Diastereoselective synthesis of (S)- and (R)-α-phenylserine by a sulfinimine-mediated strecker reaction

Article abstract of DOI:10.1055/s-2004-837308

A straightforward and efficient diastereoselective synthesis of (S)- and (R)-α-phenylserine is reported. The key step involves an asymmetric Strecker reaction of a chiral N-sulfinyl ketimine, which was obtained from the commercially available 2-hydroxyace

Full text of DOI:10.1055/s-2004-837308

PAPER
575
Diastereoselective Synthesis of (S)- and (R)-a-Phenylserine by a Sulfinimine-
Mediated Strecker Reaction
D
iastereoselective
l
Synthe
b
sis of
(
S
)
-
a
n
e
d (
R
)-
a
-P
h
r
enylserin
t
e
o Avenoza,* Jesús H. Busto, Francisco Corzana, Jesús M. Peregrina,* David Sucunza, María M. Zurbano
Departamento de Química, Universidad de La Rioja, Grupo de Síntesis Química de La Rioja, U.A.-C.S.I.C., 26006 Logroño, Spain
Fax +34(941)299655; E-mail: alberto.avenoza@dq.unirioja.es; E-mail: jesusmanuel.peregrina@dq.unirioja.es
Received 9 November 2004
The key step in our synthesis of a-phenylserine (S)-1 in-
Abstract: A straightforward and efficient diastereoselective syn-
volves the stereoselective addition of ‘CN–’ to a chiral N-
sulfinyl ketimine derived from the appropriately protected
2-hydroxyacetophenone (Scheme 1).
thesis of (S)- and (R)-a-phenylserine is reported. The key step in-
volves an asymmetric Strecker reaction of a chiral N-sulfinyl
ketimine, which was obtained from the commercially available 2-
hydroxyacetophenone.
The first step in the synthesis of (S)-1 was to protect the
hydroxyl group of commercially available 2-hydroxyace-
tophenone with tert-butyldiphenylsilyl chloride (TBDP-
SCl) to give compound 2 in 95% yield (Scheme 2).
Key words: amino acids, asymmetric synthesis, imines, nitriles,
nucleophilic addition
Following Ellman’s procedure, standard Ti(OEt)4 mediat-
ed condensation of (R)-tert-butanesulfinamide8 with de-
rivative 2 gave N-sulfinyl ketimine (R)-3 in 65% yield
(Scheme 2). The 1H NMR spectrum of this compound re-
vealed that the Z isomer was obtained exclusively in the
reaction. This isomer was unequivocally identified be-
cause the methylene proton signals of CH2OTBDPS ap-
pear at high field (d > 4.9 ppm) due to the proximity of the
oxygen of the sulfinimine group.
Enantiomerically pure a,a-disubstituted amino acids are
important building blocks for pharmaceutical and artifi-
cially designed peptides.1 One of the most direct methods
to synthesize such amino acids is the so-called Strecker
reaction.2 In recent years sulfinyl imines have proven to
be extremely effective substrates for the 1,2-addition of a
wide range of nucleophiles. Moreover, these imines serve
as chiral directing groups and are straightforward to re-
move under mild conditions.3 In this sense, several a-ami-
no acids have been obtained from N-sulfinyl aldimines.
However, it is important to note that the application of this
methodology to the synthesis of a,a-disubstituted amino
acids involves the use of ketimines, which are generally
more difficult to obtain and give poorer selectivities than
aldimines4 (Scheme 1).
R
O
O
S
O
N
a
b
Ph
Ph
Ph
OH
2-hydroxy-
acetophenone
OTBDPS
OTBDPS
(R)-3
2
Scheme 2 a) TBDPSCl, imidazole, DMAP, CH2Cl2, 25 °C, 95%; b)
(R)-tert-butanesulfinamide, Ti(OEt)4, THF, reflux, 65%.
" CN– "
O
H2N CO2H
R'
S
O
N
R
R
R'
α,α-disubstituted
Compound (R)-3 was treated with ethylaluminium cy-
anoisopropoxide [EtAl(O-i-Pr)CN], which was generated
in situ by addition of i-PrOH to diethylaluminium cyanide
(Et2AlCN).9 Interestingly, the cyanide addition to deriva-
tive (R)-3 at –20 °C gave moderate diastereoselectivity
[(R,R)-4a/(R,S)-4b = 81:19] in favor of a-amino nitrile
(R,R)-4a (Scheme 3). The diastereoselectivity of this reac-
tion could be easily determined by HPLC.10 In an effort to
improve the stereoselectivity, we decided to decrease the
reaction temperature. However, all attempts to carry out
the reaction at temperatures lower than –20 °C were un-
successful. Diastereomerically pure (R,R)-4a could be ob-
tained by simple column chromatography.
R
R'
ketone
amino acids
N-sulfinyl
ketimine
(S)-1: R = Ph
R' = CH2OH
Scheme 1 Retrosynthesis of a,a-disubstituted amino acids using the
sulfinimine-mediated asymmetric Strecker reaction.
In an effort to combine the two aforementioned processes,
and in connection with our research into the asymmetric
synthesis of conformationally restricted amino acids,5 we
focused our attention on a-phenylserine (1), an a,a-disub-
stituted b-hydroxy-a-amino acid. Compound 1 has previ-
ously been described in racemic form6 but to the best of
our knowledge, there is only one method in the literature
for the diastereoselective synthesis of this amino acid.7
In order to confirm unambiguously the absolute configu-
ration of (R,R)-4a, it was transformed into alcohol (R,R)-
5 by treatment with HF in pyridine. This reaction selec-
tively removed the TBDPS group11 to give alcohol (R,R)-
5 in good yield (Scheme 4). Fortunately, we were able to
obtain single crystals of (R,R)-5 by slow evaporation at
low temperature (approximately –20 °C) of a solution in
SYNTHESIS 2005, No. 4, pp 0575–0578
Advanced online publication: 23.12.2004
DOI: 10.1055/s-2004-837308; Art ID: P13304SS
© Georg Thieme Verlag Stuttgart · New York
x
x
.
x
x
.2
0
0
5

576
A. Avenoza et al.
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nylserine in which the key step is an asymmetric Strecker
reaction of a N-sulfinyl ketimine derived from the com-
mercially available 2-hydroxyacetophenone.
R
R
R
S
R
O
S
S
O
S
a
O
N
HN
Ph
HN
CN
CN
+
Ph
Ph
OTBDPS
(R)-3
OTBDPS
81 : 19
(R,R)-4a
OTBDPS
Solvents were purified according to standard procedures. Analytical
TLC was performed using Polychrom SI F254 plates. Column chro-
matography was performed using Silica gel 60 (230–400 mesh).
1H NMR (300 MHz) and 13C NMR (75 MHz) spectra were recorded
on a Bruker ARX-300 spectrometer. 1H NMR and 13C NMR spectra
were recorded in CDCl3 with TMS as the internal standard and in
D2O with TMS as the external standard using a coaxial microtube
(chemical shifts are reported in ppm on the d scale, coupling con-
stants in Hz). The assignment of all separate signals in the 1H NMR
spectra was made on the basis of coupling constants, selective 1H–
(R,S)-4b
Scheme 3 a) Et2AlCN, i-PrOH, THF, –20 °C, 52%.
hexane and CH2Cl2. The new stereogenic center was
found to have the (R)-configuration. This situation is
shown in the ORTEP diagram obtained from the X-ray
analysis of these monocrystals (Figure 1).12
1
1H homonuclear decoupling experiments, H–1H COSY experi-
ments and 1H–13C HETCOR experiments. Melting points were de-
termined on a Büchi SMP-20 melting point apparatus and are
uncorrected. Optical rotations were measured on a Perkin-Elmer
341 polarimeter in 1.0 dm and 0.5 dm cells of 1.0 mL and 3.4 mL
capacity, respectively. Microanalyses were carried out on a CE In-
struments EA-1110 analyser and are in good agreement with the
calculated values. Mass spectra were obtained by electrospray ion-
ization (ESI) technique on a HP 5989B mass spectrometer.
R
S
R
O
a
HN
Ph
CN
R
S
R
O
HN
OH
CN
(R,R)-5
Ph
OTBDPS
H2N
CO2H
2-(tert-Butyldiphenylsilyloxy)acetophenone (2)
b, c
(R,R)-4a
S
Ph
To a stirred solution of 2-hydroxyacetophenone (0.75 g, 5.51
mmol), imidazole (0.47 g, 6.89 mmol) and DMAP (0.17 g, 1.39
mmol) in anhyd CH2Cl2 (15 mL) at 0 °C under an inert atmosphere
was added TBDPSCl (1.89 g, 6.89 mmol) dropwise. The reaction
mixture was stirred at r.t. for 12 h and then H2O (10 mL) was added.
The phases were separated and the organic layer was dried
(Na2SO4), concentrated in vacuo and purified by column chroma-
tography (hexane–EtOAc, 9.5:0.5) to give 2 in 95% yield (1.96 g,
5.23 mmol) as a white solid; mp 58–59 °C.
OH
(S)-1
Scheme 4 a) 14% HF/pyridine, THF, 25 °C, 93%; b) 12 N HCl, re-
flux; c) propylene oxide, EtOH, reflux, 93%.
The acid-catalyzed hydrolysis of diastereomerically pure
(R,R)-4a not only removed the sulfinyl auxiliary and the
silyl group, but also hydrolyzed the nitrile group (Scheme
4).
1H NMR (CDCl3): d = 1.13 [s, 9 H, (CH3)3CSi], 4.94 (s, 2 H, CH2O),
7.38–7.83 (m, 15 H, Ph).
13C NMR (CDCl3): d = 19.3 [(CH3)3CSi], 26.7 [(CH3)3CSi], 67.5
(CH2O), 127.8, 128.5, 129.9, 130.4, 132.9, 133.2, 135.3, 135.6 (Ph),
196.7 (PhCO).
Liberation of the amino acid from its hydrochloride salt
was achieved by treatment with propylene oxide in EtOH
under reflux to give (S)-1 in high yield (Scheme 4).
ESI+: m/z = 375.
Anal. Calcd for C24H26O2Si: C, 76.96; H, 7.00. Found: C, 76.77; H,
7.15.
(R,R)-tert-Butanesulfinic Acid [2-(tert-Butyldiphenylsilyloxy)-
1-cyano-1-phenylethyl]amide [(R,R)-4a]
Ti(OEt)4 (0.69 mL, 3.33 mmol) and (R)-tert-butanesulfinamide
(200 mg, 1.65 mmol) were added to a stirred solution of 2 (620 mg,
1.65 mmol) in THF (20 mL) under an inert atmosphere. The reac-
tion mixture was heated under reflux for 12 h. The solvent was re-
moved and the crude product was purified by flash chromatography
(hexane–EtOAc, 9:1) to give N-sulfinyl ketimine (R)-3 (520 mg,
65%), which was dissolved in THF (5 mL) at –20 °C. In a separate
round-bottomed flask, 1 M Et2AlCN in toluene (1.62 mL, 1.62
mmol) was added to a solution of i-PrOH (64.7 mL, 1.08 mmol) in
THF (5 mL) and the mixture was stirred at r.t. for 30 min. This mix-
ture was transferred to the solution of (R)-3 at –20 °C. After 3 d at
–20 °C, the reaction was quenched with 0.05 M aq HCl (10 mL) and
extracted with EtOAc (2 × 10 mL). The combined organic layers
were dried (Na2SO4), concentrated in vacuo and purified by column
chromatography (hexane–EtOAc, 7:3) to give (R,R)-4a in 42%
yield (350 mg, 0.69 mmol) and (R,S)-4b (82 mg, 0.17 mmol), both
as colorless oils; overall yield: 52%.
Figure 1 ORTEP drawing of the molecular structure of compound
5.
Finally, (R)-a-phenylserine [(R)-1] was obtained using
the same strategy as described above for its enantiomer
(S)-1, but starting from sulfinimine (S)-3. The spectro-
scopic data and the optical activity of (R)-1 was found to
be similar to those previously reported.7
In summary, we have developed a straightforward and ef-
ficient diastereoselective synthesis of (S)- and (R)-a-phe-
Synthesis 2005, No. 4, 575–578 © Thieme Stuttgart · New York

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Diastereoselective Synthesis of (S)- and (R)-a-Phenylserine
577
Compound (R)-3
1H NMR (CDCl3): d = 1.27 [s, 9 H, (CH3)3CSO], 3.85–4.20 (m, 3
H, CH2O, OH), 4.93 (br s, 1 H, NH), 7.35–7.49 (m, 3 H, Ph), 7.60–
7.68 (m, 2 H, Ph).
13C NMR (CDCl3): d = 22.4 [(CH3)3CSO], 57.5, 64.1 [PhCNH,
(CH3)3CSO], 69.2 (CH2O), 119.5 (CN), 127.2, 129.1, 129.8, 134.0
(Ph).
1H NMR (CDCl3): d = 0.89 [s, 9 H, (CH3)3CSi], 1.23 [s, 9 H,
(CH3)3CSO], 4.96 (d, J = 14.7 Hz, 1 H, CH2O), 5.18 (d, J = 14.7 Hz,
1 H, CH2O), 7.36–7.72 (m, 15 H, Ph).
Compound (R,R)-4a
[a]25D +3.5 (c = 0.88, MeOH).
ESI+: m/z = 267.
1H NMR (CDCl3): d = 1.08 [s, 9 H, (CH3)3CSi], 1.31 [s, 9 H,
(CH3)3CSO], 3.87 (d, J = 9.9 Hz, 1 H, CH2O), 3.97 (d, J = 9.9 Hz,
1 H, CH2O), 4.99 (br s, 1 H, NH), 7.37–7.45 (m, 10 H, Ph), 7.56–
7.66 (m, 5 H, Ph).
13C NMR (CDCl3): d = 19.2 [(CH3)3CSi], 22.4 [(CH3)3CSi], 26.6
[(CH3)3CSO], 57.2, 64.3 [PhCNH, (CH3)3CSO], 71.0 (CH2O),
119.6 (CN), 127.4, 128.8, 128.9, 129.8, 130.2, 131.4, 135.4, 135.6
(Ph).
Anal. Calcd for C13H18N2O2S: C, 58.62; H, 6.81; N, 10.52. Found:
C, 58.86; H, 6.75; N, 10.40.
(S,S)-tert-Butanesulfinic Acid [2-(tert-Butyldiphenylsilyloxy)-1-
cyano-1-phenylethyl]amide [(S,S)-4a]
As described for (R,R)-4a but using (S)-tert-butanesulfinamide, the
enantiomer (S,S)-4a was obtained (282 mg, 52% overall yield) from
2 (500 mg, 1.33 mmol); [a]25D –3.6 (c = 0.89, MeOH).
ESI+: m/z =505.
ESI+: m/z = 505.
Anal. Calcd for C29H36N2O2SSi: C, 69.01; H, 7.19; N, 5.55. Found:
C, 68.85; H, 7.25; N, 5.38.
Anal. Calcd for C29H36N2O2SSi: C, 69.01; H, 7.19; N, 5.55. Found:
C, 68.80; H, 7.24; N, 5.36.
Compound (R,S)-4b
(R)-a-Phenylserine [(R)-1]
[a]25D –38.0 (c = 1.41, MeOH).
As described for enantiomer (S)-1, compound (R)-1 (132 mg, 92%)
1H NMR (CDCl3): d = 1.10 [s, 9 H, (CH3)3CSi], 1.24 [s, 9 H,
(CH3)3CSO], 3.88 (s, 2 H, CH2O), 4.69 (br s, 1 H, NH), 7.37–7.68
(m, 15 H, Ph).
13C NMR (CDCl3): d = 19.3 [(CH3)3CSi], 22.4 [(CH3)3CSi], 26.6
[(CH3)3CSO], 56.8, 62.5 [PhCNH, (CH3)3CSO], 71.6 (CH2O),
118.9 (CN), 127.4, 128.0, 128.9, 129.7, 130.1, 131.4, 135.4, 135.7
(Ph).
was obtained from compound (S,S)-4a (400 mg, 0.79 mmol); [a]25
+27.1 (c = 0.59, H2O).
ESI–: m/z = 180.
D
Anal. Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.50; H, 6.29; N, 7.78.
ESI+: m/z = 505.
Acknowledgment
Anal. Calcd for C29H36N2O2SSi: C, 69.01; H, 7.19; N, 5.55. Found:
C, 68.83; H, 7.28; N, 5.41.
We thank the Ministerio de Ciencia y Tecnología (project
PPQ2001-1305), the Gobierno de La Rioja (project ANGI-2001/30)
and the Universidad de La Rioja (project API-04/02). D. S. thanks
the Comunidad Autónoma de La Rioja for a doctoral fellowship. J.
H. B. and F. C. thank the Ministerio de Ciencia y Tecnología for a
Ramón y Cajal contract.
(S)-a-Phenylserine [(S)-1]
A suspension of (R,R)-4a (300 mg, 0.59 mmol) in 12 N aq HCl so-
lution (7 mL) was heated under reflux for 12 h to give, after removal
of the solvent, a-phenylserine hydrochloride as a white solid. This
compound was dissolved in EtOH–propylene oxide (3:1, 4 mL) and
the mixture was heated under reflux for 2 h. The a-phenylserine (S)-
1 partially precipitated as a white solid (75 mg). The filtrate was
concentrated and the residue was dissolved in H2O and eluted
through a C18 reverse-phase Sep-pak cartridge to give, after removal
of the H2O, (S)-1 (25 mg) as a white solid; total amount: 100 mg,
0.55 mmol; yield: 93%; [a]25D –26.9 (c = 0.60, H2O).
References
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1H NMR (D2O): d = 4.26 (d, J = 11.7 Hz, 1 H, CH2), 4.39 (d, J =
11.7 Hz, 1 H, CH2), 7.49 (m, 5 H, Ph).
13C NMR (D2O): d = 63.6 (CNH2), 67.7 (CH2OH), 125.9, 129.3,
129.4, 134.7 (Ph), 173.4 (CO2H).
ESI–: m/z = 180.
Anal. Calcd for C9H11NO3: C, 59.66; H, 6.12; N, 7.73. Found: C,
59.49; H, 6.33; N, 7.62.
(4) Bloch, R. Chem. Rev. 1998, 98, 1407.
(5) (a) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Sucunza, D.; Zurbano, M. M. In Targets in Heterocyclic
Systems; Attanasi, O. A.; Spinelli, D., Eds.; Italian Society of
Chemistry: Rome, 2002, 231–244; and references cited
therein. (b) Avenoza, A.; Busto, J. H.; Corzana, F.;
Peregrina, J. M.; Sucunza, D.; Zurbano, M. M. Tetrahedron:
Asymmetry 2004, 15, 131. (c) Avenoza, A.; Busto, J. H.;
Corzana, F.; Peregrina, J. M.; Sucunza, D.; Zurbano, M. M.
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Busto, J. H.; Corzana, F.; Jiménez-Osés, G.; Peregrina, J. M.
Chem. Commun. 2004, 980.
(R,R)-tert-Butanesulfinic Acid (1-Cyano-2-hydroxy-1-phenyl-
ethyl)amide (5)
To a solution of (R,R)-4a (100 mg, 0.20 mmol) in THF (5 mL) in a
polypropylene flask was added 14% HF–pyridine (1.0 mL) and the
solution was stirred at r.t. for 24 h. The reaction was quenched with
sat. NaHCO3 (10 mL) and extracted with EtOAc (3 × 10 mL). The
combined organic layers were dried (Na2SO4), concentrated in vac-
uo and purified by column chromatography (hexane–EtOAc, 3:7) to
give (R,R)-5 (49 mg, 0.19 mmol) as a white solid; yield: 93%; mp
147–148 °C; [a]25D –14.4 (c = 0.93, MeOH).
(6) Olma, A. Pol. J. Chem. 1996, 70, 1442.
Synthesis 2005, No. 4, 575–578 © Thieme Stuttgart · New York

578
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PAPER
(7) (a) Marco, J. A.; Carda, M.; Murga, J.; González, F.;
Falomir, E. Tetrahedron Lett. 1997, 38, 1841. (b) Carda,
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2000, 65, 8704.
(10) HPLC conditions: Lichrospher Si (5 mm, 250 × 4.6 mm),
hexane–MTBE = 70:30, 0.6 mL/min, 265 nm, 25 °C.
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Å, b = 18.4770 (10) Å, c = 18.5730 (10) Å, a = 90.000(10),
b = 90.000(10), g = 90.000(10)°, V = 4304.4 (5) Å3, dcalc
=
1.233 g cm–3, F(000) = 1704, l = 0.71073 Å (Mo, Ka), m =
0.086 mm–1, Nonius kappa CCD diffractometer, q range
1.55–25.01°, 7270 collected reflections, 7241 unique, full-
matrix least-squares (SHELXL9712b), R1 = 0.0586, wR2 =
0.1142, (R1 = 0.1026, wR2 = 0.1304 all data), goodness of
fit = 1.029, residual electron density between 0.254 and
–0.263 e Å–3. Hydrogen atoms fitted at theoretical positions.
Further details on the crystal structure are available on
request from Cambridge Crystallographic Data Centre, 12
Union Road, Cambridge, UK on quoting the depository
number 246445. (b) Sheldrick, G. M. SHELXL97, Program
for the Refinement of Crystal Structures; University of
Göttingen: Germany, 1997.
(12) (a) Crystal data of compound 1: C39H54N6O6S3, Mw = 799.06,
colorless prism of 0.30 × 0.12 × 0.10 mm, T = 173 K,
orthorhombic, space group P 21 21 21, Z = 4, a = 12.5430 (10)
Synthesis 2005, No. 4, 575–578 © Thieme Stuttgart · New York