JACS Year in Review 1994
Baran Group Meeting
N. Z. Burns
4/27/05
CO2H
Me
This survey of the Journal of the American Chemical Society in the year 1994 (volume 116) is not meant to
be comprehensive by any means.
A strong emphasis has been placed on total synthesis from
this year as opposed to pure methodology. It was an exciting 12 months for natural product synthesis as
two daunting targets, taxol and zaragozic acid, both succumbed to their first construction in a
laboratory. In addition, many extremely creative solutions to nature's many other synthetic challenges posed as of
1994 were revealed. In this handout a small fraction of that is presented. Enjoy!
Me Me
O
Me
Me
O
Me H Me
Me
O
H
Me
HO
O
Me
O
H
O
H
Me
H
Me
(±)-Perovskone
O
O
Me
(+)-Epoxydictymene
Natural products discussed in part or full:
OH
(–)-Chlorothricolide
O
Me
Me
O
HO
MeO
O
Me
Me
Me
O
O
Me
MeO
O
Me
Me
O
Me
Me
Me
O
OMe
O
O HO O
OMe
HN
Me
AcO
Ph
O
OH
OH O
Ph
O
H
H
O
N
O
O
Me
OAc
CO2H
CO2H
HO
Me
H
H
Me
H
Me
NC
H
O
(–)-Hapalindole G
OH
HO
HO
O
O
OH
O
O
OBz
Me
OH
(–)-Paeoniflorin
1
H
H
OAc
O
CO2H
(+)-Zaragozic Acid C
OH OH OH OH OH
(–)-Roxaticin
Me
OH
O
Me
OH
NH
(+)-Xestospongin A
H
H
(±)-Papuamine
Ph
OH
O
Me
Cl
O
H
H
N
H
O
(±)-Fredericamycin A
Me
(–)-Taxol
N
OH
H
N
O
O OH
Me
NH O
Ph
H
Me
Me
(±)-Thielocin A1b
O
OMe
HO
OH
O
O
Me OHOH
O
Ph
Me
JACS 1994
Baran Group Meeting
R. N. Young, 759, (±)-Thielocin A1b
Me
1. Zn-Hg/HCl, EtOH, ∆
2. TMS(CH2)2ONa, ∆
HO
OTMSE 1. PhI(OAc)2, AcOH
TBDPSO
3. TBDPSCl
(50%)
R. A. Holton, 1597, 1599, (–)-Taxol
O
Me
OH
O
Me
OTMSE
Me
HO
2. LiOH, 12-crown-4
THF/H2O (40%)
Me
Me
Me
O
H
OEt
HO
OH
Me
1. HOCH2CCl3, H+
2. (MeO)2SO2, K2CO3
Me
3. Et3SiH, TFA, (52%)
HO
O
Me
(75% conv.)
93%
OH
TESCl,
pyr.
TESO
Me
H
2. phosgene, pyr;
EtOH
75%
B
Me
Me
(98%)
O
OMe
Me
OH
1. (i-Pr)2NMgBr, THF;
OTCE
Me
BF3•OEt2, -80 °C
O
Me 2. Ti(Oi-Pr)4
t-BuOOH
O
(+)-patchino
Me
OH
Me
1. t-BuLi, hexane
reflux
O
A
O
N. Z. Burns
4/27/05
HO
OTES
Me
Me
1. Ti(Oi-Pr)4
t-BuOOH
O
2. TBS protection
Me
OH
93% (3 steps)
1. HOCH2CCl3, H+, 60%
2. (MeO)2SO2, K2CO3, 91%
OTf
TESO
TESO
O
Me
O
H
OTCE
HO
1. Piperidine,
NaCNBH3
Me
N
Me
Me
Me
OTCE
2. TBSCl, NaH
TBSO
3. MeOTf (78%)
OMe
O
1.05 eq. TBAF
Me
OCO2Et
OTCE
then A, –20° - RT
OMe
O
O
Me
1. LDA, THF
(+)-camphorsulfonyl
oxaziridine
Me
Me
O
O
TBSO
2. 20 eq. Red-Al
-78 °C – RT
3. phosgene, pyr.
O
TBSO
OMe
Me
Me
82%
1. Swern
2. LiTMP, -10 °C
86%
mechanism?
95%
TESO
O
Me
O
HO
MeO
O
Me
Me
O
Me
Me
OH
Me O O
O
4. B, Et3N (87%)
5. Cd, DMF/AcOH
82%
OMe
Me
Me
O
Me
Me
O
TBSO
O
OTCE
O
Me OHOH
O
Me
O
O
TBSO
H O
O
R O
KOt-Bu; AcOH
Me
SmI2
R=H
(enol taut.)
LiTMP, Davis
oxaziridine
-40 °C
88%
Me
O
MeO
TBSO
Me
Me
SiO2
O
R=OH
Me
HO
+
6 : 1 ratio
91% overall
OMe
O
1. TFAA, B
2. Cd, DMF/AcOH
3. 0.5 N NaOH
(41%)
H O
TESO
Me
Me
O
1. (Imid)2CO, 95%
O
2. TBAF, DMF, 81%
3. Cl2CHOCH3
TMSEO
O
TESO
Me
Me
Me
O
OH
Me
Me
O
Me
O
MeO
O
Me
O
Me
Me
Me
O
O
Me OHOH
OMe
TESO
OH
O
Me
O
Me
OMe
3
Me
TBSO
OH O
Me
(±)-Thielocin A1b
Me
2
O
H O
1. Red-Al
2. Cl2CO, pyr.
88%
(+ 8% of C3 epimer from purification)
TESO
Me
Me
O
TBSO
O O
O
H O
1. O3
2. KMnO4, KH2PO4
3. CH2N2
93%
JACS 1994
Baran Group Meeting
N. Z. Burns
4/27/05
S. D. Rychnovsky, 1753, (–)-Roxaticin
TESO
TESO
Me
Me
TBSO
O O
OH
Me
Me
O CO Me
2
OMe
1. TsOH,
2. PhSK, DMF
86 °C
LDA, THF
TBSO
93%
H O
H
O O
O
CO2Me
OBn O
3. acid work-up
OH
Br
Me
O
Me
O
O
Me Me
O
LiNEt2
63%
Me
Me
Me
Me
OMe
Me
TESO
OBOM
Me
Me
1. MeMgBr
2. Burgess
TBSO
(60%)
O O
H
1. BOMCl,
Hünig's base
2. LDA, TMSCl
3. m-CPBA
OTMS
TESO
TBSO
79%
O
O
OH
Me
Me
O O
O
H
O
OTBS
TESO
O
Me
Me
O
O
Me
Me
Me
TESO
TBSO
O
H
1. MsCl, pyr
2. OsO4
Me
HO
O
OTBS
OH
65%
O
O
O
H
OH
OMs
OH
Cl
3. Ac2O, DMAP
TBSO
?%
mechanism?
H
OH OBz OAc
O
Me
1. HF•pyr, CH3CN, 0 °C
2. PhLi, -78 °C
TBSO
3. TPAP, NMO
O
1. +S(NEt2)3 Me3Si-F2 (TASF)
2. a) LiHMDS, THF
TESO
Ph
b)
NBz
O
O
H
N
S
TFA
S
O
H
O
S
O
DCM, 5% NaOH
S
H2O
99%
OAc
OAc
MeO
CN
CN
S
42%
OMe
HO
OMe
OH
MeO
NC
Cl
3. HF•pyr.
4. H2, Pd/C, EtOH, reflux
87%
LAH, 92%
AcO
O
NH O
Ph
Me
1. LAH, 78%
2. TFA, H2O
3. DCM, 5% NaOH
(70%)
O OH
Me
O
OH
O
Me
Cl
OBOM
Me
85%
Ph
O
HO
O
O
O OBOM
Me
H
OH OBz OAc
OBOM
Me
O
Me Me
H2N
Cl
OMe
TESO
O
O
T. R. Hoye, 2617, (+)-Xestospongin A
2. Ac2O, pyr.
(62%)
OMe
Me
O
Me Me
(–)-Roxaticin
O
1. KOt-Bu, -78° – 0°;
(PhSeO)2O , 0°
2. KOt-Bu, -78 °C
O
O
Me Me
OH OH OH OH OH
1. DBU, 105°
TBSO
O
Me
OBOM
Me
Me
Me
OH
O
Me
O
OBOM
Me
Me
TBSO
O
Me Me
2. LIDBB, 63%
O
Me
Me
AcO
O
1. LiNEt2, 91%
CN
O
Me
Me
O
Me Me
O
Me
O
Me
CN
O
Br
O
O
92%
Br
2 eq. O
NC
OtBu
OH O
Ph
O
(–)-Taxol
H
O
OAc
N
3
O
H
H
O
(+)-Xestospongin A
N
RaNi, H2
69%
N
O
S
S
O
N
JACS 1994
Baran Group Meeting
N. Z. Burns
4/27/05
W. Oppolzer, 3139
T. Fukuyama, 3125, (–)-Hapalindole G, 3125
∆
1.
Me MeO
Me
O
HOHN
O
OH 2. ArSO2N3, DBU
(95%)
H
Cl
Me
Me
O
Cl
Me
O
60%
OMe
H
O
Me
Ph
Me
1. DIBAL;
NaBH4, EtOH
LDA, Ti(OiPr)4
Me
O
68%
Cl
2. Zn-Cu
3. Jones [O]
(67%)
I
HO
O
H
Me
Me
H
Cl
Me
Li
Me
O
H
I
1. Pd, CO
Me
O
H
2. DPPA, Et3N,
allyl alcohol
(72%)
NHAlloc
O
S
Cl
Me
SMe
Me
H
Me
O
Me
Cl
NC
H
NH
Ac2O, Pyr
2. COCl2, Et3N
(76%)
Me
Me
CO2Me
O
H
CO2Me
MeO
CO2Me
59%
(6 other examples, 40–73% yield
pronucleophile pKa ≤ 16)
CO2Me
H
CO2Me
MeO
N3
O
50 mol % NaOAc,
Toluene, 80 or 110°
mechanism?
Me
H
35 mol % PPh3,
50 mol % AcOH,
CO2Me
MeO
1. Na/Hg; HCO2H, Me
N
H
B. M. Trost, 3167
NAlloc
Me
H
Me
O
O
H
–78°; aq. HgCl2, HClO4
69%
Ph
O N
H
Me
H
Me
1. NaBH4
2. Ms2O, Pyr
3. LiN3
(72%)
Cl
N
O
Me
Ph
Me
Me
Ph
Me Br
1. Ac2O, Pyr, 60°
2. DBU, PhH, ∆
3. TFA/MsOH (10:1)
(88%)
Cl
Complete diastereocontrol
Me
H
80°, 81%
HOHN
Cl
HO
N
HO
I
O
Me
HOHN
1. LiCl, CSA, DMF,
140°
2. LDA, CBr4
(56%)
Stepwise-radical or concerted process?
n
Ph
H
80°, 81%
Me
O
N
HO
Ph
O
Me
N2
Me
n
Me CO2Me
Cu(II)
O
Me
PPh3
CO2Me
PPh3
CO2Me
CO2Me
CO2Me
PPh3
NH
CO2Me
CO2Me
(–)-Hapalindole G
pdct.
4
CO2Me
PPh3 CO2Me
CO2Me
PPh3 CO2Me
JACS 1994
Baran Group Meeting
N. Z. Burns
4/27/05
G. Majetich, 4979, (±)-Perovskone
S. Hatakeyama, 4081, (–)-Paeoniflorin
OMe
Br
TBSO
O
O
Me
Li
1. TBSO
O
H
Me
2. PivCl, Et3N
3. TsOH, MeOH
Me
Me Me
HO
TMS
1. NaOH, MeOH, ∆
2. CH2N2
3. Swern
(86%)
3. LAH
4. PhCOCl
5. Swern
(35%)
O
Me
MeO2C
Me
hv, 64%
OBz
optically
pure
O
2. PhI(OAc)2, I2, hv
(92%)
OBz
CN
Me
1. HCl/Dioxane
2. (COCl2)
3. HO N
BnO
BnO
1.
(6 eq.)
O
O
OH
OBz
O
O
Me
OH
(–)-Paeoniflorin
Me
Eu(fod)3
45°, 72 h;
110°, 48 h
Me Me
O
O
O
OBz
Me
O
Me
Me
Me
Me
Me
O
O
Me
Me
Me
Me
(±)-Perovskone
OH
Li
1. BnOCOCl
2. O3, MeOH/DCM
3. p-NO2PhCOCl
Et3N-DMAP
(43%)
Me
H
H
OTf
O
Me
Me H
H
EtO Me Me
74%
H
TMS
H
1. Co2(CO)8
O
EtO Me Me
H
TMS
2. TMSOTf
73%
H
CCl3
NH
18 eq. BF3•Et2O
2. H2, Pd(OH)2
(67%)
Amberlyst ® 15,
DCM, ∆, 30 min,
90%
O
Me Me
O
S. L. Schreiber, 5505, (+)-Epoxydictymene
O
BnO
O
Me
Me
Me
Me
mechanism?
HO
HO
Me
O
OBn
OH
OH
Me
82%
S
4. O2, hv
(54%)
mechanism?
O
O
Me
Me
Me
Me
Me
Me
CO2Me
Me
O
O
O
Me
O
Me
O
Me
Me
Me
O
ene
Me
O
MeO2C
1. TMSCN, KCN
O
18-crown-6
then 0.1 N HCl
Me
Me Me
HO
Me
Me
O
HO
HO
Me
Me
Me
OMe
1. CAN
2. H+ or HO–
(99%)
Me
Me
2. NaSEt, DMF
(48%)
Me
Me
(55% overall)
1. NaBH4; R*CO2H
2. separate
Me
O
4. TMSOTf
OH
MeO O
OMe
CO2Me
OH
1. TsNHNH2,
NaBH3CN
Me
OMe
30%
Me
HO
OMe
Me
9 Steps
PivO
1. Swern
2. NaClO2
3. CH2N2
PivO
MeO
O
OMe
HO
OBz
O
O
Co(CO)3
Co(CO)3
O
Me
Me
CH3CN, ∆, air
85%
Me
HO
NC
Me H Me
OCOBn
H
Me
H
O
H
5
Me
H
(+)-Epoxydictymene
1. PPh3, I2, 81%
2. tBuLi, 74%
3. K, 18-crown-6
82%
O
Me H
H
Me
H
O
H
H
9 steps, 20%
Me H
H
Me
Me
O
H
H
Me
JACS 1994
Baran Group Meeting
W. R. Roush, 6457, (–)-Chlorothricolide
N. Z. Burns
4/27/05
S. M. Weinreb, Papuamine
OTBDPS
TBDPSO
O
Me
TMS
Me
O
10 Steps
O
2 eq.
32%
CO2All
CO2Me
O
H
OTr
O
tBu
O
120°, 40-45%
H
tBu
O
OAc
1. Me2PhSiLi, CuCN
2. TsOH, MeOH
H
3. MsCl; KCN
4. DIBALH
(46% overall)
H
CHO
SiMe2Ph
NH2
1. H2N
PhMe, ∆, 16h
70%
2. TBAF, 74%
mechanism?
CO2All
Me
Me
H
TMS OMOM
TMS OMOM
H
N
H
N
H
H
H
H
H
1. Bu3SnH, AIBN, ∆
H
1. K2CO3, MeOH
2. DCC, DMAP
HO2C
O
H
N
H
H
H
N
H
H
2. PdCl2(PPh3)2
DMF, O2, RT
(38%)
H
H
H
H
H
Papuamine
(91%)
OTBDPS
OTBDPS
OTBDPS
Me
Me
Me
O
PO
O
O
O
PO
BOP-Cl
O
100°, 50%
Me
P = MOM
TMS OMOM
R. D. Bach, 9921, (±)-Fredericamycin A
OTMS
O
O
OH
CO2H
1. LHMDS, –78°
then MOMCl
MeO
OH
EtSH, SnCl4
Me
TMS OMOM
HO
O
O
Me
O
1. ethylene glycol
2. NBS
3. MeI, KH
(93%)
0.48 eq CI4
THF, –65°
O
EtO2C
O
1. nBuLi; ClCO2Me
MeOO
O
Br
2. LiTMP; CuCN;
O
Me
Me
N
1.05 eq NaH
O
O
O
O
Me
Cl
(59%)
OMe
O
1.
O MeO O
CO2Et
O
HN
N
Me
53% isolated
(best yield for oxindole
oxidative coupling)
Me
O
O
OMe
2. NaOEt/EtOH, –78°, (78%)
3. 3 eq. BBr3; air, 80%
6
OMe
HO
O
NC
OMe
LDA, –78°
Me
"...routinely afforded ~ 100mg
of the fredericamycin A precursor"
OH
(–)-Chlorothricolide
O
O MeOO
Me
R. Rodrigo, 9480
N
Me
Me
mechanism?
3. 1 eq PTT
(39%)
O
O
Hg(OTFA)2,
–40° - RT, (54%)
Me
1. NH3, MeOH, 70°
2. HCl/CH3CN, ∆
O
OTMS
TMS OMOM
EtO2C
O
HO O
SEt
Me
1. HF–Et3N
2. MnO2
3. NaClO2
4. BF3•Et2O, EtSH
(68% overall)
CO2H
Me
HO EtS
O
OAll
CO2All
2. Pd(PPh3)4,
dimedone
(88%)
Me
OO
O HO O
HN
OH
O
(±)-Fredericamycin A
JACS 1994
Baran Group Meeting
E. M. Carreira, 10825, (+)-Zaragozic Acid C
O
HO
D. A. Evans, 12111, (+)-Zaragozic Acid C
OEt
Et
1. Me2NH, MeOH
2. (MeO)2CEt2, H+ Et
O
HO
1.
O
O
O
Et
Et
Li
2. TMS
OBn
OBn
3. O3, (71% overall)
Et
O
3. HCl, MeOH
4. TBSCl
OH
TBSO
OHC
OTBS
OTMS
O
OBn
OTBS
OHOH
O
OPiv
Me
Ph
46%
BnO
O
OPiv
t
OBn
3. DMP
4. NaClO2; tBuiU
(63%)
O
H
OH
OAc
AcO
OH
Me
O
AcO
1. HF•Pyr
2. DMP
t
BuO2C
3. NaClO2; tBuiU
(64%)
OPiv
OAc
O
OH
Me
HO
t
BuO2C O
OTBS OAc
O
R OBn
O
CO2tBu
Ph
Me
OTBS
OAc
O
CO2tBu
Ph
Me
1. O3
2. DMP
3. NaClO2; tBuiU
4. K2CO3, MeOH
(67%)
Ph
O
OH
Me
HO2C
HO2C
O
O
CO2H
OH
(+)-Zaragozic Acid C
OAc
Ph
Me
2. TFA, quant.
HO
t
BuO2C
t
BuO2C
OH
O
OH
O
CO2tBu
3,
Ph
OH
O
O
O
CO2H
OH
(+)-Zaragozic Acid C
OAc
Ph
Me
Me
Me
7
N
H
OtBu Me
N
Me
OtBu
1. DMP
2. vinylMgBr
3. OsO4, NMO
4. Pb(OAc)4
O
CO2tBu
R = CO2tBu
1. TPAP, NMO
2. O3
OH OTBS
O
O
O
3. NaClO2
4. tBuiU
(55% overall)
20:10:1 DCM/TFA/H2O
R OBn
CO2tBu
tBuiU
Ph
Me
HO2C O
OH OAc
HO
R' OBn
HO
R' = CO2H
CO2H
BnO
t
3. TBAF
4. TFA
(77%)
Ph
1. tBuiU
2. TBSCl
(52%)
1. H2, , Pd/C,
750 psi
2. RCO2H, DCC,
DMAP
OAc
Me
HO2C
HO2C
O
Ph
R OBn
CO2tBu
O
Me
Ph
O
O
1. DMAP, RCOCl
87%, 1:3 favoring
undesired ester
t
Ph
2. DDQ; Ac2O
(66%)
OPiv
O
O
OTMS
, TsOH
O
BuO2C O
OTBS
O
R OBn
O
CO2tBu
OPMB
Me
O
3. DIBALH
4. Ac2O
(59%)
OTBS
Ph
O
CO2tBu
Ph
Me
OH OTBS
(iPrO)TiCl
2. LHMDS, TMSCl
(82%)
OH
H
1. PivCl
2. Pd(OH)2, H2
3. Swern
(86%)
Me
PivO
Li
TBSO
1. TMS
2. AgNO3
OAc
O
OAc
TBSO
O
OAc
Ph
OBn
OMe
CO2tBu
BuO2C
1. Li
OTBS
AcO
1. Cl2CHCO2H
TBSO
2. H2/Pd–C
OMe
1.
30 - 40 g scale
Ph
O
H
3. LiBH4, MeOH
4. Swern, (88%)
O
OH
OPiv
TBSO
3
OBn OH O
OH
OTBS
–78° to –40°
76%
OTBS
OTMS
O
O
2. DMP
3. [Cr(OAc)2•H2O]2
(52%)
HO
Et
Et
OPiv
Ph
3
Ph
3
Me
O
1. NaBH4, MeOH
2. K2CO3, MeOH
3. TBSCl; TMSCl
(69%)
1. nBuLi, LiBr; Me
1. TBAF
2. Sharpless AD Et
O
TMS
OBn
N
Ph
MgBr
1. Bu2BOTf, Et3N
cinnamaldehyde
2. TBSOTf
O
Me
O HO CO2Et
O
NMe2
3. NaH, BnCl
(86%)
N. Z. Burns
4/27/05
BuO2C
t
BuO2C
OTBS
O
OH
O
CO2tBu
OAc
Ph
Me