Due: Monday, Nov.

5th

Chem 206
Problem Set 6: Carbonyl Additions

Name:_________________________

General Instructions: Neatly, in the space allocated, provide concise answers to the following questions using
clear three-dimensional representations for all relevant structures. Address stereochemical and stereoelectronic
issues where appropriate.
Question 1. The Myers pseudoephedrine-derived propionamide 1, upon successive enolization with LiN(I-Pr)2 (LDA)
and alkylation with alkyl halide RX, affords 2 with high diastereoselection (Myers, JACS 1997, 119, 6496).
Me

O
N

OH

Me

Me

2 equiv Li-NR2
RX

O
Me

Me
2

OH

Me

Part A. Enolization of 1 with LDA affords a single enolate. Provide an analysis of this enolization event and draw the
structure of the enolate produced.
Allylic Strain controls Enolate Geometry. In the deprotonation of conformer B, developing A(1,3) strain
strongly disfavors the formation of the (E) enolate.
B strongly disfavored
A strongly favored
OLi
H
H
OLi

Me

N
R

O
Me

N
H

R
R

O
H

N
Me

R
R

N
R

Me

A(1,3) Strain
Part B. Provide a 3-dimensional drawing of the transition state for this reaction
in Box-1. Hint: In answering this question, you do not need to assume that
chelation is involved. Rather, a suitable transition state model may be derived
purely from the consideration of non-bonding interactions.

Ph

minimize A(1,3)
OLi
H

H
Me

Me

OLi

N
H

Me
R
X

Box-1

Question 2. Rappoport has recently reported the transformation illustrated below (JACS 1996, 118, 12580). The
kinetic stereochemical outcome of this reaction is superficially unanticipated in that the Grignard reagent adds to
ketene 1 from the "more hindered" face. This value judgement evolves from the assumption that the mesityl
substituent is more sterically demanding than the phenyl substituent.
Ph
C
Mes

Ph

1. MesMgBr

2. AcCl

Ph

OAc

Mes
Me

+
Mes

Mes

Mes

OAc

Me

(Z)-2 (disfavored)

(E)-2 (favored)

Me

Mes =

(E)/(Z) = 3:1 (kinetic ratio)

Provide a rationalization for this "contrasteric" ketene addition.
We start by analyzing the conformation of the ketene.
The all out-of-plane
orientation has a steric
clash between ortho
substituents and also lacks
any resonance stabilization
from the phenyl groups

The all in-plane orientation of

the aryl groups results in a
very unfavorable clash
between ortho groups

An in-plane orientation of
the mesityl group has an
unfavorable interaction
between the methyl group
and the ketene carbon

The in-plane
orientation of the
phenyl group provides
some resonance
stabilization and has
no major steric clashes
FAVORED
H

H
C
Me

H
Me

Me

C
Me

Me

Me

Me
Me

Me

Nu
Me

Me

Now we analyze the addition.

Nu

The LUMO of the ketene is in the plane of the substituents.

Attack from the face syn to the phenyl group is blocked by
the ortho CH group. Attack from the face syn to the mesityl
is open because the mesityl group is out-of-plane.

LUMO

O
Me

Me
Nu

Me

Me

Question 3. The Still synthesis of monensin (JACS 1980, 102, 218) contains the diastereoselective iodolactonization shown below.
Me
Me

Me

Me

Me

I2, NaHCO3
I

87%

CO2H

*
O

Me
O

Provide a concise mechanism for this reaction in the space below. Be sure to identify all intermediates. In your
answer, predict the stereochemical outcome of this transformation and identify the relevant stereochemical control
element(s) operating in this reaction.
minimized A1,3
Me

Me

Me

Me

H
Me

I2

Me

Me

H
H

NaHCO3

CO2H

I H

HO

Me

Me
O

O
Me

iodolactonization

Me
I

Me

Me

H
O

O
Me

Me
O

See the class notes of Oct. 26th for a discussion of two analyses that would lead to a common product in this case.

Question 4. Stoltz and co-workers reported the following rearrangement (JACS 2003, 125, 13624).
O

MeO

MeO
N2

AgOBz, Et3N
Me

Me

THF, 45

95% yield

Please provide a mechanism for this transformation. Your answer should include clear 3-D drawings where relevant
and should provide the configuration of the major product.
O
H
H
AgOBz, Et3N

H
Me

N
N

After the Ag(I)induced Wolff rearrangement, the Cope rearrangement can

occur through the two conformations, A and B. Conformer A leads to the
cis/cis cycloheptodienone while conformer B leads to the "impossible" cis/trans
isomer.
O
MeO
O

N2

Cope Rearr.

Me

Me

Wolff Rearr.
H

Me
H
carbene intermediate

A
MeO

H
H
H

H
cis olefin

Cope Rearr.
O

O
H

Me

Me
H
impossible trans double bond

Question 5. Taber has reported the following transformation (J. Org. Chem. 2001, 66, 143), wherein the enantiopure
starting material was converted to the cyclopentene derivative with complete retention of configuration.
OMe

OMe
OMe

OMe

KN(TMS)2
BnO

Cl

BnO

Et2O, rt

Me
Me

Provide a concise mechanism for this reaction in the space below.

OMe

BnO

stereospecific
C-H insertion

N
TMS

Cl

OMe

OMe

TMS

-elimination

OMe

OMe

OMe

BnO

BnO

Me
Me
Me

Question 6. Give your choice of a protecting group and reagent for the following transformations, and justify
your answer with 3D drawings:
a)

OH

reagent?

Me

Me

Me

Me
OPG

OPG

Syn-relationship of the two hydroxyl groups of the product imply that the Felkin-Anh model is
operational during the transformation. To prevent chelation, a non-chelating group (such as TMS,
TES, TBS, etc. should be chosen). Any hydride source such as LAH, NaBH4, L-Selectride, or Red-Al
would give the Felkin selectivity with a non-chelating group. However, if L-Selectride is used, a
chelating protecting group (such as MOM-, or BnO-) could still give good Felkin selectivity if an
appropriate solvent is used.

= L-Selectride

Li

HB

Me

Me
O

Nakata, TL 1983, 24, 2653.

HO
TBSO

Me
OTBS

Me
OH

b)

MgBr
Me

reagent?
Me

Me

Me

Me

Me

OPG

OPG

This case is the opposite to the one above. Chelate controled addition is desired. Note that the
chelate-control addition and Felkin reduction (or Felkin addition and chelate reduction) are
complementary methods to construct the same relative configuration. In order to promote
chelation, any non-silicon protecting group can be used: PMB-, Bn-, MOM-, BOM-, THP-, etc.

Nu

Et

Et

HO
O OBn

Nu
OBn

Mg
BrR

=PMB
OCH3

R'

R'= Benzyl = BOM

R'= Methyl = MOM

=THP
O

Question 6, continued
c)

OPG

OPG

OH

reagent?

Me

Me

Me

Me
Me

Me

In this case, either chelate-controlled syn-reduction or Felkin-product selective reduction are the
options to consider. However, one has to note that if 1,3-syn reduction is used, there is no great
preference for the desired diaxial ring opening illustrated below right. The pseudoaxial substituents
on the undesired opening on the left are not subject to 1,3 diaxial interactions so this conformation is
not particularly disfavoured.
H
H
Me

O R
O
Zn

Et

Me Me
Et

Me

O
O

Me
O

H
Et

vs.

Zn
R

TBSO

gives undesired product

H
Me

gives desired product

Felkin reduction is apparently the solution since 1,3-induction reinforces this case. Thus, one
needs a non-chelating protecting group and a bulky nucleophile (such as L-Selectride)

OPG

OTMS

d)

Me
O
Me

t-Bu

Me

OH

OPG

reagent?

Me
t-Bu
Me

Me

This case is similar to the one above. Felkin is thought to be stereoreinforced by a 1,3induction. If a monodentate Lewis-Acid (such as BF3-Et2O) is used, there is no specific
requirements to the protecting group. It could be a chelating group (PMB), or a non-chelating
group (TBS).

F3 B

Me
O

i Pr
H

H
Et

OTBS

Evans et al., JACS 1996, 118, 4322

Question 7.In each of the following reactions, provide the configuration of the major product and rationalize the
stereochemical outcome using clear 3D-drawings or Newman projections
Me
Ph

H
+

OTMS

Nu

Me

Ph

BF3-OEt2

Me
O

OTMS O

CH2Cl2, -78 C

H
C

diastereoselectivity 16:1

R(large)

Me

Me

MeO

Ph

Zn(BH4)2

MeO

Me Ph

Ph

Et2O
O

ZnL2

OH

diastereoselectivity 32:1

Me
Nu

O
O

HO
Me4N(AcO)3BH

HO

CO2Me

HO
N

CO2Me

TMS

R2B

LiEt3BH

C8H17
TMS

CO2R
O

TMS

OH
Me

CO2Me

O
C8H17

CO2Me

Me
C8H17
H

O
Me

R
O

Question 8.
Chiral amino alcohol 1 efficiently mediates the addition of diethylzinc to aromatic aldehydes. While a number of
other amino alcohols are also effective in controling the stereochemical course of the addition process, this amino
alcohol has been the focus of a recent computational investigation that addresses the preferred transition state
geometry for the reaction.

OH

O
6 mol-% 1

N
Ph
Ph

(R)

(S)

Et

97% ee

Et2Zn, 0 C
toluene

Ph
OH

Provide a detailed mechanism for the overall transformation in the space below. Use three-dimensional
representations to derive the stereochemical course of this reaction.
R

R
Ph
Ph

Ph

Et2Zn

Ph

Ph C2H6

Ph

OH

Ph

R
R
Zn Et

Et2Zn Ph

N
H

Ph

O
Zn

Et

Ph
Ph

Zn

O
Zn

Et

Et

Ph
H

Ph

H
Et

Ph

Zn
O
Et

Zn
Et

O
Et

Ph

Et

Ph

O
Zn

Et

R
Zn

Et
Ph

O
Et

Ph
disfavored transition state

Ph

Zn

O
Zn

Ph

Ph

Ph

O
Et

Et

Et

Et

Zn

O
Zn

favored transition state

Ph

Ph

Ph
Et

Ph

Ph

R
Zn Et

PhCHO

Ph

Ph

Ph

Et
H

Ph

O
A

R
Zn

Et

Et

Zn

O
Et

H
(S)

Ph

Ph
Forms insoluble aggregate

(Pericas, et al. J. Org. Chem. 2000, 65, 7303 and references cited therein)

Question 9. The following transformation was reported by Kabalka (Tetrahedron Lett. 1996, 37, 2181). Treatment of 1
with allylboronic acid afforded product 3a with 10:1 diastereoselectivity. On the other hand, the analogous reaction of 2
was nonstereoselective. Propose a mechanism for this transformation that accounts for the stereochemical outcome of
the two addition processes.
OR

Ph

1, R = H
2, R = Me

OR

25 C
B(OH)2

Me

45-55%

OH

Ph
Me

3, a (R = H) diastereoselectivity 10:1
b (R = CH3)

Ph

Ph
O

OH HO Me

OH
Ph

OH
O

OH

cyclic transition state with all substituents equatorial; transesterification not possible with OMe group