Norgestrel, synthesis

Norgestrel Synthesis with Intramolecular Diels/Alder Reaction... 

Norgestrel Synthesis with Intermolecular Diels/Alder-ResLCtion... 

It is not without appeal to compare the (-)-norgestrel synthesis of the constitutional type AB+D ABCD with that one following the pattern A+D AD... 

Elaboration of a commercially viable route for total synthesis of 19-nor steroids led to the introduction of the totally synthetic product norgestrel (71) as the progestational component of an oral contraceptive. As was observed in the "natural" 19-nor-compounds, reduction of the 17-ethynyl group to 17-ethyl affords compounds with androgenic/anabolic... 

SCHEME 6. Outline of Smith and Hughes (Wyeth s) synthesis of Norgestrel (see footnote 53). 

In producing the (-) form of Norgestrel optical resolutions were carried out as early in the synthesis as possible, with such as compound XXVII being a favored starting point. Both chemical resolution (of the hemisuccinate58) and dehydrogenation methods59 were used for resolution. 

Another efficient synthesis of i7-norgestrel (209) begins with the condensation of 2-ethyl-1,3-cyclopentanedione (200, R = C2H5) with methyl vinyl ketone (199), producing (201). An asymmetric, intramolecular aldol condensation of (201) that is catalyzed by (T)-(—)-prohne followed by an acid-catalyzed dehydration yields hydrindandione (202) in 97% optical purity (205). Condensation of (202) with formaldehyde and benzenesulfinic acid generates (203) in 85% yield. 

Nonanedioic add, 5-hydroxy-2,4,6,8-tetramethyl- diastereoselective lactonization, 168, 327-328 2,4-Nonanedione retro-synthesis, 204 Norbomane etc. See Bicyclo[2.2.1 ] heptane ere. Norphedrine = (/ , S )-a-benzene-methanol, ( + H S)- chiral auxiliary, 61 —, ( ) synthesis, 302 Norgestrel, ( )- total synth., 278 19-Norpregna-1,3,5(10)-trien-2-yne-3,l 7-diol, (17a)- [ethynylestradiofy 62-63 A-Norpregn-3(5)-eri-20-one, 3-methyl- synthesis, 91-92, 279-280 Noyori hydrogenation, 102-103, 325-326 SI Nuclease, 242... 

Table 3.3.1 lists a few commercial steroids, in particular those that can be used as inexpensive starting materials. Most industrial syntheses of steroids are based on these naturally occurring compounds. Only norgestrel is made by total synthesis and is therefore expensive. 

---