Abstract Reduction of the acetoxymethylene ketone 1b yielded a mixture of two epimeric diols 3a and 4a , which were converted into the p ‐toluenesulfonates 3d and 4d . Solvolysis of 3d in dry acetic acid afforded 5b after inversion at C‐17. As an explanation for the formation of 5b , it was assumed that the cyclic cation 8 may be an intermediate. This was confirmed by methanolysis of 3d leading to the orthoester 10 . The neighbouring group participation (AcO‐6) observed during solvolysis of 3d was completely absent in the case of 4d , solvolysis of which yielded 17β‐acetoxy‐16α‐acetoxymethyl‐3‐methoxyestra‐1,3,5(10)‐triene ( 4b ) with retention in both acetic acid and methanol.

Stereoselective glycosylations are one of the most challenging tasks of synthetic glycochemists. The protecting building blocks on the glycosides contribute significantly in attaining the required stereochemistry of the resulting glycosides. Strategic installation of suitable protecting groups in the C-2 position, vicinal to the anomeric carbon, renders neighbouring group participation, whereas protecting groups in the distal C-3, C-4, and C-6 positions are often claimed to exhibit remote group participation with the anomeric carbon. Neighbouring group participation and remote group participation are being widely studied to help the glycochemists design the synthetic protocols for multistep synthesis of complex oligosaccharides and in turn, standardise the process of the glycosylation towards a particular stereochemical output. While neighbouring group participation has been quite effective in achieving the required stereochemistry of the produced glycosides, remote participation exhibits comparatively less efficacy in achieving complete stereoselectivity in the glycosylation reactions. Remote participation is a still highly debated topic in the scientific community. However, implementing the participating role of the remote groups in glycosylation reactions is widely practised to achieve better stereocontrol and to facilitate the formation of synthetically challenging glycosidic linkages.

Abstract The sodium tetrahydroborate reduction of 16‐<[acetyl(alkyl)‐amino]methylene>‐17‐ketosteroids 1aa , 2aa and 2ba affords (Z)‐16‐ and ( E )‐16‐<[acetyl(alkyl)amino]methylene>‐17β‐hydroxysteroids (Z)‐ 3 , ( E )‐ 3 , (Z)‐ 4b , (Z)‐ 4a , (Z)‐ 5c and ( E )‐ 5a . The N ‐acetyl group of the (Z) isomers (Z)‐ 3 , (Z)‐ 4b , and (Z)‐ 5c migrates to the 17β‐hydroxyl in inert solvents, and the products suffer secondary transformation into unsaturated aldehydes 6 and 9a ; intermediate 8 has been isolated. The ( E ) isomers ( E )‐ 3 , and ( E )‐ 5a do not change, even not under more drastic conditions.

Mechanism of the reaction of papain with substrate-derived diazomethyl ketones. Implications for the difference in site specificity of halomethyl ketones for serine proteinases and cysteine proteinases and for stereoelectronic requirements in the papain catalytic mechanism. The reactions of papain (EC 3.4.22.2) with substrate-derived diazomethyl ketones reported by Leary, Larsen, Watanabe & Shaw [Biochemistry (1977) 16, 5857--5861] are unusual in that (i) these reagents fail to react with low-molecular-weight thiols and (ii) the rate of reaction with the papain thiol group does not decrease to near-zero values across a pKa of 4 as the pH is decreased. Existing data are shown to suggest an interpretation involving neighbouring-group participation via transient thiohemiketal formation, rate-determining protonation by imidazolium ion and alkylation on sulphur via a three-membered cyclic transition state. Implications for (a) the difference in site-specificity exhibited by halomethyl ketones in their reactions with serine proteinases and cysteine proteinases and (b) stereoelectronic requirements in the mechanism of papain-catalysed hydrolysis are discussed.

The diverse presence as well as their very specific bio-responses of glycoconjugates found in all living species requires scientists to synthesize the precise structure of these complex oligosaccharides for various studies on glycoscience. Very few approaches were able to offer the sole α- or β-glycosylated products, even at the cost of complicating the preparative route or usage of exotic chiral auxiliaries to drive the stereoselectivity. In this report, the unification of solvent assistance and neighbouring group participation concepts have led us to the use of 2-cyanobenzyl ether as the dual-directing auxiliary for stereospecific construction of α- and β-glycosidic bonds from a single starting material, and both isomers can be obtained in exclusive stereoselectivity. This work demonstrates the difference in reactivities of glycosyl acceptors can be employed to completely drive the stereoselectivity, drawing the parallel comparison with the arming/disarming concept, which has been exclusively confined to glycosyl donors. In this report, the unification of solvent assistance and neighbouring group participation concepts have led us to the use of 2-cyanobenzyl ether as the dual-directing auxiliary for stereospecific construction of a- and b-glycosidic bonds from a single starting material, and both isomers can be obtained in exclusive stereoselectivity. This work demonstrates the difference in reactivities of glycosyl acceptors can be employed to completely drive the stereoselectivity, drawing the parallel comparison with the arming/disarming concept, which has been exclusively confined to glycosyl donors. On the other hand, neighbouring hydroxyl groups of the donor could show influence on the anomeric preference through their protecting substituents, many of which were routinely exploited in various glycosylation methods, such as 2 -O-ester-type8–10 or 2-O-picolyl-type11–13 for 1,2- trans glycosylation, and several sulfide auxiliaries 14–18 as well as intramolecular aglycon delivery IAD-type19,20 for 1,2- cis glycosylation reactions. We envisage that a combination of these two directions could deliver an attractive solution to construct most types of glycosidic bonds, with the potential to overcome current drawbacks. Herein, we demonstrate a highly stereoselective glycosylation method through 2-cyanobenzyl ether functionalization at C-2 position of various glycosyl donors. The results come with a surprising twist: from a single glycosyl donor, either a-o r b-glycosylated products can be predicted and obtained through modification of the glycosyl acceptors. Compatibility with a wide collection of protective choice, leaving groups and versatile activations under acidic or basic conditions highlight the potential of 2-cyanobenzyl ether as the universal auxiliary for glycosylation reactions. Results Design and optimize From these optimized conditions, we made a tentative suggestion that pure b-anomers would typically be obtained, whereas sole a-anomers were produced with glycosyl acceptors with electron-withdrawing functional groups. Subsequently, evaluation on the versatility of this reaction was carried out by studying a diversified substrate scope. As seen from Table 2, reaction of various common alcohols, including n-butanol 2b, benzyl alcohol 2c, 1-adamantanol 2d proceeded smoothly to give glycosylated products with b-only stereo- selectivity. More bulky and complex alcohols, such as citronellol 2e, fenchol 2f and cholesterol 2g all gave desired products in good yields. With the exception of 2,2,2-trifluoroethyl- a-D-gluco- pyranoside 3h giving a-product so far, we proceeded to prepare acceptors for disaccharide surveys. For each hydroxyl group position, pair of acceptors having electron-donating or electron- withdrawing protective groups were synthesized. To our delight, the results substantiated our earlier prediction of the correlation between stereoselectivity and acceptor structure ( 2i, 2j, 2k for 2-OH; 2l, 2m, 2n for 3-OH; 2o, 2p for 6-OH). However, with acceptors 2s and 2t for 4-OH position, reactions were extremely sluggish under optimized conditions. However, because the acidic environment was found detrimental to the acid-labile 3,4-O-isopropylidene group on galactoside 6b, its precursor 6a was directly activated instead under an identical condition to 1b to give b-7a and a-7b. Discussions A plausible mechanism to explain dual-directing outcome in stereoselectivity is depicted in Fig. 2. Activation of 1b forms oxocarbenium ion II, which exists in equilibrium with nitrilium ion Ia, resulting from the solvent-like coordination of the nitrile moiety to the anomeric carbocation. & Sharma, I. Influence of the O3 protecting group on stereoselectivity in the preparation of C-mannopyranosides with 4,6-O-benzylidene protected donors. J. Org. Chem. 75, 8383–8391 (2010). 10. Kim, K. S. & Suk, D.-H. Remote participation of protecting groups at remote positions of donors in glycosylations. Trends Glycosci. Glycotechnol. 23, 53–65 (2011). 11. Smoot, J. T. & Demchenko, A. V. How the arming participating moieties can broaden the scope of chemoselective oligosaccharide synthesis by allowing the inverse armed-disarmed approach. J. Org. Chem. 73, 8838–8850 (2008). 12. Yasomanee, J. P. & Demchenko, A. V. Neighbouring group participation vs. addition to oxacarbenium ions: studies on the synthesis of mycobacterial oligosaccharides. Org. Biomol. Chem. 7, 4842–4852 (2009). 17. Fascione, M. A. et al. Stereoselective glycosylation using oxathiane glycosyl donors. Chem. Commun. 5841–5843 (2009). 18. Coxa, D. J. & Fairbanks, A. J. Stereoselective synthesis of a-glucosides by neighbouring group participation via an intermediate thiophenium ion. Tetrahedron Asymmetry 20, 773–780 (2009). 19. Ishiwata, A., Lee, Y. J. & Ito, Y. Recent advances in stereoselective glycosylation through intramolecular aglycon delivery. Org. Biomol. Chem. 8, 3596–3608 (2010). 20. Cumpstey, I. Intramolecular aglycon delivery.

For the stereoselective assembly of bioactive glycans with various functions, 1,2-cis-O-glycosylation is one of the most essential issues in synthetic carbohydrate chemistry. The cis-configured O-glycosidic linkages to the substituents at two positions of the non-reducing side residue of the glycosides such as α-glucopyranoside, α-galactopyranoside, β-mannopyranoside, β-arabinofuranoside, and other rather rare glycosides are found in natural glycans, including glycoconjugate (glycoproteins, glycolipids, proteoglycans, and microbial polysaccharides) and glycoside natural products. The way to 1,2-trans isomers is well sophisticated by using the effect of neighboring group participation from the most effective and kinetically favored C-2 substituent such as an acyl group, although high stereoselective synthesis of 1,2-cis glycosides without formation of 1,2-trans isomers is far less straightforward. Although the key factors that control the stereoselectivity of glycosylation are largely understood since chemical glycosylation was considered to be one of the useful methods to obtain glycosidic linkages as the alternative way of isolation from natural sources, strictly controlled formation of these 1,2-cis glycosides is generally difficult. This minireview introduces some of the recent advances in the development of 1,2-cis selective glycosylations, including the quite recent developments in glycosyl donor modification, reaction conditions, and methods for activation of intermolecular glycosylation, including the bimodal glycosylation strategy for 1,2-cis and 1,2-trans glycosides, as well as intramolecular glycosylations, including recent applications of NAP-ether-mediated intramolecular aglycon delivery. The way to 1,2- trans isomers is well sophisticated due to the effect of neighboring group participation from the most effective and kinetically favored C-2 substituent such as an acyl group, although high stereoselective synthesis of 1,2- cis glycosides without formation of the 1,2- trans isomer is far less straightforward. Recent advances on 1,2- cis glycosylations by intermolecular coupling Recent development based on glycosyl donor modifications and reaction conditions for 1,2- cis glycosylation For controlling the stereoselectivity of glycosylation, the protective groups on the donor moiety are well studied as one of the main factors (recent review, Csávás et al., 2021 ), including chiral auxiliary at 2-position (recent review, Mensink and Boltje, 2017 ). The cyclic protective groups on diols for the conformationally constrained donors ( Jeanneret et al., 2020 ) could also be used for various glycosyl donors as one of the key stereocontrolling factors for glycosylation. As an alternative use of the cyclic protective group on the furanoside ring, the 1,4- O -TIPDS-protected xylurofuranosyl donor has been developed for specific glycosylation to obtain 1,2- cis glycosides with various acceptors ( Figure 2A1 ) ( Huang and Lowary, 2020a ; Huang and Lowary, 2020b ) as in the case of a similarly constrained fructofuranosyl donor whose protective group is blocking one side of the approach of the acceptor ( Oscarson and Sehgelmeble, 2000 ). FIGURE 2 Recent advances in 1,2-cis glycosylations: some examples. (A) Recent examples of intermolecular approaches: Glycosyl donor modifications and reaction conditions. a-1) Recent example of donor modification approachs; a-2) Picolinyl and picoloyl groups and remote group participation; a-3) C2-o-TsNHbenzyl ether (TAB) [Bimodal] and inorganic salts (ZnI 2 , SnCl 4 ) catalyst (not shown); a-4) Formamide as additives. (B) Recent examples of intermolecular approaches: Method for activation. b-1) Thiourea catalyst with phosphate donor; b-2) Pyrilium salt catalyst with trichloroacetimidate; b-3) Phenanthroline catalysts from glycosyl halide; b-4) halogen-bond-assisted radical activation of allyl glycosyl sulphones via glycosyl halide: b-5) From hemiacetal via glycosyl halide; b-6) Through 1,2-anhydro sugar. The direct intramolecular neighboring and remote group participation of these groups to glycosyl cation led to the trans -glycosylation of the substituents as well ( Yasomanee and Demchenko, 2012 ; McMillan and Crich, 2022 ). On the other hand in the case of manno-type glycosylation, further screening of the catalyst (recent review, Nielsen and Pedersen, 2018 ) and the leaving group and thermodynamic conditions ( Adamo and Kovác, 2007 ; Hou and Kovác, 2010 ) revealed that glycosyl diphenylphosphite ( Kondo et al., 1994 ) was the best among all tested and catalytic amounts of Cu(OTf) 2 ( Mukaiyama et al., 1979 ; Sato et al., 1986 ) at 80°C or two equivalents of ZnI 2 at −10°C afforded 1,2- trans α- or 1,2- cis β-selective glycosylations, respectively. On the other hand, the recent examples for remote group participation ( Hansen et al., 2020 ; Hettikankanamalage et al., 2020 ; Upadhyaya et al., 2021 ) introduced the 1,2- cis glycosylations selectively and practically from 6- [2,2-dimethyl-2-( ortho -nitrophenyl)acetyl: Liu et al., 2019 ; benzoyl: Shadrick et al., 2020 ; -C(=NPh)CF 3 : Liu et al., 2022a ], 4- (levulinoyl: Zhang et al., 2021 ), and 3- [2-(diphenylphosphinoyl) acetyl: Liu et al., 2022a ; Liu et al., 2022b ] positions. Improvements for IAD have also been achieved by tethering to hydroxy groups on both residues through the silaketal ( Stork and Kim, 1992 ) from sugar silanes ( Figure 2C2 ) ( Walk et al., 2015 ; Sati et al., 2020 ). In the case of the IAD, the 2- O -mixed acetal linkage and the axial O -mixed acetal substituent as the precursor for intramolecular transfer seem to be kinetically and stereoelectronically favored as in the case of neighboring group participation of acyl groups. p -Methoxybenzyl (PMB) ether-mediated IAD was well known as the most practical method to be applied for the synthesis of β-mannoside in N -glycan ( Ito and Ogawa, 1994 ).