Über Pyridyl‐Steroide. II. Über Steroide, 142. Mitteilung

Abstract

Durch Umsetzung von [Pyridyl‐(2)‐methyl]‐lithium rnit Oestron und Dehydro‐epi‐O‐acetyl‐androsteron konnten die entsprechenden 17 β‐Hydroxy‐17 α‐picolyl‐Steroide erhalten werden. Die Lithium‐ Verbindung von 2‐Athyl‐pyridin, 1‐[Pyridyl‐(2′)]‐äthyl‐lithium, reagiert mit Dehydro‐epi‐O‐acetyl‐androsteron unter Bildung von zwei C‐20‐isomeren 17 β‐Hydroxy‐20‐pyridyl‐pregnenen. Die Hydrierung dieser Verbindungen wird ebenfalls beschrieben.

Organometallic Routes to Novel Steroids Containing Heterocyclic C-17 Side-Chains

“…This approach to the preparation of a library of novel withanolide analogues is illustrated herein using the readily available 11 3-methoxypregnenolone (7) as starting material for organometallic additions. [12][13][14] It should be noted that the 20R-configuration (as shown) is believed to be optimal for bioactivity, 15 and the Felkin-Anh model indicates that these should be the major products from organometallic additions to methyl ketones of this type (and this is well precedented [12][13][14].…”

“…Nevertheless, the reactions proceeded with complete diastereoselectivity giving 9R-11R with no sign of the corresponding S-isomers by NMR spectroscopy. The diastereoselective addition of 2-lithiopyridine (prepared from 2-bromopyridine) is well precedented 13,14 and the use of 3βmethoxypregnenolone (7) gave a 9:1 mixture of adducts 12R/12S (entry 5); recrystallisation from methanol-dichloromethane gave the pure R-diastereomer 12R in 53% yield.…”

“…In each of these examples, nbutyllithium was used for the metallation reactions; the use of stronger bases would almost certainly improve these yields, particularly for N-methylindole where tert-butyllithium is often employed. 16 The configuration of the newly formed stereocentre (C-20) was assigned based upon the earlier mentioned Felkin-Anh model, ample literature precedent [12][13][14] and comparability of NMR data across all of the adducts (see experimental section). These stereochemical assignments were confirmed by X-ray crystallography in the cases of the thiazole 8R and pyridine adducts 12R as shown in Figure 2 We next proceeded to explore routes to systems 6 containing a pyrandione or lactone ring in the side-chain to mimic the withanolide (and bufadienolide) natural products (Scheme 2).…”