A short synthesis of polyhydroxylated piperidines by aldol reaction of chelated amino acid ester enolates

Article abstract of DOI:10.1002/(sici)1099-0690(199809)1998:9<1833::aid-ejoc1833>3.0.co;2-f

Aldol reactions of a chelated glycine ester enolate with a chiral aldehyde gives rise to the corresponding polyhydroxylated amino acid with excellent induced diastereoselectivity. These oxygenated amino acids can be converted into polyhydroxylated pipecol

Full text of DOI:10.1002/(sici)1099-0690(199809)1998:9<1833::aid-ejoc1833>3.0.co;2-f

FULL PAPER
Ƞ
Organisch-Chemisches Institut der Universität,
Im Neuenheimer Feld 270, D-69120 Heidelberg, Germany
Fax: (internat.) ϩ 49(0)6221/54-4205
E-mail: ck1@ix.urz.uni-heidelberg.de
Received April 30, 1998
Amino acids / Chelated enolates / Aldol reactions / Glycosidase inhibitors / Piperidine alkaloids
Aldol reactions of a chelated glycine ester enolate with a
chiral aldehyde gives rise to the corresponding
polyhydroxylated amino acid with excellent induced
azasugars by cyclization using the Mitsunobu reaction. An
interesting epimerization was observed during the
cyclization. The potential glycosidase inhibitor 1-
diastereoselectivity. These oxygenated amino acids can be deoxyaltronojirimycin (8b) was synthesized by this approach
converted into polyhydroxylated pipecolinic acids and in a highly stereoselective fashion.
dol reactions give especially good results.[19] A very high
simple diastereoselectivity of > 95% is obtained in the reac-
Based on their structural relationship to sugars, polyhy-
tions of N-sulfonylated amino acid esters in the presence of
droxylated piperidines and pipecolinic acid derivatives are
2.5 equiv. of SnCl2 with both, aliphatic as well as aromatic
interesting candidates for the inhibition of various glycosi-
aldehydes.[20] At least 2 equiv. of metal salt are necesarry
dases. In their protonated form they can act as transition-
for good selectivities. Probably one equiv. is involved in the
state analogues of these enzymes.[1] Deoxynojirimycin,[2]
formation of the chelate complex, and the second one is
isolated from Bacillus strains,[3] and Deoxymannojirimy-
responsible for the activation of the aldehyde.[19b] This pro-
cin[4] from Lonchocarpus sp.[5] are specific inhibitors of glu-
tocol can be applied to various types of amino acids, and
cosidases,[2] mannosidases,[6] as well as fucosidases.[7]
the selectivities observed are nearly independent of the sul-
(2S,3R,4R,5S)-Trihydroxypipecolinic acid,[8] isolated from
fonyl protecting group used. In cases where the tosyl group
Baphia racemosa,[9] acts as glucoronidase and fucosidase in-
is difficult to remove, the easier cleavable 2-(trimethylsilyl)-
hibitor.[10] This biological activity is important for the ther-
ethanesulfonyl (SES) protecting group, developed by Wein-
apy of diabetes,[11] cancer[12] and viral infections.[13]
reb et al.,[21] can be used.
In the meanwhile several interesting syntheses of natural
as well as synthetical deoxyazasugars[4][14] and related pipe-
In aldol reactions of chiral α-alkoxy or α-siloxy alde-
colinic acid derivatives[8][15] were described. The interesting hydes, an induction on the newly formed chiral centers is
properties of these compounds encouraged us to develop observed, and two aldol products, out of the four possible
an own approach to their synthesis, based on asymmetric stereoisomers, were formed preferentially. In general the in-
aldol reactions of chelated ester enolates.[16] The retrosyn- duced diastereoselectivity is very high (Ն 95% ds), indepen-
thetical analysis of these piperidine alkaloids (Scheme 1) dent of the amino acid ester used.[17] The formation of the
leads to the corresponding pipecolinic acid derivatives, 3,4-anti diastereomer as the mayor isomer is in accordance
which can be obtained from acyclic polyhydroxylated α-am- with the Felkin-Ahn model.[22] Also good simple diastereo-
ino acids. These are accessible by aldol reaction of amino selectivities were obtained with esters of most amino acids
acid ester enolates and chiral polyhydroxylated alde- except glycine. In this case, the chiral α center is formed as
hydes.[17]
a nearly 1:1 mixture.
Scheme 1
For some time, our group has been interested in reactions
This loss of selectivity may have two different reasons.
of metal-chelated enolates of N-protected amino acid es- First, the attack of the glycine ester enolate, in contrast to
ters.[18] Besides chelate enolate Claisen rearrangements, al- other amino acid ester enolates, proceeds unselective, what
Eur. J. Org. Chem.
, 1833Ϫ1840
WILEY-VCH Verlag GmbH, D-69451 Weinheim, 1998
1434Ϫ193X/98/0909Ϫ1833 $ 17.50ϩ.50/0
1833

U. Kazmaier, R. Grandel
FULL PAPER
Scheme 2
mately 121°. Similar interactions obviously also occur in
solution, as indicated by a strong NOE between the α-
methyl substituent and the aromatic protons of the tosyl
group.
Figure 1. Crystal structure of α-methylated pipecolinic acid deriva-
tive
is not very rational. Second, the attack of the glycine ester
enolate occurs with comparable selectivity like the enolates
of the other amino acid esters, and the aldol product sub-
sequently epimerizes under the reaction conditions used.
The configurational lability of the tosylated amino acid es-
ters may result from an acidification of the α position by
the strong electron-withdrawing sulfonyl protecting group.
On the first view this effect limits the applicability of this
aldol approach. On the other hand we were interested to
see, if it is possible to use this epimerization effect also in a
positive sense, to control the configuration of this labile
center, e.g. in cyclic derivatives like piperidines.
Our intention for the investigations described here, re-
sults from the question, if these sterical interactions can be
used as a stereocontrolling element for the synthesis of pip-
eridines, if configurationally labile derivatives like the gly-
cine esters are used.
During our studies towards the synthesis of α-alkylated
pipecolinic acids we were able to obtain crystals of an α-
methylated derivative , suitable for X-ray crystal structure
[23]
Starting from tosylated glycine ester
the aldol reac-
analysis (Figure 1).[17] The pseudo planar environment of tion with chiral aldehyd [24] in the presence of 2.5 equiv. of
the nitrogen atom leads to a close orientation of the sulfonyl SnCl2 gave the corresponding aldol product with excellent
group and the methyl substituent at C2. The expectable in- induced diastereoselectivity (> 95% ds), while the α center
teractions between these two groups results in a enlarged gave a nearly 1:1 epimeric mixture ( , ) (Scheme 3). This
bond angle (SϪNϪC2) at the nitrogen atom of approxi- mixture was directly used for the following piperidine syn-
Scheme 3
1834
Eur. J. Org. Chem.
, 1833Ϫ1840

Polyhydroxylated Piperidines by Aldol Reaction of Chelated Amino Acid Ester Enolates
FULL PAPER
thesis, with the hope, that the configuration of the labile α Cyclization of
and
with a stoichiometrical amount of
position can be controlled in the six-membered ring system. PPh3/DEAD (method a) gave the corresponding pipecolinic
Protection of the β-OH group was necessary to avoid their acid derivatives and , respectively, without epimeri-
elimination (Scheme 7) during the subsequent Mitsunobu zation (Scheme 4). If an excess of Mitsunobu reagents was
reaction,[25] which was used in the cyclization step. The used (method b),
THP protecting group was especially suitable for this pur- acid derivative
pose and the epimeric mixture of was obtained in 83% the synthesis of
as well as
with the axially oriented ester moiety. In
from both PPh3 as well as DEAD
provided the pipecolinic
yield.[26] Cleavage of the silyl protecting group with TBAF had to be used in excess. Excess of only one of the reagents
gave rise to alcohols , , which was cyclized in the pres- produced , and no epimerization was observed.
ence of an excess of Mitsunobu reagents producing only one
Also no epimerization occurred when pipecolinic acid de-
was treated with various amounts of Mitsunobu
diastereomer[26] of the pipecolinic acid derivative
in 92% rivative
yield. Addition of an excess Red-Al resulted in a simul- reagents. Obviously, basic intermediates formed during the
taneous cleavage of the N-tosyl protecting group and re- Mitsunobu reaction are responsible for the deprotonation
duction of the ester moiety.[27] Removal of the acid-labile and epimerization of the linear amino acid ester . The
groups with Dowex 50Wϫ8 gave rise to 1-deoxyaltronojiri- cyclization then occurs under kinetically controlled con-
mycin (
)
ditions from a rapid epimerization equilibrium. Cyclization
Figure 2. Coupling constants and NOESY correlations in
The configuration of
was determined by NOESY and of epimer
with the axial ester moiety obviously is faster
NMR experiments (Figure 2). In solution
exists as a than that of epimer with the equatorial ester moiety. The
mixture of two conformers in a ratio of 9:1.
In the major isomer the conformation the α-hydroxy-
methyl group (C2) and the β-hydroxy group (C3) both are
in equatorial positions. The large coupling constant (9.6
Hz) between the α-H and β-H, as well as the missing
NOESY correlation between these axial atoms are charac-
teristic for this conformation.
Scheme 4
The formation of the diastereomerically pure cyclic prod-
uct
,
out of the epimeric mixture of the linear precursor
in nearly quantitative yield (no removal of the second
diastereomer!) is quite astonishing. Although we hoped to
find such an epimerization, because of the sterical interac-
tions discussed above, the very clean and smooth conver-
sion nevertheless was surprising. Obviously, the epimeri-
zation already occurs during the Mitsunobu cyclization.
Therefore, we had a closer look at this interesting phenom-
enon, and we investigated the cyclization of the pure dia-
stereomers
and . These could be obtained after forma-
tion of the THP ether and removal of the silyl group from
Reaction conditions: a: 1.0 equiv. PPh3, 0.95 equiv. DEAD; b: 2.5
1835
the alcohols
and , which could be separated by MPLC. equiv. PPh3, 2.4 equiv. DEAD.
Eur. J. Org. Chem.
, 1833Ϫ1840

U. Kazmaier, R. Grandel
FULL PAPER
expected sterical interactions between the sulfonyl group
and the ester moiety may be the reason for this effect.
The configuration of pipecolinic acid derivatives
and the aldol products and
NOE and NMR experiments clearly indicate that in both
isomers
and (Scheme 6). For derivative
as well, was confirmed a conformation with an equatorial orientation of most
and
the ester moiety is in the axial position
this is not surprising, but for
by NMR using the deprotected triols
These were obtained by treatment of
lytic amounts of acid (Scheme 5).
and
and
respectively. of the substituents should be expected. Obviously, the steric
with cata- interactions between the sulfonyl group and the ester func-
tionality in
are extremely strong, and therefore the con-
formation shown is the only one observed. Because of the
configurations determined for these pipecolinic acid deriva-
Scheme 5
tives the aldol product
can be assigned as the 2,3-syn-
3,4-anti isomer, while aldol product
anti isomer.
is the 2,3-anti-3,4-
Attempts to perform the Mitsunobu cyclization with the
unprotected diol , obtained by desilylation from , also
gave the diastereomerically pure pipecolinic acid derivative
, although in only 40% yield (Scheme 7). The major side
product (30%) was the didehydro amino acid
obtained from the epimeric pipecolinic acid ester
probably
, and
elimination of the β-OH group under the assistance of some
basic intermediates (BϪ) formed during the Mitsunobu re-
action. In contrast, no elimination was observed when
,
with an axially oriented ester functionality, was treated with
Mitsunobu reagents.
Scheme 6
1836
Eur. J. Org. Chem.
, 1833Ϫ1840

Polyhydroxylated Piperidines by Aldol Reaction of Chelated Amino Acid Ester Enolates
Scheme 7
FULL PAPER
chromatography (hexanes/ethyl acetate, 8:2) giving rise to (743
mg, 78%) as a colorless oil and a mixture of diastereomers (
54:46). Ϫ HPLC (n-hexane/2-propanol, 8:2): tR( ) ϭ 11.50 min;
tR( ) ϭ 13.54. Ϫ HRMS (FAB); C29H43NO8SSiNa [Mϩ ϩ Na]:
calcd. 616.2376, found 616.2385. Ϫ The diastereomers could be
separated by MPLC.
In conclusion we have shown, that polyhydroxylated pip-
eridines and pipecolinic acid derivatives can easily be ob-
tained by aldol reaction of chelated enolates. Sterical inter-
actions can be used to control the configuration of the la-
bile α position in tosylated amino acid esters.
/
,
We thank Prof. Dr. G. Helmchen for his generous support of
this work. Financial support by the Graduiertenkolleg, the Deutsche
Forschungsgemeinschaft and the Fonds der Chemischen Industrie is
gratefully acknowledged.
(2S isomer): Colorless oil. Ϫ [α]D20 ϭ ϩ21.5 (c ϭ 0.8, CHCl3).
Ϫ
1H NMR (CDCl3): δ ϭ 0.10 (s, 3 H), 0.11 (s, 3 H), 0.89 (s, 9
H), 1.28 (s, 3 H), 1.37 (s, 3 H), 2.38 (s, 3 H), 3.52 (dd, J ϭ 9.2, 9.1
Hz, 1 H), 3.77 (dd, J ϭ 8.6, 7.7 Hz, 1 H), 3.85 (ddd, J ϭ 9.0, 7.7,
3.9 Hz, 1 H), 3.94 (ddd, J ϭ 8.5, 1.6, 1.5 Hz, 1 H), 3.95 (dd, J ϭ
9.2, 3.8 Hz, 1 H), 4.22 (d, J ϭ 1.6 Hz, 1 H), 4.36 (dd, J ϭ 10.5,
1.5 Hz, 1 H), 4.94 (d, J ϭ 12.5 Hz, 1 H), 5.07 (d, J ϭ 12.4 Hz, 1
H), 5.39 (d, J ϭ 10.5 Hz, 1 H), 7.19 (d, J ϭ 8.3 Hz, 2 H), 7.23Ϫ7.33
(m, 5 H), 7.72 (d, J ϭ 8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ
Ϫ5.64, Ϫ5.61, 18.29, 21.48, 25.79, 26.49, 26.72, 57.50, 64.24, 67.16,
73.37, 79.37, 79.71, 109.55, 127.24, 127.84, 128.20, 128.45, 129.38,
135.33, 137.59, 143.15, 170.14. Ϫ C29H43NO8SSi (593.82): calcd. C
58.66, H 7.30, N 2.36; found C 58.64, H 7.47, N 2.28.
All reactions were carried out in oven-dried glassware (100°C)
under argon. All solvents were dried before use. THF was distilled
from sodium benzophenone, dichloromethane from calcium hy-
dride. Dowex 50Wϫ8 was purchased from Aldrich. LDA solutions
were prepared from freshly distilled diisopropylamine and commer-
cially available n-butyllithium solution (15% in hexane) in THF at
Ϫ20°C directly before use. All other solvents were reagent-grade
quality and used as received. The starting materials and the prod-
ucts were purified by flash chromatography on silica gel (32Ϫ63
µm). Mixtures of ethyl acetate and hexanes were used as eluents.
Ϫ TLC: Commercially precoated Polygram SIL G/UV254 plates
(Macherey-Nagel). Visualization was accomplished with UV light,
iodine, and potassium permanganate solution. Ϫ 1H and 13C
NMR: Bruker AC-300 spectrometer. Ϫ Analytical HPLC: Daicel
“Chiralcel OD-H” column (flow: 0.5 ml/min), Knauer UV detector.
Ϫ Optical rotations: Perkin-Elmer 241 polarimeter.
20
(2R isomer): Colorless oil. Ϫ [α]D ϭ Ϫ26.4 (c ϭ 0.8,
CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 0.07 (s, 3 H), 0.08 (s, 3 H), 0.88
(s, 9 H), 1.28 (s, 6 H), 2.40 (s, 3 H), 3.53 (mc, 1 H), 3.71 (dd, J ϭ
9.0, 7.3 Hz, 1 H), 3.78Ϫ3.88 (m, 3 H), 3.93 (ddd, J ϭ 9.0, 4.0, 2.4
Hz, 1 H), 4.29 (dd, J ϭ 8.9, 2.3 Hz, 1 H), 4.93 (d, J ϭ 12.4 Hz, 1
H), 4.99 (d, J ϭ 12.3 Hz, 1 H), 5.64 (d, J ϭ 8.9 Hz, 1 H), 7.21Ϫ7.33
(m, 7 H), 7.72 (d, J ϭ 8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ
Ϫ5.55, 18.32, 21.52, 25.84, 26.64, 26.69, 58.75, 64.07, 67.32, 74.81,
79.24, 80.73, 109.68, 127.35, 127.87, 128.12, 128.22, 128.42, 128.52,
128.58, 129.59, 134.98, 136.85, 143.51, 168.39. Ϫ C29H43NO8SSi
(593.82): calcd. C 58.66, H 7.30, N 2.36; found C 58.74, H 7.57,
N 2.26.
Benzyl ( 2RS,3S,4S,5S) -6-tert-Butyldimethylsilyloxy-3-hydroxy-
4,5-isopropylidenedioxy-2-[ ( 4-toluenesulfonyl) amino] hexanoate
(
,
): A solution of 4 mmol of LDA in anhydrous THF (10 ml)
was added at Ϫ78°C under argon to a solution of N-tosylated
Benzyl ( 2S,3S,4S,5S) -6-tert-Butyldimethylsilyloxy-4,5-isopropyl-
[22]
benzyl glycinate
mmol) in 8 ml of THF. After 10 min, a solution of aldehyde
(527 mg, 1.92 mmol) in 3 ml of THF was added. After 30 min at 1.10 mmol) and 2,3-dihydro-2H-pyrane (200 µl, 2.19 mmol) in di-
(512 mg, 1.6 mmol) and SnCl2 (760 mg, 4.0 idenedioxy-3-( R/S) -tetrahydropyranyloxy-2-[ ( 4-toluenesulfonyl) -
[23]
amino] hexanoate ( ): To a solution of aldol product
(650 mg,
Ϫ78°C, the reaction was quenched by adding phosphate buffer
pH ϭ 7 (20 ml). The mixture was diluted with diethyl ether (20 ml)
chloromethane (5 ml) a catalytic amount of dl-10-camphorsulfonic
acid (5 mg) was added at 0°C under argon. After stirring at this
and was allowed to warm to room temp. After filtration of the temp. for 30 min and 1 h at room temp., sodium bicarbonate (10
mixture through a pad of Celite, the aqueous phase was extracted
twice with diethyl ether (20 ml each). The combined organic layers
were washed with brine, dried with Na2SO4, and the solvent was
evaporated in vacuo. The crude aldol product was purified by flash
mg) was added. After filtration, the solvent was evaporated in vac-
uo, and the crude product was purified by flash chromatography
[hexanes/ethyl acetate (2% NEt3), 9:1, 85:15] to give
as a color-
less oil (517 mg, 70%). Ϫ [α]D20 ϭ Ϫ0.9 (c ϭ 4.4, CHCl3). Ϫ HPLC
Eur. J. Org. Chem.
, 1833Ϫ1840
1837

U. Kazmaier, R. Grandel
FULL PAPER
(n-hexane/2-propanol, 9:1): tR( ) ϭ 13.96 min; tR( Ј) ϭ 14.78 (m, 5 H), 7.71 (d, J ϭ 8.3 Hz, 1 H), 7.72 (d, J ϭ 8.3 Hz, 1 H). Ϫ
1
min. Ϫ H NMR (CDCl3): δ ϭ 0.00, 0.01 (2 s, 6 H), 0.84, 0.85 (2 13C NMR (CDCl3): δ ϭ 21.01, 21.16, 21.50, 24.63, 24.71, 26.90,
s, 9 H), 1.23, 1.31, 1.33, 1.35 (4 s, 6 H), 1.51Ϫ1.75 (m, 5.5 H), 2.34, 27.00, 30.81, 30.88, 56.62, 57.12, 63.37, 63.73, 64.96, 65.32, 67.30,
2.37 (2 s, 3 H), 3.10 (mc, 0.5 H), 3.45Ϫ3.81 (m, 5 H), 3.91Ϫ4.15
(m, 2.5 H), 4.27Ϫ4.57 (m, 1.5 H), 4.92 (d, J ϭ 12.5 Hz, 0.5 H), 109.39, 109.60, 127.23, 128.03, 128.27, 128.47, 128.65, 128.77,
4.98 (d, J ϭ 12.0 Hz, 0.5 H), 5.02 (d, J ϭ 12.3 Hz, 0.5 H), 5.03 (d, 129.30, 129.43, 134.87, 135.23, 137.43, 137.83, 143.08, 143.38,
J ϭ 12.0 Hz, 0.5 H), 5.33 (d, J ϭ 10.0 Hz, 0.5 H), 5.51 (d, J ϭ 169.90, 170.37.
HRMS (FAB) C28H37NO9S [Mϩ]: calcd.
67.42, 74.66, 75.32, 78.24, 80.46, 80.51, 80.58, 100.22, 102.50,
Ϫ
10.0 Hz, 0.5 H), 7.14 (d, J ϭ 8.3 Hz, 1 H), 7.20 (d, J ϭ 8.3 Hz, 1 563.2189; found 563.2203. Ϫ MS (FAB); m/z (%): 586 [Mϩ ϩ Na]
H), 7.24Ϫ7.32 (m, 5 H), 7.71 (d, J ϭ 8.3 Hz, 1 H), 7.72 (d, J ϭ (29), 563 [Mϩ] (1), 547 (27), 503 (26), 480 (100), 422 (84).
8.3 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ Ϫ5.33, Ϫ5.29, 18.40,
Benzyl ( 2R,3S,4S,5S)-6-Hydroxy-4,5-isopropylidenedioxy-3-( R/S)-
tetrahydropyranyloxy-2-[ ( 4-toluenesulfonyl) amino] hexa-
20.83, 21.10, 21.49, 24.71, 24,81, 25.97, 27.07, 27.22, 27.38, 30.77,
30.96, 56.58, 57.21, 63.70, 64.26, 64.81, 67.21, 67.35, 73.59, 74.51,
noate ( ): According to the synthesis of
mg, 0.11 mmol) with TBAF (1  in THF, 186 µl) yielded after flash
chromatography [hexanes/ethyl acetate (2% NEt3), 7:3, 1:1] as a
treatment of
(74
78.10, 80.88, 81.00, 81.24, 99.74, 102.35, 109.50, 109.72, 127.22,
127.99, 128.19, 128.45, 128.56, 128.62, 128.69, 129.27, 129.43,
134.97, 135.55, 137.65, 138.22, 142.89, 143.25, 170.07, 170.64. Ϫ
HRMS (FAB) C34H51NO9SSi [Mϩ]: calcd. 677.3054; found
677.3052. Ϫ C34H51NO9SSi (677.95): calcd. C 60.24, H 7.58. N
2.07; found: C 59.98, H 7.44, N 1.89.
20
colorless oil (46 mg, 75%). Ϫ [α]D ϭ Ϫ15.5 (c ϭ 1.2, CHCl3). Ϫ
HPLC (hexane/2-propanol, 7:3): tR( ) ϭ 10.78 min; tR( Ј) ϭ
1
12.70 min. Ϫ H NMR (CDCl3): δ ϭ 1.23, 1.29, 1.32 (3 s, 6 H),
1.30Ϫ1.80 (m, 6 H), 2.00 (mc, 1 H), 2.37 (s, 1.5 H), 2.38 (s, 1.5 H),
3.45Ϫ3.55 (m, 1.5 H), 3.60Ϫ3.70 (m, 1 H), 3.70Ϫ4.00 (m, 3.5 H),
4.05Ϫ4.15 (m, 0.5 H), 4.24 (dd, J ϭ 9.2, 2.2 Hz, 0.5 H), 4.30Ϫ4.40
(m, 0.5 H), 4.45Ϫ4.55 (m, 1 H), 4.68 (dd, J ϭ 6.6, 2.2 Hz, 0.5 H),
4.90 (d, J ϭ 12.2 Hz, 0.5 H), 4.96 (s, 1 H), 5.01 (d, J ϭ 12.2 Hz,
0.5 H), 5.40Ϫ5.50 (m, 0.5 H), 6.57 (d, J ϭ 9.9 Hz, 0.5 H),
7.15Ϫ7.35 (m, 7 H), 7.68 (d, J ϭ 8.4 Hz, 1 H), 7.69 (d, J ϭ 8.3
Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 20.04, 20.55, 21.51, 24.71,
25.05, 26.58, 26.95, 27.01, 27.08, 30.55, 30.84, 56.99, 57.31, 63.35,
63.71, 64.46, 64.56, 66.98, 67.58, 75.45, 75.56, 78.26, 81.22, 85.75,
98.35, 102.25, 109.65, 110.00, 127.15, 127.21, 128.17, 128.25,
128.40, 128.49, 128.52, 129.45, 129.56, 134.78, 135.25, 136.88,
Benzyl ( 2R,3S,4S,5S) -6-tert-Butyldimethylsilyloxy-4,5-isopropyl-
idenedioxy-3-( R/S) -tetrahydropyranyloxy-2-[ ( 4-toluenesulfonyl) -
amino] hexanoate ( ): According to the synthesis of the reaction
of aldol product
(160 mg, 0.28 mmol) and 2,3-dihydro-2H-pyr-
ane (50 µl, 0.54 mmol) yielded after flash chromatography [hex-
anes/ethyl acetate (2% NEt3), 9:1, 85:15] a colorless oil (130 mg,
20
71%). Ϫ [α]D ϭ Ϫ19.6 (c ϭ 0.3, CHCl3). Ϫ HPLC (n-hexane/2-
propanol, 9:1): tR( ) ϭ 13.53 min; tR( Ј) ϭ 15.99 min. Ϫ 1H
NMR (CDCl3): δ ϭ 0.00, 0.04 (2 s, 6 H), 0.84, 0.87 (2 s, 9 H), 1.22,
1.27, 1.30, 1.33 (4 s, 6 H), 1.40Ϫ1.70 (m, 5 H), 2.36, 2.37 (2 s, 3
H), 3.40Ϫ3.55 (m, 2 H), 3.60Ϫ3.79 (m, 2 H), 3.75Ϫ4.10 (m, 3.5
H), 4.22 (dd, J ϭ 9.2, 2.6 Hz, 0.5 H), 4.33 (dd, J ϭ 8.8, 2.6 Hz,
0.5 H), 4.43 (mc, 0.5 H), 4.53 (dd, J ϭ 10.7, 1.8 Hz, 0.5 H), 4.67
(mc, 0.5 H), 4.84 (d, J ϭ 12.3 Hz, 0.5 H), 4.88 (d, J ϭ 12.4 Hz, 0.5
H), 5.02 (d, J ϭ 12.5 Hz, 0.5 H), 5.03 (d, J ϭ 12.3 Hz, 0.5 H), 5.44
(d, J ϭ 8.6 Hz, 0.5 H), 6.60 (d, J ϭ 10.4 Hz, 0.5 H), 7.10Ϫ7.20
(m, 2 H), 7.20Ϫ7.30 (m, 5 H), 7.67 (d, J ϭ 8.3 Hz, 1 H), 7.68 (d,
J ϭ 8.3 Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ Ϫ5.69, Ϫ5.34, Ϫ5.28,
Ϫ5.22, 18.41, 18.47, 20.11, 20.30, 21.52, 24.79, 25.17, 25.83, 25.92,
26.89, 27.15, 27.30, 27.35, 30.46, 30.93, 56.90, 57.31, 64.00, 64.29,
64.39, 66.84, 67.43, 74.43, 75.02, 81.76, 81.91, 85.79, 97.61, 102.19,
109.74, 110.04, 127.17, 127.23, 127.98, 128.15, 128.36, 128.50,
129.41, 129.51, 135.01, 135.37, 137.02, 137.95, 143.02, 143.38,
168.12, 168.84. Ϫ HRMS (FAB) C34H51NO9SSiNa [Mϩ ϩ Na]:
calcd. 700.2952; found 700.2952. Ϫ MS (FAB); m/z (%): 700 [Mϩ
ϩ Na] (12), 677 [Mϩ] (1), 594 (43), 536 (100). Ϫ C34H51NO9SSi
(677.95): calcd. C 60.24, H 7.58. N 2.07; found: C 59.78, H 7.34,
N 1.87.
137.82, 143.13, 143.53, 167.97, 168.61.
Ϫ HRMS (FAB)
C28H37NO9SNa [Mϩ ϩ Na]: calcd. 586.2087; found 586.2083. Ϫ
MS (FAB); m/z (%): 586 [Mϩ ϩ Na] (4), 563 [Mϩ] (1), 547 (42),
503 (38), 480 (22), 459 (30), 422 (30), 415 (22).
Benzyl ( 2S,3S,4S,5S) -4,5-Isopropylidenedioxy-3-( R/S) -tetrahy-
dropyranyloxy-N-( 4-toluenesulfonyl) pipecolate ( ): PPh3 (46 mg,
0.18 mmol) was added at room temp. to a solution of
(100 mg,
0.18 mmol) in 10 ml of THF. Subsequently, DEAD (25 µl, 0.16
mmol) was added dropwise as slow as possible. After complete ad-
dition, the mixture was stirred for 30 min, before the solvent was
evaporated in vacuo. The residue was stirred with hexanes/ethyl
acetate (9:1) and the residue was filtered off. After flash chromatog-
raphy [hexanes/ethyl acetate (2% NEt3), 8:2], (37 mg, 38%) was
20
obtained as a colorless oil. Ϫ [α]D ϭ ϩ27.8 (c ϭ 0.3, CHCl3). Ϫ
HPLC (n-hexane/2-propanol, 85:15): tR( ) ϭ 15.64 min; tR( Ј) ϭ
1
21.15 min. Ϫ H NMR (CDCl3): δ ϭ 1.32, 1.38, 1.39, 1.54 (4 s, 6
H), 1.30Ϫ1.70 (m, 5.5 H), 2.38 (s, 3 H), 3.35Ϫ3.65 (m, 3.5 H), 3.78
(mc, 0.5 H), 3.85Ϫ4.00 (m, 1 H), 4.15 (mc, 0.5 H), 4.25Ϫ4.30 (m,
1 H), 4.70Ϫ4.85 (m, 3 H), 4.85Ϫ4.95 (m, 0.5 H), 5.00Ϫ5.10 (m,
1.5 H), 7.20 (d, J ϭ 8.2 Hz, 2 H), 7.20Ϫ7.40 (m, 5 H), 7.62 (d, J ϭ
8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 17.81, 18.03, 21.58, 25.22,
25.31, 26.58, 26.66, 27.08, 27.15, 29.80, 48.35, 48.64, 59.20, 60.78,
60.78, 61.75, 65.57, 66.99, 67.21, 67.82, 68.89, 77.46, 78.15, 97.23,
97.94, 112.25, 127.36, 127.30, 128.17, 128.25, 128.52, 128.62,
129.65, 134.90, 135.04, 137.05, 143.83, 167.94, 168.31. Ϫ HRMS
Benzyl
( R/S) -tetrahydropyranyloxy-2-[ ( 4-toluenesulfonyl) amino] -
hexanoate ( ): To a solution of (517 mg, 0.76 mmol) in 3 ml
of THF a solution of TBAF (1  in THF, 1.3 ml) was added at
room temp. After 2 h, the reaction mixture was diluted with diethyl
ether (20 ml) and was washed with saturated NaHCO3 and brine
(20 ml each). The organic layer was dried with Na2SO4, and the
solvent was evaporated in vacuo. After flash chromatography [hex-
( 2S,3S,4S,5S) -6-Hydroxy-4,5-isopropylidenedioxy-3-
anes/ethyl acetate (2% NEt3), 7:3, 1:1],
less oil (271 mg, 63%). Ϫ [α]D20 ϭ ϩ1.8 (c ϭ 2.7, CHCl3). Ϫ HPLC
(n-hexane/2-propanol, 7:3): tR(
Ј) ϭ 11.74 min. Ϫ 1H NMR
was obtained as a color-
(FAB) C28H35NO8SNa [Mϩ
ϩ Na]: calcd. 568.1981; found
568.1994. Ϫ MS (FAB); m/z (%): 568 [Mϩ ϩ Na] (13), 546 [Mϩ]
(2), 462 (26), 404 (75), 281 (31), 207 (30).
(CDCl3): δ ϭ 1.23, 1.31, 1.34, 1.35 (4 s, 6 H), 1.20Ϫ1.80 (m, 6 H),
2.00 (mc, 1 H), 2.35, 2.37 (2 s, 3 H), 3.00Ϫ3.20 (m, 1 H), 3.50Ϫ3.80
Benzyl ( 2R,3S,4S,5S) -4,5-Isopropylidenedioxy-3-( R/S) -tetrahy-
(m, 4 H), 3.85Ϫ4.05 (m, 2 H), 4.05Ϫ4.20 (m, 1 H), 4.30Ϫ4.40 (m, dropyranyloxy-N-( 4-toluenesulfonyl) pipecolate ( ): According to
1 H), 4.93 (d, J ϭ 12.4 Hz, 0.5 H), 5.00 (s, 1 H), 5.02 (d, J ϭ 12.4 the synthesis of , stereoisomer and the epimeric mixture
,
Hz, 0.5 H), 5.34 (d, J ϭ 10.7 Hz, 0.5 H), 5.55 (d, J ϭ 9.9 Hz, 0.5
H), 7.15 (d, J ϭ 8.3 Hz, 1H), 7.21 (d, J ϭ 8.0 Hz, 1 H), 7.24Ϫ7.34
as well (710 mg, 1.26 mmol each) were treated with PPh3 (761
mg, 2.90 mmol) and DEAD (436 µl, 2.77 mmol). After flash chro-
1838
Eur. J. Org. Chem.
, 1833Ϫ1840

Polyhydroxylated Piperidines by Aldol Reaction of Chelated Amino Acid Ester Enolates
FULL PAPER
matography [hexanes/ethyl acetate (2% NEt3), 7:2],
(633 mg, δ ϭ 2.29 (s, 3 H), 2.89 (dd, J ϭ 12.6, 11.0 Hz, 1 H), 3.44 (dd, J ϭ
92%) was obtained as a colorless oil. Ϫ [α]D ϭ ϩ42.6 (c ϭ 0.7, 9.7, 2.9 Hz, 1 H), 3.79 (dd, J ϭ 12.1, 5.1 Hz, 1 H), 3.95 (ddd, J ϭ
CHCl3). Ϫ HPLC (n-hexane/2-propanol, 85:15): tR( ) ϭ 19.42 11.0, 9.7, 5.1 Hz, 1 H), 4.49 (dd, J ϭ 2.9, 2.6 Hz, 1 H), 4.86 (d,
min; tR( Ј) ϭ 20.51 min. Ϫ 1H NMR (CDCl3): δ ϭ 1.28, 1.31, J ϭ 12.1 Hz, 1 H), 4.92Ϫ4.94 (m, 1 H), 5.00 (d, J ϭ 12.1 Hz, 1
20
1.32, 1.39 (4 s, 6 H), 1.45Ϫ1.90 (m, 6 H), 2.38, 2.39 (2 s, 3 H),
H), 7.04 (d, J ϭ 8.5 Hz, 2 H), 7.10Ϫ7.18 (m, 2 H), 7.21Ϫ7.28 (m,
3.15Ϫ3.30 (m, 2 H), 3.45Ϫ3.60 (m, 1 H), 3.75Ϫ3.85 (m, 0.5 H), 3 H), 7.60 (d, J ϭ 8.5 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.47,
3.85Ϫ4.00 (m, 0.5 H), 3.95Ϫ4.10 (m, 2 H), 4.75Ϫ4.85 (m, 1 H), 46.45, 61.04, 66.37, 67.50, 69.51, 73.00, 127.27, 127.43, 128.21,
4.85Ϫ4.95 (m, 1 H), 4.95Ϫ5.05 (m, 1 H), 5.05Ϫ5.20 (m, 2 H),
7.20Ϫ7.40 (m, 7 H), 7.66 (d, J ϭ 8.3 Hz, 1 H), 7.75 (d, J ϭ 8.3 (FAB) C20H24NO7S [Mϩ ϩ H]: calcd. 422.1273, found 422.1255.
Hz, 1 H). Ϫ 13C NMR (CDCl3): δ ϭ 18.28, 18.89, 21.48, 25.35, Ϫ MS (FAB); m/z (%): 444 [Mϩ ϩ Na] (6), 422 [Mϩ ϩ H] (33),
128.39, 128.54, 129.43, 134.86, 136.33, 143.40, 168.13. Ϫ HRMS
25.38, 26.35, 26.39, 26.51, 26.63, 30.05, 30.30, 46.55, 58.85, 60.99, 286 (23), 138 (100).
61.61, 62.38, 67.49, 68.94, 69.02, 70.09, 71.52, 78.37, 79.12, 95.27,
Benzyl ( 2RS,3S,4S,5S) -3,6-Dihydroxy-4,5-isopropylidenedioxy-2-
[ ( 4-toluenesulfonyl) amino] hexanoate ( ): A solution of TBAF
(1  in THF, 0.96 ml, 0.96 mmol) was added to a solution of
99.58, 110.64, 110.67, 127.19, 127.50, 128.13, 128.27, 128.49,
128.58, 128.63, 129.37, 129.49, 134.88, 135.04, 137.11, 143.36,
143.42, 168.51, 168.65. Ϫ HRMS (FAB) C28H36NO8S [Mϩ ϩ H]:
calcd. 546.2162; found 546.2164. Ϫ C28H35NO8S (545.65): calcd. C
61.63, H 6.46, N, 2.57; found: C 61.48, H 6.46, N 2.51.
,
,
(284 mg, 0.48 mmol) in 5 ml of THF. After complete cleavage of
the protecting group (2Ϫ3 h), the reaction mixture was diluted with
diethyl ether (20 ml) and was washed with sat. NaHCO3 solution
and brine (30 ml each). The organic layer was dried with Na2SO4,
and the solvent was evaporated in vacuo. After flash chromatogra-
phy [hexanes/ethyl acetate, 3:7], a pale yellow oil (163 mg, 77%)
was obtained as a mixture of diastereomers. Ϫ1H NMR (CDCl3):
δ ϭ 1.23, 1.25, 1.29, 1.35 (4 s, 6 H), 2.38 (s, 1.5 H), 2.40 (s, 1.5 H),
3.63Ϫ3.88 (m, 3 H), 3.90Ϫ4.10 (m, 2 H), 4.18 (d, J ϭ 2.4 Hz, 0.5
H), 4.34 (d, J ϭ 1.8 Hz, 0.5 H), 4.93 (d, J ϭ 12.2 Hz, 0.5 H), 4.94
(d, J ϭ 12.1 Hz, 0.5 H), 5.00 (d, J ϭ 12.2 Hz, 0.5 H), 5.06 (d, J ϭ
12.1 Hz, 0.5 H), 7.17Ϫ7.26 (m, 4 H), 7.32Ϫ7.34 (m, 3 H), 7.71 (d,
J ϭ 8.4 Hz, 1 H), 7.72 (d, J ϭ 8.3 Hz, 1 H). Ϫ 13C NMR (CDCl3):
δ ϭ 21.54, 21.60, 26.61, 26.72, 26.84, 57.82, 58.95, 62.98, 67.52,
67.73, 73.67, 74.40, 77.10, 77.70, 79.78, 81.04, 109.62, 109.66,
127.28, 127.37, 128.11, 128.21, 128.44, 128.57, 128.61, 129.50,
129.80, 134.64, 135.03, 135.83, 137.20, 143.42, 144.02, 168.20,
170.41. Ϫ HRMS (FAB) C23H30NO8S [Mϩ ϩ H]: calcd. 480.1692,
found 480.1709. Ϫ MS (FAB); m/z (%): 502 [Mϩ ϩ Na] (16), 480
[Mϩ ϩ H] (36), 459 (17), 422 (33), 415 (29), 371 (29).
( 2S,3S,4R,5S) -3,4,5-Trihydroxy-2-( hydroxymethyl) piperidine
(
): A solution of
(120 mg, 0.22 mmol) and Red-Al (70% in
toluene, 0.77g, 2.66 mmol)) in 3 ml of THF was refluxed for 4 h.
The solution was cooled to 0°C, before 2 ml of 15% NaOH was
added carefully. The aqueous phase was extracted twice with di-
ethyl ether (5 ml each). The combined organic extracts were washed
with brine (5 ml), dried with Na2SO4, and the solvent was evapo-
rated in vacuo. To a solution of the resulting yellow oil in 5 ml of
methanol Dowex 50Wϫ8 (50 mg) was added. After refluxing and
stirring for 1 h, the resin was washed with methanol and water.
Subsequently, the product was eluted from the resin with 2 
NH4OH. The aqueous solution was concentrated in vacuo, before
toluene was added. The solution was concentrated to dryness, giv-
20
ing rise to
(16 mg, 44%) as a colorless oil. Ϫ [α]D ϭ Ϫ34.6
(c ϭ 0.3, H2O). Ϫ 1H NMR (D2O): δ ϭ 2.71 (dd, J ϭ 14.3, 3.0
Hz, 1 H), 2.76 (ddd, J ϭ 9.6, 4.8, 4.4 Hz, 1 H), 2.89 (dd, J ϭ 14.0,
2.2 Hz, 1 H), 3.67 (dd, J ϭ 9.2, 4.8 Hz, 1 H), 3.69 (dd, J ϭ 9.0,
4.4 Hz, 1 H), 3.75 (dd, J ϭ 9.6, 2.9 Hz, 1 H), 3.82 (ddd, J ϭ 3.7,
2.9, 2.2 Hz, 1 H), 3.86 (dd, J ϭ 3.7, 3.3 Hz, 1 H), 4.75 (s, 5H). Ϫ
13C NMR (D2O): δ ϭ 45.47, 56.54, 61.75, 67.08, 70.29, 71.58. Ϫ
HRMS (FAB) for C6H13NO4 [Mϩ ϩ H]: calcd. 164.0923; found
164.0937. Ϫ MS (FAB); m/z (%): 164 [Mϩ] (100), 136 (16).
Pipecolinic Acid Derivatives
thesis of the epimeric mixture
treated with PPh3 (122 mg, 0.47 mmol) and DEAD (70 µl, 0.44
mmol). A mixture of the pipecolinic acid derivatives and was
and : According to the syn-
,
(150 mg, 0.31 mmol) was
obtained, which could easily be separated by flash chromatography
[hexanes/ethyl acetate 8:2].
Benzyl ( 2S,3S,4S,5S) -3,4,5-Trihydroxy-N-( 4-toluenesulfonyl) pi-
pecolate ( ): To a solution of
(37 mg, 0.07 mmol) in 2 ml of
20
: Yield 57 mg (40%), colorless oil. Ϫ [α]D ϭ ϩ28.1 (c ϭ
methanol a catalytic amount of 4-toluenesulfonic acid was added.
After stirring for 24 h, NaHCO3 was added. The solution was fil-
tered and the solvent was evaporated in vacuo. Flash chromatogra-
phy [hexanes/ethyl acetate, 2:8] afforded (13 mg, 45%) as a color-
2.2, CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.34 (s, 3 H), 1.38 (s, 3 H),
2.40 (s, 3 H), 2.49 (bs, 1 H), 3.21 (dd, J ϭ 9.4, 2.2 Hz, 1 H), 3.26
(dd, J ϭ 11.8, 11.0 Hz, 1 H), 3.81 (ddd, J ϭ 11.0, 9.6, 4.8 Hz, 1
H), 4.11 (dd, J ϭ 11.8, 4.8 Hz, 1 H), 4.80 (dd, J ϭ 2.2, 1.9 Hz, 1
H), 5.05 (d, J ϭ 12.2 Hz, 1 H), 5.08 (d, J ϭ 1.9 Hz, 1 H), 5.17 (d,
J ϭ 12.2 Hz, 1 H), 7.22 (d, J ϭ 8.2 Hz, 2 H), 7.26Ϫ7.34 (m, 5 H),
7.72 (d, J ϭ 8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.53, 26.49,
26.60, 46.54, 61.52, 67.64, 67.67, 68.54, 78.90, 110.87, 127.47,
127.60, 128.28, 128.70, 129.53, 134.85, 136.75, 143.60, 168.40. Ϫ
HRMS (FAB) C23H28NO7S [Mϩ ϩ H]: calcd. 462.1586, found
20
less oil. Ϫ [α]D ϭ Ϫ14.5 (c ϭ 0.4, CHCl3). Ϫ 1H NMR (CDCl3):
δ ϭ 2.38 (s, 3 H), 3.54 (dd, J ϭ 14.7, 1.5 Hz, 1 H), 3.60 (dd, J ϭ
14.3, 1.8 Hz, 1 H), 3.93 (ddd, J ϭ 4.0, 1.8, 1.5 Hz, 1 H), 3.96 (dd,
J ϭ 4.0, 1.8 Hz, 1 H), 4.28 (dd, J ϭ 6.6, 1.8 Hz, 1 H), 4.85 (d, J ϭ
6.6 Hz, 1 H), 4.98 (d, J ϭ 12.1 Hz, 1 H), 5.09 (d, J ϭ 12.1 Hz, 1
H), 7.13 (d, J ϭ 8.1 Hz, 2 H), 7.16Ϫ7.20 (m, 2 H), 7.30Ϫ7.32 (m,
3 H), 7.62 (d, J ϭ 8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.52,
43.49, 55.08, 67.73, 67.76, 68.62, 71.23, 127.28, 127.91, 128.36,
128.57, 128.66, 129.55, 134.49, 136.45, 143.65, 170.78. Ϫ HRMS
(FAB) C20H24NO7S [Mϩ ϩ H]: calcd. 422.1273; found 422.1321.
Ϫ MS (FAB); m/z (%): 444 [Mϩ ϩ Na] (5), 422 [Mϩ ϩ H] (10),
391 (25), 384 (9), 286 (66), 147 (100).
462.1589. Ϫ MS (FAB); m/z (%): 484 [Mϩ ϩ Na] (6), 462 [Mϩ
ϩ
H] (6), 404 (12), 391 (10), 329 (14), 289 (20).
20
: Yield 41 mg (30%), colorless oil. Ϫ [α]D ϭ ϩ3.9 (c ϭ 0.7,
CHCl3). Ϫ 1H NMR (CDCl3): δ ϭ 1.30 (s, 3 H), 1.36 (s, 3 H), 2.42
(s, 3 H), 3.35Ϫ3.60 (m, 3 H), 3.71 (mc, 1 H), 5.26 (s, 2 H), 6.57 (d,
J ϭ 1.8 Hz, 1 H), 7.23Ϫ7.33 (m, 5H), 7.29 (d, J ϭ 8.3 Hz, 2 H),
Benzyl ( 2R,3S,4S,5S) -3,4,5-Trihydroxy-N-( 4-toluenesulfonyl) pi-
pecolate ( ): According to the synthesis of
,
(100 mg, 0.19 7.77 (d, J ϭ 8.3 Hz, 2 H). Ϫ 13C NMR (CDCl3): δ ϭ 21.60, 26.48,
mmol) was treated with 4-toluenesulfonic acid. Flash chromatogra-
26.63, 45.77, 67.67, 75.38, 77.09, 113.98, 125.00, 127.92, 128.40,
phy [hexanes/ethyl acetate, 2:8] afforded (34 mg, 43%) as a color- 128.53, 128.58, 129.75, 130.81, 134.44, 135.38, 144.51, 163.88. Ϫ
20
less oil. Ϫ [α]D ϭ ϩ29.0 (c ϭ 1.0, CHCl3). Ϫ 1H NMR (CDCl3):
HRMS (FAB) C23H25NO6SNa [Mϩ ϩ Na]: calcd. 466.1301, found
Eur. J. Org. Chem. , 1833Ϫ1840
1839

U. Kazmaier, R. Grandel
FULL PAPER
466.1318. Ϫ MS (FAB); m/z (%): 466 [Mϩ ϩ Na] (1), 444 [Mϩ
H] (8), 438 (13), 135 (6), 415 (26).
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