Chem 4322/8322 – Advanced Organic Chemistry
Spring 2011
Problem Set 1 – Due January 27, 2011
(1) For each reaction below, provide a model that explains the observed stereoselectivity:
O
O
Et–
OH
EtLi
H
O
H
H
Et
O
O
dr 72:28
OTMS
OTMS
O
+
OPMB
O
BF3•OEt2
OH
OPMB
H
H
H
dr 92:8
[Ti]
TESO
Me
TiCl2(Oi-Pr)2
CH2Cl2, –78 ºC
10
OTMS
EtO2C
OEt
Ph
BF3
H
PMBO
OTMS
H
O
H
O
TESO
TESO O
OTMS
Ph
Ph
10
Me
10
H
single diastereomer
OEt
Me
Org. Lett. ASAP, DOI: 10.1021/ol203185f
Me
O
Me
TMSI
Me
Me
Me
O
+
OTBS
Me
Me
CH3CN, rt
H
O
Me
T.S. 1
I
Me
Me
78% yield
dr > 98:2
Org. Lett. 2012, 14, 58–61.
Me
O
I–
H
Two models needed
Me
T.S. 2
[Sn] H
BnO
O
Me
O
H
OH
SnCl4
OBn
Me
Me
Me
H
[Sn]
H
BnO O
OBn
89% yield
dr > 30:1
Org. Lett. 2012, 14, 178–181.
H
H
OTBS
PMBO
O
O
DIPEA
Bu2BOTf
O
+
Me
R
H
H
PMBO
OBn
PMBO
O
OH
Bu
H
OTBS
B
O
O
Bu
O
Me
Ar
Me
Me
OBn
Org. Lett. 2012, 14, 178–181.
87% yield
dr 7:1
OTBS
PMBO
O
OH
Me4NBH(OAc)3
O
PMBO
Me
O
OAc
Me
OBn
PMBO
OH
OH
OBn Me
O
B
H
OTBS
Me
Ar
OAc
O
Me
OBn
Org. Lett. 2012, 14, 178–181.
93% yield
dr > 20:1
O
OH
Na
NaBH4
OTBS
NHBoc
OTBS
EtOH
–78 ºC
NHBoc
dr 11:1
Org. Lett. 2012, 14, 382–385.
BocHN O
TBSO
H
H
H
BH3
Me
OMe
OMe
BnO
Et2BOMe
NaBH4
O
OH
BnO
OH
H3B
H
Et
OH
THF/MeOH
–78 to 0 ºC
Me H
R
OH
Me
MeO
98% yield
dr > 20:1
OH
Me
TMS3SiH
AIBH
O
O
•Si(TMS)3
Me
Me
O
CO2Et
Me
single diastereomer
CO2Et
O
BH3
OH
OMOM
Me
1. BH3
BzO
2. H2O2
NaOH
Me
H
OMOM
Me
H
H
Me
Si(TMS)3
(This is a radical reaction
with TMS3Si• serving
as the nucleophile)
H
O
O
CO2Et
BzO
Et
O
OBn
H
Org. Lett. 2011, 13, 5816–5819
Me
B
O
Me
Me
dr 29:71
CH2OMOM
Me
H
BzOCH2
(2) The Cornforth model is another stereoinduction model for carbonyl addition reactions that predates
the Felkin-Ahn model and is based on dipole minimization. Importantly, they both favor addition to
the same face of the carbonyl group (see below). A number of theoretical studies have given more
support for the Felkin-Ahn model in a majority of cases. However, there are a growing number of
cases for which the Cornforth model appears to be the better model.
O R
X
H H
O
R
H
Nuc
Nuc
OH
Felkin-Ahn model
R
Nuc
X
X
O H
X = OR, NR2, Cl
1,2-anti
R
H X
Nuc
Cornforth model
Consider the boron-mediated aldol reactions shown below. Construct transition states for each aldol
reaction using both the Felkin-Ahn and Conforth models for the aldehyde. Using these models,
determine if these results are consistent with either the Felkin-Ahn model or the Cornforth model. Also
explain why the aldehyde facial selectivity (ratio of 3:4) is poor in the second case (another model may
need to be drawn to explain this). (Hint: consider syn-pentane interactions when building your models.)
Reaction A
(9-BBN)O
O
Me +
H
O
OH
Me
2
3
Me
OTBS
O
Me
4
OH
2
+
4
3
Me
OTBS
1
Me
OTBS
2
2,3-syn : 2,3-anti = 93:07
1 : 2 = 98:02
Reaction B
(c-Hex)2BO
O
+
H
Me
O
Me
OH
2
3
Me
OTBS
O
4
Me
OH
2
+
4
3
Me
OTBS
3
Me
OTBS
4
2,3-anti : 2,3-syn = 99:01
3 : 4 = 21:79
Reaction A
L
L
B
i-Pr
H
L
mis-matched
O
O
TBSO
I
O
OH
2
H
3
H
Me
Me
Me
4
Me
matched
L
B
i-Pr
H
O
O
Me
OTBS
H
II
1
syn-pentane
Felkin-Ahn
model
H
OTBS
Me
Cornforth
model
Reaction B
L
L
B
i-Pr
H
matched
O
OH
2
Me
O
TBSO
III
L
O
3
H
Me
H
Me
4
Me
mis-matched
L
B
i-Pr
H
O
O
Me
Me
OTBS
OTBS
H
Felkin-Ahn
model
syn-pentane
H
IV
3
Cornforth
model
O
OH
2
3
Me
4
4
Me
i-Pr
H
mis-matched
O
Me
Me
OTBS
syn-pentane
L
B
O
OTBS
H
H
V
Cornforth
model
L
In reaction A, the Felkin-Ahn model I leads to a syn-pentane interaction with the Z enolate. However,
this interaction is absent with the Cornforth model II. The observed 3,4-anti selectivity is high. This
points to the Cornforth being active in this case.
In reaction B, the Felkin-Ahn model III would give high 3,4-anti selectivity because there is no synpentane interaction. In the Cornforth model IV there is a syn-pentane interaction that would lead to low
3,4-anti selectivity. The observed 3,4-anti selectivity is low. This points to the Cornforth being active
in this case as well. The major diastereomer in reaction B (4) arises from model V for which the synpentane interaction is likely less severe than in IV.