Tethered Amides

The (E)-alkene (74) is formed from Wittig reaction of the corresponding phenyl 3-pyridyl ketone the stereochemical preference is determined by an interaction (either hydrogen bonding or salt bridging) between the carboxylic acid chain being introduced and the amide tether provided by the reactant." ... 

Lactams are another interesting class of compounds that have been thoroughly explored by Zhang [25]. Methods that are typically used in the synthesis of nonracemic lactams involve C-N bond formation of substrates with preset chiral centers. The Alder-ene carbon-carbon bond forming strategy allows for chiral centers to be set without the use of other pre-existing chirality in the substrate. Initially, enynes with secondary amide tethers were studied but no cyclization was observed. Zhang reasoned that the favored transoid conformation of the secondary amide prevents the necessary conformation required for cyclization (Scheme 8.2). 

Scheme 8.4 Synthesis of lactams from amide-tethered allenynes.

The acyclic precursor is an oc, 3-unsaturated amido aldehyde that was condensed with iV-methylhydroxylamine to generate the nitrone ( )-48, which then underwent a spontaneous cycloaddition with the alkene to afford the 5,5-ring system of the isoxazolidinyl lactam 47. The observed product arises via the ( )-nitrone transition state A [or the (Z)-nitrone equivalent] in which the position of the benzyl group ot to the nitrone effectively controls the two adjacent stereocenters while a third stereocenter is predicted from the alkene geometry. Both transition states maintain the benzyl auxiliary in an equatorial position and thus avoid the unfavorable 1,3-diaxial interaction with the nitrone methyl or oxygen found in transition state B. Semiempirical PM3 calculations confirm the extra stability, predicting exclusive formation of the observed product 47. Related cycloadducts from the intramolecular reaction of nitrones containing ester- rather than amide-tethered alkene functionality are also known (83-85). 

A similar example is found in the irradiation of vinylogous amide-tethered tryptophan derivatives 112 [114]. The more bulky the substiment on the... 

An intramolecular photocycloaddition of a vinylogous amide tethered at C-3 of a 1-acylindole has also been achieved in a stereospecific reaction, in which the cyclobutane adduct (332) undergoes a retro-Mannich reaction to give the imino ketone (333), a synthetic precursor of vindorosine (Scheme 104) <90JA8971>. 

Another reaction that has been extensively studied is the y-lactam formation. The initial cyclization study using a secondary amide tether did not afford any desired product. It was believed that the predominant trans conformation of the secondary amide prevented the cyclization (Figure 2-16). In fact, the protected enynes with a tertiary amide linked were readily transformed into a variety of y-lactams. Under the optimized conditions, enyne-amide 475 afforded functionalized y-lactams 476 in high yield and good-excellent enantioselectivities... 

Scheme 2-58. Rh-catalyzed Alder-ene reaction of enynes with a tertiary amide tether. Typical procedure ...

Enantioselective phase-transfer catalysis has also been successfiilly applied to intramolecular aza-Michael reactions, as elegantly exemplified by Bandini and Umani-Ronchi in the reaction of amide tethered indolyl a,p-unsaturated esters to yield 3,4-dihydropyrazino[l,2-a]-indol-l(2/i)-ones [109]. With the general assumption that the annulation reaction proceeds to give products with (5) configuration, a proposal for the transition state of the enantioselective step of the reaction was made by the same group two years later [110]. In this transition step a favorable ir-stacking interaction between the indole and the benzyl-CF3 groups was postulated (Scheme 11.30). 

More recently, the Brummond laboratory reported a series of Rh-catalyzed allenic Alder-ene reactions affording 5- and e-lactams 89 from amide-tethered alleneynes 88 (Scheme 46) (94). Higher temperature was required for the reaction to proceed efficiently. This observation could be attributed to the secondary amide, because the reaction of protected amides proceeded at room temperature to afford cyclized product in less than 1 h. The reaction is somewhat sensitive to terminal alkyne in that product yields for amide-tethered allenyne substrates with terminal alkyne were lower. 

The reaction mechanism has tJso been investigated by DFT calculations, lending support for the stepwise mechanism [111, 112]. The first key intermediate is the diruthenium nitrenoid species (S = 1/2). In the transition state of the C-H bond scission, the coordinated nitrenoid interacts with the allylic H atom, polarizing the C-H bond. Subsequent H atom transfer to the N atom generates a diradical species comprising a diruthenium amide tethered to an allylic radical (S = 3/2). Of interest, the unpaired electrons are primarily localized at the two Ru centers (and the allylic fragment), with litde spin density (0.14) at the N atom. Finally, radical rebound forms the cyclized amine. 

A double-Michael addition of amide-tethered dicarboxylic acids 60 with aromatic alkynones 61 could lead to highly functionalized pyroglutamic acid derivatives 62 (Scheme 2.17). With substoichiometric quantities of Mg(OTf)2 or Ni(acac)2 as additives, Lam and coworkers developed a novel reaction that provided the corresponding products with good levels of trans diastereoselectivity [30]. 

Wei, L.-L. Hsung, R. P. Skelnicka, H. M. Gerasyuto, A. I. "A Novel and Flighly Stereoselective Intramolecular Formal [3+3] Cycloaddition Reaction of Vinylogous Amides Tethered with a,p-Unsaturated Aldehydes A Formal Synthesis of (+)-Gephyrotoxin" Angew. Chem. Int Ed. 2001, 40, 1516. 

Over the last decade, we have been developing an aza-[3+3] cycloaddition reaction as a general strategy in alkaloid synthesis [4,128,129,132,134-137,166-172]. The intramolecular variant of this reaction has proven to be valuable in namral product synthesis. Specifically, the intramolecular aza-[3+3] cycloaddition of vinylogous amides tethered to a... 

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