JACS 1982:
A Survey of Papers with a Focus on
Synthetic Organic Chemistry
Baran Lab Group Meeting
15 October 2003
Carlos A. Guerrero
Reagents and Methods
R1
R2
[H]
N O
Me
N O
Me
R1
R2
Me
PhNCO,
Et3N
O
N
O
Me
R2
R2
[H]
NH
OH
R1
OH
R1
H2O
O
Me
NH
Me
OH
R1
R2
By 1982, the [3 + 2] cycloaddition of alkenes and nitrile N-oxides was well known. However, this chemistry had never been
applied to the synthesis of b-hydroxy ketones.
The major obstacle to implementing this reaction as an aldol equivalent is over-reduction to give the b-amino alcohol.
Curran found that catalytic Rany nickel under an H2 atmosphere and addition of a buffer cleanly give imino alcohols that
readily hydrolyze to give the desired compounds. Syn and anti ratios are never a problem because 1) the cycloaddition is
syn and 2) the alkene geometry is fixed.
D. P. Curran. 4024.
Reagents and Methods
Me2AlCl mediated heteroene reactions of aldehydes and alkenes:
Cl
O
R
AlMe2Cl
O
Me
R
Al
Me
OH
Me
H
R
The reaction of methylenecyclohexane with certain aldehydes demonstrates the utility of this reaction:
aldehyde,
Me2AlCl
R
R = Me (91), R = i-Bu (74), R = Ph (69), R = H (80), R= t-Bu (93)
OH
The moderate to high yields obtained highlight the mild nature of this transformation. Other protic or Lewis acids usually
isomerize the alkene.
1, 1-disubstituted alkenes are most reactive. Ene reactions with tri- and tetrasubstituted alkenes also occur readily, but due
to their slower rates, two competing reactions may take place. The first, methyl addition to the aldehyde, occurs with
hindered and aromatic aldehydes. The second, aldol reaction, occurs with some aliphatic aldehydes. Alkenes which would
give a secondary carbocation do not react with aldehydes other than formaldehyde.
B. B. Snider, D. J. Rodini, T. C. Kirk, R. Cordova. 555.
Reagents and Methods
The Evans asymmetric alkylation reaction was discovered in 1980. The focus of his paper in 1982 was transformations of the
imides that resulted after the reaction.
M
O
O
O
O
R
N
O
O
O
R
N
O
O
O
R
N
O
O
E
N
E
i-Pr
i-Pr
O
O
O
O
R
N
ROLi
O
R
RO
E
O
O
O
R
E
LiAlH4
R
RO
E
E
i-Pr
O
R2BH;
[O]
N
O
O
O
Me
O
O
Me
D. A. Evans, M. D. Ennis, D. J. Mathre. 1737.
1. O3
2. NaBH4
N
Me
Ph
i-Pr
O
N
i-Pr
O
R
i-Pr
E X
Me
i-Pr
O
O
Me
Reagents and Methods
Davis oxaziridines: reagents that serve as chiral sources of electrophilic oxygen:
O
N
Ar
R SO2 H
O2 O
S N
R
R, R
H
Ar
S, S
The oxaziridines are made in the following way:
R SO2HN2
+
EtO OEt
Ar
O2
R S N
m-CPBA
Ar
chiral (diastereisomeric)
oxaziridines
ee's for sulfide oxidations are modest (maximum of 46%). However, the reagents have been applied to asymmetric
hydroxylation of enolates. In the case of a chiral enolate (Evans imide), the R group does not need to be chiral.
F. A. Davis, R. H. Jenkins Jr., S. B. Awad, O. D. Stringer, W. H. Watson, J. Galloy. 5412.
Reagents and Methods
a-Lithiomethylenetriphenylphosphorane, a Highly Reactive Ylide Equivalent
Ph
Ph
P
Ph
Ph
Li
Ph
P
Ph
Li
The reagent is generated by treating methyltriphenylphosphonium bromide with 2 eq. of s-BuLi or by treating methylenetriphenylphosphorane with 1 eq. t-BuLi.
Reactivity:
Ph
Ph
P
Ph
OLi
PhNCO, 1st eq.
Ph
PPh3
OH
PhNCO, 2nd eq.
Ph
Li
Ph
Ph
P
O
Ph
C5H11
Ph3P
LiO
Li
E. J. Corey, J. Kang. 4293.
Ph
Ph
C5H11
PhCHO
C5H11
HO
Structure Determinations
Vancomyin:
Me
Me
H2N
Me
OH
HO
O
OH
O
O
O
HO
O
N
H
O
NH
O
Cl
O
H
N
O
O
HO
O
HO
C. M. Harris, T. M. Harris. 4293.
OH
OH
N
H
Cl
H
N
O
CONH2
OH
O
N
H
NHMe
Me
Me
Structure Determinations
OH
1: palytoxin
O
O
OH
OH
OH
O
OH
OH
O
Me
HO
OH
OH
HO
OH
OH
H2N
OH
OH
OH
OH
O
HO
N
H
O
N
H
Me
OH
Me
HO
OH
O
OH
OH
Me
Me
O
O
OH
H
OH
HO
Me
OH
O
OH
OH
HO
"Palytoxin can now be defined as structure 1!"
Y. Kishi, D. Uemura, Y. Hirata, et al. 7369.
OH
OH
HO
O
OH
O
OH
H
OH
OH
OH
OH
HO
Me
OH
OH
OH
Total Syntheses
CO2Me
Me
O
five steps
CO2Me
Me
Me
1. NaH; Tf2O
2. LiCuMe2
geranyl bromide
1. LiAlH4
2. MsCl, Et3N; LiBr
95%, two steps
81%, two steps
Me MeH
Me MeH
OMe
Br
Me
MOMO
Me
n-BuLi, HMPA, TMEDA,
Me
OMOM
Me
OMe
MOMO
CHO
aq. HCl
Me
Me MeH
HO
OMe
OH
Me
OMe
Me MeH
Me MeH
OMOM
75%
OMe
HO
65%
Me
Me MeH
E. J. Corey, J, Das. 5551.
O
CHO
1. MeOH, TsOH
2. TBA phenoxide
TBA I3; MOMCl
MOMO
Me
Me
Me MeH
OMe
MOMO
OMe
I
O
Me
CuCN
Me
90%
Me MeH
OMe
CN
O
Me
Total Syntheses
OMe
MOMO
Me
OMe
MOMO
OMe
Me
92%
Me
Me MeH
MOMO
OMe
KOH
CN
O
OMe
O
CONH2
OMe
OsO4, py
40%
Me
Me
O
HO
CONH2
Me
HO
Me MeH
Me MeH
OMe
MOMO
OMe
MOMO
aq. HCl; 0.02% TsOH,
MeOH; TsOH,
2, 2-methoxypropane
90%
O
NH
Me
Me
O
Me
O
O
Me
N2O4, NaOAc
O
Me
O
Me
O
Me MeH
MOMO
HO
HO
Me MeH
O
O
Me
Me
i-Bu2AlH;
aq. HCl
O
Me MeH
HO
CHO
CHO
Me
E. J. Corey, J, Das. 5551.
Me
CHO
aq. HCl
87%
CHO
Me
Me
O
Me
O
Me MeH
O
Me
K-76
Total Syntheses
OMe
MOMO
OMe
MOMO
O
NH
Me
Me
O
Me
O
R1
R2
Me
O
Me MeH
O
H
N
O
N2O4, NaOAc
O
N N
O
O
O
O
R1
N
Me
Me
O
Me
O
N
HONO
R2
R1
O
Me
O
Mechanism?
Me MeH
O
N
O
O
N
N
R2
+
HNO3
R1
O
N
O
R2
O
NaOAc
NaNO3 + HOAc
N2 + R1
O
R2
N
N
O
R1
E. J. Corey, J, Das. 5551.
O
N
R2
O
R1
O
N
R2
O
Total Syntheses
O
Me
O
Me
O
O
O
i-Pr
i-Pr
OMe
OH
O
H
O
triptolide
key intermediate
1. Li/NH3; isoprene;
(EtO)2(O)PCl; Li, EtNH2,
t-BuOH
2. H2SO4
O
Me O
O
Me
O
Me
B=
t-Bu
O
Me
O
O
LDA, HMPA,
TBSCl
Me
L. C. Grover, E. E. van Tamelen. 867.
Me
Me
CO2Me
O
OTBS
CO2Me
Me
OH
then HCl
89% from
butenolide
S
Me
then HCl
84%, two steps
Me
t-Bu
Me
SMe
Me
Me
Me
SMe
CS2, LiB; MeI
81%
O
O
H
Me
Total Syntheses
CO2Me
Me
OH
1. MeI, NaH
2. MeLi
3. MsCl, Et3N
4. Li/NH3
i-Pr
Me
OMe
65-70%
i-Pr
Me
m-CPBA
91%
100%
Me
O
Me
Me
i-Pr
i-Pr
Me
Me
SOCl2
OMe
OMe
84%
HO
i-Pr
Me
OMe
80%
80%
HO
i-Pr
Me
OMe
i-Pr
O
H
Me
CrO3
25%
O
L. C. Grover, E. E. van Tamelen. 867.
NMe2
OMe
72%
1. m-CPBA
2. LiN(TMS)2;
aq. HCl
Me2NOC
MeO OMe
Me
1. KOAc
2. NaOMe
Cl
i-Pr
LDA
OMe
OMe
O
O
H
O
Total Syntheses
i-Pr
i-Pr
MeO OMe
Me
OMe
Me
NMe2
80%
OMe
Me2NOC
HO
i-Pr
i-Pr
Me
Me
OMe
O
L. C. Grover, E. E. van Tamelen. 867.
Me
OMe
OMe
Me2N
i-Pr
OMe
Me2N
Me2N
O
O
Total Syntheses
Me
CO2Me
O
CO2Me
OTBS
OH
then HCl
89% from
butenolide
Me
Me
O
CO2Me
OTBS
Me
L. C. Grover, E. E. van Tamelen. 867.
Me
Me
Me
O
Me
HO
CO2Me
OH
CO2Me
Me
O
Me
Total Syntheses
OH
steps
O
Ph2t-BuSi
O
O
O
Me
HO
O
TL, 1981, 2059
OH
O
Me
O
CO2H
8
O
pseudomonic acid A
key intermediate
HO
CH2O, Me2AlCl
Ac2O, py
OH
72%
100%
O
Ph2t-BuSi
O
O
CH2O, Et2AlCl
OAc
O
O
B. B. Snider, G. B. Phillips. 1113.
1. OsO4, NMO
2. c-hexanone,
TsOH, CuSO4
82%
OAc
35-40%
Sit-BuPh2
O
O
O
1. PCC, NaOAc
2. MeMgBr
3. t-BuPh2SiCl,
Et3N, DMAP
4. PCC
52%
OH
OAc
O
Total Syntheses
N
Et
N
H H
dl-aspidospermidine
O
EtO
CHO
NH2
PhS
N
R
Me
100%
Me
PhS
Et
N
R
T. Gallager, P. Magnus, J. C. Huffman. 1140.
SPh
N
R= MeOC6H4SO2
O
Me
N
N
R
O
140 C
33%
O
PhS
N
Et
N
R
Total Syntheses
O
PhS
O
O
PhS
N
N
m-CPBA
97%
Et
O
TFAA; D
81%
Et
N
R
N
R
N
81%
N
LiAlH4
Et
N
R
54%
Et
N
H H
dl-aspidospermidine
R= MeOC6H4SO2
T. Gallager, P. Magnus, J. C. Huffman. 1140.
Et
N
R
O
Raney Ni
N
PhS
Total Syntheses
Me Me
albene
I
(i-PrO)3P,
Pd(OAc)2
CO2Me
+
LiAlH4
93%
63%
CO2Me
TMS
O
MeO2C CO2Me
KN(TMS)2, HMPA,
(Me2N)2(O)PCl
O(O)P(NMe2)2
54%
HO OH
O3; DMS
HO OH
Li, EtNH2
82%
(Me2N)2P(O)O
O(O)P(NMe2)2
Me Me
albene
B. M. Trost, P. Renaut. 6668.
82%
Total Syntheses
Me Me
OH
O
O
O
O
O
Me
O
Me
B
O
Me
O
OH
Me
O
O
O
O
Me Me
aplasmomycin
Me
vinyl MgBr, CuI
88%
O
Me
OsO4, NMO
Me
Me
HO
76%
O
O
Me
Me
70%
OH
Me
Me
Me
O
Me
1. LiAlH4
2. actone, TsOH
3. PCC
Me
Me
O
O
Me Me
Me
Me
O
O
O
O
m-CPBA
83%
Me Me
E. J. Corey, B. C. Pan, D. H. Hua, D. R. Deardorff. 6816.
Me
Me3Al,
propane-1,3dithiol
87%
Me Me
HO
Me
S
S
OH
OH
Total Syntheses
Me
Me
O
O
O
O
Me
Me3Al,
propane-1,3dithiol
HO
87%
Me2AlS
SAlMe2
O
OH
Me2AlO S
O
S
S
OH
Me Me
O
Me
Me Me
S
SAlMe2
O
SAlMe2
Me2AlO
S
S
S
Me2AlO
E. J. Corey, B. C. Pan, D. H. Hua, D. R. Deardorff. 6816.
HO
S
When the following orthoester
was subjected to the reaction
conditions, no product was
formed, proving it is not
involved in the mechanism:
S
O
S
Total Syntheses
Me
Me Me
O3; DMS; propane1, 3-dithiol, BF3 OEt2; 2, 2dimethoxypropane,
TsOH
S
HO
S
OH
Me
O
S
OMTM
73%
S
OH
Me
1. AcOH
2. BzCN, Et3N
3. MsCl, Et3N
4. n-Bu4OH
S
O
Me
O
Me
DMSO, AcOH,
NaOAc, Ac2O
S
O
80%
OH
Me Me
Me
Me Me
Me Me
O
80%
Me
S
S
OR
Me
Me
Me
O
Me
OHHO
Me
O
O
O
TsCl, py
Me
O
O
O
91%
Me Me
from d-mannose diacetonide
and MeLi
E. J. Corey, B. C. Pan, D. H. Hua, D. R. Deardorff. 6816.
O
Me
O
Me Me
1. MeOH, aq. HCl
2. NaIO4, NaHCO3
96%
OHC
O
O
Me
O
Me Me
Total Syntheses
Cl
OHC
O
O
Me
PPh3, CBrCl3
O
Cl
O
O
TfO
Me
1. n-Bu4I
2. NaBH4,
n-Bu3SNH, hu
OTIPS
56%, five steps
O
99%, two steps
O
OH
1. MeOH, aq. HCl
2. TIPSCl, DMAP
3. Tf2O, py
O
Me Me
n-Bu3Sn
O
Me
75%
1. TBSOTf, 2, 6-lut
2. AgNO3, 2, 6-lut
3. TBSOTF, 2, 6-lut.
Me
OMTM
S
O
n-Bu3SnH, AIBN
OTIPS
Me Me
TIPSO
O
Me
n-BuLi
Me Me
Me Me
O
O
Me
S
OTIPS
89% bsr epoxide
Me Me
TIPSO
85%
Me
1. n-BuLi
2. 0.5 eq. CuCN;
epoxide
Me
O
OTBS OTBS
Me
Me Me
n-BuLi, TMEDA, HMPA;
dimethyl oxalate
TIPSO
O
96%
OTBS OTBS
O
Me
S
OMe
S
O
Me
E. J. Corey, B. C. Pan, D. H. Hua, D. R. Deardorff. 6816. E. J. Corey, D. H. Hua, B. C. Pan, S. P. Seitz. 6818.
Me
S
S
Total Syntheses
O
Me
Me Me
TIPSO
S
OTBS OTBS
O
OMe
Me Me
S
O
O
Me
OH
LiI, 2, 6-lut
100%
TIPSO
Me
OTBS OTBS
O
S
S
O
Me
O
Me
Me Me
OMe
TBAF
HO
97%
O
OTBS OTBS
S
S
BOPCl,
Et3N
98%
O
Me
Me
Me Me
O
O
O
O
Me
S
S
OTBS OTBS
O
Me
OTBS OTBS
S
O
O
O
1. LiI, 2, 6-lut
2. TBAF
3. BOPCl, Et3N
O
TIPSO
65%
O
Me
S
S
O
Me
OTBS OTBS
O
Me
OTBS OTBS
MeO
Me
Me
Me Me
S
Me Me
E. J. Corey, D. H. Hua, B. C. Pan, S. P. Seitz. 6818.
Me Me
O
S
S
O
O
Total Syntheses
Me
Me Me
O
O
O
O
Me
S
S
OTBS OTBS
O
Me
OTBS OTBS
Me Me
S
S
1. NaBH4
2. 48% HF
3. HgCl2
O
O
Me
OH
O
94%, 1:1
mixture of
diastereomers
O
OH
O
O
OH
Me
O
OH
Me
Me Me
Me Me
OH
O
O
O
Me
O
B
OH
Me
O
Me Me
aplasmomycin
E. J. Corey, D. H. Hua, B. C. Pan, S. P. Seitz. 6818.
Me
O
Me
O
O
O
O
O
O
O
Me
HO
HO
Me
O
O
O
B(OMe)3
75%