α-Alkylation of (S)-Asparagine with Self-Regeneration of the Stereogenic Center: Enantioselective Synthesis of α-Substituted Aspartic Acids

Article abstract of DOI:10.1021/jo980367a

A convenient method for the α-alkylation of (S)-asparagine with "self-regeneration of the stereogenic center" is described. The synthetic protocol involves stereoselective conversion of (S)-asparagine into enantiopure imino ether (2S,6S)-9, which is then

Full text of DOI:10.1021/jo980367a

4706
J . Org. Chem. 1998, 63, 4706-4710
r-Alk yla tion of (S)-Asp a r a gin e w ith Self-Regen er a tion of th e
Ster eogen ic Cen ter : En a n tioselective Syn th esis of r-Su bstitu ted
Asp a r tic Acid s1,2
Eusebio J uaristi,* Heraclio Lo´pez-Ruiz, Domingo Madrigal, Yara Ram´ırez-Quiro´s, and
J aime Escalante
Departamento de Quı´mica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico
Nacional, Apartado Postal 14-740, 07000 Me´xico, D.F., Me´xico
Received February 26, 1998
A convenient method for the R-alkylation of (S)-asparagine with “self-regeneration of the stereogenic
center” is described. The synthetic protocol involves stereoselective conversion of (S)-asparagine
into enantiopure imino ether (2S,6S)-9, which is then alkylated with complete diastereoselectivity
to give trans products 10-13 in good yields. Hydrolysis of these alkylated heterocycles is
accomplished under mild acidic conditions to give the desired, enantiopure R-alkyl aspartic acids
in excellent yields.
In tr od u ction
Recently, (S)-asparagine was condensed with pivalal-
dehyde to afford pyrimidinone 5,13 which was then
protected, decarboxylated, and hydrogenated to give (S)-
6, a chiral derivative of â-amino propionic acid and a
useful synthon for the enantioselective synthesis of
R-alkylated â-amino acids14 (Scheme 2). The present
paper describes a convenient application of suitable
derivatives of heterocycle 5 in the preparation of enan-
tiopure R-alkylated aspartic acids.
In recent years, the preparation of enantiopure R,R-
dialkylated R-amino acids has attracted considerable
attention in view of the interesting chemical and biologi-
cal properties exhibited by these compounds. For ex-
ample, R,R-dialkylated derivatives of proteinogenic amino
acids are efficient inhibitors of those enzymes that
metabolize the natural substrates.3 Furthermore, incor-
poration of R,R-dialkylated R-amino acids into peptides
leads to modified backbone conformations,4 with in-
creased lipophilicity5 and increased resistance to both
enzymatic and chemical hydrolysis.6
Resu lts a n d Discu ssion
Condensation of (S)-asparagine with isobutyralde-
hyde15 according to the literature procedure1,13,14 was
followed by in situ benzoylation with benzoyl chloride to
afford crystalline 7, in 50% yield for the two steps. The
relative configuration in this heterocycle was assigned
from the X-ray crystallographic analysis of the methyl
ester derivative, 8, obtained by reaction with 1 equiv of
silver oxide and methyl iodide. The resulting structure
presented a cis disposition of the isopropyl and carboxy-
late groups (Figure 1).16 Thus, the absolute configuration
is securely determined as (2S,6S)-7 [and (2S,6S)-8]
(Scheme 3).
Because of their relevant role in physiological events,
aspartic acid derivatives are especially interesting sub-
jects for study. Indeed, several methods have been
reported that describe the enantioselective synthesis of
R-alkylated aspartic acids. Fadel and Salau¨n7,8 achieved
this goal via the alkylation of oxazolidinones, 1, with
ethyl bromoacetate. Aebi and Seebach9 alkylated instead
imidazolidinones, 2, whereas Crich and co-workers10
employed (S)-tryptophan derivatives, 3. Finally, Georg
and co-workers11 demonstrated that the Schmidt rear-
rangement of R,R-bis-alkylated â-keto esters, 4, provides
an alternative method (Scheme 1).12
* Corresponding author. Tel: (525) 747-7000. Fax: (525)747-7113.
E-mail juaristi@relaq.mx.
(1) Enantioselective synthesis of â-amino acids. 8. For part 7 see:
J uaristi, E.; Quintana, D.; Balderas, M.; Garc´ıa-Pe´rez, E. Tetrahe-
dron: Asymmetry 1996, 7, 2233-2246.
(2) Presented in part during the Fifth Chemical Congress of North
America, Cancu´n, Me´xico, November 13, 1997. Special Topics in
Organic Chemistry. In Book of Abstracts, Paper No. 1476.
(3) See, for example: J ung, M. J . In Chemistry and Biochemistry of
the Amino Acids; Barrett, G. C., Ed.; Chapman and Hall: New York,
1985; p 227.
(11) Georg, G. I.; Guan, X.; Kant, J . Tetrahedron Lett. 1988, 29, 403-
406.
(12) More recently, Obrecht and co-workers described the avail-
ability of (R)- and (S)-R-alkyl aspartic acids using L-phenylalanine as
resolving agent: Obrecht, D.; Bohdal, U.; Daly, J .; Lehmann, C.;
Scho¨nholzer, P.; Mu¨ller, K. Tetrahedron 1995, 51, 10883-10900.
(13) (a) Chu, K. S.; Negrete, G. R.; Konopelski, J . P. J . Org. Chem.
1991, 56, 5196-5202. (b) See, also: Konopelski, J . P. In Enantiose-
lective Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New
York, 1997; Chapter 12, pp 249-259.
(4) Paul, P. K. C.; Sukumar, M.; Bardi, R.; Piazzesi, A. M.; Valle,
G.; Toniolo, C.; Balaram, P. J . Am. Chem. Soc. 1986, 108, 6363-6370.
(5) See, for example: Christensen, H. N.; Handlogten, M. E.;
Vadgama, J . V.; de la Cuesta, E.; Ballesteros, P.; Trigo, G. C.;
Avendan˜o, C. J . Med. Chem. 1983, 26, 1374-1378.
(6) See, for example: Turk, J .; Panse, G. T.; Marshall, G. R. J . Org.
Chem. 1975, 40, 953-955.
(14) (a) J uaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992,
3, 723-726. (b) See, also: J uaristi, E.; Seebach, D. In Enantioselective
Synthesis of â-Amino Acids; J uaristi, E., Ed.; Wiley-VCH: New York,
1997; Chapter 13, pp 261-277.
(15) Owing to the high price of pivalaldehyde, we have substituted
this aldehyde with isobutyraldehyde in the synthesis of some chiral
analogues of pyrimidinone 6: Madrigal, D. Ph.D. Thesis,
CINVESTAV-IPN: Me´xico, 1996.
(16) The authors have deposited atomic coordinates for structures
cis-8 and (2S,6S)-13 with the Cambridge Crystallographic Data Centre.
The coordinates can be obtained, on request from the Director,
Cambridge Crystallographic Data Centre, 12 Union Road, CB2 IEZ,
U.K.
(7) Fadel, A.; Salau¨n, J . Tetrahedron Lett. 1987, 28, 2243-2246.
(8) See, also: Altmann, E.; Nebel, K.; Mutter, M. Helv. Chim. Acta
1991, 74, 800-806.
(9) Aebi, J . D.; Seebach, D. Helv. Chim. Acta 1985, 68, 1507-1518.
(10) Chan, C.-O.; Crich, D.; Natarajan, S. Tetrahedron Lett. 1992,
33, 3405-3408.
S0022-3263(98)00367-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 06/23/1998

Enantioselective Synthesis of R-Substituted Aspartic Acids
Sch em e 1a
J . Org. Chem., Vol. 63, No. 14, 1998 4707
a
Stereochemistry not indicated.
Sch em e 2
F igu r e 1. Structure and solid-state conformation of cis-1-
benzoyl-2-isopropyl-6(S)-methyl carboxylate-tetrahydropyrim-
idin-4-one (cis-8).16
Sch em e 3
To obtain imino ether 9 as the main product, carboxylic
acid 7 was treated with 2 equiv of silver oxide and 3 equiv
of methyl iodide. As expected, the desired O-methylated
ester 9 was obtained in 74% yield.
Fully characterized, enantiopure imino ether (2S,6S)-9
was then examined as a potentially general, convenient
substrate for the enantioselective synthesis of R-substi-
tuted aspartic acids. To this end, enolate (2S,6S)-9-Li
was generated upon treatment of the heterocycle with
lithium diisopropylamide (LDA), in THF solvent and
under nitrogen atmosphere. The electrophile (methyl
iodide, ethyl iodide, n-buthyl iodide, or benzyl bromide)
was then added at -78 °C to afford the trans-alkylated
products, apparently with complete diastereoselectivity.18
As shown in Scheme 3, in addition to the expected
methyl carboxylate derivative 8, imino ether (2S,6S)-9
was produced in low yield (ca. 14.6%). It was realized
that imino ether 9 could be a useful precursor of R-alky-
lated aspartic acids via alkylation at C(6), the most acidic
position in the heterocycle, followed by hydrolysis (Scheme
4). In this regard, hydrolysis and isolation of the desired
amino acids would be facilitated by the presence of the
labile imino group.17
(17) (a) Compare mild conditions employed to hydrolyze bis-
lactimethers: Scho¨llkopf, U.; Tiller, T.; Bardenhagen, J . Tetrahedron
1988, 44, 5293-5305. (b) Compare mild conditions used to hydrolyze
dihydroimidazoles: Hoffmann, M.; Seebach, D. Chimia 1997, 51, 90-
91. Blank, S.; Seebach, D. Angew. Chem., Int. Ed. Engl. 1993, 32,
1765-1766. (c) For related papers, see: Seebach, D.; Hoffmann, M.;
Sting, A. R.; Kinkel, J . N.; Schulte, M.; Ku¨sters, E. J . Chromatogr. A
1998, 796, 299-307. Hoffmann, M.; Blank, S.; Seebach, D.; Ku¨sters,
E.; Schmid, E. Chirality 1998, 10, 217-222.

4708 J . Org. Chem., Vol. 63, No. 14, 1998
J uaristi et al.
Sch em e 4
Ta ble 1. Dia ster eoselectivity of En ola te (2S,6S)-9-Li
Alk yla tion s
F igu r e 2. Structure and solid-state conformation of 1-benzoyl-
2(S)-isopropyl-4-methoxy-6(S)-benzyl-6(S)-carbomethoxy-
(1,2),(5,6)-tetrahypyrimidin-4-one [(2S,6S)-13].16
ds
(%)
mp
(°C)
isolated
product
RX
CH3I
CH3CH2I
n-C4H9I
[R]2D8°C yield (%)
Ta ble 2. Hyd r olysis of P r od u cts 10-13 to Give r-Alk yl
Asp a r tic Acid s 14-17
(2S,6S)-10
(2S,6S)-11
(2S,6S)-12
(2S,6S)-13
>97
>97
>97
>97
a
-47.0
-67.0
-20.0
+90.0
52.4
61.8
59.7
64.2
158-159
a
122-124
PhCH2Br
a
Oil.
The trans configuration of the alkylated products [(2S,6S)-
10-13; Scheme 4] was assigned by chemical correlation
to known R-methyl and R-benzyl aspartic acids (see
Experimental Section). Furthermore, an X-ray crystal-
lographic structure of (2S,6S)-13 (R ) PhCH2; Figure 2)16
confirms the trans relative configuration between the
benzyl and isopropyl groups. Table 1 summarizes the
chemical yields and diastereoselectivities observed in the
alkylation reaction, as well as some physical properties
of the isolated products.
The high stereoselectivity encountered in the addition
of (2S,6S)-9-Li to electrophiles is probably due to the
steric hindrance generated by the isopropyl group at C(2),
which directs addition on the opposite enolate face.19
Indeed, A1,3 strain in (2S,6S)-9-Li is responsible for the
axial orientation of the isopropyl group, which effectively
hinders syn addition.20
yield of free
amino acid (%)
mp
of 14-17
[R]2D8°C
R
of 14-17
CH3
83.8
80.0
88.3
95.4
175-176
165-167
180-182
240-242
+43.0
+35.1
+26.7
+50.0
CH3CH2
n-C4H9
PhCH2
heating with 17% HCl in a sealed tube at 95 °C. The
free amino acids 14-17 were purified by chromatography
on an ion-exchange column (Table 2).
In summary, (S)-asparagine, an inexpensive chiral
amino acid, was converted into the enantiopure pyrimi-
dinone imino ether (2S,6S)-9, which was then alkylated
with very high diastereoselectivity to give the products
of trans addition of various electrophiles. Hydrolysis of
the alkylated derivatives 10-13 was accomplished under
mild acidic conditions to afford enantiopure R-alkyl
aspartic acids 14-17.
The final step of the overall conversion of (S)-aspar-
agine to enantiopure (S)-R-alkyl aspartic acids (with self-
regeneration of the stereogenic center21), the hydrolysis
of the alkylated heterocycles 10-13, was achieved by
The present synthetic protocol constitutes a useful
application of the so-called “self-regeneration of stereo-
genic centers” concept.
(18) A single product was detected by both 1H and 13C NMR
spectroscopy (400 and 100 MHz, respectively).
(19) Compare (a) J uaristi, E.; Escalante, J .; Lamatsch, B.; Seebach,
D. J . Org. Chem. 1992, 57, 2396-2398. (b) J uaristi, E.; Escalante, J .
J . Org. Chem. 1993, 58, 2282-2285. (c) Escalante, J .; J uaristi, E.
Tetrahedron Lett. 1995, 36, 4397-4400.
(20) Compare (a) J uaristi, E.; Quintana, D.; Lamatsch, B.; Seebach,
D. J . Org. Chem. 1991, 56, 2553-2557. (b) 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, 913-934.
Exp er im en ta l Section
Gen er a l. Flasks, stirring bars, and hypodermic needles
used for the generation and reactions of organolithiums were
dried for about 12 h at 120 °C. Anhydrous THF was obtained
by distillation from benzophenone ketyl.22 The n-butyllithium
(21) Seebach, D.; Sting, A. R.; Hoffmann, M. Angew. Chem., Int. Ed.
Engl. 1996, 35, 2708-2748.
(22) Brown, H. C.; Kramer, G. W.; Levy, A. B.; Midland, M. M.
Organic Synthesis via Boranes; Wiley: New York, 1975; p 256.

Enantioselective Synthesis of R-Substituted Aspartic Acids
J . Org. Chem., Vol. 63, No. 14, 1998 4709
employed was titrated according to the method of J uaristi et
al.23 (4-biphenylmethanol indicator).
The resulting mixture was stirred at ambient temperature for
30 min, 3.2 mL (51.6 mmol, 3 equiv) of methyl iodide was
added, and stirring was continued for 72 h. The reaction
mixture was filtered over Celite (eluting with CH2Cl2) and
concentrated at reduced pressure, and the product was purified
by flash chromatography (hexanes-ethyl acetate, 9:1) to give
4.1 g (74.2% yield) of imino ether (2S,6S)-9 as a viscous oil.
[R]D28°C ) -71.8 (c ) 1.0, CHCl3). 1H NMR (DMSO-d6, 100 °C,
400 MHz) δ 0.95 (d, J ) 6.4 Hz, 3 H, CH3CHCH3), 0.97 (d, J
) 7.7 Hz, 3 H, CH3CHCH3), 1.56 (m, 1 H, CH3CHCH3), 2.54
(ddd, J 1 ) 17.2 Hz, J 2 ) 8.1 Hz, J 3 ) 1.4 Hz, 1 H, CHH′), 2.64
(dd, J 1 ) 17.2 Hz, J 2 ) 3.3 Hz, 1 H, CHH′), 3.64 (s, 3 H, OCH3),
3.69 (s, 3 H, OCH3), 4.97 (ddd, J 1 ) 7.5 Hz, J 2 ) 2.2 Hz, 1 H,
NCHCO2), 5.39 (d, J ) 9.2 Hz, 1 H, NCHN), 7.44 (s, 5 H, C6H5).
13C NMR (DMSO-d6, 100 °C, 67.8 MHz) δ 19.8, 20.0, 26.5, 34.8,
51.5, 52.3, 52.6, 73.3, 126.9, 128.9, 129.9, 136.8, 159.2, 171.2,
171.4.
Gen er a l P r oced u r e for th e Rea ction of P yr im id in e
En ola te [(2S,6S)-9-Li] w ith Electr op h iles. A solution of
(i-Pr)2NH (1.0 equiv) in THF was cooled to -20 °C before the
slow addition of 1.0 equiv of n-BuLi (ca. 1.8 M in hexane). The
resulting solution was stirred at -20 °C for 20 min and then
cooled to -78 °C before the dropwise addition of 1.0 equiv of
imino ether (2S,6S)-9 in THF. Stirring was continued for 1 h
at -78 °C in order to secure the complete formation of the
enolate. The alkylating agent (1.15 equiv) was then added
dropwise via syringe, and the reaction mixture was stirred at
-78 °C for 2 h and at ambient temperature overnight. At this
point the reaction was quenched by the addition of saturated
aqueous NH4Cl solution and extracted with three portions of
CH2Cl2. The combined extracts were dried over anhydrous
Na2SO4, filtered, and concentrated at reduced pressure, main-
taining the temperature below 30 °C.
1-Ben zoyl-2(S)-isopr opyl-4-m eth oxy-6(S)-car bom eth oxy-
6(S)-m eth yl-(1,2),(5,6)-tetr ah ydr o-1,3-pyr im idin e [(2S,6S)-
10]. The general procedure was followed with 1.0 g (3.14
mmol) of imino ether (2S,6S)-9 in 20 mL of THF and 0.22 mL
(3.49 mmol) of methyl iodide. The crude product was purified
by flash column chromatography (hexanes-ethyl acetate, 9:1)
to give 0.55 g (52.4% yield) of (2S,6S)-10 as a viscous oil.
[R]D28°C ) -47.0 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 270 MHz)
δ 0.82 (d, J ) 6.6 Hz, 6 H, (CH3)2CH), 1.62 (s, 3 H, CH3C(6)),
2.00 (m, 1 H, (CH3)2CH), 2.43 (d, J ) 15.2 Hz, 1 H, CHH′),
2.94 (d, J ) 15.2 Hz, 1 H, CHH′), 3.77 (s, 3 H, OCH3), 3.82 (s,
3 H, OCH3), 5.29 (d, J ) 9.2 Hz, 1 H, NCHN), 7.39 (s, 5 H,
C6H5). 13C NMR (CDCl3, 22.5 MHz) δ 19.1, 19.6, 22.6, 35.0,
35.7, 52.3, 53.0, 60.0, 77.3, 127.3, 128.1, 129.6, 136.2, 163.7,
170.4, 173.1.
1-Ben zoyl-2(S)-isopr opyl-4-m eth oxy-6(S)-car bom eth oxy-
6(S)-eth yl-(1,2),(5,6)-tetr a h yd r o-1,3-p yr im id in e [(2S,6S)-
11]. The general procedure was followed with 0.5 g (1.57
mmol) of imino ether (2S,6S)-9 in 20 mL of THF and 0.19 mL
(2.3 mmol) of ethyl iodide. The crude product was purified by
flash column chromatography (hexanes-ethyl acetate, 9:1) to
give 0.34 g (61.8% yield) of (2S,6S)-11, mp 158-159 °C.
[R]D28°C ) -67.0 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ 0.81 (d, J ) 6.8 Hz, 3 H, CH3CHCH3), 0.82 (J ) 6.8 Hz, 3 H,
TLC. F254 silica gel plates; detection by UV light or iodine
vapor. Flash column chromatography:24 silica gel (230-400
mesh). All melting points are uncorrected. 1H NMR spectra:
J EOL FX-90Q (90 MHz), J EOL GSX-270 (270 MHz), and
J EOL Eclipse-400 (400 MHz) spectrometers. 13C NMR spec-
tra: J EOL FX-90Q (22.5 MHz), J EOL GSX-270 (67.8 MHz),
and J EOL Eclipse-400 (100 MHz) spectrometers. Optical
rotations were measured in a Perkin-Elmer Model 241 pola-
rimeter, using the sodium D-line (589 nm).
Elemental analyses were performed by Galbraith Labora-
tories, Inc., TN. The purity of new compounds 9, 10, 12, 15,
and 16, for which elemental analyses are not provided, was
1
judged to be >97%, as evidenced by H and 13C NMR spectra
(see Supporting Information).
1-Ben zoyl-2(S)-isop r op yl-6(S)-ca r b oxy-1,3-p er h yd r o-
p yr im id in -4-on e [(2S,6S)-7]. In a 1.0 L round-bottom flask
was placed 15.0 g (113.5 mmol) of (S)-asparagine in 150 mL
of dry methanol. A methanolic solution of KOH [6.4 g (113.5
mmol) in 35 mL of CH3OH] was added, and the resulting
solution was stirred at ambient temperature until complete
dissolution of the amino acid (ca. 10 min). Isobutyraldehyde
(10.8 mL, 113.5 mmol) was then added slowly, and the reaction
mixture was heated to reflux for 10 h. The reaction flask was
submerged in an ice-water bath before the addition of 4.76 g
(67 mmol) of sodium bicarbonate and, dropwise, 13.2 mL (113.5
mmol) of benzoyl chloride. The reaction mixture was stirred
at ambient temperature overnight, before treatment with 6 N
HCl, until pH ) 3.0. The precipitate that formed was filtered,
and the solvent was removed at reduced pressure to give a
pale yellow oil, which was dissolved in 500 mL of CH2Cl2,
washed with H2O, dried over anhydrous Na2SO4, and concen-
trated. Crystallization from ethyl ether-hexane (95:5) gave
14.3 g (50% yield) of (2S,6S)-7, mp 175-177 °C. [R]D28°C
)
+156.0 (c ) 1.0, CH3OH). 1H NMR (DMSO-d6; 120 °C; 400
MHz) δ 0.81 (d, J ) 7.0 Hz, 3 H, CH3CHCH3), 0.90 (d, J ) 6.6
Hz, 3 H, CH3CHCH3), 2.04 (m, 1 H, CH3CHCH3), 2.71 (dd, J 1
) 8.4 Hz, J 2 ) 16.9 Hz, 2 H, CH2CO), 4.76 (t, J ) 8.4 Hz, 1 H,
NCHCO2H), 4.88 (d, J ) 9.9 Hz, 1 H, NCHN), 7.43 (m, 5 H,
C6H5CO), 8.25 (s, 1 H, NH).13C NMR (DMSO-d6, 120 °C; 100
MHz), δ 19.2, 19.6, 32.3, 34.0, 53.5, 70.7, 126.9, 128.9, 130.1,
136.1, 168.2, 171.2, 172.3. Anal. Calcd for C15H18N2O4: C,
62.05; H, 6.24. Found: C, 61.73; H, 6.46.
1-Ben zoyl-2(S)-isop r op yl-6(S)-ca r b om et h oxy-1,3-p er -
h yd r op yr im id in -4-on e [(2S,6S)-8]. In a 25 mL round-
bottom flask provided with magnetic stirrer, was placed 1.0 g
(3.4 mmol) of carboxylic acid (2S,6S)-7 and 0.82 g (3.4 mmol,
1.0 equiv) of silver oxide in 15 mL of dry THF. The resulting
mixture was stirred at ambient temperature for 30 min, 0.32
mL (5.1 mmol, 1.5 equiv) of methyl iodide was added, and
stirring was continued for 12 h. The reaction mixture was
filtered over Celite (eluting with CH2Cl2) and concentrated at
reduced pressure, and the product was purified by flash
chromatography (hexanes-ethyl acetate, 2:1) to give 0.85 g
(82.0% yield) of (2S,6S)-8, mp 158-159 °C. [R]2D8°C ) -149 (c
) 1.0, CHCl3). 1H NMR (CDCl3, 60 °C, 400 MHz) δ 0.92 (d, J
) 8.3 Hz, 3 H, CH3CHCH3), 0.99 (d, J ) 8.3 Hz, 3 H, CH3-
CH3CHCH3), 0.87 (t, J ) 7.7 Hz, 3 H, CH3CH2), 1.94 (dq, J 1
)
CHCH3), 2.0 (m, 1 H, CH3CHCH3), 2.71 (dd, J 1 ) 4.6 Hz, J 2
)
14.8 Hz, J 2 ) 7.3 Hz, CH3CHH′), 2.02 (m, 1 H, CH3CHCH3),
2.44 (d, J ) 16.0 Hz, 1 H, NdC-CHH′), 2.66 (ddq, J 1 ) 14.8
4.2 Hz, 1 H, CHH′), 2.86 (dd, J 1 ) 4.5 Hz, J 2 ) 4.2 Hz, 1 H,
CHH′), 3.7 (s, 3 H, OCH3), 4.94 (b, 1 H, NCHCO2), 5.1 (b, 1 H,
NCHN), 7.4 (s, 5 H, C6H5), 7.44 (s, 1 H, NH). 13C NMR (CDCl3,
60 °C, 100 MHz), δ 18.8, 19.0, 32.0, 34.4, 52.5, 53.1, 70.8, 126.7,
128.7, 130.1, 135.1, 168.2, 171.1, 171.2. Anal. Calcd for
Hz, J 2 ) 7.3 Hz, J 3 ) 1.3 Hz, 1 H, CH3CHH′), 2.87 (dd, J 1
)
16.0 Hz, J 2 ) 1.3 Hz, 1 H, NdC-CHH′), 3.74 (s, 3 H, OCH3),
3.79 (s, 3 H, OCH3), 5.38 (d, J ) 9.5 Hz, 1 H, NCHN), 7.40 (m,
5 H, C6H5). 13C NMR (CDCl3, 100 MHz) δ 8.4, 19.6, 20.0, 28.2,
33.8, 35.4, 52.5, 53.3, 62.8, 77.8, 128.2, 128.4, 130.0, 136.5,
163.6, 170.9, 173.9. Anal. Calcd for C19H26O4N2: C, 65.87;
H, 7.56. Found: C, 65.62; H, 7.50.
C
16H20N2O4: C, 63.13; H, 6.62. Found: C, 62.75; H, 6.70.
1-Ben zoyl-2(S)-isopr opyl-4-m eth oxy-6(S)-car bom eth oxy-
(1,2)(5,6)-tetr a h yd r o-1,3-p yr im id in e [(2S,6S)-9]. In a 100
mL round-bottom flask provided with magnetic stirrer was
placed 5.0 g (17.2 mmol) of carboxylic acid (2S,6S)-7 and 8.2 g
(35.3 mmol, 2.05 equiv) of silver oxide in 50 mL of dry THF.
1-Ben zoyl-2(S)-isopr opyl-4-m eth oxy-6(S)-car bom eth oxy-
6(S)-n -bu tyl-(1,2), (5,6)-tetr ah ydr o-1,3-pyr im idin e [(2S,6S)-
12]. The general procedure was followed with 1.0 g (3.14
mmol) of imino ether (2S,6S)-9 in 20 mL of THF and 0.42 mL
(3.70 mmol) of n-butyl iodide. The crude product was purified
by flash column chromatography (hexanes-ethyl acetate, 9:1)
to give 0.71 g (59.7% yield) of (2S,6S)-12 as a viscous oil.
(23) J uaristi, E.; Mart´ınez-Richa, A.; Garc´ıa-Rivera, A.; Cruz-
Sa´nchez, J . S. J . Org. Chem. 1983, 48, 2603-2606.
(24) Still, W. C.; Kahn, M.; Mitra, A. J . Org. Chem. 1978, 43, 2923-
2925.

4710 J . Org. Chem., Vol. 63, No. 14, 1998
J uaristi et al.
R]D28°C ) -20.0 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz) δ
0.77 (d, J ) 6.6 Hz, 6 H, (CH3)2CH), 0.84 (t, J ) 6.6 Hz, 3 H,
(CH2)3CH3), 1.22 (m, 4 H, CH2CH2CH3), 1.84 (dt, J 1 ) 11.7
Hz, J 2 ) 4.8 Hz, 1 H, CH3(CH2)2CHH′), 1.99 (m, 1 H,
(CH3)2CH), 2.42 (d, J ) 16.1 Hz, 1 H, NdC-CHH′), 2.56 (dt,
J 1 ) 13.7 Hz, J 2 ) 4.0 Hz, 1 H, CH3(CH2)2CHH′), 2.83 (d, J )
15.8 Hz, 1 H, NdC-CHH′), 3.70 (s, 3 H, OCH3), 3.76 (s, 3 H,
OCH3), 5.33 (d, J ) 9.5 Hz, 1 H, NCHN), 7.36 (m, 5 H, C6H5).
13C NMR (CDCl3, 100 MHz) δ 14.0, 19.4, 20.0, 22.9, 26.1, 34.1,
35.1, 35.5, 52.4, 53.2, 62.5, 77.8, 128.1, 128.4, 129.9, 136.6,
163.5, 170.7, 173.9.
1-Ben zoyl-2(S)-isopr opyl-4-m eth oxy-6(S)-car bom eth oxy-
6(S)-ben zyl-(1,2),(5,6)-tetr a h ydr o-1,3-p yr im idin e [(2S,6S)-
13]. The general procedure was followed with 1.07 g (3.35
mmol) of imino ether (2S,6S)-9 in 20 mL of THF and 0.43 mL
(3.66 mmol) of benzyl bromide. The crude product was purified
by flash column chromatography (hexanes-ethyl acetate, 9:1)
to give 0.95 g (69.4% yield) of (2S,6S)-13, mp 122-123 °C.
[R]D28°C ) +90.0 (c ) 1.0, CHCl3). 1H NMR (CDCl3, 400 MHz)
δ 0.66 (d, J ) 6.6 Hz, 3 H, CH3CHCH3), 0.68 (d, J ) 6.2 Hz,
3 H, CH3CHCH3), 1.87 (m, 1 H, CH3CHCH3), 2.69 (d, J ) 16.5
Hz, 1 H, NdC-CHH′), 2.84 (d, J ) 16.1 Hz, 1 H, NdC-CHH′),
3.17 (d, J ) 14.3 Hz, 1 H, PhCHH′), 3.27 (s, 3 H, OCH3), 3.84
(s, 3 H, OCH3), 4.03 (d, J ) 13.9 Hz, 1 H, PhCHH′), 5.26 (d, J
) 9.2 Hz, 1 H, NCHN), 7.25 (m, 10 H, Harom). 13C NMR (CDCl3,
100 MHz) δ 19.2, 20.1, 34.0, 35.6, 40.3, 52.5, 52.6, 63.0, 77.3,
127.0, 127.7, 128.2, 128.5, 130.0, 131.1, 135.7, 136.2, 162.3,
170.5, 173.6. Anal. Calcd for C24H28O4N2: C, 70.56; H, 6.90.
Found: C, 70.75; H, 7.02.
Gen er a l P r oced u r e for th e Hyd r olysis of th e Alk y-
la ted P yr im id in es 10-13. A suspension of approximately
1 mmol of adduct in 10 mL of 17% HCl was heated in a sealed
ampule to 95 °C (in a Thermolyne 21100 oven). The solution
was then allowed to cool to ambient temperature and was
extracted three times with CH2Cl2. The aqueous phase was
evaporated to afford the crude amino acid hydrochloride, which
was adsorbed to acidic ion-exchange resin Dowex 50W X 8.
The resin was washed with distilled H2O until the washings
came out neutral, and then the free amino acid was recovered
with 1 N aqueous NH3. Evaporation afforded the crystalline
amino acid, which was dried under vacuum at 40 °C.
r-Meth yl Asp a r tic Acid [(S)-14]. Derivative (2S,6S)-10
(500 mg, 1.5 mmol) was hydrolyzed according to the general
procedure to afford 200 mg (83.8% yield) of pure, free amino
acid (S)-14, mp 175-176 °C [(lit.12 mp 131-134 °C), (lit.9 mp
254.0-256.0 °C)]. [R]2D8°C ) +43.0 (c ) 1.0, H2O) [lit.12
[R]D28°C ) +36.0 (c ) 0.18, H2O), lit.9 [R]RT ) +55.3 (c ) 0.57,
D
H
2O)]. 1H NMR (D2O, 270 MHz) δ 1.45 (s, 3 H, CH3), 2.55 (d,
J ) 17.2 Hz, 1 H, CHH′), 2.83 (d, J ) 17.8 Hz, 1 H, CHH′).
13C NMR (D2O, 100 MHz) δ 36.7, 52.3, 59.2, 177.0, 177.7.
r-Eth yl Asp a r tic Acid [(S)-15]. Derivative (2S,6S)-11
(100 mg, 0.29 mmol) was hydrolyzed according to the general
procedure to afford 40 mg (80.0% yield) of pure, free amino
acid (S)-15, mp 165-167 °C. [R]2D8°C ) +35.1 (c ) 0.79, H2O).
1H NMR (D2O, 400 MHz) δ 0.90 (t, J ) 7.4 Hz, 3 H, CH2CH3),
1.79 (m, 2 H, CH2CH3), 2.60 (d, J ) 17.6 Hz, 1 H, CHH′), 2.85
(d, J ) 17.3 Hz, 1 H, CHH′). 13C NMR (D2O, 100 MHz) δ 7.5,
29.4, 41.0, 63.1, 175.8, 177.1.
r-n -Bu tyl Asp a r tic Acid [(S)-16]. Derivative (2S,6S)-12
(130 mg, 0.35 mmol) was hydrolyzed according to the general
procedure to afford 62 mg (88.3% yield) of pure, free amino
acid (S)-16, mp 180-182 °C. [R]2D8°C ) + 26.7 (c ) 0.86, H2O).
1H NMR (D2O, 400 MHz) δ 0.82 (t, J ) 7.0 Hz, 3 H), 1.15 (m,
1 H), 1.28 (m, 3 H), 1.70 (m, 2 H), 2.54 (d, J ) 17.2 Hz, 1 H),
2.79 (d, J ) 17.2 Hz, 1 H). 13C NMR (D2O, 100 MHz) δ 13.2,
22.2, 25.2, 35.2, 41.4, 62.8, 175.9, 177.3.
r-Ben zyl Asp a r tic Acid [(S)-17]. Derivative (2S,6S)-13
(200 mg, 0.49 mmol) was hydrolyzed according to the general
procedure to afford 104 mg (95.4% yield) of pure, free amino
acid (S)-17, mp 240-242 °C (lit.7 mp 235 °C). [R]D28°C ) +50.0
(c ) 0.66, H2O) [lit.7 [R]D28°C ) +50.9 (c ) 0.8, H2O)]. 1H NMR
(D2O, 270 MHz) δ 2.59 (d, J ) 17.2 Hz, 1 H, CHH′CO2), 2.90
(d, J ) 17.2 Hz, 1 H, CHH′CO2), 2.97 (d, J ) 13.9 Hz, 1H,
CHH′Ph), 3.16 (d, J ) 13.9 Hz, 1 H, CHH′Ph), 7.2-7.3 (m, 5
H, C6H5). 13C NMR (D2O, 100 MHz) δ 41.2, 41.7, 63.3, 128.0,
129.0, 130.3, 133.8, 175.0, 177.4.
Ack n ow led gm en t. We are grateful to G. Uribe and
V. M. Gonza´lez for the recording of several NMR spectra
and to CONACYT for financial support via Grant
211085-5-L0006E.
Su p p or t in g In for m a t ion Ava ila b le: 1H and 13C NMR
spectra for 9, 10, 12, 15, and 16 (10 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from ACS; see any current masthead page for ordering
information.
J O980367A