CC BY ND NC 4.0 · SynOpen 2017; 01(01): 0029-0040
DOI: 10.1055/s-0036-1588859
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Copyright with the author

Investigations towards the Synthesis of 5-Amino-l-lyxofuranosides and 4-Amino-lyxopyranosides and NMR Analysis

Alba Diez-Martinez*, Ramanarayanan Krishnamurthy*
This work was supported jointly by the NSF Center for Chemical Evolution, Grant CHE-1504217.
Further Information

Publication History

Received: 02 April 2017

Accepted after revision: 12 May 2017

Publication Date:
01 June 2017 (online)

 

Abstract

The reactivity of trifluoromethanesulfonyl esters derived from l-lyxofuranosides and l-lyxopyranosides was investigated with various 5-aminopyrimidines as nucleophiles with the expectation to synthesize N-substituted 5-amino-ribosugars. The lyxopyranoside forms were found to be unreactive, while the lyxofuranoside forms were found to be reactive with 5-aminopyrimidines, yielding novel N-substituted 5-amino-lyxofuranosides. We report on the synthesis of these novel N-substituted lyxofuranosides and the systematic analyses of NMR data that demonstrate trends within each series: furano-, pyrano-, β- and α- anomers of l-lyxose and β-d-ribopyranoside forms. The data call for caution when identifying these monosaccharides in isomeric mixtures.


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In our research exploring the self-assembly properties of alternative recognition elements such as 5-aminouracil and 2,4,5-triaminopyrimidine substituted-pyrrolidines, it was necessary to develop new N-substituted 4-amino-d-ribofuranose sugars.[1] [2] [3] We proposed the corresponding l-lyxopyranose derivatives as outlined in Scheme [1] as intermediates en route to the final pyrrolidine compounds. This synthetic approach is based on the fact that nucleophiles can attack the C(4) position of a substituted lyxopyranose sugar (with a good leaving group at the C(4)-position) through a bimolecular nucleophilic substitution (SN2) displacement, resulting in the corresponding ribopyranose framework.[4] [5] [6] [7] However, the synthesis of N-substituted 4-amino-d-ribopyranose derivatives proved problematic with amino pyrimidine heterocycles, presumably due to the poor nucleophilicity of these alternative amino nucleobases.

Zoom Image
Scheme 1 Proposed retrosynthetic route for the d-azaribofuranose and l-lyxofuranoside-attached heterocycles (R. E. = recognition elements) starting from l-lyxose

For comparison, we also studied the SN2 reaction with the l-lyxofuranosyl series with the awareness that 5-amino-heterocycles may react more readily at a primary carbon. When comparing the results of the l-lyxopyranose and l-lyxofuranose series, we found that there could be some uncertainty in the assignments as α/β anomeric mixtures of alcohols derived from l-lyxose when they are actually furanoside/pyranoside mixtures.[8] To clarify this issue, we have synthesized, measured NMR spectra and contrasted the chemical shift trends of the furanosyl and pyranosyl l-lyxose series – both from this work and those in the literature – and came to the conclusion that identifying the minor compound in isomeric mixtures of monosaccharides can be crucial and should always rely on accurate identification based on corroborating NMR techniques.

The starting lyxofuranosides 13 were obtained in a one-pot reaction, in which protection of the anomeric position and formation of the acetal were accomplished by heating the starting l-lyxose in the presence of acetone and the appropriate alcohol in acidic medium for short periods of time. Characterization of small amounts of impurities that co-eluted with the desired products showed discrepancies with the results described earlier.[8] Instead of mixtures of anomers, we identified trace amounts of pyranose products 57. In our hands, we could not find mixtures of anomers in any of the cases. The synthesis of starting materials in the l-lyxopyranose series was accomplished by following existing procedures (Scheme [2]).[5] [6] [7] , [9] [10] [11] [12] l-Lyxopyranosides 57 were prepared in a stepwise fashion. First, protection of the anomeric position by a regular Fischer glycosidation was conducted with corresponding anhydrous alcohol in the presence of an acid. The reaction produced, what we originally thought to be, anomeric mixtures of 4ac. The ketal protection of these mixtures led to the pyranosyl compounds 57 (Scheme [2]) and small amounts of the corresponding isomers. We had assumed 5 could be mixed with its anomer to a small amount and this was not considered problematic because both anomers would lead to the desired pyrrolidine scaffolds as formulated in Scheme [1]. In fact, it turned out to be a mixture of furanose and pyranose forms, which was difficult to purify. Detailed analysis by NMR (see Figure S.54 in the Supporting Information) showed that alcohols 5 and 6 indeed contained small amounts of furanose forms (1 and 2, respectively), instead of mixtures of (misassigned) anomers.[8] It is noticeable that the chemical shifts of both isomer protons (5 and 1) are quite different; for example, 0.5 ppm in CDCl3 between both isomers for the anomeric protons (see Table [2]), which may have suggested they actually were more different than simply anomers. NOESY NMR spectroscopic analysis of the pure starting materials (13 and 57) showed that the major anomer is β for l-lyxofuranosyl and α for l-lyxopyranosyl alcohols (see also Supporting Information).

Zoom Image
Scheme 2 Synthesis of the ketal-protected β-furanosides and α-pyranosides of l-lyxose. Reagents and conditions: (a) Acetone, ROH, H2SO4, 60 °C, 4 h (1: 72% and 5: <5%; 2: 48% and 6: <5%; 3: 37% and 7:<5%); (b) ROH, reflux, H+, 3 h; (c) HCl, acetone, DMP, r.t., 16 h (yields after two steps: 5: 36% and 1: <20%; 6: 41% and 2: <10%; 7: 30% and 3: <5%).

To access the sugars tagged with different alternative recognition elements, the corresponding 5-position of the furanosides and 4-position of the pyranosides were modified with good leaving groups that facilitated the attack of different nucleophiles through SN2 mechanism. In the case of the α-l-lyxopyranose series, inversion of configuration at C(4) generates the β-d-ribopyranose sugar. Four different nucleophiles were selected for this study (Figure [1]). Sodium azide 8 was chosen based on the fact that it would lead to a precursor of the corresponding amino compound.[4] [13] This approach could allow for a later introduction of heterocycles via nucleophilic aromatic substitution. Along with the heterocycles 5-aminouracil 10 and 2,4,5-triaminopyridine 11, benzyl amine 9 was also utilized for comparison.

Zoom Image
Figure 1 Nucleophiles utilized for the SN2 reactions with l-lyxose derivatives

The trifluoromethane sulfonate esters of alcohols (at (C)4 position for the pyranose and (C)5 position for the furanose series) were generated with trifluoromethanesulfonic anhydride in the presence of DMAP and pyridine at –20 °C.[6] [7] Reactions were quenched by aqueous work-up upon consumption of starting material. The subsequent SN2 reaction was conducted on the crude triflate intermediates 1t3t and 5t7t (no purification was attempted due to their instability). The corresponding mesylate leaving groups were not used because they did not react even with sodium azide; whereas the triflate intermediates promptly reacted with the latter nucleophile (Scheme [3] and Table [1], entries 1 and 2). Reaction of the triflate of 1 with 10 over three days at room temperature led to poor yields (entry 3). The use of 3.0 equivalents of heterocycles 10 and 11 and higher temperature (probably increasing the solubility of the heterocycles and the speed of the reaction) led to higher product yields. The use of N,O-bis(trimethylsilyl)acetamide (BSA) increased the solubility of 5-aminouracil 10 and resulted in further improvement of product yields (entry 5), but did not help in the case of 11 (entry 7).

Zoom Image
Scheme 3 Generation of the trifluoromethanosulfonyl esters of l-lyxose and subsequent SN2 reaction with nucleophiles 811. Reagents and conditions: (a) Tf2O, DMAP, CH2Cl2, Py, –20 °C to r.t., 4 h; (b) 811, DMF, different conditions: see Table [1].

Table 1 Reaction Conditions and Products Obtained from the SN2 Reaction Outlined in Scheme [3]

Entry

Alcohol

Nucleophile

Conditions

Product

Overall yield (%)a

1

1

8

r.t., 4 h

12a

75

2

5 b

8

r.t.,4 h

15a c

68

3

1

10

r.t., 3d

12c

<5

4

1

10

70 °C, 48 h

12c

9

5

1

10

BSA, 70 °C, 48 h

12c

47

6

1

11

70 °C, 48 h

12d

56

7

1

11

BSA, 70 °C, 48 h

12d

33

8

2

10

BSA, 70 °C, 48 h

13c

45

9

2

11

70 °C, 48 h

13d

48

10

3

11

70 °C, 48 h

14d

26

11

5 b

10

BSA, 70 °C, 48 h

12c

5

12

5

10

BSA, 70 °C, 48 h

15c

13

5 b

11

70 °C, 48 h

12d

5

14

5

11

70 °C, 48 h

15d

15

5

9

70 °C, 24 h

15b

63

16

6

10

BSA, 70 °C, 48 h

16c

17

6

11

70 °C, 48 h

16d

aYields determined after isolation and purification by column chromatography; ‘–’ indicates no reaction.

b Starting material 5 was utilized as a mixture of isomers (mixed with 1).

c By-product 12a was isolated (ca. 5%) by column chromatography.

Reactions of triflates with different nucleophiles at 70 °C for up to two days generated by-products resulting from the hydrolysis or decomposition of the starting materials. In the β-l-lyxofuranose series, 2,4,5-triaminopyrimidine 11 produced higher yields than 5-aminouracil 10 when reacting with the 1t3t triflates, perhaps reflecting the higher nucleophilicity of the 5-NH2 group in 11. For comparison, 5-aminolyxofuranose 18 was synthesized by hydrogenation of azide 12a (see Scheme [5]).

Analyses of the NMR spectra of amines 12cd, 13cd and 14d, obtained through SN2 reaction with the corresponding trifluoromethanesulfonates, showed similar features when compared with the corresponding alcohols 13, respectively (Table [2]) and with amine 18. As expected, the electronic nature of the substituents affected the 1H and 13C NMR shift values; that is, substitution of the hydroxy at C(5) with an amino group produced an upfield shift of 20 ppm in the 13C NMR spectra and up to 0.6 ppm in the 1H NMR spectra (Table [2] and Table [3], entries 1 and 5). NOESY NMR spectra of the products of the SN2 reaction confirmed the β-l-lyxofuranosyl form of the compounds. Figure [2] illustrates the NMR spectrum of compound 12c. Nuclear Overhauser effect (nOe) correlations between the proton at the anomeric position with protons at the C(2) and C(4) positions confirmed the expected β-form, in agreement with the starting materials and the anomeric effect. This was consistent with the NOESY spectra of the alcohol starting materials.

Table 2 1H and 13C NMR Chemical Shift Values [δ, ppm] of Monosaccharides in DMSO-d 6

Entry

Product

Ringa

R

X

H-1

H-2

H-3

H-4

H-5

C-1

C-2

C-3

C-4

C-5

1

1

Lf

Me

OH

4.81

4.49

4.70

3.85

3.51, 3.64

106.3

84.3

79.1

80.6

58.9

2

2

Lf

Allyl

OH

4.95

4.53

4.72

3.90

3.55, 3.64

104.8

84.4

79.1

80.7

58.9

3

3

Lf

Bn

OH

5.01

4.58

4.76

3.98

3.59, 3.68

104.7

84.4

79.1

80.8

58.9

4

19 b

Lf

H

OH

5.10

4.42

4.68

4.00

3.50, 3.62

100.0

85.6

79.5

80.0

59.2

5

18

Lf

Me

NH2

4.92

4.57

4.79

4.10

2.92, 3.15

106.2

85.4

79.1

75.8

38.0

6

12c

Lf

Me

NH-Uc

4.83

4.51

4.73

4.01

3.03, 3.17

106.3

84.4

79.5

77.8

42.8

7

12d

Lf

Me

NH-Pyd

4.86

4.55

4.79

4.03

3.08, 3.22

106.4

84.4

79.3

77.4

42.7

8

13c

Lf

Allyl

NH-Uc

4.98

4.57

4.76

4.05

3.01, 3.21

104.8

84.6

79.5

77.8

42.8

9

13d

Lf

Allyl

NH-Pyd

4.98

4.58

4.81

4.04

3.03, 3.16

104.6

84.3

79.3

77.9

43.4

10

14d

Lp

Benzyl

NH-Pyd

5.05

4.63

4.83

4.12

3.08, 3.22

105.2

84.9

79.8

77.8

43.0

11

5

Lp

Me

OH

4.59

3.95

3.95

3.58

3.38, 3.45

99.5

77.0e

74.5e

66.5

62.0

a Lf = β-l-lyxofuranoside; Lp = α-l-lyxopyranoside.

b For comparison, compound 19 was made by hydrogenolysis of 3 (see Scheme [5]).

c U = 5-uracil.

d Py = 5-(2,4-diamino)pyrimidine.

e Assignments may be interchanged.

Table 3 1H and 13C NMR Chemical Shift Values [δ, ppm] of Monosaccharides in CDCl3

Entry

Product

Ringa

R

X

H-1

H-2

H-3

H-4

H-5

C-1

C-2

C-3

C-4

C-5

1

1

Lf

Me

OH

4.92

4.56

4.76

4.03

3.90, 3.95

107.2

85.3

80.4

79.4

61.2

2

2

Lf

Allyl

OH

5.02

4.57

4.72

4.03

3.81, 3.87

105.1

85.0

80.0

79.4

60.7

3

3

Lf

Bn

OH

5.15

4.71

4.81

4.13

3.94, 4.00

105.2

85.3

80.5

79.3

61.5

4

12a

Lf

Me

N3

4.91

4.57

4.70

4.08

3.50, 3.57

106.2

84.0

78.6

77.3

48.7

5

18

Lf

Me

NH2

4.89

4.56

4.72

3.94

3.04, 3.04

107.1

85.2

80.7

80.1

40.9

6

5

Lp

Me

OH

4.64

4.12

4.23

3.81

3.71, 3.82

99.9

74.4

76.2

67.3

63.3

7

6

Lp

Allyl

OH

4.76

4.14

4.20

3.81

3.67, 3.75

97.8

74.5

76.6

67.4

62.9

8

7

Lp

Bn

OH

4.84

4.18

4.24

3.81

3.73, 3.81

97.3

74.5

76.5

67.3

62.8

9

15a

Rp

Me

N3

4.47

4.00

4.50

3.81

3.71, 3.81

100.9

75.3

72.9

54.9

60.2

10

20

Rp

Me

NH2

4.37

3.94

4.34

3.21

3.71, 3.43

101.9

75.7

75.4

49.9

65.1

11

15b

Rp

Me

NHBn

4.33

3.90

4.46

3.15

3.40, 3.85

102.4

75.8

72.9

52.1

63.5

12

21

Rp

Me

NHCHO

4.42

4.03

4.35

4.61

3.44, 3.82

100.1

75.1

72.5

43.0

61.0

13

22

Rp

Me

NHBz

4.47

4.09

4.47

4.76

3.51, 3.97

101.2

75.4

73.0

44.8

61.4

a Lf = β-l-lyxofuranoside; Lp = α-l-lyxopyranoside; Rp = β-d-ribopyranoside.

In the α-l-lyxopyranosyl series, only NaN3 and BnNH2 (Table [1], entries 2 and 15) were successful in reacting with triflate 5t, resulting in inversion of configuration at the C(4) position by nucleophilic substitution giving d-ribopyranose derivatives 15a and 15b, respectively. When reactions were run with heterocycles 10 and 11, degradation of triflate 5t was mostly observed, with only very small amounts of the substituted products being isolated; this reflects the poor nucleophilicity of heterocycles 10 and 11. Analysis of the resulting compounds revealed that the reaction products (expected 15c and 15d) had the β-l-lyxofuranose form instead of the anticipated β-d-ribopyranose form. NMR comparisons with prepared furanoses showed that these reaction products were the same as 12c and 12d. Both pyranose and furanose triflates reacted with good nucleophiles such as azide 8 and benzylamine 9 (Scheme [4]) in SN2 reactions. Therefore, in these cases, while the isolated major product was the pyranosyl derivative, a minor (furanosyl) product was isolated in small yields or, in some cases, ‘lost’ during the purification procedures. However, regarding the reaction of pyrimidines 10 and 11 with 5t (mixed with its isomer), it seemed that the minor compound (the furanose form, 1t) is the only isomer able to react with poor nucleophiles (Table [1], entries 11 and 13), whereas the pyranose form 5t is not reactive with 10 and 11. When SN2 reactions were repeated starting with pure pyranoses 57 and nu­cleophiles 10 and 11, the expected ribopyranoses 15c/d, 16c/d, and 17c/d were not formed (Table [1], entries 12, 14, 16–19), confirming our previous results that only the furanose forms undergo reaction.

Zoom Image
Figure 2 HMBC (1H–13C, CDCl3) spectra of the alcohols 1 and 5. Correlations highlighted with a dashed circle corroborate unambiguously the configuration of the furanose and pyranose forms, respectively
Zoom Image
Scheme 4 Reaction scheme for the mixture of isomers of 5 and subsequent SN2 reactions with nucleophiles

We attempted an alternative synthesis of 15c as depicted in Scheme [5]. It is known that 5-bromouracil can act as an electrophile and be attacked by amines under different reaction conditions (heat without solvent,[14] [15] [16] reflux,[16–18] or microwave[19]). Therefore, we prepared aminosugar 20 and reacted it with 5-bromouracil. Unfortunately, this ‘inverse approach’ in DMF did not generate the expected compound (15c), but rather led to the N-formylated sugar derivative 21. We did not explore this pathway further, but suspect that the 5-bromouracil assisted in the formylation process. Heterocycle-assisted N-formylation reactions under mild conditions have been described utilizing imidazole with primary amines.[20] Full characterization of 21 revealed the NMR trends to be consistent with the rest of the β-d-ribopyranose compounds and was comparable to compound 22 prepared via a different route.

Zoom Image
Scheme 5 Generation of the amines 18 and 20 for the ‘inverse approach’ in which the sugar acts as the nucleophile with a leaving group on the heterocycle. Attempted synthesis of 15c. Synthesis of 19 and 22 are shown for comparison. Reagents and conditions: (a) H2, Pd/C (5%), MeOH, r.t., 6 h (18: 95%; 20: 95%); (b) H2, Pd(OH)2, MeOH, r.t., 20 h (98%); (c) 5-bromouracil, DMF, 70 °C, 16 h (21: 56% and 15c: not found); (d) BzCl, DIPEA, CH2Cl2, r.t., 16 h (82%).

To address the question of dealing with mixtures of anomers versus mixtures of furanoses and pyranoses,[8] we scrutinized the 1H and 13C NMR data of our compounds to find trends in chemical shifts, supported by other NMR spectroscopic techniques that would prove useful in assigning the structures. Table [2] and Table [3] summarize the full characterization of the sugar derivatives that we have obtained, documenting trends within and between the furanose and pyranose series. Extensive NMR measurements were conducted using the same deuterated solvent (DMSO-d 6) system both for the already published products and related compounds originally reported in CDCl3 (Table [2]), and for the heterocycle-attached furanose compounds, which are insoluble in CDCl3 (Table [3]). Analyses were carried out by HSQC and COSY NMR spectroscopy of all the structures, in addition to NOESY spectroscopy to confirm the configuration of the pyrano or furano rings and the configuration in the anomeric position (see Figure [3] and the Supporting Information); HMBC spectroscopy was used to corroborate the configuration of the rings (see Figure [2] and the Supporting Information) of some of the starting materials and several products.

Zoom Image
Figure 3 NOESY (1H-1H, DMSO-d 6) spectrum that corroborates the β-configuration of 12c

In general, the trends in chemical shift for pyranosides versus furanosides (within a sugar series) are consistent, and independent of solvent and substituents in the anomeric position. For example, in 1H NMR spectra for the lyxo series, all shifts except for the C(5)H2, are more downfield (ca. 0.5–0.3ppm) in the furanose form when compared with the pyranose form. The same trend is observed in the 13C NMR (12–4 ppm) for both the lyxo and the ribo series, as documented in Table [2] (entries 1–3 and entries 11 and 12) and Table [3] (entries 1–3 and entries 6 and 7).

There is also a consistent trend for the different anomers within a given series. The signals for the anomeric position for β-l-lyxofuranosyl compounds appear around 4.8–5.0 ppm in 1H NMR spectra and 104–107 ppm in 13C NMR spectra; whereas the corresponding values for the α-l-lyxopyranosyl forms are consistently more upfield: around 4.6–4.8 ppm in the 1H NMR spectra and below 100 ppm in the 13C NMR spectra (Table [2], entries 1–8; Table [3]). The substitution of the hydroxyl in the C(5) position by an amine in the furanose series up-shifted the CH2-signal by 20 ppm in the 13C NMR spectra and by around 0.6 ppm in the 1H NMR spectra (Table [2], entries 1–4 versus 5–10). In the ribopyranose series, substitution in position C(4) affected the chemical shift values of position C(4) and C(5) depending on the nature of the substituent, as evidenced in Table [3], entries 10 vs. 12 and 13 and entries 10 vs. 11, respectively.

Thus, caution must be exercised to determine whether the compounds are mixtures of furanose/pyranose (in the ribo- or lyxo-series) versus mixtures of anomers (in the ­ribo- and lyxo-series).[8] Further NMR spectroscopic (e.g., HMBC and NOESY) studies need to be performed to confirm the α- or β- versus furanose- or pyranose-configuration of the sugars at hand.

In conclusion, in our attempts to synthesize N-substituted 5-amino-lyxopyranose derivatives, we have demonstrated that only the 5-O-trifluoromethanosulfonate l-lyxofuranoside derivative reacts with 5-aminouracil and 2,4,5-triaminopyrimidine as nucleophiles; SN2 reactions with 4-O-triflate l-lyxopyranoside derivatives with these heterocyclic nucleophiles were unsuccessful. A detailed NMR spectroscopic characterization of both the starting materials and products enabled us to identify trends in chemical shifts for the corresponding lyxosides and ribosides (in the pyrano and furano series versus the α- and β-anomers). Identifying trends on chemical shifts within each series and also exceptions between them, will be of utility in future investigations. These exceptions point out the potential pitfalls in attempting to recognize mixtures of anomers versus mixtures of furanosides/pyranosides based on trends in chemical shifts alone.

All reagents were obtained from commercial sources and used without purification. Anhydrous solvents were purchased from EMD Chemicals. All experiments were performed under a nitrogen or argon atmosphere. Thin-layer chromatography (TLC) was performed on silica gel 60 Å F254 from Angela Technologies, and visualized under a UV lamp and/or by staining with a solution of phosphomolybdic acid (PMA) in ethanol. Flash column chromatography was performed on silica gel 60 Å with particle size 35–70 μm purchased from Acros Organics. NMR spectra were recorded at 20 °C with a Bruker DRX-600, AV-600 (600 MHz for 1H and 150 MHz for 13C) or an AV-400 (400 MHz for 1H and 100 MHz for 13C). Chemical shifts (δ) are given in parts per million (ppm). 1H and 13C chemical shifts in CDCl3 were referenced to chloroform at δ = 7.26 and 77.16 ppm, respectively. 1H and 13C chemical shifts in DMSO-d 6 were referenced to dimethyl sulfoxide at δ = 2.50 and 39.52 ppm, respectively. NMR peak assignments were made based on COSY, HSQC and/or NOESY 2D experiments. Mass spectra were measured with an Agilent ESI-TOF or a ThermoElectron Finnigan LTQ ion trap mass spectrometer.


#

Synthesis of the Protected Furanoside Sugars

The protection of the furanose sugars was developed by following the same procedure described by Coleman et al.[21] l-Lyxose (1.20 g, 8.00 mmol, 1 equiv) was dissolved in the corresponding freshly distilled alcohol (10 equiv) and anhydrous acetone (4.70 mL, 48.0 mmol, 8 equiv). The flask was immersed in an ice bath and concentrated sulfuric acid (3–4 Pasteur pipette drops) was added dropwise. The mixture was stirred at reflux until disappearance of the starting material, as monitored by TLC (3–5 h, depending on the alcohol). The reaction was quenched with saturated aq. NaHCO3 solution and the aqueous solution was extracted three times with EtOAc. The combined organic layers were dried with anhydrous Na2SO4, filtered and evaporated to dryness. Analysis of the crude material by 1H NMR spectroscopy showed mixtures of furanose and pyranose products up to 1:0.10 ratio (depending on the reaction). The crude reaction mixture was subjected to column chromatography to afford the corresponding protected lyxofuranoside. Traces (>5%) of the corresponding 2,3-O-isopropylidene-α-l-lyxopiranoside were found in the crude material in all cases.


#

Methyl 2,3-O-Isopropylidene-β-L-lyxofuranoside (1)[22]

Yield: 1.17 g (72%); oil; Rf (hexanes/EtOAc, 8:2) = 0.18.

1H NMR (400 MHz, CDCl3): δ = 4.92 (s, 1 H, H-1), 4.74–4.78 (m, 1 H, H-3),1.29 (s, 3 H, CCH 3), 4.56 (d, J = 5.9 Hz, 1 H, H-2), 4.01–4.06 (m, 1 H, H-4), 3.87–3.97 (m, 2 H, H-5a, H-5b), 3.32 (s, 3 H, OCH 3), 2.42 (br s, 1 H, OH), 1.45 (s, 3 H, CCH 3).

13C NMR (100 MHz, CDCl3): δ = 112.8 (C(CH3)2), 107.2 (C-1), 80.4 (C-3), 85.3 (C-2), 79.4 (C-4), 61.2 (C-5), 54.8 (OCH3), 26.0 (CCH3), 24.7 (CCH3).

1H NMR (600 MHz, DMSO-d 6): δ = 4.81 (s, 1 H, H-1), 4.68–4.75 (m, 2 H, H-3, OH), 4.49 (d, J = 5.9 Hz, 1 H, H-2), 3.85 (dd, J = 9.6, 5.9 Hz, 1 H, H-4), 3.61–3.67 (m, 1 H, H-5b), 3.51–3.57 (m, 1 H, H-5a), 3.22 (s, 3 H, OCH 3), 1.34 (s, 3 H, CCH 3), 1.24 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 111.4 (C(CH3)2), 106.3 (C-1), 84.3 (C-2), 80.6 (C-4), 79.1 (C-3), 58.9 (C-5), 53.9 (OCH3), 26.0 (CCH3), 24.7 (CCH3).

ESI(+)-MS: m/z calcd. for C9H17O5 [M + H]+: 205.11; found: 205.11.

Data in agreement with the literature[22] (ent-1).


#

Allyl 2,3-O-Isopropylidene-β-l-lyxofuranoside (2)[8]

Yield: 884 mg (48%); oil; Rf (hexanes/EtOAc, 8:2) = 0.25.

1H NMR (600 MHz, CDCl3): δ = 5.81 (dddd, J = 17.5, 10.4, 6.4, 5.5 Hz, 1 H, CH=CH2), 5.21 (d, J = 17.2 Hz, 1 H, CH=CH 2-trans), 5.12 (d, J = 10.4 Hz, 1 H, CH=CH 2-cis), 5.02 (s, 1 H, H-1), 4.72 (dd, J = 5.7, 4.3 Hz, 1 H, H-3), 4.57 (d, J = 5.7 Hz, 1 H, H-2), 4.09 (dd, J = 12.3, 5.5 Hz, 1 H, OCHHCH=CH2), 4.03 (dd, J = 9.4, 5.1 Hz, 1 H, H-4), 3.90 (dd, J = 12.3, 6.4 Hz, 1 H, OCHHCH=CH2), 3.81–3.87 (m, 2 H, H-5a, H-5b), 2.75 (br. s, 1 H, OH), 1.39 (s, 3 H, CCH 3), 1.24 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 133.7 (CH=CH2), 117.4 (CH=CH2), 112.5 (C(CH3)2), 105.1 (C-1), 85.0 (C-2), 80.0 (C-3), 79.5 (C-4), 67.7 (OCH2CH=CH2), 60.7 (C-5), 25.7 (CCH3), 24.4 (CCH3).

1H NMR (600 MHz, DMSO-d 6): δ = 5.89 (dddd, J = 16.2, 10.8, 5.9, 5.0 Hz, 1 H, CH=CH2), 5.25 (dd, J = 17.3, 1.7 Hz, 1 H, CH=CH 2-trans), 5.12 (dd, J = 10.4, 1.6 Hz, 1 H, CH=CH 2-cis), 4.95 (s, 1 H, H-1), 4.70–4.75 (m, 2 H, H-3, OH), 4.53 (d, J = 5.5 Hz, 1 H, H-2), 4.09 (dd, J = 13.3, 5.0 Hz, 1 H, OCHHCH=CH2), 3.94 (dd, J = 13.3, 5.9 Hz, 1 H, OCHHCH=CH2), 3.88–3.92 (m, 1 H, H-4), 3.64 (dt, J = 11.2, 5.6 Hz, 1 H, H-5b), 3.51–3.57 (m, 1 H, H-5a), 1.34 (s, 3 H, CCH 3), 1.24 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 134.6 (CH=CH2), 116.7 (CH=CH2), 111.4 (C(CH3)2), 104.8 (C-1), 84.4 (C-2), 80.7 (C-4), 79.1 (C-3), 67.1 (OCH2CH=CH2), 58.9 (C-5), 26.0 (CCH3), 24.7 (CCH3).

ESI(+)-MS: m/z calcd. for C11H19O5 [M + H]+: 231.12; found: 231.12.

ESI(+)-MS: m/z calcd. for C11H18NaO5 [M + Na]+: 253.10; found: 253.10.

Data in agreement with the literature.[8]


#

Benzyl 2,3-O-Isopropylidene-β-l-lyxofuranoside (3)[23]

Yield: 828 mg (37%); yellow oil; Rf (hexanes/EtOAc, 9:1) = 0.10.

1H NMR (600 MHz, CDCl3): δ = 7.28–7.37 (m, 5 H, H-Bn), 5.15 (s, 1 H, H-1), 4.81 (dd, J = 5.6, 3.8 Hz, 1 H, H-3), 4.66–4.71 (m, 2 H, CHHPh, H-2), 4.50 (d, J = 11.7 Hz, 1 H, CHHPh), 4.11–4.15 (m, 1 H, H-4), 4.00 (dd, J = 11.5, 4.9 Hz, 1 H, H-5b), 3.94 (dd, J = 11.7, 4.5 Hz, 1 H, H-5a), 1.82 (br. s, 1 H, OH), 1.47 (s, 3 H, CCH 3), 1.31 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 137.2 (C-Bn), 128.5 (C-Bn), 128.1 (C-Bn), 127.9 (C-Bn), 112.7 (C(CH3)2), 105.2 (C-1), 85.3 (C-2), 80.5 (C-3), 79.3 (C-4), 69.0 (OCH2Ph), 61.5 (C-5), 25.8 (CCH3), 24.4 (CCH3).

1H NMR (600 MHz, DMSO-d 6): δ = 7.28–7.39 (m, 5 H, H-Bn), 5.01 (s, 1 H, H-1), 4.76 (dd, J = 5.9, 5.0 Hz, 1 H, H-3), 4.76 (br. s, 1 H, OH), 4.62 (d, J = 11.9 Hz, 1 H, CHHPh), 4.58 (d, J = 5.9 Hz, 1 H, H-2), 4.46 (d, J = 11.9 Hz, 1 H, CHHPh), 3.98 (dd, J = 9.3, 5.8 Hz, 1 H, H-4), 3.68 (dt, J = 11.2, 5.6 Hz, 1 H, H-5b), 3.56–3.62 (m, 1 H, H-5a), 1.35 (s, 3 H, CCH 3), 1.25 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 137.6 (C-Bn), 128.3 (C-Bn), 127.8 (C-Bn), 127.6 (C-Bn), 111.4 (C(CH3)2), 104.7 (C-1), 84.4 (C-2), 80.8 (C-4), 79.1 (C-3), 67.9 (OCH2Ph), 58.9 (C-5), 26.0 (CCH3), 24.6 (CCH3),

ESI(+)-MS: m/z calcd. for C15H21O5 [M + H]+: 281.33; found: 281.33.

Data in agreement with the literature[23] (ent-3).


#

Methyl α-l-Lyxopyranoside (4a)[4] [6] [7]

To a methanolic HCl solution (0.5 % w/v), prepared in situ by the reaction of acetyl chloride (0.1 mL, 0.7 mmol) in anhydrous MeOH (7.5 mL), was added l-lyxose (1.5 g, 10 mmol, 1.0 equiv) under an argon atmosphere. The resulting suspension was heated under reflux for 4 h until disappearance of l-lyxose. The cooled solution was neutralized with Amberlist® basic resin IRA 400 (2 g) with stirring. The resin was filtered and washed several times with MeOH. The filtrate and washings were combined and evaporated to give a colorless syrup, which was recrystallized in EtOAc to afford a mixture of isomers where the major compound was 4a.

Yield: 1.64 g (70%); white amorphous solid; Rf (CH2Cl2/MeOH, 9:1) = 0.15.

1H NMR (400 MHz, DMSO-d 6): δ = 4.76–4.81 (m, 2 H, 2 × OH), 4.65 (d, J = 5.5 Hz, 1 H, OH), 4.39–4.44 (m, 1 H, H-1), 3.55–3.61 (m, 3 H, C-2, C-4, OH), 3.36–3.50 (m, 2 H, H-3, H-5b), 3.25 (s, 3 H, OCH 3), 3.22–3.27 (m, 1 H, H-5a).

13C NMR (100 MHz, DMSO-d 6): δ = 101.7 (C-1), 71.3 (C-3), 69.8 (C-2), 66.9 (C-4), 63.1 (C-5), 54.7 (OCH3).

Data in agreement with the literature.[4] [6] [7]


#

Synthesis of the Protected Pyranose Sugars 4b and 4c

l-Lyxose (1.5 g, 10 mmol, 1 equiv) was dissolved in the corresponding freshly distilled alcohol (allyl or benzyl alcohol, 100 mmol, 10 equiv). The solution was immersed in an ice bath and H2SO4 (6.1 mol%) was added dropwise. The solution was warmed to r.t., heated to reflux for 3 h and stirred overnight at r.t. Reaction progress was monitored by TLC (90:10, CH2Cl2/MeOH) and the reaction was quenched with Amberlyst A-26(OH) resin (2 g). The mixture was shaken for 30 min, filtered, and the resin was washed with MeOH. The combined filtrate and washings was evaporated and the residue was washed several times with diethyl ether (30 mL each) to remove the excess alcohol. The residue was subjected to column chromatography (CH2Cl2/MeOH, 9:1 and hexanes/EtOAc, 2:8, respectively) to afford products 4b and 4c, respectively.


#

Allyl α-l-Lyxopyranoside (4b)[10]

Yield: 1.34 g (71%); white amorphous solid; Rf (CH2Cl2/MeOH, 9:1) = 0.40.

1H NMR (600 MHz, DMSO-d 6): δ = 5.88 (dddd, J = 17.1, 10.4, 5.6, 4.8 Hz, 1 H, CH=CH2), 5.25 (d, J = 17.1 Hz, 1 H, CH=CH 2-trans), 5.14 (d, J = 10.4 Hz, 1 H, CH=CH 2-cis), 4.76–4.81 (m, 2 H, 2 × OH), 4.65 (d, J = 5.5 Hz, 1 H, OH), 4.56 (d, J = 2.8 Hz, 1 H, H-1), 4.09 (dd, J = 13.3, 4.8 Hz, 1 H, OCHHCH=CH2), 3.91 (dd, J = 13.3, 5.6 Hz, 1 H, OCHHCH=CH2), 3.55–3.61 (m, 2 H, H-2, H-4), 3.49 (dd, J = 10.8, 4.9 Hz, 1 H, H-5b), 3.44–3.47 (m, 1 H, H-3), 3.26 (dd, J = 10.8, 9.4 Hz, 1 H, H-5a).

13C NMR (150 MHz, DMSO-d 6): δ = 134.9 (CH=CH2), 116.6 (CH=CH2), 99.8 (C-1), 71.3 (C-3), 69.9 (C-2), 67.4 (OCH2CH=CH2), 66.9 (C-4), 63.4 (C-5).

ESI(+)-MS: m/z calcd for C8H15O5 [M + H]+: 191.09; found: 191.09.

ESI(–)-MS: m/z calcd for C8H13O5 [M – H]: 189.08; found: 189.08.

ESI(+)-MS: m/z calcd for C8H14O5Na [M + Na]+: 213.07; found: 213.07.

ESI(–)-MS: m/z calcd for C8H14O5Cl [M + Cl]: 225.05; found: 225.05.

Data in agreement with the literature[10] (ent-4b).


#

Benzyl α-l-Lyxopyranoside (4c)[9] [12] [24]

Yield: 1.44 g (60%); white amorphous solid; Rf (hexanes/EtOAc, 2:8) = 0.15.

1H NMR (600 MHz, DMSO-d 6): δ = 7.26–7.39 (m, 5 H, H-Bn), 4.80 (d, J = 5.0 Hz, 2 H, 2 × OH), 4.66 (d, J = 5.6 Hz, 1 H, OH), 4.60 (s, 1 H, H-1), 4.60 (d, J = 12.0 Hz, 1 H, CHHPh), 4.41 (d, J = 12.0 Hz, 1 H, CHHPh), 3.56–3.63 (m, 2 H, H-2, H-4), 3.55 (dd, J = 10.0, 5.2 Hz, 1 H, H-5b), 3.48 (dd, J = 8.3, 5.5, 3.0 Hz, 1 H, H-3), 3.31 (dd, J = 10.0, 10.0 Hz, 1 H, H-5a).

13C NMR (150 MHz, DMSO-d 6): δ = 138.0 (C-Bn), 128.3 (C-Bn), 127.7 (C-Bn), 127.5 (C-Bn), 99.8 (C-1), 71.2 (C-3), 69.9 (C-2 or C-4), 68.2 (OCH2Ph), 66.8 (C-4 or C-2), 63.4 (C-5).

ESI(+)-MS: m/z calcd for C12H17O5 [M + H]+: 241.11; found: 241.11.

ESI(+)-MS: m/z calcd for C12H16NaO5 [M + Na]+: 263.09; found: 263.09.

ESI(–)-MS: m/z calcd for C12H15O5 [M – H]: 239.09; found: 239.09.

ESI(–)-MS: m/z calcd for C12H16O5Cl [M + Cl]: 275.07; found: 275.07.

Data in agreement with the literature[9] [12] [24] (ent-4c).


#

General Procedure for the 2,3-Di-O-isopropylidene Protection of Pyranoses

To the corresponding 1-O-protected pyranoside (5 mmol, 1 equiv), was added anhydrous acetone (1.83 mL, 215 mmol, 5 equiv), 2,2-dimethoxypropane (1.85 mL, 15 mmol, 3 equiv) and concentrated HCl (3–5 Pasteur pipette drops). The solution was stirred for 18 h at r.t. The reaction was quenched with a saturated solution NaHCO3 and extracted with CH2Cl2 (3 times). The combined organic layers were dried with anhydrous Na2SO4, filtered, and solvent was removed in vacuo. Analysis of the 1H NMR spectrum of the crude product showed mixtures of pyranose and furanose products up to 1:0.25 ratios (depending on the reaction). The products were purified and isolated by flash silica column chromatography with hexanes/EtOAc as the eluent.


#

Methyl 2,3-O-Isopropylidene-α-l-lyxopyranoside (5)[4] [6] [7] [10]

Yield: 520 mg (51%); yellow oil; Rf (hexanes/EtOAc, 1:1) = 0.55.

1H NMR (600 MHz, CDCl3): δ = 4.64 (d, J = 2.6 Hz, 1 H, H-1), 4.23 (dd, J = 6.0, 4.8 Hz, 1 H, H-3), 4.12 (dd, J = 6.0, 2.7 Hz, 1 H, H-2), 3.79–3.86 (m, 2 H, H-5b, H-4), 3.71 (dd, J = 11.2, 4.6 Hz, 1 H, H-5a), 3.46 (s, 3 H, OCH 3), 2.97 (d, J = 8.0 Hz, 1 H, OH), 1.51 (s, 3 H, CCH 3), 1.35 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 109.7 (C(CH3)2), 99.9 (C-1), 76.2 (C-3), 74.4 (C-2), 67.3 (C-4), 63.3 (C-5), 56.0 (OCH3), 27.6 (CCH3), 25.7 (CCH3).

1H NMR (400 MHz, DMSO-d 6): δ = 5.18 (d, J = 5.4 Hz, 1 H, OH), 4.59 (d, J = 1.9 Hz, 1 H, H-1), 3.90–3.97 (m, 2 H, H-3, H-2), 3.54–3.62 (m, 1 H, H-4), 3.45 (dd, J = 11.5, 4.4 Hz, 1 H, H-5b), 3.35–3.40 (m, 1 H, H-5a), 3.31 (s, 3 H, OCH 3), 1.41 (s, 3 H, CCH 3), 1.27 (s, 3 H, CCH 3).

13C NMR (100 MHz, DMSO-d 6): δ = 108.2 (C(CH3)2), 99.5 (C-1), 77.6 (C-3 or C-2), 74.5 (C-2 or C-3), 66.5 (C-4), 62.0 (C-5), 54.9 (OCH3), 28.0 (CCH3), 26.2 (CCH3).

Data in agreement with the literature[4] [6] [7] [10] (ent-5).


#

Allyl 2,3-O-Isopropylidene-α-l-lyxopyranoside (6)[4] [6] [7] [10]

Yield: 655 mg (57%); yellow oil; Rf (hexanes/EtOAc, 1:1) = 0.70.

1H NMR (600 MHz, CDCl3): δ = 5.87 (ddt, J = 16.3, 10.4, 1.2 Hz, 1 H, CH=CH2), 5.29 (dd, J = 16.3, 1.4 Hz, 1 H, CH=CH 2-trans), 5.20 (d, J = 10.4 Hz, 1 H, CH=CH 2-cis), 4.76–4.79 (m, 1 H, H-1), 4.25 (ddd, J = 12.8, 5.3, 1.2 Hz, 1 H, OCHHCH=CH2), 4.20 (t, J = 5.3 Hz, 1 H, H-3), 4.12–4.15 (m, 1 H, H-2), 4.05 (ddd, J = 12.8, 6.2, 1.2 Hz, 1 H, OCHHCH=CH2), 3.78–3.83 (m, 1 H, H-4), 3.75 (dd, J = 11.6, 3.8 Hz, 1 H, H-5b), 3.67 (dd, J = 11.6, 5.9 Hz, 1 H, H-5a), 3.38–3.44 (m, 1 H, OH), 1.47 (s, 3 H, CCH 3), 1.32 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 133.5 (CH=CH2), 118.0 (CH=CH2), 109.5 (C(CH3)2), 97.8 (C-1), 76.7 (C-3), 74.6 (C-2), 68.8 (OCH2CH=CH2), 67.4 (C-4), 62.9 (C-5), 27.7 (CCH3), 25.7 (CCH3).

ESI(+)-MS: m/z calcd for C11H19O5 [M + H]+: 231.12; found: 231.12.

ESI(+)-MS: m/z calcd for C11H18O5Na [M + Na]+: 253.10; found: 253.10.

1H NMR (600 MHz, DMSO-d 6): δ = 5.85–5.95 (m, 1 H, CH=CH2), 5.27–5.32 (m, 1 H, CH=CH 2), 5.13–5.21 (m, 2 H, CH=CH 2, OH), 4.67–4.71 (m, 1 H, H-1), 4.15 (dt, J = 16.2, 8.1 Hz, 1 H, OCHHCH=CH2), 3.93–4.04 (m, 3 H, OCHHCH=CH2, H-2, H-3), 3.54–3.62 (m, 1 H, H-4), 3.39–3.49 (m, 2 H, H-5a, H-5b), 1.41 (s, 3 H, CCH 3), 1.28 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 134.4 (CH=CH2), 116.8 (CH=CH2), 108.2 (C(CH3)2), 97.8 (C-1), 75.6 (C-3 or C-2), 74.5 (C-2 or C-3), 67.7 (OCH2CH=CH2), 66.5 (C-4), 62.4 (C-5), 28.0 (CCH3), 26.2 (CCH3).

Data in agreement with the literature[4] [6] [7] [10] (ent-6).


#

Benzyl 2,3-O-Isopropylidene-α-l-lyxopyranoside (7)[9] [12] [24]

Yield: 700 mg (50%); white amorphous solid; Rf (hexanes/EtOAc, 8:2) = 0.20.

1H NMR (600 MHz, CDCl3): δ = 7.29–7.39 (m, 5 H, H-Bn), 4.84 (d, J = 2.5 Hz, 1 H, H-1), 4.81 (d, J = 11.8 Hz, 1 H, CHHPh), 4.57 (d, J = 11.8 Hz, 1 H, CHHPh), 4.23 (d, J = 5.4 Hz, 1 H, H-3), 4.18 (dd, J = 6.0, 2.5 Hz, 1 H, H-2), 3.78–3.84 (m, 2 H, H-4, H-5b), 3.73 (dd, J = 11.4, 5.8 Hz, 1 H, H-5a), 3.00 (br s, 1 H, OH), 1.46 (s, 3 H, CCH 3), 1.34 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 136.6 (C-Bn), 128.5 (C-Bn), 128.1 (C-Bn), 127.9 (C-Bn), 109.5 (C(CH3)2), 97.3 (C-1), 74.5 (C-2), 76.5 (C-3), 69.6 (CH2Ph), 67.3 (C-4), 62.8 (C-5), 27.4 (CCH3), 25.6 (CCH3).

Data in agreement with the literature[9] [12] [24] (ent-7).


#

General Procedure for the Triflate Formation Reaction

Pyridine (0.10 mL, 1.20 mmol) and 4-(dimethylamino)pyridine (6.00 mg, 5 mol%) in anhydrous CH2Cl2 (5 mL) was treated slowly with 1 M solution of trifluoromethanesulfonic anhydride in CH2Cl2 (1.30 mL, 1.30 mmol) at –20 °C under argon atmosphere. The reaction mixture was stirred at –20 °C for 5 min. The corresponding alcohol (1.00 mmol) in CH2Cl2 (2 mL) was added via a cannula, the mixture was stirred at –20 °C for 15 min and then warmed to r.t. The reaction was monitored by TLC until disappearance of the starting material (30 min to 2 h) indicated completion of the reaction. The mixture was poured into a mixture of 25 mL ice-water and 10 mL CH2Cl2 and the organic layer was separated. The aqueous phase was extracted with CH2Cl2 three times. The combined organic layers were washed with water and brine, dried with anhydrous Na2SO4, filtered and evaporated to give the intermediate triflate product as pale-yellow gummy solid. The product was used without further purification.


#

General Procedure for the SN2 Reaction; Method A

The crude trifluoromethanesulfonate intermediate (1.00 mmol) was dissolved in freshly distilled DMF (10 mL), then the corresponding nucleophile (8 or 9, 3.00 mmol) was added. The suspension was stirred at r.t. overnight, then the reaction mixture was evaporated to dryness. The residue was dissolved in a mixture of CH2Cl2 and water. The organic layer was separated and washed with water and brine, dried with anhydrous MgSO4, filtered and evaporated to obtain an oily residue, which, on purification by silica gel flash chromatography, afforded the expected product.


#

Methyl 5-Azido-5-deoxy-2,3-O-isopropylidene-β-l-lyxofuranoside (12a)

Yield: 172 mg (overall yield 75 %); oil; Rf (Hexanes/EtOAc, 9:1) = 0.58.

1H NMR (600 MHz, CDCl3): δ = 4.91 (s, 1 H, H-1), 4.70 (dd, J = 5.9, 3.7 Hz, 1 H, H-3), 4.57 (d, J = 5.9 Hz, 1 H, H-2), 4.08 (ddd, J = 7.6, 5.2, 3.9 Hz, 1 H, H-4), 3.57 (dt, J = 12.8, 6.4 Hz, 1 H, H-5b), 3.47–3.52 (m, 1 H, H-5a), 3.34 (s, 1 H, OCH 3), 1.46 (s, 1 H, CCH 3), 1.31 (s, 1 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 111.9 (C(CH3)2), 106.2 (C-1), 84.0 (C-2), 78.6 (C-3), 77.3 (C-4), 53.7 (OCH3), 48.7 (C-5), 25.0 (CCH3), 23.8 (CCH3).

ESI(+)-MS: m/z calcd. for C9H15N3O4Na [M + Na]+: 252.10; found: 252.10.


#

Methyl 4-Azido-4-deoxy-2,3-O-isopropylidene-β-d-ribopyranoside (15a)[4] [6] [7]

Yield: 156 mg (overall yield 68 %); oil; Rf (hexanes/EtOAc, 9:1) = 0.56.

1H NMR (600 MHz, CDCl3): δ = 4.48–4.52 (m, 1 H, H-3), 4.47 (d, J = 3.8 Hz, 1 H, H-1), 4.00 (dd, J = 6.3, 3.8 Hz, 1 H, H-2), 3.78–3.84 (m, 2 H, H-4, H-5b), 3.69–3.74 (m, 1 H, H-5a), 3.41 (s, 3 H, OCH 3), 1.53 (s, 3 H, CCH 3), 1.35 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 110.8 (C(CH3)2), 100.9 (C-1), 75.3 (C-2), 72.9 (C-3), 60.2 (C-5), 56.4 (OCH3), 54.9 (C-4), 26.9 (CCH3), 25.6 (CCH3).

ESI(+)-MS: m/z calcd for C9H16N3O4 [M + H]+: 230.11; found: 230.11.

ESI(+)-MS: m/z calcd. for C9H15N3O4Na [M + Na]+: 252.10; found: 252.10.

Data in agreement with the literature[4] [6] [7]


#

Methyl 4-Benzylamino-4-deoxy-2,3-O-isopropylidene-β-d-ribopyranoside (15b)

Yield: 184 mg (overall yield 63 %); oil; Rf (hexane/EtOAc, 13:7) = 0.66.

1H NMR (600 MHz, CDCl3): δ = 7.28–7.36 (m, 4 H, H-Bn), 7.22–7.27 (m, 1 H, H-Bn), 4.46 (dd, J = 5.4, 3.8 Hz, 1 H, H-3), 4.33 (d, J = 5.3 Hz, 1 H, H-1), 3.88–3.92 (m, 2 H, NCHHPh, H-2), 3.81–3.87 (m, 2 H, H-5b, NCHHPh), 3.45 (s, 3 H, OCH 3), 3.37–3.43 (m, 1 H, H-5a), 3.15 (ddd, J = 11.0, 5.6, 3.6 Hz, 1 H, H-4), 1.35 (s, 3 H, CCH 3), 1.23 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 140.2 (C-Bn), 128.5 (C-Bn), 128.1 (C-Bn), 127.2 (C-Bn), 109.7 (C(CH3)2), 102.4 (C-1), 75.8 (C-2), 72.9 (C-3), 63.5 (C-5), 56.6 (OCH3), 52.1 (C-4), 51.1 (PhCH2NH), 27.6 (CCH3), 25.8 (CCH3).

ESI(+)-HRMS: m/z calcd for C16H24NO4 [M + H]+: 294.1700; found: 294.1701.


#

General Procedure for the SN2 Reaction; Method B

The crude trifluoromethanesulfonate intermediate (1.00 mmol) was dissolved in distilled DMF (10 mL), then the corresponding nucleophile (10 or 11, 3.00 mmol) was added. The suspension was stirred at 70 °C until consumption of the starting material was observed (reaction monitored by TLC), then the reaction mixture was evaporated to dryness. The residue was filtered through a pad of Celite® and silica. The pad was washed several times with EtOAc/MeOH (9:1) to avoid dissolving the excess of nucleobase that did not react during the reaction. The filtrate and washings were combined and evaporated. The residue was purified by silica gel flash chromatography to afford the expected product.


#

Methyl 5-Deoxy-2,3-O-isopropylidene-5-(uracil-5-ylamino)-β-l-lyxofuranoside (12c)

Yield: 147 mg (overall yield 47%); yellow amorphous solid; Rf ­(EtOAc/MeOH, 9:1) = 0.66.

1H NMR (600 MHz, DMSO-d 6): δ = 11.16 (s, 1 H, NH-uracil), 10.18 (s, 1 H, NH-uracil), 6.47 (d, J = 3.4 Hz, 1 H, CH-uracil), 4.83 (s, 1 H, H-1), 4.71–4.74 (m, 1 H, H-3), 4.51 (d, J = 5.9 Hz, 1 H, H-2), 4.21–4.23 (m, 1 H, NHCH2), 4.00–4.03 (m, 1 H, H-4), 3.21 (s, 3 H, OCH 3), 3.16–3.19 (m, 1 H, H-5b), 2.95–3.06 (m, 1 H, H-5a), 1.36 (s, 3 H, CCH 3), 1.25 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 161.4 (CO-uracil), 149.5 (CO-uracil), 123.7 (C-uracil), 113.7 (CH-uracil), 111.7 (C(CH3)2), 106.3 (C-1), 84.4 (C-2), 79.5 (C-3), 77.8 (C-4), 54.0 (OCH3), 42.8 (C-5), 26.0 (CCH3), 24.7 (C(CH3)).

ESI(+)-HRMS: m/z calcd for C13H20N3O6 [M + H]+: 314.1347; found: 314.1352.

ESI(–)-HRMS: m/z calcd for C13H18N3O6 [M – H]: 312.1201; found: 312.1199.

ESI(+)-HRMS: m/z calcd for C13HN3O6Na [M + Na]+: 336.1166; found: 336.1168.


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Methyl 5-Deoxy-5-(2,4-diaminopyrimidin-5-ylamino)-2,3-O-isopropylidene-β-l-lyxofuranoside (12d)

Yield: 174 mg (overall yield, 56%); brown-orange amorphous solid; Rf (EtOAc/MeOH, 95:5) = 0.65.

1H NMR (150 MHz, DMSO-d 6): δ = 7.39 (br. s, 2 H, NH 2-pyrimidine), 7.05 (br. s, 2 H, NH 2-pyrimidine), 7.01 (s, 1 H, CH-pyrimidine), 4.86 (s, 1 H, H-1), 4.79 (dd, J = 5.6, 3.7 Hz, 1 H, H-3), 4.68–4.72 (m, 1 H, NH), 4.55 (d, J = 5.9 Hz, 1 H, H-2), 4.03 (dd, J = 9.6, 5.9 Hz, H-4), 3.21 (s, 3 H, OCH 3), 3.20–3.23 (m, H-5b), 3.05–3.12 (m, 1 H, H-5a), 1.37 (s, 3 H, CCH 3), 1.27 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 159.0 (C-pyrimidine), 151.2 (C-pyrimidine), 121.0 (C-pyrimidine), 118.3 (CH-pyrimidine), 111.8 (C(CH3)2), 106.4 (C-1), 84.4 (C-2), 79.3 (C-3), 77.4 (C-4), 54.1 (OCH3), 42.7 (C-5), 26.0 (CCH3), 24.8 (CCH3).

ESI(+)-HRMS: m/z calcd for C13H22N5O4 [M + H]+: 312.1666; found: 312.1670.

ESI(+)-HRMS: m/z calcd for C13H21N5O4Na [M + Na]+: 334.1486; found: 334.1485.


#

Allyl 5-Deoxy-2,3-O-isopropylidene-5-(uracil-5-ylamino)-β-l-lyxofuranoside (13c)

Yield: 152 mg (overall yield 45%); pale-yellow amorphous solid; Rf (CH2Cl2/MeOH, 95:5) = 0.20.

1H NMR (600 MHz, DMSO-d 6): δ = 11.16 (s, 1 H, NH-uracil), 10.55 (s, 1 H, NH-uracil), 6.49 (d, J = 5.4 Hz, 1 H, CH-uracil), 5.83–5.92 (m, 1 H, CH=CH2), 5.24 (d, J = 17.3 Hz, 1 H, CH=CH 2-trans), 5.15 (d, J = 10.2 Hz, 1 H, CH=CH 2-cis), 4.98 (s, 1 H, H-1), 4.76 (dd, J = 10.9, 7.1 Hz, 1 H, H-3), 4.57 (d, J = 5.8 Hz, 1 H, H-2), 4.21–4.25 (m, 1 H, NH), 4.00–4.09 (m, 2 H, H-4, OCH2 CH=CH2), 392–3.98 (m, 1 H, H-5b), 3.18–3.25 (m, 1 H, H-5a), 2.98–3.04 (m, 1 H, CHHNH), 1.38 (s, 3 H, CCH 3), 1.26 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 161.4 (CO-uracil), 149.4 (CO-uracil), 134.6 (CH=CH2), 123.7 (C-uracil), 116.9 (CH=CH2), 113.7 (CH-uracil), 111.7 (C(CH3)2), 104.8 (C-1), 84.6 (C-2), 79.5 (C-3), 77.8 (C-4), 67.3 (OCH2CH=CH2), 42.8 (C-5), 26.0 (CCH3), 24.7 (CCH3).

ESI(+)-HRMS: m/z calcd. for C15H22N3O6 [M + H]+: 340.1509; found: 340.1507.

ESI(+)-HRMS: m/z calcd. for C15H21N3NaO6 [M + Na]+: 362.1328; found: 362.1325.


#

Allyl 5-Deoxy-5-(2,4-diaminopyrimidin-5-ylamino)-2,3-O-isopropylidene-β-l-lyxofuranoside (13d)

Yield: 162 mg (overall yield 48%); brown-orange solid; mp 146–148 °C; Rf (CH2Cl2/MeOH, 9:1) = 0.23; Rf (CH2Cl2/MeOH, 9:1) = 0.20.

1H NMR (600 MHz, DMSO-d 6): δ = 7.40 (s, 1 H, CH-pyrimidine), 6.34 (br. s, 2 H, NH 2), 5.82–5.93 (m, 1 H, CH=CH2), 5.49 (br. s, 2 H, NH 2), 5.24 (dd, J = 17.2, 1.7 Hz, CH=CH 2-trans), 5.14 (dd, J = 10.4, 1.5 Hz, 1 H, CH=CH 2-cis), 4.98 (s, 1 H, H-1), 4.84 (br s, 1 H, NH), 4.81 (dd, J = 5.8, 3.7 Hz, 1 H, H-3), 4.58 (d, J = 5.9 Hz, 1 H, H-2), 4.08 (dd, J = 13.2, 5.1 Hz, 1 H, OCHHCH=CH2), 4.04 (ddd, J = 6.2, 6.2, 3.8 Hz, 1 H, H-4), 3.95 (dd, J = 13.2, 5.8 Hz, 1 H, OCHHCH=CH2), 3.12–3.20 (m, 1 H, H-5b), 2.99–3.05 (m, 1 H, H-5a), 1.37 (s, 3 H, CCH 3), 1.27 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 158.0 (C-pyrimidine), 136.7 (C-pyrimidine), 134.6 (OCH2 CH=CH2), 126.7 (CH-pyrimidine), 119.4 (C-pyrimidine), 116.9 (OCH2CH=CH2), 111.6 (C(CH3)2), 104.6 (C-1), 84.3 (C-2), 79.3 (C-3), 77.9 (C-4), 67.1 (OCH2CH=CH2), 43.4 (C-5), 26.0 (CCH3), 24.8 (CCH3).

ESI(+)-HRMS: m/z calcd. for C15H24N5O4 [M + H]+: 338.1828; found: 338.1822.

ESI(+)-HRMS: m/z calcd. for C15H21N5NaO4 [M + Na]+: 362.1328; found: 362.1325.


#

Benzyl 5-Deoxy-5-(2,4-diaminopyrimidin-5-ylamino)-2,3-O-isopropylidene-β-l-lyxofuranoside (14d)

Yield: 100 mg (overall yield 26%); brown-orange amorphous solid.

1H NMR (600 MHz, DMSO-d 6): δ = 7.23–7.39 (m, 5 H, H-Bn), 7.03 (s, 1 H, CH-pyrimidine), 7.00–7.05 (br. s, 2 H, NH 2), 5.05 (s, 1 H, H-1), 4.83 (dd, J = 5.8, 3.6 Hz, 1 H, H-3), 4.73 (dd, J = 7.2, 5.0 Hz, 1 H, NH), 4.63 (d, J = 6.0 Hz, 1 H, H-2), 4.61 (d, J = 11.8 Hz, 1 H, CHHPh), 4.47 (d, J = 11.8 Hz, 1 H, CHHPh), 4.09–4.14 (m, 1 H, H-4), 3.22 (dd, J = 12.9, 5.0 Hz, 1 H, H-5b), 3.08 (dd, J = 12.9, 7.2 Hz, 1 H, H-5a), 1.34 (s, 3 H, CCH 3), 1.23 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 159.6 (C-pyrimidine), 151.6 (C-pyrimidine), 138.0 (C-Bn), 129.0 (C-Bn), 128.6 (C-Bn), 128.4 (C-Bn), 122.1 (CH-pyrimidine), 119.7 (C-pyrimidine), 112.5 (C(CH3)2), 105.2 (C-1), 84.9 (C-2), 79.8 (C-3), 77.8 (C-4), 68.8 (OCH2Ph), 43.0 (C-5), 26.4 (CCH3), 25.1 (CCH 3).

ESI(+)-HRMS: m/z calcd. for C19H25N5O4 [M + H]+: 387.1907; found: 387.1911.

ESI(+)-HRMS: m/z calcd. for C19H24N5NaO4 [M + Na]+: 409.1726; found: 409.1736.


#

General Procedure for the Reduction of the Azides

Pd/C (5% w/w) (100 mg) was added to the corresponding azide (230 mg, 1.00 mmol) in anhydrous MeOH (5 mL) and the reaction mixture was stirred under an atmosphere of hydrogen (1 atm) until completion of the reaction as monitored by TLC (hexanes/EtOAc, 9:1). The reaction mixture was filtered over a pad of Celite® and evaporated to dryness. The product was sufficiently pure to be used without any further purification.


#

Methyl 5-Amino-5-deoxy-2,3-O-isopropylidene-β-l-lyxofuranoside (18)

Yield: 193 mg (95%); white amorphous solid; Rf (CH2Cl2/MeOH, 95:5) = 0.25.

1H NMR (600 MHz, CDCl3): δ = 4.89 (s, 1 H, H-1), 4.72 (dd, J = 5.8, 3.9 Hz, 1 H, H-3), 4.56 (d, J = 5.8 Hz, 1 H, H-2), 3.92–3.96 (m, 1 H, H-4), 3.32 (s, 3 H, OCH 3), 2.99–3.09 (m, 2 H, H-5a, H-5b), 1.45 (s, 1 H, CCH 3), 1.30 (s, 1 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 112.7 (C(CH3)2), 107.1 (C-1), 85.2 (C-2), 80.7 (C-3), 80.1 (C-4), 54.6 (OCH3), 40.9 (C-5), 26.1 (CCH3), 24.8 (CCH3).

1H NMR (600 MHz, DMSO-d 6): δ = 4.92 (s, 1 H, H-1), 4.79 (dd, J = 5.9, 3.8 Hz, 1 H, H-3), 4.57 (d, J = 5.9 Hz, 1 H, H-2), 4.07–4.13 (m, 1 H, H-4), 3.27 (s, 3 H, OCH 3), 3.15 (dd, J = 13.3, 3.3 Hz, 1 H, H-5′), 2.92 (dd, J = 13.3, 9.0 Hz, 1 H, H-5), 1.37 (s, 1 H, CCH 3), 1.26 (s, 1 H, CCH 3).

13C NMR (151 MHz, DMSO-d 6): δ = 112.0 (C(CH3)2), 106.2 (C-1), 85.4 (C-2), 79.1 (C-3), 75.8 (C-4), 54.1 (OCH3), 38.0 (C-5), 25.8 (CCH3), 24.5 (CCH3),

ESI(+)-HRMS: m/z calcd. for C9H18NO4 [M + H]+: 204.1230; found: 204.1221.


#

Methyl 4-Amino-4-deoxy-2,3-O-isopropylidene-β-d-ribopyranoside (20)[4] [6] [7]

Yield: 193 mg (95%); white amorphous solid; Rf (CH2Cl2/MeOH, 95:5) = 0.25.

1H NMR (600 MHz, CDCl3): δ = 4.37 (dd, J = 5.3, 3.9 Hz, 1 H, H-1), 4.34 (d, J = 4.9 Hz, 1 H, H-3), 3.94 (dd, J = 13.2, 8.0 Hz, 1 H, H-2), 3.71 (dd, J = 10.8, 5.6 Hz, 1 H, H-5b), 3.46 (s, 3 H, OCH 3), 3.41–3.45 (m, 1 H, H-5a), 3.18–3.24 (m, 1 H, H-4), 1.53 (s, 3 H, CCH 3), 1.37 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 109.9 (C(CH3)2), 101.9 (C-1), 75.7 (C-2), 74.5 (C-3), 65.1 (C-5), 56.4 (OCH3), 49.9 (C-4), 27.5 (CCH3), 25.6 (CCH3).

ESI(+)-HRMS: m/z calcd. for C9H18NO4 [M + H]+: 204.1230; found: 204.1224.

Data in agreement with the literature.[4] [6] [7]


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2,3-O-Isopropylidene-l-lyxofuranose (19)

A suspension of the benzyl protected compound 3 (140 mg, 0.5 mmol, 1.0 equiv) with Pd(OH)2 in anhydrous MeOH was stirred at r.t. under an atmosphere of hydrogen for 1 day. The suspension was filtered through a pad of Celite® and washed several times with MeOH. The solvent was removed under reduced pressure and the crude product was purified by column chromatography (hexanes/EtOAc, 3:7) to afford the expected product 19.

Yield: 650 mg (98%); Rf (hexanes/EtOAc, 7:3) = 0.50.

1H NMR (600 MHz, DMSO-d 6): δ = 6.31 (d, J = 3.8 Hz, 1 H, C1OH), 5.10 (d, J = 3.8 Hz, 1 H, H-1), 4.65–4.72 (m, 2 H, OH, H-3), 4.42 (d, J = 5.8 Hz, 1 H, H-2), 3.97–4.03 (m, 1 H, H-4), 3.62 (dt, J = 11.2, 5.5 Hz, 1 H, H-5b), 3.46–3.53 (m, 1 H, H-5a), 1.32 (s, 3 H, CCH 3), 1.22 (s, 3 H, CCH 3).

13C NMR (150 MHz, DMSO-d 6): δ = 111.2 (C(CH3)2), 100.0 (C-1), 85.6 (C-2), 80.0 (C-4), 79.5 (C-3), 59.2 (C-5), 26.0 (CCH3), 24.7 (CCH3).

ESI(+)-HRMS: m/z calcd for C8H15O5 [M + H]+: 191.0914; found: 191.0909.


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Methyl 4-Deoxy-4-formamido-2,3-O-isopropylidene-β-d-ribopyranoside (21)

A solution of 5-bromouracil (573 mg, 3.00 mmol) and 4-deoxy-4-amino-2,3-O-isopropylidene-β-d-ribopyranoside 20 (203 mg, 1.00 mmol) in anhydrous dimethylformamide (5 mL) was stirred at 70 °C overnight. The mixture was allowed to cool, then saturated aqueous NaHCO3 was added. The aqueous phase was extracted three times with EtOAc and the organic layers were combined, dried with Na2SO4, filtered and evaporated. The oily residue was purified by column chromatography (hexanes/EtOAc, 7:3) to afford the expected pure product 21.

Yield: 231 mg (56%); white amorphous solid; Rf (hexane/EtOAc, 7:3) = 0.5.

1H NMR (600 MHz, CDCl3): δ = 8.16 (s, 1 H, COH), 6.01 (d, J = 7.7 Hz, 1 H, NH), 4.58–4.64 (m, 1 H, H-4), 4.42 (d, J = 4.2 Hz, 1 H, H-1), 4.35 (dd, J = 6.0, 4.2 Hz, 1 H, H-3), 4.03 (dd, J = 6.0, 4.4 Hz, 1 H, H-2), 3.82 (dd, J = 10.6, 5.7 Hz, 1 H, H-5b), 3.43 (s, 3 H, OCH 3), 3.42–3.45 (m, 1 H, H-5a), 1.49 (s, 3 H, CCH 3), 1.32 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 160.8 (CHO), 110.1 (C(CH3)2), 100.1 (C-1), 75.1 (C-2), 72.5 (C-3), 61.0 (C-5), 56.3 (OCH3), 43.0 (C-4), 27.1 (CCH3), 25.4 (CCH3).

ESI(+)-HRMS: m/z calcd. for C10H18NO5 [M + H]+: 232.1179; found: 232.1181.

ESI(+)-HRMS: m/z calcd. for C10H17NNaO5 [M + Na]+: 254.0999; found: 254.1003.


#

Methyl 4-Benzoylamino-4-deoxy-2,3-O-isopropylidene-α-d-ribopyranoside (22)

To a solution of methyl 4-deoxy-4-amino-2,3-O-isopropylidene-β-d-ribopyranoside 20 (190 mg, 0.80 mmol, 1.0 equiv) and DIPEA (0.31 mL, 1.76 mmol, 2.2 equiv) in anhydrous dimethylformamide (5 mL), benzoyl chloride (0.21 mL, 1.82 mmol, 2.0 equiv) was slowly added at 0 °C under an argon atmosphere. The solution was stirred at 70 °C overnight. The mixture was allowed to cool, then saturated aqueous NaHCO3 was added. The aqueous phase was extracted three times with EtOAc and the organic layers were combined, dried with Na2SO4, filtered and evaporated. The oily residue was purified by chromatography (hexanes/EtOAc, 7:3) to afford the expected pure product 22.

Yield: 201 mg (82%); white amorphous solid; Rf (hexanes/EtOAc, 9:1) = 0.50.

1H NMR (600 MHz, CDCl3): δ = 7.79 (d, J = 7.2 Hz, 2 H, H-Bz), 7.51 (dd, J = 7.4, 7.2 Hz, 1 H, H-Bz), 7.44 (dd, J = 7.4, 7.4 Hz, 2 H, H-Bz), 6.48 (d, J = 8.8 Hz, 1 H, NHCO), 4.74–4.80 (m, 1 H, H-4), 4.45–4.49 (m, 2 H, H-3, H-1), 4.09 (dd, J = 6.1, 4.5 Hz, 1 H, H-2), 3.97 (dd, J = 10.6, 6.5 Hz, 1 H, H-5b), 3.49–3.54 (m, 1 H, H-5a), 3.49 (s, 3 H, OCH 3), 1.54 (s, 3 H, CCH 3), 1.38 (s, 3 H, CCH 3).

13C NMR (150 MHz, CDCl3): δ = 167.7 (CO), 131.8 (C-Bz), 128.6 (C-Bz), 127.1 (C-Bz), 110.2 (C(CH3)2), 101.2 (C-1), 75.4 (C-2), 73.0 (C-3), 61.4 (C-5), 59.4 (OCH3), 44.8 (C-4), 27.3 (CCH3), 25.6 (CCH3).

ESI(+)-HRMS: m/z calcd. for C16H22NO5 [M + H]+: 308.1492; found: 308.1492.


#
#

Acknowledgment

We are grateful to Mr. Richard Mosesso for the purification of some starting materials and Dr. Clémentine Gibard for the assistance in running selected NMR spectra.

Supporting Information

  • References

  • 1 Mittapalli GK. Ravinder KR. Xiong H. Munoz O. De Riccardis F. Krishnamurthy R. Eschenmoser A. Angew. Chem. Int. Ed. 2007; 46: 2470
  • 2 Mittapalli GK. Osornio YM. Guerrero MA. Ravinder KR. Krishnamurthy R. Eschenmoser A. Angew. Chem. Int. Ed. 2007; 46: 2478
  • 3 Zhang X. Krishnamurthy R. Angew. Chem. Int. Ed. 2009; 48: 8124
  • 4 Kini GD. Hennen WJ. J. Org. Chem. 1986; 51: 4436
  • 5 Kini GD. Petrie CR. Hennen WJ. Dalley NK. Wilson BE. Robins RK. Carbohydr. Res. 1987; 159: 81
  • 6 Varaprasad CV. Averett D. Ramasamy KS. Tetrahedron 1999; 55: 13345
  • 7 Varaprasad CV. Ramasamy KS. Hong Z. J. Heterocycl. Chem. 2006; 43: 325
  • 8 Wakharkar RD. Sahasrabuddhe MB. Borate HB. Gurjar MK. Synthesis 2004; 1830
  • 9 Keck GE. Kachensky DF. Enholm EJ. J. Org. Chem. 1985; 50: 4317
  • 10 Mohal N. Vasella A. Helv. Chim. Acta 2005; 88: 100
  • 11 Mohal N. Bernet B. Vasella A. Helv. Chim. Acta 2005; 88: 3232
  • 12 Keck GE. Wager TT. Duarte Rodriquez JF. J. Am. Chem. Soc. 1999; 121: 5176
  • 13 Reist EJ. Fisher LV. Goodman L. J. Org. Chem. 1967; 32: 2541
  • 14 Ozerov AA. Novikov MS. Brel’ AK. Solodunova GN. Chem. Heterocycl. Compd. 1998; 34: 611
  • 15 Loksha YM. Globisch D. Pedersen EB. J. Heterocycl. Chem. 2008; 45: 1161
  • 16 Boncel S. Gondela A. Mączka M. Tuszkiewicz-Kuźnik M. Grec P. Hefczyc B. Walczak K. Synthesis 2011; 603
  • 17 Gems FR. Perrotta A. Hitching GH. J. Med. Chem. 1966; 9: 108
  • 18 Sørensen MD. Khalifa NM. Pedersen EB. Synthesis 1999; 1937
  • 19 Fang W.-P. Cheng Y.-T. Cheng Y.-R. Cherng Y.-J. Tetrahedron 2005; 61: 3107
  • 20 Suchý M. Elmehriki AA. H. Hudson RH. E. Org. Lett. 2011; 13: 3952
  • 21 Coleman RS. Felpin F.-X. Chen W. J. Org. Chem. 2004; 69: 7309
  • 22 Kawana M. Kuzuhara H. Emoto S. Bull. Chem. Soc. Jpn. 1981; 54: 1492
  • 23 Brimacombe JS. Hunedy F. Tucker LC. N. J. Chem. Soc. C 1968; 1381
  • 24 Jogireddy R. Dakas P.-Y. Valot G. Barluenga S. Winssinger N. Chem. Eur. J. 2009; 15: 11498

  • References

  • 1 Mittapalli GK. Ravinder KR. Xiong H. Munoz O. De Riccardis F. Krishnamurthy R. Eschenmoser A. Angew. Chem. Int. Ed. 2007; 46: 2470
  • 2 Mittapalli GK. Osornio YM. Guerrero MA. Ravinder KR. Krishnamurthy R. Eschenmoser A. Angew. Chem. Int. Ed. 2007; 46: 2478
  • 3 Zhang X. Krishnamurthy R. Angew. Chem. Int. Ed. 2009; 48: 8124
  • 4 Kini GD. Hennen WJ. J. Org. Chem. 1986; 51: 4436
  • 5 Kini GD. Petrie CR. Hennen WJ. Dalley NK. Wilson BE. Robins RK. Carbohydr. Res. 1987; 159: 81
  • 6 Varaprasad CV. Averett D. Ramasamy KS. Tetrahedron 1999; 55: 13345
  • 7 Varaprasad CV. Ramasamy KS. Hong Z. J. Heterocycl. Chem. 2006; 43: 325
  • 8 Wakharkar RD. Sahasrabuddhe MB. Borate HB. Gurjar MK. Synthesis 2004; 1830
  • 9 Keck GE. Kachensky DF. Enholm EJ. J. Org. Chem. 1985; 50: 4317
  • 10 Mohal N. Vasella A. Helv. Chim. Acta 2005; 88: 100
  • 11 Mohal N. Bernet B. Vasella A. Helv. Chim. Acta 2005; 88: 3232
  • 12 Keck GE. Wager TT. Duarte Rodriquez JF. J. Am. Chem. Soc. 1999; 121: 5176
  • 13 Reist EJ. Fisher LV. Goodman L. J. Org. Chem. 1967; 32: 2541
  • 14 Ozerov AA. Novikov MS. Brel’ AK. Solodunova GN. Chem. Heterocycl. Compd. 1998; 34: 611
  • 15 Loksha YM. Globisch D. Pedersen EB. J. Heterocycl. Chem. 2008; 45: 1161
  • 16 Boncel S. Gondela A. Mączka M. Tuszkiewicz-Kuźnik M. Grec P. Hefczyc B. Walczak K. Synthesis 2011; 603
  • 17 Gems FR. Perrotta A. Hitching GH. J. Med. Chem. 1966; 9: 108
  • 18 Sørensen MD. Khalifa NM. Pedersen EB. Synthesis 1999; 1937
  • 19 Fang W.-P. Cheng Y.-T. Cheng Y.-R. Cherng Y.-J. Tetrahedron 2005; 61: 3107
  • 20 Suchý M. Elmehriki AA. H. Hudson RH. E. Org. Lett. 2011; 13: 3952
  • 21 Coleman RS. Felpin F.-X. Chen W. J. Org. Chem. 2004; 69: 7309
  • 22 Kawana M. Kuzuhara H. Emoto S. Bull. Chem. Soc. Jpn. 1981; 54: 1492
  • 23 Brimacombe JS. Hunedy F. Tucker LC. N. J. Chem. Soc. C 1968; 1381
  • 24 Jogireddy R. Dakas P.-Y. Valot G. Barluenga S. Winssinger N. Chem. Eur. J. 2009; 15: 11498

Zoom Image
Scheme 1 Proposed retrosynthetic route for the d-azaribofuranose and l-lyxofuranoside-attached heterocycles (R. E. = recognition elements) starting from l-lyxose
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Scheme 2 Synthesis of the ketal-protected β-furanosides and α-pyranosides of l-lyxose. Reagents and conditions: (a) Acetone, ROH, H2SO4, 60 °C, 4 h (1: 72% and 5: <5%; 2: 48% and 6: <5%; 3: 37% and 7:<5%); (b) ROH, reflux, H+, 3 h; (c) HCl, acetone, DMP, r.t., 16 h (yields after two steps: 5: 36% and 1: <20%; 6: 41% and 2: <10%; 7: 30% and 3: <5%).
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Figure 1 Nucleophiles utilized for the SN2 reactions with l-lyxose derivatives
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Scheme 3 Generation of the trifluoromethanosulfonyl esters of l-lyxose and subsequent SN2 reaction with nucleophiles 811. Reagents and conditions: (a) Tf2O, DMAP, CH2Cl2, Py, –20 °C to r.t., 4 h; (b) 811, DMF, different conditions: see Table [1].
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Figure 2 HMBC (1H–13C, CDCl3) spectra of the alcohols 1 and 5. Correlations highlighted with a dashed circle corroborate unambiguously the configuration of the furanose and pyranose forms, respectively
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Scheme 4 Reaction scheme for the mixture of isomers of 5 and subsequent SN2 reactions with nucleophiles
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Scheme 5 Generation of the amines 18 and 20 for the ‘inverse approach’ in which the sugar acts as the nucleophile with a leaving group on the heterocycle. Attempted synthesis of 15c. Synthesis of 19 and 22 are shown for comparison. Reagents and conditions: (a) H2, Pd/C (5%), MeOH, r.t., 6 h (18: 95%; 20: 95%); (b) H2, Pd(OH)2, MeOH, r.t., 20 h (98%); (c) 5-bromouracil, DMF, 70 °C, 16 h (21: 56% and 15c: not found); (d) BzCl, DIPEA, CH2Cl2, r.t., 16 h (82%).
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Figure 3 NOESY (1H-1H, DMSO-d 6) spectrum that corroborates the β-configuration of 12c