康 · 學術 | Reaction of the Day No. 1702

來源：市場資訊

（來源：康龍化成）

Anomeric Amide Enabled Divergent Synthesis of Unsymmetrical Ureas, Carbamates, Thioesters, and Amides From Aldehydes

JasperL. Tyler, Meiyi Zeng, Julius Wiener, Marie-Christin Leusmann, Colin Stein, Constantin G. Daniliuc, Frank Glorius*

Organisch-ChemischesInstitut, Universit?t Münster, Münster, Germany

Recommended by Bingbing Chang_MC5

KEY WORDS: Lossen-type rearrangements, single-electron transfer, nucleophilic substitution, photo chemistry (反應類型), C(sp2)–N, C(sp3)–N (成鍵類型), aldehydes, anomeric amide (原料), ureas, carbamates, thiocarbamates, thioesters, amines, amides (產物)

ABSTRACT：Divergent synthetic transformations that convert a single precursor into a range of structurally distinct products are powerful tools for rapidly exploring chemical space. Although numerous strategies exist for converting versatile functional handles such as halides and boronic acids into a multitude of reactive intermediates, there remains a pressing need for methodologies that exploit alternative linchpin fragments to open complementary avenues to molecular complexity. Herein, Prof. Frank Glorius et al. report a divergent, anomeric amide-enabled, aldehyde functionalization strategy, allowing access to unsymmetrical ureas, carbamates, thiocarbamates, thioesters, amines, or amides, all in a one-pot procedure. Unique to this transformation is the formation of N-Boc-hydroxamate intermediates, which serve as privileged platforms for orthogonal activation via Lossen-type rearrangements, single-electron transfer, or nucleophilic substitution, generating a diverse selection of reactive intermediates. Overall, this work establishes N-halo-O-activated hydroxycarbamate-type anomeric amides as valuable reagents for aldehyde diversification, offering a complementary approach to molecular complexity generation from feedstock compounds.

Diversity-generating synthesis and application of aldehydes to divergent functionalization. a) Generating diversity through linchpin diversification. b) Previous work. c) Reaction design: Hydroxamate synthesis and targeted reactive intermediates. d) This work: Divergent functionalization of aldehydes

Substrate scope for the divergent synthesis of ureas, carbamates, and thiocarbamates from aldehydes (selected examples)

Substrate scope for the divergent synthesis of ureas, amides, and thioesters from alcohols and aldehydes

Substrate scope for the divergent synthesis of ureas, amides, and thioesters from alcohols and aldehydes

Proposed mechanism for N-Boc-hydroxamate formation

Summary and Comments

Prof. Frank Glorius et al. have developed a complementary approach for the synthesis of unsymmetrical ureas, carbamates, thiocarbamates, thioesters, amines, and amides via the anomeric amide-enabled diversification of aldehydes. While related divergent functionalization platforms have been reported, the distinguishing feature of this work is the use of an aldehyde-derived hydroxamate linchpin that enables controlled, condition-dependent switching between several fundamentally different reaction modes. Mechanistic studies indicated that the formation of the key N-Boc-hydroxamate intermediate occurs via light-induced N?Cl bond homolysis, aldehyde hydrogen atom transfer, chlorine radical capture, and acylation. This species could then be activated under a range of orthogonal conditions and coupled with a variety of complex and medicinally relevant nucleophiles and radical acceptors to rapidly generate molecular complexity. The applicability and utility of this strategy were further demonstrated by the late-stage diversification of the lipid-lowering agent ciprofibrate into a variety of drug analogues.