This thesis consists of four chapters which describe the collective total syntheses of natural
products and development of asymmetric synthetic strategy. Chapter one is focused on the
collective total syntheses of Protoberberine alkaloids; Chapter two presents the first asymmetric
total syntheses of 13-Methyltetrahydroprotoberbeines; Chapter three describes the total
synthesis Eburnamine-Vincamine-Tacamine alkaloids and progress on the asymmetric
alkynylation of carboline iminium ion; Chapter four is summary and the appendix containing
NMR spectra and HPLC data.
Chapter one described a general and concise strategy for the collective total syntheses of
more than 50 protoberberine alkaloids and five aporhoeadane alkaloids with 4-8 steps.
Protoberberine alkaloids are a pharmacologically important class of isoquinoline alkaloids for
their broad and potent biological activities. However, all prior strategies have been tailored for
a single class of protoberberine alkaloids with focus on semisynthesis and lack of generality
and flexibility. Our strategy is hinged on a newly established CuI-catalyzed redox-A
3 reaction
(alkyne, aldehyde and amine) and the subsequent palladium-catalyzed reductive
carbocyclization to prepare the key tetracyclic intermediate, which was elaborated within 5
steps to five types of protoberberine alkaloid natural products. (i) a subsequent PtO
2 or Pd/C
hydrogenation of tetracyclic intermediate furnished twelve 13-methyltetrahydroprotoberberines in three steps with 44-65% overall yield; (ii) after a one-pot
Rh-catalyzed olefin isomerization/aromatization process of the key tetracyclic intermediate,
fourteen 13-methylprotoberberines and analogues were obtained with 25-48% overall yield; (iii)
Ru-catalyzed oxidation of the tetracyclic intermediate followed by Rh-catalyzed reductive
decarbonylation produced eight 8-oxyprotoberberines in four steps with overall 16-36% yield;
(iv) reduction or oxidation of the eight 8-oxyprotoberberines enabled us to accomplish the
collective synthesis of the corresponding tetrahydroprotoberberines and protoberberines.
Finally, Shamma translactamization of the prechilenine intermediate generated by oxidation of
the tetracyclic intermediate gave the alkaloid chilenine, which was elaborated using the reported
methods to four aporhoeadane natural products within five steps. Notably, this strategy
represents the most efficient and shortest synthetic route to the 13-methylprotoberberines, most
of which were synthesized for the first time.
Chapter two described the first asymmetric collective total syntheses of twelve 13-methyltetrahydroprotoberberines. The importance of C13 substitution to the biological activity
of protoberberine alkaloids has been well recognized in the medicinal chemistry community;
while their synthetic methods, in particular asymmetric synthesis, are rather underdeveloped.
In continuation of our interest and previous work (Chapter one), we embarked on the
development of asymmetric synthesis by exploiting the key redox-A
3 reaction and Pd-catalyzed
reductive Heck cyclization. After extensive experimentation and exploration of chiral ligands
and reaction conditions, we fortunately identified the (S,R)-N-Pinap ligand for the highly
enantioselective CuI-catalyzed redox-A
3 reaction of tetrahydroisoquinolines, 2-bromobenzaldehydes, and alkynes, which enabled us to accomplish the first asymmetric total
syntheses of twelve natural 13-methyltetrahydroprotoberberines (13-MeTHPBs) in three
catalytic steps with 47-64% overall yields and 91-96% ee optical purity. In addition, three Pd-catalyzed
domino reactions (Heck-Suzuki, Heck-Sonogashira, and Heck-Heck) had been
developed to provide the tetracyclic tetrahydroprotoberberine core bearing otherwise poorly
accessible substituted alkene at C13, which substantially expanded the structural diversity for
medicinal chemistry.
Chapter three described the total synthesis of indole alkaloid eburnamonine and tacamonine
as well as progress on the first asymmetric alkynylation of the N-alkyl carboline iminium ion.
To further expand our synthetic strategy (Chapters one and two) for total synthesis of indole
alkaloids, we proposed a redox-A
3-like reaction: three-component reaction of alkyne, allyl
halide and carboline. After optimization, this three-component reaction was best performed
with CuI-catalyzed alkynylation of the N-alkyl carboline iminium ion, which provided the
requisite tetrahydrocarbolines for the subsequent Pd-catalyzed carbocyclization/carbonylation
reaction. With this new method, total synthesis of (±)-eburnamonine was accomplished after a
highly regioselective monohydrogenation of 1,3-diene and Michael addition of ethyl Grignard.
Similarly, the total synthesis of (±)-tacamonine was achieved in total 5 steps using this newly-established
strategy. To realize the asymmetric synthesis of eburnamonine and tacamonine and
related alkaloids, asymmetric Cu-catalyzed alkynylation of the N-Allyl carboline iminium ion
was extensively explored with various types of chiral nonracemic ligands. Preliminary results
indicated that the Cu(I)/Pybox-catalyzed alkynylation of the preformed carboline iminium ion
provided the N-Allyl tetrahydrocarboline with highest er value of 88:12. Interestingly, the same
catalytic system when applied to the reaction of N-Benzyl carboline iminium ion and
aliphatic/aromatic alkynes gave the N-benzyl tetrahydrocarboline product with excellent
enantioselectivity (5:95 er). However, the N-Allyl tetrahydrocarbolines are more easily
functionalized to eburnamonine and tacamonine and therefore we are working on improvement
of the enantioselectivity for alkynylation of the N-Allyl carboline iminium ion.
Post a Comment