molecules Review Chemistry of Bridged Lactams: Recent Developments Roman Szostak 1 and Michal Szostak 2,* 1 Department of Chemistry, Wroclaw University, F. Joliot-Curie 14, 50-383 Wroclaw, Poland; [email protected] 2 Department of Chemistry, Rutgers University, 73 Warren Street, Newark, NJ 07102, USA * Correspondence: [email protected]; Tel.: +1-973-353-5329 Academic Editor: Michal Szostak Received: 28 December 2018; Accepted: 10 January 2019; Published: 12 January 2019 Abstract: Bridged lactams represent the most effective and wide-ranging method of constraining the amide bond in a non-planar conformation. A previous comprehensive review on this topic was published in 2013 (Chem. Rev. 2013, 113, 5701–5765). In the present review, which is published as a part of the Special Issue on Amide Bond Activation, we present an overview of the recent developments in the field of bridged lactams that have taken place in the last five years and present a critical assessment of the current status of bridged lactams in synthetic and physical organic chemistry. This review covers the period from 2014 until the end of 2018 and is intended as an update to Chem. Rev. 2013, 113, 5701–5765. In addition to bridged lactams, the review covers recent advances in the chemistry of bridged sultams, bridged enamines and related non-planar structures. Keywords: amide bond; bridged lactams; twisted amides; amides; Winkler-Dunitz parameters; N–C activation; hypersensitivity; nitrogen heterocycles; distortion; bridged sultams 1. Introduction The amide bond is arguably the most important linkage in chemistry and biology [1]. Typical amide bonds are planar as a result of amidic resonance (nN ! π*C=O conjugation, 15–20 kcal/mol) (Figure1A) [2]. Figure 1. (A) Amide FigureBond 1.Resonance.(A) Amide Bond (B) Types Resonance. of Distorted (B) Types of Amide Distorted Bonds. Amide Bonds. The redesign of the amide bond geometry through structural and electronic changes of substituents comprising the amide bond has had a profound impact on the physico-chemical properties of amides [3–6]. The alteration of the amide bond geometry generally leads to a reversal of traditional Molecules 2019, 24, 274; doi:10.3390/molecules24020274 www.mdpi.com/journal/molecules Molecules 2019, 24, 274 2 of 17 Molecules 2019, 23, x FOR PEER REVIEW 2 of 16 Nproperties-C(O) bond, of amides,favored suchprotonation as lower at barrierthe nitrogen to cis-trans atom, rotation,and increased increased reactivity length in of n theucleophilic N-C(O) additionbond, favored and hydrolysis protonation [3– at6]. the The nitrogen geometric atom, and and structural increased changes reactivity of inthe nucleophilic amide bond addition are an establishedand hydrolysis technique [3–6]. to The affect geometric properties and of structural amide bonds changes in biology of the and amide medicinal bond are chemistry an established [7–10], whiletechnique recent to affectadvances properties in selective of amide metal bonds insertion in biology into and the medicinal amide bond chemistry driven [7 –by10 ],its while distortion recent readvancespresent ina selectivethriving metaland general insertion concept into the in amide organic bond synthesis driven by [11,12]. its distortion In general, represent amide a thriving bond distortionand general can concept be achieved in organic by four synthesis methods [11 (Figure,12]. In general,1B): (1) steric amide restriction, bond distortion (2) steric can repulsion, be achieved (3) conformationby four methods effects, (Figure and1 (4)B): electronic (1) steric restriction,effects. Out (2) of stericthese repulsion,methods, the (3) most conformation effective one effects, by far and is steric(4) electronic restriction. effects. Typically, Out of steric these methods,restriction the involves most effective constraining one by the far amide is steric bond restriction. in a rigid Typically, bicyclic ringsteric system restriction with involves a nitrogen constraining atom positioned the amide at a bondbridgehead in a rigid position. bicyclic This ring allows system one with to aconstrain nitrogen theatom typical positioned planar at aamide bridgehead bond position.in a non This-planar allows conformation one to constrain with thethe typicalmagnitude planar of amide distortion bond principallyin a non-planar controlled conformation by the type with of the ring magnitude system (Figure of distortion 2). To principallydate, bridged controlled lactams byrepr theesent type the of onlyring method system (Figurethat has2 ).allowed To date, for bridged a substantial lactams distortion, represent exceeding the only 60% method of the that maximum has allowed theoretical for a valuesubstantial of the distortion, amide bond exceeding [3–6,11,12 60%]. of the maximum theoretical value of the amide bond [3–6,11,12]. Figure 2. (A) Winkler-Dunitz Distortion. (B) Activation of the Amide Bond by N-/O-Protonation. Figure 2. (A) Winkler-Dunitz Distortion. (B) Activation of the Amide Bond by N-/O-Protonation. (C) (C) Types of Bridged Lactams. Types of Bridged Lactams. Amide bond distortion is measured by Winkler-Dunitz parameters: τ (twist angle), χN Amide bond distortion is measured by Winkler-Dunitz parameters: (twist angle), (pyramidalization at N) and χC (pyramidalization at C) [13] as well as by changes in N–C(O) (pyramidalization at N) and C (pyramidalization at C) [13] as well as by changes in N–C(O) and C=O and C=O bond lengths (Figure2A). Amide bond distortion leads to a change of thermodynamic bond lengths (Figure 2A). Amide bond distortion leads to a change of thermodynamic N-/O- N-/O-protonation aptitude, which is a key effect that controls the reactivity of non-planar amide bonds protonation aptitude, which is a key effect that controls the reactivity of non-planar amide bonds (Figure2B) [ 11]. The properties of amide bonds in bridged lactams are further amplified by a type of (Figure 2B) [11]. The properties of amide bonds in bridged lactams are further amplified by a type of bridged lactam scaffold (Figure2C). In general, bridged lactams are classified into amides in which bridged lactam scaffold (Figure 2C). In general, bridged lactams are classified into amides in which the N–C(O) bond is placed on a one-carbon bridge or on a larger bridge, with the former enjoying the N–C(O) bond is placed on a one-carbon bridge or on a larger bridge, with the former enjoying additional stabilization through transannular scaffolding effects. additional stabilization through transannular scaffolding effects. Molecules 2019, 24, 274 3 of 17 Molecules 2019, 23, x FOR PEER REVIEW 3 of 16 In this review,review, publishedpublished asas aa partpart ofof thethe SpecialSpecial IssueIssue onon AmideAmide BondBond ActivationActivation, wewe presentpresent anan overview of the recent developments in the fieldfield of bridged lactams and present a critical assessment of the current status of bridged lactams. This review covers the periodperiod from 2014 until the end of 2018 and is intended as an update to the previous comprehensive review on topic, Chem. Rev. 2013,, 113,, 5701–57655701–5765 [[3].3]. In addition to bridged lactams, the review covers recent advances in the chemistry of bridged sultams, bridgedbridged enamines and related non-planarnon-planar structures. For additional coverage, the reader is referredreferred toto previousprevious reviewsreviews on bridgedbridged lactams [[44–6].]. It is our hope that the review will serve as a useful reference for chemists involved in various aspects of activatingactivating the amide bond and stimulate further research inin thisthis area.area. 2. Synthesis, Properties and Reactivity of Bridged Lactams Recent advances in the fieldfield ofof bridgedbridged lactamslactams include:include: (1) identificationidentification of the additiveadditive Winkler-DunitzWinkler-Dunitz parameter,parameter, (2)(2) synthesissynthesis ofof extremelyextremely twistedtwisted non-stabilizednon-stabilized amides,amides, (3) synthesis of novel bridged lactams, and (4) new examples of reactivityreactivity ofof non-planarnon-planar amides.amides. In 2015, 2015, we we have have identified identified the the additive additive Winkler Winkler-Dunitz-Dunitz distortion distortion parameter parameter (+ (SN),τ sum+ χN of), sumtwist ofand twist pyramidalization and pyramidalization at nitrogen at angles nitrogen, as a angles, more accurate as a more prediction accurate of the prediction structural of and the structuralenergetic properties and energetic of non properties-planar ofamides non-planar than either amides twist than or eitherpyramidalization twist or pyramidalization alone (Figures alone 3–4) (Figures[14,15]. A3 computationaland4)[ 14,15]. study A computational to determine the study effect to of determine amide distortion the effect on N of-/ amideO-protonation distortion using on Na -/setO of-protonation lactams comprehensively using a set of covering lactams comprehensivelythe entire distortion covering range (Figure the entire 3) revealed distortion a rangelinear (Figurecorrelation3) revealed between a linearthe composite correlation Winkler between-Dunitz the composite parameter Winkler-Dunitz (+ N) and parameter N-/O-protonation ( Sτ + χN) andaptitudeN-/O (Figur-protonatione 4) [14] aptitude. Our subsequent (Figure4)[ 14 study]. Our demonstrated subsequent study thatdemonstrated the additive thatWinkler the additive-Dunitz Winkler-Dunitzparameter (+ parameterN) gives linear (Sτ correlations+ χN) gives vs. linear structural correlations and other vs.