Stereoselective synthesis of chiral piperidine derivatives employing arabinopyranosylamine as the carbohydrate auxiliary

625

Stereoselective synthesis of chiral piperidine

derivatives employing arabinopyranosylamine as

the carbohydrate auxiliary¹

Birgit Kranke and Horst Kunz

Abstract: Stereoselective synthesis of 2-substituted dehydropiperidinones and their further transformation to variously

disubstituted piperidine derivatives was achieved employing ^D-arabinopyranosylamine as the stereodifferentiating carbo-

hydrate auxiliary. A domino Mannich–Michael reaction of 1-methoxy-3-(trimethylsiloxy)butadiene (Danishefsky’s

diene) with O-pivaloylated arbinosylaldimines furnished N-arabinosyl dehydropiperidinones in high diastereoselectivity.

Subsequent conjugate cuprate addition gave 2,6-cis-substituted piperidinones, while enolate alkylation furnished 2,3-

trans-substituted dehydropiperidinones. Electrophilic substitution at the enamine structure afforded 5-nitro- and 5-

halogen dehydropiperidinones of which the latter were applied in palladium-catalyzed coupling reactions. The absolute

configuration of the obtained products was proven by NMR and X-ray structure analysis as well as by syntheses of the

alkaloids (+)-coniine and (+)-dihydropinidine.

Key words: piperidine alkaloids, carbohydrate auxiliary, domino Mannich–Michael reaction, conjugate cuprate and hy-

dride addition, electrophilic substitution of enamines.

Résumé : On a réalisé la synthèse stéréosélective de déhydropipéridones substituées en position 2 et leur transforma-

tion subséquente en divers dérivés disubstitués de la pipéridine en utilisant de la ^D-arabinopyranosylamine comme hy-

drate de carbone auxiliaire permettant de faire une stéréodifférenciation. Une réaction de Mannich–Michael en domino

du 1-méthoxy-3-(triméthylsiloxy)butadiène (réactif de Danishefsky) avec de O-pivaloyl-arbinosylaldimines conduit à la

formation de N-arabinosyl déhydropipéridinones avec une grande diastéréosélectivité. Une addition subséquente

conjuguée de cuprate fournit les pipéridinones 2,6-cis-substituées alors qu’une alkylation de l’énolate conduit déhydro-

pipéridinones aux 2,3-trans-substituées. Une substitution électrophile de la structure énamine conduit aux 5-nitro- et 5-

halogéno-déhydropipéridinones; ces dernières ont par la suite été utilisées dans des réactions de couplage catalysées par

le palladiium. La configuration absolue des produits obtenus a été démontrée par RMN et par diffraction des rayons X

ainsi que par synthèse des alcaloïdes (+)-coniine et (+)-dihydropinidine.

Mots clés : alcaloïde de la pipéridine, hydrate de carbone auxiliaire, réaction de Mannich–Michael en domino, addition

conjuguée de cuprate et d’hydrure, substitution électrophile d’énamines.

[Traduit par la Rédaction] Kranke and Kunz 641

Introduction

glycosylamines as chiral auxiliaries (3, 4). In this approach,

steric, stereoelectronic, and complexing effects of carbohy-

drates are exploited for diastereofacial differentiation of

nucleophilic additions to N-glycosyl aldimines. It is a spe-

cial feature that this methodology offers the possibility of

synthesizing both enantiomeric series of chiral piperidines

by varying the carbohydrate auxiliary, e.g., employing the

(pseudo-)enantiomeric carbohydrates, ^D-galactosylamine (3)

and ^D-arabinosylamine (4), respectively. Herein, we report

full experimental details for the application of ^D-arabino-

sylamine 1 in the stereoselective synthesis of 2-substituted

N-arabinosyl dehydropiperidinones 4 and their subsequent

regioselective and stereoselective modification in the prepa-

ration of variously substituted piperidines.

Due to their great diversity in biological and pharmaco-

logical activities (1), piperidine alkaloids and synthetic

piperidines containing various substitution patterns are con-

sidered interesting target structures for drug development.

Therefore, these heterocyclic structures are the subject of

numerous synthetic, often stereoselective approaches (2).

During the past years, we have developed a strategy for

the enantioselective synthesis of piperidine alkaloids using

Received 7 September 2005. Published on the NRC Research

Press Web site at http://canjchem.nrc.ca on 12 May 2006.

Dedicated to Professor Walter Szarek on the occasion of his

65th birthday.

B. Kranke and H. Kunz.²Institut für Organische Chemie,

Johannes Gutenberg Universität Mainz, Duesbergweg 10-14,

55128 Mainz, Germany.

Results and discussion

Formation of N-arabinosyl dehydropiperidinones

¹This article is part of a Special Issue dedicated to Professor

Walter A. Szarek.

Condensation of 2,3,4-tri-O-pivaloyl-α-^D-arabinopyrano-

sylamine (1) (5) with aliphatic aldehydes in the presence of

molecular sieves or with aromatic aldehydes under acidic ca-

²Corresponding author (e-mail: hokunz@uni-mainz.de).

Can. J. Chem. 84: 625–641 (2006)

doi:10.1139/V06-060

626

Can. J. Chem. Vol. 84, 2006

Scheme 1. Stereoselectve synthesis of 2-substituted N-arabinosyl

dehydropiperidinones.

Table 1. Diastereoselective synthesis of 2-substituted N-

arabinosyl dehydropiperidinones according to Scheme 1.

PivO

OPiv

PivO

OPiv

Product

R

Yield (%)

d.r.

97:3^b

RCHO

OPiv

4a

4b

4c

p-ClC₆H₄

p-NO₂C₆H₄

C₆H₄

96^a

74^a

84^a

49^d

67^d

81^d

72^d

65^d

O

NH₂

N

R

86:14,^c96:4^b

92:8^c

1

2

H

4d

4e

4f

4g

4h

Methyl

Ethyl

Propyl

Isopropyl

(CH₂)₃OTBDPS

93:7^b

96:4^c

87:13^c

1)

H₃CO

OSi(CH₃)₃

95:5,^c99:1^b

90:10,^c96:4^b

3

PivO

OPiv

O

^aBased on imine.

OPiv

^bDetermined by HPLC after flash chromatography.

^cDetermined by HPLC of the crude product.

^dBased on amine.

ZnCl₂, THF, -20 °C

2) 1 HCl

O

N

4

R

talysis furnished N-arabinopyranosylimines 2. These aldimines

reacted with 1-methoxy-3-(trimethylsiloxy)butadiene

(Danishefsky’s diene, 3) in a domino Mannich–Michael

reaction promoted by zinc chloride to give N-(2,3,4-tri-O-

pivaloyl-α-^D-arabinopyranosyl)-5,6-didehydropiperidin-4-ones

(4) in high yields and high diastereoselectivity (Scheme 1,

Table 1).

Scheme 2. A pair of (pseudo)-enantiomeric auxiliaries lead to

enantiomeric piperidine derivatives.

si side

re side

OPiv

PivO

OPiv

O

N

O O

R

N

R

O

5

H

2

The stereochemical course of the reaction and hence the

configuration of the nitrogen heterocycle in 4 was controlled

by the sterically demanding pivaloyl group at C-2 of the car-

bohydrate auxiliary, which effectively shields the si side of

aldimine 2. Thus, the initial step in the domino Mannich–

Michael reaction consists of the nucleophilic addition of

Danishefsky’s diene 3 at the re side of glycosyl imine 2.

In contrast, in galactosyl imines 5 reported earlier (3) the

re side is efficiently blocked by the C-2 pivaloyl group, lead-

ing to N-galactosyl dehydropiperidinones 6 bearing the op-

posite configuration at position 2 of the nitrogen heterocycle

(Scheme 2). This is due to the fact that although arabino-

sylamine belongs to the ^Dseries of carbohydrates, it displays

almost the mirror image of ^D-galactosylamine. Thus, by us-

ing either ^D-galactosylamine or its pseudoenantiomer, D-

arabinosylamine, enantiomeric dehydropiperidinones are

accessible offering the possibility of synthesizing both enan-

tiomers of piperidines by choosing the appropriate auxiliary.

The absolute configuration of the N-arabinosyl dehydro-

piperidinones was proven by X-ray analysis showing 4f to

have (S)-configuration (Fig. 1). This compound preferably

adopts a conformation in which the planes of the nitrogen

heterocycle and the carbohydrate are almost perpendicular to

each other allowing optimal overlap of the nonbonding or-

bital of the nitrogen and the σ* orbital of the C—O bond

within the carbohydrate ring (exo-anomeric effect).

3

OPiv

O

PivO

O

PivO

O

OPiv

O

N

*

OPiv

R

6

4

Fig. 1. X-ray structure of N-arabinosyl dehydropiperidinone 4f.

Conversion of N-arabinosyl dehydropiperidinone 4f into

the well-known alkaloid (S)-coniine 10 gave rise to further

evidence of the absolute configuration of the nitrogen

heterocycle in 4f, and in addition, demonstrated the applica-

bility of the shown reaction strategy for the stereoselective

preparation of chiral 2-substituted piperidine alkaloids.

Coniine is a highly toxic alkaloid leading to central respira-

tory paralysis and was the first alkaloid synthesized chemi-

cally (Ladenburg, 1886). In our auxiliary-mediated

synthesis, the double bond of N-arabinosyl-2-propyl-5,6-

dehydropiperidin-4-one (4f) was reduced with lithium tri-

sec-butylborohydride (^L-Selectride^®) and the intermediate

enolate was subsequently trapped as triflate 7. Hydrogena-

tion of the enol triflate afforded 2-propylpiperidine 8. The

enantiomerically pure alkaloid was released from the auxil-

iary by mild acidolysis using dilute HCl in methanol

(Scheme 3). The optical rotation value of the formed coniine

hydrochloride 10 was in agreement with literature data.

Kranke and Kunz

627

Scheme 3. Synthesis of enantiomerically pure (+)-(6R)-coniine hydrochloride.

L-Selectride

PivO

OPiv

PivO

OPiv

Pd/C, H₂

O

THF, -78 °C

OTf

OPiv

60 %

O

N

Cl

Li₂CO₃, MeOH

N

N(Tf)₂

4f

7

PivO

OPiv

Cl

OPiv

OH

1

N

HCl

+

O

N

O

N

H

MeOH

8

96%

9

10·HCl 95%

Scheme 4. Diastereoselective synthesis of 2,6-cis-substituted N-

arabinosyl piperidinones.

Derivatization of N-arabinosyl dehydropiperidinones

N-Arabinosyl dehydropiperidinones 4 represent versatile

precursors for the synthesis of variously substituted nitrogen

heterocycles, e.g., the regioselective and stereoselective pre-

paration of 2,6-, 2,5-, and 2,3-disubstituted piperidines.

PivO

R'

O

OPiv

R'CuBF₃

OPiv

4

O

N

THF, -78 °C

R

11

2,6-cis-Disubstituted piperidines

N-Arabinosyl dehydropiperidinones 4 are α,β-unsaturated

carbonyl compounds. Their reactivity as Michael acceptors

is reduced because of the vinylogous amide structure. How-

ever, cuprate addition was accomplished by activation with

hard electrophiles. For example, reaction of Yamamoto

cuprates (6) activated by boron trifluoride diethyletherate

(RCu·BF₃) or of Gilman cuprates (8) (R₂CuLi) in combina-

tion with chlorotrimethylsilane (7) resulted in the formation

of 2,6-cis-disubstituted piperidinones 11 with high

diastereoselectivity (Scheme 4, Table 2).

or

TBAF

r.t.

PivO

OPiv

R'

OPiv

OTMS

R'₂CuLi, TMSCl

THF, -78 °C

O

N

R

12

The cis configuration was confirmed by X-ray analysis of

11a (Fig. 2). The nitrogen heterocycle adopts a twisted con-

formation with the smaller substituent in axial position, the

larger substituent in equatorial position, and a pyramidally

configured nitrogen atom. The alignment of the two

heterocycles is stabilized by the exo-anomeric effect (com-

pare, Fig. 1).

The observed cis stereoselectivity of the 1,4-addition can

be explained by stereoelectronic effects using the X-ray

structure of 4f. Two rotamers A and B, stabilized by the exo-

anomeric effect, are expected for N-arabinosyl dehydro-

piperidinones 4 (Scheme 5). Compared with rotamer A,

rotamer B benefits from a smaller steric hindrance between

the substituent in position 2 of the nitrogen heterocycle and

the pivaloyl group at C-2 of the carbohydrate. Thus, the

backside of the nitrogen heterocycle is shielded by this

pivaloyl group, and the front-side attack of the cuprate re-

sults in the favoured cis-substitution pattern.

Table 2. Diastereoselective synthesis of 2,6-disubstituted N-

arabinosyl piperidinones according to Scheme 4.

Product

R

R′

Yield (%)

d.r.

11a^a

11b^a

11c^a

pCl-C₆H₅

n-Propyl

C₆H₅

Allyl

C₆H₅

72

51

44

99:1^b

98:2^b

99:1^b

11d^a

n-Propyl

Allyl

CH₃

75

88

94:6^c, 98:2^b

11e^d

91:9^c

^aSynthesized using Yamamoto cuprate.

^bDetermined by HPLC after chromatography.

^cDetermined by HPLC of the crude product.

^dSynthesized using Gilman cuprate.

Scheme 5. Favored conformation of 2-substituted N-arabinosyl

dehydropiperidinones according to Fig. 1.

R

O

PivO

OPiv

Enantiomerically pure (+)-dihydropinidine was synthe-

sized to demonstrate the applicability of N-arabinosyl

dehydropiperidinones 4 in the stereoselective synthesis of

cis-2,6-disubstituted piperidine alkaloids. For this purpose,

piperidinone derivative 11e was converted into dithiolane 13

and subsequently treated with Raney nickel to form N-

arabinosyl piperidine 14. The enantiomerically pure alkaloid

O

PivO

OPiv

Rotation

N

O

N

O

R

B

A

628

Can. J. Chem. Vol. 84, 2006

Scheme 6. Synthesis of enantiomerically pure (+)-(2S,6R)-dihydropinidine hydrochloride.

HSCH₂CH₂SH

S

PivO

OPiv

PivO

OPiv

O

BF₃·OEt₂

CH₂Cl₂

S

OPiv

O

N

11e

13 81%

PivO

OPiv

Cl

1

N

HCl

OPiv

Raney nickel, H₂

O

N

MeOH

H

Isopropanol, 70 °C

14 73%

15·HCl quant.

Scheme 7. Electrophilic substitution at the enamine structure of dehydropiperidinones.

H E

E

R

PivO

O

PivO

OPiv

O

PivO

E⁺

-H⁺

OPiv

O

OPiv

O

OPiv

N

O

N

O

N

R

4

16

Fig. 2. X-ray structure of N-arabinosyl piperidinone 11a.

Sulfolane can easily be separated from products 17 and 18,

respectively, by washing with water.

Reduction of the nitro group furnished an aminoketone,

whose functionality is known to serve as precursor for syn-

theses of pharmacological important patterns like hetero-

cycles, carbamates, or amides. Successful hydrogenation

was achieved with Raney nickel, whereas reduction condi-

tions such as zinc in hydrochloric acid or hydrogen and pal-

ladium on charcoal could not be applied. Immediate reaction

of the sensitive amine with benzoyl chloride and triethyl-

amine in ethanol gave the N-acyl compound 19 (Scheme 8).

N-Arabinosyl dehydropiperidinones that bear no substitu-

ent at C-5 of the nitrogen heterocycle, such as 4, can be

completely transformed into the corresponding piperidinones

using ^L-Selectride^®. This hydride reagent selectively reduces

the double bond of the α,β-unsaturated carbonyl function in

terms of a 1,4-addition without affecting the keto function in

terms of a 1,2-addition. Using these reaction conditions for

the hydrogenation of dehydropiperidinone 19, a conversion

of only 50% of the starting material was observed. Addition

of further equivalents of ^L-Selectride^®did not improve the

conversion, but reduced already formed piperidin-4-one 20

to the 4-hydroxypiperidine. In contrast, complete chemo-

selective addition of the hydride was achieved applying an

excess ^L-Selectride^®in the presence of the sterically de-

manding Lewis acid methylaluminum bis(2,6-di-tert-butyl-

4-methylphenoxide) (MAD). This reagent has been shown to

induce 1,4-addition of organolithiums to α,β-unsaturated ke-

tones (10) and to enable the chemoselective reduction of the

double bond of polymer-bound galactosyl dehydropi-

peridinones (11). The oxygenophilic Lewis acid effectively

shields the keto function and, thus, favours the selective hy-

hydrochloride 15 was released from the carbohydrate by

mild acidolysis with dilute HCl in methanol (Scheme 6).

The optical rotation value was in agreement with literature

data (9) and confirmed the absolute configuration.

2,5-Disubstituted piperidines

Due to their enamine structure, N-arabinosyl dehydro-

piperidinones 4 are capable of adding electrophiles. Regen-

eration of the stable conjugated enaminone π system by

abstraction of

a proton subsequently leads to 2,5-

disubstituted dehydropiperidinones 16 (Scheme 7).

In terms of this electrophilic substitution, nitration of 4d

and 4e was achieved in high yields using nitronium tetra-

fluoroborate applied as a solution in sulfolane allowing con-

venient handling of this air sensitive reagent (Scheme 8).

Kranke and Kunz

629

Scheme 8. Nitration of N-arabinosyl dehydropiperidinones and subsequent reduction of the obtained products.

O

NO₂

HN

Ph

O

PivO

O

OPiv

1.

Raney nickel, H₂

Ethanol

PivO

OPiv

NO₂BF₄

CH₂Cl₂

O

N

OPiv

O

4d, 4e

18

N

R

2. PhCOCl

NEt₃, THF

19

17 R = CH₃

83%

70% over two steps

18 R = CH₂CH₃82%

O

®

L-Selectride

HN

Ph

O

PivO

OPiv

THF, -78 °C

40 °C

OPiv

19

O

N

O

20 88%

d.r. = 89:11

Al

CH₃

dride addition at the β-position even by application of an ex-

cess of ^L-Selectride^®for complete conversion of the starting

material (Scheme 8).

2,3-trans-Disubstituted N-arabinosyl dehydropiperidinones

Functionalization of N-arabinosyl dehydropiperidinones 4

at C-3 was achieved by deprotonation with strong bases and

subsequent reaction with electrophiles. For this purpose, 4

was treated with lithium bis(trimethylsilyl)amide (LiHMDS),

and the intermediate enolate was reacted with alkylhalides to

afford 2,3-trans-disubstituted N-arabinosyl dehydropiperi-

dinones 24 in high yields (Scheme 10, Table 4).

N-Bromo succinimide and N-iodo succinimide were used

in electrophilic substitution reactions at the enamine struc-

ture of N-arabinosyl dehydropiperidinones 4 to furnish halo-

genated compounds 21 in high yields (Scheme 9, Table 3).

Halogenated dehydropiperidinones 21 constitute vinyl

halides capable of reacting in metal-catalyzed coupling reac-

tions. In this way, piperidine derivatives with functionalized

aryl substituents at C-5 were accessible. It turned out that

iododehydropiperidinones 21 were more suitable in

palladium-catalyzed syntheses than the bromo-substituted

derivatives. Thus, in Stille reactions (12) applying bromo-

dehydropiperidinone 21g and phenyltributyl tin, 68% con-

version of the starting material was observed after 24 h,

while iododehydropiperidinone 21a reacted faster and was

completely consumed under these conditions, although prod-

uct 22 was isolated in only moderate yield (Scheme 9).

Since boronic acids benefit from a much lower toxicity

and an insensitivity to water compared with the tin reagents

used in Stille-type reactions, Suzuki–Miyaura coupling con-

ditions (13) were also applied for the synthesis of 5-aryl

piperidine derivatives. Reaction of dehydropiperidinone 21c

with p-methoxybenzene boronic acid under palladium catal-

ysis resulted in the formation of 23. The reaction conditions

have not yet been optimized (Scheme 9).

The coupling constant of product 24a (J_H-2,H-3= 11.7 Hz)

1

determined by H NMR spectroscopy indicated that these

two protons are positioned in an antiperiplanar alignment,

while the methyl group, as well as the aryl substituent, are

arranged trans to each other and in an equatorial position.

The stereoselectivity of the reaction can be explained by as-

suming that deprotonation of 4 forms a 6π-electron system

resulting in an additional flattening of the dehydropiperi-

dinone. The axial position of the substituent at C-2 induces a

diastereofacial differentiation of the enolate favouring an at-

tack of the electrophile from the sterically less-hindered

side, i.e., trans to the first substituent resulting in the forma-

tion of the 2,3-trans-disubstituted compounds 24.

Conclusions

The described results show that chiral piperidine deriva-

tives of varying substitution patterns, valuable as building

blocks for the construction of drugs and natural products,

can stereoselectively be synthesized using α-^D-arabinopy-

ranosylamine (1) as the chiral auxiliary. Imines 2 of 1 un-

dergo domino Mannich–Michael reaction sequences to

furnish 2-substituted 5,6-dihydropiperidinones 4 with excel-

lent diastereoselectivity. These compounds are substrates to

a versatile modification of the piperidine structure (i) by

conjugate addition of cuprates to give 2,6-cis-disubstituted

piperidinones 11 with high stereoselectivity, (ii) to 5-

Even though the reaction conditions require further opti-

mization, it appears that palladium-catalyzed reactions at C-

5 of N-arabinosyl dehydropiperidinones 21 suffer from the

sterically demanding auxiliary hampering the palladium

complex from reaching the reaction site. However, the pre-

sented method provides access to 2,5-disubstituted piperi-

dine derivatives containing pharmacologically valuable

functionalized aryl substituents.

630

Can. J. Chem. Vol. 84, 2006

Scheme 9. Halogenation of N-arabinosyl dehydropiperidinones and Stille or Suzuki coupling of the obtained products.

X

PivO

O

OPiv

NIS or NBS

OPiv

O

4

N

THF, -78 °C

R

X = Br, I

21

21a

21c

PhenylSnBu₃

OH

B

Pd(dba)₂, AsPh₃

H₃CO

OH

THF, 60 °C

Pd(PPh₃)₂Cl₂

OCH₃

aq. Cs₂CO₃

THF, 65 °C

PivO

OPiv

O

PivO

O

OPiv

O

N

OPiv

O

N

22 44%

23 40%

Table 3. Synthesis of halogen dehydropiperidinones according to

Scheme 9.

Table 4. Synthesis of 2,3-disubstituted N-arabinosyl

dehydropiperidinones according to Scheme 10.

Product

R

X

I

Yield (%)

93

Product

R

R′

Yield (%)

d.r.

24a

24b

24c

p-ClC₆H₄

Methyl

Ethyl

73

87

70

>95:5^a

75:25^a

83:17^a

21a

p-ClC₆H₄-

21b

21c

21d

21e

Phenyl

n-Propyl

Isopropyl

-C₃H₆OTBDPS

I

67

69

87

88

C₃H₆OTBDPS

^aDetermined by H NMR.

1

21f

p-ClC₆H₄-

Br

75

Experimental

21g

21h

Isopropyl

-C₃H₆OTBDPS

Br

83

79

General methods

¹H NMR and ¹³C NMR spectra were recorded on Bruker

AC-200, AC-300, or AM-400 spectrometers. Mass spectra

were recorded on a Navigator-1 ESI mass spectrometer

(ThermoQuest) and a Finnigan MAT 95 spectrometer. Opti-

cal rotation values were measured on a PerkinElmer 241

polarimeter. Analytical HPLC were performed with a Pheno-

menex Luna C18 (2) column (5 µ, 250 mm × 4.6 mm).

Scheme 10. Stereoselective synthesis of 2,3-trans-substituted

piperidine derivatives.

PivO

OPiv

O

1) LiHMDS

2) R

OPiv

I

O

N

4

R'

THF, -78 °C

Materials

R

24

THF was distilled over potassium benzophenone ketyl and

CH₂Cl₂over calcium hydride. 2,3,4-Tri-O-pivaloyl-α-D-

arabinosylamine (1) was synthesized according to the litera-

ture procedure (5). Aldehydes used for imine formation were

distilled prior to use. A solution of zinc chloride in THF was

prepared by melting ZnCl₂under high vacuum and dissolv-

ing it in dry THF after recooling. Diene 3 was prepared from

4-methoxybut-3-ene-2-one by the silylation procedure given

by Danishefsky and Kitahara (14) followed by repeated

careful distillation at moderate temperature (oil bath temper-

ature has to be kept below 70 °C). TLC was performed on

nitrogen-substituted derivatives, and (iii) to 5-halogen-

substituted derivatives 21 of which the 5-iodo compounds

are susceptible to Stille and Suzuku coupling reactions form-

ing 5-aryl dehydropiperidinones. Enolates of the 2-substituted

dehydropiperidinones 4 are alkylated to furnish 2,3-trans-

disubstituted compounds 24 with excellent stereoselectivity.

After reduction of the enaminone structure, the carbohydrate

auxiliary can be cleaved off the enantiomerically pure sub-

stituted piperidine derivatives by a mild acidolysis.

Kranke and Kunz

631

Merck silica gel 60 F₂₅₄aluminum sheets. Flash chromatog-

raphy was carried out with ICN Biomedicals silica gel (40–

63 µm mesh).

177.0 (pivC=O), 149.9 (C-6), 137.2 (ipso-aryl), 134.2 (ipso-

aryl), 129.0, 128.4 (aryl), 102.9 (C-5), 89.3 (C-1′), 71.1,

67.9, 65.6 (C-2′, C-3′, C-4′), 66.1 (C-5′), 58.6 (C-2), 43.5 (C-

3), 38.9, 38.9, 38.7 (piv_quart.), 27.2, 27.1, 27.0 (piv-CH₃).

ESI-MS for C₃₁H₄₂ClNO₈m/z: 592.15 [M(³⁵Cl) + H]⁺,

594.14 [M(³⁷Cl) + H]⁺, 614.17 [M(³⁵Cl) + Na]⁺, 616.17

[M(³⁷Cl) + Na]⁺, 630.35 [M(³⁵Cl) + K]⁺, 655.27 [M(³⁵Cl) +

Na + CH₃CN]⁺.

General procedure for the synthesis of N-arabinosyl

imines 2

Method A (aromatic aldehydes)

The aromatic aldehyde (12 mmol) and acetic acid (12

drops) were added to a solution of amine 1 (10 mmol) in

isopropanol (20 mL) and heated to 80 °C for 3 h. The mix-

ture was cooled and kept at 4 °C overnight. The crystallized

product was filtered and washed with ice-cold isopropanol.

Concentration of the mother liquor provided further amounts

of product. The combined samples were, if necessary,

recrystallized from n-heptane. Characterization was carried

out upon the N-arabinosyl dehydropiperidinones 4.

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(p-nitrophenyl)-5,6-dehydropiperidin-4-one (4b)

Imine 2b (2.45 g, 4.6 mmol) was treated according to the

general procedure. Purification was carried out by flash

chromatography (petroleum ether – ethyl acetate, 5:1 →

3:1). Yield: 2.05 g (3.4 mmol, 74%); yellow solid; mp

179 °C. R_f0.18 (petroleum ether – ethyl acetate, 2:1). [α]²²

D

–15.1° (c 1, CHCl₃); d.r.: 86:14 (HPLC of the crude prod-

uct), 96:4 (HPLC after flash chromatography), HPLC: 80%

CH₃CN, 20% H₂O → 100% CH₃CN, 20 min. ¹H NMR

(200 MHz, CDCl₃, ppm) δ: 8.13 (d, 2H, J = 8.8 Hz, aryl),

7.43 (d, 2H, J = 8.8 Hz, aryl), 7.22 (d, 1H, J = 7.8 Hz, H-6),

5.60 (t, 1H, J_{H-2′,H-1′}= 9.5 Hz, J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.20–

5.05 (m, 2H, H-4′, H-5), 5.09 (dd, 1H, J_{H-3′,H-2′}= 6.6 Hz,

J_{H-3′,H-4′}= 3.7 Hz, H-3′), 5.00 (dd, 1H, J_H-2,H-3a= 6.8 Hz,

J_H-2,H-3b= 3.9 Hz, H-2), 4.47 (d, 1H, J_{H-1′,H-2′}= 9.3 Hz, H-

1′), 3.79 (dd, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, J_{H-5′ b,H-4′}= 2.0 Hz, H-

Method B (aliphatic aldehydes)

The aliphatic aldehyde (12 mmol) was added dropwise to

a mixture of amine 1 (10 mmol), n-pentane (60 mL), and

dried molecular sieves (6 g, 4 Å) and stirred for 36 h at

room temperature. Filtration through Hyflo^®and removal of

the solvent in vacuo yielded an amorphous solid, which was

used without further purification. Characterization was car-

ried out upon the N-arabinosyl dehydropiperidinones 4.

General procedure for the synthesis of N-arabinosyl

dehydropiperidinones 4

5 b), 3.53 (d, 1H, J

′

= 12.7 Hz, H-5 a), 3.01 (dd, 1H,

J_H-3a,H-3b= 16.4 Hz^H,^-J^5′_H^a,_-^H₃^-_a⁵_,^′_H^b_-2= 7.1 Hz, H-3a), 2.53 (dd, 1H,

J_H-3b,H-3a= 16.6 Hz, J_H-3b,H-2= 3.9 Hz, H-3b), 1.89, 1.16,

1.11 (3s, 27H, piv-CH₃). ¹³C NMR (50.3 MHz, CDCl₃, ppm)

δ: 189.9 (C-4), 177.4, 177.1, 176.8 (pivC=O), 150.3 (C-6),

147.5, 147.1, 127.4, 123.8 (aryl), 102.0 (C-5), 91.4 (C-1′),

70.7, 67.7, 66.0, 66.3 (C-2′, C-3′, C-4′, C-5′), 56.6 (C-2),

42.8 (C-3), 39.0, 38.9, 38.8 (pivC_quart.), 27.2, 27.1, 27.0 (piv-

CH₃). ESI-MS for C₃₁H₄₂N₂O₁₀m/z: 666.4 [M + Na +

MeCN]⁺, 625.3 [M + Na]⁺, 603.3 [M + H]⁺, 501.3 [M –

pivOH + H]⁺.

A solution of ZnCl₂in dry THF (1 mol/L, 11 mL) was

added to a solution of imine 2 (10.0 mmol) in dry THF

(50 mL) at –78 °C and stirred for 10 min. Danishefsky’s

diene 3 (2.5 mL, 12.5 mmol) was added. After stirring for

30 min, the solution was allowed to warm to –20 °C. After

complete consumption of the starting material (1 to 2 days),

the reaction was terminated by addition of 1 N aq. HCl

(10 mL). THF was evaporated in vacuo, the residue was dis-

solved in diethyl ether, and the layers were separated. The

organic layer was washed with satd. aq. NaHCO₃(3 ×

50 mL), 10% aq. Titriplex III^®(2 × 50 mL) and brine, dried

over MgSO₄, and concentrated.

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

phenyl-5,6-dehydropiperidin-4-one (4c)

Imine 2c (7.40 g, 15.0 mmol) was treated according to the

general procedure. Purification was carried out by flash

chromatography (petroleum ether – ethyl acetate, 3:1).

Yield: 7.06 g (12.7 mmol, 84%); colourless amorpous solid;

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(p-chlorophenyl)-5,6-dehydropiperidin-4-one (4a)

Imine 2a (5.10 g, 9.7 mmol) was treated according to the

general procedure. Purification was achieved by flash chro-

matography (petroleum ether – ethyl acetate, 3:1). Yield:

5.49 g (9.0 mmol, 96%); colourless solid; mp 180 °C. R_f

0.18 (petroleum ether – ethyl acetate, 2:1). [α]²⁵–28.03° (c

1, CHCl₃); d.r.: 97:3 (HPLC: 80% CH₃CN, 2^D0% H₂O →

100% CH₃CN, 20 min).¹H NMR (200 MHz, CDCl₃, ppm) δ:

7.32–7.19 (m, 5H, aryl, H-6), 5.60 (t, 1H, J_{H-2′,H-1′}= 9.8 Hz,

J_{H-2′,H-3′}= 9.8 Hz, H-2′), 5.25–5.10 (m, 2H, H-4′, H-5), 4.99

(dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.2 Hz, H-3′), 4.81

(dd, 1H, J_H-2,H-3b= 8.3 Hz, J_H-2,H-3a= 5.9 Hz, H-2), 4.26 (d,

R_f0.53 (petroleum ether – ethyl acetate, 4:1). [α]²²–27.3°

D

(c 1, CHCl₃); d.r.: 92:8 (HPLC of the crude product: 80%

CH₃CN, 20% H₂O → 100% CH₃CN, 20 min. ¹H NMR

(200 MHz, CDCl₃, ppm) δ: 7.40–7.25 (m, 6H, aryl, H-6),

5.60 (t, 1H, J_{H-2′,H-1′}= 9.8 Hz, J_{H-2′,H-3′}= 9.8 Hz, H-2′), 5.23

(d, 1H, J_H-5,H-6= 8.3 Hz, H-5), 5.15–5.09 (m, 1H, H-4′),

4.92 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.2 Hz, H-3′),

4.81 (t, 1H, J_H-2,H-3a= 7.8 Hz, J_H-2,H-3b= 7.8 Hz, H-2), 4.17

(d, 1H, J_{H-1′,H-2′}= 9.3 Hz, H-1′), 3.82 (dd, 1H, J_{H-5′a,H-5′b}

13.7 Hz, J_{H-5′a,H-4′}= 1.9 Hz, H-5′a), 3.34 (d, 1H, J_{H-5′b,H-5′a}

=

1H, J_{H-1′,H-2′}= 9.3 Hz, H-1′), 3.83 (dd, 1H, J_{H-5′a,H-5′b}

13.4 Hz, J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.42 (d, 1H, J_{H-5′b,H-5′a}

12.7 Hz, H-5′b), 2.79 (dd, 1H, J_H-3a,H-3b= 16.1 Hz, J_H-3a,H-2

5.9 Hz, H-3a), 2.60 (dd, 1H, J_H-3b,H-3a= 16.1 Hz, J_H-3b,H-2

=

13.2 Hz, H-5′b), 2.71 (d, 2H, J = 8.3 Hz, H-3a, H-3b), 1.23,

1.16, 1.09 (3s, 27H, piv-CH₃). ¹³C NMR (50.3 MHz, CDCl₃,

ppm) δ: 191.8 (C-4), 177.2, 177.1, 177.0 (pivC=O), 149.6

(C-6), 138.3 (ipso-aryl), 129.0, 128.7, 127.4 (aryl), 103.5

(H-5), 88.2 (C-1′), 71.4, 68.0, 65.4 (C-2′, C-3′, C-4′), 66.0

8.3 Hz, H-3b), 1.22, 1.56, 1.10 (3s, 27H, piv-CH₃). ¹³C

NMR (75.4 MHz, CDCl₃, ppm) δ: 191.1 (C-4), 177.1, 177.1,

632

Can. J. Chem. Vol. 84, 2006

(C-5′), 60.6 (C-2), 43.9 (C-3), 39.0, 38.9, 38.8 (pivC_quart.),

27.2, 27.0 (piv-CH₃).

MS for C₂₇H₄₃NO₈m/z: 306.2 [M – 2pivOH + H]⁺, 510.3

[M + H]⁺, 532.3 [M + Na]⁺, 573.3 [M + Na + MeCN]⁺,

1041.3 [2M + Na]⁺.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

methyl-5,6-dehydropiperidin-4-one (4d)

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-n-

propyl-5,6-dehydropiperidin-4-one (4f)

Crude imine 2d (12.5 mmol) was treated according to the

general procedure. Purification was achieved by flash chro-

matography (cyclohexane – ethyl acetate, 3:1 → 2:1). Yield:

3.02 g (6.09 mmol, 49%); colourless amorphous solid. R_f

Crude imine 2f (25 mmol) was treated according to the

general procedure. Purification was achieved by flash chro-

matography (petroleum ether – ethyl acetate, 3:1). X-ray

analysis: space group, P2₁2₁2₁(orthorhombic); lattice pa-

rameters: a = 9.8895(13) Å, b = 10.1820(11) Å, c =

30.614(4) Å, V = 3082.7(6) Å³, Z = 4, F(000) = 1136;

diffractometer: CAD4 Enraf Nonius; irradiation: Cu K_α

graphite monochromator.³Yield: 10.64 g (20.3 mmol, 81%);

colourless solid; mp 192 °C. R_f0.07 (petroleum ether – ethyl

acetate, 3:1). [α]²⁵_D+66.64° (c 1, CHCl₃); d.r.: 87:13 (HPLC

of the crude product: 80% CH₃CN, 20% H₂O → 100%

0.12 (cyclohexane – ethyl acetate, 2:1). [α]²²+60.48° (c 1,

D

CHCl₃); d.r.: 93:7 (HPLC after flash chromatography: 80%

1

CH₃CH, 20% H₂O → 95% CH₃CN, 5% H₂O, 30 min). H

NMR (300 MHz, CDCl₃, ppm) δ: 6.91 (d, 1H, J_H-6,H-5

7.0 Hz, H-6), 5.55 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}

9.6 Hz, H-2′), 5.26–5.20 (m, 1H, H-4′), 5.13 (dd, 1H, J_{H-3′,H-2′}

10.1 Hz, J_{H-3′,H-4′}= 3.1 Hz, H-3′), 5.01 (d, 1H, J_H-5,H-6

=

7.7 Hz, H-5), 4.44 (d, 1H, J_{H-1′,H-2′}= 8.8 Hz, H-1′), 4.02 (dd,

1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.98–

3.89 (m, H-1, H-2), 3.67 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b),

2.68 (dd, 1H, J_H-3a,H-3b= 16.6 Hz, J_H-3a,H-2= 6.3 Hz, H-3a),

2.17 (dd, 1H, J_H-3b,H-3a= 16.6 Hz, J_H-3b,H-2= 1.9 Hz, H-3b),

1.30 (d, 3H, J = 6.6 Hz, CH₃), 1.26, 1.11, 1.10 (3s, 27H,

piv-CH₃). ¹³C NMR (100.6 MHz, CDCl₃, ppm) δ: 192.1 (C-

4), 177.2, 177.1, 177.1 (pivC=O), 149.9 (C-6), 99.8 (C-5),

92.0 (C-1′), 71.0, 68.0, 65.9 (C-2′, C-3′, C-4′), 66.1 (C-5′),

49.4 (C-2), 42.6 (C-3), 38.9, 38.9, 38.8 (piv_quart), 27.1, 27.1,

27.0 (piv-CH₃), 17.7 (CH₃). ESI-MS for C₂₆H₄₁NO₈m/z:

496.3 [M + H]⁺, 518.3 [M + Na]⁺, 534.3 [M + K]⁺, 991.6

[2M + H]⁺, 1013.6 [2M + Na]⁺, 1029.6 [2M + K]⁺.

1

CH₃CN, 20 min). H NMR (200 MHz, CDCl₃, ppm) δ: 6.90

(d, 1H, J_H-6,H-5= 7.3 Hz, H-6), 5.55 (t, 1H, J_{H-2′,H-1′}

=

9.5 Hz, J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.30–5.20 (m, 1H, H-4′),

5.13 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.2 Hz, H-3′),

4.93 (d, 1H, J_H-5,H-6= 7.3 Hz, H-5), 4.44 (d, 1H, J_{H-1′,H-2′}

9.3 Hz, H-1′), 4.02 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}

2.0 Hz, H-5′a), 3.80–3.70 (m, 1H, H-2), 3.67 (d, 1H, J_{H-5′b,H-5′a}

13.2 Hz, H-5′b), 2.60 (dd, 1H, J_{H-3a, H-3b}= 16.6 Hz, J_H-3a,H-2

=

6.3 Hz, H-3a), 2.34 (d, 1H, J_H-3b,H-3a= 16.6 Hz, H-3b),

2.00–1.75 (m, 1H, CH₂), 1.65–1.50 (m, 1H, CH₂), 1.30–1.10

(m, 27H, piv-CH₃), 0.86 (t, 3H, J = 7.3 Hz, CH₃). ¹³C NMR

(50.3 MHz, CDCl₃, ppm) δ: 192.2 (C-4), 177.2, 176.8

(pivC=O), 149.9 (H-6), 99.8 (H-5), 92.1 (C-1′), 71.1, 68.0,

66.1 (C-2′, C-3′, C-4′), 66.2 (C-5′), 53.5 (C-2), 39.0 (C-3),

38.9, 38.8, 38.8 (pivC_quart.), 32.7 (CH₂), 27.2, 27.1, 27.0

(piv-CH₃), 18.9 (CH₂), 13.8 (CH₃). Anal. calcd. for

C₂₈H₄₅NO₈: C 64.22, H 8.66, N 2.69; found: C 64.20, H

8.60, N 2.63.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

ethyl-5,6-dehydropiperidin-4-one (4e)

Crude imine 2e (25 mmol) was treated according to the

general procedure. Purification was achieved by flash chro-

matography (cyclohexane – ethyl acetate, 4:1). Yield: 8.49 g

(16.7 mmol, 67%); colourless amorphous solid. R_f0.19 (cy-

clohexane – ethyl acetate, 2:1). [α]²²+79.67° (c 1, CHCl₃);

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

isopropyl-5,6-dehydropiperidin-4-one (4g)

D

d.r.: 96:4 (HPLC of the crude product: 80% CH₃CH, 20%

H₂O → 95% CH₃CN, 5% H₂O, 30 min). ¹H NMR

(300 MHz, CDCl₃, ppm) δ: 6.90 (d, 1H, J_H-6,H-5= 6.6 Hz, H-

6), 5.56 (t, 1H, J_{H-2′,H-1′}= 9.4 Hz, J_{H-2′,H-3′}= 9.4 Hz, H-2′),

5.26–5.19 (m, 1H, H-4′), 5.12 (dd, 1H, J_{H-3′,H-2′}= 10.1 Hz,

J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.93 (d, 1H, J_H-5,H-6= 7.0 Hz, H-5),

Crude imine 2g (25 mmol) was treated according to the

general procedure. Purification was carried out by flash

chromatography. Yield: 9.45 g (18 mmol, 73%); colourless

amorphous solid. R_f0.13 (cyclohexane – ethyl acetate, 3:1).

[α]²⁴+70.14° (c 1, CHCl₃); d.r.: 95:5 (HPLC of the crude

D

4.44 (d, 1H, J_{H-1′,H-2′}= 9.2 Hz, H-1′), 4.01 (dd, 1H, J_{H-5′a,H-5′b}

13.2 Hz, J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.66 (d, 1H, J_{H-5′b,H-5′a}

=

product), 99:1 (HPLC after flash chromatography), HPLC:

85% CH₃CH, 15% H₂O → 95% CH₃CN, 5% H₂O, 20 min).

13.6 Hz, H-5′b), 3.67–3.56 (m, 1H, H-2), 2.59 (dd, 1H,

J_H-3a,H-3b= 16.7 Hz, J_H-3a,H-2= 6.1 Hz, H-3a), 2.37 (d, 1H,

J_H-3b,H-3a= 16.9 Hz, H-3b), 1.98–1.79 (m, 1H, CH₂), 1.78–

1.60 (m, 1H, CH₂), 1.25, 1.11, 1.10 (3s, 27H, piv-CH₃), 0.84

(t, 3H, J = 7.53 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃,

ppm) δ: 192.1 (C-4), 177.2, 177.1, 177.0 (pivC=O), 149.9

(C-6), 99.8 (C-5), 92.1 (C-1′), 71.1, 68.0, 66.0 (C-2′, C-3′, C-

4′), 66.1 (C-5′), 55.2 (C-2), 39.0, 38.9, 38.7 (piv_quart), 38.4

(C-3), 27.1, 27.0 (piv-CH₃), 23.6 (CH₂), 10.1 (CH₃). ESI-

¹H NMR (400 MHz, CDCl₃, ppm) δ: 7.01 (d, 1H, J_H-5,H-6

7.8 Hz, H-6), 5.58 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-4′}

9.6 Hz, H-2′), 5.25–5.20 (m, 1H, H-4′), 5.12 (dd, 1H, J_{H-3′,H-2′}

9.8 Hz, J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.93 (d, 1H, J_H-5,H-6

=

7.8 Hz, H-5), 4.49 (d, 1H, J_{H-1′,H-2′}= 9.0 Hz, H-1′), 3.99 (dd,

1H, J_{H-5′a,H-5′b}= 13.3 Hz, J_{H-5′a,H-4′}= 2.4 Hz, H-5′), 3.67 (dd,

1H, J_{H-5′b,H-5′a}= 13.3 Hz, J_{H-5′b,H-4′}= 0.8 Hz, H-5′b), 3.59–

3.52 (m, 1H, H-2), 2.59 (dd, 1H, J_H-3a,H-3b= 16.2 Hz, J_H-3a,H-2

7.8 Hz, H-3a), 2.40 (dd, 1H, J_H-3b,H-3a= 16.8 Hz, J_H-3b,H-2

=

³Supplementary data for this article are available on the journal Web site (http://canjchem.nrc.ca) or may be purchased from the Depository

of Unpublished Data, Document Delivery, CISTI, National Research Council Canada, Ottawa, ON K1A 0R6, Canada. DUD 5028. For more

information on obtaining material refer to http://cisti-icist.nrc-cnrc.gc.ca/irm/unpub_e.shtml. CCDC 229785 and 229786 contain the crystal-

lographic data for this manuscript. These data can be obtained, free of charge, via http://www.ccdc.cam.ac.uk/conts/retrieving.html

(or from the Cambridge Crystallographic Data Centre, 12 Union Road, Cambridge CB2 1EZ, UK; fax +44 1223 336033; or

deposit@ccdc.cam.ac.uk).

Kranke and Kunz

633

2.0 Hz, H-3a), 2.32–2.19 (m, 1H, CH(CH₃)₂), 1.25, 1.11,

1.10 (3s, 27H, piv-CH₃), 0.89 (d, 3H, J = 7.0 Hz, CH₃), 0.89

(d, 3H, J = 6.6 Hz, CH₃). ¹³C NMR (50.3 MHz, CDCl₃,

ppm) δ: 192.5 (C-4), 177.2, 177.1, 177.0 (pivC=O), 150.3

(C-6), 100.3 (C-5), 91.8 (C-1′), 71.4, 68.0, 65.8 (C-2′, C-3′,

C-4′), 66.1 (C-5′), 58.9 (C-2), 38.9, 38.9, 38.8 (piv_quart), 35.5

(C-3), 32.2 (CH(CH₃)₃), 27.1, 27.0 (piv-CH₃), 19.5, 17.6

(CH₃). ESI-MS for C₂₈H₄₅NO₈m/z: 524.4 [M + H]⁺, 546.4

[M + Na]⁺, 587.3 [M + CH₃CN + Na]⁺, 1069.6 [2M + Na]⁺.

acetate, 3:1). [α]²²–12.46° (c 1, CHCl₃). ¹H NMR

D

(300 MHz, CDCl₃, ppm) δ: 5.72–5.64 (m, 1H, H-5), 5.40 (t,

1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.19–5.13

(m, 1H, H-4′), 5.07 (dd, 1H, J_{H-3′,H-2′}= 9.9 Hz, J_{H-3′,H-4′}

=

3.3 Hz, H-3′), 4.13 (d, 1H, J_{H-1′,H-2′}= 9.2 Hz, H-1′), 3.90 (dd,

1H, J_{H-5′a,H-5′b}= 13.1 Hz, J_{H-5′a,H-4′}= 2.0 Hz, H-5′a), 3.62 (dd,

1H, J_H-6a,H-6b= 17.6 Hz, J_H-6a,H-5= 2.6 Hz, H-6a), 3.53 (d,

1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b), 3.42 (d, 1H, J_H-6b,H-6a

=

17.3 Hz, H-6b), 3.24–3.11 (m, 1H, H-2), 2.55 (dd, 1H,

J_H-3a,H-3b= 16.4 Hz, J_H-3a,H-2= 2.8 Hz, H-3a), 2.09 (d, 1H,

J_H-3b,H-3a= 16.6 Hz, H-3b), 1.68–1.53 (m, 1H, CH₂), 1.47–

1.15 (m, 3H, CH₂), 1.23, 1.12, 1.10 (3s, 27H, pivCH₃), 0.89

(t, 3H, J = 7.2 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃,

ppm) δ: 177.3, 177.3, 177.1 (pivC=O), 146.6 (C-4), 116.1

(C-5), 92.8 (C-1′), 71.6, 68.6, 65.6 (C-2′, C-3′, C-4′), 65.1

(C-5′), 41.8 (C-6), 38.9, 38.7, 38.6 (piv_quart.), 33.6 (CH₂),

32.6 (CH₂), 27.1, 27.0, 27.0 (pivCH₃), 19.8 (CH₂), 14.1

(CH₃). ESI-MS for C₂₉H₄₆F₃NO₁₀S m/z: 406.2 [M – pivOH –

OTf]⁺, 508.5 [M – OTf]⁺, 556.3 [M – pivOH + H]⁺, 658.3

[M + H]⁺, 680.3 [M + Na]⁺, 696.1 [M + K]⁺, 721.4 [M + Na +

CH₃CN]⁺.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-(3-

tert-butyldiphenylsiloxy)propyl-5,6-dehydropiperidin-4-one

(4h)

Crude imine 2h, prepared from 4-(tert-butyldiphenyl-

siloxy)butanal (15) according to method B, was treated

according to the general procedure. Purification was carried

out by flash chromatography (cyclohexane – ethyl acetate,

4:1 → 3:1). Yield: 12.7 g (16.4 mmol, 65%); colourless

amorphous solid. R_f0.33 (petrolether – ethyl acetate, 2:1).

[α]²⁵+32.84° (c 1, CHCl₃); d.r.: 90:10 (HPLC of the crude

D

product), 96:4 (HPLC after chromatography), HPLC: 80%

CH₃CN, 20% H₂O → 100% CH₃CN, 20 min). ¹H NMR

(200 MHz, CDCl₃), δ: 7.70–7.50 (m, 4H, aryl), 7.46–7.27

(m, 6H, aryl), 6.92 (d, 1H, J_H-6,H-5= 7.8 Hz, H-6), 5.55 (t,

1H, J_{H-2′,H-1′}= 9.5 Hz, J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.29–5.19

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-n-

propylpiperidine (8)

Li₂CO₃(160 mg) and Pd/C (10%, 50 mg) were added to a

solution of enol triflate 7 (888 mg, 1.35 mmol) in methanol

(100 mL) and stirred for 20 h under a H₂atmosphere. After

filtration through Hyflo^®, the solvent was removed in vacuo,

and the remaining residue was dissolved in diethyl ether

(100 mL). The solution was washed with water (40 mL) and

brine (40 mL), dried over MgSO₄, and evaporated to dryness

to yield pure 8 as a colourless amorphous solid (665 mg,

1.30 mmol, 96%). R_f0.75 (cyclohexane – ethyl acetate, 4:1).

(m, 1H, H-4′), 5.12 (dd, 1H, J_{H-3′,H-2′}= 9.8 Hz, J_{H-3′,H-4′}

=

2.9 Hz, H-3′), 4.98 (d, 1H, J_H-5,H-6= 7.3 Hz, H-5), 4.44 (d,

1H, J_{H-1′,H-2′}= 8.8 Hz, H-1′), 4.04–3.90 (m, 1H, H-5′a),

3.81–3.50 (m, 4H, J_{H-5′b,H-5′a}= 13.2 Hz, H-2, H-5′b, CH₂-O),

2.64 (dd, 1H, J_H-3a,H-3b= 16.8 Hz, J_H-3a,H-2= 6.1 Hz, H-3a),

2.34 (d, 1H, J_H-3b,H-3a= 16.6 Hz, H-3b), 1.99–1.70 (m, 2H,

CH₂), 1.69–1.38 (m, 2H, CH₂), 1.22, 1.11, 1.11, 0.99 (4s,

36H, C(CH₃)₃). ¹³C NMR (50.3 MHz, CDCl₃, ppm) δ: 191.9

(C-4), 182.0, 177.2, 177.1 (pivC=O), 149.9 (C-6), 135.5,

133.8, 129.6, 127.7 (aryl), 99.8 (C-5), 91.8 (C-1′), 71.1,

68.0, 66.0 (C-2′, C-3′, C-4′), 66.2 (C-5′), 63.5 (CH₂-O), 53.9

(C-2), 39.1 (C-3), 39.0, 38.9, 38.8 (pivC_quart.), 28.9 (CH₂),

27.4 (CH₂), 27.2, 27.1 (pivCH₃), 26.8 (Si-C(CH₃)₃), 19.2

(Si-C(CH₃)₃). ESI-MS for C₄₄H₆₃NO₉Si m/z: 472.1 [M –

3pivOH + H]⁺, 574.2 [M – 2pivOH + H]⁺, 700.3 [M –

Phenyl], 778.3 [M + H]⁺, 800.4 [M + Na]⁺, 816.3 [M + K]⁺,

841.3 [M + Na + CH₃CN]⁺.

1

[α]²²–28.12° (c 1, CHCl₃). H NMR (300 MHz, CDCl₃,

ppm)^Dδ: 5.50 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′),

5.20–5.11 (m, 1H, H-4′), 5.07 (dd, 1H, J_{H-3′,H-2′}= 9.7 Hz,

J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.33–4.13 (m, 1H, H-1′), 3.90 (d,

1H, J_{H-5′a,H-5′b}= 12.8 Hz, H-5′a), 3.51 (d, J_{H-5′b,H-5′a}= 12.8 Hz,

H-5′b), 3.27–3.06, 2.79–2.54, 2.51–2.27 (3m, 3H, H-2, H-6a,

H-6b), 1.72–1.19 (m, 19H, 3CH₂, 2PropylCH₂, pivCH₃),

1.23, 1.14, 1.10 (3s, 27H, pivCH₃), 0.89 (t, 3H, J = 7.0 Hz,

CH₃). ¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 177.4 (pivC=O),

89.3 (C-1′), 72.1, 68.9, 65.1, 65.1 (C-2′, C-3′, C-4′, C-5′),

57.5 (C-2), 45.2 (C-6), 38.9, 38.7, 38.6 (piv_quart.), 34.8

(CH₂), 31.6 (CH₂), 27.3, 27.1, 27.0 (pivCH₃), 26.2 (CH₂),

24.1 (CH₂), 18.8 (CH₂), 14.5 (CH₃). ESI-MS for C₂₈H₄₉NO₇

m/z: 308.2 [M – 2pivOH + H]⁺, 410.3 [M – pivOH + H]⁺,

512.3 [M + H]⁺, 534.3 [M + Na]⁺, 550.3 [M + K]⁺.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-n-

propyl-4-(trifluormethansulfonyloxy)-4,5-dehydropiperidine

(7)

To a solution of 4f (1.31 g, 2.50 mmol) and 2-[N,N-

bis(trifluoromethanesulfonyl)amino]-5-chloropyridine (1.18 g,

3.00 mmol) in dry THF (50 mL), ^l-Selectride^®(1 mol/L in

THF, 2.75 mL) was added at –78 °C and stirred for 1 h. The

solution was allowed to warm slowly and stirred until the

starting material was consumed. The reaction was termi-

nated by addition of aq. NaHCO₃(5 mL). THF was removed

in vacuo, diethyl ether (100 mL) was added, and the layers

were separated. The aqueous layer was extracted with ether,

and the combined organic layers were washed with brine

and dried over MgSO₄. The solvent was evaporated in

vacuo. Flash chromatography (cyclohexane – ethyl acetate,

10:1) of the residue afforded 7 as a colourless amorphous

solid (0.98 g, 1.49 mmol, 60%). R_f0.67 (cyclohexane – ethyl

(2S)-2-n-Propylpiperidine hydrochloride (coniine

hydrochloride) (10·HCl)

N-Arabinosyl piperidine 8 (563 mg, 1.1 mmol) in metha-

nol (15 mL) was treated with 1 N HCl (2 mL) and stirred

until completion of the reaction (48 h). The solvent was

evaporated in vacuo, the residue was dissolved in diethyl

ether (35 mL) and extracted with water (5 × 10 mL).

Lyophilization of the aqueous layer gave coniine hydrochlo-

ride (10·HCl) as a colourless amorphous solid (171 mg,

1.0 mmol, 95%). [α]²²+5.33° (c = 1, ethanol); enantiomer

D

(16): [α]²²–5.8° (c 1, methanol). ¹H NMR (300 MHz,

DMSO, pp^Dm) δ: 9.14 (br s, 1H, NH), 8.99 (br s, 1H, NH),

634

Can. J. Chem. Vol. 84, 2006

3.20–3.05 (m, 1H, NCH₂), 3.00–2.84 (m, 1H, H-2), 2.84–

2.65 (m, 1H, NCH₂), 1.90–1.15 (m, 10H, CH₂), 0.86 (t, 3H,

J = 7.2 Hz, CH₃). ¹³C NMR (75.4 MHz, DMSO, ppm) δ:

55.5 (C-2), 43.8 (C-6), 35.0 (CH₂), 27.8 (CH₂), 21.9, (CH₂),

21.9 (CH₂), 17.9 (CH₂), 13.8 (CH₃). ESI-MS for C₈H₁₈ClN

m/z: 128.1 [M – Cl]⁺, 291.2 [2M(³⁵Cl) – Cl]⁺, 293.1

[M(³⁷Cl) – Cl]⁺.

38.7, 38.6 (pivC_quart.), 27.2, 27.0 (piv-CH₃). ESI-MS for

C₃₇H₄₈NO₈: 568.5 [M(³⁵Cl) – pivOH + H]⁺, 570.6 [M(³⁷Cl) –

pivOH + H]⁺, 670.6 [M(³⁵Cl) + H]⁺, 672.6 [M(³⁷Cl) + H]⁺,

692.6 [M(³⁵Cl) + Na]⁺, 694.6 [M(³⁷Cl) + Na]⁺, 708.5 [M +

K]⁺.

(2R,6R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-allyl-6-(p-chlorophenyl)-piperidin-4-one (11b)

Piperidinone 11b was prepared from 4a (592 mg,

1.0 mmol) according to the general procedure. For the for-

mation of the orange cuprate solution, CuCN (358 mg,

4 mmol) and allylmagnesium bromide (1 mol/L in ether,

4 mL) were treated in THF (30 mL) at –40 °C for 0.5 h. Pu-

rification of 11b was performed by flash chromatography

(petroleum ether – ethyl acetate, 13:1 → 10:1). Yield:

325 mg (0.5 mmol, 51%); colourless amorphous solid; mp

General procedure for the addition of R′Cu·BF₃

complexes to enaminones

The solution of the corresponding Grignard reagent in

THF or diethyl ether was added to a suspension of copper

salt (1 mmol) in dry THF (5–10 mL) at the temperature

given for the corresponding cuprate (given in the following)

and stirred until the cuprate was formed (time and change in

colour for each compound is given in the following). Subse-

quently, the cuprate was cooled to –78 °C, BF₃·OEt₂

(1 mmol) was added and the mixture stirred for 15 min.

Dehydropiperidinone 4 in dry THF (20 mL per mmol piperi-

dinone) was added dropwise, and the mixture was stirred for

15 h. In general, a slow increase of temperature was required

for complete consumption of the starting material. The reac-

tion was terminated by addition of concd. NH₄OH – satd.

NH₄Cl (1:1 v/v). The mixture was warmed to room tempera-

ture (r.t.), diluted with diethyl ether (20 mL), and the layers

were seperated. The organic layer was washed with concd.

NH₄OH – satd. NH₄Cl (1:1 v/v), washed with brine and

dried over MgSO₄. The solvent was removed in vacuo, and

the residue was purified by flash chromatography.

73 °C. R_f0.64 (petroleum ether – ethyl acetate, 3:1). [α]²⁵

D

+26.64° (c 1, CHCl₃); d.r.: 98:2 (HPLC: 80% CH₃CN, 20%

1

H₂O → 100% CH₃CN, 20 min. H NMR (400 MHz, CDCl₃,

ppm) δ: 7.40–7.35 (m, 4H, aryl), 5.84–5.71 (m, 1H,

CH=CH₂), 5.65 (t, 1H, J_{H-2 ,H-1}= 9.6 Hz, J_{H-2 ,H-3}= 9.6 Hz,

′

H-2′), 5.22–5.12 (m, 3H, ^′H-4′, CH=CH₂), 4.92 (dd, 1H,

J_{H-3 ,H-2}= 9.8 Hz, J_{H-3 ,H-4}= 3.1 Hz, H-3′), 4.68 (dd, 1H,

′

J_H-2,H-3a= 12.1 Hz, J_H-2,H-3b= 3.9 Hz, H-2), 4.12 (d, 1H,

J_{H-1 ,H-2}= 9.4 Hz, H-1′), 4.00 (dd, 1H, J_{H-5 a,H-5 b}= 13.3 Hz,

J_{H-5 a,H-4}= 2.4 Hz, H-5′a), 3.80–3.70 (m, 1^′H, H-6), 3.53 (d,

′

1H,^′J_{H-5 b,H-5 a}= 12.9 Hz, H-5′b), 2.93 (dd, 1H, J_gem.= 16.4 Hz,

′

J_vic.= 5.7 Hz, H-5a), 2.71–2.61 (m, 2H, H-5b, H-3a), 2.57

(dd, 1H, J_gem.= 18.2 Hz, J_vic.= 4.1 Hz, H-3b), 2.47–2.37 (m,

1H, CH₂-CH=CH₂), 2.10–1.99 (m, 1H, CH₂-CH=CH₂), 1.34,

1.26, 1.18 (3s, 27H, piv-CH₃). ¹³C NMR (50.3 MHz, CDCl₃,

ppm) δ: 208.9 (C-4), 177.4, 177.2, 176.8 (pivC=O), 141.0

(ipso-aryl), 134.2 (CH=CH₂), 133.7 (ipso-aryl.), 129.0,

128.9 (aryl), 118.4 (CH=CH₂), 90.7 (C-1′), 72.7, 68.7, 66.2

(C-2′, C-3′, C-4′), 65.2 (C-5′), 58.4 (C-2), 50.7 (C-6), 47.4

(CH₂), 44.0 (CH₂), 42.0 (CH₂), 38.9, 38.8, 38.8 (pivC_quart.),

27.3, 27.2, 27.1 (piv-CH₃). ESI-MS for C₃₄H₄₈ClNO₈m/z:

430.4 [M(³⁵Cl) – 2pivOH + H]⁺, 532.5 [M(³⁵Cl) – pivOH +

H]⁺, 534.5 [M(³⁷Cl) – pivOH + H]⁺, 634.5 [M(³⁵Cl) + H]⁺,

636.5 [M(³⁷Cl) + H]⁺, 656.5 [M(³⁵Cl) + Na]⁺, 658.5

[M(³⁷Cl) + Na]⁺, 672.6 [M(³⁵Cl) + K]⁺. Anal. calcd. for

C₃₄H₄₈ClNO₈(634.20): C 64.39, H 7.63, N 2.21; found:

C 64.42, H 7.83, N 2.13.

(2R,6S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-(p-chlorophenyl)-6-phenylpiperidin-4-one (11a)

Piperidinone 11a was prepared from 4a (592 mg,

1.0 mmol) according to the general procedure. For the for-

mation of the beige cuprate solution, CuI (952 mg, 5 mmol)

and phenylmagnesium bromide (1 mol/L in THF, 5 mL)

were treated in THF (30 mL) at –78 °C for 1 h. Purification

of 11a was achieved by flash chromatography (petroleum

ether – ethyl acetate, 14:1 → 10:1). Yield: 484 mg

(0.7 mmol, 72%); colourless solid; mp 179 °C. X-ray analy-

sis: space group, P1 (triklin); lattice parameters: a =

10.1869(6) Å, b = 13.1017(12) Å, c = 15.5126(12) Å, V =

1901.1(3) Å³, Z = 2, F(000) = 716; diffractometer, CAD4

Enraf Nonius; irradiation, Cu K_αgraphite monochromator.³

R_f0.55 (petroleum ether – ethyl acetate, 3:1). [α]²⁵–35.44°

(2S,6S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

phenyl-6-n-propylpiperidin-4-one (11c)

D

(c 1, CHCl₃); d.r.: 99:1 (HPLC: 80% CH₃CN, 20% H₂O →

1

Piperidinone 11c was prepared from 4f (524 mg,

1.0 mmol) according to the general procedure. For the for-

mation of the beige cuprate solution, CuI (952 mg, 5 mmol)

and phenylmagnesium bromide (1 mol/L in THF, 5 mL)

were treated in THF (30 mL) at –78 °C for 1 h. Purification

of 11c was carried out by flash chromatography (petroleum

ether – ethyl acetate, 10:1). Yield: 670 mg (0.4 mmol, 44%);

colourless solid. R_f0.55 (petroleum ether – ethyl acetate,

3:1). [α]²⁶–10.37° (c 1, CHCl₃); d.r.: 99:1 (HPLC: 80%

CH₃CN, 2^D0% H₂O → 100% CH₃CN, 20 min). ¹H NMR

(200 MHz, CDCl₃, ppm) δ: 7.35–7.10 (m, 5H, aryl), 5.38 (t,

1H, J_{H-2′,H-1′}= 9.3 Hz, J_{H-2′,H-3′}= 9.3 Hz, H-2′), 5.20–5.12

100% CH₃CN, 20 min). H NMR (200 MHz, CDCl₃, ppm)

δ: 7.50–7.15 (m, 9H, aryl), 5.36 (t, 1H, J_{H-2′,H-1′}= 9.5 Hz,

J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.15–5.00 (m, 2H, H-4′, aryl-CH-

N), 4.90–4.50 (m, 2H, H-3′, aryl-CH-N), 4.24 (d, 1H,

J_{H-1′,H-2′}= 9.3 Hz, H-1′), 3.97 (dd, 1H, J_{H-5′a,H-5′b}= 12.9 Hz,

J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.51–3.25 (m, 2H, H-5′,

CH₂C=O), 2.86 (dd, 1H, J_gem.= 16.1 Hz, J_vic.= 2.4 Hz,

CH₂C=O), 2.61 (dd, J_gem.= 18.1 Hz, J_vic.= 12.7 Hz,

CH₂C=O), 2.41 (dd, 1H, J_gem.= 18.3 Hz, J_vic.= 3.7 Hz,

CH₂C=O), 1.26, 1.08, 1.01 (3s, 27H, piv-CH₃). ¹³C NMR

(50.3 MHz, CDCl₃, ppm) δ: 208.0 (C-4), 177.5, 177.2, 175.3

(pivC=O), 144.1, 140.5, 133.8, 129.1, 128.6, 127.1, 126.3

(Aryl), 90.3 (C-1′), 72.9, 68.7, 66.3 (C-2′, C-3′, C-4′), 65.2

(C-5′), 58.3, 53.4 (C-2, C-6), 47.5, 46.4 (C-3, C-5), 39.0,

(m, 1H, H-4′), 5.06 (dd, 1H, J_{H-3′,H-2′}= 9.5 Hz, J_{H-3′,H-4′}

3.2 Hz, H-3′), 4.90–4.80 (m, 1H, H-6), 4.48 (d, 1H, J_{H-1′,H-2′}

=

Kranke and Kunz

635

9.3 Hz, H-1′), 3.98 (dd, 1H, J_{H-5′a,H-5′b}= 12.9 Hz, J_{H-5′a,H-4′}

=

colourless solution, which was then cooled to –78 °C.

Piperidinone 4f (2.51 g, 4.8 mmol) and TMSCl (3 mL) in

dry THF (80 mL) were added and the colour changed to yel-

low and finally to orange. The reaction mixture was allowed

to warm to r.t. within 14 h. The reaction was terminated by

addition of concd. NH₄OH – satd. NH₄Cl (1:1 v/v) (72 mL),

and the mixture was diluted with diethyl ether (250 mL).

The organic layer was washed with brine, dried over

MgSO₄, and concentrated in vacuo to yield silylenol ether

12 as an amorphous solid. It was dissolved in THF (48 mL)

and a solution of tetrabutylammonia fluoride in THF

(1 mol/L, 7.2 mL, 7.2 mmol) was added and the mixture was

stirred until 12 was consumed. The solvent was removed in

vacuo, the residue was dissolved in diethyl ether (240 mL),

washed with water (100 mL) and brine (100 mL), and dried

over MgSO₄. The solvent was evaporated in vacuo and the

residue was purified by flash chromatography (petroleum

ether – ethyl acetate, 5:1) to yield 11e as a colourless crys-

talline solid (2.28 g, 4.2 mmol, 88%); mp 162 °C. R_f0.46

(petroleum ether – ethyl acetate, 3:1). [α]²⁵–6.11° (c 1,

CHCl₃); d.r.: 91:9 (HPLC of the crude produc^Dt), HPLC: 80%

CH₃CN, 20% H₂O → 100% CH₃CN, 20 min). ¹H NMR

(200 MHz, CDCl₃, ppm) δ: 5.48 (t, 1H, J_{H-2′,H-1′}= 9.5 Hz,

J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.20–5.10 (m, 1H, H-4′), 5.06 (dd,

1H, J_{H-3′,H-2′}= 9.8 Hz, J_{H-3′,H-4′}= 3.4 Hz, H-3′), 4.23 (d, 1H,

J_{H-1′,H-2′}= 9.3 Hz, H-1′), 3.93 (dd, J_{H-5′b,H-5′a}= 13.2 Hz,

J_{H-5′b,H-4′}= 2.0 Hz, H-5′b), 3.85–3.70, 3.45–3.25 (2m, each

1H, H-2, H-6), 3.55 (d, 1H, J_{H-5′a,H-5′b}= 12.7 Hz, H-5′a),

2.78 (dd, 1H, J_H-3a,H-3b= 15.1 Hz, J_H-3a,H-2= 6.8 Hz, H-3a),

2.62 (dd, 1H, J_H-3b,H-3a= 15.1 Hz, J_H-3b,H-2= 5.9 Hz, H-3b),

2.27 (dd, 1H, J_gem= 15.6 Hz, J_vic.= 6.8 Hz, H-5a), 2.25–

2.10 (m, 1H, H-5b), 1.70–1.50 (m, 1H, propyl-CH₂), 1.50–

1.00 (m, 33H, piv-CH₃, CH₃, propyl-CH₂), 0.86 (t, 3H, J =

7.1 Hz, propyl-CH₃). ¹³C NMR (50.3 MHz, CDCl₃, ppm) δ:

210.7 (C-4), 177.4, 177.2, 176.8 (pivC=O), 94.7 (C-1′), 72.2,

68.7, 66.4 (C-2′, C-3′, C-4′), 65.2 (C-5′), 58.7, 48.9 (C-2, C-

6), 47.3, 44.3 (C-3, C-5), 40.3 (propyl-CH₂), 38.9, 38.7

(pivC_quart.), 27.2, 27.1, 27.1 (piv-CH₃), 24.5 (CH₃), 19.8

(propyl-CH₂), 14.0 (propyl-CH₃). Anal. calcd. for

C₂₉H₄₉NO₈(539.70): C 64.54, H 9.15, N 2.60; found:

C 64.52, H 9.27, N 2.56.

2.2 Hz, H-5′a), 3.59 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b),

3.50–3.35 (m, 1H, H-2), 3.13 (dd, 1H, J_gem.= 17.1 Hz, J_vic.

=

5.9 Hz, CH₂C=O), 2.93 (dd, 1H, J_gem.= 17.1, J_vic.= 3.4 Hz,

CH₂C=O), 2.47 (dd, 1H, J_gem.= 17.1 Hz, J_vic.= 4.4 Hz,

CH₂C=O), 2.14 (dd, 1H, J_gem.= 17.1 Hz, J_vic.= 10.8 Hz,

CH₂C=O), 1.70–1.00 (m, 31H, piv-CH₃, CH₂), 0.88 (t, 3H,

J = 6.8 Hz, propyl-CH₃). ¹³C NMR (50.3 MHz, CDCl₃,

ppm) δ: 209.8 (C-4), 177.5, 177.2, 176.0 (pivC=O), 143.8,

129.5, 128.2, 126.7 (aryl), 92.2 (C-1′), 72.7, 68.7, 66.7 (C-2′,

C-3′, C-4′), 65.3 (C-5′), 55.7 (C-6), 53.9 (C-2), 46.2, 43.8

(C-3, C-5), 39.9 (propyl-CH₂), 38.9, 38.7 (pivC_quart.), 27.3,

27.2, 27.1 (piv-CH₃), 19.2 (propyl-CH₂), 14.0 (propyl-CH₃).

ESI-MS for C₃₄H₅₁NO₈m/z: 398.5 [M – piv – 2pivOH +

H]⁺, 500.5 [M – pivOH + H]⁺, 602.5 [M + H]⁺, 624.5 [M +

Na]⁺, 640.6 [M + K]⁺.

(2R,6S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-allyl-6-n-propylpiperidin-4-one (11d)

Piperidinone 11d was prepared from 4f (1.05 g,

2.0 mmol) according to the general procedure. For the for-

mation of the orange cuprate solution, CuCN (716 mg,

8 mmol) and allylmagnesium bromide (1 mol/L in ether,

8 mL) were treated in THF (60 mL) at –40 °C for 0.5 h. Pu-

rification of 11b was accomplished by flash chromatography

(cyclohexane

– ethyl acetate, 10:1). Yield: 0.85 g

(1.50 mmol, 75%); colourless crystalline solid; mp 176 °C.

R_f0.52 (cyclohexane – ethyl acetate, 3:1). [α]²⁵+7.21° (c

D

1, CHCl₃); d.r.: 98:2 (HPLC after flash chromatography),

94:6 (HPLC of the crude product), HPLC: 80% CH₃CN,

1

20% H₂O → 100% CH₃CN, 20 min). H NMR (400 MHz,

CDCl₃, ppm) δ: 5.72–5.60 (m, 1H, CH=CH₂), 5.49 (t, 1H,

J

_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.16 (br s, 1H, H-

4′), 5.10–4.98 (m, 3H, H-3′, CH=CH₂), 4.26 (d, 1H, J_{H-1′,H-2′}

9.4 Hz, H-1′), 3.92 (dd, 1H, J_{H-5′a,H-5′b}= 13.1 Hz, J_{H-5′a,H-4′}

=

1.7 Hz, H-5′a), 3.56 (d, 1H, J_{H-5′b,H-5′a}= 12.9 Hz, H-5′b),

3.60–3.50 (m, 1H, H-6), 3.40–3.30 (m, 1H, H-2), 2.67–2.57

(m, 2H, H-3a, H-5a), 2.39 (d, 1H, J_H-5b,H-5a= 15.7 Hz, H-

5b), 2.25 (m, 2H, J_H-3b,H-3a= 15.5 Hz, J_H-3b,H-2= 6.85 Hz, H-

3b, CH₂-CH=CH₂), 2.06–1.95 (m, 1H, CH₂-CH=CH₂),

1.60–1.50 (m, 1H, CH₂-CH₂-CH₃), 1.40–1.25 (m, 2H, CH₂-

CH₂-CH₃), 1.25–1.15 (m, 28H, piv-CH₃, CH₂-CH₂-CH₃),

0.86 (t, 3H, J = 7.2 Hz, propyl-CH₃). ¹³C NMR (50.3 MHz,

CDCl₃, ppm) δ: 210.5 (C-4), 177.4, 177.2, 176.9 (pivC=O),

135.4 (CH=CH₂), 117.6 (CH=CH₂), 94.6 (C-1′), 72.3, 68.7,

66.3 (C-2′, C-3′, C-4′), 65.1 (C-5′), 58.6 (alkyl-CH-N), 44.6

(CH₂), 43.4 (CH₂), 43.0 (CH₂), 40.1 (CH₂), 38.9, 38.8, 38.7

(pivC_quart.), 27.3, 27.1, 27.1 (piv-CH₃), 19.7 (propyl-CH₂),

14.0 (propyl-CH₃). ESI-MS for C₃₁H₅₁NO₈m/z: 362.4 [M –

2pivOH + H]⁺, 464.5 [M – pivOH + H]⁺, 566.6 [M + H]⁺,

588.5 [M + Na]⁺, 604.5 [M + K]⁺. Anal. calcd. for

C₃₁H₅₁NO₈(565.74): C 65.81, H 9.09, N 2.40; found: C

66.14, H 8.91, N 2.37.

(2S,6R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-n-propyl-4-(1,3-dithiolan-2-yl)-6-methylpiperidine (13)

To a solution of piperidinone 11e (720 mg, 1.3 mmol) and

ethanedithiol (0.22 mL, 2.6 mmol) in dry dichloromethane

(9 mL) was added BF₃·OEt₂(0.78 mL, 6.7 mmol) at 0 °C.

After 1 h the reaction mixture was warmed to r.t. and stirring

was continued for 15 h. The mixture was diluted with di-

chloromethane (45 mL), washed with satd. aq. NaHCO₃(2 ×

20 mL) and water, dried over MgSO₄, and concentrated in

vacuo. The crude product was purified by flash chromatog-

raphy to yield 13 as colourless solid (662 mg, 1.1 mmol,

81%); mp 142 °C. R_f0.29 (petroleum ether – ethyl acetate,

5:1). [α]²⁶–24.46° (c 1, CHCl₃). ¹H NMR (200 MHz,

(2R,6S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

methyl-6-n-propylpiperidin-4-one (11e)

A solution of methyllithium in diethyl ether (1.6 mol/L,

9.6 mL, 15.4 mmol) was added dropwise to a cold (–35 °C)

suspension of CuI (1.50 g, 8.0 mmol) in dry THF (40 mL).

The mixture was warmed to –25 °C in 2 h. During this time,

the initially yellow solid was dissolved upon formation of a

CDCl₃, pp^Dm) δ: 5.57 (t, 1H, J_{H-2′,H-1′}= 9.8 Hz, J_{H-2′,H-3′}

=

9.8 Hz, H-2′), 5.25 – 5.15 (m, 1H, H-4′), 4.94 (dd, 1H,

J_{H-3′,H-2′}= 9.8 Hz, J_{H-3′,H-4′}= 2.9 Hz, H-3′), 4.31 (d, 1H,

J_{H-1′,H-2′}= 9.3 Hz, H-1′), 3.92 (dd, 1H, J_{H-5′b,H-5′a}= 13.2 Hz,

J_{H-5′b,H-4′}= 2.0 Hz, H-5′b), 3.53 (d, 1H, J_{H-5′a,H-5′b}= 13.2 Hz,

636

Can. J. Chem. Vol. 84, 2006

H-5′a), 3.35–3.20 (m, 4H, SCH₂CH₂S), 3.15–3.00, 2.95–

2.80 (2m, each 1H, H-2, H-6), 2.20–1.80 (m, 4H, 2CH₂),

1.40–1.10 (m, 34 H, piv-CH₃, propyl-CH₂, CH₃), 0.91 (t,

3H, J = 6.8 Hz, propyl-CH₃). ¹³C NMR (50.3 MHz, CDCl₃,

ppm) δ: 177.5, 177.4, 176.8 (piv-CH₃), 88.6 (C-1′), 72.8,

68.8, 68.2 (C-2′, C-3′, C-4′), 65.9 (C-5′), 59.2, 53.6 (C-2, C-

6), 50.0 (CH₂), 48.2 (CH₂), 38.9, 38.7, 38.7 (piv-C_quart.),

38.6 (CH₂), 38.5 (CH₂), 37.0 (CH₂), 27.3, 27.2, 27.1 (piv-

CH₃), 21.8 (CH₃), 19.8 (propyl-CH₂), 14.3 (propyl-CH₃).

Anal. calcd. for C₃₁H₃₅NO₇S₂(615.89): C 60.45, H 8.67, N

2.27, S 10.41; found: C 60.09, H 8.68, N 2.17, S 10.68.

tracted twice with diethyl ether, and the combined organic

layers were concentrated in vacuo. For the removal of

sulfolane, water was added to the oily residue and stirred un-

til a solid was formed. This was filtered, washed with water,

dissolved in diethyl ether, and dried over MgSO₄. After re-

moval of the solvent, purification was carried out by flash

chromatography (cyclohexane – ethyl acetate, 3:1) to give

17 as a colourless amorphous solid (178 mg, 0.3 mmol,

83%). R_f0.53 (cyclohexane – ethyl acetate, 1:1). [α]²²

D

1

+0.15° (c 1, CHCl₃). H NMR (300 MHz, CDCl₃, ppm) δ:

8.57 (s, 1H, H-6), 5.51 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}

9.6 Hz, H-2′), 5.32–5.26 (m, 1H, H-4′), 5.20 (dd, 1H, J_{H-3′,H-2′}

9.9 Hz, J_{H-3′,H-4′}= 3.3 Hz, H-3′), 4.76 (d, 1H, J_{H-1′,H-2′}

8.8 Hz, H-1′), 4.11 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}

=

(2R,6S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-methyl-6-n-propylpiperidine (14)

Raney nickel (5 g) was added to a solution of dithioketal

13 (500 mg, 0.8 mmol) in isopropanol (50 mL) and vigor-

ously stirred for 24 h at 70 °C under H₂atmosphere. The

mixture was filtered through Hyflo^®, and the filtrate was

concentrated in vacuo to afford pure 14 as a colourless

amorphous solid (310 mg, 0.6 mmol, 73%). R_f0.48 (petro-

leum ether – ethyl acetate, 5:1). ¹H NMR (200 MHz, CDCl₃,

ppm) δ: 5.49 (t, 1H, J_{H-2′,H-1′}= 9.5 Hz, J_{H-2′,H-3′}= 9.5 Hz, H-2′),

5.20–5.07 (m, 1H, H-4′), 5.01 (dd, 1H, J_{H-3′,H-2′}= 9.8 Hz,

J_{H-3′,H-4′}= 3.4 Hz, H-3′), 4.12 (d, 1H, J_{H-1′,H-2′}= 9.3 Hz, H-

1′), 3.89 (dd, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, J_{H-5′b,H-4′}= 2.0 Hz, H-

5′b), 3.49 (d, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, H-5′a), 3.25–3.10,

3.00–2.85 (2m, each 1H, H-2, H-6), 1.80–1.05 (m, 40 H,

piv-CH₃, CH₃, propyl-CH₂, CH₂), 0.86 (t, 3H, J = 7.1 Hz,

propyl-CH₃). ¹³C NMR (50.3 MHz, CDCl₃, ppm) δ: 177.5,

176.7 (pivC=O), 96.8 (C-1′), 72.7, 69.0, 66.0 (C-2′, C-3′, C-

4′), 64.8 (C-5′), 38.9, 38.7, 38.7 (piv-C_quart.), 38.5 (CH₂),

31.7 (CH₂), 28.4 (CH₂), 27.3, 27.1, 27.1 (piv-CH₃), 22.4

(CH₃), 21.5 (CH₂), 15.4 (CH₂), 14.4 (propyl-CH₃).

1.8 Hz, H-5′a), 4.16–4.03 (m, 1H, H-2), 3.81 (d, 1H,

J_{H-5′b,H-5′a}= 12.9 Hz, H-5′b), 2.82 (dd, 1H, J_H-3a,H-3b

=

16.2 Hz, J_H-3a,H-2= 6.2 Hz, H-3a), 2.34 (dd, J_H-3b,H-3a= 16.4,

J_H-3b,H-2= 1.7 Hz, H-3b), 1.35 (d, 3H, J = 7.0 Hz, CH₃),

1.26, 1.11, 1.08 (3s, each 9H, piv-CH₃). ESI-MS for

C₂₆H₄₀N₂O₁₀m/z: 541.7 [M + H]⁺, 563.6 [M + Na]⁺, 579.6

[M + K]⁺, 604.6 [M + MeCN + Na]⁺, 1104.2 [2M + Na]⁺.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

ethyl-5-nitro-5,6-dehydropiperidin-4-one (18)

In a similar manner, dehydropiperidinone 4e (3.02 g,

5.9 mmol) in dichloromethane (80 mL) was treated with a

solution of nitronium tetrafluoroborate in sulfolane

(0.5 mol/L, 18 mL, 9 mmol). Purification was carried out by

flash chromatography (cyclohexane – ethyl acetate, 3:1) to

give 18 as a colourless amorphous solid (2.68 g 4.8 mmol,

82%). R_f0.57 (cyclohexane – ethyl acetate, 1:1). [α]²²

D

1

+28.76° (c 1, CHCl₃). H NMR (300 MHz, CDCl₃, ppm) δ:

8.58 (s, 1H, H-6), 5.52 (t, 1H, J_{H-2′,H-1′}= 9.4 Hz, J_{H-2′,H-3′}

9.4 Hz, H-2′), 5.32–5.26 (m, 1H, H-4′), 5.19 (dd, 1H, J_{H-3′,H-2′}

10.1 Hz, J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.78 (d, 1H, J_{H-1′,H-2′}

8.8 Hz, H-1′), 4.12 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}

=

(+)-(2R,6S)-2-methyl-6-n-propylpiperidine hydrochloride

(dihydropinidine) (15)

Piperidine 14 (240 mg, 0.46 mmol) was dissolved in

methanol (6 mL), treated with 1 N HCl (0.7 mL, 0.70 mmol)

and stirred at r.t. for 48 h. The solvent was evaporated in

vacuo the residue was dissolved in diethyl ether and ex-

tracted with water (3 × 10 mL). Lyophilization of the aque-

ous layers afforded 15 as colourless solid (quant.); mp 215–

2.2 Hz, H-5′a), 3.87 – 3.71 (m, 1H, H-2), 3.81 (d, 1H,

J_{H-5′b,H-5′a}= 12.9 Hz, H-5′b), 2.74 (dd, 1H, J_H-3a,H-3b

=

16.5 Hz, J_H-3a,H-2= 6.3 Hz, H-3a), 2.57 (dd, J_H-3b,H-3a= 16.5,

J_H-3b,H-2= 1.1 Hz, H-3b), 1.87–1.72 (m, 2H, CH₂), 1.26,

1.11, 1.08 (3s, 27H, piv-CH₃), 0.88 (t, 3H, J = 7.5 Hz, CH₃).

¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 180.1 (C-4), 177.3,

176.9, 176.8 (pivC=O), 153.2 (C-6), 123.5 (C-5), 93.0 (C-

1′), 70.2, 67.5, 66.1 (C-2′, C-3′, C-4′), 66.7 (C-5′), 55.9 (C-

2), 39.0, 39.0, 38.8 (piv_quart), 38.5 (C-3), 27.1, 27.0, 27.0

(piv-CH₃), 24.6 (CH₂), 9.9 (CH₃). ESI-MS for C₂₇H₄₂N₂O₁₀

(554.63) m/z: 555.2 [M + H]⁺, 577.3 [M + Na]⁺, 618.4 [M +

Na + MeCN]⁺, 1131.5 [2M + Na]⁺.

220 °C. [α]²⁵+11.05° (c 1, ethanol) (lit. value (9) [α]²⁵

D

+11.6 to +14.^D2° (ethanol); enantiomer: lit. value (9) [α]²⁵

D

–9.1 to –12.7° (ethanol); lit. value (3) [α]²²–11.1° (c 1,

D

1

ethanol). H NMR (200 MHz, CDCl₃, ppm) δ: 9.07 (br s,

1H, NH), 8.68 (br s, 1H, NH), 3.15–2.80 (m, 2H, H-2, H-6),

1.90–1.00 (m, 13H, 5CH₂, CH₃), 0.87 (t, 3H, J = 7.1 Hz,

propyl-CH₃). ¹³C NMR (50.3 MHz, CDCl₃, ppm) δ: 56.0,

52.5 (C-2, C-6), 34.82, 29.78, 27.05, 22.01, 18.75, 17.86

(5CH₂, CH₃), 13.68 (propyl-CH₃).

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

benzamido-2-ethyl-5,6-dehydropiperidin-4-one (19)

To a suspension of Raney nickel (3 g) in ethanol, satu-

rated with H₂, was added a solution of 18 (4 g, 7.2 mmol) in

ethanol (160 mL) and stirred for 22 h under a H₂atmo-

sphere. The mixture was filtered through Hyflo^®, and the fil-

trate was concentrated in vacuo. The residue was dissolved

in diethyl ether, dried over MgSO₄, and evaporated to dry-

ness. The remaining solid was dissolved in dry THF.

Triethylamine (4.5 mL, 32.4 mmol) and freshly distilled

benzoyl chloride (2.5 mL, 21.6 mmol) were added, and the

solution was stirred for 10 h at room temperature. After ad-

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

methyl-5-nitro-5,6-dehydropiperidin-4-one (17)

A solution of nitronium tetrafluoroborate in sulfolane

(0.5 mol/L, 1.5 mL, 0.75 mmol) was added slowly to 4d

(198 mg, 0.4 mmol) in dichloromethane (4 mL) at –78 °C.

The mixture was allowed to reach r.t. and was quenched

with satd. aq. NaHCO₃. The solvent was removed in vacuo,

the residue was dissolved in diethyl ether (20 mL), and ex-

tracted with satd. aq. NaHCO₃. The aqueous layer was ex-

Kranke and Kunz

637

dition of satd. aq. NH₄Cl (200 mL), the mixture was ex-

tracted with diethyl ether (3 × 100 mL). The combined

organic layers were washed with brine and dried over

MgSO₄. The solvent was removed in vacuo and the crude

product was purified by flash chromatography to yield 19 as

a colourless amorphous solid (3.2 g, 5.1 mmol, 70%). R_f

J

_{H-3′,H-4′}= 3.5 Hz, H-3′), 4.90–4.80 (m, 1H, H-5), 4.29 (d, 1H,

J_{H-1′,H-2′}= 9.0 Hz, H-1′), 4.04 (dd, 1H, J_H-6a,H-6b= 12.7 Hz,

J_H-6a,H-5= 7.6 Hz, H-6a), 3.98 (dd, 1H, J_{H-5′a,H-5′b}= 13.1 Hz,

J_{H-5′a,H-4′}= 2.1 Hz, H-5′a), 3.61 (d, 1H, J_{H-5′b,H-5′a}= 12.9 Hz,

H-5′b), 3.44–3.35 (m, 1H, H-2), 2.87 (dd, 1H, J_H-3a,H-3b

12.9 Hz, J_H-3a,H-2= 6.3 Hz, H-3a), 2.79 (dd, 1H, J_H-6b,H-6a

13.3 Hz, J_H-6b,H-5= 10.2, H-6b), 2.47 (dd, J_H-3b,H-3a= 12.9 Hz,

J_H-3b,H-2= 1.6 Hz, H-3b), 1.63–1.51 (m, 1H, CH₂), 1.43–1.31

(m, 1H, CH₂), 1.30, 1.15, 1.13 (3s, 27H, piv-CH₃), 0.85 (t,

3H, J = 7.4 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃, ppm) δ:

206.6 (C-4), 177.7, 177.4, 177.1 (pivC=O), 166.6 (NH-

C=O), 134.1 (ipso-aryl), 131.5, 128.5, 127.1 (aryl), 95.7 (C-

1′), 71.9, 68.3, 66.2, 65.4 (C-2′, C-3′, C-4′, C-5′), 62.7 (C-5),

58.1 (C-2), 49.2 (C-6), 45.1 (C-3), 39.0, 38.8 (piv_quart.), 27.3,

27.2, 27.1 (piv-CH₃), 25.1 (CH₂), 11.3 (CH₃). ESI-MS for

C₃₄H₅₀N₂O₉m/z: 325.3 [M – 3pivOH + H]⁺, 449.5 [M –

2pivOH + Na]⁺, 551.6 [M – pivOH + Na]⁺, 631.6 [M + H]⁺,

653.6 [M + Na]⁺.

=

0.35 (cyclohexane – ethyl acetate, 2:1). [α]²²+54.52° (c 1,

D

1

CHCl₃). H NMR (300 MHz, CDCl₃, ppm) δ: 8.73 (s, 1H,

H-6), 8.40 (br s, 1H, NH), 8.12–8.04 (m, 1H, phenyl), 7.86–

7.78 (m, 2H, phenyl), 7.47–7.39 (m, 2H, phenyl), 5.56 (t,

1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.28–5.22

(m, 1H, H-4′), 5.13 (dd, 1H, J_{H-3′,H-2′}= 10.1 Hz, J_{H-3′,H-4′}

=

3.1 Hz, H-3′), 4.60 (d, 1H, J_{H-1′,H-2′}= 8.8 Hz, H-1′), 4.03 (dd,

1H, J_{H-5′a,H-5′b}= 13.4 Hz, J_{H-5′a,H-4′}= 2.0 Hz, H-5′a), 3.72–

3.59 (m, 1H, H-2), 3.69 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b),

2.79 (dd, 1H, J_H-3a,H-3b= 17.3 Hz, J_H-3a,H-2= 6.6 Hz, H-3a),

2.55 (dd, J_H-3b,H-3a= 17.3 Hz, J_H-3b,H-2= 1.5 Hz, H-3b),

2.04–1.88 (m, 1H, CH₂), 1.87–1.71 (m, 1H, CH₂), 1.26,

1.11, 1.08 (3s, 27H, piv-CH₃), 0.86 (t, 3H, J = 7.4 Hz, CH₃).

¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 184.5 (C-4), 177.4,

177.1, 177.0 (pivC=O), 164.4 (NH-C=O), 134.2 (ipso-aryl),

133.5, 131.5, 130.1, 128.6, 128.4, 126.9 (aryl, C-6), 112.4

(C-5), 92.6 (C-1′), 71.0, 68.0, 66.4 (C-2′, C-3′, C-4′), 66.1

(C-5′), 53.9 (C-2), 39.0, 38.9, 38.7 (piv_quart.), 36.8 (C-3),

27.1, 27.0 (piv-CH₃), 23.7 (CH₂), 10.2 (CH₃). ESI-MS m/z:

323.3 [M – 3pivOH + H]⁺, 425.5 [M – 2pivOH + H]⁺, 527.5

[M – pivOH + H]⁺, 651.6 [M + Na]⁺, 692.8 [M + Na +

MeCN]⁺. HRMS calcd. for C₃₄H₄₈N₂O₉: 629.3438; found:

629.3424.

General procedure for the halogenation of

dehydropiperidinones 4

To a solution of N-arabinosyl dehydropiperidinone 4

(1 mmol) in dry THF (20 mL) were added several equiva-

lents (see for each compound) of solid N-bromosuccinimide

or N-iodosuccinimide at –78 °C and stirred until complete

consumption of the starting material. The solution was di-

luted with diethyl ether (100 mL), washed with 10% aq.

Na₂S₂O₃(3 × 20 mL), and the resulting aqueous layers were

extracted with diethyl ether (3 × 20 mL). The combined or-

ganic layers were washed with brine, dried over MgSO₄, and

concentrated in vacuo. The crude product was purified by

flash chromatography.

N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

benzamido-2-ethylpiperidin-4-one (20)

(a) Preparation of the aluminum complex MAD

At r.t., trimethylaluminium (2 mol/L in toluene, 0.1 mL)

was added to a solution of 2,6-di-tert-butyl-4-methylphenol

(86 mg, 0.39 mmol) in toluene (3 mL) and stirred until the

methane evolution ceased (30 min).

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(p-chlorophenyl)-5-iodo-5,6-dehydropiperidin-4-one (21a)

Iododehydropiperidinone 21a was synthesized according

to the general procedure using 4a (1.18 g, 2 mmol) and N-

iodosuccinimide (1.35, 6 mmol). Purification was carried out

by flash chromatography (petroleum ether – ethyl acetate,

6:1) to yield 21a (1.33 g, 1.9 mmol, 93%) as a colourless

solid. R_f0.65 (petroleum ether – ethyl acetate, 2:1); mp

205 °C under decomposition. [α]²²_D+3.77° (c 1, CHCl₃). ¹H

NMR (400 MHz, CDCl₃, ppm) δ: 7.70 (s, 1H, H-6), 7.27 (d,

1H, J = 4.3 Hz, aryl), 7.17 (d, 1H, J = 8.6 Hz, aryl), 5.56 (t,

1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.18–5.13

(b) Conjugate hydride addition

The clear solution preapared under (a) was cooled to

–78 °C and a solution of 19 (25 mg, 0.04 mmol) in THF

(2 mL) was added dropwise. After 15 min, ^L-Selectride^®

(1 mol/L in THF, 0.08 mL) was added at the same tempera-

ture, and the mixture was then allowed to warm to –40 °C

within 3 h. The reaction was terminated by addition of acetic

acid (0.05 mL), and the solvent was evaporated in vacuo.

The residue was dissolved in diethyl ether (50 mL), washed

with 1 N HCl (20 mL) and water (20 mL), and dried over

MgSO₄. Evaporation of the solvent in vacuo afforded the

crude product, which was purified by flash chromatography

(cyclohexane – ethyl acetate, 5:1) to yield 20 as a colourless

amorphous solid (22 mg, 0.035 mmol, 88%). R_f0.40

(br s, 1H, H-4′), 5.05 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}

3.3 Hz, H-3′), 4.91 (t, 1H, J_H-2,H-3a= 6.3 Hz, J_H-2,H-3b

=

6.3 Hz, H-2), 4.37 (d, 1H, J_{H-1′,H-2′}= 9.0 Hz, H-1′), 3.85 (dd,

1H, J_{H-5′a,H-5′b}= 13.3 Hz, J_{H-5′a,H-4′}= 2.0 Hz, H-5′a), 3.49 (d,

1H, J_{H-5′b,H-5′a}= 12.9 Hz, H-5′b), 3.05 (dd, 1H, J_H-3a,H-3b

16.4 Hz, J_H-3a,H-2= 6.2 Hz, H-3a), 2.83 (dd, 1H, J_H-3b,H-3a

=

(toluene – ethyl acetate, 3:1). [α]²²+4.90° (c 1, CHCl₃);

16.4 Hz, J_H-3b,H-2= 6.3 Hz, H-3b), 1.23, 1.16, 1.10 (3s, 27H,

C(CH₃)₃). ¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 184.9 (C-

4), 177.2, 177.1, 177.0 (pivC=O), 154.7 (C-6), 136.8 (ipso-

aryl), 134.2 (ipso-aryl), 129.1, 128.0 (aryl), 89.8 (C-1′), 70.8,

67.7, 66.0 (C-2′, C-3′, C-4′), 66.1 (C-5′), 57.9 (C-2), 42.1 (C-

3), 39.0, 38.9, 38.8 (piv_quart.), 27.2, 27.1, 27.0 (piv-CH₃).

ESI-MS for C₃₁H₄₁ClINO₈m/z: 718.2 [M(³⁵Cl) + H]⁺, 720.2

[M(³⁷Cl) + H]⁺, 740.2 [M(³⁵Cl) + Na]⁺, 742.2 [M(³⁷Cl) + Na]⁺.

D

d.r.: 89:11 (HPLC: 80% CH₃CH, 20% H₂O → 100%

CH₃CN, 30 min); recrystallization from ether afforded the

1

pure major diastereomer. H NMR (400 MHz, CDCl₃, ppm)

δ: 7.80–7.75 (m, 2H, phenyl), 7.50–7.45 (m, 1H, phenyl),

7.44–7.37 (m, 2H, phenyl), 7.01 (d, 1H, J_NH,H-5= 5.8 Hz,

NH), 5.52 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′),

5.26–5.22 (m, 1H, H-4′), 5.15 (dd, 1H, J_{H-3′,H-2′}= 9.8 Hz,

638

Can. J. Chem. Vol. 84, 2006

6.6 mmol, 87%) as a colourless amorphous solid. R_f0.49

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-D-arabinopyranosyl)-5-

iodo-2-phenyl-5,6-dehydropiperidin-4-one (21b)

(cyclohexane – ethyl acetate, 2:1). [α]²²+122.00° (c 1,

D

1

Iododehydropiperidinone 21b was synthesized according

to the general procedure using 4c (1.40 g, 2.51 mmol) and

N-iodosuccinimide (1.70 g, 7.53 mmol). Purification was

achieved by flash chromatography (petroleum ether – ethyl

acetate, 8:1) to yield 21b (1.15 g, 1.68 mmol, 67%) as a pale

yellow amorphous solid. R_f0.58 (cyclohexane – ethyl ace-

CHCl₃). H NMR (300 MHz, CDCl₃, ppm) δ: 7.45 (s, 1H,

H-6), 5.53 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′),

5.26–5.21 (m, 1H, H-4′), 5.12 (dd, 1H, J_{H-3′,H-2′}= 9.9 Hz,

J_{H-3′,H-4′}= 3.3 Hz, H-3′), 4.51 (d, 1H, J_{H-1′,H-2′}= 9.2 Hz,

H-1′), 4.03 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}= 2.2 Hz,

H-5′a), 3.68 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b), 3.68–3.60

(m, 1H, H-2), 2.77–2.70 (m, 2H, H-3a, H-3b), 2.34–2.17 (m,

1H, CH(CH₃)₂), 1.26, 1.12, 1.11 (3s, 27H, piv-CH₃), 0.88

(d, 3H, J = 7.0 Hz, CH₃), 0.87 (d, 3H, J = 6.6 Hz, CH₃). ¹³C

NMR (75.4 MHz, CDCl₃, ppm) δ: 186.2 (C-4), 177.2, 177.0,

177.0 (pivC=O), 154.8 (C-6), 91.6 (C-1′), 71.1, 67.8, 66.2

(C-2′, C-3′, C-4′), 66.2 (C-5′), 64.2 (C-5), 58.8 (C-2), 39.0,

39.0, 38.8 (piv_quart), 34.7 (C-3), 32.3 (CH(CH₃)₃), 27.2, 27.1,

27.0 (piv-CH₃), 19.6, 17.6 (CH₃). ESI-MS for C₂₈H₄₄INO₈

m/z: 650.3 [M + H]⁺, 672.2 [M + Na]⁺, 688.2 [M + K]⁺.

1

tate, 2:1). [α]²²–11.83° (c 1, CHCl₃). H NMR (300 MHz,

CDCl₃, ppm) δ^D: 7.76 (s, 1H, H-6), 7.36–7.28 (m, 3H, aryl),

7.27–7.19 (m, 2H, aryl), 5.58 (t, 1H, J_{H-2′,H-1′}= 9.6 Hz,

J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.16–5.09 (m, 1H, H-4′), 4.99 (dd,

1H, J_{H-3′,H-2′}= 9.9 Hz, J_{H-3′,H-4′}= 2.9 Hz, H-3′), 4.91 (dd, 1H,

J_H-2,H-3b= 8.3 Hz, J_H-2,H-3a= 6.1 Hz, H-2), 4.27 (d, 1H,

J_{H-1′,H-2′}= 9.2 Hz, H-1′), 3.85 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz,

J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.41 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz,

H-5′b), 3.01 (dd, 1H, J_H-3a,H-3b= 16.5 Hz, J_H-3a,H-2= 5.9 Hz,

H-3a), 2.88 (dd, 1H, J_H-3b,H-3a= 16.2 Hz, J_H-3b,H-2= 8.5 Hz,

H-3b), 1.25, 1.17, 1.10 (3s, 27H, C(CH₃)₃). ¹³C NMR

(75.4 MHz, CDCl₃, ppm) δ: 185.5 (C-4), 177.2, 177.1, 177.1

(pivC=O), 154.8 (C-6), 137.8 (ipso-aryl), 129.0, 128.7,

126.9 (aryl), 88.7 (C-1′), 71.0, 67.8, 66.0, 65.8 (C-2′, C-3′,

C-4′, C-5′), 59.7 (C-2), 42.4 (C-3), 39.0, 38.8, 38.8 (piv_quart.),

27.2, 27.2, 27.0 (piv-CH₃). ESI-MS for C₃₁H₄₂I NO₈m/z:

322.0 [dehydropiperidinone + H + Na]⁺, 706.0 [M + Na]⁺,

747.1 [M + Na + MeCN]⁺.

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(3-tert-butyldiphenylsiloxy)propyl-5-iodo-5,6-dehydropiperi-

din-4-one (21e)

Iododehydropiperidinone 21e was synthesized according

to the general procedure using 4h (1.56 g, 2 mmol) and N-

iodosuccinimide (1.35 g, 6 mmol). Purification was per-

formed by flash chromatography (petroleum ether – ethyl

acetate, 8:1) to yield 21e (1.57 g, 1.70 mmol, 87%) as a pale

yellow amorphous solid. R_f0.58 (petroleum ether – ethyl ac-

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

iodo-2-n-propyl-5,6-dehydropiperidin-4-one (21c)

etate, 2:1). [α]²⁵+71.63° (c 1, CHCl₃). ¹H NMR

D

(400 MHz, CDCl₃, ppm) δ: 7.63–7.56 (m, 4H, aryl), 7.43–

Iododehydropiperidinone 21c was synthesized according

to the general procedure using 4f (524 mg, 1 mmol) and N-

iodosuccinimide (900 mg, 4 mmol). Purification was carried

out by flash chromatography (petroleum ether – ethyl ace-

tate, 8:1) to yield 21c (450 mg, 0.7 mmol, 69%) as a colour-

less amorphous solid. R_f0.57 (petroleum ether – ethyl

7.32 (m, 7H, aryl, H-6), 5.50 (t, J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}

=

9.6 Hz, H-2′), 5.26–5.21 (br s, 1H, H-4′), 5.12 (dd, 1H,

J_{H-3′,H-2′}= 10.2 Hz, J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.45 (d, 1H,

J_{H-1′,H-2′}= 9.0 Hz, H-1′), 3.99 (dd, 1H, J_{H-5′a,H-5′b}= 13.3 Hz,

J_{H-5′a,H-4′}= 2.0 Hz, H-5′a), 3.83–3.73 (m, 1H, H-2), 3.69–

3.50 (m, 3H, J_{H-5′b,H-5′a}= 13.3 Hz, H-5′b, O-CH₂), 2.75 (dd,

1H, J_H-3a,H-3b= 16.4 Hz, J_H-3a,H-2= 6.3 Hz, H-3a), 2.65 (dd,

1H, J_H-3b,H-3a= 16.6 Hz, J_H-3b,H-2= 1.8 Hz, H-3b), 1.90–1.77

(m, 2H, CH₂), 1.63–1.36 (m, 2H, CH₂), 1.23 (s, 9H,

C(CH₃)₃), 1.11 (s, 18H, C(CH₃)₃), 0.99 (s, 9H, C(CH₃)₃).

¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 185.6 (C-4), 177.2,

177.0 (pivC=O), 154.0 (C-6), 135.5, 135.5 (aryl), 133.7,

133.7 (ipso-aryl), 129.6, 127.7 (aryl), 91.5 (C-1′), 70.8, 67.8,

66.3 (C-2′, C-3′, C-4′), 66.3 (C-5′), 63.2 (OCH₂), 53.9 (C-2),

39.0, 38.9, 38.8 (piv_quart.), 38.2 (C-3), 28.8, 27.6 (CH₂), 27.2,

27.2, 27.0, 26.8 (piv-CH₃, SiC(CH₃)₃), 19.2 (SiC(CH₃)₃).

ESI-MS for C₄₄H₆₂INO₉Si m/z: 826.3 [M – phenyl]⁺, 904.2

[M + H]⁺, 926.2 [M + Na]⁺.

acetate, 2:1). [α]²⁶+123.19° (c 1, CHCl₃). ¹H NMR

D

(400 MHz, CDCl₃, ppm) δ: 7.37 (s, 1H, H-6), 5.50 (t, J_{H-2′,H-1′}

=

9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.27–5.23 (m, 1H, H-4′),

5.12 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.3 Hz, H-3′),

4.47 (d, 1H, J_{H-1′,H-2′}= 9.0 Hz, H-1′), 4.03 (dd, 1H, J_{H-5′a,H-5′b}

=

13.3 Hz, J_{H-5′a,H-4′}= 2.3 Hz, H-5′a), 3.85–3.76 (m, 1H, H-2),

3.69 (d, 1H, J_{H-5′b,H-5′a}= 13.3 Hz, H-5′b), 2.72 (dd, 1H,

J_H-3a,H-3b= 16.6 Hz, J_H-3a,H-2= 5.7 Hz, H-3a), 2.67 (dd, 1H,

J_H-3b,H-3a= 16.64 Hz, J_H-3b,H-2= 2.6 Hz, H-3b), 1.90–1.78

(m, 1H, CH₂), 1.67–1.55 (m, 2H, CH₂), 1.40–1.28 (m, 1H,

CH₂), 1.25 (s, 9H, piv-CH₃), 1.11 (s, 18H, piv-CH₃), 0.86 (t,

3H, J = 7.2 Hz, CH₃). ¹³C NMR (100.6 MHz, CDCl₃, ppm)

δ: 185.8 (C-4), 177.2, 177.2, 177.0 (pivC=O), 154.4 (C-6),

91.7 (C-1′), 70.8, 67.8, 66.3 (C-2′, C-3′, C-4′), 66.4 (C-5′),

63.1 (C-5), 53.5 (C-2), 38.9, 38.9, 38.8 (piv_quart), 37.9, 32.8

(C-3, CH₂), 27.1, 27.1, 27.0 (piv-CH₃), 18.8 (CH₂), 13.7

(CH₃). ESI-MS for C₂₈H₄₄INO₈m/z: 446.04 [M – 2pivOH +

H]⁺, 650.21 [M + H]⁺, 672.19 [M + Na]⁺, 713.08 [M + Na +

CH₃CN]⁺.

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

bromo-2-(p-chlorophenyl)-5,6-dehydropiperidin-4-one

(21f)

Bromodehydropiperidinone 21f was synthesized accord-

ing to the general procedure using 4a (3.5 g, 5.9 mmol) and

N-bromosuccinimide (2.1 g, 11.8 mmol). Purification was

carried out by flash chromatography (cyclohexane – ethyl

acetate, 8:1) to yield 21f (3.0 g, 4.4 mmol, 75%) as a colour-

less amorphous solid. R_f0.5 (cyclohexane – ethyl acetate,

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

iodo-2-isopropyl-5,6-dehydropiperidin-4-one (21d)

Iododehydropiperidinone 21d was synthesized according

to the general procedure using 4g (4.0 g, 7.6 mmol) and N-

iodosuccinimide (5.4 g, 24 mmol). Purification was accom-

plished by flash chromatography to yield 21d (4.31 g,

2:1). [α]²²–11.57° (c 1, CHCl₃). ¹H NMR (200 MHz,

D

CDCl₃, ppm) δ: 7.60 (s, 1H, H-6), 7.29 (d, 2H, J = 8.8 Hz,

aryl), 7.18 (d, 2H, J = 8.8 Hz, aryl), 5.56 (t, 1H, J_{H-2′,H-1′}

=

Kranke and Kunz

639

9.5 Hz, J_{H-2′,H-3′}= 9.5 Hz, H-2′), 5.22–5.13 (m, 1H, H-4′),

5.03 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.2 Hz, H-3′),

4.87 (t, 1H, J_H-2,H-3a= 6.6 Hz, J_H-2,H-3b= 6.6 Hz, H-2), 4.33

4.44 (d, 1H, J_{H-1′,H-2′}= 8.8 Hz, H-1′), 3.99 (d, 1H, J_{H-5′a,H-5′b}

=

13.2 Hz, J_H-5′a,

= 2.0 Hz, H-5′a), 3.85–3.45 (m, 4H,

J_{H-5′b, H-5′a}= 13.^H2^-4H^′z, H-5′b, CH₂-O, H-2), 2.76 (dd, 1H,

J_H-3a,H-3b= 16.6 Hz, J_H-3a,H-2= 5.9 Hz, H-3a), 2.55 (dd, 1H,

J_H-3b,H-3a= 16.6 Hz, J_H-3b,H-2= 2.0 Hz, H-3b), 1.95–1.70 (m,

2H, CH₂), 1.70–1.40 (m, 2H, CH₂), 1.23 (s, 9H, C(CH₃)₃),

1.11 (s, 18H, C(CH₃)₃), 0.99 (s, 9H, C(CH₃)₃). ¹³C NMR

(100.6 MHz, CDCl₃, ppm) δ: 184.3 (C-4), 177.2, 177.2,

177.0 (pivC=O), 149.6 (C-6), 135.5, 135.5 (aryl), 133.7,

133.6 (ipso-aryl), 129.6, 127.7 (aryl), 91.6, 91.0 (C-1′, C-5),

70.8, 67.8, 66.2 (C-2′, C-3′, C-4′), 66.3 (C-5′), 63.2 (OCH₂),

53.9 (C-2), 39.0 (C-3), 38.9, 38.9, 38.8 (piv_quart.), 28.8, 27.5

(CH₂), 27.2, 27.1, 27.0, 26.8 (pivCH₃, SiC(CH₃)₃), 19.2

(SiC(CH₃)₃). ESI-MS for C₄₄H₆₂BrNO₉Si m/z: 778.2

[(M(⁷⁹Br) – phenyl]⁺, 780.2 [M(⁸¹Br) – phenyl]⁺, 856.2

[M(⁷⁹Br) + H]⁺, 858.2 [M(⁸¹Br) + H]⁺, 878.1 [M(⁷⁹Br) +

Na]⁺, 880.1 [M(⁸¹Br) + Na]⁺, 894.1 [M(⁷⁹Br) + K]⁺, 896.1

[M(⁸¹Br) + K]⁺, 919.2 [M(⁷⁹Br) + Na + CH₃CN]⁺, 921.2

[M(⁸¹Br) + Na + CH₃CN]⁺.

(d, 1H, J_{H-1′,H-2′}= 9.3, H-1′), 3.86 (dd, 1H, J_{H-5′a,H-5′b}

13.2 Hz, J_{H-5′a,H-4′}= 2.0 Hz, H-5′a), 3.47 (d, 1H, J_{H-5′b,H-5′a}

13.2 Hz, H-5′b), 3.00 (dd, 1H, J_H-3a,H-3b= 16.6 Hz, J_H-3a,H-2

5.9 Hz, H-3a), 2.78 (dd, 1H, J_H-3b,H-3a= 16.6 Hz, J_H-3b,H-2

=

7.3 Hz, H-3b), 1.23, 1.16, 1.10 (3s, 27H, piv-CH₃). ¹³C

NMR (50.3 MHz, CDCl₃, ppm) δ: 183.7 (C-4), 177.2, 177.1,

177.0 (pivC=O), 150.2 (C-6), 136.5, 134.4 (ipso-aryl),

129.2, 128.2 (aryl), 94.5 (C-5), 89.6 (C-1′), 70.9 (C-3′), 67.8

(C-4′), 66.2 (C-5′), 65.9 (C-2′), 58.3 (C-2), 43.1 (C-3), 39.0,

38.9 (piv_quart.), 27.2, 27.2, 27.0 (piv-CH₃). ESI-MS for

C₃₁H₄₁BrClNO₈m/z: 672.5 [M(⁸¹Br) + H]⁺, 692.2 [M(⁷⁹Br)

+ Na]⁺, 694.2 [M(⁸¹Br) + Na]⁺, 708.2 [M(⁷⁹Br) + K]⁺, 710.2

[M(⁸¹Br) + K]⁺, 733.2 [M(⁷⁹Br) + Na + CH₃CN]⁺, 735.2

[M(⁸¹Br) + Na + CH₃CN]⁺.

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

bromo-2-isopropyl-5,6-dehydropiperidin-4-one (21g)

(2R)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(p-chlorophenyl)-5-phenyl-5,6-dehydropiperidin-4-one (22)

A two-necked round bottom flask equipped with a reflux

condenser and a septum was charged with iodide 21a

(180 mg, 0.25 mmol), bis(dibenzylideneacetone)palladium

(14 mg, 0.025 mmol), and triphenylarsine (31 mg,

0.10 mmol), and then evacuated and flushed with argon. Dry

THF (10 mL) was added and the mixture was stirred for

5 min for the formation of the active catalyst (colour change

from red to yellow). Phenyl tributyltin 0.16 mL (0.50 mmol)

was then added and the solution was heated to 65 °C for

17 h. After cooling, the reaction mixture was treated with

1 mol/L aq. KF (1 mL) and stirred for 30 min. It was then

diluted with diethyl ether (50 mL), washed with water, and

dried over MgSO₄. The solvent was evaporated in vacuo and

the product was purified by flash chromatography (cyclohex-

ane – ethyl acetate, 7:1) affording 22 (74 mg, 0.11 mmol,

44%), as a pale yellow amorphous solid. R_f0.46 (cyclohex-

NMR (200 MHz, CDCl₃, ppm)^Dδ: 7.54–7.10 (m, 10H, H-6,

aryl), 5.68 (t, 1H, J_{H-2′,H-1′}= 9.5 Hz, J_{H-2′, H-3′}= 9.5 Hz, H-2′),

5.20–5.12 (m, 1H, H-4′), 5.03 (dd, 1H, J_{H-3′,H-2′}= 9.8 Hz,

J_{H-3′,H-4′}= 2.9 Hz, H-3′), 4.88 (dd, 1H, J_H-2,H-3a= 7.8 Hz,

J_H-2,H-3b= 5.9 Hz, H-2), 4.37 (d, 1H, J_{H-1′,H-2′}= 9.3 Hz,

H-1′), 3.86 (dd, 1H, J_{H-5′a,H-5′b}= 13.4 Hz, J_{H-5′a,H-4′}= 1.7 Hz,

H-5′a), 3.47 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b), 2.96 (dd,

1H, J_H-3a,H-3b= 16.4 Hz, J_H-3a,H-2= 5.6 Hz, H-3a), 2.75 (dd,

1H, J_H-3a,H-3b= 16.3 Hz, J_H-3b,H-2= 8.0 Hz, H-3b), 1.20,

1.14, 1.10 (3s, 27H, piv-CH₃). ¹³C NMR (100.6 MHz,

CDCl₃, ppm) δ: 188.8 (C-4), 177.1, 177.1, 177.0 (pivC=O),

148.7 (C-6), 137.1, 135.0, 134.2 (ipso-aryl), 129.1, 128.4,

128.2, 127.9, 126.5 (aryl), 115.4 (C-5), 89.6 (C-1′), 71.1,

67.9, 65.7 (C-2′, C-3′, C-4′), 66.1 (C-5′), 58.7 (C-2), 44.1 (C-

3), 38.9, 38.9, 38.8 (piv_quart.), 27.2, 27.1, 27.0 (piv-CH₃).

ESI-MS for C₃₇H₄₆ClNO₈m/z: 668.5 [M(³⁵Cl) + H]⁺, 690.5

[M(³⁵Cl) + Na]⁺, 731.4 [M(³⁵Cl) + Na + CH₃CN]⁺.

Bromodehydropiperidinone 21g was synthesized accord-

ing to the general procedure using 4g (2.0 g, 3.8 mmol) and

N-bromosuccinimide (3.4 g, 19 mmol). Purification was

achieved by flash chromatography (cyclohexane – ethyl ace-

tate, 5:1) to yield 21g (1.7 g, 2.8 mmol, 73%) as a colourless

amorphous solid. R_f0.28 (cyclohexane – ethyl acetate, 3:1).

1

[α]²⁵108.56° (c 1, CHCl₃). H NMR (300 MHz, CDCl₃,

ppm)^Dδ: 7.33 (s, 1H, H-6), 5.53 (t, 1H, J_{H-2′,H-1′}= 9.4 Hz,

J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.26–5.20 (m, 1H, H-4′), 5.12 (dd,

1H, J_{H-3′,H-2′}= 9.9 Hz, J_{H-3′,H-4′}= 3.3 Hz, H-3′), 4.50 (d, 1H,

J_{H-1′,H-2′}= 9.2 Hz, H-1′), 4.02 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz,

J_{H-5′a,H-4′}= 2.2 Hz, H-5′), 3.69 (d, 1H, J_{H-5′b,H-5′a}= 12.9 Hz,

H-5′b), 3.63–3.55 (m, 1H, H-2), 2.76 (dd, 1H, J_H-3a,H-3b

16.9 Hz, J_H-3a,H-2= 7.4 Hz, H-3a), 2.64 (dd, 1H, J_H-3b,H-3a

=

16.9 Hz, J_H-3b,H-2= 2.6 Hz, H-3b), 2.34–2.13 (m, 1H,

CH(CH₃)₂), 1.25, 1.11, 1.11 (3s, 27H, piv-CH₃), 0.89 (d, 6H,

J = 7.0 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃, ppm) δ:

184.9 (C-4), 177.2, 177.2, 177.0 (pivC=O), 150.2 (C-6),

91.7 (C-5), 91.7 (C-1′), 71.1, 67.8, 66.2 (C-2′, C-3′, C-4′),

66.3 (C-5′), 58.9 (C-2), 39.0, 38.8 (piv_quart), 35.6 (C-3), 32.0

(CH(CH₃)₃), 27.1, 27.0 (piv-CH₃), 19.6, 17.6 (CH₃). ESI-

MS for C₂₈H₄₄BrNO₈m/z: 602.2 [M(⁷⁹Br) + H]⁺, 604.2

[M(⁸¹Br) + H]⁺, 624.2 [M(⁷⁹Br) + Na]⁺, 626.2 [M(⁸¹Br) +

Na]⁺, 665.3 [M(⁷⁹Br) + Na + CH₃CN]⁺, 667.3 [M(⁸¹Br) +

Na + CH₃CN]⁺.

1

ane – ethyl acetate, 2:1). [α]²²–21.30° (c 1, CHCl₃). H

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

bromo-2-(3′′-tert-butyldiphenylsiloxy)propyl-5,6-

dehydropiperidin-4-one (21h)

Bromodehydropiperidinone 21h was synthesized accord-

ing to the general procedure using 4h (1.17 g, 1.5 mmol)

and N-bromosuccinimide (0.53 g, 3.0 mmol). Purification

was performed by flash chromatography (petroleum ether –

ethyl acetate, 4:1) to yield 21h (1.02 g, 1.2 mmol, 79%) as a

colourless amorphous solid. R_f0.45 (petroleum ether – ethyl

acetate, 2:1). [α]²⁴+59.95° (c 1, CHCl₃). ¹H NMR

D

(200 MHz, CDCl₃, ppm) δ: 7.65–7.55 (m, 4H, aryl), 7.45–

(2S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-5-

(p-methoxyphenyl)-2-n-propyl-5,6-dehydropiperidin-4-one

(23)

7.30 (m, 6H, aryl), 7.26 (s, 1H, H-6), 5.50 (t, 1H, J_{H-2′,H-1′}

=

9.3 Hz, J_{H-2′,H-3′}= 9.3 Hz, H-2′), 5.30–5.20 (m, 1H, H-4′),

5.12 (dd, 1H, J_{H-3′,H-2′}= 10.0 Hz, J_{H-3′,H-4′}= 3.2 Hz, H-3′),

To a solution of 21c (65 mg, 0.10 mmol), 4-methoxy-

640

Can. J. Chem. Vol. 84, 2006

benzene boronic acid (30 mg, 0.60 mmol), and Pd(PPh₃)₂Cl₂

(4 mg, 0.02 mmol) in THF (3 mL), aq. Cs₂CO₃(2 mol/L,

0.25 mL) was added and the mixture was stirred at 65 °C for

20 h. The mixture was filtrated through Hyflo^®, and the fil-

trate was concentrated in vacuo. The residue was diluted in

diethyl ether (15 mL), washed with water (3 mL) and brine

(1.5 mL), and dried over MgSO₄. The product was purified

by flash chromatography (cyclohexane – ethyl acetate, 6:1)

to yield 23 as a colourless amorphous solid (25 mg,

(ipso-aryl), 129.46 (aryl), 103.45 (C-5), 87.54 (C-1′), 71.66,

68.02, 67.52 (C-2′, C-3′, C-4′), 65.96 (C-5′), 65.10 (C-2),

46.03 (CHCH₃), 38.96, 38.85, 38.77 (pivC_quart.), 27.15,

27.04 (piv-CH₃), 13.46 (CH₃).

(2S,3S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(3-tert-butyldiphenylsiloxy)propyl-3-methyl-5,6-

dehydropiperidin-4-one (24b)

Disubstituted dehydropiperidinone 24b was synthesized

similarly to 24a using 4h (1.01 g, 1.30 mmol), dry THF

(40 mL), LiHMDS (1 mol/L in THF, 3.90 mL, 3.90 mmol),

and iodomethane (0.32 mL, 5.20 mmol). Purification by

flash chromatography (cyclohexane – ethyl acetate, 5:1)

yielded 24b (0.89 g, 1.13 mmol, 87%) as a colourless amor-

phous solid. R_f0.41 (cyclohexane – ethyl acetate, 2:1).

0.04 mmol, 40%, incomplete conversion). R_f0.44 (cyclohex-

1

ane – ethyl acetate, 2:1). [α]²²+55.18° (c 1, CHCl₃). H

D

NMR (300 MHz, CDCl₃, ppm) δ: 7.09 (s, 1H, H-6), 7.21 (d,

2H, J = 8.8 Hz, aryl), 6.83 (d, 2H, J = 8.8 Hz, aryl), 5.61 (t,

J_{H-2′,H-1′}= 9.6 Hz, J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.30–5.22 (m,

1H, H-4′), 5.14 (dd, 1H, J_{H-3′,H-2′}= 9.9 Hz, J_{H-3′,H-4′}= 3.3 Hz,

H-3′), 4.53 (d, 1H, J_{H-1′,H-2′}= 9.2 Hz, H-1′), 4.05 (dd, 1H,

J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}= 2.2 Hz, H-5′a), 3.82–3.66

1

[α]²²+0.81° (c 1, CHCl₃). H NMR (300 MHz, CDCl₃,

ppm)^Dδ: 7.65–7.54 (m, 4H, aryl), 7.46–7.28 (m, 6H, aryl),

6.95 (d, 1H, J_H-6,H-5= 7.7, H-6), 5.47 (t, J_{H-2′,H-1′}= 9.6 Hz,

J_{H-2′,H-3′}= 9.6 Hz, H-2′), 5.24–5.16 (m, 1H, H-4′), 5.07 (dd,

1H, J_{H-3′,H-2′}= 9.7 Hz, J_{H-3′,H-4′}= 3.1 Hz, H-3′), 4.93 (dd, 1H,

J_H-5,H-6= 7.4 Hz, H-5), 4.44 (d, 1H, J_{H-1′,H-2′}= 9.2 Hz, H-1′),

3.92 (dd, 1H, J_{H-5′a,H-5′b}= 13.2 Hz, J_{H-5′a,H-4′}= 1.8 Hz, H-5′a),

3.72–3.40 (m, 3H, H-5′b, O-CH₂), 3.37–3.26 (m, 1H, H-2),

2.36–2.23 (m, 1H, H-3), 1.92–1.70 (m, 1H, CH₂), 1.70–1.40

(m, 2H, CH₂), 1.23 (s, 3H, C(CH₃)₃), 1.15–1.06 (m, 21H,

C(CH₃)₃, CH₃), 1.02 (C(CH₃)₃). ¹³C NMR (100.6 MHz,

CDCl₃, ppm) δ: 196.4 (C-4), 177.3, 177.1, 176.6 (pivC=O),

146.6 (C-6), 135.5, 135.4 (aryl), 133.7, 133.6 (ipso-aryl),

129.7, 127.7 (aryl), 97.8 (C-5), 90.9 (C-1′), 72.0, 68.0, 65.5

(C-2′, C-3′, C-4′), 66.1 (C-5′), 63.3 (CH₂-O), 61.9 (C-2),

42.5 (C-3), 38.9, 38.8, 38.8 (pivC_quart.), 28.3 (CH₂), 27.1,

27.1, 27.1, 26.8 (pivCH₃, Si-C(CH₃)₃), 27.0 (CH₂), 19.2

(SiC(CH₃)₃), 17.7 (CH₃). ESI-MS for C₄₅H₆₅NO₉Si m/z:

792.5 [M + H]⁺, 814.5 [M + Na]⁺, 830.5 [M + K]⁺.

(m, 1H, H-2), 3.77 (s, 3H, OCH₃), 3.71 (d, 1H, J_{H-5′b,H-5′a}

12.8 Hz, H-5′b), 2.77 (dd, 1H, J_H-3a,H-3b= 16.5 Hz, J_H-3a,H-2

6.2 Hz, H-3a), 2.54 (dd, 1H, J_H-3b,H-3a= 16.5 Hz, J_H-3b,H-2

=

1.8 Hz, H-3b), 2.00–1.83 (m, 1H, CH₂), 1.73–1.55 (m, 1H,

CH₂), 1.49–1.11 (m, 2H, CH₂), 1.26 (s, 9H, piv-CH₃), 1.12

(s, 9H, piv-CH₃), 1.08 (s, 9H, piv-CH₃), 0.87 (t, 3H, J =

7.2 Hz, CH₃). ¹³C NMR (75.4 MHz, CDCl₃, ppm) δ: 189.7

(C-4), 177.2, 177.1, 177.1 (pivC=O), 158.1 (C-OCH₃), 148.5

(C-6), 129.0 (aryl), 127.8 (ipso-aryl), 113.7 (aryl), 112.0 (C-

5), 92.3 (C-1′), 71.1, 67.9, 66.1 (C-2′, C-3′, C-4′), 66.3 (C-

5′), 55.3, 53.6 (C-2, OCH₃), 39.4 (C-3), 39.0, 38.9, 38.8

(piv_quart.), 33.1 (CH₂), 27.1, 27.1, 27.0 (piv-CH₃), 18.9

(CH₂), 13.8 (CH₃). ESI-MS for C₃₅H₅₁NO₉m/z: 630.4 [M +

H]⁺, 652.3 [M + Na]⁺, 668.2 [M + K]⁺.

(2R,3S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-

2-(p-chlorophenyl)-3-methyl-5,6-dehydropiperidin-4-one (24a)

LiHMDS (1 mol/L in THF, 1.2 mL) was added slowly to

a cold solution (–78 °C) of 4a (592 mg, 1.0 mmol) in dry

THF (30 mL) and stirred for 1 h. After addition of

iodomethane (0.12 mL, 2 mmol), the reaction mixture was

stirred for 15 h at the same temperature. The reaction was

terminated by addition of satd. aq. NH₄Cl. After warming,

the organic layer was washed with satd. aq. NH₄Cl (2 ×

50 mL) and the resulting aqueous layer was extracted with

diethyl ether (2 × 50 mL). The combined organic layers

were dried over MgSO₄and concentrated in vacuo. Flash

chromatoraphy of the residue (petroleum ether – ethyl ace-

tate, 5:1) furnished 24a (444 mg, 0.73 mmol, 73%) as a

colourless amorphous solid. R_f0.38 (petroleum ether – ethyl

(2S,3S)-N-(2′,3′,4′-Tri-O-pivaloyl-␣-^D-arabinopyranosyl)-2-

(3-tert-butyldiphenylsiloxy)propyl-3-ethyl-5,6-

didehydropiperidin-4-one (24c)

Disubstituted dehydropiperidinone 24c was synthesized

similarly to 24a using 4h (1.01 g, 1.30 mmol), dry THF

(40 mL), LiHMDS (1 mol/L in THF, 3.25 mL), and

iodoethane (0.31 mL, 3.90 mmol). Purification by flash

chromatography (cyclohexane – ethyl acetate, 6:1) yielded

24c (0.74 mg, 0.91 mmol, 70%) as a colourless amorphous

solid. R_f0.50 (cyclohexane – ethyl acetate, 2:1). [α]²²

D

1

+4.34° (c 1, CHCl₃). H NMR (400 MHz, CDCl₃, ppm) δ:

7.63–7.57 (m, 4H, aryl), 7.43–7.32 (m, 6H, aryl), 6.93 (d,

1

acetate, 2:1); mp 162 °C. [α]²⁵–73.44° (c 1, CHCl₃). H

1H, J_H-6,H-5= 7.6, H-6), 5.47 (t, J_{H-2′,H-1′}= 9.4 Hz, J_{H-2′,H-3′}

9.4 Hz, H-2′), 5.23–5.20 (m, 1H, H-4′), 5.06 (dd, 1H, J_{H-3′,H-2′}

10.0 Hz, J_{H-3′,H-4′}= 3.3 Hz, H-3′), 4.95 (d, 1H, J_H-5,H-6

=

NMR (300 MHz, CDCl₃, ppm)^Dδ: 7.37 (d, 2H, J = 8.8 Hz,

aryl), 7.31 (d, 2H, J = 8.3 Hz, aryl), 7.24–7.20 (m, 1H, H-6),

5.57 (t, 1H, J_{H-2′,H-1′}= 9.8 Hz, J_{H-2′,H-3′}= 9.8 Hz, H-2′), 5.28

(d, 1H, J_H-5,H-6= 8.3 Hz, H-5), 5.08–5.15 (m, 1H, H-4′),

4.87 (dd, 1H, J_{H-3′,H-2′}= 9.8 Hz, J_{H-3′,H-4′}= 3.4 Hz, H-3′),

7.8 Hz, H-5), 4.45 (d, 1H, J_{H-1′,H-2′}= 9.4 Hz, H-1′), 3.94 (dd,

1H, J_{H-5 a,H-5 b}= 13.3 Hz, J_{H-5 a,H-4}= 2.0 Hz, H-5 a), 3.63–

′

3.54 (m, 3H, H-5 b, O-CH ), 3.47–3.40 (m, 1H, H-2), 1.85–

′

4.35 (d, 1H, J_H-2,H-3= 11.7 Hz, H-2), 4.02 (d, 1H, J_{H-1′,H-2′}

9.3 Hz, H-1′), 3.82 (dd, 1H, J_{H-5′a,H-5′b}= 13.7 Hz, J_{H-5′a,H-4′}

=

1.76 (m, 1H, H-3), 1.24, 1².12, 1.10, 1.01 (4s, 27H, (CH₃)₃),

0.91 (t, 3H, J = 7.42 Hz, CH₂CH₃). ¹³C NMR (75.4 MHz,

CDCl₃, ppm) δ: 195.6 (C-4), 177.3, 177.1, 176.6 (pivC=O),

146.3 (C-6), 135.5 (aryl), 133.7, 133.6 (ipso-aryl), 129.7,

127 7 (aryl), 97.7 (C-5), 91.1 (C-1′), 72.0, 68.0, 65.7 (C-2′,

C-3′, C-4′), 66.2 (C-5′), 63.2 (CH₂-O), 59.6 (C-3), 49.7 (C-

2), 38.9, 38.8, 38.8 (pivC_quart.), 28.4 (CH₂), 27.1, 27.1, 27.1

1.9 Hz, H-5′a), 3.28 (d, 1H, J_{H-5′b,H-5′a}= 13.2 Hz, H-5′b),

2.57 (dq, 1H, J_H-3,H-2= 12.0 Hz, J_H-3,methyl= 6.8 Hz, H-3),

1.23, 1.16, 1.08 (3s, 27H, piv-CH₃), 0.89 (d, 3H, J = 6.8 Hz,

CH₃). ¹³C NMR (100.6 MHz, CDCl₃, ppm) δ: 194.3 (C-4),

177.2, 177.1, 176.7 (pivC=O), 148.18 (C-6), 136.18, 134.77

Kranke and Kunz

641

3. (a) H. Kunz and W. Pfrengle. Angew. Chem. Int. Ed. Engl. 28,

1067 (1989); (b) M. Weymann, W. Pfrengle, D. Schollmeyer,

and H. Kunz. Synthesis, 1151 (1997).

4. B. Kranke, D. Hebrault, M. Schultz-Kukula, and H. Kunz.

Synlett, 671 (2004).

(pivCH₃), 26.8 (SiC(CH₃)₃), 24.7 (CH₂), 19.2 (CH₂CH₃),

11.6 (CH₂CH₃). ESI-MS for C₄₆H₆₇NO₉Si m/z: 626.29 [M –

phenyl – pivOH]⁺, 728.24 [M – phenyl]⁺, 806.34 [M + H]⁺,

828.26 [M + Na]⁺, 869.24 [M + Na + CH₃CN]⁺.

5. H. Kunz, W. Pfrengle, K. Rück, and W. Sager. Synthesis, 1039

(1991).

6. Y. Yamamoto. Angew. Chem. Int. Ed. Engl. 25, 947 (1986).

7. E.J. Corey and W. Boaz. Tetrahedron Lett. 26, 6019 (1985).

8. H. Gilman, R.G. Jones, and L.A. Woods. J. Org. Chem. 17,

1630 (1952).

9. S. Ciblat, P. Besse, V. Papastergiou, H. Veschambre, J.-L.

Canet, and Y. Troin. Tetrahdron: Asymmetry, 11, 2221 (2000),

and refs. therein.

Acknowledgements

This work was supported by the Deutsche Forschungsge-

meinschaft and by the Fonds der Chemischen Industrie. We

thank Dr. D. Schollmeyer, Institut für Organische Chemie,

Universität Mainz, for the X-ray analyses. BK is grateful for

being awarded the Adolf-Todt-Preis of the Adolf-Todt-

Stiftung of the Universität Mainz.

10. K. Maruoka, K. Nonoshita, and H. Yamamoto. Tetrahedron

Lett. 28, 5723 (1987).

References

11. (a) G. Zech and H. Kunz. Angew. Chem. Int. Ed. 42, 787

(2003); (b) G. Zech and H. Kunz. Chem. Eur. J. 10, 4136

(2004).

12. (a) J.K. Stille. Angew. Chem. Int. Ed. Engl. 25, 508 (1986);

(b) M.A.J. Duncton and G. Pattenden. J. Chem. Soc. Perkin

Trans. 1, 1235 (1999).

13. N. Miyaura and A. Suzuki. Chem. Rev. 95, 2457 (1995).

14. S. Danishefsky and T. Kitahara. J. Am. Chem. Soc. 96, 7807

(1974).

15. J.A. Murphy, F. Rasheed, S.J. Roome, K.A. Scott, and N.

Lewis. J. Chem. Soc. Perkin Trans. 1, 2331 (1998).

16. L. Guerrier, J. Royer, D.S. Grierson, and H.-P. Husson. J. Am.

Chem. Soc. 105, 7754 (1983).

1. (a) J.W. Daly, H.M. Garraffo, and T.F. Spande. In The alka-

loids — Chemistry and pharmacology. Vol. 43. Edited by G.A

Cordell. Academic Press, San Diego. 1993. p. 185; (b) J.W.

Daly. Nat. Prod. 61, 162 (1998); (c) J.W. Daly, H.M. Garraffo,

and T.F. Spande. In Alkaloids — Chemical and biological per-

spectives. Vol. 13. Edited by S.W. Pelletier. Pergamon, New

York. 1999. p. 1.

2. (a) P.D. Bailey, P.A. Millwood, and P.D. Smith. Chem.

Commun. (Cambridge), 633 (1998); (b) S. Laschat and T.

Dickner. Synthesis, 1781 (2000); (c) P.M. Weintraub, J.S.

Sabol, J.M. Kane, and D.R. Borcherding. Tetrahedron, 59,

2953 (2003); (d) S. Knauer, B. Kranke, L. Krause, and H.

Kunz. Curr. Org. Chem. 8, 1739 (2004).

Article Doi

Stereoselective synthesis of chiral piperidine derivatives employing arabinopyranosylamine as the carbohydrate auxiliary

DOI: 10.1139/V06-060

Source and publish data:

Authors:

Article abstract of DOI:10.1139/V06-060

Full text of DOI:10.1139/V06-060

Products guided by the article

R&D Labs maybe for 138891-99-3

Relevant to this article

Hot Product