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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