-CHIRA-
PHOS at 500 psi, and Dr. Irmtraud Bernwieser and
Gu¨nter Mayrhofer for the determination of the optical
purity by chiral HPLC and chiral capillary electrophore-
sis (CE).
(2S,7S)-2,7-Bis(b en zyoxyca r b on yla m in o)oct a n e-1,8-
d ioic Acid Dim eth yl Ester (30). Typical experiment for the
catalytic hydrogenation of 13: 13 (3.5 g, 7.49 mmol) was
dissolved in oxygen-free MeOH (200 mL, obtained by refluxing
and storing under nitrogen). Rh(COD-S,S-EtDuPHOS)OTf
(100 mg) was added, and the mixture was hydrogenated
overnight (18 h) at 4 bar (60 psi) at ambient temperature. The
reaction was checked by NMR, indicating that no starting
material was detectable. The solution was filtered over silica
gel to remove the catalyst. The filtrate was concentrated and
degassed to yield crude 30. This was analyzed by chiral
HPLC: 100% ee, 99.0% de. The crude material was crystallized
from MeOH to give 30 (100% ee, >99.0% de, [R]20 ) -14.6;
D
5% in CHCl3) in an average yield of 85%. This material was
identical with material prepared by Kolbe electrolysis.20 Opti-
cally inactive material was prepared according to ref 20.
Retention times: D,D-isomer: 7.11 min; meso-isomer: 8.10
min; L,L-isomer: 9.04 min.
(2S,5S)-2,5-Bis(b en zyloxyca r b on yla m in o)h exa n e-1,6-
d ioic Acid Dim eth yl Ester (32). The hydrogenation was
carried out as described for compound 30 using diene 18 and
Rh-Et-(S,S)-DuPHOS as catalyst. Chiral analysis of the crude
reaction product by HPLC: 97.0% de (contains 1.5% meso-
compound), 100% ee (no D,D-compound detectable). Optically
Su p p or tin g In for m a tion Ava ila ble: Procedures for the
synthesis and characterization of compounds 22-25, 26, and
31. This material is available free of charge via the Internet
at http://pubs.acs.org.
J O982034J