Chem 206 Due: Friday, Nov.

10

Problem Set 7 Answer Key

Name:_____________ TF:_______________
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 following transformation was recently reported by Kabalka. Treatment of 1 with allylboronic acid afforded the
indicated adduct in high yield with 10:1 diastereoselection. 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 addition process.

OR O OH OH
25 °C
Ph
B(OH)2 45-55% Ph
diastereoselection 10:1
Me
1, R = H Me
2, R = Me

OH HO Me

Me O B Me
OH OH Ph
O OH
Ph Ph

cyclic transition state with all substituents equatorialtransesterification not possible with OMe ether

(Tetrahedron Lett. 1996, 37, 2181)

Chem 206 Due: Friday, Nov. 10

Question 2.

Give your choice of a protecting group and reagent, and justify your answer with 3D drawings:

a)
O OH

Me reagent? 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.
H

H
Me H Me H
O
Me HO
Nakata, TL 1983, 24, 2653.
OTBS TBSO
Me

OH
O
b) MgBr reagent?
Me 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
complementory methods to construct the same stereoarray. In order to promote chelation, any
non-silicon protecting group can be used: PMB-, Bn-, MOM-, BOM-, THP-, etc.

Nu

H H
Et H Et H

HO Nu
OBn
O OBn

Mg
BrR
Chem 206 Due: Friday, Nov. 10

Question 2, continued

c)
OPG O OPG OH

Me reagent? 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, the α-Me-group
precludes the nucleophile from approaching the correct face; low selectivity is usually observed.

H
R H3B
Me Zn H
O
R H Me
Me O vs. Zn Et O
Et Me O
H3B Me O
H
Et TBSO H
Me

Felkin reduction ia 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 O OH OPG
OTMS
d) Me reagent?
Me
O + t-Bu
t-Bu
Me Me Me Me

This case is similar to the one above. Felkin is stereoreinforced by 1,3-induction. In this case,
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).

Me H
O Et
F3B

H OTBS
iPr
Evans et al., JACS 1996, 118, 4322
Chem 206 Due: Friday, Nov. 10

Question 3.
P. A. Evans and co-workers have recently reported a highly diastereoselective approach to the construction of
linked tetrahydropyrans. One of their cases is illustrated in Eq 1. In this transformation BiBr3 is employed as a
mild Lewis acid.

OSiMe3
1 OHC
Me 1) BiBr3
(1)
2) Et3SiH Me O O Me
OTMS OSi(i-Pr)3 H H
2 A single diastereoisomer
Me diastereoselection: 95:5 (73% yield)

Please provide a mechanism for the reaction cascade that results in the production of the illustrated product.
Your answer should include clear 3-D drawings where relevant and should provide the stereochemistry of the
major product diastereoisomer.

OTMS BiBr3 (LA) –TMSO–LA

Me
OHC
Me Me O O-LA O
H
H
SiMe3

stereoelectronic bias for 2

"chair-axial" approach

OSi(i-Pr)3 OSi(i-Pr)3

Me –TMS–X Me

LA Me O O Me O O
H H
TMS

–TMSO–LA

Me O O Me Me O O Me
H LA–O H Et3SiH
Si(i-Pr)3
H
O
R Me
H
stereoelectronic bias for
"chair-axial" approach
This is the absolute stereochemistry of the product
Me O O Me
H H

(JACS 2003, 125, 11456-11457)

Chem 206 Due: Friday, Nov. 10

Question 4.
Corey's CBS catalyst for ketone reduction often delivers high yields of enantioenriched secondary alcohols.
Provide a clear illustration of the transition state which predicts the absolute stereochemistry of the product obtained
in the illustrated reaction. Include an explanation of why the reduction of this practically symmetric ketone is
selective.
1 equiv.
O O HO H
B H
O

MeO NO2
0.15 equiv. CBS MeO NO2
H
Ph 75 % ee
Ph

O
N
B

Me

The availability of ketone lone pairs must be considered. Because the antiperiplanar C-C sigma bonds have differing
electron density, the ketone lone pairs will be anisotropic. The nΟ → σ∗C-C interaction with the electron rich C-C bond
will be weak relative to the nΟ → σ∗C-C interaction with the electron deficient C-C bond. Complexation of the lone pair
anti to the p-methoxy phenyl substituent will be favored.

O nΟ → σ∗C-C nΟ → σ∗C-C O
O

MeO NO2 MeO NO2

MeO NO2
weaker interaction stronger interaction

O Me
OMe O Me
N B NO2
H N B
H
B O
RO O
RO H RO B
RO H
vs.

NO2
OMe

disfavored favored

HO H

(ACIE 1998, 1987).

MeO NO2
Chem 206 Due: Friday, Nov. 11

Question 5.
In each of the following reactions, provide the stereostructure of the major product and rationalize the stereochemical
outcome using clear 3D-drawings or Newman projections

Me Me Nu

Ph H Ph
BF3-OEt2 Me H
+
OTMS O C H
O CH2Cl2, -78 °C OTMS O

Stereoselection: 16:1
R(large)

Me Me
Zn(BH4)2 Me Ph
MeO Ph MeO Ph O
ZnL2
Et2O
H O
O Stereoselection: 32/1 OH Me
Nu

O OH
Me4N(AcO)3BH MeO2C

OH OH MeO2C
N
N N
O
CO2Me CO2Me CO2Me CO2Me O H
B
R2

TMS
O OH

Me Me
C8H17 LiEt3BH C8H17 C8H17 C O
H Me
TMS TMS

O +
Me Me C N O–
i. PhNCO, Et3N; OH
O2N Me
ii. Raney-Ni
Stereoselection: 16:1 H
Me Me H Me

This is another example of a reaction controlled by allylic strain conformational effects.

Chem 206 Due: Friday, Nov. 10

Question 6.
Chiral auxiliaries (Xc) are routinely employed to control the absolute stereochemistry of the addition or
organometallic reagents to imines (Step A). A design requirement of these controllers is that they may be readily
cleaved after the addition step (Step B). In the two parts of this question posed below are presented two well-
established chiral controllers that employ chelate organization as an integral part of the chirality transfer process.

H R" R"
R'–M chemistry
* *
Xc Xc
N R Step A N R Step B H2N R
H
Part A. Provide a mechanism for the following transformation reported by Ellman and co-workers. Include a clear
transition state representation that predicts the major product diastereomer. Clearly illustrate the absolute
stereochemistry of the product.
O H O Et
EtMgBr
S S diastereomer ratio 92:8
Me3C N Ph CH2Cl2 Me3C N Ph
H

O H Me3C O Et
EtMgBr O N
S S Ph
Me3C N Ph S
Br Et Me3C N Ph
Mg H

S H prod. stereochem: (R)

TL 1999, 8883.

Part B. The following stereoselective transformation has been reported by Fujisawa. Given the stereostructure of
the product, rationalize the stereochemical outcome.
Ph Ph
OMe R"-Li OMe
N HN diastereomer ratio >97:3

R H R R"

Me Me The stereochemical outcome of this reaction has been

R Li O Ph R Li O Ph rationalized by Fujisawa through the chelate-organized
imine complex shown on the left. In this study diastereoface
N R N selectivity was noted to be strongly dependant on the nature
R H H of the organometallic reagent.
H H
Nu
Nu

Sterically preferred C=N ([Link]. 1991, 1555).

diastereoface
Chem 206 Due: Friday, Nov. 10

Question 7.

This is a classic problem in multistep electron pushing. The following pyridine synthesis has been
reported by Tohda. Provide a plausible mechanism for this complex transformation.

O
O 2N NO2
O 2N Boc
NH3, MeOH N
+ other organic
N O N fragment(s)
N
Me Boc

In this multistep transformation, the sequence of chemical events may not be unique.
Let's now begin:

O O
O2N Me O2N Me
N + N
Boc conj addn
N Boc
N
NO2 H2N NO2
H2N
Begin by attacking the most electrophilic carbon in
pyridone ring with either the enolate or the tautomerization
illustrated enamine.
O
Me
Me O 2N Me
O N N
NH3 O N
Boc
N Boc Boc
NO2 N N
O2N NO2
O2N NO2
N
H N H2N
H

NH4

O2N Boc O
O N O2N Boc
N
+ MeHN
MeHN N
N NO2
NO2 H
Chem 206 Due: Friday, Nov. 10

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 controlling the absolute 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 this addition process. It should be noted that, while 1 is not the actual catalyst, it is modified under
the reaction conditions to the competent catalytic agent.

O OH

6 mol-% 1 (S) Et
N H 97% ee
Ph Et2Zn, 0 °C
toluene
Ph (R)
Ph
1 OH

Provide a detailed mechanism for the overall transformation in the space below. Use three-dimensional
representations to illustrate the absolute stereochemical aspects of the indicated transformation.

R R R
Ph Ph
N Ph R R
Ph Et2Zn Ph N R
Ph Et2Zn Ph N
N R Et
Ph R
Ph –C2H6 H O Zn
Zn Et H O Zn Et
H O Ph H
OH Ph Ph
Zn O
A Zn
Et Et
Et Et Ph

PhCHO
‡ ‡
Ph R Ph R

Ph R Ph R Ph N R
N
Et Ph Et
Zn N R Zn
H O H O
Ph Et Ph
H H O Zn O Ph
Zn O Zn
Ph H
Et Et Zn O Et Et
Ph H
Et Et
Ph
favored transition state
disfavored transition state

Ph R Ph R
Ph N R Ph R
N H
Et Et Et Zn O
H O Zn Zn (S)
H O Et
Ph Ph
H Ph
Zn O A
Et Et
Ph

Forms insoluble aggregate

(Pericas, et al. J. Org. Chem. 2000, 65, 7303 and references cited therein)
Chem 206 Due: Friday, Nov. 11
Question 9. Crotyltitanium reagents have been developed for addition to C=O and C=N bonds.
OH OH
O Me TiX3
+
Ph Ph
Ph H Et2 O
Me Me
major minor

R NHR NHR
N Me TiX3
+
Et Et
Et2O
Et H
Me Me

minor major
Part A. Provide an explanation, including clear 3D drawings of the transition states, which account for the divergent
stereoselectivity observed in the addition reactions illustrated above.

X H OH
H TiXn
Ti X Me
Me O anti product
O Ph Ph
Ph
H Me
H
In the Zimmerman-Traxler transition state, the aldehyde is oriented with the large substituent pseudo-equatorial.

X NHR
Et
Et TiXn
Ti X Me syn product
N Et
Me N H
H H R Me
H R

The (E)-imine, by the nature of its geometry occupies a TS conformation

in which the large substituent is psuedo-axial, leading to the syn product.
Part B. The use of a chiral imine induces useful levels of asymmetric induction in this reaction. Provide an
explanation, including a clear 3D drawing of the transition state, which accounts for the preferred production of the
indicated diastereomer.
Me Me

N Ph Me TiX3 HN Ph

Et H Et2O Et
Me
X
Et Ph TiXn
Ti X
Me +N Me
N Newman projection:
H
H Ph H
H Et
Me
Nu

Minimization of eclipsing interactions in the staggered TS (Houk), with the best donor (Me)
orthogonal to the iminium N=C.
(J. Am. Chem. Soc. 1995, 3881 and J. Org. Chem. 1995, 8136)
Chem 206 Due: Friday, Nov. 10

Question 10. Solladie has used a chiral sulfoxide as an

R=H: (+)-compactin HO O
auxiliary for the enantioselective synthesis of the lactonic
R=Me: (+)-mevinolin
moiety 1 of (+)-Compactin and (+)-Mevinolin. O
O
Me O
Me

O O O i. NaH (1 eq) O O O O
ii. t-BuLi (2 eq)
S
MeO iii. O MeO pTol
2
S pTol
MenthylO DIBAL, THF
44%

O OH OH O O O OH O
Et2BOMe, NaBH4, 99%
S S
MeO pTol MeO pTol
dr > 99:1 dr > 99:1

Explain which stereoselectivities are observed in the two reduction steps illustrated above. Use clear 3D
drawings for the transition states.
Your answer should also include an explanation for the observation, that the reduction of 2 in the presence
of ZnCl2 shows a reversal in diastereoselectivity (dr = 5:95 on a model of 2 with a truncated side-chain).

DIBAL-Reduction: Solladie sugests: However:

dipole minimized; sulfoxide is a strong donor which
ZnCl2 forms a chelate with the most attack from the less shielded coordinates the Al;
basic oxygen (S-O): face (lone pair)
internal delivery of the H-

H H
Cl iBu O
O R
S Zn Al
p-Tol Cl Bui H R
O S S
O p-Tol O
O p-Tol
R

NaBH4-Reduction: Et2BOMe is a powerful chelating agent

It reacts with ROH and activates the adjacent carbonyl.
NaBH4 delivers an external hydride

Et
H
B
R O Et
O
R
(JOC 1995, 60, 7774 and TetLett 1985, 26, 435).