Chapter 7 1

CHAPTER 7
1. Predict the correct diastereomeric product using (a) the appropriate Cram model and (b) the
Felkin-Anh model. In each case, draw the model for that specific reaction.
1. In each case, the Cram model is shown first and then the Felkin-Anh model, both in Newman
projection. The diastereomer that is predicted to be the major product is also shown.

(a)

O OH O HO
C3H7 H C H HO H H C3H7 C3H7 OH
3 7
• • • • H

H H

CRAM FELKIN-ANH

(b)
O HO
O Me Me Naphth OH
HO H H
Me H Me
•
Naphth OH Naphth • Naphth • H
• Me
H H
Me Me Me
Me Me
Naphth CRAM Naphth FELKIN-ANH

(c) In this case, reduction does not generate a chiral center, so the model used is irrelevant.
Nonetheless, the models are shown.

MeOH2C MeOH2C O HO
O H H Ph OH
HO H H
OH
• Ph • H
• • Ph MeO H
H CH2OMe
CH2OMe
H Ph Ph H H
H H H
CRAM FELKIN-ANH

(d)

O
O O OH
O Me
N H H
N O N H
O Me •
HO N H • N OH
H
• N H
• Et Et
OH Me O Me O
H Et Et
Me H Me
CRAM FELKIN-ANH
2 Organic Synthesis Solutions Manual

2. Predict the major product and explain the stereochemistry for that product.
Me O Me O
O
NaBH4 , CeCl3

CO2H
See J. Org. Chem. 1998, 63, 1259
2.
Cerium borohydride gives selective 1,2-reduction of the conjugated ketone, delivering hydride
from the bottom face to give the alcohol. This alcohol unit then reacts with the free carboxyl to form the
lactone. Examination of the molecular model clearly suggests that attack from the top face (A) is
blocked by both the methyl group and the —CH2COOH group. The bottom face (B) is unencumbered,
leading to the stereochemistry indicated for reduction of the ketone to the alcohol and shown in the
lactone. The LUMO map shows that attack from the bottom face, to give the alcohol precursor required
to give the lactone product, is slightly preferred.

Top Bottom
B

3. In each case, predict the major diastereomer. Explain your answer.

3. (a) The conformation of this molecule is shown in the usual half-chair of a cyclohexenone
derivative. Since cerium borohydride will give selective 1,2-reduction, the main issue is
stereochemistry. The bulky siloxymethyl group on the bottom blocks approach from that face.
Therefore, approach is from the top to give the stereochemistry shown for the alcohol product.

Ts A

O OH N
H
NaBH4•CeCl3 O
Via EtO
EtO N EtO N H
Ts OSiPh2t-Bu Ts OSiPh2t-Bu
B OSiPh2t-Bu
see Synthesis 1999, 1889
 Chapter 7 3

(b) To predict the stereochemistry of this reduction, we can examine a molecular model of the
ketone. The gem-dimethyl unit as well as the other bridgehead methyl sterically block path A, but path
B is relatively open and predicts the major product. Alternatively, a LUMO map of the ketone shows a
more intense blue color exposed to face B, so delivery of hydride will be from that face.

Me Me
Me Me
Me LiAlH4 , THF Me

0°C Me
Me
H H
OBn H OBn
H OH
O see J. Org. Chem. 2000, 65, 7865 B

(c) Coordination of the alcohol moiety with zinc borohydride modifies the conformation, as
shown, to deliver hydride from behind. The result is the diastereomeric trans diol shown.

Me Me
Me
H OH
H
OH O
H O
H O Zn H
H4B BH4 OH

(d) The ethyl group effectively blocks one face of the azabicyclooctane ring. Delivery of
hydride from the direction of the arrow leads to the diastereomeric alcohol shown.

O HO H

Et Et

H H N
N

Naphth Naphth
4 Organic Synthesis Solutions Manual

4. Explain why there is such a difference in selectivity for reduction of this conjugated ketone
when the reducing agent is changed.
4. The first step is to look at the actual conformation of the steroid. Using the usual model for
conjugated ketones with “R” being the steroid ring, predictions can be made for reduction of the
carbonyl. Diisobutylaluminum hydride will coordinate to the carbonyl oxygen, restricting the angle
from which hydride will be delivered. This coordination leads to delivery of hydride via a complex that
gives anti-Cram selectivity and generates the diastereomer labeled α. Selectride, however, does not
coordinate, and delivery will be from the less sterically hindered pathway (Cram selectivity), as shown,
to give the β-diastereomer. See Tetrahedron Lett. 1985, 26, 69.

H i-Bu
H Me R Al
Me O i-Bu
Me
H H
Me H • O
H Me
H Me
H
THPO
Selectride
Selectride
Me H Me OH Me
Me H Me Me
H H
O • H • H • H
iBu HO H
Al R R β R α
iBu H

5. Briefly discuss this transformation.

5. The first step of this reaction is reduction of the ketone unit to give an alcohol. Treatment with the
basic reagent tert-butoxide leads to an alkoxide product, as shown. With the tosylate unit properly
positioned, a Grob-like fragmentation is possible, leads to the aldehyde and the alkene units in the final
product.

OTs O OH O
TsO TsO CHO

LiBEt3H KOt-Bu H H
H H H H
H H
Ph N CO2Et
Ph N CO2Et Ph N CO2Et Ph N CO2Et
CO2t-Bu
CO2t-Bu CO2t-Bu CO2t-Bu
see J. Org. Chem. 1999, 64, 4304
 Chapter 7 5

6. Predict the major product of both reactions, (A and B), predict the stereochemistry of each
product, and explain your choices.
6. The reaction products shown are taken from the cited reference. The first step is epoxidation of the
C=C unit with meta-chloroperoxybenzoic acid. (mcpba). The Spartan model shown can be interpreted
in several ways: the methyl group on the adjacent allylic carbon can provide steric hindrance, or the
bridgehead methyl on the lower face could block the reaction. In fact, the lower face is more hindered,
and epoxidation occurs from the top face, in 81% yield. Lithium borohydride opens the epoxide, this
time from the lower face, and regioselectively at the less sterically hindered carbon (see model) to give
the alcohol shown.

OSiMe2Thex
OSiMe2Thex

mCPBA
A O
Na2CO3 O
O
H
H
O
O
OSiMe2Thex
see J. Org. Chem., 2003, 68, 3831

LiBEt3H , THF
B OH
O
H
O

7. Briefly discuss the following transformation, particularly focusing attention on the

stereochemistry.
7. Inspection of the molecular model shows that path A is blocked by the methyl group, so reduction
with LiAlH4 occurs by attack via path B, which gives the stereochemistry shown for the allylic alcohol.
Both 1,2- and 1,4-addition are possible, so LiAlH4 is used in ether at low temperature to maximize 1,2-
addition. The second reaction is simply a Mitsunobu reaction with the alcohol, first forming the
benzoate ester with inversion of configuration, and the treatment with methanolic KOH to give the
requisite alcohol.

LiAlH4 , ether A
-20 °C
O OH

PPh3 , DEAD , PhCOOH

then KOH/MeOH
B
OH
see Synthesis 1998, 495
6 Organic Synthesis Solutions Manual

8. Explain each of the following observations or products.

8. (a) Aluminum hydride coordinates effectively to the oxygen of the carbonyl. 1,4-Reduction
demands delivery of hydride to carbon via path B, whereas 1,2-reduction demands delivery via path A.
Once bound to oxygen, the distance between H and the terminal C of the C=C unit via path B is rather
long, making delivery difficult. Delivery via path A is facile due to the relatively short distance between
the carbonyl C and H. Coordination to oxygen therefore inhibits 1,4-addition and promotes 1,2-
addition.

H A H H
Al
H
H
O
H
H

(b) L-Selectride is much more bulky than sodium borohydride. On approach to the carbonyl
carbon, this steric bulk will maximize steric interactions with the indane ring system and lead to greater
selectivity relative to NaBH4. Using the Cram model, the diastereomer shown is predicted to be the
major product.

H O OH
H H
H H H H
H H
•

O H

(c) In this reaction, sodium transfers an electron to benzene to generate radical anion A. The
proximity of the single electron and the negative charge (2 electrons localized on that carbon) destabilize
A due to electrostatic repulsion. The resonance form (B) diminishes electrostatic interactions and is
energetically favored. Transfer of hydrogen atoms to B leads to the final product, cyclohexa-1,4-diene.
• •

A B
 Chapter 7 7

(d) Transfer of an electron from sodium to anisole can generate two different regioisomeric
radical anions, A and B. The proximity of the negative charge to the electron donating OMe group
destabilizes A, making B energetically more favorable. This leads to the product shown. Similar
reaction with benzoic acid leads to C and D as the possible radical anions. In this case, the electron
withdrawing carboxylate group stabilizes the adjacent negative change in C, making it more stable than
D where the charge is distal to the carboxylate group. Therefore, C leads to the major product shown.

OMe OMe OMe OMe

•

•
A B
CO2H CO2– CO2– CO2H

•
C D

(e) Lithium aluminum hydride is a powerful reducing agent due to the charge distribution and
polarity of the Al—H moiety. It will reduce ester groups, acid groups, and carboxylate anion groups.
Since LiAlH4 will reduce both the ester and the acid, the product is a diol. Borane coordinates with the
acid but not with the ester. It will therefore transfer hydride only to the acid and not to the ester, and the
acid is reduced and the ester is not. The product is a hydroxy-ester.

(f) This reduction occurs via a six-centered transition state, as shown.

R H
N

N
R H
When the alkene is symmetrical and not polarized, electron density is readily transferred to
hydrogen, leading eventually to expulsion of N2, which drives the reaction. When the alkene is
conjugated to a carbonyl, the electron donating ability of the alkene is diminished, slowing the reaction
by destabilizing the requisite six-centered transition state. See J. Am. Chem. Soc. 1961, 83, 4302.

(g) In A there is a neighboring group effect where the OH group coordinates with zinc
borohydride and delivers hydride from the same face as the hydroxyl group. When the OH is blocked as
the silyl derivative, zinc borohydride cannot coordinate, and the usual steric effects lead to delivery of
hydride from the face opposite the OSiR3 group.
8 Organic Synthesis Solutions Manual

(h) This transformation is taken from J. Am. Chem. Soc. 2002, 124, 12416. Birch reduction of
the naphthalene unit containing the electron releasing OMe groups is expected to give the reduced
product shown. Aqueous hydrolysis converts the vinyl ether to the ketone, but the C=C unit in the
ketone-bearing ring will move into the other ring to form the aromatic ring, rather than into conjugated
with the carbonyl. Aromatization is the driving force leading to the major product.
OMe OMe O O
Na , EtOH aq HCl
MeO MeO MeO MeO
reflux reflux
OMe A OMe OMe OMe B

9. For each transformation, give two different reagents that will successfully complete the given
conversion.
9. The first transformation can be effected with Sn/HCl (Stephen reduction; section7.11) or with
LiAlH(Ot-Bu)3. The second transformation can be effected with LiAlH4 or with LiBHEt3.

10. In each case, predict the major product of the reaction shown.
10.

O
O (CH2)4OPiv OPMB
CHO Me Me OPMB
O
(a) (b) (c) PMB = p-methoxybenzyl
Piv = pivaloyl
HO O
MeO
H OPMB OTIPS
OH
Org. Lett. 2003, 5, 4741 J. Am. Chem. Soc. 2003, 125, 12844
OMe
MeO CO2H
MeO Br PMB - p-methoxybenzyl
(d) (e) MeO2C N CO2Me (f)
MeO NH2 CO2t-Bu NHPMB
MeO
J. Org. Chem. 2002. 67, 8284 Org. Lett. 2003, 5, 999 Eur. J. Org. Chem. 2003, 1231
O
H
N
Br N Me
O
(g) (h) (i)
N
N Ph MeO H
t-BuMe2SiO HO
CO2t-Bu
OH
Org. Lett. 2002, 4, 1451 Org. Lett. 2003, 5, 1927 J. Org. Chem. 2004, 69, 1283
CO2Me H

NHCO2t-Bu Me Me
(j) (k) (l) CO2Me
HO N
N H CO2t-Bu
H t-BuMe2SiO OH
J. Am. Chem. Soc. 2003, 125, 5628 see J. Org. Chem. 1999, 64, 4477 Org. Lett. 2003, 5, 447
 Chapter 7 9

OH
PhMe2Si
CH2OH H
N H
(m) (n) (o)
O
N N Me
H
O OH
CH3
J. Org. Chem. 2003, 68, 4523 J. Org. Chem. 2003, 68, 2572 see J. Org. Chem. 1999, 64, 2184

H OSiPh2t-Bu
(p) O (q) N OSiMe2t-Bu (r) CHO
C15 H31 CN O
see Tetrahedron Lett. 2000, 41, 3467 Org. Lett. 2002, 4, 177 J. Am. Chem. Soc. 2002, 124, 4257

O I O
Me O
(s) HO (t) H (u)
OH O
OO
O
OH O O
H
Me
Org. Lett. 2003, 5, 3357 see J. Am. Chem. Soc. 1999, 121, 5176 see J. Chem. Soc., Perkin Trans. 1 2000, 2645
OMe
Me3Si MeO
Br O
Ph N
(v) (w) (x) CHO
OMe
OH OH OHC
NO2
J. Am. Chem. Soc. 2004, 126, 2194 J. Org. Chem. 2003, 68, 8162 J. Org. Chem. 2004, 69, 1598

O OTBS
OSiMe2t-Bu
O
(y) (z)
C13 H27 OH (aa) O

NHAc O

see Can. J. Chem. 1997, 75, 621 see Tetrahedron Lett. 2000, 41, 2765 see J. Org. Chem. 2002, 67, 4127
CH2OH
t-BuMe2SiO OH OH
N N
(ab) Ph Ph (ac) (ad) t-BuMe2SiO
Cl CO2Et
CH3
see Synlett, 1999, 182 J. Am. Chem. Soc. 2002, 124, 9476 J. Am. Chem. Soc. 2002, 124, 12806
10 Organic Synthesis Solutions Manual

11. In each case, provide a suitable synthesis showing all intermediate products and all reagents.
11. In each case a synthesis is shown. These are not necessarily the only approaches. It is very likely
there are many approaches for several of these questions.
(a) The acid hydrolysis of the vinyl ether to the ketone may also convert the methyl ester to the
acid. If this occurs, an esterification step (thionyl chloride; methanol) would be required. Mild acid
hydrolysis of the vinyl ether should be possible, however.

Me Me Me Me
O

a b c (a) Na , NH3 , EtOH

(b) aq H+ (c) O3 ; H2O2
MeO MeO O O
O

CO2Me CO2Me CO2Me CO2Me

(b) The first step requires a chain extension and converting the alcohol to its tosylate introduces
the requisite leaving group, allowing a subsequent reaction with NaCN to give the corresponding nitrile.
Dibal-H reduction of the nitrile gives the aldehyde.

OPMB OPMB OPMB

a b (a) 1. TsCl , pyridine 2. NaCN , DMSO (b) DIBAL-H , THF
see Tetrahedron Lett. 2000, 41, 33

HO NC OHC

(c) All steps in this synthesis are taken from Org. Lett. 2002, 4, 1379. Bromination of the allylic
alcohol (3.4.2) and SN2 displacement with cyanide gives the nitrile (3.2.1.1). Basic hydrolysis followed
by esterification with diazomethane (17.9.4), was followed by selenium dioxide oxidation to the
aldehyde (6.8.A1). Reduction of both the ester and aldehyde with LiAlH4 gave the diol (7.6.1), and
selective chlorination of the allylic alcohol with N-chlorosuccinimide (3.4.1) gave the final target.

OH Br CN CO2H

a b c d

CO2Me CO2Me OH OH
g
e f

OHC
HO Cl
(a) PBr3 t-BuOMe (b) KCN , DMSO (c) 25% KOH , MeOH (d) CH2N2 , ether
(e) SeO2 , t-BuOOH , CH2Cl2 (f) LiAlH4 , THF (g) NCS , Me2S , CHCl2
 Chapter 7 11

(d) The Wittig olefination step is discussed in Section 12.5.1.1.

OH OMe OMe OMe OMe OMe OH

a b c d e f
O O

OHC
(a) NaH ; MeI (b) Na , NH3 , EtOH (c) H2 , Pd (d) O3 ; Me2S (e) Ph3P=CH2 (f) LiAlH4

(e) All reagents are taken from the cited reference. The first reaction reduces the ester unit to an
alcohol. This is followed by conversion to a tosylate that allows Super-Hydride reduction to give the
methyl group. The O—SiR3 unit is cleaved with aqueous acid to give the corresponding alcohol
(5.3.1.2). The primary alcohol is then converted to the aldehyde by a Swern oxidation (6.2.3.1).

OSiMe2t-Bu OSiMe2t-Bu OSiMe2t-Bu

a b c
HOH2C
CO2Me CH2OTS
OSiMe2t-Bu OH H
d e
O
CH3 CH3 Me see Tetrahedron Lett. 2000, 41, 403
(a) DIBAL-H , toluene , -78 °C (b) TsCl , DMAP , NEt3 (c) LiEt3BH , THF (d) AcOH , aq THF (e) DMSO , (COCl)2 , NEt3

(f) All reagents are taken from the cited reference. Initial reduction of the acid to the alcohol
was followed by treatment with tosic acid. This led to an internal transesterification to the lactone, and
conversion of the dioxolone to the alcohol. Treatment with the dimethyl acetal of formaldehyde led to
the ether shown (a MOM group, 5.3.1.1), and Dibal-H reduction converts the lactone to a lactol.

O CO2H O
O O O O HO O
a b c d
O O
O O OH
HO O O O O
see J. Org. Chem. 2000, 65, 9129
(a) BH3 , THF ; H3O+ (b) p-TsOH , CHCl3 (c) CH2(OMe)2 , P2O5 (d) DIBAL-H , CH2Cl2
12 Organic Synthesis Solutions Manual

(g) All reagents are taken from the cited reference. Initial reduction of the ester unit (using Dibal-
H) gives the allylic alcohol. To insert the proper stereochemistry for the new alcohol unit, Sharpless
asymmetric epoxidation using (–)-DIPT (6.4.4.1) gives the epoxide and selective reduction of the less
sterically hindered carbon of the epoxide with Red-Al gives the final product.

O SiMe3 O SiMe3 O SiMe3

O a O b O
O
CO2Et
OH OH

O SiMe3
c see Tetrahedron Lett. 2000, 41, 2821
O OH

OH (a) DIBAL-H , CH2Cl2 , -78 °C (b) (-)-DIPT , t-BuOOH , Ti(OiPr)4 (c) Red-Al , THF

(h) A Friedel-Crafts acylation inserts the ketone moiety, and the Wolff-Kishner reduction
removes the carbonyl. Catalytic hydrogenation reduces not only the benzene ring but also the nitro
group in a single step.

C3H7 C3H7
O C3H7 C3H7
a b c d

Section16.4.D
NO2 NH2
(a) butanoyl chloride , AlCl3 (b) N2H4 , KOH (c) HNO3 , H2SO 4 ;
separate ortho product(d) excess H2 , Ni(R)

(i) All reagents were taken from Eur. J. Org. Chem. 2003, 4445. Reduction of the acid with
borane (7.3.1) was followed by bromination with carbon tetrabromide and triphenylphosphine (3.4.1).

CO2H HO Br

a b

Cl N OMe Cl N OMe Cl N OMe

(a) BH3•SMe2 , B(Me)3 , THF (b) CBr4 , PPh3 , benzene
 Chapter 7 13

(j) All reagents are taken from the cited reference. The first problem is how to remove the OH
group. If the OH is first converted to a tosylate, Finkelstein exchange (3.2.1.1) generates an iodide that
can be reduced with tin hydride. The ester is reduced to an alcohol with LiBH4, and aqueous acid
converts the dioxolane unit (a ketal) to the carbonyl (5.3.3.1). The final step is an oxidation. Several
methods can be used from Section 6.2, but the Dess-Martin periodinane reagent was used in this
citation.

O O
O O O O O O O O

EtO2C EtO2C EtO2C HOH2C HOH2C OHC

b c d N e N
N a N N N

O OH O OTs O O O O

OMe OMe OMe OMe OMe OMe

(a) TsCl , DMAP (b) 1. NaI , acetone 2. Bu3SnH , AIBN (c) LiBH4 , THF (d) HCl , aq. AcOH (e) Dess-Martin see J. Am. Chem. Soc. 1999, 121 , 7778

(k) Hydrogenation with a Lindlar catalyst sets the cis alkene geometry.

a b c Bu Bu
H H Bu H Bu Bu
(a) NaNH2 ; n-C4H9-I (b) NaNH2 ; n-C4H9-I (c) H2 , PdCO3 , quinoline

12. Show a complete synthesis for each of the following. Use any starting material of your
choosing, that contains six carbons or less. Show a retrosynthetic analysis and synthesis for each
molecule.
12. In each case a synthetic solution is shown. There are other approaches based on other
disconnections.

(a) An attractive starting material is the commercially available benzylacetone, but it has more than the
required five carbons. One more disconnection leads to acetone, which can be converted to
benzylacetone via enolate alkylation (13.3.1). Acetone is available and has less than five carbons. The
Wittig olefination step (a) is discussed in Section 12.5.1.1.

Br
Ph O Ph O Me
Ph Me
Me
Me Me Me
Br Me
Benzylacetone Acetone
Br
O Me O Ph Ph
a b Me c
Ph
Me
Me Me Me
Br Me
(a) LiN(iPr)2 ; BnBr (b) Ph3P=CHMe (b) Br2 , CCl4
14 Organic Synthesis Solutions Manual

(b) The starting material is 3-methyl-2-butanol. Initial conversion to a mesylate allows an SN2 reaction
with the anion of prop-1-yne. The alcohol could also be converted to a bromide using PBr3 or a similar
reagent. Lindlar reduction of the alkyne leads to the cis-alkene.

OH

OH a OMs b c

(a) MeSO2Cl , NEt3 (b) MeC≡C – Na+ , DMF (c) H2 , Pd-BaCO3-quinoline (Lindlar)

(c) The requirement that the starting material be five carbons or less makes this a very cumbersome
synthesis. The point of this exercise is first to give practice for various reactions but also to show that
setting arbitrary starting material requirements can have profound consequences. A shorter approach,
for example, would use phenetole (ethoxybenzene) and Birch reduction. In the synthesis shown, 2-
ethoxypropanoic acid was not found to be commercially available (someone probably sells it if
sufficient time was taken to find a source), but β-propiolactone can be opened with ethanol
(transesterification) to give the requisite alcohol-ester. Wittig olefination (12.5.1.1) can be done with a
carboxyl substituent.

CO2Et O O
CO2Et CO2H CHO CO2Et
CO2Et
NHBu O
O EtO2C
O
CO2H CO2Et OH
O CO2Et CO2H CO2Et O
a
CO2Et b CO2Et d
c e
OH NHBu
O CHO O O
CO2H
(a) EtOH , H+ (b) PDC , CH2Cl2 (c) Ph3P=CHCH2CO2– Na+ (d) MCPBA (e) BuNH2 , DCC

(d) This synthesis begins with benzene and bromination followed by reaction with cuprous cyanide
gives benzonitrile. Rosenmund reduction gives benzaldehyde (remember that we had to begin with
material containing only 6 carbons). A Wittig olefination (12.5.1.1) gives styrene and a radical HBr
addition gives the primary bromide. An SN2 displacement with cyanide allows selective reduction to
the aldehyde.

Ph Ph
PhCHO PhH
CHO Br
a b c d e f g
PhH PhBr PhCN PhCHO Ph Ph
Ph Ph
Br CN CHO
(a) Br2 , FeBr3 (b) CuCN , heat (c) Sn , HCl (d) Ph3P=CH2 (e) HBr , ROOR (f) NaCN , DMF (g) LiAlH(Ot-Bu)3
 Chapter 7 15

13. Give reagents that will accomplish each of the following selective transformations.
13. (a) NaBH4 (b) Na , NH3 , EtOH (c) LiAlH(Ot-Bu)3 - some diol will also be formed with
virtually any reagent (d) NaBH3CN , pH 7

(e) The first step requires reduction of the ketone to an alcohol, and the mild reagent NaBH4 was used.
The second step uses NBS to form a bromonium ion, which is opened by the proximal alcohol unit to
give the bromo-ether shown. Both reagents used here were taken from the cited reference.

O Br O
1. NaBH4 , MeOH
2. NBS , MeCN
N see Synthesis 1999, 1814
N
CO2Bn CO2Bn

(f) LiAlH4 will reduce the ester to the alcohol, the azide to the amide, and the lactam to the cyclic amine.
See J. Org. Chem. 1996, 61, 4572.