Hexacycles

Denitrocyclization reaction was also used for the preparation of hexacyclic derivative 278, which was obtained in 80% yield by heating of 277 with a solution of sodium hydroxide in aqueous DMF (66JCS(C)1245, 70JCS(C)2647). Low to moderate yields of 3,6-dinitroxanthen-9-one (281) is formed by a treatment of tetranitro derivative 279 with either potassium hydroxide or sodium... 

The structure of carpanone (1) was revealed by Australian scientists in 1969.1 Carpanone, a hexacyclic molecule and host of five contiguous stereogenic centers, is a lignan found in the bark of the car-pano tree. 

A sequence of two thermal intramolecular cycloadditions has been used to develop a short synthetic approach to tetrahydrothiopyrans [122], The multiple process includes an m m-hetero- and an intramolecular-carbon Diels-Alder reaction. An intramolecular /zctcro-Diels-Alder reaction of divinyl-thioketone 134 afforded a 9 1 mixture of cycloadducts 135 and 136 which then underwent a second intramolecular cycloaddition which syn o H-2)-exo-diastereoselectively led to hexacyclic tetrahydrothiopyrans 137 and 138, respectively (Scheme 2.51). 

FIGURE 4.2 The Funk crossover strategy for the hexacyclic core of nomofungin. 

When n electron donors are involved, the XB is preferentially along the axis of the donated lone pair on D. For instance, XBs around ethers, thioethers, and amines feature a tetrahedral arrangement with preferential axial directions for the XBs around hexacyclic amines, and equatorial directions for hexacyclic thioethers [16,17,124,139-142] (Fig. 6). 

The rigidity of the hexacyclic cage structure of koumine (18) renders some of its chemical behavior quite unusual, for instance, the resistance to Hofmann degradation shown by /Va-acetyldihydrokoumine methyl hydroxide (27). However, owing to the presence of a /J-aromatic imino system in 18, reductive cleavage by sodium-alcohol to yield dihydrokouminol (39) proceeds smoothly. This reaction has been considered to occur through a radical-anion mechanism as indicated in Scheme 12 (27). 

Another beautiful example of an early domino process is the formation of daphnilactone A (0-19), as described by Heathcock and coworkers [17]. In this process the precursor 0-17 containing two hydroxymethyl groups is oxidized to give the corresponding dialdehyde, which is condensed with methylamine leading to a 2-azabutadiene. There follow a cycloaddition and an ene reaction to give the hexacycle 0-18, which is transformed into daphnilactone A (0-19) (Scheme 0.6). 

The fungal metabolite, 5-A-acetylardeemin, possessing a hexacyclic structure with a l,4-dihydro-3,6-dioxo-pyra-zino[2,l-A]quinazoline skeleton, is the best multidrug resistance reversal agent known to date <1998MI45>. Hexahydro-3,6-dioxo-pyrazino[2,l-7]quinazolines have been claimed as endothelial nitric oxide synthetase regulators useful in the treatment of cardiovascular disorders <2004EP1471066>. 

Interesting hexacyclic mesomeric betaines 237 can be prepared by a modification of classical procedure (see CHEC-II(1996) <1996CHEC-II(8)747>) from 236 and triethylphosphite (Equation 34) <1994JHC1283>. 

Synthesis <1984CHEC(4)443, 1996CHEC-II(8)967>, spectroscopy <1996CHEC-II(8)967>, and reactivity <1984CHEC(4)443> of [2.2.3]cyclazines and their aza-derivatives have been previously reviewed. Pyridylcyclazine 485 was obtained as an intermediate in the synthesis of hexacyclic cyclazinocyclazines (Scheme 38) <1997H(45)2223>. 

In an alternative approach to annulation across the indole 2,3-tt system, Padwa and coworkers have reported approaches to the pentacyclic and hexacyclic frameworks of the aspidosperma and kopsifoline alkaloids respectively that involve as the key step a Rh(II)-promoted cyclization-cycloaddition cascade <06OL3275, 06OL5141>. As illustrated in their approach to ( )-aspidophytine 150, Rh2(OAc)4-catalyzed cyclization of a diazo ketoester 148 affords a carbonyl ylide dipole that undergoes [3+2]-cycloaddition across the indole 2,3-tt bond to generate 149 <06OL3275>. 

These hexacyclic hydrocarbons are generally recognized as two of the most potent unsubstituted carcinogenic PAH (38). The 3,4-dihydro-diol of dibenzo(a,i)pyrene (17) and the 1,2-dihydrodiol of dibenzo-(a,h) pyrene (lg) have been synthesized from 4-oxo-l,2,3,4-tetra-hydrodibenzo(a,i)pyrene and 1-oxo-l,2,3,4-tetrahydrodibenzo(a,h)py-rene, respectively, by Method I. (69). Treatment of these dihydro-diols with m-chloroperbenzoic acid gave the corresponding anti diol epoxides (66). 

For the synthesis of the bis-cyclo-octatetraene compound [5] (Krummel et al, 1987 Auchter-Krummel and Mullen, 1991), cyclo-octatetraene dianion was quenched with tetrabromoneopentane to give the bis-adduct [23], which exists in an equilibrium between valence isomers [23a] and [23b]. Hexacycle [23a] was actually isolated in about 60% yield (Fig. 2) (Krummel et al, 1987). Accordingly, in the subsequent dehydrogenation, the formation of [23a] must be avoided by working at low temperatures in this case it was possible to deprotonate the originally formed isomer [23b], obtaining a... 

The efficacy of the procedure for the synthesis of highly complex systems, and the utility of the enol ether functionality obtained in the reaction is demonstrated by the conversion of the intricate polyether 134 to enol ether 135 and its subsequent elaboration to the hexacyclic system 138 (Scheme 20) [34a]. 

Scheme 20. Synthesis of hexacyclic polyether 138. (a) 4.0 equiv of Tebbe reagent (93), THF, 25 °C, 0.5 h then reflux, 10 h, 71% (b) BH3 then H202 (c) Dess-Martin reagent, 60% for two steps (d) TBAF, 60% (e) Et3SiH, BF3.Et20,91% (Nicolaou et al.) [34a]...

The intramolecular version of the Heck reaction has been extremely fruitful, enabling elegant synthesis of many complex molecules [68, 69]. The Mori-Ban indole synthesis (Section 1.10, vide infra) is a good example of such method. In addition, Rawal et al. carried out an intramolecular Heck cyclization of pentacyclic lactam 55 with a pendant vinyl iodide moiety [70]. Employing Jeffery s ligand-free conditions, 55 was converted to a hexacyclic strychnan alkaloid precursor 56 with complete stereochemical control... 

C6 and C9 are at opposite ends of a four-carbon unit, but since one of these atoms (C7) is saturated and quaternary, a Diels-Alder reaction is unlikely (can t make diene). The combination of a diazo compound with Rh(II) generates a carbenoid at C9. The nucleophile 06 can add to the empty orbital at C9, generating the 06-C9 bond and a carbonyl ylide at C6-06-C9. Carbonyl ylides are 1,3-dipoles (negative charge on C9, formal positive charge on 06, electron deficiency at C6), so a 1,3-dipolar cycloaddition can now occur to join C2 to C6 and Cl to C9, giving the product. Note how a relatively simple tricyclic starting material is transformed into a complex hexacyclic product in just one step ... 

Dailey and colleagues109 employed a domino Diels-Alder reaction to synthesize the complex hexacycle 146. The intermolecular reaction of tetracycle 143 with maleic anhydride 144 afforded a single adduct (145) which immediately underwent an intramolecular Diels-Alder reaction to give 146 (equation 42). This reaction is similar to a reaction performed previously by Prinzbach and colleagues110. Prinzbach observed that when alkynes were used as dienophiles, either domino or pincer Diels-Alder reactions occurred. In the latter type, the triple bond reacts with both diene units. 

Itoh and coworkers111 carried out tandem [2 + 2 + 2]/[4 + 2] cycloadditions catalyzed by a ruthenium catalyst. The reaction of diyne 147 with excess norbomene 148 in the presence of ruthenium catalyst 153, for example, afforded 149. Adduct 150 either dissociated from the catalyst or reacted with another equivalent of norbornene. In the latter case, a ruthenium catalyzed Diels-Alder reaction occurred, affording hexacyclic adduct 152 via 151 (equation 43). Compounds 150 and 152 were obtained in yields of 78% and 10%, respectively. Both cycloaddition reactions proceeded with complete stereoselectivity. When 1,6-heptadiyne was used instead of 147, only trace amounts of a cycloadduct were obtained. Replacing norbornene by norbornadiene, which was expected to result in polymer formation, did not afford any adduct at all. 

Furthermore, HPLC analyses of the crude extract of C. cacti revealed the presence of another minor compound, which showed a UV spectrum similar to those of chilocorines A and B. By several cycles of preparative TLC, chilocorine C (21) was isolated. Its hexacyclic structure was proposed on the basis of UV, IR, NMR and mass spectral evidence. Interestingly, the structure of chilocorine C incorporates a l-(hydroxymethyl)-7-methylperhydro-8fo-azaacenaphtylene skeleton in place of the classical 2-methylperhydro-9fo-azaphenalene moiety [35]. 

Scheme 8.5 Alkyne metathesis reactions of polymer 35 prepared from the (a) Sonogashira condition and (b) hexacycle 36 and diphenylacetylene [35].

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