Domino Reactions That Combine an Azido-Schmidt Ring Expansion with the Diels−Alder Reaction

Zeng, Yibin; Reddy, D. Srinivasa; Hirt, Erin; Aubé, Jeffrey

doi:10.1021/ol047809r

Cited by 50 publications

(35 citation statements)

References 11 publications

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“…The Lewis acid-promoted reaction of unsubstituted diene 1a with 2 was previously reported 37 but dienes 1b-d , which contain an additional element of diversity and are readily prepared in ≤3 steps from commercially available starting material, were unknown to engage in Diels–Alder/Schmidt chemistry prior to this work. All four dienes underwent the desired conversions, which were reproducible and scalable to provide up to 12 g of lactam with no loss of efficiency.…”

Section: Resultsmentioning

confidence: 98%

“…This was pursued using the azido-Schmidt conversion of keto azides to lactams as the primary unifying technology 36 . Four variations of this reaction were used to create the desired scaffolds: (1) the combined Diels–Alder/Schmidt reaction between a silyloxy diene and an azide-containing dienophile 37 (Stemonaceae alkaloid series and one scaffold for the mesembrine series; Fig. 2a, d ), (2) the reaction of a ketone with a hydroxylalkyl azide 38 (cylindricine series; Fig.…”

Section: Resultsmentioning

confidence: 99%

“…All four dienes underwent the desired conversions, which were reproducible and scalable to provide up to 12 g of lactam with no loss of efficiency. Mechanistically, such reactions are believed to proceed by a Diels–Alder reaction, from which the product stereochemistry arises, followed by an intramolecular Schmidt reaction 37 . The relative stereochemistries of lactams 3b-d were confirmed by X-ray crystallography.…”

Section: Resultsmentioning

confidence: 99%

“…We similarly prepared secondary scaffold 21 by a modification of the previously reported Diels-Alder/Schmidt reaction of diene 20 and azide-tethered enone 19 ( Fig. 2d ) 37 . Attaching the azide to either the diene or dienophile allows access to either the cis or trans fused scaffold, (cf.…”

Section: Resultsmentioning

confidence: 99%

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Probing chemical space with alkaloid-inspired libraries

et al. 2014

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Screening of small molecule libraries is an important aspect of probe and drug discovery science. Numerous authors have suggested that bioactive natural products are attractive starting points for such libraries, due to their structural complexity and sp3-rich character. Here, we describe the construction of a screening library based on representative members of four families of biologically active alkaloids (Stemonaceae, the structurally related cyclindricine and lepadiformine families, lupin, and Amaryllidaceae). In each case, scaffolds were based on structures of the naturally occurring compounds or a close derivative. Scaffold preparation was pursued following the development of appropriate enabling chemical methods. Diversification provided 686 new compounds suitable for screening. The libraries thus prepared had structural characteristics, including sp3 content, comparable to a basis set of representative natural products and were highly rule-of-five compliant.

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Section: Resultsmentioning

confidence: 98%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

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Probing chemical space with alkaloid-inspired libraries

et al. 2014

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“…The fi rst example of a combined Diels -Alder/Schmidt reaction was made in the context of a formal total synthesis of ( ± ) -stenine, 59 which led to a detailed examination of the scope and the development of the overall sequence. 60 Since intermolecular Schmidt reactions of ketones are much less facile than their intramolecular counterparts, the prior unifi cation of ketone and azide through a Diels -Alder cycloaddition can facilitate an intramolecular Schmidt reaction. Thus, when an azide -containing diene 40 was combined with 2 -cyclopentenone in the presence of MeAlCl 2 , tricyclic lactam 41 was obtained in modest yield (Scheme 7.34 ).…”

Section: Combined Schmidt Rearrangement Cascade Reactionsmentioning

confidence: 99%

Schmidt Rearrangement Reactions with Alkyl Azides

Grecian¹,

Aubé

2009

Organic Azides

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The sobriquet ' Schmidt reaction ' refers to a number of related processes in which hydrazoic acid or an alkyl azide reacts with an electrophile. 1 -6 The product obtained will depend on the reaction partner (carboxylic acids generate amines, aldehydes give nitriles and formamides, and ketones provide amides, respectively) but all of these reactions have certain features in common. They are the initial nucleophilic addition of the azide component to an electrophile (usually promoted by acid) eventually followed by a rearrangement step driven by the energetically favorable loss of nitrogen. The classical Schmidt reaction of hydrazoic acid with ketones is generally considered to involve an intermediate dehydration step. 7,8 Despite the diversity of reactions that comprise the Schmidt family, its single most common variant is shown in Scheme 7.1 . This overall process can be regarded as an insertion of NH between the carbonyl and an α alkyl group. 9 The development of this version of the Schmidt reaction predates the experience of anyone working in organic chemistry today (Schmidt ' s original report was in 1924) but the extension of the concept to nucleophilic alkyl azides is a decidedly contemporary development. For example, if one compares the two reactions shown in Scheme 7.2 , it is clear that the direct insertion of an alkyl azide into cyclohexanone allows for the introduction of additional nitrogen atom substitution and, in the case of an alkyl azide tethered to a carbonyl substrate, the possibility of an intramolecular reaction. The goal of this chapter

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The Schmidt Reaction

et al. 2012

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The classical form of the Schmidt reaction involves the reaction of a carbon‐centered electrophile with hydrazoic acid with loss of nitrogen, usually with a rearrangement that forms a new carbon‐nitrogen bond. Although the conversion of a ketone into an amide is the most commonly used variation, mechanistically related versions utilize an aldehyde, acid, or a carbocation generated from an alkene or alcohol as the electrophilic component. In recent years, the definition of the Schmidt reaction has been modified to include analogous reactions in which the hydrazoic acid is replaced by an alkyl azide, promoted by Lewis acids. The use of an alkyl azide uniquely permits the formulation of intramolecular Schmidt reactions of the azide with a carbonyl or carbocationic electrophile.

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Domino Reactions That Combine an Azido-Schmidt Ring Expansion with the Diels−Alder Reaction

Cited by 50 publications

References 11 publications

Probing chemical space with alkaloid-inspired libraries

Probing chemical space with alkaloid-inspired libraries

Schmidt Rearrangement Reactions with Alkyl Azides

The Schmidt Reaction

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