Ring-Closing Allylation Reactions

Over the past twenty years, the intramolecular allylation of aldehydes has been used in the synthesis of natural products containing a-methylene-y-lactones [95-101] (e.g. confertin [99] and cembranolide [100, 101]), polyene-containing macro-lides [102, 103] (e.g. asperdiol [102]) and, more recently, cyclic ether containing natural products (e.g. (-i-Vlaurencin [104] and hemibrevetoxin B [105]). However, the principles that govern the stereoselectivity in these cyclization reactions have only recently been studied in a systematic manner (see below). 

Keck and co-workers have investigated the exo cyclizations of the allylstan-nanes (Z)-158 and ( )-159 these reactions can be promoted by both thermal and Lewis acidic conditions (Table 11-10) [54]. As illustrated in Table 11-10, the (Z)-stannane 158 preferentially forms the 1,2-syn adduct 160 under both thermal promotion and catalysis by Bp3 OEt2. In contrast, the (i )-stannane 159 cyclizes to form the, 2-anti carbocycle 161 as the major adduct in the BF -OEta-catalyzed allylation, while the, 2-syn carbocycle 160 is the major adduct in the thennji] allylation process. 

The thermal intramolecular allylation of (Z)-158 occurs spontaneously at 25 C. Conversely, the thermal intramolecular allylation of the ( )-stannane 159 required much higher temperature (110°C) for reaction to occur. Keck rationalized that (Z)-158 must react preferentially through the cyclic chair-chair transition state 162 (Fig. 11-14) to form the major adduct 160, while the minor adduct, 161, must arise through the sterically disfavored chair-boat transition state 163. The major 

In the BF3-OEt2-catalyzed reaction of (Z)-158, the formation of 160 as the major adduct is rationalized by preferential bond formation through the synclinal transition state 166 (Fig. 11-15). The minor adduct 161 arises through the other synclinal transition state, 167. The ( j-stannane 159, on the other hand, forms 161 preferentially through the synclinal transition state 168. In both of the preferred transition states, 166 from (Z)-158 and 168 from (F)-159, the tin-bearing carbon is in close proximity to the aldehyde oxygen. As noted previously. Keck proposed that this situation is preferable because of secondary orbital overlap be- 

Yamamoto [106] and Martin [107] have independently investigated the exo cyclizations of (y-alkoxyallyl)stannanes, potential precursors to polyether natural products. Yamamoto systematically studied the thermal and Lewis acid-promoted cyclizations of allylstannanes (Z)-170 and ( )-171 (Table 11-11). 

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The reaction of carbonyl compounds and allylmetal reagents is an important transformation in organic synthesis. Advances in stereoselective carbonyl allylation reactions have been spurred by interest in the synthesis of polypropionate-derived natural products, carbohydrates and other polyhydroxylated compounds. These reactions are ideally suited for the construction of stereochemically rich acyclic skeletons. Additionally, cyclic polyether-containing natural products, among others, have inspired chemists to investigate ring-closing allylation reactions. This review will focus on recent developments in the allylation reaction, with special emphasis on its application towards the synthesis of natural products. 

From these examples it is clear that the principles of acyclic stereocontrol that govern the allylation reactions of achiral Type II allyl- and crotylmetal reagents with chiral aldehydes can be used to excellent advantage in the stereoselective synthesis of natural products. In the following section, the factors that influence the stereoselective formation of cyclic compounds in the ring-closing allylation reaction are discussed and selected synthetic applications are reviewed. 

Selected Applications of the Ring-Closing Allylation Reaction in Natural Product Synthesis... 

These selected synthetic applications of the ring-closing allylation reaction illustrate the opportunities for obtaining with high stereoselectivity functionalized heterocycles and carbocycles, common units found in natural products. Other applications of intramolecular allylation reactions have been reported [95-101, 103]. 

The role of complexes 23-28 as catalyst precursors in the ring closing metathesis reactions was investigated. Three different diene substrates diethyldiallyl-malonate (29), diallyltosylamine (30). and dielhyldi(2-methylallyl)malonate (31) were added to the NMR tubes containing a solution of 5 mol% of catalyst precursor in an appropriate deuterated solvent. The NMR tubes were then kept at the temperatures reported in Table X. Product formation and diene disappearance were monitored by integrating the allylic methylene peaks in the H NMR spectra and the results are presented in Table X and the catalytic transformations are depicted in Scheme 3. 

This oxirane was converted into oxazolidinone 194 which subsequently was transformed into benzylidene acetal 195 and allq lated with allyl iodide 196 to diene 197. Ring closing metathesis reaction of this diene followed by hydroboration-oxidation afforded derivative 198 which, upon treatment with HCl, gave the target (- -)-deo q nojirimycin. 

Intramolecular cycloadditions of substrates with a cleavable tether have also been realized. Thus esters (37a-37d) provided the structurally interesting tricyclic lactones (38-43). It is interesting to note that the cyclododecenyl system (w = 7) proceeded at room temperature whereas all others required refluxing dioxane. In each case, the stereoselectivity with respect to the tether was excellent. As expected, the cyclohexenyl (n=l) and cycloheptenyl (n = 2) gave the syn adducts (38) and (39) almost exclusively. On the other hand, the cyclooctenyl (n = 3) and cyclododecenyl (n = 7) systems favored the anti adducts (41) and (42) instead. The formation of the endocyclic isomer (39, n=l) in the cyclohexenyl case can be explained by the isomerization of the initial adduct (44), which can not cyclize due to ring-strain, to the other 7t-allyl-Pd intermediate (45) which then ring-closes to (39) (Scheme 2.13) [20]. While the yields may not be spectacular, it is still remarkable that these reactions proceeded as well as they did since the substrates do contain another allylic ester moiety which is known to undergo ionization in the presence of the same palladium catalyst. 

Reduction of iV-(3-bromopropyl) imines gives a bromo-amine in situ, which cyclizes to the aziridine. Five-membered ring amines (pyrrolidines) can be prepared from alkenyl amines via treatment with N-chlorosuccinimide (NCS) and then BusSnH. " Internal addition of amine to allylic acetates, catalyzed by Pd(PPh3)4, leads to cyclic products via a Sn2 reaction. Acyclic amines can be prepared by a closely related reaction using palladium catalysts. Three-membered cyclic amines (aziridines)... 

A nice application of this reaction for the synthesis of cyclic a-sulfanylphos-phonates 63 has been reported [42]. It involves a Rh(II)-catalyzed [2,3]-sigmatropic rearrangement and a ring-closing metathesis of the resulting a-(S-allyl) y,d-unsaturated phosphonates 62 (Scheme 16). However, the last step occurs with a low yield (19%) when R = H. 

The synthesis and olefin metathesis activity in protic solvents of a phosphine-free ruthenium alkylidene bound to a hydrophilic solid support have been reported. This heterogeneous catalyst promotes relatively efficient ring-closing and cross-metathesis reactions in both methanol and water.200 The catalyst-catalyzed cross-metathesis of allyl alcohol in D20 gave 80% HOCH2CH=CHCH2OH. 

It is interesting to note that the two reactions involving allyl acetate and the unprotected alcohol, but-3-en-l-ol, failed when the molybdenum catalyst was used. The failure of the Schrock catalyst to tolerate unprotected alcohols has also been observed in ring-closing metathesis [40], where a tertiary alcohol has proved to be the only success [41]. 

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