Alternative procedure for the synthesis of enantiopure 1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one, a useful starting material for the enantioselective synthesis of α-substituted β-amino acids

Article abstract of DOI:10.1016/S0957-4166(03)00048-X

The title heterocycle is prepared in enantiomerically pure form and in 46-50% overall yield from (S)-asparagine, a readily available starting material. The synthetic route described in this report represents a major improvement over the original procedure (Tetrahedron: Asymmetry 1991, 3, 723), that afforded a 24-32% overall yield. Furthermore, the use of toxic reagents such as Pb(OAc)₄ and dimethyl sulfate is avoided in the present protocol.

Full text of DOI:10.1016/S0957-4166(03)00048-X

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 577–580
Alternative procedure for the synthesis of enantiopure
1-benzoyl-2(S)-tert-butyl-3-methylperhydropyrimidin-4-one, a
useful starting material for the enantioselective synthesis of
a-substituted b-amino acids
Mart´ın A. Iglesias-Arteaga, Elena Castellanos and Eusebio Juaristi*
Departamento de Qu´ımica, Centro de Investigacio´n y de Estudios Avanzados del Instituto Polite´cnico Nacional,
Apartado Postal 14-740, 07000 Mexico, D.F. Mexico
Received 14 November 2002; accepted 20 December 2002
Abstract—The title heterocycle is prepared in enantiomerically pure form and in 46–50% overall yield from (S)-asparagine, a
readily available starting material. The synthetic route described in this report represents a major improvement over the original
procedure (Tetrahedron: Asymmetry 1991, 3, 723), that afforded a 24–32% overall yield. Furthermore, the use of toxic reagents
such as Pb(OAc)4 and dimethyl sulfate is avoided in the present protocol. © 2003 Published by Elsevier Science Ltd.
1. Introduction
Indeed, enantiopure pyrimidinone (S)-1 was then pre-
pared from (S)-asparagine (Scheme 2),3 and used as an
efficient starting material for the enantioselective syn-
thesis of (R)- and (S)-a-substituted,4 and a,a-disubsti-
tuted b-amino acids.5 Furthermore, several analogues
of pyrimidinone (S)-1 have proven useful for the asym-
metric synthesis of b-substituted, a,b-disubstituted, and
b,b-disubstituted b-amino acids.6
The development of synthetic procedures for the prepa-
ration of enantiopure b-amino acids has received con-
siderable attention in the recent past.1 In 1991,
b-aminopropionic acid was converted into chiral pyrim-
idinone rac-1, that was alkylated with high diastereose-
lectivity, setting the basis for the enantioselective
synthesis of a-substituted b-amino acids2 (Scheme 1).
Replacement of butyllithium and methyl iodide for
sodium hydroxide and dimethyl sulfate in the N-methyl-
ation step [(S)-3“(S)-4] led to a significant improve-
ment in the overall yield for the preparation of (S)-1.7
Nevertheless, to avoid the use of toxic lead tetraacetate
in the decarboxylation reaction [(2S,6S)-2“(S)-3], we
have explored the use of diacetoxyiodobenzene/iodine
(DIB/I2)8 for the oxidative decarboxylation of car-
boxylic acid (2S,6S)-2.9,10 In addition, we have found
that N-methylation [(S)-3“(S)-4] can be conveniently
carried out with lithium diisopropylamide and methyl
iodide, avoiding the employment of toxic dimethyl
sulfate.
2. Results and discussion
Scheme 1.
Treatment of carboxylic acid (2S,6S)-2 with DIB/I2
gave a mixture of pyrimidinone (S)-3 and the vinylic
iodide (S)-5 in a 1:1.6 ratio (Scheme 3).9
* Corresponding author. E-mail: juaristi@relaq.mx or ejuarist@
enigma.red.cinvestav.mx
0957-4166/03/$ - see front matter © 2003 Published by Elsevier Science Ltd.
doi:10.1016/S0957-4166(03)00048-X

578
M. A. Iglesias-Arteaga et al. / Tetrahedron: Asymmetry 14 (2003) 577–580
Scheme 2. Reagents and conditions: (a) KOH, t-BuCHO; (b) C6H5COCl, NaHCO3; (c) Pb(OAc)4, Cu(OAc)4 (cat.); (d) n-BuLi,
CH3I; (e) H2, Pd(C), 75 atm.
CH3CN, led to the rapid formation of the desired
enone (S)-3 in good yield (Scheme 5).
The main advantages of the synthetic protocol
described in Scheme 5, relative to the original proce-
dure,3,7 are: (1) the replacement of toxic lead tetra-
acetate by safer reagents, (2) the use of milder reaction
conditions and shorter reaction times, and (3) the
increased facility in the isolation and purification of the
desired product, (S)-3.
Scheme 3.
As reported previously,9 iodoenone (S)-5 was cleanly
hydrodeiodinated by treatment with 1.2 equiv. of
iodotrimethylsilane (ITMS)11 to afford enone (S)-3
(Scheme 4).
N-Methylation of enone (S)-3 was then achieved via a
simple and clean procedure involving lithium diiso-
propylamide (LDA) as base and methyl iodide as elec-
trophile (Scheme 6).
Scheme 4.
We now have been able to combine the decarboxylation
and hydrodehalogenation reactions described in
Schemes 3 and 4 into a one pot procedure that is based
on the in situ generation of ITMS from chloro-
trimethylsilane (TMSCl) and sodium iodide. Thus,
treatment of carboxylic acid (2S,6S)-2 with two equiv.
of DIB and one equiv. of I2 in CH2Cl2, followed by
addition of TMSCl (2 equiv.) and NaI (2 equiv.) in
Scheme 6.
Modification of the original synthetic protocol (Scheme
1) by incorporation of the procedures described in
Schemes 5 and 6 allows conversion of (S)-asparagine
into pyrimidinone (S)-1 with and overall yield of 46–
50%. This synthetic route has also been applied to the
preparation of the isopropyl analog (S)-6.
Scheme 5.

M. A. Iglesias-Arteaga et al. / Tetrahedron: Asymmetry 14 (2003) 577–580
579
3. Experimental
g, 76% yield) with mp 99–100°C (lit.13 mp 103–
104°C). [h]2D5=+499.0 (c 1.0, CHCl3) [lit.13 [h]D29=
+509.9 (c 1.0, CHCl3)].
3.1. General
TLC, F254 silica gel plates, detection by UV light or
iodine vapor. Flash column chromatography: silica
gel (230–400 mesh). All melting points are uncor-
Acknowledgements
1
rected, H NMR spectra: Jeol Eclipse-400 (400 MHz)
spectrometer. 13C NMR spectra: Jeol Eclipse-400 (100
MHz) spectrometer. Optical rotations were measured
in a Perkin–Elmer model 241 polarimeter, using the
sodium D-line (589 nm).
We are indebted to CONACyT, Mexico, for financial
support via grant 33023-E and for the Ca´tedra Patri-
monial de Excelencia granted to M.A.I.A.
3.2. One-pot decarboxylation procedure in the prepara-
tion of 1-benzoyl-2(S)-tert-butyl-2,3-dihydro-4(H)-
pyrimidin-4-one, (S)-3
References
A suspension of the carboxylic acid (2S,6S)-23,7 (304
mg, 1.0 mmol), diacetoxyiodobenzene12 (644 mg, 2.0
mmol), and iodine (253 mg, 1.0 mmol) in 10 mL of
CH2Cl2 was stirred at ambient temperature for 4–4.5
h. Acetonitrile (20 ml), NaI (300 mg 2.0 mmol) and
Me3SiCl (217.3 mg, 2.0 mmol) were added and the
resulting dark solution was stirred for 2.5–3 h. The
reaction mixture was diluted with CH2Cl2 (20 mL),
washed with four 20-mL portions of 5% aqueous
Na2S2O3, two 15-mL portions of 5% aqueous
NaHCO3 and two 15-mL portions of brine, dried
over anh. Na2SO4 and evaporated to afford a yellow-
ish syrup that was purified by flash chromatography
(hexane–EtOAc, 100:0“50:50) The desired product
was isolated in 71% yield (0.18 g) and was identical
to the previously described material.3,7
1. For reviews, see: (a) Juaristi, E.; Quintana, D.; Escalante,
J. Aldrichim. Acta 1994, 27, 3–11; (b) Cole, D. C. Tetra-
hedron 1994, 50, 9517–9582; (c) Cardillo, G., Tomasini,
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tive Synthesis of i-Amino Acids; Juaristi, E., Ed.; Wiley-
VCH: New York, 1997; (e) Juaristi, E.; Lo´pez-Ru´ız, H.
Curr. Med. Chem. 1999, 6, 983–1004; (f) Liu, M.; Sibi, M.
P. Tetrahedron 2002, 58, 7991–8035.
2. Juaristi, E.; Quintana, D.; Lamatsch, B.; Seebach, D. J.
Org. Chem. 1991, 56, 2553–2557.
3. Juaristi, E.; Quintana, D. Tetrahedron: Asymmetry 1992,
3, 723–726.
4. Juaristi, E.; Quintana, D.; Balderas, M.; Garc´ıa-Pe´rez, E.
Tetrahedron: Asymmetry 1996, 7, 2233–2246.
5. Juaristi, E.; Balderas, M.; Ram´ırez-Quiro´s, Y. Tetra-
hedron: Asymmetry 1998, 9, 3881–3888.
6. (a) Konopelski, J. P.; Chu, K. S.; Negrete, G. R. J. Org.
Chem. 1991, 56, 1355–1357; (b) Juaristi, E.; Escalante, J.;
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thesis; 1-Benzoyl-2(S)-tert-butyl-3-methylperhydropyrim-
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3.3. N-Methylation reaction in the preparation of
1-benzoyl-2(S)-isopropyl-3-methyl-2,3-dihydro-4(H)-
pyrimidin-4-one, (2S)-6
In a 100 mL round-bottomed flask provided with
magnetic stirrer was placed 0.63 mL (4.5 mmol) of
diisopropylamine dissolved in 15 mL of dry THF.
The solution was cooled to −20°C before the addition
of 1.75 mL of 2.34 M BuLi (4.1 mmol), and the
resulting mixture was stirred at −20°C for 20 min. In
a separate 50 mL flask, a solution containing 1.0 g
(4.1 mmol) of 1-benzoyl-2(S)-isopropyl-2,3-dihydro-
4(H)-pyrimidin-4-one13 in 15 mL of dry THF was
cooled to −78°C and added to the previously pre-
pared lithium diisopropylamide. The resulting mixture
was stirred at −78°C for 30 min, and then 0.39 mL
(6.15 mmol) of iodomethane was added. The reaction
temperature was allowed to reach 0°C and the reac-
tion mixture was stirred at this temperature for 4 h,
before quenching with 3 mL of aqueous saturated
ammonium chloride solution. The N-methylated
product was extracted with three 15-mL portions of
ethyl acetate, the combined organic extracts were
dried over anh. Na2SO4 and concentrated to afford a
yellowish solid. Final purification was accomplished
by flash chromatography, with EtOAc/hexane (7:3) as
eluent. Pure (S)-6 was obtained as a white solid (0.79

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12. Purchased from Aldrich or prepared according to: Pau-
10. Decarboxylation can also be accomplished by electrolysis.
See: Lakner, F. J.; Chu, K. S.; Negrete, G. R.; Konopel-
ski, J. P. Org. Synth. 1995, 73, 201–214.
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13. Ram´ırez-Quiro´s, Y.; Balderas, M.; Escalante, J.; Quin-
tana, D.; Gallardo, I.; Madrigal, D.; Molins, E.; Juaristi,
E. J. Org. Chem. 1999, 64, 8668–8680.
11. For the hydrodehalogenation of a-haloketones with
ITMS, see: (a) Olah, G. A.; Arvanaghi, M.; Dankar, Y.
D. J. Org. Chem. 1980, 45, 3531–3532; (b) Ho, T.-L.