lecture threegjrowlan/chem312/lct3.pdflecture three CÐX disconnections get m ore com plex F3C Me...
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lecture three C–X disconnections get more complex F 3 C Me HN Me fenfluramine neuroactive drug
Transcript of lecture threegjrowlan/chem312/lct3.pdflecture three CÐX disconnections get m ore com plex F3C Me...
lecture threeC–X disconnections get more complex
F3C Me
HN Me
fenfluramineneuroactive drug
F3C Me
HN MeFGI
reduction
F3C Me
HN Me
O
C–N
amide
F3C Me
NH2FGI
reductionF3C Me
NH
C–N
imine
F3C Me
O reductive amination
N-unsubstituted imines are notoriously unstable.
synthesis
F3C Me
O
F3C Me
NOH
F3C Me
NH2
F3C Me
HN Me
NH2OH
H
H2
cat.
i. AcCl
ii. LiAlH4
?F3C Me
O
F3C Me
HN Mei. EtNH2
ii. NaBH4
Amide formation followed by reduction
© www.schimmel-schimmelpilze.de
NH
N
N
N
OHH
Me
Me
O
H
O
Me Me
H
okaramine N
NH
NH2
CO2MeH
NH
N
CO2MeH
MeMe
NH
NH
CO2MeH
MeMe
NH
N
MeMe
O
R1MeO2C
H
tryptophan ester
O
Me
Me
NaBH4
amide formation
70%three steps
J. Am. Chem. Soc. 2003, 125, 5628
other amine syntheses
R1 Cl N
O
O
K N
O
O
R1
R1 NH2
NH2NH2
R1 Cl NaN3 R1 N3
LiAlH4or
PPh3
Azides have a nasty habit of suddenly reverting to nitrogen gas when heated or, with the smaller examples, tapped with a metal spatula. In English, this means they can explode.
O
O
O
MeMe
BnOOTIPS
H
HOTf
O
O
O
MeMe
BnOOTIPS
H
HN3
NaN3
O
O
O
MeMe
BnOH
HN3
CHO
O
O
O
MeMe
BnOH
H HNN
H
HOH
O
O
Me
Me
N
H
HO
HO
HO
H2
Pd / C
H2
Pd / C
AcOHH3O
N
H
HO
HO
HO
swainsonine
C–N
reductive
amination
C–N
azide addition
Tetrahedron 1987, 43, 3083
Tf = triflate = trifluoromethanesulfonate or F3CSO2-
remember that an acetal is just a protected carbonyl
two-group C–X disconnections
one-group disconnection
R1
XR2 R
1
XR2
two-group disconnection
R1
XR2
R1
X
R2
OH OH
retrosynthesis
Me OPh
Me
OH
Me
Me
OPh
OH
Me O
Me
Ph
OH
C–X
route A A
C–X
route BB
route A
Me OPh
Me
OHA
C–X
route A Me
MeO
Ph
OH
! !
Me
Me
Br
HOPh
OH
chemoselectivity
HOPh
OH
© Sony Pictures
route B
Me OPh
Me
OH
Me O
Me Ph
OH
C–X
route BB
! !
Me OH
Me Ph
OH
Br
!
Ph
O
route B: synthesis
Me OH
Me
NaH Me O
Me
Ph
O
OPh
OH
Me
Me
Sn2 reaction of epoxides favours attack at the least hindered end.
R1
O
one functional group gives two functional groups
R2X
R1
OH
R2X
R1
XH
1
2
1,2-diX
O NH
Me
Me
OH
propranololbeta-blocker
OO1,2-diX
H2N Me
Me
O
O!
OH
OCl
C–X
retrosynthesis
synthesisOH
OCl
OO
base
H2N Me
Me
O NH
Me
Me
OH
Why do we get mono-alkylation of the amine?Its because of the electron withdrawing effect of the hydroxyl formed from opening the epoxide...
did you know?
OCl
1
2
3 more electrophilic than chloride
did you know?
OCl
Nuc
1
2
3Cl
1
2
3
Nuc
O
1
2
3
NucO
does this make a difference?
yes!OH
OCl
OO
base
OH
OCl
OO
base
© Pinay06
N
N
Me
OAc
OHCO2Me
H
H
MeO
NH
N
MeO2C
OH
Et
H
Me
vinblastine
NH
N
OTBDPS
OH
Et
Ns
MeO2C
1,2-diX
NH
MeO2CH2
NsN
EtOH
NH
MeO2CH2
NsHN
EtO
!
retrosynthesis
J. Am. Chem. Soc. 2002, 124, 2137
Ns = 2-nitrobenzenesulfonyl, a good nitrogen protecting group
1,3-diX
S OMe
O
Ph
Ph S
OMe
O
! !
Ph SH
OMe
O
Br
C–X
retrosynthesis
?
S OMe
O
PhPh S
OMe
O
! !
Ph SHOMe
O
1,3-diX
retrosynthesis
synthesis
Ph S
OMe
O
S OMe
O
Ph
S OMe
O
Ph
H
conjugate addition or Michael reaction
Proton can be replaced by other electrophiles to allow more complex molecules to be prepared.
1,3-diXR
O
R
O
1
2
3
!
O NH2 O
N
ON!OH
N
FGI
reduction
1,3-diX
retrosynthesis
not just carbonyl groups
retrosynthesis
Ph
N O1,3-diX
NPh
O
! !
NH
Ph
O
