Cytochalasin synthesis

Fuchs has used this reaction type for the construction of an 11-membered ring in the course of model studies for the [ll]cytochalasin synthesis. These cytostatic compounds, e.g. cytochalasin C (109), are metabolites of microorganisms. Reductive fragmentation of the benzenesulfonates (110 Scheme 37) produces the dienols (111). In contrast, both the sulfonates (112) on treatment with LDA afford the tricyclic ketones (113), the products of internal alkylation. Less than 1% of (111) is formed. In conclusion, the author points out that the enolate conformation (Scheme 37, in parentheses) appears to be all important in determining the reaction products of the four diastereoisomers (110) and (112). Whenever the enolate can easily assume a folded conformation, the tricyclic cyclobutane (113) will result. Models of the enolates of (110), where the intraannular fragmentation successfully occurs, show that the folded conformations are more strained than are the extended conformations. 

Nakamura, E., New acyl anion equivalent. A short route to the enol lactam intermediate in cytochalasin synthesis. Tetrahedron Lett., 22, 663, 1981. 

The sequence of drawings (19) to endo- 9) should show clearly how to draw the stereochemistry of the endo adduct. All four drawings are not usually necessary. The imide (21), used in Weinreb s cytochalasin synthesis, will have all four chiral centres correct, that is with all four hydrogen atoms cis, if the correct geometrical isomer of diene (22) is used. One diagram (23) should be enough to show all four hydrogen atoms cis in the endo transition state if the , -diene (24) is used. ... 

Haidle HM, Myers AG (2004) An Enantioselective, Modular, and General Route to the Cytochalasins Synthesis of L-696,474 and Cytochalasin B. Proc Natl Acad Sd USA 101 12048... 

An example for synthesis of the chiral [l-keto ester 69 is illustrated in equation 64. It involves conjugate addition of the dipotassium / -keto ester 68 to vinyl sulfone 67 followed by in situ quenching with allyl bromide54. The method provides a new procedure to sevenring annulation product 70 that is a potential precursor for (l)-(-)-cytochalasin C. 

Recent synthetic applications of the photochemical [2 + 2] cycloaddition of unsaturated sulfones have been noted. Musser and Fuchs84 have effected an intramolecular [2 + 2] addition of a 6-membered ring vinyl sulfone and a five-membered ring vinylogous ester in excellent yield, as part of a synthetic approach to the synthesis of the mould metabolite, cytochalasin C. The stereospecificity of the addition was only moderate, however, and later problems with this synthetic approach led to its abandonment. Williams and coworkers85 have used the facile [2 + 2] photoaddition of 73 and... 

Thus, (2R)-pumiliotoxin C (214) has been prepared from (R)-norvaline (212). The asymmetric center in the triene (213) controls the configuration at three carbon atoms 210). a-Kainic acid, isolated from the algae Digena simplex and Centrocerus clavulatum, was prepared by total synthesis. Its enantioselective synthesis involved a stereocon trolled intramolecular cycloaddition of a (S)-glutamic acid211). Asymmetric cycloadditions also play a decisive role in the synthesis of chiral cytochalasins. In this case 212> the primary chiral information was carried by (S)-alanine and (S)-phenylalanine, respectively. 

The overall sequence occurs under nearly neutral conditions at room temperature and was shown to be an efficient tool for an oxidative desulfurization step required in sulfur-mediated synthesis of complex molecules such as methynolide and cytochalasin [253]. 

These adducts easily undergo cycloreversion reactive unstable thioaldehydes can thus be conveniently stored and recovered, and their chemistry has been greatly developed over the last 10 years, mainly by Vedejs and Kirby [126, 253]. Vedejs elegantly used the thiopyranic heterocycles, via a [2,3] sigmatropic shift of a sulfur ylide [508], as precursors for medium sulfide rings, applied to the synthesis of complex natural products in the cytochalasin-zygosporin family [522, 523] for instance. 

Disconnection will be needed to discover which geometrical isomer of diene or dienophile is needed for a given product. The imide 33, needed for Weinreb s cytochalasin synthesis7 is easily disconnected to the imide 34 and the diene 35. We clearly need either E, E-or the Z,Z-diene to get the two substituents on the same side. But which All the Hs are on the same side so we need the molecules shown in diagram 36 and hence E,E-35. The synthesis of this diene is. discussed in the workbook for chapter 15. 

Trost and coworkers [116] found that palladium-catalyzed intramolecular allylic alkylation to a-sulfonyl ketones is a good means of performing macrocyclization. This reaction involves the intermediacy of a tt-allylpalladium complex as an enolonium equivalent to initiate cyclization. For instance, this method was used in the synthesis of the cytochalasin ( — )-aspochalasin B (201) [117]. As shown in Scheme 66, cyclization of the linear precursor 199 using 10 mol% (Ph3P)4Pd in the presence of 10 mol% DPPP in THF created the 11-membered carbocycle 200 as a single diastereoisomer in 49% yield. 

The non-catalyzed [4 + 2] cycloaddition of the chiral pyrrolone (295) to triene (296) occurred widi ir-facial selection owing to the allylic benzyl substituent of dienophile (295) affording two regioisomers (Scheme 72). The majOT product (297) is a key intermediate in a synthesis of cytochalasin B. 

Vedejs and Ahmad have used this Sml2-promoted macrocyclization technique as a key step in the total synthesis of a cytochalasin (equation 56). In this reaction, the 11-membered ring product is isolated in... 

Stork, G., and Nakamura, E., A simplified total synthesis of cytochalasins via an intramolecular Diels-Alder reaction, 7. Am. Chem. Soc., 105, 5510, 1983. 

The only syntheses of members of the cytochalasin class that contain a macrocyclic lactone come from the Stork group at Columbia. The first of these studies resulted in the synthesis of cytochalasin B (20) by clever elaboration of the stereochemical centers at the two bridgehead positions as well as at C-5 and C-8 by means of a Diels-Alder cycloaddition (Scheme 3.1). ... 

The second synthesis, that of the carbocyclic cytochalasin proxiphomin (61) by Thomas, is described in Scheme 3.4.The strategy is rather similar to the second synthesis of cytochalasin B by Stork with the necessary modifications. 

Figure 1. Demonstration of transcriptional competence of one-cell embryos by nuclear transplantation. Donor two-cell nuclei from a-amanitin-treated embryos are transferred to enucleated one-cell embryos in which both the male and female pronuclei have been removed. Following transplantation, the cells are analyzed for TRC synthesis was shown to occur at a time that corresponds to C2 of the one-cell stage. Cytochalasin D, which has no effect on ZGA, is used to generate these donor cells since it is easier to remove nuclei from such treated embryos.

Tricnc 2 adds to the lactam 1 affording a mixture of the adduct 3 and its regioisomer with 40 % overall yield. The main product of the cycloaddition has been used for the synthesis of cytochalasin B26. 

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