Biosynthetic hypothesis

A comprehensive compilation of data derived from feeding and other biosynthetic studies performed by Kirby [21], Sammes [22], and Taylor [23], genomic studies conducted by Howlett [lc, 24], as well as our own synthetic studies probing the innate reactivity of various intermediates (vide infra) culminated in our formulation of the biosynthetic hypothesis delineated below (Scheme 9.1). The biosynthesis features two distinct phases an oxidative dimerization phase and a thiolation phase in which diketopiperazine structures are elaborated to afford the defining epipolysulfide motifs (Scheme 9.1) [25, 26]. 

The biosynthetic hypothesis commences with the action of a nonribosomal peptide synthetase on natural amino acid precursors. While the incorporation of... 

The most recent chapter (but certainly not the last ) in this perplexing saga evaluates a biosynthetic hypothesis raised earlier [7, 86] and suggested from... 

A chief problem in the early development of taxane pharmaceuticals was the establishment of a steady and dependable supply. Taxanes are present in low quantities in plants. In contrast, taxines are relatively abundant in plants (especially in Taxus baccata and Taxus cuspidate), they can serve as an alternative starting material for semisynthetic production of paclitaxel derivatives. The major taxines are taxine A and taxine There is a significant structural resemblance between taxine B and taxanes (Fig. 1). Both groups share the main taxane ring moreover, the C-5 side chain of the taxines has a close spatial position to the C-13 side chain of the taxanes (the latter is essential for antitumor activity). A biosynthetic hypothesis involved the intermediacy of a C-5 to a C-13 ester transfer it was also demonstrated that taxine B can be converted into a baccatin V derivative. Taxines do not show antitumor activity, whereas the cardiotoxicity of taxol is lower compared to taxines but is undesirable for... 

At first sight the title compounds characterized by the general formula 111, are rather unrelated to diarylheptanoids. At closer look, however, the two classes of compounds can be linked by a very plausible biosynthetic hypothesis first forwarded by Thomas (80) and shown in the following scheme below. 9-Phenylphenalenones were isolated from Haemodorum (74), Lachnates (75, 76), Xiphidium (77), Wachendoifia (78), and Anigozanthos (79) (Haemodoraceae) species. 

Three sesquilignans 34, 35 and 36 are the first confounds to be reported from Salicaceae. Also, the occurrence of these confounds 34, 35 and 36, along with neolignans 30 and 31, lends support to the biosynthetic hypothesis of their formation by the sequiential coupling of individual phenylpropane units. 

In 1992, however, this bleak situation began to brighten when Sir Jack Baldwin and his co-worker Roger Whitehead at the University of Oxford advanced an intriguing biosynthetic hypothesis which could account, on paper, for the formation of the polycyclic framework of virtually all the manzamine alkaloids. In their elegant and insightful conception, which is shown in Scheme 1 for manzamine B (2), initial retrosynthetic excision of the P-carboline... 

Although Baldwin and Whitehead s perceptive biosynthetic hypothesis serves as a useful framework from which to develop a coherent synthetic approach towards manzamine A (1), other elegant solutions to the problems posed by this complex molecular architecture based on stepwise chemical synthesis are also conceivable. In this chapter, we shall focus in detail on two such constructions of manzamine A from the groups of Jeffrey Winkler at the University of Pennsylvania and Stephen Martin at the University of Texas, Austin. While both serve to illustrate the current state-of-the-art in methods for complex molecule construction through routes that effectively combine modem and classical reactions, perhaps the more significant feature of each approach resides in the... 

If this evidence were not incriminating enough, additional substantiation for its likelihood was provided in 2002 by Professor Matthew Shair and two of his graduate students at Harvard University through the first chemical synthesis of longithorone A (1) predicated on these same Diels-Alder reactions. This accomplishment is the subject of this chapter, an achievement whose success ultimately relied not only on the power of [4- -2]-cycloadditions, but also on an inventive strategy to atropselectively construct both [12]-paracyclophanes at the heart of Schmitz biosynthetic hypothesis. 

Many naturally occurring polyethers such as brevitoxin B (123) have been proposed to biosynthetically derive from the polyepoxidation of polyenes and subsequent cyclization of the resulting polyepoxides (Scheme 3.40) [79, 80]. Such a biomimetic polyene-polyepoxide-polycyclization approach would provide a potentially powerfid and versatile strategy for the synthesis of polyethers, with quick assembly of stereochemically complex molecules from relatively simple achiral polyalkene precursors. The epoxidation with ketone 42 should provide a valuable method to investigate this biosynthetic hypothesis and possible application of the proposed pathway in the synthesis of polyethers. 

The 6k conrotatory mode of electrocyclisation is promoted imder photoehemi-cal conditions. Furthermore, a photochemical [4 + 2] cycloaddition of 9 with singlet oxygen ( 02) would furnish tridachiahydropyrone B (12), with a further E/Z isomerisation leading to tridachiahydropyrone C (13). These observations, coupled with the fact that the molluscs reside in areas exposed to direct sunhght, underpin the biosynthetic hypothesis proposed by Moses et al. [10]. 

A further biosynthetic hypothesis, namely that tridachiahydropyrones B (12) and C (13), isolated as an inseparable mixture in 2000 by Schmitz and co-workers [7], were derived from a photochemical [4 -I- 2] cycloaddition of tridachi-ahydropyrone (9) with singlet oxygen, was also explored [10]. Thus a solution of tridachiahydropyrone (9) in CHCI3 was irradiated under a continuous flow of molecular oxygen in the presence of methylene blue. This resulted in complete conversion to a new product, the NMR spectroscopic data for which was in agreement with that reported for the inseparable mixture of 12 and 13 (Scheme 1.20). 

The experimental work which has subsequently been carried out in this area has demonstrated the validity of this biosynthetic hypothesis in relation to the 9-phenylperinaphthenone pigments... 

To this point, all of the experiments that we conducted have supported the biosynthetic hypothesis outlined at the top of Scheme 2 (see Section 2.2). However, there remained a mildly vexing set of data from the 2009 report describing the flinderoles that on the surface seemed to contradict the possibility of an enzyme-free acid-promoted dimerization of borrerine. While the borreverines and related compounds like yuechukene were reported to be isolated as racemates, the flinderoles A-C were reported to have specific rotations of —6.4, —7.3, and —7.4 (c = 0.03), respectively. Since enantioenrichment implies an element of chiral control, and all acids studied in the dimerization produced racemic compounds, the report of optical activity in the natural samples suggested some biological involvement in their formation. Of note, however, is the low concentration used for the polarimetry experiments, which is not an extremely sensitive analytical technique. Furthermore, all three compounds exhibited similar specific rotations, even the two diastereomers. These... 

Home was able to provide support for the biosynthetic hypothesis that mauritiamine (197) results from dimerization of an oroidin-like species. Upon examination of the natural product stmcture, it appears to be the union of oroidin (25) and dispacamide (196) (Scheme 13.34). Home was able to dimerize vinyl aminoimidazole 26 under oxidative conditions to provide the core of mauritiamine (199) [130]. After installation of the dibromopyrroles via acylation, the natural product was realized in six steps from ornithine methyl ester (198), without the need for PGs. 

Studies of structure-activity relationships have shown that the presence of the hydroxyl group at position 8 is necessary for nematocidal activity (Capon et al, 2001a). No biosynthetic hypothesis has yet been made to describe the formation of these particularly atypical natural derivatives. 

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