Chapter 6 1

CHAPTER 6
1. The following reaction was reported in the synthesis of niphatoxin B. Give the product and
suggest a mechanistic rationale for this reaction.
1. The product is the aldehyde, and the mechanism is analogous to the DMSO-based oxidations
discussed in Section 6.2.C3. 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 atom, 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 α-hydrogen susceptible to removal by a base. See J. Org.
Chem. 1999, 64, 3778.

base
Br O N N
–
H O N H O
R – Br–
R = C5H11 OTHP R R

2. The product of this reaction was expected to be a diol-acid, and the infrared (IR) showed an OH
peak and a strong carbonyl, but there was no apparent CO2H absorption. Likewise, the 1H NMR
showed there was no CO2H group. Show the actual product and explain why the anticipated diol-
acid was not isolated.
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.

OH OBn Ti(OiPr)4 , D-(-)-DET OH OBn OH OBn

t-BuOOH , MS 4Å O
+
-20 °C , 4 d
OMOM MOMO A
MOMO
see Synthesis 1993, 615 MOMO
"O" OH
Via D-(-)-DET
H
OBn
2 Organic Synthesis Solutions Manual

3. Explain each of the following

(a) The following reaction was reported in Paquette and Geng's synthesis of ceratopicanol.
Explain the product as well as the stereochemistry of the alcohol unit.
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 α-hydrogen with the base (DBU), formation of the C=C unit
and opening the epoxide ring. The stereochemistry of epoxidation is discerned from the molecular
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-chloroperoxybenzoic acid from the bottom.
Remember that the transition state for this epoxidation is rather bulky (sec. 6.4.3).

B
H O H
A H
1. mcpba , CH2Cl2
H H B
O O A
OH OH OH
2. DBU
H
PhH

H
O
OH

(b) Explain the regioselectivity of this reaction.

(b) This reaction 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) Explain why p-quinone is the major product.

(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) Explain why the nonconjugated alkene reacts preferentially.

(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.
 Chapter 6 3

4. Give the major product of each reaction and explain the regiochemistry and/or stereochemistry
where applicable.
4. (a) In this reaction, the active reagent is the hydroperoxide anion (HOO–). Conjugate addition to the
α,β-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.

Too hindered

Me
O
Me
–OH
H
–
–OOH H O

(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.

H cat OsO4 , NMO , aq THF H

Br Br
-10 °C → RT OH
O see Synthesis 1996, 219 O OH
4 Organic Synthesis Solutions Manual

(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 molecular 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.

1
2
O O

OsO4 A
C 69% C
D B
B A OH HO HO OH D

(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 molecular
model, however, shows that the conformation of the 8-membered ring places the OH more or less at
right angles to the π-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.

A
2 O
OH
1 OH
MCPBA , CH2Cl2
N
74%
1 O N
see J. Org. Chem. 2000, 65, 9129
2 O
O
O
 Chapter 6 5

(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-α delivers dihydroxylation from the top face to give
the diol shown, with high diastereoselectivity and enantioselectivity. Using the Sharpless model, AD-
mix-α 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 (taken from Lee and Rho's synthesis of amphidinolide B1; see reference).

HO
OSiMe2t-Bu OPMB OSiMe t-Bu OPMB OSiMe2t-Bu OPMB
2
a b
OH
OH O ?a O ?b
OSiiPr3 OSiiPr3 OSiiPr3
OSiMe2t-Bu OSiMe2t-Bu OSiMe2t-Bu
(a) Dess-Martin periodinane , pyridine, CH2Cl2 (b) AD-mix-α , MeSO2NH2 , aq t-BuOH see Tetrahedron Lett. 2000, 41, 2573

5. Predict the major product. Draw an appropriate transition state for each reaction.
5. These three reactions involve Sharpless asymmetric epoxidation. The model in Figure 6.1 and
structure 154/155 is used to predict delivery of the reagent from the re or si face.

O
OH t-BuOOH , (-)-DET OH
Ti(Oi-Pr)4 , CH2Cl2

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

(a) When oriented according to Figure 6.1 and structure 154/155, (-) tartrate delivers O from the
bottom face to give the epoxide with the stereochemistry shown.
(b) Using the same model from Figure 6.1 and structure 154/155, 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.

OAc OAc
t-BuOOH , (-)-DET

Ti(OiPr)4 , CH2Cl2 O OAc

OH
OH see Tetrahedron Lett. OH (-)-tartrate
2000, 41, 2181
6 Organic Synthesis Solutions Manual

(c) Using the model from Figure 6.1 and structure 154/155, 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.

O H
OH
OH
(-)-Tartrate

6. (a) Identify each product (?) in the following sequence, taken from Taber's synthesis of (-)-
fumagillin.
6. The major products of each reaction are shown in the following sequence.

(a)
OH
O
O OH
O
OSiMe2t-Bu
O
a b
OSiMe2t-Bu
OMe
OSiMe2t-Bu OMe
O
OMe O O
O
OH ?a ?b
O Ph
Ph

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

OSiMe2t-Bu
OMe
J. Am. Chem. Soc. 1999, 121, 5589
O
O ?c
Ph

(b) Identify ?a, ?b, and ?c in the following sequence, taken from Smith's synthesis of (+)-
thiazinotrienomycin E.
(b)

OH OMe H OMe OH OMe

a b c
O O
?a ?b ?c
(a) BuLi , ether-DMSO ; MeI (b) O3 ; PPh3 (c) PDC , DMF J. Org. Chem. 2000, 65, 3738
 Chapter 6 7

7. Briefly explain how the product shown is formed in this Swern oxidation, taken from Feldman
and Saunders’ synthesis of (-)-agelastatin A.
7. This sequence is taken from J. Am. Chem. Soc. 2002, 124, 9060. Swern oxidation (6.2.3.1) gives the
ketone, which eliminates the tosyl group in the presence of triethylamine (via removal of the acidic α-
hydrogen with concomitant loss of the tosyl) to give the conjugated ketone. An internal conjugate
addition of the pyrrole unit (also see Section 13.7) leads to the observed product.

O2N
Me O2N
O Me
OH O
N O
N
NH NEt3
NO2 H NH
NO2
TolO2S DMSO , (COCl)2
N TolO2S
67% N
H
N H
O N O

O2N
O2N O Me
O Me O
O N
N
NH
NH -H+
- Ts
NO2
NO2
N N
N
H
N O O
8 Organic Synthesis Solutions Manual

8. Provide a mechanism to explain the following transformation.

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

OH
H
O O
H -H+
OH OH
O

MnO2

OH
MnO2
O
OH
MnO2 , CH2Cl2 CHO O
+
OH

see Heterocycles 1996, 42, 589 98%

2%

9. Give the major product for each reaction.

9.

HO O
H
O O
H H
H OSiMe2t-Bu H OSiMe2t-Bu
(a)
O O
H H
OPMB OPMB
A B
OH
Ac
N O O
MeO
(b) (c) (i-Pr)3SiO (d)
HO
N H
O O
Me H
O
Org. Lett. 2002, 4, 443 J. Org. Chem. 2003, 68, 4215 J. Org. Chem. 2002, 67, 2566
 Chapter 6 9

O O O

H OSiMe2t-Bu
(e) O (f) (g)

MeO OMe OPMB

Org. Lett. 2002, 4, 19 J. Org. Chem. 2003, 68, 1030 PMB - p-methoxybenzyl
J. Am. Chem. Soc. 2002, 124, 5654
SiMe3
Cl
NH O
(h) (i) CHO (j) OH
CHO
N NHCO2t-Bu OH
O
H
see J. Am. Chem. Soc. 1999, 121, 9574 J. Org. Chem. 2003, 68, 1242 see J. Chem. Soc., Perkin Trans 1 1993, 1095
HO O

HO CHO
O OHC O2N Br
Me
(k) (m)
O (l) O
H HO
O
OH
Me J. Org. Chem. 2003, 68, 7428
Me
see J. Am. Chem. Soc. 1979, 101, 4400 Tetrahedron 2003, 59, 9239
Me
H OH
PMBO
O
(n) O OH (o) O (p) OBn
N O Me
O OH
O
O OCH2Ph O Me
PMB = p-methoxybenzyl see J. Org. Chem. 2000, 65, 9129 Et O
J. Org. Chem. 2003, 68, 7818
see J. Am. Chem. Soc. 1987, 109, 5878

O OSiMe2t-Bu
C12 H25
(q) (r) (s) O
O
O CHO OAc
see J. Org. Chem. 2000, 65, 3432 see Sect. 3.7.B J. Org. Chem. 2003, 68, 7548
(Cope elimination)
t-BuMe2SiO
HO OH
Me
O HO
O HO
(t) Me (u) (v) N
Me O
CO2t-Bu
HO
O AcO (C6H4-O2N-4)CO2
see J. Am. Chem. Soc. 1999, 121, 5087 see J. Org. Chem. 2002, 67, 7774
J. Am. Chem. Soc. 2004, 126, 2194
10 Organic Synthesis Solutions Manual

OHC N
MeO OAc CO2Me OHC CO2t-Bu
OAc
N O
(w) (x) Me (y) O
Me
HN
H O t-BuPh2SiO
Si(i-Pr)3
Org. Lett. 2003, 5, 3931 Org. Lett. 2002, 4, 1543 Angew. Chem. Int. Ed. 2003, 42, 694

OMe
CHO
O OH
CO2t-Bu
(z) (aa) N (ab)

O Me
OMe
see Chem. Commun. 2000, 837 see Synthesis 1998, 479 Org. Lett. 2002, 4, 909

t-BuMe2SiO Me CO2Et HO OH
CHO Me
(ac) (ad) (ae)
O Me N

OSiMe2t-Bu MeO2C
O OMe
J. Am. Chem. Soc. 2002, 124, 11102 see Org. Lett. 2000, 2, 3177 see Org. Lett. 2000, 2, 3039

10. In each case, provide a suitable synthesis. Give all reagents that are necessary and show all
intermediate products.
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 11.4.3.1.

a OH b CHO c OH d O
O
OH
Ph Ph
(a) aq H+ (b) OsO4 , NaIO4 (c) PhCH2CH2MgBr ; H2O (d) PCC
 Chapter 6 11

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

Me
O O HO MeO2C CHO
HO2C MeO2C MeO2C MeO2C e
a b c d
H H
H H H H H H H H H H Me Me
Me Me Me Me Me Me Me Me Me Me
(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 1.2) provides several
possible reagents, including sodium borohydride, which will be discussed in Section 7.4.

Me
Me Me
Me a b c d
Me O
O OH
Br HO2C HO2C
O
(a) KOH , EtOH (b) O3 ; H2O2 (c) NaBH4 ; H3O+ (d) H+

(d) This reaction uses a Baeyer-Villiger rearrangement (Section 6.6.1) to set the oxygen on the
cyclohexane ring. Eventual oxidation leads to the ketone that can be converted to its dioxolane ketal.
O O
O OH O
a b c d
O O

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

(e) The conversion of the alcohol to the alkene involves a Chugaev elimination (see Section 3.7.3).
Other syn elimination methods could be used if the alcohol were converted to another functional group.

Ph a Ph b Ph c d
Ph Ph
O OH O

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

(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.

O O
OH d
a b c OH NH2
Br

(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-methoxycyclohexanol. Oxidation gives the ketone and Swern
oxidation was used here, although most of the milder conditions in this chapter would suffice.

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

(h)
O OH OMe OMe
a b c d
CN CN CO2H

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

(i)
OH O
a b c
CO2H
NMe2
(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.

a b HO (a) OsO4 , NMO (b) Dess-Martin periodinane

HO
OH O
 Chapter 6 13

(k) Elimination of the alcohol with POCl3 (Section 3.5.1) and pyridine gives the alkene, and ozonolysis
leads to the methyl ketone. The final step is a Baeyer-Villiger rearrangement.

O c
a b
OH OAc
Me

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

(l)
O OAc OH O OH
a b c d e
N3

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

(m) This diol to ketone rearrangement is the pinacol rearrangement (see Section 16.2.D4).

HO O
b
a
(a) OsO4 ; NMO (b) H+

OH