Calyculin A and

In their synthesis of (+)-calyculin A and (—)-calyculin B, Smith and co-workers observed partial epimerization when the (3-hydroxy amide 4 was reacted with SOCI2 despite the mild reaction conditions, 4 °C in tetrahydrofuran (THF)." The mechanism of this epimerization was not discussed (Scheme 8.5). 

Fig. 25 BVMO-catalyzed synthesis of a precursor to calyculin A and tirandamycin...

At present okadaic acid is a widespread laboratory tool used to detect the participation of PPs, or more strictly of PPA2, in many physiological processes. For that reason an increasing number of research studies deal more or less specifically with the activity of this toxin and related ones, such as calyculin A and others. For the purpose of the present review, a selection was made of recent papers focusing on those aspects with major pathological incidence. 

Ishihara H, Martin BL, Brautigan DL et al (1989) Calyculin A and okadaic acid ... 

Synthesis of 7 -amino acid-oxazole fragment 68 of calyculins A and B from D-erythronol-actone 58 has been reported by conversion to 59," which was subjected to oxidation reaction to afford the hemiaminal 60 (Scheme 9) Acetylation of 60 furnished 61, which was converted to ketone 62 in 88% yield. Conversion of 62 to a silyl enol ether, ozonolysis with reductive workup and O-methylation of the resultant alcohol 63 furnished 7 -lactam 64. Treatment of 64 with CAN led to 65 (60%), which was reacted with (CHj)2 A1 derivative of 66 to provide 67 (62%), which upon removal of the silyl group provided 68. 

The oxazole derivative 237 is a key component for the synthesis of cell permeable phosphatase inhibitors calyculins A and B and it is prepared via coupling of alkylamino oxazole 235 and -/V-protected acid 236.87... 

The calyculins have aroused considerable synthetic interest due not only to their unique polyfunctional structure but also to their intriguing biological activities[ 180]. However, initial synthetic efforts were addressed to (-t-)-calyculin (arbitrarily depicted in the 1986 original paper), which is enantiomeric to the natural occurring compound. The Evans group reported the total synthesis of ent-calyculin A in 1992 [181], which allowed to establish the actual absolute configuration of the natural product. In 1994 Masamune et al. published the total synthesis of the natural enantiomer [182]. Shoiri et al. have also reported a formal total synthesis of calyculin A [183]. Very recently an alternative synthesis of (+)-calyculin A and (-)-calyculin B was reported by Smith [184] whereas the natural calyculin C was obtained by Armstrong and co-workers [185]... 

Smith s retrosynthetic approach, Fig. (11), to enr-calyculin A and to (-)-calyculin B (the C2 geometrical isomer of calyculin A) begins with the disconnection at C(2) via a Peterson olefination which would provide both molecules from a common advanced intermediate. Further... 

Ishihara H, Martin BL, Brautigan DL, Karaki H, Ozaki H, Kato Y, Fusetani N, Watabe S, Hashimoto K, Uemura D, Hartshorne DJ (1989) Calyculin A and okadaic acid inhibitors of protein phosphatase activity. Biochem Biophys Res Commun 159 871-877... 

Serine/threonine protein phosphatases are inhibited also by other natural toxins, such as cyclic peptides (microcystins and nodularins), terpenoids (cantharidin and thyrsiferyl 23-acetate), polyketides (calyculin A and tautomycin), and other compounds, such as fostriecin. A comparative study revealed the following order of potency for some compounds microcystin-LR > calyculin A > tautomycin > okadaic acid for PPl, and okadaic acid > microcystin-LR > calyculin A > tautomycin for PP2A. Calyculin A, microcystin-LR and tautomycin are inhibitors of both PPl and PP2A, with IC50 values ranging from 0.1 nM to 0.7 nM. Okadaic acid, microcystin-LR, calyculin A, tautomycin, cantharidin, and fostriecin inhibit also PP4 with an IC50 of 0.1 nM, 0.15 nM, 0.2 nM,... 

Smith and co-workers ° ° described the total syntheses of (-l-)-calyculin A and (-)-calyculin B in later studies. At that time, the most efficient synthesis of 1394 employed the Burgess reagent for cyclization of 1392a followed by CuBr2/ HMTA/DBU oxidation of 1393. In this manner, 1394 was prepared in 67% yield with little epimerization. 

This group of natural compounds is also structurally diverse ranging from the simple dienes like a sex pheromone (4E,7Z)-4,7-tridecadienyl acetate or ( )- , )-coriolic acid through typical polyenes like the all-trans-stereomer of ethyl retinoate to the more complex, optically active calyculins A and B. In the total syntheses of polyenes presented below, the structurally complex phosphonate or bisphosphonate reagents were used in the Horner-Wittig olefination reactions solely or in combination with the Suzuki coupling. 

Inhibitors of ser/thr protein phosphatases I and 2A, calyculin A and okadaic acid, which each inhibit both phosphatases [236], have been shown to inhibit N-formyl peptide-induced neutrophil migration without... 

Treatment of cells with inhibitors of ser/thr phosphatases 1 and 2A (calyculin A and okadaic acid) but not 2B (cypermethrin) prevent N-formyl peptide—induced moesin dephosphorylation, rear retraction, and cell migration, suggesting that activation of phosphatases is stimulated by N-formyl peptides and calyculin A-sensitive phosphatases play a crucial role in rear release by dephosphorylating ERM. 

Related to the incorporation of known pharmacophores into libraries, are those libraries utilizing biologically active natural products as design anchors. Library 2.6, based on the protein phosphatase inhibitor, calyculin-A, and library 4.10, derived from the antibacterial, neomycin B, illustrate this strategy. 

Suganuma, M., Fujiki, H., Furuya-Suguri, H., Yoshizawa, S., Yasumoto, S., Kato, Y., Fusetani, N., and Sugimura, T. (1990) Calyculin A, and inhibitor of protein phosphatases, a potent tumor promoter on CD-I mouse skin. Cancer Res., 50, 3521-3525. 

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