--- dead ends and detours
DESCRIPTION
The Journey of Azadirachtin. --- Dead Ends and Detours. Supervisors: Prof. Zhen Yang & Jiahua Chen. Reporter: Weiwu Ren 2008-01-11. Introduction. Dead Ends and Detours – An Example. Total Synthesis of Azadirachtin. Summary. Acknowledgement. Contents. Introduction. - PowerPoint PPT PresentationTRANSCRIPT
--- Dead Ends and Detours
Supervisors: Prof. Zhen Yang & Jiahua ChenSupervisors: Prof. Zhen Yang & Jiahua Chen
Reporter: Weiwu RenReporter: Weiwu Ren2008-01-112008-01-11
The Journey of Azadirachtin
2
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
3
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
4
OPSS 2008-01-11Weiwu RenGuanacastepene
O
AcO
CHOOH
Guanacastepene A
O
O PMB
AcO
E. J. Sorensen2004
I
CO2EtOHC
TBSO
O
Z. Yang2006
CO2Me
I. Hanna2004
OEtO
O
OO
S. J. Danishefsky2002
O
B. B. Snider2003
O TfO
CO2R
L. E. Overman2006
Tandem CyclizationTandem CyclizationIMDAIMDA
HeckHeck RCM/RobinsonRCM/Robinson
TandemTandem RCMRCM Stille/[2+2]Stille/[2+2]
5
OPSS 2008-01-11Weiwu Ren
Dead EndsDead Ends DetoursDetours
Dead Ends and Detours
PlanningPlanning
Target Target MoleculeMolecule
Starting Starting MaterialsMaterials
6
OPSS 2008-01-11Weiwu RenOur Attitudes
Starting Starting MaterialsMaterials
ProductProduct
Condition BCondition B
Condition ACondition A
Condition CCondition C
Several StepsSeveral Steps
OROR
RealityReality
7
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
8
OPSS 2008-01-11Weiwu Ren
O
O
O
O
O
O
OO
Me OO
O O
H H HH H H Me
H
H
H
HO
H Me H HMe Me H
H
H
Me
Me
CHO
Brevetoxin BBrevetoxin B
Brevetoxin B
A marine neurotoxinA marine neurotoxinFirst reported by Nakanishi in 1981First reported by Nakanishi in 198123 stereocenters23 stereocentersAll trans-contiguous ether ringsAll trans-contiguous ether rings
Lin, Y.; Nakanishi, K. J. Am. Chem. Soc. 1981, 103, 6773.
9
OPSS 2008-01-11Weiwu RenFirst-generation Retrosynthetic Analysis
Nicolaou, K. C.; Hwang, C. -K.. J. Am. Chem. Soc. 1986, 108, 6800.
O
O
O
O
O
O
OO
Me OO
O O
H H HH H H Me
H
H
H
HO
H Me H HMe Me H
H
H
Me
Me
CHO
O
O
O
O
O
O
O
Me OO
O O
H H HH H Me
H
H
H
BnO
H Me HMe Me H
H
H
Me
Me
OTPS
MeO
S
S
O
O
O
O
O
O
O
Me OO
O O
H H HH H Me
H
H
H
BnO
H Me HMe Me H
H
H
Me
Me
OTPS
MeO
O
O
A B C DE F G H
IJ
KBridging Reaction
Brevetoxin B
1
2
O
O
S
O
SO
e-
S-
O
SO
e-
S-
O
S-O
1 2 3
1. Coupling
2. e-
O
OS-
S-
4
MeI
O
OSMe
MeS
-[MeSSMe]
56
10
OPSS 2008-01-11Weiwu Ren
O
O
O
OO
OH
H
HH
Lawesson's Reagent
toluene,
78% O
O
O
OS
SH
H
HH
Na-naphthalide, THFthen MeI, -78 - 25 oC
80%
O
O
O
O
HH
HH
MeS
SMe
TBTH/AIBN
toluene, 110 oC
99%O
O
O
O
HH
HH
Work with Model
Lawesson's Reagent:
P
S P
S
OMe
MeO
S
S
Nicolaou, K. C.; Hwang, C. -K. J. Am. Chem. Soc. 1990, 112, 3040.
11
OPSS 2008-01-11Weiwu RenBut…
Lawesson's Reagent
O
O
O
O
O
O
O
Me OO
O O
H H HH H Me
H
H
H
BnO
H Me HMe Me H
H
H
Me
Me
OTPS
MeO
S
S
1
Lawesson's Reagent
O
O
O
O
O
O
O
Me OO
O O
H H HH H Me
H
H
H
BnO
H Me HMe Me H
H
H
Me
Me
OTPS
MeO
S
O1314
3
A F G I J KO
O
O
MeOPMB
COOH
Me
HHHEMO
HMeH
B CO
O
TBSO
H H Me
PPh3
IMe Me H
OTMS
BOMO O
O
O
EtS
EtS
H Me
H H HOTPS
OBn
H
O
O
O
O
O
O
O
O
Me OO
O O
H H HH H Me
H
H
H
BnO
H Me HMe Me H
H
H
Me
Me
OTPS
MeO
O
O
2
40 steps37 steps 26 steps
Nightmare!!!Nightmare!!!
12
OPSS 2008-01-11Weiwu RenIs the Strategy Useless?
Unfortunately, however, all attempts to achieve the bis(thionation) Unfortunately, however, all attempts to achieve the bis(thionation) of the macrodilactone precursor failed… The lactone carbonyl flanked of the macrodilactone precursor failed… The lactone carbonyl flanked by the methyl group, defiantly resists the action of Lawesson’s by the methyl group, defiantly resists the action of Lawesson’s reagent, presumably due to its hindered nature…reagent, presumably due to its hindered nature…
------ K. C. Nicolaou------ K. C. Nicolaou
Significance:Significance:
1. Investigation of the chemistry of the molecule 1. Investigation of the chemistry of the molecule Brevetoxin B and the basis of the following total Brevetoxin B and the basis of the following total synthesis;synthesis;2. Developing a full body of methodology to build 2. Developing a full body of methodology to build fused seven-membered rings;fused seven-membered rings;
O
O
O
O
HH
HH
13
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
14
OPSS 2008-01-11Weiwu Ren
16 16 ContiguousContiguous Stereogenic Centers Stereogenic Centers
7 Tetrasubstituted Carbons7 Tetrasubstituted Carbons
4 Different Ester Groups4 Different Ester Groups
2 Hydroxy Groups2 Hydroxy Groups
1 Acid and Base-Sensitive Hemiketal1 Acid and Base-Sensitive Hemiketal
1 Strained and Sterically-hindered Epoxide 1 Strained and Sterically-hindered Epoxide
2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH – C20OH)2 Intramolecular Hydrogen Bonds (strong: C11OH - O13 weak: C7OH – C20OH)
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
13
11 20
7
Azadirachtin
15
OPSS 2008-01-11Weiwu Ren
19681968
2007
2006
1996
198619861986
20062006
19961996
20072007
BeginningIsolation and Structure
Determination of Azadirachtin
Story Line
16
OPSS 2008-01-11Weiwu Ren
1975
1985-1986
1968
First report of the First report of the isolation of isolation of
Azadirachtin by Azadirachtin by Morgan groupMorgan group
The first The first complete complete
structure was structure was reported but not reported but not
correctcorrect
The correct The correct structure was structure was submitted and submitted and
was confirmed by was confirmed by X-ray analysisX-ray analysis
Hop Skip and Jump
17
OPSS 2008-01-11Weiwu Ren
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.
Isolated from the seeds of Isolated from the seeds of Azadirachta indica A. Juss in IndiaAzadirachta indica A. Juss in India( ( 印度苦楝树 印度苦楝树 ))
Named AzadirachtinNamed Azadirachtin( ( AzadirachtAzadirachta a inindica )dica )
High activity against the desert locustHigh activity against the desert locust（沙漠蝗虫）（沙漠蝗虫）
Molecular formulaMolecular formula ：： CC2929HH3838OO1616(642.222)(642.222)
First Isolation
18
OPSS 2008-01-11Weiwu Ren
O
H
H
OH H
HTigO
OAc
O
O
Molecular Formula : CMolecular Formula : C3535HH4444OO16 16 （（ TriterpenoidTriterpenoid ））
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Perkin Trans. I 1972, 2445.
Right Molecular Formula & Partial Structure
Butterworth, J. H.; Morgan, E. D. J. Chem. Soc., Chem. Commun. 1968, 23.
19
OPSS 2008-01-11Weiwu Ren
MeO2C OHAcO
O
H
OH
O
OMeO2CO
OHO
H
H
O
H
HO
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Zanno, P. R.; Muira, I.; Nakanishi, K. J. Am. Chem. Soc. 1975, 97, 1975.
Nakanishi’s AzadirachtinNakanishi’s Azadirachtin
Based on: PRFT/CWD Based on: PRFT/CWD 1313C NMRC NMR Hypothetical Relationship with Known TerpenoidsHypothetical Relationship with Known Terpenoids
Correct StructureCorrect Structure
The First Complete Structure
20
OPSS 2008-01-11Weiwu Ren
MeO2C OHAcO
O O
H
CO2Me
OH
O
OOH OOH
O
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Ley’s ModificationLey’s Modification Correct StructureCorrect Structure
Bilton, J. N.; Broughton, H. B.; Ley, S. V. J. Chem. Soc., Chem. Commun. 1985, 986.
Based on: 1D NOE & 2D NOESYBased on: 1D NOE & 2D NOESY
Ley’s Modification
21
OPSS 2008-01-11Weiwu Ren
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
AzadirachtinAzadirachtin
W. Kraus.; M. Bokel.; A. Klenk.; H. P. Khnl. Tetrahedron Lett. 1985, 26, 6435.
Finally, the Correct Structure
MeO2C OHAcO
HO O
H
OHCO2Me
OH
O
O
OOH
22,23-dihydrodetigloylazadirachtin
2223
Broughton, H. B.; Ley, S. V. J. Chem. Soc. Chem. Commun. 1986, 46.
22
OPSS 2008-01-11Weiwu Ren
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
MeO2C OHAcO
O
H
OH
O
OMeO2CO
OHO
H
H
O
H
HO
AzadirachtinAzadirachtin
First isolated by Morgan(1968)First isolated by Morgan(1968)
Partial structure(1972)Partial structure(1972)
O
H
H
OH H
HTigO
OAc
O
O
The first complete structureThe first complete structure(1975)(1975)Ley’s modificationLey’s modification
(1985)(1985)
MeO2C OHAcO
O O
H
CO2Me
OH
O
OOH OOH
O
Confirmed by X-ray analysis(1986)Confirmed by X-ray analysis(1986)
2222
23
OPSS 2008-01-11Weiwu Ren
19681968
2007
2006
1996
198619861986
20062006
19961996
20072007
Ley’s Monodrama （独角戏）
Story Line
24
OPSS 2008-01-11Weiwu RenLey’s Idea
We recognise this coupling involves the formation of a We recognise this coupling involves the formation of a difficult bond, but therein lies the challenge.difficult bond, but therein lies the challenge.
---- S. V. Ley---- S. V. Ley
Ley, S. V. Pure Appl. Chem. 1994, 66, 2099.
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
8 14
MeO2C OHAcO
O O
H
OHCO2Me
O
O
X8 O O
OH14Y
Left half: Decalin Right half: Hydroxyfuran acetal
coupling
25
OPSS 2008-01-11Weiwu Ren1st Synthesis
Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
OO
OH
HOO
OH
H
ⅠⅠ. . Develop a flexible approach Develop a flexible approach for the total synthesisfor the total synthesisⅡⅡ. . Study the functional groups Study the functional groups responsible for activity responsible for activity (potential active center)(potential active center)
26
OPSS 2008-01-11Weiwu RenConstruction of This FragmentConstruction of This Fragment
O O
1. LDA, THF, -78 oC2. MoOPH, -78oC to 0oC
67%
O O
OH TBSCl, imidazole
DMF, r.t.
94%
O O
OTBS
O O
OTBS1. KDA, -78 oC2. allyl bromide, -78 oC
87%
Ley, S. V.; Santafianosa, D. Tetrahedron Lett. 1987, 28(2), 221.
DIBAL
toluene, -78 oC O
OTBS
OH67% 1
1. O3, DCM, -78 oC2. PPh3, r.t.
93% O
OTBS
OH
OHPhSH, MeCN
Amberlyst 15 4A sieves
O
OTBS
OH
SPh
82%
m-CPBA
DCM, r.t.
82%
O
OTBS
OH
SPhO Toluene
92%O
OTBS
OH
TBAF
THF, r.t.
84%O
OH
OH
3
MeOH, H2SO4
60% O
OTBS
OMe
1. O3, MeOH, -78 oC2. NaBH4, r.t.
88% O
OTBS
OMe
OH
Amberlyst 15, MeCN
64%O
OTBS
OH
TBAF
THF, r.t.
100%
O
OH
OH2
27
OPSS 2008-01-11Weiwu RenAbsolute Configuration
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Modified Mosher methodology using high field FT NMR techniquesModified Mosher methodology using high field FT NMR techniques
Method:Method:
Ley, S. V.; Lovell, H. J. Chem. Soc., Chem. Commun. 1992, 1304.
28
OPSS 2008-01-11Weiwu RenLey’s Other Work
AzadirachtinAzadirachtinMeO2C O
HAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
O
O
Ph
HMeO2C O
OH
CO2Me
1989
OO
O
OH1990
HOH
MeO2C O
1992
O OHCO2Me
HO
O
HOH
MeO2C O
O OMeCO2Me
HO
OHO O
OO
Degradation1993
MeO2C OH
O
H
OBnCO2Me
O
O
OOH
O
O
PhOP
O
Relay Route1995
29
OPSS 2008-01-11Weiwu Ren
19681968
2007
2006
1996
198619861986
20062006
19961996
20072007
LeyLeyCambridgeCambridge
NicolaouNicolaouScrippsScripps
MuraiHokkaido
WatanabeWatanabeTokyoTokyo
Story Line
30
OPSS 2008-01-11Weiwu RenLey’s Attempts on the Direct Coupling
O O
OTBS
O OMe 6 steps
O O
OTBS
OMe
Me3Sn
OMe
Br
PdCl2(dppf), DMF80 oC
O O
OTBS
OMe
OMe
Complex ‘Right’ to Simple ‘Left’ Complex ‘Right’ to Simple ‘Left’
Complex ‘Left’ to Simple ‘Right’ Complex ‘Left’ to Simple ‘Right’
Ley, S. V. Pure Appl. Chem. 2005, 77, 1115.
O
O
Ph
HMeO2C O
CO2MeO OMe
OTBS
1. NBS, THF, -20 oC, 85%;2. PPTS, CH3CN(aq), 98%
HO
HOH
MeO2C O
CO2MeO OMe
Br
1. PhSeCl, CH2Cl2, -78 oC, 74%;2. PPTS, CH3CN(aq), 92%
HO
HOH
MeO2C O
CO2MeO OMe
SePh
O
O
SnBu3 hv, C6H6, 70%
HO
HOH
MeO2C O
CO2MeO OMe
O
SnBu3
hv, C6H6, 27%
31
OPSS 2008-01-11Weiwu RenWays to Go
MeO2C OHAcO
O O
H
OHCO2Me
O
O
X8
O OOH
14Y
Coupling
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Dead EndsDead Ends
DetourDetour
Introduce this bond in an Introduce this bond in an earlier stepearlier step of the synthesis! of the synthesis!
Prof. WatanabeProf. Watanabe
Connect the two parts through other Connect the two parts through other functional groups and then close the functional groups and then close the desired bonddesired bond intramolecularly!intramolecularly!
Prof. Ley & Prof. Nicolaou & Prof. MuraiProf. Ley & Prof. Nicolaou & Prof. Murai
32
OPSS 2008-01-11Weiwu RenFirst Participant — Watanabe
1) Watanabe, H.; Watanabe, T.; Mori, K. Tetrahedron 1996, 52, 13939. 2) Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.3) Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T. Angew. Chem. Int. Ed. 2007, 46, 1512.
O
OO
TBSO
H
OMe
1996
OH
O O
O
OH
1997
OH
O
O
MeO2C
O
OPh
OH
2007
33
OPSS 2008-01-11Weiwu RenWatanabe’s Model
Watanabe, H.; Mori, N.; Itoh, D.; Kitahara, T.; Mori, K. Angew. Chem. Int. Ed. 2007, 46, 1512.
OH
O
O
MeO2C
O
OPh
OHO
H
O
O
MeO2C
O
OPh
OH
Radical Cyclization
I
CHO
OH
O
O
MeO2C
O
OPh
OTBS
OAcIntramolecular D-AO
O
MeO
O
TMS
O
OTBS
O
O
1 2
3 45
8 814 14
34
OPSS 2008-01-11Weiwu Ren
Watanabe, H.; Watanabe, T.; Mori, K.; Kitahara, T. Tetrahedron Lett. 1997, 38, 4429.
O
TBSO H
CO2MeMe
OH O
ROH
MeO2C
OR'OR'
OO
Me
Tandem Radical Cyclization
OH
O
O
MeO2C
O
OPh
I
nBu3SnH, AIBN
toluene,
90%
OH
O
O
MeO2C
O
OPh
OH
OH
O
O
MeO2C
O
OPh
OHOH
OH
TBSOCO2Me
OH
SePh
nBu3SnH, AIBN
toluene,
28%O
H
TBSO
OH
CO2Me
OH
OOH
CO2Me
OH
35
OPSS 2008-01-11Weiwu RenMurai’s Model Study
O
OR
OH
OMeHO
1999
H
OO
CO2H
OODEIPS
OH
OMe
2002
Ireland – Claisen RearrangementIreland – Claisen Rearrangement
1) Ishihara, J.; Fukuzaki, T.; Murai, A. Tetrahedron Lett. 1999, 40, 1907.2) Yamamoto, Y.; Ishihara, J.; Kanoh, N.; Murai, A. Synthesis 2000, 1894.3) Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
OH
O O
OMPMBnOHO
OH
2000
36
OPSS 2008-01-11Weiwu RenIreland-Claisen Rearrangement
O
OTBS
O
LDA, TMSCl
Et3N, THF
COOH
HOTBS
LDA, TMSCl, HMPA
Et3N, THF
Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
H
OOR1
CO2H
OOR
OH
OMeR3O
R3OR2O OR2
Ireland-Claisen Rearrangement
H
O
OR1
OOR
OH
OMeR3O
R3OR2O OR2
OOSi
H
OOR1
R3O
R3OR2O OR2
COOR
Left
OOR
OH
OMe
HO
Right
KHMDS, TMSCl
Et3N, PhMe-110 oC to 70 oC, 6.5 h
77%
37
OPSS 2008-01-11Weiwu RenDiastereoselectivity
Fukuzaki, T.; Kobayashi, S.; Ishihara, J.; Kanoh, N.; Murai, A. Org. Lett. 2002, 4, 2877.
H
OO
OODEIPS
OH
OMe
OO
COOH
H
OODEIPS
OH
OMe
HO
EDCI, DMAP
CH2Cl223 oC
72%
O
O
H
OO
CO2H
OODEIPS
OH
OMe
H
OO
CO2H
OODEIPS
OH
OMe
A: desired
B: undesired
148
814
O
OSi
O O
product A
Z - chair
product B
SiOO
O
O
E - chair
38
OPSS 2008-01-11Weiwu RenK. C. Nicolaou’s Model Study
MOMO
BnOH
O
OH
EtO2C
BnOH
HO
O O
OMe
AcOH
O
H
R
O
O O
TBSO H
O
H
O
O OTESO
OMeO2C
OBz
AcO H
O
H
O
O OAcO
MeO2COAc
OBz
20022002RadicalRadical
20052005
20032003
20022002OrganometallicOrganometallic
39
OPSS 2008-01-11Weiwu RenFrom Radical Chemistry
Nicolaou, K. C.; Follmann, M.; Roecker, A. J. Angew. Chem. Int. Ed. 2002, 41, 2103.
COOEt
HOH
O
15 steps
HOH
OMOM
OH1
(rac) 2MeO
1. Br2, N,N-dimethylaniline CH2Cl2, 71%;
2. nBu3SnH, AIBN toluene, 110 oC, 70%
MOMO
HBnO O
OMe
H
(labile)3
4
(1:1.5)
MOMO
HBnO O
OMe
H
(stable)
work-upMOMO
HBnO OH
O
5
PPTS
acetone/H2O65 oC
85%
MOMO
HBnO O
OH
H
6
8 14
8 14
MOMO
HBnO OH
OMOMO
HBnO O
OMe
HMOMO
HBnO O
OMe
8 14
40
OPSS 2008-01-11Weiwu RenFrom Organometallic Chemistry
EtO2C
BnOH
O
OMe
HO
O
8
14EtO2C
BnOH
O
OSEM
HO
8
14EtO2C
BnOH
O
OSEM
8
CHO
BrTransition Metal
14
Nicolaou, K. C.; Roecker, A.; J Follmann, M. Angew. Chem. Int. Ed. 2002, 41, 2107.
HO
COOEt
HO
11 steps
BnO
EtOOC
HOSEM
OH
OH
OO
Br
Br
4 steps
EtO2C
BnOH
O
OSEM
CHO
Br [Ni(cod)2], NaI
DMF, 80 oC
55%
EtO2C
BnOH
O
OSEM
HO
(desired)
EtO2C
BnOH
O
OSEM
HO
(undesired)
1. HCl(aq.)/dioxane, 50 oC, 85%2. NaH, MeI, THF, 50 oC, 89% 3. PCC, CH2Cl2, 50 oC, 79%
EtO2C
BnOH
O
OMe
HO
O
8
14
(12:1)
41
OPSS 2008-01-11Weiwu Ren
Greatest Challenge: C8-C14 Bond Greatest Challenge: C8-C14 Bond
AzadirachtinAzadirachtin
Ley NicolaouWatanabe Murai
Brief Summary
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
148
42
OPSS 2008-01-11Weiwu Ren
19681968
2007
2006
1996
198619861986
20062006
19961996
20072007Total SynthesisTotal Synthesis
Story Line
43
OPSS 2008-01-11Weiwu RenRelay Study
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Azadirachtin
1. NBS, MeOH, r.t, quant.;2. nBu3SnH, AIBN, toluene,reflux, 91%;3. BnBr, Ag2O, DMF, r.t., 60%
MeO2C OHAcO
O O
H
OBnCO2Me
OH
O
O
O
OOBn
OMe
1. DMP, CH2Cl2, r.t., 99%;2. Et3N/MeOH/H2O (1:5:1), 65 oC, 99%;
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOBn
OMe
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOBn
OMe
TBSOTf, iPr2NEt, CH2Cl2, -78 oC, 90%
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O
OOBn
OMe
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O
OOBn
OMe
O O
OO
44
OPSS 2008-01-11Weiwu RenBack to ‘Azadirachtin’
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7633.
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O
OOBn
OMe1. TBAF, THF, 0 oC, quant.;2. Pd/C, 10bar H2, MeOH, r.t., 90%
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOH
OMe
Amberlyst 15, 3A MS
MeOH/MeCNr.t.49%
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOH
OMe
1. Ac2O, Et3N, DMAP, CH2Cl2, 74%;2. CH3CH=C(CH3)(CO)O(CO)C6H2Cl3 Cs2CO3, toluene, reflux, 6d, 50%;
3. NaBH4, CeCl3.7H2O, MeOH, 0 oC, 49%
MeO2C OHAcO
O O
H
OBnCO2Me
OH
O
O
OOH
OMe
O
6
1. Pd/C, H2, MeOH, r.t. 81%;2. PhSH, PPTS, CH2ClCH2Cl, 80 oC, 70%
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
OOH
SPh
O
DMDO
CH2Cl2-78 oC to r.t. to reflux
67%MeO2C O
HAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Azadirachtin7
O O
O
45
OPSS 2008-01-11Weiwu RenRetrosynthetic Analysis
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Azadirachtin
Degradation
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O
O
OOBn
OMeEpoxidation
MeO2C OHHO
HO O
H
OBnCO2Me
O
O OOBn
OMe
Radical cyclization
MeO2C OHHO
HO O
H
OBnCO2Me
O O
OOMe
OBn
Claisen rearrangement
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOMe
OBn
O-alkylation
R MeO2C OHHO
HO O
H
OBnCO2Me
OO O
OMe
OBnR
MsO
decalin fragment pyran fragment
8
9
10
3
46
OPSS 2008-01-11Weiwu RenLeft ‘Shoulder’
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
OEt
OEt
8 steps
SiMe2Ph
Br
MeO2C
SS
OMe
OMeTBSO
OH
5 steps
SS
OMe
OMe
SS
OMe
OMe
OPhMe2Si
CO2Me
O
DIPEA, hydroquinone
toluene85 oC
O
OHMeO2C
PhMe2SiS
S
OMe
OMe
O
OHMeO2C
PhMe2Si
undesired(exo) desired(endo)
57%
(2:5)
steps
OHMeO2C
OCN
O
O
O
O
PhLiHMDS
THF0 oC to r.t.
100%
OHMeO2C
O
O
O
Ph
OO
CN 1. dimethyldioxirane, acetone, 0 oC;2. PPTS, MeOH
70%(two steps)
OHMeO2C
O
HO
HO
O OHCO2Me
steps
MeO2C OHTESO
TESO O
H
OBnCO2Me
O
11
12 13 14
15 16 17
47
OPSS 2008-01-11Weiwu RenRight ‘Arm’
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
O
O
O
PhOH
OH
O
9 steps
O
MeS2CO
TBSO
MOMO
OO
OBn1. AIBN, nBu3SnH, toluene, 110 oC, 70%; 2. CH2Cl2/TFA/H2O (20:1:1), r,t., 80%;
3. a) SO3.py, DMSO, iPr2NEt, CH2Cl2, 0 oC;
b) tBuOK, Ph3PCHBr2.Br, THF, r.t., 80%
1.TMSBr, CH2Cl2, 0 oC, 82%;
O
PMBO
O
OBn
Br
Br
1. DIBAL, CH2Cl2, -78 oC;2. Amberlyst15, MeOH, r.t.
70%
OMe
O
PMBO
O
OBn
Br
BrO
MeLi.LiBr
THF-78 oC to 0 oC
80%
O
PMBO
O
OBn
OMeiPrMgCl, (CH2O)n
THF
45 oC80%
O
PMBO
O
OBn
OMe
HO
Ms2O, iPr2NEt
CH2Cl20 oC90%
O
PMBO
O
OBn
OMe
MsO
O
MOMO
OO
OBn
Br
Br
2. PMBTCA, La(OTf)3, THF, r.t., 90%
18 19 20
21 22
23 24 25
48
OPSS 2008-01-11Weiwu RenTotal Synthesis
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
O
PMBO
O
OBn
OMe
MsOMeO2C OHTESO
TESO O
H
OBnCO2Me
O
NaH, [15]crown-5
THF0 oC MeO2C O
HTESO
TESO O
H
OBnCO2Me
O
O
OOMe
OBn
OPMB
TBAF, THF, 0 oC [(Ph3PAu)3O]BF4
r.t.MeO2C O
HHO
HO O
H
OBnCO2Me
O O
OOMe
OBn
OPMB
CH2Cl2
26
27
MeO2C OHHO
HO O
H
OBnCO2Me
O
O
OOMe
OBn
OPMB
28
49
OPSS 2008-01-11Weiwu RenTotal Synthesis
Veitch, G. E.; Beckmann, E.; Burke, B. J.; Ley, S. V. Angew. Chem. Int. Ed. 2007, 46, 7629.
MeO2C OHHO
HO O
H
OBnCO2Me
O O
OOMe
OBn
OPMB
MeO2C OHTBSO
HO O
H
OBnCO2Me
O O
OOMe
OBn
O
SMeS
nBu3SnH, AIBN
toluene, high dilution
100 oC
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O OOBn
OMe
S
HO OH
MMPP.H2O
NaHCO3, MeOH
105 oC 7days
MeO2C OHTBSO
HO O
H
OBnCO2Me
O
O
O
OOBn
OMe
only
Relay route
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
:20% (85%based on recovered starting material:50%(85%based on recovered starting material
Azadirachtin
28 29
30
3
3 steps
50
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
51
OPSS 2008-01-11Weiwu RenSummary
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Azadirachtin
Ley and More Than 35 Co-workers
Isolation and Structure Determination (18 years)
Total Synthesis (22 years) Total Yield: 0.00015%
71 Steps (longest linear sequence 48 steps)
52
OPSS 2008-01-11Weiwu Ren
MeO2C OHAcO
O O
H
OHCO2Me
OH
O
O
O
OOH
Azadirachtin
Summary
Logic!
Convergence!
Accuracy!
Dead Ends ? Detours ? Beginning !
53
OPSS 2008-01-11Weiwu Ren
Introduction
Dead Ends and Detours – An Example
Total Synthesis of Azadirachtin
Summary
Acknowledgement
Contents
54
OPSS 2008-01-11Weiwu Ren
Prof. Yang & Prof. ChenProf. Yang & Prof. Chen
Prof. Shi & Prof. YuProf. Shi & Prof. Yu
All the Members of Our LabAll the Members of Our Lab
All theAll the AudienceAudience
Acknowledgement
No Dead EndsNo Dead Ends
Less DetoursLess Detours
More success!!!More success!!!
56
OPSS 2008-01-11Weiwu Ren
Thank You！！！