Copper(I)-Catalyzed Stereodivergent Propargylation of N-Acetyl Mannosamine for Protecting Group Minimal Synthesis of C3-Substituted Sialic Acids

Abstract

Copper­(I)-catalyzed stereodivergent nucleophilic propargylation at the anomeric carbon of unprotected N-acetyl mannosamine was developed using 3-substituted allenylboronates as a nucleophile. The homopropargylic alcohol products contained two contiguous stereocenters, and two stereoisomers out of the four possible isomers were selectively obtained in a catalyst-controlled manner by applying either basic conditions: a MesCu/(R,R,R)-Ph-SKP catalyst with a B­(OiPr)3 additive or acidic conditions: a CuBF4/(S,S,S)-Ph-SKP catalyst with an MeB­(OiPr)2 additive. Mechanistic studies suggested the presence of distinct active nucleophilic species depending on the conditions: an allenylcopper species under the basic conditions or an allenylboronate activated by the Lewis acidic copper catalyst under the acidic conditions. The propargylation products were concisely transformed into C3-substituted sialic acids in two steps without the use of protecting groups.

Synthesis and Reactivity of Allenylboron Compounds

“…[40] Here, the participating aldehydes were found to be unreactive under catalyst-free conditions, but the treatment of the reaction mixture with 20 mol% diethylzinc resulted in the formation of homopropargyl alcohol 41 via a rapid B/Zn transmetalation. Further, the Lewis acidity of the Cu I salt was successfully applied towards the stereodivergent homopropargylation of unprotected masked aldoses (Scheme 10b), [41] and N-acetyl mannosamine (Scheme 10c) [42] respectively by Kanai's group. The developed chemistry was further employed in the synthesis of C3-substituted sialic acids.…”

Synthesis of Chiral Tertiary α,α‐Difluoromethyl Carbinols by Cu‐Catalyzed Asymmetric Propargylation

“…Spiroketal-based diphosphine (SKP) ligands are ac lass of chiral diphosphines developed in our group [25] featured by large P-P distance (6.293 in free ligand) and flexible coordination modes, [26] and have demonstrated unique reactivities and selectivities in Pd, [26,27] Au, [28] and Rh [29] catalyzed asymmetricr eactions.E specially,S himizu and Kanai recently developed a copper(I)-catalyzeds tereodivergent anomeric propargylation of unprotected aldoses in which the SKP ligand was found to be superior on stereocontrol. [30] The studies were initiated by examining the reaction of a,a-difluoroketone 1a and (pinacolato)allenylboron (2)w ith in situ generated Cu I complexes as the catalysts. The reactions were generally run in THF for 24 h, and the results were summarized in Ta ble 1.…”

1,5-Hydrogen Atom Transfer/Surzur–Tanner Rearrangement: A Radical Cascade Approach for the Synthesis of 1,6-Dioxaspiro[4.5]decane and 6,8-Dioxabicyclo[3.2.1]octane Scaffolds in Carbohydrate Systems

“…The synthetic interest is apparent; the 3-deoxy-hept-2-ulopyranose framework present in VIII is intimately related to the ring system of octulosonic (Kdo, Kdn) and sialic acids. 27 Procedures for the preparation of analogous [4.5] spiroketals in 2-deoxy-pyranose systems using different methodologies have been described in previous publications. 28 In general, deoxy-pyranoses are important targets and are frequently found in bioactive secondary metabolites of microbial origin.…”

“…In fact, we would gain access to a series of ketoses with 5-deoxy-non-4-ulopyranose (i.e., VII) and 5-deoxy-hept-6-ulopyranose (also named 3-deoxy-hept-2-ulopyranose) (i.e., VIII) structures by long-range selective oxidation at C1 and C5 ring carbon atoms, respectively. The synthetic interest is apparent; the 3-deoxy-hept-2-ulopyranose framework present in VIII is intimately related to the ring system of octulosonic (Kdo, Kdn) and sialic acids . Procedures for the preparation of analogous [4.5] spiroketals in 2-deoxy-pyranose systems using different methodologies have been described in previous publications .…”