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:
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.
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.
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
Chem 330 final exam p. 4 of 10
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:
Chem 330 final exam p. 4 of 10
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
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:
CHO
OTMS
OMe
BF3
O
H H
HOTMS
OMe
E F
Chem 330 final exam p. 4 of 10
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
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:
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
Chem 330 final exam p. 5 of 10
Chem 330 final exam p. 5 of 10
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
Chem 330 final exam p. 6 of 10 Chem 330 final exam p. 6 of 10
(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
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.
Chem 330 final exam p. 6 of 10
(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.
Chem 330 final exam p. 6 of 10
(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.
Chem 330 final exam p. 6 of 10
(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.
Xc OTES
O
OMe
OH
O
O
OO
O
H
H
Chem 330 final exam p. 7 of 10
Chem 330 final exam p. 7 of 10
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
Chem 330 final exam p. 7 of 10
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
Chem 330 final exam p. 7 of 10
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
Chem 330 final exam p. 7 of 10
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
Chem 330 final exam p. 7 of 10
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
Ph N
OH
H
H O
Ph
OH
H
H O
Ph
TBSO OH
OEt
O
OHOH
OH
Ph OEt
OH
H
H O
Chem 330 final exam p. 8 of 10 Chem 330 final exam p. 8 of 10
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
Chem 330 final exam p. 9 of 10
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.
Chem 330 final exam p. 9 of 10
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
Chem 330 final exam p. 10 of 10
alternative answers may be acceptable
Happy Holidays !
Chem 330 final exam p. 10 of 10
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