Stereoselective synthesis of 3-substituted and 3,4-disubstituted piperidine und piperidin-2-one derivatives

Stereoselective Synthesis of 3-Substituted and 3,4-Disubstituted

Piperidine und Piperidin-2-one Derivatives

Ellen Klegraf and Horst Kunz

Institut fu¨r Organische Chemie, Universita¨t Mainz, Duesbergweg 10–14, 55128 Mainz, Germany

Reprint requests to Prof. Dr. Horst Kunz. Fax: +49 6131 39 24786. Email: hokunz@uni-mainz.de

Z. Naturforsch. 2012, 67b, 389 – 405; received February 13, 2012

The stereoselective synthesis of 3-substituted and 3,4-disubstituted piperidine and piperidin-2-one

derivatives was achieved starting from 2-pyridone. After N-galactosylation and subsequent O-sil-

ylation, nucleophilic addition of organometallic reagents proceeded with high regio- and stereo-

selectivity at 4-position. Substituents at position 3 were stereoselectively introduced by reaction of

electrophiles with amide enolates of the N-galactosyl-2-piperidones.

Key words: N-Galactosyl Pyridone, 3-Alkyl-piperidines, 3,4-Dialkyl-piperidines,

Carbohydrate Auxiliaries, Stereoselective Reactions

Introduction

In contrast to 2- and 2,6-subsituted piperidine

derivates which constitute a whole subclass of piperi-

dine alkaloids [1], 3- and 3,4-substituted piperidines

are only rarely found in Nature. Derivates of 3-hydro-

xypiperidine, as for example (+)-febrifugine (1) occur-

ring in Chinese medicinal plants [2], or products of

Scheme 2. 3,4-Disubstituted piperidines of pharmacological

interest.

degradation of quinine, as for example, meroquinene substituted piperidines have been shown to exhibit at-

or meroquinene aldehyde (2) [3] belong to the few ex- tractive biological effects. For example, hexahydro-

ceptions (Scheme 1).

indeno[1,2-c]pyridines 3 have been reported to act

as gonadotrophic hormone-releasing hormone ago-

nists/antagonists and integrin antagonists [6]. 4-Aryl-

3,4-dimethyl-piperidines 4 obviously exhibit efﬁcient

opoid receptor antagonist activity [7] (Scheme 2).

We report here on stereoselective syntheses of 3-

alkyl- and 3,4-dialkyl-piperidine derivatives from 2-

pyridone according to the strategy of stereoselective

desymmetrization induced by N-galactosylation [8].

O-Pivaloylated N-galactosyl-pyridin-2-one 5 [8], after

activation with trialkylsilyl triﬂuoromethanesulfonate

to afford the silyloxy-pyridinium intermediate 6, re-

acted with Grignard compounds or organocuprates

to afford 4-subsituted 5,6-dehydro-piperidin-2-ones 7

with complete regio- and excellent stereoselectivity [8]

(Scheme 3).

Scheme 1. 3-Substituted piperidine natural products.

The rare occurrence in Nature certainly is the rea-

son that only a few syntheses of 3-alkyl and 3,4-di-

alkyl-piperidines lacking a 2-substituent have been re-

ported in the literature [4], although access to these

compounds through reduction of the corresponding

alkyl-pyridines had been described early [5]. Opti-

In contrast to N-galactosyl-dehydropiperidin-4-ones

cally active 3-alkyl and 3,4-dialkyl-piperidines have obtained either by analogous reactions of N-galacto-

been obtained by separation of racemic mixtures [5c] syl-gamma-pyridone [9] or by tandem-Michael-

in most cases, whereas stereoselective syntheses have Mannich reactions [10] of N-glycosyl-aldimines with

rarely been reported. This is surprising since 3,4-di- the Danishefsky diene, compounds of type 7 should

c

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E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

Scheme 3. Stereoselective synthesis of

4-alkyl-5,6-dihydro-piperidin-2-ones.

Scheme 4. Formation of pyridine- and piperidin-

2-thiones.

Scheme 5. Formation of 4-substituted piperidin-

2-thiones.

provide stereoselective access to 3-substituted and 3,4- be discussed. As the N-glycosyl amide bond is stable

disubstituted piperidines which do not contain an addi- towards acidic conditions, a reduction of the amide car-

tional substituent at 2-position.

bonyl must be achieved at ﬁrst. Using N-galactosyl-

pyrid-2-one (5) as the model substrate, catalytic hy-

drogenation gave N-galactosyl valerolactam (8), while

Results and Discussion

R

reduction with L-Selectride^ꢀin THF at −78 ^◦C regio-

selectively afforded the 5,6-dehydropiperidin-2-one 9

corresponding to compounds 7 (Scheme 4).

Before the introduction of a 3-substituent is out-

lined, the removal of the carbohydrate auxiliary should

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391

Scheme 6. Detachment of the carbohydrate aux-

iliary.

Scheme 7. Alkylation in 3-position; d. r. = ratio

of diastereomers.

Scheme 8. 3,4-Dialkyl-piperidin-

ones.

Table 1. Alkylation of N-

galactosyl-5,6-dehydro-

piperidin-2-ones.

Educt

9

R¹

H

n-Pr

c-Hex

n-Pr

R²

Temp. (^◦C)

−78

Product

19a

Yield (%)

44^a

Diastereomeric ratio cis : trans

Me

n-Bu

Me

Bu

92 : 8

93 : 7

71 : 29

67 : 33

58 : 42

9

−78

19b

27^a

7b

7e

7b

−78

19c

90

−10

19d

92

57^am

a

−10

19e

Incomplete conversion.

All three types of N-galactosyl amides 5, 8 and 9

For the introduction of a 3-substituent, N-galacto-

were converted to the corresponding thioamides 10 – syl-valerolactam (8) was deprotonated using lithium

12 using Lawesson’s reagent [11].

hexamethyldisilazane (LiHMDS) in tetrahydrofuran

at −78 ^◦C. The alkylation of the amide enolate

proceeded slowly. However, the 3-n-butyl-piperidin-

2-one 18a was formed with high diastereoselec-

tivity. The 3-methyl derivative 18b was obtained

more efﬁciently, but with lower diastereoselctivity

(Scheme 7).

The diastereomers could not be separated by chro-

matography, and their conﬁguration is not yet clar-

iﬁed. However, in view of the stereochemistry of

compounds 7 conﬁrmed by X-ray analysis [8] and

the stereocontrol governing their formation, it can

be concluded that the enolate is attacked from the

(si)-side, and the major diastereomers 18 have (3S)-

conﬁguration.

The same transformation was also applied to the

4-substituted dehydropiperidin-2-ones 7 and their hy-

drogenated analogs 13 without affecting their stereo-

genic centers (Scheme 5) and gave the 4-substituted

thioamides 14 and 15.

While deoxygenation of N-galactosyl amides 8, 13

neither with borane nor with superhydride [12] even in

the presence of BF₃etherate [13] was successful, the

thioamides 14 were readily desulfurized by hydrogena-

tion in the presence of Raney-nickel with concomitant

hydrogenation of the C=C double bond to give the N-

galactosyl piperidines 16 (Scheme 6).

Treatment of the N-galactosyl piperidine 16a with

diluted hydrogen chloride in methanol smoothly

cleaved the N-glycosidic bond to afford the free piperi-

dine [10] which was converted to the corresponding O- and 9 can be alkylated after deprotonation with

benzyl-urethane 17 for easier characterization.

Similar to 8, the 5,6-dehydropiperidin-2-ones 7

LiHMDS (Scheme 8).

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E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

Scheme 9. Stereoselective aldol reaction at posi-

tion 3.

Table 2. Stereoselective aldol reaction of N-galactosyl-de-

hydropiperidin-2-ones 7.

which were formed almost exclusively in reactions

with benzaldehyde (20a, b) and isobutyraldehyde

(20d), should have (3R,αR)-conﬁguration. The lower

selectivity found in the reaction with 5-methyl-fur-

fural can be traced back to a coordinating effect of

the furan oxygen. The reaction of pivalaldehyde obvi-

ously is sterically more hindered, therefore, incomplete

and of slightly reduced selectivity, whereas acrolein

is very reactive and logically less selective. It should

also be noticed that ketones, as for example ace-

tophenone, did not undergo this aldol reaction. These

ﬁndings suit with the suggested Zimmerman-Traxler

mechanism (Scheme 10). The intramolecular version

of the enantioselective aldol reaction should provide

access to 3,4-annulated piperidine frameworks as is

present, for example, in the monoterpene alkaloid α-

skytanthin [15]. As a suitable starting material, 4-but-

enyl-5,6-dehydropiperidin-2-one7f [8] was selectively

reduced at the enamine double bond by protonation

with conc. hydrochloric acid and subsequent treatment

with sodium cyanoborohydride. The quantitatively ob-

tained N-galactosyl-valerolactam 21 was subjected to

osmate-promoted dihydroxylation to give 22, and its

subsequent diol-cleavage using lead tetraacetate [16]

led to valerolactam 23 containing an aldehyde function

in the side chain (Scheme 11).

It is noteworthy, that the LiHMDS-promoted

deprotonation of 23 did not induce the cyclizing

aldol reaction. Obviously, the lithium ion-coordinated

Zimmerman-Traxler transition state is too much

strained and the lithium-coordinated amide enolate

too weakly nucleophilic. Only deprotonation with

potassium hexamethyldisilazane (KHMDS) producing

the more nucleophilic potassium enolate resulted in

the desired aldol reaction. Again, of the four possible

diastereomers only the two cis-diastereomers have

been formed. However, due to the weaker coordinating

effect of the potassium ion, the stereodifferentiation of

the prochiral aldehyde only amounts to 4 : 1 and cannot

Product R¹

R²

n-Pr Ph

Ph Ph

Yield (%) Diastereomeric ratio^a

20a

20b

20c

20d

20e

20f

a

81

49

68

73

36

78

> 99 : 1 : 0 : 0

62 : 38 : 0 : 0

98 : 2 : 0 : 0

91 : 6 : 3 : 0

87 : 9 : 4 : 0

n-Pr 5-Me-furfuryl

n-Bu Me₂CH

Ph

Me₃C

n-Bu H₂C=CH^b

b

Determination by analyt. HPLC; no activation of the

acrolein with BF₃·OEt₂.

The results displayed in Table 1 show that high

diastereo_◦selectivity is achieved in these 3-alkylations

at −78 C, if no substituent is present in 4-posi-

tion. The amide enolates of the 4-substituted de-

hydropiperidinones 7 are also alkylated, but with

distinctly lower stereoselectivity. This behavior is

in agreement with a stereodifferentiation during the

amide enolate alkylation predominantly inﬂuenced by

the shielding 2-pivaloyloxy substituent of the carbohy-

drate auxiliary.

Aldehydes as more reactive electrophiles also can

be used for the introduction of a 3-substituent. To this

end, 4-substituted dehydropiperidinones 7 were con-

verted to their amide enolates at −78 ^◦C. These cyclic

(E-)amide enolates only react with aldehydes after

their pre-activation with BF₃etherate [13b] (Scheme 9,

Table 2).

In this aldol reaction, two new stereogenic cen-

ters are formed. As a rule, only two out of four dia-

stereomers could be detected by analytical HPLC.

Both of which probably have 3,4-cis conﬁguration, and

one of them is generated in a high excess. These re-

sults are in agreement with a back-side (si-side) at-

tack of the aldehyde at the amide enolate passing

a Zimmerman-Traxler transition state [14] as is dis-

played in Scheme 10.

According to this interpretation, the major diastere-

omers of the 3,4-disubsituted piperidin-2-ones 20,

Scheme 10. Hypothesis of the diastereodifferen-

tiation.

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393

Scheme 11. 3,4-Annulated piperidinones.

be predicted by a six-membered ring transition state. Experimental Section

The conﬁguration of the major diastereomer could

not be conﬁrmed so far, because the compound did

not crystallize, and overlap of the crucial signals in

the ¹H NMR spectrum rendered the interpretation

difﬁcult.

General instrumentation

Reagents and solvents were distilled before use: Tetrahy-

drofuran, dioxane, and Et₂O were distilled from potassium-

benzophenone ketyl. CH₂Cl₂was distilled from CaH₂. Light

petroleum refers to bp 60 – 80 ^◦C. All reactions and distilla-

tions were carried out in ﬂame-dried glassware under argon

atmosphere.

Conclusion

Reversed-phase analytical HPLC was carried out us-

ing a Knauer system (Knauer MaxiStar K1000 pump and

DAD2062 for diode array detection), acetonitrile-water, ﬂow

rate: 1 cm³min⁻¹. Column: A: Luna C8, 5 µ, 250 × 4 mm,

Phenomenex; for chiral analytical HPLC: “Chiralpak AD,

Daicel Chemical Industries and n-hexane-iso-propanol as

eluents, ﬂow rate: 1 cm³min⁻¹. Thin-layer chromatography

(TLC) was performed on Merck silica gel 60_F254, ﬂash chro-

matography on silica (32 – 63 µm, ICN Biochemicals). FD

mass spectra were measured on a Finnigan MAT 95 spec-

trometer, ESI mass spectra on a ThermoQuest Navigator in-

strument. High-resolution ESI mass spectra were recorded

on a Q-TOF Ultima 3 instrument (Waters, NaI-CsI as the

internal reference). Melting points were taken on a Bu¨chi

Dr. Tottoli apparatus and are uncorrected. ¹H and ¹³C NMR

spectra were recorded on a Bruker AC-300 or a Bruker AM-

400 NMR instrument. Chemical shifts δ are given in ppm.

Optical rotation values were measured with a Perkin-Elmer

241 polarimeter.

Although their conﬁgurations have not yet been

conﬁrmed by X-ray analyses, 3-substituted and 3,4-

disubstituted piperidine derivatives have been ob-

tained stereoselectively starting from 2-pyridone

via N-galactosylation. The N-galactosyl auxiliary

in N-galactosyl valerolactam (9), N-galactosyl-5,6-

dehydropiperidin-2-ones 10 and their 4-substituted

derivatives 7 as well as in their amide enolates obvi-

ously causes an efﬁcient stereodifferentiation in sub-

stitution reactions at position 3 of the piperidinone

ring. This holds for alkylation processes as well as

for aldol reactions. In some cases of the aldol re-

actions, only one out of four diastereomers was ob-

tained. The observed effects of a substituent at 4-

position in substitution reactions at 3-position support

the hypothesis that amide enolates of N-D-galacto-

syl-piperidin-2-ones are preferably attacked from the

si-side due to the shielding effect of the large 2-

pivaloyloxy substituent of the carbohydrate auxiliary.

Model reactions have shown that the N-galactosyl

auxiliary can be removed from the chiral piperidine

products via conversion of the piperidinones into the

corresponding thioamides, their reductive desulfuriza-

tion and subsequent acidolysis of the N-glycosidic

bond.

The synthesis of the 4-substituted 5,6-dehydropiperidin-

2-ones 7 has been described in reference [8].

N-Galactosyl-piperidin-2-ones 8 and 13 through hydrogena-

tion – General procedure

To the solution of N-galactosyl-2-pyridone (5) or

N-galactosyl-5,6-dehydropiperidin-2-one (7) [8] in dry

methanol palladium on charcoal (10 %, 15 mg) was added.

The mixture was stirred under hydrogen atmosphere at r. t.

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E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

until monitoring by TLC showed complete conversion. Sub- 0.45 g (0.7 mmol) 7b; reaction time: 24 h. Yield: 0.331 g

sequently, the hydrogen was substituted by argon, the cata- (74 %), colorless amorphous solid, R_f= 0.27 (cyclohexane-

lyst was ﬁltered off, and the solvent was evaporated in vacuo. ethyl acetate 4 : 1), [α]²_D⁵: 14.81 (c = 1.0, CHCl₃). – MS

The remaining crude product was puriﬁed by ﬂash chro- ((+)-ESI): m/z = 662.39 [M+Na]⁺. – ¹H NMR (300 MHz,

matography.

CDCl₃): δ = 0.87 (t, 3H, -CH₃), 1.08, 1.14, 1.24 (3s,

36H, PivCH₃), 1.28 (m, 4H, (CH₂)₂CH₃), 1.62 (m, 2H,

NCH₂CH₂), 1.95 (m, 1H, CHpropyl), 2.28, 2.46 (2m, 2H,

COCH₂), 3.24, 3.50 (2m, 2H, NCH₂), 3.90 – 4.13 (m, 3H,

H-5, H-6a, H-6b), 5.21 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz,

H-3), 5.37 (m, 2H, J_4,3= 2.9 Hz,J_2,1= 9.6 Hz, H-2, H-4),

5.99 (d, 1H, J_1,2= 9.2 Hz, H-1). – ¹³C NMR (75.5 MHz,

N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)piper-

idin-2-one (8)

Educt N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-

yl)-2-pyridone [8] (5): 5.00 g (8.4 mmol); reaction time:

10 h. Yield: 4.59 g (91 %), colorless amorphous solid, R_f=

0.4 (cyclohexane-ethyl acetate 2 : 1), [alpha]²_D⁵: 24.77 (c =

1.0; CHCl₃). – MS ((+)-ESI): m/z = 620.35 [M+Na]⁺. –

¹H NMR (300 MHz, CDCl₃): δ = 1.08, 1.14, 1.23 (3s,

36H, PivCH₃), 1.74 (m, 4H, NCH₂CH₂CH₂), 2.32 (m, 2H,

COCH₂), 3.35 (m, 2H, NCH₂), 3.88 – 4.11 (m, 3H, H-5,

H-6a, H-6b), 5.22 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz,

H-3), 5.37 (m, 2H, J_4,3= 2.9 Hz, J_2,1= 9.2 Hz, H-4, H-2),

6.01 (d, 1H, J_1,2= 9.2 Hz, H-1). – ¹³C NMR (75.5 MHz,

CDCl₃): δ = 20.61, 22.70 (NCH₂CH₂CH₂−), 26.87, 26.97,

27.02, 27.18 (PivCH₃), 32.51 (COCH₂), 38.68, 38.77, 39.03

(PivC_t), 41.15 (NCH₂), 60.73 (C-6), 65.03, 66.83, 71.51,

72.76 (C-5, C-4, C-3, C-2), 79.39 (C-1), 170.60 (NC=O),

176.47, 176.94, 177.40, 177.77 (PivC=O). – C₃₁H₅₁NO₁₀

(597.35): calcd. C 62.29, H 8.60, N 2.34; found C 62.22,

H 8.55, N 2.23.

CDCl⁾: δ = 10.98 (CH₃), 26.97, 27.03, 27.18 (PivCH₃),

3

28.34, 28.44 (CH₂CH₃, NCH₂CH₂), 33.97 (CHpropyl),

38.65 (CH₂), 38.71, 38.79 (PivC_t), 38.54 (COCH₂), 39.04

(PivC_t), 40.12 (NCH₂), 60.76 (C-6), 65.24, 66.84, 71.65,

72.67 (C-5, C-4, C-3, C-2), 79.33 (C-1), 170.57 (NC=O),

176.49, 176.95, 177.37, 177.80 (PivC=O). – C₃₄H₅₇NO₁₀

(639.39): calcd. C 63.83, H 8.98, N 2.19; found C 63.10,

H 9.32, N 2.24.

(4S)-4-Isopropyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-

pyranosyl)piperidin-2-one (13c)

Educt (4R)−3,4-dihydro-4-isopropyl-N-(2,3,4,6-tetra-O-

pivaloyl-β-D-galactopyranosyl)pyridine-2(1H)-one [8] (7c):

370 mg (0.58 mmol); reaction time: 12 h. Yield: 305 mg

(82 %), colorless amorphous solid, R_f= 0.52 (cyclohexane-

ethyl acetate 2 : 1), [α]²_D⁵: 13.15 (c = 1.0; CHCl₃). – MS

((+)-ESI): m/z = 662.42 [M+Na]⁺. – ¹H NMR (300 MHz,

CDCl₃): δ = 0.85, 0.87 (2d, 6H, J = 6.3, CH(CH₃)₂), 1.08,

1.14, 1.24 (3s, 36H, PivCH₃), 1.39 (m, 1H, CH (CH₃)₂),

1.92, 2.13 (2m, 2H, NCH₂CH₂), 2.38 (m, 2H, COCH₂), 3.24

(m, 1H, CHipropyl), 3.44, 3.56 (2m, 2H, NCH₂), 3.96 – 4.11

(4S)-4-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyran-

osyl)piperidin-2-one (13a)

Educt (4R)-4-ethyl-3,4-dihydro-N-(2,3,4,6-tetra-O-piva-

loyl-β-D-galactopyranosyl)pyridine-2(1H)-one [8] (7a): 480

mg (0.77 mmol); reaction time: 10 h. – Yield: 454 mg (95 %),

colorless amorphous solid, R_f= 0.47 (cyclohexane-ethyl ac-

etate 2 : 1), [α]²_D⁵: 15.31 (c = 1.0; CHCl₃). – MS ((+)-ESI):

m/z = 648.49 [M+Na]⁺. – ¹H NMR (300 MHz, CDCl₃):

δ = 0.87 (t, 3H, -CH₃), 1.10, 1.13, 1.23 (3s, 36H, PivCH₃),

1.38 (m, 2H, CH₂CH₃), 1.94 (m, 2H, NCH₂CH₂), 2.47 (m,

2H, COCH₂), 3.24 (m, 1H, CHethyl), 3.46 (m, 2H, NCH₂),

(m, 3H, H-5, H-6a, H-6b), 5.20 (dd, 1H, J_3,4= 2.9 Hz, J_3,2

=

9.9 Hz, H-3), 5.39 (m, 2H, J_4,3= 2.9 Hz, J_2,1= 9.6 Hz,

H-4, H-2), 5.98 (d, 1H, J_1,2= 9.6 Hz, H-1). – ¹³C NMR

(75.5 MHz, CDCl₃): δ = (signals of the major rotamer)

19.18, 19.42 (-CH₃), 26.24 (NCH₂CH₂), 26.96, 27.03, 27.17

(PivCH₃), 31.85 (CHipropyl), 36.33 (COCH₂), 38.70, 37.79

(PivC_t), 38.83 (CH(CH₃)₂), 39.03, 39.06 (PivC_t), 40.42

(NCH₂), 60.75 (C-6), 65.28, 66.83, 71.63, 72.64 (C-5, C-4,

C-3, C-2), 79.30 (C-1), 170.90 (NC=O), 176.49, 176.97,

177.34, 177.79 (PivC=O). – C₃₄H₅₇NO₁₀(639.39): calcd.

C 63.83, H 8.98, N: 2.19; found C 63.85, H 9.01, N 2.22.

3.89 – 4.10 (m, 3H, H-5, H-6a, H-6b), 5.20 (dd, 1H, J_3,4

=

2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.41 (m, 2H, J_4,3= 2.9 Hz,

J_2,1= 9.6 Hz, H-4, H-2), 5.98 (d, 1H, J_1,2= 9.6 Hz, H-1). –

¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the ma-

jor rotamer) 10.96 (-CH₃), 26.96, 27.03, 27.18 (PivCH₃),

28.43, 28.44 (CH₂CH₃, NCH₂CH₂), 33.95 (CHethyl), 38.65

(COCH₂), 38.70, 38.77, 39.03 (PivC_t), 40.41 (NCH₂), 60.75

(C-6), 65.22, 66.83, 71.65, 72.65 (C-5, C-4, C-3, C-2), 79.32,

(C-1), 170.54 (NC=O), 176.47, 176.97, 177.35, 177.79

(PivC=O). – C₃₃H₅₅NO₁₀(625.38): calcd. C 63.34, H 8.86,

N 2.24; found C 63.15, H 8.92, N 2.24.

(4S)-4-(4-Fluorophenyl)-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)piperidin-2-one (13d)

Educt (4S)−3,4-dihydro-4-(4-ﬂuorophenyl)-N-(2,3,4,6-

tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-2(1H)-one

[8] (7d): 2.4 g (3.48 mmol); reaction time: 24 h. Yield:

1.76 g (2.55 mmol, 73 %), colorless amorphous solid, R_f=

(4S)-4-Propyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyr-

anosyl)piperidin-2-one (13b)

Educt (4R)-3,4-dihydro-4-propyl-N-(2,3,4,6-tetra-O-pi- 0.21 (cyclohexane-ethyl acetate 4 : 1), [α]²_D⁵: 4.64 (c = 1.0,

valoyl-β-D-galactopyranosyl)pyridine-2(1H)-one [8] (7b): CHCl₃). – MS ((+)-ESI): m/z = 714.7 [M+Na]⁺. – ¹H NMR

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395

(300 MHz, CDCl₃): δ = 1.10, 1.12, 1.15, 1.24 (4s, 36H, stirred and heated under reﬂux. After completion of the con-

PivCH₃), 1.83, 2.09 (2m, 2H, NCH₂CH₂), 2.46, 2.62 (2m, version (TLC monitoring) and cooling to r. t., ethyl acetate

COCH₂), 2.88 (m, 1H, CHAr), 3.40, 3.58 (2m, 2H, NCH₂), (mL) and water (50 mL) were added. The organic solution

3.91 – 4.13 (m, 3H, H-5, H-6a, H-6b), 5.24 (dd, 1H, J_3,4

=

was dried with MgSO₄, and the solvent was evaporated in

2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.40 (t, 1H, J_2,1= 9.6 Hz, vacuo. The remaining residue was puriﬁed by ﬂash chro-

J_2,3= 9.9 Hz, H-2), 5.41 (d, 1H, J_4,3= 2.9 Hz, H-4), 6.03 matography.

(d, 1H, J_1,2= 9.6 Hz, H-1), 6.99 (m, 2H, aryl), 7.10 (m,

2H, aryl). – ¹³C NMR (75.5 MHz, CDCl₃): δ = 27.03,

N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)pyri-

27.18 (PivCH₃), 30.15 (NCH₂CH₂), 37.47 (CHaryl), 38.70,

38.73, 38.83, 39.04 (PivC_t), 39.75 (COCH₂), 40.03 (NCH₂),

60.79 (C-6), 65.34, 66.80, 71.53, 72.79 (C-5, C-4, C-3,

C-2), 79.41 (C-1), 115 (d, ²J(¹³C,¹⁹F) = 21 Hz, aryl), 127

(d, ³J(¹³C,¹⁹F) = 8 Hz, aryl), 138.95 (ipso-aryl), 162 (d,

¹J(¹³C,¹⁹F) = 243 Hz, CF), 169.70 (NC=O), 176.46, 176.97,

177.55, 177.80 (PivC=O). – C₃₇H₅₄FNO₁₀(691.37): calcd.

C 64.24, H 7.87, N 2.02; found C 64.56, H 7.83, N 2.04.

dine-2(1H)-thione (10)

Educt N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-

yl)pyridine-2(1H)-one [8] (5): 0.5 g (0.84 mmol), 170 mg

(0.42 mmol, 0.5 equiv.) of Lawesson’s reagent; reaction

time: 18 h. Yield: 0.327 g (64 %), yellow, amorphous

solid, R_f= 0.52 (cyclohexane-ethyl acetate 2 : 1), [α]_D²⁵

:

170.51 (c = 1.0; CHCl₃). – MS ((+)-ESI): m/z = 632.34

[M+Na]⁺. – HRMS ((+)-ESI): m/z = 632.2869 [M+Na]⁺

(calcd.: 632.2869). – ¹H NMR (300 MHz, CDCl₃): δ =

1.01, 1.09, 1.14, 1.29 (4s, 36H, PivCH₃), 4.05 (dd, 1H,

3,4-Dihydro-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyran-

osyl)pyridine-2(1H)-one (9)

J_6a,5= 7.7 Hz, J_6a,6b= 11.1 Hz, H-6a), 4.14 (dd, 1H, J_6b,5

=

6.3 Hz, J_6b,6a= 11.1 Hz, H-6b), 4.30 (t, 1H, J = 6.9 Hz,

H-5), 5.39 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.50

(m, 2H, J_4,3= 2.9 Hz, J_2,1= 9.6 Hz, H-4, H-2), 6.63 (dt,

1H, J = 1.1 Hz, J = 6.9 Hz, NCH=CH), 7.04 (dt, 1H, J =

1.5 Hz, J = 6.9 Hz, NCH=CH), 7.54 (d, 1H, J = 8.5 Hz,

CSCH), 7.65 (bd, 2H, J = 8.8 Hz, CSCH=CH, H-1). –

¹³C NMR (75.5 MHz, CDCl₃): δ = 26.99, 26.90, 27.02,

27.26 (PivCH₃), 38.70, 38.74, 38.86, 39.09 (PivC_t), 60.42

(C-6), 66.72, 68.55, 71.06, 74.24 (C-5, C-4, C-3, C-2), 84.59

(C-1), 113.19 (NCH=CH), 133.62 (NCH=CH), 135.57,

136.26 (CSCH, CSCH=CH), 176.35, 176.83, 177.25, 177.71

(PivC=O), 182.93 (C=S).

To a solution of N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-

pyranosyl)pyridine-2(1H)-one [8] (5) (5 g, 8.4 mmol) in

100 mL of dry THF at −78 ^◦C were dropwise added

16.8 mL of a 1.0 M solution of L-Selectride (16.8 mmol,

2 equiv.). After stirring for 2 h at this temperature, acetic

acid (0.5 mL, 8.4 mmol) was added. The mixture was di-

luted with diethyl ether (200 mL) and washed with 50 mL of

sat. NH₄Cl solution. The organic solution was dried with

MgSO₄, and the solvents were evaporated in vacuo. Pu-

riﬁcation was carried out by ﬂash chromatography. Yield:

3.71 g (6.23 mmol, 74 %), colorless amorphous solid, R_f=

0.63 (cyclohexane-ethyl acetate 2 : 1), [α]²_D⁵: 21.57 (c = 1.0;

CHCl₃). – MS ((+)-ESI): m/z = 618.41 [M+Na]⁺. – HRMS

((+)-ESI): m/z = 596.3452 [M+H]⁺(calcd. 596.3435). –

C₃₁H₄₉NO₁₀(595.33): calcd. C 62.50, H 8.29, N 2.35; found

C 62.67, H 8.28, N 2.27. – ¹H NMR (300 MHz, CDCl₃):

δ = 1.07, 1.08, 1.14, 1.25 (3s, 36H, PivCH₃), 2.20 (m, 2H,

COCH₂CH₂), 2.46 (m, 2H, COCH₂CH₂), 3.93 – 4.11 (m,

N-(2,3,4,6-Tetra-O-pivaloyl-β-D-galactopyranosyl)piper-

idin-2-thione (11)

Educt N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-

yl)-piperidin-2-one (8): 2 g (3.34 mmol), 1.35 g (3.34 mmol,

1 equiv.) of Lawesson’s reagent; reaction time: 8 h. Yield:

1.95 g (95 %), colorless amorphous solid, R_f= 0.74 (cyclo-

hexane-ethyl acetate 3 : 1), [α]²_D⁵: 6.69 (c = 1.0; CHCl₃). –

MS (FD): m/z = 614.4 [M+H]⁺. – ¹H NMR (300 MHz,

CDCl₃): δ = 1.09, 1.10, 1.14, 1.25 (4s, 36H, PivCH₃),

1.36 – 1.90 (m, 4H, NCH₂CH₂CH₂), 2.81 (td, 1H, J =

17.6 Hz, J = 6.9 Hz, CSCH^a₂), 3.03 (td, 1H, J = 17.6 Hz, J =

6.3 Hz, CSCH^b₂), 3.60 (m, 2H, NCH₂), 3.92 – 4.17 (m, 3H,

H-5, H-6a, H-6b), 5.29 (dd, 1H, J_3,4= 3.3 Hz, J_3,2= 9.9 Hz,

H-3), 5.42 (m, 2H, J_4,3= 3.3 Hz, J_2,1= 9.2 Hz, J_2,3= 9.9 Hz,

H-4, H-2), 7.13 (d, 1H, J_1,2= 9.2 Hz, H-1). – ¹³C NMR

(75.5 MHz, CDCl₃): δ = 19.54, 22.05 (NCH₂CH₂CH₂),

27.03, 27.12, 27.21 (PivCH₃), 38.70, 38.73, 38.89, 39.04

3H, H-5, H-6a, H-6b), 5.21 (dd, 1H, J_3,4= 2.9 Hz, J_3,2

=

9.9 Hz, H-3), 5.29 (m, 2H, NCH=CH, H-2), 5.44 (d, 1H,

J_4,3= 2.9 Hz, H-4), 5.91 (d, 1H, J_1,2= 9.2 Hz, H-1), 6.24

(d, J = 8.1 Hz, NCH). – ¹³C NMR (75.5 MHz, CDCl₃):

δ = 19.28 (COCH₂CH₂), 26.53, 26.97, 27.54 (PivCH₃),

31.51 (COCH₂), 38.68, 38.71, 38.77, 39.03 (PivC_t), 60.73

(C-6), 66.23, 66.83, 71.51, 73.04 (C-5, C-4, C-3, C-2),

78.51 (C-1), 107.74 (NCH=CH), 123.79 (NCH=C), 169.60

(NC=O), 176.49, 176.70, 177.00, 177.77 (PivC=O).

Synthesis of pyridine-2- and hydropyridin-2-thiones – Gen-

eral procedure

To the solution of the corresponding N-galactosyl-de- (PivC_t), 42.65, 43.66 (NCH₂, CSCH₂), 60.49 (C-6), 66.12,

hydropiperidin-2-one or N-galactosyl-pyrid-2-one in dry 66.69, 71.27, 73.10 (C-2, C-3, C-4, C-5), 84.12 (C-1),

toluene, Lawesson’s reagent [9] was added. The solution was 176.44, 176.91, 177.70, 177.74 (PivC=O), 205.95 (C=S). –

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396

E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

C₃₁H₅₁NO₉S (613.32): calcd. C 60.66, H 8.37, N 2.28; (4R)-3,4-Dihydro-4-propyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

found C 60.62, H 8.27, N 2.11.

galactopyranosyl)pyridine-2(1H)-thione (14b)

Educt (4R)-3,4-dihydro-4-propyl-N-(2,3,4,6-tetra-O-pi-

valoyl-β-D-galactopyranosyl)pyridine-2(1H)-one (7b): 0.2

g (0.313 mmol), 65 mg (0.16 mmol, 0.5 equiv.) of Lawes-

son’s reagent; reaction time: 16 h. Yield: 0.15 g (74 %),

yellow amorphous solid, R_f= 0.35 (cyclohexane-ethyl

acetate 8 : 1), [α]²_D⁵: 86.10 (c = 1.0; CHCl₃). – MS ((+)-ESI):

m/z = 676.50 [M+Na]⁺. – ¹H NMR (300 MHz, CDCl₃): δ =

0.86 (t, 3H, -CH₃), 1.07, 1.09, 1.14, 1.28 (4s, 36H, PivCH₃),

1.31 (m, 4H, (CH₂)₂CH₃), 2.18 (CHpropyl), 2.75 (dd, 1H,

J = 10.6 Hz, J = 16.2 Hz, CSCH^a₂), 3.07 (dd, 1H, J = 5.9 Hz,

J = 16.2 Hz, CSCH^b₂), 3.95 – 4.17 (m, 3H, H-5, H-6a, H-6b),

5.27 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.39 (t, 1H,

J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2), 5.46 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.55 (dd, 1H, J = 2.9 Hz, J = 7.7 Hz, NCH=CH), 6.72

(d, 1H, J = 7.7 Hz, NCH=CH), 7.03 (d, 1H, J_1,2= 9.2 Hz,

H-1). – ¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the

major rotamer) 13.90 (CH₃), 19.36 (CH₂CH₃), 27.03, 27.17,

27.23 (PivCH₃), 29.56 (CHpropyl), 35.69 (CH₂CH₂CH₃),

38.70, 38.74, 38.79, 39.06 (PivC_t), 48.21 (CSCH₂), 60.61

(C-6), 66.69, 66.95, 71.39, 73.30 (C-5, -4, C-3, C-2), 82.78

(C-1), 118.18 (NCH=CH), 123.08 (NCH), 176.47, 177.00,

177.74 (PivC=O), 202.08 (C=S). – C₃₄H₅₅NO₉S (653.35):

calcd. C 62.45, H 8.48, N 2.14, S 4.90; found C 62.05,

H 8.41, N 2.06, S 5.20.

3,4-Dihydro-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyran-

osyl)pyridine-2(1H)-thione (12)

Educt 3,4-dihydro-N-(2,3,4,6-tetra-O-pivaloyl-β-D-ga-

lactopyranosyl)pyridine-2(1H)-one (9): 2 g (3.36 mmol),

679 mg (1.68 mmol, 0.5 equiv.) of Lawesson’s reagent;

reaction time: 3 h. Yield: 1.81 g (88 %), colorless amorphous

solid, R_f= 0.74 (cyclohexane-ethyl acetate 2 : 1), [α]_D²⁵

:

88.60 (c = 1.0; CHCl₃). – MS ((+)-ESI): m/z = 634.345

[M+Na]⁺. – HRMS ((+)-ESI): m/z = 634.3044 [M+Na]⁺

(calcd.: 634.3026). – ¹H NMR (300 MHz, CDCl₃): δ = 1.08,

1.14, 1.26 (3s, 36H, PivCH₃), 2.08 (m, 2H, CSCH₂CH₂),

3.02 (m, 2H, CSCH₂), 3.95 – 4.18 (m, 3H, H-5, H-6a, H-6b),

5.27 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.39 (t, 1H,

J_1,2= 9.2 Hz, J_2,3= 9.9 Hz, H-2), 5.46 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.64 (dd, 1H, J = 7.7 Hz, J = 8.5 Hz, NCH=CH), 6.37

(d, 1H, J = 8.1 Hz, NCH), 7.06 (d, 1H, J_1,2= 9.2 Hz, H-1). –

¹³C NMR (75.5 MHz, CDCl₃): δ = 18.56 (CSCH₂CH₂),

27.03, 27.17, 27.23 (PivCH₃), 38.73, 38.88, 39.06 (PivC_t),

41.99 (CSCH₂), 60.52 (C-6), 66.65, 66.93, 71.39, 73.30

(C-5, C-4, C-3, C-2), 82.82 (C-1), 112.95 (NCH=CH),

124.05 (NCH=CH), 176.46, 176.98, 177.73 (PivC=O),

202.11 (C=S). – C₃₁H₄₉NO₉S (611.31): calcd. C 60.86,

H 8.07, N 2.07, S 5.24; found C 60.63, H 8.11, N 2.15,

S 4.78.

(4S)-4-Isopropyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-

pyranosyl)-5,6-dehydro-piperidin-2-thione (14c)

(4R)-4-Ethyl-3,4-dihydro-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)pyridine-2(1H)-thione (14a)

Educt (4R)-4-ethyl-3,4-dihydro-N-(2,3,4,6-tetra-O-piva-

loyl-β-D-galactopyranosyl)pyridine-2(1H)-one [8] (7a): 443

mg (0.71 mmol), 144 mg (0.36 mmol, 0.5 equiv.) of Lawes-

son’s reagent; reaction time: 3 h. Yield: 380 mg (84 %),

yellow amorphous solid, R_f= 0.6 (cyclohexane-ethyl ac-

etate 5 : 1), [α]²_D⁵: 68.47 (c = 1.0; CHCl₃). – MS ((+)-ESI):

m/z = 662.37 [M+Na]⁺. – HRMS ((+)-ESI): m/z = 662.3364

[M+Na]⁺(calcd.: 662.3339). – ¹H NMR (300 MHz,

CDCl₃): δ = 0.85 (t, 3H, J = 7.3 Hz, -CH₃), 1.08, 1.09, 1.13,

1.26 (4s, 36H, PivCH₃), 1.60 (m, 2H, CH₂CH₃), 2.15 – 2.3

(m, 1H, CHethyl), 2.69 – 3.17 (m, 1H, CSCH^a₂), 3.10 (m, 1H,

Educt

(4S)-3,4-dihydro-4-isopropyl-N-(2,3,4,6-tetra-

O-pivaloyl-β-D-galactopyranosyl)pyridine-2(1H)-one [8]

(7c): 2.79 g (4.37 mmol), 1.76 g (4.37 mmol, 1 equiv.) of

Lawesson’s reagent; reaction time: 3 h. Yield: 2.13 g (75 %),

yellow amorphous solid, R_f= 0.69 (cyclohexane-ethyl ac-

etate 3 : 1), [α]²_D⁵: 40.59 (c = 1.0; CHCl₃). – MS (FD): m/z =

653.36 [M]⁺. – H NMR (300 MHz, CDCl₃): δ = 0.87 (d,

1

6H, J = 6.6 Hz, (CH(CH₃)₂), 1.08, 1.09, 1.13, 1.26 (4s, 36H,

PivCH₃), 1.61 (m, 1H, CHMe₂),2.08 (m, 1H, CHipropyl),

2.80 – 3.12 (m, 2H, CSCH₂), 3.98 – 4.17 (m, 3H, H-5, H-6a,

H-6b), 5.27 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3),

CSCH^b₂), 3.95 – 4.17 (m, 3H, H-5, H-6a, H-6b), 5.25 (m, 1H, 5.44 (m, H-2, H-4), 5.57 (m, 1H, NCH=CH), 6.36 (d, 1H,

H-3), 5.44 (t, 1H, J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2), 5.45 (d, J = 8.1 Hz, NCH), 7.02 (d, 1H, J_1,2= 9.2 Hz, H-1). –

1H, J_4,3= 2.5 Hz, H-4), 5.56 (m, 1H, NCH=CH), 6.34 (d, 1H, ¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the major

J = 7.7 Hz, NCH=CH), 7.02 (d, 1H, J_1,2= 9.2 Hz, H-1). – rotamer) 17.60, 13.39 (CH(CH₃)₂), 27.02, 27.12, 27.18,

¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the major ro- 27.26 (PivCH₃), 30.37, 36.59 (CHipropyl, CHMe₂), 38.70,

tamer) 17.73 (CH₃), 26.50 (CH₂CH₃), 27.00, 27.03, 27.19, 38.73, 38.80, 39.06 (PivC_quart.), 45.68 (CSCH₂), 60.67

27.23 (PivCH₃), 31.39 (CHethyl), 38.38, 38.73, 38.80, 39.06 (C-6), 66.56, 66.87, 71.38, 73.31 (C-5, -4, C-3, C-2), 82.82

(PivC_quart.), 47.91 (CSCH₂), 60.60 (C-6), 66.69, 66.92, (C-1), 116.25 (NCH=CH), 123.62 (NCH=CH), 176.47,

71.39, 73.28 (C-5, C-4, C-3, C-2), 82.78 (C-1), 116.25 176.97, 177.71 (PivC=O), 202.49 (C=S). – C₃₄H₅₅NO₉S

(NCH=CH), 123.62 (NCH=CH), 176.48, 177.00, 177.75 (653.35): calcd. C 62.45, H 8.48, N 2.14, S 4.90; found

(PivC=O), 202.15 (C=S).

C 62.38, H 8.59, N 2.07, S 4.84.

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397

(4R)-3,4-Dihydro-4-(4-ﬂuoro-phenyl)-N-(2,3,4,6-tetra-O-pi-

valoyl-β-D-galactopyranosyl)pyridine-2(1H)-thione (14d)

177.82 (PivC=O), 204.18 (C=S). – C₃₇H₅₄FNO₉S (707.35):

calcd. C 62.78, H 7.69, N 1.98; found C 61.56, H 8.00,

N 1.77.

Educt (4R)-3,4-dihydro-4-(4-ﬂuoro-phenyl)-N-(2,3,4,6-

tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-2(1H)-one

[8] (7d): 0.2 g (0.29 mmol), 59 mg (0.145 mmol, 0.5 equiv.)

of Lawesson’s reagent; reaction time: 5 h. Yield: 0.128 g

(62 %), yellow amorphous solid, R_f= 0.4 (cyclohexane-

ethyl acetate 6 : 1), [α]²_D⁵: 95.11 (c = 1.0; CHCl₃). – MS

((+)-ESI): m/z = 728.38 [M+Na]⁺. – HRMS ((+)-ESI):

m/z = 728.3277 [M+Na]⁺(calcd.: 728.3277). – ¹H NMR

(300 MHz, CDCl₃): δ = 1.10, 1.11, 1.15, 1.27 (4s, 36H,

PivCH₃), 3.11 (dd, 1H, J = 9.6 Hz, J = 16.2 Hz, CSCH^a₂),

3.26 (dd, 1H, J = 6.6 Hz, J = 16.2 Hz, CSCH^b₂), 3.45 (m,

1H, CHaryl), 4.01 – 4.20 (m, 3H, H-5, H-6a, H-6b), 5.30

(dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.43 (t, 1H,

J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2), 5.49 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.70 (dd, 1H, J = 4.1 Hz, J = 8.1 Hz, NCH=CH),

6.52 (dd, 1H, J = 1.8 Hz, J = 8.1 Hz, NCH), 6.96 (m, 2H,

aryl), 7.06 (d, 1H, J_1,2= 9.2 Hz, H-1), 7.10 (m, 2H, aryl). –

¹³C NMR (75.5 MHz, CDCl₃): δ = 27.02, 27.05, 27.20,

27.24 (PivCH₃), 35.78 (CHaryl), 38.71, 38.76, 38.94, 39.07

(PivC_t), 50.14 (CSCH₂-), 60.69 (C-6), 66.68, 67.04, 71.27,

73.40 (C-5, C-4, C-3, C-2), 82.87 (C-1), 115.20 (NCH=CH),

115 (d, ²J(¹³C,¹⁹F) = 21 Hz, aryl), 124.17 (NCH), 128

(d, ³J(¹³C,¹⁹F) = 8 Hz, aryl), 137.23 (ipso-aryl), 162 (d,

¹J(¹³C,¹⁹F) = 243 Hz, CF), 176.46, 176.97, 177.18, 177.76

(PivC=O), 200.28 (C=S).

Reductive Sulfurization – General procedure

To a solution of the thiolactam in dry isopropanol freshly

prepared, neutrally washed Raney nickel was added. The sus-

pension was stirred under hydrogen atmosphere at 70 ^◦C

and the conversion montored by TLC. After completion of

the reaction, the catalyst was ﬁlterred off through Celite

and thouroughly washed with isopropanol. The combined ﬁl-

trates were evaporated to dryness in vacuo, and the remaining

crude product was puriﬁed by ﬂash chromatography.

4-Ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-

piperidine (16a)

Educt (4R)-4-ethyl-3,4-dihydro-N-(2,3,4,6-tetra-O-piva-

loyl-β-D-galactopyranosyl)pyridine-2(1H)−thione (14a):

0.24 g (0.377 mmol) in 20 mL of dry iso-propanol, 1.5 g

of Ni-Al-alloy; reaction time: 3 d. Yield: 0.23 g (99 %)

colorless amorphous solid, R_f= 0,6 (cyclohexane-ethyl

acetate 6 : 1), [α]²_D⁵: −6.24 (c = 1.0; CHCl₃). – MS ((+)-ESI):

m/z = 634.3 [M+Na]⁺. – ¹H NMR (300 MHz, CDCl₃):

δ = 0.82 (t, 3H, -CH₃), 1.08, 1.12, 1.15, 1.23 (4s, 38H,

CH₂CH₃, PivCH₃), 1.58 (m, 5H, CHethyl, 2 × NCH₂CH₂),

2.34 (t, 1H, J = 11.4 Hz, NCH^a₂), 2.70 (bd, 1H, J = 11.4 Hz,

NCH^b₂), 2.74 (bt, 1H, J = 11.1 Hz, NCH^c₂), 3.06 (bd, 1H, J =

11.4 Hz, NCH^d₂), 3.82 (t, 1H, J_5,6a= 6.9 Hz, J_5,6b= 6.6 Hz,

H-5), 3.90 (dd, 1H, J_6a,5= 6.9 Hz, J_6a,6b= 10.7 Hz, H-6a),

3.93 (d, 1H, J_1,2= 9.2 Hz, H-1), 4.10 (m, 1H, J_6b,5= 6.6 Hz,

(4S)-4-(4-Fluorophenyl)-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)piperidin-2-thione (15)

Educt (4S)-4-(4-ﬂuorophenyl)-N-(2,3,4,6-tetra-O-piva-

loyl-β-D-galactopyranosyl)-piperidin-2-one 13d: 0.2 g (0.29

mmol), 59 mg (0.145 mmol, 0.5 equiv.) of Lawesson’s

reagent; reaction time: 7 h. Yield: 0.202 g (98 %), yellow

amorphous solid, R_f= 0.44 (cyclohexane-ethyl acetate 4 : 1),

[α]²_D⁵: 47.79 (c = 1.0; CHCl₃). – MS ((+)-ESI): m/z =

730.44 [M+Na]⁺. – HRMS ((+)-ESI): m/z = 708.3586

[M+H]⁺calcd.: 708.3582). – ¹H NMR (300 MHz, CDCl₃):

δ = 1.10, 1.13, 1.14, 1.25 (4s, 36H, PivCH₃), 1.91, 2.24

(2m, 2H, NCH₂CH₂), 2.88 (m, 1H, CHaryl), 3.07 (dd,

1H, J = 9.2 Hz, J = 18.1 Hz, CSCH^a₂), 3.27 (dd, 1H J =

5.9 Hz, J = 18.1 Hz, CSCH^b), 3.57, 3.74 (2m, 2H, NCH₂),

J_6b,6a= 10.7 Hz, H-6b), 5.09 (dd, 1H, J_3,4= 2.9 Hz, J_3,2

9.9 Hz, H-3), 5.34 (m, 2H, J_4,3= 2.9 Hz, J_2,1= 9.2 Hz, J_2,3

=

9.9 Hz, H-4, H-2). – ¹³C NMR (75.5 MHz, CDCl₃): δ =

11.23 (-CH₃), 27.07, 27.17, 27.28 (PivCH₃), 31.99, 32.77

(2× NCH₂CH₂), 37.69 (CHethyl), 38.63, 38.70, 39.05

(PivC_t), 44.19, 52.00 (2× NCH₂), 61.38 (C-6), 65.03, 67.28,

71.67, 71.95 (C-5, C-4, C-3, C-2), 94.42 (C-1), 176.80,

176.93, 177.27, 177.91 (PivC=O).

4-Propyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-

yl)piperidine (16b)

3.95 – 4.18 (m, 3H, H-5, H-²6a, H-6b), 5.31 (dd, 1H, J_3,4

=

Educt (4R)-4-propyl-3,4-dihydro-N-(2,3,4,6-tetra-O-pi-

2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.46 (m, 2H, H-2, H-4), 6.97 valoyl-β-D-galactopyranosyl)pyridine-2(1H)−thione (14b):

(m, 2H, aryl), 7.11 (m, 2H, aryl), 7.19 (d, 1H, J_1,2= 9.2 Hz, 0.132 g (0.2 mmol) in 20 mL of dry isopropanol, 0.5 g Ni-Al

H-1). – ¹³C NMR (75.5 MHz, CDCl₃): δ = 27.02, 27.05, alloy; reaction time: 3 d. Yield: 0.105 g (83 %) colorless

27.17, 27.20 (PivCH₃), 30.12 (NCH₂CH₂), 36.86 (CHaryl), oil, R_f= 0,28 (cyclohexane-ethyl acetate 20 : 1), [α]_D²⁵

:

38.70, 38.74, 38.92, 39.04 (PivC_t), 43.49 (NCH₂), 49.63 −8.94 (c = 1.0; CHCl₃). – MS ((+)-ESI): m/z = 626.44

(CSCH₂-), 60.55 (C-6), 66.17, 66.86, 71.29, 73.15 (C-5, [M+H]⁺. – HRMS ((+)-ESI): m/z = 626.4260 [M+H]⁺

C-4, C-3, C-2), 84.18 (C-1), 115 (d, ²J(¹³C,¹⁹F) = 21 Hz, (calcd.: 626.4268). – ¹H NMR (300 MHz, CDCl₃): δ = 0.83

3

aryl), 128 (d, J(¹³C,¹⁹F) = 8 Hz, aryl), 139.10 (ipso-aryl), (t, 3H, -CH₃), 1.08, 1.12, 1.15, 1.22 (4s, 40H, -(CH₂)₂CH₃,

162 (d, ¹J(¹³C,¹⁹F) = 243 Hz, CF), 176.41, 176.91, 177.73, PivCH₃), 1.60 (m, 5H, CHpropyl, 2× NCH₂CH₂), 2.34 (t,

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E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

1H, J = 11.7 Hz, NCH^a₂), 2.69 (bd, 1H, J = 10.7 Hz, NCH^b₂),

Yield: 52 mg (84 %) 17, colorless oil, R_f= 0.14 (cyclo-

1

2.77 (bt, 1H, J = 11.4 Hz, NCH^c₂), 3.06 (bd, 1H, J = 11.4 Hz, hexane-ethyl acetate 4 : 1). – H NMR (300 MHz, CDCl₃):

δ = 0.86 (t, 3H, J = 7 Hz, -CH₃), 1.06 (m, 2H, NCH₂CH^a₂,

NCH^d₂), 3.81 (t, 1H, J_5,6a= 6.9 Hz, J_5,6b= 6.6 Hz, H-5),

3.90 (dd, 1H, J_6a,5= 6.9 Hz, J_6a,6b= 10.7 Hz, H-6a), 4.02 NCH₂CH^b₂), 1.22 (q, 3H, J = 7 Hz, CHethyl, CH₂CH₃),

1.64 (bd, 2H, J = 12.5 Hz, NCH₂CH^c₂, NCH₂CH₂^d), 2.72

(d, 1H, J_1,2= 9.2 Hz, H-1), 4.09 (m, 1H, J_6b,5= 6.6 Hz,

(bt, 2H, J = 12.1 Hz, NCH^a₂, NCH₂^b), 4.12 (m, 2H, NCH₂^c,

NCH^d), 5.09 (s, 2H, CH₂Ph), 7.33 (m, 5H, aryl). – ¹³C NMR

(75.5²MHz, CDCl₃): δ = 11.13 (-CH₃), 29.11, 31.74

(CH₂CH₃, NCH₂CH₂), 37.59 (CHethyl), 44.30 (NCH₂),

66.86 (CH₂Ph), 127.78, 127.84, 128.43 (aryl), 137.02 (ipso-

aryl), 155.29 (NC=O).

J_6b,6a= 10.7 Hz, H-6b), 5.08 (dd, 1H, J_3,4= 2.9 Hz, J_3,2

9.9 Hz, H-3), 5.34 (m, 2H, J_4,3= 2.9 Hz, J_2,1= 9.2 Hz, J_2,3

=

9.9 Hz, H-4, H-2). – ¹³C NMR (75.5 MHz, CDCl₃): δ =

14.21 (-CH₃), 19.72 (CH₂CH₃), 27.00, 27.05, 27.14, 27.24

(PivCH₃), 32.33, 33.14 (2× NCH₂CH₂), 35.61 (CHpropyl),

38.61, 38.67, 38.95 (PivC_t), (CH₂CH₂CH₃), 39.01 (PivC_t),

44.17, 52.54 (2× NCH₂), 61.34 (C-6), 65.00, 67.25, 71.63,

71.93 (C-5, C-4, C-3, C-2), 94.40 (C-1), 176.77, 176.88,

177.22, 177.86 (PivC=O).

C-3 Alkylation of N-galactosyl piperidin-2-ones - General

procedure

To the solution of the N-galactopyranosyl-piperidin-2-one

in THF at −78 ^◦C, lithium hexamethyldisilazane (LiHMDS,

1 M solution in THF) was added. After 1 h stirring at this

temperature, the alkyl iodide was added and the stirring con-

tinued for 15 h at the given temperature. The reaction was

terminated by addition of sat. NH₄Cl solution (20 mL) at the

low temperature. After warming to r. t., the solution was ex-

tracted three times with diethyl ether (100 mL). The com-

bined organic solutions were dried with MgSO₄, the solvent

was evaporated in vacuo, and the residue was puriﬁed by

ﬂash chromatography.

Detachment of the carbohydrate auxiliary from piperidines –

General procedure

The N-galactosyl-piperidine (0.5 mmol) dissolved in

methanol (15 mL) and 1N solution of HCl in methanol

(6 mL) was stirred for 24 h. Subsequently, HCl and the sol-

vent were removed in vacuo, and the remaining crude piperi-

dinium chloride was stirred in water (50 mL) and diethyl

ether (50 mL) for 5 min. The separated water solution was

extracted twice with diethyl ether (50 mL). The combined

ether solutions were washed with water (50 mL). The ether

solution contained the tetra-O-pivaloyl-galactose. The com-

bined water solutions were evaporated to dryness to give the

piperidine hydrochloride.

3-Butyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-

piperidin-2-one (18a)

The reaction was carried out at −10 ^◦C starting from

piperidinone 8 (0.2 g, 0.335 mmol) dissolved in 3 mL of

dry THF, treated with 0.57 mL (0.57 mmol, 1.7 equiv.) of

LiHMDS solution, and using 0.114 mL (1.0 mmol, 3 equiv.)

of butyl iodide. Puriﬁcation was achieved by ﬂash chro-

matography (20 × 1 cm, cyclohexane-ethyl acetate 6 : 1).

Yield: 90 mg (41 %), colorless amorphous solid, R_f= 0.37

(cyclohexane-ethyl acetate 4 : 1). Diastereomeric ratio: 91 : 9

(¹H NMR after chromatography and analytical HPLC). An-

alytical HPLC: Chiral Pack AD; hexane-iso-propanol 98 : 2,

isocratic, R_t(min): 4.65 (major diastereomer), 5.80 (minor

N-(Benzyloxycarbonyl)-4-ethyl-piperidine (17)

The hydrochloride of 4-ethyl-piperidine was obtained

from 4-ethyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyran-

osyl)piperidine (16a) (220 mg, 0.36 mmol) in methanol

(10 mL) and 4 mL of 1 N methanolic HCl (reaction time

24 h). Yield: 37 mg (70 %), colorless amorphous solid. –

¹H NMR (300 MHz, [D₆]DMSO): δ = 0.81 (t, 3H, -CH₃),

1.16 (q, 2H, CH₂CH₃), 1.29 (m, 3H, CHethyl, NCH₂CH^a₂,

NCH₂CH^b₂), 1.71 (bd, 2H, J = 11.7 Hz, NCH₂CH^c₂,

NCH₂CH^d₂), 2.75 (q, 2H, J = 11.8 Hz, NCH₂^a, NCH^b₂), 3.16

(bd, 2H, J = 12.1 Hz, NCH^c₂, NCH₂^d), 9.01, 9.24 (2 bs, diastereomer), [α]_D²⁵: 24.59 (c = 1.0, CHCl₃). – MS ((+)-

NH). – ¹³C NMR (75.5 MHz, [D₆]DMSO): δ = 10.93 (- ESI): m/z = 676.43 [M+Na]⁺. – HRMS ((+)-ESI): m/z =

CH₃), 28.02, 28.23 (CH₂CH₃, NCH₂CH₂), 34.78 (CHethyl), 654.4220 [M+Na]⁺(calcd.: 654.4217).

◦

43.10 (NCH₂).

The reaction performed at −78 C gave 80 mg (35 %)

This hydrochloride was dissolved in 2 mL of water. Af- of 18a as a colorless solid, R_f= 0.37 (cyclohexane: ethyl ac-

ter addition 2 mL of sat. Na₂CO₃solution, the mixture was etate 4 : 1). Diastereomeric ratio: 96 : 4 (¹H NMR after chro-

stirred for 1 h at r. t. Subsequently, benzyl chloroformate matography and analytical HPLC). Analytical HPLC: Chi-

(53 µL, 0.38 mmol, 1.5 equiv.) was added and the mix- ral Pack AD; hexane-iso-propanol 98 : 2 isocratic, R_t(min):

ture stirred for 2 h. The solution was extracted three times 4.70 (major diastereomer), 5.85 (minor diastereomer), [α]_D²⁵

:

with diethyl ether (30 mL), the combined organic solutions 30.81 (c = 0.5, CHCl₃). – HRMS ((+)-ESI): m/z = 654.4196

were dried with MgSO₄, and the solvent was evaporated in [M+H]⁺(calcd.: 654.4217). – ¹H NMR (300 MHz, CDCl₃):

vacuo. Puriﬁcation of the crude product was performed by δ = (signals of the major diastereomer): 0.88 (t, 3H, CH₃),

ﬂash chromatography.

1.08, 1.13, 1.23 (3s, 38H, CH₂CH₃, PivCH₃), 1.25 (m, 4H,

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399

(CH₂)₂CH₃), 1.86 (m, 4H, NCH₂(CH₂)₂), 2.12 (m, 1H, etate 8 : 1). – Yield: 89 mg (44 %), pale-yellow amorphous

COCHbutyl), 3.32 (m, 2H, NCH₂), 3.90, 4.12 (2m, 3H, H-5, solid, R_f= 0.25 (cyclohexane-ethyl acetate 4 : 1). Diastereo-

H-6a, H-6b), 5.18 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, meric ratio: 92 : 8 (¹H NMR and analytical HPLC). Analyt-

H-3), 5.35 (t, 1H, J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2), 5.41 (d, ical HPLC: Luna C18, gradient: acetonitrile-water 80 : 20 to

1H, J_4,3= 2.9 Hz, H-4), 5.90 (d, 1H, J_1,2= 9.2 Hz, H-1). – 100 : 0 within 40 min, R_t(min): 21.62 (major diastereomer),

¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the major di- 22.53 (minor diastereomer). [α]_D²⁵: 17.74 (c = 1.0, CHCl₃). –

astereomer): 13.99 (CH₃), 21.36, 22.72, 25.79 ((CH₂)₂CH₃, MS ((+)-ESI): m/z = 632.3 [M+Na]⁺. – HRMS ((+)-ESI):

N(CH₂)₂CH₂), 26.017, 27.05, 27.14, 27.21 (PivCH₃), 29.23, m/z = 632.3391 [M+Na]⁺(calcd.: 632.3411). – ¹H NMR

31.24 (CH₂(CH₂)₂CH₃, NCH₂CH₂), 38.68, 38.79, 39.03 (400 MHz, CDCl₃): δ = (signals of the major diastereomer)

(PivC_t), 41.17 (NCH₂), 41.59 (COCH), 60.73 (C-6), 65.16, 1.06, 1.09, 1.14, 1.25 (4s, 36 H, CH₃, PivCH₃), 2.08, 2.28,

66.86, 71.53, 72.76 (C-2, C-3, C-4, C-5), 79.72 (C-1), 173.82 2.44 (3m, 3H, CH₂, COCHMe), 3.91 – 4.14 (m, 3H, H-5,

(NC=O), 176.55, 177.00, 177.43, 177.80 (PivC=O).

H-6a, H-6b), 5.22 (m, 2H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3,

NCH=CH), 5.33 (t, 1H, J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2),

5.44 (d, 1H, J_4,3= 2.9 Hz, H-4), 5.89 (d, 1H, J_1,2= 9.2 Hz,

H-1), 6.22 (d, 1H, J_f= 6.2 Hz, NCH=CH). – ¹³C NMR

(100.6 MHz, CDCl₃): δ = (signals of the major diastereo-

mer: 15.58 (CH₃), 26.94, 27.00, 27.20, 27.24 (PivCH₃),

27.54 (CH₂), 35.72 (COCHMe), 38.65, 38.68 38.74, 39.03

(PivC_t), 60.49 (C-6), 66.20, 66.74, 71.51, 73.00 (C-2,

C-3, C-4, C-5), 78.79 (C-1), 106.29 (NCH=CH), 123.51

(NCH), 172.59 (NC=O), 176.50, 176.80, 176.97 177.70

(PivC=O).

3-Methyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranos-

yl)piperidin-2-one (18b)

The reaction was carried out at −78 ^◦C starting from

piperidinone 8 (0.2 g, 0.335 mmol) dissolved in 3 mL of

dry THF, treated with 0.57 mL (0.57 mmol, 1.7 equiv.) of

LiHMDS solution, and using 63 µL (1.0 mmol, 3 equiv.)

of methyl iodide. Puriﬁcation was achieved by ﬂash chro-

matography (20 × 1 cm, cyclohexane-ethyl acetate 5 : 1).

Yield: 171 mg (83 %), colorless amorphous solid, R_f

=

0.3 (cyclohexane-ethyl acetate 4 : 1). Diastereomeric ra-

tio: 67 : 33 (¹H NMR after chromatography and analyti-

cal HPLC). Analytical HPLC: Chiral Pack AD; hexane-iso-

propanol 98 : 2 isocratic, R_t(min): 4.95 (minor diastereo-

mer), 5.77 (major diastereomer), [α]²_D⁵: 26.50 (c = 1.0,

CHCl₃). – MS ((+)-ESI): m/z = 634.38 [M+Na]⁺. – HRMS

((+)-ESI): m/z = 634.3586 [M+Na]⁺(calcd.: 634.3567). –

¹H NMR (300 MHz, CDCl₃): δ = (signals of the major dia-

stereomer) 1.07, 1.08, 1.13, 1.23 (4s, 39H, CH₃, PivCH₃),

1.69, 1.86 (2m, 4H, NCH₂(CH₂)₂), 2.24 (m, 1H, COCHMe),

3.33 (m, 2H, NCH₂), 3.93, 4.07 (2m, 3H, H-5, H-6a, H-6b),

5.22 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.35

(t, 1H, J_2,1= 9.6 Hz, J_2,3= 9.9 Hz, H-2), 5.41 (d, 1H,

J_4,3= 2.9 Hz, H-4), 5.90 (d, 1H, J_1,2= 9.2 Hz, H-1). –

¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the ma-

jor diastereomer) 17.43 (CH₃), 21.34 (N(CH₂)₂CH₂), 26.97,

27.02, 27.08, 27.17 (PivCH₃), 28.78 (NCH₂CH₂), 36.60

(NCH₂), 38.67, 38.70, 38.77, 39.01 (PivC_t), 41.40 (COCH),

60.65 (C-6), 65.19, 66.80, 71.48, 72.71 (C-2, C-3, C-4, C-5),

79.68 (C-1), 174.24 (NC=O), 176.50, 176.97, 177.41, 177.77

(PivC=O).

3-Butyl-3,4-dihydro-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)pyridine-2(1H)-one (19b)

The reaction was carried out at −78 ^◦C starting from

5,6-dehydropiperidinone 9 (0.2 g, 0.335 mmol) dissolved

in 3 mL of dry THF, treated with 0.57 mL (0.57 mmol,

1.7 equiv.) of LiHMDS solution, and using 0.114 mL

(1.0 mmol, 3 equiv.) of butyl iodide. Puriﬁcation was

achieved by ﬂash chromatography (20 ×1 cm, cyclohexane-

ethyl acetate 9 : 1). Yield: 59 mg (27 %), pale-yellow waxy

solid, R_f= 0.37 (cyclohexane-ethyl acetate 4 : 1). Diastere-

omeric ratio: 93 : 7 (¹H NMR and analytical HPLC). Analy-

tical HPLC: Luna C18, gradient: acetonitrile-water 80 : 20 to

100 : 0 within 40 min, R_t(min): 32.95 (major diastereomer),

34.65 (minor diastereomer), [α]²_D⁵: 23.26 (c = 1.0, CHCl₃). –

MS ((+)-ESI): m/z = 674.4 [M+Na]⁺. – HRMS ((+)-ESI):

m/z = 674.3859 [M+Na]⁺(calcd.: 674.3880). – ¹H NMR

(300 MHz, CDCl₃): δ = (signals of the major diastereomer):

0.86 (t, 3H, CH₃), 1.06, 1.08, 1.13, 1.25 (4s, 42 H, (CH₂)₃,

PivCH₃), 2.07, 2.72 (2m, 3H, CH₂, COCHbutyl), 3.91 – 4.14

(m, 3H, H-5, H-6a, H-6b), 5.20 (m, 2H, J_3,4= 2.9 Hz, J_3,2

9.9 Hz, H-3, NCH=CH), 5.32 (t, 1H, J_2,1= 9.2 Hz, J_2,3

=

9.9 Hz, H-2), 5.43 (d, 1H, J_4,3= 2.9 Hz, H-4), 5.88 (d, 1H,

J_1,2= 9.2 Hz, H-1), 6.20 (d, 1H, J_f= 7.7 Hz, NCH=CH). –

¹³C NMR (75.5 MHz, CDCl₃): δ = (signals of the major

3,4-Dihydro-3-methyl-N-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)pyridine-2(1H)-one (19a)

The reaction was carried out at −78 ^◦C starting from diastereomer): 13.87 (CH₃), 22.49, 24.76 (2× CH₂), 26.76,

5,6-dehydropiperidinone 9 (0.2 g, 0.335 mmol) dissolved 26.85, 27.09, 27.18 (PivCH₃), 29.10, 29.64 (2× CH₂), 38.65,

in 3 mL of dry THF, treated with 0.57 mL (0.57 mmol, 38.70, 38.76, 39.03 (PivC_t), 40.74 (COCH), 60.79 (C-6),

1.7 equiv.) of LiHMDS solution, and using 63 µL (1.0 mmol, 66.32, 66.81, 71.57, 73.04 (C-2, C-3, C-4, C-5), 78.69 (C-1),

3 equiv.) of methyl iodide. Puriﬁcation was achieved by 106.24 (NCH=CH), 123.38 (NCH), 172.10 (NC=O), 176.52,

ﬂash chromatography (20 × 1 cm, cyclohexane-ethyl ac- 176.77, 176.98, 177.71 (PivC=O).

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(4R)-3,4-Dihydro-3-methyl-4-propyl-N-(2,3,4,6-tetra-O-pi-

valoyl-β-D-galactopyranosyl)pyridine-2(1H)-one (19c)

1H, CHcyclohexyl), 2.59 – 2.63 (m, 1H, COCHMe), 4.06 –

4.19 (m, 3H, H-5, H-6a, H-6b), 5.23 – 5.32 (m, 2H, H-3,

NCH=CH), 5.46 (dd, 1H, J_2,1= 9.4 Hz, H-2), 5.52 (d,

1H, J_4,3= 2.7 Hz, H-4), 5.95 (d, 1H, J_1,2= 9.4 Hz,

H-1), 6.32 (d, 1H, J_f= 8.2 Hz, NCH=CH). – ¹³C NMR

(100.6 MHz, CDCl₃): δ = (signals of the major diastereomer)

17.09 (CH₃), 26.51 (C-4cyclohexyl), 26.36 (C-3cyclohexyl,

C-5cyclohexy_l), 27.02, 27.05, 27.13, 27.24 (PivCH₃), 28.18

(C-2cyclohexyl, C-6cyclohexyl), 29.35 (CHcyclohexy_l),

38.73, 39.02 (PivC_t), 41.05 (CHcyclohexyl), 44.56 (CHMe),

61.01 (C-6), 65.80, 66.79, 71.72, 72.79 (C-2, C-3, C-4, C-5),

78.59 (C-1), 108.59 (NCH=CH), 122.54 (NCH), 173.32

(NC=O), 176.57, 176.77, 177.82 (PivC=O).

◦

The reaction was carried out at −78 C starting from 4-

propyl-5,6-dehydropiperidin-2-one (7b) (0.1 g, 0.157 mmol)

dissolved in 3 mL of dry THF, treated with 0.27 mL

(0.27 mmol, 1.7 equiv.) of LiHMDS solution, and using

0.03 mL (0.47 mmol, 3 equiv.) of methyl iodide. Puriﬁca-

tion was performed by ﬂash chromatography (20 × 1 cm,

light petroleum-ethyl acetate 8 : 1). Yield: 92 mg (90 %),

colorless amorphous solid, R_f= 0.48 (light petroleum-eth-

yl acetate 8 : 1). Diastereomeric ratio: 71 : 29 (¹H NMR and

analytical HPLC). Analytical HPLC: Luna C18, gradient:

acetonitrile-water 90 : 10 to 100 : 0 within 40 min, R_t(min):

17.39 (major diastereomer), 17.69 (minor diastereomer),

[α]²_D⁹: 57.42 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z = 674.4

[M+Na]⁺. – HRMS ((+)-ESI): m/z = 674.3873 [M+Na]⁺

(calcd.: 674.3880). – ¹H NMR (400 MHz, CDCl₃): δ =

(signals of the major diastereomer) 0.86 (m, 6H, -CH₃);

1.06, 1.07, 1.14, 1.25 (4s, 36H, PivCH₃), 1.38 – 1.28 (m, 4H,

(CH₂)₂CH₃), 2.25 – 2.38 (m, 1H, CHpropyl), 3.47 – 3.42 (m,

1H, COCH), 3.91 – 4.02 (m, 1H, H-5), 4.04 – 4.12 (m, 2H,

H-6a, H-6b), 5.15 – 5.22 (m, 2H, H-3, NCH=CH), 5.31 (dd,

1H, J_2,1= 9.2 Hz, H-2), 5.42 (d, 1H, J_4,3= 2.7 Hz, H-4),

5.85 (d, 1H, J_1,2= 9.2 Hz, H-1), 6.20 (d, 1H, J_f= 6.7 Hz,

J_l= 1.6 Hz, NCH=CH). – ¹³C NMR (100.6 MHz, CDCl₃):

δ = (signals of the major diastereomer) 14.12 (propylCH₃),

15.19 (COCHCH₃), 19.00 (CH₂CH₃), 27.05, 27.10, 27.21

(PivCH₃), 35.43 (CH₂Et), 37.81 (CHPropyl), 38.72, 39.05

(PivC_t), 40.92 (COCHMe), 60.89 (C-6), 66.03, 66.76, 71.67,

72.84 (C-2, C-3, C-4, C-5), 78.63 (C-1), 111.53 (NCH=CH),

122.11 (NCH), 172.78 (NC=O), 176.57, 176.77, 177.82

(PivC=O).

(4R)-3-Butyl-3,4-dihydro-4-propyl-1-(2,3,4,6-tetra-O-pi-

valoyl-β-D-galactopyranosyl)pyridine-2(1H)-one (19e)

◦

The reaction was carried out at −10 C starting from 4-

propyl-5,6-dehydropiperidin-2-one (7b) (0.2 g, 0.314 mmol)

dissolved 3 mL of dry THF, treated with 0.53 mL

(0.53 mmol, 1.7 equiv.) of LiHMDS solution, and using

0.11 mL (0.942 mmol, 3 equiv.) of butyl iodide. Puriﬁcation

was carried out by ﬂash chromatography (20 × 1 cm, light

petroleum-ethyl acetate 15 : 1). Yield: 0.124 g (57 %), color-

less, amorphous soid, R_f= 0.17 (cyclohexane-ethyl acetate

15 : 1). Diastereomeric ratio: 58 : 42 (¹H NMR and analytical

HPLC). Analytical HPLC: Luna C18, gradient: acetonitrile-

water 80 : 20 to 100 : 0 within 60 min, R_t(min): 42.32 and

42.93. [α]²_D⁰: 32.55 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z =

1

716.7 [M+Na]⁺. – H NMR (400 MHz, CDCl₃): δ = (sig-

nals of the major diastereomer) 0.95 (m, 6H, 2× -CH₃),

1.15, 1.17, 1.18, 1.23 (4s, 36 H, PivCH₃), 1.35 (m, 10 H,

5× -CH₂-), 2.24 (m, 1H, CHpropyl), 2.38 – 2.42 (m, 1H,

COCH), 4.03 – 4.18 (m, 3H, H-5, H-6a, H-6b), 5.27 – 5.49

(m, 3H, H-3, NCH=CH, H-2), 5.51 (d, 1H, J_4,3= 3.1 Hz,

H-4), 5.95 (m, 1H, J_1,2= 9.4 Hz, H-1), 6.26 (d, 1H, J_f=

8.2 Hz, J_l= 2.4 Hz, NCH=CH). – ¹³C NMR (100.6 MHz,

CDCl₃): δ = (signals of the major diastereomer) 13.92, 14.07

(2× CH₃), 19.38, 19.76, 22.61 (3× CH₂), 27.02, 27.07,

27.12, 27.22 (PivCH₃), 29.24, 29.53 (2× CH₂), 34.76 (CH-

propyl), 38.67, 39.05 (PivC_t), 46.85 (COCHbutyl), 60.96

(C-6), 65.38, 66.82, 71.90, 72.78 (C-2, C-3, C-4, C-5), 78.59

(C-1), 110.08 (NCH=CH), 122.07 (NCH), 172.61 (NC=O),

176.60, 177.07, 177.82 (PivC=O).

(4S)-4-Cyclohexyl-3,4-dihydro-3-methyl-N-(2,3,4,6-tetra-O-

pivaloyl-β-D-galacto-pyranosyl)pyridine-2(1H)-one (19d)

The reaction was carried out at −10 ^◦C starting from

4-cyclohexyl-5,6-dehydropiperidin-2-one [8] (7e) (0.2 g,

0.295 mmol) dissolved in 3 mL of dry THF, treated with

0.5 mL (0.501 mmol, 1.7 equiv.) of LiHMDS solution,

and using 50 µL (0.885 mmol, 3 equiv.) of methyl io-

dide. Puriﬁcation was carried out by ﬂash chromatogra-

phy (20 × 1 cm, light petroleum-ethyl acetate 8 : 1). Yield:

0.188 g (92 %), colorless amorphous solid, R_f= 0.4 (light

petroleum-ethyl acetate 8 : 1). Diastereomeric ratio: 67 : 33

(¹H NMR and analytical HPLC). Analytical HPLC: Luna

C18, gradient: acetonitrile-water 90 : 10 to 100 : 0 within

40 min, R_t(min): 26.70 und 27.30. [α]²_D⁰: 36.38 (c = 1.0 g

Aldol addition reaction at N-galactosylpiperidin-2-ones –

General procedure

To the solution of the N-galactosyl-piperidin-2-one (7) in

mL⁻¹, CHCl₃). – MS ((+)-ESI): m/z = 714.6 [M+Na]⁺. – dry THF at −78 ^◦C, 1.0 M LiHMDS solution was added. Af-

¹H NMR (400 MHz, CDCl₃): δ = (signals of the ma- ter stirring at this temperature for 15 min, a solution of the

jor diastereomer) 0.86 (m, 3H, CH₃), 1.07, 1.16, 1.18, aldedyde and BF₃· OEt₂, stirred for some time (see: indi-

1.23 (4s, 36 H, PivCH₃), 1.35 (m, 5 H, CHcyclohexyl, vidual compounds) was added. The mixture was stirred at

2× CH₂), 1.59 – 1.79 (m, 6H, 3× CH₂), 1.94 – 1.96 (m, r. t. for 12 h. Subsequently, sat. NH₄Cl solution was added

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401

and the solution extracted three times with diethyl ether. 100 : 0 within 40 min, R_t(min): 29.58, [α]²_D⁵: 68.86 (c =

The combined organic solutions were dried with MgSO₄and 1.0, CHCl₃). – MS ((+)-ESI): m/z = 800.29 [M+Na]⁺. –

evaporated in vacuo. Puriﬁcation was carried out by ﬂash ¹H NMR (300 MHz, CDCl₃): δ = 1.11, 1.14, 1.16, 1.27

chromatography using cyclohexane-ethyl acetate containing (4s, 36H, PivCH₃), 3.02 (m, 1H, CHphenyl), 3.31 (dd, 1H,

1 % (v/v) of NEt₃as the eluent.

J = 5.5 Hz, J = 5.2 Hz, COCH), 4.06 (m, 3H, H-5, H-6a,

H-6b), 4.58 (d, 1H, J = 6.9 Hz, CHOH), 5.25 (dd, 1H,

J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.34 (dd, 1H, J =

4.8 Hz, J = 8.0 Hz, NCH=CH), 5.47 (m, 2H, J_4,3= 2.9 Hz,

J_2,1= 9.6 Hz, H-2, H-4), 5.92 (d, 1H, J_1,2= 9.6 Hz, H-1),

6.47 (d, 1H, J = 8.0 Hz, NCH), 6.98 (m, 3H, aryl), 7.31

(m, 7H, aryl). ¹³C NMR (75.5 MHz, CDCl₃): δ = 27.05,

27.09, 27.15, 27.26 (PivCH₃), 40.56 (CHphenyl), 38.70,

38.77, 38.92, 39.07 (PivC_t), 56.55 (COCH), 60.76 (C-6),

65.82, 66.65, 71.66, (C-5, C-4, C-3), 72.86 (CHOH), 72.94

(C-2), 78.82 (C-1), 110.72 (NCH=CH), 123.47 (NCH),

1226.28, 127.26, 127.44, 127.95, 128.58, 128.93 (aryl),

141.22, 141.89 (ipso-aryl), 170.11 (NC=O), 176.52, 177.07,

177.31, 177.79 (PivC=O). – C₄₄H₅₉NO₁₁(777.40): calcd.

C 67.93, H 7.64, N 1.80; found C 67.80, H 7.57, N 1.84.

(4R)-3-(α-Hydroxy-phenyl-methyl)-3,4-dihydro-4-propyl-

1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-

2(1H)-one (20a)

The reaction was carried out starting from 4-propyl-5,6-

dehydropiperidin-2-one (7b) (0.2 g, 0.314 mmol), treated

with 0.345 mL (0.345 mmol, 1.1 equiv.) of LiHMDS solu-

tion, and using 48 µL (0.471 mmol, 1.5 equiv.) of freshly

distilled benzaldehyde pre-activated by stirring with 60 µL

(0.471 mmol, 1.5 equiv.) of BF₃· OEt₂for 30 min. Yield:

190 mg (81 %), colorless oil, R_f= 0.24 (cyclohexane-eth-

yl acetate 3 : 1). Diastereoselectivity: Only one diastereomer

was detected by ¹H NMR and analytical HPLC). Analyti-

cal HPLC: Luna C18, gradient: acetonitrile-water 80 : 20 to

100 : 0 within 40 min, R_t(min): 27.78, [α]²_D⁵: 38.42 (c = 1.0,

CHCl₃). – MS ((+)-ESI): m/z = 744.49 [M+H]⁺. – HRMS

((+)-ESI): m/z = 766.4141 [M+Na]⁺(calcd.: 766.4142). –

¹H NMR (300 MHz, CDCl₃): δ = 0.67 (t, 3H, -CH₃), 1.10,

1.12, 1.13 1.26 (4s, 40H, CH₂CH₂CH₃, PivCH₃), 1.77 (m,

1H, CHpropyl), 2.67 (bd, 1H, J = 9.6 Hz, COCH), 2.81 (d,

1H, J = 3.3 Hz, CHOH), 3.92 – 4.12 (m, 3H, H-5, H-6a,

H-6b), 4.56 (dd, 1H, J = 3.3 Hz, J = 9.6 Hz, CHOH), 5.18

(dd, 1H, J = 6.9 Hz, J = 7.0 Hz, NCH=CH), 5.25 (dd,

1H, J_3,4= 2.9 Hz, J_2,3= 9.9 Hz, H-3), 5.42 (m, 2H, H-2,

H-4), 5.93 (d, 1H J_1,2= 9.2 Hz, H-1), 6.25 (d, 1H, J =

7.0 Hz, NCH), 7.29 (m, 5H, aryl). – ¹³C NMR (75.5 MHz,

CDCl₃): δ = 13.70 (-CH₃), 18.96 (CH₂CH₃), 27.02, 27.06,

27.23 (PivCH₃), 33.28 (CHpropyl), 36.09 (CH₂CH₂CH₃),

38.67, 38.76, 38.89, 39.06 (PivC_t), 54.60 (COCH), 60.94

(C-6), 65.46, 66.72, 71.80 (C-5, C-4, C-3), 72.85 (CHOH),

73.24 (C-2), 78.81 (C-1), 110.06 NCH=CH), 122.39 (NCH),

126.73, 128.26, 128.64 (aryl), 141.28 (ipso-aryl), 170.90

(NC=O), 176.56, 177.07, 177.41, 177.79 (PivC=O).

(4R)-4-Benzyl-3-(α-hydroxy-pyridine-4-yl-methyl)-3,4-di-

hydro-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-

pyridine-2(1H)-one (20g)

The reaction was carried out starting from 4-benzyl-

5,6-dehydropiperidin-2-one [8] (7g) (0.225 g, 0.328 mmol),

0.49 mL (0.49 mmol, 1.5 equiv.) of LiHMDS solution, and

using 31 µL (1.64 mmol, 5 equiv.) pyridine-4-carbaldehyde

(freshly distilled). Yield : 81 mg (31 %) 20g, 47 mg (18 %)

20g’, 47 mg (18 %) 20g”. Diastereomeric ratio: 44 : 36 : 17 : 1

(analytical HPLC). Analytcal HPLC: Luna C18, gradient:

acetonitrile-water 80 : 20 to 100 : 0 within 40 min, R_t(min):

16.98 (44 %), 18.13 (1 %), 18.77 (17 %), 20.58 (36 %),

separated through preparative HPLC (Luna C8, gradient:

acetonitrile-water 80 : 20 to 100 : 0 within 120 min).

Analytical data of 20g: colorless amorphous solid, [α]_D²⁵

:

20.59 (c = 1.0, CHCl₃). - MS ((+)-ESI): m/z = 815.44

[M+Na]⁺. - HRMS ((+)-ESI): m/z = 793.4250 [M+H]⁺

(calcd.: 793.4275). - ¹H NMR (300 MHz, CDCl₃): δ = 1.08,

1.09, 1.11, 1.25 (4s, 36H, PivCH₃), 2.23 (m, 1H, CHbenzyl),

2.53 – 2.71 (m, 3H, CH₂Ph, CO CH), 3.78 (bs, 1H, CHOH),

3.93 – 4.11 (m, 3H, H-5, H-6a, H-6b), 4.69 (d, 1H, J = 7.7 Hz,

CHOH), 5.23 (m, 2H, J_3,4= 2.9 Hz, J_3,2= 9.6 Hz, H-3,

NCH=CH), 5.40 (m, 2H, J_2,1= J_2,3= 9.6 Hz, H-2, H-4), 5.84

(4R)-3-(α-Hydroxy-phenyl-methyl)-3,4-dihydro-4-phenyl-

1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-

2(1H)-one (20b)

The reaction was carried out starting from 4-phenyl-5,6- (bs, 1H, H-1), 6.29 (d, 1H, J = 8.0 Hz, NCH), 6.89 (m, 2H,

dehydropiperidin-2-one [8] (7f) (0.3 g, 0.446 mmol), treated aryl), 7.18 (m, 7H, aryl). - ¹³C NMR (75.5 MHz, CDCl₃):

with 0.67 mL (0.67 mmol, 1.5 equiv.) of LiHMDS solution, δ = 26.78, 26.99, 27.02, 27.21 (PivCH₃), 35.06 (CHben-

and using 0.227 mL (2.23 mmol, 5 equiv.) of freshly dis- zyl), 38.67, 38.74, 38.85, 39.04 (PivC_t), 39.15 (CH₂Ph),

tilled benzaldehyde pre-activated by stirring with 0.284 mL 52.31 (COCH), 60.78 (C-6), 65.78, 66.57 (C-5, C-4), 71.21

(2.23 mmol, 5 equiv.) of BF₃· OEt₂for 30 min. Yield: (CHOH), 71.60, 72.94 (C-3, C-2), 78.87 (C-1), 110.48

170 mg (49 %), colorless oil, R_f= 0.16 (cyclohexane-eth- (NCH=CH), 123.05 (NCH), 126.69 (para-phenyl), 128.59,

yl acetate 5 : 1). Diastereoselectivity: Only one diastereomer 129.10 (ortho-phenyl, meta-phenyl), 138.16 (ipso-phenyl),

was detected by ¹H NMR and analytical HPLC). Analyti- 147.84, 153 (pyridyl), 169.48 (NC=O), 176.50, 177.07,

cal HPLC: Luna C18, gradient: acetonitrile-water 80 : 20 to 177.32, 177.77 (PivC=O).

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402

E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

Analytical data of 20g’: colorless amorphous solid, [α]_D²⁵

:

0.179 mL (1.8 mmol, 5 equiv.) of freshly distilled 5-meth-

75.00 (c = 1.0, CHCl₃). - MS ((+)-ESI): m/z = 815.45 ylfurfural pre-activated by stirring with 0.230 mL (1.8 mmol,

[M+Na]⁺. - HRMS ((+)-ESI): m/z = 793.4288 [M+H]⁺5 equiv.) of BF₃· OEt₂for 30 min. Yield: 113 mg (42 %) 20c,

(calcd.: 793.4275). - ¹H NMR (300 MHz, CDCl₃): δ = 70 mg (26 %) 20c’. Diastereomeric ratio: 67 : 33 (analytical

0.99, 1.08, 1.14, 1.25 (4s, 36H, PivCH₃), 2.34 (d, 1H, HPLC). Analytical HPLC: Luna C18, gradient: acetonitrile-

J = 12.0 Hz,CH^a₂Ph), 2.39 (m, 1H, CHbenzyl), 2.84 (t, water 80 : 20 to 100 : 0 within 40 min, R_t(min): 28.23 (major

1H, J = 5.5 Hz, COCH), 3.21 (dd, 1H, J = 2.6 Hz, J = diastereomer), 29.651 min (minor diastereomer), separated

12.0 Hz, CH^b₂Ph), 3.96 – 4.18 (m, 4H, CHOH, H-5, H-6a, by ﬂash chromatography:

H-6b), 5.07 (dd, J = 8.0 Hz, J = 6.3 Hz, NCH=CH),

ane-ethyl acetate 4 : 1), [α]²_D⁵: 26.38 (c = 1.0, CHCl₃). – MS

5.24 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 10.3 Hz, H-3), 5.33

Analytcal data of 20c: colorless oil, R_f= 0.37 (cyclohex-

((+)-ESI): m/z = 770.40 [M+Na]⁺, 730.47 [M–H₂O+H]⁺. –

¹H NMR (300 MHz, CDCl₃): δ = 0.76 (t, 3H, -(CH₂)₂CH₃),

1.08, 1.10, 1.12, 1.24 (4s, 40H, CH₂CH₂CH₃, PivCH₃),

1.95 (m, 1H, CHpropyl), 2.22 (s, 3H, -CH₃), 2.79 (d, 1H,

J = 6.6 Hz, CHOH), 2.90 (dd, 1H, J = 8.8 Hz, J =

3.3 Hz, COCH), 3.89 – 4.06 (m, 3H, H-5, H-6a, H-6b),

4.56 (dd, 1H, J = 6.9 Hz, J = 8.8 Hz, CHOH), 5.17

(m, 2H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, J = 8.0 Hz, H-3,

NCH=CH), 5.36 (t, 1H, J_2,1= 9.6 Hz, J_2,3= 9.9 Hz,

H-2), 5.42 (d, 1H, J_3,4= 2.9 Hz, H-4), 5.86 (m, 2H, H-1,

CH₃-C=CH), 6.11 (d, 1H, J = 2.9 Hz, R-C=CH), 6.21 (d,

1H, J = 8.0 Hz, NCH). ¹³C NMR (75.5 MHz, CDCl₃):

δ = 13.49, 13.73 (-CH₃), 18.93 (CH₂CH₃), 27.00, 27.06,

27.21 (PivCH₃), 33.55 (CHpropyl), 35.75 (CH₂CH₂CH₃),

38.67, 38.73, 38.86, 39.04 (PivC_t), 51.69 (COCH), 60.88

(C-6), 65.49 (CHOH), 66.47, 66.68, 71.77, 72.80 (C-5, C-4,

C-3, C-2), 78.79 (C-1), 106.15 (R-C=CH), 108.94 (CH₃-

C=CH), 111.02 (NCH=CH), 122.11 (NCH), 151.85, 152.16

(ipso-aryl), 170.29 (NC=O), 176.53, 177.06, 177.37, 177.76

(PivC=O). – C₄₀H₆₁NO₁₂(747.42): calcd. C 64.24, H 8.22,

N 1.87; found C 63.99, H 8.24, N 1.79.

(t, 1H, J_2,1= 9.2 Hz, J_2,3= 10.3 Hz, H-2), 5.40 (d,

1H, J = 5.5 Hz, CHOH), 5.46 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.89 (d, 1H, J_1,2= 9.2 Hz, H-1), 6.15 (d, 1H, J =

8.0 Hz, NCH), 6.91 (d, 2H, J = 6.3 Hz, aryl), 7.18 (m,

5H, aryl), 7.42 (m, 2H, aryl). - ¹³C NMR (75.5 MHz,

CDCl₃): δ = 26.84, 27.02, 27.20 (PivCH₃), 33.64 (CHben-

zyl), 35.73 (CH₂Ph), 38.70, 38.73, 39.06 (PivC_t), 51.25

(COCH), 60.94 (C-6), 65.73, 66.71 (C-5, C-4), 69.73

(CHOH), 71.24, 73.28 (C-3, C-2), 78.76 (C-1), 113.78

(NCH=CH), 122.69 (NCH), 126.16 (para-phenyl), 128.19,

128.93 (ortho-phenyl, meta-phenyl), 139.22 (ipso-phenyl),

149.23, 151.62 (pyridyl), 170.36 (NC=O), 176.52, 176.95,

177.03, 177.79 (PivC=O).

Analytical data of 20g”: colorless amorphous solid,

[α]²_D⁵: 23.13 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z = 793.48

[M+H]⁺. – HRMS ((+)-ESI): m/z = 793.4296 [M+H]⁺

calcd.: 793.4275). – ¹H NMR (300 MHz, CDCl₃): δ =

1.10, 1.15, 1.25 (3s, 36H, PivCH₃), 2.01 (m, 1H, CHben-

zyl), 2.35 (m, 1H, J = 12.0 Hz, CH^a₂Ph), 2.76 (dd, 1H,

J = 5.5 Hz, J = 9.2 Hz, COCH), 2.84 (dd, 1H, J =

3.7 Hz, J = 12.0 Hz, CH^b₂Ph), 3.96 – 4.20 (m, 4H, CHOH,

H-5, H-6a, H-6b), 5.02 (dd, J = 8.0 Hz, J = 7.0 Hz,

NCH=CH), 5.15 (d, 1H, J = 9.2 Hz, CHOH), 5.27 (dd,

1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.35 (t, 1H,

Analytcal data of 20c’: colorless oil, R_f= 0.12 (cyclohex-

ane-ethyl acetate 4 : 1), [α]²_D⁵: −10.30 (c = 1.0, CHCl₃). – MS

((+)-ESI): m/z = 770.47 [M+Na]⁺, 730.47 [M–H₂O+H]⁺. –

HRMS ((+)-ESI): m/z = 770.4109 [M+Na]⁺(calcd.:

770.4091). – ¹H NMR (300 MHz, CDCl₃): δ = 0.76 (t,

3H, -(CH₂)₂CH₃), 1.08, 1.14 1.25 (3s, 40H, CH₂CH₂CH₃,

PivCH₃), 1.91 (m, 1H, CHpropyl), 2.23 (s, 3H, -CH₃), 2.82

(bs, 1H, CHOH), 2.89 (d, 1H, J = 9.4 Hz, COCH), 3.93 –

4.13 (m, 3H, H-5, H-6a, H-6b), 4.71 (d, 1H, J = 9.4 Hz,

CHOH), 5.17 (m, 2H, J_3,4= 2.9 Hz, J_3,2= 9.6 Hz, H-3,

NCH=CH), 5.31 (t, 1H, J_2,1= 9.2 Hz, J_2,3= 9.6 Hz,

H-2), 5.43 (d, 1H, J_3,4= 2.9 Hz, H-4), 5.85 (m, 2H,

H-1, CH₃-C=CH), 6.13 (d, 1H, J = 2.9 Hz, R-C=CH),

6.22 (d, 1H, J = 7.7 Hz, NCH). – ¹³C NMR (75.5 MHz,

CDCl₃): δ = 13.51, 13.58 (-CH₃), 19.41 (CH₂CH₃), 27.00,

27.03, 27.09, 27.23 (PivCH₃), 33.25 (CHpropyl), 35.78

(CH₂CH₂CH₃), 38.68, 38.73, 39.04 (PivC_t), 51.67 (COCH),

60.70 (C-6), 66.53 (CHOH), 66.56, 66.86, 71.66, 72.85

(C-5, C-4, C-3, C-2), 78.79 (C-1), 106.11 (R-C=CH), 109.37

J_2,1= 9.2 Hz, J_2,3= 9.9 Hz, H-2 ), 5.48 (d, 1H, J_4,3

=

2.9 Hz, H-4), 5.94 (d, 1H, J_1,2= 9.2 Hz, H-1), 6.18

(d, 1H, J = 8.0 Hz, NCH), 6.86 (d, 2H, J = 5.9 Hz,

aryl), 7.17 (m, 5H, aryl), 7.42 (m, 2H, aryl). – ¹³C NMR

(75.5 MHz, CDCl₃): δ = 26.84, 27.02, 27.20 (PivCH₃),

33.64 (CHbenzyl), 35.73 (CH₂Ph), 38.70, 38.73, 39.06

(PivC_t), 51.25 (COCH), 60.94 (C-6), 65.73, 66.71 (C-5,

C-4), 69.73 (CHOH), 71.24, 73.28 (C-3, C-2), 78.76 (C-1),

113.78 (NCH=CH), 122.69 (NCH), 126.16 (para-phenyl),

128.19, 128.93 (ortho-phenyl, meta-phenyl), 139.22 (ipso-

phenyl), 149.23, 151.62 (pyridyl), 170.36 (NC=O), 176.52,

176.95, 177.03, 177.79 (PivC=O).

(4R)-3-[α-Hydroxy-(5-methyl-furfuryl)-methyl]-3,4-di-

hydro-4-propyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyr-

anosyl)pyridine-2(1H)-one (20c)

The reaction was carried out starting from 4-propyl-5,6- (CH₃-C=CH), 110.53 (NCH=CH), 121.21 (NCH), 151.30,

dehydropiperidin-2-one (7b) 0.23 g (0.36 mmol), 0.54 mL 152.30 (ipso-aryl), 169.94 (NC=O), 176.52, 176.58, 177.03,

(0.54 mmol, 1.5 equiv.) of LiHMDS solution, and using 177.77 (PivC=O).

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403

(4R)-4-Benzyl-3-(1-hydroxy-2-methyl-propyl)-3,4-dihydro-

1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-

2(1H)-one (20d)

m/z = 780.52 [M+Na]⁺. – HRMS ((+)-ESI): m/z = 758.4484

[M+H]⁺(calcd.: 758.4479). – ¹H NMR (300 MHz, CDCl₃):

δ = 0.63 (s, 9H, (tBuCH₃), 1.09, 1.13, 1.15, 1.25 (4s, 36H,

PivCH₃), 2.78 (d, 1H, J = 11.7 Hz, CHphenyl), 3.17 (d,

1H, J = 11.7 Hz, COCH), 3.53 (bd, 1H, J = 12.1 Hz,

CHOH), 3.75 (d, 1H, J = 12.1 Hz, CHOH), 3.96 – 4.16

(m, 3H, H-5, H-6a, H-6b), 5.22 (dd, 1H, J_3,4= 2.9 Hz,

J_2,3= 9.9 Hz, H-3), 5.37 (m, 2H, J = 2.6 Hz, J = 7.7 Hz,

J_2,1= 9.2 Hz, H-2, NCH=CH), 5.46 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.92 (d, 1H J_1,2= 9.2 Hz, H-1), 6.37 (dd, 1H, J_l=

2.2 Hz, J_f= 7.7 Hz, NCH), 7.23 (m, 5H, aryl). – ¹³C NMR

(75.5 MHz, CDCl₃): δ = 26.36 (tBuCH₃), 27.03, 27.14,

27.21 (PivCH₃), 35.79 (tBuC_t), 38.70, 38.73, 38.89, 39.06

(PivC_t), 43.57 (CHphenyl), 47.57 (COCH), 60.61 (C-6),

66.23, 66.59, 71.62, 72.95 (C-5, C-4, C-3, C-2), 78.42

(CHOH), 78.61 (C-1), 113.87 (NCH=CH), 122.97 (NCH),

127.33 (para-aryl), 128.65, 128.76 (ortho-aryl, meta-aryl),

141.89 (ipso-aryl), 170.66 (NC=O), 176.49, 177.07, 177.18,

177.74 (PivC=O).

The reaction was carried out starting from 4-benzyl-

5,6-dehydropiperidin-2-one [8] (7g) (0.22 g, 0.328 mmol),

treated with 0.49 mL (0.49 mmol, 1.5 equiv.) of LiHMDS

solution, and using 0.148 mL (1.64 mmol, 5 equiv.) of

freshly distilled isobutyraldehyde pre-activated by stirring

with 0.210 mL (1.64 mmol, 5 equiv.) BF₃· OEt₂for 5 min.

Yield: 182 mg (73 %), colorless oil, R_f= 0.54 (cyclohexane-

ethyl acetate 3 : 1). Diastereomeric ratio: 98 : 2 (analytical

HPLC). Analytical HPLC: Luna C18, gradient: acetonitrile-

water 80 : 20 to 100 : 0 within 40 min, R_t(min): 32.72

(minor diastereomer), 33.08 (major diastereomer), [α]_D²⁵

:

23.41 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z = 780.46

[M+Na]⁺. – ¹H NMR (300 MHz, CDCl₃): δ = 0.60, 0.83

(2d, 6H, J = 6.6 Hz, CH(CH₃)₂), 1.08, 1.09, 1.13, 1.25

(4s, 36H, PivCH₃), 1.79 (m, 1H, CH(CH₃)₂), 1.95 (d, 1H,

J = 6.9 Hz, CHOH), 2.43 – 2.63 (m, 4H, CH₂Ph, CHben-

zyl, COCH), 3.39 (dd, 1H, J = 6.9 Hz, J = 11.7 Hz,

CHOH), 3.92 – 4.14 (m, 3H, H-5, H-6a, H-6b), 5.19 (m,

1H, J = 2.9 Hz, J = 7.7 Hz, NCH=CH), 5.23 (dd, 1H,

(4R)-4-Benzyl-3-(1-hydroxy-allyl)-3,4-dihydro-1-(2,3,4,6-

tetra-O-pivaloyl-β-D-galactopyranosyl)pyridine-2(1H)-one

(20f)

J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3), 5.37 (t, 1H, J_2,1

=

9.6 Hz, J_2,3= 9.9 Hz, H-2) 5.44 (d, 1H, J_4,3= 2.9 Hz,

H-4), 5.91 (d, 1H J_1,2= 9.6 Hz, H-1), 6.22 (d, 1H, J =

8.0 Hz, NCH), 7.18 (m, 5H, aryl). – ¹³C NMR (75.5 MHz,

CDCl₃): δ = 14.93, 19.87 (CH(CH₃)₂), 26.97, 27.03, 27.08,

27.23 (PivCH₃), 30.67 (CH(CH₃)₂), 35.75 (CHbenzyl),

38.68, 38.74, 38.82, 39.04 (PivC_t), 39.76 (CH₂Ph), 49.80

(COCH), 60.89 (C-6), 65.37, 66.72, 71.78, 72.88 (C-5, C-4,

C-3, C-2), 74.21 (CHOH), 78.66 (C-1), 110.48 (NCH=CH),

122.91 (NCH), 126.49 (para-aryl), 128.50, 129.28 (ortho-

aryl, meta-aryl), 138.33 (ipso-aryl), 170.81 (NC=O), 176.55,

177.09, 177.25, 177.77 (PivC=O). – C₄₂H₆₃NO₁₁(757.44):

calcd. C 66.55, H 8.38, N 1.85; found C 66.52, H 8.39,

N 1.70.

The reaction was carried out starting from 4-benzyl-

5,6-dehydropiperidin-2-one [8] (7g) (0.2 g, 0.291 mmol),

0.44 mL (0.44 mmol, 1.5 equiv.) of LiHMDS solution,

and using 20 µL (1.45 mmol, 5 equiv.) freshly dis-

tilled acrolein. Yield: 166 mg (78 %), colorless oil, R_f=

0.35 (cyclohexane-ethyl acetate 3 : 1). Diastereomeric ra-

tio: 87 : 9 : 4 : 0 (¹H NMR and analytical HPLC). Analyt-

ical HPLC: Luna C18, gradient: acetonitrile-water 80 : 20

to 100 : 0 within 40 min, R_t(min): 23.77 (minor diastereo-

mer), 24.67 (major diastereomer), 26.18 (minor diastereo-

mer), [α]²_D⁵: 38.57 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z =

764.49 [M+Na]⁺. – HRMS ((+)-ESI): m/z = 764.3981

[M+Na]⁺(calcd.: 764.3986). – ¹H NMR (300 MHz,

CDCl₃): δ = 1.08, 1.13, 1.24 (3s, 36H, PivCH₃), 2.40,

2.57, 2.63 (3m, 5H, CH₂Ph, CHbenzyl, CHOH, COCH),

3.91 – 4.17 (m, 4H, CHOH, H-5, H-6a, H-6b), 5.17 (m,

(4R)-3-(1-Hydroxy-2,2-dimethyl-propyl)-3,4-dihydro-4-

phenyl-1-(2,3,4,6-tetra-O-pivaloyl-β-D-galactopyranosyl)-

pyridine-2(1H)-one (20e)

The reaction was carried out starting from 4-phenyl- 4H, J_3,4= 2.9 Hz, H-3, CH=CH₂, NCH=CH), 5.36 (t, 1H,

5,6-dehydropiperidin-2-one [8] (7f) (0.215 g, 0.319 mmol), J_2,1= J_2,3= 9.6 Hz, H-2) 5.66 (m, 1H, CH=CH₂), 5.89

0.479 mL (0.479 mmol, 1.5 equiv.) of LiHMDS solution, (d, 1H J_1,2= 9.6 Hz, H-1), 6.21 (d, 1H, J = 8.1 Hz,

and using 0.17 mL (1.6 mmol, 5 equiv.) of freshly dis- NCH), 7.07, 7.21 (2m, 5H, aryl). – ¹³C NMR (75.5 MHz,

tilled pivalaldehyde pre-activated by stirring with 0.204 mL CDCl₃): δ = 26.78, 27.05, 27.21 (PivCH₃), 35.19 (CHben-

(1.6 mmol, 5 equiv.) BF₃· OEt₂for 30 min. Yield: 90 mg zyl), 38.68, 38.73, 38.82, 39.04 (PivC_t), 39.67 (CH₂Ph),

(36 %), colorless oil, R_f= 0.64 (cyclohexane-ethyl acetate 52.09 (COCH), 60.86 (C-6), 65.45, 66.68, 71.78 (C-5, C-4,

3 : 1). Diastereomeric ratio: 90 : 6 : 3 : 0 (analytical HPLC). C-3), 71.92 (CHOH), 72.86 (C-2), 78.79 (C-1), 110.53

Analytical HPLC: Luna C18, gradient: acetonitrile-water (NCH=CH), 117.64 (CH=CH₂), 122.67 (NCH), 126.45

80 : 20 to 100 : 0 within 40 min, R_t(min): 30.03 (minor di- (para-aryl), 128.44, 129.22 (ortho-aryl, meta-aryl), 138.16

astereomer), 34.27 (minor diastereomer), 36.267 (major di- (ipso-aryl), 138.56 (CH=CH₂), 170.00 (NC=O), 176.53,

astereome), [α]_D²⁵: 68.46 (c = 1.0, CHCl₃). – MS ((+)-ESI): 177.09, 177.25, 177.77 (PivC=O).

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404

E. Klegraf – H. Kunz et al. · 3-Substituted and 3,4-Disubstituted Piperidine und Piperidin-2-one Derivatives

(4S)-4-(3-Butenyl)-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto- 1N HCl. The aqueous layer was extracted twice with ethyl

pyranosyl)piperidin-2-one (21)

acetate (2 × 10 mL). The combined organic solutions were

washed with sat. NaHCO₃solution, and the aqueous layer

again extracted with ethyl acetate. The combined organic so-

lutions were dried with MgSO₄, and the solvent was evap-

orated in vacuo to give the crude diol 22. Yield: 310 mg

(52 %), colorless oil. – MS ((+)-ESI): m/z = 685.4 [M]⁺.

This product 22 (0.310 g, 0.452 mmol) was directly

subjected to glycol cleavage: It was dissolved in dry

dichloromethane (20 mL). Na₂CO₃(96 mg, 0.904 mmol, 2

equiv.) was added, and the mixture was cooled to 0 ^◦C. Un-

der argon atmosphere lead tetraacetate (242 mg, 0.542 mmol,

1.2 equiv.) was added. The lemon-yellow solution was stirred

for 90 min. Addition of water (50 mL) terminated the

reaction. After ﬁltration and separation, the residue was

washed with dichloromethane, and the aqueous layer was

extracted with dichloromethane (3 × 30 mL). The com-

bined organic solutions were dried with MgSO₄, and the

solvent was evaporated in vacuo. Puriﬁcation was car-

ried out by ﬂash chromatography. Yield: 144 mg (49 %)

23, colorless amorphous solid, R_f= 0.52 (cyclohexane-

ethyl acetate 1 : 1), [α]²_D⁵: 8.92 (c = 1.0, CHCl₃). – MS

((+)-ESI): m/z = 676.37 [M+Na]⁺. – HRMS ((+)-ESI):

m/z = 676.3693 [M+Na]⁺(calcd.: 676.3673). – ¹H NMR

(300 MHz, CDCl₃): δ = 1.08, 1.09, 1.14, 1.23 (4s, 36H,

PivCH₃), 1.67 (m, 4H, NCH₂CH₂, CH₂CH₂CHO), 1.95 (m,

2H, CH₂CHO) 2.46 (m, 3H, COCH₂, CHR), 3.27, 3.54

(2m, 2H, NCH₂), 3.90 – 4.19 (m, 3H, H-5, H-6a, H-6b),

5.20 (dd, 1H, J_3,4= 2.9 Hz, J_2,3= 9.9 Hz, H-3), 5.35 (t,

To a solution of (4R)-(3-butenyl)-5,6-dehydropiperidin-

2-one [8] (7h) (0.382 g, 0.58 mmol) in 20 mL of dioxane

2 mL of conc. HCl was added. The mixture was stirred at r. t.

for 1 h. Then, NaCNBH₃was cautiously added (fume hood!)

until evolution of gas did no longer occur. The mixture was

stirred for 12 h. It is then adjusted to weakly basic conditions

by addition of diluted NaOH solution. After addition of di-

ethyl ether (100 mL) the solution was washed with sat. NaCl

solution. After separation, the aqueous layer was extracted

once more with diethyl ether (100 mL). The combined or-

ganic solutions were dried with MgSO₄, and the solvent

was evaporated to dryness. The puriﬁcation of the remain-

ing residue was achieved by ﬂash chromatography. Yield:

0.377 g (quant.), colorless amorphous solid, R_f= 0.26 (cyclo-

hexane-ethyl acetate 4 : 1), [α]²_D⁷: 9.64 (c = 1.0; CHCl₃). –

MS ((+)-ESI): m/z = 674.38 [M+Na]⁺. – HRMS ((+)-ESI):

m/z = 674.3854 [M+Na]⁺(calcd.: 674.3880). – ¹H NMR

(300 MHz, CDCl₃): δ = 1.08, 1.14, 1.23 (3s, 36H, PivCH₃),

1.37 (m, 2H, CH₂CH₂CH=CH₂), 1.61 (m, 1H, CHR), 1.81 –

2.10 (m, 5H, NCH₂CH₂, COCH^a₂, CH₂CH=CH₂), 2.46 (dd,

1H, ³J= 3.3 Hz, ²J= 18.1 Hz, COCH^b₂), 3.24, 3.52 (2m, 2H,

NCH₂), 3.89 – 4.11 (m, 3H, H-5, H-6a, H-6b), 4.95 (m, 2H,

CH=CH₂), 5.20 (dd, 1H, J_3,4= 2.9 Hz, J_3,2= 9.9 Hz, H-3),

5.42 (m, 2H, J_2,3= 9.9 Hz, J_4,3= 2.9 Hz, H-2, H-4), 5.73 (m,

1H, CH=CH₂), 5.98 (d, 1H, J_1,2= 9.2 Hz, H-1). – ¹³C NMR

(75.5 MHz, CDCl₃): δ = 26.96, 27.03, 27.18 (PivCH₃),

28.69, 30.60 (CH₂CH₂CH=CH₂, NCH₂CH₂), 31.50 (CHR),

34.69 (CH₂CH=CH₂), 38.68, 38.71, 38.77, 38.98 (PivC_t),

39.03 (COCH₂), 40.05 (NCH₂), 60.75 (C-6), 65.24, 66.84,

71.63, 72.70, (C-5, C-4, C-3, C-2), 79.33 (C-1), 115.07

(CH=CH₂), 137.91 (CH=CH₂), 170.33 (NC=O), 176.47,

176.97, 177.37, 177.79 (PivC=O).

1H, J_2,1= 9.6 Hz, J_2,3= 9.9 Hz, H-2), 5.42 (d, 1H, J_4,3

=

2.9 Hz, H-4), 5.97 (d, 1H J_1,2= 9.6 Hz, H-1), 9.76 (s, 1H,

CHO). – ¹³C NMR (75.5 MHz, CDCl₃): δ = 26.96, 27.03,

27.18 (PivCH₃), 27.54 (NCH₂CH₂), 28.52 (CH₂CH₂CHO),

31.78 (CHR), 38.58 (COCH₂), 38.67, 38.71, 39.03 (PivC_t),

39.93 (CH₂CHO), 40.89 (NCH₂), 60.75 (C-6), 65.27, 66.80,

71.56, 72.71 (C-5, C-4, C-3, C-2), 79.33 (C-1), 169.72

(NC=O), 176.46, 176.97, 177.43, 177.79 (PivC=O), 201.10

(CHO).

(4S)-4-(3-Oxo-propyl)-1-(2,3,4,6-tetra-O-pivaloyl-β-D-

galactopyranosyl)piperidin-2-one (23)

To a solution of N-methylmorpholine-1-oxide (NMO,

128 mg (0.95 mmol), 1.1 equiv.) in water (5.7 mL), ace-

tone (3.7 mL), tert-butanol (3.7 mL) and THF (3.7 mL)

catalytic amouts of potassium osmate(VI)-dihydrate (about

(6S)-9-Hydroxy-N-(2,3,4,6-tetra-O-pivaloyl-β-D-galacto-

pyranosyl)-3-aza-bicyclo[4.3.0]nonan-2-one (24)

To potassium hexamethyldisilazane [KHMDS, 23 mg

1 mol-%) were added. A solution of (4S)−4-(3-butenyl)-N- (0.115 mmol, 1.5 equiv.)] in 2 mL of dry THF at

(2,3,4,6-tetra-O-pivaloyl-β -D-galactopyranosyl)-piperidin- −78 ^◦C a solution of (4S)-4-(3-oxo-propyl)-N-(2,3,4,6-

2-one (21) (0.562 mg, 0.863 mmol) in 3 mL of acetone was tetra-O-pivaloyl-β-D-galactopyranosyl)piperidin-2-one (23)

added dropwise. All solvents had been carefully degassed (50 mg, 0.0765 mmol) in 2 mL of dry THF was added drop-

under ultrasound. The mixture was stirred at r. t. until mon- wise. The solution was stirred for 12 h while warming to

itoring by TLC indicated complete conversion (about 2 d). r. t.. After addition of 5 mL sat. aqueous NH₄Cl, the solution

Subsequently, 5 g of talkum (magnesium silicate hydrate) was extracted with diethyl ether (3 ×20 mL). The combined

and 20 mL of a 10 % solution of sodium dithionite in wa- organic solutions were dried with MgSO₄, and the solvents

ter were added, and the mixture was stirred for 15 min and were evaporated to dryness. Puriﬁcation of the crude prod-

ﬁltered. The residue was thouroughly washed with ethyl ac- uct was carried out by ﬂash chromatography. Yield: 18 mg

etate. The combined ﬁltrates were extracted with 10 mL of (36 %) 24, pale-yellow amorphous solid, R_f= 0.05 (cyclo-

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405

hexane-ethyl acetate 3 : 1). Diastereomeric ratio: 78 : 22 : 0 : 0 4H, H-5, H-6a, H-6b, CHOH), 5.20 (dd, 1H, J_3,4= 2.9 Hz,

(analytical HPLC). Analytcal HPLC: Luna C18, gradient: J_3,2= 9.9 Hz, H-3), 5.35 (t, 1H, J_2,1= 9.6 Hz, J_2,3= 9.9 Hz,

acetonitrile-water 80 : 20 to 100 : 0 within 40 min, R_t(min): H-2), 5.41 (d, 1H, J_4,3= 2.9 Hz, H-4), 5.97 (d, 1H, J_1,2

=

13.78 (minor diastereomer), 14.30 (major diastereomer), 9.6 Hz, H-1). – ¹³C NMR (75.5 MHz, CDCl₃): δ = 26.99,

[α]²_D⁵: 3.02 (c = 1.0, CHCl₃). – MS ((+)-ESI): m/z = 676.42 27.03, 27.18 (PivCH₃), 28.49 (NCH₂CH₂), 29.65, 30.28

[M+Na]⁺. – HRMS ((+)-ESI): m/z = 676.3699 [M+Na]⁺(CH₂CH₂CHOH), 32.11 (CHR), 38.71 (COCH), 38.80,

(calcd.: 676.3673). – ¹H NMR (300 MHz, CDCl₃): δ = 38.86, 39.04 (PivC_t), 40.05 (NCH₂), 60.72 (C-6), 65.30,

1.08, 1.13 1.23 (3s, 36H, PivCH₃), 1.32, 1.63 (2m, 4H, 66.78, 71.56, 72.70 (C-5, C-4, C-3, C-2), 79.32 (C-1), 82.82

CHOHCH₂CH₂), 1.95 (m, 2H, NCH₂CH₂), 2.47 (m, 2H, (CHOH), 170.03 (NC=O), 176.46, 176.97, 177.46, 177.80

COCH, CHR), 3.28, 3.54 (2m, 2H, NCH₂), 3.90 – 4.19 (m, (PivC=O).

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Stereoselective synthesis of 3-substituted and 3,4-disubstituted piperidine und piperidin-2-one derivatives

DOI: 10.1515/znb-2012-0413

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