Indoles tetracyclic

A synthetic approach to the same tetracyclic y-carboline nucleus (235) is the consecutive Fischer indole and Bischler-Napieralski ring closure of o-acetamidoacetophenone methylphenyUiydrazone (234). The Bischler-Napieralski reaction has also been used in the synthesis of 3,4-benz-j8-carbolines (236) and 3,4-benz-3-carbolines, e.g. 237... 

Further elaboration of tetracycle 159c resulted in the syntheses of the racemate of indole alkaloids of the ajmalicine (61JA2594), tetrahydroalstunine (56JOC1315, 71JA5907), and akuammigine type (ajmalicinoid alkaloids). Similarly, 159d can be converted into yohimboid alkaloids (79JA5370). 

Formylation of the V-allyl indole derivatives 311 (obtained by allylation of the indole 310) afforded l-allyl-7-formyl-indole 312. Subsequent condensation of 7-formyl indole derivatives 312 with ethyl acetate in presence of sodium ethoxide gave 313 (89S322). Reaction of 312 with N-methylhydroxylamine hydrochloride afforded the cycloadduct, tetracyclic... 

The aniline derivative 332, prepared from 2-fluoro-6-nitrotoluene, was transformed through successive reactions as shown in Scheme 60 to give the functionalized indole 333. It was then reduced with LiAlH4 to the dimethylaminopropyl derivative which was quaternized with Mel to the trimethyl ammonium salt 334. Subsequent cyclization and functionalization afforded the pyrroloquinoline 335. The latter could be transformed to the tetracyclic acid 336 (90JHC2151). (Scheme 60)... 

Fig. 8.10 The X-ray crystal structure of a tetracyclic compound bound to hepatitis C virus NS5B544 polymerase. The observed dihedral angle between the indole ring and phenyl ring is 47°, which is in agreement with the predictions.

Waldmann used (R) and (5>aminoacid methyl esters and chiral amines as chiral auxiliaries in analogous aza-Diels-Alder reactions with cyclodienes.111 The diastereoselectivity of these reactions ranged from moderate to excellent and the open-chain dienes reacted similarly. Recently, the aza-Diels-Alder reaction was used by Waldmann in the asymmetric synthesis of highly functionalized tetracyclic indole derivatives (Eq. 12.45), which is useful for the synthesis of yohimbine- and reserpine-type alkaloids.112... 

MgS04, the tetracycles 2-648 were obtained with excellent diastereoselectivity in reasonable yield. The reaction presumably starts with a condensation of the aldehydes 2-645 with the benzyl-protected amine moiety of 2-644 to give an iminium ion which can subsequently cyclize to afford the spirocyclic intermediates 2-646. A [3,3] sigmatropic Cope rearrangement then forms the nine-membered cyclic enamines 2-647 which, after protonation, act as the starting point for another indole iminium cyclization to provide the tetracycles 2-648 via 2-647. 

The pyrido[3, 4 4,5]furo[3,2-A]indole 24 can be prepared by Curtius rearrangement of 3-[5-(2-nitrophenyl)-2-furyl]-propenoic azide 25, followed by reduction of the nitrophenyl functionality of the product 26, chlorination of the tetracyclic product (PCI5), then reduction (Zn/AcOH) to give the parent compound 24 <1987CCC192> (Scheme 7). 

Dimethyl-3/7-indole reacts with diethyl oxaloacetate in acetic acid to give the pyrrolizine 157. Upon reaction of this product with guanidine for extended periods of time, the tetracyclic product 158 is formed in low yield <1988J(P1)451> (Scheme 46). 

Treatment of the protected aldehyde 342 with a TFA/water/chloroform mixture results in the formation of a 10-membered intermediate iminium cation intramolecular attack of this electrophile at C-2 of the indole (an intramolecular Pictet-Spengler reaction) gives the isolated tetracyclic product 343 in good yield (Equation 124) <1995T4841>. 

Scheme 4.6 The common core structure of many indole monoterpene alkaloids might be accessed through a tetracyclic Zincke aldehyde-derived building block...

We became particularly interested in strychnine when we noticed that the tetracycle 21 (Scheme 4.6), which might be readily available by an intramolecular Diels-Alder cycloaddition of a tryptamine-derived aminodiene, contains much of the complexity of this popular alkaloid target. In fact, this tetracycle is common to many indole monoterpene alkaloids including members of the Strychnos, Aspidosperma, and... 

Another tetracyclic /Tcarbolinc that has been evaluated for antitumor activity is indolizino [8,7-fo]indole 88 (Fig. 28). Alkylation of 1-ethyl-/3-carboline... 

Additional work around the benzimidazole scaffold on compounds related to 29 [72,73] suggested that the dihedral angle between the heterocycle and the phenyl ring is a crucial determinant of binding affinity, leading to the design of tetracyclic compounds with the aromatic moieties linked [74], Thus, indole... 

Arylthioindole-2-carboxylic acids 303, obtained from aryl disulfides and indole-2-carboxylic acids, afford tetracyclic 5H-indolo-[3,2-fc][l,5]benzothiazepin-6(7H)-ones 304 on treatment with EDC-DMAP (Scheme 65 (1998MI139)). 

A more recent publication (96F1(43)15) reports the synthesis of tetracyclic derivative azocino[4,3-f>]indole 49 using an intramolecular aldol condensation of carbazole 48. The possible elaboration of effective synthetic methods of the... 

Unusual recyclizations of hexahydroazocino[4,5- 7]indole derivatives under the action of aliphatic aldehydes have been described (01JCXI 5303). Thus, azocinoin-dole 109, in the presence of aldehyde 110, has been transformed into tetracyclic 111 in quantitative yield and isolated as a mixture of two diastereoisomers (Scheme 31). 

Intramolecular Heck-type reaction of 2-bromo-A -(I//-indol-l-yl)-A -methylnicotinamide 241 yielded tetracyclic 6-methylpyrido[3, 2 4,5]-pyridazino[I,6- ]indol-5(6//)-one 242 in 92% yield (Equation 57) <1995TI94I>. 

Especially interesting is the alkylation of 3 (R = CH2OCH3) with 4-bromo-l-chlorobutane to afford the chloroalkyl derivative with very high enantioselectivity46. Depending on the mode of deprotection of both nitrogen atoms, tetracyclic indole derivatives 5 or 6 were obtained. 

A number of reduction products of 2,8-dichloro-6,12-diphenyldibenzo[f>,/][l,5]diazocine (283) have been obtained (66JOC3356). LAH in ether gives mainly the frans-diphenyl-tetrahydro compound (282), whereas reduction in pyridine stops at the dihydro stage (284) (78%). Catalytic hydrogenation or zinc-acid reduction gives the tetracyclic indolo[3,2-6]indole system (286) which is readily oxidized back to the diazocine. Transannular cycliz-ation to (286) occurs on treatment of the dihydrodiazocine with NaH. Troeger s base derivatives, e.g. (287), were formed from the tetrahydro derivatives with formaldehyde. 

The susceptibility of the indole ring towards electrophilic attack has also been exploited by Merour in the annulation of a coumarin unit to the indole ring. The heating of the o-bromophenyl ester of indole-2-carboxylic acid in the presence of a palladium-triphenylphosphine catalyst led to the formation of the tetracyclic product in 66% yield (4.32.)40... 

Kozikowski s group has been particularly active in the application of the INOC reaction toward the construction of a variety of natural products. One of the many examples from his laboratory involves the synthesis of tetracyclic compounds possessing suitably functionalized C rings for elaboration to a diverse number of ergot alkaloids via the INOC reaction. A total synthesis of chanoclavine I (65) was accomplished by this chemistry (Scheme 15). The key step in the synthesis involved the conversion of the nitro group of indole (62) into the corresponding nitrile oxide using the phenyl isocyanate procedure developed by Mukaiyama.57 The major product corresponded to isoxazoline (64). The isoxazoline nucleus was converted into chanoclavine I (65) in a series of subsequent steps. The application of nitrile oxide cycloaddition chemistry to the construction of other natural products can be expected to be an active area in future years. 

Treatment of the product derived from reaction of the iV-oxide 1 with trifluoroacetic anhydride with sodium borohydride gives the tetracyclic indole derivative 2. 

Many of the most elegant syntheses of complex natural products are based on mechanistic speculation, as illustrated by the following postulated entry to stiychnine-based alkaloids. Thus, it was reasoned that treatment of the indole 1 with methyl chloroformate and a non-nucleophilic base followed by acid catalysed rearrangement would lead to the tetracycle 2. In practice, the first step worked well when Hiinig s base was used, but the second step, the acid catalysed rearrangement, failed to give 2. The only product, isolated in good yield, was the carbazole 3. 

Tetracyclic pyrimido[l, 2 l,2]pyrido[3,l- >]indole derivative 606 (R = H) was obtained when 9-bromotetrahydropyrido[ 1,2- ]pyrimidin-4-one 604 (R = H) reacted with Af-methylaniline in boiling ethanol for 8 hours under nitrogen in 37% yield (Scheme 40) (91JHC1405). In the reac-... 

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