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Overbred IntermediatesNathan WildeIntroductionJanuary 2013
This dog can barely squintthrough its overbred facialfolds to see anything.
This group meeting is based on a section in Hoffman's book Elements ofSynthesis Planning called "'Overbred' Intermediates." This section defines"overbred intermediates" as intermediates en route to cyclic structures thathave one or more excess C-C bonds, and these surplus bonds will need tobe cleaved in subsequent steps. This goes against logical retrosyntheticplanning (instead of finding good retrosynthetic disconnections you look forgood "add bond" connections) and even the parameters for measuringagainst the ideal synthesis, but the goal of this presentation is to learn whensuch intermediates might be strategic.
Notes:-I only care about making and cleaving C-C bonds.-Using DA/retro-DA to protect olefins doesn't count because I say so andbecause it is not interesting.-No degradation of commercially available SM. Make the complexity andthen destroy it (there may be one exception in this presentation).-This is not meant to be a bashing party. There are lots of both good andbad examples here. We can learn from both types.-By nature we must somehow fragment extraneous bonds in overbredintermediates, so I consider this topic a subset of Shenvi's 2005"Fragmentation Reactions in Synthesis" group meeting.
longifolene
O
O
add bond
retroaldol
O
OH
O
OH
HO2C
H
H
O
H
Oppolzer. JACS 1978, 2583
add bond
metalreduction
H
O
h
Coates. JACS 1985, 3541
H
O
O
OH
H
H
O
add bond
MsCl,Grob
H
H
OH
OH
HO
West. JOC 1998, 2806
h
A. Medium Rings
HO2C
Overbred IntermediatesNathan Wilde10-membered rings!
January 2013
Marshall. Synthesis 1971, 229
O
O
OMs
4 steps1. BH32. NaOH
Zhabinskii. JOC 1996, 4022
O
Ph
NH2
H1.2. EVK3. H2O, HOAc4. NaOMe
O
10 steps
OMs
OH
1. BH3 THF
2. NaOMe
OH
( )-allohedycaryol
Minnaard. Tetrahedron 1994, 4755
OH
( )-guaiol
1. RuO2, NaIO42. TESCl
O
O
OTES
KOH
OH
O
OTES
3 steps
OMs
OTES
1. BH3 THF
2. NaOMe
OH
( )-hedycaryol
Saicic. Org. Lett. 2004, 1221
MeO
3 steps
MeO
CO2Me
1. K;allyl bromide, LiBr
2. HCl3. Zn. allyl bromide
HO
MeO2C
7:1 dr
1. Grubbs I2. LAH3. MsCl
HO
OMsKOH
O
h , PhSSPh
O
38% + 58% SM
Eschenmosersalt
O
periplanone C
O
Schreiber. Tet. Lett. 1981, 4651Tet. Lett. 1985, 5971
allene
h
OH
H
MgBr
H
H
HO
KH
O
1. 175°C
2. h
O1. LiHMDS,Tf2NPh
2. Me2CuLi
germacrene-D
Overbred IntermediatesNathan WildeMedium RingsJanuary 2013
Sorensen. JACS 2006, 7025
O
O PMP
O
hO
O PMP
O SmI2,then PhSeBr
O
O
OSePh
PMP
OHO
H
6 steps
(+)-guanacastepene E20 steps (longest linear)
AcO
O
Carreira. ACIE 2011, 2962
O
OMe7 steps
HO
O
O IPh
KOCEt3
HO
O
OH
H
[Fe2(CO)9],then DBU
HO
O
O 1. DIBAL2. ZnEt2, CH2I23. PDC
HO
O
O
Li/NH3, O2
HO
O
OOOH
10 steps OHO
H
AcO
O
O
(±)-guanacastepene O
Mander. JACS 1998, 1914
MeO
H CO2Me
OMe
MeO2C
4 steps
MeO
H CO2Me
MeOOMe
OTBS
O
N2
1. [Rh]2. DBU
MeO
OMeO OMe
OTBS
CO2Me
MeO
H CO2Me
MeOOMe
OTBS
O
O
O
O
HO
hainanolidol
7 steps
Review: Synlett 2011, 2437
BF4
Overbred IntermediatesNathan WildeMedium RingsJanuary 2013
Tan. Nat. Chem. Bio. 2013, 21
HO
HO
O
O
O
TfO
PhI(AcO)2 Tf2O
45% 91%
HO2C
HO
O
OO
O
TfO
42% 62%
OMeMeO
HO
O TfO
OMe
OMe
72% 84%
O
O
11 steps
Winkler. JACS 1987, 2850JACS 2002, 9726
OO
Cl
O
H
H
H
Cl
O
O
h
1. K2CO3MeOH
2. DBU
H
O
OMe
O
H 31 steps
HO
O
OH
H
H
H
HO
HO
( )-ingenol
B. Setting Cyclic Substitution
Winkler. JACS 1999, 7425O
O
OH
O
+
1. pyrrolidineAcOH
2. TMSIHMDS
O
OTMS
O
OTMS
O3
O
OTMS
O
OOMe
OMeOMe
O
5 steps
OO
OO
O
O
O
h
O
O
O H
O
OO
O
1. n-BuLi,Tf2O
2. (3-furyl)SnBu3Pd(AsPh3)4
O
O
O H
O
OO
O
LiOH,MeOH;thenPPTS
O
OO
O
O
O
H
O
( )-saudin
O
Winkler's review of 2+2 then fragmentation in synthesis:Chem. Rev. 1995, 2003
OMeMeO
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
Taber. JOC 2001, 1876
O
N2
O
TBDPSO
N2
R
[Rh]
O
TBSO
R
R = (CH2)3CO2Et
1.4:1 dr
PhSH
O
TBDPSO SPh
R
7 steps
HO
HO OH
R
8-F2t-isoprostane
Danishefsky. ACIE 2007, 2199
OH
CO2Et
OPMB7 steps
O
TBSO
H
O
Et2AlCN
O
TBSO
H
O
CN
1. NaBH4, CeCl32. n-BuLi, CH2I2, Zn
O
TBSO
H
OH
O
TBSO
H
O
1. TPAP,NMO
2. Li/NH3
5 steps
O
OH
OHO
paecilomycine A
Covey. JOC 2002, 4893
O O
OMe
1. n-BuLi,crotyl bromide
2. p-TsN3, EtN3
O O
OMe
N2
[Cu]HMeO2C
O
1. Mg, CuI
BrMeO2C
H
O
21 steps
HO
H
H
H
H
ent-cholesterol
RO2C
O add bond
retroaldol
RO2COH
h
RO2COR
+
Pearlman. JACS 1979, 6398
CO2R add bond CO2R
h
CO2R
+
Wender. JACS 1977, 267
H
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
O
Koreeda. Org. Lett. 2004, 537
HO
OMe
O
4 steps
Pd(OAc)2PPh3HOAc
COreflux
OH
O
H
1. K2CO3,MeI
2. CHBr3,NaOH
OMe
O
HBr
Br
HS OMe
H
OMe
O
HBr
ArS
OMe
O
HBr
SAr
11 steps
OH
H
acanthodoral
Kibayashi. Tet. Lett. 2005, 2327
6 stepsO
NTs
h
NTs
HH
H
H
O
SmI2
NTs
H
O
H
6 steps
NMe
H
HO
H
( )-incarvilline
O
MeO2C O
Danishefsky. JACS 2010, 9567
O
OMOMO
O
N2
6 steps
O
OMOM
O
O
H
[Cu]
1. NaBH4, CeCl32. I2, PPh3, Im
I
OMOM
O
O
H
SmI2
O
O
OMOM
8 steps
OH
H
O
O ( )-aplykurodinone-1
1. HCl2. DMP
O
O
O OHHO
O
K2CO3H2O
Crimmins. JACS 1999, 10249; JACS 2000, 8453
O
O
H
6 steps O
OCO2Et
O
Et3SiO t-Bu
h
OCO2Et
Et3SiO t-Bu
4 steps O
O
t-Bu
O
ODMDO,
acetone, H2Othen
p-TsOH
O
O
t-Bu
O
O
HO
OH
OH12 steps
O
t-Bu
O
O
O
OHO
HO
HO
H
OHO
ginkgolide B
O H
O
OTBS
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
O
Srikrishna. Synlett 2012, 1021
7 steps
N2
O
[Cu]O
5 stepsO
O
PTSAO
O
11 steps
OH
ent-allothapsenol
Corey. JACS 1972, 4014
Corey. Tet. Lett 1970, 307
5 steps
O
O
H
H
OH
H2Cr2O7,(NH4)2Ce(NO3)6
HOAcH2O
O
O
CHO
HO
steps PGF2 , E2
HO
HO
3 stepsO
THPO
O
N2
CO2Me
[Cu] O
O
H
THPO
H
H
CO2Me
CuLi2
O
O
THPO
stepsCO2Me
PG's
Nakada. Tetrahedron 2006, 8054
MeSO2ArO
OEt
1. n-BuLi, then
2. TsN3, Et3NO
SO2Ar
N2 CuOTfBOX ligand
O
SO2Ar
83% ee
NaCN
O
SO2Ar
CN
5 steps
O
CO2Me
( )-methyl jasmonate
Srikrishna. Synlett 2007, 655
MeO
OMe
O
6 steps MeO
OMe
N2
O
[Cu]
MeO
OMe
O1. Li/NH3
2. CAN O
O
O
( )-lagopodin ACorey. JACS 1984, 2735
O
H
H
OTsEtBu3Sn
H
H
OTs
1. BuLi,then
H
Et
OH
K2CO3
MeOH
O
EtH
H
H
O
H
H
11 steps
O
Et
O
H
H
hydridalactone
OMe
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
Wender. JACS 1981, 688
OMe
O
Cl
+ Li/NH3
OMe
h
H
OMe
H
Br2
thenBu3SnH+
O
H
NH2NH2
KOH
200°CH
( )- -cedrene
Yamada. Tet. Lett. 2001, 9233
OMOM
O
LDA, then
CO2Et
O OO
OMOM
EtO2C
OO
7 steps
OH
OO
OBn
O
K2CO3
MeOH
O
O
O
H
O
H
BnO19 steps
O
H
OH
OH
stolonitriene
CO2Et
Danishefsky. JACS 2012, 18860
22 steps
O
OMOM
OH
O
O
CH2I2,Zn, Ag
O
OMOM
OH
O
O
1. PCC2. H2,
PtO2
O
OMOM
O
O
O
5 steps
O
O
O
OO
maoecrystal V
h
HH
+
1:2
H
PhSH (neat)100°C
ultrasound
H
H
SPh
1. Li/NH3
2. CrO3-DMP3. LDA, MeI4. NaBH4
H
H
Chanon. JOC 1996, 3576
OH
ceratopicanol
Review of meta- olefin-arene photocycloadditions:Chem. Rev. 1993, 615
Overbred IntermediatesNathan WildeCyclic Substitution
January 2013
Tanaka. JOC 2001, 7107
O
O
1. CrO3-DMP2. LDA, TMSCl
O
O
OTMS
O
(neat)
O
O
O
O
mCPBA
O
O
O
O
O
Pd(PPh3)4PBu3
O
O
O
O
O
6 steps
O
O
H
O
(±)-stemodinone
Corey. JACS 1987, 4717
O O
13 steps
O O
N2
CO2t-Bu
[Cu]
O
O
CO2t-Bu
1. NaBH42. NaH, BnBr3. DIBAL
O
OBn
H
OH
O
H
OBn
H
Tf2O
O
H
H
OH OH10 steps
Chen. Org. Lett. 2011, 5724
TMS
TMS
7 steps
NO2
TBSO
Pd(OAc)2PPh3
NO2
HOTBS
H
4 steps
O
HOTBS
HH
O
TsNHNH2,TFAthenHCl
HOH
HH
O
6 steps
HO2C
H
H
echinopine A
(±)-cafestol
Perali. Tetrahedron 2012, 3725
OOAc
OAc
OAc
7 steps
O
OBn
N2OMe
O
[Rh]
O
OBn
CO2Me NBSH2O/dioxane
O
OBn
OH
CO2Me
Br
4 stepsO
O
O
O
( )-longianone
O
O
OBn
O
OH
K2CO3MeOH
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
Buszek. Org. Lett. 2009, 201
Et
NH2
6 steps
NTBS
Br
Br
Et n-BuLi
NTBS
Et
NTBS
Et
CHO
OHC NH
Et
2 steps
( )-cis-trikentrin
1. OsO4
2. NaIO4
O
Toshimitsu. JOC 2004, 9262Org. Lett. 2000, 3751
MeO
OOBn
LDA,H
O
MeO2C
H
BnO
H
H
(CH2)4
33 steps
O
O
O
OEt
SEMO
TBDPSOHO
PhI(OAc)2,
I2,
h(CH2)4
O
O
O
EtO
SEMO
TBDPSOO
I
10 steps CP-263,114 precursor
O
O
B(OH)2
Fukuyama. Org. Lett. 2012, 1632
7 steps O
OH
O
PhI(OAc)2,
MeOH
then
then CSA
OO
O
OMe
H
O
O
OMe
H
4 steps
OBn
O3
O
O
O
CHO
OBn
MeOOH
27 steps
O
O
O
O
HO
anisatin
Iwata. Tet. Lett. 1986, 3161
O
7 stepsO
N2[Cu]
H
O3 steps
H
O
O
OH
O
p-TsOH
O
O
H
OBn
OBn
O
O
O
BnO
11 steps
OOO
quadrone
Overbred IntermediatesNathan WildeCyclic SubstitutionJanuary 2013
9 steps
Galano. JOC 2010, 2411
H
H
EEO
TBSO
O3thenNaBH4
EEO
TBSOOH
OH 13 steps
O
HO
OH
CO2H
an isoprostane
C. Spirocycle synthesis
Valenta. Can. J. Chem. 1979, 3346Can. J. Chem. 1991, 853
OAc
O
O
+ BF3 OEt2
AcO H
H
O
O
H
O
OBr
HH
CO2EtOsO4thenZnthenH2S
H
O
HH
CO2Et
HO
HO
HO
O
O
OHHEtO2C
H5IO6
~14 steps
O
O
OMe
HO
MeO
H HO
d,l-quassin
6 steps
O
add bond
Li/NH3
O
h
O Cl
Oppolzer. Acc. Chem. Res. 1982, 135
CO2R
Oadd bond
Retro-Claisen
O O
h O3
O
Becker. JOC 1982, 3297
Oadd bond
nucleophileR
O R
[Cu]
O
N2
Heathcock. Tet. Lett. 1975, 529
Woodward. Tetrahedron 1958, 1
O
O CO2Me
+
H
H
O
O
MeO2CH
9 steps
H
H
OH
MeO2CHOMe
OAc
H
O
OH
1. HIO42. CH2N2
MeO2C
H
H
O
MeO2CHOMe
OAc
H
H
8 steps
H
H
MeO2CHOMe
O
H
NNH H
O
OMe
OMe
OMe
(±)-reserpine
Cl
Overbred IntermediatesNathan WildeOlefin MetathesisJanuary 2013
A. Olefin metathesis: [2+2]/retro [2+2]
White. JACS 1992, 9673
( )-byssochlamic acid
O
O
O
OO
O
+ O
O
O
Br1. h ,
then Na2CO3
2. CH2N2
3. DBU
4. LiOH
COOH
COOH
O1. NaH, (MeO)2CO2. Br23. NaOMe4. DIBAL-n-BuLi
HO
HO
O
O
O
O
O
OO
O
R1R2
R4
R3
h
O
O
O
O
2:1 cis:trans
1. LiOH2. KMnO4
toluene,
DCC
Mehta. Tet. Lett. 2003, 5243Tetrahedron 1981, 4543
OO
OO
h
OO
H H
HOO
12 steps
H
H
O
O
OH
pleurotellol
