Enantioselective synthesis of (S)- and (R)-α-methylserines: Application to the synthesis of (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinals

Article abstract of DOI:10.1016/S0957-4166(01)00159-8

This report describes the synthesis of enantiomerically pure (S)- and (R)-α-methylserines on a multigram scale, starting from the Weinreb amide of 2-methyl-2-propenoic acid and using a stereodivergent synthetic route that involves a Sharpless asymmetric dihydroxylation reaction. As a synthetic application of these quaternary α-amino acids, they were used as starting materials in the synthesis of the well-known valuable homochiral (S)- and (R)-N-Boc-N,O-isopropylidene-α-methylserinal building blocks.

Full text of DOI:10.1016/S0957-4166(01)00159-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 12 (2001) 949–957
Enantioselective synthesis of (S)- and (R)-a-methylserines:
application to the synthesis of (S)- and
(R)-N-Boc-N,O-isopropylidene-a-methylserinals
Alberto Avenoza,a,* Carlos Cativiela,b Francisco Corzana,a Jesu´s M. Peregrina,a,* David Sucunzaa
and Mar´ıa M. Zurbanoa
aDepartamento de Qu´ımica, Universidad de La Rioja, Grupo de S´ıntesis Qu´ımica de La Rioja, U.A.-C.S.I.C.,
26006 Logron˜o, Spain
bDepartamento de Qu´ımica Orga´nica, Instituto de Ciencia de Materiales de Arago´n, Universidad de Zaragoza-C.S.I.C.,
50009 Zaragoza, Spain
Received 21 March 2001; accepted 3 April 2001
Abstract—This report describes the synthesis of enantiomerically pure (S)- and (R)-a-methylserines on a multigram scale, starting
from the Weinreb amide of 2-methyl-2-propenoic acid and using a stereodivergent synthetic route that involves a Sharpless
asymmetric dihydroxylation reaction. As a synthetic application of these quaternary a-amino acids, they were used as starting
materials in the synthesis of the well-known valuable homochiral (S)- and (R)-N-Boc-N,O-isopropylidene-a-methylserinal
building blocks. © 2001 Elsevier Science Ltd. All rights reserved.
1. Introduction
hydroxylation (AA)6 of different 2-methyl-2-propanoic
acid derivatives 1a–1d, but all attempts using literature
methods (Table 1, entries 2 and 5)7 and other experi-
ments (Table 1, entries 1, 3 and 4) gave the regioisomer
3a–3d as the major product and poor enantioselectivi-
ties (Scheme 1). Considering these results and given
that the Sharpless asymmetric dihydroxylation (AD)8
on benzyl tiglate had already been applied to the syn-
thesis of different a-methyl-a-amino acids,9 we explored
the AD on olefins 1a–1c. The enantiomeric excess (e.e.)
obtained with 2-methylpropenoates 1a and 1b (Table 1,
entries 6 and 7) in the presence of (DHQ)2PHAL
(AD-mix a) was smaller than that obtained with olefin
1c (Table 1, entry 8), according to the results obtained
by Sharpless et al.10 when AD-mix b was used (Table 1,
entry 9). Therefore, we decided to use olefin 1c as a
starting material in the synthesis of enantiomerically
pure a-methylserines.
In recent years, much attention has been focused on the
synthesis of a,a-disubstituted a-amino acids with a view
to the design and synthesis of short chain peptides
having well defined conformation, which can be altered
by the nature of the a-substituent.1 In connection with
a research project directed towards the synthesis of new
quaternary a-amino acids,2 we have been interested in
the synthesis of conformationally restricted hydroxy-a-
amino acids.3 In this context, especially interesting are
(S)- and (R)-a-methylserines which can be regarded as
potential C-terminal a-helix stabilising building blocks.4
Herein, we present a novel strategy to synthesise on a
multigram scale both (S)- and (R)-a-methylserines and
their synthetic application to afford (S)- and (R)-N-
Boc-N,O-isopropylidene-a-methylserinals, which are
known to be excellent chiral building blocks for the
synthesis of different a-methyl-a-amino acids.5
Olefin 1c was formed from commercially available 2-
methyl-2-propenoic acid, which was transformed into
the corresponding 2-methyl-2-propionyl chloride by the
action of PCl5. Further in situ addition of
methoxymethylamine gave 1c according to the protocol
described in the literature.11 The AD reaction of 1c in
the presence of AD-mix a proceeded smoothly to yield
the diol (R)-4c with excellent e.e. The amide group of
diol (R)-4c was converted into the corresponding
2. Results and discussion
The quickest method to obtain (S)- and (R)-a-
methylserines is the Sharpless asymmetric amino-
* Corresponding authors. Fax: +34 941 299621; e-mail:
alberto.avenoza@dq.unirioja.es
0957-4166/01/$ - see front matter © 2001 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(01)00159-8

950
A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
Table 1. AA and AD on olefins 1a–1c
Entry
Olefins
R
R%
Methoda
% Rtob
(2/3)
10/90
\10/90
10/90
5/95
\10/90
–
–
–
–
(S)/(R)c
Ref.
1
2
3
4
5
6
7
8
9
1a
1a
1b
1c
1d
1a
1b
1c
1c
COOMe
COOMe
COOBn
Ac
Ts
Ac
Ts
Ts
–
–
–
–
A
B
A
B
B
C
C
C
D
26
–
81
64
–
90
90
81
81
49/51d
45.5/54.5
49/51d
50/50d
41/59
–
7
–
CON(OMe)Me
–
COOtBu
7
COOMe
COOBn
CON(OMe)Me
CON(OMe)Me
50/50d
25/75d
3.5/96.5d
96.5/3.5
–
–
–
9
a Method A: K2OsO4·2H2O, LiOH·H2O, (DHQ)2PHAL, MeCONHBr, tert-BuOH/H2O (1:1), 4°C, 12 h. Method B: K2OsO4·2H2O,
t
(DHQ)2PHAL, TsNClNa·3H2O, tert-BuOH/H2O (1:1), 25°C, 12 h. Method C: AD-mix a, MeSO2NH2, BuOH/H2O (1:1), 0°C, 12 h. Method
t
D: AD-mix b, MeSO2NH2, BuOH/H2O (1:1), 0°C, 12 h.
b Determined after column chromatography.
c In the case of AA reactions, the enantioselectivity (S)/(R) corresponds to the main regioisomer 3a–3d.
d The method to measure the enantioselectivity is described in the Experimental section.
Scheme 1. Asymmetric aminohydroxylations (AA) and dihydroxylations (AD) on olefins 1a–1d.
via sulfate, it is clearly unnecessary to carry out the
oxidation of sulfite to sulfate to obtain the required
a-methylserines (Scheme 3).
methyl ester group to obtain diol (R)-5 in two steps:
basic hydrolysis with LiOH in the presence of MeOH
(3:1) at room temperature and subsequent esterification
with AcCl in refluxing MeOH. Diol (R)-5 was then
transformed into its 2,3-cyclic sulfite (R)-6 with thionyl
chloride (Scheme 2). Diol (R)-5 has been previously
reported by Ziffer et al.12 using a chromatographic
separation of the (−)-menthyl esters of rac-2,3-di-
hydroxy-2-methylpropanoic acid, followed by hydroly-
sis and methylation.
Scheme 2. Synthesis of cyclic sulfite (R)-6 from diol (R)-4c.
Reagents and conditions: (a) (i) LiOH·H2O, H2O/MeOH (1:3),
room temperature, 2 h; (ii) AcCl, MeOH, reflux, 12 h, 85%;
(b) SOCl2, CCl4, reflux, 4 h, 90%.
Reaction of sulfite (R)-6 with NaN3 at 50°C in DMF
gave a mixture of the azido esters (R)-7 and (S)-8 with
a regioselectivity13a,c,g of 4:1 in favour of the a-azido
ester (S)-8. Nucleophilic substitution by NaN3 at the
a-carbon of cyclic sulfite (R)-6 occurred with clean
inversion of configuration (Scheme 3). Alternatively,
the mixture of azido esters (R)-7 and (S)-8 could be
obtained with a similar regioselectivity from sulfite
(R)-6 using three steps: oxidation of sulfite (R)-6 into
sulfate (R)-9, nucleophilic substitution by NaN3 in the
presence of acetone–H2O as a solvent at room tempera-
ture and further acidic hydrolysis. Alternatively, the
yield of azido esters (R)-7 and (S)-8 was similar to that
obtained by the first method. Indeed, we have demon-
strated that the cyclic sulfate and sulfite groups behave
as effective leaving groups in highly regioselective reac-
tions, as reported in several articles on the nucleophilic
substitution of cyclic sulfites and sulfates.13 Taking into
account the yields of a-azido ester (S)-8 via sulfite or
Scheme 3. Synthesis of a-azido ester (S)-8. Reagents and
conditions: (a) NaN3, DMF, 50°C, 2 days, 93%; (b) NaIO4,
RuCl3, H2O/CH3CN/CCl4 (1:1:1), 40°C, 7 h, 86%; (c) NaN3,
acetone/H2O (9:1), room temperature, 2 days; (d) H2SO4 20%,
room temperature, 2 days, 75% from 9.

A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
951
As part of our research project directed towards the
synthesis of restricted a-amino acids, we have recently
reported two syntheses of (S)- and (R)-N-Boc-N,O-iso-
propylidene-a-methylserinals, which are known to be
excellent building blocks in new approaches to the
synthesis of different quaternary a-methylamino
acids.5a
Once separated, a-azido ester (S)-8 was readily hydro-
genated in MeOH in the presence of palladium to give
the corresponding a-amino ester, which was then
hydrolysed in acid to provide the a-methylserine hydro-
chloride. The free amino acid a-methylserine (S)-12 was
obtained in 59% yield by treatment of the hydrochlo-
ride with propylene oxide in refluxing EtOH. Alterna-
tively, the yield of a-methylserine (S)-12 was increased
to 83% by hydrolysis of the methyl ester group of (S)-8
in aqueous acid and further hydrogenation of the corre-
sponding azido acid (Scheme 4).
The best procedure for the achievement of both (S)-
and (R)- forms of N-Boc-N,O-isopropylidene-a-
methylserinal is described by a stereodivergent synthe-
sis, on a multigram scale, from (R)-2-methylglycidol,
which is no longer commercially available. Because of
this and taking into account that in the original synthe-
sis of (S)-N-Boc-N,O-isopropylidene-a-methylserinal,
carried out in a milligram scale, (S)-a-methylserine was
used as starting material,15 our goal was to obtain (S)-
and (R)-a-methylserines in large quantities to be used
as starting materials in the synthesis of (S)- and (R)-N-
Boc-N,O-isopropylidene-a-methylserinals on a multi-
gram scale. Thus, we actually used the protected
N-Boc-a-methylserine methyl esters (S)-13 and (R)-13
as starting materials, which were obtained starting from
azido esters (S)-8 and (R)-8 instead of starting from the
a-methylserines (S)-12 and (R)-12. In this way, (S)-8
and (R)-8 were, respectively, hydrogenated in the pres-
ence of palladium catalyst and subsequently treated
with (Boc)2O in basic medium. We also attempted these
transformations in one single step using (Boc)2O,
hydrogen, palladium–carbon and MeOH as a solvent
or PMe3, Boc-ON in toluene at −20°C, as described in
the literature,17 but the yield of 13 decreased dramati-
cally (Scheme 6).
In order to improve the yield of a-methylserine (S)-12,
we also explored the conversion of diol (S)-5 into the
corresponding amino alcohol using the cyclic iminocar-
bonate rearrangement process described by Ko et al.14
The cyclic iminocarbonate intermediate was obtained in
a one-pot operation, with net retention of configuration
at the a-carbon and was subjected to acid hydrolysis.
Liberation of the free amino acid gave a-methylserine
(S)-12 in 30% yield. The method that gave the best
result involved using the cyclic sulfite and the second
transformation (method b) of (S)-8 into (S)-12 (Scheme
4).
The enantiomer (R)-a-methylserine (R)-12 was
obtained using the same strategy described above and
also starting from olefin 1c, but changing the Sharpless
chiral catalytic ligand to (DHQD)2PHAL (AD-mix b)
in the AD reaction (Scheme 5). The absolute configura-
tion and the enantiomeric purity of these amino acids
(S)-12 and (R)-12 were determined by comparing their
specific rotations with those reported in the literature.15
The spectral data of these compounds also proved to be
identical to those previously reported.15,16
In this way, we have developed a new synthesis of both
enantiomers of a-methylserine (S)-12 and (R)-12 start-
ing from the Sharpless AD reaction on olefin 1c on a
multigram scale (6 g of 1c) in eight steps with 39%
overall yield and 93% e.e.
Compounds (S)-13 and (R)-13 were converted into
oxazolidines (S)-14 and (R)-14 by the use of 2,2-
dimethoxypropane (DMP) in acetone at room tempera-
ture with boron trifluoride etherate as a catalyst. When
DMP and p-TsOH were used in toluene at reflux, a
decrease in yield was observed. Reduction of the methyl
Scheme 4. Synthesis of a-methylserine (S)-12. Reagents and conditions: (a) (i) H2/Pd–C, MeOH, room temperature, 24 h, (ii) HCl
6N, reflux, 12 h, (iii) EtOH/propylene oxide (3:1), reflux, 2 h, 59%; (b) (i) HCl 6N, reflux, 12 h, (ii) H2/Pd–C, MeOH, room
temperature, 24 h, 83%; (c) (i) Bu2SnO, BzNCS, Et3N, Bu4NBr, dichloroethane, reflux, 21 h, 45%; (d) (i) HCl 6N, reflux, 12 h,
(ii) EtOH/propylene oxide (3:1), 60%.
Scheme 5. Synthesis of a-methylserine (R)-12. Reagents and conditions: (a) (i) LiOH·H2O, H2O/MeOH (1:3), room temperature,
2 h; (ii) AcCl, MeOH, reflux, 12 h, 85%; (b) SOCl2, CCl4, reflux, 4 h, 85%; (c) NaN3, DMF, 50°C, 2 days, 75%; (d) (i) HCl 6N,
reflux, 12 h, (ii) H2/Pd–C, MeOH, room temperature, 24 h, 83%.

952
A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
Scheme 6. Synthesis of chiral building blocks N-Boc-a-methylserinal acetonides (S)-16 and (R)-16. Reagents and conditions:
(a) (i) H2/Pd–C, MeOH, room temperature, 24 h, (ii) Boc2O, Na2CO3·10H2O, H2O/THF (1:5), room temperature, 19 h, 70%;
(b) DMP, BF3·OEt2, acetone, room temperature, 1 h, 93%; (c) LiAlH4, THF, room temperature, 6 h, 91%; (d) DMSO, oxalyl
chloride, Et3N, dichloromethane, room temperature, 12 h, 96%.
ester groups of (S)-14 and (R)-14 into the correspond-
ing required aldehydes (S)-16 and (R)-16 was carried
out more conveniently in two steps involving a reduc-
tion–oxidation sequence, since the treatment of (S)-14
with DIBAL-H, in toluene at −78°C, gave only a 35%
yield of aldehyde (S)-16. Since the attempts of reduc-
tion with LiBH4 or NaBH4 were unsuccessful, the
reduction was carried out with LiAlH4 in THF at room
temperature and the alcohols (R)-15 and (S)-15 were
oxidised under Swern conditions to give the desired
aldehydes (S)-16 and (R)-16 (Scheme 6).
ment of the valuable chiral building blocks N-Boc-
N,O-isopropylidene-a-methylserinals (S)-16 and (R)-16
in three steps with an overall yield of 81% from N-Boc
protected a-methylserine methyl esters (S)-13 and (R)-
13 (or in 10 steps with a 23% yield from commercially
available 2-methyl-2-propenoic acid).
4. Experimental
Solvents were purified according to standard proce-
dures. Analytical TLC was performed using Polychrom
SI F254 plates. Column chromatography was performed
The enantiomeric purity of the two quaternary amino
acids a-methylserines and the two quaternary a-methyl-
aldehydes was examined by preparation of the Mosher
esters of alcohols (S)-13 and (R)-13 (Scheme 7).18 Alco-
hol (S)-13 was coupled with (S)-(−)-methoxytrifluoro-
phenylacetic acid [(S)-MTPA] in the presence of DCC
and DMAP to give Mosher ester 17. For comparison
the mixture of alcohols (S)-13 and (R)-13 (in a ratio of
1:3) was transformed into Mosher esters 17 and 18,
respectively. Analysis of the NMR spectra of ester 17
showed that the enantiomeric purity of compound (S)-
13 was at least 96% (only one isomer was observed in
1
using silica gel 60 (230–400 mesh). H and 13C NMR
spectra were recorded on a Bruker ARX-300 spectrom-
1
eter. H and 13C NMR spectra were recorded in CDCl3
with TMS as the internal standard (chemical shifts are
reported in ppm on the l scale, coupling constants in
1
Hz). The assignment of all separate signals in the H
NMR spectra was made on the basis of coupling
constants, selective proton–proton homonuclear decou-
pling experiments, proton–proton COSY experiments
and proton–carbon HETCOR experiments. Melting
points were determined on a Bu¨chi SMP-20 melting
point apparatus and are uncorrected. Optical rotations
were measured on a Perkin–Elmer 341 polarimeter in a
1 dm cell of 1 mL capacity. Microanalyses were carried
out on a CE Instruments EA-1110 analyser and were in
good agreement with the calculated values. IR spectra
were recorded on a Perkin Elmer FT-IR Spectrum 1000
spectrometer. Mass spectra were obtained by one of the
1
the H and 19F NMR spectra) (Scheme 7).
3. Conclusion
In conclusion, we have developed a straightforward
synthetic route on a multigram scale for the achieve-
Scheme 7. Determination of enantiomeric purity of (S)-13. Reagents and conditions: (a) (S)-MTPA, DCC, DMAP,
dichloromethane, room temperature, 6 h, 48%.

A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
953
following ionization techniques: electron impact (EI) or
electrospray ionization (ESI) on a Hewlett Packard
5989B mass spectrometer.
7.51. Found: C, 44.61; H, 7.45%. Spectral data were
identical to those reported in the literature.12
As described for its enantiomer (R)-5, compound (S)-5
(5.95 g, 85%) was obtained from compound (S)-4c
(8.62 g, 52.7 mmol). [h]2D5=+0.8 (c 2.66, MeOH). Anal.
calcd for C5H10O4: C, 44.77; H, 7.51. Found: C, 44.58;
H, 7.48%.
4.1. Determination of enantioselectivity in AA and AD
reactions
The enantioselectivity of the major regioisomer
obtained in the AA reaction with olefins 1a and 1b was
determined by the acid hydrolysis of compounds 3a and
3b to a-methylisoserines and further comparison of the
optical activities with the values reported.19
4.3. Methyl 4-methyl-2-oxo-2l4-[1,3,2]dioxathiolane-4-
carboxylates (R)-6 and (S)-6
Diol (R)-5 (5.70 g, 42.5 mmol) was dissolved in CCl4
(75 mL) and SOCl2 (7.74 g, 65.0 mmol) was then
added. The resulting solution was heated under reflux
for 4 h. The solvent and excess SOCl2 were evaporated
and the crude product was purified by column chro-
matography (hexane:ethyl acetate, 4:1) to give (R)-6 as
a colourless liquid (6.90 g, 38.3 mmol); yield: 90%.
[h]2D5=−49.8 (c 1.16, MeOH); 1H NMR (CDCl3): l
1.63, 1.81 (2s, 3H, CH3), 3.79, 3.82 (2s, 3H, CO2CH3),
4.26, 4.48 (2d, 1H, J=9.0 Hz, CH2), 4.83, 5.04 (2d, 1H,
J=9.0 Hz, CH2); 13C NMR (CDCl3): l 21.5, 23.1
(CH3), 53.4 (CO2CH3), 73.7, 73.8 (CH2), 86.0, 87.6
(C(CH3)O), 170.1, 170.5 (CO2CH3); IR (CH2Cl2) 1759,
1743 (CꢀO); MS (EI) (m/z)=57, 121, 181; ESI+ (m/
z)=180+Na. Anal. calcd for C5H8O5S: C, 33.33; H,
4.48; S, 17.80. Found: C, 33.28; H, 4.50; S, 17.84%.
The enantioselectivity of the main regioisomer obtained
in the AA reaction with olefin 1c was determined by
transformation of compounds 3c into methyl 2-
hydroxy-2-methyl-3-(tosylamino)-propanoates and fur-
ther comparison with the data reported in the
literature.7 In this way, compounds 3c were hydrolysed
into the corresponding carboxylic acids by the action of
LiOH·H2O. These acids were esterified using AcCl and
MeOH.
The enantioselectivity obtained in the AD reaction with
olefins 1a and 1b was determined by their transforma-
tion into cyclic sulfites 6 and further comparison of
their optical rotation with enantiomerically pure (R)-6.
In this way, compounds 4a were transformed into cyclic
sulfites 6 using the method described in the experimen-
tal section for the synthesis of compound (R)-6 from
(R)-5. Compounds 4b were treated with hydrogen/pal-
ladium on carbon to remove the benzyl group, obtain-
ing the corresponding carboxylic acids, which were
transformed into cyclic sulfites 6 following the method
described in the experimental section. The enantioselec-
tivity of AD reactions with olefin 1 was determined by
comparing our results with those reported in the
literature.9
As described for its enantiomer (R)-6, cyclic sulfite
(S)-6 (6.92 g, 90%) was obtained from compound (S)-5
(5.73 g, 42.7 mmol). [h]D25=+49.1 (c 1.15, MeOH). Anal.
calcd for C5H8O5S: C, 33.33; H, 4.48; S, 17.80. Found:
C, 33.25; H, 4.53; S, 17.87%.
4.4. Methyl 2-azido-3-hydroxy-2-methylpropanoates
(S)-8 and (R)-8
4.4.1. Method A. To a solution of cyclic sulfite (R)-6
(5.70 g, 31.6 mmol) in DMF (30 mL) was added NaN3
(2.72 g, 41.8 mmol). The mixture was stirred at 50°C
for 2 days to give a mixture of azido alcohols (R)-7 and
(S)-8 in a ratio of 1:4. The solvent was then removed
and the residue partitioned between H2O (30 mL) and
ethyl acetate (70 mL). The aqueous layer was succes-
sively washed with ethyl acetate (4×40 mL), dried
(Na2SO4), concentrated and the crude product was
chromatographed (hexane:ethyl acetate, 4:1) to give
(R)-7 (0.90 g, 18%) and the required a-azido ester (S)-8
as a colourless liquid (3.77 g, 23.7 mmol); yield: 75%.
Overall yield: 93%. Compound (R)-7: [h]2D5=+59.4 (c
4.2. Methyl 2,3-dihydroxy-2-methylpropenoates (R)-5
and (S)-5
To a solution of (R)-4c (8.60 g, 52.7 mmol) in H2O/
MeOH (1:3, 120 mL) was added LiOH·H2O (11.1 g,
264 mmol) and the mixture was stirred at room temper-
ature for 2 h. The N,O-dimethylhydroxylamine formed
in the reaction and MeOH were removed and the
mixture was acidified with conc. HCl to pH 1–2. After
removing the solvent, the white solid was dissolved in
HCl in MeOH, previously prepared by dropwise addi-
tion of AcCl (30 mL) to a pre-cooled MeOH (120 mL)
at 0°C, and the mixture was heated under reflux for 12
h. The mixture was concentrated and the residue parti-
tioned between H2O (50 mL) and CHCl3/propan-2-ol
(3:1, 100 mL). The aqueous layer was successively
washed with CHCl3/propan-2-ol (4×100 mL), dried
(Na2SO4), concentrated and the crude product was
purified by column chromatography (hexane:ethyl ace-
tate, 3:7) to give (R)-5 as a colourless oil (5.98 g, 44.6
mmol); yield: 85%. [h]2D5=−1.0 (c 2.66, MeOH). 1H
NMR (CDCl3): l 1.35 (s, 3H, CH3), 3.57 (d, 1H,
J=11.2 Hz, CH2), 3.80 (d, 1H, J=11.2 Hz, CH2), 3.81
(s, 3H, CO2CH3). Anal. calcd for C5H10O4: C, 44.77; H,
1
1.51, MeOH); H NMR (CDCl3): l 1.38 (s, 3H, CH3),
3.37–3.47 (m, 2H, CH2), 3.62–3.67 (br s, 1H, OH), 3.79
(s, 3H, CO2CH3); 13C NMR (CDCl3): l 23.3 (CH3),
53.2 (CO2CH3), 58.3 (CH2), 75.2 (C(CH3)OH), 175.1
(CO2CH3); MS (EI) (m/z)=15, 43, 103, 160; ESI−
(m/z)=158. Anal. calcd for C5H9N3O3: C, 37.74; H,
5.70; N, 26.40. Found: C, 37.68; H, 5.66; N, 26.31%.
Compound (S)-8: [h]2D5=−2.2 (c 0.98, MeOH); 1H
NMR (CDCl3): l 1.48 (s, 3H, CH3), 2.08 (br s, 1H,
OH), 3.63 (d, 1H, J=11.6 Hz, CH2), 3.80 (d, 1H,
J=11.6 Hz, CH2), 3.83 (CO2CH3); 13C NMR (CDCl3):
l 19.1 (CH3), 52.9 (CO2CH3), 67.4 (CH2), 67.5
(C(CH3)N3), 172.0 (CO2CH3); IR (CH2Cl2) 3593 (OH),

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A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
1743 (CꢀO); MS (EI) (m/z)=59, 85, 160; ESI+ (m/z)=
159+Na. Anal. calcd for C5H9N3O3: C, 37.74; H, 5.70;
N, 26.40. Found: C, 37.70; H, 5.72; N, 26.35%.
give the corresponding amino alcohol as a pale yellow
oil. To this compound was added an aqueous HCl
solution (6N, 20 mL) and the mixture was heated under
reflux for 12 h. The solvent was removed to give
a-methylserine 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.
After this time, the a-methylserine (S)-12 partially pre-
cipitated as a white solid (312 mg). The filtrate was
concentrated and the residue was dissolved in water
and eluted through a C18 reverse-phase Sep-pak car-
tridge to give, after removal of the water, 218 mg of
(S)-12 as a white solid; total amount (530 mg, 4.45
As described for its enantiomer (S)-8, a-azido ester
(R)-8 (3.85 g, 75%) was obtained from compound (S)-6
(5.72 g, 31.7 mmol). [h]2D5=+1.9 (c 1.49, MeOH). Anal.
calcd for C5H9N3O3: C, 37.74; H, 5.70; N, 26.40.
Found: C, 37.67; H, 5.69; N, 26.31%.
4.4.2. Method B. To a stirred solution of cyclic sulfate
(R)-9 (0.42 g, 2.14 mmol) in acetone (20 mL) and water
(2 mL) was added NaN3 (0.35 g, 5.38 mmol). The
mixture was stirred at room temperature for 2 days to
give a mixture of (R)-10 and (S)-11 in a ratio of 1:9.
The reaction was concentrated under reduced pressure,
ethyl ether (30 mL) and water (1 mL) were added and
the solution was chilled to 0°C followed by addition of
20% aqueous H2SO4 (3 mL). The solution was vigor-
ously stirred at room temperature for 2 days. The
organic layer was collected and concentrated and the
crude product was chromatographed (hexane:ethyl ace-
tate, 4:1) to give the compound (R)-7 (26 mg, 8%) and
the required a-azido ester (S)-8 as a colourless liquid
(0.23 g, 1.44 mmol); yield: 67%. Overall yield: 75%.
1
mmol); yield: 59%. [h]2D5=+5.3 (c 1.02, H2O). H NMR
(D2O): l 1.28 (s, 3H, CH3), 3.52 (d, 1H, J=12.0 Hz,
CH2), 3.77 (d, 1H, J=12.0 Hz, CH2). ESI− (m/z)=118.
Anal. calcd for C4H9NO3: C, 40.33; H, 7.62; N, 11.76.
Found: C, 40.25; H, 7.66; N, 11.68%. Spectral data
were identical to those reported in the literature.15
4.6.2. Method B. A suspension of a-azido ester (S)-8
(1.50 mg, 9.42 mmol) in aqueous HCl solution (6N, 15
mL) was heated under reflux for 12 h to give, after
complete evaporation, the crude acid. This compound
was dissolved in MeOH (50 mL) and was hydrogenated
using palladium on carbon as catalyst (1:5 catalyst/sub-
strate by weight). The resulting suspension was stirred
at room temperature for 24 h. The catalyst was then
removed by filtration and the solvent was evaporated to
give (S)-12 as a white solid (0.93 g, 7.82 mmol); yield:
83%.
4.5. Methyl 4-methyl-2-dioxo-2l6-[1,3,2]dioxathiolane-4-
carboxylates (R)-9 and (S)-9
Compound (R)-6 (0.50 g, 2.78 mmol) was dissolved in
a mixture of water (15 mL), CH3CN (10 mL) and CCl4
(10 mL). NaIO4 (1.16 g, 5.42 mmol) and RuCl3 hydrate
(10 mg, 0.05 mmol) were added and the solution was
vigorously stirred for 7 h at 40°C. Ethyl ether (75 mL)
was added to the cooled mixture. The organic layer was
removed, dried (Na2SO4) and concentrated. The crude
product was chromatographed (hexane:ethyl acetate,
4:1) to give compound (R)-9 as a colourless liquid (0.38
g, 2.36 mmol); yield: 86%. [h]2D5=−20.4 (c 1.42, MeOH);
1H NMR (CDCl3): l 1.78 (s, 3H, CH3), 3.85 (s, 3H,
CO2CH3), 4.47 (d, 1H, J=9.3 Hz, CH2), 4.98 (d, 1H,
J=9.0 Hz, CH2); 13C NMR (CDCl3): l 22.2 (CH3),
54.0 (CO2CH3), 74.8 (CH2), 86.2 (C(CH3)O), 168.3
(CO2CH3); IR (CH2Cl2) 1748 (CꢀO), 1400 (sulfate),
1217 (sulfate); MS (EI) (m/z)=57, 137, 197; ESI+ (m/
z)=197. Anal. calcd for C5H8O6S: C, 30.61; H, 4.11; S,
16.35. Found: C, 31.21; H, 4.23; S, 16.21%.
4.6.3. Method C. Diol (S)-5 (300 mg, 2.24 mmol) was
dissolved in dichloroethane (30 mL). Dibutyltin oxide
(0.62 g, 2.46 mmol) was added and the mixture heated
to reflux for 7 h using a Dean–Stark trap to remove the
water formed in the reaction. Benzoyl isothiocyanate
(0.53 mL, 3.8 mmol) and triethylamine (0.38 mL, 2.7
mmol) were added and the mixture was heated to
reflux. After stirring for 7 h, tetrabutylammonium bro-
mide (0.8 g, 2.46 mmol) was added and heating was
continued for a further 7 h to give a mixture of two
cyclic iminocarbonates in a ratio of 1:4 in favour of the
desired regioisomer. The reaction mixture was parti-
tioned between ethyl acetate and water. The organic
phase was separated, washed with brine and dried
(Na2SO4). The concentrated crude product was chro-
matographed on a silica column (hexane:ethyl acetate,
8:2) to give the desired iminocarbonate (0.26 g, 1.01
mmol) as a colourless oil. A suspension of this com-
pound in aqueous HCl solution (6N, 7 mL) was heated
under reflux for 12 h to give, after removing the sol-
vent, the a-methylserine hydrochloride as a white solid.
Compound (S)-12 (70 mg, 0.59 mmol) was obtained
using the same procedure described in Method A; yield:
26% from (S)-5.
As described for its enantiomer (R)-9, compound (S)-9
(0.52 g, 86%) was obtained from compound (S)-6 (0.68
g, 3.78 mmol). [h]2D5=+19.8 (c 1.43, MeOH). Anal.
calcd for C5H8O6S: C, 30.61; H, 4.11; S, 16.35. Found:
C, 31.00; H, 4.15; S, 16.62%.
4.6. a-Methylserines (S)-12 and (R)-12
4.6.1. Method A. A solution of a-azido ester (S)-8 (1.20
g, 7.54 mmol) in MeOH (40 mL) was hydrogenated
using palladium on carbon as catalyst (1:5 catalyst/sub-
strate by weight) and the resulting suspension was
stirred at room temperature for 24 h. The catalyst was
removed by filtration and the solvent was evaporated to
As described for a-methylserine (S)-12 (Method B), its
enantiomer (R)-12 (195 mg, 83%) was obtained from
(R)-8 (313 mg, 1.97 mmol). [h]2D5=−5.4 (c 1.01, H2O).
Anal. calcd for C4H9NO3: C, 40.33; H, 7.62; N, 11.76.
Found: C, 40.29; H, 7.65; N, 11.70%.

A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
955
4.7. N-(tert-Butoxycarbonyl)-a-methylserine methyl
esters (S)-13 and (R)-13
C13H23NO5: C, 57.13; H, 8.48; N, 5.12. Found: C,
57.08; H, 8.41; N, 5.06%.
A solution of a-azido ester (S)-8 (5.50 g, 34.6 mmol) in
MeOH (50 mL) was hydrogenated using palladium on
carbon as catalyst (1:5 catalyst/substrate by weight) and
the resulting suspension was stirred at room tempera-
ture for 24 h. The catalyst was removed by filtration
and the solvent was evaporated to give the corres-
ponding amino alcohol as a pale yellow oil. This
compound was dissolved in H2O/THF (1:5, 60 mL)
and Na2CO3·10H2O (12.9 g, 45.0 mmol) and Boc2O
(9.82 g, 45.0 mmol) were then added. The mixture
was stirred at room temperature for 19 h and the
reaction was quenched with saturated NH4Cl (20 mL)
and extracted with ethyl acetate (3×50 mL). The
combined organic layers were dried (Na2SO4), filtered
and concentrated. The residue was purified by flash
chromatography (hexane:ethyl acetate, 7:3) to give
(S)-13 as a colourless oil (5.64 g, 24.2 mmol); yield:
4.9. N-(tert-Butoxycarbonyl)-4-hydroxymethyl-2,2,4-
trimethyl-3-oxazolidines (S)-15 and (R)-15
To a suspension of LiAlH4 (301 mg, 7.92 mmol) in
THF (20 mL) was added dropwise a solution of (S)-14
(1.03 g, 3.77 mmol) in THF (30 mL). The mixture was
vigorously stirred for 6 h at room temperature and was
then carefully quenched by addition of water (0.4 mL),
NaOH solution (1N, 1.5 mL) and water (1.5 mL). After
stirring at room temperature for 3 h, the white precipi-
tate was filtered off and washed with ethyl ether. The
filtrate was concentrated and the residue purified by
column chromatography (hexane:ethyl acetate, 8:2) to
give (S)-15 as a white solid (0.84 g, 3.42 mmol); yield:
91%. Mp 59–60°C. [h]2D5=−1.7 (c 1.99, CHCl3). 1H
NMR (CDCl3) l 1.43, 1.49, 1.56 (3s, 18H, (CH3)3C,
CH3, (CH3)2C), 3.52–3.75 (m, 4H, CH2, CH2OH), 4.55,
4.57 (2br s, 1H, OH). Anal. calcd for C12H23NO4: C,
58.75; H, 9.45; N, 5.71. Found: C, 58.72; H, 9.38; N,
5.60%. Spectral data were identical to those reported in
the literature.5a
1
70%. [h]2D5=−10.8 (c 2.26, MeOH). H NMR (CDCl3):
l 1.41 (s, 9H, (CH3)3C), 1.44 (s, 3H, CH3), 3.25
(br s, 1H, OH), 3.75 (s, 3H, CO2CH3), 3.73–3.78 (m,
1H, CH2), 3.92 (br d, 1H, J=11.4 Hz, CH2), 5.26 (br s,
1H, NH). Anal. calcd for C10H19NO5: C, 51.49; H,
8.21; N, 6.00. Found: C, 51.38; H, 8.16; N, 6.10%.
Spectral data were identical to those reported in the
literature.16
As described for compound (S)-15, its enantiomer (R)-
15 (0.86 g, 91%) was obtained from (R)-14 (1.05 g, 3.84
mmol). [h]2D5=+1.3 (c 1.99, CHCl3). Anal. calcd for
C12H23NO4: C, 58.75; H, 9.45; N, 5.71. Found: C,
58.70; H, 9.41; N, 5.65%.
As described for N-Boc protected a-methylserine
methyl ester (S)-13, its enantiomer (R)-13 (5.63 g, 70%)
was obtained from (R)-8 (5.52 g, 34.7 mmol). [h]2D5=+
11.8 (c 2.84, MeOH). Anal. calcd for C10H19NO5: C,
51.49; H, 8.21; N, 6.00. Found: C, 51.40; H, 8.13; N,
6.12%.
4.10. N-(tert-Butoxycarbonyl)-4-formyl-2,2,4-trimethyl-
3-oxazolidines (S)-16 and (R)-16
DMSO (2.23 g, 28.6 mmol) was added, at −78°C, to a
solution of oxalyl chloride (2.18 g, 17.2 mmol) in
CH2Cl2 (30 mL). The resulting solution was stirred for
5 min at −78°C, then a solution of (S)-15 (3.52 g, 14.3
mmol) in CH2Cl2 (30 mL) was added. The resulting
mixture was stirred for 15 min at −78°C and Et3N (5.79
g, 57.2 mmol) was then added. The solution was
allowed to warm to room temperature and quenched by
the addition of saturated NaHCO3 (70 mL) and then
diluted with ethyl ether (70 mL). The phases were
separated and the organic phase was washed with 1 M
KHSO4 (30 mL), saturated NaHCO3 (30 mL) and brine
(30 mL), dried (Na2SO4), filtered and concentrated. The
crude product was purified by column chromatography
(hexane:ethyl acetate, 9:1) to give (S)-16 as a white
solid (3.34 g, 96%). Mp 54–55°C; [h]2D5=−21.8 (c 2.06,
CHCl3). 1H NMR (CDCl3) l 1.30–1.70 (m, 18H,
(CH3)3C, CH3, (CH3)2C), 3.65, 3.68 (2d, 1H, J=6.9 Hz,
CH2), 3.92 (d, 1H, J=9.3 Hz, CH2), 9.39, 9.46 (2s, 1H,
CHO). Anal. calcd for C12H21NO4: C, 59.24; H, 8.70;
N, 5.76. Found: C, 59.20; H, 8.65; N, 5.78%. Spectral
data were identical to those reported in the literature.5a
4.8. N-(tert-Butoxycarbonyl)-4-methoxycarbonyl-2,2,4-
trimethyl-3-oxazolidines (S)-14 and (R)-14
Compound (S)-13 (6.25 g, 26.8 mmol) was dissolved in
a mixture of acetone (70 mL) and DMP (35.7 g, 343
mmol) before adding BF3·OEt2 (0.2 mL, 1.58 mmol).
The resulting solution was stirred at room temperature
for 1 h and the solvent was then removed. The residual
oil was taken up in CH2Cl2 (100 mL) and the resulting
solution was washed with a mixture of saturated
NaHCO3/H2O (1:1, 40 mL) and brine (40 mL), and
then dried (Na2SO4). The solvent was evaporated and
the crude product was purified by chromatography
(hexane:ethyl acetate, 9.5:0.5) to give (S)-14 as a liquid
(6.80 g, 24.9 mmol); yield: 93%. [h]2D5=−18.6 (c 1.04,
MeOH). 1H NMR (CDCl3, 333 K): l 1.40 (s, 3H,
CH3), 1.43 (s, 9H, (CH3)3C), 1.56 (s, 6H, (CH3)2C), 3.72
(s, 3H, CO2CH3), 3.76 (d, 1H, J=8.7 Hz, CH2), 4.07 (d,
1H, J=8.7 Hz, CH2). Anal. calcd for C13H23NO5: C,
57.13; H, 8.48; N, 5.12. Found: C, 57.00; H, 8.40; N,
5.10%. Spectral data were identical to those reported in
the literature.16
As described for aldehyde (S)-16, its enantiomer (R)-16
(3.35 g, 96%) was obtained from (R)-15 (3.53 g, 14.3
mmol). [h]2D5=+22.0 (c 2.05, CHCl3). Anal. calcd for
C12H21NO4: C, 59.24; H, 8.70; N, 5.76. Found: C,
59.22; H, 8.75; N, 5.76%.
As described for compound (S)-14, its enantiomer (R)-
14 (6.86 g, 93%) was obtained from (R)-13 (6.28 g, 26.9
mmol). [h]2D5=+18.1 (c 1.12, MeOH). Anal. calcd for

956
A. A6enoza et al. / Tetrahedron: Asymmetry 12 (2001) 949–957
3. (a) Avenoza, A.; Cativiela, C.; Peregrina, J. M. Tetra-
hedron 1994, 50, 10021; (b) Avenoza, A.; Cativiela, C.;
Ferna´ndez-Recio, M. A.; Peregrina, J. M. Synlett 1995,
891; (c) Avenoza, A.; Cativiela, C.; Ferna´ndez-Recio, M.
A.; Peregrina, J. M. Tetrahedron: Asymmetry 1996, 7,
721; (d) Avenoza, A.; Cativiela, C.; Par´ıs, M.; Peregrina,
J. M.; Sa´enz-Torre, B. Tetrahedron: Asymmetry 1997, 8,
1123; (e) Avenoza, A.; Busto, J. H.; Cativiela, C.; Pere-
grina, J. M. An. Qu´ım. Int. Ed. 1998, 94, 50; (f) Avenoza,
A.; Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina, J.
M. Tetrahedron: Asymmetry 1999, 10, 3999; (g) Avenoza,
A.; Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina, J.
M. J. Chem. Soc., Perkin Trans. 1 1999, 3375; (h)
Avenoza, A.; Busto, J. H.; Cativiela, C.; Peregrina, J. M.
Amino Acids 2000, 18, 117; (i) Avenoza, A.; Barriobero,
J. I.; Cativiela, C.; Ferna´ndez-Recio, M. A.; Peregrina, J.
M.; Rodr´ıguez, F. Tetrahedron 2001, 57, 2745–2755.
4. Obrecht, D.; Altorfer, M.; Lehmann, C.; Scho¨nholzer, P.;
Mu¨ller, K. J. Org. Chem. 1996, 61, 4080.
5. (a) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J.
M.; Zurbano, M. M. J. Org. Chem. 1999, 64, 8220; (b)
Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 1999, 10, 4653;
(c) Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J.
M.; Zurbano, M. M. Tetrahedron: Asymmetry 2000, 11,
2195.
6. (a) Sharpless, K. B.; Bruncko, M.; Schlingloff, G. Angew.
Chem., Int. Ed. Engl. 1997, 36, 1483; (b) Sharpless, K. B.;
Tao, B.; Schlingloff, G. Tetrahedron Lett. 1998, 39, 2507;
(c) Song, C. E.; Oh, C. R.; Roh, E. J.; Lee, S.; Choi, J. H.
Tetrahedron: Asymmetry 1999, 10, 671; (d) O’Briean, P.
Angew. Chem., Int. Ed. Engl. 1999, 38, 326.
4.11. (2S,2%S)-3%,3%,3%-Trifluoro-2%-methoxy-2%-phenylpro-
pionic acid 2-tert-butoxycarbonylamino-2-methoxycar-
bonylpropyl ester 17
To a solution of alcohol (S)-13 (47 mg, 0.19 mmol),
DCC (42 mg, 0.20 mmol) and DMAP (3 mg, 0.02
mmol) in CH2Cl2 (3 mL) was added a solution of
(S)-(−)-MTPA (53 mg, 0.22 mmol) in CH2Cl2 (3 mL).
After stirring the mixture at room temperature for 6 h,
the resulting white suspension was filtered to remove
N,N%-dicyclohexylurea. The filtrate was concentrated to
give a white slurry, to which Et2O was added. The
resulting suspension was filtered to remove the dicyclo-
hexylurea and the solvent was evaporated. The residue
was purified by column chromatography (hexane/ethyl
acetate, 9:1) to give 17 (42 mg, 0.09 mmol) as a
colourless oil; yield: 48%. [h]2D5=−41.7 (c 0.88, MeOH);
1H NMR (CDCl3): l 1.41 (s, 9H, (CH3)3C), 1.49 (s, 3H,
CH3), 3.52 (s, 3H, OCH3), 3.68 (s, 3H, CO2CH3),
4.65–4.90 (m, 2H, CH2O), 5.28 (br s, 1H, NHCO),
7.35–7.42 (m, 3H, Ph), 7.45–7.55 (m, 2H, Ph); 13C
NMR (CDCl3): l 20.5 (CH3), 28.2 ((CH3)3C), 52.9
(CO2CH3), 55.4 (OCH3), 58.6 (C(CH3)NH), 66.7
(CH2), 80.0 ((CH3)3C), 121.3 (C(CF3)), 125.1 (CF3),
127.3, 128.4, 129.6, 132.0 (Ph), 153.8 (OCON), 165.8
(CO2CH2), 172.3 (CO2CH3); 19F NMR (CDCl3): l
−72.0; MS (EI) (m/z)=57, 102, 189, 290; ESI+ (m/z)=
449+Na. Anal. calcd for C20H26F3NO7: C, 53.45; H,
5.83; N, 3.12. Found: C, 53.92; H, 5.62; N, 3.13%.
Acknowledgements
7. Sharpless, K. B.; Li, G.; Chang, H.-T. Catalytic asym-
metric aminohydroxylation of olefins with sulfonamides.
PCT Int. Appl. (1997), 77 pp. CODEN: PIXXD2 WO
9744316 A1 19971127 CAN 128:48387 AN 1997:776148
CAPLUS.
8. For reviews on AD reactions, see: (a) Kolb, H. C.;
VanNiewenhze, M. S.; Sharpless, K. B. Chem. Rev. 1994,
94, 2483; (b) Berrisford, D. J.; Bolm, C.; Sharpless, K. B.
Angew. Chem., Int. Ed. Engl. 1995, 34, 1059; (c) Johnson,
R. A.; Sharpless, K. B. In Catalytic Asymmetric Synthe-
sis; Ojima, I., Ed.; VCH Publishers: New York, 1993; pp.
227–272.
This work has been supported by the Direccio´n Gen-
eral de Ensen˜anza Superior (project PB97-0998-C02-02)
and the Universidad de La Rioja (project API-00/B02).
F.C. and D.S. thank the Ministerio de Educacio´n y
Ciencia and the Gobierno de La Rioja, respectively, for
their doctoral grants.
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