Domino 1,3-dipolar cycloadditions of n- alkyl-α-amino esters with paraformaldehyde: A direct access to α-hydroxymethyl α-amino acids

Article abstract of DOI:10.1055/s-0033-1340816

N-Alkyl-α-amino esters undergo a domino reaction, based on the iminium cation generation, with paraformaldehyde, followed by a 1,3-dipolar cycloaddition of the stabilized azomethA?ine ylide with another equivalent of formaldehyde. The resulting products are oxazolidines, which can be transformed after hydrolysis into α-hydroxymethyl α-amino acid or its derivatives. The diastereoselective 1,3-dipolar cycloaddition was performed using sarcosine (-)-menthyl or (-)-8-phenylmenthyl esters affording the cyclic product with moderate enantiomeric ratio. Georg Thieme Verlag Stuttgart · New York.

Full text of DOI:10.1055/s-0033-1340816

PAPER
▌967
paper
Domino 1,3-Dipolar Cycloadditions of N-Alkyl-α-Amino Esters with
Paraformaldehyde: A Direct Access to α-Hydroxymethyl α-Amino Acids
Synthesis of α-Hydroxymethyl α-Amino Acids
Luis M. Castelló, Carmen Nájera,* José M. Sansano*
Departamento de Química Orgánica e Instituto de Síntesis Orgánica (ISO), Facultad de Ciencias, Universidad de Alicante, 03080 Alicante, Spain
Fax +34(96)5903549; E-mail: cnajera@ua.es; E-mail: jmsansano@ua.es
Received: 04.12.2013; Accepted after revision: 22.01.2014
tion of the 1,3-dipole through the iminium route. Immedi-
Abstract: N-Alkyl-α-amino esters undergo a domino reaction,
ately, this reactive ylide is trapped by a dipolarophile.12,13
based on the iminium cation generation, with paraformaldehyde,
The generation of chiral azomethine ylides by reaction of
(5R)-5-phenylmorpholin-2-one (1) with long chain alde-
followed by a 1,3-dipolar cycloaddition of the stabilized azometh-
ine ylide with another equivalent of formaldehyde. The resulting
products are oxazolidines, which can be transformed after hydroly- hydes and further reaction with a second equivalent of the
sis into α-hydroxymethyl α-amino acid or its derivatives. The dia-
stereoselective 1,3-dipolar cycloaddition was performed using
sarcosine (–)-menthyl or (–)-8-phenylmenthyl esters affording the
cyclic product with moderate enantiomeric ratio.
aldehyde was reported in a very highly diastereoselective
manner (Scheme 1).14
O
N
O
O
O
Key words: cycloaddition, azomethine ylides, paraformaldehyde,
serine
2 RCHO
heat
*
R
Ph
*
O
Ph
N
H
*
R
1
2
Serine and serine derivatives belong to a family of polar
α-amino acids bearing a hydroxymethyl group at the α-po-
sition. This arrangement allows serine residues to play an
important role in the catalytic function of many enzymes,
for example, in the active site of acetylcholine esterase.1
In proteins, this residue can undergo phosphorylation by
kinases,2 direct O-linked glycosylation,3 or even can act as
linker in modified biopharmaceuticals.4 D-Serine itself
has been one of the most extensively studied ‘unnatural
amino acid’.5 This brain-enriched transmitter-like mole-
cule plays a pivotal role in the human central nervous sys-
tem by modulating the activity of N-methyl-D-aspartate
(NMDA) receptors, serving as both a neurotransmitter
and a gliotransmitter. This amino acid is employed for the
treatment of neurological disorders such as schizophrenia,
Alzheimer’s disease, and amyotrophic lateral sclerosis.6
In addition, α-substituted serine structures are often ob-
served as a subunit of many biologically active natural
products, such as conagenin,7 myriocin,8 mycestericins,9
among others.
Scheme 1
To the best of our knowledge, the azomethine ylide gen-
erated from formaldehyde was never captured by formal-
dehyde itself.15 So, in this work the thermal domino
reaction of N-alkyl-α-amino esters and two equivalents of
formaldehyde, focused on the preparation of α-hydroxy-
methyl-α-amino acids, is studied.
Sarcosine methyl ester hydrochloride (3) was allowed to
react with paraformaldehyde in the presence of one equiv-
alent of triethylamine in toluene at 110 °C. Conventional
heating and microwave-assisted reactions were evaluated
finding a better yield (61%, Scheme 2) when the reaction
was refluxed for 24 hours. The use of formalin (37%) or
other different solvents such as 1,4-dioxane, chloroform,
and xylene, furnished very low conversions. Despite the
high efficiency of microwave-assisted 1,3-DC,16 only a
17% yield of oxazolidine 4 was achieved after 30 minutes
at 110 °C.
One of the most employed strategies to synthesize α-ami-
no acids consists on the introduction of the α-side chain,
in this case the hydroxymethyl group.10 Particularly, an al-
dol type reaction from enolates generated from glycine or
other α-substituted α-amino acid templates and formalde-
hyde is very useful. In addition, formaldehyde can be in-
corporated at the α-position via 1,3-dipolar cycloaddition
(1,3-DC)11 employing stabilized azomethine ylides in a
straightforward manner.
HCl
(CH2O)n
O
H
O
O
N
Me
N
Et3N, toluene
Me
O
_
O
Me
Me
= 110 °C, 24 h, 61%
MW = 110 °C, 30 min, 17%
Δ
3
4
CH2O
H
O
CH2O
_
H
O
Formaldehyde has been employed in these 1,3-DCs with
N-alkyl-substituted amino acids or esters, for the genera-
O
+N
Me
Me
N
Me
+
O
Me
O
A
SYNTHESIS 2014, 46, 0967–0971
Advanced online publication: 11.02.2014
Scheme 2
0
0
3
9
-
7
8
8
1
1
4
3
7
-
2
1
0
X
DOI: 10.1055/s-0033-1340816; Art ID: SS-2013-Z0783-OP
© Georg Thieme Verlag Stuttgart · New York

968
L. M. Castelló et al.
PAPER
The domino process was triggered by the generation of 58% was the overall yield calculated from proline methyl
the free N-substituted α-amino ester (sarcosine methyl es- ester hydrochloride (9) (Scheme 5).
ter in this example), which formed the iminium salt with
one equivalent of formaldehyde. The resulting transient
CO2Me
(CH2O)n
MeO2C
azomethine ylide A was captured by the reaction of anoth-
er equivalent of formaldehyde yielding the expected oxa-
zolidine 4 (Scheme 2).
O
Δ or MW
NH⋅HCl
N
Et3N, toluene
9
10
62%
In the case of using ethyl N-benzylglycinate (5), a less wa-
ter soluble oxazolidine 6 was isolated in 85% yield em-
ploying both conventional and microwave-assisted
heating (Scheme 3). Here, triethylamine was not used be-
cause the starting amino ester 5 could be isolated as a free
secondary amine.
Δ
= 110 °C, 24 h
Δ
MW = 110 °C, 30 min
MW 34%
1) 6 M HCl
EtOH, 78 °C
94%
2) propylene oxide
EtOH, 78 °C
–O2C
(CH2O)n
OH
OEt
N
Δ or MW
Ph
EtO2C
O
NH2
11
N
H
toluene
O
5
6
Scheme 5
Δ
85%
Δ
= 110 °C, 24 h
MW 85%
MW = 110 °C, 30 min
Pipecolic acid methyl ester hydrochloride (12) was a suit-
able substrate to run the optimized domino process with
paraformaldehyde (Scheme 6). Under conventional heat-
Scheme 3
N-Benzylaminomalonate 7, prepared from diethyl α-ami- ing conditions the chemical yield was higher (82%) than
nomalonate and benzyl bromide, underwent almost quan- the described for the transformation involving proline
titative domino 1,3-DC with paraformaldehyde methyl ester 9. This homoproline derivative 13 has not
independently of the heating mode (95 and 93%, respec- been described previously and a promising biological ac-
tively) (Scheme 4). Oxazolidine 8 was easily generated tivity can be envisaged.
because of the aid of the geminally substituted α-position
and also by the high stabilization of the dipole once the
(CH2O)n
CO2Me
CO2Me
NH⋅HCl
iminum salt was generated. The employment of the free
amino ester 7 avoided the addition of Et3N to the reaction
media.
Δ or MW
O
N
Et3N, toluene
12
13
Δ
= 110 °C, 24 h
Δ
82%
Ph
MW = 110 °C, 30 min
MW 32%
EtO2C
Ph
CO2Et
(CH2O)n
O
N
Scheme 6
NH
toluene
EtO2C
CO2Et
Δ or MW
7
8
During our study of the diastereoselective process,
(2S,4R)-4-hydroxyproline methyl ester hydrochloride and
its O-TBDMS protected derivative were tested as enantio-
merically enriched starting materials. Disappointingly,
(2S,4R)-4-hydroxyproline gave a complex reaction mix-
ture with multiple signals in crude 1H NMR spectra origi-
nated by polymeric substances formed in the process. On
the other side, the enantiopure silyl ether decomposed un-
der both thermal reaction conditions.
Δ
= 110 °C, 24 h
Δ
95%
MW = 110 °C, 30 min
MW 93%
Scheme 4
Quaternary α-amino acid surrogates are known as key
building blocks of proteins to obtain useful information on
their bioactive conformations and to achieve beneficial
physiological effects.17 Proline methyl ester hydrochlo-
ride (9) was an appropriate substrate to run the thermal 2,3-Dihydro-1H-indole-2-carboxylic acid methyl ester 14
1,3-DC affording bicyclic compound 10 in 62% isolated was submitted to the standard reaction conditions using
yield (Scheme 5). In this example, microwave irradiation conventional heating and microwave assisted one obtain-
did not give the expected improvement of the chemical ing, after acidic hydrolysis, the hydroxymethyl derivative
yield. Perhydropyrrolooxazole 10 was next transformed 15 in 56% and 30% yield, respectively (Scheme 7).
into the new quaternary α-hydroxymethylproline 11 by
hydrolysis in a refluxing 6 M 1:1 HCl–EtOH mixture. The
zwitterionic amino acid could be isolated by treatment
with propylene oxide and final recrystallization. The
Next, we decided to use a chiral auxiliary incorporated
into the α-imino ester in order to obtain in situ the chiral
enantiopure azomethine ylide and analyze the diastereo-
selection of the thermal process. In this way, N-Boc-sar-
chemical yield of the hydrolysis process was 94% whilst
cosine (16) was treated with DCC, DMAP, and L-menthol
Synthesis 2014, 46, 967–971
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Hydroxymethyl α-Amino Acids
969
1. (CH2O)n
toluene, 110 °C
tween the corresponding (−)-8-phenylmenthol proline es-
ter and paraformaldehyde despite testing several reaction
conditions.
CO2Me
OH
CO2Me
2. 1 M HCl
3. aq NH4Cl/NH3
N
H
N
H
In summary, the introduction of formaldehyde as dipola-
rophile was achieved from N-alkylamino esters and fol-
lowing the generation of the stabilized azomethine ylide
through the iminium route. This strategy represents a
straightforward access to interesting quaternized α-(hy-
droxymethyl)amino acids. The major diastereoselection
was achieved when (−)-8-phenylmenthol was employed
as chiral auxiliary in the formation of the corresponding
chiral N-methyl-D-serine.
15
56%
MW 30%
14
Δ
Scheme 7
[(1R,2S,5R)-(−)-menthol]18 or (−)-8-phenylmenthol19 in
CH2Cl2 under mild conditions to give the corresponding
esters. Without previous purification, the removal of the
Boc group took place with TFA giving the free amines
17a and 17b in quantitative yield (Scheme 8). The micro-
wave-assisted 1,3-DC of 17a with paraformaldehyde (in 1
Microwave experiments were performed in a CEM Discover Syn-
thesis Unit (CEM Corp., Matthews, NC, USA) with a continuous
focused microwave power delivery system in glass vessels (10 mL)
sealed with a septum under magnetic stirring. Melting points were
determined with a Reichert Thermovar hot plate apparatus and are
uncorrected. Only the structurally most important peaks of the IR
spectra (recorded on a Nicolet 510 P-FT) are listed. For solid sam-
ples ATR device was employed. 1H NMR (300 MHz) and 13C NMR
(75 MHz) spectra were obtained on a Bruker AC-300 using CDCl3
as solvent and TMS as internal standard, unless otherwise stated.
Optical rotations were measured on a PerkinElmer 341 polarimeter.
Low-resolution electron impact (EI) mass spectra were obtained at
70eV on a Shimadzu QP-5000 and high-resolution mass spectra
were obtained on a Finnigan VG Platform. HRMS (EI) were record-
ed on a Finnigan MAT 95S. Microanalyses were performed on a
PerkinElmer 2400 and a Carlo Erba EA1108 instruments. Analyti-
cal TLC was performed on Schleicher & Schuell F1400/LS silica
gel plates and the spots were visualized under UV light (λ = 254
nm). Flash chromatography was done using Merck silica gel 60
(0.040–0.063 mm).
1
h) furnished a 63:31 dr of 18a determined by H NMR
spectrum of the crude product.20 The crude reaction mix-
ture was very pure and the conversion was almost com-
plete. Moreover, a 88:12 dr was isolated for 18b21 when
the 1,3-DC was carried out under the same reaction con-
ditions using the 8-phenylmenthol derived ester.15b How-
ever, the conventional heating did not give a good
conversion and small signals of unidentified impurities
were recorded by 1H NMR spectra in both diastereoselec-
tive transformations. Immediately, the generation of N-
methyl-D-serine 19 as major enantiomer (38% ee) was
achieved after hydrolysis of 18a with 6 M HCl–EtOH and
further treatment with propylene oxide. N-Methyl-D-ser-
ine (19) was obtained in 76% ee once the hydrolysis was
completed. The absolute configuration of α-methyl-α-
amino acid 19 was established according to its specific
optical rotation.22 Compound 19 was isolated in 54 and
59% overall yield from N-Boc-sarcosine (16) (Scheme 8).
Oxazolidines 4, 6, 8, 10, 13, and 15; General Procedure
To a solution of the corresponding amino ester hydrochloride (0.43
mmol) in toluene (2 mL), Et3N (if needed) (1.5 equiv, 90 μL, 0.645
mmol, see text) and paraformaldehyde (15 equiv, 306 mg, 6.45
mmol) were added. The resulting mixture was refluxed at 111 °C
for 24 h or irradiated with microwaves (111 °C, 30 min). EtOAc (5
mL) and H2O (5 mL) were added and the organic phase was sepa-
rated, dried (MgSO4), and evaporated to obtain the pure heterocycle
in good chemical yields (see also text). The yields given below for
the products are for the thermal reaction.
1) chiral alcohol
DCC, CH2Cl2
25 °C, 24 h
Boc
Me
HN
O
N
CO2H
Me
2) TFA, CH2Cl2
O
16
R
17a R = H
17b R = Ph
Methyl 3-Methyloxazolidine-4-carboxylate (4)23
Yield: 38 mg (61%); colorless oil.
MW, 1 h
110 °C
IR (neat): 1746, 1705 cm–1.
(CH2O)n
1H NMR: δ = 2.53 (s, 3 H, NCH3), 3.49–3.55 (dd, J = 7.7, 5.8 Hz, 1
H, CH2CH2O), 3.77 (s, 3 H, OCH3), 3.85–3.91 (dd, J = 7.7, 6.1 Hz,
1 H, CH2CH2O), 4.18 (t, J = 8.2 Hz, 1 H, CH), 4.27 (d, J = 4.8 Hz,
1 H, NCH2), 4.47 (d, J = 4.8 Hz 1 H, NCH2).
13C NMR: δ = 41.7 (NCH3), 52.4 (OCH3), 66.6 (CH), 67.3
(OCH2CH), 88.8 (NCH2), 172.1 (C=O).
1) 6 M HCl
EtOH, 78 °C
2) propylene oxide
EtOH, 78 °C
_
H2
N
O
Me
CO2
Me
+
N
O
HO
O
19
N-methyl-D-serine
ME (EI): m/z (%) = 145 (M+, 2), 100 (11), 86 (100), 56 (13), 42.0
(23).
R
18a R = H, 69:31 dr
18b R = Ph, 88:12 dr
R = H, 54% from 16, 38% ee
R = Ph, 59% from 16, 76% ee
HRMS: m/z calcd for C6H11NO3: 145.0739; found: 145.0730.
Ethyl 3-Benzyloxazolidine-4-carboxylate (6)
Yield: 86 mg (85%); colorless oil.
Scheme 8
IR (neat): 1732, 1186 cm–1.
1H NMR: δ = 1.24 (t, J = 7.1 Hz, 3 H, CH3CH2CO2), 3.66 (dd,
J = 7.9, 5.3 Hz, 1 H, CH2CH2O), 3.85–3.89 (m, 3 H, PhCH2N and 1
By using this diastereoselective approach the synthesis of
enantiomerically enriched α-(hydroxymethyl)proline was
attempted. Unexpectedly, no reaction was observed be-
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 967–971

970
L. M. Castelló et al.
PAPER
H of CH2CH2O), 4.12–4.20 (m, 3 H, CH3CH2CO2, CH), 4.44 (s, 2
H, NCH2O), 7.23–7.40 (m, 5 H, C6H5).
13C NMR: δ = 36.4, 52.9, 66.8, 71.2, 111.1, 120.2, 124.6, 127.7,
149.3, 175.1.
13C NMR: δ = 14.1 (CH2CH3), 58.7 (NCH2Ph), 61.0 (CH2CH3),
64.4 (NCH), 67.1 (OCH2CH), 87.0 (NCH2O), 127.4, 128.4, 128.7,
138.08 (ArC), 171.9 (C=O).
MS: m/z (%) = 207 (M+, 42), 176 (30), 175 (73), 148 (17), 144 (35),
143 (100), 130 (31), 118 (66), 89 (40).
Anal. Calcd for C11H13NO3: C, 63.8; H, 6.3; N, 6.7. Found: C, 63.9;
H, 6.1; N, 6.5.
MS (EI): m/z (%) = 235 (M+, 2), 234 (119), 162 (32), 91 (100).
HRMS: m/z calcd for C13H17NO3: 235.1208; found: 235.1201.
α-(Hydroxymethyl)proline (11)
The bicyclic product 10 (68 mg, 0.4 mmol) was suspended in 1.1 6
M HCl–EtOH mixture (2 mL) and refluxed for 24 h. H2O was evap-
orated under vacuo and the remaining residue was dissolved in
EtOH (2 mL). Propylene oxide (140 μL, 2 mmol) was added and the
solution refluxed for 30 min. The mixture was cooled at 0 °C and
the free amino acid was isolated as pale yellow prisms; yield: 54 mg
(94%); mp 195 °C (dec.).
Diethyl 3-Benzyloxazolidine-4,4-dicarboxylate (8)
Yield: 125 mg (95%); colorless oil.
IR (neat): 1732, 1265 cm–1.
1H NMR (acetone-d6): δ = 1.32 (t, J = 7.12 Hz, 6 H, CH3CH2), 4.04
(s, 3 H, NCH2Ph and 1 H of CCH2O), 4.30 (q, J = 7.1 Hz, 5 H,
CH3CH2 and 1 H of CCH2O), 4.43 (s, 2 H, NCH2O), 7.23–7.40 (m,
5 H, C6H5).
IR (ATR): 3350, 3600–3100, 1643–1600 cm–1.
13C NMR (acetone-d6): δ = 14.1 (2 × CH3), 51.3 (NCH2Ph), 61.8 (2
× CH2CH3), 72.7 (quat-C), 73.6 (OCH2C), 85.7 (NCH2O), 127.3,
128.1, 128.3, 138.5 (ArC), 168.7 (2 × C= O).
MS (EI): m/z (%) = 307 (M+, 5), 235 (17), 234 (100), 92 (19), 91
(100), 65 (13).
1H NMR (D2O): δ = 1.90–2.06 (m, 3 H, CCH2CH2), 2.12–2.23 (m,
1 H, CCH2), 3.33 (ddd, J = 11.5, 7.7, 3.4 Hz, 1 H, NCH2), 3.39–3.48
(m, 1 H, NCH2), 3.73 (d, J = 12.1 Hz, 1 H, CH2OH), 4.03 (d,
J = 12.1 Hz, 1 H, CH2OH).
13C NMR (D2O): δ = 24.1 (CH2CH2CH2), 32.0 (CCH2), 46.9
(CH2OH), 63.7 (NCH2), 75.8 (quat-C), 175.6 (C=O).
HRMS: m/z calcd for C16H21NO5: 307.1420; found: 307.1412.
MS (EI): m/z (%) = 145 (M+, 0.7), 128 (16), 114 (100), 100 (90), 96
(75), 86 (15), 84 (21), 82 (28), 73 (19), 70 (27), 68 (42), 55 (20), 44
(27), 41 (48).
Methyl Hexahydropyrrolo[1,2-c]oxazole-7a-carboxylate (10)24
Yield: 46 mg (62%); pale yellow oil.
IR (neat): 2924, 1779, 1731, 1656 1051 cm–1.
Anal. Calcd for C6H11NO3: C, 49.7; H, 7.6; N, 9.7. Found: C, 49.5;
H, 7.8; N, 9.7.
1H NMR: δ = 1.80–1.90 (m, 3 H, CH2CH2C), 2.40–2.50 (m, 1 H,
CH2C), 2.82–2.91, 3.32–3.42 (2 m, 2 H, NCH2), 3.77 (d, J = 8.7 Hz,
2 H, OCH2C), 3.77 (s, 3 H, OCH3), 4.32, 4.55 (2 d, J = 6.5 Hz, 2 H,
NCH2O).
13C NMR: δ = 26.1 (CH2CH2CH2), 36.7 (CCH2), 52.6 (OCH3), 56.1
(NCH2), 74.3 (OCH2C), 77.2 (C), 88.7 (NCH2O), 175.2 (C=O).
MS (EI): m/z (%) = 171 (M+, 9), 170 (16), 154 (16), 143 (60), 142
(19), 141 (16), 138 (50), 128 (93), 126 (17), 125 (18), 124 (100),
122 (18), 112 (24), 111 (17), 110 (33), 100 (57), 97 (25), 96 (34), 91
(45), 83 (33), 82 (23), 71 (24), 70 (21), 69 (28), 58 (36), 55 (39), 43
(40).
Diastereoselective Synthesis of N-Methyl-D-serine (19)
To a solution of N-Boc-sarcosine 16 (193 mg, 1 mmol) in CH2Cl2
(4 mL) was added DCC (206 mg, 1 mmol). After 10 min, (–)-men-
thol or (–)-8-phenylmenthol (1 mmol) was slowly added at r.t. and
stirring was continued at this temperature overnight. The solvent
was evaporated and the residue purified by flash chromatography
(SiO2) affording the enantiomerically enriched esters 17a and 17b
(301 mg, 0.9 mmol, 90% and 390 mg, 0.95 mmol, 95%, respective-
ly). These compounds were dissolved in TFA (2 mL) and the reac-
tion was monitored by TLC (eluent: hexanes–EtOAc, 70:30). After
6 h, the reaction was completed and TFA was removed giving a res-
idue, which was treated with Et3N (270 μL, 2 mmol) and was imme-
diately allowed to undergo the reaction with paraformaldehyde
assisted by microwave irradiation (see above) affording a 69:31 dr
of compound 18a and a 88:12 dr of compound 18b. This crude ma-
terial was suspended in a 6 M 1.1 HCl–EtOH mixture (5 mL) and
the resulting solution refluxed for 24 h. H2O was evaporated under
vacuo and the remaining residue was dissolved in EtOH (4 mL).
Propylene oxide (280 μL, 4 mmol) was added and the solution re-
fluxed for 30 min. The mixture was cooled at 0 °C and the free ami-
no acid 19 was isolated as colorless needles; yield: 66 mg (54%) or
72 mg (59%) from 16; mp 195 °C (dec.) [Lit.20 mp 198–200 °C
(dec.)]; [α]D21 –11.6 (c 1.0, 6 N HCl, 38% ee); or [α]D21 –24.2 (c 1.0,
HRMS: m/z calcd for C8H13NO3: 171.0895; found: 171.0885.
Methyl Hexahydro-1H-oxazolo[3,4-a]pyridine-8a-carboxylate
(13)
Yield: 65 mg (82%); pale yellow oil.
IR (neat): 2924, 1769 cm–1.
1H NMR: δ = 1.50–1.55 (m, 2 H, NCH2CH2), 1.64–1.69 (m, 2 H,
NCH2CH2CH2), 1.96–1.99 (dd, J = 10.0, 4.3 Hz, 1 H, CCH2), 2.71
(ddd, J = 11.7, 9.4, 3.6 Hz, 1 H, CCH2), 3.02–3.13 (m, 2 H, NCH2),
3.67 (d, J = 7.7 Hz, 1 H, CCH2O), 3.76 (s, 3 H, OCH3), 4.17 (d,
J = 7.9 Hz, 1 H, CCH2O), 4.41 and 4.47 (2 d, J = 4.8 Hz, 2 H,
NCH2O).
13C NMR: δ = 20.1 (NCH2CH2CH2), 23.3 (NCH2CH2), 27.9
(CCH2CH2), 46.9 (NCH2), 52.6 (CH3), 53.4 (C), 68.5 (CCH2O),
86.9 (NCH2O), 174.7 (C=O).
21
6 M HCl, 76% ee); for N-methyl-L-serine: {Lit.22a [α]D +30.5 (c
1.0, 6 M HCl)}.
MS (EI): m/z (%) = 185 (M+, 1), 126 (100), 98 (36).
Acknowledgment
Anal. Calcd for C9H15NO3: C, 58.4; H, 8.2; N, 7.6. Found: C, 58.5;
H, 8.3; N, 7.7.
This work was supported by the Spanish Ministerio de Ciencia e In-
novación (MICINN) (Consolider INGENIO 2010 CSD2007-
00006, CTQ2010-20387), FEDER, Generalitat Valenciana (PRO-
METEO/2009/039), and by the University of Alicante. L.M.C.
thanks the MICINN for a FPI fellowship.
Methyl 2-(Hydroxymethyl)indoline-2-carboxylate (15)
Yield: 51 mg (56%); pale yellow sticky oil.
IR (ATR): 3475, 2992, 1733 cm–1.
1H NMR: δ = 3.16 (d, J = 16.5 Hz, 1 H, CH2C), 3.41 (d, J = 10.9 Hz,
1 H, CH2C), 3.69 (d, J = 10.9 Hz, 1 H, CH2OH), 3.78 (s, 3 H, CH3),
3.84 (d, J = 10.9 Hz, 1 H, CH2OH), 4.75 (br, 1 H, NH), 6.78 (dd,
J = 14.0, 6.9 Hz, ArH), 7.06 (dd, J = 4.4, 3.1 Hz, ArH).
Supporting Information for this article is available online at
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Synthesis 2014, 46, 967–971
© Georg Thieme Verlag Stuttgart · New York

PAPER
Synthesis of α-Hydroxymethyl α-Amino Acids
971
azomethine ylides by reaction of (5R)-5-phenylmorpholin-
2-one with long-chain aldehydes. In the presence of a second
equiv of aldehydes, the azomethine ylide can be trapped:
Brome, V. A.; Harwood, L. M.; Osborn, H. M. I. Can. J.
Chem. 2006, 84, 1448.
References
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(4) (a) Walsh, G. Biopharmaceuticals: Biochemistry and
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(6) Sacchi, S.; Caldinelli, L.; Cappelletti, P.; Pollegioni, L.;
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(7) Nakano, K.; Kotsuki, H.; Ichikawa, Y. Org. Prep. Proced.
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(9) Byun, H.-S.; Lu, X.; Bittman, R. Synthesis 2006, 2447.
(10) For examples of general synthesis of α-amino acids, see:
(a) Duthaler, R. O. Tetrahedron 1994, 50, 1539. (b) Nájera,
C.; Sansano, J. M. Chem. Rev. 2007, 107, 4273.
(15) The 1,3-DC of metallo-azomethine ylides derived from
benzaldehyde imines and benzophenone imines was
previously published: (a) Seashore-Ludlow, B.; Torssell, S.;
Somfai, P. Eur. J. Org. Chem. 2010, 3927. (b) Seashore-
Ludlow, B.; Villo, P.; Somfai, P. Chem. Eur. J. 2012, 18,
7219.
(16) Pineiro, M.; Pinho e Melo, T. M. V. D. Eur. J. Org. Chem.
2009, 5287.
(17) Cativiela, C.; Ordóñez, M. Tetrahedron: Asymmetry 2009,
20, 1.
(18) For a recent example of the 1,3-DC using naturally occurring
(–)-menthol as chiral auxiliary, see: Bonini, B. F.; Boschi,
F.; Franchini, M. C.; Fochi, M.-F.; Fini, F.; Mazzanti, A.;
Ricci, A. Synlett 2006, 543.
(19) Chiral oxazolidine acetates derived from (–)-8-phenyl-
menthol have been employed in 1,3-DC using a different
method: Deprez, P.; Royer, J.; Husson, H. P. Tetrahedron:
Asymmetry 1991, 2, 1189.
(20) Crude NMR spectral data of 18a are supplied in the
Supporting Information.
(c) Asymmetric Synthesis and Application of α-Amino Acids,
ACS Symposium Series 1009; Soloshonok, V. A.; Izawa, K.,
Eds.; American Chemical Society: New York, 2009.
(d) Saladino, R.; Botta, G.; Crucianelli, M. Rev. Med. Chem.
2012, 12, 277.
(21) Crude NMR spectra of 18b did not give information about
the diastereomeric ratio, but the hydrolyzed product 18b′
(Figure 1, see Supporting Information) allowed this problem
to be solved.
(11) For reviews, see: (a) Nájera, C.; Sansano, J. M. Curr. Org.
Chem. 2003, 7, 1105. (b) Hashimoto, T.; Maruoka, K.
Handbook of Cyclization Reactions; Ma, S., Ed.; Wiley-
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(12) (a) Izquierdo, M.; Osuna, S.; Filippone, S.; Martin-
Domenech, A.; Sola, M.; Martin, N. J. Org. Chem. 2009, 74,
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M.; Ehli, C.; Sgobba, V.; Guldi, D. M. A.; Prato, M. Chem.
Eur. J. 2009, 15, 4419. (c) Milic, D.; Prato, M. Eur. J. Org.
Chem. 2010, 476.
O
Me
HN
O
HO
Ph
18b'
Figure 1 Structure of 18b′
(13) (a) Chinchilla, R.; Falvello, L. R.; Galindo, N.; Nájera, C.
Eur. J. Org. Chem. 2001, 3133. (b) Aldous, D. J.; Hamelin,
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1841. (c) Begue, J.-P.; Bonnet-Delpon, D.; Chennoufi, A.;
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Chem. 2001, 107, 275. (d) Cardoso, A. L.; Kaczor, A.;
Silva, A. M. S.; Fausto, R.; Pinho e Melo, T. M. V. D.; Rocha
Gonsalves, A. M. d’A. Tetrahedron 2006, 62, 9861.
(14) The synthetic approach to threo-2-amino-3-hydroxy esters
possessing long alkyl chains was performed from chiral
(22) L-N-Methylserine was prepared and characterized: mp 190
°C (dec.); [α]D21 +30.5 (c 1.0, 6 N HCl). (a) F. Hoffmann-La
Roche & Co. A.-G. Patent BE 616021, 1963; Chem. Abstr.
1963, 58, 66783. (b) Aurelio, L.; Brownlee, R. T. C.;
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(23) Lubineau, A.; Bouchain, G.; Queneau, Y. J. Chem. Soc.,
Perkin Trans. 1 1995, 2433.
(24) Bureau, R.; Mortier, J.; Joucla, M. Bull. Soc. Chim. Fr. 1993,
130, 584.
© Georg Thieme Verlag Stuttgart · New York
Synthesis 2014, 46, 967–971