Synthesis and evaluation of lipophilic Aza-C-glycosides as inhibitors of glucosylceramide metabolism

FULL PAPER

DOI: 10.1002/ejoc.200901208

Synthesis and Evaluation of Lipophilic Aza-C-glycosides as Inhibitors of

Glucosylceramide Metabolism

Tom Wennekes,^[a]Richard J. B. H. N. van den Berg,^[a]Thomas J. Boltje,^[a]

Wilma E. Donker-Koopman,^[b]Bastiaan Kuijper,^[a]Gijsbert A. van der Marel,^[a]

Anneke Strijland,^[b]Carlo P. Verhagen,^[a]Johannes M. F. G. Aerts,*^[b]and

Herman S. Overkleeft*^[a]

Keywords: Azasugars / Glucosylceramide synthase / Glucocerebrosidase / β-Glucosidase 2 / Structure–activity relation-

ships / Enzymes

The structure–activity relationship of lipophilic aza-C-glycos-

ides as inhibitors of the three enzymes of glucosylceramide

metabolism is investigated. A library of β-aza-C-glycosides

was synthesized with variations in N-alkylation and the

possessing analogous linker variations. Evaluation of both li-

braries did not reveal a potent or selective inhibitor of glucos-

ylceramide synthase. However, β-aza-C-glycoside 43 was

found to be a selective inhibitor of β-glucosidase 2. The α-

linker length/type to the lipophilic moiety. A cross-metathe- aza-C-glycosides – especially with a

D-xylo core (e.g. 80) –

sis reaction was used to prepare a second library of α-aza-C-

proved to be very potent and selective inhibitors of gluco-

cerebrosidase.

glycosides with

D-gluco, L-ido and D-xylo iminosugar cores

substrate of the target enzyme will often inhibit additional

carbohydrate-processing enzymes that also create or cleave

a glycosidic bond with this monosaccharide. A way to

achieve selectivity for a specific enzyme is to add structural

elements to the iminosugar that resemble the anomeric sub-

stituent/aglycon of the enzyme glycoside substrate or transi-

tion state. This should result in additional interactions with

the aglycon binding site and as a consequence more selec-

tive binding. However, a true iminosugar mimic of the gly-

coside substrate would result in a labile N,O-acetal func-

tion, making it unsuitable as a potential drug or probe in

biological research. Replacing the oxygen atom of the imi-

nosugar’s pseudo-anomeric centre for a methylene group re-

sults in a stable mimic of the target glycoside or transition

state. This class of iminosugars is called the aza-C-glycos-

ides. The first piperidine-based aza-C-glycoside to be dis-

covered was α-homonojirimycin (1) that was synthesized in

1987^[9]and later also discovered as a natural product^[10]

(Figure 1).

Since then many synthetic strategies have been developed

for the synthesis of aza-C-glycosides.^[8,11,12]Most of these

can be roughly divided into two general categories de-

pending on the disconnection(s) made in the retrosynthetic

analysis. Disconnecting C1–N and C5–N results in ap-

proaches that use a final intramolecular cyclization to con-

struct the aza-C-glycoside (Figure 1, A–C). A convenient

method for cyclization that uses the ability of amines to

form imines with carbonyl compounds is the reductive am-

ination. Both a double-reductive amination of a C-1/C-5

diketone (A)^[13,14]or a single-reductive amination of a C-1/

Introduction

The first synthesis^[1]of carbohydrate analogues with a

nitrogen atom in the ring – so-called iminosugars or aza-

sugars – and their concurrent discovery as natural products

in microorganisms^[2,3]were reported during the 1960s. The

continuously increasing amount of research on iminosugars

since then can mainly be attributed to the subsequent dis-

covery of their ability to inhibit glycoprocessing en-

zymes^[4–6]combined with major advances in the field of gly-

cobiology.^[7]Recently, attention has focused on their ability

to stabilize certain deficient glycosidases, associated with ly-

sosomal storage disorders, during folding and transport as

so-called pharmacological chaperones.^[8]However, a recur-

ring problem in the development of iminosugars as inhibi-

tors or chaperones of these enzymes is their lack of specific-

ity. The countless complex carbohydrate structures and con-

jugates involved in human physiological processes are com-

posed of a relatively limited selection of monosaccharide

building blocks. Therefore, an iminosugar inhibitor that

only mimics one monosaccharide subunit of the complex

[a] Leiden Institute of Chemistry, Gorlaeus Laboratories, Leiden

University,

P. O. Box 9502, 2300 RA Leiden, The Netherlands

Fax: +31-71-527-4307

E-mail: h.s.overkleeft@chem.leidenuniv.nl

[b] Department of Medical Biochemistry, Academic Medical Cen-

ter, University of Amsterdam,

1105 AZ Amsterdam, The Netherlands

E-mail: j.m.aerts@amc.uva.nl

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.200901208.

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Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

moiety on the 1-deoxynojirimycin ring and the functionali-

zation of the endocyclic nitrogen atom. The main message

from that library of compounds was that changing the posi-

tion of the hydrophobic moiety in 2 abolished all GCS in-

hibitory activity except for β-aza-C-glucoside 3 (GCS: IC₅₀

= 9 µ).^[28]Additionally, the N-butylated (5) derivative of

3, but not its N-methylated (4) counterpart, also inhibits

GCS with modest activity. Expanding on these findings, the

here reported study consisted of the synthesis and evalu-

ation of two libraries of lipophilic aza-C-glycosides based

on compound 3. This enabled the further investigation of

the structure–activity relationship of this class of com-

pounds as inhibitors of GCS, GBA1 and GBA2.

Figure 1. α-Homonojirimycin (1) and examples of strategies (A–E)

for the synthesis of aza-C-glycosides.

C-5 amino ketone penultimate (B)^[15–17]has proven to be

a popular method for the preparation of aza-C-glycosides.

Another method to achieve cyclization is to activate, with

a suitable leaving group, the C-1 or C-5 position of an inter-

mediate with an amine function on the opposing carbon

centre (C).^[18,19]Alternatively, a disconnection made at C-

1–CH₂R results in approaches that use a cyclic electrophilic

precursor (Figure 1, D–E). For example, in this category

organometal additions^[20]and Ugi multicomponent reac-

tions^[21]have been used on cyclic imines to produce aza-C-

glycosides (D). Carbohydrate-derived cyclic nitrones have

also been used. Aza-C-glycosides were constructed from

these by 1,3-dipolar cycloadditions or nucleophilic ad-

ditions (E).^[22,23]

We recently reported three β-aza-C-glycoside derivatives

(3–5) based on lipophilic iminosugar 2 (Figure 2). Imi-

nosugar 2 is the lead compound in an ongoing study in

which we aim to develop selective inhibitors of the enzymes

involved in glucosylceramide metabolism.^[24–28]Glucosyl-

ceramide is a β--glucoside of the lipid ceramide and be-

Figure 2. Lead compound 2, β-aza-C-glycosides 3–5 and the here

reported libraries A/B. R¹= adamant-1-ylmethoxy–spacer; R²= H

or N-alkylated.

The first library (A; Figure 2) consists of derivatives of 3

longs to the family of glycosphingolipids (GSLs) that are that retain the pseudo β-orientation [(S)-C-1] of the hydro-

membrane components in eukaryotes and involved in many phobic moiety, but vary in the length and the saturation of

(patho)physiological processes.^[29–31]The biosynthesis of the pentyl spacer. The influence of the nitrogen atom on

glucosylceramide occurs on the cytosolic leaflet of the inhibition is also further investigated with C-glycoside de-

Golgi apparatus by the membrane-bound enzyme glucosyl- rivatives and additional N-alkylated derivatives. For the sec-

ceramide synthase (GCS). Catabolism of glucosylceramide ond library (B) the C-1 stereochemistry was altered to

occurs in the lysosomes by glucocerebrosidase (GBA1). A pseudo-α [(R)-C-1)]. For this library the iminosugar core

second catabolic pathway for glucosylceramide, the mem- was varied to also encompass -ido and -xylo substitution

brane-bound β-glucosidase 2 (GBA2), is located at or close patterns. This variation is based on our recently reported

to the cell surface.^[32,33]Selective inhibitors of these enzymes finding that epimerization of the C-5 position in 2 is a suit-

can be used to probe the diverse functions of GSLs, but able strategy to obtain more selective inhibitors of GCS.^[26]

also have potential as therapeutics for diseases associated Additionally, analogous spacer variations to library A were

with abnormal GSL metabolism such as lysosomal sphingo- prepared for all three α-aza-C-glycoside cores. Both librar-

lipidoses and type-2 diabetes.^[26,31,34]Lead compound 2 is ies were evaluated in an enzyme assay for inhibitory activity

a potent inhibitor of GCS (IC₅₀= 150 n), GBA1 (IC₅₀

=

against GCS, GBA1, GBA2. The library entries were also

200 n) and GBA2 (IC₅₀= 1 n). It also inhibits several evaluated as inhibitors of the three intestinal glycosidases

intestinal glycosidases (IC₅₀= 0.4–35 µ). The β-aza-C-gly- (sucrase, lactase and maltase) that are not associated with

cosides (3–5) are part of a series of derivatives of 2 that vary glucosylceramide metabolism, but which are known to be

in the position of the hydrophobic adamant-1-ylmethoxy inhibited by 2.

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Results and Discussion

The entries of the first library of β-(aza)-C-glycosides

with -gluco stereochemistry could be synthesized by the

route described previously^[28]for 3–5 or via synthetic inter-

mediates from this route. Alkyne 9 was synthesized from

but-3-yn-1-ol (6) by the previously reported three-step pro-

tocol (Scheme 1). The synthesis of alkyne 11 was also at-

tempted by this route but this proved low-yielding. The in-

termediate triflate proved susceptible to side reactions^[35]

and only produced approximately 30% of the desired trieth-

ylsilyl (TES) protected intermediate of 11 upon reaction

with adamantylmethanol. An alternative higher yielding

route for the synthesis of 11 was found in treating known

aldehyde 10^[25]with the Bestmann–Ohira reagent^[36,37]to

produce 11 in 87% yield. Alkynes 9 and 11 were deproton-

ated to the acetylenic anion and condensed with 2,3,4,6-

Scheme 1. Reagents and conditions: (a) i: BuLi, THF, –68 °C, 1 h;

ii: TESCl, –68 °C to room temp., 20 h; iii: 2  HCl, 48 h, 71%. (b)

i: Tf₂O, Et₃N, DCM, –40 °C, 1 h; ii: adamantylmethanol, K₂CO₃,

DCM, reflux, 3 d, 84%. (c) 4 equiv. NaOMe, THF/MeOH (2:1),

90 °C, 20 h, 87%. (d) Bestmann–Ohira reagent, K₂CO₃, MeOH,

0 °C Ǟ room temp., 16 h, 87%.

tetra-O-benzyl--glucono-1,5-lactone (12) to yield 13 and formaldehyde or butyraldehyde and hydrogenolysis of the

14 (Scheme 2).^[38]Next, ketoses 13 and 14 were transformed crude intermediate produced the N-methylated (19 and 20)

into 15 and 16 by a tandem reduction/Swern oxidation/ and N-butylated (21 and 22) derivatives, which together

double reductive amination reaction sequence.^[28]

with 17 and 18 completed the butyl/hexyl spacer-length

The double-reductive amination solely yielded the β-aza- variations based on 3–5 (i.e. pentyl spacer length). Re-

C--glucoside stereoisomer in both cases. This indicates ductive elimination of ketoses 13, 14 and previously re-

that the intramolecular cyclization probably occurs exclu- ported 23^[28]with boron trifluoride–diethyl ether/triethyl-

sively by axial hydride addition onto cyclic imines (C-1=N/ silane and subsequent Pd/C-catalyzed hydrogenolysis of the

C-5=N) that are in equilibrium with a bis(hemiaminal) in- intermediates 24, 25 and 26 produced the β-C-glycosides

termediate.^[13,14,39]Compounds 15 and 16 were deprotected 27, 28 and 29. The synthesis of two β-butyl-aza-C-glycoside

by Pd-catalyzed hydrogenolysis to produce β-aza-C-glycos- derivatives started with the addition of butyllithium to lac-

ides 17 and 18. Reductive amination of 15 and 16 with tone 12 and subsequent transformation of ketose 30 into

Scheme 2. Reagents and conditions: (a) i: BuLi, THF, –50 °C, 1 h; ii: 12, –50 °C, 2 h, 13: 60%, 14: 86%. (b) i: NaBH₄, MeOH/DCM

(5:1), 2 h; ii: DMSO, (COCl)₂, DCM, –75 °C, 2 h; iii: Et₃N, –75 °C Ǟ room temp., 0.5 h; iv: NaBH₃CN, NH₄HCO₂, 3 Å molecular

sieves, MeOH/DCM (5:1), 0 °C Ǟ room temp., 20 h, 15: 53%; 16: 59%; 31: 67% 3 steps. (c) Pd/C, H₂, EtOH, HCl, 20 h, 17: 90%, 18:

75%, 27: 81%, 28: 89%, 29: 90%, 32: 97%. (d) i: Pd/C (Degussa), H₂, formaldehyde, n-propanol, 1 h; ii: Pd/C, H₂, EtOH, HCl, 20 h,

19: 89%, 20: 69%. (e) i: butyraldehyde, NaBH₃CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H₂4 bar, EtOH, HCl, 20 h, 21: 60%, 22: 66%. (f)

BF₃·Et₂O, Et₃SiH, CH₃CN, –30 °C, 1.5 h, 24: 89%, 25: 79%, 26: 60%. (g) BuLi, THF, –50 °C, 2 h, 72%. (h) 10, NaBH₃CN, Na₂SO₄,

CH₃CN/MeOH (5:1), 75 °C, 18 h, 79%. (i) Pd/C, H₂4 bar, EtOH, HCl, 20 h, 85%.

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Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

Scheme 3. Reagents and conditions: (a) i: aldehyde, NaBH₃CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H₂4 bar, EtOH, HCl, 20 h, 36: 71%,

37: 63%, 38: 79%. (b) i: 10, NaBH₃CN, EtOH/AcOH (3:1), 20 h; ii: Pd/C, H₂, EtOH, HCl, 20 h, 41%. (c) BnBr, K₂CO₃, DMF, 85 °C,

18 h, 71%. (d) Lindlar cat., H₂, EtOAc, 18 h, 74%. (e) Na, NH₃, –60 °C, 1 h, 67%. (f) Na, NH₃, –60 °C, 0.5 h, 24%. (g) Li, NH₃, –60 °C,

3 h, 70%. AMP = 5-(adamant-1-ylmethoxy)pentyl.

iminosugar 31 (Scheme 2). Straight deprotection of 31 pro- the same site as in library one entries 42 and 44 is not pos-

duced library entry 32. Reductive amination of 31 with al- sible, because Compain and Martin have previously re-

dehyde 10 and deprotection gave 34, which is an analogue ported that α-vinyl-aza-C-glycosides are not suitable for

of 5 with the C-1/N substituents inverted.

cross-metathesis.^[41]Therefore -gluco, -ido and -xylo α-

Manipulation of previously reported 35^[28]provided the allyl-aza-C-glycosides were selected as cross-metathesis

final two classes of derivatives for the first library partner (Scheme 5).

(Scheme 3). Reductive amination of 35 with hexanal, non-

anal or aldehyde 10 and subsequent deprotection gave 36,

37 and 38, respectively. During the synthesis of 38, palla-

dium-catalyzed hydrogenolysis of the alkyne function in the

crude reductive amination product at atmospheric H₂pres-

sure proceeded sluggishly and gave a separable approxi-

mately 1:1 mixture of 38 and (Z)-alkene 39. Alkylation of

3 with benzyl bromide under the agency of potassium car-

bonate at 85 °C in DMF produced the final N-alkylated

derivative 40. Hydrogenolysis of 35 in the presence of Lind-

lar’s catalyst and subsequent Birch reduction of intermedi-

ate 41 produced (Z)-alkene 42. A Birch reduction of 35 with

sodium for 30 min achieved complete debenzylation but

only minor reduction of the alkyne function to yield alkyne

derivative 43. A Birch reduction of 35 with lithium for 3 h

was able to reduce the alkyne function to give (E)-alkene

derivative 44.

For the preparation of the second library, the adamant-

1-ylmethoxy-functionalized α-aza-C-glycosides, a cross-me-

tathesis reaction approach was chosen.^[40,41]In this way the

three distinct spacer lengths can be prepared by using three

appropriate adamant-1-ylmethoxy-functionalized terminal

alkenes in combination with the same iminosugar cross-

metathesis partner. Additionally, unsaturated spacer deriva-

tives can be generated by a Birch reduction of the cross-

metathesis products. Positioning of this alkene function at

The adamant-1-ylmethoxy-functionalized alkenes 45 and

47 could be prepared by a Williamson etherification of ada-

mantylmethanol with allyl bromide and 5-bromopent-4-ene

(Scheme 4). Alkene 46 could be prepared by substitution of

the triflate of 3-buten-1-ol with adamantylmethanol. The

synthesis of the α-allyl-aza-C-glycosides started with a

Grignard reaction of allylmagnesium bromide on the ano-

meric p-methoxybenzyl aminoglycoside 49, which in turn

was prepared from commercially available 48 (Scheme 5).

The Grignard reaction produced (R)-50, which can be ra-

tionalized by taking into account an O-2/NPMB-chelated

Felkin–Anh-type intermediate (see ref.^[42]).^[18,42]Selective

mesylation of the 5-OH group in 50 and subsequent S_N2-

like cyclization with a Walden inversion at C-5 produced -

ido compound 51. Intermediate 50 could be transformed

into -gluco α-allyl-aza-C-glycoside 54 by a procedure

adapted from Nicotra and co-workers. This procedure con-

sisted of Fmoc protection of 50 to 52, oxidation of the 5-

hydroxy group in 52 to 53 and finally removal of the Fmoc

group and cyclization to 54 by a reductive amination.^[15]

Compain and Martin have previously shown that the cross-

metathesis reaction is incompatible with certain endocyclic

tertiary amines similar to 51 and 54.^[41]The p-methoxy-

benzylamines in 51, 54 were therefore oxidatively cleaved

with ammonium cerium(IV) nitrate and protected as a benz-

yloxy carbamate (55 and 66) to make them suitable for

cross-metathesis. Starting from the -xylose (57) derived 58,

the -xylo α-allyl-aza-C-glycoside 62 was synthesized by a

similar sequence of reactions as described for 55. Except

now amino alcohol 60, obtained from a stereoselective^[43]

Grignard reaction on 59, was cyclized to 61 by an intramo-

lecular Mitsunobu reaction.^[44,45]

Scheme 4. Reagents and conditions: (a) adamantylmethanol, NaH,

DMF, 16 h, 45: 80%, 47: 53%. (b) i: Tf₂O, Et₃N, DCM, –40 °C Ǟ

0 °C, 1 h; ii: adamantylmethanol, K₂CO₃, DCM, 50 °C, 20 h, 99%. glycosides 55, 56, 62 and adamant-1-ylmethoxy alkenes 45–

Initial attempts at cross-metathesis between α-allyl-aza-C-

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Scheme 5. Reagents and conditions: (a) NH₂PMB, pTsOH, Na₂SO₄, toluene, reflux, 18 h, used crude. (b) AllylMgBr, Et₂O, 0 °C Ǟ room

temp., 16 h, 93%. (c) MsCl, pyridine, 0 °C Ǟ room temp., 4 h; ii: 90 °C, 16 h, 78%. (d) FmocCl, aq. NaHCO₃, DCM, 16 h, 91%. (e)

Dess–Martin periodinane, DCM, 0 °C, 6 h, 98%. (f) i: piperidine, DMF, 0 °C, 0.5 h; ii: NaCNBH₃, AcOH, Na₂SO₄, MeOH, –35 °C Ǟ

–20 °C, 16 h, 81%. (g) i: CAN, THF/H₂O (5:1), 0 °C, 3 h; ii: ZCl, aq. NaHCO₃, dioxane, 20 h, 55: 75%, 56: 65%, 62: 87%. (h) i: BnBr,

NaH, DMF, 0 °C Ǟ room temp., 20 h; ii: 1  HCl/AcOH (1:2.2), 105 °C, 4 h, 55%. (i) NH₂PMB, CSA, Na₂SO₄, toluene, reflux, 2.5 h,

used crude. (j) AllylMgBr, THF, 0 °C Ǟ room temp., 16 h, 97%. (k) PPh₃, DEAD, DCM, 20 h, 88%. (l) 45, 46, 47 or non-1-ene, 25 mol-

% Grubbs’ 1st generation catalyst, DCM, 45 °C, 24 h, 65–88%.

47 by using Grubbs’ generation 2 catalyst showed little con- (GBA2). To further establish the selectivity profile of the

version of the aza-C-glycoside metathesis partners. Cross- library entries they were also tested in inhibition assays for

metathesis of 55, 56 and 62 with a threefold excess of 45, 46 the intestinal glycosidases sucrase, lactase and maltase. As

and 47 under the agency of 25 mol-% of Grubbs’ generation an unwanted side-effect most 1-deoxynojirymycin-based in-

1 catalyst proved more productive. By using these condi- hibitors of glucosylceramide metabolism also inhibit these

tions, the nine penultimates (63–71) were obtained in moder- glycosidases.

ate to good yields (65–88%) as (E)/(Z) mixtures varying

In our previous study^[28]the hydrophobic moiety of lead

from 2:1 to 5:1 (Scheme 5). As a reference compound in compound 2 was translocated to produce β-aza-C-glycoside

the enzyme assay the potent GBA1 inhibitor 82 (Table 1), 3. When comparing the structures of 2 and 3 this translo-

reported by Compain and co-workers,^[46]was synthesized cation lengthens the carbon chain connecting the endo-

from 62 by cross-metathesis with oct-1-ene to produce 72. cyclic nitrogen atom and the adamant-1-ylmethoxy group

Deprotection of all the cross-metathesis products by Pd/C- from five to six atoms. The influence of this change on the

catalyzed hydrogenation at 4 bar gave library entries 73–82 SAR could be assessed with derivatives 17 and 18. The as-

(for structures see Table 1). The final entries for the second say results for the first library show that neither shortening

library were made by a Birch reduction of protected cross- (17) nor lengthening (18) this carbon chain by one carbon

metathesis products 64, 67, 70 and 72 to provide double- atom improves inhibition of GCS, but instead abolishes it

bond-containing α-aza-C-glycosides 83–86. In the case of 86 (Table 1). Evidently, the carbon chain length of 3 is already

this solely provided the (E) isomer, but for 83, 84 and 85 it optimal for GCS inhibition. Altering the saturation of the

gave an inseparable mixture of (E)/(Z) isomers. These mix- pentyl spacer of 3 into the (Z)-alkene 42, alkyne 43 or (E)-

tures were tested as such in the enzyme assay.^[47,48]

alkene 44 derivatives also prevented GCS inhibition. When

compared to 3, 42 is a more selective inhibitor of GBA1,

and both 43 and 44 are more selective for GBA2.

Biological Evaluation

The β-C-glycoside derivatives 27, 28 and 29 did not in-

The inhibitory potency and selectivity of the two libraries hibit any of the tested enzymes to a significant extent.

of lipophilic aza-C-glycosides A (17–22; 27–29; 32, 34; 36– When combined with the fact^[24]that derivatives of 2 with

40; 42–44) and B (73–86) were assessed by evaluating the an endocyclic amide are also inactive as inhibitors of gluco-

compounds in assays for the three enzymes involved in glu- sylceramide metabolism this strongly suggests that a basic

cosylceramide metabolism; glucosylceramide synthase nitrogen function is essential for inhibition. The previously

(GCS), glucocerebrosidase (GBA1) and β-glucosidase 2 reported observation, that GCS is inhibited by the N-butyl-

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Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

Table 1. Enzyme inhibition assay results for α- and β-(aza)-C-glycosides (apparent IC₅₀values in µ).^[a]

[a] AM = adamant-1-ylmethyl; AMP = 5-(adamant-1-ylmethoxy)pentyl.

ated 5 and not N-methylated 4, is not reproduced for the in the ability of 3 to inhibit GCS, GBA1 and GBA2. The

lengthened or shortened N-alkylated derivatives 19, 20 and only derivative from the first library that still very modestly

21, 22. Compound 19 is a relatively selective inhibitor of inhibits GCS is 34 (15% at 10 µ) – the C-1/N-substituent-

GBA2. Also the synthesized derivatives of 3 with alternate/ inverted derivative of 5. The related entry, 32, did not signif-

lengthened N-alkyl moieties 36–40, all lost the ability to icantly inhibit any of the enzymes in the assay. Compound

inhibit GCS and showed no improvement of GBA1 or 32 is a β-aza-C-glycoside derivative of the known clinically

GBA2 inhibition. These findings indicate that the second- used GCS inhibitor N-butyl-1-deoxynojirimycin (GCS:

ary endocyclic nitrogen atom of 3 plays an important part IC₅₀= 50 µ in this assay). This reconfirms the observation

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from our previous study^[28]that relocating the hydrophobic by Compain, Martin and co-workers. Their study showed

moiety from the nitrogen atom to C-1 does not lead to more that 82 holds potential as a pharmacological chaperone for

potent GCS inhibitors.

improving the activity of a deficient variant of GBA1 in

Almost all the entries of the second library of lipophilic N370S fibroblasts from patients with the lysosomal storage

α-aza-C-glycosides showed very modest inhibition of GCS disorder, Gaucher disease.^[46]Therefore, it might prove

(Յ20% at 10 µ) with none being as potent as 3 (Table 1). interesting to also evaluate the novel derivatives (79–81, 85,

These results corroborate an earlier study by Boucheron 86) presented here to this end.

and co-workers that showed that N-alkylated α-aza-C-gly-

cosides are poor inhibitors of GCS.^[49]The three different

iminosugar cores did, however, have a distinct effect on

GBA2 inhibition. The -gluco derivatives (76–78, 84) in ge-

neral were Ͼ25-fold more potent GBA2 inhibitors than the

-ido (73–75, 83) or -xylo (79–81, 82, 85, 86) derivatives.

Experimental Section

For GBA1 inhibition the effect of the iminosugar core was

even more pronounced. The -xylo α-aza-C-glycosides were

all 1–2 n inhibitors of GBA1 as opposed to the -ido de-

rivatives that were 2–6 µ inhibitors of the same enzyme.

General Methods: All solvents and reagents were obtained commer-

cially and used as received unless stated otherwise. Reactions were

executed at ambient temperatures unless stated otherwise. All

moisture-sensitive reactions were performed under argon. Residual

-xylo analogue 85 is an (E)/(Z) mixture, and these isomers water was removed from starting compounds by repeated coevapo-

ration. All solvents were removed by evaporation under reduced

pressure. Reaction grade acetonitrile, dimethyl sulfoxide, 2-propa-

nol and methanol were stored over 3 Å molecular sieves. Other

reaction grade solvents were stored over 4 Å molecular sieves. THF

was distilled prior to use from LiAlH₄. Ethanol was purged of acet-

aldehyde contamination by distillation from zinc/KOH. DCM was

distilled prior to use from P₂O₅. R_fvalues were determined from

TLC analysis by using DC-Fertigfolien (Schleicher & Schuell,

F1500, LS254) with detection by spraying with a solution of

(NH₄)₆Mo₇O₂₄·4H₂O (25 g/L) and (NH₄)₄Ce(SO₄)₄·2H₂O (10 g/L)

in 10% sulfuric acid or a solution of phosphomolybdic acid hydrate

(7.5 wt.-% in ethanol) followed by charring at ca. 150 °C. Visualiza-

tion of all deprotected iminosugar compounds during TLC analysis

was accomplished by exposure to iodine vapour. Column

chromatography was performed on silica gel (40–63 µm). Imi-

nosugars (43, 73–86) were purified with an automated HPLC sys-

tem fitted with a semi-preperative C₁₈column (21 mm dia-

meterϫ150 mm length, 5 µm particle size, 25 mL/min). Isocratic

or gradient elution was performed with eluent A: 0.1% aq. TFA

and eluent B: CH₃CN. Iminosugar samples were dissolved in a

mixture of 0.1% aq. TFA/tBuOH/CH₃CN (3:1:1, v/v/v, 2 mL) with

should be tested separately to fully elucidate their relative

contributions to GBA1 inhibition. In general, the unsatu-

rated pentyl spacer derivatives (83, 84 and 85) did not show

a significantly different inhibition profile for the tested en-

zymes compared to their saturated counterparts (74, 77 and

80). However, introduction of an (E)-alkene into the

known^[46]potent GBA1 inhibitor 82 to give 86 does reduce

inhibition of GCS and GBA2 to make it more selective.

Conclusions

The syntheses and biological evaluation of two libraries

of lipophilic aza-C-glycosides is reported. The structures of

the library entries are based on the previously reported β-

aza-C-glycosides 3.^[28]The aim was to investigate the struc-

ture–activity relationship of this class of iminosugars as in-

hibitors of three enzymes, GCS, GBA1 and GBA2, involved

in glucosylceramide metabolism.

The first library consisted of β-aza-C-glycosides and optional MeOH for full solvation of the compound. The solution

was filtered through a 5 µm filter and injected onto the column

in 500 µL portions for preparative runs. Compound detection was

carried out by a charged aerosol detector (Esa Corona, sensitivity

setting: 100 pA). Appropriate fractions were collected, concen-

showed that for GCS inhibition an aliphatic pentyl-spacer

length between C-1 and the adamant-1-ylmethoxy group

combined with a secondary endocyclic nitrogen atom is op-

timal in this library. β-C-Glycoside derivatives showed the

importance of a basic endocyclic nitrogen atom for inhibi-

tion of the here evaluated glycosidases and the glycosyl-

transferase GCS. From this first library the alkyne-contain-

ing 43 was found to be a potent and selective inhibitor of

GBA2 and the (Z)-alkene-containing 42 a selective inhibi-

tor of GBA1.

The second library of α-aza-C-glycosides did not contain

a potent inhibitor of GCS, which indicates that a pseudo-β

orientation of the hydrophobic moiety is necessary for po-

tent inhibition of GCS. The type of iminosugar core in the

α-aza-C-glycosides proved to exert a pronounced influence

on inhibition of GBA1 and GBA2. The -gluco iminosugar

core proved most suitable for GBA2 inhibition, and the -

xylo core is optimal for GBA1 inhibition. All -xylo ana-

logues (79–81, 82, 85, 86) were very potent and selective

1

trated, coevaporated with water (2ϫ) and lyophilized. H and ¹³C

APT NMR spectra were recorded with a Bruker DMX 600 (600/

150 MHz), Bruker DMX 500 (500/125 MHz), Bruker AV 400 (400/

100 MHz), or Bruker AC 200 (200/50 MHz) spectrometer in CDCl₃

or MeOD. Chemical shifts (δ) are given in ppm relative to tet-

ramethylsilane as internal standard (¹H NMR in CDCl₃) or the

signal of the deuterated solvent. Coupling constants (J) are given

in Hz. Where indicated, NMR peak assignments were made by

using COSY and HSQC experiments. All presented ¹³C APT spec-

tra are proton-decoupled. High-resolution mass spectra were re-

corded by direct injection (2 µL of a 2 µ solution in water/acetoni-

trile; 50:50; v/v and 0.1% formic acid) with a mass spectrometer

(Thermo Finnigan LTQ Orbitrap) equipped with an electrospray

ion source in positive mode (source voltage 3.5 kV, sheath gas flow

10, capillary temperature 250 °C) with resolution R = 60000 at m/z

= 400 (range m/z = 150–2000) and dioctyl phthalate (m/z =

391.28428) as a “lock mass”. Optical rotations were measured with

GBA1 inhibitors. Iminosugar 82 has already been reported a Propol automatic polarimeter (sodium -line, λ = 589 nm). ATR-

1264

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Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

IR spectra were recorded with a Shimadzu FTIR-8300 fitted with

a single-bounce Durasample IR diamond crystal ATR-element and

are reported in cm^–1.

stirred for an additional 20 h. After removal of the molecular sieves

with the aid of a glass microfibre filter, the filtrate was concen-

trated, dissolved in EtOAc and washed with satd. aq. NaHCO₃.

The aqueous phase was back-extracted with EtOAc (3ϫ), and the

combined organic layers were dried (MgSO₄) and concentrated.

The residue was purified by silica gel column chromatography to

provide the β-aza-C-glycoside product (R_f≈ 0.5 in EtOAc/toluene,

1:3).

Enzyme Assays: The enzyme assays used for determining the inhibi-

tion of activity of glucosylceramide synthase (GCS), glucocerebros-

idase (GBA1), β-glucosidase 2 (GBA2), sucrase, lactase and malt-

ase were carried out as described previously.^[28]

General Procedure A. Addition of Acetylenic Anions of 9 and 11 to

Gluconolactone (12): A dry solution of the acetylene in THF (0.1 )

was cooled to –50 °C, and BuLi (1.2 equiv., 1.6  in toluene) was

added slowly to the solution. After stirring at –50 °C for 1 h, a dry

solution of 12^[38](2 equiv.) in THF (0.33 ) was slowly added, and

the reaction mixture was stirred at –50 °C for 2 h. The reaction

mixture was quenched (satd. aq. NH₄Cl), warmed to room temp.

and poured into satd. aq. NH₄Cl. The aqueous layer was extracted

with Et₂O (3ϫ), and the combined organic layers were dried

(MgSO₄) and concentrated. The residue was purified by silica gel

column chromatography to provide the ketose product.

General Method D. N-Alkylation of β-Aza-C-glycosides by Re-

ductive Amination: A dry mixture of the tetrabenzylated imi-

nosugar, the aldehyde (10 equiv.) and Na₂SO₄(10 equiv.) in a mix-

ture of EtOH/AcOH (0.1 , 3:1, v/v) was charged with NaBH₃CN

(4 equiv.). The reaction mixture was stirred for 20 h and sub-

sequently concentrated by coevaporation with toluene. The residue

was dissolved EtOAc, poured into satd. aq. NaHCO₃and extracted

with EtOAc (3ϫ). The combined organic layers were dried

(Na₂SO₄) and concentrated. The crude N-alkylated iminosugar was

used in the Pd/C-catalyzed hydrogenolysis.

General Method E. Oxidative Cleavage of the PMB Group and Re-

protection as Benzyloxy Carbamate: A solution of the PMB-pro-

tected amine in THF (0.5 ) was slowly added to a cooled (0 °C)

solution of ammonium cerium(IV) nitrate (4 equiv.) in H₂O/THF

(0.05 , 1:5, v/v). The resulting suspension was stirred at 0 °C for

3 h, after which it was diluted with EtOAc (3ϫ reaction volume)

and washed with satd. aq. NaHCO₃(3ϫ reaction volume). The

aqueous phase was back-extracted with EtOAc (2ϫ). The com-

bined organic phases were concentrated. The residue was sus-

pended in a mixture of dioxane/satd. aq. NaHCO₃(0.1 , 2:1, v/

v) after which benzyloxy chloroformate (2 equiv.) was added. The

reaction mixture was stirred for 20 h. The mixture was diluted with

water and extracted with Et₂O (2ϫ). The combined organic phases

were dried (Na₂SO₄) and concentrated. To facilitate the separation

of the product from p-anisaldehyde during column chromatog-

raphy, the crude benzyloxy carbamate was dissolved in MeOH

(0.2 ), cooled to 0 °C and treated with sodium borohydride

(3 equiv.). After 15 min, the reaction was quenched by slow ad-

dition of acetone. The mixture was acidified to pH = 2 with 1 

aq. HCl, diluted with water (3ϫ reaction volume) and extracted

with Et₂O (3ϫ). The combined organic phases were dried

(Na₂SO₄) and concentrated. The residue was purified by silica gel

column chromatography to afford the benzyloxy carbamate pro-

tected iminosugar.

General Procedure B. Transformation of Ketose 13, 14 and 23 into β-

C-Glycosides by Reductive Elimination: Triethylsilane (5 equiv.) and

BF₃·O(Et)₂(6 equiv.) were successively added to a cooled (–30 °C)

solution of the ketose in anhydrous acetonitrile (0.1 ). After stir-

ring at –30 °C for 1.5 h, TLC analysis showed complete disappear-

ance of the starting material. The reaction mixture was quenched

by addition of aq. Na₂CO₃(6ϫ reaction volume, 10 wt.-%) and

subsequently extracted with Et₂O (3ϫ). The combined organic

phases were dried (MgSO₄) and concentrated. The residue was

purified by silica gel column chromatography to provide the β-C-

glycoside.

General Procedure C. Transformation of Ketose 13 and 14 into β-

Aza-C-glycosides: Reduction of Ketal: A dry solution of the ketose

in MeOH/DCM (0.1 , 5:1, v/v) was cooled to 0 °C and NaBH₄

(5 equiv.) was added. After stirring at 0 °C for 2 h, TLC analysis

indicated full conversion to a slower running product. The reaction

was quenched by addition of acetone and additional stirring

(15 min). The reaction mixture was concentrated, transferred into

satd. aq. NH₄Cl and extracted with EtOAc (3ϫ). The combined

organic phases were dried (MgSO₄) and concentrated to provide

the glucitol derivative, which was used without further purification

in the Swern oxidation [R_f(diol) ≈ 0.4 in EtOAc/toluene; 1:3].

Swern Oxidation of Diol: A solution of oxalyl chloride (4 equiv.) in

DCM (1 ) was cooled to –78 °C. After dropwise addition of a

solution of DMSO (5 equiv.) in DCM (2 ) over 10 min, the reac-

tion mixture was stirred for 40 min, while being kept below –70 °C.

Next, a dry solution of the glucitol intermediate in DCM (0.5 )

was added dropwise to the reaction mixture over a 15 min period,

while keeping the reaction mixture below –70 °C. After stirring the

reaction mixture below –65 °C for 2 h, Et₃N (12 equiv.) was added

dropwise over a 10 min period, while keeping the reaction mixture

below –65 °C. After addition, the reaction mixture was warmed to

–5 °C over 2 h [R_f(diketone) ≈ 0.80 in EtOAc/toluene, 1:3].

General Procedure F. Cross Metathesis: The iminosugar cross me-

tathesis partner was coevaporated with DCE (3ϫ). Next, the sec-

ond alkene cross-metathesis partner (3 equiv.) was added, and to-

gether they were dissolved in DCM (0.067 , relative to imi-

nosugar). Alkenes 45, 46 and 47 are not coevaporated because 46

and 47 are volatile. The solution was degassed by sonication under

an argon flow for 10 min. Grubbs’ first generation catalyst (25 mol-

%) was added, and the reaction mixture was refluxed at 45 °C for

24 h. The reaction mixture was concentrated and exposed to air at

room temp. for 48 h. The residue was purified by by silica gel col-

umn chromatography to afford the cross-metathesis product. In

cases were the product was difficult to isolate from residual imi-

nosugar cross-metathesis partner or catalyst breakdown products,

the residue was purified once and then used impure in general pro-

cedure G or general procedure H (in a Parr apparatus).

Double-Reductive Amination: The Swern reaction mixture was con-

centrated at a moderate temperature (ca. 30 °C) with simultaneous

coevaporation of toluene (3ϫ). The residue was dissolved in a mix-

ture of MeOH/DCM (0.02 , relative to starting compound, 5:1,

v/v), and NH₄HCO₂(20 equiv.) was added. The mixture was cooled

to 0 °C and stirred until all NH₄HCO₂had dissolved. Activated

3 Å molecular sieves (10 g/mmol) was added, and the reaction mix-

ture was stirred for 15 min, after which NaBH₃CN (4 equiv.) was

added. The reaction mixture was kept at 0 °C for 1 h, after which

the cooling source was removed, and the reaction mixture was

General Procedure G. Birch Reduction: A dry (100 mL) three-neck

roundbottom flask was cooled to –60 °C, and ammonia gas

(through a CaO-filled drying column) was passed through it until

20–30 mL of ammonia had condensed. The ammonia gasflow was

stopped, and sodium (50–100 mg, rinsed beforehand with heptane)

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1265

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

was added to the liquid ammonia. After stirring the dark blue mix-

ture at –60 °C for 1 min, a solution of the benzylated iminosugar

(50–200 mg) in tBuOH/THF (0.5 mL/ 2 mL) was added. The reac-

tion mixture was stirred at –60 °C for 1–2 h, and additional sodium

was added if the blue colour of the mixture disappeared. The reac-

tion was quenched by slow addition of satd. aq. NH₄HCO₂(1 mL).

The ammonia was evaporated, and the resulting residue was co-

evaporated with dioxane. The solid residue was redissolved in

MeOH and concentrated in the presence of Celite. The Celite/com-

pound mixture was purified by silica gel column chromatography

to afford the deprotected iminosugar.

reaction mixture was concentrated at room temp. by means of a

nitrogen flow. The residue was purified by silica gel column

chromatography (isocratic 10% EtOAc in PE), and the product-

containing fractions were concentrated under a nitrogen flow at

room temp. to provide the intermediate triflate. [R_f= 0.67 (EtOAc/

PE, 1:9)]. The triflate (ca. 12 mmol) was dissolved in DCM

(80 mL), to which adamantylmethanol (9.98 g, 60 mmol) and

K₂CO₃(8.17 g, 60 mmol) were successively added. The reaction

mixture was refluxed (ca. 55 °C) for 3 d, after which the solids were

removed by filtration, and the filtrate was concentrated. The resi-

due was purified by silica gel column chromatography (0% Ǟ 20%

EtOAc in PE) to provide 8 (3.37 g, 10.1 mmol) in 84% yield as a

colourless oil. R_f= 0.83 (EtOAc/PE, 1:9). ¹H NMR (200 MHz,

CDCl₃): δ = 3.52 (t, J = 7.1 Hz, 2 H, OCH₂-4 butynyl), 3.02 (s, 2

H, OCH₂-Ada), 2.49 (t, J = 7.1 Hz, 2 H, CH₂-3 butynyl), 1.95 (s,

3 H, 3ϫ CH Ada), 1.79-1.57 (m, 6 H, 3ϫ CH₂Ada), 1.53 (d, J =

2.7 Hz, 6 H, 3ϫ CH₂Ada), 0.98 (t, J = 7.8 Hz, 9 H, 3ϫ CH₃

SiEt₃), 0.57 (q, J = 7.7 Hz, 6 H, 3ϫ CH₂SiEt₃) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 105.5 (C_q-2 butynyl), 82.6 (C_q-1 butynyl),

82.2 (OCH₂-Ada), 70.2 (OCH₂-4 butynyl), 39.9 (CH₂Ada), 37.5

(CH₂Ada), 34.3 (C_qAda), 28.6 (CH Ada), 21.4 (CH₂-3 butynyl),

General Procedure H. Pd/C-Catalyzed Hydrogenolysis at Atmo-

spheric H₂Pressure: A solution of the compound (ca. 50–250 µmol)

in “acetaldehyde-free” EtOH (4 mL) was acidified to pH ≈ 2 with

1  aq. HCl. Argon was passed through the solution for 5 min,

after which a catalytic amount of Pd/C (ca. 50 mg, 10 wt.-% Pd on

C) was added. Hydrogen was passed through the reaction mixture

for 15 min, and the reaction mixture was stirred under atmospheric

hydrogen pressure for 20 h. The Pd/C was removed by filtration

through a glass microfibre filter, followed by thorough rinsing of

the filter cake with MeOH. The filtrate was concentrated by co-

evaporation with toluene. In the case of incomplete reduction, hy-

drogenolysis was repeated after workup and coevaporation (3ϫ)

with “acetaldehyde-free” EtOH, at atmospheric pressure in the

presence of Pd/C (ca. 50 mg) and Pd black (ca. 5 mg) or at higher

H₂pressure in a Parr apparatus.

7.6 (CH SiEt ), 4.7 (CH SiEt ) ppm. IR (thin film): ν_max.= 2901,

˜

3

2

3

2874, 2849, 2175, 1456, 1236, 1157, 1111, 1003, 723 cm^–1. HRMS:

found 333.2609 [M + H]⁺, calcd. for [C₂₁H₃₆OSi + H]⁺333.2608.

4-(Adamant-1-ylmethoxy)but-1-yne (9): A dry solution of 8 (3.37 g,

10.1 mmol) in a mixture of THF (50 mL) and MeOH (25 mL) was

charged with NaOMe (2.86 g, 52.95 mmol) and refluxed at 90 °C

for 20 h. The reaction was quenched (water, 0.5 mL) and the mix-

ture concentrated. The residue was dissolved in EtOAc (200 mL)

and washed with water (2ϫ200 mL). The organic phase was dried

(MgSO₄) and concentrated. The residue was purified by silica gel

column chromatography (2% Ǟ 10% acetone in PE) to provide 9

(1.92 g, 8.80 mmol) in 87% yield as a colourless oil. R_f= 0.70

(EtOAc/PE, 1:9). ¹H NMR (200 MHz, CDCl₃): δ = 3.53 (t, J =

7.2 Hz, 2 H, OCH₂-4 butynyl) 3.01 (s, 2 H, OCH₂-Ada), 2.43 (td,

J = 2.7, 7.2 Hz, 2 H, CH₂-3 butynyl), 1.97 (br. s, 3 H, 3ϫ CH

Ada), 1.94 (t, J = 2.6 Hz, 1 H, CH-1 butynyl), 1.78–1.57 (m, 6 H,

3ϫ CH₂Ada), 1.53 (d, J = 2.8 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 82.1, (OCH₂-Ada), 81.6 (C_qbutynyl),

69.8 (OCH₂-4 butynyl), 69.2 (C_qbutynyl), 39.8 (CH₂Ada), 37.3

(CH₂Ada), 34.2 (C_qAda), 28.4 (CH Ada), 19.8 (CH₂-3 butynyl)

Pd/C-Catalyzed Hydrogenolysis in a Parr Apparatus: A solution of

the compound (ca. 50–250 µmol) in “acetaldehyde-free” EtOH

(50 mL) was acidified to pH ≈ 2 with 1  aq. HCl. Argon was

passed through the solution for 5 min, after which a catalytic

amount of Pd/C (50 mg, 10 wt.-% Pd on C) was added. The reac-

tion vessel was placed under vacuum and subsequently ventilated

with hydrogen gas. This cycle was repeated one more time, after

which the vessel was placed under 4 bar of hydrogen gas and me-

chanically shaken for 20 h. Workup was the same as described in

general procedure H.

4-(Triethylsilyl)but-3-yn-1-ol (7): A dry and cooled (–68 °C) solu-

tion of but-3-yn-1-ol (6; 3.11 g, 44.3 mmol) in THF (50 mL) was

charged with BuLi (60.9 mL, 97.5 mmol, 1.6  in toluene) and

stirred at –68 °C for 1 h. Triethylsilyl chloride (22.5 mL,

132.9 mmol) was added dropwise to the reaction mixture, and the

mixture was stirred at –68 °C for 1 h, after which cooling was ce-

ased and the solution was stirred for 18 h. 2  aq. HCl (200 mL)

was added, and the reaction mixture was stirred for 48 h [R_f(inter-

mediate disilyl compound) = 0.80 (EtOAc/PE, 1:2)]. The mixture

was extracted with Et₂O (2ϫ200 mL), and the combined organic

layers were washed with water (2ϫ200 mL). The organic phase was

dried (MgSO₄), concentrated, and the resulting residue was puri-

fied by silica gel column chromatography (0% Ǟ 30% EtOAc in

PE) to provide product 7 (5.82 g, 31.5 mmol) in 71% yield as a

colourless oil. R_f= 0.10 (EtOAc/PE, 1:9). ¹H NMR (200 MHz,

CDCl₃): δ = 3.72 (t, J = 5.8 Hz, 2 H, OCH₂-1 butynyl), 2.53 (t, J

= 6.6 Hz, 2 H, CH₂-2 butynyl), 1.82 (br. s, 1 H, OH), 0.99 (t, J =

8.0 Hz, 9 H, 3ϫ CH₃SiEt₃), 0.58 (q, J = 8.0 Hz, 6 H, 3ϫ

ppm. IR (thin film): ν

= 3312, 2899, 2847, 1450, 1362, 1157,

˜

max.

1103, 1070 cm^–1. MS (ESI): found 219.9 [M + H]⁺, calcd. for

[C₁₅H₂₂O + H]⁺219.2.

6-(Adamant-1-ylmethoxy)hex-1-yne (11): (1-Diazo-2-oxopropyl)-di-

O-methyl phosponate (1.44 g, 7.5 mmol)^[50,51]and K₂CO₃(1.38 g,

10.0 mmol) were added to a cooled (0 °C) solution of 10^[25](1.25 g,

5.0 mmol) in methanol (25 mL). After 30 min, the reaction mixture

was warmed to room temp. and stirred for an additional 16 h. The

reaction mixture was transferred into satd. aq. NH₄Cl (20 mL) and

extracted with Et₂O (4ϫ50 mL). The combined organic phases

were washed with satd. aq. NaCl (50 mL), dried (MgSO₄) and con-

centrated. The crude product was purified by silica gel column

chromatography (0% Ǟ 6% EtOAc in PE) to furnish 11 (1.07 g,

4.34 mmol) in 87% yield as a colourless oil. R_f= 0.6 (PE/acetone,

CH SiEt ) ppm. IR (thin film): ν = 3323, 2953, 2876, 2174,

˜

max.

2

3

1

19:1). H NMR (200 MHz, CDCl₃): δ = 3.40 (t, J = 6.0 Hz, 2 H,

1458, 1414, 1236, 1018, 1004, 972, 889, 721 cm^–1. MS (ESI): found

OCH₂-6 hex-1-yn), 2.95 (s, 2 H, OCH₂-Ada), 2.28–2.17 (m, 2 H,

CH₂-3 hexynyl), 1.96 (br. s, 3 H, 3ϫ CH Ada), 1.94 (t, J = 2.6 Hz,

1 H, CH-1 hexynyl), 1.78–1.57 (m, 10 H, 3ϫ CH₂Ada, 2ϫ CH₂

hexynyl), 1.53 (d, J = 2.8 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR

(50 MHz, CDCl₃): δ = 84.3 (C_qhexynyl), 82.0 (OCH₂-Ada), 70.9

(OCH₂-6 hexynyl), 68.6 (C_qhexynyl), 39.9 (CH₂Ada), 37.4 (CH₂

Ada), 34.2 (C_qAda), 28.8 (CH₂-5 hexynyl), 28.5 (CH Ada), 25.5

185.2 [M + H]⁺, calcd. for [C₁₀H₂OSi + H]⁺185.1.

[4-(Adamant-1-ylmethoxy)but-1-ynyl]triethylsilane (8): A dry solu-

tion of 7 (2.21 g, 12.0 mmol) in DCM (120 mL) was cooled to

–40 °C followed by addition of Et₃N (1.66 mL, 12.0 mmol). Next,

Tf₂O (2.42 mL, 14.4 mmol) was added dropwise, and the reaction

mixture was stirred at –40 °C for 1 h. Cooling was ceased, and the

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Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

(CH -4 hexynyl), 18.3 (CH -3 hexynyl) ppm. IR (thin film): ν 1.65 (dd, J = 12.0, 43.7 Hz, 6 H, 3ϫ CH₂Ada), 1.49 (d, J = 2.4 Hz,

˜

max.

2

= 3311, 2899, 2847, 1452, 1360, 1157, 1113, 1056, 625 cm^–1. 6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 138.9,

HRMS: found 247.2058 [M + H]⁺, calcd. for [C₁₇H₂₆O + H]⁺

247.2056.

138.6, 138.4, 138.1 (4ϫ C_qBn), 128.65, 128.62, 128.5, 128.4, 128.2,

128.17, 128.12, 128.0, 127.97, 127.95, 127.8 (CH_ArBn), 87.0 (C-3),

84.6 (C-2), 82.2 (OCH₂-Ada), 81.3 (C_qbutynyl), 80.1 (C-4), 76.0,

75.7, 75.3, 73.6 (4ϫ CH₂Bn), 70.3 (C-6), 70.0 (CH₂-4 butynyl),

58.9 (C-5), 51.9 (C-1), 39.8 (CH₂Ada), 37.4 (CH₂Ada), 34.2 (C_q

Ada), 28.4 (CH Ada), 20.2 (CH₂-3 butynyl) ppm. IR (thin film):

α/β-Mixture of 1-C-[4-(Adamant-1-ylmethoxy)but-1-ynyl]-2,3,4,6-

tetra-O-benzyl-

D

-glucopyranose (13): Compound

9

(1.0 g,

4.58 mmol) was subjected to general procedure A to produce 13

(2.09 g, 2.76 mmol) in 60% yield after silica gel column purification

(0% Ǟ 5% acetone in toluene). R_f= 0.46 (toluene/acetone, 19:1).

¹H NMR (300 MHz, CDCl₃, α/β mixture): δ = 7.42–7.09 (m, 20

H, H_ArBn), 5.07–4.43 (m, 8 H, 4ϫ CH₂Bn), 4.06–3.56 (m, 6 H,

2-H, 3-H, 4-H, 5-H, CH₂-6), 3.55–3.44 (m, 2 H, OCH₂-4 butynyl),

3.01–2.90 (m, 2 H, OCH₂-Ada), 2.56–2.43 (m, 2 H, CH₂-3 butynyl),

1.91 (br. s, 3 H, 3ϫ CH Ada), 1.74–1.54 (m, 6 H, 3ϫ CH₂Ada),

ν

= 2901, 2847, 1454, 1360, 1151, 1096, 1070, 1028, 1007, 735,

˜

max.

696 cm^–1. [α]²_D⁰= 6.8 (c = 0.8, CHCl₃). HRMS: found 740.4309 [M

+ H]⁺, calcd. for [C₄₉H₅₇NO₅+ H]⁺740.4310.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hex-1-ynyl]-2,3,4,6-tetra-O-benz-

yl-1-deoxynojirimycin (16): Compound 14 (0.40 g, 0.51 mmol) was

subjected to general procedure C to give 16 (234 mg, 0.30 mmol)

1.48 (s, 6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR (75 MHz, CDCl₃, α/β as a colourless oil in 59% yield after silica gel column chromatog-

mixture): δ = 138.5, 138.46, 138.42, 138.3, 137.93, 137.91, 137.8

raphy (0% Ǟ 20% EtOAc in toluene). R_f= 0.6 (toluene/acetone,

(C_qBn α/β), 128.1, 128.0, 127.86, 127.81, 127.7, 127.6, 127.5, 127.4, 9:1). ¹H NMR (400 MHz, C₆D₆): δ = 7.23–7.05 (m, 20 H, H_ArBn),

127.2 (CH_ArBn α/β), 95.3, 91.4, 86.2, 84.1, 84.0, 83.5, 82.9, 82.3,

81.9, 81.8 (OCH₂-Ada), 80.3, 78.0, 77.5, 77.3, 77.0, 76.8, 76.7, 76.4,

75.6, 75.5, 75.4, 74.9, 74.7, 74.4, 73.8, 73.2, 71.5, 69.2, 69.0 (OCH₂-

4 butynyl), 68.3, 39.4 (CH₂Ada), 36.9 (CH₂Ada), 33.8 (C_qAda),

5.20 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.97–4.93 (m, 2 H, CHH Bn,

CHH Bn), 4.88 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.81 (d, J =

11.3 Hz, 1 H, CHH Bn), 4.47 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.25

(d, J = 11.9 Hz, 1 H, CHH Bn), 4.19 (d, J = 11.9 Hz, 1 H, CHH

28.0 (CH Ada), 19.8, 19.7 (CH₂-3 butynyl) ppm. IR (thin film): Bn), 3.65 (dd, J = 2.4, 8.9 Hz, 1 H, 6a-H), 3.59–3.48 (m, 4 H, 1-

ν

_max.= 3321, 3032, 2905, 2847, 1496, 1454, 1367, 1209, 1146, 1103,

H, 2-H, 3-H, 6b-H), 3.45 (dd, J = 9.1, 9.1 Hz, 1 H, 4-H), 3.21 (t,

J = 5.9 Hz, 2 H, CH₂-6 hexenyl), 2.87 (s, 2 H, OCH₂-Ada), 2.76

(ddd, J = 2.4, 6.2, 9.0 Hz, 1 H, 5-H), 2.08 (t, J = 6.5 Hz, 2 H, CH₂-

3 hexenyl), 1.94 (s, 3 H, 3ϫ CH Ada), 1.73–1.50 (m, 16 H, 6ϫ

CH₂Ada, 2ϫ CH₂hexenyl) ppm. ¹³C NMR (100 MHz, C₆D₆): δ

= 140.2, 140.0, 139.8, 139.1 (4ϫ C_qBn), 129.0, 128.8, 128.7, 128.5,

128.3, 128.2, 128.0, 127.9 (CH_ArBn), 87.9 (C-3), 85.6 (C-2), 84.2

(C_qhexenyl), 82.6 (OCH₂-Ada), 80.9 (C-4), 80.9 (C_qhexenyl), 76.0,

75.8, 75.4, 73.9 (4ϫ CH₂Bn), 71.4 (CH₂-6 hexenyl), 71.0 (C-6),

59.8 (C-5), 52.9 (C-1), 40.5 (CH₂Ada), 38.0 (CH₂Ada), 34.7 (C_q

Ada), 29.7 (CH₂hexenyl), 29.2 (CH Ada), 26.3 (CH₂hexenyl), 19.3

˜

1045, 1028, 1007, 986, 951, 910, 808, 754, 742 cm^–1. [α]²_D⁰= 36.1 (c

= 4.6, CHCl₃). HRMS: found 774.4367 [M + NH₄]⁺, calcd. for

[C₄₉H₅₆O₇+ NH₄]⁺774.4364.

α/β-Mixture of 1-C-[6-(Adamant-1-ylmethoxy)hex-1-ynyl]-2,3,4,6-

tetra-O-benzyl-D-glucopyranose (14): Compound 11 (493 mg,

2.0 mmol) was subjected to general procedure A to produce 14

(1.35 g, 1.72 mmol) in 86% yield after silica gel column purification

(0% Ǟ 5% acetone in toluene). R_f= 0.50 (toluene/acetone, 19:1).

¹H NMR (200 MHz, CDCl₃, α/β mixture): δ = 7.44–7.08 (m, 20

H, H_ArBn), 5.07–4.45 (m, 8 H, 4ϫ CH₂Bn), 3.96–3.25 (m, 8 H,

CH₂-6 hexenyl, 2-H, 3-H, 4-H, 5-H, CH₂-6), 2.92, 2.91 (s, 2 H,

OCH₂-Ada α/β), 2.36–2.21 (m, 2 H, CH₂-3 hexenyl), 1.93 (br. s, 3

H, 3ϫ CH Ada), 1.76–1.54 (m, 10 H, 3ϫ CH₂Ada, 2ϫ CH₂

hexenyl), 1.50 (d, J = 2.0 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR

(C-3 hexenyl) ppm. IR (thin film): ν

= 3031, 2901, 2848, 1497,

˜

max.

1452, 1359, 1209, 1071, 1027, 1007, 734, 696 cm^–1. [α]²_D⁰= 6.2 (c =

1.0, CHCl₃). HRMS: found 768.4623 [M + H]⁺, calcd. for

[C₅₁H₆₁NO₅+ H]⁺768.4623.

(50 MHz, CDCl₃, α/β mixture): δ = 138.7, 138.7, 138.6, 138.1, (1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxynojirimycin (17):

138.1, 138.0, 138.0 (C_qBn α/β), 128.3, 128.2, 128.1, 127.99, 127.97,

127.94, 127.92, 127.87, 127.85, 127.7, 127.6, 127.5, 127.4, 127.3

(CH_ArBn α/β), 95.6, 91.6 (C-1 α/β), 89.1, 84.8 (C_qhexenyl α/β),

84.4, 84.3, 83.7, 82.5, 81.8 (OCH₂-Ada), 79.9, 77.8, 77.4, 77.1, 76.4,

75.6, 75.6, 75.0, 74.8, 74.4, 73.8, 73.6, 73.4, 73.2, 73.2, 71.5, 70.8,

Compound 15 (66 mg, 89 µmol) was subjected to hydrogenolysis at

atmospheric H₂(see general procedure H) to produce 17 (30 mg,

79 µmol) as a colourless oil in 90% yield after purification (silica

gel: 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). R_f= 0.22

(MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

70.7, 68.5, 39.6 (CH₂Ada), 37.1 (CH₂Ada), 34.0 (C_qAda), 28.8, MeOD): δ = 3.92 (dd, J = 3.1, 10.8 Hz, 1 H, 6a-H), 3.50 (dd, J =

28.7 (CH₂hexenyl α/β), 28.2 (CH Ada), 25.1, 24.9 (CH₂hexenyl α/ 7.8, 10.8 Hz, 1 H, 6b-H), 3.41 (t, J = 6.2 Hz, 2 H, OCH₂-4 butyl),

β), 18.5 (CH -3 hexenyl) ppm. IR (thin film): ν = 3362, 3032, 3.20 (dd, J = 8.9, 8.9 Hz, 1 H, 3-H), 3.11 (dd, J = 9.3, 9.3 Hz, 1

˜

2

max.

2902, 2849, 1497, 1453, 1360, 1211, 1067, 1027, 910, 733, 695 cm^–1. H, 4-H), 2.99 (dd, J = 9.2, 9.2 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH₂-

[α]²_D⁰= 33.4 (c = 2.2, CHCl₃). HRMS: found 802.4681 [M +

Ada), 2.56 (ddd, J = 3.1, 7.8, 9.9 Hz, 1 H, 5-H), 2.43 (td, J = 2.8,

9.2 Hz, 1 H, 1-H), 1.94 (s, 3 H, 3ϫ CH Ada), 1.93–1.89 (m, 1 H,

CHH-1 butyl), 1.72 (dd, J = 11.9, 44.4 Hz, 6 H, 3ϫ CH₂Ada),

1.65–1.52 (m, 3 H, CHH-2 butyl, CH₂-3 butyl), 1.56 (d, J = 2.1 Hz,

6 H, 3ϫ CH₂Ada), 1.45–1.28 (m, 2 H, CHH-1 butyl, CHH-2

butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 83.2 (OCH₂-Ada),

80.7 (C-3), 76.7 (C-2), 73.7 (C-4), 72.6 (CH₂-4 butyl), 63.7 (C-6),

62.6 (C-5), 60.9 (C-1), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_q

Ada), 32.9 (CH₂-1 butyl), 31.1 (CH₂-3 butyl), 29.9 (CH Ada), 23.7

NH₄]⁺, calcd. for [C₅₁H₆₀O₇+ NH₄]⁺802.4677.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)but-1-ynyl]-2,3,4,6-tetra-O-benz-

yl-1-deoxynojirimycin (15): Compound 13 (371 mg, 0.49 mmol) was

subjected to general procedure C to give 15 (191 mg, 0.26 mmol)

as a colourless oil in 53% yield after silica gel column chromatog-

raphy (0% Ǟ 20% EtOAc in toluene). R_f= 0.19 (toluene/EtOAc,

9:1). ¹H NMR (600 MHz, CDCl₃): δ = 7.39–7.16 (m, 20 H, H_Ar

Bn), 5.02 (d, J = 10.5 Hz, 1 H, CHH Bn), 4.91 (d, J = 10.8 Hz, 1

H, CHH Bn), 4.83 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.81 (m, 2 H,

2ϫ CHH Bn), 4.49–4.42 (m, 3 H, CH₂Bn, CHH Bn), 3.68 (dd, J

= 2.4, 9.0 Hz, 1 H, 6a-H), 3.54–3.48 (m, 4 H, 3-H, 6b-H, OCH₂-4

(CH -2 butyl) ppm. IR (thin film): ν

= 3356, 2899, 2847, 1448,

˜

2

max.

1092, 999 cm^–1. [α]²_D⁰= 3.3 (c = 0.3, MeOH). HRMS: found

384.2746 [M + H]⁺, calcd. for [C₂₁H₃₇NO₅+ H]⁺384.2744.

butynyl), 3.44–3.43 (m, 2 H, 1-H, 2-H), 3.37 (dd, J = 9.4, 9.4 Hz, (1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxynojirimycin (18):

1 H, 4-H), 2.95 (s, 2 H, OCH₂-Ada), 2.77–2.73 (m, 1 H, 5-H), 2.47 Compound 16 (75 mg, 98 µmol) was subjected to hydrogenolysis at

(t, J = 7.3 Hz, 2 H, CH₂-3 butynyl), 1.93 (br. s, 3 H, 3ϫ CH Ada),

atmospheric H₂(see general procedure H) to produce 18 (30 mg,

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1267

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

73 µmol) as a colourless oil in 75% yield after purification (silica

NH₄OH). ¹H NMR (400 MHz, MeOD + CDCl₃): δ = 3.94 (s, 2

gel: 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). R_f= 0.24 H, CH₂-6), 3.48 (dd, J = 9.4, 9.4 Hz, 1 H, 4-H), 3.38 (t, J = 6.4 Hz,

(MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (400 MHz,

MeOD): δ = 3.92 (dd, J = 3.0, 11.1 Hz, 1 H, 6a-H), 3.62 (dd, J =

2 H, CH₂-6 hexyl), 3.34–3.25 (m, 2 H, 2-H, 3-H), 2.97 (s, 2 H,

OCH₂-Ada), 2.56 (s, 3 H, NCH₃), 2.50–2.42 (s, 2 H, 1-H, 5-H),

6.8, 11.1 Hz, 1 H, 6b-H), 3.38 (t, J = 6.4 Hz, 2 H, CH₂-6 hexyl), 1.95 (s, 3 H, 3ϫ CH Ada), 1.80–1.65 (m, 8 H, 3ϫ CH₂Ada, CH₂

3.28–3.20 (m, 2 H, 3-H, 4-H), 3.12–3.06 (m, 1 H, 2-H), 2.96 (s, 2 hexyl), 1.60–1.54 (m, 8 H, 3ϫ CH₂Ada, CH₂-5 hexyl), 1.50–1.32

H, OCH₂-Ada), 2.71–2.64 (m, 1 H, 1-H), 2.61–2.54 (m, 1 H, 5-H), (m, 6 H, 3ϫ CH₂hexyl) ppm. ¹³C NMR (100 MHz, MeOD +

1.94 (br. s, 4 H, 3ϫ CH Ada, CHH-1 hexyl), 1.72 (dd, J = 12.1,

32.0 Hz, 6 H, 3ϫ CH₂Ada), 1.59–1.51 (m, 8 H, 3ϫ CH₂Ada,

CDCl₃): δ = 81.1 (OCH₂-Ada), 77.7 (C-3), 70.8 (CH₂-6 hexyl), 70.5

(C-2), 67.9 (C-4), 67.8 (C-5), 66.3 (C-1), 57.0 (C-6), 38.9 (CH₂

CH₂hexyl), 1.39 (m, 7 H, 3ϫ CH₂hexyl, CHH-1 hexyl) ppm. ¹³C Ada), 36.4 (CH₂Ada), 34.3 (NCH₃), 33.2 (C_qAda), 28.9 (CH₂

NMR (100 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 80.2 (C-3), 75.9

hexyl), 28.7 (CH₂hexyl), 27.7 (CH Ada, CH₂hexyl), 25.3 (CH₂

(C-2), 72.8 (CH₂-6 hexyl), 72.6 (C-4), 62.5 (C-5), 62.5 (C-6), 60.9 hexyl), 24.7 (CH hexyl) ppm. IR (thin film): ν

= 3324, 2902,

˜

2

max.

(C-1), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 32.6 (CH₂- 2849, 1637, 1452, 1362, 1158, 1102, 1025, 753 cm^–1. [α]²_D⁰= –1.6 (c

1 hexyl), 30.9 (CH₂hexyl), 30.8 (CH₂-5 hexyl), 29.9 (CH Ada), = 1.0, MeOH). HRMS: found 426.3212 [M + H]⁺, calcd. for

27.4 (CH₂hexyl), 26.9 (CH₂hexyl) ppm. IR (thin film): ν

=

[C₂₄H₄₃NO₅+ H]⁺426.3214.

˜

max.

3344, 2901, 2849, 1606, 1452, 1360, 1156, 1095, 753 cm^–1. [α]²_D⁰

–6.5 (c = 1.0, MeOH). HRMS: found 412.3056 [M + H]⁺, calcd.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-N-butyl-1-deoxynojirimy-

cin (21): Compound 15 (62 mg, 83 µmol) was N-butylated (see ge-

neral procedure D), and the crude intermediate (R_f= 0.80 in

EtOAc/PE, 1:3) was subjected to hydrogenolysis at 4 bar H₂(see

general procedure H) to furnish 21 (22 mg, 50 µmol) as a colourless

oil in 60% yield after purification (silica gel, 0% Ǟ 20% MeOH

in CHCl₃with 0.5% NH₄OH). R_f= 0.45 (MeOH/CHCl₃, 1:4 +

0.5% NH₄OH). ¹H NMR (600 MHz, MeOD): δ = 3.87 (dd, J =

3.1, 11.8 Hz, 1 H, 6a-H), 3.84 (dd, J = 2.7, 11.8 Hz, 1 H, 6b-H),

3.41 (t, J = 6.1 Hz, 2 H, CH₂-4 butyl), 3.34 (dd, J = 9.3, 9.3 Hz, 1

H, 4-H), 3.18 (dd, J = 9.3, 9.3 Hz, 1 H, 2-H), 3.11 (dd, J = 9.1,

9.1 Hz, 1 H, 3-H), 2.98 (s, 2 H, OCH₂-Ada), 2.88–2.81 (m, 1 H,

NCHH butyl), 2.75–2.68 (m, 1 H, NCHH butyl), 2.39 (dt, J = 3.6,

7.6 Hz, 1 H, 1-H), 2.33 (dt, J = 2.8, 9.7 Hz, 1 H, 5-H), 1.95 (s, 3

H, 3ϫ CH Ada), 1.72 (dd, J = 11.6, 46.1 Hz, 8 H, 3ϫ CH₂Ada,

CH₂-1 butyl), 1.62–1.33 (m, 12 H, 3ϫ CH₂Ada, 2ϫ CH₂butyl,

CH₂N-butyl), 1.30–1.24 (m, 2 H, CH₂CH₃N-butyl), 0.96 (t, J =

7.3 Hz, 3 H, CH₃N-butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ

= 83.2 (OCH₂-Ada), 80.6 (C-3), 73.0 (C-2), 72.7 (CH₂-4 butyl),

71.6 (C-4), 65.8 (C-5), 63.7 (C-1), 60.0 (C-6), 47.3 (NCH₂butyl),

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 31.5 (CH₂-3 bu-

tyl), 29.9 (CH Ada), 29.0 (CH₂-1 butyl), 25.4 (CH₂N-butyl), 21.8

(CH₂-CH₃N-butyl), 21.6 (CH₂-2 butyl), 14.6 (CH₃N-butyl) ppm.

for [C₂₃H₄₁NO₅+ H]⁺412.3057.

(1S)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxy-N-methylnojiri-

mycin (19): Argon was passed through a solution of compound 15

(62 mg, 84 µmol) and formaldehyde (1 mL, 37 wt.-% in water) in

n-propanol (4 mL) for 5 min, after which a catalytic amount of Pd/

C (Degussa type, 50 mg, 5 wt.-% Pd on C) was added. Hydrogen

was passed through the reaction mixture for 15 min. After stirring

the reaction mixture under atmospheric hydrogen pressure for 2 h,

the Pd/C was removed by filtration through a glass microfibre filter,

followed by thorough rinsing with MeOH [R_f(intermediate) = 0.73

(EtOAc/PE, 1:3)]. The filtrate was concentrated, and the resulting

residue was subjected to Pd/C-catalyzed hydrogenolysis at atmo-

spheric H₂(see general procedure H). The crude product was puri-

fied by silica gel column chromatography (0% Ǟ 20% MeOH in

CHCl₃with 0.5 % NH₄OH) to give 19 (30 mg, 75 µmol) as a

colourless oil in 89% yield. R_f= 0.35 (MeOH/CHCl₃, 1:4 + 0.5%

NH₄OH). ¹H NMR (600 MHz, MeOD): δ = 3.92 (dd, J = 3.0,

11.8 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.9, 11.9 Hz, 1 H, 6b-H), 3.40

(t, J = 6.3 Hz, 2 H, CH₂-4 butyl), 3.39 (dd, J = 9.1, 10.0 Hz, 1 H,

4-H), 3.23 (dd, J = 9.4, 9.4 Hz, 1 H, 2-H), 3.17 (dd, J = 9.1, 9.4 Hz,

1 H, 3-H), 2.98 (s, 2 H, OCH₂-Ada), 2.32 (s, 3 H, NCH₃), 2.12–

2.07 (m, 2 H, 1-H, 5-H), 1.94 (s, 3 H, 3ϫ CH Ada), 1.82–1.66 (m,

8 H, 3ϫ CH₂Ada, CH₂-1 butyl), 1.60–1.54 (m, 8 H, 3ϫ CH₂Ada,

CH₂-3 butyl), 1.51–1.43 (m, 2 H, CH₂-2 butyl) ppm. ¹³C NMR

(150 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 80.6 (C-3), 72.9 (C-2),

72.7 (CH₂-4 butyl), 71.0 (C-4), 70.0 (C-5), 68.1 (C-1), 60.4 (C-6),

41.0 (CH₂Ada), 38.5 (CH₂Ada), 36.3 (NCH₃), 35.3 (C_qAda),

31.2 (CH₂-3 butyl), 29.9 (CH Ada), 29.7 (CH₂-1 butyl), 22.5 (CH₂-

IR (thin film): ν

= 3366, 2903, 2849, 1636, 1454, 1343, 1158,

˜

max.

1103 cm^–1. [α]²_D⁰= –1.0 (c = 0.1, MeOH). HRMS: found 440.3368

[M + H]⁺, calcd. for [C₂₅H₄₅NO₅+ H]⁺440.3370.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-N-butyl-1-deoxynojirimy-

cin (22): Compound 16 (77 mg, 100 µmol) was N-butylated (see

general procedure D), and the crude intermediate (R_f= 0.77 in

EtOAc/PE, 1:3) was subjected to hydrogenolysis at 4 bar H₂(see

general procedure H) to furnish 22 (31 mg, 66 µmol) as a colourless

oil in 66% yield after purification (silica gel, 0% Ǟ 20% MeOH

2 butyl) ppm. IR (thin film): ν

= 3358, 2900, 2848, 1652, 1452,

˜

max.

1362, 1158, 1095, 1014 cm^–1. [α]²_D⁰= 2.6 (c = 0.3, MeOH). HRMS:

found 398.2898 [M + H]⁺, calcd. for [C₂₂H₃₉NO₅+ H]⁺398.2901.

(1S)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxy-N-methylnojiri- in CHCl₃with 0.5% NH₄OH). R_f= 0.45 (MeOH/CHCl₃, 1:4 +

mycin (20): Argon was passed through a solution of compound 16

(76 mg, 99 µmol) and formaldehyde (1 mL, 37 wt.-% in water) in

n-propanol (4 mL) for 5 min, after which a catalytic amount of Pd/

0.5% NH₄OH). ¹H NMR (400 MHz, MeOD): δ = 3.98 (d, J =

12.0 Hz, 1 H, 6a-H), 3.88 (d, J = 12.0 Hz, 1 H, 6b-H), 3.53–3.43

(m, 1 H, 4-H), 3.38 (t, J = 6.1 Hz, 2 H, CH₂-5 hexyl), 3.34–3.29

C (Degussa type, 50 mg, 5 wt.-% Pd on C) was added. Hydrogen (m, 1 H, 2-H), 3.28–3.20 (m, 1 H, 3-H), 3.16–3.09 (m, 1 H, NCHH

was passed through the reaction mixture for 15 min. After stirring

the reaction mixture under atmospheric hydrogen pressure for 2 h,

the Pd/C was removed by filtration through a glass microfibre filter,

followed by thorough rinsing with MeOH [R_f(intermediate) = 0.75

(EtOAc/PE, 1:3)]. The filtrate was concentrated, and the resulting

residue was subjected to Pd/C-catalyzed hydrogenolysis at atmo-

spheric H₂(see general procedure H). The crude product was puri-

fied by silica gel column chromatography (0% Ǟ 20% MeOH in

CHCl₃with 0.5 % NH₄OH) to give 20 (29 mg, 68 µmol) as a

colourless oil in 69% yield. R_f= 0.36 (MeOH/CHCl₃, 1:4 + 0.5%

butyl), 3.01–2.93 (m, 3 H, NCHH butyl, OCH₂-Ada), 2.80–2.68

(m, 2H. 1-H, 5-H), 1.94 (s, 3 H, 3ϫ CH Ada), 1.88–1.21 (m, 26

H, 6ϫ CH₂Ada, 5ϫ CH₂hexyl, 2ϫ CH₂N-butyl), 0.98 (t, J =

7.2 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR (100 MHz, MeOD): δ =

83.2 (OCH₂-Ada), 79.5 (C-3), 72.7 (CH₂-6 hexyl), 72.6 (C-2), 70.1

(C-4), 66.7 (C-5), 65.1 (C-1), 58.4 (C-6), 48.5 (NCH₂butyl), 41.0

(CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 31.0 (CH₂), 30.8 (2ϫ

CH₂), 29.9 (CH Ada), 29.2 (CH₂), 27.4 (CH₂), 26.1 (CH₂), 21.4

(CH -CH N-butyl), 14.3 (CH N-butyl) ppm. IR (thin film): ν

˜

max.

2

3

= 3364, 2902, 2847, 1720 1453, 1366, 1258, 1011, 926 cm^–1. [α]²_D⁰

=

1268

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

–1.0 (c = 0.2, MeOH). HRMS: found 468.3679 [M + H]⁺, calcd.

6.5 Hz, 2 H, CH₂-3 hexynyl), 1.60 (s, 3 H, CH Ada), 1.38–1.18 (m,

for [C₂₇H₅₀NO₅+ H]⁺468.3684.

16 H, 6ϫ CH₂Ada, 2ϫ CH₂hexenyl) ppm. ¹³C NMR (75 MHz,

C₆D₆): δ = 139.4, 139.1, 139.0, 138.8 (4ϫ C_qBn), 128.5, 128.48,

128.46, 128.42, 128.2, 128.1, 127.96, 127.93, 127.8, 127.7, 127.65,

127.62, 127.54, 127.50 (CH_ArBn), 86.4 (C_qhexynyl), 86.3 (C-3),

83.2 (C-2), 82.0 (OCH₂-Ada), 79.3 (C-5), 78.6 (C_qpentynyl), 78.1

(C-4), 75.4, 75.2, 74.9, 73.5 (4ϫ CH₂Bn), 70.9 (CH₂-6 hexynyl),

70.6 (C-1), 69.3 (C-6), 40.0 (CH₂Ada), 37.5 (CH₂Ada), 34.2 (C_q

Ada), 29.1 (CH₂hexynyl), 28.6 (CH Ada), 25.6 (CH₂hexynyl), 18.8

4-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-D-gluco-

pyranosyl)but-1-yne (24): Compound 13 (100 mg, 132 µmol) was

subjected to general procedure B to produce 24 (86 mg, 116 µmol)

in 89% yield after silica gel column purification (0% Ǟ 5% acetone

1

in toluene). R_f= 0.50 (toluene/EtOAc, 9:1). H NMR (600 MHz,

CDCl₃): δ = 7.40–7.09 (m, 20 H, H, H_ArBn), 5.02 (d, J = 10.5 Hz,

1 H, CHH Bn), 4.91 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.83–4.77

(m, 3 H, CH₂Bn, CHH Bn), 4.60 (d, J = 12.2 Hz, 1 H, CHH Bn),

4.54–4.49 (m, 2 H, 2ϫ CHH Bn), 4.03 (dt, J = 2.0, 9.0 Hz, 1 H,

1-H), 3.73 (dd, J = 1.6, 10.7 Hz, 1 H, 6a-H), 3.67 (dd, J = 4.4,

10.8 Hz, 1 H, 6b-H), 3.64–3.55 (m, 3 H, 2-H, 3-H, 4-H), 3.50 (t, J

= 7.3 Hz, 2 H, CH₂-4 butenyl), 3.42 (ddd, J = 1.8, 4.2, 9.1 Hz, 1

H, 5-H), 2.97-2.93 (m, 2 H, OCH₂-Ada), 2.51 (td, J = 1.8, 7.3 Hz,

2 H, CH₂-3 butenyl), 1.92 (s, 3 H, 3ϫ CH Ada), 1.65 (dd, J = 11.9,

(CH -3 hexynyl) ppm. IR (thin film): ν

= 3031, 2901, 2848,

˜

2

max.

1497, 1453, 1360, 1294, 1210, 1155, 1091, 1064, 1027, 1005, 910,

734, 696 cm^–1. [α]²_D⁰= 2.6 (c = 1.0, CHCl₃). HRMS: found 786.4730

[M + NH₄]⁺, calcd. for [C₅₁H₆₀O₆+ NH₄]⁺786.4728.

1-(Adamant-1-ylmethoxy)-4-C-(β-

D-glucopyranosyl)butane

(27):

Compound 24 (86 mg, 116 µmol) was subjected to Pd/C-catalyzed

hydrogenolysis at atmospheric H₂(see general procedure H). The

45.5 Hz, 6 H, 3ϫ CH₂Ada), 1.49 (d, J = 2.4 Hz, 6 H, 3ϫ CH₂resulting residue was purified by silica gel column chromatography

Ada) ppm. ¹³C NMR (151 MHz, CDCl3): δ = 138.7, 138.3, 138.2, (0% Ǟ 15% MeOH in CHCl₃with 0.5% NH₄OH) to give 27

138.2 (4ϫ C_qBn), 128.6, 128.6, 128.6, 128.4, 128.2, 128.1, 128.0,

(36 mg, 94 µmol) as a colourless oil in 81% yield. R_f= 0.29

127.9, 127.8 (CH_ArBn), 86.2 (C-3), 84.1 (C_qbutynyl), 82.7 (C-2), (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

82.2 (OCH₂-Ada), 79.1 (C-5), 78.4 (C_qbutynyl), 77.9 (C-4), 75.9, MeOD): δ = 3.83 (dd, J = 2.3, 11.8 Hz, 1 H, 6a-H), 3.63 (dd, J =

75.6, 75.3, 73.7 (4ϫ CH₂Bn), 70.3 (C-1), 69.8 (CH₂-4 butynyl),

69.0 (C-6), 39.8 (CH₂Ada), 37.4 (CH₂Ada), 34.2 (C_qAda), 28.4

5.7, 11.8 Hz, 1 H, 6b-H), 3.39 (t, J = 6.3 Hz, 2 H, CH₂-4 butyl),

3.30 (dd, J = 8.8, 9.2 Hz, 1 H, 3-H), 3.25 (dd, J = 9.2, 9.4 Hz, 1

H, 4-H), 3.18 (ddd, J = 2.3, 5.6, 9.4 Hz, 1 H, 5-H), 3.15–3.09 (m,

1 H, 1-H), 3.04 (dd, J = 8.8, 9.3 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH₂-

Ada), 1.95 (s, 3 H, 3ϫ CH Ada), 1.91–1.83 (m, 1 H, CHH-1 butyl),

1.72 (dd, J = 11.8, 44.2 Hz, 6 H, 3ϫ CH₂Ada), 1.66–1.52 (m, 9

H, 3ϫ CH₂Ada, CH₂-3 butyl, CHH butyl), 1.48–1.39 (m, 2 H,

CHH-1 butyl, CHH butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ

= 83.2 (OCH₂-Ada), 81.7 (C-5), 81.0 (C-1), 80.0 (C-3), 75.6 (C-2),

72.9 (CH₂-6 hexyl), 72.2 (C-4), 63.3 (C-6), 41.0 (CH₂Ada), 38.5

(CH₂Ada), 35.3 (C_qAda), 32.9 (CH₂-1 butyl), 30.9 (CH₂-3 butyl),

(CH Ada), 20.3 (CH -3 butynyl) ppm. IR (thin film): ν_max.= 3036,

˜

2

2901, 2849, 1734, 1497, 1452, 1360, 1209, 1094, 1063, 1028, 1003,

733, 696 cm^–1. [α]²_D⁰= –1.7 (c = 0.6, CHCl₃). HRMS: found

758.4416 [M + NH₄]⁺, calcd. for [C₄₉H₅₆O₆+ NH₄]⁺758.4415.

5-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-D-gluco-

pyranosyl)pent-1-yne (25): Compound 23 (250 mg, 337 µmol) was

subjected to general procedure B to produce 25 (201 mg, 266 µmol)

in 79% yield after silica gel column purification (0% Ǟ 5% acetone

1

in toluene). R_f= 0.55 (toluene/EtOAc, 9:1). H NMR (200 MHz,

29.9 (CH Ada), 23.3 (CH butyl) ppm. IR (thin film): ν_max.= 3365,

˜

2

CDCl₃): δ = 7.40–7.08 (m, 20 H, H_ArBn), 5.07–4.46 (m, 8 H, 4ϫ

CH₂Bn), 4.05 (d, J = 8.6 Hz, 1 H, 1-H), 3.78–3.53 (m, 6 H, 2-H,

3-H, 4-H, 5-H, CH₂-6), 3.41 (t, J = 6.0 Hz, 2 H, CH₂-5 pentenyl),

2.90 (s, 2 H, OCH₂-Ada), 2.35 (td, J = 1.6, 7.1 Hz, 2 H, CH₂-3

pentenyl), 1.93 (s, 3 H, 3ϫ H Ada), 1.84–1.55 (m, 8 H, 3ϫ CH₂

Ada, CH₂-4 pentenyl), 1.49 (d, J = 2.7 Hz, 6 H, 3ϫ CH₂Ada)

ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 138.7, 138.3, 138.2, 138.1

(4ϫ C_qBn), 128.5, 128.4, 128.29, 128.23, 128.04, 128.02, 127.9,

2901, 2848, 1593, 1453, 1342, 1092, 1013 cm^–1. [α]²_D⁰= –1.0 (c =

0.2, MeOH). HRMS: found 385.2586 [M + H]⁺, calcd. for

[C₂₁H₃₆O₆+ H]⁺385.2585.

1-(Adamant-1-ylmethoxy)-5-C-(β-

D-glucopyranosyl)pentane

(28):

Compound 25 (95 mg, 126 µmol) was subjected to Pd/C-catalyzed

hydrogenolysis at atmospheric H₂(see general procedure H). The

resulting residue was purified by silica gel column chromatography

127.8, 127.7 (CH_ArBn), 86.7 (C_qpentynyl), 86.1 (C-3), 82.7 (C-2), (0% Ǟ 15% MeOH in CHCl₃with 0.5% NH₄OH) to give 28

81.9 (OCH₂-Ada), 79.0 (C-5), 77.8 (C-4), 77.4 (C_qpentynyl), 75.8, (45 mg, 112 µmol) as a colourless oil in 89% yield. R_f= 0.32

75.4, 75.1, 73.6 (4ϫ CH₂Bn), 70.3 (C-1), 69.9 (CH₂-5 pentynyl), (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

68.9 (C-6), 39.8 (CH₂Ada), 37.3 (CH₂Ada), 34.1 (C_qAda), 28.7

(CH₂-4 pentynyl), 28.3 (CH Ada), 15.9 (CH₂-3 pentynyl) ppm. IR

MeOD): δ = 3.83 (dd, J = 2.3, 11.8 Hz, 1 H, 6a-H), 3.63 (dd, J =

5.7, 11.9 Hz, 1 H, 6b-H), 3.38 (t, J = 6.5 Hz, 2 H, CH₂-5 pentyl),

3.31–3.28 (dd, J = 8.8, 9.1 Hz, 1 H, 3-H), 3.25 (dd, J = 9.1, 9.4 Hz,

1 H, 4-H), 3.17 (ddd, J = 2.3, 5.7, 9.4 Hz, 1 H, 5-H), 3.15–3.09 (m,

1 H, 1-H), 3.04 (dd, J = 8.8, 9.3 Hz, 1 H, 2-H), 2.97 (s, 2 H, OCH₂-

Ada), 1.95 (s, 3 H, 3ϫ CH Ada), 1.90–1.82 (m, 1 H, CHH-1 pen-

tyl), 1.72 (dd, J = 11.7, 44.9 Hz, 6 H, 3ϫ CH₂Ada), 1.65–1.51 (m,

9 H, 3ϫ CH₂Ada, CH₂-4 pentyl, CHH pentyl), 1.45–1.31 (m,

4 H, CHH-1 pentyl, CH₂pentyl, CHH pentyl) ppm. ¹³C NMR

(150 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 81.7 (C-5), 81.0 (C-1),

80.0 (C-3), 75.6 (C-2), 72.8 (CH₂-5 pentyl), 72.1 (C-4), 63.3 (C-6),

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 33.0 (CH₂-1 pen-

tyl), 30.8 (CH₂-4 pentyl), 29.9 (CH Ada), 27.6 (CH₂pentyl), 26.5

(thin film): ν_max.= 3033, 2901, 2848, 1724, 1452, 1361, 1269, 1090,

˜

1065, 1026, 735, 696 cm^–1. [α]²_D⁰= 3.5 (c = 0.4, CHCl₃). HRMS:

found 772.4572 [M + NH₄]⁺, calcd. for [C₅₀H₅₈O₆+ NH₄]⁺

772.4572.

6-(Adamant-1-ylmethoxy)-1-C-(2,3,4,6-tetra-O-benzyl-β-

pyranosyl)hex-1-yne (26): Compound 14 (428 mg, 0.56 mmol) was

subjected to general procedure to produce 26 (257 mg,

D-gluco-

B

0.33 mmol) in 60% yield after silica gel column purification (0% Ǟ

1

5% acetone in toluene). R_f= 0.65 (toluene/EtOAc, 9:1). H NMR

(300 MHz, C₆D₆): δ = 7.12–6.69 (m, 20 H, H_ArBn), 4.77 (d, J =

11.0 Hz, 1 H, CHH Bn), 4.62–4.41 (m, 4 H, CH₂Bn, CHH Bn,

CHH Bn), 4.25 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.15 (d, J =

12.1 Hz, 1 H, CHH Bn), 4.04 (d, J = 12.1 Hz, 1 H, CHH Bn), 3.76

(dt, J = 1.8, 9.3 Hz, 1 H, 1-H), 3.42 (dd, J = 8.9, 9.6 Hz, 1 H, 4-

(CH pentyl) ppm. IR (thin film): ν

= 3362, 2902, 2849, 1453,

˜

2

max.

1362, 1091, 1016 cm^–1. [α]²_D⁰= –12.0 (c = 0.2, MeOH). HRMS:

found 399.2739 [M + H]⁺, calcd. for [C₂₂H₃₈O₆+ H]⁺399.2741.

H), 3.36–3.27 (m, 3 H, 2-H, CH₂-6), 3.22 (dd, J = 8.8, 8.9 Hz, 1 1-(Adamant-1-ylmethoxy)-6-C-(β-

D-glucopyranosyl)hexane

(29):

H, 3-H), 2.96 (dt, J = 2.7, 10.1 Hz, 1 H, 5-H), 2.86 (t, J = 5.8 Hz,

2 H, CH₂-6 hexynyl), 2.52 (s, 2 H, OCH₂-Ada), 1.78 (td, J = 1.4,

Compound 26 (75 mg, 97 µmol) was subjected to Pd/C-catalyzed

hydrogenolysis at atmospheric H₂(see general procedure H). The

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1269

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

resulting residue was purified by silica gel column chromatography

59.2 (C-1, C-5), 31.8 (CH₂-2 butyl), 28.2, 23.1 (CH₂-1 butyl, CH₂-

(0% Ǟ 15% MeOH in CHCl₃with 0.5% NH₄OH) to give 29 3 butyl), 14.2 (CH -4 butyl) ppm. IR (thin film): ν_max.= 3032, 2924,

˜

3

(36 mg, 87 µmol) as a colourless oil in 90% yield. R_f= 0.33

(MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 3.83 (dd, J = 2.4, 11.9 Hz, 1 H, 6a-H), 3.63 (dd, J =

5.7, 11.9 Hz, 1 H, 6b-H), 3.37 (t, J = 6.5 Hz, 2 H, CH₂-6 hexyl),

3.32–3.28 (dd, J = 8.7, 9.2 Hz, 1 H, 3-H), 3.25 (dd, J = 9.2, 9.4 Hz,

1 H, 4-H), 3.18 (ddd, J = 2.4, 5.7, 9.4 Hz, 1 H, 5-H), 3.14–3.09 (m,

1 H, 1-H), 3.04 (dd, J = 8.7, 9.4 Hz, 1 H, 2-H), 2.96 (s, 2 H, OCH₂-

Ada), 1.95 (s, 3 H, 3ϫ CH Ada), 1.88–1.81 (m, 1 H, CHH-1 hexyl),

1.72 (dd, J = 11.7, 44.9 Hz, 6 H), 1.60–1.53 (m, 9 H, 3ϫ CH₂Ada,

CH₂-5 hexyl, CHH hexyl), 1.45–1.29 (m, 6 H, CHH-1 hexyl, 2ϫ

CH₂hexyl, CHH hexyl) ppm. ¹³C NMR (150 MHz, MeOD): δ =

83.2 (OCH₂-Ada), 81.7 (C-5), 81.0 (C-1), 80.0 (C-3), 75.6 (C-2),

72.9 (CH₂-6 hexyl), 72.2 (C-4), 63.3 (C-6), 41.0 (CH₂Ada), 38.5

(CH₂Ada), 35.3 (C_qAda), 33.0 (CH₂-1 hexyl), 30.9 (CH₂hexyl),

30.8 (CH₂-5 hexyl), 29.9 (CH Ada), 27.5 (CH₂hexyl), 26.6 (CH₂

2862, 1458, 1358, 1312, 1211, 1072, 1026, 1003, 741, 694 cm^–1

.

[α]²_D⁰= 11.9 (c = 2.2, CHCl₃). HRMS: found 580.3417 [M + H]⁺,

calcd. for [C₃₈H₄₅NO₄+ H]⁺580.3421.

(1S)-1-C-Butyl-1-deoxynojirimycin (32): Compound 31 (60 mg,

104 µmol) was subjected to hydrogenolysis at atmospheric H₂(see

general procedure H) to furnish 32 (23 mg, 100 µmol) as a colour-

less oil in 97% yield after purification (silica gel, 10% Ǟ 20%

MeOH in CHCl₃with 0.5% NH₄OH). R_f= 0.12 (MeOH/CHCl₃,

1

1:4 + 0.5% NH₄OH). H NMR (400 MHz, MeOD): δ = 4.00–3.86

(m, 2 H, CH₂-6), 3.60–3.51 (m, 1 H, 4-H), 3.42–3.33 (m, 2 H, 2-H,

3-H), 3.09–3.00 (m, 1 H, 5-H), 3.00–2.94 (m, 1 H, 1-H), 2.05–1.95

(m, 1 H, CHH-1 butyl), 1.72–1.61 (m, 1 H, CHH-1 butyl), 1.60–

1.46 (m, 2 H, CH₂-2 butyl), 1.46–1.33 (m, 2 H, CH₂-3 butyl), 0.97

(t, J = 7.0 Hz, 3 H, CH₃-4 butyl) ppm. ¹³C NMR (100 MHz,

MeOD): δ = 78.7 (C-3), 73.6 (C-2), 69.4 (C-4), 62.3 (C-5), 60.9 (C-

1), 59.0 (C-6), 31.1 (CH₂-1 butyl), 29.1 (CH₂-2 butyl), 24.0 (CH₂-

hexyl) ppm. IR (thin film): ν

= 3361, 2901, 2849, 1453, 1361,

˜

max.

1092, 1012 cm^–1. [α]²_D⁰= –9.2 (c = 1.0, MeOH). HRMS: found

3 butyl), 14.3 (CH -4 butyl) ppm. IR (thin film): ν

= 3331,

˜

413.2896 [M + H]⁺, calcd. for [C₂₃H₄₀O₆+ H]⁺413.2898.

3

max.

2959, 2932, 2870, 1636, 1436, 1380, 1098, 1014 cm^–1. [α]²_D⁰= –6.1

(c = 0.5, MeOH). HRMS: found 220.1545 [M + H]⁺, calcd. for

[C₁₀H₂₁NO₄+ H]⁺220.1543.

α/β-Mixture of 2,3,4,6-Tetra-O-benzyl-1-C-butyl-D-glucopyranose

(30): A solution of 12 (1.02 g, 1.9 mmol) in THF (3 mL) was added

to a cooled (–50 °C) solution of BuLi (0.59 mL, 0.95 mmol, 1.6 

in toluene) in THF (10 mL). The reaction mixture was stirred at

–50 °C for 2 h. The reaction mixture was quenched (satd. aq.

NH₄Cl), warmed to room temp. and poured into satd. aq. NH₄Cl

(150 mL). The aqueous layer was extracted with Et₂O (3ϫ150 mL)

and the combined organic layers were dried (MgSO₄) and concen-

trated. The residue was purified by silica gel column chromatog-

raphy (5% Ǟ 20% EtOAc in PE) to give 30 (409 mg, 0.69 mmol)

in 72% yield as colourless oil. R_f= 0.45 (EtOAc/PE, 1:3). ¹H NMR

(200 MHz, CDCl₃, α/β mixture): δ = 7.41–7.15 (m, 20 H, H_ArBn),

4.96–4.41 (m, 9 H, 2ϫ CH₂Bn, 6a-H), 4.12–3.57 (m, 4 H, 3-H, 4-

H, 5-H, 6b-H), 3.43 (d, J = 9.2 Hz, 1 H, 2-H), 2.57 (s, 1 H, OH-

1), 1.70–1.50 (m, 2 H, CH₂butyl), 1.49–1.13 (m, 4 H, 2ϫ CH₂

butyl), 0.86 (t, J = 6.8 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR

(50 MHz, CDCl₃, α/β mixture): δ = 138.9, 138.7, 138.5, 138.2 (4ϫ

C_qBn), 128.6, 128.5, 128.3, 128.2, 128.14, 128.12, 127.99, 127.94,

127.8, 127.7 (CH_ArBn), 98.6 (C_q-1), 84.1, 81.6, 76.6 (C-2, C-3, C-

4), 75.8, 75.6, 75.1, 73.5 (2ϫ CH₂Bn), 71.8 (C-5), 69.0 (C-6), 38.6

(CH₂butyl), 24.9 (CH₂butyl), 23.0 (CH₂butyl), 14.3 (CH₃butyl)

(1S)-N-[5-(Adamant-1-ylmethoxy)pentyl]-2,3,4,6-tetra-O-benzyl-1-

C-butyl-1-deoxynojirimycin (33): A solution of 31 (210 mg,

360 mmol) and 10^[25](900 mg, 3.6 mmol) in acetonitrile/MeOH

(1.8 mL, 5:1, v/v) was acidified to pH = 5–6 with AcOH (10 µL).

Sodium sulfate (100 mg) and sodium cyanoborohydride (90 mg,

1.44 mmol) were added, and the reaction mixture was heated at

75 °C for 18 h. The mixture was diluted with satd. aq. NaHCO₃

(20 mL) and extracted with Et₂O (3ϫ20 mL). The combined or-

ganic phases were dried (MgSO₄) and concentrated. Purification

by silica gel column chromatography (0% Ǟ 10% MeOH in CHCl₃

with 0.5% NH₄OH) gave 33 (230 mg, 283 mmol) as a colourless

1

oil in 79% yield. R_f= 0.75 (EtOAc/PE, 1:3). H NMR (200 MHz,

CDCl₃): δ = 7.36–7.15 (m, 20 H, H_ArBn), 4.95–4.79 (m, 4 H, 2ϫ

CH₂Bn), 4.67–4.39 (m, 4 H, 2ϫ CH₂Bn), 4.01–3.26 (m, 8 H, 2-

H, 3-H, 4-H, CH₂-6, CH₂-5 pentyl), 2.94 (m, 2 H, OCH₂-Ada),

2.78-2.45 (m, 4 H, NCH₂-1 pentyl, 1-H, 5-H), 1.95 (s, 3 H, 3ϫ CH

Ada), 1.78–1.07 (m, 24 H, 6ϫ CH₂Ada, 3ϫ CH₂butyl, 3ϫ CH₂

pentyl), 0.89 (t, J = 6.9 Hz, 3 H) ppm. NMR (50 MHz, CDCl₃): δ

= 139.1, 138.8, 138.2 (C_qBn), 128.5, 128.2, 128.1, 128.0, 127.8,

127.7, 127.6 (CH_ArBn), 88.7 (C-3), 82.1 (OCH₂-Ada), 80.6 (C2),

78.8 (C4), 75.3, 75.1, 73.5, 71.7 (4ϫ CH₂Bn), 67.7, 65.0 (C-6, CH₂-

5 pentyl), 63.2, 62.5 (C1, C-5), 46.9 (NCH₂-1 pentyl), 39.9 (CH₂

Ada), 37.4 (CH₂Ada), 34.3 (C_qAda), 29.7, 29.6 (CH₂pentyl/

butyl), 28.5 (CH Ada), 27.2, 24.0, 23.5 (CH₂pentyl/butyl), 14.5

ppm. IR (thin film): ν

= 3032, 2911, 2860, 1460, 1350, 1360,

˜

max.

1211, 1008, 736, 694 cm^–1. [α]²_D⁰= 0.7 (c = 2.9, CHCl₃). HRMS:

found 596.3140 [M + H]⁺, calcd. for [C₃₈H₄₄O₆+ H]⁺596.3138.

(1S)-2,3,4,6-Tetra-O-benzyl-1-C-butyl-1-deoxynojirimycin

(31):

Compound 30 (600 mg, 1.0 mmol) was subjected to general pro-

cedure procedure C to give 31 (387 mg, 0.67 mmol) as a colourless

oil in 67% yield after silica gel column chromatography (0% Ǟ

20% EtOAc in toluene). R_f(diol) = 0.33, R_f(diketone) = 0.77,

(CH -4 butyl) ppm. IR (thin film): ν

= 2900, 2847, 1450, 1358,

˜

3

max.

1065, 941, 841, 733, 694 cm^–1. [α]²_D⁰= –2.3 (c = 1.2, CHCl₃).

HRMS: found 814.5406 [M + H]⁺, calcd. for [C₅₄H₇₁NO₅+ H]⁺

814.5405.

R_f(aza-C-glycoside)

=

0.56 (toluene/EtOAc, 3:1). ¹H NMR

(600 MHz, CDCl₃): δ = 7.40–7.16 (m, 20 H, H_ArBn), 4.93–4.88

(m, 3 H, CHH Bn, CH₂Bn), 4.84 (d, J = 10.9 Hz, 1 H, CHH Bn),

4.64 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.52–4.45 (m, 3 H, CHH Bn,

(1S)-N-[5-(Adamant-1-ylmethoxy)pentyl]-1-C-butyl-1-deoxynojiri-

mycin (34): Compound 33 (76 mg, 93 µmol) was subjected to hydro-

CH₂Bn), 3.71 (dd, J = 2.4, 9.0 Hz, 1 H, 6a-H), 3.60 (dd, J = 9.1, genolysis at 4 bar H₂(see general procedure H) to furnish 34

9.3 Hz, 1 H, 3-H), 3.45 (dd, J = 7.1, 9.0 Hz, 1 H, 6b-H), 3.35 (dd,

J = 9.1, 9.4 Hz, 1 H, 4-H), 3.14 (dd, J = 9.1, 9.3 Hz, 1 H, 2-H),

2.78 (ddd, J = 2.4, 7.1, 9.4 Hz, 1 H, 5-H), 2.57–2.53 (m, 1 H, 1-

(36 mg, 79 µmol) as a colourless oil in 85% yield after purification

(silica gel, 0% Ǟ 15% MeOH in CHCl₃with 0.5% NH₄OH). R_f

= 0.44 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

H), 1.88–1.81 (m, 1 H, CHH-2 butyl), 1.41–1.24 (m, 4 H, CH₂-1 MeOD): δ = 3.92 (dd, J = 2.7, 11.9 Hz, 1 H, 6a-H), 3.86 (dd, J =

butyl, CHH-2 butyl, CH₂-3 butyl), 0.89 (t, J = 6.9 Hz, 3 H, CH₃- 2.5, 11.9 Hz, 1 H, 6b-H), 3.41–3.34 (m, 3 H, 4-H, CH₂-5 pentyl),

4 butyl) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 138.9, 138.6,

138.4, 138.2 (4ϫ C_qBn), 128.6, 128.4, 128.28, 128.24, 128.0,

3.23 (dd, J = 9.4, 9.4 Hz, 1 H, 2-H), 3.16 (dd, J = 9.1, 9.1 Hz, 1

H, 3-H), 2.98–2.92 (m, 3 H, OCH₂-Ada, NCHH-1 pentyl), 2.83–

127.98, 127.95, 127.91, 127.7, 127.3 (CH_ArBn), 88.5 (C-3), 84.4 (C- 2.73 (m, 1 H, NCHH-1 pentyl), 2.52 (d, J = 4.8 Hz, 1 H, 1-H),

2), 80.9 (C-4), 75.8, 75.6, 75.2, 73.5 (4ϫ CH₂Bn), 70.7 (C-6), 59.2, 2.47 (d, J = 8.1 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3ϫ CH Ada), 1.84–

1270

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

1.66 (m, 7 H, 3ϫ CH₂Ada, CHH-1 butyl), 1.62–1.53 (m, 9 H, 3ϫ

= 3395, 2903, 2850, 1622, 1456, 1361, 1259, 1110, 1037 cm^–1. [α]²_D⁰

CH₂Ada, CHH-1 butyl, CH₂-4 pentyl), 1.45–1.29 (m, 8 H, CH₂- = –3.0 (c = 0.2, MeOH). HRMS: found 524.4304 [M + H]⁺, calcd.

2 butyl, CH₂-3 butyl, CH₂-2 pentyl, CH₂-3 pentyl), 0.95 (t, J =

7.2 Hz, 3 H, CH₃-4 butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ

= 83.2 (OCH₂-Ada), 80.2 (C-3), 72.9 (C-2), 72.4 (CH₂-5 pentyl),

71.1 (C-4), 66.1 (C-5), 64.2 (C-1), 59.4 (C-6), 48.0 (NCH₂-1 pentyl),

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.6 (CH₂-4 pen-

tyl), 29.9 (CH Ada), 28.9 (CH₂-1 butyl), 27.4 (CH₂-2 pentyl), 25.1,

24.5, 23.2 (3ϫ CH₂butyl, CH₂-3 pentyl), 14.6 (CH₃-4 butyl) ppm.

for [C₃₁H₅₈NO₅+ H]⁺524.4310.

(1S)-1-C,N-Bis[5-(adamant-1-ylmethoxy)pentyl]-1-deoxynojirimycin

(38): A solution of 35^[28](271 mg, 0.36 mmol) and 10^[25](900 mg,

3.6 mmol) in acetonitrile/MeOH (1.8 mL, 5:1, v/v) was acidified to

pH = 5–6 with AcOH (10 µL). Sodium sulfate (100 mg) and so-

dium cyanoborohydride (90 mg, 1.44 mmol) were added, and the

reaction mixture was heated at 75 °C for 18 h. The mixture was

diluted with satd. aq. NaHCO₃(20 mL) and extracted with Et₂O

(3ϫ20 mL). The combined organic phases were dried (MgSO₄)

and concentrated. Half of the resulting crude residue was subjected

to Pd/C-catalyzed hydrogenolysis at 4 bar H₂(see general pro-

cedure H). The resulting crude product was purified by silica gel

column chromatography (0% Ǟ 10% MeOH in CHCl₃with 0.5%

NH₄OH) to give 38 (90 mg, 142 mmol) as a colourless oil in 79%

IR (thin film): ν

= 3348, 2901, 2847, 1450, 1366, 1234, 1096,

˜

max.

1003, 833 cm^–1. [α]²_D⁰= –1.5 (c = 0.2, MeOH). HRMS: found

454.3523 [M + H]⁺, calcd. for [C₂₆H₄₈NO₅+ H]⁺454.3527.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-N-hexylnojiri-

mycin (36): Compound 35^[28](292 mg, 220 µmol) was N-alkylated

(see general procedure D), and the crude intermediate was sub-

jected to hydrogenolysis at 4 bar H₂(see general procedure H) to

furnish 36 (75 mg, 156 µmol) as a colourless oil in 71% yield after

1

yield. R_f= 0.57 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). H NMR

purification (silica gel, 0% Ǟ 10% MeOH in CHCl₃with 0.5% (600 MHz, MeOD): δ = 3.89 (dd, J = 2.9, 11.9 Hz, 1 H, 6a-H),

NH₄OH). R_f= 0.49 (MeOH/CHCl₃, 1:4 + 0.5 % NH₄OH). ¹H

NMR (600 MHz, MeOD): δ = 3.88 (dd, J = 3.1, 11.8 Hz, 1 H, 6a-

H), 3.84 (dd, J = 2.8, 11.7 Hz, 1 H, 6b-H), 3.39 (t, J = 6.5 Hz, 2

H, CH₂-5 pentyl), 3.34 (dd, J = 9.3, 9.6 Hz, 1 H, 4-H), 3.18 (dd, J

= 9.0, 9.2 Hz, 1 H, 2-H), 3.11 (dd, J = 9.0, 9.3 Hz, 1 H, 3-H), 2.97

3.85 (dd, J = 2.5, 11.8 Hz, 1 H, 6b-H), 3.41–3.37 (m, 4 H, 2ϫ CH₂-

5 pentyl), 3.35 (dd, J = 8.8, 10.2 Hz, 1 H, 4-H), 3.19 (t, J = 9.3 Hz,

1 H, 2-H), 3.12 (t, J = 9.0 Hz, 1 H, 3-H), 2.97 (s, 4 H), 2.92–2.85

(m, 1 H, NCHH-1 pentyl), 2.75–2.66 (m, 1 H, NCHH-1 pentyl),

2.45–2.40 (m, 1 H, 1-H), 2.38–2.32 (m, 1 H, 5-H), 1.95 (s, 6 H, 6ϫ

(s, 2 H, OCH₂-Ada), 2.88–2.79 (m, 1 H, NCHH hexyl), 2.73–2.64 CH Ada), 1.87–1.66 (m, 14 H, 6ϫ CH₂Ada, 2ϫ CHH-1 pentyl),

(m, 1 H, NCHH hexyl), 2.39 (dt, J = 3.5, 9.2 Hz, 1 H, 1-H), 2.33

(dt, J = 2.9, 9.6 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3ϫ CH Ada), 1.83–

1.66–1.53 (m, 18 H, 6ϫ CH₂Ada, 2ϫ CHH-1 pentyl, 2ϫ CH₂-4

pentyl), 1.52–1.26 (m, 8 H, 4 ϫ CH₂pentyl) ppm. ¹³C NMR

1.67 (m, 7 H, 3ϫ CH₂Ada, CHH-1 pentyl), 1.66–1.51 (m, 9 H, (150 MHz, MeOD): δ = 83.2, 83.1 (2ϫ OCH₂-Ada), 80.5 (C-3),

3ϫ CH₂Ada, CHH-1 pentyl, CH₂-4 pentyl), 1.41–1.18 (m, 14 H,

CH₂-2 pentyl, CH₂-3 pentyl, CH₂-4 pentyl, 4ϫ CH₂hexyl), 0.91 (t,

J = 7.0 Hz, 3 H, CH₃hexyl) ppm. ¹³C NMR (150 MHz, MeOD): δ

73.0 (C-2), 72.5, 72.4 (2ϫ CH₂-5 pentyl), 71.4 (C-4), 65.9 (C-5),

63.7 (C-1), 59.8 (C-6), 47.8 (NCH₂-1 pentyl), 41.1, 41.0 (2ϫ CH₂

Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.8, 30.6 (2ϫ CH₂-4 pen-

= 83.1 (OCH₂-Ada), 80.6 (C-3), 73.1 (C-2), 72.6 (CH₂-5 pentyl), tyl), 29.9 (CH Ada), 29.1 (CH₂pentyl), 28.1 (CH₂pentyl), 25.2

71.7 (C-4), 65.9 (C-5), 63.8 (C-1), 60.1 (C-1), 47.7 (NCH₂hexyl), (CH pentyl) ppm. IR (thin film): ν

= 3368, 2902, 2848, 1452,

˜

2

max.

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 33.1 (CH₂hexyl),

30.8 (CH₂-4 pentyl), 29.9 (CH Ada), 29.2 (CH₂-1 pentyl), 28.4,

28.0, 24.6, 24.0, 23.4 (2ϫ CH₂pentyl, 3ϫ CH₂hexyl), 14.6 (CH₃

1157, 1111 cm^–1. [α]²_D⁰= 0.9 (c = 0.2, MeOH). HRMS: found

632.4881 [M + H]⁺, calcd. for [C₃₈H₆₅NO₆+ H]⁺632.4885.

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-N-[5-(adamant-

1-ylmethoxy)pentyl]-1-deoxynojirimycin (39): The other half of the

crude product residue from the reductive amination was subjected

to Pd/C-catalyzed hydrogenolysis at atmospheric H₂pressure (see

general procedure H). This resulted in a product mixture of 38 and

39. Purification by silica gel column chromatography produced 38

(60 mg, 95 mmol) in 53% and (Z)-alkene 39 (47 mg, 74 mmol) in

41% yield. R_f= 0.43 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H

NMR (600 MHz, MeOD): δ = 5.72 (dt, J = 7.5, 11.0 Hz, 1 H,

=CH-2 pentenyl), 5.24 (dd, J = 9.9, 11.0 Hz, 1 H, =CH-1 pentenyl),

3.93 (dd, J = 2.2, 11.9 Hz, 1 H, 6a-H), 3.82 (dd, J = 2.4, 11.9 Hz,

1 H, 6b-H), 3.47–3.34 (m, 6 H, CH₂-5 pentyl, CH₂-5 pentenyl),

hexyl) ppm. IR (thin film): ν

= 3366, 2903, 2849, 1592, 1454,

˜

max.

1358, 1157, 1098, 1012 cm^–1. [α]²_D⁰= –2.3 (c = 0.3, MeOH). HRMS:

found 482.3835 [M + H]⁺, calcd. for [C₂₈H₅₁NO₅+ H]⁺482.3840.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-N-nonylnojiri-

mycin (37): Compound 35^[28](35 mg, 46 µmol) was N-alkylated (see

general procedure D), and the crude intermediate was subjected to

hydrogenolysis at 4 bar H₂(see general procedure H) to furnish 37

(15 mg, 29 µmol) as a colourless oil in 63% yield after purification

(silica gel, 0% Ǟ 10% MeOH in CHCl₃with 0.5% NH₄OH). R_f

= 0.53 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 3.88 (dd, J = 3.2, 11.8 Hz, 1 H, 6a-H), 3.84 (dd, J =

2.9, 11.8 Hz, 1 H, 6b-H), 3.39 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.27 (t, J = 9.5 Hz, 1 H), 3.21 (t, J = 9.2 Hz, 1 H), 3.05 (t, J =

3.35 (dd, J = 9.3, 9.3 Hz, 1 H, 4-H), 3.19 (dd, J = 9.3, 9.3 Hz, 1 9.1 Hz, 1 H), 2.99–2.94 (m, 5 H, 2ϫ OCH₂-Ada), 2.90–2.79 (m, 2

H, 2-H), 3.13 (dd, J = 9.0, 9.0 Hz, 1 H, 3-H), 2.97 (s, 2 H, OCH₂- H, NCH₂-1 pentyl), 2.34 (dt, J = 2.4, 9.2 Hz, 1 H, 5-H), 2.32–2.27

Ada), 2.89–2.80 (m, 1 H, NCHH nonyl), 2.74–2.66 (m, 1 H,

NCHH nonyl), 2.42 (dt, J = 3.6, 7.6 Hz, 1 H, 1-H), 2.37 (dt, J =

(m, 1 H, CHH-3 pentenyl), 2.25–2.17 (m, 1 H, CHH-3 pentenyl),

1.95 (s, 6 H, 6ϫ CH Ada), 1.73 (dd, J = 12.3, 46.5 Hz, 12 H, 6ϫ

2.8, 9.7 Hz, 1 H, 5-H), 1.95 (s, 3 H, 3ϫ CH Ada), 1.83–1.66 (m, 7 CH₂Ada), 1.66–1.52 (m, 16 H, 6ϫ CH₂Ada, CH₂-4 pentyl, CH₂-

H, 3ϫ CH₂Ada, CHH-1 pentyl), 1.66–1.55 (m, 9 H, 3ϫ CH₂Ada, 4 pentenyl), 1.48–1.17 (m, 4 H, CH₂-2 pentyl, CH₂-3 pentyl) ppm.

CHH-1 pentyl, CH₂-4 pentyl), 1.49-1.36 (m, 6 H, 2ϫ CH₂pentyl, ¹³C NMR (150 MHz, MeOD): δ = 135.6 (=CH-2 pentenyl), 130.1

NCH₂CH₂nonyl), 1.36–1.18 (m, 12 H, 6ϫ CH₂nonyl), 0.90 (t, J

(=CH-1 pentenyl), 83.1, 83.1 (2ϫ OCH₂-Ada), 79.5 (C-3), 74.9 (C-

= 7.0 Hz, 3 H, CH₃nonyl) ppm. ¹³C NMR (150 MHz, MeOD): δ 2), 72.6, 72.3 (CH₂-5 pentenyl/pentyl), 71.7 (C-4), 64.9 (C-5), 63.0

= 83.2, 80.5 (C-3), 73.1 (C-2), 72.6 (CH₂-5 pentyl), 71.6 (C-4), 66.0 (C-1), 59.3 (C-6), 49.0 (NCH₂-1 pentyl), 41.1, 41.1 (CH₂-Ada), 38.5

(C-5), 64.0 (C-1), 60.1 (C-6), 47.8 (NCH₂nonyl), 41.0 (CH₂Ada), (CH₂-Ada), 35.3 (C_qAda), 31.0 (CH₂-4 pentyl), 30.8 (CH₂-4 pen-

38.5 (CH₂Ada), 35.3 (C_qAda), 33.2 (CH₂nonyl), 30.9 (CH₂

tenyl), 29.9 (CH Ada), 26.6 (CH₂-3 pentenyl), 25.3 (C-3), 22.0 (C-

2) ppm. IR (thin film): ν = 3362, 2901, 2848, 1452, 1157, 1109,

nonyl), 30.8 (CH₂-4 pentyl), 30.7, 30.6 (2ϫ CH₂nonyl), 29.9 (CH

˜

max.

Ada), 29.3 (CH₂-1 pentyl), 28.6, 28.0, 24.8, 23.9, 23.6 (2ϫ CH₂1011 cm^–1. [α]²_D⁰= 23.7 (c = 0.4, MeOH). HRMS: found 630.4725

pentyl, 3ϫ CH nonyl), 14.6 (CH nonyl) ppm. IR (thin film): ν

[M + H]⁺, calcd. for [C₃₈H₆₃NO₆+ H]⁺630.4728.

˜

2

3

max.

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1271

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-N-benzyl-1-deoxynojiri-

mycin (40): A suspension of 3^[28](40 mg, 101 µmol), benzyl bromide

(25 µL, 211 µmol) and K₂CO₃(42 mg, 303 µmol) in DMF (0.5 mL)

was heated at 85 °C for 18 h. The reaction mixture was filtered

through a glass fibre filter and concentrated. The residue was puri-

fied by silica gel column chromatography (0% Ǟ 20% MeOH in

CHCl₃with 0.5 % NH₄OH) to give 40 (35 mg, 72 µmol) as a

colourless oil in 71% yield. R_f= 0.67 (MeOH/CHCl₃, 1:4 + 0.5%

2848, 1497, 1453, 1360, 1209, 1152, 1096, 1072, 1027, 734,

697 cm^–1. [α]²_D⁰= 49.4 (c = 1.0, CHCl₃). HRMS: found 756.4622

[M + H]⁺, calcd. for [C₅₀H₆₁NO₅+ H]⁺756.4623.

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-1-deoxynojiri-

mycin (42): Compound 41 (45 mg, 60 µmol) was subjected to a

Birch reduction (see general procedure G) to produce 42 (16 mg,

40 µmol) as a colourless oil in 67% yield after purification (silica

gel: 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). R_f= 0.34

(MeOH/CHCl₃, 1:4 + 0.5 % NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 5.69 (dt, J = 7.6, 10.8 Hz, 1 H, =CH-2 pentenyl), 5.32

(dd, J = 9.2, 10.8 Hz, 1 H, =CH-1 pentenyl), 3.91 (dd, J = 3.1,

10.9 Hz, 1 H, 6a-H), 3.48 (dd, J = 7.9, 10.9 Hz, 1 H, 6b-H), 3.41

(t, J = 6.3 Hz, 2 H, CH₂-5 pentenyl), 3.36 (dd, J = 9.2, 9.2 Hz 1

H, 1-H), 3.28 (dd, J = 8.9, 9.1 Hz, 1 H, 3-H), 3.14 (dd, J = 8.9,

9.6 Hz, 1 H, 4-H), 3.09 (d, J = 9.1, 9.2 Hz 1 H, 2-H), 3.01–2.96

(m, 2 H, OCH₂-Ada), 2.64 (ddd, J = 3.1, 7.9, 9.6 Hz, 1 H, 5-H),

2.28–2.18 (m, 2 H, CH₂-3 pentenyl), 1.95 (s, 3 H, 3ϫ CH Ada),

1.73 (dd, J = 11.5, 41.9 Hz, 6 H, 3ϫ CH₂Ada), 1.67–1.59 (m, 2

H, CH₂-4 pentenyl), 1.58 (d, J = 2.4 Hz, 6 H, 3ϫ CH₂Ada) ppm.

¹³C NMR (150 MHz, MeOD): δ = 135.7 (=CH-2 pentenyl), 130.4

(=CH-1 pentenyl), 83.1 (OCH₂-Ada), 80.3 (C-3), 76.5 (C-2), 73.8

(C-4), 72.0 (CH₂-5 pentenyl), 63.8 (C-6), 62.5 (C-5), 58.5 (C-1),

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.8 (CH₂-4 pen-

tenyl), 29.9 (CH Ada), 25.9 (CH₂-3 pentenyl) ppm. IR (thin film):

1

NH₄OH). H NMR (600 MHz, MeOD): δ = 7.43 (d, J = 7.4 Hz,

2 H, o-CH_ArBn), 7.30 (t, J = 7.7 Hz, 2 H, m-CH_ArBn), 7.20 (t, J

= 7.4 Hz, 1 H, p-CH_ArBn), 3.95–3.87 (m, 3 H, 6a-H, CH₂Bn),

3.82 (dd, J = 4.5, 11.6 Hz, 1 H, 6b-H), 3.53 (dd, J = 9.1, 9.8 Hz, 1

H, 4-H), 3.35 (dd, J = 9.0, 9.7 Hz, 1 H, 2-H), 3.26 (t, J = 6.6 Hz,

2 H,CH₂-5 pentyl), 3.24 (dd, J = 9.0, 9.1 Hz, 1 H, 3-H), 2.93 (s, 2

H, OCH₂-Ada), 2.61 (ddd, J = 4.0, 4.5, 9.8 Hz, 1 H, 5-H), 2.56

(ddd, J = 3.5, 6.3, 9.7 Hz, 1 H, 1-H), 1.96 (s, 3 H, 3ϫ CH Ada),

1.80–1.67 (m, 7 H, 3ϫ CH₂Ada, CHH-1 pentyl), 1.60–1.54 (m, 7

H, 3ϫ CH₂Ada, CHH-1 pentyl), 1.45–1.28 (m, 4 H, CH₂-2, CH₂-

4 pentyl), 1.10–1.02 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR

(151 MHz, MeOD): δ = 143.1 (C_qBn), 129.3 (m-CH_ArBn), 129.0

(o-CH_ArBn), 127.6 (p-CH_ArBn), 83.1 (OCH₂-Ada), 80.8 (C-3),

73.1 (C-2), 72.8 (CH₂-5 pentyl), 72.1 (C-4), 68.2 (C-5), 67.1 (C-1),

62.4 (C-6), 52.4 (CH₂Bn), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3

(C_qAda), 30.7 (CH₂-4 pentyl), 30.1 (CH₂-1 pentyl), 29.9 (CH

Ada), 27.6 (CH₂-2 pentyl), 26.4 (CH₂-3 pentyl) ppm. IR (thin film):

ν

= 3319, 2900, 2848, 1661, 1448, 1344, 1096, 1005 cm^–1. [α]²_D⁰

˜

= 3368, 2901, 2848, 1700, 1454, 1285, 1094, 729, 699 cm^–1.

max.

ν

˜

max.

= 10.5 (c = 0.3, MeOH). HRMS: found 396.2742 [M + H]⁺, calcd.

[α]²_D⁰= –4.0 (c = 0.5, MeOH). HRMS: found 488.3365 [M + H]⁺,

for [C₂₂H₃₇NO₅+ H]⁺396.2744.

calcd. for [C₂₉H₄₅NO₅+ H]⁺488.3370.

(1S)-1-C-[5-(Adamant-1-ylmethoxy)pent-1-ynyl]-1-deoxynojirimycin

(43): Compound 35^[28](149 mg, 198 µmol) was subjected to a Birch

reduction for 30 min (see general procedure G) to produce a ca.

4:1 mixture of 43 and 44 after silica gel column purification (0% Ǟ

10% MeOH in CHCl₃with 0.5% NH₄OH), from which 43 (19 mg,

48 µmol) could be obtained in 24% yield as a colourless oil after

HPLC purification [1 min: isocratic 30% B Ǟ 11.5 min: 45% B Ǟ

12.5 min: 100 % B, 20 min: isocratic 100% B; t_R(43) = 6.0 min;

t_R(44) = 8.2 min]. R_f= 0.37 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH).

¹H NMR (600 MHz, MeOD): δ = 3.92–3.87 (m, 2 H, 1-H, 6a-H),

3.84 (dd, J = 4.9, 11.9 Hz, 1 H, 6b-H), 3.56–3.51 (m, 2 H, 2-H, 4-

H), 3.48 (t, J = 6.0 Hz, 2 H, CH₂-5 pentynyl), 3.35 (dd, J = 9.1 Hz,

1 H, 3-H), 3.07 (ddd, J = 3.3, 4.9, 10.6 Hz, 1 H, 5-H), 2.98 (s, 2 H,

OCH₂-Ada), 2.39 (td, J = 1.6, 7.2 Hz, 2 H, CH₂-3 pentynyl), 1.94

(s, 3 H, 3ϫ CH Ada), 1.84–1.64 (m, 8 H, 3ϫ CH₂Ada, CH₂-4

pentynyl), 1.56 (d, J = 2.4 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR

(150 MHz, MeOD): δ = 90.2 (C_qpentynyl), 83.1 (OCH₂-Ada), 77.9

(C-3), 73.8 (C_qpentynyl), 73.3 (C-2), 70.9 (CH₂-5 pentynyl), 69.2

(C-4), 61.5 (C-5), 59.0 (C-6), 52.4 (C-1), 41.0 (CH₂Ada), 38.5 (CH₂

Ada), 35.3 (C_qAda), 29.9 (CH Ada), 29.6 (CH₂-4 pentynyl), 16.4

(1S)-1-C-[(Z)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-2,3,4,6-tetra-

O-benzyl-1-deoxynojirimycin (41): A solution of 35^[28](151 mg,

0.2 mmol) in EtOAc (2 mL) was charged with Lindlar catalyst

(25 mg). Argon was passed through the reaction mixture for 5 min,

and the mixture was subsequently exposed to atmospheric hydro-

gen pressure for 18 h. After 18 h, the conversion was ca. 80% of

a single slower running product. Longer or repeated exposure to

hydrogen led to overreduction [R_f(starting material) = 0.57;

R_f(overreduced product) = 0.49 (EtOAc/PE, 1:2)]. The reaction

mixture was passed through a glass fibre filter and concentrated.

The residue was purified by silica gel column chromatography (0%

Ǟ 5% acetone in toluene) to furnish 41 (112 mg, 0.15 mmol) in

74% yield as a colourless oil (20% starting material recovered). R_f

= 0.52 (EtOAc/PE, 1:2). ¹H NMR (600 MHz, CDCl₃): δ = 7.36–

7.16 (m, 20 H, H_ArBn), 5.62 (dt, J = 7.4, 10.8 Hz, 1 H, =CH-2

pentenyl), 5.35 (dd, J = 9.2, 10.8 Hz, 1 H, =CH-1 pentenyl), 4.91

(d, J = 10.8 Hz, 1 H, CHH Bn), 4.84 (m, 2 H, CHH Bn, CHH

Bn), 4.73 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.69 (d, J = 10.7 Hz, 1

H, CHH Bn), 4.50 (d, J = 11.0 Hz, 1 H, CHH Bn), 4.46 (s, 2 H,

CH₂Bn), 3.72 (dd, J = 2.6, 9.0 Hz, 1 H, 6a-H), 3.61 (dd, J = 9.0,

9.0 Hz, 1 H, 3-H), 3.50 (dd, J = 9.2, 9.2 Hz 1 H, 1-H), 3.38 (dd, J

= 7.7, 8.9 Hz, 1 H, 6b-H), 3.34–3.31 (m, 3 H, 4-H, CH₂-5 pentenyl),

3.25 (dd, J = 9.2, 9.2 Hz 1 H, 2-H), 2.93–2.86 (m, 3 H, 5-H, OCH₂-

Ada), 2.28–2.20 (m, 1 H, CHH-3 pentenyl), 2.20–2.12 (m, 1 H,

CHH-3 pentenyl), 1.95 (s, 3 H, 3ϫ CH Ada), 1.77 (s, 1 H, NH),

1.67 (dd, J = 11.7, 36.7 Hz, 6 H, 3ϫ CH₂Ada), 1.62–1.54 (m, 2

(CH -3 pentynyl) ppm. IR (thin film): ν

= 3366, 2902, 2849,

˜

2

max.

1444, 1201, 1141, 1114, 1078, 1024 cm^–1. [α]²_D⁰= –3.3 (c = 0.2,

MeOH). HRMS: found 394.2586 [M + H]⁺, calcd. for [C₂₂H₃₅NO₅

+ H]⁺394.2588.

(1S)-1-C-[(E)-5-(Adamant-1-ylmethoxy)pent-1-enyl]-1-deoxynojiri-

mycin (44): Compound 35^[28](100 mg, 133 µmol) was subjected to a

H, CH₂-4 pentenyl), 1.52 (d, J = 2.5 Hz, 6 H, 3ϫ CH₂Ada) ppm. Birch reduction for 3 h with lithium instead of sodium (see general

¹³C NMR (150 MHz, CDCl₃): δ = 139.0, 138.7, 138.5, 138.1 (4ϫ procedure G) to produce 44 (36 mg, 92 µmol) in 70% yield as a

C_qBn), 134.3 (=CH-2 pentenyl), 129.5 (=CH-1 pentenyl), 128.68, colourless oil after purification (0% Ǟ 10% MeOH in CHCl₃with

128.63, 128.6, 128.4, 128.3, 128.2, 128.1, 128.0, 127.96, 127.91,

0.5% NH₄OH). R_f= 0.35 (MeOH/CHCl₃, 1:4 + 0.5% NH₄OH).

127.8, 127.7 (CH_ArBn), 87.9 (C-3), 84.6 (C-2), 82.0 (OCH₂-Ada), ¹H NMR (600 MHz, MeOD): δ = 6.03 (dt, J = 6.9, 15.4 Hz, 1 H,

80.6 (C-4), 75.9, 75.4, 75.2, 73.6 (4ϫ CH₂Bn), 70.9 (CH₂-5 pen- =CH-2 pentenyl), 5.47 (dd, J = 8.7, 15.4 Hz, 1 H, =CH-1 pentenyl),

tenyl), 71.0 (C-6), 59.1 (C-5), 56.9 (C-1), 39.9 (CH₂Ada), 37.5 3.92 (dd, J = 3.9, 11.9 Hz, 1 H, 6a-H), 3.86 (dd, J = 2.9, 11.9 Hz,

(CH₂Ada), 34.3 (C_qAda), 29.7 (CH₂-4 pentenyl), 28.5 (CH Ada),

25.1 (CH -3 pentenyl) ppm. IR (thin film): ν = 3031, 2900,

1 H, 6b-H), 3.60–3.52 (m, 2 H, 1-H, 4-H), 3.44–3.35 (m, 7 H, 2-H,

3-H, CH₂-5 pentenyl), 3.08 (dt, J = 3.3, 10.7 Hz, 1 H, 5-H), 2.98

˜

2

max.

1272

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

(s, 2 H, OCH₂-Ada), 2.23 (dd, J = 6.7, 14.4 Hz, 2 H, CH₂-3 pen- was added. After stirring at 0 °C for 1 h, 5-bromopent-1-ene (2.5 g,

tenyl), 1.95 (s, 3 H, 3ϫ CH Ada), 1.83-1.65 (m, 8 H, 3ϫ CH₂Ada,

16.8 mmol) was added. The resulting mixture was warmed to ambi-

ent temperature and stirred at ambient temperature for an ad-

ditional 16 h. The reaction mixture was cooled to 0 °C and

quenched by addition of water. The mixture was diluted with Et₂O

CH₂-4 pentenyl), 1.57 (d, J = 2.4 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³

C

NMR (150 MHz, MeOD): δ = 142.3 (=CH-2 pentenyl), 123.9

(=CH-1 pentenyl), 83.1 (OCH₂-Ada), 78.3 (C-3), 72.5 (C-2), 71.7

(CH₂-5 pentenyl), 69.1 (C-4), 62.9 (C-1), 61.6 (C-5), 58.6 (C-6), (200 mL) and washed with water (3ϫ200 mL). The organic phase

41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.4 (C-3), 29.9

was dried (Na₂SO₄) and concentrated. The residue was purified by

silica gel column chromatography (0% Ǟ 5% EtOAc in PE) to

produce 47 (1.036 g, 4.42 mmol) in 53% yield as a volatile colour-

less liquid. R_f= 0.73 (100% toluene). ¹H NMR (200 MHz, CDCl₃):

δ = 5.82 (ddt, J = 6.6, 10.1, 16.9 Hz, 1 H, =CH-2 pentenyl), 5.09–

4.88 (m, 2 H, =CH₂-1 pentenyl), 3.38 (t, J = 6.4 Hz, 2 H, CH₂-5

pentenyl), 2.95 (s, 2 H, OCH₂-Ada), 2.20–2.05 (m, 2 H, CH₂-3

pentenyl), 1.95 (s, 3 H, 3ϫ CH Ada), 1.64 (m, 8 H, CH₂-4 pentenyl,

3ϫ CH₂Ada), 1.53 (d, J = 2.8 Hz, 6 H, 3ϫ CH₂Ada) ppm. ¹³C

NMR (50 MHz, CDCl₃): δ = 138.7 (=CH-2 pentenyl), 114.7

(=CH₂-1 pentenyl), 82.1 (OCH₂-Ada), 71.0 (CH₂-5 pentenyl), 40.0

(CH₂Ada), 37.5 (CH₂Ada), 34.3 (C_qAda), 30.5, 29.1 (CH₂-3,

(CH Ada), 29.8 (C-4) ppm. IR (thin film): ν_max.= 3366, 2904, 2850,

˜

1440, 1203, 1140 cm^–1. [α]²_D⁰= –3.4 (c = 0.1, MeOH). HRMS: found

396.2743 [M + H]⁺, calcd. for [C₂₂H₃₇NO₅+ H]⁺396.2744.

3-(Adamant-1-ylmethoxy)prop-2-ene (45): A stirred solution of ada-

mantylmethanol (1.38 g, 8.3 mmol) in DMF (25 mL) was cooled

to 0 °C, and sodium hydride (60% in mineral oil, 0.5 g, 12.5 mmol)

was added. After stirring at 0 °C for 1 h, allyl bromide (1.46 mL,

16.8 mmol) was added. The resulting mixture was warmed to ambi-

ent temperature and stirred at ambient temperature for an ad-

ditional 16 h. The reaction mixture was cooled to 0 °C and

quenched by addition of water. The mixture was diluted with Et₂O

(200 mL) and washed with water (3ϫ200 mL). The organic phase

was dried (Na₂SO₄) and concentrated. The residue was purified by

silica gel column chromatography (0% Ǟ 5% EtOAc in PE) to

produce 45 (1.359 g, 6.59 mmol) in 80% yield as a colourless liquid.

CH -4 pentenyl), 28.5 (CH Ada) ppm. IR (thin film): ν_max.= 2899,

˜

2

2848, 1641, 1451, 1361, 1157, 1111, 1050, 990, 910 cm^–1. MS (ESI):

found 235.3 [M + H]⁺, calcd. for [C₁₆H₂₆O + H]⁺235.2.

α/β-Mixture of 2,3,4,6-tetra-O-benzyl-N-(4-methoxybenzyl)-D-

1

glucopyranosylamine (49): A suspension of commercially availabe

2,3,4,6-tetra-O-benzyl--glucopyranose (48, 21.6 g, 40 mmol), (p-

methoxybenzyl)amine (15.7 mL, 200 mmol), p-toluenesulfonic acid

(200 mg, 1 mmol) and Na₂SO₄(17 g, 120 mmol) in toluene

(400 mL) was refluxed for 18 h. The reaction mixture was cooled

to room temp., diluted with EtOAc (300 mL) and successively

washed with aq. 1  HCl (2ϫ300 mL), satd. aq. NaHCO₃

(2ϫ200 mL) and satd. aq. NaCl (200 mL). The organic phase was

dried (Na₂SO₄) and concentrated to provide 49 as a white solid

that was used crude in the subsequent reaction. A small sample of

crude 49 was purified by silica gel column chromatography (0% Ǟ

10% EtOAc in PE) for characterization. R_f= 0.75 (EtOAc/PE, 1:2).

¹H NMR (400 MHz, CDCl₃): δ = 7.52–7.10 (m, 44 H, H_Ar-α/β Bn/

PMB), 6.83 (d, J = 7.7 Hz, 4 H, H_Ar-α/β PMB), 5.06–4.43 (m, 17

H, CH₂-α/β Bn, 1α-H), 4.14–4.05 (m, 2 H, CHH-6, CHH PMB),

4.03 (d, J = 8.8 Hz, 1 H, 1β-H), 3.94–3.54 (m, 20 H, OMe-α/β

PMB, CH₂-α/β PMB), 3.40 (d, J = 7.2 Hz, 1 H), 3.30 (dd, J = 8.1,

8.8 Hz, 1 H, 2β-H), 2.21 (br. s, 2 H, NHPMB) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 158.8, 158.7 (p-C_q-α/β PMB), 139.1, 138.9,

138.64, 138.62, 138.4, 138.3, 138.2 (C_q-α/β Bn), 132.5, 132.4 (C_q-α/

β PMB), 129.6, 129.5, 128.6, 128.58, 128.55, 128.51, 128.4, 128.1,

128.06, 128.02, 127.84, 127.81, 127.78, 127.73 (CH_Ar-α/β Bn/PMB),

113.9, 113.9 (CH_Ar-α/β PMB), 90.2 (C-1β), 84.1 (C-1α), 86.1, 82.7,

82.7, 80.4, 78.4, 78.3 (C-2, C-3, C-4 α/β), 75.8 (C-5β), 75.9, 75.7,

75.1, 75.1, 75.0, 73.7, 73.6, 73.0 (CH₂-α/β Bn), 69.0 (C-5α), 69.1,

68.9 (C-6α/β), 55.4, 55.3 (OMe-α/β PMB), 49.4, 49.3 (CH₂-α/β

R_f= 0.67 (100% toluene). H NMR (400 MHz, CDCl₃): δ = 5.94–

5.80 (m, 1 H, =CH-2 propenyl), 5.25 (d, J = 17.3 Hz, 1 H, =CHH-

1 propenyl), 5.12 (d, J = 10.4 Hz, 1 H, =CHH-1 propenyl), 3.92

(d, J = 5.0 Hz, 2 H, CH₂-3 propenyl), 2.98 (s, 2 H, OCH₂-Ada),

1.96 (s, 3 H), 1.68 (dd, J = 12.1, 26.0 Hz, 6 H), 1.55 (s, 6 H) ppm.

¹³C NMR (100 MHz, CDCl₃): δ = 135.5 (=CH-2 propenyl), 116.1

(=CH₂-1 propenyl), 81.4 (OCH₂-Ada), 72.3 (CH₂-3 propenyl), 39.8

(CH₂Ada), 37.4 (CH₂Ada), 34.1 (C_qAda), 28.4 (CH Ada) ppm.

IR (thin film): ν

= 2902, 2849, 1733, 1453, 1378, 1258, 1158,

˜

max.

1090, 989, 919 cm^–1. MS (ESI): found 207.2 [M + H]⁺, calcd. for

[C₁₄H₂₂O + H]⁺207.2.

4-(Adamant-1-ylmethoxy)but-2-ene (46): A solution of 3-buten-1-ol

(0.35 mL, 4.0 mmol) and Et₃N (0.55 mL, 4.0 mmol) in DCM

(40 mL) was cooled to –40 °C, and Tf₂O (0.73 mL, 4.4 mmol) was

slowly added over 30 s. The mixture was warmed to 0 °C over a

period of 1 h, after which TLC analysis indicated complete conver-

sion to the volatile intermediate triflate [R_f(triflate) = 0.80 (EtOAc/

PE, 1:2)]. The crude reaction mixture was poured into a stirred

suspension of anhydrous K₂CO₃(2.76 g, 10 mmol) and adamantyl-

methanol (3.32 g, 20 mmol) in DCM (80 mL). The resulting mix-

ture was refluxed at 50 °C for 20 h. The suspension was cooled to

ambient temperature and filtered. The solid residue was rinsed, and

the combined filtrates were concentrated. The concentrate was

purified by silica gel column chromatography (2% Ǟ 5% EtOAc in

PE) to afforded 46 (875 mg, 3.97 mmol) in 99% yield as a volatile

1

colourless liquid. R_f= 0.85 (EtOAc/PE, 1:9). H NMR (400 MHz,

PMB) ppm. IR (thin film): ν

= 3318, 3030, 2864, 1611, 1514,

˜

max.

1454, 1354, 1244, 1121, 1058, 1028, 1011, 971, 748, 732, 693 cm^–1.

[α]²_D⁰= 25.7 (c = 1.8, CHCl₃). HRMS: found 660.3317 [M + H]⁺,

calcd. for [C₄₂H₄₅NO₆+ H]⁺660.3320.

CDCl₃): δ = 5.89–5.76 (m, 1 H, =CH-2 butenyl), 5.06 (d, J =

17.2 Hz, 1 H, =CHH-1 butenyl), 5.00 (d, J = 10.2 Hz, 1 H, =CHH-

1 butenyl), 3.42 (t, J = 6.8 Hz, 2 H, CH₂-4 butenyl), 2.97 (s, 2 H,

OCH₂-Ada), 2.36–2.26 (m, 2 H, CH₂-3 butenyl), 1.95 (s, 3 H, 3ϫ

CH Ada), 1.68 (dd, J = 12.1, 26.2 Hz, 7 H, 3ϫ CH₂Ada), 1.54 (s,

6 H, 3ϫ CH₂Ada) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 135.6

(=CH-2 butenyl), 116.1 (=CH₂-1 butenyl), 82.0 (OCH₂-Ada), 71.0

(CH₂-4 butenyl), 39.9 (CH₂Ada), 37.4 (CH₂Ada), 34.3 (CH₂-3

(1R/S)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-[(4-methoxybenzyl)amino]-

1-C-(prop-2-enyl)-D-glucitol (50): Allylmagnesium bromide (1  in

Et₂O, 350 mL, 350 mmol) was slowly added over a period of 30 min

to a dry and cooled (0 °C) solution of 49 (23.1 g, 35 mmol) in Et₂O

(50 mL). The reaction mixture was stirred for an additional 16 h

and warmed to room temp. The reaction was quenched with satd.

aq. NH₄Cl, poured into Et₂O (200 mL), and washed with satd.

aq. NH₄Cl (2ϫ200 mL). The organic phase was dried (Na₂SO₄),

butenyl), 34.2 (C Ada), 28.5 (CH Ada) ppm. IR (thin film): ν

˜

q

max.

= 2899, 2848, 1641, 1451, 1359, 1157, 1109, 992, 911 cm^–1. MS

(ESI): found 221.4 [M + H]⁺, calcd. for [C₁₅H₂₄O + H]⁺221.2.

5-(Adamant-1-ylmethoxy)pent-2-ene (47): A stirred solution of ada- concentrated and purified by silica gel column chromatography

mantylmethanol (1.38 g, 8.3 mmol) in DMF (25 mL) was cooled (0% Ǟ 40% EtOAc in PE) to provide 50 [2.28 g, 32.5 mmol, in-

to 0 °C, and sodium hydride (60% in mineral oil, 0.5 g, 12.5 mmol)

separable (R)/(S) = 9:1 isomer mixture] in 93% yield as a colourless

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1273

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

oil. R_f= 0.40 (EtOAc/PE, 1:2). H NMR (400 MHz, CDCl₃): δ =

7.39–7.17 (m, 22 H, H_ArBn, H_ArPMB), 6.81 (d, J = 8.5 Hz, 2 H,

1

7.61–6.66 (m, 32 H, CH_ArBn/PMB/Fmoc), 5.56–5.29 (m, 1 H,

=CH propenyl), 4.97–3.64 (m, 21 H, 6ϫ CH₂Bn/PMB/Fmoc, CH

H_ArPMB), 5.65–5.53 (m, 1 H, =CH propenyl), 5.01–4.93 (m, 2 H, Fmoc, =CH propenyl, =CH₂, propenyl, 1-H, H2, 3-H, 4-H, CH₂-

=CH₂propenyl), 4.85 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.78 (d, J 6), 3.45–3.36 (m, 3 H, OMe PMB), 2.71–2.12 (m, 2 H, CH₂pro-

= 11.3 Hz, 1 H, CHH Bn), 4.69 (d, J = 11.3 Hz, 1 H, CHH Bn), penyl) ppm. ¹³C NMR (125 MHz, C₆D₆, 343 K): δ = 159.5, 145.6,

4.60–4.49 (m, 5 H, CHH Bn, CHH Bn, CH₂Bn), 4.40 (d, J =

11.4 Hz, 1 H, CHH Bn), 4.27 (dd, J = 2.8, 7.5 Hz, 1 H, 3-H), 4.09–

144.9, 142.1, 141.5, 139.7, 139.4, 139.0, 136.6, 135.9, 134.6, 134.1,

133.1, 130.5, 129.8, 129.6, 129.3, 129.1, 128.8, 128.7, 128.4, 128.26,

4.04 (m, 1 H, 5-H), 3.87–3.78 (m, 2 H, 2-H, CHH PMB), 3.76 (s, 128.21, 128.0, 127.9, 127.8, 127.5, 127.3, 125.5, 125.4, 124.6, 120.4,

3 H, OMe PMB), 3.66–3.51 (m, 2 H, 4-H, CH₂-6, CHH PMB), 120.3, 117.3, 114.4, 114.2, 81.0, 79.7, 78.0, 76.0, 75.4, 74.6, 74.3,

2.62 (t, J = 5.1 Hz, 1 H, 1-H), 2.46–2.33 (m, 1 H, CHH propenyl), 74.2, 73.9, 72.3, 67.5, 65.6, 55.2, 51.1, 48.3, 35.4 ppm. [α]²_D⁰= 14.5

2.33–2.19 (m, 1 H, CHH propenyl) ppm. ¹³C NMR (100 MHz, (c = 4.9, CHCl ).IR (thin film): ν

= 3065, 3031, 2866, 1685,

˜

3

max.

CDCl₃): δ = 158.8 (p-C_qPMB), 139.1, 138.6, 138.35, 138.31 (C_q1611, 1513, 1453, 1412, 1301, 1244, 1177, 1089, 1065, 1029, 916,

Bn/PMB), 136.30 (=CH propenyl), 129.8, 128.6, 128.5, 128.3, 735, 696 cm^–1. HRMS: found 946.4292 [M + Na]⁺, calcd. for

128.0, 127.97, 127.92, 127.6 (CH_ArBn/PMB), 117.3 (=CH₂pro-

penyl), 113.9 (CH_ArPMB), 80.3 (C-2), 79.6 (C-3), 77.9 (C-4), 74.7,

73.6, 73.0 (4ϫ CH₂Bn), 71.8 (C-6), 70.8 (C-5), 57.0 (C-1), 55.5

(OMe PMB), 50.5 (CH₂PMB), 35.2 (CH₂propenyl) ppm. IR (thin

[C₄₅H₅₁NO₆+ Na]⁺946.4289.

(1R)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-{[(9H-fluoren-9-ylmethoxy)-

carbonyl](4-methoxybenzyl)amino}-1-C-(prop-2-enyl)-D-arabino-

hex-5-ulose (53): Dess–Martin periodinane (0.73 g, 1.7 mmol) was

added to a solution of 52 (1.0 g, 1.43 mmol) in DCM (17 mL).

After the reaction mixture had been stirred for 6 h, satd. aq.

Na₂S₂O₃(5 mL) and satd. aq. NaHCO₃(5 mL) were added and

vigorously mixed for 10 min. The mixture was diluted with EtOAc

(50 mL) and washed with water (2ϫ15 mL). The organic phase

was dried (MgSO₄), concentrated and purified by silica gel column

chromatography (0% Ǟ 20% EtOAc in PE) to afforded 53 (1.32 g,

1.4 mmol) in 98% yield as a white foam. R_f= 0.55 (EtOAc/PE,

1:2). ¹H NMR (500 MHz, C₆D₆): δ = 7.96–6.69 (m, 32 H, CH_Ar

Bn/PMB/Fmoc), 5.87–3.53 (m, 21 H, 6ϫ CH₂Bn/PMB/Fmoc, CH

Fmoc, =CH propenyl, =CH₂, propenyl, 1-H, H2, 3-H, 4-H, CH₂-

6), 3.43 (s, 3 H, OMe PMB), 2.88–2.03 (m, 2 H, CH₂propenyl)

ppm. ¹³C NMR (125 MHz, C₆D₆): δ = 207.1, 159.6, 144.9, 142.24,

142.21, 139.3, 138.8, 138.4, 135.8, 129.5, 129.2, 129.1, 128.98,

128.92, 128.7, 128.6, 127.8, 127.7, 127.3, 125.6, 120.6, 118.0, 114.2,

film): ν

= 3031, 2863, 1610, 1513, 1454, 1245, 1067, 1028, 912,

˜

max.

825, 733, 696 cm^–1. [α]²_D⁰= –0.4 (c = 2.6, CHCl₃). HRMS: found

702.3786 [M + H]⁺, calcd. for [C₄₅H₅₁NO₆+ H]⁺702.3789.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(4-methoxybenzyl)amino]-1-C-

(prop-2-enyl)-L-ido-1-deoxynojirimycin (51): Methanesulfonyl chlo-

ride (0.56 mL, 7.2 mmol) was added to a cooled (0 °C) solution of

50 (4.21 g, 6.0 mmol) in pyridine (77 mL). The mixture was stirred

for 4 h, warmed to room temp., and subsequently heated at 90 °C

for 16 h [R_f(mesylate) = 0.73 (EtOAc/PE, 1:2)]. The reaction mix-

ture was concentrated, redissolved in EtOAc (100 mL) and washed

extensively with aq. satd. CuSO₄(5ϫ50 mL). The organic phase

was dried (MgSO₄), concentrated and purified by silica gel column

chromatography (0% Ǟ 10% EtOAc in PE) to provide 51 (3.21 g,

4.68 mmol) in 78% yield as a yellow oil. R_f= 0.70 (EtOAc/PE,

1

1:6.5). H NMR (500 MHz, CDCl₃): δ = 7.34–7.20 (m, 20 H, H_Ar

Bn), 7.16 (d, J = 8.6 Hz, 2 H, H_ArPMB), 6.81 (d, J = 8.7 Hz, 2

H, H_ArPMB), 5.91–5.82 (m, 1 H, =CH propenyl), 5.00–4.90 (m, 2

H, =CH₂propenyl), 4.81 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.79 (d,

J = 10.9 Hz, 1 H, CHH Bn), 4.60 (d, J = 11.3 Hz, 1 H, CHH Bn),

4.57–4.51 (m, 3 H, CHH Bn, CH₂Bn), 4.49–4.45 (m, 2 H, CH₂

Bn), 4.03 (d, J = 14.5 Hz, 1 H, CHH PMB), 3.98 (d, J = 14.5 Hz,

1 H, CHH PMB), 3.83–3.67 (m, 7 H, 3-H, 5-H, CH₂-6, OMe

PMB), 3.60 (dd, J = 5.8, 8.2 Hz, 1 H, 2-H), 3.49 (dd, J = 5.6,

11.6 Hz, 1 H, 4-H), 3.20–3.16 (m, 1 H, 1-H), 2.51–2.43 (m, 1 H,

CHH propenyl), 2.37–2.29 (m, 1 H, CHH propenyl) ppm. ¹³C

NMR (100 MHz, CDCl₃): δ = 158.7 (p-C_qPMB), 139.3 (C_qBn),

138.9 (=CH propenyl), 138.8 (C_qBn), 132.8 (C_qPMB), 129.8,

129.3, 128.5, 128.4, 128.2, 128.0, 127.9, 127.8, 127.6 (CH_ArBn/

PMB), 115.6 (=CH₂propenyl), 113.8 (CH_ArPMB), 81.0 (C-2), 80.2

(C-3), 78.8 (C-5), 75.3, 73.4, 72.8, 72.7 (CH₂Bn), 70.6 (C-6), 59.6

(C-1), 58.9 (C-4), 57.4 (CH₂PMB), 55.4 (OMe PMB) 33.8 (CH₂

114.1, 75.4, 73.6, 55.1, 48.1 ppm. IR (thin film): ν_max.= 2934, 1728,

˜

1693, 1611, 1513, 1453, 1412, 1301, 1246, 1177, 1106, 1029, 917,

738, 698 cm^–1. HRMS: found 944.4140 [M + Na]⁺, calcd. for

[C₆₀H₅₉NO₈+ Na]⁺944.4133.

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(4-methoxybenzyl)amino]-1-C-

(prop-2-enyl)-1-deoxynojirimycin (54): Piperidine (75 µL,

0.76 mmol) was added to a cooled (0 °C) solution of 53 (0.5 g,

0.725 mmol) in DMF (5 mL). The resulting mixture was stirred at

0 °C for 30 min. The mixture was diluted with Et₂O (50 mL) and

washed with water (2 ϫ 50 mL). The organic layer was dried

(MgSO₄) and concentrated. The residue was dissolved in MeOH

(15 mL), and the mixture was cooled to –35 °C. The mixture was

acidified to pH = 5 with AcOH followed by the successive addition

of Na₂SO₄(280 mg, 2 mmol) and NaCNBH₃(160 mg, 2.53 mmol).

The reaction mixture was stirred at –20 °C under argon for 16 h.

The mixture was diluted with EtOAc (50 mL) and washed with

satd. aq. NaHCO₃(2 ϫ 50 mL). The organic layer was dried

(MgSO₄), concentrated and purified by silica gel column

chromatography (0% Ǟ 10% EtOAc in PE) to provide 54 (403 mg,

propenyl) ppm. IR (thin film): ν_max.= 3030, 2865, 1609, 1511, 1454,

˜

1364, 1243, 1072, 1029, 908, 825, 733, 695 cm^–1. [α]²_D⁰= 0.5 (c =

3.8, CHCl₃). HRMS: found 684.3680 [M + H]⁺, calcd. for

[C₄₅H₄₉NO₅+ H]⁺684.3684.

(1R)-2,3,4,6-Tetra-O-benzyl-1-deoxy-1-{[(9H-fluoren-9-ylmethoxy)-

0.59 mmol) in 81% yield as a colourless oil. R_f= 0.30 (EtOAc/PE,

1

carbonyl](4-methoxybenzyl)amino}-1-C-(prop-2-enyl)-

(52): Aqueous NaHCO₃(10 wt.-%, 6.3 mL, 15 mmol) was added

to a solution of 50 (2.1 g, 3.0 mmol) in DCM (9 mL) and (9H- =CH propenyl), 5.02–4.92 (m, 3 H, =CH₂propenyl, CHH Bn),

D

-glucitol 1:6.5). H NMR (600 MHz, CDCl₃): δ = 7.38–7.15 (m, 22 H, H_Ar

Bn/PMB), 6.80 (d, J = 8.7 Hz, 2 H, H_ArPMB), 5.76–5.67 (m, 1 H,

fluoren-9-ylmethoxy)carbonyl chloride (0.93 g, 3.6 mmol). The

mixture was stirred vigorously for 16 h. The mixture was diluted

with EtOAc (100 mL) and washed with water (2ϫ100 mL). The

organic layer was dried (MgSO₄), concentrated and purified by sil-

ica gel column chromatography (0% Ǟ 20%, EtOAc in PE) to

4.90 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.80 (d, J = 10.9 Hz, 1 H,

CHH Bn), 4.58 (d, J = 10.7 Hz, 1 H, CHH Bn), 4.51–4.46 (m, 2

H, CH₂Bn), 4.38–4.34 (m, 2 H, CH₂Bn), 3.95 (d, J = 13.9 Hz, 1

H, CHH PMB), 3.84 (dd, J = 4.9, 10.4 Hz, 1 H, 6a-H), 3.81–3.69

(m, 8 H, 6b-H, 4-H, 3-H, 2-H, CHH PMB, OMe PMB), 3.07–3.04

afford 52 (2.602 g, 2.75 mmol) in 91% yield as a white foam. R_f= (m, 2 H, 1-H, 5-H), 2.42–2.33 (m, 2 H, CH₂propenyl) ppm. ¹³C

0.50 (EtOAc/PE, 1:2). ¹H NMR (500 MHz, C₆D₆, 343 K): δ =

NMR (150 MHz, CDCl₃): δ = 158.5 (p-C_qPMB), 139.2, 138.8,

1274

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

138.6, 138.3 (4ϫ C_qBn), 137.9 (=CH propenyl), 132.7 (C_qPMB),

129.6 (=CH propenyl), 128.5, 128.5, 128.4, 128.1, 128.0, 128.0,

room temp. The reaction mixture was quenched with water and

concentrated. The residue was dissolved in Et₂O (400 mL) and

127.7, 127.6, 127.6, 127.6 (CH_ArBn/PMB), 115.4 (=CH₂propenyl), washed successively with water (300 mL) and satd. aq. NaCl

113.6 (CH_ArPMB), 84.2, 79.3, 78.8 (C-2, C-3, C-4), 75.6, 75.3, (200 mL). The organic phase was dried (Na₂SO₄) and concentrated

73.0, 72.2 (4ϫ CH₂Bn), 68.5 (C-6), 57.5, 56.6 (C-5, C-1), 55.3 to provide a yellow oil that was used crude in the next reaction

(OMe PMB), 52.2 (CH₂PMB), 29.1 (CH₂propenyl) ppm. IR (thin [R_f(tetrabenzylated intermediate) = 0.69 (EtOAc/PE, 1:3)]. The

film): ν_max.= 3031, 2862, 1610, 1511, 1454, 1362, 1301, 1244, 1171, crude intermediate was suspended in a mixture of AcOH (210 mL)

˜

1091, 1066, 1028, 908, 827, 733, 696 cm^–1. [α]²_D⁰= 21.5 (c = 3.7,

CHCl₃). HRMS: found 684.3679 [M + H]⁺, calcd. for [C₄₅H₄₉NO₅

+ H]⁺684.3684.

and aq. 1  HCl (93 mL) and refluxed at 105 °C for 4 h, after which

TLC analysis indicated complete consumption of the starting mate-

rial. The reaction mixture was concentrated and coevaporated with

toluene (2ϫ200 mL). The residue was transferred into aq. satd.

NaHCO₃(400 mL) and extracted with EtOAc (3ϫ300 mL). The

combined organic phases were dried (Na₂SO₄) and concentrated.

The product was precipitated from PE/EtOAc to provide 58

(11.34 g, 27 mmol) as a white fluffy solid after drying at 50 °C for

20 h. The mother liquor was concentrated and purified by silica gel

column chromatography (10% Ǟ 33% EtOAc in PE) to provide

additional 49 (4.10 g, 9.76 mmol) and an overall yield of 55%. R_f

= 0.20 (EtOAc/PE, 1:3). ¹H NMR (400 MHz, CDCl₃, major α-

anomer): δ = 7.40–7.25 (m, 15 H, H_ArBn), 5.08 (d, J = 2.1 Hz, 1

H, 1α-H), 4.90–4.82 (m, 2 H, CH₂Bn), 4.76–4.60 (m, 4 H, 2ϫ CH₂

Bn), 3.87 (dd, J = 9.1 Hz, 1 H, 3-H), 3.79 (dd, J = 10.6 Hz, 1 H,

5a-H), 3.65 (dd, J = 4.8, 11.8 Hz, 1 H, 5b-H), 3.59–3.50 (m, 1 H,

4-H), 3.47 (d, J = 8.9 Hz, 1 H, 2-H), 3.29 (s, 1 H, OH-1) ppm. ¹³C

NMR (100 MHz, CDCl₃, α/β-mixture): δ = 138.8, 138.4, 138.0 (C_q

Bn), 128.7, 128.6, 128.5, 128.2, 127.9, 127.8 (CH_ArBn), 97.9 (C-

1β), 91.6 (C-1α), 83.4 (C-3β), 82.6 (C-2β), 80.7 (C-3α), 79.6 (C-2α),

77.8 (C-4β), 77.7 (C-4α), 75.7 (CH₂Bn α), 75.6 (CH₂Bn β), 74.9

(CH₂Bn β), 73.5 (CH₂Bn α), 73.4 (CH₂Bn β), 73.3 (CH₂Bn α),

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-1-C-

(prop-2-enyl)-L-ido-nojirimycin (55): Compound 51 (3.02 g,

4.41 mmol) was subjected to general procedure E to provide 55

(2.32 g, 3.31 mmol) in 75% yield as a colourless oil after purifica-

tion (0% Ǟ 5% EtOAc in toluene). R_f(intermediate amine) = 0.60

(EtOAc/PE, 2:1); R_f(55) = 0.53 (EtOAc/PE, 1:4). ¹H NMR

(500 MHz, C₆D₆, 343 K, major rotamer): δ = 7.38–6.96 (m, 25 H),

6.17–5.93 (m, 1 H, =CH propenyl), 5.25–4.80 (m, 7 H, 5-H, CH₂

Z, CH₂Bn, =CH₂propenyl), 4.66–4.28 (m, 7 H, 1-H, 3ϫ CH₂

Bn), 3.95–3.89 (m, 2 H, 3-H, 6a-H), 3.74 (dd, J = 6.1, 10.1, 1 Hz,

6b-H), 3.54 (dd, J = 7.3, 9.3 Hz, 1 H, 4-H), 3.47 (dd, J = 6.7,

9.2 Hz, 1 H, 2-H), 2.82-2.71 (m, 1 H, CHH propenyl), 2.54–2.40

(m, 1 H, CHH propenyl) ppm. ¹³C NMR (125 MHz, C₆D₆, 343 K,

major rotamer): δ = 156.6 (C=O Z), 140.1, 139.2, 139.1, 137.6 (C_q

Bn/Z), 137.4 (=CH propenyl), 128.8, 128.7, 128.6, 128.4, 128.3,

128.28, 128.22, 128.1, 128.0, 127.9, 127.8, 127.7 (CH_ArBn/Z), 116.5

(=CH₂propenyl), 80.7 (C-2), 80.0 (C-4), 79.2 (C-3), 75.7, 73.7,

73.5, 73.4 (CH₂Bn), 70.3 (C-6), 68.1 (CH₂Z), 54.4 (C-1), 53.8 (C-

5), 34.7 (CH₂propenyl) ppm. IR (thin film): ν

= 3065, 3031,

˜

63.9 (C-5β), 60.4 (C-5α) ppm. IR (thin film): ν

= 3040, 2870,

˜

max.

1599, 1454, 1357, 1071, 1060, 747, 693 cm^–1. [α]²_D⁰= +16.3 (c = 0.6,

CHCl₃). MS (ESI): found 421.3 [M + H]⁺, calcd. for [C₂₆H₂₈O₅+

H]⁺421.2.

2868, 1696, 1496, 1453, 1416, 1364, 1308, 1210, 1092, 1026, 995,

911, 733, 695 cm^–1. [α]²_D⁰= –9.9 (c = 5.5, CHCl₃). HRMS: found

698.3476 [M + H]⁺, calcd. for [C₄₅H₄₈NO₆+ H]⁺698.3476.

α/β-Mixture of 2,3,4-Tri-O-benzyl-N-(4-methoxybenzyl)-D-xylopyr-

(1R)-2,3,4,6-Tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-1-C-

(prop-2-enyl)nojirimycin (56): Compound 54 (2.07 g, 3.03 mmol)

was subjected to general procedure E to provide 56 (1.38 g,

1.98 mmol) in 65% yield as a colourless oil after purification (0%

Ǟ 5% EtOAc in toluene). R_f(intermediate amine) = 0.65 (EtOAc/

PE, 2:1); R_f(56) = 0.56 (EtOAc/PE, 1:4). ¹H NMR (600 MHz,

CDCl₃, major rotamer): δ = 7.44–7.16 (m, 25 H, CH_ArBn Z), 5.85

(s, 1 H, =CH propenyl), 5.14–5.09 (m, 2 H, CH₂Z), 4.98–4.88 (m,

2 H, =CH₂propenyl), 4.68–4.33 (m, 9 H, 1-H, 4ϫ CH₂Bn), 4.28–

4.23 (m, 1 H, 5-H), 3.98 (dd, J = 2.0, 3.6 Hz, 1 H, 4-H), 3.88 (d, J

= 8.3 Hz, 1 H, 3-H), 3.75 (dd, J = 5.5, 8.1 Hz, 1 H, 2-H), 3.66 (s,

1 H, 6a-H), 3.56 (s, 1 H, 6b-H), 2.65–2.59 (m, 1 H, CHH propenyl),

2.59–2.52 (m, 1 H, CHH propenyl) ppm. ¹³C NMR (150 MHz,

CDCl₃): δ = 156.0 (C=O Z), 138.4, 138.3, 138.3, 137.9 (C_qBn),

136.7 (=CH propenyl), 136.5 (C_qZ), 128.6, 128.57, 128.52, 128.45,

128.41, 128.3, 128.2, 128.17, 128.12, 128.05, 128.02, 127.98, 127.95,

127.86, 127.82, 127.79, 127.74, 127.5, 127.3 (CH_ArBn/Z), 116.1

(=CH₂propenyl), 81.5 (C-3), 80.6 (C-2), 77.0 (C-4), 73.0, 72.5,

72.3, 71.7 (4ϫ CH₂Bn), 69.9 (C-6), 67.3 (CH₂Z), 54.6 (C-5), 52.8

anosylamine (59): A suspension of 58 (2.1 g, 5 mmol), (p-meth-

oxybenzyl)amine (6.5 mL, 50 mmol), (Ϯ)-camphor-10-sulfonic acid

(1.162 g, 5 mmol) and Na₂SO₄(2.8 g, 20 mmol) in toluene (50 mL)

was refluxed for 2.5 h, after which TLC analysis indicated complete

consumption of 58 (R_f= 0.20 in EtOAc/PE, 1:3). The reaction

mixture was cooled to room temp., diluted with EtOAc (200 mL)

and successively washed with aq. 1  HCl (2ϫ200 mL), satd. aq.

NaHCO₃(2ϫ100 mL) and satd. aq. NaCl (100 mL). The organic

phase was dried (Na₂SO₄) and concentrated to provide 59 as a

white solid that was used crude in the subsequent reaction. A small

sample of crude 59 was purified by silica gel column chromatog-

raphy (10% Ǟ 25% EtOAc in PE) for characterization. R_f= 0.55

1

(EtOAc/PE, 1:3). H NMR (400 MHz, CDCl₃): δ = 7.44–7.20 (m,

34 H, H_Ar-α/β Bn/PMB), 6.90–6.80 (m, 4 H, H_Ar-α/β PMB), 4.99–

4.58 (m, 11 H, CH₂-α/β Bn), 4.50–4.44 (m, 2 H, 1α-H, CHH-α Bn),

4.03–3.75 (m, 14 H, 1β-H, OMe-α/β PMB, CH₂-α/β PMB), 3.63–

3.56 (m, 4 H), 3.56–3.44 (m, 4 H), 3.24–3.13 (m, 2 H), 2.05–1.79

(m, 1 H, NHPMB), 1.75–1.48 (m, 1 H, NHPMB) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 158.8, 158.8 (p-C_q-α/β PMB), 138.9, 138.7,

138.7, 138.5, 138.3 (C_q-α/β Bn), 132.5, 132.4 (C_q-α/β PMB), 129.6,

(C-1), 34.1 (CH propenyl) ppm. IR (thin film): ν_max.= 3032, 2871,

˜

2

1698, 1495, 1453, 1417, 1270, 1206, 1093, 1026, 995, 913, 734,

694 cm^–1. [α]²_D⁰= 9.2 (c = 4.6, CHCl₃). HRMS: found 698.3477 [M

+ H]⁺, calcd. for [C₄₅H₄₈NO₆+ H]⁺698.3476.

129.5, 128.7, 128.6, 128.4, 128.2, 128.1, 128.0, 127.9, 127.8 (CH_Ar

-

α/β Bn/PMB), 114.0, 113.9 (CH_Ar-α/β PMB), 90.7 (C-1β), 84.2 (C-

1α), 85.2, 82.3, 80.2, 79.3, 78.6, 77.7 (H-2, H-3, H-4 α/β), 75.9,

75.3, 75.2, 73.5, 73.2, 73.1 (CH₂-α/β Bn), 65.2 (C-5β), 60.3 (C-5α),

55.5, 55.5 (OMe-α/β PMB), 49.5 (CH₂-β PMB), 49.1 (CH₂-α PMB)

α/β-Mixture of 2,3,4-Tri-O-benzyl-D-xylopyranose (58): A dry and

cooled (0 °C) solution of -xylose (57; 10 g, 66.6 mmol) in DMF

(333 mL) was charged with sodium hydride (60% in mineral oil,

11.72 g, 293 mmol) and stirred at 0 °C for 1 h. Next, benzyl bro-

mide (34 mL, 286 mmol) was added to the suspension over a period

of 5 min. The reaction mixture was stirred for 20 h and warmed to

ppm. IR (thin film): ν

= 3302, 3030, 2861, 1611, 1514, 1455,

˜

max.

1358, 1242, 1179, 1071, 1030, 933, 894, 814, 748, 693 cm^–1. [α]²_D⁰

=

0.8 (c = 0.5, CHCl₃). MS (ESI): found 540.4 [M + H]⁺, calcd. for

[C₃₄H₃₇NO₅+ H]⁺540.3.

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1275

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

(1R/S)-2,3,4-Tri-O-benzyl-1-deoxy-1-[(4-methoxybenzyl)amino]-1-

NMR (400 MHz, CDCl₃, mixture of rotamers, a/b ≈ 1:1): δ = 7.41–

7.20 (m, 40 H, H_ArBn Z), 5.78–5.65 (m, 1 H, =CH^apropenyl),

a/b

C-(prop-2-enyl)-

D

-xylitol (60): Allylmagnesium bromide (1  in

5.62–5.50 (m, 1 H, =CH^bpropenyl), 5.16–4.90 (m, 8 H, CH₂Z,

a/b

Et₂O, 23 mL, 23 mmol) was slowly added over a period of 2 min

to a dry and cooled (0 °C) solution of 59 (2.14 g, 2.3 mmol) in THF

(23 mL). The reaction mixture was stirred at 0 °C for an additional

5 min and then warmed to room temp. After stirring at room temp.

for 1 h, the reaction was quenched with satd. aq. NH₄Cl. The mix-

ture was poured into additional satd. aq. NH₄Cl (100 mL) and ex-

tracted with EtOAc (3ϫ100 mL). The combined organic phases

were dried (Na₂SO₄), concentrated and purified by silica gel col-

umn chromatography (10% Ǟ 50% EtOAc in PE) to provide 60

[1.31 g, 2.25 mmol, inseparable (R)/(S) = 5:1 isomer mixture] in

97% yield as a colourless oil. R_f= 0.11 (EtOAc/PE, 1:3). ¹H NMR

(300 MHz, CDCl₃): δ = 7.38–7.18 (m, 15 H, H_ArBn), 7.16 (d, J =

a/b

=CH₂propenyl), 4.89–4.81 (m, 4 H, CH₂Bn), 4.77–4.72 (m,

a/b

1 H, 1^a-H), 4.72–4.59 (m, 8 H, 2ϫ CH₂Bn), 4.45–4.39 (m, 2 H,

1^b-H, CHH-5^a), 4.17 (dd, J = 5.7, 13.7 Hz, 1 H, CHH-5^a), 3.68

(dd, J = 8.6, 8.6 Hz, 2 H, 3^a/b-H), 3.60–3.37 (m, 4 H, 2^a/b-H, 4^a/b

-

H), 2.80–2.70 (m, 2 H, CH₂-5^b), 2.64–2.50 (dd, 2 H, CHH^a/bpro-

penyl), 2.35–2.25 (dt, 2 H, CHH^a/bpropenyl) ppm. ¹³C NMR

(100 MHz, CDCl₃, mixture of rotamers, a/b ≈ 1:1): δ = 155.7, 155.6

(C=O^a/bZ), 138.9, 138.2, 138.2 (3ϫ C_qBn), 136.7, 136.6 (C_q

a/b

Z), 134.5, 134.4 (=CH^a/bpropenyl), 128.65, 128.61, 128.5, 128.4,

128.27, 128.22, 128.1, 128.08, 128.03, 127.96, 127.92, 127.8, 127.7

a/b

(CH_Ar

Bn Z), 117.6, 117.4 (=CH₂

propenyl), 82.2, 82.0

8.6 Hz, 2 H, H_ArPMB), 6.79 (d, J = 8.7 Hz, 2 H, H_ArPMB), 5.71– (C-3^a/b), 79.8 (C-2^a/b), 78.4, 78.3 (C-4^a/b), 75.8 (CH₂Bn), 73.3

5.51 (m, 1 H, =CH propenyl), 5.01–4.91 (m, 2 H, =CH₂propenyl), (CH₂Bn), 73.2 (CH₂Bn), 72.8 (CH₂Bn), 67.6, 67.5 (CH₂

a/b

a

a/b

b

a/b

Z), 53.0, 52.3 (C-1^a/b), 41.1, 40.8 (C-5^a/b), 29.8, 29.7 (CH₂pro-

penyl) ppm. IR (thin film): ν = 3032, 2872, 1698, 1495, 1453,

a/b

4.80 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.75 (d, J = 11.4 Hz, 1 H,

CHH Bn), 4.67 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.58–4.50 (m, 2

H, CHH Bn, CHH Bn), 4.37 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.07

˜

max.

1423, 1349, 1314, 1209, 1095, 1026, 991, 913, 734, 695 cm^–1. [α]²_D⁰

(dd, J = 4.1, 7.0 Hz, 1 H, 3-H), 3.81–3.60 (m, 7 H, 2-H, CH₂-5, = 13.8 (c = 3.4, CHCl₃). HRMS: found 578.2899 [M + H]⁺, calcd.

CHH PMB, OMe PMB), 3.51 (d, J = 12.7 Hz, 1 H, CHH PMB), for [C₃₇H₃₉NO₅+ H]⁺578.2801.

3.44–3.35 (m, 1 H, 4-H), 2.64–2.57 (m, 1 H, 1-H), 2.48–2.31 (m, 2

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4,6-tetra-

H, CH₂propenyl) ppm. ¹³C NMR (75 MHz, CDCl₃): δ = 158.5 (p-

O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin (63):

C_qPMB), 138.7, 138.3, 138.2 (C_qBn), 136.0 (=CH propenyl), 132.5

(C_qPMB), 129.6, 129.2, 128.2, 127.9, 127.8, 127.6, 127.5, 127.3

(CH_ArBn/PMB), 116.9 (=CH₂propenyl), 113.5 (CH_ArPMB), 79.9,

79.8, 78.5 (C-2, C-3, C-4), 74.5, 74.1, 71.9 (CH₂Bn), 61.5 (C-5),

56.0 (C-1), 55.0 (OMe PMB), 50.2 (CH₂PMB), 35.1 (CH₂pro-

Compound 55 (275 mg, 395 µmol) underwent a cross-metathesis

reaction (see general procedure F) with alkene 45 to produce 63

(306 mg, 349 µmol) in 88% yield as a mixture of (E)/(Z) isomers

in an unassignable ca. 2:1 ratio after purification (0% Ǟ 10%

EtOAc in PE). R_f= 0.47 (EtOAc/PE, 1:5). ¹H NMR [400 MHz,

CDCl₃, (E)/(Z) isomers]: δ = 7.45–7.19 (m, 25 H, H_ArBn Z H),

5.83–5.40 (m, 2 H, =CH-2 butenyl, =CH-3 butenyl), 5.23–4.93 (m,

3 H, 5-H, CH₂Z), 4.93–4.39 (m, 9 H, 1-H, 4ϫ CH₂Bn), 3.99–3.45

(m, 7 H, 2-H, 3-H, 4-H, CH₂-6, CH₂-4 butenyl), 2.98–2.84 (m, 2

H, OCH₂-Ada), 2.75–2.52 (m, 2 H, CH₂-4 butenyl), 2.42–2.24 (m,

2 H, CH₂-1 butenyl), 2.06–1.84 (m, 3 H, 3ϫ CH Ada), 1.83–1.43

(m, 12 H, 6ϫ CH₂Ada) ppm. ¹³C NMR [100 MHz, CDCl₃, (E)/

(Z) isomers]: δ = 156.4 (C=O Z), 139.0, 138.4 (C_qBn), 131.3, 131.1,

129.9, 129.3 [=CH (E)/(Z) butenyl], 128.6, 128.5, 128.5, 128.2,

128.1, 127.9, 127.7, 127.5 [=CH (E)/(Z) butenyl, CH_ArBn/Z], 81.3

(OCH₂-Ada), 80.2 (C-2), 79.6 (C-4), 78.7 (C-3), 75.9, 74.1, 73.6,

73.4, 73.1 (CH₂Bn), 72.2 (CH₂-4 butenyl), 69.6 (C-6), 67.8 (CH₂

Z), 54.1, 53.5, 53.2, 52.7 (C-1, C-5), 40.0 (CH₂Ada), 37.4 (CH₂

Ada), 34.2 (C_qAda), 33.0, 33.0 (CH₂-1 butenyl), 28.5 (CH Ada)

penyl) ppm. IR (thin film): ν

= 2868, 1610, 1513, 1454, 1245,

˜

max.

1028, 913, 824, 733, 696 cm^–1. [α]²_D⁰= –17.7 (c = 3.3, CHCl₃).

HRMS: found 582.3209 [M + H]⁺, calcd. for [C₃₇H₄₄NO₅+ H]⁺

582.3214.

(1R)-2,3,4-Tri-O-benzyl-1,5-dideoxy-1,5-imino-N-[(4-methoxyben-

zyl)amino]-1-C-(prop-2-enyl)-D-xylitol (61): Diethyl azodicarboxyl-

ate (1.8 mL, 3.92 mmol, 2.2  in toluene) was added over a period

of 1 min to a dry solution of 60 (1.14 g, 1.96 mmol) and PPh₃

(1.03 g, 3.92 mmol) in DCM (10 mL). The reaction mixture was

stirred for 20 h and subsequently quenched by addition of water.

The mixture was concentrated and purified by silica gel column

chromatography (0% Ǟ 20% EtOAc in toluene) to produce 61

(976 mg, 1.73 mmol) in 88% yield as a colourless oil.^[45]R_f= 0.60

1

(EtOAc/PE, 1:4). H NMR (400 MHz, CDCl₃): δ = 7.40–7.08 (m,

17 H, H_ArBn/PMB), 6.78 (d, J = 8.7 Hz, 2 H, H_ArPMB), 5.92–

5.79 (m, 1 H, =CH propenyl), 5.14–4.37 (m, 8 H, =CH₂propenyl,

ppm. IR (thin film): ν

= 3032, 2900, 2848, 1698, 1453, 1403,

˜

max.

1360, 1302, 1209, 1069, 1026, 734, 695 cm^–1. [α]²_D⁰= –6.0 (c = 0.6,

3ϫ CH₂Bn), 3.73–3.46 (m, 8 H, 2-H, 3-H, 4-H, OMe PMB, CH₂CHCl₃). HRMS: found 876.4840 [M + H]⁺, calcd. for [C₅₇H₆₅NO₇

PMB), 3.13 (dt, J = 4.9, 7.6 Hz, 1 H, 1-H), 2.78 (dd, J = 5.2, + H]⁺876.4834.

12.3 Hz, 1 H, 5a-H), 2.53 (dd, J = 10.5, 11.9 Hz, 1 H, 5b-H), 2.49–

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4,6-

2.32 (m, 2 H, CH₂propenyl) ppm. ¹³C NMR (100 MHz, CDCl₃):

tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin

δ = 158.6 (p-C_qPMB), 139.2, 138.6, 138.5 (3ϫ C_qBn), 138.2 (=CH

propenyl), 131.0 (C_qPMB), 129.2, 128.1, 128.0, 127.7, 127.6, 127.5,

127.3, 127.2 (CH_ArBn/PMB), 115.3 (=CH₂propenyl), 113.5 (CH_Ar

PMB), 82.6, 80.3, 78.2 (C2, C-3, C-4), 75.2, 72.5, 72.2 (3ϫ CH₂

Bn), 59.5 (C-2), 58.0 (CH₂PMB), 54.8 (OMe PMB), 47.7 (C-5),

(64): Compound 55 (275 mg, 395 µmol) underwent a cross-metath-

esis reaction (see general procedure F) with alkene 46 to produce

64 (260 mg, 292 µmol) in 74% yield as a mixture of (E)/(Z) isomers

in an unassignable ca. 2:1 ratio after purification (0% Ǟ 10%

EtOAc in PE). R_f= 0.50 (EtOAc/PE, 1:5). ¹H NMR [400 MHz,

CDCl₃, (E)/(Z) isomers]: δ = 7.48–7.14 (m, 25 H, H_ArBn Z H H),

5.87–5.23 (m, 2 H, =CH-2 pentenyl, =CH-3 pentenyl), 5.23–4.92

(m, 3 H, 5-H, CH₂Z), 4.92–4.36 (m, 9 H, 1-H, 4ϫ CH₂B), 3.97–

3.44 (m, 5 H, 2-H, 3-H, 4-H, CH₂-6), 3.40–3.17 (m, 2 H, CH₂-5

27.6 (CH propenyl) ppm. IR (thin film): ν_max.= 3031, 2904, 1610,

˜

2

1512, 1455, 1364, 1244, 1069, 1029, 908, 822, 734, 696 cm^–1. [α]²_D⁰

= 27.1 (c = 2.8, CHCl₃). HRMS: found 564.3103 [M + H]⁺, calcd.

for [C₃₇H₄₁NO₄+ H]⁺544.3108.

(1R)-2,3,4-Tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5- pentenyl), 2.99–2.86 (m, 2 H, OCH₂-Ada), 2.77–2.47 (m, 1 H,

imino-1-C-(prop-2-enyl)- -xylitol (62): Compound 61 (1.42 g, CHH-1 pentenyl), 2.40–2.09 (m, 3 H, CHH-1 pentenyl, CH₂-4 pen-

D

2.52 mmol) was subjected to general procedure E to provide 62

(1.27 g, 2.20 mmol) in 87% yield as a colourless oil after purifica-

tion (0% Ǟ 5% EtOAc in toluene). R_f(intermediate amine) = 0.11

(EtOAc/PE, 1:1 + 2% Et₃N); R_f(62) = 0.50 (EtOAc/PE, 1:4). ¹H

tenyl), 2.09–1.87 (m, 3 H, 3ϫ CH Ada), 1.81–1.43 (m, 12 H, 6ϫ

CH₂Ada) ppm. ¹³C NMR [100 MHz, CDCl₃, (E)/(Z) isomers]: δ

= 156.4 (C=O Z), 138.9, 138.5, 138.2, 138.1 (C_qBn), 136.6 (C_q

Z), 131.2, 130.9 [=CH (E)/(Z) pentenyl], 128.5, 128.4, 128.3, 128.1,

1276

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

128.07, 128.03, 127.99, 127.92, 127.7, 127.6, 127.3 (CH_ArBn Z), 1453, 1403, 1302, 1209, 1069, 1026, 734, 695 cm^–1. [α]²_D⁰= 6.5 (c =

126.9, 126.7, 125.6 [=CH (E)/(Z) pentenyl], 81.9 (OCH₂-Ada), 80.1,

79.5, 79.4, 79.2, 78.9, 78.8, 78.7, 78.6 (C-2, C-3, C-4), 75.8, 75.7,

73.9, 73.4, 73.1, 72.9, 72.5, 72.2, 72.0, 71.9, 71.4 (CH₂Bn, CH₂-5

pentenyl), 69.1 (C-6), 67.7 (CH₂Z), 54.6, 53.9, 53.6, 53.2, 52.5 (C-

1, C-5), 39.8, 39.6, 39.1 (CH₂Ada), 37.3, 37.2, 37.2 (CH₂Ada),

34.5, 34.1, 33.7 (C_qAda), 32.7 (CH₂-1 pentenyl), 28.4, 28.2, 28.1

2.8, CHCl₃). HRMS: found 876.4840 [M + H]⁺, calcd. for

[C₅₇H₆₅NO₇+ H]⁺876.4834.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4,6-

tetra-O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (67):

Compound 56 (275 mg, 395 µmol) underwent a cross-metathesis

reaction (see general procedure F) with alkene 46 to produce 67

(289 mg, 325 µmol) in 82% yield as a 2.5:1 mixture of (E)/(Z) iso-

mers after purification (0 % Ǟ 10 % EtOAc in PE). R_f= 0.53

(EtOAc/PE, 1:5). ¹H NMR [400 MHz, CDCl₃, (E) isomer]: δ =

7.47–7.15 (m, 25 H, H_ArBn Z), 5.55–5.29 (m, 2 H, =CH-2 pen-

tenyl, =CH-3 pentenyl), 5.19–5.07 (m, 2 H, CH₂Z), 4.74–4.39 (m,

8 H, 4ϫ CH₂Bn), 4.39–4.27 (m, 1 H, 1-H), 4.27–4.16 (m, 1 H, 5-

H), 3.99–3.91 (m, 1 H, 4-H), 3.88–3.76 (m, 1 H, 3-H), 3.73 (dd, J

= 5.5, 9.0 Hz, 1 H, 2-H), 3.71–3.50 (m, 2 H, CH₂-6), 3.26 (t, J =

7.1 Hz, 2 H, CH₂-5 pentenyl), 2.90 (s, 2 H, OCH₂-Ada), 2.62–2.48

(m, 2 H, CH₂-1 pentenyl), 2.29–2.09 (m, 2 H, CH₂-4 pentenyl),

1.93 (s, 3 H, 3ϫ CH Ada), 1.77–1.45 (m, 12 H, 6ϫ CH₂Ada)

ppm. ¹³C NMR [100 MHz, CDCl₃, (E) isomer]: δ = 156.2 (C=O

Z), 138.5 (C_qBn), 129.8, 129.5, 129.0, 128.78, 128.74, 128.6, 128.59,

128.54, 128.47, 128.44, 128.3, 128.2, 128.0, 127.9, 127.85, 127.82,

127.7, 127.5, 127.1 [=CH-2, =CH-3 (E)/(Z) pentenyl, CH_ArBn Z],

82.1 (OCH₂-Ada), 81.8 (C-3), 80.8 (C-2), 77.3 (C-4), 73.1, 72.7,

72.4, 71.9, 71.7 (CH₂Bn, CH₂-5 pentenyl), 70.1 (C-6), 67.4 (CH₂

Z), 54.7 (C-5), 53.0 (C-1), 39.9 (CH₂Ada), 37.5 (CH₂Ada), 34.3

(C_qAda), 33.2 (CH₂-1 pentenyl), 28.5 (CH Ada), 28.0 (CH₂-4 pen-

(CH Ada, CH -4 pentenyl) ppm. IR (thin film): ν_max.= 2902, 2849,

˜

2

1698, 1453, 1416, 1271, 1093, 1026, 734, 695 cm^–1. [α]²_D⁰= –7.8 (c

= 1.0, CHCl₃). HRMS: found 890.4996 [M + H]⁺, calcd. for

[C₅₈H₆₇NO₇+ H]⁺890.4990.

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4,6-tetra-

O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxy-L-ido-nojirimycin (65):

Compound 55 (275 mg, 395 µmol) underwent a cross-metathesis

reaction (see general procedure F) with alkene 47 to produce 65

(312 mg, 345 µmol) in 87% yield as a mixture of (E)/(Z) isomers

in an unassignable ca. 2:1 ratio after purification (0% Ǟ 10%

EtOAc in PE). R_f= 0.52 (EtOAc/PE, 1:5). ¹H NMR [400 MHz,

CDCl₃, (E)/(Z) isomers]: δ = 7.45–7.14 (m, 25 H, H_ArBn Z H),

5.58–5.24 (m, 2 H, =CH-2 hexenyl, =CH-3 hexenyl), 5.23–4.98 (m,

3 H, 5-H, CH₂Z), 4.94–4.37 (m, 9 H, 1-H, 4ϫ CH₂Bn), 3.95–3.45

(m, 5 H, 2-H, 3-H, 4-H, CH₂-6), 3.38–3.26 (m, 2 H, CH₂-6 hex-

enyl), 2.93 (s, 2 H, OCH₂-Ada), 2.79–2.51 (m, 1 H, CHH-1 hex-

enyl), 2.32–2.18 (m, 1 H, CHH-1 hexenyl), 2.09–1.80 (m, 5 H, CH₂-

4 hexenyl, 3ϫ CH Ada), 1.77–1.40 (m, 16 H, CH₂-5 hexenyl, 6ϫ

CH₂Ada) ppm. ¹³C NMR [100 MHz, CDCl₃, (E)/(Z) isomers]: δ

= 156.5 (C=O Z), 139.0, 138.5, 138.4, 138.3, 137.9 (C_qBn), 136.8,

136.6 (C_qZ), 132.4, 132.3, 130.9 [=CH (E)/(Z) hexenyl], 128.6,

128.5, 128.4, 128.3, 128.2, 128.2, 128.1, 127.9, 127.8, 127.7, 127.5,

127.4 [=CH (E)/(Z) hexenyl, CH_ArBn Z], 127.1, 127.0 [=CH

(E)/(Z) hexenyl], 82.0 (OCH₂-Ada), 80.3, 80.2 (C-2), 79.5 (C-4),

78.7, 78.7 (C-3), 75.9, 75.8, 73.6, 73.4, 73.3, 73.1 (CH₂Bn), 71.3,

71.2, 71.1 (CH₂-6 hexenyl), 69.9, 69.7 (C-6), 67.8, 67.7 (CH₂Z),

55.5, 54.3, 53.8, 53.4, 53.2, 52.7 (C-1, C-5), 39.9 (CH₂Ada), 37.4

(CH₂Ada), 34.3 (C_qAda), 33.2, 32.8 (CH₂-1 hexenyl), 29.6, 29.3

(CH₂hexenyl), 28.5 (CH Ada), 27.6, 27.2 (CH₂hexenyl), 24.3, 24.2

tenyl) ppm. IR (thin film): ν

= 2902, 2849, 1698, 1453, 1404,

˜

max.

1268, 1090, 1069, 1026, 734, 695 cm^–1. [α]²_D⁰= 3.4 (c = 1.1, CHCl₃).

HRMS: found 890.4996 [M + H]⁺, calcd. for [C₅₈H₆₇NO₇+ H]⁺

890.4990.

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4,6-tetra-

O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (68): Com-

pound 56 (275 mg, 395 µmol) underwent a cross-metathesis reac-

tion (see general procedure F) with alkene 47 to produce 68

(305 mg, 338 µmol) in 85% yield as a 2:1 mixture of (E)/(Z) isomers

after purification (0% Ǟ 10% EtOAc in PE). R_f= 0.55 (EtOAc/

(CH hexenyl) ppm. IR (thin film): ν

= 3031, 2901, 2848, 1698,

˜

2

max.

1

1453, 1416, 1364, 1273, 1094, 1026, 734, 695 cm^–1. [α]²_D⁰= –10.5 (c

= 2.0, CHCl₃). HRMS: found 904.5153 [M + H]⁺, calcd. for

[C₅₉H₆₉NO₇+ H]⁺904.5147.

PE, 1:5). H NMR [400 MHz, CDCl₃, (E) isomer]: δ = 7.41–7.12

(m, 25 H, H_ArBn Z H), 5.52–5.27 (m, 2 H, =CH-2 hexenyl, =CH-

3 hexenyl), 5.16–5.06 (m, 2 H, CH₂Z), 4.68–4.38 (m, 8 H, 4ϫ CH₂

Bn), 4.38–4.28 (m, 1 H, 1-H), 4.24–4.14 (m, 1 H, 5-H), 3.98–3.91

(m, 1 H, 4-H), 3.90–3.83 (m, 1 H, 3-H), 3.77–3.69 (m, 1 H, 2-H),

3.69–3.50 (m, 2 H, CH₂-6), 3.36–3.21 (m, 2 H, CH₂-6 hexenyl),

2.97–2.87 (m, 2 H, OCH₂-Ada), 2.61–2.39 (m, 2 H, CH₂-1 hexenyl),

2.07–1.88 (m, 5 H, CH₂-4 hexenyl, 3ϫ CH Ada), 1.77–1.45 (m, 14

H, CH₂-5 hexenyl, 6 ϫ CH₂Ada) ppm. ¹³C NMR [100 MHz,

CDCl₃, (E) isomer]: δ = 156.1 (C=O Z), 138.5, 138.5, 138.4, 138.1

(C_qBn), 136.7 (C_qZ), 131.9 [=CH-3 (E) hexenyl], 130.5 [=CH-3

(Z) hexenyl], 128.78, 128.72, 128.54, 128.52, 128.4, 128.36, 128.32,

128.29, 128.24, 128.06, 128.02, 127.97, 127.95, 127.7, 127.68,

127.64, 127.4 [=CH-2 (E)/(Z) hexenyl, CH_ArBn Z], 82.0 (OCH₂-

Ada), 81.8 (C-3), 80.8 (C-2), 77.4 (C-4), 73.1, 72.8, 72.4, 72.0, 71.3

(CH₂Bn, CH₂-6 hexenyl), 70.0 (C-6), 67.4 (CH₂Z), 54.7 (C-5),

53.4 (C-1), 39.9 (CH₂Ada), 37.5 (CH₂Ada), 34.3 (C_qAda), 32.8

(CH₂-1 hexenyl), 29.3 (CH₂-5 hexenyl), 28.5 (CH Ada), 23.9 (CH₂-

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4,6-tetra-

O-benzyl-N-[(benzyloxy)carbonyl]-1-deoxynojirimycin (66): Com-

pound 56 (275 mg, 395 µmol) underwent a cross-metathesis reac-

tion (see general procedure F) with alkene 45 to produce 66

(303 mg, 346 µmol) in 87% yield as a 3.3:1 mixture of (E)/(Z) iso-

mers after purification (0 % Ǟ 10 % EtOAc in PE). R_f= 0.51

(EtOAc/PE, 1:5). ¹H NMR [400 MHz, CDCl₃, (E) isomer]: δ =

7.45–7.19 (m, 25 H, H_ArBn Z), 5.74–5.40 (m, 2 H, =CH-2 butenyl,

=CH-3 butenyl), 5.21–5.06 (m, 2 H, CH₂Z), 4.72–4.38 (m, 8 H,

4ϫ CH₂Bn), 4.33 (s, 1 H, 1-H), 4.22 (s, 1 H, 5-H), 4.00–3.70 (m,

5 H, 2-H, 3-H, 4-H, CH₂-4 butenyl), 3.68–3.51 (m, 2 H, CH₂-6),

2.89 (s, 2 H, OCH₂-Ada), 2.66–2.47 (m, 2 H, CH₂-1 butenyl), 1.93

(s, 3 H, 3ϫ CH Ada), 1.73–1.45 (m, 12 H, 6ϫ CH₂Ada) ppm.

¹³C NMR [100 MHz, CDCl₃, (E) isomer]: δ = 156.0 (C=O Z),

138.5, 138.4, 138.4, 138.0 (4ϫ C_qBn), 136.7 (C_qZ), 131.4 [=CH-

2 (E) isomer butenyl], 130.3 [=CH-2 (Z) isomer butenyl], 128.8,

128.77, 128.74, 128.69, 128.64, 128.58, 128.52, 128.51, 128.36,

128.33, 128.28, 128.24, 128.05, 128.02, 127.9, 127.8, 127.6, 127.4

[=CH-3 (E)/(Z) butenyl, CH_ArBn Z], 81.6 (C-3), 81.2 (OCH₂-Ada),

80.8 (C-2), 77.2 (C-4), 73.1, 72.7, 72.4, 72.3, 71.8 (CH₂Bn, CH₂-4

4 hexenyl) ppm. IR (thin film): ν

= 3031, 2901, 2848, 1698,

˜

max.

1453, 1403, 1361, 1267, 1210, 1089, 1070, 1026, 734, 695 cm^–1

.

[α]²_D⁰= 4.8 (c = 2.8, CHCl₃). HRMS: found 904.5152 [M + H]⁺,

calcd. for [C₅₉H₆₉NO₇+ H]⁺904.5147.

(1R)-1-C-[(E/Z)-4-(Adamant-1-ylmethoxy)but-2-enyl]-2,3,4-tri-O-

butenyl), 70.0 (C-6), 67.4 (CH₂Z), 54.7 (C-5), 53.1 (C-1), 39.9 (CH₂benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino-

Ada), 37.4 (CH₂Ada), 34.2 (C_qAda), 32.8 (CH₂-1 butenyl), 28.5 (69): Compound 62 (200 mg, 346 µmol) underwent a cross-metath-

esis reaction (see general procedure F) with alkene 45 to produce

D-xylitol

(CH Ada) ppm. IR (thin film): ν

= 3032, 2900, 2848, 1698,

˜

max.

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1277

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

69 (170 mg, 225 µmol) in 65% yield as a 5:1 mixture of (E)/(Z) 4^a/b(E)/(Z) pentenyl], 28.6, 28.5, 28.2 [CH₂-1^a/b(E)/(Z) pentenyl],

isomers after purification (0% Ǟ 10% EtOAc in PE). R_f= 0.51

28.4 (CH^a/bAda), 23.2 [CH₂-1^a/b(E)/(Z) pentenyl]. IR (thin film)

(EtOAc/PE, 1:4). ¹H NMR [500 MHz, CDCl₃, (E) isomer rota-

ppm. ν_max.= 2901, 2848, 1700, 1453, 1423, 1360, 1314, 1237, 1198,

˜

a/b

mers, a/b ≈ 1:1]: δ = 7.39–7.21 (m, 40 H, H_ArBn Z), 5.61–5.51

1158, 1098, 970, 734, 696 cm^–1. [α]²_D⁰

=

–11.6 (c

=

1.7,

(m, 3 H, =CH-3^a/bbutenyl, =CH-2^abutenyl), 5.49–5.39 (m, 1 H, CHCl₃).HRMS: found 770.4416 [M + H]⁺, calcd. for [C₅₀H₅₉NO₆

=CH-2^bbutenyl), 5.16–5.02 (m, 4 H, CH₂^a/bZ), 4.91–4.81 (m, 4 H, + H]⁺770.4415.

a/b

CH₂Bn), δ = 4.75–4.57 (m, 9 H, 2ϫ CH₂Bn, 1^a-H), 4.48–

4.38 (m, 2 H, 1^b-H, CHH-5^a), 4.16 (dd, J = 5.7, 13.6 Hz, 1 H,

CHH-5^a), 4.00–3.71 (m, 4 H, CH₂-4^a/bbutenyl), 3.68 (dd, J = 9.2,

9.4 Hz, 2 H, 3^a/b-H), 3.56 (dd, J = 5.9, 9.4 Hz, 1 H, 2^a-H), 3.53–

3.35 (m, 3 H, 2^b-H, 4^a/b-H), 2.98–2.85 (m, 4 H, OCH₂-Ada^a/b),

2.79–2.69 (m, 2 H, CH₂-5^b), 2.63–2.51 (m, 2 H, CHH-1^a/bbutenyl),

2.36–2.26 (m, 2 H, CHH-1^a/bbutenyl), 1.94 (s, 6 H, 6 ϫ CH

Ada^a/b) 1.67 (dd, J = 11.7, 30.7 Hz, 12 H, 6ϫ CH₂Ada^a/b), 1.51

(s, 12 H, 6ϫ CH₂Ada^a/b) ppm. ¹³C NMR [125 MHz, CDCl₃, (E)

isomer rotamers, a/b ≈ 1:1]: δ = 155.5, 155.5 (C=O^a/bZ), 138.9,

(1R)-1-C-[(E/Z)-6-(Adamant-1-ylmethoxy)hex-2-enyl]-2,3,4-tri-O-

benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino- -xylitol

D

(71): Compound 62 (200 mg, 346 µmol) underwent a cross-metath-

esis reaction (see general procedure F) with alkene 47 to produce

71 (222 mg, 280 µmol) in 82% yield as a 3:1 mixture of (E)/(Z)

isomers after purification (0% Ǟ 10% EtOAc in PE). R_f= 0.55

1

(EtOAc/PE, 1:4). H NMR [500 MHz, CDCl₃, (E)/(Z) isomers, Z

a/b

rotamers, a/b ≈ 1:1]: δ = 7.39–7.19 (m, 40 H, H_ArBn/Z), 5.52–

5.39 (m, 2 H, =CH-3^a/bhexenyl), 5.37–5.29 (m, 1 H, =CH-2^ahex-

enyl), 5.25–5.18 (m, 1 H, =CH-2^bhexenyl), 5.15–5.01 (m, 4 H,

a/b

138.3, 138.2, 138.1, 138.0 (3ϫ C_qBn), 136.7, 136.6 (C_qZ),

130.3, 130.1 (=CH-3^a/bbutenyl), 128.9 (=CH-2^abutenyl), 128.65,

128.62, 128.57, 128.55, 128.52, 128.4, 128.27, 128.23, 128.06,

a/b

CH₂Z), 4.90–4.80 (m, 4 H, CH₂Bn), 4.73–4.59 (m, 9 H, 2ϫ

a/b

CH₂Bn, 1^a-H), 4.45–4.36 (m, 2 H, 1^b-H, CHH-5^a), 4.20–4.13

(m, 1 H, CHH-5^a), 3.71–3.65 (m, 2 H, 3^a/b-H), 3.59–3.53 (m, 1 H,

2^a-H), 3.53–3.43 (m, 2 H, 2^b-H, 4^a-H), 3.43–3.37 (m, 1 H, 4^b-H),

3.36–3.29 (m, 4 H, CH₂-6^a/bhexenyl), 2.97–2.92 (m, 4 H, OCH₂-

Ada^a/b), 2.79–2.70 (m, 2 H, CH₂-5^b), 2.57–1.93 (m, 14 H, CH₂-

1^a/b, CH₂-4^a/bhexenyl, 6ϫ CH Ada^a/b), 1.74–1.48 (m, 28 H, CH₂-

5^a/bhexenyl, 12ϫ CH₂Ada^a/b) ppm. ¹³C NMR [125 MHz, CDCl₃,

(E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ = 155.7, 155.6, 155.57,

155.55 [C=O^a/b(E)/(Z) Z], 139.0, 138.9, 138.3, 138.28, 138.23,

138.21, 138.20 [3ϫ C_q^a/b(E)/(Z) Bn], 136.75, 136.72, 136.66, 136.63

a/b

128.02, 127.98, 127.96 (=CH-2^bbutenyl, CH_ArBn/Z), 82.1, 82.0

(C-3^a/b), 81.1, 81.0 (OCH₂-Ada^a/b), 79.7 (C-2^a/b), 78.3, 78.2

(C-4^a/b), 75.8, 75.8, 73.3, 73.2, 72.8 (CH₂

Bn), 71.8, 71.7

a/b

(CH₂-4^a/bbutenyl), 67.5, 67.5 (CH₂Z), 53.1, 52.3 (C-1^a/b), 41.1,

a/b

40.8 (C-5^a/b), 39.8 (CH₂Ada), 37.3 (CH₂Ada), 34.1, 34.1

Ada), 28.3, 28.2 (CH-1^a/bbutenyl). IR

a/b

(C_qAda), 28.4 (CH

(thin film): ν_max.= 2901, 2848, 1700, 1452, 1423, 1352, 1314, 1238,

˜

1199, 1158, 1097, 970, 734, 696 cm^–1. [α]²_D⁰= –7.8 (c = 1.6, CHCl₃).

HRMS: found 778.4076 [M + Na]⁺, calcd. for [C₄₉H₅₇NO₆

Na]⁺778.4078.

+

[C_q(E)/(Z) Z], 133.3, 133.0 [=CH-3^a/b(E) hexenyl], 132.1, 131.9

a/b

[=CH-3^a/b(Z) hexenyl], 128.68, 128.63, 128.59, 128.55, 128.4,

128.2, 128.06, 128.02, 128.01, 127.97, 127.95, 127.93, 127.92,

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-2,3,4-tri-O-

benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-imino- -xylitol

a/b

127.87, 127.85, 127.6 [H_Ar(E)/(Z) Bn Z], 125.9, 125.7 [=CH-

D

2^a/b(E) hexenyl], 125.6, 125.4 [=CH-2^a/b(Z) hexenyl], 82.4, 82.26,

82.25 [C-3^a/b(E)/(Z)], 82.1, 82.05, 82.03 [OCH₂-Ada^a/b(E)/(Z)],

79.9, 79.8 [C-2^a/b(E)/(Z)], 78.4, 78.3, 78.2 [C-4^a/b(E)/(Z)], 75.9,

(70): Compound 62 (200 mg, 346 µmol) underwent a cross-metath-

esis reaction (see general procedure F) with alkene 46 to produce

70 (190 mg, 247 µmol) in 71% yield as a 2:1 mixture of (E)/(Z)

isomers after purification (0% Ǟ 10% EtOAc in PE). R_f= 0.53

a/b

75.84, 75.83, 75.82, 73.34, 73.33, 73.2, 73.1, 72.9, 72.7 [CH₂

(E)/(Z) Bn], 71.03, 71.01, 70.8 [CH₂-6^a/b(E)/(Z) hexenyl], 67.54,

1

(EtOAc/PE, 1:4). H NMR [500 MHz, CDCl₃, (E)/(Z) isomers, Z

67.51, 67.50, 67.4 [CH₂(E)/(Z) Z], 53.6, 53.3, 53.0, 52.4 [C-1^a/b

a/b

rotamers, a/b ≈ 1:1]: δ = 7.38–7.21 (m, 40 H, H_ArBn Z), 5.53–

a/b

(E)/(Z)], 41.1, 41.1, 40.9, 40.8 [C-5^a/b(E)/(Z)], 39.9 [CH₂(E)/(Z)

5.42 (m, 2 H, =CH-3^a/bpentenyl), 5.42–5.34 (m, 1 H, =CH-2^apen-

tenyl), 5.28–5.20 (m, 1 H, =CH-2^bpentenyl), 5.17–4.99 (m, 4 H,

a/b

Ada], 37.4, 37.4 [CH₂(E)/(Z) Ada], 34.2 [C_q(E)/(Z) Ada],

a/b

29.6, 29.54, 29.51, 29.3, 29.2, 28.9, 28.52, 28.51 [CH₂(E)/(Z)

a/b

CH₂Z), 4.91–4.80 (m, 4 H, CH₂Bn), 4.76–4.60 (m, 9 H, 2ϫ

hexenyl], 28.42, 28.41 (CH^a/bAda), 24.21, 24.20, 23.0, 22.9

CH₂Bn, 1^a-H), 4.45–4.36 (m, 2 H, 1^b-H, CHH-5^a), 4.22–4.13

a/b

[CH₂(E)/(Z) hexenyl] ppm. IR (thin film): ν

= 2901, 2848,

˜

(m, 1 H, CHH-5^a), 3.73–3.64 (m, 2 H, 3^a/b-H), 3.56 (dd, J = 5.9,

9.4 Hz, 1 H, 2^a-H), 3.53–3.25 (m, 7 H, 2^b-H, 4^a/b-H, CH₂-5^a/bpen-

tenyl), 2.98–2.88 (m, 4 H, OCH₂-Ada^a/b), 2.77–2.70 (m, 2 H, CH₂-

5^b), 2.59–2.10 (m, 8 H, CH₂-1^a/b, CH₂-4^a/bpentenyl), 1.95 (s, 6 H,

6 ϫ CH Ada^a/b), 1.67 (dd, J = 11.7, 29.8 Hz, 12 H, 6 ϫ CH₂

Ada^a/b), 1.56–1.50 (m, 12 H, 6ϫ CH₂Ada^a/b) ppm. ¹³C NMR

[125 MHz, CDCl₃, (E)/(Z) isomers, Z rotamers, a/b ≈ 1:1]: δ =

155.63, 155.61, 155.57, 155.53 [C=O^a/b(E)/(Z) Z], 138.9, 138.3,

max.

1700, 1452, 1423, 1360, 1314, 1239, 1206, 1157, 1098, 969, 734,

696 cm^–1. [α]²_D⁰= –10.4 (c = 2.0, CHCl₃). HRMS: found 784.4572

[M + H]⁺, calcd. for [C₅₁H₆₁NO₆+ H]⁺784.4572.

(1R)-2,3,4-Tri-O-benzyl-N-[(benzyloxy)carbonyl]-1,5-dideoxy-1,5-

imino-1-C-[(E/Z)-non-2-enyl]-D-xylitol (72): Compound 62 (200 mg,

346 µmol) underwent a cross-metathesis reaction (see general pro-

cedure F) with oct-1-ene to produce 72 (197 mg, 297 µmol) in 86%

yield as a 5:1 mixture of (E)/(Z) isomers after purification (0% Ǟ

a/b

138.27, 138.25, 138.23, 138.21 [3 ϫ C_q(E)/(Z) Bn], 136.76,

136.72, 136.68, 136.61 [C_q(E)/(Z) Z] 130.1, 129.8 [=CH-3^a/b(E) 10 % EtOAc in PE). R_f= 0.61 (EtOAc/PE, 1:4). ¹H NMR

a/b

pentenyl], 128.8, 128.7, 128.66, 128.62, 128.61, 128.5, 128.4, 128.26, [500 MHz, CDCl₃, (E) isomer rotamers, a/b ≈ 1:1]: δ = 7.41–7.03

a/b

128.22, 128.06, 128.05, 128.02, 127.98, 127.95, 127.93, 127.8, 127.7

(m, 40 H, H_ArBn Z), 5.39–5.30 (m, 2 H, =CH-3^a/bnonenyl),

[=CH-3^a/b(Z) pentenyl, CH_Ar^a/b(E)/(Z) Bn Z], 127.4, 127.3 [=CH- 5.24–5.17 (m, 1 H, =CH-2^anonenyl), 5.13–5.06 (m, 1 H, =CH-2^b

2^a/b(E) pentenyl], 126.8, 126.7 [=CH-2^a/b(Z) pentenyl], 82.3, 82.2,

nonenyl), 5.06–4.93 (m, 4 H, CH₂

Z), 4.82–4.72 (m, 4 H,

a/b

82.14, 82.11 [C-3^a/b(E)/(Z)], 82.1, 82.07, 82.0, 82.02 [OCH₂- CH₂Bn), 4.65–4.50 (m, 9 H, 2ϫ CH₂Bn, 1^a-H), 4.35–4.27

Ada^a/b(E)/(Z)], 79.95, 79.92, 79.85, 79.82 [C-2^a/b(E)/(Z)], 78.4,

(m, 2 H, 1^b-H, CHH-5^a), 4.07 (dd, J = 5.7, 13.7 Hz, 1 H, CHH-

5^a), 3.63–3.55 (m, 2 H, 3^a/b-H), 3.47 (dd, J = 5.9, 9.5 Hz, 1 H, 2^a-

78.38, 78.33 [C-4^a/b(E)/(Z)], 75.96, 75.94, 75.87, 75.82, 73.37,

a/b

73.34, 73.22, 73.20, 73.1, 72.9, 72.7 [CH₂(E)/(Z) Bn], 71.6, 71.4, H), 3.44–3.36 (m, 2 H, 2^b-H, 4^a-H), 3.32 (ddd, J = 5.9, 8.8, 11.2 Hz,

71.2, 71.1 [CH₂-5^a/b(E)/(Z) pentenyl], 67.6, 67.59, 67.54, 67.4

1 H, 4^b-H), 2.68–2.62 (m, 2 H, CH₂-5^b), 2.50–2.34 (m, 2 H, CHH-

1^a/bnonenyl), 2.19–2.09 (m, 2 H, CHH-1^a/bnonenyl), 1.87–1.74 (m,

[CH₂(E)/(Z) Z], 53.5, 53.2, 53.0, 52.9 [C-1^a/b(E)/(Z)], 41.15,

a/b

41.12, 40.9, 40.8 [C-5^a/b(E)/(Z)], 39.9 [CH₂(E)/(Z) Ada], 37.4

4 H, CH₂-4^a/bnonenyl), 1.29–1.11 (m, 16 H, 4ϫ CH₂nonenyl),

a/b

[CH₂(E)/(Z) Ada], 34.2 [C_q(E)/(Z) Ada], 33.1, 33.0 [CH₂-

1278

0.83–0.75 (m, 6 H, CH₃-9^a/bnonenyl) ppm. ¹³C NMR [125 MHz,

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

CDCl₃, (E) isomer rotamers, a/b ≈ 1:1]: δ = 155.8, 155.6 (C=O^a/bgenolysis at 4 bar H₂(see general procedure H) to furnish 75

a/b

Z), 139.0, 138.4, 138.33, 138.31, 138.2 (3ϫ C_qBn), 136.8, 136.7

(51 mg, 124 µmol) as a colourless oil in 73% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

(C_qZ), 134.0, 133.7 (=CH-3^a/bnonenyl), 128.7, 128.67, 128.62,

a/b

128.61, 128.5, 128.2, 128.16, 128.12, 128.07, 128.03, 128.02, 127.96, ditional HPLC purification was required for removal of minor 5–

a/b

127.92, 127.7 (CH_ArBn/Z), 125.5, 125.3 (=CH-2^a/bnonenyl),

82.3, 82.1 (C-3^a/b), 80.0 (C-2^a/b), 78.5, 78.4 (C-4^a/b), 75.9, 75.9, 73.4,

73.3, 73.2, 72.8 (CH₂^a/bBn), 67.54, 67.53 (CH₂^a/bZ), 53.3, 52.5 (C-

10% impurities (1 min: isocratic 10% B Ǟ 12 min: 100% B Ǟ

12 min: 100% B, 15 min: isocratic 100% B; t_R= 7.8 min). R_f= 0.53

(MeOH/CHCl₃, 1:3 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD):

1^a/b), 41.1, 40.8 (C-5^a/b), 32.8, 32.7 (CH₂-4^a/bnonenyl), 31.9 δ = 4.02 (dd, J = 3.5 Hz, 1 H, 3-H), 3.92–3.90 (m, 1 H, 4-H), 3.90–

a/b

(CH₂nonenyl), 29.6, 29.5 (CH₂nonenyl), 29.1, 29.0 (CH₂

nonenyl), 28.6, 28.5 (CH₂-1^a/bnonenyl), 22.8 (CH₂^a/bnonenyl), 14.3

(CH -9 nonenyl) ppm. IR (thin film): ν = 2926, 2855, 1700,

3.87 (m, 1 H, 2-H), 3.86–3.80 (m, 2 H, CH₂-6), 3.53–3.49 (m, 1 H,

5-H), 3.43–3.37 (m, 3 H, 1-H, CH₂-6 hexyl), 2.97 (s, 2 H, OCH₂-

Ada), 1.99–1.91 (m, 4 H, CHH-1 hexyl, 3ϫ CH Ada), 1.79–1.65

(m, 7 H, CHH-1 hexyl, 3ϫ CH₂Ada), 1.60–1.54 (m, 8 H, CH₂-5

hexyl, 3ϫ CH₂Ada), 1.51–1.31 (m, 6 H, 3ϫ CH₂hexyl) ppm.

¹³C NMR (150 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 72.7 (CH₂-

6 hexyl), 69.2 (C-4), 69.0 (C-2), 68.2 (C-3), 60.6 (C-6), 58.8 (C-5),

57.0 (C-1), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.7

(CH₂-5 hexyl), 30.5 (CH₂hexyl), 29.9 (CH Ada), 29.0 (CH₂-1

hexyl), 27.3 (CH₂hexyl), 26.1 (CH₂hexyl) ppm. IR (thin film):

˜

3

max.

1454, 1423, 1359, 1313, 1203, 1096, 968, 734, 696 cm^–1. [α]²_D⁰

=

–11.9 (c = 1.7, CHCl₃). HRMS: found 662.3839 [M + H]⁺, calcd.

for [C₄₃H₅₁NO₅+ H]⁺662.3840.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxy-L-ido-nojirimy-

cin (73): Compound 63 (141 mg, 161 µmol) was subjected to hydro-

genolysis at 4 bar H₂(see general procedure H) to furnish 73

(33 mg, 86 µmol) as a colourless oil in 53% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

ditional HPLC purification was required for removal of minor 5–

10% impurities (1 min: isocratic 25% B Ǟ 11.5 min: 45% B Ǟ

12.5 min: 100% B, 15 min: isocratic 100% B; t_R= 9.0 min). R_f=

0.49 (MeOH/CHCl₃, 1:3 + 2 % NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 4.02 (dd, J = 3.5, 3.5 Hz, 1 H, 3-H), 3.93–3.90 (m, 1

H, 4-H), 3.90–3.88 (m, 1 H, 2-H), 3.87–3.81 (m, 2 H, CH₂-6), 3.54–

3.50 (m, 1 H, 5-H), 3.44–3.39 (m, 3 H, 1-H, CH₂-4 butyl), 2.98 (s,

2 H, OCH₂-Ada), 2.00–1.92 (m, 4 H, CHH-1 butyl, 3ϫ CH Ada),

1.79–1.66 (m, 7 H, CHH-1 butyl, 3ϫ CH₂Ada), 1.66–1.58 (m, 2

H, CH₂-3 butyl), 1.58–1.50 (m, 7 H, 3ϫ CH₂Ada, CHH-2 butyl),

1.46–1.38 (m, 1 H, CHH-2 butyl) ppm. ¹³C NMR (150 MHz,

MeOD): δ = 83.3 (OCH₂-Ada), 72.3 (CH₂-4 butyl), 69.2 (C-4), 69.0

(C-2), 68.2 (C-3), 60.6 (C-6), 58.8 (C-5), 56.9 (C-5), 41.0 (CH₂

Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.6 (CH₂-3 butyl), 29.9

(CH Ada), 28.9 (CH₂-1 butyl), 22.9 (CH₂-2 butyl) ppm. IR (thin

ν

= 3327, 2901, 2848, 1590, 1451, 1203, 1111, 1068, 999 cm^–1.

˜

max.

[α]²_D⁰= –11.0 (c = 0.3, MeOH). HRMS: found 412.3055 [M + H]⁺,

calcd. for [C₂₃H₄₁NO₅+ H]⁺412.3057.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1-deoxynojirimycin (76):

Compound 66 (155 mg, 177 µmol) was subjected to hydrogenolysis

at 4 bar H₂(see general procedure H) to furnish 76 (38 mg,

99 µmol) as a colourless oil in 56% yield after purification (silica

gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Additional

HPLC purification was required for removal of minor 5–10% im-

purities (1 min: isocratic 25% B Ǟ 11.5 min: 45% B Ǟ 12.5 min:

100% B, 15 min: isocratic 100% B; t_R= 8.3 min). R_f= 0.32

(MeOH/CHCl₃, 1:3 + 2% NH₄OH). ¹H NMR (500 MHz, MeOD):

δ = 3.90–3.80 (m, 2 H, CH₂-6), 3.73 (dd, J = 4.1, 7.1 Hz, 1 H, 2-

H), 3.64 (dd, J = 7.0, 7.1 Hz, 1 H, 3-H), 3.49 (dd, J = 7.0, 7.0 Hz,

1 H, 4-H), 3.41 (t, J = 6.2 Hz, 2 H, CH₂-4 butyl), 3.38–3.32 (m, 1

H, 1-H), 3.22–3.14 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH₂-Ada), 1.94

(s, 3 H, 3ϫ CH Ada), 1.91–1.85 (m, 1 H, CHH-1 butyl), 1.71 (dd,

J = 12.1, 39.6 Hz, 7 H, 3ϫ CH₂Ada), 1.65–1.58 (m, 3 H, CHH-1

butyl, CH₂-3 butyl), 1.58–1.54 (m, 7 H, 3ϫ CH₂Ada), 1.54–1.44

(m, 2 H, CH₂-2 butyl) ppm. ¹³C NMR (100 MHz, MeOD): δ =

83.3 (OCH₂-Ada), 74.1 (C-3), 72.4 (CH₂-4 butyl), 72.0 (C-2), 71.5

(C-4), 60.7 (C-6), 58.3 (C-5), 56.2 (C-1), 41.0 (CH₂Ada), 38.5 (CH₂

Ada), 35.3 (C_qAda), 30.7 (CH₂-3 butyl), 29.9 (CH Ada), 26.8

film): ν

= 3328, 2902, 2848, 1451, 1068, 996 cm^–1. [α]²_D⁰= –14.0

˜

max.

(c = 0.2, MeOH). HRMS: found 384.2747 [M + H]⁺, calcd. for

[C₂₁H₃₇NO₅+ H]⁺384.2744.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxy-L-ido-nojiri-

mycin (74): Compound 64 (139 mg, 156 µmol) was subjected to hy-

drogenolysis at 4 bar H₂(see general procedure H) to furnish 74

(46 mg, 116 µmol) as a colourless oil in 73% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

ditional HPLC purification was required for removal of minor 5–

10 % impurities (1 min: isocratic 10 % B Ǟ 12 min: 100 % B Ǟ

12 min: 100% B, 15 min: isocratic 100% B; t_R= 7.4 min). R_f= 0.50

(MeOH/CHCl₃, 1:3 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD):

δ = 4.02 (t, J = 3.5 Hz, 1 H, 3-H), 3.93–3.91 (m, 1 H, 4-H), 3.91–

3.88 (m, 1 H, 2-H), 3.86–3.80 (m, 2 H, CH₂-6), 3.54–3.50 (m, 1 H,

5-H), 3.43–3.38 (m, 3 H, 1-H, CH₂-5 pentyl), 2.97 (s, 2 H, OCH₂-

Ada), 2.00–1.91 (m, 4 H, CHH-1 pentyl, 3ϫ CH Ada), 1.79–1.65

(m, 7 H, CHH-1 pentyl, 3ϫ CH₂Ada), 1.64–1.57 (m, 2 H, CH₂-4

pentyl), 1.56 (d, J = 2.2 Hz, 6 H, 3ϫ CH₂Ada), 1.53–1.41 (m, 3

H, CHH-2 pentyl, CH₂-3 pentyl), 1.41–1.33 (m, 1 H, CHH-2 pen-

tyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 83.2 (OCH₂-Ada),

72.5 (CH₂-5 pentyl), 69.2 (C-4), 69.0 (C-2), 68.2 (C-3), 60.6 (C-6),

58.8 (C-5), 56.9 (C-1), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_q

Ada), 30.6 (CH₂-4 pentyl), 29.9 (CH Ada), 29.0 (CH₂-1 pentyl),

(CH -1 butyl), 24.1 (CH -2 butyl) ppm. IR (thin film): ν =

˜

max.

2

3326, 2902, 2848, 1594, 1452, 1362, 1157, 1094 cm^–1. [α]²_D⁰= 10.9

(c = 0.2, MeOH). HRMS: found 384.2746 [M + H]⁺, calcd. for

[C₂₁H₃₇NO₅+ H]⁺384.2744.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1-deoxynojirimycin (77):

Compound 67 (148 mg, 155 µmol) was subjected to hydrogenolysis

at 4 bar H₂(see general procedure H) to furnish 77 (54 mg,

136 µmol) as a colourless oil in 82% yield after purification (silica

gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Additional

HPLC purification was required for removal of minor 5–10% im-

purities (1 min: isocratic 10% B Ǟ 12 min: 100% B Ǟ 12 min:

100% B, 15 min: isocratic 100% B; t_R= 7.2 min). R_f= 0.33

(MeOH/CHCl₃, 1:3 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD):

δ = 4.00 (dd, J = 7.1, 12.0 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.8,

12.0 Hz, 1 H, 6b-H), 3.78 (dd, J = 3.6, 6.5 Hz, 1 H, 2-H), 3.72 (t,

J = 6.5, 6.6 Hz, 1 H, 3-H), 3.63 (t, J = 6.6, 6.6 Hz, 1 H, 4-H), 3.47

(td, J = 3.6, 6.9 Hz, 1 H, 1-H), 3.40 (t, J = 6.3 Hz, 2 H, CH₂-5

pentyl), 3.36–3.32 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH₂-Ada), 1.98–

1.91 (m, 4 H, CHH-1 pentyl, 3ϫ CH Ada), 1.72 (dd, J = 11.9,

48.4 Hz, 6 H, 3ϫ CH₂Ada), 1.66–1.57 (m, 3 H, CHH-1 pentyl,

CH₂-4 pentyl), 1.56 (d, J = 2.5 Hz, 6 H, 3ϫ CH₂Ada), 1.52–1.41

(m, 4 H, CH₂-2, CH₂-3 pentyl) ppm. ¹³C NMR (150 MHz,

27.3 (CH -3 pentyl), 25.9 (CH -2 pentyl) ppm. IR (thin film): ν

˜

max.

2

= 3331, 2902, 2849, 1590, 1451, 1259, 1068, 998 cm^–1. [α]²_D⁰= –14.3

(c = 0.3, MeOH). HRMS: found 398.2897 [M + H]⁺, calcd. for

[C₂₂H₃₉NO₅+ H]⁺398.2901.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxy-

cin (75): Compound 65 (154 mg, 170 µmol) was subjected to hydro-

L-ido-nojirimy-

Eur. J. Org. Chem. 2010, 1258–1283

www.eurjoc.org

1279

J. M. F. G. Aerts, H. S. Overkleeft et al.

FULL PAPER

MeOD): δ = 81.7 (OCH₂-Ada), 71.2 (C-3), 71.0 (CH₂-5 pentyl),

ditional HPLC purification was required for removal of minor 5–

68.8 (C-2), 68.0 (C-4), 58.0 (C-5), 57.0 (C-6), 53.5 (C-1), 48.0 (C- 10% impurities (1 min: isocratic 30% B Ǟ 11.5 min: 50% B Ǟ

6), 39.4 (CH₂Ada), 36.9 (CH₂Ada), 33.8 (C_qAda), 29.0 (CH₂-4

12.5 min: 100% B, 15 min: isocratic 100% B; t_R= 6.5 min). R_f=

0.31 (MeOH/CHCl₃, 1:4 + 2 % NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 3.96 (dd, J = 3.2 Hz, 1 H, 3-H), 3.92–3.89 (m, 1 H,

4-H), 3.86–3.83 (m, 1 H, 2-H), 3.43–3.37 (m, 4 H, 1-H, CHH-5,

CH₂-5 pentyl), 3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.97 (s, 2 H,

OCH₂-Ada), 1.94 (s, 3 H, 3ϫ CH Ada), 1.90–1.83 (m, 1 H, CHH-

1 pentyl), 1.72 (dd, J = 11.9, 49.3 Hz, 6 H, 3ϫ CH₂Ada), 1.66–

1.57 (m, 3 H, CHH-1 pentyl, CH₂-4 pentyl), 1.56 (d, J = 2.3 Hz, 6

H, 3ϫ CH₂Ada), 1.52–1.38 (m, 4 H, 2ϫ CH₂pentyl) ppm. ¹³C

NMR (150 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 72.5 (CH₂-5 pen-

tyl), 69.6 (C-2), 68.4 (C-4), 68.0 (C-3), 56.4 (C-1), 47.4 (C-5), 41.0

(CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5 (CH₂-4 pentyl),

29.9 (CH Ada), 29.8 (CH₂-1 pentyl), 27.3 (CH₂pentyl), 25.8 (CH₂

pentyl), 28.4 (CH Ada), 26.0, 25.8, 25.5 (3ϫ CH₂pentyl) ppm. IR

(thin film): ν

= 3328, 2901, 2849, 1454, 1363, 1087 cm^–1. [α]²_D⁰

˜

max.

= 7.6 (c = 0.6, MeOH). HRMS: found 398.2898 [M + H]⁺, calcd.

for [C₂₂H₃₉NO₅+ H]⁺398.2901.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1-deoxynojirimycin (78):

Compound 68 (158 mg, 175 µmol) was subjected to hydrogenolysis

at 4 bar H₂(see general procedure H) to furnish 78 (58 mg,

141 µmol) as a colourless oil in 81% yield after purification (silica

gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Additional

HPLC purification was required for removal of minor 5–10% im-

purities (1 min: isocratic 10% B Ǟ 12 min: 100% B Ǟ 12 min:

100% B, 15 min: isocratic 100% B; t_R= 7.8 min). R_f= 0.35

(MeOH/CHCl₃, 1:3 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD):

δ = 4.00 (dd, J = 7.1, 12.0 Hz, 1 H, 6a-H), 3.83 (dd, J = 3.8,

12.0 Hz, 1 H, 6b-H), 3.78 (dd, J = 3.6, 6.6 Hz, 1 H, 2-H), 3.71 (dd,

J = 6.6, 6.7 Hz, 1 H, 3-H), 3.62 (dd, J = 6.7, 6.7 Hz, 1 H, 4-H),

3.46 (td, J = 3.6, 6.9 Hz, 1 H, 1-H), 3.38 (t, J = 6.4 Hz, 2 H, CH₂-

6 hexyl), 3.34–3.32 (m, 1 H, 5-H), 2.97 (s, 2 H, OCH₂-Ada), 1.98–

1.90 (m, 4 H, CHH-1 hexyl, 3ϫ CH Ada), 1.72 (dd, J = 11.8,

48.2 Hz, 6 H, 3ϫ CH₂Ada), 1.65–1.60 (m, 1 H, CHH-1 hexyl),

1.59–1.54 (m, 8 H, CH₂-5 hexyl, 3ϫ CH₂Ada), 1.50–1.44 (m, 2

H, CH₂-2 hexyl), 1.44–1.39 (m, 4 H, 2ϫ CH₂hexyl) ppm. ¹³C

NMR (150 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 72.8 (C-3), 72.7

(CH₂-6 hexyl), 70.4 (C-2), 69.5 (C-4), 59.5 (C-5), 58.6 (C-6), 55.3

(C-1), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.7 (CH₂-

5 hexyl), 30.5 (CH₂hexyl), 29.9 (CH Ada), 27.6 (CH₂-1 hexyl),

pentyl) ppm. IR (thin film): ν

= 3367, 2903, 2849, 1450, 1202,

˜

max.

1139, 1060 cm^–1. [α]²_D⁰= –15.8 (c = 0.3, MeOH). HRMS: found

368.2796 [M + H]⁺, calcd. for [C₂₁H₃₇NO₄+ H]⁺368.2795.

(1R)-1-C-[6-(Adamant-1-ylmethoxy)hexyl]-1,5-dideoxy-1,5-imino-D-

xylitol (81): Compound 71 (173 mg, 221 µmol) was subjected to

hydrogenolysis at 4 bar H₂(see general procedure H) to furnish 81

(75 mg, 197 µmol) as a colourless oil in 89% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

ditional HPLC purification was required for removal of minor 5–

10 % impurities (1 min: isocratic 10 % B Ǟ 12 min: 100% B Ǟ

12 min: 100% B, 15 min: isocratic 100% B; t_R= 7.9 min). R_f= 0.33

(MeOH/CHCl₃, 1:4 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD):

δ = 3.96 (dd, J = 3.3 Hz, 1 H, 3-H), 3.92–3.90 (m, 1 H, 4-H), 3.85–

3.83 (m, 1 H, 2-H), 3.43–3.36 (m, 4 H, 1-H, CHH-5, CH₂-6 hexyl),

3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.97 (s, 2 H, OCH₂-Ada), 1.94

(s, 3 H, 3ϫ CH Ada), 1.89–1.82 (m, 1 H, CHH-1 hexyl), 1.79–1.61

(m, 7 H, CHH-1 hexyl, 3ϫ CH₂Ada), 1.61–1.53 (m, 8 H, CH₂-5

hexyl, 3ϫ CH₂Ada), 1.50–1.43 (m, 1 H, CHH-2 hexyl), 1.43–1.37

(m, 5 H, CHH-2 hexyl, 2ϫ CH₂hexyl) ppm. ¹³C NMR (150 MHz,

MeOD): δ = 83.2 (OCH₂-Ada), 72.7 (CH₂-6 hexyl), 69.6 (C-2), 68.3

(C-4), 68.0 (C-3), 56.4 (C-1), 47.4 (C-5), 41.0 (CH₂Ada), 38.5 (CH₂

Ada), 35.3 (C_qAda), 30.7 (CH₂-5 hexyl), 30.4 (CH₂hexyl), 29.9

(CH Ada), 29.7 (CH₂-1 hexyl), 27.3 (CH₂hexyl), 26.0 (CH₂hexyl)

27.3 (CH hexyl), 27.2 (CH -2 hexyl) ppm. IR (thin film): ν =

˜

max.

2

3328, 2901, 2848, 1593, 1452, 1361, 1096, 1046 cm^–1. [α]²_D⁰= 9.2 (c

= 0.7, MeOH). HRMS: found 412.3055 [M + H]⁺, calcd. for

[C₂₃H₄₁NO₅+ H]⁺412.3057.

(1R)-1-C-[4-(Adamant-1-ylmethoxy)butyl]-1,5-dideoxy-1,5-imino-D-

xylitol (79): Compound 69 (111 mg, 147 µmol) was subjected to

hydrogenolysis at 4 bar H₂(see general procedure H) to furnish 79

(41 mg, 116 µmol) as a colourless oil in 79% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

ditional HPLC purification was required for removal of minor 5–

10% impurities (1 min: isocratic 25% B Ǟ 11.5 min: 45% B Ǟ

12.5 min: 100% B, 15 min: isocratic 100% B; t_R= 9.2 min). R_f=

0.30 (MeOH/CHCl₃, 1:4 + 2 % NH₄OH). ¹H NMR (600 MHz,

MeOD): δ = 3.96 (dd, J = 3.3 Hz, 1 H, 3-H), 3.92–3.89 (m, 1 H,

4-H), 3.86–3.83 (m, 1 H, 2-H), 3.44–3.38 (m, 4 H, 1-H, CHH-5,

CH₂-4 butyl), 3.19 (d, J = 13.1 Hz, 1 H, CHH-5), 2.98 (s, 2 H,

OCH₂-Ada), 1.95 (s, 3 H, 3ϫ CH Ada), 1.91–1.84 (m, 1 H, CHH-

1 butyl), 1.72 (dd, J = 11.6, 49.2 Hz, 6 H, 3ϫ CH₂Ada), 1.66–

1.59 (m, 3 H, CHH-1 butyl, CH₂-3 butyl), 1.56 (d, J = 2.3 Hz, 6

H, 3ϫ CH₂Ada), 1.55–1.49 (m, 1 H, CHH-2 butyl), 1.49–1.42 (m,

1 H, CHH-2 butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 83.3

(OCH₂-Ada), 72.2 (CH₂-4 butyl), 69.6 (C-2), 68.3 (C-4), 68.0 (C-

3), 56.5 (C-1), 47.5 (C-5), 41.0 (CH₂Ada), 38.5 (CH₂Ada), 35.3

(C_qAda), 30.6 (CH₂-3 butyl), 29.9 (CH Ada), 29.6 (CH₂-1 butyl),

ppm. IR (thin film): ν

= 3370, 2902, 2849, 1449, 1202, 1139,

˜

max.

1061 cm^–1. [α]²_D⁰= –13.7 (c = 0.6, MeOH). HRMS: found 382.2954

[M + H]⁺, calcd. for [C₂₂H₃₉NO₄+ H]⁺382.2952.

(1R)-1,5-Dideoxy-1,5-imino-1-C-nonyl-D-xylitol (82): Compound

72 (305 mg, 461 µmol) was subjected to hydrogenolysis at 4 bar H₂

(see general procedure H) to furnish 82 (113 mg, 438 µmol) as a

colourless oil in 95% yield after purification (silica gel, 0% Ǟ 20%

MeOH in CHCl₃with 0.5% NH₄OH). Additional HPLC purifica-

tion was required for removal of minor 5–10% impurities (1 min:

isocratic 10% B Ǟ 12 min: 100% B Ǟ 12 min: 100% B, 15 min:

isocratic 100% B; t_R= 6.7 min). R_f= 0.25 (MeOH/CHCl₃, 1:4 +

1

2% NH₄OH). H NMR (600 MHz, MeOD): δ = 3.97–3.96 (m, 1

H, 3-H), 3.93–3.89 (m, 1 H, 4-H), 3.85–3.82 (m, 1 H, 2-H), 3.41

(dd, J = 1.7, 13.1 Hz, 1 H, 5a-H), 3.37 (d, J = 7.4 Hz, 1 H, 1-H),

3.19 (d, J = 13.1 Hz, 1 H, 5b-H), 1.88–1.81 (m, 1 H, CHH-1 nonyl),

1.63 (ddd, J = 5.0, 10.5, 18.5 Hz, 1 H, CHH-1 nonyl), 1.48–1.41

(m, 1 H, CHH-2), 1.41–1.25 (m, 13 H, CHH-2 nonyl, 6ϫ CH₂

nonyl), 0.90 (t, J = 7.0 Hz, 3 H, CH₃-9 nonyl) ppm. ¹³C NMR

(150 MHz, MeOD): δ = 69.6 (C-2), 68.3 (C-4), 68.0 (C-3), 56.5 (C-

1), 47.4 (C-6), 33.2, 30.7, 30.6, 30.5, 30.4 (5ϫ CH₂nonyl), 29.8

(CH₂-1 nonyl), 26.0 (CH₂-1 nonyl), 23.9 (CH₂nonyl), 14.6 (CH₃-

22.9 (CH -2 butyl) ppm. IR (thin film): ν

= 3368, 2903, 2849,

˜

2

max.

1451, 1203, 1139, 1060 cm^–1. [α]²_D⁰= –13.4 (c = 0.2, MeOH).

HRMS: found 354.2639 [M + H]⁺, calcd. for [C₂₀H₃₅NO₄+ H]⁺

354.2639.

(1R)-1-C-[5-(Adamant-1-ylmethoxy)pentyl]-1,5-dideoxy-1,5-imino-

D-xylitol (80): Compound 70 (140 mg, 182 µmol) was subjected to

hydrogenolysis at 4 bar H₂(see general procedure H) to furnish 80

(62 mg, 169 µmol) as a colourless oil in 93% yield after purification

(silica gel, 0% Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Ad-

9 nonyl) ppm. IR (thin film): ν_max.= 3367, 2927, 2857, 1438, 1200,

˜

1139, 1061 cm^–1. [α]²_D⁰= –19.6 (c = 0.4, MeOH). HRMS: found

260.2222 [M + H]⁺, calcd. for [C₁₄H₂₉NO₃+ H]⁺260.2220.

1280

www.eurjoc.org

Eur. J. Org. Chem. 2010, 1258–1283

Lipophilic Aza-C-glycosides as Inhibitors of Glucosylceramide Metabolism

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1-deoxy-

L

-

[CH₂-5 pentenyl (Z)], 72.1 [CH₂-5 pentenyl (E)], 70.1 [C-2 (E)], 70.1

[C-2 (Z)], 69.6 [C-4 (E)], 69.4 [C-4 (Z)], 59.5 [C-5 (E)/(Z)], 58.6 [C-

6 (E)], 58.5 [C-6 (Z)], 54.7 [C-1 (E)/(Z)], 41.0 (CH₂Ada), 38.4 (CH₂

Ada), 35.3 [C_qAda (E)/(Z)], 34.1 [CH₂-4 pentenyl (E)], 30.7 [CH₂-

1 pentenyl (E)], 29.9 (CH Ada), 29.2 [CH₂-4 pentenyl (Z)], 25.8

ido-nojirimycin (83): Compound 64 (95 mg, 107 µmol) was sub-

jected to a Birch reduction (see general procedure G) to furnish 83

(30 mg, 75 µmol) as a colourless oil in 70% yield as a 1.3:2 mixture

of (E)/(Z) isomers after purification (silica gel, 0% Ǟ 20% MeOH

in CHCl₃with 0.5% NH₄OH). Additional HPLC purification was

[CH -1 pentenyl (Z)] ppm. IR (thin film): ν_max.= 3351, 2903, 2849,

˜

2

required for removal of minor 5–10% impurities (30% B Ǟ 11 min: 1443, 1203, 1139, 1050 cm^–1. [α]²_D⁰= 5.5 (c = 0.3, MeOH). HRMS:

100% B, 15 min: isocratic 100% B; t_R= 3.8 min). R_f= 0.41/0.45

found 396.2741 [M + H]⁺, calcd. for [C₂₂H₃₇NO₅+ H]⁺396.2744.

1

(MeOH/CHCl₃, 1:4 + 2% NH₄OH). H NMR [600 MHz, MeOD,

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1,5-dideoxy-

(E)/(Z) isomers, integrals for (Z) isomer]: δ = 5.72 [dt, J = 6.7,

15.4 Hz, =CH-3 (E) pentenyl], 5.67 [dt, J = 7.3, 10.9 Hz, 1 H,

=CH-3 (Z) pentenyl], 5.52–5.39 [m, 1 H, =CH-2 (E)/(Z) pentenyl],

4.01 [dd, J = 3.3 Hz, 1 H, 3-H (E)/(Z)], 3.93–3.89 [m, 1 H, 4-H

(E)/(Z)], 3.89–3.81 [m, 5 H, 2-H (E)/(Z), CH₂-6 (E)/(Z)], 3.55–3.50

[m, 1 H, 5-H (E)/(Z)], 3.47–3.39 [m, 5 H, 1-H (E)/(Z), CH₂-5

(E)/(Z) pentenyl], 3.00 [s, 2 H, OCH₂-Ada (Z)], 2.99 [s, OCH₂-Ada

(E)], 2.80–2.74 [m, 1 H, CHH-1 (Z) pentenyl], 2.64–2.58 [m, CHH-

1 (E) pentenyl], 2.50–2.43 [m, 1 H, CHH-1 (Z) pentenyl, CHH-1

(E) pentenyl], 2.43–2.37 [m, 2 H, CH₂-4 (Z) pentenyl], 2.31–2.28

[m, CH₂-4 (E) pentenyl], 1.94 (s, 3 H, 3ϫ CH Ada), 1.72 (dd, J =

11.9, 47.0 Hz, 6 H, 3ϫ CH₂Ada), 1.56 (d, J = 1.8 Hz, 6 H, 3ϫ

CH₂Ada) ppm. ¹³C NMR (150 MHz, MeOD): δ = 134.0 [=CH-3

(E) pentenyl], 132.5 [=CH-3 (Z) pentenyl], 126.0 [=CH-2 (E) pen-

tenyl], 124.9 [=CH-2 (Z) pentenyl], 83.3 [OCH₂-Ada (Z)], 83.2

[OCH₂-Ada (E)], 72.3 [CH₂-5 (E) pentenyl], 72.2 [CH₂-5 (Z) pen-

tenyl], 69.3 [C-4 (E)], 69.2 [C-4 (Z)], 69.1 [C-2 (Z)], 69.0 [C-2 (E)],

68.2 [C-3 (E)/(Z)], 60.7 [C-6 (Z)], 60.6 [C-6 (E)], 58.9 [C-5 (Z)],

58.8 [C-5 (E)], 56.8 [C-1 (E)], 56.7 [C-1 (Z)], 41.0 [CH₂Ada (E)],

40.9 [CH₂Ada (Z)], 38.5 [CH₂Ada (E)], 38.4 [CH₂Ada (Z)], 35.3

[C_qAda (Z)], 35.2 [C_qAda (E)], 34.1 [CH₂-4 (E) pentenyl], 32.5

[CH₂-1 (E) pentenyl], 29.9 [CH Ada (E)], 29.8 [CH Ada (Z)], 29.2

[CH₂-4 (Z) pentenyl], 27.3 [CH₂-1 (Z) pentenyl] ppm. 432IR (thin

1,5-imino-D-xylitol (85): Compound 70 (110 mg, 143 µmol) was

subjected to a Birch reduction (see general procedure G) to furnish

85 (34 mg, 93 µmol) as a colourless oil in 65% yield as a 1.2:1

mixture of (E)/(Z) isomers after purification (silica gel, 0% Ǟ 20%

MeOH in CHCl₃with 0.5% NH₄OH). Additional HPLC purifica-

tion was required for removal of minor 5–10% impurities (1 min:

isocratic 10% B Ǟ 12 min: 100% B Ǟ 12 min: 100% B, 15 min:

isocratic 100% B; t_R= 7.3 min). R_f= 0.39/0.45 (MeOH/CHCl₃,

1

1:4 + 2% NH₄OH). H NMR [600 MHz, MeOD, (E)/(Z) isomers,

integrals for (E) isomer]: δ = 5.75–5.67 [m, 2 H, =CH-3 (E)/(Z)

pentenyl], 5.52–5.42 [m, 2 H, =CH-2 (E)/(Z) pentenyl], 3.96 (dd, J

= 3.6 Hz, 2 H, 3-H), 3.93–3.90 (m, 2 H, 4-H), 3.84–3.82 [m, 1 H,

2-H (E)], 3.82–3.80 [m, 2-H (Z)], 3.46–3.37 [m, 4 H, 1-H (E)/(Z),

CHH-5 (E)/(Z), CH₂-5 pentenyl (E)/(Z)], 3.23–3.21 [m, 1 H, CHH-

5 (E)], 3.21–3.19 [m, CHH-5 (Z)], 3.00 [s, OCH₂-Ada (Z)], 2.99 [s,

2 H, OCH₂-Ada (E)], 2.67–2.61 [m, CHH-1 (Z) pentenyl], 2.56–

2.49 [m, 1 H, CHH-1 (E) pentenyl], 2.49–2.43 [m, CHH-1 (Z) pen-

tenyl], 2.43–2.35 [m, 1 H, CHH-1 (E) pentenyl, CH₂-4 (Z) pen-

tenyl], 2.35–2.28 [m, 2 H, CH₂-4 (E) pentenyl], 1.94 [s, 3 H, 3ϫ

CH Ada (E)/(Z)], 1.72 [dd, J = 11.8, 47.5 Hz, 6 H, 3ϫ CH₂Ada

(E)/(Z)], 1.56 [d, J = 2.6 Hz, 6 H, 3ϫ CH₂Ada (E)/(Z)] ppm. ¹³C

NMR [150 MHz, MeOD, (E)/(Z) isomers]: δ = 134.2 [=CH-3

(E)/(Z) pentenyl], 132.8 [=CH-3 (Z) pentenyl], 125.9 [=CH-2 (E)

pentenyl], 124.9 [=CH-2 (Z) pentenyl], 83.3 [OCH₂-Ada (Z)], 83.2

[OCH₂-Ada (E)], 72.2 [CH₂-5 (E) pentenyl], 72.1 [CH₂-5 (Z) pen-

tenyl], 69.7 [C-2 (E)], 69.7 [C-2 (Z)], 68.4 [C-4 (E)], 68.3 [C-4 (Z)],

68.0 [C-3 (E)/(Z)], 56.4 [C-1 (Z)], 56.4 [C-1 (E)], 47.5 [C-5 (E)/(Z)],

40.9 [CH₂Ada (E)/(Z)], 38.4 [CH₂Ada (E)/(Z)], 35.3 [C_qAda (Z)],

35.2 [C_qAda (E)], 34.1 [CH₂-4 (E) pentenyl], 33.3 [CH₂-1 (E) pen-

tenyl], 29.9 [CH Ada (E)/(Z)], 29.2 [CH₂-4 (Z) pentenyl], 28.0

film): ν

= 3365, 2903, 2849, 1444, 1203, 1140, 1075, 1011 cm^–1.

˜

max.

[α]²_D⁰= –10.1 (c = 0.3, MeOH). HRMS: found 396.2741 [M + H]⁺,

calcd. for [C₂₂H₃₇NO₅+ H]⁺396.2744.

(1R)-1-C-[(E/Z)-5-(Adamant-1-ylmethoxy)pent-2-enyl]-1-deoxynoji-

rimycin (84): Compound 67 (105 mg, 118 µmol) was subjected to a

Birch reduction (see general procedure G) to furnish 84 (34 mg,

85 µmol) as a colourless oil in 72 % yield as a 3:1 mixture of

(E)/(Z) isomers after purification (silica gel, 0% Ǟ 20% MeOH in

CHCl₃with 0.5% NH₄OH). Additional HPLC purification was

required for removal of minor 5–10% impurities (1 min: isocratic

30% B Ǟ 12 min: 100% B Ǟ 12 min: 100% B, 15 min: isocratic

[CH -1 (Z) pentenyl] ppm. IR (thin film): ν_max.= 3367, 2902, 2849,

˜

2

1444, 1200, 1137, 1064, 1012, 940 cm^–1. [α]²_D⁰= 12.0 (c = 0.5,

MeOH). HRMS: found 366.2639 [M + H]⁺, calcd. for [C₂₁H₃₅NO₄

+ H]⁺366.2639.

100 % B; t_R= 4.5 min). R_f= 0.30 (MeOH/CHCl₃, 1:4 + 2 %

NH₄OH). H NMR [600 MHz, MeOD, (E)/(Z) isomers, integrals Compound 72 (110 mg, 166 µmol) was subjected to a Birch re-

(1R)-1,5-Dideoxy-1,5-imino-1-C-[(E)-non-2-enyl]-

D

-xylitol

(86):

1

for (E) isomer]: δ = 5.74 [dt, J = 6.8, 15.4 Hz, 1 H, =CH-3 (E)

pentenyl], 5.73–5.71 [m, =CH-3 (E) pentenyl], 5.52–5.44 [m, 1 H,

=CH-2 (E)/(Z) pentenyl], 4.02 [dd, J = 7.3, 11.9 Hz, 6a-H (Z)], 3.97

duction (see general procedure G) to furnish 86 (30 mg, 115 µmol)

as a colourless oil in 69% yield after purification (silica gel, 0%

Ǟ 20% MeOH in CHCl₃with 0.5% NH₄OH). Additional HPLC

[dd, J = 7.4, 11.9 Hz, 1 H, 6a-H (E)], 3.84–3.78 [m, 2 H, 6b-H purification was required for removal of minor 5–10% impurities

(E)/(Z), 2-H (E)/(Z)], 3.76 [t, J = 6.0 Hz, 3-H (Z)], 3.73 [t, J = (1 min: isocratic 20% B Ǟ 11.5 min: 40% B Ǟ 12.5 min: 100% B,

6.5 Hz, 1 H, 3-H (E)], 3.65 [t, J = 6.1 Hz, 4-H (Z)], 3.62 [t, J = 20 min: isocratic 100% B; t_R= 7.6 min). R_f= 0.32 (MeOH/CHCl₃,

1

6.6 Hz, 1 H, 4-H (E)], 3.54–3.48 [m, 1 H, 1-H (E)/(Z)], 3.44 [t, J =

6.6 Hz, 2 H, CH₂-5 (E)/(Z) pentenyl], 3.38–3.33 [m, 1 H, 5-H

(E)/(Z)], 3.00 [s, OCH₂-Ada (Z)], 2.99 [s, 2 H, OCH₂-Ada (E)],

2.77–2.71 [m, CHH-1 (Z) pentenyl], 2.70–2.64 [m, 1 H, CHH-1 (E)

pentenyl], 2.51–2.45 [m, CHH-1 (Z) pentenyl], 2.43–2.36 [m, 1 H,

1:4 + 2% NH₄OH). H NMR (600 MHz, MeOD): δ = 5.69 (dt, J

= 6.8, 15.2 Hz, 1 H, =CH-2 nonenyl), 5.40 (dt, J = 7.2, 15.2 Hz, 1

H, =CH-3 nonenyl), 3.97–3.93 (m, 1 H, 3-H), 3.93–3.89 (m, 1 H,

4-H), 3.84–3.80 (m, 1 H, 2-H), 3.42–3.36 (m, 2 H, 1-H, 5a-H), 3.20

(d, J = 13.2 Hz, 1 H, 5b-H), 2.55–2.48 (m, 1 H, CHH-1 nonenyl),

CHH-1 (E) pentenyl], 2.34–2.28 [m, 2 H, CH₂-4 (E)/(Z) pentenyl], 2.38 (dt, J = 6.8, 13.7 Hz, 1 H, CHH-1 nonenyl), 2.09–2.02 (m, 2

1.95 [s, 3 H, 3ϫ CH Ada (E)/(Z)], 1.72 [dd, J = 11.9, 47.7 Hz, 6

H, 3ϫ CH₂Ada (E)/(Z)], 1.56 [d, J = 2.4 Hz, 6 H, 3ϫ CH₂Ada

(E)/(Z)] ppm. ¹³C NMR [150 MHz, MeOD, (E)/(Z) isomer]: δ =

134.3 [=CH-3 (E) pentenyl], 132.6 [=CH-3 (Z) pentenyl], 126.4

H, CH₂-4 nonenyl), 1.43–1.36 (m, 2 H, CH₂-5 nonenyl), 1.36–1.26

(m, 6 H, 3ϫ CH₂nonenyl), 0.90 (t, J = 7.0 Hz, 3 H, CH₃-9 non-

enyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 137.7 (=CH-3 non-

enyl), 124.0 (=CH-2 nonenyl), 69.7 (C-2), 68.4 (C-4), 68.0 (C-3),

[=CH-2 (E) pentenyl], 125.4 [=CH-2 (Z) pentenyl], 83.3 [OCH₂- 56.4 (C-1), 47.5 (C-6), 33.8 (CH₂-4 nonenyl), 33.2 (CH₂-1 nonenyl),

Ada (Z)], 83.2 [OCH₂-Ada (E)], 72.7 [C-3 (E)], 72.5 [C-3 (Z)], 72.3 33.0 (CH₂nonenyl), 30.4 (CH₂-5 nonenyl), 30.1 (CH₂nonenyl),

Eur. J. Org. Chem. 2010, 1258–1283

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1281

J. M. F. G. Aerts, H. S. Overkleeft et al.

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Received: October 22, 2009

Published Online: January 28, 2010

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1283

Article Doi

Synthesis and evaluation of lipophilic Aza-C-glycosides as inhibitors of glucosylceramide metabolism

DOI: 10.1002/ejoc.200901208

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Article abstract of DOI:10.1002/ejoc.200901208

Full text of DOI:10.1002/ejoc.200901208

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