De Mayo photocycloaddition

A short enantiospecific total synthesis of (+)-aphanamol I and II from limonene was achieved and the absolute stereochemistry of I and II established in the laboratory of B. Wickberg. The key steps were a de Mayo photocycloaddition, a Corey-Chaykovsky epoxidation and finally a base-cataiyzed fragmentation of the j,8-epoxyalcohol intermediate. Upon treating the photocycloadduct with dimethylsulfoxonium methylide, only the endo epoxide diastereomer was formed due to the steric hindrance provided by the methyl and isopropyl groups. 

Winkler implemented the de Mayo photocycloaddition/fragmentation approach to gain access to a number of structurally complex natural products [141,142]. Irradiation of 222, for example, produced cycloadduct 224 as a single diastereomer in 80% yield (Scheme 18.36). Three subsequent steps, including the retroaldol fragmentation, completed the synthesis of saudin (225), a compound with potent hypoglycemic activity [141]. 

From a preparative point of view the heteroatom in P-position has an influence because important latent cyclobutane cleavage pathways exist in the product. The prototypical reaction of this type is the [2 + 2]-photocycloaddition/retro-aldol reaction sequence (de Mayo reaction) [55-57], the course of which is illustrated for substrate A3 (Q = O, PG = protecting group) in the reaction with ethylene as a generic olefin. 

A very useful extension of the de Mayo reaction has been recently introduced by Blechert et al. (Scheme 6.26) [78]. The retro-aldol fragmentation was combined with an intramolecular enantioselective allylation (asymmetric ring-expanding allylation) catalyzed by a chiral Pd complex. Bicycloheptane 68, for example, was accessible by intermolecular [2 + 2]-photocycloaddition of cyclopentenone 67 with allene. Further transformation in the presence of Pd2(dba)3 (dba = dibenzylideneacetone) and the chiral oxazoline ligand 69 (tBu-phox) resulted in the enantioselective formation of cycloheptadione 70. 

An early synthetic application of such intermolecular enone + alkene photocycloadditions was presented by de Mayo in 1964. 5,5-Dimethyl-3-hydroxycyclohex-2-enone (1), i.e., the enol of dimedone, adds to e.g., cyclohexene, and the primarily formed cyclobutane 2 undergoes a... 

The utility of /f-enaminones (vinylogous amides) and / -enamidones (vinylogous imides) has been successfully demonstrated in both inter- and intramolecular [2 + 2] photocycloaddition reactions. The vinylogous amide, which reacts as a /Mieteroatom substituted enone, serves as the nitrogen analogue of the enol form of a / -diketone in the de Mayo reaction24. 

A modified de-Mayo reaction (shown in Scheme 21) also served as a tool in the first synthesis of a saturated taxane framework with a geminal dimethyl group (79,80). Photocycloaddition of cyclohexene (functioning as a ring C model) to a bicyclic 1,3-diketone derivative from 85 is the key step. In the course of the cyclobutane annealing, the C-8 a ring connection is established contrary to C-3,... 

The importance of the ethylene ketal described above with respect to stereocontrol of the de-Mayo reaction is emphasized by later published works of two other teams. Fetizon and co-workers obviously followed a similar concept and carried out photocycloaddition reactions with 96a in model studies (Scheme 23) (Si). As can be seen from retroaldol product 98, exclusive a attack of the cyclohexene has taken place. Thus, the relative stereochemistry of the BC ring connection is opposite to that of taxane. Totally comparable results were obtained by Berkowitz et al. in the course of cycloaddition reactions of cyclopentene, cyclohexene, or those of a cyclohexenone ketal to the camphor derivative 96b (.84). 

Corey Eaton, de Mayo - and many others began to investigate the various synthetic and mechanistic ramifications of the photocycloaddition which resulted in the total synthesis of caryophyllene " and bour-bonene" as well as a proposed mechanistic rationale for the reaction. Subsequently, numerous natural and unnatural products have been prepared by synthetic routes which have a [2 -t- 2] photocycloaddition as a crucial step in their synthesis, and the reaction has become recognized as an important transformation in the repertoire of the synthetic organic chemist. 

The photocycloaddition of alkenes to the enol acetate (30) affords the adducts (31) in an example of the well-established de Mayo reaction. ... 

The use of silica gel surfaces to modify photoprocesses continues to be of interest. The present report deals with photoaddition of alkenes to the steroidal enone (44).It is presumed that, in the adsorbed state on silica gel, the steroid will present the normally hindered side, i.e., the g-face is attacked by the alkene and the a-face is adsorbed on to the gel. The photoadditions were compared with those carried out in methanol. Thus with allene the two photoproducts (45) and (46) were obtained in 90 and 10% yields, respectively, at -78 °C in methanol, while on silica gel, both at -78 °C and at ambient temperature, the same two products were obtained in 46 and 53% yield. Similar results were obtained using ethene and cyclopentene. The photocycloaddition of ethyne and propyne to progesterone and testosterone in solution yields the cycloadducts (47) and (48), with a preference for the former mode of addition being observed. These results are in conflict with those of de Mayo and co-workers. ... 

The photocycloaddition of chloroprene to methyl 2,4-dioxopentanoate (4) has been reported. Only two de Mayo style products were obtained from this process and these were identified as the adducts (5) and (6) arising from the two paths of addition of the enol (7) to the diene. Precise kinetic data has been obtained for the photochemical dimerisation of the cyclopentanone derivative (8). ... 

The photocycloadditions of alkenes with the enol form of 1,3-diketones (the de Mayo reaction-, e.g. Scheme 6.68) or electron transfer-mediated reaction (see below) can also be utilized for synthesis of large rings. 

The reaction of an olefin with a 1,3-diketone enol, known as the de Mayo reaction [116], is an important member of the [23-2] photocycloaddition reaction family. This and related processes were discussed by Sato et al. [117]. 1,3-Dioxi-nones (62) react with ethylene to give cyclobutane products. (Kaneko et al. [118] and Demuth et al. [119] have written reviews on this subject.) The intermolecular reactions of olefins with enones, carried out by Organ et al. [120], are complementary to the work on spirodioxinone derivatives (e.g., 63) by Sato et al. [121]. Reaction of enone 64 with cyclohexene led to a mixture of seven products, with the all-cis isomer formed in 32% yield. However, higher selectivity was seen for the reaction with a protected cyclohexenone (65), which afforded the all-cis isomer (66) in 54% yield, and reaction with cyclopentene (67), which gave 68 as a single product in 90% yield, as shown in Scheme 17 (also see Fig. 8). 

Intermolecular de Mayo reactions are efficient for cyclic 1,3-diketones such as dimedone (5,5-dimethyl-l,3-cyclohexanedione)96,103,104 and acyclic systems such as acetylacetone93-95. Unsymmetrical acyclic /l-diketones, such as 1-phenyl-1,3-butanedione98 can enolize in two directions, however, reaction normally occurs preferentially from a single enol form. Examples of alkene photocycloaddition to trapped ends of /(-dicarbonyl compounds (e.g., 2,2-dimethyl-3(2/f)-furanone and 2,2.6-trimethyl-4/f-l,3-dioxin-4-one) are given in Table 1 (entries 26, 27) and Table 2 (entry 35) 10°. If the enol is stabilized by derivatization (e.g., acetylated dimedone 3-acetoxy-5,5-dimethyl-2-cyclohexenone), the primary cyclobutane photoproducts can be isolated96. 

I, 5-dicarbonyl compounds and their interesting and varied chemistry, e.g., the formation of cyclohexenones from aldol condensation of the products. As an extension of the de Mayo reaction (the photocycloaddition of enolated /i-diketones to double bonds) enol esters, enol ethers, vinylogous esters and amides, and dioxinone have been employed as the enone components. Some intermolecular examples have already been discussed in Section 1.6.1.4.2.1.6. (cf. Table 4, entries 2 and 3) and some intramolecular systems are collected in Table 5, entries 10,... 

Intermolecular.— The control of regiospecificity in photocycloadditions remains a much sought after goal, de Mayo and Syndes have found that some control can be exercised on the reaction when the cycloadditions are carried out in micellar potassium dodecanoate (KDC). The ratios of products are sufficiently different (Table 1) from those obtained in non-polar solvents to merit further study of this... 

In another approach to enantioselective 2 + 2 photocycloadditions, the easily available chiral l,3-dioxin-4-ones have been used as synthetic equivalents of acetylacetates in de Mayo reactions. Chiral information is introduced through a ketalic functional group and menthone derivatives efficiently control the facial selectivity, as indicated in Scheme 30 [155-157]. 

Additions to Cyclohexenones and Related Systems - A re-investigation of the photodimerization of isophorone (37) has been reported. The study examined the influence of solvent and of the concentration of the enone. Some of the results and the yields of dimers obtained are shown in Scheme 4. From this detailed study the authors suggest that supramolecular structures are involved in the dimerization. These apparently take part even at low concentrations of enone. The photocycloaddition of enones such as (39) to buckminsterfullerene (Ceo) has been studied. The outcome of the addition is the formation of low yields of furanylfullerenes. This addition occurs to the exclusion of de Mayo type of addition. Photocycloaddition of the cyanocyclohexenone derivative (40) to alkenes has been reported. ... 

Photochemistry, in the shape of the de Mayo reaction, also features in a new synthesis of the linear fused triquinane hirsutene (20). Thus, photocycloaddition between dimedone and 2-methyl-cyclopent-2-enol was accompanied by spontaneous retro-aldolization of the intermediate adduct (17), leading to (l8a). McMurry coupling of the dione (l8b), derived from (l8a), followed by manipulation of the functional groups in (19) then led to (+)-hirsutene... 

The de Mayo reaction is a sequence of reactions involving the photocycloaddition of an olefin with an enol or enol derivative of a P-dicarbonyl compound, followed by a rerra-aldol fragmentation reaction to give a 1,5-diketone. 

In the meantime, Corey, Eaton, de Mayo, and others examined intermolecular enone-olefin photocycloadditions. In 1962, Eaton reported... 

The classic de Mayo reaction involves the [2 + 2] photocycloaddition of an alkene to the hydrogen-bonded enol tautomer of a P-dicarbonyl compound as exemplified by the formation of 1,5-diketone 9 from pentane-2,4-dione and cyclohexene (vide supra). In addition to alkenes, allenes are also used as the olefinic component. For example, irradiation of a mixture of dimedone and allene results in the formation of 3,3-dimethyl-7-methylenecycloocta-l,5-dione 12 via the cyclobutane intermediate 11, together with the corresponding head-to-tail product 13, which spontaneously dimerizes to the hetero Diels-Alder adduct 14. Diketone 12 is a versatile building block for the preparation of substituted cyclooctadienones and 8-valerolactones. 

The intramolecular variant of the de Mayo reaction has been applied in the synthesis of -bulnesene (21), epiprecapnelladiene (22), and of the zizaane carbon skeleton (23). Coates et have described a variant of this general strategy for ring synthesis whereby but-2-enolides are used as one of the TT-components in the photocycloaddition. 

The photocycloaddition of thiobenzophenone to acrylonitrile at 366 nm is known to give the thietan (130). It has now been shown that the reactive state of the thione under these conditions is the second excited (tt, n ) singlet, and that the 1,3-dithian (131) is an intermediate in this reaction. " In contrast to earlier findings, irradiation at longer wavelengths (>500 nm) has been found also to result in product formation. The heterocyclic compounds (132) and (133) were the main products in the latter photolysis reaction, and their formation was interpreted in terms of an intermediate lowest triplet state of thiobenzophenone. The irradiation of thiobenzophenone in tetramethylethylene solution at -78 C afforded two 1 1 adducts, (134) and (135), respectively. Various thietans were the products in the photocycloaddition reactions of some aromatic thioketones with tetramethylallene, 2,4-dimethylpenta-1,3-diene, dimethyl fumarate, and dimethyl maleate, respectively. The nitrile function has also been found to be susceptible to addition by the excited thione group. Thus several alicyclic and aromatic thioketones, on irradiation in acetonitrile solution, have been converted into N-thioacylketimines (136), probably via an intermediate 1,3-thiazetine (137). Two recent papers by de Mayo and his... 

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