✍ Scribed by Mulzer, Johann ;Graske, Klaus-Dieter ;Kirste, Burkhard
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Thc carbacyclin precursors 11, 17, 18 have been prepared from the en-ynes 10, 15, 16 by cobalt-mediated cyclization (Pauson-Khand reaction) with varying degrees of diastereoselectiviiy.
Prostacyclin (1 a) shows outstanding effects on the mammalian organism, in particular with respect to vasodilation and inhibition of platelet aggregation. A clinical application, however, is prohibited by the instability of 1 a under hydrolytic conditions').
A number of more stable analogues has thus been tested, the most promising candidate so far being carba-prostacyclin (carbacyclin) (1 b) or derivates thereof with varying substitution patterns in the eight-carbon appendage*). The usual synthesis of 1 h proceeds via bicyclic ketones of type 2, which in turn are prepared either from Corey's lactone aldehyde in optically pure form, or from simpler precursors as racemates, which have to be resolved on a later stage3). Clearly, an attractive alternative could be seen in the cobaltmediated (Pauson-Khand) cyclization4) of an enantiomerically and diastereomerically pure en-yne 3 to form the desired bicyclic intermediate 4 in one step. The terminal trimethylsilyl group is introduced to increase the stereoselectivity of the reaction4). The pivotal issue of this approach is the availability of 3 in a variety of suitable substitution pat-891 Asymmetrische Syntbese von CarbacycbVorkufem durcb Pauson-Khand-C y c l i s i g Die Carbacyclia-Vorliufer 11, 17, 18 wurden durch kobaltkatalysierte Cyclisierung (Pauson-Khand-Reaktion) aus den En-inen 10, 15, 16 mit wechselnden Diastcreoselektivitlitcn hergcstcllt.
terns and the stereocontrol which is exerted onto the newly created stereocenter during the cyclization. Magnus recently described5) a Pauson-Khand-based carbacyclin synthesis in which high stereocontrol was achieved by means of an acetonide bridge between OR' and R2. Independently, we studied the cyclization of the acyclic en-ynes 10, 15, and 16, which are readily accessible from (R)-6) and (S)-2,3-0-is~propylideneglyceraldehyde~) 5a/b.
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