Esperamicin synthesis

The use of vinylallenes as the diene component in Diels-Alder reactions is very common, thus resulting in their ubiquitous use in natural product synthesis. A vinylal-lene has even been proposed by Schreiber and Kiessling [10] as a biogenetic intermediate in the synthesis of the skeleton of esperamicin A (32 —> 33). Their synthetic approach to esperamicin A (34) was modeled after this biogenetic proposal in which a Type II intramolecular Diels-Alder cycloaddition was used to gain access to the highly unsaturated bicyclic core of 34 (Scheme 19.8) [10]. 

The availability of ctetq) advanced synthons that carry the required chirality is an advantage, particularly in projects aimed at industrial total synthesis. Natural products are often used as synthons, ideally fi om a renewable source, such as microbial fermentations. In a few cases, biotechnology has become an ahemative source. The total theses of the antitumor agent esperamicin A and the immunosuppressant FK-506 are exanq>les. In both cases, the synthon was quinic acid (Barco 1997), cheaply obtained by biotechnology (Chapter 14.1.e) rather than fi om the environmentally noxious extraction fi om the bark of Cinchona spp. Used to build up combinatorial libraries, quinic acid has gained further inq)ortance in organic thesis (Phoon 1999). 

In the synthesis of analogues of calicheamicin 71 and esperamicin Ajb, Moutel and Prandi employed the glycosyla-tion of a nitrone with a trichloroacetimidate as a key step - /3-N-O glycosidic bond formation. Preparation of the nitrone begins with the alkylation of the known alcohol 69 <1992CC1494> with 1,4-dibromobutane in the presence of sodium hydride. Subsequent aminoalkylation, amine protection with 9-fluorenylmethoxycarbonyl (Fmoc), and reduction with NaBHsCN were followed by nitrone 70 formation with 4-methoxybenzaldehyde (Scheme 8) <2001J(P1)305>. 

In the studies on the synthesis of the antitumor agents esperamicin and calicheamicin by Magnus et al. [93], an aldol reaction was found suitable for macrocyclization after a number of unsuccessful attempts. Thus, as shown in Scheme 54, the diynene core structure (165) of the two antitumor agents was synthesized from the dicobalt hexacarbonyl derivative 163. When 163 was treated with n-BujBOTf/DABCO/EtjN in CHzClj-THF the aldol product 164 was isolated as a single stereoisomer in 45% yield. Although alkynyl aldehydes undergo similar crossed aldol condensation, their dicobalt hexacarbonyl derivatives react with moderate to excellent syn diastereoselectivity [94]. 

In the synthesis of the core structure of the diynene antitumor antibiotics esperamicins and calicheamicins by Danishefsky et al. [108], an acetylene-aldehyde coupling reaction was used to achieve the cyclization. As shown in Scheme 60, reaction of a toluene solution of acetylene aldehyde 182 with potassium hexame-thyldisilazide at —78 °C for 20 min afforded a 52% yield of a 10 1 ratio of 183 and 184. 

Prabhakaran, J. Lhermitte, H. Das, J. Sasi-Kumar, T.K. Grierson, D.S. The synthesis of a sulfone containing analogue of the esperamicin-A(l) aglycone A hetero Diels-Alder approach. Synlett 2000, 658-662. 

Magnus, P. Carter, P. Elliott, J. Lewis, R. Harling, J. Pittema, T. Bauta, W. E. Fortt, S. Synthetic and mechanistic studies on the antitumor antibiotics esperamicin Al and calicheamicin yj- synthesis of 2-ketobicyclo[7.3.1] enediyne and 13-ketocyclo[7.3.1] enediyne cores mediated by 17-2 dicobalt hexacarbonyl alkyne complexes cycloaromatization rate studies. J. Am. Chem. Soc. 1992, 114, 2544-2559. 

Mastalerz, H. Doyle, T.W. Kadow, J.F. Vyas, D.M. Synthesis of an esperamicin core analog with an epoxide trigger. Tetrahedron Lett. 1996, 37, 8683-8686. 

Magnus, P., Lewis, R.T., and Bennett, E, Synthesis of the esperamicin Aj/calicheamicin y-trisulphide functionaUty. Thermal stability and reduction, 7. Chem. Soc., Chem. Commun., 916, 1989. 

Scheme 7-58 Synthesis of esperamicin Aj sugar fragment 279 (Nicolaou et al.).

Scheme 7-60 Synthesis of the esperamicin A, trisaccharide 288 (Danishefsky and co-workers). (PMB, p-methoxybenzyl TEOC, 2-(trimethylsilyl)ethoxycarbonyl).

Scheme 7-62 The Kahne synthesis of the calicheamicin/esperamicin core trisaccharide fragment 300.

F. Badalassi, P. Crotti, L. Favero, F. Macchia, and M. Pineschi, Improved stereoselective synthesis of both methyl a- and P-glycosides corresponding to the amino sugar component of the E ring of calicheamicin gll and esperamicin Al, Tetrahedron, 53 (1997) 14369-14380. 

Danishefsky SJ, Halcomb RL (1991) The synthesis of the core trisaccharide of esperamicin corroboration of the proposed structure for its rearrangement product and stabilization of the core trisaccharide domain. J Am Chem Soc 113 5080-5802... 

Scheme 18.21 Regioselective f2.31 rearrangement of bis-allylic sulfoxide 87 in synthesis of esperamicin sugar.—...

DNA cleavage (mimic of esperamicin) [89]. The related diradical mechanism was operated in the photoannulation reaction of 2-aryl-3-isopropoxy-l,4-naphthoquinone available from 5 (R = i-Pr) and was fruitful in synthesis of dimethylnaphthogeranine E [90]. 

Alkyne- Co2(CO)6) complexes for application in the Pauson-JChand cyclopentenone synthesis have been prepared in simple and convenient fashion by reduction of cobalt bromide by zinc in the presence of alkynes under carbon monoxide. An intramolecular Pauson-Khand reaction has been used 172 to incorporate the proper stereochemistry at the C/D/E rings of Xestobergsterol D. The use of Co2(CO)6l-alkyne complexes as stable intermediates for the construction of the core structures of the anti-tumor enediyne agents esperamicin, calicbeamicin, dynemicin and neocarzinostatin has been reviewe(H73,... 

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