Carbenes stereoselectivity

In 1999, Bob Atkinson wrote [1] that aziridination reactions were epoxida-tion s poor relation , and this was undoubtedly true at that time the scope of the synthetic methods available for preparation of aziridines was rather narrow when compared to the diversity of the procedures used for the preparation of the analogous oxygenated heterocycles. The preparation of aziridines has formed the basis of several reviews [2] and the reader is directed towards those works for a comprehensive analysis of the area this chapter presents a concise overview of classical methods and focuses on modern advances in the area of aziridine synthesis, with particular attention to stereoselective reactions between nitrenes and al-kenes on the one hand, and carbenes and imines on the other. 

This area of research has only recently attracted the attention of synthetic organic chemists, but there has been a flurry of impressive activity in the area. Simple (i. e., unstabilized) carbenes suffer from many of the problems of nitrenes (vide infra) and most reported synthetically useful procedures use carbenoids the majority of recent reports have focussed upon reactions between a-diazoesters and imines in the presence of a range of catalysts. In one of the earliest reports of enantioselective carbene-imine reactions, for instance, Jacobsen and Finney reported that ethyl diazoacetate reacts with N-arylaldimines in the presence of cop-per(i) hexafluorophosphate with mediocre stereoselectivity to give N-arylaziridine carboxylates. Though the diastereoselectivities of the reaction were often acceptable (usually >10 1, in favor of the cis isomers) the observed enantioselectivity was low (no more than 44% ee Scheme 4.27) [33],... 

Carbene complexes which have an all-carbon tether between the diene and the dienophile react via intramolecular Diels-Alder reaction to give the corresponding bicyclic compound. The stereoselectivities of these reactions are comparable to those observed for the Lewis acid-catalysed reactions of the corresponding methyl esters and much higher than those of the thermal reactions of the methyl esters which are completely unselective. Moreover, the ris-sub-stituted complexes undergo endo-selective reactions where the corresponding reaction of the ester fails [109] (Scheme 61). 

A similar tandem Dotz-Mitsunobu reaction has been reported starting from a l,6-methano[10]annulene carbene complex, but no conclusion could be reached on the influence of the chiral information regarding the stereoselective course of the reaction since the chromium fragment could not be kept coordinated to the benzannulation product [47]. 

The inherent plane of chirality in the metal carbene-modified cyclophane 45 was also tested in the benzannulation reaction as a source for stereoselectivity [48]. The racemic pentacarbonyl(4-[2.2]metacyclophanyl(methoxy)carbene)-chromium 45 reacts with 3,3-dimethyl-1-butyne to give a single diastereomer of naphthalenophane complex 46 in 50% yield the sterically less demanding 3-hexyne affords a 2 1 mixture of two diastereomers (Scheme 30). These moderate diastereomeric ratios indicate that [2.2]metacyclophanes do not serve as efficient chiral tools in the benzannulation reaction. 

A pathway may be considered which involves a double regioselective alkyne insertion followed by a stereoselective cyclisation to undergo a novel [3+2+2]-cyclisation. These examples illustrate the scope in which the reactivity of Fischer carbene complexes can be tuned in a qualitative manner by transmetalation. 

Of perhaps greater use for organic synthesis was the observation that photo-driven reactions of alkoxycarbenes with unsubstituted optically active ene carbamates [65] produced aminocyclobutanones in fair yield with high dia-stereoselectivity (Table 12) [66]. In contrast, with a gem-disubstituted ene carbamate, the syn-anti selectivity was low but high asymmetric induction a to nitrogen was observed (Eq. 16). Trans-monosubstituted ene carbamates failed to react, as did a,/J-unsaturated chromium carbene complexes. 

The best known of metal carbene reactions, cydopropanation reactions, have been used since the earliest days of diazo chemistry for addition reactions to the carbon-carbon double bond. Electron-donating groups (EDG) on the carbon-carbon double bond facilitate this catalytic reaction [37], whereas electron-withdrawing groups (EWG) inhibit addition while facilitating noncatalytic dipolar cycloaddition of the diazo compound [39] (Scheme 5). There are several reviews that describe the earlier synthetic approaches [1, 2,4, 5,40-43], and these will not be duplicated here. Focus will be given in this review to control of stereoselectivity. 

Which isomer is predominantly formed depends on R, R, and on the method by which the carbene or carbenoid is generated. Most studies have been carried out on monosubstituted species (R = H), and in these studies it is found that aryl groups generally prefer the more substituted side (syn addition) while carbethoxy groups usually show anti stereoselectivity. When R = halogen, free halocarbenes show little or no stereochemical preference, while halocarbenoids exhibit a preference for syn addition. Beyond this, it is difficult to make simple generalizations. 

Cyclopenta[fc]dioxanes (44) are accessible from the reaction of the dioxenylmolybdenum carbene complex (43) with enynes <96JOC159>, whilst an intramolecular and stereoselective cyclisation of (Ti5-dienyl)tricarbonyliron(l+) cations affords chiral frans-2,3-disubstituted 1,4-dioxanes <96JOC1914>. 2,3-Dimethylidene-2,3-dihydro-1,4-benzodioxin is a precursor of the 3,8-dioxa-lff-cyclopropa[i]anthracene, which readily dimerises to dihydrotetraoxaheptacene (45) and the analogous heptaphene <96AJC533>. 

A singlet carbene was proposed to account for this stereoselectivity. Attempts to produce triplet carbene by collisional deactivation with octafluorocyclo-butane were unsuccessful and stereospecific addition to olefin still occurred. However, nonstereospecific addition to olefins and larger amounts of olefinic (insertion) products result from irradiation of the phenyldiazomethane in a frozen m-butene matrix at — 196°C ... 

Taking together the results of reactivity and stereoselectivity comparisons, one may conclude that the cyclopropanation mechanism as such is quite similar in all cases and involves a metal carbene, but that the stereoselectivity is determined by the nature of the diazoalkane substituent. Doyle has developed a mechanistic scheme which accounts for these observations (Scheme 44). 

When the cis/trans stereoselectivity of cyclopropanation with ethyl diazoacetate in the presence of CuCl P(0-z-Pr)3, Rh6(CO)16 or PdCl2 2 PhCN was plotted against that obtained with Rh2(OAc)4, a linear correlation was observed in every case, with slopes of 1.74,1.04 and 0.59, respectively (based on 22 olefins, T = 298 K) S9). These relationships as well as the results of regioselectivity studies carried out with 1,3-dienes point to the similar nature of the intermediates involved in Cu-, Rh-and Pd-catalyzed cyclopropanation. Furthermore, obvious parallels in reactivity in the transformations of Scheme 45 for a variety of catalysts based on Cu, Rh, Fe, Ru, Re and Mo suggest the conclusion that electrophilic metal carbenes are not only involved in cyclopropanation but also in ylide-forming reactions66. ... 

Inhibition of diazoester decomposition by a large excess of olefin speaks in favor of intermediarily liberated W(CO)5 as direct metal precursor of425. Stereoselectivities in the cyclopropanation reaction are very similar to those observed in the Rh2(OAc)4 catalyzed version, which underlines once more the close relationship of tungsten and rhodium carbene complexes. 

Addition of halogens and pseudohalogens to the cyclopropylthiocarbene chromium complexes 122 affords the 1,4-dihalo-1-phenylthio-l-alkenes 123 stereoselectively [65]. Electrophilic halogen is likely to activate the carbene complexes, followed by the homo-Michael addition of halide anion. (Scheme 44)... 

Z,Z)-l,4-Dialkoxy-l,3-dienes can be readily prepared from propargyl ethers and molybdenum carbene complexes (equation 185)307. High stereoselectivity in this reaction may be due to the formation of stable vinyl hydride complex with the enol ether. 

As a tool to improve the regio- and stereoselectivity of C-H insertion, activation of a specific C-H bond of substrates to be inserted seems to be appropriate in conjunction with the manipulation of carbene character. These two tools for the improvement of insertion selectivity will provide us with useful tools of the C-C bond formation by carbenes and carbenoids. 

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