Polyhydroxyamino-piperidine-type iminosugars and pipecolic acid analogues from a D -mannose-derived aldehyde

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DOI: 10.1002/ejoc.201402427

Polyhydroxyamino-Piperidine-Type Iminosugars and Pipecolic Acid Analogues

from a -Mannose-Derived Aldehyde

D

Camilla Matassini,^[a]Stefania Mirabella,^[a]Xhenti Ferhati,^[a]Cristina Faggi,^[a]

Inmaculada Robina,^[b]Andrea Goti,^[a]Elena Moreno-Clavijo,^[b]Antonio J. Moreno-Vargas,^[b]

and Francesca Cardona*^[a]

Dedicated to C.I.N.M.P.I.S on the occasion of its 20th anniversary

Keywords: Nitrogen heterocycles / Alkaloids / Carbohydrates / Amination / Glycomimetics / Biological activity

A general strategy for the synthesis of diversely substituted

3,4,5-trihydroxypiperidines (including two natural products),

5-amino-3,4-dihydroxypiperidines, 3,4,5-trihydroxypipecolic

acids, and 2-(aminomethyl)-3,4,5-trihydroxypiperidines is re-

ported. The procedure used a double reductive amination or

a Strecker reaction, starting from differently protected alde-

hydes readily synthesized on a gram scale from -mannose.

The biological activities of the target compounds were evalu-

D

ated, and some of them showed moderate inhibition of α-

fucosidase and β-glucosidase.

L-

Introduction

Polyhydroxylated piperidines such as 1-deoxynojirimycin

(1) and 1-deoxymannojirimycin (2) (Figure 1), also com-

monly known as iminosugars or iminocyclitols, are natural

products widely found in plants and microorganisms, and

are among the most attractive carbohydrate mimetics re-

ported to date.^[1]In these compounds, an imino group gen-

erally replaces the endocyclic oxygen of the parent sugar.

Their inhibitory activity against glycosidic enzymes^[2]has

prompted intense research into the synthesis of the natural

products and their unnatural analogues^[3]in order to de-

velop new therapies against cancer, viruses, diabetes, and

hereditary metabolic disorders.^[4]Synthetic amino deriva-

tives such as 6-(acetylamino)-1,6-dideoxymannojirimycin

(3, Figure 1) also showed very high activities as glycosidase

inhibitors.^[5]More recently, the antibacterial activity of syn-

thetic (hydroxyamino)-piperidines and other iminosugar de-

rivatives was discovered.^[6]Polyhydroxypipecolic acid 4, the

only natural trihydroxypipecolic acid known, was isolated

from the seeds of Bathia racemosa.^[7]It proved to be a spe-

cific inhibitor of human liver β-d-glucuronidase,^[8]and was

found to show anti-HIV^[9]and antimetastatic properties.^[10]

Figure 1. Natural and synthetic piperidine-type iminosugars 1, 2,

5–8, amino derivative 3, and polyhydroxypipecolic acid 4.

3,4,5-Trihydroxypiperidines 5–7 (Figure 1) were isolated

from Eupatorium fortunei TURZ in 1995,^[11]a plant used in

folk medicine for the treatment of several pathologies. They,

together with their unnatural relative isofagomine (8), may

be referred to as 1-N-iminosugars. Compounds 5–7 were

synthesized by Ganem^[12]and subsequently by several other

groups, using either a chiral pool approach^[13]or enantiose-

lective synthesis.^[14]These molecules were recently found to

have potential therapeutic applications for the treatment of

energy-utilization diseases, viral infections, and lysosomal

storage disorders.^[15,16]

[a] Dipartimento di Chimica “Ugo Schiff”, Università di Firenze,

Polo Scientifico e Tecnologico,

Via della Lastruccia 13, 50019 Sesto Fiorentino, Firenze, Italia

E-mail: francesca.cardona@unifi.it

www2.chim.unifi.it

[b] Departamento de Química Orgánica, Facultad de Química,

Universidad de Sevilla,

Due to our ongoing interest in polyhydroxylated alka-

loids and their unnatural analogues,^[17]we recently envis-

aged d-mannose-derived aldehyde 9^[18]as a possible com-

Prof. García González 1, 41012 Sevilla, Spain

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201402427.

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F. Cardona et al.

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mon building block for the synthesis of natural 5, ent-6, not versatile, and it also showed unexpected drawbacks.

and some new unnatural N-alkylated analogues (Scheme 1), Most of the problems encountered probably derived from

using a double reductive amination procedure.^[19]

the tendency of 9 to undergo quick hydration from air hu-

midity. The results are shown in Scheme 2. Although the

reductive amination reaction with benzylamine gave a satis-

factory yield, the same protocol with butylamine or oc-

tylamine gave 16a and 16b in moderate yields after pro-

longed reaction times.^[19]Moreover, upon reaction of 9 with

benzylamine and AcOH for 4 d, N-isopropyl piperidine 16c

was isolated in 27% yield (Scheme 2), probably as a result

of partial acetonide deprotection and subsequent reductive

amination of the acetone liberated in situ with the formed

piperidine. Therefore, in this case, a one-pot triple reductive

amination took place, together with debenzylation and

acetonide deprotection. Deprotection of 16c was carried

out as usual to give compound 11a in quantitative yield.

Scheme 1. Retrosynthetic analysis of polyhydroxyamino-piper-

idines and pipecolic acid analogues from d-mannose-derived alde-

hydes 9 and 10.

In this paper, we describe our exploration of the scope of

this strategy, which allowed access to 1-N-alkyl-substituted

polyhydroxypiperidines 11 and aminopiperidines 12

(Scheme 1). A change in the anomeric hydroxy protecting

group on aldehyde 9 gave us the opportunity to exploit the

Strecker reaction of aldehyde 10 en route to the synthesis

of new polyhydroxypipecolic acid analogues 13 and 14, and

6-(aminomethyl)piperidine iminosugars 15 (Scheme 1). The

results of the Strecker reaction of 10 also gave strong evi-

dence about the mechanism proposed for the stereoselective

formation of piperidine-2-carbonitriles as by-products of

the double reductive amination reaction. The biological

evaluation of the compounds synthesized against a panel of

commercially available glycosidase enzymes is also re-

ported.

Scheme 2. The double reductive amination strategy using aldehyde

9 and hydrogen as reducing agent.

Due to the problems encountered with the reductive am-

ination strategy on aldehyde 9, we sought to perform the

same task by working on dialdehyde 17, obtained quantita-

tively by catalytic hydrogenation of 9 (Scheme 3).^[19]It is

worth noting that this compound can be viewed (in its

open-chain form) either as a 2,3-di-O-protected d-lyxaric

aldehyde or a 3,4-di-O-protected d-arabinaric aldehyde. In

1

solution, the H NMR spectrum of 17 was rather compli-

cated, showing the presence of a complex mixture of dif-

ferent forms. While many examples of reductive amination

Results and Discussion

Aldehyde 9 was easily synthesized in four steps and 80% reactions of diketones or ketoaldehyde derivatives have

overall yield from d-mannose, without the need for any been reported,^[21]the same reaction with dialdehydes has

chromatographic purification.^[19]Our first aim was the in- been much less exploited. The reaction was used in Bols’s

troduction of lipophilic chains onto the nitrogen atom of synthesis of isofagomine with ammonia as the nitrogen

the target piperidine-type iminosugars, which is expected to source,^[15a]and a few other recent reports.^[22]In particular,

improve the pharmacokinetic properties in vivo, and the Crich and co-workers used a double reductive amination

suitability of such molecules as pharmacological chap- strategy on functionalized 1,5-dialdehydes with various hy-

erones.^[20]

droxylamines en route to the synthesis of polyhydroxylated

We initially investigated the reductive amination reaction N-alkoxypiperidines.^[15g,15i]In our hands, the reaction of di-

of 9 using different amine sources, and using hydrogen as aldehyde 17 with different amine sources (0.9 equiv.),

the reducing agent. This could allow removal of the benzyl NaBH₃CN (3.0 equiv.), and AcOH (2 equiv.)^[22b]was much

protecting group at the anomeric position of 9 in the same more reliable and reproducible than the hydrogenation pro-

step, resulting in the liberation of the second aldehyde moi- cedure on masked dialdehyde 9 described above, giving pro-

ety necessary to perform the required cyclization. However, tected piperidines 16a and 16b in slightly higher yields (48

in our hands, this reaction was poorly reproducible, it was and 56%, respectively). This procedure allowed the prepa-

2

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Piperidine-Type Iminosugars

ration of N-benzyl-substituted piperidine 16d in excellent C–O bond, according to a Felkin–Anh model, could be ex-

yield (93%). Deprotection of 16a, 16b, and 16d with meth- tended to the reduction of C=N bonds formed by the reac-

anolic HCl, followed by treatment with ion-exchange resin, tion of 20 with different amines (Figure 2).

gave N-alkylated piperidines 11b–11d (Scheme 3).^[19]

Scheme 4. The oxidation–reduction procedure. Synthesis of natural

5 and amino piperidines 12.

Scheme 3. Double reductive amination strategy using dialdehyde

17 and NaBH₃CN as reducing agent.

The use of NaBH₃CN instead of H₂as the reducing

agent for the double reductive amination of 17 also allowed

the synthesis of piperidines functionalized on the alkyl

chain. Thus, the reaction of 17 with 3-azidopropyl-1-

Figure 2. Favoured axial attack of the hydride anion on the C=N

bond.

Therefore, we investigated the reductive amination reac-

amine^[23](1 equiv.), NaBH₃CN (3.0 equiv.), and AcOH tion of ketone 20 (Scheme 4). We initially used the best re-

(2 equiv.) gave N-alkylated piperidine 16e in 67% yield action conditions previously found for the synthesis of pip-

(Scheme 3), which upon conventional deprotection, gave eridine 16d from dialdehyde 17: dry MeOH, 3 Å molecular

compound 11e in 88% yield. Catalytic hydrogenation fol- sieves, BnNH₂(0.9 equiv.), NaBH₃CN (3.0 equiv.), and

lowed by ion-exchange resin treatment, eluting with 15% AcOH (2.0 equiv.). After 6 d, the conversion was complete,

NH₄OH, gave primary amine 11f. This compound showed but unexpectedly a 1:2 mixture of the desired aminopiper-

a high tendency to be protonated, possibly through reaction idine (i.e., 22a) together with alcohol 21 was recovered

with atmospheric CO₂, as evidenced by the NMR spectra, (Table 1, entry 1). When

a slight excess of BnNH₂

–

which showed signals for an HCO₃counterion. However, (1.1 equiv.) was used, and we waited 40 min before the ad-

the presence of a single compound was demonstrated by dition of NaBH₃CN in lower excess (1.5 equiv.), the result

acetylation of 11f with an excess of acetic anhydride in pyr- was similar (Table 1, entry 2). The critical point in this reac-

idine, which gave 18 in 86% yield. Treatment of 18 with tion was the formation of the imine intermediate, since the

the strongly basic resin Ambersep 900 OH in MeOH gave chemoselectivity of NaBH₃CN in this reaction appeared to

trihydroxypiperidine 11g in 71% yield (Scheme 3).

be quite low. The formation of alcohol 21 could be com-

The inversion of configuration at C5–OH in compound pletely suppressed by stirring a mixture of 20, BnNH₂

19 to access natural trihydroxypiperidine 5 (Scheme 4) was (1.5 equiv.), and AcOH (2 equiv.) for 3 h before the addition

achieved through an oxidation–reduction sequence to give of NaBH₃CN, thus ensuring complete formation of the

alcohol 21, which was transformed into 5 by deprotection imine intermediate (Table 1, entry 3) prior to hydride

in acidic medium.^[19]We envisaged that ketone 20 would attack. Under these conditions, amine 22a could be reco-

be a suitable intermediate to introduce an exocyclic amino vered in 48% yield after purification on silica gel. Due to

moiety into the piperidine skeleton to give piperidines 22. the low chemoselectivity of NaBH₃CN, alkylpiperidines 22b

Indeed, the high stereoselectivity observed in the reduction and 22c were more easily accessed by using hydrogen as the

of 20 to 21 by the hydride anion, deriving from a favoured reducing agent. Ketone 20 was stirred in MeOH with 3 Å

axial attack on the C-5 carbonyl group anti to the vicinal molecular sieves and the appropriate amine for 40 min, then

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Pd(OH)₂/C was added, and the mixture was stirred under

H₂(1 atm) for 20–24 h. Both reactions (Table 1, entries 4

and 5) gave the desired amines in good yields. Hydrogen-

ation also showed complete diastereofacial selectivity, re-

sulting from the steric hindrance to attack at the opposite

face.

Table 1. The reductive amination of ketone 20 in MeOH.

Figure 3. Structural assignments by 1D NOESY and ¹H NMR

spectra of piperidines 12 and 11a.

Entry RNH₂

(equiv.)

Reducing agent Time 22/21^[a]Yield of 22

(equiv.)

[h]

ratio

[%]

1^[b]

2^[c]

3^[d]

4

BnNH₂

(0.9)

BnNH₂

(1.1)

BnNH₂

(1.1)

C₄H₉NH₂Pd(OH)₂/C

(1.5) H₂

C₈H₁₇NH₂Pd(OH)₂/C

(1.5) H₂

NaBH₃CN

(3.0)

NaBH₃CN

(1.5)

NaBH₃CN

(3.0)

144

1:2

17

group,^[26,27]a motif that also occurs in natural products

with antitumor activity such as Saframycin A, and in re-

lated synthetic hybrids.^[28]

20

25

24

20

1:2

19

48

68

53

Ͼ98:2

We reasoned that such compounds could be obtained re-

gioselectively by

a Strecker reaction performed on

“masked” dialdehyde 9. Due to the chirality of 9, we ex-

pected to obtain diastereoselective Strecker reaction. The

enantioselective version of this reaction has also been

widely investigated.^[29]The results with different amines

(Scheme 5) show that the Strecker reaction of 9 using

TMSCN (TMS = trimethylsilyl) as the cyanide source led

to major diastereoisomers 23 with high stereoselectivities

and in very good yields.^[19]

5

[a] Determined by isolation of compounds after flash column

chromatography. [b] All reagents, including 3 Å MS and AcOH

(2.0 equiv.) were mixed together at the same time. [c] Ketone,

amine, and 3 Å MS were stirred for 40 min before addition of

NaBH₃CN and AcOH (2.0 equiv.). [d] Ketone, amine, 3 Å MS, and

AcOH (2.0 equiv.) were stirred for 3 h before addition of

NaBH₃CN.

Treatment of 22a–22c with methanolic HCl, followed by

ion-exchange resin treatment, gave new N-alkylamino pip-

eridines 12a–12c (Scheme 4) in good to quantitative yields.

Moreover, 5-amino piperidine 12d was also accessed in

quantitative yield by catalytic hydrogenation of compound

22a under acidic conditions: the acetonide, Boc (tert-

butoxycarbonyl), and benzyl protecting groups were all re-

moved in the same step.

Scheme 5. The Strecker reaction of aldehyde 9.

The structures of aminopiperidines 12 were established

1

on the basis of careful analysis of their H NMR and 1D

The observed stereoselectivities varied from excellent

NOESY spectra. In particular, for 12d, a strong NOE corre- (Ͼ95:5, R = Bn, C₄H₉) to good (81:19, R = H), depending

lation peak between 3-H and 5-H was observed (Figure 3), on the amine used. Initial experiments were done in the

which also established the structure of 12a since both com- presence of Cu(OTf)₂as a Lewis acid catalyst,^[30]but we

pounds are derived from 22a. Moreover, the ¹H NMR spec- subsequently found that the addition of copper was not

trum of 12d showed a pseudo triplet with J = 2.5 Hz for 4- necessary for the reaction to occur, and neither did it im-

H, consistent with two eq-ax relationships with both 3-H prove the stereoselectivity. Without the copper catalyst, the

and 5-H. For piperidines 12b and 12c, due to overlapping reaction gave very clean products that did not even require

NMR signals, 1D NOESY spectra could not be used for purification on silica gel in the case of α-amino nitriles 23a

1

structural assignment. However, the H NMR spectra of and 23b (Scheme 5). The (S) configuration at the newly

both 12b and 12c showed a broad singlet for 4-H, consistent formed stereocentre was unambiguously assigned for 23c by

with two eq-ax relationships with both 3-H and 5-H. In single-crystal X-ray analysis (Figure 4), and the same con-

1

contrast, the H NMR spectrum of 11a (with the opposite figuration was attributed accordingly to 23a and 23b.

configuration at C-5) showed a dd for 4-H with J = 8.3 Hz

CCDC-849588 contains the supplementary crystallo-

and J = 2.9 Hz, consistent with an ax-ax relationship and graphic data for 23c. These data can be obtained free of

an ax-eq relationship with the vicinal protons (Figure 3).^[24]charge from The Cambridge Crystallographic Data Centre

Another synthetic strategy that could give access to func- via www.ccdc.cam.ac.uk/data_request/cif.

tionalized piperidines from aldehyde 9, and in particular to

This stereochemical outcome was in agreement with our

compounds 13–15 (Scheme 1), uses a Strecker reaction,^[25]expectations. It can be rationalized by a preferred approach

followed by deprotection at the anomeric carbon, and cycli- of cyanide through a Cram-chelated transition state (Fig-

zation. We envisaged that aldehyde 9 would afford piperi- ure 5), where the chelation involves the iminium proton and

dines functionalized at the α-position with a cyano the endocyclic oxygen atom of the sugar in a five-membered

4

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Piperidine-Type Iminosugars

Scheme 6. Synthesis of 2-cyano piperidine 24 by Strecker reaction

of 17, and as a by-product in the reductive amination of 17 under

neutral conditions.

Following these results, we considered that the regio- and

stereoselective formation of compound 24 from 17 during

the reductive amination was the result of a Strecker reaction

occurring at the more reactive aldehyde at C-5, followed

by intramolecular reductive amination at C-1. To get solid

evidence, we modified the anomeric protecting group of the

starting sugar derivative, in order to demonstrate that the

product of the Strecker reaction (i.e., 23a) is transformed

into piperidine 24 upon subjection to a reductive amin-

ation/ring closure procedure. The use of a different protect-

ing group could enable the cyclization to piperidines func-

tionalized at C-2 that failed starting from α-aminonitriles

23. The simplest protecting group that could be orthogo-

nally removed with respect to the acetonide moiety was en-

visaged to be an acetyl group. Therefore, the differently pro-

tected “masked” dialdehyde 10 was synthesized in three

steps from protected d-mannose 26 (Scheme 7). Compound

26 was acetylated at the anomeric position to give 27,^[33]

which was deprotected at the C-5 and C-6 hydroxy groups

by treatment with aqueous acetic acid to give 28.^[33a]Subse-

quent oxidative cleavage of glycol 28 using silica-gel-sup-

ported sodium metaperiodate in dichloromethane^[34]led to

aldehyde 10^[35]in 65% yield over three steps (Scheme 7).

Figure 4. X-ray crystal structure of 23c.

ring. According to this model, the cyanide anion would at-

tack from the less hindered Si face of the double bond, thus

giving adducts 23a–23c with the (S) absolute configuration

at the newly formed stereocentre. This stereochemical out-

come is consistent with a recent proposal about nucleophilic

attack on acyclic polyhydroxylated aldehydes.^[31]Unfortu-

nately, attempted deprotection at the anomeric position by

catalytic hydrogenation of α-aminonitriles 23, which would

induce subsequent cyclization, failed under both neutral

and acidic conditions and using different solvents (MeOH,

EtOH, CH₃CN), probably due to catalyst deactivation by

the cyanide group. However, the direct Strecker reaction

with benzylamine on dialdehyde 17, followed by cyclization

and in situ reduction of the iminium ion intermediate by

NaBH₃CN, gave 2-cyano piperidine 24 highly regio- and

stereoselectively in 50% isolated yield (Scheme 6). Com-

pound 24 has previously been observed as a by-product

formed in the reductive amination of 17 with NaBH₃CN

under neutral conditions. Its identity was confirmed by

comparison of ¹H NMR spectra of the corresponding acet-

ylated derivative 25 (Scheme 6). The formation of cyano-

substituted compounds as by-products during reductive

amination reactions with NaBH₃CN under neutral or basic

reaction conditions has occasionally been reported.^[32]

Scheme 7. Synthesis of aldehyde 10.

We were delighted to observe that the Strecker reaction

of 10 was also highly stereoselective. Indeed, the reaction

of 10 with BnNH₂in the presence of TMSCN gave the two

Figure 5. Cram chelate model for the Strecker reaction of 9 to

stereoselectively give α-aminonitriles 23.

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diastereoisomers 29a and 29b in an 86:14 ratio. Major iso- between the amido group and the free hydroxy group at C-

mer 29a could be isolated in 68% yield after chromatog- 3. Remarkably, the relative stereochemistry of C-2 in 30 is

raphy on silica gel (Scheme 8). The structural assignment of the same as that found for piperidine-2-carbonitrile 24. This

the major product as 29a was based on the similarity of its finding supports the hypothesis that the selective formation

spectroscopic data to those of 23a, but it was unequivocally of 24 during the reductive amination (see Scheme 6) is

established by successive transformations (see below). A driven by a Strecker reaction, combined with subsequent

reason for the lower diastereoselectivity of the Strecker re- double reductive amination, in agreement with our expecta-

action of aldehyde 10 compared to its relative 9 may be due tions.

to the presence of the electron-withdrawing acetoxy group,

On the basis of these data, a plausible mechanism for the

which makes the anti lone pair of the endocyclic oxygen less regio- and stereoselective formation of compound 24 in the

available for intramolecular hydrogen bonding. A solution reductive amination of dialdehyde 17 under neutral condi-

of 29a in MeOH was stirred with Ambersep^®900-OH ion- tions is shown in Scheme 9. Probably, imine A, formed pref-

exchange resin at room temperature to remove the acetyl erentially over imine B (path a vs. b, Scheme 9), leads to

group at the anomeric position. After 2 h, the ion-exchange adduct C through attack of the hydride ion, and therefore

resin was simply filtered off, and to perform the reductive to piperidine 16d as the major product. However, imine A

amination reaction, NaBH₃CN (1.1 equiv.) and AcOH can undergo stereoselective attack of the cyanide ion ac-

(2.0 equiv.) were added, and the reaction mixture was cording to the Cram chelate model to give α-amino nitrile

stirred at room temperature overnight. To our pleasure, the D, and, after cyclization and reduction by the hydride ion,

ring closure finally worked, leading to 2-amido-piperidine piperidine-2-carbonitrile 24. The alternative pathway

30 in 79% yield (Scheme 8). The formation of this com- (path b, Scheme 9) would involve reaction of the open-

pound instead of the expected 2-cyanopiperidine 24 was chain form of aldehyde 17 to give imine B. Attack of the

probably due to concomitant hydrolysis of the cyano group cyanide ion on B can be ruled out, since piperidines E were

under basic conditions during treatment with the resin.^[36]never observed. Alternatively, reduction of imine B and for-

Treatment of 30 with methanolic HCl, or catalytic hydro- mation of iminium ion F might lead to piperidine 24 by

genation under acidic conditions, gave the hydrochloride stereoselective cyanide addition at this level. This seems un-

salts of 13a and 13b, respectively. Final elution through ion- likely, but it cannot be completely excluded.

exchange resin (DOWEX^®50XW8-100) led to the corre-

sponding free amines in 80 and 82% yields, from 30

(Scheme 8).

Scheme 8. The Strecker reaction of aldehyde 10, and synthesis of

piperidine-2-carboxamides 13a and 13b by reductive amination.

The structure of 30 was assigned on the basis of its 1D

1

and 2D NMR spectra. The H NMR spectrum showed for

2-H a doublet with J = 4.4 Hz, consistent with an eq-ax

relationship with 3-H, and therefore of a cis relationship reductive amination of 17 via intermediate cyanide D.

Scheme 9. Proposed mechanism for the formation of 24 during the

6

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Piperidine-Type Iminosugars

Amide 30 is also a suitable intermediate for the synthesis 13b, 14a–14b·HCl, and 15a–15b were assayed as glycosidase

of new trihydroxypipecolic acid 14a, recently synthesized inhibitors against a panel of commercially available glycos-

14b,^[37]and 2-aminomethylpiperidine iminosugars 15a and idases, following well established procedures.^[41]The results

15b (Scheme 10). Hydrolysis of the amido moiety and con- are summarized in Table 2. The compounds tested did not

comitant deprotection of the acetonide group of 30 was show significant activity against β-galactosidase from Esch-

achieved by heating in HCl (6 m) for 16 h.^[38]Purification erichia coli, α-glucosidases from rice, β-mannosidase from

of this hydrochloride salt was achieved by stirring in an snail, and β-N-acetylglucosaminidase from Jack bean. In

aqueous NaOH solution for 1 h, followed by elution on an our hands, known compound ent-6^[13f]showed the best ac-

anion-exchange resin (Ambersep 900 OH) eluting sequen- tivity against α-l-fucosidase, showing moderate inhibition,

tially with MeOH, H₂O, and HCl (6 m). Concentration of IC₅₀= 90.3 μm, of this enzyme. Previous results for this

the acidic fractions gave pure 14a·HCl in 71% yield compound showed worse results, with an IC₅₀= 450 μm

(Scheme 10). Alternatively, catalytic hydrogenation, fol- against the same enzyme, and no selectivity.^[42]N-Substitu-

lowed by heating in HCl (6 m) for 16 h, gave 14b·HCl in tion of compound ent-6 reduces the inhibitory activity, iso-

100% yield. This compound was characterized as the hy- propyl derivative 11a being affected to a greater extent. N-

drochloride salt, since earlier isolation of the free amine^[37]Butyl derivative 11b showed moderate activity, which is

had resulted in great variability in the optical rotation mea- consistent with data reported^[13f]for this compound. The

surement.

presence of a free amino group or an acetamido group at

the 1-N-alkyl side-chain is detrimental to α-l-fucosidase in-

hibition, as seen for compounds 11f and 11g. These com-

pounds showed weak-to-moderate inhibitory activity

against α-galactosidase from coffee beans.

Inversion of configuration at 5-OH, as in epimer 5,

greatly diminished the activity against α-l-fucosidase, and

compound 5 also showed weak to moderate inhibition of

the other enzymes.^[43]The substitution of an OH group in

5 by an amino moiety (to give 12d) reduced the inhibitory

activity against the panel of tested enzymes, and this com-

pound showed only a poor inhibition against amyloglucosi-

dase from Aspergillus niger. Interestingly, the introduction

of an aromatic moiety (in compound 12a), increased the

inhibitory activity against β-glucosidase from almonds to

IC₅₀= 65.3 μm, which is consistent with data reported for

other aryl iminosugars.^[40,44]Changing the aryl moiety to

alkyl chains (in 12b and 12c) resulted in a slight reduction

of the inhibitory activity against β-glucosidase, and amino-

piperidine 12d did not inhibit this enzyme at all.

The inhibitory activity of the series of 3,4,5-trihydroxy-

pipecolic acids have been evaluated,^[37]and they were found

to be weak inhibitors. In our hands, known compound

14b·HCl showed only weak inhibition of α- and β-gluco-

sidases.^[37b]Significantly, benzyl derivative 14a·HCl showed

moderate inhibition of α-mannosidases, which is lost in N-

benzyl aminomethyl derivative 15a, and somewhat reduced

in aminomethyl derivative 15b. Changing the acid group to

an amide group in 13a and 13b led to a complete loss of

inhibitory activity.

Scheme 10. Synthesis of trihydroxypipecolic acids 14a and 14b and

of aminopiperidines 15a and 15b.

On the other hand, reduction of 30 with LiAlH₄in re-

fluxing THF gave diamine 31 in 79% yield. Treatment with

methanolic HCl or catalytic hydrogenation under acidic

conditions gave the hydrochloride salts of 15a and 15b,^[39]

respectively. Final elution through ion-exchange resin

(DOWEX^®50XW8-100) led to the corresponding free

amines in 89 and 95% yields, respectively (Scheme 10).

Conclusions

In conclusion, a straightforward strategy for the synthe-

sis of diversely functionalized polyhydroxy and polyhy-

droxyamino piperidines, including natural products 5 and

Biological Evaluation

Since natural compounds 5 and ent-6 were reported to ent-6, is presented. The synthesis involves a double re-

be unselective moderate inhibitors of glycosidases,^[13f]our ductive amination or a Strecker reaction on d-mannose-de-

aim was to investigate the effect of the introduction of alkyl, rived aldehydes 9 and 10. This strategy also allowed the

aryl, or additional amino moieties on the activity and/or synthesis of trihydroxypipecolic acids 14a and 14b, and of

selectivity.^[40]Compounds 5, ent-6, 11a–11g, 12a–12d, 13a– (aminomethyl)piperidine iminosugars 15a and 15b. Bio-

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Table 2. Inhibitory activities of compounds 5, ent-6, 11a–11g, 12a–12d, 13a–13b, 14a–14b·HCl, and 15a–15b against glycosidases. Percen-

tage inhibition at 1 mm (IC₅₀in parentheses [μm]). Optimal pH, 37 °C.^[a,b,c]

α-l-Fuc-ase

α-Gal-ase

β-Gal-ase

α-Glc-ase

Amylogluc-ase

β-Glc-ase

α-Man-ase

5

38

89 (90.3)

–

22

–

47^[d]

–

50

–

15

–

20

–

36

–

27

–

24

21

16

35

–

79

–

48

–

17

–

35

–

70

–

51

ent-6

11a

46

72

77

–

62

–

18

–

37

11b

11c

11d

11e

–

11f

32

64

–

11g

–

12a

83 (65.3)

12b

75

66

–

35

–

12c

12d

13a

13b

–

37

–

14a·HCl

14b·HCl

15a

–

15b

–

[a] For conditions of measurements see ref.^[41b]and Exp. Section. [b] No inhibition was detected at 1 mm concentration of the correspond-

ing compound. [c] α-l-Fucosidase from bovine kidney, α-galactosidase from coffee beans, β-galactosidase from Aspergillus oryzae, α-

glucosidase from rice, Amyloglucosidase from Aspergillus niger, β-glucosidase from almonds, α-mannosidase from Jack bean. [d] β-Ga-

lactosidase from Aspergillus oryzae and from Escherichia coli.

ment by direct inlet; relative percentages are shown in brackets.

Elemental analyses were carried out with a Perkin–Elmer 2400

analyzer. Optical rotation measurements were carried out with a

JASCO DIP-370 polarimeter.

logical evaluation of all the synthesized compounds against

a range of commercially available glycosidases revealed that

symmetrical compound 5 is an unselective and moderate-

to-weak β-glucosidase inhibitor. Substitution of 5-OH by

amino or alkyamino moieties does not greatly affect the in-

hibitory activity, except for the benzylamino group, which

increases its specificity and activity against this enzyme.

Compound ent-6 (the C-5 epimer of 5) is a moderate-to-

good inhibitor of α-l-fucosidases; other structural varia-

tions of this compound diminish the inhibitory activity. The

introduction of a substituent at position 2 of the piperidine

skeleton led to a decrease in the inhibitory properties, as

observed for amides 13, trihydroxy pipecolic acids 14, and

aminomethyl derivatives 15. Although the compounds pre-

pared in this paper are not good inhibitors, significant in-

formation can be derived from their structure–activity rela-

tionships that will be valuable in the search for better en-

zyme inhibitors. Further exploitation of the potential of al-

dehydes 9 and 10 for the synthesis of other iminosugar mi-

metics is underway.

(3R,4S,5R)-5-Hydroxy-1-isopropyl-3,4-isopropylidenedioxypiperid-

ine (16c): Aldehyde 9 (570 mg, 2.05 mmol) and benzylamine

(220 μL, 2.05 mmol) were dissolved in MeOH (90 mL) under a ni-

trogen atmosphere, and molecular sieves (3 Å pellets; 300 mg) were

added. The reaction mixture was stirred at room temperature for

40 min, then Pd(OH)₂/C (285 mg) was added. The mixture was

stirred at room temperature under a hydrogen atmosphere for 4 d.

The disappearance of benzyl signals was checked by ¹H NMR spec-

troscopy. The catalyst and the molecular sieves were removed by

filtration, washing several times with MeOH, and the solvent was

evaporated under vacuum. Purification of the residue by flash col-

umn chromatography on silica gel gave pure 16c (121 mg,

0.56 mmol, 27%). R_f

= 0.70 [CH₂Cl₂/MeOH/NH₄OH (6%),

10:1:0.1]. [α]²_D⁴= +23.0 (c = 1.04 in CHCl₃). H NMR (400 MHz,

1

CDCl₃): δ = 4.30–4.25 (m, 1 H, 3-H), 4.08 (dd, ³J_H,H= 5.0, 3.6 Hz,

3

1 H, 4-H), 3.92 (dd, J_H,H= 6.4, 3.6 Hz, 1 H, 5-H), 2.84–2.76 (m,

2

2 H, 2a-H, CH-iPr), 2.61–2.59 (m, 2 H, 6-H), 2.38 (dd, J_H,H

=

3

11.6, J_H,H= 8.0 Hz, 1 H, 2b-H), 1.49 (s, 3 H, Me), 1.34 (s, 3 H,

3

Me), 1.00 (d, J_H,H= 6.6 Hz, 3 H, CH₃-iPr), 0.99 (d, J_H,H

=

6.6 Hz, 3 H, CH₃-iPr) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 108.9

(s, acetal), 77.3 (d, C-4), 71.9 (d, C-3), 66.5 (d, C-5), 54.0 [d,

NCH(CH₃)₂], 51.7 (t, C-2), 50.3 (t, C-6), 28.0 (q, Me), 26.1 (q, Me),

Experimental Section

General Methods: Commercially sourced reagents were used as re-

ceived. All reactions were magnetically stirred and monitored by

TLC on 0.25 mm silica gel plates (Merck F254). Column

chromatography was carried out on silica gel 60 (32–63 μm), yields

refer to spectroscopically and analytically pure compounds, unless

otherwise stated. ¹H NMR spectra were recorded with Varian Mer-

cury-400, Varian INOVA-400, or Bruker AVANCE-500 instru-

ments. ¹³C NMR spectra were recorded with Varian Gemini-200

or Bruker AVANCE-500 instruments. Infrared spectra were re-

corded with a Perkin–Elmer Spectrum BX FTIR System spectro-

photometer. ESI full MS were recorded with a Thermo LTQ instru-

18.0 [q, NCH(CH ) ], 17.5 [q, NCH(CH ) ] ppm. IR (CDCl ): ν =

˜

3 2

3

3469, 2938, 2970, 2837, 2249, 1660, 1459, 1405, 1383, 1325, 1291,

1253, 1219, 1163, 1058 cm^–1. MS (ESI): m/z (%) = 216.11 (100) [M

+ H]⁺. C₁₁H₂₁NO₃(215.29): calcd. C 61.37, H 9.83, N 6.51; found

C 61.57, H 10.02, N 6.31.

(3R,4S,5R)-3,4,5-Trihydroxy-1-isopropylpiperidine (11a): A solution

of 16c (40 mg, 0.19 mmol) in MeOH (10.0 mL) was stirred with

HCl (12 m; 8 drops) at room temperature for 24 h. The crude mix-

ture was concentrated to give the hydrochloride salt of 11a. The

corresponding free amine was obtained by passing the hydrochlo-

8

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Piperidine-Type Iminosugars

ride salt through DOWEX^®50XW8-100 ion-exchange resin. Elu-

sphere for 3 d. The catalyst was filtered through Celite^®, and the

filtrate was concentrated under vacuum to give the hydrochloride

salt of 11f, which was then passed through ion-exchange resin

tion with 6% ammonia gave free base 11a (33 mg, 0.19 mmol,

100%). [α]²_D⁴= –41.9 (c = 0.65 in H₂O). ¹H NMR (400 MHz, D₂O):

3

δ = 3.86 (m, 1 H, 3-H), 3.72 (td, J_H,H= 8.8, 4.4 Hz, 1 H, 5-H), (DOWEX^®50XW8–100). Elution with MeOH, H₂O, and NH₄OH

3.34 (dd, J_H,H= 8.3, 2.9 Hz, 1 H, 4-H), 2.77–2.64 (m, 3 H, 2a-H, (15%) gave amine 11f (34 mg, 0.18 mol, quantitative). [α]²_D³= –37.1

3

6a-H, CH-iPr), 2.31 (dd, ²J_H,H= 12.4, J_H,H= 1.7 Hz, 1 H, 2b-H),

(c = 0.77 in H₂O). ¹H NMR (500 MHz, CD₃OD): δ = 3.94 (td,

3

2.12 (t, J_H,H= 10.0 Hz, 1 H, 6b-H), 0.91 (d, J_H,H= 9.2 Hz, 3 H,

³J_H,H= 5.5, 2.6 Hz, 1 H, 3-H), 3.81 (td, J_H,H= 8.0, 4.1 Hz, 1 H,

3

CH₃-iPr), 0.89 (d, J_H,H= 9.2 Hz, 3 H, CH₃-iPr) ppm. ¹³C NMR 5-H), 3.42 (br. s, 1 H, 4-H), 3.11 (t, J_H,H= 6.6 Hz, 0.5 H, 3Ј-H of

–

3

(50 MHz, D₂O): δ = 73.6 (d, C-4), 67.7 (d, C-5), 67.5 (d, C-3), 54.0

HCO₃salt), 2.90 (t, J_H,H= 6.6 Hz, 1.5 H, 3Ј-H of free amine),

[d, NCH(CH₃)₂], 52.2 (t, C-6), 50.6 (t, C-2), 17.6 [q, NCH(CH₃)₂], 2.87–2.78 (m, 2 H, 6a-H, 2a-H), 2.59–2.49 (m, 1.5 H, 1Ј-H of free

–

16.2 [q, NCH(CH₃)₂] ppm. MS (ESI): m/z (%) = 198.17 (100) [M

+ Na]⁺. C₈H₁₇NO₃(175.23): calcd. C 54.84, H 9.78, N 7.99; found

C 55.15, H 9.92, N 7.68.

amine), 2.48–2.41 (m, 0.5 H, 1Ј-H of HCO₃salt), 2.37–2.24 (m, 1

2

H, 2b-H), 2.21–2.10 (m, 1 H, 6b-H), 1.76 (dquint, J_H,H= 13.9,

³J_H,H= 6.6 Hz, 1.5 H, 2Ј-H of free amine), 1.68 (quint, J_H,H

=

3

–

7.1 Hz, 0.5 H, 2Ј-H of HCO₃salt) ppm. ¹³C NMR (125 MHz,

(3R,4S,5R)-1-(3-Azidopropyl)-5-hydroxy-3,4-(isopropylidenedioxy)-

piperidine (16e): Compound 17 (147 mg, 0.78 mmol) was dissolved

in dry MeOH (10 mL), and a solution of 3-azidopropyl-1-amine

(78 mg, 0.78 mmol) in dry MeOH (13 mL) and molecular sieves

(3 Å powdered) were added. The mixture was stirred under a nitro-

gen atmosphere for 4 h. The disappearence of the aldehyde was

checked by ¹H NMR spectroscopy. Then NaBH₃CN (147 mg,

2.34 mmol) and AcOH (90 μL, 1.56 mmol) were added. The reac-

tion mixture was stirred at room temperature for a week, and then

it was concentrated under vacuum. The crude product was purified

by gradient flash column chromatography (CH₂Cl₂/MeOH, 20:1 to

10:1), to give 16e (132 mg, 0.52 mmol, 67%) as a pale yellow oil.

R_f= 0.26 (CH₂Cl₂/MeOH, 20:1). [α]²_D³= +16.3 (c = 0.92 in CHCl₃).

–

CD₃OD): δ = 164.5, 160.1 (s, HCO₃), 74.0 (d, C-4), 68.3 (d, C-5),

–

67.9 (d, C-3), 56.9 (t, C-6), 56.0 (t, C-2), 55.8, 55.4 (C-1Ј, HCO₃

and free amine), 39.9, 39.6 (C-3Ј, HCO₃^–salt and free amine), 27.2–

–

1

26.0 (C-2Ј, HCO₃salt and free amine) ppm. H NMR (400 MHz,

D₂O): δ = 3.90–3.87 (m, 1 H, 3-H), 3.77–3.71 (m, 1 H, 5-H), 3.39–

3.37 (m, 1 H, 4-H), 2.89 (t, J_H,H= 6.8 Hz, 0.8 H, 3Ј-H of HCO₃

3

–

3

salt), 2.78 (t, J_H,H= 6.8 Hz, 1.2 H, 3Ј-H of free amine), 2.80–2.69

2

(m, 2 H, 6a-H, 2a-H), 2.48–2.26 (m, 2 H, 1Ј-H), 2.21 [br. d, J_H,H

= 11.7 Hz, 1 H, 2b-H), 2.60–1.94 (m, 1 H, 6b-H), 1.65 (quint, ³J_H,H

3

= 7.3 Hz, 1.3 H, 2Ј-H of free amine), 1.52 (quint, J_H,H= 7.3 Hz,

0.7 H, 2Ј-H of HCO₃salt) ppm. ¹³C NMR (50 MHz, D₂O): δ =

–

73.6 (d, C-4), 67.6 (d, C-3), 67.5 (d, C-5), 56.4 (t, C-6), 55.5 (t, C-

2), 54.7 (C-1Ј, HCO₃^–and free amine), 39.4, 38.8 (C-3Ј, HCO₃^–salt

and free amine), 26.4–25.5 (C-2Ј, HCO₃^–salt and free amine) ppm.

MS (ESI): m/z (%) = 191.08 (100) [M + H]⁺.

3

¹H NMR (400 MHz, CDCl₃): δ = 4.29 (pq, J_H,H= 5.9 Hz, 1 H,

3

3-H), 4.04 (pseudo-t, J_H,H= 4.7 Hz, 1 H, 4-H), 3.96–3.93 (m, 1

3

2

H, 5-H), 3.34 (t, J_H,H= 6.8 Hz, 2 H, 3Ј-H), 2.73 (ddd, J_H,H

=

3

4

2

(3R,5R)-3,4,5-tri-O-Acetyl-1-[3-(acetylamino)propyl]piperidine-

3,4,5-trihydroxypiperidine (18): A solution of 11f (13 mg,

0.07 mmol) in pyridine (0.3 mL) and Ac₂O (0.2 mL) was stirred at

room temperature for 18 h, and then concentrated under vacuum.

The crude product was purified by flash column chromatography

on silica gel (CH₂Cl₂/MeOH, 15:1) to give 18 (22 mg, 0.06 mmol,

12.0, J_H,H= 6.0, J_H,H= 1.5 Hz, 1 H, 2a-H), 2.60 (dd, J_H,H

11.7, J_H,H= 2.9 Hz, 1 H, 6a-H), 2.50–2.41 (m, 4 H, 2b-H, 6b-H,

1Ј-H), 1.75 (quint, J_H,H= 6.8 Hz, 2 H, 2Ј-H), 1.50 (s, 3 H, Me),

3

1.36 (s, 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 109.0 (s,

acetal), 76.7 (d, C-4), 71.8 (d, C-3), 67.5 (d, C-5), 55.3 (t, C-6), 55.2

(t, C-2), 54.3 (t, C-1Ј), 49.2 (t, C-3Ј), 28.0 (q, Me), 26.0 (t, C-2Ј),

25.9 (q, Me) ppm. MS (ESI): m/z (%) = 279.14 (100) [M + Na]⁺,

86%) as a colourless oil. R_f= 0.32 (CH₂Cl₂/MeOH, 15:1). [α]²_D⁵

–58.5 (c = 0.93 in CHCl₃). H NMR (400 MHz, CDCl₃): δ = 6.65

=

1

257.27 (20) [M + H]⁺. IR (CDCl ): ν = 3677, 3608, 3487, 2987,

˜

3

2944, 2823, 2237, 2099, 1456, 1378, 1219, 1060 cm^–1. C₁₁H₂₀N₄O₃

(256.30): calcd. C 51.55, H 7.87, N 21.86; found C 51.91, H 7.94,

N 21.61.

(br. s, 1 H, NH), 5.30 (dt, J_H,H= 5.2, 2.7 Hz, 1 H, 3-H), 5.11 (dt,

³J_H,H= 8.6, 4.3 Hz, 1 H, 5-H), 4.95 (dd, J_H,H= 8.6, 3.6 Hz, 1 H,

3

4-H), 3.46 (td, ²J_H,H= 12.1, ³J_H,H= 5.8 Hz, 1 H, 3Јa-H), 3.20–3.12

(m, 1 H, 3Јb-H), 3.04–3.02 (m, 1 H, 6a-H), 2.86–2.83 (m, 1 H, 2a-

H), 2.46 (t, ³J_H,H= 6.3 Hz, 2 H, 1Ј-H), 2.44 (d, J_H,H= 11.7 Hz, 1

2

(3R,5R)-1-(3-Azidopropyl)-3,4,5-trihydroxypiperidine (11e): A solu-

tion of 16e (44 mg, 0.17 mmol) in MeOH (2.0 mL) was stirred with

HCl (12 m; 142 μL, 1.7 mmol) at room temperature for 18 h. The

crude mixture was concentrated to give the hydrochloride salt of

11e. The corresponding free amine was obtained by passing the

hydrochloride salt through DOWEX^®50XW8–100 ion-exchange

resin. Elution with 6% ammonia gave free base 11e (33 mg,

0.15 mmol, 88%). [α]²_D¹= –21.2 (c = 0.74 in MeOH). ¹H NMR

H, 2b-H), 2.24–2.18 (m, 1 H, 6b-H), 2.08 (s, 3 H, Me), 2.04 (s, 3

H, Me), 2.02 (s, 3 H, Me), 1.98 (s, 3 H, Me), 1.64 (quint, J_H,H

3

=

6.3 Hz, 2 H, 2Ј-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 173.5–

169.9 (s, 4 C, COCH₃), 70.7 (d, C-4), 67.9 (d, C-5), 67.7 (d, C-3),

56.0 (t, C-1Ј), 54.0 (t, C-6), 53.8 (t, C-2), 38.9 (t, C-3Ј), 25.5 (t, C-

2Ј), 23.2–20.7 (q, 4 C, COCH₃) ppm. MS (ESI): m/z (%) = 381.41

(100) [M + Na]⁺. IR (CDCl ): ν = 3689, 3606, 3451, 3312, 3950,

˜

3

2825, 2257, 2245, 1743, 1660, 1522, 1372, 1230, 1050 cm^–1

.

(400 MHz, CD₃OD): δ = 3.89 (dt, J_H,H= 5.8, 2.9 Hz, 1 H, 3-H),

3

3.78 (td, J_H,H= 7.8, 4.3 Hz 1 H, 5-H), 3.40–3.38 (m, 1 H, 4-H),

C₁₆H₂₆N₂O₇(358.39): calcd. C 53.62, H 7.31, N 7.82; found C

53.20, H 7.42, N 8.16.

3

3.36 (t, J_H,H= 6.8 Hz, 2 H, 3Ј-H), 2.82–2.74 (m, 2 H, 6a-H, 2a-

3

2

H), 2.46 (t, J_H,H= 6.8 Hz, 2 H, 1Ј-H), 2.31 (d, J_H,H= 11.2 Hz, 1

(3R,5R)-1-[3-(Acetylamino)propyl]-3,4,5-trihydroxypiperidine (11g):

Compound 18 (74 mg, 0.21 mmol) was dissolved in MeOH (7 mL),

and Ambersep^®900-OH (300 mg) was added. The mixture was

stirred at room temperature. After 2 h, the ion-exchange resin was

removed by filtration, washing with MeOH. The solvent was evap-

orated under vacuum to give pure 11g (48 mg, 0.15 mmol, 71%).

[α]²_D⁴= –33.1 (c = 1.17 in H₂O). ¹H NMR (400 MHz, D₂O): δ =

3.88–3.86 (m, 1 H, 3-H), 3.73 (td, J_H,H= 8.8, 4.4 Hz, 1 H, 5-H),

3.37 (dd, J_H,H= 8.3, 2.4 Hz 1 H, 4-H), 3.06 (t, J_H,H= 6.9 Hz, 2

H, 3Ј-H), 2.77–2.71 (m, 2 H, 6a-H, 2a-H), 2.36–2.25 (m, 2 H, 1Ј-

3

H, 2b-H), 2.12–2.09 (m, 1 H, 6b-H), 1.76 (quint, J_H,H= 6.8 Hz,

2 H, 2Ј-H) ppm. ¹³C NMR (50 MHz, CD₃OD): δ = 72.9 (d, C-4),

67.2 (d, C-5), 66.8 (d, C-3), 55.8 (t, C-6), 55.2 (t, C-2), 53.7 (t, C-

1Ј), 48.2 (t, C-3Ј), 24.8 (t, C-2Ј) ppm. MS (ESI): m/z (%) = 217.17

(100) [M + H]⁺. C₈H₁₆N₄O₃(216.24): calcd. C 44.44, H 7.46, N

25.91; found C 44.29, H 7.79, N 25.71.

3

(3R,5R)-1-(3-Aminopropyl)-3,4,5-trihydroxypiperidine (11f): Com-

pound 11e (40 mg, 0.18 mmol) was dissolved in MeOH (3 mL) and

HCl (12 m; 6 drops), and Pd/C (25 mg) was added. The reaction

mixture was stirred at room temperature under a hydrogen atmo-

3

2

H), 2.18 (d, J_H,H= 12.2 Hz, 1 H, 2b-H), 2.02–1.92 (m, 1 H, 6b-

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FULL PAPER

H), 1.85 (s, 3 H, Me), 1.57 (quint, ³J_H,H= 6.8 Hz, 2 H, 2Ј-H) ppm.

H, 2Ј-H), 1.53–1.13 (m, 25 H, 3Ј-H–7Ј-H, Me, tBu), 0.87 (t, J =

¹³C NMR (50 MHz, D₂O): δ = 173.91 (s, COCH₃), 75.6 (d, C-4), 6.3 Hz, 3 H, 8Ј-H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 155.2

67.6 (d, C-3), 67.5 (d, C-5), 56.4 (t, C-1Ј), 55.5 (t, C-2), 54.5 (t, C-

6), 37.6 (t, C-3Ј), 25.1 (q, COCH₃), 21.8 (t, C-2Ј) ppm. MS (ESI):

(s, C=O), 108.8 (s, acetal), 79.6 (s, OCtBu), 72.4 (d, 2 C, C-3, C-

4), 53.5, 46.9 (2 C, C-5, C-1Ј), 42.4 (t, 2 C, C-2, C-6), 31.8–22.6 (11

m/z (%) = 255.08 (100) [M + Na]⁺, 233.17 (72) [M + H]⁺. C, C-2Ј–C-7Ј, Me, tBu), 14.0 (q, C-8Ј) ppm. MS (ESI): m/z (%) =

C₁₀H₂₀N₂O₄(232.28): calcd. C 51.71, H 8.68, N 12.06; found C

51.61, H 8.39, N 12.10.

385.33 (100) [M + H]⁺.

General Procedure for the Synthesis of 5-N-Alkylated Aminopiper-

idines 12a–12c: A solution of 22a–22c in MeOH (0.02 m) was

stirred with HCl (12 m; 5 drops) at room temperature overnight.

The crude mixture was concentrated to give the hydrochloride salts

of 12a–12c. The corresponding free amines were obtained by pass-

ing the hydrochloride salts through DOWEX^®50XW8–100 ion-

exchange resin. Elution with ammonia (6%) gave free bases 12a–

12c.

(3R,4S,5S)-N-Boc-5-(Benzylamino)-3,4-(isopropylidenedioxy)piper-

idine (22a): A solution of ketone 20 (69 mg, 0.25 mmol) in dry

MeOH (4.5 mL) was stirred in the presence of molecular sieves

(3 Å powder) for 15 min under a nitrogen atmosphere, and then

benzylamine (43 μL, 0.39 mmol) and AcOH (22 μL, 0.39 mmol)

were added. The reaction mixture was stirred for 3 h, and then

NaBH₃CN (49 mg, 0.78 mmol) and more AcOH (8 μL, 0.13 mmol)

were added. The mixture was stirred for 25 h under a nitrogen at-

mosphere. The molecular sieves were removed by filtration through

Celite^®, and the filtrate was concentrated under vacuum. The resi-

due was purified by flash chromatography on silica gel (petroleum

ether/EtOAc/NEt₃, 2:1:0.1) to give 22a (43 mg, 0.12 mmol, 48%).

R_f= 0.26 (petroleum ether/EtOAc/NEt₃, 2:1:0.1). [α]²_D⁵= +16.25 (c

(3R,4S,5S)-5-(Benzylamino)-3,4-dihydroxypiperidine (12a): Appli-

cation of this procedure to 22a (28 mg, 0.08 mmol) gave free amine

12a (17 mg, 0.08 mmol, 100%). [α]²_D⁵= –3.6 (c = 0.74 in MeOH).

¹H NMR (400 MHz, D₂O): δ = 7.32–7.22 (m, 5 H, Ar), 4.04 (br.

2

s, 1 H, 4-H), 3.76 (d, J_H,H= 13.1 Hz, 1 H, Bn), 3.69 (d, J_H,H

=

3

13.1 Hz, 1 H, Bn), 3.53 (ddd, J_H,H= 10.5, 4.7, 1.9 Hz, 1 H, 3-H),

1

= 0.8 in CHCl₃). H NMR (400 MHz, CDCl₃): δ = 7.39–7.23 (m,

2

2.77–2.64 (m, 3 H, 6a-H, 2a-H, 5-H), 2.55 (t, J_H,H= 11.5 Hz, 1

3

H, 2b-H), 2.43 (t, J_H,H= 11.5 Hz, 6b-H) ppm. ¹³C NMR

5 H, Ar), 4.41 (dd, J_H,H= 6.8, 2.5 Hz, 1 H, 4-H), 4.27 (br. s, 1 H,

2

3-H), 3.90 (m, 2 H, Bn), 3.66–3.55 (m, 2 H, 2a-H, 6a-H), 3.28 (dd,

(50 MHz, D₂O): δ = 137.4 (s, Ar), 127.8–126.6 (d, 5 C, Ar), 67.6

(d, C-3), 67.2 (d, C-4), 54.4 (d, C-5), 48.2 (t, Bn), 43.15 (t, C-2),

41.6 (t, C-6) ppm. MS (ESI): m/z (%) = 223.17 (100) [M + H]⁺.

C₁₂H₁₈N₂O₂(222.28): calcd. C 64.84, H 8.16, N 12.60; found C

65.15, H 8.34, N 12.36.

2

²J_H,H= 14.0, J_H,H= 3.9 Hz, 1 H, 2b-H), 2.98 (t, J_H,H= 11.7 Hz,

1 H, 6b-H), 2.84 (m, 1 H, 5-H), 1.45 (s, 12 H, tBu, Me), 1.34 (s, 3

H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 155.2 (s, C=O),

139.9 (s, Ar), 128.4–127.1 (d, 5 C, Ar), 108.8 (s, acetal), 79.7 (s,

OCtBu), 72.4 (d, 2 C, C-3, C-4), 52.4 (d, C-5), 50.5 (t, Bn), 42.5 (t,

2 C, C-2, C-6), 28.4 (3 C, q, tBu), 26.9 (q, Me), 24.9 (q, Me) ppm.

(3R,4S,5S)-5-(Butylamino)-3,4-dihydroxypiperidine (12b): Applica-

tion of this procedure to 22b (20 mg, 0.06 mmol) gave free amine

12b (12 mg, 0.06 mmol, 100%) as a colourless oil. [α]²_D⁶= –8.1 (c =

MS (ESI): m/z (%) = 385.25 (100) [M + Na]⁺. IR (CDCl ): ν =

˜

3

3333, 2981, 2933, 2248, 1685, 1454, 1413, 1163 cm^–1.

1

0.44 in H₂O). H NMR (400 MHz, D₂O): δ = 4.04 (br. s, 1 H, 4-

General Procedure for the Synthesis of 5-N-Alkylated Aminopiper-

idines 22b and 22c: Ketone 20 and the appropriate amine

(1.5 equiv.) were dissolved in MeOH (0.05 m), and molecular sieves

(3 Å pellets; 25 mg) were added. The reaction mixture was stirred

H), 3.56 (m, 1 H, 3-H), 2.77–3.89 (m, 7 H, 2-H, 5-H, 6-H, 1Ј-H),

3

1.38 (quint, J_H,H= 7.4 Hz, 2 H, 2Ј-H), 1.22 (sext, ³J_H,H= 7.3 Hz,

3

2 H, 3Ј-H), 0.78 (t, J_H,H= 7.3 Hz, 3 H, 4Ј-H) ppm. ¹³C NMR

(50 MHz, D₂O): δ = 68.6 (d, C-3), 67.9 (d, C-4), 56.2 (d, C-5), 44.9

(t, C-1Ј), 44.3, (t, C-2), 42.3 (t, C-6), 30.1 (t, C-2Ј), 19.7 (t, C-3Ј),

13.1 (q, C-4Ј) ppm. MS (ESI): m/z (%) = 189.17 (100) [M + H]⁺.

C₉H₂₀N₂O₂(188.27): calcd. C 57.42, H 10.71, N 14.88; found C

57.68, H 10.98, N 14.56.

1

at room temperature for 50 min, and when H NMR spectroscopy

indicated that the conversion into the imine was complete, Pd(OH)

₂/C (50wt.-%) was added. The mixture was stirred at room tem-

perature under a hydrogen atmosphere for 24 h. The catalyst and

the molecular sieves were removed by filtration, washing several

times with MeOH, and the solvent was evaporated under vacuum.

(3R,4S,5S)-3,4-Dihydroxy-5-(octylamino)piperidine (12c): Applica-

tion of this procedure to 22c (38 mg, 0.10 mmol) gave free amine

12c (14 mg, 0.06 mmol, 60%) as a colourless oil. [α]²_D⁴= –2.5 (c =

(3R,4S,5S)-N-Boc-5-Butylamino-3,4-(isopropylidenedioxy)piperidine

(22b): Application of this procedure to 20 (68 mg, 0.25 mmol) with

butylamine (37 μL, 0.38 mmol) gave, after purification by flash col-

umn chromatography (petroleum ether/EtOAc, 2:1), compound

22b (57 mg, 0.17 mmol, 68%) as a colourless oil. R_f= 0.16 (petro-

leum ether/EtOAc, 2:1). ¹H NMR (200 MHz, CDCl₃): δ = 4.46 (m,

1 H, 4-H), 4.29 (br. s, 1 H, 3-H), 3.59–3.50 (m, 2 H), 3.31, (dd,

1

0.36 in MeOH). H NMR (400 MHz, D₂O): δ = 4.03 (br. s, 1 H,

3

4-H), 3.57 (d, J_H,H= 7.2 Hz, 1 H, 3-H), 2.78–2.47 (m, 7 H, 2-H,

5-H, 6-H, 1Ј-H), 1.42 (br. s, 2 H, 2Ј-H), 1.17 (m, 10 H, 3Ј-H–7Ј-

3

H), 0.74 (t, J_H,H= 6.8 Hz, 3 H, 8Ј-H) ppm. ¹³C NMR (50 MHz,

D₂O): δ = ppm = 67.7 (d, C-3), 66.8 (d, C-4), 55.6 (d, C-5), 44.8

(t, C-1Ј), 43.7 (t, C-2), 41.4 (t, C-6), 30.6–21.4 (t, 6 C, C-2Ј–C-7Ј),

12.8 (q, C-8Ј) ppm. MS (ESI): m/z (%) = 245.25 (100) [M + H]⁺.

C₁₃H₂₈N₂O₂(244.37): calcd. C 63.89, H 11.55, N 11.46; found C

64.15, H 11.78, N 11.63.

3

²J_H,H= 4.3, J_H,H= 3.7 Hz, 1 H), 2.98–2.65 (m, 4 H), 1.56–1.16

3

(m, 19 H, tBu, Me, 2Ј-H, 3Ј-H), 0.86 (t, J_H,H= 7.1 Hz, 3 H, 4Ј-

H) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 155.2 (s, C=O), 108.8

(s, acetal), 79.7 (s, OCtBu), 72.4 (d, 2 C, C-3, C-4), 53.5, 46.6, 42.8

(4 C, C-2, C-5, C-6, C-1Ј), 32.4–20.3 (7 C, tBu, Me, C-2Ј, C-3Ј),

13.9 (q, C-4Ј) ppm. MS (ESI): m/z (%) = 329.25 (100) [M + H]⁺.

(3R,4S,5S)-5-Amino-3,4-dihydroxypiperidine (12d): Compound 22a

(35 mg, 0.10 mmol) was dissolved in MeOH (5 mL) and HCl (12 m;

3 drops), and Pd/C (18 mg) was added. The reaction mixture was

stirred at room temperature under a hydrogen atmosphere for 6 d.

The catalyst was filtered through Celite^®, and the filtrate was con-

centrated under vacuum to give the hydrochloride salt of 12d

(quantitative). This was eluted through an ion-exchange resin

(DOWEX^®50XW8–100) with MeOH, H₂O, and NH₄OH (6%) to

give free amine 12d (13 mg, 0.10 mmol, 100%). [α]²_D⁵= +3.84 (c =

0.25 in MeOH). ¹H NMR (400 MHz D₂O): δ = 3.84 (pseudo-t,

(3R,4S,5S)-N-Boc-3,4-(Isopropylidenedioxy)-5-octylaminopiperidine

(22c): Application of this procedure to 20 (52 mg, 0.19 mmol) with

octylamine (47 μL, 0.28 mmol) gave, after purification by gradient

flash column chromatography (petroleum ether/EtOAc, from 5:1 to

2.1), compound 22c (39 mg, 0.10 mmol, 53%). R_f= 0.39 (petro-

leum ether/EtOAc, 2:1). ¹H NMR (200 MHz, CDCl₃): δ = 4.44 (m,

1 H, 4-H), 4.30 (br. s, 1 H, 3-H), 3.79–3.55 (m, 2 H), 3.32 (dd,

3

²J_H,H= 14.1, J_H,H= 3.5 Hz, 1 H), 2.98–2.68 (m, 4 H), 1.99 (m, 2 ³J_H,H= 2.5 Hz, 1 H, 4-H), 3.61 (m, 1 H, 3-H), 2.81 (m, 1 H, 5-H),

10

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Piperidine-Type Iminosugars

2

3

2.68 (dt, J_H,H= 11.3, J_H,H= 4.6 Hz, 2 H, 2a-H, 6a-H), 2.55 (t, ¹³C NMR (50 MHz, CDCl₃): δ = 169.1 (s, OC=OCH₃), 138.0 (s,

J_H,H= 11.1 Hz, 1 H, 2b-H), 2.45 (t, J_H,H= 11.4 Hz, 1 H, 6b-H) Ar), 128.6–127.7 (d, 5 C, Ar), 117.7, 114.2 (2 C, CN, acetal), 100.3

ppm. ¹³C NMR (50 MHz, D₂O): δ = 70.3 (d, C-4), 68.4 (d, C-3), (d, C-1), 84.5 (d, C-2), 80.3 (d, C-4), 78.8 (d, C-3), 51.7 (t, Bn),

50.0 (d, C-5), 44.7 (t, C-6), 44.2 (t, C-2) ppm. MS (ESI): m/z (%)

49.2 (d, C-5), 25.1 (q, Me), 24.5 (q, Me), 21.0 (q, OC=OCH₃) ppm.

= 155.11 (100) [M + Na]⁺, 133.09 (32) [M + H]⁺. C₅H₁₂N₂O₂MS (ESI): m/z (%) = 369.08 (100) [M + Na]⁺. IR (KBr): ν = 3483,

˜

(132.16): calcd. C 45.44, H 9.15, N 21.20; found C 45.32, H 9.45,

N 21.17.

3350, 2988, 2943, 2920, 2359, 2231, 1747, 1605, 1460 cm^–1

.

C₁₈H₂₂N₂O₅(346.38): calcd. C 62.42, H 6.40, N 8.09; found C

62.79, H 6.27, N 8.05.

1-O-Acetyl-2,3-O-isopropylidene-α-D-lyxo-pentofuranose-5-ulose

(10): Compound 26 (7.22 g, 27.8 mmol) was dissolved in pyridine

(12 mL) and Ac₂O (8 mL), and the mixture was stirred at room

temperature for 3 h. The mixture was diluted with EtOAc

(100 mL), and washed sequentially with a CH₃COOH (1 m; 2ϫ

150 mL), saturated aqueous NaHCO₃(2 ϫ 60 mL), and brine

(60 mL). The combined organic layers were dried with Na₂SO₄,

filtered, and concentrated under reduced pressure to give 27

(8.21 g, 27.2 mmol, 98%).

(2S,3R,4S,5R)-2-(Aminocarbonyl)-1-benzyl-3-hydroxy-4,5-(isoprop-

ylidenedioxy)piperidine (30): Compound 29a (376 mg, 1.09 mmol)

was dissolved in MeOH (43 mL), Ambersep^®900-OH (8.5 g) was

added, and the mixture was stirred at room temperature. After 2 h,

the ion-exchange resin was removed by filtration, washing with

MeOH, and NaBH₃CN (75 mg, 1.20 mmol) and CH₃COOH

(125 μL, 2.18 mmol) were added. The solution was stirred at room

1

temperature for 18 h, until H NMR spectroscopic analysis of the

crude mixture showed the complete formation of a new product.

The solvent was evaporated under vacuum, and the residue was

purified using silica gel flash chromatography [CH₂Cl₂/MeOH/

NH₄OH (6%), 10:1:0.1] to give compound 30 (262 mg, 0.86 mmol,

79%) as a waxy solid. R_f= 0.43 [CH₂Cl₂/MeOH/NH₄OH (6%),

10:1:0.1]. [α]²_D⁹= –5.6 (c = 0.76 in CHCl₃). ¹H NMR (400 MHz,

CDCl₃): δ = 7.35–7.25 (m, 5 H, Ar), 5.99 (br. s, 2 H, NH₂), 4.29

A solution of 27 (8.21 g, 27.15 mmol), glacial AcOH (102 mL), and

water (44 mL) was stirred for 18 h at room temperature, and then

it was concentrated under reduced pressure. The residue was dis-

solved in EtOAc (200 mL), and this solution was washed sequen-

tially with saturated aqueous NaHCO₃(2ϫ 70 mL), water (2ϫ

40 mL), and brine (2ϫ 50 mL), then it was dried (Na₂SO₄), and

the solvent was removed in vacuo to give 28 (5.81 g, 22.2 mmol,

82%) as a colourless oil.

3

(dt, ³J_H,H= 6.9, 3.4 Hz, 1 H, 5-H), 4.24 (t, J_H,H= 6.4 Hz, 1 H, 4-

2

H), 4.17 (m, 1 H, 3-H), 4.02 (d, J_H,H= 13.2 Hz, 1 H, Bn), 3.86

2

3

A solution of 28 (1.57, 5.99 mmol) in CH₂Cl₂(25 mL) was added

to a vigorously stirred suspension of silica-gel-supported NaIO₄

reagent^[34](12.1 g) in CH₂Cl₂(25 mL), and the mixture was stirred

at room temperature for 1 h. The reaction mixture was then fil-

tered, washing the residue with CHCl₃. The combined filtrates were

concentrated under reduced pressure and the residue was purified

by gradient flash chromatography (EtOAc/petroleum ether, from

1:1 to 7:1), to give 10 as a colourless oil (1.12 g, 4.87 mmol, 81%).

R_f= 0.68 (EtOAc/petroleum ether, 7:1). ¹H NMR (400 MHz,

(d, J_H,H= 13.2 Hz, 1 H, Bn), 3.51 (d, J_H,H= 4.4 Hz, 1 H, 2-H),

3.15 (dd, ²J_H,H= 14.2, J_H,H= 3.0 Hz, 1 H, 6a-H), 2.94 (dd, ³J_H,H

3

= 14.2, ³J_H,H= 3.7 Hz, 1 H, 6b-H), 1.56 (s, 3 H, Me), 1.34 (s, 3 H,

Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 176.4 (s, C=O), 138.2

(s, Ar), 128.9–127.5 (d, 5 C, Ar), 109.2 (s, acetal), 76.0 (d, C-4),

73.6 (d, C-5), 68.8 (d, C-3), 62.3 (d, C-2), 61.0 (t, Bn), 45.9 (t, C-

6), 27.4 (q, Me), 24.6 (q, Me) ppm. MS (ESI): m/z (%) = 329.33

(100) [M + Na]⁺. IR (CDCl ): ν = 3687, 3608, 3498, 3364, 3031,

˜

3

2991, 2935, 1676, 1384, 1210, 1049 cm^–1. C₁₆H₂₂N₂O₄(306.36):

3

CDCl₃): δ = 9.59 (d, J_H,H= 1.6 Hz, 1 H, aldehyde), 6.29 (s, 1 H,

calcd. C 62.73, H 7.24, N 9.14; found C 62.76, H 7.24, N 9.19.

3

1-H), 5.11 (dd, J_H,H= 5.8, 4.3 Hz, 1 H, 3-H), 4.73 (d, J_H,H

=

3

(2R,3R,4R,5R)-2-(Aminocarbonyl)-1-benzyl-3,4,5-trihydroxy-

piperidine (13a): A solution of 30 (17 mg, 0.05 mmol) in MeOH

(4.0 mL) and HCl (1 m; 4 drops) was stirred at room temperature

overnight. The crude mixture was concentrated to give the hydro-

chloride salt of 13a, which was eluted through ion-exchange resin

(DOWEX^®50XW8-100) with MeOH, H₂O, and NH₄OH (6%) to

give free amine 13a (11 mg, 0.04 mmol, 80%). [α]²_D⁶= +17.0 (c =

5.8 Hz, 1 H, 2-H), 4.42 (dd, J_H,H= 4.3, 1.6 Hz, 1 H, 4-H), 2.05

(s, 3 H, OAc), 1.43 (s, 3 H, Me), 1.28 (s, 3 H, Me) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 197.7 (d, HC=O), 169.2 (s, OC=OCH₃),

114.0 (s, acetal), 100.1 (d, C-1), 85.3 (d, C-4), 84.5 (d, C-2), 80.9

(d, C-3), 25.8 (q, Me), 24.5 (q, Me), 20.9 (q, OC=OCH₃) ppm. MS

(ESI): m/z (%) = 285.17 (100) [(M + MeOH) + Na]⁺.

1-O-Acetyl-5-(benzylamino)-5-cyano-5-deoxy-2,3-O-(1-methylethyl-

idene)-β-L-erythro-pentofuranose (29a): Aldehyde 10 (505 mg,

1

0.56 in H₂O). H NMR (400 MHz, D₂O): δ = 7.30–7.21 (5 H, Ar),

2

3.90–3.85 (m, 3 H, 3-H, 4-H, 5-H), 3.71 (d, J_H,H= 13.5 Hz, 1 H,

2.19 mmol) was dissolved in dry CH₃CN (11.0 mL) under a nitro-

gen atmosphere, and BnNH₂(240 μL, 2.19 mmol) and molecular

sieves (3 Å pellets) were added. The mixture was stirred at room

temperature for 40 min, then TMSCN (274 μL, 2.19 mmol) was

added dropwise. The solution was stirred at room temperature for

18 h, then it was diluted with EtOAc, washed with satd. aq.

NaHCO₃, H₂O, and brine, dried (Na₂SO₄), filtered, and concen-

trated under vacuum. The ¹H NMR spectrum of the crude mixture

showed the formation of two diasteroisomers in an 86:14 ratio. Pu-

rification of the crude product using silica gel gradient flash

chromatography (EtOAc/petroleum ether, from 1:2 to 1:1) gave the

major diastereoisomer 29a (516 mg, 1.49 mmol, 68%) as a white

solid. R_f= 0.43 (EtOAc/petroleum ether, 1:2), m.p. 80–82 °C. [α]¹_D⁹

= +70.2 (c = 0.98 in CHCl₃). ¹H NMR (400 MHz, CDCl₃): δ =

2

Bn), 3.45 (d, J_H,H= 13.5 Hz, 1 H, Bn), 3.26 (br. s, 1 H, 2-H), 2.86

(dd, ²J_H,H= 12.2, ³J_H,H= 3.4 Hz, 1 H, 6a-H), 2.36 (pseudo-t, J_H,H

= 9.0 Hz, 1 H, 6b-H) ppm. ¹³C NMR (50 MHz, D₂O): δ = 175.7

(s, C=O), 136.4 (s, Ar), 129.8–127.9 (d, 5 C, Ar), 69.7, 69.4, 66.1

(d, 3 C, C-3, C-4, C-5), 64.6 (d, C-2), 59.2 (t, Bn), 50.5 (t, C-6)

ppm. MS (ESI): m/z (%) = 289.13 (100) [M + Na]⁺, 267.33 (48) [M

+ H]⁺. C₁₃H₁₈N₂O₄(266.29): calcd. C 58.63, H 6.81, N 10.52;

found C 58.15, H 7.26, N 10.32.

(2R,3R,4R,5R)-2-(Aminocarbonyl)-3,4,5-trihydroxypiperidine (13b):

Compound 30 (50 mg, 0.16 mmol) was dissolved in MeOH (4 mL)

and HCl (1 m; 30 drops), and Pd/C (25 mg) was added. The reac-

tion mixture was stirred at room temperature under a hydrogen

atmosphere for 48 h. The catalyst was removed by filtration

through Celite^®, and the filtrate was concentrated under vacuum,

to give the hydrochloride salt of 13b (quantitative). This was eluted

through ion-exchange resin (DOWEX^®50XW8–100) with MeOH,

H₂O, and NH₄OH (6%) to give free amine 13b (23 mg, 0.13 mmol,

3

7.16–7.04 (m, 5 H, Ar), 6.00 (s, 1 H, 1-H), 4.68 (dd, J_H,H= 5.8,

3

3.9 Hz, 1 H, 3-H), 4.50 (d, J_H,H= 5.8 Hz, 1 H, 2-H), 4.03 (dd,

³J_H,H= 7.8, 3.9 Hz, 1 H, 4-H), 3.89 (d, ²J_H,H= 12.9 Hz, 1 H, Bn),

3

2

3.75 (d, J_H,H= 7.8 Hz, 1 H, 5-H), 3.64 (d, J_H,H= 12.9 Hz, 1 H,

1

Bn), 1.83 (s, 3 H, OAc), 1.32 (s, 3 H, Me), 1.11 (s, 3 H, Me) ppm.

82%). [α]²_D¹= +27.2(c = 0.38 in H₂O). H NMR (400 MHz, D₂O):

Eur. J. Org. Chem. 0000, 0–0

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F. Cardona et al.

FULL PAPER

δ = 4.02 (dd, J_H,H= 4.3, 2.4 Hz, 1 H, 3-H), 3.90 (pseudo-t, J_H,H

3

The reaction solution was cooled to room temperature, then an

aqueous saturated solution of Na₂SO₄was added, and the mixture

was stirred for 15 min. The mixture was extracted with EtOAc (3ϫ

10 mL), the combined organic layers were dried with Na₂SO₄and

3

= 3.7 Hz, 1 H, 4-H), 3.83 (ddd, J_H,H= 11.0, 5.1, 3.1 Hz, 1 H, 5-

H), 3.55 (d, ³J_H,H= 2.4 Hz, 1 H, 2-H), 2.84 (dd, ²J_H,H= 12.7, ³J_H,H

2

3

= 5.1 Hz, 1 H, 6a-H), 2.62 (dd, J_H,H= 12.7, J_H,H= 11.0 Hz, 1

H, 6b-H) ppm. ¹³C NMR (50 MHz, D₂O): δ = 174.6 (s, C=O), 69.7 concentrated. The crude product was purified by flash chromatog-

(d, C-3), 69.1 (d, C-4), 63.9 (d, C-5), 55.7 (d, C-2), 42.7 (t, C-6)

raphy [CH₂Cl₂/MeOH/NH₄OH (6%), 10:2:0.2] to give 31 (76 mg,

ppm. MS (ESI): m/z (%) = 199.08 (100) [M + Na]⁺. C₆H₁₂N₂O₄0.26 mmol, 79 %). R_f= 0.23 [CH₂Cl₂/MeOH/NH₄OH (6 %),

1

(176.17): calcd. C 40.91, H 6.87, N 15.90; found C 40.35, H 6.85,

N . 16.05.

10:2:0.2]. [α]²_D⁵= +24.3 (c = 1.01 in CHCl₃). H NMR (400 MHz,

3

CDCl₃): δ = 7.35–7.21 (m, 5 H, Ar), 4.31 (dt, J_H,H= 6.8, 3.4 Hz,

1 H, 5-H), 4.16–4.12 (m, 2 H, 4-H, 3-H), 3.89 (s, 2 H, Bn), 3.26–

3.20 (m, 2 H, 6a-H, CH₂NH₂), 2.88 (dt, J_H,H= 3.9, 2.0 Hz, 1 H,

(2R,3R,4R,5R)-1-Benzyl-2-carboxy-3,4,5-trihydroxypiperidinium

Chloride [(2R,3R,4R,5R)-1-Benzyl-3,4,5-trihydroxypipecolid Acid

Hydrochloride Salt] (14a·HCl): A solution of 30 (50 mg, 0.17 mmol)

in HCl (6 m; 1 mL) was heated to gentle reflux. After 16 h, TLC

revealed that the reaction was complete. The solution was cooled

to room temperature and then extracted with Et₂O (3ϫ 4 mL) to

remove ether-soluble material. The hydrochloric acid was evapo-

rated to dryness under reduced pressure, then the residue was dis-

solved in MeOH (5 mL), and NaOH (13 mg, 0.32 mmol) was

added. The reaction mixture was stirred for 1 h to obtain the corre-

sponding sodium salt, which was passed over Ambersep^®900-OH,

eluting with MeOH, water, and HCl (6 m). This procedure allowed

us to obtain pure 14·HCl (35 mg, 0.12 mmol, 71%) as a waxy solid.

3

2-H), 2.84–2.80 (m, 2 H, 6b-H, CH₂NH₂), 1.54 (s, 3 H, Me), 1.34

(s, 3 H, Me) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 140.4 (s, Ar),

128.4–126.9 (d, 5 C, Ar), 108.4 (s, acetal), 74.9 (d, C-4), 73.3 (d, 2

C, C-5, C-3), 60.4 (t, Bn), 56.5 (d, C-2), 47.9 (t, C-6), 43.3 (t,

CH₂NH₂), 27.2 (q, Me), 24.2 (q, Me) ppm. MS (ESI): m/z (%) =

293.25 (100) [M + H]⁺. IR (CDCl ): ν = 3689, 3604, 3399, 3086,

˜

3

3065, 3029, 2991, 2922, 2868, 2247, 1601, 1561, 1383, 1209,

1027 cm^–1. C₁₆H₂₄N₂O₃(292.37): calcd. C 65.73, H 8.27, N 9.58;

found C 66.12, H 8.12, N 9.22.

(2S,3R,4R,5R)-2-(Aminomethyl)-1-benzyl-3,4,5-trihydroxypiperid-

ine (15a): A solution of 31 (25 mg, 0.09 mmol) in MeOH (2.3 mL)

was stirred with HCl (12 m; 75 μL, 0.9 mmol) at room temperature

for 48 h. The crude mixture was concentrated to give the hydro-

chloride salt of 15a. The corresponding free amine was obtained

by passing the hydrochloride salt through DOWEX^®50XW8–100

[α]²_D³= +26.6 (c = 0.32 in MeOH). H NMR (400 MHz, D₂O): δ =

1

2

7.44–7.35 (5 H, Ar), 4.54 (d, J_H,H= 12.7 Hz, 1 H, Bn), 4.27 (d,

²J_H,H= 11.7 Hz, 2 H, Bn, 3-H), 4.10–4.07 (m, 1 H, 5-H), 3.91

3

(pseudo-t, J_H,H= 3.9 Hz, 1 H, 4-H), 3.90 (d, J_H,H= 11.7 Hz, 1

2

3

H, 2-H), 3.16 (dd, J_H,H= 11.2, J_H,H= 4.4 Hz, 1 H, 6a-H), 3.02 ion-exchange resin. Elution with ammonia (33%) gave free base

(t, J = 11.2 Hz, 1 H, 6b-H) ppm. ¹³C NMR (50 MHz, D₂O): δ =

15a (20 mg, 0.08 mmol, 89%). [α]²_D⁴= +21.2 (c = 1.29 in MeOH).

169.0 (s, COOH), 130.9 (s, Ar), 129.6–126.7 (d, 5 C, Ar), 68.7 (d, ¹H NMR (400 MHz, D₂O): δ = 7.33–7.24 (m, 5 H, Ar), 4.00 (dd,

3

C-3), 67.0 (d, C-4), 62.2 (d, C-2), 61.0 (d, C-5), 59.7 (t, Bn), 47.1 ³J_H,H= 6.9, 3.9 Hz, 1 H, 3-H), 3.89 (dt, J_H,H= 7.2, 3.6 Hz, 1 H,

2

3

(t, C-6) ppm. MS (ESI): m/z (%) = 266.33 (100) [M – H]⁺. 5-H), 3.85 (d, J_H,H= 13.1 Hz, 1 H, Bn), 3.70 (dd, J_H,H= 6.9,

2

C₁₃H₁₈ClNO₅(303.74): calcd. C 51.41, H 5.97, N 4.61; found C

51.57, H 5.83, N 4.50.

3.6 Hz, 1 H, 4-H), 3.62 (d, J_H,H= 13.1 Hz, 1 H, Bn), 2.99 (d,

³J_H,H= 6.4 Hz, 2 H, CH₂NH₂), 2.76–2.73 (m, 1 H, 2-H), 2.64 (dd,

3

2

²J_H,H= 13.0, J_H,H= 3.4 Hz, 1 H, 6a-H), 2.46 (dd, J_H,H= 13.0,

³J_H,H= 7.2 Hz, 1 H, 6b-H) ppm. ¹³C NMR (50 MHz, D₂O): δ =

137.6 (s, Ar), 129.7–127.6 (d, 5 C, Ar), 70.1 (d, C-4), 69.0 (d, C-3),

67.1 (d, C-5), 59.1 (d, C-2), 57.7 (t, Bn), 49.9 (t, C-6), 36.7 (t,

CH₂NH₂) ppm. MS (ESI): m/z (%) = 253.28 (100) [M + H]⁺,

275.29 (27) [M + Na]⁺. C₁₃H₂₀N₂O₃(252.31): calcd. C 61.88, H

7.99, N 11.10; found C 61.38, H 8.04, N 10.72.

(2R,3R,4R,5R)-2-Carboxy-3,4,5-trihydroxypiperidinium Chloride

[(2R,3R,4R,5R)-3,4,5-Trihydroxypipecolid Acid Hydrochloride Salt]

(14b·HCl): Compound 30 (49 mg, 0.16 mmol) was dissolved in

MeOH (4 mL) and HCl (1 m; 15 drops), and Pd/C (25 mg) was

added. The reaction mixture was stirred at room temperature under

a hydrogen atmosphere for 16 h. The catalyst was removed by fil-

tration through Celite^®, and the filtrate was concentrated under

vacuum. Then HCl (6 m; 1 mL) was added, and the mixture was

heated to gentle reflux. After 16 h at reflux, TLC showed that the

reaction was complete. The solution was cooled to room tempera-

ture, and then extracted with Et₂O (4 mL) to remove ether-soluble

material. The aqueous layer was evaporated and dried under vac-

uum to give 14b·HCl (34 mg, 0.16 mmol, 100%). A small portion

of the product was dissolved in MeOH and treated with excess

NaOH. The reaction mixture was stirred for 1 h to obtain the cor-

responding sodium salt, which was passed over Ambersep^®900-

OH, eluting with MeOH, water, and a HCl (6 m). This procedure

allowed us to obtain pure 14b·HCl. [α]²_D⁵= –79.1 (c = 0.32, H₂O).

¹H NMR (400 MHz, CD₃OD): δ = 4.33 (br. m, 1 H, 3-H), 4.15

(2S,3R,4R,5R)-2-(Aminomethyl)-3,4,5-trihydroxypiperidine (15b):^[39]

Compound 31 (19 mg, 0.07 mmol) was dissolved in MeOH (4 mL)

and HCl (12 m; 7 drops), and Pd/C (15 mg) was added. The reac-

tion mixture was stirred at room temperature under a hydrogen

atmosphere for 3 d. The catalyst was filtered through Celite^®, and

the filtrate was concentrated under vacuum to give the hydrochlo-

ride salt of 15b. This was eluted through ion-exchange resin

(DOWEX^®50XW8–100) with MeOH, H₂O, and NH₄OH (15%)

to give free amine 15b (10 mg, 0.06 mmol, 95%). The NMR spectra

showed that a mixture of the free amine and the corresponding

protonated form was recovered. [α]²_D³= +4.30 (c = 0.58 in H₂O).

¹H NMR (400 MHz, D₂O): δ = 3.89–3.72 (m, 3 H, 3-H, 4-H, 5-

(br. m, 2 H, 5-H, 2-H), 3.93 (br. m, 1 H, 4-H), 3.04 (br. m, 2 H, H), 3.01–2.57 (m, 5 H, 6-H, 2-H, CH₂NH₂) ppm. ¹³C NMR

6a-H, 6b-H) ppm. ¹³C NMR (100 MHz, CD₃OD): δ = 168.6 (s,

(50 MHz, D₂O): δ = 69.4, 69.0, 68.8, 68.2 (d, 2 C, C-3, C-4), 64.9,

COOH), 69.0 (d, C-3), 68.7 (d, C-4), 61.9 (d, C-5), 55.9 (d, C-2), 64.6 (d, 1 C, C-5), 52.4, 52.0 (d, 1 C, C-2), 43.3, 43.2 (t, 1 C, C-6),

42.0 (t, C-6) ppm. MS (ESI): m/z (%) = 212.00 (100) [M – H]⁺.

40.2, 39.6 (t, 1 C, CH₂NH₂) ppm. MS (ESI): m/z (%) = 185.10

(100) [M + Na]⁺.

(2S,3R,4S,5R)-2-(Aminomethyl)-1-benzyl-3-hydroxy-4,5-(isoprop-

ylidenedioxy)piperidine (31): A solution of 30 (103 mg, 0.33 mmol)

in dry THF (15 mL) was cooled to 0 °C, and LiAlH₄(1 m, THF;

0.99 mL) was added. The reaction mixture was heated to reflux

and stirred for 1.5 h, under a nitrogen atmosphere, after which time

TLC showed the complete disappearance of the starting material.

Biological Evaluation: The percentage inhibition of the correspond-

ing glycosidase was determined in the presence of 1 mm of the in-

hibitor in the well. Each enzymatic assay (final volume 0.12 mL)

contained 0.01 to 0.5 unitsmL^–1of the enzyme, and 10 mm aqueous

solution of the appropriate p-nitrophenyl glycoside substrate buff-

12

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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42427

/KAP1

Date: 26-05-14 19:24:34

Pages: 15

Piperidine-Type Iminosugars

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cle): H NMR and ¹³C NMR spectra of all new compounds.

Acknowledgments

The authors thank the Italian Ministero dell’Università e della

Ricerca (MIUR) (PRIN 2008, 200824M2HX, and PRIN 2010–

2011, 2010L9SH3K 006) and Ente Cassa di Risparmio di Firenze

(CRF, 2009/3141) for financial support. The authors also thank the

NMR Platform of CIC biomaGUNE for the spectra recorded with

the Bruker AVANCE (500 MHz) instrument. The Spanish Minis-

terio de Economia y Competitividad (MEC) (CTQ2012-31247), the

European Commission (FP7, PANACREAS, HEALTH-F2-2011-

256986), and the Spanish Junta de Andalucía (FQM 345) are

thanked for financial support of this work.

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Received: April 15, 2014

Published Online: ᭿

14

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Eur. J. Org. Chem. 0000, 0–0

Job/Unit: O42427

/KAP1

Date: 26-05-14 19:24:34

Pages: 15

Piperidine-Type Iminosugars

Iminosugars

C. Matassini, S. Mirabella, X. Ferhati,

C. Faggi, I. Robina, A. Goti,

E. Moreno-Clavijo, A. J. Moreno-Vargas,

F. Cardona* .................................... 1–15

Polyhydroxyamino-Piperidine-Type

Im-

inosugars and Pipecolic Acid Analogues

from a d-Mannose-Derived Aldehyde

Keywords: Nitrogen heterocycles / Alka-

loids / Carbohydrates / Amination / Glyco-

mimetics / Biological activity

The synthesis of diversely substituted po-

lyhydroxypiperidines, polyhydroxyamino-

piperidines, and trihydroxypipecolic acid

derivatives is reported, using Strecker reac-

tions and double reductive aminations,

starting from a d-mannose-derived alde-

hyde.

Eur. J. Org. Chem. 0000, 0–0

www.eurjoc.org

15

Article Doi

Polyhydroxyamino-piperidine-type iminosugars and pipecolic acid analogues from a D -mannose-derived aldehyde

DOI: 10.1002/ejoc.201402427

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Authors:

Article abstract of DOI:10.1002/ejoc.201402427

Full text of DOI:10.1002/ejoc.201402427

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