Concise Construction of Novel Bridged Bicyclic Lactams by Sequenced Ugi/RCM/Heck Reactions

Ribelin, Timothy; Judd, Andrew S.; Akritopoulou‐Zanze, Irini; Henry, Rodger F.; Cross, Jeffrey L.; Whittern, David N.; Djurić, Stevan W.

doi:10.1021/ol7023373

Cited by 99 publications

(40 citation statements)

References 19 publications

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“…The X-ray structures of lactams 133 indicate significant degrees of pyramidalization at nitrogen ( 133a : τ = 33.4°; χ N = 49.1°; 133b : τ = 7.1°; χ N = 35.3°; 133c : τ = 17.6°; χ N = 26.2°; 133d : τ = 19.8°; χ N = 31.1°; 133e : τ = 19.8°; χ N = 15.9°). 296 Impressively, this study provided full structural characterization of four different ring systems of bridged lactams. Currently, the Heck reaction is one of the most reliable methods for the synthesis of bridged lactams with the N–(CO) bond on a larger bridge.…”

Section: Synthesis Of Bridged Lactams With N–(co) Bond On Two-carbmentioning

confidence: 99%

“…Judd and coworkers found that lactam 133a containing a [3.3.1] ring system was significantly more labile under acidic conditions than the regioisomeric lactams with [4.3.1] ring systems (Figure 13). 296 Denzer and Ott discovered that the hydrolytic behavior of bridged lactams containing an additional nitrogen atom at the bridgehead position in [3.3.1] and [3.2.1] ring systems corresponds to the degree of strain associated with the bridged amide bond (Scheme 117). 290 Hall investigated the hydrolytic stability of a family of unsubstituted bridged lactams, 279 bridged ureas 378,379 and bridged urethanes 380,381 (Table 12 and Figure 14).…”

Section: Reactivity Of Bridged Lactams and Related Heterocyclesmentioning

confidence: 99%

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Chemistry of Bridged Lactams and Related Heterocycles

2013

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CONTENTS 1. Introduction 5702 2. General Properties of Bridged Lactams 5703 2.1. Distortion Parameters of Bridged Lactams 5703 2.2. Bond Lengths of Bridged Lactams 5703 2.3. Spectroscopic Properties of Bridged Lactams 5703 2.4. Analogy of Bridged Lactams to Bridgehead Olefins 5704 2.5. Chemical and Biological Significance of Distorted Amides 5704 3. Synthesis of Historically Important Bridged Lactams 5704 3.1. Quinuclidone Derivatives 5704 3.2. Adamantanone Derivatives 5707 4. Synthesis of Bridged Lactams with the N−(CO) Bond on a Two-Carbon or Larger Bridge, ([m. (≥2).n] Type) 5708 4.1. Condensation Reactions Forming the N− C(O) Bond 5708 4.2. Heck Reactions 5711 4.3. Diels−Alder Reactions 5712 4.4. Carbene Insertion Reactions 5713 4.5. Reactions via Radical Intermediates 5714 4.6. Miscellaneous Examples 5714 5. Synthesis of Bridged Lactams with the N−(CO) Bond on a One-Carbon Bridge, ([m.1.n] Type) 5715 5.1. Carbene Insertion Reactions 5715 5.2. Schmidt Reactions 5716 5.3.

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Section: Synthesis Of Bridged Lactams With N–(co) Bond On Two-carbmentioning

confidence: 99%

Section: Reactivity Of Bridged Lactams and Related Heterocyclesmentioning

confidence: 99%

Chemistry of Bridged Lactams and Related Heterocycles

2013

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“…The most effective way of capturing an amide bond in a twisted conformation is to constrain it into a bicyclic ring system in which the amide nitrogen is present at a bridgehead position; 7,19,25–31 iconic examples include the parent quinuclidone 1 21 and the adamantane analog 2 (Figure 1c). 22–24 Such compounds are challenging to prepare, in part due to the extreme lability of their amide bond relative to ordinary amides.…”

Section: Introductionmentioning

confidence: 99%

Stability of Medium-Bridged Twisted Amides in Aqueous Solutions

2009

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“Twisted” amides containing non-standard dihedral angles are typically hypersensitive to hydrolysis, a feature that has stringently limited their utility in water. We have synthesized a series of bridged lactams that contain a twisted amide linkage but which exhibit enhanced stability in aqueous environments. Many of these compounds were extracted unchanged from aqueous mixtures ranging from the strongly basic to the strongly acidic. NMR experiments showed that tricyclic lactams undergo reversible hydrolysis at extreme pH ranges, but that a number of compounds in this structure class are indefinitely stable under physiologically relevant pH conditions; one bicyclic example was additionally water-soluble. We examined the effect of structure on the reversibility of amide bond hydrolysis, which we attributed to the transannular nature of the amino acid analogs. These data suggest that medium-bridged lactams of these types should provide useful platforms for studying the behavior of twisted amides in aqueous systems.

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“…4 As a matter of fact, although this condensation affords a linear peptide backbone, a plethora of strategies are available to rigidify Ugi adducts into more appealing drug-like species. 5 To date, Ugi-Diels Alder, 6 Ugi Buchwald-Hartwig, 7 Ugi-Heck, 8 Ugi-nucleophilic additions/substitutions 9 and Ugi-ring closing metatheses 10 pathways constitute the most well-established routes to gain access into a wide variety of cyclic scaffolds, in line with the post-condensation modification approach. 2 Recently, more elaborated processes involving extensive manipulations of Ugi products rendering natural product-like complex frameworks have also been reported.…”

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confidence: 99%