康 · 学术 | Reaction of the Day No. 1702

孔骏喆

来源：市场资讯
（来源：康龙化成）
. t8 }7 @2 p# f9 OAnomeric Amide Enabled Divergent Synthesis of Unsymmetrical Ureas, Carbamates, Thioesters, and Amides From Aldehydes
6 o* Y4 C. \  R& x& E# wJasperL. Tyler, MEIyi Zeng, Julius Wiener, Marie-Christin Leusmann, Colin Stein, Constantin G. Daniliuc, Frank Glorius*
Organisch-ChemischesInstitut, Universität Münster, Münster, Germany
Recommended by Bingbing Chang_MC5

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KEY WORDS: Lossen-type rearrangements, single-electron transfer, nucleophilic substitution, photo chemistry (反应类型), C(sp2)–N, C(sp3)–N (成键类型), aldehydes, anomeric amide (原料), ureas, carbamates, thiocarbamates, thioesters, amines, amides (产物)
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.
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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
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Substrate scope for the divergent synthesis of ureas, carbamates, and thiocarbamates from aldehydes (selected examples)

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4 G2 A, {$ ^0 E2 TSubstrate scope for the divergent synthesis of ureas, amides, and thioesters from alcohols and aldehydes
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Substrate scope for the divergent synthesis of ureas, amides, and thioesters from alcohols and aldehydes

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5 v3 W& Z6 N' }+ K2 g/ xProposed mechanism for N-Boc-hydroxamate formation




0 e, Y6 ^" ^. `! \6 |5 GSummary and Comments
1 S) a& u8 A$ _. v8 W7 e$ u4 |; {  j# hProf. 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.