Stereoselective synthesis of enantiomerically pure piperidine derivatives by N-galactosylation of pyridones

Article abstract of DOI:10.1002/ejoc.200400169

Stereoselective desymmetrization of 4-pyridone has been achieved through selective N-galactosylation, activation of the N-(galactosyl)pyridone by O-silylation and immediate addition of Grignard compounds. Chiral piperidine derivatives, e.g. (S)-(+)-coniine and (5S,9S)-(+)-indolozidine 167B, were synthesised in enantiomerically pure form using these highly regio- and stereoselective reactions. After N-galactosylation of 2-pyridone and O-silylation of the N-galactosyl-2-pyridone, addition of a Grignard compound proceeded with high 1,4-regioselectivity and complete diastereoselectivity, to furnish 4-substituted 5,6-dehydro-2-piperidones. Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim, Germany, 2004.

Full text of DOI:10.1002/ejoc.200400169

FULL PAPER
Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by
N-Galactosylation of Pyridones
Ellen Klegraf,[a] Markus Follmann,[a] Dieter Schollmeyer,[a] and Horst Kunz*[a]
Dedicated to Professor Karsten Krohn on the occasion of his 60th birthday
Keywords: Chiral auxiliaries / Pyridones / Conjugate addition / (S)-Coniine / (5S,9S)-Indolizidine 167B
Stereoselective desymmetrization of 4-pyridone has been
achieved through selective N-galactosylation, activation of
the N-(galactosyl)pyridone by O-silylation and immediate
ylation of 2-pyridone and O-silylation of the N-galactosyl-2-
pyridone, addition of a Grignard compound proceeded with
high 1,4-regioselectivity and complete diastereoselectivity, to
addition of Grignard compounds. Chiral piperidine derivat- furnish 4-substituted 5,6-dehydro-2-piperidones.
ives, e.g. (S)-(+)-coniine and (5S,9S)-(+)-indolozidine 167B,
were synthesised in enantiomerically pure form using these
( Wiley-VCH Verlag GmbH & Co. KGaA, 69451 Weinheim,
highly regio- and stereoselective reactions. After N-galactos- Germany, 2004)
Introduction
Results and Discussion
The piperidine ring is an important structural motif in
natural compounds, e.g. in alkaloids,[1] and also in pharma-
ceuticals.[2,3] Hence, the development of stereoselective
syntheses leading to polysubstituted chiral piperidines is of
general interest in natural product and medicinal chemis-
try.[4] Since piperidinones can be smoothly converted into
piperidines, they are attractive intermediates for the syn-
thesis of chiral piperidines. The chemistry of chiral piperidi-
nones has been reviewed recently.[5] Apart from enantiose-
lective catalysis, most general routes in asymmetric syn-
thesis are based on the use of chiral auxiliaries[6] or pro-
cedures exploiting the chiral pool.[7] We recently reported a
desymmetrization reaction at 4-pyridone, for the synthesis
of chiral 2-substituted N-glycosyl-5,6-didehydro-4-piperidi-
nones,[8] during which the stereodifferentiating tool was in-
troduced by N-galactosylation. An analogous procedure
was applied to 2-pyridinone and resulted in the un-
precedented regio- and stereoselective formation of 4-
substituted N-galactosyl-5,6-didehydro-2-piperidinones.[9]
Further transformations of the thus obtained piperidone
derivatives and detailed preparations of two alkaloids are
described in this article.
The N-(galactosyl)pyridones 3 and 5 are obtained readily
in multigram quantities by the Vorbrüggen reaction[10]
starting from O-pivaloylated galactosyl fluoride[8,11] 1 and
(trimethylsilyloxy)pyridines[12] 2 or 4 (Scheme 1). The
choice of the Lewis acid is crucial for the chemoselectivity
of the glycosylation reaction between galactosyl fluoride 1
and the O-silylated pyridone 2. While boron trifluoride
(BF3) favours the formation of the α-O-galactosylated com-
pound, application of tin tetrachloride (SnCl4) produces a
mixture (4:3) of the β-N- and α-O-galactosylated com-
pounds. In contrast, titanium tetrachloride (TiCl4) quanti-
tatively and selectively promotes the formation of the N-
glycosylated pyridone 3. Interestingly, in the series of the 2-
pyridones, the use of either SnCl4 or TiCl4 results in quanti-
tative formation of the N-glycosylated 2-pyridone 5.
Syntheses Based on Stereoselective Conjugate Addition
Reactions at N-Galactosyl-4-pyridone
The initial aim of this work was to study the reactivity of
the N-galactosyl-4-pyridone 3 towards organomagnesium,
-lithium and -copper compounds. However, the pyridone
compounds proved to be inert towards all of these reagents.
To overcome this problem, the methodology published by
Beifuss et al.[13] was adopted. In this way, activation of the
N-(galactosyl)pyridone 3 was achieved by O-silylation using
trimethylsilyl trifluoromethanesulfonate (TMSOTf). The in-
termediate pyridinium salt reacted readily with Grignard
reagents at the 2-position (Scheme 2). The addition reaction
[a]
Institut für Organische Chemie, Universität Mainz,
Duesbergweg 10Ϫ14, 55128 Mainz, Germany
Fax: (internat.) ϩ 49-6131-3924786
E-mail: hokunz@uni-mainz.de
[b]
Aventis Pharma Deutschland GmbH,
Industriepark Hoechst, G 838, 206 F, 65926 Frankfurt am
Main, Germany
E-mail: markus.follmann@aventis.com
3346
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
DOI: 10.1002/ejoc.200400169
Eur. J. Org. Chem. 2004, 3346Ϫ3360

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
Scheme 1. Chemoselective synthesis of N-(galactosyl)pyridones
upper and lower back-side sites can be obtained by refer-
ence to the X-ray analysis of the products (Figure 1). An
electronic participation of the carbonyl oxygen atom of the
2-pivaloyl group might block the upper site favouring ad-
dition of the Grignard compound not only to the other
face, but also to the lower site.
Scheme 2. Reagents and conditions: (a) TMSOTf, CH2Cl2, room
temp., 1 h; (b) 2,6-lutidine, RMgX, CH2Cl2, room temp., 1Ϫ2 h
Scheme 3
proceeded with good to excellent diastereoselectivity,
thereby desymmetrizing the pyridine (Table 1).
The absolute configuration of N-(galactosyl)dehydropip-
The reason for this differentiation remains open to specu- eridinones 6 was proven by X-ray analyses of several deriva-
lation. It can be assumed from previous experiments[11,14] tives of 6 as well as by comparison with analogous com-
that the front side of the heterocycle (Scheme 3) is effec- pounds obtained in previous work by domino-
tively shielded by the 2-pivaloyl group leaving two dia- MannichϪMichael reactions using N-(galactosyl)imines,[14]
stereotopic back-side sites accessible to the addition reac- which lead selectively to the opposing diastereomers. As an
tion. An interpretation of the differentiation between these example, the X-ray structure analysis of compound 6h
Table 1. Stereoselective synthesis of dehydropiperidinones 6
Compound
Grignard reagent, RMgX
Yield [%]
Diastereoselectivity (S)/(R)
6a
6b
6c
6d
6e
6f
6g
6h
6i
MeMgCl
nPrMgCl
iPrMgCl
nBuMgCl
nDecMgBr
vinylMgBr
1-butenylMgBr
PhMgCl
m-MeOC6H4MgBr
ClMg(CH2)3OMgCl
ClMg(CH2)3SiPhMe2
74
84
89
50
71
51
19
83
35
30
66
95:5
89:11
8:92
Ͼ 99:1
79:21
1:99
Ͼ 99:1
Ͻ 1:99
Ͻ 1:99
92:8
6j
6k
Ͼ 99:1
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E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
FULL PAPER
route to chiral 2-substituted piperidines. After introduction
of the n-propyl chain by Grignard addition, the dehydropi-
peridinone 6b was treated with lithium tris(sec-butyl)-
borohydride (-Selectride) in THF at Ϫ78 °C, affording pip-
eridinone 7 in almost quantitative yield. The dithiolane 8
was formed by reaction of 7 with 1,2-ethanedithiol in the
presence of boron trifluorideϪdiethyl ether (BF3·OEt2) in a
yield of 88%. Subsequent desulfurization using Raney
nickel yielded the N-galactosylated coniine 9 almost quanti-
tatively. The enantiomerically pure (S)-(ϩ)-coniine (10) was
isolated as its hydrochloride in quantitative yield after mild
acidolysis of 9 with dilute hydrochloric acid in aqueous
methanol. This total synthesis requires 5 steps starting from
the N-galactosyl-4-pyridone 3 and gave the natural alkaloid
in an overall yield of 44%.
Subsequently, compounds 6 were deprotonated by using
lithium hexamethyldisilazane (LiHMDS), and the alky-
lation of the thus formed enolates was investigated. These
alkylation reactions yielded exclusively the trans-2,3-disub-
stituted piperidinones 11 (Scheme 5), which is in agreement
with observations reported by Comins et al.[15] and previous
results obtained from the analogous diastereomeric N-(gly-
cosyl)dehydropiperidinones.[14]
Figure 1. X-ray analysis of 1-galactosyl-2-phenyl-5,6-dehydropiper-
idinone 6h
shown in Figure 1 provides evidence that the introduced
substituent adopts a pseudo-axial position.
Variation of the silylating reagent influenced neither the
yield nor the diastereoselectivity of the reaction. The reac-
tions proceeded with almost identical results when either
TMSOTf, triisopropylsilyl trifluoromethanesulfonate (TIP-
SOTf) or the less expensive trimethylsilyl chloride (TMSCl)
was used for activation of the (galactosyl)pyridone 3. Ac-
cording to this methodology, side chains containing further
functional groups can be introduced into the pyridone ring
(see, for example, Entries 6f, 6g, 6iϪ6k in Table 1).
In the syntheses of a number of different alkaloids, Com-
ins et al.[6a] have demonstrated the utility of synthons like
6. According to the strategy outlined here, the synthesis of
the (S) enantiomer of coniine, a major alkaloid from co-
nium maculatum (hemlock), was achieved by the method
shown in Scheme 4. This conversion illustrates a general
Scheme 5. Reagents and conditions: (a) 1.2 equiv. LiHMDS, THF,
Ϫ78 °C, 1 h, 3 equiv. R2I, Ϫ10 °C, 12 h
The absolute configuration of compounds 11 was proven
by an X-ray analysis of compound 11a (see Figure 2), show-
ing both substituents in an antiperiplanar position.
Scheme 4. Reagents and conditions: (a) -Selectride, THF, Ϫ78 °C,
2 h, 61%; (b) 1,2-ethanethiol, BF3·OEt2, CH2Cl2, room temp., 12 h,
88%; (c) Raney nickel, H2, isopropyl alcohol, 70 °C, 12 h, 97%; (d)
2  HCl, methanol, 20 °C, 36 h, quantitative yield
Figure 2. X-ray analysis of the trans-2,3-disubstituted 1-galactosyl-
5,6-dehydropiperidinone 11a
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Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
Further transformations at the enaminone group of com- (Scheme 7) was assigned as the cis derivative cis-13a (50%),
pounds 6 are also of interest. In general, cis-2,6-disubsti- whereas the minor product (44%) was assigned as the trans
tuted 4-piperidinones are important synthons for the syn- diastereomer trans-13b.
thesis of piperidine alkaloids. To achieve this substitution
The influence of the substituent in 2-position of the pip-
pattern from precursors like 6, a diastereoselective 1,4-ad- eridone 6 on the side differentiation can be rationalized by
dition at the vinylogous amide structure of 6 is required. the following considerations. For the N-(galactosyl)dehyd-
For these conversions organocuprates, in combination with ropiperidinones 6, the axial orientation of substituent R
hard electrophiles such as TMSCl[16]or BF3·OEt2,[17] were and the existence of rotamers are typical (Scheme 8). The
allowed to react with compounds 6 (Scheme 6) to give 2,6- exo-anomeric effect[18] stabilizes the two rotamers in which
disubstituted piperidinones 12 in high yields (Table 2).
the substituent R could occupy the axial position.
Scheme 6. Activated addition of organocuprates
Table 2. Synthesis of 2,6-disubstituted piperidinones 12 according
to Scheme 6
Compound R1
R2
Cuprate
Yield cis/trans
[%]
ratio
12a
12b
12c
12b
propyl propyl R2Cu·BF3
phenyl phenyl R2Cu·BF3
83
99
73
1.5:1
3:1
2:1
Scheme 8. Possible scenario for the stereochemical addition of
organocuprates
methyl vinyl
R2Cu·BF3
phenyl phenyl R22CuLi/TMSCl 47
2.7:1
Case A represents piperidinone diastereomers obtained
by reactions of a Danishefsky diene with galactosylim-
ines.[14,19] Rotamer A is destabilized by an unfavourable
steric interaction between R and the 2-pivaloyl group. How-
ever, this steric interaction, is minimized upon conversion
to rotamer B and addition of the organocuprate then pro-
ceeds from the unhindered back side (‘‘matched case’’).
In contrast, case B represents the ‘‘mismatched’’ situation
in which both rotamers C and D are not favoured sterically.
In C, substituent R and the 2-pivaloyl group interfere with
each other. The amount of trans-2,6-disubstituted product
in 12 results from a back-side attack at rotamer C. In rot-
amer D, the steric repulsion of substituents is minimized,
and a back-side attack should give the cis-substituted prod-
uct. The reason for the limited contribution of rotamer D
(case B) in the conjugate addition entailing a low cis selec-
tivity is more difficult to explain. Obviously, the electro-
philic reactivity of the enaminone system in rotamer D is
reduced (see also, Scheme 3).
Compared to previous results obtained with the dia-
stereomers of 6,[14] the opposite configuration at position 2
given in compounds 6 resulted in lower diastereoselectivity
(Scheme 6, Table 2).
These reactions obviously represent the mismatched case
in which the carbohydrate auxiliary on the one hand and
the stereogenic center in the 2-position of the piperidinone
6 on the other hand exhibit opposing influences on the con-
jugate addition of the cuprates.
In order to simultaneously prove the existence of two dia-
stereomers in compounds 12 and their absolute configura-
tion, the auxiliary of 12a was replaced by a nonchiral
benzyloxycarbonyl (Z) group and the diastereomers were
separated by chromatography (Scheme 7).
As a consequence of these results, the strategy for the
synthesis of the 2,6-disubstituted piperidinones from pre-
cursors 6 was changed. The mismatching interference by
the carbohydrate auxiliary indicates that it should be re-
moved prior to the functionalization of the enone system
(Scheme 9). However, acid hydrolysis of the N-glycoside
bond of compound 6 is not possible because of the acid
stability of (vinylogous) N-glycosylamides. This problem
was circumvented by conjugate hydride addition of 6b using
Scheme 7. Reagents and conditions: (a) 2  HCl/methanol (1:5,
v/v), 25 °C, 36 h; (b) BnOCOCl, aq. satd. Na2CO3, 25 °C, 1 h, 94%
(two steps)
On the basis of the optical rotation values of products -Selectride, and subsequent trapping of the resulting lith-
cis-13a and trans-13b, the major diastereomer in 12a ium enolate with phenylselenium chloride, affording 14 in a
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E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
FULL PAPER
yield of 70%. After mild acidolysis of the sensitized N-gly- formed under basic conditions (Li2CO3) and furnished the
cosidic bond, the piperidone was N-protected as benzyl car- target (ϩ)-indolizidine 167B 19 in an overall yield of 6.3%
bamate 15. Oxidation of this compound to the selenium after nine steps from the N-galactosyl-4-pyridone 3.
oxide with H2O2·urea complex and subsequent elimination,
Regio- and Stereoselective Conjugate Addition Reactions at
N-Galactosyl-2-pyridone
reinstalled the vinylogous amide 16 in a yield of 53% over
three steps.[20]
In contrast to the number of stereoselective syntheses of
2-substituted and 2,6-disubstituted piperidines, only a few
methods are known for the stereoselective formation of pip-
eridines bearing a substituent at 4-position.[28] We recently
reported a stereoselective access to 4-substituted piperidines
which resembles the reactions outlined for the N-galactosyl-
4-pyridones.[9]
Activation of the N-galactosyl-2-pyridone 5 with either
TMSOTf or TIPSOTf, formed the corresponding 2-(silyl-
oxy)pyridinium triflate which was thus rendered susceptible
to nucleophilic addition of Grignard reagents (Scheme 10).
However, in contrast to our expectations, the conjugate
addition of Grignard compounds took place selectively at
4-position. The same regioselectivity was obtained using
organocuprates as nucleophiles. The diastereoselectivity of
these conjugate addition reactions is excellent regardless of
whether Grignard reagents or organocuprates are used
(Table 3).
Scheme 9. Reagents and conditions: (a) -Selectride, PhSeCl, 70%;
(b) 1  HCl, methanol, 12 h; (c) separation; (d) aq. Na2CO3, BnO-
COCl, 53% yield over three steps; (e) H2O2·urea, CH2Cl2/H2O
(20:2), 69%; (f) Mg, THF, Br(CH2)3OEE (EE ϭ 1-ethoxyethyl); (g)
CuBr·SMe2, BF3·OEt2, THF, Ϫ78 °C, 1 h, 73%, dr ϭ 2:1; (h) PPh3,
NCS, CH2Cl2, Ϫ40 to ϩ20 °C, 95%; (i) LiHMDS, THF; (j) 2-
amino-5-chloropyridine triflate, Pd/C, H2, 41% over two steps
Scheme 10. Reagents and conditions: (a) R3SiOTf, 1 h, CH2Cl2,
room temp., 2,6-lutidine, RMgX, CH2Cl2, room temp., 1Ϫ2 h; (b)
TMSCl, THF, 1 h, room temp., R22CuLi, THF, Ϫ78 °C to room
temp.
Comins et al. have reported that benzyloxycarbonyl-pro-
tected 2,3-dehydropiperidin-4-ones undergo conjugate ad-
dition of organocuprates with cis diastereoselec-
tivity.[15a,21,22] According to those observations the synthesis
of indolizidine 167B 19 (Scheme 9), an alkaloid from the
secretions of frogs belonging to the family dendrobates,[23]
should be possible by introduction of an O-protected
hydroxypropyl side chain to precursor 16.[24] However, the
conjugate addition of the (1-ethoxyethyl)cuprateϪboron
trifluoride complex[25] to 16 proceeded with disappointingly
low diastereoselectivity (cis/trans ϭ 2:1). This unexpected
result might be due to an interfering coordination of the
ethoxyethyl protecting group to the metal ion of this com-
plex. Non-substituted alkylcuprates react with high stereo-
selectivity under identical conditions.[22,26]
Table 3. Stereoselective addition of Grignard reagents and organo-
cuprates
Compound Reagent
Yield [%] Diastereoselectivity (R)/(S)
20a
20b
20c
20d
20e
20f
20g
20h
20i
EtMgCl
54
68
88
75
22
55
Ͼ 99:1
Ͼ 99:1
Ͻ 1:99
Ͼ 99:1
Ͻ 1:99
Ͼ 99:1
Ͻ 1:99
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
Ͼ 99:1
92:8
nPrMgCl
iPrMgCl
nBuMgCl
tBuMgCl
nDecMgCl
cyclohexylMgCl 79
benzylMgCl
phenylMgCl
butenylMgBr
nBu2CuLi
tBu2CuLi
nHex2CuLi
34
76
86
64
39
93
20j
20d
20e
20k
Acidolytic removal of the 1-ethoxyethyl (EE) group gave
17 which was transformed into the chloride 18 by a modi-
fied Appel reaction using N-chlorosuccinimide/tri-
phenylphosphane.[14] At this stage the diastereomers were
separated by column chromatography. Reduction of the car-
Ͼ 99:1
The carbohydrate auxiliary obviously controls both the
bonyl group was achieved by deprotonation with LiHMDS, facial selectivity as well as the regioselectivity during this
trapping the lithium enolate as enol triflate using 2-amino- addition. Only in two experiments (20c and 20f) was the
5-chloropyridine triflate,[27] followed by hydrogenation, regioisomeric 6-substituted product detectable by 1H NMR
which simultaneously effected removal of the N-benzyloxy- spectroscopy of the crude products. However, they com-
carbonyl group. The ring-closing N-alkylation was per- posed less than 5% of the products and could be separated
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Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
by flash chromatography. The absolute configuration of the domino-MannichϪMichael reaction sequences using N-
4-substituted 2-pyridone was determined by X-ray analysis (galactosyl)imines.[14] The application of this methodology
of products 20b and 20c showing that the substituent ad- was demonstrated by total syntheses of enantiomerically
opts a pseudo-equatorial position (Figure 3).
pure (S)-coniine and (5S,9S)-indolizidine 167B. Nucleo-
philic addition reactions of N-(galactosyl)pyridinium ions
derived from 2-pyridone furnished 4-substituted pyridone
derivatives with surprising regioselectivity and excellent
stereoselectivity. This class of compounds is of substantial
importance for developments in the area of CNS-active
drugs.[3]
Experimental Section
Materials and Methods: Reactions were carried out in flame-dried
glassware under argon. Solvents were distilled before use. Analyti-
cal TLC was performed on aluminium-backed TLC plates coated
with silica gel 60F254 (E. Merck, Darmstadt, Germany). Column
chromatography was performed on silica (63Ϫ200 µm, Baker or
40Ϫ63 µm, E. Merck). Melting points were measured with a Dr.
Tottoli apparatus (Büchi) and are uncorrected. Optical rotation val-
ues were measured with a PerkinϪElmer 241 polarimeter. NMR
spectra were recorded with a Bruker WT-200, a Bruker AC-300 or
a Bruker AM 400 spectrometer; chemical shifts given are expressed
in δ (ppm) downfield from tetramethylsilane. ESI-MS data were
measured with a navigator (Thermo Quest) spectrometer, FD-MS
data with a MAT 95-spectrometer (Finnigan). HPLC analyses were
performed with a Knauer system equipped with a Luna C-18-2
column (Phenomenex, 250 ϫ 4.6 mm, 5 µm particle size) and a
diode array UV detector at a flow rate of 1 mL/min.
Figure 3. X-ray analysis of 1-galactosyl-4-propyl-5,6-dehydropiper-
idin-2-one 20b
The selective formation of one diastereomer can be ra-
tionalized in terms of the different stability of rotamers A
and B of the N-galactosyl-2-pyridone 5 (Scheme 11). Rot-
amer B is favoured because the electrostatic repulsion be-
tween the carbonyl oxygen atom of the lactam and the car-
bonyl oxygen atom of the 2-pivaloyl group is minimized.
1,4-Dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
D-galactopyranosyl)-
pyridin-4(1H)-one (3): 4-(Trimethylsilyloxy)pyridine (2, 9.8 mL,
After activation by O-silylation, any incoming nucleophile 57.8 mmol) was added slowly to 2,3,4,6-tetra-O-pivaloyl-α--galac-
topyranosyl fluoride[11] (1, 20 g, 30.8 mmol), dissolved in 1,2-
preferentially attacks from the less shielded si-face (back
dichloroethane (350 mL) at 70 °C through a syringe. Then TiCl4
(33.8 mL, 308 mmol) was added, turning the previously colourless
solution to yellow. The mixture was refluxed for 1 h. After cooling
to room temperature, the reaction was terminated by careful ad-
dition of aq. satd. NaHCO3 (500 mL). The organic layer was di-
luted with CH2Cl2 (500 mL), the aqueous layer extracted with
CH2Cl2 (3 ϫ 500 mL) and the combined organic layers were dried
with MgSO4. After evaporation of the solvent in vacuo and flash
chromatography (ethyl acetate/methanol, 9:1), colourless crystals of
3 were isolated (18.28 g, 30.8 mmol, yield quant.). M.p. 115 °C.
Rf ϭ 0.11 (ethyl acetate/light petroleum ether, 4:1). [α]2D0 ϭ 3.7 (c ϭ
1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ 0.97, 1.05, 1.10,
1.26 (4 s, 36 H, piv CH3), 3.99 (dd, J6a,6b ϭ 11.0, J6a,5 ϭ 7.4 Hz, 1
H, H-6a), 4.11 (dd, J6b,6a ϭ 11.0, J6b,5 ϭ 6.7 Hz, 1 H, H-6b), 4.19
(t, J5,6a ϭ 6.7, J5,6b ϭ 7.0 Hz, 1 H, H-5), 4.97 (d, J1,2 ϭ 9.4 Hz, 1
H, H-1), 5.21 (dd, J3,2 ϭ 10.2, J3,4 ϭ 3.1 Hz, 1 H, H-3), 5.45 (m,
J2,3 ϭ 10.3, J2,1 ϭ 8.8, J4,3 ϭ 3.0 Hz, 2 H, H-2, H-4), 6.31 (d, J ϭ
7.8 Hz, 2 H, NϪCHϭCHϪ), 7.34 (d, J ϭ 7.4 Hz, 2 H, NϪCHϭ
CHϪ) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 26.7, 27.2 (piv
CH3), 38.7, 38.8, 39.1 (piv Cquat.), 60.5 (C-6), 66.4, 67.5, 70.8, 74.0
(C-2, C-3, C-4, C-5), 90.9 (C-1), 118.7 (NϪCHϭCHϪ), 137.2
(NϪCHϭCHϪ), 176.1, 176.3, 177.0, 177.7 (piv CϭO), 179.5 (Cϭ
O) ppm. C31H47NO10 (593.71): calcd. C 62.71, H 7.98, N 2.36;
found C 62.68, H 7.95, N 2.11.
side).
Scheme 11
It is worth noting that the electrophilic reactivity at 6-
position is obviously reduced, probably because of the par-
ticipation of the carbonyl oxygen atom of the 2-pivaloyl
group (see Scheme 8, rotamer D).
Conclusion
The results described are evidence that efficient stereodif-
ferentiation of enantiotopic sites of 4- and 2-pyridone can
be achieved in conjugate addition reactions of Grignard
and organocuprate reagents to the corresponding O-silyl-
ated N-(galactosyl)pyridinium salts. In the 4-pyridone series
these conversions result in an enantioselective desymmetriz-
ation giving 2-substituted 5,6-dehydropiperidinones of the
General Procedure for the Preparation of Compounds 6: The N-(ga-
lactosyl)pyridone 3 in CH2Cl2 or toluene (30 mL·gϪ1) was treated
opposite configuration compared to those obtained from with the corresponding silylating agent (1.2Ϫ1.8 equiv.) at ambient
Eur. J. Org. Chem. 2004, 3346Ϫ3360
www.eurjoc.org  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim 3351

E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
FULL PAPER
temperature. After stirring for 30 min, 2,6-lutidine (1.2Ϫ1.8 equiv.)
(2R)-2,3-Dihydro-2-isopropyl-1-(2,3,4,6-tetra-O-pivaloyl-β-
D-galac-
was added followed by addition of a solution of the corresponding
topyranosyl)pyridine-4(1H)-one (6c): (4.35 g, 7.33 mmol),
3
Grignard reagent (1.2Ϫ1.8. equiv.). Relevant experimental details TMSOTf (2.11 mL, 11.72 mmol), 2,6-lutidine (1.36 mL,
and analytical data are given for each compound. After stirring for 11.72 mmol), iPrMgCl (2  in THF, 5.86 mL, 11.72 mmol); sol-
10Ϫ60 min (until TLC monitoring indicated complete conversion), vent: CH2Cl2; yield 4.15 g (6.50 mmol, 89%), mixture of dia-
the reaction was terminated by addition of aq. satd. NaHCO3. The
aqueous solution was extracted with CH2Cl2, the combined organic
layers were dried with MgSO4, and the solvent was evaporated in
vacuo. Purification by flash chromatography (light petroleum ether/
ethyl acetate) afforded the following compounds.
stereomers, ratio 92:8 (1H NMR). Data for the mixture of dia-
stereomers: Rf ϭ 0.63 (light petroleumether/ethyl acetate, 1:1).
[α]2D8 ϭ 22.3 (c ϭ 1.0, CHCl3). NMR spectroscopic data for the
unseparated major (R) diastereomer: 1H NMR (200 MHz, CDCl3):
δ ϭ 0.89, 0.93 (2d, J ϭ 6.3, J ϭ 6.8 Hz, 6 H, ϪCH3), 1.08, 1.12,
1.13, 1.26 (4s, 36 H, piv CH3), 2.09 (dd, J ϭ 6.3, J ϭ 6.8 Hz, 1 H,
(CH3)2CH], 2.44 (d, Jgem ϭ 16.6 Hz, 1 H, ϪCH2ϪCϭO), 2.60 (dd,
Jgem ϭ 16.6, Jvic ϭ 7.8 Hz, 1 H, ϪCH2ϪCϭO), 3.31 (m, 1 H,
NCH), 4.03 (m, 3 H, H-5, H-6a, H-6b), 4.36 (d, J1,2 ϭ 9.3 Hz, 1
(2S)-2,3-Dihydro-2-methyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
pyranosyl)pyridine-4(1H)-one (6a): Compound 3 (4 g, 6.74 mmol),
TIPSOTf (3.27 mL, 12.13 mmol), 2,6-lutidine (1.41 mL,
12.13 mmol), MeMgCl (3  in THF, 4.1 mL, 12.13 mmol); solvent:
CH2Cl2; yield 3.03 g (4.96 mmol, 74%); mixture of diastereomers,
ratio Ͼ 95:5 (1H NMR). Data for the mixture of diastereomers:
M.p. 88 °C. Rf ϭ 0.58 (light petroleum ether/ethyl acetate, 1:1).
[α]2D8 ϭ Ϫ16.3 (c ϭ 1.0, CHCl3). NMR spectroscopic data for the
unseparated major (S) diastereomer: 1H NMR (400 MHz,
CDCl3,): δ ϭ 1.08Ϫ1.25 (m, 39 H, piv CH3, ϪCH3), 2.19 (d, Jgem ϭ
16.1 Hz, 1 H, ϪCH2ϪCϭO), 2.68 (dd, Jgem ϭ 16.2, Jvic ϭ 6.6 Hz,
1 H, ϪCH2ϪCϭO), 3.73 (m, 1 H, NCH), 4.02 (m, 3 H, H-5, H-
6a, H-6b), 4.42 (d, J1,2 ϭ 9.4 Hz, 1 H, H-1), 5.11 (d, J ϭ 7.9 Hz,
1 H, NCHϭCH), 5.13 (dd, J3,2 ϭ 10.0, J3,4 ϭ 3.2 Hz, 1 H, H-3),
5.37 (t, 1 H, H-2), 5.40 (d, J4,3 ϭ 3.2 Hz, 1 H, H-4), 7.05 (d, J ϭ
7.9 Hz, 1 H, NCHϭC) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ
16.3 (ϪCH3), 27.0, 27.2 (piv CH3), 38.7, 38.7, 39.1 (piv Cquat.), 42.9
(CH2CϭO), 56.1 (MeCHN), 61.5 (C-6), 66.7, 66.8, 71.4, 73.1 (C-
2, C-3, C-4, C-5), 90.4 (C-1), 101.7 (NCHϭCH), 146.4 (NCHϭ
CH), 176.5, 176.6, 177.1, 177.8 (piv CϭO), 191.6 (CϭO) ppm. MS
(FD): m/z ϭ 610.0 [M]ϩ. C32H51NO10 (609.76): calcd. C 62.93, H
8.58, N 2.29; found C 63.12, H 8.63, N 2.23.
H, H-1), 5.05 (d, J ϭ 7.8 Hz, 1 H, NCHϭCH), 5.13 (dd, J3,2
ϭ
10.0, J3,4 ϭ 3.2 Hz, 1 H, H-3), 5.33 (t, J ϭ 10.2 Hz, 1 H, H-2),
5.41 (d, J4,3 ϭ 3.4 Hz, 1 H, H-4), 7.19 (d, J ϭ 8.3 Hz, 1 H, NCHϭ
CH) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 18.1, 19.2 (2 ϫ
methyl), 27.0, 27.0, 27.1, 27.2 (piv CH3), 31.6 (CHMe2), 37.0
(CH2CϭO), 38.7, 38.8, 38.9, 39.1 (piv Cquat.), 61.8 (iPrCHN), 66.0,
67.0, 68.1, 71.4, 73.3 (C-2, C-3, C-4, C-5, C-6), 89.8 (C-1), 101.0
(NCHϭCH), 146.8 (NCHϭCH), 176.3, 177.1, 177.8 (piv CϭO),
191.6 (CϭO) ppm. MS (FD): m/z ϭ 638.9 [M ϩ H]ϩ. C34H55NO10
(637.81): calcd. C 64.03, H 8.69, N 2.20; found C 63.17, H 8.57,
N 1.92.
(2S)-2-Butyl-2,3-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
pyranosyl)pyridine-4(1H)-one (6d): 3 (1.62 g, 2.73 mmol), TMSOTf
(0.31 mL, 4.09 mmol), 2,6-lutidine (0.74 mL, 4.09 mmol),
nBuMgCl (2  in THF, 2.73 mL, 5.46 mmol); solvent: toluene;
yield 0.89 g (1.37 mmol, 50%); single diastereomer, ratio Ͼ 99:1 (1H
NMR). Rf: 0.25 (light petroleum ether/ethyl acetate, 2:1). [α]2D8
ϭ
1
2.8 (c ϭ 1.0, CHCl3). H NMR (400 MHz,CDCl3): δ ϭ 0.88 (t, 3
H, ϪCH3), 1.08Ϫ1.27 (m, 40 H, piv CH3, ϪCH2Ϫ), 1.52 (m, 1 H,
ϪCH2Ϫ), 1.86 (m, 1 H, ϪCH2Ϫ), 2.39 (d, Jgem ϭ 15.8 Hz, 1 H,
ϪCH2ϪCϭO), 2.63 (dd, Jgem ϭ 16.4, Jvic ϭ 6.7 Hz, 1 H,
ϪCH2ϪCϭO), 3.50 (m, 1 H, NCH), 4.04 (m, 3 H, H-5, H-6a, H-
6b), 4.40 (d, J1,2 ϭ 9.1 Hz, 1 H, H-1), 5.11 (d, J ϭ 7.9 Hz, 1 H,
NCHϭCH), 5.14 (dd, J3,2 ϭ 10.0, J3,4 ϭ 2.9 Hz, 1 H, H-3), 5.36
(t, 1 H, H-2), 5.42 (d, J4,3 ϭ 3.2 Hz, 1 H, H-4), 7.10 (d, J ϭ 7.9 Hz,
1 H, NCHϭC) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 13.9
(ϪCH3), 22.3 (ϪCH2Ϫ), 27.0, 27.1, 27.1, 27.2 (piv CH3), 27.8, 29.1
(ϪCH2Ϫ), 38.6, 38.7, 38.8, 38.9 (piv Cquat.), 39.6 (CH2CϭO), 60.2
(butylϪCHN), 61.38 (C-6), 66.6, 67.5, 71.2, 73.0 (C-2, C-3, C-4, C-
5), 90.2 (C-1), 101.4 (NCHϭCH), 146.6 (NCHϭCH), 176.3, 176.5,
176.9, 177.7 (piv CϭO), 191.5 (CϭO) ppm. MS (FD): m/z ϭ 652.0
[M]ϩ; calcd. for C35H57NO10 (651.83).
(2S)-2,3-Dihydro-2-propyl-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)pyridine-4(1H)-one [(S)-6b] and (2R)-2,3-Dihydro-2-pro-
pyl-1-(2,3,4,6-tetra-O-pivaloyl-β- -galactopyranosyl)pyridine-4(1H)-
D-galacto-
D
one [(R)-6b]: 3 (1 g, 1.68 mmol), TIPSOTf (0.73 mL, 2.69 mmol),
2,6-lutidine (0.31 mL, 2.69 mmol), nPrMgCl (2  in diethyl ether,
1.35 mL, 2.69 mmol); solvent: CH2Cl2; yield 0.90 g (1.41 mmol,
84%); mixture of diastereomers, ratio 8:1 (1H NMR). The dia-
stereomers were separated by preparative HPLC [Luna 10 µ, Kro-
masil C-18(2), 250 ϫ 50 mm (Phenomenex), eluent: MeCN/H2O
(85:15), flow 20 mL·minϪ1, UV detection at 310 nm, Rt [min] ϭ
31.64 [(S) isomer], 40.92 [(R) isomer]. The minor diastereomer [(R)
isomer] is identical to the compound obtained from the tandem-
MannichϪMichael reaction of galactosylimine.[14] Data for the
pure (S) isomer: M.p. 161 °C. Rf ϭ 0.70 (light petroleum ether/
ethyl acetate, 1:1). [α]2D8 ϭ 13.7 (c ϭ 1.0, CHCl3). 1H NMR
(2S)-2-Decyl-2,3-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)pyridine-4(1H)-one [(S)-6e] and (2R)-2-Decyl-2,3-dihydro-
-galactopyranosyl)pyridine-4(1H)-one
piv CH3), 1.54 (m, 1 H, ϪCH2Ϫ), 1.79 (m, 1 H, ϪCH2Ϫ), 2.34 (d, [(R)-6e]: 3 (1 g, 1.68 mmol), TMSOTf (0.55 mL, 3.03 mmol), 2,6-
Jgem ϭ 16.0 Hz, 1 H, ϪCH2ϪCϭO), 2.61 (dd, Jgem ϭ 16.0, Jvic lutidine (0.33 mL, 3.03 mmol), nDecMgCl (1  in diethyl ether,
D-galacto-
(400 MHz, CDCl3): δ ϭ 0.86 (t, 3 H, ϪCH3), 1.08Ϫ1.25 (m, 38 H, 1-(2,3,4,6-tetra-O-pivaloyl-β-
D
ϭ
6.7 Hz, 1 H, ϪCH2ϪCϭO), 3.50 (m, 1 H, NCH), 4.03 (m, 3 H, H- 3.03 mL, 3.03 mmol); solvent: CH2Cl2; yield 0.88 g (1.19 mmol,
5, H-6a, H-6b), 4.39 (d, J1,2 ϭ 9.0 Hz, 1 H, H-1), 5.09 (d, J ϭ 71%); mixture of diastereomers, ratio 3.8:1 (HPLC). Rf ϭ 0.29
8.2 Hz, 1 H, NCHϭCH), 5.14 (dd, J3,2 ϭ 10.2, J3,4 ϭ 3.2 Hz, 1 H,
H-3), 5.35 (t, 1 H, H-2), 5.40 (d, J4,3 ϭ 3.1, 1 H, H-4), 7.10 (d, J ϭ
(light petroleum ether/ethyl acetate, 4:1). The diastereomers were
separated by HPLC {MeCN/H2O [gradient 88:12 to 100:0 (40 min),
7.9 Hz, 1 H, NCHϭC) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ flow 1 mL·minϪ1, UV detection at 310 nm, Rt [min] ϭ 22.28 (major
13.9 (ϪCH3), 18.6 (ϪCH2Ϫ), 27.0, 27.1, 27.2 (piv CH3), 31.6 isomer), 27.28 (minor isomer)}. Data given for the pure major (S)
(ϪCH2Ϫ), 38.6, 38.7, 38.8, 39.1 (piv Cquat.), 39.7 (CH2CϭO), 60.4 compound isolated by HPLC: [α]2D0 ϭ 3.0 (c ϭ 1.0, CHCl3). 1H
(propylϪCHN), 61.5 (C-6), 66.8, 67.4, 71.4, 73.2 (C-2, C-3, C-4, C-
NMR (200 MHz, CDCl3): δ ϭ 0.79Ϫ1.25 (m, 55 H, piv CH3,
5), 90.3 (C-1), 101.5 (NCHϭCH), 146.4 (NCHϭCH), 176.3, 176.5, ϪCH2Ϫ, ϪCH3), 1.49 (m, 1 H, ϪCH2Ϫ), 1.80 (m, 1 H, ϪCH2Ϫ),
177.1, 177.8 (piv CϭO), 191.5 (CϭO) ppm. C34H55NO10 (637.81):
calcd. C 64.03, H 8.69, N 2.20; found C 63.78, H 8.86, N 2.15.
2.37 (d, Jgem ϭ 16.1 Hz, 1 H, ϪCH2ϪCϭO), 2.61 (dd, Jgem ϭ 16.1,
Jvic ϭ 6.3 Hz, 1 H, ϪCH2ϪCϭO), 3.47 (m, 1 H, NCH), 4.01 (m,
3352
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3346Ϫ3360

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
3 H, H-5, H-6a, H-6b), 4.39 (d, J1,2 ϭ 8.8 Hz, 1 H, H-1), 5.12 (m, H-1), 4.91Ϫ5.00 (m, 2 H, alkene), 5.09 (d, J ϭ 9.1 Hz, 1 H, NCHϭ
2 H, NCHϭCH, H-3), 5.31 (t, J ϭ 9.3 Hz, 1 H, H-2), 5.40 (d, CH), 5.12 (dd, J3,2 ϭ 10.0, J3,4 ϭ 2.9 Hz, 1 H, H-3), 5.33 (t, 1 H,
J
4,3 ϭ 2.9 Hz, 1 H, H-4), 7.08 (d, J ϭ 7.8 Hz, 1 H, NCHϭC) ppm. H-2), 5.4 (d, J4,3 ϭ 3.2 Hz, 1 H, H-4), 5.66 (m, 1 H, alkene), 7.09
13C NMR (50.3 MHz, CDCl3): δ ϭ 14.1 (ϪCH3), 22.6, 25.5, 25.6
(d, J ϭ 7.9 Hz, NCHϭCH) ppm. 13C NMR (100.6 MHz, CDCl3):
(ϪCH2Ϫ), 27.0, 27.1, 27.2 (piv CH3), 29.2, 29.4, 29.5, 31.5, 31.8 δ ϭ 27.03, 27.22 (piv CH3), 28.45, 29.78 (ϪCH2Ϫ), 38.76, 38.81,
(ϪCH2Ϫ), 38.6, 38.7, 38.8, 39.1 (piv Cquat.), 39.6 (CH2CϭO), 60.7 38.91, 39.10 (piv Cquat.), 39.62 (CH2CϭO), 59.68 (butenyl CHN),
(decylϪCHN), 61.4 (C-6), 66.8, 67.3, 71.4, 73.1 (C-2, C-3, C-4, C- 61.54 (C-6), 66.85, 67.31, 71.40, 73.19 (C-2, C-3, C-4, C-5), 90.23
5), 90.2 (C-1), 101.5 (NCHϭCH), 146.6 (NCHϭCH), 176.3, 176.5, (C-1), 101.69 (NCHϭCH), 116.00 (CϭCH2), 136.91 (CϭCH2),
177.1, 177.7 (piv CϭO), 191.5 (CϭO) ppm. C41H70NO10 (737.00):
146.58 (NCHϭCH), 176.39, 176.57, 177.16, 177.83 (piv CϭO),
191.42 (CϭO) ppm. C35H57NO10 (651.81): calcd. C 64.49, H 8.81,
N 2.15; found C 63.85, H 8.13, N 2.02.
calcd. C 66.82, H 9.57, N 1.90; found C 66.83, H 9.43, N 1.96.
Data for the minor (R) compound separated by HPLC: [α]2D0
ϭ
Ϫ59.8 (c ϭ 1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 0.81
(t, 3 H, ϪCH3), 1.06Ϫ1.23 (m, 52 H, piv CH3, ϪCH2Ϫ), 1.43, 1.78
(m, 2 H, ϪCH2Ϫ), 2.31 (d, Jgem ϭ 16.6 Hz, 1 H, ϪCH2ϪCϭO),
2.57 (dd, Jgem ϭ 16.6, Jvic ϭ 6.8 Hz, 1 H, ϪCH2ϪCϭO), 3.79 (m,
(2R)-2,3-Dihydro-2-phenyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
pyranosyl)pyridine-4(1H)-one (6h): 3 (2 g, 3.37 mmol), TMSOTf
(1.10 mL, 6.06 mmol), 2,6-lutidine (0.70 mL, 6.06 mmol), PhMgCl
(2  in THF, 3.03 mL, 6.06 mmol); solvent: CH2Cl2; yield 1.87 g
(2.78 mmol, 83%). M.p. 173 °C. Single diastereomer, ratio ϾϾ 99:1
1 H, NCH), 3.87Ϫ4.13 (m, 3 H, H-5, H-6a, H-6b), 4.52 (d, J1,2
ϭ
8.8 Hz, 1 H, H-1), 4.90 (d, J ϭ 7.3 Hz, 1 H, NCHϭCH), 5.12 (dd,
J3,2 ϭ 10.2, J3,4 ϭ 2.9 Hz, 1 H, H-3), 5.38 (d, J4,3 ϭ 2.9 Hz, 1 H,
H-4), 5.48 (t, J ϭ 10.3, J ϭ 9.3 Hz, 1 H, H-2), 6.86 (d, J ϭ 7.8 Hz,
1 H, NCHϭC) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 14.1
(ϪCH3), 22.6, 25.8 (ϪCH2Ϫ), 27.0, 27.1, 27.2 (piv CH3), 29.2, 29.4,
29.5, 30.6, 31.8 (ϪCH2Ϫ), 38.7, 38.7, 38.8 (piv Cquat.), 39.0
(CH2CϭO), 53.7 (decylϪCHN), 60.8 (C-6), 65.7, 66.5, 71.3, 72.8
(C-2, C-3, C-4, C-5), 91.5 (C-1), 99.9 (NCHϭCH), 149.7 (NCHϭ
CH), 176.4, 177.0, 177.1, 177.6 (piv CϭO), 192.1 (CϭO) ppm.
C41H70NO10 (737.00): calcd. C 66.82, H 9.57, N 1.90; found C
66.81, H 9.46, N 1.91.
1
(HPLC, H NMR). Rf ϭ 0.58 (light petroleum ether/ethyl acetate,
1:1). [α]2D5 ϭ Ϫ65.8 (c ϭ 1.0, CHCl3). 1H NMR (200 MHz, CDCl3):
δ ϭ 1.07Ϫ1.27 (4 s, 36 H, piv CH3), 2.65 (dd, Jgem ϭ 16.1, Jvic
ϭ
5.8 Hz, 1 H, ϪCH2ϪCϭO), 2.84 (dd, Jgem ϭ 16.1, Jvic ϭ 6.8 Hz,
1 H, ϪCH2ϪCϭO), 3.74 (m, 1 H, H-5), 3.95 (m, 2 H, H-6a, H-
6b), 4.34 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1), 4.69 (m, 1 H, NCH), 5.01
(dd, J3,2 ϭ 10.3, J3,4 ϭ 2.9 Hz, 1 H, H-3), 5.22 (d, J ϭ 8.3 Hz, 1
H, NCHϭCH), 5.34 (d, J4,3 ϭ 2.9, 1 H, H-4), 5.43 (t, 1 H, H-2),
7.30 (m, 5 H, ar.), 7.36 (d, J ϭ 7.8 Hz, 1 H, NCHϭCH) ppm. 13C
NMR (50.3 MHz, CDCl3): δ ϭ 27.0, 27.1 27.2 (piv CH3), 38.6,
38.7, 38.8, 39.0 (piv Cquat.), 44.0 (CH2CϭO), 61.0 (phenylϪCHN),
(2R)-2,3-Dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
D-galactopyranosyl)- 63.3 (C-6), 66.7, 67.7, 71.6, 73.1 (C-2, C-3, C-4, C-5), 88.4 (C-1),
2-vinylpyridine-4(1H)-one (6f): (5 g, 8.42 mmol), TMSOTf
3
102.1 (NCHϭCH), 126.7, 128.5, 128.9 (o-, m-, p-C, phenyl), 138.2
(2.30 mL, 12.63 mmol), 2,6-lutidine (1.50 mL, 12.63 mmol), vi- (ipso-C, phenyl), 147.3 (NCHϭCH), 176.2, 176.4, 177.1, 177.6 (piv
nylMgBr (1  in THF, 4.1 mL, 12.6 mmol); solvent: CH2Cl2; yield CϭO), 190.4 (CϭO) ppm. C37H53NO10 (671.82): calcd. C 66.15, H
2.65 g (4.26 mmol, 51%); ratio of diastereomers Ͼ 99:1 (HPLC). 7.95, N 2.08; found C 66.27, H 8.14, N 2.12. Crystal data: size:
Rf ϭ 0.56 (light petroleum ether/ethyl acetate, 1:1). [α]2D5 ϭ Ϫ40.7
0.032 ϫ 0.064 ϫ 0.126 mm; colourless needles; P21 (monoclinic);
(c ϭ 1.0, CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ 1.09, 1.14, a ϭ 15.409(3) A, b ϭ 10.767(2) A, c ϭ 24.761(6) A, β ϭ 96.00(1)°,
˚
˚
˚
4
3
˚
1.15, 1.27 (4s, 36 H, piv CH3), 2.42 (dd, Jgem ϭ 16.1, J ϭ 2.6 Hz, V ϭ 4085(1) A , Z ϭ 4, F(000) ϭ 1448; T ϭ 298 K; ρ ϭ 1.092
1 H, ϪCH2CϭO), 2.72 (dd, Jgem ϭ 16.3, Jvic ϭ 6.9 Hz, 1 H, g·cmϪ3. Data collection: Diffractometer: CAD4 (EnrafϪNonius);
ϪCH2CϭO), 3.96Ϫ4.09 (m, 4 H, H-5, H-6a, H-6b, NCHR), 4.41
radiation: Cu-Kα, graphite monochromator; scan-type: ω/2Θ; scan
(d, J1,2 ϭ 9.1 Hz, 1 H, H-1), 5.13 (d, J ϭ 7.6 Hz, 1 H, NCHϭCH), width 0.8 ϩ 0.14·tanΘ and 25% left and right for determination of
5.13Ϫ5.18 (m, 2 H, H-3, RHCϭCH2), 5.26 (d, Jtrans ϭ 17.3 Hz, 1 background; measurement range 1Ϫ5° Յ Θ Յ 75°; 0 Յ h Յ 19, 0
H, RHCϭCH2), 5.39 (t, J ϭ 9.6 Hz, 1 H, H-2), 5.41 (d, J4,3
3.2 Hz, 1 H, H-4), 5.94 (ddd, Jtrans ϭ 17.2, Jcis ϭ 10.3, J ϭ 7.0 Hz, pairs), independent 16489 (Rint ϭ 0.0340), observed 8484 (|F|/σ(F)
1 H, RHCϭCH2), 7.14 (d, J ϭ 8.2 Hz, 1 H, NCHϭCH) ppm. 13C
Ͼ 4.0). CCDC-237631 contains the supplementary crystallographic
NMR (50.3 MHz, CDCl3): δ ϭ 27.0, 27.1, 27.2 (piv CH3), 38.7, data for this paper. These data can be obtained free of charge at
38.8, 38.9, 39.1 (piv Cquat.), 41.5 (CH2CϭO), 61.3, 62.3 (C-6, www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
ϭ
Յ k Յ 13, Ϫ31 Յ l Յ 31; reflections: measured 18201 (with Friedel
NCHR), 66.8, 67.2, 71.5, 73.2 (C-2, C-3, C-4, C-5), 89.7 (C-1), Crystallographic Data Centre, 12 Union Road, Cambridge
102.1 (NCHϭCH), 118.1 (H2CϭCHR), 133.7 (H2CϭCHR), 146.8 CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; E-mail:
(NCHϭCH), 176.4, 176.6, 177.2, 177.8 (piv CϭO), 191.0 (CϭO) deposit@ccdc.cam.ac.uk].
ppm. C32H51NO10 (621.77): calcd. C 63.75, H 8.27, N 2.25; found
C 63.18, H 8.19, N 2.16.
(2R)-2,3-Dihydro-2-(3-methoxyphenyl)-1-(2,3,4,6-tetra-O-pivaloyl-
β- -galactopyranosyl)pyridine-4(1H)-one (6i): 3 (0.5 g, 0.84 mmol),
D
(2S)-2-(3-Butenyl)-2,3-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
D
-
TMSOTf (0.18 mL, 1.01 mmol), 2,6-lutidine (0.12 mL, 1.01 mmol),
galactopyranosyl)pyridine-4(1H)-one) (6g): 3 (1.18 g, 1.98 mmol),
3-MeOC6H4MgBr (1  in THF, 1.01 mL, 1.01 mmol); solvent:
TIPSOTf (0.81 mL, 2.97 mmol), 2,6-lutidine (0.34 mL, 2.97 mmol), CH2Cl2; yield 0.28 g (0.4 mmol, 47%); single diastereomer, ratio
butenylMgBr [freshly prepared from Mg (72 mg, 2.96 mmol) and 4-
ϾϾ 99:1 (1H NMR). Rf ϭ 0.58 (light petroleum ether/ethyl acetate,
bromobutene (0.30 mL, 2.99 mmol)]; solvent: CH2Cl2; yield 0.25 g 1:1). [α]2D0 ϭ Ϫ57.4 (c ϭ 1.0, CHCl3). 1H NMR (200 MHz, CDCl3):
(0.38 mmol, 79%); 24% conversion; single diastereomer, ratio ϾϾ δ ϭ 1.07, 1.11, 1.16, 1.27 (4 s, 36 H, piv CH3), 2.65 (dd, Jgem
99:1 (1H NMR). Rf ϭ 0.62 (light petroleum ether/ethyl acetate, 16.1, Jvic ϭ 5.8 Hz, 1 H, ϪCH2ϪCO), 2.83 (dd, Jgem ϭ 16.1, Jvic ϭ
1:1). [α]2D0 ϭ 4.9 (c ϭ 0.5, CHCl3). 1H NMR (400 MHz, CDCl3):
6.8 Hz, 1 H, ϪCH2ϪCO), 3.77 (m, 4 H, ϪOCH3, NCHϪphenyl),
ϭ
δ ϭ 1.07, 1.10, 1.12, 1.24 (4s, 36 H, piv CH3), 1.65Ϫ1.72 (m, 1 H, 3.97 (d, J6,5 ϭ 6.8 Hz, 2 H, H-6a, H-6b), 4.36 (d, J1,2 ϭ 9.3 Hz, 1
ϪCH2Ϫ), 1.83Ϫ1.99 (m, 2 H, ϪCH2Ϫ), 2.08Ϫ2.11 (m, 1 H, H, H-1), 4.66 (t, 1 H, H-5), 5.02 (dd, J3,2 ϭ 10.3, J3,4 ϭ 2.9 Hz, 1
ϪCH2Ϫ), 2.35 (d, Jgem ϭ 16.4 Hz, 1 H, ϪCH2ϪCO), 2.61 (dd, H, H-3), 5.24 (d, J ϭ 7.8 Hz, 1 H, NCHϭCH), 5.38 (m, 2 H, H-
J
gem ϭ 16.1, Jvic ϭ 6.5 Hz, 1 H, ϪCH2ϪCO), 3.52 (m, 1 H, NCH), 2, H-4), 6.83 (m, 3 H, ar.), 7.18 (1 H, ar.), 7.35 (d, J ϭ 8.8 Hz, 1
3.98Ϫ4.07 (m, 3 H, H-5, H-6a, H-6b), 4.38 (d, J1,2 ϭ 9.4 Hz, 1 H, H, NCHϭCH) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 27.00,
Eur. J. Org. Chem. 2004, 3346Ϫ3360
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3353

E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
27.07 (piv CH3), 38.67, 38.78, 38.91, 39.11 (piv Cquat.), 60.88 (C-6), (2S)-2-Propyl-1-(2,3,4,6-tetra-O-pivaloyl-β- -galactopyranosyl)-
FULL PAPER
D
63.24, 66.64, 67.78, 71.61, 73.07, 75.52 (C-2, C-3, C-4, C-5, NCH- piperidin-4-one (7): Dehydropiperidinone 6b (1.07 g, 1.67 mmol) in
phenyl), 88.38 (C-1), 102.05 (NCHϭCH), 147.60 (NCHϭCH), dry THF (30 mL), -Selectride (2.09 mL, 1  in THF, 2.09 mmol);
112.97, 113.42, 118.83, 129.93 (2 ϫ o-, m-, p-C, phenyl), 139.62 yield 0.65 g (1.01 mmol, 61%). Rf ϭ 0.60 (light petroleum ether/
(Cipso), 159.95 (MeOϪCar), 176.29, 176.52, 177.20, 177.78 (piv ethyl acetate, 4:1). [α]2D0 ϭ 3.9 (c ϭ 1.0, CHCl3). 1H NMR
CO), 190.66 CϭO) ppm. MS (FD): m/z ϭ 701.9 [M]ϩ. C38H55NO11
(701.85): calcd. C 65.03, H 7.90, N 2.00; found C 64.12, H 8.61,
N 1.76.
(200 MHz, CDCl3): δ ϭ 0.87 (t, 3 H, ϪCH3), 1.02Ϫ1.60 (m, 40 H,
piv CH3, ϪCH2Ϫ), 2.29Ϫ2.57 (m, 2 H, ϪCH2Ϫ), 3.13Ϫ3.42 (m, 3
H, ϪCH2Ϫ, NCH), 3.92Ϫ4.11 (m, 3 H, H-5, H-6a, H-6b), 4.38 (d,
J1,2 ϭ 8.8 Hz, 1 H, H-1), 5.13 (dd, J3,2 ϭ 10.3, J3,4 ϭ 3.0 Hz, 1 H,
H-3), 5.37 (d, J4,3 ϭ 2.9 Hz, 1 H, H-4), 5.45 (t, 1 H, H-2) ppm. 13
C
(2S)-2,3-Dihydro-2-(3-hydroxypropyl)-1-(2,3,4,6-tetra-O-pivaloyl-β-
D
-galactopyranosyl)pyridine-4(1H)-one (6j): 3 (1.13 g, 1.90 mmol),
NMR (50.3 MHz, CDCl3): δ ϭ 13.0 (ϪCH3), 19.8 (ϪCH2Ϫ), 27.0,
27.1, 27.2 (piv CH3), 34.5 (ϪCH2Ϫ), 38.7, 39.0 (piv Cquat.), 41.8,
43.5, 46.6 (ϪCH2Ϫ), 59.0 (propylCHN), 62.0 (C-6), 65.3, 67.3,
71.9, 72.1 (C-2, C-3, C-4, C-5), 92.7 (C-1), 176.7, 177.0, 177.2 (piv
CϭO), 210.0 (CϭO) ppm. C34H57NO10 (639.81): calcd. C 63.83, H
8.98, N 2.19; found C 63.74, H 9.01, N 2.21.
TMSOTf (0.447 mL, 2.47 mmol), 2,6-lutidine (0.286 mL,
2.47 mmol). The Grignard reagent was prepared according to the
procedure of ref.[29] using 3-chloro-1-propanol (0.83 mL, 10 mmol)
in anhydrous THF (10 mL), iPrMgCl (5 mL, 2.0  in THF,
10 mmol), Mg (240 mg, 10 mmol); solvent: CH2Cl2; yield 0.315 g
(0.48 mmol, 71%), 35% conversion; mixture of diastereomers, ratio
Ͼ12:1 (1H NMR). Rf ϭ 0.08 (light petroleum ether/ethyl acetate,
1:1). Data given for the mixture of diastereomers: [α]2D0 ϭ 3.1 (c ϭ
1.0, CHCl3). NMR spectroscopic data given for the unseparated
major (S) diastereomer: 1H NMR (200 MHz, CDCl3): δ ϭ 1.07,
1.11, 1.13, 1.25 (4s, 36 H, piv CH3), 1.43Ϫ1.87 (m, 4 H, ϪCH2Ϫ),
2.02 (br. s, 1 H, OH), 2.36 (m, 3 H, NCH, ϪCH2ϪOH), 4.05 (m,
3 H, H-5, H-6a, H-6b), 4.46 (d, J1,2 ϭ 8.8 Hz, 1 H, H-1), 5.10 (d,
J ϭ 7.3 Hz, 1 H, NCHϭCH), 5.13 (dd, J3,2 ϭ 10.2, J3,4 ϭ 2.9 Hz,
1 H, H-3), 5.32 (t, 1 H, H-2), 5.40 (d, J4,3 ϭ 2.9 Hz, 1 H, H-4),
7.10 (d, J ϭ 7.8 Hz, 1 H, NCHϭCH) ppm. 13C NMR (50.3 MHz,
CDCl3): δ ϭ 26.17 (ϪCH2Ϫ), 27.05, 27.10, 27.22 (piv CH3), 28.31
(ϪCH2Ϫ), 38.70, 38.76, 38.84, 39.11 (piv Cquat.), 39.82 (ϪCH2Cϭ
O), 60.23 (propylϪCHN), 61.28 (C-6), 62.19 (ϪCH2ϪOH), 66.80,
67.39, 71.46, 73.06 (C-2, C-3, C-4, C-5), 90.13 (C-1), 101.56
(NCHϭCH), 146.79 (NCHϭCH), 176.52, 176.58, 177.19, 177.87
(piv CO), 191.68 (CϭO) ppm. MS (FD): m/z ϭ 653.9 [M]ϩ.
(2S)-4-(1,3-Dithiolan-2-yl)-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)-2-propylpiperidine (8): Piperidinone
D
-galacto-
(0.65 g,
7
1.01 mmol), 1,2 ethanedithiol (0.176 mL, 2.13 mmol) in dry di-
chloromethane (10 mL), boron trifluoride diethyl ether (0.63 mL,
5.05 mmol); yield 0.64 g (0.87 mmol, 88%). Rf: 0.81 (light petro-
leum ether/ethyl acetate, 4:1). [α]2D0 ϭ 1.8 (c ϭ 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): δ ϭ 0.85 (t, 3 H, ϪCH3), 1.04Ϫ1.21 (m,
40 H, piv CH3, ϪCH2Ϫ), 1.74Ϫ2.17 (m, 5 H, ϪCH2Ϫ), 2.60Ϫ2.90
(m, 3 H, ϪCH2Ϫ), 3.20 (m, 4 H, ϪSCH2Ϫ), 3.70Ϫ4.10 (m, 4 H,
NCH, H-5, H-6a, H-6b), 4.25 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1), 5.04
(dd, J3,2 ϭ 10.2, J3,4 ϭ 3.0 Hz, 1 H, H-3), 5.28 (d, J4,3 ϭ 2.5 Hz, 1
H, H-4), 5.40 (t, 1 H, H-2) ppm. 13C NMR (50.3 MHz, CDCl3):
δ ϭ 14.1 (ϪCH3), 19.7 (ϪCH2Ϫ), 27.0, 27.1, 27.2 (piv CH3), 34.0,
38.1, 38.2 (ϪCH2Ϫ), 38.6 (piv Cquat.), 42.5 (ϪCH2Ϫ), 44.8, 45.8
(ϪSCH2Ϫ), 59.2 (propylCHN), 62.1 (CS2), 65.1 (C-6), 67.2, 67.4,
71.7, 72.2 (C-2, C-3, C-4, C-5), 89.2 (C-1), 176.7, 176.8, 177.2,
177.9 (piv CϭO) ppm. No correct elemental analysis was obtained.
(2S)-2,3-Dihydro-2-{3-[dimethyl(phenyl)silyl]propyl}-1-(2,3,4,6-
tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-4(1H)-one (6k): 3
(2S)-2-Propyl-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)piperidine (9): N-(Galactosyl)piperidine
D
-galacto-
(0.64 g,
8
(5 g, 8.42 mmol), TIPSOTf (3.4 mL, 12.63 mmol), 2,6-lutidine
(1.47 mL, 12.63 mmol); Mg (0.48 g, 20 mmol), anhydr. THF
(10 mL), 1,2-dibromomethane (0.57 mL, 3.16 mmol), 3-[dimeth-
yl(phenyl)silyl]propyl chloride (3.58 mL, 16.8 mmol) (prepared ac-
cording to ref.[30]); solvent: CH2Cl2; yield 4.3 g (5.57 mmol, 66%);
single diastereomer, ratio ϾϾ 99:1 (1H NMR). Rf ϭ 0.68 (light
petroleum ether/ethyl acetate, 1:1). [α]2D0 ϭ Ϫ11.7 (c ϭ 1.0, CHCl3).
1H NMR (200 MHz, CDCl3): δ ϭ 0.25 (s, 6 H, SiϪMe), 0.67 (t, 2
H, ϪSiϪCH2Ϫ), 1.03Ϫ1.19 (m, 38 H, piv CH3, ϪCH2Ϫ),
1.35Ϫ1.98 (m, 2 H, ϪCH2Ϫ), 2.33 (d, Jgem ϭ 16.1 Hz, 1 H,
0.89 mmol), dry 2-propanol (50 mL), Raney-nickel (3 g), hydrogen,
70 °C, 9 h; yield 0.54 g (0.86 mmol, 97%). Rf ϭ 0.95 (light petro-
leum ether/ethyl acetate, 4:1). [α]2D0 ϭ 4.2 (c ϭ 1.0, CHCl3). 1H
NMR (200 MHz, CDCl3): δ ϭ 0.83 (t, 3 H, ϪCH3), 1.03Ϫ1.69 (m,
46 H, piv CH3, ϪCH2Ϫ), 2.72Ϫ2.83 (m, 3 H, ϪNCH2Ϫ, NCH),
3.78Ϫ3.99 (m, 3 H, H-5, H-6a, H-6b), 4.04 (d, J1,2 ϭ 8.7 Hz, 1 H,
H-1), 5.04 (dd, J3,2 ϭ 10.2, J3,4 ϭ 2.9 Hz, 1 H, H-3), 5.26Ϫ5.35
(m, 2 H, H-2, H-4) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 14.3
(ϪCH3), 20.0, 20.2, 25.8 (ϪCH2Ϫ), 26.9, 27.0, 27.1 (piv CH3), 29.6,
31.0, 31.8 (ϪCH2Ϫ), 38.5, 38.6, 39.0, 40.5 (piv Cquat.), 60.1 (pro-
pylCHN), 62.0 (C-6), 65.2, 67.4, 71.5, 72.0 (C-2, C-3, C-4, C-5),
93.8 (C-1), 176.7, 177.2, 177.9 (piv CϭO) ppm. C34H59NO9
(625.84): calcd. C 65.25, H 9.50, N 2.04; found C 64.26, H 9.67,
N 2.04.
ϪCH2ϪCO), 2.60 (dd, Jgem
ϭ 16.6, Jvic ϭ 6.8 Hz, 1 H,
ϪCH2ϪCO), 3.47 (m, 1 H, NCH), 3.89Ϫ4.15 (m, 3 H, H-5, H-6a,
H-6b), 4.25 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1), 5.08Ϫ5.14 (m, 2 H,
NCHϭCH, H-3), 5.27 (t, 1 H, H-2), 5.39 (d, J4,3 ϭ 2.9 Hz, 1 H,
H-4), 7.07 (d, J ϭ 8.3 Hz, 1 H, NCHϭCH), 7.31Ϫ7.49 (m, 5 H,
phenyl) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ Ϫ3.23, Ϫ3.07
(SiϪCH3), 15.69, 19.85 (ϪCH2Ϫ), 26.17 (ϪCH2Ϫ), 27.06, 27.24
(piv CH3), 32.73 (ϪCH2Ϫ), 38.71, 38.79, 38.84, 39.11 (piv Cquat.),
39.50 (ϪCH2CϭO), 60.27 (CHN), 61.30 (C-6), 66.75, 67.30, 71.38,
72.99 (C-2, C-3, C-4, C-5), 90.18 (C-1), 101.54 (NCHϭCH),
127.78, 129.04, 133.52 (o-, m-, p-C, phenyl), 138.98 (Cipso), 146.56
(NCHϭCH), 176.39, 176.57, 177.20, 177.76 (piv CO), 191.50 (Cϭ
O) ppm. MS (FD): m/z ϭ 772.1 [M]ϩ. C42H65NO10Si (772.07):
calcd. C 65.34, H 8.49, N 1.81; found C 65.31, H 8.44, N 1.84.
(S)-(؉)-Coniine·HCl (10): Piperidine 9 (0.38 g, 0.61 mmol) in meth-
anol (10 mL), 2  HCl (1 mL), 48 h; yield 0.1 g (0.61 mmol, 100%).
M.p. 214Ϫ215 °C (ref.[14] 221 °C). [α]2D2 ϭ 6.8 (c ϭ 1.0, MeOH)
{ref.[14] [α]2D5 ϭ Ϫ6.8 (c ϭ 0.6, MeOH) (enantiomer)}. 1H NMR
(CDCl3, 200 MHz): δ ϭ 0.80 (t, 3 H, ϪCH3), 1.0Ϫ2.10 (m, 10 H,
ϪCH2Ϫ), 2.72Ϫ3.00 (m, 2 H, NCH2), 3.40 (m, 1 H, NCH), 9.13,
9.39 (2 s, 2 H, NH) ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 13.7
(CH3), 18.5, 22.2, 22.4, 28.1, 35.3 (CH2), 44.8 (NCH2), 57.1 (pro-
pylCHN) ppm.
The following intermediates in the synthesis of (S)-coniine were
prepared according to the method for their stereoisomeric ana-
logues obtained in the published synthesis of (R)-coniine.[14]
(2S,3S)-2,3-Dihydro-3-methyl-2-propyl-1-(2,3,4,6-tetra-O-pivaloyl-
β-
D-galactopyranosyl)pyridine-4(1H)-one (11a): A solution of 6b
(1.01 g, 1.58 mmol) in THF (10 mL) was added slowly through a
3354
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3346Ϫ3360

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
syringe to a solution of LiHMDS (0.32 g, 1.90 mmol) in THF
(ϪCH2Ϫ), 26.36, 26.47, 27.45 (piv CH3), 32.65 (ϪCH2Ϫ), 38.38,
(50 mL ) at Ϫ78 °C. Stirring was continued for 1 h before methyl 38.60, 38.73, 38.97 (piv Cquat.), 49.76 [ϪCH(Et)CϭO], 59.65
iodide (0.296 mL, 4.75 mmol) was added, and the mixture was (CHN), 61.39 (C-6), 66.51, 66.79, 72.08, 72.47 (C-2, C-3, C-4, C-
warmed up to Ϫ10 °C. After stirring at this temperature for 12 h,
5), 90.45 (C-1), 99.34 (NCHϭCH), 127.65, 128.88, 133.89 (o-, m-,
the reaction was terminated by addition of aq. satd. NH4Cl p-C, phenyl), 138.90 (Cipso), 147.49 (NCHϭCH), 176.29, 176.44
(150 mL). The mixture was extracted three times with diethyl ether
(200 mL). The combined organic layers were dried with MgSO4,
and the solvent was evaporated in vacuo. Flash chromatography
(light petroleum ether/ethyl acetate, 1:1) yielded 11a together with
some unreacted starting material. The compounds were separated
by preparative HPLC [Luna 10 µ, Kromasil C-18(2), 250 ϫ 50 mm
(Phenomenex), eluent: MeCN/H2O, 85:15, flow: 20 mL·minϪ1, UV
detection at 310 nm, Rt [min]: 41.92 (6b), 49.70 (11a)]; yield 0.99 g
(69%), 69% conversion. M.p. 115 °C. Single diastereomer, ratio ϾϾ
99:1 (1H NMR, HPLC). Rf ϭ 0.78 (light petroleum ether/ethyl
acetate, 1:1). Data for the pure (2S,3S) diastereomer: [α]2D5 ϭ Ϫ61.3
(piv CO), 195.50 (CϭO) ppm. MS (FD): m/z ϭ 800.1 [M]ϩ.
General Procedure for the Cuprate Addition: A solution of the Grig-
nard reagent (1 mmol) in diethyl ether or THF was added dropwise
to a suspension of CuI (1 mmol) in THF (10 mL) at the tempera-
ture quoted for each compound. After stirring for 1 h, BF3·OEt2
(1 mmol) was added, and stirring was continued for an additional
15 min. Then a solution of the corresponding enaminone 6 in THF
(20 mL mmolϪ1) was added through a syringe and stirring was
continued at Ϫ78 °C until TLC showed complete conversion
(1Ϫ10 h). The reaction was terminated by addition of concd.
NH4OH/aq. satd. NH4Cl (1:1) (100 mL), the mixture was warmed
up to ambient temperature and was extracted twice with diethyl
ether (200 mL). The combined organic layers were washed with aq.
satd. NH4Cl (100 mL) and dried with MgSO4. Evaporation of the
solvent in vacuo and purification of the residue by flash chromatog-
raphy afforded the following compounds.
1
(c ϭ 1.0, CHCl3). H NMR (200 MHz, CDCl3): δ ϭ 0.86 (t, 3 H,
CH3), 1.10Ϫ1.27 (m, 41 H, piv CH3, CH2, CH3), 1.39Ϫ1.89 (m, 2
H, CH2), 2.34 (m, 1 H, ϪCHMe), 3.24 (br. d, J ϭ 10.3 Hz, 1 H,
NCH), 4.03 (m, 3 H, H-5, H-6a, H-6b), 4.47 (d, J1,2 ϭ 9.3 Hz, 1
H, H-1), 5.00 (d, J ϭ 7.8 Hz, 1 H, NCHϭCH), 5.13 (dd, J3,2
10.2, J3,4 ϭ 3.2 Hz, 1 H, H-3), 5.38 (t, 1 H, H-2), 5.40 (d, J4,3
ϭ
ϭ
3.4 Hz, 1 H, H-4), 7.04 (d, J ϭ 7.8 Hz, 1 H, NCHϭC) ppm. 13C
(2S)-2,6-Dipropyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-
NMR (100.6 MHz, CDCl3):
δ ϭ 13.9, 17.8 (ϪCH3), 18.6
piperidin-4-one (12a): 6b (1.36 g, 2.31 mmol), 4.6 equiv. RCu·BF3
(propylMgCl, 2  in THF); temperature, time: Ϫ78 °C, 2 h; yield
1.31 g (1.92 mmol, 83%); mixture of diastereomers, ratio: 1.1:1 (1H
NMR). Rf ϭ 0.74 (light petroleum ether/ethyl acetate, 8:1). Only
characteristic signals are given for the mixture: 1H NMR
(200 MHz, CDCl3): δ ϭ 4.38 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1minor), 4.58
(d, J1,2 ϭ 9.3 Hz, 1 H, H-1major), 5.45 (t, J ϭ 9.8 Hz, 1 H, H-2minor),
5.61 (t, J ϭ 9.8 Hz, 1 H, H-2major) ppm. C37H63NO10 (681.90):
calcd. C 65.17, H 9.31, N 2.05; found C 64.94, H 9.28, N 2.07.
(ϪCH2Ϫ), 27.0, 27.1 (piv CH3), 31.8 (ϪCH2Ϫ), 38.6, 38.7, 38.8,
39.0 (piv Cquat.), 42.9 (CHMeCϭO), 61.4 (propylϪCHN), 64.5 (C-
6), 66.7, 66.8, 71.9, 72.7 (C-2, C-3, C-4, C-5), 90.4 (C-1), 99.4
(NCHϭCH), 146.7 (NCHϭCH), 176.4, 176.5, 177.2, 177.8 (piv
CϭO), 196.6 (CϭO) ppm. MS (FAB): m/z ϭ 652.6 [M ϩ H]ϩ.
C35H57NO10 (651.83): calcd. C 64.49, H 8.81, N 2.15; found C
63.79, H 8.67, N 2.07. Crystal data: Size: 0.128 ϫ 0.256 ϫ 0.512
˚
mm; colourless crystal; P21 (monoclinic); a ϭ 13.243(2) A, b ϭ
3
˚
˚
˚
10.4162(6) A, c ϭ 15.703(2) A, β ϭ 112.477(7)°, V ϭ 2001.6(5) A ,
Z ϭ 2, F(000) ϭ 708; T ϭ 295 K; ρ ϭ 1.082 g·cmϪ3. Data collec-
tion: diffractometer: CAD4 (Enraf-Nonius); radiation: Cu-Kα,
graphite monochromator, scan-type: ω/2Θ; scan-width: 0.8 ϩ
0.14·tan(Θ) and 25% left and right for determination of back-
ground; measurement range: 1.5° Յ Θ Յ 74°; 0 Յ h Յ 16 0 Յ k
Յ 12 Ϫ19 Յ l Յ 19; reflections: measured 8664 (with Friedel pairs),
independent 7808 (Rint ϭ 0.0468), observed 3185 (|F|/σ(F) Ͼ 4.0).
CCDC-237632 contains the supplementary crystallographic data
for this paper. These data can be obtained free of charge at
www.ccdc.cam.ac.uk/conts/retrieving.html [or from the Cambridge
Crystallographic Data Centre, 12 Union Road, Cambridge
CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-033; E-mail:
deposit@ccdc.cam.ac.uk].
(2R)-2,6-Diphenyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
pyranosyl)piperidin-4-one (12b): 6h (2.15 g, 2.97 mmol), 4.3 equiv.
RCu·BF3 (phenylMgCl, 2  inTHF); temperature, time: Ϫ78 °C,
18 h; yield 2.2 g (2.94 mmol, 99%); mixture of diastereomers, ratio:
3:1 (1H NMR). Rf ϭ 0.60 (light petroleum ether/ethyl acetate, 6:1).
Only characteristic signals are given for the mixture. 1H NMR
(200 MHz, CDCl3): δ ϭ 4.33 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1major), 4.40
(d, J1,2 ϭ 9.3 Hz, 1 H, H-1minor), 4.87 (dd, J3,2 ϭ 9.8, J3,4 ϭ 3.4 Hz,
1 H, H-3major), 5.74 (t, J ϭ 9.8 Hz, 1 H, H-2major) ppm.
C43H59NO10 (747.91): calcd. C 68.87, H 7.93, N 1.87; found C
68.94, H 7.65, N 1.59.
(2S)-2-Methyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-6-
vinylpiperidin-4-one (12c): 6a (2.43 g, 3.97 mmol), 5.0 equiv.
RCu·BF3 (vinylMgCl, 1  in THF); temperature, time: Ϫ78 °C,
5 h; yield 1.85 g (2.9 mmol, 73%); mixture of diastereomers, ratio
ca. 2:1 (1H NMR). Rf ϭ 0.37 (light petroleum ether/ethyl acetate,
4:1). Only characteristic signals are given for the mixture: 1H NMR
(200 MHz, CDCl3): δ ϭ 5.47 (t, J ϭ 9.8 Hz, 1 H, H-2major), 6.07
(2S,3S)-2-{[Dimethyl(phenyl)silyl]propyl}-3-ethyl-2,3-dihydro-1-
(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-4(1H)-one
(11b): Procedure see above; dehydropiperidinone 6k (3.4 g,
4.40 mmol) in dry THF (50 mL), LiHMDS (1.1 g, 6.60 mmol) in
dry THF (10 mL), EtI (1.05 mL, 13.2 mmol); yield 2.84 g
(3.55 mmol, 81%); single diastereomer, only trans (HPLC). Rf ϭ
0.68 (light petroleum ether/ethyl acetate, 1:1). [α]2D0 ϭ Ϫ25.4 (c ϭ
1.0, CHCl3). 1H NMR (200 MHz, CDCl3): δ ϭ 0.22 (s, 6 H,
SiϪCH3), 0.66 (t, 2 H, ϪSiϪCH2Ϫ), 0.88 (t, J ϭ 7.3 Hz, 3 H,
(d, Jtrans ϭ 15.6 Hz, 1 H, vinylmajor), 7.02 (dd, Jtrans ϭ 15.6, Jcis
ϭ
11.2 Hz, 1 H, vinylmajor) ppm. MS (FAB): m/z ϭ 638.5 [M ϩ H]ϩ.
C34H55NO10 (637.81): calcd. C 64.03, H 8.69, N 2.20; found C
63.54, H 8.62, N 2.18.
ϪCH3), 1.09Ϫ1.22 (m, 40 H, piv CH3, ϪCH2Ϫ), 1.33Ϫ1.54 (m, 3 (2R)-2,6-Diphenyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
H, ϪCH2Ϫ), 2.01Ϫ2.03 [m, 2 H, ϪCH(Et)ϪCO, ϪCH2Ϫ], pyranosyl)piperidin-4-one (12b): CuI (1 mmol) in dry Et2O (10 mL )
3.38Ϫ3.41 (m, 1 H, NCH), 3.93Ϫ4.09 (m, 3 H, H-5, H-6a, H-6b), and PhLi (2 mmol, 1.7  in cylohexane) were stirred at 0 °C for
4.39 (d, J1,2 ϭ 9.4 Hz, 1 H, H-1), 4.95 (d, J ϭ 7.7 Hz; 1 H, NCHϭ
CH), 5.09 (dd, J3,2 ϭ 9.7, J3,4 ϭ 3.3 Hz, 1 H, H-3), 5.32 (t, 1 H, (0.5 g, 0.74 mmol) and TMSCl (6 mmol, 4.3 mL) in Et2O was ad-
H-2), 5.37 (d, J4,3 ϭ 2.9 Hz, 1 H, H-4), 6.94 (d, J ϭ 7.9 Hz, 1 H, ded slowly through a syringe. After 18 h, TLC showed complete
NCHϭCH), 7.31Ϫ7.47 (m,
H, phenyl) ppm. 13C NMR conversion, and the reaction was terminated by addition of 1.5 mL
(50.3 MHz, CDCl3): δ ϭ Ϫ3.66 (SiϪCH3), 15.67, 19.71, 24.29 of a TBAF solution (1  in THF). The aqueous layer was separated
10 min. The solution was cooled to Ϫ78 °C, and a mixture of 6h
5
Eur. J. Org. Chem. 2004, 3346Ϫ3360
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3355

E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
FULL PAPER
and extracted with Et2O (2 ϫ 50 mL). After combination of the
organic layers and drying with MgSO4, the solvent was evaporated
in vacuo. Further purification was carried out by flash chromatog-
raphy. Yield 0.26 g (0.35 mmol, 47%); mixture of diastereomers, ra-
tio 2.7:1 (1H NMR). Rf ϭ 0.60 (light petroleum ether/ethyl acetate,
6:1). Analytical data are identical to those obtained from cuprate
addition using RCu·BF3 (see above).
of diastereomers, ratio ca. 3:1 (1H NMR). Rf ϭ 0.49 (light petro-
leum ether/ethyl acetate, 4:1). MS (FD): m/z ϭ 796.1 [M,80Se]ϩ;
calcd. for C40H61NO10Se 795.83. The product was used in the next
step without further purificaton.
(2S)-1-(Benzyloxycarbonyl)-5-phenylselenyl-2-propylpiperidin-4-one
(15): HCl (1 mL, 1 ) was added to 14 (460 mg, 0.58 mmol), dis-
solved in methanol (10 mL). TLC showed complete conversion
after 12 h. The solvent was evaporated in vacuo. After addition of
diethyl ether (50 mL) and water (50 mL) and thorough extraction,
the layers were separated and extracted again until TLC showed
complete separation. The aqueous layer was concentrated in vacuo
to a volume of 10 mL, and satd. Na2CO3 (1 mL ) was added.
Benzyl chloroformate (0.16 mL, 1.13 mmol) was added under vig-
orous stirring. After 2 h, the reaction mixture was extracted with
diethyl ether (3 ϫ 20 mL). The combined organic layers were dried
(MgSO4), filtered and concentrated in vacuo. Flash chromatogra-
phy yielded 15 as a yellow oil; yield 0.133 g (0.31 mmol, 53%, two
steps). Rf ϭ 0.47 (light petroleum ether/ethyl acetate, 4:1). MS
(FD): m/z ϭ 431.6 [M,80Se]ϩ; calcd. for C22H25NO3Se 431.10. This
product was used for the oxidation without further purification.
(2S,6R)-1-(Benzyloxycarbonyl)-2,6-dipropylpiperidin-4-one (cis-13a)
and (2S,6S)-1-(Benzyloxycarbonyl)-2,6-dipropylpiperidin-4-one
(trans-13b): Piperidine 12a (0.78 g, 1.14 mmol) was dissolved in
MeOH (10 mL) and treated with aq. HCl (2 , 2 mL). After stirring
overnight, the solvent was evaporated yielding a colourless residue
which was dissolved in a mixture of water (50 mL) and diethyl ether
(50 mL). The phases were separated and the aqueous layer was
extracted twice with diethyl ether (50 mL). The aqueous layer con-
taining the heterocycle as its hydrochloride was concentrated to
dryness in vacuo. The residue was dissolved in water (10 mL) and
treated, whilst stirring, with aq. satd. Na2CO3 (10 mL). After 1 h,
benzyl chloroformate (0.25 mL, 0.17 mmol) was added, and stir-
ring was continued for 1 h. The reaction mixture was extracted
twice with diethyl ether (50 mL), the combined organic layers were
dried with MgSO4 and the solvent was evaporated in vacuo. Purifi-
cation by flash chromatography (light petroleum ether/ethyl acet-
ate, 20:1) yielded 13a and 13b as colourless oils (0.18 g, 0.57 mmol,
50%, cis-13a and 0.16 g, 0.5 mmol, 44%, trans-13b). MS (FAB):
m/z ϭ 318.0 [M ϩ H]ϩ; calcd. for C19H27NO3 317.42. cis-13a: Rf ϭ
0.68 (ethyl acetate/light petroleum ether, 4:1). [α]2D8 ϭ 0 (c ϭ 1.0,
(2S)-1-(Benzyloxycarbonyl)-2,3-dihydro-2-propylpyridine-4(1H)-one
(16): The piperidinone 15 (133 mg, 0.31 mmol) was dissolved in
CH2Cl2/water (20:1) (10 mL). Under vigorous stirring H2O2/urea
complex (80 mg, 0.85 mmol) was added. The stirring was continued
for 2 h until TLC showed complete conversion. The reaction mix-
ture was extracted with aq. satd. NaHCO3 (10 mL), and the layers
were separated. After extraction of the aqueous solution with
CH2Cl2 (2 ϫ 10 mL), the combined organic layers were dried with
MgSO4, and the solvent was evaporated in vacuo. Flash chroma-
tography (light petroleum ether/ethyl acetate, 5:1) yielded 16 as a
colourless oil; yield 58 mg (69%). Rf ϭ 0.23 (light petroleum ether/
ethyl acetate, 4:1). [α]2D0 ϭ 122.6 (c ϭ 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ. 0.84 (t, 3 H, ϪCH3), 1.20 (m, 2 H,
ϪCH2Ϫ), 1.58 (q, 2 H, ϪCH2Ϫ), 2.40 (d, Jgem ϭ 16.6 Hz, 1 H,
ϪCH2ϪCϭO), 2.75 (dd, Jgem ϭ 16.6, Jvic ϭ 6.8 Hz, 1 H,
ϪCH2ϪCϭO), 4.58 (m, 1 H, NCH propyl), 5.22 (s, 2 H, PhCH2),
5.27 (d, J ϭ 8.0 Hz, 1 H, NCHϭCH), 7.35 (m, 5 H, Ph), 7.72 (d,
J ϭ 7.8 Hz, 1 H, NCHϭC) ppm. 13C NMR (50.3 MHz CDCl3):
δ ϭ 13.7 (ϪCH3), 18.9, 32.6 (ϪCH2Ϫ), 39.6 (CH2CϭO), 53.2 (pro-
pylCHN), 68.9 (PhCH2Ϫ), 107.1 (NCHϭCH), 126.9, 127.5, 128.7
(o-, m-, p-Ph), 135.0 (ipso-C), 141.5 (NCHϭCH), 152.5 (NCO),
193.1 (CϭO) ppm. MS (FD): m/z ϭ 273.4 [M]ϩ; calcd. for
C16H19NO3 273.33.
1
CHCl3). H NMR (CDCl3, 200 MHz): δ ϭ 0.86 (t, J ϭ 7.3, J ϭ
6.7 Hz, 6 H, propyl CH3), 1.23Ϫ1.46 (m, 8 H, ϪCH2Ϫ), 2.31 (dd,
Jgem ϭ 15.1, J ϭ 2.4 Hz, 2 H, H-3a, H-5a), 2.64 (dd, Jgem ϭ 15.1,
Jvic ϭ 7.8 Hz, 2 H, H-3b, H-5b), 4.63 (m, 2 H, NCH), 5.13 (s, 2
H, PhCH2Ϫ), 7.25Ϫ7.33 (m, 5 H, Ph) ppm. 13C NMR (CDCl3,
50.3 MHz):
δ ϭ 13.7 (ϪCH3), 20.0, 38.8 (ϪCH2Ϫ), 43.6
(ϪCH2ϪCϭO), 52.9 (NCH), 67.6 (PhCH2), 127.5, 128.0, 128.1,
136.4 (Ph), 155.7 (OCϭO), 208.2 (CϭO) ppm. trans-13b: Rf ϭ 0.51
(ethyl acetate/light petroleum ether, 4:1). [α]2D8 ϭ Ϫ141.3 (c ϭ 1.0,
1
CHCl3). H NMR (CDCl3, 200 MHz): δ ϭ 0.83 (t, J ϭ 7.3, J ϭ
6.8 Hz, 6 H, propyl CH3), 1.22Ϫ1.35 (m, 6 H, ϪCH2Ϫ), 1.71Ϫ1.75
(m, 2 H, ϪCH2Ϫ), 2.48 (dd, Jgem ϭ 18.1, J ϭ 2.4 Hz, 2 H, H-3a,
H-5a), 2.67 (dd, Jgem ϭ 18.1, Jvic ϭ 4.9 Hz, 2 H, H-3b, H-5b), 4.17
(m, 2 H, NCH), 5.08 (d, Jgem ϭ 12.2 Hz, 1 H, phenylCH2Ϫ), 5.20
(d, Jgem ϭ 12.2 Hz, 1 H, PhCH2Ϫ), 7.28Ϫ7.35 (m, 5 H, phenyl)
ppm. 13C NMR (CDCl3, 50.3 MHz): δ ϭ 13.7 (ϪCH3), 19.8, 39.0
(ϪCH2Ϫ), 41.5 (ϪCH2ϪCϭO), 51.2 (NCH), 67.2 (PhCH2), 128.0,
128.5, 136.5 (Ph), 155.3 (OCϭO), 207.6 (CϭO) ppm.
(2S)-1-(Benzyloxycarbonyl)-6-(3-hydroxypropyl)-2-propylpiperidin-
4-one (17): Preparation of the Grignard reagent: Mg filings (0.42 g,
17.2 mmol) in THF (15 mL) were treated with 1,2-dibromoethane
(0.1 mL, 8.61 mmol) at ambient temperature. After the violent re-
action had ceased, the solvent was taken up in a syringe and THF
(10 mL) was added. This washing process was repeated three times.
To this activated Mg in THF (10 mL) was added 3-(1-ethoxy-
ethoxy)propyl bromide[24](1.13 mL) and the mixture was stirred un-
til the metal was consumed (2 h). Cuprate addition: BF3·OEt2
Synthesis of ent-Indolizidine 167B
(2S)-1-(Benzyloxycarbonyl)-2,3-dihydro-2-propylpyridine-4(1H)-
one (16)
(2S)-5-(Phenylselenyl)-2-propyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-
galactopyranosyl)piperidin-4-one (14): A solution of enaminone 6b
(2.17 g, 3.40 mmol) in THF (50 mL) at Ϫ78 °C was treated with -
Selectride (1  in THF, 3.74 mL, 3.74 mmol). The solution was (1.51 mL, 2.39 mmol) was added to a suspension of enaminone 16
maintained at this temperature for 40 min, then the intermediate
lithium enolate was trapped by the addition of PhSeCl (0.78 g,
(218 mg, 0.79 mmol) and CuBr·SMe2 (0.49 g, 2.39 mmol) in THF
(15 mL) at Ϫ78 °C, and stirring was continued for 10 min. Sub-
4.08 mmol) in THF (5 mL). Stirring was continued for 2 h before sequently, the previously prepared Grignard reagent (3.8 mL) was
the reaction was terminated by addition of aq. satd. NaHCO3
(50 mL). After extracting with diethyl ether (3 ϫ 80 mL), the com-
bined organic fractions were dried with MgSO4. After evaporation
of the solvent, purification by flash chromatography (light petro-
leum ether/ethyl acetate, 10:1) yielded 14 as a slightly yellow
added through a syringe, and the reaction mixture was stirred at
Ϫ78 °C. After 5 h, a mixture of aq. satd. NH4Cl and concd.
NH4OH (1:1, 30 mL) was added to the cold reaction mixture, and
it was warmed to ambient temperature. Separation of the phases,
extraction of the aqueous layer with diethyl ether (3 ϫ 50 mL),
amorphous solid (1.90 g, 70%) composed of an inseparable mixture drying of the combined organic layers with MgSO4 and evapor-
3356  2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim www.eurjoc.org
Eur. J. Org. Chem. 2004, 3346Ϫ3360

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
ation of the solvent yielded a colourless oil. The residue was dis-
solved in THF (10 mL) and treated with aq. HCl (2 , 0.5 mL).
After 20 min, the mixture was neutralized by addition of aq. satd.
NaHCO3 and extracted twice with diethyl ether (50 mL). The com-
bined organic layers were dried with MgSO4 and the solvent was
less oil. The residue was purified by passing it through a short plug
of silica which gave a mixture of regioisomers of the vinyl triflates
(102 mg, 76%). Rf ϭ 0.69 (0.87 (light petroleum ether/ethyl acetate,
4:1). Reduction and ring closure: The crude vinyl triflates (100 mg,
0.20 mmol) were dissolved in ethyl acetate (20 mL). Li2CO3 (30 mg,
evaporated in vacuo. Flash chromatography (light petroleum ether/ 0.4 mmol) and Pd/C (10%, 30 mg) were added. Hydrogen was
ethyl acetate, 4:1) gave 17 (193 mg, colourless oil, 73%) as a mixture bubbled through the solution for 1 h. After TLC showed complete
of diastereomers, ratio 2:1 (1H NMR). Rf ϭ 0.24 (light petroleum
ether/ethyl acetate, 1:1). [α]2D0 ϭ Ϫ34.9 (c ϭ 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 0.84 (t, 3 H, ϪCH3), 1.1Ϫ1.7 (m, 8 H,
consumption of the vinyl triflates, the mixture was passed through
a plug of Celite, which was then washed several times with CH2Cl2.
The volume of the combined solutions was reduced in vacuo and
ϪCH2-, ϪOH), 2.1Ϫ2.7 (m, 5 H, ϪCH2Ϫ), 3.5 (m, 2 H, the resulting residue was dissolved in methanol (10 mL), treated
ϪCH2OH), 4.15, 4.6 (2 m, 2 H, NCH), 5.15 (m, PhCH2), 7.35 (m,
with Li2CO3 (30 mg) and stirred overnight. The solvents were evap-
Ph) ppm. 13C NMR (50.3, MHz CDCl3): δ ϭ 13.7 (ϪCH3), 19.8, orated to dryness in vacuo, the residue dissolved in CH2Cl2 (10 mL)
20.0 (ϪCH2), 29.1, 29.4 (ϪCH2Ϫ), 33.0, 33.3 (ϪCH2Ϫ), 38.8, 39.0 and the solution washed with aq. satd. NaCl (10 mL). The organic
(ϪCH2Ϫ), 41.4, 43.7 (ϪCH2Ϫ), 50.8, 51.2, 52.7, 52.9 (CHN), 61.7
layer was dried with MgSO4, the solvent was evaporated in vacuo
(ϪCH2OϪ), 67.4, 67.7 (benzyl ϪCH2Ϫ), 128.1, 128.3 (o-, m-, p- and the residue was purified by flash chromatography (ethyl acet-
Ph), 136.2, 136.3 (ipso-C), 155.5, 155.8 (NCO), 207.4, 208.0 (CϭO) ate/methanol, 9:1) to yield a clear, volatile oil; yield 24.3 mg, 70%.
ppm. MS (FD): m/z ϭ 333.7 [M]ϩ; calcd. for C19H27NO4 (333.42).
Rf ϭ 0.07 (ethyl acetate/methanol, 9:1). [α]2D0 ϭ 101.4 (c ϭ 0.22,
CH2Cl2). H NMR (200 MHz, CDCl3): δ ϭ 0.88 (t, 3 H, ϪCH3),
1
(2S,6R)-cis-1-(Benzyloxycarbonyl)-6-(3-chloropropyl)-2-propyl-
piperidin-4-one (cis-18) and (2S,6S)-trans-1-(Benzyloxycarbonyl)-6-
(3-chloropropyl)-2-propylpiperidin-4-one (trans-18): The N-(galactos-
yl)piperidinones 17 (183 mg, 0.55 mmol) were dissolved in CH2Cl2
(20 mL) and cooled to Ϫ40 °C. Subsequently, PPh3 (216 mg,
0.82 mmol) in CH2Cl2 (10 mL) and N-chlorosuccinimide in CH2Cl2
(10 mL) were added slowly through a syringe. The reaction mixture
was stirred overnight and slowly warmed to room temperature. The
reaction was terminated by addition of methanol (10 mL) and the
mixture stirred for an additional 15 min. Evaporation of the solvent
in vacuo and purification of the residue by flash chromatography
(light petroleum ether/ethyl acetate, 4:1) yielded two separable
products [126 mg, cis-18; Rf ϭ 0.76 (light petroleum ether/ethyl
acetate, 1:1) and 58 mg, trans-18; Rf ϭ 0.87 (light petroleum ether/
1.02Ϫ1.52 (m, 7 H), 1.52Ϫ2.02 (m, 10 H), 3.26 (td, J ϭ 8.3 Hz,
2.0 Hz, 1 H, NCH) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 14.5
(ϪCH3), 19.1, 20.4, 24.6, 30.5, 30.8, 30.9, 36.8, 51.5 (NCH2), 63.7,
65.0 (NCHR) ppm. GC-MS (MS-Finnigan ion-trap): m/z ϭ 166
[M Ϫ H]Ϫ; calcd. for C11H21N 167.29.
1,2-Dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-
pyridin-2(1H)-one (5): 2,3,4,6-Tetra-O-pivaloyl-α--galactopyrano-
syl fluoride[11] (1) (36.7 g, 71 mmol) in 1,2-dichloroethane (200 mL)
was heated to 70 °C. Then, 2-(trimethylsilyloxy)pyridine (4,
17.66 mL, 105 mmol) was added slowly through a syringe. To this
solution TiCl4 (14 mL, 128 mmol) was added. The colour of the
solution turned to red. The mixture was refluxed for 2 h. After
cooling to room temperature, aq. satd. NaHCO3 (500 mL) was ad-
ethyl acetate, 1:1)]; overall yield 95%. cis-18: [α]2D0 ϭ Ϫ2.7 (c ϭ 1.0, ded carefully. The mixture was diluted with CH2Cl2 (500 mL), the
1
CHCl3). H NMR (200 MHz, CDCl3): δ ϭ 0.85 (t, 3 H, ϪCH3),
aqueous layer extracted with CH2Cl2 (3 ϫ 500 mL) and the com-
1.19Ϫ1.80 (m, 8 H, ϪCH2Ϫ), 2.23 (t, Jgem ϭ 13.5 Hz, 2 H, bined organic layers were dried with MgSO4. Evaporation of the
ϪCH2ϪCϭO), 2.61Ϫ2.69 (m, 2 H, ϪCH2ϪCϭO), 3.45 (m, 2 H, solvent in vacuo and flash chromatography (light petroleum ether/
ϪCH2Cl), 4.62 (m, 2 H, NCH), 5.12 (s, 2 H, PhCH2), 7.32 (m, 5 ethyl acetate, 2:1) yielded 5 as colourless crystals (40.6 g, 97%).
H, Ph) ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 13.7 (ϪCH3),
19.8, 29.7, 34.0, 38.8, 43.5, 43.8, 44.3 (ϪCH2Ϫ), 52.4, 52.9 (CHN),
M.p. 120 °C. Rf ϭ 0.48 (light petroleum ether/ethyl acetate, 4:1).
1
[α]2D7 ϭ 73.6 (c ϭ 1.0, CHCl3). H NMR (200 MHz, CDCl3): δ ϭ
67.7 (PhCH2Ϫ), 128.1, 128.2 (o-, m-, p-Ph), 136.2 (ipso-C), 155.6 0.97, 1.08, 1.13, 1.28 (4 s, 36 H, piv CH3), 4.0Ϫ4.22 (m, 3 H, H-
(NCO), 207.4 (CϭO) ppm. MS (FD): m/z ϭ 351.5 [M]ϩ; calcd. for 6a, H-6b, H-5), 5.31 (dd, J3,2 ϭ 10.25, J3,4 ϭ 2.93 Hz, 1 H, H-3),
C19H26ClNO3 351.87. trans-18: [α]2D0 ϭ Ϫ68.9 (c ϭ 1.0, CHCl3). 1H
5.44 (t, J2,3 ϭ 10.3, J2,1 ϭ 9.28 Hz, 1 H, H-1), 5.51 (d, J4,3
NMR (200 MHz, CDCl3): δ ϭ 0.83 (t, 3 H, ϪCH3), 1.20Ϫ1.92 (m, 2.9 Hz, 1 H, H-4), 6.21 (t, J ϭ 6.83 Hz, 1 H, NϪCHϭCH), 6.37
8 H,ϪCH2Ϫ), 2.49 (t, 2 H, ϪCH2ϪCϭO), 2.54 (m, 2 H, (d, J1,2 ϭ 9.28 Hz, 1 H, H-1), 6.45 (d, J ϭ 9.27 Hz, 1 H, OCϪCH),
ϪCH2ϪCϭO), 3.42 (m, 2 H, ϪCH2Cl), 4.09 (m, 2 H, NCH), 5.08 7.22Ϫ7.34 (m, 2 H, OCϪCHϭCHϪ, NϪCHϭCHϪ) ppm. 13C
ϭ
(d, Jgem ϭ 12.0 Hz, 1 H, PhCH2), 5.19 (d, Jgem ϭ 12.3 Hz, 1 H,
NMR (50.3 MHz, CDCl3): δ ϭ 27.03 (piv CH3), 38.70, 38.75,
PhCH2), 7.29Ϫ7.34 (m, 5 H, Ph) ppm. 13C NMR (50.3 MHz, 38.81, 39.11 (piv Cquat.), 60.72 (C-6), 66.88, 67.76, 71.22, 74.01 (C-
CDCl3): δ ϭ 13.7 (ϪCH3), 19.8, 29.6, 34.4, 38.9, 41.5, 41.8, 44.3 2, C-3, C-4, C-5), 79.52 (C-1), 106.55 (NϪCHϭCHϪ), 120.57
(ϪCH2Ϫ), 50.8, 51.3 (CHN), 67.4 (PhCH2Ϫ), 128.2, 128.6 (o-,
(OCϪCH), 132.66 (NϪCH), 139.89 (OCϪCHϭCHϪ), 161.72
m-, p-Ph), 136.3 (ipso-C), 155.3 (NCO), 207.0 (CϭO) ppm. MS (NCO), 176.42, 176.88, 177.0, 177.76 (piv CϭO) ppm. FD-MS:
(FD): m/z ϭ 351.5 [M]ϩ; calcd. for C19H26ClNO3 351.87.
m/z [Mϩ] found: 594.0. C31H47NO10 (593.71): calcd. C 62.71, H
7.98, N 2.36; found C 62.70, H 8.13, N 2.30.
(5S,9S)-(؉)-Indolizidine 167B (ent-19): Synthesis of the vinyl tri-
flates: A solution of LiHMDS (69.5 mg, 0.42 mmol) in THF (5 mL) General Procedure for the Regioselective Addition of Grignard Com-
was added dropwise to
0.27 mmol) in THF (7 mL) at Ϫ78 °C with stirring. After 1 h, the
a
solution of ketone 18 (97.9 mg,
pounds To Furnish Compounds 20: The 1,2-dihydropyridin-2-one
derivative 5 (1 g, 1.68 mmol) in dry CH2Cl2 (20 mL) was treated
with 2.0 equiv. (3.36 mmol) of the corresponding silylating reagent
at room temperature. After stirring for 1 h, 2.0 equiv. of 2,6-lutidine
(0.39 mL, 3.36 mmol) was added. Subsequently, 1.5 equiv.
(2.52 mmol) of a solution of the corresponding Grignard reagent
(in THF or Et2O) was added slowly through a syringe. Details are
given for each compound. After stirring for 2 h (until TLC indi-
cated complete conversion), satd. NH4Cl (10 mL) was added, the
enolates were trapped by addition of a solution of 2-amino-
5-chloro-N,N-bis(trifluoromethylsulfonyl)pyridine[27]
(163.4 mg,
0.42 mmol) in THF (1 mL). The mixture was warmed to ambient
temperature overnight. Addition of aq. satd. NH4Cl (10 mL), sep-
aration of the layers, extraction of the aqueous phase with diethyl
ether (10 mL), subsequent drying of the combined organic layers
with MgSO4 and evaporation of the solvent in vacuo gave a colour-
Eur. J. Org. Chem. 2004, 3346Ϫ3360
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 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3357

E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
mixture was diluted with CH2Cl2 (20 mL) and the layers were sepa- H, H-2), 5.43 (d, J4,3 ϭ 2.35 Hz, 1 H, H-4), 5.87 (d, J1,2 ϭ 9 Hz, 1
FULL PAPER
rated. After extraction of the aqueous solution with CH2Cl2 the
combined organic layers were dried with MgSO4, filtered and the
H, H-1), 6.24 (dd, Jallyl ϭ 1.96, Jolef ϭ 8.22 Hz, 1 H, NCHϭCH)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 19.12 (ϪCH3), 19.44
solvent was removed in vacuo. Further purification was carried out (ϪCH3), 26.98, 27.05, 27.24 (piv CH3), 31.33 [CH(CH3)2], 35.06
by flash chromatography and afforded the compounds 20.
(COϪCH2Ϫ), 37.82 (CHϪiPr), 38.75, 38.83, 39.08 (piv Cquat.),
60.94 (C-6), 66.21, 66.88, 71.70, 73.0 (C-2, C-3, C-4, C-5), 78.45
(C-1), 111.80 (NCHϭCH), 123.398 (NCHϭCH), 169.93 (NCϭO),
176.55, 176.84, 177.03, 177.81 (piv CϭO) ppm. MS (FD): m/z ϭ
638.1 [Mϩ]. C34H55NO10 (637.81): calcd. C 64.03, H 8.69, N 2.20;
found C 64.02, H 8.66, N 2.16.
(4R)-4-Ethyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β- -galacto-
D
pyranosyl)pyridine-2(1H)-one (20a): TMSOTf (3.36 mmol,
0.61 mL), EtMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield 0.56 g
(0.91 mmol, 54%); single diastereomer, ratio ϾϾ 99:1 (1H NMR
and HPLC). M.p. 124 °C. Rf ϭ 0.31 (light petroleum ether/ethyl
1
acetate, 8:1). [α]2D3 ϭ 40.60 (c ϭ 1.0, CHCl3). H NMR (200 MHz,
(4R)-4-Butyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
D-galacto-
CDCl3): δ ϭ 0.89 (m, 3 H, ϪCH3), 1.07, 1.08, 1.13, 1.25 (4 s, 36
pyranosyl)pyridine-2(1H)-one (20d): TMSOTf (3.36 mmol,
H, piv CH3), 1.40 (m, 2 H, ϪCH2ϪMe), 2.25Ϫ2.52 (m, 3 H, 0.61 mL), nBuMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield
ϪCH2CO, ϪCHϪethyl), 3.89Ϫ4.12 (m, 3 H, H-6a, H-6b, H-5), 0.824 g (1.26 mmol, 75%); single diastereomer, ratio ϾϾ 99:1 (1H
5.18Ϫ5.23 (m, 2 H, H-3, NϪCHϭCH), 5.27 (t, J2,1ϭ 8.79 Hz, 1 NMR and HPLC). M.p. 57 °C. Rf ϭ 0.21 (light petroleum ether/
H, H-2), 5.43 (d, J4,3 ϭ 2.92 Hz, 1 H, H-4), 5.87 (d, J1,2 ϭ 8.79 Hz,
ethyl acetate, 6:1). [α]2D7 ϭ 59.71 (c ϭ 1.0, CHCl3). 1H NMR
1 H, H-1), 6.21 (dd, Jolef ϭ 8.3 Hz, 1 H, NCHϭCH) ppm. 13C (200 MHz, CDCl3): δ ϭ 0.86 (m, 3 H, ϪCH3), 1.06, 1.07, 1.14,
NMR (50.3 MHz, CDCl3): δ ϭ 10.82 (ϪCH3), 27.05, 27.24 (piv 1.25 (4 s, 36 H, piv CH3), 1.28 (m, 6 H, ϪCH2Ϫ), 2.24Ϫ2.65 (m,
CH3), 27.29 (ϪCH2-Me), 32.75 (CHϪethyl), 37.42 (COCH2Ϫ), 3 H, ϪCH2CO, CHϪbutyl), 3.95Ϫ4.14 (m, 3 H, H-5, H-6a, H-6b),
38.71, 38.75, 39.08 (piv Cquat.), 60.85 (C-6), 66.27; 66.85, 71.57,
5.16Ϫ5.27 (m, 2 H, H-3, NCHϭCH), 5.31 (t, 1 H, H-2), 5.44 (d,
73.06 (C-2, C-3, C-4, C-5), 78.45 (C-1), 112.68 (NCHϭCH), 122.88 J4,3 ϭ 2.93 Hz, 1 H, H-4), 5.85 (d, J1,2 ϭ 8.79 Hz, 1 H, H-1), 6.20
(NCHϭCH), 169.69 (NCϭO), 176.55; 176.80, 177.03, 177.79, (piv (d, Jolef ϭ 7.79 Hz, 1 H, NCHϭCH) ppm. 13C NMR (50.3 MHz,
CϭO) ppm. MS (FD): m/z ϭ 624.4 [Mϩ]. C33H53NO10 (623.77): CDCl3): δ ϭ 13.95 (ϪCH3), 22.56 (ϪCH2ϪCH3), 27.05, 27.24 (piv
calcd. C 63.54, H 8.56, N 2.25; found C 63.54, H 8.54, N 2.21.
CH3), 31.18 (CHϪbutyl), 34.09 (ϪCH2ϪEt), 37.80 (COCH2Ϫ),
38.73, 38.81, 39.08 (piv Cquat.), 60.83 (C-6), 66.29, 66.83, 71.56,
73.04 (C-2, C-3, C-4, C-5), 78.45 (C-1), 113.11 (NCHϭCH), 122.74
(NCHϭCH), 169.67 (NCϭO), 176.53, 176.79, 177.01 (piv CϭO)
ppm. MS (FD): m/z ϭ 652.3 [Mϩ]. C35H57NO10 (651.3): calcd. C
64.49, H 8.81, N 2.15; found C 63.81, H 8.83, N 2.13.
(4R)-3,4-Dihydro-4-propyl-1-(2,3,4,6-tetra-O-pivaloyl-β- -galacto-
D
pyranosyl)pyridine-2(1H)-one (20b): TIPSOTf (3.36 mmol,
0.68 mL), nPrMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield 0.73 g
(1.14 mmol, 68%); single diastereomer, ratio ϾϾ 99:1 (1H NMR
and HPLC). M.p. 118 °C. Rf ϭ 0.42 (light petroleum ether/ethyl
acetate, 8:1). [α]2D7 ϭ 49.4 (c ϭ 1.0, CHCl3). H NMR (200 MHz,
(4R)-4-tert-Butyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galac-
1
CDCl3): δ ϭ 0.87 (m, 3 H, ϪCH3), 0.98, 1.07, 1.08, 1.14 (4s, 36 H, topyranosyl)pyridine-2(1H)-one (20e): TMSOTf (3.36 mmol,
piv CH3), 1.19Ϫ1.33 (m, 4 H, ϪCH2ϪCH2Ϫ), 2.15Ϫ2.65 (m, 3 H, 0.61 mL), tBuMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield
ϪCH2CO, ϪCHpropyl), 3.90Ϫ4.10 (m, 3 H, H-5, H-6a, H-6b), 0.243 g (0.37 mmol, 22%); single diastereomer, ratio ϾϾ 99:1 (1H
5.16Ϫ5.27 (m, 2 H, H-3, NϪCHϭCH), 5.36 (t, J2,3 ϭ 10.26 Hz, NMR and HPLC). M.p. 82 °C. Rf ϭ 0.23 (light petroleum ether/
J
2,1ϭ 8.79 Hz, 1 H, H-2), 5.43 (d, J4,3 ϭ 2.9 Hz, 1 H, H-4), 5.87 ethyl acetate, 15:1). [α]2D3 ϭ 18.38 (c ϭ 1.0, CHCl3). 1H NMR
(d, J1,2 ϭ 9.28 Hz, 1 H, H-1), 6.20 (d, Jolef ϭ 8.3 Hz, 1 H, NCHϭ
(400 MHz, CDCl3): δ ϭ 0.87 (s, 9 H, ϪCH3), 0.98, 1.07, 1.08, 1.14
(4 s, 36 H, piv CH3), 1.19Ϫ1.33 (m, 4 H, ϪCH2Ϫ), 2.04Ϫ2.56 (m,
CH) ppm. 13C NMR (50.3 MHz,CDCl3): δ ϭ 13.91 (ϪCH3), 19.52
(ϪCH2CH3), 27.05, 27.22 (piv CH3), 30.93 (ϪCH2Ϫethyl), 37.76 3 H, ϪCH2CO, ϪCHϪtBu), 3.90Ϫ3.98 (m, 1 H, H-6a), 4.02Ϫ4.08
(CHpropyl), 38.70 (COϪCH2Ϫ), 38.73, 38.81, 39.07 (piv Cquat.), (m, 2 H, H-5, H-6b), 5.17Ϫ5.25 (m, 2 H, H-3, NϪCHϭCH), 5.31
60.83 (C-6), 66.29, 66.85, 71.54, 73.04 (C-2, C-3, C-4, C-5), 78.44
(C-1), 113.05 (NCHϭCHϪ), 122.75 (NCHϭCH), 169.64 (NCϭ 1 H, H-4), 5.86 (d, J1,2 ϭ 9.3 Hz, 1 H, H-1), 6.20 (dd, Jolef ϭ 8.21,
O), 176.52, 176.73, 176.77, 177.00 (piv CϭO) ppm. MS (FD):
Jallyl ϭ 1.95 Hz, 1 H, NCHϭCH) ppm. 13C NMR (100.6 MHz,
m/z ϭ 638.1 [Mϩ]. C34H55NO10 (637.81): calcd. C 64.03, H 8.69, N CDCl3): δ ϭ 26.72 (ϪCH3), 27.02, 27.22 (piv CH3), 33.09
2.20; found C 66.30, H 8.66, N 2.16. Crystal data: P212121, (ortho- (COCH2Ϫ), 38.67 (tBu Cquat.), 38.72, 38.78, 39.05 (piv Cquat.),
rhombic), a ϭ 6.34549(4) A, b ϭ 24.4408 (14) A, c ϭ 24.5635(13) 41.78 (CHϪtBu), 60.98 (C-6), 66.09, 66.86, 71.47, 73.04 (C-2, C-3,
(t, J2,3 ϭ 10.17 Hz, J2,1 ϭ 9.39 Hz, 1 H, H-2), 5.42 (d, J4,3 ϭ 2.7 Hz,
˚
˚
3
˚
˚
A, V ϭ 3815.1(4) A , Z ϭ 4, F(000) ϭ 1384, Turbo CAD4, Cu-Kα, C-4, C-5), 78.33 (C-1), 110.03 (NCHϭCH), 123.48 (NCHϭCH),
SIR92, SHELXL-97. CCDC-165221 contains the supplementary 170.02 (NCϭO), 176.54, 176.82, 176.98, 177.01 (piv CϭO) ppm.
crystallographic data for this paper. These data can be obtained
free of charge at www.ccdc.cam.ac.uk/conts/retrieving.html [or
from the Cambridge Crystallographic Data Centre, 12 Union
Road, Cambridge CB2 1EZ, UK; Fax: (internat.) ϩ 44-1223-336-
033; E-mail: deposit@ccdc.cam.ac.uk].
MS (FD): m/z ϭ 652.2 [Mϩ]. C35H57NO10 (651.83): calcd. C 64.49,
H 8.81, N 2.15; found C 64.36, H 8.76, N 2.04.
(4R)-4-Decyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)pyridine-2(1H)-one (20f): TMSOTf (3.36 mmol,
0.61 mL), n-decylMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield
D
-galac- 0.70 g (0.95 mmol, 55%); mixture of diastereomers, ratio 96:4 (1H
D-galacto-
(4S)-3,4-Dihydro-4-isopropyl-1-(2,3,4,6-tetra-O-pivaloyl-β-
topyranosyl)pyridine-2(1H)-one (20c): TMSOTf (3.36 mmol,
0.61 mL), iPrMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield 0.95 g
(1.49 mmol, 88%); single diastereomer, ratio ϾϾ 99:1 (1H NMR
NMR). Rf ϭ 0.82 (light petroleum ether/ethyl acetate, 8:1); the dia-
stereomers were separated by HPLC [MeCN/H2O (gradient: 80:20
to 100:0 (80 min); flow: 20 mL·minϪ1; UV detection at 200 nm; Rt
and HPLC). M.p. 74 °C. Rf ϭ 0.34 (light petroleum ether/ethyl [min]: 57.417 (major isomer), 65.565 (minor isomer)]. Analytical
1
acetate, 8:1). [α]2D3 ϭ 32.20 (c ϭ 1.0, CHCl3). H NMR (400 MHz,
CDCl3): δ ϭ 0.86 (m, 6 H, ϪCH3), 1.07, 1.08, 1.13, 1.25 (4 s, 36
H, piv CH3), 1.27 [m, 1 H,CH(CH3)2], 2.14Ϫ2.56 (m, 3 H,
data for the pure major (R) diastereomer separated by prepatrative
HPLC: [α]2D5 ϭ 48.82 (c ϭ 1.0, CHCl3). 1H NMR (200 MHz,
CDCl3): δ ϭ 0.81 (t, 3 H, ϪCH3), 1.03Ϫ1.41 (m, 54 H, piv CH3),
ϪCH2CO, ϪCHϪiPr), 3.39Ϫ4.25 (m, 3 H, H-6a, H-6b, H-5), 2.11Ϫ2.48 (m, 3 H, ϪCH2CO, CHϪdecyl), 3.93Ϫ4.09 (m, 3 H, H-
5.16Ϫ5.23 (m, 2 H, H-3, NϪCHϭCH), 5.32 (t, J2,1 ϭ 9.78 Hz, 1 5, H-6a, H-6b), 5.15Ϫ5.33 (m, 3 H, H-2, H-3, NCHϭCH), 5.40
3358
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3346Ϫ3360

Stereoselective Synthesis of Enantiomerically Pure Piperidine Derivatives by N-Galactosylation of Pyridones
FULL PAPER
(d, J4,3 ϭ 2.4 Hz, 1 H, H-4), 5.84 (d, J1,2 ϭ 8.8 Hz, 1 H, H-1), 6.17
CHPh), 4.01Ϫ4.13 (m, 3 H, H-5, H-6a, H-6b), 5.24 (dd, J3,2 ϭ
(d, J ϭ 7.8 Hz, NCHϭCH) ppm. 13C NMR (50.3 MHz, CDCl3): 10.9, J3,4 ϭ 3.2 Hz, 1 H, H-3), 5.34Ϫ5.41 (m, 2 H, H-2, NCHϭ
δ ϭ 14.04 (ϪCH3), 23.86, 25.56 (ϪCH2Ϫ), 26.36, 26.63, 26.89, CH), 5.46 (d, J4,3 ϭ 2.9 Hz, 1 H, H-4), 5.92 (d, J1,2 ϭ 9.4 Hz, 1 H,
27.19 (piv CH3), 29.63Ϫ39.02 (ϪCH2Ϫ, piv Cquat.), 31.49 H-1), 6.39 (dd, Jolef ϭ 7.9, 4J ϭ 2.1 Hz, NCHϭCH) ppm. 13C
(CHϪdecyl), 60.77 (C-6), 66.29, 66.79, 71.53, 72.99 (C-2, C-3, C-4,
NMR (50.3 MHz, CDCl3): δ ϭ 27.05, 27.26, 27.37 (piv CH3), 37.81
C-5), 78.40 (C-1), 113.08 (NCHϭCH), 122.70 (NCHϭCH), 169.61 (CHϪphenyl), 38.74, 38.90, 39.10, (piv Cquat.), 40.60 (ϪCH2Ϫ),
(NCO), 176.45, 176.66, 176.93, 177.68 (piv CO) ppm. MS (FD): 60.90 (C-6), 66.36, 66.84, 71.50, 73.18 (C-2, C-3, C-4, C-5), 78.57
m/z ϭ 736.8 [M ϩ Hϩ]. C41H69NO10 (735.49): calcd. C 66.91, H (C-1), 111.83 (NCHϭCH), 123.91 (NCHϭCH), 127.02, 127.12,
9.45, N 1.90; found C 66.92, H 9.44, N 1.88.
128.90 (o-, m-, p-C, phenyl), 142.31 (ipso-C, phenyl), 169.43 (NCO),
176.56, 176.95, 177.83 (piv CO) ppm. MS (ESI): m/z ϭ 694.4 [M
ϩ Naϩ]. C37H53NO10 (671.82): calcd. C 66.15, H 7.95, N 2.08;
found C 66.20, H 7.98, N 2.07.
(4S)-4-Cyclohexyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galac-
topyranosyl)pyridine-2(1H)-one (20g): TMSOTf (3.36 mmol,
0.61 mL), cyclohexylMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield
0.9 g (1.33 mmol, 79%); single diastereomer, ratio ϾϾ 99:1 (1H
NMR and HPLC). M.p. 114 °C. Rf ϭ 0.24 (light petroleum ether/
ethyl acetate, 15:1). [α]2D3 ϭ 74.48 (c ϭ 1.0, CHCl3). 1H NMR
(200 MHz, CDCl3): δ ϭ 1.07, 1.08, 1.14, 1.26 (4 s, 36 H, piv CH3),
1.66 (br. s, 11 H, cyclohexyl CH2Ϫ and CHϪ), 2.17Ϫ2.49 (m, 3 H,
ϪCH2CO, ϪCHϪcyclohexyl), 3.96Ϫ4.26 (m, 3 H, H-6a, H-6b, H-
5), 5.16Ϫ5.24 (m, 2 H, H-3, NϪCHϭCH), 5.32 (t, J2,1 ϭ 9.28 Hz,
(4R)-4-(3-Butenyl)-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-
galactopyranosyl)pyridine-2(1H)-one (20j): TIPSOTf (4.2 mmol,
0.85 mL, 2.5 equiv.), 2,6-lutidine (4.2 mmol, 0.48 mL, 2.5 equiv.),
butenylMgBr [freshly prepared from Mg (4.2 mmol), butenyl bro-
mide (4.2 mmol) in THF]; yield 0.93 g (1.44 mmol, 86%); single
diastereomer, ratio ϾϾ 99:1 (1H NMR and HPLC). Rf ϭ 0.44
(light petroleum ether/ethyl acetate, 6:1). [α]2D5 ϭ 33.14 (c ϭ 1.0,
CHCl3). 1H NMR (400 MHz, CDCl3): δ ϭ 1.16, 1.23, 1.35 (4 s, 36
H, piv CH3), 1.6 (m, 2 H, ϪCH2Ϫ), 2.25 (m, 2 H, ϪCH2Ϫ),
2.30Ϫ2.65 (m, 3 H, CH2CO, CHϪbutenyl), 4.03Ϫ4.21 (m, 3 H, H-
5, H-6a, H-6b), 5.02Ϫ5.13 (m, 2 H, CHϭCH2), 5.32 (m, 2 H, H-
3, NCHϭCH), 5.41 (t, J2,1 ϭ 9.78, J2,3 ϭ 9.79 Hz, 1 H, H-2), 5.54
(d, J4,3 ϭ 2.35 Hz, 1 H, H-4), 5.77Ϫ5.89 (m, 1 H, CHϭCH2), 5.98
J2,3 ϭ 10.25 Hz, 1 H, H-2), 5.42 (d, J4,3 ϭ 2.93 Hz, 1 H, H-4), 5.86
(d, J1,2 ϭ 9.28 Hz, 1 H, H-1), 6.20 (dd, Jolef ϭ 8.3, Jallyl ϭ 1.95 Hz,
1 H, NCHϭCH) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 26.33
(C-4 cyclohexyl), 27.05, 27.24 (piv CH3), 29.44, 29.59 (C-2, C-3, C-
5, C-6 cyclohexyl), 34.69 (C-3), 36.90 (C-1 cyclohexyl), 38.71,
38.81, 39.08 (piv Cquat.), 41.40 (C-4), 60.93 (C-6), 66.21, 66.87,
71.54, 73.06 (C-2, C-3, C-4, C-5), 78.44 (C-1), 111.15 (NCHϭCH),
123.14 (NCHϭCH), 169.93 (NCϭO), 176.55, 176.82, 177.01,
177.81 (piv CϭO) ppm. MS (FD): m/z ϭ 678.2 [Mϩ]. C37H59NO10
(677.87): calcd. C 65.56, H 8.77, N 2.07; found C 65.49, H 8.78,
N 2.05.
4
(d, J1,2 ϭ 9.39 Hz, 1 H, H-1), 6.39 (dd, Jolef ϭ 8.21, J ϭ 1.95 Hz,
NCHϭCH) ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 26.99, 27.19
(piv CH3), 30.39 (ϪCH2Ϫ), 30.45 (CHϪbutenyl), 33.36 (ϪCH2Ϫ),
37.53 (ϪCH2ϪCO), 38.94, 38.76, 39.04, (piv Cquat.), 60.77 (C-6),
66.23, 66.74, 71.44, 73.01 (C-2, C-3, C-4, C-5), 78.34 (C-1), 112.66
(NCHϭCH), 115.23 (CHϭCH2), 122.90 (NCHϭCH), 137.60
(CHϭCH2), 169.41 (NCO), 176.50, 176.77, 176.98, 177.76 (piv CO)
ppm. MS (ESI): m/z ϭ 672.6 [M ϩ Naϩ] for C35H55NO10 (649.38):
calcd. C 64.69, H 8.53, N 2.16; found C 64.46, H 8.05, N 2.01.
(4R)-4-Benzyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)pyridine-2(1H)-one (20h): TMSOTf (3.36 mmol,
D-galacto-
0.61 mL), benzylMgCl (1  in THF, 2.52 mL, 2.52 mmol); yield
0.392 g (0.57 mmol, 34%); single diastereomer, ratio ϾϾ 99:1 (1H
NMR and HPLC). M.p. 137 °C. Rf ϭ 0.24 (light petroleum ether/
ethyl acetate, 8:1). [α]2D3 ϭ 56.62 (c ϭ 1.0, CHCl3). 1H NMR
(400 MHz, CDCl3): δ ϭ 1.15, 1.17, 1.23, 1.34 (4 s, 36 H, piv CH3),
2.38Ϫ2.44 (m, 1 H, ϪCHHbϪphenyl), 2.53 (dd, Jvic ϭ 5.47, Jgem ϭ
16.04 Hz, 1 H, ϪCHHaϪphenyl), 2.67Ϫ2.82 (m, 3 H, ϪCH2CO,
ϪCHϪbenzyl), 4.03Ϫ4.09 (m, 1 H, H-6b), 4.14Ϫ4.21 (m, 2 H, H-
General Procedure for the 1,4-Addition of Activated Organocuprates
to N-Galactosyl-2-pyridone 5
A) Formation of Organocuprate: A suspension of CuI in dry THF
was cooled to Ϫ35 °C, and the corresponding organolithium com-
pound was added. The reaction mixture was warmed up during
1.5 h until the solution became clear. Details are given for each
compound. After formation of the organocuprate, the reaction
mixture was cooled to Ϫ78 °C.
6a, H-5), 5.28Ϫ5.33 (m, 2 H, H-3, NϪCHϭCH), 5.32 (t, J2,1
ϭ
9.39 Hz, J2,3 ϭ 10.17 Hz, 1 H, H-2), 5.42 (d, J4,3 ϭ 2.74 Hz, 1 H,
H-4), 5.96 (d, J1,2 ϭ 9.39 Hz, 1 H, H-1), 6.32 (dd, Jolef ϭ 7.83,
Jallyl ϭ 0.78 Hz, 1 H, NCHϭCH), 7.19Ϫ7.44 (m, 5 H, phenyl H)
ppm. 13C NMR (100.6 MHz, CDCl3): δ ϭ 27.02, 27.21 (piv CH3),
33.11 (C-3), 37.26 (ϪCH2Ϫphenyl), 38.72, 38.79, 39.05 (piv Cquat.),
40.37 (CHϪbenzyl), 60.78 (C-6), 66.27, 66.76, 73.02 (C-2, C-3, C-
4, C-5), 78.41 (C-1), 112.10 (NCHϭCH), 123.17 (NCHϭCH),
126.45, 126.95, 127.62, 128.51, 129.03 (2 ϫ o-, m-, p-C, phenyl),
138.54 (ipso-C, phenyl), 169.23 (NCϭO), 176.53, 176.82, 177.01,
177.79 (piv CϭO) ppm. MS (FD): m/z ϭ 686.3 [Mϩ]. C38H55NO10
(685.84): calcd. C 66.55, H 8.08, N 2.04; found C 66.12, H 8.69,
N 1.96.
B) 1,4-Addition: The 1,2-dihydropyridin-2-one 5 was dissolved in
dry THF at ambient temperature and treated with TMSCl. After
stirring for 30 min, this solution was added to the solution of the
organocuprate through a syringe. The reaction mixture was
warmed up overnight. After hydrolysis with 100 mL of concd.
NH4OH/satd.NH4Cl (1:1, v/v) and addition of 100 mL of diethyl
ether, the aqueous layer was separated and extracted with diethyl
ether (2 ϫ 100 mL). The combined organic layers were washed with
brine and dried with MgSO4. Evaporation of the solvent in vacuo
and flash chromatography (light petroleum ether/ethyl acetate)
yielded compounds 19.
(4R)-3,4-Dihydro-4-phenyl-1-(2,3,4,6-tetra-O-pivaloyl-β-
pyranosyl)pyridine-2(1H)-one (20i): TIPSOTf (3.36 mmol,
0.68 mL), PhMgCl (1  in THF, 2.52 mL, 2.52 mmol); reaction
D-galacto-
(4R)-4-Butyl-3,4-dihydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-
time 12 h; yield 0.86 g (1.28 mmol, 76%); single diastereomer, ratio pyranosyl)pyridin-2(1H)-one (20d): CuI (1.603 g, 8.42 mmol), dry
ϾϾ 99:1 (1H NMR and HPLC). M.p. 145 °C. Rf ϭ 0.73 (light THF (55 mL), nBuLi (10.51 mL, 16.84 mmol, 1.6  in pentane);
petroleum ether/ethyl acetate, 4:1). [α]2D8 ϭ 76.2 (c ϭ 1.0, CHCl3).
1H NMR (400 MHz, CDCl3): δ ϭ 1.10, 1.12, 1.15, 1.27 (4 s, 36 H,
temperature, time for formation of organocuprate: Ϫ35 °C to Ϫ20
°C, 1.5 h; galactosyl-2-pyridone 5 (1 g, 1.68 mmol), dry THF
piv CH3), 2.64 (dd, Jgem ϭ 16.1, Jvic ϭ 10.3 Hz, 1 H, CH2CO), (50 mL), TMSCl (3.23 mL, 25.26 mmol); yield 0.7 g (1.07 mmol,
2.74 (dd, Jgem ϭ 16.1, Jvic ϭ 6.1 Hz, 1 H, CH2CO), 3.58 (m, 1 H, 64%); single diastereomer, ratio ϾϾ 99:1 (1H NMR and HPLC).
Eur. J. Org. Chem. 2004, 3346Ϫ3360
www.eurjoc.org
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
3359

E. Klegraf, M. Follmann, D. Schollmeyer, H. Kunz
FULL PAPER
The product is identical to the compound obtained from the Grig-
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[6c]
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´
Vanucci-Bacque, G. Lhommet, Synlett 1999, 405Ϫ408.
galactopyranosyl)pyridin-2(1H)-one (20e): CuI (1.603 g, 8.42
mmol), dry THF (55 mL), tBuLi (9.9 mL, 16.84 mmol, 1.7  in
pentane); temperature, time for formation of organocuprate: Ϫ35
to Ϫ20 °C, 1.5 h; galactosyl-2-pyridone 5 (1 g, 1.68 mmol), dry
THF (50 mL), TMSCl (3.23 mL, 25.26 mmol); yield 0.42 g
(0.65 mmol, 39%); mixture of diastereomers, ratio 92:8 (1H NMR
and HPLC). Rf ϭ 0.36 (light petroleum ether/ethyl acetate, 8:1).
The major diastereomer is identical to the major diastereomer ob-
tained from the Grignard addition to 20e (see above).
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pyranosyl)pyridin-2(1H)-one (20k): CuI (1.603 g, 8.42 mmol), dry
THF (55 mL), n-hexylLi (7.3 mL, 16.84 mmol, 2.3  in pentane);
formation of organocuprate: temperature, time: Ϫ35 to Ϫ20 °C,
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TMSCl (3.23 mL, 25.26 mmol); yield 1.07 g (1.57 mmol, 93%); sin-
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5889Ϫ5892.
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3 H, ϪCH3), 1.03Ϫ1.49 (m, 57 H, piv CH3, ϪCH2Ϫ), 2.13Ϫ2.68
(m, 3 H, ϪCH2CO, CHϪhexyl), 3.89Ϫ4.16 (m, 3 H, H-5, H-6a,
H-6b), 5.15Ϫ5.29 (m, 2 H, H-3, NCHϭCH), 5.32 (t, J2,1 ϭ 9.28,
J2,3 ϭ 10.26 Hz, 1 H, H-2), 5.45 (d, J4,3 ϭ 2.4 Hz, 1 H, H-4), 5.88
(d, J1,2 ϭ 8.79 Hz, 1 H, H-1), 6.21 (d, J ϭ 7.8 Hz, NCHϭCH)
ppm. 13C NMR (50.3 MHz, CDCl3): δ ϭ 14.03 (ϪCH3), 22.58,
26.36 (ϪCH2Ϫ), 26.63, 27.05, 27.24 (piv CH3), 29.65 (ϪCH2Ϫ),
31.18 (CHϪhexyl), 31.92, 34.39, 37.80 (ϪCH2Ϫ), 38.71, 38.75,
39.01(piv Cquat.), 60.83 (C-6), 66.31, 66.83, 71.56, 73.06 (C-2, C-3,
C-4, C-5), 78.45 (C-1), 113.15 (NCHϭCH), 122.74 (NCHϭCH),
169.69 (NCO), 176.53, 176.80, 177.03, 177.79 (piv CO) ppm. MS
(FD): m/z ϭ 680.2 [Mϩ]. C37H61NO10 (679.88): calcd. C 65.36, H
9.04, N 2.06; found C 65.62, H 9.12, N 1.96.
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Acknowledgments
This work was supported by Aventis Pharma Deutschland GmbH
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Received May 15, 2004
3360
 2004 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
Eur. J. Org. Chem. 2004, 3346Ϫ3360