Palladium-catalysed C-C coupling reactions in the enantioselective synthesis of 2,4-disubstituted 4,5-dehydropiperidines using galactosylamine as a stereodifferentiating auxiliary

Article abstract of DOI:10.1016/j.tetasy.2004.11.074

Stereoselective synthesis of enantiomerically pure 2,4-disubstituted piperidine derivatives, which are considered interesting pharmacophoric structures, was achieved starting with a tandem Mannich-Michael reaction sequence on O-pivaloylated N-galactosyl a

Full text of DOI:10.1016/j.tetasy.2004.11.074

Tetrahedron:
Asymmetry
Tetrahedron: Asymmetry 16 (2005) 529–539
Palladium-catalysed C–C coupling reactions in the
enantioselective synthesis of 2,4-disubstituted
4,5-dehydropiperidines using galactosylamine as a
stereodifferentiating auxiliary
Stephan Knauer and Horst Kunz*
Institut fu¨r Organische Chemie, Johannes Gutenberg-Universita¨t Mainz, Duesbergweg 10-14, 55128 Mainz, Germany
Received 15 November 2004; accepted 29 November 2004
Available online 5 January 2005
Abstract—Stereoselective synthesis of enantiomerically pure 2,4-disubstituted piperidine derivatives, which are considered interest-
ing pharmacophoric structures, was achieved starting with a tandem Mannich–Michaelreaction sequence on O-pivaloylated N-
galactosyl aldimines. Subsequent conversion of the thus formed 2-substituted dehydropiperidinones into the corresponding enol tri-
flates was carried out by conjugate hydride addition and trapping the enolate with N,N-bis(trifluoromethanesulfonyl)aniline. Their
Suzuki–Miyaura coupling with aryl and heteroaryl boronic acids was performed under conditions compatible with the carbohydrate
structure, in particular, with the sensitive N-glycosidic bond.
ꢀ 2004 Elsevier Ltd. All rights reserved.
1. Introduction
auxiliary. As an extension of this methodology, we have
developed a general method to install functionality at
the 4-position of the piperidine ring structure. As few
methods have been reported for the synthesis of 2,4-
disubstituted piperidine derivatives,4,11–15 we considered
these attractive compounds, containing additionalstruc-
turalinformation compared to the 1,4-disubstituted
derivatives shown in Figure 1, as interesting targets for
stereoselective syntheses.
Substituted piperidines are important pharmacophoric
structures since they enable the development of efficient
ligands for quite a number of receptors and enzymes.1
There have been numerous reports on the synthesis of
substituted piperidines in the literature,2,3 but not sur-
prisingly 1,4-substitution of the piperidine ring domi-
nates due to the ease of synthesis and the absence of
complicating stereochemical issues.4 Over the recent
years, severalcommercialdrugs have appeared that pos-
sess the 1,4-substitution pattern as the common motif
(Fig. 1). Risperdalꢁ (risperidone, 1) is an antipsychotiꢁc
drug used for treatment of schizophrenia.5 Naramig
(naratriptan, 2), an agonist of serotonin receptors 5-
HT1D and 5-HT1B, is applied to treat migraine.6 Finally,
Ariceptꢁ (donepezil, 3), a cholinesterase inhibitor,7 is
currently being prescribed for the treatment of Alzhei-
merꢀs disease.
2. Results and discussion
The synthesis of these 2,4-disubstituted dehydropiper-
idines begins with the condensation of 2,3,4,6-tetra-O-
b-D-galactosylamine 4 and an aldehyde to give the cor-
responding Schiff bases 5 with the trans configuration
at the imine double bond.16 This method was extended
to halogen-substituted phenyl acetaldehydes that re-
quired a variation in the choice of solvent. Instead of
pentane, isopropyl alcohol proved to be suitable for
the dehydrating reaction conditions commonly used in
the synthesis of aliphatic N-galactosyl imines 5. Further-
more, the formation of the undesired enamine was not
detected. The aldimines 5 were reacted with 1-meth-
In preceding work,8–10 we described the stereoselective
synthesis of 2-substituted 5,6-dehydropiperidin-4-ones
using galactosylamine 4 as a diastereodifferentiating
*
Corresponding author. Tel.: +49(0) 6131 39 22334/22272; fax: +49(0)
6131 39 24786; e-mail: hokunz@uni-mainz.de
oxy-3-trimethylsilyloxy-butadiene
6
(Danishefskyꢀs
0957-4166/$ - see front matter ꢀ 2004 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetasy.2004.11.074

530
S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
Me
N
O
N
N
F
N
O
Me
MeHNO2S
N
1, Risperidone
HN
MeO
MeO
2, Naratriptan
N
O
3, Donepezil
Figure 1. Drug launches containing a 1,4-disubstituted piperidine ring as structural feature.
diene) to form 2-substituted dehydropiperidinones 7
with high diastereoselectivity (Scheme 1).8,9
creases slightly with the size of the halogen substituent.
The lower yields obtained for the 2-chloro-7e and 2-
iodo-benzyl 7g derivatives resulted from impurities that
could not be separated from the phenyl acetaldehydes as
the starting materials.
OPiv
O
OPiv
O
PivO
PivO
PivO
PivO
R1-CHO
R1
N
NH2
To target the carbonylfunctionality in the 4-position we
took advantage of the enone conjugation. Chemoselec-
tive hydride transfer to the C@C double bond was car-
ried out using the sterically demanding boron hydride
reagent L-Selectrideꢁ. Subsequent trapping of the gener-
ated enolate with N,N-bis(trifluoromethanesulfonyl)ani-
line (PhNTf2) leads to the regioselective formation of N-
galactosyl 4-triflyl 4,5-dehydropiperidines 8 (Scheme 2).
Prior work on the formation of these heterocyclic enol
triflates tended to hydrogenate the carbonylmoiety of
piperidin-4-ones to obtain saturated 2-substituted pip-
eridines.9,17 The formation of regioisomers as described
by Garbaccio et al. (application of 2-[N,N-bis(tri-
fluoromethanesulfonyl)amino]-5-chloropyridine as sulfo-
nation reagent) was not observed.18 Even after warming
to ambient temperature to complete sulfonation of the
enolate intermediate, that required generation at
ꢀ78 ꢂC to prevent 1,2-addition, no 3,4-dehydro isomer
could be detected. The N-galactosyl enol triflates 8 pos-
sess an astonishing stability towards hydrolysis. These
compounds could be isolated by flash chromatography
on silica gel. If no further purification was carried out,
following conversions suffered from remaining traces
of the sulfonation reagent.
OPiv
OPiv
H
5
4
Me3SiO
OPiv
O
PivO
PivO
O
OMe
ZnCl2, THF, -20 °C
6
N
OPiv
R1
7
Scheme 1. Diastereoselective synthesis of dehydropiperidinones 7.
In this tandem Mannich–Michaelreaction the Lewis
acid plays a decisive role. It increases the electrophilic
reactivity of the imine and coordinates both the imine
nitrogen and the carbonyloxygen of the 2-pivaolyl
group of the carbohydrate auxiliary. This leads to effi-
cient shielding of the (Re)-face of the imine. Therefore,
the nucleophilic attack occurs preferentially from the
less hindered (Si)-face. Thus, the 2-substituted dehydro-
piperidinones 7 were obtained in excellent diastereose-
lectivity (Table 1). Pure diastereomers of the chiral
piperidinone derivatives were obtained following flash
chromatography. Diastereoselectivity in the synthesis
of the benzyl-substituted dehydropiperidinones 7e–g in-
Table 1. Stereoselective synthesis of 2-substituted N-galactosyl dehy-
dropiperidinones 7
OPiv
O
PivO
PivO
L-Selectride
PhNTf2, THF,
-78 °C - r.t.
OTf
7
N
Compound
R1
Yield [%]
D.r.a (S):(R)
OPiv
3:97b
96:4
98:2
R1
7a
7b
7c
7d
7e
7f
nPr
iPr
96
84
89
8
66-84 %
4-Cl–Ph
3-Pyridyl63
2-Cl–Bn
2-Br–Bn
2-I–Bn
97:3
Scheme 2. Regioselective formation of 4-triflyl-4,5-dehydropiperidines
8.
53
70
32
10:90b
6:94b
5:95b
7g
a Determined by analytical HPLC of the crude product.
b Reversalof the configuration due to the ol wer priority of substituent R.
By this procedure, a variety of enoltriflates of N-glyco-
sylpiperidine derivatives are accessibel, which are suit-

S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
531
able for transition metal-catalysed C–C-bond forma-
tion reactions, particularly for the Suzuki–Miyaura
cross-coupling.19 The cross-coupling of organic triflates
is well known,20–23 and offers a generalaccess to insert
aryl-, alkenyl- and even alkyl-substituents.24
Cleavage of the N-glycosidic bond was readily achieved
by treatment of the dehydropiperidines 9 with dilute
HClin methanolat ambient temperature ( Scheme 4).
The heterocycles 10 were separated from the hemiacetal
of the carbohydrate auxiliary 11, which was quantita-
tively recovered. After neutralisation, the 2,4-disubsti-
tuted 4,5-dehydropiperidines 10 were obtained in high
yields and in an enantiomerically pure form.
The coupling of phenyl and heteroaryl boronic acids to
N-galactosyl enol triflates 8 gave 2,4-disubstituted 4-aryl
4,5-dehydropiperidines 9 (Scheme 3). For all boronic
acid derivatives (except 3,5-dimethyl-isoxazol-4-boronic
acid) bis(triphenylphosphine)palladium(II) chloride
[Pd(PPh3)2Cl2] in combination with aqueous caesium
carbonate as the base and THF as the solvent proved
to be successful and led to the desired cross-coupled
products in good yields (Table 2). Severalcatayl tic sys-
tems were investigated for the analogous conversion of
the isoxazole-derived boronic acid, but none was capa-
ble to promote this cross-coupling reaction. Tetrakis(tri-
phenylphosphine)palladium(0) [Pd(PPh3)4] showed low
reactivity for the employed substrates. When 1,10-
bis(diphenylphosphino)ferrocene palladium(II) chloride
[Pd(dppf)Cl2] was used as the catalyst instead of
Pd(PPh3)2Cl2 under similar conditions, the yield de-
creased (see yields in parentheses in Table 2). In general,
the reaction of electron-poor heterocyclic boronic acids,
such as pyrimidine-5- and pyridine-3-boronic acid, pro-
ceeded in high conversion rates. However, the reaction
with the electron-rich isoxazole-boronic acid failed.
R2
OPiv
O
PivO
PivO
aq. HCl
MeOH, r.t.
+
9
OH
R1
OPiv
N
H
11
10a: R1 = iPr,
R2 = 5-pyrimidyl; 85 %
10b: R1 = 3-pyridyl,
R2 = 5-pyrimidyl; 91 %
Scheme 4. Detachment of the 2,4-disubstituted piperidine derivatives
10 from the carbohydrate scaffold.
3. Conclusion
The described results show that the efficient diastereodif-
ferentiation achieved with N-glycosyl aldimines in tan-
dem Mannich–Michaelreaction sequences with syill
dienolethers giving 2-substituted dehydropiperidinones
can be exploited to a highly stereoselective synthesis
of enantiomerically pure 2,4-disubstituted piperidine
derivatives. Conjugate hydride addition to these dehy-
dropiperidinones and trapping of the intermediate eno-
late with N,N-bis(trifluoromethanesulfonyl)aniline gave
the enoltriflates, which proved efficient components in
Suzuki–Miyaura cross-coupling reactions. Neither the
carbohydrate structure nor the sensitive N-glycosidic
bond is affected under the required reaction conditions.
The products thus obtained are considered interesting
pharmacophoric groups. They are also promising sub-
strates for further derivatisations, for example, at the
C@C double bond. The scope of the methodology de-
scribed herein can be expanded to stereoselective synthe-
ses of piperidine derivatives with opposite enantiomeric
configuration by using O-pivaloylated D-arabinopyr-
anosylamine as an auxiliary virtually enantiomeric to
the D-galactosylamine.26
OPiv
O
PivO
PivO
R2-B(OH)2, aq. Cs2CO3
Pd(PPh3)2Cl2 (5 mol%)
THF, reflux
R2
8
N
OPiv
R1
9
Scheme 3. Suzuki–Miyaura cross-coupling reaction on N-galactosyl
enoltriflates 8.
Table 2. Palladium-catalysed cross-coupling to yield 2,4-disubstituted
dehydropiperidines 9
Compound
R1
R2
Time
[h]
Yield
[%]
9a
9b
9c
9d
9e
9f
nPr
nPr
nPr
nPr
iPr
5-Pyrimidine
8-Chinoline
3-Pyridine
16
16
19
16
22
20
83
72
83
64
64
—
Ph
5-Pyrimidine
4-(3,5-dimethyl-
isoxazol)
iPr
4. Experimental section
4.1. Instruments
9g
9h
9i
4-Cl–Ph
4-Cl–Ph
4-Cl–Ph
5-Pyrimidine
8-Chinoline
4-(3,5-dimethyl-
isoxazol)
15
21
16
69 (38)a
66 (66)b
—
b
1H NMR and 13C NMR spectra were recorded on Bru-
ker AC-200, AC-300 and AM-400 spectrometers. Mass
spectra were recorded on a Navigator-1 ESI mass spec-
trometer (ThermoQuest). Accurate mass spectra
(HRMS) were measured on a Waters Q-TOF-Ultima 3
with a lockspray interface, using NaICsI clusters as
externalreference. Opticalrotation vaules were mea-
sured on a Perkin–Elmer 241 polarimeter. Thin layer
chromatography was performed on Merck TLC plates
9j
3-Pyridyl5-Pyrimidine
3-Pyridyl8-Chineol
3-Pyridyl3-Pyridine
3-PyridylPh
17
90 (71)
b
9k
9l
16
71 (65)
19
16
79
79
9m
9n
2-Cl–Bn
5-Pyrimidine
16
57
a Yield in parentheses when Pd(PPh3)4/LiCl/aq Na2CO3 was used as
catalytic system.
b Yields in parentheses when Pd(dppf)Cl2ÆCH2Cl2 was used instead of
Pd(PPh3)2Cl2.

532
S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
silica gel 60 F254. Flash chromatography was carried out
on ICN Biomedicals silica gel (40–63 lm mesh). Analyt-
icalHPLC runs were performed with a Phenomenex
Luna C-18 (2) column (5l, 250 · 4.6 mm) using
MeCN/H2O mixtures.
12.85 (CH3) ppm; MS (ES+): m/z 638.5 [M+H]+, 660.5
[M+Na]+.
4.3.2. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-isopropyl-5,6-dehydro-piperidin-4-one 7b. Puri-
fication by flash chromatography (cyclohexane/ethyl ace-
tate (3:1)); yield: 84%; yellow amorphous solid; Rf = 0.19
4.2. Materials
22
D
(cyclohexane/ethyl acetate (2:1)); Lit.:9 ½aŠ ¼ ꢀ69:8 (c
1.0, CHCl3); d.r. 96:4 (analytical HPLC); 1H NMR
THF was distilled over potassium benzophenone ketyl.
Aldehydes used for imine formation were distilled and
stored at 4 ꢂC. Diene 6 was prepared by the procedure
of Danishefsky and Kitahara followed by repeated care-
fuldistailltion at moderate temperature (oilbath tem-
perature has to be kept below 70 ꢂC).25 Schiff bases 5
were prepared according to known procedures for ali-
phatic/benzylic and aromatic aldehydes.16 Pd(PPh3)2Cl2
and Pd(dppf)Cl2ÆCH2Cl2 were purchased from Acros
Organics. THF and aqueous alkaline solutions applied
in Suzuki reactions were degassed in an ultrasonic bath
under argon atmosphere for at least 4 h.
(CDCl3, 200 MHz): d = 7.00 (d, 1H, 3J = 7.8 Hz,
3
NCH@CH); 5.56 (t, 1H, J = 9.8 Hz, H-2); 5.42 (d, 1H,
3J = 2.9 Hz, H-4); 5.16 (dd, 1H, 3J = 2.9, 3J = 9.8 Hz,
H-3); 4.95 (d, 1H, 3J = 7.3 Hz, NCH@CH); 4.60 (d,
1H, 3J = 8.8 Hz, H-1); 4.16 (dd, 1H, 3J = 5.4, 2J =
8.8 Hz, H-6a); 4.05–3.91 (m, 2H, H-5, H-6a); 3.58–3.49
(m, 1H, CHN); 2.60 (dd, 1H, 3J = 7.3, 2J = 17.0 Hz,
CH2C@O); 2.41 (dd, 1H, 3J = 6.5, 2J = 17.0 Hz,
CH2C@O); 2.36–2.19 (m, 1H, CH(CH3)2); 1.27, 1.16,
3
1.11, 1.10 (4s, 36H, PivCH3); 0.91 (d, 6H, J = 6.8 Hz,
CH3) ppm; 13C NMR (CDCl3, 100.6 MHz): d = 192.48
(C@O); 177.72, 177.13, 176.98, 176.48 (PivC@O);
149.94 (NCH@CH); 100.58 (NCH@CH); 90.98 (C-1);
72.78, 71.61, 66.56, 65.59 (C-2, C-3, C-4, C-5); 60.95
(C-6); 58.93 (CHN); 39.03, 38.87, 38.72, 38.65 (PivCMe3);
35.71 (CH2C@O); 31.76 (CH(CH3)2); 27.10, 27.08, 26.98
(PivCH3); 19.63, 17.71 (CH3) ppm; MS (ES+): m/z 536.7
[MꢀPivOH+H]+, 558.7 [MꢀPivOH+Na]+, 638.6
[M+H]+, 660.6 [M+Na]+.
4.3. General procedure for the synthesis of N-galactosyl
dehydropiperidinones 7
To a solution of glycosyl imine 5 (10 mmol) in dry THF
(50 mL), a solution of ZnCl2 (1 M in THF/CH2Cl2 (1:1),
11 mL) was added at ꢀ78 ꢂC and stirred for 10 min.
Danishefskyꢀs diene 6 (2.5 mL, 12.5 mmol) was added,
and after stirring for 30 min the mixture was allowed
to warm up to ꢀ20 ꢂC. The reaction was terminated
by the addition of 1 M HCl(10 mL) after complete con-
sumption of the starting material(TLC monitoring, 1–
2 d). THF was evaporated in vacuo, diethylether
(200 mL) was added and the layers were separated.
The organic layer was washed with saturated aq NaH-
CO3 (2 · 50 mL), 10% aq TitriplexꢁIII (50 mL), and
brine (50 mL), dried over MgSO4 and concentrated.
4.3.3. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(4-chlorophenyl)-5,6-dehydro-piperidin-4-one 7c.
Purification by flash chromatography (cyclohexane/
ethyl acetate (2:1)); yield: 89%; yellow amorphous solid;
22
Rf = 0.27 (cyclohexane/ethyl acetate (2:1)); ½aŠ ¼ þ15:6
D
1
(c 1.0, CHCl3); d.r. 98:2 (analytical HPLC); H NMR
(CDCl3, 200 MHz): d = 7.31–7.20 (m, 5H, Ar,
NCH@CH); 5.56 (t, 1H, 3J = 9.4 Hz, H-2); 5.31 (d,
1H, 3J = 2.9 Hz, H-4); 5.20 (d, 1H, 3J = 7.8 Hz,
3
3
NCH@CH); 5.01 (dd, 1H, J = 3.2, J = 10.0 Hz, H-3);
4.3.1. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-5,6-dehydro-piperidin-4-one 7a. Puri-
fication by flash chromatography (petroleum ether/ethyl
acetate (3:1)); yield: 96%; orange amorphous solid;
3
3
4.80 (dd, 1H, J = 5.9, J = 8.3 Hz, CHN); 4.34 (d, 1H,
3J = 9.3 Hz, H-1); 3.93–3.70 (m, 3H, H-5, H-6a, H-6b);
2.77 (dd, 1H, 3J = 5.9, 2J = 16.6 Hz, CH2C@O);
3
2
2.62 (dd, 1H, J = 8.8, J = 16.6 Hz, CH2C@O); 1.23,
1.15, 1.14, 1.08 (4s, 36H, PivCH3) ppm; 13C NMR
(CDCl3, 50.3 MHz): d = 191.17 (C@O); 177.72, 177.34,
177.07, 176.44 (PivC@O); 149.74 (NCH@CH); 137.28,
134.38 (ipso-aryl); 128.47, 129.09 (aryl); 103.26
(NCH@CH); 88.72 (C-1); 72.76, 71.39, 66.63, 65.24
(C-2, C-3, C-4, C-5); 61.01 (C-6); 59.05 (CHN); 43.57
(CH2C@O); 39.07, 38.94, 38.78, 38.69 (PivCMe3);
27.05, 27.18 (PivCH3) ppm; MS (ES+): m/z 706.5
[M+H]+, 728.5 [M+Na]+; elemental analysis: calcd (%)
for C37H52ClNO10 (706.26): C 62.92, H 7.42, N 1.98;
found: C 62.86, H 7.45, N 1.95.
Rf = 0.18 (petroleum ether/ethyl acetate (3:1)); Lit.:9
22
D
½aŠ ¼ ꢀ73:5 (c 1.0, CHCl3); d.r. 3:97 (analytical HPLC);
1H NMR (CD3OD, 400 MHz): d = 7.30 (d, 1H,
3J = 7.4 Hz, NCH@CH); 5.53 (t, 1H, J = 9.0 Hz, H-2);
5.47 (d, 1H, J = 3.1 Hz, H-4); 5.33 (dd, 1H, J = 3.1,
3
3
3
3J = 10.2 Hz, H-3); 5.01 (d, 1H, J = 9.0 Hz, H-1); 4.90
3
3
(d, 1H, J = 7.4 Hz, NCH@CH); 4.31–4.20 (m, 2H, H-
5, H-6b); 4.00 (dd, 1H, 3J = 6.2, 2J = 10.6 Hz, H-6a);
3.83–3.80 (m, 1H, CHN); 2.64 (dd, 1H, 3J = 6.4,
2J = 16.6 Hz, CH2C@O); 2.32 (d, 1H, 2J = 16.8 Hz,
CH2C@O); 1.91–1.87 (m, 1H, CH2); 1.71–1.68 (m, 1H,
CH2); 1.41–1.38 (m, 1H, CH2); 1.33–1.21 (m, 10H,
PivCH3, CH2); 1.17, 1.14, 1.12 (3s, 27H, PivCH3); 0.94
(t, 3H, 3J = 7.4 Hz, CH3) ppm; 13C NMR (CDCl3,
100.6 MHz): d = 193.31 (C@O); 177.56, 177.23, 176.87,
4.3.4. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(3-pyridyl)-5,6-dehydro-piperidin-4-one 7d. Puri-
fication by flash chromatography (cyclohexane/ethyl ace-
176.56
(PivC@O);
152.57
(NCH@CH);
97.76
(NCH@CH); 90.83 (C-1); 72.56, 71.28, 66.91, 66.22 (C-
2, C-3, C-4, C-5); 60.70 (C-6); 52.37 (CHN); 38.71,
38.54, 38.37, 38.31 (PivCMe3); 37.93 (CH2C@O); 32.40
(CH2); 26.24, 26.21, 26.16, 26.04 (PivCH3); 18.60 (CH2);
tate (1:1)); yield: 63%; yellowish amorphous solid;
Rf = 0.10 (cyclohexane/ethyl acetate (1:1)); Lit.:9 ½aŠ
22
D
¼
1
þ19:6 (c 3.0, CHCl3); d.r. 97:3 (analytical HPLC); H
NMR (CDCl3, 300 MHz): d = 8.56 (s, 1H, aryl); 8.54 (d,

S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
533
1H, 3J = 4.8 Hz, aryl); 7.72 (d, 1H, 3J = 8.1 Hz, aryl); 7.29
(dd, 1H, 3J = 5.0, 3J = 7.9 Hz, aryl ); 7.21 (d, 1H,
NCH@CH); 5.52 (t, 1H, 3J = 9.7 Hz, H-2); 5.47 (d,
1H, 3J = 2.6 Hz, H-4); 5.20 (dd, 1H, 3J = 3.3, 3J =
10.3 Hz, H-3); 5.09 (d, 1H, 3J = 7.7 Hz, NCH@CH);
4.61 (d, 1H, 3J = 9.2 Hz, H-1); 4.24–4.16 (m, 1H,
3
3J = 8.1 Hz, NCH@CH); 5.56 (t, 1H, J = 9.7 Hz, H-2);
5.32 (d, 1H, J = 2.9 Hz, H-4); 5.16 (d, 1H, J = 7.8 Hz,
3
3
NCH@CH); 5.09 (dd, 1H, 3J = 2.9, 3J = 9.9 Hz, H-3);
4.94 (t, 1H, J = 5.9, CHN); 4.52 (d, 1H, J = 9.2 Hz, H-
CHN); 4.13 (dd, 1H, J = 5.9, J = 9.9 Hz, H-6a); 4.06
3
2
3
3
3
3
2
(t, 1H, J = 6.6 Hz, H-5); 3.96 (dd, 1H, J = 6.6, J =
9.9 Hz, H-6b); 3.23 (dd, 1H, 3J = 5.2, 2J = 13.2 Hz,
CH2–BrPh); 3.14 (dd, 1H, 3J = 10.3, 2J = 13.2 Hz,
CH2–BrPh); 2.48 (dd, 1H, 3J = 7.0, 2J = 17.3 Hz,
3
3
1); 3.85 (t, 1H, J = 6.6 Hz, H-5); 3.77 (dd, 1H, J = 6.4,
3
2
2J = 10.8 Hz, H-6a); 3.68 (dd, 1H, J = 7.4, J = 11.0 Hz,
3
2
H-6b); 2.96 (dd, 1H, J = 6.6, J = 16.5 Hz, CH2C@O);
2.59 (dd, 1H, 3J = 5.1, 2J = 16.5 Hz, CH2C@O); 1.22,
1.14, 1.10, 1.08 (4s, 36H, PivCH3) ppm; 13C NMR
(CDCl3, 75.5 MHz): d = 190.36 (C@O); 177.58, 177.20,
176.99, 176.34 (PivC@O); 150.18 (NCH@CH); 149.52,
148.36 (aryl); 135.16 (ipso-aryl); 134.09, 123.26 (aryl);
102.48 (NCH@CH); 90.16 (C-1); 72.73, 71.04, 66.38,
65.39 (C-2, C-3, C-4, C-5); 60.65 (C-6); 55.90 (CHN);
42.97 (CH2C@O); 38.99, 38.93, 38.73, 38.60 (PivCMe3);
27.14, 26.99, 26.96 (PivCH3) ppm; MS (ES+): m/z 673.4
[M+H]+, 695.3 [M+Na]+, 736.4 [M+CH3CN+Na]+;
HRMS: calcd for C36H53N2O10 (M+H): 673.3700; found:
673.3704.
2
CH2C@O); 2.11 (d, 1H, J = 16.9 Hz, CH2C@O); 1.29,
1.25, 1.10, 1.09 (4s, 36H, PivCH3) ppm; 13C NMR
(CDCl3, 75.5 MHz): d = 191.66 (C@O); 177.75, 177.11,
176.96, 176.66 (PivC@O); 148.96 (NCH@CH); 136.53
(ipso-aryl); 132.89, 132.50, 128.61, 127.64 (aryl); 124.78
(ipso-CBr); 100.62 (NCH@CH); 91.66 (C-1); 73.27,
71.29, 66.41, 66.10 (C-2, C-3, C-4, C-5); 60.77 (C-6);
52.42 (CHN); 39.05, 38.91, 38.76, 38.67 (PivCMe3);
38.20 (CH2C@O); 36.55 (CH2–BrPh); 27.25, 27.16,
27.07, 27.02 (PivCH3) ppm; MS (ES+): m/z 764.2
[M(79Br)+H]+, 766.2 [M(81Br)+H]+, 786.3 [M(79Br)+
Na]+, 788.3 [M(81Br)+Na]+, 827.4 [M(79Br)+CH3CN+
Na]+, 829.4 [M(81Br)+CH3CN+Na]+; HRMS: calcd
for C38H54BrNNaO10 (M+Na): 786.2829; found:
786.2806.
4.3.5. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-chlorobenzyl)-5,6-dehydro-piperidin-4-one 7e.
Purification by flash chromatography (cyclohexane/
ethyl acetate (2:1)); yield: 53%; yellowish amorphous
4.3.7. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-iodobenzyl)-5,6-dehydro-piperidin-4-one 7g.
Purification by flash chromatography (cyclohexane/
solid; Rf = 0.13 (cyclohexane/ethyl acetate (2:1));
22
½aŠ ¼ ꢀ10:2 (c 1.0, CHCl3); d.r. 10:90 (analytical
D
HPLC); 1H NMR (CDCl3, 300 MHz): d = 7.35–7.30
(m, 1H, aryl); 7.19–7.16 (m, 1H, aryl); 7.12–7.09 (m,
1H, aryl); 6.95 (dd, 1H, 4J = 0.7, 3J = 7.7 Hz,
NCH@CH); 5.51 (t, 1H, 3J = 9.5 Hz, H-2); 5.47 (d,
1H, 3J = 3.3 Hz, H-4); 5.20 (dd, 1H, 3J = 3.3,
3J = 10.3 Hz, H-3); 5.08 (d, 1H, 3J = 7.7 Hz,
ethyl acetate (2:1)); yield: 32%; yellow amorphous solid;
22
D
Rf = 0.13 (cyclohexane/ethyl acetate (2:1)); ½aŠ ¼ ꢀ0:8
(c 1.0, CHCl3); d.r. 5:95 (analytical HPLC); 1H
NMR (CDCl3, 400 MHz): d = 7.80 (d, 1H, 3J = 7.8
Hz, aryl); 7.26 (t, 1H, J = 7.4 Hz, aryl); 7.10 (dd, 1H,
3
4J = 1.4, 3J = 7.6 Hz, aryl); 6.97 (d, 1H, 3J = 7.4 Hz,
3
NCH@CH); 4.60 (d, 1H, J = 9.2 Hz, H-1); 4.22–4.17
4
3
NCH@CH); 6.92 (dt, 1H, J = 1.4, J = 7.6 Hz, aryl);
5.53 (t, 1H, J = 9.8 Hz, H-2); 5.45 (d, 1H, J = 3.1 Hz,
(m, 1H, CHN); 4.16 (dd, 1H, 3J = 6.1, 2J = 10.1 Hz,
H-6a); 4.07 (t, 1H, 3J = 6.4 Hz, H-5); 3.98 (dd, 1H,
3J = 7.0, 2J = 9.9 Hz, H-6b); 3.26 (dd, 1H, 3J = 4.8,
2J = 13.2 Hz, CH2–ClPh); 3.12 (dd, 1H, 3J = 10.7,
2J = 13.2 Hz, CH2–ClPh); 2.46 (dd, 1H, 3J = 6.3,
2J = 16.9 Hz, CH2C@O); 2.10 (d, 1H, 2J = 16.9 Hz,
CH2C@O); 1.29, 1.15, 1.10, 1.09 (4s, 36H, PivCH3)
ppm; 13C NMR (CDCl3, 75.5 MHz): d = 191.65
(C@O); 177.75, 177.09, 176.96, 176.69 (PivC@O);
149.17 (NCH@CH); 134.78, 134.29 (ipso-aryl); 132.53,
129.57, 128.37, 127.04 (aryl); 100.51 (NCH@CH);
91.86 (C-1); 73.27, 71.23, 66.41, 66.13 (C-2, C-3, C-4,
C-5); 60.78 (C-6); 52.12 (CHN); 39.05, 38.90, 38.76,
38.67 (PivCMe3); 38.17 (CH2C@O); 34.30 (CH2–ClPh);
27.19, 27.16, 27.05, 27.01 (PivCH3) ppm; MS (ES+): m/z
3
3
H-4); 5.19 (dd, 1H, 3J = 3.3, 10.0 Hz, H-3); 5.11 (d,
3
3
1H, J = 7.4 Hz, NCH@CH); 4.67 (d, 1H, J = 9.0 Hz,
H-1); 4.18–4.12 (m, 1H, CHN); 4.11–4.03 (m, 2H, H-5,
3
2
H-6a); 3.94 (dd, 1H, J = 6.3, J = 9.8 Hz, H-6b); 3.16
3
3
(d, 2H, J = 8.6 Hz, CH2–IPh); 2.52 (dd, 1H, J = 6.7,
2J = 16.8 Hz, CH2C@O); 2.14 (d, 1H, 2J = 16.8 Hz,
CH2C@O); 1.28, 1.15, 1.11, 1.05 (4s, 36H, PivCH3)
ppm; 13C NMR (CDCl3, 75.5 MHz): d = 191.59
(C@O); 177.76, 177.17, 176.99, 176.61 (PivC@O);
148.32 (NCH@CH); 139.93 (ipso-aryl); 139.65, 131.52,
128.75, 128.49 (aryl); 100.90 (ipso-CI); 100.86
(NCH@CH); 91.18 (C-1); 73.26, 71.49, 66.44, 65.99
(C-2, C-3, C-4, C-5); 60.80 (C-6); 53.25 (CHN); 40.73
(CH2C@O); 39.09, 38.94, 38.79, 38.70 (PivCMe3);
38.30 (CH2–ClPh); 27.32, 27.19, 27.08, 27.04 (PivCH3)
ppm; MS (ES+): m/z 812.6 [M+H]+, 834.6 [M+Na]+,
875.5 [M+CH3CN+Na]+; HRMS: calcd for C38H54IN-
NaO10 (M+Na): 834.2690; found: 834.2684.
720.4
[M+H]+,
742.4
[M+Na]+,
783.5
[M+CH3CN+Na]+; HRMS: calcd for C38H55ClNO10
(M+H): 720.3515; found: 720.3510.
4.3.6. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-bromobenzyl)-5,6-dehydro-piperidin-4-one 7f.
Purification by flash chromatography (cyclohexane/
ethyl acetate (2:1)); yield: 70%; yellowish amorphous
4.4. General procedure for the conjugated hydride addi-
tion and subsequent formation of the enol triflates 8
solid; Rf = 0.15 (cyclohexane/ethyl acetate (2:1));
22
D
½aŠ ¼ ꢀ5:0 (c 1.0, CHCl3); d.r. 6:94 (analytical
To a solution of enone 7 (1.0 mmol) and N,N-bis(tri-
fluoromethanesulfonyl)aniline (1.1 mmol) in dry THF
(20 mL), a 1 M solution of L-Selectrideꢁ in THF
(1.1 mmol) was added dropwise at ꢀ78 ꢂC. After 1 h,
1
HPLC); H NMR (CDCl3, 300 MHz): d = 7.52 (d, 1H,
3J = 8.1 Hz, aryl); 7.23 (dt, 1H, 3J = 1.1, 3J = 7.4 Hz,
aryl); 7.12–7.06 (m, 2H, aryl); 6.95 (d, 1H, J = 7.7 Hz,
3

534
S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
the solution was allowed to warm up to ambient temper-
ature and stirred for another hour. The solvent was
evaporated in vacuo; the residue was dissolved in diethyl
ether (25 mL), washed with brine (10 mL), dried over
MgSO4 and concentrated in vacuo to give crude 8 which
was further purified.
HRMS: calcd for C35H56F3NNaO12S (M+Na):
794.3373; found: 794.3398.
4.4.3. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(4-chlorophenyl)-4-(trifluoro-methanesulfonyl-
oxy)-4,5-dehydro-piperidine 8c. Purification by flash
chromatography (cyclohexane/ethyl acetate (10:1));
yield: 72%; colourless amorphous solid; Rf = 0.56 (cyclo-
4.4.1. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-4-(trifluoro-methanesulfonyloxy)-4,5-
dehydro-piperidine 8a. Purification by flash chromato-
graphy (cyclohexane/ethyl acetate (10:1)); yield: 75%;
22
D
hexane/ethylacetate (2:1)); ½aŠ ¼ ꢀ13:4 (c 1.0, CHCl3);
1H NMR (CDCl3, 400 MHz): d = 7.35 (d, 2H,
3
3J = 8.6 Hz, aryl); 7.21 (d, 2H, J = 8.6 Hz, aryl); 5.82
3
(br s, 1H, CH@COTf); 5.42 (t, 1H, J = 9.8 Hz, H-2);
5.24 (d, 1H, J = 2.8 Hz, H-4); 4.84 (dd, 1H, J = 2.9,
colourless oil; Rf = 0.62 (cyclohexane/ethyl acetate
3
3
22
(2:1)); ½aŠ ¼ ꢀ10:5 (c = 1.0, CHCl3); 1H NMR (CDCl3,
3
3
3J = 9.9 Hz, H-3); 4.04 (dd, 1H, J = 3.9, J = 9.8 Hz,
D
300 MHz): d = 5.67 (br s, 1H, CH@COTf); 5.38–5.32
3
2
CHN); 3.99 (dd, 1H, J = 6.6, J = 11.4 Hz, H-6a); 3.88
(dd, 1H, 3J = 6.6, 2J = 11.3 Hz, H-6b); 3.82 (d,
1H, 3J = 9.4 Hz, H-1); 3.75 (dd, 1H, 3J = 1.9,
2J = 16.8 Hz, NCH2); 3.67 (dd, 1H, 3J = 1.9,
2J = 16.8 Hz, NCH2); 3.42 (t, 1H, 3J = 6.8 Hz, H-5);
(m, 2H, H-2, H-4); 5.10 (dd, 1H, 3J = 3.1, 3J =
3
10.1 Hz, H-3); 4.20 (d, 1H, J = 9.2 Hz, H-1); 4.05 (dd,
1H, 3J = 6.1, 2J = 10.5 Hz, H-6a); 3.92–3.82 (m, 2H,
H-5, H-6b); 3.57 (dd, 1H, 3J = 2.6, 2J = 17.6 Hz,
NCH2); 3.41 (d, 1H, 2J = 16.9 Hz, NCH2); 3.16–3.14
(m, 1H, CHN); 2.56 (dd, 1H, 3J = 2.6, 2J = 16.5 Hz,
CHCH2); 2.04 (d, 1H, 2J = 16.5 Hz, CHCH2); 1.64–
1.50 (m, 1H, CH2); 1.40–1.26 (m, 3H, CH2); 1.23,
1.14, 1.10, 1.08 (4s, 36H, PivCH3); 0.88 (t, 3H, 3J =
7.0 Hz, CH3) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 177.82, 177.18, 177.11, 176.66 (PivC@O); 146.58
(CH@COTf); 116.18 (CH@COTf); 92.56 (C-1); 71.80,
67.09, 65.41 (C-2, C-3, C-4, C-5); 61.48 (C-6); 55.37
(CHN); 41.71 (NCH2); 39.00, 38.70, 38.66 (PivCMe3);
33.61 (CHCH2); 32.74 (CH2); 27.13, 27.02 (PivCH3);
19.89 (CH2); 14.08 (CH3) ppm; MS (ES+): m/z 622.7
[MꢀOTf]+, 670.6 [MꢀPivOH+H]+, 772.7 [M+H]+,
794.6 [M+Na]+, 835.7 [M+CH3CN+Na]+; HRMS:
calcd for C35H56F3NNaO12S (M+Na): 794.3373; found:
794.3386.
2
2.74–2.68 (m, 1H, CHCH2); 2.43 (d, 1H, J = 16.8 Hz,
CHCH2); 1.23, 1.17, 1.16, 1.06 (4s, 36H, PivCH3)
ppm; 13C NMR (CDCl3, 100.6 MHz): d = 177.85,
177.20, 177.12, 176.52 (PivC@O); 145.04 (CH@COTf);
137.49, 134.48 (ipso-aryl); 129.63, 129.21 (aryl); 116.16
(CH@COTf); 87.57 (C-1); 71.80 (C-3); 71.61 (C-5);
67.18 (C-4); 64.79 (C-2); 61.59 (C-6); 60.00 (CHN);
41.61 (NCH2); 39.03, 38.76, 38.69 (PivCMe3); 36.32
(CHCH2); 27.17, 27.13, 27.10, 27.01 (PivCH3) ppm;
MS
(ES+):
m/z
690.5
[MꢀOTf]+,
738.4
[MꢀPivOH+H]+, 840.4 [M+H]+, 862.4 [M+Na]+,
903.5
[M+CH3CN+Na]+;
HRMS:
calcd
for
C38H53ClF3NNaO12S (M+Na): 862.2827; found:
862.2819.2
4.4.4. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(3-pyridyl)-4-(trifluoro-methanesulfonyloxy)-4,
5-dehydro-piperidine 8d. Purification by flash chroma-
tography (cyclohexane/ethyl acetate (2:1)); yield: 84%;
4.4.2. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-isopropyl-4-(trifluoro-methanesulfonyloxy)-4,5-
dehydro-piperidine 8b. Purification by flash chromato-
graphy (cyclohexane/ethyl acetate (4:1)); yield: 76%; col-
colourless amorphous solid; Rf = 0.25 (cyclohexane/
22
D
ethylacetate (2:1)); ½aŠ ¼ ꢀ12:7 (c 1.0, CHCl3); 1H
ourless oil; Rf = 0.59 (cyclohexane/ethyl acetate (2:1));
22
½aŠ ¼ ꢀ5:8 (c 1.0, CHCl3); 1H NMR (CDCl3,
NMR (CDCl3, 400 MHz): d = 8.62 (dd, 1H, 4J = 1.2,
D
4
3J = 4.7 Hz, aryl); 8.55 (d, 1H, J = 1.6 Hz, aryl); 7.61
400 MHz): d = 5.67 (br s, 1H, CH@COTf); 5.38 (t,
1H, J = 9.4 Hz, H-2); 5.34 (d, 1H, J = 3.1 Hz, H-4);
3
3
(dd, 1H, 4J = 1.6, 3J = 7.8 Hz, aryl); 7.34 (dd, 1H,
3
5.10 (dd, 1H, J = 3.1, J = 9.8 Hz, H-3); 4.24 (d, 1H,
3
3
3J = 4.9, J = 8.0 Hz, aryl); 5.85 (br s, 1H, CH@COTf);
3
2
3J = 9.4 Hz, H-1); 3.99 (dd, 1H, J = 7.0, J = 11.3 Hz,
3
3
5.44 (t, 1H, J = 9.6 Hz, H-2); 5.25 (d, 1H, J = 2.7 Hz,
H-4); 4.86 (dd, 1H, 3J = 3.1, 3J = 9.8 Hz, H-3); 4.15
(dd, 1H, 3J = 4.1, 3J = 9.2 Hz, CHN); 3.96 (dd, 1H,
3J = 6.4, 2J = 11.2 Hz, H-6a); 3.91 (dd, 1H, 3J =
3
2
H-6a); 3.92 (dd, 1H, J = 6.3, J = 11.3 Hz, H-6b); 3.85
(t, 1H, 3J = 6.6 Hz, H-5); 3.59 (d, 1H, 2J = 17.9 Hz,
NCH2); 3.41 (dd, 1H, 3J = 2.7, 2J = 18.4 Hz, NCH2);
2.67 (m, 1H, CHN); 2.55 (dd, 1H, 3J = 2.7,
2J = 16.4 Hz, CHCH2); 2.27 (d, 1H, 2J = 17.2 Hz,
CHCH2); 1.89–1.77 (m, 1H, CH(CH3)2); 1.23, 1.15,
2
3
7.0, J = 11.0 Hz, H-6b); 3.83 (d, 1H, J = 9.4 Hz, H-1);
3.79–3.66 (m, 2H, NCH2); 3.44 (t, 1H, J = 6.8 Hz, H-
3
5); 2.77–2.71 (m, 1H, CHCH2); 2.51 (d, 1H,
2J = 16.4 Hz, CHCH2); 1.23, 1.17, 1.16, 1.06 (4s, 34H,
PivCH3) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 177.81, 177.24, 177.12, 176.49 (PivC@O); 149.91,
149.76 (aryl); 144.88 (CH@COTf); 135.69 (aryl);
134.74 (ipso-aryl); 123.86 (aryl); 116.36 (CH@COTf);
88.13 (C-1); 71.70, 67.01, 64.81 (C-2, C-3, C-4, C-5);
61.36 (C-6); 58.07 (CHN); 41.76 (NCH2); 39.02, 38.78,
38.69, 38.66 (PivCMe3); 35.86 (CHCH2); 27.16, 27.10,
27.08, 26.99 (PivCH3) ppm; MS (ES+): m/z 657.6
[MꢀOTf]+, 705.4 [MꢀPivOH+H]+, 807.6 [M+H]+,
829.6 [M+Na]+, 870.5 [M+CH3CN+Na]+; HRMS:
3
1.11, 1.09 (4s, 36H, PivCH3); 0.90 (d, 3H, J = 3.1 Hz,
3
CH3); 0.88 (d, 3H, J = 3.1 Hz, CH3) ppm; 13C NMR
(CDCl3, 100.6 MHz): d = 177.48, 177.28, 176.87,
176.65 (PivC@O); 146.55 (CH@COTf); 116.43
(CH@COTf); 92.41 (C-1); 72.06 (C-3); 71.68 (C-5);
67.11 (C-4); 65.75 (C-2); 64.44 (CHN); 61.73 (C-6);
39.75 (NCH2); 39.01, 38.72, 38.70 (PivCMe3); 28.85
(CHCH2); 27.74 (CH(CH3)2); 27.17, 27.14, 27.04
(PivCH3); 20.72, 18.93 (CH3) ppm; MS (ES+): m/z
622.7 [MꢀOTf]+, 670.7 [MꢀPivOH+H]+, 772.7
[M+H]+, 794.7 [M+Na]+, 835.8 [M+CH3CN+Na]+;

S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
535
calcd for C37H53F3N2NaO12S (M+Na): 829.3169;
found: 829.3160.
for C39H55BrF3NNaO12S (M+Na): 920.2478; found:
920.2499.
4.4.7. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-iodobenzyl)-4-(trifluoro-methanesulfonyloxy)-
4,5-dehydro-piperidine 8g. Purification by flash chro-
matography (cyclohexane/ethyl acetate (2:1)); yield:
82%; yellowish amorphous solid; Rf = 0.66 (cyclohex-
4.4.5. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-chlorobenzyl)-4-(trifluoro-methanesulfonyl-
oxy)-4,5-dehydro-piperidine 8e. Purification by flash
chromatography (cyclohexane/ethyl acetate (5:1)); yield:
66%; yellow amorphous solid; Rf = 0.56 (cyclohexane/
22
1
ane/ethylacetate (2:1)); ½aŠ ¼ þ8:5 (c 1.0, CHCl3); H
22
D
ethylacetate (2:1)); ½aŠ ¼ þ10:5 (c 1.0, CHCl3); 1H
D
NMR (CDCl3, 300 MHz): d = 7.81 (d, 1H, 3J =
7.7 Hz, aryl); 7.40–7.34 (m, 1H, aryl); 7.27 (d, 1H,
3J = 8.3 Hz, aryl); 6.90 (dt, 1H, 4J = 2.2, 3J = 7.6 Hz,
aryl); 5.79 (br s, 1H, CH@COTf); 5.45–5.39 (m, 2H,
NMR (CDCl3, 300 MHz): d = 7.36–7.33 (m, 1H, aryl);
7.20–7.15 (m, 3H, aryl); 5.78 (t, 1H, 3J = 2.2 Hz,
CH@COTf); 5.44–5.37 (m, 2H, H-2, H-4); 5.16 (dd,
1H, 3J = 3.3, 3J = 10.3 Hz, H-3); 4.26 (d, 1H,
3
3
H-2, H-4); 5.16 (dd, 1H, J = 3.1, J = 10.1 Hz, H-3);
3
2
3J = 9.2 Hz, H-1); 4.08 (dd, 1H, J = 6.4, J = 10.8 Hz,
3
3
4.29 (d, 1H, J = 9.2 Hz, H-1); 4.05 (dd, 1H, J = 6.4,
2J = 10.8 Hz, H-6a); 3.92 (dd, 1H, 3J = 7.5,
2J = 10.9 Hz, H-6b); 3.83 (t, 1H, 3J = 6.8 Hz, H-5);
3.78 (d, 1H, 2J = 17.4 Hz, NCH2); 3.70–3.66 (m, 1H,
3
H-6a); 3.94 (dd, 1H, J = 7.4, J = 10.7 Hz, H-6b); 3.87
2
(t, 1H, 3J = 6.8 Hz, H-5); 3.78–3.68 (m, 2H, CHN,
NCH2); 3.48 (br d, 1H, J = 16.9 Hz, NCH2); 3.09 (dd,
2
1H, 3J = 3.5, 2J = 13.0 Hz, CH2–ClPh); 2.91 (dd, 1H,
2
CHN); 3.51 (br d, 1H, J = 17.3 Hz, NCH2); 3.08 (dd,
1H, 3J = 3.7, 2J = 13.6 Hz, CH2–IPh); 2.92 (dd, 1H,
3J = 11.0, J = 13.2 Hz, CH2–ClPh); 2.45–2.37 (m, 1H,
2
CHCH2); 1.96 (d, 1H, 2J = 16.9 Hz, CHCH2); 1.27,
1.14, 1.12, 1.10 (4s, 36H, PivCH3) ppm; 13C NMR
(CDCl3, 75.5 MHz): d = 177.81, 177.18, 177.14, 176.69
(PivC@O); 146.39 (CH@COTf); 136.49, 134.26 (ipso-
aryl); 131.40, 129.76, 128.03, 126.99 (aryl); 115.91
(CH@COTf); 93.40 (C-1); 72.16, 71.65, 67.03, 65.33
(C-2, C-3, C-4, C-5); 61.27 (C-6); 54.34 (CHN); 43.00
(NCH2); 39.02, 38.72, 38.66 (PivCMe3); 34.92 (CH2–
ClPh); 30.99 (CHCH2); 27.20, 27.17, 27.04, 26.99
(PivCH3) ppm; MS (ES+): m/z 704.5 [MꢀOTf]+, 854.6
[M+H]+, 876.6 [M+Na]+; HRMS: calcd for
C39H56ClF3NO12S (M+H): 854.3164; found: 854.3163.
2
3
3J = 10.7, J = 13.6 Hz, CH2–IPh); 2.41 (dd, 1H, J =
2
2
2.2, J = 16.5 Hz, CHCH2); 1.98 (d, 1H, J = 16.2 Hz,
CHCH2); 1.25, 1.14, 1.13, 1.10 (4s, 36H, PivCH3) ppm;
13C NMR (CDCl3, 75.5 MHz): d = 177.85, 177.27,
177.21, 176.64 (PivC@O); 146.37 (CH@COTf); 141.51
(ipso-aryl); 139.86, 130.33, 129.54, 128.49 (aryl); 116.03
(CH@COTf); 101.19 (ipso-CI); 93.09 (C-1); 72.01,
71.70, 67.01, 65.30 (C-2, C-3, C-4, C-5); 61.30 (C-6);
55.39 (CHN); 42.72 (NCH2); 41.86 (CHCH2); 39.03,
38.73, 38.70, 38.67 (PivCMe3); 31.11 (CH2–IPh); 27.17,
27.04 (PivCH3) ppm; MS (ES+): m/z 946.4 [M+H]+,
968.3 [M+Na]+; HRMS: calcd for C39H55F3INNaO12S
(M+Na): 834.2690; found: 834.2704.
4.4.6. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(2-bromobenzyl)-4-(trifluoro-methanesulfonyl-
oxy)-4,5-dehydro-piperidine 8f. Purification by flash
chromatography (cyclohexane/ethyl acetate (2:1)); yield:
78%; yellowish amorphous solid; Rf = 0.57 (cyclohex-
4.5. General procedure for the palladium-catalysed
Suzuki reactions
A two-necked round bottom flask provided with a sep-
tum and a reflux condenser was charged with enoltri-
22
1
ane/ethylacetate (2:1)); ½aŠ ¼ þ9:2 (c 1.0, CHCl3); H
D
NMR (CDCl3, 400 MHz): d = 7.52 (d, 1H,
3J = 7.8 Hz, aryl); 7.24–7.22 (m, 2H, aryl); 7.11–7.05
(m, 1H, aryl); 5.78 (t, 1H, 3J = 1.8 Hz, CH@COTf);
5.43–5.38 (m, 2H, H-2, H-4); 5.16 (dd, 1H, 3J = 3.1,
flate
8
(1 mmol), boronic acid (2 mmol) and
Pd(PPh3)2Cl2 (5 mol%), evaporated and flushed with
argon. Degassed THF (10 mL) and 2 M aq Cs2CO3
(5 mmol) were added by syringe and the suspension
heated to reflux. After completed reaction (TLC moni-
toring), the accumulated colloidal palladium was filtered
off (hyflo gel), the solvent evaporated in vacuo and the
residue, dissolved in diethyl ether (50 mL), washed with
water (10 mL) and brine (5 mL). Drying over MgCO3
and concentration in vacuo gave the crude products 9.
3
3J = 10.2 Hz, H-3); 4.27 (d, 1H, J = 9.4 Hz, H-1); 4.06
(dd, 1H, 3J = 6.3, 2J = 10.9 Hz, H-6a); 3.93 (dd, 1H,
2
3
3J = 7.4, J = 11.0 Hz, H-6b); 3.85 (t, 1H, J = 6.8 Hz,
H-5); 3.79 (br d, 1H, J = 17.6 Hz, NCH2); 3.71–3.68
2
2
(m, 1H, CHN); 3.50 (br d, 1H, J = 17.6 Hz, NCH2);
3
3.08 (dd, 1H, J = 3.7, J = 13.1 Hz, CH2–BrPh); 2.93
2
3
2
(dd, 1H, J = 10.8, J = 13.1 Hz, CH2–BrPh); 2.40 (br
d, 1H, 2J = 15.7 Hz, CHCH2); 1.97 (d, 1H, 2J =
16.8 Hz, CHCH2); 1.26, 1.14, 1.11, 1.10 (4s,
36H, PivCH3) ppm; 13C NMR (CDCl3, 75.5 MHz): d =
177.81, 177.21, 177.14, 176.66 (PivC@O); 146.40
(CH@COTf); 138.21 (ipso-aryl); 133.10, 131.34, 128.25,
127.62 (aryl); 124.85 (ipso-CBr); 115.94 (CH@COTf);
93.31 (C-1); 72.12, 71.65, 67.03, 65.32 (C-2, C-3, C-4,
C-5); 61.24 (C-6); 54.39 (CHN); 42.84 (NCH2); 39.03,
38.72, 38.67 (PivCMe3); 37.34 (CH2–BrPh); 31.01
(CHCH2); 27.26, 27.19, 27.05 (PivCH3) ppm; MS
(ES+): m/z 748.5 [M(79Br)ꢀOTf]+, 750.5 [M(81Br)
ꢀOTf]+, 898.5 [M(79Br)+H]+, 900.4 [M(81Br)+H]+, 920.5
[M(79Br)+Na]+, 922.4 [M(81Br)+Na]+; HRMS: calcd
4.5.1. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-4-(5-pyrimidyl)-4,5-dehydro-piperidine
9a. Purification by flash chromatography (cyclohex-
ane/ethyl acetate (5:1)); yield: 83%; colourless amor-
phous solid; Rf = 0.25 (cyclohexane/ethyl acetate (2:1));
22
½aŠ ¼ ꢀ23:3 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
300 MHz): d = 9.05 (s, 1H, aryl); 8.66 (s, 2H, aryl);
3
6.16 (br s, 1H, CH@CAr); 5.45 (t, 1H, J = 9.6 Hz, H-
2); 5.37 (d, 1H, 3J = 2.9 Hz, H-4); 5.13 (dd, 1H,
3
3
3J = 3.1, J = 10.1 Hz, H-3); 4.31 (d, 1H, J = 9.2 Hz,
3
2
H-1); 4.07 (dd, 1H, J = 5.7, J = 9.8 Hz, H-6a); 3.94–
3.85 (m, 2H, H-5, H-6b); 3.74 (dd, 1H, 3J = 2.6,
2J = 18.4 Hz, NCH2); 3.47 (d, 1H, 2J = 18.8 Hz,

536
S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
NCH2); 3.22–3.17 (m, 1H, CHN); 2.53 (dd, 1H, 3J = 2.5,
2J = 16.3 Hz, CHCH2); 2.17 (d, 1H, 2J = 16.2 Hz,
CHCH2); 1.72–1.58 (m, 1H, CH2); 1.42–1.29 (m, 3H,
CH2); 1.25, 1.14, 1.10, 1.09 (4s, 36H, PivCH3); 0.91 (t,
3H, 3J = 7.0 Hz, CH3) ppm; 13C NMR (CDCl3,
75.5 MHz): d = 177.84, 177.23, 177.08, 176.73
(PivC@O); 157.01, 153.02 (aryl); 134.24 (CH@CAr);
128.43 (ipso-aryl); 125.67 (CH@CAr); 91.87 (C-1);
72.01, 71.76, 67.30, 65.35 (C-2, C-3, C-4, C-5); 61.65
(C-6); 53.70 (CHN); 44.20 (NCH2); 39.03, 38.72, 38.66
(PivCMe3); 33.79 (CHCH2); 31.52 (CH2); 27.17, 27.08,
27.04 (PivCH3); 20.03 (CH2); 14.32 (CH3) ppm; MS
H-3); 4.31 (d, 1H, 3J = 9.2 Hz, H-1); 4.08 (dd, 1H,
2
3J = 5.9, J = 9.9 Hz, H-6a); 3.94–3.84 (m, 2H, H-5, H-
6b); 3.72 (dd, 1H, J = 2.8, J = 17.8 Hz, NCH2); 3.44
3
2
(d, 1H, 2J = 17.4 Hz, NCH2); 3.20–3.16 (m, 1H,
CHN); 2.52 (dd, 1H, J = 2.4, J = 16.4 Hz, CHCH2);
3
2
2
2.18 (d, 1H, J = 17.0 Hz, CHCH2); 1.72–1.59 (m, 1H,
CH2); 1.46–1.30 (m, 3H, CH2); 1.25, 1.14, 1.10, 1.09
(4s, 36H, PivCH3); 0.90 (t, 3H, 3J = 7.0 Hz, CH3)
ppm; 13C NMR (CDCl3, 75.5 MHz): d = 177.84,
177.23, 177.03, 176.75 (PivC@O); 147.81, 146.43 (aryl);
136.88 (CH@CAr); 132.07 (aryl); 131.10 (ipso-aryl);
123.82 (aryl); 123.82 (CH@CAr); 91.93 (C-1); 72.09,
71.67, 67.33, 65.35 (C-2, C-3, C-4, C-5); 61.65 (C-6);
53.62 (CHN); 44.37 (NCH2); 39.02, 38.69, 38.64
(PivCMe3); 33.78 (CHCH2); 32.01 (CH2); 27.16, 27.07,
27.02 (PivCH3); 20.06 (CH2); 14.34 (CH3) ppm; MS
(ES+): m/z 599.7 [MꢀPivOH+H]+, 701.7 [M+H]+,
723.8 [M+Na]+, 764.88 [M+CH3CN+Na]+; HRMS:
calcd for C39H61N2O9 (M+H): 701.4377; found:
701.4367.
(ES+):
m/z
600.4
[MꢀPivOH+H]+,
622.3
[MꢀPivOH+Na]+, 702.4 [M+H]+, 724.4 [M+Na]+,
765.5
[M+CH3CN+Na]+;
HRMS:
calcd
for
C38H59N3NaO9 (M+Na): 724.4149; found: 724.4161;
elemental analysis: calcd (%) for C38H59N3O9 (701.89):
C 65.03, H 8.47, N 5.99; found: C 64.94, H 8.47, N 5.98.
4.5.2. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-4-(8-chinolyl)-4,5-dehydro-piperidine
9b. Purification by flash chromatography (cyclohex-
ane/ethyl acetate (10:1)); yield: 72%; yellow amorphous
4.5.4. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-4-phenyl-4,5-dehydro-piperidine 9d.
Purification by flash chromatography (cyclohexane/
ethyl acetate (8:1)); yield: 64%; colourless amorphous
solid; Rf = 0.56 (cyclohexane/ethyl acetate (2:1));
22
½aŠ ¼ ꢀ15:2 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
300 MHz): d = 8.83 (dd, 1H, 4J = 1.8, 3J = 4.4 Hz, aryl);
8.08 (dd, 1H, J = 1.7, J = 8.3 Hz, aryl); 7.70–7.65 (m,
1H, aryl); 7.44–7.42 (m, 2H, aryl); 7.33 (dd, 1H,
solid; Rf = 0.59 (cyclohexane/ethyl acetate (2:1));
22
D
4
3
½aŠ ¼ ꢀ28:8 (c 1.0, CHCl3); 1H NMR (CDCl3,
300 MHz): d = 7.34–7.28 (m, 3H, aryl); 7.26–7.18 (m,
2H, aryl); 6.00 (br s, 1H, CH@CAr); 5.48 (t, 1H,
3
3J = 4.1, J = 8.5 Hz, aryl); 5.85 (br s, 1H, CH@CAr);
5.54 (t, 1H, J = 9.6 Hz, H-2); 5.39 (d, 1H, J = 2.9 Hz,
3
3
3
3J = 9.7 Hz, H-2); 5.37 (d, 1H, J = 2.9 Hz, H-4); 5.13
3
H-4); 5.16 (dd, 1H, J = 3.1, 3J = 10.1 Hz, H-3); 4.37
(dd, 1H, 3J = 3.1, 3J = 10.1 Hz, H-3); 4.32 (d, 1H,
(d, 1H, 3J = 9.2 Hz, H-1); 4.16 (dd, 1H, 3J = 6.6,
2J = 10.7 Hz, H-6a); 3.99–3.87 (m, 2H, H-5, H-6b);
3.81 (dd, 1H, 3J = 2.7, 2J = 17.1 Hz, NCH2); 3.48 (d,
1H, 2J = 16.9 Hz, NCH2); 3.29–3.22 (m, 1H, CHN);
3J = 9.2 Hz, H-1); 4.09 (dd, 1H, J = 6.1, J = 10.1 Hz,
H-6a); 3.95–3.84 (m, 2H, H-5, H-6b); 3.72 (dd, 1H,
3J = 2.6, 2J = 17.6 Hz, NCH2); 3.42 (br d, 1H,
2J = 16.9 Hz, NCH2); 3.20–3.14 (m, 1H, CHN); 2.53
(dd, 1H, 3J = 1.8, 2J = 15.8 Hz, CHCH2); 2.22 (br d,
1H, 2J = 15.8 Hz, CHCH2); 1.72–1.54 (m, 2H, CH2);
1.39–1.30 (m, 2H, CH2); 1.26, 1.15, 1.10, 1.09 (4s,
36H, PivCH3); 0.90 (t, 3H, 3J = 7.2 Hz, CH3) ppm;
13C NMR (CDCl3, 75.5 MHz): d = 177.90, 177.28,
177.05, 176.82 (PivC@O); 141.66 (CH@CAr); 133.69
(ipso-aryl); 128.25, 126.74, 124.84 (aryl); 121.87
(CH@CAr); 91.99 (C-1); 72.21, 71.64, 67.40, 65.38 (C-
2, C-3, C-4, C-5); 61.68 (C-6); 53.56 (CHN); 44.59
(NCH2); 39.05, 38.72, 38.67 (PivCMe3); 33.81 (CHCH2);
32.38 (CH2); 27.17, 27.08, 27.05 (PivCH3); 20.12 (CH2);
14.41 (CH3) ppm; MS (ES+): m/z 598.6
[MꢀPivOH+H]+, 620.6 [MꢀPivOH+Na]+, 700.6
[M+H]+, 722.7 [M+Na]+, 763.8 [M+CH3CN+Na]+;
HRMS: calcd for C40H62NO9 (M+H): 700.4425; found:
700.4415.
3
2
3
2
2.78 (dd, 1H, J = 2.4, J = 16.4 Hz, CHCH2); 2.49 (d,
1H, 2J = 16.5 Hz, CHCH2); 1.79–1.64 (m, 2H, CH2);
1.48–1.30 (m, 2H, CH2); 1.27, 1.18, 1.15, 1.10 (4s,
36H, PivCH3); 0.94 (t, 3H, 3J = 7.2 Hz, CH3) ppm;
13C NMR (CDCl3, 75.5 MHz): d = 177.93, 177.31,
177.03, 176.88 (PivC@O); 149.32 (aryl); 146.49, 143.14,
136.68 (ipso-aryl, CH@CAr); 135.92, 128.37 (aryl);
128.33 (ipso-aryl); 126.93, 126.27, 124.03 (aryl); 120.73
(CH@CAr); 92.37 (C-1); 72.33, 71.64, 67.50, 65.39 (C-
2, C-3, C-4, C-5); 61.77 (C-6); 53.70 (CHN); 44.83
(NCH2); 39.06, 38.73, 38.67 (PivCMe3); 35.14 (CHCH2);
33.70 (CH2); 27.19, 27.14, 27.07 (PivCH3); 20.19 (CH2);
14.49 (CH3) ppm; MS (ES+): m/z 649.6
[MꢀPivOH+H]+, 751.7 [M+H]+, 773.7 [M+Na]+;
HRMS: calcd for C43H63N2O9 (M+H): 751.4534; found:
751.4506.
4.5.3. (2R)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-n-propyl-4-(3-pyridyl)-4,5-dehydro-piperidine 9c.
Purification by flash chromatography (cyclohexane/
ethyl acetate (5:1)); yield: 83%; colourless amorphous
4.5.5. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-isopropyl-4-(5-pyrimidyl)-4,5-dehydro-piperidine
9e. Purification by flash chromatography (cyclohex-
ane/ethyl acetate (3:1)); yield: 64%; yellowish amor-
solid; Rf = 0.38 (cyclohexane/ethyl acetate (2:1));
phous solid; Rf = 0.29 (cyclohexane/ethyl acetate (2:1));
22
½aŠ ¼ ꢀ24:7 (c 1.0, CHCl3); 1H NMR (CDCl3,
22
½aŠ ¼ ꢀ25:3 (c 1.0, CHCl3); 1H NMR (CDCl3,
D
D
300 MHz): d = 8.58 (s, 1H, aryl); 8.43 (d, 1H,
300 MHz): d = 9.04 (s, 1H, aryl); 8.67 (s, 2H, aryl);
3
3
3J = 3.7 Hz, aryl); 7.58 (d, 1H, J = 8.1 Hz, aryl); 7.20
6.15 (br s, 1H, CH@CAr); 5.47 (t, 1H, J = 9.7 Hz, H-
(dd, 1H, 3J = 4.8, 3J = 7.7 Hz, aryl); 6.06 (br s, 1H,
2); 5.35 (d, 1H, 3J = 2.9 Hz, H-4); 5.12 (dd, 1H,
3
3
3
CH@CAr); 5.46 (t, 1H, J = 9.6 Hz, H-2); 5.37 (d, 1H,
3J = 3.1, J = 10.1 Hz, H-3); 4.37 (d, 1H, J = 9.2 Hz,
H-1); 4.01–3.85 (m, 3H, H-5, H-6a, H-6b); 3.66 (dd,
3
3
3J = 2.9 Hz, H-4); 5.13 (dd, 1H, J = 3.1, J = 10.1 Hz,

S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
537
1H, 3J = 2.6, 2J = 18.8 Hz, NCH2); 3.58 (dd, 1H,
2.98–2.85 (m, 2H, CHCH2); 1.26, 1.23, 1.19, 1.08 (4s,
36H, PivCH3) ppm; 13C NMR (CDCl3, 100.6 MHz):
d = 177.93, 177.20, 177.11, 176.70 (PivC@O); 149.51
(aryl); 146.27, 141.60, 140.61 (CH@CAr, ipso-aryl);
136.15 (aryl); 135.99, 133.25 (ipso-aryl); 129.87, 128.67,
128.56 (aryl); 128.40 (ipso-aryl); 127.23, 126.24, 124.53
(aryl); 120.78 (CH@CAr); 88.18 (C-1); 72.28, 71.30,
67.43, 65.05 (C-2, C-3, C-4, C-5); 61.83 (CHN); 59.61
(C-6); 43.80 (NCH2); 39.48 (CHCH2); 39.04, 38.81,
38.68 (PivCMe3); 27.24, 27.20, 27.12, 27.04 (PivCH3)
ppm; MS (ES+): m/z 717.5 [MꢀPivOH+H]+, 739.5
[MꢀPivOH+Na]+, 819.6 [M+H]+, 841.5 [M+Na]+;
HRMS: calcd for C46H59ClN2NaO9 (M+Na):
841.3807; found: 841.3793.
3J = 2.8, J = 18.9 Hz, NCH2); 2.76 (dd, 1H, J = 5.5,
3J = 11.4 Hz, CHN); 2.51–2.45 (m, 1H, CHCH2); 2.37–
2.30 (m, 1H, CHCH2); 2.01–1.90 (m, 1H, CH(CH3)2);
1.24, 1.11, 1.10, 1.09 (4s, 36H, PivCH3); 0.95 (d, 3H,
3J = 6.6 Hz, CH3); 0.88 (d, 3H, 3J = 6.6 Hz, CH3)
ppm; 13C NMR (CDCl3, 75.5 MHz): d = 177.84,
177.30, 177.09, 176.72 (PivC@O); 156.90, 152.99 (aryl);
134.27 (CH@CAr); 128.46 (ipso-aryl); 126.05
(CH@CAr); 91.09 (C-1); 72.30, 71.65, 67.40, 65.63 (C-
2, C-3, C-4, C-5); 61.96 (C-6, CHN); 42.37 (NCH2);
39.05, 38.73, 38.61 (PivCMe3); 27.61 (CHCH2); 27.20,
27.17, 27.07, 27.02 (PivCH3); 26.72 (CH(CH3)2); 21.03
(CH3); 18.01 (CH3) ppm; MS (ES+): m/z 600.5
[MꢀPivOH+H]+, 702.5 [M+H]+, 724.5 [M+Na]+,
2
3
765.6
[M+CH3CN+Na]+;
HRMS:
calcd
for
4.5.8. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(3-pyridyl)-4-(5-pyrimidyl)-4,5-dehydro-piper-
idine 9j. Purification by flash chromatography
(cyclohexane/ethyl acetate (1:1)); yield: 90%; colourless
amorphous solid; Rf = 0.05 (cyclohexane/ethyl acetate
C38H59N3NaO9 (M+Na): 724.4149; found: 724.4156.
4.5.6. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(4-chlorophenyl)-4-(5-pyrimidyl)-4,5-dehydro-
piperidine 9g. Purification by flash chromatography
(cyclohexane/ethyl acetate (3:1)); yield: 69%; orange
amorphous solid; Rf = 0.23 (cyclohexane/ethyl acetate
22
1
(1:1)); ½aŠ ¼ ꢀ33:9 (c 1.0, CHCl3); H NMR (CDCl3,
D
300 MHz): d = 9.06 (s, 1H, aryl); 8.70 (s, 2H, aryl);
8.62 (dd, 1H, J = 1.5, J = 4.8 Hz, aryl); 8.59 (d, 1H,
4
3
22
D
1
3
(2:1)); ½aŠ ¼ ꢀ26:8 (c 1.0, CHCl3); H NMR (CDCl3,
4J = 1.5 Hz, aryl); 7.45 (d, 1H, J = 7.7 Hz, aryl); 7.33
300 MHz): d = 9.05 (s, 1H, aryl); 8.70 (s, 2H, aryl);
7.35 (d, 2H, 3J = 8.5 Hz, aryl); 7.26 (d, 2H,
3J = 8.5 Hz, aryl); 6.30 (br s, 1H, CH@CAr); 5.48 (t,
(dd, 1H, 3J = 4.8, 3J = 7.7 Hz, aryl); 6.32 (br s, 1H,
3
CH@CAr); 5.51 (t, 1H, J = 9.6 Hz, H-2); 5.26 (d, 1H,
3J = 2.9 Hz, H-4); 4.87 (dd, 1H, J = 3.3, J = 9.9 Hz,
3
3
3
3
3
3
1H, J = 9.5 Hz, H-2); 5.25 (d, 1H, J = 2.9 Hz, H-4);
H-3); 4.16 (dd, 1H, J = 3.7, J = 9.9 Hz, CHN); 4.02–
3.88 (m, 5H, H-6a, H-6b, H-1, NCH2); 3.48 (t, 1H,
3J = 6.6 Hz, H-5); 2.79–2.71 (m, 1H, CHCH2); 2.58 (d,
3
4.86 (dd, 1H, J = 2.9, J = 9.9 Hz, H-3); 4.08–3.99 (m,
3
3
2H, CHN, H-6a); 3.92 (d, 1H, J = 9.2 Hz, H-1); 3.90–
3.84 (m, 3H, H-6b, NCH2); 3.46 (t, 1H, 3J = 6.8 Hz,
H-5); 2.74–2.65 (m, 1H, CHCH2); 2.52 (d, 1H,
3J = 15.1 Hz, CHCH2); 1.25, 1.17, 1.15, 1.06 (4s, 36H,
PivCH3) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 177.87, 177.14, 177.11, 176.58 (PivC@O); 157.02,
152.90 (aryl); 139.29, 134.02 (ipso-aryl); 134.00
(CH@CAr); 129.61, 129.09 (aryl); 128.01 (ipso-aryl);
125.38 (CH@CAr); 87.69 (C-1); 72.01, 71.46, 67.27,
64.90 (C-2, C-3, C-4, C-5); 61.71 (C-6); 59.43 (CHN);
43.84 (NCH2); 39.05, 38.78, 38.69 (PivCMe3); 35.81
(CHCH2); 27.20, 27.11, 27.02 (PivCH3) ppm; MS
1H, J = 15.1 Hz, CHCH2); 1.25, 1.17, 1.16, 1.07 (4s,
2
36H, PivCH3) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 177.84, 177.15, 176.55 (PivC@O); 157.28, 152.95,
149.98, 149.80 (aryl); 136.28 (CH@CAr); 135.60 (aryl);
132.92, 128.07 (ipso-aryl); 125.35 (aryl); 123.74
(CH@CAr); 88.08 (C-1); 71.94, 71.58, 67.15, 64.90 (C-
2, C-3, C-4, C-5); 61.54 (C-6); 57.58 (CHN); 43.96
(NCH2); 39.05, 38.81, 38.70 (PivCMe3); 35.57 (CHCH2);
27.20, 27.12, 27.10, 27.04 (PivCH3) ppm; MS (ES+): m/z
635.6 [MꢀPivOH+H]+, 737.6 [M+H]+, 759.7 [M+Na]+,
800.6
[M+CH3CN+Na]+;
HRMS:
calcd
for
(ES+):
m/z
668.5
[MꢀPivOH+H]+,
690.5
C40H57N4O9 (M+H): 737.4126; found: 737.4155.
[MꢀPivOH+Na]+, 770.6 [M+H]+, 792.6 [M+Na]+,
833.5
[M+CH3CN+Na]+;
C41H56ClN3NaO9 (M+Na): 792.3603; found: 792.3602.
HRMS:
calcd
for
4.5.9. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galacto-
pyranosyl)-2-(3-pyridyl)-4-(8-chinolyl)-4,5-dehydro-piper-
idine 9k. Purification by flash chromatography
(cyclohexane/ethyl acetate (2:1)); yield: 71%; yellowish
amorphous solid; Rf = 0.18 (cyclohexane/ethyl acetate
4.5.7. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galacto-
pyranosyl)-2-(4-chlorophenyl)-4-(8-chinolyl)-4,5-dehydro-
piperidine 9h. Purification by flash chromatography
(cyclohexane/ethyl acetate (10:1)); yield: 66%; yellowish
amorphous solid; Rf = 0.54 (cyclohexane/ethyl acetate
22
D
1
(2:1)); ½aŠ ¼ ꢀ24:4 (c 1.0, CHCl3); H NMR (CDCl3,
300 MHz): d = 8.85 (dd, 1H, 4J = 1.7, 3J = 4.2 Hz, aryl);
8.67 (br s, 1H, aryl); 8.55 (br s, 1H, aryl); 8.09 (dd, 1H,
4J = 1.8, 3J = 8.5 Hz, aryl); 7.77 (d, 1H, 3J = 8.1 Hz,
aryl); 7.70 (dd, 1H, 4J = 1.5, 3J = 8.1 Hz, aryl); 7.53
(dd, 1H, 4J = 1.7, 3J = 7.2 Hz, aryl); 7.45 (t, 1H,
22
D
1
(2:1)); ½aŠ ¼ ꢀ19:4 (c 1.0, CHCl3); H NMR (CDCl3,
400 MHz): d = 8.85 (dd, 1H, 4J = 2.0, 3J = 4.3 Hz, aryl);
8.09 (dd, 1H, J = 1.6, J = 8.2 Hz, aryl); 7.69 (dd, 1H,
4
3
4J = 1.4, 3J = 8.0 Hz, aryl); 7.53 (dd, 1H, 4J = 1.6,
3J = 7.5 Hz, aryl); 7.34 (dd, 1H, J = 4.2, J = 8.3 Hz,
aryl); 7.28 (dd, 1H, 3J = 5.5, 3J = 8.1 Hz, aryl); 6.05
(br s, 1H, CH@CAr); 5.58 (t, 1H, 3J = 9.7 Hz, H-2);
3
3
3J = 7.0 Hz, aryl); 7.45 (t, 1H, J = 7.4 Hz, aryl); 7.36–
3
7.29 (m, 5H, aryl); 6.05 (br s, 1H, CH@CAr); 5.56 (t,
1H, J = 9.8 Hz, H-2); 5.27 (d, 1H, J = 2.7 Hz, H-4);
3
3
3
3
5.28 (d, 1H, J = 2.6 Hz, H-4); 4.89 (dd, 1H, J = 3.3,
3
3
3
3
4.88 (dd, 1H, J = 3.1, J = 9.8 Hz, H-3); 4.31 (dd, 1H,
3J = 4.1, 3J = 9.6 Hz, CHN); 4.04 (dd, 1H, 3J = 6.7,
2J = 10.9 Hz, H-6a); 3.96 (d, 1H, 3J = 9.8 Hz, H-1);
3.94–3.91 (m, 2H, H-6b, NCH2); 3.81 (br d, 1H,
2J = 16.8 Hz, NCH2); 3.49 (t, 1H, 3J = 6.6 Hz, H-5);
3J = 9.9 Hz, H-3); 4.38 (dd, 1H, J = 4.4, J = 8.8 Hz,
CHN); 4.05–3.93 (m, 4H, H-1, H-6a, H-6b, NCH2);
3
3.85–3.79 (m, 1H, NCH2); 3.51 (t, 1H, J = 6.6 Hz, H-
5); 3.06–2.90 (m, 2H, CHCH2); 1.26, 1.23, 1.18, 1.08
(4s, 36H, PivCH3) ppm; 13C NMR (CDCl3,

538
S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
75.5 MHz): d = 177.85, 177.20, 177.12, 176.67
(PivC@O); 150.27, 149.50, 149.10 (aryl); 146.31,
141.55, 137.57, 136.15 (ipso-aryl, CH@CAr); 136.13,
135.89, 128.58 (aryl); 128.40 (ipso-aryl); 127.32, 126.26,
124.49, 123.84 (aryl); 120.84 (CH@CAr); 88.73 (C-1);
72.22, 71.44, 67.33, 65.08 (C-2, C-3, C-4, C-5); 61.66
(C-6); 57.78 (CHN); 43.92 (NCH2); 39.09 (CHCH2);
38.84, 38.69 (PivCMe3); 27.23, 27.20, 27.11, 27.05
(PivCH3) ppm; MS (ES+): m/z 684.5 [MꢀPivOH+H]+,
786.6 [M+H]+, 808.7 [M+Na]+, 824.5 [M+K]+; HRMS:
calcd for C45H60N3O9 (M+H): 786.4330; found:
786.4316.
67.24, 64.96 (C-2, C-3, C-4, C-5); 61.57 (C-6); 57.69
(CHN); 43.95 (NCH2); 39.06, 38.78, 38.70, 38.67
(PivCMe3); 36.53 (CHCH2); 27.22, 27.17, 27.10, 27.04
(PivCH3) ppm; MS (ES+): m/z 633.7 [MꢀPivOH+H]+,
655.6 [MꢀPivOH+Na]+, 735.7 [M+H]+, 757.7
[M+Na]+, 798.7 [M+CH3CN+Na]+; HRMS: calcd for
C42H59N2O9 (M+H): 735.4221; found: 735.4198.
4.5.12.
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galacto-
pyranosyl)-2-(2-chlorobenzyl)-4-(5-pyrimidyl)-4,5-dehydro-
piperidine 9n. Purification by flash chromatography
(cyclohexane/ethyl acetate (4:1)); yield: 57%; colourless
amorphous solid; Rf = 0.20 (cyclohexane/ethyl acetate
22
D
1
4.5.10. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(3-pyridyl)-4-(3-pyridyl)-4,5-dehydro-piperidine
9l. Purification by flash chromatography (cyclohexane/
ethyl acetate (2:1)); yield: 79%; yellowish amorphous
(2:1)); ½aŠ ¼ þ18:2 (c 1.0, CHCl3); H NMR (CDCl3,
300 MHz): d = 9.04 (s, 1H, aryl); 8.61 (s, 2H, aryl);
7.30 (dd, 1H, J = 3.9, J = 5.7 Hz, aryl); 7.20–7.10 (m,
3
3
3H, aryl); 6.22 (br s, 1H, CH@CAr); 5.51 (t, 1H,
3
solid; Rf = 0.06 (cyclohexane/ethyl acetate (1:1));
3J = 9.6 Hz, H-2); 5.44 (d, 1H, J = 2.9 Hz, H-4); 5.19
22
D
½aŠ ¼ ꢀ30:6 (c 1.0, CHCl3); 1H NMR (CDCl3,
(dd, 1H, 3J = 3.3, 3J = 10.3 Hz, H-3); 4.33 (d, 1H,
3
2
300 MHz): d = 8.61–8.59 (m, 3H, aryl); 8.45 (d, 1H,
3J = 4.1 Hz, aryl); 7.67–7.59 (m, 2H, aryl); 7.32 (dd,
1H, 3J = 4.8, 3J = 7.7 Hz, aryl); 7.21 (dd, 1H,
3J = 4.8,8.0 Hz, aryl); 6.23 (br s, 1H, CH@CAr); 5.52
3J = 9.2 Hz, H-1); 4.12 (dd, 1H, J = 6.4, J = 10.5 Hz,
H-6a); 4.03–3.88 (m, 3H, H-5, H-6b, NCH2); 3.79–3.76
2
(m, 1H, CHN); 3.49 (br d, 1H, J = 17.6 Hz, NCH2);
3
3.16 (dd, 1H, J = 3.9, J = 13.1 Hz, CH2–ClPh); 3.05
2
3
3
3
(dd, 1H, J = 10.7, J = 12.9 Hz, CH2–ClPh); 2.35–2.30
2
(t, 1H, J = 9.8 Hz, H-2); 5.26 (d, 1H, J = 2.6 Hz, H-
3
3
4); 4.87 (dd, 1H, J = 3.3, J = 9.9 Hz, H-3); 4.15 (dd,
2
(m, 1H, CHCH2); 2.07 (d, 1H, J = 16.9 Hz, CHCH2);
3
3
1H, J = 3.9, J = 9.7 Hz, CHN); 4.02–3.91 (m, 3H, H-
1, H-6a, H-6b); 3.84 (br s, 2H, NCH2); 3.49–3.44 (m,
1H, H-5); 2.79–2.69 (m, 1H, CHCH2); 2.58 (d, 1H,
2J = 13.6 Hz, CHCH2); 1.26, 1.17, 1.16, 1.07 (4s, 36H,
PivCH3) ppm; 13C NMR (CDCl3, 75.5 MHz):
d = 177.81, 177.12, 177.09, 176.57 (PivC@O); 150.00,
149.56, 148.26, 146.37 (aryl); 136.71, 136.36 (ipso-aryl,
CH@CAr); 135.63, 132.10 (aryl); 130.75 (ipso-aryl);
123.67, 123.46, 123.16 (aryl, CH@CAr); 88.23 (C-1);
72.00, 71.49, 67.18, 64.91 (C-2, C-3, C-4, C-5); 61.54
(C-6); 57.62 (CHN); 43.92 (NCH2); 39.03, 38.76,
38.67, 38.64 (PivCMe3); 36.08 (CHCH2); 27.19, 27.08,
27.01 (PivCH3) ppm; MS (ES+): m/z 634.7
[MꢀPivOH+H]+, 656.6 [MꢀPivOH+Na]+, 736.7
[M+H]+, 758.7 [M+Na]+, 799.8 [M+CH3CN+Na]+;
HRMS: calcd for C41H58N3O9 (M+H): 736.4173; found:
736.4166.
1.30, 1.14, 1.11, 1.09 (4s, 36H, PivCH3) ppm; 13C
NMR (CDCl3, 75.5 MHz): d = 177.82, 177.18, 177.08,
176.76 (PivC@O); 157.07, 153.19 (aryl); 137.55, 134.18,
134.11 (ipso-aryl, CH@CAr); 131.20, 129.69 (aryl);
128.69 (ipso-aryl); 127.71, 126.87 (aryl); 125.09
(CH@CAr); 93.46 (C-1); 72.16, 71.83, 67.19, 65.38 (C-
2, C-3, C-4, C-5); 61.38 (C-6); 52.60 (CHN); 45.79
(NCH2); 39.06, 38.73, 38.69 (PivCMe3); 34.29 (CHCH2);
29.60 (CH2–ClPh); 27.22, 27.05 (PivCH3) ppm;
MS (ES+): m/z 682.5 [MꢀPivOH+H]+, 704.5
[MꢀPivOH+Na]+, 784.5 [M+H]+, 806.6 [M+Na]+,
847.6
[M+CH3CN+Na]+;
HRMS:
calcd
for
C42H58ClN3NaO9 (M+Na): 806.3759; found: 806.3767.
4.6. General procedure for the cleavage of the N-
glycosidic bond to detach the dehydropiperidines 10
To a solution of N-galactosyl dehydropiperidine 9
(0.2 mmol) in methanol (6 mL) was added 1 M aq HCl
(1.2 mL) and stirred at ambient temperature for 12–
24 h (TLC monitoring). The solvent was evaporated in
vacuo, the residue dissolved in diethyl ether (10 mL)
and the organic layer extracted with water (3 · 5 mL).
4.5.11. (2S)-N-(2,3,4,6-Tetra-O-pivaloyl-b-D-galactopyr-
anosyl)-2-(3-pyridyl)-4-phenyl-4,5-dehydro-piperidine 9m.
Purification by flash chromatography (cyclohexane/
ethyl acetate (2:1)); yield: 79%; yellow amorphous solid;
22
D
Rf = 0.28 (cyclohexane/ethyl acetate (2:1)); ½aŠ ¼ ꢀ34:1
1
(c 1.0, CHCl3); H NMR (CDCl3, 300 MHz): d = 8.61–
8.59 (m, 2H, aryl); 7.68 (dt, 1H, J = 1.7, J = 8.0 Hz,
aryl); 7.37–7.29 (m, 4H, aryl); 7.27–7.17 (m, 2H, aryl);
The hemiacetalof the carbohydrate auxilary
11 was
4
3
quantitatively recovered by concentration of the organic
layer. The combined aqueous layer was alkalised with
Na2CO3 and extracted with CH2Cl2 (3 · 10 mL) to give
the dehydropiperidine 10 after evaporation of the sol-
vent in vacuo.
3
6.17 (br s, 1H, CH@CAr); 5.54 (t, 1H, J = 9.6 Hz, H-
2); 5.26 (d, 1H, 3J = 2.6 Hz, H-4); 4.87 (dd, 1H,
3J = 3.1, 3J = 10.1 Hz, H-3); 4.15 (dd, 1H, 3J = 3.9,
3J = 9.4 Hz, CHN); 4.02–3.90 (m, 3H, H-1, H-6a, H-
3
6b); 3.81 (br s, 2H, NCH2); 3.47 (t, 1H, J = 6.8 Hz,
4.6.1. (2S)-2-Isopropyl-4-(5-pyrimidyl)-4,5-dehydropiper-
idine 10a. Yield: 85%; yellow oil; Rf = 0.08 (ethylace-
H-5); 2.79–2.69 (m, 1H, CHCH2); 2.64–2.58 (m, 1H,
CHCH2); 1.26, 1.17, 1.16, 1.07 (4s, 36H, PivCH3)
ppm; 13C NMR (CDCl3, 75.5 MHz): d = 177.87,
177.20, 177.12, 176.64 (PivC@O); 149.88, 149.25 (aryl);
139.99, 137.34 (ipso-aryl, CH@CAr); 135.89 (aryl);
133.25 (ipso-aryl); 128.39, 127.13, 124.67, 123.71
(aryl); 115.46 (CH@CAr); 88.44 (C-1); 72.10, 71.47,
22
D
1
tate/methanol(9:1)); ½aŠ ¼ ꢀ94:9 (c 0.5, CHCl3); H
NMR (CDCl3, 300 MHz): d = 9.05 (s, 1H, aryl); 8.71
(s, 2H, aryl); 6.22 (br s, 1H, CH@CAr); 3.68–3.53 (m,
2H, NCH2); 2.59 (ddd, 1H, 3J = 4.1, 3J = 5.9,
3J = 9.9 Hz, CHN); 2.35 (br d, 1H, 2J = 15.8 Hz,
CHCH2); 2.30–2.19 (m, 1H, CHCH2); 1.78–1.67 (m,

S. Knauer, H. Kunz / Tetrahedron: Asymmetry 16 (2005) 529–539
539
1H, CH(CH3)2); 1.01 (d, 3H, 3J = 4.8 Hz, CH3); 0.98 (d,
3H, 3J = 4.8 Hz, CH3) ppm; MS (ES+): m/z 204.0
[M+H]+, 245.0 [M+CH3CN+H]+; HRMS: calcd for
C12H18N3 (M+H): 204.1501; found: 204.1508.
K.; Leysen, J. E. Psychopharmacology 1996, 124, 57–
73.
6. Yevich, J. P.; Yocca, F. D. Curr. Med. Chem. 1997, 4,
295–312.
7. Yamanishi, Y.; Ogura, H.; Kosasa, T. Tanpakushitsu
Kakusan Koso 2000, 45(6), 1047–1051.
8. Kunz, H.; Pfrengle, W. Angew. Chem. 1989, 101, 1041–
1042; Kunz, H.; Pfrengle, W. Angew. Chem., Int. Ed. Engl.
1989, 28, 1067–1068.
9. Weymann, M.; Pfrengle, W.; Schollmeyer, D.; Kunz, H.
Synthesis 1997, 1151–1160.
10. Weymann, M.; Schultz-Kukula, M.; Knauer, S.; Kunz, H.
Monatsh. Chem. 2002, 133, 571–587.
11. Comins, D. L.; Killpac, M. O. J. Am. Chem. Soc. 1992,
114, 10972–10974.
12. Eynde, J.-J. V.; DꢀOrazio, P.; Mayence, A.; Maguestiau,
A. Tetrahedron 1992, 48, 1263–1268.
13. Matsumura, Y.; Yoshimoto, Y.; Horikawa, C.; Maki, T.;
Watanabe, M. Tetrahedron Lett. 1996, 37, 5715–5718.
14. Dwyer, M. P.; Lamar, J. E.; Meyers, A. I. Tetrahedron
Lett. 1999, 40, 8965–8968.
15. Hanessian, S.; van Otterlo, W. A. L.; Nilsson, I.; Bauer,
U. Tetrahedron Lett. 2002, 43, 1995–1998.
16. Kunz, H.; Sager, W.; Schanzenbach, D.; Decker, M.
Liebigs Ann. Chem. 1991, 649–654.
4.6.2. (2S)-2-(3-Pyridyl)-4-(5-pyrimidyl)-4,5-dehydro-
piperidine 10b. Yield: 91%; yellow solid; Rf = 0.07
22
D
(ethylacetate/methanol(2:1));
½aŠ ¼ ꢀ100:0 (c 1.0,
1
CHCl3); H NMR (CDCl3, 300 MHz): d = 9.03 (s, 1H,
aryl); 8.70 (s, 2H, aryl); 8.62 (d, 1H, J = 2.2 Hz, aryl);
4
4
3
8.50 (dd, 1H, J = 1.5, J = 4.8 Hz, aryl); 7.74 (dt, 1H,
4J = 1.8, 3J = 7.7 Hz, aryl); 7.27 (dd, 1H, 3J = 4.8,
3J = 7.7 Hz, aryl); 6.30 (d, 1H, J = 1.5 Hz, CH@CAr);
3
3.99 (t, 1H, 3J = 7.0 Hz, CHN); 3.83–3.66 (m, 2H,
NCH2); 2.58–2.56 (m, 2H, CHCH2) ppm; 13C NMR
(CDCl3, 75.5 MHz): d = 157.29, 153.13, 149.19 (aryl);
149.17 (CH@CAr); 148.57 (aryl); 138.93 (ipso-aryl);
134.18 (aryl); 129.76 (ipso-aryl); 126.26, 123.71 (aryl,
CH@CAr); 55.31 (CHN); 46.34 (NCH2); 35.14
(CHCH2) ppm; MS (ES+): m/z 239.4 [M+H]+, 280.3
[M+CH3CN+H]+; HRMS: calcd for C14H15N4
(M+H): 239.1297; found: 239.1292.
17. Comins, D. L.; Dehghani, A. Tetrahedron Lett. 1992, 33,
6299–6302.
18. Tasber, E. S.; Garbaccio, R. M. Tetrahedron Lett. 2003,
44, 9185–9188.
19. Miyaura, N.; Suzuki, A. Chem. Rev. 1995, 95, 2457–
2483.
20. For a review on Suzuki cross-coupling with triflates see:
Ritter, K. Synthesis 1993, 735–762.
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft and by Aventis Pharma Deutschland
GmbH.
21. Oh-e, T.; Miyaura, N.; Suzuki, A. Synlett 1990, 221–223.
22. Oh-e, T.; Miyaura, N.; Suzuki, A. J. Org. Chem. 1993, 58,
2201–2208.
References
1. Patchett, A. A.; Nargund, R. P. In Ann. Rep. Med. Chem.
Trainor, G. L., Ed.; 2000, Vol. 35; Academic, 2000; pp
289–298.
2. Bailey, P. D.; Millwood, P. A.; Smith, P. D. Chem.
Commun. 1998, 633–640.
3. Laschat, S.; Dickner, T. Synthesis 2000, 1781–1813.
4. Watson, P. S.; Jiang, B.; Scott, B. Org. Lett. 2000, 2, 3679–
3681.
23. Fu, J.-m.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665–
1668.
24. For a recent review on B-alkyl Suzuki–Miyaura cross-
coupling see: Chemler, S. R.; Trauner, D.; Danishefsky, S.
J. Angew. Chem. 2001, 113, 4676–4701; Angew. Chem.,
Int. Ed. 2001, 40, 4544–4568.
25. Danishefsky, S. J.; Kitahara, T. J. Am. Chem. Soc. 1974,
96, 7807–7808.
5. Schotte, A.; Janssen, P. F. M.; Gommeren, W.; Luyten,
W. H. M. L.; van Gompel, P.; Lesage, A. S.; de Loore,
26. Kranke, B.; Hebrault, D.; Schultz-Kukula, M.; Kunz, H.
Synlett 2004, 671–674.