Total synthesis of Adda, the unique C20 amino acid of cyanobacterial hepatotoxins

Michio Namikoshi; Kenneth L. Rinehart; Andrew M. Dahlem; Val R. Beasley; Wayne W. Carmichael

doi:10.1016/S0040-4039(00)99357-2

Total synthesis of Adda, the unique C₂₀ amino acid of cyanobacterial hepatotoxins

Michio Namikoshi, Kenneth L. Rinehart, Andrew M. Dahlem, Val R. Beasley, Wayne W. Carmichael

Veterinary and Biomedical Sciences

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108 Scopus citations

Abstract

Synthetic (2S,3R)-3-Amino-4-hydroxy-2-methylbutanoic acid, γ-lactone, and (4S,5S)-2,4-dimethyl-5- methoxy-6-phenyl-2-hexen-1-ol were oxidized and linked to give (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyl-4,6-decadienoic acid (Adda).

Original language	English (US)
Pages (from-to)	4349-4352
Number of pages	4
Journal	Tetrahedron Letters
Volume	30
Issue number	33
DOIs	https://doi.org/10.1016/S0040-4039(00)99357-2
State	Published - 1989

All Science Journal Classification (ASJC) codes

Biochemistry
Drug Discovery
Organic Chemistry

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10.1016/S0040-4039(00)99357-2

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@article{7d1d982db08d4d1bbeea0bda702cc154,

title = "Total synthesis of Adda, the unique C20 amino acid of cyanobacterial hepatotoxins",

abstract = "Synthetic (2S,3R)-3-Amino-4-hydroxy-2-methylbutanoic acid, γ-lactone, and (4S,5S)-2,4-dimethyl-5- methoxy-6-phenyl-2-hexen-1-ol were oxidized and linked to give (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyl-4,6-decadienoic acid (Adda).",

author = "Michio Namikoshi and Rinehart, {Kenneth L.} and Dahlem, {Andrew M.} and Beasley, {Val R.} and Carmichael, {Wayne W.}",

note = "Funding Information: The 1~ NMR spectrum( CD3OD) of 10 is very similar to thato f the Adda protons in nodularin,w ith chemical shifts within 0.03 ppm and coupling constantsw ithin 0.1 Hz for H-5 throught he phenyl ring. The chemical shifts are quite close for H-3, H-4 and the 2-CH3 protons (SO.1 3ppm), but their coupling constants differ (as does the chemical shift of H-2) becauseC -2 and C-3 of Adda are incorporatedi nto the constrained peptider ing. Deprotection of 10 gave Adda itself (11, C20H30N03, M + H, AO.0 mmu).4c Both 10 and 11 show little or no toxicity in the mousel iver assay. Unfortunately,o ne cannotc omparet he syntheticp roductd irectly with naturalA dda, becausec onditions vigorous enought o hydrolyze the peptidel inks of Adda in nodularinO T microcystin lead to decomposition,w ith loss of methanol. The producto f hydrolysis of either 1 or 2 is the samea s thato btainedb y similar hydrolysis of 10, with identical reversed-phaseH PLC behavior (C-18, MeOH:O.l% TFA in H20 : 85:1.5c, o-elution) and essentially identical 500-MHz 1~ NMR spectra( 1.05, 1.10, 1.30, 1.48, 1.58, 2.51, 2.93, 3.30, 3.63, 7.27, 7.33,7.40,7.58,7.77,8.24 ppm, CDC13). Particularly compelling are the identical collisionally induced metastableio n spectra( MS/MS, B/E scan, &z 300 + 226, 209, 195, 181, 169, 155, 141, 128, 115, 102, 95, 84) obtainedi n our four-sectort andemm ass spectrometer(V G 70.SE4F). Acknowledgment. This work was supportedi n part by grantsf rom the National Institute of Allergy and Infectious Diseases (AI04769 to K.L.R.) and the National Instituteo f General Medical Sciences (GM27029 to K.L.R.) and by U.S. Army Medical Researcha nd DevelopmentC ommandC ontractsD AMD 17-85-C-5241t o V.R.B. and DAMD 17-87-C-7019t o W.W.C. References (1) Reportedi n part: (a) at the IUPAC Symposiumo n the Chemistry of Natural Products, Kyoto, May 29-June 3, 1988;A bstract CLa6. (b) in Pure Aool. Chem. 1989,fl, 525-528. (c) at the 197thA CS National Meeting, Dallas, TX, April 9-14, 1989,O RGN 23. (2) Rinehart, K. L.; Harada, K.-I.; Namikoshi, M.; Chen, C.; Harvis, C. A.; Munro, M. H. G.; Blunt, J. W.; Mulligan, P. E.; Beasley, V. R.; Dahlem, A. M.; Carmichael, W. W. J. Am. Chem. Sot. 1988,110, 8557-8558. (3) (a) Dahlem, A. M.; Beasley, V. R.; Harada, K.-I.; Matsuura,K .; Suzuki, M.; Ha&s, C. A.; Rinehart, K. L.; and Carmichael, W. W. Toxicoloeist 1989,2, 168. (b) Dahlem, A. M.; Beasley, V. R.; Hooser, S. B.; Harada, K.; Matsuura, K.; Suzuki, M.; Rinehart, K. L.; Harvis, C. A.; Carmichael, W. W. Chem. Res. Toxicol. 1989, in press. (4) (a) Satisfactory 1H NMR dataw ere obtained. (b) HREIMS. (c) HRFABMS. (d) HRCIMS. (5) Geometrieso f theset wo isomers were determinedb y NOE experiments. (6) Takahashie t al. madea diastereomericm ixtureo f 2-methylateda minolactonesfr om L-Asp, but they did not separatet hese isomers; Takahashi,Y .; Hasegawa,S .; Izawa, T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, &!, 3020-3024. (7) The stereochemistryo f thesec ompoundsi s establishedf rom their lH NMR spectrawithaid of NOE experiments. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.",

year = "1989",

doi = "10.1016/S0040-4039(00)99357-2",

language = "English (US)",

volume = "30",

pages = "4349--4352",

journal = "Tetrahedron Letters",

issn = "0040-4039",

publisher = "Elsevier Limited",

number = "33",

}

TY - JOUR

T1 - Total synthesis of Adda, the unique C20 amino acid of cyanobacterial hepatotoxins

AU - Namikoshi, Michio

AU - Rinehart, Kenneth L.

AU - Dahlem, Andrew M.

AU - Beasley, Val R.

AU - Carmichael, Wayne W.

N1 - Funding Information: The 1~ NMR spectrum( CD3OD) of 10 is very similar to thato f the Adda protons in nodularin,w ith chemical shifts within 0.03 ppm and coupling constantsw ithin 0.1 Hz for H-5 throught he phenyl ring. The chemical shifts are quite close for H-3, H-4 and the 2-CH3 protons (SO.1 3ppm), but their coupling constants differ (as does the chemical shift of H-2) becauseC -2 and C-3 of Adda are incorporatedi nto the constrained peptider ing. Deprotection of 10 gave Adda itself (11, C20H30N03, M + H, AO.0 mmu).4c Both 10 and 11 show little or no toxicity in the mousel iver assay. Unfortunately,o ne cannotc omparet he syntheticp roductd irectly with naturalA dda, becausec onditions vigorous enought o hydrolyze the peptidel inks of Adda in nodularinO T microcystin lead to decomposition,w ith loss of methanol. The producto f hydrolysis of either 1 or 2 is the samea s thato btainedb y similar hydrolysis of 10, with identical reversed-phaseH PLC behavior (C-18, MeOH:O.l% TFA in H20 : 85:1.5c, o-elution) and essentially identical 500-MHz 1~ NMR spectra( 1.05, 1.10, 1.30, 1.48, 1.58, 2.51, 2.93, 3.30, 3.63, 7.27, 7.33,7.40,7.58,7.77,8.24 ppm, CDC13). Particularly compelling are the identical collisionally induced metastableio n spectra( MS/MS, B/E scan, &z 300 + 226, 209, 195, 181, 169, 155, 141, 128, 115, 102, 95, 84) obtainedi n our four-sectort andemm ass spectrometer(V G 70.SE4F). Acknowledgment. This work was supportedi n part by grantsf rom the National Institute of Allergy and Infectious Diseases (AI04769 to K.L.R.) and the National Instituteo f General Medical Sciences (GM27029 to K.L.R.) and by U.S. Army Medical Researcha nd DevelopmentC ommandC ontractsD AMD 17-85-C-5241t o V.R.B. and DAMD 17-87-C-7019t o W.W.C. References (1) Reportedi n part: (a) at the IUPAC Symposiumo n the Chemistry of Natural Products, Kyoto, May 29-June 3, 1988;A bstract CLa6. (b) in Pure Aool. Chem. 1989,fl, 525-528. (c) at the 197thA CS National Meeting, Dallas, TX, April 9-14, 1989,O RGN 23. (2) Rinehart, K. L.; Harada, K.-I.; Namikoshi, M.; Chen, C.; Harvis, C. A.; Munro, M. H. G.; Blunt, J. W.; Mulligan, P. E.; Beasley, V. R.; Dahlem, A. M.; Carmichael, W. W. J. Am. Chem. Sot. 1988,110, 8557-8558. (3) (a) Dahlem, A. M.; Beasley, V. R.; Harada, K.-I.; Matsuura,K .; Suzuki, M.; Ha&s, C. A.; Rinehart, K. L.; and Carmichael, W. W. Toxicoloeist 1989,2, 168. (b) Dahlem, A. M.; Beasley, V. R.; Hooser, S. B.; Harada, K.; Matsuura, K.; Suzuki, M.; Rinehart, K. L.; Harvis, C. A.; Carmichael, W. W. Chem. Res. Toxicol. 1989, in press. (4) (a) Satisfactory 1H NMR dataw ere obtained. (b) HREIMS. (c) HRFABMS. (d) HRCIMS. (5) Geometrieso f theset wo isomers were determinedb y NOE experiments. (6) Takahashie t al. madea diastereomericm ixtureo f 2-methylateda minolactonesfr om L-Asp, but they did not separatet hese isomers; Takahashi,Y .; Hasegawa,S .; Izawa, T.; Kobayashi, S.; Ohno, M. Chem. Pharm. Bull. 1986, &!, 3020-3024. (7) The stereochemistryo f thesec ompoundsi s establishedf rom their lH NMR spectrawithaid of NOE experiments. Copyright: Copyright 2014 Elsevier B.V., All rights reserved.

PY - 1989

Y1 - 1989

N2 - Synthetic (2S,3R)-3-Amino-4-hydroxy-2-methylbutanoic acid, γ-lactone, and (4S,5S)-2,4-dimethyl-5- methoxy-6-phenyl-2-hexen-1-ol were oxidized and linked to give (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyl-4,6-decadienoic acid (Adda).

AB - Synthetic (2S,3R)-3-Amino-4-hydroxy-2-methylbutanoic acid, γ-lactone, and (4S,5S)-2,4-dimethyl-5- methoxy-6-phenyl-2-hexen-1-ol were oxidized and linked to give (2S,3S,8S,9S)-3-amino-9-methoxy-2,6,8- trimethyl-10-phenyl-4,6-decadienoic acid (Adda).

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UR - http://www.scopus.com/inward/citedby.url?scp=0010620248&partnerID=8YFLogxK

U2 - 10.1016/S0040-4039(00)99357-2

DO - 10.1016/S0040-4039(00)99357-2

M3 - Article

AN - SCOPUS:0010620248

SN - 0040-4039

VL - 30

SP - 4349

EP - 4352

JO - Tetrahedron Letters

JF - Tetrahedron Letters

IS - 33

ER -

Total synthesis of Adda, the unique C₂₀ amino acid of cyanobacterial hepatotoxins

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