DIBAL 836 Subject

R2=C02CH3) exhibit little difference in face selectivity, i.e., syn selectivity when subject to NaBH symanti = 65 35 in 18d 62 38 in 18e) and DIBAL-H syn.anti = 66 34 in 18d 61 39 in 18e) reduction. The behavior of 18d and 18e is also consistent with orbital unsymmetrization, as in 19. On the other hand, Mehta et al. suggested the presence of significant electrostatic contributions from exo-electron-withdrawing groups, rationalizing the syn face selectivity in 18b [75]. 

To investigate the feasibility of employing 3-oxidopyridinium betaines as stabilized 1,3-dipoles in an intramolecular dipolar cycloaddition to construct the hetisine alkaloid core (Scheme 1.8, 77 78), a series of model cycloaddition substrates were prepared. In the first (Scheme 1.9a), an ene-nitrile substrate (i.e., 83) was selected as an activated dipolarophile functionality. Nitrile 66 was subjected to reduction with DIBAL-H, affording aldehyde 79 in 79 % yield. This was followed by reductive amination of aldehyde x with furfurylamine (80) to afford the furan amine 81 in 80 % yield. The ene-nitrile was then readily accessed via palladium-catalyzed cyanation of the enol triflate with KCN, 18-crown-6, and Pd(PPh3)4 in refluxing benzene to provide ene-nitrile 82 in 75 % yield. Finally, bromine-mediated aza-Achmatowicz reaction [44] of 82 then delivered oxidopyridinium betaine 83 in 65 % yield. 

To this methylated material (1.94 g, 7.72 mmol) in dry CH2C12 (53 mL) at —100 °C was added, over lOmin, 1.5M DIBAL-H in toluene (10.3mL, 15.4mmol). After 1.5h, dry MeOH (2mL) was added and the soln was warmed to 0°C. To this was added cold 1 M tartaric acid (50 mL) and the mixture was stirred at 0°C for 20 min. The aqueous phase was extracted with CH2C12 (2 x). The organic phases were dried (MgS04), filtered, and concentrated to give aldehyde 82 as an oil, which was subjected to chromatography (silica gel, EtOAc/hexanes 6 94) yield 1.17 g (79%). 

The Aspidosperma family of indole alkaloids has inspired many synthetic strategies for the construction of their pentacyclic framework of the parent compound aspidospermidine (366), since the initial clinical success of two derivatives, vinblastine (10) and vincristine, as anticancer agents. The alkaloids such as (-)-rhazinal (369) and (-)-rhazinilam (6) have been identified as novel leads for the development of new generation anticancer agents [10,11]. Bis-lactams (-)-leucunolam (370) and (-t-)-epi-leucunolam (371) have bio-genetic and structural relationships with these compounds [236]. Recently, enantioselective or racemic total syntheses of some of the these natural product were achieved. One successful synthesis was the preparation of the tricyclic ketone 365, an advanced intermediate in the synthesis of aspidospermidine (366), from pyrrole (1) (Scheme 76) [14]. The key step is the construction of the indolizidine 360, which represents the first example of the equivalent intramolecular Michael addition process [14,237,238]. The DIBAL-H mediated reduction product was subject to mesylation under the Crossland-... 

DIBAL diisobutylaluminum hydride LD50 dose that is lethal to 50% of test subjects... 

The challenge of this reaction is to reduce the Weinreb amide to the aldehyde while simultaneously reducing the methyl ester to the primary allylic alcohol. Different reagents were tested, but only an excess of sodium aluminum hydride delivered the desired product 13. The substrate was either inert or degraded if LiAlH4 or DIBAL were used. NaBH4 in methanol selectively reduced only the amide, but to form the primary alcohol. Because of its instability, hydroxyaldehyde 13 was not purified but directly subjected to the next reaction. 

Similarly, in connection with the cytotoxic meroterpenoid sargaol, the phenol 470 was subjected to PhI(OAc)2-promoted oxidation in MeOH, followed by DIBAL-H reduction to afford in 57% overall yield the target molecule 471 similar to sargaol. 

Scheme (5) Oxygenation of cyperone afforded a mixture of alcohols (60 and (61), whose trimethyl silyl derivatives were converted to diols (64) and (66) repectively and then to (3-rotunol (67) by oxidation. Subjection of p rotunol (67) to oxidation, epoxidation and reduction, respectively yielded tetraol (69). Formyl y-lactone (70), obtained from (69), was converted to phytuberol (56) by treatment with DIBAL. Phytuberol was converted phytuberin (55) by acetylation.

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