Formal synthesis of the antitumour antibiotic CC-1065

Bolton, R.; Moody, Christopher J.; Pass, Martin; Rees, Charles W.; Tojo, Gabriel

doi:10.1039/p19880002491

Cited by 28 publications

(7 citation statements)

References 17 publications

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“…Selective reduction of the unsubstituted pyrrole followed by introduction of the Ncarbamoyl group and hydrogenolysis of the benzyl ethers provided PDE-I 2 and together with their synthesis of CPI 72 completed a formal total synthesis of CC-1065. 111…”

Section: Rees−moody Synthesis Of Pde-imentioning

confidence: 99%

“…These two intermediates were coupled using the carbodiimide reagent CMC to produce the dimer in 63%. Selective reduction of the unsubstituted pyrrole followed by introduction of the N -carbamoyl group and hydrogenolysis of the benzyl ethers provided PDE-I 2 and together with their synthesis of CPI 72 completed a formal total synthesis of CC-1065 31 Rees−Moody Synthesis of PDE-I 2 …”

Section: Rees−moody Synthesis Of Pde-i2mentioning

confidence: 99%

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CC-1065 and the Duocarmycins: Synthetic Studies

et al. 1997

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Born August 22, 1953, Dale L. Boger (seated) received his B.Sc. in chemistry from the University of Kansas (1975) and Ph.D. in chemistry from Harvard University (1980). Immediately following graduate school, he returned to the University of Kansas as a member of the faculty in the Department of Medicinal Chemistry (1979Chemistry ( −1985, moved to the Department of Chemistry at Purdue University (1985University ( −1991, and joined the faculty at The Scripps Research Institute (1991 to present) as the Richard and Alice Cramer Professor of Chemistry. His research interests span the fields of organic and bioorganic chemistry and include the development of synthetic methodology, the total synthesis of natural products, heterocyclic chemistry, bioorganic chemistry, medicinal chemistry, the study of DNA−agent and protein−ligand interactions, and antitumor agents.Christopher W. Boyce (standing left) was born January 30, 1972, and grew up in Richmond, MA. Following a year abroad at the Swiss Federal Institute (ETH-Zurich), he received his B.Sc. in chemistry from Rensselaer Polytechnic Institute (1994, summa cum laude). He is currently pursuing a Ph.D. under the direction of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylation agents related to the CC-1065 and duocarmycin families. Robert M. Garbaccio (standing right) was born on January 20, 1972, and grew up in Old Tappan, NJ. He received his B.A. in chemistry and graduated summa cum laude from Boston University in 1994 where he conducted research in the laboratory of Professor James S. Panek. Presently, he is pursuing a Ph.D. in chemistry at The Scripps Research Institute under the guidance of Professor Dale L. Boger where he is addressing the synthesis and evaluation of potent DNA alkylating agents from the duocarmycin and mitomycin families of antitumor antibiotics. Joel A. Goldberg (standing center) was born June 17, 1972, and grew up in Bedford, NH. After receiving his B.Sc. from Tufts University he joined Professor Boger's laboratory at The Scripps Research Institute where he is pursuing his Ph.D. in Chemistry. His research concentrates on the synthesis and evaluation of potent alkylating agents related to CC-1065 and the duocarmycins.

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Section: Rees−moody Synthesis Of Pde-imentioning

confidence: 99%

Section: Rees−moody Synthesis Of Pde-i2mentioning

confidence: 99%

CC-1065 and the Duocarmycins: Synthetic Studies

et al. 1997

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“…The reaction of β-azidostyrene ( 3l ) gave trisubstituted pyrrole 2l in good yield (entry 12). It is known that the pyrrolysis of β-aryl vinyl azides results in the formation of indoles via intramolecular C−H amination, , while the reaction with acetylacetone gave pyrroles selectively without any indole formation (entries 2−12). For the β-substituents of vinyl azides (R 1 ), ethoxycarbonyl ( 3m ), alkyl ( 3n ), and hydrogen ( 3o , 3p ) could be introduced, giving the corresponding pyrroles in good yield (entries 13−16).…”

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Synthesis of Polysubstituted N-H Pyrroles from Vinyl Azides and 1,3-Dicarbonyl Compounds

et al. 2007

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Two synthetic methods for tetra- and trisubstituted N-H pyrroles are presented: (i) the thermal pyrrole formation by the reaction of vinyl azides with 1,3-dicarbonyl compounds via the 1,2-addition of 1,3-dicarbonyl compounds to 2H-azirine intermediates generated in situ from vinyl azides; (ii) the Cu(II)-catalyzed synthesis of pyrroles from alpha-ethoxycarbonyl vinyl azides and ethyl acetoacetate through the 1,4-addition reaction of the acetoacetate to the vinyl azides. By applying these two methods, regioisomeric pyrroles can be prepared selectively starting from the same vinyl azides.

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“…The cooling bath was removed and stirring was continued at room temperature for 15 h. Work-up and purification gave the title compound (20 ( (14), and 165 (12). Spiro [7,8,9,1 O-tetrahydrobenzo-octene-5,2'-oxirane] (2g).-This compound was prepared from sodium hydride (60%; 0.149 g, 3.73 mmol), trimethylsulphonium iodide (0.76 g, 3.73 mmol), and 7,8,9,10-tetrahydrobenzocyclo-octen-5(6H)-one ' ' (0.50 g, 2.87 mmol) as described for compound (2a). Work-up and purification gave the title compound (2g) (0.28 g, 52%) as a colourless liquid, b.p.…”

Section: Spiro~6789-tetrahydro-5h-benzocycloheptene-52'-oxirane~ (2dmentioning

confidence: 99%

Preparation of tetrahydrobenz[cd]indoles from 1-tetralones

Beck¹,

Coates²,

Moody³

1990

J. Chem. Soc., Perkin Trans. 1

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Bridged indoles (5) are prepared from readily available aromatic ketones (1 ) by conversion into the epoxides (2), ring opening with azide ion to give the azido alcohols (3), dehydration, and thermolysis of the resulting vinyl atides (4).The tetrahydrobenz[cd]indole ring system is a key structural feature in a number of naturally occurring indoles, such as the well known ergot alkaloids,' a-cyclopiazonic acid,2 and the more recently isolated ha pal in dole^.^ Since many of these indoles possess important pharmacological properties, new routes to them are of interest: and therefore we now report the full details of a novel approach to this, and related, ring systems which starts from readily available aromatic ketones. Results and DiscussionThe route, which is shown in the Scheme, is based on cyclisation reactions of vinylnitrenes,6 obtained by thermolysis of vinyl azides, and stems from our use of such reactions in the synthesis of the left-hand unit of the antitumour antibiotic CC-1065.' The required vinyl azides (4) were prepared from the commercially avaiIable aromatic ketones (1) by conversion into the corresponding epoxides (2), ring opening with azide ion, and dehydration of the resulting azido alcohols (3).Preparation of Ep0xide.s.-The epoxides were readily prepared from aromatic ketones by reaction with dimethylsulphoxonium methylide in dimethyl sulphoxide (DMSO). Thus 1-tetralone (la), and its 5and 7-methoxy derivatives (lb,c) were converted into the corresponding epoxides in good yield. The epoxide derived from 6-methoxy-1 -tetralone is known to be very unstable, rapidly rearranging into the corresponding acetaldehyde deri~ative,~ and therefore was not investigated. Benzosuberone (la) was also readily converted into its epoxide (2d), and the epoxides (h), (20, and (2g) were prepared from 4,4-dimethyl-1-tetralone, l o dibenzosuberone, and benzocyclo-octanone ' respectively, although in the case of dibenzosuberone, the more reactive dimethylsulphonium methylide had to be used. No spiro-epoxides could be obtained from anthrone due to rapid enolisation, or from chroman-4-one due to competing attack of the sulphur ylide at C-2 with formation of the cyclopropyl ketone (6) in 29% yield.12 A variety of other conditions were tried to prepare these epoxides, but without success. To investigate the effect of an electronwithdrawing group, the glycidic ester (2b) of 1-tetralone was prepared using the Darzen's reaction. 'Ring Opening of Epoxides with Azide.-In general, this proved to be a troublesome step. The epoxides (2a-d) could be opened to the corresponding azido alcohols (3) using sodium a i d e and lithium chloride in dimethylforrnamide (DMF). The presence of lithium chloride is necessary for this reaction, which presumably involves the in situ formation of lithium azide. The

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Formal synthesis of the antitumour antibiotic CC-1065

Cited by 28 publications

References 17 publications

CC-1065 and the Duocarmycins: Synthetic Studies

CC-1065 and the Duocarmycins: Synthetic Studies

Synthesis of Polysubstituted N-H Pyrroles from Vinyl Azides and 1,3-Dicarbonyl Compounds

Preparation of tetrahydrobenz[cd]indoles from 1-tetralones

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