The development of an aza-C-glycoside library based on a tandem staudinger/aza-wittig/ugi three-component reaction

FULL PAPER

DOI: 10.1002/ejoc.201200923

The Development of an Aza-C-Glycoside Library Based on a Tandem

Staudinger/Aza-Wittig/Ugi Three-Component Reaction

Tom Wennekes,^[a][‡]Kimberly M. Bonger,^[a][‡‡]Katrin Vogel,^[a]

Richard J. B. H. N. van den Berg,^[a]Anneke Strijland,^[b]Wilma E. Donker-Koopman,^[b]

Johannes M. F. G. Aerts,^[b]Gijsbert A. van der Marel,^[a]and Herman S. Overkleeft*^[a]

Keywords: Medicinal chemistry / Drug discovery / Multicomponent reactions / Enzyme inhibitors / Carbohydrates /

Glycosides / Azasugars

We report the tandem Staudinger/aza-Wittig/Ugi three-com-

ponent reaction mediated synthesis of a 64-member com-

pound library of aza-C-glycosides. The library is composed

of four pyrrolidine and three piperidine scaffolds, onto which

a number of functional groups is grafted to form seven subli-

braries. Variation in the library is achieved by transformation

pentanal and 5-azidohexanal derivatives as precursors for

the Staudinger/aza-Wittig process. Further variation is

achieved by using different isocyanides as well as protective-

and functional-group manipulations on the fully protected

Ugi-3CR intermediates. Preliminary biological evaluation of

the compound library revealed several low micromolar inhib-

of two pentoses and a hexose into the corresponding 4-azido- itors of human acid glucosylceramidase.

ever, the search for such compounds is somewhat compro-

Introduction

mised by the relatively complex synthetic routes towards

aza-C-glycosides. Indeed, although many effective and at-

tractive synthetic routes have been described in recent

years,^[1,3]transposing such a given synthetic strategy

towards a configurational or functional group isomer of the

original target compound is not always straightforward (in

fact this intrinsic difficulty is experienced for the construc-

tion of iminosugar-type alkaloids in general). A straightfor-

ward and flexible route towards aza-C-glycosides would

therefore be desirable, especially when preparing compound

libraries.^[3j–3m,5b]We have previously reported on a route

that transforms carbohydrate-derived azido aldehydes into

cyclic dipeptides that are, in effect, aza-C-glycosides.^[4,5]The

azido aldehyde is transformed into an intermediate cyclic

imine through a Staudinger/aza-Wittig cyclization, after

which a Ugi three-component reaction (Ugi-3CR) yields

the product. In this study we further investigate the effi-

ciency and versatility of this route in constructing aza-C-

glycosides.

Aza-C-glycosides, also known as iminosugar C-glycos-

ides, are iminosugars that have a carbon substituent at the

position corresponding to the anomeric carbon of the par-

ent glycoside.^[1]This distinguishing feature can be designed

such that it resembles the aglycon of the target glycoconjug-

ate, thereby potentially endowing the structure with en-

hanced enzyme inhibitory potency and/or specificity. More-

over, appending a bulky substituent at the carbon next to

the nitrogen of an iminosugar may profoundly affect its

conformational behavior, potentially locking the compound

in its bioactive conformer. Aza-C-glycosides have therefore

become important targets in the quest for iminosugar-type

glycosidase and glycosyl transferase inhibitors for medicinal

chemistry purposes.^[2]A number of potent and selective in-

hibitors of various glycoprocessing enzymes from various

biological origins have been described in recent years, how-

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

Laboratories,

Our interest in aza-C-glycosides, and in iminosugar alk-

aloids in general, is related to our research on human glyco-

lipid metabolism, in particular on the glycoprocessing en-

zymes involved in the biosynthesis and degradation of glu-

cosylceramide.^[6]The lysosomal enzyme responsible for de-

gradation of this glycolipid, acid glucosylceramidase

(GBA), exists in genetically disabled isoforms, leading to

partially impaired degradation – and thereby accumu-

lation – of glucosylceramide. Such genetic deficiency in

GBA activity causes the lysosomal storage disorder

Einsteinweg 55, 2300 RA Leiden, The Netherlands

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

Homepage: http://biosyn.lic.leidenuniv.nl

[b] Department of Medical Biochemistry, Academic Medical

Center, University of Amsterdam,

Amsterdam, The Netherlands

[‡] Current address: Laboratory of Organic Chemistry,

Wageningen University,

Dreijenplein 8, 6703 HB Wageningen, The Netherlands

[‡‡]T. Wennekes and K. M. Bonger contributed equally to this

work.

Supporting information for this article is available on the

WWW under http://dx.doi.org/10.1002/ejoc.201200923.

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An Aza-C-Glycoside Library

Gaucher disease. GBA inhibitors that bind tightly to the closer, it is a considerably weaker inhibitor of all three en-

enzyme active site have been proposed as a conceptually zymes when compared to

new therapy known as chemical chaperone therapy for the IC₅₀(GBA2) 40 nM, IC₅₀(GCS) 3 μm].

treatment of Gaucher.^[7]Two intrinsically different therapies

With the aim of exploring the positioning and nature of

1 [3: IC₅₀(GBA) 3 μm,

are already in clinical practice: enzyme replacement ther- the lipophilic group in more detail, while also considering

apy^[8]is based on administering to Gaucher patients recom- the configuration and ring size of the iminosugar core, we

binant GBA, whereas substrate reduction therapy^[9]is based set out to apply the Staudinger/aza-Wittig/Ug-3CR se-

on inhibition of glucosylceramide synthase (GCS), the en- quence of events to generate a concise library of aza-C-

zyme responsible for the synthesis of glucosylceramide glycosides. The general strategy (Figure 1 right) is as fol-

through condensing ceramide with UDP-glucose. A second, lows. A partially protected, carbohydrate-derived azidoalde-

non-lysosomal glucosylceramidase (GBA2) exists,^[10]and in hyde I can be made to react with trimethylphosphane to

the design of GBA and/or GCS inhibitors of this enzyme generate cyclic imine III, via phosphazene II, after a Staud-

(which has itself recently emerged as a drug target in rela- inger/aza-Wittig sequence.^[12]In this process, the nature of

tion to Parkinsonism^[11]) has to be taken into account. In azido aldehyde I is translated into that of imine III, and in

our work on the development of potent and selective inhibi- addition to configurational aspects (that is, the nature of

tors of each of these glucosylceramide-processing enzymes, the parent sugar) the ring size can be readily varied: 4-azido

we have discovered deoxynojirimycin derivatives equipped aldehydes give rise to 1-pyrroline precursors whereas 5-

with a large hydrophobic group as valuable leads. Relevant azido aldehydes give 1-piperideine precursors. In the next

examples (see Figure 1) are compounds 1–3. N-Adamant- step, imine III is reacted with a variety of isocyanides and

anemethoxypentyldeoxynojirimycin (1)^[6b,6c]is a highly po- pentenoic acid to give Ugi-3CR^[13]products IV, in which R¹

tent (IC₅₀200 nM) GCS inhibitor that is remarkably more can be a variety of lipophilic groups. The pentenoyl moiety

potent than the marketed substrate reduction therapy drug, in IV can be selectively removed and the resulting second-

Zavesca (N-butyldeoxynojirimycin, IC₅₀25–50 μm). Both ary amine functionalized through reductive amination to

compounds, however, feature broad-spectrum inhibition install R², which again denotes a series of lipophilic moie-

towards other glucosylceramide-processing enzymes [Za- ties. We have previously experienced^[6b]that N-acyl deoxy-

vesca: IC₅₀(GBA) 400 μm, IC₅₀(GBA2) 230 nM; 1: nojirimycin derivatives are poor inhibitors of the human

IC₅₀(GBA) 200 nM, IC₅₀(GBA2) 1 nM] and also towards glucosylceramide-processing enzymes and, therefore, opted

intestinal glycosidases (maltase, lactase, sucrase). The l-ido- to pursue diversity through tertiary amines rather than the

configurational isomer of 1, compound 2,^[6d]is at least as corresponding amides. Global deprotection provides aza-C-

potent in inhibiting GCS (IC₅₀100 nM) and is significantly glycosides VI for ensuing biological evaluation. In this work

more selective. With this compound, GBA (IC₅₀2 μm) and we divulge the results of our efforts in the generation and

GBA2 (IC₅₀30 nM), and especially the intestinal glycosid- preliminary evaluation as GBA inhibitors of a 64 com-

ases (no inhibition up to 1 mm), are much less strongly in- pound library based on seven iminosugar scaffolds and with

hibited. More recently, we have worked on aza-C-glycosides a bulky hydrophobic group, positioned either at the ring

having related structural features. Interestingly, although nitrogen (corresponding to compounds 1 and 2) or at C1

aza-C-glycoside 3^[6f]structurally resembles the natural GCS (the anomeric carbon when related to the parent sugars, in

product and GBA/GBA2 substrate, glucosylceramide, much analogy to aza-C-glycoside 3).

Figure 1. (Left) Previously reported relevant inhibitors of enzymes involved in glucosylceramide metabolism. (Right) General strategy for

library synthesis through a tandem Staudinger/aza-Wittig/Ugi three-component reaction.

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63–65, 69–71 and 75–77 and the 2,3-cis-fused l-arabino-

pyrrolidine derivatives 66–68, 72–74 and 78–80.

Results

The results of our library synthesis are summarized in

2,3,4,6-Tetra-O-benzyl-d-glucitol (81) served as the start-

Schemes 1, 2, 3, and 4, with Schemes 1 and 2 outlining the ing compound for both the l-ido-piperidine series

assembly of pyrrolidine aza-C-glycosides starting from l- (Scheme 3) and d-gluco-piperidine series (Scheme 4) of

ribose (Scheme 1) and d-xylose (Scheme 2) and Schemes 3 compounds. The requisite 5-azido aldehydes 85 (Scheme 3)

and 4 outlining the construction of piperidine aza-C-glycos- and 120 (Scheme 4) were readily prepared by using estab-

ides starting from d-glucose. As hydrophobic isocyanide lished procedures,^[3h,3n]with, as distinguishing feature be-

reagents for the Ugi-3CR, we opted for adamantaneme- tween the two routes, introduction of the azide at C5 with

thoxypentane derivative 10 (readily available in a four-step inversion of configuration (82 to 83; Scheme 3) and with

sequence from 5-adamantanemethoxy-1-bromopentane 6 retention of configuration involving first Mitsunobu-based

as depicted in Scheme 1), 1,1,3,3-tetramethylbutyl iso- inversion (82 to 115; Scheme 4)^[16]followed by a second in-

cyanide 11 and pentyl isocyanide 12. l-Ribose 4 was trans- version (117 to 118; Scheme 4). Staudinger/aza-Wittig reac-

formed into 4-azidopentanal 5 according to our previous tions under the agency of trimethylphosphane on 5-azido

report.^[4b]In our previous work^[4c]we had also found that aldehyde 85 provided 2,3,4,6-tetra-O-benzyl-l-ido-1-piper-

the outcome in stereochemical terms of an Ugi-3CR involv- ideine, which was subjected to an Ugi-3CR with 1-pent-

ing the d-lyxo-pyrroline that emerges upon treatment of 5 enoic acid and isocyanides 10–12 (Scheme 1) to give 2,3-

with trimethylphosphane can be influenced by including in- trans-l-ido-piperidines 86, 88 and 90 and 2,3-cis-l-ido-pip-

dium trichloride in the reaction mixture. In agreement with eridines 87, 89 and 91 in about equal amounts as separable

our previous^[6c]finding, performing the Ugi-3CR in meth- mixtures. As before, and following the same procedure,

anol in the absence of InCl₃yields predominantly the 2,3- these scaffolds were brought forwards to give the third two

cis adducts (13, 15 and 17).^[14]As we had also observed sets of aza-C-glycosides: the 2,3-trans-fused l-ido-piperidine

before,^[4a]tertiary isocyanide 11 gives higher yields in com- derivatives 98–100, 103–105 and 109–111 and the 2,3-cis-

parison with primary isocyanides (10, 12), but in all cases fused l-ido-piperidine derivatives 101 and 102, 106–108 and

useful quantities of the Ugi-3CR products could be ob- 112–114 (reductive amination of 2,3-cis-fused secondary

tained. Including InCl₃(1.1 equiv.) in the reaction and amine 93 with adamantanemethoxypentanal did not yield

switching from methanol to acetonitrile as the solvent led any product). Finally, treatment of azido aldehyde 120 with

to partial inversion of stereochemistry, with the 2,3-trans trimethylphosphane led to the formation of 2,3,4,6-tetra-O-

adducts (14, 16 and 18) being obtained as the major prod- benzyl-d-gluco-1-piperideine. The stereochemical outcome

ucts. The diastereomeric product mixtures were readily sep- of an ensuing Ugi-3CR could not be influenced by adding

arated by silica gel chromatography in all instances, giving InCl₃and we therefore took this cyclic imine to produce,

two sets of fully protected aza-C-glycosides. In the next again using the procedures discussed above, the seventh and

step, the N-pentenoyl group was selectively removed by final set of aza-C-glycosides: the 2,3-cis-fused d-gluco-pip-

treatment with iodine according to the procedure developed eridine derivatives 127–129, 130–132 and 133–135.

by Madsen and Fraser-Reid^[15]and the resulting secondary

The configuration of the new chiral center, introduced

amines 19–24 were either globally deprotected or employed during the Ugi-3CR, was previously reported by us^[4b,4c]for

in a reductive amination event with butanal or adamant- d-lyxo-pyrrolidine aza-C-glycosides and for the new exam-

anemethoxypentanal^[6c]followed by global deprotection to ples described here it was established by H- and NOESY-

1

provide the first two sets of aza-C-glycosides: the 2,3-cis- NMR experiments (Figure 2).

fused d-lyxo-pyrrolidine derivatives 25–27, 31–33 and 37–

39 and the 2,3-trans-fused d-lyxo-pyrrolidine derivatives in hand and their structures established, they were then all

28–30, 34–36 and 40–42. evaluated in an in vitro enzyme assay for inhibition of hu-

With the 62 aza-C-glycosides from the seven sub-libraries

4-Azido aldehyde 50, a configurational isomer of 5, was man acid glucosylceramidase (GBA) using pure recombi-

prepared through standard functional group manipulations nant enzyme and the artificial substrate 4-methylumbelli-

starting from fully protected d-xylofuranose 43 (Scheme 2). feryl-beta-d-glucoside under appropriate conditions.^[17]The

Subjection of 50 to a trimethylphosphane-mediated Staud- results are summarized in Table 1.

inger/aza-Wittig event led to the generation of tri-O-benzyl-

As can be seen, none of the aza-C-glycosides emulate the

l-arabino-pyrroline, which was treated with 1-pentenoic GBA inhibitory potential of our lead compound, 1

acid and isocyanides 10–12 to give the series of fully pro- [IC₅₀(GBA) 200 nM]. That said, some interesting trends

tected 2,3-trans-l-arabino-pyrrolidines 51, 53 and 55 and can be observed. Within the individual sub-libraries, almost

2,3-cis-l-arabino-pyrrolidines 52, 54 and 56. In each case, without exception, those compounds featuring a single ada-

both diastereomers were formed in roughly equal amounts mantane-containing lipophilic side chain at C2 with no sub-

and were readily separated by column chromatography. In stituent on the ring nitrogen are the most potent GBA in-

this case, addition of InCl₃had no influence on the stereo- hibitors. Replacing this bulky side chain by either 1,1,3,3-

chemical outcome of the Ugi-3CR reaction. The resulting tetramethylbutyl or pentyl gives a considerable drop in inhi-

six scaffolds were elaborated in the same vein as in the d- bition, whereas introducing added bulk on the pyrrolidine/

lyxo series to provide the second two sets of aza-C-glycos- piperidine nitrogen results in comparatively weaker inhibi-

ides: the 2,3-trans-fused l-arabino-pyrrolidine derivatives tion. The most potent GBA inhibitors within the 62 com-

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An Aza-C-Glycoside Library

Scheme 1. Preparation of d-lyxo-pyrrolidine library entries from azidopentanal 5. Reagents and conditions: (a) NaN₃, DMSO, room temp.,

20 h, 95%; (b) PMe₃, H₂O, THF, 0 °C, 3 h, 84%; (c) acetic formic anhydride, CH₂Cl₂, 0 °CǞroom temp., 20 h, 82%; (d) POCl₃, Et₃N,

CH₂Cl₂, 30 °C, 1 h, 81%; (e) 1. PMe₃, MeOH, 0 °C, 3 h; 2. acid, isocyanide 10–12, MeOH, 0 °C, 18 h; (f) 1. PMe₃, MeOH, 0 °C, 3 h;

2. pent-4-enoic acid, isocyanide 10–12, InCl₃, CH₃CN, 0 °C, 18 h; (g) I₂, H₂O, THF, 0.5 h; (h) Pd/C, H₂, EtOH, 18 h; (i) BCl₃, CH₂Cl₂,

0 °C, 18 h; (j) 1. Aldehyde, NaCNBH₃, Na₂SO₄, AcOH, EtOH, 18 h; 2. (h) or (i). For yields of library synthesis steps, e–j, see Exp.

Section.

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Scheme 2. Preparation of azidopentanal 50 and l-arabino-pyrrolidine library entries. Reagents and conditions: (a) aq. HCl, dioxane, reflux,

5 h, 70%; (b) NaBH₄, MeOH, 0 °C, 3 h, 87%; (c) TrCl, pyridine, 40 °C, 20 h, 94%; (d) MsCl, Et₃N, CH₂Cl₂, 85%; (e) NaN₃, 15-crown-

5, DMF, 90 °C, 48 h, 88%; (f) BF₃·OEt₂, MeOH toluene, 3 h, 98%; (g) Dess–Martin periodinane, CH₂Cl₂, 0 °CǞroom temp., 1.5 h,

76%; (h) 1. PMe₃, MeOH, 0 °C, 3 h; 2. pent-4-enoic acid, isocyanide 10–12, MeOH, 0 °C, 18 h; (i) I₂, H₂O, THF, 0.5 h; (j) Pd/C, H₂,

EtOH, 18 h; (k) BCl₃, CH₂Cl₂, 0 °C, 18 h; (l) 1. Aldehyde, NaCNBH₃, Na₂SO₄, AcOH, EtOH, 18 h; 2. (j) or (k). For yields of library

synthesis steps, h–l, see Exp. Section.

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An Aza-C-Glycoside Library

Scheme 3. Preparation of azidohexanal 85 and l-ido-piperidine library entries. Reagents and conditions: (a) TBDPSCl, imidazole, DMF,

20 h, 99%; (b) DPPA, DIAD, PPh₃, THF, 0 °CǞroom temp., 20 h, 66%; (c) TBAF, THF, 20 h, 71%; (d) Dess–Martin periodinane,

CH₂Cl₂, 0 °CǞroom temp., 1.5 h, 89%; (e) 1. PMe₃, MeOH, 0 °C, 3 h; 2. pent-4-enoic acid, isocyanide 10–12, MeOH, 0 °C, 18 h; (f) I₂,

H₂O, THF, 0.5 h·(g) Pd/C, H₂, EtOH, 18 h; (h) BCl₃, CH₂Cl₂, 0 °C, 18 h; (i) 1. Aldehyde, NaCNBH₃, Na₂SO₄, AcOH, EtOH, 18 h; 2. (g)

or (h). For yields of library synthesis steps, e–i, see experimental section.

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Figure 2. Configuration of the new chiral center as determined by

¹H- and NOESY-NMR for representative examples of l-arabino-

pyrrolidine (59 and 60); l-ido-piperidine (96 and 97) and d-gluco-

piperidine (126)^[14]libraries.

pound library are 2,3-trans-d-lyxo-pyrrolidine 28, 2,3-cis-

l-arabino-pyrrolidine 66 and 2,3-cis-d-gluco-piperidine 127.

Although weaker than 1, these compounds for instance in-

hibit GBA rather more potently than N-butyldeoxynojiri-

mycin [Zavesca: IC₅₀(GBA) 400 μm] and the archetypal

iminosugar glycosidase inhibitor,

deoxynojirimycin

[IC₅₀(GBA) 250 μm].

When comparing the general structures of the library of

aza-C-glycosides with those of leads 1–3, several differences

become apparent. Arguably, compound 127 is the closest

analogue of aza-C-glycoside 3, with the major difference,

apart from the way the side chain is appended (amide vs.

alkyl), being the configuration at the anomeric carbon:

“beta” in 3 as opposed to “alpha” in 127. This difference

may be the cause of the slight decrease [127: IC₅₀(GBA) 7

μm, 3: IC₅₀(GBA) 3 μm] in observed inhibitory activity. As

mentioned above, the stereochemical outcome in the d-

gluco series could not be influenced through manipulation

(addition of a Lewis acid) of the Ugi-3CR conditions and

we therefore had no access to the corresponding “beta” iso-

mer by means of the chemistry described here. When com-

paring the compounds with N-alkylated deoxynojirimycin

derivatives 1 and 2, it is clear that the compound series do

not contain close analogues; all compounds contain a

rather bulky side chain at the anomeric carbon. With the

aim of arriving at the closest analogues of 1 available

through the Staudinger/aza-Wittig/Ugi-3CR sequence of re-

actions, we turned our attention to the use of isocyanide

Scheme 4. Preparation of azidohexanal 120 and d-gluco-piperidine

library entries. Reagents and conditions: (a) p-NO₂-benzoic acid,

DIAD, PPh₃, 0 °CǞroom temp., 20 h, by-product^[16]116: 46%;

(b) LiOH, H₂O/THF/EtOH, 2 h, 38% 2 steps; (c) DPPA, DIAD,

PPh₃, THF, 0 °CǞroom temp., 20 h, 63%; (d) TBAF, THF, 20 h,

74%; (e) Dess–Martin periodinane, CH₂Cl₂, 0 °CǞroom temp.,

1.5 h, 96%; (f) 1. PMe₃, MeOH, 0 °C, 3 h; 2. pent-4-enoic acid, iso-

cyanide 10–12, MeOH, 0 °C, 18 h; (g) I₂, H₂O, THF, 0.5 h; (h) Pd/

C, H₂, EtOH, 18 h; (i) BCl₃, CH₂Cl₂, 0 °C, 18 h; (j) 1. Aldehyde,

NaCNBH₃, Na₂SO₄, AcOH, EtOH, 18 h; 2. (h) or (i). For yields

of library synthesis steps, f–j, see experimental section.

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An Aza-C-Glycoside Library

Table 1. GBA inhibition assay results with apparent IC₅₀values (IC₅₀values in μm, NI indicates no inhibition up to 1 mm). NT: library

entry not synthesized.

2,3-cis

d-lyxo

IC₅₀

2,3-trans

d-lyxo

IC₅₀

2,3-trans

l-arabino

IC₅₀

2,3-cis

l-arabino

IC₅₀

2,3-trans

l-ido

IC₅₀

2,3-cis

l-ido

IC₅₀

2,3-cis

d-gluco

IC₅₀

25

26

27

31

32

33

37

38

39

80

28

29

30

34

35

36

40

41

42

4

20

15

400

150

50

350

650

50

63

64

65

69

70

71

75

76

77

45

50

25

NI

100

NI

40

66

67

68

72

73

74

78

79

80

4

40

20

100

500

300

450

NI

500

98

30

40

50

NI

250

NI

70

101

102

NT

106

107

108

112

113

114

150

20

–

NI

250

NI

130

127

128

129

130

131

132

133

134

135

7

200

100

NI

800

NI

140

99

45

30

400

NI

40

NI

70

100

103

104

105

109

110

111

137 (available from cyclohexanone following the literature primary carboxamide appended in an alpha fashion to the

procedure,^[18]see Scheme 5). Treatment of 120 with trimeth- anomeric carbon) were assayed in a preliminary study as

ylphosphane, followed by Ugi-3CR of the resulting piperid- inhibitor of the three enzymes involved in glucosylceramide

eine with 1-pentenoic acid and isocyanide 137, gives α-aza- metabolism, GBA, GBA2 and GCS. Of the two new ana-

C-glycoside 138. Acid-mediated hydrolysis gives carboxyl- logues, carboxylate 144 is the most potent inhibitor against

ate 139, which can be transformed into the corresponding all three enzymes [IC₅₀(GBA) 5 μm, IC₅₀(GBA2) 100 nM,

carboxamide 140 and further elaborated into N-adamant- IC₅₀(GCS) 20 μm]; in all cases however, 144 is a consider-

anemethoxypentyl derivative 143. Alternatively, the pen- ably weaker inhibitor than

1 [IC₅₀(GBA) 200 nM,

tenoyl group in carboxylic acid 139 can be removed and IC₅₀(GBA2) 1 nM, IC₅₀(GCS) 200 nM]. Carboxamide 143,

secondary amine 141 N-alkylated and globally deprotected in contrast, is a relatively poor inhibitor of the two hydro-

to give compound 144; both close analogues of 1 (essen- lases [IC₅₀(GBA) 200 μm, IC₅₀(GBA2) 7 μm] and has no

tially the same structure but with either a carboxylate or a significant inhibitory activity against GCS.

Scheme 5. Preparation of d-gluco-piperidine library entries 143 and 144. Reagents and conditions: (a) POCl₃, Et₃N, CH₂Cl₂, 30 °C, 1 h,

65%; (b) PMe₃, MeOH, 0 °C, 3 h; 2. pent-4-enoic acid, isocyanide 137, MeOH, 0 °C, 18 h, 80%; (c) aq. HCl, THF, 20 h, 82%;

(d) 1. ClC(O)OEt, Et₃N, THF, 0 °C; 2. 25% aq. NH₃, 0 °C, 1 h, 64%; (e) I₂, H₂O, THF, 0.5 h, 141: 35%, 142: 79%; (f) 1. Adamantaneme-

thoxypenanal, NaCNBH₃, Na₂SO₄, AcOH, EtOH, 18 h; 2. Pd/C, H₂, EtOH, 18 h, 143: 39%, 144: 30%.

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and (NH₄)₄Ce(SO₄)₄·2H₂O (10 g/L) in 10% sulfuric acid or a solu-

tion of phosphomolybdic acid hydrate (7.5 wt.-% in ethanol) fol-

Discussion

This paper reports the synthesis of a 64-member aza-C- lowed by charring at ca. 150 °C. Visualisation of all deprotected

iminosugar compounds during TLC analysis was accomplished by

exposure to iodine vapor. Column chromatography was performed

glycoside library in a combinatorial approach based on our

previously reported Staudinger/aza-Wittig/Ugi-3CR meth-

odology. From a synthetic point of view, we believe our

approach has value specifically in terms of the numbers of

structural and configurational analogues that can be pre-

pared with relative ease. The number of compounds we pre-

pared may appear at a first glance unspectacular. However,

we believe that within the field of aza-C-glycosides, and in

general in the field of iminosugars, the number is in fact

1

on silica gel (40–63 μm). H and ¹³C-APT NMR spectra were re-

corded with a Bruker DMX 600 (600/150 MHz), Bruker DMX 500

(500/125 MHz), or Bruker AV 400 (400/100 MHz) spectrometer in

CDCl₃or MeOD. Chemical shifts are given in ppm (δ) relative to

tetramethylsilane 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 on the

basis of COSY and HSQC experiments. All presented ¹³C-APT

quite substantial, the more so when taking into consider- spectra are proton decoupled. High-resolution mass spectra were

recorded by direct injection (2 μL of a 2 μm solution in water/aceto-

nitrile, 50:50; v/v and 0.1% formic acid) into the mass spectrometer

(Thermo Finnigan LTQ Orbitrap), which was equipped with an

electrospray ion source operated in the positive mode (source volt-

age 3.5 kV, sheath gas flow 10, capillary temperature 250 °C) with

resolution R = 60000 at m/z 400 (mass range m/z = 150–2000) and

dioctylphthalate (m/z 391.28428) as a “lock mass”. The high-reso-

lution mass spectrometer was calibrated prior to measurements

with a calibration mixture (Thermo Finnigan). Optical rotations

were measured with a Propol automatic polarimeter (Sodium d-

ation the potential to diversify at several points in the syn-

thetic strategy. Carbohydrate-derived azido aldehydes are

readily available in various configurational and structural

isomers. The Ugi-3CR may, or may not, proceed stereose-

lectively (in some cases the stereochemical outcome can be

partially controlled by tuning the conditions) and in all the

examples we investigated the diastereoisomers could be

readily separated, leading to productive amounts of Ugi-

3CR products. Furthermore, both carboxylic acid and iso-

cyanide reaction partners can be selected such that they end line, λ = 589 nm). ATR-IR spectra are reported in cm^–1and were

recorded with a Shimadzu FTIR-8300 fitted with a single bounce

Durasample IR diamond crystal ATR-element.

up in the Ugi-3CR product as protective groups that can

be removed selectively for further functionalisation. On the

downside, we recognize that our combinatorial approach

brings limitations, or rather introduces obligatory structural

features into the library members, which can be avoided in

Enzyme Assays: The enzyme assays used to determine the inhibi-

tion of activity of glucosylceramide synthase (GCS), human acid

glucosylceramidase (GBA1) and non-lysosomal glucosylceramid-

target-oriented approaches. In our initial biological assays ase (GBA2) were performed as reported previously.^[6c]All com-

pounds were stored (–20 °C) and tested as their hydrochloric acid

salt.

we found that these constraints, that is, the appended carb-

oxylate/carboxamide, brings a partial dampening of the ac-

tivity towards the enzymes assayed (compare lead structure

1 with aza-C-glycoside 144). A more in-depth analysis of

our compounds in assays including a broader panel of

General Procedure A. Dess–Martin Periodinane-Mediated Oxi-

dation of Azido Alcohols 49, 84 and 119: Dess–Martin periodinane

(1.5 equiv.) was added to a cooled (0 °C), anhydrous solution of

glycoprocessing enzymes is required to assess the value of azido alcohol (1 equiv.) in CH₂Cl₂(0.2 m). The reaction mixture

was stirred for 30 min at 0 °C and for a further hour at room temp.

The reaction mixture was quenched by the addition of satd. aq.

NaHCO₃(5 mL/mmol) and 1M aq. Na₂S₂O₃(5 mL/mmol). The

resulting two-phase mixture was rapidly stirred/mixed for 15 min.

The mixture was diluted with additional CH₂Cl₂and washed suc-

cessively with satd. NaHCO₃and brine. The organic phase was

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

gel column 923 to provide the aldehyde, which should preferably

be used immediately but can be stored for 20 h at –20 °C under

argon.

our aza-C-glycoside library, which may then be expanded

by including a more diverse set of azido aldehydes, carbox-

ylic acids and isocyanides in the tandem Staudinger/aza-

Wittig/Ugi-3CR sequence of reactions.

Experimental Section

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 an argon atmo-

sphere. Residual water was removed from starting compounds by

repeated coevaporation with dioxane, toluene or dichloroethane.

All solvents were removed by evaporation under reduced pressure.

Reaction grade acetonitrile, n-propanol and methanol were stored

on 3 Å molecular sieves. Other reaction grade solvents were stored

on 4 Å molecular sieves. Methanol used in the Staudinger/aza-Wit-

tig/Ugi-3CR sequence was distilled from magnesium (5 g/L)/molec-

ular iodine (0.5 g/L) and stored on activated 3 Å molecular sieves

under argon. Ethanol was purged of acetaldehyde contamination

by distillation from zinc/KOH. CH₂Cl₂was distilled prior to use

from P₂O₅. R_Fvalues were determined from TLC analysis using

DC-fertigfolien (Schleicher & Schuell, F1500, LS254) with detec-

tion by spraying with a solution of (NH₄)₆Mo₇O₂₄·4H₂O (25 g/L)

General Procedure B. The Tandem Staudinger/Aza-Wittig/Ugi

Three-Component Reaction of Azido Aldehydes 5,^[4b]50, 85 and 120:

Trimethylphosphane (2 equiv., 1 m in toluene) was added to a co-

oled (0 °C), anhydrous solution of the appropriate azido aldehyde

(1 equiv.) in anhydrous MeOH (0.2 m). The reaction mixture was

stirred for 3 h at 0 °C until TLC analysis indicated complete con-

sumption of the azido aldehyde and the appearance of the interme-

diate phosphazene [R_f= 0 (EtOAc/toluene, 1:2)]. The reaction mix-

ture was concentrated and coevaporated with toluene (3ϫ), con-

comitant TLC analysis showed complete disappearance of the

baseline phosphazene intermediate and emergence of the cyclic im-

ine [R_fof imine from 5 = 0.34 (EtOAc/toluene, 1:4); imine from 50

= 0.38 (EtOAc/PE, 1:1); imine from 85 = 0.15 (EtOAc/toluene, 1:4);

imine from 120 = 0.33 (EtOAc/toluene, 1:3)]. The crude cyclic imine

was dissolved in anhydrous MeOH (0.3 m) or CH₃CN (0.3 m for

6428

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

reactions with InCl₃), divided into the appropriate amount of por-

tions and cooled to 0 °C. Where appropriate, InCl₃(1.1 equiv.) was

added to the CH₃CN solutions of cyclic imine. The appropriate

carboxylic acid (1.1 equiv.) and isocyanide (1.3 equiv.) were then

successively added and the reaction mixture was stirred for 20 h at

0–5 °C. Saturated aq. NaHCO₃was added to the mixture, which

was warmed to room temperature whilst stirring. Ethyl acetate was

added and the organic phase was washed with aq. sat. NaHCO₃.

The organic phase was dried (Na₂SO₄), concentrated and the prod-

uct was isolated by silica gel column chromatography (EtOAc in

toluene, 5 to 50%) to afford the product as a light-yellow oil.

with MeOH. The filtrate was concentrated by coevaporation with

toluene. In the case of incomplete reduction, hydrogenolysis was

repeated at higher H₂pressure (ca. 5 bar) in a Parr apparatus. The

obtained residue was purified by silica gel column chromatography

(MeOH/CH₂Cl₂, 5Ǟ20% + 2% NH₄OH) to yield the deprotected

iminosugar as a colorless oil.

All iminosugars that do not contain a 5-(adamantane-1-yl-meth-

oxy)-1-pentyl moiety were deprotected by a BCl₃-mediated debenz-

ylatyion. Boron-trichloride-mediated debenzylation: Boron trichlo-

ride (10 equiv., 1 m in CH₂Cl₂) was added to a cooled (0 °C) solu-

tion of the benzylated iminosugar (1 equiv.) in CH₂Cl₂(0.05 m).

The reaction mixture was stirred for 20 h at 0–5 °C after which

MeOH (0.5 mL) was carefully added. The reaction mixture was

concentrated and coevaporated with toluene (3ϫ). The obtained

residue was purified by silica gel column chromatography (MeOH/

CH₂Cl₂, 5Ǟ20% + 2% NH₄OH) to yield the deprotected imi-

nosugar as a colorless oil.

General Procedure C. Acid-Mediated Isomerization and Hydrolysis

of 1-Cyclohexenecarboxamides: The 1-cyclohexenecarboxamide-

containing iminosugar was dissolved in THF (0.05 m) containing

1.6% aq. HCl (from 36% aq. HCl). The reaction mixture was

stirred for 20 h during which it became brown. Sodium carbonate

was added to quench the reaction mixture and subsequently re-

moved by filtration. The filtrate was concentrated and the resulting

residue was purified by silica gel column chromatography (EtOAc/

toluene, 0Ǟ100%; 5% AcOH was added to the eluent if the hy-

drolysis produced a carboxylic acid) to provide the product as a

colorless oil.

General Method G. N-Alkylation of Deprotected Iminosugars by Re-

ductive Amination: Sodium cyanoborohydride (5 equiv.) was added

to an anhydrous solution of the iminosugar (1 equiv.) and either

butyraldehyde (5 equiv.) or 5-(adamantane-1-ylmethoxy)-1-penta-

nal (3 equiv.)^[6c]in a mixture of anhydrous MeOH and AcOH

(0.05 m, 100:1, v/v). The reaction mixture was stirred for 20 h and

subsequently 4 m HCl (0.5 mL; in dioxane/H₂O) was added. The

mixture was stirred for 3 h and subsequently concentrated and co-

evaporated with toluene (3ϫ). The obtained residue was purified

by silica gel column chromatography (5Ǟ20% MeOH in CH₂Cl₂

+ 2% NH₄OH) to yield the deprotected iminosugar as a colorless

oil.

General Procedure D. Iodine-Mediated Deprotection of Pent-4-en-

amides: Molecular iodine (3 equiv.) was added to a solution of the

pent-4-enamide (1 equiv.) in THF/H₂O (0.05 m; 3:1, v/v). The reac-

tion mixture was stirred for 30–60 min until TLC analysis indicated

complete conversion into a lower running product. Aqueous 1 m

Na₂S₂O₃was added and the mixture was vigorously stirred for

30 min. The suspension was poured into a mixture of 1 m aq.

Na₂S₂O₃/sat aq. NaCl (1:1, v/v) and extracted with EtOAc (3ϫ).

The combined organic layers were dried (Na₂SO₄) and concen-

trated. The residue was purified by silica gel column chromatog-

raphy [25% EtOAc in toluene until (R/S)-γ-iodomethyl-gamma-

butyrolactone has eluted, then 25 to 100% EtOAc in toluene; then

optional isocratic 10% MeOH in EtOA + 2% NH₄OH for low

running products] to yield the deprotected secondary amine as a

colorless oil. R_f(R/S)-γ-iodomethyl-gamma-butyrolactone = 0.70

(EtOAc/toluene, 2:1).

5-(Adamantan-1-yl-methoxy)pentyl Azide (7): Sodium azide (1.56 g,

240 mmol) was added to an anhydrous solution of 5-(adamantan-

1-yl-methoxy)pentyl bromide (6; 6.0 g, 191 mmol)^[6c]in DMSO

(20 mL). The reaction mixture was stirred for 20 h. The mixture

was diluted with Et₂O (500 mL) and washed successively with H₂O

(2ϫ 500 mL) and satd. aq. NaCl (200 mL). The organic phase was

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

gel column chromatography (toluene/PE, 10Ǟ70%) to give 7

(5.14 g, 185 mmol, 95%) as a colorless oil. R_f(6) = 0.60 (4%

EtOAc/PE); R_f(7) = 0.70 (1:4; EtOAc/PE). ¹H NMR (400 MHz,

CDCl₃): δ = 3.38 (t, J = 6.3 Hz, 2 H, CH₂-5 pentyl), 3.27 (t, J =

7.0 Hz, 2 H, CH₂-1 pentyl), 2.95 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H,

3ϫCH Ada), 1.77–1.54 (m, 12 H, 3ϫCH₂Ada, CH₂-2, CH₂-4

pentyl), 1.53 (d, J = 2.7 Hz, 6 H, 3ϫCH₂Ada), 1.49–1.39 (m, 2 H,

CH₂-3 pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 82.2

(OCH₂-Ada), 71.4 (CH₂-5 pentyl), 51.6 (CH₂-1 pentyl), 39.9 (CH₂

Ada), 37.4 (CH₂Ada), 34.3 (C_qAda), 29.3 (CH₂-4 pentyl), 28.9

(CH₂-2 pentyl), 28.5 (CH Ada), 23.7 (CH₂-3 pentyl) ppm. IR (thin

General Method E. N-Alkylation of Benzyl-Protected Iminosugars

by Reductive Amination: Sodium sulfate (10 equiv.) was added to

an anhydrous solution of the iminosugar (1 equiv.) and either but-

yraldehyde (5 equiv.) or 5-(adamantane-1-ylmethoxy)-1-pentanal

(3 equiv.)^[6c]in a mixture of EtOH and AcOH (0.05 m, 20:1, v/v).

Subsequently, NaBH₃CN (4 equiv.) was added to the mixture and

the reaction mixture was stirred for 20 h, then Et₂O (2-fold reaction

volume) and satd. aq. NaHCO₃(2-fold reaction volume) were

added and vigorously mixed with the reaction mixture. The organic

phase was isolated and the aqueous phase was extracted with Et₂O

(2ϫ). The combined organic layers were dried (Na₂SO₄) and con-

centrated. The crude N-alkylated compound was used in the ensu-

ing benzyl ether deprotection reaction.

film): ν

= 2902, 2848, 2093, 1727, 1453, 1358, 1259, 1158,

˜

max

1112 cm^–1. HRMS: calcd. for [C₁₆H₂₇N₃O + H]⁺278.2227 [M +

H]⁺; found 278.2228.

5-(Adamantan-1-yl-methoxy)pentan-1-amine (8): Trimethylphos-

phane (33 mL, 33 mmol, 1 m in THF) was added over a 2 min

period to a cooled (0 °C) solution of 7 (4.57 g, 16.5 mmol) in THF

(83 mL) and H₂O (7 mL). The reaction mixture stirred for 3 h at

0 °C after which it was concentrated and coevaporated three times

with toluene. The residue was purified by silica gel column

chromatography (MeOH/EtOAc, 10Ǟ70% + 5% NH₄OH). Puri-

fied 8 contained some dissolved silica gel that could be removed by

redissolving 8 in CH₂Cl₂and passing it over a glassfibre filter to

provide 8 (3.48 g, 13.86 mmol, 84%) after concentration as a color-

less oil. R_f= 0.10 (25% MeOH/EtOAc). ¹H NMR (200 MHz,

CDCl₃): δ = 3.38 (t, J = 6.4 Hz, 1 H, CH₂-5 pentyl), 2.95 (s, 2 H,

General Procedure F. Deprotection of Benzyl Ethers: All 5-(ada-

mantane-1-yl-methoxy)-1-pentyl moiety containing iminosugars

were deprotected by Pd/C catalyzed hydrogenation. Hydrogenolysis

at atmospheric H₂pressure: A solution of compound (ca. 50–

250 μmol) in EtOH (4 mL) was acidified to pH ca. 2 with 1 m aq.

HCl. Argon was passed through the solution for 5 min, after which

a catalytic amount of Pd/C (ca. 50 mg, 10 wt.-% on act. carbon)

was added. Hydrogen was passed through the reaction mixture for

15 min and the reaction was stirred for 20 h under atmospheric

hydrogen pressure. Pd/C was removed by filtration through a glass

microfibre filter, followed by thorough rinsing of the filter cake

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6429

H. S. Overkleeft et al.

FULL PAPER

OCH₂-Ada), 2.70 (t, J = 6.7 Hz, 1 H, CH₂-1 pentyl), 1.94 (s, 3 H,

enyl), 5.06–4.89 (m, 2 H), 4.85–4.66 (m, 2 H, =CH₂pentenyl), 4.85–

3ϫCH Ada), 1.73–1.44 (m, 18 H, 6ϫCH₂Ada, 3ϫCH₂pent- 4.66 (m, 2 H), 4.64 (d, J = 6.0 Hz, 1 H, 2-H), 4.60–4.46 (m, 3 H),

yl) ppm. ¹³C NMR (50 MHz, CDCl₃): δ = 81.8 (OCH₂-Ada), 71.3

4.44–4.40 (m, 1 H, 4-H), 4.39–4.33 (m, 1 H, 5-H), 4.14 (t, J =

(CH₂-5 pentyl), 41.9 (CH₂-1 pentyl), 39.6 (CH₂Ada), 37.2 (CH₂10.1 Hz, 1 H, 6a-H), 3.88 (dd, J = 5.0, 6.7 Hz, 1 H, 3-H), 3.82 (dd,

Ada), 34.0 (C_qAda), 29.4, 29.3 (2ϫCH₂pentyl), 28.2 (CH Ada),

J = 3.3, 10.1 Hz, 1 H, 6b-H), 3.29–3.20 (m, 2 H, CH₂-5 pent-

yl), 3.18–2.97 (m, 1 H, NCH₂-1 pentyl), 2.90 (s, 2 H, OCH₂-Ada),

2.87–2.72 (m, 2 H, NCH₂pentenyl), 2.45–2.27 (m, 2 H, CH₂pent-

enyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.67 (dd, J = 12.7, 38.4 Hz, 6 H,

3ϫCH₂Ada), 1.59–0.97 (m, 12 H, 3ϫCH₂Ada, 3ϫCH₂pent-

yl) ppm. ¹³C NMR (150 MHz, CDCl₃, major rotamer): δ = 173.7

(NC=O pentenyl), 167.7 [NHC(O)-1], 138.3, 137.7, 137.4 (3ϫC_q

Bn), 137.2 (=CH pentenyl), 128.6–127.5 (CH_ArBn), 115.2 (=CH₂

pentenyl), 81.8 (OCH₂-Ada), 78.8 (C-3), 76.7 (C-4), 74.8, 73.5, 72.4

(3ϫCH₂Bn), 71.3 (CH₂-5 pentyl), 69.3 (C-6), 64.3 (C-2), 58.5 (C-

5), 39.7 (CH₂Ada), 39.4 (NCH₂-1 pentyl), 37.3 (CH₂Ada), 34.0

(C_qAda), 33.4 (NCH₂pentenyl), 29.3, 29.2, 28.9 (CH₂pentenyl,

CH₂-2, CH₂-4 pentyl), 28.3 (CH Ada), 23.4 (CH₂-3 pentyl) ppm.

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

= 3358, 2899, 2847,

˜

2

max

1575, 1453, 1297, 1156, 1111, 945, 860, 745 cm^–1. HRMS: calcd.

for [C₁₆H₂₉NO + H]⁺252.2322 [M + H]⁺; found 252.2321.

N-[5-(Adamantan-1-yl-methoxy)pentyl]formamide (9): Acetic formic

anhydride was prepared by heating a mixture of acetic anhydride

(1.51 mL, 16.0 mmol) and formic acid (0.66 mL, 17.6 mmol) at

55 °C for 2 h. The prepared acetic formic anhydride (16.0 mmol)

was cooled to 0 °C and added to a cooled (0 °C) solution of 8

(2.01 g, 8.0 mmol) in CH₂Cl₂(22 mL). The reaction mixture was

stirred at room temp. for 20 h, after which it was concentrated. The

residue was purified by silica gel column chromatography (EtOAc/

PE, 30Ǟ90%) to afford 9 (1.84 g, 6.6 mmol, 82%) as a colorless

oil. R_f= 0.39 (EtOAc); KMnO₄staining. ¹H NMR (500 MHz,

CDCl₃): δ = 8.17 [s, 1 H, HC(O)N], 5.56–5.41 [m, 1 H, C(O)NH],

3.38 (t, J = 6.3 Hz, 2 H, CH₂-5 pentyl), 3.32 (dd, J = 6.7, 13.4 Hz,

1 H, CHH-1 pentyl), 3.25 (dd, J = 7.0, 13.0 Hz, 1 H, CHH-1 pent-

yl), 2.95 (s, 2 H, OCH₂-Ada), 1.96 (s, 3 H, 3ϫCH Ada), 1.68 (dd,

J = 12.0, 34.5 Hz, 6 H, 3ϫCH₂Ada), 1.62–1.53 (m, 4 H, CH₂-2,

CH₂-4 pentyl), 1.52 (d, J = 2.3 Hz, 6 H, 3ϫCH₂Ada), 1.45–1.32

(m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR (50 MHz, CDCl₃): δ =

161.5 (C=O), 81.9 (OCH₂-Ada), 71.3 (CH₂-5 pentyl), 39.7 (CH₂

Ada), 38.1 (CH₂-1 pentyl), 37.2 (CH₂Ada), 34.0 (C_qAda), 29.1,

29.1 (2ϫCH₂pentyl), 28.2 (CH Ada), 23.5 (CH₂-3 pentyl) ppm. IR

IR (thin film): ν

= 3316, 2901, 2848, 1653, 1532, 1453, 1407,

˜

max

1359, 1212, 1097, 911, 733, 696 cm^–1. [α]²_D⁰= 6.3 (c = 9.0, CHCl₃).

HRMS: calcd. for [C₄₈H₆₂O₆N₂+ H]⁺763.4681 [M + H]⁺; found

763.4683.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-(pent-4-enimido)-D-talo-hexonamide (14): Subjecting azido alde-

hyde 5 (750 μmol) to the tandem SAWU-3CR (General Procedure

B in the presence of InCl₃in CH₃CN) produced a separable 1.7:1

mixture of 14 (170 mg, 223 μmol) and 13 (100 mg, 131 μmol) in a

1

combined yield of 47%. R_f= 0.49 (EtOAc/toluene, 2:3). H NMR

(600 MHz, CDCl₃, 10:1 mixture of rotamers; major rotamer): δ =

7.36–7.23 (m, 15 H, H_ArBn), 6.63 [t, J = 5.6 Hz, 1 H, C(O)NH],

5.76 (ddt, J = 6.5, 10.2, 16.8 Hz, 1 H, =CH pentenyl), 5.00–4.91

(m, 2 H, =CH₂pentenyl), 4.67 (d, J = 12.0 Hz, 1 H, CHH Bn),

4.61 (d, J = 11.6 Hz, 1 H, CHH Bn), 4.59–4.55 (m, 2 H, 2ϫCHH

Bn), 4.48 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.46 (dd, J = 4.3, 7.8 Hz,

1 H, 4-H), 4.42 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.39 (s, 1 H, 2-

H), 4.38–4.35 (m, 1 H, 5-H), 4.13 (dd, J = 3.5, 10.6 Hz, 1 H, 6a-

H), 4.06 (d, J = 4.3 Hz, 1 H, 3-H), 3.70 (dd, J = 6.1, 10.6 Hz, 1 H,

6b-H), 3.35 (t, J = 6.6 Hz, 2 H, CH₂-5 pentyl), 3.20 (dt, J = 7.1,

13.5 Hz, 1 H, NCHH-1 pentyl), 3.07 (dt, J = 7.1, 12.7 Hz, 1 H,

NCHH-1 pentyl), 2.94 (s, 2 H, OCH₂-Ada), 2.75 (ddd, J = 6.3, 8.8,

15.4 Hz, 1 H, NCHH pentenyl), 2.53 (ddd, J = 6.4, 8.9, 15.6 Hz, 1

H, NCHH pentenyl), 2.40–2.25 (m, 2 H, CH₂pentenyl), 1.95 (s, 3

H, 3ϫCH Ada), 1.67 (dd, J = 12.1, 36.2 Hz, 6 H, 3ϫCH₂Ada),

1.59–1.49 (m, 8 H, 3ϫCH₂Ada, CH₂-4 pentyl), 1.49–1.42 (m, 2 H,

CH₂-2 pentyl), 1.36–1.29 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR

(150 MHz, CDCl₃, major rotamer): δ = 174.3 (NC=O pentenyl),

169.6 [NHC(O)-1], 138.2, 137.9, 137.9 (3ϫC_qBn), 137.6 (=CH

pentenyl), 128.6, 128.5, 128.0, 128.0, 127.9, 127.8, 127.7 (CH_ArBn),

115.2 (=CH₂pentenyl), 82.1 (OCH₂-Ada), 78.9 (C-4), 78.4 (C-3),

73.5, 72.7 (3ϫCH₂Bn), 71.7 (C-6), 71.6 (CH₂-5 pentyl), 65.4 (C-

2), 59.3 (C-5), 39.9 (CH₂Ada), 39.8 (NCH₂-1 pentyl), 37.4 (CH₂

Ada), 34.2 (C_qAda), 33.8 (NCH₂pentenyl), 29.4, 29.3, 29.3 (CH₂

pentenyl, CH₂-2, CH₂-4 pentyl), 28.4 (CH Ada), 23.7 (CH₂-3 pent-

(thin film): ν

= 3288, 2899, 2847, 1666, 1540, 1452, 1382, 1232,

˜

max

1157, 110, 753 cm^–1. HRMS: calcd. for [C₁₇H₂₉NO₂+ H]⁺

280.2271 [M + H]⁺; found 280.2272.

N-[5-(Adamantan-1-yl-methoxy)pentyl] Isocyanide (10): Phosphoryl

chloride (0.51 mL, 5.49 mmol) was added dropwise to an anhy-

drous and cooled (–30 °C) solution of 9 (1.02 g, 3.66 mmol) and

Et₃N (2.54 mL, 18.3 mmol) in CH₂Cl₂(19 mL). The reaction mix-

ture was stirred for 1 h at –30 °C, after which TLC analysis indi-

cated complete consumption of 9. The dark-brown reaction mix-

ture was quenched by addition of satd. aq. NaHCO₃(5 mL). The

reaction mixture was diluted with Et₂O (100 mL) and washed suc-

cessively with satd. aq. NaHCO₃(2ϫ 100 mL) and brine (50 mL).

The organic phase was dried (Na₂SO₄) and concentrated. The re-

sulting residue was purified by silica gel column chromatography

(CH₂Cl₂/hexane, 20Ǟ100%) to afford 10 (773 mg, 2.96 mmol,

81%) as a colorless oil. Isocyanide 10 was preferably used immedi-

ately but was stable when stored at –20 °C under argon. R_f= 0.90

(EtOAc); 0.40 (EtOAc/PE, 1:9); KMnO₄staining. ¹H NMR

(400 MHz, CDCl₃): δ = 3.43–3.34 (m, 4 H, CH₂-1 pentyl, CH₂-5

pentyl), 2.95 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH Ada), 1.76–

1.45 (m, 18 H, 6ϫCH₂Ada, 3ϫCH₂pentyl) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 155.9 (t, J_CN= 5.5 Hz, NC), 81.9 (OCH₂-

Ada), 71.0 (CH₂-5 pentyl), 41.5 (t, J_N–C1= 6.4 Hz, CH₂-1), 39.7

(CH₂Ada), 37.2 (CH₂Ada), 34.0 (C_qAda), 28.9, 28.6, 28.3 (CH

yl) ppm. IR (thin film): ν_max= 3308, 2901, 2848, 1651, 1622, 1545,

˜

1452, 1360, 1146, 1097, 1054, 1027, 911, 734, 696 cm^–1. [α]²_D⁰= 25.5

(c = 2.4, CHCl₃). HRMS: calcd. for [C₄₈H₆₂O₆N₂+ H]⁺763.4681

[M + H]⁺; found 763.4684.

Ada), 23.2 (CH -3 pentyl) ppm. IR (thin film): ν

= 2900, 2847,

˜

2

max

2146, 1453, 1358, 1157, 1102, 2929, 1652, 1460, 1058 cm^–1.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-(pent-4-enimido)-D-galacto-hexonamide (13): Subjecting azido

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-

aldehyde 5 (200 μmol) to the tandem SAWU-3CR (General Pro-

cedure B in MeOH) produced a separable 1:20 mixture of 14 (4 mg,

5 μmol) and 13 (91 mg, 119 μmol) in a combined yield of 62%. R_f

= 0.15 (EtOAc/toluene, 2:3). ¹H NMR (600 MHz, CDCl₃, 2:1 mix-

ture of rotamers; major rotamer): δ = 7.41–7.12 (m, 15 H, H_ArBn),

6.22 [t, J = 5.7 Hz, 1 H, C(O)NH], 5.84–5.72 (m, 1 H, =CH pent-

4-enimido)-D-galacto-hexonamide (15): Subjecting azido aldehyde 5

(500 μmol) to the tandem SAWU-3CR (General Procedure B in

MeOH) produced a separable 1:15 mixture of 16 (15 mg, 23 μmol)

and 15 (216 mg, 338 μmol) in a combined yield of 72%. R_f= 0.24

1

(EtOAc/toluene, 2:3). H NMR (400 MHz, CDCl₃, 2:1 mixture of

rotamers; major rotamer): δ = 7.32–7.25 (m, 15 H, H_ArBn), 6.02

6430

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

[s, 1 H, C(O)NH], 5.85–5.73 (m, 1 H, =CH pentenyl), 5.06–4.91 CH₂pentenyl), 1.35–0.94 (m, 6 H, 3ϫCH₂pentyl), 0.80–0.73 (m,

(m, 2 H, =CH₂pentenyl), 4.75 (d, J = 11.5 Hz, 1 H, CHH Bn), 6 H, CH₃-5 pentyl) ppm. ¹³C NMR (150 MHz, CDCl₃, major rot-

4.69 (d, J = 11.6 Hz, 1 H, CHH Bn), 4.58 (d, J = 11.6 Hz, 1 H,

CHH Bn), 4.53–4.47 (m, 3 H, 2-H, CHH Bn, CHH Bn), 4.44–4.36

amer): δ = 173.8 (NC=O pentenyl), 167.7 [NHC(O)-1], 138.4,

137.8, 137.5 (3ϫC_qBn), 137.2 (=CH pentenyl), 128.7–127.5 (CH_Ar

(m, 2 H, 4-H, CHH Bn), 4.34–4.27 (m, 1 H, 5-H), 4.11 (dd, J = Bn), 115.2 (=CH₂pentenyl), 78.8 (C-4), 76.8 (C-3), 74.9, 73.6, 72.4

10.2 Hz, 1 H, 6-Ha), 3.87 (d, J = 9.9 Hz, 1 H, 6-Hb), 3.83 (dd, J

= 4.8 Hz, 1 H, 3-H), 2.89–2.84 (m, 1 H, NCHH pentenyl), 2.46–

2.31 (m, 3 H, NCHH pentenyl, CH₂pentenyl), 1.61 (d, J = 14.8 Hz,

1 H, CH2-H tMB), 1.46 (d, J = 15.2 Hz, 1 H, CH2-H tMB), 1.00

(3ϫCH₂Bn), 69.4 (C-6), 64.4 (C-2), 58.6 (C-5), 39.4 (NCH₂-1

pentyl), 33.5 (NCH₂pentenyl), 29.0, 22.3, 14.1 (CH₃-5

pentyl) ppm. IR (thin film): ν

= 3320, 2939, 2868, 1652, 1532,

˜

max

1454, 1406, 1212, 1142, 1096, 1025, 911, 734, 696 cm^–1. [α]²_D⁰= 8.9

(d, J = 5.6 Hz, 6 H, 2ϫCH₃tMB), 0.87 (s, 9 H, 2ϫCH₃, CH₃-4 (c=4.2,CHCl₃).HRMS:calcd.for[C₃₇H₄₆O₅N₂+H]⁺599.3479[M+

tMB) ppm. ¹³C NMR (100 MHz, CDCl₃, major rotamer): δ =

173.8 (NC=O pentenyl), 166.3 [NHC(O)-1], 138.0, 137.5 (2ϫC_q

Bn), 137.1 (=CH pentenyl), 137.0 (C_qBn), 128.3–127.1 (CH_ArBn),

114.9 (=CH₂pentenyl), 78.7 (C-4), 76.6 (C-3), 74.6, 73.3, 72.0

(3ϫCH₂Bn), 69.8 (C-6), 64.7 (C-2), 59.0 (C-5), 55.6 (NHC_q-1

tMB), 53.3 (CH₂-2 tMB), 33.3 (CH₂pentenyl), 31.4 (C_q-3 tMB),

31.3, 31.2 (2ϫCH₃-2 tMB), 31.1 (3ϫCH₃tMB), 28.6 (CH₂pent-

H]⁺; found 599.3478.

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-4-enimido)-D-talo-

hexonamide (18): Subjecting azido aldehyde 5 (750 μmol) to the

tandem SAWU-3CR (General Procedure B in the presence of InCl₃

in CH₃CN) produced a separable 5.4:1 mixture of 18 (128 mg,

215 μmol) and 17 (24 mg, 40 μmol) in a combined yield of 34%.

1

R_f= 0.72 (EtOAc/toluene, 2:3). H NMR (600 MHz, CDCl₃, 5.5:1

enyl) ppm. IR (thin film): ν

= 3323, 2951, 1666, 1521, 1400,

˜

max

mixture of rotamers; major rotamer): δ = 7.35–7.24 (m, 15 H, H_Ar

Bn), 6.76 [t, J = 5.6 Hz, 1 H, C(O)NH], 5.76 (ddt, J = 6.5, 10.2,

16.8 Hz, 1 H, =CH pentenyl), 4.99–4.89 (m, 2 H, =CH₂pentenyl),

1098, 734, 697 cm^–1. [α]²_D⁰= 11.4 (c = 9.0, CHCl₃). HRMS: calcd.

for [C₄₀H₅₂O₅N₂+ H]⁺641.3949 [M + H]⁺; found 641.3949.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent- 4.67–4.52 (m, 4 H, 2ϫCH₂Bn), 4.50–4.45 (m, 2 H, 4-H, CHH Bn),

4-enimido)-

D

-talo-hexonamide (16): Subjecting azido aldehyde 5

4.43 (s, J = 12.2 Hz, CHH Bn), 4.42 (s, 1 H, H2), 4.40–4.36 (m, 1

H, 5-H), 4.13 (dd, J = 3.5, 10.6 Hz, 1 H, 6a-H), 4.04 (d, J = 4.3 Hz,

1 H, 3-H), 3.70 (dd, J = 6.2, 10.6 Hz, 1 H, 6b-H), 3.20 (dt, J = 7.1,

13.5 Hz, 1 H, NCHH-1 pentyl), 3.04 (dt, J = 7.2, 12.7 Hz, 1 H,

NCHH-1 pentyl), 2.75 (ddd, J = 6.2, 8.9, 15.5 Hz, 1 H, NCHH

pentenyl), 2.54 (ddd, J = 6.3, 9.0, 15.6 Hz, 1 H, NCHH pentenyl),

2.44–2.26 (m, 2 H, CH₂pentenyl), 1.46–1.39 (m, 2 H, CH₂-2 pent-

yl), 1.33–1.21 (m, 4 H, CH₂-3, CH₂-4 pentyl), 0.88 (t, J = 7.2 Hz,

3 H, CH₃-5 pentyl) ppm. ¹³C NMR (150 MHz, CDCl₃, major rot-

amer): δ = 174.3 (NC=O pentenyl), 169.6 [NHC(O)-1], 138.2,

137.9, 137.8 (3ϫC_qBn), 137.6 (=CH pentenyl), 129.0, 128.6, 128.6,

128.5, 128.4, 128.3, 128.0, 128.0, 127.9, 127.8, 127.7, 127.6 (CH_Ar

Bn), 115.2 (=CH₂pentenyl), 78.8 (C-4), 78.4 (C-3), 73.4, 72.6, 72.5

(3ϫCH₂Bn), 71.7 (C-6), 65.4 (C-2), 59.2 (C-5), 39.7 (NCH₂-1 pent-

(600 μmol) to the tandem SAWU-3CR (General Procedure B in the

presence of InCl₃in CH₃CN) produced a separable 5.3:1 mixture

of 16 (204 mg, 318 μmol) and 15 (38 mg, 60 μmol) in a combined

yield of 63%. R_f= 0.72 (EtOAc/toluene, 2:3). ¹H NMR (400 MHz,

CDCl₃, 6:1 mixture of rotamers; major rotamer): δ = 7.33–7.22 (m,

15 H, H_Ar), 6.28 [s, 1 H, C(O)NH], 5.81–5.74 (m, 1 H, =CH pent-

enyl), 4.97 (ddd, J = 1.2, 16.8, 37.2 Hz, 2 H, =CH₂pentenyl), 4.65

(d, J = 12.0 Hz, 1 H, CHH Bn), 4.63 (d, J = 12.0 Hz, 1 H, CHH

Bn), 5.58 (d, J = 12.0 Hz, 1 H, CHH Bn), 4.55 (d, J = 12.0 Hz, 1

H, CHH Bn), 4.47 (d, J = 12.0 Hz, 1 H, CHH Bn), 4.44 (dd, J =

4.2, 7.8 Hz, 1 H, 4-H), 4.41 (d, J = 12.0 Hz, 1 H, CHH Bn), 4.34–

4.32 (m, 2 H, 2-H, 5-H), 4.16 (dd, J = 3.6, 10.8 Hz, 1 H, 6a-H),

4.08 (d, J = 4.2 Hz, 1 H, 3-H), 3.69 (dd, J = 5.4, 10.8 Hz, 1 H, 6b-

H), 2.76–2.71 (m, 1 H, NCHH pentenyl), 2.56–2.51 (m, 1 H, yl), 33.8 (NCH₂pentenyl), 29.3 (CH₂pentenyl), 29.2, 29.1, 22.5

NCHH pentenyl), 2.41–2.31 (m, 2 H, CH₂pentenyl), 1.71 (d, J = (3ϫCH pentyl), 14.2 ppm. IR (thin film): ν_max= 3312, 2956, 2929,

15.0 Hz, 1 H, CHH-2 tMB), 1.60 (d, J = 15.0 Hz, 1 H, CHH-2 2869, 1652, 1622, 1557, 1453, 1434, 1361, 1143, 1097, 1027, 1000,

˜

2

tMB), 1.32 (d, J = 14.4 Hz, 6 H, 2ϫCH₃tMB), 0.95 (s, 9 H,

911, 734, 697 cm^–1. [α]²_D⁰= 26.6 (c = 2.5, CHCl₃). HRMS: calcd.

2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (100 MHz, CDCl₃, major for [C₃₇H₄₆O₅N₂+ H]⁺599.3479 [M + H]⁺; found 599.3478.

rotamer): δ = 174.1 (NC=O pentenyl), 168.1 [NHC(O)-1], 137.8,

137.7, 137.6 (3ϫC_qBn), 137.3 (=CH pentenyl), 128.4, 128.3, 128.2,

128.0, 127.6, 127.5, 127.4 (CH_ArBn), 114.9 (=CH₂pentenyl), 78.7

(C-4), 77.9 (C-3), 73.2, 72.4 (3ϫCH₂Bn), 71.5 (C-6), 65.8 (C-2),

59.1 (C-5), 55.2 (NHC_q-1 tMB), 51.4 (CH₂-2 tMB), 33.6 (NCH₂

pentenyl), 31.4 (C_q-3 tMB), 31.3 (CH₃-4, 2ϫCH₃tMB), 29.0 (CH₂

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-imino-D-galacto-hexonamide (19): Compound 19 (385 mg,

0.57 mmol) was synthesized in 97% yield from 13 (0.58 mmol) by

deprotection of the pent-4-enamide (General Procedure D). R_f=

1

0.25 (EtOAc/toluene, 2:1). H NMR (600 MHz, CDCl₃): δ = 7.68

[t, J = 5.5 Hz, 1 H, C(O)NH], 7.38–7.18 (m, 15 H, H_ArBn), 5.91–

5.73 (s, NH), 4.95 (dd, J = 4.1, 5.8 Hz, 1 H, 3-H), 4.84 (d, J =

6.0 Hz, 1 H, 2-H), 4.74 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.70 (d, J

= 11.3 Hz, 1 H, CHH Bn), 4.62–4.46 (m, 4 H, 2ϫCH₂Bn), 4.35

(dd, J = 3.8, 6.4 Hz, 1 H, 4-H), 4.16 (dt, J = 5.4, 10.8 Hz, 1 H, 5-

H), 3.96 (dd, J = 10.4 Hz, 1 H, 6a-H), 3.70 (dd, J = 4.6, 10.4 Hz,

1 H, 6b-H), 3.37 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.32–3.16 (m,

2 H, CH₂-1 pentyl), 2.91 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH

Ada), 1.67 (dd, J = 12.4, 40.4 Hz, 6 H, 3ϫCH Ada), 1.61–1.54 (m,

pentenyl), 28.8, 28.6 (2ϫCH₃tMB) ppm. IR (thin film): ν

=

˜

max

3329, 2950, 1679, 1624, 1544, 1422, 1096, 733, 696 cm^–1. [α]²_D⁰

22.3 (c = 6.1, CHCl₃). HRMS: calcd. for [C₄₀H₅₂O₅N₂+ H]⁺

641.3949 [M + H]⁺; found 641.3949.

Pentyl

3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-4-enimido)-D-

galacto-hexonamide (17): Subjecting azido aldehyde 5 (194 μmol) to

the tandem SAWU-3CR (General Procedure B in MeOH) pro-

duced a separable 1:21 mixture of 18 (5 mg, 8 μmol) and 17

(104 mg, 174 μmol) in a combined yield of 94%. R_f= 0.40 (EtOAc/ 2 H, CH₂-4 pentyl), 1.52 (d, J = 6.6 Hz, 6 H, 3ϫCH Ada), 1.47–

toluene, 2:1). ¹H NMR (600 MHz, CDCl₃, 2:1 mixture of rotamers; 1.36 (m, 3 H, CH₂-2, CHH-3 pentyl), 1.31–1.23 (m, 1 H, CHH-3

major rotamer): δ = 7.38–7.20 (m, 15 H, H_ArBn), 6.19 [t, J =

5.5 Hz, 1 H, C(O)NH], 5.84–5.74 (m, 1 H, =CH pentenyl), 5.07–

pentyl) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 164.8 [C(O)-1],

137.3, 137.1, 136.9 (3ϫC_qBn), 128.7, 128.7, 128.6, 128.3, 128.1,

4.91 (m, 2 H, =CH₂pentenyl), 4.86–4.46 (m, 7 H, 2-H, 3ϫCH₂128.1, 127.7, 127.7 (CH_ArBn), 82.1 (C-3), 82.0 (C-4), 78.7, 78.4,

Bn), 4.44–4.41 (m, 1 H, 4-H), 4.39–3.34 (m, 1 H, 5-H), 4.14 (dd, J

= 10.2 Hz, 1 H, 6a-H), 3.88 (dd, J = 5.0, 6.7 Hz, 1 H, 3-H), 3.83

74.7, 73.7, 73.7, 71.4, 71.4 (3ϫCH₂Bn), 66.1 (C-6), 59.9 (C-2), 58.5

(C-5), 40.5 (CH₂-1 pentyl), 39.9 (CH₂Ada), 37.4 (CH₂Ada), 34.2

(dd, J = 3.6, 10.3 Hz, 1 H, 6b-H), 3.19–2.97 (m, 2 H, NCH₂-1 (C_qAda), 29.3 (CH₂pentyl), 29.2, 29.0 (CH₂pentyl), 28.4 (CH

pentyl), 2.97–2.69 (m, 2 H, NCH₂pentenyl), 2.46–2.29 (m, 2 H,

Ada), 23.7, 23.7 (CH -3 pentyl) ppm. IR (thin film): ν

= 3242,

˜

2

max

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6431

H. S. Overkleeft et al.

FULL PAPER

2900, 2847, 1686, 1544, 1453, 1359, 1153, 1097, 1026, 734,

697 cm^–1. [α]²_D⁰= 13.5 (c = 1.8, CHCl₃). HRMS: calcd. for

[C₄₃H₅₆O₅N₂+ H]⁺681.4262 [M + H]⁺; found 681.4262.

(dd, J = 4.7, 6.0 Hz, 1 H, 4-H), 3.78 (dd, J = 9.3 Hz, 1 H, 6a-H),

3.72 (dd, J = 4.8, 9.6 Hz, 1 H, 6b-H), 3.67 (d, J = 3.2 Hz, 1 H, 2-

H), 3.52 (ddd, J = 4.8, 5.9, 8.9 Hz, 1 H, 5-H), 2.55 (s, 1 H, NH),

1.72 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.63 (d, J = 14.8 Hz, 1

H, CHH-2 tMB), 1.36 (d, J = 17.3 Hz, 6 H, 2ϫCH₃tMB), 0.94 (s,

9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (150 MHz, CDCl₃): δ

= 171.0 [C(O)-1], 138.1, 138.0, 137.8 (3ϫC_qBn), 128.3, 128.2,

127.8, 127.7, 127.6, 127.4 (CH_ArBn), 81.1 (C-3), 78.2 (C-4), 73.2,

73.4, 71.5 (3ϫCH₂Bn), 70.3 (C-6), 64.6 (C-2), 58.8 (C-5), 54.2

(NHC_q-1 tMB), 51.7 (CH₂-2 tMB), 31.5 (C_q-3 tMB), 31.3 (2ϫCH₃,

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-imino-D-talo-hexonamide (20): Compound 20 (75 mg,

0.11 mmol) was synthesized in 75% yield from 14 (0.15 mmol) by

deprotection of the pent-4-enamide (General Procedure D). R_f=

1

0.46 (EtOAc/toluene, 1:1). H NMR (600 MHz, CDCl₃): δ = 7.41

[t, J = 5.8 Hz, 1 H, C(O)NH], 7.38–7.24 (m, 15 H, H_ArBn), 4.73

(d, J = 12.2 Hz, 1 H, CHH Bn), 4.65 (d, J = 12.2 Hz, 1 H, CHH

Bn), 4.63 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.53 (d, J = 11.9 Hz, 1

H, CHH Bn), 4.50 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.45 (d, J =

11.8 Hz, 1 H, CHH Bn), 4.10 (dd, J = 4.0 Hz, 1 H, 3-H), 3.95 (dd,

J = 5.1 Hz, 1 H, 4-H), 3.79 (d, J = 3.4 Hz, 1 H, 2-H), 3.77 (dd, J

CH -4 tMB), 29.1, 28.6 (2ϫCH tMB) ppm. IR (thin film): ν =

˜

max

3

3317, 2950, 1668, 1515, 1093, 734, 696 cm^–1. [α]²_D⁰= –14.6 (c = 3.7,

CHCl₃). HRMS: calcd. for [C₃₅H₄₆O₄N₂+ H]⁺559.3530 [M +

H]⁺; found 559.3528.

= 9.2 Hz, 1 H, 6a-H), 3.72 (dd, J = 5.0, 9.5 Hz, 1 H, 6b-H), 3.55– Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-

3.48 (m, 1 H, 5-H), 3.35 (t, J = 6.5 Hz, 2 H, CH₂-5 pentyl), 3.27– amide (23): Compound 23 (341 mg, 0.66 mmol) was synthesized

3.21 (m, 1 H, NCHH-1 pentyl), 3.21–3.09 (m, 1 H, NCHH-1 from 17 (0.86 mmol, 77%) by deprotection of the pent-4-enamide

D-galacto-hexon-

1

pentyl), 2.94 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH Ada), 1.67

(dd, J = 12.1, 37.4 Hz, 6 H, 3ϫCH₂Ada), 1.58–1.49 (m, 8 H,

3ϫCH₂Ada, CH₂-4 pentyl), 1.49–1.41 (m, 2 H, CH₂-2 pentyl),

(General Procedure D). R_f= 0.15 (EtOAc/toluene, 1:1). H NMR

(600 MHz, CDCl₃): δ = 7.70 [s, 1 H, C(O)NH], 7.38–7.19 (m, 15

H, H_ArBn), 6.34–6.11 (s, 1 H, NH), 4.74–4.48 (m, 7 H, 3-H,

1.38–1.29 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR (150 MHz, 3ϫCH₂Bn), 4.47 (d, J = 5.6 Hz, 1 H, 2-H), 4.20 (dd, J = 3.9,

CDCl₃): δ = 172.5 [C(O)-1], 138.4, 138.3, 138.2 (3ϫC_qBn), 128.7,

6.2 Hz, 1 H, 4-H), 3.92–3.86 (m, 1 H, 5-H), 3.83 (dd, J = 9.6 Hz,

128.6, 128.5, 128.2, 128.1, 128.1, 128.0, 127.9, 127.9, 127.8 (CH_Ar

1 H, 6a-H), 3.74–3.67 (m, 1 H, 6b-H), 3.16–3.10 (m, 2 H, NCH₂-

Bn), 82.1 (OCH₂-Ada), 81.7 (C-3), 78.9 (C-4), 73.5, 72.9, 72.0 1 pentyl), 1.39–1.32 (m, 2 H, CH₃-2 pentyl), 1.23–1.13 (m, 4 H,

(3ϫCH₂Bn), 71.5 (CH₂-5 pentyl), 70.6 (C-6), 64.3 (C-2), 59.2 (C-

2ϫCH₂pentyl), 0.80 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C

5), 39.9 (CH₂Ada), 39.3 (NCH₂-1 pentyl), 37.4 (CH₂Ada), 34.3 NMR (150 MHz, CDCl₃): δ = 167.7 [C(O)-1], 137.8, 137.6, 137.4

(C_qAda), 29.6 (CH₂-2 pentyl), 29.4 (CH₂-4 pentyl), 28.5 (CH (3ϫC_qBn), 128.8, 128.4, 128.4, 128.3, 128.3, 128.0, 127.9, 127.9,

Ada), 23.8 (CH -3 pentyl) ppm. IR (thin film): ν

= 3328, 2900, 127.8, 127.7, 127.6, 127.6, 127.5, 127.5, 127.2 (CH_ArBn), 79.1 (C-

˜

2

max

2848, 1667, 1653, 1519, 1453, 1360, 1096, 1058, 1027, 734,

697 cm^–1. [α]²_D⁰= –4.2 (c = 0.6, CHCl₃). HRMS: calcd. for

[C₄₃H₅₆O₅N₂+ H]⁺681.4262 [M + H]⁺; found 681.4261.

3), 78.8 (C-4), 74.0, 73.4, 73.2 (3ϫCH₂Bn), 68.3 (C-6), 60.6 (C-2),

58.0 (C-5), 39.9 (NCH₂-1 pentyl), 29.0 (CH₂-2 pentyl), 28.8, 22.2

(2ϫCH pentyl), 14.0 (CH -5 pentyl) ppm. IR (thin film): ν =

˜

max

2

3

3231, 2929, 2862, 1682, 1652, 1543, 1454, 1358, 1257, 1210, 1092,

1026, 734, 696 cm^–1. [α]²_D⁰= 14.4 (c = 5.5, CHCl₃). HRMS: calcd.

for [C₃₂H₄₀O₄N₂+ H]⁺517.3061 [M + H]⁺; found 517.3059.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-

D-galacto-hexonamide (21): Compound 21 (301 mg, 0.54 mmol) was

synthesized in 92% yield from 15 (0.58 mmol) by deprotection of

the pent-4-enamide (General Procedure D). R_f= 0.40 (EtOAc/tolu-

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-D-talo-hexonamide

ene, 1:2). ¹H NMR (600 MHz, CDCl₃): δ = 7.46 [s, 1 H, C(O)NH], (24): Compound 24 (81 mg, 0.16 mmol) was synthesized from 18

7.37–7.25 (m, 15 H, H_ArBn), 5.56–5.19 (s, 1 H, NH), 4.76 (d, J = (0.20 mmol, 80%) by deprotection of the pent-4-enamide (General

11.4 Hz, 1 H, CHH Bn), 4.73 (d, J = 11.4 Hz, 1 H, CHH Bn), 4.64

(d, J = 11.7 Hz, 1 H, CHH Bn), 4.61 (dd, J = 3.8, 6.1 Hz, 1 H, 3-

H), 4.57 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.55–4.49 (m, 2 H,

2ϫCHH Bn), 4.28 (d, J = 6.3 Hz, 1 H, 2-H), 4.18 (dd, J = 3.8,

Procedure D). R_f= 0.85 (EtOAc/toluene, 1:1). ¹H NMR (600 MHz,

CDCl₃): δ = 7.43–7.21 [m, 16 H, C(O)NH, H_ArBn], 4.73 (d, J =

12.0 Hz, 1 H, CHH Bn), 4.65 (d, J = 12.0 Hz, 1 H, CHH Bn), 4.63

(d, J = 11.8 Hz, 1 H, CHH Bn), 4.53 (d, J = 11.7 Hz, 1 H, CHH

6.2 Hz, 1 H, 4-H), 3.89–3.84 (m, 1 H, 5-H), 3.81 (dd, J = 9.2 Hz, Bn), 4.50 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.45 (d, J = 11.8 Hz, 1

1 H, 6a-H), 3.76 (dd, J = 4.6, 9.7 Hz, 1 H, 6b-H), 1.66–1.57 (m, 2 H, CHH Bn), 4.10 (dd, J = 3.6, 4.5 Hz, 1 H, 3-H), 3.95 (dd, J =

H, CH₂-2 tMB), 1.33 (d, J = 29.4 Hz, 6 H, 2ϫCH₃tMB), 0.95 (s, 4.9, 5.5 Hz, 1 H, 4-H), 3.79 (d, J = 3.6 Hz, 1 H, 2-H), 3.77–3.71

9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (150 MHz, CDCl₃): δ

= 167.1 [C(O)-1], 137.8, 137.7, 137.5 (3ϫC_qBn), 128.3, 128.1,

127.9, 127.7, 127.6, 127.5, 127.4 (CH_ArBn), 79.2 (C-3), 78.7 (C-4),

(m, 2 H, CH₂-6), 3.52 (dt, J = 5.3, 8.8 Hz, 1 H, 5-H), 3.26–3.11

(m, 2 H, NCH₂-1 pentyl), 1.48–1.41 (m, 2 H, CH₂-2 pentyl), 1.34–

1.28 (m, 2 H, CH₂pentyl), 1.28–1.21 (m, 2 H, CH₂pentyl), 0.88

73.7, 73.2, 73.0 (3ϫCH₂Bn), 69.2 (C-6), 60.9 (C-2), 57.9 (C-5), 55.2 (t, J = 7.2 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (150 MHz,

(NHC_q-1 tMB), 52.4 (CH₂-2 tMB), 31.6 (C_q-3 tMB), 31.4 (2ϫCH₃,

CDCl₃): δ = 172.5 [C(O)-1], 138.4, 138.3, 138.2 (3ϫC_qBn), 128.6,

128.5, 128.2, 128.0, 127.9, 127.9, 127.8 (CH_ArBn), 81.7 (C-3), 78.9

(C-4), 73.6, 72.9, 72.0 (3ϫCH₂Bn), 70.6 (C-6), 64.3 (C-2), 59.2 (C-

5), 39.2 (NCH₂-1 pentyl), 29.5 (CH₂-2 pentyl), 29.2, 22.5 (2ϫCH₂

CH -4 tMB), 28.4 (2ϫCH tMB) ppm. IR (thin film): ν_max= 3274,

˜

3

2951, 1681, 1668, 1530, 1093, 732, 696 cm^–1. [α]²_D⁰= 4.2 (c = 6.0,

CHCl₃). HRMS: calcd. for [C₃₅H₄₆O₄N₂+ H]⁺559.3530 [M +

H]⁺; found 559.352.

pentyl), 14.2 (CH -5 pentyl) ppm. IR (thin film): ν_max= 3325, 2929,

˜

3

2867, 1667, 1521, 1454, 1360, 1209, 1096, 1027, 735, 698 cm^–1.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-

[α]²_D⁰= –4.0 (c = 0.8, CHCl₃). HRMS: calcd. for [C₃₂H₄₀O₄N₂

+

D-talo-hexon-amide (22): Compound 22 (212 mg, 0.38 mmol) was

H]⁺517.3061 [M + H]⁺; found 517.3059.

synthesized in 69% yield from 16 (0.55 mmol) by deprotection of

the pent-4-enamide (General Procedure D). R_f= 0.59 (EtOAc/tolu-

5-(Adamantan-1-yl-methoxy)pentyl

2,5-Dideoxy-2,5-imino-D-

ene, 1:2). ¹H NMR (600 MHz, CDCl₃): δ = 7.40 [s, 1 H, C(O)NH], galacto-hexonamide (25): Compound 25 (20 mg, 49 μmol) was syn-

7.39–7.21 (m, 15 H, H_ArBn), 4.73 (d, J = 12.0 Hz, 1 H, CHH Bn), thesized from 19 (131 μmol, 37%) by deprotection of the benzyl

4.65–4.59 (m, 2 H, CHH Bn, CHH Bn), 4.52 (d, J = 11.8 Hz, 1 H,

CHH Bn), 4.48 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.42 (d, J =

11.8 Hz, 1 H, CHH Bn), 4.08 (dd, J = 3.2, 4.7 Hz, 1 H, 3-H), 3.91

ethers (appropriate method in General Procedure F). R_f= 0.14

(MeOH/CH₂Cl₂, 1:9

2% NH₄OH). ¹H NMR (500 MHz,

MeOD): δ = 4.27–4.21 (m, 2 H, 3-H, 4-H), 3.75 (d, J = 5.3 Hz, 1

+

6432

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

H, 2-H), 3.69 (dd, J = 5.1, 11.1 Hz, 1 H, 6a-H), 3.63 (dd, J = 4.3,

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Dideoxy-2,5-imino-

D-talo-

11.1 Hz, 1 H, 6b-H), 3.42–3.35 (m, 4 H, 5-H, CH₂-5 pentyl), 3.24

hexonamide (28): Compound 28 (11 mg, 27 μmol, 82%) was synthe-

(dt, J = 1.4, 7.0 Hz, 2 H, NCH₂-1 pentyl), 2.97 (s, 2 H, OCH₂- sized in from 20 (33 μmol) by deprotection of the benzyl ethers

Ada), 1.94 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J = 11.7, 38.7 Hz, 6 H,

(appropriate method in General Procedure F). R_f= 0.16 (MeOH/

3ϫCH₂Ada), 1.62–1.51 (m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), CH₂Cl₂, 1:9 + 2% NH₄OH). ¹H NMR (600 MHz, MeOD): δ =

1.45–1.37 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR (125 MHz, 4.07 (t, J = 4.1 Hz, 1 H, 4-H), 4.02 (dd, J = 4.3, 7.1 Hz, 1 H, 3-H),

MeOD): δ = 174.6 [C(O)-1], 83.2 (OCH₂-Ada), 74.4 (C-3), 74.2 (C- 3.77 (dd, J = 5.9, 10.9 Hz, 1 H, 6a-H), 3.65 (dd, J = 6.3, 10.9 Hz, 1

4), 72.7 (CH₂-5 pentyl), 63.8 (C-2), 62.7 (C-6), 61.5 (C-5), 41.0

H, 6b-H), 3.52 (d, J = 7.1 Hz, 1 H, 2-H), 3.38 (t, J = 6.3 Hz, 2 H,

(CH₂Ada), 40.2 (NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), CH₂-5 pentyl), 3.30–3.27 (m, 1 H, 5-H), 3.23 (t, J = 7.0 Hz, 2 H,

30.5, 30.5 (2ϫCH₂pentyl), 29.9 (CH Ada), 24.8 (CH₂-3

NCH₂-1 pentyl), 2.96 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH

Ada), 1.72 (dd, J = 11.9, 45.9 Hz, 6 H, 3ϫCH₂Ada), 1.61–1.51

(m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.44–1.36 (m, 2 H, CH₂-

3 pentyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 175.5 [C(O)-1],

83.2 (OCH₂-Ada), 78.6 (C-3), 74.3 (C-4), 72.6 (CH₂-5 pentyl), 65.9

(C-2), 62.7 (C-5), 62.5 (C-6), 41.0 (CH₂Ada), 40.5 (NCH₂-1 pent-

yl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5, 30.5 (2ϫCH₂pentyl),

pentyl) ppm. IR (thin film): ν

= 3320, 2902, 2848, 1637, 1543,

˜

max

1456, 1114 cm^–1. [α]²_D⁰= 27.1 (c = 0.3, MeOH). HRMS: calcd. for

[C₂₂H₃₈O₅N₂+ H]⁺411.2853 [M + H]⁺; found 411.2851.

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Butylimino-2,5-dideoxy-D-

galacto-hexonamide (26): Compound 26 (36 mg, 77 μmol, 48%) was

synthesized in two steps from 19 (161 μmol) through reductive

amination with the appropriate aldehyde (General Procedure E)

and a subsequent benzyl ether deprotection (appropriate method

in General Procedure F). R_f= 0.31 (MeOH/CH₂Cl₂, 1:9 + 2%

NH₄OH); R_f(N-alkylated penultimate) = 0.61 (EtOAc/toluene, 1:1

29.9 (CH Ada), 24.8 (CH -3 pentyl) ppm. IR (thin film): ν

=

˜

2

max

3319, 2902, 2849, 1652, 1543, 1454, 1112. [α]²_D⁰= –1.0 (c = 0.2,

MeOH). HRMS: calcd. for [C₂₂H₃₈O₅N₂+ H]⁺411.2853 [M +

H]⁺; found 411.2851.

1

+ 2% Et₃N). H NMR (600 MHz, MeOD): δ = 4.30 (dd, J = 4.5,

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Butylimino-2,5-dideoxy-D-

7.9 Hz, 1 H, 4-H), 4.18 (dd, J = 4.9 Hz, 1 H, 3-H), 3.72 (dd, J =

2.8, 11.2 Hz, 1 H, 6a-H), 3.62 (dd, J = 4.3, 11.2 Hz, 1 H, 6b-H),

talo-hexonamide (29): Compound 29 (11 mg, 24 μmol, 67%) was

synthesized in two steps from 20 (36 μmol) through reductive amin-

3.41–3.31 (m, 4 H, 2-H, CH₂-5, NCHH-1 pentyl), 3.22–3.15 (m, 1 ation with the appropriate aldehyde (General Procedure E) and a

H, NCHH-1 pentyl), 3.04–2.99 (m, 1 H, 5-H), 2.96 (s, 1 H, OCH₂- subsequent benzyl ether deprotection (appropriate method in Ge-

Ada), 2.68–2.61 (m, 1 H, NCHH butyl), 2.57–2.49 (m, 1 H, NCHH

neral Procedure F). R_f= 0.30 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH);

butyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J = 11.6, 46.0 Hz, 6 H, R_f(N-alkylated penultimate) = 0.85 (EtOAc/toluene, 1:1 + 2%

3ϫCH₂Ada), 1.62–1.26 (m, 16 H, 3ϫCH₂Ada, 5ϫCH₂pentyl/ Et₃N). ¹H NMR (600 MHz, MeOD): δ = 4.31 (dd, J = 5.7, 6.5 Hz,

butyl), 0.94 (t, J = 7.4 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR

(150 MHz, MeOD): δ = 174.4 [C(O)-1], 83.2 (OCH₂-Ada), 74.2 (C-

3), 73.2 (C-4), 72.7 (CH₂-5 pentyl), 72.3 (C-2), 67.8 (C-5), 61.7 (C-

6), 57.4 (NCH₂butyl), 41.0 (CH₂Ada), 40.1 (NCH₂-1 pentyl), 38.5

1 H, 4-H), 3.87 (dd, J = 1.0, 5.7 Hz, 1 H, 3-H), 3.80 (d, J = 8.2 Hz,

1 H, 6a-H), 3.70 (dd, J = 1.4, 11.6 Hz, 1 H, 6b-H), 3.39–3.37 (m,

3 H, 2-H, CH₂-5 pentyl), 3.35–3.32 (m, 1 H, 5-H), 3.28–3.20 (m, 1

H, NCHH-1 pentyl), 3.20–3.11 (m, 1 H, NCHH-1 pentyl), 2.96 (s,

(CH₂Ada), 35.3 (C_qAda), 29.9 (CH Ada), 32.0, 30.6, 30.5, 24.9, 2 H, OCH₂-Ada), 2.93–2.85 (m, 1 H, NCHH butyl), 2.60–2.47 (m,

21.7 (5ϫCH₂pentyl/butyl), 14.6 (CH₃butyl) ppm. IR (thin film): 1 H, NCHH butyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J = 12.1,

ν

= 3319, 2902, 2849, 1651, 1637, 1458, 1113 cm^–1. [α]²_D⁰= 34.7

46.3 Hz, 8 H, 3ϫCH₂Ada), 1.62–1.27 (m, 16 H, 3ϫCH₂Ada,

5ϫCH₂pentyl/butyl), 0.94 (t, J = 7.4 Hz, 3 H, CH₃butyl) ppm.

¹³C NMR (150 MHz, MeOD): δ = 175.8 [C(O)-1], 83.2 (OCH₂-

Ada), 76.2 (C-3), 76.2 (C-2), 72.7 (C-4), 72.6 (CH₂-5 pentyl), 64.9

(C-5), 58.3 (C-6), 50.7 (NCH₂butyl), 41.0 (CH₂Ada), 40.0 (NCH₂-

1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 32.2, 30.6, 30.5 (3ϫCH₂

pentyl/butyl), 29.9 (CH Ada), 25.0 (CH₂-3 pentyl), 21.9 (CH₂but-

˜

max

(c = 0.7, MeOH). HRMS: calcd. for [C₂₆H₄₆O₅N₂+ H]⁺467.3479

[M + H]⁺; found 467.3475.

5-(Adamantan-1-yl-methoxy)pentyl 2,5-[5-(Adamantan-1-yl-meth-

oxy)pentyl]imino-2,5-dideoxy-D-galacto-hexonamide (27): Com-

pound 27 (56 mg, 87 μmol, 59%) was synthesized in two steps from

19 (148 μmol) through reductive amination with the appropriate

aldehyde (General Procedure E) and subsequent benzyl ether de-

protection (appropriate method in General Procedure F). R_f= 0.37

(MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated penultimate)

= 0.69 (EtOAc/toluene, 1:1 + 2% Et₃N). ¹H NMR (500 MHz,

MeOD): δ = 4.29 (dd, J = 4.5, 7.9 Hz, 1 H, 4-H), 4.18 (dd, J = 4.5,

yl), 14.6 (CH butyl) ppm. IR (thin film): ν_max= 3328, 2903, 2850,

˜

3

1652, 1456, 1097, 1016 cm^–1. [α]²_D⁰= –29.7 (c = 0.2, MeOH).

HRMS: calcd. for [C₂₆H₄₆O₅N₂+ H]⁺467.3479 [M + H]⁺; found

467.3475.

5-(Adamantan-1-yl-methoxy)pentyl 2,5-[5-(Adamantan-1-yl-meth-

5.5 Hz, 1 H, 3-H), 3.72 (dd, J = 3.0, 11.2 Hz, 1 H, 6a-H), 3.64 (dd, oxy)pentyl]imino-2,5-dideoxy-

J = 4.5, 11.2 Hz, 1 H, 6b-H), 3.41–3.36 (m, 2 H, 2ϫCH₂-5 pentyl), 30 (17 mg, 26 μmol, 72%) was synthesized in two steps from 20

3.37–3.34 [m, 1 H, C(O)NCHH-1 pentyl], 3.33 (d, J = 5.5 Hz, 1 H, (36 μmol) through reductive amination with the appropriate alde-

D-talo-hexonamide (30): Compound

2-H), 3.18 [dt, J = 6.8, 13.5 Hz, 1 H, C(O)NCHH-1 pentyl], 3.02

(ddd, J = 3.0, 4.5, 7.6 Hz, 1 H, 5-H), 2.97 (s, 4 H, 2ϫOCH₂-Ada),

hyde (General Procedure E) and a subsequent benzyl ether depro-

tection (appropriate method in General Procedure F). R_f= 0.37

2.70–2.62 (m, 1 H, NCHH-1 pentyl), 2.54 (ddd, J = 6.3, 9.3, (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated penultimate)

12.5 Hz, 1 H, NCHH-1 pentyl), 1.95 (s, 6 H, 3ϫCH₂Ada), 1.72

(dd, J = 11.8, 39.2 Hz, 12 H, 6ϫCH₂Ada), 1.63–1.30 (m, 24 H,

= 0.88 (EtOAc/toluene, 1:1 + 2% Et₃N). ¹H NMR (600 MHz,

MeOD): δ = 4.31 (dd, J = 6.0, 7.1 Hz, 1 H, 4-H), 3.88 (dd, J = 1.5,

6ϫCH₂Ada, 6ϫCH₂pentyl) ppm. ¹³C NMR (125 MHz, MeOD): 5.8 Hz, 1 H, 3-H), 3.81 (dd, J = 3.5, 11.7 Hz, 1 H, 6a-H), 3.71 (dd,

δ = 174.4 [C(O)-1], 83.2 (2ϫOCH₂-Ada), 74.2 (C-3), 73.3 (C-4),

J = 1.9, 11.7 Hz, 1 H, 6b-H), 3.41–3.36 (m, 5 H, 2-H, 2ϫCH₂-5

72.7, 72.6 (2ϫCH₂-5 pentyl), 72.3 (C-2), 67.9 (C-5), 61.8 (C-6), pentyl), 3.35–3.32 (m, 1 H, 5-H), 3.26 [dt, J = 7.0, 13.8 Hz, 1 H,

57.6 (NCH₂-1 pentyl), 41.0, 41.0 (2ϫCH₂Ada), 40.1 [C(O)NCH₂- C(O)NCHH-1 pentyl], 3.16 [dt, J = 6.9, 13.5 Hz, 1 H, C(O)NCHH-

1 pentyl], 38.5 (2ϫCH₂Ada), 35.3, 35.3 (2ϫC_qAda), 30.8, 30.6,

1 pentyl], 2.98–2.95 (m, 4 H, 2ϫOCH₂-Ada), 2.94–2.87 (m, 1 H,

30.6, 29.7 (4ϫCH₂pentyl), 29.9 (2ϫCH Ada), 25.3, 24.9 (2ϫCH₂- NCHH pentyl), 2.53 (ddd, J = 7.1, 9.3, 12.3 Hz, 1 H, NCHH

3 pentyl) ppm. IR (thin film): ν_max= 3319, 2902, 2848, 1651, 1455,

pentyl), 1.95 (s, 6 H, 6ϫCH Ada), 1.72 (dd, J = 11.9, 46.7 Hz, 12

H, 6ϫCH₂Ada), 1.63–1.47 (m, 20 H, 6ϫCH₂Ada, 4ϫCH₂

pentyl), 1.47–1.31 (m, 4 H, 2ϫCH₂-3 pentyl) ppm. ¹³C NMR

˜

1361, 1113 cm^–1. [α]²_D⁰= 24.3 (c = 0.7, MeOH). HRMS: calcd. for

[C₃₈H₆₄O₆N₂+ H]⁺645.4837 [M + H]⁺; found 645.4834.

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6433

H. S. Overkleeft et al.

(150 MHz, MeOD): δ = 175.8 [C(O)-1], 83.3, 83.2 (2ϫOCH₂-Ada), Ada, CHH-2 tMB), 1.80–1.65 (m, 7 H, 3ϫCH₂Ada, CHH tMB),

FULL PAPER

76.3 (C-3), 76.2 (C-2), 72.7 (C-4), 72.6, 72.5 (2ϫCH₂-5 pentyl), 64.8

(C-5), 58.3 (C-6), 50.9 (NCH₂-1 pentyl), 41.0, 41.0 (2ϫCH₂Ada),

1.65–1.31 (m, 18 H, 3ϫCH₂Ada, 3ϫCH₂pentyl, 2ϫCH₃tMB),

1.04 (s, 9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (150 MHz,

40.1 [C(O)NCH₂-1 pentyl], 38.5 (2ϫCH₂Ada), 35.3, 35.3 (2ϫC_qMeOD): δ = 173.3 [C(O)-1], 83.2 (OCH₂-Ada), 74.3 (C-3), 73.3 (C-

Ada), 29.9 (2ϫCH Ada), 30.8, 30.6, 30.5, 29.8 (4ϫCH₂pentyl),

4), 72.5 (C-2), 72.5 (CH₂-5 pentyl), 67.5 (C-5), 61.9 (C-6), 57.7

(NCH₂-1), 56.2 (NHC_q-1 tMB), 53.6 (CH₂-2 tMB), 41.0 (CH₂

Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 32.6 (C_q-3 tMB), 32.3 (CH₃-

4, 2ϫCH₃tMB), 30.8 (CH₂pentyl), 29.9 (CH Ada), 29.5, 29.4

(2ϫCH₃tMB, CH₂pentyl), 25.4 (CH₂-1 pentyl) ppm. IR (thin

25.4, 25.0 (2ϫCH -3 pentyl) ppm. IR (thin film): ν

= 3332,

˜

2

max

2902, 2848, 1652, 1454, 1361, 1158, 1112 cm^–1. [α]²_D⁰= –14.6 (c =

0.3, MeOH). HRMS: calcd. for [C₃₈H₆₄O₆N₂+ H]⁺645.4837 [M

+ H]⁺; found 645.4834.

film): ν

= 3325, 2903, 2850, 1651, 1454, 1366, 1228, 1110,

˜

max

1,1,3,3-Tetramethylbutyl 2,5-Dideoxy-2,5-imino-D-galacto-hexon-

amide (31): Compound 31 (14 mg, 47 μmol, 53%) was synthesized

in from 21 (90 μmol) by deprotection of the benzyl ethers (appro-

1055 cm^–1. [α]²_D⁰= 28.4 (c = 0.7, MeOH). HRMS: calcd. for

[C₃₀H₅₄O₅N₂+ H]⁺523.4105 [M + H]⁺; found 523.4101.

priate method in General Procedure F). R_f= 0.15 (MeOH/CH₂Cl₂,

1:9 + 2% NH₄OH). H NMR (600 MHz, MeOD): δ = 4.25–4.18 (34): Compound 34 (15 mg, 52 μmol, 93%) was synthesized from

(m, 2 H, 3-H, 4-H), 3.71–3.61 (m, 2 H, CH₂-6), 3.59 (d, J = 5.9 Hz, 22 (56 μmol) by deprotection of the benzyl ethers (appropriate

1,1,3,3-Tetramethylbutyl 2,5-Dideoxy-2,5-imino-D-talo-hexonamide

1

1 H, 2-H), 3.37–3.32 (m, 1 H, 5-H), 1.87 (d, J = 14.8 Hz, 1 H, method in General Procedure F). R_f= 0.16 (MeOH/CH₂Cl₂, 1:9 +

1

CHH-2 tMB), 1.65 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.41 (d, J

= 20.5 Hz, 6 H, 2ϫCH₃tMB), 1.03 (s, 9 H, 2ϫCH₃, CH₃-4

tMB) ppm. ¹³C NMR (150 MHz, MeOD): δ = 173.8 [C(O)-1], 74.6,

2% NH₄OH). H NMR (600 MHz, MeOD): δ = 4.06 (m, 1 H, 4-

H), 4.02 (dd, J = 4.2, 6.8 Hz, 1 H, 3-H), 3.76 (dd, J = 5.9, 10.9 Hz,

1 H, 6a-H), 3.65 (dd, J = 6.1, 10.9 Hz, 1 H, 6b-H), 3.45 (d, J =

74.2 (C-3, C-4), 63.9 (C-2), 62.8 (C-6), 61.3 (C-5), 55.9 (NHC_q-1 6.8 Hz, 1 H, 2-H), 3.24 (dd, J = 5.8, 10.1 Hz, 1 H, 5-H), 1.83 (d, J

tMB), 53.1 (CH₂-2 tMB), 32.6 (C_q-3 tMB), 32.1 (CH₃-4, 2ϫCH₃= 14.8 Hz, 1 H, CHH-2 tMB), 1.75 (d, J = 14.9 Hz, 1 H, CHH-2

tMB), 29.7, 29.4 (2ϫCH tMB) ppm. IR (thin film): ν

= 3325,

tMB), 1.40 (d, J = 8.2 Hz, 6 H, 2ϫCH₃tMB), 1.02 (s, 9 H, CH₃-

4, 2ϫCH₃tMB) ppm. ¹³C NMR (150 MHz, MeOD): δ = 174.4

[C(O)-1], 78.2 (C-3), 74.4 (C-4), 66.3 (C-2), 62.6 (C-5), 62.4 (C-6),

55.9 (NHC_q-1 tMB), 52.4 (CH₂-2 tMB), 32.7 (C_q-3 tMB), 32.1

(CH₃-4, 2ϫCH₃tMB), 29.8, 29.7 (2ϫCH₃tMB) ppm. IR (thin

˜

3

max

2952, 1651, 1537, 1452, 1390, 1366, 1227, 1120, 1034 cm^–1. [α]²_D⁰

=

33.1 (c = 0.3, MeOH). HRMS: calcd. for [C₁₄H₂₈O₄N₂+ H]⁺

289.2122 [M + H]⁺; found 289.2123.

1,1,3,3-Tetramethylbutyl

2,5-Butylimino-2,5-dideoxy-D-galacto-

film): ν

= 3309, 2970, 2904, 1652, 1529, 1391, 1366, 1227,

˜

max

hexonamide (32): Compound 32 (27 mg, 78 μmol, 87%) was synthe-

sized in two steps from 21 (90 μmol) through reductive amination

with the the appropriate aldehyde (General Procedure E) and sub-

sequent benzyl ether deprotection (appropriate method in General

Procedure F). R_f= 0.31 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f

(N-alkylated penultimate) = 0.82 (EtOAc/toluene, 1.5:1 + 2%

Et₃N). ¹H NMR (600 MHz, MeOD): δ = 4.27 (dd, J = 4.5, 7.7 Hz,

1050 cm^–1. [α]²_D⁰= –7.1 (c = 0.3, MeOH). HRMS: calcd. for

[C₁₄H₂₈O₄N₂+ H]⁺289.2122 [M + H]⁺; found 289.2123.

1,1,3,3-Tetramethylbutyl 2,5-Butylimino-2,5-dideoxy-D-talo-hexon-

amide (35): Compound 35 (23 mg, 67 μmol, 85%) was synthesized

in two steps from 22 (79 μmol) through reductive amination with

the appropriate aldehyde (General Procedure E) and a subsequent

1 H, 4-H), 4.20–4.12 (m, 1 H, 3-H), 3.71 (dd, J = 2.6, 10.8 Hz, 1 benzyl ether deprotection (appropriate method in General Pro-

H, 6a-H), 3.63 (dd, J = 4.8, 10.8 Hz, 1 H, 6b-H), 3.18 (d, J = cedure F). R_f= 0.29 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-

5.7 Hz, 1 H, 2-H), 3.03–2.99 (m, 1 H, 5-H), 2.66–2.59 (m, 1 H, alkylated penultimate) = 0.93 (EtOAc/toluene, 1.5:1 + 2% Et₃N).

NCHH butyl), 2.57–2.49 (m, 1 H, NCHH butyl), 1.93 (d, J = ¹H NMR (600 MHz, MeOD): δ = 4.23 (dd, J = 5.8, 6.8 Hz, 1 H,

14.8 Hz, 1 H, CHH-2 tMB), 1.63 (d, J = 14.9 Hz, 1 H, CHH-2 4-H), 3.92 (d, J = 5.3 Hz, 1 H, 3-H), 3.83 (dd, J = 3.5, 11.9 Hz, 1

tMB), 1.55–1.26 (m, 10 H, 2ϫCH₂butyl, 2ϫCH₃tMB), 1.04 (s, 9 H, 6a-H), 3.75 (d, J = 10.9 Hz, 1 H, 6b-H), 3.41 (s, 1 H, 5-H), 3.31

H, 2ϫCH₃, CH₃-4 tMB), 0.94 (t, J = 7.4 Hz, 3 H, CH₃butyl) ppm. (s, 1 H, 1-H), 3.03–2.95 (m, 1 H, NCHH butyl), 2.61–2.51 (m, 1

¹³C NMR (150 MHz, MeOD): δ = 173.5 [C(O)-1], 74.4 (C-3), 73.3 H, NCHH butyl), 1.83 (d, J = 14.9 Hz, 1 H, CHH-2 tMB), 1.73

(C-4), 72.5 (C-2), 67.5 (C-5), 61.9 (C-6), 57.4 (NCH₂butyl), 56.2

(NHC_q-1 tMB), 53.6 (CH₂-2 tMB), 32.6 (C_q-3 tMB), 32.3 (CH₂butyl, 2ϫCH₃tMB), 1.02 (s, 9 H, 2ϫCH₃, CH₃-4 tMB), 0.96 (t,

butyl), 32.2 (CH₃-4, 2ϫCH₃tMB), 29.4, 29.3 (2ϫCH₃tMB), 21.8

J = 7.4 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR (150 MHz, MeOD,

(CH₂butyl), 14.6 (CH₃butyl) ppm. IR (thin film): ν = 3292, collapsed iminosugar signals): δ = 76.7 (C-2), 75.9 (C-3), 72.7 (C-

(d, J = 14.9 Hz, 1 H, CHH-2 tMB), 1.61–1.27 (m, 10 H, 2ϫCH₂

˜

max

2957, 2928, 1639, 1461, 1440, 1366, 1229, 1149, 1128, 1034 cm^–1.

4), 65.1 (C-5), 57.9 (C-6), 56.0 (NHC_q-1 tMB), 52.8 (CH₂-2 tMB),

50.9 (NCH₂butyl), 32.6 (C_q-3 tMB), 32.1 (CH₃-4, 2ϫCH₃tMB),

30.9 (CH₂butyl), 29.9, 29.1 (2ϫCH₃tMB), 22.0 (CH₂butyl), 14.6

[α]²_D⁰= 37.8 (c = 0.5, MeOH). HRMS: calcd. for [C₁₈H₃₆O₄N₂

+

H]⁺345.2748 [M + H]⁺; found 345.2748.

(CH₃butyl) ppm. IR (thin film): ν

= 3328, 2957, 2929, 1652,

˜

max

1,1,3,3-Tetramethylbutyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]-

imino-2,5-dideoxy- -galacto-hexonamide (33): Compound 33

(35 mg, 67 μmol, 74%) was synthesized in two steps from 21

(90 μmol) through reductive amination with the appropriate alde-

hyde (General Procedure E) and a subsequent benzyl ether depro-

tection (appropriate method in General Procedure F). R_f= 0.35

1432, 1366, 1227, 1166, 1046 cm^–1. [α]²_D⁰= –33.6 (c = 0.5, MeOH).

HRMS: calcd. for [C₁₈H₃₆O₄N₂+ H]⁺345.2748 [M + H]⁺; found

345.2748.

D

1,1,3,3-Tetramethylbutyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]-

imino-2,5-dideoxy-D-talo-hexonamide (36): Compound 36 (34 mg,

(MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated penultimate) 65 μmol, 72%) was synthesized in two steps from 22 (90 μmol)

= 0.84 (EtOAc/toluene, 1.5:1 + 2% Et₃N). ¹H NMR (600 MHz,

MeOD): δ = 4.28 (dd, J = 4.5, 7.7 Hz, 1 H, 4-H), 4.17 (t, J =

through reductive amination with the appropriate aldehyde (Gene-

ral Procedure E) and subsequent benzyl ether deprotection (appro-

5.0 Hz, 1 H, 3-H), 3.72 (dd, J = 1.6, 10.5 Hz, 1 H, 6a-H), 3.64 (dd, priate method in General Procedure F). R_f= 0.32 (MeOH/CH₂Cl₂,

J = 4.5, 10.5 Hz, 1 H, 6b-H), 3.39 (t, J = 6.3 Hz, 2 H, CH₂-5

pentyl), 3.20 (d, J = 3.4 Hz, 1 H, 2-H), 3.07–3.01 (m, 1 H, 5-H),

1:9 + 2% NH₄OH); R_f(N-alkylated penultimate) = 0.89 (EtOAc/

toluene, 1:2 + 2% Et₃N). H NMR (600 MHz, MeOD): δ = 4.22

1

2.96 (s, 2 H, OCH₂-Ada), 2.70–2.61 (m, 1 H, NCHH-1 pentyl), (dd, J = 5.9, 7.2 Hz, 1 H, 4-H), 3.89 (dd, J = 1.6, 5.8 Hz, 1 H, 3-H),

2.60–2.48 (m, 1 H, NCHH-1 pentyl), 1.98–1.91 (m, 4 H, 3ϫCH 3.83 (dd, J = 3.4, 11.8 Hz, 1 H, 6a-H), 3.72 (dd, J = 2.1, 11.8 Hz, 1

6434

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Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

H, 6b-H), 3.39 (t, J = 6.2 Hz, 2 H, CH₂-5 pentyl), 3.37–3.33 (m, 1 signals): δ = 4.50–4.03 (m, 2 H), 4.03–3.55 (m, 2 H), 3.38 (t, J =

H, 5-H), 3.25 (d, J = 1.6 Hz, 1 H, 2-H), 3.00–2.94 (m, 3 H, OCH₂- 6.3, 2 H, CH₂-5 pentyl AMP), 3.27–3.00 (m, 2 H), 2.96 (s, 2 H,

Ada, NCHH-1 pentyl), 2.49 (dt, J = 8.2, 12.5 Hz, 1 H, NCHH-1

pentyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.86 (d, J = 14.9 Hz, 1 H, CHH-

OCH₂-Ada), 2.84–2.48 (m, 1 H), 1.95 (s, 3 H, 3ϫCH Ada), 1.72

(dd, J = 12.1, 48.0, 6 H, 3ϫCH₂Ada), 1.63–1.32 (m, 18 H, 3ϫCH₂

2 tMB), 1.79–1.66 (m, 7 H, 3ϫCH₂Ada, CHH-2 tMB), 1.64–1.45 Ada, 6ϫCH₂pentyl/pentyl AMP), 0.93 (t, J = 7.0, 3 H, CH₃-5

(m, 11 H, 3ϫCH₂Ada, 2ϫCH₂pentyl, CHH-3 pentyl), 1.44–1.37

(m, 7 H, CHH-3pentyl, 2ϫCH₃tMB), 1.03 (s, 9 H, 2ϫCH₃, CH₃-

4 tMB) ppm. ¹³C NMR (150 MHz, MeOD): δ = 174.3 [C(O)-1],

83.2 (OCH₂-Ada), 77.2 (C-2), 75.9 (C-3), 72.7 (C-4), 72.4 (CH₂-5

pentyl) ppm. ¹³C NMR (150 MHz, MeOD, collapsed iminosugar

signals): δ = 83.2 (OCH₂-Ada), 72.4 (CH₂-5 pentyl AMP), 41.0

(CH₂Ada), 38.5 (CH₂Ada), 35.3 (C_qAda), 29.9 (CH Ada), 30.6,

30.5, 30.4, 30.3, 25.3, 23.6 (6ϫCH₂pentyl/pentyl AMP), 14.6

pentyl), 64.3 (C-5), 57.9 (C-6), 56.0 (NHC_q-1 tMB), 52.8 (CH₂-2 (CH -5 pentyl) ppm. IR (thin film): ν_max= 3280, 1638, 1471, 1360,

˜

3

tMB), 50.9 (NCH₂-1 pentyl), 41.1 (CH₂Ada), 38.5 (CH₂Ada),

35.3 (C_qAda), 32.7 (C_q-3 tMB), 32.1 (CH₃-4, 2ϫCH₃tMB), 30.8,

30.0 (2ϫCH₂pentyl), 29.9 (CH Ada), 30.1, 29.2 (2ϫCH₃tMB),

1114, 1010 cm^–1. [α]²_D⁰= 22.2 (c = 0.2, MeOH). HRMS: calcd. for

[C₂₇H₄₈O₅N₂+ H]⁺481.3636 [M + H]⁺; found 481.3631.

Pentyl 2,5-Dideoxy-2,5-imino-D-talo-hexonamide (40): Compound

40 (10 mg, 41 μmol, 89%) was synthesized from 24 (46 μmol) by

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

= 3328, 2903, 2849,

˜

2

max

1652, 1429, 1366, 1228, 1159, 1109 cm^–1. [α]²_D⁰= –34.2 (c = 0.5,

MeOH). HRMS: calcd. for [C₃₀H₅₄O₅N₂+ H]⁺523.4105 [M +

H]⁺; found 523.4100.

deprotection of the benzyl ethers (appropriate method in General

1

Procedure F). R_f= 0.09 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH). H

NMR (600 MHz, MeOD): δ = 4.10 (dd, J = 4.0 Hz, 1 H, 4-H),

4.05 (dd, J = 4.2, 7.2 Hz, 1 H, 3-H), 3.79 (dd, J = 5.8, 11.0 Hz, 1

H, 6a-H), 3.69 (dd, J = 6.4, 11.0 Hz, 1 H, 6b-H), 3.58 (d, J =

7.2 Hz, 1 H, 2-H), 3.39–3.33 (m, 1 H, 5-H), 3.22 (t, J = 7.1 Hz, 2

H, NCH₂-1 pentyl), 1.57–1.49 (m, 2 H, CH₂-2 pentyl), 1.41–1.28

Pentyl 2,5-Dideoxy-2,5-imino-D-galacto-hexonamide (37): Com-

pound 37 (22 mg, 89 μmol, 66%) was synthesized from 23

(135 μmol) by deprotection of the benzyl ethers (appropriate

method in General Procedure F). R_f= 0.08 (MeOH/CH₂Cl₂. 1:9 +

1

2% NH₄OH). H NMR (500 MHz, MeOD): δ = 4.28–4.21 (m, 2 (m, 4 H, 2ϫCH₂pentyl), 0.92 (t, J = 6.9 Hz, 3 H, CH₃-5

H, 3-H, 4-H), 3.76 (d, J = 5.4 Hz, 1 H, 2-H), 3.69 (dd, J = 5.2,

11.1 Hz, 1 H, 6a-H), 3.63 (dd, J = 4.4, 11.1 Hz, 1 H, 6b-H), 3.37

pentyl) ppm. ¹³C NMR (150 MHz, MeOD): δ = 174.7 [C(O)-1],

78.4 (C-3), 74.1 (C-4), 65.5 (C-2), 63.0 (C-5), 62.1 (C-6), 40.6

(dd, J = 5.1, 11.6 Hz, 1 H, 5-H), 3.28–3.17 (m, 2 H, NCH₂-1 (NCH₂-1 pentyl), 30.3, 23.6 (3ϫCH₂pentyl), 14.5 (CH₃-5 pentyl).

pentyl), 1.58–1.50 (m, 2 H, CH₂-2 pentyl), 1.39–1.30 (m, 4 H, IR (thin film): ν = 3350, 2930, 2857, 1652, 1544, 1464, 1317,

2ϫCH₂pentyl), 0.92 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C 1127 cm^–1. [α]²_D⁰= –2.0 (c = 0.2, MeOH). HRMS: calcd. for

˜

max

NMR (151 MHz, MeOD): δ = 174.4 [C(O)-1], 74.3 (C-3), 74.1 (C-

[C₁₁H₂₂O₄N₂+ H]⁺247.1652 [M + H]⁺; found 247.1654.

4), 63.8 (C-2), 62.6 (C-6), 61.5 (C-5), 40.3 (NCH₂-1 pentyl), 30.3,

Pentyl 2,5-Butylimino-2,5-dideoxy- -talo-hexonamide (41): Com-

D

23.6 (3ϫCH pentyl), 14.5 (CH -5 pentyl) ppm. IR (thin film): ν

˜

max

2

3

pound 41 (7 mg, 23 μmol, 44%) was synthesized in two steps from

24 (52 μmol) through reductive amination with the appropriate al-

dehyde (General Procedure E) and subsequent benzyl ether depro-

tection (appropriate method in General Procedure F). R_f= 0.23

(MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated penultimate)

= 0.83 (EtOAc/toluene, 1:1 + 2% Et₃N). ¹H NMR (600 MHz,

MeOD): δ = 4.32 (dd, J = 5.8, 7.2 Hz, 1 H, 4-H), 3.87 (dd, J = 1.7,

5.8 Hz, 1 H, 3-H), 3.80 (dd, J = 3.6, 11.6 Hz, 1 H, 6a-H), 3.71 (dd,

J = 2.1, 11.6 Hz, 1 H, 6b-H), 3.39 (d, J = 1.4 Hz, 1 H, 2-H), 3.35–

3.32 (m, 1 H, 5-H), 3.26–3.19 (m, 1 H, NCHH-1 pentyl), 3.19–3.11

(m, 1 H, NCHH-1 pentyl), 2.88 (ddd, J = 4.8, 9.5, 12.6 Hz, 1 H,

NCHH butyl), 2.54 (ddd, J = 6.8, 9.8, 12.5 Hz, 1 H, NCHH butyl),

1.56–1.26 (m, 10 H, 5ϫCH₂pentyl/butyl), 0.96–0.90 (m, 6 H,

2ϫCH₃pentyl/butyl) ppm. ¹³C NMR (150 MHz, MeOD): δ =

= 3325, 2959, 2930, 1636, 1543, 1456, 1408, 1251, 1118, 1048 cm^–1.

[α]²_D⁰= 53.6 (c = 0.3, MeOH). HRMS: calcd. for [C₁₁H₂₂O₄N₂

+

H]⁺247.1652 [M + H]⁺; found 247.1654.

Pentyl

2,5-Butylimino-2,5-dideoxy-D-galacto-hexonamide

(38):

Compound 38 (55 mg, 182 μmol, 86%) was synthesized in two

steps from 23 (212 μmol) through reductive amination with the ap-

propriate aldehyde (General Procedure E) and subsequent benzyl

ether deprotection (appropriate method in General Procedure F).

R_f= 0.24 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated

penultimate) = 0.56 (EtOAc/toluene, 1:1 + 2% Et₃N). ¹H NMR

(600 MHz, MeOD): δ = 4.32 (dd, J = 4.6, 8.0 Hz, 1 H, 4-H), 4.20

(dd, J = 4.6, 5.4 Hz, 1 H, 3-H), 3.75 (dd, J = 2.9, 11.2 Hz, 1 H,

6a-H), 3.64 (dd, J = 4.4, 11.2 Hz, 1 H, 6b-H), 3.37–3.30 (m, 2 H,

H-2, NCHH-1 pentyl), 3.25–3.16 (m, 1 H, NCHH-1 pentyl), 3.06– 175.8 [C(O)-1], 76.2 (C-3), 76.0 (C-2), 72.7 (C-4), 65.0 (C-5), 58.4

3.00 (m, 1 H, 5-H), 2.72–2.62 (m, 1 H, NCHH butyl), 2.59–2.50 (C-6), 50.7 (NCH₂butyl), 40.1 (NCH₂-1 pentyl), 32.2, 30.5, 30.4,

(m, 1 H, NCHH butyl), 1.60–1.29 (m, 10 H, 5ϫCH₂pentyl/butyl), 23.6, 21.9 (5ϫCH₂pentyl/butyl), 14.6, 14.5 (2ϫCH₃pentyl/but-

0.99–0.90 (m,

6

H, 2ϫCH₃pentyl/butyl) ppm. ¹³C NMR

yl) ppm. IR (thin film): ν_max= 3312, 2927, 2856, 1652, 1528, 1461,

˜

(150 MHz, MeOD): δ = 174.4 [C(O)-1], 74.2 (C-3), 73.2 (C-4), 72.4

1167 cm^–1. [α]²_D⁰= –32.3 (c = 0.1, MeOH). HRMS: calcd. for

(C-2), 67.8 (C-5), 61.7 (C-6), 57.4 (NCH₂butyl), 40.1 (NCH₂-1 [C₁₅H₃₀O₄N₂+ H]⁺303.2278 [M + H]⁺; found 303.2279.

pentyl), 32.0, 30.4, 30.4, 23.6, 21.7 (5ϫCH₂pentyl/butyl), 14.6, 14.5

Pentyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,5-dideoxy-

(2ϫCH pentyl/butyl) ppm. IR (thin film): ν_max= 3327, 2957, 2930,

˜

3

D-talo-hexonamide (42): Compound 42 (17 mg, 35 μmol, 73%) was

2862, 1650, 1636, 1539, 1463, 1141, 1030, 1011 cm^–1. [α]²_D⁰= 60.6

(c = 0.9, MeOH). HRMS: calcd. for [C₁₅H₃₀O₄N₂+ H]⁺303.2278

[M + H]⁺; found 303.2279.

synthesized in two steps from 24 (48 μmol) through reductive amin-

ation with the appropriate aldehyde (General Procedure E) and a

subsequent benzyl ether deprotection (appropriate method in Ge-

Pentyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,5-dideoxy- neral Procedure F). R_f= 0.29 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH);

D

-galacto-hexonamide (39): Compound 39 (71 mg, 148 μmol, 69%)

R_f(N-alkylated penultimate) = 0.87 (EtOAc/toluene, 1:1 + 2%

Et₃N). ¹H NMR (600 MHz, MeOD): δ = 4.31 (dd, J = 5.8, 7.4 Hz,

1 H, 4-H), 3.87 (dd, J = 1.6, 5.8 Hz, 1 H, 3-H), 3.81 (dd, J = 3.4,

11.5 Hz, 1 H, 6a-H), 3.70 (d, J = 11.5 Hz, 1 H, 6b-H), 3.39–3.37

(m, 3 H, H-2, CH₂-5 pentyl AMP), 3.36–3.32 (m, 1 H, 5-H), 3.27–

3.20 (m, 1 H, NCHH-1 pentyl AMP), 3.19–3.11 (m, 1 H, NCHH-1

pentyl AMP), 2.96 (s, 2 H, OCH₂-Ada), 2.94–2.85 (m, 1 H, NCHH

was synthesized in two steps from 23 (213 μmol) through reductive

amination with the appropriate aldehyde (General Procedure E)

and a subsequent benzyl ether deprotection (appropriate method

in General Procedure F). R_f= 0.26 (MeOH/CH₂Cl₂, 1:9 + 2%

NH₄OH); R_f(N-alkylated penultimate) = 0.62 (EtOAc/toluene, 1:1

+ 2% Et₃N). ¹H NMR (600 MHz, MeOD, collapsed iminosugar

Eur. J. Org. Chem. 2012, 6420–6454

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6435

H. S. Overkleeft et al.

FULL PAPER

pentyl), 2.58–2.50 (m, 1 H, NCHH pentyl), 1.95 (s, 3 H, 3ϫCH 2,3,5-Tri-O-benzyl-D-xylitol (45): Sodium borohydride (10.78 g,

Ada), 1.72 (dd, J = 12.1, 48.4 Hz, 6 H, 3ϫCH₂Ada), 1.60–1.27

(m, 18 H, 3ϫCH₂Ada, 6ϫCH₂pentyl/pentyl AMP), 0.93 (t, J =

285 mmol) was added to a cooled solution (0 °C) of 44 (20 g,

48.0 mmol) in MeOH (240 mL). The reaction mixture was stirred

7.1 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (150 MHz, MeOD): δ for 3 h at room temp., then the pH was adjusted to pH 5 by ad-

= 175.8 [C(O)-1], 83.2 (OCH₂-Ada), 76.3 (C-3), 76.2 (C-2), 72.7

dition of acetic acid. The mixture was concentrated, dissolved in

(C-4), 72.6 (CH₂-5 pentyl AMP), 64.9 (C-5), 58.3 (C-6), 50.9 Et₂O (500 mL), and washed successively with water (200 mL), 1 M

(NCH₂pentyl), 41.0 (CH₂Ada), 40.1 (NCH₂pentyl AMP), 38.5 aq. HCl (300 mL), 10% aq. NaHCO₃(300 mL), and satd. aq. NaCl

(CH₂Ada), 35.3 (C_qAda), 29.9 (CH Ada), 30.7, 30.5, 30.4, 29.7, (200 mL). The organic phase was dried (MgSO₄), concentrated,

25.4, 23.6 (6ϫCH₂pentyl/pentyl AMP), 14.6 (CH₃-5 pentyl) ppm.

and the residue was purified by silica gel column chromatography

(EtOAc/PE, 20Ǟ60%) to give 45 (17.6 g, 41.6 mmol, 87%) as a

colorless oil. R_f= 0.45 (EtOAc/PE, 1:1). ¹H NMR (CDCl₃,

200 MHz): δ = 7.26–7.19 (m, 15 H, H_ArBn), 4.94–4.37 (m, 6 H,

3ϫCH₂Bn), 4.15–4.01 (m, 1 H), 3.77–3.70 (m, 4 H), 3.63–3.36 (m,

2 H), 2.94 (br. s, 2 H, OH-1, OH-4) ppm. ¹³C NMR (CDCl₃,

50 MHz): δ = 137.9, 137.8, 137.7 (3ϫC_qBn), 128.1, 127.6, 127.5,

127.4 (CH_ArBn), 78.7, 77.3 (C-2, C-3), 73.9, 72.9, 72.0 (3ϫCH₂

Bn), 70.9 (C-5), 68.4 (C-4), 60.2 (C-1) ppm.

IR (thin film): ν

= 3319, 2902, 2849, 1652, 1458, 1112 cm^–1.

˜

max

[α]²_D⁰= –17.3 (c = 0.3, MeOH). HRMS: calcd. for [C₂₇H₄₈O₅N₂+

H]⁺481.3636 [M + H]⁺; found 481.3631.

Mixture of 2,3,5-Tri-O-benzyl-1-O-methyl-α/β-D-xylofuranoside

(43): An anhydrous solution of HCl [prepared by careful addition

of AcCl (2 mL) to MeOH (100 mL)] was added to an anhydrous

solution of d-xylose (20.07 g, 133.7 mmol) in MeOH (340 mL). The

reaction mixture was stirred for 20 h at room temp., then the reac-

tion was quenched by adjusting the pH of the reaction mixture to

ca. pH 7 by addition of 3 M aq. NaOH. The mixture was concen-

trated and coevaporated with toluene (4ϫ 100 mL). The crude resi-

due was dissolved in DMF (500 mL) and cooled to 0 °C. Sub-

sequently, NaH (60% in mineral oil, 30.04 g, 751 mmol), tetrabut-

ylammonium iodide (32.312 g, 88 mmol) and benzyl bromide

(52 mL, 437 mmol) were added. After stirring the reaction mixture

for 48 h at room temp., MeOH (10 mL) was added and the mixture

was concentrated. The residue was dissolved in ethyl acetate

(100 mL) and washed successively with H₂O (4ϫ 50 mL) and satd.

aq. NaCl (50 mL). The organic layer was dried (MgSO₄), concen-

trated, and the resulting residue was purified by silica gel column

chromatography (EtOAc/toluene, 5Ǟ20%) to provide 43 (53.9 g,

2,3,5-Tri-O-benzyl-1-O-trityl-D-xylitol (46): Triphenylmethyl chlor-

ide (14.1 g, 50.6 mmol) was added to a solution of 45 (17.6 g,

40.5 mmol) in pyridine (210 mL). The reaction mixture was stirred

for 20 h at 40 °C, then excess triphenylmethyl chloride was

quenched by addition of H₂O (5 mL) and the mixture was concen-

trated. The residue was redissolved in Et₂O (100 mL) and washed

successively with 0.1 M aq. HCl (2ϫ 100 mL), satd. aq. NaHCO₃

(100 mL) and satd. aq. NaCl (50 mL). The organic phase was dried

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

column chromatography (EtOAc/toluene, 0Ǟ20%) to give 46

(25.3 g, 38.1 mmol, 94%) as a colorless oil. R_f= 0.45 (EtOAc/PE,

1:4). ¹H NMR (400 MHz, CDCl₃): δ = 7.48–7.43 (m, 6 H, H_ArTr),

7.35–7.13 (m, 24 H, H_ArBn/Tr), 4.73–4.65 (m, 2 H, 2ϫCHH Bn),

124.1 mmol, 93%) as a colorless oil. R_f= 0.58 (β-anomer), 0.42 4.55–4.48 (m, 2 H, 2ϫCHH Bn), 4.42 (s, 2 H, CH₂Bn), 3.91 (dd,

(α-anomer) (EtOAc/PE, 5:1). ¹H NMR (CDCl₃, 200 MHz): δ (β- J = 3.1, 5.6 Hz, 1 H, 3-H), 3.85–3.79 (m, 2 H, 2-H, 4-H), 3.44 (dd,

anomer) = 7.28–7.26 (m, 15 H, H_ArBn), 4.91 (d, J = 1.8 Hz, 1 H, J = 4.2, 10.2 Hz, 1 H, 1a-H), 3.38 (d, J = 6.0 Hz, 2 H, CH₂-5),

1-H), 4.56–4.40 (m, 7 H), 4.04 (dd, J = 2.5, 2.6 Hz, 1 H), 3.97 (m,

1 H), 3.77–3.71 (m, 2 H), 3.37 (s, 3 H, OMe) ppm; δ (α-anomer) =

7.29–7.25 (m, 15 H, H_ArBn), 4.80 (d, J = 4.0 Hz, 1 H, 1-H), 4.67–

4.46 (m, 6 H, 3ϫCH₂Bn), 4.43–4.26 (m, 2 H, 3-H, 4-H), 4.03–4.01

(m, 1 H, 2-H), 3.74–3.53 (m, 2 H, CH₂-5), 3.39 (s, 3 H, OMe) ppm.

¹³C NMR (CDCl₃, 50 MHz): δ (β-anomer) = 139.1, 138.6, 138.1

(3ϫC_qBn), 129.0, 128.6, 128.4, 127.7, 127.5 (CH_ArBn), 108.1 (C-

1), 87.0, 82.0, 80.0 (C-2, C-3, C-4), 73.3, 72.1, 71.8 (3ϫCH₂Bn),

3.32 (dd, J = 5.0, 10.2 Hz, 1 H, 1b-H), 2.45 (d, J = 6.3 Hz, 1 H,

O4-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 144.1 (C_q-Ph Tr),

138.5, 138.4, 138.3 (3ϫC_qBn), 128.9, 128.5, 128.5, 128.4, 128.4,

128.2, 128.0, 127.9, 127.8, 127.8, 127.2 (CH_ArBn/Tr), 87.0 (C_qTr),

79.6 (C-2), 78.3 (C-3), 75.0, 73.3, 73.0 (3ϫCH₂Bn), 71.2 (C-5),

70.0 (C-4), 63.0 (C-1) ppm. IR (thin film): ν_max= 3031, 2956, 1726,

˜

1491, 1452, 1285, 1069, 747, 700 cm^–1. [α]²_D⁰= –3.3 (c = 2.2, CHCl₃).

HRMS: calcd. for [C₄₅H₄₄O₅+ Na]⁺687.3080 [M + Na]⁺; found

69.9 (C-5), 55.9 (OMe) ppm; δ (α-anomer) = 138.4, 138.2, 137.9 687.3080.

(3ϫC_qBn), 127.9, 127.5, 127.4 (CH_ArBn), 100.5 (C-1), 84.0, 81.5,

2,3,5-Tri-O-benzyl-4-methanesulfonyl-1-O-trityl-

D-xylitol

(47):

76.0 (C-2, C-3, C-4), 73.2, 72.3 (3ϫCH₂Bn), 69.3 (C-5), 54.9

Methanesulfonyl chloride (6.7 mL, 86 mmol) was added to an an-

hydrous solution of 46 (14.4 g, 21.7 mmol) and Et₃N (10.9 mL,

78.0 mmol) in CH₂Cl₂(110 mL). The reaction mixture and stirred

for 20 h, then quenched by addition of H₂O (5 mL). The reaction

mixture was washed successively with 0.1 M aq. HCl (50 mL), satd.

aq. NaHCO₃(50 mL) and satd. aq. NaCl (50 mL). The organic

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

fied by silica gel column chromatography (EtOAc/PE, 5Ǟ25%) to

(OMe) ppm.

Mixture of 2,3,5-Tri-O-benzyl-α/β-D-xylose (44): The combined α/

β-anomers of 43 (25.11 g, 57.8 mmol) in dioxane (200 mL) and 4 M

aq. HCl (200 mL) were heated to reflux for 5 h until TLC analysis

indicated complete conversion of the starting material. The reac-

tion mixture was cooled to room temp., diluted with Et₂O (200 mL)

and washed successively with satd. aq. NaHCO₃(100 mL), H₂O

(3ϫ 50 mL) and satd. aq. NaCl (50 mL). The organic phase was produce 47 (13.7 g, 18.5 mmol, 85%) as a colorless oil. R_f= 0.60

1

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

gel column chromatography (EtOAc/toluene, 5Ǟ20%) to provide

(EtOAc/toluene, 1:9). H NMR (400 MHz, CDCl₃): δ = 7.44–7.38

(m, 6 H, H_ArTr), 7.34–7.08 (m, 26 H, H_ArBn/Tr), 4.79 (ddd, J =

2.8, 5.3, 6.9, 1 H, 4-H), 4.62–4.55 (m, 2 H, 2ϫCHH Bn), 4.52 (d,

44 (16.9 g, 40.2 mmol, 70%) as a colorless oil. R_f= 0.38 (EtOAc/

1

toluene, 1:1). H NMR (CDCl₃, 200 MHz): δ = 7.34–7.17 (m, 15 J = 11.2, 1 H, CHH Bn), 4.47 (d, J = 11.9, 1 H, CHH Bn), 4.32–

H, H_ArBn), 5.46 (d, J = 4.4 Hz, 1 H, 1α-H), 5.23 (s, 1 H, 1β-H),

4.27 (m, 2 H, 2ϫCHH Bn), 4.11 (dd, J = 3.4, 6.8, 1 H, 3-H), 3.73

4.65–4.46 (m, 6 H, 3ϫCH₂Bn), 4.42–4.33 (m, 1 H), 4.10–3.90 (m, 2 (ddd, J = 3.5, 5.1, 6.1, 1 H, 2-H), 3.62 (dd, J = 2.8, 11.5, 1 H, 6a-

H), 3.79–3.60 (m, 2 H), 2.34 (s, 1 H, OH) ppm. ¹³C NMR (CDCl₃,

H), 3.47 (dd, J = 5.1, 9.8, 1 H, 1a-H), 3.39 (dd, J = 5.3, 11.5, 1 H,

6b-H), 3.35 (dd, J = 6.2, 9.8, 1 H, 1b-H), 2.81 (s, 3 H, CH₃

50 MHz): δ = 137.3, 136.8, 136.6, 136.1 (3ϫC_qBn α/β), 128.2,

127.6, 127.3, 127.1, 127.0, 126.9, 126.5, 126.0 (CH_ArBn α/β), 100.8 Ms) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 143.9 (C_q-Ph Tr),

(C-1 β), 95.1 (C-1 α), 85.8, 80.6, 80.4, 80.2, 78.9, 72.7, 72.5, 71.9,

137.9, 137.8, 137.7 (3ϫC_qBn), 128.8, 128.7, 128.6, 128.5, 128.5,

71.6, 71.4, 71.9, 67.9, 67.6, 64.0 ppm.

128.5, 128.1, 128.0, 127.3 (CH_ArBn/Tr), 87.3 (C_qTr), 82.1 (C-4),

6436

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

77.3 (C-3), 76.9 (C-2), 75.3, 73.4, 72.6 (3ϫCH₂Bn), 69.3 (C-5),

137.7, 137.1, 136.9 (3ϫC_qBn), 128.8, 128.7, 128.7, 128.6, 128.6,

128.3, 128.3, 128.1, 128.0 (CH_ArBn), 83.4 (C-2), 78.0 (C-3), 74.5,

73.9, 73.6 (3ϫCH₂Bn), 69.3 (C-5), 60.9 (C-4) ppm. IR (thin film):

62.1 (C-1), 38.3 (CH Ms) ppm. IR (thin film): ν

= 3032, 1492,

˜

3

max

1452, 1358, 1213, 1175, 1073, 918, 748, 701 cm^–1. [α]²_D⁰= 23.5 (c =

1.6, CHCl₃). HRMS: calcd. for [C₄₆H₄₆O₇S + Na]⁺765.2862 [M +

Na]⁺; found 765.2860.

ν

_max= 2867, 2097, 1728, 1496, 1454, 1315, 1266, 1210, 1093, 1026,

˜

912, 734, 695 cm^–1. [α]²_D⁰= 12.6 (c = 1.8, CHCl₃). HRMS: calcd.

for [C₂₆H₂₇N₃O₄+ Na]⁺468.1899 [M + Na]⁺; found 468.1891.

4-Azido-2,3,5-tri-O-benzyl-4-deoxy-1-O-trityl-L-arabinitol (48): So-

dium azide (7.80 g, 120 mmol) and 15-crown-5 (0.25 mL,

1.25 mmol) were added to an anhydrous solution of 47 (9.21,

12.4 mmol) in DMF (60 mL). The resulting suspension was stirred

at 90 °C for 48 h. The reaction mixture was concentrated and the

residue was dissolved in Et₂O (100 mL) and washed successively

with water (100 mL) and satd. aq. NaCl (100 mL). The organic

layer was dried (MgSO₄), concentrated, and the resulting residue

was purified by silica gel column chromatography (EtOAc/PE,

5Ǟ20%) to produce 48 (7.5 g, 10.9 mmol, 88%) as a colorless oil.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-(pent-4-enimido)-L-gulo-hexonamide (51): Subjecting azido alde-

hyde 50 (1.04 mmol) to the tandem SAWU-3CR (General pro-

cedure B in MeOH) produced a separable 1:1.9 mixture of 51

(114 mg, 0.15 mmol) and 52 (213 mg, 0.28 mmol) in a combined

yield of 41%. R_f= 0.63 (EtOAc/PE, 1:1). ¹H NMR (400 MHz,

CDCl₃, 2:1 mixture of rotamers; major rotamer): δ = 7.37–7.20 (m,

15 H, H_ArBn), 6.17 [t, J = 5.8 Hz, 1 H, C(O)NH], 5.84–5.71 (m,

1 H, =CH pentenyl), 5.10–4.92 (m, 2 H, =CH₂pentenyl), 4.70–4.41

(m, 7 H, 3ϫCH₂Bn, 5-H), 4.38 (s, 1 H, 2-H), 4.22 (s, 1 H, 3-H),

4.18 (s, 1 H, 4-H), 3.98 (dd, J = 4.4, 8.8 Hz, 1 H), 3.49 (dd, J =

8.8, 10.5 Hz, 1 H, 6b-H), 3.27 (t, J = 6.5 Hz, 2 H, CH₂-5 pentyl),

3.17–2.92 (m, 2 H, NCH₂-1 pentyl), 2.91 (s, 2 H, OCH₂-Ada),

2.47–2.19 (m, 4 H, 2ϫCH₂pentenyl), 1.95 (s, 3 H, 3ϫCH Ada),

1.68 (dd, J = 12.0, 27.2 Hz, 6 H, 3ϫCH₂Ada), 1.51 (d, J = 2.6 Hz,

1

R_f= 0.80 (EtOAc/toluene, 1:9). H NMR (400 MHz, CDCl₃): δ =

7.46–7.39 (m, 6 H, H_ArTr), 7.33–7.02 (m, 24 H, H_ArBn/Tr), 4.63

(d, J = 11.6 Hz, 1 H, CHH Bn), 4.49 (d, J = 11.6 Hz, 1 H, CHH

Bn), 4.46–4.38 (m, 4 H, 2ϫCH₂Bn), 3.86 (dd, J = 3.3, 7.4 Hz, 1

H, 3-H), 3.82–3.78 (m, 1 H, 2-H), 3.77–3.71 (m, 2 H, 4-H, 5a-H),

3.63 (dd, J = 6.5, 10.2 Hz, 1 H, 5b-H), 3.45 (dd, J = 5.3, 9.8 Hz, 1

H, 1a-H), 3.30 (dd, J = 6.5, 9.8 Hz, 1 H, 1b-H) ppm. ¹³C NMR 6 H, 3ϫCH₂Ada), 1.48–1.35 (m, 2 H, CH₂-2 pentyl), 1.35–1.04

(100 MHz, CDCl₃): δ = 144.1 (C1-Ph Tr), 138.5, 138.1, 138.1

(3ϫC_qBn), 128.9, 128.7, 128.6, 128.5, 128.2, 128.0, 128.0, 127.8,

(m, 4 H, 2ϫCH₂pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃, major

rotamer): δ = 173.0 (NC=O pentenyl), 169.9 [NHC(O)-1], 138.5,

127.4 (CH_ArBn/Tr), 87.4 (C_qTr), 78.3 (C-3), 78.2 (C-2), 75.0, 73.5, 137.1 (3ϫC_qBn), 137.0 (=CH pentenyl), 128.8–127.8 (CH_ArBn),

73.4 (3ϫCH₂Bn), 70.0 (C-5), 62.9 (C-1), 61.3 (C-4) ppm. IR (thin 115.8 (=CH₂pentenyl), 85.9 (C-4), 82.1 (OCH₂-Ada), 80.9 (C-3),

film): ν

= 3032, 2870, 2096, 1492, 1452, 1073, 747, 699 cm^–1. 73.3, 71.9 (2ϫCH₂Bn), 71.5 (CH₂-5 pentyl), 71.4 (CH₂Bn), 69.1

˜

max

[α]²_D⁰= 11.2 (c = 1.2, CHCl₃). HRMS: calcd. for [C₄₅H₄₃N₃O₄

+

(C-2), 66.8 (C-6), 64.1 (C-5), 39.9 (CH₂Ada), 39.8 (NCH₂-1

pentyl), 37.5 (CH₂Ada), 34.3 (C_qAda), 34.1 (CH₂pentenyl), 29.3,

29.1, 29.0 (CH₂pentenyl, 2ϫCH₂pentyl), 28.5 (CH Ada), 23.7

Na]⁺712.3151 [M + Na]⁺; found 712.3147.

4-Azido-2,3,5-tri-O-benzyl-4-deoxy-L-arabinitol (49): Boron tri-

(CH -3 pentyl) ppm. IR (thin film): ν_max= 3338, 2901, 2848, 1654,

˜

2

fluoride diethyletherate (4.8 mL, 38.0 mmol) was added to a solu-

tion of 48 (7.3 g, 10.5 mmol) in a mixture of toluene/MeOH

(265 mL, 16:1, v/v). The reaction mixture was stirred for 3 h, after

which the reaction was successively washed with satd. aq. NaHCO₃

(100 mL) and satd. aq. NaCl (100 mL). The organic phase was

dried (MgSO₄) and concentrated, and the residue was dissolved

in EtOAc, cooled to 0 °C and the triphenylmethoxymethane that

precipitated was removed by filtration. Subsequent concentration

and purification of the residue by silica gel column chromatography

1648, 1454, 1407, 1206, 1096, 734, 698 cm^–1. [α]²_D⁰= 12.8 (c = 2.2,

CHCl₃). HRMS: calcd. for [C₄₈H₆₂O₆N₂+ H]⁺763.4681 [M +

H]⁺; found 763.4683.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-(pent-4-enimido)-L-ido-hexonamide (52): R_f= 0.50 (EtOAc/PE,

1

1:1). H NMR (400 MHz, CDCl₃, 6:1 mixture of rotamers; major

rotamer): δ = 7.65 [t, J = 5.9 Hz, 1 H, C(O)NH], 7.45–7.19 (m, 15

H, H_ArBn), 5.87–5.71 (m, 1 H, =CH pentenyl), 5.09–4.92 (m, 2 H,

(EtOAc/toluene, 5Ǟ50%) afforded 49 (4.6 g, 10.3 mmol, 98%) as a =CH₂pentenyl), 4.78 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.67–4.36

colorless oil. R_f= 0.15 (EtOAc/toluene, 1:19). ¹H NMR (400 MHz,

CDCl₃): δ = 7.39–7.15 (m, 15 H, H_ArBn), 4.62–4.51 (m, 4 H,

2ϫCH₂Bn), 4.49 (s, 2 H, CH₂Bn), 3.82–3.61 (m, 7 H, CH₂-1, 2-H,

3-H, 4-H, CH₂-5), 2.27 (s, 1 H, OH-1) ppm. ¹³C NMR (100 MHz,

(m, 6 H, 2-H, 6a-H, CHH Bn, CHH Bn, CH₂Bn), 4.26–4.20 (m,

3 H, CHH Bn, 3-H, 4-H), 3.84–3.79 (m, 1 H, 5-H), 3.48 (dd, J =

1.3, 9.6 Hz, 1 H, 6b-H), 3.26 (t, J = 6.6 Hz, 2 H, CH₂-5 pentyl),

2.92 (s, 2 H, OCH₂-Ada), 2.68–2.56 (m, 2 H, NCH₂-1 pentyl),

CDCl₃): δ = 138.1, 137.7, 137.7 (3ϫC_qBn), 128.5, 128.4, 128.2, 2.41–2.31 (m, 4 H, 2ϫCH₂pentenyl), 1.96 (s, 3 H, 3ϫCH Ada),

128.1, 128.0, 127.9, 127.8, 127.7, 126.9 (CH_ArBn), 79.1, 78.0 (C-2,

C-3), 74.4, 73.4, 73.1 (3ϫCH₂Bn), 69.6 (C-5), 61.3 (C-4), 61.3 (C-

1.68 (dd, J = 11.8, 27.1 Hz, 6 H, 3ϫCH₂Ada), 1.53 (d, J = 2.6 Hz,

6 H, 3ϫCH₂Ada), 1.46–1.33 (m, 2 H, CH₂-2 pentyl), 1.13–1.01

1) ppm. IR (thin film): ν

= 3465, 3033, 2868, 2096, 1496, 1454, (m, 4 H, 2ϫCH₂pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃, major

˜

max

1267, 1211, 1093, 1027, 735, 698 cm^–1. [α]²_D⁰= 18.5 (c = 7.0, CHCl₃).

HRMS: calcd. for [C₂₆H₂₉N₃O₄+ Na]⁺470.2056 [M + Na]⁺; found

470.2046.

rotamer): δ = 173.3 (NC=O pentenyl), 168.8 [NHC(O)-1], 138.2,

137.7, 137.0 (3ϫC_qBn), 137.1 (=CH pentenyl), 128.8, 128.7, 128.6,

128.5, 128.4, 128.3, 128.1, 128.1, 128.0, 127.9 (CH_ArBn), 115.7

(=CH₂pentenyl), 82.1 (OCH₂-Ada), 82.1, 79.0 (C-3, C-4), 73.8,

73.4, 73.0 (3ϫCH₂Bn), 71.7 (CH₂-5 pentyl), 66.6 (C-6), 63.4 (C-

2), 60.2 (C-5), 40.0 (CH₂Ada), 39.2 (NCH₂-1 pentyl), 37.5 (CH₂

Ada), 34.3 (C_qAda), 33.5 (CH₂pentenyl), 29.8, 29.5, 29.3, 28.8

(CH₂pentenyl, 2ϫCH₂pentyl), 28.5 (CH Ada), 23.6 (CH₂-3 pent-

4-Azido-2,3,5-tri-O-benzyl-4-deoxy-L-arabinose (50): Azido alcohol

49 (2.00 g, 4.47 mmol) was subjected to a Dess–Martin mediated

oxidation (General Procedure A) to produce 50 (1.51 g, 3.39 mmol,

1

76%) as a colorless oil. R_f= 0.60 (EtOAc/toluene, 1:9). H NMR

(400 MHz, CDCl₃): δ = 9.66 [d, J = 1.1 Hz, 1 H, C(O)H-1], 7.37–

7.14 (m, 15 H, H_ArBn), 4.75 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.60

(d, J = 11.7 Hz, 1 H, CHH Bn), 4.53 (s, 2 H, CH₂Bn), 4.44 (s, 2

H, CH₂Bn), 4.03 (dd, J = 1.2, 3.0 Hz, 1 H, 2-H), 3.96 (dd, J =

3.0, 8.1 Hz, 1 H, 3-H), 3.85 (dt, J = 2.7, 5.7 Hz, 1 H, 4-H), 3.81

(dd, J = 2.7, 9.9 Hz, 1 H, 5a-H), 3.70 (dd, J = 5.6, 9.9 Hz, 1 H,

yl) ppm. IR (thin film): ν_max= 3322, 2902, 2848, 1664, 1560, 1454,

˜

1406, 1095, 1028, 737, 698 cm^–1. [α]²_D⁰= 16.8 (c = 4.0, CHCl₃).

HRMS: calcd. for [C₄₈H₆₂O₆N₂+ H]⁺763.4681 [M + H]⁺; found

763.4684.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-

5b-H) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 203.2 [C(O)H-1], 4-enimido)-

L-gulo-hexonamide (53): Subjecting azido aldehyde 50

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6437

H. S. Overkleeft et al.

FULL PAPER

(1.59 mmol) to the tandem SAWU-3CR (General procedure B in

71.9, 71.5 (3ϫCH₂Bn), 69.1 (C-2), 66.8 (C-6), 64.1 (C-5), 39.8

MeOH) produced a separable 1:1.1 mixture of 53 (269 mg,

(NCH₂-1 pentyl), 34.1 (NCH₂pentenyl), 29.2, 28.9, 22.4 (CH₂

0.42 mmol) and 54 (282 mg, 0.44 mmol) in a combined yield of

pentyl/pentenyl), 14.1 (CH -5 pentyl) ppm. IR (thin film): ν

=

˜

3

max

54%. R_f= 0.75 (EtOAc/PE, 1:1). H NMR (400 MHz, CDCl₃, 4:1 3325, 2930, 1652, 1540, 1455, 1366, 1097, 737, 699 cm^–1. [α]²_D⁰

1

mixture of rotamers; major rotamer): δ = 7.40–7.18 (m, 15 H, H_Ar17.3 (c = 0.3, CHCl₃). HRMS: calcd. for [C₃₇H₄₆O₅N₂+ H]⁺

Bn), 6.13 [s, 1 H, C(O)NH], 5.88–5.73 (m, 1 H, =CH pentenyl),

5.08–4.93 (m, 2 H, =CH₂pentenyl), 4.70–4.39 (m, 7 H, 5-H,

3ϫCH₂Bn), 4.24 (s, 1 H, 2-H), 4.21 (s, 1 H, 3-H), 4.16 (s, 1 H, 4-

H), 3.99 (dd, J = 4.3, 8.8 Hz, 1 H, 6a-H), 3.45 (dd, J = 8.8, 10.9 Hz,

1 H, 6b-H), 2.43–2.24 (m, 4 H, 2ϫCH₂pentenyl), 1.48–1.32 (m, 2

H, CH₂-2 tMB), 1.23 (s, 3 H, CH₃tMB), 1.18 (s, 3 H, CH₃tMB),

0.85 (s, 9 H, CH₃-4, 2ϫCH₃tMB) ppm. ¹³C NMR (100 MHz,

CDCl₃, major rotamer): δ = 172.9 (NC=O pentenyl), 168.7

[NHC(O)-1], 138.5, 137.2, 136.9 (3ϫC_qBn), 137.1 (=CH pentenyl),

128.7, 128.7, 128.5, 128.4, 128.3, 128.1, 128.0, 127.8, 127.8 (CH_Ar

Bn), 115.8 (=CH₂pentenyl), 85.9 (C-4), 81.3 (C-3), 73.3, 71.8

(3ϫCH₂Bn), 70.0 (C-2), 66.7 (C-6), 64.0 (C-5), 55.8 (NHC_q-1

tMB), 53.4 (CH₂-2 tMB), 34.2 (NCH₂pentenyl), 31.6 (CH₃-4,

2ϫCH₃tMB, C_q-3 tMB), 28.9 (CH₂pentenyl), 28.3, 27.3 (2ϫCH₃

599.3479 [M + H]⁺; found 599.3478.

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-4-enimido)-

L

-ido-

1

hexonamide (56): R_f= 0.55 (EtOAc/PE, 1:1). H NMR (600 MHz,

CDCl₃, 9:1 mixture of rotamers; major rotamer): δ = 7.65 [t, J =

5.8 Hz, 1 H, C(O)NH], 7.43–7.15 (m, 15 H, H_ArBn), 5.83–5.76 (m,

1 H, =CH pentenyl), 5.05–4.97 (m, 3 H, =CH₂pentenyl, CHH Bn),

4.78 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.60–4.55 [m, J = 6.9 Hz, 2

H, 2-H (d), CHH Bn], 4.53 (d, J = 11.2 Hz, 1 H, CHH Bn), 4.45–

4.39 (m, 2 H, 6a-H, CHH Bn), 4.25–4.21 (m, 3 H, 3-H, 4-H, CHH

Bn), 3.81 (d, J = 4.4 Hz, 1 H, 5-H), 3.48 (d, J = 10.6 Hz, 1 H, 6b-

H), 2.69 (dt, J = 6.4, 13.4 Hz, 1 H, NCHH-1 pentyl), 2.60 (dt, J =

6.1, 13.4 Hz, 1 H, NCHH-1 pentyl), 2.41–2.32 (m, 3 H, NCHH

pentenyl, CH₂pentenyl), 2.23–2.15 (m, 1 H, NCHH pentenyl),

1.22–1.12 (m, 2 H, CH₂-2 pentyl), 1.11–0.98 (m, 4 H, 2ϫCH₂

pentyl), 0.81 (t, J = 7.4 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR

(150 MHz, CDCl₃, major rotamer): δ = 173.4 (NC=O pentenyl),

168.8 [NHC(O)-1], 138.2, 137.7, 137.1 (3ϫC_qBn), 137.0 (=CH

pentenyl), 128.8, 128.8, 128.6, 128.6, 128.6, 128.6, 128.5, 128.2,

128.1 (CH_ArBn), 115.7 (=CH₂pentenyl), 82.1, 79.0 (C-3, C-4),

73.8, 73.4, 73.1 (3ϫCH₂Bn), 66.5 (C-6), 63.4 (C-2), 60.2 (C-5),

39.2 (NCH₂-1 pentyl), 33.5 (CH₂pentenyl), 29.6, 29.1, 28.8, 22.6

(CH₂pentyl/pentenyl), 14.2 (CH₃-5 pentyl) ppm. IR (thin film):

tMB) ppm. IR (thin film): ν

= 2952, 1654, 1560, 1458, 1096,

˜

max

736, 698, 668 cm^–1. [α]²_D⁰= 11.2 (c = 2.0, CHCl₃). HRMS: calcd.

for [C₄₀H₅₂O₅N₂+ H]⁺641.3949 [M + H]⁺; found 641.3949.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-

4-enimido)-L

-ido-hexonamide (54): R_f= 0.65 (EtOAc/PE, 1:1). ¹H

NMR (400 MHz, CDCl₃, 5:1 mixture of rotamers; major rotamer):

δ = 7.41–7.14 (m, 15 H, H_ArBn), 6.99 [s, 1 H, C(O)NH], 5.83 (ddd,

J = 6.3, 12.3, 16.8 Hz, 1 H, =CH pentenyl), 5.09–4.90 (m, 2 H,

=CH₂pentenyl, CHH Bn), 4.65 (d, J = 11.7 Hz, 1 H, CHH Bn),

4.59–4.41 (m, 5 H, 2-H, CH₂Bn, 2ϫCHH Bn), 4.26–4.20 (m, 2 H,

3-H, 4-H), 4.17 (dd, J = 4.3, 9.7 Hz, 1 H, 6a-H), 3.95–3.89 (m, 1

H, 5-H), 3.50 (dd, J = 2.3, 9.7 Hz, 1 H, 6b-H), 2.45–2.29 (m, 4 H,

2ϫCH₂pentenyl), 1.92 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.59

(d, J = 14.5 Hz, 1 H, CHH-2 tMB), 1.32 (d, J = 9.6 Hz, 6 H,

2ϫCH₃tMB), 0.93 (s, 9 H, CH₃-4, 2ϫCH₃tMB) ppm. ¹³C NMR

(100 MHz, CDCl₃, major rotamer): δ = 173.8 (NC=O pentenyl),

167.9 [NHC(O)-1], 138.0, 137.7, 137.6 (3ϫC_qBn), 137.1 (=CH

pentenyl), 128.7, 128.5, 128.2, 128.2, 128.0, 127.8 (CH_ArBn), 115.7

(=CH₂pentenyl), 82.7, 79.3 (C-3, C-4), 73.4, 73.0, 72.8 (3ϫCH₂

Bn), 66.1 (C-6), 64.5 (C-2), 60.7 (C-5), 55.7 (NHC_q-1 tMB), 51.5

(CH₂-2 tMB), 33.7 (NCH₂pentenyl), 31.7 (CH₃-4, 2ϫCH₃tMB),

31.6 (C_q-3 tMB), 29.4, 28.8 (2ϫCH₃tMB), 28.8 (CH₂pent-

ν

= 3330, 2940, 1667, 1538, 1365, 1096, 737, 700 cm^–1. [α]²_D⁰

=

˜

max

23.3 (c = 0.3, CHCl₃). HRMS: calcd. for [C₃₇H₄₆O₅N₂+ H]⁺

599.3479 [M + H]⁺; found 599.3477.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

2,5-imino-L-gulo-hexonamide (57): Compound 57 (54 mg, 79 μmol,

55%) was synthesized from 51 (144 μmol) by deprotection of the

pent-4-enamide (General Procedure D). R_f= 0.38 (EtOAc/PE, 1:1).

¹H NMR (600 MHz, CDCl₃): δ = 7.68 [t, J = 5.9 Hz, 1 H, C(O)

NH], 7.39–7.18 (m, 15 H, H_ArBn), 4.77 (d, J = 11.8 Hz, 1 H, CHH

Bn), 4.62 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.55–4.45 (m, 3 H, CHH

Bn, CH₂Bn), 4.41 (d, J = 11.6 Hz, 1 H, CHH Bn), 4.36 (dd, J =

2.9 Hz, 1 H, 3-H), 3.88 (dd, J = 3.2, 5.7 Hz, 1 H, 4-H), 3.74 (d, J

= 2.3 Hz, 1 H, 2-H), 3.58 (dd, J = 4.0, 9.6 Hz, 1 H, 6a-H), 3.53

(dd, J = 5.6, 9.6 Hz, 1 H, 6b-H), 3.34 (t, J = 6.5 Hz, 2 H, CH₂-5

pentyl), 3.29–3.15 (m, 3 H, 5-H, NCH₂-1 pentyl), 2.93 (s, 2 H,

OCH₂-Ada), 2.66 (s, 1 H, NH), 1.95 (s, 3 H, 3ϫCH Ada), 1.67

(dd, J = 11.6, 36.7 Hz, 6 H, 3ϫCH₂Ada), 1.58–1.43 (m, 10 H,

3ϫCH₂Ada), 1.39–1.30 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 171.9 [NHC(O)-1], 138.1, 137.9, 137.9

(3ϫC_qBn), 128.5, 128.4, 128.3, 128.0, 127.9, 127.8, 127.8, 127.7,

127.6 (CH_ArBn), 87.2 (C-3), 84.9 (C-4), 81.9 (OCH₂-Ada), 73.2,

71.8, 71.6 (3ϫCH₂Bn), 71.4 (CH₂-5 pentyl), 68.8 (C-6), 65.7 (C-

2), 62.4 (C-5), 39.7 (CH₂Ada), 39.1 (NCH₂-1 pentyl), 37.3 (CH₂

Ada), 34.1 (C_qAda), 29.5, 29.2 (2ϫCH₂pentyl), 28.3 (CH Ada),

enyl) ppm. IR (thin film): ν

= 2952, 2361, 2343, 1668, 1540,

˜

max

1455, 1398, 1365, 1206, 1096, 1028, 736, 698, 668 cm^–1. [α]²_D⁰= 12.1

(c = 2.1, CHCl₃). HRMS: calcd. for [C₄₀H₅₂O₅N₂+ H]⁺641.3949

[M + H]⁺; found 641.3949.

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-(pent-4-enimido)-L-gulo-

hexonamide (55): Subjecting azido aldehyde 50 (3.39 mmol) to the

tandem SAWU-3CR (General procedure B in MeOH) produced a

separable 1:2.1 mixture of 55 (285 mg, 0.48 mmol) and 56 (585 mg,

0.98 mmol) in a combined yield of 43%. R_f= 0.65 (EtOAc/PE,

1:1). ¹H NMR (600 MHz, CDCl₃, 3.5:1 mixture of rotamers; major

rotamer): δ = 7.39–7.20 (m, 15 H, H_ArBn), 6.16 [t, J = 5.6 Hz, 1

H, C(O)NH], 5.83–5.72 (m, 1 H, =CH pentenyl), 5.07–4.93 (m, 2

H, =CH₂pentenyl), 4.68–4.39 (m, 7 H, 5-H, 3ϫCH₂Bn), 4.38 (s,

1 H, 2-H), 4.22 (s, 1 H, 3-H), 4.18 (s, 1 H, 4-H), 3.98 (dd, J = 4.4,

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

= 2901, 1669, 1513,

˜

2

max

1455, 1097, 735, 697 cm^–1. [α]²_D⁰= –0.5 (c = 0.8, CHCl₃). HRMS:

calcd. for [C₄₃H₅₆O₅N₂+ H]⁺681.4262 [M + H]⁺; found 681.4259.

8.8 Hz, 1 H, 6a-H), 3.49 (dd, J = 9.7 Hz, 1 H, 6b-H), 3.13–3.05 5-(Adamantan-1-yl-methoxy)pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-

(m, 1 H, NCHH-1 pentyl), 2.97–2.86 (m, 1 H, NCHH-1 pentyl), 2,5-imino- -ido-hexonamide (58): Compound 58 (111 mg, 163 μmol,

L

2.48–2.24 (m, 4 H, 2ϫCH₂pentenyl), 1.28–1.06 (m, 6 H, 3ϫCH₂62%) was synthesized from 52 (262 μmol) by deprotection of the

pentyl), 0.81 (t, J = 7.2 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR

(150 MHz, CDCl₃, major rotamer): δ = 173.0 (NC=O pentenyl),

pent-4-enamide (General Procedure D). R_f= 0.16 (EtOAc/PE, 1:1).

¹H NMR (600 MHz, CDCl₃): δ = 7.39 [t, J = 5.6 Hz, 1 H, C(O)

169.9 [NHC(O)-1], 138.5, 137.7, 137.1 (3ϫC_qBn), 137.0 (=CH NH], 7.37–7.19 (m, 15 H, H_ArBn), 4.59 (d, J = 11.7 Hz, 1 H, CHH

pentenyl), 128.7, 128.7, 128.6, 128.3, 128.2, 127.9, 127.9, 127.8

(CH_ArBn), 115.8 (=CH₂pentenyl), 85.9 (C-4), 80.9 (C-3), 73.3,

Bn), 4.53–4.39 (m, 5 H, CHH Bn, 2ϫCH₂Bn), 4.29 (dd, J = 1.7,

5.6 Hz, 1 H, 3-H), 4.16 (d, J = 5.6 Hz, 1 H, 2-H), 3.85 (dd, J =

6438

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

2.1 Hz, 1 H, 4-H), 3.56–3.47 (m, 3 H, 5-H, CH₂-6), 3.30 (t, J = CDCl₃): δ = 7.62 [t, J = 5.6 Hz, 1 H, C(O)NH], 7.40–7.19 (m, 15

6.6 Hz, 2 H, CH₂-5 pentyl), 3.23–3.18 (m, 2 H, NCH₂-1 pentyl),

2.92 (s, 2 H, OCH₂-Ada), 2.55–2.14 (m, 1 H, NH), 1.95 (s, 3 H,

H, H_ArBn), 4.77 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.62 (d, J =

11.8 Hz, 1 H), CHH Bn, 4.54–4.39 (m, 4 H, 2ϫCH₂Bn), 4.36 (dd,

3ϫCH Ada), 1.67 (dd, J = 11.6, 38.8 Hz, 6 H, 3ϫCH₂Ada), 1.54– J = 2.9 Hz, 1 H, 3-H), 3.89 (dd, J = 3.3, 5.6 Hz, 1 H, 4-H), 3.78

1.37 (m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.34–1.26 (m, 2 H,

(d, J = 2.3 Hz, 1 H, 2-H), 3.58 (dd, J = 4.1, 9.6 Hz, 1 H, 6a-H),

3.55 (dd, J = 5.7, 9.6 Hz, 1 H, 6b-H), 3.28–3.15 (m, 3 H, 5-H,

CH₂-3 pentyl) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 170.5

[NHC(O)-1], 138.2, 138.0, 137.8 (3ϫC_qBn), 128.7, 128.4, 128.4, NCH₂-1 pentyl), 1.51–1.42 (m, 2 H, CH₂-2 pentyl), 1.32–1.24 (m,

128.3, 128.0, 127.8, 127.8, 127.7, 127.7, 127.7, 127.6 (CH_ArBn), 4 H, 2ϫCH₂pentyl), 0.87 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm.

83.2 (C-4), 83.0 (C-3), 81.9 (OCH₂-Ada), 73.2, 72.9 (2ϫCH₂Bn), ¹³C NMR (150 MHz, CDCl₃): δ = 171.8 [NHC(O)-1], 138.3, 138.1,

72.0 (C-6), 71.5 (CH₂Bn), 71.4 (CH₂-5 pentyl), 64.5 (C-2), 62.3

(C-5), 39.8 (CH₂Ada), 39.1 (NCH₂-1 pentyl), 37.3 (CH₂Ada), 34.1

(C_qAda), 29.5, 29.2 (2ϫCH₂pentyl), 28.3 (CH Ada), 23.6 (CH₂-

138.0 (3ϫC_qBn), 128.7, 128.6, 128.5, 128.2, 128.2, 128.2, 128.1,

128.0, 128.0, 127.9 (CH_ArBn), 87.3 (C-3), 85.0 (C-4), 73.4, 72.1,

71.9 (3ϫCH₂Bn), 68.9 (C-6), 65.8 (C-2), 62.7 (C-5), 39.3 (NCH₂-

3 pentyl) ppm. IR (thin film): ν_max= 3030, 2903, 1668, 1512, 1454,

1 pentyl), 29.5, 29.3, 22.6 (3ϫCH₂pentyl), 14.2 (CH₃-5

˜

1096, 735, 699 cm^–1. [α]²_D⁰= –4.6 (c = 2.2, CHCl₃). HRMS: calcd.

pentyl) ppm. IR (thin film): ν

= 3325, 2930, 2860, 1668, 1526,

˜

max

for [C₄₃H₅₆O₅N₂+ H]⁺681.4262 [M + H]⁺; found 681.4259.

1455, 1096, 736, 698 cm^–1. [α]²_D⁰= –1.6 (c = 4.4, CHCl₃). HRMS:

calcd. for [C₃₂H₄₀O₄N₂+ H]⁺517.3061 [M + H]⁺; found 517.3055.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-

L-gulo-hexon-amide (59): Compound 59 (175 mg, 313 μmol, 95%)

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-L-ido-hexonamide

was synthesized from 53 (330 μmol) by deprotection of the pent-4-

(62): Compound 62 (410 mg, 0.79 mmol, 83%) was synthesized

enamide (General Procedure D). R_f= 0.69 (EtOAc/PE, 1:1). ¹H from 56 (0.95 mmol) by deprotection of the pent-4-enamide (Gene-

NMR (600 MHz, CDCl₃): δ = 7.72 [s, 1 H, C(O)NH], 7.39–7.20

(m, 15 H, H_ArBn), 4.78 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.62 (d,

ral Procedure D). R_f= 0.35 (EtOAc/PE, 1:1). ¹H NMR (600 MHz,

CDCl₃): δ = 7.40 [t, J = 5.7 Hz, 1 H, C(O)NH], 7.35–7.21 (m, 15

J = 11.8 Hz, 1 H, CHH Bn), 4.59–4.41 (m, 4 H, 2ϫCH₂Bn), 4.34 H, H_ArBn), 4.60 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.52–4.40 (m, 5

(dd, J = 2.8, 3.3 Hz, 1 H, 3-H), 3.90 (dd, J = 3.4, 6.0 Hz, 1 H, 4- H, CHH Bn, 2ϫCH₂Bn), 4.30 (dd, J = 1.5, 5.6 Hz, 1 H, 3-H),

H), 3.61 (d, J = 2.6 Hz, 1 H, 2-H), 3.59–3.51 (m, 2 H, CH₂-6),

4.17 (d, J = 5.7 Hz, 1 H, 2-H), 3.85 (s, 1 H, 4-H), 3.56–3.47 (m, 3

3.20–3.13 (m, 1 H, 5-H), 2.74–2.61 (m, 1 H, NH), 1.76 (d, J = H, 5-H, CH₂-6), 3.26–3.12 (m, 2 H, NCH₂-1 pentyl), 2.44 (s, 1 H,

14.9 Hz, 1 H, CHH-2 tMB), 1.60 (d, J = 13.7 Hz, 1 H, CHH-2 NH), 1.46–1.38 (m, 2 H, CH₂-2 pentyl), 1.29–1.19 (m, 4 H, 2ϫCH₂

tMB), 1.39 (d, J = 12.9 Hz, 6 H, 2ϫCH₃tMB), 0.98 (s, 9 H, CH₃- pentyl), 0.84 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR

4, 2ϫCH₃tMB) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 171.0

(150 MHz, CDCl₃): δ = 170.7 [NHC(O)-1], 138.3, 138.2, 137.9

[NHC(O)-1], 138.5, 138.2, 138.1 (3ϫC_qBn), 128.6, 128.5, 128.5, (3ϫC_qBn), 128.8, 128.6, 128.6, 128.5, 128.0, 128.0, 127.9, 127.9,

128.1, 128.1, 128.0, 128.0, 127.8, 127.7 (CH_ArBn), 87.7 (C-3), 85.2 127.9, 127.8 (CH_ArBn), 83.4 (C-4), 83.2 (C-3), 73.4, 73.1 (2ϫCH₂

(C-4), 73.4, 72.1, 71.9 (3ϫCH₂Bn), 68.8 (C-6), 66.3 (C-2), 62.3 (C- Bn), 72.1 (C-6), 71.7 (CH₂Bn), 64.6 (C-2), 62.6 (C-5), 39.3 (NCH₂-

5), 54.5 (NHC_q-1 tMB), 52.8 (CH₂-2 tMB), 31.8 (C_q-3 tMB), 31.7 pentyl), 29.5, 29.3, 22.5 (3ϫCH₂pentyl), 14.2 (CH₃-5

(CH₃-4, 2ϫCH₃tMB), 29.3, 28.6 (2ϫCH₃tMB) ppm. IR (thin pentyl) ppm. IR (thin film): ν = 3325, 3032, 2929, 2861, 1668,

1

˜

max

film): ν

= 3322, 2948, 1670, 1516, 1092, 738, 698 cm^–1. [α]²_D⁰

=

1532, 1497, 1455, 1363, 1208, 1093, 1028, 735, 698 cm^–1. [α]²_D⁰

=

˜

max

–1.5 (c = 2.0, CHCl₃). HRMS: calcd. for [C₃₅H₄₆O₄N₂+ H]⁺

–5.8 (c = 8.2, CHCl₃). HRMS: calcd. for [C₃₂H₄₀O₄N₂+ H]⁺

559.3530 [M + H]⁺; found 559.3525.

517.3061 [M + H]⁺; found 517.3056.

1,1,3,3-Tetramethylbutyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Dideoxy-2,5-imino-L-gulo-

L

-ido-hexonamide (60): Compound 60 (151 mg, 270 μmol, 75%)

hexonamide (63): Compound 63 (7 mg, 17 μmol, 85%) was synthe-

sized from 57 (20 μmol) by deprotection of the benzyl ethers (ap-

was synthesized from 54 (360 μmol) by deprotection of the pent-4-

enamide (General Procedure D). R_f= 0.47 (EtOAc/PE, 1:1). ¹H propriate method in General Procedure F). R_f= 0.29 (MeOH/

NMR (600 MHz, CDCl₃): δ = 7.40–7.22 [m, 16 H, C(O)NH, H_Ar

Bn], 4.62 (d, J = 11.7 Hz, 1 H, CHH Bn), 4.56 (d, J = 12.0 Hz, 1

CH₂Cl₂, 1:9 + 2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ =

4.02 (dd, J = 5.2 Hz, 1 H, 3-H), 3.79 (dd, J = 5.7 Hz, 1 H, 4-H),

H, CHH Bn), 4.53–4.45 (m, 3 H, CHH Bn, CHH Bn, CHH Bn), 3.70 (dd, J = 4.1, 11.1 Hz, 1 H, 6a-H), 3.60 (dd, J = 5.8, 11.1 Hz,

4.43 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.26 (dd, J = 1.4, 5.5 Hz, 1

H, 3-H), 4.02 (d, J = 5.5 Hz, 1 H, 2-H), 3.88 (dd, J = 1.7 Hz, 1 H,

4-H), 3.57 (dd, J = 5.5, 7.0 Hz, 1 H, 6a-H), 3.53–3.47 (m, 2 H, 5-

H, 6b-H), 2.33 (s, 1 H, NH), 1.81 (d, J = 14.9 Hz, 1 H, CHH-2

tMB), 1.51 (d, J = 14.9 Hz, 1 H, CHH-2 tMB), 1.40 (d, J =

29.5 Hz, 6 H, 2ϫCH₃tMB), 0.98 (s, 9 H, CH₃-4, 2ϫCH₃

1 H, 6b-H), 3.49 (d, J = 5.3 Hz, 1 H, 2-H), 3.38 (t, J = 6.4 Hz, 2

H, CH₂-5 pentyl), 3.22 (t, J = 7.0 Hz, 2 H, NCH₂-1 pentyl), 3.08

(dd, J = 5.8, 10.2 Hz, 1 H, 5-H), 2.97 (s, 2 H, OCH₂-Ada), 1.94 (s,

3 H, 3ϫCH Ada), 1.72 (dd, J = 11.9, 31.5 Hz, 6 H, 3ϫCH₂Ada),

1.63–1.49 (m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.46–1.35 (m, 2

H, CH₂-3 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 175.0

tMB) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 169.5 [NHC(O)-1], [C(O)-1], 83.2 (OCH₂-Ada), 82.6 (C-3), 80.0 (C-4), 72.7 (CH₂-5

138.3, 138.1, 137.9 (3ϫC_qBn), 128.4, 128.4, 128.2, 128.1, 127.9, pentyl), 67.0 (C-2), 66.0 (C-5), 63.3 (C-6), 41.0 (CH₂Ada), 40.4

127.8, 127.7, 127.7, 127.7, 127.7, 127.5 (CH_ArBn), 83.5 (C-4), 83.1

(NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5, 30.4

(C-3), 73.2, 72.9 (2ϫCH₂Bn), 72.6 (C-6), 71.4 (CH₂Bn), 65.4 (C- (2ϫCH₂pentyl), 29.9 (CH Ada), 24.8 (CH₂-3 pentyl) ppm. IR

2), 62.5 (C-5), 54.4 (NHC_q-1 tMB), 53.0 (CH₂-2 tMB), 31.6 (C_q-3

(thin film): ν_max= 3313, 2902, 2849, 1652, 1452, 1109 cm^–1. [α]²_D⁰

=

˜

tMB), 31.5 (CH₃-4, 2ϫCH₃tMB), 28.9, 28.2 (2ϫCH₃tMB) ppm.

1.5 (c = 0.1, MeOH). HRMS: calcd. for [C₂₂H₃₈O₅N₂+ H]⁺

IR (thin film): ν_max= 3320, 2950, 1669, 1522, 1096, 738, 698 cm^–1.

411.2853 [M + H]⁺; found 411.2851.

˜

[α]²_D⁰= –6.1 (c = 2.1, CHCl₃). HRMS: calcd. for [C₃₅H₄₆O₄N₂

+

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Butylimino-2,5-dideoxy-L-

H]⁺559.3530 [M + H]⁺; found 559.3525.

gulo-hexonamide (64): Compound 64 (7 mg, 15 μmol, 75%) was

synthesized in two steps from 57 (20 μmol) through reductive amin-

ation with the appropriate aldehyde (General Procedure E) and

subsequent benzyl ether deprotection (appropriate method in Ge-

neral Procedure F). R_f= 0.76 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH);

Pentyl 3,4,6-Tri-O-benzyl-2,5-dideoxy-2,5-imino-L-gulo-hexonamide

(61): Compound 61 (220 mg, 0.43 mmol, 95%) was synthesized

from 55 (0.45 mmol) by deprotection of the pent-4-enamide (Gene-

ral Procedure D). R_f= 0.57 (EtOAc/PE, 1:1). ¹H NMR (600 MHz,

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6439

H. S. Overkleeft et al.

FULL PAPER

R_fN-alkylated penultimate = 0.80 (EtOAc/PE, 1:1). ¹H NMR

synthesized in two steps from 58 (53 μmol) through reductive amin-

(400 MHz, MeOD): δ = 3.96 (dd, J = 1.7 Hz, 1 H, 4-H), 3.89 (dd, ation with the appropriate aldehyde (General Procedure E) and

J = 1.8 Hz, 1 H, 3-H), 3.79 (dd, J = 5.0, 11.4 Hz, 1 H, 6a-H), 3.69 subsequent benzyl ether deprotection (appropriate method in Ge-

(dd, J = 3.2, 11.4 Hz, 1 H, 6b-H), 3.40 (s, 1 H, 2-H), 3.38 (t, J = neral Procedure F). R_f= 0.54 (MeOH/CH₂Cl₂. 1:4 + 2% NH₄OH);

5.6 Hz, 2 H, CH₂-5 pentyl), 3.28–3.11 [m, 3 H, 5-H, C(O)NCH₂-1 R_f(N-alkylated penultimate) = 0.85 (EtOAc/PE, 1:1). ¹H NMR

pentyl], 2.97 (s, 2 H, OCH₂-Ada), 2.88–2.79 (m, 1 H, NCHH-1 (400 MHz, MeOD, collapsed iminosugar signals): δ = 4.19–3.49

pentyl), 2.65–2.55 (m, 1 H, NCHH-1 pentyl), 1.95 (s, 3 H, 3ϫCH

Ada), 1.72 (dd, J = 11.7, 31.6 Hz, 6 H, 3ϫCH₂Ada), 1.64–1.23

(m, 16 H, 3ϫCH₂Ada, 3ϫCH₂pentyl, 2ϫCH₂butyl), 0.94 (t, J =

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

83.3 (OCH₂-Ada), 82.3 (C-3), 81.5 (C-4), 76.3 (CH₂-5 pentyl), 72.7

(m, 5 H), 3.38 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.22 (s, 1 H),

2.97 (s, 2 H, OCH₂-Ada), 2.91–2.55 (m, 3 H), 1.95 (s, 3 H, 3ϫCH

Ada), 1.72 (dd, J = 12.1, 32.0 Hz, 6 H, 3ϫCH₂Ada), 1.64–1.25

(m, 16 H, 3ϫCH₂Ada, 3ϫCH₂pentyl, 2ϫCH₂butyl), 0.94 (t, J =

7.3 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR (100 MHz, MeOD, col-

(C-2), 70.9 (C-5), 61.0 (C-6), 49.8 (NCH₂-1 pentyl), 41.0 (CH₂lapsed iminosugar signals): δ = 83.3 (OCH₂-Ada), 79.3 (CH), 78.4

Ada), 40.2 [C(O)NCH₂-1 pentyl], 38.5 (CH₂Ada), 35.3 (C_qAda), (CH), 72.7 (CH₂-5 pentyl), 41.0 (CH₂Ada), 40.3 (NCH₂-1 pentyl),

29.9 (CH Ada), 32.1, 30.5, 30.5, 24.9, 21.8 (3ϫCH₂pentyl, 2ϫCH₂

butyl), 14.6 (CH₃butyl) ppm. IR (thin film): ν = 3324, 2904,

38.5 (CH₂Ada), 35.3 (C_qAda), 30.5 (CH₂), 29.9 (CH Ada), 24.9

(CH₂), 21.8 (CH₂), 14.5 (CH₃butyl) ppm. IR (thin film): ν

=

˜

max

2851, 1651, 1457, 1057 cm^–1. [α]²_D⁰= 14.3 (c = 0.1, MeOH). HRMS:

3295, 2902, 2849, 1637, 1456, 1360, 1110, 756 cm^–1. [α]²_D⁰= –16.7

calcd. for [C₂₆H₄₆O₅N₂+ H]⁺467.3479 [M + H]⁺; found 467.3476. (c = 0.4, MeOH). HRMS: calcd. for [C₂₆H₄₆O₅N₂+ H]⁺467.3479

[M + H]⁺; found 467.3476.

5-(Adamantan-1-yl-methoxy)pentyl 2,5-[5-(Adamantan-1-yl-meth-

oxy)pentyl]imino-2,5-dideoxy-

L

-gulo-hexonamide (65): Compound

5-(Adamantan-1-yl-methoxy)pentyl 2,5-[5-(Adamantan-1-yl-meth-

oxy)pentyl]imino-2,5-dideoxy- -ido-hexonamide (68): Compound 68

65 (8 mg, 13 μmol, 65%) was synthesized in two steps from 57

(20 μmol) through reductive amination with the appropriate alde-

hyde (General Procedure E) and subsequent benzyl ether deprotec-

tion (appropriate method in General Procedure F). R_f= 0.80

(MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_fN-alkylated penultimate

= 0.82 (EtOAc/PE, 1:1). ¹H NMR (400 MHz, MeOD): δ = 3.96

L

(27 mg, 42 μmol, 79%) was synthesized in two steps from 58

(53 μmol) through reductive amination with the appropriate alde-

hyde (General Procedure E) and subsequent benzyl ether deprotec-

tion (appropriate method in General Procedure F). R_f= 0.56

(MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH); R_f(N-alkylated penultimate)

(dd, J = 1.6 Hz, 1 H, 4-H), 3.89 (dd, J = 1.7 Hz, 1 H, 3-H), 3.80 = 0.72 (EtOAc/PE, 1:1). ¹H NMR (400 MHz, MeOD, collapsed

(dd, J = 5.0, 11.4 Hz, 1 H, 6a-H), 3.69 (dd, J = 3.2, 11.4 Hz, 1 H,

6b-H), 3.42–3.35 (m, 5 H, 2-H, 2ϫCH₂-5 pentyl), 3.27–3.16 [m, 3

iminosugar signals): δ = 4.47–3.50 (m, 5 H), 3.39 (t, J = 6.4 Hz, 4

H, 2ϫCH₂-5 pentyl), 3.27–3.16 (m, 1 H), 2.97 (s, 4 H, 2ϫOCH₂-

H, 5-H, C(O)NCH₂-1 pentyl], 2.97 (s, 4 H, 2ϫOCH₂-Ada), 2.88– Ada), 2.94–2.49 (m, 2 H), 1.95 (s, 6 H, 6ϫCH Ada), 1.72 (dd, J =

2.79 (m, 1 H, NCHH-1 pentyl), 2.65–2.53 (m, 1 H, NCHH-1 12.0, 32.1 Hz, 12 H, 6ϫCH₂Ada), 1.65–1.48 (m, 20 H, 6ϫCH₂

pentyl), 1.95 (s, 6 H, 6ϫCH Ada), 1.72 (dd, J = 12.1, 31.4 Hz, 12

H, 6ϫCH₂Ada), 1.63–1.52 (m, 20 H, 6ϫCH₂Ada, 4ϫCH₂

pentyl), 1.49–1.34 (m, 4 H, 2ϫCH₂-3 pentyl) ppm. ¹³C NMR

(100 MHz, MeOD): δ = 83.3, 83.3 (2ϫOCH₂-Ada), 82.4 (C-3), 81.6

Ada, 4ϫCH₂pentyl), 1.48–1.32 (m, 4 H, 2ϫCH₂-3 pentyl) ppm.

¹³C NMR (100 MHz, MeOD, collapsed iminosugar signals): δ =

83.3 (OCH₂-Ada), 78.4 (CH), 72.7 (CH₂-5 pentyl), 41.0 (CH₂Ada),

40.3 (NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3, 35.3 (2ϫC_qAda),

(C-4), 76.5 (C-2), 72.7, 72.7 (2ϫCH₂-5 pentyl), 70.8 (C-5), 61.0 30.7, 30.5, 30.5 (CH₂), 29.9 (CH Ada), 25.2, 24.9 (2ϫCH₂-3

(C-6), 50.0 (NCH₂-1 pentyl), 41.0 (CH₂Ada), 40.2 [C(O)NCH₂-1 pentyl) ppm. IR (thin film): ν

= 3295, 2900, 2848, 1652, 1453,

˜

max

pentyl], 38.5 (CH₂Ada), 35.4, 35.3 (2ϫC_qAda), 29.9 (CH Ada),

1361, 1157, 1109, 755 cm^–1. [α]²_D⁰= –18.1 (c = 0.5, MeOH). HRMS:

30.8, 30.5, 30.5, 29.7, 25.4 (CH₂pentyl), 24.9 (CH₂-3 pentyl) ppm.

calcd. for [C₃₈H₆₄O₆N₂+ H]⁺645.4837 [M + H]⁺; found 645.4835.

IR (thin film): ν

= 3328, 2902, 2849, 1651, 1454, 1157,

˜

max

1,1,3,3-Tetramethylbutyl 2,5-Dideoxy-2,5-imino-L-gulo-hexonamide

(69): Compound 69 (10 mg, 35 μmol, 58%) was synthesized from

59 (60 μmol) by deprotection of the benzyl ethers (appropriate

1111 cm^–1. [α]²_D⁰= 13.8 (c = 0.2, MeOH). HRMS: calcd. for

[C₃₈H₆₄O₆N₂+ H]⁺645.4837 [M + H]⁺; found 645.4834.

5-(Adamantan-1-yl-methoxy)pentyl

2,5-Dideoxy-2,5-imino-L-ido- method in General Procedure F). R_f= 0.43 (MeOH/CH₂Cl₂, 1:4 +

hexonamide (66): Compound 66 (12 mg, 29 μmol, 55%) was synthe-

sized from 58 (53 μmol) by deprotection of the benzyl ethers (ap-

propriate method in General Procedure F). R_f= 0.10 (MeOH/

2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ = 4.02 (dd, J =

5.2 Hz, 1 H, 3-H), 3.78 (dd, J = 5.4, 6.1 Hz, 1 H, 4-H), 3.69 (dd,

J = 4.1, 11.2 Hz, 1 H, 6a-H), 3.60 (dd, J = 5.7, 11.2 Hz, 1 H, 6b-

CH₂Cl₂, 1:9 + 2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ = H), 3.39 (d, J = 5.2 Hz, 1 H, 2-H), 3.02 (dt, J = 4.1, 6.0 Hz, 1 H,

4.17 (dd, J = 2.1, 5.1 Hz, 1 H, 3-H), 4.04 (d, J = 5.1 Hz, 1 H, 2-

5-H), 1.81 (d, J = 14.9 Hz, 1 H, CHH-2 tMB), 1.74 (d, J = 14.8 Hz,

H), 3.92 (dd, J = 2.4 Hz, 1 H, 4-H), 3.71–3.68 (m, 2 H, CH₂-6), 1 H, CHH-2 tMB), 1.41 (s, 6 H, 2ϫCH₃tMB), 1.02 (s, 9 H,

3.38 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.27–3.22 (m, 3 H, 5-H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (100 MHz, MeOD): δ =

NCH₂-1 pentyl), 2.97 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH 174.1 [C(O)-1], 82.4 (C-3), 80.0 (C-4), 67.4 (C-2), 65.9 (C-5), 63.2

Ada), 1.72 (dd, J = 12.1, 31.7 Hz, 7 H, 3ϫCH₂Ada), 1.62–1.52

(m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.46–1.37 (m, 2 H, CH₂-

3 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 175.0 [C(O)-1],

83.2 (OCH₂-Ada), 79.8 (C-4), 79.0 (C-3), 72.7 (CH₂-5 pentyl), 67.9

(C-6), 55.8 (NHC_q-1 tMB), 52.9 (CH₂-2 tMB), 32.6 (C_q-3 tMB),

32.1 (2ϫCH₃, CH₃-4 tMB), 29.6, 29.4 (2ϫCH₃tMB) ppm. IR (thin

film): ν

= 3304, 2954, 1652, 1453, 1366, 1227, 1055 cm^–1. [α]²_D⁰

˜

max

= 8.0 (c = 0.2, MeOH). HRMS: calcd. for [C₁₄H₂₈O₄N₂+ H]⁺

(C-5), 65.8 (C-2), 63.5 (C-6), 41.0 (CH₂Ada), 40.4 (NCH₂-1 289.2122 [M + H]⁺; found 289.2123.

pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5, 30.4 (2ϫCH₂pentyl),

1,1,3,3-Tetramethylbutyl 2,5-Butylimino-2,5-dideoxy-L-gulo-hexon-

29.9 (CH Ada), 24.8 (CH -3 pentyl) ppm. IR (thin film): ν

=

˜

2

max

amide (70): Compound 70 (11 mg, 32 μmol, 53%) was synthesized

in two steps from 59 (60 μmol) through reductive amination with

the appropriate aldehyde (General Procedure E) and subsequent

benzyl ether deprotection (appropriate method in General Pro-

cedure F). R_f= 0.85 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_f(N-

3326, 2902, 2849, 1652, 1454, 1050 cm^–1. [α]²_D⁰= –22.4 (c = 0.1,

MeOH). HRMS: calcd. for [C₂₂H₃₈O₅N₂+ H]⁺411.2853 [M +

H]⁺; found 411.2851.

5-(Adamantan-1-yl-methoxy)pentyl 2,5-Butylimino-2,5-dideoxy-

L-

ido-hexonamide (67): Compound 67 (18 mg, 39 μmol, 74%) was

alkylated penultimate)

=

0.95 (EtOAc/PE, 1:1). ¹H NMR

6440

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

(400 MHz, MeOD): δ = 3.97 (s, 1 H, 4-H), 3.89 (s, 1 H, 3-H), 3.81

(dd, J = 5.1, 11.5 Hz, 1 H, 6a-H), 3.69 (dd, J = 3.0, 11.5 Hz, 1 H,

(400 MHz, MeOD, collapsed iminosugar signals): δ = 4.15–4.07

(m, 1 H, 3-H), 4.02 (dd, J = 2.6 Hz, 1 H, 4-H), 3.68 (s, 2 H, CH₂-

6b-H), 3.29 (s, 2 H, 2-H, 5-H), 2.94–2.82 (m, 1 H, NCHH butyl), 6), 3.41 (s, 1 H, 2-H), 2.88–2.57 (m, 3 H, 5-H, NCH₂butyl), 1.87

2.67–2.51 (m, 1 H, NCHH butyl), 1.88 (d, J = 14.8 Hz, 1 H, CHH-

2 tMB), 1.73 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.63–1.25 (m, 10

H, 2ϫCH₃tMB, 2ϫCH₂butyl), 1.02 (s, 9 H, 2ϫCH₃, CH₃-4 tMB),

(d, J = 14.7 Hz, 1 H, CHH-2 tMB), 1.70 (d, J = 14.2 Hz, 1 H,

CHH-2 tMB), 1.65–1.21 (m, 10 H, 2ϫCH₂butyl, 2ϫCH₃tMB),

1.06 (s, 9 H, 2ϫCH₃, CH₃-4 tMB), 0.97 (t, J = 7.3 Hz, 3 H, CH₃

0.95 (t, J = 7.3 Hz, 3 H, CH₃butyl) ppm. ¹³C NMR (100 MHz, butyl) ppm. ¹³C NMR (100 MHz, MeOD, collapsed iminosugar

MeOD): δ = 82.1 (C-3), 81.5 (C-4), 77.5, 70.5 (C-2, C-5), 60.8 (C- signals): δ = 79.7 (C-4), 78.7 (C-3), 74.2 (C-2), 73.4 (C-5), 63.7 (C-

6), 52.8 (CH₂-2 tMB), 49.9 (NCH₂butyl), 32.6 (C_q-3 tMB), 32.2

6), 57.5 (NCH₂butyl), 56.2 (C_q-3 tMB), 53.9 (CH₂-2 tMB), 32.6

(2ϫCH₃, CH₃-4 tMB), 29.6, 29.4 (2ϫCH₃tMB), 21.9 (CH₂butyl), (C_q-3 tMB), 32.3 (CH₂butyl), 32.2 (2ϫCH₃, CH₃-4 tMB), 29.7,

14.6 (CH₃butyl) ppm. IR (thin film): ν

= 3312, 2957, 1651,

29.1 (2ϫCH₃tMB), 21.9 (CH₂butyl), 14.4 (CH₃butyl) ppm. IR

˜

max

1439, 1366, 1226, 1155, 1066 cm^–1. [α]²_D⁰= 20.9 (c = 0.2, MeOH).

HRMS: calcd. for [C₁₈H₃₆O₄N₂+ H]⁺345.2748 [M + H]⁺; found

345.2748.

(thin film): ν

= 3290, 2957, 2420, 1651, 1458, 1366, 1227, 1072,

˜

max

756 cm^–1. [α]²_D⁰= –30.7 (c = 0.3, MeOH). HRMS: calcd. for

[C₁₈H₃₆O₄N₂+ H]⁺345.2748 [M + H]⁺; found 345.2748.

1,1,3,3-Tetramethylbutyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]- 1,1,3,3-Tetramethylbutyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]-

imino-2,5-dideoxy- -gulo-hexonamide (71): Compound 71 (13 mg, imino-2,5-dideoxy- -ido-hexonamide (74): Compound 74 (28 mg,

L

25 μmol, 42%) was synthesized in two steps from 59 (60 μmol)

through reductive amination with the appropriate aldehyde (Gene-

ral Procedure E) and subsequent benzyl ether deprotection (appro-

priate method in General Procedure F). R_f= 0.85 (MeOH/CH₂Cl₂,

1:4 + 2% NH₄OH); R_f(N-alkylated penultimate) = 0.83 (EtOAc/

54 μmol, 86%) was synthesized in two steps from 60 (63 μmol)

through reductive amination with the appropriate aldehyde (Gene-

ral Procedure E) and subsequent benzyl ether deprotection (appro-

priate method in General Procedure F). R_f= 0.25 (MeOH/CH₂Cl₂,

1:9 + 2% NH₄OH); R_f(N-alkylated penultimate) = 0.83 (EtOAc/

PE, 1:1). ¹H NMR (400 MHz, MeOD): δ = 3.97 (s, 1 H, 4-H), 3.89 PE, 1:1). ¹H NMR (400 MHz, MeOD, collapsed iminosugar sig-

(s, 1 H, 3-H), 3.81 (dd, J = 5.1, 11.5 Hz, 1 H, 6a-H), 3.68 (dd, J = nals): δ = 4.72–3.44 (m, 6 H), 3.39 (t, J = 6.2 Hz, 2 H, CH₂-5

3.1, 11.5 Hz, 1 H, 6b-H), 3.39 (t, J = 6.3 Hz, 2 H, CH₂-5 pentyl), pentyl), 3.26–3.02 (m, 1 H), 2.97 (s, 2 H, OCH₂-Ada), 2.94–2.47

3.30–3.23 (m, 2 H, 2-H, 5-H), 2.97 (s, 2 H, OCH₂-Ada), 2.93–2.84

(m, 1 H), 2.20–1.31 (m, 23 H, CH₂-2 tMB, 3ϫCH Ada, 6ϫCH₂

(m, 1 H, NCHH pentyl), 2.61–2.53 (m, 1 H, NCHH pentyl), 1.95 Ada, 3ϫCH₂pentyl), 1.04 (s, 9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C

(s, 3 H, 3ϫCH Ada), 1.89 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), NMR (101 MHz, MeOD, collapsed iminosugar signals): δ = 83.2

1.81–1.65 (m, 7 H, CHH-2 tMB, 3ϫCH₂Ada), 1.64–1.37 (m, 18

H, 3ϫCH₂Ada, 2ϫCH₃tMB, 3ϫCH₂pentyl), 1.03 (s, 9, 2ϫCH₃,

CH₃-4 tMBH) ppm. ¹³C NMR (100 MHz, MeOD): δ = 83.2

(OCH₂-Ada), 78.4 (CH), 72.3 (CH₂-5 pentyl), 41.0 (CH₂Ada), 38.5

(CH₂Ada), 35.3 (C_qAda), 32.6 (C_q-3 tMB), 32.2 (2ϫCH₃, CH₃-4

tMB), 30.7 (CH₂pentyl), 29.9 (CH Ada), 29.6 (2ϫCH₃tMB) ppm.

(OCH₂-Ada), 82.1 (C-3), 81.6 (C-4), 77.7 (C-2), 72.6 (CH₂-5 IR (thin film): ν

= 3291, 2902, 2849, 2409, 1668, 1452, 1366,

˜

max

pentyl), 70.4 (C-5), 60.9 (C-6), 56.1 (NHC_q-1 tMB), 52.8 (CH₂-2 1225, 1156, 1110, 755 cm^–1. [α]²_D⁰= –21.4 (c = 0.6, MeOH). HRMS:

tMB), 50.1 (NCH₂-1 pentyl), 41.0 (CH₂Ada), 38.5 (CH₂Ada),

35.3 (C_qAda), 32.6 (C_q-3 tMB), 32.2 (2ϫCH₃, CH₃-4 tMB), 30.9

(CH₂pentyl), 29.9 (CH Ada), 29.7, 29.4 (2ϫCH₃tMB), 25.5 (CH₂-

calcd. for [C₃₀H₅₄O₅N₂+ H]⁺523.4105 [M + H]⁺; found 523.4101.

Pentyl 2,5-Dideoxy-2,5-imino- -gulo-hexonamide (75): Compound

75 (19 mg, 77 μmol, 51%) was synthesized from 61 (150 μmol) by

deprotection of the benzyl ethers (appropriate method in General

Procedure F). R_f= 0.24 (MeOH/CH₂Cl₂, 1:5 + 2% NH₄OH). H

NMR (400 MHz, MeOD): δ = 4.24–4.11 (m, 1 H, 3-H), 4.06–3.94

(m, 1 H, 4-H), 3.91–3.81 (m, 1 H, 6a-H), 3.81–3.71 (m, 2 H, 2-H,

6b-H), 3.43–3.36 (m, 3 H, 5-H, NCH₂-1 pentyl), 1.68–1.55 (m, 2

H, CH₂-2 pentyl), 1.51–1.33 (m, 4 H, 2ϫCH₂pentyl), 1.07–0.91

(m, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ =

172.3 [C(O)-1], 81.7 (C-3), 78.8 (C-4), 66.2, 66.1 (C-2, C-5), 61.9

L

3 pentyl) ppm. IR (thin film): ν_max= 3342, 2903, 2850, 1651, 1440,

˜

1227, 1064 cm^–1. [α]²_D⁰= 24.6 (c = 0.3, MeOH). HRMS: calcd. for

1

[C₃₀H₅₄O₅N₂+ H]⁺523.4105 [M + H]⁺; found 523.4101.

1,1,3,3-Tetramethylbutyl 2,5-Dideoxy-2,5-imino-L-ido-hexonamide

(72): Compound 72 (14 mg, 49 μmol, 78%) was synthesized from

60 (63 μmol) by deprotection of the benzyl ethers (appropriate

method in General Procedure F). R_f= 0.38 (MeOH/CH₂Cl₂, 1:4 +

2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ = 4.11 (dd, J = 2.4,

5.4 Hz, 1 H, 3-H), 3.90 (dd, J = 2.7 Hz, 1 H, 4-H), 3.81 (d, J = (C-6), 40.7 (NCH₂-1 pentyl), 30.3, 30.2, 23.5 (3ϫCH₂pentyl), 14.5

5.4 Hz, 1 H, 2-H), 3.66 (dd, J = 4.1, 10.1 Hz, 1 H, 6a-H), 3.62 (dd, (CH -5 pentyl) ppm. IR (thin film): ν_max= 3290, 2930, 1652, 1544,

˜

3

J = 4.3, 10.1 Hz, 1 H, 6b-H), 3.14 (dt, J = 2.9, 4.9 Hz, 1 H, 5-H), 1377, 1055 cm^–1. [α]²_D⁰= 1.1 (c = 0.4, MeOH). HRMS: calcd. for

1.83 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.69 (d, J = 14.8 Hz, 1 [C₁₁H₂₂O₄N₂+ H]⁺247.1652 [M + H]⁺; found 247.1653.

H, CHH-2 tMB), 1.41 (d, J = 6.0 Hz, 6 H, 2ϫCH₃tMB), 1.03 (s,

Pentyl 2,5-Butylimino-2,5-dideoxy-L-gulo-hexonamide (76): Com-

9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (100 MHz, MeOD): δ

= 172.9 [C(O)-1], 80.3 (C-4), 79.4 (C-3), 67.3 (C-5), 66.2 (C-2), 64.6

(C-6), 56.0 (NHC_q-1 tMB), 53.2 (CH₂-2 tMB), 32.6 (C_q-3 tMB),

32.1 (2ϫCH₃, CH₃-4 tMB), 29.6 (2ϫCH₃tMB) ppm. IR (thin

pound 76 (13 mg, 43 μmol, 31%) was synthesized in two steps from

61 (140 μmol) through reductive amination with the appropriate

aldehyde (General Procedure E) and subsequent benzyl ether de-

protection (appropriate method in General Procedure F). R_f= 0.69

(MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_f(N-alkylated penultimate)

film): ν

= 3328, 2955, 2481, 1667, 1559, 1454, 1367, 1226,

˜

max

1042 cm^–1. [α]²_D⁰= –44.1 (c = 0.3, MeOH). HRMS: calcd. for

1

= 0.77 (EtOAc/PE, 1:1). H NMR (400 MHz, MeOD): δ = 4.01 (s,

[C₁₄H₂₈O₄N₂+ H]⁺289.2122 [M + H]⁺; found 289.2123.

1 H, 4-H), 3.94 (s, 1 H, 3-H), 3.85 (dd, J = 4.5, 11.8 Hz, 1 H, 6a-

H), 3.75 (dd, J = 3.1, 11.8 Hz, 1 H, 6b-H), 3.61–3.51 (m, 1 H, 2-

H), 3.41–3.33 (m, 1 H, 5-H), 3.23 (t, J = 7.0 Hz, 2 H, NCH₂-1

pentyl), 3.04–2.90 (m, 1 H, NCHH-1 butyl), 2.83–2.67 (m, 1 H,

NCHH-1 butyl), 1.59–1.48 (m, 4 H, 2ϫCH₂-2 pentyl/butyl), 1.43–

1.28 (m, 6 H, 3ϫCH₂pentyl/butyl), 0.98–0.90 (m, 6 H, 2ϫCH₃

1,1,3,3-Tetramethylbutyl 2,5-Butylimino-2,5-dideoxy-L-ido-hexon-

amide (73): Compound 73 (12 mg, 35 μmol, 55%) was synthesized

in two steps from 60 (63 μmol) through reductive amination with

the appropriate aldehyde (General Procedure E) and subsequent

benzyl ether deprotection (appropriate method in General Pro-

cedure F). R_f= 0.66 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_f(N- butyl/pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 81.9 (C-3),

alkylated penultimate)

=

0.88 (EtOAc/PE, 1:1). ¹H NMR

80.7 (C-4), 75.5 (C-2), 71.3 (C-5), 60.3 (C-6), 50.4 (NCH₂butyl),

Eur. J. Org. Chem. 2012, 6420–6454

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6441

H. S. Overkleeft et al.

FULL PAPER

40.4 (NCH₂-1 pentyl), 31.4, 30.3, 30.3, 23.5, 21.7 (5ϫCH₂pentyl/

(2ϫCH butyl/pentyl) ppm. IR (thin film): ν_max= 3274, 2959, 2931,

˜

3

butyl), 14.5, 14.4 (2ϫCH₃pentyl/butyl) ppm. IR (thin film): ν

2871, 1637, 1464, 1376, 1118, 1069, 754 cm^–1. [α]²_D⁰= –39.3 (c =

0.3, MeOH). HRMS: calcd. for [C₁₅H₃₀O₄N₂+ H]⁺303.2278 [M

+ H]⁺; found 303.2279.

˜

max

= 3294, 2959, 2930, 2871, 1652, 1461, 1378, 1066 cm^–1. [α]²_D⁰= 27.7

(c = 0.3, MeOH). HRMS: calcd. for [C₁₅H₃₀O₄N₂+ H]⁺303.2278

[M + H]⁺; found 303.2279.

Pentyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,5-dideoxy-L-

Pentyl 2,5-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,5-dideoxy-

L

-

ido-hexon-amide (80): Compound 80 (40 mg, 83 μmol, 52%) was

synthesized in two steps from 62 (160 μmol) through reductive am-

ination with the appropriate aldehyde (General Procedure E) and

subsequent benzyl ether deprotection (appropriate method in Ge-

neral Procedure F). R_f= 0.69 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH);

R_f(N-alkylated penultimate) = 0.80 (EtOAc/PE, 1:1). ¹H NMR

(400 MHz, MeOD): δ = 4.08 (dd, J = 3.2, 6.1 Hz, 1 H, 3-H), 3.97

gulo-hexonamide (77): Compound 77 (15 mg, 31 μmol, 22%) was

synthesized in two steps from 61 (140 μmol) through reductive am-

ination with the appropriate aldehyde (General Procedure E) and

subsequent benzyl ether deprotection (appropriate method in Ge-

neral Procedure F). R_f= 0.37 (MeOH/CH₂Cl₂, 1:9 + 2% NH₄OH);

R_f(N-alkylated penultimate) = 0.80 (EtOAc/PE, 1:1). ¹H NMR

(400 MHz, MeOD): δ = 3.96 (dd, J = 1.7 Hz, 1 H, 4-H), 3.89 (dd, (dd, J = 3.1 Hz, 1 H, 4-H), 3.69–3.66 (m, 2 H, CH₂-6), 3.51 (d, J

J = 1.8 Hz, 1 H, 3-H), 3.80 (dd, J = 5.0, 11.4 Hz, 1 H, 6a-H), 3.69 = 6.1 Hz, 1 H, 2-H), 3.38 (t, J = 6.3 Hz, 2 H, CH₂-5 pentyl), 3.35–

(dd, J = 3.2, 11.4 Hz, 1 H, 6b-H), 3.40 (s, 1 H, 2-H), 3.38 (t, J = 3.26 [m, 1 H, C(O)NCHH-1 pentyl], 3.17 [dt, J = 6.9, 13.5 Hz, 1

4.9 Hz, 2 H, CH₂-5 pentyl), 3.28–3.12 [m, 3 H, 5-H, C(O)NCH₂-1 H, C(O)NCHH-1 pentyl], 2.96 (s, 2 H, OCH₂-Ada), 2.80 (dd, J =

pentyl], 2.97 (s, 2 H, OCH₂-Ada), 2.90–2.78 (m, 1 H, NCHH-1 3.6, 7.1 Hz, 1 H, 5-H), 2.70 (ddd, J = 5.8, 9.1, 12.5 Hz, 1 H, NCH1

pentyl), 2.66–2.52 (m, 1 H, NCHH-1 pentyl), 1.95 (s, 3 H, 3ϫCH

Ada), 1.72 (dd, J = 12.1, 32.1 Hz, 6 H, 3ϫCH₂Ada), 1.64–1.26

pentyl-H), 2.59 (ddd, J = 6.5, 9.1, 12.5 Hz, 1 H, NCHH-1 pentyl),

1.95 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J = 11.9, 32.3 Hz, 6 H, 3ϫCH₂

(m, 18 H, 3ϫCH Ada, 6ϫCH₂pentyl), 0.93 (t, J = 6.9 Hz, 3 H, Ada), 1.60–1.29 (m, 18 H, 3ϫCH₂Ada, 6ϫCH₂pentyl), 0.92 (t, J

CH₃-5 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 175.9 = 6.9 Hz, 3 H, CH₃pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ

[C(O)-1], 83.2 (OCH₂-Ada), 82.4 (C-3), 81.6 (C-4), 76.4 (C-2), 72.7

(CH₂-5 pentyl), 70.8 (C-5), 61.0 (C-6), 50.0 (NCH₂-1 pentyl), 41.0

= 174.6 [C(O)-1], 83.2 (OCH₂-Ada), 79.4 (C-4), 78.4 (C-3), 73.4

(C-2), 73.2 (C-5), 72.6 (CH₂-5 pentyl), 63.1 (C-6), 57.4 (NCH₂-1

(CH₂Ada), 40.2 [C(O)NCH₂-1 pentyl], 38.5 (CH₂Ada), 35.3 (C_qpentyl), 41.0 (CH₂Ada), 40.1 [C(O)NCH₂-1 pentyl], 38.5 (CH₂

Ada), 29.9 (CH Ada), 30.8, 30.4, 30.4, 29.7, 25.4, 23.6 (6ϫCH₂Ada), 35.3 (C_qAda), 29.9 (CH Ada), 30.7, 30.4, 30.4, 29.5, 25.3,

pentyl), 14.5 (CH pentyl) ppm. IR (thin film): ν

= 3297, 2902,

23.6 (6ϫCH pentyl), 14.6 (CH pentyl) ppm. IR (thin film): ν

˜

2 3 max

˜

3

max

2849, 1651, 1456, 1361, 1157, 1111 cm^–1. [α]²_D⁰= 11.4 (c = 0.3,

MeOH). HRMS: calcd. for [C₂₇H₄₈O₅N₂+ H]⁺481.3636 [M +

H]⁺; found 481.3632.

= 3343, 2903, 2850, 1637, 1457, 1374, 1157, 1072 cm^–1. [α]²_D⁰= –32.1

(c = 0.7, MeOH). HRMS: calcd. for [C₂₇H₄₈O₅N₂+ H]⁺481.3636

[M + H]⁺; found 481.3632.

Pentyl 2,5-Dideoxy-2,5-imino-L-ido-hexonamide (78): Compound 78

2,3,4,6-Tetra-O-benzyl-1-O-tert-butyldiphenylsilyl-D-glucitol (82):

(52 mg, 211 μmol, 78%) was synthesized from 62 (270 μmol) by

tert-Butyl-diphenylsilyl chloride (21 mL, 80.7 mmol) was added

over a 2 min period to an anhydrous solution of 2,3,4,6-tetra-O-

benzyl-d-glucitol (81; 39.0 g, 71.9 mmol)^[6c]and imidazole (10.8 g,

158.6 mmol) in DMF (75 mL). The reaction mixture was stirred

deprotection of the benzyl ethers (appropriate method in General

1

Procedure F). R_f= 0.15 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH). H

NMR (400 MHz, MeOD): δ = 4.29 (dd, J = 2.1, 4.9 Hz, 1 H, 3-

H), 4.25 (d, J = 4.9 Hz, 1 H, 2-H), 3.99 (dd, J = 2.4 Hz, 1 H, 4- for 20 h and subsequently concentrated. The residue was purified

H), 3.79 (d, J = 6.0 Hz, 2 H, CH₂-6), 3.41 (dt, J = 2.7, 6.0 Hz, 1

H, 5-H), 3.25 (t, J = 7.1 Hz, 2 H, NCH₂-1 pentyl), 1.61–1.49 (m,

2 H, CH₂-2 pentyl), 1.40–1.31 (m, 4 H, 2ϫCH₂pentyl), 0.92 (t, J (EtOAc/toluene, 1:1). H NMR (600 MHz, CDCl₃): δ = 7.66–7.61

= 6.9 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): (m, 4 H, H_ArTBDPS), 7.42–7.07 (m, 26 H, H_ArTBDPS/Bn), 4.64

δ = 169.5 [C(O)-1], 79.0 (C-4), 78.4 (C-3), 68.5 (C-5), 65.3 (C-2), (s, 2 H, CH₂Bn), 4.63 (d, J = 11.6 Hz, 1 H, CHH Bn), 4.54–4.45

by silica gel column chromatography (EtOAc/PE, 20Ǟ25%) to

provide 82 (55.7 g, 71.4 mmol, 99%) as a colorless oil. R_f= 0.85

1

62.0 (C-6), 40.7 (NCH₂-1 pentyl), 30.3, 30.2, 23.5 (3ϫCH₂pentyl),

(m, 5 H, CHH Bn, 2ϫCH₂Bn), 3.97 (dd, J = 4.5 Hz, 1 H, 3-H),

3.96–3.92 (m, 1 H, 5-H), 3.88 (dd, J = 4.9, 10.6 Hz, 1 H, 1a-H),

3.83 (dd, J = 4.9, 9.9 Hz, 1 H, 2-H), 3.78 (dd, J = 3.9, 6.5 Hz, 1

H, 4-H), 3.76 (dd, J = 4.9, 10.1 Hz, 1 H, 1b-H), 3.60 (dd, J = 2.5,

8.9 Hz, 1 H, 6b-H), 3.58 (dd, J = 4.2, 8.9 Hz, 1 H, 6b-H), 2.91 (d,

J = 4.8 Hz, 1 H, OH-5), 1.04 (s, 9 H, tBu-Si) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 138.6, 138.4, 138.3, 138.3 (4ϫC_qBn), 135.8

(CH_ArTBDPS), 133.5 (C_qSi-Ph), 129.9, 129.9, 128.6, 128.6, 128.5,

128.5, 128.4, 128.1, 128.0, 127.9, 127.8, 127.7 (CH_ArBn/TBDPS),

79.8 (C-2), 78.1 (C-3), 77.6 (C-4), 74.4, 73.6, 73.5, 73.2 (4ϫCH₂

Bn), 71.4 (C-6), 71.2 (C-5), 63.3 (C-1), 27.1 (CH₃tBu), 19.4 (C_q

14.5 (CH -5 pentyl) ppm. IR (thin film): ν

= 3287, 2957, 2931,

˜

3

max

2871, 1666, 1638, 1652, 1560, 1470, 1377, 1310, 1066, 1034 cm^–1.

[α]²_D⁰= –54.5 (c = 1.0, MeOH). HRMS: calcd. for [C₁₁H₂₂O₄N₂+

H]⁺247.1652 [M + H]⁺; found 247.1654.

Pentyl 2,5-Butylimino-2,5-dideoxy-L-ido-hexonamide (79): Com-

pound 79 (24 mg, 79 μmol, 49%) was synthesized in two steps from

62 (160 μmol) through reductive amination with the appropriate

aldehyde (General Procedure E) and subsequent benzyl ether de-

protection (appropriate method in General Procedure F). R_f= 0.58

(MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_f(N-alkylated penultimate)

= 0.75 (EtOAc/PE, 1:1). ¹H NMR (400 MHz, MeOD): δ = 4.08

(dd, J = 3.2, 6.1 Hz, 1 H, 3-H), 3.96 (dd, J = 3.2 Hz, 1 H, 4-H),

3.67 (d, J = 4.0 Hz, 2 H, CH₂-6), 3.51 (d, J = 6.2 Hz, 1 H, 2-H),

3.35–3.25 (m, 1 H, NCHH-1 pentyl), 3.17 (dt, J = 6.9, 13.5 Hz, 1

tBu) ppm. IR (thin film): ν

= 3030, 2929, 2862, 1490, 1454,

˜

max

1358, 1208, 1080, 1027, 823, 735, 698 cm^–1. [α]²_D⁰= 16.2 (c = 2.1,

CHCl₃). HRMS: calcd. for [C₅₀H₅₆O₆Si + Na]⁺803.3744 [M +

Na]⁺; found 803.3739.

H, NCHH-1 pentyl), 2.80 (dd, J = 3.7, 7.2 Hz, 1 H, 5-H), 2.70 5-Azido-2,3,4,6-tetra-O-benzyl-tert-1-O-butyldiphenylsilyl-

L-iditol

(ddd, J = 5.9, 9.3, 12.5 Hz, 1 H, NCHH-1 butyl), 2.59 (ddd, J = (83): Diisopropyl azodicarboxylate (2.52 mL, 12.8 mmol) and di-

6.4, 9.3, 12.5 Hz, 1 H, NCHH-1 butyl), 1.59–1.26 (m, 10 H, 5ϫCH₂phenylphosphoryl azide (2.76 mL, 12.8 mmol) were successively

pentyl/butyl), 0.96–0.89 (m, 6 H, 2ϫCH₃butyl/pentyl) ppm. ¹³C

NMR (100 MHz, MeOD): δ = 174.6 [C(O)-1], 79.3 (C-4), 78.4 (C-

added over 2 min to a cooled (0 °C), anhydrous solution of 82

(5.00 g, 6.4 mmol) and triphenylphosphane (3.36 g, 12.8 mmol) in

3), 73.3, 73.2 (C-2, C-5), 63.0 (C-6), 57.1 (NCH₂-1 butyl), 40.1 THF (48 mL). The reaction mixture was stirred for 20 h and

(NCH₂-1 pentyl), 31.9, 30.4, 23.6, 21.8 (5ϫCH₂pentyl/butyl), 14.5 warmed to room temp. The mixture was concentrated and the re-

6442

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

sulting residue was purified by silica gel column chromatography

(EtOAc/PE, 0Ǟ10%) to afford 83 (3.70 g, 4.2 mmol, 66%) as a

colorless oil. R_f= 0.60 (EtOAc/PE, 1:6). ¹H NMR (400 MHz,

CDCl₃): δ = 7.67 (dd, J = 6.7, 19.6 Hz, 4 H, H_ArTBDPS), 7.43–

7.13 (m, 26 H, H_ArTBDPS/Bn), 4.78–4.71 (m, 2 H, CHH Bn,

CHH Bn), 4.64 (d, J = 11.3 Hz, 1 H, CHH Bn), 4.59 (d, J =

12.0 Hz, 1 H, CHH Bn), 4.52 (d, J = 11.5 Hz, 1 H, CHH Bn),

4.39–4.32 (m, 2 H, CH₂Bn), 4.29 (d, J = 12.0 Hz, 1 H, CHH Bn),

4.04 (dd, J = 2.7, 7.6 Hz, 1 H, 3-H), 3.93 (dd, J = 6.3, 10.5 Hz, 1

H, 1a-H), 3.87 (dd, J = 5.6, 10.5 Hz, 1 H, 1b-H), 3.82 (dd, J = 3.0,

7.7 Hz, 1 H, 4-H), 3.61–3.56 (m, 1 H, 2-H), 3.53 (dd, J = 8.1,

9.2 Hz, 1 H, 6a-H), 3.34 (dd, J = 4.8, 9.5 Hz, 1 H, 6b-H), 3.30–

3.23 (m, 1 H, 5-H), 1.08 (s, 9 H, tBu-Si) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 138.9, 138.8, 138.6, 138.4 (4ϫC_qBn), 136.3, 136.2

(CH_ArTBDPS), 133.9 (C_qSi-Ph), 130.5, 130.4, 129.0, 128.9, 128.6,

128.5, 128.4, 128.3, 128.2 (CH_ArBn/TBDPS), 79.6, 79.0, 78.6 (C-

2, C-2, C-4), 75.8, 75.5, 73.8, 73.0 (4ϫCH₂Bn), 70.4 (C-6), 63.0

(C-1), 61.9 (C-5), 27.5 (CH₃tBu), 19.8 (C_qtBu) ppm. IR (thin

Bn), 69.5 (C-6), 61.6 (C-1) ppm. IR (thin film): ν

= 3032, 2864,

˜

max

2097, 1729, 1496, 1454, 1352, 1264, 1210, 1092, 1027, 734,

697 cm^–1. [α]²_D⁰= 23.7 (c = 10.7, CHCl₃). HRMS: calcd. for

[C₃₄H₃₅N₃O₅+ Na]⁺588.2474 [M + Na]⁺; found 588.2468.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dide-

oxy-2,6-(pent-4-enimido)-L-glycero-D-gulo-heptonamide (86): Sub-

jecting azido aldehyde 85 (1.16 mmol) to the tandem SAWU-3CR

(General procedure B in MeOH) produced a separable 1.25:1 mix-

ture of 87 (314 mg, 0.36 mmol) and 86 (248 mg, 0.28 mmol) in a

1

combined yield of 55%. R_f= 0.27 (EtOAc/toluene, 1:3). H NMR

(500 MHz, CDCl₃, 2.5:1 mixture of rotamers; major rotamer/col-

lapsed iminosugar signals): δ = 7.37–7.16 (m, 20 H, H_ArBn), 6.18

[s, 1 H, C(O)NH], 5.83–5.74 (m, 1 H, =CH pentenyl), 5.03–4.91

(m, 2 H, =CH₂pentenyl), 4.81–3.60 (m, 15 H, 4ϫCH₂Bn, 2-H, 3-

H, 4-H, 5-H, 6-H, CH₂-7), 3.30 (t, J = 6.6 Hz, 2 H, CH₂-5 pentyl),

3.27–3.09 (m, 2 H, NCH₂-1 pentyl), 2.92 (s, 2 H, OCH₂-Ada),

2.71–2.40 (m, 2 H, CH₂pentenyl), 2.40–2.23 (m, 2 H, CH₂pent-

enyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.67 (dd, J = 11.8, 30.7 Hz, 6 H,

3ϫCH₂Ada), 1.56–1.13 (m, 12 H, 3ϫCH₂Ada, 3ϫCH₂

pentyl) ppm. ¹³C NMR (125 MHz, CDCl₃, major rotamer/col-

lapsed iminosugar signals): δ = 174.1 [NC(O) pentenyl], 169.0

[NHC(O)-1], 138.3, 138.0, 138.0, 137.8, 137.6 (C_qBn, =CH pent-

enyl), 128.6–127.7 (CH_ArBn), 115.0 (=CH₂pentenyl), 82.0 (OCH₂-

Ada), 78.1, 73.4, 71.9, 71.5 (CH₂-5 pentyl), 59.0, 54.8 (C-2, C-6),

39.9 (NCH₂-1 pentyl), 39.8 (CH₂Ada), 37.3 (CH₂Ada), 34.2 (C_q

Ada), 29.4, 29.3, 29.0, 28.4 (CH Ada), 23.6 (CH₂-3 pentyl) ppm.

film): ν_max= 3030, 2928, 2857, 2955, 2097, 1494, 1454, 1428, 1358,

˜

1208, 1080, 1027, 734, 699 cm^–1. [α]²_D⁰= 21.3 (c = 8.2, CHCl₃).

HRMS: calcd. for [C₅₀H₅₅N₃O₅Si + Na]⁺828.3809 [M + Na]⁺;

found 828.3807.

5-Azido-2,3,4,6-tetra-O-benzyl-L-iditol (84): Tetrabutylammonium

fluoride (1 M in THF, 12 mL, 12 mmol) was added to an anhy-

drous solution of 83 (7.25 g, 9.0 mmol) in THF (150 mL) and the

resulting reaction mixture was stirred for 20 h. The mixture was

concentrated, redissolved in Et₂O (100 mL) and washed with satd.

aq. NaCl (100 mL). The organic phase was dried (Na₂SO₄), con-

centrated, and the resulting residue was purified by silica gel col-

umn chromatography (EtOAc/PE, 9Ǟ25%) to produce 84 (3.62 g,

IR (thin film): ν

= 3328, 2902, 2849, 1635, 1543, 1453, 1361,

˜

max

1092, 910, 732, 696 cm^–1. [α]²_D⁰= –11.7 (c = 4.7, CHCl₃). HRMS:

calcd. for [C₅₆H₇₀N₂O₇+ H]⁺883.5256 [M + H]⁺; found 883.5265.

1

5-(Adamantan-1-yl-methoxy)pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dide-

6.38 mmol, 71%) as a colorless oil. R_f= 0.20 (EtOAc/PE, 1:4). H

oxy-2,6-(pent-4-enimido)-L-glycero-D-ido-heptonamide (87): R_f=

NMR (600 MHz, CDCl₃): δ = 7.38–7.17 (m, 20 H, H_ArBn), 4.75

(d, J = 11.5 Hz, 1 H, CHH Bn), 4.67 (d, J = 11.1 Hz, 1 H, CHH

Bn), 4.65–4.60 (m, 2 H, CHH Bn, CHH Bn), 4.55–4.52 (m, 2 H,

CHH Bn, CHH Bn), 4.38 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.35 (d,

J = 11.8 Hz, 1 H, CHH Bn), 3.91 (dd, J = 4.0, 7.3 Hz, 1 H, 3-H),

3.87 (dd, J = 2.8, 7.4 Hz, 1 H, 4-H), 3.78 (dd, J = 5.0, 11.5 Hz, 1

H, 1a-H), 3.71 (dd, J = 5.0, 11.6 Hz, 1 H, 1b-H), 3.60 (dd, J = 4.9,

9.2 Hz, 1 H, 2-H), 3.59–3.52 (m, 2 H, 5-H, 6a-H), 3.46 (dd, J =

4.5, 8.9 Hz, 1 H, 6b-H), 3.24–2.79 (m, 1 H, OH-1) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 137.8, 137.7, 137.5 (4ϫC_qBn), 128.2,

128.1, 128.1, 128.1, 127.9, 127.7, 127.6, 127.5, 127.5, 127.4, 127.4,

127.3 (CH_ArBn), 78.9 (C-3), 78.1 (C-2), 78.0 (C-4), 74.6, 74.5, 72.9,

72.1 (4ϫCH₂Bn), 69.3 (C-6), 61.0 (C-1), 60.8 (C-5) ppm. IR (thin

1

0.46 (EtOAc/toluene, 1:3). H NMR (500 MHz, CDCl₃, 3.5:1 mix-

ture of rotamers; major rotamer): δ = 7.41–7.18 (m, 20 H, H_ArBn),

6.69 [t, J = 5.7 Hz, 1 H, C(O)NH], 5.80–5.68 (m, 1 H, =CH pent-

enyl), 5.13 (d, J = 6.7 Hz, 1 H, 2-H), 5.00–4.91 (m, 2 H, =CH₂

pentenyl), 4.89–4.59 (m, 7 H, 3ϫCH₂Bn, 4-H), 4.45 (d, J =

11.9 Hz, 1 H, CHH Bn), 4.38 (d, J = 11.9 Hz, 1 H, CHH Bn),

4.26–4.19 (m, 1 H, 6-H), 4.07 (dd, J = 10.1 Hz, 1 H, 7a-H), 3.81

(dd, J = 4.3, 9.9 Hz, 1 H, 7b-H), 3.54 (dd, J = 6.5, 9.4 Hz, 1 H, 5-

H), 3.48 (dd, J = 6.7, 9.3 Hz, 1 H, 3-H), 3.28 (t, J = 6.6 Hz, 2 H,

CH₂-5 pentyl), 3.26–3.13 (m, 1 H, NCHH-1 pentyl), 2.97–2.84 (m,

3 H, OCH₂-Ada, NCHH-1 pentyl), 2.66–2.17 (m, 4 H, 2ϫCH₂

pentenyl), 1.94 (s, 3 H, 3ϫCH Ada), 1.67 (dd, J = 11.7, 32.0 Hz, 6

H, 3ϫCH₂Ada), 1.51 (d, J = 2.4 Hz, 6 H, 3ϫCH₂Ada), 1.48–1.15

(m, 6 H, 3ϫCH₂pentyl) ppm. ¹³C NMR (125 MHz, CDCl₃, major

rotamer): δ = 175.1 [NC(O) pentenyl], 169.1 [NHC(O)-1], 139.0,

138.5, 138.3, 138.1 (4ϫC_qBn), 137.4 (=CH pentenyl), 128.8, 128.7,

128.5, 128.4, 128.4, 128.3, 128.1, 128.0, 127.8, 127.7, 127.6, 127.1

(CH_ArBn), 115.4 (=CH₂pentenyl), 82.1 (OCH₂-Ada), 79.3 (C-5),

78.8 (C-4), 78.5 (C-3), 75.7, 74.0, 74.0, 73.1 (4ϫCH₂Bn), 71.5

(CH₂-5 pentyl), 67.0 (C-7), 55.8 (C-6), 53.4 (C-2), 39.9 (CH₂Ada),

39.5 (NCH₂-1 pentyl), 37.4 (CH₂Ada), 34.2 (C_qAda), 33.0 (CH₂

pentenyl), 29.4, 29.4, 29.3 (CH₂pentenyl, 2ϫCH₂pentyl), 28.5 (CH

film): ν_max= 3469, 3032, 2866, 2097, 1496, 1454, 1353, 1263, 1210,

˜

1061, 1027, 734, 698 cm^–1. [α]²_D⁰= 17.8 (c = 13.2, CHCl₃). HRMS:

calcd. for [C₃₄H₃₇N₃O₅+ Na]⁺590.2631 [M + Na]⁺; found

590.2620.

5-Azido-2,3,4,6-tetra-O-benzyl-L-idose (85): Azido alcohol 84

(2.22 g, 3.9 mmol) was subjected to a Dess–Martin mediated oxi-

dation (General Procedure A) to produce 85 (1.97 g, 3.5 mmol,

89%) as a colorless oil. R_f= 0.55 (EtOAc/PE, 1:4). ¹H NMR

(400 MHz, CDCl₃): δ = 9.66 (s, 1 H, 1-H), 7.36–7.21 (m, 18 H, H_Ar

Bn), 7.21–7.13 (m, 2 H, H_ArBn), 4.81 (d, J = 11.9 Hz, 1 H, CHH

Bn), 4.63 (d, J = 11.1 Hz, 1 H, CHH Bn), 4.56–4.50 (m, 3 H, CHH

Bn, CH₂Bn), 4.47 (d, J = 11.9 Hz, 1 H, CHH Bn), 4.41 (d, J =

12.2 Hz, 1 H, CHH Bn), 4.38 (d, J = 12.2 Hz, 1 H, CHH Bn), 3.96

(dd, J = 4.8, 4.8 Hz, 1 H, 3-H), 3.92 (d, J = 4.6 Hz, 1 H, 2-H), 3.86

(dd, J = 5.0, 5.0 Hz, 1 H, 4-H), 3.58–3.51 (m, 1 H, 5-H), 3.51–3.43

(m, 2 H, CH₂-6) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 200.8

(CH-1), 137.8, 137.6, 137.2, 137.0 (4ϫC_qBn), 128.7, 128.6, 128.5,

Ada), 23.7 (CH -3 pentyl) ppm. IR (thin film): ν

= 3361, 2902,

˜

2

max

2849, 1727, 1681, 1638, 1530, 1497, 1453, 1364, 1092, 1027, 911,

733, 697 cm^–1. [α]²_D⁰= –45.4 (c = 1.7, CHCl₃). HRMS: calcd. for

[C₅₆H₇₀N₂O₇+ H]⁺883.5256 [M + H]⁺; found 883.5265.

1,1,3,3-Tetramethylbutyl

(pent-4-en-imido)- -glycero-

azido aldehyde 85 (1.16 mmol) to the tandem SAWU-3CR (Gene-

3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-

L

D-gulo-heptonamide (88): Subjecting

128.5, 128.4, 128.4, 128.3, 128.2, 127.9, 127.9, 127.8 (CH_ArBn), ral procedure B in MeOH) produced a separable 0.94:1 mixture of

80.9 (C-2), 79.3 (C-3), 77.4 (C-4), 74.5, 74.1, 73.3, 73.2 (4ϫCH₂89 (260 mg, 0.34 mmol) and 88 (278 mg, 0.37 mmol) in a combined

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6443

H. S. Overkleeft et al.

FULL PAPER

yield of 61%. R_f= 0.59 (EtOAc/toluene, 1:3). ¹H NMR (500 MHz, mers): δ = 7.39–7.14 (m, 20 H, H_ArBn), 6.67 [t, J = 5.7 Hz, 1 H,

CDCl₃, complex mixture of rotamers; major signals): δ = 7.38–7.17 C(O)NH], 5.79–5.68 (m, 1 H, =CH pentenyl), 5.13 (d, J = 6.7 Hz,

(m, 20 H, H_ArBn), 5.89–5.75 (m, 1 H, =CH pentenyl), 5.67 [s, 1 1 H, 2-H), 5.03–4.50 (m, 9 H, =CH₂pentenyl, 3ϫCH₂Bn, 4-H),

H, C(O)NH], 5.12–3.65 (m, 17 H, =CH₂pentenyl, 4ϫCH₂Bn, 2- 4.45 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.38 (d, J = 11.8 Hz, 1 H,

H, 3-H, 4-H, 5-H, 6-H, CH₂-7), 2.76–2.30 (m, 4 H, 2ϫCH₂pent- CHH Bn), 4.27–4.19 (m, 1 H, 6-H), 4.07 (dd, J = 10.1 Hz, 1 H,

enyl), 1.66–1.10 (m, 8 H, CH₂-2 tMB, 2ϫCH₃tMB), 0.94–0.82 (m,

9 H, CH₃-4, 2ϫCH₃tMB) ppm. ¹³C NMR (125 MHz, CDCl₃): δ

(major signals) = 174.3 [NC(O) pentenyl], 168.1 [NHC(O)-1],

7a-H), 3.82 (dd, J = 4.3, 9.9 Hz, 1 H, 7b-H), 3.54 (dd, J = 6.5,

9.5 Hz, 1 H, 5-H), 3.48 (dd, J = 6.7, 9.4 Hz, 1 H, 3-H), 3.26–3.16

(m, 1 H, NCHH-1), 2.97–2.85 (m, 1 H, NCHH-1), 2.67–2.21 (m,

138.2, 137.7 (C_qBn), 136.7 (=CH pentenyl), 128.7–127.1 (CH_Ar4 H, 2ϫCH₂pentenyl), 1.40–1.27 (m, 2 H, CH₂pentyl), 1.27–1.12

Bn), 115.7 (=CH₂pentenyl), 71.8, 65.4, 53.0, 33.4, 31.7 (CH₃-4, (m, 4 H, 2ϫCH₂pentyl), 0.82 (t, J = 7.1 Hz, 3 H, CH₃-5

2ϫCH₃tMB), 29.3 (CH₂pentenyl), 28.6, 28.3 (2ϫCH₃tMB) ppm. pentyl) ppm. ¹³C NMR (125 MHz, CDCl₃, major rotamer): δ =

IR (thin film): ν

= 3347, 2953, 2869, 1725, 1682, 1636, 1537,

175.0 [NC(O) pentenyl], 169.1 [NHC(O)-1], 139.0, 138.5, 138.3,

138.1 (4ϫC_qBn), 137.4 (=CH pentenyl), 128.7, 128.6, 128.4, 128.3,

128.3, 127.9, 127.9, 127.8, 127.4, 127.1 (CH_ArBn), 115.3 (=CH₂

pentenyl), 79.3 (C-4), 78.8 (C-5), 78.5 (C-3), 75.7, 74.0, 74.0, 73.0

(4ϫCH₂Bn), 67.0 (C-7), 55.8 (C-6), 53.4 (C-2), 39.5 (NCH₂-1

pentyl), 33.0 (CH₂pentenyl), 29.2, 29.2, 29.2, 22.4 (CH₂pentenyl,

˜

max

1454, 1365, 1276, 1209, 1073, 1027, 911, 734, 696 cm^–1. [α]²_D⁰

=

–16.8 (c = 3.2, CHCl₃). HRMS: calcd. for [C₄₈H₆₀N₂O₆+ H]⁺

761.4524 [M + H]⁺; found 461.4531.

1,1,3,3-Tetramethylbutyl

(pent-4-en-imido)- -glycero-

3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-

-ido-heptonamide (89): R_f0.67

L

D

=

3ϫCH₂pentyl), 14.1 (CH -5 pentyl) ppm. IR (thin film): ν

=

˜

3

max

(EtOAc/toluene, 1:3). ¹H NMR (500 MHz, CDCl₃, 3.5:1 mixture

of rotamers; major rotamer): δ = 7.35–7.22 (m, 20 H, H_ArBn), 6.66

[s, 1 H, C(O)NH], 5.86–5.70 (m, 1 H, =CH pentenyl), 5.19 (d, J =

6.8 Hz, 1 H, 2-H), 5.01–4.35 (m, 11 H, =CH₂pentenyl, 4ϫCH₂

Bn, 4-H), 4.23–4.16 (m, 1 H, 6-H), 4.05 (dd, J = 9.8 Hz, 1 H, 7a-

H), 3.85 (dd, J = 3.7, 9.9 Hz, 1 H, 7b-H), 3.49 (dd, J = 6.5, 9.7 Hz,

1 H, 5-H), 3.44 (dd, J = 6.7, 9.6 Hz, 1 H, 3-H), 2.46–2.18 (m, 4 H,

2ϫCH₂pentenyl), 1.73 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.49

(d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.37 (s, 3 H, CH₃tMB), 1.27

(s, 3 H, CH₃tMB), 0.93 (s, 9 H, CH₃-4, 2ϫCH₃tMB) ppm. ¹³C

NMR (125 MHz, CDCl₃): δ = 174.7 [NC(O) pentenyl], 167.9

[NHC(O)-1], 139.0, 138.6, 138.3, 138.1 (4ϫC_qBn), 137.4 (=CH

pentenyl), 128.7, 128.6, 128.5, 128.4, 128.2, 128.1, 127.9, 127.7,

127.6, 127.4 (CH_ArBn), 115.3 (=CH₂pentenyl), 79.4 (C-5), 78.8,

78.7 (C-3, C-4), 75.8, 74.1, 73.9, 73.0 (4ϫCH₂Bn), 67.1 (C-7), 56.6

(C-6), 55.2 (NHC_q-1 tMB), 54.0 (C-2), 52.7 (CH₂-2 tMB), 33.3 (C_q-

3 tMB), 32.8 (CH₂pentenyl), 31.6 (CH₃-4, 2ϫCH₃tMB), 29.3

3364, 2930, 2862, 1681, 1531, 1454, 1365, 1208, 1091, 1027, 911,

733, 696 cm^–1. [α]²_D⁰= –58.1 (c = 2.0, CHCl₃). HRMS: calcd. for

[C₄₅H₅₄N₂O₆+ H]⁺719.4055 [M + H]⁺; found 719.4059.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dide-

oxy-2,6-imino-L-glycero-D-gulo-heptonamide (92): Compound 92

(108 mg, 0.14 mmol, 50%) was synthesized from 86 (0.27 mmol) by

deprotection of the pent-4-enamide (General Procedure D). R_f=

0.17 (EtOAc/toluene, 1:2). ¹H NMR (400 MHz, CDCl₃): δ = 7.34–

7.20 (m, 20 H, H_ArBn), 6.86 [t, J = 5.7 Hz, 1 H, C(O)NH], 4.72–

4.45 (m, 8 H, 4ϫCH₂Bn), 4.01 (dd, J = 5.7 Hz, 1 H, 3-H), 3.77

(dd, J = 6.1 Hz, 1 H, 4-H), 3.63–3.52 (m, 3 H, CH₂-7, 5-H), 3.50

(d, J = 5.6 Hz, 1 H, 2-H), 3.39 (dt, J = 4.2, 8.3 Hz, 1 H, 6-H), 3.30

(t, J = 6.5 Hz, 2 H, CH₂-5 pentyl), 3.29–3.20 (m, 1 H, NCHH-1

pentyl), 3.19–3.08 (m, 1 H, NCHH-1 pentyl), 2.91 (s, 2 H, OCH₂-

Ada), 2.47 (s, 1 H, NH), 1.94 (s, 3 H, 3ϫCH Ada), 1.67 (dd, J =

12.1, 24.3 Hz, 6 H, 3ϫCH₂Ada), 1.55–1.36 (m, 10 H, 3ϫCH₂Ada,

2ϫCH₂pentyl), 1.36–1.24 (m, 2 H, CH₂-3 pentyl) ppm. ¹³C NMR

(100 MHz, CDCl₃): δ = 170.6 [C(O)-1], 138.5, 138.4, 138.3, 138.3

(4ϫC_qBn), 128.6, 128.5, 128.4, 128.1, 128.1, 128.0, 128.0, 127.9,

127.8, 127.8, 127.8, 127.7, 127.6 (CH_ArBn), 82.0 (OCH₂-Ada), 77.3

(C-4), 76.9 (C-5), 76.7 (C-3), 73.7, 73.6, 73.5, 72.3 (4ϫCH₂Bn),

71.5 (CH₂-5 pentyl), 68.9 (C-7), 58.1 (C-2), 52.2 (C-6), 39.9 (CH₂

Ada), 39.5 (NCH₂-1 pentyl), 37.4 (CH₂Ada), 34.2 (C_qAda), 29.5,

29.4 (2ϫCH₂pentyl), 28.4 (CH Ada), 23.7 (CH₂-3 pentyl) ppm. IR

(CH pentenyl), 28.8, 28.5 (2ϫCH tMB) ppm. IR (thin film): ν

˜

max

2

3

= 2952, 1726, 1683, 1638, 1532, 1454, 1365, 1227, 1091, 1027, 911,

734, 696 cm^–1. [α]²_D⁰= –51.0 (c = 3.0, CHCl₃). HRMS: calcd. for

[C₄₈H₆₀N₂O₆+ H]⁺761.4524 [M + H]⁺; found 461.4531.

Pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-(pent-4-enimido)-

L-

glycero- -gulo-heptonamide (90): Subjecting azido aldehyde 85

D

(1.16 mmol) to the tandem SAWU-3CR (General procedure B in

MeOH) produced a separable 1.6:1 mixture of 91 (297 mg,

0.41 mmol) and 90 (182 mg, 0.25 mmol) in a combined yield of

57%. R_f= 0.27 (EtOAc/toluene, 1:3). ¹H NMR (500 MHz, CDCl₃,

complex mixture of rotamers; major signals): δ = 7.38–7.19 (m, 20

H, H_ArBn), 5.82–5.74 (m, 1 H, =CH pentenyl), 5.02–4.92 (m, 2 H,

=CH₂pentenyl), 4.81–3.61 (m, 15 H, 4ϫCH₂Bn, 2-H, 3-H, 4-H,

5-H, 6-H, CH₂-7), 3.23–3.12 (m, 2 H, NCH₂-1 pentyl), 2.68–2.22

(m, 4 H, 2ϫCH₂pentenyl), 1.73–0.97 (m, 6 H, 3ϫCH₂pentyl),

0.85 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (125 MHz,

CDCl₃) major signals δ = 174.2 [NC(O) pentenyl], 169.1 [NHC(O)-

1], 138.4, 138.2, 138.2, 137.8 (4ϫC_qBn), 138.0 (=CH pentenyl),

128.8–127.7 (CH_ArBn), 115.0 (=CH₂pentenyl), 80.8, 78.7, 78.2,

73.6, 72.0, 70.1, 69.1, 64.5, 59.1, 54.9, 40.1 (NCH₂-1 pentyl), 33.3

(CH₂pentenyl), 29.3, 29.2, 22.5 (CH₂pentyl/pentenyl), 14.2 (CH₃-

(thin film): ν

= 3313, 2901, 2849, 1667, 1524, 1497, 1453, 1363,

˜

max

1207, 1092, 1027, 908, 730, 696 cm^–1. [α]²_D⁰= –8.4 (c = 2.1, CHCl₃).

HRMS: calcd. for [C₅₁H₆₄N₂O₆+ H]⁺801.4837 [M + H]⁺; found

801.4840.

5-(Adamantan-1-yl-methoxy)pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dide-

oxy-2,6-imino-L-glycero-D-ido-heptonamide (93): Compound 93

(130 mg, 0.16 mmol, 65%) was synthesized from 87 (0.25 mmol) by

deprotection of the pent-4-enamide (General Procedure D). R_f=

0.20 (EtOAc/toluene, 1:3). ¹H NMR (400 MHz, CDCl₃): δ = 7.37–

7.12 (m, 20 H, H_ArBn), 7.05 [t, J = 5.9 Hz, 1 H, C(O)NH], 4.62

(d, J = 11.7 Hz, 1 H, CHH Bn), 4.55–4.25 (m, 7 H, CHH Bn,

3ϫCH₂Bn), 4.18–4.13 (m, 1 H, 3-H), 3.67 (dd, J = 2.6 Hz, 1 H,

4-H), 3.60 (d, J = 1.9 Hz, 1 H, 2-H), 3.53 (dd, J = 6.7, 9.2 Hz, 1

H, 7a-H), 3.45 (dd, J = 7.5, 9.2 Hz, 1 H, 7b-H), 3.43–3.40 (m, 1

H, 5-H), 3.33 (t, J = 6.5 Hz, 2 H, CH₂-5 pentyl), 3.30–3.23 (m, 2

H, NCH₂-1 pentyl), 3.20 (dt, J = 2.3, 7.2 Hz, 1 H, 6-H), 2.93 (s, 2

H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH Ada), 1.90 (s, 1 H, NH), 1.67

(dd, J = 12.2, 24.6 Hz, 6 H, 3ϫCH₂Ada), 1.58–1.46 (m, 10 H,

5 pentyl) ppm. IR (thin film): ν_max= 3325, 2929, 2862, 1726, 1636,

˜

1543, 1454, 1417, 1363, 1279, 1072, 1027, 911, 724, 967 cm^–1.

[α]²_D⁰= –12.4 (c = 0.9, CHCl₃). HRMS: calcd. for [C₄₅H₅₄N₂O₆+

H]⁺719.4055 [M + H]⁺; found 719.4058.

Pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-(pent-4-enimido)-

glycero-

-ido-heptonamide (91): R_f= 0.45 (EtOAc/toluene, 1:3). ¹H

NMR (500 MHz, CDCl₃, major rotamer; 3.5:1 mixture of rota-

L

-

3ϫCH₂Ada, 2ϫCH₂pentyl), 1.40–1.28 (m, 2 H, CH₂-3

D

pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.3 [C(O)-1],

138.8, 138.4, 138.4, 138.0 (4ϫC_qBn), 128.6, 128.5, 128.4, 128.4,

6444

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Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

128.3, 128.2, 128.0, 127.9, 127.9, 127.8, 127.7 (CH_ArBn), 82.1

(OCH₂-Ada), 73.7, 73.4 (2ϫCH₂Bn), 73.3 (C-3), 73.1 (C-5), 72.3,

72.2 (2ϫCH₂Bn), 71.7 (C-4), 71.5 (CH₂-5 pentyl), 70.6 (C-7), 60.1

(C-2), 56.0 (C-6), 39.9 (CH₂Ada), 39.3 (NCH₂-1 pentyl), 37.4 (CH₂

Ada), 34.3 (C_qAda), 29.7, 29.4 (2ϫCH₂pentyl), 28.5 (CH Ada),

NCHH-1 pentyl), 2.35 (s, 1 H, NH), 1.48–1.32 (m, 2 H, CH₂-2

pentyl), 1.32–1.13 (m, 4 H, 2ϫCH₂pentyl), 0.84 (t, J = 6.9 Hz, 3

H, CH₃-5 pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.6

[C(O)-1], 138.5, 138.5, 138.4, 138.3 (4ϫC_qBn), 128.5, 128.5, 128.4,

128.1, 128.1, 128.0, 128.0, 127.9, 127.8, 127.8, 127.8, 127.7, 127.6

(CH_ArBn), 77.3 (C-4), 76.9 (C-5), 76.7 (C-3), 73.6, 73.6, 73.5, 72.3

(4ϫCH₂Bn), 68.9 (C-7), 58.1 (C-2), 52.2 (C-3), 39.5 (NCH₂-1

penty), 29.3, 29.2, 22.5 (3ϫCH₂pentyl), 14.1 (CH₃-5 pentyl) ppm.

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

= 2902, 2849, 1726,

˜

2

max

1670, 1454, 1363, 1288, 1208, 1093, 1028, 909, 735, 698 cm^–1.

[α]²_D⁰= 0.4 (c = 0.9, CHCl₃). HRMS: calcd. for [C₅₁H₆₄N₂O₆

+

H]⁺801.4837 [M + H]⁺; found 801.4839.

IR (thin film): ν

= 3306, 2928, 2861, 1725, 1653, 1527, 1497,

˜

max

1454, 1365, 1208, 1069, 1027, 908, 733, 696 cm^–1. [α]²_D⁰= –9.9 (c =

1.5, CHCl₃). HRMS: calcd. for [C₄₀H₄₈N₂O₅+ H]⁺637.3636 [M

+ H]⁺; found 637.3633.

1,1,3,3-Tetramethylbutyl

3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-

imino- -glycero- -gulo-heptonamide (94): Compound 94 (94 mg,

L

D

0.14 mmol, 40%) was synthesized from 88 (0.35 mmol) by depro-

tection of the pent-4-enamide (General Procedure D). R_f= 0.37

Pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-imino-

L-glycero-D-

1

(EtOAc/toluene, 1:3). H NMR (400 MHz, CDCl₃): δ = 7.37–7.19

ido-hepton-amide (97): Compound 97 (181 mg, 0.28 mmol, 77%)

(m, 20 H, H_ArBn), 6.99 [s, 1 H, C(O)NH], 4.71–4.43 (m, 8 H, was synthesized from 91 (0.37 mmol) by deprotection of the pent-

4ϫCH₂Bn), 4.11 (dd, J = 4.9 Hz, 1 H, 3-H), 3.78 (dd, J = 5.4 Hz,

1 H, 4-H), 3.61–3.48 (m, 3 H, 5-H, CH₂-7), 3.44 (d, J = 4.7 Hz, 1

H, 2-H), 3.41–3.33 (m, 1 H, 6-H), 2.38 (s, 1 H, NH), 1.76 (d, J =

4-enamide (General Procedure D). R_f= 0.20 (EtOAc/toluene, 1:3).

¹H NMR (400 MHz, CDCl₃): δ = 7.37–7.12 (m, 20 H, H_ArBn),

7.04 [t, J = 5.9 Hz, 1 H, C(O)NH], 4.62 (d, J = 11.7 Hz, 1 H, CHH

14.8 Hz, 1 H, CH2-H tMB), 1.61 (d, J = 14.8 Hz, 1 H, CH2-H Bn), 4.54–4.27 (m, 7 H, CHH Bn, 3ϫCH₂Bn), 4.18–4.16 (m, 1 H,

tMB), 1.32 (d, J = 11.7 Hz, 6 H, 2ϫCH₃tMB), 0.94 (s, 9 H, CH₃- 3-H), 3.67 (dd, J = 2.7 Hz, 1 H, 4-H), 3.60 (d, J = 2.0 Hz, 1 H, 2-

4, 2ϫCH₃tMB) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 169.2

H), 3.53 (dd, J = 6.7, 9.3 Hz, 1 H, 7a-H), 3.45 (dd, J = 7.2, 9.3 Hz,

[C(O)-1], 138.4, 138.4, 138.3, 138.3 (4ϫC_qBn), 128.4, 128.4, 128.3, 1 H, 7b-H), 3.43–3.40 (m, 1 H, 5-H), 3.31–3.17 (m, 3 H, NCH₂-1

128.3, 128.0, 127.9, 127.8, 127.7, 127.7, 127.6, 127.6, 127.6 (CH_Arpentyl, 6-H), 2.01 (s, 1 H, NH), 1.53–1.44 (m, 2 H, CH₂-2 pentyl),

Bn), 75.9, 75.8 (C-4, C-5), 75.2 (C-3), 73.4, 73.1, 73.0, 72.0 (4ϫCH₂1.35–1.22 (m, 4 H, 2ϫCH₂pentyl), 0.87 (t, J = 7.0 Hz, 3 H, CH₃-

Bn), 69.4 (C-7), 58.7 (C-2), 54.6 (NHC_q-1 tMB), 52.0 (CH₂-2 tMB),

51.6 (C-6), 31.6 (C_q-3 tMB), 31.5 (CH₃-4, 2ϫCH₃tMB), 28.8, 28.7

5 pentyl) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 171.3 [C(O)-1],

138.8, 138.4, 138.4, 138.0 (4ϫC_qBn), 128.6, 128.5, 128.4, 128.4,

(2ϫCH tMB) ppm. IR (thin film): ν_max= 3329, 2867, 1671, 1517, 128.2, 128.0, 127.9, 127.8, 127.7 (CH_ArBn), 73.7, 73.4 (2ϫCH₂

˜

3

1454, 1366, 1208, 1093, 1027, 734, 697 cm^–1. [α]²_D⁰= –4.6 (c = 1.0,

CHCl₃). HRMS: calcd. for [C₄₃H₅₄N₂O₅+ H]⁺679.4105 [M +

H]⁺; found 679.4102.

Bn), 73.3 (C-3), 73.1 (C-5), 72.3, 72.2 (2ϫCH₂Bn), 71.7 (C-4), 70.6

(C-7), 60.2 (C-2), 56.0 (C-6), 39.3 (NCH₂-1 penty), 29.6, 29.3, 22.6

(3ϫCH pentyl), 14.2 (CH -5 pentyl) ppm. IR (thin film): ν =

˜

max

2

3

3387, 2927, 2862, 1725, 1668, 1521, 1497, 1454, 1364, 1288, 1208,

1070, 908, 735, 698 cm^–1. [α]²_D⁰= 2.1 (c = 0.6, CHCl₃). HRMS:

calcd. for [C₄₀H₄₈N₂O₅+ H]⁺637.3636 [M + H]⁺; found 637.3633.

1,1,3,3-Tetramethylbutyl

3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-

imino- -glycero- -ido-heptonamide (95): Compound 95 (120 mg,

L

D

0.18 mmol, 55%) was synthesized from 89 (0.32 mmol) by depro-

tection of the pent-4-enamide (General Procedure D). R_f= 0.59

5-(Adamantan-1-yl-methoxy)pentyl

2,6-Dideoxy-2,6-imino-L-

1

(EtOAc/toluene, 1:3). H NMR (400 MHz, CDCl₃): δ = 7.35–7.13

glycero- -gulo-heptonamide (98): Compound 98 (7 mg, 16 μmol,

D

(m, 20 H, H_ArBn), 7.05 [s, 1 H, C(O)NH], 4.62 (d, J = 11.5 Hz, 1

H, CHH Bn), 4.56–4.28 (m, 7 H, CHH Bn, 3ϫCH₂Bn), 4.20–4.17

(m, 1 H, 3-H), 3.68 (dd, J = 2.7 Hz, 1 H, 4-H), 3.54–3.48 (m, 2 H,

CH₂-7), 3.47 (d, J = 2.0 Hz, 1 H, 2-H), 3.44 (s, 1 H, 5-H), 3.19 (dt,

41%) was synthesized from 92 (39 μmol) by deprotection of the

benzyl ethers (appropriate method in General Procedure F). ¹H

NMR (400 MHz, MeOD, collapsed iminosugar signals): δ = 4.01–

3.35 (m, 9 H, 2-H, 3-H, 4-H, 5-H, 6-H, CH₂-7, CH₂-5 pentyl),

J = 2.1, 7.3 Hz, 1 H, 6-H), 1.90 (s, 1 H, NH), 1.79 (d, J = 14.8 Hz, 3.28–3.22 (m, 2 H, NCH₂-1 pentyl), 2.96 (s, 2 H, OCH₂-Ada), 1.95

1 H, CHH-2 tMB), 1.65 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.40 (s, 3 H, 3ϫCH Ada), 1.72 (d, J = 21.1 Hz, 6 H, 3ϫCH₂Ada),

(d, J = 11.9 Hz, 6 H, 2ϫCH₃tMB), 0.96 (s, 9 H, CH₃-4, 2ϫCH₃1.63–1.49 (m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.49–1.35 (m, 2

tMB) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 170.1 [C(O)-1],

H, CH₂-5 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 171.8

138.9, 138.6, 138.5, 138.1 (4ϫC_qBn), 128.6, 128.6, 128.4, 128.4, [C(O)-1], 83.2 (OCH₂-Ada), 74.3, 73.3, 71.9 (C-3, C-4, C-5), 72.6

128.3, 128.2, 128.0, 127.9, 127.9, 127.8, 127.8, 127.6 (CH_ArBn), (CH₂-3 pentyl), 59.2 (C-7), 59.1, 57.7 (C-2, C-6), 41.0 (CH₂Ada),

73.6, 73.4 (2ϫCH₂Bn), 73.1, 73.0 (C-3, C-5), 72.3, 72.2 (2ϫCH₂40.7 (NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5, 30.3

Bn), 71.9 (C-4), 70.5 (C-7), 60.5 (C-2), 56.2 (C-6), 54.7 (NHC_q-1 (2ϫCH₂pentyl), 29.9 (CH Ada), 24.8 (CH₂-3 pentyl) ppm. [α]²_D⁰

=

tMB), 52.3 (CH₂-2 tMB), 31.8 (C_q-3 tMB), 31.7 (CH₃-4, 2ϫCH₃–3.0 (c = 1.0, MeOH). IR (thin film): ν

= 3312, 2901, 2848,

˜

max

tMB), 29.1, 29.0 (2ϫCH tMB) ppm. IR (thin film): ν

= 3371,

1652, 1455, 1099 cm^–1. HRMS: calcd. for [C₂₃H₄₀N₂O₆+ H]⁺

˜

3

max

2868, 1678, 1518, 1454, 1365, 1208, 1071, 1028, 911, 724, 698 cm^–1. 441.2959 [M + H]⁺; found 441.2957.

[α]²_D⁰= 4.7 (c = 0.4, CHCl₃). HRMS: calcd. for [C₄₃H₅₄N₂O₅

+

5-(Adamantan-1-yl-methoxy)pentyl 2,6-Butylimino-2,6-dideoxy-

L-

H]⁺679.4105 [M + H]⁺; found 679.4102.

glycero- -gulo-heptonamide (99): Compound 99 (17 mg, 34 μmol,

D

Pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-imino-

L

-glycero-

D

-

83%) was synthesized in two steps from 92 (41 μmol) through re-

ductive amination with the appropriate aldehyde (General Pro-

cedure E) and subsequent benzyl ether deprotection (appropriate

method in General Procedure F). R_f= 0.36 (MeOH/CH₂Cl₂, 1:4 +

gulo-hepton-amide (96): Compound 96 (98 mg, 0.15 mmol, 59%)

was synthesized from 90 (0.26 mmol) by deprotection of the pent-

4-enamide (General Procedure D). R_f= 0.17 (EtOAc/toluene, 1:2).

¹H NMR (400 MHz, CDCl₃): δ = 7.36–7.18 (m, 20 H, H_ArBn), 2% NH₄OH); R_f(N-alkylated penultimate) = 0.62 (EtOAc/toluene,

6.84 [t, J = 5.6 Hz, 1 H, C(O)NH], 4.73–4.45 (m, 8 H, 4ϫCH₂Bn),

4.02 (dd, J = 5.7 Hz, 1 H, 3-H), 3.78 (dd, J = 6.1 Hz, 1 H, 4-H), = 4.16–3.47 (m, 6 H, 2-H, 3-H, 4-H, 5-H, CH₂-7), 3.39 (t, J =

3.60 (dd, J = 8.4, 9.6 Hz, 1 H, 7a-H), 3.57–3.52 (m, 2 H, 5-H, 7b- 6.4 Hz, 3 H, 6-H, CH₂-5 pentyl), 3.30–3.17 (m, 2 H, NCH₂-1

1:2). ¹H NMR (400 MHz, MeOD, collapsed iminosugar signals): δ

H), 3.50 (d, J = 5.7 Hz, 1 H, 2-H), 3.40 (dt, J = 4.2, 8.4 Hz, 1 H, pentyl), 3.10–2.86 (m, 3 H, OCH₂-Ada, NCHH butyl), 2.81–2.57

6-H), 3.32–3.21 (m, 1 H, NCHH-1 pentyl), 3.20–3.06 (m, 1 H, (m, 1 H, NCHH butyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.80–1.26 (m,

Eur. J. Org. Chem. 2012, 6420–6454

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6445

H. S. Overkleeft et al.

FULL PAPER

22 H, 6ϫCH₂Ada, 3ϫCH₂pentyl, 2ϫCH₂butyl), 0.94 (t, J =

71.8, 71.7, 70.0 (C-3, C-4, C-5), 71.1 (CH₂-5 pentyl), 63.8 (C-2),

60.3 (C-7), 59.5 (C-6), 52.7 (NCH₂butyl), 39.5 (CH₂Ada), 38.8

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

83.3 (OCH₂-Ada), 75.3, 73.1 (C-3, C-4, C-5), 72.6 (CH₂-5 pentyl), (NCH₂-1 pentyl), 36.9 (CH₂Ada), 35.3 (C_qAda), 28.4 (CH Ada),

68.1, 62.9 (C-2, C-5), 56.2 (C-7), 52.2 (NCH₂butyl), 41.0 (CH₂

Ada), 40.7 (NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5,

30.2 (CH₂pentyl/butyl), 29.9 (CH Ada), 24.9 (CH₂-3 pentyl), 21.4

29.0, 28.7, 23.5, 20.1 (3ϫCH₂pentyl, 2ϫCH₂butyl), 12.9 (CH₃

butyl) ppm. IR (thin film): ν = 3315, 2904, 2850, 1651, 1590,

˜

max

1456, 1065 cm^–1. [α]²_D⁰= –6.7 (c = 0.1, MeOH). HRMS: calcd. for

= 3316, [C₂₇H₄₈N₂O₆+ H]⁺497.3585 [M + H]⁺; found 497.3580.

(CH₂butyl), 14.3 (CH₃butyl) ppm. IR (thin film): ν

˜

max

2903, 2849, 1652, 1458, 1074 cm^–1. [α]²_D⁰= –1.0 (c = 0.2, MeOH).

HRMS: calcd. for [C₂₇H₄₈N₂O₆+ H]⁺497.3585 [M + H]⁺; found

497.3581.

1,1,3,3-Tetramethylbutyl 2,6-Dideoxy-2,6-imino-L-glycero-D-gulo-

heptonamide (103): Compound 103 (17 mg, 53 μmol, 88%) was syn-

thesized from 94 (60 μmol) by deprotection of the benzyl ethers

(appropriate method in General Procedure F). R_f= 0.30 (MeOH/

5-(Adamantan-1-yl-methoxy)pentyl 2,6-[5-(Adamantan-1-yl-meth-

oxy)pentyl]imino-2,6-dideoxy-L-glycero-D

-gulo-heptonamide (100): CH₂Cl₂, 1:4 + 2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ =

Compound 100 (22 mg, 33 μmol, 79%) was synthesized in two

steps from 92 (42 μmol) through reductive amination with the ap-

propriate aldehyde (General Procedure E) and subsequent benzyl

ether deprotection (appropriate method in General Procedure F).

R_f(N-alkylated penultimate) = 0.66 (EtOAc/toluene, 1:2). ¹H NMR

3.95–3.55 (m, 7 H, 2-H, 3-H, 4-H, 5-H, 6-H, CH₂-7), 1.88 (s, 1 H,

CHH-2 tMB), 1.72 (s, 1 H, CHH-2 tMB), 1.41 (s, 6 H, 2ϫCH₃

tMB), 1.02 (s, 9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR

(100 MHz, MeOD): δ = 166.5 [C(O)-1], 72.2, 70.9, 69.0 (C-3, C-4,

C-5), 57.3 (C-2), 57.0 (C-7), 56.0 (C-6), 55.3 (NHC_q-1 tMB), 51.2

(400 MHz, MeOD): δ = 3.96–3.82 (m, 2 H, CH₂-7), 3.77–3.69 (m, (CH₂-2 tMB), 31.0 (C_q-3 tMB), 30.5 (2ϫCH₃, CH₃-4 tMB), 28.0,

1 H, 5-H), 3.67–3.53 (m, 1 H, 3-H), 3.53–3.43 (m, 1 H, 4-H), 3.43– 27.7 (2ϫCH tMB) ppm. IR (thin film): ν

= 3319, 2953, 2438,

˜

3

max

3.34 (m, 5 H, 2ϫCH₂-5 pentyl, 2-H), 3.33–3.12 [m, 3 H, 5-H, C(O)-

NCH₂-1 pentyl], 3.00–2.95 (m, 3 H, 2ϫOCH₂-Ada), 2.86–2.73 (m,

1667, 1444, 1366, 1226, 1062 cm^–1. [α]²_D⁰= –13.6 (c = 0.8, MeOH).

HRMS: calcd. for [C₁₅H₃₀N₂O₅+ H]⁺319.2222 [M + H]⁺; found

1 H, NCHH pentyl), 2.61–2.49 (m, 1 H, NCHH pentyl), 1.95 (s, 6 319.2229.

H, 6ϫCH Ada), 1.82–1.26 (m, 24 H, 6ϫCH₂Ada, 6ϫCH₂

1,1,3,3-Tetramethylbutyl 2,6-Butylimino-2,6-dideoxy-L-glycero-D-

pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 83.3, 83.2

(2ϫOCH₂-Ada), 75.9 (C-4), 73.6 (C-3), 72.7, 72.6 (2ϫCH₂-5

pentyl), 71.8 (C-5), 68.0 (C-2), 62.5 (C-6), 56.9 (C-7), 51.7 (NCH₂-

1 pentyl), 41.0 (CH₂Ada), 40.6 [C(O)NCH₂-1 pentyl], 38.5 (CH₂

Ada), 35.3 (C_qAda), 30.7, 30.6, 30.3 (CH₂pentyl), 29.9 (CH Ada),

gulo-hepton-amide (104): Compound 104 (11 mg, 29 μmol, 59%)

was synthesized in two steps from 94 (49 μmol) through reductive

amination with the appropriate aldehyde (General Procedure E)

and subsequent benzyl ether deprotection (appropriate method in

General Procedure F). R_f= 0.47 (MeOH/CH₂Cl₂, 1:4 + 2%

NH₄OH); R_f(N-alkylated penultimate) = 0.74 (EtOAc/toluene,

25.1, 25.0 (2ϫCH -3 pentyl) ppm. IR (thin film): ν

= 3366,

˜

2

max

2901, 2848, 1652, 1455, 130, 1157, 1110 cm^–1. [α]²_D⁰= –2.3 (c = 0.4,

MeOH). HRMS: calcd. for [C₃₉H₆₆N₂O₇+ H]⁺675.4943 [M + H]

⁺; found 675.4941.

1

1:3). H NMR (400 MHz, MeOD): δ = 3.87 (dd, J = 4.1, 11.8 Hz,

1 H, 7a-H), 3.79 (dd, J = 6.8, 11.7 Hz, 1 H, 7b-H), 3.70 (dd, J =

5.6, 9.7 Hz, 1 H, 5-H), 3.59 (dd, J = 9.2 Hz, 1 H, 3-H), 3.40 (dd,

J = 9.1 Hz, 1 H, 4-H), 3.23–3.17 (m, 1 H, 6-H), 3.16 (d, J = 9.5 Hz,

1 H, 2-H), 2.71 (ddd, J = 5.5, 9.6, 12.6 Hz, 1 H, NCHH-1 pentyl),

2.54 (ddd, J = 5.6, 9.7, 12.6 Hz, 1 H, NCHH-1 pentyl), 1.92 (d, J

= 14.8 Hz, 1 H, CHH-2 tMB), 1.68 (d, J = 14.8 Hz, 1 H, CHH-2

5-(Adamantan-1-yl-methoxy)pentyl

2,6-Dideoxy-2,6-imino-L-

glycero- -ido-heptonamide (101): Compound 101 (14 mg, 32 μmol,

D

71%) was synthesized from 93 (45 μmol) by deprotection of the

benzyl ethers (appropriate method in General Procedure F). ¹H

NMR (400 MHz, MeOD): δ = 4.10 (s, 1 H, 3-H), 3.97 (dd, J = tMB), 1.61–1.38 (m, 8 H, 2ϫCH₃tMB, CH₂butyl), 1.36–1.24 (m,

3.1 Hz, 1 H, 4-H), 3.90 (s, 1 H, 2-H), 3.86–3.73 (m, 3 H, 5-H, CH₂- 2 H, CH₂butyl), 1.03 (s, 9 H, 2ϫCH₃, CH₃-4 tMB), 0.92 (t, J =

7), 3.39 (t, J = 6.4, 2 Hz, CH₂-5 pentyl), 3.34–3.23 (m, 3 H, 6-H,

NCH₂-1 pentyl), 2.97 (s, 2 H, OCH₂-Ada), 1.95 (s, 3 H, 3ϫCH 1], 76.1 (C-4), 73.6 (C-3), 71.8 (C-5), 67.8 (C-2), 62.2 (C-6), 57.4

7.3 Hz, 3 H) ppm. ¹³C NMR (100 MHz, MeOD): δ = 173.1 [C(O)-

Ada), 1.72 (dd, J = 11.7, 32.5 Hz, 6 H, 3ϫCH₂Ada), 1.63–1.52

(m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.47–1.37 (m, 2 H, CH₂-

3 pentyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 171.3 [C(O)-1],

(C-7), 56.5 (NHC_q-1 tMB), 52.9 (CH₂-2 tMB), 51.1 (NCH₂butyl),

32.6 (C_q-3 tMB), 32.2 (2ϫCH₃, CH₃-4 tMB), 32.0 (CH₂butyl),

29.6, 29.2 (2ϫCH₃tMB), 21.6 (CH₂butyl), 14.6 (CH₃butyl) ppm.

83.2 (OCH₂-Ada), 72.6 (CH₂-5 pentyl), 71.3 (C-3), 69.7, 69.7 (C- IR (thin film): ν

= 3374, 2957, 2497, 1728, 1652, 1434, 1366,

˜

max

4, C-5), 62.2 (C-7), 59.9 (C-2), 57.6 (C-6), 41.0 (CH₂Ada), 40.6 1276, 1228, 1122, 1072 cm^–1. [α]²_D⁰= –7.8 (c = 0.2, MeOH). HRMS:

(NCH₂-1 pentyl), 38.5 (CH₂Ada), 35.3 (C_qAda), 30.5, 30.3

calcd. for [C₁₉H₃₈N₂O₅+ H]⁺375.2853 [M + H]⁺; found 375.2854.

(2ϫCH₂pentyl), 29.9 (CH Ada), 24.8 (CH₂-3 pentyl) ppm. IR

1,1,3,3-Tetramethylbutyl 2,6-[5-(Adamantan-1-yl-methoxy)pentyl]-

imino-2,6-dideoxy-L-glycero-D-gulo-heptonamide (105): Compound

(thin film): ν_max= 3304, 2902, 2848, 1652, 1453, 1056 cm^–1. [α]²_D⁰

=

˜

–11.3 (c = 0.3, MeOH). HRMS: calcd. for [C₂₃H₄₀N₂O₆+ H]⁺

105 (20 mg, 36 μmol, 69%) was synthesized in two steps from 94

(52 μmol) through reductive amination with the appropriate alde-

hyde (General Procedure E) and subsequent benzyl ether deprotec-

tion (appropriate method in General Procedure F). R_f(N-alkylated

penultimate) = 0.77 (EtOAc/toluene, 1:3). ¹H NMR (400 MHz,

MeOD): δ = 3.98–3.80 (m, 2 H, CH₂-7), 3.80–3.65 (m, 1 H, 4-H),

3.65–3.50 (m, 1 H, 3-H), 3.50–3.21 (m, 5 H, CH₂-5 pentyl, 2-H, 4-

441.2959 [M + H]⁺; found 441.2957.

5-(Adamantan-1-yl-methoxy)pentyl 2,6-Butylimino-2,6-dideoxy-

L-

glycero- -ido-heptonamide (102): Compound 102 (6 mg, 12 μmol,

D

41%) was synthesized from 93 (29 μmol) through reductive amin-

ation with the appropriate aldehyde (General Procedure G). ¹H

NMR (400 MHz, MeOD, collapsed iminosugar signals): δ = 3.99–

3.60 (m, 6 H, 3-H, 4-H, 5-H, 6-H, CH₂-7), 3.53 (d, J = 3.4 Hz, 1 H, 6-H), 3.03–2.91 (m, 2 H, OCH₂-Ada), 2.89–2.74 (m, 1 H,

H, 2-H), 3.39 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.34–3.15 (m, 4 NCHH-1 pentyl), 2.73–2.53 (m, 1 H, NCHH-1 pentyl), 2.03–1.17

H, 5-H, NCH₂-1 pentyl), 2.97 (s, 2 H, OCH₂-Ada), 2.84–2.64 (m, (m, 27 H, 3ϫCH Ada, CH₂-2 tMB, 6ϫCH₂Ada, 3ϫCH₂pentyl,

2 H, NCH₂butyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J = 12.0,

2ϫCH₃tMB), 1.03 (s, 9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR

31.0 Hz, 6 H, 3ϫCH₂Ada), 1.62–1.23 (m, 16 H, 3ϫCH₂Ada, (100 MHz, MeOD): δ = 81.6 (OCH₂-Ada), 74.3 (C-4), 71.9 (C-3),

3ϫCH₂pentyl, 2ϫCH₂butyl), 0.94 (t, J = 7.3 Hz, 3 H, CH₃but- 71.0 (CH₂-5 pentyl), 70.0 (C-5), 66.5 (C-2), 60.8 (C-6), 55.5 (NHC_q-

yl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 81.7 (OCH₂-Ada),

1 tMB), 55.1 (C-7), 51.4 (CH₂-2 tMB), 50.1 (NCH₂-1 pentyl), 39.5

6446

www.eurjoc.org

Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

(CH₂Ada), 36.9 (CH₂Ada), 33.7 (C_qAda), 31.0, 30.7, 29.2, 28.4 Pentyl 2,6-Dideoxy-2,6-imino-L-glycero-D-gulo-heptonamide (109):

(CH Ada), 28.0, 27.7 (2ϫCH₃tMB), 23.6 (CH₂-3 pentyl) ppm. IR Compound 109 (13 mg, 46 μmol, 92%) was synthesized from 96

(thin film): ν

= 3342, 2902, 2849, 1652, 1449, 1366, 1227, 1157,

(50 μmol) by deprotection of the benzyl ethers (appropriate method

in General Procedure F). R_f= 0.85 (MeOH/CH₂Cl₂, 1:4 + 2%

NH₄OH). ¹H NMR (400 MHz, MeOD): δ = 3.89 (dd, J = 4.5,

11.7 Hz, 1 H, 7a-H), 3.86–3.75 (m, 3 H, 2-H, 5-H, 7b-H), 3.73 (t,

J = 7.3 Hz, 1 H, CH), 3.67 (t, J = 7.3 Hz, 1 H, CH), 3.57 (dt, J =

4.7, 9.0 Hz, 1 H, 6-H), 3.24 (dt, J = 2.7, 7.0 Hz, 2 H, NCH₂-1

pentyl), 1.61–1.47 (m, 2 H, CH₂-2 pentyl), 1.46–1.23 (m, 4 H,

2ϫCH₂pentyl), 0.92 (t, J = 6.8 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C

NMR (100 MHz, MeOD): δ = 170.0 [C(O)-1], 73.7, 72.7, 70.9 (C-

3, C-4, C-5), 58.9 (C-2), 58.8 (C-7), 57.7 (C-6), 40.9 (NCH₂-1

pentyl), 30.3, 30.1, 23.6 (3ϫCH₂pentyl), 14.5 (CH₃pentyl) ppm.

˜

max

1111 cm^–1. [α]²_D⁰= –3.1 (c = 0.4, MeOH). HRMS: calcd. for

[C₃₁H₅₆N₂O₆+ H]⁺553.4211 [M + H]⁺; found 553.4208.

1,1,3,3-Tetramethylbutyl

2,6-Dideoxy-2,6-imino-L-glycero-D-ido-

heptonamide (106): Compound 106 (12 mg, 37 μmol, 81%) was syn-

thesized from 95 (46 μmol) by deprotection of the benzyl ethers

(appropriate method in General Procedure F). R_f= 0.41 (MeOH/

CH₂Cl₂, 1:4 + 2% NH₄OH). ¹H NMR (400 MHz, MeOD): δ =

4.13 (s, 1 H, CH), 3.97 (s, 1 H, CH), 3.87 (s, 1 H, CH), 3.82 (s, 3

H, CH₂-7, CH), 3.33 (s, 1 H, 6-H), 1.81 (s, 2 H, CH₂-2 tMB), 1.42

(s, 6 H, 2ϫCH₃tMB), 1.02 (d, J = 4.6 Hz, 9 H, 2ϫCH₃, CH₃-4

tMB) ppm. ¹³C NMR (100 MHz, MeOD): δ = 71.1, 69.6, 69.5 (C-

3, C-4, C-5), 61.8 (C-7), 60.1 (C-2), 57.7 (C-5), 56.7 (NHC_q-1 tMB),

52.4 (CH₂-2 tMB), 32.6 (C_q-3 tMB), 32.0 (2ϫCH₃, CH₃-4 tMB),

IR (thin film): ν

= 3312, 2931, 1652, 1460, 1062 cm^–1. [α]²_D⁰

=

˜

max

–7.5 (c = 0.8, MeOH). HRMS: calcd. for [C₁₂H₂₄N₂O₅+ H]⁺

277.1758 [M + H]⁺; found 277.1759.

29.8, 29.5 (2ϫCH tMB) ppm. IR (thin film): ν

= 3311, 2955,

Pentyl

2,6-Butylimino-2,6-dideoxy-L-glycero-D-gulo-heptonamide

˜

3

max

2409, 1667, 1752, 1453, 1391, 1366, 1225, 1056 cm^–1. [α]²_D⁰= –4.5

(c = 0.6, MeOH). HRMS: calcd. for [C₁₅H₃₀N₂O₅+ H]⁺319.2222

[M + H]⁺; found 319.2229.

(110): Compound 110 (10 mg, 30 μmol, 64%) was synthesized in

two steps from 96 (47 μmol) through reductive amination with the

appropriate aldehyde (General Procedure E) and subsequent benzyl

ether deprotection (appropriate method in General Procedure F).

R_f= 0.37 (MeOH/CH₂Cl₂, 1:4 + 2% NH₄OH); R_f(N-alkylated

penultimate) = 0.59 (EtOAc/toluene, 1:2). ¹H NMR (400 MHz,

MeOD): δ = 3.88 (dd, J = 4.2, 11.8 Hz, 1 H, 7a-H), 3.82 (dd, J =

6.4, 11.8 Hz, 1 H, 7b-H), 3.76–3.69 (m, 1 H, 5-H), 3.63–3.57 (m, 1

H, 3-H), 3.41 (dd, J = 8.9, 9.9 Hz, 1 H, 4-H), 3.29–3.14 (m, 4 H,

2-H, 6-H, NCH₂-1 pentyl), 2.70 (ddd, J = 5.4, 9.6, 12.5 Hz, 1 H,

NCHH butyl), 2.47 (ddd, J = 5.7, 9.7, 12.5 Hz, 1 H, NCHH butyl),

1.62–1.23 (m, 10 H, 3ϫCH₂pentyl, 2ϫCH₂butyl), 0.96–0.88 (m,

6 H, 2ϫCH₃pentyl/butyl) ppm. ¹³C NMR (100 MHz, MeOD): δ

= 174.2 [C(O)-1], 76.1 (C-4), 73.8 (C-3), 72.1 (C-5), 67.9 (C-2), 62.3

(C-6), 57.1 (C-7), 51.1 (NCH₂butyl), 40.6 (NCH₂-1 pentyl), 31.6,

30.5, 30.2, 23.6, 21.6 (3ϫCH₂pentyl, 2ϫCH₂butyl), 14.5, 14.5

1,1,3,3-Tetramethylbutyl 2,6-Butylimino-2,6-dideoxy-L-glycero-D-

ido-heptonamide (107): Compound 107 (7 mg, 19 μmol, 49%) was

synthesized from 95 (39 μmol) through reductive amination with

the appropriate aldehyde (General Procedure G). ¹H NMR

(400 MHz, MeOD): δ = 3.88–3.78 (m, 2 H, 7a-H, CH), 3.77–3.70

(m, 2 H, 2ϫCH), 3.66 (dd, J = 6.6, 11.3 Hz, 1 H, 7b-H), 3.40 (d,

J = 3.3 Hz, 1 H, 2-H), 2.97 (dd, J = 5.9, 9.8 Hz, 1 H, 6-H), 2.88–

2.65 (m, 2 H, NCH₂-1 butyl), 1.86 (d, J = 14.8 Hz, 1 H, CHH-2

tMB), 1.72 (d, J = 14.8 Hz, 1 H, CHH-2 tMB), 1.59–1.46 (m, 2 H,

CH₂butyl), 1.42 (d, J = 1.7 Hz, 6 H, 2ϫCH₃tMB), 1.37–1.26 (m,

2 H, CH₂butyl), 1.03 (s, 9 H, 2ϫCH₃, CH₃-4 tMB), 0.94 (t, J =

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

73.2, 73.1, 71.8 (C-3, C-4, C-5), 65.0 (C-2), 61.9 (C-6), 61.4 (C-7),

56.4 (NHC_q-1 tMB), 54.9 (NCH₂butyl), 53.0 (CH₂-2 tMB), 32.6

(C_q-3 tMB), 32.1 (2ϫCH₃, CH₃-4 tMB), 29.3 (CH₂butyl), 29.1,

29.1 (CH₂-2 tMB), 21.6 (CH₂butyl), 14.5 (CH₃butyl) ppm. IR

(2ϫCH butyl/pentyl) ppm. IR (thin film): ν_max= 3329, 2958, 2931,

˜

3

2871, 1730, 1637, 1462, 1378, 1278, 1122, 1073 cm^–1. [α]²_D⁰= –7.8

(c = 0.2, MeOH). HRMS: calcd. for [C₁₆H₃₂N₂O₅+ H]⁺333.2384

[M + H]⁺; found 333.2385.

(thin film): ν

= 3339, 2955, 1638, 1434, 1366, 1227, 1048 cm^–1.

˜

max

[α]²_D⁰= –1.4 (c = 0.1, MeOH). HRMS: calcd. for [C₁₉H₃₈N₂O₅

+

Pentyl 2,6-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,6-dideoxy-

glycero- -gulo-heptonamide (111): Compound 111 (13 mg, 25 μmol,

L-

H]⁺375.2853 [M + H]⁺; found 375.2856.

D

51%) was synthesized in two steps from 96 (49 μmol) through re-

ductive amination with the appropriate aldehyde (General Pro-

cedure E) and subsequent benzyl ether deprotection (appropriate

method in General Procedure F). R_f(N-alkylated penultimate) =

1,1,3,3-Tetramethylbutyl 2,6-[5-(Adamantan-1-yl-methoxy)pentyl]-

imino-2,6-dideoxy- -glycero- -ido-heptonamide (108): Compound

108 (5 mg, 9 μmol, 21%) was synthesized from 95 (43 μmol)

L

D

through reductive amination with the appropriate aldehyde (Gene-

1

0.62 (EtOAc/toluene, 1:2). H NMR (400 MHz, MeOD): δ = 3.89

1

ral Procedure G). H NMR (400 MHz, MeOD): δ = 3.85 (dd, J =

(dd, J = 2.8, 11.6 Hz, 1 H, 7a-H), 3.84 (dd, J = 6.1, 11.7 Hz, 1 H,

7b-H), 3.72 (dd, J = 5.6, 9.8 Hz, 1 H, 5-H), 3.60 (dd, J = 9.2 Hz,

1 H, 3-H), 3.46–3.39 (m, 1 H, 4-H), 3.36 (t, J = 6.4 Hz, 2 H, CH₂-

5 pentyl), 3.30–3.09 [m, 4 H, 2-H, 6-H, C(O)NCH₂-1 pentyl], 2.96

(s, 2 H, OCH₂-Ada), 2.83–2.68 (m, 1 H, NCHH pentyl), 2.56–2.43

(m, 1 H, NCHH pentyl), 1.94 (s, 3 H, 3ϫCH Ada), 1.72 (dd, J =

12.2, 33.0 Hz, 6 H, 3ϫCH₂Ada), 1.64–1.26 (m, 18 H, 3ϫCH₂Ada,

6ϫCH₂pentyl), 0.92 (t, J = 6.2 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C

NMR (100 MHz, MeOD): δ = 81.7 (OCH₂-Ada), 74.5 (C-4), 72.2

(C-3), 71.1 (CH₂-5 pentyl), 70.4 (C-5), 66.4 (C-2), 60.9 (C-6), 55.5

(C-7), 49.9 (NCH₂-1 pentyl), 39.5 (CH₂Ada), 39.1 [C(O)NCH₂-1

pentyl], 36.9 (CH₂Ada), 33.8 (C_qAda), 28.4 (CH Ada), 29.2, 28.9,

28.7, 27.5, 23.5, 22.1 (6ϫCH₂pentyl), 13.0 (CH₃pentyl) ppm. IR

5.7, 11.4 Hz, 1 H, 7a-H), 3.82–3.79 (m, 1 H, 5-H), 3.77–3.71 (m, 2

H, 3-H, 4-H), 3.68 (dd, J = 6.4, 11.4 Hz, 1 H, 7b-H), 3.42 (d, J =

3.3 Hz, 1 H, 2-H), 3.39 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.02–

2.95 (m, 3 H, 6-H, OCH₂-Ada), 2.90–2.64 (m, 2 H, NCH₂-1

pentyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.87 (d, J = 14.8 Hz, 1 H, CHH-

2 tMB), 1.81–1.64 (m, 7 H, 3ϫCH₂Ada, CHH-2 tMB), 1.63–1.50

(m, 10 H, 3ϫCH₂Ada, 2ϫCH₂pentyl), 1.42 (d, J = 1.9 Hz, 6 H,

2ϫCH₃tMB), 1.39–1.25 (m, 2 H, CH₂-3 pentyl), 1.03 (s, 9 H,

2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR (100 MHz, MeOD): δ = 81.7

(OCH₂-Ada), 71.1 (CH₂-5 pentyl), 71.5, 71.5, 70.1 (C-3, C-4, C-5),

63.5 (C-2), 60.3 (C-6), 60.0 (C-7), 54.9 (NHC_q-1 tMB), 53.5

(NCH₂-1 pentyl), 51.4 (CH₂-2 tMB), 39.5 (CH₂Ada), 36.9 (CH₂

Ada), 33.8 (CH Ada), 31.0 (C_q-3 tMB), 30.6 (2ϫCH₃, CH₃-4 tMB),

29.2 (CH₂pentyl), 28.4 (CH Ada), 27.8, 27.6 (2ϫCH₃tMB), 25.1

(thin film): ν

= 3342, 2903, 2849, 1651, 1458, 1157, 1051 cm^–1.

˜

max

[α]²_D⁰= –1.1 (c = 0.2, MeOH). HRMS: calcd. for [C₂₈H₅₀N₂O₆

+

(CH pentyl), 23.6 (CH pentyl) ppm. IR (thin film): ν = 3367,

˜

max

H]⁺511.3742 [M + H]⁺; found 511.3738.

2

2903, 2849, 1638, 1451, 1227, 1056 cm^–1. [α]²_D⁰= –2.0 (c = 0.1,

MeOH). HRMS: calcd. for [C₃₁H₅₆N₂O₆+ H]⁺553.4211 [M +

H]⁺; found 553.4207.

Pentyl 2,6-Dideoxy-2,6-imino-L-glycero-D-ido-heptonamide (112):

Compound 112 (13 mg, 46 μmol, 79%) was synthesized from 97

Eur. J. Org. Chem. 2012, 6420–6454

www.eurjoc.org

6447

H. S. Overkleeft et al.

FULL PAPER

(58 μmol) by deprotection of the benzyl ethers (appropriate method

1

(EtOAc/PE, 1:6). H NMR (200 MHz, CDCl₃): δ = 7.64–7.55 (m,

6 H, H_ArTBDPS/p-NO₂Bz), 7.45–7.07 (m, 28 H, H_ArBn/TBDPS/

NH₄OH). H NMR (400 MHz, MeOD): δ = 4.13–4.10 (m, 1 H, 3- p-NO₂Bz), 5.49 (dd, J = 5.3, 9.5 Hz, 1 H, 5-H), 4.84–4.27 (m, 8 H,

in General Procedure F). R_f= 0.29 (MeOH/CH₂Cl₂, 1:4 + 2%

1

H), 3.98 (m, 1 H, 4-H), 3.92 (d, J = 2.1 Hz, 1 H, 2-H), 3.86–3.80

4ϫCH₂Bn), 4.19–3.48 (m, 7 H, CH₂-1, 2-H, 3-H, 4-H, CH₂-6),

(m, 1 H, 7a-H), 3.80–3.75 (m, 2 H, 7b-H, 5-H), 3.36–3.32 (m, 1 H, 0.90 (s, 9 H, tBu-Si) ppm. MS (ESI): calcd. for [C₅₇H₅₉NO₉Si + H]⁺

6-H), 3.24 (dt, J = 0.9, 7.0 Hz, 2 H, NHCH₂-1 pentyl), 1.60–1.50

(m, 2 H, CH₂-2 pentyl), 1.39–1.29 (m, 4 H, 2ϫCH₂pentyl), 0.92

(t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR (100 MHz,

MeOD): δ = 169.1 [C(O)-1], 69.8 (C-3), 68.1, 67.9 (C-4, C-5), 60.4

(C-7), 58.3 (C-2), 56.2 (C-6), 39.1 (NCH₂-1 pentyl), 28.8, 28.7, 22.0

930.4 [M + H]⁺; found 930.4.

2,5-Anhydro-1-O-tert-butyldiphenylsilyl-3,4,6-tri-O-benzyl-L-iditol

(116): Byproduct 116^[16]was formed during the Mitsunobu raction

of 82 and could be separated from 117 (the saponification product

of 115) by silica gel column chromatography (EtOAc/PE, 5Ǟ15%)

to provide 116 (5.94 g, 8.83 mmol, 46%) as a colorless oil. R_f=

0.65 (EtOAc/PE, 1:6). ¹H NMR (400 MHz, CDCl₃): δ = 7.70–7.63

(m, 4 H, H_ArTBDPS), 7.42–7.16 (m, 21 H, H_ArTBDPS/Bn), 4.59

(d, J = 12.0 Hz, 1 H, CHH Bn), 4.56–4.44 (m, 5 H, CHH Bn,

2ϫCH₂Bn), 4.37–4.30 (m, 2 H, 2-H, 5-H), 4.09 (dd, J = 1.5,

4.0 Hz, 1 H, 3-H), 4.04 (dd, J = 1.4, 4.0 Hz, 1 H, 4-H), 3.98 (dd,

J = 7.9, 9.9 Hz, 1 H, 1a-H), 3.87 (dd, J = 5.2, 10.0 Hz, 1 H, 1b-

H), 3.71 (dd, J = 5.8, 9.9 Hz, 1 H, 6a-H), 3.66 (dd, J = 6.5, 9.8 Hz,

1 H, 6b-H), 1.06 (s, 9 H, tBu-Si) ppm. ¹³C NMR (100 MHz,

CDCl₃): δ = 138.4, 138.2, 138.1 (3ϫC_qBn), 135.7, 135.7 (CH_Ar

TBDPS), 133.7, 133.5 (2ϫC_qSi-Ph), 129.7, 129.7, 128.5, 128.5,

128.4, 127.9, 127.9, 127.8, 127.7, 127.7, 127.6 (CH_ArBn/TBDPS),

81.9 (C-4), 81.3 (C-3), 80.5 (C-2), 79.2 (C-5), 73.5, 72.6, 72.4

(3ϫCH₂Bn), 68.8 (C-6), 61.7 (C-1), 27.0 (CH₃tBu), 19.3 (C_q

(3ϫCH₂pentyl), 12.9 (CH₃pentyl) ppm. IR (thin film): ν

=

˜

max

3259, 2929, 1652, 1460, 1058 cm^–1. [α]²_D⁰= –9.8 (c = 0.8, MeOH).

HRMS: calcd. for [C₁₂H₂₄N₂O₅+ H]⁺277.1758 [M + H]⁺; found

277.1758.

Pentyl

2,6-Butylimino-2,6-dideoxy-L-glycero-D-ido-heptonamide

(113): Compound 113 (5 mg, 15 μmol, 33%) was synthesized from

97 (45 μmol) through reductive amination with the appropriate al-

1

dehyde (General Procedure G). H NMR (400 MHz, MeOD): δ =

3.98 (dd, J = 3.9, 8.0 Hz, 1 H, 7a-H), 3.91–3.52 (m, 5 H, 2-H, 3-

H, 4-H, 5-H, 7b-H), 3.29–3.10 (m, 2 H, NCH₂-1 pentyl), 3.10–2.94

(m, 1 H, 6-H), 2.94–2.64 (m, 2 H, NCH₂butyl), 1.76–1.25 (m, 10

H, 3ϫCH₂pentyl, 2ϫCH₂butyl), 0.97–0.88 (m, 6 H, 2ϫCH₃

pentyl/butyl) ppm. ¹³C NMR (100 MHz, MeOD): δ = 71.7, 71.6,

71.1 (C-3, C-4, C-5), 63.7 (C-2), 60.2 (C-7), 59.8 (C-6), 52.6 (NCH₂

butyl), 38.8 (NCH₂-1 pentyl), 36.4 (CH₂butyl), 28.9, 28.7 (2ϫCH₂

pentyl), 22.0 (CH₂pentyl), 20.0 (CH₂butyl), 12.9, 12.7 (2ϫCH₃

tBu) ppm. IR (thin film): ν

= 3032, 2931, 2858, 1494, 1454,

˜

max

1428, 1358, 1208, 1080, 1027, 823, 735, 699, 611, 504 cm^–1. [α]²_D⁰

=

9.4 (c = 10.6, CHCl₃). HRMS: calcd. for [C₄₃H₄₈O₅Si + Na]⁺

pentyl/butyl) ppm. IR (thin film): ν

= 3344, 2959, 2931, 2872,

˜

max

695.3169 [M + Na]⁺; found 695.3161.

1638, 1461, 1061 cm^–1. [α]²_D⁰= –2.0 (c = 0.1, MeOH). HRMS: calcd.

for [C₁₆H₃₂N₂O₅+ H]⁺333.2384 [M + H]⁺; found 333.2385.

2,3,4,6-Tetra-O-benzyl-1-O-tert-butyldiphenylsilyl-

L-iditol

(117):

The crude residue containing 115 and 116 from the previous reac-

tion was dissolved in a mixture of H₂O/EtOH/THF (100 mL, 1:2:2,

v/v/v). Lithium hydroxide (2.85 g, 119 mmol) was added to the

solution and the resulting yellow reaction mixture was stirred for

2 h, after which TLC analysis showed complete consumption of the

starting material. The pH of reaction mixture was adjusted to pH

ca. 7 with 1 M aq. HCl. The mixture was concentrated to ca.

1/4 of its initial volume, diluted with Et₂O (100 mL) and washed

successively with satd. aq. NaHCO₃(3ϫ 100 mL) and satd. aq.

NaCl (100 mL). The organic phase was dried (Na₂SO₄) and con-

centrated. The resulting residue was purified by silica gel column

chromatography (EtOAc/PE, 5Ǟ15%) to provide 117 (5.68 g,

7.28 mmol, 38%) over the two steps as a colorless oil. R_f= 0.35

(EtOAc/PE, 1:61:6). ¹H NMR (600 MHz, CDCl₃): δ = 7.67–7.63

(m, 4 H, H_ArTBDPS), 7.47–7.16 (m, 26 H, H_ArTBDPS/Bn), 4.77–

4.70 (m, 2 H, CHH Bn, CHH Bn), 4.67–4.58 (m, 2 H, CHH Bn,

CHH Bn), 4.49 (d, J = 11.2 Hz, 1 H, CHH Bn), 4.43 (d, J =

11.9 Hz, 1 H, CHH Bn), 4.41 (d, J = 8.9 Hz, 1 H, CHH Bn), 4.38

(d, J = 11.9 Hz, 1 H, CHH Bn), 4.02 (dd, J = 3.1, 7.7 Hz, 1 H, 3-

H), 3.87 (dd, J = 4.5, 9.1 Hz, 1 H, 1a-H), 3.85 (dd, J = 4.5, 9.1 Hz,

1 H, 1b-H), 3.80 (dd, J = 2.3, 7.7 Hz, 1 H, 4-H), 3.75–3.69 (m, 2

H, 2-H, 5-H), 3.42 (dd, J = 6.8, 9.2 Hz, 1 H, 6a-H), 3.26 (dd, J =

5.7, 9.2 Hz, 1 H, 6b-H), 2.51 (d, J = 6.5 Hz, 1 H, OH-5), 1.04 (s,

9 H, tBu-Si) ppm. ¹³C NMR (150 MHz, CDCl₃): δ = 138.5, 138.5,

138.4, 138.3 (4ϫC_qBn), 135.9, 135.8 (CH_ArTBDPS), 133.5 (C_qSi-

Ph), 130.0, 129.9, 128.6, 128.5, 128.4, 128.0, 127.9, 127.9, 127.9,

127.8 (CH_ArBn/TBDPS), 79.0 (C-3), 78.9 (C-2), 78.7 (C-4), 75.1,

75.0, 73.4, 73.1 (4ϫCH₂Bn), 71.6 (C-6), 69.9 (C-5), 63.2 (C-1),

Pentyl 2,6-[5-(Adamantan-1-yl-methoxy)pentyl]imino-2,6-dideoxy-

L-

glycero- -ido-heptonamide (114): Compound 114 (6 mg, 12 μmol,

D

24%) was synthesized from 97 (50 μmol) through reductive amin-

ation with the appropriate aldehyde (General Procedure G). ¹H

NMR (400 MHz, MeOD): δ = 3.90–3.81 (m, 2 H, 5-H, 7a-H),

3.80–3.68 (m, 3 H, 3-H, 4-H, 7b-H), 3.53 (d, J = 3.5 Hz, 1 H, 2-

H), 3.38 (t, J = 6.4 Hz, 2 H, CH₂-5 pentyl), 3.30–3.12 [m, 2 H,

C(O)NCH₂-1 pentyl], 3.00–2.93 (m, 3 H, 6-H, OCH₂-Ada), 2.85–

2.63 (m, 2 H, NCH₂-1 pentyl), 1.95 (s, 3 H, 3ϫCH Ada), 1.72 (dd,

J = 11.8, 31.6 Hz, 6 H, 3ϫCH₂Ada), 1.65–1.49 (m, 10 H, 3ϫCH₂

Ada, 2ϫCH₂pentyl/butyl), 1.42–1.26 (m, 6 H, 3ϫCH₂pentyl/bu-

tyl), 0.93 (t, J = 7.0 Hz, 3 H, CH₃-5 pentyl) ppm. ¹³C NMR

(100 MHz, MeOD): δ = 83.2 (OCH₂-Ada), 72.7 (CH₂-5 pentyl),

73.3, 73.3, 71.5 (C-3, C-4, C-5), 65.4 (C-2), 61.9 (C-7), 61.1 (C-6),

54.5 (NCH₂-1 pentyl), 41.0 (CH₂Ada), 40.4 [C(O)NCH₂-1 pentyl],

38.5 (CH₂Ada), 35.3 (C_qAda), 29.9 (CH Ada), 30.7, 30.5, 30.2,

25.9, 25.2, 23.6 (6ϫCH₂pentyl), 14.5 (CH₃pentyl) ppm. IR (thin

film): ν_max= 3327, 2903, 2850, 1649, 1638, 1455, 1362, 1157, 1096,

˜

1057 cm^–1. [α]²_D⁰= –1.7 (c = 0.1, MeOH). HRMS: calcd. for

[C₂₈H₅₀N₂O₆+ H]⁺511.3742 [M + H]⁺; found 511.3737.

2,3,4,6-Tetra-O-benzyl-1-O-tert-butyldiphenylsilyl-5-O-para-nitro-

benzoyl-L-iditol (115): Diisopropyl azodicarboxylate (7.54 mL,

38.4 mmol) was added over a 2 min period to a cooled (0 °C), anhy-

drous solution of 82 (15.02 g, 19.2 mmol), p-nitrobenzoic acid

(6.42 g, 38.4 mmol) and triphenylphosphane (10.07 g, 38.4 mmol)

in THF (77 mL). The reaction mixture was stirred for 20 h and

allowed to warm to room temp. The reaction mixture was diluted

with EtOAc (200 mL) and successively washed with satd. aq.

NaHCO₃(3ϫ 100 mL) and satd. aq. NaCl (100 mL). The organic

phase was dried (Na₂SO₄) and concentrated, and the residue was

used crude in the next reaction. A portion of the residue was puri-

fied for characterization by silica gel column chromatography

(EtOAc/PE, 2Ǟ5%) to provide 115 as a colorless oil. R_f= 0.60

27.1 (CH₃tBu), 19.3 (C_qtBu) ppm. IR (thin film): ν

= 3031,

˜

max

2929, 2861, 1495, 1454, 1358, 1208, 1080, 1027, 823, 734, 699 cm^–1.

[α]²_D⁰= 13.0 (c = 0.3, CHCl₃). HRMS: calcd. for [C₅₀H₅₆O₆Si +

Na]⁺803.3744 [M + Na]⁺; found 803.3736.

5-Azido-2,3,4,6-tetra-O-benzyl-1-O-tert-butyldiphenylsilyl-

D-gluci-

tol (118): Diisopropyl azodicarboxylate (2.87 mL, 14.6 mmol) and

6448

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Eur. J. Org. Chem. 2012, 6420–6454

An Aza-C-Glycoside Library

diphenylphosphoryl azide (3.15 mL, 14.6 mmol) were successively

added over 2 min periods to a cooled (0 °C) anhydrous solution of

5-(Adamantan-1-yl-methoxy)pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dide-

oxy-2,6-(pent-4-enimido)- -glycero- -ido-heptonamide (121): Sub-

D

117 (5.68, 7.3 mmol) and triphenylphosphane (3.83 g, 14.6 mmol) jecting azido aldehyde 120 (1.01 mmol) to the tandem SAWU-3CR

in THF (55 mL). The reaction mixture was stirred for 20 h and

allowed to warm to room temp. The mixture was concentrated and

the resulting residue was purified by silica gel column chromatog-

raphy (EtOAc/PE, 0Ǟ10%) to afford 118 (3.70 g, 4.60 mmol,

63%) as a colorless oil. R_f= 0.6 (EtOAc/PE, 1:6). ¹H NMR

(General procedure B in MeOH) produced 121 (655 mg,

0.74 mmol, 73%). R_f= 0.50 (EtOAc/toluene, 1:2). ¹H NMR

(500 MHz, CDCl₃, collapsed iminosugar signals): δ = 7.44–7.16 [m,

21 H, H_ArBn, C(O)NH], 5.85–5.74 (m, 1 H, =CH pentenyl), 4.97

(dd, J = 13.5, 34.2 Hz, 2 H, =CH₂pentenyl), 4.86–3.43 (m, 15 H,

(400 MHz, CDCl₃): δ = 7.68–7.63 (m, 4 H, H_ArTBDPS), 7.42– 4ϫCH₂Bn, 2-H, 3-H, 4-H, 5-H, 6-H, CH₂-7), 3.25 (t, J = 6.6 Hz,

7.11 (m, 26 H, H_ArTBDPS/Bn), 4.69–4.64 (m, 3 H, CHH Bn, CH₂

Bn), 4.58 (d, J = 11.2 Hz, 1 H, CHH Bn), 4.54 (d, J = 11.2 Hz, 1

H, CHH Bn), 4.48–4.43 (m, 3 H, CHH Bn, CH₂Bn), 3.93–3.61

2 H, CH₂-5 pentyl), 3.02–2.87 (m, 4 H, NCH₂-1 pentyl, OCH₂-

Ada), 2.50–2.21 (m, 4 H, 2ϫCH₂pentenyl), 1.95 (s, 3 H, 3ϫCH

Ada), 1.67 (dd, J = 11.9, 32.0 Hz, 6 H, 3ϫCH₂Ada), 1.52 (d, J =

(m, 8 H, CH₂-1, 2-H, 3-H, 4-H, 5-H, CH₂-6), 1.06 (s, 9 H, tBu- 1.9 Hz, 6 H, 3ϫCH₂Ada), 1.43–1.34 (m, 2 H, CH₂pentyl), 1.20–

Si) ppm. ¹³C NMR (100 MHz, CDCl₃): δ = 138.4, 138.3, 138.2, 1.07 (m, 4 H, 2ϫCH₂pentyl) ppm. ¹³C NMR (125 MHz, CDCl₃,

138.0 (4ϫC_qBn), 135.8 (CH_ArTBDPS), 133.4 (C_qSi-Ph), 129.9, collapsed iminosugar signals): δ = 174.5 (NC=O pentenyl), 168.2

129.9, 128.6, 128.5, 128.4, 128.2, 128.0, 127.9, 127.9, 127.8, 127.8,

127.7 (CH_ArBn/TBDPS), 79.5, 78.9, 78.7 (C-2, C-2, C-4), 75.1,

74.5, 73.4, 72.9 (4ϫCH₂Bn), 69.8 (C-6), 63.1 (C-1), 61.9 (C-5),

[NHC(O)-1], 138.3, 137.8, 137.6, 137.2 (4ϫC_qBn), 137.4 (=CH

pentenyl), 128.5, 128.5, 128.5, 128.4, 128.3, 128.0, 127.9, 127.8,

127.7 (CH_ArBn), 115.3 (=CH₂pentenyl), 82.0 (OCH₂-Ada), 73.4,

27.0 (CH₃tBu), 19.3 (C_qtBu) ppm. IR (thin film): ν

= 3031, 73.2, 72.0, 71.5 (CH₂-5 pentyl), 70.9, 68.8 (C-7), 39.8 (CH₂Ada),

˜

max

2926, 2864, 2097, 1495, 1454, 1354, 1209, 1076, 1027, 734,

699 cm^–1. [α]²_D⁰= –4.1 (c = 0.7, CHCl₃). HRMS: calcd. for

[C₅₀H₅₅N₃O₅Si + Na]⁺828.3809 [M + Na]⁺; found 828.3805.

39.4 (NCH₂-1 pentyl), 37.4 (CH₂Ada), 34.2 (C_qAda), 33.2, 29.2,

29.2, 29.1 (2ϫCH₂pentenyl, 2ϫCH₂pentyl), 28.4 (CH Ada), 23.5

(CH -3 pentyl) ppm. IR (thin film): ν_max= 3352, 2902, 2849, 1667,

˜

2

1541, 1454, 1365, 1209, 1090, 909, 731, 697 cm^–1. [α]²_D⁰= 11.1 (c =

3.8, CHCl₃). HRMS: calcd. for [C₅₆H₇₀N₂O₇+ H]⁺883.5256 [M

+ H]⁺; found 883.5263.

5-Azido-2,3,4,6-tetra-O-benzyl-D-glucitol (119): Tetrabutylammo-

nium fluoride (1 M in THF, 4.2 mL, 4.2 mmol) was added to an

anhydrous solution of 118 (2.26 g, 2.8 mmol) in THF (47 mL) and

the resulting reaction mixture was stirred for 20 h. The mixture was

concentrated, redissolved in Et₂O (100 mL), and washed with satd.

aq. NaCl (100 mL). The organic phase was dried (Na₂SO₄) and

concentrated and the resulting residue was purified by silica gel

column chromatography (EtOAc/PE, 9Ǟ25%) to produce 119

(1.17 g, 2.07 mmol, 74%) as a colorless oil. R_f= 0.20 (EtOAc/PE,

1:4). ¹H NMR (600 MHz, CDCl₃): δ = 7.42–7.15 (m, 20 H, H_Ar

Bn), 4.70 (d, J = 11.2 Hz, 1 H, CHH Bn), 4.68–4.61 (m, 3 H, CHH

Bn, CHH Bn), 4.58 (d, J = 11.8 Hz, 1 H, CHH Bn), 4.47 (s, 2 H,

CH₂Bn), 3.86–3.83 (m, 1 H, 4-H), 3.82–3.78 (m, 3 H, 1a-H, 3-H,

5-H), 3.76–3.66 (m, 3 H, 1b-H, 2-H, 6a-H), 3.59 (dd, J = 4.9,

11.7 Hz, 1 H, 6b-H), 3.09–2.72 (m, 1 H, OH-1) ppm. ¹³C NMR

(150 MHz, CDCl₃): δ = 138.0, 138.0, 137.8, 137.6 (4ϫC_qBn),

128.3, 128.3, 128.2, 128.2, 128.2, 127.9, 127.8, 127.7, 127.6, 127.5

(CH_ArBn), 79.1 (C-4), 78.8 (C-3), 78.3 (C-2), 74.8, 74.0, 73.1, 72.6

(4ϫCH₂Bn), 69.4 (C-6), 61.4 (C-5), 61.3 (C-1) ppm. IR (thin film):

1,1,3,3-Tetramethylbutyl

3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-

D-ido-heptonamide (122): Subjecting

(pent-4-enimido)- -glycero-

D

azido aldehyde 120 (1.01 mmol) to the tandem SAWU-3CR (Gene-

ral procedure B in MeOH) produced 122 (625 mg, 0.82 mmol,

81%). R_f= 0.48 (EtOAc/toluene, 1:3). ¹H NMR (400 MHz, CDCl₃,

collapsed iminosugar signals): δ = 7.44–7.22 (m, 20 H, H_ArBn),

7.08 [s, 1 H, C(O)NH], 5.95–5.80 (m, 1 H, =CH pentenyl), 5.04

(dd, J = 13.1, 25.0 Hz, 2 H, =CH₂pentenyl), 4.86–3.53 (m, 15 H,

4ϫCH₂Bn, 2-H, 3-H, 4-H, 5-H, 6-H, CH₂-7), 2.50–2.26 (m, 4 H,

2ϫCH₂pentenyl), 1.88–1.52 (m, 2 H, CH₂-2 tMB), 1.23 (s, 6 H,

2ϫCH₃tMB), 0.92 (s, 9 H, 2ϫCH₃, CH₃-4 tMB) ppm. ¹³C NMR

(100 MHz, CDCl₃, collapsed iminosugar signals): δ = 174.7

(NC=O pentenyl), 167.0 [NHC(O)-1], 138.4, 137.7, 137.6, 137.4

(4ϫC_qBn), 137.4 (=CH pentenyl), 128.5, 128.4, 128.4, 128.3, 128.1,

128.0, 127.9 (CH_ArBn), 115.2 (=CH₂pentenyl), 75.1, 73.7, 73.2,

71.5, 70.6, 68.8, 65.2, 55.3 (NHC_q-1 tMB), 51.3 (CH₂-2 tMB), 33.3

(CH₂pentenyl), 31.5 (CH₃-4, 2ϫCH₃tMB), 29.2 (CH₂pentenyl),

ν

_max= 3031, 2865, 2095, 1495, 1454, 1353, 1353, 1264, 1209, 1094,

˜

29.4, 28.5 (2ϫCH tMB) ppm. IR (thin film): ν

= 3363, 2950,

˜

3

max

1027, 734, 697 cm^–1. [α]²_D⁰= –3.1 (c = 11.5, CHCl₃). HRMS: calcd.

1667, 1531, 1454, 1366, 1208, 1073, 1027, 911, 734, 697 cm^–1.

for [C₃₄H₃₇N₃O₅+ Na]⁺590.2631 [M + Na]⁺; found 590.2621.

[α]²_D⁰= 6.6 (c = 2.8, CHCl₃). HRMS:; calcd. for [C₄₈H₆₀N₂O₆

+

H]⁺761.4524 [M + H]⁺; found 461.4529.

5-Azido-2,3,4,6-tetra-O-benzyl-D-glucose (120): Azido alcohol 119

(1.80 g, 3.2 mmol) was subjected to a Dess–Martin mediated oxi-

dation (General Procedure A) to produce 120 (1.71 g, 3.0 mmol,

96%) as a colorless oil. R_f= 0.60 (EtOAc/PE, 1:4). ¹H NMR

Pentyl 3,4,5,7-Tetra-O-benzyl-2,6-dideoxy-2,6-(pent-4-enimido)-D-

glycero-

D-ido-heptonamide (123): Subjecting azido aldehyde 120

(1.01 mmol) to the tandem SAWU-3CR (General procedure B in

(400 MHz, CDCl₃): δ = 9.75 (s, 1 H, 1-H), 7.40–7.20 (m, 18 H, H_ArMeOH) produced 123 (556 mg, 0.77 mmol, 77%). R_f= 0.45

1

Bn), 7.20–7.14 (m, 2 H, H_ArBn), 4.85 (d, J = 12.0 Hz, 1 H, CHH (EtOAc/toluene, 1:2). H NMR (400 MHz, CDCl₃, collapsed imi-

Bn), 4.64 (d, J = 11.5 Hz, 1 H, CHH Bn), 4.59 (d, J = 11.5 Hz, 1

H, CHH Bn), 4.56–4.47 (m, 4 H, CH₂Bn, CHH Bn, CHH Bn),

4.37 (d, J = 10.9 Hz, 1 H, CHH Bn), 4.02 (dd, J = 2.9, 5.8 Hz, 1

nosugar signals): δ = 7.45–7.16 [m, 21 H, H_ArBn, C(O)NH], 5.90–

5.71 (m, 1 H, =CH pentenyl), 4.97 (dd, J = 13.6, 28.1 Hz, 2 H,

=CH₂pentenyl), 4.87–3.29 (m, 15 H, 4ϫCH₂Bn, 2-H, 3-H, 4-H,

H, 3-H), 3.89 (d, J = 5.9 Hz, 1 H, 2-H), 3.86–3.78 (m, 2 H, 4-H, 5-H, 6-H, CH₂-7), 3.08–2.87 (m, 2 H, NCH₂-1 pentyl), 2.56–2.20

6a-H), 3.75–3.67 (m, 2 H, 5-H, 6b-H) ppm. ¹³C NMR (100 MHz,

(m, 4 H, 2ϫCH₂pentenyl), 1.24–0.97 (m, 6 H, 3ϫCH₂pentyl),

CDCl₃): δ = 200.2 (CH-1), 137.7, 137.5, 137.4, 137.3 (4ϫC_qBn), 0.79 (t, J = 7.1 Hz, 3 H, CH₃pentyl) ppm. ¹³C NMR (100 MHz,

128.8, 128.7, 128.7, 128.6, 128.5, 128.4, 128.3, 128.3, 128.0, 128.0, CDCl₃, collapsed iminosugar signals): δ = 174.5 (NC=O pentenyl),

127.9 (CH_ArBn), 80.0 (C-2), 79.9 (C-3), 76.7 (C-4), 74.3, 74.0, 73.6, 168.2 [NHC(O)-1], 138.3, 137.7, 137.6, 137.1 (4ϫC_qBn), 137.4

73.3 (4ϫCH Bn), 69.5 (C-6), 60.8 (C-5) ppm. IR (thin film): ν

(=CH pentenyl), 128.5, 128.4, 128.4, 128.2, 128.0, 128.0, 127.9,

127.7, 127.6 (CH_ArBn), 115.3 (=CH₂pentenyl), 77.7, 76.0, 73.4,

73.2, 71.9, 70.9, 68.8 (C-7), 39.4 (NCH₂-1 pentyl), 33.1 [NC(O)CH₂

pentenyl], 29.1, 29.0, 28.9, 22.3 (CH₂pentenyl, 3ϫCH₂pentyl),

˜

2

max

= 3064, 3032, 2865, 2096, 1727, 1496, 1454, 1328, 1265, 1211, 1072,

1027, 734, 697 cm^–1. [α]²_D⁰= 3.8 (c = 10.2, CHCl₃). HRMS: calcd.

for [C₃₄H₃₅N₃O₅+ Na]⁺588.2474 [M + Na]⁺; found 588.2466.

Eur. J. Org. Chem. 2012, 6420–6454

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6449

Article Doi

The development of an aza-C-glycoside library based on a tandem staudinger/aza-wittig/ugi three-component reaction

DOI: 10.1002/ejoc.201200923

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Article abstract of DOI:10.1002/ejoc.201200923

Full text of DOI:10.1002/ejoc.201200923

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