1,3-syn-Diaxial Repulsion of Typical Protecting Groups Used in

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1,3-syn-Diaxial repulsion of typical protecting groups used in carbohydrate chemistry in 3-O-substituted derivatives of isopropyl D-idopyranosides Bozhena Sergeyevna Komarova, Alexey G. Gerbst, Anastasiia M. Finogenova, Andrey S. Dmitrenok, Yury Evgenievich Tsvetkov, and Nikolay E. Nifantiev J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01167 • Publication Date (Web): 27 Jul 2017 Downloaded from http://pubs.acs.org on July 28, 2017

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The Journal of Organic Chemistry

1,3-syn-Diaxial repulsion of typical protecting groups used in carbohydrate chemistry in 3-O-substituted derivatives of isopropyl Didopyranosides

Bozhena S. Komarova, Alexey G. Gerbst, Anastasiia M. Finogenova, Andrey S. Dmitrenok, Yury E. Tsvetkov, Nikolay E. Nifantiev* Laboratory of Glycoconjugate Chemistry, N.D. Zelinsky Institute of Organic Chemistry, Russian Academy of Sciences, Leninsky Prospect 47, 119991 Moscow, Russia *

Corresponding author. Tel, Fax: +7-499-135-87-84

[email protected]

ABSTRACT: The strength of 1,3-syn-diaxial repulsion was evaluated for main types of protecting groups (alkyl, silyl and acyl) usually used in carbohydrate chemistry. As molecular probes for this study, derivatives of isopropyl 2-O-benzyl-4,6-O-benzylidene-α-D-idopyranoside bearing allyl, acetyl and tert-butyldiphenylsilyl (TBDPS) protecting groups at O-3 were prepared from pmethoxyphenyl D-galactopyranoside. The equilibrium between OS2 and 4C1 conformations in these compounds was investigated using 3JH,H and 3JС,H coupling constants that were determined from 1D 1

H-NMR and 2D J-resolved HMBC spectra in various solvents. The analysis of the corresponding

coupling constants calculated using DFT/B3LYP/pcJ-1 approximation applied to conformations

ACS Paragon Plus Environment


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optimized at DFT/B3LYP/6-311++G** level supported the investigation. Proportions of conformers in the equilibrium revealed the highest repulsion between the 3-allyloxy group and the isopropoxy aglycon and its dependence on the solvent polarity. Differences in the conformational behavior of 3O-allyl and 3-O-acetyl-α-D-idopyranoside derivatives complied with the notion that higher electron density on O-3 increased 1,3-syn-diaxial repulsion. 3-O-TBDPS derivative existed mainly in 4C1 conformation. The attenuation of the 1,3-syn-diaxial repulsive interaction indicates that TBDPS has stereoelectronic properties that may have significance in context of fixing unnatural pyranoside conformation with the help of silyl groups but have been disregarded until now. Introduction Protecting groups have a profound effect on the result of glycosylation, a key reaction of oligosaccharide synthesis.1 We have long been studying so-called remote anchimeric assistance, its manifestations2-4 and possibility to adjust it for the targeted stereoselective oligosaccharide synthesis.1 A puzzling fact found during our studies is that the anchimeric assistance by remote acyl groups comes into effect in some cases and almost does not appear in others. For example, presence of potentially participating groups at O-3 and O-4 of fucosyl donors5 allows for stereoselective preparative synthesis of 1,2-cis-fucosides, while an acyl group at O-3 in glucosyl donors has almost no influence6 on stereochemistry of glucosylations. To find a root cause of this discrepancy, we performed analysis of putative conformational equilibrium of oxacarbenium ions derived from a 3-O-acetylated glucosyl donor (Scheme 1a) in a manner how it is usually done for predicting selectivity of glycosylations with substituted pyranosydes.7-10 It can be seen that benzyloxy substituents at C-2 and C-4 in conformer B can undergo destabilizing 1,3-syn-diaxial repulsion that might preclude the formation of bicyclic stabilized cation C (Scheme 1a). This explains the lack of α-directing influence of potentially participating acyl groups at O-3 of the glucoside ring. An additional argument in favor of this


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explanation is the behavior of 4,6-O-benzylidene-protected mannopyranosyl donors, in which 1,3syn-diaxial interaction between substituents at C-2 and C-4 cannot occur. These donors exhibit excellent β-selectivity when they bear a benzyl group at O-3, but become completely α-selective upon replacement of this benzyl group with a potentially participating benzoyl one.11 The 1,3-syn-diaxial destabilizing interactions were involved for the explanation12,13 of glycosylation selectivity with diverse pyranosyl donors with flexible conformations. In these works, Woerpel and Marel pointed at possible development of a disfavoring 1,3-syn-diaxial interaction between alkoxy substituents at C-2 and C-4 in 3H4 conformation of the oxacarbenium ion with the gluco configuration. The energy of this disfavoring 1,3-syn-diaxial interaction reaches 3 kcal/mol in 1,3-dimethoxycyclohexane.14 However, there is no experimental data that would clearly show the effect of 1,3-syn-diaxial repulsion in case of typical carbohydrate protecting groups. This work represents an attempt to assess the impact of this repulsion between O-3 bearing conventional protecting groups and a bulky alkoxy aglycon on the conformational equilibrium of pyranosides on the example of frequently used acetyl, allyl and tert-butyldiphenylsilyl protections in α-Didopyranoside derivatives 2a-c as model compounds (Scheme 1b). The idopyranose ring is known1518

for its conformational mobility. α-Idopyranose has four axial oxygens at C-2, C-3, C-4 and C-1,

whose destabilizing 1,3-syn-diaxial interactions are outweighed by anomeric effect of axially directed oxygen at C-1 and equatorial orientation of the alkoxymethylene group at C-5. Conformational behavior of unprotected idopyranosides has been extensively investigated in context of studies of heparin and its analogues.19 An array of protected and partially protected idopyranosides was studied by Angyal15,16 and Paulsen.17,18 Conformational features of idopyranosides along with their NMR coupling constants have been well established, and those data served us as a starting point in the present research. Recently,20 an efficient method was reported for the preparation of 4,6-O-benzylidene-protected


D-


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idopyranosides from corresponding 4,6-O-benzylidene-protected

D-galactopyranosides.

Taking

advantage of the availability of 4,6-O-benzylidene-protected D-idopyranosides, α-isopropyl idosides 2a-c along with their β-isopropyl counterparts 12a-c (Scheme 2) were chosen as suitable models for our investigation. SCHEME 1. (a) Putative 1,3-syn-diaxial interactions in conformer B of oxacarbenium ion derived from glucopyranosyl donor 1. (b) idopyranoside models 2a-c used in this study


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Results and discussion Synthesis of α- and β-isopropyl idopyranosides. The synthesis of idopyranoside derivatives 2a-c and 12a-c was started from preparation of dimesylate 4. Galactose diol 321 was mesylated with mesyl chloride in pyridine and dimesylate 4 was treated with potassium tert-butoxide in allyl alcohol according to the recently developed method.20 As a result, D-idopyranoside 5 was obtained in 71% yield. A small amount of the epoxy intermediate, p-methoxyphenyl 2,3-anhydro-4,6-Obenzylidene-β-D-talopyranoside 6, was also isolated. Inversion of configurations of C-2 and C-3 was confirmed by reduced vicinal coupling constants between H-1, H-2 and H-3 in the 1H NMR spectrum of product 5 relatively to starting 4. Benzylation of 5 with BnBr in DMF easily gave 7a. Attempts of PdCl2-catalyzed deallylation of 7a in order to obtain alcohol 8 failed. To overcome this problem, allyl removal was performed with low-valent titanium.22 More than fourfold excess of Ti(OPr-i)4/Mg relative to starting 7a was used to prepare 8 and minimize the formation of diol 9, the main byproduct of this reaction. Target product 8 was obtained under these conditions in 59% yield. The structures of 8 and 9 were proved by their NMR spectra and HRMS data. N-Phenyltrifluoroacetimidoyl group was shown to be one of the most reliable leaving groups for

performing

glycosylations

with

2-O-benzylated

donors.2,6,23-25

Therefore,

N-

phenyltrifluoroacetimidates 11a-c were used to prepare isopropyl D-idosides 2a-c and 12a-c. These donors were synthesized from 7a, acetate 7b and silyl ether 7c; the latter two derivatives were obtained from 8 by conventional acetylation and silylation, respectively. Anomeric p-methoxyphenyl groups in 7a-7c were removed by treatment with CAN in a two-phase acetonitrile–benzene–water mixture to produce hemiacetals 10a-c. Donors 11a-c were prepared by the reaction of 10a-c with N-phenyltrifluoroacetimidoyl chloride in the presence of K2CO3. It should be noted that imidates 11a-c proved to be much more sensitive to hydrolysis upon silica gel column



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chromatography than the similarly protected glucosyl donor,6 and the usual addition of a drop of Et3N to the eluent was not enough to fully prevent the product decomposition. SCHEME 2. Synthesis of idopyranoside probes 2a-c.a

a

Conditions and reagents: (a) MsCl, Py, CH2Cl2 (93%); (b) t-BuOK, AllOH, benzene (71% for 5; 5 % for 6); (c) BnBr,

NaH, DMF (99%); (d) Ti(OPr-i)4, Mg, TMSCl, THF (59% for 8; 5% for 9); (e) Ac2O, Py (89%); (f) TBDMSCl, Py, imidazole (79%); (g) CAN, benzene-CH3CN-H2O (90% for 10a; 90% for 10b; 57% for 10c); (h) CF3C(NPh)Cl, K2CO3, acetone (77% for 11a; 84% for 11b, 78% for 11c); (i) i-PrOH, TfOH (5 mol %), AW-300, CH2Cl2 (40% for 2a, 46% for 12a; 28% for 2b, 60% for 12b; 42% for 2c, 54% for 12c).

To minimize the loss of the donors, the time of contact with silica gel upon chromatographic purification should not exceed 40-60 min independently of the scale. To avoid decomposition of especially labile silylated 11c, its purification was carried out at a temperature below –10 °C. TfOH-catalyzed glycosylation of isopropyl alcohol with imidates 11a-c afforded mixtures of isopropyl idosides 2a-c and 12a-c in yields of about 90% and α:β ratios ranging from 1:1.15 to 1:2.2. Anomeric configurations of 2a-c and 12a-c were deduced from their ROESY spectra and


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1

JC1,H1 coupling constant values. Thus, β-anomers 12a-c were featured with the presence of

correlations between H-1 and H-5 in their ROESY spectra, while such correlations were not observed in the spectra of α-anomers 2a-c. In addition, β-anomers 12a-c and α-anomers 2a-c had the 1JC1,H1 coupling constant values of 156-157 Hz and 169-171 Hz respectively. These values are characteristic for the axial and equatorial orientation of the anomeric protons.26-28 Instrumentation for NMR study. NMR spectra were recorded in CDCl3, CD2Cl2, CD3CN or toluene-d8 solutions on Bruker spectrometer AV-600 with 0.05% TMS as reference (1H 0.0 ppm, 13C 0.0 ppm) at different temperatures. The resonance assignment in 1H and

13

C NMR spectra was

performed by gradient enhanced 2D gCOSY, gNOESY, gHSQC, gJ-HMBC experiments as well as TOCSY and ROESY experiments. Standard pulse sequences were used. A mixing time was set to 100 ms in the TOCSY experiments. A spin-lock time of 150 ms was used in the ROESY experiments. Experimental 3JC–H constants were measured using J-HMBC29 experiment. The experimental error of thus measured 3JC–H was found by us to have the value of 0.5 Hz.30 The spectral widths were about 2 ppm for 1H region and 40 ppm for

13

C region and did not include resonances of aglycon

groups. The data were collected in the echo/anti-echo mode. The length of gradients was 1 ms, and the recovery time was 100 µs. The spectra were acquired with 80–120 t1 increments and 64–256 scans per increment. 1024 points were collected during the acquisition time t2. The HMBC preparation delay was optimized for JC–Hmin = 1.5 and 2.0 Hz. In cases when there was a necessity to measure the 3JC,H that had values less than 2 Hz J-HMBC experiments were optimized for 1.5 Hz. In all other cases delay in the pulse sequence was optimized for 2 Hz in order to overcome the weak sensitivity of J-HMBC experiments and simplify developing of all needed cross correlations. The upscaling coefﬁcient k was 25–60. The relaxation delay was 1s. The third order low-pass J-ﬁlter was introduced for the suppression of one bond constant (1JC–H) in the range from 125 to 180



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Hz. The forward linear prediction to 1024 points was used in F1. The processing was performed with p/2 shifted sine square function in both dimensions. Computational details. All calculations were performed in gas phase using DALTON2015 software.31 6-311++G** basis set was used as supplied with the program, pcJ-1 basis set32 was obtained from EMSL Basis Set Exchange.33 Before the calculation of the constants, starting structures representing OS2 and 4C1 conformations were built for each molecule. They were then subjected to the first order geometry optimization at DFT/B3LYP/6-311++G** level, Baker conditions were used to determine convergence. Hessian indices were zero in all the cases. Then coupling constants were calculated for the optimized structures using DFT/B3LYP/pcJ-1 approximation. Preliminary calculations showed that the greatest contribution to all the constants of interest was provided by the Fermi-contact term, while the summary contributions from all other terms did not exceed 2% of each JC,H/JH,H value due to the mutual compensation of diamagnetic and paramagnetic spin-orbit terms (Sample table of JC,H calculated using all the terms is given in Supporting Information, Section 1, Table S1). Hence only this term was further computed which resulted in a considerable speed-up. Cremer-Pople parameters for the optimized conformers were computed using an on-line service.34 All the absolute energies are provided in the Supporting Information (Section 1.3, Table S20). Identification of conformer ratio in equilibrium in CDCl3 solution. Influence of O-3 substituents. According to the classic works,16,18 in benzylidene-protected α-idopyranosides like 2a-c, 1,3-syn-diaxial repulsion between aglyc1on and a substituent at O-3 causes distortion of the normal 4C1 conformation towards preference of

O

S2. Additionally, 1S5 conformer can also be

regarded as possible. Its formation might be expected either from 4C1 through 4H5-like conformation which seems unfavorable in the case of 4,6-O-benzylidene derivatives, or from OS2 conformation through B2,5. DFT calculations of 1S5 conformers for α-compounds 2a-c showed that their energies


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lay in the middle between 4C1 and OS2 except for 2c where it had the highest relative energy (Supporting information, Section 1.3, Table S20). Hence B2,5 conformers were examined only for compounds 2a and 2b and their geometry optimizations led to OS2 conformers. In our opinion, this means that the 1S5 conformer cannot be reached in the structures under study due to kinetic reasons and is not considered further. It was suggested based on the work by Lemieux35 that the proportion of OS2 conformation in the equilibrium of a 3-O-substituted α-idopyranoside derivative should reflect the degree of 1,3-syndiaxial repulsive interaction between the O-3 substituent and the aglycon. For the detection of the conformational changes in the sugar ring, vicinal proton-proton and carbon-proton coupling constants were measured in the hope that the two datasets would complement each other. While 3

JH,H constants are routinely used in conformational analysis of pyranoside rings, 3JC,H coupling

constants are more seldom employed for this task. Two examples are inspiring: the first is the determination of conformation of C-5–C-6 side chain in pyranosides36 and the second describes evaluation of pyranoside conformation of unprotected idopyranosides.37 Assuming observable vicinal constants (3J) to be linear combinations of the corresponding constants for separate conformers in the equilibrium, proportions of the conformers were to be calculated on the basis of experimental 3J magnitudes and values of the corresponding constants for separate conformers calculated using a quantum mechanical approach. Geometry optimization of studied structures 2a-c and 12a-c (Scheme 2) gave the following results. Starting 4C1 conformations for both α- (2a-c) and β-idosides (12a-c) during the optimization showed just a slight change in the ring shape producing the same conformation very slightly distorted towards OН5 or OН1 in case of α- and β-isomers respectively (Table 1). For convenience, this conformation is further on denoted simply as 4C1. However, when starting OS2 conformations were subjected to the optimization, there was significant difference depending on the anomeric



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configuration. Thus, α-idosides 2a-c all retained OS2 conformation, while their β-counterparts ended up in a conformation almost exactly intermediate between 1S5 and B2,5 (Table 1). In our opinion, this suggests that in the studied β-idosides neither pure skew, nor pure boat conformations seem to exist. The 1H-1H coupling constants for the optimized conformations of 2a-c and 12a-c along with those measured experimentally are presented in Table 2. Since the quantity of OS2 (or 1S5/B2,5 in case of compounds 12a-c) conformer reflects the degree of 1,3-syn-diaxial repulsion, it seemed reasonable to calculate their proportions (PS) from these data. To this end, equation (1) was used, PS=100•(e-b)/(a-b)

(1)

that is a general solution for the proportion brought from assumption that observable coupling constants are linear combinations of the constants calculated for the separate conformers. In this equation e stands for the experimental magnitude of the vicinal coupling constant, and a and b are the corresponding values computed for the skew and 4C1 conformers respectively. The proportion of the skew conformers was calculated for each compound under investigation (Table 2). TABLE 1. Cremer-Pople Parameters of the DFT Optimized Structures for 2a-c, 12a-c Cremer-Pople Starting Compound

2a

parameters

4

φ

θ

Q

330.25

11.48

0.48

Slightly distorted 4C1 (→OH5)

S2

326.32

86.40

0.73

O

C1

335.56

11.13

0.48


S2

325.78

87.92

0.74

O

C1

330.69

10.65

0.48


324.63

86.78

0.72

O

C1

O

2b

4

O

2c

4

O

Resulting conformation

conformation

S2


S2

S2

S2

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12a

4

35.68

11.01

0.54


S2

284.43

97.18

0.69

1

C1

32.11

11.96

0.53


S2

283.13

97.80

0.69

1

C1

36.48

11.19

0.54


285.73

97.55

0.69

1

C1

O

12b

4

O

12c

4

O

S2

S5/B2,5

S5/B2,5

S5/B2,5

As it can be seen, for instance, from the percentage of OS2 conformer in 2a, there is a considerable dispersion in calculated proportions. Thus, calculations using data for J2,3 suggest that 2a exists at 73% in the OS2 conformation, meanwhile, this value calculated from J4,5 is 60%, and, finally, consideration of J6S,5 demonstrates the value of only 20%. In order to estimate which of the values could be treated as reliable, a degree of uncertainty (or uncertainty propagation, σgen) was calculated that arises from the implementation of equation (1) to three values each of which is measured or calculated with its proper independent uncertainty (Supporting information. Section 2). The uncertainty propagation calculations demonstrate that in case of compounds 2a-c only proportions calculated using J1,2 and J2,3 values can be treated as reliable (Table 2), while proportions calculated using other constants should be neglected as non-significant. It can be concluded from the data for compounds 2a-c that 3-O-allylidopyranoside 2a persists as mainly OS2 conformer with OS2 proportion 73±9%. Acetylated idosyl derivative 2b seems to have predominantly 4C1 conformer with the range of OS2 proportion 32±8%. Conformer ratio for idosyl derivative 2c bearing a TBDPS protective group was found to be 26±9%. The latter result evidences that silylated α-isopropyl idoside 2c tends to adopt the 4C1 conformation despite the fact that in this case the bulky TBDPS substituent in axial position is supposed to have a steric repulsion with the isopropyl group in the aglycon.



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TABLE 2. Experimental and calculated

3

JH,H coupling constants (Hz) and conformer

percentages of 2a-c, 12a-c Compound

Coupling constants

J1,2

J2,3

J3,4

J4,5

J6S,5

J6R,5

2a

Exp. values

5.0

9.0

3.4

2.5

1.5

2.5

Calculated OS2

6.2

11.7

3.7

2.9

1.1

3.4

Calculated 4C1

0.8

1.7

2.2

1.9

1.6

2.5

Percentage of OS2 conformer

78

73

80

60

20

-a

Uncertainty σgen

±17

±9

(±60)b

--b

--b

--b

Exp. values

3.0

5.3

3.1

2.5

0.9

2.3

Calculated OS2

6.1

12.6

4.7

3.0

1.1

3.5

Calculated 4C1

0.8

1.8

2.5

1.9

1.7

2.4


42

32

27

55

-a

-a

Uncertainty σgen

±15

±8

±40

--b

--b

--b

Exp. Values

2.5

4.4

2.7

2.2

1.5

2.1

Calculated OS2

6.0

11.8

3.8

2.8

1.2

3.4

Calculated 4C1

0.8

1.8

2.3

1.9

1.6

2.4


33

26

27

33

25

-a

Uncertainty σgen

±16

±9

--b

--b

--b

--b

Exp. values

1.4

3.4

2.8

2.0

1.2

2,1

Calculated 1S5/B2,5

3.3

10.0

0.7

2.6

1.5

2.5

Calculated 4C1

1.2

2.8

2.3

2.1

1.4

2.7

Percentage of 1S5/B2,5 conformer

10

8

-a

-a

-a

-a

Uncertainty σgen

±50

±18

--b

--b

--b

--b

Exp. Values

1.5

3.2

2.6

1.8

1.4

2.2

2b

2c

12a

12b


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12c

a

Calculated 1S5/B2,5

2.9

10.6

0.8

2.6

1.5

2.4

Calculated 4C1

1.2

2.8

2.4

2.0

1.6

2.6


18

5

-a

-a

-a

-a

Uncertainty σgen

--b

±14

--b

--b

--b

--b

Exp. Values

0c

2.8

-d

0c

0c

1.8

Calculated 1S5/B2,5

3.0

10.2

0.9

2.7

1.4

2.7

Calculated 4C1

1.3

2.8

2.3

2.1

1.5

2.6


-a

0

-a

-a

-a

-a

Uncertainty σgen

--b

±15

--b

--b

--b

--b

Percentage of conformer cannot be calculated because experimental value falls out of the range between two

corresponding constants calculated for separate conformers. bUncertainties with values more than 50% are omitted; also the corresponding percentage values can be neglected and are given only to demonstrate their dispersion. cMeasurement of coupling constant with 0.1 Hz exactness was not possible because of signal broadening. dCoupling constant cannot be determined because of signals overlap.

Manifestations of TBDPS, TBDMS and TIPS bulkiness are well known. Thus, these groups are used in carbohydrate chemistry not only as protective groups but also as substituents capable of changing the pyranose conformation.38-40 Main driving force for the conformational flip induced by TBDPS, TBDMS38 or TIPS is thought to be a steric repulsion between them when these groups have a vicinal arrangement. But the example of 2c clearly showed that the ability of TBDPS to exert steric hindrances plays a subordinate role in the case of the 1,3-syn-relashionship. The propensity of TBDPS to be axial in 2c also correlates with observations41,42 that the O-TBDPS group in silylated cyclohexanol is prone to adopt an axial orientation. The reason for weakening of the 1,3-syn-diaxial interaction in silylated 2c may lie in the properties of the Si–O linkages, which are remarkable for low basicity of oxygen in both Si-O-Si43,44 and Si-O-C45,46 structures, despite higher anionicity relative to C–O bond. NBO analysis showed that the lone pair of oxygen is involved in a resonance



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type nO→s*Si-C interaction.43,44 This effect might diminish the electron density on O-3 in 2c and thus lead to predominance of the 4C1 conformer. Three β-isomers, 12a-c, were also studied in order to get an estimation of the repulsive interaction strength between substituents at C-2 and C-4, which also had mutual 1,3-syn-diaxial spatial relationship in 4C1 conformation in both α- (2a-c) and β- (12a-c) isopropyl glycosides. On the other hand, both chair and skew conformations of β-idosides lack O-3–O-1 1,3-syn-diaxial repulsion. As can be seen from Table 2, the J3,4, J4,5 and J5,6 values fall out of the range between two corresponding constants calculated for 4C1 and 1S5/B2,5 conformers of 12a-c. Meanwhile, the values of J1,2 appear to be inaccurate since uncertainty propagation for proportion calculated using this constant is more than 20%. Taking the values of J2,3, allylated β-idopyranoside 12a as well as its acetylated and silylated counterparts 12b and 12c, all adopt mainly 4C1 conformation, likely having the percentage of OS2 between 0-26%, 0-19% and 0-15% respectively. Therefore, it should be concluded that the interaction between the substituents at C-2 and C-4 does not contribute much to the preference for OS2 conformer in 2a-c, which is thus mainly governed by the relative instability of the 4C1 conformer due to repulsion between the substituents at C-1 and C-3. In this way, the validity of compounds 2a-c as models for the study of 1,3-syn-diaxial repulsion is proved. Relative energies of the conformers obtained after the geometry optimization calculations demonstrated (Supporting information, Section 1.3, Table S20) that 2a-c and 12a-c may not exist as pure OS2 or 4C1, which are actually the conformers found by simple conformational analysis.17 However, no strict correlation between the calculated energies and the supposed percentage of conformers could be established. Influence of solvents on the conformation. The dielectric constant of solvent was shown to influence the conformational equilibrium of pyranosides by way of modulating the 1,3-syn-diaxial


Page 15 of 40

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repulsion.16-18,35 This may consequently have an effect on stereoselectivity of glycosylations through the influence on the conformational equilibrium of oxacarbenium ions, when one of the putative conformers has 1,3-syn-diaxial substituent arrangement. Although the influence of solvents on the selectivity of glycosylations has been comprehensively investigated,47-49 we suggested that 1,3-syndiaxial repulsion may be one of the driving forces that define the pattern of solvent effects. To investigate this question in-depth, conformational behavior of α-idopyranosides 2a-с was studied in three solvents, CD2Cl2, CD3CN and toluene-d8, which are deuterated analogues of the most frequently used solvents in glycosylation reactions. 1

H NMR and J-HMBC spectra were recorded for compounds 2a,c in CD2Cl2, CD3CN and

toluene-d8, for compound 2b in CD3CN and toluene-d8 (Tol-d8). Besides, spectra of allyl idoside 2a were recorded in a CD2Cl2-toluene-d8 mixture (1:1). The resulting set of 1H-1H coupling constants is presented in Table 3. The computed values of constants for distinct conformers and dielectric constants are also given. The major changes of magnitudes were observed for the J2,3 constants. TABLE 3. 3JH,H coupling constants (Hz) of 2a-с determined in different solvents Solvent

2a

Calculated OS2

6.2 11.7 3.7 2.9

1.1

3.4

Calculated 4C1

0.8

1.7

2.2 1.9

1.6

2.5

Tol-d8

5.3

9.5

3.4 2.7

0

2.8

78

2

CDCl3

5.0

9.0

3.5 2.3

1.5

2.5

73

5

CD2Cl2-Tol-d8, (1:1) 4.8

8.8

3.5

-b

0

2.4

72

2b

J1,2

J2,3

J3,4 J4,5 J6S,5 J6R,5 OS2 (%)a ε

Compound

CD2Cl2

4.7

8.5

3.4 2.8

-b

2.5

68

9

CD3CN

4.5

8.2

3.4

-b

0.9

-b

65

36

Calculated OS2

6.1 12.6 4.7 3.0

1.1

3.5

Calculated 4C1

0.8

1.7

2.4

1.8

2.5 1.9



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Page 16 of 40

2с

a

Tol-d8

3.4

5.8

3.3 2.3

1.0

2.4

37

CDCl3

3.0

5.3

3.1 2.5

0.9

2.3

32

CD3CN

3.4

6.4

3.4 2.3

-b

-b

43

Calculated OS2

6.0 11.8 3.8 2.8

1.2

3.4

Calculated 4C1

0.8

1.8

2.3 1.9

1.6

2.4

Tol-d8

3.5

6.2

3.3 2.6

1.5

2.4

44

CDCl3

2.5

4.4

2.7 2.2

1.5

2.1

26

CD2Cl2

2.1

4.0

-b

1.6

1.8

22

CD3CN

2.3

4.3

2.8 2.3

0

0

25

2.4

Percentage of the OS2 conformation calculated by eq. 1 from the J2,3 values. bCoupling constant cannot be determined

due to signals overlap.

Changes in coupling constant values for 2a measured in different solvents correlated with solvent dielectric constants (comparison of main peak forms can be found in the Supporting information, Page S54). It is particularly noticeable for the J2,3 values. That is, OS2/4C1 ratio depends on solvent polarity as long as J2,3 is considered as estimation for this ratio. Decrease of the relative proportion of OS2 in CD2Cl2 in comparison to CDCl3 correlates with higher polarity of CD2Cl2. A mixture of CD2Cl2 and toluene-d8 (1:1) generates an equilibrium in which the percentage of OS2 becomes a mean of those in CD2Cl2 and in toluene-d8. The conformer ratios were also the same in CDCl3 and in the 1:1 mixture of CD2Cl2 and toluene-d8. In the most polar solvent, CD3CN, the percentage of the OS2 conformer demonstrated the lowest value among all the tested solvents. These results suggest that in context of glycosylation mechanism, the largest impact from the 1,3-syn-diaxial repulsion on the conformation of the intermediate oxacarbenium cations should be expected in toluene. In acetonitrile this influence should be the smallest. Conformational effects of the 1,3-syn-diaxial repulsion in CD2Cl2 and CDCl3 lie in the middle between those in toluene-d8 and


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CD3CN, but still one would expect stronger repulsion in CDCl3 than in CD2Cl2. Mixing of solvents of different polarity reveals an additive effect. 1

H-1H coupling constants in spectra of 2b,c demonstrate the same tendencies as observed for

structure 2a, that is, they suggest that the skewed conformer is prevalent in a less polar solvent (toluene-d8). However, in a more polar solvent (CD3CN) definite preference for 4C1 chair conformation can only be observed for compound 2a. For structure 2c the effect is less pronounced when comparing CDCl3 and CD3CN, and for 2b the trend is reversed. This means that the behavior of the studied compounds in different solvents can be regulated also by other forces besides the 1,3syn-diaxial repulsion. For example, changes in overall dipole moments upon the conformational transformations can be regarded as one of such factors. To study this question in detail, the same experiments were performed for the β-idosides, 12a-c (Table S33, Section 3.4 in Supporting information) and the results for all the compounds in the work were analyzed in comparison with the calculated dipole moments (Table S21, Section 1.4 in Supporting information). This analysis showed that in all the α-structures differences in dipole moments between chair and skewed conformations were rather small. Molecule 2b was the only example where the skewed conformation was even slightly more polar than 4C1. In the β-series all the chair conformers were strongly more polar than the skewed ones. However, coupling constant changes in different solvents in this series were weak and contradictory. Some deviations in 1H-1H coupling changes for compounds 2b and 2c in CD3CN as compared to 2a could possibly be explained by the fact that in the former two the 1,3-syn-diaxial repulsion is expectedly decreased and, especially in the polar solvent, dipole moments started to have some effect. In summary, all this indicates that changes of the dipoles play a minor role as compared to the 1,3-syn-diaxial repulsion in compound 2a, while in 2b and 2c in polar CD3CN their influence might be stronger. For the β-compounds only absence of the 1,3-syn-diaxial repulsion can be clearly established.



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In case when the proposed conformer for the oxacarbenium ion has a 1,3-syn-diaxial relationship of two substituents, the difference in stereoselectivity of glycosylations in different solvents can be explained by the influence of solvent polarity on the strength of 1,3-syn-diaxial interaction. Indeed, there is plenty of examples,50-52 when selectivity differs depending on solvent polarity. For example, donors with the gluco configuration, whose plausible oxacarbenium ions may have 1,3-syn-diaxial relationship between 2-OBn and 4-OBn, demonstrate53,54 different stereoselectivity in CH2Cl2 and CH3CN. There is little evidence that toluene changes selectivity of glucosylations relative to CH2Cl2. In the only found literature example demonstrating consistent comparison of glucosylation selectivities in CH2Cl2 and toluene without ether co-solvents, a pronounced difference between these two solvents is shown. However, the resulting selectivities are overshadowed by the presence of modulating DMF additive.55 The idea that the influence of solvent polarity on the oxacarbenium ion conformation and, hence, on selectivity can be mediated by 1,3syn-diaxial interaction correlates well with the hypothesis that the stereoselectivity is explained by solvent-induced variations in conformational preferences of the oxacarbenium cation.56,47 Applicability of 3JC,H couplings for study of conformational equilibria in idopyranosides. Although knowledge of 3JH,H couplings allows for estimation of conformer ratio, in case of idopyranosides 2a-c and 12a-c even thorough examination of JH3,H4, JH4,H5 and JH5,H6 couplings provided little information about real torsional angles at C3-C5. In order to learn more about the conformational shape of the studied compounds, J-resolved HMBC spectra were registered for 2a-c and 12a-c in different solvents and vicinal carbon-proton (3JC,H) coupling constants were extracted from them (Tables S27-S32, Section 3.3 in Supporting information). Applicability of the resulting 3JC,H constants for the calculation of conformer proportions of αD-idosides

2a-c was evaluated by analysis of uncertainty propagation. Calculated percentage and

uncertainties are provided only for the case of 2a in CDCl3 (Table S26, Section 3.2 in Supporting information) since resulting uncertainties in all the other cases were very much alike.


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Large uncertainties preclude determination of the conformer percentage from 3JC,H couplings. The limitation comes from everywhere: experimental uncertainties increase, same as does the uncertainty of calculations due to the smaller range of constants; another difficulty is the small difference between putative values of coupling constants of separate conformers. As it was found (Supporting information Section 2) uncertainty of 3JC,H coupling constants derived from computer modelling is ≤ 2.1 Hz, measurement uncertainty is 0.5 Hz and maximum range between couplings of putative values of coupling constants of separate conformers is 3.9 Hz (Supporting information Table S28, JC5,H3). These values give uncertainty propagation minimum ±43%. Nevertheless, vicinal and geminal JC,H coupling constants are being increasingly introduced into the field of analysis of pyranoside conformations. Serianni tested conformity of experimental JC,H (and JC,C) of D-idosides with percentage of 4C1 conformer calculated from 3JH,H by building plots of the percentages of 4C1 against some JC,H values.37 Changes in 3JC,H couplings in α-D-idosides 2a-c and β-D-idosides 12a-c correlate well with the tendencies demonstrated by 3JH,H couplings manifested in different solvents. In particular, decrease of JC1,H5, JC3,H1, JC1,H3, JC4,H2 and JC5,H3 is consistent with enlargement of proportion of

O

S2

conformer. Two plots (Figures S2 and S3, Section 3.5, Supporting information) of the percentages of 4C1 against JC3,H1 and JC2,H4 values were built throughout compounds 2a-c to see if behavior of 3JC,H coupling constants is consistent for different compounds. Analysis of the plots reveals that changes of JC1,H3 and JC2,H4 values for 2b and c conform one trend. However values JC3,H1 and JC2,H4 of 2a fall out. Influence of temperature on the conformer ratio. In an attempt to freeze out separate conformers and measure coupling constants for each of them, 1D 1H NMR spectra of 2a in CD2Cl2 solution were recorded at temperatures as low as –80°C. But even at that temperature, only



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Page 20 of 40

decreased values of some inter-proton constants (J1,2, J2,3 and J3,4) were observed (Table 4). This might mean that with the lowering of the temperature, the proportion of OS2 conformer goes down. If this percentage is calculated using J2,3 constants, the quantity of the OS2 conformation changes from 68% at RT to 48% at –80 °C. This lack of success coincides with Paulsen’s results,17 when he also failed to acquire spectra containing signals of separate conformers of idose even at –100 °C and observed only decrease of coupling constants. TABLE 4. 3JH,H coupling constants (Hz) of 2a determined in CD2Cl2 at different temperatures Temperature/ Coupling constants 273 K 193 K a

O

S2 (%)a

J1,2

J2,3

J3,4

4.8

8.5

3.3

68

3.2

7.0

2.6

48

Percentage of OS2 conformation calculated by eq. 1 from values of J2,3.

This observation also means that the impact of 1,3-syn-diaxial repulsion on the conformational equilibrium might decrease at lower temperatures. Therefore, in case when this interaction is important for the equilibrium of oxacarbenium ions formed during glycosylation, the ratio of anomeric products would depend on the temperature at which the glycosylation was carried out. Indeed, sometimes temperature influences the stereochemical result of glycosylations and this influence seems to be differently directed for different glycosyl donors.57-59,6 Probably, the complex pattern of the temperature dependence can be partly explained by the increasing intervention of 1,3syn-diaxial repulsion into the conformational equilibrium with the rise of the temperature. Conclusions The substituents at C-1 and C-3 in isopropyl 2-O-benzyl-4,6-O-benzylidene-α-D-idopyranosides experience repulsive 1,3-syn-diaxial interaction to different extent depending on the type of the protecting group at O-3. Among the three studied O-3 substituents (allyl, acetyl, and TBDPS), which represent the principal types of protecting groups in carbohydrate chemistry, the allyl


Page 21 of 40

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derivative displays the largest repulsive force. The destabilizing O-1/O-3 interaction caused a shift in the conformational equilibrium 4C1↔OS2 towards OS2. The percentage of the latter conformer reaches 73±9%, which shows that the anomeric effect and the strain resulting from ring puckering are outweighed by 1,3-syn-diaxial repulsion. In accordance with the assumption that electron density on oxygen atoms determines the strength of this repulsion, the 3-O-acetyl derivative adopts predominantly 4C1 conformation with the relative proportion of OS2 dropping down to 32±8%. In the case of the 3-O-TBDPS derivative, the weight of OS2 conformer is only 26±9%, despite presumably unfavorable spatial interactions between TBDPS and the isopropyl group. The observable decrease of syn-1,3-diaxial interaction in 2c is in accordance with the known feature of the Si-O linkage consisting in lower basicity of oxygen in comparison to C-O bond. The conformer ratios for 2b and 2c show that TBDPS diminishes electron density on oxygen more effectively than the acetyl group. The repulsive interaction between the substituent at C-3 and 1-isopropoxy groups in the αidosides depends on polarity of the solvent. Particularly, in the case of the 3-allyloxy group the lower content of the OS2 conformer in the equilibrium correlates with the higher solvent dielectric constant in accordance with our hypothesis of 1,3-syn-diaxial repulsion. In case of 3-acetoxy and 3silyloxy substituents, due to the expected decrease of this repulsion, other factors influencing the conformational state, such as overall dipole moments, seem to play some role in polar solvents. Assuming that stereoselectivity of glycosylation is regulated by the conformational equilibrium of oxacarbenium ions, this opens a way to understanding how the solvent dielectric constant affects stereoselectivity through destabilization of conformers with a 1,3-syn-diaxial relationship between two alkoxy substituents. This is, for example, the case of donors with the gluco configuration bearing simultaneously two alkyl protecting groups at O-2 and O-4. Analysis of experimentally measured vicinal proton-proton couplings in combination with DFT/B3LYP/pcJ-1 calculations of constants for separate previously optimized conformers represents a reliable tool for determination of conformer ratio with 15% precision in case of



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Page 22 of 40

pyranosides. The use of carbon-proton vicinal couplings is limited due to adverse factors: the greater uncertainties of coupling measurement from J-HMBC spectra and insufficient prediction accuracy of couplings for separate conformers by computer calculations. Experimental section General experimental methods. Molecular sieves MS AW-300 for glycosylation reactions were activated prior to application at 180 °C in vacuum of an oil pump for 2 h. Dichloromethane was successively distilled from diethanolamine, P2O5, and CaH2 under Ar. Pyridine was dried by distillation from P2O5. Analytical TLC was performed on Silica Gel 60 F254 aluminium sheets (Merck), and visualization was accomplished using UV light or by charring at 150 °C with 10% (v/v) H3PO4 in isopropyl alcohol. Column chromatography was performed on Silica Gel 60, 40–63 µm (Merck). Low-temperature chromatography of 11c was carried out using a jacketed column connected to a Lauda Eco RE 1050 S cooling thermostat. Signal assignment in 1H and

13

C NMR

spectra was made using COSY and 1H-13C HSQC techniques. p-Methoxyphenyl 2,3-di-O-mesyl-4,6-O-benzylidene-β-D-galactopyranoside (4). Mesyl chloride (19.4 mL, 0.25 mol) was added to a chilled solution of diol 3 (28.3 g, 0.075 mol) in a mixture of dry CH2Cl2 (340 mL) and pyridine (200 mL). Cooling was removed and the reaction mixture was stirred at rt for 5 days. After completion of the reaction (TLC control), the solvents were evaporated and residual pyridine was removed by addition and evaporation of toluene (3×25 mL). The residue was purified by chromatography on silica gel in CH2Cl2-CH3OH (200:1→175:1) to afford 4 (38.1 g, 95%): white crystals, mp 227–229 °C, Rf = 0.20 (toluene–MTBE, 2.5:1); [α]D24 –9.6 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.57–7.53 (2H, m, Ph), 7.43–7.36 (3H, m, Ph), 7.05 (2H, d, J 9.0 Hz, OCH4OCH3), 6.86 (2H, d, J 9.0 Hz, OCH4OCH3), 5.61 (1H, s, CHPh), 5.14 (1H, dd, J2,1 7.9 Hz, J2,3 10.0 Hz, H-2), 5.02 (1H, d, J1,2 7.9 Hz, H-1); 4.86 (1H, dd, J3,2 9.9 Hz, J3,4


Page 23 of 40

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3.7 Hz, H-3), 4.56 (1H, d, J4,3 3.7 Hz, H-4), 4.37 (1H, br dd, J6A,6B 12.7, H-6A), 4.10 (1H, dd, J6B,5 1.5 Hz, J6B,6A 12.6 Hz, H-6B), 3.79 (3H, s, OCH3), 3.60 (1H, br m, H-5), 3.20, 3.18 (6H, 2s, SCH3); 13

C NMR (150 MHz, CDCl3): δC 129.2, 129.0, 126.3 (Ph), 119.2, 114.8 (MeOC6H4O), 101.1

(PhCH), 100.0 (C-1), 76.6 (C-3), 76.2 (C-2), 74.8 (C-4), 68.4 (C-6), 66.3 (C-5), 55.7 (OCH3), 39.4, 39.2 (SCH3). Anal. Calcd (%) for C22H26S2O11: C, 49.80; H, 4.94. Found: C, 49.85; H, 4.83. p-Methoxyphenyl 3-O-allyl-4,6-O-benzylidene-β-D-idopyranoside (5). A solution of potassium tert-butoxide (16.2 g, 0.14 mol) in allyl alcohol (56.0 mL) was added to a solution of the dimesylate 4 (7.0 g, 0.013 mmol) in a mixture of allyl alcohol (60.0 mL), dry benzene (45.0 mL) and dioxane (47.0 mL). After 4 days, the reaction mixture was evaporated to dryness, redissolved in ethyl acetate (230 mL), and washed with saturated sodium chloride solution (230 mL). The aqueous layer was extracted back with EtOAc (3×30 mL). The combined organic layers were dried with sodium sulfate, filtered, and evaporated to dryness. The resulting solid was purified by column chromatography on silica gel using toluene–MTBE (50:1→25:1) to give the idopyranoside 5 (3.9 g, 71%) as a white foam and anhydro-D-talopyranoside 6 (215 mg, 5 %) as a yellowish crystal solid. 5: Rf = 0.20 (toluene–EtOAc, 20:1); [α]D24 –74.9 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.50–7.46 (2H, m, Ph), 7.38–7.31 (3H, m, Ph), 7.06 (2H, d, J 9.1 Hz, OCH4OCH3) , 6.82 (2H, d, J 9.1 Hz, OCH4OCH3), 5.88 (1H, m, CH2=CHCH2O), 5.51 (1H, s, CHPh), 5.29 (1H, m, CH2=CHCH2OA), 5.27 (1H, br s, H-1), 5.22 (1H, m, CH2=CHCH2OB), 4.40 (1H, dd, J6A,5 1.33 Hz, 12.6 Hz, H6A), 4.15 (2H, m, CH2=CHCH2), 4.12 (1H, dd, J6B,5 1.8 Hz, J6B,6A 12.5 Hz, H-6B), 4.08 (1H, m, H-4), 3.96–3.91 (2H, m, H-2, H-3), 3.89 (1H, m, H-5), 3.79 (3H, s, OCH3), 3.43 (1H, d, JOH,H2 11.5 Hz, OH-2);

13

С NMR (150 MHz, CDCl3): δC 155.1, 151.5 (ipsoMeOC4H6), 137.2

(ipsoPh), 133.7 (CH2=CHCH2O), 129.2, 128.3, 126.0 (Ph), 118.2 (MeOC4H6), 118.0 (CH2=CHCH2), 114.4 (MeOC4H6), 101.5 (PhCH), 98.5 (C-1), 76.2 (C-3), 73.4 (C-4), 71.5



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Page 24 of 40

(CH2=CHCH2), 69.5 (C-6), 67.4 (C-2), 66.8 (C-5), 55.6 (OCH3); Anal. Calcd (%) for C23H26O7: C, 66.65; H, 6.32. Found: C, 66.44; H, 6.31; 6: Rf = 0.37 (toluene–EtOAc, 20:1); mp 149–152 °C, [α]D24 –135 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.56–7.51 (2H, m, Ph), 7.40–7.32 (3H, m, Ph), 7.12 (2H, d, J 9.1 Hz, OC6H4OCH3), 6.80 (2H, d, J 9.1 Hz, OC6H4OCH3), 5.59 (1H, s, PhCH), 5.40 (1H, s, H-1), 4.35 (1H, m, H-4), 4.33 (1H, br d, J6A,6B 12.7 Hz, H-6A), 4.07 (1H, dd, J6B,5 2.2 Hz, J6B,6A 12.7 Hz, H-6B, H-6B), 3.76 (3H, s, OCH3), 3.52–3.47 (2H, m, H-3, H-2), 3.41 (1H, m, H-5); 13С NMR (150 MHz, CDCl3): δC 129.2, 128.3, 126.4 (Ph), 118.8, 114.5 (MeOC4H6), 101.3 (PhCH), 96.7 (C-1), 70.2 (C3), 69.6 (C-6), 62.5 (C-5), 55.6 (OCH3), 53.5 (C-2), 51.7 (C-3). The NMR data of 6 were in accordance with those of similar anhydrotalopyranosides.20,60 HRMS (ESI-TOF) m/z [M + K]+ Calcd for C20H20O6K 395.0891; Found 395.0891. p-Methoxyphenyl

3-O-allyl-2-O-benzyl-4,6-O-benzylidene-β-D-idopyranoside

(7a).

Sodium hydride (60% suspension, 827 mg, 20.7 mmol) and benzyl bromide (3 mL, 25 mmol) were added to a solution of idopyranoside 5 (3.51 g, 8.5 mmol) in dry DMF (41 mL) at +4 °C, and then cooling was removed. After 15 min of stirring at rt, TLC showed full conversion of the starting material. The excess of NaH was quenched by addition of MeOH (3 mL) upon cooling. The reaction mixture was diluted with heptane (250 mL) and washed with water (300 mL). The aqueous phase was extracted back with heptane (3×50 mL), and the combined heptane solutions were extracted with acetonitrile (3×50 mL). The combined acetonitrile extracts were taken to dryness, and the residue was subjected to silica gel chromatography in toluene–MTBE (70:1 → 25:1) to afford 7a (4.26 g, 99%) as a foam: Rf = 0.20 (PE–EtOAc, 5:1); [α]D20 –46.0 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.54–7.44 (4H, m, Ph), 7.35–7.25 (6H, m, Ph), 7.06 (2H, d, J 9.1 Hz, MeOC6H4O), 6.83 (2H, d, J 9.1 Hz, MeOC6H4O), 5.85 (1H, m, CH2=CHCH2O), 5.50 (1H, s, PhCH), 5.30 (1H, d, J1,2 1.6 Hz, H-1), 5.24 (1H, m, CH2=CHCH2OA), 5.17 (1H, m,


Page 25 of 40

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CH2=CHCH2OB), 4.96 (1H, d, JBnA,BnB 12.1, PhCH2A), 4.78 (1H, d, JBnB,BnA 12.1, PhCH2B), 4.34 (1H, dd, J6A,5 1.5 Hz, J6A,6B 12.6 Hz, H-6A), 4.07 (1H, dd, J6B,5 2.1 Hz, J6B,6A 12.6 Hz, H-6B), 4.05 (2H, m, CH2=CHCH2), 3.95 (1H, m, H-4), 3.92 (1H, m, H-3), 3.76 (1H, m, H-5), 3.75–3.73 (4H, m, OCH3, H-2); 13C NMR (150 MHz, CDCl3): δC 154.9, 151.7 (ipsoMeOC4H6), 138.6, 138.0 (ipsoPh), 134.0 (CH2=CHCH2O), 128.8, 128.1, 128.0, 127.7, 127.3, 126.7 (Ph), 118.3 (MeOC4H6), 117.6 (CH2=CHCH2), 114.3 (MeOC4H6), 101.3 (PhCH), 98.8 (C-1), 76.5 (C-3), 73.9 (C-2), 73.22 (PhCH2), 73.19 (C-4), 71.3 (CH2=CHCH2), 69.5 (C-6), 66.7 (C-5), 55.6 (OCH3); Anal. Calcd (%) for C30H32O7: C, 71.41; H, 6.39. Found: C, 71.32; H, 6.50. p-Methoxyphenyl

2-O-benzyl-4,6-O-benzylidene-β-D-idopyranoside

(8).

Magnesium

turnings were merged into a 5% v/v solution of AcOH in EtOH until gas started to evolve, then washed consecutively with EtOH and Et2O and dried for 15 min. Thus activated Mg (370 mg) was added to a solution of 3-O-allyl-idopyranoside 7a (462 mg, 0.92 mmol) in dry THF (16 mL). Ti(OPr-i)4 (1.3 mL, 4.23 mmol), TMSCl (470 µL, 3.70 mmol) and a drop of 1,2-dibromoethane were added consecutively to this stirred heterogeneous mixture. The reaction mixture started immediately to darken. After 6 h, when TLC showed full conversion of the starting compound 7a, the reaction was quenched by sequential addition of Celite (3.45 g), NaF (10.1 g) and aqueous saturated NaHCO3 (7 mL). The reaction mixture was diluted with Et2O (50 mL) and stirred for several hours until its color became off-white. Then the solids were filtered off through a pad of Celite, washed with Et2O (3×30 mL), and the filtrate was evaporated. The solid residue was purified on a silica gel column (toluene–MTBE, 10:1→3:1) to give product 8 (250 mg, 59%) as a crystal solid. Byproduct 9 (5%) was also isolated as white crystals. 8: Rf = 0.20 (toluene–MTBE, 5:1); mp 137–139 °C, [α]D24 –46.1 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.48–7.38 (4H, m, Ph), 7.31-7.21 (7H, m, Ph + residual toluene), 7.02 (2H, d, J 9.3 Hz, OC6H4OCH3), 6.80 (2H, d, J 9.3 Hz, OC6H4OCH3), 5.46 (1H, s, PhCH), 5.38 (1H, d, J1,2 1.8



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Page 26 of 40

Hz, H-1), 4.90 (1H, d, JBnA,BnB 12.1 Hz, PhCH2A), 4.72 (1H, d, JBnB,BnA 12.1 Hz, PhCH2B), 4.31 (1H, dd, J6A,5 1.5 Hz, J6A,6B 12.3 Hz, H-6A), 4.30 (1H, dd, J3,2 4.7 Hz, J3,4 2.1 Hz, H-3), 4.02 (1H, dd, J6B,5 2.1 Hz, J6B,6A 12.6 Hz, H-6B), 3.93 (1H, t, J4,3 2.1 Hz, H-4), 3.80 (1H, dt, J5,4 2.0 Hz, J5,6A = J5,6B 1.8 Hz, H-5), 3.76 (3H, s, OCH3), 3.67 (1H, dd, J2,1 1.8 Hz, J2,3 4.7 Hz, H-2); 13C NMR (150 MHz, CDCl3): δC 128.9, 128.2, 128.0, 127.8, 127.5, 126.7 (Ph), 118.6, 114.4 (OC4H6OCH3), 101.3 (PhCH), 98.0 (C-1), 76.3 (C-2), 75.7 (C-4), 73.0 (CH2Ph), 69.9 (C-3), 69.5 (C-6), 66.3 (C-5), 55.6 (OCH3); HRMS (ESI-TOF) m/z [M+NH4]+ Calcd for C27H32NO7 482.2173; Found 482.2173; 9: Rf = 0.23 (toluene–MTBE, 3:1); mp 166–168 °C, [α]D22 –108.6 (c 1, CHCl3); 1H NMR (300 MHz, CDCl3): 7.52–7.46 (2H, m, Ph), 7.38–7.33 (5H, m, Ph), 7.07 (2H, d, J 9.1 Hz, OC6H4OCH3), 6.82 (2H, d, J 9.1 Hz, OC6H4OCH3), 5.52 (1H, s, CHPh), 5.34 (1H, d, J1,2 1.0 Hz, H-1), 4.43 (1H, dd, J6A,5 1.6 Hz, J6A,6B 12.6 Hz, H-6A), 4.30 (1H, dt, H-3), 4.11 (1H, dd, J6B,5 1.9 Hz, J6A,6B 12.6 Hz, H-6B), 4.02 (1H, m, H-4), 3.91 (1H, dt, H-5), 3.85 (1H, ddt, J2,1 1.0 Hz, J2,3 3.3 Hz, J2,OH2 11.7 Hz, H-2), 3.78 (3H, s, OCH3), 3.38 (1H, d, JOH2,2 11.7 Hz, OH2), 2.05 (1H, d, JOH3,3 4.5 Hz, OH3); 13C NMR (150 MHz, CDCl3): δC 129.4, 128.4, 126.2 (Ph), 118.5, 114.6 (MeOC4H6), 101.7 (PhCH), 98.3 (C-1), 75.3 (C-4), 70.0 (C-3), 69.8 (C-2), 69.7 (C-6), 66.6 (C-5), 55.8 (OCH3); Anal. Calcd (%) for C20H22O7: C, 64.16; H, 5.92. Found: C, 64.25; H, 6.05; HRMS (ESI-TOF) m/z [M+NH4]+ for C20H26NO7 392.1704; Found 392.1697; [M+Na]+ Calcd for C20H22O7Na 397.1258; Found 397.1256. p-Methoxyphenyl

3-O-acetyl-2-O-benzyl-4,6-O-benzylidene-β-D-idopyranoside

(7b).

Acetic anhydride (4 mL) was added to a solution of 8 (280 mg, 0.60 mmol) in pyridine (4 mL). When TLC showed full conversion of the starting material (2 h), the solvents were removed and traces of pyridine were coevaporated with toluene (3×5 ml). Silica gel chromatography of the resulting solid (12:1, toluene–MTBE) afforded acetate 7b (267 mg, 89%) as white crystals. 7b: Rf = 0.20 (toluene–MTBE, 12:1); mp 167–169 °C, [α]D22 –36.0 (c 1, CHCl3); 1H NMR (600 MHz, CDCl3): δH 7.52–7.43 (4H, m, Ph), 7.35–7.22 (6H, m, Ph), 7.03 (2H, d, J 9.2 Hz,


Page 27 of 40

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MeOC6H4O), 6.82 (2H, d, J 9.2 Hz, MeOC6H4O), 5.52 (1H, s, CHPh), 5.38 (1H, br t, J3,2=J3,4 2.7 Hz, H-3), 5.20 (1H, d, J1,2 1.5 Hz, H-1), 4.92 (1H, d, JBnA,BnB 12.0 Hz, BnA), 4.87 (1H, d, JBnB,BnA 12.0 Hz, BnB), 4.40 (1H, br d, J6A,6B 12.5 Hz, H-6A), 4.11 (1H, dd, J6B,5 2.1 Hz, J6B,6A 12.5 Hz, H6B), 3.93 (1H, br d, J4,3=J4,5 1.8 Hz, H-4), 3.78 (4H, m, H-5, OC6H4OCH3), 3.70 (1H, br d, J2,3 3.2 Hz, H-2), 2.1 (3H, s, CH3CO);

13

C NMR (150 MHz, CD3Cl) δC 168.9 (CH3CO), 155.1, 151.7

(ipsoOC6H4OCH3), 138.2, 137.7 (ipsoPh (PhCH, Bn), 128.9, 128.1, 128.0, 127.8, 127.3, 126.7 (Ph (Bn, CHPh)), 118.3, 114.4 (OC6H4OCH3), 101.4 (PhCH), 98.9 (C-1), 72.9 (PhCH2), 72.8 (C-2), 72.0 (C-4), 70.1 (C-3), 69.3 (C-6), 67.0 (C-5), 55.6 (OC6H4OCH3). HRMS (ESI-TOF) m/z [M+NH4]+ Calcd for C29H34NO8 524.2279; Found 524.2272; [M+Na]+ Calcd for C29H30O8Na 529.1833, found 529.1828. 3-O-Allyl-2-O-benzyl-4,6-O-benzylidene-D-idopyranose (10a). Water (7.4 mL) was added to a solution of idopyranoside 7a (232 mg, 0.46 mmol) in a mixture of CH3CN (29.4 mL) and benzene (2.4 mL). The resulting biphasic mixture was cooled to –9 °C. At this temperature, CAN (1.26 g, 2.3 mmol) was added to the vigorously stirred mixture, and 45 seconds later the reaction was quenched by adding saturated aqueous NaHCO3. The mixture was diluted with EtOAc (150 mL) and washed with saturated aqueous NaHCO3. The aqueous phase was extracted back with EtOAc (3×30 mL) and the solvent was evaporated from the combined organic phases. The solid residue was chromatographed in toluene–MTBE (15:1 → 4:1) to give 10a (164 mg, 90%) as an α,βmixture in a ratio of 1:1.3; yellowish foam: Rf = 0.20 (toluene–MTBE, 5:1); 1H NMR (600 MHz, CDCl3): δH 7.53-7.47 (2H, m, Ph), 7.41-7.22 (8H, m, Ph), 5.94-5.82 (1H, m, CH2=CHCH2O), 5.52 (1H, s, CHPh), 5.36 (0.41H, br d, J1,OH1 9.0 Hz, H-1 ), 5.32-5.20 (2H, m, CH2=CHCH2O), 5.01 α

(0.57H, br d, J1b,OH1b 12.5 Hz, H-1 ), 4.75 (0.56H, d, JBnA,BnB 11.3 Hz, PhCH2A ), 4.67 (0.83H, br s, β

β

CH2Ph ), 4.56 (0.56H, d, JBnB,BnA 11.3 Hz, PhCH2B ), 4.39–4.31 (1H, m, H-6A ), 4.27 (0.42H, br d, α

β

α,β

JOH1,H1 9.3 Hz, OH1 ), 4.21-4.00 (4H, m, CH2=CHCH2, H-6B , , H-4 , OH1 ), 3.98 (0.42H, br m, Hα

α β


α

β


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Page 28 of 40

5 ), 3.95-3.88 (1.56H, m, H-3 , H-4 , H-3 ), 3.73 (0.56H, br m, H-5 ), 3.55 (0.42H, br m, H-2 ), 3.50 β

β

(0.56H, br m, H-2 ); β

13

β

α

α

α

C NMR (150 MHz, CDCl3): δC 137.9 (ipsoPh), 133.9, 133.4

(CH2=CHCH2O), 128.9, 128.3, 128.2, 128.1, 127.9, 127.7, 127.6, 126.5 (Ph), 118.5, 117.9 (CH2=CHCH2 ), 101.3, 101.1 (PhCH ), 94.1 (C-1 ), 92.2 (C-1 ), 74.9 (C-3 ), 74.1 (C-2 ), 73.6 (Cα,β

α,β

α

β

3 ), 73.2 (C-2 ), 72.9 (C-4 ), 72.4 (PhCH2 ), 72.2 (C-4 ), 72.1 (CH2=CHCH2 β

α

(CH2=CHCH2

α

α

or

β

β

β

α

α

or β

β

), 72.0 (PhCH2 ), 71.5 α

), 69.91, 69.88 (C-6 ), 66.4 (C-5 ), 59.4 (C-5 ); Anal. Calcd (%) for C23H26O6: C, α,β

α

β

69.33; H, 6.58. Found: C, 69.54; H, 6.77; HRMS (ESI-TOF) m/z [M+NH4]+ Calcd for C23H30NO6 416.2075; Found 416.2068. 3-O-Allyl-2-O-benzyl-4,6-O-benzylidene-α-D-idopyranosyl N-phenyltrifluoroacetimidate (11a). N-Phenyltrifluoroacetimidoyl chloride (47 µL, 0.18 mmol) and K2CO3 (50 mg, 0.36 mmol) were added to a solution of 10a (55 mg, 0.14 mmol) in acetone (4.5 mL). The mixture was intensively stirred until TLC showed disappearance of the starting material (20 h) and then filtered through a Celite pad. The filtrate was concentrated under reduced pressure and the residue was purified by column chromatography (PE–EtOAc, 10:1 → 7:1 + 1% (v/v) of Et3N). Chromatographic purification should not last more than 1 h to minimize hydrolysis of the product 11a on silica gel. Thus, donor 11a (61 mg, 77%) was obtained as a white foam: Rf = 0.20 (PE–EtOAc, 7:1); 1H NMR (600 MHz, (CDCl3, 323 K)): δH 7.52, 7.41, 7.36–7.24 (12H, m, Ph (Bn, Ph, NPh)), 7.09 (1H, t, NPh), 6.85 (2H, d, NPh), 6.11 (1H, br s, H-1), 5.88 (1H, m, CH2=CHCH2O), 5.51 (1H, s, PhCH), 5.27 (1H, m, CH2=CHCH2OA), 5.21 (1H, m, CH2=CHCH2OB), 4.86 (1H, d, JBnA.BnB 12.0 Hz, PhCH2A), 4.74 (1H, d, JBnB,BnA 12.0Hz, PhCH2B), 4.34 (1H, br d, JH-6A,H-6B 12.8 Hz, H-6A), 4.144.07 (2H, m, CH2=CHCH2), 4.03 (1H, br d, JH-6B,H-6A 12.7 Hz, H-6B), 3.97 (1H, m, H-4), 3.93 (1H, m, H-3), 3.77 (1H, m, H-2), 3.65 (1H, br m, H-5);

13

C NMR (150 MHz, CDCl3): δC 134.0

(CH2=CHCH2O), 129.0, 128.6, 128.3, 128.1, 127.7, 127.6 (Ph (Bn, CHPh, NPh)), 124.0, 119.4 (NPh), 117.7 (CH2=CHCH2), 101.4 (PhCH), 95.0 (C-1), 76.6 (C-3), 73.6 (C-4), 73.2 (C-2), 73.1


Page 29 of 40

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(PhCH2), 71.4 (CH2=CHCH2), 69.3 (C-6), 67.3 (C5); Anal. Calcd (%) for C31H30F3NO6: C, 65.37; H, 5.31; N, 2.46. Found: C, 65.42; H, 5.36; N, 2.37. Isopropyl 3-O-allyl-2-O-benzyl-4,6-O-benzylidene-α- and –β-D-idopyranosides (2a and 12a). Donor 11a (59.5 mg, 0.11 mmol) was dried by evaporation of its solution in dry toluene and then dissolved in CH2Cl2 (0.7 mL, freshly distilled over CaH2) under Ar atmosphere. Powdered molecular sieves AW-300 (39 mg) were added to the solution of 11a at +10 °C, the resulting mixture was stirred at this temperature for 1 h, and then i-PrOH (32 µL, 0.42 mmol) was added. The reaction mixture was cooled to –35 °C and a 3% v/v solution of TfOH in CH2Cl2 (15 µL, 5.5 µmol) was added. One min later, the reaction was quenched by addition of Et3N (4 µL), diluted with CH2Cl2 (5 mL), and filtered through a Celite pad. The filtrate was diluted with CH2Cl2 (25 mL) and washed with saturated aqueous NaHCO3. The aqueous phase was extracted back with CH2Cl2 (3×5 mL) and combined organic extracts were taken to dryness. The residue was purified by silica gel chromatography (PE–EtOAc, 7:1→4:1 + 1% v/v of Et3N) to provide 2a (18.4 mg, 40%) and 12a (21 mg, 46%), both as amorphous solid. 2a: Rf = 0.33 (PE–EtOAc, 5:1); [α]D24 +64.5 (c 1, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.52–7.49 (2H, m, Ph), 7.38–7.25 (8H, m, Ph), 5.94 (1H, m, CH2=CHCH2O), 5.54 (1H, s, PhCH), 5.30 (1H, m, CH2=CHCH2OA), 5.17 (1H, m, CH2=CHCH2OB), 5.01 (1H, d, J1,2 5.1 Hz, H-1), 4.76 (2H, s, PhCH2), 4.26 (1H, dd, J6A,5 1.3 Hz, J6A,6B 12.8 Hz, H-6A), 4.23 (2H, m, CH2=CHCH2), 4.14 (1H, dd, J6B,5 2.7 Hz, H-6B), 4.13 (1H, m, H-4), 4.00 (1H, h, JCH,CH3 6.1Hz, CH(CH3)2), 3.80 (1H, m, H-5), 3.76 (1H, dd, J3,2 9.0 Hz, J3,4 3.4 Hz, H-3), 3.54 (1H, dd, J2,1 5.1 Hz, J2,3 9.0 Hz, H-2), 1.22 (3H, d, JCH3A,CH 6.2 Hz, CH3A), 1.19 (3H, d, JCH3B,CH 6.2 Hz, CH3B); 13C NMR (150 MHz, CDCl3): δC 138.5, 138.0 (ipsoPh (PhCH, Bn), 134.9 (CH2=CHCH2O), 128.8, 128.2, 128.1, 127.8, 127.5, 126.2 (Ph (Bn, CHPh)), 116.8 (CH2=CHCH2), 100.3 (C-1), 100.1 (PhCH), 80.3 (C-3), 78.9 (C-4), 78.8 (C-2), 73.7 (PhCH2), 72.0 (CH2=CHCH2), 69.8 (CH(CH3)2), 69.3 (C-6), 62.1 (C-5), 23.7



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Page 30 of 40

(CH3A(iPr)), 21.9 (CH3B(iPr)). Anal. Calcd (%) for C26H32O6: C, 70.89; H, 7.32. Found: C, 70.99; H, 7.45. 12a: Rf = 0.23 (PE–EtOAc, 5:1); [α]D24 –38.9 (c 1, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.53–7.50 (2H, m, Ph), 7.43–7.40 (2H, m, Ph), 7.30–7.22 (6H, m, Ph), 5.85 (1H, m, CH2=CHCH2O), 5.49 (1H, s, PhCH), 5.24 (1H, m, CH2=CHCH2OA), 5.17 (1H, m, CH2=CHCH2OB), 4.94 (1H, d, JBnA,BnB 12.3 Hz, PhCH2A), 4.84 (1H, d, J1,2 1.45 Hz, H-1), 4.69 (1H, d, JBnB.BnA 12.2 Hz, PhCH2B), 4.33 (1H, dd, J6A,5 1.3 Hz, J6A,6B 12.5 Hz, H-6A), 4.07 (1H, hpt, JCH,CH3 6.1 Hz, CH(CH3)2), 4.07 (1H, dd, J6B,5 2.3 Hz, J6B,6A 12.5 Hz, H-6B), 4.04 (2H, m, CH2=CHCH2), 3.87 (1H, t, = 2.0Hz, H-4), 3.82 (1H, t, J 2.9 Hz, H-3), 3.64 (1H, dt, J 1.7 Hz, H-5), 3.50 (1H, br d, J 3.3 Hz, H-2), 1.27 (3H, d, JCH3A,CH 6.2 Hz, CH3A), 1.18 (3H, d, JCH3B,CH 6.2 Hz, CH3B); 13C NMR (150 MHz, CDCl3): δC 139.2, 138.2 (ipsoPh (PhCH, Bn), 134.2 (CH2=CHCH2O), 128.7, 128.0, 127.7, 127.1, 126.7 (Ph (Bn, CHPh)), 117.5 (CH2=CHCH2), 101.2 (PhCH), 97.5 (C-1), 76.8 (C-3), 74.1 (C-2), 73.3 (C-4), 73.2 (PhCH2), 71.3 (CH2=CHCH2), 70.4 (CH(CH3)2), 69.9 (C-6), 66.7 (C-5), 23.5 (CH3A(iPr)), 21.5 (CH3B(iPr)). Anal. Calcd (%) for C26H32O6: C, 70.89; H, 7.32. Found: C, 70.85; H, 7.38. 3-O-Acetyl-2-O-benzyl-4,6-O-benzylidene-D-idopyranose (10b). Hemiacetal 10b was prepared from 7b (254 mg, 0.50 mmol) according to the procedure described for the preparation of 10a as an anomeric mixture (187 mg, 93%), foam: Rf = 0.20 (toluene–MTBE, 2:1); 1H NMR (600 MHz, (CDCl3): δH 7.52–7.47 (2.5H, m, Ph), 7.36–7.13 (10.0H, m, Ph), 5.52-5.50 (1.25H, m, PhCH), 5.42 (1H, br t, J3,4~J3,2 2.4 Hz, H-3 ), 5.38 (0.25H, m, H-1 ), 5.24 (0.25H, m, H-3 ), 4.93 (1H, br d, β

α

α

JH1,OH 12.2 H, H-1 ), 4.87 (1H, d, JBnA,BnB 11.3 Hz, BnA ), 4.71 (0.25H, d, JBnA,BnB 11.8 Hz, BnA ), β

β

α

4.62 (0.25H, d, JBnB,BnA 11.9Hz, BnB ), 4.55 (1H, d, JBnB,BnA 11.3 Hz, BnB ), 4.38 (1H, dd, J6A,6B α

β

12.5 Hz, J6A,5 0.9Hz, H-6A ), 4.29 (0.25H, br d, J6A,6B 12.5 Hz, H-6A ), 4.16-4.05 (2.2H, m, JOH,H1 β

α

12.4Hz, OH , J6B,5 2.0 Hz, H-6B , J6b,6A 12.6 Hz, J6B,5 2.0 Hz, H-6B ), 4.03-4.00 (0.50H, m, H-4 , Hβ

α


β

α

Page 31 of 40

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5 ), 3.89 (1H, m, H-4 ), 3.69 (1H, m, H-5 ), 3.49 (0.25H, dd, J2,3 4.3 Hz, J2,1 2.7 Hz, H-2 ), 3.44 (1H, α

β

β

α

m, H-2 ), 3.28 (0.25H, d, JOH,H1 4.8 Hz, OH ), 2.11 (3H, s, CH3CO ), 2.08 (0.73H, s, CH3CO ); 13C β

α

β

α

NMR (150 MHz, CDCl3): δC 169.0 (CH3CO), 137.6, 137.1 (ipsoPh (PhCH, Bn), 128.9, 128.3, 128.2, 128.0, 127.9, 127.6, 127.4, 126.4 (Ph (Bn, CHPh)), 101.2, 100.9 (PhCH), 94.4 (C-1 ), 92.1 α

(C-1 ), 73.6 (C-2 ), 73.2 (C-4 ), 72.9 (C-2 ), 72.2 (PhCH2 ), 71.9 (PhCH2 ), 71.5 (C-4 ), 69,5 (C-6 , ), β

α

α

β

β

α

β

α β

69.3 (C-3 ), 68.0 (C-3 ), 66.6 (C-5 ), 60.1 (C-5 ), 21.0 (CH3CO ), 20.8 (CH3CO ); HRMS (ESI-TOF) α

β

β

α

α

β

m/z [M+NH4]+ Calcd for C22H28NO7 418.1854; Found 418.1860. 3-O-Acetyl-2-O-benzyl-4,6-O-benzylidene-α-D-idopyranosyl

N-

phenyltrifluoroacetimidate (11b). Donor 11b was prepared from 10b (90 mg, 0.23 mmol) according to the procedure described for the preparation of 11a and purified on silica gel (PE– EtOAc, 30:1→3:1 + 0.5% v/v of Et3N), yield 116 mg (91%), foam: Rf 0.18 (PE–EtOAc, 4:1); 1H NMR (600 MHz, (CDCl3, 323 K)): δH 7.50–7.47 (2H, m, Ph), 7.41–7.37 (2H, m, Ph), 7.32–7.23 (8H, m, Ph), 7.08 (1H, m, PhN), 6.81 (2H, m, Ph), 5.98 (1H, br s, H-1), 5.48 (1H, s, PhCH), 5.32 (1H, m, H-3), 4.80, 4.78 (2H, 2d, JBnA,BnB = JBnB,BnA 12.0Hz, Bn), 4.34 (1H, d, J6A,6B 13.0 Hz, H6A), 4.03 (1H, d, J6B,6A 13.0 Hz, H-6B), 3.90 (1H, br m, H-4), 3.72 (1H, br m, H-2), 3.62 (1H, br m, H-5), 2.07 (3H, s, CH3CO); 13C NMR (150 MHz, (CDCl3, 323 K)): δC 129.0, 128.7, 128.3, 128.1, 127.8, 127.6, 126.6 (Ph (Bn, CHPh, NPh)), 124.2, 119.6 (NPh), 101.4 (PhCH), 94.8 (C-1), 72.8 (PhCH2), 72.4 (C-4), 71.9 (C-2), 70.4 (C-3), 69.0 (C-6), 67.8 (C-5), 20.8 (CH3CO); JC1,H1 = 168.0 Hz (α-anomer). Anal. Calcd (%) for C30H28F3NO7: C, 63.04; H, 4.94; N, 2.45. Found: C, 62.97; H, 4.94; N, 2.48. Isopropyl 3-O-acetyl-2-O-benzyl-4,6-O-benzylidene-α- and –β-D-idopyranosides (2b and 12b). Donor 11c (99 mg, 0.173 mmol) was coupled with isopropyl alcohol according to the procedure described for the preparation of 2a and 12a. Individual anomers 2b (21.6 mg, 28%) and



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12b (46 mg, 60%), both as foams, were isolated by silica gel chromatography (PE–EtOAc, 18:1→9:1). 2b: Rf = 0.20 (PE–EtOAc, 3:1); [α]D23 +65.0 (c 0.8, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.54–7.52 (2H, m, Ph(Bn, PhCH)), 7.37–7.26 (8H, m, Ph), 5.55 (1H, s, PhCH), 5.23 (1H, dd, J3,4 3.0 Hz, J3,2 5.2 Hz, H-3), 5.16 (1H, d, J1,2 3.0, JC1,H1 171.1 Hz, H-1), 4.76 (1H, d, JBnA,BnB 11.8 Hz, PhCH2A), 4.71 (1H, d, JBnB,BnA 11.8 Hz, PhCH2B), 4.32 (1H, br d, J6A,6B 12.6 Hz, H-6A), 4.16 (1H, dd, J6B,6A 12.6 Hz, J6B,5 2.3 Hz, H-6B), 4.08 (1H, br t, J4,3~J4,5 2.5 Hz, H-4), 4.00 (1H, hpt, JCH,CH3 6.1Hz, CH(CH3)2), 3.92 (1H, m, H-5), 3.54 (1H, dd, J2,1 3.0 Hz, J2,3 5.2 Hz, H-2), 2.09 (3H, s, CH3CO), 1.24 (3H, d, JCH3A,CH 6.2 Hz, CH3A), 1.19 (3H, d, JCH3B,CH 6.1 Hz, CH3B); 13C NMR (150 MHz, CDCl3): δC 169.2 (CH3CO), 137.6, 137.3 (ipsoPh (PhCH, Bn), 128.4, 127.6, 127.1, 126.9, 125.9 (Ph (Bn, CHPh)), 100.3 (PhCH), 97.7 (C-1), 73.78 (C-2), 73.75 (C-4), 71.7 (PhCH2), 69.7 (C3), 69.0 (C-6), 68.6 (CH(CH3)2), 60.0 (C-5), 22.9 (CH3CO), 20.9 (CH3A(iPr)), 20.5 (CH3B(iPr)). HRMS (ESI-TOF) m/z [M+Na]+ Calcd for C25H30O7Na 465.1884; Found 465.1874; [M+K]+ Calcd for C25H30O7K 481.1623; Found 481.1618. 12b: Rf = 0.20 (PE–EtOAc, 2:1); [α]D24 –26.3 (c 1, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.51–7.49 (2H, m, Ph), 7.44–7.41 (2H, m, Ph), 7.31–7.21 (6H, m, Ph), 5.48 (1H, s, PhCH), 5.27 (1H, t, J3,4~J3,2 2.5 Hz, H-3), 4.89 (1H, d, JBnA,BnB 12.1 Hz, PhCH2A), 4.77 (1H, br d, J1,2 1.4 Hz, JC1,H1 155.5 Hz, H-1), 4.75 (1H, d, JBnB,BnA 12.2 Hz, PhCH2B), 4.36 (1H, d, J6A,6B 12.6 Hz, H-6A), 4.11-4.04 (2H, m, CH(CH3)2, H-6B), 3.84 (1H, m, H-4), 3.62 (1H, m, H-5), 3.44 (1H, m, H-2), 2.09 (3H, s, CH3CO), 1.29 (3H, d, JCH3A,CH 6.2 Hz, CH3A), 1.18 (3H, d, JCH3B,CH 6.1 Hz, CH3B);

13

C

NMR (150 MHz, CDCl3): δC 169.2 (CH3CO), 138.7, 137.8 (ipsoPh (PhCH, Bn), 128.7, 127.9, 127.6, 127.0, 126.6 (Ph (Bn, CHPh)), 101.2 (PhCH), 97.5 (C-1), 73.3 (C-2), 72.8 (PhCH2), 72.2 (C4), 70.8 (CH(CH3)2), 70.6 (C-3), 69.5 (C-6), 67.0 (C-5), 23.4 (CH3CO), 21.5 (CH3A(iPr)), 21.0


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(CH3B(iPr)). HRMS (ESI-TOF) m/z [M+Na]+ Calcd for C25H30O7+Na 465.1884; Found 465.1871; [M+K]+ Calcd for C25H30O7K 481.1623; Found 481.1612. p-Methoxyphenyl

2-O-benzyl-4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-β-D-

idopyranoside (7с). Imidazole (227 mg, 3.34 mmol), DMAP (31.0 mg, 0.25 mmol) and TBDPSCl (450.0 µL, 1.76 mmol) were added consecutively to a solution of 8 (380.0 mg, 0.82 mmol) in DMF (5.0 mL). After a month, when TLC showed ~80-90% conversion of the starting material, the reaction mixture was diluted with EtOAc (70 mL) and washed with aqueous saturated NaHCO3 (50 mL). The organic layer was separated and the aqueous phase was extracted with EtOAc (3×10 mL). The combined organic extracts were taken to dryness and the solid residue was purified on silica gel (toluene–MTBE, 60:1→10:1) to give 7c (455 mg, 79%) as a foam: Rf = 0.21 (toluene–MTBE, 30:1); [α]D24 –13.0 (c 0.3, CHCl3); 1H NMR (600 MHz, (CD3)2CO): δH 7.65–7.59 (4H, m, Ph), 7.49–7.30 (8H, m, Ph), 7.29–7.14 (11H, m, Ph), 7.02 (2H, d, J 9.0 Hz, MeOC6H4O), 6.83 (2H, d, J 9.0 Hz, MeOC6H4O), 5.44 (1H, d, J1,2 1.3 Hz, H-1), 5.29 (1H, s, PhCH), 4.55 (1H, d, JBnA,BnB 11.8 Hz, BnA), 4.37 (1H, dd, J6A,6B 12.5 Hz, J6A,5 1.1 Hz, H-6A), 4.33 (1H, d, JBnB,BnA 11.8 Hz, BnB), 4.32 (1H, t, J3,4 = J3,2 2.7 Hz, H-3), 4.03 (1H, dd, J6B,6A 12.5 Hz, J6B,5 2.1 Hz, H-6B), 3.85 (1H, m, H-5), 3.78 (3H, s, OC6H4OCH3), 3.75 (1H, m, H-4), 3.52 (1H, br d, J2,1 3.2 Hz, H-2), 1.08 (9H, s, C(CH3)3); 13C NMR (150 MHz, CDCl3): δC 138.7, 138.0 (ipsoPh (Bn or Bd)), 135.7 (Ph (TBDPS)), 133.0, 132.7, 130.2, 128.8, 127.9, 127.6, 127.0, 126.8 (Ph), 118.4, 114.4 (MeOC4H6), 101.2 (PhCH), 98.9 (C-1), 75.7 (C-2), 74.3 (С-4), 73.0 (PhCH2), 70.6 (С-3), 69.6 (C-6), 69.7 (C-5), 55.7 (OCH3), 27.0 (C(CH3)3), 19.2 (C(CH3)3); Anal. Calcd (%) for C43H46O7Si: C, 73.48; H, 6.60. Found: C, 73.65; H, 6.76. 2-O-Benzyl-4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-D-idopyranose

(10c).

Compound 10c was prepared from 7c (410 mg, 0.584 mmol) according to the procedure described for the synthesis of 10a. Hemiacetal 10c (189 mg, 57%) was obtained as a mixture of anomers after



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chromatography on silica gel (toluene–MTBE, 15:1→4:1), foam: Rf = 0.18 (toluene–MTBE, 3:1); 1

H NMR (600 MHz, (CD3)2CO, 323 K): δH 7.69–7.60 (m, Ph), 7.52–7.14 (m, Ph), 7.10–7.07 (m,

Ph), 5.37-5.34 (m, PhCH , H-1 ), 5.24 (s, PhCH ), 5.18 (br s, H-1 ), 4.38 (d, J6A,6B 12.3 Hz, H-6A ), β

α

α

β

β

4.36 (m, H-6A ), 4.33 (m, H-3 ), 4.29 (d, JBnA,BnB 11.7 Hz, BnA ), 4.27 (m, H-3 ), 4.24 (d, JBnB,BnA α

β

α

α

11.6 Hz, BnB ), 4.16 (d, JBnA,BnB 11.3 Hz, BnA ), 4.10 (m, H-5 ), 4.07 (dd, J6B,5 1.9 Hz, J6B,6A 12.4 α

β

α

Hz, H-6B ), 4.04 (dd, J6B,5 2.5 Hz, J6B,6A 12.4 Hz, H-6B ), 3.87 (m, H-5 ), 3.84 (d, JBnB,BnA 11.2 Hz, β

α

β

BnB ), 3.81 (m, H-4 ), 3.74 (m, H-4 ), 3.45 (m, H-2 ), 3.24 (m, H-2 ), 1.12-1.11 (m, C(CH3)3); β

β

α

α

β

13

C

NMR (150 MHz, CDCl3): δC 135.9, 135.8 (Ph (TBDPS)), 130.6, 130.4, 130.3, 129.1, 128.9, 128.2, 128.0, 127.8, 127.6, 126.6, 125.3 (Ph), 101.1 (PhCH), 94.2 (C-1 ), 91.8 (C-1 ), 75.9 (C-2 ), 74.1 (Cα

β

β

4 ), 73.5 (C-4 , C-2 ), 71.9 (Bn ), 71.5 (Bn ), 70.0 (C-6), 68.7 (C-3 ), 68.0 (C-3 ), 66.1 (C-5 ), 58.5 (Cβ

α

α

β

α

α

β

β

5 ), 27.0 (C(CH3)3); Anal. Calcd (%) for C43H46O7Si: C, 73.48; H, 6.60. Found: 73.46; H, 6.81. α

2-O-Benzyl-4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-α-D-idopyranosyl

N-

phenyltrifluoroacetimidate (11с). Donor 11c was prepared from 10c (143 mg, 0.25 mmol) similarly to 11a except the purification procedure. Column chromatography was carried out at a temperature below –10 °C (PE–EtOAc, 20:1→1:1, + 0.5% v/v of Et3N) to yield 11c (144 mg, 78%) as a mixture of syn- and anti-isomers, foam: Rf = 0.43 (PE–EtOAc, 5:1); 1H NMR (600 MHz, (CDCl3, 323 K, the isomers are designated A and B): δH 7.69–7.65 (m, Ph), 7.63–7.08 (m, Ph), 6.80 (2H, d, J 7.8 Hz, PhN), 6.36 (1.0H, s, H-1A), 5.51 (0.3H, s, H-1B), 5.47 (1.1 H, s, PhCHA), 5.24 (0.3H, s, PhCHB), 4.49 (1.0H, d, J6A,6B 12.3 Hz, H-6AA), 4.39-4.35 (1.4H, m, H-3A, BnAB), 4.28 (d, JBnA,BnB 11.3 Hz, BnAA), 4.22 (d, JBnB,BnA 11.3 Hz, BnBA), 4.20 (d, BnBB), 4.18 (d, J6B,6A 12.3 Hz, H-6BA), 4.14 (d, H-6AB), 4.11 (s, H-3B), 4.10 (s, H-5A), 3.96 (s, H-4A), 3.85 (d, J6B,6A 12.4 Hz, H6BB), 3.55 (s, H-2A), 3.52 (s, H-4B), 3.27 (s, H-2B), 2.45 (s, H-5B), 2.12, 1.93, 1.73, 1.64, 1.27 (s, C(CH3)3B), 1.11 (s, C(CH3)3A); 13C NMR (150 MHz, CDCl3, 298 K): δC 143.3, 143.0, 142.9, 142.6, 137.7, 137.5, 137.0, 135.5, 135.3, 132.0, 131.8, 131.6, 130.0, 129.9, 128.7, 128.3, 127.8, 127.7,


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127.7, 127.6, 127.6, 127.5, 127.3, 127.0, 126.2, 126.0, 123.7, 119.5, 118.9 (PhNB), 116.2 (PhNA), 114.3, 100.6 (PhCHA), 100.2 (PhCHB), 95.2 (C-1B), 94.8 (C-1A), 73.6 (C-2B), 73.5 (C-4A), 72.9 (C2A), 72.7 (C-4B), 72.6 (PhCH2B), 72.0 (PhCH2A), 69.2 (C-3B), 69. 1 (C-3A), 69.0 (C-6A), 68.4 (C-6B), 67.0 (C-5A), 66.3 (C-5B), 29.4, 26.4 (C(CH3)3), 18.7 (C(CH3)3); Anal. Calcd (%) for C44H44F3NO6Si: C, 68.82; H, 5.78; N, 1.82. Found: C, 68.71; H, 5.74; N, 1.83. Isopropyl

2-O-benzyl-4,6-O-benzylidene-3-O-tert-butyldiphenylsilyl-α-

and

–β-D-

idopyranosides (2с and 12с). Donor 11c (60 mg, 0.08 mmol) was coupled with isopropyl alcohol according to the procedure described for the preparation of 2a and 12a. Individual anomers 2b (21 mg, 42%) and 12b (27 mg, 54%) were isolated, both as amorphous solids, by chromatography on silica gel (PE–EtOAc, 18:1→9:1). 2c: Rf = 0.19 (PE-EtOAc, 15:1), [α]D24 +50.7 (c 0.5, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.72-7.70 (2H, m, Ph), 7.66–7.63 (2H, m, Ph), 7.41–7.11 (16H, m, Ph), 5.30 (1H, s, PhCH), 5.04 (1H, d, J1,2 2.6, JC1,H1 168.8 Hz, Hz, Hz, H-1), 4.24 (2H, d, J 6.05 Hz, Bn), 4.23 (1H, m, H-6A), 4.13 (1H, m, H-3), 4.04 (1H, dd, J6B,5 2.1 Hz, J6B,6A 12.5 Hz, H-6B), 4.00 (1H, m, H-5), 3.95 (1H, hpt, J CH,CH3

6.2 Hz, CH(CH3)2), 3.90 (1H, m, H-4), 3.36 (1H, dd, J2,1 2.5 Hz, J2,3 4.4 Hz, H-2), 1.25 (d,

JCH3,CH 6.2 Hz, CH3A), 1.15 (d, JCH3,CH 6.2 Hz, CH3B), 1.07 (9H,s, C(CH3)3); 13C NMR (150 MHz, CDCl3): δC 138.4, 138.1 (ipsoPh (Bn or Bd)), 136.1, 135.9 (Ph (TBDPS)), 133.7, 133.5, 129.8, 129.7, 128.6, 127.9, 127.6, 127.5, 127.1, 126.5(Ph), 100.7 (PhCH), 98.7 (C-1), 77.2 (C-2, C-4), 71.9 (PhCH2), 70.2 (C-3), 69.8 (C-6), 69.5 (CH(CH3)2), 60.0 (C-5), 27.0 (C(CH3)3), 23.6 (CH3A(iPr)), 21.7 (CH3B(iPr)), 19.3 (C(CH3)3); HRMS (ESI-TOF) m/z [M+NH4]+ Calcd for C39H50NO6Si 656.3402; Found 656.3396; [M+Na]+ Calcd for C39H46O6SiNa 661.2956; Found 661.2950. 12c: Rf 0.27 (PE–EtOAc, 7:1), [α]D23 –18.2 (c 1, CHCl3); 1H NMR (600 MHz, (CDCl3)): δH 7.63-7.59 (4H, m, Ph), 7.47–7.34 (8H, m, Ph), 7.27–7.14 (8, m, Ph), 5.29 (1H, s, PhCH), 5.04 (1H, s, JC1,H1 155.7 Hz, H-1), 4.53 (1H, d, JBnA,BnB 12.0 Hz, BnA), 4.34 (1H, d, J6A,6B 12.4, H-6A), 4.26



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4.23 (2H, m, BnB, H-3), 4.10 (1H, hpt, JCH,CH3 6.1 Hz, CH(CH3)2), 4.02 (1H, dd, J6B,5 1.7 Hz, J6B,6A 12.5 Hz, H-6B), 3.76 (1H, br s, H-5), 3.70 (1H, br s, H-4), 3.28 (1H, br d, J2,1 2.8 Hz, H-2), 1.28 (3H, d, JCH3,CH 6.2 Hz, CH3A), 1.20 (3H, d, JCH3,CH 6.2 Hz, CH3B), 1.09 (9H,s, C(CH3)3); 13C NMR (150 MHz, CDCl3): δC 139.8, 138.8 (ipsoPh (Bn or Bd)), 136.4, 136.3 (Ph (TBDPS)), 130.8, 129.3, 128.5, 128,4, 128.2, 127.4 (Ph), 101.8 (PhCH), 97.9 (C-1), 76.8 (C-2), 75.2 (C-4), 73.4 (PhCH2), 71.4 (C-3), 70.9 (CH(CH3)2), 70.5 (C-6), 67.3 (C-5), 27.6 (C(CH3)3), 24.0 (CH3A(iPr)), 22.0 (CH3B(iPr)), 19.8 (C(CH3)3); HRMS (ESI-TOF) m/z [M+NH4]+ Calcd for C39H50NO6Si 656.3402; Found 656.3396; [M+Na]+ Calcd for C39H46O6SiNa 661.2956; Found 661.2956. Acknowledgements This work was supported by the Russian Science Foundation (grant number 14-50-00126). We would like to thank Dr. Mikhail B. Lagutin (The Lomonosov Moscow State University, Faculty of Mechanics and Mathematics, Department of Mathematical Statistics and Stochastic Processes) for consultations on mathematical statistics and Dr. Elena V. Sukhova (N.D. Zelinsky Institute of Organic Chemistry, Laboratory of Glycoconjugate Chemistry) for samples of 2,4-di-O-benzoyl- and 3-O-acetyl-2,4-di-O-benzoyl-D-levoglucosans. Supporting Information 1

H and

13

C NMR spectra for all new compounds, 3JH,H and heteronuclear coupling constants for

model compounds p-methoxyphenyl 3-O-acetyl-2-O-benzyl-4,6-O-benzylidene-β-D-glucoside, 2,4di-O-benzoyl-D-levoglucosan

and

3-O-acetyl-2,4-di-O-benzoyl-D-levoglucosan,

uncertainty estimation of coupling constants obtained by computer modelling. References (1) Komarova, B. S.; Tsvetkov, Y. E.; Nifantiev, N. E. Chem. Rec. 2016, 16, 488–506.


details

of

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(2) Komarova, B. S.; Tsvetkov, Y. E.; Knirel, Y. A.; Zähringer, U.; Pier, G. B.; Nifantiev, N. E. Tetrahedron Lett. 2006, 47, 3583–3587. (3) Ustyuzhanina, N.; Komarova, B.; Zlotina, N.; Krylov, V.; Gerbst, A.; Tsvetkov, Y.; Nifantiev, N. Synlett 2006, 921–923. (4) Gerbst, A. G.; Ustuzhanina, N. E.; Grachev, A. A.; Khatuntseva, E. A.; Tsvetkov, D. E.; Whitfield, D. M.; Berces, A.; Nifantiev, N. E. J. Carbohydr. Chem 2001, 20, 821–831. (5) Ustyuzhanina, N.; Krylov, V.; Grachev, A.; Gerbst, A.; Nifantiev, N. Synthesis 2006, 4017–4031. (6) Komarova, B. S.; Orekhova, M. V.; Tsvetkov, Y. E.; Nifantiev, N. E. Carbohydr. Res. 2014, 384, 70–86. (7) Pedersen, C. M.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc. 2007, 129, 9222–9235. (8) Jensen, H. H.; Nordstrøm, L. U.; Bols, M. J. Am. Chem. Soc. 2004, 126, 9205–9213. (9) Douglas, N. L.; Ley, S. V.; Lücking, U.; Warriner, S. L. J. Chem. Soc., Perkin Trans. 1 1998, 51– 65. (10) Yang, M. T.; Woerpel, K. A. J Org Chem. 2009, 74, 545–553. (11) Crich, D.; Cai, W.; Dai, Z. J. Org. Chem. 2000, 65, 1291–1297. (12) Lucero, C. G.; Woerpel, K. A. J. Org. Chem. 2006, 71, 2641–2647. (13) Walvoort, M. T. C.; Dinkelaar, J.; van den Bos, L. J.; Lodder, G.; Overkleeft, H. S.; Codée, J. D. C.; van der Marel, G. A. Carbohydr. Res. 2010, 345, 1252–1263. (14) de Oliveira, P. R., Rittner, R. Spectrochim. Acta, Part A 2005, 61, 1737–1745. (15) Angyal, S. J.; Pickles, V. A. Aust. J. Chem. 1972, 25, 1695–1710. (16) Angyal, S. J.; Kondo, Y. Carbohydr. Res. 1980, 35–48. (17) Paulsen, H.; Friedmann M. Chem. Ber. 1972, 105, 705–717. (18) Paulsen, H.; Friedmann, M. Chem. Ber. 1972, 105, 718 –730. (19) Sattelle, B. M.; Bose-Basu, B.; Tessier, M.; Woods, R. J.; Serianni, A. S.; Almond, A. J. Phys. Chem. B 2012, 116, 6380–6386.



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