Chapter 4

CHAPTER 4

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

H n-C H HO
3 7

n- C3 H 7

HO

OH

H H

n-C 3 H 7

n-C 3 H 7

OH

H
H

FELKIN-AHN

C RAM

(b)
O
O
Me

HO
H Me

H H

Na phth

OH

Na phth

Me

Me
Na phth

Me
Na phth

HO

Me

Me

Me

Na phth
H

Na phth

OH

Me

Me

FELKIN-AHN

C R AM

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

Me OH 2 C
O

C H 2 OM e
HO

H
CR AM

(d)

Ph

Ph

OH
H

HO

O
Ph

Ph

C H 2 OM e

FELKIN-AHN

H
C H 2 OM e

H Ph
MeO

OH
H

Organic Synthesis Solutions Manual

O
N
O

O
N
HO

O
N

Et

Me

Me

Me

Me
H
OH

Et

Et

OH

H
H
Et

Me

Me
H
OH

FELKIN-AHN

CRAM

2.

(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
O
EtO

N
Ts

OH

NaBH 4CeCl3
EtO

OSiPh2 t-Bu

N
Ts

H
via

EtO

OSiPh2 t-Bu

H
B

OSiPh2 t-Bu

see Synthesis, 1999, 1889

(b) To predict the stereochemistry of this reduction, we can examine a 3D model of the ketone. The gemdimethyl 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

LiAlH4 , THF

Me
H OBn

H O
see J. Org. Chem., 2000, 65, 7865

Me
Me
Me

0C

H
H OH

OBn

(c) Coordination of the alcohol moiety with zinc borohydride modifies the conformation, as shown, to deliver

Chapter 4

hydride from behind. The result is the diastereomeric trans diol shown.
Me

Me

Me

H
OH

OH

HO

O
O
Zn
H4 B
BH 4

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
Et

Et
H

Naphth

Naphth
Me

NaBH 4 , CeCl3

Me

CO2 H

3.

see J. Org. Chem., 1998, 63, 1259

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 3D figure 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
B

4.

bottom

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

Organic Synthesis Solutions Manual

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
. Selectride, however, does not coordinate, and delivery will be from the less sterically
hindered pathway (Cram selectivity), as shown, to give the -diastereomer.
see Tetrahedron Lett., 1985, 26, 69.
H
R

Me H Me O
H

Me
H

THPO

i-Bu

H
Me

Selectride
Me
H

O
iBu

i-Bu

Me

Selectride

Me
iBu

Me

Al

Al

Me

Me
H

Me
H

HO
R

OH Me
H

H
R

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.
see J. Org. Chem., 1999, 64, 4304
OTs O

H
Ph

OH

TsO
LiBEt3 H

CO2 Et
N
CO2 t-Bu

TsO

CHO

KOt-Bu
H
Ph

H
CO2 Et
N
CO2 t-Bu

H
Ph

H
CO2 Et
N
CO2 t-Bu

H
Ph

H
CO2 Et
N
CO2 t-Bu

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. The Spartan model shown can be interpreted in several way: 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.

Chapter 4

OSiMe2 Thex

OSiMe2 Thex
mCPBA
Na2 CO3

O
H

OSiMe 2 Thex

see J. Org. Chem., 2003, 68, 3831

LiBEt3H , THF

OH
O
H
O

7. Inspection of the 3D 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.
A

LiAlH 4 , ether
20C
O

OH

PPh3 , DEAD , PhCOOH

then KOH/MeOH
OH

see Synthesis, 1998, 495

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.

Organic Synthesis Solutions Manual

Coordination to oxygen therefore inhibits 1,4-addition and promotes 1,2-addition.

B
H

A H

H
O

H H

Al

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
H

O
H

H H

OH
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
hydrogens to B leads to the final product, 1,4-cyclohexadiene.

(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. For this
reason, C leads to the major product shown.

Chapter 4

OMe

OMe

OMe

OMe

CO 2H

CO 2

CO 2

CO2 H

(e) Lithium aluminum hydride is a powerful reducing agent due to the charge distribution and polarity of the
AlH 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

N
N

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.
(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.

Organic Synthesis Solutions Manual

OMe
Na , EtOH , reflux
MeO

MeO
OMe

OMe

aq HCl
reflux

OMe

MeO
OMe

O
MeO
OMe

9. The first transformation can be effected with Sn/HCl (Stephen reduction) or with LiAlH(Ot-Bu)3. The second
transformation can be effected with LiAlH4 or with LiBHEt3.
10.
O

(CH 2) 4O Piv OPM B

Me

O PM B

Me

(c)

(a)
(b)

HO

CHO

H
OH
Org. Lett., 2003, 5, 4741

M eO

J. Am. Chem. Soc.,

2003, 125, 12844

O
OPM B

O TIPS

PMB = p-methoxybenzyl
Piv = pivaloyl

OMe

(d)

MeO

CO2 H

MeO

NH2

(e) MeO2 C

Eur. J. Org. Chem.,

2003, 1231

Br

NHPMB
MeO
PMB - p-methoxybenzyl

N Me

Br

(h)
OH
Org. Lett., 2002, 4, 1451

MeO

(f)

H
N

O
t-BuMe 2 SiO

N
CO2 t-Bu

Org. Lett., 2003,

5, 999

J. Org. Chem., 2002. 67, 8284

(g)

CO2 Me

N
Ph MeO
CO2 t-Bu
Org. Lett. 2003, 5, 1927

(i)

HO
J. Org. Chem.,2004, 69, 1283

Chapter 4

CO2 Me

NHCO 2t-Bu

Me Me

(j)

(k) t-BuMe SiO

2
N
H
J. Am. Chem. Soc., 2003,
125, 5628

(l)
OH

N H

(n)

C 15 H31

(r)

HO
OO

OH

J. Am. Chem. Soc., 2002, 124, 4257

MeO

OH

(u)

see J. Am. Chem. Soc.,

1999, 121, 5176

Org. Lett. 2003, 5, 3357

(t)

(s)

OSiPh2t-Bu
CHO

Org. Lett. 2002, 4, 177

Me

see J. Org. Chem., 1999, 64, 2184

OSiMe 2 t-Bu

N
O

see Tetrahedron Lett.,

2000, 41, 3467

N
CH3

OH

J. Org. Chem., 2003

68, 2572

(q)
CN

(o)
O

J. Org. Chem. 2003, 68, 4523

OH

CH2 OH

N
H

(p)

Org. Lett., 2003,

5, 447

see J. Org. Chem., 1999, 64, 4477

PhMe 2Si

(m)

CO2 Me
N
H CO t-Bu
2

HO

H
Me
see J. Chem. Soc., Perkin Trans. 1
2000, 2645

OMe
Me3 Si

MeO

Br

Ph
OH

(v)

OMe

OH

(w) J. Org. Chem. 2003, 68, 8162

(x) J. Org. Chem., 2004, 69, 1598

TBSO
O

OSiMe 2 t-Bu
C 13 H27

see Can. J. Chem.,

(y) 1997, 75, 621

CHO

OHC

NO2

J. Am. Chem. Soc., 2004,

126, 2194

OH

NHAc
(z) see Tetrahedron Lett., 2000, 41, 2765

(aa)

O
see J. Org. Chem., 2002, 67, 4127

10

Organic Synthesis Solutions Manual

CH2 OH
N

Cl

t-BuMe2 SiO
t-BuMe2 SiO

CO2 Et
CH3

Ph
Ph
(ab) see Synlett, 1999, 182

J. Am. Chem. Soc., 2002,

124, 9476
(ac)

OH

OH

J. Am. Chem. Soc., 2002, 124, 12806

(ad)

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
a

MeO

Me
b

MeO
CO2 Me

Me
(a) Na , NH3 , EtOH
(b) aq H+ (c) O3 ; H2 O2

c
O

O
CO2 Me

CO2 Me

CO2 Me

(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
a

HO

OPMB
b

NC

OHC

(a) 1. TsCl , pyridine

(b) DIBAL-H , THF

2. NaCN , DMSO

see Tetrahedron Lett., 2000, 41, 33

(c) All steps in this synthesis are taken from Org. Lett., 2002, 4, 1379. Bromination of the allylic alcohol (2.8)
and SN2 displacement with cyanide gives the nitrile (2.6.A.i). Basic hydrolysis to the carboxylic acid, and
esterification with diazomethane (2.5.C; 13.9.C), was followed by selenium dioxide oxidation to the aldehyde
(3.8.A). Reduction of both the ester and aldehyde with LiAlH4 gave the diol (4.2.B), and selective chlorination of
the allylic alcohol with N-chlorosuccinimide (2.8) gave the final target.

Chapter 4

OH

Br
a

CN

CO2 H

CO 2Me

11

CO2 Me
e

OH

OH

f
OHC

OH

Cl

(a) PBr3 t-BuOMe (b) KCN , DMSO (c) 25% KOH , MeOH (d) CH 2N 2 , ether
(e) SeO 2 , t-BuOOH , CH 2Cl2 (f) LiAlH4 , THF (g) NCS , Me 2 S , CHCl2

(d) The Wittig olefination step is discussed in chapter 8.

OH

OMe

OMe

OMe

OMe

OHC
OMe
e

OH
(a) NaH ; MeI (b) Na , NH3 , EtOH (c) H2 , Pd
(d) O3 ; Me 2 S (e) Ph3 P=CH2 (f) LiAlH 4

(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 (see chap. 7, sec. 7.3.A.i). The primary alcohol
is then converted to the aldehyde by a Swern oxidation (see chap. 3, sec. 3.2.C.i).
a

OSiMe 2 t-Bu

OSiMe2 t-Bu

CO2 Me

CH2 OH
d

c
OSiMe2 t-Bu

OSiMe 2 t-Bu

CH2 OTS

CH3

CH3

see Tetrahedron Lett., 2000, 41, 403

H
O
Me

OH

(a) DIBAL-H , toluene , 78C (b) TsCl , DMAP , NEt 3

(d) AcOH , aq THF (e) DMSO , (COCl)2 , NEt 3

(c) LiEt 3 BH , THF

12

Organic Synthesis Solutions Manual

(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 - see.
chap. 7, sec. 7.3.A.i), and DIBAL-H reduction converts the lactone to a lactol.
O

CO2 H

O
O

(a) BH3 , THF ; H3 O+

b
OH

HO

(b) p-TsOH , CHCl3

(c) CH2 (OMe)2 , P2 O5

HO

d
O

(d) DIBAL-H , CH2 Cl2

see J. Org. Chem, 2000, 65, 9129

(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 (see Sec. 3.4.D.i) gives the epoxide and selective reduction of the less sterically hindered carbon of
the epoxide with Red-Al gives the final product.

SiMe 3
CO2 Et

SiMe 3

O
b

OH
O
c

SiMe3
OH
OH

SiMe3
O
OH

see Tetrahedron Lett., 2000, 41, 2821

(a) DIBAL-H , CH2 Cl2 , 78C
(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.

n-C 3 H7

a
Section
12.4.D
p 1090

n-C 3 H7

n-C 3 H7

n-C 3H 7

c
b
NO 2

NH 2

(a) butanoyl chloride , AlCl3 (b) N2 H4 , KOH (c) HNO 3 , H2 SO 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 (4.6.A) was

Chapter 4

13

followed by bromination with carbon tetrabromide and triphenylphosphine (2.8.A).

HO

CO2 H

Br

b
(a) BH3 SMe 2 , B(Me) 3 , THF

Cl

OMe

Cl

OMe

Cl

(b) CBr4 , PPh3 , benzene

OMe

(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 (chap. 2) 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 (see chap. 7, sec. 7.3.B.i). The final step is an oxidation. Several methods can be used from chap. 3,
sec. 3.2, but the Dess-Martin periodinane reagent was used in this citation.

O
a

EtO2 C

O
b

EtO2 C

c
N

OH

OTs

OMe

OMe

HOH2 C
N
O

OMe

OMe
O

see J. Am. Chem. Soc., 1999,

121 , 7778

OHC

HOH2 C
d

EtO2 C

(a) TsCl , DMAP (b) 1. NaI , acetone 2. Bu3 SnH , AIBN

(c) LiBH4 , THF (d) HCl , aq. AcOH (e) Dess-Martin

OMe

OMe

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

Bu

Bu

Bu

Bu

Bu

(a) NaNH2 ; n-C 4H 9-I (b) NaNH2 ; n-C4 H9 -I (c) H2 , PdCO3 , quinoline

12. In each case a synthetic solution is shown. There are other approaches based on other disconnections. The
Aldrich catalog (2000-2001) was used as a source for the starting material for convenience. There are, obviously,
other sources of chemicals.

14

Organic Synthesis Solutions Manual

(a) An attractive starting material is the commercially available benzylacetone at $95.40/Kg, but it has more than
the required five carbons. One more disconnection leads to acetone, which can be converted to benzylacetone via
enolate alkylation (see Sec. 9.3.A). Acetone is available from Aldrich ($18.30/L) and has less than five carbons.
The Wittig olefination step(a) is discussed in Section 8.8.A.
Br
Me

Br
Me

Ph

Me

Ph

Me

Me

Me

Ph

Me

Ph

Me
benzylacetone
Ph

Me
acetone
Br

Me

Me
(a) LiN(iPr) 2 ; BnBr (b) Ph3 P=CHMe (b) Br2 , CCl4

Me

Me

Ph
Br

Me

(b) The starting material is 3-methyl-2-butanol at $43.10/100 mL. Initial conversion to a mesylate allows an SN2
reaction with the anion of 1-propyne. 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) MeSO2 Cl , NEt3

OMs

(b) MeC
C Na + , DMF

(c) H2 , Pd-BaCO 3-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
(ethoxy benzene) and Birch reduction. In the synthesis shown, 2-ethoxy-propanoic acid was not found to be
commercially available (someone probably sells it if sufficient time was taken to find a source), but the expensive

-propiolactone at $76.20/5 mL can be opened with ethanol (transesterification) to give the requisite alcohol-ester.
Wittig olefination (see Sec. 8.8.A) can be done with a carboxyl substituent.

Chapter 4

O
EtO 2C

EtO2 C
O

CHO

OH
O
EtO2 C

CO2 H

c
CHO

CO 2H

EtO2 C

EtO2 C

OH

EtO 2C

EtO2 C

CO2 H

CO2 H

EtO2 C

NHBu
O

15

EtO2 C

O
EtO2 C

NHBu
O
(d) MCPBA (e) BuNH2 , DCC

(a) EtOH , H+ (b) PDC , CH2 Cl2 (c) Ph3 P=CHCH 2CO2 Na+

(d) This synthesis begins with benzene at $31.00/L 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 (see Sec. 8.8.A) gives styrene and a radical HBr addition gives the
primary bromide. An SN2 displacement with cyanide allows selective reduction to the aldehyde.
CHO

Ph

Ph
a

PhH

reagent

(b) CuCN , heat

Br

Ph

d) Ph3 P=CH2

PhCN

e
Ph

13. (a) NaBH4

PhCHO

PhBr
(a) Br2 , FeBr3

PhCHO

Br

PhCHO

(c) Sn , HCl
f
Ph

(e) HBr , ROOR

(b) Na , NH3 , EtOH

PhH

CN

(f) NaCN , DMF

g
Ph

CHO

(g) LiAlH(Ot-Bu) 3

(c) LiAlH(Ot-Bu)3 - some diol will also be formed with virtually any

(d) NaBH3 CN , 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

1. NaBH4 , MeOH
2. NBS , MeCN
N
CO2 Bn

see Synthesis, 1999, 1814

O
N
CO2 Bn

16

Organic Synthesis Solutions Manual

(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.