An expedient stereoselective synthesis of polysubstituted piperidin-2-ones

Article abstract of DOI:10.1016/S0040-4020(02)00015-7

A versatile approach to the synthesis of various chiral substituted azido compounds is described. The utility and flexibility of this methodology has been demonstrated by the stereoselective synthesis of optically active polysubstituted piperidin-2-ones w

Full text of DOI:10.1016/S0040-4020(02)00015-7

TETRAHEDRON
Pergamon
Tetrahedron 5812002) 1519±1524
An expedient stereoselective synthesis of polysubstituted
piperidin-2-ones
d,e
M. Teresa Barros,a,b,p M. Adilia Januario-Charmier, Christopher D. Maycock
c,b
Â
and Thierry Michaudb
a
Â
Departamento de Quõmica, Faculdade de Ciencias e Tecnologia, Universidade Nova de Lisboa, 2825-114 Monte de Caparica, Portugal
b
Â
Centro de Quõmica Fina e Biotecnologia, FCT, Universidade Nova de Lisboa, 2825 Caparica, Portugal.
c
Â
Universidade Lusofona de Humanidades e Tecnologias, Av. de Campo Grande 376, 1749 Lisboa, Portugal
d
Â
Instituto de Tecnologia Quõmica e Biologica, Universidade Nova de Lisboa, Apartado 127, 2780 Oeiras, Portugal
e
Â
Departamento de Quõmica, Universidade de Lisboa, Rua Ernesto de Vasconcelos, 1700 Lisboa, Portugal
Received 8May 2001; revised 7 September 2001; accepted 18December 2001
AbstractÐA versatile approach to the synthesis of various chiral substituted azido compounds is described. The utility and ¯exibility of this
methodology has been demonstrated by the stereoselective synthesis of optically active polysubstituted piperidin-2-ones which are promising
precursors for the synthesis of several indolizidine and piperidine alkaloids. q 2002 Published by Elsevier Science Ltd.
Many sugar-like alkaloids 1azasugars) such as polyhydroxyl-
ated piperidines and pyrrolidines have been isolated from
plants and microorganisms and received a great deal of
attention since some of these compounds have been
shown to possess potent inhibitory activity against various
glycosidases and others exhibit antibiotic, antiviral or anti-
cancer activity.1 Some lactams have also been shown to be
effective glycosidases inhibitors2,3 and have proven to be
effective intermediates for the synthesis of indolizidine,
piperidine and pyrrolidine alkaloids.4
Our interest was to develop a facile synthesis of new
optically active substituted d-lactams via various func-
tionalized azido compounds, starting from readily available
polyhydroxylated enoates and dienoates.5 With that aim, the
azido function had to be introduced with good regio- and
stereoselectivity in various positions on the polyols before
achieving the chemoselective transformation of those azides
in a stereoselective and ef®cient way, to the corresponding
substituted piperidin-2-ones, which are precursors for poly-
hydroxylated indolizidines and piperidines.
Our approach to these compounds started from the octadiene-
dioate 1 readily available from d-mannitol according to a
previously reported method.5 It has been shown5 that the
bulky tert-butyldimethylsilyl protecting group on the central
diol leads to a high facial selectivity in the reactions on the
CvC double bonds of this class of compounds. The key
step was the introduction of the azido function that would
allow us to obtain the lactam derivatives. Three ways were
investigated to prepare the necessary 4-azidodienedioate:
treatment of the monosilylated compound 1 under Mitsu-
nobu conditions 1TPP, DEAD, HN3) gave, with a moderate
yield 156%) an inseparable mixture of azide 5a and another
compound we tentatively assign structure 5b 15a/5b varying
from 50:50 to 80:20). A similar mixture was obtained when
the tosylate group of 2 was displaced by sodium azide in
dimethylformamide as outlined in Scheme 1. Mitsunobu
Keywords: stereoselective synthesis; piperidin-2-ones; indolizidine .
Â
Ciencias e Tecnologia, Universidade Nova de Lisboa, 2825-114 Monte de
Caparica, Portugal. Fax: 1351-212-948-550;
e-mail: mtbarros@dq.fct.unl.pt
p
Corresponding author. Address: Departamento de Quõmica, Faculdade de
0040±4020/02/$ - see front matter q 2002 Published by Elsevier Science Ltd.
PII: S0040-4020102)00015-7

1520
M. T. Barros et al. / Tetrahedron 58 :2002) 1519±1524
Scheme 1. 1a) TsCl, Pyr/CHCl3, 1b) NaN3, DMF, 1c) HF, CH3CN, 1d) HN3, TPP, DEAD, THF.
displacement of the hydroxyl group of compound 3 was
successful however.
d-lactam 9 by catalytic hydrogenation. The intermediate
amine could be isolated as its Boc-derivative 10 by protec-
tion of the crude product immediately after hydrogenation
of the azide 8 1Scheme 2).
Catalytic hydrogenation of the mixture of 5a and 5b in order
to obtain lactams directly through a reductive cyclization
led to a complex mixture that was not further investigated.
In order to synthesize a series of chiral polyhydroxylated
d-lactams we studied the synthesis of the azide synthon 12
starting from the allylic alcohol 11 prepared according to a
previously reported method.5 Selective Mitsunobu inversion
using TPP, DEAD, HN3 at the allylic hydroxyl of 11,
afforded the desired azide 12 with no isomerisation. Cata-
lytic hydrogenation of compound 12 in ethanol in the
presence of Pd/C led to the corresponding amine which
underwent spontaneous cyclization to give a sole product
An alternative pathway to functionalize the 5-position of
compound 1 was thus devised. After catalytic hydrogena-
tion of 1, all attempts to introduce the azido group on the
saturated compound 6, using Mitsunobu technology, failed.
Substitution of the tosyl group of 7 was successful and azide
8 was formed in good yield. Compound 8 was easily
converted into the desired monohydroxylated chiral
Scheme 2. 1a) H2, 10% Pd/C 1b) TsOTs, CH2Cl2, Pyr, 1c) NaN3, DMF, 1d) HN3, TPP, DEAD, THF, 1e) 1Boc)2O, CH2Cl2.

M. T. Barros et al. / Tetrahedron 58 :2002) 1519±1524
1521
Scheme 3. 1a) HN3, TPP, DEAD, THF, 1b) H2, 10% Pd/C, 1c) TPP, THF/H2O, re¯ux.
in 62% yield that appeared to be the d-lactam 13, according
to the presence in the 13C NMR spectrum of the signal
corresponding to an amide carbonyl at 172 ppm. However,
the formation of the corresponding g-lactam could not be
excluded. To con®rm and prove the formation of the lactam
13, selective reduction of the azide function on 12 should
allow us to obtain only the d-lactam 14 with a trans
unsaturated side-chain 1Scheme 3). The azide 12 was
reacted with triphenylphosphine in re¯uxing THF in the
presence of water 1Staudinger reaction). This afforded
directly the expected d-lactam 14 in 62% yield. Catalytic
hydrogenation of lactam 14 with H2 in the presence of Pd/C
led quantitatively to the lactam 13, proving its structure. The
IR bands appearing at 1669, 1683, 1691 cm±1, respectively
for d-lactams 9, 13 and 14 were attributed to the amido
carbonyl which characterized the six-membered ring and
were consistent with literature data.1b The structures of
novel compounds 2±14 were all characterized and
con®rmed on the basis of spectral data and where possible,
elemental analysis.
Melting Point apparatus IA6304 and are uncorrected. Infra-
red spectra 1neat product) were recorded on a Perkin±Elmer
SPECTRUM 1000 FTIR spectrometer. Optical rotations
were recorded on an Optical Activity AA 1000 polarimeter
using a 0.5 dm cell at 208C. Concentrations are given in
g/100 mL. NMR spectra were recorded on a BruÈker
ARX400 spectrometer 11H: 400 MHz, 13C 100 Hz
100 MHz) in CDCl3 using Me4Si as an internal reference
for 1H and the solvent peak at d 77.1 ppm for 13C. Chemical
shifts are expressed in parts per million down®eld. Analy-
tical thin layer chromatography were performed on
precoated Merck plates 1silica gel 60) with ¯uorescence
indicator 1254 nm). Elemental analyses were performed by
the Microanalytical Laboratory, operated by the analytical
Â
department at Instituto Superior Tecnico 1Portugal).
1.1.1. Diethyl &4R,5R)-4-&tert-butyl-dimethyl-silanyloxy)-
5-&toluene-4-sulfonyloxy)-octa-2&E),6&E)-dienedioate 2.
To 500 mg 11.34 mmol) of 1 in 5 mL of chloroform was
added 384 mg 11.5 equiv.) of tosyl chloride in 3 mL of
chloroform and 216 mL of pyridine 12 equiv.) at 08C. The
mixture was stirred at rt for 72 h. The solvent was evapo-
rated, the crude product was dissolved in toluene, ®ltered
and concentrated under reduced pressure. The resulting
syrup 1900 mg) was puri®ed by ¯ash chromatography
1Hex/AcOEt 4:1) to give 570 mg 181%) of 2 as a colorless
syrup which crystallized after standing below 48C for
We have demonstrated an ef®cient synthesis of enantiopure
diversely functionalized azide synthons, using stereo- and
chemoselective reactions, which offers excellent oppor-
tunities for the synthesis of various optically active
polysubstituted d-lactams. This approach allows for the
stereoselective introduction of variable substituents on the
piperidin-2-one ring. As such this methodology represents a
highly attractive and facile procedure for the preparation of
indolizidine and piperidine alkaloids which is currently
under investigation in our laboratory.
20
several days. Mp 49±528C; [a]D ˆ16.7 1c 0.60, CHCl3);
IR 1cm±1, n): 1723.481C vO), 1663.12 1CvC), 1597.93
1
1arom.); H NMR 1400 MHz, CDCl3): d 7.781d, 2H, Jˆ
8.0 Hz, arom.); 7.34 1d, 2H, arom.); 6.80 1dd, 1H, Jˆ15.6,
5.0 Hz, H-6); 6.67 1dd, 1H, Jˆ15.8, 5.0 Hz, H-3); 6.03 1dd,
1H, Jˆ15.6, 1.5 Hz, H-7); 5.86 1d, 1H, Jˆ15.8, 1.7 Hz,
H-2); 4.96 1ddd, 1H, Jˆ1.5, 5.0, 5.0 Hz, H-5); 4.51 1dt,
1H, Jˆ1.7, 5.0, 5.0 Hz, H-4); 4.26±4.09 1m, 4H, 2£
OCH2CH3); 2.04 1s, 3H, CH3, Ts); 1.32±1.23 1m, 6H, 2£
OCH2CH3); 0.88 1s, 9H, tBu); 0.05 1s, 3H, CH3, TBDMS);
0.03 1s, 3H, CH3, TBDMS); 13C NMR: 165.77, 165.14
1. Experimental
1.1. General procedures
Melting points were determined on an Electrothermal

1522
M. T. Barros et al. / Tetrahedron 58 :2002) 1519±1524
1CvO); 145.47 1quat. Ts); 143.581C-6); 13.879 1C-3);
133.29 1quat Ts); 130.18, 130.03 1Ts); 124.88 1C-2);
123.89 1C-7); 80.31 1C-4); 72.15 1C-5); 60.75, 60.67 12£
OCH2CH3); 25.74 1tBu); 21.72 1CH3, Ts); 18.13 1quat. tBu);
14.26, 14.19 12£OCH2CH3); 24.86, 25.04 1SiCH3).
AcOEt 4:1). The solvent was evaporated and the crude
product was puri®ed by preparative TLC to yield 15 mg
175%) of a 80:20 mixture of 5a and 5b. 5a: IR 1cm±1, n)
1
2109.94 1N3), 1726.181C vO), 1658.10 1CvC); H NMR
1400 MHz, CDCl3): d 6.80 1dd, 1H, Jˆ4.8, 15.6 Hz, H-6);
6.75 1dd, 1H, Jˆ6.28, 15.6 Hz, H-3); 4.37 1m, 1H, H-5);
4.20±4.07 1m, 5H, 2£OCH2CH3, H-4); 1.25 12t, superposed,
6H, 2£OCH2CH3); 0.88 1s, 9H, tBu); 0.06 1s, 3H, SiCH3);
Anal. calcd for C25H36O8SSi: C 57.01; H 7.27. Found: C
56.99; H 7.21.
20
0.01 1s, 3H, SiCH3). 5b: [a]D ˆ179.81 c 1.08, CHCl3); IR
1.1.2. Diethyl &4R,5R)-4-hydroxy-5-&toluene-4-sulfonyl-
oxy)-octa-2&E),6&E)-dienedioate 3. To a stirred solution
of 2 1250 mg, 0.475 mmol) in acetonitrile 110 mL) was
added 337 mL of 40% aqueous HF 116 equiv.). The mixture
was stirred for 40 h at rt then quenched with saturated
NaHCO3, extracted with CH2Cl2 13£10 mL) and dried
1MgSO4). Evaporation of the solvent and puri®cation of
1cm±1, n): 2112.45 1N3), 1727.33 1CvO), 1657.52 1CvC);
1H NMR 1400 MHz, CDCl3), d 6.94 1dd, 1H, Jˆ15.6,
3.2 Hz, H-3); 6.21 1dd, 1H, Jˆ15.6, 2.4 Hz, H-2); 5.05
1dd, 1H, Jˆ7.2, 6.8Hz, H-6); 4.97 1dd, 1H, Jˆ3.2,
2.4 Hz, H-4); 4.21 1q, 2H, CH2, Et); 4.14 1q, 2H, CH2, Et);
3.12 1m, 2H, AB part of an ABX system, H-7,70); 1.35±1.23
1m, 6H, CH3, Et); 0.94 1s, 9H, SitBu); 0.12 1s, 6H, Si1CH3)2).
13C NMR: 170.89, 165.39 1CvO); 146.67 1C-3); 136.96
1C-5); 122.52 1C-2); 109.30 1C-6); 75.22 1C-4); 60.75,
60.57 1OCH2CH3); 31.86 1C-7); 25.58 1SitBu); 18.07
1quat. tBu), 14.13 1OCH2CH3); 25.06, 25.34 1Si1CH3)2).
Anal. calcd for C18H31N3O5Si: C 54.38; H 7.86; N 10.57.
Found: C 54.20; H 7.72; N 10.11.
the crude product by preparative TLC 1Hex/AcOEt 7:3)
ˆ
20
yielded 150 mg 172%) of 3 as a colorless oil. [a]D
125.2 1c 0.53, CHCl3); IR 1cm±1, n): 3474.54 1OH),
1722.71, 1712.29 1CvO), 1663.12 1CvC), 1597.93
1
1arom.); H NMR 1400 MHz, CDCl3): d 7.70 1d, 2H, Jˆ
8.0 Hz, arom. Ts); 7.27 1d, 2H, Jˆ7.8Hz, arom. Ts); 6.75±
6.65 1m, 2H, H-3, H-6); 6.05 1d, 1H, Jˆ15.6 Hz, H-7); 5.89
1d, 1H, Jˆ15.7 Hz, H-2); 5.04 1dd, 1H, Jˆ5.1, 5.1 Hz, H-5);
4.46 1bm, 1H, H-4); 4.15±4.04 1m, 4H, 2£OCH2CH3); 3.76
1bs, 1H, OH); 2.37 1s, 3H, CH3 Ts); 1.21 12 partially
overlapped t, 6H, 2£OCH2CH3); 13C NMR: 165.8, 165.1
1CvO); 145.4 1quat. Ts); 143.2 1C-6); 139.1 1C-3); 132.8
1quat. Ts); 129.9, 127.9 1arom. Ts); 125.2 1C-7); 123.7
1C-2); 81.0 1C-5); 71.3 1C-4); 60.8, 60.6 1OCH2CH3); 21.6
1CH3 Ts); 14.0 1OCH2CH3).
1.1.5. Diethyl &4R,5R)-4-&tert-butyl-dimethyl-silanyloxy)-
5-hydroxy-octanedioate 6. 138mg 10.37 mmol) of 1 were
shaken for 0.5 h under pressure of hydrogen 110 psi) in the
presence of 20 mg 15% mol of Pd) of 10% Pd/C. When TLC
1Hex/AcOEt 4:1) monitoring showed total disappearing of
starting material and formation of a single compound
1invisible by UV), the mixture was ®ltered and solvent
evaporated. Flash chromatography of the crude product
20
gave 6 1122 mg, 87%) as a clear oil. [a]D ˆ17.3 1c 0.55,
1.1.3. Diethyl &4S,5R)-4-azido-5-&toluene-4-sulfonyloxy)-
octa-2&E),6&E)-dienedioate 4. To 200 mg 10.485 mmol) of
3 dissolved in 5 mL of dry THF was added triphenylphos-
phine 1254 mg, 2 equiv.) and 647 mL of a 1.5 M solution of
hydrazoic acid in benzene 12 equiv.). The mixture was
stirred for 15 min then DEAD 1169 mL in 1 mL of THF,
2 equiv.) was added dropwise for 5 min. After 10 min the
solvent was evaporated and the crude product was puri®ed
by ¯ash chromatography 1Hex/EtOAc 4:1) to yield 4
CHCl3); IR 1cm±1, n): 3527.76 1OH); 1779.02, 1722.90
1CvO); 1H NMR 1400 MHz, CDCl3): d 4.11 1m, 4H,
2£OCH2CH3); 3.59 1m, 1H, H-4); 3.44 1m, 1H, H-5);
2.52±2.39 1m, 2H, H-2, H-20); 2.38±2.30 1m, 2H, H-7, H-
70); 2.27 1d, 1H, Jˆ7.2 Hz, OH); 2.00±1.85 1m, 1H, H-3);
1.82±1.63 1m, 3H, H-3, H6, H-60); 1.23 1m, 6H, 2£
OCH2CH3); 0.89 1s, 9H, tBu); 0.081s, 3H, SiCH ); 0.07
3
1s, 3H, SiCH3); 13C NMR: 173.79, 173.35 1CvO); 73.98
1C-4); 72.181C-5); 60.31 1CH , Et); 30.86, 29.62 1C-2,
2
20
1101 mg, 48%) as a yellow syrup. [a]D ˆ11.4 1c 0.74,
C-7); 28.77, 28.46 1C-3, C-6); 25.81 1tBu); 18.02 1quat.
tBu); 14.15 1CH3, Et); 24.37, 24.67 1SiCH3). Anal. calcd
for C18H36O6Si: C 57.41; H 9.64. Found: C 57.38; H 9.59.
CHCl3); IR 1cm±1, n): 2112.64 1N3), 1722.71, 1712.29
1CvO), 1663.12 1CvC), 1597.74 1arom.); 1H NMR
1400 MHz, CDCl3): d 7.79 1d, 2H, Jˆ8.0 Hz, arom Ts);
7.36 1d, 2H, Jˆ7.9 Hz, arom Ts); 6.70±6.60 1m, 2H, H-3,
H-6); 6.081d, 1H, Jˆ15.5 Hz, H-7); 5.981d, 1H, Jˆ
16.7 Hz, H-2); 5.11 1m, 1H, Jˆ4.6 Hz, H-5); 4.40 1m, 1H,
Jˆ4.6 Hz, H-4); 4.25±4.12 1m, 4H, 2£OCH2CH3); 2.45 1s,
3H, CH3, Ts); 1.33±1.25 1m, 6H, 2£OCH2CH3); 13C NMR:
164.76, 164.67 1CvO); 145.581quat. Ts); 137.69, 137.52
1C-3, C-6); 132.981quat. Ts); 129.97, 127.94 1arom. Ts);
126.60, 126.36 1C-2, C-7); 79.44 1C-5); 64.39 1C-4); 60.95,
60.89 1OCH2CH3); 21.61 1CH3 Ts); 14.06 1OCH2CH3).
1.1.6. Diethyl &4R,5R)-4-&tert-butyl-dimethyl-silanyloxy)-
5-&toluene-4-sulfonyloxy)-octanedioate 7. To 0.721 g
11.92 mmol) of 6 dissolved in 20 mL of dry CH2Cl2 was
added 0.31 mL of pyridine followed by 1.289 g 12 equiv.)
of TsOTs. The mixture was stirred for 2 h at rt then 7 mL of
1N aqueous HCl was added. The organic phase was sepa-
rated, washed with saturated NaHCO3, dried over sodium
sulfate and concentrated under reduced pressure. The crude
product was puri®ed by ¯ash column chromatography
1eluent Hex/EtOAc 6:1) to yield 0.966 g 195%) of 7 as a
colorless syrup. [a]D ˆ134.5 1c 0.84, CHCl3); IR 1cm±1,
20
The product was too unstable to obtain a good micro-
analysis.
n): 1732.54 1CvO), 1598.32 1arom.); 1H NMR 1400 MHz,
CDCl3): d 7.80 1d, 2H, Jˆ8.0 Hz, arom. ortho); 7.35 1d, 2H
Jˆ8.0 Hz, arom. meta); 4.47 1ddd, 1H, Jˆ10.3, 3.9, 2.7 Hz,
H-4); 4.18±4.00 1m, 4H, 2£OCH2CH3); 3.80 1ddd, 1H,
Jˆ9.4, 3.9, 1.9 Hz, H-5); 2.47±2.03 1m, 8H with 1s
12.47), CH3 1Ts), H-2,20,7,70,3); 1.95±1.59 1m, 3H,
H-30,6,60); 1.30±1.20 1m, 6H, 2£OCH2CH3); 0.86 1s, 9H,
1.1.4. Diethyl &4S,5R)-4-azido-5-&tert-butyl-dimethyl-sil-
anyloxy)-octa-2&E),6&E)-dienedioate 5. To 31 mg 10.059
mmol) of 2 in 1 mL of DMF was added 11 mg 12.7
equiv.) of NaN3 with stirring under argon. The solution
became orange-red and was stirred for 1 h 1TLC Hex/

M. T. Barros et al. / Tetrahedron 58 :2002) 1519±1524
1523
SitBu); 0.06 1s 3H, SiCH3); 0.01 1s 3H, SiCH3). Irradiation
at 4.47 ppm showed inter alias the signal of H-5 at 3.80 ppm
as a dd 1Jˆ9.4, 1.9 Hz). Irradiation at 3.80 ppm showed
inter alias the signal of H-4 at 4.47 ppm as a dd 1Jˆ10.3,
2.2 Hz). 13C NMR: 173.34, 172.71 1CvO); 145.10 1Ts
quat.); 134.01 1Ts quat.); 130.03 1arom. ortho); 128.08
1arom. meta); 82.62 1C-4); 71.21 1C-5); 60.41 12£
OCH2CH3); 30.67, 29.981C-2, C-7); 25.64 1Si tBu); 21.55
1C-3, C-6); 17.74 1quat. SitBu); 14.14, 14.0812 £OCH2CH3);
24.65, 25.22 1SiCH3). Anal. calcd for C25H42O8SSi: C
56.57; H 7.98; S 6.04. Found: C 56.37; H 8.07; S 6.21.
azide 8 10.270 g, 0.67 mmol) was hydrogenated as
described earlier. Evaporation of the solvent yielded
0.243 g of a syrup that was dissolved in 6 mL of dry
DCM under argon. 0.166 g 11.1 equiv.) of 1Boc)2O and
0.206 mL of Et3N were added at room temperature and
the mixture was stirred overnight. The reaction was
quenched with HCl 1N 110 mL) and the organic phase
was decanted. The aqueous phase was extracted with
3£12 mL of DCM and the combined organic extract were
dried over sodium sulfate. Evaporation of the solvent
yielded 0.333 g of crude product that was puri®ed by
medium pressure column chromatography 1Hex/AcOEt
1:7 then 1:1) to give 0.184 g 157% from 8) of 10 as a color-
less syrup. [a]D ˆ214.0 1c 2.0, CHCl3); IR 1cm , n):
3380.73 1NH), 1735.16 1CvO); 1H NMR 1400 MHz,
CDCl3): d 4.53 1bd, 1H, Jˆ9.28Hz, NH); 4.15±4.081m,
4H, 2£OCH2CH3); 3.73 1bs, 1H, H-5); 3.53 1bs, 1H, H-4);
2.36 1m, 4H, H-2,20,7,70); 1.92±1.51 1m, 4H, H-3,30,6,60);
1.41 1s, 9H, tBu 1Boc)); 1.24 1m, 6H, 2£OCH2CH3); 0.88 1s,
9H, SitBu); 0.07 1s, 3H, SiCH3); 0.05 1s, 3H, SiCH3). 13C
NMR: 173.89, 173.55 1C-1, C-8); 155.70 1CvO, Boc);
79.23 1tBu quat); 73.681C-5); 60.43 12 £OCH2CH3); 53.66
1C-4); 31.03, 30.11, 1C-7, C-2); 28.75 1C-6p); 28.30 1tBu,
Boc) 25.81 1SitBu); 23.681C-3 p); 17.981quat. Si tBu); 14.11
12£OCH2CH3); 24.56, 24.76 1SiCH3). Anal. calcd for
C23H45NO7Si: C 58.07; H 9.53; N 2.94. Found: C 58.24;
H 9.56; N 3.02.
1.1.7. Diethyl &4S,5R)-4-azido-5-&tert-butyl-dimethyl-sil-
sanyloxy)-octanedioate 8. To 0.205 g 10.39 mmol) of 7
dissolved in 6 mL of dry DMF and kept under argon was
added 31 mg 11.2 equiv.) of NaN3. The mixture was warmed
to 808C and stirred for 5 h 1followed by TLC, hex/AcOEt
4:1). It was then cooled to rt and diluted with 50 mL of
CH2Cl2, washed with water and dried over sodium sulfate.
Evaporation of the solvent and puri®cation by ¯ash column
chromatography 1eluent Hex/AcOEt 1:6) yielded 8 10.137 g,
±1
20
20
88%) as a colorless oil. [a]D ˆ215.6 1c 0.36, CHCl3); IR
1cm±1, n): 2101.63 1N3), 1735.36 1CvO); 1H NMR
1400 MHz, CDCl3): d 4.17±4.10 1m, 4H, 2£OCH2CH3);
3.82 1m, 1H, Jˆ3.5 Hz, H-5); 3.481dt, 1H, Jˆ3.20,
10.56 Hz, H-4); 2.59±2.281m, 4H, H-2,2 0,7,70); 1.90±
1.57 1m, 4H, H-3,30,6,60); 1.28±1.23 1m, 6H, 2£
OCH2CH3); 0.91 1s, 9H, SitBu); 0.10 1s, 3H, SiCH3); 0.07
1s, 3H, SiCH3). 13C NMR: 173.65, 173.10 1CvO); 74.00
1C-5); 66.50 1C-4); 60.59, 60.44 12£OCH2CH3); 31.15,
29.80, 1C-2, C-7); 26.97 1C-3); 25.75 1SitBu); 25.63
1C-6); 17.93 1quat. SitBu); 14.14 12£OCH2CH3); 24.39,
24.97 1SiCH3). Anal. calcd for C18H35N3O5Si: C 53.84; H
8.78; N 10.46. Found: C 54.23; H 8.72; N 10.56.
1.1.10. Diethyl &4R,5S,6S,7R)-4-azido-7-benzoyloxy-5-
&tert-butyl-dimethyl-silanyloxy)-6-hydroxy-oct-2-ene-
dioate 12. To 151 mg 10.3 mmol) of diol 115 in 5 mL of
anhydrous THF was added triphenylphosphine 10.123 g,
1.5 equiv.) and 0.63 mL of a 1.12 M solution of hydrazoic
acid in benzene. DEAD 1123 mg in 1 mL of THF) was then
added dropwise in 5 min. The mixture was stirred for
15 min then concentrated under reduced pressure to give
495 mg of a residue. Puri®cation by ¯ash chromatography
1Hex/AcOEt 7:3) gave 12 192 mg, 77%) as a viscous oil.
1.1.8. &5R,6S)-5-&tert-Butyl-dimethyl-silanyloxy)-6-&2-eth-
8
oxycarbonylethyl)-piperidin-2-one 9. The azide
10.336 g, 0.84 mmol) was dissolved in 10 mL of absolute
ethanol and shook for 3.5 h under a pressure of 50 psi of H2
in the presence of 75 mg of 10% Pd/C. The catalyst was
®ltered off and washed several time with ethanol and
AcOEt. The solvent was evaporated and the remaining
syrup was allowed to stand overnight at room temperature.
Puri®cation of the resulting crude solid product 10.205 g,
95%) by medium pressure column chromatography
1AcOEt) yielded analytically pure 9 178%) as a white
[a]D ˆ29.9 1c 0.83, CHCl3); IR 1n, cm±1): 3431.581OH),
20
2102.381N 3), 1727.72 1CvO); 1H NMR 1400 MHz,
CDCl3): d 8.07 1d, 2H, Jˆ7.6 Hz, arom. ortho); 7.62 1t,
1H, Jˆ7.2, 7.6 Hz, arom. para); 7.481t, 2H, Jˆ7.6 Hz,
arom. meta); 6.981dd, 1H, Jˆ7.2, 15.6 Hz, H-3); 6.12 1d,
1H, Jˆ15.6 Hz, H-2); 5.37 1s, 1H, H-7); 4.61 1d, 1H, Jˆ
7.6 Hz, H-4); 4.32±4.20 1m, 4H, 2£OCH2CH3); 4.08±3.95
1m, 2H, H-5, H-6); 2.64 1d, 1H, Jˆ8.4 Hz, HO-6); 1.35±
1.20 1m, 6H, 2£OCH2CH3); 0.87 1s, 9H, tBu); 0.11 1s, 3H,
SiCH3); 20.10 1s, 3H, SiCH3); 13C NMR: 168.6, 165.7
1CvO); 140.3 1C-3); 133.7, 129.9, 129.1, 128.7 1arom.);
125.4 1C-2); 74.0, 72.6, 72.0 1C-5,C-6,C-7); 65.2 1C-4);
62.2, 60.9 1OCH2CH3); 25.9, 18.2 1tBu); 14.2, 14.1
1OCH2CH3); 23.7, 25.3 1SiCH3).
20
solid. Mp 79±808C; [a]D ˆ231.5 1c 0.55, CHCl3); IR
1cm±1, n): 3188.26, 3079.78 1NH), 1726.29 1CO2Et),
1669.51, 1N±CvO); H NMR 1400 MHz, CDCl3): d 6.51
1
1bs, 1H, NH); 4.12 1q, 2H, OCH2CH3); 3.71 1m, 1H, H-5);
3.25 1m, 1H, H-6); 2.52 1ddd, 1H, Jˆ6.8, 7.2, 18.0 Hz, H-8);
2.39 1m, 2H, Jˆ16.4 Hz, H-3,30); 2.27 1ddd, 1H, Jˆ6.4, 6.8,
18.0 Hz, H-80); 1.92 1m, 2H, H-4, H-7); 1.82±1.66 1m, 2H,
H-40, H70); 1.24 1t, 3H, OCH2CH3); 0.86 1s, 9H, tBu); 0.06
1s, 6H, SiCH3); 13C NMR: 173.13, 172.01 1CvO); 68.08
1C-5); 60.59 1OCH2CH3); 58.82 1C-6); 30.27 1C-3); 29.15
1C-4); 27.63 1C-8); 27.00 1C-7); 25.59 1SitBu); 17.82 1quat.
SitBu); 14.081OCH 2CH3); 24.59 1SiCH3), 25.01 1SiCH3).
Anal. calcd for C16H31NO4Si: C 58.32; H 9.48; N 4.25.
Found: C 58.14; H 9.47; N 4.14.
The product was too unstable to obtain good microanalysis.
1.1.11. &3R,4S,5S,6S)-3-Benzoyloxy-5-&tert-butyl-dimethyl-
silylanyloxy)-6-&2-ethoxycarbonylethyl)-4-hydroxy-piperi-
din-2-one 13. The azide 12 1220 mg, 0.4 mmol) was
dissolved in 15 mL of ethanol and submitted to a 20 psi
pressure of hydrogen in the presence of 10% Pd/C catalyst
122 mg) for 20 min. Then 60 mg more of catalyst was added
and the pressure was raised to 45 psi for 6 h. The catalyst
was ®ltered and the solvent evaporated. The crude was
1.1.9. Diethyl &4S,5R)-4-&tert-butoxycarbonylamino)-5-
&tert-butyl-dimethyl-silanyloxy)-octanedioate 10. The

1524
M. T. Barros et al. / Tetrahedron 58 :2002) 1519±1524
puri®ed by preparative TLC 1Hex/EtOAc 7:3) to yield
ˆ
Acknowledgements
20
119 mg 162%) of lactam 13 as a viscous oil. [a]D
124.7 1c 1.0, CHCl3); IR 1n, cm±1): 1727 1CvO), 1683
1N±CvO); H NMR 1400 MHz, CDCl3): d 8.11 1d, 2H,
FundacËaÄo para Ciencia e Tecnologia is acknowledged for a
post-doctoral fellowship to T. M. and generous ®nancial
support 1PCEX/C/QUI/93/96).
Ã
1
Jˆ7.2 Hz, arom. ortho); 7.581t, 1H, Jˆ7.2 Hz, arom.
para); 7.45 1t, 2H, arom. meta); 6.62 1bs, 1H exchangeable
with D2O, NH); 5.54 1d, 1H, J2,3ˆ8.4 Hz, H-3); 4.22 1dd,
1H, Jˆ2.0, 8.8 Hz, H-4); 4.13 1q, 2H, OCH2CH3); 4.07 1bs,
References
0
1H, H-5); 3.481bm, 1H, H-6); 2.51±2.40 1m, 3H, H-8,8
1. 1a) Pandit, U. K.; Overkleeft, H. S.; Borer, B. C.; Bieraugel, H.
Eur. J. Org. 1999, 959±968. 1b) Overkleeft, H. S.; Wiltenburg,
J. V.; Pandit, U. K. Tetrahedron 1994, 50, 4215±4224.
1c) Comins, D. L.; Green, G. M. Tetrahedron Lett. 1999, 40,
217±218. 1d) Lofstedt, J.; Pettersson-Fasth, H.; Backvall, J. E.
Tetrahedron 2000, 56, 2225±2230. 1e) Xu, X.; Dubois, K.;
Rogiers, J.; Toppet, S.; Compernolle, F.; Hoornaert, G. J.
Tetrahedron 2000, 56, 3043±3051. 1f) Asano, N.; Nash, R. J.;
Molyneux, R. J.; Fleet, G. W. J. Tetrahedron: Asymmetry 2000,
11, 1645±1680.
HO-4 exchangeable with D2O); 1.96 1m, 1H, H-7); 1.85 1m,
1H, H-70); 1.25 1t, 3H, OCH2CH3); 0.93 1s, 9H, tBu); 0.16
1s, 3H, SiCH3); 0.14 1s, 3H, SiCH3); 13C NMR: 172.55,
167.41, 166.67 1CvO); 133.43, 130.17, 129.54 1quat.),
128.44 1arom.); 73.03, 72.32, 69.20 1C-3, C-4, C-5); 60.96
1OCH2CH3); 56.20 1C-6); 30.65, 29.69 1C-7, C-8); 25.76
1tBu); 18.08 1quat. tBu); 14.25 1OCH2CH3); 24.59, 24.69
1SiCH3). Anal. calcd for C23H35NO7Si: C 59.33; H 7.58; N
3.01. Found: C 59.47; H 7.59; N 3.03.
2. 1a) Davis, B. G.; Hull, A.; Smith, C.; Nash, R. J.; Watson, A. A.;
Winkler, D. A.; Grif®ths, R. C.; Fleet, G. W. J. Tetrahedron:
Asymmetry 1998, 9, 2947±2960. 1b) Kilonda, A.; Compernolle,
F.; Peeters, K.; Joly, G. J.; Toppet, S.; Hoornaert, G. J.
Tetrahedron 2000, 56, 1005±1012.
1.1.12. &3R,4S,5S,6S)-3-Benzoyloxy-5-&tert-butyl-dimethyl-
silanyloxy)-6-&2-ethoxycarbonyl-vinyl)-4-hydroxy-piperi-
din-2-one 14. Azide 12 10.433 g, 0.8mmol) in 5 mL of dry
THF was re¯uxed in the presence of triphenylphosphine
10.234 g, 1.1 equiv.) and 150 mL of H2O. Reaction was
followed by TLC 1Hex/AcOEt 3:7). After 2 h the solvent
was evaporated and the crude product puri®ed by prepara-
tive TLC 1Hex/AcOEt 3:7) to yield 14 10.234 g, 62%) as a
3. 1a) Shilvock, J. P.; Wheatley, J. P.; Davis, B.; Nash, R. J.;
Grif®ths, R. C.; Jones, M. G.; Muller, M.; Crook, S.; Watkin,
D. J.; Smith, C.; Besra, G. S.; Brennan, P. J.; Fleet, G. W. J.
Tetrahedron Lett. 1996, 37, 8569. 1b) Davis, B. G.;
Brandstetter, T. W.; Hackett, L.; Winchester, B. G.; Nash,
R. J.; Watson, A. A.; Grif®ths, R. C.; Smith, C.; Fleet, G. W. J.
Tetrahedron 2000, 55, 4489±4500. 1c) Battistini, L.; Rassu, G.;
Pinna, L.; Zanardi, F.; Casiraghi, G. Tetrahedron: Asymmetry
1999, 10, 765±773.
20
slightly yellow viscous oil. [a]D ˆ14.4 1c 0.41, CHCl3);
IR 1n, cm±1): 1719.97, 1691, 47; 1H NMR 1400 MHz,
CDCl3): d 8.11 1d, 2H, Jˆ8.0 Hz, arom. ortho); 7.581t,
1H, Jˆ7.2 Hz, arom. para); 7.45 1t, 2H, arom. meta); 6.92
1dd, 1H, Jˆ16.0, 4.4 Hz, H-7); 6.62 1bs, 1H, NH); 6.14 1d,
1H, Jˆ16.0 Hz, H-8); 5.65 1d, 1H, Jˆ8.8 Hz, H-3); 4.25±
4.13 1m, 4H, 2£OCH2CH3, H-5, H-6); 4.12 1d, 1H, Jˆ
8.8 Hz, H-4); 2.57 1bs, 1H, OH-4); 1.31 1t, 3H, 2£
4. 1a) Huang, P. Q.; Wang, S. L.; Ye, J. L.; Ruan, Y. P.; Huang,
Y. Q.; Zheng, H.; Gao, J. X. Tetrahedron 1998, 54, 12547±
12560. 1b) Crosby, S. R.; Hateley, M. J.; Willis, C. L.
Tetrahedron Lett. 2000, 41, 397±401. 1c) Green, D. L. C.;
Kiddle, J. J.; Thompson, C. M. Tetrahedron 1995, 51, 2865±
2874. 1d) Toyooka, N.; Yoshida, Y.; Yotsui, Y.; Momose, T.
J. Org. Chem. 1999, 64, 4914±4919.
OCH2CH3); 0.94 1s, 9H, tBu); 0.181s, 3H, SiCH ); 0.15 1s
3
3H, SiCH3); 13C NMR: 167.62, 166.56, 165.40 1CvO);
143.95 1C-7), 133.42 1arom. ortho); 130.09 1arom. para);
129.25 1arom. quat.), 128.36 1arom. meta); 124.17 1C-8);
72.27, 71.87, 68.83 1C-3, C-4, C-5); 60.90 1OCH2CH3);
58.01 1C-6); 25.64 1tBu); 18.01 1quat. tBu); 14.15
1OCH2CH3); 24.68, 24.88 1SiCH3). Anal. calcd for
C23H33NO7Si: C 59.59; H 7.17; N 3.02. Found: C 59.50;
H 7.18; N 2.97.
5. Barros, M. T.; Januario-Charmier, M. O.; Maycock, C. D.;
Pires, M. Tetrahedron 1996, 23, 7861±7874.