Asymmetric Addition Reactions of Lithium (Trimethylsilyl)acetylide with Chiral α-Amino Nitrones. Synthesis of Diastereomerically Pure N-Hydroxy-α-amino Acids

Full text of DOI:10.1021/jo9714775

J . Org. Chem. 1998, 63, 5627-5630
5627
Asym m etr ic Ad d ition Rea ction s of Lith iu m
(Tr im eth ylsilyl)a cetylid e w ith Ch ir a l
r-Am in o Nitr on es. Syn th esis of
Dia ster eom er ica lly P u r e
N-Hyd r oxy-r-a m in o Acid s†
is the observation that the stereoselectivity of the reaction
depends on the protecting groups in the starting mate-
rial.6 In addition, the obtained propargyl hydroxylamines
can be further converted into the corresponding N-hy-
droxy-R-amino acids by the oxidation of the acetylene
group.2i N-Hydroxy-R-amino acids are an important class
of unnatural R-amino acids. These amino acid deriva-
tives are both intermediates in metabolic pathways and
components of naturally occurring metabolites such as
mycelianamide.7 Because of that interest, several meth-
odologies for their synthesis8 and those of some phos-
phonate derivatives9 have recently been reported.
Pedro Merino,* Santiago Franco,
Francisco L. Merchan, and Tomas Tejero
Departamento de Quimica Organica, ICMA,
Facultad de Ciencias, Universidad de Zaragoza,
E-50009 Zaragoza, Aragon, Spain
Received August 7, 1997
The nucleophilic addition of alkynyl organometallic
reagents to unsaturated CdX systems (X ) O, NR) is a
very convenient and reliable strategy for carbon-carbon
bond formation, but it has not been used as extensively
as other organometallic nucleophilic additions to those
systems.1 Several reports on the addition of alkynyl
organometallic reagents to carbonyl compounds can be
found in the literature.2 Also, successful examples of
ethynylation of carbon-nitrogen double bonds have been
reported.3 In previous papers, we have described the
stereoselective addition of (trimethylsilyl)acetylene to
R-alkoxy nitrones;4 in addition, we found that the ster-
eochemical course of the reaction could be controlled by
the appropriate use of Lewis acids. To expand our
knowledge of nucleophilic additions to nitrones, we wish
to extend this reaction toward the preparation of deriva-
tives containing other functionalities such as an amino
group at the R-position of the nitrone moiety.5
Nitrone 1 (Scheme 1), readily available from L-serine,10
was treated with an excess amount (3.0 equiv) of lithium
(trimethylsilyl)acetylide, at -80 °C, in THF as a solvent,
to provide the propargyl hydroxylamine 2 in quantitative
yield. The diastereoselectivity was sufficiently high so
that the minor diastereomer was not observed by NMR
spectroscopy. The 3S,4R configuration of 2 was con-
firmed by an independent synthesis (vide infra). Desi-
lylation with tetrabutylammonium fluoride in anhydrous
THF, followed by acetylation (Ac2O, Py) of the N-hydroxy
group, afforded compound 4 in 88% purified yield. The
ethynyl group was oxidized according to the method of
Czernecki.2h,11 Unfortunately, the use of sodium bicar-
bonate in the reaction medium results in the loss of the
acetyl group.12 In addition, workup with sodium bisulfite
gave a complex mixture from which we could not identify
optimal conditions for purifying the desired carboxylic
acid. As a remedy for this situation, a simple isolation
procedure was developed, as follows. The oxidation was
conducted in the usual way, with the exception that no
sodium bicarbonate is added to the reaction mixture to
prevent the hydrolysis of the acetyl group. At the
completion of the reaction, water and ethyl acetate were
added, and the organic layer was separated, filtered
through a pad of Florisil, and eluted with ethyl acetate.
The ruthenium is retained on the Florisil, while the
filtrate contained only the desired carboxylic acid, which
In this paper, the ethynylation of R-amino nitrones
derived from L-serine is detailed. Of particular interest
* To whom correspondence should be addressed: Fax: +34 976
761194. E-mail: pmerino@posta.unizar.es.
† Dedicated to the memory of Professor Stanislas Czernecki.
(1) For general treatises on nucleophilic additions to unsaturated
systems see: (a) Comprehensive Organic Synthesis, Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: New York, 1991; Vol. 1 (Schreiber,
S. L., Ed.), Vol. 2 (Heathcock, C. H., Ed.). (b) Stereoselective Synthesis;
Helmchen, G., Hoffmann, R. W., Mulzer, J ., Schaumann, E., Eds.;
Houben-Weyl, Thieme: Stuttgart, 1996; Vols. 2 and 3.
(2) (a) Carda, M.; Gonzalez, F.; Rodriguez, S.; Marco, J . A. Tetra-
hedron: Asymmetry 1993, 4, 1799-1802. (b) Ipaktschi, J .; Eckert, T.
Chem. Ber. 1995, 128, 1171-1174. (c) Mulzer, J .; Greifenberg, S.;
Beckstett, A.; Gottwald, M. Liebigs Ann. Chem. 1992, 1131-1135. (d)
Yasuda, M.; Miyai, T.; Shibata, I.; Baba, A.; Nomura, R.; Matsuda, H.
Tetrahedron Lett. 1995, 36, 9497-9500. (e) Nagano, H.; Ohno, M.;
Miyamae, Y.; Kuno, Y. Bull. Chem. Soc. J pn. 1992, 65, 2814-2820. (f)
Fujisawa, T.; Nagai, M.; Koike, Y.; Shimizu, M. J . Org. Chem. 1994,
59, 5865-5867. (g) Herold, P. Helv. Chim. Acta 1988, 71, 354-361.
(h) Czernecki, S.; Franco, S.; Horns, S.; Valery. J .-M. Tetrahedron Lett.
1996, 37, 4003-4006. (i) Czernecki, S.; Horns, S.; Valery, J .-M. J . Org.
Chem. 1995, 60, 650-655.
(3) (a) Tronchet, J . M. J .; Mihaly, M. E. Helv. Chim. Acta 1972, 55,
1266-1271. (b) Enders, D.; Schankat, J . Helv. Chim. Acta 1995, 78,
970-992. (c) Denis, J .-N.; Tchertchian, S.; Tomassini, A.; Vallee, Y.
Tetrahedron Lett. 1997, 38, 5503-5506. (d) Huffman, M. A.; Yasuda,
N.; DeCamp, A. E.; Grabowski, E. J . J . J . Org. Chem. 1995, 60, 1590-
1594. (e) Myers, A. G.; Tom, N. J .; Fraley, M. E.; Cohen, S. B.; Madar,
D. J . J . Am. Chem. Soc. 1997, 119, 6072-6094. (f) Osipov, S. N.;
Golubev, A. S.; Sewald, N.; Burger, K. Tetrahedron Lett. 1997, 34,
5965-5966.
(6) Such a tunable stereoselectivity in the addition of organometallic
reagents to R-amino nitrones has been well-demonstrated in our
laboratory. See: Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Tetrahedron Lett. 1997, 38, 1813-1816.
(7) For a review see: Ottenheijm, H. C. J .; Herscheid, J . D. M. Chem.
Rev. 1986, 86, 697-707.
(8) (a) Hanessian, S.; Yang, R.-Y. Synlett 1995, 633-634. (b)
Oppolzer, W.; Tamura, O.; Deerberg, J . Helv. Chim. Acta 1992, 75,
1965-1978. (c) Oppolzer, W.; Tamura, O. Tetrahedron Lett. 1990, 31,
991-994. (d) Murahashi, S.-I.; Shiota, T. Tetrahedron Lett. 1987, 28,
6469-6472.
(9) (a) Gouverneur, V.; Lalloz, H. N. Tetrahedron Lett. 1996, 37,
6331-6334. (b) Ohler, E.; Kanzler, S. Phosphorous, Sulfur, Silicon
1996, 112, 71-90. (c) Vasella, A.; Huber, R. Helv. Chim. Acta 1987,
70, 1461-1476.
(4) (a) Merino, P.; Anoro, S.; Castillo, E.; Merchan, F. L.; Tejero, T.
Tetrahedron: Asymmetry 1996, 7, 1887-1890. (b) Merino, P.; Franco,
S.; Merchan, F. L.; Tejero, T. Tetrahedron: Asymmetry 1997, 8, 3489-
3496.
(5) For other nucleophilic additions to R-amino nitrones see: (a)
Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1997, 8, 2381-2401. (b) Merino, P.; Lanaspa, A.; Merchan,
F. L.; Tejero, T. J . Org. Chem. 1996, 61, 9028-9032. See also ref 6.
(10) Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T. Tetrahedron:
Asymmetry 1998, 9, 629-646.
(11) Czernecki, S.; Franco, S.; Valery, J .-M. J . Org. Chem. 1997,
62, 4845-4847.
(12) The lability of the acetoxyamino group under both basic and
acidic conditions has been registered in several instances in our
laboratory.
S0022-3263(97)01477-1 CCC: $15.00 © 1998 American Chemical Society
Published on Web 07/17/1998

5628 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
Sch em e 1
Sch em e 2
It is worth mentioning that oxidation of the furan ring
according to our previous report17 needed more reaction
time than the ethynyl group. As a consequence, some
byproducts coming from the oxidation of the benzyl
groups were observed.17 In such cases, the acetylene
route becomes a more advisable option. Unfortunately,
oxidation of 9 after acetylation of the hydroxylamino
group following our own procedure failed. All efforts to
find conditions that would promote furan oxidation over
side reactions were unsuccessful. We thus turned to
change the protecting group arrangement of the furfu-
rylhydroxylamine 9, and compound 11 was synthesized.
The oxidation of compound 11 followed by esterification
(CH2N2, Et2O) afforded the expected hydroxyamino ester
8 in an acceptable yield (45%). Their physical and
spectroscopic (1H and 13C NMR) properties were identical
to those of the compound obtained from 3.
can be purified as the corresponding methyl ester 5.
With this procedure, which is more similar to that
originally reported by Sharpless,13 the N-hydroxy-R-
amino ester 5 was isolated in 72% yield.
With the completion of an efficient synthesis of the
(3S,4R)-3-amino-4-hydroxy-2-(hydroxyamino)butanoic acid
derivatives with two different protecting groups18 (5 and
8), we focused our attention on the preparation of the
3R,4R isomer. The precursor nitrone 12 (Scheme 2) was
prepared following our previously published procedure.10
The choice of protecting groups was described by our
previous results.6 Addition of lithium (trimethylsilyl)-
acetylide to 12 under the conditions described above gave
an 85:15 mixture of diastereomers. The desired 3R,4R
diastereomer 13 was isolated in 68% yield by chroma-
tography. To improve the obtained results from the
nitrone 12, we set out to examine other conditions for
the nucleophilic addition of the acetylide moiety. These
included (i) addition at lower temperatures, (ii) change
of solvent, and (iii) addition in the presence of HMPT.19
Unfortunately, none of these attempts afforded better
results than that obtained in THF at -80 °C (80% yield,
ds ) 85%). Addition at lower temperatures (-100 °C)
Markedly, the H and 13C NMR spectra in CDCl3 at
1
room temperature showed compounds 4 and 5 to be
rather complex mixtures of rotamers, due to the amide
conformational isomers. First-order spectra could be
obtained in most cases by registering them in DMSO-d6
at high temperatures (80-120 °C). The existence of a
high-energy dynamic equilibrium for 4-substituted 3-(tert-
butoxycarbonyl)oxazolidines had been reported by Garner
and Park.14
For comparison purposes (vide infra), hydroxylamine
3 was deprotected to afford amino alcohol 6 (94%), which
was diacetylated to give 7 in 97% yield. Ruthenium-
mediated oxidation of compound 7 as described above
followed by esterification with diazomethane provided the
corresponding methyl ester 8 in 80% overall yield.
The assigned 3S,4R stereochemistry of 2 was confirmed
by an independent synthesis of the N-hydroxy-R-amino
ester 8 starting from the furan derivative15 9, whose
absolute configuration had been unambiguously con-
firmed by us.16 The strategy for that synthesis is
illustrated in Scheme 1.
(17) Dondoni, A.; J unquera, F.; Merchan, F. L.; Merino, P.; Tejero,
T. Synthesis 1994, 1450-1456.
(18) Homologated serines having different functionalities at the
R-position are versatile building blocks for asymmetric synthesis. X )
N3: Nitta, H.; Ueda, I.; Hatanaka, M. J . Chem. Soc., Perkin Trans. 1
1997, 1793-1798. X ) OH: Wagner, R.; Tilley, J . W. J . Org. Chem.
1990, 55, 6289-6291. X ) N(OR)R: This work.
(13) Carlsen, H. J .; Katsuki, T.; Martin, V. S.; Sharpless, K. B. J .
Org. Chem. 1981, 46, 3936-3938.
(14) Garner, P.; Park, J . M. J . Org. Chem. 1987, 52, 2361-2364.
(15) Compound 9 was prepared by us from nitrone 1 and 2-lithio-
furan. See: Merino, P.; Lanaspa, A.; Merchan, F. L.; Tejero, T.
Electronic Conference on Trends in Organometallic Chemistry; Rzepa,
H. S., Leach, C., Eds.; Royal Society of Chemistry: London, 1997;
Article 003, CD-ROM, ISBN 0-85404-889-8. Internet: http://www.ch.i-
c.ac.uk/ectoc/ectoc-3/.
(19) The addition in the presence of Lewis acids (in a way similar
to that described by us for R-alkoxy nitrones) were not considered due
to the lower chemical yield observed under these conditions with other
nucleophiles (Merino, P.; Franco, S.; Lanaspa, A.; Merchan, F. L.;
Tejero, T. Unpublished results).
(16) Merino, P.; Merchan, F. L.; Tejero, T.; Lanaspa, A. Acta
Crystallogr. Sect. C 1996, 52, 2536-2538.

Notes
J . Org. Chem., Vol. 63, No. 16, 1998 5629
(2.5 mmol) of a 1.0 M solution of Bu4NF in anhydrous THF. After
1 h, the reaction was quenched by the addition of saturated
NaHCO3 and the resulting mixture partitioned between Et2O
(30 mL) and H2O (50 mL). The layers were separated, and the
aqueous solution was extracted with Et2O (3 × 25 mL). The
organic extracts were combined, washed with brine, dried
(MgSO4), and filtered under reduced pressure. The resulting
oil was chromatographed on silica gel (20:80 EtOAc/hexane) to
give propargyl hydroxylamine 3 (0.73 g, 88%) as a white solid:
mp 73-75 °C; Rf 0.33; [R]D +37.1 (c 0.50, CHCl3); 1H NMR
(CDCl3) δ 1.30 (s, 3H), 1.46 (s, 3H), 1.52 (s, 9H), 2.43 (d, 1H, J
) 2.2 Hz), 3.39 (dd, 1H, J ) 2.2, 10.1 Hz), 3.87 (d, 1H, J ) 13.0
Hz), 3.94 (dd, 1H, J ) 5.0, 9.3 Hz), 4.03 (d, 1H, J ) 9.3 Hz),
4.18 (d, 1H, J ) 13.0 Hz), 4.23 (dd, 1H, J ) 5.0, 10.1 Hz), 7.14-
7.31 (m, 5H), 7.52 bs, 1H, ex. D2O); 13C NMR (CDCl3) δ 24.6,
27.3, 28.4, 58.6, 60.2, 60.8, 65.7, 75.4, 79.0, 81.2, 94.1, 127.2,
128.1, 128.9, 137.6, 154.3. Anal. Calcd for C20H28N2O4: C,
66.64; H, 7.83; N, 7.77. Found: C, 66.57; H, 7.99; N, 7.53.
(3S,4R)-3-(N-acetoxy-N-ben zylam in o)-5-h ydr oxy-4,5-N,O-
isop r op ylid e n e -4-[(t er t -b u t oxyca r b on yl)a m in o]-1-p e n -
tyn e (4). A solution of hydroxylamine 3 (0.70 g, 1.94 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 (20:80
EtOAc/hexane) to give the acetylated product 4 as a colorless
oil (0.78 g, 100%): Rf 0.19; [R]D -29.8 (c 0.50, CHCl3); 1H NMR
(DMSO-d6, 120 °C) δ 1.35 (s, 9H), 1.41 (s, 3H), 1.49 (s, 3H), 1.85
(s, 3H), 3.31 (bs, 1H), 3.95 (dd, 1H, J ) 6.2, 8.9 Hz), 4.07 (d, 1H,
J ) 13.0 Hz), 4.09 (m, 1H), 4.14 (m, 1H), 4.21 (m, 1H), 4.26 (d,
1H, J ) 13.0 Hz), 7.30-7.47 (m, 5H); 13C NMR (DMSO-d6, 80
°C) δ 18.5, 25.9, 26.8, 27.5, 58.0, 58.6, 59.6, 64.2, 77.8, 78.6, 80.9,
93.1, 127.1, 127.6, 129.0, 135.1, 151.1, 168.3. Anal. Calcd for
C22H30N2O5: C, 65.65; H, 7.51; N, 6.96. Found: C, 65.73; H,
7.79; N, 7.11.
gave a poor conversion (20% after 24 h) without substan-
tial increasing of the diastereoselectivity. The use of
diethyl ether as a solvent or HMPT as an additive
afforded lower selectivities (55% and 65%, respectively)
without increasing the chemical yield.
Desilylation of 13 (Bu4NF, THF) provided 14 (70%),
whose physical and spectroscopic (1H and 13C NMR)
properties were rather different than those of its dias-
tereomer 6, whose relative stereochemistry had been
proven by an independent synthesis as described above.
Hence, the 3R,4R stereochemistry of compound 13 had
been established.
Protection of 14 as the di-O-acetyl derivative 15 and
subsequent cleavage of the ethynyl group by the ruthe-
nium protocol afforded the anti N-hydroxy-R-amino ester
16 in 76% isolated yield. Also, the physical and spectro-
scopic properties of this compound were quite different
from those of 8. This further confirmed the stereodiver-
gency of the described process.
In summary, we have demonstrated that secondary
N-hydroxy-R-amino esters derived from L-serine can be
prepared in a highly stereocontrolled manner by chang-
ing the protecting groups in the starting R-amino nitrones
1 and 12. Thus, quite conveniently, both 8 (ds g 95%)
and 16 (ds ) 85%) are available from L-serine via three-
and five-step routes that diverge following the initial
acetylide nucleophilic addition to the corresponding ni-
trones. The use of the ethynyl group as a surrogate of
the carboxylic acid, instead of the furan ring, allows
releasing of the carboxyl moiety under milder conditions.
Exp er im en ta l Section
Gen er a l Meth od s. For general experimental information
see ref 5a. Nitrones 1 and 12 were prepared as described.10
Compound 9 was prepared as described.15 Commercial-grade
(trimethylsilyl)acetylene was used without further purification.
(3S,4R)-3-(N-Ben zyl-N-h yd r oxya m in o)-5-h yd r oxy-4,5-
N,O-isop r op ylid en e-4-[(ter t-bu toxyca r bon yl)a m in o]-1-(tr i-
m eth ylsilyl)-1-p en tyn e (2). To a solution of (trimethylsilyl)-
acetylene (0.89 g, 9.0 mmol) in THF (25 mL) at -20 °C was
added n-butyllithium (5.7 mL, 1.6 M in hexanes, 9.12 mmol).
This solution was stirred for 15 min and then cooled to -80 °C.
A cold (-80 °C) solution of nitrone 1 (1.0 g, 3.0 mmol) in THF
(40 mL) was then quickly added with a cannula over a period of
15 min. The solution turned yellow and orange as the addition
progressed. Stirring at -80 °C was continued for an additional
15 min until all the nitrone was consumed (TLC). The reaction
was quenched with saturated NH4Cl (5 mL), and the result
mixture was allowed to warm to room temperature. The
reaction mixture was partitioned between Et2O (25 mL) and
saturated aqueous NH4Cl (50 mL) and then shaken vigorously.
The layers were separated, and the aqueous layer was further
extracted with Et2O (3 × 25 mL). The organic extracts were
combined, washed with brine, dried (MgSO4), and filtered. The
solvent was removed under reduced pressure to give a slightly
yellow oil (ds g 95% by 1H NMR). The crude product was
chromatographed on silica gel (15:85 EtOAc/hexane) to give the
hydroxylamine 2 as a clear oil (1.26 g, 97%): Rf 0.28; [R]D +37.9
(c 1.70, CHCl3); 1H NMR (CDCl3) δ 0.22 (s, 9H), 1.31 (s, 3H),
1.47 (s, 3H), 1.54 (s, 9H), 3.43 (d, 1H, J ) 10.0 Hz), 3.88 (d, 1H,
J ) 12.9 Hz), 3.95 (dd, 1H, J ) 5.0, 9.2 Hz), 4.07 (d, 1H, J ) 9.2
Hz), 4.18 (d, 1H, J ) 12.9 Hz), 4.22 (dd, 1H, J ) 5.0, 10.0 Hz),
7.18-7.28 (m, 5H), 7.43 (bs, 1H, ex. D2O); 13C NMR (CDCl3) δ
0.1, 24.6, 27.3, 28.4, 58.5, 60.8, 61.1, 65.9, 81.0, 92.6, 94.0, 100.9,
127.1, 128.1, 128.9, 137.8, 154.2. Anal. Calcd for C23H36N2O4-
Si: C, 63.85; H, 8.39; N, 6.48. Found: C, 63.80; H, 8.09; N, 6.40.
(3S,4R)-3-(N-Ben zyl-N-h yd r oxya m in o)-5-h yd r oxy-4,5-
N,O-isop r op ylid en e-4-[(ter t-bu toxyca r bon yl)a m in o]-1-p en -
tyn e (3). A solution of hydroxylamine 2 (1.0 g, 2.3 mmol) in
THF (30 mL) at ambient temperature was treated with 2.5 mL
1,1-Dim eth yleth yl [R-(R)]-4-[[(N-Acetoxy-N-ben zylam in o)-
m eth oxyca r bon yl]m eth yl]-2,2-d im eth yl-3-oxa zolid in eca r -
boxyla te (5). To a well-stirred mixture of CH3CN (1.3 mL),
CCl4 (1.3 mL), and H2O (2 mL) were added NaIO4 (0.265 g, 1.24
mmol) and RuCl3‚H2O (9.7 mg, 0.043 mmol) sequentially. The
resulting yellowish mixture was allowed to stir for 30 min, at
which time it was poured into a flask containing pure 4 (0.3 g,
0.75 mmol). The resulting mixture turned black, and additional
NaIO4 (0.133 mg, 0.62 mmol) was added. After 5 min, the
reaction mixture was partitioned between EtOAc (25 mL) and
H2O (25 mL), the layers were separated, and the aqueous layer
was extracted with additional portions of EtOAc (5 × 10 mL).
The organic extracts were combined, dried (MgSO4), and filtered
through a short plug of Florisil, and the filtrate was concentrated
under reduced pressure to give the crude carboxylic acid. This
crude material was dissolved in Et2O and treated with an
ethereal solution of diazomethane to give, after purification by
column chromatography on silica gel (15:85 EtOAc/hexane), the
ester 5 (0.236 mg, 72%) as a colorless oil: Rf 0.24; [R]D -30.7 (c
1
0.66, CHCl3); H NMR (DMSO-d6, 120 °C) δ 1.41 (bs, 6H), 1.43
(s, 9H), 1.82 (s, 3H), 3.96 (s, 3H), 3.93 (m, 1H), 4.10 (d, 1H, J )
13.7 Hz), 4.13 (d, 1H, J ) 4.2 Hz), 4.18 (d, 1H, J ) 13.7 Hz),
4.26-4.31 (m, 2H), 7.19-7.43 (m, 5H); 13C NMR (DMSO-d6, 100
°C) δ 18.8, 25.2, 27.2, 28.3, 60.6, 63.1, 64.6, 71.9, 82.9, 83.3, 109.4,
126.1, 126.9, 128.4, 135.3, 150.2, 168.8, 173.5. Anal. Calcd for
C22H32N2O7: C, 60.54; H, 7.39; N, 6.42. Found: C, 60.79; H,
7.13; N, 6.69.
(3S,4R)-3-(N-Ben zyl-N-h yd r oxya m in o)-4-[(ter t-b u t oxy-
ca r bon yl)a m in o]-5-h yd r oxy-1-p en tyn e (6). A solution of
hydroxylamine 3 (0.5 g, 1.39 mmol) in MeOH (35 mL) at room
temperature was treated with catalytic p-TosOH (10 mg, 2%
w/w). The resulting solution was warmed to reflux, where it
was maintained until all starting material disappeared (TLC, 3
h). The mixture was allowed to cool to room temperature, at
which time the solvent was removed under reduced pressure.
The crude product was then partitioned between CH2Cl2 (30 mL)

5630 J . Org. Chem., Vol. 63, No. 16, 1998
Notes
and saturated aqueous NaHCO3 (30 mL), the layers were
separated, and the aqueous layer was extracted with additional
portions of CH2Cl2 (3 × 15 mL). The organic extracts were
combined, dried (MgSO4), and concentrated under reduced
pressure. Chromatography of the crude product on silica gel
(40:60 EtOAc/hexane) gave 0.42 g (94%) of amino alcohol 6 as a
sticky foam: Rf 0.38; [R]D +13.8 (c 0.36, CHCl3); 1H NMR (CDCl3)
δ 1.48 (s, 9H), 1.85 (bs, 1H, ex. D2O), 2.50 (d, 1H, J ) 2.3 Hz),
3.50 (dd, 1H, J ) 2.3, 9.9 Hz), 3.83 (m, 2H), 3.86 (dt, 1H, J )
2.5, 9.9 Hz), 4.12 (bd, 1H, J ) 9.1 Hz), 4.19 (d, 1H, J ) 13.3 Hz),
5.13 (d, 1H, J ) 9.5 Hz), 6.71 (bs, 1H, ex. D2O), 7.17-7.37 (m,
5H); 13C NMR (CDCl3) δ 28.3, 53.1, 59.7, 61.0, 62.1, 76.2, 78.4,
80.2, 127.1, 128.1, 128.7, 137.6, 157.7. Anal. Calcd for
1H, ex. D2O), 3.39 (dd, 1H, J ) 2.9, 11.2 Hz), 3.66 (dd, 1H, J )
2.9, 11.2 Hz), 3.70 (d, 1H, J ) 13.9 Hz), 3.75 (d, 1H, J ) 13.9
Hz), 3.87 (d, 1H, J ) 10.3 Hz), 4.11 (tdd, 1H, J ) 2.9, 9.3, 10.3
Hz), 5.30 (d, 1H, J ) 9.3 Hz), 6.43 (dd, 1H, J ) 1.7, 3.2 Hz),
6.46 (bd, 1H, J ) 3.2 Hz), 6.68 (bs, 1H, ex. D2O), 7.22-7.32 (m,
5H), 7.45 (bd, 1H, J ) 1.7 Hz); 13C NMR (CDCl3) δ 28.2, 53.3,
50.6, 62.5, 64.1, 80.1, 110.0, 110.6, 127.0, 128.1, 128.6, 138.9,
142.1, 150.5, 157.9. Anal. Calcd for C19H26N2O5: C, 62.97; H,
7.23; N, 7.73. Found: C, 62.78; H, 7.59; N, 7.46.
(3R,4R)-3-(N-Ben zyl-N-h yd r oxya m in o)-4-[(ter t-b u t oxy-
ca r bon yl)a m in o]-5-(ter t-bu tyld ip h en ylsiloxy)-1-(tr im eth -
ylsilyl)-1-p en tyn e (13). By applying the procedure described
above for the preparation of 2, 1.60 g (3.0 mmol) of nitrone 12
was converted to 13. Chromatography of the crude mixture of
diastereomers (ds ) 85% by 1H NMR) on silica gel (15:85 EtOAc/
hexane) afforded 1.29 g (68%) of 13 as a colorless oil: Rf 0.29;
[R]D -37.4 (c 0.88, CHCl3); 1H NMR (CDCl3, 55 °C) δ 0.17 (s,
9H), 1.04 (s, 9H), 1.44 (s, 9H), 3.72 (dd, 1H, J ) 6.6, 10.2 Hz),
3.76-3.87 (m, 3H), 4.19-4.35 (m, 1H), 4.32 (d, 1H, J ) 13.6 Hz),
4.72 (d, 1H, J ) 9.9 Hz), 5.94 (bs, 1H), 7.03-7.43 (m, 11H), 7.46-
7.76 (m, 4H); 13C NMR (CDCl3, 55 °C) δ -0.2, 19.1, 26.7, 28.2,
52.8, 61.3, 61.4, 63.6, 65.5, 79.5, 83.2, 126.9, 127.5, 127.6, 127.9,
129.0, 129.4, 129.6, 133.2, 134.7, 135.5 (2C), 137.7, 156.5. Anal.
Calcd for C36H50N2O4Si2: C, 68.53; H, 7.99; N, 4.44. Found: C,
68.39; H, 8.14; N, 4.09.
C
17H24N2O4: C, 63.73; H, 7.55; N, 8.74. Found: C, 63.52; H,
7.40; N, 8.88.
(3S,4R)-5-Acetoxy-3-(N-Acetoxy-N-ben zyla m in o)-4-[(ter t-
bu toxyca r bon yl)a m in o]-1-p en tyn e (7). Applying the proce-
dure described above for the preparation of 4, 0.50 g (1.56 mmol)
of compound 6 was converted to 7. Chromatography of the crude
product on silica gel (25:75 EtOAc/hexane) gave 0.61 g (97%) of
7 as a colorless oil: Rf 0.24; [R]D +15.6 (c 0.66, CHCl3); 1H NMR
(CDCl3, 55 °C) δ 1.42 (s, 9H), 1.90 (s, 3H), 1.96 (s, 3H), 2.51 (d,
1H, J ) 2.3 Hz), 3.87 (dd, 1H, J ) 2.3, 8.7 Hz), 4.00 (ddd, 1H, J
) 3.7, 5.0, 8.7 Hz), 4.08 (d, 1H, J ) 12.9 Hz), 4.28 (d, 1H, J )
12.9 Hz), 4.30 (dd, 1H, J ) 5.0, 11.4 Hz), 4.41 (dd, 1H, J ) 3.7,
11.4 Hz), 5.02 (d, 1H, J ) 6.8 Hz), 7.21-7.42 (m, 5H); 13C NMR
(CDCl3, 55 °C) δ 19.1, 20.5, 28.4, 51.7, 57.6, 59.6, 63.8, 76.7, 77.1,
79.7, 127.9, 128.4, 129.6, 135.3, 155.5, 168.9, 170.4. Anal. Calcd
for C21H28N2O6: C, 62.36; H, 6.98; N, 6.93. Found: C, 62.60;
H, 7.29; N, 6.73.
(3R,4R)-3-(N-Ben zyl-N-h yd r oxya m in o)-4-[(ter t-b u t oxy-
ca r bon yl)a m in o]-5-h yd r oxy-1-p en tyn e (14). By applying the
procedure described above for the preparation of 3, 1.50 g (2.38
mmol) of compound 13 was converted to 14. Chromatography
of the crude product on silica gel (40:60 EtOAc/hexane) gave 0.53
g (70%) of 14 as a white solid: mp 164-166 °C; Rf 0.32; [R]D
-65.7 (c 0.51, CHCl3); 1H NMR (CDCl3, 55 °C) δ 1.42 (s, 9H),
1.60 (bs, 1H, ex. D2O), 2.50 (d, 1H, J ) 2.2 Hz), 3.71 (dd, 1H, J
) 5.4, 11.4 Hz), 3.72 (dd, 1H, J ) 2.2, 4.9 Hz), 3.81 (d, 1H, J )
13.1 Hz), 3.86 (dd, 1H, J ) 4.9, 11.4 Hz), 4.10 (dt, 1H, J ) 4.9,
5.4 Hz), 4.29 (d, 1H, J ) 13.1 Hz), 5.04 (bd, 1H, J ) 8.7 Hz),
6.05 (bs, 1H, ex. D2O), 7.23-7.40 (m, 5H); 13C NMR (CDCl3, 55
°C) δ 28.3, 53.4, 60.7, 61.8, 62.7, 76.6, 78.0, 80.0, 127.3, 128.2,
129.1, 137.1, 156.6. Anal. Calcd for C17H24N2O4: C, 63.73; H,
7.55; N, 8.74. Found: C, 63.66; H, 7.61; N, 8.68.
Meth yl (2R,3R)-4-Acetoxy-2-(N-a cetoxy-N-ben zyla m in o)-
3-[(ter t-bu toxyca r bon yl)a m in o]bu ta n oa te (8). F r om 7. Ap-
plying the procedure described above for the preparation of 5,
0.30 g (0.74 mmol) of compound 7 was converted to 8. Chro-
matography of the crude product on silica gel (30:70 EtOAc/
hexane) gave 0.26 g (80%) of 8 as a colorless oil: Rf 0.33; [R]D
1
+13.4 (c 0.78, CHCl3); H NMR (CDCl3) δ 1.41 (s, 9H), 1.88 (s,
3H), 1.94 (s, 3H), 3.80 (s, 3H), 3.82 (d, 1H, J ) 8.3 Hz), 4.09 (dd,
1H, J ) 4.9, 11.5 Hz), 4.10 (d, 1H, J ) 12.9 Hz), 4.16 (dd, 1H, J
) 4.6, 11.5 Hz), 4.25 (ddd, 1H, J ) 4.6, 4.9, 8.3 Hz), 4.27 (d, 1H,
J ) 12.9 Hz), 5.21 (bd, 1H, J ) 6.6 Hz), 7.21-7.30 (m, 5H); 13
C
(3R,4R)-5-Acetoxy-3-(N-a cetoxy-N-ben zyla m in o)-4-[(ter t-
bu toxyca r bon yl)a m in o]-1-p en tyn e (15). By applying the
procedure described above for the preparation of 4, 0.25 g (0.78
mmol) of compound 14 was converted to 15. Chromatography
of the crude product on silica gel (25:75 EtOAc/hexane) gave
0.315 g (100%) of 15 as a colorless oil: Rf 0.19; [R]D -31.8 (c
0.59, CHCl3); 1H NMR (CDCl3, 55 °C) δ 1.42 (s, 9H), 1.89 (s,
3H), 1.94 (s, 3H), 2.45 (d, 1H, J ) 2.3 Hz), 3.79 (dd, 1H, J ) 2.3,
6.9 Hz), 4.10 (d, 1H, J ) 12.5 Hz), 4.10-4.21 (m, 2H), 4.22 (d,
1H, J ) 12.5 Hz), 4.29 (dd, 1H, J ) 5.3, 10.7 Hz), 4.85 (bs, 1H),
7.20-7.42 (m, 5H); 13C NMR (CDCl3, 55 °C) δ 19.1, 20.4, 28.2,
51.1, 57.4, 60.5, 63.8, 76.2, 76.7, 79.7, 127.9, 128.4, 129.5, 135.0,
155.0, 168.8, 170.1. Anal. Calcd for C21H28N2O6: C, 62.36; H,
6.98; N, 6.93. Found: C, 62.21; H, 6.85; N, 6.78.
NMR (CDCl3) δ 19.1, 20.6, 28.3, 49.2, 52.1, 59.2, 63.7, 65.6, 79.8,
127.9, 128.4, 129.4, 135.4, 155.4, 168.5, 169.1, 170.4. Anal.
Calcd for C21H30N2O8: C, 57.52; H, 6.90; N, 6.39. Found: C,
57.76; H, 6.68; N, 6.54.
F r om 10. A solution of furfurylhydroxylamine 10 (0.15 g,
0.41 mmol) in CH2Cl2 (2 mL) was treated as described above
for the preparation of 4 to afford crude 11 (0.183 g, 100%; 95%
pure by 1H NMR), which was used for the next reaction without
further purification: 1H NMR (CDCl3) δ 1.43 (s, 9H), 1.88 (s,
3H), 1.92 (s, 3H), 3.65 (d, 1H, J ) 12.9 Hz), 3.82 (dd, 1H, J )
4.2, 11.1 Hz), 4.51 (d, 1H, J ) 12.9 Hz), 4.18-4.28 (m, 3H), 5.30
(bs, 1H), 6.37 (bd, 1H, J ) 3.8 Hz), 6.41 (dd, 1H, J ) 3.8, 1.9
Hz), 7.25-7.36 (m, 5H), 7.43 (bd, 1H, J ) 1.9 Hz).
To a well-stirred solution of NaIO4 (0.351 g, 1.65 mmol) in
H2O-CCl4-CH3CN 3:2:2 (7.4 mL) was added RuCl3 (2.8 mg,
0.013 mmol). After 15 min of stirring, the 2-furyl derivative 11
(0.121 g, 0.27 mmol) in CH3CN (0.5 mL) was added. The solution
turned instantaneously from yellowish to black. Then enough
NaIO4 was added to restore the yellowish color. After 5 min,
the mixture was diluted with water (5 mL) and extracted with
EtOAc (3 × 10 mL). The organic combined extracts were washed
successively with 20% aqueous NaHSO3 and brine until colorless
and dried over magnesium sulfate, and the solvent was evapo-
rated under reduced pressure. The residue was dissolved in
Et2O and treated with an ethereal solution of diazomethane to
give, after purification by column chromatography on silica gel
(30:70 EtOAc/hexane), the ester 8 (81 mg, 45%) as an oil. The
characteristics of this material were identical to those of the
product obtained from 7 as described above.
Meth yl (2S,3R)-4-Acetoxy-2-(N-a cetoxy-N-ben zyla m in o)-
3-[(ter t-bu toxyca r bon yl)a m in o]bu ta n oa te (16). By applying
the procedure described above for the preparation of 5, 0.20 g
(0.49 mmol) of compound 15 was converted to 16. Chromatog-
raphy of the crude product on silica gel (30:70 EtOAc/hexane)
gave 0.163 g (76%) of 16 as an oil: Rf 0.26; [R]D -3.6 (c 1.00,
CHCl3); 1H NMR (CDCl3, 55 °C) δ 1.41 (s, 9H), 1.91 (s, 3H), 1.94
(s, 3H), 3.72 (d, 1H, J ) 7.6 Hz), 3.81 (s, 3H), 4.13 (dd, 1H, J )
4.5, 11.2 Hz), 4.17 (d, 1H, J ) 12.6 Hz), 4.22 (d, 1H, J ) 12.6
Hz), 4.30-4.39 (m, 2H), 5.01 (bd, 1H, J ) 11.2 Hz), 7.26-7.43
(m, 5H); 13C NMR (CDCl3, 55 °C) δ 19.0, 20.4, 28.2, 49.2, 51.7,
60.4, 63.9, 66.1, 80.4, 127.9, 128.4, 129.6, 135.1, 154.9, 168.4,
168.8, 170.2. Anal. Calcd for C21H30N2O8: C, 57.52; H, 6.90;
N, 6.39. Found: C, 57.71; H, 7.01; N, 6.60.
(1R,2R)-3-Acet oxy)1-(N-b en zyl-N-h yd r oxya m in o)-1-(2-
fu r yl)-2-[(ter t-bu toxyca r bon yl)a m in o]p r op a n e (10). By ap-
plying the procedure described above for the preparation of 6,
0.20 g (0.50 mmol) of compound 9 was converted to 10. Chro-
matography of the crude product on silica gel (40:60 EtOAc/
hexane) gave 0.174 g (96%) of 10 as a sticky oil: Rf 0.34; [R]D
+6.6 (c 0.52, CHCl3); 1H NMR (CDCl3) δ 1.51 (s, 9H), 2.0 (bs,
Ack n ow led gm en t. Financial support was provided
by the Ministerio de Educacio´n y Cultura (Madrid,
Spain). We are also grateful to the MEC for a contract
to S.F.
J O9714775