Chapter 7 1 CHAPTER 7

Chapter 7 1

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

Copyright © 2011 Elsevier Inc. All rights reserved.

2 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.

A

OO

O

O

O

HN

OMOM

O

O

CF3

OO

O

OH

OH

HN

O

O

O

CF3

O

OO

O

O

O

HN

OMOM

O

O

CF3

H

OHH

H+

O

O

O

HN

OMOM

O

O

CF3

H

OH

OO

OO

O

O

O

HN

OMOM

O

O

CF3

H

OO

O

OH

OH

HN

O

O

O

CF3

OH

HOO

NH2O

OHOH

OO

O

OH

OH

NH2

OH

O

MeOH

MeO–

OO

O

O

O

HN

OMOM

O

O

CF3

H

OO

O

OH

OH

HN

OH

O

O

CF3

OMe

O

OO

O O

HN

OMOM

O

O

CF3

H

OH2

B

OO

O

OH

OH

HN

OH

O

O

CF3

– CH2=OMe

+ H2O

+ H+

+ H+

- Me2C=OH

– CF3CO2Me


Chapter 7 3

HOO

NHO

OHOH

O

O NH

O OH

OH

OH

O

MeOH

C

O

O NH

HO OH

OH

OH

Osee J. Org. Chem., 1999, 64, 4465

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

OC12H25

HO

O

Me

Me

O

O

Me

Me

OC12H25

O

O

Me

MeOMe

H

O

Me

H

O

Me

OC12H25

O

O

Me

MeOMe

H

H

Me

Me O Me

–H+

OO

C12H25

CO2Me

H

Me

Me

O

O

Me

Me

H

–H+

OC12H25

O

O

Me

MeOMe

O

Me

H

OC12H25

O

O

H

Me

MeOMe

–H+

O

O

Me

MeOMe

H

O

Me

OC12H25

–H+

+H+

OO

C12H25

CO2Me

OC12H25

O

O

Me

MeO

O

Me

H

H

Me

OC12H25

O

O

Me

MeOMe

+H+

+H+

OC12H25

O

O

Me

MeOMe

H

O

Me

H

OC12H25

O

O

Me

MeOMe

H

OC12H25

O

O

Me

Me

O

Me

H

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

+ H+

+MeOH

-MeOH

–MeOH

4.

(a)

O

OAc

OAc

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

(b)

N O

HH

H

O

I

O

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

(c)

CO2Me

MeO2C S

S

S

S

see Synthesis, 1996, 71



(d)

Br

OHO

O

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

(e)

N Boc

HO

H2N

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

(f)

NHHOMe2CH2CH2C

O'

see J. Org. Chem., 1999, 64, 3736

(g)

MeO2CCO2Me

O

OH

O

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

(h)

BzO OAc

OAc

OAc

NH

O

O

OH O

Org. Lett. 2002, 4, 1343

(i)

NBoc

O

J. Org. Chem., 2003, 68, 3838

(j)

OO

Eur. J. Org. Chem., 2004, 499

(k)

OH

O

O

Ph O O

OH

Ph

Angew. Chem. Int. Ed., 2003, 42, 4779 (l)

OBz

OSiPh2t-Bu

OO

OH

J. Am. Chem. Soc., 2003, 125, 8238

(m)

N

N

Me

CHOHO

Me

H

H H

H

Org. Lett. 2002, 4, 687 (n)

CHO

OSEM

see Tetrahedron Lett., 2000, 41, 2821 (o)

HN O

Ph

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 HO t-BuMe2SiO

OH

OH

HO

OH

OH

a bc

d

(a) NBS , h (b) NaOAc , DMF ; H3O+ (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.


Chapter 7 5

(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.

Me

OH

Me

OH

OMe

OH

OHMe

OH

Oa b c

(a) MCPBA (b) LiAlH4 (c) PDC , CH2Cl2

(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.

CO2HOH OH

HO

CHO

HOa

b

(a) LiAlH4 (b) Hg(OAc)2 , H2O ; NaBH4 (c) PDC , CH2Cl2

c

(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.

O O

OHEt

CO2HO

CO2H

O O

OHEt

O

CHO

O O

OHEt

OH

a b c

d e f

(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.



Me Me

O

Me

OH

H Me

OSi(iPr)3

H

B

Cl

H

n-Bu

Me

OH

n-Bua b

c

d

(a) 1. 9-BBN ; NaOH,H2O2 2. PCC (b) HC C-Na+ (c) NaH , iPr3SiCl (d) 1.

NaOMe ; AcOH , reflux 2. TBAF

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

OH

O

OSiMe2t-Bu

CHO

O

OSiMe2t-Bu

OH

O

OH

OBz

O

OSiMe2t-Bu

I

O

OSiMe2t-Bu

OH

O

OSiMe2t-Bu

OBz

O

OSiMe2t-Bu

CN

O

OH

OH

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

a b c

d e f

g h

(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

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 7

OHMeO

MeO

S

S

t-BuMe2SiO O

OMeO

O

S

S

HO OH

MeO

S

S

t-BuMe2SiO

S

S

ab

c

d

e

f

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.

HO O

O

OMe

TsO OPMB

OHC OPMB OPMBHO

O OPMB

EtO

NC OPMB

see Tetrahedron Lett., 2000, 41, 33

a

b

c d e

(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

(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).

O O

OH

O O

OTHP

OH

OTHP

OH

O O

CHO

PhOH

OH

OH O O

Ph

OHsee Synthesis, 1993, 137

a b c

d e

(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

(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.

OO

BnO

OO O

O

HO

OO

BnO

ab

c

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

d

(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)

OBn

OH OTBS

S S

OBn

OH OTBS

O

NaOMe

MeOH

OBn

OAc OTBS

S S

PCC OBn

O OTBS

H

O

OBn

OAc OTBS

O

Ac2O , DMAP NEt3

NBS , aq acetone

(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 9

Ph3CO

CO2Et

OMOM

TrO

OMOMNH2

O

N

HO HOMOM

MsO

Boc

TrO

OMOM

OH

NH

HOH

OMOM

TrO

TrO

OMOMNPhth

N

HOH

OMOM

TrOBoc

N

HO HOH

TrO

OMOMNPhth

O

N

HOH

OMOM

HOBoc

see Synthesis, 1993, 615

a b c

d

e f

g h

(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 (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).

N CO2H

H

N CH2OH

H

N CH2OH

Boc

N CHO

O Ot-Bu

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

a b c

(a) BH3•THF ; aq NaOH (b) Boc2O (c) (COCl)2 , DMSO

(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).



OO

CHOO

O C14H29HO

HO C14H29

C14H29HOOCOMOM

TBDMSOHO C14H29

HOMOMO C14H29

a b c

d e

(a) C15H31PPh3Br , 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 (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)

Me3Si

O

O

OH

Me3Si

HO

HO

OH

Me3Si

OPivOH

OH

Me3Si

OPivO

Oa b c

(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.

O

OAc

BnOOAc

O

OAc

HOOAc

O

OAc

TBDPSOOAc

O

OH

TBDPSOOH

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

a b c

(a) DDQ , CH2Cl2 (b) t-BuPh2SiCl , imidazole , THF (c) K2CO3 , MeOH

(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)


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