Total Synthesis of the Proposed Structure of Ardimerin, and Proposal for its Structural Revision

Abstract

We report the first total synthesis of the proposed structure of ardimerin, which was achieved in 14 steps starting from 2,3,4‐trimethoxybenzoic acid. The key steps include the β‐selective formation of the crucial C‐glycoside linkage and stepwise construction of the strained eight‐membered salicylide core. The synthesis revealed that the proposed structure 1 does not match the natural product. A proposal is made for reassigning the isolated natural product to the already known structure of bergenin. Interesting properties of the synthetic eight‐membered salicylides are documented, including their susceptibility toward nucleophilic ring opening and the bowl chirality.

Fluorine‐Directed Glycosylation Enables the Stereocontrolled Synthesis of Selective SGLT2 Inhibitors for Type II Diabetes

“…For completeness, the 2‐OBn lactone 17 c was processed to 22 c , delivering the α‐product; this observation is in good agreement with previous studies from Suzuki and co‐workers . The stereochemistry at C1 was established by detailed nOe analysis (full details are provided in the Supporting Information).…”

“…Independent reduction of the lactols with triethylsilane and BF 3 ⋅Et 2 O furnished compounds 23 a – c in good to high yields. Notably, for the fluorinated system 23 a the stereochemical integrity of the anomeric center was retained delivering exclusively the β‐anomer (the α:β ratio was assigned due to the higher priority of carbon over hydrogen, with the same anti ‐relationship to F as stated above), whilst for the 2‐deoxy 23 b the α:β ratio was improved (α:β 1:25) and for the 2‐OBn 23 c a loss in selectivity was observed (α:β 1:4) . For the remainder of the synthetic sequence, only the β‐anomer was utilized, with final benzyl‐deprotection affording the Dapagliflozin surrogates 5 , 9 , and 11 .…”

“…[29] The stereochemistry at C1 was established by detailed nOe analysis (full details are provided in the Supporting Information).I ndependent reduction of the lactols with triethylsilane and BF 3 ·Et 2 Of urnished compounds 23 a-c in good to high yields. [29] The stereochemistry at C1 was established by detailed nOe analysis (full details are provided in the Supporting Information).I ndependent reduction of the lactols with triethylsilane and BF 3 ·Et 2 Of urnished compounds 23 a-c in good to high yields.…”

“…For completeness, the 2-OBn lactone 17 c was processed to 22 c,d elivering the a-product;t his observation is in good agreement with previous studies from Suzukia nd co-workers. [29] The stereochemistry at C1 was established by detailed nOe analysis (full details are provided in the Supporting Information).I ndependent reduction of the lactols with triethylsilane and BF 3 ·Et 2 Of urnished compounds 23 a-c in good to high yields. Notably, for the fluorinated system 23 a the stereochemicali ntegrity of the anomeric center was retained delivering exclusively the b-anomer (the a:b ratio was assigned due to the higherp riority of carbon over hydrogen, with the same anti-relationship to Fa ss tated above), whilst for the 2-deoxy 23 b the a:b ratio was improved (a:b 1:25) and for the 2-OBn 23 c al oss in selectivity was observed (a:b 1:4).…”

“…Notably, for the fluorinated system 23 a the stereochemicali ntegrity of the anomeric center was retained delivering exclusively the b-anomer (the a:b ratio was assigned due to the higherp riority of carbon over hydrogen, with the same anti-relationship to Fa ss tated above), whilst for the 2-deoxy 23 b the a:b ratio was improved (a:b 1:25) and for the 2-OBn 23 c al oss in selectivity was observed (a:b 1:4). [29] For the remainder of the synthetic sequence, only the b-anomer was utilized, with final benzyl-deprotection affording the Dapagliflozin surrogates 5, 9,and 11. In vitro analysis:T he ability of the target compounds to selectively inhibit human and mouse SGLT1 and SGLT2 was explored (Table 1).…”