The [2+2]-photocycloaddition of aromatic aldehydes and ketones to 3,4-dihydro-2-pyridones: regioselectivity, diastereoselectivity, and reductive ring opening of the product oxetanes.

3,4-Dihydro-2-pyridones [3,4-Dihydropyridin-2(1H)-ones] 6 were evaluated with respect to their use as alkene components in stereoselective Paternò-Büchi reactions. The parent compound 6a was shown to be a versatile synthetic building block that reacted with various photoexcited aromatic carbonyl compounds (benzaldehyde, benzophenone, acetophenone, methyl phenylglyoxylate, 3-pivaloyloxybenzaldehyde) with high regio- and diastereo-selectivity (51-63% yield). The products can be subjected to hydrogenolysis, opening a new and efficient route for the synthesis of 2-arylmethyl-3-piperidinols. As examples, the oxetanes 7a and 8a were hydrogenolytically cleaved and yielded the products 12 (88%) and 13 (93%). The ability of compound 6a to bind to a chiral lactam host through two hydrogen bonds was used favorably to differentiate the enantiotopic faces of its double bond. In the photocycloaddition to the chiral aldehyde 15, which was conducted at -10 degrees C in toluene, a high facial diastereoselectivity (>90% de. 56% yield) was recorded. The stereoselectivity results from a 1:1 association of dihydropyridone 6a to the aldehyde. The 4-substituted dihydropyridones 6b-6d (R = methyl, isopropyl, phenyl) were found to be less suited for potential use in photochemistry. The yields and facial diastereoselectivities recorded in their photocycloaddition to benzophenone remained low.

The synthesis of (+)-preussin and related pyrrolidinols by diastereoselective Paternò-Büchi reactions of chiral 2-substituted 2,3-dihydropyrroles.

The N-alkoxycarbonyl substituted 2,3-dihydropyrroles 3 and 8 are converted to 2-benzyl-3-pyrrolidinols by the Paternò - Büchi reaction followed by hydrogenolysis. Since the addition of the photoexcited benzaldehyde at the unsaturated heterocycle proceeds in a syn fashion, the benzyl group at C-2 and the hydroxy group at C-3 of the product are cis oriented. The simple and facial diastereoselectivities of the Paternò-Büchi reaction were studied more closely and the relative configuration of the products was elucidated. The thermodynamically less stable endo product is formed as a result of simple diastereoselection. The face differentiation in 2-substituted 2,3-dihydropyrroles is presumably due to the nonplanarity of these heterocycles, which forces attack of the carbonyl group on the face with the existing substituent. All-cis-pyrrolidinols are consequently formed after hydrogenolysis. Following this route, a total synthesis of the pyrrolidinol alkaloid (+)-preussin (1) was conducted, which yielded the target compound in a total yield of 11% over nine steps starting from L-pyroglutaminol (11).

Inhibition of cyclin-dependent kinase activity and induction of apoptosis by preussin in human tumor cells.

In this paper, we report that (+)-preussin, a pyrrolidinol alkaloid originally identified as an antifungal agent, has growth-inhibitory and cytotoxic effects on human cancer cells. Preussin was found to be a potent inhibitor of cyclin E kinase (CDK2-cyclin E) in vitro (50% inhibitory concentration; approximately 500 nM) and to inhibit cell cycle progression into S phase. In agreement with these findings, the level of the cyclin-dependent kinase inhibitor p27(KIP-1) is increased in response to preussin treatment while the expression of both cyclin A and the transcription factor E2F-1 is down-regulated. Preussin also induces programmed cell death (apoptosis), which requires caspase activation and involves the release of cytochrome c from mitochondria. This induction of apoptosis is not blocked by high levels of Bcl-2, which usually confers resistance to chemotherapeutic agents. Taken together, our data indicate that preussin could be a promising lead compound for the development of a new class of potent antitumor drugs.