Nathan Wilde
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
1986 was an eventful year:
- The UN designated it the International Year of Peace.
- Atomic force microscopy was first described.
- The Chernobyl nuclear power plant exploded.
- Argentina beat West Germany in the FIFA World Cup in Mexico City.
- The Mets beat the Red Sox in 7 games in the World Series.
- March 28: The world changed forever with Lady Gaga's birth.
- Herschbach, Lee, and Polanyi won the Nobel Prize in chemistry for studying the
dynamics of chemical elementary processes.
- At least three current Baran labbers were born.
Journal of Organic Chemistry 1986
- 5505 pages.
- 1344 articles, communications, and notes.
Authors with the most papers:
General Comparing and Contrasting 1986 and 2013
- K. Houk had multiple JOC and JACS papers on computational theoretical chemistry
in 1986 (and one in Science!). This has not changed.
- There was quite a bit of aryl-aryl coupling with Pd, only instead of boronic acids
they used organo-thallium or mercury compounds.
- There were many papers describing NMR studies on molecules. This seems more
rare today.
- There was a whole field on the synthesis of various crown ethers and the study of
host-guest interactions. Not so much in today's JOC.
- There was a ton of papers on nothing but photochemistry.
- There were many "studies towards" syntheses where they couldn't form
macrocyclic rings. We have made a lot of progress in that regard.
Suarez Decarboxylation
RCO2H PhI(OAc)2
Suarez, 402
I2
(RCO2)2IPh
2RI + 2CO2
2RCO2I
-IPh
1. Brown HC (25)
2. Clardy J (11)
3. Faulkner DJ (8)
4. Marshall JA (8)
5. Paquette LA (7)
O
I
Me
Me
Important Papers:
1. Trost, 2370. Description of determining the absolute configuration of secondary
alcohols using mandelate esters. 652 citations.
2. Sharpless, 1922. Sharpless lets us know that we need molecular sieves if we want
our asymmetric epoxidations to actually be catalytic in Ti and tartrate. 418 citations.
3. Wilkes, 480. Friedel-Crafts reactions in ambient temperature molten salts. 354
citations.
4. Dalcanale, 567. Selective oxidation of aldehydes with NaClO2 and H2O2. 333
citations.
5. Noyori, 629. How to make non-racemic BINAPS. 331 citations.
Also: Molander introduced a lot of the reactivity of SmI2. 1135, 1778, 2596, 5259.
Best Title Award:
AcO
Me
Me
OH
Me
Me
PhI(OAc)2
I2
H
h
CCl4
reflux
Me
OH
Me
AcO
O
Me
H
OH PhI(OAc)2
I2
h
CCl4
reflux
Me
Me
Me
60%
"Total synthesis of a slightly unnatural product. Confirmation of the stereostructure of
the archebacterial C40 diol by synthesis of a stereoisomer." Heathcock, 4322.
94%
H
O
Me
Me
Me
O
Me
I
O
Me
+
Me
Me
10%
O
Me
Me
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
Synthesis of Compactin
Keck, 2487
HO
THPO
OMe
Me
HO
1. LAH
2. I2
3 steps
H
Me
C
Me
C
O
N
O
Cyclooctenes
k cis/k trans
Me
"Rebek peracid"
Me
Me
tBu
"vinylallene"
75%
Me
O O
Me
PPh3
Me
H O
OEt
O
N
O
Me
O
nBuLi, TsCl;
OLi
PPh3
O
C
Me
HO
Rebek, 1649
Selective Peracid Epoxidation
tBu
tBu
Et Et
k cis/k trans
Et
k cyclic/k acyclic
k endo/k exo
Me
OAc
OH
OAc
h
2. TBSCl
3. O3
9 steps
O
MeO
O
OAc
O
OTBS
SnBu3
1.
MeO
O
TBSO
2.2
mCPBA
1.2
1.0
0.84
1.1
Rigby, 3298
4 steps
AcO
OMe
H
OH
H
84%
C
55%
36%
AcO
O
R = OMEM
Me
OMe
Br
LDA
OMe
R
1. Me2CuLi;
H3O+
O
2. NaH, toluene
reflux
O
66%
HO
Me
O
H
O
Me
H
R
48%
Me
O
O
O
Me
O
Me 2
Me
1.
2. aq. HCl
3. Ag2CO3, celite
R
O
O
1.
2. LiB(sBu)3H
H
1:1 mix of
diastereomers
3.2
O
O
"vinylallene"
74%
7.8
O
OMe
O
7.7
Towards Ingenol?
OPh
S
TBSO
"Rebek peracid"
Me
(+)-compactin
H
1. TMSCl,
NaI
2. PDC
56%
O
Me
O
O
H
H
Me
Me
HO
Me
Me
HO
HO
ingenol
OH
Convergent Vitamin A Synthesis
Me
Me
Otera, 3834
SO2Ph 1. nBuLi, then
Me
OAc
Me
2. EtOCHCH2, H
Me
Me
Me
Me
O
Me
Boger, 3250
N N
Me
E
MeO2C
E
9 steps
CO2Me MeO
N N
OEE
100°C, 71%
MeO
Me
O
TBSO
Me
OTBS
N N
OH
38°C
MeO
N N
OAc
+
Diels-Alder Reactions of Heterocyclic Azadienes
Me
SO2Ph Me
O
Me
MeOK
cyclohexane
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
230°C,
NAc
NAc
83% yield
95:5 all trans : any cis
82%
Me
MeO
vitamin A
MeO
O
1. AcOH
2. MnO2
3. NaOMe
O
N3
O
O
OMe
MeO
O
Baeyer-Villiger Alternative
OH
Me
cat. TsOH
10 eq. H2O2
H
O
O
xylene
N3
Boger, 5436
NAc
Me
MeO
OH
reflux
56%
HN
NAc
1. HCl, MeOH
2. NaBH4
3. H2O2, Ac2O
Me
MeO
O
O
Me
H2N
OMe
mCPBA
HN
OAc
OH
Me
OMe
OMe
NAc
MeO
OMe
OH
CC-1065
N
PDE-II
1. cat. TsOH
10 eq. H2O2
O
OH
OBn
Me
2. BnBr
86% (2 steps)
OH
NH
60%
OMe
O
N
O
O
OMe
Me
NH
N
OMe
O
N
H
O
OMe
Minisci Reaction: Polar Effects
N
CO2Me
O
N
60°C
Bn
51:49
N
Bn
N
CO2Me
OHC
NH
CO2Me
1. AgBF4
then LiBr
2. DBU
CN
N
O
OAc
MeO2C
H
H
O
H
N
MeO2C
O
CO2Me
OSEM
O
MeO2C
1. LiBHEt3
2. TBSCl TBSO
3. mCPBA
MeO
O
MeO
O
MeO2C
OAc
O
MeO
O
OSEM
Me
5 steps
PhS
O
O
H
OSEM
Me
O
lycorine
N
O
MeO
O O
H
O
OSEM
Me
OMOM
KHMDS
TESCl
O
HO2C
Me
O
MeO
O O
H
O
O
OSEM
Me
OMOM
1. Cl2POOPh
PhSeH
2. Bu3SnH
AIBN
O
MeO
O O
H
O
Me
Me
OMOM
AgTFA
Na2HPO4
O
O HO
MeO
O O
H
Me
Me
N
O
HO
TBSO
O
O
MeO
OSEM
Me
"acid
chloride"
DMAP
Me
1. LiMe2Cu
2. SEMCl
TBSO
3. H2, Pd/C
O
BnO
OAc
O
LiHMDS
then
OBn MeOSO F
2
O
OH
HO
H
O
1. butadiene
2. MeOH
3. CH2N2
OMOM
O
O
O
mechanism?
OAc
O
O
BnO
HClO4
then KCN
O
CO2Me
O
O
Boeckman, 3740
O
OBn
O
18:82
1. K phthalimide
2. Fe(CO)5
3. OsO4, NaIO4
4. MeO2CCH2CO2H
5. NH2NH2-nH2O
O
"acid chloride" H
O
Towards Lycorine
Cl
Me
7
Explanation: Subsequent H abstraction is faster in H2O. This might be because of
HSAB theory applying to radicals.
tBu
O
O O
perkadox 16
O O
O
tBu
O
20 steps
Me
toluene
perkadox 16
MeCN/H2O (1:1)
60°C
"Epimerization of the C-7 center
was delayed ... For the sake of
convergency, we felt that
inversion of this center be
completed as early as possible."
COCl
H
H
N
Bn
O
Ireland, 635
Towards Chlorotricholide
Minisci, 476
Bn
toluene
perkadox 16
N
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
OMOM
OMOM
Formal Synthesis of Asperdiol
Marshall, 858
H
O
9 steps
O
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
O
O
Me
Me
BnO
SO2Ph
"sulfone"
I
Me
1. p-benzoquinone
2. h
5 steps
OTBS
Me
"sulfone"
H
Me
OTBS
H
O
H
HO
not this
H
Me
Me
Me
BnO
SO2Ph
1. DIBAL
2. BnBr
3. TBAF
4. I2, PPh3
Me
Me
BnO
OTBS
SO2Ph
1. KHMDS
18-c-6
2. Na, NH3
3. PhCOCl
H
I
Me
Me
OBz
OH
Pyridone Synthesis
H
Ph
O
Me HO
Me
Ogliaruso, 1544
Ph Ph
Ph
Me HO
Me
Me
Ph
H+
NaN3
Ph Ph
N
N
NH
Me
tBuOK
MeI
Ph
Me
O
Me
asperdiol
+
H
Mechanism
Taylor, 101
O
H3O+
N
O
H
OBn
CO2Me
25%
H
FVP
25%
O
NaBH4
O
700°C
46%
OTBS
Me
69%
CO2Et
88%
O
CO2Et
H
H2, Pd/C
CO2Et
PPh3
O
(EtO)2P
O
O
CO2Me
1. PPh3
2. KHMDS
ClCO2Me
Marchand, 1897
Synthesis of 1,3-Bishomopentaprismane
OAc
NO
N
N
O
N
N
Discovered during
functionalizations of
2-nitrosopyridine
N
Ph
Ph
NMe
Me
Ph
OH
Me
O
Ph
N
N
NMe
Ph
O
Ph Ph
N
NMe
Me
O
Milbemycin Synthesis
N
Me
Barrett, 4840
Me
nBuLi
(3 eq)
O
NHTs
H
N
Me
OH
H
N
Cy
Me
O
SO2Ph
7 steps
Cy
Me
O
(+)-citronellene
Me
N
other
isomers
O
[3,3]
N
O
Me
Me
Me
Me
73%
resolution and separation of
diastereomers. They commented:
"While on an analytic scale resolution
was straightforward, preparative HPLC
was at best synthetic lunacy."
N
O
Me
82
Me
14
4
15
81
4
Me
Me
[3,3]
O
O
O
C(OMe)3
Me
OTBS
Me
Me
Me
Me They had another route that involved a
O
Kurth, 1377
Me
"sulfone"
Me
4 steps
Me
Aza-Claisen Utility
Me
O
Me
O
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
O
O
MeO
N
H
O
75%
8 steps
O
O
Me
Me
+
then H
84%
O
nBuLi
"sulfone"
PhO2S
Me
Me
O
O
O
3 steps
CO2Et
CO2Et
O
S
47%
CO2Et
OAc
S
CO2Et
Me
OTBDPS
OTBS
O
Me Me
OMe
nBuLi
O
Conjugate Reduction
O
Me
Me
then TFA,
TBAF
MacDowell, 183
250°C
E:Z = 5:3
Me
OTBDPS
CO2H
Mechanism
OTBDPS
Me
O
OTBDPS
O
O
Me
O
O
O
O
O
Me
OMe
(+)-milbemycin
O
Me
"MeCu"
DIBAL
H
H
H
1. KH, 18-c-6
Me
2. DEAD, PPh3
3. NaSEt
H
THF/HMPA
5:1
-50°C
H
O
H
HO
Me
Me
H
84%
Me
Me
H
Me
Saegusa, 537
+
H
H
H
H
H
O
6%
"MeCu" is premixed MeLi with CuI. No mechanistic explanation is offered.
Me
3
OH
Me
Tufariello, 3556
Lolium Alkaloid Synthesis
"These alkaloids have not yielded to the thrusts of several synthetic attempts,
although the skeleton has been assembled."
OMe
O
CO2Me
HO
CO2Me
MeO
HO
OAc
OTBS
TBSOTf
PPh3
CO2Me
nBuLi
iPrCHO
N
OAc
OH
N
1. Jones
2. H+, EtOH
3. NH2NH2
4. RONO
5. LAH
OTBS
O
TBAF
Me
Me
PPh3
Me
OMe CO2Me
OH
NaOMe O
N
O
O
OMe CO2Me
MeO
OH 1. MsCl
2. H2, Pd/C
N O
Cl
Kozikowski, 3400
Phosphonosilylation/Wittig
N
N
N
MeO
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
O
6 steps
1. TBSOTf,
PPh3
2. nBuLi
H
nPrCHO
Me
TBSO
OTBS
CO2Me
DMAD
81%
NHMe
CO2Me
79% overall
N
98%
nPr
nPr
O
HCl
CO2Me
loline
CO2Me
nPr
Chiral Directed Lithiation
N
Gawley, 3076
tBuLi
O
N
N
Li
N
N
Me
90% yield
90% de
Me
MeO
N
O
1. tBuLi
2. MeI
N
Me
Me
O
PPh3
N
Me
NH2NH2
O
LDA
R'CHO
100%
PPh3
RCHO
R'
R
Me
93%
Me
EtO P
EtO
R
R = R' = Ph : 70% yield
R = R' = nPr : 83% yield
R = nPr, R' = Ph : 20% yield + other products
Me N
Ph
MeO
MeO
O
EtO P
EtO
LiP(O)(OEt)2
Me
MeO
MeO
Minami, 3572
O
Me N
Me
Me
MeO
MeI
O
One-Pot Diolefination
Ph
DMAD
MeO2C
CO2Me
MeO2C
CO2Me
NH (+)-salsodine
Me
Ph
Ph
Deoxygenation
Leone-Bay, 2378
O
Me OH
Ph2PLi
Me
Me
Me
Ph2P
Halide Reduction
Me OH
MeI
OH
Me
R-X
Ph
Me
DMBI+ X-
O
72%
O
EtO2C
R
CO2Et
N
50°C R
N3
R
silica R
N
N
Rh2(OAc)4
93%
"Furthermore, the possibilities of dihydropyridines as practical reducing agents in
organic synthesis seem to be somewhat low because of their poor reactivity and
their instability is a disadvantage to their use."
-Oxidation of Iminium Groups
CO2Et
R
O
NH
O
O
Me
Polymer-Supported LAH Reduction
H
Frechet, 3462
tBuNHOH
Me
Me
1-x
x
N
Cl
HO
OH
O
Me
-15°C
Me
Me
ArO
ArO
H
Al
Me
N
O Li
Ph
Ph
DF = 28-35%
33% ee
84% yield
tBu
O
R
H
R
O
Cl
Me
DF = 9%
78.8% ee
97% yield
Me
N
tBu
H
Me
Ph
LAH
ArOH
l-ephedrine
N
Me
1-x
x
Ph
Ph
Coates, 1383
CO2Et
R
R
1-x
80%
NH
N
x
H
Cl
R
R
R
N N
DMBI
H
This reagent was originally used to isomerize olefins through their respective
epoxides. Cis-cyclooctene to tr ans-cyclooctene. Fuchs, JOC 1973, 1178.
Sha, 1120
EtO2C
O
O
Br DMBI
1,2-dehyrdoisoquinoline Synthesis
+ R-H
Me
DMBI
all one-pot
X
N
Me
Me
O
N
N
O
Me OH
Me
N
Ph
OH
Chikashita, 5400
Me
Me
MePh2P
OH
MePh2P
Baran Lab GM
May 2013
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
R
O
varied
functionalization
R
O
N
O
tBu
O
[3,3]
H
Me
tBu
H
Me Me
Me
N
Me
23 citations. Sorensen used it in a synthesis of fumagillol; he called this an "underutilized method." ACIE 1999, 971.
Year in Review: Journal of Organic Chemistry 1986
Nathan Wilde
Towards Ikarugamycin
O
H
H
1. LDA, TMSCl
2. O3, then DMS
3. MeOH, H+
OMe
H
H
O
ArSO2Cl, then
DMAP,
O
H3N
OMe
NHAlloc
MeO
H
Me
O
Me
O
H
O
MeO2C
H
NHAlloc
H
O
1. H+
2. tBuOK,
Me
O O
(EtO)2P
OMe
MeO2C
NHAlloc
H
H
O
OK
Me
O
O
N
H
Me
O
1. Pd(PPh3)
2. H2, Pd-BaSO4,
quinoline
3. ArCHO,
NaBH3CN
H
Me
O
O
H
MeO2C N Ar
H
HN
PhMe,
H
O
N
H
O
OH O
O
H
H
MeO2C
H
9 steps
H
H
O
Boeckman, 5486
MeO
H
OMe
O
HN
O
N Ar
KOtBu
O
H
H
N Ar
H
OMe
HN
OH O
O
Me
HH
H
Et H
H
O
H
N
OMe
H
HN
O
ikarugamycin
Baran Lab GM
May 2013