- Total synthesis of the protein phosphatase inhibitor okadaic acid
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The total synthesis of the protein phosphatase inhibitor okadaic acid 1 is reported using a convergent coupling strategy of three components, all of which may be prepared using chemistry developed in our laboratories.
- Ley, Steven V.,Humphries, Alexander C.,Eick, Holger,Downham, Robert,Ross, Andrew R.,Boyce, Richard J.,Pavey, John B. J.,Pietruszka, Joerg
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p. 3907 - 3911
(2007/10/03)
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- Efficient synthesis of okadaic acid. 2. Synthesis of the C1-C14 domain and completion of the total synthesis
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Described here are the full details of the preparation of a synthetic intermediate representing carbons 1' 14 (C1-C14) of the marine natural product okadaic acid (1), the coupling of this fragment with the previously prepared C15-C38 domain, and the completion of an efficient total synthesis of 1. The C1-C14 intermediate was prepared in 11 steps and ~20% overall yield from a functionalized δ-valerolactone derivative representing C3-C8 of 1. This featured a classic spiroketalization strategy to construct the highly substituted 1,7-dioxaspiro-[5.5]undec-4-ene system, followed by incorporation of the intact C1-C2 α-hydroxyl, α-methyl carboxylate moiety using cis-(S)- lactate pivalidene enolate. The complete C1-C14 intermediate was converted into 1 in five additional steps. Coupling of the C1-C14 fragment with the C15-C38 domain of 1 via C14 aldehyde and C15 β-keto phosphonate moieties provided the complete carbon skeleton of 1 bearing a ketone at C16 and a mixed-methyl acetal at C19. Reduction of the C16 ketone using Corey's (S)- CBS/BH3 system and subsequent acid-triggered spiroketalization formed the Central 1,6-dioxaspiro[4.5]decane ring system. Saponification of the C1-C2 pivalidene group and final reductive cleavage of the three benzyl ethers using lithium di-tert-butylbiphenylide in THF provided 1 in 48% yield from the C1-C14 aldehyde, and in 26 steps and ~2% overall yield in the longest linear sequence from the C22-C27 synthon methyl 3-O-benzyl-α-D- altropyranoside.
- Sabes, Steven F.,Urbanek, Rebecca A.,Forsyth, Craig J.
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p. 2534 - 2542
(2007/10/03)
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- Transformation of a Marine Toxic Polyether, Okadaic Acid
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Natural okadaic acid 1 was transformed into the 7,24,27-tri-O-benzyl-1,2-acetonide derivative (4) in a 66 percent overall xield.The corresponding synthetic derivative (4) was identified with this authentic sample.
- Ichikawa, Yoshiyasu,Isobe, Minoru,Goto, Toshio
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p. 975 - 982
(2007/10/02)
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- SYNTHESIS OF A MARINE POLYETHER TOXIN, OKADAIC ACID (4).TOTAL SYNTHESIS.
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Three segments A, B and C for okadaic acid synthesis were coupled with each other in order of A+(B+C), the key steps of the twice couplings being between sulfone carbanions and aldehydes.After the B+C coupling , the asymmetric center C-27 was generated by a hydride reduction of the corresponding ketone 16 under electronic control.The second coupling was followed to form the C-14/15 double bond.Oxidation of the α-oxy aldehyde 36 into the carboxylic acid group was achieved with sodium chlorite without C-1/C-2 bond cleavage.The total synthesis of okadaic acid was accomplished in 106 steps from commercially available D-glucose derivative s and butyne-diol.
- Isobe, Minoru,Ichikawa, Yoshiyasu,Bai, Dong-Lu,Masaki, Hisanori,Goto, Toshio
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p. 4767 - 4776
(2007/10/02)
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- SYNTHETIC STUDIES TOWARD MARINE TOXIC POLYETHERS THE TOTAL SYNTHESIS OF OKADAIC ACID
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The total synthesis of okadaic acid has been accomplished through the coupling of all the segments, A, B and C, by means of sulfone-carbanion strategy.
- Isobe, Minoru,Ichikawa, Yoshiyasu,Goto, Toshio
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p. 963 - 966
(2007/10/02)
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