Diazoesters, synthesis

Diazoester synthesis [431] is less interesting. Elements of the strategy of the Sagami-synthesis can be applied [432, 433] as shown in Reaction scheme 149. 

Helquist s work on the use of diazomalonate in the synthesis of oxazoles has been extended to other diazocarbonyl compounds in our own laboratory.<92TL7769, 94T3761> Thus it was found that sulfonyl-, phosphonyl- and cyano-substituted diazoesters gave the corresponding 4-functionalised oxazoles 30 in acceptable yield (Scheme 20). In many cases the yield of oxazole was significantly improved by the use of rhodium(II) trifluoroacetamide as catalyst. The 4-cyano-oxazole 30 (R = Me, Z = CN) proved interesting in that it allowed the formation of a bis-oxazole 31 by a second rhodium catalysed reaction (Scheme 20). 

Another Rhn-catalyzed decomposition of a a-diazoester as described by Sabe and coworkers [198] was used for the synthesis of indolizidine alkaloids (Scheme 6/2.8). It can be assumed that, first, an ammonium ylide is formed which then undergoes a 1,2-shift with ring-expansion. Thus, reaction of 6/2-40 with Rh2(OAc)4 led to a 72 28 mixture of 6/2-41 and 6/2-42 in 85 % yield. Cu(acac)2 can also be used with even better yields, but lower selectivity (65 35). 

Rh2(OAc)4-catalyzed decomposition of diazoester 352a results in intramolecular C/S insertion, whereby a quaternary benzylic carbon atom without a heterosubstituent is generated. This transformation was used in a synthesis of ( )-cuparene339a>. 

Some examples of transformations involving carbonyl ylides are listed in Table 4.20. Entry 1 illustrates the conversion of P-acyloxy-a-diazoesters into a-acyloxyacrylates by ring fission of a cyclic carbonyl ylide [978]. This reaction has been used for the synthesis of the natural aldonic acid KDO (3-deoxy-Z)-manno-2-octulosonic acid), which is an essential component of the cell wall lipopolysaccharide of gram-negative bacteria (Figure 4.15). 

A very elegant synthetic approach was reported a year later by Davies et al., leveraging asymmetric C-H activation chemistry to accomplish a one-pot synthesis of d-threo methyiphenidate (Scheme 17.10) (Davies et al., 1999). A-Boc piperidine (33) was selectively alkylated by the carbene formed by decomposition of diazoester 34 in a reaction mediated by 25 mol% of chiral Rh (II) catalyst 35, giving the A-Boc protected (2R,2 R) isomer in a single step. TFA was added to accomplish removal of the Boc group after the C-H insertion reaction was complete, affording (R,R)-methylphenidate (2) with an ee of 86% in 52% overall yield. 

Some examples that illustrate the scope of this transformation are given in Table 8.3 [for further examples, see (368,369)]. Note that this reaction, in contrast to the synthesis of dihydrofurans and furans, is not limited to a-diazoketones as the a-carbonylcarbene moiety concealed in diazoesters also works. 

Intramolecular cyclopropanation using diazoesters is a powerful synthetic tool. Diazoesters are readily prepared from the corresponding alcohol via House s methods56-57. Numerous examples using the application of this transformation in synthesis have been reported. These include the potent synthetic pyrethroid NRDC 182 (22)58, (1 R)-( )-cis-chrysanthemic acid (23)59, the highly strained bicyclic system 2460, antheridic acid 2561,62 and cycloheptadiene 26 (equations 33-37). 

Essentially all of the early studies were directed towards enantioselective cyclopropanation and Maas has reviewed the literature up to 198 54. The most successful of these early studies were those of Aratani and coworkers"2 174 who developed chiral copper(II) chelates of type 153 from salicylaldehyde and optically active amino alcohols with which to catalyse intermolecular cyclopropanation with diazoesters. Enantioselectivities exceeding 90% ee could be achieved in selected cases (equations 133 and 134) including the synthesis of permethrinic acid 154 and /ram-chrysanthemic acid 155. 

Dichlorocarbene is a typical singlet ground-state carbene which is commonly used for cydopropanation reactions, since it gives satisfactory yields in many cases, but in general, carbene synthesis implies a metal catalyst (usually copper) together with a diazo compound as the carbene precursor. In (he particular case of the O -H insertion reaction, sulfur dioxide has been reported as being an efficient catalyst for the insertion of carbalkoxycarbenes generated from diazoesters. 

In the search for more efficient catalyst systems for diazoester additions several groups" "" have employed rhodium(II) acetate. Transition metal complexes have been widely used in cyclopropane synthesis but copper(I) triflate and palladium(II) acetate are ineffective for substituted ethenes. Rhodium(II) carboxylates have been shown" to... 

Practical applications include the synthesis of rran5-2-phenylcyclopropanamine (trade name tranylcypromine), an antidepressant acting as a monoamine oxidase inhibitor [20 a], of 2,2-dimethylcyclopropane carboxylate from isobutene [20 b], a key step in the commercial production of cilastatin, 3 (eq. (4)), and of esters of chrysanthemic acid 4 (using the methylene bis(diphenyloxazoline) 5) [ 17, 21 ] (eq. (5)). Cilastatin is a dehydropeptidase which acts as an in vivo stabilizer of the car-bapenem antibiotic imipenem with achiral diazoesters. 

The need to prepare fullerene derivatives for possible applications to medicine and material sciences resulted in the development of novel synthetic methods for the functionalization of Cso. R. Pellicciari et al. reacted Ceo with carboalkoxycarbenoids generated by the Rh2(OAc)4-catalyzed decomposition of a-diazoester precursors. This reaction was the first example of a transition metal carbenoid reacting with a fullerene and the observed yields and product ratios were better than those obtained by previously reported methods. The reaction conditions were mild and the specificity was high for the synthesis of carboalkoxy-substituted[6,6]-methanofullerenes. When the same reaction was carried out thermally, the rearranged product (the [6,5]-open fullerene) was the major product. 

The asymmetric insertion of a-diazoesters into the O—H bond of water provides an extremely simple approach for the synthesis of chiral a-hydroxyesters in an efficient and atom-economical way. The challenges of asymmetric O—H insertion of water are mainly attributed to two considerations first, the active metal carbene intermediates are generally sensitive to water and secondly, the small molecular structure of water makes chiral discrimination quite difficult. Zhou and co-workers discovered a highly enantioselective O—H insertion of water catalyzed by chiral spiro Cu [112] and Fe catalysts [111]. Under mild conditions, both Cu andFe complexes of ligand (S, 5,5)-23a... 

The direct transfer of carbene from diazocompounds to olefins catalyzed by transition metals is the most straightforward synthesis of cyclopropanes [3,4]. Reactions of diazoesters with olefins have been studied using complexes of several transition metals as catalysts. In most cases trans-isomers are preferably obtained, but the selectivity depends on the nature of the complex. In general the highest trans-selectivity is obtained with copper catalysts and it is reduced with palladium and rhodium complexes. Therefore, the rhodium mesotetraphenylporphyrin (RhTPPI) [5] and [(r 5-C5H5)Fe(CO)2(THF)]BF4 [6] are the only catalysts leading to a preference for the cis-isomer in the reaction of ethyl diazoacetate with styrene. 

Diazo compounds, most commonly diazoesters or diazoketones, are the reagents of choice for metal-catalyzed cyclopropanation of alkenes (Eq. 1) [31]. Of the two, diazoesters, and particularly ethyl diazoacetate (EDA), are the more frequently used in synthesis. 

The consistency of the high levels of enantiocontrol accessible in these diazoester cyclizations is underpinned by their growing applications in enantiose-lective synthesis of bioactive molecules containing cyclopropane units. Notable examples include the preparation of multifunctional cyclopropanes as peptide isosteres for renin inhibitors (Scheme 4) [42] presqualene alcohol from farnesyl diazoacetate (Scheme 5) [43] the GABA analogue 3-azabicyclo[3.1.0]hexan-2-one from N-allyldiazoacetamide, Eq. (26) [23] and precursors of lR,3S)-cis-chrysanthemic acid and the pheromone, E-(-)-dictyopterene C (Scheme 6) [44, 45],... 

Examples of enantioselective intramolecular C-H insertion reactions of diazoacetamides are known and though less extensive than those with diazoester substrates, there already are indications that excellent levels of stereocontrol are attainable. It is very likely that catalyst development will extend further the scope of this approach to the enantioselective synthesis of iY-heterocycles. 

Ducept and Marsden described a general synthesis of 5-ethoxy-2-substituted 4-(triethylsilyl)oxazoles 176 from the rhodium(II)octanoate-catalyzed diazo-transfer reaction of ethyl (triethylsilyl)diazoacetate 175 and nitriles (Scheme 1.48). The reaction conditions tolerate a wide variety of functional groups on the nitrile, including alkyl, aryl, heteroaryl, vinyl, carbonyl, sUyloxy, and dialkylamino. Desilylation of 176 with TBAF afforded the corresponding 2-alkyl(aryl)-5-ethoxy-oxazoles 177, which are normally inaccessible from diazoesters using conventional rhodium-carbene methodology. The authors noted that carbonyl groups in the 2 position of 176 are not compatible with TBAF deprotection. 

Lewis acids efficiently catalyze the transfer of diazoketones and diazoesters to amides and nitriles to furnish 2,4,5-trisubstimted oxazoles (Scheme 1.49). In particular, Eguchi and co-workers found that BF3 OEt2 was the best catalyst for reaction of the adamantyl diazoketoester 180 with acetonitrile. Attempts to prepare 181 using Rh(II)acetate or photolysis were unsuccessful. Similarly, Ibata and Isogami °° described a general synthesis of 5-aryl-2-(chloromethyl)oxazoles 183 from a BF3.0Et2-catalyzed addition of a-diazoacetophenones 182 with chloro-acetonitrile. The yields were quite respectable (Table 1.12). 

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