Hexahydropyrroloindoles

Fig. 9.1 Representative dimeric hexahydropyrroloindole alkaloids, (a) Dimeric epipolythiodiketopiperazine alkaloids, (b) Calycanthaceous alkaloids, (c) Dimeric diketopiperazine alkaloids...

These epipolythiodiketopiperazine alkaloids, together with the calycanthaceous alkaloids (Fig. 9.1b), form a superfamily of natural products termed the dimeric hexahydropyrroloindole alkaloids [6-8]. The main dichotomy within this superfamily arises from the biogenetic elaboration of tryptamine versus tryptophan building blocks. The tryptamine-based calycanthaceous alkaloids, boasting members such as chimonanthine (7), calycanthine (9), and folicanthine (8), are largely plant derived and have a long and rich history in the context of natural product synthesis [7, 9]. 

Finally, Crich [31] and Danishefsky [32] demonstrated that enantioselective hexahydropyrroloindole formation could precede C3-quatemary center formation. The carbon-carbon bond formation could be accomplished through a stereoretentive cationic or radical process as demonstrated through the reverse-prenylation reaction in Danishefsky s synthesis of amouramine [32a, b] or the allylation reaction en route to Crich s synthesis of (+)-debromofhistramine [33], respectively. 

The versatile oxindole nucleus has been stitched into designs for the total synthesis of other heterocyclic systems including the hexahydropyrroloindoles esermethole and physostigmine <07CEJ961> as well as pyrrolidinoindoline natural products <07TL1805>. ... 

Okaramine A (1) is a novel heptacyclic compound containing a hexahydropyrroloindole moiety and a dihydroazocinoindole moiety. The azocinoindole moiety has been reported to constitute only two compounds a metabolite (48) of Aspergillus ustus [31] and cycloechinulin (49) produced by A. ochraceus [32] (Fig. (8)). One of the structural characteristics of the okaramine family is the presence of a reverse-prenylated hexahydro[2,3-Z>]pyrroloindole moiety. Some related... 

An intermolecular cyclization approach to C3 asymmetric oxindoles has been devised by Smith and coworkers who paired chiral A-phenylnitrone nucleophiles with ketene electrophiles, e.g., intermolecular fusion of 54 and 55 [37]. As illustrated in Scheme 16, the oxindole skeleton 57 materialized in 87% ee following a proposed sequence of nitrone addition to the ketene, a hetero-Claisen rearrangement, imine hydrolysis and, finally, cyclization to generate the lactam linkage. As an extension of this methodology, (5)-3-allyl-3-phenyloxindole 57 was transformed into enantiopure 3-phenyl-hexahydropyrroloindole scaffold 58. 

Using molecular oxygen as the oxidizing agent, the Itoh group has achieved the enantioselective preparation of 3-allyl-3-hydroxyoxindole 90 (85% ee) under phase-transfer conditions with the cinchonidine derived catalyst 89 [54]. The oxindole 90 was further manipulated to a key intermediate that has been applied in a prior synthesis of the hexahydropyrroloindole CPC-1 [55] (Scheme 24). 

The Kobayashi group has observed the intramolecular diastereoselective spirocyclization of racemic 2-haloindoles bearing a C3-tethered allylic alcohol [71, 72]. For example, CuCl-catalyzed intramolecular Ullmann coupling of 117 followed by spontaneous Claisen rearrangement of the intermediate pyranoindole 118 afforded, in a one-pot synthesis, the all-carbon quaternary center of spiro-oxindole 119 in 95% de (Scheme 31). The methodology has been extended to the synthesis of hexahydropyrroloindoles, e.g., ( )-debromoflustramine B and E. 

Oxindoles with defined stereochemistry at C3 have served as valuable precursors for entry into tetrahydro- or hexahydropyrroloindole natural product scaffolds. As illustrated in Table 1, a variety of approaches to asymmetric oxindole synthesis have been applied for introduction of the key C3 stereocenters embodied within (+)-aUine [84, 85], CPC-1 [86], ( )-esermethole (a formal synthesis of ( )-physostigmine) [87-90], (+)-gliocladin C [91], and (-l-)-asperazine [92]. 

Scheme 27 Synthesis of indolyl-hexahydropyrroloindole 40, a precursor of psychotrimine.

Z.-tryptophan, and the subsequent cyclization to form the hexahydropyrroloindole moiety the y-hydroxylation of the pipeiazic acid (Pip) motif catalyzed by HmtN and the biaryl aromatic coupling between cyclic depsipeptide monomers catalyzed by HmtS to create the active dimer form of himastatin... 

In 2012, Zhang and coworkers [123] synthesized interesting hexahydropyrroloindole alkaloids (moieties that appear in a wide selection of alkaloids and drug candidates) using a highly useful copper-catalyzed intramolecular arylation-alkylation of o-bromoanilides (Scheme 8.72). 

More recently, Qin has developed a new cascade reaction to afford 3-substituted hexahydropyrroloindole III-38 [67]. The key steps are the formation of a cyclopropane intermediate III-36 and the consecutive nucleophilic attack of a pendant amine on the C=N bond of the resulting indolenium ni-37 (Scheme 4.18). This methodology has been applied for the total synthesis of (-)-ardeemin. [69]... 

The conditions reported by the Qin group for the intermolecular cyclopropanation of 3-substituted hexahydropyrroloindole provided unsuccessful results (Table 4.3, entry 3) [65, 69]. Furthermore, no conversion was observed using Cu(OTf)2, CuOTf, IMF copper(l) 27 or IMes gold(I) 15 complexes as catalysts (Table 4.3, entries 3-7) [116, 117]. Only starting material was recovered under the optimized conditions. This is probably due to the higher steric hindrance of the indole III-35, in comparison with methyl l//-indole-l-carboxylate, preventing the nucleophilic attack of the enamine moiety. 

Later, Savige 339) reported that the hexahydropyrroloindole (46) reacted readily with thiols in aqueous acetic acid to give the correspond-... 

The isolation of the hexahydropyrroloindole derivative (46) on photooxidation of tryptophan irradiated in water in the presence of methylene... 

Photooxidation of the tryptamine derivative (73) in the presence of pyridine N-oxide in methylene chloride solution using 2537A light affords the analogous hexahydropyrroloindole (75), the epoxide (74) being the proposed intermediate 274, 275),... 

Conversion of (144) to (145) has been previously shown to occur on treatment of the hexahydropyrroloindole (147) obtained by peracetic acid oxidation of tryptophan (see Section III. 1.1.). (147) is converted by 2N HCl to the oxindole (145) in dilute acetic acid (147) can also add thiols giving 2-thioether indole compounds (141) 339). 

The reaction of hexahydropyrroloindole (HPI) (46) with thiols to give the corresponding 2-thioether-tryptophan compounds has been further investigated (464). Reaction of cysteine with HPI (1.2 equiv) in 25% tri-fluoroacetic acid produces quantitatively tryptathionine, an amino acid contained in the toxic peptides of Amanita phalloides (see Section VI.2.4.). Reduced ribonuclease, a protein containing 8 cysteine residues per molecule, was treated with HPI, and the modified protein purified by gel filtration. The completeness of the reaction was confirmed by hydrolysis with /7-toluenesulfonic acid (233) and analysis of the hydrolyzate. A value of 7.6 (theory 8) residues per mole of protein of oxindolylalanine, the product of hydrolysis of the tryptathionine residues (431) (see Section III.4.2.), was obtained. This new reaction of cysteine residues should be of value in peptide synthesis, providing a simple method for linking tryptophan and cysteine as a basic step in the chemical synthesis of the peptides of Amanita phalloides. 

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