Diastereoselective Electrophilic Amination of Chiral 1-Benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one for the Asymmetric Syntheses of α-Substituted α,β-Diaminopropanoic Acids)

Article abstract of DOI:10.1002/hlca.200490073

The chiral compounds (R)- and (S)-1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one ((R)- and (S)-1), derived from (R)- and (S)-asparagine, respectively, were used as convenient starting materials for the preparation of the enanti

Full text of DOI:10.1002/hlca.200490073

1016
Helvetica Chimica Acta Vol. 87 (2004)
Diastereoselective Electrophilic Amination of Chiral 1-Benzoyl-2,3,5,6-
tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one for the
Asymmetric Syntheses of a-Substituted a,b-Diaminopropanoic Acids1)
by Elena Castellanos, Gloria Reyes-Rangel, and Eusebio Juaristi*
¬
¬
Departamento de QuÌmica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico
¬
¬
Nacional, Apartado Postal 14-740, 07000 Mexico, D.F., Mexico
(e-mail: juaristi@relaq.mx)
The chiral compounds (R)- and (S)-1-benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-
4(1H)-one ((R)- and (S)-1), derived from (R)- and (S)-asparagine, respectively, were used as convenient
starting materials for the preparation of the enantiomerically pure a-alkylated (alkyl ˆ Me, Et, Bn) a,b-diamino
acids (R)- and (S)-11 13. The chiral lithium enolates of (R)- and (S)-1 were first alkylated, and the resulting
diasteroisomeric products 5 7 were aminated with −di(tert-butyl) azodicarboxylate× (DBAD), giving rise to the
diastereoisomerically pure (ꢀ 98%) compounds 8 10. The target compounds (R)- and (S)-11 13 could then be
obtained in good yields and high purities by a hydrolysis/hydrogenolysis/hydrolysis sequence.
1. Introduction.
The enantioselective synthesis of amino acids is receiving
increased attention, owing in great part to their relevant role in biological systems.
Indeed, an impressive number of new synthetic procedures have been developed for
the asymmetric synthesis of both natural and unnatural amino acids [2]. Some relevant
topics in this regard are the preparation of peptidomimetics [3], the synthesis of
peptides and proteins that are more resistant to hydrolytic reactions [4], and the
development of amino acid analogs as enzyme inhibitors [5].
a,b-Diamino acids are particularly attractive synthetic targets in view of the various
biologically relevant activities exhibited by these compounds [6]. One example is (S)-
2,3-diaminopropanoic acid, which is present in nature as a peptidic residue in several
antibiotic cyclopeptides [7]. In other cases, diamino acids have been used to induce
specific conformations in peptide segments [8], or as precursors of imidazoline
derivatives with therapeutic activity and increased resistance to hydrolysis [9].
Furthermore, several diamino acids are convenient precursors of b-lactams presenting
antibiotic activity [10].
Several procedures have been described for the enantioselective synthesis of a,b-
diamino acids [11]. Most of these methods are based on the diastereoselective
alkylation of enolates of chiral glycine equivalents, e.g., chiral imidazolidinones [12],
oxazolidinones [13], and bis-lactims [14]. Some a,b-diamino acids have also been
prepared from suitable b-lactams [15].
Given the importance of chiral a,b-diamino acids, and taking into account our
experience concerning the application of chiral pyrimidinones derived from (R)- or
1
)
Enantioselective Syntheses of b-Amino Acids: Part 15. For Part 14, see [1].

Helvetica Chimica Acta Vol. 87 (2004)
1017
(S)-asparagine for the preparation of enantiomerically pure b-amino acids [16], we
decided to undertake an enantioselective synthesis of (2R)- and (2S)-2-alkyl-2,3-
diaminopropanoic acids, following the retrosynthetic strategy presented in Scheme 1.
Scheme 1
2. Results and Discussion. 2.1. Synthesis of (R)-1 from (R)-Asparagine. The
general procedure developed by Konopelski et al. [17] was followed, with isobutyr-
aldehyde instead of pivalaldehyde. As indicated in Scheme 2, (2R,4R)-2 was obtained
in 81% yield. This product was subjected to oxidative decarboxylation with Pb(OAc)4
under Cu(OAc)2 catalysis [17][18], resulting in (R)-3 (76%). The latter was then N-
methylated [19] to (R)-4, which was hydrogenated catalytically with Pd on charcoal
[18], affording (R)-1 in 78% yield for the two steps (Scheme 2). The enantiomer (S)-1
was prepared by a similar synthetic strategy, and according to literature procedures
[20].
Scheme 2
2.2. Electrophilic Alkylation/Amination of (R)- and( S)-1. As expected [16][21],
addition of various alkyl halides to the chiral enolate of either (R)- or (S)-1 proceeded
predominantly on the enolate×s face opposite to the i-Pr group. As shown in Scheme 3,
all reactions proceeded in good yield and with high diastereoselectivity.

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 3
The alkylated products 5 7 (diastereoisomeric mixtures) were treated with lithium
diisopropylamide (LDA) to give the corresponding enolates, which were immediately
aminated with di-(tert-butyl) azodicarboxylate2) (DBAD) [22] (Scheme 4). Most
gratifyingly, 1H-NMR analyses of the crude amination products 8 10 showed a single
set of signals, indicating a diasteroisomeric purity of ꢀ 98%.
Chemical correlation with known a-alkylated a,b-diamino acids (vide infra)
confirmed that the addition of the electrophilic reagent took place from the enolate×s
face opposite to the isopropyl group (Scheme 4). The very high diastereoselectivity
observed is, thus, induced by the pseudoaxial orientation adopted by the isopropyl
group [21][23], which effectively hinders the approach of the bulky DBAD reagent
from the syn face.
2.3. Isolation of the a-Alkylated a,b-Diamino Acids (R)- and( S)-11 13. The final
part in the synthesis consisted of a hydrolysis/hydrogenolysis/hydrolysis sequence of
reactions (Scheme 5) that gave the expected diamino acids (R)- and (S)-11 13 from
the intermediates (2'S,5'R)-8 10 and (2'R,5'S)-8 10, respectively. The final products
could be readily purified by silica-gel column chromatography, with MeOH/i-PrOH/aq.
NH3 as eluent [24].
3. Conclusions. The chiral pyrimidinones (R)- and (S)-1 are convenient starting
materials for the preparation of the enantiomerically pure a-alkylated a,b-diamino
acids (R)- and (S)-11 13. The chiral enolates (R)- and (S)-1ÀLi are readily prepared
by treatment of the starting heterocycle with lithium diisopropylamide (LDA).
Although the subsequent alkylation of (R)- and (S)-1ÀLi with various alkyl halides is
not fully diastereoselective, treatment of the resulting alkylated products 5 7
2
)
Systematic name: di(tert-butyl) (E)-diazene-1,2-dicarboxylate.

Helvetica Chimica Acta Vol. 87 (2004)
1019
Scheme 4
a) iPr2NLi (LDA), THF, À788, 2 h. b) DBAD, À788, r.t., 12 h.
(diastereoisomeric mixture) with a second equivalent of LDA affords the correspond-
ing Li enolates, which are now aminated with DBAD with complete (> 98%)
diastereoselectivity. A hydrolysis/hydrogenolysis/hydrolysis sequence finally provides
the desired a,b-diamino acids in enantiomerically pure form.
¬
We are grateful to CONACyT (Mexico) for financial support (grant No. 33023-E) and to FredGarcÌa-
Flores for technical assistance.
Experimental Part
General. All commercial reagents were used as received. Anhydrous (anh.) solvents were obtained by
distillation. Flash-column chromatography (FC) was performed on silica gel (Merck 60, 230 400 mesh).
Reactions were monitored by thin-layer chromatography (TLC; aluminium-backed plates (0.2 mm), Merck
silica-gel 60 F254). Melting points (m.p.) were determined on a Mel Temp apparatus, and are uncorrected.
1
Optical rotations were measured on a Perkin-Elmer-241 polarimeter (l ˆ 589 nm). H- and 13C-NMR Spectra
were recorded on Jeol Eclipse-400 (400/100 MHz), Bruker Ultra-Shield (300/75 MHz), and Jeol GSX-270 (270/
67.5 MHz) spectrometers; chemical shifts d in ppm rel. to SiMe4 (ˆ0 ppm) as internal reference, coupling
constants J in Hz. Elemental analyses were determined by the combustion method with a Thermo-Finnigan-
Serie-Flash-1112 apparatus.
(2R,4R)-3-Benzoyl-1,2,3,4,5,6-hexahydro-2-(1-methylethyl)-6-oxopyrimidine-4-carboxylic Acid ((2R,4R)-
2). In an Erlenmeyer flask (1000 ml), equipped with a magnetic bar, KOH (13.2 g, 0.2 mol) was dissolved in
distilled H2O (300 ml). Then, under stirring, (R)-asparagine monohydrate (30 g, 0.2 mol) and isobutyraldehyde

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Helvetica Chimica Acta Vol. 87 (2004)
Scheme 5
a) CF3COOH, CH2Cl2, r.t., 30 min. b) Raney Ni/H2 (69 bar), MeOH, r.t., 27 h. c) 6n HCl, 908, 36 56 h.
(36.3 ml, 0.4 mmol) were added, and the mixture was vigorously stirred for 6 h at r.t. Then, the mixture was
cooled to 08 in an ice bath, and NaHCO3 (8.4 g, 0.1 mol) and benzoyl chloride (BzCl; 11.6 ml, 0.1 mol) were
added. After 30 min of stirring, additional portions of NaHCO3 and BzCl (8.4 g and 11.6 ml, resp.) were added,
and the resulting mixture was stirred at 08 for 1 h, and then at r.t. for 1 h. Unreacted isobutyraldehyde and BzCl
were removed by extraction with CH2Cl2 (200 ml). The aq. phase was adjusted to pH 2.0 with 10% aq. HCl soln.,
an the desired product was extracted with CH2Cl2 (3 Â 500 ml). The org. layers were combined, dried (Na2SO4),
and concentrated in a rotary evaporator at reduced pressure. The resulting crude solid was recrystallized from
hexane/acetone 8 :2 to afford pure (2R,4R)-2: 47.0 g (81%). M.p. 191 1928. [a]205 ˆ ‡149 (c ˆ 1, MeOH).
1H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.87 (d, J ˆ 6.7, 3 H); 0.96 (d, J ˆ 6.6, 3 H); 2.10 (m, 1 H); 2.64 (dd,
J ˆ 16.7, 8.3, 1 H); 2.80 (dd, J ˆ 16.7, 8.9, 1 H); 4.80 (t, J ˆ 8.6, 1 H); 4.93 (d, J ˆ 10.0, 1 H); 7.38 7.45 (m, 5 H).
13C-NMR (75 MHz, (D6)DMSO, Tˆ 1208): 18.1; 18.5; 31.4; 32.9; 52.4; 69.5; 126.2; 127.7; 128.8; 135.3; 166.3;
169.8; 171.0. Anal. calc. for C15H18N2O4 (290.31): C 62.06, H 6.25, N9.65; found: C 61.84, H 6.25, N9.65.
(R)-1-Benzoyl-2,3-dihydro-2-(1-methylethyl)pyrimidin-4(1H)-one ((R)-3). In a round-bottom flask,
equipped with a magnetic stirrer, was placed (2R,4R)-2 (20.0 g, 68.9 mmol) in toluene (200 ml) and THF
(300 ml), and this soln. was treated with pyridine (10 ml) and Cu(OAc)2 (0.5 g, 2.4 mmol). The resulting
mixture was stirred at r.t. for 2 h. Then, the flask was placed in an ice bath, and Pb(OAc)4 (54.0 g, 121.8 mmol)
was added. The ice bath was removed, and the mixture was heated to reflux for 18 h. The resulting suspension
was filtered, and the filtrate was concentrated in vacuo. The crude product was washed with H2O (200 ml) and
extracted with AcOEt (250 ml). The org. extracts were combined, dried (Na2SO4), and evaporated to a viscous
oil, which was purified by FC (SiO2; hexane/AcOEt 1:1) to afford (R)-3: 12.8 g (76%). White solid. M.p. 159
1608. [a]2D5 ˆ À490 (c ˆ 1, CHCl3). H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.88 (d, J ˆ 6.9, 3 H); 0.96 (d,
1
J ˆ 6.7, 3 H); 2.22 (m, 1 H); 5.12 (d, J ˆ 8.01, 1 H); 5.42 (dd, J ˆ 7.26, 1.5, 1 H); 7.09 (dd, J ˆ 8.1, 1.6, 1 H); 7.04
7.11 (m, 5 H). 13C-NMR (75 MHz, (D6)DMSO, Tˆ 1208): 16.9; 17.5; 32.2; 68.0; 104.6; 127.0; 128.0; 130.2; 133.0;
136.3; 161.5; 167.6. Anal. calc. for C14H16N2O2 (244.29): C 68.83, H 6.60, N11.47; found: C 69.11, H 6.52, N11.54.
(R)-1-Benzoyl-2,3-dihydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one ((R)-4) In a dried, 100-ml
round-bottom flask, equipped with a magnetic stirrer, were placed anh. THF (15.0 ml) and (i-Pr)2NH (1.14 ml,

Helvetica Chimica Acta Vol. 87 (2004)
1021
8.1 mmol), and the resulting soln. was cooled to À208. Then, BuLi (2.37m in hexane, 3.11 ml, 7.4 mmol) was
added. The resulting LDA (lithium diisopropylamide) soln. was stirred for 20 min, and then cooled to À788
(dry-ice/acetone bath). To this soln., a cooled (À 788) soln. of (R)-3 (1.8 g, 7.4 mmol) in anh. THF (15.0 ml) was
added, and the mixture was stirred for 1 h at this temp. Then, MeI (0.55 ml, 8.8 mmol) was added, the temp. was
allowed to come to À308, and stirring was continued at this temp. for 4 h. Then, sat. aq. NH4Cl soln. (3.0 ml) was
added, and the mixture was extracted with AcOEt (3 Â 15 ml). The org. extracts were combined, dried
(Na2SO4), and concentrated to afford crude (R)-4 as a yellowish solid, which was purified by FC (SiO2; hexane/
AcOEt 3 :7): 15.6 g (82.0%). White solid. M.p. 104 1058. [a]2D5 ˆ À511 (c ˆ 1, CHCl3). 1H-NMR (300 MHz,
(D6)DMSO, Tˆ 1208): 0.92 (d, J ˆ 6.9, 3 H); 1.00 (d, J ˆ 6.8, 3 H); 2.38 (m, 1 H); 3.02 (s, 3 H); 5.22 (d, J ˆ 7.87,
1 H); 5.60 (dd, J ˆ 7.3, 1.6, 1 H); 7.05 (dd, J ˆ 7.9, 1.7, 1 H); 7.49 7.52 (m, 5 H). 13C-NMR (75 MHz, (D6)DMSO,
Tˆ 1208): 17.7; 18.2; 32.0; 34.0; 73.9; 105.3; 127.0; 128.0; 130.3; 132.8; 135.6; 160.8; 167.5. Anal. calc. for
C15H18N2O2 (258.31): C 69.74, H 7.02, N10.84; found: C 69.95, H 6.98, N10.95.
(R)-1-Benzoyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one ((R)-1). In a hydroge-
nation flask was placed Pd/C (0.2 g) under a stream of anh. N2 gas. MeOH (20 ml) and (R)-4 (2.0 g, 7.8 mmol)
were added, and the flask was pressurized with H2 (55 bar) and shaken at r.t. for 12 h. The catalyst was removed
by filtration over Celite, the solvent was evaporated under reduced pressure, and the crude (R)-1 was purified by
FC (SiO2; AcOEt/hexane 9 :1): 1.9 g (95%). White solid. M.p. 99 1008. [a]2D5 ˆ À25.0 (c ˆ 1.0, CHCl3).
1H-NMR (400 MHz, (D6)DMSO, Tˆ 1208): 0.95 (d, J ˆ 6.6, 3 H); 1.00 (d, J ˆ 6.6, 3 H); 2.35 (m, 1 H); 2.50 (m,
2 H); 2.95 (s, 3 H); 3.58 (qt, J ˆ 13.9, 7.7, 1 H); 3.86 (br. t, J ˆ 7.0, 1 H); 5.15 (d, J ˆ 7.0, 1 H); 7.39 7.48 (m, 5 H).
13C-NMR (100 MHz, (D6)DMSO, Tˆ 1208): 19.2; 19.2; 30.4; 33.3; 35.5; 39.5; 74.8; 127.2; 128.9; 130.2; 136.2;
167.5; 170.3. Anal. calc. for C15H20N2O2 (260.33): C 69.20, H 7.74, N10.76; found: C 69.20, H 7.67, N10.79.
General Procedure (GP1) for the Alkylation of (R)-1 and( S)-1 (Scheme 2). A soln. of (i-Pr)2NH (1.0 ml,
7.3 mmol) in anh. THF (15 ml) was cooled to À208 under N2 gas. Then, BuLi (2.4m in hexane; 2.75 ml, 6.6 mmol)
was added, and the resulting mixture was stirred for 20 min at this temp. Then, the temp. was lowered to À788
(dry-ice/acetone bath), and a cooled (À 788) soln. of (R)- or (S)-1 (1.7 g, 6.6 mmol) in anh. THF (20 ml) was
added slowly. The resulting soln. was stirred at this temp. for 2 h. Then, the electrophile (MeI, EtI, or BnBr;
7.2 mmol, 1.1 equiv.) was added slowly. The temp. was raised to À308, and stirring was continued for 3 7 h, until
no starting material was visible by TLC. An aq. sat. soln. of NH4Cl (3 ml) was then added to quench the reaction,
the resulting mixture was washed with brine (10 ml), and extracted with AcOEt (3 Â 20 ml). The combined org.
extracts were driede (Na2SO4), filtered, and concentrated in vacuo to afford the crude product, which was
analyzed by 1H-NMR to determine the diastereoisomeric ratio. The crude diastereoisomerically enriched
products 5 7 were purified by FC (SiO2; AcOEt/hexane 7:3).
(2R,5S)- and(2 R,5R)-1-Benzoyl-2,3,5,6-tetrahydro-3,5-dimethyl-2-(1-methylethyl)pyrimidin-4(1H)-one
((2R,5S)-5 and (2R,5R)-5, resp.). Prepared according to GP1. Yield: 80%; diastereoisomer ratio: (2R,5S)/
(2R,5R) 81:19.
Data for (2R,5S)-5 (major product, trans-isomer): 1H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.94 (d, J ˆ
6.8, 3 H); 0.98 (d, J ˆ 6.7, 3 H); 1.03 (d, J ˆ 6.8, 3 H); 2.38 (m, 1 H); 2.72 (m, 1 H); 2.94 (s, 3 H); 3.40 (dd, J ˆ 7.0,
13.0, 1 H); 3.8 (dd, J ˆ 7.8, 13.0, 1 H); 5.19 (d, J ˆ 8.8, 1 H); 7.35 7.46 (m, 5 H). 13C-NMR (75 MHz, (D6)DMSO,
Tˆ 1208): 14.9; 18.1; 18.3; 32.4; 33.2; 34.5; 46.4; 74.2; 126.1; 127.8; 129.0; 135.3; 169.2; 169.8.
1
Data for (2R,5R)-5 (minor product, cis-isomer): H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.94 (d, J ˆ
6.8, 3 H); 1.00 (d, J ˆ 7.7, 3 H); 1.05 (d, J ˆ 7.2, 3 H); 2.28 (m, 1 H); 2.72 (m, 1 H); 2.94 (s, 3 H); 3.19 (dd, J ˆ11.0,
14.0, 1 H); 4.03 (dd, J ˆ 8.0, 13.4, 1 H); 5.22 (d, J ˆ 7.5, 1 H); 7.35 7.46 (m, 5 H). 13C-NMR (75 MHz,
(D6)DMSO, Tˆ 1208): 13.9; 17.6; 18.0; 32.3; 34.0; 34.7; 44.9; 72.8; 125.9; 127.8; 129.1; 134.9; 168.7; 169.5.
(2S,5R)- and(2 S,5S)-1-Benzoyl-2,3,5,6-tetrahydro-3,5-dimethyl-2-(1-methylethyl)pyrimidin-4(1H)-one
((2S,5R)-5 and (2S,5S)-5, resp.). Prepared according to GP1. Yield: 76%; diastereoisomer ratio: (2S,5R)/
(2S,5S) 85 :15. The spectral data of the (2S,5R)- and the (2S,5S)-isomers were identical with those of
enantiomeric (2R,5S)-and (2R,5R)-5, resp. (see above).
(2R,5S)- and(2 R,5R)-1-Benzoyl-5-ethyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-
one ((2R,5S)-6 and (2R,5R)-6, resp.). Prepared according to GP1. Yield: 83%; diastereoisomer ratio:
(2R,5S)/(2R,5R) 80 :20.
Data for (2R,5S)-6 (major product, trans-isomer): 1H-NMR (270 MHz, (D6)DMSO, T ˆ1208): 0.79 (t, J ˆ
7.4, 3 H); 0.96 (d, J ˆ 6.7, 3 H); 1.00 (d, J ˆ 6.7, 3 H); 1.40 (m, 1 H); 1.72 (m, 1 H); 2.30 (m, 1 H); 2.38 (m, 1 H);
2.95 (s, 3 H); 3.62 (dd, J ˆ 13.0, 18.8, 1 H); 3.75 (dd, J ˆ 7.7, 13.6, 1 H); 5.23 (d, J ˆ 7.8, 1 H); 7.38 7.50 (m, 5 H).
13C-NMR (67.5 MHz, (D6)DMSO, T ˆ1208): 11.4; 19.3; 19.2; 24.0; 33.4; 35.6; 41.0; 43.7; 73.9; 127.3; 129.0; 130.3;
136.4; 170.0; 170.3.

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Helvetica Chimica Acta Vol. 87 (2004)
Data for (2R,5R)-6 (minor product, cis-isomer): 1H-NMR (270 MHz, (D6)DMSO, T ˆ1208): 0.84 (t, J ˆ 7.4,
3 H); 0.96 (d, J ˆ 6.7, 3 H); 1.06 (d, J ˆ 6.7, 3 H); 1.50 (m, 1 H); 1.72 (m, 1 H); 2.35 (m, 1 H); 2.40 (m, 1 H); 2.93
(s, 3 H); 3.28 (dd, J ˆ 11.0, 14.0, 1 H); 4.02 (dd, J ˆ 7.7, 13.6, 1 H); 5.14 (d, J ˆ 7.9, 1 H); 7.38 7.52 (m, 5 H).
13C-NMR (67.5 MHz, (D6)DMSO, T ˆ1208): 11.1; 18.9; 19.2; 23.1; 33.5; 35.4; 42.2; 44.0; 75.0; 127.1; 129.0; 130.3;
136.0; 170.2; 170.3.
(2S,5R)- and(2 S,5S)-1-Benzoyl-5-ethyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-one
((2S,5R)-6 and (2S,5S)-6, resp.). Prepared according to GP1. Yield: 82%; diastereoisomer ratio: (2S,5R)/(2S,5S)
86 :14. The spectral data of the (2S,5R)- and the (2S,5S)-isomers were identical with those of enantiomeric
(2R,5S)-and (2R,5R)-6, resp. (see above).
(2R,5S)- and(2 R,5R)-1-Benzoyl-5-benzyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-
one ((2R,5S)-7 and (2R,5R)-7, resp.). Prepared according to GP1. Yield: 85%; diastereoisomer ratio: (2R,5S)/
(2R,5R) 87:13.
Data of (2R,5S)-7 (major product, trans-isomer): 1H-NMR (400 MHz, (D6)DMSO, Tˆ 1208): 0.91 (d, J ˆ
6.6, 3 H); 0.99 (d, J ˆ 6.9, 3 H); 2.37 (m, 1 H); 2.56 (dd, J ˆ 13.9, 8.8, 1 H); 2.80 (m, 1 H); 2.98 (s, 3 H); 3.10 (m,
1 H); 3.13 (dd, 1 H); 3.59 (dd, J ˆ 7.2, 13.0, 1 H); 5.16 (d, J ˆ 7.4, 1 H); 7.03 7.50 (m, 5 H). 13C-NMR (100 MHz,
(D6)DMSO, Tˆ 1208): 19.3; 19.4; 33.4; 35.3; 36.7; 41.8; 44.2; 75.2; 127.4; 128.6; 128.9; 129.2; 129.4; 130.3; 136.1;
139.5; 169.9; 170.1.
Data of (2R,5R)-7 (minor product, trans-isomer): 1H-NMR (400 MHz, (D6)DMSO, Tˆ 1208): 0.79 (d, J ˆ
6.9, 3 H); 0.91 (d, J ˆ 6.9, 3 H); 1.91 (m, 1 H); 2.38 (dd, J ˆ 14.0, 8.8, 1 H); 2.90 (m, 1 H); 2.94 (s, 3 H); 3.12 (m,
1 H); 3.80 (dd, 1 H); 4.06 (dd, J ˆ 7.6, 13.5, 1 H); 5.14 (d, J ˆ 7.6, 1 H); 7.03 7.42 (m, 5 H). 13C-NMR (100 MHz,
(D6)DMSO, Tˆ 1208): 18.6; 19.1; 33.3; 35.5; 35.9; 42.1; 43.1; 73.9; 126.5; 126.6; 126.9; 128.6; 129.4; 130.2; 135.2;
138.8; 169.9; 170.1.
(2S,5R)- and(2 S,5S)-1-Benzoyl-5-benzyl-2,3,5,6-tetrahydro-3-methyl-2-(1-methylethyl)pyrimidin-4(1H)-
one ((2S,5R)-7 and (2S,5S)-7, resp.). Prepared according to GP1. Yield: 87%; diastereoisomer ratio: (2S,5R)/
(2S,5S) 73 :27. The spectral data for (2S,5R)-and (2S,5S)-7 were identical with those of the corresponding
enantiomers (2R,5S)- and (2R,5R)-7, resp.
General Procedure (GP2) for the Electrophilic Amination of Compounds 5 7 (Scheme 4). To a cooled
(À208) soln. of (i-Pr)2NH (1.2 mmol) in anh. THF (15 ml) was added under N2 atmosphere BuLi (2.3m soln. in
hexane; 0.43 ml, 1.0 mmol). The resulting LDA soln. was stirred at À208 for 20 min. Then, the temp. was
lowered to À788 (dry-ice/acetone bath), and a cooled (À 788) soln. of the substrate (5, 6 or 7; 1.0 mmol) in anh.
THF (20 ml) was added dropwise. The resulting soln. was stirred at À788 for 2 h. Then, a cooled (À 788) soln. of
di(tert-butyl)azodicarboxylate (DBAD; 1.5 mmol)2) in anh. THF (15 ml) was added. The mixture was stirred at
À788 for 6 h, and then at r.t. for another 3 6 h, until no more substrate was detected (TLC). The reaction was
then quenched with sat aq. NH4Cl soln. (4 ml), treated with brine (15 ml), and the mixture was extracted with
AcOEt (3 Â 20 ml). The org. extracts were combined, dried (Na2SO4), filtered, and evaporated in vacuo to
afford the crude products, wich were analyzed by 1H-NMR (determination of diastereoisomer ratio). Only one
set of signals was observed, indicating diastereoisomer purities of ꢀ 98%. The compounds were purified by FC
(SiO2; AcOEt/hexane 6 :4), affording the desired pure products 8 10 as white foams.
Di(tert-butyl) 1-[(2R,5S)-1-Benzoyl-1,2,3,4,5,6-hexahydro-3,5-dimethyl-2-(1-methylethyl)-4-oxopyrimidin-
5-yl]hydrazine-1,2-dicarboxylate ((2'R,5'S)-8). Prepared according to GP2. White foam. Yield: 227 mg (45%).
[a]2D5 ˆ ‡2.0 (c ˆ 1.0, CHCl3). 1H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.93 (d, J ˆ 6.7, 3 H); 1.02 (d, J ˆ 6.6,
3 H); 1.31 (s, 9 H); 1.34 (s, 3 H); 1.36 (s, 9 H); 2.35 (br. s, 1 H); 2.91 (s, 3 H); 3.54 (br s, 1 H); 4.60 (br s, 1 H); 5.21
(br. s, 1 H); 7.38 7.45 (m, 5 H). 13C-NMR (75 MHz, (D6)DMSO, Tˆ 1208): 17.7; 17.8; 27.3; 32.1; 34.1; 47.1; 61.3;
73.7; 78.8; 79.9; 126.3; 126.6; 127.4; 128.6; 153.0; 154.5; 168.5; 169.1. Anal. calc. for C26H40N4O6 (504.62): C 61.88,
H 7.99, N11.10; found: C 62.10, H 8.39, N10.70.
Di(tert-butyl) 1-[(2S,5R)-1-Benzoyl-1,2,3,4,5,6-hexahydro-3,5-dimethyl-2-(1-methylethyl)-4-oxopyrimidin-
5-yl]hydrazine-1,2-dicarboxylate ((2'S,5'R)-8). Prepared according to GP2. White foam. Yield: 207 mg (41%).
[a]2D5 ˆ À1.9 (c ˆ 1.0, CHCl3). The NMR-spectral data were identical with those of (2R,5S)-8. Anal. calc. for
C26H40N4O6 (504.62): C 61.88, H 7.99, N11.10; found: C 61.78, H 8.32, N10.86.
Di(tert-butyl) 1-[(2R,5S)-1-Benzoyl-5-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-2-(1-methylethyl)-4-oxopyri-
midin-5-yl]hydrazine-1,2-dicarboxylate ((2'R,5'S)-9). Prepared according to GP2. White foam. Yield: 347 mg
(67%). [a]2D5 ˆ ‡2.3 (c ˆ 0.6, CHCl3). 1H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.86 (d, J ˆ 7.0, 3 H); 0.90 (d,
J ˆ 6.5, 3 H); 0.99 (d, J ˆ 6.5, 3 H); 1.29 (s, 9 H); 1.36 (s, 9 H); 1.83 (br. s, 2 H); 2.31 (br. s, 1 H); 2.92 (s, 3 H); 3.63
(br. s, 1 H); 4.53 (br. s, 1 H); 5.35 (br. s, 1 H); 7.37 7.45 (m, 5 H). 13C-NMR (75 MHz, (D6)DMSO, Tˆ 1208):
7.9; 17.9; 18.0; 27.3; 27.4; 29.0; 32.0; 35.4; 49.9; 73.4; 79.0; 80.0; 126.8; 127.3; 128.7; 135.3; 153.4; 154.6; 167.1;
168.9. Anal. calc. for C27H42N4O6 (518.65): C 62.53, H 8.16, N10.80; found: C 62.25, H 8.43, N10.66.

Helvetica Chimica Acta Vol. 87 (2004)
1023
Di(tert-butyl) 1-[(2S,5R)-1-Benzoyl-5-ethyl-1,2,3,4,5,6-hexahydro-3-methyl-2-(1-methylethyl)-4-oxopyri-
midin-5-yl]hydrazine-1,2-dicarboxylate ((2'S,5'R)-9). Prepared according to GP2. White foam. Yield: 192 mg
(37%). [a]2D5 ˆ À2.5 (c ˆ 1.0, CHCl3). The NMR-spectral data were identical with those of (2'R,5'S)-9. Anal.
calc. for C27H42N4O6 (518.65): C 62.53, H 8.16, N10.80; found: C 62.30, H 8.45, N10.68.
Di(tert-butyl) 1-[(2R,5S)-1-Benzoyl-5-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-2-(1-methylethyl)-4-oxopyri-
midin-5-yl]hydrazine-1,2-dicarboxylate ((2'R,5'S)-10). Prepared according to GP2. White foam. Yield: 423 mg
1
(73%). [a]2D5 ˆ À11.5 (c ˆ 0.99, CHCl3). H-NMR (300 MHz, (D6)DMSO, Tˆ 1208): 0.44 (br. s, 6 H); 1.34 (s,
9 H); 1.41 (s, 9 H); 2.05 (br. s, 2 H); 2.84 (br. s, 4 H); 2.98 (br. s, 1 H); 3.47 (br. s, 1 H); 4.88 (br. s, 1 H); 7.19 7.40
(m, 10 H). 13C-NMR (75 MHz, (D6)DMSO, Tˆ 1208): 17.0; 17.9; 18.3; 27.4; 27.4; 29.5; 31.9; 35.5; 46.5; 65.7;
79.0; 79.3; 80.0; 125.8; 126.3; 127.3; 127.4; 130.4; 135.1; 135.2; 153.1; 154.5; 165.0; 168.5. Anal. calc. for
C32H44N4O6 (580.71): C 66.18, H 7.64, N9.65; found: C 66.19, H 7.90, N9.38.
Di(tert-butyl) 1-[(2S,5R)-1-Benzoyl-5-benzyl-1,2,3,4,5,6-hexahydro-3-methyl-2-(1-methylethyl)-4-oxopyri-
midin-5-yl]hydrazine-1,2-dicarboxylate ((2'S,5'R)-10). Prepared according to GP2. White foam. Yield: 145 mg
(25%). [a]2D5 ˆ ‡11.5 (c ˆ 1.0, CHCl3). The NMR-spectral data were identical with those of (2'R,5'S)-10. Anal.
calc. for C32H44N4O6 (580.71): C 66.18, H 7.64, N9.65; found: C 66.29, H 7.97, N9.45.
General Procedure (GP3) for the Preparation of the Target Compounds 11 13 (Scheme 5). To a soln. of
compound 8, 9, or 10 (0.5 mmol) in CH2Cl2 (2.0 ml) was added CF3COOH (TFA; 3 ml), and the resulting soln.
was stirred at r.t. for 30 min. The soln. was then transfered to a hydrogenation flask, and treated with MeOH
(25 ml) and Raney Ni (10 mol-%; 0.5 g). The flask was pressurized to 69 bar of H2 and shaken for 24 h at r.t. The
mixtrue was filtered over Celite, the solvent was removed at reduced pressure, and the remaining crude product
was dissolved in H2O (10 ml). Then, sat. aq. Na2CO3 soln (10 ml) was added, and the mixture was extracted with
AcOEt (2 Â 15 ml). The combined org. layers were dried (Na2SO4) and concentrated in vacuo to afford a crude
intermediate, which was treated with 6m aq. HCl soln (3.0 ml). This mixture was placed in a sealed tube and
heated to 908, until the starting material had disappeared (typically after 36 96 h). The mixture was extracted
with CH2Cl2 (2 Â 15 ml), and the aq. phase was evaporated to afford the crude a,b-diamino acid (11, 12, or 13,
resp.), which was purified by FC (SiO2, 70 230 mesh; i-PrOH/MeOH/aq. NH3 3:2:1) according to [24].
(S)-2,3-Diamino-2-methylpropanoic Acid ((S)-11). Prepared according to GP3. White solid. Yield: 224 mg
(89%). M.p. 200 2018 (dec.) (lit. 203 2058 [8b]). [a]2D5 ˆ ‡5.0 (c ˆ 0.2, MeOH) (lit. [a]D25 ˆ ‡5.0 (c ˆ 0.2,
MeOH) [8b]). 1H-NMR (300 MHz, D2O): 1.40 (s, 3 H); 2.96 (d, J ˆ 13.5, 1 H); 3.11 (d, J ˆ 13.5, 1 H). 13C-NMR
(75 MHz, D2O): 22.3; 47.4; 60.0; 178.6.
(R)-2,3-Diamino-2-methylpropanoic Acid ((R)-11). Prepared according to GP3. White solid. Yield:
214 mg (85%). M.p 203 2058 (dec.) (lit. 202 2048 [8b]). [a]2D5 ˆ À4.8 (c ˆ 0.2, MeOH) (lit. [a]D25 ˆ À4.5 (c ˆ
0.2, MeOH) [8b]). The NMR-spectral data were identical with those of (S)-11 (see above).
(S)-2-Amino-2-(aminomethyl)butanoic Acid ((S)-12). Prepared according to GP3. White solid. Yield:
1
194 mg (75%). M.p. 205 2068. [a]2D5 ˆ ‡6.8 (c ˆ 0.08, H2O). H-NMR (300 MHz, D2O): 0.98 (t, J ˆ 7.5, 3 H);
1.79 (dt, J ˆ 14.8, 7.3, 1 H); 3.20 (d, J ˆ 11.0, 1 H); 3.28 (d, J ˆ 3.3, 1 H). 13C-NMR (75 MHz, D2O): 7.7; 28.1; 44.3;
62.6; 175.3.
(R)-2-Amino-2-(aminomethyl)butanoic Acid ((R)-12). Prepared according to GP3. White solid. Yield:
145 mg (56%). M.p. 206 2088. [a]2D5 ˆ À7.2 (c ˆ 0.08, H2O). The NMR-spectral data were identical with those
of (S)-12 (see above).
(S)-2,3-Diamino-2-benzylpropanoic Acid ((S)-13). Prepared according to GP3. White solid. Yield: 78 mg
(27%). M.p. 224 2258. [a]2D5 ˆ ‡9.2 (c ˆ 0.8, H2O). 1H-NMR (300 MHz, D2O): 2.95 (d, J ˆ 14.3, 1 H); 3.26 (d,
J ˆ 14.3, 1 H); 3.35 (d, J ˆ 1.3, 1 H); 3.37 (d, J ˆ 1.2, 1 H); 7.10 (m, 5 H). 13C-NMR (75 MHz, D2O): 39.4; 42.7;
61.4; 129.0; 129.6; 130.4; 131.1; 170.0.
(R)-2,3-Diamino-2-benzylpropanoic Acid ((R)-13). Prepared according to GP3. White solid. Yield:
72.5 mg (25%). M.p 221 2228 (lit. 2228 (dec) [11a]). [a]2D5 ˆ À9.8 (c ˆ 0.6, H2O) (lit. [a]D25 ˆ À 8.25 (c ˆ 0.8,
H2O) [11a]). The NMR-spectral data were identical with those of (S)-13 (see above).
REFERENCES
[1] O. Munƒoz-Munƒiz, E. Juaristi, Tetrahedron 2003, 59, 4223.
[2] Tetrahedron-Symposium-in-Print, Ed. M. J. O×Donnell, Tetrahedron 1988, 44, 5253; R. M. Williams,
−Synthesis of Optically Active a-Amino Acids×, Pergamon Press, Oxford, 1989; R. O. Duthaler,
Tetrahedron 1994, 50, 1539; M. Calmes, J. Daunis, Amino Acids 1999, 16, 215; E. Juaristi, D. Quintana,
J. Escalante, Aldrichim. Acta 1994, 27, 3; D. C. Cole, Tetrahedron 1994, 50, 9517; G. Cardillo, C. Tomasini,

1024
Helvetica Chimica Acta Vol. 87 (2004)
Chem. Soc. Rev. 1996, 23, 117; −Enantioselective Synthesis of b-Amino Acids×, Ed. E. Juaristi, J. Wiley &
¬
Sons, N.Y., 1997; E. Juaristi, H. Lopez-Ruiz, Curr. Med. Chem. 1999, 6, 983; M. Liu, M. P. Sibi, Tetrahedron
2002, 58, 7991; M. Brenner, D. Seebach, Helv. Chim. Acta 1999, 82, 2365.
[3] J. Gante, Angew. Chem., Int. Ed. 1994, 33, 1699; Tetrahedron-Symposium-in-Print, Eds. V. Hruby, V. A.
Soloshonok, Tetrahedron 2001, 57, 6329; G. Haberhauer, F. Rominger, Synlett 2003, 780.
[4] S. Thaisrivongs, D. T. Pals, J. A. Lawson, S. R. Turner, D. W. Harris, J. Med. Chem. 1987, 30, 536.
[5] M. G. Hinds, J. H. Welsh, D. M. Brennand, J. Fisher, M. J. Glennie, N. G. J. Richards, D. L. Turner, J. A.
Robinson, J. Med. Chem. 1991, 34, 1777; L. W. Boteju, K. Wegner, V. J. Hruby, Tetrahedron Lett. 1992, 33,
7491.
[6] J. Tamariz, in −Enantioselective Synthesis of b-Amino Acids×, Ed. E. Juaristi, J. Wiley & Sons, N.Y., 1997, p.
45.
[7] S. Kobayashi, M. Otsuka, M. Narita, M. Ohno J. Am. Chem. Soc. 1980, 102, 6630; N. Shimada, K.
Morimoto, H. Naganawa, T. Takita, M. Hamada, K. Maeda, T. Takeuchi, H. Umezawa, Antibiotics 1981, 34,
1613; F. H. Van der Steen, G. Van Koten, Tetrahedron 1991, 47, 7503; D. F. Rane, V. M. Girijavallabhan,
A. K. Ganguly, R. E. Pike, A. K. Saksena, A. T. McPhail, Tetrahedron Lett. 1993, 34, 3201; M. Wang, S. J.
Gould, J. Org. Chem. 1993, 58, 5176.
[8] a) D. Seebach, A. Studer, E. Pfammatter, H. Widmer, Helv. Chim. Acta 1994, 77, 2035; b) D. Obrecht, H.
Karajiannis, C. Lehmann, P. Schˆnholzer, C. Spiegler, K. M¸ller, Helv. Chim. Acta 1995, 78, 703.
[9] I. H. Gilbert, D. C. Rees, A. K. Crockett, R. C. F. Jones, Tetrahedron 1995, 51, 6315.
[10] M. F. Loewe, R. J. Cvetovich, G. G. Hazen, Tetrahedron Lett. 1991, 32, 2299; T. Murayama, T. Kobayashi, T.
Miura, Tetrahedron Lett. 1995, 36, 3703.
¬
[11] a) R. Badorrey, C. Cativiela, M. D. DÌaz-de-Villegas, J. A. Galvez, Tetrahedron: Asymmetry 1995, 6, 2787;
b) H. Han, J. Yoon, K. D. Janda, J. Org. Chem. 1998, 63, 2045; c) P. Merino, A. Lanaspa, F. L. Merchan, T.
Tejero, Tetrahedron: Asymmetry 1998, 9, 629; d) K. R. Knudsen, T. Risgaard, N. Nishiwaki, K. V. Gothelf,
K. A. Jorgensen, J. Am. Chem. Soc. 2001, 123, 5843; e) A. J. Robinson, C. Y. Lim, L. He, P. Ma, H. Y. Li, J.
Org. Chem. 2001, 66, 4141.
[12] E. Pfammatter, D. Seebach, Liebigs Ann. Chem. 1991, 1323; G. Cardillo, M. Orena, M. Penna, S. Sandri, C.
Tomasini, Tetrahedron 1991, 47, 2263.
[13] R. C. F. Jones, A. K. Crockett, D. C. Rees, I. H. Gilbert, Tetrahedron: Asymmetry 1994, 5, 1661; F. M. Rossi,
E. T. Powers, R. Yoon, L. Rosenberg, J. Meinwald, Tetrahedron 1996, 52, 10279.
[14] W. Hartwig, J. Mittendorf, Synthesis 1991, 939.
[15] P. J. Colson, L. S. Hegedus, J. Org. Chem. 1993, 58, 5918; I. Ojima, Acc. Chem. Res. 1995, 28, 383; C.
Palomo, J. M. Aizpurua, I. Ganboa, in −Enantioselective Synthesis of b-Amino Acids×, Ed. E. Juaristi, J.
Wiley & Sons, N.Y., 1997, p. 279.
[16] E. Juaristi, D. Quintana, Tetrahedron: Asymmetry 1992, 3, 723; E. Juaristi, D. Quintana, M. Balderas, E.
¬
¬
GarcÌa-Perez, Tetrahedron: Asymmetry 1996, 7, 2233; E. Juaristi, M. Balderas, Y. RamÌrez-Quiroz,
¬
¬
¬
Tetrahedron: Asymmetry 1998, 9, 3881; E. Juaristi, M. Balderas, H. Lopez-Ruiz, V. M. Jimenez-Perez, M. L.
¬
Kaiser-Carril, Y. RamÌrez-Quiroz, Tetrahedron: Asymmetry 1999, 10, 3493.
[17] J. P. Konopelski, K. S. Chu, G. R. Negrete, J. Org. Chem. 1991, 56, 1355; K. S. Chu, G. R. Negrete, J. P.
Konopelski, F. J. Lakner, N. Woo, M. M. Olmstead, J. Am. Chem. Soc. 1992, 114, 1800.
[18] E. Juaristi, in −e-EROS Encyclopedia of Reagents for Organic Synthesis×, Eds. L. A. Paquette, J. H. Rigby,
W. R. Roush, P. Wipf, J. Wiley & Sons, N.Y., 2002 (see also at http://www3.interscience.wiley.com/cgi-bin/
mrwhome/104554785/HOME).
[19] M. A. Iglesias-Arteaga, E. Castellanos, E. Juaristi Tetrahedron: Asymmetry 2003, 14, 577.
¬
[20] Y. RamÌrez-Quiros, M. Balderas, J. Escalante, D. Quintana, I. Gallardo, D. Madrigal, E. Molins, E. Juaristi,
J. Org. Chem. 1999, 64, 8668.
[21] E. Juaristi, J. L. Anzorena, A. Boog, D. Madrigal, D. Seebach, E. V. GarcÌa-Baez, O. GarcÌa-Barradas, B.
Gordillo, A. Kramer, I. Steiner, S. Z¸rcher, J. Org. Chem. 1995, 60, 6408.
[22] E. Erdik, M. Ay, Chem. Rev. 1989, 89, 1947.
¬
[23] D. Seebach, B. Lamatsch, R. Amstutz, A. K. Beck, M. Dobler, M. Egli, R. Fitzi, M. Gautschi, B. Herradon,
P. C. Hidber, J. J. Irwin, R. Locher, M. Maestro, T. Maetzke, A. Mourinƒo, E. Pfammatter, D. A. Plattner, C.
Schickli, W. B. Schweizer, P. Seller, G. Stucky, W. Petter, J. Escalante, E. Juaristi, D. Quintana, C.
Miravitlles, E. Molins, Helv. Chim. Acta 1992, 75, 913.
[24] A. J. Mota, E. Castellanos, E. Juaristi, Org. Prep. Proc. Int. 2003, 35, 414.
ReceivedNovember 3, 2003