Intramolecular Approach

Intramolecular Approaches (type I) Intermolecular Approaches (type II) 

The intramolecular condensation of ort/ro-(2-oxoalkyl)analines continues to provide reliable access to the indole ring system. Kerr and Jackson prepared the indole core of herbindole B 89 in three steps (80%) via oxidation of the Diels-Alder adduct 81 (Plieninger indolization) as illustrated below 07JOC1405 . A similar strategy was applied by the same group in the total synthesis of ( )-decursivine 07EJOC237 . 

A few type lb intramolecular strategies for construction of the indole core have appeared. In their synthesis of (+)-vinblastine, the Fukuyama group employed radical cyclization of thioanilide 93 to generate the indole skeleton of 94 in 77% yield 07OL4737 . 

Alternative approaches to indole construction that rely on radical cyclization have been reported by Bowman and co-workers who used aniline derived imidoyl selanides 95 as radical precursors 07T191 . The Ogawa group has also reported the photoinduced thiotelluration of isocyanides, e.g., 97 to 98 07TL5953 . 

Intramolecular nucleophilic additions by nitrogen functional groups onto pendant alkynes and allenes represent an important class of type la approaches to functionalized pyrroles. A platinum-catalyzed (PtCl4) cyclization of homopropargyl azides provided an entry to 2,5-disubstituted pyrroles and 4,5,6,7-tetrahydroindoles (fused pyrroles) 06OL5349 . 

The addition of a carbonylation step extended a pyrrole synthesis to pyrrole-2-acetic acid derivatives 06ASC2212 . Treatment of enyne amine 1 with palladium diiodide in the presence of CO and methanol produced pyrrole-2-acetic ester 2 via a 5-exo-dig cyclization, oxidative carbonylation, and isomerization. 

A ring opening reaction of (1-lactams promoted by methoxide generated nitrogen nucleophiles in situ that subsequently added to proximal allenes producing trisubstituted pyrroles 06CC2616 . In the event, treatment of (3-lactam 3 with MeONa led to pyrrole-2-acetic ester 4 after cleavage of the amide bond, 5-exo-dig cyclization, and loss of methanol. The sequence was notable as no metal catalyst was required. 

A thermal ring opening reaction of an imine-substituted cyclopropene led to a mixture of 2,3,4-trisubstituted and 3,4,5-trisubstituted pyrroles 06TL5793 . 

Two type la syntheses of (3-hydroxypyrroles have appeared. An aza-Nazarov cyclization of l-azapenta-l,4-dien-3-ones produced (3-hydroxypyrroles including 2,2 -bipyrroles 06EJO5339 . A second approach to a (3-hydroxypyrrole involved an intramolecular N-H insertion into a rhodium carbene derived from the decomposition of a diazoketone 06JOC5560 . On the other hand, the photochemical decomposition of the diazoketone led to pyrrolidin-2-ones. 

Treatment of hydrazonium salt 4 with palladium(0) led to the formation of p3UTole 5 via 5-exo-trig amino-Heck cyclization 05H(65)273 . The reaction presumably proceeds by the oxidative addition of palladium(O) into an A-Abond. An oxidative addition into the A-O bond of benzoyloximes was the key step in the 5-endo-trig amino-Heck cyclization leading to 5-fluoro-3A-pyrroles 05CC4684 . 

Treatment of azidoketones 8 with triphenylphosphine led to the formation of pyrrolidine 9 via a Staudiner-aza-Wittig reductive cyclization 05JOC4751 . The latter were converted into 2,3-disubstituted pyrroles 10 upon heating. Azidoketones 8 were prepared by the novel condensation of 1,3-bis-sUyl enol ethers 6 with azidoacetal 7. This sequence was exploited for the synthesis of a cyclododecyl-fused pyrrole. 

A type Ib cyclization involving ketene-iV,S-acetals led to the formation of highly functionalized pyrroles including 4-acetylpyrrole-2-carboxylates 05SC693 and 3,4-diarylpyrroles 05TL475 . The latter are useful building blocks for the preparation of the lamellarin alkaloids. Another approach to the lamellarin framework involved a 1,5-electrocyclization of azomethine ylides 05TL7531 . 

A novel s3mthesis of [fc]-fused pyrroles involved an intramolecular cyclization of enaminones (Knorr-t) e p3rrole synthesis) 0583152 . Treatment of Weinreb amide 20 with two equivalents with thienyUithium led to intermediate ketone 21 which cycloisomerized into pyrrole 22 upon heating. 

A one-pot Trofimov reaction (type Ilac cyclization) has been developed 05ARK(vii)ll . Treatment of ketoximes with acetylene in the presence of superbase (KOH/DMSO) gave 2-substituted and 2,3-disubstituted p)Troles. 

---

The intramolecular approach of Staab and Graf, shown in Scheme 4, precluded formation of 5, but was considerably more involved [12]. The cyclic dienyne 6 was afforded by Wittig reaction of o-phthaldialdehyde with the corresponding bis(ylide) derived from tolane. Bromination of 6 and subsequent treat-... 

In order to minimize the formation of side products, PAM 4 can be assembled via an intramolecular approach [23]. The Sonogashira protocol [15] and conversion of masked iodides [24] comprises most of the chemistry involved in Scheme 7. Using these proven methods, diyne 16 and subsequently triyne 17 can be prepared quickly. lodination, desilylation, and intramolecular alkynylation with Pd(dba)2 under high dilution conditions furnished 4 as the sole product. 

As with the corresponding section on pyrroles, indole syntheses have been categorized utilizing a systematic approach. Intramolecular approaches (type I) and intermolecular approaches (type II) are classified by the number and location of the new bonds that describe the indole forming step (2 examples shown below). In addition, the synthesis of azaindoles,... 

To this point, all the examples presented have been ones in which the origin of the asymmetric induction has been unimolecular in nature, that is, the molecules adopt homochiral conformations in the solid state that favor the formation of one enantiomer over the other, usually through the close intramolecular approach of reactive centers bimolecular crystal packing effects appear to play little or no role in governing the stereochemical outcome of such reactions. This raises the interesting question of whether the soUd-state ionic chiral auxiUary approach to asymmetric synthesis could be made to work for conformationally unbiased reactants, i.e., those possessing symmetrical, conformationally locked structures. Two such cases are presented and discussed below. 

It is possible to carry out the [2+2+2] cyclotrimerization reaction in a regioselective manner by using a partially or completely intramolecular approach. Rhodium-catalyzed intramolecular cyclotrimerization of 1,6,11-triynes, which construct fused 5-6-5 ring-systems, has been studied extensively [33-36]. Cyclization of 1,6,11-triyne 47 catalyzed by RhCl(PPh3)3, gives the tricyclic benzene 48 in good yield (Eq. 14) [33a]. 

Halogen displacement in 2,3-dihalogeno-l,4-oxathiins has been exploited. An intramolecular approach with a carboxamide function as nucleophile affords the bicyclic /3-lactam 97 <1999H(50)713>. An intermolecular substitution with sodium A,A-dimethyldithiocarbamate in acetonitrile was also reported to give 98 after HBr elimination <1996S198>. 

The rare reports of quinolizidine formation by a nitrone cycloaddition strategy include the racemic total synthesis of lasubine II (58), one of a series of related alkaloid isolated from the leaves of Lagerstoemia subcostata Koehne (Scheme 1.14) (104). While these alkaloids were previously accessed by infennolecular nitrone cycloaddition reactions, this more recent report uses an intramolecular approach to form the desired piperidine ring. Thus, cycloaddition of nitrone 59 affords predominantly the desired bridged adduct 60 along with two related... 

Muthusamy et al. (89) approached the formation of decahydrobenzocarbazoles 191 utilizing an indolic five-membered olefin 190 as the dipolarophile in reaction with a carbonyl yhde derived from 189. This intermolecular approach is strategically similar to an intramolecular approach to aspidosperma alkaloids developed by Padwa (Scheme 4.47). 

In an approach to a dihydrooritidine analogue, the intermolecular [2 + 2]-photo-cycloaddition of 2, 3 -0-isopropylideneuridine to chiral and achiral acrylates was found to be unsatisfactory both with respect to regio- and diastereoselectivity. The intramolecular approach was more successful, and uridine 143 produced selectively the single diastereomerically pure product 144. Due to concurrent photodimerization and polymerization reactions, however, the yield was only moderate (Scheme 6.50) [136]. 

Another independent intramolecular approach to cyclophanes was based on a macro-cyclization [74]. 

Negishi and co-workers demonstrated the feasibility of this carbopalladation mode on an allene in an intramolecular approach to medium and large rings [80]. The new C —C bond is fornied at the central carbon atom of the allene moiety to give a jr-allylpalladium complex, which in turn can be trapped by a variety of nucleophiles (arylstannanes to give arylated products, malonates, phenols, amines, etc.) (Scheme 3-27). The yields are remarkably good without using sophisticated nucleophile delivery techniques. 

Another intramolecular approach to C-linked disaccharides has been described by Skrydstrup and Beau [116] using 2-pyridyl sulfones to generate anomeric radicals. Tethering sulfone 280 with chlorosilane 279 provides silyl ether 281 (O Scheme 60). 

---