Chapter 5 1

CHAPTER 5
1. In each of the following, discuss the relative merits of protecting functional groups or finding a
chemoselective reagent for: (i) reduction with hydrides (Sections 7.3-7.8), (ii) oxidation with Jones
reagent or PCC (Section 6.2.1,2), (iii) catalytic hydrogenation (Section 7.10), and (iv) reaction with
MeMgBr (Section 11.4).
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 (see section 7.8). 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 (see section 6.2), 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 7.5) 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 (see
section 7.10). 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 7.4-7.8 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 solubility problems) or protection of those groups.
2 Organic Synthesis Solutions Manual

2. In the transformation of A to B, and then to C, taken from the synthesis of 7-

deoxypancratistatin, deprotection was followed by conversion of a lactone to a lactam. Provide a
mechanism for the deprotection of both the O-MOM group and the dioxolane, giving a triol, and
also for the lactone-lactam conversion in the second step.
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 OMOM OMOM
H H
O O O O O O O O O
H+
O O O

HN CF3 HN CF3 HN CF3

O O O
O A O O O O O
+ H2O
OMOM OMOM OMOM
H H H
O O O O O O O O O
H OH + H+
OH OH2
O O O

HN CF3 HN CF3 HN CF3

O O O
O O O O O O
- Me2C=OH
H O OH
O O O
O O OH
O O O O OH
OH
+ H+ – CH2=OMe
OH
OH OH
HN CF3
HN CF3 HN CF3 O
O B
O O O
O O O O
MeO–
 Chapter 5 3

OH OH
O O OH O O OH
OH – CF3CO2Me
OH
O HO OH MeOH OH

NH2 HN CF3
NH2 O O
O
O O O OMe
OH OH
O OH HO OH

OH O
OH OH O
OH
O HO
NH NH
O O
NH2 O C O
O

3. Explain the following transformation.

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

H
Me O Me
+ H+ Me O Me
Me O Me
Me O Me
Me -MeOH
Me Me Me
OMe OMe OMe
HO Me Me Me
Me O Me -H+ +H+
H O O O
O O
C12 H25 O O O O
O O
C12 H25 C12 H25 C12 H25
H
Me Me Me
OMe OMe OMe
Me Me Me Me Me Me
+MeOH -H+ +H+
O O H O O O O
O O O O O O
C12 H25 C12 H25 C12 H25
H H H H
Me Me H Me
OMe OMe Me
Me Me O Me Me
Me Me Me Me Me
-H+
O O O O O O O
+H+ O
- MeOH
O O O O O O O
C12 H25 H C12 H25 O C12 H25
H H C12 H25 H
H
H -H+
O O O O see J. Org. Chem. 1999, 64 7067
CO2Me CO2Me
C12 H25 C12 H25
4 Organic Synthesis Solutions Manual

4. In each of the following, give the major product. Show stereochemistry where it is appropriate.
4.
H
OAc S
N O
O CO2Me
(a) OAc (b) H (c) S S
O H
O MeO2C S
I
see J. Am. Chem. Soc. 1999, 121, 5653 Angew. Chem. Int. Ed. 2002, 41, 4316 see Synthesis 1996, 71
OH H2N H
O HOMe2CH2CH2C
HO N
(d) (e) (f)
N Boc O
O
Br
J. Org. Chem. 2002, 567, 9248 see J. Org. Chem. 2000, 65, 1738 see J. Org. Chem. 1999, 64, 3736
OAc
BzO OAc
O
O O
(g) (h) O (i)
OAc NBoc
CO2Me
MeO2C NH
O
OH
OH O
J. Org. Chem. 2002, 67, 4200 Org. Lett. 2002, 4, 1343 J. Org. Chem. 2003, 68, 3838

O O OH
O OBz O O
(j) (k) Ph (l)
O O O
OH
OH Ph OSiPh2t-Bu
Eur. J. Org. Chem. 2004, 499 Angew. Chem. Int. Ed. 2003, 42, 4779 J. Am. Chem. Soc. 2003, 125, 8238

H
HO H CHO
Ph
OSEM
(m) N (n) CHO (o) H
N O
N
H
Me H
Org. Lett. 2002, 4, 687 Me see Tetrahedron Lett. 2000, 41, 2821 J. Org. Chem. 2002, 67, 4337
 Chapter 5 5

5. For each of the following, determine if protection is required in the given sequence. If so,
choose the protecting group(s), explain your choice(s), and provide all necessary reagents for the
entire sequence.
5. (a) Step b may cause problems due to the poor nucleophilicity of acetate, but the allylic bromide
moiety is rather reactive. Protection is required to set the proper stereochemistry of the product.

Br HO t-BuMe2SiO HO
a b c OH d OH

OH OH
(a) NBS , hν (b) NaOAc , DMF ; H3 O+ (c) 1. Me2t-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.

(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 O
a b c
Me Me Me Me
O OH OH
(a) MCPBA (b) LiAlH4 (c) PDC , CH2Cl2

(c) Incorporation of the tertiary alcohol via oxymercuration 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.

a b HO c HO
OH OH
CO2H CHO
(a) LiAlH4 (b) Hg(OAc)2 , H2O ; NaBH4 (c) PDC , CH2Cl2

(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.
6 Organic Synthesis Solutions Manual

a b O c O
O O O
CO2H CO2H CHO
O
d O O f OH
e

Et OH Et OH Et OH

(a) O3 ; H2O2 (b) ethylene glycol , H+ (c) i. CH2N2 ii. DIBAL-H , -78 °C (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.

O
O O O
O O O
a O b c d

HO BnO BnO

(a) (MeO)3CH , MeOH , TsOH (b) 1. BH3•THF 2. NaOH , H2O2 (c) KH , BnBr , Nu4NI (d) TsOH , aq acetone

6. In each case, complete the synthesis showing all reagents and all intermediate products.
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 O O OBz Cl n-Bu
OH OBz b c
a
B
OH OH OSiMe2t-Bu H

O OH O I O CN
d e f

OSiMe2t-Bu OSiMe2t-Bu OSiMe2t-Bu

O O OH O OH
CHO h
g
see J. Org. Chem. 1999, 64, 4798
OSiMe2t-Bu OSiMe2t-Bu OH

(a) PhCOCl , NEt3 , DMAP (b) t-BuMe2SiCl , imidazole (c) NaOMe , MeOH
(d) I2 , imidazole , PPh3 (e) KCN , DMSO (f) DIBAL-H (g) NaBH4 (h) TBAF , THF
 Chapter 5 7

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. 8.4.3), 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. 4.9.5) 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.

MeO OH MeO O S
a b MeO c
S

S S S
MeO d O e t-BuMe2SiO f
S S S

t-BuMe2SiO O HO OH
g

(a) PDC (b) 1,3-propanedithiol , BF3 (c) Na , NH3 , EtOH (d) aq H+

(e) 1. Zn(BH4)2 2. t-BuMe2SiCl , imidazole (f) HgCl2 , aq THF , BF3 (g) crotyl MgBr ; H3O+

(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.

OMe a b
HO O
TsO OPMB NC OPMB
O
EtO
c d HO e
O OPMB
OPMB
OHC OPMB

(a) TsCl , pyridine (b) NaCN , DMSO (c) DIBAL-H , THF , -78 °C
(d) Ipc2BCH2CH=CH2 , ether , -100 °C (e) CH2=CHCH(OEt)2 , p-TsOH see Tetrahedron Lett. 2000, 41, 33
8 Organic Synthesis Solutions Manual

(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 7.6.1). 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 [Link]).
OH OTHP OTHP
a b c
OH
O O
O O OH
OH CHO
d OH e
OH O O O O
see Synthesis 1993, 137
OH
Ph Ph
(a) dihydropyran , TsOH , CH2Cl2 (b) LiAlH4 , ether (c) TsOH , MeOH (d) PhCHO , TsOH (e) PDC , CH2Cl2

(e) This sequence is taken from J. Am. Chem. Soc. 2003, 125, 1567. Protection of the ketone unit as the
dioxolane ([Link]) was followed by hydroboration to give the alcohol (9.4.1). Protection of the alcohol
as the benzyl ether ([Link]), and deprotection of the ketone unit gave the target.

O
O O O
O O c O
a O b d

HO BnO BnO
(a) (MeO)3CH , MeOH , TsOH (b) 1. BH3•THF 2. NaOH , H2O2 (c) KH , BnBr , Nu4NI (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 ([Link])

OH OTBS OAc OTBS OAc OTBS

OBn OBn OBn

Ac2O , DMAP NBS , aq acetone

NEt3
S S S S
O
OH OTBS O OTBS
OBn OBn
NaOMe PCC H
MeOH

O O
 Chapter 5 9

(g) All steps are taken directly from the cited reference. Reduction of the ester unit with DIBAL-H
gave the alcohol ([Link]), and Mitsunobu reaction with phthalimide converts the OH unit to
phthalimidoyl ([Link]). Epoxidation with mcpba (6.4.3) was followed by deprotection of the
phthalimide by reaction with hydrazine (the Gabriel synthesis, see [Link]) 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 (7.10.6). 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.
OMOM OMOM OMOM OMOM
CO2Et OH NPhth NPhth
a b c d

O
Ph3CO TrO TrO TrO

OMOM OMOM OMOM OMOM

NH2
H H f H
e HO
HO HO
N N N
O H
Boc Boc
TrO TrO TrO HO
HO OMOM OH
H HO H
g h
MsO see Synthesis 1993, 615
N N
Boc
(a) DIBAL-H , THF (b) phthalimide, DEAD , PPh3 (c) MCPBA , NaHCO3 , CH2Cl2 (d) N2H4 , EtOH
(e) Boc2O , THF , i-Pr2NH (f) H2 , Pd-C , MeOH , cat. HCl (g) MeSO2Cl , Py , CH2Cl2 (h) CF3COOH, MeOH

(h) The reagents used are taken form the reference. Reduction of the carboxylic acid with borane (7.2
was followed by protection of the amine as the Boc derivative. This allowed Swern oxidation to give
the aldehyde ([Link]).

a b c
N CHO
N CO2H N CH2OH N CH2OH
H H Boc O Ot-Bu
(a) BH3•THF ; aq NaOH (b) Boc2O (c) (COCl)2 , DMSO ssee J. Am. Chem. Soc. 1999, 121, 700
10 Organic Synthesis Solutions Manual

(i) These reagents are taken from J. Org. Chem. 2003, 58, 2790. In this particular synthesis, Wittig
olefination of the aldehyde unit ([Link]) 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 ([Link]).

CHO
O a O b c
HO
O O C14 H29
HO C14 H29

d e
TBDMSO HO HOOC C14 H29
HO C14 H29 MOMO C14 H29 OMOM
(a) C15 H31PPh3Br , BuLi , -78 °C (b) H+ , rt (c) TBDMSCl , NEt3 , cat DMAP , CH2Cl2
(d) 1. MOMCl , i-Pr2NEt , CH2Cl2 2. Bu4NF , THF (e) PDC , DMF , 40-50 °C

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

O HO OPiv OPiv
OH O
O HO
a OH b OH c O
OH

Me3Si Me3Si Me3Si

Me3Si

(a) 3N HCl , MeOH (b) pivaloyl chloride , Py , 23 °C (c) p-TsOH , 10 eq Me2C(OMe)2 , DMF , 70 °C

(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 OAc OH

a b c
OAc OAc OAc OH
O O O O
BnO HO TBDPSO TBDPSO

(a) DDQ , CH2Cl2 (b) t-BuPh2SiCl , imidazole , THF (c) K2CO3 , MeOH see J. Am. Chem. Soc. 1999, 121, 5653
 Chapter 5 11

(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 (6.5.2). 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.