Total Synthesis of the Ammosamides
虚谷Chambers C.Hughes and William Fenical*
Center for Marine Biotechnology and Biomedicine,Scripps Institution of Oceanography,Uni V ersity of California,
San Diego,La Jolla,California 92093-0204
Received December 17,2009;E-mail:wfenical@ucsd.edu
The condary metabolites of actinomycetes often display exceptional biological activities.1The genetically encoded small molecules,which were subjected to evolutionary pressures over millions of years,generally posss high affinities for their protein targets.Our studies of marine actinomycetes have focud on tho strains isolated from deep-ocean diments.2
The ammosamides A -B (1-2)are chlorinated alkaloids char-acterized by a den array of heteroatoms (N,O,S)and a relative paucity of hydrogen atoms (Chart 1).The molecules are related to the pyrroloiminoquinone class of natural products,3although they exhibit veral distinct features.The isolation and structural elucidation of ammosamides A and B (1,2)from a marine diment-derived Stre
ptomyces strain CNR-698was described in a previous communication by our group.4In a back to back communication,we also showed that the metabolites target the cellular cytokinetic protein myosin.5Few natural products have been demonstrated to target this protein.6
The pronounced bioactivity of the ammosamides,derived from a disruption in cellular cytokinesis,encouraged us to undertake a total synthesis of this unique class of metabolites.An examination of synthetic analogues with different functional groups on the pyrroloquinoline core,we thought,might provide a molecule with incread potency and/or overall improved properties.Although interest in related pyrroloiminoquinones culminated in veral total synthes,7none of the reported routes was directly amenable to the ammosamide class.
We envisioned a total synthesis commencing from 4-chloroisatin (3),itlf derived from reaction of 3-chloroaniline with chloral hydrate (Scheme 1).8The synthesis was designed with veral key principles in mind,namely that (1)the aromatic amines,to which we ascribed much of the natural products’hydrophilicity and lack of solubility,would be disguid as nitro groups;(2)the C-4chlorine substituent in 3would be displaced by ammonia (or its equivalent)in a nucleophilic aromatic substitution reaction;(3)the C-3carbonyl of 3would be elongated at a later stage through Wittig olefination;(4)the C-7chlorine substituent would be installed late in the synthesis.A late-stage chlorin
ation would mean that the synthesis could be adapted to provide deschloro derivatives or derivatives with bromine or iodine at C-7.Since comparable activity
was obrved for ammosamides A (1)and B (2),we pursued a synthesis specifically of 2to avoid manipulations with the thiolac-tam in 1.We had shown earlier that 2could be converted to 1using Lawesson’s reagent.4
Isatin 3was first mononitrated at 0°C to give 4.The position of the nitro group at C-5was determined by X-ray crystallographic analysis of N -methyl 4.9Nitroisatin 4was treated with t -butylamine in dioxane at elevated temperatures to produce 5in 87%yield.N -methylation of this material was followed by acidic deprotection of the C-4amine to give 6.The quinoline ring was then constructed via olefination with t -butyl (triphenylphosphoranylidene)acetate and acidic deprotection/condensation.The Wittig reagent was added over a 3h period using a syringe pump,minimizing the formation of phosphorus-containing byproducts that are derived from conju-gate addition of excess reagent to the intermediate enone.10,11The quinoline scaffold was lectively nitrated at C-7,and the C-2alcohol was then converted to the chloride to give 7in 34%yield from 3.
Treatment of 7with hydroiodic acid led to reduction of the nitro groups to amines and substitution at C-4with iodide (Scheme 2).This compound (not shown),and subquent diamino intermediates,adopted physical characteristics similar to the ammosamides.Its solubility in organic solvents was verely limited,purification with silica gel chromatography became unmanageable,and the material assumed a dark purple color (λmax )520nm).Thus,the iodide was directly converted to 8upon treatment with trifluoroacetic anhydride.Iodide 8was then transformed into the corresponding C-4nitrile employing copper(I)cyanide.Conversion of the aromatic amines to trifluoroacetamides improved yields and allowed for purification by silica gel chromatography.The amines were subquently deprotected under acidic conditions.Ester 10was
Chart 1.Ammosamides A (1)and B (2实在论
)
Scheme 1.Synthesis of the Ammosamide
Core
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obtained by conversion of the nitrile to the imidate with methanolic KOH and subquent acidic ester
ification.
Deschloro ammosamide B (12)was prepared after installation of the final nitrogen atom.First,ester 10was converted to 11to facilitate silica gel purification.Deprotection and conversion to the C-4amide resulted from treatment with magnesium nitride.12The 1
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H NMR spectrum of 12was similar to that of ammosamide B (2)except for the additional C-7signal at 6.16ppm.
Ammosamide B (2)was also synthesized from ester 10after chlorination in neat thionyl chloride under UV light (254nm).13The reaction reprents the first example of the chlorination of an unsubstituted 1,3-dianiline.Synthetic 2,indistinguishable from natural ammosamide B (LC/MS,NMR,HRMS),was obtained after trifluoroacetylation to 13and amidation.
Though their biological properties are comparable,there is a dramatic difference in the stability of natural ammosamide B (2)and synthetic deschloro ammosamide B (12).Expod to air and light,12readily degraded within a week via a nitroso intermediate.14Natural 2,however,could be stored in this way for much longer (degradation t 1/2≈1month).The exact role of the biosynthetic chlorination may be to confer stability toward oxidative degradation.In an effort to generate additional
analogues for structure -activity studies,veral misynthetic derivatives of the ammosamides were prepared.In one ca,conversion of ammosamide A (1)to quinolinium 14was accomplished via S -methylation and reduction with sodium borohydride (e Scheme 1).The conspicuous UV profile of this derivative was recognized later,in very low titer,in the LC/MS chromatogram of the crude CNR-698extract.The structure of a third member of the ammosamide class,ammosamide C (14),was thus elucidated.Metabolite 14is likely a biosynthetic precursor to 1and 2,the latter species arising from nucleophilic oxidation or sulfuration at C-2.妇女节是几月几号
The ammosamides are one of the first class of natural products known to target myosin.6Our synthesis of the ammosamides has provided new analogues with which to asss the role of each functional group on the pyrroloquinoline core.Bad on obrva-tions of the deschloro compound,halogenation of the 1,3-diamino moiety helps protect the natural product from oxidative degradation.Studies detailing the bioactivity of each synthetic compound will soon be disclod.
Acknowledgment.Financial support was provided by the National Cancer Institute,NIH (under grant R37CA44848).We
thank Phil S.Baran (The Scripps Rearch Institute)for indispen-sable advice,and Drs.Arnold L.Rheingold and Antonio G.D’Pasquale (UCSD)for assistance with X-ray diffraction experiments.
Supporting Information Available:Details of the isolation and spectral data for 14.Crystallographic data for N -methyl 4(CCDC 756061)in CIF format.HRMS data,proton,and carbon NMR spectra for lected intermediates.This material is available free of charge via the Internet at pubs.acs.References
(1)Cragg,G.M.;Grothaus,P.G.;Newman,D.J.Chem.Re V .2009,109,
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(2)(a)Fenical,W.;Jenn,P.R.Nat.Chem.Biol.2006,2,666–673,and
references therein.(b)Hughes,C.C.;Prieto-Davo ´,A.;Jenn,P.R.;Fenical,W.Org.Lett.2008,10,629–631.(c)Kwon,H.C.;Kauffman,C.A.;Jenn,P.R.;Fenical,W.J.Org.Chem.2009,74,675–684.(3)For a review:Antunes,E.M.;Copp,B.R.;Davies-Coleman,M.T.;Samaai,
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(6)The marine natural product pentabromopudilin also inhibits myosin motor
activity:Fedorov,R.;Bo ¨hl,M.;Tsiavaliaris,G.;Hartmann,F.K.;Taft,M.H.;Baruch,P.;Brenner,B.;Martin,R.;Kno ¨lker,H.-J.;Gutzeit,H.O.;Manstein,D.J.Nat.Struct.Biol.2009,16,80–88.
(7)For example:(a)Peat,A.J.;Buchwald,S.L.J.Am.Chem.Soc.1996,
118,1028–1030.(b)Roberts,D.;Joule,J.A.;Bros,M.A.;Alvarez,M.J.Org.Chem.1997,62,568–577.For the first and only synthesis of lymphostin:(c)Tatsuta,K.;Imamura,K.;Itoh,S.;Kasai,S.Tetrahedron Lett.2004,45,2847–2850.
(8)Sandmeyer,T.Hel V .Chim.Acta 1919,2,234–242.
(9)Material for X-ray analysis was prepared via nitration of N -methyl-4-chloroisatin.This isatin derivative was identical (1H NMR,LC/MS)to the product resulting from methylation of 4.
(10)This reactivity has been obrved with other electron-deficient enones:(a)
Faber,K.;Stueckler,H.;Kappe,T.J.Heterocycl.Chem.1984,21,1177–1181.(b)Augustin,M.;Jeschke,P.J.Prakt.Chem.1987,329,637–648.(11)With 4-amino-1-methyl-5,7-dinitroisatin,formation of the undesirable
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phosphocycle [LRESIMS:m/z (MH +))741]was predominant.
(12)Veitch,G.E.;Bridgwood,K.L.;Ley,S.V.Org.Lett.2008,10,3623–
3625.Concerning the potential for magnesium nitride to explode:Crane,S.Chem.and Engineer.News 2009,87,2–4.
(13)Thionyl chloride is reduced to sulfur monoxide.For similar examples:(a)
Kim,D.H.;Santilli,A.A.Tetrahedron Lett.1971,12,2441–2442.(b)Soidinsalo,O.;Wa ¨ha ¨la ¨,K.Phosphorus,Sulfur,Silicon 2007,182,2761–2767.
(14)The difference in stability between a 2-halo-1,3-nitrosoanilines and their
nonhalogenated analogues has been noted:Frumkin,A.E.;Churakov,A.M.;Strelenko,Y.A.;Smirnov;Tartakovsky,V.A.Russ.Chem.Bull.1999,48,2103–2107.
JA9106572
Scheme 2.Total Synthesis of Ammosamides A (1),B (2),C (14)and Deschloro Ammosamide B (12
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