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. 2018 Oct 22;10(2):508-514.
doi: 10.1039/c8sc02788a. eCollection 2019 Jan 14.

Stereoselective organocatalyzed glycosylations - thiouracil, thioureas and monothiophthalimide act as Brønsted acid catalysts at low loadings

G A Bradshaw  1 , A C Colgan  1 , N P Allen  1 , I Pongener  1 , M B Boland  1 , Y Ortin  1 , E M McGarrigle  1
Affiliations

Stereoselective organocatalyzed glycosylations - thiouracil, thioureas and monothiophthalimide act as Brønsted acid catalysts at low loadings

G A Bradshaw et al. Chem Sci. .

Abstract

Thiouracil catalyzes stereoselective glycosylations with galactals in loadings as low as 0.1 mol%. It is proposed that in these glycosylations thiouracil, monothiophthalimide, and the previously reported catalyst, Schreiner's thiourea, do not operate via a double H-bonding mechanism but rather by Brønsted acid/base catalysis. In addition to the synthesis of 2-deoxyglycosides and glycoconjugates, we report the first organocatalytic synthesis of 1,1'-linked trehalose-type sugars.

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Figures

Fig. 1
Fig. 1. Selected examples of proposed interactions in thiourea catalysis via double H-bonding: (a) enolate binding in Pápai's model for enolate addition to nitroalkenes using Takemoto's catalyst;, (b) proposed complex between Schreiner's catalyst and an N-acyloxazolidinone in Diels–Alder reaction; (c) ketone binding in Jacobsen's ketone cyanosilylation; (d) cyanide binding in Jacobsen's enantioselective Strecker reaction.
Scheme 1
Scheme 1. (a) Galan and McGarrigle's thiourea-catalyzed glycosylation reaction; (b) Schreiner's THP-protection of alcohols; (c) original proposal with catalyst acting as a double hydrogen-bond donor to alcohol; (d) analogue of Pápai proposal with catalyst acting as a Brønsted acid and accepting a H-bond from the alcohol.
Scheme 2
Scheme 2. Synthesis of trehalose-type 1,1′-linked dimers and proposed intermediate 8.
Scheme 3
Scheme 3. Glycosylation of p-toluenesulfonamide.
Scheme 4
Scheme 4. Mechanistic studies on glycosylation: α/β-5a doesn't epimerize under reaction conditions. 13 is a viable catalyst (84% yield of 5a). Reaction of D2O with 3a gives addition of C–D and C–O bonds to same face of 3a. Schreiner's catalyst and thiouracil give the same outcomes in glycosylation of CD3OD.
Scheme 5
Scheme 5. Proposed glycosylation mechanism.
Scheme 6
Scheme 6. Lower catalyst loadings and gram-scale synthesis of 5a.
See this image and copyright information in PMC

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