Efficient O- and S-glycosylation with ortho-2,2-dimethoxycarbonylcyclopropylbenzyl thioglycoside donors by catalytic strain-release

Ding, Han; Lv, Jian; Zhang, Xiao-Lin; Xu, Yuan; Zhang, Yu-Han; Liu, Xue-Wei

doi:10.1039/d3sc06619c

“…To effectively advance toward our objective of synthesizing pseudo-steroidal glycosides and other C -3 steroid derivatives, several key issues should be keenly addressed: (1) overcoming the conventional shared challenge of i -steroid rearrangement in a steroid donor despite the various types of O -centered acceptors; (2) ensuring the versatility of steroidation with diverse donors and acceptors to achieve diversity-oriented steroid chemical modification; (3) realizing the target-oriented synthesis of pseudo-steroidal glycosides for further biological investigations. With these in mind, we herein disclose our development of a strain-triggered steroidation with steroid-3-yl ortho -2,2-dimethoxycarbonylcyclopropylbenzoate (CCBz) donors employing a low-cost and readily accessible Sc(III) catalyst under mild conditions . Compared to all previous works, our protocol enjoys a substantially broader substrate scope of O -, C -, N -, S -, and P -nucleophiles and cholest-5-en-3-yl, diosgen-3-yl, and pregnant-5-en-3-yl CCBz donors, producing desired steroid derivatives or pseudo-steroidal glycosides in good to excellent yields.…”

Section: Introductionmentioning

confidence: 99%

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides

Ding,

Zhang,

Guo

et al. 2024

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The development of novel agents with immunoregulatory effects is a keen way to combat the growing threat of inflammatory storms to global health. To synthesize pseudosteroidal glycosides tethered by ether bonds with promising immunomodulatory potential, we develop herein a highly effective deoxygenative functionalization of a novel steroidal donor (steroidation) facilitated by strain-release, leveraging cost-effective and readily available Sc(OTf) 3 catalysis. This transformation produces a transient steroid-3-yl carbocation which readily reacts with O-, C-, N-, S-, and P-nucleophiles to generate structurally diverse steroid derivatives. DFT calculations were performed to shed light on the mechanistic details of the regioselectivity, underlying an acceptor-dependent steroidation mode. This approach can be readily extended to the etherification of sugar alcohols to enable the achievement of a diversity-oriented, pipeline-like synthesis of pseudo-steroidal glycosides in good to excellent yields with complete stereo-and regiospecific control for anti-inflammatory agent discovery. Immunological studies have demonstrated that a meticulously designed cholesteryl disaccharide can significantly suppress interleukin-6 secretion in macrophages, exhibiting up to 99% inhibition rates compared to the negative control. These findings affirm the potential of pseudo-steroidal glycosides as a prospective category of lead agents for the development of novel anti-inflammatory drugs.

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“…As a paradigm shift, we reasoned that a lesser explored C-glycosylation approach that taps upon thermodynamically desired ring expansion [24] from strained cyclopropanated glycosyl donors [25] could offer a broad strategy to access chiral and diverse α,α'-C-disubstituted oxepanes from naturally available saccharides (Figure 1C, right). The develop- ment of this underexploited strain-release glycosylation approach is lately also gaining substantial traction through works by Liu [26] and us. [7a,12,27] In spite of the fore-mentioned promising route, literature precedents of C-glycosylations to access septanosides this way were plagued with stereoselectivity challenges.…”

Section: Introductionmentioning

confidence: 99%

Stereoselective Entry into α,α’‐C‐Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain‐Release C‐Septanosylation Strategy

Ma,

Schmidt,

Strohmann

et al. 2024

Angewandte Chemie

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The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7‐membered ring α,α’‐C‐disubstituted oxepane core through an α‐selective strain‐release C‐glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring‐expansion approach. In light of the general lack of stereoselective methods to access C‐septanosides, a remarkable palette of silyl‐based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl‐allyl, silyl‐enol ether, silyl‐ketene acetal, vinylogous silyl‐ketene acetal, silyl‐alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

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Stereoselective Entry into α,α’‐C‐Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain‐Release C‐Septanosylation Strategy

Ma,

Schmidt,

Strohmann

et al. 2024

Angew Chem Int Ed

1

0

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The utility of unconventional noncovalent interactions (NCIs) such as chalcogen bonding has lately emerged as a robust platform to access synthetically difficult glycosides stereoselectively. Herein, we disclose the versatility of a phosphonochalcogenide (PCH) catalyst to facilitate access into the challenging, but biologically interesting 7‐membered ring α,α’‐C‐disubstituted oxepane core through an α‐selective strain‐release C‐glycosylation. Methodically, this strategy represents a switch from more common but entropically less desired macrocyclizations to a thermodynamically favored ring‐expansion approach. In light of the general lack of stereoselective methods to access C‐septanosides, a remarkable palette of silyl‐based nucleophiles can be reliably employed in our method. This include a broad variety of useful synthons, such as easily available silyl‐allyl, silyl‐enol ether, silyl‐ketene acetal, vinylogous silyl‐ketene acetal, silyl‐alkyne and silylazide reagents. Mechanistic investigations suggest that a mechanistic shift towards an intramolecular aglycone transposition involving a pentacoordinate silicon intermediate is likely responsible in steering the stereoselectivity.

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Efficient O- and S-glycosylation with ortho-2,2-dimethoxycarbonylcyclopropylbenzyl thioglycoside donors by catalytic strain-release

Abstract: An efficient glycosylation reaction utilizing a meticulously designed thioglycoside has been developed. The well-established protocol was demonstrated in the total synthesis of TD139 and a one-pot assembly of E. coli O33 antigen tetrasaccharide.

Cited by 4 publications

References 57 publications

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides

A Strain-Promoted Divergent Chemical Steroidation Unveils Potent Anti-Inflammatory Pseudo-Steroidal Glycosides

Stereoselective Entry into α,α’‐C‐Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain‐Release C‐Septanosylation Strategy

Stereoselective Entry into α,α’‐C‐Oxepane Scaffolds through a Chalcogen Bonding Catalyzed Strain‐Release C‐Septanosylation Strategy

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