Chiral carbenes

Another interesting and more general methodology to a carbene with only one chiral carbon atom in the backbone was introduced by Hahn et al. [61] (see Figure 5.16). Here, an arylamine is treated with n-BuLi and carbon disulfide to the corresponding thiocarbonic acid amide. Second deprotonation with 5ec-BuLi and subsequent reaction with an asymmetrically substituted Schiff base affords the imidazolidinone that can be reduced with Na/K alloy to the respective carbene. Chirality is introduced via the prochiral N=C bond of the Schiff base and the prodnct is usually a racemate since no chiral discriminator is present in the formative step. 

N-heterocyclic salt such as chiral imidazolium salt 2.87 is the precursor of N-heterocyclic carbene, chiral imidazol-2-ylidene ° 2.88. 

The transformation of ethylene to the carbene requires the re-pairing of three electron pairs. It is a phase-preserving reaction, so that the loop is an ip one. The sp -hybridized carbon atom formed upon H transfer is a chiral center consequently, there are two equivalent loops, and thus conical intersections, leading to two enantiomers. 

The triazole 76, which is more accurately portrayed as the nucleophilic carbene structure 76a, acts as a formyl anion equivalent by reaction with alkyl halides and subsequent reductive cleavage to give aldehydes as shown (75TL1889). The benzoin reaction may be considered as resulting in the net addition of a benzoyl anion to a benzaldehyde, and the chiral triazolium salt 77 has been reported to be an efficient asymmetric catalyst for this, giving the products (/ )-ArCH(OH)COAr, in up to 86% e.e. (96HCA1217). In the closely related intramolecular Stetter reaction e.e.s of up to 74% were obtained (96HCA1899). 

In 20 years of usage, a,/J-unsaturated Fischer carbene complexes demonstrated their multitalented versatility in organic synthesis, yet new reaction types are still being discovered every year. In view of their facile preparation and multifold reactivity, their versatile chemistry will undoubtedly be further developed and applied in years to come. The application of chirally modified Fischer carbene complexes in asymmetric synthesis has only begun, and it will probably be an important area of research in the near future. 

Asymmetric versions of the cyclopropanation reaction of electron-deficient olefins using chirally modified Fischer carbene complexes, prepared by exchange of CO ligands with chiral bisphosphites [21a] or phosphines [21b], have been tested. However, the asymmetric inductions are rather modest [21a] or not quantified (only the observation that the cyclopropane is optically active is reported) [21b]. Much better facial selectivities are reached in the cyclopropanation of enantiopure alkenyl oxazolines with aryl- or alkyl-substituted alkoxy-carbene complexes of chromium [22] (Scheme 5). 

The Diels-Alder reaction of simple alkoxy alkenylcarbene complexes leads to mixtures of endo and exo cycloadducts, with the endo isomer generally being the major one [96,97]. Asymmetric examples of endo Diels-Alder reactions have also been reported by the use of chiral auxiliaries both on the carbene complex and the diene. Thus, the reaction of cyclopentadiene with chiral alkenylcarbene complexes derived from (-)-menthol proceeds to afford a 4 1... 

A chiral version of this [4+3] heterocyclisation was achieved using chiral, non-racemic carbene complexes derived from menthol and oximes as depicted... 

Due to the inherent unsymmetric arene substitution pattern the benzannulation reaction creates a plane of chirality in the resulting tricarbonyl chromium complex, and - under achiral conditions - produces a racemic mixture of arene Cr(CO)3 complexes. Since the resolution of planar chiral arene chromium complexes can be rather tedious, diastereoselective benzannulation approaches towards optically pure planar chiral products appear highly attractive. This strategy requires the incorporation of chiral information into the starting materials which may be based on one of three options a stereogenic element can be introduced in the alkyne side chain, in the carbene carbon side chain or - most general and most attractive - in the heteroatom carbene side chain (Scheme 20). 

The second option involves the incorporation of either chiral amines or chiral alcohols into the heteroatom-carbene side chain (R ), which represents the most versatile approach to diastereoselective benzannulation. The optically pure (2R,3R)-butane-2,3-diol was used to tether the biscarbene complex 37. The double intramolecular benzannulation reaction with diphenylbutadiyne allowed introduction of an additional stereogenic element in terms of an axis... 

Scheme 26 Carbene complexes with chiral amino substituents...

Scheme 27 Rigid chiral carbene complex chelates in diastereoselective benzannulation...

Scheme 29 Tandem benzannulation-Mitsunobu reaction of a chiral decalin-derived carbene complex...

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. 

Scheme 30 A chiral [2.2]metacyclophane carbene complex in a benzannulation reaction...

The use of a stereogenic carbon centre allowed an efficient asymmetric induction in the benzannulation reaction towards axial-chiral intermediates in the synthesis of configurationally stable ring-C-functionalised derivatives of al-locolchicinoids [51]. The benzannulation of carbene complex 52 with 1-pen-tyne followed by oxidative demetalation afforded a single diastereomer 53 (Scheme 33). 

Photodriven reactions of Fischer carbenes with alcohols produces esters, the expected product from nucleophilic addition to ketenes. Hydroxycarbene complexes, generated in situ by protonation of the corresponding ate complex, produced a-hydroxyesters in modest yield (Table 15) [103]. Ketals,presumably formed by thermal decomposition of the carbenes, were major by-products. The discovery that amides were readily converted to aminocarbene complexes [104] resulted in an efficient approach to a-amino acids by photodriven reaction of these aminocarbenes with alcohols (Table 16) [105,106]. a-Alkylation of the (methyl)(dibenzylamino)carbene complex followed by photolysis produced a range of racemic alanine derivatives (Eq. 26). With chiral oxazolidine carbene complexes optically active amino acid derivatives were available (Eq. 27). Since both enantiomers of the optically active chromium aminocarbene are equally available, both the natural S and unnatural R amino acid derivatives are equally... 

Abstract The dirhodium(II) core is a template onto which both achiral and chiral ligands are placed so that four exist in a paddle wheel fashion around the core. The resulting structures are effective electrophilic catalysts for diazo decomposition in reactions that involve metal carbene intermediates. High selectivities are achieved in transformations ranging from addition to insertion and association. The syntheses of natural products and compounds of biological interest have employed these catalysts and methods with increasing frequency. 

The use of dirhodium(II) catalysts to generate ylides that, in turn, undergo a vast array of chemical transformations is one of the major achievements in metal carbene chemistry [1,103]. Several recent reviews have presented a wealth of information on these transformations [1, 103-106], and recent efforts have been primarily directed to establishing asymmetric induction, which arises when the chiral catalyst remains bound to the intermediate ylide during bond formation (Scheme 11). 

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>. 

The high simple diastereoselectivities observed running the [4-1-3] cycloadditions raised the question concerning the induction of chirality. Preliminary experiments involving chiral menthyloxy Fischer carbenes 169 (R = (-)-men-thyl) resulted in the formation of the diastereomeric lactim ethers 173-1 and 173-2 in a 7 3 ratio, which could be separated by means of a crystallization. A final acidic hydrolysis gave the enantiomerically pure e-caprolactams 175 and ent-175 and the acyclic esters, respectively. No signs of racemization have been detected,Eqs. (18,19) [39b]. 

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