Diene precursor

Ring-closing metathesis has been used effectively to prepare the pyrido[3,2-h oxepine derivative 71 in good yield from the pyridyl diene precursor 70 <06TL6235>. 

The oxepine-fused beta-carboline 73 was synthesized in good yield (71%) from the diene precursor 72 using ring-closing metathesis and Grubbs I catalyst <06TL6895>. 

Ring-closing metathesis on the dienes 116 and 117 with Grubbs ruthenium catalyst II 18 afforded the 7-membered ring sulfones 118 and 119 respectively. The diene precursor 116 was accessed from reaction of the sulfonyl chloride 115 with 3-buten-l-ol 114 <06T9017>. 

Condensed benzo[i>]furan molecules can be prepared by inter- or intra-molecular Diels-Alder reactions from furo[3,4-b]benzofurans, and some interesting intermolecular examples are listed below. As can be seen, the furo[3,4-i>]benzofuran 60 underegoes Diels-Alder reactions with naphtho-l,4-quinone in the presence of Znl2 as a Lewis acid to form the aromatized cycloadduct. When the diene precursor reacts with benzo-l,4-quinone in the absence of Znl2, the product is obtained as an endo-exo mixture <00JCS(P1)1387>. 

A nice and convergent approach to both compounds makes use of RCM to form the 5-membered building block 71, which mimics the carbohydrate part of the nucleosides. The necessary diene precursor 69 is readily assembled via Evans aldol chemistry. RCM then affords the ring in almost quantitative yield (69->70), leaving the chiral centers and the free hydroxyl group intact. Removal of the chiral auxiliary by reductive cleavage, attachment of the base by means of jt-allylpalladium chemistry, and a final deprotection step complete these highly efficient syntheses [46]. 

With the C12,C13 disconnection producing an effective solution to the synthesis of epothilone A (4), it would seem likely that the metathesis approach could be extended readily to the preparation of epothilone B (5). However, installation of the desired C12 methyl group requires ring-closure of a diene precursor in which one of the olefins is disubstituted. Recently, such reactions have been shown to be problematic for Grubbs initiator 3 but more successful with Schrock s molybdenum initiator 1 [19]. Consistent with these reports, Danishefsky demonstrated that triene 38 would not undergo RCM with 3, whereas 1 was effective in promoting the transformation of 38 into a 1 1 mixture of 39a and 39b in good yield [14b] (Scheme 8). 

To gain insight into this remarkably efficient cyclization reaction (77—>76), and to determine the extent to which existing stereogenic centers preorganize diene precursor 77, we examined the catalytic RCM of 79 and 82. When 79 was subjected to 25 mol% 2 (50°C, 18 h), <2% 80 was formed (Scheme 20). Instead, dimer 81 was obtained in 52% yield (3 1 mixture of olefin isomers identity of major product not determined). When diene 82 was treated with identical conditions, macrolactam 83 was obtained in 41% isolated yield [33] along with 20% of the... 

The opportunity of employing various electrophiles and functionalized diene precursors greatly enhances the synthetic potential of p3-allyltitanocenes. Besides aldehydes and ketones, carbon dioxide [11,15,16], acid chlorides [17], imines [11], nitriles [11], isocyanides [11], and organotin halides [18] react to afford the corresponding allylated products after hydrolysis. Examples are given in Scheme 13.8. 

The required 1-oxa-l,3-diene precursor was synthesized according to the synthesis design (Scheme 8). Cycloadditon with enol ether furnished exclusively the endo-isomer. Raney nickel treatment in refluxing ethanol yielded in one step the desired tetrahydropyran derivative in a favorable 6 1 cis/trans ratio. Transformation into the lactone and ring closure with potassium tert.-butoxide afforded (+)-ramulosin. 

With minor variations on the haloepoxide route a remarkable number of mono- and di-substituted oxepins have been prepared and are included in Table 8. The electron donating or withdrawing capacity of substituent X present in the diene precursor will determine which bond will be more readily epoxidized or brominated (Scheme 33). 

The synthesis of the eight possible diastereoisomeric racemates of dactyl-oxene-B (44) has been carried out recently by Ohloff and co-workers (15). In the course of this work, they have observed that the spiro bicyclic ethers 46 and 49 are formed more rapidly than their C-5 epimers 47 and j>0 respectively on acid cyclization (p-TSA in CHgClg) of the hydroxy-diene precursors 45 and 48 (R- = CH3 and R3= C=CH or the opposite configuration). 

A dominant feature of the type c ring-construction approach to azepine systems has been ruthenium-catalyzed ringclosing metathesis reactions. Examples include the synthesis of the azepine derivative 157 from 156 using either the Grubbs type I catalyst 159 or type II 160. The diene precursor 156 was prepared in turn from 154 via 155, as shown in Scheme 21. Hydrogenation of the C-C double bond in 157 afforded the azepane 158 <2005SL631>. 

Ring closing metathesis mediated by Grubbs II catalyst in a type c ring construction process has been used to access stereoisomeric 1,2-disubstituted tetrahydroazepine-3-ol derivatives preparation of the required diene precursor started from an optically pure substituted aziridine carboxylate ester <2007T3321>. 

Ring-closing metathesis methodology has been used in the synthesis of the 1,2-oxazepine derivatives 21 and 22. These derivatives were synthesized from the respective diene precursors 20 and 19, which were derived from 18 by N-acylation or N-alkylation respectively (Scheme 1) <2003SL1043>. 

The first Diels-Alder cycloaddition on endohedral metallofullerenes was recently reported. Sc3N C80 endohedral metallofullerene was reacted with the diene precursor 6,7-dimethoxyisochroman-3-one to yield the corresponding adduct [ 142 ], while its structure was also verified by X-ray diffraction measurements [143]. 

Ring-closing metathesis methodology has been used to access 7-membered ring sultones (e.g. 278, n = 1, m = 1) efficiently from the acyclic diene precursor 277, which could readily be made in turn fom the appropriate olefinic sulfonyl chloride and alcohol [02SL2019]. 

RCM methodology can be used for the synthesis of 1,2-oxazepine derivatives. Thus, compounds 189 and 191 were prepared in good yields from the respective diene precursors 188 and 190 both accessed in turn from 187 (Scheme 92) C2003SL1043, CHEC-III(13.07.3)239>. 

The full potential of ring-closing metathesis methodology in the synthesis of seven-membered heterocyclic systems is still to be realised, and there are many opportunities to investigate different substituents in the diene precursors. A combination of ring-closing metathesis with other reaction types in a cascade context is also likely to realise novel seven-membered ring based systems. 

Several hydroxylated analogues of vitamin D have been prepared by irradiation of a steroidal A -diene precursor, following a sequence similar to that used in the synthesis of retroprogesterone. " " Photobromination of cholesteryl benzoate also gave a triene derivative analogous to vitamin D3 (378)/ ... 

Transannulation of the mesylate (33), derived from 4,8-dimethylcycloocta-4-en-l-ol, using sodium carbonate in aqueous dioxane has provided the bicyclo[3.3.0]octanol (34), a central precursor to the monoterpene iridomyrmecin (35 equation 13). In studies of the biomimetic synthesis of the natural tri-quinanes capnellene (37 equation 14) and pentalenene (40 equation IS) Pattenden et al. have shown that both molecules can be produced from appropriate cycloocta-l,S-diene precursors, i.e. (36) and (39) [or indeed their corresponding positional isomers (38) and (41), respectively] by treatment with boron trifluoride. Mehta et al. have described an alternative transannulation approach to the triquinane unit found in pentalenene, i.e. (42) - (43 equation 16), and also to the ring system (44 equation 17) found... 

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