An efficient and scalable synthesis of 2,4-di-N-acetyl-l-altrose (l-2,4-Alt-diNAc)

Abstract

An efficient and scalable synthesis of pseudaminic acid precursor l-2,4-Alt-diNAc was developed from l-fucose. The desired l-altro configuration and N-acetamido substitutions ensued from a sequence of highly regio- and stereoselective transformations.

Regiospecific O → N Acyl Migration as a Methodology to Access l-Altropyranosides with an N2,N4-Differentiation

“…Despite the simplicity and straightforwardness of the above N -acyl differentiation strategy, many shortcomings were noticed, including the long reaction sequence and reduced efficiency and regioselectivity during the opening of the epoxide functionality when compared to our previously report using 3 as a substrate . This decreased performance could be explained by the competitive coordination of the lithium ion to the neighboring electron-rich N -acetyl group in compound 4 in addition to a possible preferential build-up of positive charge on C3 during the opening of the activated epoxide, with C2 being adjacent to the more electron-withdrawing anomeric substituent …”

“…The biosynthesis of Pse includes an enzymatic extension of 2,4-diacetamido-2,4,6-trideoxy- l -altrose (Alt-diNAc, 2 ) by a Pse synthase (Figure ). There has been much interest lately in investigating the chemical and chemoenzymatic syntheses of Pse and its analogs − because of their challenging and unique stereochemistries as well as the opportunities to develop novel antibacterial strategies from them. In the latter case, both vaccines to prevent drug-resistant bacterial infections and antibiotics to target bacterial motility, including small-molecule inhibitors for bacterial Pse synthases, are being considered. , Most existing chemical and chemoenzymatic syntheses for Pse and its l - altro precursor have focused on producing their N 5, N 7-diacetylated (Pse5Ac7Ac) or N 2, N 4-diacetylated (Alt-2,4-diNAc) analogs. , There exist a limited number of reports ,− on the successful installation of differentiated N -acyl groups, where a specific N -substitution pattern is demonstrated, a long reaction sequence is required, or both.…”

“…Despite the simplicity and straightforwardness of the above N-acyl differentiation strategy, many shortcomings were noticed, including the long reaction sequence and reduced efficiency and regioselectivity during the opening of the epoxide functionality when compared to our previously report using 3 as a substrate. 13 This decreased performance could be explained by the competitive coordination of the lithium ion to the neighboring electron-rich N-acetyl group in compound 4 in addition to a possible preferential build-up of positive charge on C3 during the opening of the activated epoxide, with C2 being adjacent to the more electron-withdrawing anomeric substituent. 23 While there is no general method to regioselectively activate one azido group over the other in carbohydrate chemistry, the specific functional group relationship in compound 7 presented us with an opportunity to design an amido group differentiation strategy that exploited the cis-relationship between the axial 3-OH group and the equatorial 4-azido group on the pyranosyl ring as opposed to the trans-diaxial relationship between the same 3-OH group and the axial 2azido group (Scheme 2).…”

“…We recently published a scheme achieving the synthesis of Alt-diNAc ( 2 ) from l -fucose in 10 steps and a 23% overall yield via the benzyl 2,3-anhydro-4-azido-4,6-dideoxy- l -allopyranoside 3 (Scheme ). This intermediate was initially considered to be a good starting point for obtaining the desired N 2, N 4-differentiated Alt-diNAc analogs via a sequential approach beginning with the reduction of the C4-azide of 3 by a Staudinger reduction using trimethylphosphine, − followed by an in situ N -acetylation (→ 4 ).…”

“…This intermediate was initially considered to be a good starting point for obtaining the desired N 2, N 4-differentiated Alt-diNAc analogs via a sequential approach beginning with the reduction of the C4-azide of 3 by a Staudinger reduction using trimethylphosphine, − followed by an in situ N -acetylation (→ 4 ). An epoxide opening activated by lithium perchlorate was then performed with a second azide, affording the desired 2-azido-4-acetamido- l -altropyranoside intermediate 5 along with the undesired 3-azido-4-acetamido- l -glucopyranoside 6 in a 2:1 ratio. With compound 5 in hand, a second Staudinger reduction of the 2-azido functionality, followed by N -acylation with another type of acylating reagent, would afford the N 2, N 4-differentiated Alt-diNAc analogs.…”