Total Synthesis of Phalarine: Racemic and Enantiopure Routes

Report
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
Pure Appl. Chem. 2010, 82, 1735-1748
3
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
5
Retrosynthesis
6
Initial Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
7
Reasons For Incorrect Regiochemistry
Tetrahedron Lett. 2006, 47, 4839-4841
8
Reasoning For Second Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
9
Second Model Study
Tetrahedron Lett. 2006, 47, 4839-4841
10
Reasons For Undesired Product
Tetrahedron Lett. 2006, 47, 4839-4841
11
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
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
12
Retrosynthesis
13
Retrosynthesis
14
Synthesis of Azaspiro Oxindole
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
15
Formation of C2-Aryl Bond
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
16
Rearrangement Unsuccessful
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
17
Reasons for Failed Rearrangement
Reasons:
1. urethane-bound methylene has low propensity for migration
2. hydrogen bonding (
Pure Appl. Chem. 2010, 82, 1735-1748
) would restrict rotation
18
Reasons for Failed Rearrangement
1. urethane-bound methylene has low propensity for migration
Pure Appl. Chem. 2010, 82, 1735-1748
19
Reasons for Failed Rearrangement
2. hydrogen bonding (
Pure Appl. Chem. 2010, 82, 1735-1748
) would restrict rotation
20
What’s Next?.....Improve Migratory Tendency
1. Replace urethane with an N-methyl function
REASONS: N-METHYL IS ELECTRON DONATING
HIGHER LIKELYHOOD OF MIGRATION
Pure Appl. Chem. 2010, 82, 1735-1748
21
What’s Next?.....Remove Hydrogen Bonding
2. Incorporate an activating tosyl (Ts) function
REASONS: ELIMINATES HYDROGEN BONDING
PERMITS FREE ROTATION
Pure Appl. Chem. 2010, 82, 1735-1748
22
Preparation of New Substrate
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
23
Preparation of New Substrate
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
24
Rearrangement Achieved
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
25
Phalarine’s Core Synthesized
Result:
- appropriate activating functions allow for desired rearrangement
- can proceed with the total synthesis of phalarine
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
26
Introduction of Amine
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
27
Gassman Oxindole Synthesis
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
28
Completion of Racemic Synthesis
Angew. Chem. Int. Ed. 2007, 46, 1448-1450
29
Important Mechanistic Questions Remain
- concerning the pathway of the key skeletal rearrangement….
RECALL
- at this point, two possible pathways present themselves….
Pure Appl. Chem. 2010, 82, 1735-1748
30
?
Pure Appl. Chem. 2010, 82, 1735-1748
31
Wagner-Meerwein Gives Single Enantiomer
Pure Appl. Chem. 2010, 82, 1735-1748
32
Retro-Mannich Gives Achiral Intermediate
Pure Appl. Chem. 2010, 82, 1735-1748
33
Achiral Intermediate Leads to Racemate
Pure Appl. Chem. 2010, 82, 1735-1748
34
Why Is This Important?
CORRECT MECHANISTIC INSIGHTS LEAD TO…..
NATURAL ENANTIOMER OF PHALARINE
35
Initiate Synthesis With Single Enantiomer
Pure Appl. Chem. 2010, 82, 1735-1748
36
Enantiopure Oxindole
Pure Appl. Chem. 2010, 82, 1735-1748
37
Racemization During Cyclization
Pure Appl. Chem. 2010, 82, 1735-1748
38
Rules Out Wagner-Meerwein Pathway
39
Retro-Mannich Then Pictet-Spengler
40
Pictet-Spengler Reaction Mechanism
Chem. Rev. 1995, 95, 1797-1842
41
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
J. Am. Chem. Soc. 2010, 132, 8506-8512
Pure Appl. Chem. 2010, 82, 1735-1748
44
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
Pure Appl. Chem. 2010, 82, 1735-1748
45
Synthesizing New Indole
J. Am. Chem. Soc. 2010, 132, 8506-8512
Pure Appl. Chem. 2010, 82, 1735-1748
46
Synthesizing New Indole
J. Am. Chem. Soc. 2010, 132, 8506-8512
Pure Appl. Chem. 2010, 82, 1735-1748
47
Pictet-Spengler Attempt Successful
J. Am. Chem. Soc. 2010, 132, 8506-8512
Pure Appl. Chem. 2010, 82, 1735-1748
48
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
Pure Appl. Chem. 2010, 82, 1735-1748
49
What is the Minimum Rearrangement Criteria?
RECALL
Pure Appl. Chem. 2010, 82, 1735-1748
50
Arrested Pictet-Spengler Reaction
Pure Appl. Chem. 2010, 82, 1735-1748
51
Arrested Pictet-Spengler Reaction Mechanism
CONCLUSION:
- aryl group at C2 of indole
- cyclization at C3
Pure Appl. Chem. 2010, 82, 1735-1748
52
Likely Order of Rearrangement Mechanism
53
?
54
Retro-Mannich – C3 Cyclization Equilibrium
55
Chirality Transfer
- loss of chirality a major
obstacle
J. Am. Chem. Soc. 2010, 132, 8506-8512
56
Recommencement of Enantiopure Synthesis
J. Am. Chem. Soc. 2010, 132, 8506-8512
Organometallics 2005, 24, 6001-6004
57
Suzuki Coupling and Benzylation
J. Am. Chem. Soc. 2010, 132, 8506-8512
58
Cyclization Gives Single Diastereomer
J. Am. Chem. Soc. 2010, 132, 8506-8512
59
Saponification, Decarboxylation,
and Debenzylation
J. Am. Chem. Soc. 2010, 132, 8506-8512
60
Introduction of Amine
J. Am. Chem. Soc. 2010, 132, 8506-8512
61
Gassman Oxindole Synthesis
J. Am. Chem. Soc. 2010, 132, 8506-8512
62
Enantiopure Phalarine
J. Am. Chem. Soc. 2010, 132, 8506-8512
63
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
65
Acknowledgements
Dr. William Ogilvie
Daniel Carter Ramirez
Robyn Biggs
66

similar documents