Formation of Aziridine-2-amides through 5-Halo-6-methylperhydropyrimidin-4-ones. A Route to Enantiopure L- and D-Threonine and allo-Threonine

Full text of DOI:10.1021/jo971388s

3458
J . Org. Chem. 1998, 63, 3458-3462
Ta ble 1. Dia ster eom er ic P r od u ct Ra tios a n d Ch em ica l
F or m a tion of Azir id in e-2-a m id es th r ou gh
Yield for th e Ha logen a tion Rea ction s of
6-Meth ylp er h yd r op yr im id in -4-on e 1
5-Ha lo-6-m eth ylp er h yd r op yr im id in -4-on es.
A Rou te to En a n tiop u r e L- a n d D-Th r eon in e
a n d a llo-Th r eon in e
diastereo-
temp
(°C)
yield meric ratio
(%)
entry
X
reagent (equiv)
time
2:3a
Giuliana Cardillo,* Luca Gentilucci,
Alessandra Tolomelli, and Claudia Tomasini*
1
2
3
4
5
6
7
Cl TsCl (1.5)
Cl TsCl (1.5)
Cl TsCl (1.5)
-30
-30
-30 to rt 16 h
15 min 74
10:90
16:84
78:22
38:62
41:59
61:39
85:15
1 h
85
87
Dipartimento di Chimica “G. Ciamician” and C.S.F.M.,
Universita` di Bologna, Via Selmi, 2-40126 Bologna, Italy
Br PhSO2Br (1.5) -30
15 min 98
Br PhSO2Br (1.5) -30
1 h
98
98
Br PhSO2Br (1.5) -30 to rt 16 h
Received J uly 28, 1997
I
I2 (3)
-30
15 min 85
The synthesis of stereodefined aziridine-2-carboxylates
is an area of increasing interest in organic chemistry.1
These compounds are useful starting materials for the
preparation of R- and â-amino acids and amino alcohols;
indeed, ring-opening performed with a variety of nucleo-
philes is one of the most interesting features of this class
of compounds. We will describe the synthesis of both cis
and trans chiral aziridine-2-amides starting from (1′S,6R)-
and (1′S,6S)-1-benzyloxycarbonyl-3-(1′-phenylethyl)-6-
methylperhydropyrimidin-4-ones. These compounds are
useful intermediates to R-substituted â-amino acids3 and
have easily been prepared starting from (()-3-aminobu-
tanoic acid, following a known procedure.2 We tested the
reactivity of lithium enolates of both diastereoisomers
with p-toluenesulfonyl chloride and benzenesulfonyl bro-
mide and iodine as electrophiles.4
Indeed (1′S,6R)-6-methylperhydropyrimidin-4-one 1
was treated with LiHMDS in dry THF at 0 °C for 1 h.
The enolate was cooled at -30 °C, and the halogenating
agent was then added dropwise.5 After the scheduled
time, the reaction was quenched with water and worked
up following the usual procedure. The results obtained
are reported in Table 1.
a
The diastereomeric ratios were determined by means of HPLC
analysis.
Table 1 shows some unexpected results, deserving a
few considerations. The chlorination reaction is far more
selective than the bromination and, in both cases, the
5,6-cis adducts 3a and 3b are preferentially obtained
after a short reaction time (entries 1 and 4). After longer
reaction times, there is a reversal of diastereoselectivity
with both reagents. Thus we can infer that the 5,6-cis
adducts 3a and 3b are the kinetically preferred products,
while the 5,6-trans adducts 2a and 2b are the thermo-
dynamically preferred compounds. This assumption was
confirmed when we treated pure 3a or a 1:1 mixture of
2a and 3a with gaseous ammonia in ethanol at room
temperature: in both cases an equilibrium was reached,
and a mixture containing 2a and 3a in 3:1 ratio was
obtained as established by NMR and HPLC analysis.
By contrast, when the lithium enolate was treated with
iodine, we observed the direct preferential formation of
the 5,6-trans adduct 2c (entry 7).6
Then trans- and cis-5-halo-6-methylperhydropyrimi-
din-4-ones 2 and 3 have been transformed under mild
acid conditions into the corresponding 2-carboxyaziri-
dines, synthetic precursors of enantiomerically pure
threonines or allo-threonines.
allo-Threonines represent one of the most common
families of nonproteinogenic amino acids, and they are
the building blocks of many bioactive peptides and
glycopeptides associated with biological recognition and
selectivity.7 Furthermore, it has been shown that sub-
stitution of threonines by allo-threonines in peptide
sequences can make the molecules more resistant to
proteolysis under physiological conditions.8
The hydrolysis of 2a was performed with 11 M HCl in
ethanol and was stopped after 2 h to open the heterocycle
without destroying the carbon-halogen bond. As the
highly reactive erythro-halo derivative 4 cannot be iso-
lated, the aziridine 5 was directly recovered pure in 65%
yield after concentration, addition of 5 M NaOH, and
extraction with ethyl acetate. The coupling constant of
(1) (a) Fanta, P. E. Heterocyclic Compounds with Three and Four-
membered Rings; Weissemberg, A., Ed.; Wiley-Interscience: New York,
1964; Part 1, p 524. (b) Tanner, D. Angew. Chem., Int. Ed. Engl. 1994,
33, 599.
(2) (a) Amoroso, R.; Cardillo, G.; Tomasini, C. Tetrahedron Lett.
1992, 33, 2725. (b) Braschi, I.; Cardillo, G.; Tomasini, C. Tetrahedron
1994, 50, 2955. (c) Braschi, I.; Cardillo, G.; Tomasini, C.; Venezia, R.
J . Org. Chem. 1994, 59, 7292. (d) Amoroso, R.; Cardillo, G.; Mobbili,
G.; Tomasini, C. Tetrahedron: Asymmetry 1993, 4, 2241. (e) Cardillo,
G.; Tolomelli, A.; Tomasini, C. Tetrahedron 1995, 51, 11831.
(3) For recent reviews on â-amino acids, see: (a) Cole, D. C.
Tetrahedron 1994, 50, 9517. (b) J uaristi, E.; Quintana, D.; Escalante,
J . Aldrichimica Acta 1994, 27, 3. (c) Cardillo, G.; Tomasini, C. Chem.
Soc. Rev. 1996, 25, 117. (d) Enantioselective Synthesis of â-Amino Acids;
J uaristi, E., Ed.; VCH Publishers: New York, 1996.
(4) (a) Muth, F. Methoden zur Herstellung und Umwandlung von
aromatischen Sulfinsauren. In Methoden der organischen Chemie
(Houben-Weyl-Muller); Thieme Publisher: Stuttgart, 1955; 4. Aufl.,
Board 9, S. 310.; (b) Stotter, P. L.; Hill, K. A. J . Org. Chem. 1973, 38,
2576. (c) Hirsch, E.; Hunig, S.; Reiâig, H.-U. Chem. Ber. 1982, 115,
399. (d) Hirsch, E.; Hunig, S.; Reiâig, H.-U. Chem. Ber. 1982, 115, 3687.
(e) Kuhlein, K.; J ensen, H. Liebigs Ann. Chem. 1974, 369.
(5) If the reaction is conducted at -78 °C, similar diastereoselec-
tivities and lower yield are obtained and a larger amount of starting
material is recovered.
(6) For compounds 2 and 3 the comparison of the H5 and H6 coupling
constants were not diagnostic and disagreed with NOEDIFF experi-
ments. The absolute configuration at C5 was attributed by transforming
the 5-haloperhydropyrimidin-4-one into 2-carboxyaziridines; so we
ascertained that 5,6-trans derivatives always have smaller coupling
constants than 5,6-cis derivatives (2.0-4.4 Hz versus 5.3-5.9 Hz).
(7) (a) Okonya, J . F.; Kolasa, T.; Miller, M. J . J . Org. Chem. 1995,
60, 1932. (b) Rossner, E.; Zeeck, A.; Konig, W. A. Angew. Chem., Int.
Ed. Engl. 1990, 29, 64. (c) Gurjar, M. K.; Saha, U. K. Tetrahedron
Lett. 1991, 32, 6621.
(8) Allen, M. C.; Wade, R. Int. J . Pept. Protein Res. 1988, 32, 89.
S0022-3263(97)01388-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 04/28/1998

Notes
J . Org. Chem., Vol. 63, No. 10, 1998 3459
Sch em e 1a
Sch em e 2a
a
Reagent and conditions: (i) 11 M HCl/EtOH 1:1, ∆, 2 h; (ii) 5
a
Reagent and conditions: (i) 11 M HCl/EtOH 1:1, ∆, 2 h; (ii) 5
M NaOH; (iii) Ac2O (2.5 equiv), Py (2 equiv), DMAP (0.2 equiv),
CH2Cl2, 1 h; (iv) Ac2O (10 equiv), Py, ∆, 1 h; (v) 11 M HCl/MeOH
10:1; (vi) cation exchange resin, 0.5 M NH4OH.
M NaOH; (iii) NH3, DMSO, 16 h; (iv) Ac2O (2.5 equiv), Py (2 equiv),
DMAP (0.2 equiv), CH2Cl2, 1 h; (v) Ac2O (10 equiv), Py, ∆, 1 h;
(vi) 11 M HCl/MeOH 10:1; (vii) cation exchange resin, 0.5 M
NH4OH.
Ta ble 2. Dia ster eom er ic P r od u ct Ra tios a n d Ch em ica l
Yield for th e Ha logen a tion Rea ction of
the aziridine ring hydrogens (J H2,H3 ) 2.5 Hz) accounts
for a trans relationship of the substituent,9a thus making
it possible to attribute the relative trans configuration
to the perhydropyrimidin-4-one 2a .
(1′S,6S)-6-Meth ylp er h yd r op yr im id in -4-on e 14
diastereo-
temp
(°C)
yield meric ratio
(%)
15:16a
It is reported that N-acyloylaziridines are easily opened
by a range of nucleophiles.9b-d Accordingly, to synthesize
L-allo-threonine 8, aziridine 5 was transformed into the
corresponding N-acetyl derivative 6. Then, on refluxing
6 with acetic anhydride in pyridine for 1 h, the erythro-
N,O-diacetyl derivative 7 was isolated in 85% yield and,
after acid hydrolysis of product 7 and purification on
cation-exchange resin, (2S,3S)-L-allo-threonine 8 was
obtained pure in 75% yield (Scheme 1). The specific
rotation and the NMR spectrum of 8 are in agreement
with the data reported in the literature.10
Following the same route, (1′S,5S,6R)-3a was hydro-
lyzed into the corresponding threo-R-chloro-â-amino amide
9 in 70% yield (Scheme 2). The aziridine 10 was obtained
in 95% yield by bubbling gaseous NH3 in a DMSO
solution of 9. The coupling constant of the aziridine
hydrogens (J H2,H3 ) 6.9 Hz) accounts for a cis relationship
of the substituents,9a thus confirming the stereochemical
assignment of the pyrimidin-4-one 3a . The aziridine 10
was then subjected to the reactions of N-acylation, ring
opening, acid hydrolysis, and purification as described
above. This made it possible to obtain pure (2R,3S)-D-
threonine10a 13 in good yield.
entry
X
reagent (equiv) time
1
2
3
4
5
6
7
Cl TsCl (1.5)
Cl TsCl (1.5)
Cl TsCl (1.5)
Br PhSO2Br (1.5) 15 min -30
Br PhSO2Br (1.5) 1 h
Br PhSO2Br (1.5) 16 h
15 min -30
82
85
28:72
55:45
76:24
25:75
34:66
84:16
82:18
1 h
-30
16 h
-30 to rt 86
82
98
-30
-30 to rt 98
15 min -30 93
I
I2 (3)
a
The diastereomeric ratios were determined by means of HPLC
analysis.
affording the 5,6-trans adduct (1′S,5S,6S)-5-halo-6-meth-
ylperhydropyrimidin-4-one 15 and the 5,6-cis adduct
(1′S,5R,6S)-5-halo-6-methylperhydropyrimidin-4-one 16.
The results obtained are reported in Table 2.
As observed in the halogenation of 1, both bromination
and chlorination reactions proceed with an excess of the
kinetically preferred 5,6-cis products 16a and 16b (en-
tries 1 and 4). However, in this case, diastereoselectivity
is overall less satisfactory. Furthermore, an excess of the
thermodynamically preferred 5,6-trans compounds 15a
and 15b was obtained in both cases after prolonged
reaction times.Treatment of a 25:75 mixture of 15a and
16a with ammonia in dry ethanol furnishes an increase
of the trans adduct 15a (63:37 trans/cis ratio). Moreover,
iodination (entry 7) affords an excess of trans adduct
15c.6
The halogenation reaction was also tested for (1′S,6S)-
6-methylperhydropyrimidin-4-one 14. The heterocycle
reacted under the same conditions held for compound 1,
(9) (a) Nagel, D. L.; Woller, P. B.; Cromwell, N. H. J . Org. Chem.
1971, 36, 3911. (b) Legters, J .; Thijs, L.; Zwanenburg, B. Recl. Trav.
Chim. Pays-Bas 1992, 111, 16. (c) Legters, J .; Willems, J . G. H.; Thijs,
L.; Zwanenburg, B. Recl. Trav. Chim. Pays-Bas, 1992, 111, 59. (d)
Dauban, P.; Dubois, L.; Tran Huu Dau, M. E.; Dodd, R. H. J . Org.
Chem. 1995, 60, 2035 and references therein.
(10) (a) Beilstein 4 (3), 1625-9. (b) Genet, J . P.; J uge, S.; Mallart, S.
Tetrahedron Lett. 1988, 51, 6765. (c) Kuzuhara, H.; Watanabe, N.;
Ando, M. J . Chem. Soc., Chem. Commun. 1987, 95. (d) Pons, D.;
Savignac, M.; Genet, J . P. Tetrahedron Lett. 1990, 35, 5023.

3460 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
Sch em e 3a
1H, J ) 12.5 Hz), 4.38 (m, 1H), 5.02 (d, 1H, J ) 12.5 Hz), 5.15
(s, 2H), 5.91 (q, 1H, J ) 7.0 Hz), 7.31 (m, 10H); 13C NMR (CDCl3,
50 °C) δ 15.6, 18.5, 50.9, 51.6, 54.0, 58.0, 67.7, 127.2, 127.8, 128.0,
128.2, 128.5, 128.7, 135.9, 138.8, 153.8, 163.8; [R]D -16.2 (c 0.3,
CHCl3); HRMS calcd for (M+) C21H23N2O3Cl 386.1397206, found
386.1394773.
(1′S,5S,6R)-1-Ben zyloxyca r b on yl-5-ch lor o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (3a ): IR (film)
1701, 1690 cm-1; 1H NMR (CDCl3, 50 °C) δ 1.31 (d, 3H, J ) 6.7
Hz), 1.53 (d, 3H, J ) 7.1 Hz), 4.37 (d, 1H, J ) 12.9 Hz), 4.50 (m,
1H), 4.57 (d, 1H, J ) 5.8 Hz), 4.97 (m, 1H), 5.17 (AB, 2H, J )
11.9 Hz), 5.85 (q, 1H, J ) 7.1 Hz), 7.31 (m, 10H); 13C NMR
(CDCl3, 50 °C) δ 13.8, 15.7, 50.4, 50.9, 51.4, 58.3, 67.7, 126.8,
127.6, 128.1, 128.3, 128.4, 135.6, 138.7, 153.6, 164.4; [R]D -78.3
(c 0.3, CHCl3); HRMS calcd for (M+) C21H23N2O3Cl 386.1397206,
found 386.1393392.
(1′S,5R,6R)-1-Ben zyloxyca r b on yl-5-b r om o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (2b): IR (film)
1710, 1676 cm-1; 1H NMR (CDCl3, 50 °C), δ 1.25 (d, 3H, J ) 6.9
Hz), 1.55 (d, 3H, J ) 7.1 Hz), 4.29 (d, 1H, J ) 2.7 Hz), 4.40 (d,
1H, J ) 11.3 Hz), 4.50 (dq, 1H, J ) 2.7 Hz, 6.9 Hz), 5.02 (d, 1H,
J ) 11.3 Hz), 5.14 (s, 2H), 5.95 (q, 1H, J ) 7.1 Hz), 7.34 (m,
10H); 13C NMR (CDCl3, 50 °C) δ 15.3, 19.2, 46.6, 51.0, 52.1, 53.9,
67.8, 127.3, 127.9, 128.1, 128.3, 128.6, 128.8, 136.0, 138.9, 153.9,
163.9; [R]D +11.6 (c 1.1, CHCl3). Anal. Calcd for C21H23N2O3-
Br: C, 58.48; H, 5.37; N 6.49. Found: C, 58.45; H, 5.36; N 6.52.
(1′S,5S,6R)-1-Ben zyloxyca r b on yl-5-b r om o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (3b): IR (film)
1710, 1675 cm-1; 1H NMR (CDCl3, 50 °C), δ 1.36 (d, 3H, J ) 6.3
Hz), 1.51 (d, 3H, J ) 6.6 Hz), 4.37 (m, 1H), 4.39 (d, 1H, J ) 13.4
Hz), 4.65 (d, 1H, J ) 5.6 Hz), 4.97 (d, 1H, J ) 13.4 Hz), 5.18
(AB, 2H, J ) 12.1 Hz), 5.81 (q, 1H, J ) 6.6 Hz); 7.30 (m, 10H);
13C NMR (CDCl3, 50 °C) δ 16.0, 19.2, 50.1, 50.2, 50.4, 51.5, 68.1,
127.1, 127.8, 128.1, 128.2, 128.5 128.7, 135.7, 138.9, 154.0, 165.0;
[R]D -67.8 (c 0.8, CHCl3). Anal. Calcd for C21H23N2O3Br: C,
58.48; H, 5.37; N 6.49. Found: C, 58.49; H, 5.39; N 6.45.
a
Reagents and conditions: (i) 11 M HCl/EtOH 1:1, ∆, 2 h; (ii)
5 M NaOH.
To confirm the absolute configuration assigned to C5
of compounds 15 and 16, 15c was transformed into the
corresponding aziridine 18 following the procedure previ-
ously described (Scheme 3).
The 2-iodo derivative 17 was not isolated and the
aziridine 18 was directly recovered pure in 65% yield,
after acid hydrolysis with 11 M HCl and ethanol for 2 h
at reflux, elimination of the ethanol under reduced
pressure, treatment with 5 M NaOH, and extraction with
ethyl acetate. The coupling constant of the aziridine ring
hydrogens (J H2,H3 ) 2.1 Hz) accounts for a trans relation-
ship of the substituents, thus confirming the relative
trans configuration assigned to the perhydropyrimidin-
4-one 15c. Moreover, the aziridine 18 can easily be
transformed into D-allo-threonine by acetylation, opening
of the aziridine ring, and acid hydrolysis of the adduct,
as previously described for aziridine 5.
In conclusion, trans- or cis-2-carboxyaziridines can be
obtained in good yield by acid hydrolysis of the 5-halo
perhydropyrimidin-4-ones and are selectively trans-
formed into enantiomerically pure threonines or allo-
threonines, depending on the stereochemistry of the
starting 5-halo-6-methylperhydropyrimidin-4-one.
(1′S,5R,6R)-1-Ben zyloxyca r bon yl-5-iod o-6-m eth yl-3-(1′-
p h en yleth yl)p er h yd r op yr im id in -4-on e (2c): IR (film) 1697,
1
1658 cm-1; H NMR (CDCl3, 50 °C) δ 1.22 (d, 3H, J ) 6.7 Hz),
1.52 (d, 3H, J ) 7.0 Hz), 4.43 (d, 1H, J ) 11.7 Hz), 4.46 (m, 1H),
4.49 (d, 1H, J ) 1.8 Hz), 4.97 (d, 1H, J ) 11.7 Hz), 5.10 (m, 2H),
5.95 (q, 1H, J ) 7.0 Hz), 7.30 (m, 10H); 13C NMR (CDCl3, 50 °C)
δ 14.6, 19.7, 22.6, 50.8, 52.3, 54.7, 67.6, 127.2, 127.8 128.0, 128.2,
128.5, 128.7, 136.0, 138.8, 153.7, 165.1; [R]D +35.9 (c 2.2, CHCl3).
Anal. Calcd for C21H23N2O3I: C, 52.73; H, 4.85; N 5.86. Found:
C, 52.70; H, 4.85; N 5.89.
Exp er im en ta l Section
Gen er a l. 1H NMR spectra were recorded at 300 or 200 MHz.
Chemical shifts are reported in ppm relative to the solvent peak
of CHCl3, defined to be δ 7.27 ppm. Infrared spectra were
recorded with an FT-IR spectrometer. Melting points were
determined in open capillaries and are uncorrected. Flash
chromatography was performed with Merck silica gel 60 (230-
400 mesh). THF was distilled from sodium benzophenone ketyl.
Dichloromethane was distilled from P2O5. p-Toluenesulfonyl
chloride was dissolved in methylene chloride and washed with
water. Benzenesufonyl bromide was prepared according to ref
11.
Gen er a l P r oced u r e for th e Ha logen a tion of P er h yd r o-
p yr im id in -4-on es 1 a n d 14. LiHMDS (1 M solution in THF,
1 mL) was added in one portion under argon at 0 °C to a stirred
solution of perhydropyrimidin-4-one 1 or 14 (1 mmol, 0.35 g) in
dry THF (20 mL). The formation of the enolate was complete
in 30 min and the solution was then cooled to -30 °C and the
halogenating agent (1.5 mmol for chlorination and bromination,
3 mmol for iodination) in dry THF (10 mL) was added dropwise.
After the scheduled time, the reaction was quenched with water,
and the organic solvent was removed under reduced pressure
and replaced with ethyl acetate, which was washed twice with
water. The organic layer was dried over Na2SO4, concentrated,
and chromatographed on silica gel (cyclohexane/ethyl acetate 9:1
as eluant). All the products were obtained as oils.
(1′S,5S,6R)-1-Ben zyloxyca r bon yl-5-iod o-6-m et h yl-3-(1′-
p h en yleth yl)p er h yd r op yr im id in -4-on e (3c): IR (film) 1695,
1
1672 cm-1; H NMR (CDCl3, 50 °C) δ 1.34 (d, 3H, J ) 6.2 Hz),
1.52 (d, 3H, J ) 6.9 Hz), 3.84 (false p, 1H, J ) 6.3 Hz), 4.33 (d,
1H, J ) 13.6 Hz), 4.87 (d, 1H, J ) 5.9 Hz), 4.99 (d, 1H, J ) 13.6
Hz), 5.17 (AB, 2H, J ) 12.3 Hz), 5.80 (q, 1H, J ) 6.9 Hz), 7.30
(m, 10H); 13C NMR (CDCl3, 50 °C) δ 14.5, 16.2, 23.9, 50.1, 50.8,
51.8, 68.1, 127.3, 127.8, 128.0, 128.2, 128.5, 128.7, 135.9, 139.1,
154.8, 166.1; [R]D -78.9 (c 0.2, CHCl3). Anal. Calcd for
C21H23N2O3I: C, 52.73; H, 4.85; N 5.86. Found: C, 52.75; H,
4.81; N 5.89.
(1′S,5S,6S)-1-Ben zyloxyca r bon yl-5-ch lor o-6-m eth yl-3-(1′-
p h en yleth yl)p er h yd r op yr im id in -4-on e (15a ): IR (film) 1709,
1
1681 cm-1; H NMR (CDCl3, 50 °C), δ 1.35 (d, 3H, J ) 6.7 Hz),
1.58 (d, 3H, J ) 7.0 Hz), 4.24 (d, 1H, J ) 3.1 Hz), 4.46 (dq, 1H,
J ) 3.1 Hz, 6.7 Hz), 4.67 (AB, 2H, J ) 12.0 Hz), 5.10 (m, 2H),
5.93 (q, 1H, J ) 7.0 Hz), 7.32 (m, 10H); 13C NMR (CDCl3, 50 °C)
δ 14.2, 15.6, 50.8, 52.2, 53.9, 57.5, 67.8, 127.1, 127.8, 128.0, 128.3,
128.6, 128.8, 136.0, 138.7, 154.1, 163.9; [R]D -76.4 (c 0.5, CHCl3);
HRMS calcd for (M+) C21H23N2O3Cl 386.1397206, found
386.1391934.
(1′S,5R,6S)-1-Ben zyloxyca r b on yl-5-ch lor o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (16a ): IR (film)
1720, 1690 cm-1; 1H NMR (CDCl3, 50 °C), δ 1.38 (d, 3H, J ) 6.3
Hz), 1.56 (d, 3H, J ) 7.2 Hz), 4.51 (m, 1H), 4.60 (d, 1H, J ) 5.4
Hz), 4.76 (AB, 2H, J ) 13.3 Hz), 5.08 (m, 2H), 5.90 (q, 1H, J )
7.2 Hz), 7.32 (m, 10H); 13C NMR (CDCl3, 50 °C) d 15.4, 15.9,
51.3, 52.0, 52.1, 58.5, 67.9, 127.1, 127.9, 128.0, 128.3, 128.6,
128.7, 135.8, 139.2, 153.8, 164.7; [R]D -31.1 (c 0.4, CHCl3); HRMS
calcd for (M+) C21H23N2O3Cl 386.1397206, found 386.1399492.
(1′S,5R,6R)-1-Ben zyloxyca r b on yl-5-ch lor o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (2a ): IR (film)
1710, 1683 cm-1; 1H NMR (CDCl3, 50 °C) δ 1.28 (d, 3H, J ) 6.6
Hz), 1.55 (d, 3H, J ) 7.0 Hz), 4.22 (d, 1H, J ) 4.4 Hz), 4.31 (d,
(11) Cristol, S. J .; Harrington, J . K.; Singer, M. S. J . Am. Chem.
Soc. 1966, 88, 1529.

Notes
(1′S,5S,6S)-1-Ben zyloxyca r bon yl-5-br om o-6-m eth yl-3-(1′-
J . Org. Chem., Vol. 63, No. 10, 1998 3461
δ 18.7, 21.9, 34.2, 38.1, 48.7, 126.2, 127.3, 142.8, 169.6; [R]D
-65.3 (c 0.3, CHCl3). Anal. Calcd for C12H16N2O: C, 70.56; H,
7.89; N 13.71. Found: C, 70.54; H, 7.92; N 13.70.
p h en yleth yl)p er h yd r op yr im id in -4-on e (15b): IR (film) 1704,
1
1644 cm-1; H NMR (CDCl3, 50 °C), δ 1.36 (d, 3H, J ) 6.8 Hz),
1.59 (d, 3H, J ) 7.1 Hz), 4.28 (d, 1H, J ) 2.4 Hz), 4.55 (dq, 1H,
J ) 2.4 Hz, J ) 6.8 Hz), 4.65 (AB, 2H, J ) 11.8 Hz), 5.11 (s,
2H), 5.95 (q, 1H, J ) 7.1 Hz), 7.32 (m, 10H); 13C NMR (CDCl3,
50 °C) δ 15.5, 19.2, 45.9, 50.5, 52.4, 53.7, 67.7, 127.0, 127.7, 127.9,
128.2, 128.5, 128.7, 135.9, 138.5, 153.8, 163.9; [R]D -104.6 (c 0.1,
CHCl3). Anal. Calcd for C21H23N2O3Br: C, 58.48; H, 5.37; N
6.49. Found: C, 58.48; H, 5.40; N 6.47.
(1′S,2R,3R)-3-Met h yl-2-(1′-p h en ylet h yl)a m id oa zir id in e
(10). Gaseous NH3 was bubbled through a solution of chloro
derivative 9 (1 mmol, 0.24 g) in dimethyl sulfoxide (10 mL), for
1 h. The reaction mixture was allowed to stir overnight and
then was extracted twice with ethyl acetate and water. The
organic layer was dried over Na2SO4 and concentrated under
reduced pressure to give compound 10 in 95% yield, after flash
chromatography (cyclohexane/ethyl acetate 2:8, as eluant).
(1′S,5R,6S)-1-Ben zyloxyca r b on yl-5-b r om o-6-m et h yl-3-
(1′-p h en yleth yl)p er h yd r op yr im id in -4-on e (16b): IR (film)
1712, 1675 cm-1; 1H NMR (CDCl3, 50 °C), δ 1.41 (d, 3H, J ) 6.9
Hz), 1.52 (d, 3H, J ) 7.3 Hz), 4.38 (false p, 1H, J ) 5.9 Hz), 4.67
(d, 1H, J ) 5.3 Hz), 4.74 (d, 1H, J ) 12.6 Hz), 4.89 (d, 1H, J )
12.6 Hz), 5.07 (m, 2H), 5.86 (q, 1H, J ) 7.3 Hz), 7.32 (m, 10H);
13C NMR (CDCl3, 50 °C) δ 15.5, 19.3, 46.0, 50.6, 52.4, 53.8, 67.7,
127.1, 127.8, 128.0, 128.2, 128.6, 128.8, 136.0, 138.6, 153.9, 163.9;
[R]D -108.5 (c 0.1, CHCl3). Anal. Calcd for C21H23N2O3Br: C,
58.48; H, 5.37; N 6.49. Found: C, 58.50; H, 5.34; N 6.44.
10: IR (film) 3378, 1651 cm-1 1H NMR (CDCl3) δ 1.04 (d,
;
3H, J ) 5.7 Hz), 1.51 (d, 3H, J ) 6.9 Hz), 1.5 (bs, 1H), 2.35 (dq,
1H, J ) 5.7 Hz, 6.9 Hz), 2.72 (d, 1H, J ) 6.9 Hz), 5.16 (dq, 1H,
J ) 6.9 Hz, 8.5 Hz), 6.8 (bs, 1H), 7.23 (m, 5H); 13C NMR (CDCl3)
δ 13.5, 21.3, 323, 36.4, 48.3, 126.2, 127.3, 128.6, 143.0 168.1;
[R]D -10.3 (c 0.3, CHCl3). Anal. Calcd for C12H16N2O: C, 70.56;
H, 7.89; N 13.71. Found: C, 70.51; H, 7.87; N 13.74.
Gen er a l P r oced u r e for th e Acetyla tion of Azir id in es 5
a n d 10. To a stirred solution of aziridine 5 and 10 (1 mmol, 0.2
g) in CH2Cl2 (10 mL) at 0 °C were added acetic anhydride (2.5
mmol, 0.24 mL), pyridine (2 mmol, 0.16 mL) and (dimethyl-
amino)pyridine (0.2 mmol, 0.02 g). The reaction mixture was
stirred for 3 h and then washed twice with water. The organic
layer was dried over Na2SO4 and concentrated under reduced
pressure. Compounds 6 and 11 were obtained pure, after flash
chromatography on silica gel (ethyl acetate as eluant).
(1′S,5S,6S)-1-Ben zyloxyca r b on yl-5-iod o-6-m et h yl-3-(1′-
p h en yleth yl)p er h yd r op yr im id in -4-on e (15c): IR (film) 1690,
1
1668 cm-1; H NMR (CDCl3, 50 °C) δ 1.33 (d, 3H, J ) 6.8 Hz),
1.59 (d, 3H, J ) 7.2 Hz), 4.48 (d, 1H, J ) 2.0 Hz), 4.55 (dq, 1H,
J ) 2.0 Hz, 6.8 Hz), 4.65 (AB, 2H, J ) 11.8 Hz), 5.14 (s, 2H),
5.97 (q, 1H, J ) 7.2 Hz), 7.32 (m, 10H); 13C NMR (CDCl3, 50 °C)
δ 14.1, 15.4, 21.6, 50.1, 52.3, 54.5, 67.6, 127.1, 127.7, 127.9, 128.2,
128.5, 128.8, 135.7, 138.2, 154.5, 164.1; [R]D -99.7 (c 1.5, CHCl3).
Anal. Calcd for C21H23N2O3I: C, 52.73; H, 4.85; N 5.86. Found:
C, 52.73; H, 4.81; N 5.89.
(1′S,2S,3R)-N-Acetyl-3-m eth yl-2-(1′-p h en yleth yl)a m id o-
a zir id in e (6): 85% yield; IR (film) 1701, 1634 cm-1 1H NMR
;
(CDCl3) δ 1.38 (d, 3H, J ) 5.2 Hz), 1.49 (d, 3H, J ) 6.9 Hz), 2.14
(s, 3H), 2.80 (m, 2H), 5.11 (dq, 1H, J ) 6.9 Hz, 7.0 Hz), 6.34 (d,
1H, J ) 7.0 Hz), 7.30 (m, 5H); 13C NMR (CDCl3) δ 16.1, 21.7,
24.3, 40.0, 43.0, 49.0, 126.2, 127.5, 128.7, 14.6, 166.1, 180.0; [R]D
-90.0 (c 0.5, CHCl3). Anal. Calcd for C14H18N2O2: C, 68.25; H,
7.37; N 11.38. Found: C, 68.23; H, 7.41; N 11.38.
(1′S,5R,6S)-1-Ben zyloxyca r b on yl-5-iod o-6-m et h yl-3-(1′-
p h en yleth yl)p er h yd r op yr im id in -4-on e (16c): IR (film) 1696,
1
1670 cm-1; H NMR (CDCl3, 50 °C) δ 1.39 (d, 3H, J ) 6.2 Hz),
1.50 (d, 3H, J ) 7.2 Hz), 3.92 (false p, 1H, J ) 5.9 Hz), 4.71 (d,
1H, J ) 12.7 Hz), 4.90 (d, 1H, J ) 5.5 Hz), 4.93 (d, 1H, J ) 12.7
Hz), 5.05 (AB, 2H, J ) 14.6 Hz), 5.85 (q, 1H, J ) 7.2 Hz), 7.31
(m, 10H); 13C NMR (CDCl3, 50 °C) δ 14.1, 15.2, 22.7, 22.9, 50.1,
51.8, 67.6, 127.1, 127.3, 127.9, 128.2, 128.5, 128.6, 135.6, 139.2,
153.9, 166.0; [R]D +10.6 (c 0.3, CHCl3). Anal. Calcd for
C21H23N2O3I: C, 52.73; H, 4.85; N 5.86. Found: C, 52.70; H,
4.85; N 5.83.
(1′S,2R,3R)-N-Acetyl-3-m eth yl-2-(1′-p h en yleth yl)a m id o-
1
a zir id in e (11): 85% yield; IR (film) 1716, 1656 cm-1; H NMR
(CDCl3) δ 1.15 (d, 3H, J ) 5.7 Hz), 1.54 (d, 3H, J ) 7.0 Hz), 2.17
(s, 3H), 2.74 (dq, 1H, J ) 5.7 Hz, 3.7 Hz), 3.16 (d, 1H, J ) 3.7
Hz), 5.17 (dq, 1H, J ) 7.0 Hz, 8.7 Hz), 6.45 (d, 1H, J ) 8.7 Hz),
7.28 (m, 5H),13C NMR (CDCl3) δ 1.2, 21.4, 2.2, 38.5, 46.0, 48.6,
126.2, 127.6, 128.7, 141.0, 145.8, 166.7, 17.8; [R]D +26.6 (c 0.2,
CHCl3). Anal. Calcd for C14H18N2O2: C, 68.25; H, 7.37; N 11.38.
Found: C, 68.24; H, 7.34; N 11.40.
P a r tia l Hyd r olysis of 1-Ben zyloxyca r bon yl-5-h a lo-6-
m eth yl-3-(1′-ph en yleth yl)per h ydr opyr im idin -4-on es 2a, 3a,
a n d 15c. A solution of 5-halo-6-methylperhydropyrimidinone
(1 mmol) in 11 M HCl (3 mL) and ethanol (3 mL) was refluxed
for 2 h. The mixture was then concentrated under reduced
pressure to remove ethanol and washed twice with ethyl acetate.
Then a 2 M solution of NaOH was added to the aqueous layer
until pH 10 was reached, and the mixture was extracted with
ethyl acetate. The organic layer, dried over Na2SO4 and
concentrated, gave compound 5, 9, or 18 as an oil. Compounds
5 and 18 were purified by flash chromatography on silica gel
(cyclohexane/ethyl acetate 2:8 as eluant).
Gen er a l P r oced u r e for th e Syn th esis of Dia ceta tes 7
a n d 12. To a stirred solution of compound 6 or 11 (0.4 mmol,
0.1 g) in pyridine (5 mL) was added acetic anhydride (4 mmol,
0.38 mL) in one portion. The reaction mixture was refluxed for
1 h and washed twice with water and the organic layer
concentrated and dried over Na2SO4. The solvent was removed
under reduced pressure and compounds 7 and 12 were purified
by flash chromatography on silica gel (ethyl acetate as eluant).
(1′S,2S,3S)-Dia ceta te (7): 85% yield; mp 159-161 °C; IR
(Nujol) 3284, 1733, 1648, 1594 cm-1 1H NMR (CDCl3) δ 1.15
;
(1′S,2S,3R)-3-Meth yl-2-(1′-ph en yleth yl)am idoazir idin e (5):
65% yield; IR (film) 3278, 1670 cm-1 1H NMR (CDCl3) δ 1.25
;
(d, 3H, J ) 6.4 Hz), 1.50 (d, 3H, J ) 7.0 Hz), 1.86 (s, 3H), 2.05
(s, 3H), 4.77 (dd, 1H, J ) 5.5 Hz, 8.3 Hz), 4.94 (dq, 1H, J ) 5.5
Hz, 6.4 Hz), 5.09 (dq, 1H, J ) 7.0 Hz, 11 Hz), 6.53 (d, 1H, J )
8.3 Hz), 6.61 (d, 1H, J ) 11 Hz), 7.30 (m, 5H); 13C NMR (CDCl3)
δ 15.4, 20.9, 21.7, 23.2, 49.2, 55.3, 71.1, 126.1, 127.5, 128.7, 142.8,
167.7, 170.2, 170.8; [R]D -30.1 (c 0.2, CHCl3). Anal. Calcd for
C16H22N2O4: C, 62.71; H, 7.24; N, 9.15. Found: C, 62.70; H,
7.21; N, 9.14.
(d, 3H, J ) 5.4 Hz), 1.48 (d, 3H, J ) 6.9 Hz), 2.13 (dq, 1H, J )
5.4 Hz, 2.5 Hz), 2.17 (d, 1H, J ) 2.5 Hz), 5.10 (false p, 1H, J )
7.4 Hz), 6.6 (bs, 1H), 7.29 (m, 5H); 13C NMR (CDCl3) δ 22.3, 30.2,
34.7, 38.7, 49.3, 126.6, 127.9, 128.0, 129.2, 143.4, 173.7; [R]D
-60.4 (c 0.1, CHCl3). Anal. Calcd for C12H16N2O: C, 70.56; H,
7.89; N 13.71. Found: C, 70.55; H, 7.87; N, 13.67.
(1′S,2S,3R)-N-(1′-P h en ylet h yl)-3-a m in o-2-ch lor ob u t a n -
a m id e (9): 70% yield; IR (film) 3427, 1637 cm-1 1H NMR
;
(1S′,2R,3S)-Dia ceta te (12): 80% yield; mp 157-159 °C; IR
(Nujol) 3290, 1729, 1637, 1542 cm-1 1H NMR (CDCl3) δ 1.25
;
(CDCl3) δ 1.23 (d, 3H, J ) 6.5 Hz), 1.52 (d, 3H, J ) 7.0 Hz), 2.65
(m, 1H), 3.65 (dq, 1H, J ) 6.5 Hz, 2.8 Hz), 4.28 (d, 1H, J ) 2.8
Hz), 5.10 (false p, 1H, J ) 7.4 Hz), 7.30 (m, 6H); 13C NMR
(CDCl3) δ 18.8, 21.8, 48.4, 49.5, 51.6, 126.1, 126.9, 127.2, 127.4,
128.5, 128.6, 128.9, 142.5, 166.6; [R]D -28.2 (c 1.4, CHCl3). Anal.
Calcd for C12H17N2OCl: C, 59.87; H, 7.12; N 11.64. Found: C,
59.84; H, 7.16; N 11.65.
(d, 3H, J ) 6.4 Hz), 1.48 (d, 3H, J ) 6.9 Hz), 1.96 (s, 3H), 2.05
(s, 3H), 4.64 (dd, 1H, J ) 8.5 Hz, 4.7 Hz), 5.07 (dq, 1H, J ) 6.9
Hz, 7.7 Hz), 5.36 (dq, 1H, J ) 4.4 Hz), 6.43 (d, 1H, J ) 8.5 Hz),
6.84 (d, 1H, J ) 6.8 Hz), 7.30 (m, 5H); 13C NMR (CDCl3) δ 16.6,
21.1, 21.7, 23.1, 49.2, 56.2, 70.0, 126.0, 27.5, 128.7, 142.7, 67.7,
170.0, 170.5; [R]D -44.1 (c 0.3, CHCl3). Anal. Calcd for
C16H22N2O4: C, 62.71; H, 7.24; N, 9.15. Found: C, 62.67; H,
7.23; N, 9.12.
(1′S,2R,3S)-3-Met h yl-2-(1′-p h en ylet h yl)a m id oa zir id in e
1
(18): 65% yield; IR (film) 3277, 1654 cm-1; H NMR (CDCl3) δ
1.26 (d, 3H, J ) 5.2 Hz), 1.51 (d, 3H, J ) 7.0 Hz), 2.11 (dq, 1H,
J ) 5.2 Hz, J ) 2.1 Hz), 2.17 (d, 1H, J ) 2.1 Hz), 5.11 (false p,
1H, J ) 7.0 Hz), 6.43 (bs, 1H), 7.31 (m, 5H); 13C NMR (CDCl3)
Gen er a l P r oced u r e for th e Hyd r olysis of Dia ceta tes 7
a n d 12. A solution of compound 7 or 12 (0.1 g, 0.33 mmol) in
11 M HCl (10 mL) and MeOH (1 mL) was refluxed for 25 h. The

3462 J . Org. Chem., Vol. 63, No. 10, 1998
Notes
1
mixture was then concentrated under reduced pressure and
extracted with ethyl acetate/aqueous Na2CO3 to separete the (S)-
1-phenylethylamine. To the aqueous layer was added 6 N HCl
until the solution reached pH 1. The solvent was then elimi-
nated and replaced with water (1 mL). The mixture was
adsorbed on cation-exchange resin and the resin was washed
with distilled water, until the washing came out neutral, then
with 0.5 M aqueous NH4OH to recover the R-amino-â-hydroxy
acid, which was obtained pure after evaporation.
(2R,3S)-D-Th r eon in e (13): 74% yield; H NMR (D2O+DCl)
δ 1.14 (d, 3H, J ) 6.6 Hz), 3.72 (d, 1H, J ) 3.7 Hz), 4.20 (m,
1H), [R]D +26.1 (c 0.1, H2O).
Ack n ow led gm en t. This work was supported in part
by M.U.R.S.T. (40%), by C.N.R., by University of Bolo-
gna (funds for Selected Research Topics), and by a
NATO Collaborative Research Grant with Professor
J oseph P. Konopelski of the University of California,
Santa Cruz (CRG 950049).
(2S,3S)-L-a llo-Th r eon in e (8): 70% yield; 1H NMR (D2O+DCl)
δ 1.04 (d, 3H, J ) 6.6 Hz), 3.82 (d, 1H, J ) 3.5 Hz), 4.13 (m,
1H); [R]D +9.7 (c 0.1, H2O).
J O971388S