Synthesis of enantiopure (αMe)Dip and other α-methylated β-branched amino acid derivatives

Article abstract of DOI:10.1016/S0957-4166(02)00828-5

This report describes the synthesis of the two enantiomerically pure α-methylated β-branched phenylalanine derivatives, (S)- and (R)-α-methyl-β,β-diphenylalanine - (αMe)Dip - starting from the chiral building blocks (R)- and (S)-N-Boc-N,O-isopropylidene-α

Full text of DOI:10.1016/S0957-4166(02)00828-5

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 14 (2003) 399–405
Synthesis of enantiopure (aMe)Dip and other a-methylated
b-branched amino acid derivatives
Alberto Avenoza,a,* Jesu´s H. Busto,a Carlos Cativiela,b 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 14 November 2002; accepted 3 December 2002
Abstract—This report describes the synthesis of the two enantiomerically pure a-methylated b-branched phenylalanine derivatives,
(S)- and (R)-a-methyl-b,b-diphenylalanine—(aMe)Dip—starting from the chiral building blocks (R)- and (S)-N-Boc-N,O-iso-
propylidene-a-methylserine methyl esters, respectively. The key step involves a double alkylation with a Grignard reagent on an
ester group. The use of the same protocol for the preparation of other a-methylated b-branched serine derivatives is also
described. © 2003 Elsevier Science Ltd. All rights reserved.
1. Introduction
mation of each enantiomerically pure compound.11
Taking into account the importance of the a-methyl-
ated b-branched a-amino acids (S)- and (R)-1, as well
as our experience in the synthesis of quaternary a-
amino acids from the chiral building blocks N-Boc-
In the last few years the synthesis of quaternary a-
amino acids has received a great deal of attention,1,2
particularly a-methylated a-amino acids since they are
capable of stabilising certain conformations when they
are incorporated into peptides.3–5 In this context, sev-
eral authors have focused their interest on the special
case of a-methylated a-amino acids with a b-branched
side chain.6,7 For example, a-methyl-b,b-diphenylala-
nine—(aMe)Dip—has been the subject of several theo-
N,O-isopropylidene-a-methylserinals
(S)-
and
(R)-2,12–15 we wanted in the first instance to develop a
new and straightforward synthesis of both enantiomers
of (aMe)Dip (Fig. 1).
retical calculations and these indicate
a marked
preference for folded conformations.8 This predicted
behaviour has been demonstrated experimentally by
incorporation of this unit into peptides.9 However,
(aMe)Dip has only been synthesised on two occasions.
The R-isomer was obtained by asymmetric synthesis
from highly stereoselective enolate trapping of lithium
(1S,2R,4R)-10-dicyclohexylsulfamoylisobornyl-2-cyano-
3,3-diphenylpropanoate combined with the appropriate
rearrangement process.10 More recently, both isomers
of (aMe)Dip were obtained by HPLC resolution of a
racemic precursor, followed by the convenient transfor-
Figure 1. (S)- and (R)-a-Methyl-b,b-diphenylalanines and
chiral building blocks (R)- and (S)-2.
* Corresponding authors. Tel./fax: +34-941-299655; e-mail: alberto.
avenoza@dq.unirioja.es; jesusmanuel.peregrina@dq.unirioja.es
0957-4166/03/$ - see front matter © 2003 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(02)00828-5

400
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
2. Results and discussion
Catalytic dehydroxylation of (R)-4 followed by hydro-
lysis in basic medium gave the corresponding amino
alcohol, the amine group of which was protected with
CbzCl to give compound (S)-5. Oxidation of the alco-
hol to the carboxylic acid, using Jones’ reagent, and
subsequent hydrogenolysis in the presence of Pd/C as a
catalyst in order to deprotect the Cbz carbamate group,
gave the required (aMe)Dip of S-configuration in 85%
yield [overall yield of 59% from starting material (R)-3].
The (aMe)Dip of R-configuration was obtained in a
similar way but starting from chiral building block
(S)-3 (Scheme 1).
2.1. Synthesis of (aMe)Dip
Our synthesis started from the methyl ester derivative
(R)-3, a precursor of the chiral building block (R)-2,
and the key step was the double alkylation with phenyl-
magnesium bromide to give the alcohol (R)-4 in good
yield (Scheme 1). Single crystals of (R)-4 were obtained
in order to confirm its structure by X-ray diffraction
(Fig. 2).†
2.2. Synthesis of a-methylated b-branched serine deriva-
tives (aMe)Dps and (aMe)Dms
Another aspect of our research programme is focused
on other valuable unnatural quaternary a-amino acids;
the b-branched serine derivatives. In this respect, and in
order to increase the number of available a-methylser-
ine derivatives14–17 (Fig. 3), we recently reported the
synthesis of all stereoisomers of a-methylated b-
phenylserine—new ‘chimeras’ that are a combination of
a-methylated phenylalanine and serine—in their enan-
tiomerically pure forms.14 We wish to report herein the
synthesis of suitably protected a-methylated b,b-
diphenylserine—(aMe)Dps—(S)-7.
Scheme 1. Reagents and conditions: (a) PhMgBr, THF, 35°C,
12 h, 87%; (b) (i) Pd(OH)2, 5 atms H2, HCOOH, 60°C, 36 h;
(ii) NaOH, H2O/MeOH (1:1), reflux, 12 h; (iii) CbzCl,
Na2CO3·10H2O, H2O/THF (1:5), rt, 12 h, 80%; (c) (i) Jones
reagent, acetone, 0°C, 3 h, rt, 3 h; (ii) Pd/C, H2, MeOH, rt, 24
h, 85%.
The starting material for this synthesis was N-Boc
protected N,O-acetal compound (R)-4 and this
approach utilises the propensity of the N-Boc protect-
ing group to react intramolecularly with nucleophiles.18
Treatment of (R)-4 with sodium hydride in DMF, as a
solvent, led to nucleophilic attack of the alkoxide anion
on the carbamate to give compound (R)-6 (Scheme 2).
Cleavage of the N,O-acetal in acidic medium, followed
by Jones’ oxidation and addition of diazomethane,
afforded the requisite a-methylated b-branched amino
acid, in which the amine and hydroxyl groups are
protected as the oxazolidine ring and the carboxylic
acid group as the methyl ester (Scheme 2). In a similar
way, but starting from (S)-4 [prepared from (S)-3], the
enantiomer (R)-7 was obtained. The structure of
Figure 2. ORTEP diagram of compound (R)-4.
† Crystal data: C24H31NO4, Mw=397.50, colourless prism, T=293 K,
monoclinic, space group C2, Z=4, a=20.0527(4), b=6.3789(2),
3
,
,
c=18.6631(4) A, i=111.042(2)°, V=2228.10(10) A , Dcalcd=1.185
g cm−3, F(000)=856, u=0.71073 A (Mo, Ka), v=0.080 mm
,
−1
,
Nonius kappa CCD diffractometer, q range 2.18–26.73°, 9391
collected reflections, 4402 unique, full-matrix least-squares
(SHELXL97a), R1=0.0469, wR2=0.1216, (R1=0.0617, wR2=
0.1299 all data), goodness of fit=1.300, residual electron density
between 0.314 and −0.190 e A−3. Hydrogen atoms were located
,
from mixed methods (electron-density maps and theoretical posi-
tions). Further details on the crystal structure are available on
request from Cambridge Crystallographic Data Center, 12 Union
Road, Cambridge, UK on quoting the depository number 195672.
(a) Sheldrick, G. M. SHELXL97. Program for the refinement of
crystal structures. University of Go¨ttingen, Germany, 1997.
Figure 3. Unnatural quaternary a-methylated b-branched ser-
ine derivatives.

A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
401
Scheme 2. Reagents and conditions: (a) NaH, DMF, rt, 6 h,
99%; (b) (i) 4N HCl/THF (1:1), rt, 4 h; (ii) Jones reagent,
acetone, 3 h, 0°C and another 3 h, rt; (iii) CH2N2, MeOH,
0°C, 30 min, 85%.
bicyclic compound (R)-6 was confirmed by X-ray anal-
Scheme 3. Reagents and conditions: (a) MeMgBr, THF, rt, 12
h, 91%; (b) Sc(TfO)3, H2O/acetonitrile, rt, 36 h, 82%; (c) (i) 6N
HCl/THF (1:1), rt, 2 h; (ii) CbzCl, Na2CO3·10H2O, H2O/THF
(1:5), rt, 15 h, 74%; (d) (i) Jones reagent, acetone, 3 h, 0°C and
another 3 h, rt; (ii) Pd/C, H2, MeOH, rt, 24 h, 64%.
ysis (Fig. 4).‡
Nevertheless, all attempts to oxidize the primary alcohol
(Jones’ reagent, Swern, Dess–Martin) were unsuccessful.
Therefore, (R)-8 was treated in an acid medium to get
the cleavage of N,O-acetal and the N-Boc group, giving
the corresponding aminodiol. This aminodiol was pro-
tected with CbzCl to give compound (R)-9b, which was
selectively oxidized at the primary alcohol using Jones’
reagent. The resulting product was hydrogenated in the
presence of Pd/C as a catalyst and MeOH as a solvent
to give (aMe)Dms (S)-10 (Scheme 3). The other enan-
tiomer of (aMe)Dms [(R)-10] was obtained in the same
way, but starting from the chiral building block (S)-3.
3. Conclusions
Figure 4. ORTEP diagram of compound (R)-6.
In summary, we have developed a versatile route to
synthesize both enantiomers of (aMe)Dip [(S)- and
(R)-1] from the N-Boc-N,O-isopropylidene-a-methylser-
ine methyl esters (R)- and (S)-3, respectively. These
syntheses were achieved by double alkylation of the
methyl ester group of the aforementioned chiral building
blocks with a Grignard reagent. Moreover, following the
same protocol, we have synthesised both enantiomers of
other a-methylated b-branched serine derivatives such as
a suitably protected (aMe)Dps [(S)- and (R)-7] and
(aMe)Dms [(S)- and (R)-10]. These b-branched quater-
nary a-amino acids are of great interest for incorporation
into peptides.
Moreover, using the same protocol as described above
for the synthesis of (aMe)Dip, we obtained the a-methy-
lated b,b-dimethylserine—(aMe)Dms—(S)-10. The only
previous synthesis of the R-enantiomer of this amino
acid was reported by Scho¨llkopf.17 The double alkylation
of the chiral building block (R)-3 gave the tertiary
alcohol (R)-8, which was treated with Sc(TfO)3 in
H2O/acetonitrile to drive the cleavage of N,O-acetal
exclusively. This route gave compound (R)-9a (Scheme
3).
‡ Crystal data: C20H21NO3, Mw=323.38, colourless prism of 0.38×
0.2×0.15 mm, T=173 K, monoclinic, space group P21/c, Z=4,
4. Experimental
,
a=8.3083(3), b=7.3248(3), c=28.0136(11) A, i=101.5410(17)°,
3
V=1670.34(11) A , Dcalcd=1.286 g cm−3, F(000)=688, u=0.71073
,
A (Mo, Ka), v=0.086 mm−1, Nonius kappa CCD diffractometer, q
,
4.1. General procedures
range 3.48–27.89°, 12353 collected reflections, 3967 unique, full-
matrix least-squares (SHELXL97a), R1=0.0510, wR2=0.1113,
(R1=0.0962, wR2=0.1312 all data), goodness of fit=1.024, residual
Solvents were purified according to standard proce-
dures. Analytical TLC was performed using Polychrom
SI F254 plates. Column chromatography was performed
electron density between 0.222 and −0.204 e A−3. Hydrogen atoms
,
fitted at theoretical positions. Further details on the crystal struc-
ture are available on request from Cambridge Crystallographic
Data Center, 12 Union Road, Cambridge, UK on quoting the
depository number 195673. (a) Sheldrick, G. M. SHELXL97. Pro-
gram for the refinement of crystal structures. University of Go¨ttin-
gen, Germany, 1997.
using silica gel 60 (230–400 mesh). H and 13C NMR
1
spectra were recorded on a Bruker ARX-300 spectrom-
eter. H and 13C NMR spectra were recorded in CDCl3
1
with TMS as the internal standard and in D2O with

402
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
TMS as the external standard using a coaxial micro-
tube (chemical shifts are reported in ppm on the l
scale, coupling constants in Hz). The assignment of
under reflux for 12 h. The MeOH was removed, the
aqueous layer was extracted with CHCl3/isopropanol
(3:1) (4×20 mL) and the combined organic extracts
were dried (Na2SO4) and concentrated to give the
corresponding amino alcohol. This compound was
dissolved in H2O/THF (1:5, 15 mL) and then
1
all separate signals in the H NMR spectra was made
on the basis of coupling constants, selective proton–
proton homonuclear decoupling experiments, proton–
proton COSY experiments and proton–carbon
HETCOR experiments. Melting points were deter-
mined on a Bu¨chi SMP-20 melting point apparatus
and are uncorrected. Optical rotations were measured
on a Perkin–Elmer 341 polarimeter in 1.0 and 0.5 dm
cells of 1.0 and 3.4 mL capacity, respectively. Micro-
analyses were carried out on a CE Instruments EA-
1110 analyser and are in good agreement with the
calculated values. IR spectra were recorded on a
Perkin–Elmer FT-IR Spectrum 1000 spectrophotome-
ter.
Na2CO3·10H2O
(0.27
g,
0.95
mmol)
and
ClCO2CH2Ph (0.13 mL, 0.88 mmol) were added. The
mixture was stirred at room temperature for 12 h.
The reaction was quenched with saturated NH4Cl (10
mL) and extracted with ethyl acetate (2 15 mL). The
combined organic layers were dried (Na2SO4), filtered
and concentrated. The residue was purified by column
chromatography (hexane:ethyl acetate, 8:2) to give
compound (S)-5 as a white solid (0.22 g, 0.59 mmol);
yield: 80%. Mp: 59°C. [h]2D5=−2.5 (c 1.02, MeOH);
1H NMR (CDCl3): l 1.40 (s, 3H, CH3), 3.62 (d, 1H,
J=12.0 Hz, CH2OH), 3.84 (d, 1H, J=12.0 Hz,
CH2OH), 4.65 (s, 1H, CHPh2), 4.98 (br s, 1H, NH),
5.02 (d, 1H, J=12.3 Hz, OCH2Ph), 5.12 (d, 1H, J=
12.3 Hz, OCH2Ph), 7.27–7.52 (m, 15H, Ph); 13C
NMR (CDCl3): l 21.5 (CH3), 56.1 (CPh2), 60.3
[C(CH3)NH], 66.7 (OCH2Ph), 67.8 (CH2OH), 126.7,
126.8, 128.0, 128.1, 128.3, 128.4, 128.5, 129.8, 130.0,
136.2, 139.8, 140.0 (Ph), 156.1 (OCON); MS (EI) (m/
z)=56, 100, 167, 346; ESI+ (m/z)=376.2. Anal. calcd
for C24H25NO3: C, 76.77; H, 6.71; N, 3.73. Found: C,
76.91; H, 6.80; N, 3.60%.
4.1.1. (R)-N-(tert-Butoxycarbonyl)-4-(hydroxydiphenyl-
methyl)-2,2,4-trimethyloxazolidine, (R)-4. To a pre-
cooled solution of (R)-3 (0.50 g, 1.83 mmol) in THF
(15 mL) at 0°C was added dropwise a 3 M solution
of phenylmagnesium bromide (4.3 mL, 12.8 mmol) in
THF. The cooling bath was removed and the mixture
warmed to 35°C for 12 h. The reaction was quenched
with saturated NH4Cl solution (10 mL) and extracted
with ethyl acetate (20 mL). The organic layer was
washed with brine (10 mL), dried (Na2SO4), concen-
trated and the crude product was purified by column
chromatography (hexane:ethyl acetate, 9.5:0.5) to give
(R)-4 as a white solid (0.63 g, 1.59 mmol); yield:
87%. Mp: 96°C. [h]D25=+54.1 (c 1.10, MeOH); 1H
NMR (CDCl3): l 1.11 (s, 3H, CH3), 1.37 [s, 9H,
(CH3)3C], 1.48 (s, 3H, CH3), 1.82 (s, 3H, CH3), 3.64
(d, 1H, J=9.6 Hz, CH2O), 4.69 (d, 1H, J=9.6 Hz,
CH2O), 7.25 (m, 5H, Ph), 7.48 (m, 2H, Ph), 7.64 (m,
3H, Ph); 13C NMR (CDCl3): l 21.7, 25.6, 26.4
(3CH3), 28.1 [(CH3)3C], 71.4 [C(CH3)NH], 73.6
(CH2O), 81.4, 82.0 [(CH3)3C, C(OH)Ph2], 95.5
[C(CH3)2], 126.6, 126.9, 127.0, 127.6, 127.8, 128.4,
144.5, 145.9 (Ph), 154.1 (OCON); MS (EI) (m/z)=56,
100, 167, 331; ESI+ (m/z)=398. Anal. calcd for
C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C,
72.71; H, 7.93; N, 3.63%.
4.1.4.
(R)-(1-Hydroxymethyl-1-methyl-2,2-diphenyl-
ethyl)carbamic acid benzyl ester, (R)-5. As described
for enantiomer (S)-5, compound (R)-5 (0.23 g, 80%)
was obtained from compound (S)-4 (0.30 g, 0.76
mmol). [h]2D5=+2.7 (c 0.90, MeOH). Anal. calcd for
C24H25NO3: C, 76.77; H, 6.71; N, 3.73. Found: C,
76.60; H, 6.81; N, 3.62%.
4.1.5. (S)-2-Amino-2-methyl-3,3-diphenylpropionic acid,
(S)-1. To a solution of alcohol (S)-5 (0.18 g, 0.48
mmol) in acetone (10 mL) at 0°C was added drop-
wise a 1.5-fold excess of Jones’ reagent over 5 min.
The mixture was stirred at 0°C for 3 h and then at
room temperature for a further 3 h. The excess Jones’
reagent was destroyed with 2-propanol. The mixture
was diluted with H2O (10 mL) and extracted with
ethyl acetate (4×20 mL). The combined organic
extracts were dried with anhydrous Na2SO4 and con-
centrated in vacuo. The residual yellow oil was dis-
solved in MeOH (15 mL) and palladium on carbon
(1:5 catalyst/substrate by weight) was added. The
resulting suspension was subjected to hydrogenolysis
at room temperature for 24 h. The catalyst was
removed by filtration and the solvent was evaporated
to give (S)-1 as a white solid (0.10 g, 0.41 mmol);
yield: 85%. Taking into account that this compound
is not soluble in H2O and in order to measure its
physical properties, the amino acid was transformed
into the corresponding hydrochloride salt. Mp: 271°C.
[h]D25=−6.8 (c 1.16, HClaq 1N); [lit.11 −8.5 (c 1.0,
HClaq 1N]. Spectroscopic data were identical to those
described in the literature.11 ES− (m/z)=254. Anal.
calcd for C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80.
Found: C, 65.97; H, 6.12; N, 4.71%.
4.1.2. (S)-N-(tert-Butoxycarbonyl)-4-(hydroxydiphenyl-
methyl)-2,2,4-trimethyloxazolidine, (S)-4. As described
for enantiomer (R)-4, compound (S)-4 (0.61 g, 87%)
was obtained from compound (S)-3 (0.48 g, 1.76
mmol). [h]2D5=−54.3 (c 1.20, MeOH). Anal. calcd for
C24H31NO4: C, 72.52; H, 7.86; N, 3.52. Found: C,
72.69; H, 7.95; N, 3.65%.
4.1.3.
(S)-(1-Hydroxymethyl-1-methyl-2,2-diphenyl-
ethyl)carbamic acid benzyl ester, (S)-5. To a solution
of compound (R)-4 (0.29 g, 0.73 mmol) in formic
acid (15 mL) was added Pd(OH)2 on carbon (1:5 cat-
alyst/substrate by weight). The resulting suspension
was stirred with a pressure of 5 atmospheres of H2 at
60°C for 36 h. The catalyst was removed by filtration
and the solvent was evaporated. The mixture was dis-
solved in H2O/MeOH (1:1, 20 mL) and NaOH (0.29
g, 7.30 mmol) was added. The suspension was heated

A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
403
4.1.6. (R)-2-Amino-2-methyl-3,3-diphenylpropionic acid,
(R)-1. As described for enantiomer (S)-1, compound
(R)-1 (87 mg, 85%) was obtained from compound (R)-5
(0.15 g, 0.40 mmol). [h]2D5=+7.0 (c 1.09, HClaq 1N);
[lit.10 +8.2 (c 1.0, 1N HClaq]. Anal. calcd for
C16H18ClNO2: C, 65.86; H, 6.22; N, 4.80. Found: C,
66.01; H, 6.15; N, 4.70%.
1H NMR (CDCl3): l 1.41 (s, 3H, CH3), 3.96 (s, 3H,
CO2CH3), 7.14 (br s, 1H, NH), 7.28–7.45 (m, 8H, Ph),
7.67–7.70 (m, 2H, Ph); 13C NMR (CDCl3): l 24.3
(CH3), 52.6 (CO2CH3), 69.8 [C(CH3)NH], 90.6
(COPh2), 126.2, 127.2, 128.0, 128.1, 128.3, 128.4, 137.2,
139.4 (Ph), 157.6 (OCON), 171.6 (CO2CH3). Anal.
calcd for C18H17NO4: C, 69.44; H, 5.50; N, 4.50.
Found: C, 69.27; H, 5.44; N, 4.41%.
4.1.7.
(R)-5,5,7a-Trimethyl-1,1-diphenyldihydrooxa-
zolo[3,4-c]oxazol-3-one, (R)-6. To a solution of (R)-4
(0.36 g, 0.91 mmol) in DMF (10 mL) at 0°C was added
NaH (43 mg, 1.09 mmol). The resulting suspension was
stirred at room temperature for 6 h before being
quenched at 0°C with H2O (5 mL). The resulting mix-
ture was concentrated and washed with ethyl acetate
(4×10 mL). The combined organic layers were dried
(Na2SO4), filtered and concentrated. The residue was
purified by column chromatography (hexane:ethyl ace-
tate, 8:2) to give compound (R)-6 as a white solid (0.29
g, 0.90 mmol); yield: 99%. Mp: 114°C. [h]2D5=−0.8 (c
4.1.10. (R)-4-Methyl-5,5-diphenyloxazolidin-2-one-4-car-
boxylic acid methyl ester, (R)-7. As described for enan-
tiomer (S)-7, compound (R)-7 (0.19 g, 85%) was
obtained from compound (S)-6 (0.23 g, 0.72 mmol).
[h]2D5=+15.7 (c 1.53, MeOH). Anal. calcd for
C18H17NO4: C, 69.44; H, 5.50; N, 4.50. Found: C,
69.29; H, 5.46; N, 4.48%.
4.1.11.
(R)-N-(tert-Butoxycarbonyl)-4-(1-hydroxy-1-
methylethyl)-2,2,4-trimethyloxazolidine, (R)-8. To a pre-
cooled solution of (R)-3 (0.22 g, 0.80 mmol) in THF
(10 mL) at 0°C was added dropwise a 3 M solution of
methylmagnesium bromide (1.34 mL, 4.0 mmol) in
THF. The cooling bath was removed and the mixture
warmed to room temperature for 12 h. The reaction
was quenched with saturated NH4Cl solution (10 mL)
and extracted with ethyl acetate (15 mL). The organic
layer was washed with brine (10 mL), dried (Na2SO4),
concentrated and the crude product was purified by
column chromatography (hexane:ethyl acetate, 9.5:0.5)
to give (R)-8 as a colourless oil (0.20 g, 0.73 mmol);
yield: 91%. [h]2D5=+4.1 (c 0.66, MeOH); 1H NMR
(CDCl3): l 1.06 (s, 3H, CH3), 1.18 (s, 3H, CH3), 1.42 (s,
3H, CH3), 1.44 (s, 3H, CH3), 1.47 (s, 9H, (CH3)3C),
1.57 (s, 3H, CH3), 3.58 (d, 1H, J=9.0 Hz, CH2O), 3.71
(d, 1H, J=9.0 Hz, CH2O), 6.20 (br s, 1H, OH); 13C
NMR (CDCl3): l 18.0, 24.8, 25.4, 25.8, 28.0 (5CH3),
28.3 [(CH3)3C], 70.9 [C(CH3)NH], 72.1 (CH2O), 72.2
[COH(CH3)2], 81.1 [(CH3)3C], 95.2 [C(CH3)2], 154.1
(OCON); MS (EI) (m/z)=57, 97, 114, 214; ESI+ (m/
z)=274.4. Anal. calcd for C14H27NO4: C, 61.51; H,
9.96; N, 5.12. Found: C, 61.37; H, 10.04; N, 5.23%.
1
1.02, MeOH); H NMR (CDCl3): l 1.29 (s, 3H, CH3),
1.46 (s, 3H, CH3), 1.48 (s, 3H, CH3), 3.33 (d, 1H,
J=8.4 Hz, CH2O), 3.64 (d, 1H, J=8.4 Hz, CH2O),
7.22–7.40 (m, 10H, Ph); 13C NMR (CDCl3): l 24.0,
24.7, 28.9 (3CH3), 72.4 (CH2O), 73.4 [C(CH3)NH],
87.8, 94.9 [C(CH3)2, COPh2], 125.5, 127.0, 128.0, 128.1,
128.2, 128.4, 139.0, 139.9 (Ph), 155.9 (OCON); MS (EI)
(m/z)=42, 83, 105, 182, 323; ESI+ (m/z)=324.2. Anal.
calcd for C20H21NO3: C, 74.28; H, 6.55; N, 4.33.
Found: C, 74.41; H, 6.60; N, 4.22%.
4.1.8.
(S)-5,5,7a-Trimethyl-1,1-diphenyldihydro-oxa-
zolo[3,4-c]oxazol-3-one, (S)-6. As described for enan-
tiomer (R)-6, compound (S)-6 (0.26 g, 99%) was
obtained from compound (S)-4 (0.32 g, 0.81 mmol).
[h]2D5=+1.1 (c 0.75, MeOH). Anal. calcd for
C20H21NO3: C, 74.28; H, 6.55; N, 4.33. Found: C,
74.42; H, 6.61; N, 4.19%.
4.1.9. (S)-4-Methyl-5,5-diphenyloxazolidin-2-one-4-car-
boxylic acid methyl ester, (S)-7. 4N HCl (5 mL) was
added to a solution of compound (R)-6 (0.27 g, 0.83
mmol) in THF (5 mL). The solution was stirred at
room temperature for 4 h. The reaction mixture was
extracted with ethyl acetate (2×10 mL). The combined
organic layers were dried (Na2SO4), filtered and concen-
trated to give the corresponding alcohol, which was
used without further purification. A 1.5-fold excess of
Jones’ reagent was added dropwise over 5 min to a
solution of this alcohol (0.22 g, 0.77 mmol) in acetone
(10 mL) at 0°C. The mixture was stirred at 0°C for 3 h
and then at room temperature for a further 3 h. The
excess Jones’ reagent was destroyed with 2-propanol.
The mixture was diluted with H2O (10 mL) and
extracted with ethyl acetate (4×15 mL). The combined
organic extracts were dried with anhydrous Na2SO4
and concentrated in vacuo. The residual yellow oil was
dissolved in MeOH (10 mL), cooled in an ice-bath, and
treated with ethereal diazomethane. After 30 min at
0°C the solvent was evaporated and the crude product
was purified by column chromatography (hexane:ethyl
acetate, 6:4) to give (S)-7 as a colourless oil (0.22 g,
0.71 mmol); yield: 85%. [h]2D5=−15.2 (c 1.20, MeOH);
4.1.12.
(S)-N-(tert-Butoxycarbonyl)-4-(1-hydroxy-1-
(S)-8. As
methylethyl)-2,2,4-trimethyloxazolidine,
described for enantiomer (R)-8, compound (S)-8 (0.19
g, 91%) was obtained from compound (S)-3 (0.21 g,
0.76 mmol). [h]2D5=−3.9 (c 0.84, MeOH). Anal. calcd
for C14H27NO4: C, 61.51; H, 9.96; N, 5.12. Found: C,
61.32; H, 9.94; N, 5.02%.
4.1.13. (R)-(2-Hydroxy-1-hydroxymethyl-1,2-dimethyl-
propyl)carbamic acid tert-butyl ester, (R)-9a. A solution
of compound (R)-8 (0.1 g, 0.37 mmol) in acetonitrile (3
mL) and H2O (33 ml, 1.83 mmol) was added to a
solution of Sc(OTf)3 (18 mg, 0.04 mmol) in acetonitrile
(3 mL) at room temperature. The reaction mixture was
stirred for 36 h and quenched with a phosphate buffer
(pH 7). The organic materials were extracted with ethyl
acetate (2×15 mL) and the combined organic layers
were dried (Na2SO4), filtered and concentrated. The
residue was purified by column chromatography (hex-
ane:ethyl acetate, 6:4) to give compound (R)-9a as a
colourless oil (70 mg, 0.30 mmol); yield: 82%. [h]2D5=

404
A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
1
−3.1 (c 1.07, MeOH); H NMR (CDCl3): l 1.18 (s, 6H,
2CH3), 1.27 (s, 3H, CH3), 1.43 [s, 9H, (CH3)3C], 3.78
(d, 1H, J=11.7 Hz, CH2OH), 3.85 (d, 1H, J=11.7 Hz,
CH2OH), 5.41 (br s, 1H, NH); 13C NMR (CDCl3): l
18.7, 25.0, 25.4 (3CH3), 28.3 [(CH3)3C], 61.1
[C(CH3)NH], 65.9 (CH2OH), 75.5 [COH(CH3)2], 79.6
[(CH3)3C], 156.4 (OCON). Anal. calcd for C11H23NO4:
C, 56.63; H, 9.94; N, 6.00. Found: C, 56.54; H, 9.81; N,
6.06%.
3H, CH3), 1.62 (s, 3H, CH3); 13C NMR (D2O): l 17.8,
24.4, 24.7 (3CH3), 67.6 [C(CH3)NH2], 72.2
[COH(CH3)2], 175.2 (COOH). Anal. calcd for
C6H13NO3: C, 48.97; H, 8.90; N, 9.52. Found: C, 49.07;
H, 9.02; N, 9.46%.
4.1.17. (R)-2-Amino-3-hydroxy-2,3-dimethylbutyric acid,
(R)-10. As described for enantiomer (S)-10, compound
(R)-10 (30 mg, 64%) was obtained from compound
(S)-9b (85 mg, 0.32 mmol). [h]2D5=−6.0 (c 1.0, H2O);
[lit.17 +18.3 (c 1.1, 5N HClaq from asymmetric synthesis
with e.e.:70–75%]. Anal. calcd for C6H13NO3: C,
48.97; H, 8.90; N, 9.52. Found: C, 49.10; H, 8.72; N,
9.69%.
4.1.14. (R)-(2-Hydroxy-1-hydroxymethyl-1,2-dimethyl-
propyl)carbamic acid benzyl ester, (R)-9b. Aqueous HCl
(6N, 5 mL) was added to a solution of compound (R)-8
(0.19 g, 0.70 mmol) in THF (5 mL). The solution was
stirred at 25°C for 2 h and the HCl was removed to
give the corresponding aminoalcohol. This compound
was dissolved in H2O/THF (1:5, 10 mL) and
Na2CO3·10H2O (0.50 g, 1.74 mmol) and ClCO2CH2Ph
(0.14 mL, 0.90 mmol) were added. The mixture was
stirred at room temperature for 15 h. The reaction was
quenched with saturated NH4Cl (10 mL) and extracted
with ethyl acetate (2×15 mL). The combined organic
layers were dried (Na2SO4), filtered and concentrated.
The residue was purified by column chromatography
(hexane:ethyl acetate, 6:4) to give compound (R)-9b as
a white solid (0.13 g, 0.49 mmol); yield: 74%. Mp: 67°C.
Acknowledgements
We thank the Ministerio de Ciencia y Tecnolog´ıa (pro-
ject PPQ2001-1305), the Gobierno de La Rioja (project
ANGI-2001/30) and the Universidad de La Rioja (pro-
ject API-01/B02). D.S. thanks the Comunidad
Auto´noma de La Rioja for a doctoral fellowship.
1
[h]2D5=−5.8 (c 1.34, MeOH); H NMR (CDCl3): l 1.18
(s, 3H, CH3), 1.21 (s, 3H, CH3), 1.29 (s, 3H, CH3), 3.78
(d, 1H, J=11.7 Hz, CH2OH), 3.95 (d, 1H, J=11.7 Hz,
CH2OH), 5.02–5.08 (m, 2H, OCH2Ph), 5.79 (br s, 1H,
NH), 7.33–7.36 (m, 5H, Ph); 13C NMR (CDCl3): l
18.5, 24.9, 25.2 (3CH3), 61.2 [C(CH3)NH], 65.8, 66.6
(OCH2Ph, CH2OH), 75.7 [COH(CH3)2], 128.0, 128.1,
128.5, 136.4 (Ph), 156.4 (OCON); ESI+ (m/z)=268.3.
Anal. calcd for C14H21NO4: C, 62.90; H, 7.92; N, 5.24.
Found: C, 63.03; H, 7.80; N, 5.30%.
References
1. Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 1998, 9, 3517–3599 and references cited
therein.
2. Cativiela, C.; D´ıaz-de-Villegas, M. D. Tetrahedron:
Asymmetry 2000, 11, 645–732 and references cited
therein.
3. Karle, I. L.; Balaram, P. Biochemistry 1990, 29, 6747–
6756.
4. Marshall, G. In Intra-Science Chemistry Report; Kha-
rasch, N., Ed.; Gordon and Breach: New York, 1971; p.
305.
4.1.15. (S)-(2-Hydroxy-1-hydroxymethyl-1,2-dimethyl-
propyl)carbamic acid benzyl ester, (S)-9b. As described
for enantiomer (R)-9b, compound (S)-9b (0.11 g, 74%)
was obtained from compound (S)-8 (0.15 g, 0.55
mmol). [h]2D5=+5.3 (c 0.92, MeOH). Anal. calcd for
C14H21NO4: C, 62.90; H, 7.92; N, 5.24. Found: C,
63.07; H, 7.88; N, 5.30%.
5. Peggion, C.; Formaggio, F.; Crisma, M.; Toniolo, C.;
Kaptein, B.; Broxterman, Q. B.; Kamphuis, J. J. Pept.
Sci. 1999, 5, 547–554.
6. Toniolo, C.; Crisma, M.; Bonora, G. M.; Klajc, B.; Lelj,
F.; Griamaldi, P.; Rosa, A.; Polinelli, S.; Boesten, W. H.
J.; Mejer, E. M.; Schoemaker, H. F.; Kamphuis, J. Int. J.
Pept. Protein Res. 1991, 38, 242–252.
7. Valle, G.; Crisma, M.; Toniolo, C.; Polinelli, S.; Boesten,
W. H. J.; Schoemaker, H. F.; Mejer, E. M.; Kamphuis, J.
Int. J. Pept. Protein Res. 1991, 37, 521–527.
8. Go´mez-Catala´n, J.; Pe´rez, J. J.; Jime´nez, A. I.; Cativiela,
C. J. Pept. Sci. 1999, 5, 251–262.
9. Lapen˜a, Y.; Lo´pez, P.; Cativiela, C.; Kaptein, B.; Brox-
terman, Q. B.; Kamphuis, J.; Mossel, E.; Peggion, C.;
Formaggio, F.; Crisma, M.; Toniolo, C. J. Chem. Soc.,
Perkin Trans. 2 2000, 631–636.
4.1.16. (S)-2-Amino-3-hydroxy-2,3-dimethylbutyric acid,
(S)-10. To a solution of alcohol (R)-9b (90 mg, 0.34
mmol) in acetone (7 mL) at 0°C was added dropwise a
1.5-fold excess of Jones’ reagent over 5 min. The mix-
ture was stirred at 0°C for 3 h and then at room
temperature for a further 3 h. The excess Jones’ reagent
was destroyed with 2-propanol. The mixture was
diluted with H2O (7 mL) and extracted with ethyl
acetate (4×15 mL). The combined organic extracts were
dried with anhydrous Na2SO4 and concentrated in
vacuo. The residual yellow oil was dissolved in MeOH
(15 mL) and palladium on carbon (1:5 catalyst/sub-
strate by weight) was added. The resulting suspension
was subjected to hydrogenolysis at room temperature
for 24 h. The catalyst was removed by filtration and the
solvent was evaporated to give (S)-10 as a white solid
(32 mg, 0.22 mmol); yield: 64%. [h]2D5=+6.3 (c 1.2,
10. Cativiela, C.; D´ıaz-de-Villegas, M. D.; Ga´lvez, J. A.
Tetrahedron 1994, 50, 9837–9846.
11. Royo, S.; Lo´pez, P.; Jime´nez, A. I.; Oliveros, L.;
Cativiela, C. Chirality 2002, 14, 39–46.
12. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
1
H2O); H NMR (D2O): l 1.42 (s, 3H, CH3), 1.54 (s,
Zurbano, M. M. J. Org. Chem. 1999, 64, 8220–8225.

A. A6enoza et al. / Tetrahedron: Asymmetry 14 (2003) 399–405
405
13. Avenoza, A.; Cativiela, C.; Peregrina, J. M.; Sucunza, D.;
Zurbano, M. M. Tetrahedron: Asymmetry 1999, 10, 4653–
4661.
Sucunza, D.; Zurbano, M. M. Tetrahedron: Asymmetry
2001, 12, 949–953.
16. Shao, H.; Rueter, J. K.; Goodman, M. J. Org. Chem.
1998, 63, 5240–5244.
17. Scho¨llkopf, U.; Groth, U.; Hartwig, W. Liebigs Ann.
Chem. 1981, 12, 2407–2418.
14. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;
Zurbano, M. M. Tetrahedron: Asymmetry 2000, 11, 2195–
2204.
18. Agami, C.; Couty, F. Tetrahedron 2002, 58, 2701–2724.
15. Avenoza, A.; Cativiela, C.; Corzana, F.; Peregrina, J. M.;