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Phosphine Oxide-Catalysed Chlorination Reactions of Alcohols Under Appel conditions
Denton, R. M.; An, J.; Adeniran, B. Chem. Commun. 2010, 46, 3025-3027
A Concise Synthesis of HonokiolDenton, R. M.; Scragg, J. T.; Galofré, A. M.; Gui, X.; Lewis, W. Tetrahedron 2010, 66, 8029-8035
Catalysis of Phosphorus(V)-Mediated Transformations: Dichloronation Reactions of Epoxides Under Appel Conditions
Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678-4681
R1 R2
OH+ Cl
OCl
O
PO
PhPhPh
catalytic
R1 R2
Cl+ CO
CO2
R1R2
O+ Cl
OCl
O
PO
PhPhPh
catalytic
+ COCO2R1
R2
Cl
Cl
OHOH
Ross M. Denton
2001 - 2004: PhD with Professor J.C. Anderson (University of Nottingham)
2005 - 2007: Postdoctoral studies with K.C. Nicolaou (Scripps Research Institute)
2007 - 2009: Postdoctoral studies with Steven Ley (University of Cambridge)
June 2009: Appointed to a permanent lectureship (University of Nottingham)
Research Interests
New Chemistry and catalysis: Atom efficient and environmentally friendly construction of chemical bonds. New catalytic organophosphorus chemistry
Natural Products and Biological Study: Construction of plant derived natural products (>10 steps) for study of neurodegenerative diseases.
Appel Reaction
R
OH
R'
CX4, PPh3
X= Br, Cl R
X
R'
Mechanism
Ph3PBr
Br BrBr
P BrPhPhPh
+ CBr3
R
O
R'
H
P BrPhPhPh R
O
R'
R
O
R'
PPh
PhPh
BrR
Br
R'+ P
PhPhPh
O
Development of a Catalytic Chlorination Reaction
C9H19 OH5
X mol % Ph3PO,
1 equiv (COCl)2 CHCl3
C9H19 OH6
+ C9H19 O
7
+
O
O
ClC9H19 O
O
O
O C9H19
8
Entry Ph3PO (mol %) Addition protocol/addition time (% of 6) (% of 7) (% of 8) 1 100 5 added to (COCl)2 + Ph3PO 80 - -
2 0 5 added to (COCl)2 - 78 22
3 30 5 added to (COCl)2 + Ph3PO 46 44 10
4 25 5 added to (COCl)2 + Ph3PO over 2 hrs 65 - -
5 15 5 and (COCl)2 added to (COCl)2 + Ph3PO over 7hrs 83 - -
6 0 5 and (COCl)2 added to (COCl)2 over 7hrs - 89 -
7 10 5 and (COCl)2 added to (COCl)2 + Ph3PO over 7hrs 75 - -
8 18 5 and (COCl)2 added to (COCl)2 + Ph3PO over 5hrs 73 - -
Substrate Scope
R OH15 mol % Ph3PO,
1 equiv (COCl)2 CHCl3
R Cl
C9H19 Cl
83%
Ph Cl
80%
Ph Cl
73%
Me Cl
70%
C9H19 Br
48% 67%
Ph Cl
88%
C6H15Cl
Substrate Scope Continued
R OH
15 mol % Ph3PO,
1 equiv (COCl)2 CHCl3
R Cl
R' R'
Cl
7%
MeMe
Cl
69%
Me
Cl
64%
Mechanistic Studies
Cycle 1
PCl
PhPhPh
Cl
CO + CO2
PO
PhPhPh
Cl
R
R OH
R Cl
Cycle 2
PO
PhPhPh
Cl
COCOCl
PO
PhPhPh Cl
O
ClO P
O
PhPhPh
PO
PhPhPh
R OHO
O
ClO
R
OO
OPPh3
O
RCl
R Cl
1H NMR Study
C9H19 OH(COCl)2CDCl3
OO
ClO
C9H191 eq. PPh3
23°C, 16 hrs; reflux 2hrs
C9H19 Cl!!
Catalysis of Phosphorus(V)-Mediated Transformations: Dichloronation Reactions of Epoxides Under Appel Conditions
R1R2
O+ Cl
OCl
O
PO
PhPhPh
catalytic
+ COCO2R1
R2
Cl
Cl
Denton, R. M.; Tang, X.; Przeslak, A. Org. Lett. 2010, 12, 4678-4681
Previous Dichloronation of Epoxides
BnOOTBDPS
O O PPh3/NCS
toluene, 90°C BnOOTBDPS
Cl
ClCl
Cl
42% yield
Yoshimitsu, T.; Fukumoto, N.; Tanaka, T. J. Org. Chem. 2009, 74, 696-702
Croft, A. P.; Bartsch, R. A. J. Org. Chem. 1983, 48, 3353-3354
n(H2C) OPh3P, CCl4
reflux 2-5 daysn =1, 2, 6
n(H2C)Cl
Cl70-80% yield
shorter reaction times
MeO
9
Ph3PO, (COCl)2
2,6-tBuPyCHCl3
Me9
ClCl
Entry Ph3PO (mol %) (COCl)2 (mol %) 2,6-tBuPy (mol %) time (h) yield (%) 1 100 100 0 6 84
2 20 100 0 6 58
3 20 100 0 16 73
4 20 100 150 6 69
5 15 100 150 16 56
6 15 130 150 6 91
7 0 130 150 6 0
Reaction Optimization
Substrate Scope
R1
15 mol % Ph3PO,
1.3 equiv (COCl)2 1.5 equiv 2,6-tBuPy
6h
R2R1 R2O
Cl
Cl
81%
Cl
78%
PhCl
57%
Ph Cl
66%
Me
Cl
Cl
9 Cl4
Cl
Cl
62% 57% 66%
ClCl
TBDPSO 2 MeCl
MeCl
Me
Cl Cl
4 7CO2Et7
Mechanistic Studies
PO
PhPhPh
Cl
COCOCl
PCl
PhPhPh
Cl
Cl
PO
PhPhPh Cl
O
CO + CO2
Cl
O
R1 R2O
R1 R2
OPPh3
Cl
R1 R2
Cl
Cl
A Concise Synthesis of Honokiol
• Family or biaryl neolignans isolated from Magnoliae officinalis in 1972
• Extracts from this bark used for traditional Chinese and Japanese medicine
• Honokiol used a muscle relaxant as early as 1975
• Obtained by extraction from magnolia bark
• Anticancer activity and neurotrophic activity
• 1986 first total synthesis (4 steps, 16% yield)
• 2004 second total synthesis (14 steps, 21% yield)
OH
OH
honokiolOH
chavicol
OH
magnololHO
Initial Retrosynthetic Approach
OH
OHhonokiol
sigmatropicrearrangements
retro FriedelCrafts alkylation
O
O
MeMeMe
alkylation demethylation
OH
OMe
MeMeMe
directarylation
OH OMeMeMe
Me
Br
+
Forward Synthesis, First Approach
OH OMeMe
Me
Me
Br
+[RhCl(COD)]2 (10 mol%)
P(NMe2)3 (30 mol%),Cs2CO3, toluene,
reflux, 18 hrs45% yield
OH
OMe
MeMeMe
O
O
MeMeMe
1) BCl3·SMe2, DCE, reflux, 18 hrs, 66% yield2) Allyl bromide, Cs2CO3 DMF, 23°C, 15 hrs 92% yield
DMF, MW, 200°C, 1hr
49%
OH
OH
MeMeMe
Retro Friedel-Crafts Alkylation
OH
OH
MeMeMe
AlCl3, toluene:MeNO2 (10:1)
60°C, 2 hrs63% yield
OH
OH
OH
OH
MeMeMe
AlCl3, toluene:MeNO2 (10:1)
60°C, 2 hrsdecomposition
OH
OH
OH
OH
MeMeMe
AlCl3, toluene:MeNO2 (10:1)
23°C, 2 hrsno reaction
OH
OH
Revised Retrosynthetic Approach
OH
OHhonokiol
lithiation
OMe
Claisenrearrangement
deprotection
OMe
O
Suzukicoupling allylation
OMe OH
Br
+(HO)2B
Forward Synthesis, Second Approach
PCy2OMeMeO
S-Phos
OMe OH
Br
+(HO)2B
OMe
OH
Pd(dba)3 (10 mol%)
S-Phos (30 mol%)KF (5 equiv.)
THF/H2O, 15 hrs 94% yield
allyl bromide, K2CO3acetone, reflux, 18 hr
99% yield
OMe
O
BCl3·SMe2, DCE,reflux, 18 hrs,
47% yield
OH
OH
+OH
OH
honokiol
Forward Synthesis, Second Approach
PCy2OMeMeO
S-Phos
OMe OH
Br
+(HO)2B
OMe
OH
Pd(dba)3 (10 mol%)
S-Phos (30 mol%)KF (5 equiv.)
THF/H2O, 15 hrs 94% yield
allyl bromide, K2CO3acetone, reflux, 18 hr
99% yield
OMe
O
1) 1,2-dichlorobenzene200°C, MW, 15 min
86% yield
OH
OHhonokiol
2) BCl3·SMe2, DCE,reflux, 18 hrs,
91% yield
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