Studies on the oxazoline-mediated asymmetric addition of tetrahydroisoquinoline Grignards to aldehydes and its applications in the synthesis of optically pure isoquinoline alkaloids and directed metalation/Snieckus rearrangement of benzylic carbamates

Date of Award




Degree Name

Doctor of Philosophy (Ph.D.)



First Committee Member

Robert E. Gawley, Committee Chair


Chapter one. Two kinds of chiral oxazoline auxiliaries have been studied for the asymmetric addition reactions of tetrahydroisoquinoline Grignards to aldehydes. Amino acid-derived auxiliaries give 100% erythro to threo selectivity and no better than 71% ds. Camphor-derived auxiliary provides exclusively the erythro products with $\sim$80% ds and the major isomer can be isolated by a single recrystallization or chromatography in fairly good overall yield. So far, this auxiliary is considered the best for accomplishing carbonyl addition.Chapter two. A preliminary dynamic $\sp $C NMR study shows that (S)-1-$\sp6$Li-1-$\sp $C-2-(4,5-dihydro-4-isopropyl-2-oxazyl)-1,$2 $,3,4-tetrahydroisoquinoline in THF probably exists as a monomer. Inversion at C-1 is observed, which is very fast even at $-$100$\sp\circ$C. The THF solution of the corresponding magnesium compound consists of an equilibrium mixture of organomagnesium bromide and diorganomagnesium. The former is the only reactive species in the solution. Inversion at C-1 is observed in organomagnesium bromide, which is slow at low temperatures and faster at enhanced temperatures. The coalescence temperature is $-$65$\sp\circ$C.Chapter three. Optically pure (+)-corlumine is synthesized in 17% total yield through a key step of asymmetric carbonyl addition reaction.Chapter four. Lithiated benzylic carbamates, derived by treatment with strong base such as LDA or s-butyllithium in THF at $-$78$\sp\circ$C, undergo two different carbamoyl migration reactions, 1,4-transfer to the ortho position or 1,2-transfer to the benzylic position. Methylenedioxy substituted benzylic carbamates branched at the benzylic position give exclusively the 1,4-transferred products. Unsubstituted, 3-methoxy, and 3-methoxymethoxy substituted benzylic carbamates give only the 1,2-transferred products. The 1,4-transferred products can be easily converted into phthalides. A rapid pyramidal inversion of the intermediary lithium alkanide was observed. 1,2-Carbamoyl migration of O-alkyl carbamate can be achieved via tin-lithium exchange.


Chemistry, Organic

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