Diasteroselektive Hydroxyalkylierungen in 1‐Stellung von Tetrahydroisochinolinen und Synthese von Aporphin‐, Protoberberin‐ und Phthalid‐Alkaloider

Abstract

Unsubstituted and 6,7-dialkoxy-N-pivaloyl-tetrahydroisoqu~nolines 1-3 are converted to l-bromomagnesium derivatives by sequential treatment with 1-BuLi (-75"/THF) and MgBrz.0Et2. Addition of the metalated tetrahydroisoquinolines to aliphatic or aromatic aldehydes occurs with relative topicity ul (Scheme 2). The I-hydroxyalkylated 2-pivaloyl-tetrahydroisoquinolines a of u-configuration thus obtained (14 examples) can be converted to free aminoalcohols c of either Ior u-configuration (9 examples; Scheme 3). The depivdloylation with retention (+ u-c) is best achieved by heating in EtOH/KOH, the conversion to 1 -aminoalcohols I-c by treatment with CF,COOH/(CF,CO),O (+ I -pivalates I-b), followed by alkaline saponification or by LiAIH4 reduction of the esters. The configuration of the products is assigned by 'H-NMR spectroscopy, by X-ray crystal structure analysis, by chemical correlation, and by comparison of the chemical properties of the Iand the u-isomers. The diastereoselective hydroxybenzylation of the tetrahydroisoquinoline is used for short syntheses of ushinsunine/ oliveroline (Scheme 4 ) , p-hydrastine, and ophiocarpine/epiophiocarpine (Scheme 6: aporphine, phthalide, and protoberberine alkaloids, respectively).

A General, Concise Strategy that Enables Collective Total Syntheses of over 50 Protoberberine and Five Aporhoeadane Alkaloids within Four to Eight Steps

“…AlCl 3 -mediated LiAlH 4 reduction of 8-oxyprotoberberine furnished lambertine (15 a)a sa nu nstable intermediate, which withouti solation (purification) couldb ee asily reducedw ith NaBH 4 to canadine (12 a,6 3% yield over two steps)o ro xidized by iodine to protoberberine (13 a,5 7% yield over two steps) in aone-pot fashion. DirectBH 3 reduction of 15 a produced amixture of compounds, including ophiocarpine [31] (17 a), epiophiocarpine [31] At wo-stepp rocedure, m-CPBA oxidation of 15 a to 13-oxidoberberine (16 a)a nd LiAlH 4 reduction;h owever,c ould reproducibly and cleanly provide 17 a and 17 b as a1 :1 separablem ixture in 62 %c ombined yield. It was noted that both 17 a and 17 b could be readily oxidized by air and meticulous care should be taken in the course of workup and purification.…”

Evaluation of Phenyldiazenyl as a Protective/Activating Group in Lithiation–Substitution Reactions of Tetrahydroisoquinolines

“…complexation in N-Me THIQs [26][27][28] or via functionalization of N-H THIQ using a protecting group like Boc, [29][30][31] oxazolines, [32][33][34][35][36] pivaloyl, [37][38][39][40][41] chiral formamidines, [42][43][44] and nitroso. 45 Although various protecting groups are known but triazene as a protecting group acquires a attention because it provides simple and economic pathways.…”

Advances Towards the Synthesis of Aporphine Alkaloids: C‐Ring Formation via Approaches Based on One‐ and Two‐Bond Disconnections

“…[113] In 1987, Seebach et 24 Lenz (1988) [116] yl-1,2,3,4-tetrahydroisoquinolines, which on irradiation provided (�)-oliveroline and (�)-ushinsunine (entry 22). [114] In 1988, Castedo et al determined the structure of goudotianine, an aporphine alkaloid isolated from Guatteria goudotiana R. E. Fries, by a total synthesis involving the photocyclization of a 1-(2-bromobenzylidene)-2-carbethoxy-1,2,3,4-tetrahydroisoquinoline derivative (entry 23). [115] In the same year, Lenz reported his findings on photocyclizations, which allowed the synthesis of some 7-oxygenated aporphine compounds (entry 24), [116] and Soicke et al published routes involving photochemical cyclizations, which allowed the synthesis of two aporphine alkaloids, (�)-bulbocapnine and (�)-cassythicine (entry 25).…”

“…We obtained aryne precursor 108 b upon the protection of 3-methoxyphenol (114) with hexamethyldisilazane (HMDS), followed by treatment with lithium diisopropylamide (LDA) and trimethylsilyl chloride (TMSCl) to produce disilylated compound 115. Intermediate 115 was deprotected using nbutyllithium (n-BuLi) and treated with trifluoromethanesulfonic anhydride (Tf 2 O) to provide aryne precursor 108 b [149] (Scheme 21b).…”