Chapter 12 1

CHAPTER 12
1. Give a mechanistic explanation for the formation of the product shown from the designated
starting material.
1. Initial reaction with the strong base generates the α-carbanion of the sulfoxide. Acyl addition to the
ketone generates the alkoxide as it forms the new C—C bond. The alkoxide regenerates a carbonyl with
concomitant breakage of the bond to generate an ester enolate (see 13.4.2). In the second step, acetic
acid protonates the carbanion to give the final product.

O O
1. LiN(SiMe3)2
Ph Ph
S S
CO2Et CO2Et
O O O O
Ph
O
S O S O S
Ph 2. AcOH Ph
O

CO2Et CO2Et CO2Et

see Tetrahedron Lett. 2000, 41, 377

2. Give the major product for each of the following when treated with (1) n-BuLi/THF/–78 °C; (2)
MeI/–78→0 °C; (3) aq NH4Cl.
SPh
(a) (b)
S CH3 CH3
2.

3. For each of the following give a complete reaction that illustrates its use for the formation of a
carbon–carbon bond:
3.
(a)
O

CdCl2 Cl O
Ph
2 MgBr )2Cd
Ph
O Cp2TiMe2 O
O
(b)

1. t-BuLi I
2. CuCN
Br Bu2Cu(CN)Li2 Bu
-78 °C
(c)
2 Organic Synthesis Solutions Manual

O PhCu • BF3 Ph O

(d) OBu OBu

PPh3 1. n-BuLi
Br PPh3
2. PhCHO
Ph
(e)

O Ph
PhCHO , NaH
EtO P CO2Et
CO2Et
(f) EtO
O 1. NaH
2. PhCHO Ph
MeO P CH3

(g) OMe

O
MeI 1. n-BuLi
DMSO Me2SOCH3
2. DMSO O
O
(h)

4. Give the major product of each reaction, with correct stereochemistry, and justify your choice.
4. (a) In general, exo attack is preferred in bicyclic systems such as this (see 7.9.6). If the exo face is
the lowest energy face for approach of the organocuprate, the major product will be the exo methyl
derivative shown.

Me
Me
Me2CuLi O
O Me
Me
Me
H

(b) Initial addition of the cuprate occurs from the less sterically hindered exo face (see answer in a).
This conjugate addition leads to an enolate anion (see 13.7). Since the bromide moiety is on a face
easily accessible by the enolate, displacement of the bromide is facile, leading to a five-membered ring
and the tricyclic ketone shown.
 Chapter 12 3

Me
Me
H Me2CuLi H
H
O
O O
Me Me
Me
Br Br

5. In each of the following reactions, predict the major product, with the correct stereochemistry
where appropriate:
5.
Me CO2Me
H OTBS
OHC
(a) O (b) (c)
CO2Me
i-Pr Me
for a spirodecane derivative, Org. Lett. 2003, 5, 4641
see Bull. Chem. Soc. Jpn. 1978, 51, 3590 Org. Lett. 2003, 5, 991

SPh

S Ph
OH
(d) (e) (f)
OH S OSiMe3 OH

Me

see Org. Lett. 2000, 2, 4169 see Tetrahedron: Asymmetry 1999, 10, 1877 J. Org. Chem. 2002, 67, 3134

OMe Me Me
(g) N (h) (i)
CH2 N
Cbz O
see J. Org. Chem. 1999, 64, 1410 see J. [Link]. Soc. 1980, 102, 4274
Me
t-BuMe2SiO OH Ph N
S S
(j) (k) via Sommelet-Hauser (l) OSEM
rearrangement
O N
OBn OBn H
J. Am. Chem. Soc. 2003, 125, 14435 see J. Chem. Soc., Perkin Trans. 1 1992, 2851 J. Org. Chem. 2003, 68, 6096
O Me
N CO2Me
OTBS O
Ph
(m) N (n) (o) Br
Ph N Boc Me
HO (CH2)12 CH=CH2
Me OTIPS
Org. Lett. 2003, 5, 765 J. Org. Chem. 2002, 67, 9192 J. Am. Chem. Soc. 2002, 124, 11616
4 Organic Synthesis Solutions Manual

S
O O
S
(p) (q) (r)
TBDMSO O CO2H

C3H7
see Tetrahedron Lett. 1984, 25, 5501 Tetrahedron 2002, 58, 1647
see J. Org. Chem. 1999, 64, 6610

Ph CH2
N O
(s) (t) (u)
O O

BnO O
Ph
see Synthesis 1993, 137 see Tetrahedron Lett. 2000, 41, 1975 Org. Lett. 2002, 4, 643

TBDPSO
(v)

J. Am. Chem. Soc. 2003, 125, 1712

6. Provide a synthesis for each of the following transformations. Show all reagents and
intermediate products.
6. In each case, a possible synthesis is presented. Other solutions are possible for each problem.

(a) This sequence is taken from J. Org. Chem. 2003, 68, 9533. Initial protection of the alcohol as the
triisopropylsilyl ether ([Link]) was followed by a Wittig reaction ([Link]), which gave a 4:1 Z:E
mixture of the alkene. Deprotection of the alcohol ([Link]) allowed oxidation to the aldehyde with the
Dess-Martin reagent (6.2.4). A second Wittig reaction gave a vinyl ether, and hydrolysis liberated the
ketone product.

OMe OMe OMe OMe

MeO MeO MeO MeO

MeO OH MeO OTIPS MeO OTIPS MeO

a b c,d CHO
MeO CHO MeO CHO MeO MeO

MeO MeO MeO MeO

OMe OMe OMe OMe OMe OMe
MeO MeO
OMe O
MeO MeO (a) TIPSCl , DMAP , imidazole
e f
(b) Ph3PCH2CH3 , KN(TMS)2 , THF
MeO MeO (c) TBAF , THF (d) Dess-Martin periodinane, CH2Cl2
(e) Ph3PCH(OMe)Me , BuLi , THF (f) p-TsOH , THF

MeO MeO
OMe OMe
 Chapter 12 5

(b) All reagents are taken from J. Am. Chem. Soc. 2003, 125, 12836. Initial protection of the alcohol as
the benzyl ether ([Link]) allowed the Grignard reaction (11.4.6) to form the homoallylic alcohol. This
alcohol was protected as the triethylsilyl ether ([Link]), and ozonolysis (6.7.2) generated the ketone.

O O OH OTES
a b c d
O OTES

OH OBn OBn
OBn OBn
(a) NaH , BnBr , DMF (b) isopropenylmagnesium bromide , Li2CuCl4 , THF (c) TESCl , imidazole, DMF
(d) 1. O3 , NaHCO3 , MeOH 2. Me2S

(c) All reagents are taken from the J. Am. Chem. Soc. 2003, 125, 15433. Protection of the alcohol as
the t-butyldimethylsilyl ether ([Link]) allowed ozonolysis to the aldehyde (6.7.2). Wittig reaction
([Link]) gave the conjugated ester, which was reduced to the alcohol with diisobutylaluminum hydride
([Link]) and then oxidized to the aldehyde with tetrapropylammonium perruthenate ([Link]). Horner-
Wadsworth-Emmons olefination ([Link]) gave a new conjugated ester, which was reduced and then
oxidized as above. A second Horner-Wadsworth-Emmons olefination gave the requisite triene unit, and
both the alcohol and the alkyne were deprotected with tetrabutylammonium fluoride ([Link]).

OH OTBS OTBS OTBS

b CHO c CO2Et d
a

Et3Si Et3Si Et3Si Et3Si

TBSO TBSO
OTBS OH OTBS
e g h
CHO f
Et3Si Et3Si
Et3Si Et3Si
TBSO HO
CO2Et
TBSO HO

(a) t-BuMe2SiOTf , 2,6-lutidine (b) O3 ; PPh3

i j
(c) PPh3=CMeCO2Et , toluene , 100°C (d) Dibal-H , toluene, -78 °C
(e) TPAP , NMO (f) NaH , (EtO)2P(=O)CHMeCO2Et
Et3Si (g) Dibal-H , toluene, -78 °C (h) TPAP , NMO
(i) NaH , (EtO)2P(=O)CHMeCO2Et (j) 4 eq TBAF

CHO
CO2Me CO2Me
6 Organic Synthesis Solutions Manual

(d) All reagents in this sequence are taken from Org. Lett. 2002, 4, 1715. Conjugate addition of divinyl
cuprate ([Link]) was followed by reduction of the ester with Super hydride ([Link]). The resulting
alcohol was oxidized to the aldehyde with the Swern oxidation ([Link]), followed by Wittig olefination
([Link]), and catalytic hydrogenation of both vinyl groups (7.10.2). The silyl protecting group was
removed with tetrabutylammonium fluoride ([Link]), and a Swern oxidation to the aldehyde ([Link]
followed by NaClO2 oxidation to the acid, and esterification with diazomethane (17.9.4), was followed
by introduction of the phenylselenide via the enolate anion (13.2) and syn elimination (3.7.4). A second
conjugate addition with divinyl cuprate ([Link]) and reduction of the ester with Super hydride
([Link]), allowed formation of the alkoxide with sodium hydride. The alkoxide attacked the carbamate
unit, and acyl substitution (4.2.1) led to the oxazolidinone product shown.

a b c e
d
MeO2C N N
MeO2C N N OHC N
OR R' OR
R' R' OR OH R' OR R' OR

f OH g h i
N N N CHO N CO2Me N CO2Me
R' OR R' R' R' R'

R' = CO2Me;
j OR = OSiPh2t-Bu
k l
N CO2Me N OH N
R' R' O
O
(a) (vinyl)2CuLi (b) Super Hydride (c) Swern oxidation (d) Ph3PEt+Br– , BuLI (e) H2 , 5% Pd/C (f) TBAF (g) Swern oxidation
(h) 1. NaClO2 , NaH2PO4 2. CH2N2 (i) LiN(TMS)2 ; PhSeCl (j) (vinyl)2CuLi (k) Super hydride (l) NaH

(e)

OH O OH
a b c d

Et
(a) Hg(OAc)2 , H2O ; NaBH4 (b) CrO3 (c) SPh2 , LDA ; HBF4 (d) EtC≡CNa ; H3O+
 Chapter 12 7

(f) All reagents are taken from the cited reference. Wittig olefination gives the conjugated ester,
allowing conjugate addition with the higher order cuprate, in the presence of the trapping agent
chlorotrimethylsilane. DIBAL-H reduction of the ester gives an aldehyde, which reacts with the alkyne
anion to give the diastereomeric mixture of alcohols shown.

O O O
O O
EtO2C
a b c d

OHC EtO2C OHC

EtO2C
CMe3 CMe3 OH CMe3
(a) Ph3P=CHCO2Et, CH2Cl2 (b) t-Bu2CuCNLi , ether , TMSCl (c) DIBAL-H, PhMe , -78 °C (d) EtO2C≡CLi, THF, -78 °C

see J. Am. Chem. Soc. 2000, 122, 8453

(g) All reagents are taken from J. Am. Chem. Soc. 2003, 125, 4680. This sequence includes a "cheat",
in that phosphonate ester is used, containing the Weinreb's amide unit. Horner-Wadsworth-Emmons
olefination with a ([Link]) leads to the conjugated amide, and reduction to the aldehyde with
diisobutylaluminum hydride ([Link]) was followed by a Wittig reaction (12.5.1.1i) to give the diene.
Deprotection of the trityl group ([Link]) and iodination (3.4.1) gave the target.

OTr Me OMe OTr H OTr

OTr N
a b c
CHO
O O
OH I
Me OMe
d e O N
P
EtO O
OEt
A

(a) NaH + A (b) Dibal-H , THF , -78 °C (c) Ph3P=CHMe (d) BCl3 (e) I2 , PPh3 , imidazole

(h) All reagents in this sequence are taken from J. Am. Chem. Soc. 2002, 124, 9682. Reduction of the
ester with LiAlH4 (7.6.1) was followed by PCC oxidation ([Link]) to the aldehyde. Wittig olefination
([Link]) gave the vinyl group, and hydroboration generated the anti-Markovnikov alcohol (9.4.1).
Reaction with thionyl chloride converted the alcohol to the chloride (3.4.1).

CO2Et OH CHO OH Cl

a b c d e

(a) LiAlH4 (b) PCC (c) Ph3P=CH2 (d) BH3•THF; H2O2 , NaOH (e) SOCl2 , LiCl , Py
8 Organic Synthesis Solutions Manual

(i) All reagents are taken from J. Org. Chem. 2003, 68, 2376. Asymmetric reduction of the ketone unit
by hydrogenation (7.10.8) using a chiral catalyst was followed by protection of the resulting alcohol and
an SN2 displacement ([Link]) of the chloride to give the azide. DIBAL-H reduction ([Link]) of the
ester stopped at the aldehyde, and a simple Wittig olefination ([Link]) gave the alkene unit.
Dihydroxylation using osmium tetroxide (6.5.2) gave the final product.

O OH TBDMSO TBDMSO TBDMSO TBDMSO TBDMSO OH

a b c d e f

Cl CO2Et Cl CO2Et Cl CO2Et N3 CO2Et N3 CHO N3 N3 OH

(a) H2 , Ru(OAc)2/BINAP (b) TBDMS-Cl , imidazole (c). NaN3 , DMF (d) Dibal (e) Ph3P=CH2 (f) K3[Fe(CN) 6] , K2CO3 , 10% aq OsO4

(j) All reagents are taken from Org. Lett. 2002, 4, 2125. Reduction of both ester units with LiAlH4
gave the diol (7.6.1), and the symmetry of the molecule allowed on hydroxyl to be protected as the
OTBDMS ether ([Link]). Swern oxidation ([Link]), followed by Wittig olefination (8.8.1.i) gave the
conjugated ester, which was reduced with diisobutylaluminum hydride ([Link]) to the allylic alcohol.
Another Swern oxidation gave the aldehyde, and this was followed by a second Wittig olefination and
Dibal reduction of the ester. Final Swern oxidation to the conjugated aldehyde completed the synthesis.

CO2Et OH CO2Et
OH CHO
a b c d
Et Et e
Et Et
Et
CO2Et OH OSiMe2t-Bu OTBS
OTBS
OH
OH CHO
f g
EtO2C OHC
h i
Et Et
OTBS OTBS TBSO TBSO
TBSO

(a) LiAlH4 , THF (b) Me2t-BuSiCl , NaH , THF (c) (COCl)2 , DMSO , -78 °C (d) Ph3P=CHCO2Et , PhH (e) Dibal-H , THF (f) (COCl)2 , DMSO , -78 °C
(g) Ph3P=CHCO2Et , toluene (h) Dibal-H , THF (i) (COCl)2 , DMSO , -78 °C
 Chapter 12 9

(k) This sequence is taken from J. Am. Chem. Soc. 2002, 124, 6981. Swern oxidation ([Link]) of the
primary alcohol unit was followed by a Wittig reaction ([Link]). Dibal reduction of the ester ([Link])
to the primary alcohol, allowed an allylic manganese dioxide oxidation ([Link]) to the aldehyde.
Subsequent Horner-Wadsworth-Emmons olefination ([Link]) and deprotection of the O-silyl group
with tetrabutylammonium fluoride ([Link]) gave the target.

OSiMe2t-Bu OSiMe2t-Bu OSiMe2t-Bu

a CHO b CO2Me
I OH I I
Me Me Me Me Me Me Me Me Me Me
OSiMe2t-Bu OSiMe2t-Bu
c d CHO e
I OH I
Me Me Me Me Me Me Me Me

OSiMe2t-Bu OH
CO2Me f CO2Me
I I
Me Me Me Me OMe Me Me Me Me OMe

(a) DMSO , (COCl)2 , NEt3 (b) Ph3P=C(Me)CO2Me (c) Dibal , -78 °C (d) MnO2 , CH2Cl2
(e) (i-PrO)2POCH(OMe)CO2Me , KN(TMS)2 , THF , 18-crown-6 (f) TBF , THF

7. Synthesize each of the following molecules from a starting material of no more than six
carbons. That starting material must be commercially available from a chemical company. Show
your retrosynthetic analysis and all reagents and intermediate products of the synthesis.
7. In each case a synthesis is shown. There are other syntheses based on other starting materials. In
each of the provided solutions, the source of starting material was the current online Sigma-Aldrich
Chemical catalog. There are, obviously, other sources of organic chemicals. Other synthetic routes are
available based on other starting materials.

(a) This is a very simple synthesis. Disconnection to the commercially available cyclopentane
carbaldehyde allows a synthesis. Cyclopentanecarbonitrile is another obvious starting material.

O O
1. i-PrMgBr
CHO CHO
2. H3O+ , heat
3. PCC , CH2Cl2

(b)
O O O O
a b

(a) Me2SOCH2– (b) Me2C=PPh3

10 Organic Synthesis Solutions Manual

The 2-cyclohexen-1-one starting material is available.

(c)
Bu Bu
Bu

O CHO
Et Et
Bu Bu Bu
Bu
a b c (a) n-PrMgBr ; H3O+ (b) CrO3 (c) Ph3P=CH2
CHO HO O
Et Et Et
The hexanal starting material is available.

(d)
Bu O Pr Pr

Et
Pr Et Et SPh
O Bu O O O

Pr Pr Pr
a b c d e
Et Et Et
SPh SPh
SPh SPh SPh
O O O O CHPr Bu
Pr Bu O
f g (a) 1. LiN(i-Pr)2 2. PhSCl (b) NBS , hν ; KOH , EtOH (c) (Pr)2CuLi ; EtI
Et
Et Pr (d) Ph3P=CHPr (e) HN=NH (f) NaIO4 ; 120°C (g) O3 ; Me2S

Bu O

Cyclohexanone is available. The enolate chemistry used here is described in detail in 13.4.
Reduction of the alkene (step e) used diimide, described in 7.12.2 and was chosen to be compatible with
the SPh moiety, which is known to poison many hydrogenation catalysts and is itself subject to
hydrogenolysis.
(e)
O
CHO

a OH O
CHO b

(a) C6H13 MgBr ; H3O+ (b) CrO3

Pentanal is available, and also known as valeraldehyde.
 Chapter 12 11

(f)

O O HO2C
O
a b c d

HO2C HO2C O O
(a) AlCl3 , succinic anhydride (b) Zn(Hg) , HCl (c) PPA (d) Me2S=CH2
Friedel-Crafts acylation is described in 16.4.4. Benzene is available, with restrictions.

(g)

CHCH2Ph O
CN OH

O
Me Me
Me Me
O CHCH2Ph

a OH b
CN c d

O
Me Me
Me Me
(a) MeMgBr ; H3O+ (b) 1. TsCl , pyridine 2. NaCN , DMF (c) PrMgBr ; H3O+ , heat (d) Ph3P=CHCH2Ph
Cyclopentene oxide is available.

(h)
O
CHO

O
O
CHO a b

SPh2
(a) [ / BuLi ] (b) HClO4

The hexanal starting material is available.