Fukuyama reaction

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... 

The reaction of thioesters in the presence of nonpyrophoric Pd(OH)2/C (Pearlman s catalyst) with various functionalized organozinc halides such as 457 leads to functionalized unsynunetrical ketones such as 458 in high yields (Fukuyama reaction. Scheme 2-139, eq. (a)). This catalyst can also be used for Sonogashira and Suzuki reactions. Thus, the Ni(acac)2-catalyzed cross-coupling of a functionalized zinc reagent 457 with various thioesters like 459 provides under mild conditions the desired acylation... 

Until now, the most efficient approach to synthesize Freidinger lactams 147 started from a resin-bound cinnamylamine 144. A Fukuyama-Mitsunobu reaction to 145 followed by sulfonamide cleavage and a consecutive appropriate acylation built up the diene 146, which underwent ring-closing metathesis involving Grubb s catalyst 123 to generate the desired lactams 147 (Scheme 27, Table 5) [35d]. 

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...

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. 

Fukuyama employed a vinyltin derivative in the carbonylation of 3-carbomethoxymethyl-2-iodoindole to afford 320 [176]. Buchwald effected the carbonylation of 4-iodoindole 321 to give lactam 322 [136], and a similar carbonylation reaction on 4-iodoindole malonate 125 gives ketone 323 in 68% yield. 

Many pyridine-indole compounds are biologically active. A growing number of methods for the preparation of indolylstannanes have been developed. 2-Trialkylstannylindoles, for example, have been synthesized via directed metalation followed by reaction with tin chloride [91-93]. The latest indolylstannane syntheses include Fukuyama s free radical approach to 2-trialkylstannylindoles from novel isonitrile-alkenes [94], and its extension to an isonitrile-alkyne cascade [95]. Assisted by the chelating effect of the SEM group oxygen atom, direct metalation of 1-SEM-indole and transmetalation with BujSnCl afforded 2-(tributylstannyl)-l//-indole 108, which was then coupled with 2,6-dibromopyridine to give adduct 109. 

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). 

Hatakeyama, S., K. Izumi, T. Fukuyama, H. Akimoto, and N. Washida, Reactions of OH with a-Pinene and /3-Pinene in Air Estimate of Global CO Production from the Atmospheric Oxidation of Terpenes, J. Geophys. Res., 96, 947-958 (1991). 

Fukuyama, Y., Y. Kiriyama, and M. Kodama. 1993. Concise synthesis of belamcan-daquinones A and by palladium (0) catalyzed cross-coupling reaction of bromo-quinone with arylboronic acids. Tetrahedron Lett. 34 7637-7638. 

The first synthesis of optically pure N-methylated derivatives of Ala, Leu, Phe, and Tyr was published by Fischer and Lipschitz in 1915 73 using the sulfonamide method. Two main developments have ensured that this method remains useful for the preparation of TV-alkyl amino acids both in solution and solid phase (1) the introduction of the Mitsunobu reaction for the alkylation step and (2) the introduction of replacements for Tos (such as the Fukuyama Nbs) that allow easy removal of the sulfonamide protecting group after the alkylation step. Sulfonamide-protected amino acid derivatives can be alkylated in two different ways. Because of the acidity of the sulfonamide hydrogen it is possible to introduce the N-substituent either by direct alkylation (e.g., alkyl halides) or by the Mitsunobu reaction 74 (Scheme 4). 

Synthesis of Fmoc-(Me)Xaa1-OH by On-Resin Methylation Using the Fukuyama/Mitsunobu Reactions General Procedure 92 ... 

A palladium-catalysed reduction of ethyl thiolesters to aldehydes with triethylsilane has been proposed by Fukuyama [2611. The reaction, coupled with a mild conversion of carboxylic acids to thiolesters (see [261], footnote 2), affords a versatile method for the overall transformation of... 

Specific ester substrates are also hydrolyzed with carboxypeptidase A. For instance, Makinen, Fukuyama, and Kuo (27) have recently studied the enzymic hydrolysis of 0-(trans-p-ch1orocinnamoyl)-L-B-phenyl actate (CICPI.) (47),and the spin labeled nitroxide ester substrate 0-3-(2,2,5,5-tetramethylpyrrol-inyl-l-oxyl)-propen-2-oyl-L-B-phenyllactate (TEPOPL) (48). They have shown that these reactions take place via the formation of a covalent intermediate (the mixed anhydride) which can be isolated under subzero temperature conditions. The hydrolysis of CICPL and TEPOPL catalyzed by carboxypeptidase A is consequently governed by the rate-limiting breaking of the acyl-enzyme. 

Ecteinascidin 743 262 (Scheme 12.37) represents a powerful antitumor agent, which has been submitted to clinical trial. This complex polyazacydic, polyaromatic compound was isolated from the marine tunicate, Ecteinascidia turbinate [131]. A total synthesis of this natural product, which featured an Ugi four-component reaction as pivotal step, was recently reported by Fukuyama and co-workers [132]. The highly decorated phenylglycinol 263 was obtained via an asymmetric Mannich-type reaction [133], and was engaged in a multicomponent condensation process involving the protected amino acid 264, p-methoxyphenyl isocyanide 265 and acetaldehyde to afford dipeptide 266 in high yield. This com-... 

Although the asymmetric total syntheses developed by Nicolaou and by Shair provide easy routes to enantiomerically pure CP compounds, the target molecules (+)-CP-263,114 (ent-1) and (—)-CP-225,917 (ent-2) are only the enantiomers of the natural occurring phomoidrides. After the establishment of the absolute configuration of the CP molecules by chemical synthesis, the focus of synthetic interest is the asymmetric total syntheses of (—)-CP-263,114 (1) and (-l-)-CP-225,917 (2). The first total synthesis furnishing (—)-CP-263,114 (1) as the correct enantiomer has recently been reported by Fukuyama et al. [23]. As the stereoselectivitydetermining step, an intramolecular Diels-Alder reaction was chosen, similar to that in Nicolaou s synthesis (Figure 11). The Diels-Alder precursor 42 is prepared in four easy... 

Utilizing a commercially available microreactor, fabricated from FOR-TURAN glass, Fukuyama et al. (2004) evaluated a series of [2 + 2] cycloadditions as a means of reducing the reaction times conventionally associated with the synthetic transformation (Table 27). Using a high-pressure mercury lamp (300 W), the reaction of cyclohex-2-eneone 179 with vinyl acetate 168 (Scheme 51), to afford the cycloadduct 180, was used to compare photochemical efficiency within the microreactor [1,000 pm (wide) x 500 pm (deep)] and a conventional batch reactor (10 ml). 

Fukuyama, Ryu and coworkers reported intermolecular [2 + 2]-type cycloaddition of various cyclohexenone derivatives and alkenes using a micro reactor made entirely of glass, which was supplied by Mikroglas (Scheme 4.26) [39]. The device was equipped with a heat exchanger channel system through which water flowed to maintain isothermal reaction conditions. The remarkable photochemical efficiency of this device was manifested in rapid cycloaddition of vinyl acetate to cyclohex-2-enone. With this device, the desired product was obtained in 88% yield after 2 h, whereas the same reaction carried out in a Pyrex flask was very sluggish (only 8%... 

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