Diastereoselective synthesis of a novel lactam peptidomimetic exploiting vinylogous Mannich addition of 2-silyloxyfuran reagents

Article abstract of DOI:10.1016/S0957-4166(99)00051-8

The total synthesis of a potential inhibitor of HIV-protease-the chiral nonracemic six-membered hydroxy lactam 6-has been accomplished, that involves, as key reaction, the highly diastereoselective vinylogous Mannich addition of furan-based silyloxy diene 7 to glyceraldeyde imine 8.

Full text of DOI:10.1016/S0957-4166(99)00051-8

TETRAHEDRON:
ASYMMETRY
Pergamon
Tetrahedron: Asymmetry 10 (1999) 765–773
Diastereoselective synthesis of a novel lactam peptidomimetic
exploiting vinylogous Mannich addition of 2-silyloxyfuran
reagents
Lucia Battistini,a Gloria Rassu,b Luigi Pinna,c Franca Zanardi a and Giovanni Casiraghi a,∗
aDipartimento Farmaceutico dell’Università, Viale delle Scienze, I-43100 Parma, Italy
bIstituto per l’Applicazione delle Tecniche Chimiche Avanzate ai Problemi Agrobiologici del CNR, Via Vienna 2,
I-07100 Sassari, Italy
cDipartimento di Chimica dell’Università, Via Vienna 2, I-07100 Sassari, Italy
Received 18 January 1999; accepted 10 February 1999
Abstract
The total synthesis of a potential inhibitor of HIV-protease— the chiral nonracemic six-membered hydroxy
lactam 6 — has been accomplished, that involves, as key reaction, the highly diastereoselective vinylogous Mannich
addition of furan-based silyloxy diene 7 to glyceraldeyde imine 8. © 1999 Elsevier Science Ltd. All rights reserved.
1. Introduction
In recent years, fruitful effort has been devoted to the design and construction of cyclic inhibitors
of HIV-protease, whose structures mimic the extended conformation of protease substrates (transition-
state dipeptide isosteres).1 In particular, a number of six- and seven-membered candidates have been
introduced (e.g. compounds 1–5, Fig. 1), based on the known C2-symmetric structure of the target
protease homodimer, which exhibited potency in the micromolar–nanomolar inhibitory concentration
range.1a,b,f,g Hence the search for a methodology aimed at the assembly of piperidinone-based units
equipped with proper binding elements at the P1/P10 and P2/P20 subsites, and a required stereochemical
arrangement becomes an attractive challenge, especially when the synthetic scheme is flexible and
stereogovernable.
Among the existing techniques available for forging the requisite piperidinone scaffold, we chose the
scantily exploited vinylogous version of a Mannich-type addition2,3 as the leading carbon–carbon bond-
forming manoeuvre to access chiral nonracemic hydroxylactam 6, a potential candidate of an emerging
progeny of HIV-protease inhibitors.1a,c
∗
Corresponding author. E-mail: casirag@ipruniv.cce.unipr.it
0957-4166/99/$ - see front matter © 1999 Elsevier Science Ltd. All rights reserved.
PII: S0957-4166(99)00051-8

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Figure 1.
Retrosynthetically, a generic piperidinone structure A (Scheme 1) is disconnected along the indicated
bonds to identify lactam B as the immediate precursor. Aldehyde B, in turn, is traced to lactam C by
stereoselective enolate alkylation, followed by oxidative fission of the diol side chain. The six-membered
ring within C is formed by a γ-lactone to δ-lactam intramolecular annulation of substituted furanone D,
which ultimately springs from furan-based silyloxy diene E and chiral nonracemic imine F by exploiting
the vinylogous version of a Lewis acid-assisted Mannich reaction. Thus, the silyloxy diene unit E
provides the C-2–C-5 portion of the piperidinone A (target numbering), and chiral imine F constitutes
the chiral primer, while furnishing the N-1–C-6–C-10 segment of the target compound.
Scheme 1.
2. Results and discussion
The total synthesis of piperidinone 6 commenced with the regio- and diastereoselective addition of 2-
(tert-butyldimethylsilyloxy)furan 7 to protected D-glyceraldehyde N-benzylimine 8, a 3-carbon synthon
readily available from the natural chiral pool (Scheme 2).4 The key vinylogous coupling was carried out
in the presence of 0.6 mol equiv. of tert-butyldimethylsilyl trifluoromethanesulfonate (TBSOTf) as the
Lewis acid catalyst (CH2Cl2, −80°C), leading to 5,6-anti–6,10-anti-configured butenolide 9 in 83% yield
and 80% diastereomeric excess.5 The addition regiosense (attack at the remote C-5 position of furan 7), as
well as the simple diastereoselectivity (5,6-anti) of the vinylogous Mannich-type coupling may possibly

L. Battistini et al. / Tetrahedron: Asymmetry 10 (1999) 765–773
767
be governed by transition state TS1, where the indicated carbon–carbon bond-forming trajectory (re
face of dienolate vs si face of imine) would seemingly be preferred, due to favorable stereoelectronic
requirements. Whereas, for facial diastereoselection (6,10-anti), a Felkin-type model clearly applies,
resulting in a preferential attack of the nucleophile on the less demanding si face.
Scheme 2.
Catalytic hydrogenation of lactone 9 (Pd/C, THF) effected saturation of the butenolide double
bond with concomitant removal of the amine benzyl group, providing an amino lactone intermediate
(not shown), which underwent five-to-six-membered ring expansion upon treatment with neat 1,8-
diazabicyclo[5:4:0]undec-7-ene (DBU) at 80°C. Lactam 10 was thus produced in 62% yield (over two
stages), which was then subjected to sequential protection at the secondary hydroxyl (TBSCl, imidazole,
DMF) and amide nitrogen (Boc2O, DMAP, MeCN), to furnish the fully protected intermediate 11 in 60%
yield.
Having established the piperidinone moiety, we next turned to implementation of the alkyl chains at
the C-3 and C-6 positions. Thus, when 11 was treated with LiHMDS (THF, −78°C to room temperature),
a lactam enolate was formed, which was stereoselectively benzylated (BnBr, −78 to −15°C) to afford
the advanced intermediate 12 as the sole diastereoisomer in 50% yield. The cis relationship between
the benzyl and the protected C-5 hydroxyl groups had not yet been proved at this point, because the 1H

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NMR data (i.e. coupling constants) had not allowed a firm stereochemical assignment (vide infra). The
manipulation of the C-6 side chain began with acidic treatment of lactam 12 (70% aq. AcOH, 50°C) that
produced concomitant removal of both the acetonide and the N-tert-butoxycarbonyl protecting groups.
In the event, a diol intermediate was obtained (not shown), which was subjected to periodate oxidative
fission to produce aldehyde 13 (60%), ready for the subsequent Wittig elongation.
The cis stereodisposition between the C-3 and C-5 substituents, as well as the C-5–C-6 trans rela-
tionship were now established based on careful inspection of its 1H NMR spectrum, revealing diagnostic
coupling constants for axially disposed H-3–H-4α and H-5–H-6 proton couples (J3,4α=12.0 Hz; J5,6=9.2
Hz). Thus, as expected, the piperidinone substituents within 13 are located in thermodynamically stable
all-equatorial conformation.
The coupling reaction between aldehyde 13 and benzylidene triphenylphosphorane allowed the pre-
paration of 1:1 E/Z mixture 14 (50% yield), which was hydrogenated (Pd/C, THF) to furnish saturated
lactam 15 in 80% yield. Clean N-benzylation of 15 (NaH, DMF; then BnBr, 0°C) followed by acidic
removal of the TBS-ether protecting group (ethanolic HCl) completed the synthesis of the hydroxy
piperidinone 6 in 92% yield.
In conclusion, furan-based silyloxy diene 7 readily engages in a Lewis acid-promoted vinylogous
Mannich addition to chiral nonracemic imine 8 with a high chemical efficiency and diastereoselectivity.
The chiral unsaturated lactone 9 so generated constitutes a valuable, functionality dense scaffold on
which the constitutional and stereochemical elements of the target lactam 6 are implemented. No doubt,
by varying the core substituents at the C-3, C-10, and N-1 positions during the molecular assemblage, the
prospect of creating diversified ensembles within this promising class of lactam peptidomimetics could
soon be within our reach.6
3. Experimental
3.1. General procedures
Melting points were determined using an Electrothermal apparatus and are uncorrected. Optical
rotations were measured on a Perkin–Elmer 241 polarimeter and [α]D values are given in units of 10−1
1
deg cm2 g−1. H (300 MHz) and 13C (75 MHz) NMR spectra were recorded using a Bruker AC-300
spectrometer. Chemical shifts are quoted in parts per million (δ) relative to tetramethylsilane (0.0 ppm)
or to the specific deuterated solvent as an internal standard, and coupling constants (J) are measured in
hertz (Hz). Elemental analyses were performed by the Microanalytical Laboratory of the University of
Sassari. All the solvents were dried according to common methods and distilled before use. All reactions
were carried out in oven-dried glassware under a nitrogen or argon atmosphere unless otherwise noted.
Analytical thin-layer chromatography was performed on 0.25 mm silica gel glass-backed plates (Merck
Kieselgel 60 F254). Flash chromatography was carried out on 32–63 µm silica gel (ICN Biomedicals),
using the reported solvent mixtures. The compounds were visualized by dipping the plates in an aqueous
H2SO4 solution of cerium sulfate and ammonium molybdate, followed by heating.
3.2. Materials
2-[(tert-Butyldimethylsilyl)oxy]furan 7 was prepared on a multigram scale from 2-furaldehyde (Al-
drich) according to a reported procedure.7 2,3-O-Isopropylidene-D-glyceraldehyde N-benzylimine 8

L. Battistini et al. / Tetrahedron: Asymmetry 10 (1999) 765–773
769
was obtained by reacting benzylamine (Aldrich) and 2,3-O-isopropylidene-D-glyceraldehyde (ex D-
mannitol)8 in dry diethyl ether at room temperature in the presence of anhydrous MgSO4. The crude
material so obtained was used in the subsequent coupling process.
3.3. 5-(N-Benzylamino)-6,7-O-isopropylidene-2,3,5-trideoxy-D-ribo-hept-2-enonic acid 1,4-lactone 9
To a stirring solution of imine 8 (4.6 g, 20.6 mmol) in anhydrous CH2Cl2 (80 mL) under nitrogen
atmosphere cooled to −80°C were sequentially added dienol ether 7 (4.1 g, 20.6 mmol) and TBSOTf
(2.4 mL, 10.3 mmol), and the resulting mixture was allowed to react for 3 h at −80°C. The reaction was
then quenched at the same temperature by addition of saturated aqueous NaHCO3 and, after ambient
temperature was reached, the mixture was extracted with CH2Cl2 (3×20 mL). The combined organic
layers were washed with brine (2×15 mL), dried with MgSO4, filtered, and concentrated to furnish an
oily yellowish crude residue which was subjected to flash chromatographic purification on silica gel
(hexanes:EtOAc, 60:40). Pure lactone 9 was obtained (5.2 g, 83%) as white crystals; mp 66–67°C;
20
1
[α] =−35.2 (c=0.8, CHCl3); H NMR (300 MHz, CDCl3) δ 7.53 (dd, J=5.8, 1.6 Hz, 1H), 7.28 (m,
D
5H), 6.16 (dd, J=5.8, 2.1 Hz, 1H), 5.35 (app. quint, J=2.1 Hz, 1H), 4.07 (dd, J=8.3, 6.3 Hz, 1H), 3.95
(m, 1H), 3.7–3.9 (m, 4H), 3.08 (dd, J=7.5, 4.2 Hz, 1H), 1.39 (s, 3H), 1.31 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 172.7, 154.3, 139.5, 128.1 (5C), 122.2, 109.6, 83.6, 75.5, 67.5, 61.2, 52.9, 26.5, 25.0. Anal.
calcd for C17H21NO4: C, 67.31; H, 6.98; N, 4.62. Found: C, 67.04; H, 7.15; N, 4.50.
3.4. 5-Amino-6,7-O-isopropylidene-2,3,5-trideoxy-D-ribo-heptonic acid 1,5-lactam 10
To a stirring solution of butenolide 9 (5.0 g, 16.5 mmol) in anhydrous THF (150 mL) was added 10%
Pd on carbon (0.5 g) and a small amount of sodium acetate (120 mg) at room temperature. The reaction
vessel was evacuated and thoroughly purged with hydrogen (four times), and the resulting heterogeneous
mixture was allowed to stir under a balloon of hydrogen for 24 h at room temperature. After hydrogen
evacuation, the catalyst was filtered off, and the filtrate concentrated to afford a crude oily residue that
was subjected to flash chromatographic purification (EtOAc:MeOH, 90:10). A 2.7 g (75% yield) was
20
1
obtained of a lactone intermediate as white crystals: mp 62–65°C; [α] =+19.1 (c=0.6, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 4.59 (ddd, J=8.0, 7.3, 4.7 Hz, 1H), 4.07 (dd, J=7.7, 6.2 Hz, 1H), 3.99 (ddd,
J=6.9, 6.2, 5.9 Hz, 1H), 3.88 (dd, J=7.7, 5.9 Hz, 1H), 3.24 (dd, J=6.9, 4.7 Hz, 1H), 2.54 (m, 2H), 2.21
(m, 2H), 2.01 (bs, 2H), 1.40 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 176.9, 109.2, 81.0,
75.6, 66.4, 54.8, 28.5, 26.4, 25.0, 22.1. This intermediate (2.7 g, 12.5 mmol) was dissolved in 10 mL of
DBU and the resulting solution warmed to 80°C and allowed to react for 4 h. The reaction mixture was
concentrated under vacuum, leaving a brown crude residue that was purified by flash chromatography
eluting with EtOAc:MeOH (75:25). Pure lactam 10 was obtained (2.2 g, 62% yield for the two steps
from 9) as a white crystalline solid: mp 110–113°C; [α]20=+22.3 (c=0.8, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 6.47 (bs, 1H), 4.50 (bs, 1H), 4.23 (app. quint, J=6.3 Hz, 1H), 4.06 (dd, J=8.4, 6.4 Hz, 1H),
3.79 (dd, J=8.4, 6.3 Hz, 1H), 3.75 (m, 1H), 3.42 (td, J=6.5, 1.4 Hz, 1H), 2.46 (dt, J=18.0, 5.8 Hz, 1H),
2.29 (ddd, J=18.0, 9.5, 6.3 Hz, 1H), 1.98 (m, 1H), 1.86 (m, 1H), 1.41 (s, 3H), 1.32 (s, 3H); 13C NMR (75
MHz, CDCl3) δ 172.2, 109.5, 76.3, 65.8, 65.2, 59.4, 28.1, 27.4, 26.2, 24.8. Anal. calcd for C10H17NO4:
C, 55.80; H, 7.96; N, 6.51. Found: C, 55.74; H, 8.02; N, 6.60.

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3.5. 4-O-tert-Butyldimethylsilyl-5-(tert-butoxycarbonyl)amino-6,7-O-isopropylidene-2,3,5-trideoxy-D-
ribo-heptonic acid 1,5-lactam 11
A stirring solution of lactam 10 (2.0 g, 10.0 mmol) in dry DMF (50 mL) under nitrogen atmosphere was
sequentially treated with TBSCl (2.1 g, 14.0 mmol) and imidazole (0.96 g, 14.0 mmol). The resulting
mixture was warmed to 40°C and allowed to stir for 3 days, and during this period further quantities
of TBSCl (3×1.4 g, 3×10.0 mmol) and imidazole (3×0.64 g, 3×10.0 mmol) were added in three
sequential operations. The reaction mixture was then quenched with 5% aqueous citric acid and extracted
with EtOAc (4×30 mL). The combined organic layers were washed with brine (2×20 mL), dried over
MgSO4, filtered, and concentrated to furnish a crude residue that was purified by flash chromatography
(EtOAc:MeOH, 98:2). A monoprotected silylated intermediate (2.48 g, 8.0 mmol, 80%) was obtained as
a white crystalline solid, which was then dissolved in 100 mL of MeCN. To this stirring solution were
sequentially added Boc2O (1.7 g, 8.0 mmol) and DMAP (46 mg, 0.4 mmol) and the resulting mixture
warmed to 40°C. Further amounts of Boc2O (3×1.7 g) and DMAP (3×46 mg) were added in three
sequential operations over a period of 24 h, after which time the reaction mixture was concentrated under
vacuum. The crude residue so obtained was subjected to flash chromatographic purification on silica gel
(hexanes:EtOAc, 70:30) affording 2.4 g (60% yield for the two steps from 10) of pure, fully protected
20
1
lactam 11 as a colorless oil: [α] =−26.2 (c=1.3, CHCl3); H NMR (300 MHz, CDCl3) δ 4.34 (app.
D
quint, J=3.2 Hz, 1H), 4.27 (ddd, J=8.9, 3.1, 1.6 Hz, 1H), 4.02 (dd, J=8.5, 6.0 Hz, 1H), 3.96 (dd, J=8.5,
5.6 Hz, 1H), 3.88 (dt, J=8.9, 5.8 Hz, 1H), 2.73 (ddd, J=17.7, 10.3, 8.1 Hz, 1H), 2.42 (ddd, J=17.4, 7.4,
3.0 Hz, 1H), 2.15 (dddd, J=13.8, 10.4, 7.5, 2.9 Hz, 1H), 1.83 (m, 1H), 1.50 (s, 9H), 1.42 (s, 3H), 1.33
(s, 3H), 0.87 (s, 9H), 0.09 (s, 6H); 13C NMR (75 MHz, CDCl3) δ 171.4, 152.8, 109.5, 83.0, 76.9, 67.3,
64.2, 62.8, 29.9, 29.5, 27.8 (3C), 26.6, 25.5 (3C), 25.4, 17.7, −4.9, −5.1. Anal. calcd for C21H39NO6Si:
C, 58.71; H, 9.15; N, 3.26. Found: C, 58.75; H, 9.00; N, 3.30.
3.6. (3R,5S,6S,40S)-3-Benzyl-5-[(tert-butyldimethylsilyl)oxy]-6-(2,2-dimethyldioxolan-4-yl)piperidin-
2-one 12
A 2 M solution of LiHMDS in THF (3.6 mL, 7.3 mmol) cooled to −78°C was injected by syringe into
a stirred solution of piperidinone 11 (2.4 g, 5.6 mmol) in dry THF (80 mL). The resulting solution was
stirred at this temperature for 30 min, warmed to room temperature for an additional 30 min, and again
cooled to −78°C. The solution was then treated with benzyl bromide (1.2 mL, 9.5 mmol), and stirring
was continued for 2 h at −78°C. The reaction mixture was allowed to warm to −15°C and then quenched
with 5% aqueous citric acid. The mixture was extracted with CH2Cl2 (3×40 mL) and the combined
organic layers were dried over MgSO4, filtered, and concentrated under reduced pressure. Purification of
the oily crude residue through flash chromatography on silica gel (hexanes:EtOAc, 85:15) furnished pure
lactam 12 (1.5 g, 50% yield) along with 0.6 g (25%) of starting piperidinone 11, which was recovered
and subjected to the same alkylating reaction. Lactam 12, colorless oil: [α]20=−48.4 (c=1.0, CHCl3); 1H
D
NMR (300 MHz, CDCl3) δ 7.28 (m, 2H), 7.19 (m, 3H), 4.35 (ddd, J=7.5, 3.0, 1.1 Hz, 1H), 4.28 (m, 1H),
4.01 (m, 2H), 3.90 (m, 1H), 3.45 (1/2 AB q, J=10.0 Hz, 1H), 2.67 (m, 1H), 2.63 (1/2 AB q, J=10.0 Hz,
1H), 2.10 (ddd, J=14.1, 7.9, 5.2 Hz, 1H), 1.62 (m, 1H), 1.53 (s, 9H), 1.40 (s, 3H), 1.31 (s, 3H), 0.87 (s,
9H), 0.07 (s, 3H), 0.06 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 173.9, 153.4, 139.7, 129.2 (2C), 128.4,
126.2 (2C), 109.8, 83.1, 76.3, 67.0, 65.4, 63.5, 41.8, 38.2, 32.4, 28.0 (3C), 26.6, 25.7 (3C), 25.4, 17.8,
−4.5, −5.0. Anal. calcd for C28H45NO6Si: C, 64.71; H, 8.73; N, 2.69. Found: C, 64.62; H, 8.91; N, 2.65.

L. Battistini et al. / Tetrahedron: Asymmetry 10 (1999) 765–773
771
3.7. (3R,5S,6S)-3-Benzyl-5-[(tert-butyldimethylsilyl)oxy]-6-formylpiperidin-2-one 13
Piperidinone 12 (2.0 g, 3.9 mmol) was dissolved in 30 mL of 70% aqueous acetic acid and the resulting
solution warmed to 50°C under stirring. The reaction mixture was allowed to stir at this temperature for 5
h and was then concentrated under vacuum, giving an oily residue (1.3 g) which was used as such in the
subsequent reaction. The diol residue (1.3 g, 3.5 mmol) was dissolved in 30 mL of CH2Cl2 and treated
with chromatography grade SiO2 (2.0 g). To this heterogeneous mixture was added a 0.65 M aqueous
solution of NaIO4 (35 mL) dropwise and the resulting slurry stirred vigorously at room temperature
for 20 min. The reaction mixture was filtered under suction and thoroughly washed with CH2Cl2. The
filtrates were concentrated under vacuum to directly produce aldehyde 13 (0.8 g, 60% from 12) as a
yellowish glassy solid: 1H NMR (300 MHz, CDCl3) δ 9.7 (s, 1H), 7.28 (m, 2H), 7.19 (m, 3H), 6.35 (bs,
1H), 3.92 (ddd, J=10.6, 9.3, 3.8 Hz, 1H), 3.80 (d, J=9.2 Hz, 1H), 3.28 (dd, J=13.7, 4.2 Hz, 1H), 2.84
(dd, J=13.7, 9.0 Hz, 1H), 2.58 (dddd, J=12.0, 9.0, 6.1, 4.2 Hz, 1H), 1.93 (ddd, J=12.9, 6.2, 3.8 Hz, 1H),
1.69 (app. quint, J=12.0 Hz, 1H), 0.86 (s, 9H), 0.02 (s, 3H), 0.01 (s, 3H); 13C NMR (75 MHz, CDCl3)
δ 196.9, 171.8, 138.7, 129.1 (2C), 128.4, 126.4 (2C), 67.4, 66.5, 40.5, 37.1, 35.8, 25.5 (3C), 17.8, −4.2,
−5.1. Anal. calcd for C19H29NO3Si: C, 65.67; H, 8.41; N, 4.03. Found: C, 65.54; H, 8.60; N, 3.98.
3.8. (E/Z)-(3R,5S,6R)-3-Benzyl-5-[(tert-butyldimethylsilyl)oxy]-6-[(2-phenyl)ethen-1-yl]piperidin-
2-one 14
A 0.5 M solution of NaHMDS in THF (8.6 mL, 4.3 mmol) was injected dropwise by syringe to
a solution of benzyl triphenylphosphonium (2.5 g, 5.8 mmol) in anhydrous THF (30 mL) at −40°C.
The resulting red-orange solution was cooled to −78°C and treated with aldehyde 13 (0.8 g, 2.3 mmol)
previously dissolved in 50 mL of dry THF. The reaction mixture was allowed to stir at −78°C for 30 min,
and then it was slowly warmed to room temperature. After 16 h, the heterogeneous reaction mixture was
quenched with a saturated aqueous solution of NH4Cl (50 mL), and extracted with EtOAc (3×50 mL).
The combined organic layers were dried (MgSO4), filtered, and concentrated, to provide an oily crude
residue, which was purified by flash chromatography (hexanes:EtOAc, 60:40) furnishing a 1:1 mixture
of E/Z alkenes 14 (485 mg, 50%) as a colorless oil. A portion of this olefin mixture was subjected to a
further chromatographic purification, allowing characterization of the two geometric isomers.
E-14: 1H NMR (300 MHz, CDCl3) δ 7.30 (m, 6H), 7.22 (m, 4H), 6.55 (d, J=15.9 Hz, 1H), 6.03 (dd,
J=15.9, 7.6 Hz, 1H), 5.67 (bs, 1H), 3.81 (app. t, J=7.9 Hz, 1H), 3.69 (ddd, J=10.7, 8.2, 3.5 Hz, 1H),
3.35 (dd, J=13.6, 4.0 Hz, 1H), 2.85 (dd, J=13.6, 9.1 Hz, 1H), 2.64 (dddd, J=11.6, 9.5, 5.7, 4.0 Hz, 1H),
1.88 (ddd, J=13.1, 5.8, 3.6 Hz, 1H), 1.66 (app. quint, J=12.3 Hz, 1H), 0.80 (s, 9H), −0.05 (s, 3H), −0.08
(s, 3H); 13C NMR (75 MHz, CDCl3) δ 171.0, 139.2, 135.9, 133.5, 129.2 (2C), 128.6 (2C), 128.3 (2C),
128.0, 127.7, 126.4 (2C), 126.2, 70.7, 62.6, 38.0, 37.1, 34.8, 25.6 (3C), 17.9, −4.6, −4.8.
Z-14: 1H NMR (300 MHz, CDCl3) δ 7.1–7.4 (m, 10H), 6.72 (d, J=11.4 Hz, 1H), 5.64 (bs, 1H), 5.43
(dd, J=11.3, 10.1 Hz, 1H), 4.27 (app. t, J=9.2 Hz, 1H), 3.72 (ddd, J=11.3, 8.5, 3.6 Hz, 1H), 3.32 (dd,
J=13.5, 3.8 Hz, 1H), 2.73 (dd, J=13.4, 9.3 Hz, 1H), 2.62 (m, 1H), 1.85 (ddd, J=13.0, 5.6, 3.6 Hz, 1H),
1.61 (app. quint, J=13.0 Hz, 1H), 0.78 (s, 9H), −0.04 (s, 3H), −0.05 (s, 3H).
3.9. (3R,5S,6R)-3-Benzyl-5-[(tert-butyldimethylsilyl)oxy]-6-[(2-phenyl)ethyl]piperidin-2-one 15
A solution of olefin mixture 14 (421 mg, 1.0 mmol) in THF (30 mL) was subjected to catalytic
hydrogenation with 10% Pd on carbon (100 mg), in the presence of NaOAc (100 mg) at room temperature
for 24 h. The catalyst was then removed by filtration, and the filtrate was concentrated to give a

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crude residue that was purified by flash chromatography on silica gel (hexanes:EtOAc, 60:40). Pure
20
1
piperidinone 15 (340 mg, 80% yield) was obtained as a white solid: [α] =+27.7 (c=0.2, CHCl3); H
D
NMR (300 MHz, CDCl3) δ 7.27 (m, 4H), 7.16 (m, 6H), 5.74 (bs, 1H), 3.57 (ddd, J=11.4, 8.3, 3.6 Hz,
1H), 3.34 (dd, J=13.5, 3.9 Hz, 1H), 3.13 (td, J=8.2, 2.4 Hz, 1H), 2.73 (dd, J=13.5, 9.4 Hz, 1H), 2.4–2.7
(m, 3H), 2.06 (dddd, J=16.9, 6.6, 6.6, 2.9 Hz, 1H), 1.81 (ddd, J=13.0, 5.8, 3.7 Hz, 1H), 1.67 (dddd,
J=14.0, 9.5, 8.2, 5.6 Hz, 1H), 1.51 (app. quint, J=11.4 Hz, 1H), 0.82 (s, 9H), 0.05 (s, 3H), −0.01 (s, 3H);
13C NMR (75 MHz, CDCl3) δ 169.4, 141.0, 139.1, 129.2 (2C), 128.6 (2C), 128.4 (2C), 128.3 (2C), 126.3
(2C), 70.0, 59.0, 40.8, 37.2, 35.0, 34.6, 31.2, 25.7 (3C), 17.9, −4.1, −4.8. Anal. calcd for C26H37NO2Si:
C, 73.71; H, 8.80; N, 3.31. Found: C, 73.84; H, 8.17; N, 3.25.
3.10. (3R,5S,6R)-1,3-Dibenzyl-5-hydroxy-6-[(2-phenyl)ethyl]piperidin-2-one 6
To a stirring solution of piperidinone 15 (340 mg, 0.8 mmol) in dry DMF (15 mL) at room temperature
was added NaH (96 mg, 2.4 mmol, 60% dispersion in mineral oil). After 30 min, the reaction mixture
was cooled to 0°C and benzyl bromide was added (0.14 mL, 1.2 mmol). The temperature was allowed to
raise to room temperature and the reaction was left stirring for 2 h before being quenched with water (15
mL) and extracted with Et2O (3×20 mL). The combined organic layers were dried (MgSO4), filtered,
and concentrated under reduced pressure providing an oily crude residue which was purified by flash
chromatography (hexanes:EtOAc, 80:20). A solution of 390 mg (95% yield) of a N-benzylated pure
intermediate was obtained, as a colorless, glassy solid: [α]20=−4.1 (c=0.1, CHCl3); 1H NMR (300 MHz,
D
CDCl3) δ 7.25 (m, 13H), 7.07 (m, 2H), 5.27 (d, J=14.8 Hz, 1H), 3.99 (d, J=15.0 Hz, 1H), 3.96 (dt,
J=6.3, 4.0 Hz, 1H), 3.55 (dd, J=13.6, 3.7 Hz, 1H), 3.22 (app. quint, J=4.2 Hz, 1H), 2.83 (dd, J=13.5,
10.5 Hz, 1H), 2.4–2.7 (m, 3H), 1.98 (m, 2H), 1.80 (m, 1H), 1.63 (m, 1H), 0.80 (s, 9H), −0.04 (s, 3H),
−0.10 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 169.4, 140.8, 140.4, 137.2, 129.3 (2C), 128.5 (2C), 128.4
(2C), 128.3 (2C), 128.2 (2C), 128.1 (2C), 127.1, 126.2, 125.9, 67.5, 62.8, 48.2, 39.8, 38.6, 32.9, 30.8,
29.6, 25.8 (3C), 18.0, −4.5, −4.9. This intermediate (390 mg, 0.76 mmol) was dissolved in a 1% ethanolic
solution of HCl (25 mL) and the resulting mixture was stirred at room temperature for 5 h. After being
concentrated, the reaction mixture was dissolved in a 1:1 THF:HCl solution (25 mL) and it was allowed to
stir for an additional 3 h at room temperature. The reaction was concentrated furnishing a crude residue,
from which pure piperidinone 6 (290 mg, 92% yield from 15) was isolated by flash chromatographic
20
1
purification (hexanes:EtOAc, 70:30) as a white glassy solid: [α] =−18.0 (c=0.5, CHCl3); H NMR
D
(300 MHz, CDCl3) δ 7.1–7.3 (m, 15H), 5.41 (d, J=14.6 Hz, 1H), 3.91 (dt, J=6.7, 4.4 Hz, 1H), 3.85
(d, J=14.9 Hz, 1H), 3.49 (dd, J=13.6, 4.1 Hz, 1H), 3.20 (app. quint, J=4.0 Hz, 1H), 2.84 (dd, J=13.3,
9.7 Hz, 1H), 2.5–2.7 (m, 3H), 2.32 (bs, 1H), 2.01 (m, 2H), 1.87 (m, 1H), 1.63 (m, 1H); 13C NMR (75
MHz, CDCl3) δ 172.0, 140.7, 140.3, 138.2, 129.5, 129.4 (2C), 128.8, 128.6 (2C), 128.4 (2C), 128.2 (4C),
127.4, 126.2 (2C), 67.2, 62.0, 47.9, 39.6, 38.1, 32.0, 31.1, 29.3. Anal. calcd for C27H29NO2: C, 81.17;
H, 7.32; N, 3.51. Found: C, 81.04; H, 7.23; N, 3.60.
Acknowledgements
We are grateful to Ministero dell’Università e della Ricerca Scientifica e Tecnologica (MURST),
Italy, and to Consiglio Nazionale delle Ricerche (CNR), Italy, for financial support and to Centro
Interdipartimentale di Misure ‘G. Casnati’ for instrumental facilities.

L. Battistini et al. / Tetrahedron: Asymmetry 10 (1999) 765–773
773
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