Catalytic Asymmetric Total Synthesis of the Muscarinic Receptor Antagonist (R)-Tolterodine

Abstract

A convenient and high yielding method for the preparation of (R)-tolterodine, utilizing a catalytic asymmetric Me-CBS reduction was developed. Highly enantioenriched (R)-6-methyl-4-phenyl-3,4-dihydrochromen-2-one (94% ee) was recrystallized to yield practically enantiopure material (ee > 99%) and converted to (R)-tolterodine in a four-step procedure. The configuration of the crucial stereocenter was preserved during the synthesis and the obtained product was identified by chiral HPLC to be the (R)-tolterodine enantiomer.

Asymmetric synthesis of γ-branched amines via rhodium-catalyzed reductive amination

“…A highly enantioselective synthesis of ( R )-Tolterodine was then demonstrated in Fig. 5b 32 – 34 . The ( E )-vinyl bromide 6 , prepared from trans -cinnamyl chloride 35 , was coupled with aryl boronic acid 7 to afford the diastereopure ( E )-allylic amine 8 in 91% yield.…”

Anticholinergic Drugs

“…Other publications patents are based on very close two approaches [57][58][59][60][61][62][63][64][65] which propose asymmetric hydrogenation of [57][58][59][60][61][62][63][64] or enantioselective synthesis of [65] (Scheme 14.4.). …”

On the Absolute Stereochemistry of Tolterodine: A Circular Dichroism Study

“…The procedure was replicated by the same authors two years later in a paper, which also provided the first explicit correlation between the OR sign of 1 and 2 [22]. Chromanone 3 is a common intermediate in the route to 1 [23,24,25,26], although with unexpected implications. In fact, in a later report by Chen et al, the correlation was between ( R )-(−)- 3 and ( R )-(+)- 1 [23], that is, the AC of 3 was reversed with respect to Piccolo et al [21,22].…”

“…Available OR data for ( R )- 3 in chloroform are negative and span from [α]normalD20 − 2.2 ( c 0.3) to [α]normalD20 − 6.2 ( c 1) [23,26,27,28,29]. A very large positive value was however obtained in dichloromethane [α]normalD20 + 36 ( c 1) [24]. For ( S )- 3 , Piccolo et al reported a negative [α]normalD20 − 2.8 ( c 1.44, chloroform) [21,22].…”

“…For ( S )- 3 , Piccolo et al reported a negative [α]normalD20 − 2.8 ( c 1.44, chloroform) [21,22]. In none of the syntheses of 1 involving 3 as intermediate [23,24,25,26], was the AC of this latter assigned independently from that of 1 . Since the AC of 1 was (incorrectly) given for established in the aforementioned patents [5,15,21], it is logical that the reported enantioselective syntheses of ( R )-(+)- 1 were not further concerned with the stereochemical assignment [1].…”