A catalyst that plays multiple roles: Asymmetric synthesis of β-substituted aspartic acid derivatives through a four-stage, one-pot procedure

Article abstract of DOI:10.1021/ol017087t

(Matrix Presented) We report a new method for the catalytic, asymmetric synthesis of β-substituted aspartic acid derivatives in which the nucleophilic catalyst serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic dehydrohalogenation of α-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl β-lactams; and finally, nucleophilic ring opening to afford optically enriched β-substituted aspartic acids in high enantioselectivity and diastereoselectivity.

Full text of DOI:10.1021/ol017087t

ORGANIC
LETTERS
2002
Vol. 4, No. 3
387-390
A Catalyst that Plays Multiple Roles:
Asymmetric Synthesis of â-Substituted
Aspartic Acid Derivatives through a
Four-Stage, One-Pot Procedure
Travis Dudding, Ahmed M. Hafez, Andrew E. Taggi, Ty R. Wagerle, and
Thomas Lectka*
Department of Chemistry, Johns Hopkins UniVersity, 3400 North Charles St.,
Baltimore, Maryland 21218
lectka@jhunix.hcf.jhu.edu
Received November 21, 2001
ABSTRACT
We report a new method for the catalytic, asymmetric synthesis of â-substituted aspartic acid derivatives in which the nucleophilic catalyst
serves up to four discrete roles in a one-pot procedure: catalytic dehydrohalogenation of acid chlorides to form ketenes; catalytic
dehydrohalogenation of r-chloroamines to form the corresponding imines; catalyzed [2 + 2]-cycloaddition to produce intermediate acyl â-lactams;
and finally, nucleophilic ring opening to afford optically enriched â-substituted aspartic acids in high enantioselectivity and diastereoselectivity.
Extensive progress in the field of asymmetric catalysis over
the past several years has led to the development of highly
selective and efficient catalysts. Normally an asymmetric
catalyst promotes one particular chemical transformation in
a synthetic sequence.1 One of the prime challenges of
asymmetric synthesis would be to utilize catalysts to perform
a number of tasks in a one-pot process.2 We report herein a
system for the synthesis of â-substituted amino acid deriva-
tives (especially substituted aspartic acids)3 that involves the
use of inexpensive starting materials and an optically pure
nucleophilic catalyst to produce highly optically enriched
products in a one-pot procedure.4 Our method involves up
to four discrete stages, each catalyzed by the chiral nucleo-
philic catalyst benzoylquinine (2a, (BQ)):5 catalytic dehydro-
(3) For example, derivatives of â-hydroxyaspartic acid are known
inhibitors of L-asparagine synthetase: (a) Mokotoff, M.; Bagaglio, J. F.;
Parikh, B. S. J. Med. Chem. 1975, 18, 354-358. â-Hydroxyaspartic acids
are present in many microorganisms: (b) Kornberg, H. L.; Morris, J. G. J.
Biochem. 1965, 95, 577-586. (c) Ishiyama, T.; Furuta, T.; Takai, M.;
Okimoto, Y.; Aizawa, S.; Shiman, A.; Yonehara, H. J. Antibiot. 1975, 28,
821-823. Various syntheses of L-erythro-â-hydroxyaspartic acid, a constitu-
ent of several proteins involved in the blood clotting cascade, have been
reported: (d) Hansson, T. G.; Kihlberg, J. O. J. Org. Chem. 1986, 51, 4490-
4492. (e) Wagner, R.; Tilley, J. W. J. Org. Chem. 1990, 55, 6289-6291.
(f) Wagner, R.; Tilley, J. W.; Lovey, K. Synthesis 1990, 785-786.
Derivatives of â-alkoxy and hydroxy aspartates are known nontransportable
glutamate transporter blockers: (g) Shimamoto, K.; Shigeri, Y.; Yasuda-
Kamatani, Y.; Lebrun, B.; Yumoto, N.; Nakajima, T. Bioorg. Med. Chem.
Lett. 2000, 10, 2407-2410.
(1) For example, see Jacobsen’s synthesis of FR901464: Thompson, C.
F.; Jamison, T. F.; Jacobsen, E. N. J. Am. Chem. Soc. 2001, 123, 9974-
9983.
(2) (a) Annunziata, R.; Benaglia, M.; Cinquini, M.; Cozzi, F. Eur. J.
Org. Chem. 2001, 1045-1048. (b) Yu, H.-B.; Hu, Q.-S.; Pu, L. J. Am.
Chem. Soc. 2000, 122, 6500-6501. (c) Schenning, A. P. H. J.; Lutje
Spelberg, J. H.; Hurbert, D. H. W.; Feiters, M. C.; Nolte, R. J. M. Chem.
Eur. J. 1998, 4, 871-880. (d) Sibi, M. P.; Cook, G. R.; Liu, P. Tetrahedron
Lett. 1999, 40, 2477-2480. (e) Hamashima, Y.; Kanai, M.; Shibasaki, M.
J. Am. Chem. Soc. 2000, 122, 7412-7413. (f) Bolm, C.; Dinter, C. L.;
Seger, A.; Hocker, H.; Brozio, J. J. Org. Chem. 1999, 64, 5730-5731. (g)
Shibasaki, M. Chemtracts: Org. Chem. 1999, 12, 979-998.
(4) For a summary of recent asymmetric catalysis using nucleophiles,
see: Dalko, P. I.; Moisan, L. Angew. Chem., Int. Ed. 2001, 40, 3726-
3748.
10.1021/ol017087t CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/15/2002

halogenation of acid chlorides 1 to form ketenes 3 (or derived
zwitterionic intermediates 4, (step A)), dehydrohalogenation
of R-chloroamine 5 to form the corresponding imine 6 (step
B),6 catalyzed cycloaddition to produce intermediate â-lac-
tams 7 (step C), and nucleophilic ring opening to form final
products 9 (step D, Scheme 1).
We performed a number of experiments to examine the
role of catalyst 2a in each step of the amino acid synthesis.
Since the overall reaction involves intermediates that can
be both isolated and characterized, we were able to perform
each stage separately to assess the catalytic activity. Initial
experiments established that addition of R-chloroamine 5 to
a solution of highly basic proton sponge produces no
reaction, even at elevated temperatures. However, we found
that, in the presence of a catalytic amount of BQ (or other
tertiary amine bases), 5 underwent dehydrohalogenation to
afford intermediate imine 6 (Scheme 2). We believe that after
Scheme 1. A Four-Stage, One-Pot Procedure
Scheme 2. BQ-Catalyzed Dehydrohalogenation of
R-Chloroglycine
The synthesis of optically enriched â-amino acid deriva-
tives is a topic of intense interest in organic chemistry.7
Catalytic, asymmetric methodology for this purpose has
focused on the azidation of R,â-unsaturated carbonyl com-
pounds and subsequent reduction of the products to the free
amines.8 Another approach would be to access â-lactam
intermediates.9 The success of our reaction is dependent on
the intermediacy of chemically reactive N-acyl-â-lactams 7,
which are activated toward nucleophilic ring opening by
alcohols and amines at the carbonyl carbon.
dehydrohalogenation by BQ, the proton is relayed to the
stoichiometric base, proton sponge.10 This is another example
of shuttle deprotonation, which we have previously docu-
mented in the case of reactive ketene synthesis.9c,11
A second function BQ serves is ketene (or zwitterionic
enolate) formation from acid chlorides using proton sponge
as a nonnucleophilic, stoichiometric base. Aside from the
role of BQ in the stereochemistry-determining cycloaddition,9c
we found that in the presence of methanol, BQ greatly
enhanced the rate of â-lactam ring opening.12 Even at
elevated temperatures, a large rate difference was observed
between the BQ-catalyzed and uncatalyzed methanolysis
reactions. To address whether proton sponge or byproduct
salts were responsible for the increased rate of methanolysis,
polymer-supported BQ 2b was utilized in the reaction.9b
Removal of 2b prior to methanolysis resulted in a reduced
rate of ring opening, relative to when BQ was present. These
facts suggest that BQ acts as a nucleophilic catalyst in the
â-lactam alcoholysis (Scheme 3). An additional control
experiment confirmed that the enantioselectivity of the
â-lactam intermediate and the final product were the same,
discounting a potential chiral resolution by BQ in the ring-
opening reaction.
(5) For other, excellent uses of cinchona alkaloids in asymmetric synthesis
see the following. Ester synthesis from ketenes: (a) Samtleben, R.; Pracejus,
H. J. Prakt. Chem. 1972, 314, 157-169. Lactone synthesis from ketenes:
(b) Wynberg, H.; Staring, E. G. J. J. Am. Chem. Soc. 1982, 104, 166-168.
Ketene dimerization: (c) Calter, M. A. J. Org. Chem. 1996, 61, 8006-
8007. Baylis-Hillman reaction: (d) Iwabuchi, Y.; Nakatani, M.; Yokoyama,
N.; Hatakeyama, S. J. Am. Chem. Soc. 1999, 121, 10219-10220. Osmy-
lation reactions: (e) Kolb, H. C.; VanNieuwenzhe, M. S.; Sharpless, K. B.
Chem. ReV. 1994, 94, 2483-2547. Phase-transfer catalysis: (f) Corey, E.
J.; Bo, Y.; Busch-Petersen, J. J. Am. Chem. Soc. 1999, 120, 13000-13001.
(g) O’Donnell, M. J.; Bennett, W. D.; Wu, S. J. Am. Chem. Soc. 1989,
111, 2353-2355. Kacprzak, K.; Gawronski, J. Synthesis-Stuttgart 2001, 7,
961-998.
(6) R-Chloroamine 5 is easily made by the condensation of benzamide
with ethyl glyoxylate followed by reaction with oxalyl chloride. See
Supporting Information.
(7) (a) EnantioselectiVe Synthesis of â-Amino Acids; Juaristi, E., Ed.;
Wiley-VCH: New York, 1997. (b) Rzasa, R. M.; Shea, H. A.; Romo, D.
J. Am. Chem. Soc. 1998, 120, 591-592. (c) Cole, D. C. Tetrahedron 1994,
50, 9517-9582. (d) Kobayashi, S.; Nagayama, S. J. Am. Chem. Soc. 1997,
119, 10049-10053. (e) Ferraris, D.; Young, B.; Dudding, T.; Lectka, T. J.
Am. Chem. Soc. 1998, 120, 4548-4549. (f) Sibi, M. P.; Shay, J. J.; Liu,
M.; Jasperse, C. P. J. Am. Chem. Soc. 1998, 120, 6615-6616.
(8) (a) Myers, J. K.; Jacobsen, E. N. J. Am. Chem. Soc. 1999, 121, 8959-
8960. (b) Horstmann, T. E.; Guerin, D. J.; Miller, S. J. Angew. Chem., Int.
Ed. 2000, 39, 3635-3638.
(10) For discussions concerning proton sponge basicity, see: (a) Hibbert,
F.; Emsley, J. AdV. Phys. Org. Chem. 1990, 26, 255-279. (b) Alder, R.
W. Chem. ReV. 1989, 89, 1215-1223.
(9) We have recently reported a catalytic, asymmetric synthesis of
â-lactams: (a) Hafez, A. M.; Taggi, A. E.; Dudding, T.; Lectka, T. J. Am.
Chem Soc. 2001, 123, 10853-10859. (b) Hafez, A. M.; Taggi, A. E.; Wack,
H.; Drury, W. J., III; Lectka, T. Org. Lett. 2000, 2, 3963-3965. (c) Taggi,
A. E.; Hafez, A. M.; Wack, H.; Young, B.; Drury, W. J., III; Lectka, T. J.
Am. Chem. Soc. 2000, 122, 7831-7832.
(11) We have used powered carbonates as effective nonnucleophilic,
stoichiometric bases for ketene generation: Hafez, A. M.; Taggi, A. E.;
Wack, H.; Esterbrook, J.; Lectka, T. Org. Lett. 2001, 3, 2049-2051.
(12) The ring opening of â-lactams is known to be catalyzed by
nucleophiles including azides: Palomo, C.; Aizpurua, J. M.; Galarza, R.;
Mielgo, A. J. Chem. Soc., Chem. Commun. 1996, 633-634.
388
Org. Lett., Vol. 4, No. 3, 2002

Following the same procedure, R,â-amino acid derivatives
9b-e were prepared (Table 1). The use of p-methoxy-
phenylacetyl chloride 1c and p-chlorophenylacetyl chloride
1d demonstrates that the reaction tolerates electron-donating
and withdrawing groups on the aromatic ring without
diminishing the yield or selectivity (entries 3 and 4, Table
1).
Scheme 3. BQ-Catalyzed Ring-Opening Methanolysis
We anticipated that the use of p-methoxyphenoxyacetyl
chloride 1e would provide 9e (entry 5, Table 1), which
subsequently could be converted to â-hydroxyaspartic acid
11 (Scheme 4). Exemplifying this, 9e was converted to the
Scheme 4. Conversion of 9e to â-Hydroxyaspartic Acid 11
To establish the scope and practicality of the reaction, we
screened a number of acid chlorides with R-chloroamine 5
(Table 1) to furnish the final products in a one-pot procedure.
Table 1. One-Pot Multicomponent R,â-Amino Acid Synthesis
Using MeOH as the Ring-Opening Nucleophile
known glutamate uptake inhibitor (R,R)-2-amino-3-hydroxy-
aspartic acid (11) through a ceric ammonium nitrate (CAN)
oxidation, followed by hydrolysis of the ester and amide
groups, to afford 11 of known stereochemistry.
Additionally, the use of nucleophilic amines 8b-d af-
forded ring-opened products 9f-h (Table 2). For example,
Table 2. One-Pot Multicomponent R,â-Amino Acid Synthesis
with R-Chloroglycine 5
a Isolated yield of product after column chromatography. b Enantiomeric
ratio was determined by chiral HPLC. c Diastereomeric ratio as determined
by crude H NMR.
a Isolated yield of product after column chromatography. b Enantiometic
ratio was determined by chiral HPLC. c Diastereomeric ratio as determined
by crude H NMR.
1
1
For example, a 25-mL round-bottom flask was charged with
R-chloroamine 5 (0.26 mmol), proton sponge (0.39 mmol),
catalyst 2a (0.013 mmol), and toluene (1 mL). The resulting
suspension was stirred vigorously for 1 h, then further diluted
with toluene (8 mL), and cooled to -78 °C. A solution of
phenylacetyl chloride 1a (0.13 mmol) in 1 mL of toluene
was then added. The reaction was stirred for 6 h while
gradually warming to room temperature. Methanol (4 mL)
was added, and the mixture was heated at reflux for 4 h.
The reaction was purified by column chromatography to
afford 9a (62%, 97.5/2.5 er, 12/1 dr, entry 1, Table 1).
the addition of benzylamine (0.26 mmol) at room temperature
afforded product 9f (61%, 97.5/2.5 er, 11/1 dr, entry 1, Table
2). Likewise, ring opening by glycine methyl ester 8c and
(S)-serine methyl ester 8d13 afforded products 9g and 9h in
similar selectivities and yield (entries 2 and 3, Table 2).
Unlike methanolysis, ring opening of the intermediate
â-lactams by amine nucleophiles proceeds rapidly in the
absence of BQ.
(13) Epimerization of the hydroxymethyl group in 9h was not observed
under the reaction conditions.
Org. Lett., Vol. 4, No. 3, 2002
389

In summary, we have developed a multistage, one-pot
procedure for the synthesis of â-substituted aspartic acid
derivatives. Hallmarks of the process involve the use of
inexpensive starting materials and a chiral nucleophilic
catalyst that performs up to four discrete roles. Further studies
will center on the development of an iterative synthesis of
polypeptides based on our â-substituted aspartic acid deriva-
tives.
Dreyfus Foundation for a Teacher-Scholar Award, and the
Alfred P. Sloan Foundation for a Fellowship. A.T. thanks
the Organic Division of the American Chemical Society for
a Fellowship sponsored by Organic Reactions, Inc.
Supporting Information Available: General experimen-
tal procedures and compound characterization. This material
is available free of charge via the Internet at http://pubs.acs.org.
Acknowledgment. T.L. thanks DuPont, Eli Lilly, the
NIH, and the NSF Career Program for grant support, the
OL017087T
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Org. Lett., Vol. 4, No. 3, 2002