ANSWERS

CHEM 330

Final Exam December 5, 2014

Your name:

This a closed-notes, closed-book exam

The use of molecular models is allowed

This exam consists of 12 pages

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

This exam counts for 50% of your CHEM 330 final grade

Chem 330 final exam p. 2 of 12

1. (30 pts.) Write a chemical equation and a brief sentence to illustrate each of the following mechanistic models: a. Principle of vinylogy the interposition of a C=C unit between the components of a functional group generates a new functional entity, which retains the chemical characteristics of the original. For instance:

b. Fürst-Plattner rule electrophilic cyclohexene derivatives (epoxides, halonium ions, ...) react with nucleophiles to form trans-diaxial products selectively. Example:

c. Felkin-Ahn model an α-heterosubstituted aldehyde is most reactive toward nucleophilic addition when the C–α-heteroatom σ bond is approximately perpendicular to the plane of the C=O group. Nucleophilic attack then occurs preferentially from a conformation in which the incoming nucleophile can approach along a Dunitz-Bürgi angle from the side of the smaller α-substituent. To illustrate:

OC CH2

H: B

an enolizable carbonyl compound: deprotonation is possible because of resonance delocalization of (–) charge on the eletronegative O atom

a vinylog of the original: resonance delocalization of (–) charge on the O atom still possible through the C=C bond: can undergo deprotonation

OC C=C–CH2

HB :

Br2H

Br

HBr

H

Br

H HBr

H

only

=

HMeONu

OMe

H Ph

H OH

Nuproduct formed selectively

OMe

H PhH O Nu

OH

HMeOH

O Nu= =

Chem 330 final exam p. 3 of 12

2. (30 pts.) Write a chemical equation to show an example of a reaction that involves the use of the following nitrogen-containing reactants (do not write mechanisms – just the reactions):

a. Me3Si NHSiMe3

O

TMS2NH

TMS–I OTMS(Miller reaction)

b. NN

(Baylis-Hillman reaction)O

H

COOMe+

NN

catalyticCOOMe

OH

Chem 330 final exam p. 4 of 12

c. H2N N(CH3)2

O

H

H2N–NMe2 N

H

NMe2 BuLi, then

PhCH2Br

N

H

NMe2

Ph

H3O+ O

H

Ph

d. N N NN

O

O

OH + N N NN

O

N N

Oused, e.g., forcross-Claisencondensations

e.N

N

catalytic+ strong amidine base,

used, e.g., to promoteMichael addition ofstabilized enolates

N

N

O O

OEt CHO

O O

OEt

CHO

Chem 330 final exam p. 5 of 12

3. (30 pts.) Check the appropriate box to indicate whether the following statements are true or false:

a. Reaction of A with catalytic MeONa yields B: true false

H

H

O

OA B

H

H

O

O

cat.

MeONa

b. Reaction of C with maleic anhydride yields D: true false

AcO

Me3Si

O

O

O

+

C D

Me3Si

O

AcO

H

H H

H O

O

c. The reactants shown below are stereochemically matched: true false

O

H +O N

Ph

OB

Cy Cy

BnMes

OH O

Xc

d. The copper atom undergoes oxidative addition in the course of the following reaction:

true false

CuCl2 + 2 LiCl Li2CuCl4

e. The following procedure is satisfactory for the preparation of the cyclic product shown

true false

O

OEt

O

OEtO 2 equiv NaH

I–(CH2)4–I

O

Chem 330 final exam p. 6 of 12

f. The following procedure is satisfactory for the synthesis of the triol shown

true false

O

H

excess H–CHO

NaOH HO OHHO

O

O

O

+

g. The Diels-Alder reaction of furan with maleic anhydride gives the exo-adduct due to a lack of secondary orbital interactions

true false

O

O

HH O

OO

h. The process shown below is a reverse Claisen condensation: true false

O

OEtEtOH

cat. EtONa

O COOEt+ CH3–COOEt

i. Treatement of E with NaH / cat. EtOH, followed by mild H3O+, will produce F:

true false

NaH, cat. EtOH

then mild H3O+

O

COOEt

EtOOCEtOOC COOEt

EtOOC

E F

j. Treatment of G with Li in liquid NH3, followed by allyl bromide and then catalytic MeONa, will produce H

true false

1. Li, NH3 (liq), then CH2=CH-CH2Br

2. cat. CH3ONaOO H

H

HG H

Chem 330 final exam p. 7 of 12

4. (40 pts.) Provide a succinct explanation for the following experimental observations:

the remaining 0.05 equivalents of ketone A act a proton source ("shuttle") and induce equilibration of the initially formed kinetic enolate to the thermodynamic one

the cuprate tends to attack in an axial mode, in such a way that the 6-membered ring evolves toward a chair (or half-chair) conformer. This constitutes the more energetically favorable reaction pathway

as expressed by the principle of least motion, atoms within a molecule tend to undergo the least possible extent of repositioning during a reaction. In the present case, compound F (the resultant of α-alkylation of the dienolate of E) forms through a process that requires the repositioning 3 out of 5 non-H atoms of the substrate. The hypothetical γ-alkylation requires the repositioning of all 5 atoms. Therefore, compound F is formed preferentially

a COOMe group lowers the LUMO energy of a π bond, while a CH3O group increases it. This is a regular-demand DA reaction, so the key FMO interaction is between the HOMO of the diene and the LUMO of the dienophile. The HOMO-LUMO energy gap for reaction at the COOMe-substituted π bond is smaller. Therefore reaction at the COOMe-substituted π bond is faster

a. Deprotonation of ketone A with 0.95 equiv of LDA, followed by reaction with TMS-Cl, produces silyl enol ether B, BECAUSE: O

1. LDA (0.95 equiv)

2. TMSCl TMSOA B

b. Reaction of compound C with Me2CuLi, followed by mild H3O+, selectively yields D, BECAUSE:

O

O

Me2CuLi

thenmild H3O+

O

OC D

PhH

H

Ph

c. Treatment of compound E with LDA, followed by benzyl bromide, selectively yields F, BECAUSE:

EtOOCLDA

thenPh-CH2Br

EtOOC

E FPh

d. Benzoquinone G undergoes Diels-Alder reaction selectively at the double bond bearing the COOMe group, BECAUSE:

MeOOC

H

O

OG HOCH3

MeOOCO

OOCH3

Chem 330 final exam p. 8 of 12

5. (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.

O

1. NaH, cat. EtOH

2. NaH,

3. NaI, aq. DMSO reflux

EtO

O

OEt

Br

a.O

OCH3

CHO

OTMS

BF3b.

OCH3

OH O

OCH3

CHO

OTMS

TiCl4c.

OCH3

OH O

COOMe

COOMe

Ph2CuLid.OH

COOMePh

O

OEt

1. LDA, THF HMPA, –78 °C

2.3. TBAF4. TPAP / NMO

e.

CHOTBSO

O O

OEt

O

H

H

Chem 330 final exam p. 9 of 12

f.

O 1. LDA, THF –78 °C

2. Me–CHO3. NaBH(OAc)3

OH OHH

HH

g.

1.

NH4OAc, heat

2.

cat. NaOEt3. NH3, NH4OAc

O O

OEt

O O

OEt

Cl

CHO

Cl

NH

COOEt

EtOOC

ON

OO1. LDA, THF, –78 °C

2.

3. DIBAL4. O3, then Zn / H+

h.I

Ph

O

H

OH

Bn

ON

OO

1. Bu2BOTf, Et3N2.

3. TBSCl, Et3N4. MeOH, cat. K2CO3

h.

O

H OTBSCOOMe

j.O

O

H heat

OMeMeOPh3P COOMe

O

MeO

MeOH

COOMe

Chem 330 final exam p. 10 of 12

6. (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 do not need to be included in your answers.

a.

O

O

MeO

MeOOH

OHH

H

1. CH2=CH–CH=CH22. NaH, CH3I

3. cat. OsO4, NMO

1. LDA, then CH3I2. TMS2NH, TMS-I3. MeLi, then CH2=CH-CO-Et

4. NaOMe5. LDA, then PhSeBr6. MCPBA, then heat

b.O

Me

O

c.O

OH

O O

OEt1. CDI2. add to enolate of

Ph–CH2COOEt (prepared by deprotonation with LDA)

Me2CuLi, then

CH2=CH-CH2Br TMEDA

d.O O

Chem 330 final exam p. 11 of 12

7. (40 pts.) Propose a method to achieve the enantioselective synthesis of the molecules shown below starting with the suggested compounds plus any additional building blocks that might be required (simple carbonyl compounds, alkyl halides,…). 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.

OHHHO OO TBSO O

Hstarting witha.

OHHO OO

H

O OO

HO OO

OLi

Et2BOMeNaBH4

Pyr•SO3DMSO

thenEt3N

TBSO OOTBAF

TBSO OHOH

TBSO OOH

Xc

Ph

ON

OOBBu Bu

H H

+

DIBAL

O, cat. H+

Chem 330 final exam p. 12 of 12

Happy Holidays !

ON

OOBBu Bu

Bn

starting with

TBSO

I

TBSOb.

O

O

O

t-BuLi Li

TBSO

(Bu3P)2CuBr

Cu(PBu3)2

TBSO

TBSO

O

Xc

CH2=CH-CH2BrTMEDA

TBSO

OH

O

COOEt

TBSO

TESO

O

COOEt

TBSO

TESO

N

O

TBSO

TESO O

OH

TBSO

TESO O

Xc TBSO

O

H

TBSO

OH

TBSO

O

Xc

ON

O

Bn

O

DIBAL

cat. acidor base

TBAF(1 equiv)

N

OLi

OEt

CDI

aq. LiOH, thenmild H+

pyr•SO3DMSOthen Et3N