Polyene precursors

A beautiful example of electrocyclic reactions at work is provided by the chemistry of the endiandric acids. This family of natural products, of which endiandric acid D is one of the simplest, is remarkable in being racemic—most chiral natural products are enantiomerically pure (or at least enantiomerically enriched) because they are made by enantiomerically pure enzymes (we discuss all this in Chapter 45). So it seemed that the endiandric acids were formed by non-enzymatic cyclization reactions, and in the early 1980s their Australian discoverer, Black, proposed that their biosynthesis might involve a series of electrocyclic reactions, starting from an acyclic polyene precursor. 

In principle, conjugated materials may either be directly synthesized via metathesis polymerization of acetylene or 1-alkynes, via ROMP of various cyclooctatetraenes (COTs) or via ROMP of polyene precursors as realized in the Durham route [107-111]. The first direct polymerization of acetylene to yield black untreatable unsubstituted polyacetylene was achieved with W(N-2,6-i-Pr2-C6H3)(CH-t-Bu)(OC-t-Bu)2 [112]. In order to obtain soluble polymers, polyenes were prepared via the ROMP of a polyene-precursor, 7,8-bis(trifluoromethyl)tricyclo[4.2.2.02 5]deca-3,7,9-triene (TCDTF6), using initiators such as W(N-2,6-i-Pr2-C6H3)(CH-t-Bu)(OC-t-Bu)2) (Scheme 5.10) [113, 114]. 

Recent developments include asymmetric polyene cyclisations but also include new ways to initiate cyclisations. Iron tricarbonyl stabilises pentadienyl cations and its complexes with dienes are chiral. Addition of the achiral lithium derivative 268 to the chiral complex 269 gives the polyene precursor 270 that cyclises with Lewis acid to give a single diastereoisomer of the bicyclic compound43 271. 

Crounse JB, Feldman RP and Clayton RJ (1963) Accumulation of polyene precursors of neurosporene in mutant strains of Rhodopseudomonas spheroides. Nature 198 1227-1228... 

Scheme 15 Reprentative selective RCM reactions using polyene precursors.

First, the proposed polyene precursors were synthesised using a convergent strategy dependent upon a late-stage Suzuki coupling. Their photochemical, bio-mimetic conversion into tridachiahydropyrone, phototridachiahydropyrone and oxytridachiahydropyrone, was then accomplished. 

The earliest example of a biomimetic electrocyclisation cascade sequence in natural product synthesis is in Nicolaou s syntheses of the endiandric acids, isolated by Black in the early 1980s [15]. To explain the racemic nature of these natural products, Black proposed that they are formed spontaneously from achiral polyene precursors through non-enzymatically assisted electrocyclisation and cycloaddition cascades. In 1982 Nicolaou reported the synthesis of the methyl esters of all endiandric acids A-G in a one-operation cascade approach from linear polyene precursors [16]. The synthesis of endiandric acids A, D and E methyl esters (32, 30 and 31 respectively) is outlined below (Scheme 1.5). 

Moses and co-workers took this hypothesis one step further, speculating that the original biosynthetic polyene precursor was not the ( ,Z,Z, )-telraene 35 but the all E isomer 40 [17], Furthermore, they postulated that this polyene was the precursor to a number of y-pyrone polypropionate natural products, diversification occurring via selective double bond isomerisations followed by varying electro-cyclisations or cycloadditions. Thus the polyene 40 was synthesised by a Suzuki... 

The first aim of this work was to explore the feasibility of the sunscreen hypothesis, specifically the likelihood that the polyene precursors (44 and 43) to tridachiahydropyrone (9) are located in the phospholipid bilayer of the cell membrane. This was achieved by studying the interactions of the molecules with a series of model membrane systems, utilising fluorescence-based biophysical techniques. 

Ireland and Scheuer s experiments demonstrated that the in vivo photochemical transformation of 9,10-deoxytiidachione (2) into photodeoxytridachione (3) was non-enzymatic [17], suggesting that the origin of chirality in sacoglossan natural products, derived from achiral polyene precursors, does not lie in enzymatic assistance. 

Figure 5. Final domain assignments of nine-membered enediyne PKSEs from C-1027producer S. globisporus and the NCSproducer S. carzinostaticus. Active site serines within ACP domains arephosphopantetheinylated by PPTdomain (in cis) followed by production of the polyene precursor to the enediyne core. R, 3, 5 -adenosine diphosphate.

Since its original report, the StiU-Gennari modified HWE olefination has been widely used in natural product synthesis to access Z-alkenes [18]. One example from the Roush group is shown in Fig. 5, where the olefinatimi reaction was used to provide the conjugated polyene precursor for their key one-pot tandem intramolecular Diels-Alder reaction and vinylogous Baylis-Hilhnan cycUzation [19]. 

The first successful application of RRCM in complex namral product synthesis was reported by Porco et al. in 2005 (Fig. 16) [59]. In the synthesis of oximidine III (51) they successfully cyclized the polyene precursor (52) to access macrolide (53) with a Z-double bond using Hoveyda-Grubbs catalyst... 

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