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

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

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

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

 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.

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

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

Step 1: Transamination Step 2: Nitrogen Protection vs.

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

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

Triflation

- add beta-aminoethyl

Suzuki RXN

cyclohexadienyl aryl triflate precursor

Asymmetric Heck Cyclization

 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 still being studied to this day  Makes tertiary and quaternary stereocenters  Needs precatalyst, a chiral ligand, a base, a polar aprotic solvent, heat

BINAPPMP Problem:

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

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

Asymmetric Heck Cyclization

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

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

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.

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

 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!

 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.

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

 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.

 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!

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

 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.

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

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

 Fail.  Why?  Thoughts:

 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

 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)

 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.

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

 Beta-keto ester exists nearly exclusively as enol tautomer

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

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

Step E: Protection of the Alcohol Mechanism:

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

 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)

 Pd selectively reduces the less hindered double bond.

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