total synthesis of (+) plicamine
DESCRIPTION
Total Synthesis of (+) Plicamine. Ley et al, ACIE ( 2002 ) 41 , 2194. Bryan Klebon May 8, 2012. Steven Ley. BP Professor of Organic Chemistry, University of Cambridge Completed over 130 netural product synthesises - PowerPoint PPT PresentationTRANSCRIPT
Total Synthesis of (+) Plicamine
Bryan KlebonMay 8, 2012
Ley et al, ACIE (2002) 41, 2194
Steven Ley
• BP Professor of Organic Chemistry, University of Cambridge
• Completed over 130 netural product synthesises
• In 2011, included in The Times list of 100 most important people in British science
• Pioneered use of immobilized reagents in synthesis
• President of RSC 2000-2002
2
(+) Plicamine
• 1999: Isolated from Crinum bulbispermum, a herbaceous plant native to South Africa
• Used by Zulu, Sotho and Tswana people to treat rheumatism, aching joints, septic sores, varicose veins and kidney and bladder infections
3
N
O
O
N
MeO
O
MeH
H
OH
O
Solid supported reagents• Benefits
– Easily use excess of reagent to drive reaction to completion– Combination of traditionally incompatible reagents for novel cascade reactivity– Recovery and reuse of reagents– Simplify purification
4
O
HO OHR1 R2
O
O
O O
R1R2
Dioxane
R1 R2
O
+ impurities
Retrosynthesis
5
N
O
O
N
MeO
O
MeH
H
OH
O
Alkylation
Stereocontrolled Reduction
N
O
O
O
CF3
N
O
O
MeH
H
Conjugate Addition
N
O
O
O
O
NHMe
O
Intramolecular penolic
oxidative coupling
O
O
OH
N
O
NHMe
O CF3
Reductive amination
O
O
O
OH
H2N
O
NHMe
+
1)TMSCl, MeOH
2)
3) NH2Me, MeOH
Synthesis of 17
6
OH
H2N
O
OH
NEt2
OH
H2N
O
NHMe
O
O
OH
NH
O
NHMe
1)
2)
O
O
O
NMe3BH4
20 19
24
O
O
OH
N
O
NHMe
O CF3
24
Tf2O, PVP,poly-DMAP
N
N
Me
N
PVP
Poly-DMAP
17
100%
91% from 19
Phenolic Oxidative Coupling
7
O
O
OH
N
O
NHMe
O CF3
17
O
O
O
N
O
NHMe
O CF3
I
OAc
Ph
O
O
O
N
O
NHMe
O CF3
I
OAc
Ph
N
O
O
O
O
NHMe
O
H
R
N
O
O
O
O
NHMe
O
16
PhI(OAc)2
CF3CH2OH
82%
8
N
O
O
O
O
NHMe
O
16
N
O
O
O
CF3
N
O
O
MeH
H
15
CF2SO3H
15
NMe3BH4
100%
100% N
O
O
O
CF3
N
HO
O
MeH
H
28
9
N
O
O
O
CF3
N
HO
O
MeH
H
28
TMSCHN2
95%
SO3H
N
O
O
O
CF3
N
MeO
O
MeH
H
29
NH
O
O
N
MeO
O
MeH
H
31
Microwave, 100C20 min96%
NMe3OH
10
NH
O
O
N
MeO
O
MeH
H
31
OH
Br
OH
HO
CBr4, 0C100%
PPh2
14
N
O
O
N
MeO
O
MeH
H
OH
1) 14, microwave,140C, 30 min
2)
90%
NEt3(NaCO3)
NHCH2CH2SH 33
11
N
O
O
N
MeO
O
MeH
H
OH
33
1) CrO3,3,5-dimethylpyrazole
2)
3) Clay Scavenger
70%
SO3HN
O
O
N
MeO
O
MeH
H
OH
O
1
Conclusions
• Total synthesis of (+) plicamine in 40% total yield with 10 steps
• Showcases the advantages of solid supported reagents
• Entire total synthesis without a single traditional purification eg. Column chromatography.
12