Chapter 7

CHAPTER 7

1. (a) Reducing an aldehyde in the presence of a ketone is very difficult. Although the aldehyde is more reactive,
the difference in reactivity is so small that finding a reagent to selectively reduce one in the presence of the other is
difficult. The use of mono-hydride reagents such as DIBAL-H or lithium trimethoxyaluminum hydride at low
temperature offers the best solution. This system is, however, a candidate for protection. A similar argument
applies to catalytic hydrogenation and reaction with Grignard reagents. Since the ketone is unlikely to be affected
by Jones oxidation or the use of PCC, protection is unnecessary.
(b) In this example, it is possible that oxidation with Jones reagent can cleave the ketone moiety, but this option
requires very stringent conditions and will be ignored. Since vigorous oxidation is not an issue here, the focus will
be on reduction and Grignard reactions. Cerium borohydride, zinc borohydride, and aluminum hydride (see Secs.
4.3, 4.4.B) are reagents that will react with conjugated ketones to give 1,2-reduction. These reagents also react with
non-conjugated ketones, and protection may be necessary.

The use of palladium catalysts should allow

hydrogenation of the alkene moiety in the presence of ketone moieties, and platinum catalysts can be used to
maximize reduction of carbonyl moieties. There will be a mixture of products, however, and the highest yields of
selective reduction will be realized by using protecting groups. Similar arguments apply to Grignard reagents,
although addition of cuprous salts to the Grignard reagent will give predominately Michael addition to the
conjugated ketone.
(c) Only the ketone reacts with hydrides, or with hydrogenation and a catalyst. If the resulting alcohol is to be
differentiated from the existing alcohol, then protection of that alcohol moiety will be required. The alcohol can
easily be oxidized in the presence of the ketone, but if that new ketone is to be differentiated from the original
ketone, then the original ketone must be protected. The use of excess Grignard reagent will allow the ketone to
react normally. This is not a problem with methylmagnesium bromide, but this is not as attractive with an
expensive Grignard reagent, and protection of the alcohol will give better results.
(d) Hydride reduction of the aldehyde with sodium borohydride or any of the other selective hydride reagents
discussed in Sections 4.3 & 4.4.B will selectively reduce the aldehyde. If the resulting secondary alcohol is to be
differentiated from the primary alcohol, best results are obtained if the primary alcohol is protected. Borane might
selectively reduce the carboxyl group in the presence of the aldehyde, but protection of the aldehyde is probably
necessary. Protection of the existing primary alcohol is required if it is to be differentiated from the primary
alcohol product. Carboxylic acids resist catalytic hydrogenation, so hydrogenation of the aldehyde is quite easy,
without protection.

The comments concerning formation of the new alcohol made previously also apply.

Oxidation of the primary alcohol with PCC in the presence of the aldehyde is facile, but if the resulting aldehyde is
to be differentiated from the existing aldehyde, the latter must be protected. Oxidation with Jones reagent will
likely convert the aldehyde to an acid, and protection of the aldehyde is required. Both the alcohol and the acid will
react with a Grignard reagent, and excess Grignard reagent is required (although a dianion will likely have

Organic Synthesis Solutions Manual

solubility problems) or protection of those groups.

2. The sequence of the events depicted in this mechanism can be called into question, in that the OMOM may come
off first. Nonetheless, transfer of a proton (from the acidic Dowex) to the dioxolane oxygen and ring opening leads
to an O-stabilized cation, which reacts with water (water is present in the Dowex resin) to give an oxonium ion.
Loss of a proton and transfer to the other oxygen allows loss of protonated acetone to give the diol. The oxygen of
the MOM group is then protonated and loss of the CH2=OMe]+ unit leads to the triol, B. In the second step,
methanolic potassium carbonate contains some methoxide (MeO-), which attacks the amide carbonyl and acyl
substitution leads to methyl trifluoroacetate and the amide anion, which is quickly protonated by methanol. This
amine is now positioned to react with the carbonyl of the lactone (see crude conformational drawing). One again,
acyl substitution leads to the amide and an alkoxide. The alkoxide is protonated by methanol to give the final
product, C.
OMOM
O

OMOM
O

HN
O

CF 3

CF 3

HN

OH

O
O

CF3

+ H+

HN
O
O

OH

OH

CH2 =OMe

OH

HN
O
O

CF3

HN
O
O

MeO
OH

OH
OH
NH2

OH

OH

OHO

CF 3

OH

NH2
O

CF3
O

OH

OH
O

OH2

O
H

OH

CF 3

OH
HN

O
- Me2 C=OH
O
O
O

CF3

OMOM

+ H+

HN
O
O
+ H2 O

O
O

CF 3

OMOM

O
H OH
O
HN

HN
O
O

OMOM
O

H+

O
O

OMOM

O
CF 3 CO 2Me

OH
OH

MeOH
O
O

HN

CF 3

OMe

Chapter 7

OH
OH
O

OH
OH

OH

OH MeOH
O

OHO

OH

NH

OH
NH

NH

O
see J. Org. Chem., 1999, 64, 4465

HO

3. One mechanistic rationale is presented here, based on the cited reference.

Me

+ H+

O Me

Me

Me O Me
Me
HO

-MeOH

C 12 H25

see J. Org. Chem., 1999, 64 7067

Me O Me
Me
Me
H O

Me O Me
O

H
O Me

H
O

C12 H25
Me
+MeOH

Me

OMe

O
O

C 12 H25
Me
Me

H+

Me
O

O
O O
H

H+

Me

C12 H25

+H+

C12 H25

H
Me
O Me

O
H

Me
O
O
H

O
H

Me
Me
O

C 12 H25

OMe

+H+

OMe

O O
H

C 12 H25

H+

+Me

Me

Me
O
O
H

Me

O O
H

Me

Me
O

+H

C12 H25

OMe

Me

OMe

Me
OMe

Me

Me

C 12H 25
Me

OMe

C 12 H25

Me
O H
O
H

Me

OMe

Me

Me
O

O
MeOH
C 12 H25

O O
H

CO 2Me

CO 2Me

C 12H 25

C 12 H25

4.
H
OAc

(a)

O
OAc

O
see J. Am. Chem. Soc., 1999, 121, 5653

(b)

N
H
H

I
Angew. Chem. Int. Ed.,
2002, 41, 4316

(c)
S
MeO2 C

CO 2Me
S
S

see Synthesis, 1996, 71

Organic Synthesis Solutions Manual

OH

H2 N

(d)

HOMe2 CH2 CH 2C

HO

Br
J. Org. Chem., 2002, 567, 9248

O'

N Boc

(e)

H
N

(f)
see J. Org. Chem., 1999,
64, 3736

see J. Org. Chem., 2000, 65, 1738

OAc
BzO

(g)

(h)

CO2 Me

MeO2 C

OH O
Org. Lett. 2002, 4, 1343

J. Org. Chem., 2003,

68, 3838

OH

OBz O

(k)

HO

OH

Angew. Chem. Int. Ed., 2003,

42, 4779

O
Ph

(l)

OSiPh2 t-Bu

J. Am. Chem. Soc., 2003,

125, 8238

CHO

Ph
OSEM
CHO

N
N
H
Me

Ph

OH

Eur. J. Org. Chem.,

2004, 499

(m)

NBoc

NH

(j)

(i)

OAc

OH
J. Org. Chem., 2002,
67, 4200

OAc

H
N

Org. Lett. 2002, 4, 687

Me

(n)

see Tetrahedron Lett.,

2000, 41, 2821

(o)

J. Org. Chem., 2002,

67, 4337

5. (a) Step b may cause problems due to the poor nucleophilicity of acetate, but the allylic bromide moiety is
rather reactive. Protection is definitely required to set the proper stereochemistry of the product.
Br
a

t-BuMe2 SiO

HO
b

c
+

(a) NBS , h
(b) NaOAc , DMF ; H3 O

HO
OH d

OH

OH

OH

(c) 1. Me 2t-BuSiCl , DMAP 2. OsO4 , NMO (d) TBAF

If the alcohol moiety is not protected, osmylation will proceed with a neighboring group effect giving primarily
the all-cis product. When protected with the bulky silyl group, osmylation occurs from the opposite face to give the
desired cis-trans triol as the major product. The silyl group was also chosen because it is removed under mild
conditions that should not effect the diol moiety of the triol product.

Chapter 7

(b) Protection of the alcohol is not necessary since the neighboring group effect of the OH is required to set the
stereochemistry. Sharpless asymmetric epoxidation is probably preferable to give enantiopure material. Reduction
of the epoxide proceeds without the need of a protecting group. Oxidation of the secondary alcohol in the presence
of a tertiary alcohol also does not require a protecting group.
OH

OH

OH

Me

O
c

Me
Me
O
OH
(a) MCPBA (b) LiAlH4 (c) PDC , CH 2Cl2

Me
OH

(c) Incorporation of the tertiary alcohol via oxy-mercuration does not require that the first alcohol be protected.
Although this reaction is done under aqueous conditions with a Lewis acid, loss of a primary OH under these
conditions is unlikely. The oxidation step is also straightforward, without protection, since the tertiary alcohol will
not react.

OH

CO2 H

HO

HO

OH

CHO

(a) LiAlH 4 (b) Hg(OAc)2 , H2 O ; NaBH 4 (c) PDC , CH2 Cl2

(d) Since an aldehyde and a ketone moiety are involved in the sequence, they must be incorporated at different
times. For this reason, ozonolysis used an oxidative workup to give the ketone-acid. This allowed protection of the
ketone moiety and then selective reduction of the acid to the aldehyde, via a methyl ester. The aldehyde reacted
with the alkyne anion and the ketone was unmasked, allowing reduction to the targeted diol.

Et

O
CO2 H
O

OH
+

(a) O 3 ; H2 O2 (b) ethylene glycol , H

CO2 H
e

CHO

Et

OH

OH

Et

OH
-

(c) i. CH2 N2 ii. DIBAL-H , -78C (d) EtC
C Na (e) aq H+ (f) NaBH4

(e) Conversion to the alkynyl alcohol is straightforward. The next step involves hydroboration and requires
protection of the tertiary alcohol. The TIPS group was chosen for ease and mildness of removal in the final step.

Organic Synthesis Solutions Manual

Me

Me

Me
a

Me

Me

n-Bu

c
OSi(iPr)3
OH
OH
Cl
+
(a) 1. 9-BBN ; NaOH,H 2O 2 2. PCC (b) HC
C Na (c) NaH , iPr3 SiCl (d) 1.
B
H
NaOMe ; AcOH , reflux
2. TBAF

n-Bu

6. In each case a synthesis is provided. These are not the only possible syntheses, however. In many cases there
are several other possible routes.
(a)
O

OH

OBz

OH
O

OH

CHO
OSiMe2 t-Bu

OBz

OH

CN

see J. Org. Chem., 1999, 64, 4798

OSiMe 2t-Bu

OSiMe2 t-Bu
g

OSiMe 2t-Bu

OH

OSiMe 2 t-Bu
O

OH

OSiMe 2t-Bu

OH

(a) PhCOCl , NEt3 , DMAP (b) t-BuMe 2SiCl , imidazole (c) NaOMe , MeOH
(d) I2 , imidazole , PPh3 (e) KCN , DMSO (f) DIBAL-H (g) NaBH4 (h) TBAF , THF

This sequence is taken directly from the cited paper. Other protecting groups can be used of course, but the idea
is to take advantage of the grater reactivity of the primary alcohol to protect it first with a short term group. This
allows the secondary alcohol to be blocked with a longer term group. The primary alcohol is then liberated and
chain extended. Steps a-g are taken directly form the paper in the order in which they were done. Step h is added
and simply deprotects the OTBS group with tetrabutylammonium fluoride.
(b) Since the last step is a Grignard reaction (Sec. 8.4.C), the alcohol in the starting material must be oxidized to a
ketone. That ketone must then be protected, with a group impervious to aqueous acid, allowing Birch reduction of
the aromatic ring (Sec. 4.9.E) and conversion of the vinyl ether to a conjugated ketone. Selective reduction of the
carbonyl and protection allows unmasking of the ketone and Grignard reaction. The Lewis acid used to unmask the
dithiane could affect the silane, although this is probably not a significantly problem. Sulfur compounds such as
the dithiane can be reduced by sodium in ammonia. If this is a problem, then the ketone moiety may have to be
protected as an imine. Alternatively, the original alcohol may have to be protected, unmasked after the allylic
alcohol is protected and then oxidized before reaction with crotyl magnesium bromide. The procedure shown here
is more straightforward, however, and should produce the targeted diol.

Chapter 7

MeO

MeO

OH

MeO

a
S

MeO

S
O

c
t-BuMe 2SiO

HO

t-BuMe 2SiO

OH

f
(a) PDC (b) 1,3-propanedithiol , BF 3 (c) Na , NH3 , EtOH (d) aq H +
(e) 1. Zn(BH4 )2 2. t-BuMe2 SiCl , imidazole (f) HgCl2 , aq THF , BF3 (g) crotyl MgBr ; H3 O+

(c) The aldehyde unit was incorporated by conversion of the alcohol to a tosylate and displacement with NaCN.
The authors of this paper used the allyl borane shown in order to add to the aldehyde, and the reaction proceeded
with high stereoselectivity (not indicated in the answer shown here). The final step is a protection of the alcohol
using a variation of the ethoxyethyl ether group.

HO

OMe

TsO

OPMB

NC

OPMB

O
c

d
OHC

EtO

HO

OPMB

OPMB

(a) TsCl , pyridine (b) NaCN , DMSO (c) DIBAL-H , THF , -78C
(d) Ipc2 BCH2 CH=CH2 , ether , 100C (e) CH2 =CHCH(OEt)2 , p-TsOH

OPMB

see Tetrahedron Lett., 2000, 41, 33

(d) These reagents are taken form the cited reference. Short term protection of the alcohol as the tetrahydropyran
derivative allowed LiAlH4 reduction of the lactone to give the diol (see chap. 4, sec. 4.2.B). The OTHP group is
removed to give the triol, and two hydroxy groups are protected as the dioxane by treatment with benzaldehyde.
This allowed oxidation of the hydroxymethyl unit to the aldehyde with pyridinium dichromate (see Sec. 3.2.B.iii).
OH
O

OTHP

O
OH
OH

OTHP

OH

OH

d
O

OH

CHO

e
O

OH

Ph
(a) dihydropyran , TsOH , CH2 Cl2 (b) LiAlH4 , ether
(d) PhCHO , TsOH (e) PDC , CH2 Cl2

O
Ph

(c) TsOH , MeOH

see Synthesis, 1993, 137

Organic Synthesis Solutions Manual

(e) This sequence is taken from J. Am. Chem. Soc., 2003, 125, 1567. Protection of the ketone unit as the dioxolane
(7.3.B.i) was followed by hydroboration to give the alcohol (5.4.A). Protection of the alcohol as the benzyl ether
(7.3.A.i), and deprotection of the ketone unit gave the target.

O
a

O
O

HO
(a) (MeO)3 CH , MeOH , TsOH

d
BnO

BnO

(b) 1. BH3 THF 2. NaOH , H2 O2 (c) KH , BnBr , Nu4 NI (d) TsOH , aq acetone

(f) This sequence is taken from J. Org. Chem., 2004, 69, 3857. Protection of the free hydroxyl unit as the acetate
was followed by deprotection of the ketone, by treatment of the dithiolane with aqueous N-bromosuccinimide.
Saponification of the acetate group was followed by oxidation to the aldehyde with pyridinium chlorochromate
(3.2.B.ii)
OH

OTBS

OAc OTBS
OBn

OAc OTBS
OBn

Ac2 O , DMAP
NEt3

OBn

NBS , aq acetone
S

O
O

OH OTBS
OBn

NaOMe

PCC

OTBS
OBn

MeOH
O

(g) All steps are taken directly from the cited reference. Reduction of the ester unit with DIBAL-H gave the
alcohol (Sec. 4.6.C), and Mitsunobu reaction with phthalimide converts the OH unit to phthalimidoyl (Sec.
2.6.A.ii). Epoxidation with MCPBA (Sec. 3.4.C) was followed by deprotection of the phthalimide by reaction with
hydrazine (the Gabriel synthesis, see Sec. 2.6.A.ii.) to give the amine, which opened the epoxide intramolecularly
to give the pyrrolidine derivative. The amine was protected as the Boc derivative, and the trityl group removed by
catalytic hydrogenation. This is possible because the Ph3CO group is benzylic and subject to hydrogenolysis (Sec.
4.8.E). The primary alcohol is selectively converted to a mesylate and deprotection of the N-Boc unit allows
cyclization to give the pyrrolizidine product. The OMOM group is sensitive to acid, and it is removed during the
deprotection-cyclization sequence, accounting for the final product.

Chapter 7

OMOM
CO2 Et
a

OMOM

OMOM

OMOM
NPhth
c

OH
b

NPhth
d
O

Ph3 CO

TrO

TrO

TrO

OMOM

OMOM
NH2
HO

OMOM
e

HO

N
H

O
TrO

TrO
HO

OMOM

g
MsO

TrO

HO

N
Boc

H
N
Boc

HO
OH

HO H

OMOM

see Synthesis, 1993, 615

Boc

(a) DIBAL-H , THF (b) phthalimide, DEAD , PPh3 (c) MCPBA , NaHCO3 , CH 2Cl2 (d) N2 H4 , EtOH
(e) Boc2 O , THF , i-Pr2 NH (f) H2 , Pd-C , MeOH , cat. HCl (g) MeSO2 Cl , Py , CH2 Cl2 (h) CF 3 COOH, MeOH

(h) The reagents used are taken form the reference. Reduction of the carboxylic acid with borane (Sec. 4.6.A) was
followed by protection of the amine as the Boc derivative. This allowed Swern oxidation to give the aldehyde (Sec.
3.2.C.i).

a
N
H

CO 2H

(a) BH3 THF ; aq NaOH

N
H

CH2 OH

(b) Boc2 O

c
N
CH2 OH
Boc

(c) (COCl) 2 , DMSO

N
O

CHO
Ot-Bu

ssee J. Am. Chem. Soc., 1999, 121, 700

(i) These reagents are taken from J. Org. Chem., 2003, 58, 2790. In this particular synthesis, Wittig olefination of
the aldehyde unit (Sec. 8.8.A.i) was followed by treatment with acid to convert the dioxolane to the diol shown.
Protection of the primary alcohol unit as the t-butyldimethylsilyl ether was followed by protection of the secondary
alcohol unit as the methoxymethyl ether. Subsequent treatment with tetrabutylammonium fluoride deprotected the
silyl ether to give the free primary alcohol, and oxidation to the acid was accomplished with PDC in DMF (Sec.
3.2.B.iii).

10

Organic Synthesis Solutions Manual

CHO

O
O

O
d

TBDMSO
HO

C 14H 29

C 14 H29

HO
e

HO
MOMO

C 14H 29

HO

HOOC

C14 H29

C14 H29
OMOM

(a) C 15H 31 PPh3 Br , BuLi , 78C (b) H+ , rt (c) TBDMSCl , NEt3 , cat DMAP , CH2 Cl2
(d) 1. MOMCl , i-Pr 2NEt , CH2 Cl2 2. Bu4 NF , THF (e) PDC , DMF , 40-50C

(j) All steps are taken from Angew. Chem. Int. Ed., 2002, 41, 1062. Deprotection of the diol (7.3.B.i) was followed
by conversion of the primary alcohol unit to the pivaloyl ester (7.3.A.ii). The diol unit that remains was then
converted to a new acetonide. (7.3.B.i)

HO

O
O

a
OH

OPiv

HO
OH

(a) 3N HCl , MeOH

OH
Me3 Si

Me 3Si

Me3 S
i

OPiv

OH

(b) pivaloyl chloride , Py , 23C

Me 3Si
(c) p-TsOH , 10 eq Me2 C(OMe)2 , DMF , 70C

(k) The reagents are taken from the cited reference. The first step is to deprotect the benzyloxy group and DDQ
was chosen as the reagent. This allowed the protecting group to be changed to TBDPS and methanolic potassium
carbonate deprotected the acetate groups to give the final diol.

OAc

OAc a

BnO
(a) DDQ , CH 2Cl2

OAc
HO

OAc
TBDPSO

(b) t-BuPh2 SiCl , imidazole , THF

OAc

b
O

(c) K2 CO3 , MeOH

OH

OAc
TBDPSO

OH

see J. Am. Chem. Soc.,

1999, 121, 5653

(l) All reagents are taken from the cited reference. Protection of the free hydroxyl as a MOM is followed by
dihydroxylation of the alkene with OsO4 (Sec. 3.5.B). Protection of the diol as an acetonide allows the
alcohol to be converted to a mesylate. Methanesulfonic anhydride was used, but based on information
provided in most undergraduate courses, methanesulfonyl chloride would probably have been chosen.
Reaction with potassium t-butoxide leads to elimination and formation of the diene. Deprotection of the
diol with aqueous acetic acid allows oxidative cleavage with sodium periodate to give the aldehyde.
(m)