Preparation of both enantiomers of β2-(3,4-dihydroxybenzyl) -β-alanine, higher homologues of Dopa

Article abstract of DOI:10.1016/j.tet.2005.06.094

β²-(3,4-Dihydroxybenzyl)-β-alanine [β²-Homo-Dopa, 1] is a novel β-amino acid homologue of Dopa, the most successful therapeutic agent in the treatment of Parkinson's disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of β-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired β-amino acids were purified by silica gel chromatography. Alternatively, enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-chain β-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary α-phenylethylamine. Finally, nearly enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4- dibenzyloxybenzyl)-3-aminopropionic acid, rac-12, with (R)- or (S)-α-phenylethylamine, followed by catalytic hydrogenolysis.

Full text of DOI:10.1016/j.tet.2005.06.094

Tetrahedron 61 (2005) 8372–8381
Preparation of both enantiomers of
b2-(3,4-dihydroxybenzyl)-b-alanine, higher homologues of Dopa*
*
Claudia G. Avila-Ortiz, Gloria Reyes-Rangel and Eusebio Juaristi
´ ´ ´
Departamento de Quımica, Centro de Investigacion y de Estudios Avanzados del Instituto Politecnico Nacional,
´
Apartado Postal 14-740, 07000 Mexico, D. F., Mexico
Received 18 April 2005; revised 8 June 2005; accepted 27 June 2005
Available online 19 July 2005
Abstract—b2-(3,4-Dihydroxybenzyl)-b-alanine [b2-Homo-Dopa, 1] is a novel b-amino acid homologue of Dopa, the most successful
therapeutic agent in the treatment of Parkinson’s disease. Enantioenriched (R)-1 and (S)-1 were obtained via the diastereoselective alkylation
of enantiopure pyrimidinone (R)- and (S)-3, chiral derivatives of b-alanine, with veratryl iodide. The major diastereomeric products (2S,5R)-
4 and (2R,5S)-4 were hydrolyzed with 57% HBr, and the desired b-amino acids were purified by silica gel chromatography. Alternatively,
enantioenriched (R)- and (S)-1 were prepared by means of the highly diastereoselective alkylation (3,4-dimethoxybenzyl iodide) of open-
chain b-aminopropionic acid derivatives (R,R,S)-8 and (S,S,R)-8 containing the chiral auxiliary a-phenylethylamine. Finally, nearly
enantiopure (R)- and (S)-1 were obtained by resolution of racemic N-benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-3-aminopropionic acid,
rac-12, with (R)- or (S)-a-phenylethylamine, followed by catalytic hydrogenolysis.
q 2005 Elsevier Ltd. All rights reserved.
1. Introduction
acid analogues of L-Dopa is a highly attractive goal in view
of their potential as brain neurotrasmitters9 and biologically
relevant metal chelators.10 Basically, b-amino acid homo-
logues of L-Dopa are possible with the benzylic side chain in
the 2- or 3-position; that is, b2-homoDopa or b3-homoDopa
(Fig. 1a).11 Interestingly, in 1998, Steglich and co-workers12
reported the isolation of a novel b-amino acid from
mushroom Cortinarius violaceus, which is regioisomeric
to L-Dopa (Fig. 1b).
Several hydroxylated derivatives of the twenty proteino-
genic a-amino acids present relevant biological activity on
their own. Salient examples include 4-hydroxyproline,
5-hydroxylysine, and 3,4-dihydroxyphenylalanine (Dopa).
In particular, Parkinson’s disease is associated with a low
neurotransmitter dopamine level in the body, and it is
treated with L-Dopa. Indeed, the Monsanto process for the
large-scale production of L-Dopa became the first successful
asymmetric protocol carried out in industry,2 and was
recently recognized with the Nobel Prize granted to its
leader W. S. Knowles.3 Academic interest in the asym-
metric synthesis of L-Dopa and derivatives continues to
this day.4
Very recently, Mazaleyrat and co-workers13 reported the
synthesis of terminally protected (S)-b3-homoDopa, from
L-Dopa by means of the Arndt-Eistert homologation
protocol. In the present paper, we describe our work
directed to the enantioselective preparation of (R)- and (S)-
b2-homoDopa.
b-Amino acids are not as ubiquitous as their a-analogues,
but have attracted extraordinary interest in recent years,5
owing to their presence in numerous natural products,6 and
as precursors of b-lactams7 and unnatural b-peptides.8
2. Results and discussion
For the enantioselective preparation of b-amino acid
(R)-b2-homoDopa, (R)-1, we chose the general method
developed by Juaristi et al.14,15 employing pyrimidinone
(S)-2, as outlined in Scheme 1.
In this context, the enantioselective preparation of b-amino
* See Ref. 1.
Preliminary examination of the alkylation reaction was
carried out on the racemic 2-isopropyl-pyrimidinone
analogue rac-3, that was prepared according to the
described procedure16 (Scheme 2). In the event, generation
Keywords: b-Amino acids; Diastereoselective alkylation; Resolution; Dopa
homologues.
*
Corresponding author. Tel.: C52 55 5061 3722; fax: C52 55 5061 3389;
e-mail: juaristi@relaq.mx
0040–4020/$ - see front matter q 2005 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2005.06.094

C. G. Avila-Ortiz et al. / Tetrahedron 61 (2005) 8372–8381
8373
Figure 1. b-Amino acid analogues of Dopa.
Scheme 1.
of enolate rac-3-Li with LDA and subsequent addition of
veratryl chloride as electrophile afforded the expected
product rac-4 as a 4:1 mixture of the trans- and cis-
diastereomers, respectively, in a low 30% yield (Scheme 2).
obtained in 81% yield, as a 4:1 trans:cis diastereomeric
mixture. (The diastereomeric ratio was determined by
integration of suitable signals in H NMR spectra, or by
1
means of HPLC analysis). The trans configuration was
assigned to the major product based on literature
precedent,14–16 and confirmed by NOE experiments. The
substantial predominance of the trans isomer can be
ascribed to the quasi-axial orientation of the isopropyl
group16 (as a consequence of allylic A1,3-strain18) that
causes steric hindrance during electrophilic approach to the
syn face of the enolate (S)-3-Li.
In order to improve the yield of the alkylation reaction,
veratryl iodide17 was next used as electrophile. As it can be
appreciated in Scheme 2, the desired product rac-4 was
The preparation of enantiopure (R)-b2-(3,4-dihydroxy-
benzyl)-b-alanine, (R)-1, required of the alkylation of
enantiopure pyrimidinone (S)-3, that was synthesized from
(S)-asparagine following a slightly modified literature
procedure.1 (Scheme 3).
As anticipated, the alkylation reaction of (S)-3-Li with
veratryl iodide proceeded in a higher 81% yield, affording
diastereomeric (2S,5R)-4 and (2S,5S)-4 in a 4:1 ratio,
respectively. These products were separated by flash
chromatography,19 and then the major unlike20 isomer
was hydrolyzed with 57% HBr to give the expected b-amino
Scheme 2.

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Scheme 3.
Scheme 4.
Scheme 5.

C. G. Avila-Ortiz et al. / Tetrahedron 61 (2005) 8372–8381
8375
Scheme 6.
Scheme 7.

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Figure 2. The enantiomeric purity of (R)-b2-homoDopa and (S)-b2-homoDopa, (R)- and (S)-1, was established by HPLC on a Chirobiotic T column (lZ
210 nm, elution system: methanol–water, 70:30).
acid (R)-1 in 29% yield. Unfortunately, and in contrast with
other alkylated analogues,14–16 the acid hydrolysis of
(2S,5R)-4 proceeded with significant racemization: chiral
phase HPLC analysis showed the isolated b-amino acid of
only 34% ee (Scheme 4).
racemic b2-homoDopa (rac-1) with a-phenylethylamine as
resolving agent.22a,24 To this end, the N-protected methyl
ester of b-aminopropionic acid (10) was alkylated with
3,4-dibenzyloxybenzyl iodide to give rac-11 which was
saponified with sodium hydroxyde in methanol and water
(Scheme 6).
By the same token, enantiomer (S)-1 was prepared from
(R)-3 via its alkylation with veratryl iodide (80% yield)
followed by hydrolysis with 57% HBr (32% yield, 34.5%
ee). Isolation of the free b-amino acid (S)-1 was achieved by
means of silica gel chromatography, according to the
general protocol described recently.21
Two samples of racemic b2-homoDopa carboxylic acid
derivative rac-12 were treated separately with half equiva-
lent of (R)- and (S)-a-phenylethylamine, respectively. In
each case, the precipitated salt was recrystallized (three
times, EtOAc–hexane, 2:8) to constant values of optical
rotation and melting point. When (R)-a-phenylethylamine
was used, the recovered b2-homoDopa corresponded to
the (S) enantiomer (96% ee) whereas the use of (S)-a-
phenylethylamine afforded (R)-b2-homoDopa (94% ee).
This means that the diastereomeric salt that precipitates is of
unlike relative configuration (Scheme 7 and Fig. 2).
An alternative method for the enantioselective synthesis of
b2-amino acids involves the diastereoselective alkylation
of open-chain chiral derivatives of b-aminopropionic acid
(b-alanine) containing the (R)- or (S)-a-phenylethylamine
auxiliary.22 In particular, C-alkylation of the lithium dianion
derived from (R,R,S)-8 has been shown to proceed with
high diastereoselectivity to afford as the main product
the diastereoisomer produced from addition on the Si face
of the enolate.23 In the system of interest, treatment of
(R,R,S)-8-Li2 with 3,4-dimethoxybenzyl iodide proceeded
in 86% yield and higher than 95% diastereoselectivity to
give (R,R,S,S)-9, which was hydrogenolyzed (H2, Pd(OH)2,
600 psi) and hydrolyzed (57% HBr) to provide (S)-1 (50%
yield for the last two steps). Unfortunately, chiral phase
HPLC analysis evidenced partial racemization during
hydrolysis since the isolated (S)-b2-homoDopa, (S)-1,
presented a low 28% ee (Scheme 5).
In summary, enantioenriched (eeZ28–35%) b2-homoDopa
was obtained via highly diastereoselective alkylation of
chiral substrates (R)- or (S)-3 and (R,R,S)- or (S,S,R)-8
(Schemes 4 and 5, respectively). Unfortunately, these
approaches suffered of partial racemization during acid
hydrolysis of the alkylated derivatives. Nearly enantiopure
(R)- and (S)-b2-homoDopa were obtained via classical
resolution of racemic b-aminopropionic acid derivative
rac-12 with (R)- and (S)-a-phenylethylamine (Scheme 7).
3. Experimental
3.1. General
Similar observations were recorded in the preparation of
(R)-1 by means of highly diastereoselective alkylation of
enantiomeric substrate (S,S,R)-823 with 3,4-dimethoxybenzyl
iodide (veratryl iodide) followed by hydrogenolysis and
hydrolysis, as described in Scheme 5 for enantiomeric (S)-1.
Flasks, stirring bars, and hypodermic needles used for the
generation and reactions of organolithiums were dried for
ca. 12 h at 120 8C and allowed to cool in a desiccator over
anhydrous CaSO4. Anhydrous solvents were obtained by
distillation from benzophenone/ketyl radical.25 n-Butyl-
lithium was titrated according to the method of Juaristi et al.26
In view of the low enantiomeric purities in the samples of
(R)- and (S)-1 obtained by the two routes depicted in
Schemes 4 and 5, we decided to explore the resolution of

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8377
TLC: Merck DC-F254 plates, detection UV light, iodine
vapour, or ninhydrine spray. Flash chromatography:19 Merk
silica gel (0.040–0.063 mm). Melting points: Melt Temp
apparatus, not corrected. 1H NMR spectra: Jeol Eclipse-400
(400 MHz), Bruker Ultra Shield (300 MHz), Jeol GSX-270
(270 MHz) spectrometers; 13C NMR spectra: Jeol Eclipse-
400 (100 MHz), and Bruker Ultra Shield (75 MHz).
Chemical shifts d in ppm relative to Me4Si as internal
reference, coupling constants in J (Hz). Mass spectra were
obtained in a Hewlett-Packard HP-5986 instrument. High-
resolution mass spectra (HR-MS) were obtained at Instituto
(lit.16 mp 154–156 8C). [a]D25 C509 (c 1, CHCl3), [lit.16
[a]2D5 C517 (c 1, CHCl3)].
3.2.4. 1-Benzoyl-(2S)-isopropyl-3-methyl-2,3-dihydro-
4(H)-1,3-pyrimidin-4-one, (S)-7. In a 250-mL flask
provided with magnetic stirrer and nitrogen atmosphere,
was placed 5.0 g (20.5 mmol) of (S)-6 and 150 mL of dry
THF. The resulting solution was cooled to K78 8C before
the dropwise addition of 20.5 mL (20.5 mmol) of 1 M
LHMDS. Stirring was continued for 2 h at K78 8C and then
methyl iodide (1.9 mL, 30.8 mmol) was added. The tem-
perature was allowed to raise to 25 8C and the reaction
mixture was stirred at this temperature for 3 h, before
quenching with aq. satd NH4Cl. The product was extracted
with two 200-mL portions of EtOAc, dried over anhyd.
Na2SO4, and concentrated in the rotary evaporator. The
expected product, (S)-7, was obtained after purification by
flash chromatography (hexane–EtOAc, 1:1) as a white solid
(4.4 g, 83% yield). mp 99–100 8C (lit.15 mp 103–104 8C).
[a]2D5 C497 (c 1, CHCl3), [lit.15 [a]D25 C510 (c 1, CHCl3)].
´
´
de Quımica, UNAM, Mexico. HPLC: Waters 600 provided
with UV/Vis detector and a mporasile column, hexane/
EtOAc (70:30) eluent, 1 mL/min flow and Chirobiotic T
column, MeOH/H2O (1:1) eluent, 1 mL/min.
3.2. Route 1: diastereoselective alkylation of
pyrimidinones (R)- and (S)-3
3.2.1. rac-1-Benzoyl-2-isopropyl-3-methylperhydropyri-
midin-4-one, rac-3. In a dry 250-mL round-bottom flask
provided with magnetic stirrer and addition funnel, was
placed 9.5 g (69 mmol) of N-methyl b-aminopropionamide
and suspended in 70 mL of dry CH2Cl2. To the resulting
mixture was added dropwise 19 mL (117 mmol) of
triethylamine and then 11 mL (117 mmol) of isobutyralde-
hyde before heating to reflux for 4 h with water removal
(Dean-Stark trap). The precipitate of triethylamine hydro-
chloride was removed by filtration, and the filtrate was
concentrated to dryness, redissolved in toluene, and treated
with 7.5 g (61 mmol, 0.8 equiv) of 4-DMAP and 8.9 mL
(76 mmol, 1.1 equiv) of benzoyl chloride. The reaction
mixture was heated to reflux for 4 h, the precipitate that
formed was removed by filtration, and the filtrate was
concentrated in a rotary evaporator. The crude product was
purified by flash chromatography19 using hexane–ethyl
acetate (1:1) as eluent to give 10.5 g (59% yield) of rac-3 as
a white solid, mp 100–101 8C. 1H NMR (DMSO-d6, 100 8C,
400 MHz) d 0.95 (d, JZ6.8 Hz, 3H), 0.99 (d, JZ6.8 Hz,
3H), 2.34 (dh, J1Z9.0 Hz, J2Z6.8 Hz, 1H), 2.44 (ddd, J1Z
17.6 Hz, J2Z6.8 Hz, J3Z5.1 Hz, 1H), 2.52 (ddd, J1Z
17.6 Hz, J2Z6.8 Hz, J3Z5.1 Hz, 1H), 2.92 (s, 3H), 3.58
(ddd, J1Z13.6 Hz, J2Z7.6 Hz, J3Z7.6 Hz, 1H), 3.86 (br s,
1H), 5.15 (br s, 1H), 7.47 (m, 5H). 13C NMR (DMSO-d6,
100 8C, 100 MHz) d 19.2, 30.4, 33.2, 35.5, 40.2, 74.6, 127.1,
128.9, 130.2, 136.2, 167.4, 170.2. Anal. Calcd for
C15H20N2O2 C, 69.20; H, 7.74; N, 10.76. Found: C,
69.49; H, 7.86; N, 10.95.
3.2.5. 1-Benzoyl-(2S)-isopropyl-3-methyl-perhydropyri-
midin-4-one, (S)-3. The literature procedure1 was followed
with 2.0 g (7.7 mmol) of unsaturated heterocycle (S)-7, to
give 1.9 g (94% yield) of saturated derivative (S)-3, as a
white solid with mp 98–100 8C (lit.15 mp 101–102 8C). [a]2D5
C28.0 (c 1, CHCl3), [lit.15 [a]D25 C21.0 (c 1, CHCl3)].
3.3. General procedure for the alkylation of perhydro-
pyrimidinones 3
A round-bottom flask provided with magnetic stirrer, dry
nitrogen atmosphere, and cooling bath (K20 8C) was loaded
with 0.06 mL (0.42 mmol, 1.1 equiv) of diisopropylamine
and 20 mL of dry THF. Butyllithium (0.16 mL of 2.3 N
hexane solution, 0.38 mmol, 1.0 equiv) was added dropwise
and the resulting solution was stirred at K20 8C for 20 min.
The reaction flask was then cooled to K78 8C before the
addition of 0.38 mmol (100 mg, 1.0 equiv) of heterocycle 3.
The reaction mixture was stirred at K78 8C for 1 h and then
0.76 mmol (211 mg, 2.0 equiv) of the electrophile was
added. The temperature was allowed to raise to K30 8C and
the reaction mixture was stirred at this temperature for 17 h,
before quenching with aq. satd NH4Cl. The product was
extracted with two 40-mL portions of EtOAc, dried over
anhyd. Na2SO4, and concentrated in the rotary evaporator.
3.3.1. rac-trans- and rac-cis-1-Benzoyl-5-(3,4-dimethoxy)
benzyl-2-isopropyl-3-methyl-perhydropyrimidin-4-one,
rac-4. The general procedure for the alkylation reaction of
rac-3 (200 mg, 0.77 mmol) with 422 mg (1.5 mmol,
2 equiv) of veratryl iodide was followed. The expected
product, rac-4, was obtained as a pale-yellow oil (256 mg,
81% yield) after purification by flash chromatography
(hexane–EtOAc, 1:1). 1H and 13C NMR spectroscopy
show a 4:1 mixture of the trans and cis isomers, respec-
tively. MS (20 eV): m/z 411 (MC1), 410, 367, 245, 151,
105, 85, 83, 71, 57, 45. HRMS (FAB) calcd for C24H3N2O2
(MCCH) 411.2284; found: 411.2296.
3.2.2. 1-Benzoyl-(2S)-isopropyl-(6S)-carboxyperhydro-
pyrimidin-4-one, (2S,6S)-5. The literature procedure1,27
was followed with 30.0 g (0.2 mol) of (S)-asparagine
monohydrate, 13.2 g (0.2 mol) of 85% KOH, and 42.0 mL
(0.4 mol) of isobutyraldehyde to give 45.5 g (78.4% yield)
of (2S,6S)-5, mp 175–177 8C (lit.27 mp 177–178 8C). [a]2D5
K150.0 (c 1, MeOH), [lit.27 [a]D25 K156 (c 1, MeOH)].
3.2.3. 1-Benzoyl-(2S)-isopropyl-2,3-dihydro-4(1H)-1,3-
pyrimidin-4-one, (S)-6. According to the literature pro-
cedure,1,27 10.1 g (34.8 mmol) of (2S,6S)-5 was decarboxyl-
ated with 27.0 g (52.2 mmol, 1.5 equiv) of lead tetraacetate
and 2.0 g (12 mmol) of copper diacetate. The desired
product was obtained in 75% yield (6.4 g), mp 152–154 8C
1
3.3.2. Major isomer, rac-trans-4. Colorless oil, H NMR
(DMSO-d6, 120 8C, 400 MHz) d 0.89 (d, JZ6.15 Hz, 3H),
0.97 (d, JZ6.15 Hz, 3H), 2.35 (m, 1H), 2.51 (m, 1H), 2.86

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(m, 1H), 2.97 (s, 3H), 3.02 (m, 1H), 3.5 (m, 2H), 3.66 (s,
3H), 3.69 (s, 3H), 5.12 (br, 1H), 6.50–6.72 (m, 3H), 7.28–
7.44 (m, 5H). 13C NMR (DMSO-d6, 120 8C, 100 MHz) d
19.4, 33.4, 36.0, 36.4, 40.9, 44.4, 56.7, 56.8, 75.0, 114.0,
115.0, 121.9, 127.4, 128.9, 130.3, 132.5, 136.2, 148.7,
149.9, 170.0, 170.2.
(2R,5S)-4. Colorless oil, 150 mg (64% yield), [a]2D5 C93
1
(c 1, CHCl3). H and 13C NMR spectra were identical to
those recorded for enantiomeric (2S,5R)-4. MS (20 eV): m/z
410 (MC), 367, 245, 151, 105, 85, 57, 45. HRMS (FAB)
calcd for C24H3N2O4 (MCCH) 411.2284; found 411.2285.
(2R,5R)-4. Colorless oil, 45 mg (15% yield) [a]2D5 C23.0
1
(c 1, CHCl3). H and 13C NMR spectra were identical to
3.3.3. Minor isomer, rac-cis-4. Colorless oil, 1H NMR
(DMSO-d6, 120 8C, 400 MHz) d 0.79 (d, JZ7.0 Hz, 3H),
0.90 (d, JZ7.0 Hz, 3H), 1.88 (m, 1H), 2.75 (m, 1H), 2.86
(br, 1H), 2.92 (s, 3H), 2.96 (m, 1H), 3.20 (m, 1H), 3.69 (s,
3H), 3.70 (s, 3H), 3.79 (m, 1H), 5.15 (br, 1H), 6.62–6.78
(m, 3H), 7.29–7.43 (m, 5H). 13C NMR (DMSO-d6, 120 8C,
100 MHz) d 18.7, 19.2, 33.4, 34.9, 35.6, 42.3, 43.5, 56.8,
57.0, 73.8, 114.2, 115.1, 122.1, 127.0, 129.0, 130.2, 132.0,
135.9, 149.0, 150.0, 169.6, 170.2.
those recorded for enantiomeric (2S,5S)-4. MS: m/z 411
(MC), 410, 367, 245, 151, 105, 85, 57, 45. HRMS (FAB)
calcd for C24H3N2O4 (MCCH) 411.2284; found 411.2291.
3.4. General procedure for the acid hydrolysis of the
a-alkylated perhydropyrimidinones
An ampoule was loaded with 150 mg (0.36 mmol) of the
alkylated pyrimidinone (4) and 3 mL of 48% HBr. The
sealed ampoule was heated to 90 8C for 48 h, allowed to
cool to ambient temperature, and the reaction mixture was
extracted with three 30 mL portions of CH2Cl2. The
aqueous phase was concentrated at reduced pressure and
the residue (amino acid hydrobromide) was purified by
silica gel column chromatography21 with CH2Cl2/MeOH/
AcOH (90:10:1) eluent.
3.3.4. 1-Benzoyl-(2S)-isopropyl-(5R)-(3,4-dimethoxy-
benzyl)-3-methyl-perhydropyrimidin-4-one, (2S,5R)-4.
The general alkylation procedure was followed with 500 mg
(1.9 mmol) of (S)-3 and 1.05 mg (3.8 mmol, 2.0 equiv) of
veratryl iodide. Following purification of the crude product by
flash chromatography (hexane–EtOAc, 1:1), the alkylated
product (654 mg, 83% yield) was isolated as a 4:1 mixture of
(2S,5R)-4 and (2S,5S)-4. These diastereoisomers were
separated by flash chromatography (CH2Cl2–EtOAc, 9:1).
3.4.1. (rac)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, rac-1. The general procedure for hydrolysis was
followed with 150 mg (0.36 mmol) of rac-4 to give 44 mg
(2S,5R)-4. Colorless oil, 521 mg (66% yield), [a]2D5 K86.9
(c 0.8, CHCl3), H NMR (DMSO-d6, 120 8C, 400 MHz) d
1
(32% yield) of rac-1 as a yellowish foam. H NMR (D2O,
1
400 MHz) d 2.67–3.18 (m, 5H), 6.54–6.74 (m, 3H). 13C
NMR (D2O, 100 MHz) d 34.8, 39.7, 44.5, 116.6, 117.0,
121.7, 130.1, 143.1, 144.2, 176.4. MS: m/z 211 (MC), 191,
183, 167, 149, 71.
0.89 (d, JZ6.15 Hz, 3H), 0.97 (d, JZ6.15 Hz, 3H), 2.35 (m,
1H), 2.51 (m, 1H), 2.86 (m, 1H), 2.97 (s, 3H), 3.02 (m, 1H),
3.5 (m, 2H), 3.66 (s, 3H), 3.69 (s, 3H), 5.12 (br, 1H), 6.50–
6.72 (m, 3H), 7.28–7.44 (m, 5H).13C NMR (DMSO-d6,
120 8C, 100 MHz) d 19.4, 33.4, 36.0, 36.4, 40.9, 44.4, 56.7,
56.8, 75.0, 114.0, 115.0, 121.9, 127.4, 128.9, 130.3, 132.5,
136.2, 148.7, 149.9, 170.0, 170.2. MS (20 eV): m/z 410
(MC), 367, 245, 151, 105, 85, 57, 45. HRMS (FAB) calcd
for C24H3N2O4 (MCCH) 411.2284; found 411.2302.
3.4.2. (R)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (R)-1. The general procedure for hydrolysis was
followed with 500 mg (1.21 mmol) of (2S,5R)-4 to give
75 mg (29% yield) of (R)-1 as a yellowish foam, [a]2D5 K7.0
(c 1, MeOH). Chiral phase HPLC (Chirobiotic T column,
lZ210 nm, elution system: MeOH–water, 70:30) showed
(2S,5S)-4. Colorless oil, 123 mg (16% yield), [a]2D5 K23.5
(c 0.75, CHCl3). 1H NMR (DMSO-d6, 120 8C, 400 MHz) d
0.79 (d, JZ7.0 Hz, 3H), 0.90 (d, JZ7.0 Hz, 3H), 1.88 (m,
1H), 2.75 (m, 1H), 2.86 (br, 1H), 2.92 (s, 3H), 2.96 (m, 1H),
3.2 (m, 1H), 3.69 (s, 3H), 3.70 (s, 3H), 3.79 (m, 1H), 5.15
(br, 1H), 6.62–6.78 (m, 3H), 7.29–7.43 (m, 5H). 13C NMR
(DMSO-d6, 120 8C, 100 MHz) d 18.7, 19.2, 33.4, 34.9, 35.6,
42.3, 43.5, 56.8, 57.0, 73.8, 114.2, 115.1, 122.1, 127.0,
129.0, 130.2, 132.0, 135.9, 149.0, 150.0, 169.6, 170.2. MS
(20 eV): m/z 411 (MC), 410, 367, 245, 151, 105, 85, 57, 45.
HRMS (FAB) calcd for C24H3N2O4 (MCCH) 411.2284;
found 411.2281.
1
this material to present 34% ee. H and 13C NMR spectra
were identical with those recorded for rac-1. HRMS (FAB)
calcd for C10H14NO4 (MCCH) 212.0923; found 212.0926.
3.4.3. (S)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (S)-1. The general procedure for hydrolysis was
followed with 300 mg (0.73 mmol) of (2R,5S)-4 to give
49 mg (32% yield) of (S)-1 as a yellowish foam, [a]2D5 C6.8
(c 1, MeOH). Chiral phase HPLC (Chirobiotic T column,
lZ210 nm, elution system: MeOH–water, 70:30) showed
this material to present 34.5% ee. 1H and 13C NMR spectra
were identical with those recorded for rac-1. HRMS (FAB)
calcd for C10H14NO4 (MCCH) 212.0923; found 212.0922.
3.3.5. 1-Benzoyl-(2R)-isopropyl-(5S)-(3,4-dimethoxy-
benzyl)-3-methyl-perhydropyrimidin-4-one, (2R,5S)-4.
The general alkylation procedure was followed with
150 mg (0.57 mmol) of (R)-3 and 320 mg (1.15 mmol,
2.0 equiv) of veratryl iodide. After purification of the crude
product by flash chromatography (hexane–EtOAc, 1:1), the
alkylated product (189 mg, 80% yield) was isolated as a 4:1
mixture of (2R,5S)-4 and (2R,5R)-4. These diastereoisomers
were separated by flash column chromatography (CH2Cl2–
EtOAc, 9:1).
3.5. Route 2: diastereoselective alkylation of
b-aminopropionic acid derivatives (R,R,S)- and (S,S,R)-8
3.5.1. N,N-Bis-[(S)-1-phenylethyl]-3-{[(R)-1-phenylethyl]
amino}propanamide, (S,S,R)-8. A mixture of 3.0 g
(10.7 mmol) of N,N-bis-[(S)-1-phenylethyl]prop-2-
enamide23 and 1.95 g (16.1 mmol) of (R)-1-phenylethyl-
amine was dissolved in 130 mL of ethanol, and the resulting
mixture was heated to reflux for 36 h. Solvent removal at

C. G. Avila-Ortiz et al. / Tetrahedron 61 (2005) 8372–8381
8379
reduced pressure and purification by flash column chro-
matography19 (hexane–EtOAc, 7:3) afforded 3.9 g (92%
yield) of (S,S,R)-8 as a yellow oil. [a]2D5 K 99.2 (c 1,
CHCl3), 1H NMR (DMSO-d6, 100 8C, 300 MHz) d 1.20 (d,
JZ6.5 Hz, 3H), 1.64 (d, JZ7.1 Hz, 6H), 2.28 (m, 1H), 2.44
(m, 1H), 2.62 (m, 2H), 3.65 (q, JZ6.5 Hz, 1H), 5.05 (q, JZ
7.0 Hz, 2H), 7.0–7.25 (m, 15H). 13C NMR (DMSO-d6,
120 8C, 100 MHz) d 19.6, 24.5, 36.7, 44.4, 54.2, 58.1, 127.2,
127.3, 127.4, 128.2, 128.5, 128.8, 142.6, 172.5. MS (20 eV):
m/z 401 (MCCH), 295, 191, 120, 105. HRMS (FAB) calcd
for C27H33N2O (MCCH) 401.2593; found: 401.2584.
pressure to give 1.8 g (w100% yield) of debenzylated
amine (Scheme 5), which was transferred to a hydrolysis
tube and dissolved in 18 mL of 48% HBr. The tube was
sealed and heated to 90 8C for 5 days. The reaction mixture
was extracted with CH2Cl2 (3!100 mL) and the aqueous
phase was concentrated to afford the crude product 1 which
was purified as described in Section 3.2.
3.7.1. (R)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (R)-1. The general procedure for hydrolysis was
followed with 600 mg (1.1 mmol) of (S,S,R,R)-9 to give
120 mg (52% yield) of (R)-1 as a yellow foam, [a]2D5 K4.5
(c 1, MeOH). Chiral phase HPLC (Chirobiotic T column,
lZ210 nm, elution system methanol–water, 70:30) showed
3.6. General procedure for the alkylation of (R,R,S)-8
and (S,S,R)-8
1
this material to present 24% ee. H and 13C NMR spectra
To a solution of 0.2 g (0.5 mmol) of 8 in 30 mL of dry THF,
under nitrogen atmosphere and at K78 8C, was added drop-
wise 1.1 mL of LHMDS (1 M solution in hexane, 2.2 equiv).
The resulting solution was stirred at K78 8C for 1 h before
the slow addition of 153 mg of veratryl iodide (5.5 mmol,
1.1 equiv) diluted in 10 mL of dry THF. The reaction
mixture was allowed to warm to K30 8C and stirred at this
temperature for 4 h. The reaction was quenched with 2 mL
of saturated NH4Cl and the product was extracted with three
10 mL portions of EtOAc. The organic extracts were com-
bined, dried with anhyd. Na2SO4, filtered, and concentrated.
The product was purified by flash column chromatography19
(hexane–EtOAc, 8:2).
were identical with those recorded for (R)-1 in Section 3.2.
HRMS (FAB) calcd for C10H14NO4 (MCCH) 212.0923;
found 212.0929.
3.7.2. (S)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (S)-1. The general procedure for hydrolysis was
followed with 600 mg (1.1 mmol) of (R,R,S,S)-9 to give
115 mg (50% yield) of (S)-1 as a yellow foam, [a]2D5 C4.2
(c 1, MeOH). Chiral phase HPLC (Chirobiotic T column,
lZ210 nm, elution system methanol–water, 70:30) showed
1
this material to present 28% ee. H and 13C NMR spectra
were identical with those recorded for (S)-1 in Section 3.2.
HRMS (FAB) calcd for C10H14NO4 (MCCH) 212.0923;
found 212.0919.
3.6.1. (2S)-N,N-Bis-[(R)-1-phenylethyl]-2-(3,4-dimethoxy-
benzyl)-3-{[(S)-1-phenylethyl]-amino}propanamide,
(R,R,S,S)-9. The general procedure was followed with 3.0 g
(7.5 mmol) of (R,R,S)-8 and 2.3 g (11.25 mmol) of veratryl
iodide. The desired product (3.5 g, 86% yield) was obtained
as a slightly yellow oil, in greater than 98% ds. [a]2D5 C70.1
3.8. Route 3: via the resolution of racemic 12
3.8.1. N-Benzyloxycarbonyl-3-aminopropionic acid
methyl ester, 10. To a solution of 10.0 g (112 mmol) of
b-aminopropionic acid in 112 mL of 1 N NaOH was added
at 0 8C 17.6 mL (21.0 g, 123 mmol) of benzyl chlorofor-
mate and additional (30–40 mL) 1 N NaOH to maintain a
basic pH in the reaction mixture. The temperature was
allowed to reach ambient temperature and the reaction
mixture was stirred at this temperature overnight. Side
products were removed by extraction with two 100-mL
portions of EtOAc, and then the aqueous phase was
acidulated with 6 N HCl to pHZ2.0. The precipitate that
formed was filtered and the filtrate was extracted with three
200-mL portions of EtOAc. The precipitate and the organic
layers were combined, dried with anhyd. Na2SO4, and
concentrated in the rotary evaporator. The residue was
redissolved in MeOH and 4 drops of conc. HCl were added.
The mixture was heated to reflux for 20 min. and then
concentrated again at reduced pressure to give a colorless oil
that was purified by flash chromatography19 (hexane–
EtOAc, 1:1) to give 22.7 g (86% yield) of the desired
product 10. 1H and 13C NMR spectra were similar to those
reported in the literature:28 1H NMR (CDCl3, 270 MHz) d
2.51 (t, JZ6.05 Hz, 2H), 3.42 (m, 2H), 3.64 (s, 3H), 5.06 (s,
2H), 5.51 (br, 1H), 7.30 (m, 5H). 13C NMR (CDCl3,
67.5 MHz) d 34.3, 36.6, 51.8, 66.7, 128.1, 128.5, 136.6,
156.4, 172.8.
1
(c 1, CHCl3), H NMR (DMSO-d6, 100 8C, 300 MHz) d
1.24 (d, JZ6.5 Hz, 3H), 1.24–1.27 (br, 6H), 2.55 (m, 1H),
2.65 (m, 2H), 2.75 (m, 1H), 2.88 (br, 1H), 3.28 (m, 1H), 3.66
(m, 1H), 3.75 (s, 6H), 6.6–7.4 (m, 18 H). 13C NMR (DMSO-
d6, 100 8C, 75 MHz) d 17.9, 23.1, 36.1, 44.7, 50.0, 52.9,
55.6, 55.8, 57.0, 113.1, 114.4, 121.1 125.7, 126.9, 127.4,
132.4, 145.6, 147.5, 148.8, 173.5. MS (20 eV): m/z 551
(MCCH), 445, 269, 151, 120, 105. HRMS (FAB) calcd for
C36H43N2O3 (MCCH) 551.3274; found: 551.3278.
3.6.2. (2R)-N,N-Bis-[(S)-1-phenylethyl]-2-(3,4-dimethoxy-
benzyl)-3-{[(R)-1-phenylethyl]-amino}propanamide,
(S,S,R,R)-9. The general procedure was followed with 3.0 g
(7.5 mmol) of (S,S,R)-8 and 2.3 g (11.25 mmol) of veratryl
iodide. The desired product (3.4 g, 82% yield) was obtained
as a slightly yellow oil, in greater than 98% ds. [a]2D5 K 69.7
1
(c 1, CHCl3). H and 13C NMR spectra were identical to
those recorded for enantiomeric (R,R,S,S)-9. HRMS (FAB)
calcd for C36H43N2O3 (MCCH) 551.3274; found:
551.3287.
3.7. General procedure for the hydrolysis of 9
In a hydrogenation flask was placed 2.2 g (4.0 mmol) of 9,
440 mg of 20% Pd(OH)2, 40 mL of methanol, and 10 drops
of acetic acid. The flask was pressurized to 600 psi of
hydrogen and stirred at 60 8C for 12 h. The reaction mixture
was filtered over Celite and concentrated at reduced
3.8.2. N-Benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-
3-aminopropionic acid methyl ester, rac-11. In a 500-mL
flask provided with magnetic stirrer an nitrogen atmosphere
was placed 2.6 mL (18.5 mmol) of diisopropylamine and

8380
C. G. Avila-Ortiz et al. / Tetrahedron 61 (2005) 8372–8381
30 mL of dry THF. The resulting solution was cooled to
K20 8C before the addition of 8.4 mL (16.9 mmol) of
2.02 M n-BuLi in hexane. Stirring was continued for 20 min
and then the temperature was lowered to K78 8C before the
slow addition of 2.0 g (8.43 mmol) of 10 in 100 mL of dry
THF. The resulting suspension was stirred at K78 8C for 1 h
and then 3.99 g (9.27 mmol) of 3,4-dibenzyloxybenzyl
iodide in 50 mL of dry THF was added dropwise. The
reaction mixture was stirred for 5 h at K78 8C and then
quenched with 25 mL of saturated NH4Cl, extracted with
three 150-mL portions of EtOAc. The organic layers were
combined, dried with anhyd. Na2SO4, and concentrated in
the rotary evaporator. The crude product was purified by
flash chromatography19 (hexane–EtOAc, 9:1) to give 2.4 g
(R)-12 was recrystallized from EtOAc–hexane (2:8) to give
335 mg (42% yield, 84% of theoretical yield) of a white
solid, mp 112–114 8C. 1H and 13C NMR spectra were
identical to those described above for rac-12. Anal. Calcd
for C32H31NO6: C, 73.13; H, 5.94; N, 2.66. Found: C, 72.97;
H, 6.15; N, 2.65.
3.8.5. N-Benzyloxycarbonyl-(2S)-(3,4-dibenzyloxybenzyl)-
3-aminopropionic acid, (S)-12. The same procedure
described above for the isolation of (R)-12 was followed,
only that (R)-a-phenylethylamine was used. The unlike
diastereomeric salt (see discussion in the main text) pre-
sented the following physical properties: mp 154–155 8C,
C18.0 (c 1, MeOH). The
25
Hg365
[a]2D5 C7.0 (c 1, MeOH), [a]
1
(53% yield) of rac-11 as a white solid, mp 80–82 8C. H
liberated carboxylic acid (S)-12 was obtained in 44% yield
(355 mg, 88% of theoretical yield) and presented the
NMR (CDCl3, 270 MHz) d 2.72 (m, 1H), 2.86 (m, 2H), 3.32
(m, 2H), 3.58 (s, 3H), 5.09 (s, 2H), 5.12 (s, 2H), 5.14 (s, 2H),
6.68–6.86 (m, 3H), 7.24–7.35 (m, 5H). 13C NMR (CDCl3,
67.5 MHz) d 35.4, 41.8, 47.3, 51.9, 66.9, 71.3, 71.4, 115.2,
115.9, 121.8, 127.4, 127.5, 127.9, 128.3, 128.6, 128.6,
147.8, 148.9, 156.4, 174.7. MS (20 eV): m/z 539 (MC), 431,
340, 181, 108, 91. Anal. Calcd for C33H33NO6: C, 73.45; H,
6.16; N, 2.60. Found: C, 73.13; H, 6.00; N, 2.65.
1
following physical properties: mp 112–114 8C. H and 13C
NMR spectra were identical to those recorded for rac-12.
Anal. Calcd for C32H31NO6 C, 73.13; H, 5.94; N, 2.66.
Found: C, 73.12; H, 6.25; N, 2.54.
3.8.6. (R)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (R)-1. In a hydrogenation flask provided with
magnetic stirrer was placed 300 mg (0.57 mmol) of (R)-12
and 30 mL of methanol. The resulting solution was treated
with 30 mg of 10% palladium on charcoal and the flask was
pressurized to 1 atm of hydrogen. The reaction mixture was
filtered over Celite and concentrated in a rotary evaporator
to give 96 mg (80% yield) of (R)-1 as a yellow foam, [a]D25
K24.5 (c 1, MeOH). 1H and 13C NMR spectra were
identical with those recorded for (R)-1 in Section 3.2. Chiral
phase HPLC (Chirobiotic T column, lZ210 nm, elution
system methanol–water, 70:30) showed this material to be
94% ee. HRMS (FAB) calcd for C10H14NO4 (MCCH)
212.0923; found 212.0925.
3.8.3. N-Benzyloxycarbonyl-2-(3,4-dibenzyloxybenzyl)-
3-aminopropionic acid, rac-12. In a 100-mL flask provided
with magnetic stirrer was placed 2.3 g (4.3 mmol) of rac-11
and 40 mL of methanol. The resulting solution was treated
with 683 mg (17.2 mmol) of NaOH dissolved in the
minimum amount of water. The reaction mixture was
stirred at ambient temperature for 48 h, and then concen-
trated in a rotary evaporator. The residue was redissolved in
100 mL of EtOAc, washed with two 100-mL portions of 1 N
HCl and then with 100 mL of aq saturated sodium and
potassium tartrate. The organic phase was dried with anhyd.
Na2SO4 and concentrated in a rotary evaporator. The
product was recrystallized from EtOAc–hexane (2:8) to
give 1.9 g (85% yield) of rac-12 as a white solid, mp 108–
110 8C. 1H NMR (CDCl3, 60 8C, 300 MHz) d 2.73 (m, 1H),
2.96 (m, 2H), 3.42 (m, 2H), 5.11 (s, 4H), 5.13 (s, 2H), 6.70–
6.88 (m, 3H), 7.27–7.45 (m, 5H). 13C NMR (CDCl3, 60 8C,
75 MHz) d 35.4, 42.0, 47.3, 67.3, 72.0, 72.1, 116.2, 117.1,
122.3, 127.7, 127.8, 128.0, 128.2, 128.4, 128.7, 128.8,
131.8, 136.7, 137.8, 137.8, 148.6, 149.5, 156.9, 170.8,
178.0. MS (20 eV): m/z 525 (MC), 417, 326, 181, 91, 79.
Anal. Calcd for C32H31NO6 C, 73.13; H, 5.94; N, 2.66.
Found: C, 73.10; H, 6.09; N, 2.67.
3.8.7. (S)-2-(3,4-Dihydroxybenzyl)-3-aminopropionic
acid, (S)-1. The same procedure described above for the
hydrogenolysis of (R)-12 was followed, with 300 mg
(0.57 mmol) of (S)-12 and 20 mg of 10% palladium on
charcoal. Free b-amino acid (S)-1 (112 mg, 93% yield) was
obtained as a yellow foam, [a]2D5 C23.5 (c 1, MeOH). Chiral
phase HPLC (Chirobiotic T column, lZ210 nm, elution
system methanol–water, 70:30) showed this material to be
1
96% ee (Fig. 2). H and 13C NMR spectra were identical
with those recorded for (S)-1 in Section 3.2. HRMS (FAB)
calcd for C10H14NO4 (MCCH) 212.0923; found 212.0918.
3.8.4. N-Benzyloxycarbonyl-(2R)-(3,4-dibenzyloxybenzyl)-
3-aminopropionic acid, (R)-12. In a 50-mL Erlenmeyer
flask was placed 0.8 g (1.5 mmol) of rac-12 and 5.0 mL of
EtOAc. The resulting solution was heated to reflux and then
0.1 mL (0.76 mmol, 0.5 equiv) of (S)-a-phenylethylamine
was added. The resulting mixture was allowed to stand at
ambient temperature for 15 h upon which a precipitate was
formed, mp 147–149 8C. This solid material was recrystal-
Acknowledgements
´
We are grateful to Conacyt, Mexico, for financial support
via grant 33023-E, and to Fred Garcıa for technical
´
assistance.
ized twice from EtOAc to give a white solid with mp 154–
155 8C, [a]2D5 K6.3 (c 1, MeOH), [a]
25
Hg365
K17.9 (c 1,
References and notes
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asymmetric synthesis, see: (a) Juaristi, E.; Escalante, J.; Leon-
Romo, J. L.; Reyes, A. Tetrahedron: Asymmetry 1998, 9,
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715–740. (b) Juaristi, E.; Leon-Romo, J. L.; Reyes, A.;
Escalante, J. Tetrahedron: Asymmetry 1999, 10, 2441–2495.
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23. Gutierrez-Garcıa, V. M.; Reyes-Rangel, G.; Mun˜oz-Mun˜iz, O.;
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side chains, in order to distinguish positional isomers: (a)
Hintermann, T.; Seebach, D. Synlett 1997, 437–438. (b)
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2004, 87, 3131–3159. See also: (d) Juaristi, E. Structural
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27. Juaristi, E.; Lopez-Ruiz, H.; Madrigal, D.; Ramırez-Quiros,
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