Benzylation reactions natural products synthesis

In contrast, the reaction of aUcenylalanes with benzylic chlorides was reported to proceed faster and in higher yields in the presence of a Ni catalyst than in the presence of a Pd catalyst,as detailed later in the discussion of natural products synthesis. However, a more recent investigation has indicated that, aside from the rate of cross-coupling, the Pd-catalyzed reaction can proceed very satisfactorily in >90% yields in the same and closely related cases. It is therefore advisable to consider and compare Pd and Ni catalysts for a given case of benzylation. 

Oishi T, Akita H 0983) Asymmetric reduction by yeasts. Formation of optically active synthons having two chiral centers useful for natural product synthesis. J Synth Org Chem Jpn 41 1031-1043 Okamoto T, Ohno A, Oka S (1977a) Reaction of N-propyl-1,4-dihydro-nicotinamide with ferricyanide ion. J Chem Soc Chem Commun 181-182 Okamoto T, Ohno A, Oka S (1977b) Alkali-metal ion acceleration of the electron-transfer reaction between N-propyl-1,4-dihydronicotinamide and ferricyanide ion. J Chem Soc Chem Commun 784-785 Okamoto T, Ohno A, Oka S (1979) Reduction of transition-metal salts by N-propyl-1,4-dihydronicotinamide. Bull Chem Soc Jpn 52 3745-3746 Ono N, Tamura R, Kaji A (1980) 1-Benzyl-1,4-dihydronicotinamide as a reagent for replacing aliphatic nitro groups by hydrogen An... 

Several new methods for oxidative coupling of enolates, enol silanes, and enamines have been reviewed and illustrated with reference to natural product synthesis. Copper(II)-catalysed oxidative cross-coupling of aldehydes and alkylbenzenes, to form benzyl esters on reaction with t-BuOOH, has been demonstrated. ... 

Another microwave-mediated intramolecular SN2 reaction forms one of the key steps in a recent catalytic asymmetric synthesis of the cinchona alkaloid quinine by Jacobsen and coworkers [209]. The strategy to construct the crucial quinudidine core of the natural product relies on an intramolecular SN2 reaction/epoxide ringopening (Scheme 6.103). After removal of the benzyl carbamate (Cbz) protecting group with diethylaluminum chloride/thioanisole, microwave heating of the acetonitrile solution at 200 °C for 2 min provided a 68% isolated yield of the natural product as the final transformation in a 16-step total synthesis. 

Allenylsilanes 159 (Eq. 13.53) and 161 (Eq. 13.54) differ in the axial stereochemistry of the allene function. In each case, formation of the benzyl imine, followed either by treatment with tin(IV) chloride in benzene at room temperature or heating in toluene, leads to diastereomeric products 160 and 162 [63], Significantly, there is no crossover, pointing to a concerted (or fast, stepwise) process. Since the absolute stereochemistry of the allenylsilanes is easily controlled, the methodology is ideal for applications in total synthesis. Weinreb and co-workers have used the reaction for his synthesis of the marine natural product (-)-papuamine. 

The enantioselective intramolecular C-H insertion of alkyl diazoacetates has been used to prepare a variety of pharmaceutical and natural products [1], One example is the synthesis of (-)-enterolactone (8) shown in Scheme4 [2], The Rh2(4S-MPPIM)4-catalyzed reaction of 6 favors C-H insertion to form the y-lac-tone 7 in 93 % ee, which was the readily converted to 8. Competing C-H insertion at the highly activated benzylic C-H bond to form a /3-lactone was not observed, which illustrates the strong preference for five-membered ring formation over six-membered. 

Few synthetically useful examples of the oxidation of ethers by oxygen or ozone have been publish-ed.7 96 Q0 In 1978, Ourisson and coworkers reported that ozonization of the natural product cedrane oxide (43) on silica gel at -78 °C led to the formation of the corresponding lactone (44) in 30% yield (equation 32).A small amount of the tertiary alcohol (45) was also produced. Later, in the course of a chiral total synthesis of compactin, Hirama examined the ozonolysis of the alkene (46 equation 33). ° Under carefully controlled conditions, selective ozonolysis of the double bond could be achieved in 88% yield. However, when excess ozone was employed, significant amounts of the benzoate (47) were obtained, even at -78 C. In subsequent studies, benzyl ethers of primary and secondary alcohols,and carbohydrates were oxidized to the corresponding benzoates in excellent yields. Surprisingly, no further synthetic rqrplications of this reaction have been reported. 

As mentioned above, the photooxidation was discovered by exposure of compound 22 to sunlight. The reaction proved to be of great value for angucycline synthesis because the -hydroxy group present in most natural products which is easily eliminated under basic or acidic conditions (see Scheme 2) and the carbonyl group at C-1 can thus be introduced under mild neutral conditions. We assume that the reaction is initiated by Norrish type II y-hydrogen abstraction of the excited carbonyl in 25 to yield a diradical 26 as shown in Scheme 8 with 1-deoxyrabelomycin (25) as the example [39]. The H-abstraction requires a very definite steric environment in which the benzylic protons have to be in proximity of the excited carbonyl group. Subsequent addition of the diradical 26 with... 

The asymmetric total synthesis of cytotoxic natural product (-)-FRI 82877 was accomplished by D.A. Evans and co-workers." " To establish the absolute stereochemistry, a boron mediated aldol reaction was utilized applying (R)-4-benzyl-A/-propionyl-2-oxazolidinone" as a chiral auxiliary to yield the syn aldol product. 

The absolute stereochemistry of natural roseophilin was determined by means of asymmetric total synthesis by M.A. Tius and co-workers. The trisubstituted pyrrole moiety of the natural product was installed using the Paai-Knorr pyrrole synthesis starting from a macrocyclic 1,4-diketone. This diketone was prepared by reacting an exocyclic a, 3-unsaturated ketone with excess 6-heptenal in the presence of 3-benzyl-5-(hydroxyethyl)-4-methylthiazolium chloride as the catalyst. The major product was the trans diastereomer and the macrocyclization was achieved via aikene metathesis. It is worth noting that when the aldehyde was tethered to the cyclopentenone, all attempts to close the macrocycle in an intramolecular Stetter reaction failed. 

---