Stereoselective synthesis of bromopiperidinones and their conversion to annulated heterocycles

Article abstract of DOI:10.1515/znb-2009-11-1251

N-Galactopyranosyl- and N-glucopyranosyl imines of aliphatic, aromatic and heteroaromatic aldehydes react with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene in a domino Mannich-Michael reaction cascade to give 2-substituted 5,6-dehydro-piperidin-4-ones with high diastereoselectivity. Treatment of these cyclic enaminones with N-bromo-succinimide yields the corresponding 2-substituted 5-bromo-5,6-dehydropiperidinones which react with L-Selectride or methylcuprate to afford the saturated bromo-piperidinones with high diastereoselectivity. Condensation reactions of these products with thioamides afford thiazolopiperidines.

Full text of DOI:10.1515/znb-2009-11-1251

Stereoselective Synthesis of Bromopiperidinones and their Conversion
to Annulated Heterocycles
Stefan Knauer, Markus Weymann, and Horst Kunz
Institut fu¨r Organische Chemie, Universita¨t Mainz, Duesbergweg 10 – 14, D-55128 Mainz, Germany
Reprint requests to Prof. Dr. Horst Kunz. Fax: +49 61313924786. E-mail: hokunz@uni-mainz.de
Z. Naturforsch. 2009, 64b, 1639 – 1652; received August 26, 2009
Dedicated to Professor Hubert Schmidbaur on the occasion of his 75th birthday
N-Galactopyranosyl- and N-glucopyranosyl imines of aliphatic, aromatic and heteroaromatic alde-
hydes react with 1-methoxy-3-trimethylsilyloxy-1,3-butadiene in a domino Mannich-Michael reac-
tion cascade to give 2-substituted 5,6-dehydro-piperidin-4-ones with high diastereoselectivity. Treat-
ment of these cyclic enaminones with N-bromo-succinimide yields the corresponding 2-substituted
5-bromo-5,6-dehydropiperidinones which react with L-SelectrideꢀR or methylcuprate to afford the
saturated bromo-piperidinones with high diastereoselectivity. Condensation reactions of these prod-
ucts with thioamides afford thiazolopiperidines.
Key words: Glycosylamines, Stereoselective Mannich Reactions, Bromopiperidinones,
Stereoselective Michael Addition, Thiazolopiperidinones
Introduction
aldimines 2 (Scheme 1). Lewis acid-catalyzed re-
actions of these aldimines 2 with 1-methoxy-3-tri-
methylsilyloxy-butadiene (Danishefsky-diene [4]) af-
ford 2-substituted dehydropiperidinones 3 in a Man-
nich-Michael-condensation reaction sequence in high
yield and high diastereoselectivity [5, 6]. The config-
uration at C-2 of the major diastereomer 3 of the
piperidine derivative is opposite to those of piperidi-
nones formed by analogous reactions of N-D-arabino-
pyranosylimines [3], as has been confirmed by X-ray
crystal structure analysis [6].
Aldimines 5 formed analogously from 2,3,4,6-tetra-
O-pivaloyl-β-D-glucopyranosylamine (4) undergo the
Mannich-Michael condensation sequence with the
Danishefsky diene under identical conditions to give
N-glucosyl-dehydropiperidinones 6 (Scheme 2). Com-
parison of these reactions of the glucosylimines with
those of the corresponding galactosyl imines displayed
in Table 1 shows that the yields are similar to those
obtained with the N-galactosylimines 2. However, the
diastereoselectivity is slightly lower in case of the N-
glucosyl derivatives 6.
Substituted piperidines constitute interesting phar-
macophoric motifs contained in numerous natural
products, e. g. alkaloids and drugs. Therefore, efficient
stereoselective syntheses of functionalized piperidine
derivatives are of interest in medicinal chemistry. This
also holds for aryl-substituted piperidines. The 4-
imidazolyl derivative thioperamide [1] was shown to
act as a histamine H3 and H4 antagonist, while the
heteroaryl-condensed piperidine ticlopidine [2] has the
effect of an P2Y12 adenosine diphosphate receptor an-
tagonist and impairs the ADP-mediated activation of
integrin IIb/IIIa.
Recently we reported the stereoselective synthe-
sis of 2-substituted N-arabinopyranosyl-dehydropiper-
idinones and their further conversion to 2,3-, 2,5- and
2,6-substituted piperidinones [3]. In the present article,
we describe the stereoselective synthesis of piperidi-
nones with opposite configuration at position 2 and
their conversion to the 5-bromo-piperidines. These α-
bromoketones can then be transformed into condensed
piperidines.
Due to the higher diastereoselectivity achieved in
their formation, N-galactosyl-dehydropiperidones 3
were mostly used for further conversions.
Results and Discussion
2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosylami-
Reactions with N-bromosuccinimide (NBS) can-
ne (1) reacts with aliphatic, aromatic and hetero- not be performed with N-galactosyl piperidinones 3
aromatic aldehydes to afford the corresponding having C=C double bonds (3e) or electron-rich aro-
c
0932–0776 / 09 / 1100–1639 $ 06.00 ꢀ 2009 Verlag der Zeitschrift fu¨r Naturforschung, Tu¨bingen · http://znaturforsch.com
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1640
S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
Scheme 1. d. r. = ratio of diastere-
omers.
Scheme 2.
Table 1. Domino Mannich-Michael condensation of N-
glucopyranosyl imine 4 with the Danishefsky diene to give
N-glucosyl-dehydropiperidinones 6 and comparison with
analogous reactions to give the corresponding N-galactosyl
derivatives 3.
30 : 1) and 2-ethyl-dehydropiperidinone (3j, from pro-
pionaldehyde, yield 88 %, d. r. 28 : 1) were synthesized
according to Scheme 1.
The reactions of N-galactosyl-dehydropiper-
idinones 3 with NBS were performed in tetrahydro-
furan at −78 ◦C (Scheme 3). In case of piperidinones
with aliphatic side chains (3a, 3f, 3j), NBS can be
applied in large excess. Piperidones with aromatic side
chains (3c, 3h) can form by-products containing more
than one bromine atom, if NBS was applied in large
excess. Provided these limitations are considered,
the 5-bromo-dehydropiperidinones 7 were obtained
in high yield and in enantiomerically pure form
(Scheme 3, Table 2).
The electrophilic substitution reaction can also be
carried out with N-iodosuccinimide (NIS) under iden-
tical conditions, as was shown for the conversion of 3a
to give the 5-iodo-piperidinone 8 (Scheme 4).
The yield was high and comparable to those
achieved with the corresponding N-arabinosyl
N-Glucosyl piperidinones 6
N-Galactosyl piperidinones (3)
R
Yield (%) d. r.
Yield (%) d. r.
ref.
[6]
[7]
6a Isopropyl
57 > 12:1a 3a
58
72
> 30:1a
6b3,4-Dimethoxy- 71
>
9:1b 3b
15:1b
phenyl
3-Furyl
6c
72 > 20:1a 3c
72
71
68
> 20:1b
> 20:1b
> 40:1a
[8]
[6]
[9]
6d 4-Cyanophenyl 79 > 20:1a 3d
6e Hex-5-enyl
64
>
6:1a 3e
Analytical HPLC of crude product; b 1H NMR after chromatogra-
a
phy.
matic groups in the side chain. Therefore, in addi-
tion to the 2-isopropyl-piperidinone 3a, the known 2-
propyl- (3f) [5] and the 2-(4-chlorophenyl)-dehydro-
piperidinone (3g) [5] were also used for bromination
reactions. In addition, the 2-phenyl- (3h, from ben-
zylaldehyde, yield 88 %, d. r. 26 : 1), 2-(4-bromophen-
yl)- (3i, from 4-bromobenzaldehyde, yield 91%, d. r.
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S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1641
Scheme 3.
Scheme 4.
Scheme 5.
Scheme 6.
Table 2. Bromination of N-galactosyl-dehydropiperidin- Table 3. Bromopiperidinones 10 according to Scheme 6.
ones 3 to form compounds 7 (see Scheme 3).
d. r.a
10
R
L-SelectrideꢀR Reaction time Yielda
Educt
3
R
NBS
equiv.
2
10a
1.5b
5
2
1.5
2
5
b
Reaction time Product Yielda
equiv.
1.25
1.25
1.25
1.25
1.75
1.75
(h)
2.5
1
2
3
(%)
(h)
14
12
7
7a
7b
(%)
95
36
62
48b
89
86
87
87
10a iPr
94 94 : 6 : 0 : 0
82 91 : 9 : 0 : 0
91 92 : 8 : 0 : 0
72b 83 : 17 : 0 : 0
71 91 : 9 : 0 : 0
21c 88 : 12 : 0 : 0
3a
iPr
3-Furyl
10b nPr
10c Et
3c
10d Ph
3f
3g
3h
3i
nPr [5]
Ph
4-Cl-Ph [5]
4-Br-Ph
Et
24
14
4
2
2
7c
7d
7e
7f
10e 4-Cl-Ph
4
3
10f 4-Br-Ph
a
b
Analytical HPLC of crude product 10; 13 % of educt 3g were
recovered; c isolated by prep. HPLC.
3j
7g
◦
a
at −78 C (Scheme 6). The 2,5-trans-disubstituted
After chromatography; Reaction time was extended to 12 h at
room temperature. This resulted in a decrease of yield.
piperidinones 10 were formed in high diastereoselec-
tivity (Table 3).
piperidines of opposite configuration [10]. N-Glucos-
yl-dehydropiperidinones 6 react more slowly with
NBS, as is shown for the conversion of 6d in Scheme 5.
Because the use of 5-halo-dehydropiperidinones in
the Knochel transmetallation and C–C bond form-
ing reactions [11] has already been described for
N-D-arabinosyl derivatives [10], the conversion of
compounds 7 to saturated α-bromoketones (piperidi-
nones) was investigated. The conjugate addition
The formation of the trans-2,5-disubstituted com-
pounds 10 was confirmed by H NMR spectroscopy
(J5ax,6ax = 11.7 Hz) and by X-ray crystal struc-
ture analysis of the 4-chloro-phenyl-piperidinone 10e
(Fig. 1) [20].
1
Additional evidence is given by positive NOE con-
tacts between axial 3-H and 5-H in the NMR spectrum
of compound 10e.
As an alternative to the hydride transfer, conjugate
of hydride to the enaminine structure [5, 10] of addition of organocopper complexes to the enaminone
these compounds was achieved with lithium tri-(sec- structure [3, 6] of 7 was investigated, as is shown for 7d
butyl)borohydride (L-SelectrideꢀR ) in tetrahydrofuran in Scheme 7.
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1642
S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
Scheme 7.
Scheme 8.
Scheme 9.
Scheme 10.
However, the bromo-substituted CH group adjacent to
the carbonyl group obviously is too CH-acidic. There-
fore, the thermodynamically preferred 5,6-trans iso-
mer 11 is obtained with high selectivity.
Efforts to further convert the N-glycosyl-bromo-
piperidinones to condensed heterocycles according
to Hantzsch syntheses [12] were of moderate suc-
cess. Reaction of 10b with thiobenzamide in boiling
ethanol afforded thiazolo-piperidine 12 in moderate
yield (Scheme 8).
Electron-donating groups in the thioamide reagents,
e. g. in 1-methyl-1-aryl-thiourea (Scheme 9), did
not improve the yield of the desired thiazolo-piper-
idines 13.
Instead, a number of by-products were formed in
these reactions which hardly could be separated. The
isolation of the thiazolo-piperidinones 13 was only
achieved by preparative HPLC and resulted in low
yield of pure compounds.
Fig. 1. Molecular structure of N-galactosyl-bromo-piper-
idinone 10e as determined by single-crystal X-ray diffrac-
tion [20].
The 2,5,6-trisubstituted piperidinone 11 was formed
slowly (70 % conversion after 14 h), but with high di-
astereoselectivity to give the 2,6-cis-2,5-trans major
diastereomer. Kinetic protonation of the intermediate
enolate should produce the all-cis diastereomer [8].
In contrast, the reaction of bromo-piperidinone 10c
with unsubstituted thiourea in boiling THF in the
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S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1643
presence of DBU as a strong base [13] gave the 2- m. p. 97 ◦C; [α]D23 = −16.9 (c = 1, CHCl3)], which
was deacetylated using NaOMe in methanol to give
β-D-galactopyranosylazide (quant., m. p. 149 ◦C). O-
Pivaloylation with pivaloyl chloride in pyridine gave tetra-O-
pivaloyl-β-D-galactopyranosylazide (91 %, m. p. 90 – 91 ◦C),
which was hydrogenated in methanol over neutral-washed
Raney-nickel to give 1 [(90 %, m. p. 66 – 67 ◦C), [α]D23 = +8.0
(c = 1, CHCl3)].
amino-thiazolo-piperidine 14 (Scheme 10) in satisfac-
tory yield.
Epimerization at C-2 of the piperidine portion was
not observed in these reactions. The outcome of these
Hantzsch-type reactions [14] suggests that the nucle-
ophilic attack of the thionucleophile is sterically hin-
dered in these N-glycosyl-bromo-piperidinones. Con-
siderable amounts of re-isolated starting material 10
after these conversions support this conclusion. There-
fore, more promising results might be achieved if the
N-glycosyl group is removed and substituted by a
small N-protecting group prior to the Hantzsch reac-
tion. However, the chiral bromo-piperidinones are ef-
ficiently accessible with high stereoselectivity by the
strategy outlined above. These α-bromoketones are
valuable components for further preparative use.
2,3,4,6-Tetra-O-pivaloyl-β-D-glucopyranosylamine (4)
[18]
Compound 4 was prepared in analogy to the synthesis
of 1 from penta-O-acetyl-glucopyranose via 2,3,4,6-tetra-
O-acetyl-glucopyranosylazide [19], β-glucopyranosyl azide
and its O-pivaloylation.
N-(Tetra-O-pivaloyl-β-D-galactopyranosyl)-aldimines 2 and
N-(tetra-O-pivaloyl-β-D-glucopyranosyl)-aldimines 5
Compounds 2 and 3 were obtained according to the gen-
eral procedures given in ref. [15b] for aliphatic and aromatic
aldehydes.
Experimental Section
General procedures
Reagents and solvents were distilled before use: Tetrahy-
drofuran, dioxane, and Et2O were distilled from potas-
sium/benzophenone ketyl. CH2Cl2 was◦distilled from CaH2.
Light petroleum refers to b. p. 60 – 80 C. All reactions and
distillations were carried out in flame-dried glassware under
argon atmosphere.
N-Galactopyranosyl-dehydropiperidinones 3 and N-Gluco-
pyranosyl-dehydropiperidinones 6
These compounds were synthesized from aldimines 2 or 5
according to the general procedure described in ref. [6].
The procedure was slightly modified: To the solution of
the aldimine 2 or 5 (10 mmol) in tetrahydrofuran (50 mL)
Analytical HPLC was carried out using a Knauer system
(Knauer MaxiStar K1000 pump and DAD 2062 for diode ar-
ray detection), flow rate: 1 cm3 min−1. Preparative HPLC
was performed using two Knauer Ministar K500 pumps.
Columns: A: Eurospher 100, C8, 5 µ, 250×4 mm, Knauer,
B: Kromasil C18, 5 µ, 250 × 4 mm, Knauer; flow rate:
1 cm3 min−1. Thin layer chromatography (TLC) was per-
formed on Merck silica gel 60F254, column chromatography
on silica gel 60 (0.6 – 0.2 mm, Baker), flash-chromatography
on silica (0.032 – 0.063 mm, ICN Biomedicals, Eschwege,
Germany). FAB mass spectra were measured on a Finni-
gan MAT 95 spectrometer, ESI mass spectra on a Thermo-
quest Navigator instrument. Melting points were taken on
a Bu¨chi Dr. Tottoli apparatus and are uncorrected. 1H and
13C NMR spectra were recorded on Bruker WT 200, Bruker
AC 300 and Bruker AM 400 instruments. Optical rotation
values were measured with a Perkin-Elmer 241 polarimeter.
◦
at −78 C, 11 mL of a solution of 1 M ZnCl2 in tetrahy-
◦
drofuran was added. After 15 min stirring at −78 C, 1-
methoxy-3-trimethylsilyloxy-1,3-butadiene (Danishefsky di-
ene, 2.5 mL, 12.5 mmol) wa◦s added through a syringe. T◦he
mixture was stirred at −78 C for 30 min, then at −20 C
for 24 – 48 h (TLC monitoring). Work-up was performed as
described in [6].
N-Galactopyranosyl-dehydropiperidinones 3
Compounds 3a – 3h were prepared according to published
procedures: 3a – 3e [6 – 9], 3f, g [5], and 3h [15b]; see also
Table 1.
(S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl-2-(4-
bromophenyl)-5,6-dehydropiperidin-4-one (3i)
Purification was carried out by flash-chromatography in
light petroleum/ethyl acetate 4 : 1. Yield: 91 %, colorless
amorphous solid; [α]D22 = +16.8 (c = 1.0, CHCl3). Rf = 0.18
2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosylamine (1)
[15]
Compound 1 was prepared in analogy to O-pivaloyl- (light petroleum/ethyl acetate 3 : 1). Analytical RP-HPLC
protected L-fucosylamine and D-arabinosylamine [16] from of the crude product on column LUNA C18 in MeCN-
penta-O-acetyl-galactopyranose by conversion to the tetra- H2O = 80 : 20 to 100 : 0 within 40 min: Rf = 14.5 min (ma-
O-acetyl-β-D-galactopyranosyl azide [17] [yield: 97 %, jor diastereomer), ratio of diastereomers (d. r.) = 98 : 2. –
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1644
S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
C37H52BrNO10 (750.71): calcd. C 59.20, H 6.98, N 1.87; (58 %, based on glucosylamine 4); colorless, amorphous
found C 59.07, H 6.90, N 1.84. – MS ((+)-ESI): m/z = solid, [α]2D2= −73.1 (c = 1.1, CHCl3). Rf = 0.11 (light
772.5 [M(79Br)+Na]+, 774.5 [M(81Br)+Na]+. – 1H NMR petroleum/ethyl acetate 3 : 1). HPLC (crude product): Eu-
(200 MHz, CDCl3): δ = 1H NMR (200 MHz, CDCl3): δ = rospher C-18; methanol, 20 % water; UV detection at
7.45 (d, 2H, 3J = 8.3 Hz, aryl), 7.24 (d, 1H, 3J = 7.8 Hz, 309.5 nm; Rt = 8.03 (minor diastereomer), 9.10 min (major
NCH=CH), 7.17 (d, 2H, 3J = 8.3 Hz, aryl), 5.56 (t, 1H, 3J = diastereomer); d. r.: 10 : 1 (HPLC). – C34H55NO10 (637.81):
9.8 Hz, H-2), 5.31 (d, 1H, 3J = 3.4 Hz, H-4), 5.20 (d, 1H, 3J = calcd. C 64.03, H 8.69, N 2.20; found C 63.13, H 8.99,
7.8 Hz, NCH=CH), 5.01 (dd, 1H, 3J = 3.4 Hz, 3J = 9.8 Hz, N 2.15. – 1H NMR (400 MHz, CDCl3): δ = 0.87 (2d, 6H,
H-3), 4.79 (dd, 1H, 3J = 6.3 Hz, 3J = 8.3 Hz, CHN), 4.35 (d, J = 6.9 Hz, CH3), 1.08, 1.11 and 1.17 (4s, each 9H, Piv-
1H, 3J = 9.8 Hz, H-1), 3.93 – 3.70 (m, 3H, H-5, H-6a, H-6b), CH3), 2.19 (m, 1H, CH(CH3)2), 2.37 (dd, 1H, Jvic = 2.5 Hz,
2.77 (dd, 1H, 3J = 5.9 Hz, 2J = 16.6 Hz, CH2C=O), 2.61 (dd, Jgem = 16.9 Hz, CH2C=O), 2.55 (dd, 1H, Jvic = 7.4 Hz,
1H, 3J = 8.5 Hz, 2J = 16.4 Hz, CH2C=O), 1.23, 1.15, 1.14, Jgem = 16.9 Hz, CH2C=O), 3.48 (m, 1H, isoproylCHN), 3.76
1.08 (4s, 36H, PivCH3). – 13C NMR (50.3 MHz, CDCl3): (ddd, 1H, J5 ,6b = 1.8 Hz, J5,6a = 5.0b Hz, J5,4 = 10.2 Hz,
ꢀ
ꢀ
ꢀ
δ = 212.56 (C=O), 177.70, 177.07, 176.44 (PivC=O), H-5ꢀ), 4.03 (dd, 1H, J6a ,5 = 5.0 Hz, J6a ,6b = 12.4 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
149.71 (NCH=CH), 137.82 (ipso-aryl), 132.05, 128.77 H-6aꢀ), 4.14 (dd, 1H, J6b ,5 = 1.8 Hz, J6b ,6a = 12.4 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
(aryl), 122.45 (ipso-CBr), 103.26 (NCH=CH), 88.73 (C-1), H-6bꢀ), 4.57 (d, 1H, J1 ,2 = 8.9 Hz, H-1ꢀ), 4.92 (d, 1H, J =
ꢀ
ꢀ
ꢀ
ꢀ
72.74, 71.37, 66.63, 65.24 (C-2, C-3, C-4, C-5), 61.00 (C-6), 7.7 Hz, olefin), 5.10 (dd, 1H, J4,5 = 9.9 Hz, J4 ,3 = 9.5 Hz,
59.07 (CHN), 43.52 (CH2C=O), 39.05, 38.93, 38.78, 38.69 H-4ꢀ), 5.30 (dd, 1H, J2 ,3 = 9.2 Hz, J2 ,1 = 8.8 Hz, H-2ꢀ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(PivCMe3), 27.18, 27.05 (PivCH3).
5.36 (dd, 1H, J3 ,2 = 9.1 Hz, J3 ,4 = 9.3 Hz, H-3ꢀ), 6.96 (d,
1H, J = 7.8 Hz, alkene). – 13C NMR (100.6 MHz, CDCl3):
δ = 17.85 and 19.73 (isopropyl-CH3), 27.01 und 27.11 (Piv-
CH3), 31.39 (CH(CH3)2), 35.89 (CH2C=O), 38.74, 38.81
and 38.89 (Piv-Cquart), 58.87 (isopropylCHN), 61.56 (C-6ꢀ),
67.50, 68.33, 72.78 and 74.43 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 90.59
(C-1ꢀ), 100.96 and 149.43 (alkene), 176.26, 176.83, 176.99
and 177.78 (PivC=O), 192.51 (C=O).
(2R)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-2-
ethyl-5,6-dehydropiperidin-4-one (3j)
The compound was purified by flash chromatography in
light petroleum/ethyl acetate 3 : 1. Yield: 88 %; colorless
amorphous solid; [α]2D2 = −77.3 (c = 1.0, CHCl3). Rf =
0.14 (light petroleum/cyclohexane 3 : 1); d. r.: 97 : 3 (analyti-
cal HPLC of crude product, Eurospher C-18, 80 % → 100 %
CH3CN, 20 min, λ = 220 nm, Rt = 8.42 min (minor di-
astereomer), 9.30 min (major diastereomer). – C33H53NO10
(623.77): calcd. C 63.54, H 8.56, N 2.25; found C 63.48,
H 8.52, N 2.24. – MS ((+)-ESI): m/z = 624.4 [M+H]+, 646.4
[M+Na]+. – 1H NMR (CDCl3, 400 MHz): δ = 6.90 (d, 1H,
3J = 7.8 Hz, NCH=CH), 5.53 (t, 1H, 3J = 9.6 Hz, H-2), 5.41
N-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-(3ꢀꢀ,
4ꢀꢀ-dimethoxy-phenyl)-5,6-dehydropiperidin-4-one (6b)
Purification was carried out by column chromatogra-
phy with light petroleum/ethyl acetate 2 : 1. Yield: 5.17 g
(71 %, based on glucosylamine 4), colorless, amorphous
solid; [α]2D2= −5.0 (c = 1.0, CHCl3). Rf = 0.08 (light
petroleum/ethyl acetate 3 : 1); d. r.: > 9 : 1. – C39H57NO12
(731.87): calcd. C 64.00, H 7.85, N 1.91; found C 63.96,
H 7.68, N 2.04. – 1H NMR (200 MHz, CDCl3): δ = 1.08,
1.08, 1.15 and 1.20 (4s, each 9H, Piv-CH3), 2.60 (dd, 1H,
Jvic = 5.2 Hz, Jgem = 16.5 Hz, CH2C=O), 2.76 (m, 1H,
3
3
(d, 1H, J = 2.8 Hz, H-4), 5.15 (dd, 1H, 3J = 3.1 Hz, J =
10.2 Hz, H-3), 4.95 (d, 1H, 3J = 7.8 Hz, NCH=CH), 4.55
3
2
(d, 1H, J = 9.0 Hz, H-1), 4.15 (dd, 1H, 3J = 6.4 Hz, J =
10.7 Hz, H-6a), 4.01 (t, 1H, 3J = 7.0 Hz, H-5), 3.94 (dd,
3
2
1H, J = 7.0 Hz, J = 10.6 Hz, H-6b), 3.63 – 3.59 (m, 1H,
CHN), 2.58 (dd, 1H, J = 6.1 Hz, 2J = 16.6 Hz, CH2C=O),
3
ꢀ
ꢀ
CH2C=O), 3.35 (ddd, 1H, J5,4 = 9.6 Hz, J5 ,6a = 4.6 Hz,
2.37 (dd, 1H, 3J = 1.0 Hz, 2J = 16.6 Hz, CH2C=O),
1.91 – 1.81 (m, 1H, CH2), 1.72 – 1.65 (m, 1H, CH2), 1.27,
1.15, 1.10, 1.09 (4s, 36H, PivCH3), 0.86 (t, 3H, 3J =
7.4 Hz, CH3). – 3C NMR (CDCl3, 100.6 MHz): δ = 192.18
(C=O), 177.81, 177.17, 177.06, 176.52 (PivC=O), 149.78
(NCH=CH), 100.10 (NCH=CH), 91.47 (C-1), 72.80, 71.31,
66.48, 65.70 (C-2, C-3, C-4, C-5), 60.83 (C-6), 55.25 (CHN),
39.09, 38.90, 38.78, 38.72 (PivCMe3), 38.62 (CH2C=O),
27.18, 27.12, 27.03 (PivCH3), 23.77 (CH2), 10.26 (CH3).
J5 ,6b = 1.6 Hz, H-5ꢀ), 3.85 (s, 3H, OCH3), 3.90 (m, 1H,
ꢀ
ꢀ
H-6aꢀ), 3.91 (s, 3H, OCH3), 4.09 (dd, 1H, J6b ,5 = 1.8 Hz,
ꢀ
ꢀ
J6b ,6a = 12.6 Hz, H-6bꢀ), 4.25 (d, 1H, J1 ,2 = 9.6 Hz, H-1ꢀ),
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
4.72 (dd, 1H, Jvic = 5.0 Hz, Jvic = 12.1 Hz, arylCHN), 5.04 (t,
1H, J = 9.4 Hz, H-4ꢀ), 5.13 (d, 1H, J = 8.5 Hz, alkene), 5.20
(m, 1H, H-3ꢀ), 5.35 (dd, 1H, J2 ,3 = 9.0 Hz, J2 ,1 = 9.3 Hz,
H-2ꢀ), 6.82 (m, 3H, aryl), 7.29 (d, 1H, J = 8.2 Hz, alkene). –
13C NMR (100.6 MHz, CDCl3): δ = 26.94 and 27.07 (Piv-
CH3), 38.67, 38.74 and 38.79 (Piv-Cquart), 44.02 (CH2C=O),
55.90 and 56.06 (OCH3), 61.14 (arylCHN), 61.60 (C-6ꢀ),
67.47, 67.56, 72.80 and 74.02 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 86.47
(C-1ꢀ), 104.05 (alkene), 110.70, 111.50, 120.52 and 129.78
ꢀ
ꢀ
ꢀ
ꢀ
N-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-
isopropyl-5,6-dehydropiperidin-4-one (6a)
Purification was carried out by column chromatogra- (aryl), 148.94 (alkene), 149.55 and 149.62 (aryl), 176.18,
phy with light petroleum/ethyl acetate 3 : 1. Yield: 3.7 g 176.56, 176.91 and 177.76 (PivC=O), 192.06 (C=O).
Unauthenticated
Download Date | 12/13/16 10:18 AM

S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1645
N-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-(3ꢀꢀ-
furyl)-5,6-dehydropiperidin-4-one (6c)
N-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-(4ꢀꢀ-
pentenyl)-5,6-dehydropiperidin-4-on (6e)
Purification was achieved by recrystallization from
CH2Cl2 and light petroleum. Yield: 4.76 g (72 %); color-
less cryst. solid, m. p. 98 ◦C, [α]D22= −25.5 (c = 1.0, CHCl3).
Rf = 0.13 (light petroleum/ethyl acetate 3 : 1); HPLC (crude
product): Lichrospher C18; methanol, 25 % water; UV detec-
tion at 308.5 nm; Rt = 14.77 (minor diastereomer), 17.00 min
(major diastereomer); d. r.: 21.2 : 1 (HPLC). – C35H51NO11
(661.79): calcd. C 62.85, H 7.91, N 2.16; found C 62.81,
H 7.84, N 2.13. – 1H NMR (200 MHz, CDCl3): δ = 1.06,
1.08 and 1.16 (3s, 36H, Piv-CH3), 2.61 (m, 2H, CH2C=O),
Purification was carried out by column chromatogra-
phy in light petroleum/ethyl acetate 4 : 1. Yield: 4.25 g
(64 %, related on glucosylamine 4), colorless, amorphous
solid, [α]2D2 = −84.9 (c = 1.0, CHCl3). Rf = 0.57 (light
petroleum/ethyl acetate 1 : 1). HPLC (crude product): Euro-
spher C18; methanol, 20 % water; UV detection at 309.0 nm;
Rt = 9.65 (minor diastereomer), 11.52 min (major diastere-
omer); d. r.: 6.2 : 1 (HPLC). – C36H57NO10 (663.84): calcd.
C 65.14, H 8.65, N 2.11; found C 64.89, H 8.60, N 2.07. –
1H NMR (400 MHz, CDCl3): δ = 1.05, 1.06, 1.10 and 1.16
(4s, each 9H, Piv-CH3), 1.25, 1.38, 1.59 and 1.83 (4m, each
1H, CH2), 1.96 (m, 2H, CH2), 2.29 (d, 1H, J = 16.6 Hz,
CH2C=O), 2.55 (dd, 1H, Jvic = 6.4 Hz, Jgem = 16.8 Hz,
ꢀ
ꢀ
ꢀ
ꢀ
3.63 (ddd, 1H, J5 ,6b = 1.7 Hz, J5 ,6a = 4.7 Hz, J5,4 = 10.4 Hz,
H-5ꢀ), 3.99 (dd, 1H, J6a ,5 = 4.8 Hz, J6a ,6b = 12.5 Hz, H-6aꢀ),
ꢀ
ꢀ
ꢀ
ꢀ
4.12 (dd, 1H, J6b ,5 = 1.8 Hz, J6b ,6a = 12.5 Hz, H-6bꢀ), 4.48
ꢀ
ꢀ
ꢀ
ꢀ
(d, 1H, J1 ,2 = 8.8 Hz, H-1ꢀ), 4.77 (dd, 1H, Jvic = 5.8 Hz,
ꢀ
ꢀ
CH2C=O), 3.67 (m, 1H, alkylCHN), 3.75 (dd, 1H, J5,4
=
Jvic = 7.1 Hz, furylCHN), 5.11 (dd, 1H, J4 ,3 = 7.9 Hz, H-4ꢀ),
5.30 (m, 3H, H-3ꢀ, H-2ꢀ, alkene), 6.37 (s, 1H, aryl), 7.03 (d,
1H, J = 7.9 Hz, alkene), 7.34 (m, 2H, aryl). – 13C NMR
(50.3 MHz, CDCl3): δ = 26.93 and 27.03 (Piv-CH3), 38.67
and 38.78 (Piv-Cquart), 42.10 (CH2C=O), 50.56 (furyl CHN),
61.54 (C-6ꢀ), 67.28, 68.07, 72.46 and 74.23 (C-2ꢀ, C-3ꢀ,
C-4ꢀ, C-5ꢀ), 88.31 (C-1ꢀ), 102.59 (alkene), 109.59 and 122.68
(furyl), 148.78 (alkene), 176.21, 176.77, 176.91 and 177.79
(PivC=O), 191.86 (C=O).
ꢀ
ꢀ
10.1 Hz, J5 ,6a = 3.8 Hz, H-5ꢀ), 4.00 (m, 2H, H-6aꢀ, H-6bꢀ),
ꢀ
ꢀ
4.51 (d, 1H, J1 ,2 = 9.1 Hz, H-1ꢀ), 4.91 (m, 3H, alkene,
ꢀ
ꢀ
ꢀ
ꢀ
alkene-CH2), 5.11 (dd, 1H, J4,5 = 9.8 Hz, J4 ,3 = 9.6 Hz,
H-4ꢀ), 5.26 (t, 1H, J = 9.3 Hz, H-3ꢀ), 5.34 (t, 1H, J = 9.4 Hz,
H-2ꢀ), 5.68 (dd, 1H, J1 = 10.3 Hz, J2 = 17.0 Hz, alkeneꢀ-CH),
6.84.(d, 1H, J = 7.7 Hz, olefin). – 13C NMR (100.6 MHz,
CDCl3): δ = 24.85 (CH2), 26.95, 27.00 and 27.07 (Piv-
CH3), 30.18 and 33.43 (CH2), 38.66, 38.67, 38.82 and
38.96 (Piv-Cquart), 53.33 (alkylCHN), 61.42 (C-6ꢀ), 67.24,
68.38, 72.42 and 74.48 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 91.25 (C-1ꢀ),
100.08 (alkene), 114.93 and 137.88 (alkene-Cquart, alkene-
Ctert), 149.49 (alkene), 176.16, 176.83, 176.90 and 177.66
(PivC=O), 191.90 (C=O).
N-(2ꢀ,3ꢀ,4ꢀ,6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-(4ꢀꢀ-
cyano-phenyl)-5,6-dehydropiperidin-4-one (6d)
Purification was carried out by column chromatography
in light petroleum/ethyl acetate 3 : 1.◦Yield: 5.5 g (79 %);
colorless, crystalline solid, m. p. 121 C, [α]2D2 = 22.2 (c =
1.0, CHCl3). Rf = 0.44 (light petroleum/ethyl acetate 1 : 1);
HPLC (crude product): Lichrospher C18; methanol, 15 %
water; UV detection at 309.0 nm; Rt = 2.95 (major diastere-
omer), 3.31 min (minor diastereomer); d. r.: 22.4:1 (HPLC). –
C38H52N2O10 (696.84): calcd. C 65.50, H 7.52, N 4.02;
found C 65.47, H 7.50, N 3.97. – 1H NMR (200 MHz,
Bromination of N-Galactosyl-dehydropiperidinones 3 –
General procedure
To a solution of dehydropiperidinone 3 (see, Table 2,
◦
1 mmol) in tetrahydrofuran (20 mL) at −78 C, N-bromo-
succinimide (NBS, equivalents are given for the correspond-
ing compound) was added. The solution was stirred at this
temperature for the indicated time. Then, the solution was
warmed up to r. t. Diethyl ether (100 mL) was added, and the
solution was washed three times with 20 mL of 10 % aqueous
Na2S2O3. The combined aqueous solutions were extracted
with diethyl ether (50 mL). The combined ether solutions
were washed with brine (50 mL). After drying with MgSO4,
the solvent was evaporated, and the crude product was puri-
fied by chromatography.
CDCl3): δ = 1.07 (m, 36H, Piv-CH3), 2.50 (dd, 1H, Jvic
=
=
=
4.6 Hz, Jgem = 16.5 Hz, CH2C=O), 2.90 (dd, 1H, Jvic
ꢀ
ꢀ
7.0 Hz, Jgem = 16.5 Hz, CH2C=O), 3.57 (ddd, 1H, J5 ,6a
1.7 Hz, J5 ,6b = 4.2 Hz, J5,4 = 10.2 Hz, H-5ꢀ), 3.85 (m,
ꢀ
ꢀ
2H, H-6aꢀ, H-6bꢀ), 4.52 (d, 1H, J1 ,2 = 8.6 Hz, H-1ꢀ), 4.97
(m, 2H, H-4ꢀ, arylCHN), 5.08 (d, 1H, J = 7.9 Hz, alkene),
5.31 (m, 2H, H-2ꢀ, H-3ꢀ), 7.17 (d, 1H, J = 7.9 Hz, alkene),
7.37 (d, 2H, J = 8.3 Hz, aryl), 7.54 (d, 2H, J = 8.3 Hz,
aryl). – 13C NMR (50.3 MHz, CDCl3): δ = 26.91, 27.06
and 27.13 (Piv-CH3), 38.67 and 38.90 (Piv-Cquart), 42.66
(CH2C=O), 56.77 (arylCHN), 61.13 (C-6ꢀ), 66.89, 68.12,
72.04 and 74.41 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 90.13 (C-1ꢀ), 102.42
ꢀ
ꢀ
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
5-bromo-2-isopropyl-5,6-dehydro-piperidin-4-one (7a)
From 3a: reaction time: 14 h (2 eq. NBS). Purifica-
(alkene), 111.78, 118.25, 127.86 and 132.30 (aryl), 144.47 tion by flash-chromatography in cyclohexane/ethyl acetate
(CN), 149.88 (alkene), 176.15, 176.84, 177.06 and 177.45 5 : 1. Yield: 0.71 g (> 95 %); colorless amorphous solid;
(PivC=O), 190.04 (C=O).
Rf = 0.33 (cyclohexane/ethyl acetate 3 : 1); [α]2D2 = −104.2
Unauthenticated
Download Date | 12/13/16 10:18 AM

1646
S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
(c = 1.0, CHCl3). C34H54BrNO10 (716.70): calcd. C 56.98, ((+)-ESI): m/z = 716.4 [M(79Br)+H]+, 718.4 [M(81Br)+H]+,
H 7.59, N 1.95; found C 56.82, H 7.66, N 1.92. – MS 738.5 [M(79Br)+Na]+, 740.5 [M(81Br)+Na]+. – 1H NMR
((+)-ESI): m/z = 716.5 [M(79Br)+H]+, 718.5 [M(81Br)+H]+, (200 MHz, CDCl3): δ = 7.25 (s, 1H, CH=CBr), 5.52 – 5.42
738.4 [M(79Br)+Na]+, 740.4 [M(81Br)+Na]+. – 1H NMR (m, 2H, H-2, H-4), 5.15 (dd, 1H, 3J = 3.2 Hz, 3J = 10.0 Hz,
(200 MHz, CDCl3): δ = 7.32 (s, 1H, CH=CBr), 5.49 (t, H-3), 4.56 (d, 1H, 3J = 8.8 Hz, H-1), 4.21-3.90 (m, 3H, H-5,
1H, 3J = 10.1 Hz, H-2), 5.41 (d, 1H, 3J = 2.9 Hz, H-4), H-6a, H-6b), 3.84-3.73 (m, 1H, CHN), 2.74 (dd, 1H, 3J =
5.14 (dd, 1H, 3J = 3.2 Hz, 3J = 10.1 Hz, H-3), 4.62 (d, 5.9 Hz, 2J = 16.6 Hz, CH2C=O), 2.57 (dd, 1H, 3J = 1.9 Hz,
1H, 3J = 8.8 Hz, H-1), 4.18 – 3.90 (m, 3H, H-5, H-6a, 2J = 16.6 Hz, CH2C=O), 1.65 – 1.59 (m, 1H, CH2), 1.85 –
H-6b), 3.59 – 3.52 (m, 1H, CHN), 2.75 (dd, 1H, 3J = 6.8 Hz, 1.78 (m, 1H, CH2), 1.36 – 1.10 (m, 38H, PivCH3, CH2),
2J = 17.1 Hz, CH2C=O), 2.63 (dd, 1H, 3J = 2.9 Hz, 2J = 0.88 (t, 3H, 3J = 7.3 Hz, CH3). – 13C NMR (50.3 MHz,
17.1 Hz, CH2C=O), 2.27 – 2.14 (m, 1H, CH(CH3)2), 1.25, CDCl3): δ = 184.53 (C=O), 177.77, 177.16, 177.11, 176.49
1.14, 1.10, 1.09 (4s, 36H, PivCH3), 0.91, 0.86 (2d, 6H, (PivC=O), 149.68 (CH=CBr), 91.36 (CH=CBr), 91.30 (C-1),
3J = 7.1 Hz, CH3). – 13C NMR (50.3 MHz, CDCl3): δ = 73.66, 71.08, 66.46, 66.06 (C-2, C-3, C-4, C-5), 60.87 (C-6),
184.90 (C=O), 177.78, 177.14, 176.49 (PivC=O), 149.95 53.43 (CHN), 39.10 (CH2C=O), 38.99, 38.96, 38.80, 38.75
(CH=CBr), 92.10 (CH=CBr), 90.94 (C-1), 73.13, 71.37, (PivCMe3), 32.93 (CH2), 27.20, 27.13, 27.05 (PivCH3),
66.50, 66.01 (C-2, C-3, C-4, C-5), 61.00 (C-6); 59.00 (CHN), 18.87 (CH2), 13.70 (CH3).
39.10, 39.02, 38.79, 38.31 (PivCMe3), 35.94 (CH2C=O),
31.63 (CH(CH3)2), 27.20, 27.15 (PivCH3), 19.79, 17.86
(CH3).
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-5-
bromo-2-phenyl-5,6-dehydro-piperidin-4-one (7d)
From 3g: reaction time: 14 h (2 eq. NBS). Purification
N-(2ꢀ,3ꢀ,4ꢀ6ꢀ-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
2-(3ꢀꢀ-furyl)-5-b romo-5,6-dehydropiperidin-4-one (7b)
by flash-chromatography with light petroleum/ethyl acetate
8 : 1. Yield: 0.67 g (89 %); colorless amorphous solid, [α]D22
=
7.1 (c = 1.0, CHCl3). Rf = 0.27 (light petroleum/ethyl acetate
5 : 1). – C37H52BrNO10 (750.71): calcd. C 59.20, H 6.98,
N 1.87; found C 58.97, H 7.12, N 1.81. – MS ((+)-ESI): m/z =
772.3 [M(79Br)+Na]+, 774.3 [M(81Br)+Na]+. – 1H NMR
(200 MHz, CDCl3): δ = 7.65 (s, 1H, NCH=CBr), 7.36 – 7.23
(m, 5H, aryl), 5.53 (t, 1H, 3J = 9.8 Hz, H-2), 5.31 (d, 1H,
From 3c: reaction time: 12 h (1.5 eq. NBS). Purifica-
tion by column chromatography with light petroleum/ethyl
acetate 3 : 1. Yield: 0.46 g (62 %); colorless amorphous
solid; Rf = 0.37 (light petroleum/ethyl acetate 3 : 1). –
C35H50NO11Br (740.68): calcd. C 56.76, H 6.80, N 1.89;
found C 56.68, H 6.96, N 1.86. – 1H NMR (400 MHz,
CDCl3): δ = 7.35 – 7.39 (m, 3H, alkene, furyl), 6.35 (d, 1H,
3J = 2.9 Hz, H-4), 4.99 (dd, 1H, J = 2.9 Hz, J = 9.8 Hz,
H-3), 4.86 (dd, 1H, 3J = 6.3 Hz, 3J = 9.3 Hz, CHN), 4.32 (d,
1H, 3J = 9.3 Hz, H-1), 3.96 – 3.68 (m, 3H, H-5, H-6a, H-6b),
2.93 – 2.87 (m, 2H, CH2C=O), 1.26, 1.16, 1.15, 1.08 (4s,
36H, PivCH3). – 13C NMR (50.3 MHz, CDCl3): δ = 184.26
(C=O), 177.70, 177.08, 177.03, 176.51 (PivC=O), 150.14
(CH=CBr), 137.44 (ipso-aryl), 129.09, 128.98, 127.13 (aryl),
95.37 (CH=CBr), 88.00 (C-1), 72.82, 71.31, 66.60, 65.39
(C-2, C-3, C-4, C-5), 61.08 (C-6), 60.39 (CHN), 43.30
(CH2C=O), 38.96, 38.78, 38.69 (PivCMe3), 27.21, 27.18,
27.07, 27.04 (PivCH3).
3
3
ꢀ
ꢀ
ꢀ
ꢀ
J = 0.7 Hz, furyl), 5.50 (dd, 1H, J2 ,1 = 9.4 Hz, J2 ,3 =
9.8 Hz, H-2ꢀ), 5.40 (d, 1H, J4 ,3 = 3.0 Hz, H-4ꢀ), 5.11 (dd,
ꢀ
ꢀ
1H, J3 ,4 = 3.1 Hz, J3 ,2 = 10.1 Hz, H-3ꢀ), 4.82 (t, 1H, J =
ꢀ
ꢀ
ꢀ
ꢀ
5.8 Hz, furylCHN), 4.55 (d, 1H, J1 ,2 = 9.2 Hz, H-1ꢀ), 3.96 –
4.07 (m, 3H, H-5ꢀ, H-6aꢀ, H-6bꢀ), 2.92 (dd, 1H, Jvic = 7.7 Hz,
Jgem = 16.6 Hz, CH2C=O), 2.78 (dd, 1H, Jvic = 6.2 Hz,
Jgem = 16.7 Hz, CH2C=O), 1.08, 1.11, 1.14 and 1.25 (4s,
each 9H, Piv-CH3). – 13C NMR (100.6 MHz, CDCl3): δ =
184.35 (C=O), 41.64 (CH2C=O), 177.73, 177.09, 177.04 and
176.453 (PivC=O), 149.11 (CH=), 122.47 and 109.57 (furyl),
73.23, 71.21, 66.62 and 66.00, (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 89.04
(C-1ꢀ), 94.05 (CBr), 61.17 (C-6ꢀ), 50.44 (furylCHN), 39.09,
38.95, 38.77 and 38.71 (Piv-Cquart), 27.21, 27.11 and 27.03
(Piv-CH3).
ꢀ
ꢀ
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
5-bromo-2-(4-chlorphenyl)-5,6-dehydro-piperidin-4-
one (7e)
From 3h: reaction time: 4 h + 4 h (1.5 eq. + 1.5 eq.
NBS). Since after 4 h considerable amounts of starting
material 3h were detectable, additional 1.5 eq. of NBS
were added, and stirring was continued for additional
(2R)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
5-bromo-2-n-propyl-5,6-dehydro-piperidin-4-one (7c)
From 3f: reaction time: 24 h (5 eq. NBS). Purification by 4 h. Purification by flash-chromatography with cyclo-
flash-chromatography in light petroleum/ethyl acetate 8 : 1. hexane/ethyl acetate 5 : 1. Yield: 0.68 g (86 %); colorless
Yield: 0.34 g (48 %); colorless amorphous solid; [α]D22
=
amorphous solid, [α]2D2 = 7.3 (c = 1.0, CHCl3). Rf
=
−87.0 (c = 1.0, CHCl3). Rf = 0.44 (light petroleum/ethyl 0.37 (cyclohexane/ethyl acetate 3 : 1). – C37H51BrClNO10
acetate 3 : 1). – C34H54BrNO10 (716.70): calcd. C 56.98, (785.16): calcd. C 56.60, H 6.55, N 1.78; found C 56.65,
H 7.59, N 1.95; found C 56.89, H 7.61, N 1.95. – MS H 6.56, N 1.70. – MS ((+)-ESI): m/z = 784.2 [M(79Br)+H]+,
Unauthenticated
Download Date | 12/13/16 10:18 AM

S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1647
786.2 [M(81Br)+H]+, 806.3 [M(79Br)+Na]+, 808.3 calcd. C 56.41, H 7.46, N 1.99; found C 56.32, H 7.47,
[M(81Br)+Na]+, 847.3 [M(79Br)+CH3CN+Na]+, 849.3 N 1.98. – MS ((+)-ESI): m/z = 702.5 [M(79Br)+H]+,
[M(81Br)+CH3CN+Na]+. – 1H NMR (200 MHz, CDCl3): 704.5 [M(81Br)+H]+, 724.4 [M(79Br)+Na]+, 726.4
3
δ = 7.59 (s, 1H, CH=CBr), 7.30 (d, 2H, J = 8.3 Hz, aryl), [M(81Br)+Na]+, 765.4 [M(79Br)+CH3CN+Na]+, 767.4
7.19 (d, 2H, 3J = 8.8 Hz, aryl), 5.52 (t, 1H, 3J = 9.8 Hz, H-2), [M(81Br)+CH3CN+Na]+. – 1H NMR (200 MHz, CDCl3):
3
5.33 (d, 1H, J = 3.4 Hz, H-4), 5.05 (dd, 1H, 3J = 2.9 Hz, δ = 7.26 (s, 1H, CH=CBr), 5.48 (t, 1H, 3J = 10.0 Hz, H-2),
3
3
3J = 10.2 Hz, H-3), 4.86 (t, 1H, 3J = 6.8 Hz, CHN), 4.42 5.42 (d, 1H, J = 3.4 Hz, H-4), 5.15 (dd, 1H, J = 2.9 Hz,
(d, 1H, 3J = 9.3 Hz, H-1), 3.89 – 3.78 (m, 3H, H-5, H-6a, 3J = 10.3 Hz, H-3), 4.57 (d, 1H, 3J = 8.8 Hz, H-1), 4.15
H-6b), 2.99 (dd, 1H, J = 5.9 Hz, 2J = 16.6 Hz, CH2C=O), (dd, 1H, 3J = 5.9 Hz, 2J = 9.3 Hz, H-6a), 4.02 (dd, 1H, 3J =
3
2.79 (dd, 1H, 3J = 7.6 Hz, 2J = 16.3 Hz, CH2C=O), 1.24, 5.9 Hz, 2J = 11.7 Hz, H-6b), 3.93 (t, 1H, 3J = 6.4 Hz, H-5),
1.16, 1.13, 1.09 (4s, 36H, PivCH3). – 13C NMR (50.3 MHz, 3.63 – 3.58 (m, 1H, CHN), 2.73 (dd, 1H, J = 6.1 Hz, J =
CDCl3): δ = 183.72 (C=O), 177.70, 177.16, 177.05, 176.43 16.8 Hz, CH2C=O), 2.60 (dd, 1H, 3J = 2.4 Hz, 2J = 16.6 Hz,
(PivC=O), 150.10 (CH=CBr), 136.50, 134.60 (ipso-aryl), CH2C=O), 1.92 – 1.61 (m, 2H, CH2), 1.26, 1.15, 1.10,
129.21, 128.22 (aryl), 94.72 (CH=CBr), 88.99 (C-1), 72.97, 1.09 (4s, 36H, PivCH3), 0.86 (t, 3H, 3J = 7.3 Hz, CH3). –
71.12, 66.50, 65.58 (C-2, C-3, C-4, C-5), 60.97 (C-6), 58.62 13C NMR (50.3 MHz, CDCl3): δ = 184.47 (C=O), 177.78,
(CHN), 43.03 (CH2C=O), 39.01, 38.78, 38.69 (PivCMe3), 177.14, 177.10, 176.44 (PivC=O), 149.71 (CH=CBr), 91.37
3
2
27.20, 27.04 (PivCH3).
(CH=CBr), 91.21 (C-1), 73.09, 71.10, 66.44, 65.99 (C-2,
C-3, C-4, C-5), 60.87 (C-6), 55.40 (CHN), 39.10 (CH2C=O),
38.97, 38.78, 38.74, 38.50 (PivCMe3), 27.20, 27.12, 27.04
(PivCH3), 24.09 (CH2), 10.23 (CH3).
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
5-bromo-2-(4-bromophenyl)-5,6-dehydropiperidin-4-
one (7f)
(2S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-5-
iodo-2-isopropyl-5,6-dehydropiperidin-4-one (8)
From 3i; reaction time: 2 h (2 eq. NBS). Purification
by flash-chromatography with light petroleum/ethyl acetate
8 : 1. Yield: 0.72 g (87 %); colorless amorphous solid; [α]D22
=
Compound 8 was synthesized from N-galactosyl-2-
11.0 (c = 1.0, CHCl3). Rf = 0.41 (cyclohexane/ethyl acetate isoproyl-dehydropiperidinone 3a (2.13 g, 3.33 mmol) ac-
3 : 1). – C37H51Br2NO10 (829.61): calcd. C 53.57, H 6.20, cording to the general procedure for the bromination reac-
N 1.69; found C 53.48, H 6.19, N 1.66. – MS ((+)-ESI): tion, but using N-iodosuccinimide (NIS, 2 eq.) instead of
m/z = 828.4 [M(2 79Br)+H]+, 830.4 [M(79Br + 81Br)+H]+, NBS. Reaction time: 2.5 h. Purification was carried out by
832.4 [M(2 81Br)+H]+, 850.4 [M(2 79Br)+Na]+, 852.4 flash-chromatography with cyclohexane/ethyl acetate 11 : 1.
[M(79Br + 81Br)+Na]+, 854.3 [M(2 81Br)+Na]+. – 1H NMR Yield: 2.84 g (90 %); colorless amorphous solid, [α]2D2
=
(400 MHz, CDCl3): δ = 7.59 (s, 1H, CH=CBr), 7.44 (d, −123.9 (c = 1.0, CHCl3). Rf = 0.47 (cyclohexane/ethyl
2H, 3J = 8.2 Hz, aryl), 7.13 (d, 2H, 3J = 8.6 Hz, aryl), acetate 2 : 1). – C34H54INO10 (763.70): calcd. C 53.47,
5.51 (t, 1H, 3J = 9.6 Hz, H-2), 5.33 (d, 1H, 3J = 3.1 Hz, H 7.13, N 1.83; found C 53.19, H 7.18, N 1.75. – ESI-
H-4), 5.05 (dd, 1H, 3J = 3.1 Hz, 3J = 10.2 Hz, H-3), 4.84 MS (ES+): m/z = 764.3 [M+H]+, 786.3 [M+Na]+, 827.4
(t, 1H, 3J = 6.8 Hz, CHN), 4.42 (d, 1H, 3J = 9.4 Hz, [M+CH3CN+Na]+. – 1H NMR (200 MHz, CDCl3): δ =
3
H-1), 3.90 – 3.78 (m, 3H, H-5, H-6a, H-6b), 2.98 (dd, 1H, 7.44 (s, 1H, NCH=CI), 5.50 (t, 1H, J = 9.5 Hz, H-2), 5.41
3
3
3
3J = 6.2 Hz, 2J = 16.4 Hz, CH2C=O), 2.79 (dd, 1H, 3J = (d, 1H, J = 2.9 Hz, H-4), 5.14 (dd, 1H, J = 2.9 Hz, J =
2
3
7.8 Hz, J = 16.4 Hz, CH2C=O), 1.24, 1.15, 1.13, 1.08 (4s, 9.8 Hz, H-3), 4.62 (d, 1H, J = 9.3 Hz, H-1), 4.15 (dd, 1H,
36H, PivCH3). – 13C NMR (50.3 MHz, CDCl3): δ = 183.67 3J = 5.4 Hz, 2J = 8.8 Hz, H-6a), 4.07 – 3.90 (m, 2H, H-5,
(C=O), 177.69, 177.16, 177.03, 176.41 (PivC=O), 150.06 H-6b), 3.65 – 3.57 (m, 1H, CHN), 2.74 (d, 2H, 3J = 4.9 Hz,
(CH=CBr), 137.02 (ipso-aryl), 132.16, 128.50 (aryl), 122.69 CH2C=O), 2.30 – 2.15 (m, 1H, CH(CH3)2), 1.26, 1.15, 1.11,
(ipso-CBr), 94.72 (CH=CBr), 89.01 (C-1), 72.98, 71.12, 1.10 (4s, 36H, PivCH3), 0.90, 0.86 (2d, 6H, 3J = 4.6 Hz,
66.50, 65.59 (C-2, C-3, C-4, C-5), 60.97 (C-6), 58.64 (CHN), CH3). – 13C NMR (50.3 MHz, CDCl3): δ = 186.16 (C=O),
42.96 (CH2C=O), 39.07, 38.99, 38.78, 38.69 (PivCMe3), 177.78, 177.14, 176.49 (PivC=O), 154.48 (NCH=), 90.90
27.20, 27.04 (PivCH3).
(C-1), 73.13, 71.37, 66.49, 66.02 (C-2, C-3, C-4, C-5), 64.68
(=CI), 61.00 (C-6), 58.94 (CHN), 39.10, 39.05, 38.80, 38.74
(PivCMe3), 35.08 (CH2C=O), 31.90 (CH(CH3)2), 27.20,
27.04, 26.91 (PivCH3), 19.78 (CH3), 17.83 (CH3).
(2R)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-5-
bromo-2-ethyl-5,6-dehydropiperidin-4-one (7g)
From 3j: reaction time: 2 h (5 eq. NBS). Purification
by flash-chromatography with light petroleum/ethyl acetate
8 : 1. Yield: 0.61 g (87 %); colorless amorphous solid,
[α]2D2 = −108.4 (c = 1.0, CHCl3). Rf = 0.34 (cyclo-
N-(2ꢀ,3ꢀ,4ꢀ6ꢀ-Tetra-O-pivaloyl-β-D-glucopyranosyl)-2-
(4ꢀꢀ-cyanophenyl)-5-bromo-5,6-dehydropiperidin-4-one (9)
Compound 9 was obtained from N-glucopyranosyl-de-
hexane/ethyl acetate 3 : 1). – C33H52BrNO10 (702.67): hydropiperidinone 6d according to the general procedure for
Unauthenticated
Download Date | 12/13/16 10:18 AM

1648
S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
the bromination of the N-galactosyl derivatives using 5 eq. 5.52 – 5.46 (m, 1H, H-2), 5.37 (d, 1H, 3J = 2.3 Hz, H-4),
of NBS. Reaction time 4 h. Purification was carried out by 5.14 (dd, 1H, 3J = 2.9 Hz, 3J = 10.0 Hz, H-3), 4.87 (dd,
column chromatography with light petroleum/ethyl acetate 1H, 3J = 6.7 Hz, 3J = 11.2 Hz, CHBr), 4.42 (d, 1H, 3J =
3 : 1. Yield: 0.295 g (38 %); conversion 50 %; colorless amor- 9.4 Hz, H-1), 4.02 – 3.86 (m, 4H, H-5, H-6a, H-6b, NCH2),
phous solid, [α]2D2 = −43.9 (c = 1.0, CHCl3). Rf = 0.30 (light 3.10 (dd, 1H, 3J = 11.1 Hz, 2J = 15.1 Hz, NCH2), 2.99 (dd,
petroleum/ethyl acetate 3 : 1). – C38H51N2O10Br (775.73): 1H, 3J = 5.7 Hz, 2J = 12.7 Hz, CH2CO), 2.89 – 2.82 (m,
calcd. C 58.84, H 6.63, N 3.61; found C 58.59, H 6.72, 2H, CHN, CH2CO), 1.64 – 1.55 (m, 1H, CH(CH3)2), 1.27,
N 3.76. – 1H NMR (400 MHz, CDCl3): δ = 7.57 (d, 2H, J = 1.14, 1.12, 1.11 (4s, 36H, PivCH3), 0.88, 0.82 (2d, 6H, 3J =
8.4 Hz, aryl), 7.54 (s, 1H, alkene), 7.36 (d, J = 8.3 Hz, aryl), 6.7 Hz, CH3). – 13C NMR (50.3 MHz, CDCl3): δ = 200.51
5.33 (dd, 1H, J2 ,3 = 2.5 Hz, J2 ,1 = 6.8 Hz, H-2ꢀ), 5.30 (dd, (C=O), 177.83, 177.35, 177.14, 176.76 (PivC=O), 95.39
ꢀ
ꢀ
ꢀ
ꢀ
1H, J3 ,2 = 2.5 Hz, J3 ,4 = 6.7 Hz, H-3ꢀ), 5.01 (m, 2H, H-1ꢀ, (C-1), 72.20, 72.03, 67.30, 66.47 (C-2, C-3, C-4, C-5), 65.74
ꢀ
ꢀ
ꢀ
ꢀ
H-4ꢀ), 4.58 (dd, 1H, Jvic = 2.3 Hz, Jvic = 6.4 Hz, arylCHN), (CHN), 62.08 (C-6), 53.51 (CHBr), 49.79 (NCH2), 44.37
ꢀ
3.92 (dd, 1H, J6b ,5 = 1.6 Hz, J6b ,6a = 12.6 Hz, H-6bꢀ), 3.82 (CH2C=O), 38.70, 38.80 (PivCMe3), 29.77 (CH(CH3)2),
ꢀ
ꢀ
ꢀ
ꢀ
(dd, 1H, J6a ,5 = 4.6 Hz, J6a ,6b = 12.6 Hz, H-6aꢀ), 3.63 (ddd, 27.28, 27.23, 27.10, 27.07 (PivCH3), 20.19, 19.71 (CH3).
ꢀ
ꢀ
ꢀ
ꢀ
1H, J5 ,6b = 1.5 Hz, J5 ,6a = 4.5 Hz, J5 ,4 = 10.1 Hz, H-5ꢀ),
3.09 (dd, 1H, Jvic = 6.8 Hz, Jgem = 16.7 Hz, CH2C=O), 2.77
(dd, 1H, Jvic = 4.4 Hz, Jgem = 16.7 Hz, CH2C=O), 1.12, 1.08,
1.07 and 1.06 (4s, je 9H, Piv-CH3). – 13C NMR (100.6 MHz,
CDCl3): δ = 182.77 (C=O), 177.40, 177.14, 176.79, 176.14
(PivC=O), 149.58 (NCH=), 143.55 (CN), 132.50, 127.22,
118.04 and 112.27 (aryl), 94.00 (=CBr), 89.93 (C-1ꢀ), 74.71,
71.92, 68.45 and 66.88 (C-2ꢀ, C-3ꢀ, C-4ꢀ, C-5ꢀ), 61.11 (C-6ꢀ),
56.80 (arylCHN), 42.24 (CH2C=O), 38.96 and 38.69 (Piv-
Cquart), 27.13, 27.06, 26.94 (Piv-CH3).
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
ꢀ
(2R,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyr
-anosyl)-5-bromo-2-n-propyl-piperidin-4-one (10b)
From 3f. Reaction time: 1 h. Purification by flash-
chromatography with cyclohexane/ethyl acetate 8 : 1. Yield:
1.18 g (82 %); colorless amorphous solid, [α]2D2 = 1.2 (c =
1.0, CHCl3). Rf = 0.41 (light petroleum/ethyl acetate 3 : 1);
d. r.: 91 : 9 : 0 : 0 (analytical HPLC of the crude product,
Luna C-18, 80 % → 100 % CH3CN, 40 min, λ = 215 nm,
Rt = 27.60 (minor diastereomer), 30.32 min (major diastere-
omer)). – C34H56BrNO10 (718.71): calcd. C 56.82, H 7.85,
N 1.95; found C 56.89, H 7.81, N 1.95. – MS ((+)-ESI):
m/z = 718.4 [M(79Br)+H]+, 720.4 [M(81Br)+H]+, 740.3
N-Galactosyl bromopiperidinones (10) – General
procedure
To a solution of 5-bromo-5,6-dehydropiperidinone 7 [M(79Br)+Na]+, 742.3 [M(81Br)+Na]+. – 1H NMR (CDCl3,
(2 mmol) in 25 mL of dry tetrahydrofuran at −78 ◦C, 1.25 eq. 400 MHz): δ = 5.47 (t, 1H, 3J = 9.6 Hz, H-2), 5.38 (d,
(or 1.75 eq., see Table 3) of a 1 M solution of L-SelectrideꢀR 1H, 3J = 2.7 Hz, H-4), 5.14 (dd, 1H, 3J = 2.9 Hz, 3J =
in tetrahydrofuran was added dropwise. After stirring for the 9.9 Hz, H-3), 4.89 (dd, 1H, 3J = 6.8 Hz, 3J = 11.1 Hz,
reaction time given in Table 3 the solution was warmed up CHBr), 4.43 (d, 1H, 3J = 9.4 Hz, H-1), 4.05 – 3.90 (m,
to r. t. and stirred for 15 min. Then, the mixture was cooled 3H, H-5, H-6a, H-6b), 3.86 (dd, 1H, 3J = 6.1 Hz, 2J =
◦
to −78 C, and 1 mL glacial acetic acid was added. At r. t., 15.1 Hz, NCH2), 3.35 – 3.29 (m, 1H, CHN), 3.14 (dd, 1H,
the solvent was evaporated in vacuo. The remainder was dis- 3J = 11.3 Hz, 2J = 14.5 Hz, NCH2), 3.02 (dd, 1H, 3J =
solved in diethyl ether (50 mL), and the solution was washed 6.3 Hz, 2J = 13.3 Hz, CH2C=O), 2.52 (dd, 1H, 3J =
2
with brine (20 mL). After drying the organic solution with 1.4 Hz, J = 13.1 Hz, CH2C=O), 1.42 – 1.30 (m, 4H, CH2),
3
MgSO4 the solvent was evaporated in vacuo to give the crude 1.27, 1.14, 1.13, 1.10 (4s, 36H, PivCH3), 0.84 (t, 3H, J =
5-bromo-piperidinones 10.
7.2 Hz, CH3). – 13C NMR (50.3 MHz, CDCl3): δ = 200.05
(C=O), 177.29, 177.10, 176.92, 176.75 (PivC=O), 95.42
(C-1), 72.31, 71.93, 67.06, 65.56 (C-2, C-3, C-4, C-5), 63.04
(CHN), 62.05 (C-6), 54.23 (CHBr), 49.68 (NCH2), 47.35
(CH2C=O), 39.13, 38.78, 38.74, 38.70 (PivCMe3), 35.14
(CH2), 27.18, 27.26 (Piv-CH3), 19.62 (CH2), 13.65 (CH3).
(2S,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyr-
anosyl)-5-bromo-2-isopropyl-piperidin-4-one (10a)
From 3a. Reaction time: 2.5 h. Purification by flash-
chromatography with cyclohexane/ethyl acetate 6 : 1. Yield:
1.35 g (94 %); yellow amorphous solid; [α]2D2 = −1.2 (c =
1.0, CHCl3). Rf = 0.44 (cyclohexane/ethyl acetate 3 : 1);
d. r.: 94 : 6 : 0 : 0 (analytical HPLC of the crude product,
Luna C-18, 80 % → 100 % CH3CN, 40 min, λ = 240 nm,
(2R,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyr-
anosyl)-5-bromo-2-ethyl-piperidin-4-one (10c)
From 3h. Reaction time: 2 h. Purification by flash-
Rt = 27.62 (minor diastereomer), 31.47 min (major di- chromatography with cyclohexane/ethyl acetate 8 : 1. Yield:
astereomer)). – MS ((+)-ESI): m/z = 718.4 [M(79Br)+H]+, 1.28 g (91 %); colorless amorphous solid, [α]D22 = 3.3
720.4 [M(81Br)+H]+, 740.3 [M(79Br)+Na]+, 742.3 (c = 1.0, CHCl3). Rf = 0.38 (cyclohexane/ethyl acetate
[M(81Br)+Na]+. – 1H NMR (400 MHz, CDCl3): δ = 3 : 1); d. r.: 92 : 8 : 0 : 0 (analytical HPLC of the crude
Unauthenticated
Download Date | 12/13/16 10:18 AM

S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1649
product, Luna C-18, 80 % → 100 % CH3CN, 40 min, (CH2C=O), 39.06, 38.69, 38.66, 38.57 (PivCMe3), 27.41,
λ = 228 nm, Rt = 24.37 (minor diastereomer), 27.58 min 27.37, 27.06, 26.89 (PivCH3).
(major diastereomer)). – C33H54BrNO10 (704.69): calcd.
C 56.25, H 7.72, N 1.99; found C 56.50, H 7.81, N 1.94. –
(2S,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranos-
yl)-5-bromo-2-(4-chlorphenyl)-piperidin-4-one (10e)
MS ((+)-ESI): m/z
=
602.3 [M(79Br)–PivOH+H]+,
604.3 [M(81Br)–PivOH+H]+, 704.7 [M(79Br)+H]+,
706.5 [M(81Br)+H]+, 726.3 [M(79Br)+Na]+, 728.4
[M(81Br)+Na]+, 767.3 [M(79Br)+CH3CN+Na]+, 769.4
[M(81Br)+CH3CN+Na]+. – 1H NMR (400 MHz, CDCl3):
δ = 5.47 (t, 1H, 3J = 9.8 Hz, H-2), 5.37 (d, 1H, 3J = 2.8 Hz,
H-4), 5.13 (dd, 1H, 3J = 3.1 Hz, 3J = 9.8 Hz, H-3), 4.87 (dd,
1H, 3J = 6.8 Hz, 3J = 11.2 Hz, CHBr), 4.42 (d, 1H, 3J =
9.0 Hz, H-1), 4.06 – 3.89 (m, 3H, H-5, H-6a, H-6b), 3.84 (dd,
1H, 3J = 6.6 Hz, 2J = 14.9 Hz, NCH2), 3.24 – 3.18 (m, 1H,
CHN), 3.13 (dd, 1H, 3J = 11.3 Hz, 3J = 14.9 Hz, NCH2),
3.00 (dd, 1H, 3J = 6.3 Hz, 2J = 13.3 Hz, CH2C=O), 2.55
(dd, 1H, J = 2.0 Hz, J = 13.3 Hz, CH2C=O), 1.47 – 1.34
(m, 2H, CH2), 1.26, 1.13, 1.12, 1.09 (4s, 36H, PivCH3),
0.81 (t, 3H, 3J = 7.4 Hz, CH3). – 13C NMR (100.6 MHz,
CDCl3): δ = 200.04 (C=O), 177.79, 177.25, 176.88, 176.70
(PivC=O), 95.26 (C-1), 72.22, 71.87, 66.98, 65.46 (C-2,
C-3, C-4, C-5), 64.73 (CHN), 62.00 (C-6), 54.05 (CHBr),
49.57 (NCH2), 46.91 (CH2C=O), 39.07, 38.72, 38.68, 38.65
(PivCMe3), 27.20, 27.15, 27.01 (PivCH3), 26.01 (CH2),
11.01 (CH3).
From 3h. Reaction time: 4 h. 1.75 eq. L-SelectrideꢀR . Pu-
rification by flash-chromatography with cyclohexane/ethyl
acetate 6 : 1. Yield: 1.12 g (71 %); colorless amorphous
solid, [α]2D2 = −25.9 (c = 1.0, CHCl3). Rf = 0.41 (cy-
clohexane/ethyl acetate 3 : 1); d. r.: 91 : 9 : 0 : 0 (analyti-
cal HPLC of the crude product, Luna C-18, 80 % →
100 % CH3CN, 40 min, λ = 219 nm, Rt = 29.71 (mi-
nor diastereomer), 30.18 min (major diastereomer)). –
C37H53BrClNO10 (787.17): calcd.
C 56.45, H 6.79,
N 1.78; found C 56.28, H 6.85, N 1.74. – MS ((+)-
ESI): m/z = 786.5 [M(79Br)+H]+, 788.5 [M(81Br)+H]+,
808.3 [M(79Br)+Na]+, 810.3 [M(81Br)+Na]+. – 1H NMR
(400 MHz, CDCl3): δ = 7.35 (d, 2H, 3J = 8.2 Hz, aryl),
7.17 (d, 2H, 3J = 8.6 Hz, aryl), 5.37 (t, 1H, 3J = 9.6 Hz,
H-2), 5.25 (d, 1H, 3J = 2.7 Hz, H-4), 4.90 (dd, 1H, 3J =
3
2
3
3
3
3.1 Hz, J = 9.8 Hz, H-3), 4.55 (dd, 1H, J = 6.2 Hz, J =
11.7 Hz, CHBr), 4.14 (dd, 1H, 3J = 3.9 Hz, 3J = 11.0 Hz,
CHN), 4.05 – 3.98 (m, 2H, H-6a, NCH2), 3.90 (dd, 1H, 3J =
6.4 Hz, 2J = 11.2 Hz, H-6b), 3.76 (d, 1H, 3J = 9.4 Hz, H-1),
3.48 (t, 1H, 3J = 6.4 Hz, H-5), 3.10 (t, 1H, 3J = 11.9 Hz,
NCH2), 2.80 (dd, 1H, 3J = 3.5 Hz, 2J = 14.5 Hz, CH2C=O),
3
2
(2S,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyr-
anosyl)-5-bromo-2-phenyl-piperidin-4-one (10d)
2.63 (dd, 1H, J = 11.2 Hz, J = 14.3 Hz, CH2C=O), 1.24,
1.20, 1.18, 1.07 (4s, 36H, PivCH3). – 13C NMR (50.3 MHz,
CDCl3): δ = 198.31 (C=O), 177.78, 177.46, 177.03, 176.65
(PivC=O), 137.20, 134.87 (ipso-aryl), 129.48, 129.21 (aryl),
86.98 (C-1), 72.03, 71.34, 67.01, 65.31 (C-2, C-3, C-4, C-5),
63.39 (CHN), 61.67 (C-6), 53.13 (NCH2), 51.74 (CHBr),
48.04 (CH2C=O), 39.07, 38.88, 38.72 (PivCMe3), 27.44,
27.21, 27.13, 27.04 (PivCH3). Single crystals suitable for X-
ray diffraction analysis [20] were obtained after recrystalliza-
tion from isopropanol.
From 3g. Reaction time: 3 h. Purification by flash-
chromatography with light petroleum/ethyl acetate 5 : 1.
Yield: 1.08 g (72 %, conversion 87 %); yellow amorphous
solid, [α]2D2 = −41.5 (c = 1.0, CHCl3). Rf = 0.47 (light
petroleum/ethyl acetate 3:1); d. r.: 83 : 17 : 0 : 0 (analytical
HPLC of the crude product, Luna C-18, 80 % → 100 %
CH3CN, 40 min, λ = 207 nm, Rt = 27.25 (minor diastere-
omer), 29.02 min (major diastereomer)). – MS ((+)-ESI):
m/z = 752.2 [M(79Br)+H]+, 754.2 [M(81Br)+H]+, 774.2
[M(79Br)+Na]+, 776.2 [M(81Br)+Na]+, 815.4 [M(79Br)+
CH3CN+Na]+, 817.4 [M(81Br)+ CH3CN+Na]+. – 1H NMR
(200 MHz, CDCl3): δ = 7.37 – 7.26 (m, 5H, aryl), 5.36
(2S,5S)-N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranos-
yl)-5-bromo-2-(4-bromphenyl)-piperidin-4-one (10f)
From 3i. Reaction time: 3 h. 1.75 eq. L-SelectrideꢀR . Pu-
(t, 1H, 3J = 9.3 Hz, H-2), 5.23 (d, 1H, 3J = 2.9 Hz, rification by flash-chromatography with cyclohexane/ethyl
H-4), 4.86 (dd, 1H, 3J = 3.2 Hz, 3J = 9.9 Hz, H-3), acetate 7 : 1 and subsequent preparative HPLC (Luna C-18,
4.58 (dd, 1H, 3J = 5.9 Hz, 3J = 11.7 Hz, CHBr), 4.23 – 80 % → 100 % CH3CN, 80 min, λ = 207 nm, Rt
=
3.82 (m, 4H, CHN, H-5, H-6a, H-6b), 3.77 (d, 1H, 3J = 66.03 min). Yield: 0.35 g (21 %); colorless amorphous solid,
9.8 Hz, H-1), 3.51 – 3.41 (m, 2H, NCH2), 2.82 (dd, 1H, [α]2D2 = −58.6 (c = 1.0, CHCl3). Rf = 0.56 (cyclohexane/ethyl
3J = 4.2 Hz, 2J = 14.9 Hz, CH2C=O), 2.66 (dd, 1H, 3J = acetate 2 : 1); d. r.: 88 : 12 : 0 : 0 (analytical HPLC of the
11.7 Hz, 2J = 15.1 Hz, CH2C=O), 1.24, 1.21, 1.18, 1.07 crude product, Luna C-18, 80 % → 100 % CH3CN, 40 min,
(4s, 36H, PivCH3). – 13C NMR (50.3 MHz, CDCl3): δ = λ = 212 nm, Rt = 30.45 (minor diastereomer), 32.67 min
200.24 (C=O), 178.10, 178.06, 177.89, 177.68 (PivC=O), (major diastereomer)). – C37H53Br2NO10 (831.63): calcd.
141.21 (ipso-aryl), 129.52, 129.40, 129.12 (aryl), 92.16 C 53.44, H 6.42, N 1.68; found C 53.54, H 6.43, N 1.63. –
(C-1), 71.90, 71.73, 66.74, 65.65 (C-2, C-3, C-4, C-5), 62.41 MS ((+)-ESI): m/z = 830.5.4 [M(2 79Br)+H]+, 832.5
(C-6), 60.89 (CHN), 53.82 (CHBr), 49.71 (NCH2), 44.75 [M(79Br + 81Br)+H]+, 834.5 [M(2 81Br)+H]+, 852.4 [M(2
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S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
79Br)+Na]+, 854.4 [M(79Br + 81Br)+Na]+, 856.3 [M(2 38.69, 38.72, 38.96 (Piv-Cquart), 43.59 (CH2C=O), 55.42
81Br)+Na]+. – 1H NMR (300 MHz, CDCl3): δ = 7.47 (d, (alkylCHN), 58.10 (arylCHN), 61.62 (C-6), 64.34, 65.52,
2H, 3J = 8.1 Hz, aryl), 7.19 (d, 2H, 3J = 8.5 Hz, aryl), 5.51 66.99, 71.31, 72.94 (C-2, C-3, C-4, C-5, CHBr), 88.15 (C-1),
(t, 1H, 3J = 9.6 Hz, H-2), 5.29 (d, 1H, 3J = 2.9 Hz, H-4), 127.99, 128.65, 129.03 (aryl), 139.95 (arylquart), 176.47,
4.96 (dd, 1H, 3J = 3.1 Hz, 3J = 9.7 Hz, H-3), 4.57 – 4.54 176.59, 177.37, 177.87 (PivC=O), 201.75 (C=O). – Minor
(m, 1H, CHBr), 4.25 (dd, 1H, 3J = 4.4 Hz, 3J = 9.2 Hz, diasteromer: 1H NMR (400 MHz, CDCl3): δ = 1.05, 1.16,
CHN), 4.21 (d, 1H, 3J = 9.6 Hz, H-1), 4.03 (dd, 1H, 3J = 1.21, 1.22 (4s, 36H, Piv-CH3), 1.39 (d, 3H, J = 7.0 Hz, CH3),
7.2 Hz, 2J = 11.2 Hz, H-6a), 3.92 (dd, 1H, 3J = 6.1 Hz, 2J = 2.36 (dd, 1H, J1 2.3 Hz, J2 = 14.9 Hz, CH2C=O), 2.62 – 2.75
11.2 Hz, H-6b), 3.66 (t, 1H, 3J = 6.4 Hz, H-5), 3.54 (dd, (m, 1H, CH2C=O), 3.25 – 3.29 (m, 1H, alkylCHN), 3.49 –
3
2
3
1H, J = 3.9 Hz, J = 14.5 Hz, NCH2), 3.43 (dd, 1H, J = 3.55 (m, 1H, ArCHN), 3.81 – 3.86 (m, 1H, H-6a), 3.97 (d,
5.5 Hz, 2J = 14.7 Hz, NCH2), 3.36 (dd, 1H, 3J = 9.0 Hz, 2J = 1H, J = 6.6 Hz, CHBr), 3.99 – 4.08 (m, 2H, H-5, H-6b), 4.48
14.5 Hz, CHCH2C=O), 2.65 (ddd, 1H, 4J = 1.2 Hz, 3J = (d, 1H, J1,2 = 9.8 Hz, H-1), 4.83 (dd, 1H, J3,4 = 2.9 Hz,
2
4.4 Hz, J = 14.3 Hz, CHCH2C=O), 1.24, 1.19, 1.17, 1.08 J3,2 = 9.6 Hz, H-3), 5.20 (d, 1H, J4,3 = 3.1 Hz, H-4),
(4s, 36H, PivCH3). – 13C NMR (75.5 MHz, CDCl3): δ = 5.42 (t, 1H, J2,1 = J2,3 = 9.4 Hz, H-2), 7.34 – 7.39 (m, 5H,
199.99 (C=O), 177.81, 177.21, 176.60, 176.51 (PivC=O), Ar). – 13C NMR (100.6 MHz, CDCl3 ): δ = 24.92 (CH3),
138.58 (ipso-aryl), 132.16, 129.21 (aryl), 122.47 (ipso-CBr), 27.01, 27.07, 27.18, 27.32 (Piv-CH3), 38.69, 38.72, 38.96
90.00 (C-1), 72.16, 72.09, 67.04, 64.46 (C-2, C-3, C-4, C-5), (Piv-Cquart), 43.59 (CH2C=O), 55.42 (alkylCHN), 57.56
63.96 (CHN), 61.78 (C-6), 49.94 (CHBr), 49.56 (NCH2), (ArCHN), 61.62 (C-6), 64.34, 65.52, 66.99, 71.63, 71.84
44.29 (CHCH2C=O), 39.08, 38.70 (PivCMe3), 27.31, 27.22, (C-2, C-3, C-4, C-5, CHBr), 87.86 (C-1), 128.21, 128.65,
27.11, 27.05 (PivCH3).
129.15 (Ar), 139.95 (Arquart), 176.47, 176.59, 177.37, 177.87
(PivC=O), 201.75 (C=O).
2S,5R,6S-N-(Tetra-O-pivaloyl-β-D-galactopyranosyl)-5-
bromo-6-methyl-2-phenyl-piperidin-4-one (11)
(6R)-N5-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
2-phenyl-6-n-propyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyr-
idine (12)
To a stirred mixture of CuI (0.38 g, 2 mmol) in dry
tetrahydrofuran under argon atmosphere at −78 ◦C was
added dropwise a 3 M solution of MeMgBr in diethyl ether
A solution of 5-bromo-2-propyl-piperidinone 7d (0.29 g,
(0.67 mL, 2 mmol). After 1 h BF3 · OEt2 (0.25 mL, 2 mmol) 0.40 mmol) and thiobenzamide (82 mg, 0.60 mmol)
was added. The mixture was stirred for 15 min. A solution in ethanol (5 mL) was stirred and heated under reflux
of the N-glycosyl-5-bromo-dehydropiperidinone 7d (0.33 g, for 20 h. After evaporation of the solvent and purifica-
0.44 mmol) in tetrahydrofuran (20 mL) was added via a sy- tion of the remaining residue by flash-chromatography with
◦
ringe. The mixture was stirred at −40 C for 15 h. By addi- light petroleum/ethyl acetate 15 : 1, product 12 was obtained.
tion of NH4OH/sat. NH4Cl (1 : 1, 20 mL) the reaction was Yield: 0.103 g (34 %); pale yellow amorphous solid, [α]D22
=
terminated. Diethyl ether (50 mL) was added. The diethyl −17.7 (c = 1.0, CHCl3). Rf = 0.59 (light petroleum/ethyl
ether layer was washed twice with NH4OH/sat. NH4Cl so- acetate 3 : 1). – C41H60N2O9S (756.99): calcd. C 65.05,
lution (2 × 29 mL) and brine (30 mL). The combined aque- H 7.99, N 3.70; found C 65.17, H 8.04, N 3.71. – MS ((+)-
ous solutions were extracted with diethyl ether (25 mL). The ESI): m/z = 655.4 [M–PivOH+H]+, 757.3 [M+H]+, 779.4
1
combined diethyl ether solutions were dried with MgSO4. [M+Na]+. – H NMR (200 MHz, CDCl3): δ = 7.88 – 7.83
The solvent was evaporated in vacuo. The crude product was (m, 2H, aryl), 7.40 – 7.35 (m, 3H, aryl), 5.45 (t, 1H, 3J =
purified by flash-chromatography with light petroleum/ethyl 9.5 Hz, H-2), 5.34 (d, 1H, 3J = 2.9 Hz, H-4), 5.13 (dd,
acetate 10 : 1. Yield: 0.174 g (50 %), conversion 70 %; col- 1H, 3J = 3.2 Hz, 3J = 9.9 Hz, H-3), 4.33 (d, 1H, 3J =
orless amorphous solid, [α]2D5 = −48.2 (c = 1.0, CHCl3). 9.3 Hz, H-1), 4.10 (br s, 2H, NCH2), 3.92 – 3.78 (m, 3H, H-5,
3
Rf = 0.68 (light petroleum/ethyl acetate 5 : 1); d. r.: 8 : 1 : 0 : 0 H-6a, H-6b), 3.34 – 3.20 (m, 1H, CHN), 2.98 (dd, 1H, J =
(analytical HPLC). – 1H NMR (400 MHz, CDCl3): δ = 5.1 Hz, 2J = 15.9 Hz, CH2C=O), 2.69 (d, 1H, 3J = 15.6 Hz,
1.05, 1.16, 1.21, 1.22 (4s, 36H, Piv-CH3), 1.43 (d, 3H, J = CH2C=O), 1.63 – 1.55 (m, 1H, CH2), 1.41 – 1.32 (m, 3H,
7.0 Hz, CH3), 2.36 (dd, 1H, J1 = 2.3 Hz, J2 = 14.9 Hz, CH2), 1.24, 1.13, 1.10, 1.09 (4s, 36H, PivCH3), 0.87 (t, 3H,
CH2C=O), 2.62 – 2.75 (m, 1H, CH2C=O), 3.25 – 3.29 (m, 3J = 6.8 Hz, CH3). – 13C NMR (50.3 MHz, CDCl3): δ =
1H, alkylCHN), 3.49 – 3.55 (m, 1H, arylCHN), 3.81 – 3.86 177.90, 177.29, 177.19, 176.75 (PivC=O), 164.89, 149.50,
(m, 1H, H-6a), 3.97 (d, 1H, J = 6.6 Hz, CHBr), 3.99 – 137.58 (ipso-aryl), 129.57, 128.84 (aryl), 126.30 (ipso-aryl),
4.08 (m, 2H, H-5, H-6b), 4.49 (d, 1H, J1,2 = 9.8 Hz, H-1), 126.25 (aryl), 93.54 (C-1), 71.93, 71.75, 67.25, 65.79 (C-2,
4.79 (dd, 1H, J3,4 = 2.9 Hz, J3,2 = 9.6 Hz, H-3), 5.19 (d, C-3, C-4, C-5), 61.67 (C-6), 56.90 (CHN), 40.73 (NCH2),
1H, J4,3 = 3.1 Hz, H-4), 5.51 (t, 1H, J2,1 = J2,3 = 9.4 Hz, 39.07, 38.75, 38.72, 38.67 (PivCMe3), 34.30 (CH2), 31.57
H-2), 7.34 – 7.39 (m, 5H, Ar). – 13C NMR (100.6 MHz, (CHCH2), 27.23, 27.13, 27.09 (PivCH3), 20.19 (CH2), 14.17
CDCl3 ): δ = 16.79 (CH3), 27.01, 27.18, 27.32 (Piv-CH3), (CH3).
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S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
1651
Reaction of N-galactosyl-bromo-piperidinones 10 with N- (C-2, C-3, C-4, C-5), 61.76 (C-6), 60.65 (CHN), 40.65
methyl-N-aryl-thioureas to give thiazolo-tetrahydropyridines (NCH2), 40.47 (NCH3), 39.05, 38.78, 38.72 (PivCMe3),
13 – General procedure
34.28 (CHCH2), 27.23, 27.15, 27.05 (PivCH3).
5-Bromo-piperidinone 10 (0.20 mmol) and N-methyl-N-
aryl-thiourea (0.23 mmol) were dissolved in dry ethanol
(10 mL). The solution was heated under reflux for 1 – 6 d. Af-
ter cooling to r. t. the solvent was evaporated in vacuo. The
remaining residue was dissolved in diethyl ether (10 mL),
and the solution was washed with 10 mL of sat. NaHCO3
solution and 10 mL of brine. The organic solution was dried
with MgSO4. After removal of the solvent, the product was
purified by chromatography.
(6S)-N5-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranos-
yl)-6-(4-chlorophenyl)-2-(N-methyl-N-(4-methoxyphenyl-
amino)-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine (13c)
From 10e. Reaction time: 3.5 d. Purification by column-
chromatography with cyclohexane/ethyl acetate 14 : 1 and
subsequent preparative HPLC (Luna C-18, 90 % → 100 %,
100 min, λ = 214 nm, Rt = 91.97 min). Yield: 22 mg (12 %);
yellow, amorphous solid; Rf = 0.43 (cyclohexane/ethyl ac-
etate 3:1). – MS ((+)-ESI): m/z = 884.4 [M+H]+. – 1H NMR
(400 MHz, CDCl3): δ = 7.34 – 7.22 (m, 6H, aryl), 6.96 – 6.94
(m, 2H, aryl), 5.38 (t, 1H, 3J = 9.8 Hz, H-2), 5.24 (d, 1H, 3J =
(6S)-N5-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
6-isopropyl-2-(N-methyl-N-phenylamino)-4,5,6,7-tetra-
hydrothiazolo[5,4-c]pyridine (13a)
3
2.7 Hz, H-4), 4.87 (dd, 1H, J = 3.1 Hz, 3J = 9.8 Hz, H-3),
3
4.12 (dd, 1H, J = 4,3 Hz, 3J = 9.0 Hz, CHN), 3.95 (s, 2H,
From 10a. Reaction time: 5 d. Purification by flash-
chromatography with cyclohexane/ethyl acetate 13 : 1 and
subsequent preparative HPLC (Luna C-18, 90 % → 100 %
CH3CN, 80 min, λ = 283 nm, Rt = 93.14 min). Yield:
20 mg (13 %); yellow amorphous solid; Rf = 0.32 (cyclo-
hexane/ethyl acetate 3 : 1). – MS ((+)-ESI): m/z = 786.7
[M+H]+. – 1H NMR (400 MHz, CDCl3): δ = 7.37 – 7.24
(m, 4H, aryl), 7.21 – 7.16 (m, 1H, aryl), 5.42 (t, 1H, 3J =
NCH2), 3.94 – 3.84 (m, 3H, H-1, H-6a, H-6b), 3.82 (s, 3H,
OCH3), 3.52 (s, 3H, NCH3), 3.47 (t, 1H, 3J = 6.7 Hz, H-5),
2.96 (dd, 1H, 3J = 9.0 Hz, 2J = 16.4 Hz, CHCH2), 2.87 (dd,
2
1H, 3J = 4.3 Hz, J = 16.4 Hz, CHCH2), 1.20, 1.17, 1.12,
1.05 (4s, 36H, PivCH3).
(6R)-N5-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
2-amino-6-ethyl-4,5,6,7-tetrahydrothiazolo[5,4-c]pyridine
(14)
3
9.6 Hz, H-2), 5.31 (d, 1H, J = 3.1 Hz, H-4), 5.11 (dd, 1H,
3J = 3.1 Hz, 3J = 9.8 Hz, H-3), 4.32 (d, 1H, 3J = 9.2 Hz,
H-1), 3.93 – 3.72 (m, 5H, H-5, H-6a, H-6b, NCH2), 3.47 (s,
3H, NCH3), 2.75 – 2.64 (m, 3H, CHCH2, CHCH2), 1.88 –
1.76 (m, 1H, CH(CH3)2), 1.20, 1.15, 1.10, 1.05 (4s, 36H,
PivCH3), 0.91, 0.88 (2d, 6H, 3J = 6.7 Hz, CH(CH3)2).
A solution of 5-bromo-2-ethyl-piperidinone (10c) (0.21 g,
0.30 mmol), thiourea (0.05 g, 0.60 mmol) and diazabicy-
cloundecene (DBU, 0.07 g, 0.45 mmol) in dry tetrahydro-
furan (5 mL) was heated under reflux for 19 h. The solvent
was evaporated in vacuo, and the crude product was puri-
fied by flash-chromatography in cyclohexane/ethyl acetate
2 : 1. Subsequent preparative HPLC (Luna C-18, 80 % →
100 % CH3CN, 80 min, λ = 250 nm, Rt = 42.02 min) af-
(6S)-N5-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)-
6-(4-chlorophenyl)-2-(N-methyl-N-phenylamino)-4,5,6,7-
tetrahydrothiazolo[5,4-c]pyridine (13b)
From 10e. Reaction time: 1 d. Purification by flash- forded the pure thiazolopyridine derivative 14. Yield: 0.13 g
chromatography with cyclohexane/ethyl acetate 16 : 1 and (62 %); yellow amorphous solid; [α]2D2 = −12.5 (c = 1.0,
subsequent preparative HPLC (Luna C-18, 90 % → 100 %, CHCl3). Rf = 0.08 (cyclohexane/ethyl acetate 2 : 1). – MS
100 min, λ = 254 nm, Rt = 92.83 min). Yield: 20 mg (12 %); ((+)-ESI): m/z = 580.1 [M–PivOH+H]+, 682.1 [M+H]+.
yellow, amorphous solid; Rf = 0.28 (cyclohexane/ethyl ac- HRMS ((+)-ESI): m/z = 682.3758 (calcd. 682.3737 for
etate 3 : 1). – MS ((+)-ESI): m/z = 854.6 [M+H]+, 876.5 C34H56N3O9S, [M+H]+). – 1H NMR (300 MHz, CDCl3):
[M+Na]+. – 1H NMR (400 MHz, CDCl3): δ = 7.42 – 7.24 δ = 5.42 (t, 1H, 3J = 9.9 Hz, H-2), 5.34 (d, 1H, 3J = 2.9 Hz,
(m, 9H, aryl), 5.41 (t, 1H, 3J = 9.6 Hz, H-2), 5.24 (d, H-4), 5.12 (dd, 1H, 3J = 3.3 Hz, 3J = 9.9 Hz, H-3), 4.29
1H, 3J = 2.7 Hz, H-4), 4.87 (dd, 1H, 3J = 3.1 Hz, 3J = (d, 1H, 3J = 9.2 Hz, H-1), 3.96 – 3.76 (m, 5H, H-5, H-6a,
9.8 Hz, H-3), 4.15 (dd, 1H, 3J = 4.3 Hz, 3J = 9.0 Hz, H-6b, NCH2), 3.09 – 3.07 (m, 1H, CHN), 2.69 (dd, 1H, 3J =
2
2
CHN), 3.99 (s, 2H, NCH2), 3.98 – 3.88 (m, 2H, H-1, H-6a), 5.2 Hz, J = 15.8 Hz, CHCH2), 2.39 (d, 1H, J = 15.8 Hz,
3.86 (dd, 1H, 3J = 7.0 Hz, 2J = 11.1 Hz, H-6b), 3.50 CHCH2), 1.72 – 1.57 (m, 1H, CH2CH3), 1.44 – 1.35 (m, 1H,
(s, 3H, NCH3), 3.46 (t, 1H, 3J = 6.7 Hz, H-5), 2.93 (dd, CH2CH3), 1.24, 1.15, 1.09, 1.08 (4s, 36H, PivCH3), 0.88 (t,
1H, 3J = 9.0 Hz, 2J = 16.1 Hz, CHCH2), 2.83 (dd, 1H, 3H, 3J = 7.4 Hz, CH3). – 13C NMR (75.5 MHz, CDCl3): δ =
2
3J = 4.3 Hz, J = 16.1 Hz, CHCH2), 1.20, 1.17, 1.12, 1.05 177.91, 177.23, 177.12, 176.67 (PivC=O), 166.11 (NCSN),
(4s, 36H, PivCH3). – 13C NMR (50.3 MHz, CDCl3): δ = 140.31, 114.53 (ipso-aryl), 93.16 (C-1), 71.88, 71.73, 67.18,
177.94, 177.16, 177.11, 176.62 (PivC=O), 168.67, 145.96, 65.66 (C-2, C-3, C-4, C-5), 61.62 (C-6), 58.20 (CHN), 40.16
141.88, 138.96, 133.87 (ipso-aryl), 129.96, 129.67, 128.97, (NCH2), 39.05, 38.72, 38.67 (PivCMe3), 29.97 (CHCH2),
127.07, 125.07 (aryl), 88.94 (C-1), 71.99, 71.56, 67.27, 65.13 27.22, 27.05, 24.78 (PivCH3), 24.78 (CH2), 11.39 (CH3).
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S. Knauer et al. · Stereoselective Synthesis of Bromopiperidinones
Acknowledgements
This work was supported by the Deutsche Forschungs-
gemeinschaft and by the Fonds der Chemischen Industrie.
We thank Dr. Dieter Schollmeyer for performing the crystal
structure determination.
[15] a) H. Kunz, W. Sager, Angew. Chem. 1987, 99,
595; Angew. Chem., Int. Ed. Engl. 1987, 26, 557;
b) H. Kunz, W. Sager, D. Schanzenbach, M. Decker,
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Diss. Universita¨t Mainz, 1992.
[16] H. Kunz, W. Pfrengle, K. Ru¨ck, W. Sager, Synthesis
1991, 1039.
[17] A. Bertho, J. Maier, Liebigs Ann. Chem. 1932, 498, 50.
[18] a) W. Pfrengle, Diss. Universita¨t Mainz 1987;
b) H. Kunz, W. Pfrengle, Tetrahedron 1988, 44, 5487.
[19] A. Bertho, Ber. Dtsch. Chem. Ges. 1930, 63, 836.
[1] H. Stark, M. Kathmann, E. Schlicker, W. Schunack,
R. Schlegel, W. Sippl, Mini-Reviews Med. Chem. 2004,
4, 965.
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31, 174.
[3] a) B. Kranke, D. Hebrault, M. Schultz-Kukula,
H. Kunz, Synlett 2004, 671; b) B. Kranke, H. Kunz,
Can. J. Chem. 2006, 84, 625.
[4] S. Danishefsky, M. E. Langer, C. Vogel, Tetrahedron
Lett. 1985, 26, 5983.
[5] H. Kunz, W. Pfrengle, Angew. Chem. 1989, 101, 1041;
Angew. Chem., Int. Ed. Engl. 1989, 28, 1067.
[6] M. Weymann, W. Pfrengle, D. Schollmeyer, H. Kunz,
Synthesis 1997, 1151.
[7] M. Weymann, H. Kunz, Z. Naturforsch. 2008, 63b, 425.
[8] A. Stoye, G. Quandt, B. Brunnho¨fer, E. Kapatsina,
J. Baron, A. Fischer, M. Weymann, H. Kunz, Angew.
Chem. 2009, 121, 2262; Angew. Chem. Int. Ed. 2009,
48, 2228.
[9] M. Weymann, M. Schultz-Kukula, S. Knauer, H. Kunz,
Monatsh. Chem. 2002, 133, 571.
[10] B. Kranke, H. Kunz, Org. Biomol. Chem. 2007, 5, 349.
[11] L. Be´rillon, A. Lepreˆte, A. Turck, N. Ple´, G. Queringer,
G. Cahiez, P. Knochel, Synlett 1998, 1359.
[12] a) A. Hantzsch, Ber. Dtsch. Chem. Ges. 1888, 21, 942;
b) R. H. Sprague, J. Am. Chem. Soc. 1957, 79, 2275.
[13] J. Habermann, S. V. Ley, J. S. Scott, J. Chem. Soc.,
Perkin Trans. 1 1998, 3127.
[14] J. Habermann, S. V. Ley, J. J. Scicinski, R. Smith, A. W.
Thomas, J. Chem. Soc., Perkin Trans. 1 1999, 2455.
[20] Crystal structure data of 10e: mol weight
=
787.16 g mol−1, crystal size: 0.10×0.30×0.30 mm3,
orthorhombic space group P212121, lattice parame-
ters: a = 50.241 (13), b = 14.959 (2), c = 11.0402
3
˚
˚
(15) A, V = 8298 (3) A , Z = 8, F(000) = 3312 e,
T = −80 ◦C, Dcalcd. = 1.26 g cm−3, µ(MoKα ) =
2.4 mm−1. Enraf-Nonius Turbo-CAD4 diffractometer,
MoKα radiation, graphite monochromator, number
of reflections: measured: 11586, independent: 11538,
observed: 8204 with |F| ≥ 4.0σ(F), discrepancy
factors: wR2 = 0.1881 (R1 = 0.064 for all observed
reflections, 0.1043 for all reflections), x(Flack) = 0.02,
−3
˚
∆ρfin (max/min) = 1.03 / −0.60 e A
.
CCDC 745336 contains the supplementary crystal-
lographic data for this paper. These data can be ob-
tained free of charge from The Cambridge Crystal-
lographic Data Centre via www.ccdc.cam.ac.uk/data
request / cif.
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