Enantiomerically pure tetrahydropyrimidinones in asymmetric synthesis: Preparation of a protected α-methylasparagine derivative and corresponding dipeptides

Article abstract of DOI:10.1021/jo9909296

Methyl ester 5a, available in enantiomerically pure form from the amino acid asparagine via a one-pot cyclization/protection sequence, followed by esterification, can be effectively deprotonated with LDA/DMPU/LiCl. Treatment with MeI affords the corresponding alkylated adduct in enantiomerically pure form, from which α-methylaspartic acid is obtained. Variation of the amine protection group allows for the isolation of a protected carboxylic acid/free amine derivative of α-methylasparagine. The utility of H-MeAsn-OMe is demonstrated in the formation of dipeptides.

Full text of DOI:10.1021/jo9909296

J . Org. Chem. 1999, 64, 7885-7889
7885
En a n tiom er ica lly P u r e Tetr a h yd r op yr im id in on es in Asym m etr ic
Syn th esis: P r ep a r a tion of a P r otected r-Meth yla sp a r a gin e
Der iva tive a n d Cor r esp on d in g Dip ep tid es
Stephanie A. Hopkins, Todd A. Ritsema, and J oseph P. Konopelski*
Department of Chemistry and Biochemistry, University of California, Santa Cruz, California 95064
Received J une 8, 1999
Methyl ester 5a , available in enantiomerically pure form from the amino acid asparagine via a
one-pot cyclization/protection sequence, followed by esterification, can be effectively deprotonated
with LDA/DMPU/LiCl. Treatment with MeI affords the corresponding alkylated adduct in
enantiomerically pure form, from which R-methylaspartic acid is obtained. Variation of the amine
protection group allows for the isolation of a protected carboxylic acid/free amine derivative of
R-methylasparagine. The utility of H-MeAsn-OMe is demonstrated in the formation of dipeptides.
One of the attractions of the chemical approach to
biological molecules is the ability to prepare derivatives
with novel designed properties. In recent years there has
been considerable interest in the synthesis of unnatural
amino acids, fueled by the desire for synthetic polypep-
tides with increased hydrolytic stability,1 enzyme inhibi-
tion properties, and/or unique conformational restric-
tions.2 One class of monomer that has been the focus of
intense synthetic effort is the R-methyl amino acids. The
restricted conformational space available to these rela-
tively simple derivatives of the common building blocks
of proteins and polypeptides, coupled with their resis-
tance to hydrolytic attack, make them attractive compo-
nents in tailored biologically active materials.3
The side chain amide of the amino acid asparagine is
the attachment point for the polysaccharide antenna in
N-linked glycopeptides,4 ubiquitous cell surface macro-
molecules that mediate cell-cell interactions. It is be-
lieved that the mobility of the oligosaccharide chain is
largely determined by the conformational flexibility of
the asparagine side chain.5 Specific conformations also
play an important role in the stabilization of local
structures in polypeptides when asparagine is present
either as an N-6 or a C-terminal7 R-helix cap, and in the
formation of â-hairpin loops by the Asn-Gly dipeptide.8
Given the flexibility of the asparagine side chain, both
glycopeptide and peptide secondary structure conforma-
tional studies would benefit from the availability of
conformationally restricted asparagine derivatives.
Herein we disclose our work on the asymmetric syn-
thesis of enantiomerically pure R-methylasparagine de-
rivatives.9 We note that this appears to be one of the last
of the common amino acids to be made available in the
R-methylated form. Undoubtedly this is due to the nature
of asparagine as “an interesting, quirky, opinionated
residue with many unique properties”,10 something we
have experienced directly (vide supra). In addition,
R-methylaspartic acid, an important compound in the
synthesis of novel peptide-based therapeutics11 and pep-
tide structure,12 is available from this protocol.13 Finally,
methods for the formation of R-Me-Asn-containing dipep-
tides are described.
Some years ago we began a study of enantiomerically
pure dihydropyrimidinones and their chemistry that
resulted in an efficient synthesis of both enantiomers of
2-tert-butyl-1-carbomethoxy-2,3-dihydro-4(1H)-pyrimidi-
none (1).14 Since that time, synthetic pathways from
reagent 1 to enantiomerically pure â-aryl15 and â-alkyl-
â-amino acids16 have been defined in this laboratory as
well as others.17 In addition, 1 functions as an efficient
chiral auxiliary for the synthesis of enantiomerically pure
* Corresponding author. Phone 831-459-4676; Fax 831-459-2935;
e-mail joek@chemistry.ucsc.edu.
(1) Thaisrivongs, S.; Pals, D. T.; Lawson, J . A.; Turner, S. R.; Harris,
D. W. J . Med. Chem. 1987, 30, 536-41.
(8) Sharman, G. J .; Searle, M. S. J . Am. Chem. Soc. 1998, 120,
5291-5300.
(2) Hinds, M. G.; Welsh, J . H.; Brennand, D. M.; Fisher, J .; Glennie,
M. J .; Richards, N. G. J .; Turner, D. L.; Robinson, J . A. J . Med. Chem.
1991, 34, 1777-89. (b) Boteju, L. W.; Wegner, K.; Hruby, V. J .
Tetrahedron Lett. 1992, 33, 7491-4. (c) Kazmierski, W. M.; Urbanczyk-
Lipkowska, Z.; Hruby, V. J . J . Org. Chem. 1994, 59, 1789-95.
(3) Goodman, M.; Ro, S. In Burger’s Medicinal Chemistry and Drug
Discovery, 5th ed.; Wolff, M. E., Ed.; J ohn Wiley & Sons: New York,
1995; Vol. 1, pp 803-861.
(9) Recently Aoyagi and Williams published their successful ap-
proach to the synthesis of unprotected R-methylasparagine. See Aoyagi,
Y.; Williams, R. M. SYNLETT 1998, 1099-1101.
(10) Richardson, J . S.; Richardon, D. C. In Prediction of Protein
Structure and The Principles of Protein Conformation; Fasman, G. D.,
Ed.; Plenum: New York, 1989; p 66.
(11) J ackson, S.; DeGrado, W.; Dwivedi, A.; Parthasarathy, A.;
Higley, A.; Krywko, J .; Rockwell, A.; Markwalder, J .; Wells, G.; Wexler,
R.; Mousa, S.; Harlow, R. J . Am. Chem. Soc. 1994, 116, 3220-30.
(12) Altmann, K.-H.; Altmann, E.; Mutter, M. Helv. Chim. Acta
1992, 75, 1198-1210.
(4) Rademacher, T. W.; Parekh, R. B.; Dwek, R. A. Annu. Rev.
Biochem. 1988, 57, 785-838. (b) Opdenakker, G.; Rudd, P. M.; Ponting,
C. P.; Dwek, R. A. FASEB J . 1993, 7, 1330-7.
(5) Wormald, M. R.; Wooten, E. W.; Bazzo, R.; Edge, C. J .; Feinstein,
A.; Rademacher, T. W.; Dwek, R. A. Eur. J . Biochem. 1991, 198, 131-
9. (b) Perczel, A.; Kollat, E.; Hollosi, M. Fasman, G. D. Bioploymers
1993, 33, 665-85.
(6) Lyu, P. C.; Zhou, H. X.; J elveh, N.; Wemmer, D. E.; Kallenbach,
N. R. J . Am. Chem. Soc. 1992, 114, 6560-62. (b) Forood, B.; Feliciano,
E. J .; Nambiar, K. P. Proc. Natl. Acad. Sci. U.S.A. 1993, 90, 838-42.
(c) Doig, A. J .; Baldwin, R. L. Protein Sci. 1995, 4, 1325-36.
(7) Zhou, H. X.; Lyu, P. C.; Wemmer, D. E.; Kallenbach, N. R. J .
Am. Chem. Soc. 1994, 116, 1139-40.
(13) For other syntheses of 2-methyl aspartic acid, see (a) Chan, C.-
O.; Crich, D.; Natarajan, S. Tetrahedron Lett. 1992, 33, 3405-8. (b)
Aebi, J . D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507-18.
(14) Lakner, F. J .; Chu, K. S.; Negrete, G. R.; Konopelski, J . P. Org.
Synth. 1995, 73, 201-14. (b) Chu, K. S.; Negrete, G. R.; Konopelski,
J . P.; Lakner, F. J .; Woo, N.-T.; Olmstead, M. M. J . Am. Chem. Soc.
1992, 114, 1800-1812.
(15) Konopelski, J . P.; Chu, K. S.; Negrete, G. R. J . Org. Chem. 1991,
56, 1355-6.
(16) Chu, K. S.; Konopelski, J . P. Tetrahedron 1993, 49, 9183-90.
10.1021/jo9909296 CCC: $18.00 © 1999 American Chemical Society
Published on Web 09/23/1999

7886 J . Org. Chem., Vol. 64, No. 21, 1999
Hopkins et al.
R-substituted carboxylic acids.18 The synthesis of 1 begins
with the one-pot formation of 2 from the amino acid
asparagine, which is available at low cost in both enan-
tiomeric forms. Such ready availability of a “protected”
form of asparagine (i.e., 2) opened the possibility for
synthetic modifications to the amino acid itself.
that the C2 aromatic substituent directs the alkylation
stereochemistry at C6. Based on the X-ray structure
determinations of 1,14b 4, and related compounds,22,23 as
well as the stereochemistry of the product â-amino acids
derived from 1, the absolute stereochemistry of the
product of the alkylation event is predicted to be that of
the starting material. That is, the incoming alkyl elec-
trophile is expected to approach the nucleophilic C6
position from the face of 5a opposite to the aromatic
group, regenerating the original absolute configuration
at C6.
Deprotonation of 5a results in the formation of dianion
6a . While deprotonation of N3 ensures that there will
be no reaction at C5 (R-position to a lactam anion), the
formation of insoluble aggregates was expected to pose
serious problems for reactivity. Indeed, deprotonation
with 2.3 equiv of LDA at -75 °C afforded a solid mass
from which no methylated product was isolated upon
addition of MeI. Alkyllithium reagents were not effective,
either giving low yield of methylated product (t-BuLi,
lithium mesitylide) or reacting with the ester functional-
ity (n-BuLi). Potassium hydride led to dimethylated
product (N3 and C6) in 72% yield. With limited amounts
of MeI (1.7 equiv vs 6 equiv), N3 methylation dominates
the product mixture, with unreacted starting material
making up the bulk of the remaining material. The use
of LiHMDS as base was completely ineffective, presum-
ably due to steric problems, and resulted in no methyl-
ated product. A mixture of LDA and LiCl24 led to
monoalkylation at long reaction times (18 h at -75 °C)
with yields between 35 and 50%. Addition of DMPU
afforded dialkylation product after 18 h, but a high yield
of desired product 7a was obtained after only 7 h reaction
time. Analysis of the crude reaction material by GC and
enantiomerically pure stationary phase HPLC20 indicated
small amounts of impurities that were removed by a
single recrystallization from EtOAc/hexane to give ana-
lytically pure material. Enantiomeric product ent-7a was
prepared from (R)-asparagine in similar fashion.
In itia l Stu d ies. Recrystallization brings 1 to enan-
tiomeric purity without chromatography through the
entire reaction sequence, as verified by analysis of the
corresponding O-methyl mandelic acid derivative.14b In-
vestigations of 2 indicate high enantiomeric purity as
well.14a However, our more recent work has focused on
the use of aromatic aldehydes in a two-step synthesis of
the tetrahydropyrimidinone ring system.19 We were
intrigued with the prospect of extending our one-pot
procedure to aromatic aldehydes. A number of aromatic
aldehydes were investigated, as well as a wide variety
of cyclization conditions. As opposed to the synthesis of
2, water alone is no longer an acceptable solvent for this
reaction. The best results involve the addition of p-
chlorobenzadehyde (dissolved in DME) to a solution of
the potassium salt of asparagine in water (3:5 ratio of
DME to water). After 48 h, 1 equiv of NaHCO3 is added,
along with methyl chloroformate. Product 3a is isolated
in a modest 40% yield, but the ease of the reaction and
the lack of expensive reagents allows for the production
of large quantities of the desired material, which now
possesses a UV-active chromophore. Proton and 13C NMR
analysis indicates the presence of a single diastereomer.20
In addition, a single-crystal X-ray analysis of the related
compound 4 verifies the expected cis relationship of the
substituents at C2 and C6 of the newly formed hetero-
cycle.19 Methyl ester formation occurs in straightforward
fashion with K2CO3/MeI in DMF to afford 5a in good
yield.
Acid hydrolysis of 7a (6 N HCl, ion-exchange resin) led
to the isolation of R-methylaspartic acid 8 in 77% yield,
identical to the material described in the literature13 by
NMR and optical rotation.25 Hydrogenolysis experiments
on 7a , designed to cleave the benzylic bonds of the N,N-
(21) Seebach, D.; Boes, M.; Naef, R.; Schweizer, W. B. J . Am. Chem.
Soc. 1983, 105, 5390-8.
(22) Seebach, D.; Lamatsch, B.; Amstutz, R.; Beck, A. K.; Dobler,
M.; Egli, M.; Fitzi, R.; Gautschi, M.; Herrado´n, B.; Hidber, P. C.; Irwin,
J . J .; Locher, R.; Maestro, M.; Maetzke, T.; Mourin˜o, A.; Pfammatter,
E.; Plattner, D. A.; Schickli, C.; Schweizer, W. B.; Seiler, P.; Stucky,
G.; Petter, W.; Escalante, J .; J uaristi, E.; Quintana, D.; Miravitlles,
C.; Molins, E. Helv. Chim. Acta 1992, 75, 913-34. (b) Lamatsch, B.
M., Ph.D. Thesis, ETH, Zurich, 1993.
Alkylation of 5a follows the theme of “self-reproduction
of chirality” pioneered by Seebach and co-workers21 in
(17) J uaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992, 3,
723-6. (b) Beaulieu, F.; Arora, J .; Veith, U.; Taylor, N. J .; Chapell, B.
J .; Snieckus, V. J . Am. Chem. Soc. 1996, 118, 8727-8.
(18) Negrete, G. R.; Konopelski, J . P. Tetrahedron: Asymmetry 1991,
2, 105-8.
(19) Konopelski, J . P.; Filonova, L. K.; Olmstead, M. M. J . Am.
Chem. Soc. 1997, 119, 4305-6.
(20) Analyses were performed on a Chiralcel OJ -R reversed-phase
chiral HPLC column.
(23) Konopelski, J . P., Wei, Y.; Olmstead, M. M., J . Org. Chem. 1999,
64, 5148-51.
(24) Seebach, D.; Bossler, H.; Gru¨ndler, H.; Shoda, S.; Wenger, R.
Helv. Chim. Acta 1991, 74, 197-224. (b) Seebach, D.; Beck, A. K.;
Studer, A. In Modern Synthetic Methods 1995; Ernst, B.; Leuman, C.,
Eds.; VHCA: Basel, 1995; pp 1-178.

Tetrahydropyrimidinones in Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 21, 1999 7887
acetal, were not successful under a variety of conditions.
However, treatment of 7a with mild aqueous HCl (0.25
N) under reflux for only 1 h resulted in cleavage of the
N,N-acetal while leaving both the carbamate and ester
functionalities intact. Flash column chromatography
afforded a 68% yield of MeO2C-MeAsn-OMe 9. Much to
our dismay, however, none of the desired protected
amine/free carboxylic acid derivative 10 was isolated
upon treatment of 9 with a 0.025 N solution of KOH in
MeOH/H2O (3:1) at 0 °C. Rather, the corresponding
succinimide was isolated in excellent yield, with no
indication of free acid formation. To date, no conditions
have been found to prepare 10 in acceptable yield. This
cyclization proclivity of asparagine is well-known and
thought to be involved in the accelerated racemization
of this amino acid in biological systems.26
HCl 11 was subjected to silylation, followed by treatment
with the desired amino acid fluoride.32,33 Following
standard workup, the coupled dipeptides 12a ,b were
isolated in 40-50% yield. Even better results were
obtained from the direct reaction of the amino acid
fluoride with 11 without silylation. These conditions
afforded the desired material in 66% yield.
In conclusion, the synthesis of a protected derivative
of R-methylasparagine in enantiomerically pure form,
and its use in the synthesis of model dipeptides, has been
accomplished. The further use of 11 and related deriva-
tives in the synthesis of polypeptides is underway in our
laboratory and will be reported in due course.
P r ep a r a tion of r-Meth yla sp a r a gin e Der iva tive.
Given the difficulty of working with R-methylasparagine
derivatives once the pyrimidinone ring is opened, we
opted for a different amine protection scheme that would
allow for clean deprotection prior to ring opening via N,N-
acetal cleavage. To this end, heterocycle 3b was prepared
according to the procedure defined for 3a . The allyloxy-
carbonyl (Alloc) group was chosen for protection of the
amine nitrogen because of its easy removal under stan-
dard palladium chemistry conditions.27 Treatment of 3b
with DBU/MeI in CH3CN afforded methyl ester 5b
without difficulty. For the preparation of 7b, LDA proved
inffective. Optimum alkylation conditions involved an in
situ quench with MeI of the enolate formed from treat-
ment of 5b with KOBut/THF at -78 °C.28 Again, the
desired material was obtained in analytically pure form
following a single recrystallization. Treament of 7b with
catalytic dichloro-bis-triphenylphosphine palladium (0.02
mol %) and Bu3SnH, followed by acid hydrolysis of the
intermediate tin carbamate, resulted in an 84% yield of
11 as the corresponding hydrochloride salt.
Free amine 11 was an ideal building block for further
elaboration of R-methylasparagine peptides. Of the many
methods available for peptide coupling, a subset of special
conditions have been developed for use with hindered
amino acids, including N- and R-alkylated amino acids.29
Silylation of the free amine terminus, as an activation
method to facilitate/accelerate the coupling process, has
been reported many times for both solution30 and solid
phase31 peptide synthesis. In the event, H-MeAsn-OMe‚
Exp er im en ta l Section
MeO2C-(cyclo-p-ClC6H4CH)-Asn -H (3a ). In an Erlenm-
eyer flask equipped with a magnetic stir bar, KOH (3.30 g, 50
mmol, 1 equiv, 85% assay) was dissolved in water (75 mL).
L-Asparagine monohydrate (7.51 g, 50 mmol, 1 equiv) was
added with vigorous stirring, followed by a solution of 4-chlo-
robenzaldehyde (8.64 g, 60 mmol, 1.2 equiv) in DME (45 mL).
At the end of 2 days, the solution was placed in an ice bath,
and NaHCO3 (4.2 g, 50 mmol, 1 equiv) was added, followed
by methyl chloroformate (4.0 mL, 50 mmol, 1 equiv). After 1
h of vigorous stirring at ice temperature, additional sodium
bicarbonate (2.1 g, 25 mmol, 0.5 equiv) and methyl chlorofor-
mate (2.0 mL, 25 mmol, 0.5 equiv) was added. The ice bath
was removed, and the solution was allowed to warm to room
temperature for 2 h. Sodium bicarbonate was added until the
solution reached pH 8. Excess 4-chlorobenzaldehyde was
extracted with 3 × 20 mL of CH2Cl2. The aqueous layer was
cooled to 0 °C and acidified slowly with 10% HCl to pH 2. The
resulting two-phase system was extracted with 80% CHCl3/
MeOH, and the combined organic layers were dried with
anhydrous Na2SO4 and concentrated. The resulting solid (40%
yield) could be used in the next step without further purifica-
tion. An analytical sample was obtained by column chroma-
tography with silica gel (100:1:1 CHCl3, MeOH, AcOH): mp
1
183-84 °C (dec); [R]D ) -19.5 (c 3.3, MeOH); H NMR (D2O,
K2CO3) δ 2.59-2.75 (m, 2 H), 3.87 (s, 3 H), 4.54-4.57 (m, 1
H), 6.58 (s, 1 H), 7.47 (d, J ) 8.5 Hz, 2 H), 7.65 (d, J ) 9 Hz,
2 H); 13C NMR (D2O, K2CO3) δ 34.2, 54.7, 56.3, 57.0, 66.0,
129.1, 129.5, 134.6, 138.7, 158.4, 166.1, 174.7, 177.7; IR (thin
film): 3398, 2916, 1868, 1690, 1449, 1091 cm-1. Anal. Calcd
for C13H13ClN2O5: C, 49.93; H, 4.19. Found: C, 49.76; H, 4.26.
Alloc-(cyclo-p-ClC6H4CH)-Asn -H (3b). Following the pro-
cedure given above, the title compound was obtained in 40%
yield through the use of allyl chloroformate. The solid was
employed in the next step without purification: 1H NMR (CD3-
(25) While this work was in progress, J uaristi et al. published a
similar approach to R-substituted aspartic acids. See J uaristi, E.;
Lopez-Ruiz, H.; Madrigal, D.; Ram´ırez-Quiro´s, Y.; Escalante, J . J . Org.
Chem. 1998, 63, 3, 4706-10.
(26) Radkiewicz, J . L.; Zipse, H.; Clarke, S.; Houk, K. N. J . Am.
Chem. Soc. 1996, 118, 9148-55, and references therein.
(27) Guibe´, F.; Dangles, O.; Balavoine, G. Tetrahedron Lett. 1986,
27, 2365-8. (b) Dangles, O.; Guibe´, F.; Balavoine, G.; Lavielle, S.;
Marquet, A. J . Org. Chem. 1987, 52, 4984-93. (c) Beugelmans, R.;
Neuville, L.; Bois-Choussy, M.; Chastanet, J .; Zhu, J . Tetrahedron Lett.
1995, 36, 3129-32.
(30) Wenschuh, H.; Beyermann, M.; Winter, R.; Bienert, M.; Ionescu,
D.; Carpino, L. A. Tetrahedron Lett. 1996, 37, 5483-6.
(31) Bambino, F.; Brownlee, R. T. C.; Chiu, F. C. K. Tetrahedron
Lett. 1994, 35, 4615-8. (b) Brunissen, A.; Ayoub, M.; Lavielle, S.
Tetrahedron Lett. 1996, 37, 6713-6.
(28) O′Donnell, M. J .; Fang, Z.; Ma, X.; Huffman, J . C. Heterocycles
1997, 46, 617-630.
(29) Spencer, J . R.; Antonenko, V. V.; Delaet, N. G. J .; Goodman,
M. Int. J . Pept. Protein Res. 1992, 40, 282-93, and references therein.

7888 J . Org. Chem., Vol. 64, No. 21, 1999
Hopkins et al.
OD) δ 2.38 (br dd, 2H), 2.64 (dd, J ) 5 Hz, J ) 15 Hz, 2H),
4.58 (br m, 1H), 4.66 (d, J ) 5 Hz), 5.18 (apparent dq, J ) 1.4,
J ) 10.5), 5.36 (br m, 1H), 5.94 (m, 1H), 6.48 (s, 1H), 7.35 (d,
J ) 9.5 Hz, 2H), 7.62 (d, J ) 9.5 Hz, 2H); 13C NMR (CD3OD)
δ 33.9, 55.0, 66.5, 68.3, 118.5, 129.4, 129.6, 133.5, 135.4, 139.8,
and quenched by addition of saturated NH4Cl. The organic
layer was washed with brine, dried, and evaporated. The
resulting oil was passed through a plug of silica gel with
EtOAc/hexanes (1:1) and the product evaporated to a light
yellow foam, affording 3.33 g (80.4%, 9.0 mmol). This material
is pure enough to be used in the next step or may be
recrystallized in good yield from EtOAc/hexanes (1:2): mp
156.8, 172.0, 173.2; IR (thin film) 3302, 2360, 1713 cm-1
;
HRMS calcd for [M + 1]+ C15H15ClN2O5: 339.07480; found
339.07478.
1
151-152 °C; [R]D ) -39.1 (c 2.03, CHCl3); H NMR δ 1.72 (s,
MeO2C-(cyclo-p-ClC6H4CH)-Asn -OMe (5a ). To a suspen-
sion of 3a (3.11 g, 10 mmol, 1 equiv) and oven-dried K2CO3
(1.66 g, 12 mmol, 1.2 equiv) in DMF (50 mL) was added CH3I
(3 mL, 50 mmol, 5 equiv) in DMF (50 mL) at room tempera-
ture. The mixture was allowed to react for 24 h, water was
added, and 5a was extracted with CH2Cl2. The organic phase
was washed with water, dried with Na2SO4, evaporated to a
small volume, and passed through a small amount of silica
gel to remove residual DMF and provide the title compound
3H), 2.29 (d, J ) 15 Hz, 1H), 2.58 (d, J ) 15 Hz, 1H), 3.72 (s,
3H) 4.64 (m, 3H), 5.25 (m, 2H), 5.85 (m, 1H), 6.48 (br s, 1H),
7.31 (d, J ) 8.5, 2H), 7.47 (d, J ) 7 Hz, 2H); 13C NMR δ 42.0,
53.1, 65.4, 67.2, 118.8, 127.6, 128.8, 131.7, 134.4, 138.6, 160.6,
170.7, 172.5; IR (film) 3284, 2951, 2361, 1745, 1697, 1491, 1092
cm-1. Anal. Calcd for C17H19ClN2O5: C, 55.67; H, 5.22.
Found: C, 55.80; H, 5.24.
MeO2C-MeAsn -OMe (9). To a sample of 7a (777 mg, 2.28
mmol) was added 0.25 M HCl (52 mL) in which the substrate
was insoluble. The suspension was refluxed for 1 h (110 °C
sand bath), during which time the solution became homoge-
neous and a white solid deposited on the glassware above the
liquid. The solution was cooled to room temperature and
concentrated under reduced pressure. Acetonitrile was added
to the product and removed under reduced pressure to aid in
water removal. The resulting crude material was purified on
silica gel with 5% MeOH/CHCl3 to afford the desired product
(304 mg, 68%) as an oil: [R]D ) 14.5 (c 2.80, CHCl3); 1H NMR
δ 1.61 (s, 3H), 2.88 (d, J ) 15 Hz, 1H), 3.15 (d, J ) 15 Hz,
1H), 3.64 (s, 3H), 3.80 (s, 3H), 5.91 (br s, 1H), 5.99 (br s, 1H),
6.12 (s, 1H); 13C NMR δ 23.6, 42.0, 51.5, 52.6, 57.8, 155.5,
171.5, 173.7; IR (thin film) 3350, 2955, 2361, 1713, 1672, 1618,
cm-1; HRMS calcd for [M + 1]+ C8H15N2O5: 219.09810; found
219.09810.
H-MeAsn -OMe‚HCl (11). To a solution of 7b (580 mg, 1.58
mmol) in dry CH2Cl2 (5 mL) was added PdCl2(PPh3)2 (22.4 mg,
0.032 mmol) and Bu3SnH (638 uL, 2.37 mmol). The reaction
was allowed to stir overnight. The resulting solution was
passed through Celite and concentrated in vacuo to afford an
oil. The oil was dissolved in THF (3 mL) and treated with 0.5
M aqueous HCl (3.7 mL) for 1 h with vigorous stirring. The
aqueous layer was extracted with hexanes and evaporated
under reduced pressure to yield a white foam (213 mg, 84%).
This material was sufficiently pure to use directly in peptide
coupling procedures. Analytically pure material was obtained
from recrystallization from 2-propanol/CH3CN: mp 84-87 °C;
[R]D ) 44.6 (c 2.03, CH3OH); 1H NMR (CD3OD) δ 1.78 (s, 3H),
3.057 (d, J ) 18 Hz, 1H), 3.35 (d, J ) 18 Hz, 1H), 4.01 (s, 3H);
13C NMR (CD3OD) δ 23.1, 41.3, 55.3, 58.9, 174.5, 175.6; IR
(film) 3176, 2359, 1748, 1670, 1230 cm-1; HRMS calcd for [M
+ 1]+ C6H12N2O3: 161.09234; found 161.09262.
F m oc-Ala -MeAsn -OMe (12a ). Method 1. Compound 11
(86.4 mg, 0.441 mmol) was suspended in CH2Cl2 (2 mL). The
suspended solid dissolved shortly after the addition of (C3H7)2-
NEt (77 µL, 0.441 mmol) and BSA (215 uL, 0.882 mmol). The
solution was stirred for 2 h, followed by addition of Fmoc-Ala-F
(124 mg, 0.397 mmol) dissolved in CH2Cl2 (1 mL). The mixture
was stirred for 2 h. TLC (3:1 CH2Cl2/EtOAc) indicated disap-
pearance of the acyl fluoride. Additional CH2Cl2 was added,
and the organic phase was washed sequentially with 10% HCl,
saturated NaHCO3, and brine and dried (MgSO4). The result-
ing residue was purified by column chromatography on silica
gel with EtOAc/hexanes to afford 86.8 mg (43%) of dipeptide
as an oil.
1
in 60% yield: mp 131-33 °C; [R]D ) -17.9 (c 4, CHCl3); H
NMR δ 2.35-2.67 (m, 2H), 3.57 (s, 3H), 3.82 (s, 3H), 4.48 (br
s, 1H), 6.52-6.66 (br s, 1H), 7.33 (d, J ) 10 Hz, 2H), 7.47 (d,
J ) 10 Hz, 2H), 8.15-8.46 (s, 1H); 13C NMR δ 41.7, 52.9, 53.3,
61.4, 65.1, 76.5, 127.4, 128.5, 134.0, 138.4, 170.7, 172.3; IR
(thin film) 3260, 2954, 2847, 1746-1693, 1746-1693, 770 cm-1
.
Anal. Calcd for C14H15ClN2O5: C, 51.46; H, 4.63. Found: C,
51.62; H, 4.77.
Alloc-(cyclo-p-ClC6H4CH)-Asn -OMe (5b). To a solution
of 3b (5 g, 14.7 mmol) in CH3CN (50 mL) were added DBU
(2.23 g, 14.7 mmol) and MeI (10.4 g, 73.5 mmol). The resulting
mixture was allowed to stir for 1-2 days. The solution was
diluted with ethyl acetate, washed with 0.1 M KHSO4 and
water, dried, and evaporated under reduced pressure. The
crude material was purified on silica gel (2:1 EtOAc/hexanes)
to yield a clear oil. Yield 69% (3.56 g); [R]D ) -20.4 (c 2.91,
CHCl3); 1H NMR δ 2.55 (m, 1H) 2.67 (dd, J ) 5.5, 16 Hz, 1H),
3.57 (s, 3H), 4.68 (m, 3H), 5.27 (d, J ) 10 Hz, 1H), 5.33 (d, J
) 17.5 Hz, 1H), 5.91 (m, 1H), 6.66 (br d, 1H), 7.55 (d, J ) 8.5
Hz, 2H), 7.48 (d, J ) 8.5 Hz, 2H); 13C NMR δ 32.6, 52.1, 53.3,
65.1, 67.2, 118.2, 127.8, 128.6, 131.8, 134.4, 137.7, 154.7, 169.4,
170.2; IR (film) 3281, 2953, 2360, 1752, 1692 cm-1; HRMS calcd
for [M + 1]+ C16H17ClN2O5: 353.09040; found 353.09043.
MeO2C-(cyclo-p-ClC6H4CH)-MeAsn -OMe (7a ). A dry, 50
mL, two-necked, round-bottom flask equipped with a magnetic
stir bar was charged with LiCl (0.400 g, 9.4 mmol, 3 equiv),
diisopropylamine (0.93 mL, 7 mmol, 2.3 equiv), DMPU (2 mL,
16 mmol, 5 equiv), and anhydrous THF (15 mL). The resulting
suspension was cooled to -72 °C, and n-butyllithium (1.96 M,
3.60 mL, 7 mmol, 2.3 equiv) was added slowly via syringe.
After stirring at -72 °C for 30 min, a solution of compound
5a (1.0 g, 3 mmol, 1 equiv) was added dropwise via syringe.
The resulting green solution was stirred at -72 °C for 2 h
before the addition of CH3I (2.0 mL, 30 mmol, 10 equiv).
Following stirring at -72 °C for 3 h, the cold bath was
removed, and the reaction mixture was stirred for 5 min at
room temperature. The mixture was quenched with 10 mL of
an aqueous solution of saturated NH4Cl, followed by 30 mL of
water. The solution was extracted with EtOAc, and the
combined organic layers were washed with water, dried, and
concentrated. Purification through a silica gel plug with ethyl
acetate followed by recrystallization from 7:3 ethyl acetate/
hexanes afforded the desired compound in analytically pure
form. Additional material was obtained by chromatography
(3:2 EtOAc/hexanes) of the mother liquors to give a total yield
of desired product of 54%: mp 193-94 °C; [R]D ) -47 (c 1.2,
EtOAc); 1H NMR δ 1.70 (s, 3H), 2.72 (d, J ) 16 Hz, 1H), 2.55
(d, J ) 16 Hz, 1H), 3.74 (s, 3H), 6.40-6.50 (br s, 1H), 7.30 (d,
J ) 8 Hz, 2H), 7.46 (d, J ) 8 Hz, 2H), 8.75-8.79 (br s, 1H);
13C NMR δ 42.0, 48.0, 53.1, 53.5, 61.8, 65.4, 77.0, 127.6, 128.0,
134.3, 138.7, 170.8, 172.6; IR (thin film) 3283, 2953, 1744,
1695, 1443, 600 cm-1. Anal. Calcd for C15H17ClN2O5: C, 52.87;
H, 5.03. Found: C, 53.02; H, 4.98.
Method 2. To a solution of Fmoc-Ala-OH (508 mg, 1.63
mmol) and (C3H7)2NEt (852 µL, 4.89 mmol) in CH2Cl2 (8 mL)
was added TFFH33 (0.645 mg, 2.44 mmol). The resulting
mixture was stirred for 2 h and used directly. In a separate
flask, compound 11 (267 mg, 1.36 mmol) was dissolved in CH2-
Cl2 (2 mL) and (C3H7)2NEt (237 µL, 1.36 mmol). Molecular
sieves (3 Å) were added, and the mixture was stirred for 15
min. The solution of 11 was added to the solution of Fmoc-
Alloc-(cyclo-p-ClC6H4CH)-MeAsn -OMe (7b). To a solu-
tion of 5b (4 g, 11 mmol) in dry THF (110 mL) was added MeI
(6.8 mL, 110 mmol). The solution was cooled to -78 °C. A 1 M
solution of KOBut (110 mmol) in THF was added via addition
funnel over 2 h. The reaction mixture was diluted with EtOAc
(32) Carpino, L. A.; Mansour, E. M. E., Sadat-Aalaee, D. J . Org.
Chem. 1991, 56, 2611-4.
(33) Carpino, L. A.; El-Faham, A. J . Am. Chem. Soc. 1995, 117,
5401-2.

Tetrahydropyrimidinones in Asymmetric Synthesis
J . Org. Chem., Vol. 64, No. 21, 1999 7889
Ala-F, and the coupling was monitored by TLC (3:1 EtOAc/
CH2Cl2; product Rf ∼ 0.2) and judged to be complete after 2.5
h. The reaction mixture was washed with 10% HCl, NaHCO3,
and brine, dried (MgSO4), and evaporated to an oil. The crude
material was purified on silica gel with EtOAc/CH2Cl2 to yield
405 mg (0.89 mmol) of a white foam, 65.7%: [R]D ) 4.60 (c
Ack n ow led gm en t. We are pleased to thank the
University of California Biotechnology Research and
Education Program for support in the form of a fellow-
ship to T.A.R. Partial support of this work by the
American Chemical Society, Petroleum Research Fund
(32051-AC1), is also gratefully acknowledged. Purchase
of the 500 MHz NMR used in these studies was
supported by funds from the Elsa U. Pardee Foundation
and the National Science Foundation (BIR-94-19409).
In addition, we thank our collaborators in the group of
Professor G. Cardillo (Bologna) for many stimulating
discussions and NATO (Collaborative Research Grant
CRG 950049) for funding of that collaboration.
1
1.65, CHCl3); H NMR δ 1.37 (d, J ) 7 Hz, 3H), 1.63 (s, 3H),
2.92 (d, J ) 15 Hz, 1H), 3.20 (d, J ) 15 Hz, 1H), 3.76 (s, 3H),
4.19 (t, J ) 10 Hz, 1H), 4.32 (m, 1H), 4.36 (d, J ) 7.5 Hz, 2H),
5.9 (br d, J ) 7.5 Hz, 1H), 6.07 (br s, 1H), 6.22 (s, 1H), 7.28
(dt, J ) 7, 1.5 Hz, 2H), 7.37 (t, J ) 10 Hz, 2H), 7.58 (br m,
2H), 7.74, (d, J ) 8 Hz, 2H), 7.78 (s, 1H); 13C NMR δ 18.6,
23.1, 41.6, 47.3, 51.1, 52.7, 58.1, 67.1, 119.8, 125.0, 127.0, 127.6,
141.3, 143.9, 155.8, 172.0, 172.3, 173.7; IR (thin film) 3313,
1670 cm-1; HRMS calcd for [M + 1]+ C24H28N3O6: 454.1978;
found 454.1976.
Cbz-Gly-MeAsn -OMe (12b). Following the procedure for
method 1 given above, the title compound was obtained in 40%
yield: [R]D ) 9.70 (c 1.73, CHCl3); 1H NMR δ 1.60 (s, 3H), 2.92
(d, J ) 10 Hz, 1H), 3.18 (d, J ) 10 Hz, 1H ) 3.74 (s, 3H), 3.81
(m, 1H), 5.09 (s, 2H), 5.92 (br s, 1H), 6.05 (br s, 1H), 6.17 (br
s, 1H), 7.30 (m, 5H), 7.64 (br s, 1H); 13C NMR δ 23.3, 41.6,
44.9, 52.7, 58.3, 67.0, 127.9, 128.0, 128.4, 136.5, 156.5, 168.9,
171.9, 173.7; IR (thin film) 3326, 1735, 1664 cm-1; HRMS calcd
for [M + 1]+ C16H21N3O6: 352.1509; found 352.1510.
Su p p or tin g In for m a tion Ava ila ble: General experimen-
tal and synthetic procedures for R-methylaspartic acid and
compounds not specifically numbered in the text, as well as
1H and 13C NMR spectra for key compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
J O9909296