Lecture3 123713B
52
LECTURE THREE total synthesis ©Michael Budde@flickr 1
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Transcript of Lecture3 123713B
LECTURE THREEtotal synthesis
©Michael Budde@flickr1
OO
OAc
O
OO
O
O
OOHO
OH
Cl
AcO
OHOH
OH
HO
OMeHO
(+)-spongistatin 1 altohyrtin A
©Saad.Akhtar@flickr2
?PPh3I
O
O
OHHO
OH
Cl OHOH
OH
OO
OHO
AcO
HO O
O
OO
OHO
OMe
how
total synthesis
do wedesign a
3
©_Max-B@flickr
retrosynthesisnys
backwardsthinking
4
R1 R2
?
how
alkene
do wemake an
5
R1 R2R1
R2
R1 R2
OR1
IPh3PR2
OR1
OR2
Wittigalkene
metathesis
reduction
McMurry
targetsnew
6
morereactions
you know...
7
©spackletoe@flickr
...the easierretrosynthesis is
8
RETROSYNTHESIS
123.312REVISE
©jeffrey_bos@flickr9
readthisbook
10
guidelinesretrosynthesis
11
representations0. draw multiple
N
NH
HN N
N
N
H
H
H
H
N N
H
HN N
H
H
12
1. identifyfunctional groups
N
OO
O
Ococaine
N
OO
O
Oester
N
OO
O
Oester
N
OO
O
Otertiary amine
N
OO
O
O
N
OO
O
Opyrrolidine piperidine
13
2. identify patterns
N
OO
O
Oaldol
N
OO
O
OMannich
N
OO
O
O1,3-diX
(conjugate addition)
14
N
OH
HOCO2H
OHN
FOEtEtO
NH2
O
Ot-Bu
OR*O
F
CHO
CHO
O
HN
O
atorvastatin(lipitor®)
3. simplification
15
O
O NH
O
OH
HN
OO
O
OH
HH
bistramide A
peptide coupling
O
O
O
HHOH
H2NOTBS
OTIPS
O
H2NO
O
OTBS
4. convergent
16
N
O
O
Cl
OH
H
H
NO
H
H
OH
OH
Cl
HO(+)-halichlorine
Angew. Chem. Int. Ed. Engl. 1999, 38, 3542
lactone formation
C–X
C–X5. disconnections
17
C–X5. disconnections
EtO2C
O
NH3•H2PO4
NHAcC–X
EtO2C NH3•H2PO4
NHAc
TamifluAngew. Chem. Int. Ed. Engl. 2009, 38, 1070
aziridine opening
18
C–C next to functional group6. disconnections
O
OOH
O
H
bipinnatin JOrg. Lett. 2006, 8, 345
C–CO
O
O
OBr
nucleophilic addition
Nozaki-Hiyama-Kishi
19
C–C next to functional group6. disconnections
O
OH
OHH
H
O
halicholactoneJ. Org. Chem. 1997, 62, 6638
C–C
nucleophilic addition
Nozaki-Hiyama-Kishi
OH
I
O
O
HH
CHO
20
C–C next to functional group6. disconnections
N
N NH
N
H
OH
manzamine AJ. Am. Chem. Soc. 2012, 134, 17482
C–C
N
N
H
OH
OTf
Bu3Sn
N NH
Pd-cross coupling
21
N
N
H
OH
OTf
N
N
H
OH
OTf
precursor manzamine AJ. Am. Chem. Soc. 2012, 134, 17482
RCM
C=C
C=C7. disconnections
22
O
TIPSO
O
O
OH
MeO2CO
TIPSO
O
OH
MeO2C
O
OP(O)(OMe)2
C=C
precursor to palmerolide AJ. Am. Chem. Soc. 2007, 129, 6386
Horner-Wadsworth-Emmons
C=C7. disconnections
23
group interconversions8. functional
TBSO
OON
O
O
O
precursor to penarolide sulfate A1Eur. J. Org. Chem. 2008, 6213
FGI
NO O
OO
OOTBS
C–C
Sonogashira
TBSO
OON
O
O
O
I
simplification24
NO
O
HO
OO
O
C7H15
hapalosinTetrahedron Lett. 1996, 37, 6557
C7H15
OTBSCO2H
C7H15
OH O
ON
O
Bn
O
ON
O
Bn
O
C7H15
FGI
C–C
Evans aldol
group interconversions8. functional
control25
recognition9. pattern
HO
H
H H
NH
OH
OH
hirsutellone BJ. Org. Chem. 2013, 78, 9584
≡ HO
H
H H
NH
OH
OH
O O
Diels-Alder
HO
H
H H
NH
O
O
OP
HO
H
NH
O
OP
O
26
9. pattern
R
OH OH
R2 R
O OH
R2 R
O O
R2FGI C–C
aldol
recognition
OHO
O
O
OO
HO
OH
OH O
rutamycin B
≡
OHO
O
O
OO
HO
OH
OH O
6 obvious aldol disconnections
27
©Christian Puff
Angew. Chem. Int. Ed., 1996, 35, 904
(–)-stenine
N
OH
H
H H
O
H
28
N
OH
H
H H
O
H
N
OH
H
H H
O
H
6-membered ring
6 contiguous stereocentres29
R1
R2
R3
R4
R1
R2
R3
R4
Diels-Alder reaction
30
normally poor choiceearly C–C disconnection
2 xC–C
N
OH
H
H H
O
H
N
OH
H
H H
O
H
enolate alkylation
alkylation
31
N
OH
H
H H
O
H 2 xC–N
NH2
CHO
OH
H
H H
O
H
I
reductive amination
alkylation
C–X disconnectionsimple
32
NH2CHO
OH
H
H H
O
H
I
C–O
NH2CHO
HOH
H H
O
H
I
≡
(CH2)4INH2
CHO
CO2H
Diels-Alder4 of the 7
stereocentres of stenine
iodolactonisation
C–X disconnectionsimple
33
(CH2)4INH2
CHO
CO2H
(CH2)4I
CO2H CHO
NH2
Diels-Alder
Diels-Alder reaction34
(CH2)4I
CO2H CHO
NH2
regiochemistryof Diels-Alder
reactivity
enantioselectivity
issues?
35
N
OH
H
H H
O
H
O
I(CH2)4
O
N
OPh
O
intramolecular DAsolution
+ auxiliary36
S S
THPO
Cl
(CH2)4OPMB
i. BuLi, then R–Cl
ii. H+
68%OH
(CH2)4OPMB
SS
synthesis
umpolung37
OH
(CH2)4OPMB
SS
ON
OO(EtO)2(O)P
i. Parikh-Doering oxidation
ii. LiCl, Et3N, imide
77%
PMBO(CH2)4
SS
N
O
O
O
Ph
synthesis
activated DMSO (Swern)38
synthesis
intramolecular Diels-Alder (IMDA)
PMBO(CH2)4
SS
N
O
O
O
Ph
S S
PMBO(CH2)4
H
H
O
ON
O
Ph
Me2AlCl
85%
39
HH
R NOAlO
O
HH
SS
Ph
H
HPMBO(CH2)4
H
H S
S
aux
O
diastereoselectivity40
S S
PMBO(CH2)4
H
H
O
ON
O
Ph
HH
R NOAlO
O
HH
SS
Ph
H H
determining stereochemistry41
S S
PMBO(CH2)4
H
H
O
ON
O
Ph
i. AgNO3, NCSii. LiSEt
iii. Et3SiH, Pd/Civ. NaClO2, NaH2PO4
53%
PMBO(CH2)4
H
H
O
OH
O
synthesis
removalauxiliary
42
PMBO(CH2)4
H
HCO
OH
O
OP
N3PhO
PhO
DPPA, Et3N, 60°C
then MeOH
82%
PMBO(CH2)4
H
HNH
C
O
OMe
O
synthesis
rearrangementCurtius
43
synthesis
PMBO(CH2)4
H
HNH
C
O
OMe
O
i. TMSCl, Et3N, 50°C
ii. mCPBAiii. H5IO6
then I2, NaHCO3
50%NCO2Me
OH
IH
H
O
H
(CH2)4OPMB
OH
44
PMBO(CH2)4
H
HNHCO2Me
O
TMSCl, Et3N 50°C
PMBO(CH2)4
H
HNHCO2Me
OTMS
mCPBA
PMBO(CH2)4
H
HNHCO2Me
OTMSO
PMBO(CH2)4
H
HNHCO2Me
OOH
oxidation
45
cleavage
PMBO(CH2)4
H
HNHCO2Me
OOH
H5IO4
PMBO(CH2)4
H
HNHCO2Me
OIOHO
OHOHOOH
PMBO(CH2)4
H
HNHCO2Me
OHO
O
NCO2Me
HOH
H
O
H
(CH2)4OPMB
OH
oxidative
46
NCO2Me
HOH
H
O
H
(CH2)4OPMB
OH
I2
NCO2Me
HOH
H
O
H
(CH2)4OPMB
OHINCO2Me
OH
H
O
H
(CH2)4OPMB
OHI
H
O
O
I H
(CH2)4OPMB
H
synthesis
iodolactonisation47
NCO2Me
OH
H
O
H
(CH2)4OPMB
OHI
i. H+, CH(OMe)3, MeOHii. CH2=CHCH2SnBu3, AIBN
iii. LDA, MeI
53%NCO2Me
OH
H
O
H
(CH2)4OPMB
OMe
synthesis
alkylation (twice)48
stereoselectivity
H
RN
O
O
HH
H
H
H
IHMeO2C
H
O
HI
O R
HN
H
CO2Me
OMe
MeO
or
49
NCO2Me
OH
H
O
H
(CH2)4OPMB
OMe
i. Et3SiH, BF3•OEt2ii. OsO4, NaIO4
iii. HSCH2CH2SH
50% N
OH
H
O
HS
S
OH
CO2Me
synthesis
50
synthesis
N
OH
H
O
HS
S
OH
CO2Me
i. Raney Niii. MsCl, Et3N
iii. NaI
73% N
OH
H
O
H
I
CO2Me
51
synthesis
N
OH
H
O
H
I
CO2Me
i. TMSIii. heat
70% N
OH
H
H H
O
H
52
