answersanswers chem 330 final exam december 8, 2010 your name: this a closed-notes, closed-book exam...

ANSWERS

CHEM 330

Final Exam December 8, 2010

Your name:

This a closed-notes, closed-book exam

The use of molecular models is allowed

This exam contains 10 pages

Time: 2h 30 min 1. ________ / 20 2. ________ / 20 3. ________ / 20 4. ________ / 30 5. ________ / 40 6. ________ / 40 7. ________ / 40 8. ________ / 40 TOTAL ________ / 250 = ________ / 100

This exam counts for 45% of your CHEM 330 final grade

Chem 330 final exam p. 2 of 10 Chem 330 final exam p. 2 of 10

1. (20 pts.) Indicate the approximate pKa for the dissociation of the H in boldface in the substances listed below

O

H

tert-BuO–H

NH

O

OEtH

approx.pKa =

EtO

O O

OEtH

O

O HH

approx.pKa =

OSO

CF3 O–HH–H

H OH

H

2. (20 pts.) Write a chemical equation to show an example of (do not write mechanisms – just the reactions): a. A cross-Claisen reaction that will work well under conditions of reversible enolate formation: b. An Evans aldol reaction that occurs between stereochemically matched reactants: c. A nucleophilic addition to a chiral aldehyde that occurs in accord with the Felkin-Ahn reactivity model: d. A nucleophilic addition to a chiral aldehyde that occurs in accord with the Cram-Felkin reactivity model:

1. (20 pts.) Indicate the approximate pKa for the dissociation of the H in boldface in the substances listed below –2 20 25 19 14 40 50 37 –10 5

2. (20 pts.) Write a chemical equation to show an example of (do not write mechanisms – just the reactions):

a. A cross-Claisen reaction that works well under conditions of reversible enolate formation: b. An Evans aldol reaction that occurs between stereochemically matched reactants: c. A nucleophilic addition to a chiral aldehyde that occurs in accord with the Felkin-Ahn reactivity model: d. A nucleophilic addition to a chiral aldehyde that occurs in accord with the Cram-Felkin reactivity model:

COOEt CH3–COEt

NaH, cat.EtOH

COOEtN

O

N

N

O

O

OBBu Bu

Bn

HCHO

+H

O

Xc

OH

H

H

OTMS

OMeHCHO +

OMeH

OOHHEt2O•BF3

OTMS

HCHO +

H

OOHHEt2O•BF3

Chem 330 final exam p. 3 of 10

e. An Evans aldol reaction that occurs between stereochemically mismatched reactants: 3. (20 pts.) Write accurate mechanisms for the following known reactions:



a.O

N 150 °C

COOEt O

EtOOC+ CH3–CN

N

O

OCOOMe

May be rendered as

while writing the mechanismN

NN

OEtOH

catalyst A =catalyst A

N

HO

O

COOMe

Me Me

b.



a.O

N 150 °C

COOEt O

EtOOC+ CH3–CN

N

O

OCOOMe

May be rendered as

while writing the mechanismN

NN

OEtOH

catalyst A =catalyst A

N

HO

O

COOMe

Me Me

b.

O

N

EtOOC

N

EtOOC

OO

EtOOC

Me CN

Diels-

Alder

retro-Diels-

Alder

clearly aBaylis-Hillmanreaction: N

MeOOC

N

MeOOC

NMe

O

O

NMe

O

OMeOOC N

± H+

NMe

O

HOMeOOC N

NMe

O

HOCOOMe

N+

N

O

O

OBBu Bu

BnOMeHCHO

+OMeH

O

Xc

OH

H

H


4. (30 pts.) Briefly rationalize the stereochemical outcome of the following reactions and write clear diagrams to illustrate your arguments: a. The major product of the Mukaiyama aldol reaction of A with B is compound C if BF3 is used as the promoter, but compound D if TiCl4 is used instead:

b. In the presence of BF3, the Danishefsky diene undergoes a Diels-Alder-like reaction with aldehyde E, acting now as a dienophile, to give F as the major product:


4. (30 pts.) Briefly rationalize the stereochemical outcome of the following reactions and write clear diagrams to illustrate your arguments:

a. The major product of the Mukaiyama aldol reaction of A with B is compound C if BF3 is used as the promoter, but compound D if TiCl4 is used instead:

CHO

MeO

OTMS+

BF3 TiCl4O

MeO

OHO

MeO

OH

A BCD


CHO

OTMS

OMe

BF3

O

H H

HOTMS

OMe

E F


4. (30 pts.) Briefly rationalize the stereochemical outcome of the following reactions and write clear diagrams to illustrate your arguments:

a. The major product of the Mukaiyama aldol reaction of A with B is compound C if BF3 is used as the promoter, but compound D if TiCl4 is used instead:

CHO

MeO

OTMS+

BF3 TiCl4O

MeO

OHO

MeO

OH

A BCD


CHO

OTMS

OMe

BF3

O

H H

HOTMS

OMe

E F

the regiochemical course of the reaction is in accod with atomic polarization:

the diene attacks the C=O group inaccord with the Cram-Felkin reactivity model:

the reaction occurs with exo topology due to the lack of secondary orbital interactions:

HOF3BPh

MeH

OTMSMeO

Si-faceattack(Cram-Felkin)R

O

H

OMe

OTMS(–)

(+)(–)

(+)

(–)(+)

Ph

OH

MeH

OTMS

MeO

exo-topology(less steric

compression)prevails

PhH

MeH

MeO

OTMSO

NO SOI's!!!

So:

Ph

OH

MeH

OTMS

MeOH

F

Product C forms in accord with the Felkin-Anh model from the aldehyde-BF3 complex i :

O

HOMe

BF3

H O BF3

MeO

H

OTMS

Re-faceattack

(Felkin-Anh)

i

H O BF3

MeO

H

OTMS

C

Product D forms in accord with the Felkin-Anh chelated model from the aldehyde-TiCl4 complex ii :

H

OMeO TiCl4

2ii

HOCl4TiO

H

OTMS

Me

2

Si-faceattack

(chelatedFelkin-Anh)

OCl4Ti

H

OTMS

DMeOH

2



5. (40 pts.) Complete the following diagrams by writing all the missing reagents / intermediate products in the appropriate boxes. Important: (i) aqueous workups are understood; (ii) compounds must be drawn with the correct configuration of all stereogenic centers. a.

NN

EtOOCO

PhPhheat, then

mild H3O+NBn

COOEt COOEt

(Org. Lett. 2010, 12, 5146) b.

(Org. Lett. 2010, 12, 5530)

Cy2B-ClEt3N, then

OHCOTBS

NaBH(OAc)3

OTBSOHBnO OH c.

EtOOCTES-O

OHCTES-O

1.

2.

O

OMeNO

O

Ph

A B

and

then:

5. (40 pts.) Complete the following diagrams by writing all the missing reagents / intermediate products in the appropriate boxes. Important: (i) aqueous workups are understood; (ii) compounds must be drawn with the correct configuration of all stereogenic centers.

PhCH2NH2 NaH, cat. EtOH

DIBAL Bu2BOTf

Py•SO3 DMSO Et3N then Et3N

NO

O OOMe

BBu Bu

Ph

N

NH H

EtOOC COOEtPh

Ph

BnO O OTBSOHBnO O


(Org. Lett. 2006, 8, 2791)

1.

2.

3.

XcCHO

O

OMe

OTIPS

A + B

6. (40 pts.) Predict the structure of the major product expected from the following reactions. Notes: (i) it is not necessary to draw mechanisms; (ii) aqueous workups at appropriate stages are understood.

1. NaH, cat. EtOH then CH2=CH-CH2Br

2. Aq. NaBr, DMSO, reflux

EtOOC COOEta.

b.

I I

COOH

1. SOCl22. Meldrum's acid, Et3N

3. , reflux

4. excess NaH,

HO

O

Me 1. Li, liq. NH3then

O2. CH3ONa

c.

TIPSOTf Et3N TBAF Py•SO3 DMSO then Et3N



(Org. Lett. 2006, 8, 2791)

1.

2.

3.

XcCHO

O

OMe

OTIPS

A + B




EtOOC COOEta.

b.

I I

COOH


3. , reflux

4. excess NaH,

HO

O


O2. CH3ONa

c.


(Org. Lett. 2006, 8, 2791)

1.

2.

3.

XcCHO

O

OMe

OTIPS

A + B




EtOOC COOEta.

b.

I I

COOH


3. , reflux

4. excess NaH,

HO

O


O2. CH3ONa

c.


(Org. Lett. 2006, 8, 2791)

1.

2.

3.

XcCHO

O

OMe

OTIPS

A + B




EtOOC COOEta.

b.

I I

COOH


3. , reflux

4. excess NaH,

HO

O


O2. CH3ONa

c.

Xc OTES

O

OMe

OH

O

O

OO

O

H

H



d.O

N1. LDA, THF

2. Ph-CHO

e.

O 1. 9-BBN-OTf Et3N

2. Ph–CHO

f.O-TBS

CHO

Me

OEt

O 1. LDA, THF

2.

CHO

excessHCHO

aq. NaOHg.

h. OEt

O 1. LDA, THF / HMPA

2. Ph–CHO


d.O

N1. LDA, THF

2. Ph-CHO

e.

O 1. 9-BBN-OTf Et3N

2. Ph–CHO

f.O-TBS

CHO

Me

OEt

O 1. LDA, THF

2.

CHO

excessHCHO

aq. NaOHg.

h. OEt


2. Ph–CHO


d.O

N1. LDA, THF

2. Ph-CHO

e.

O 1. 9-BBN-OTf Et3N

2. Ph–CHO

f.O-TBS

CHO

Me

OEt

O 1. LDA, THF

2.

CHO

excessHCHO

aq. NaOHg.

h. OEt


2. Ph–CHO


d.O

N1. LDA, THF

2. Ph-CHO

e.

O 1. 9-BBN-OTf Et3N

2. Ph–CHO

f.O-TBS

CHO

Me

OEt

O 1. LDA, THF

2.

CHO

excessHCHO

aq. NaOHg.

h. OEt


2. Ph–CHO


d.O

N1. LDA, THF

2. Ph-CHO

e.

O 1. 9-BBN-OTf Et3N

2. Ph–CHO

f.O-TBS

CHO

Me

OEt

O 1. LDA, THF

2.

CHO

excessHCHO

aq. NaOHg.

h. OEt


2. Ph–CHO

Ph N

OH

H

H O

Ph

OH

H

H O

Ph

TBSO OH

OEt

O

OHOH

OH

Ph OEt

OH

H

H O


7. (40 pts.) Complete the following equations by indicating all the reagents that are necessary to effect the transformations shown. Provide your answers as a numbered list of reagents, in the correct order, written over/under the reaction arrows.

Note: aqueous workups are understood and are not to be included in your answers.

a.

OPh Ph

O O

b.

OMe

TBSO O

OMeOMe

TBSO O O

OEt

O OCOOEtc.

d. CHO

TBSO TBSO OTBS

e.

O O

7. (40 pts.) Complete the following equations by indicating all the reagents that are necessary to effect the transformations shown. Provide your answers as a numbered list of reagents, in the correct order, written over/under the reaction arrows.

Note: aqueous workups are understood and are not to be included in your answers. 1. TMS-I, TMS2NH 2. O3, then Zn / H+

3. EtOH, H+ 4. tert-BuOK 1. aq. LiOH 4. tert-BuOK 2. CDI 5. (EtO)2C=O 3. Me-CH=C(OEt)OLi (from EtCOOEt + LDA)

1. LDA, then PhSeBr 4. tert-BuOK 2. MCPBA, then heat 5. (EtO)2C=O 3. Me2CuLi, then NaH, cat. I–(CH2)5–I , TMEDA EtOH

OEt

OLiCOOEt

LDA, THF

–78 °C1.

2. TBSCl, Et3N 4. Py•SO3, DMSO, then Et3N3. DIBAL 5. Ph3P=CH2

1. TMSOTf, Et3N

2. , TiCl4PhCl


8. (40 pts.) Propose a method to achieve the enantioselective synthesis of the molecules shown below starting with the suggested building blocks. Be careful about protecting groups and configurations of stereocenters. Assume the availability of all needed reagents, auxiliaries, etc. Present your answer as a clear flowchart.

It is not necessary to draw mechanisms or to indicate aqueous workups.


8. (40 pts.) Propose a method to achieve the enantioselective synthesis of the molecules shown below starting with the suggested building blocks. Be careful about protecting groups and configurations of stereocenters. Assume the availability of all needed reagents, auxiliaries, etc. Present your answer as a clear flowchart.

It is not necessary to draw mechanisms or to indicate aqueous workups.

starting with:a.

I

OTBSOTBS

TBSO OH

OH

COOEt

1. tert-BuLi2. (Bu3P)2CuI

3. COOEt

COOEt

OTBSOTBS

OEt

TBSO OH O

DIBAL

OTBSH

TBSO O

OEt

OLi LDATHF

–78 °C

(Cram-Felkin)

OTBSXc

TBSO O

1. DIBAL2. Py•SO3, DMSO then Et3N

Bu2BOTf, Et3N

OTBSXc

HO O

TBSCl, Et3N

OTBSH

O

N O

O O

Me Ph

N O

O O

Me Ph

BBu Bu

+

OTBSO

Ph3P=CH–CHO

H

TPAPNMO

OTBSOH

DIBAL


alternative answers may be acceptable

Happy Holidays !


TBSO

Ob. starting with:

OHCOOH

Happy Holidays !

Xc

OH O

Cy2BOTf

Et3N

N O

O O

Bn

N O

O O

Bn

Li

LDA

TBSO

1. aq. LiOH2. TBAF

XcOBCy2 N O

Me PhO

BnSO2

O

TBSO

H

Py•SO3DMSOthen Et3N

OH

TBSODIBAL

O

TBSO

XcBr

TBSO

OH

TBSO

PBr3

COOEt

TBSO

DIBAL

Ph3P=CHCOOEt

O

TBSO

H

H

O

answersanswers chem 330 final exam december 8, 2010 your name: this a closed-notes, closed-book exam...

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