Hyellazole

For the quinone imine cyclization of iron complexes to carbazoles the arylamine is chemoselectively oxidized to a quinone imine before the cyclodehydrogenation [99]. The basic strategy of this approach is demonstrated for the total synthesis of the 3-oxygenated tricyclic carbazole alkaloids 4-deoxycarbazomycin B, hyellazole, carazostatin, and 0-methylcarazostatin (Scheme 17). 

Since the late 1960s, several carbazole alkaloids oxygenated in the 3-position were isolated from diverse natural sources, the majority of which were isolated from different plant sources. However, in 1979, Moore et al. reported the isolation of two unusual, non-basic, 3-oxygenated carbazole alkaloids, hyellazole (245) and chloro-hyellazole (246), from the blue-green marine algae Hyella caespitosa (225). These alkaloids have structures entirely different from those of the carbazole alkaloids isolated from terrestrial plants. 

Danheiser et al. developed a new aromatic annotation methodology for the total s)mthesis of hyellazole (245) by irradiation of the heteroaryl a-diazo ketone 675 in the presence of 1-methoxypropyne (590). This reaction proceeds via the photochemical Wolff rearrangement of the heteroaryl a-diazo ketone 675 to generate a vinylketene, followed by a cascade of three pericyclic reactions. 

Moody et al. reported the sjmthesis of the 3-oxygenated carbazoie alkaloids, hyellazole (245) (591,592) and carazostatin (247) (593,594) based on their pyrano[3,4- 7]indol-3-one methodology (Scheme 5.57). This synthetic strategy involves the use of a 1-substituted pyrano[3,4- 7]indol-3-one 542 as a stable... 

Sakamoto et al. reported the synthesis of hyellazole (245) and carazostatin (247) based on the benzannulation of indoles. This method involves an electrocyclization of the 3-(l,3-butadienyl)indoles 685, which derive from the indolin-3-one 686 and the phosphorus ylides 687 (Scheme 5.59). 

IV-acetylhyellazole, which on deacetylation with sodium hydroxide under phase transfer conditions afforded hyellazole (245) (538,539). Removal of the acetyl group from N-acetylcarazostatin (691b), by reduction with lithium aluminum hydride, provided carazostatin (247) (595) (Scheme 5.60). 

The total syntheses of carazostatin (247), hyellazole (245), and 6-chlorohyellazole (246) based on our iron-mediated annotation require 1,3-cyclohexadiene (597) and the corresponding arylamines 708 and 709 as precursors (597-600) (Scheme 5.65). 

The arylamine 709 required for the total synthesis of hyellazole (245) was synthesized by Diels-Alder reaction of l-methoxycyclohexa-l,3-diene (710) and ethyl phenylpropynoate 711. The biphenyl derivative 719 thus obtained was transformed to the arylamine 709 by excecuting a similar reaction sequence as shown in Scheme 5.66. The arylamine 709 was obtained in six steps and 7% overall yield based on 1-methoxycyclohexa-l,3-diene (710) (599,600) (Scheme 5.68). 

Electrophilic substitution at the arylamine 709 using the complex salt 602, provided the iron complex 725 quantitatively. Sequential, highly chemoselective oxidation of the iron complex 725 with two, differently activated, manganese dioxide reagents provided the tricarbonyliron-complexed 4b,8a-dihydrocarbazol-3-one (727) via the non-cyclized quinone imine 726. Demetalation of the tricarbonyliron-complexed 4b,8a-dihydrocarbazol-3-one (727), followed by selective O-methylation, provided hyellazole (245) (599,600) (Scheme 5.70). 

An alternative method for the oxidative cyclization of the arylamine-substituted tricarbonyl(r -cyclohexa-l,3-diene)iron complex (725) is the iron-mediated arylamine cyclization. Using ferricenium hexafluorophosphate in the presence of sodium carbonate provided hyellazole (245) directly, along with the complex 727, which was also converted to the natural product (599,600) (Scheme 5.71). 

An attempt to directly convert hyellazole (245) to 6-chlorohyellazole (246) by reaction with N-chlorosuccinimide in the presence of a catalytic amount of hydrochloric acid led exclusively to 4-chlorohyellazole. On the other hand, bromination of 245 using NBS and a catalytic amount of hydrobromic acid gave only the expected 6-bromohyellazole (733). Alternatively, a direct one-pot transformation of the iron complex 725 to 6-bromohyellazole (733) was achieved by reaction with an excess of NBS and switching from oxidative cyclization conditions (basic reaction medium) to electrophilic substitution conditions (acidic reaction medium). Finally, a halogen exchange reaction with 4 equivalents of cuprous chloride in N,N-dimethylformamide (DMF) at reflux, transformed 6-bromohyellazole (733) into 6-chlorohyellazole (246) (602) (Scheme 5.73). 

Finally, cleavage of the ethyl ether of 741 using boron tribromide afforded carazostatin (247). Similarly, cleavage of the ethyl ether of 742 led to the hydroxy-carbazole 728, which, on O-methylation, provided hyellazole (245) (536,537) (Scheme 5.74). 

Duval and Cuny reported the total syntheses of hyellazole (245) and 6-chlorohyellazole (246) starting from diketoindoles 777a and 777b (606). In this methodology, the key step is the base-catalyzed intramolecular aldol condensation of the ketoindoles to fully functionalized 3-hydroxycarbazoles. 

Witulski and Alayrac reported the synthesis of clausine C (clauszoline-L) (101) by a rhodium-catalyzed alkyne cyclotrimerization of diyne 1014 and propiolic ester 635 (561). Analogous to the hyellazole (245) synthesis (see Scheme 5.75), the diyne precursor 1014 required for this key cyclotrimerization reaction was obtained starting from readily available 2-iodo-5-methoxyaniline. Using Wilkinson s catalyst, [RhClfPPhsls], crossed-alkyne cyclotrimerization of 1014 and 635 led to N-tosylclausine C (1015) in 78% yield in an isomeric ratio of 3.8 1. Finally, deprotection of the tosyl group with TBAF in refluxing TFIF afforded clausine C (clauszoline-L) (101) (561) (Scheme 5.147). 

R.L. Danheiser and co-workers have used the modified Danheiser benzannuiation for the synthesis of the marine carbazole alkaloid hyellazole. The required diazoketone was prepared from the A/-Boc derivative of 3-acetylindole using a diazo transfer reaction. The diazoketone was irradiated in the presence of the alkyne to afford the desired carbazole annulation product in 56% yield. Finally, in order to install the phenyl group of hyellazole at Cl, the phenolic hydroxyl group was converted to the corresponding triflate and a Stiiie cross-coupiing was performed. 

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