Doyle’s catalyst

In intramolecular cyclopropanation, Doyle s catalysts (159) show outstanding capabilities for enantiocontrol in the cyclization of allyl and homoallyl diazoesters to bicyclic y-and <5-lactones, respectively (equations 137 and 138)198 205. The data also reveal that intramolecular cyclopropanation of Z-alkenes is generally more enantioselective than that of E-alkenes in bicyclic y-lactone formation198. Both Rh(II)-MEPY enantiomers are available and, through their use, enantiomeric products are accessible. In a few selected cases, the Pfaltz catalyst 156 also results in high-level enandoselectivity in intramolecular cyclopropanation (equation 139)194. On the other hand, the Aratani catalyst is less effective than the Doyle catalyst (159) or Pfaltz catalyst (156) in asymmetric intramolecular cyclo-propanations201. In addition, the bis-oxazoline-derived copper catalyst 157b shows lower enantioselectivity in the intramolecular cyclopropanation of allyl diazomalonate (equation 140)206. 

Doyle s catalysts have also been applied to asymmetric intermolecular cyclo-propanation, mainly in the styrene-diazoester reaction. Diazoesters include EDA, dicyclohexylmethyl diazoacetate, and d-menthyl diazoacetate. In general the effectiveness of Doyle s rhodium (II) carboxamidates in enantiocontrol is lower... 

Doyle s catalysts and methodology have been extended to C-H insertion reactions of diazoacetates derived from secondary acyclic and cyclic alcohols where diastereoselectivity becomes an integral component of the overall stereocontrol objective. Two outstanding examples in the acyclic series are shown in Scheme 11... 

Scheme 12 Catalytic cyclopropanation with Doyle s catalyst...

Figure 18.3. McKervery s and Doyle s catalysts tor enantioselective carbene insertions.

Doyle s rhodium(n) carboxamidate complexes are undisputedly the best catalysts for enantioselective cyclizations of acceptor-substituted carbenoids derived from diazo esters and diazoacetamides, displaying outstanding regio- and stereocontrol.4 These carboxamidate catalysts consist of four classes of complexes pyrrolidinones... 

Che has reported that both achiral and chiral rhodium catalysts function competently for intramolecular aziridination reactions of alkyl- and arylsulfonamides (Scheme 17.29) [59, 97]. Cyclized products 87 are isolated in 90% yield using 2 mol% catalyst, PhI(OAc)2, and AI2O3. Notably, reactions of this type can be performed with catalyst loadings as low as 0.02 mol% and display turnover numbers in excess of 1300. In addition, a number of chiral dimeric rhodium systems have been examined for this process, with some encouraging results. To date, the best data are obtained using Doyle s Rh2(MEOX)4 complex. At 10 mol% catalyst and with a slight excess of Phl=0, the iso-... 

Asymmetric C-H insertion using chiral rhodium catalysts has proven rather elusive (Scheme 17.30). Dimeric complexes derived from functionalized amino acids 90 and 91 efficiently promote oxidative cychzation of suifamate 88, but the resulting asymmetric induction is modest at best ( 50% ee with 90). Reactions conducted using Doyle s asymmetric carboxamide systems 92 and 93 give disappointing product yields ( 5-10%) and negligible enantiomeric excesses. In general, the electron-rich carboxamide rhodium dimers are poor catalysts for C-H amination. Low turnover numbers with these systems are ascribed to catalyst oxidation under the reaction conditions. 

Rhodium(II) carboxylate dimers and their carboxamide counterparts have been demonstrated to be exceptionally useful catalysts for carbene transfer processes involving diazocarbonyl substrates [1]. Doyle s seminal work identified Rh2(OAc)4 as the catalyst of choice for a variety of cyclopropanation, C-H insertion, and ylide rearrangement transformations using diazoketones or diazoesters [2]. Important contributions by Taber [3], Padwa [4], and Davies [5] further established the superior catalytic activity of dirho-dium catalysts and the excellent selectivity of rhodium-[Pg.417]

Hodgson et al. (138) chose to investigate a system that had previously been shown to undergo an effective intramolecular addition of a tethered olehn (Scheme 4.72). In his first attempt, using Doyle s Rh2[(5/ )-MEPY]4, the yield of cycloadduct 270 obtained was comparable to that with rhodium acetate, but no asymmetric induction was observed. Changing to the Davies catalysts in dichloromethane resulted in a... 

The most significant breakthrough in this area was Doyle s introduction of chiral rhodium (II) carboxamidates (Fig. 4). These catalysts show an exceptional ability to direct highly enantioselective intramolecular cyclopropanation of al-lylic and homoallylic diazoesters, Eq. (19), and diazoamides, Eq. (20). 

Similarly, significant improvements with methallyl and ( -butyl)allyl diazoacetates can be achieved by switching catalysts from Rh2(MEPY)4 to Rh2(MP-PIM)4. Allyl diazo esters other than diazo acetates have not yet been examined in detail. Encouragingly, Doyle s group [41] have found that high levels of enantio-control in intramolecular cyclopropanation can be realized with allyl diazopropionates and the Rh2(4S-MEOX)4 catalyst, Eq. (25). 

In a useful extension of this methodology for enantioselection in intramolecular cyclopropanation, Doyle s group have used chiral rhodium (II) carbox-amidates to effect enantiomer differentiation in reactions of racemic secondary allylic diazoacetates [47]. The catalyst-enantiomer matching approach has also been applied very successfully to intramolecular C-H insertion reactions vide infra). The (R)- and (S)-enantiomers, (10) and (11), respectively, of cyclohex-2-en-1 -yl diazoacetate are displayed in Scheme 7. On exposure to Rh2(4i -MEOX)4 the (R)-enantiomer (10) undergoes cyclopropanation to form tricyclic ketone... 

Doyle s chiral rhodium (II) carboxamidates have proved to be exceptionally successful for asymmetric C-H insertion reactions of diazoacetates and some diazoacetamides leading to lactones and lactams, respectively. With 2-alkoxyethyl diazoacetates and the Rh2(5S- and 5R-MEPY)4 catalysts, for example, highly enantioselective intramolecular C-H insertion reactions occur, the 5S-catalyst, Eq. (40), and 5R-catalyst furnishing the S- and R-lactone, respectively [58]. A polymer-bound version of Rh2(5S-MEPY)4 has also been applied to the cycliza-tion in Eq. (40) to yield the lactone with 69% ee (R=Me) the catalyst could be recovered by filtration and reused several times, but with decreasing enantiose-lection [59]. 

Figure 6.11. Depiction of the structure of Doyle s Rh2[5-5-MEPY]4 catalyst, showing the cis arrangement of the nitrogens [113].

In additional papers, Doyle s group reported that the same catalyst also gives very high optical yields in alkyne cyclopropenations and in other CH insertions (Doyle et al., 1991b Doyle et al., 1992b, 1993c, 1994 Protopopova et al., 1992). Mechanistically most important are the X-ray structures determined for [Rh2((5iS)-... 

The two main families of catalysts used are the Davies/McKervey dirhodium car-boxylate catalysts (9.24a-c) and Doyle s carboxamidates, including Rh2(MEPY)4 (9.25), Rh2(MPPIM)4 (9.26) and the azetidinones such as Rh2(IBAZ)4 (9.27). ... 

Using Doyle s second-generation imidazolidinone catalyst system, Rh2(MPPlM)4, a series of benzyl substituted y-butyrolactones was synthesized by intramolecular C-H activation. The strategy was applied to the synthesis of various ligands such as enterolactone (202), hinokinin, and isodeoxypodophyllotoxin. " ... 

In this case the use of the Doyle dirhodium catalyst Rh2(S-MPPIM)4 (a complex containing the hgand methyl (4S)-2-oxo-3-(3-phenylpropa-noyl)-4-imidazohdine carboxylate) converted the diazoacetate (S)-97 into the ds-flised bicychc lactam (—)-98 in 70% yield together with some dimeric by-products (c. 18%). Elaboration of the piperidine ring entailed lactone cleavage with the anion of phenyl methyl sulfone followed by reduction... 

The most commonly used protected derivatives of aldehydes and ketones are 1,3-dioxolanes and 1,3-oxathiolanes. They are obtained from the carbonyl compounds and 1,2-ethanediol or 2-mercaptoethanol, respectively, in aprotic solvents and in the presence of catalysts, e.g. BF, (L.F. Fieser, 1954 G.E. Wilson, Jr., 1968), and water scavengers, e.g. orthoesters (P. Doyle. 1965). Acid-catalyzed exchange dioxolanation with dioxolanes of low boiling ketones, e.g. acetone, which are distilled during the reaction, can also be applied (H. J. Dauben, Jr., 1954). Selective monoketalization of diketones is often used with good success (C. Mercier, 1973). Even from diketones with two keto groups of very similar reactivity monoketals may be obtained by repeated acid-catalyzed equilibration (W.S. Johnson, 1962 A.G. Hortmann, 1969). Most aldehydes are easily converted into acetals. The ketalization of ketones is more difficult for sterical reasons and often requires long reaction times at elevated temperatures. a, -Unsaturated ketones react more slowly than saturated ketones. 2-Mercaptoethanol is more reactive than 1,2-ethanediol (J. Romo, 1951 C. Djerassi, 1952 G.E. Wilson, Jr., 1968). 

Arylation of activated double bonds with diazonium salts in the presence of copper catalysts is known as the Meerwin reaction. The reaction is postulated to either proceed through an organocopper intermediate or through a chlorine atom transfer from chiral CuCl complex to the a-acyl radical intermediate. Brunner and Doyle carried out the addition of mesityldiazonium tetrafluoroborate with methyl acrylate using catalytic amounts of a Cu(I)-bisoxazoline ligand complex and were able to obtain 19.5% ee for the product (data not shown) [79]. Since the mechanism of the Meerwin reaction is unclear, it is difficult to rationalize the low ee s obtained and to plan for further modifications. 

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