Dibenzyl azodicarboxylate

Preparation of 7-(N,N -Dicarbobenzyloxyhydrazino)-6-Demethyttetracydine A 1.0 g portion of O-demethyltetracycline was dissolved in a mixture of 9.6 ml of tetrahydrofuran and 10.4 ml of methanesulfonic acid at -10°C. The mixture was allowed to warm to 0°C. A solution of 0.86 g of dibenzyl azodicarboxylate in 0.5 ml of tetrahydrofuran was added dropwise and the mixture was stirred for 2 hours while the temperature was maintained at 0°C. The reaction mixture was added to ether. The product was filtered off, washed with ether and then dried. The 7-(N,N -dicarbobenzyloxyhydrazino)-6-demethyltetracycline was identified by paper chromatography. 

DBAD = di-terf-butyl azodicarboxylate CbzN = NCbz = dibenzyl azodicarboxylate... 

Dihydrooxadiazines can be made in related fashion and they too offer novel access to important products. For example, the (9-silylated D-glucal 70, irradiated at 350 nm in cyclohexane with dibenzyl azodicarboxylate, affords adduct 74 in 71% yield,74 and this with an acid catalyst can be used as a glycosylating agent to make /J-linked 2-amino-2-deoxy-D-glucosides.75 This chemistry also is applicable to furanoid glycals.74 Scheme 6 outlines the regio- and stereoselectivities of these cycloaddition reactions and their applications in synthetically useful processes. 

Barbas and colleagues have applied the organocatalytic direct amination of aldehydes in a series of reports [7]. By combining acetone, various aldehydes, dibenzyl azodicarboxylate and i-proline as the catalyst, a one-pot synthesis of functionalized /Tamino alcohols was achieved [7a]. The scope of the reaction was found to be quite general for various aldehydes, and the optically active / -amino alcohols were obtained in high yields with low diastereoselective control. However, excellent enantioselectivity of especially the anti-adduct was obtained. 

The same authors have shown that the direct a-amination reaction could also be used to construct the quaternary stereocenter in the enantioselective total synthesis of the cell-adhesion inhibitor BIRT-377 [7b]. The i-proline-derived tetrazole 3c catalyzed the direct a-amination of 3-(4-bromophenyl)-2-methylpropanal 8 with dibenzyl azodicarboxylate 2b to give the amino aldehyde 9 in 95% yield and with... 

The [4 + 2] cycloaddition reaction of dibenzyl azodicarboxylate and glycals allows the stereoselective introduction of an amino group at the C-2 of a carbohydrate, the key step in the reaction is shown in Equation (1) <89JA2295>. The nature of the products was determined by x-ray crystallography NMR and IR data proved insufficient as the two possible products from [4 4- 2] and [2 + 2] addition are so similar. X-ray analysis confirmed that the reaction of diethyl azodicarboxylate with cyclopropylfuran gives compound (4), by a [4 4- 2] addition, in 94% yield. Further comparison of the NMR and IR data for all the adducts with spectral data of compound (4) confirmed that [4 + 2] adducts were formed consistently. 

The double bond in glycals such as (35) contribute two atoms in a photochemical [4 + 2] cycloaddition reaction with dibenzyl azodicarboxylate (Equation (9)). The adducts so formed are useful intermediates in the preparation of carbohydrates with an amino function at the C-2 position... 

Direct Asymmetric a-Amination Reaction of 2-Keto Esters. The cir-DiPh-Box copper complex catalyzes highly enantioselective direct a-amination reaction of 2-keto esters with dialkyl azodicarboxylates and thus provides convenient access to optically active jyn-3-amino-a-hydroxy esters (eq 2). This enantioselective, direct a-amination is applicable to a range of 2-keto esters when dibenzyl azodicarboxylate is used as the nitrogen source. The immediate product of the amination reaction is prone to racemization. Stereoselective reduction of the keto functionality by L-selectride enables further synthetic operations to be carried out without loss of enantiopurity. 

Catalytic asymmetric construction of nitrogen-substituted quaternary stereocenter has been another important and challenging task in asymmetric synthesis. The first a-amination using cinchona alkaloids was shown in 1,3-dicarbonyl substrate systems. In 2004, Pihko and coworkers showed enantioselective a-amination of cyclic fi-ketoesters 130, with dibenzyl azodicarboxylate (131) in the presence of... 

S )-Dibenzyl l-(l-Oxo-l,2,3,4-tetrahydronaphthalen-2-yl)hydrazine-l,2-dicarboxylate (Catalyzed Asymmetric Amination of a Ketone Silyl Enol Ether with an Azo Ester).244 A solution of silver perchlorate (0.040 mmol) and (R)-BINAP (0.048 mmol, 12 mol%) in THF (1 mL) was stirred at room temperature for 30 minutes, cooled to —45°, and treated with dibenzyl azodicarboxylate (0.44 mmol). After stirring for 10 minutes, (3,4-dihydronaphthalen-l-yloxy)trimethylsilane (0.4 mmol) in THF (0.5 mL) was added and the mixture was stirred at —45° for 5 hours. Aqueous HF (20%) and THF (1 1) were added and the mixture was stirred at room temperature for one hour after which time it was made basic with aqueous NaHCC>3 solution and extracted with CH2CI2. 

Cyclohexanone and related cyclic ketones generally gave poor results with L-proline catalyst. L-Azetidinone carboxyhc acid catalyst (4) showed improved enantioselectivities (88-90% ee. Table 11.2) for the a-amination of cyclohexanone with DEAD or dibenzyl azodicarboxylate (DEAD) [13]. The benzimidazole-pyrrolidine (EIP) catalyst 5 was comparable to L-proUne in terms of enantioselectivity with cyclohexanone and l-silacyclohexa-4-one as substrates [14]. In a comparison between the efficiencies of L-proUne and 4-silyloxyproline 6 in the a-amination of cyclohexanone and derivatives, catalyst 6 provided higher yields and enantioselectivities [15]. 

Figure 1. The (4+2) cycloaddition reaction of dibenzyl azodicarboxylate with glycals.

Finally, the first total syntheses of two cemuane-type Lycopodium alkaloids, ( )-cernuine and (+)-cermizine D, reported by Takayama et al., included as a key step a L-proline-catalysed amination of an aldehyde derived from (+)-citronellal. As shown in Scheme 4.4, this amination performed with dibenzyl azodicarboxylate, followed by an in-situ reduction with NaBH4 and treatment of the resulting mixture with K2CO3, furnished the expected oxazolidinone in a high yield and a good diastereoselectivity. 

Full details have been published on the [4+2]cyclo-addition of dibenzyl azodicarboxylate to O-silylated glycals, and the conversion of the adducts to 1,2-trans-related 2-amino-2-deoxy-glycosides by reaction with alcohol in the presence of an acid catalyst (c Vol.22, p.97). By using bis(trichloroethyl) azodicarboi late, this route has now been extended for use with acetylated... 

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