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Anna Giarratana, Katherine Redford, Sarah Burke, and Stephanie Vrakas.

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Presentation on theme: "Anna Giarratana, Katherine Redford, Sarah Burke, and Stephanie Vrakas."— Presentation transcript:

1 Anna Giarratana, Katherine Redford, Sarah Burke, and Stephanie Vrakas

2  Alkaloid: a chemical compound that contains a basic nitrogen.  Used traditionally in Chinese medicine.  Show anticancer, cytoxicity, antimalarial properties.

3  Minfiensine is a pentacyclic indole strychnos alkaloid.  It can be extracted from the African plantstrychnos minfiensis.  Discovered in 1989 by Massiot and coworkers.

4  Synthetic interest: Challenging to synthesize which gives organic chemists a chance to showcase cascade ring formation reactions. Tetracyclic Core

5  Minfiensine has a pentacyclic ring system.  Integrated into this ring system is an aminal functionality. Two amines bonded to same carbon atom (similar to acetal).  Several chiral carbons.

6 Sequential Catalytic Asymmetric Heck-Iminium Ion Cyclization: Enantioselective Total Synthesis of the Strychnos Alkaloid Minfiensine Overman et al.



9 This molecule undergoes Heck Asymmetric Cyclization to produce the tetracyclic core. 5 Steps

10 Step 1: Transamination Step 2: Nitrogen Protection vs.


12 Tried: LHMDS, KHMDS, NaHMDS, NaH Yielded a mixture of 8 and carbamate


14 Mandar’s Reagent 60% to 89% yield Why? L.G.?

15 Triflation


17 - add beta-aminoethyl

18 Suzuki RXN

19 cyclohexadienyl aryl triflate precursor


21 Asymmetric Heck Cyclization

22  The Heck rxn was discovered in 1970  In 1977 Mori and Ban reported the first INTRAmolecuar Heck  Shibasaka and Overman discovered the Asymmetric Heck Cyclization in 1989- still being studied to this day  Makes tertiary and quaternary stereocenters  Needs precatalyst, a chiral ligand, a base, a polar aprotic solvent, heat


24 BINAPPMP Problem:

25 Use chiral (phosphinoaryl) oxazolines ligands! However, to improve enantioselectivity to 96 % e.e. ACN was used at 80 C Problem: 10% alkene isomerization i-Pr PHOX

26 With the replacement of the PHOX ligand and a consideration of time:

27 Asymmetric Heck Cyclization


29  It is important to recognize that although the core is formed the absolute configuration was not established


31  The authors were initially concerned about the facial selectively of epoxidation.  Using mCPBA the epoxide adds to the back face with 10:1 stereoselectivity.

32 Favored Conformation of Cyclohexene Ring  Computational studies showed that the cyclohexene ring prefers to exist in a half chair conformation.  Therefore mCPBA will approach anti to the indole bridge.


34  However, the acid conditions used to remove Boc promoted fragmentation of the molecule.

35  Because the fragmentation only occurred under acid conditions, other methods were attempted to remove the Boc protecting group. Heating in DMSO Heating in a microwave reactor  None of these methods worked!

36  However, the Boc protecting group can be removed immediately following epoxidation.  Why here and not later? The same protonation and initial ring opening will occur in the presence of acid, but the epoxide ensures that further fragmentation will not.

37  So following epoxidation, the Boc protecting group is removed with TFA.

38  Then the amine is REPROTECTED with alloc (allyloxy carbonyl)!  Alloc can be removed using catalytic reduction conditions later in the scheme which will not cause a ring opening like acid did.


40  Before using the organoselenide method, the authors attempted using lithium amide bases. They tried lithium diisopropylamide and lithium diethylamide and even heated the reaction to 45 degrees C!

41  This did not work because there was a rapid loss of the methyl carbamate group.

42  Note that the hydroxyl group is protected with TES and not Bn as in the initial scheme. Bn will be removed by the catalytic reduction conditions used to remove Alloc.

43  To form the final ring of minfiensine  Heck cyclization-carbonylation sequence  First Attempt:

44  Inability to create desired product  Led to attempt using reductive conditions  Second Attempt:

45  Fail.  Why?  Thoughts:

46  Rational behind undesired product formation:  Double bond migration  Pd (II) functions as a Lewis acid  Activates aminal functionality towards ring cleavage  Facilitates double bond migration

47  Heck reaction under Jeffrey Conditions  Inorganic bases and tetraalkylammonium halides  Hope that Heck cyclization faster than double bond isomerization  After optimization:  DMF, 30 min, 80 C  1 mol % Pd(OAc) 2, K 2 CO 3 (5 eq), (n-Bu) 4 -NCl (2.5 eq), NaO 2 CH (1.2 eq)  No pentacyclic isomer (57)  Limited deallylation product (46)


49  These conditions do not contain a phosphine ligand!!! But Pd(II) cannot do a Heck and Pd(0) cannot exist without any ligands… We think that water might act as a ligand in this reaction.  Note that the salt Bu 4 NCl is believed to speed up the reaction.


51  Made tetracyclic core!  Last Step:  A double bond and a one carbon side chain installed in the cyclohexane ring


53  Beta-keto ester exists nearly exclusively as enol tautomer


55  First:  Tried traditional methods to dehydrate beta-hydroxy ester  Tried reaction with:  Methanesulfonyl chloride  Triflic anhydride and triethylamine  Next:  Tried two step dehydration



58 Nine-Step Enantioselective Total Synthesis of (+)- Minfiensine MacMillan et al








66 Step E: Protection of the Alcohol Mechanism:



69  Using AIBN and Bu 3 SnH, the reaction was unsuccessful. Therefore the authors used the more hindered tBu 3 SnH.

70  6-exo-dig  A six-membered ring is formed (6)  The bond broken to form the ring lies outside of the ring (exo)  The electrophilic carbon is sp hybridized (dig)

71  Pd selectively reduces the less hindered double bond.



74 Overman et al.MacMillan et al.  Linear Progression  2005:  22 Steps  4.1 % overall yield  2008:  15 steps  6.5% overall yield  Original Synthesis  Noteworthy reactions  Asymmetric Heck  Retrosynthetic Approach  9 Steps  21% overall yield  New Synthesis  Noteworthy reactions  Diels-Alder  Alkyne Radical Coupling

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