Supplementary Figure 1. Traditional synthesis of carbohydrates. I. Regioselective protection

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1 I. Regioselective protection of hydroxyls in monosaccharides 6 H 4 5 H 1 H H 3 2 H anomeric protection H H A B C D hexoses fully protected 2- or 3- or 4- monosaccharides or 6-alcohols II. Stereoselective assembly of oligosaccharides and glycoconjugates (i). From nonreducing end to reducing end H H P multisteps P 3 P 2 P 4 P 1 building blocks P or H P 3 P 2 P 1 P C transformation of anomeric P into leaving group (LG) transformation of anomeric P into leaving group (LG) (Protocol Repeating) P 3 P 2 promoter, D (ii). From reducing end to nonreducing end P 4 P 3 P 2 P 1 E LG P 4 P 1 promoter, D P 3 G P 2 P 1 P 3 P 2 P 3 P 2 P 1 P 4 P 1 P P 3 P P 2 P 1 F E conjugate, promoter P 3 P 2 P 4 Conj P 1 H 1. selective removal of one protecting group 2. promoter, E P 3 P 2 P 4 P 1 P 3 Conj P 2 P 1 I 1. selective removal of one protecting group 2. promoter, E (Protocol Repeating) P 3 P 2 P 4 P 1 P 3 P 3 Conj P 2 P 1 P 2 P 1 J Supplementary Figure 1. Traditional synthesis of carbohydrates. I. Regioselective protection of sugar polyols, a prerequisite to the glycosylation step, is the first problem in carbohydrate synthesis. The anomeric hydroxy group of a hexose A can be protected to provide the pyranosyl tetraol B. However, conversion of tetraol B into either the fully protected monosaccharide C or 1

2 the individual alcohols D with a free hydroxyl at C2, C3, C4, or C6 as building blocks often require an independent and multi-step route to prepare each compound that involves tedious workup at each synthetic step, time-consuming purification of different regioisomers, and poor differentiation of hydroxyls. The carbon atoms of hexopyranosides A are numbered (1-6); C1 is the anomeric carbon. P, P 1, P 2, P 3, and P 4 are non-specialized protecting groups of hydroxyls. II. A target oligosaccharide can be stereoselectively synthesized starting from either the nonreducing end (i) or the reducing end (ii) of the monosaccharide unit. The former strategy requires selective transformation of the anomeric protecting group in compound C into a labile leaving group (E) followed by coupling with the glycosyl acceptor D in the presence of a promoter to give the disaccharide F. Repetition of this protocol leads to the trisaccharide G and higher oligosaccharides. The latter methodology involves the introduction of a conjugate group at the anomeric center of compound E to yield the reducing end saccharide H. ne of the protecting groups (P 1 -P 4 ) in H should be then selectively removed and subsequently the freed H is coupled with the glycosyl donor E to get the disaccharide I. Reiteration of this deprotection-glycosylation sequence furnishes the trisaccharide J and higher oligomers. 2

3 I. Combinatorial, regioselective, orthogonal, and one-pot protection of hydroxyls H H H H K = α- or β-r, α- or β-sr, α- or β-ser combinatorial, regioselective, orthogonal, and one-pot protection P 4 P 3 P 2 P 1 L fully protected monosaccharides or P 3 H P 2 P 1 M 2- or 3- or 4- or 6-alcohols II. ne-pot coupling to the synthesis of oligosaccharides and glycoconjugates L promoter, M n P 3 P 2 P 4 P 1 P 3 P 2 P 1 N n Supplementary Figure 2. Straightforward synthesis of carbohydrates. I. A diverse set of the fully protected monosaccharide L and the individual alcohols M with a free hydroxy group at the C2, C3, C4, or C6 position can be prepared from a common tetraol K via a combinatorial, regioselective, and orthogonal protection strategy in a one-pot manner. II. Rapid assembly of monosaccharide building blocks L with M employing one-pot glycosylation may yield a panoply of oligosaccharides with diversified linkages and various sugar units N. P, P 1, P 2, P 3, and P 4 are non-specialized protecting groups of hydroxyls. 3

4 1 R R 2 R R = R 1 = R 2 = H R = Ph, R 1 = R 2 = H R = CN, R 1 = R 2 = H R = N 3, R 1 = R 2 = H R = NHPiv, R 1 = R 2 = H R = Me, R 1 = R 2 = H R = Ac, R 1 = R 2 = H R =, R 1 = R 2 = H R = R 2 = H, R 1 = N 2 R = R 1 = Me, R 2 = H R = N 3, R 1 = H, R 2 = Cl R, R 2 =, R 1 = H (Pd/C, H 2 or Na, NH 3 ) (FeCl 3 ) (electrolytic reduction) (PPh 3, H 2 ; DDQ) (DDQ) (DDQ or TFA) (NaMe) (PdL n, 2 o amine; acid) (photolysis) (CeCl 3 /7H 2, NaI) (TFA) (DDQ) Supplementary Figure 3. Cleavage of substituted and unsubstituted benzyl ethers under various conditions. Benzyl-type protecting groups are appropriate for regioselective one-pot protection strategy. Most of the substituted benzyl ethers can be selectively deprotected using unique reagent combination and the reaction conditions can be tuned further. For example, paramethoxybenzyl (PMB) group can be cleaved by DDQ, CAN, or TFA whereas, 2-naphthylmethyl group (2-NAP), which is more stable than PMB in acidic condition is susceptible to only DDQ, thus be differentiated by CAN or TFA. Likewise, halogen-substituted benzyl ethers can be converted to acid-labile amino-benzyl ethers by a Pd-catalyzed reaction in the following order of reactivity I > Br > Cl > F. Reagents: Pd/C, palladium on charcoal; FeCl 3, ferric chloride; CN, cyano; N 3, azido; PPh 3, triphenylphosphine; DDQ, 2,3-dichlro-5,6-dicyano-1,4-benzoquinone; CAN, cerium ammonium nitrite, Piv, pivaloyl; TFA, trifluoroacetic acid; NaMe, sodium methoxide; PdL n, palladium complex; N 2, nitro; CeCl 3 /7H 2, cerium trichloride heptahydrate. 4

5 H H H H : = α-me P: = β-stol TMSCl, Et 3 N CH 2 Cl 2 TMS TMS TMS TMS 1a: = α-me, 95% 1b: = β-stol, 97% Supplementary Figure 4. Preparation of the 2,3,4,6-tetra--trimethylsilyl ethers 1a and 1b. Treatment of compounds and P with TMSCl and Et 3 N in CH 2 Cl 2 led to the corresponding 2,3,4,6-tetra--trimethylsilyl ethers 1a and 1b in 95% and 97% yields, respectively. Reagents: TMSCl, chlorotrimethylsilane; Et 3 N, triethylamine; STol, thiotoluenyl; CH 2 Cl 2, dichloromethane. 5

6 I. 2-Azido-2-deoxy-D-glucoside TMS TMS TMS 1. cat. TMSTf, PhCH, 3A MS, CH 2 Cl 2, 0 o C 2. Ac 2, -20 o C Bn Ac STol 3. BH N 3 /THF, -20 to 0 o C 3 N 3 Q 71% R H STol II. D-Mannoside TMS TMS TMS S TMS STol 1. cat. TMSTf, PhCH, 3A MS, CH 3 CN, 0 o C 2. DIBAL-H, CH 2 Cl 2, -40 to 0 o C 70% Ph Bn T H STol III. D-Galactoside TMS TMS TMS TMS -i-pr U 1. cat. TMSTf, PhCH, 3A MS, CH 2 Cl 2, -78 o C 2. p-mephch, Et 3 SiH, -78 o C 53% PMB Ph H -i-pr V Supplementary Figure 5. A representative example for the one-pot protection of each 2- azido-2-deoxy-d-glucoside, D-mannoside, and D-galactoside. I. TMSTf-catalyzed one-pot transformation of 2-azido2-deoxy-D-thioglucoside Q into the 6-alcohol R via 4,6- benzylidenation, 3-acetylation, and regioselective 6-ring opening of benzylidene acetal using BH 3 THF complex in good overall yield. II. TMSTf-catalyzed regioselective 4,6- benzylidenation of the tetra--tms α-d-thiomannoside S with stoichiometric PhCH furnished the corresponding 2,3-diol as a sole isomer. Reaction of S with two equivalents of PhCH in the presence of TMSTf as a catalyst led to a single 2,3:4,6-di--benzylidenated exo-isomer, which could be regioselectively opened at 2 using DIBAL-H to give the 2-alcohol T in 70% yield. Use of acetonitrile in the first step and dichloromethane in the subsequent step is essential for achieving the high selectivity in this one-pot transformation. III. The tetra--silylated α-d- 6

7 galactoside U could be similarly converted into the 2-alcohol V (53%) via TMSTf-catalyzed one-pot 4,6-benzylidenation with PhCH followed by Et 3 SiH-reductive etherification with p- MePhCH. None of the 3-alcohol was detected, but two side products, the corresponding 2,3- diol and 2,3-di-PMB, were isolated in small amounts, respectively. Reagents: TMS, trimethylsilyl; STol, thiotoluenyl; TMSTf, trimethylsilyl trifluoromethanesulfonate; PhCH, benzaldehyde; MS, molecular sieves; CH 2 Cl 2, dichloromethane; Ac 2, acetic anhydride; BH 3, borane; THF, tetrahydrofuran; CH 3 CN, acetonitrile; DIBAL-H, diisobutylaluminum hydride; p- MePhCH, p-methoxybenzaldehyde; Et 3 SiH, triethylsilane; PMB: p-methoxybenzyl, i-pr, i- propyl. 7

8 p-tolscl 6b2 6a2, p-tolscl 3b2 AgTf n+2 equiv 15 min 1.5 h 1.5 h 1.5 h -80 o C -80 o C -60 o C -40 o C n -80 o C 3 h -30 o C W,, Y or Z Ph Bn 3b2 Bz STol H Bn Bn Bz 6b2: = β-stol 6a2: = α-me Ph Bn Bz Bn Bn Bz W: n = 0, 91%; : n = 1, 72% Y: n = 2, 67%; Z: n = 3, 41% Bn n Bn Bz Me Supplementary Figure 6. Synthesis of β-1,6-glucans via iterative one-pot glycosylation. The preparation of β-1,6-glucans with two, three, four, and five sugar units was carried out employing monosaccharides 3b2, 6b2, and 6a2 as the starting, elongation, and termination units, respectively. The progress of reaction is indicated from left to right with the reaction conditions including the coupling time alongside the arrow. The coupling partners are placed in the figure with the same order of addition in the iterative reaction. Coupling of 3b2 with 6a2 could be activated by p-tolstf (generated from AgTf and p-tolscl in situ), and the β-linked disaccharide W was obtained in 91% yield. In another experiment, the thioglycoside 3b2 was promoted first, the acceptor 6b2 was introduced in the coupling stage (n = 1), and the formed disaccharide was activated again to couple with 6a2 to afford the β-trisaccharide (72%). Similarly, the assembly of the elongation unit 6b2 was repeated twice (n = 2) and thrice (n = 3), and the β-tetrasaccharide Y (67%) and β-pentasaccharide Z (41%) were rapidly synthesized in a one-pot manner, respectively. Reagents: AgTf, silver trifluoromethanesulfonate; p-tolscl, p- toluenylsulfenyl chloride; p-tolstf, p-toluenylsulfenyl trifluoromethanesulfonate. 8