Nathan Wilde
Introduction
January 2013
Overbred Intermediates
A. Medium Rings
This group meeting is based on a section in Hoffman's book Elements of
Synthesis Planning called "'Overbred' Intermediates." This section defines
"overbred intermediates" as intermediates en route to cyclic structures that
have one or more excess C-C bonds, and these surplus bonds will need to
be cleaved in subsequent steps. This goes against logical retrosynthetic
planning (instead of finding good retrosynthetic disconnections you look for
good "add bond" connections) and even the parameters for measuring
against the ideal synthesis, but the goal of this presentation is to learn when
such 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 and
because it is not interesting.
-No degradation of commercially available SM. Make the complexity and
then 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 and
bad examples here. We can learn from both types.
-By nature we must somehow fragment extraneous bonds in overbred
intermediates, so I consider this topic a subset of Shenvi's 2005
"Fragmentation Reactions in Synthesis" group meeting.
Oppolzer. JACS 1978, 2583
O
OH
add bond
O
O
O
retroaldol
h
longifolene
Coates. JACS 1985, 3541
HO2C
H
add bond HO2C
H
H
O
O
H
O
O
metal
reduction
h
West. JOC 1998, 2806
H
This dog can barely squint
through its overbred facial
folds to see anything.
OH
H
O
OH add bond
MsCl,
Grob
H
OH
OH
H
HO
H
10-membered rings!
January 2013
Overbred Intermediates
Nathan Wilde
Schreiber. Tet. Lett. 1981, 4651
T et. Lett. 1985, 5971
Marshall. Synthesis 1971, 229
O
OMs
1. BH3
2. NaOH
4 steps
O
H
allene
h
O
H
HO
O
KH
MgBr
O
H
H
Zhabinskii. JOC 1996, 4022
NH2
O
1. Ph H
2. EVK
3. H2O, HOAc
4. NaOMe
O
1. LiHMDS,
Tf 2NPh
2. Me2CuLi
1. 175°C
2. h
10 steps
O
germacrene-D
OMs
1. BH3 THF
2. NaOMe
Saicic. Org. Lett. 2004, 1221
OH
OH
1. K;
allyl bromide, LiBr
2. HCl
3. Zn. allyl bromide
3 steps
( )-allohedycaryol
MeO
MeO
Minnaard. Tetrahedron 1994, 4755
1. RuO2, NaIO4
2. TESCl
OH
CO2Me
7:1 dr
O
1. Grubbs I
2. LAH
HO
3. MsCl
KOH
O
O
KOH
h , PhSSPh
OMs
OTES
( )-guaiol
O
O
O
OMs
3 steps
1. BH3 THF
2. NaOMe
OTES
OTES
Eschenmoser
salt
OH
OH
HO
MeO2C
( )-hedycaryol
38% + 58% SM
periplanone C
Medium Rings
January 2013
Overbred Intermediates
Nathan Wilde
Mander. JACS 1998, 1914
Review: Synlett 2011, 2437
O
MeO
MeO
H
H
CO2Me
1. [Rh]
2. DBU
4 steps
SmI2,
then PhSeBr
O
h
OMe
O MeO
OMe
MeO
H
O
O
OTBS
N2
MeO
PMP
O
PMP
O
CO2Me
MeO2C
Sorensen. JACS 2006, 7025
PMP
O
O
O
CO2Me
CO2Me
7 steps
H
O
SePh
6 steps
O
OH
AcO
OTBS
O MeO OMe
O MeO
OTBS
OMe
(+)-guanacastepene E
20 steps (longest linear)
O
Carreira. ACIE 2011, 2962
BF4
O
OH
O
O
OMe
O
O H OH
Ph I
O
7 steps
O
KOCEt3
HO
H
hainanolidol
O
[Fe2(CO)9],
then DBU
H
O
O
1. DIBAL
2. ZnEt2, CH2I2
3. PDC
O
H
O
O
O
O
H
Li/NH3, O2
O
O
O
OOH
H
10 steps
O
OH
AcO
(±)-guanacastepene O
Medium Rings
January 2013
Overbred Intermediates
Nathan Wilde
H
Tan. Nat. Chem. Bio. 2013, 21
HO
O
O
PhI(AcO)2
HO
45%
HO HO
HO
OMe
91%
O
OH
( )-ingenol
HO2C
O
O
O
HO
B. Setting Cyclic Substitution
Winkler. JACS 1999, 7425
O
TfO
O
42%
OMe
OMe
5 steps
HO
O
O
O
O
O
O
h
O
72%
O
84%
O
O
Cl
Cl
11 steps
h
H
O
O O
O
O
H
O
1. K2CO3
MeOH
2. DBU
O
LiOH,
MeOH;
then
PPTS
H
O
H
O
O
O
O
O
O
O
O
O
O
O
O
H
1. n-BuLi,
Tf 2O
2. (3-furyl)SnBu3
Pd(AsPh3)4
H
O
O
Winkler. JACS 1987, 2850
JACS 2002, 9726
O
TfO
O
O
O
OMe
OTMS
O
O
O
OMe
O
O
O3
OTMS
OMe
OMe
MeO
+
62%
OH
OMe
OTMS
1. pyrrolidine
AcOH
2. TMSI
HMDS
O
MeO
H
H
31 steps
H
TfO
O
O
H
O
Tf 2O
O
O
O
( )-saudin
Winkler's review of 2+2 then fragmentation in synthesis:
Chem. Rev. 1995, 2003
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
Danishefsky. ACIE 2007, 2199
Pearlman. JACS 1979, 6398
O
RO2C
add bond
RO2C
OR
H Et2AlCN
7 steps
CN
CO2Et
h
TBSO
TBSO
O
O
Wender. JACS 1977, 267
CO2R
CO2R add bond
1. NaBH4, CeCl3
2. n-BuLi, CH2I2, Zn
CO2R
+
O
O
O
H
h
1. TPAP,
NMO
2. Li/NH3
H
OH
5 steps
TBSO
TBSO
O
O
OH
Taber. JOC 2001, 1876
OH
paecilomycine A
O
O
H
OPMB
+
retroaldol
O
O
OH
RO2C
OH
N2
R = (CH2)3CO2Et
R
N2
TBDPSO
Covey. JOC 2002, 4893
O
O
[Rh]
O
O
PhSH
OMe
R
TBSO
TBDPSO
1.4:1 dr
H
1. n-BuLi,
crotyl bromide
2. p-TsN3, EtN3
O
O
MeO2C
OMe [Cu]
N2
R
H
O
SPh
HO
1. Mg, CuI
Br
7 steps
R
H
21 steps
MeO2C
H
H
HO
OH
8-F2t-isoprostane
O
H
H
HO
ent-cholesterol
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
Koreeda. Org. Lett. 2004, 537
Pd(OAc)2
PPh3
HOAc
O
4 steps
H
O
O
1. K2CO3,
MeI
2. CHBr3,
NaOH
OH
[Cu]
6 steps
H
N2
O
O
O
H
O
O
OMe
1. NaBH4, CeCl3
2. I2, PPh3, Im
O
OMe
1. HCl
2. DMP
SmI2
H
OMe
OMOM
OMe
O
Br
Br
Br
O
Br
H
H
K2CO3
H2O
SAr
ArS
H
OMOM
O
O
H H
OMOM
OMOM
O
I
O
HS
O
O
O
MeO2C
CO
reflux
OMe
Danishefsky. JACS 2010, 9567
O
O
O
H
8 steps
HO
O
H
O
O
H
O
O
11 steps
O
O ( )-aplykurodinone-1
Crimmins. JACS 1999, 10249; JACS 2000, 8453
H
acanthodoral
OTBS
6 steps
O
Et3SiO
SmI2
h
H
DMDO,
acetone, H2O
then
p-TsOH
O
NTs
NTs
O
4 steps
O
H
H
6 steps
O
H
HO O
HO
NMe
O
O H
H
( )-incarvilline
Et3SiO
CO2Et
O
O
O
O
H
HO
H
O
t-Bu OH
ginkgolide B
O
t-Bu
O
O
HO
O
OH
O
OH
t-Bu
t-Bu
NTs
h
t-Bu
O
H
O
O
H
H
H
O
CO2Et
6 steps
O
Kibayashi. Tet. Lett. 2005, 2327
O
O
O
12 steps
Corey. Tet. Lett 1970, 307
Nakada. Tetrahedron 2006, 8054
N2
CuOTf
BOX ligand
SO2Ar
H2Cr2O7,
(NH4)2Ce(NO3)6
O
5 steps
SO2Ar
O
83% ee
O
H
O
steps
HOAc
H2O
H
CO2Me
CN
NaCN
O
O
1. n-BuLi, then
OEt
O
2. TsN3, Et3N
MeSO2Ar
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
PGF2 , E2
CHO
HO
OH
5 steps
Corey. JACS 1972, 4014
SO2Ar
O
O
O
H
HO
( )-methyl jasmonate
CO2Me
O
3 steps
Srikrishna. Synlett 2007, 655
N2
O
MeO
[Cu]
N2
O
CuLi
H
2
THPO
O
HO
[Cu]
6 steps MeO
H
CO2Me
THPO
O
O
O
OMe
OMe
PG's
O
O
1. Li/NH3
2. CAN
MeO
CO2Me steps
O
THPO
O
OMe
Corey. JACS 1984, 2735
( )-lagopodin A
Srikrishna. Synlett 2012, 1021
Bu3Sn
1. BuLi,
then
Et
H
H
OTs
N2
[Cu]
7 steps
H O
O
H OH H
O
O
H
11 steps
PTSA
O
O
O
O
H
H
O
O
5 steps
H
K2CO3
Et MeOH
OTs
H
11 steps
O
OH
H
H
ent-allothapsenol
O
Et
hydridalactone
Et
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
Wender. JACS 1981, 688
Yamada. T et. Lett. 2001, 9233
OMOM
O
+
Li/NH3
CO2Et
h
Cl
O O
OMe
OMe
OMOM
LDA, then
OH
7 steps
EtO2C
O
OBn
O
O
O
O
O
K2CO3
MeOH
O
OMe
H
+
O
O
Br2
then
Bu3SnH
NH2NH2
KOH
O
BnO
19 steps
O
OMe
200°C
H
H
H
O
OH
O
( )- -cedrene
H
H
H
OH
stolonitriene
Chanon. JOC 1996, 3576
Danishefsky. JACS 2012, 18860
h
+
OMOM
1. PCC
2. H2,
PtO2
OMOM
CO2Et
H
PhSH (neat)
100°C
ultrasound
H
H
1:2
H
22 steps
1. Li/NH3
2. CrO3-DMP
3. LDA, MeI
SPh 4. NaBH4
CH2I2,
Zn, Ag
OH
OH
O
O
O
O
O
OMOM
H
O
H
O
O
5 steps
OH
O
H
O
ceratopicanol
O
O
O
O
maoecrystal V
Review of meta- olefin-arene photocycloadditions:
Chem. Rev. 1993, 615
O
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
Tanaka. JOC 2001, 7107
O
O
O
CO2t-Bu
Corey. JACS 1987, 4717
O
O
N2
O
O
13 steps
1. CrO3-DMP
2. LDA, TMSCl
O
(neat)
O
CO2t-Bu
O
O
O
O
O
O
mCPBA
1. NaBH4
2. NaH, BnBr
3. DIBAL
O
OTMS
O
O
O
OH
Tf 2O
H
OBn
O
Pd(PPh3)4
PBu3
[Cu]
H
6 steps
H
OBn
O
O
O
O
O
O
O
O
O
10 steps
O
O
OH OH
H
H
(±)-cafestol
H
(±)-stemodinone
Chen. Org. Lett. 2011, 5724
TBSO
TMS
Perali. Tetrahedron 2012, 3725
O
O
N2
OAc
7 steps
O
O
OMe
CO2Me
[Rh]
OAc
O
CO2Me
K2CO3
MeOH
H
O
O
O
O
4 steps
OBn
O
( )-longianone
H
TsNHNH2,
TFA
then
HCl
H
O
NO2
OH
H
H
H
O
O
OH
OBn Br
OTBS
O
OH
4 steps
NO2
OBn
O
OTBS
TMS
NBS
H2O/dioxane
H
OBn
OAc
H
Pd(OAc)2
PPh3
7 steps
6 steps
H
H
HO2C
echinopine A
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
Toshimitsu. JOC 2004, 9262
Org. Lett. 2000, 3751
Iwata. Tet. Lett. 1986, 3161
N2
H
O
[Cu]
7 steps
O
O
O
H
MeO2C
LDA,
O
3 steps
H
OBn
MeO
H
O
33 steps
BnO
H
H
O
O
O OBn
H
O
p-TsOH
11 steps
O
O
BnO
O
O
(CH2)4
OEt
TBDPSO
O
O
(CH2)4
TBDPSO
HO
10 steps
O
SEMO
PhI(OAc)2,
I2,
h
O
O
OBn
OH
O
O
SEMO
I
EtO
O
CP-263,114 precursor
O
O
quadrone
Fukuyama. Org. Lett. 2012, 1632
Buszek. Org. Lett. 2009, 201
OH
O
7 steps
Et
Et
O
Et
n-BuLi
N
TBS
NH2
OHC
N
TBS
CHO
2 steps
H
N
H
( )-cis-trikentrin
O
OMe
O
O
O
OBn
O
Et
4 steps
OMe
O
N
TBS
Br
Et
O
O
H
B(OH)2
1. OsO4
2. NaIO4
6 steps
Br
PhI(OAc)2,
MeOH
then
then CSA
O
HO
O
O3
O
27 steps
O
MeO
CHO
OBn
OH
O
O
anisatin
Woodward. T etrahedron 1958, 1
Galano. JOC 2010, 2411
EEO
O3
then
NaBH4
H
9 steps
EEO
O
13 steps
OH
H
+
O
TBSO
MeO2C
H
H
MeO2C
Valenta. Can. J. Chem. 1979, 3346
Can. J. Chem. 1991, 853
O
OAc
AcO
H
BF3 OEt2
+
6 steps
H
H
H
CO2Et
H
O
Br
OMe
O
O
H
O
OMe
OMe
OMe
Li/NH3
h
H5IO6
Becker. JOC 1982, 3297
O
O
add bond
O
O
HO
O
O
~14 steps
O
MeO
H
O
H
H
O
d,l-quassin
O3
Heathcock. T et. Lett. 1975, 529
H
O
add bond
H
h
OMe
O
OMe
Cl
O
Cl
Retro-Claisen
EtO2C
MeO2C
CO2Et
CO2R
O
H
(±)-reserpine
add bond
O
OMe
H
C. Spirocycle synthesis
O
H
OAc
H
OAc
O
H
OsO4
H
then
HO
Zn
then HO
H2S
H
N
N
H H
H
H
H
Oppolzer. Acc. Chem. Res. 1982, 135
O
O
MeO2C
H
1. HIO4
2. CH2N2
H
H
8 steps
H
an isoprostane
OH
9 steps
O
CO2H
HO
O
H
MeO2C
CO2Me
O
OH
OH
O
OH
H
TBSO
O
Cyclic Substitution
January 2013
Overbred Intermediates
Nathan Wilde
O
R
O
N2
O
R
nucleophile
[Cu]
Olefin Metathesis
January 2013
Overbred Intermediates
Nathan Wilde
Mehta. Tet. Lett. 2003, 5243
T etrahedron 1981, 4543
A. Olefin metathesis: [2+2]/retro [2+2]
White. JACS 1992, 9673
O
Br
+
O
O
COOH
h
COOH
DCC
O
O
O
O
1. NaH, (MeO)2CO
2. Br2
3. NaOMe
4. DIBAL-n-BuLi
O
O
H
O
O
12 steps
O
HO
H
OH
HO
pleurotellol
O
O
O
O
O
h
O
R4
O
R3
R1
O
R2
O
O
O
O
O
O
1. LiOH
2. KMnO4
O
O
O
O
2:1 cis:trans
H
H
1. h ,
then Na2CO3
2. CH2N2
3. DBU
4. LiOH
( )-byssochlamic acid
toluene,
O
H
O