Substitution of the Participating Group of Glycosyl Donors by a

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Substitution of the Participating Group of Glycosyl Donors by a Halogen Atom: Influence on the Rearrangement of Transient Orthoesters Formed during Glycosylation Reactions Antoine Joosten, Mélissa Boultadakis-Arapinis, Vincent Gandon, Laurent Micouin, and Thomas Lecourt J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.6b03088 • Publication Date (Web): 07 Feb 2017 Downloaded from http://pubs.acs.org on February 10, 2017

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The Journal of Organic Chemistry

Substitution of the Participating Group of Glycosyl Donors by a Halogen Atom: Influence on the Rearrangement of Transient Orthoesters Formed during Glycosylation Reactions

Antoine Joosten,[a] Mélissa Boultadakis-Arapinis,[b] Vincent Gandon,[c] Laurent Micouin,[b] and Thomas Lecourt*[a]

[a] Normandie Univ, INSA Rouen, UNIROUEN, CNRS, COBRA UMR 6014, 76000 Rouen, France ; [b] Université Paris Descartes, Sorbonne Paris Cité, CNRS (UMR 8601), 75006 Paris, France ; [c] Institut de Chimie Moléculaire et des Matériaux d’Orsay, CNRS UMR 8182, Univ. Paris-Sud, Université Paris-Saclay, bâtiment 420, 91405 Orsay cedex, France.

Graphical Abstract: Ph

O O PivO

O

X=H SPh

O O

X = H, Cl, Br +

ROH

Ph

O O PivO

Disaccharide

O OO

X RO

X

Degradation X = Cl, Br

Abstract: Substitution of the participating group of glycosyl donors by a halogen atom is shown to specifically induce degradation of transient orthoesters formed during glycosylation reactions, depending on the nature of the acceptor, and to affect the protonation profile of those intermediates. Following these findings, bromo- and chloroacetates, which are major protecting groups in glycochemistry because being orthogonal to other esters, should be considered with care as participating groups in the future.

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Due to the prominent role played by complex carbohydrates in numerous biological processes, the development of new synthetic methodologies represents a major field of glycosciences.1 In this context, we recently reported a new approach toward ketopyranosides where quaternarization of the anomeric position was performed in a late stage of the synthetic process.2 Our sequence relied on a key bromoacetate at position 2, which first induced the formation of a 1,2-trans glycosidic linkage before being converted into a diazo ester. Rh(II)-catalysed decomposition of this carbene precursor then resulted in functionalization of the anomeric C-H bond, with retention of configuration, to give quaternary sugars of high value for potential biological applications.

Although

glycosylation

with

phenyl

2-O-bromoacetyl

manno-

thiopyranoside donors delivered α-dimannosides in high yields under NIS/TfOH conditions, reaction between the permethylated acceptor 1 and glucopyranosyl donor 2 resulted in massive degradation of the starting materials. Coupling of 1 and 2 could only be successfully performed under preactivation conditions to give a 1:1 inseparable mixture of β-glucoside 3 and orthoester 4 in 93 % yield (Scheme 1). Treatment of this mixture with TsNHNHTS and DBU selectively promoted the diazo transfer on disaccharide 3, without affecting the neo-pentylbromide 4. After separation by careful flash chromatography, the carbene precursor 5 was obtained in a modest 40% yield over two steps. Selective functionalization of the axial anomeric C-H bond was finally performed under Rh2(acam)2 catalysis to give the quaternary β-glucoside 6 in pure form.3


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Ph

O O PivO 2

O

1) Tf2O, Ph2SO SPh

O O

2) Br

O O PivO

O

MeO MeO

O

O

O O PivO

61%

OMe OMe

O

Ph +

MeO OMe

Rh2(acam)4

(1:1) 93% 4

3

O

O

O

OMe

MeO

MeO 5

43%

N2

Ph

O O PivO

O O

+

O

O Br

MeO MeO

OMe OMe

O

OO

MeO OMe

TsNHNHTs DBU O O PivO

O O

MeO

Ph

O O PivO

OMe Br

OMe OMe

O O

O

O

OH O

OMe 6

O O

1 Ph

Ph

MeO MeO 4 38%

OO O Br

MeO OMe

Scheme 1. Glycosylation and carbene-mediated C-H functionalization in the β-gluco series. Though we developed the first stereoselective route toward quaternary β-glycosides, our synthetic sequence suffered from the formation of large amounts of orthoester 4 that made the glycosylation step unsatisfactory. In order to improve efficiency of the quaternarization process in the β-gluco series, the acid-catalysed rearrangement of 4 was attempted (see Table S1),4 but 3 could not be obtained despite extensive efforts. Thus, under typical reaction conditions (0.2 eq. TMSOTf, CH2Cl2, 0 °C), only 18% of impure 3 could be obtained. Addition of Et2O as co-solvant, variation of the temperature, diminution of the catalyst loading, or addition of acceptor 1 to the reaction mixture did not have any beneficial effect. Switching toward bulky Lewis acids or Brønsted acids also resulted in massive degradation of the starting material. Being aware that the formation of an epi-bromonium species might have hampered the rearrangement of orthoester 4,5 we moved to a chloroacetate at position 2, which is a participating group widely used in glycochemistry,6 in contrary to bromoacetate. Unfortunately, glycosylation of 1 with donor 7 under NIS/TfOH conditions again led to a very messy reaction from which disaccharide 8 (11%), orthoester 9 (29%), and compound 10 (31%) resulting from degradation of 9, were identified (Scheme 2).4 Glycosylation of the primary acceptor 1



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under NIS/TfOH conditions could be achieved with the halogen-free 2-O-acetyl donor 11 to give disaccharide 12 in 86% yield (Scheme 2). Ph

O O PivO

O

Ph Ph

SPh

O

O O PivO

O 1, NIS, TfOH

Cl

O O

11

O O O

SPh CH3

OMe MeO Cl 8 11%

Ph O O PivO

O O PivO

O O

1, NIS, TfOH

O

O

O

7 Ph

OMe OMe

MeO MeO 20

OO O

Cl

O O PivO

O O

+

O Cl

MeO MeO 9 29%

O O PivO

CH3 12

O

+ MeO MeO

MeO OMe

MeO OMe

Ph

O

O

OO

10 31%

O

O O O 86% O

OMe OMe

CH3 OMe OMe

MeO OMe

Scheme 2. Glycosylation of acceptor 1 with donors 7 and 11. Degradation of the starting materials when glycosylating acceptor 1 was thus only observed with the 2-O-bromo- and chloroacetyl donors 2 and 7. Even if substitution of the participating group of glycosyl donors by a halogen atom has already been shown to increase the amount of orthoesters formed during glycosylation reactions,7 it has never been reported to specifically induce degradation of those intermediates to the best of our knowledge.8,9 Moreover, rearrangement of an orthoester formed when coupling the analogous 2-O-bromoacetyl mannopyranosyl donor with acceptor 1 was achieved in high yield.3 Degradation of the transient orthoesters thus only occurred in the β-gluco series. In this context, we next investigated the influence of the nature of the acceptor on the outcome of glycosylations with 2 and 7 under NIS/TfOH conditions. Coupling of 1310 having a free equatorial hydroxyl at position 3 with donors 2 and 7 nicely delivered disaccharides 14 and 15 in 83 and 93% yield respectively. Similarly, glycosylation of acceptor 16,11 with an equatorial alcohol at position 2, smoothly gave 17 in high yield. However, with the corresponding mannosyl acceptor 18,12 complete degradation of the


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starting material occurred with donor 2. The outcome of glycosylations with 2-O-bromoand chloroacetyl donors 2 and 7 under acidic conditions is thus also strongly influenced by the nature of the glycosyl acceptor. Ph

O O HO

Ph

O

O O AcO

AcO OMe

13

Ph

O HO OMe

16

Ph Ph

O O PivO

X = Br

14

X = Cl

15

O

18 Ph

OO O

O

O O

AcO X

Ph

O O PivO

OMe

OH O

O O AcO

O O AcO O O

17

OMe

O O OMe O Br

At this stage, we could not say if disaccharides 14, 15 and 17 were directly formed from the glycosyl cation and the acceptor, or after rearrangement of a transient orthoester. Orthoester 19 was thus prepared in pure form from 13 and 2 under preactivation conditions, and could be converted in 75% yield into the thermodynamically favored disaccharide 14 under Lewis acid conditions (Scheme 3). The transient formation of 19 during the coupling of 13 by 2 under NIS/TfOH conditions would then not have been detrimental to the efficiency of this glycosylation reaction. Nature of the acceptor is thus also an important parameter influencing the outcome of the acid-catalysed rearrangement of transient orthoesters derived from 2-O-haloacetyl glycosyl donors. Ph Ph2SO Tf2O

O O PivO Br

2 + 13 93 %

AcO MeO

O OO

Ph

O O O O

TMSOTf 14 75 %

19

Scheme 3. Preparation and rearrangement of orthoester 19. Being intrigued by the strong influence of the substitution pattern of the participating group on the outcome of glycosylations, we next decided to draw a more detailed mechanistic scheme of these transformations.13 Treatment of exo-4 (δ(C9) = 118.2), which was kinetically obtained14 from 1 and 2 after glycosylation under preactivation



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conditions, with TMSOTf at -78 °C resulted in partial epimerization into the endostereoisomer 4 (δ(C9) = 119.2). Neither the reaction time (from 30 mn to 2 h) nor the amount of Lewis acid (from 0.2 to 1 equiv.) markedly changed the exo/endo ratio (from 65:35 to 55:45). Rearrangement of 4 might thus be an equilibration process where cleavage of the Ccarbonyl-OA bond, giving rise to disaccharide 3, did not occur. The acidcatalysed rearrangement of 4 thus involved activation of either O1 or O2, followed by cleavage of the C1-O1, Ccarbonyl-O1, or Ccarbonyl-O2 bond. Rotation around the single C-O bond and cyclisation then provided the endo-4 stereoisomer at -78 °C, whereas degradation occurred at higher temperature (Scheme 4). Ph

O O PivO

O2 O BrH2C

H

O

H O2 O1 1

C9

BrH2C C9

exo-4 δ(C9) = 118.2

H O2 O1 ROA C9

MeO MeO

O MeO OMe

H O2 O1 Br C9 OAR

Br

ROA

O1 C9

O

O

O

OAR

OAR

R=

O

ROA

C9

CH2Br Epimerization

O Br +

Degradation

H

H O2 O1

Ph

O O PivO

O O2 O

ROA

1

C9

CH2Br endo-4 δ(C9) = 119.2

O2H

Scheme 4. Plausible mechanistic pathways for the acid-catalysed rearrangement of 4. Having shown that a reaction pathway involving activation of the O1 or O2 atoms of orthoester 4 was favoured under acidic conditions, we wondered if substitution of participating groups by a halogen atom might have influenced the protonation profile of transient orthoesters. Regarding the use of strong Brønsted or hard Lewis acids as catalysts, we assumed that the protonation of orthoesters would be under chargecontrol, i.e. occurring at the most negatively charged oxygen atom.15 The natural partial charge of the O1, O2 and OA atoms4 was thus computed at the M06-2X/6-31+G(d,p) level of theory for the three staggered conformers A, B, and C of orthoester exo-4 (R = CH2Br), 9 (R = CH2Cl), and 20 (R = CH3), for which strong stereoelectronic effects governing the rearrangement could be anticipated (Figure 1).16 For conformer A, in which one lone


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pair of OA is delocalized into the σ*C-O2 orbital, the partial negative charge was the strongest on OA when R = CH3, whereas the three oxygen atoms almost had the same charge with R = CH2Cl or CH2Br. For conformer B with two lone pairs of OA overlapping antibonding orbitals of the neighbouring C-O bonds, O1 and OA, respectively, were the strongest and the least negatively charged atoms whatever the substitution pattern of the orthoester. For conformer C having one lone pair of OA delocalized into the σ*C-O1 orbital, the strongest negative charge was always found located on O1. O

O

O

Glc O2

O1

O2

O1

O2

O1

OA

OA

OA

R

R

R

A

B

C

OA >> O2 > O1

O1 > O2 >> OA

O1 >> OA >> O2

R=CH2Cl 9

O2 = OA = O1

O1 > O2 >> OA

O1 >> OA >> O2

R=CH2Br 4

O2 = OA = O1

O1 > O2 >> OA

O1 >> OA > O2

Glc

R=CH3

20

Glc

Figure 1. Evolution of the partial negative charge of oxygen atoms depending on the conformation and substitution of orthoesters. As disaccharide 12 was obtained in high yield when coupling the 2-O-acetyl donor 11 with 1, rearrangement of the putative orthoester intermediate 20 (Scheme 2) should have involved cleavage of the Ccarbonyl-OA bond, and thus activation of OA. In view of our calculations with R=CH3, cleavage of the Ccarbonyl-OA bond might have occurred directly after protonation of the most stable conformer A, or after a proton shift if conformers B or C would have suffered protonation preferentially (Scheme 5).



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O

O

CH3

O1

O1

O2 OA

O2 OA Glc

A

O O

OA

B

H+ O1

Glc

H+

CH3

H+

Glc

C

H O

H

Glc

O1

O2 OA

Glc

CH3

O2 OA

O

CH3

H-Shift

O1

CH3

O2 OA Glc

O2 H3C

O1

Degradation

Scheme 5. Plausible pathways for the rearrangement of a putative transient orthoester 20 formed during the coupling of 1 and 11. Computation of the partial negative charges of the 3 oxygen atoms with R = CH2Br or CH2Cl revealed that protonation of OA was not favoured for any of the 3 conformers. A complex Curtin-Hammet kinetic profile requiring additional theoretical studies can thus be anticipated for the degradation of 4 and 9 because it could either have involved the cleavage of the C1-O1, Ccarbonyl-O1, or Ccarbonyl-O2 bonds.17

In conclusion, 2-O-chloro- or bromoacetyl glycosyl donors were shown to give rise to transient orthoesters that might decompose under the acidic conditions of glycosylation reactions, depending on the nature of the glycosyl acceptor, whereas the corresponding 2-O-acetyl donor nicely delivered the desired disaccharides. Preliminary theoretical studies revealed that substitution of the participating group by a halogen atom was affecting the protonation profile of the corresponding orthoesters, and thus perhaps the outcome of their rearrangement. However, our findings, together with data from the literature,8,9 do not allow identifying any reactivity trends regarding the nature of the acceptor, and the outcome of glycosylations with 2-O-chloro- or bromoacetyl donors cannot thus be predicted at this stage. Chloro- and bromoacetate, which are major protecting groups in glycochemistry because they induce the formation of 1,2 trans glycosidic linkages and are selectively deprotected from other esters under mild


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conditions,18 should be considered with care as participating group in the future since they could specifically result in degradation of highly valuable starting materials.

Experimental Section General Information and Method. For reactions, solvents were purchased anhydrous (dichloromethane,

and

sodium/benzophenone, glycosylations). All

pyridine)

or

dichloromethane

distilled over

(tetrahydrofuran

phosphorous

pentoxide

over for

reactions were conducted under an argon atmosphere.

Glycosylations reactions were performed in flame-dried glassware. All reagents were used as received unless otherwise indicated. Reactions were monitored by thin-layer chromatography with silica gel 60 F254 pre-coated aluminium plate (0.25 mm). Visualization was performed under UV light and phosphomolybdic acid oxidation. 1H, NMR spectra were recorded at 300 or 400 Mhz, and 13C NMR spectra at 75 or 100 MHz. Abbreviations used for peak multiplicities are s: singlet, d: doublet, t: triplet, q: quadruplet and m: multiplet. Coupling constants J are in Hz and chemical shifts are given in ppm and calibrated with CDCl3 (residual solvent signals). Carbon multiplicities were assigned by distortionless enhancement by polarization transfer (DEPT) experiments. The 1H and

13C

signals were assigned by COSY and HSQC experiments. Accurate mass

measurements (HRMS) were performed with a Q-TOF analyser. Infrared spectra (IR) were recorded by application of foams and solids on a Single Reflection Attenuated Total Reflectance (ATR) Accessories, and data are reported in cm-1. Optical rotations were determined with a water-jacketed 10 cm cell. Specific rotations are reported in 10-1deg cm2 g-1 and concentrations in g per 100 mL. Melting points are uncorrected.



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Phenyl 4,6-O-benzylidene-2-O-chloroacetyl-3-O-pivaloyl-1-thio-β-D-glucopyranoside (7). To a stirred solution of 4,6-O-benzylidene-3-O-pivaloyl-1-thio-β-D-glucopyranoside3a (260 mg, 0.585 mmol) and pyridine (61 µL, 0.761 mmol) in anhydrous dichloromethane (3.5 mL) at 0 °C was added chloroacetyl chloride (56 µL, 0.702 mmol). After being stirred for 2 hours at 0 °C, TLC (dichloromethane / ethyl acetate 30:1) showed complete consumption of the starting material, and hydrochloride acid (1N, 5 mL) was added. The reaction mixture was diluted with dichloromethane (5 mL) and the organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane) to give 7 as a white foam (296 mg, 97%): Rf = 0.75 (silica, dichloromethane); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.55–7.31 (m, 10H, Harom.), 5.52 (s, 1H, H7), 5.36 (t, J = 9.2 Hz, 1H, H3), 5.10 (dd, J = 10.0, 9.2 Hz, 1H, H2), 4.83 (d, J = 10.0 Hz, 1H, H1), 4.41 (dd, J = 10.4, 4.9 Hz, 1H, H6eq), 4.08 (ABsyst, ∆δ = 0.06 ppm, JAB = 15.1 Hz, 2H, H8, H8’), 3.80 (t, J = 10.4 Hz, 1H, H6ax), 3.69 (t, J = 9.6 Hz, 1H, H4), 3.58 (td, J = 9.6, 4.9 Hz, 1H, H5), 1.17 (s, 9H, (CH3)3C); 13C

NMR (75 MHz, CDCl3): δ (ppm) 177.5 (C=O), 166.0 (C=O), 136.8 (Cquat. arom.), 133.2

(CHarom.), 131.3 (Cquat. arom.), 129.2 (CHarom.), 129.12 (CHarom.), 129.06 (CHarom.), 128.6 (CHarom.), 128.3 (CHarom.), 125.9 (CHarom.), 101.1 (C7), 86.1 (C1), 78.2 (C4), 72.4 (C3), 72.1 (C2), 70.7 (C5), 68.4 (C6), 40.6 (C8), 38.9 ((CH3)3C), 27.0 ((CH3)3C) ; FT-IR (film) 2971, 1737, 1479, 1277, 1098, 1010 cm-1; HRMS (ESI): m/z Calcd for C26H30ClO7S [M + H]+ 521.1401, found 521.1391; [α]D20 = -33 (c = 1.0, CHCl3). Coupling of (7) and (1) under NIS/TfOH conditions. A solution of donor 7 (200 mg, 0.384 mmol) and acceptor 11 (118 mg, 0.499 mmol) in distilled dichloromethane (7 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (350 mg). Niodosuccinimide (173 mg, 0.768 mmol) was added, and after cooling to –20 °C, trifluoromethanesulfonic acid (11 µL, 0.115 mmol) was added dropwise. After being


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stirred for 2 hours at –20 °C, the reaction mixture became dark brown. A saturated aqueous solution of sodium hydrogen carbonate (6 mL) was added, followed by a saturated aqueous solution of sodium thiosulfate (4 mL). The colorless reaction mixture was then diluted with dichloromethane (15 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 4:1 to 2:1) to give: a first fraction at Rf = 0.55 (silica, cyclohexane / ethyl acetate 2:1) containing a 83:17 mixture of 9a, the first diastereoisomer of orthoester 9, and unreacted acceptor 1 which was used in excess (white foam, 34 mg); a second fraction at Rf = 0.33 (silica, cyclohexane / ethyl acetate 2:1) containing a 46:30:24 mixture of 9b, the second diastereoisomer of orthoester, disaccharide 8, and methyl 6O-chloroacetyl-2,3,4-tri-O-methyl-α-D-glucopyranoside 10 (white foam, 77 mg); a third fraction at Rf = 0.31 (silica, cyclohexane / ethyl acetate 2:1) containing pure 10 (white foam, 27 mg). Yields of compounds 8, 9 and 10 were evaluated to be 11%, 29%, and 31% respectively. NMR data of orthoester 9a deduced from the 83:17 mixture of 9a and 1 (Fraction 1): 1H NMR (400 MHz, CDCl3): δ (ppm) 7.46–7.28 (m, 5H, Harom.), 5.87 (d, J = 6.2 Hz, 1H, H1B), 5.85 (dd, J = 9.9, 4.7 Hz, 1H, H3B), 5.56 (s, 1H, H7B), 4.62 (d, J = 3.5 Hz, 1H, H1A), 4.44 (dd, J = 10.7, 5.5 Hz, 1H, H6B), 4.39 (dd, J = 6.2, 4.7 Hz, 1H, H2B), 4.28 (td, J = 9.7, 5.5 Hz, 1H, H5B), 4.15 (dd, J = 9.6, 2.2 Hz, 1H, H6A), 3.86 (dd, J = 9.6, 3.8 Hz, 1H, H6A), 3.78–3.34 (m, 12H, H3A, H4B, H5A, H6B, 2×H8B, 2×OMe), 3.27 (s, 3H, OMe), 3.23 (dd, J = 9.8, 9.1 Hz, 1H, H4A), 3.04 (s, 3H, OMe), 3.02 (dd, J = 9.7, 3.5 Hz, 1H, H2A), 1.24 (s, 9H, (CH3)3C);

13C

NMR (100 MHz, CDCl3): δ (ppm) 177.4 (C=O), 137.3 (Cquat. arom.), 129.0

(CHarom.), 128.2 (CHarom.), 125.8 (CHarom.), 119.7 (C9B), 100.5 (C7B), 100.3 (C1B), 96.7 (C1A), 83.5 (C3A), 81.7 (C2A), 79.3 (C4A), 78.7 (C2B), 77.3 (C4B), 73.9 (C3B), 69.0 (C5A), 68.8 (C6B), 62.7 (C6A), 62.2 (C5B), 61.0 (2 × OMe), 58.2 (OMe), 55.2 (OMe), 44.3



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(C8B), 38.9 ((CH3)3C), 27.3 ((CH3)3C). NMR data of orthoester 9b deduced from the 46:33:24 mixture of 9b, 8 and 10 (Fraction 2): 1H NMR (400 MHz, CDCl3): δ (ppm) 7.47– 7.31 (m, 5H, Harom.), 5.89 (d, J = 5.5 Hz, 1H, H1B), 5.52 (s, 1H, H7B), 5.37 (dd, J = 9.2, 4.2 Hz, 1H, H3B), 4.82-4.76 (m, 1H, H1A), 4.46-4.32 (m, 2H, H2B, H6B), 4.15-3.97 (m, 1H, H5B), 3.89-3.79 (m, 3H, 2xH8B, H6B), 3.78-3.44 (m, 14H, 3xOMe, 2xH6A, H5A, H3A, H4B), 3.38 (s, 3H, OMe), 3.22-3.13 (m, 2H, H2A, H4A), 1.22 (s, 9H, (CH3)3C);

13C

NMR

(100 MHz, CDCl3): δ (ppm) 177.4 (C=O), 136.91 or 136.87 (Cquat. arom.), 129.2, 129.1, 128.3, 126.1, 126.0 (CHarom.), 118.8 (C9B), 101.40 or 101.37 (C7B), 98.9 (C1B), 97.60 (C1A), 83.64 (C3A), 81.9 (C2A), 79.2 (C4A), 78.5 (C4B), 77.9 (C2B), 71.5 (C3B), 69.36 (C5A), 68.7 (C6B), 63.0 (C5B), 62.2 (C6A), 60.95 (OMe), 60.6 (OMe), 59.14 (OMe), 55.3 (OMe), 44.6 (C8B), 39.0 or 38,9 ((CH3)3C), 27.2 or 27,1((CH3)3C). NMR data of disaccharide 8 deduced from the 46:33:24 mixture of 9b, 8 and 10 (Fraction 2): 1H NMR (400 MHz, CDCl3): δ (ppm) 7.47–7.31 (m, 5H, Harom.), 5.52 (s, 1H, H7B), 5.33 (t, J = 9.4 Hz, 1H, H3B), 5.14 (dd, J = 9.4, 7.9 Hz, 1H, H2B), 4.82-4.76 (m, 1H, H1A), 4.70 (d, J = 7.9 Hz, 1H, H1B), 4.46-4.32 (m, 2H, 2xH6B), 4.15-3.97 (m, 3H, 2xH8B, H6A), 3.78-3.44 (m, 14H, 3xOMe, H5B, H4B, H6A, H5A, H3A), 3.38 (s, 3H, OMe), 3.22-3.13 (m, 1H, H2A), 3.01 (t, J = 9.0 Hz, 1H, H4A), 1.16 (s, 9H, (CH3)3C);

13C

NMR (100 MHz, CDCl3): δ (ppm) 177.7

(C=O), 166.0 (C=O), 136.91 or 136.87 (Cquat. arom.), 129.2, 129.1, 128.3, 126.1, 126.0, (CHarom.), 101.40 or 101.37 (C7B), 101.31 (C1B), 97.48 (C1A), 83.59 (C3A), 81.9 (C2A), 79.6 (C4A), 77.4 (C4B), 73.9 (C2B), 73.4 (C3B), 69.6 (C5A), 69,35 (C6A), 68.6 (C6B), 66.6 (C5B), 60.95 (OMe), 60.4 (OMe), 59.10 (OMe), 55.3 (OMe), 40.6 (C8B), 39.0 or 38,9 ((CH3)3C), 27.2 or 27,1((CH3)3C). Methyl 6-O-chloroacetyl-2,3,4-tri-O-methyl-α-Dglucopyranoside 10 (Fraction 3): Rf = 0.31 (silica, cyclohexane / ethyl acetate 2:1); 1H NMR (300 MHz, CDCl3): δ (ppm) 4.76 (d, J = 3.6 Hz, 1H, H1), 4.39 (dd, J = 11.7, 2.3 Hz, 1H, H6), 4.31 (dd, J = 11.7, 4.9 Hz, 1H, H6), 4.07 (s, 2H, H7), 3.69 (ddd, J = 9.8, 4.9, 2.3 Hz, 1H,


Page 13 of 22

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H5), 3.58 (s, 3H, OMe), 3.52–3.43 (m, 7H, H3, 2 × OMe), 3.37 (s, 3H,OMe), 3.15 (dd, J = 9.6, 3.6 Hz, 1H, H2), 3.04 (dd, J = 9.8, 9.0 Hz, 1H, H4); 13C NMR (75 MHz, CDCl3): δ (ppm) 167.2 (C=O), 97.5 (C1), 83.5 (C3), 81.8 (C2), 79.6 (C4), 68.4 (C5), 64.9 (C6), 61.0 (OMe), 60.7 (OMe), 59.2 (OMe), 55.4 (OMe), 40.8 (C7); FT-IR (film) 2934, 1740, 1447, 1290, 1157, 998 cm-1; HRMS (ESI): m/z Calcd for C12H25ClNO7 [M + NH4]+ 330.1320, found 330.1317; [α]D20 = +126 (c = 1.0, CHCl3). Phenyl 4,6-O-benzylidene-2-O-acetyl-3-O-pivaloyl-1-thio-β-D-glucopyranoside (11). To a stirred solution of 4,6-O-benzylidene-3-O-pivaloyl-1-thio-β-D-glucopyranoside3a (490 mg, 1.102 mmol) and pyridine (357 µL, 4.412 mmol) in anhydrous dichloromethane (25 mL) at 0 °C was added acetyl chloride (103 µL, 1.452 mmol). After being stirred for 2 hours at 0 °C, TLC (dichloromethane / cyclohexane 4:1) showed complete consumption of the starting material, and methanol (1 mL) was added. The reaction mixture was then stirred for 20 minutes at room temperature after addition of hydrochloride acid (1N, 10 mL) and the organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane / cyclohexane 4:1) to give 11 as a white foam (525 mg, 98%): Rf = 0.57 (silica, dichloromethane); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.54–7.31 (m, 10H, Harom.), 5.53 (s, 1H, H7), 5.37 (t, J = 9.3 Hz, 1H, H3), 5.10 (dd, J = 10.0, 9.3 Hz, 1H, H2), 4.84 (d, J = 10.0 Hz, 1H, H1), 4.42 (dd, J = 10.3, 4.9 Hz, 1H, H6eq), 3.82 (t, J = 10.3 Hz, 1H, H6ax), 3.71 (t, J = 9.3 Hz, 1H, H4), 3.59 (td, J = 9.3, 4.9 Hz, 1H, H5), 2.10 (s, 3H, CH3C=O), 1.19 (s, 9H, (CH3)3C); 13C NMR (75 MHz, CDCl3): δ (ppm) 177.5 (C=O), 169.4 (C=O), 136.9 (Cquat. arom.),

132.8 (CHarom.), 132.1 (Cquat. arom.), 129.1 (CHarom.), 129.0 (CHarom.), 128.4 (CHarom.),

128.3 (CHarom.), 125.9 (CHarom.), 101.1 (C7), 86.8 (C1), 78.4 (C4), 72.6 (C3), 70.7 (C5), 70.5 (C2), 68.5 (C6), 38.9 ((CH3)3C), 27.1 ((CH3)3C), 20.8 (CH3C=O); FT-IR (film) 2973, 2872, 1747, 1480, 1279, 1223, 1178, 1153, 1138, 1100, 1064, 1031, 1008, 898, 750, 699



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Page 14 of 22

cm-1; HRMS (ESI) m/z: Calcd for C26H30NaO7S [M + Na]+ 509.1610, found 509.1609; [α]D20 = -41 (c = 1.0, CHCl3). Methyl

(4,6-O-benzylidene-2-O-acetyl-3-O-pivaloyl-β-D-glucopyranoside)-(16)-2,3,4-O-

methyl-α-D-glucopyranoside (12). A solution of donor 11 (155 mg, 0.319 mmol) and acceptor 13a (91 mg, 0.385 mmol) in distilled dichloromethane (5 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (250 mg). Niodosuccinimide (133 mg, 0.592 mmol) was added, and after cooling to –20 °C, trifluoromethanesulfonic acid (8 µL, 0.089 mmol) was added dropwise. After being stirred for 2 hours at –20 °C, the reaction mixture became dark brown. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, followed by a saturated aqueous solution of sodium thiosulfate (3 mL). The colorless reaction mixture was then diluted with dichloromethane (10 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (dichloromethane / ethyl acetate 5:1) to give disaccharide 12 (155 mg, 86%) as a white foam: Rf = 0.37 (silica, cyclohexane / ethyl acetate 70:30); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.41–7.27 (m, 5H, Harom.), 5.47 (s, 1H, H7B), 5.27 (t, J = 9.4 Hz, 1H, H3B), 5.07 (dd, J = 9.4, 7.9 Hz, 1H, H2B), 4.80–4.73 (m, 1H, H1A), 4.64 (d, J = 7.9 Hz, 1H, H1B), 4.34 (dd, J = 10.4, 4.9 Hz, 1H, H6B), 4.03 (dd, J = 10.6, 1.4 Hz, 1H, H6A), 3.78 (t, J = 10.4 Hz, 1H, H6B), 3.72–3.31 (m, 17H, H3A, H4B, H5A, H5B, H6A, 4 × OMe), 3.20–3.11 (m, 1H, H2A), 3.03 (td, J = 10.0, 4.4 Hz, 1H, H4A), 1.97 (s, 3H, CH3C=O), 1.12 (s, 9H, (CH3)3C);

13C

NMR (75 MHz, CDCl3): δ

(ppm) 177.6 (C=O), 169.2 (C=O), 136.9 (Cquat. arom.), 129.0 (CHarom.), 128.3 (CHarom.), 125.9 (CHarom.), 101.6 (C1B), 101.2 (C7B), 97.4 (C1A), 83.5 (C3A), 81.7 (C2A), 79.7 (C4A), 78.6 (C4B), 72.0 (C2B), 71.6 (C3B), 69.6 (C5A), 68.7 (C6A), 68.6 (C6B), 66.5 (C5B), 61.0 (OMe), 60.4 (OMe), 59.1 (OMe), 55.2 (OMe), 38.9 ((CH3)3C), 27.1 ((CH3)3C), 20.8


Page 15 of 22

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(CH3C=O); FT-IR (film) 2936, 2833, 1742, 1720, 1454, 1372, 1280, 1230, 1155, 1100, 1063, 1046, 1031, 1000, 899, 752, 699 cm-1; HRMS (ESI): m/z Calcd for C30H44NaO13 [M + Na]+ 635.2679, found 635.2681; [α]D20 = +30 (c = 1.0, CHCl3). Methyl

(4,6-O-benzylidene-2-O-bromoacetyl-3-O-pivaloyl-β-D-glucopyranoside)-(13)-

4,6-O-benzylidene-2-O-acetyl-α-D-glucopyranoside (14). A solution of donor 23a (97 mg, 0.172 mmol) and acceptor 1319 (73 mg, 0.223 mmol) in distilled dichloromethane (6 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (170 mg). N-iodosuccinimide (66.4 mg, 0.295 mmol) was added, and after cooling to –20 °C, trifluoromethanesulfonic acid (5 µL, 0.052 mmol) was added dropwise. After being stirred for 1 hour at –20 °C, the reaction mixture became dark brown. A saturated aqueous solution of sodium hydrogen carbonate (6 mL) was added, followed by a saturated aqueous solution of sodium thiosulfate (3.5 mL). The colorless reaction mixture was then diluted with dichloromethane (12 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 80:20) to give disaccharide 14 (111 mg, 83%) as a white solid: Rf = 0.37 (silica, cyclohexane / ethyl acetate 70:30); δ (ppm) 7.54–7.45 (m, 2H, Harom.), 7.43–7.29 (m, 8H, Harom.), 5.56 (s, 1H, H7A or H7B), 5.42 (s, 1H, H7A or H7B), 5.26 (t, J = 9.3 Hz, 1H, H3B), 5.09 (dd, J = 9.3, 7.8 Hz, 1H, H2B), 4.94–4.83 (m, 3H, H1A, H1B, H2A), 4.35–4.20 (m, 3H, H3A, H6A, H6B), 3.90-3.59 (m, 7H, H8B, H8B’, H4A, H4B, H5B, H6A’, H6B’), 3.50–3.34 (m, 4H, H5A, OMe), 2.19 (s, 3H, CH3C=O), 1.17 (s, 9H, (CH3)3C); δ (ppm) 177.5 (C=O), 170.5 (C=O), 166.0 (C=O), 137.3 (Cquat. arom.), 136.9 (Cquat. arom.), 129.3 (CHarom.), 129.1 (CHarom.), 128.4 (CHarom.), 128.3 (CHarom.), 126.1 (CHarom.), 126.0 (CHarom.), 101.4 (C7A or C7B), 101.2 (C7A or C7B), 100.4 (C1B), 97.7 (C1A), 79.8 (C4A), 78.8 (C4B), 75.1 (C3A), 74.1 (C2B), 72.9 (C2A), 71.4 (C3B), 68.9 (C6A or C6B), 68.6 (C6A or C6B),



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

66.5 (C5A), 62.6 (C5B), 55.5 (OMe), 39.0 ((CH3)3C), 27.1 ((CH3)3C), 25.4 (C8B), 21.2 (CH3C=O); FT-IR (film) 2966, 2927, 2871, 1739, 1454, 1371, 1278, 1235, 1183, 1144, 1124, 1099, 1053, 1000, 752, 699; HRMS (ESI): m/z Calcd for C36H47BrNO14 [M + NH4]+ 796.2180, found 796.2179; [α]D20 = +2 (c = 1.0, CHCl3) ; m.p. = +123-125 °C. Methyl

(4,6-O-benzylidene-2-O-chloroacetyl-3-O-pivaloyl-β-D-glucopyranoside)-(13)-

4,6-O-benzylidene-2-O-acetyl-α-D-glucopyranoside (15). A solution of donor 7 (72 mg, 0.138 mmol) and acceptor 1319 (47 mg, 0.179 mmol) in distilled dichloromethane (5 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (130 mg). N-iodosuccinimide (62 mg, 0.276 mmol) was added, and after cooling to –20 °C, trifluoromethanesulfonic acid (4 µL, 0.042 mmol) was added dropwise. After being stirred for 1 hour at –20 °C, the reaction mixture became dark brown. A saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added, followed by a saturated aqueous solution of sodium thiosulfate (3 mL). The colorless reaction mixture was then diluted with dichloromethane (10 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 3.5:1) to give disaccharide 15 (94 mg, 93%) as a white foam: Rf = 0.24 (silica, cyclohexane / ethyl acetate 3.5:1); δ (ppm) 7.53–7.46 (m, 2H, Harom.), 7.44–7.30 (m, 8H, Harom.), 5.55 (s, 1H, H7A or H7B), 5.42 (s, 1H, H7A or H7B), 5.23 (t, J = 9.2 Hz, 1H, H3B), 5.09 (dd, J = 9.2, 7.7 Hz, 1H, H2B), 4.94–4.81 (m, 3H, H1A, H1B, H2A), 4.31–4.22 (m, 3H, H3A, H6A, H6B), 4.10 (d, J = 15.3 Hz, 1H, H8B), 4.00 (d, J = 15.3 Hz, 1H, H8B’), 3.88–3.60 (m, 5H, H4A, H4B, H5B, H6A’, H6B’), 3.47–3.36 (m, 4H, H5A, OMe), 2.17 (s, 3H, CH3C=O), 1.15 (s, 9H, (CH3)3C); δ (ppm) 177.6 (C=O), 170.5 (C=O), 166.3 (C=O), 137.2 (Cquat. arom.), 136.9 (Cquat. arom.), 129.3 (CHarom.), 129.0 (CHarom.), 128.32 (CHarom.), 128.26 (CHarom.), 126.0 (CHarom.), 125.9 (CHarom.), 101.3 (C7A or C7B), 101.1 (C7A or C7B), 100.4


Page 16 of 22

Page 17 of 22

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(C1B), 97.6 (C1A), 79.8 (C4A), 78.3 (C4B), 75.2 (C3A), 74.2 (C2B), 72.7 (C2A), 71.4 (C3B), 68.9 (C6A or C6B), 68.5 (C6A or C6B), 66.5 (C5A), 62.5 (C5B), 55.4 (OMe), 40.5 (C8B), 38.9 ((CH3)3C), 27.1 ((CH3)3C), 21.1 (CH3C=O); FT-IR (film) 2972, 1740, 1454, 1371, 1234, 1185, 1146, 1099, 1053, 998, 751, 698; HRMS (ESI): m/z Calcd for C36H44ClO14 [M + H]+ 735.2420, found 735.2415; [α]D20 = -8 (c = 1.0, CHCl3). Methyl

(4,6-O-benzylidene-2-O-bromoacetyl-3-O-pivaloyl-β-D-glucopyranoside)-(12)-

4,6-O-benzylidene-3-O-acetyl-α-D-glucopyranoside (17). A solution of donor 23a (125.5 mg, 0.222 mmol) and acceptor 1619 (110 mg, 0.339 mmol) in distilled dichloromethane (10 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (230 mg). N-iodosuccinimide (100 mg, 0.444 mmol) was added, and after cooling to –20 °C, trifluoromethanesulfonic acid (6 µL, 0.067 mmol) was added dropwise. After being stirred for 1 hour at –20 °C, the reaction mixture became dark brown. A saturated aqueous solution of sodium hydrogen carbonate (10 mL) was added, followed by a saturated aqueous solution of sodium thiosulfate (6 mL). The colorless reaction mixture was then diluted with dichloromethane (20 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 80:20) to give disaccharide 17 (131.5 mg, 76%) as a white solid: Rf = 0.34 (silica, cyclohexane / ethyl acetate 70:30); 1H NMR (300 MHz, CDCl3): δ (ppm) 7.50–7.28 (m, 10H, Harom.), 5.53 (t, J = 9.8 Hz, 1H, H3A), 5.52 (s, 1H, H7A or H7B), 5.47 (s, 1H, H7A or H7B), 5.33 (t, J = 9.6 Hz, 1H, H3B), 5.13 (dd, J = 9.6, 7.9 Hz, 1H, H2B), 4.79 (d, J = 3.6 Hz, 1H, H1A), 4.75 (d, J = 7.9 Hz, 1H, H1B), 4.38 (dd, J = 10.5, 4.9 Hz, 1H, H6B), 4.29 (dd, J = 10.1, 4.7 Hz, 1H, H6A), 3.98–3.64 (m, 7H, H2A, H4B, H5A H6A’, H6B’, H8B, H8B’), 3.61– 3.48 (m, 2H, H4A, H5B), 3.42 (s, 3H, OMe), 2.14 (s, 3H, CH3C=O), 1.17 (s, 9H, (CH3)3C); 13C NMR (75 MHz, CDCl3): δ (ppm) 177.5 (C=O), 170.1 (C=O), 166.0 (C=O), 137.0 (Cquat. arom.),



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

136.8 (Cquat. arom.), 129.24 (CHarom.), 129.17 (CHarom.), 128.4 (CHarom.), 126.3 (CHarom.), 125.9 (CHarom.), 101.8 (C7A or C7B), 101.7 (C7A or C7B), 101.3 (C1B), 100.0 (C1A), 79.5 (C4A), 78.7 (C4B), 77.6 (C2A), 73.1 (C2B), 71.1 (C3B), 70.8 (C3A), 69.1 (C6A), 68.5 (C6B), 66.7 (C5A), 62.3 (C5B), 55.7 (OMe), 39.0 ((CH3)3C), 27.2 ((CH3)3C), 25.4 (C8B), 21.4 (CH3C=O); FT-IR (film) 2979, 2931, 2878, 1743, 1455, 1371, 1279, 1233, 1122, 1093, 1057, 752, 698 cm-1; HRMS (ESI): m/z Calcd for C36H47BrNO14 [M + NH4]+ 796.2180, found 796.2179; [α]D20 = -24 (c = 1.0, CHCl3); m.p. = +202-205 °C. Preparation of orthoester (19). A solution of donor 23a (100 mg, 177 µmol), diphenylsulfoxide (53.7 mg, 266 µmol) and 2,4,6-tri-tert-butylpyridine (131.5 mg, 531 µmol) in distilled dichloromethane (7.5 mL) was stirred for 1 hour at room temperature over activated 4 Å molecular sieves (275 mg) and cooled to –70 °C under argon. Trifluoromethanesulfonic anhydride (51 µL, 301 µmol) was then added and the mixture was stirred at –20 °C for 10 minutes. The reaction mixture was then cooled to –70 °C, and a solution of acceptor 1319 (115 mg, 354 µmol) in distilled dichloromethane (1.5 mL) was added dropwise. After 2 hours of stirring at –70 °C, a saturated aqueous solution of sodium hydrogen carbonate (5 mL) was added. The reaction mixture was then diluted with dichloromethane (5 mL) and filtered through a Celite pad. The organic layer was dried (anhydrous magnesium sulfate), filtered, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 80:20) to orthoester 19 (130 mg, 94%) as a white solid: Rf = 0.37 (silica, cyclohexane / ethyl acetate 70:30); δ (ppm) 7.53–7.28 (m, 10H, Harom.), 5.75 (d, J = 5.6 Hz, 1H, H1B), 5.50-5.41 (m, 3H, H7A, H7B, H3B), 4.95 (d, J = 3.4 Hz, 1H, H1A), 4.75 (dd, J = 9.6, 3.4 Hz, 1H, H2A), 4.43-4.23 (m, 3H, H6B, H6A, H3A), 4.19 (dd, J = 5.6, 4.4 Hz, 1H, H2B), 4.14-4.03 (m, 1H, H5B), 3.93-3.67 (m, 3H, H5A, H8B, H6A’), 3.66-3.50 (m, 4H, H4B, H4A, H8B’, H6B’), 3.39 (s, 3H, OMe), 2.14 (s, 3H, CH3C=O), 1.19 (s, 9H, (CH3)3C); δ (ppm)


Page 18 of 22

Page 19 of 22

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177.1 (C=O), 170.0 (C=O), 136.94 (Cquat. arom.), 136.86 (Cquat. arom.), 128.6 (CHarom.), 128.3 (CHarom.), 126.4 (CHarom.), 126.0 (CHarom.), 117.7 (C9B), 102.4 (C7A or C7B), 101.2 (C7A or C7B), 98.7 (C1B), 97.6 (C1A), 80.6 (C4A), 77.2 (C4B), 72.8 (C3B), 72.6 (C2A), 70.21 (C2B or C3A), 70.19 (C2B or C3A), 69.0 (C6A), 68.6 (C6B), 62.8 (C5A), 62.6 (C5B), 55.4 (OMe), 38.8 ((CH3)3C), 32.2 (C8B), 27.1 ((CH3)3C), 21.2 (CH3C=O); FT-IR (film) 2974, 2934, 2870, 1737, 1456, 1372, 1235, 1127, 1097, 1047, 1028, 752, 699; HRMS (ESI): m/z Calcd for C36H47BrNO14 [M + NH4]+ 796.2180, found 796.2172; [α]D20 = +32 (c = 1.0, CHCl3); m.p. = +102-103 °C. Rearrangement of orthoester (19) into disaccharide (14). A solution of 19 (70 mg, 0.090 mmol) in distilled dichloromethane (1.5 mL) was stirred for 1 hour over activated 4 Å molecular

sieves

(100

mg).

After

cooling

to

0 °C,

trimethylsilyl

trifluoromethanesulfonate (3 µL, 0.018 mmol) was added dropwise to give a bright yellow solution which was stirred 30 minutes. The reaction mixture was then quenched with triethylamine (0.1 mL), filtered through a Celite pad, and concentrated under vacuum. The residue was purified by silica gel chromatography (cyclohexane / ethyl acetate 80:20) to give 14 as a white solid (52.6 mg, 75%) with analytical data identical to those obtained by direct coupling of 2 and 13 under NIS/TfOH conditions.

Associated Content The supporting Information is available free of charge on the ACS publications website. They include data related to the attempted rearrangement of orthoester 4 into disaccharide 3, copy of the NMR spectra (1H and

13C)

of 7, 8, 9, 10, 11, 12, 14, 15, 17,

19, and computational details for orthoesters 4, 9, 20.

Author Informations



1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20 21 22 23 24 25 26 27 28 29 30 31 32 33 34 35 36 37 38 39 40 41 42 43 44 45 46 47 48 49 50 51 52 53 54 55 56 57 58 59 60

Corresponding Author: *E-mail: [email protected] The authors declare no competing financial interest.

Acknowledgments The authors would like to thank LABEX SynOrg (ANR-11-LABX-0029) and ANR (JCJC2013-QuatGlcNAc) for their financial support. We used the computing facility of the CRIHAN, project 2006-013.

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Protonation profile of the analogous manno orthoester was also investigated. Computations revealed that OA, O1 and O2 oxygen atoms had very close negative charges (see the SI). A complex Curtin-Hammet kinetic profile involving proton shifts might thus also be anticipated in the manno series.

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Substitution of the Participating Group of Glycosyl Donors by a

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