SmI₂-Mediated Coupling of Nitrones and <i>tert</i>-Butanesulfinyl Imines with Allenoates: Synthesis of β-Methylenyl-γ-lactams and Tetramic Acids

Nitrones and <i>tert</i>-butanesulfinyl imines undergo conjugate addition to alkyl allenoates under SmI₂-mediated reductive coupling conditions to produce novel β-methylenyl-substituted γ-amino esters. The latter were readily transformed into the corresponding β-methylenyl-γ-lactams by simple zinc reduction (<i>N</i>-hydroxy amines) or by acid hydrolysis (sulfinamides). The diastereoselective preparation of various β-methylenyl-γ-lactams offers a route to tetramic acids, the key structural features of an important class of bioactive natural products

Metal-Free Intermolecular Coupling of Arenes with Secondary Amides: Chemoselective Synthesis of Aromatic Ketimines and Ketones, and <i>N</i>‑Deacylation of Secondary Amides

The direct transformation of common secondary amides into aromatic ketimines and aromatic ketones with C–C bond formation is described. The reaction can also be used for <i>N</i>-deacylation of secondary amides to release amines. This method consists of <i>in situ</i> amide activation with triflic anhydride and intermolecular capture of the resulting highly electrophilic nitrilium intermediate with an arene. The reaction is applicable to various kinds of secondary amides (electrophiles), but only electron-rich and moderately electron-rich arenes can be used as nucleophiles. Thanks to the use of bench stable arenes instead of reactive and basic organometallics as nucleophiles, the reaction proceeded with high chemoselectivity at the secondary amido group in the presence of a series of sensitive functional groups such as aldehyde, ketone, ester, cyano, nitro, and tertiary amido groups. The reaction can be viewed as a Friedel–Crafts-type reaction using secondary amides as acylating agents or as an intermolecular version of the Bischler–Napieralski reaction

Mild Metal-Free Hydrosilylation of Secondary Amides to Amines

The combination of amide activation by Tf₂O with B­(C₆F₅)₃-catalyzed hydrosilylation with TMDS constitutes a method for the one-pot reduction of secondary amides to amines under mild conditions. The method displays a broad applicability for the reduction of many types of substrates, and shows good compatibility and excellent chemoselectivity for many sensitive functional groups. Reductions of a multifunctionalized α,β-unsaturated amide obtained from another synthetic methodology, and a C–H functionalization product produced the corresponding amines in good to excellent yield. Chemoselective reduction of enantiomeric pure (ee >99%) tetrahydro-5-oxo-2-furaneamides yielded 5-(aminomethyl)­dihydrofuran-2­(3<i>H</i>)-ones in a racemization-free manner. The latter were converted in one pot to <i>N</i>-protected 5-hydroxypiperidin-2-ones, which are building blocks for the synthesis of many natural products. Further elaboration of an intermediate led to a concise four-step synthesis of (−)-<i>epi</i>-pseudoconhydrine

One-Pot Reductive 1,3-Dipolar Cycloaddition of Secondary Amides: A Two-Step Transformation of Primary Amides

The one-pot reductive 1,3-dipolar cycloaddition of secondary aromatic <i>N</i>-(trimethylsilylmethyl)­amides with reactive dipolarophiles is reported. The method relies on the in situ generation of nonstabilized NH azomethine ylide dipoles via amide activation with triflic anhydride, partial reduction with 1,1,3,3-tetramethyldisiloxane (TMDS), and desilylation with cesium fluoride (CsF). Running under mild conditions, the reaction tolerated several sensitive functional groups and provided cycloadducts in 71–93% yields. The use of less reactive dipolarophile methyl acrylate led to the cycloadduct in only 40% yield. A (<i>Z</i>) geometric intermediate of NH-azomethine 1,3-dipole was postulated to account for the observed higher yields and higher <i>cis</i> diastereoselectivity for the substrates bearing an electron-withdrawing group. This model features an unconventional cyclic transition state via carbanion–aryl ring interaction. Because the starting secondary amides can be prepared from common primary amides, the current method also constitutes a two-step transformation of primary amides

General and Chemoselective Bisphosphonylation of Secondary and Tertiary Amides

With Tf₂O as the activation reagent, a mild and general method has been developed for the bisphosphonylation of both secondary and tertiary amides. The protocol is highly efficient and chemoselective, and it tolerates a number of sensitive functional groups such as cyano, ester, and aldehyde groups

Asymmetric Total Synthesis and Absolute Configuration Determination of (−)-Verrupyrroloindoline

The first asymmetric total synthesis of (−)-verrupyrroloindoline (20% overall yield in 6 steps) is described. The short approach was enabled by Buchwald’s Cu­(II)-catalyzed asymmetric conjugate reduction, DMDO-triggered one-pot four-step tandem reaction, and the first amide-selective Ir-catalyzed direct reduction of β-carboethoxy tertiary lactam. Along with the total synthesis, the absolute configuration of natural verrupyrroloindoline was determined as 7<i>R</i>,10<i>R</i>,11<i>R</i>

Enantioselective Total Syntheses of (−)-FR901483 and (+)-8-<i>epi</i>-FR901483

The enantioselective total syntheses of the potent immunosuppressant FR901483 (<b>1</b>) and its 8-epimer (<b>47</b>) have been accomplished. Our approach features the use of building block <b>6</b> as the chiron, the application of the one-pot amide reductive bis-alkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and RCM to form the 3-pyrrolin-2-one ring

A Formal Enantioselective Total Synthesis of FR901483

A formal enantioselective total synthesis of the potent immunosuppressant FR901483 (<b>1</b>) has been accomplished. Our approach features the use of chiron <b>6</b> as the starting material, the application of the one-pot amide reductive bisalkylation method to construct the chiral aza-quaternary center (dr = 9:1), regio- and diastereoselective intramolecular aldol reaction to build the bridged ring, and ring closing metathesis to form the 3-pyrrolin-2-one ring

SmI₂‑Mediated Intermolecular Coupling of γ‑Lactam <i>N</i>‑α-Radicals with Activated Alkenes: Asymmetric Synthesis of 11-Hydroxylated Analogues of the Lead Compounds CP-734432 and PF-04475270

We report, for the first time, the synthesis of 8-aza-analogues of PGE₂. The SmI₂-mediated cross coupling reactions of γ-lactam-hemiaminal <b>9</b>, lactam 2-pyridyl sulfide <b>17</b>, and lactam 2-pyridyl sulfone <b>18</b> with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49–78%, 45–75%, and 75–90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 <i>trans</i>-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam <i>N</i>-α-alkyl radicals of types <b>B</b>, <b>B1</b>, and <b>B2</b> with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP₄ receptor agonist PF-04475270 (<b>30</b>), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (<b>31</b>), compounds <b>35</b> and <b>36</b> have been achieved on the basis of this method

SmI₂‑Mediated Intermolecular Coupling of γ‑Lactam <i>N</i>‑α-Radicals with Activated Alkenes: Asymmetric Synthesis of 11-Hydroxylated Analogues of the Lead Compounds CP-734432 and PF-04475270

We report, for the first time, the synthesis of 8-aza-analogues of PGE₂. The SmI₂-mediated cross coupling reactions of γ-lactam-hemiaminal <b>9</b>, lactam 2-pyridyl sulfide <b>17</b>, and lactam 2-pyridyl sulfone <b>18</b> with activated alkenes/alkyne were first developed, giving the corresponding γ-lactams in 49–78%, 45–75%, and 75–90%, respectively. The reactions of lactam 2-pyridyl sulfide and 2-pyridyl sulfone proceeded with ≥12:1 <i>trans</i>-diastereoselectivities. This represents the first intermolecular coupling reaction of the γ-lactam <i>N</i>-α-alkyl radicals of types <b>B</b>, <b>B1</b>, and <b>B2</b> with activated alkenes. Two radical-based mechanisms were suggested. The asymmetric synthesis of the 11-hydroxylated analogue of the highly selective EP₄ receptor agonist PF-04475270 (<b>30</b>), the 11-hydroxylated analogue of ocular hypotensive CP-734432 (<b>31</b>), compounds <b>35</b> and <b>36</b> have been achieved on the basis of this method