Fukuyama synthesis

From ortho-Isocyano-Styrenes The Fukuyama Synthesis ... 

From ortho-isocyano styrenes The Fukuyama synthesis ... 

The Fukuyama synthesis commenced with the copper-catalyzed asymmetric reduction of butenolide 26 to give lactone 27 in 98% enantiomeric excess (Scheme 9). Sequential alkylation with CbzCl followed by methyl acrylate provided lactone 28 and installed both of the required contiguous stereocenters. The key Curtius rearrangement was performed by conversion of the benzyl ester to the acyl azide followed by heating. Subsequent treatment with aqueous HCI provided cyclized lactam 8. This compound was then dibromi-nated to lactam 29 using bromine, ZnCl2, and formic acid, which were the only conditions that were able to introduce the orf/to-bromine. The fully elaborated aromatic compound 29 was treated with methylamine followed by PDC to obtain cyclic A -methylimide 23. 

In a versatile stereocontrolled total synthesis of (+)-vinblastine, Fukuyama used a base-promoted macrocyclization of the N-nosylate and the terminal epoxide moiety present in 88 as one of the key steps, giving the 11-membered-ring product 89 in 82% yield (Scheme 8.23) [42],... 

The two alkaloids vinblastine and vincristine found in Catharanthus roseus have been recent targets of total synthesis because of their potency in cancer chemotherapy. The reduced tree diagram for the Fukuyama plan to vincristine is shown in Figure 4.66. There are three points of convergence, four branches leading to the target product and four tiers of reaction yields. 

Tables 4.32 and 4.33 summarize the metrics for the synthesis plans for both products. The Fukuyama plans to both targets are very similar differing only in the very late stages of each plan. The Kuehne plan to vinblastine is considerably shorter than the Fukuyama one since it uses (—) -vindoline as an available starting material in stage 11. This explains why its overall kernel RME is 17 times larger than that of the Fukuyama plan. For a more fair comparison, if the upper two branches leading to (—)-vindoline are omitted from the Fukuyama plan, the number of stages remain the same at 27 but the number of reactions and inputs decreases to 29 and 47, respectively. These changes result in an increase in overall kernel RME from 0.3% to 0.5% but it is still an order of magnitude less than that determined for the Kuehne...

Figure 4.66 Reduced synthesis tree for synthesis of vincristine by Fukuyama method. Step counts are shown in parantheses.

Kaburagi, Y, Tokuyama, H., Fukuyama, T. (2004) Total Synthesis of (—)-Strychnine. Journal of the American Chemical Society, 126, 10246-10247. 

Tin-mediated-radical cyclization of isonitriles provides a useful strategy for the preparation of indoles (Fukuyama reaction).90 This radical cyclization is used for synthesis of 6-hydroxy-indole-3-acetic acid, which is the aromatic subunit of Nephilatoxin. The requisite isonitriles are prepared from nitroarenes via amines (Eq. 10.66).91... 

Very many naturally occurring 3-alkyl- or 3-acylfurans are now routinely synthesized by preparing a substrate for treatment with 3-furyllithium, itself made from 3-bromofuran according to Fukuyama, Tokoroyama, and Kubota, who used it to obtain pyroangensolide and fraxinellone.212 Equally, 2-lithiofuran is used for such natural products as the acetylenic furans from Alphonsea ventricosa213 and other compounds.214 For the synthesis of the sesquiterpenoid sponge-metabolite pleraplysillin-2 78, the lithiofuran 79 and therefore the bromofuran 80 was needed to secure the orientation a suitable preparation was devised for 80.215... 

The Fukuyama indole synthesis involving radical cyclization of 2-alkenylisocyanides was extended by the author to allow preparation of2,3-disubstituted derivatives <00S429>. In this process, radical cyclization of 2-isocyanocinnamate (119) yields the 2-stannylindole 120, which upon treatment with iodine is converted into the 2-iodoindole 121. These N-unprotected 2-iodoindoles can then undergo a variety of palladium-catalyzed coupling reactions such as reaction with terminal acetylenes, terminal olefins, carbonylation and Suzuki coupling with phenyl borate to furnish the corresponding 2,3-disubstituted indoles. 

Tokuyama H, Kuboyama T, Amano A, Yamashita T, Fukuyama T. Synthesis 2000 1299-1304. 

The potential power of Fukuyama s method is illustrated by the synthesis of biindolyl 168 which was used in a synthesis of indolocarbazoles [176]. The isonitriles (e.g., 167) are generally prepared by dehydration of the corresponding formamides with POCI3. 

Rikimaru K, Yanagisawa A, Kan T, Fukuyama T (2004) A versatile synthesis of a-amino acid derivatives via the ugi four-component condensation with a novel convertible isonitrile. Synlett 1 41-44... 

Scheme 1 Ugi reaction as a central step in the total synthesis of Ecteinascidin 743 by Fukuyama et al.

Recently, the piperazine intermediate 15 for the total synthesis of (—)-lemon-omycin (9) was reported by Fukuyama et al. [14], (—)-Lemonomycin possesses interesting antibiotic activity against methiciUin-resistant Staphylococcus aureus and vancomycin-resistant Enterococcus faecium, as well as cytotoxicity against the human colon tumor cell line HCT-116 [15]. The reaction of 2-isocyanoethyl phenyl carbonate 11 gave Ugi product 14, which was further transformed to a piperazine intermediate 15 (Scheme 2). 

Fukuyama and Yang (49) developed a highly efficient synthesis of the tetracyclic intermediate 241, used in a total synthesis of mitomycin A (Scheme 9.49). The required azide 240 was produced from 239 in several steps. Upon heating in refluxing toluene, the azide 240 underwent smooth intramolecular cycloaddition with the unsaturated lactone followed by extrusion of nitrogen to give aziridine 241 in 85% yield. 

A strategy similar to that described above has been used for the total synthesis of saframycin A by Fukuyama and co-workers (90JA3712, 90TL5989). The aldol condensation has been extensively used in the synthesis of bicyclomycin (85JA3253 83TL5627), neoechinulin A(80TL2817), etc. The X-ray structure and photoelectron spectra of cyclo(dehydro-Ala)2 have been determined (85T2015). 

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