Isolation and synthesis of biologically active carbazole alkaloids

Heterocyclic structural architectures occur in many bioactive natural products and synthetic drugs, and these structural units serve as important intermediates in organic synthesis. This Account documents our recent progress in the development of cascade reactions to construct complex carbocycles and heterocycles. We describe the rational design of cascade reactions and in-depth investigations of their mechanism as well as their applications in the synthesis of drugs, natural products, and related molecular analogs.Relying on knowledge about the dipole-type reactivity of sulfur ylides, we have developed three different types of cascade reactions: a [4 + 1] annulation/rearrangement cascade, a [4 + 1]/[3 + 2] cycloaddition cascade, and a Michael addition/N-alkylation cascade. Using these processes, we can generate oxazolidinones, fused heterocycles, and pyrrolines starting with simple and readily available substances such as nitroolefins and unsaturated imines. We have also developed corresponding enantiose...

Development of cascade reactions for the concise construction of diverse heterocyclic architectures.

Intramolecular [4+2] and [3+2] Cycloadditions in Organic Synthesis

A concise 11-step total synthesis of (-)- and ent-(+)-vindoline (3) is detailed based on a unique tandem intramolecular [4 + 2]/[3 + 2] cycloaddition cascade of a 1,3,4-oxadiazole inspired by the natural product structure, in which three rings and four C-C bonds are formed central to the characteristic pentacyclic ring system setting all six stereocenters and introducing essentially all the functionality found in the natural product in a single step. As key elements of the scope and stereochemical features of the reaction were defined, a series of related natural products of increasing complexity were prepared by total synthesis including both enantiomers of minovine (4), 4-desacetoxy-6,7-dihydrovindorosine (5), 4-desacetoxyvindorosine (6), and vindorosine (7) as well as N-methylaspidospermidine (11). Subsequent extensions of the approach provided both enantiomers of 6,7-dihydrovindoline (8), 4-desacetoxyvindoline (9), and 4-desacetoxy-6,7-dihydrovindoline (10).

Total synthesis of (-)- and ent-(+)-vindoline and related alkaloids

Some 25 years have elapsed since the topic of metalation reactions was reviewed by Gilman and Morton. The intervening years have been notable for intensive explorations in this area, in part because many organolithium reagents are now commercially available. Specifically, research efforts have been characterized by the discovery of new functional groups that promote metalation, elaboration of novel heterocyclic and olefinic substrates as metalatable species, recognition of new types of lithiating agents, and the continuation of efforts to define accurately the mechanism of metalation. Accordingly, heteroatom-facilitated lithiation has become recognized as an increasingly important tool, not only in the elaboration of carbocyclic aromatic and heteroaromatic systems, but also in synthetic aliphatic chemistry. A few recent reviews have covered the topic in a more limited or less specific sense. It is the purpose of this chapter to survey and classify the vast accumulation of heteroatom-facilitated lithiations recorded since the first coverage in Organic Reactions.



As outlined by Gilman and Morton, the terms “metalation” in general and “lithiation” in particular denote any replacement of a hydrogen atom by metal or lithium. In this review, however, lithiation is defined as the exchange of a hydrogen atom attached to an sp2-hybridized carbon atom by lithium to form a covalent lithium-carbon bond. More specifically, discussion is limited to those metalations that, through the influence of a heteroatom, are characterized by rate enhancement and regioselectivity. In fact, lithiation reactions of this type are noted for an extraordinarily high degree of regioselectivity, metalation generally occurring on the sp2-carbon atom closest to the heteroatom. Based on the relative position of the heteroatom, such lithiations are conveniently classified into two principal categories: alpha and beta (ortho) lithiations.



In alpha lithiations the metalating agent deprotonates the sp2-carbon atom alpha to the heteroatom to form a carbonlithium bond. This sp2-carbon atom may be part of an olefinic or heteroaromatic π system.



In beta lithiations the metalating agent is directed to deprotonate the sp2-carbon atom beta to the heteroatom-containing substituent. The sp2-carbon atom can be part of an aromatic or an olefinic π system. It should be noted that the designation “ortho metalation” is used specifically for the beta metalation of carbocyclic aromatic systems.



This chapter surveys all systems in which alpha and beta lithiations have been observed, with the exception of ferrocenes.


Keywords:

lithiations;
alpha lithiations;
beta lithiations;
scope;
limitations;
alpha activating atom;
oxygen;
sulfur;
nitrogen;
selenium;
tellurium;
halogens;
beta-directing atom;
substrates;
enamines;
vinyl isocyanides;
formamides;
pyrroles;
indoles;
pyrazoles;
imidazoles;
triazoles;
tetrazoles;
alkyl vinyl ethers;
pyrazoles;
pyridines;
pyrimidines;
furans;
oxazolines;
oxazoles;
sulfides;
sulfoxides;
thiophenes;
electron-withdrawing groups;
vinyl halogens;
amines;
ethers;
sulfones;
amides;
alcohols;
ketones;
experimental procedures

Ernest B. Spitzner

Papers

Die dimerisierung von 2-vinyl-indolen und ihrer carbinol-vorstufen