Enantiodivergent Approach to D- and L-Secondary N-Hydroxy-α-amino Acids by Using N-Benzyl-2,3-O-isopropylidene-D-glyceraldehyde Nitrone as an Effective N-Hydroxyglycine Cation Equivalent

Full text of DOI:10.1021/jo971913n

J . Org. Chem. 1998, 63, 2371-2374
2371
Sch em e 1a
En a n tiod iver gen t Ap p r oa ch to D- a n d
L-Secon d a r y N-Hyd r oxy-r-a m in o Acid s by
Usin g N-Ben zyl-2,3-O-isop r op ylid en e-D-
glycer a ld eh yd e Nitr on e a s a n Effective
N-Hyd r oxyglycin e Ca tion Equ iva len t
Pedro Merino,* Elena Castillo, Santiago Franco,
Francisco L. Merchan, and Tomas Tejero
Departamento de Quimica Organica, ICMA,
Universidad de Zaragoza, CSIC, Plza. S. Francisco, s/ n,
E-50009 Zaragoza, Spain
Received October 16, 1997
The development of efficient asymmetric syntheses of
both natural and unnatural R-amino acids is one of the
most important and challenging goals in organic synthe-
sis. However, although there are numerous methods for
the asymmetric synthesis of R-amino acids,1 relatively
few publications have appeared concerning the synthesis
of the corresponding N-hydroxy-R-amino acids in optically
pure form.2 N-Hydroxy-R-amino acids are important
compounds since they can be found in human and animal
tumors and they are key intermediates in metabolic
pathways.3
a
Reagents and conditions: (i) ZnBr2, Et2O, rt, 5 min, then
RMgBr, Et2O, -60 °C, 6 h; (ii) Ac2O, Py, rt, 1 h; (iii) H5IO6, Et2O,
rt, 4 h; (iv) NaClO2, NaH2PO4, CH3CN‚H2O, 10 °C, 2 h, then
Na2SO3, 10% HCl (aq), then CH2N2, Et2O, 0 °C, 15 min; (v) H2,
Pd(OH)2-C, MeOH-AcOEt, Boc2O, 70 psi, 5 days.
synthetic equivalent of the N-hydroxyglycine cation syn-
thon. In addition, since N-hydroxy-R-amino acids are
immediate precursors of the corresponding R-amino acids
by reduction, BIGN (2) also constitutes a new equivalent
of the glycine cation synthon.5
In connection with our general program aimed at the
development of new nitrone-based methodologies for the
preparation of nitrogenated compounds of biological
interest,4 we report herein a new and efficient general
method for the asymmetric synthesis of secondary N-hy-
droxy-R-amino acids 1. A retrosynthetic analysis leads
to a carbanion synthon A and a N-hydroxy glycine cation
synthon B by disconnection of the R-C bond. The
nucleophilic addition of an organometallic compound, like
a Grignard reagent, to the nitrone 2, namely, N-benzyl-
2,3-O-isopropylidene-D-glyceraldehyde nitrone (hereafter
BIGN) should open a new enantiodivergent pathway to
secondary N-hydroxy-R-amino acids 1. According to this
strategy, BIGN 2 can be considered as a convenient
The addition of Grignard reagents to BIGN (2) accord-
ing to our previously established conditions6 afforded the
corresponding syn-hydroxylamines 3 (R ) Me, ds ) 91%;
R ) Ph, ds ) 90%). It is worth mentioning that by
carrying out the addition reaction 20 °C below (i.e., -60
°C) the temperature given in our previous paper6 better
results regarding both selectivity and chemical yield were
obtained with similar reaction times. The relative syn-
configuration of hydroxylamines 3 had been unambigu-
ously ascertained as described.6 After chromatographic
purification, the obtained syn-hydroxylamines 3 were
acetylated (Ac2O, pyridine) to give compounds 4 in good
overall yields (75% and 77% for R ) Me and R ) Ph,
respectively). Oxidation of the dioxolane ring was achieved
by employing periodic acid in dry diethyl ether, following
the procedure given by Wu7 (Scheme 1). Under that
treatment, the N-acetoxy-R-amino aldehydes D-5 were
obtained, and they were used in the following step
without further purification. Subsequent oxidation of
aldehydes D-5 with sodium chlorite according to the
Dalcanale and Montanari procedure8 followed by esteri-
fication with diazomethane afforded the secondary N-hy-
droxy-R-amino acid derivatives D-6. These compounds
were further converted to the N-(tert-butoxycarbonyl)
* To whom correspondence should be addressed. Tel.: +34 976 76
20 75. Fax: +34 976 76 11 94. E-mail: pmerino@posta.unizar.es.
(1) (a) Williams, R. M. Synthesis of Optically Active R-Amino Acids;
Pergamon Press: Oxford, 1989. (b) Duthaler, R. O. Tetrahedron 1994,
50, 1539-1650. (c) Heimgartner, H. Angew. Chem., Int. Ed. Engl. 1991,
30, 238-264. (d) Ojima, I. Acc. Chem. Res. 1995, 28, 383-389.
(2) (a) Oppolzer, W. A.; Tamura, O. Tetrahedron Lett. 1990, 31, 991-
994. (b) Oppolzer, W.; Tamura, O.; Deerberg. Helv. Chim. Acta 1992,
75, 1965-1978. (c) Hanessian, S.; Yang, R.-Y. Synlett 1995, 633-634.
(d) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 5273-5276.
(e) Hanessian, S.; Yang, R.-Y. Tetrahedron Lett. 1996, 37, 8997-9000.
(3) For a review see: Ottenheijm, H. C. J .; Herscheid, J . D. M. Chem.
Rev. 1986, 86, 697-707. See also ref 2c and references therein.
(4) For some recent examples see: (a) Merino, P.; Lanaspa, A.;
Merchan, F. L.; Tejero T. J . Org. Chem. 1996, 61, 9028-9032. (b)
Merino, P.; Anoro, S.; Castillo, E.; Merchan, F. L.; Tejero, T. Tetrahe-
dron: Asymmetry 1996, 7, 1887-1890. (c) Dondoni, A.; Franco, S.;
J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. J . Org. Chem. 1997,
62, 5497-5507. (d) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Tetrahedron Lett. 1997, 38, 1813-1816. (e) Merino, P.; Lanaspa, A.;
Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry 1997, 8, 2381-
2401.
(5) For a review concerning R-cation equivalents of R-amino acids
see: Bailey, P. D.; Clayson, J .; Boa, A. N. Contemp. Org. Chem. 1995,
2, 173-188. See also: Lamaty, F.; Lazaro, R.; Martinez, J . Tetrahedron
Lett. 1997, 38, 3385-3386. O’Donnel, M. J .; Bennett, W. D. Tetrahe-
dron 1988, 44, 5389-5401. Bretschneider, T.; Miltz, W.; Munster, P.;
Steglich, W. Tetrahedron 1988, 44, 5403-5414. Abood, N. A.; Nosai,
R. Tetrahedron Lett. 1994, 35, 3669-3672. Yamamoto, Y.; Onuki, S.;
Yumoto, M.; Asao, N. J . Am. Chem. Soc. 1994, 116, 421-422.
(6) Merino, P.; Castillo, E.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 1725-1729.
(7) Wu, W.-L.; Wu, Y.-L. J . Org. Chem. 1993, 58, 3586-3588.
(8) Dalcanale, E.; Montanari, F. J . Org. Chem. 1986, 51, 567-569.
S0022-3263(97)01913-0 CCC: $15.00 © 1998 American Chemical Society
Published on Web 03/12/1998

2372 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
Sch em e 2a
Sch em e 3a
a
Reagents and conditions: (i) p-TosOH, MeOH, 4 h, reflux; (ii)
NaIO4, CH2Cl2-NaHCO3 (aq), rt, 2 h, then NaClO2, NaH2PO4,
CH3CN‚H2O, 10 °C, 2 h, then Na2SO3, 10%, HCl (aq); then CH2N2,
Et2O, 0 °C, 15 min; (iii) NaIO4, RuCl3, CH3CN-CCl4‚H2O, rt, 15
min.
methyl ester forms of D-alanine D-7a and D-phenylglycine
D-7b by catalytic hydrogenation (H2, Pd(OH)2-C) in the
presence of an excess of di-tert-butyl dicarbonate.
The successful conversion of the diastereomerically
pure hydroxylamines 4 to R-amino esters D-7 in homo-
chiral forms, as shown in Scheme 1, provided not only
an additional confirmation of the absolute configuration
of each product but also a basis for determining the
enantiomeric purity of the obtained compound; the [R]D
value and melting point of D-7a were in excellent agree-
ment with those found for an authentic sample.9 Simi-
larly, the physical and spectroscopic properties of D-7b
were identical to those reported for its enantiomer, except
for the sign of the optical rotation10 (see the Experimental
Section).
Since the dioxolane-carboxylic acid equivalence is a
well-known subject and several examples can be found
in the literature,11 we also decided to study alternative
elaborations of compounds 4 in order to improve the
preparation of the targeted N-hydroxy-R-amino acid
derivatives. As an example, deprotection of compounds
4b to the corresponding diol 8 was achieved by using
catalytic p-toluenesulfonic acid in refluxing methanol
(Scheme 2); however, this cleavage appeared to be
troublesome. This was mainly due to the partial deacety-
lation of the acetoxyamino group, gave 9 as a byproduct.12
In addition, the poor solubility of the deprotected com-
pounds in organic solvents made purification of 8 rather
difficult. Nevertheless, diol 8 was oxidized in a two-step
procedure consisting of (i) sodium periodate oxidation and
(ii) treatment with sodium chlorite as described above.
The obtained N-hydroxy-R-amino acid derivative was
identical with the compound obtained by the oxidation
of D-4b; however, it was obtained in an even lower overall
yield (40%). Oxidation of diol 8 was also attempted in a
one-pot procedure by using the system NaIO4-RuCl3.
Surprisingly, with the conditions analogous to those
reported by Sharpless,13 only 15% of D-6b could be
obtained from 8, merely due to undesired ruthenium-
a
Reagents and conditions: (i) Et2AlCl, Et2O, rt, 5 min, then
RMgBr, Et2O, -60 °C, 6 h; (ii) Ac2O, Py, rt, 1 h; (iii) H5IO6, Et2O,
rt, 4 h; (iv) NaClO2, NaH2PO4, CH3CN‚H2O, 10 °C, 2 h, then
Na2SO3, 10% HCl (aq), then CH2N2, Et2O, 0 °C, 15 min; (v) H2,
Pd(OH)2-C, MeOH-AcOEt, Boc2O, 70 psi, 5 days.
mediated oxidation of the N-benzyl group. A similar
situation had been reported by Pericas and co-workers,11a
and in that case better results were obtained by changing
the oxidation conditions to NaIO4-KMnO4 according to
the Martin procedure.14 Unfortunately, oxidation of 8
under these conditions also led to a poor yield of D-6.
Thus, the first reaction sequence outlined in Scheme 1
remains as the most effective for the transformation of
the dioxolane ring into a carboxylic acid derivative.
To demonstrate the enantiodivergency of our strategy,
we also prepared the anti-hydroxylamines 10 according
to our previously described protocol6 for the anti-addition
of Grignard reagents to 2 (Scheme 3). That protocol
consists of precomplexing BIGN 2 with 1.0 equiv of Et2-
AlCl before carrying out the addition of the nucleophile.
Also in this case, better results were obtained by carrying
out the reaction at -60 °C (R ) Me, ds ) 82%; R ) Ph,
ds ) 85%). Conversion of the N-acetoxy derivatives 11
into the N-hydroxy-R-amino acid derivatives was per-
formed by the similar two-step sequence employed for
the conversion of 4 to D-6, affording L-6a and L-6b in 61%
and 65% overall yield, respectively. Catalytic hydrogena-
tion of those compounds in the presence of di-tert-butyl
dicarbonate furnished L-7a and L-7b. The physical and
spectroscopic properties of L-7a were identical to those
of an authentic sample.9 Analogously, physical and
spectroscopic properties of L-7b were coincident to those
reported in the literature.10
In conclusion, a short and efficient route toward
optically active N-acetoxy-R-amino acid derivatives has
been developed. We have established a method for a
preparation of a pair of enantiomers of N-hydroxy-R-
amino acid derivatives starting with nitrone 2 as the only
chiral source. The substituent on the nitrogen atom
could be changed by starting from the corresponding
N-substituted nitrone, which, in turn, could be prepared
from D-glyceraldehyde and the appropriate N-substituted
hydroxylamine15 as described.16 Deacetylation of the
acetoxy moiety under standard conditions would yield
free hydroxyamino derivatives. These considerations
(9) N-(tert-Butoxycarbonyl)-D-alanine methyl ester (cat. no. 41,464-
6) and N-(tert-butoxycarbonyl)-L-alanine methyl ester (cat. no. 42,357-
2) can be purchased from Aldrich.
(10) Dondoni, A.; Perrone, D.; Semola, T. Synthesis 1995, 181-186.
(11) See inter alia: (a) Medina, E.; Vidal-Ferran, A.; Moyano, A.;
Pericas, M. A.; Riera, A. Tetrahedron: Asymmetry 1997, 8, 1581-1586.
(b) Chattopadhyay, A.; Mamdapur, V. R. J . Org. Chem. 1995, 60, 585-
587. (c) Poch, M.; Alcon, M.; Moyano, A.; Pericas, M. A.; Riera, A.
Tetrahedron Lett. 1993, 34, 7781-7784.
(12) A variety of conditions were checked, including HCl (aq), AcOH
(aq), and Dowex-50, and in all cases deacetylated 9 was found as a
byproduct. Following the periodic acid hydrolysis/cleavage outlined in
Scheme 1, only the expected aldehydes were found.
(13) Carlsen, P. H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B.
J . Org. Chem. 1981, 46, 3936-3938.
(14) Martin, T.; Rodriguez, C. M.; Martin, V. S. J . Org. Chem. 1996,
61, 6450-6453.
(15) The use of sugar-derived hydroxylamines would allow the
introduction, on the nitrogen atom, of a group that could be removed
without reducing the N-O bond. For an example see: Huber, R.;
Vasella, A. Helv. Chim. Acta 1987, 70, 1461-1476.

Notes
J . Org. Chem., Vol. 63, No. 7, 1998 2373
169.9. Anal. Calcd for C16H23NO4: C, 65.51; H, 7.90; N, 4.77.
Found: C, 65.46; H, 8.11; N, 4.83.
show that the present method will be applicable to
syntheses of other N-hydroxy-R-amino acid derivatives
as a general method.
(2S,3R)-N-Ben zyl-3-(acetoxyam in o)-1,2-O-isopr opyliden e-
3-p h en yl-1,2-p r op a n ed iol (4b). The hydroxylamine 3b (0.80
g, 2.55 mmol) was treated as described above for the preparation
of 4a . Column chromatography (80:20 hexane-diethyl ether)
of the crude product gave 0.907 g (100%) of 4b as a white solid:
mp 76 °C; [R]D -5.7 (c 0.34, CHCl3); 1H NMR (CDCl3) δ 1.30 (s,
3H), 1.34 (s, 3H), 1.76 (s, 3H), 3.34 (t, 1H, J ) 8.5 Hz), 3.46 (dd,
1H, J ) 6.2, 8.5 Hz), 3.92 (d, 1H, J ) 13.4 Hz), 3.95 (d, 1H, J )
6.2 Hz), 3.97 (d, 1H, J ) 13.4 Hz), 4.63 (dt, 1H, J ) 6.2, 8.5 Hz),
7.20-7.40 (m, 10H); 13C NMR (CDCl3) δ 19.4, 25.8, 26.7, 60.8,
67.5, 74.2, 77.8, 109.9, 127.4, 128.1, 128.6, 128.7, 128.9, 129.3,
130.4, 136.4, 170.2. Anal. Calcd for C21H25NO4: C, 70.96; H,
7.09; N, 3.94. Found: C, 71.04; H, 7.13; N, 3.88.
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental information
see ref 4e. Methyl- and phenylmagnesium bromide were used
in diethyl ether from a 1.0 M commercial solution. N-Benzyl-
2,3-O-isopropylidene-D-glyceraldehyde nitrone (BIGN, 2) was
prepared as described.16
(2S,3R)-N-Ben zyl-3-(h ydr oxyam in o)-1,2-O-isopr opyliden e-
1,2-bu ta n ed iol (3a ). To a well-stirred solution of nitrone 2
(0.94 g, 4 mmol) in diethyl ether (80 mL) was added anhydrous
ZnBr2 (0.9 g, 4 mmol) in one portion at room temperature, and
the resulting mixture was stirred for 5 min. The mixture was
then cooled to -60 °C and treated with methylmagnesium
bromide (6 mmol, 6.0 mL of a 1.0 M solution in Et2O). The
mixture was stirred for 6 h at -60 °C and then treated with 1
N aqueous NaOH (25 mL). After additional stirring for 15 min
at ambient temperature, the mixture was extracted with diethyl
ether (3 × 30 mL). The combined organic extracts were washed
with brine and dried (MgSO4), and the solvent was evaporated
in vacuo to give the crude product. The diastereoselectivity (ds
) 91%) was established by 1H NMR analysis. Purification by
column chromatography on silica gel (70:30 hexane-diethyl
ether) gave pure 3a (0.754 g, 75%) as a sticky oil: [R]D -19.8 (c
1.0, CHCl3); 1H NMR (CDCl3) δ 1.02 (d, 3H, J ) 6.6 Hz), 1.33 (s,
3H), 1.34 (s, 3H), 2.91 (dq, 1H, J ) 6.6, 7.0 Hz), 3.72 (dd, 1H, J
) 7.5, 8.5 Hz), 3.80 (d, 1H, J ) 13.2 Hz), 3.88 (dd, 1H, J ) 5.8,
8.5 Hz), 3.92 (d, 1H, J ) 13.2 Hz), 4.23 (ddd, 1H, J ) 5.8, 7.0,
7.5 Hz), 6.10 (bs, 1H, ex. D2O), 7.20-7.42 (m, 5H); 13C NMR
(CDCl3) δ 9.1, 25.6, 26.5, 60.9, 63.7, 66.7, 76.7, 108.8, 127.3,
128.3, 129.2, 137.7. Anal. Calcd for C14H21NO3: C, 66.91; H,
8.42; N, 5.57. Found: C, 67.04; H, 8.38; N, 5.61.
(2S,3R)-N-Ben zyl-3-(h ydr oxyam in o)-1,2-O-isopr opyliden e-
3-p h en yl-1,2-p r op a n ed iol (3b). The nitrone 2 (0.94 g, 4 mmol)
was treated as described above for the preparation of 3a using
phenylmagnesium bromide (6 mmol, 6.0 mL of a 1.0 M solution
in Et2O) as a Grignard reagent. 1H NMR analysis of the crude
product revealed a diastereoselectivity of 90%. Column chro-
matography (80:20 hexane-diethyl ether) of that crude product
gave 0.965 g (77%) of 3b as an oil: [R]D -6.5 (c 1.0, CHCl3); 1H
NMR (CDCl3) δ 1.40 (s, 3H), 1.43 (s, 3H), 3.43 (dd, 1H, J ) 6.6,
8.5 Hz), 3.66 (dd, 1H, J ) 6.6, 8.5 Hz), 3.67 (d, 1H, J ) 13.2
Hz), 3.73 (d, 1H, J ) 8.8 Hz), 3.82 (d, 1H, J ) 13.2 Hz), 4.79 (dt,
1H, J ) 6.6, 8.8 Hz), 6.64 (bs, 1H, ex. D2O), 7.21-7.44 (m, 10H);
13C NMR (CDCl3) δ 25.8, 26.7, 61.5, 67.3, 72.4, 76.2, 109.8, 127.2,
127.7, 128.1, 128.7, 129.4, 129.8, 135.9, 137.5. Anal. Calcd for
C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found: C, 73.02; H, 7.57;
N, 4.40.
Meth yl (2R)-N-Ben zyl-2-(a cetoxya m in o)p r op a n oa te (D-
6a ). To a well-stirred suspension of periodic acid (0.912 g, 4.0
mmol) in dry diethyl ether was added compound 4a (0.5 g, 1.7
mmol) at ambient temperature under argon atmosphere in one
portion. Stirring was maintained for an additional 4 h, at which
time the reaction mixture was filtered. The filtrate was
evaporated under reduced pressure to give the crude aldehyde
D-5a (1H NMR (CDCl3) δ 1.49 (d, 3H, J ) 7.0 Hz), 1.89 (s, 3H),
3.74 (dq, 1H, J ) 3.9, 7.0 Hz), 3.99 (d, 1H, J ) 13.4 Hz), 4.14 (d,
1H, J ) 13.4 Hz), 7.22-7.37 (m, 5H), 9.58 (d, 1H, J ) 3.9 Hz)),
which was dissolved in CH3CN (5 mL). To the resulting mixture
was added a solution of NaClO2 (0.226 g, 2.6 mmol) in 5 mL of
water dropwise. The resulting mixture was then treated with
a solution of NaH2PO4 (50 mg, 0.417 mmol) in H2O (2 mL) and
35% H2O2 (0.14 mL, 1.5 mmol), keeping the temperature of the
mixture below 10 °C. After the mixture was stirred for 1 h, Na2-
SO3 (15 mg, 0.12 mmol) was added and the resulting mixture
was acidified (pH ) 2-3) with 10% aqueous HCl. The resulting
mixture was partitioned between brine (30 mL) and dichlo-
romethane (30 mL), the layers were separated, and the aqueous
layer was extracted with dichloromethane (3 × 25 mL). The
combined organic extracts were washed with brine, dried
(MgSO4), and concentrated under reduced pressure to give a
residue that was taken up in diethyl ether (25 mL) and treated
with a freshly distilled ethereal solution of diazomethane at 0
°C for 5 min. The solvent was removed under reduced pressure,
and the residue was subjected to purification by column chro-
matography on silica gel (80:20 hexane-diethyl ether) to give
the N-hydroxy-R-amino acid derivative D-6a as a colorless oil
(0.265 g, 62%): [R]D +10.9 (c 2.8, CHCl3); 1H NMR (CDCl3) δ
1.44 (d, 3H, J ) 6.9 Hz), 1.88 (s, 3H), 3.77 (s, 3H), 3.83 (q, 1H,
J ) 6.9 Hz), 4.11 (d, 1H, J ) 13.3 Hz), 4.21 (d, 1H, J ) 13.3 Hz),
7.24-7.39 (m, 5H); 13C NMR (CDCl3) δ 14.2, 19.0, 51.8, 59.2,
62.8, 127.7, 128.2, 129.5, 135.5, 169.5, 171.4. Anal. Calcd for
C
13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.13; H, 6.75;
N, 5.50.
Met h yl (2R)-N-Ben zyl-2-(a cet oxya m in o)-2-p h en ylet h -
(2S,3R)-N-Ben zyl-3-(acetoxyam in o)-1,2-O-isopr opyliden e-
1,2-bu ta n ed iol (4a ). A solution of hydroxylamine 3a (0.70 g,
2.79 mmol) in CH2Cl2 (5 mL) at room temperature was treated
sequentially with pyridine (5 mL) and acetic anhydride (5 mL).
The resulting mixture was allowed to stir for 1 h, at which time
it was diluted with CH2Cl2 (15 mL) and then poured into
saturated aqueous CuSO4 (25 mL). After the mixture was
stirred vigorously for 5 min, the layers were separated and the
organic layer was sequentially washed with saturated aqueous
CuSO4, water, and brine. The solution was dried (MgSO4) and
concentrated under reduced pressure to give a colorless oil that
was subjected to purification by column chromatography on silica
gel (80:20 hexane-diethyl ether) to give the acetylated product
4a as a colorless oil (0.817 g, 100%): [R]D +4.4 (c 0.74, CHCl3);
1H NMR (CDCl3) δ 1.11 (d, 3H, J ) 6.7 Hz), 1.29 (s, 3H), 1.35
(s, 3H), 1.79 (s, 3H), 3.19 (dq, 1H, J ) 5.7, 6.7 Hz), 3.79 (dd, 1H,
J ) 7.8, 8.1 Hz), 3.90 (dd, 1H, J ) 6.4, 8.1 Hz), 4.00 (d, 1H, J )
13.3 Hz), 4.14 (d, 1H, J ) 13.3 Hz), 4.24 (ddd, 1H, J ) 5.7, 6.4,
7.8 Hz), 7.20-7.40 (m, 5H); 13C NMR (CDCl3) δ 10.5, 19.1, 25.1,
26.2, 60.1, 61.6, 65.8, 76.5, 108.6, 127.4, 128.1, 129.3, 136.1,
a n oa te (D-6b). The compound 4b (0.604 g, 1.7 mmol) was
treated as described above for the preparation of crude D-5b (1H
NMR (CDCl3) δ 1.81 (s, 3H), 3.79 (d, 1H, J ) 13.8 Hz), 4.11 (d,
1H, J ) 13.8 Hz), 4.44 (d, 1H, J ) 3.7 Hz), 7.24-7.6 (m, 10H),
9.63 (d, 1H, J ) 3.7 Hz)). Further treatment of aldehyde D-5b
as indicated above for the preparation of D-6a afforded, after
column chromatography (80:20 hexane-diethyl ether), 0.320 g
(60%) of pure D-6b as an oil: [R]D -24.5 (c 1.10, CHCl3); 1H NMR
(CDCl3) δ 1.82 (s, 3H), 3.65 (s, 3H), 3.79 (d, 1H, J ) 13.5 Hz),
4.05 (d, 1H, J ) 13.5 Hz), 4.70 (s, 1H), 7.20-7.42 (m, 10H); 13
NMR (CDCl3) δ 19.4, 52.3, 59.9, 73.6, 127.9, 128.3, 128.6, 129.1,
129.2, 130.1, 133.8, 135.0, 168.8, 169.9. Anal. Calcd for C18H19
C
-
NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 68.82; H, 6.08; N,
4.54.
N-(ter t-Bu toxyca r bon yl)-D-a la n in e Meth yl Ester (D-7a ).
To a solution of D-6a (0.20 g, 0.80 mmol) in methanol (20 mL)
were added Boc2O (0.46 g, 2.1 mmol) and 20% palladium
hydroxide on activated charcoal (Pearlman’s catalyst) (30 mg).
The resulting mixture was hydrogenated at 70 psi for 5 days
(Parr hydrogenation apparatus). Filtration of the catalyst and
evaporation of the solvent afforded a residue that was purified
by column chromatography on silica gel (90:10 hexane-diethyl
ether) to give 0.151 g (93%) of pure D-7a as a solid. The physical
and spectroscopic data were identical to those of an authentic
sample (Aldrich, cat. no. 41,464-6).
(16) (a) Merino, P.; Franco, S.; Merchan, F. L.; Tejero, T. Tetrahe-
dron: Asymmetry 1997, 8, 3489-3496. (b) Dondoni, A.; Franco, S.;
J unquera, F.; Merchan, F. L.; Merino, P.; Tejero, T. Synth. Commun.
1994, 24, 2537-2550.

2374 J . Org. Chem., Vol. 63, No. 7, 1998
Notes
N-(ter t-Bu toxyca r bon yl)-D-p h en ylglycin e Meth yl Ester
(D-7b). The N-hydroxy-R-amino acid derivative D-6b (0.20 g,
0.638 mmol) was treated as described above for the preparation
of D-7a . Column chromatography (80:20 hexane-diethyl ether)
of the crude product gave 0.162 g (96%) of L-7a as a white solid:
mp 112-114 °C; [R]D -132.3 (c 1.1, CHCl3) [lit. for enantiomer:
(2S,3R)-N-Ben zyl-3-(acetoxyam in o)-1,2-O-isopr opyliden e-
1,2-b u t a n ed iol (11a ). The hydroxylamine 10a (0.70 g, 2.79
mmol) was treated as described above for the preparation of 4a .
Column chromatography (80:20 hexane-diethyl ether) of the
crude product gave 0.816 g (100%) of 11b as an oil: [R]D -9.4 (c
1
1.31, CHCl3); H NMR (CDCl3) δ 1.27 (d, 3H, J ) 6.5 Hz), 1.30
10
1
(s, 3H), 1.34 (s, 3H), 1.81 (s, 3H), 2.96 (dq, 1H, J ) 5.5, 6.5 Hz),
3.91 (d, 1H, J ) 13.5 Hz), 3.92-3.99 (m, 2H), 4.08 (d, 1H, J )
13.5 hz), 4.09-4.15 (m, 1H), 7.20-7.40 (m, 5H); 13C NMR
(CDCl3) δ 9.1, 19.2, 25.2, 26.7, 59.3, 63.0, 68.4, 77.4, 109.1, 127.6,
128.3, 129.1, 136.2, 169.4. Anal. Calcd for C16H23NO4: C, 65.51;
H, 7.90; N, 4.77. Found: C, 65.46; H, 8.11; N, 4.83.
[R]D +135.7 (c 0.8, CHCl3)]; H NMR (CDCl3) δ 1.41 (s, 9H),
3.73 (s, 3H), 5.34 (d, 1H, J ) 7.3 Hz), 5.55 (d, 1H, J ) 7.3 Hz),
7.30-7.44 (m, 5H); 13C NMR (CDCl3) δ 28.3, 52.7, 57.5, 79.90,
127.2, 128.6, 129.1, 137.0, 154.8, 171.6. Anal. Calcd for C14H19
-
NO4: C, 63.38; H, 7.22; N, 5.28. Found: C, 63.44; H, 7.10; N,
5.19.
(2S,3R)-N-Ben zyl-3-(acetoxyam in o)-1,2-O-isopr opyliden e-
3-p h en yl-1,2-p r op a n ed iol (11b). The hydroxylamine 10b
(0.80 g, 2.55 mmol) was treated as described above for the
preparation of 4a . Column chromatography (80:20 hexane-
diethyl ether) of the crude product gave 0.904 g (100%) of 11b
(2S,3R)-N-Ben zyl-3-(a cet oxya m in o)-3-p h en yl-1,2-p r o-
p a n ed iol (8) a n d (2S,3R)-N-Ben zyl-3-(h yd r oxya m in o)-3-
p h en yl-1,2-p r op a n ed iol (9). A solution of 4b (0.2 g, 0.563
mmol) in MeOH (30 mL) was treated with p-toluenesulfonic acid
monohydrate (19 mg, 0.1 mmol), and the resulting solution was
refluxed for 4 h. After the solution was cooled to ambient
temperature, the solvent was evaporated under reduced pressure
and the residue was partitioned between saturated aqueous
NaHCO3 (30 mL) and EtOAc (30 mL). The aqueous layer was
separated and extracted with EtOAc (3 × 25 mL). The combined
organic extracts were dried (MgSO4) and evaporated under
reduced pressure to give the crude product. 1H NMR analysis
of this crude material revealed an 8:1 mixture of 8 and 9,
respectively. Attempts to purify of this material both by column
chromatography and preparative TLC only afforded enriched
mixtures of the products.
8: 1H NMR (CDCl3 + D2O) (selected signals) δ 2.15 (s, 3H),
3.15 (dd, 1H, J ) 4.3, 11.8 Hz), 3.48 (dd, 1H, J ) 2.8, 11.8 Hz),
3.65 (s, 2H), 3.81 (d, 1H, J ) 9.5 Hz), 4.20 (ddd, 1H, J ) 2.8,
4.3, 9.5 Hz), 7.20-7.45 (m, 5H).
9: 1H NMR (CDCl3 + D2O) (selected signals) δ 3.19 (dd, 1H,
J ) 3.7, 11.6 Hz), 3.56 (dd, 1H, J ) 2.9, 11.6 Hz), 3.69 (s, 2H),
3.86 (d, 1H, J ) 9.8 Hz), 4.26 (ddd, 1H, J ) 2.9, 3.7, 9.8 Hz),
7.20-7.40 (m, 5H).
(2S,3S)-N-Ben zyl-3-(h ydr oxyam in o)-1,2-O-isopr opyliden e-
1,2-bu ta n ed iol (10a ). The nitrone 2 (0.94 g, 4 mmol) was
treated as described above for the preparation of 3a using diethyl
aluminum chloride (4 mmol, 4.0 mL of a 1.0 M solution in
hexanes) as a Lewis acid. 1H NMR analysis of the crude product
revealed a diastereoselectivity of 82%. Column chromatography
(70:30 hexane-diethyl ether) of that crude product gave 0.633
g (63%) of 10a as a white solid: mp 84-86 °C; [R]D -8.3 (c 1.0,
CHCl3); 1H NMR (CDCl3) δ 1.24 (d, 3H, J ) 6.6 Hz), 1.34 (s,
3H), 1.39 (s, 3H), 2.84 (dq, 1H, J ) 6.6, 7.3 Hz), 3.71 (d, 1H, J
) 13.2 Hz), 3.86 (dd, 1H, J ) 6.3, 8.4 Hz), 3.96 (d, 1H, J ) 13.2
Hz), 4.08 (dd, 1H, J ) 6.3, 8.4 Hz), 4.20 (dt, 1H, J ) 6.3, 7.3
Hz), 5.60 (bs, 1H, ex. D2O), 7.26-7.38 (m, 5H); 13C NMR (CDCl3)
δ 9.0, 25.4, 26.7, 61.0, 63.7, 66.7, 76.7, 108.8, 127.3, 128.3, 129.2,
137.7. Anal. Calcd for C14H21NO3: C, 66.91; H, 8.42; N, 5.57.
Found: C, 66.85; H, 8.40; N, 5.77.
1
as a white solid: mp 87-89 °C; [R]D -37.9 (c 0.34, CHCl3); H
NMR (CDCl3) δ 1.22 (s, 3H), 1.24 (s, 3H), 1.85 (s, 3H), 3.71 (d,
1H, J ) 13.3 Hz), 3.81 (d, 1H, J ) 13.3 Hz), 3.84 (d, 1H, J ) 8.1
Hz), 4.10 (dd, 1H, J ) 6.8, 10.6 Hz), 4.16 (dd, 1H, J ) 5.9, 10.6
Hz), 4.51 (ddd, 1H, J ) 5.9, 6.8, 10.6 Hz), 7.22-7.38 (m, 10H);
13C NMR (CDCl3) δ 19.3, 25.2, 26.7, 60.4, 8.4, 72.1, 75.9, 109.3,
127.7, 128.2, 128.3, 128.4, 129.3, 130.4, 135.0, 135.9, 169.7.
Anal. Calcd for C21H25NO4: C, 70.96; H, 7.09; N, 3.94. Found:
C, 71.04; H, 7.13; N, 3.88.
Meth yl (2S)-N-Ben zyl-2-(a cetoxya m in o)p r op a n oa te (L-
6a ). Compound 11a (0.5 g, 1.7 mmol) was treated as described
above for the preparation of D-6a . Column chromatography (80:
20 hexane-diethyl ether) of the residue gave 0.261 g (61%) of
L-6a as an oil: [R]D -10.1 (c 1.7, CHCl3); 1H NMR (CDCl3) δ
1.44 (d, 3H, J ) 6.9 Hz), 1.88 (s, 3H), 3.77 (s, 3H), 3.83 (q, 1H,
J ) 6.9 Hz), 4.11 (d, 1H, J ) 13.3 Hz), 4.21 (d, 1H, J ) 13.3 Hz),
7.24-7.39 (m, 5H); 13C NMR (CDCl3) δ 14.2, 19.0, 51.8, 59.2,
62.8, 127.7, 128.2, 129.5, 135.5, 169.5, 171.4. Anal. Calcd for
C13H17NO4: C, 62.14; H, 6.82; N, 5.57. Found: C, 62.29; H, 6.92;
N, 5.68.
Met h yl (2S)-N-Ben zyl-2-(a cet oxya m in o)-2-p h en ylet h -
a n oa te (L-6b). Compound 11b (0.604 g, 1.7 mmol) was treated
as described above for the preparation of D-6b. Column chro-
matography (80:20 hexane-diethyl ether) of the residue gave
1
0.346 g (65%) of L-6b as an oil: [R]D +24.5 (c 1.10, CHCl3); H
NMR (CDCl3) δ 1.82 (s, 3H), 3.65 (s, 3H), 3.79 (d, 1H, J ) 13.5
Hz), 4.05 (d, 1H, J ) 13.5 Hz), 4.70 (s, 1H), 7.20-7.42 (m, 10H);
13C NMR (CDCl3) δ 19.4, 52.3, 59.9, 73.6, 127.9, 128.3, 128.6,
129.1, 129.2, 130.1, 133.8, 135.0, 168.8, 169.9. Anal. Calcd for
C18H19NO4: C, 68.99; H, 6.11; N, 4.47. Found: C, 69.02; H, 5.93;
N, 4.60.
N-(ter t-Bu toxyca r bon yl)-L-a la n in e Meth yl Ester (L-7a ).
The N-hydroxy-R-amino acid derivative L-6a (0.20 g, 0.80 mmol)
was treated as described above for the preparation of D-7a .
Column chromatography (90:10 hexane-diethyl ether) of the
crude product gave 0.151 g (93%) of L-7a as a solid. The physical
and spectroscopic data were identical to those of an authentic
sample (Aldrich, cat. no. 42,357-2).
(2S,3S)-N-Ben zyl-3-(h ydr oxyam in o)-1,2-O-isopr opyliden e-
3-p h en yl-1,2-p r op a n ed iol (10b). The nitrone 2 (0.94 g, 4
mmol) was treated as described above for the preparation of 3a
using diethyl aluminum chloride (4 mmol, 4.0 mL of a 1.0 M
solution in hexanes) as a Lewis acid and phenylmagnesium
bromide (6 mmol, 6.0 mL of a 1.0 M solution in Et2O) as a
Grignard reagent. 1H NMR analysis of the crude product
revealed a diastereoselectivity of 85%. Column chromatography
(80:20 hexane-diethyl ether) of that crude product gave 0.852
g (68%) of 10b as a white solid: mp 141-143 °C; [R]D -17.5 (c
N-(ter t-Bu toxyca r bon yl)-L-p h en ylglycin e Meth yl Ester
(L-7b). The N-hydroxy-R-amino acid derivative L-6b (0.20 g,
0.638 mmol) was treated as described above for the preparation
of D-7a . Column chromatography (80:20 hexane-diethyl ether)
of the crude product gave 0.159 g (94%) of L-7a as a white solid:
mp 111-113 °C; [R]D +133.1 (c 1.0, CHCl3) [lit.10 [R]D +135.7 (c
1
0.8, CHCl3)]; H NMR (CDCl3) δ 1.41 (s, 9H), 3.73 (s, 3H), 5.34
(d, 1H, J ) 7.3 Hz), 5.55 (d, 1H, J ) 7.3 Hz), 7.30-7.44 (m, 5H);
13C NMR (CDCl3) δ 28.3, 52.7, 57.5, 79.90, 127.2, 128.6, 129.1,
137.0, 154.8, 171.6. Anal. Calcd for C14H19NO4: C, 63.38; H,
7.22; N, 5.28. Found: C, 63.27; H, 7.15; N, 5.41.
1
1.0, CHCl3); H NMR (CDCl3) δ 1.24 (s, 3H), 1.29 (s, 3H), 3.52
(d, 1H, J ) 13.4 Hz), 3.67 (d, 1H, J ) 13.4 Hz), 3.70 (d, 1H, J )
6.7 Hz), 3.94 (dd, 1H, J ) 6.7, 8.4 Hz), 4.15 (dd, 1H, J ) 6.3, 8.4
Hz), 4.75 (dt, 1H, J ) 6.3, 6.7 Hz), 4.86 (bs, 1H, ex. D2O), 7.23-
7.43 (m, 10H); 13C NMR (CDCl3) δ 24.5, 26.5, 62.3, 68.3, 73.6,
76.4, 109.1, 127.3, 128.0, 128.2, 128.3, 129.3, 130.1, 136.3, 137.3.
Anal. Calcd for C19H23NO3: C, 72.82; H, 7.40; N, 4.47. Found:
C, 72.77; H, 7.60; N, 4.55.
Ack n ow led gm en t. Financial support was provided
by the MEC (DGES, Madrid, Spain). S.F. also thanks
MEC for a contract under the program Acciones para
la incorporacio´n a Espan˜a de Doctores y Tecnologos.
J O971913N