Chapter 11

CHAPTER 11
1.

(a) From Table 11.1, HOMO/LUMO values for methyl acrylate are used for styrene: HOMO = -8.48 eV;

LUMO = 0.8 eV. The values for 2-butyne are HOMO = -9.9 eV; LUMO = -3.43 eV. From Table 11.2), values for
2-methoxy-1,3-butadiene are HOMO = -8.62 eV; LUMO = +3.60 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene). Therefore, the
coefficients of the LUMO are required for the alkenes and those of the HOMO for the diene. Styrene has the
following coefficients: c3 = 48; c4 = -.33. No values are given for 2-butyne, but this is a symmetrical system, and
the orbitals coefficients should be the same (0.5). The orbital coefficients for the HOMO of methoxy-butadiene
are: c1 = .352; c2 = .103.
The rate of reaction is determined by the HOMO-LUMO energy difference. The
E for styrene and methoxybutadiene is 9,42 eV. The
E for 2-butyne is 12.05 eV. Since the energy gap for styrene is smaller, that reaction is
expected to be faster. For the styrene reaction, the larger coefficients are correlated and the para product shown is
expected to be the major product as a racemic mixture. A single diastereomer (cis) is produced as a racemic
mixture, with none of the trans diastereomer.
.103

MeO

.352

Ph

-.33 Ph
.48

MeO

(b) From Table 11.1, the HOMO/LUMO values for maleic anhydride are : HOMO = -11.95 eV; LUMO = -0.57
eV. The values for cyclopentenone are: HOMO = -9.34 eV; LUMO = -0.64 eV. From Table 11.2, the values of 2methyl-1,3-butadiene are: HOMO = -9.04 eV; LUMO = +3.38 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene). Therefore, the
coefficients of the LUMO are required for the alkenes and those of the HOMO for the diene. No values are given
for either maleic anhydride or cyclopentenone. Maleic anhydride is a symmetrical molecule so the coefficients are
expected to be 0.5 for both carbons. The coefficients for acrolein are known (the only conjugated ketone or
aldehyde available) so using this as an basis, the coefficient proximal to the carbonyl is the largest. The orbital
coefficients for the HOMO of methyl-butadiene are c1 = 0.340; c2 = 0.296.
The rate of reaction is determined by the HOMO-LUMO energy difference. This
E for maleic anhydride and
methyl-butadiene is 8.47 eV. The
E for cyclopentenone is 8.40 eV. Since the energy gap for cyclohexenone is
slightly smaller, that reaction is expected to be slightly faster. The regiochemistry is not an issue because maleic
anhydride is symmetrical, and the cycloadducts is the one shown. Only the cis diastereomer will be produced.
O

(c) From Table 11.1, the HOMO/LUMO values for chloroethene are: HOMO = 10.15 eV; LUMO = 0.5 eV.

Organic Synthesis Solutions Manual

The values for methyl vinyl ether are: HOMO = 9.05 eV; LUMO = +2.0 eV. From Table 11.2, the values of
pyrrole are HOMO = 8.2 eV; LUMO = +2.38 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene - LUMOalkene). Therefore, the
coefficients of the LUMO are required for the alkenes and those of the HOMO for the diene. Chloroethene has the
following coefficients: c3 = 0.67; c4 = 0.54. Methyl vinyl ether has: c3 = 0.66; c4 = 0.72. The orbital coefficients
for the HOMO of pyrrole are not given but those for CH2 =CHNMe2 suggest the coefficient distal to the N is larger.
The rate of reaction is determined by the HOMO-LUMO energy difference. This
E for chloroethene and
pyrrole is 8.7 eV. The
E for methyl vinyl ether is 10.2 eV. Since the energy gap for chloroethene is smaller, that
reaction is expected to be faster.
Since pyrrole is a symmetrical diene, regioselectivity is not important. The cycloadduct is a bicyclic amine,
however, and both endo and exo diastereomers can be formed but endo approach is favored, and the endo
diastereomers is shown as the major product.

It is noted, however, that secondary orbital interactions for

chloroethene may not be great. The reaction may be driven more by steric considerations and will give more exo
product.
H
N

Cl
NH

Cl

(d) From Table 11.1, the HOMO/LUMO values for acrolein are HOMO = 10.89 eV; LUMO = 0.60. The
values for nitroethene are HOMO = 11.4 eV; LUMO = +0.7 eV. From Table 11.2, the values for 12-cyano-1,3butadiene are HOMO = 9.58 eV; LUMO = +2.12 eV.
Assume that each reaction proceeds by normal electron demand (HOMOdiene LUMOalkene). There-fore, the
coefficients of the LUMO are required for the alkenes and those of the HOMO for the diene. Acrolein has the
following coefficients: c3 = 0.404; c4 = 0.58. The coefficients for nitroethene are c3 = 0.54 c4 = 0.32. The
orbital coefficients for the HOMO of cyanobutadiene are c1 = 0.595; c2 = 0.490.
The rate of reaction is determined by the HOMO-LUMO energy difference.

The
E for acrolein and

cyanobutadiene is 10.18 eV. The
E for nitroethene is 10.28 eV. The energy gap for acrolein is slightly smaller,
and that reaction is expected to be slightly faster. The orbital coefficient of the diene is largest proximal to the
cyano group and proximal to the CHO unit in acrolein. This leads to the meta regioisomer shown.
.490
.404
NC

-.581
.595

CHO

NC

CHO

2. This mechanistic rationale is taken from J. Org. Chem., 2004, 69, 112. Formation of and trapping of the enolate
anion is followed by an Ireland-Claisen reagent. Hydrolysis liberates the carboxylic acid product fro the silyl-ester.

Chapter 11

3
5

OMe

OMe

5
1

O
2

OSiMe2 t-Bu

LiN(TMS)2
O
Me 2t-BuSiCl
HMPA , THF

PhH , reflux

OSiMe2 t-Bu

CO2 SiMe 2t-Bu

O
OMe

H 2O

THF

629

CO2 H
OMe

OMe

630

3. This reaction is taken from J. Org. Chem., 2003, 68, 3593. An initial Diels-Alder reaction of the tetrazine leads
to the bicyclic species shown. Boger and co-worker's reported that this cycloaddition was an inverse electron
demand reaction. Subsequent retro Diels-Alder reaction releases nitrogen, and re-aromatization generates the
diazine product.
OMe

OMe

MeO

MeO
O
Me
N
N

N
N
NEt2
O

N Ar
N
O
N
Me
N
Ar
NEt2
O

MeO

N
N

Me

N
N

NEt2
O

MeO
OMe

OMe

4. Heating to 220C induces a vinyl-cyclopropane rearrangement, which is a [1,3]-sigmatropic carbon shift. The
allowed processes are a suprafacial inversion and an antarafacial retention migration. Forbidden pathways are the
suprafacial retention and the antarafacial inversion. The major product arises by an allowed suprafacial inversion
process, as indicated.

D
H
14%

Ph

allowed antarafacial
retention

Ph
H

allowed suprafacial
inversion

see J. Org. Chem., 1999, 64, 3567

D
H

Ph
86%

5. As allene approaches the fused six-membered rings, the A strain imparted by the axial hydrogens destabilizes

Organic Synthesis Solutions Manual

approach from that face. Approach is from the lower-energy bottom face. If attack occurred from the top face, one
six-membered ring would have to distort more to accommodate the ring flattening induced by the presence of the
fused four-membered ring (see Section 1.5.B).

In the five-membered ring system, the relatively planar

cyclopentanone causes the second ring to distort, and the allene approaches opposite that fragment. In both cases,
the fact that two hydrogens are coplanar with the carbons and two hydrogen atoms are perpendicular to that plane
exacerbates the steric interactions when approaching the conjugated ketone moiety.

H
H
O

H
H

H
C
H
H C C
H

H
H C
H

H
O

see Tetrahedron, 1980, 36, 719; and 1975, 31, 4981, 1655

6. Upon heating, the cycloheptatriene unit undergoes an electrocyclic ring closure to give the norcaradiene system.
Via 1,5-sigmatropic shifts of the norcaradiene ring, the CMe(CO2Me) unit can "walk" around the ring, as shown.
Finally, the norcaradiene unit opens to give the new cycloheptatriene.

Me
CO2 Me

Me

MeO 2C
CO 2Me

Me

Me

Me

Me
MeO2 C Me
Me

MeO 2C
Me

Me
see J. Am. Chem. Soc.,
1999, 121, 4524

7. This transformation is taken from J. Am. Chem. Soc., 2004, 126, 2194. Initial oxidation to the selenoxide
(2.9.C.vi), which did not spontaneously undergo syn-elimination product , but was isolated. Upon heating, in the
presence of DBU, the vinyl ether was formed and a Claisen rearrangement (11.12.D) led to the observed product.

Chapter 11

PhMe2 Si

PhMe 2 Si
NaIO4 , MeOH

Ph
O

Ph
O

OMe

Se
O

SePh

Ph

DBU , xylene
sealed tube
185C
Ph

Claisen
rearrangement

Ph
O

OTBS

NaHCO 3 , H2 O

PhMe 2 Si

PhMe2 Si

8. This intermediate is taken from Org. Lett., 2003, 5, 4037. This reaction proceeds by the enol form of the ketoester, which is stabilized by hydrogen-bonding with the keto moiety.

The [3+3]-sigmatropic rearrangement

proceeds to give the keto-acid, and decarboxylation leads to the final product.
OBn
OBn

OBn

neutral Al2 O3
OMOM 60C
OMOM
O

O
O
O

OMOM
O

O
O H

O
O H

OBn

606
CO2

OMOM

O
607

9. When the starting material is viewed in a conformational drawing, it is clear that the carbonyl on the 8membered ring and the alkene unit of the cyclohexenone unit are in close proximity. With photolysis, a PaternoBchi reaction is possible that forms another oxetane ring in the molecule, as shown.

AcO
Me

O
OTES
Me

OAc Me
Me

O
BzO

AcO

Me O
Me
O

OTES

OBz OAc

h

OAc Me
Me
Me O

Me
see J. Org. Chem., 1997, 62, 4900 O

OTES

OBz OAc

Organic Synthesis Solutions Manual

10. In Chapter 8 (sec. 8.8.B), we saw that sulfonium salts react with base to form sulfur ylids, and they reacted
with ketones and aldehydes to give epoxides. Sulfur ylids also react with imines to give aziridines, and this
explains formation of the aziridine product, as shown. Close inspection of this particular aziridine, however,
reveals that it is a 1,5-diene with a three-membered ring that can accelerate a Cope rearrangement (Sec. 11.12.C.i).
Cope rearrangement leads to the dihydroazepine product shown.
KOH
Me2 S

Ph

Me2 S

Ph

SMe 2

N Ts
Ts
N

Ph
Cope-rearrangement

Ts
N

N Ts

Ph

Ph

Ph

Ph

see J. Org. Chem., 1996, 61, 4641

Ph

Ph

11. (a) Using the coefficients for a simple nitrile oxide, and estimating that the carbon bearing the alkyl group on
the alkyne will have the largest coefficient, the regiochemistry of the product can be estimated as shown. See J.
Chem. Soc., Chem. Commun., 1978, 962.
(b) In this case the nitrile oxide reacts with the alkene moiety to give the product. Using the coefficients for a
simple nitrile oxide and the coefficients of 1-propene from Table 11.1 to approximate those of the alkenyl
aldehyde, the regiochemistry shown is predicted. See J. Am. Chem. Soc., 1978, 100, 7069.
HOMO

1.24
R C N O
0.81

Me

N O

LUMO
H 2C C R 1
S
*
R = Me ;
R 1 = see structure

CHO

(c) The "carbanion" is within the ring, leading to the bicyclic product shown.
0.43
O

OMe

OMe

N
1.28
CH3

1.28

0.33

OMe

CO2 Me
N
CH3

see Tetrahedron Lett., 1977, 4075

major
product
CO 2Me

Chapter 11

12. This reaction was taken from J. Am. Chem. Soc., 2003, 125, 13531. The sequence involves a normal electrondemand transannular Diels-Alder reaction, followed by an inverse electron -demand hetero-Diels-Alder reaction.

TBSO

TBSO

CO 2Et

TBSO
Me

TBSO

Me

CO2 Et
Me

Me

OTBS
Br

OTBS
Br

Me
OTBS
Me

Br

Br

Br

O
H

Me

Me

O
CO2 Et

CO 2Et

H
Me

OTBS

OTBS

CO2 Et
OTBS

OTBS
Me

OTBS
Me

OTBS

Me

Me

Me
OTBS

Me
OTBS

13. See J. Am. Chem. Soc., 2002, 124, 2080. This result is not discussed in the cited reference. There are two
possible explanations. One is that the OTBS group offers significant steric hindrance to the methyl groups,
destabilizing the endo transition state and forcing the methyl groups endo and the anhydride unit exo.
Alternatively, one could argue formation of the endo product, but under the thermal conditions of the reaction, the
product epimerizes at both centers adjacent to the carbonyl units, leading to the product shown. Models are shown
for both the isolated exo product, and the endo product that would be predicted by the Alder endo rule. Energy
minimization of the two models shown reveal energies of 16.4 kcal for the exo and 18.8 kcal for the endo.
Without calculating the thermodynamic energies and the transition state energies, we cannot document a potential
effect, but it seems unlikely that an initially formed endo product would equilibrate to the exo. It is more likely that
steric hindrance drives the reaction to give the exo product. Models shown for the endo and exo approach suggest
that an endo approach leads to a steric interaction of one methyl group with the OTBS unit that apparently overrides
the energy gain of a secondary orbital interaction. Without further information, this is a reasonable explanation.

Organic Synthesis Solutions Manual

exo approach
t-BuMe2 SiO

t-BuMe2 SiO

O
+

O
O

endo approach

mesitylene , 165C
O

metylene blue, collidine

74%

O
exo
endo

exo

14.
H

(a) t-BuMe SiO

2

(b)

CO2 Et

Ph
CO2 Et
J. Am. Chem. Soc , 2002, 124, 4628

(d)
H

(c)

O
CO2 Et
4:1 endo NO2 :exo
Org.
Lett. 2003, 5, 239
NO 2

OBn

(e) via internal Diels-Alder

reaction of an acylnitroso
O
compound
Org. Lett., 2003, 5, 3839

(g)

N
Me

see J. Org. Chem.,

1985, 50, 3816

O
(h) Ph
N

t-Bu

Ph
see J. Am. Chem. Soc.,
1999, 121, 3845

Me

J. Org. Chem.,
1999, 64, 6042

Ph

(f)

t-Bu

via a [1,5]-H shift

see Tetrahedron, 1999, 55, 11595

OBn
CF 3

N
O

MOMO

see Org. Lett., 2000, 2, 1835

OBn
OH

(i)

SiMe 3
N
OBn
Angew. Chem. Int. Ed.,
2002, 41, 4688

Chapter 11

Me
O

(j) Me

(k)

(l)

O
see Tetrahedron Lett.,
2000, 41, 4173
EtO2 C

see J. Chem. Soc., Chem.

Commun., 1973, 598

BnO

Me

J. Am. Chem. Soc., 2003,

125, 3793

CO 2Me

(m)

(n)

O
CO2 Et
CO2 Et

HO

(o)
CO2 Me

HN

H
J. Am. Chem. Soc., 2002
124, 11342

see J. Org. Chem., 2002, 67, 3127

Me
N

t-BuO

OBn

CO2 Et

[3,3]-sigmatropic
rearrangement

J. Org. Chem.,

(q) 2003, 68, 3981

(p)
N O

Br

(r)

CN
O
MeO

Eur. J. Org. Chem.,

2003, 4373

MeO
see J. Org. Chem., 1998, 63, 1706

OBn

(s)

(t)

(u)
H
1.8:1 dr
J. Am. Chem. Soc., 2002,
124, 10998

O
Org. Lett. 2002, 4, 1611

OH

Me

OEt

(w)

(v)
MeO

t-BuMe 2 SiO

Bn N CO Bn
2
see Synthesis,
1994, 601

SiPh2 t-Bu
OBz

OH

see J. Org. Chem.,

1999, 64, 6677

Ot-Bu

(x)

OH
O

J. Am. Chem. Soc., 2003,

125, 13155

OMe
N

BnO

OMOM

J. Org. Chem. 2003, 68, 5274

Me
J. Am. Chem. Soc. 2005,
127, 18046

10

Organic Synthesis Solutions Manual

OMe
O

Me

EtO2 C
H

O
OTBS

(y) see J. Chem. Soc.,

Perkin Trans. 1,
2000, 1245

Bn N

(aa)

Tetrahedron, 2002, 58, 6531

(z)

see J. Am. Chem. Soc.,

1999, 121, 1976

CO2 Me

Ph

Me
Me

Bn N

CO2 Me

(ab)
Me Me see J. Org. Chem.,
2000, 65, 4189

(ac)

via Fries rearrangment

& then cyclization
OH Tetrahedron, 2002,
58, 6179

Ph

(ad)

see Synlett,
1999, 590

O
CO2 Et

(ae) Tetrahedron Lett., 2004, 45, 9653

15. Most of the following problems were taken from published syntheses (a - g). If you devise your own synthesis,
you may find that some of the steps you used were tried in the literature and discussed. Other solutions are
possible, however. You may also devise a novel and useful alternative synthesis. In all cases, your syntheses
should be critiqued by and discussed with your instructor.
(a) All reagents in this sequence are taken from Org. Lett., 2002, 4, 909. Heating gives the Claisen rearrangement
(11.12.D), and ozonolysis with a reductive workup gives the dialdehyde (3.7.B).

Treatment with m-

chloroperoxybenzoic acid gives a selective Baeyer-Villiger rearrangement (3.6.A) to the phenol, and treatment with
aqueous hydroxide leads to the hemi-acetal. When the hemi-acetal reacted with the Wittig reagent, (8.8.A.i) the
aldehyde in equilibrium with the hemi-acetal led to the alkene, and a final esterification produced the target.

Chapter 11

OMe

OMe
O

OMe
O

11

OMe
O

CHO
OH

CHO
CHO
OMe

OMe
OMe

e
OH

OH

OMe
(a) 140C

OMe

OMe
O

OMe

OMe

OMe

OMe

(b) 1. O3 2. Me2 S

(c) mcpba

(d) aq NaOH

(e) Ph3 P=CH 2

(f) CH2 =CHCOCl , NEt3 , DMAP

(b) All reagents are taken from the cited reference. The ketone is converted to an alkene by Horner-WadsworthEmmons olefination (Sec. 8.8.A.iii) and catalytic hydrogenation of the double bond is followed by LiAlH4
reduction of the ester to an alcohol. Conversion of the alcohol to the bromide using CBr4/PPh3 (Sec. 8.8.D)
allowed a substitution reaction with the methyl malonate anion, and Krapcho decarboxylation gave the ester.
Condensation with the anion from CH2Br2 was followed by an internal Diels-Alder reaction to give the target.

a
O

CO2 Et

e EtO2 C
Br

EtO2 C

O
EtO2 C

HO
Me

O
EtO2 C

Br2 HC

O
h

(a) (EtO)2 P)=CHNaCO2 Et , toluene , reflux (b) H2 , Pd-C , EtOH (c) LiAlH4 , ether
(d) CBr 4 , ether , PPh3 (e) MeCNa(CO 2Et) 2 , DMF , 100C (f) LiCl , DMSO-H2 O , 180C
(g) CH2 Br 2 , LDA , THF , 78C (h) CF 3 CH 2ONa/CF3 CH2 OH , RT , 6 d

Br
O

Me

see Tetrahedron Lett.,

2000, 41, 1375

(c) All reagents are taken from the cited reference. The initial reaction involves conjugate reduction with DIBALH and cuprous ion (Sec. 4.6.C), and the resultant enolate anion is trapped with formaldehyde. Protection with tertbutyldimethylsilyl chloride is followed by heating to induce a retro-Diels-Alder reaction to give a cyclopentenone.
Catalytic hydrogenation of the conjugated ketone allows a Baeyer-Villiger rearrangement (Sec. 3.6.A) to give the
lactone. The lactone is opened with the amine shown to give a Weinreb's amide, which reacts with methyllithum to
give the ketone target.

12

Organic Synthesis Solutions Manual

O
Me

OTBS

Me

f
OTBS

Me

g
OTBS

Me
O

Me

Me
N
MeO

OTBS

OTBS

Me

b
OH

Me

OTBS
OH

see Tetrahedron Lett.,

2000, 41, 3631

OH
O
(a) DIBAL-H , CuI , THF-HMPA ; HCHO (b) TMSCl , NEt3 , DMAP (c) PhOPh , 280C ( cyclopentadiene)
(d) H2 , Pd-C , AcOEt (e) MCPBA , NaHCO3 , CH2 Cl2 , 3 d (f) MeONHMeHCl , Me3 Al , 3 h (g) MeLi

(d) All reagents are taken from the cited reference. When the amine is converted to the N-allyl derivative, heating
in the presence of BF3 leads to a Claisen rearrangement, placing the allyl group on the benzene ring. Protection of
the amine as the N-Boc derivative is followed by oxidative cleavage of the C=C unit with OsO4/periodate, and the
resulting aldehyde is reacted with the vinyl Grignard reagent shown to give an alcohol. When the alcohol reacts
with the ortho ester, a Johnson ester Claisen rearrangement follows and deprotection of the amine gives the target.

N
H

N
H

N
Boc
OH

N
Boc

MeO 2C

N
Boc

MeO 2C

N
Boc
OHC
N
H
see Tetrahedron,
2000, 56, 2583

(a) allyl bromide , NEt3 , DMF (b) BF 3 OEt2 , sulfolane , 210C (c) Boc 2O , dioxoane
(d) OsO4 , NaIO4 , aq THF (e) CH2 =CMeBr , Mg , THF (f) MeC(OMe)3 , EtCO 2H , 110C
(g) 4M HCl, dioxane

(e)

All reagents are taken from the cited reference.

An initial [3+2]-nitrone cycloaddition is followed by

hydrogenation to give the amino alcohol. Acetylation of the amine incorporates the second aryl unit, and Collins
oxidation gives the ketone. Aldol condensation leads to the lactam and the indolizidine structure, and a final
LiAlH4 reduction removes the lactam carbonyl to give the final product.

Chapter 11

N
O

a
MeO
MeO

MeO

N
H
OH

MeO

MeO

O
e

MeO

MeO
MeO

OMe

(d) Collins oxidation

MeO

, toluene , reflux

MeO
OMe MeO

OMe

MeO

N
OH

MeO

MeO
N

N O

MeO

MeO

(a)

13

OMe

(b) H2 , Pd-C, MeOH

MeO

see Synthesis, 1999, 907

OMe
(c) (3,4-dimethoxyphenyl)acetyl chloride

(f) LiAlH4 , AlCl3 , ether-THF

(e) KOH

(f) All reagents are taken from Tetrahedron, 2003, 59, 1349. A Diels-Alder reaction with cyclopentadiene (11.4)
gave the cycloadduct. Substitution of Cl with SMe was accomplished under phase transfer conditions, allowing a
retro-Diels-Alder reaction (11.5.B) to generate the bis-methylthio-substituted quinone.

A hetero-Diels-Alder

reaction with the azadiene (11.7.C.v) generated the imine, and treatment with acid liberated the conjugated lactam
unit.

O
Cl

Cl
O

SMe

MeS

O
OTBDMS MeS

MeS
O

O
SMe

Cl

O
d

O
Cl

MeS

O
O
NH

MeS

OTBDMS

MeS

(a) cyclopentadiene , heat (b) 2 eq NaSMe , CH2 Cl2-water , phase transfer catalyst
(d) TBDMSO-CH=N-C(OTBDMS)=CH2 , PhH , reflux (e) conc HCl

(c) 170C , 0.2 mmHg

(g) All reagents are taken from Tetrahedron Lett., 2002, 43, 2297. An initial Wittig reaction (8.8.A.i) generates the
allyl vinyl ether required for a Claisen rearrangement (11.12.D). A Robinson annulation sequence using methyl
vinyl ketone (9.7.C) sets the cyclohexenone unit, and oxidative cleavage with osmium tetroxide/sodium periodate
(3.7.A.ii) liberates the aldehyde. Jones oxidation with chromium trioxide in acetone/sulfuric acid gives the acid
(3.2.A.iii), which forms the lactone under the reaction conditions (2.10.C). Final reaction with methylamine
converts the lactone to the N-methyl lactam (2.5.C).

14

Organic Synthesis Solutions Manual

MeO

MeO

MeO
b

MeO

MeO

CHO

MeO
CHO

MeO

MeO

MeO
CHO

H
O

MeO

e MeO

MeO

OMe

MeO

N
H Me

(a) CH2 =CHCH2 PCH2 PPh3 Cl , KOt-Bu , THF , 0C (b) xylene , reflux (c) MVK , cat EtOH/KOH , ether
(d) cat. OsO4 , 1.5 NaIO4 (e) Jones oxidation (f) MeNH 2 , MeOH , 80C (sealed tube)

(h) All reagents are taken from J. Am. Chem. Soc., 2003, 125, 10772. A photo-[2+2]-cycloaddition gave the fourmembered ring (11.10.C), and treatment with zinc and heating lead to elimination to the cyclobutene (4.9.G).
Reduction of the anhydride unit to the diol with LiAlH4 (4.2.B) was followed by protection of the hydroxyl units
and their benzyl ethers (7.3.A.i). Dihydroxylation with OsO4 (3.5.B) followed by Swern oxidation (3.2.C.i) gave
the diketone, and a Grignard reaction (8.4.C.i) led to the final target.
O
O

Cl

O
Cl

OBn

HO

O
O

OBn
d

OH

OBn
f

OBn

e HO

OH

OBn

HO
g

OBn
OBn

OBn

HO

(a) ClCH=CHCl , h
, acetone (b) Zn , TMSCl, Ac2 O , toluene , 85C (c) LiAlH 4 , THF
(d) 2 eq BnBr , 2 eq NaH , THF/DMF (e) OsO4 , NMO , aq t-BuOH/t-BuOMe
(f) (COCl) 2 , DMSO , NEt3 , CH 2Cl2 , 78C (g) 2 eq allylmagneisum bromide

(i)

The reagents in steps b-i are taken from the cited reference. The actual starting material here was 1,4-

cyclohexadiene, but we begin with benzene, and a Birch reduction gives the diene. Generation of dichloroketene
and a [2+2]-cycloaddition gives the bicyclic ketone, and Zn/acetic acid are used to reduce the chlorine atoms.
Hydrogen peroxide reacts with the cyclobutanone to give the lactone via Baeyer-Villiger reaction (Sec. 3.6.A), and
enolate alkylation with LDA and MeI give the methylated lactone. Reduction with DIBAL-H gives the aldehydealcohol (which probably exists as the hemi-acetal), but the aldehyde can be trapped as the dithiolane as shown.
Reaction with Raney nickel removes the dithiane unit to give a methyl group, and a modified Chugaev sequence

Chapter 11

15

leads to the diene.

O
a

Cl
H

OH

CHO
Me
H

S
OH

O
Cl

OH

Me
H

Me
i

(a) Na/NH3 /EtOH (b) CCl3 COCl , Zn , ether

(f) DIBAL-H (g) BF3 OEt2 , HSCH2 CH2 SH

e
H

Me

Me

O
O

(c) Zn , AcOH (d) H2 O2 , AcOH

(h) Raney Ni , EtOH , trace acetone

(e) 1. LDA 2. MeI

(i) 1. BuLi 2. PhOCSCl 3. heat

see J. Org. Chem., 1996, 61, 4617

(j) Taken from J. Org. Chem., 2004, 69, 4185. Initial epoxidation with basic hydroperoxide (3.4.B) was followed
by bromination-elimination (2.10.A and 2.9.A) to give the vinyl bromide. Addition of the vinyllithium reagent to
the carbonyl (8.5.C) was followed by trapping the resulting alkoxide with propanoic anhydride to give the vinyl
ether (9.3.B). Treatment with base induced the Ireland-Claisen rearrangement (11.12.D.ii) to give the final product.

a
O

Br
O

c,d

Br
O

MeO OMe

MeO OMe

MeO OMe
MeO OMe

Br
e

O
OTMS
MeO
MeO

(a) H2 O2 , K2 CO3 , aq THF (b) Br2 , NEt3 , hexane-ether

(d) (EtCO)2 O (e) KHMDS , TMSCl , ether , 78C
rt

(c) R-propenyl Li , THF

16. As in Chapter 10, your syntheses should be checked and discussed with your instructor. There may be many
possible syntheses based on different retrosynthetic analyses.