The Total Synthesis of Phalarine:
Racemic and Enantiopure Routes
Anthony Pianosi
CHM 8256S
December 9, 2010
Where Does Phalarine Come From?
Phalaris coerulescens
(Blue Canary Grass)
• Colgate and colleagues isolated phalarine in 1999
• currently, no promising biological activity known
• possesses a novel furanobisindole alkaloid structure
Phytochemistry 1999, 51, 153-157
2
Structure of Phalarine
C3
C2
• novel furanobisindole alkaloid structure
• two stereocenters: C2 and C3
• gramine-related moiety (EF) interlocked with
carboline-related subunit (ABC) via ring (D)
Phytochemistry 1999, 51, 153-157
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Propeller-Like Interlocking
C3
C3
C2
C2
C2
C3
4
Danishefsky Attempts A Total Synthesis
Samuel J. Danishefsky
• structural novelty draws attention
of Danishefsky’s lab
• began synthesis of phalarine with
model studies
Li, C.; Chan, C.; Heimann, A.; Danishefsky, S. J. Angew. Chem. Int. Ed. 2007, 46, 1448-1450
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Retrosynthesis
6
Initial Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
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Reasons For Incorrect Regiochemistry
Tetrahedron Lett. 2006, 47, 4839-4841
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Reasoning For Second Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
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Second Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
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Reasons For Undesired Product
Tetrahedron Lett. 2006, 47, 4839-4841
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Attempt at Reordering of Bond Formation
C3
C2
SEQUENCE FOR BOND FORMATION
1. C
C between carboline C2 and aryl moiety
2. C
O at carboline C3
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Retrosynthesis
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Retrosynthesis
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Synthesis of Azaspiro Oxindole
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Formation of C2-Aryl Bond
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Rearrangement Unsuccessful
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Reasons for Failed Rearrangement
Reasons:
1. urethane-bound methylene has low propensity for migration
2. hydrogen bonding (
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) would restrict rotation
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Reasons for Failed Rearrangement
1. urethane-bound methylene has low propensity for migration
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Reasons for Failed Rearrangement
2. hydrogen bonding (
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) would restrict rotation
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What’s Next?.....Improve Migratory Tendency
1. Replace urethane with an N-methyl function
REASONS: N-METHYL IS ELECTRON DONATING
HIGHER LIKELYHOOD OF MIGRATION
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What’s Next?.....Remove Hydrogen Bonding
2. Incorporate an activating tosyl (Ts) function
REASONS: ELIMINATES HYDROGEN BONDING
PERMITS FREE ROTATION
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Preparation of New Substrate
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Preparation of New Substrate
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Rearrangement Achieved
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Phalarine’s Core Synthesized
Result:
- appropriate activating functions allow for desired rearrangement
- can proceed with the total synthesis of phalarine
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Introduction of Amine
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Gassman Oxindole Synthesis
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Completion of Racemic Synthesis
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Important Mechanistic Questions Remain
- concerning the pathway of the key skeletal rearrangement….
RECALL
- at this point, two possible pathways present themselves….
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?
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Wagner-Meerwein Gives Single Enantiomer
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Retro-Mannich Gives Achiral Intermediate
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Achiral Intermediate Leads to Racemate
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Why Is This Important?
CORRECT MECHANISTIC INSIGHTS LEAD TO…..
NATURAL ENANTIOMER OF PHALARINE
35
Initiate Synthesis With Single Enantiomer
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Enantiopure Oxindole
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Racemization During Cyclization
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Rules Out Wagner-Meerwein Pathway
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Retro-Mannich Then Pictet-Spengler
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Pictet-Spengler Reaction Mechanism
Chem. Rev. 1995, 95, 1797-1842
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Pictet-Spengler Reaction Mechanism
Chem. Rev. 1995, 95, 1797-1842
42
?
43
Retro-Mannich Cleavage Problems
• retro-Mannich cleavage step was preventing progress towards
enantiopure phalarine
• at this point, Danishefsky and colleagues investigated an
alternative to the chemistry described earlier
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Build a New Indole System
C3
C2
1. suitable aromatic structure at C2
2. ethylamino group at C3
REASONS:
1. determine feasibility of achiral
intermediate
2. develop further insights into the
mechanism of the Pictet-Spengler
reaction
J. Am. Chem. Soc. 2010, 132, 8506-8512
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Synthesizing New Indole
J. Am. Chem. Soc. 2010, 132, 8506-8512
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Synthesizing New Indole
J. Am. Chem. Soc. 2010, 132, 8506-8512
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Pictet-Spengler Attempt Successful
J. Am. Chem. Soc. 2010, 132, 8506-8512
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Achiral Intermediate is Feasible
C3
C2
BUT………….MECHANISTIC UNCERTAINTY REMAINS!
CYCLIZATION AT C2
OR
CYCLIZATION AT C3
J. Am. Chem. Soc. 2010, 132, 8506-8512
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What is the Minimum Rearrangement Criteria?
RECALL
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Arrested Pictet-Spengler Reaction
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Arrested Pictet-Spengler Reaction Mechanism
CONCLUSION:
- aryl group at C2 of indole
- cyclization at C3
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Likely Order of Rearrangement Mechanism
53
?
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Retro-Mannich – C3 Cyclization Equilibrium
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Chirality Transfer
- loss of chirality a major
obstacle
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Recommencement of Enantiopure Synthesis
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Organometallics 2005, 24, 6001-6004
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Suzuki Coupling and Benzylation
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Cyclization Gives Single Diastereomer
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Saponification, Decarboxylation,
and Debenzylation
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Introduction of Amine
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Gassman Oxindole Synthesis
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Enantiopure Phalarine
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Conclusions
• Danishefsky and colleagues successfully synthesized phalarine
as both the racemate and the natural enantiomer
RACEMATE
ENANTIOPURE
14 STEPS
20 STEPS
18.2 % YIELD
4.0 % YIELD
64
Conclusions
• Important insights were gained into the operative mechanism of
the Pictet-Spengler reaction
• When an indole system is C2 aryl
substituted the Pictet-Spengler reaction
initiates with attack from C3
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Acknowledgements
Dr. William Ogilvie
Daniel Carter Ramirez
Robyn Biggs
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