lecture8: 123.702
DESCRIPTION
MacMillan's synthesis, highlighting the use of organocatalysis.TRANSCRIPT
callipeltoside C©oxmox@flickr gareth j rowlands
LECTURE EIGHT
©Islands in the Stream Expedition 2002. NOAA Office of Ocean Exploration
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
callipeltoside CAngew. Chem. Int. Ed., 2008, 47, 3568
©mararie@flickr
anti-tumoractivity
retrosynthesis
simplification
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
glycosylationremove sensitive
sugar
into fragments
O
O O
Cl
MeOH OH
OHYamaguchi
lactonisationform macrocycle by esterification
retrosynthesis
allows molecule to be split
in half
retrosynthesis
divide
O
OH
Cl
MeOH OH
OH
chelation controlled alkylation
CO2H
in half
retrosynthesis
divide
O
OH
Cl
MeOH OH
OH
chelation controlled alkylation
CO2H
HO O
MeO OH
H
OH
OH OH
OH
CO2H
O
OH
Cl
X
3 targets
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
©YaniG@flickr
synthesismaychange order
retrosynthesisbottom half
OH
Cl
XHorner-Wadsworth-
Emmons
OHO
ICl
PO
MeOMeO
O
I
organocatalysis
retrosynthesismiddle section
OH OH
OH
CO2Me
O
Semmelhack cyclisation
PGO
OH OH
13
5
73
57
difficultto see
see forwardreaction
©bitterlysweet@flickr
PGO
OH OH
retrosynthesismiddle section
PGO
OH OH
retrosynthesismiddle section
patternrecognition
R1
OH
R2
O
©lecates@flickr
aldolthink
PGO
OH OH
PGO
OH O
PGO
O O
alkylkationsubstrate
control
aldolorganocatalysis
retrosynthesismiddle section
HO O
MeO OH
H
OH
retrosynthesissugar section
HO O
MeO OH
H
OH
retrosynthesissugar section
aldol
aldolHO O
MeO OH
H
OH
retrosynthesissugar section
retrosynthesissugar section
HO O
MeO OH
H
OH
HO O
MeO OTIPS
HOTIPS
OHFGI
C–C
MeO
TESO
OOTIPS
TIPSOOTIPS
aldolchelation control
retrosynthesissugar section
OOTIPS
TIPSOOTIPS
C–C
OOTIPS
OOTIPS
aldolorganocatalysis
©Time Inc
the synthesis
the synthesis
©euthman@flickr
OH
1. AlMe3, ....Cp2ZrCl2 then I22. (COCl)2, ....DMSO, Et3N
O
I
synthesisbottom half
OH
Cl
I
Negishicarbometallation-
iodinationmechanism
complex!©Toby Maloy@flickr
mechanism
R H
ZrCl
Cl MeAlMe
Me
R H
AlMe Me
MeZrCl Cl
CpCp
δ+δ–
R H
Me AlMe2
I2R H
Me I
possible
organocatalysis
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
synthesisbottom half
O
I NH
CO2HPhNO
99%ee O
IO
NHPh
OH
Cl
I
see lecture six
O
IO
NHPh
1. NaBH42. Zn, AcOH3. Bu2Sn(OMe)2, PMBCl4. TBSCl, imidazole
62% OPMB
IOTBS
synthesisbottom half
I
OSnO
BuBu
PG
OH
Cl
I
OPMBO
O
NH
CO2H OHPMBO O
99%ee12:1 syn:anti
synthesisof middle section O
H OPG
OH
CO2Me
PGO
see lecture six
OHPMBO OBr
Zn
98%6:1 syn
OHPMBO OH
OH OPG
OH
CO2Me
PGO
synthesisof middle section
R
H
Me O
HZn
RH
Me OH
H
Felkin-Ahnsubstrate
control
OHPMBO OH
synthesisof middle section
OHPMBO OH
OH OMe
OH
PMBO
[PdCl2(MeCN)2]CO, MeOH
OMe
OO O
75%20:1dr
OH OMe
OH
PMBO
OMe
O
©New Line Cinema
nightmare mechansim
Pd2+
HO Pd2+
OPd+
O Pd+
O
O OMe
O
Pd0
OO
OHHO
O OMe
O
Pd2+O OMe
O
Pd+O OMe
O
OMe
HO
C O
MeOH
Pd2+
MeOH
OH OMe
OTBS
CO2Me
O
synthesisof middle section
OH OMe
OH
PMBO
OMe
O
1. TBSCl2. DDQ3. SO3•pyr, ....DMSO, Et3N
80% OH OMe
OTBS
CO2Me
O
OMeNC
NC O
Cl
ClO
callipeltoside Csynthesis
O
O O
ClMeO
H OH
O O
MeOOH
H
OH
OH OMe
OTBS
CO2Me
O
OPMB
IOTBS
OPMB
BrMgOTBS
OH OMe
OTBS
CO2Me
HO OTBSOPMB
MgBr•Et2O98%16:1dr
controlchelation
O
O O
ClMeO
H OH
O O
MeOOH
H
OH
OH OMe
OTBS
CO2Me
O
OPMB
IOTBS
OPMB
BrMgOTBS
OH OMe
OTBS
CO2Me
HO OTBSOPMB
MgBr•Et2O98%16:1dr
OH OMe
OTBS
CO2Me
HO OTBSOPMB
1. MeOTf, base2. DDQ3. SO3•pyr, ....DMSO, Et3N
84%O
H OMe
OTBS
CO2Me
MeO OTBSO
callipeltoside Csynthesis
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
OH OMe
OTBS
CO2Me
MeO OTBSO
ClPO
MeOMeO
1. HWE2. TBAF3. Ba(OH)2
84%
O
OH
Cl
MeOH OMe
OTBS
CO2H
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
callipeltoside Csynthesis
Org. Lett., 2001, 3, 503
O
OH
Cl
MeOH OMe
OTBS
CO2H 2,4,6-Cl3C6H2COCl, iPr2NEt, DMAP
83%
O
O
Cl
MeOH
OTBS
O
aglyconesynthesis
aglyconesynthesis
O
O
Cl
MeOH
OTBS
O
1. PPh3•HBr, H2O2. TFA
81%
O
O
Cl
MeOH
OH
OOH
HO O
MeO OH
H
OH
portionsugar
disaster
O
O O
Cl
MeOH OH
O O
MeO OH
H
OH
©dawn m. armfield@flickr
HO O
MeO OHOH
portionsugar
real
O
OTIPSO
OTIPS
NH
CO2H
75%99%ee
O
TIPSO
OH
OTIPS
see lecture six
of sugarsynthesisHO O
MeO OHOH
HO O
MeO OHOH
of sugarsynthesis
O
TIPSO
OH
OTIPS
OTESOMe
MgBr2•OEt2
47%>20:1dr HO O
MeO OTIPS
TIPSO
OH
controlsubstrate
HO O
MeO OHOH
of sugarsynthesis
O
TIPSO
OH
OTIPS
OTESOMe
MgBr2•OEt2
47%>20:1dr HO O
MeO OTIPS
TIPSO
OH
controlsubstrate
H
RTIPSOR
H
TIPSO O
HMeO
TESO
OH
HMeO
O
H≡
O
OMe
OH
OTIPS
OH
OTIPSHO O
MeO OTIPSOH
OTIPS
HO O
MeO OHOH
HO O
MeO OTIPS
TIPSO
OH1. AcCl, BnOH2. PhOC(S)Cl3. Bu3SnH, AIBN4. DMP
47%BnO O
MeO OTIPSO
of sugarsynthesis
OI
O
OAcAcO OAc
BnO O
MeO OTIPSO
1. MeMgBr, ....MgBr2•OEt22. H2, Pd/C then ....Cl3CCN
86%O O
MeO OTIPSOH
HN
CCl3
of sugarsynthesis
callipeltoside Csynthesisendgame
O
O
Cl
MeOH
OH
OOH
O O
MeO OTIPSOH
HN
CCl3
1. TMSOTf2. TASF
63% O
O
Cl
MeOH
OOH
O O
MeO OHOH
sequence
12%PMBO H
O
18-steps longest linear
correctedstereochemistry