Chiral imine 2+21 cycloaddition

P-Lactams. Diketene can function as an equivalent to acetylketene, CH3C0CH=C=0, to provide 3-acetyl-p-lactams by [2 + 2]cycloaddition with imines.1 A stereoselective cycloaddition of this type can furnish a useful precursor (2) to lp-methylcarbapenems. Thus reaction of diketene with the chiral imine 1, prepared in a few steps from the readily available methyl (S)-3-hydroxy-2-meth-ylpropionate (Aldrich), can provide the desired 3,4-frpreviously developed for synthesis of the antibacterial carbapenem 4. 

The 2 + 2-cycloaddition reaction of a-alkoxyketene-derived imines yields /l-lactams with quaternary stereogenic centres at C(4).33 The 2 + 2-cycloaddition of chiral aminoketenes with chiral imines yields cis-fi-lactams with the absolute stereochemistry of file C(3) and C(4) positions being controlled by the ketene partner only.34 The 2 + 2-cycloaddition of ketenes with (W)-2-/-butyldihydrooxazole (19) yields predominately the regioisomer (20) from steric control rather than the expected electronic control (Scheme 7).35 The double 2 + 2-cycloaddition reaction between ketenylidenetriphe-nylphosphorane (21) and carbon suboxide (22) produces the bis(ylidic) spirocyclobut-anedione (23) (Scheme 8).36 Semiempirical and ab initio calculations have been used to investigate the Lewis acid-promoted 2 + 2-cycloaddition leading to the formation of jS-lactones.37... 

Chiral imines derived from D-(+)-glucose have allowed an asymmetric synthesis of p-lactams by the [2+2] cycloaddition with ketenes [85]. c/A-p-Lac tarns were formed with very high diastereoselectivity and the stereochemistry at the C-3 and the C-4 was established as 3S and 4R from the known absolute configuration of the sugar moiety (Scheme 24). 

The carbonylative [2+2] cycloaddition was performed also on chiral imines with allyl halides affording p-lactams with good stereoselectivity [160]. 

A diastereoselective synthesis of /3-sultams by 1,3-asymmetric induction in [2+2] cycloaddition of a sulfene intermediate and a chiral imine has been described (Scheme 48), and it was found that jV-alkylirnines give better diastereo-selectivity than iV-arylimines. The best selectivity was found in the case ofiV-(l-/-butylethyl)imine (67% yield, >95% de), and the diastereoselectivity was independent of the size and conformation of the N-substituents in the imines. Diastereoisomers bearing an /V-aryl group were separable by silica gel column chromatography <1998JOC8355>. 

Borer, B C, Balogh, D W, An asymmetric synthesis of a 3-hydroxy-(3-lactam by ketene-imine cycloaddition utilization of chiral ketenes from carbohydrates. Tetrahedron Lett., 32, 1039-1040, 1991. 

Ecteinascidin (ET)-743 is a marine natural product that exhibits potent antitumor activity. R.M. Williams and coworkers developed an approach for the synthesis of the pentacyclic framework of the molecule. At an early stage in the synthesis, they used a ketene-imine cycloaddition utilizing a chiral A/-protected ketene derivative to control the stereoselectivity. Subsequently, the chiral auxiliary was removed and the intermediate 3-lactam was converted to the target structure. 

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]. 

Asymmetric aza-DA reactions using chiral imines derived from a-amino esters an carbohydrates were extensively studied by Waldmann [310] and Kunz [311], re P o tively, at the end of fhe nineteen-eighties. After these significant works Yamamoto e al. reported the utility of homochiral N-(l-phenylefhyl)imines in asymmetric cy dition [219, 312]. In fhe presence of a stoichiometric amount of chiral boron tors 83 and 84, the cycloaddition of Danishefsky s diene 102 to these imines rea iz s almost complete diastereocontrol in the matched cases (Scheme 10.115), a e... 

Cycloaddition of phthalimidoketene with imine 18 also gives a single cis-fi-lactam 19 indicating that the presence of the oxygen in a ring is not necessary for stereoselective cycloaddition63. Cycloaddition of chiral imine 20 with diketene as an acetylketene equivalent under carefully optimized conditions gives a 15 1 mixture of the fr n.r-/ -lactam 21 and the tra s-disubstituted diastereomer 2267. 

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. 

Chiral imines obtained from a-phenylethylamine have been used with some success for asymmetric induction in cycloadditions with enolates. Addition of the tin enolate obtained by addition of tin(II) chloride to the lithium enolate of the thioester 7 to imine 8 followed by treatment with mercury(II) bis(trifluoracetate) to induce cyclization affords a 91 9 mixture of cis- and fram-j8-lactams 9. The cw-/ -lactam 9 is obtained with d.r. [(2S,3S)/(2R,3R)] 85 1584. 

Hetero-Diels-Alder reactions. The cycloaddition of Danishefsky s diene (and analogs) to chiral imines catalyzed by boronates derived from commercially available BINOL ligands proceeds with good diastereoselectivity. The double asymmetric induction operates for matching pairs, which exhibit fast reaction rates. On the other hand, the reaction of achiral substrates in the presence of chiral binol-boronates gives rise to products in good ee. ... 

Cycloaddition of chiral imines with diketene allows one to gain access to chiral lactams. An interesting example of this is the reaction of lactate-derived imine 573 with diketene, which produces a 7.3 1 mixture of 574 and 575 [117]. Chromatographic separation of the major isomer furnishes 574 with an enantiomeric excess of 96%. 

The j -lactam nucleus can also be assembled efficiently by a ketene-imine cycloaddition known as the Staudinger reaction. The reaction of chiral imine 759 with alkoxyketenes generated tfom benzyloxyacetyl chloride or acetoxyacetyl chloride affords cw-3,4-di-substituted )S-lactams 764a (75% yield) or 764b (61% yield) with diastereoselectivities greater than 95% [218]. 

Optically active 3-amino-2-hydroxycarboxylic acid derivatives are often key components of medicinally important compounds. The synthesis of isopropyl (2i ,35)-3-amino-4-cyclo-hexyl-2-hydroxybutyrate (126) (Scheme 28) takes advantage of a [2 + 2]-cycloaddition reaction of the chiral imines 123, prepared from 63, to assemble the important diastereomeric azetidinone 124 as the crucial precursor for completion of this novel synthesis. Protection of the hydroxy group of 63 as either the TBS ether 119 or the tert-buty ether 120, followed by a DIBAL reduction at —78 °C, produces smoothly one of the aldehydes 121 or 122. Condensation of these aldehydes with either di-p-anisylmethylamine or benzylamine in the presence of anhydrous magnesium sulfate affords the four possible chiral imines 123a—d (Scheme 26). 

The imines undergo [2 + 2]-cycloaddition with benzyloxyketene, generated in situ, to furnish separable mixtures of 3,4-cis-2-azetidinones 124 and 125. The best chemical yield (88%) and diastereoselectivity (15 1) is realized for the reactions employing 123a and 123d as chiral imines (Scheme 27). 

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