Total synthesis of (±)-fredericamycin A. Use of radical spirocyclization

Clive, Derrick L. J.; Tao, Yong; Khodabocus, Ahmad; Wu, Yong‐Jin; Angoh, A. G.; Bennett, Stephanie; Boddy, Christopher N.; Bordeleau, Luc; Kellner, Dorit; Kleiner, G. I.; Middleton, Donald S.; Nichols, Christopher J.; Richardson, S. R.; Vernon, Peter G.

doi:10.1039/c39920001489

Cited by 30 publications

(21 citation statements)

References 27 publications

Supporting

Mentioning

Contrasting

Unclassified

Order By: Relevance

“…[30] The asymmetric total synthesis of natural 1: Based on the promising results obtained during the synthesis of the DEring analogues, we restarted our studies towards the asymmetric total synthesis of natural 1 (Scheme 10). Thus, (R)-8 (95 % ee) was treated with 33 (1.0 equiv), 34 (4 equiv), and LiN(TMS) 2 (2.0 equiv) in THF at À78 8C for 1-1.5 h. Quenching the reaction mixture at the same temperature with an aqueous solution of NH 4 Cl provided a separable mixture of (8R)-35 a [28] and its diastereomer (8R)-35 b. [28] This reaction was found to be reproducible, producing 35 a and 35 b in a ratio of 19-21:1.…”

Section: Resultsmentioning

confidence: 99%

“…Thus, (R)-25 (90 % ee) was treated with lithium phenylthioacetylide at À78 8C for 30 min to ensure complete consumption of (R)-25; then the reaction mixture was warmed to the temperature indicated in Table 1 and stirred for a further 30 min before being quenched with an aqueous solution of NH 4 Cl. The results of these experiments (Table 1) provided us with useful information about the relation of the quenching temperature to both the optical purity and the diastereoselectivity of the products: In the range from À60 to À20 8C, partial racemization and/or isomerization took place to give a mixture of (1R)-39 a [28] and (1R)-39 b [28] (entries 2-6).…”

Section: Resultsmentioning

confidence: 99%

“…A mixture of 27 (96 mg), KOH (2 n, 0.13 mL), MeOH (1.3 mL), and CH 2 Cl 2 (0.80 mL) was stirred at 0 8C for 5 h. After this time, the reaction mixture was quenched with saturated aqueous NH 4 Cl, and the product extracted with EtOAc. The combined organic layers were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo.…”

Section: Hydrolysis Of 27mentioning

confidence: 99%

“…(R)-8-Acetyl-8-formyl-1,9-dimethoxy-3-methyl-6,7-dihydro-8H-cyclopenta[g]isoquinoline ((R)-8): Under a nitrogen atmosphere, DMSO (0.94 mL, 11.8 mmol) was added to a solution of oxalyl chloride (0.56 mL, 5.9 mmol) in anhydrous CH 2 Cl 2 (3.0 mL), and the reaction mixture was stirred at À78 8C for 1 h. After this time, a solution of (R)-32 (160 mg, 0.49 mmol) in anhydrous CH 2 Cl 2 (3.0 mL) was added at À78 8C, and the reaction mixture was stirred for 2 h. Finally, Et 3 N (2.8 mL, 17.6 mmol) was added at À78 8C, and the reaction mixture was warmed to RT and stirred for a further 45 min. The reaction mixture was then quenched with saturated aqueous NH 4 Cl, and the product was extracted with CH 2 Cl 2 . The combined organic layers were washed with brine, dried (Na 2 SO 4 ), and concentrated in vacuo.…”

Section: Hydrolysis Of 27mentioning

confidence: 99%

“…These studies have, thus far, resulted in five total syntheses of racemic 1, [3][4][5][6][7] and the first synthesis of the optically pure natural 1. [8,9] The last accomplishment by Bogers group in this area required the optical resolution of a fully protected racemic compound by using a chiral HPLC column at the final stage, and therefore the absolute configuration of 1 was not determined by this group.…”

Section: Introductionmentioning

confidence: 99%

See 4 more Smart Citations

Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

Akai

Tsujino

Fukuda

et al. 2005

Chemistry A European J

View full text Add to dashboard Cite

The asymmetric total synthesis of the potent antitumor antibiotic fredericamycin A ((S)-1) was achieved by the intramolecular [4+2] cycloaddition of the silylene-protected styrene derivative (S)-7 followed by the aromatic Pummerer-type reaction of the sulfoxide (S)-5. Although we had already succeeded in the total synthesis of racemic 1 by the same approach, synthesis of its asymmetric version was more complicated than we had expected due to the difficulties involved in constructing the quaternary carbon center and the tendency of this center to undergo facile racemization. Racemization of this center during the installation of the acetylene moiety on the dione (R)-8 was the most serious aspect. Systematic studies of its DE-ring analogue (R)-25 revealed that racemization of the quaternary carbon center proceeded by a retro-aldol-aldol reaction of the initial adduct, (1R)-39 a-Li, and that the degree of racemization was dependent on the reaction temperature. The racemization process could be completely depressed by keeping the reaction temperature at -78 degrees C. The construction of the stereogenic quaternary carbon center was achieved by the lipase-catalyzed desymmetrization of the prochiral 1,3-diol 9 a bearing the DEF-ring moiety. These studies enabled us to attain the asymmetric total synthesis of (S)-1 while completely retaining the chiral integrity created by the enzymatic reactions.

show abstract

Section: Resultsmentioning

confidence: 99%

Section: Resultsmentioning

confidence: 99%

Section: Hydrolysis Of 27mentioning

confidence: 99%

Section: Hydrolysis Of 27mentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 3 more Smart Citations

Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

Akai

Tsujino

Fukuda

et al. 2005

Chemistry A European J

View full text Add to dashboard Cite

show abstract

Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

Clark¹,

Jahangir²

1995

Organic Reactions

View full text Add to dashboard Cite

Heteroatom‐facilitated lithiation reactions have assumed an increasingly important role in the elaboration of carbocyclic aromatic and heteroaromatic systems in the 40 years subsequent to the seminal review on metalation with organolithium reagents by Gilman and Morton. Of particular note has been the development of methodology for the lateral lithiation of alkyl‐substituted aromatic systems promoted by an extensive array of heteroatomic substituents. These lithiations involve deprotonation at a benzylic (side chain) position that is lateral to, or flanked by, a heteroatom‐containing substituent (G); this substituent facilitates lithiation relative to the parent system in which G is not present. The derived lithiated species have great synthetic utility for functionalization of benzylic sites, for chain extensions, and for the synthesis of fused carbocyclic and heterocyclic systems via annelation processes. This chapter summarizes the significant amount of work reported on heteroatom‐facilitated lateral lithiations and the synthetic applications thereof. The survey covers the substituents that promote these reactions, and the methods of formation, stability, reactivity, and synthetic utility of the lithiated species. Coverage is limited to examples in which the R 1 group in the representative equation is hydrogen (toluene derivatives), alkyl, or aryl. Examples that would be better classified as alpha ‐lithiations are not covered, for example, where R 1 is an anion‐stabilizing group such as cyano, carboxy, and so on. Rare examples of lithiations of alkyl groups that are meta or para to the facilitating group G are included in the chapter, although these are not, strictly speaking, lateral lithiations. Also included are a limited number of older lateral metalations that were originally effected with sodium or potassium bases but would now be more conveniently carried out with lithium dialkylamide bases. The aromatic nucleus may be carbocyclic or heterocyclic, but lateral lithiations of heterocycles lacking the heteroatomic substituent are not covered. For example, lithiation of nicotinamides (Eq. 2) are included; however, lithiations of picolines, and other heterocyclic systems, are considered beyond the scope of this chapter. The relationship of lateral lithiation reactions to heteroatom‐facilitated ortho lithiations is obvious and the two fields have developed, for the most part, in concert. With several notable exceptions, the same heteroatomic substituents (G) promote both types of lithiations. A number of reviews cover various aspects of ortho lithiation reactions, including the comprehensive chapter in Organic Reactions by Gschwend and Rodriguez that surveyed the literature to 1979. In the present chapter, the relationship of lateral lithiation and ortho lithiation reactions is discussed within the contexts of mechanism, reactivity, and synthetic utility. In addition, the sequential use of these two lithiation processes for the synthesis of complex aromatic and heteroaromatic systems is covered.

show abstract

Programmierung organischer Moleküle: Design und Management organischer Synthesen über radikalische Kaskaden

McCarroll

Walton

2001

Angew. Chem.

View full text Add to dashboard Cite

1. Einleitung 1.1. Beschreibung, Anwendungsbereich und Nutzen von Kaskadenreaktionen Chemische Prozesse, bei denen zwei oder mehr molekulare Veränderungen räumlich und zeitlich eng verknüpft sind (¹Eintopfreaktionenª), wurden als Kaskaden-, Domino-oder Tandemreaktionen oder auch Reaktionsfolgen bezeichnet. Die Wahrnehmung und das chemische Verständnis solcher Prozesse lassen noch zu wünschen übrig, doch das Tempo der Entwicklung ist in letzter Zeit deutlich schneller geworden, da man ihre tatsächlichen und potentiellen Vorteile mehr und mehr erkennt. Mit ihrer Hilfe kann man die Zahl der für den Aufbau eines komplexen Moleküls nötigen Arbeitsschritte im Labor verringern und damit Arbeits-und Gerätezeit sparen und muss weniger Laborplatz beanspruchen. Damit einher geht ein geringerer Verbrauch von Lösungsmitteln und Chemikalien, und es fallen weniger unerwünschte Begleitprodukte an. All diese Faktoren können die Effizienz einer Synthese beträchtlich verbessern und die Umweltbelastung reduzieren. Dieses Potential im Hinblick auf rationelle Synthesen im Labor und im industriellen Maûstab garantiert den Kaskadenprozessen eine glänzende Zukunft.Je gröûer die Zahl der Kaskadenstufen ist, um so mehr Funktionalitäten müssen sich im sorgfältig entworfenen Startmolekül genau an der richtigen Position befinden. Diese Bedingung kann sehr wohl einige der möglichen Vorteile der Kaskadenmethode aufwiegen. Die Struktur der Vorstufe(n) muss sorgfältig ¹programmiertª werden, wenn eine komple-

show abstract

Total synthesis of (±)-fredericamycin A. Use of radical spirocyclization

Abstract: f)-Fredericamycin A 1 is synthesized using 5-exo-digonal radical closure of selenide 15 (Scheme 2), and an unusual procedure for both selective demethylation of the advanced intermediate 22 and adjustment of the stereochemistry in the pentadienyl side chain.

Cited by 30 publications

References 27 publications

Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

Asymmetric Total Synthesis of Fredericamycin A: An Intramolecular Cycloaddition Pathway

Lateral Lithiation Reactions Promoted by Heteroatomic Substituents

Programmierung organischer Moleküle: Design und Management organischer Synthesen über radikalische Kaskaden

Contact Info

Product

Resources

About