Synthesis of monocyclic and bicyclic imino sugars

Article abstract of DOI:10.1002/ejoc.200300079

A diastereoselective aldol reaction between the chelated alanine ester enolate 5 and the protected threose derivative 6, followed by cyclization under Mitsunobu conditions, gave the pipecolinic acid derivative 9. This compound could easily be converted in

Full text of DOI:10.1002/ejoc.200300079

FULL PAPER
Synthesis of Monocyclic and Bicyclic Imino Sugars
Markus Kummeter[a] and U. Kazmaier*[a]
Dedicated to Prof. W. Steglich on the occasion of his 70th birthday
Keywords: Aldol reactions / Amino acids / Enolates / Imino sugars / Inhibitors
A diastereoselective aldol reaction between the chelated ala-
nine ester enolate 5 and the protected threose derivative 6,
followed by cyclization under Mitsunobu conditions, gave
the pipecolinic acid derivative 9. This compound could easily
be converted into the versatile protected derivative 11, which
amino acid 17. The imino alcohol 13, an intermediate in the
synthesis of imino sugar 14, was also used in a straightfor-
ward approach to indolizidinone 19, involving an intramolec-
ular Horner−Emmons reaction for ring-closure.
could be transformed in excellent yields either into the cor- ( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
responding piperidine imino sugar 14 or into the unnatural Germany, 2003)
Introduction
Thanks to their structural relationship to carbohydrates,
polyhydroxylated derivatives of monocyclic or bicyclic ni-
trogen-containing ring systems (imino sugars) are interest-
ing substrates for the inhibition of various glycosidases.[1]
In this process, protonated imino sugars act as transition
state analogues of these enzymes.[2] Piperidine derivatives
such as deoxynojirimycine (1)[3] and isofagomine (2),[4] and
indolizidine derivatives such as castanospermine (3)[5] and
swainsonine (4),[6] are specific inhibitors of glucosidases,
mannosidases and fucosidases. This biological activity of-
fers a promising approach to the treatment of diabetes,[7]
cancer[8] and viral infections such as HIV[9] and influ-
enza.[10] Some of the naturally occurring indolizidines inter-
Figure 1. Examples of naturally occurring imino sugars
fere with the formation of metastases, others activate the
immune system to fight against cancer cells. Swainsonine 4
is currently under investigation as a chemotherapeutic
against cancer.[11] In accordance with this biological im-
portance, a vast amount of work has been dedicated to this
area over the past few years.[1Ϫ5,12]
Results and Discussion
The aldol reaction between the metal-chelated N-pro-
tected alanine tert-butyl ester 5 and the protected threose
derivative 6 provided a mixture of three diastereomers in an
overall yield of 94% (Scheme 1).[16] The desired 2,3-anti,3,4-
anti isomer 7 could be isolated in 62% yield. After removal
of the benzyl group,[17] a cyclization under Mitsunobu con-
ditions yielded the pipecolinic acid derivative 9 in 72%
yield.[16] As all attempts to remove the tosyl protecting
group at this stage either resulted in low yields or failed
completely, we decided to replace the potentially labile iso-
propylidene ketal with benzyl protecting groups. The cleav-
age was carried out in quantitative yield by use of catalytic
amounts of the strong acidic ion-exchange resin Dowex
50WX8 in a methanol/water mixture. The resulting triol 10
Our group has a longstanding interest in the reactions
of metal-chelated amino acid esters. These nucleophiles are
capable of a number of highly selective reactions, such as
Claisen rearrangements,[13] aldol reactions[14] and Pd-cata-
lysed processes.[15] Here we would like to report an efficient
route which benefits from a diastereoselective aldol reaction
to synthesize various imino sugar derivatives.
[a]
Universität des Saarlandes, Institut für Organische Chemie,
66123 Saarbrücken, Germany
Fax: (internat.) ϩ49-(0)681/3022409
E-mail: ukazmaier@mx.uni-saarland.de
3330
 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200300079
Eur. J. Org. Chem. 2003, 3330Ϫ3334

Synthesis of Monocyclic and Bicyclic Imino Sugars
FULL PAPER
Scheme 1. Synthesis of precursors; conditions: i) Ϫ78 °C, THF, ii)
Pd/C, 3 bar H2, MeOH, room temp., iii) DEAD, PPh3, THF, room
temp., iv) Dowex 50WX8, MeOH/H2O, v) NaH, BnBr, DMF, 0 °C
Scheme 2. Synthesis of piperidine derivatives 14 and 16; conditions:
i) LiAlH4, THF, room temp., 2 h, ii) sodium naphthalide, DME,
Ϫ60 °C, iii) Pd/C, 1 bar H2, THF, room temp., 3 d, iv) sodium
naphthalide, DME, Ϫ60 °C, v) 1. TFA, room temp., 2 h, 2. Pd/C,
1 bar H2, THF, room temp., 3 d
was perbenzylated with BnBr/NaH to give 11 in 99%
yield.[18]
By modifications of the pipecolinic acid derivative 11 it
was possible to obtain both a piperidine imino sugar 14 and
an unnatural amino acid 16 in high yields (Scheme 2). The
imino sugar 14 was accessible by reduction of the tert-butyl
ester with LiAlH4, deprotection of the tosyl amide by ti-
tration with sodium naphthalide solution[19] and cleavage of
the benzyl ethers with H2/Pd/C.[17] The unnatural amino
acid 16 could be obtained after removal of the tosyl protect-
ing group and acidic cleavage of the tert-butyl ester in tri-
fluoroacetic acid (TFA).[20] The resulting salt was dissolved
in THF and the Bn groups were removed under conditions
identical to those above.
Furthermore, the imino alcohol 13 was transformed into
the indolizidine derivative 19 in a three-step synthesis
(Scheme 3). The first step was a TBTU-mediated [TBTU
ϭ O-(1H-benzotriazol-1-yl)-N,N,NЈ,NЈ-tetramethyluronium
tetrafluoroborate] coupling[21] of 13 with diethyl phos-
phonoacetate.[22] At 0 °C the reaction resulted in a mixture
of amide and ester, but by lowering the temperature to Ϫ20
°C it was possible to obtain only the desired amide in 88%
yield. The second reaction was a DessϪMartin oxidation
of the primary hydroxy group and the third step involved
an intramolecular HornerϪEmmons reaction[23] through
Scheme 3. Synthesis of indolizidinone 19; conditions: i)
(EtO)2(O)PCH2CO2H, TBTU, NEt3, CH2Cl2, Ϫ20 °C Ǟ room
temp., ii) DessϪMartin periodinane, CH2Cl2, room temp., 8 h, iii)
DBU, THF, room temp., 72 h, iv) Pd/C, 1 bar H2, THF, room
temp., 4 d
the use of DBU, which yielded the indolizinone derivative groups and simultaneous hydrogenation of the double
18 in 74% yield. After cleavage of the benzyl protecting bond, the indolizidinone 19 was isolated in 96% yield.
Eur. J. Org. Chem. 2003, 3330Ϫ3334
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 2003 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3331

M. Kummeter, U. Kazmaier
FULL PAPER
CHCl3). 1H NMR (300 MHz, CDCl3): δ ϭ 1.46 (s, 9 H), 1.77 (s, 3
H), 2.31 (s, 3 H), 3.14 (m, 1 H), 3.52Ϫ3.72 (m, 2 H), 3.75 (m, 1
H), 4.09Ϫ4.30 (m, 3 H), 4.50Ϫ4.70 (m, 4 H), 7.06 (m, 2 H),
7.24Ϫ7.31 (m, 15 H), 7.85 (m, 2 H) ppm. 13C NMR (75 MHz,
CDCl3): δ ϭ 18.3, 21.5, 27.8, 53.4, 68.0, 71.0, 72.8, 72.9, 74.3, 77.2,
80.1, 82.1, 127.3, 127.4, 127.5, 127.6, 127.6, 127.7, 127.9, 128.2,
128.2, 128.3, 129.1, 136.1, 137.8, 137.9, 138.3, 143.0, 171.1 ppm.
C39H45NO7S (671.85): calcd. C 69.72, H 6.75, N 2.08, S 4.77; found
C 69.44, H 6.56, N 2.15, S 4.81. HRMS: calcd. for C39H46NO7S
[M ϩ H]ϩ 672.2969; found 672.2943.
Conclusion
In conclusion, we have shown that polyhydroxylated pi-
pecolinic acid derivatives, which can be easily obtained
through aldol reactions of chelated enolates and subsequent
Mitsunobu cyclization, are valuable building blocks for a
short and high-yielding approach to piperidine and indolizi-
dine imino sugars. The transformation of the piperidine
into an indolizidine framework involved a chemoselective
coupling process followed by an intramolecular
HornerϪEmmons reaction.
(2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-hydroxymethyl-2-methyl-1-
(p-toluenesulfonyl)piperidine (12): LiAlH4 (17 mg, 0.45 mmol) was
added at 0 °C to a solution of ester 11 (305 mg, 0.45 mmol) in THF
(5 mL). The suspension was warmed to room temperature and
stirred for 1 h. The mixture was diluted with Et2O and quenched
by addition of 1  HCl. The organic layer was washed with brine
and dried with Na2SO4. After purification by flash chromatography
(PE/EtOAc 85:15), alcohol 12 (267 mg, 0.44 mmol, 98%) was ob-
tained as a colourless oil. [α]2D0 ϭ Ϫ30.6 (c ϭ 1.1, CHCl3). 1H NMR
(500 MHz, CDCl3): δ ϭ 0.84 (s, 3 H), 1.56 (br. s, 1 H), 2.39 (s, 3
H), 3.40 (d, J ϭ 13.5 Hz, 1 H), 3.59 (m, 1 H), 3.72 (d, J ϭ 13.5 Hz,
1 H), 3.79 (dd, J ϭ 3.4, 3.0 Hz, 1 H), 3.97 (d, J ϭ 13.1 Hz, 1 H),
4.16 (m, 1 H), 4.19 (d, J ϭ 3.0 Hz, 1 H), 4.41, 4.46, 4.68 (3d, J ϭ
12.1 Hz, 3 H), 4.59Ϫ4.65 (m, 3 H), 7.18Ϫ7.36 (m, 17 H), 7.69 (d,
J ϭ 8.2 Hz, 2 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 13.7,
21.5, 42.5, 64.7, 66.8, 70.3, 73.2, 73.2, 73.3, 75.3, 76.0, 127.0, 127.4,
127.5, 127.5, 127.6, 127.7, 127.8, 127.9, 128.3, 128.4, 129.8, 138.0,
138.5, 138.5, 138.6, 143.5 ppm. C35H39NO6S (601.76): calcd. C
69.86, H 6.53, N 2.33; found C 69.33, H 6.58, N 2.35. HRMS:
calcd. for C35H40NO6S [M ϩ H]ϩ 602.2548; found 602.2519.
Experimental Section
General Remarks: Most reactions were carried out under argon in
oven-dried glassware (100 °C). All solvents were dried before use.
THF was distilled from sodium benzophenone, dichloromethane
and dimethoxyethane (DME) from calcium hydride. Dowex
50WX8 was purchased from Aldrich. The starting materials and
the products were purified by flash chromatography on silica gel
(32Ϫ63 µm). Mixtures of ethyl acetate (EtOAc) and petroleum
ether (PE, 40Ϫ60 °C) were generally used as eluents. TLC: com-
mercially precoated Polygram SIL-G/UV 254 plates
(MachereyϪNagel). Viewing was accomplished with UV light and
potassium permanganate solution. 1H and 13C NMR: Bruker DRX
300, Bruker DRX 500, Bruker Avance 500 and Bruker Aspect 3000
spectrometers. Optical rotations were measured with
PerkinϪElmer PE 341 polarimeter.
a
tert-Butyl (2S,3R,4S,5R)-3,4,5-Trihydroxy-2-methyl-1-(p-toluene-
sulfonyl)piperidine-2-carboxylate (10): The pipecolinic acid deriva-
tive 9[16] (970 mg, 2.20 mmol) was dissolved in methanol/water
(40 mL, 1:1). A spatula of the strong acidic ion exchange resin
Dowex 50WX8 was added and the mixture was shaken at room
temperature for 10 h. After filtration, the solvent was evaporated
in vacuo. In order to remove traces of water, the residue was dis-
solved in THF and the solvents were evaporated. The triol 10
(881 mg, 2.20 mmol, quantitative yield) was obtained as a colour-
less oil. [α]2D0 ϭ Ϫ20.5 (c ϭ 0.8, CHCl3). 1H NMR (300 MHz,
CDCl3): δ ϭ 1.40 (s, 9 H), 1.64 (s, 3 H), 2.38 (s, 3 H), 2.87 (dd,
J ϭ 13.8, 9.8 Hz, 1 H), 3.12 (br. s, 3 H), 3.55 (dd, J ϭ 8.8, 2.9 Hz,
1 H), 3.85 (m, 1 H), 4.06Ϫ4.13 (m, 2 H), 7.25 (d, J ϭ 8.3 Hz, 2
H), 7.76 (d, J ϭ 8.3 Hz, 2 H) ppm. 13C NMR (75 MHz, CDCl3):
δ ϭ 20.5, 21.3, 27.5, 48.2, 67.6, 68.6, 73.4, 73.5, 82.9, 127.1, 129.3,
138.6, 143.2, 170.4 ppm. C18H27NO7S (401.48): calcd. C 53.85, H
6.78, N 3.49; found C 53.96, H 7.12, N 3.30. HRMS: calcd. for
C18H28NO7S [M ϩ H]ϩ 402.1583; found 402.1579.
(2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-hydroxymethyl-2-methyl-
piperidine (13): A solution of alcohol 12 (205 mg, 0.34 mmol) in
DME (5 mL) was cooled to Ϫ60 °C. The dark green sodium naph-
thalide solution (1  in DME) was added dropwise until the solu-
tion stayed green. The reaction mixture was diluted with EtOAc
and quenched by addition of a small amount of water. The re-
sulting suspension was warmed to room temperature, and Na2SO4
was added. After filtration, the solvent was evaporated in vacuo.
The residue was purified by flash chromatography (MeOH/CH2Cl2,
19:1 ϩ 2% NEt3) to yield amine 13 (150 mg, 0.34 mmol, 99%) as
a colourless oil. [α]2D2 ϭ Ϫ15.8 (c ϭ 0.9, CHCl3). 1H NMR
(300 MHz, CDCl3): δ ϭ 1.23 (s, 3 H), 2.63 (br. s, 2 H), 2.73 (dd,
J ϭ 14.3, 4.3 Hz, 1 H), 3.13 (dd, J ϭ 14.3, 2.5 Hz, 1 H), 3.17 (d,
J ϭ 10.8 Hz, 1 H), 3.61 (d, J ϭ 10.8 Hz, 1 H), 3.65 (m, 1 H), 3.72
(m, 1 H), 3.86 (m, 1 H), 4.46Ϫ4.74 (m, 6 H), 7.31Ϫ7.34 (m, 15 H)
ppm. 13C NMR (75 MHz, CDCl3): δ ϭ 17.7, 41.0, 57.7, 66.3, 71.5,
72.6, 73.0, 75.8, 76.2, 76.3, 127.3, 127.4, 127.4, 127.5, 127.5, 127.6,
127.6, 127.7, 128.0, 128.3, 128.3, 128.4, 138.4, 138.6, 138.8 ppm.
C28H33NO4 (447.57): calcd. C 75.14, H 7.43, N 3.13; found C
75.21, H 7.72, N 3.14. HRMS: calcd. for C28H34NO4 [M ϩ H]ϩ
448.2515; found 448.2542.
tert-Butyl (2S,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methyl-1-(p-
toluenesulfonyl)piperidine-2-carboxylate (11): The triol 10 (881 mg,
2.20 mmol) and catalytic amounts of tetra-n-butylammonium iod-
ide were dissolved in DMF (15 mL). The solution was cooled to 0
°C, and NaH (264 mg, 11.0 mmol) was carefully added in small
portions. The mixture was stirred for 10 min, and BnBr (1.31 mL,
11.0 mmol), dissolved in DMF (5 mL), was added dropwise. The
mixture was warmed to room temperature. The solvent was evapo-
rated in vacuo, and CH2Cl2 and water were added. The organic
layer was washed consecutively with 1  NaOH, 1  KHSO4 and
brine, and dried with Na2SO4. After filtration, the solvent was eva-
porated in vacuo and the crude product was purified by flash chro-
matography (PE/EtOAc, 9:1, 8:2). Ester 11 (1.46 g, 2.17 mmol,
99%) was obtained as a colourless oil. [α]2D2 ϭ Ϫ10.0 (c ϭ 0.9,
(2R,3R,4S,5R)-2-Hydroxymethyl-2-methylpiperidine-3,4,5-triol
(14): A mixture of trifluoroacetic acid (12 µl, 0.16 mmol) and imino
alcohol 13 (60 mg, 0.13 mmol) in THF (10 mL) was hydrogenated
in the presence of 10% Pd/C for 72 h. The catalyst was removed by
filtration through Celite. A few drops of 1  NaOH were added to
the filtrate first, and then Dowex 50WX8 (1.0 g). The mixture was
shaken for 48 h and the resin was washed consecutively with meth-
anol and water. Finally, the product was eluted with 2  aqueous
ammonia solution. After evaporation, the triol 14 (22 mg,
0.12 mmol, 92%) was obtained as a colourless oil. [α]2D0 ϭ Ϫ11.6
1
(c ϭ 1.5, H2O). H NMR (500 MHz, CD3OD): δ ϭ 1.32 (s, 3 H),
3332
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Synthesis of Monocyclic and Bicyclic Imino Sugars
FULL PAPER
2.90 (dd, J ϭ 12.6, 5.0 Hz, 1 H), 3.27 (d, J ϭ 12.0 Hz, 1 H), 3.40 0.33 mmol) was added at room temperature to a solution of amide
(d, J ϭ 11.7 Hz, 1 H), 3.72 (d, J ϭ 11.7 Hz, 1 H), 3.78 (m, 1 H), 17 (190 mg, 0.30 mmol) in CH2Cl2 (10 mL). After stirring for 10 h,
3.81 (m, 1 H), 3.91 (m, 1 H), 4.87 (br. s, 2 H) ppm. 13C NMR
the mixture was diluted with Et2O. A solution of Na2S2O3 (0.26 )
(125 MHz, CD3OD): δ ϭ 16.0, 42.7, 63.9, 64.3, 67.4, 67.5,
in saturated NaHCO3 was added, and the two-layer system was
72.1 ppm. HRMS: calcd. for C7H16NO4 [M ϩ H]ϩ 178.1079; stirred vigorously until both phases became clear. The organic layer
found 178.1059.
was washed with saturated NaHCO3 and dried with Na2SO4. After
filtration, the solvent was evaporated and the crude product was
dissolved in THF (2 mL). DBU (90 µL, 0.60 mmol) was added at
room temperature and the solution was stirred for 72 h. The reac-
tion mixture was diluted with CH2Cl2, washed with 1  KHSO4
and dried with Na2SO4. After filtration, the solvent was evaporated
in vacuo and the residue was purified by flash chromatography
(PE/EtOAc, 6:4) to yield lactam 18 (105 mg, 0.22 mmol, 74%) as a
colourless oil. [α]2D0 ϭ ϩ8.7 (c ϭ 1.0, CHCl3). 1H NMR (500 MHz,
CDCl3): δ ϭ 1.43 (s, 3 H), 3.09 (dd, J ϭ 14.3, 1.3 Hz, 1 H), 3.24
(d, J ϭ 3.0 Hz, 1 H), 3.65 (m, 1 H), 3.78 (dd, J ϭ 3.3, 2.9 Hz, 1
H), 4.42 (m, 1 H), 4.35 (d, J ϭ 11.8 Hz, 1 H), 4.46 (d, J ϭ 11.8 Hz,
1 H), 4.57 (d, J ϭ 11.8 Hz, 1 H), 4.60 (d, J ϭ 11.8 Hz, 1 H), 4.74
(d, J ϭ 11.8 Hz, 1 H), 4.75 (d, J ϭ 12.1 Hz, 1 H), 6.02 (d, J ϭ
5.8 Hz, 1 H), 7.09 (d, J ϭ 5.8 Hz, 1 H), 7.15Ϫ7.31 (m, 15 H) ppm.
13C NMR (125 MHz, CDCl3): δ ϭ 15.8, 34.1, 66.7, 70.6, 72.0, 73.4,
74.7, 75.4, 79.1, 125.1, 127.5, 127.6, 127.7, 127.8, 128.3, 128.4,
137.8, 137.9, 138.2, 154.2, 170.3 ppm. C30H31NO4 (469.58): calcd.
C 76.73, H 6.65, N 2.98; found C 76.73, H 6.66, 2.97. HRMS:
calcd. for C30H32NO4 [M ϩ H]ϩ 470.2338; found 470.2345.
tert-Butyl (2S,3R,4S,5R)-3,4,5-Tris(benzyloxy)-2-methylpiperidine-
2-carboxylate (15): Compound 11 (270 mg, 0.40 mmol) was treated
with sodium naphthalide according to the synthesis of 13. After
flash chromatography (PE/EtOAc, 7:3), the amine 15 (203 mg,
0.39 mmol, 98%) was obtained as a colourless oil. [α]2D0 ϭ ϩ17.7
(c ϭ 1.0, CHCl3). 1H NMR (500 MHz, CDCl3): δ ϭ 1.22 (s, 3 H),
1.41 (s, 3 H), 2.07 (br. s, 1 H), 2.56 (dd, J ϭ 12.4, 10.5 Hz, 1 H),
3.12 (dd, J ϭ 12.5, 5.3 Hz, 1 H), 3.47 (dd, J ϭ 9.3, 2.4 Hz, 1 H),
3.91 (m, 1 H), 4.15 (d, J ϭ 2.4 Hz, 1 H), 4.62Ϫ5.01 (m, 6 H),
7.25Ϫ7.41 (m, 15 H) ppm. 13C NMR (125 MHz, CDCl3): δ ϭ 23.2,
27.7, 45.9, 63.7, 72.3, 72.7, 75.3, 75.6, 78.6, 81.4, 82.3, 127.2, 127.3,
127.4, 127.6, 128.0, 128.1, 128.1, 128.3, 138.3, 138.5, 138.7,
173.4 ppm. HRMS: calcd. for C32H40NO5 [M ϩ H]ϩ 518.2907;
found 518.2905.
(2S,3R,4S,5R)-2-Carboxy-3,4,5-trihydroxy-2-methylpiperidinium
Trifluoroacetate (16): Ester 15 (108 mg, 0.21 mmol) was dissolved
in a mixture of CH2Cl2 (2 mL) and trifluoroacetic acid (0.3 mL).
The solution was stirred at room temperature for 10 h, after which
the volatile components were evaporated in vacuo. The residue was
dissolved in THF (2 mL) and hydrogenated in the presence of 10%
Pd/C for 14 h. After the catalyst had been removed by filtration
through Celite, the solvent was evaporated in vacuo to yield salt 16
(62 mg, 0.20 mmol, 97%) as a colourless solid. [α]2D0 ϭ Ϫ3.8 (c ϭ
0.3, MeOH). 1H NMR (300 MHz, D2O): δ ϭ 1.47 (s, 3 H), 3.00
(m, 1 H), 3.30 (dd, J ϭ 12.7, 5.7 Hz, 1 H), 3.47 (dd, J ϭ 9.7, 2.5 Hz,
1 H), 3.95 (m, 1 H), 4.19 (d, J ϭ 2.4 Hz, 1 H) ppm. 13C NMR
(75 MHz, D2O): δ ϭ 21.3, 45.1, 64.7, 67.6, 72.2, 72.5, 116.3, 159.2,
173.8 ppm. HRMS: calcd. for C7H14NO5 [M ϩ H]ϩ 192.0896;
found 192.0920.
(6R,7S,8R,8aR)-6,7,8-Trihydroxy-8a-methylindolizidin-3-one (19):
A solution of indolizinone 18 (22 mg, 0.047 mmol) in THF (5 mL)
was hydrogenated in the presence of 10% Pd/C for 4 d. The catalyst
was removed by filtration through Celite. After evaporation, the
crude product was purified by flash chromatography (CH2Cl2/
MeOH, 9:1) to yield unprotected indolizidinone 19 (9.1 mg,
0.045 mmol, 96%) as a colourless oil. [α]2D0 ϭ ϩ26.0 (c ϭ 0.9,
1
EtOH). H NMR (500 MHz, [D6]DMSO):
δ ϭ 1.21 (s, 3 H), 1.71 (ddd, J ϭ 16.7, 10.2, 4.1 Hz, 1 H), 1.79 (m,
1 H), 2.13 (ddd, J ϭ 17.0, 9.8, 4.1 Hz, 1 H), 2.27 (m, 1 H), 2.90
(d, J ϭ 13.6 Hz, 1 H), 3.42 (d, J ϭ 3.2 Hz, 1 H), 3.63 (m, 1 H),
3.64 (m, 1 H), 3.67 (m, 1 H), 4.53Ϫ4.64 (m, 3 H) ppm. 13C NMR
(125 MHz, [D6]DMSO): δ ϭ 19.1, 29.5, 33.4, 38.3, 62.6, 69.2, 72.2,
72.8, 173.6 ppm. HRMS: calcd. for C9H16NO4 [M ϩ H]ϩ 202.1079;
found 202.1078.
(2R,3R,4S,5R)-3,4,5-Tris(benzyloxy)-1-[2Ј-(diethoxyphosphoryl)-
acetyl]-2-hydroxymethyl-2-methylpiperidine (17): The imino alcohol
13 (160 mg, 0.36 mmol) and diethyl phosphonoacetate (71 mg,
0.36 mmol) were dissolved in CH2Cl2 (10 mL). The mixture was
cooled to Ϫ20 °C, after which TBTU (116 mg, 0.36 mmol) and
NEt3 (155 µl, 1.11 mmol) were consecutively added. The mixture
was warmed to room temperature and stirred for 10 h. After ad-
dition of 1  KHSO4, the organic layer was washed with brine and
dried with Na2SO4. The solvent was removed in vacuo and the
crude product was purified by flash chromatography (MeOH/
CH2Cl2, 19:1), giving amide 17 (197 mg, 0.32 mmol, 88%) as a
colourless oil. [α]2D0 ϭ ϩ2.8 (c ϭ 1.0, CHCl3). 1H NMR (500 MHz,
CDCl3): δ ϭ 1.28, 1.31 (2t, J ϭ 7.4 Hz, 6 H), 1.30 (m, 1 H), 1.35
(s, 3 H), 2.93 (dd, J ϭ 22.9, 14.7 Hz, 1 H), 3.19 (dd, J ϭ 20.7,
14.7 Hz, 1 H), 3.71Ϫ3.85 (m, 5 H), 3.76 (d, J ϭ 12.1 Hz, 1 H), 3.99
(d, J ϭ 12.1 Hz, 1 H), 4.06Ϫ4.16 (m, 4 H), 4.52 (s, 2 H), 4.54 (d,
J ϭ 12.0 Hz, 1 H), 4.58 (d, J ϭ 11.4 Hz, 1 H), 4.67 (d, J ϭ 12.0 Hz,
1 H), 4.71 (d, J ϭ 11.4 Hz, 1 H), 7.25Ϫ7.37 (m, 15 H) ppm. 13C
NMR (125 MHz, CDCl3): δ ϭ 15.3, 16.1, 16.2, 35.9, 46.6, 62.3,
62.4, 62.5, 67.1, 71.4, 72.3, 74.4, 77.5, 78.5, 78.9, 127.3, 127.5,
127.5, 127.6, 127.7, 128.1, 128.2, 128.3, 128.6, 137.8, 138.0, 138.0,
166.4 ppm. C34H44NO8P (625.70): calcd. C 65.27, H 7.09, N 2.24;
found C 64.91, H 7.16, N 2.35. HRMS: calcd. for C34H45NO8P [M
ϩ H]ϩ 626.2878; found 626.2874.
Acknowledgments
We thank Dr. R. Graf and Dr. J. Gross (University of Heidelberg)
for mass spectra. Financial support by the Graduiertenkolleg, the
Deutsche Forschungsgemeinschaft and the Fonds der Chemischen
Industrie is gratefully acknowledged.
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Received February 7, 2003
3334
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