Chapter 3 1 CHAPTER 3 - Textbooks.elsevier.com

Chapter 3 1

CHAPTER 3

1. The product is the aldehyde, and the mechanism is analogous to the DMSO-based oxidations discussed in

Section 3.2.C. A reasonable mechanism is shown. Pyridine N-oxide attacks the bromomethyl moiety via an SN2

mechanism. Upon heating, pyridine N-oxide (or eventually the pyridine by-product) removes the hydrogen, as

shown, with displacement of pyridine (the leaving group) to generate the aldehyde. This is related to DMSO

oxidations of alcohols in that a leaving group is attached to the oxygen in A, making the -hydrogen susceptible to

removal by a base. See J. Org. Chem., 1999, 64, 3778.

R

Br

R = C5H11OTHP R

O NH

R

OH

baseNO N–

– Br–

2. These reagents are used for the Sharpless asymmetric epoxidation. Using the Sharpless model shown,

(–)-DET will deliver the epoxide oxygen from the front of the (R)-enantiomer of the racemic alcohol to give the

epoxide shown. Since the (S)-enantiomer is mismatched for this chiral additive, it will react much slower so it is

possible to convert the (R)-enantiomer to the epoxide while the (S)-enantiomer does not react. Therefore, the

authors in the cited paper isolated the unreacted enantiopure alcohol for use in their synthesis. This process is

called kinetic resolution.

OMOM

OBnOH

MOMO

OBnOH

A

MOMO

OBn

OH

H

MOMO

OBnOHO

+

Ti(OiPr)4 , D-(–)-DETt-BuOOH , MS 4Å

–20°C , 4 d

see Synthesis, 1993, 615

"O"D-(–)-DET

via

3. (a) This reaction is taken from J. Am. Chem. Soc., 2002, 124, 9199. The epoxidation must take place from the

top face, as the molecule is drawn, to give the proper stereochemistry of the alcohol unit. The alcohol is formed by

removal of the ketone a-hydrogen with the base (DBU - sec. 2.9.A), formation of the C=C unit and opening the

epoxide ring. The stereochemistry of epoxidation is discerned from the model (C=C alkene carbons A and B are

marked. It is not completely obvious from the model that the top face is less hindered because of the methyl group,

but the fused five-membered rings are somewhat puckered, and this blocks approach of the bulky meta-

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2 Organic Synthesis Solutions Manual

chloroperoxybenzoic acid from the bottom. remember that the transition state for this epoxidation is rather bulky

(sec. 3.4.C).

A

O

OH

H

H

B

O

OH

H

H

OH PhH

O

OH

H

H

OH

A

B

1. mcpba , CH2Cl2

2. DBU

(b) This is a Baeyer-Villiger rearrangement, and the carbon best able to bear a positive charge is the one that

migrates. The tertiary bridgehead carbon therefore migrates in preference to the primary carbon.

(c) Oxidation of phenol with Fremy's salt shows a preference for the para quinone. The reason is formation of

the intermediate Ar-ON(SO3K)2. This rather bulky substituent shows less steric hindrance with the oxygen in the

para position than it does in the ortho position. Relief of steric hindrance therefore drives this reaction to give the

para intermediate and, thereby, the para quinone.

(d) In general, alkenes bearing electron withdrawing groups react slower than simple alkenes. There is also a

steric effect that may lay a role, since dihydroxylation usually occurs at the less sterically hindered site. See J. Am.

Chem. Soc., 1999, 121, 7582

4. (a) In this reaction, the active reagent is the hydroperoxide anion (HOO–). Conjugate addition to the , -

unsaturated carbonyl occurs from the face of the molecule opposite the methyl groups in order to minimize steric

hindrance. The resulting enolate anion attacks the electrophilic oxygen to generate an epoxide, with loss of

hydroxyl. Steric hindrance with the methyl groups dictates delivery of HOO– from the bottom face of the

molecule, and the reaction proceeds with high diastereoselectivity for the product shown.

Me

Me O

O

H

H– –OH

–OOH

too hindered


Chapter 3 3

(b) The reagents will induce cis hydroxylation of the alkene. As drawn, the reagent will be delivered from the

less sterically hindered exo face to give the major product. The primary source of this steric hindrance is the

hydrogen bridging ether unit on the bottom side of the ring, which interacts with any reagent approaching from that

face. In a simple bicyclo[2.2.1]heptene, about 20-30% delivery of regent from the endo face is common, but here

the bridging ether effectively prevents this.

O

Br cat OsO4 , NMO , aq THF

–10°C RT

see Synthesis, 1996, 219 O

Br

OHOH

H H

(c) The major product described in J. Am. Chem. Soc., 2002, 124, 9726 is the diol shown. There may be a

neighboring group effect involving the allylic alcohol unit to direct the dihydroxylation via path 1. Inspection of

the model suggests that the top face is less hindered, and that approach to carbons A/B (path 1) may be somewhat

less hindered than approach to carbons C/D (path 2). It is likely that the regioselectivity arises from a combination

path 1 being less hindered and the neighboring group assistance provided by the allylic OH.

O

OH

O

OHHOHO

OsO4 69%

A

C

BD

A

BC

D

12

(d) In this reaction, the presence of the hydroxyl group might be expected to provide a neighboring group

effect, placing the epoxy-oxygen syn to the OH. A quick look at the 3D model, however, shows that the

conformation of the 8-membered ring places the OH more or less at right angles to the -bond so one face is not

favored over the other via coordination. This reaction is dominated by a steric effect, and the top face (A) is less

hindered, leading to the stereochemistry shown.

NO

OH

O

NO

OH

O

O

MCPBA , CH2Cl2

74%

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

A

12

1

2



(e) In the first reaction, the mild Dess-Martin procedure converts the allylic alcohol unit to a conjugated ketone. In

the second step, the AD-mix- delivers dihydroxylation from the top face to give the diol shown, with high

diastereoselectivity and enantioselectivity. Using the Sharpless model, AD-mix- should deliver the hydroxyls

from the bottom but in that model, bottom is relative to the methyl groups at the allylic position. Therefore,

delivery opposite the methyl groups leads to the stereochemistry shown. This sequence is take from Lee's synthesis

of amphidinolide B1 (see reference).

OSiiPr3

OSiMe2t-Bu OPMB

OSiMe2t-Bu

OH

OSiiPr3

OSiMe2t-Bu OPMB

OSiMe2t-Bu

O

OH

HO

OSiiPr3

OSiMe2t-Bu OPMB

OSiMe2t-Bu

O?a

?b

a

b

(a) Dess-Martin periodinane , pyridine, CH2Cl2

(b) AD-mix- , MeSO2NH2 , aq t-BuOH

see Tetrahedron Lett., 2000, 41, 2573

5. These three reactions involve Sharpless asymmetric epoxidation. The model in Figure 3.2 is used to predict

delivery of the reagent from the re or si face.

OH t-BuOOH , (–)-DET

Ti(Oi-Pr)4 , CH2Cl2

OHO

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

(a) When oriented according to Figure 3.2, (–) tartrate delivers O from the bottom face to give the epoxide with

the stereochemistry shown.

(b) Using the same model from Figure 3.2, the allylic alcohol is aligned as shown, and (–)-tartrate should

approach from the back for best selectivity. This would lead to the stereochemistry shown with the epoxy unit to

the rear and the methyl projected to the front. Notice that the allylic acetate unit was not epoxidized under these

conditions, only the allylic alcohol unit.


Chapter 3 5

OAc

OH

OAc

OH

OOAcOH

(–)-tartrate

t-BuOOH , (–)-DET

Ti(OiPr)4 , CH2Cl2

see Tetrahedron Lett., 2000, 41, 2181

(c) Using the model from Figure 3.2, the orientation of the allylic alcohol using (–)-DIPT delivers the oxygen

from the bottom, as shown. The smaller ethyl group is on that face, and the epoxide shown is generated with good

stereoselectivity.

OH

(–)-tartrate

OHO H

H

6. The major products of each reaction are shown in the following sequence.

(a)

O

O

OHOMe

OSiMe2t-Bu

O

OOMe

OSiMe2t-Bu

O

Ph

O

O

OOMe

OSiMe2t-Bu

O

Ph

OH

OH

OOMe

OSiMe2t-Bu

O

Ph?a ?b

?c

a b

c(a) benzoyl chloride (b) MeOH, H+ (c) NaIO4

J. Am. Chem. Soc., 1999, 121, 5589

(b)

OH OMe

O

OMeH

O

OMeOH

?a ?b ?c

a b c

(a) BuLi , ether-DMSO ; MeI (b) O3 ; PPh3 (c) PDC , DMF

J. Org. Chem., 2000, 65, 3738



7. This sequence is taken from J. Am. Chem. Soc., 2002, 124, 9060. Swern oxidation (3.2.C.i) gives the ketone,

which eliminates the tosyl group in the presence of triethylamine (via removal of the acidic -hydrogen with

concomitant loss f the tosyl) to give the conjugated ketone. An internal conjugate addition of the pyrrole unit (also

see 9.7.A) leads to the observed product.

NH

OH

TolO2S N

OHN

ON

MeO2N

NO2NEt3

NH

O

N

OHN

ON

MeO2N

NO2

–H+

NH

O

TolO2S N

OHN

ON

MeO2N

NO2

H

NH

O ON

MeO2N

N N

O

NO2

DMSO , (COCl)2

67%

– Ts

8. The initial reaction is the expected oxidation of the benzylic alcohol to the aldehyde. This is susceptible to

attack by the pendant OH unit, to form a protonated hemiacetal, and loss of the proton gives the hemi-acetal. If the

OH unit is oxidized further with MnO2 that is still present, the observed lactone is obtained.

MnO2

OH

OH

OH

O

HO

OH

H

OH

CHO

–H+O

OH

MnO2

O

O

see Heterocycles, 1996, 42, 589

+MnO2 , CH2Cl2

2% 98%


Chapter 3 7

9.

(a)

HO

OPMB

OSiMe2t-Bu

O

H

O

HH

A B

OPMB

OSiMe2t-Bu

O

H

O

HH

OH

(b)

N

MeO

NAc

OMe H

Org. Lett. 2002, 4, 443

(c)

O O

(i-Pr)3SiO

J. Org. Chem., 2003, 68, 4215

(d)

O

OH

H

O

HO

J. Org. Chem., 2002, 67, 2566

(e)

O

OMeMeO

O

Org. Lett., 2002, 4, 19

(f)

O

J. Org. Chem., 2003, 68, 1030

(g)

H OSiMe2t-Bu

OPMB

PMB - p-methoxybenzoylJ. Am. Chem. Soc., 2002, 124, 5654

O

(h)

NH

NO H

SiMe3

O

NHCO2t-Bu

see J. Am. Chem. Soc., 1999, 121, 9574

(i)

CHOCHO

J. Org. Chem., 2003, 68, 1242

(j)

Cl

see J. Chem. Soc., Perkin Trans 1, 1993, 1095

OH

OH

(k)

O

OCHO

Me

Me Me

H

HO

see J. Am. Chem. Soc., 1979, 101, 4400

(l)

OHC

O

O

OHO

J. Org. Chem., 2003, 68, 7428

(m)

HO

O H

BrO2N

Tetrahedron,2003, 59, 9239



(n)

NO

PMBO

O

H

OCH2PhPMB = p-methoxybenzyl J. Org. Chem., 2003, 68, 7818

OH

OH

(o)

OH

OO

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

O

(p)

O

O

Me

Me

Me

OBn

Et

O

O

see J. Am. Chem. Soc.,1987, 109, 5878

(q)

O

O

OSiMe2t-Bu

CHO

see J. Org. Chem., 2000, 65, 3432

(r)

OC12H25

OAc

O

J. Org. Chem., 2003, 68, 7548

(s)

see p 137 (Cope elimination)

(t)

O

Me

HO

Me

Me

see J. Am. Chem. Soc., 1999, 121, 5087

(u)

OO HO

AcO

t-BuMe2SiO

O

J. Am. Chem. Soc., 2004, 126, 2194

(v)

see J. Org. Chem., 2002, 67, 7774

N

CO2t-Bu

HO

O2C(4-NO2-C6H4)

HO OH

(w)

MeO OAc

H O

Org. Lett. 2003, 5, 3931

(x)

CO2MeOAc

Me

Me

t-BuPh2SiO

OHC

Org. Lett. 2002, 4, 1543

(y)

N O

Si(i-Pr)3

OHCN

HN

O

CO2t-Bu

Angew. Chem. Int. Ed., 2003, 42, 694

(z)

O

see Chem. Commun., 2000, 837

O

(aa)

N

CHO

CO2t-Bu

Me

see Synthesis, 1998, 479

(ab)

OMe

OH

OMe

Org. Lett. 2002, 4, 909


Chapter 3 9

(ac)

OSiMe2t-Bu

CHOt-BuMe2SiO

J. Am. Chem. Soc., 2002, 124, 11102 (ad)

Me CO2EtMe

O

O

see Org. Lett., 2000, 2, 3177 (ae)

NMe

OMeMeO2C

OHHO

see Org. Lett., 2000, 2, 3039

10. In each case one example of a suitable synthesis is shown. In many, perhaps most, cases there are other

synthetic approaches that are reasonable.

(a) The shortest approach is to use the appropriate Grignard reagent with the aldehyde derived from oxidative

cleavage of a diol, derived from hydrolysis of the starting epoxide. The Grignard reaction is discussed in Section

8.4.C.

OOH

OH

O

Ph

CHO OH

Ph

a c

(a) aq. H+ (b) OsO4 , NaIO4 (c) PhCH2CH2MgBr ; H2O (d) PCCd

b

(b) See the actual synthesis in Chem. Lett., 1979, 1245. This pertinent reactions are outlined below.

Me Me

Me

H H

CHO

Me Me

H H

MeO2C

Me Me

H H

HO2CO

Me Me

H H

MeO2CO

Me Me

H H

MeO2CHO

Me Me

H H

MeO2C

a b c d

e(a) O3 ; H2O2 (b) SOCl2 ; MeOH (c) NaBH4 ; H3O+ (d) POCl3, pyridine (e) O3 ; Me2S

(c) It is very possible that the hydroxy acid will spontaneously cyclize to the lactone. The acid catalysis in step d is

added as a formalism since six-membered ring lactones are somewhat harder to form than five-membered ring

lactones, which spontaneously form from hydroxy acids in virtually all cases. Step c is a reduction and the

functional group reaction wheel in Chapter 1 (Figure 1.1) provides several possible reagents, including sodium

borohydride, which will be discussed in Section 4..4.A.



Me

BrMe

HO2CO

Me

HO2COH

Me

O

Me

O

a b cd

(a) KOH , EtOH (b) O3 ; H2O2 (c) NaBH4 ; H3O+ (d) H+

(d) This reaction uses a Baeyer-Villiger rearrangement (Sec. 3.6.A) to set the oxygen on the cyclohexane ring.

Eventual oxidation leads to the ketone that can be converted to its dioxolane ketal.

OO

O

Oa b d

(a) MCPBA (b) i. aq KOH ii. aq H+ (c) PCC (d) 1,2-ethanediol, cat H+

O

OOHc

(e) The conversion of the alcohol to the alkene involves a Chugaev elimination (see Sec. 2.9.C.iv). Other syn

elimination methods could be used if the alcohol were converted to another functional group.

Ph Ph

O

Ph

OHPh Ph

Oa b c d

(a) O3 ; Me2S (b) NaBH4 ; H3O+ (c) i. CS2 ii. MeI iii. 200°C (d) MCPBA

(f) An E2 reaction gives the alkene, allowing a selenium dioxide oxidation to the allylic alcohol. Oxidation to the

acid with PDC in DMF is followed by conversion to the acid chloride and quenching with ammonia to give the

amide.

BrOH

OHO

NH2

Oa b

c d

(a) KOH , EtOH (b) SeO2 (c) PDC , DMF (d) i. oxalyl chloride ii. NH3

(g) An E2 reaction gives cyclohexene and epoxidation followed by an acid-catalyzed ring opening in the presence

of methanol gives 2-methoxy cyclohexanol. Oxidation gives the ketone and Swern oxidation was used here,

although most of the milder conditions in this chapter would suffice.

BrO

OH

OMe

O

OMeab c d

(a) KOH , EtOH (b) MCPBA (c) MeOH , cat H+ (d) Swern oxidation


Chapter 3 11

(h)

O

CN

OH

CN

OMe

CO2H

OMe(a)

(a) MCPBA (b) NaCN , DMF ; hydrolysis (c) i. NaH ii. MeI (d) i. aq NaOH ii. H3O+

(b) (c) (d)

(i)

OHCO2H

NMe2

Oa b c

(a) POCl3 , pyridine (b) O3 ; H2O2 (c) i. SOCl2 ii. HNMe2

(j) Oxidation of the secondary alcohol in the presence of the tertiary alcohol requires a mild oxidizing agent.

Several reagents are available, including tetrapropylperruthenate and the Dess-Martin reagent shown.

HOO

HOOH

(a) OsO4 , NMO (b) Dess-Martin periodinanea b

(k) Elimination of the alcohol with POCl3 (Sec. 2.8.A) and pyridine gives the alkene, and ozonolysis leads to the

methyl ketone. The final step is a Baeyer-Villiger rearrangement.

OH

O

MeOAc

b c

(a) POCl3 , pyridine (b) O3 , Me2S (c) MCPBA

a

(l)

O OAc OH O OH

N3a b c e

(a) MCPBA (b) i. aq KOH ii. aq H+ (c) POCl3 , pyridine (d) MCPBA (e) NaN3 , THF

d

(m) This diol to ketone rearrangement is the pinacol rearrangement (see Sec. 12.3.A).

OH

HO Oa b

(a) OsO4 ; NMO (b) H+


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