1.5- Electrocyclisation reaction

Further types of photochemical reactions suitable for the induction of enantioselectivity by chiral templates (+)-12 and (-)-12 are 4n- and 6n-electrocyclisation reactions (Scheme 8) (Bach et al. 2001c, 2003). 

The first chapter provides an informative introduction to this area of biomimetic natural product synthesis, in particular focusing on the role of electrocyclisation reaction cascades, from K.C. Nicolaou s seminal synthesis of the endiandric acids, to the more recent research carried out on the tridachiahydropyrones and related sacoglossan metabolites. The thesis then sets out to explore the hypothesis that these secondary metabolites function as photo-protective membrane antioxidants, shielding the producing organisms from the damaging effects of UV radiation. 

Furthermore, many elegant biomimetic syntheses of natural products have been carried out using electrocyclisation reactions—often as part of cascade sequences—to generate high structural complexity from relatively simple precursors. 

Having conclusively established the propensity of the tridachiahydropyrone precursors, 44 and 43 (along with the natural product 9 itself), to insert into the model membrane systems, the key electrocyclisation reaction was attempted utilising the phosphohpid vesicles (PLVs) as chiral reaction media. The main aim of these reactions was to ascertain if any asymmetry had been conferred on the reaction by chiral HPLC analysis of the isolated product. 

Fluorescence spectroscopy-based biophysical studies of the interactions of 9, 43 and 44 with phospholipid vesicles (PLVs) demonstrated their propensity to bind to membranes, supporting the theory that these compounds are located in the cell membrane of the producing mollusc. The photochemical isomerisation and electrocyclisation reactions of the precursors 43 and 44 to form tridachiahydropyrone (9) were conducted in the PLVs. The racemic nature of the product isolated from these experiments indicates that if the cell membrane is the biological site of this transformation, then any enantioselectivity conferred in the natural system must be due to the presence of other bilayer components, such as integral membrane proteins, not present in the membrane models here used. This raises a limitation of liposomes as models of biological membranes—they are very simplistic versions of a far more complex system (Fig. 5.1). 

Merlic developed a new variation of the thermally induced benzannulation reaction. The dienylcarbene complex 132 was reacted with isonitrile to give an orf/zo-alkoxyaniline derivative 135 [76] (Scheme 56). This annulation product is regiocomplementary to those reported from photochemical reaction of chromium dienyl(amino)carbene complexes. The metathesis of the isocyanide with the dienylcarbene complex 132 generates a chromium-complexed di-enylketenimine intermediate 133 which undergoes electrocyclisation. Final tau-tomerisation and demetalation afford the orf/zo-alkoxyaniline 135. 

Heterocycles can be formed in a number of systems and perhaps the most surprising involves reaction of the diene (38) (Scheme 47) in moist ether Obviously, the process depends on the high reactivity of the vinylic fluorine atoms in (38) and the subsequent step is most likely an electrocyclisation, to form (88). Also, pyrroles, e.g. (89) and, more remarkably, pyrrolopyri-dines, e.g. (90) may be synthesised from (38) using aniline derivatives [44, 106],... 

A one-pot reaction between the phosphonodithioacetate 58 and a,P-unsaturated aldehydes proceeds via a Knoevenagel reaction and a 1,6-electrocyclisation and leads to a 277-thiopyran-5-yl phosphonate (Scheme 42). When 5-membered heterocyclic aldehydes are used, the intermediate is obtained admixed with the thiopyran or as the only product <07EJO4948>. 

Photocyclisation - A wide variety of ring-forming reactions has again been reported. Irradiation of azepine derivative (16) results in 4-n-electrocyclisation to a mixture of the corresponding exo and endo cyclobutenes.6-Ti-Electrocyclisa-tion has been employed in a scaled-up synthesis (>300g) of 6-aza-l,10-phenan-throic anhydride (18) from the stilbazole (17). f-Azobenzene, incorporated into water-swollen acid-form Nafion fluorocarbon membranes, exists as the proto-nated form (19) and exhibits ambient temperature fluorescence, previously... 

Two groups have reported the synthesis of the pentaketide epoxyquinols which differ in the approach to the epoxide 5, oxidation and subsequent electrocyclisation of which generates a 2//-pyran. Various dimerisation modes in which the pyran acts as either diene or dienophile then yield the epoxyquinols <05JOC79, 05TL547>. The reaction of this epoxide and a related cyclohexenone with reactive dienophiles circumvented the dimerisation and the cascade reaction produced the endo DA products <05JOC79>. 

Benzoxepine formation by the 1,7-electrocyclisation of conjugated carbonyl ylides studied by Sharp was reported in last year s review. This work has now been extended in a study of the relative rates of cyclisation via intramolecular competition reactions <97JCS3025>. It has been found, for example and not unexpectedly, that the rate of cyclisation for alkenyl groups and the thiophene ring are ca. 10-20 times that for phenyl. The selectivity is unaffected by the nature of the substituent on the terminal atom of the ylide. 

Irradiation of chromium dienyl(amino) carbene complexes produces o-amino aromatic alcohols. An intermediate in this reaction is presumably a photogenerated dienylketene which undergoes electrocyclisation and aromatisation. Irradiation of optically active chromium aminocarbenes,... 

The Pummerer rearrangement has been employed in tandem with other reactions to enable complex transformations to be carried out efficiently and in a one-pot manner. Studies of these have been reported mainly by Padwa who has utilized such transformations in the syntheses of natural products. A particularly intriguing cascade sequence involving the Pummerer rearrangement was employed in the synthesis of the alkaloid jamtine, 57. " Padwa et al. synthesized the bromo-enamide 55 in a 4 1 (Z/ ) mixture of isomers. Treatment of the isomeric mixture with camphorsulfonic acid caused the the sulfoxide to undergo a Pummerer/Mannich ion cyclization, which was then followed by a spontaneous Pictet-Spengler reaction to furnish the isoquinoline core. Although a 5 2 1 1 mixture of diastereoisomers was obtained, the desired diastereoisomer 56 was formed preferentially. This was attributed to a 4 r-Nazarov-type conrotatory electrocyclisation which controls the direction of closure from the a-acylthionium ion intermediate. 

Electrocyclisations Using PLVs as Chiral Reaction Media... 

Electrocyclisations Using PLVs eis Chiral Reaction Media 57... 

Table 3.4 Electrocyclisations utilising PLVs as chiral reaction media-stereochemical outcome...

Tridachiahydropyrone (9) and phototridachiahydropyrone (93) were synthesised by photochemically-induced electrocyclisation and sigmatropic rearrangement reactions of the biomimetic precursors. Oxytridachiahydropyrone (10) was also synthesised, by the photochemical [4 - - 2] cycloaddition of singlet oxygen to tridachiahydropyrone (9) (Scheme 5.2). 

The mechanism of the photoconversion of a-phenylcinnamic esters, e.g. (384), in a protic solvent, into 9,10-dihydrophenanthrenes has been studied. The primary step is the concerted photo-induced electrocyclisation of (384) to (385), which undergoes proton exchange with the solvent to give (386). The final product (387) results from a homolytic H abstraction-addition reaction. 

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