Highly Enantioselective Alkylation of Tetrahydroisoquinolines via a Valine Chiral Auxiliary; Asymmetric Synthesis of (S)‐Isoquinoline Alkaloids

Abstract

The utilization of natural amino acids as a source of chirality for the preparation of various enantiomerically enriched compounds has been reviewed recently"]. We have reported that tetrahydroisoquinolines, via their N-iminomethyl derivatives (i.e. as formamidine derivatives), are metalated and alkylated to give l-alkyltetrahydroisoquinolines in good while enantioselective alkylations via chiral formamidines provide these products in high enantiomeric excessE4]. These enantioselective alkylations were performed using the disilyl ethers of (1S,2S)-(+)-2-amino-l-phenyl-1,3-propanediol, whose availability and stability posed some technical problems. We now report that the tert-butyl ether 8d of valinol 8a can not only be conveniently prepared, but also leads to higher enantioselectivity than the propanediol derivative when transformed into the formamidine 9. By simple exchange between the isoquinolines 1 or 2 and 9, the chiral formamidines 3a or 3b are obtained in 70-90% yield'']. Metalation with lithium diisopropylamide (for 3a) and tert-butyllithium (for 3b) gave the lithiated formamidines, which were alkylated with alkyl halides and then hydrazinolyzed to remove the iminomethyl group@'. The high efficiency of this process is outlined in Table 1. The enantiomeric excesses of 4 were determined by chiral-column HPLC analysis, as developed by Pirkle, and applied to chiral N-heterocycles and other amine~[~.*I. The optical rotations in Table

A Novel Asymmetric Route to the 1,3-Disubstituted Tetrahydroisoquinoline, (−)-Argemonine

“…Following formalin−formic acid treatment, the Pictet−Spengler cyclization ensued to give (−)-xylopinine 14 in 90% yield. The latter possessed [α] 23 D −283 ( c 0.32, CHCl 3 ) and compared well with the literature value of [α] 23 D −275 …”

A Novel Straightforward Synthesis of Enantiopure Tetrahydroisoquinoline Alkaloids

“…The absolute configuration at C-1 in the tetrahydroisoquinolines 11a , 11b , , 12a , 4a,, and 12e 4a, was assigned as R and 12c as S by comparison of the sign of the optical rotations with those previously described. However, compounds 12d , 12e , and 12f were transformed into the enantiopure known alkaloids ( R )- O -methylarmepavine ( 13d ), ( R )-laudanosine 20 ( 13e ), and ( R )-homolaudanosine ( 13f ) respectively, by methylation with dimethylpyrocarbonate followed by carbamate reduction with LiAlH 4 (Scheme ).…”

Asymmetric Synthesis of the Protoberberine Alkaloid (S)-(−)-Xylopinine Using Enantiopure Sulfinimines

“…Indeed the majority of these asymmetric syntheses has been of ( S )-(−)-xylopinine ( 1 ) (Figure ). Meyers reported two asymmetric synthesis of (−)- 1 employing his chiral formamidine anions and chiral bicyclic lactam technologies . A chiral auxiliary mediated Pictet−Spengler synthesis was used by Comins and by Czarnocki to prepare this alkaloid while Kametani employed a photochemical cyclization strategy with an enantiomerically pure eneamide …”