Enantioselective synthesis of (2R,4S)- and (2S,4R)-4-hydroxypipecolic acid from D-glucoheptono-1,4-lactone

Article abstract of DOI:10.1021/jo990445+

Enantiomerically pure (2R,4S)-4-hydroxypipecolic acid [(+)-1] was synthesized from D-glucoheptono-1,4-lactone (2) via the 3,5-dideoxy-D-xylo- heptono-1,4-lactone (7). The latter was readily prepared by benzoylation of 2, followed by β-elimination and diastereoselective hydrogenation of the resulting furanones (4). Compound 7 was converted into the 6,7-O- cyclohexylidene derivative 11, which on treatment with tosyl chloride for long periods afforded the 2-chloro derivative 14, the precursor of the azide 15. Hydrogenolysis of 15 and protection of the amine gave the N- benzyloxycarbonyl derivative 19, having the required configuration for the stereocenters at C-2 and C-4. Removal of the cyclohexylidene group by hydrolysis and subsequent oxidative degradation of the resulting glycol system afforded the hexurono-6,3-lactone 21 as a key intermediate. Chemoselective reduction of the aldehyde function of 21 led to the alcohol 23, which was derivatized as the mesylate 24. Releasing of the amino group by hydrogenation, and dissolution of resulting 25 in aqueous alkali, promoted the intramolecular nucleophilic displacement of the mesylate to give (+)-1. Its enantiomer [(-)-1] was prepared by a similar sequence starting from 2.

Full text of DOI:10.1021/jo990445+

VOLUME 64, NUMBER 17
AUGUST 20, 1999
© Copyright 1999 by the American Chemical Society
Articles
En a n tioselective Syn th esis of (2R,4S)- a n d
(2S,4R)-4-Hyd r oxyp ip ecolic Acid fr om D-Glu coh ep ton o-1,4-la cton e
Christia´n Di Nardo and Oscar Varela*
CIHIDECAR-CONICET, Departamento de Quı´mica Orga´nica, Facultad de Ciencias Exactas y Naturales,
Universidad de Buenos Aires, Ciudad Universitaria, Pabello´n 2, 1428, Buenos Aires, Argentina
Received March 11, 1999
Enantiomerically pure (2R,4S)-4-hydroxypipecolic acid [(+)-1] was synthesized from D-glucoheptono-
1,4-lactone (2) via the 3,5-dideoxy-D-xylo-heptono-1,4-lactone (7). The latter was readily prepared
by benzoylation of 2, followed by â-elimination and diastereoselective hydrogenation of the resulting
furanones (4). Compound 7 was converted into the 6,7-O-cyclohexylidene derivative 11, which on
treatment with tosyl chloride for long periods afforded the 2-chloro derivative 14, the precursor of
the azide 15. Hydrogenolysis of 15 and protection of the amine gave the N-benzyloxycarbonyl
derivative 19, having the required configuration for the stereocenters at C-2 and C-4. Removal of
the cyclohexylidene group by hydrolysis and subsequent oxidative degradation of the resulting glycol
system afforded the hexurono-6,3-lactone 21 as a key intermediate. Chemoselective reduction of
the aldehyde function of 21 led to the alcohol 23, which was derivatized as the mesylate 24. Releasing
of the amino group by hydrogenation, and dissolution of resulting 25 in aqueous alkali, promoted
the intramolecular nucleophilic displacement of the mesylate to give (+)-1. Its enantiomer [(-)-1]
was prepared by a similar sequence starting from 2.
In tr od u ction
potent peptidomimetic-based HIV protease inhibitor.4
Also, substituted D- and L-pipecolic acids have been used
as key intermediates in the synthesis of different types
of other piperidine natural products.5 For these reasons,
cis-4-hydroxypipecolic acid (1) is an interesting target
molecule for synthesis, which has attracted significant
attention in recent years. In fact, racemic 1 has been
The naturally occurring (2S,4R)-4-hydroxypipecolic
acid (cis-4-hydroxy-2-piperidinecarboxylic acid, (-)-1) has
been isolated from leaves of Calliandra pittieri and
Strophantus scandeus.1 It was also identified as a con-
stituent of cyclopeptide antibiotics, such as virginiamycin
S2.2 Compound 1 was employed as precursor in the
preparation of selective N-methyl-D-aspartate (NMDA)
receptor antagonists.3 Furthermore, (-)-1 has served as
a building block in a recent synthesis of palinavir, a
(4) (a) Beaulieu, P. L.; Lavalle´e, P.; Abraham, A.; Anderson, P. C.;
Boucher, C.; Bousquet, Y.; Duceppe, J .-S.; Gillard, J .; Gorys, V.; Grand-
Maitre, C.; Grenier, L.; Guindon, Y.; Guse, I.; Plamondom, L.; Soucy,
F.; Valois, S.; Wernic, D.; Yoakim, C. J . Org. Chem. 1997, 62, 3440.
(b) Anderson, P. C.; Soucy, F.; Yoakim, C.; Lavalle´e, P.; Beaulieu, P.
L. U.S. Patent 5 614 533, 1997; Chem. Abstr. 1997, 126, 305785v.
(5) (a) Barluenga, J .; Aznar, F.; Valde´s, C.; Ribas, C. J . Org. Chem.
1998, 63, 3918. (b) Angle, S. R.; Henry, R. M. J . Org. Chem. 1997, 62,
8549. (c) Holmes, A. B.; Swithenbank, C.; Williams, S. F. J . Chem.
Soc., Chem. Commun. 1986, 265. (d) Herdeis, C.; Nagel, U. Heterocycles
1983, 20, 2163.
(1) (a) Romeo, J . T.; Swain, L. A.; Bleecker, A. B. Phytochemistry
1983, 22, 1615. (b) Schenk, V. W.; Schutte, H. R. Flora 1963, 153, 426.
(2) Vanderhaeghe, H.; J anssen, G.; Compernolle, F. Tetrahedron
Lett. 1971, 28, 2687.
(3) Hays, S. J .; Malone, T. C.; J ohnson, G. J . Org. Chem. 1991, 56,
4084 and references therein.
10.1021/jo990445+ CCC: $18.00 © 1999 American Chemical Society
Published on Web 07/29/1999

6120 J . Org. Chem., Vol. 64, No. 17, 1999
Di Nardo and Varela
synthesized in our laboratory,6 and some other proce-
dures for the synthesis of racemic derivatives of 1 have
appeared in the literature. These procedures include
hydrogenation of 2-cyano-4-methoxypyridines at high
pressures,7 low-temperature acid-induced cyclization of
a glycine cation equivalent,8 or condensation of N-3-
butenylbenzenemethanamine with glyoxylic acid followed
by iminium ion cyclization.3 Also, a patent on the
preparation of an amide derivative of 1 from 4-hydroxy-
piperidine has been issued.4b The first synthesis of
enantiomerically pure (-)-1 was reported by Clark-Lewis
and Mortimer,9 who performed the chemical transforma-
tion of (-)-trans-4-hydroxypipecolic acid, isolated from
leaves of Acacia oswaldii. Such a hydroxy acid was
oxidized to the 4-oxo-L-pipecolic acid, which was then
reduced to (-)-1. The same 4-ketoacid has been also
synthesized in racemic10 or chiral11 forms, and it was
employed as intermediate in another synthesis of (-)-1
from L-aspartic acid.12 Enzymatic or quinine resolution
of racemic 1 led to the optically pure compound.13 Gillard
et al.14 reported the chemical resolution of the racemic
lactone prepared by the already mentioned procedure3
consisting of the cyclization of a homoallylic iminium
cation. As the lactone having the proper configuration
was obtained in poor yields, an asymmetric version of
this cyclization using a chiral homoallylic amine was
developed. However, low levels of diastereoselective
induction were observed, and a “resolving” agent was
required for the separation of the resulting diastereo-
meric lactones.
Sch em e 1
Sch em e 2
We wish to report here an efficient synthesis of
enantiomerically pure (2S,4R)- and (2R,4S)-4-hydroxy-
pipecolic acids [(-)-1 and (+)-1, respectively] using com-
mercially available and inexpensive D-glycero-D-gulo-
heptono-1,4-lactone (2, D-glucoheptono-1,4-lactone) as
chiral template.
Resu lts a n d Discu ssion
double â-elimination process to give a mixture of 2-fura-
nones 4-E and 4-Z (∼1:1 ratio) in 90% yield (Scheme 2).
Hydrogenation of the mixture of furanones, under various
conditions, took place with stereocontrol induced by the
stereocenter in the lateral chain to give two diastereo-
isomers of the four theoretically possible. The stereo-
isomers obtained are those which have a cis relationship
for the substituents of the lactone ring. The 3,5-dideoxy-
lactone derivative 5 (xylo configuration) was isolated pure
(40% yield) by recrystallization from the reaction mixture.
However, attempts to isolate the other isomer (6) or to
separate the mixture of the free lactones (7 and 8) by
simple chromatographic procedures were unsuccessful.
Therefore, other derivatives that could facilitate the
separation of the diastereoisomers and could be useful
for the synthesis of 1 were prepared. The acetonation of
the mixture of 7 and 8 was first attempted. The resulting
acetonides 9 and 10 showed different mobility on TLC,
but they were rather sensitive to the acidity of the silica
gel and they underwent considerable hydrolysis during
the column chromatography purification. For this reason,
the isopropylidene was replaced by the cyclohexylidene
group, which is known to be more stable to acidic
conditions.16 Cyclohexylidenation of 7 and 8 with cyclo-
hexanone catalyzed by p-toluenesulfonic acid in the
A retrosynthetic analysis for 1 (Scheme 1) suggests the
disconnection of the C-6-N bond to produce a synthon
equivalent to a 2-aminohexono-1,4-lactone having an
aldehyde group at C-6. This function may be generated
by oxidative degradation of a terminal glycol and the
amino group at C-2 by substitution of HO-2 in the
precursor 3,5-dideoxyheptono-1,4-lactone, which can be
obtained from D-glycero-D-gulo-heptono-1,4-lactone (D-
glucoheptono-1,4-lactone, 2). We have already reported15
that the per-O-benzoyl-heptonolactone 3, when treated
with 10% triethylamine in chloroform, undergoes a
(6) Nin, A. P.; Varela, O.; de Lederkremer, R. M. Tetrahedron 1993,
49, 9459.
(7) Orstein, P. L.; Schoepp, D. D.; Arnold, M. B.; Leander, J . D.;
Lodge, D.; Paschal, J . W.; Elzey, T. J . Med. Chem. 1991, 34, 90.
(8) (a) Esch, P. M.; de Boer, R. F.; Hiemstra, H.; Boska, I. M.;
Speckamp, W. N. Tetrahedron 1991, 47, 4063. (b) Esch, P. M.; Boska,
I. M.; Hiemstra, H.; Speckamp, W. N. Syntlett 1989, 38.
(9) Clark-Lewis, J . W.; Mortimer, P. I. J . Chem. Soc. 1961, 189.
(10) Hartmann, P.; Obrecht, J .-P. Synth. Commun. 1988, 18, 553.
(11) J ackson, R. F. W.; Graham, L. J .; Rettie, A. B. Tetrahedron Lett.
1994, 35, 4417.
(12) Golubev, A.; Sewald, N.; Burger, K. Tetrahedron Lett. 1995, 36,
2037.
(13) J olles, G.; Poiget, G.; Robert, J .; Terlain, B.; Thomas, J .-P. Bull.
Soc. Chim. Fr. 1965, 2252.
(14) Gillard, J .; Abraham, A.; Anderson, P. C.; Beaulieu, P. L.; Bogri,
T.; Bousquet, Y.; Grenier, L.; Guse, I.; Lavalle´e, P. J . Org. Chem. 1996,
61, 2226.
(15) Di Nardo, C.; J eroncic, L. O.; de Lederkremer, R. M.; Varela,
O. J . Org. Chem. 1996, 61, 4007.
(16) Greene, T. W.; Wuts, P. G. M. Protective Groups in Organic
Synthesis, 2nd ed.; J ohn Wiley: New York, 1991; pp 127-128.

Enantioselective Synthesis of (2R,4S)/(2S,4R)-4-Hydroxypipecolic Acid
J . Org. Chem., Vol. 64, No. 17, 1999 6121
Sch em e 3
Sch em e 4
presence of anhydrous CuSO4 afforded a mixture of 11
and 12. These compounds were also differentiated by
TLC (Rf 0.39 and 0.35, respectively) and were successfully
separated by column chromatography. The 6,7-O-cyclo-
hexylidene derivatives 11 and 12 are conveniently pro-
tected for the introduction of the amino group at C-2. As
the ketal derivative 11 can be readily obtained from
crystalline and enantiomerically pure 5, the synthetic
sequences were conducted in the first instance starting
from such a compound.
The replacement of HO-2 by NH2 in 11 should be
accomplished with retention of C-2 configuration (R) to
obtain a suitable precursor of (2R,4S)-(+)-1. The sulfo-
nylation of the HO-2 of 11 (Scheme 3) was performed
with tosyl chloride in pyridine, and the progress of the
reaction was monitored by TLC. The tosylation took place
quite rapidly, affording the less polar tosylate 13 (Rf
0.41). However, together with 13, an even less polar
product (Rf 0.61) was detected. The proportion of the
latter in the mixture increased with the reaction time,
and it was the very major component after 22 h. At this
time, small amounts of 13 still remained, but longer
periods result in incipient epimerization at C-2. There-
fore, the reaction mixture was processed and the com-
pound was isolated by column chromatography in 82%
yield, and it was identified as the 2-chloro derivative 14.
The configuration of C-2 in 14 was established by 1H
NMR spectroscopy. As we have previously described15,17
and in agreement with earlier studies on the elucidation
of the geometry of 2,4-disubstituted butyrolactones18 (4,5-
dihydro-3,5-disubstituted-(3H)-furan-2-ones), the large
values for the coupling constants (J ) between H-3,3′ with
H-2 and H-4 indicate a threo relationship for the sub-
stituents on C-2 and C-4. This situation is encountered
the nucleophilic substitution by azide. In fact, this
reaction was readily performed by treatment of 14 with
sodium azide in DMF at room temperature for 24 h. The
crystalline azide derivative 15 was obtained in 89% yield.
The stereochemistry at C-2 was confirmed on the basis
of the 1H NMR spectrum of 15, which showed again large
values for J 2,3 (8.4 Hz) and J 2,3′ (10.6 Hz) indicating a cis
relationship for the substituents at C-2 and C-4 of the
1,4-lactone ring. Thus, compound 15 posseses the desired
R configuration at C-2, and the whole transformation
from 11 to 15 proceeded in a yield higher than 70%.
Therefore, although it has been described that the
substitution of a triflate group at C-2 of aldonolactones
by azide may occur with retention of C-2 configuration,19
in view of our satisfactory results, the alternative route
via the triflate derivative of 11 was not investigated.
The aldehyde postulated as retrosynthetic precursor
of (+)-1 (Scheme 1) could be prepared from 15, after
hydrolysis of the protecting ketal followed by degradative
oxidation of the glycol system (Scheme 4). The removal
of the cyclohexylidene group was carried out with 0.5 N
aqueous HCl in methanol. Evaporation of the solvent
from the reaction mixture at 50 °C, under diminished
pressure, produced also the elimination of the cyclohex-
anone released by hydrolysis. After five evaporations, 16
was obtained in 86% yield, after filtration through a short
silica gel column. The oxidative degradation of the glycol
group of 16 was conducted with sodium periodate under
a variety of conditions, but the expected aldehyde 17
could not be obtained. Also, intractable mixtures were
formed when sodium periodate adsorbed on silica gel20
was employed as oxidizing agent, or when the “one-pot”
removal of the ketal and oxidation with periodic acid
pentahydrate21 was attempted. Examples of unstable
molecules containing both azido and aldehyde functions
were found in the literature.22 The fact that the prepara-
tion of 17 from 16 was unsuccessful was rather disap-
pointing, as we expected to obtain (+)-1 as product of the
hydrogenolysis of the azide group of 17 to amine, followed
by intramolecular reductive amination of the aldehyde.
in tosylate 13 (J 2,3 ) 8.4 Hz, J 2,3 ) J 3′,4 ) 10.2 Hz, J 3,4
′
) 5.2 Hz), which bears a cis orientation for the ring
substituents. On the contrary, the relatively small J
values for the H-2 signal of 14 (J 2,3 ) 2.6 Hz, J 2,3′ ) 7.0
Hz) indicate that H-2 bisects the H-3-C-3-H-3′ angle
and dictates a trans relationship for the substituents of
the lactone ring at C-2 and C-4. Furthermore, the similar
J 3,4 and J 3′,4 values found for 13 and 14 (5.5 and 8.0 Hz,
respectively) suggest that no important conformational
changes have occurred.
The in situ conversion of 11 into 14, in one step and
with high yield, was very convenient for the synthesis,
as the chloride at C-2 has the proper configuration for
(19) Baird, P. D.; Dho, J . C.; Fleet, G. W. J .; Peach, J . M.; Prout, K.;
Smith, P. W. J . Chem. Soc., Perkin Trans. 1 1987, 1785.
(17) (a) Varela, O.; Nin, A. P.; de Lederkremer, R. M. Tetrahedron
Lett. 1994, 35, 9359. (b) Marino, M. C.; Varela, O.; de Lederkremer,
R. M. Carbohydr. Res. 1991, 220, 145. (c) Moradei, O.; du Mortier, C.;
Varela, O.; de Lederkremer, R. M. J . Carbohydr. Chem. 1991, 10, 469.
(18) Hussain, S. A. M. T.; Ollis, W. D.; Smith, C.; Stoddart, J . F.J .
Chem. Soc., Perkin Trans. 1 1975, 1480.
(20) Shing, T. K. M.; Zhong, Y.-L. J . Org. Chem. 1997, 62, 2662.
(21) Wu, W.-L.; Wu, Y.-L. J . Org. Chem. 1993, 58, 3586.
(22) (a) Bashyal, B. P.; Chow, H.-F.; Fellows, L. E.; Fleet, G. W. J .
Tetrahedron 1987, 43, 415. (b) Bashyal, B. P.; Chow, H.-F.; Fleet, G.
W. J . Tetrahedron 1987, 43, 423. (c) Bashyal, B. P.; Fleet, G. W. J .;
Gough, M. J .; Smith, P. W. Tetrahedron 1987, 43, 3083.

6122 J . Org. Chem., Vol. 64, No. 17, 1999
Di Nardo and Varela
Sch em e 5
Sch em e 6
In view of these negative results, the original strategy
was modified, and the reduction of the azide prior to the
oxidation of the 1,2-diol system was studied.
Hydrogenation of 15 in EtOAc afforded the corre-
sponding amine 18. This crude product, dissolved in
EtOAc, was treated with benzyl chloroformate in the
presence of saturated aqueous NaHCO3 to give the
crystalline benzyl carbamate 19. The benzyloxycarbonyl
was a convenient protective group for the amine, as it
may be removed during the hydrogenolysis, also required
for the intramolecular reductive amination of the alde-
hyde. For the preparation of the aldehyde 21 from 19 the
cyclohexylidene group of the latter was removed by
hydrolysis with HCl in H2O/MeOH, affording the diol 20
in crystalline form and in 94% yield. The oxidative
cleavage of the glycol with sodium periodate gave the
hexurono-6,3-lactone derivative 21, which, in contrast
with the azido aldehyde 17, could be purified by flash
chromatography (84% yield). This relatively higher sta-
bility of carbamates with respect to azides in molecules
that also hold an aldehyde function has been previously
observed.22c The next step of the synthesis, the hydro-
genolysis of 21 to promote the cyclization to the piperi-
dine, was attempted. Unfortunately, this reaction led to
(+)-1 as a minor product (<20%), and the major product
was spectroscopically identified as pipecolic acid (22). The
formation of this compound suggests the â-elimination
of the HO group at C-4 in the intermediate imine
derivative (Scheme 4), favored by the acetic acid em-
ployed as solvent, and the total hydrogenation. The
conversion of 21 into (+)-1 was also unsuccessful when
milder acidic or neutral conditions were employed. There-
fore, a different strategy was employed for the construc-
tion of the piperidine ring.
We still considered that 21 was a suitable precursor
of (+)-1, as the amino and hydroxyl functions are properly
located and with the required configuration. Ring closure
may be promoted by the nucleophilic displacement of a
leaving group at C-6 by intramolecular attack of the
amine. To introduce a nucleofuge at C-6, the aldehyde
group of 21 was reduced to alcohol (Scheme 5). We have
previously succeeded in the chemoselective reduction of
an aldehyde, without affecting the lactone carbonyl,
employing a methanolic solution of NaBH3CN at pH ∼
4.23 Such a reaction when applied to 21 afforded 2-(N-
benzyloxycarbonyl)amino-2,3,5-trideoxy-L-threo-hexono-
1,4-lactone (23) in 89% yield. This compound gave the
same spectral data as the corresponding racemate, previ-
ously synthesized in this laboratory.6 Mesylation of 23
employing 1.5 molar equiv of methanesulfonyl chloride
and pyridine in dichloromethane gave the 6-O-methane-
sulfonyl derivative 24 in 85% yield.
Removal of the N-protecting benzyloxycarbonyl group
was readily accomplished by hydrogenolysis with 10%
Pd/C to give 25 in almost quantitative yield. Since 25
decomposes on storage, it was immediately used after the
hydrogenation step. The crude syrup was dissolved in 0.1
M aqueous KOH, conditions that promoted the opening
of the lactone and the cyclization by nucleophilic dis-
placement of the mesylate by the amino group. The
resulting (2R,4S)-4-hydroxypipecolic acid [(+)-1] was
purified by ion exchange with Dowex 50W (H+) resin. Its
optical rotation ([R]D +22.0) was in excellent agreement
with the absolute value reported for the enantiomer,9,14
but opposite in sign. Also, the NMR spectra were coin-
cident with those described6 and showed that (+)-1 was
obtained in high degree of purity.
The synthetic route described above was employed for
the preparation of (-)-1, starting from 12 (Scheme 6).
The 2-chloro derivative 26 was obtained by tosylation of
12 in pyridine, for long periods, as it was already
described for the preparation of 14. Treatment of 26 with
sodium azide led to the 2-azido derivative 27 having (as
12) the S configuration at C-2, because of the double
configurational inversion (from 12 to 26 and from 26 to
27). The similar pattern of chemical shifts and coupling
1
constant values for the H NMR signals of azide deriva-
tives 15 and 27 indicated that both of them possess the
same relative stereochemistry for the ring substituents
at C-2 and C-4.
The azide group of 27 was reduced to amine and
N-protected as the carbobenzoxy derivative. The ketal
was hydrolyzed with 0.5 N HCl in H2O-MeOH to afford
crystalline 28, the analogue of arabino configuration of
20. Sodium periodate oxidation of the 1,2-diol system of
28 led to the aldehyde 29 in 89% yield. The removal of
the stereocenter at C-6, which makes it possible to
discriminate between compounds 20 and 28, led to the
enantiomeric aldehyde derivatives 21 and 29. Therefore,
compound 29 and the subsequents in the D-threo series
(30, 31) exhibited spectral properties identical to those
of their respective analogues in the L-threo configuration
(23, 24).
The aldehyde function of 29 was chemoselectively
reduced to the alcohol 30, which was converted into the
mesylate derivative 31. Hydrogenolysis of the N-protect-
ing carbamate led to the free amino group at C-2, which
attacks C-6 with nucleophilic substitution of the mesy-
late. The resulting (2S,4R)-4-hydroxypipecolic acid [(-)-
1] was purified by ion exchange chromatography and
(23) Varela, O.; Zunszain, P. A. J . Org. Chem. 1993, 58, 7860.

Enantioselective Synthesis of (2R,4S)/(2S,4R)-4-Hydroxypipecolic Acid
J . Org. Chem., Vol. 64, No. 17, 1999 6123
a syrup, which was chromatographed using 8:1 cyclohexane-
acetone as solvent. Fractions of the column having the product
of Rf 0.61 were collected and concentrated to give syrupy 14
isolated in 73% yield. The optical rotation ([R]D -22.8)
and the spectral properties were in good agreement with
the reported data.6,9,14
1
(0.88 g, 82%): [R]D -41.5 (c 1.0, CHCl3); H NMR (200 MHz,
CDCl3) δ 4.89 (m, 1H), 4.38 (dd, J ) 2.6, 7.0 Hz, 1H, H-2),
4.21 (m, 1H), 4.05 (dd, J ) 5.9, 8.0 Hz, 1H), 3.50 (dd, J ) 7.0,
8.0 Hz, 1H), 2.73 (ddd, J ) 2.6, 5.5, 14.3 Hz, 1H, H-3), 2.36
(ddd, J ) 7.0, 8.0, 14.3 Hz, 1H, H-3′), 1.86 (m, 2H), 1.53-1.37
(m, 10 H-cyclohexylidene); 13C NMR (50 MHz, CDCl3) δ 171.7,
109.8, 77.1, 72.0, 69.0, 51.1, 39.4, 36.5, 34.9, 24.9, 23.8, 23.7.
Anal. Calcd for C13H19ClO4: C, 56.83; H, 6.97. Found: C,
57.22; H, 7.05.
From later fractions of the column the compound having Rf
0.41 was obtained and spectroscopically characterized as 13
(0.08 g, 5%): 1H NMR (200 MHz, CDCl3) δ 7.84, 7.35 (d, J )
8.5 Hz, 4 H-aromatic), 5.10 (dd, J ) 8.4, 10.2 Hz, 1H, H-2),
4.57 (m, 1H), 4.20 (m, 1H), 4.05 (dd, J ) 6.2, 8.0 Hz, 1H), 3.50
(dd, J ) 6.6, 8.0 Hz, 1H), 2.85 (ddd, J ) 5.2, 8.4, 13.2 Hz, 1H,
H-3), 2.43 (s, 3H), 2.10 (td, J ) 10.2, 13.2 Hz, 1H, H-3′), 1.87
(m, 2H), 1.55-1.37 (m, 10 H-cyclohexylidene); 13C NMR (50
MHz, CDCl3) δ 169.7, 109.9, 74.7, 73.2, 71.8, 69.0, 40.1, 36.6,
36.1, 35.0, 25.0, 23.9, 23.7.
2-Azid o-6,7-O-cycloh exylid en e-2,3,5-t r id eoxy-D-xylo-
h ep ton o-1,4-la cton e (15). To a solution of 14 (1.47 g, 5.36
mmol) in anhydrous DMF (10 mL) was added sodium azide
(0.52 g, 8.0 mmol). The mixture was stirred at room temper-
ature for 24 h. Then, EtOAc (20 mL) was added, and the salts
were filtered off and washed with EtOAc. The filtrate and
washing liquids were collected and washed with saturated
aqueous NaCl (2 × 50 mL). The extract was dried (MgSO4)
and concentrated. The resulting syrup was filtered through a
short column of silica gel, affording 15, which crystallized upon
addition of hexane (1.34 g, 89%): mp 57-57.5 °C; [R]D +10.3
(c 1.0, CHCl3); 1H NMR (200 MHz, CDCl3) δ 4.63 (m, 1H), 4.33
(dd, J ) 8.4, 10.6 Hz, 1H, H-2), 4.25 (m, 1H), 4.05 (dd, J )
6.2, 8.0 Hz, 1H), 3.55 (dd, J ) 6.6, 8.0 Hz, 1H), 2.73 (ddd, J )
5.5, 8.4, 13.0 Hz, 1H, H-3), 2.01-1.81 (m, 3H), 1.55-1.38 (m,
10 H-cyclohexylidene); 13C NMR (50 MHz, CDCl3) δ 172.8,
109.8, 75.5, 72.0, 69.0, 57.6, 40.1, 36.7, 35.5, 35.0, 25.1, 24.0,
23.8.
Exp er im en ta l Section
Gen er a l Meth od s. Melting points are uncorrected. Optical
rotations were measured at 25 °C. Column chromatographic
separations were performed with silica gel 60, 240-400 mesh
(Merck). Analytical TLC was performed on silica gel 60 F254
(Merck) precoated plates (0.2 mm). Visualization of the spots
was effected by exposure to UV light or charring with a
solution of 5% sulfuric acid in EtOH, containing 0.5% p-
anisaldehyde; for amino acids, 0.25% ninhydrin in acetone was
used. Solvents were reagent grade and in most cases were
dried and distilled prior to use, according to standard proce-
dures.
6,7-O-Cycloh exylid en e-3,5-d id eoxy-D-xylo-h ep ton o-1,4-
la cton e (11). To a solution of 7 (0.59 g, 3.36 mmol) in dry
cyclohexanone (5 mL) were added anhydrous CuSO4 (∼2 g)
and p-toluenesulfonic acid (10 mg). The mixture was vigorously
stirred at room temperature for 20 h, when TLC showed
complete conversion of starting 7 (Rf 0.45, 4:1 EtOAc-EtOH)
into a less polar product (Rf 0.88). The suspension was filtered
and the solvent evaporated. The resulting syrup was purified
by filtration through a short column of silica gel, with 4:1
toluene-EtOAc as eluent. Fractions containing the product
of Rf 0.39 (1:1 toluene-EtOAc) were collected and concentrated
to afford 11 (0.77 g, 89%), which crystallized spontaneously.
After recrystallization from 1:1 Et2O-hexane it gave the
following data: mp 87.5-88 °C; [R]D -30.4 (c 1.0, CHCl3); 1H
NMR (200 MHz, CDCl3) δ 4.64-4.50 (m, 2H), 4.26 (m, 1H),
4.08 (dd, J ) 5.9, 8.0 Hz, 1H), 3.54 (dd, J ) 7.0, 8.0 Hz, 1H),
3.25 (bs, 1H), 2.75 (ddd, J ) 5.1, 8.4, 13.0 Hz, 1H, H-3), 2.00-
1.83 (m, 3H), 1.56-1.38 (m, 10 H-cyclohexylidene); 13C NMR
(50 MHz, CDCl3) δ 177.4, 109.8, 74.6, 72.1, 69.1, 68.4, 40.1,
37.6, 36.6, 35.0, 25.0, 23.9, 23.8.
Anal. Calcd for C13H20O5: C, 60.92; H, 7.87. Found: C, 61.29;
H, 7.73.
6,7-O-Cycloh exylid en e-3,5-d id eoxy-D-xylo- (11) a n d -D-
a r a bin o-h epton o-1,4-lacton e (12). An approximately equimo-
lar mixture of the dideoxyheptonolactones 7 and 8 (0.87 g, 4.96
mmol) was treated with cyclohexanone (7 mL) in the presence
of CuSO4 (∼2 g) and p-toluenesulfonic acid (10 mg), in the
conditions described above. After the same workup, TLC
showed two main spots having Rf 0.39 and 0.35 (1:1 toluene-
EtOAc). Two successive chromatographic purifications led to
two pure fractions corresponding to compounds 11 (0.41 g,
32%) and 12 (0.45 g, 35%). The third fraction was a mixture
of 11 and 12 (0.10 g, 7.5%; overall yield 74.5%).
Anal. Calcd for C13H19N3O4: C, 55.51; H, 6.81. Found: C,
55.73; H, 6.94.
2-Azid o-2,3,5-tr id eoxy-D-xylo-h ep ton o-1,4-la cton e (16)
a n d It s At t em p t ed Oxid a t ive Degr a d a t ion t o 5-Azid o-
2,4,5-tr id eoxy-L-th r eo-h exu r on o-6,3-la cton e (17). To a so-
lution of 15 (0.372 g, 1.32 mmol) in MeOH (3 mL) was added
0.5 N aqueous HCl (4 mL). The turbid mixture was concen-
trated at 50 °C under diminished pressure. The residue was
dissolved in HCl-MeOH, and it was concentrated as before.
The procedure was repeated three more times, when total
consumption of the starting material was observed by TLC.
The residue was purified by column chromatography (EtOAc)
to give a syrup that was spectroscopically characterized as 16
(0.263 g, 86%):
Compound 11 gave the same physical and spectral proper-
ties as the acetal obtained from pure 7, described above.
Compound 12 was isolated as a syrup: [R]D -18.3 (c 1.3,
1H NMR (200 MHz, D2O) δ 4.75 (m, 1H), 4.71
1
CHCl3); H NMR (200 MHz, CDCl3) δ 4.54 (m, 2H), 4.22 (m,
(dd, J ) 8.7, 11.3 Hz, 1H, H-2), 3.84 (m, 1H), 3.57 (dd, J )
4.4, 11.7 Hz, 1H), 3.46 (dd, J ) 6.4, 11.7 Hz, 1H), 2.83 (ddd, J
) 5.5, 8.7, 12.8 Hz, 1H, H-3), 2.00-1.69 (m, 3H); 13C NMR (50
MHz, CDCl3) δ 175.8, 76.5, 68.5, 65.8, 58.4, 38.3, 34.9.
To a solution of 16 (0.050 g, 0.25 mmol) in CH2Cl2 (3 mL)
was added the NaIO4-SiO2 reactive20 (0.76 g), and the mixture
was stirred in the dark. After 6 h, no starting material was
detected by TLC. The suspension was filtered and the silica
gel washed with CH2Cl2 (20 mL). Evaporation of the solvent
gave a syrup (22 mg) that was shown by NMR to be a complex
mixture, which was not further analyzed.
1H), 4.07 (dd, J ) 6.3, 8.0 Hz, 1H), 3.76 (bs, 1H), 3.62 (dd, J
) 6.9, 8.0 Hz, 1H), 2.76 (ddd, J ) 5.2, 8.4, 12.8 Hz, 1H, H-3),
2.18-1.83 (m, 3H), 1.58-1.37 (m, 10 H-cyclohexylidene); 13C
NMR (50 MHz, CDCl3) δ 177.3, 109.9, 74.2, 71.3, 68.6, 68.4,
38.5, 36.8, 36.5, 35.0, 25.0, 23.9, 23.8.
Anal. Calcd for C13H20O5: C, 60.92; H; 7.87. Found: C, 61.36;
H, 7.75.
6,7-O-Cycloh exyliden e-3,5-dideoxy-2-O-(p-tolu en esu lfo-
n yl)-D-xylo-h ep ton o-1,4-la cton e (13) a n d -2-ch lor o-6,7-O-
cycloh exylid en e-2,3,5-t r id eoxy-D-lyxo-h ep t on o-1,4-la c-
ton e (14). To a solution of 12 (1.0 g, 3.90 mmol) in dry pyridine
(10 mL), cooled at 0 °C, was added tosyl chloride (2.23 g, 11.70
mmol), and the mixture was allowed to warm to room tem-
perature. A less polar product (Rf 0.41, 3:1 cyclohexane-
acetone) was first formed, which was further transformed into
an even faster moving compound (Rf 0.61). The latter was the
major product after 22 h. The reaction mixture was diluted
with dichloromethane (200 mL) and washed with aqueous HCl,
saturated aqueous NaHCO3, and saturated aqueous NaCl. The
organic extract was dried (MgSO4) and concentrated, affording
2-Am in o-6,7-O-cycloh exylid en e-2,3,5-t r id eoxy-D-xylo-
h ep ton o-1,4-la cton e (18) a n d 2-(N-Ben zyloxyca r bon yl)-
a m in o-6,7-O-cycloh exylid en e-2,3,5-tr id eoxy-D-xylo-h ep -
ton o-1,4-la cton e (19). Compound 15 (0.41 g, 1.46 mmol)
dissolved in EtOAc (25 mL) was hydrogenated at atmospheric
pressure for 1 h, in the presence of 10% Pd/charcoal. TLC
showed that the starting material (Rf 0.31, 3:1 toluene-EtOAc)
disappeared and a more polar product was detected (Rf 0.00).
The catalyst was filtered, and the filtrate was concentrated
to a syrup that was purified through a short column of silica

6124 J . Org. Chem., Vol. 64, No. 17, 1999
Di Nardo and Varela
gel (5 g) using mixtures of EtOAc with increasing amounts of
EtOH (from 0 to 25%). Fractions containing the product of Rf
0.30 (4:1 EtOAc-EtOH) were pooled and concentrated, afford-
ing 18 (0.32 g, 85%) as a colorless syrup: 1H NMR (200 MHz,
CDCl3) δ 4.52 (m, 1H), 4.24 (m, 1H), 4.05 (dd, J ) 5.8, 8.0 Hz,
1H), 3.73 (dd, J ) 8.4, 12.0 Hz, 1H, H-2), 3.51 (dd, J ) 7.0, 8.0
Hz, 1H), 2.70 (ddd, J ) 5.1, 8.4, 13.1 Hz, 1H, H-3), 1.88-1.70
(m, 3H), 1.55-1.36 (m, 10 H-cyclohexylidene).
2-(N-Ben zyloxyca r bon yl)a m in o-2,3,5-tr id eoxy-L-th r eo-
h exon o-1,4-la cton e (23). To a solution of crude 21 (97 mg,
0.35 mmol) in MeOH (7 mL) were added a small crystal of
methyl orange and NaBH3CN (11 mg, 0.18 mmol). The mixture
was stirred at room temperature, and the red color of the
solution (pH 3.1, red; pH 4.4, yellow) was maintained by
dropwise addition of 1 N methanolic HCl. After 1 h, no starting
21 was detected by TLC, and the reaction solvent was
evaporated. The residue was extracted with EtOAc and the
extract concentrated to afford an oil, which was chromato-
graphed on silica gel using 1:1 toluene-EtOAc as solvent.
Compound 23 (87 mg, 89%) gave [R]D -29.5 (c 0.9, CHCl3) and
spectral properties identical to those of the racemic product:6
13C NMR (50 MHz, CDCl3) δ 174.6, 156.1, 135.9, 128.5, 128.3,
128.1, 75.7, 67.3, 58.6, 51.7, 37.6, 36.1.
Hydrogenation of 15 (0.72 g, 2.56 mmol) was repeated as
above. The catalyst was filtered and the filtrate concentrated
to a final volume of about 10 mL. This EtOAc solution was
energically stirred at 0 °C with saturated aqueous NaHCO3
(10 mL), and benzyl chloroformate (0.55 mL, 3.84 mmol) was
added. After 3 h, the mixture was diluted with EtOAc, and
the organic layer was separated, washed with 5% aqueous HCl,
with saturated aqueous NaCl, and then with 10% aqueous
NaHCO3, dried, and concentrated. The syrup was chromato-
graphed on silica gel with 15:1 to 5:1 toluene-EtOAc as eluent.
Upon evaporation of the solvent, compound 19 (0.70 g, 70%)
crystallized spontaneously: mp 95-96 °C; [R]D -39.0 (c 1.0,
2-(N-Ben zyloxyca r bon yl)a m in o-6-O-m eth a n esu lfon yl-
2,3,5-tr id eoxy-L-th r eo-h exon o-1,4-la cton e (24). A solution
of 23 (0.17 g, 0.62 mmol) and pyridine (0.16 mL) in dry CH2-
Cl2 (5 mL) was cooled at 0 °C, and methanesulfonyl chloride
(0.07 mL, 0.93 mmol) was added. The mixture was allowed to
warm to room temperature, and it was stirred for 24 h, when
no starting material but a faster moving spot (Rf 0.69, 1:3
toluene-EtOAc) was detected by TLC. The solution was
diluted with CH2Cl2 (40 mL), washed with 5% aqueous HCl
and saturated aqueous NaHCO3, dried (MgSO4), and concen-
trated. The residue was purified by column chromatography
with 1:1 toluene-EtOAc as solvent, affording 24 (0.19 g, 85%):
1
CHCl3); H NMR (200 MHz, CDCl3) δ 7.31 (s, 5 H-aromatic),
5.61 (d, J ) 6,2 Hz, 1H, NH), 5.13 (s, 2H, PhCH2), 4.59 (m,
1H), 4.43 (m, 1H), 4.23 (m, 1H), 4.07 (dd, J ) 5.8, 8.0 Hz, 1H),
3.52 (dd, J ) 7.3, 8.0 Hz, 1H), 2.82 (m, 1H), 1.96-1.80 (m,
3H), 1.57-1.39 (m, 10 H-cyclohexylidene); 13C NMR (50 MHz,
CDCl3) δ 174.2, 155.9, 135.9, 128.4, 128.0, 109.7, 75.4, 72.1,
69.0, 67.2, 51.6, 39.9, 36.6, 35.0, 35.0, 23.9, 23.7.
1
[R]D -40.9 (c 1.2, CHCl3); H NMR (200 MHz, CDCl3) δ 7.32
Anal. Calcd for C21H27NO6: C, 64,77; H, 6.99; N, 3.50.
Found: C, 64.76; H, 7.08; N, 3.55.
(s, 5 H-aromatic), 5.75 (d, J ) 6.7 Hz, 1H, NH), 5.09 (s, 2H,
PhCH2), 4.50 (m, 2H), 4.33 (m, 2H), 3.00 (s, 3H), 2.73 (m, 1H),
2.14-1.80 (m, 3H); 13C NMR (50 MHz, CDCl3) δ 173.9, 155.9,
135.9, 128.5, 128.3, 128.1, 73.8, 67.3, 65.7, 51.5, 37.2, 35.4, 34.7.
Anal. Calcd for C15H19NO7S: C, 50.41; H, 5.76; S, 8.97.
Found: C, 50.80; H, 5.62; S, 9.22.
2-(N-Ben zyloxyca r bon yl)a m in o-2,3,5-tr id eoxy-D-xylo-
h ep ton o-1,4-la cton e (20). To a solution of 19 (0.46 g, 1.18
mmol) in MeOH (2 mL) was added 0.5 N aqueous HCl (4 mL),
and the turbid mixture was concentrated. The dissolution and
evaporations were repeated four more times, as described for
the preparation of 16. The residue crystallized upon addition
of MeOH-Et2O, affording compound 20 (0.34 g, 94%): Rf 0.36
(2R,4S)-4-Hyd r oxyp ip ecolic Acid [(+)-1]. Compound 24
(0.10 g, 0.28 mmol) was dissolved in absolute EtOH (10 mL)
and hydrogenated in the presence of 10% Pd/C (20 mg) at
normal pressure and room temperature for 2 h. The reaction
mixture showed by TLC a single spot having Rf 0.34 (3:1
EtOAc-MeOH) and no starting material remaining. The
catalyst was filtered and the filtrate concentrated to give 25
(61 mg, 96%), which was employed without further purification
for the next step. The free amine 25 (61 mg, 0.27 mmol) was
dissolved in 0.1 M aqueous KOH (5 mL) and stirred at room
temperature for 30 min. The solution was made neutral with
1 M aqueous HCl and concentrated to a final volume of about
0.5 mL. This solution was acidified (pH 4) with 1 M HCl and
applied to a column filled with Dowex 50 W (H+) resin. The
column was washed with water and then eluted with 0.5 M
aqueous pyridine. Fractions that gave the positive ninhydrin
test were pooled and freeze-dried, affording (+)-1 (32 mg, 81%),
Rf 0.21 (13:4:2:1 MeCN-EtOH-H2O-AcOH). The compound
could not be induced to crystallize: [R]D +22.0 (c 0.8, H2O)
(lit.9 [R]D -17; lit.14 [R]D -23.5 for the enantiomer); 13C NMR
(50 MHz, D2O) δ 174.3, 66.4, 58.8, 42.3, 35.6, 30.8.
1
(EtOAc); mp 145 °C; [R]D -29.2 (c 1.0, MeOH); H NMR (200
MHz, CD3OD) δ 7.35 (s, 5 H-aromatic), 5.15 (s, 2H, PhCH2),
4.77 (m, 1H), 4.60 (dd, J ) 8.4, 10.2 Hz, 1H, H-2), 3.88 (m,
1H), 3.52 (m, 2H), 2.72 (ddd, J ) 5.2, 8.4, 12.3 Hz, 1H, H-3),
2.13-1.69 (m, 3H); 13C NMR (50 MHz, CD3OD) δ 177.0, 158.2,
138.0, 129.5, 129.1, 128.9, 76.3, 69.8, 67.8, 67.5, 52.7, 40.5, 36.4.
Anal. Calcd for C15H19NO6: C, 58,25; H, 6.20; N, 4,53.
Found: C, 57,96; H, 6,53; N, 4.44.
5-(N-Ben zyloxyca r bon yl)a m in o-2,4,5-tr id eoxy-L-th r eo-
h exu r on o-6,3-la cton e (21). To a solution of 20 (0.18 g, 0.58
mmol) in dry MeOH (10 mL) was added sodium periodate (0.15
g, 0.70 mmol). After 3 h, a main spot was detected by TLC (Rf
0.74, EtOAc) and no starting 20 remained. The reaction
mixture was diluted with EtOAc (15 mL), and the salts were
filtered. The filtrate was concentrated and the residue purified
by flash chromatography. Compound 21 (0.14 g, 84%) was
obtained as a rather unstable syrup that, in subsequent
preparations, was used crude for the next step: 1H NMR (200
MHz, CDCl3) (numbered as a lactone derivative) δ 9.68 (bs,
1H, HCO), 7.32 (s, 5 H-aromatic), 5.75 (d, J ) 7.0 Hz, 1H, NH),
5.08 (s, 2H, PhCH2), 4.81 (m, 1H), 4.44 (m, 1H), 3.05-2.70 (m,
3H), 1.94 (m, 1H); 13C NMR (50 MHz, CDCl3) δ 198.4, 174.1,
156.0, 135.9, 128.4, 128.2, 128.0, 72.0, 67.2, 51.2, 48.1, 35.0.
Hyd r ogen olysis of 21. Compound 21 (53 mg) dissolved in
10:1 EtOH-glacial acetic acid (10 mL) was hydrogenated at
atmospheric pressure in the presence of 10% Pd-C as catalyst.
The suspension was filtered, and the liquids were concentrated
to a syrup, which was purified through a column of Dowex 50
W (H+) resin. The column was washed with water and then
eluted with 0.5 M aqueous pyridine. Concentration of the
fractions, which showed by TLC a main spot (ninhydrin
positive) having Rf 0.25 (13:4:2:1 MeCN-EtOH-H2O-AcOH),
afforded syrupy pipecolic acid (22, 12 mg). Its spectral proper-
ties were identical to those reported in the literature24 for
authentic 22.
2-Ch lor o-6,7-O-cycloh exylid en e-2,3,5-tr id eoxy-D-r ibo-
h ep ton o-1.4-la cton e (26). Compound 12 (0.40 g, 1.56 mmol),
dissolved in pyridine (5 mL), was treated with tosyl chloride
(0.89 g, 4.68 mmol) as described for the preparation of 14. The
2-chloro derivative 26 was isolated by precipitation with
cyclohexanes-EtOAc (0.36 g, 83%). Recrystallization from the
same solvents gave crystals: mp 79-80 °C; [R]D -1.6 (c 1.0,
1
CHCl3); H NMR (200 MHz, CDCl3) δ 4.89 (m, 1H), 4.45 (t, J
≈ 5.1 Hz, 1H, H-2), 4.19 (m, 1H), 4.06 (dd, J ) 6.2, 8.0 Hz,
1H), 3.61 (dd, J ) 6.6, 8.0 Hz, 1H), 2.55 (t, J ≈ 5.1 Hz, 2H),
2.14-1.85 (m, 2H), 1.57-1.37 (m, 10 H-cyclohexylidene); 13C
NMR (50 MHz, CDCl3) δ 172.0, 110.0, 76.4, 71.1, 68.5, 51.0,
38.6, 37.6, 36.5, 35.0, 25.0, 23.9, 23.7.
Anal. Calcd for C13H19ClO4: C, 56.83; H, 6.97. Found: C,
57.15; H, 7.10.
2-Azido-6,7-O-cycloh exyliden e-2,3,5-tr ideoxy-D-a r a bin o-
h ep ton o-1,4-la cton e (27). It was prepared starting from 26
(0.35 g, 1.27 mmol), employing the procedure described for 15.
Syrupy 27 was obtained in 90% yield (0.32 g): [R]D -74.8 (c
(24) (a) J ohnson, R. L.; Rajakumar, G.; Mishra, R. M. J . Med. Chem.
1986, 29, 2100. (b) Aldrich Library of 13C and 1H FT NMR Spectra;
Aldrich: Milwaukee, 1992; Vol. 1, pp 889 A-C, 1085 B.
1
1.3, CHCl3); H NMR (200 MHz, CDCl3) δ 4.60 (m, 1H), 4.33

Enantioselective Synthesis of (2R,4S)/(2S,4R)-4-Hydroxypipecolic Acid
J . Org. Chem., Vol. 64, No. 17, 1999 6125
(dd, J ) 8.8, 11.0 Hz, 1H, H-2), 4.18 (m, 1H), 4.05 (dd, J )
6.2, 8.0 Hz, 1H), 3.59 (dd, J ) 6.6, 8.0 Hz, 1H), 2.70 (ddd, J )
5.5, 8.8, 12.9 Hz, 1H, H-3), 2.17-2.01 (m, 3H), 1.55-1.36 (m,
10 H-cyclohexylidene); 13C NMR (50 MHz, CDCl3) δ 172.8,
109.8, 74.9, 71.1, 68.5, 57.6, 38.2, 36.5, 34.9, 34.6, 25.0, 23.9,
23.7.
h exon o-1,4-la cton e (30). Crude compound 29 (80 mg, 0.29
mmol) was reduced with NaBH3CN as described for the
preparation of 23. The EtOAc extract was washed with
saturated aqueous solution of NaCl, which was made alkaline
with NaHCO3. This way the indicator is retained in the
aqueous layer and the chromatographic purification could be
avoided. Compound 30 (68 mg, 85%) gave [R]D +28.6 (c 0.8,
CHCl3), and it showed the same spectral properties as 23.
Anal. Calcd for C13H19N3O4: C, 55.51; H, 6.81. Found: C,
55.45; H, 6.62.
2-(N-Ben zyloxyca r b on yl)a m in o-2,3,5-t r id eoxy-D-a r a -
bin o-h ep ton o-1,4-la cton e (28). Compound 27 (0.34 g, 1.22
mmol) was hydrogenated and N-protected as described for the
preparation of 19. The resulting syrupy product (0.43 g, 91%)
was treated with 0.5 N aqueous HCl in MeOH, as indicated
above, affording an oil that was purified by column chroma-
tography on silica gel with EtOAc as eluent. Evaporation of
the solvent from the chromatographic fractions that showed
the spot of Rf 0.36 (EtOAc) led to crystalline 28 (0.30 g, 78%),
which was recrystallized from EtOAc: mp 122 °C; [R]D -18.3
(c 1.0, MeOH); 1H NMR (200 MHz, CD3OD) δ 7.33 (s, 5
H-aromatic), 5.10 (s, 2H, PhCH2), 4.66 (m, 1H), 4.52 (dd, J )
8.4, 12.0 Hz, 1H, H-2), 3.75 (m, 1H), 3.50 (m, 2H), 2.68 (ddd,
J ) 5.6, 8.4, 12.3 Hz, 1H, H-3), 2.07-1.80 (m, 3H); 13C NMR
(50 MHz, CD3OD) δ 177.1, 158.3, 138.0, 129.5, 129.1, 128.9,
76.8, 69.6, 67.8, 67.1, 52.7, 39.8, 35.9.
2-(N-Ben zyloxyca r bon yl)a m in o-6-O-m eth a n esu lfon yl-
2,3,5-tr id eoxy-D-th r eo-h exon o-1,4-la cton e (31). Compound
30 (60 mg, 0.21 mmol) was mesylated as described for 24. After
identical purification, 31 (71 mg, 93%) was obtained. It gave
[R]D +39.5 (c 1.0; CHCl3) and the same spectroscopic properties
as 24.
(2S,4R)-4-Hyd r oxyp ip ecolic Acid [(-)-1]. Compound 31
(38 mg, 0.11 mmol) was hydrogenated as above, and the
resulting syrup was also treated with 0.1 M aqueous KOH, as
described in the preparation of (+)-1. After the same workup
and purification, (-)-1 (12 mg, 73%) was obtained: [R]D -22.8
(c 0.38, H2O) (lit.9 [R]D -17; lit.14 [R]D -23.5). It showed the
same spectral properties as (+)-1.
Ack n ow led gm en t. This work was supported by
grants from the Universidad de Buenos Aires (Project
EX-170) and ANPCYT (National Agency for Promotion
of Science and Technology, PICT-01698). We Thank
UMYMFOR-CONICET for the microanalyses. O.V. is
a Research Member of the National Research Council
(CONICET).
Anal. Calcd for C15H19NO6: C, 58,25; H, 6.20; N, 4.53.
Found: C, 58.06; H, 6.42; N, 4.41.
5-(N-Ben zyloxyca r bon yl)a m in o-2,4,5-tr id eoxy-D-th r eo-
h exu r on o-6,3-la cton e (29). Compound 29 was prepared as
described for the L-threo enantiomer 21. Starting from 28 (0.10
g, 0.32 mmol), chromatographically homogeneous 29 (80 mg,
89%) was obtained. Compounds 29 and 21 showed identical
spectroscopic properties.
2-(N-Ben zyloxyca r bon yl)a m in o-2,3,5-tr id eoxy-D-th r eo-
J O990445+