Enolate-imine, cycloaddition

The common methods for the S5mthesis of p-lactams are cycloaddition reactions such as the Staudinger s ketene-imine cycloadditions, ester enolate-imine cycloadditions, alkyne-nitrone cycloadditions (Kinugasa reaction), alkene-isocyanate cycloadditions, and Torii s cyclocarbonylation of allyl halides with imines. Several cyclizahon reactions of p-amino esters, p-amino acids, p-hydroxamate esters, and a-diazocarbonyls have been developed for the formation of p-lactam ring. N,N-Disubstituted a-haloamides cyclize by C3-C4 bond formation leading to the formation of P-lactam ring. 

Enantiomerically pure trans-2-phenylcyclohexanol, first used by Whitesell as a chiral auxiliary has become a popular reagent in a number of asymmetric transformations. Some recent applications include asymmetric azo-ene reactions, [4 + 2]-cycloaddition reactions, ketene-olefin [2 + 2]-reactions, enolate-imine cyclocondensations, Pauson-Khand reactions," palladium annulations and Reformatsky reactions. Despite its potential, use of this chiral auxiliary on a preparative scale is currently limited by its prohibitive cost. 

An unusual course of thermolysis occurs in 5-amino- and 5-alkoxytri-azolines, which are formed only as intermediates in the reaction of enamines and enol ethers with azides bearing electron-withdrawing groups it involves cleavage of the N-l/N-2 as well as the C-4/C-5 bonds of the triazoline ring to yield diazoalkanes and imines with one fewer carbon than in the triazolines (amidines and imino ethers) (Scheme 144)233.250 272 431-433 in a cycloelimination reaction, the reverse of diazoalkane-imine cycloaddition. The intermediate formation of a diazonium zwitterion is suggested,233,247 but whether the thermolysis occurs in a one- or two-step reaction is not established. 

After examining the feasibility of an asymmetric [2 + 2] ketene-imine cycloaddition route and an asymmetric ester enolate-imine cyclocondensation route, we chose the latter route for the efficient asymmetric synthesis of (3/ ,4Sj-3-hydroxy-4-phenylazetidin-2-one and (2R,35)-/V-benzoyl-3-phenylisoserine. The cyclocondensation of the lithium enolate of (-)-(1 / ,2S)-2-phenyl-1 -cyclohexyltriiso-propylsiloxyacetate (5a P = (i-Pr)3Si (TIPS) and R = (-)-(lR,2S)-2-phenyl-1 -cyclohexyl) with A-trimethylsilylbenzaldimine (6a R1 = Ph) in THF at -78 °C gives (3/ ,4S)-3-triisopropylsiloxy-4-phenylazetidin-2-one (7a P = TIPS and R1 = Ph)... 

Another catalytic application of chiral ketene enolates to [4 + 2]-type cydizations was the discovery of their use in the diastereoselective and enantioselective syntheses of disubstituted thiazinone. Nelson and coworkers described the cyclocondensations of acid chlorides and a-amido sulfones as effective surrogates for asymmetric Mannich addition reactions in the presence of catalytic system composed of O-TM S quinine lc or O-TMS quinidine Id (20mol%), LiC104, and DIPEA. These reactions provided chiral Mannich adducts masked as cis-4,5 -disubstituted thiazinone heterocycles S. It was noteworthy that the in situ formation of enolizable N-thioacyl imine electrophiles, which could be trapped by the nucleophilic ketene enolates, was crucial to the success of this reaction. As summarized in Table 10.2, the cinchona-catalyzed ketene-N-thioacyl-imine cycloadditions were generally effective for a variety of alkyl-substituted ketenes and aliphatic imine electrophiles (>95%ee, >95%cis trans) [12]. 

The majority of reported solid-phase combinatorial syntheses of the lactam core utilize a [2-i-2] cycloaddition reaction of ketenes with resin-bound imines [33-41]. A further development of the Staudinger reaction was reported by Mata and coworkers using Mukaiyama s reagent [42]. In addition, a stereoselective synthesis of chi-rally pure P-lactams has been performed as a first utilization of polymer-supported oxazolidine aldehydes [43]. Other strategies include an ester enolate-imine condensation [44], an Hg(OCOCF3)2-mediated intramolecular cydization [45], and Miller hydroxamate synthesis [46]. Because of the variability derived from the scaffold synthesis, not many attempts have been made to derivatize the resin-bound lactam template [47]. One of the most detailed descriptions of a versatile (3-lactam synthesis on a resin employed amino acids tethered as esters on Sasrin resin [48]. 

The mechanism of 3-lactam formation in enolate-imine condensations proceeds by the stepwise pathway depicted in Scheme 19, in which diastereomeric 3-lactams (100) and (101) are formed by cycliza-tion of intermediate, metalated amine adducts (98) and (99), respectively. The possibility of a less likely [2 -I- 2] cycloaddition mechanism has been discussed. - Equilibration between 3-lactams (100) and (101) via epimerization at C-3 does not normally occur. The stepwise mechanism is supported by the fact that trans 3-lactam (101 R = Pr R = R = Ph) is formed from (99 M = MgBr) without loss of... 

Analogous condensations using lithium enolates of MA -diethyl-o-toluamide (149) have been described by Clark and Jahangir for the synthesis of 3,4-dihydro-l(2//)-isoquinolones (151 Scheme 31). It is fortunate that the enolate-imine addition-cyclization process occurs at low temperature, since warming the reaction mixture to room temperature, a common practice in many enolate-imine additions, leads to side reactions due to the instability of the 4-Iithiated derivative (150) formed by release of lithium diethylamide. The authors have exploited the in situ formation of (150) for the synthesis of 4-sub-stituted isoquinolones by trapping it with electrophiles. A cycloaddition mechanism via an... 

The reaction of ester enolates with imines is a general method for the preparation of /5-lactams. This reaction is clearly not a concerted cycloaddition. The enolate adds to the imine generating an arnido ester intermediate. This intermediate, which is usually not isolated, cyclizes to give the /3-lactam. Since this subject has been recently reviewed81, only the stereochemical aspects of this reaction will be discussed here. In this reaction there are four possible sites for the chiral auxiliary. As in ketene imine cycloadditions, stereogenic centers can be introduced into the substituent on the imine carbon (R1), the substituent on the imine nitrogen (R2) or the substituent on the acyl portion of the ester (R3). There is a fourth possibility in these cycloadditions since the stereogenic center can also be introduced into the alkyl portion of the ester (R4), In some cases /r K-/ -lactams are obtained exclusively, while in other cases, mixtures of cis- and trans-isomers are isolated. 

Solid-phase and combinatorial synthesis of 6-lactams using the Staudinger reaction has widely been studied. Carbohydrates as a chiral pool, however, were not employed except for one report [148]. The polymer supported-imines were employed to prepare several -lactams by enolate/imine condensation and ketene/imine cycloaddition (Scheme 46) [146]. The reactions carried out on the polymer-boimd imines showed a remarkable similarity to those in solution, both in terms of yield and stereoselectivity [54,55]. )S-Lactams were removed from the polymer by CAN oxidation [ 148]. 

Ester-Enolate Cycloaddition The ester enolate-imine cyclocondensation method (Scheme 3.13) provides fS-lactams in good yields with higher stereoselectivity. Various types of esters and imines can be utilized. Some recent reactions have been mediated by zinc [47], rhodium [48], indium [49], and diethylzinc [50]. 

Our approach was based on the ring opening of fluoroalkyl p-lactams. These p-lactams can be obtained either through a [2+2] ketene-imine cycloaddition with a fluoroacetaldimine, or by the cyclocondensation of an alkoxy or silyloxy ester enolate on this same fluoroacetaldimine. The preparation of fluoroalkyl P-lactams 16 (Rf = CF3, CFjH and CF2CI) and the preparation of homochiral P-lactams and isoserines 14 and 15, have been have investigated with success by these two approaches. 

The Staudinger reaction [92], a [2 + 2]-cycloaddition of a ketene and a nucleophilic imine, usually proceeds by an initial imine attack on the ketene thus forming a zwitterionic enolate which subsequently cyclizes. This reaction is an expedient route to p-lactams, the core of numerous antibiotics (e.g., penicillins) and other biologically active molecules [93]. In contrast, for Lewis-base catalyzed asymmetric reactions, nonnucleophilic imines are required (to suppress a noncatalyzed background reaction), bearing, for example, an N-Ts [94] or -Boc-substituent [95]. 

In a recent publication, Perumal and coworkers [441] described the condensation of an aldehyde 2-863 with an aniline 2-864 to give an imine which is trapped by a dienophile. However, when using this approach an intermolecular cycloaddition takes place as the reaction is performed as a three-component process using enol ethers or cyclopentadiene as dienophiles (Scheme 2.192). When using enol ether 2-... 

IrCl2H(cod)]2 catalyzed the synthesis of substituted quinolines, where the reachon of aniline derivahves, aromatic and alkyl aldehydes efficiently proceeds under an oxygen atmosphere (Scheme 11.34) [46]. The plausible mechanism consists of a Mannich reaction, a Friedel-Craft-type aromahc substituhon, dehydration, and dehydrogenation. This can be recognized as a formal [4+2] cycloaddition of N-aryl imine and enol (Scheme 11.35). 

Trifluoroacetylacetonitrile (396) can also react with nitrile imines 395 via two reaction paths depending on their structure. Those with an electron donating N substituent reacted via cycloaddition to the enolic double bond to give 397 while... 

The DFT study of the 3 + 2-cycloaddition between ketene and TV-silyl-, IV-germyl-, and TV-stannyl-imines shows that the TV-germylimine reaction is a two-step process the TV-stannylimine reaction is a competition between two- and three-step processes whereas the TV-silyl process follows a three-step process44 A new and convenient synthesis of functionalized furans and benzofurans based on 3 + 2-cycloaddition/oxidation has been reported. The cyclization of cyclic 1,3-bis-silyl enol ethers (48) with l-chloro-2,2-dimethoxyethane (49), via a dianion, produced 5,6-bicyclic 2-alkylidenetetrahydrofurans (50), which are readily oxidized with DDQ to 2,3-unsubstituted benzofurans (51) (Scheme 13)45 The Evans bis(oxazoline)-Cu(II) complex catalyses the asymmetric 1,3-dipolar cycloaddition of a -hydroxyenones with nitrones to produce isoxazolidines.46 The... 

---