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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-
Copyright © 2011 Elsevier Inc. All rights reserved.
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
Copyright © 2011 Elsevier Inc. All rights reserved.
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
Copyright © 2011 Elsevier Inc. All rights reserved.
4 Organic Synthesis Solutions Manual
(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.
Copyright © 2011 Elsevier Inc. All rights reserved.
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
Copyright © 2011 Elsevier Inc. All rights reserved.
6 Organic Synthesis Solutions Manual
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%
Copyright © 2011 Elsevier Inc. All rights reserved.
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
Copyright © 2011 Elsevier Inc. All rights reserved.
8 Organic Synthesis Solutions Manual
(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
Copyright © 2011 Elsevier Inc. All rights reserved.
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.
Copyright © 2011 Elsevier Inc. All rights reserved.
10 Organic Synthesis Solutions Manual
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
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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+
Copyright © 2011 Elsevier Inc. All rights reserved.