Total synthesis

About: Total synthesis is a research topic. Over the lifetime, 25578 publications have been published within this topic receiving 489319 citations.

β-Lactones: Intermediates for natural product total synthesis and new transformations

Abstract: The exploration of β-lactone reactivity and transformations has continued since the first synthesis of these strained heterocycles by Einhorn in 1883. The principal reactivity modes of β-lactones include nucleophilic addition resulting in either acyl C2-O1 or alkyl C4-O1 cleavage, rearrangement leading to ring expansion, decarboxylation, and electrophilic reactions of β-lactone enolates. Recent advances in asymmetric β-lactone synthesis has led to further developments in the area of novel transformations of (3-lactones and significantly increased applications in natural product total synthesis. The latter topic is the focus of this review and covers the period inclusive to the end of 2003.

Total Synthesis of the Turrianes and Evaluation of Their DNA-Cleaving Properties

Abstract: The first total synthesis of three naturally occurring cyclophane derivatives belonging to the turriane family of natural products is described. Their sterically hindered biaryl entity is formed by reaction of the Grignard reagent derived from aryl bromide 10 with the oxazoline derivative 18, and the macrocyclic tether of the targets is efficiently forged by ring closing metathesis. While conventional RCM catalyzed by the ruthenium-carbene complexes 33 or 34 invariably leads to the formation of mixtures of both stereoisomers with the undesirable (E)-alkene prevailing, ring closing alkyne metathesis (RCAM) followed by Lindlar reduction of the resulting cycloalkynes 37 and 38 opens a convenient and stereoselective entry into this class of compounds. RCAM can either be accomplished by using the tungsten alkylidyne complex [(tBuO)3 [triple bond] WCCMe3] or by means of a catalyst formed in situ from [Mo(CO)6] and para-trifluoromethylphenol. The latter method is significantly accelerated when carried out under microwave heating. Furthermore, the judicious choice of the protecting groups for the phenolic -OH functions turned out to be crucial. PMB-ethers were found to be compatible with the diverse reaction conditions en route to 3-5; their cleavage, however, had to be carried out under carefully optimized conditions to minimize competing O-C PMB migration. Turrianes 3-5 are shown to be potent DNA cleaving agents under oxidative conditions when administered in the presence of copper ions.

The First Total Syntheses of Ircinol A, Ircinal A, and Manzamines A and D.

Abstract: In 1986, Higa, Jefford, and co-workers reported the isolation of a structurally novel polycyclic alkaloid, manzamine A, 1, from a sponge harvested near the coast of Okinawa.1 The unique structure of 1 consists of a β-carboline heterocycle attached to a novel pentacyclic diamine core containing both eight- and thirteen-membered rings on a pyrrolo[2,3-i]isoquinoline framework. The cytotoxic activity (IC50 = 0.07 µg/mL against P-388 mouse leukemia cells) and unique structure of 1 have stimulated considerable interest and activity directed toward the total synthesis of manzamine A which has not yet been successfully achieved to date.2 The intramolecular vinylogous amide photoaddition/fragmentation/Mannich closure sequence that we have developed has been applied to the stereoselective synthesis of complex structural types including mesembrine and the aspidosperma alkaloids from simple precursors.3 We have described the application of this methodology to the construction of the tetracyclic core of the manzamine alkaloids, in which the single stereocenter on the unsaturated eight-membered ring template 2 dictates all of the requisite stereochemical relationships embodied in 3, which represents the tetracyclic core of manzamine A.4 Outlined herein is the extension of these preliminary investigations to the first total synthesis of manzamine A.

Total synthesis of (+)-haplophytine.

Abstract: Despite the many impressive accomplishments in the field of total synthesis in recent years, a number of natural products have proven stubbornly resistant to its advances. Among them is haplophytine (1, Scheme 1a), which has only very recently succumbed to synthesis following the elegant work of Fukuyama, Tokuyama and co-workers. Haplophytine was first isolated by Snyder and co-workers in 1952, and identified as the principle bioactive component of the wild flower Haplophyton cimicidum, valued for centuries by the Aztecs and subsequent settlers of Central America for its insecticidal properties. A heterodimeric indole alkaloid, haplophytine features a particularly complex polycyclic array of ten rings, six stereocenters (five of which are quaternary) and a highly congested carbon carbon bond adjoining the two distinct halves of the molecule. The tetracyclic left-hand domain features a unique bridged ketone structure, while the righthand domain consists of the naturally occurring aspidosperma alkaloid, aspidophytine (2, Scheme 1b). A complete appreciation of haplophytine s molecular structure was only reached some 21 years subsequent to its isolation, following extensive chemical degradation, spectroscopic, and X-ray crystallographic studies from the groups of Cava, Yates, and Zacharias, which included identification of the dihydrobromide derivative 3 (Scheme 1a). As depicted, this compound is formed through a unique acid-mediated skeletal rearrangement of the left-hand domain involving the 1,2-shift of an aminal C N bond. Under basic conditions, however, this process can be reversed such as to return haplophytine through a complementary semi-pinacol type mechanism. As