MO D ER N MET HODS OF

O R G A N I C SY NTHESIS

W. C A R RU T HE RS
Formerly of the University of Exeter

IAIN COLDHAM
University of Sheffield
 Contents

Preface to the first edition page vii

Preface to the fourth edition ix
1 Formation of carbon–carbon single bonds 1
1.1 Main-group chemistry 1
1.1.1 Alkylation of enolates and enamines 1
1.1.2 Conjugate addition reactions of enolates and enamines 19
1.1.3 The aldol reaction 27
1.1.4 Asymmetric methodology with enolates and enamines 36
1.1.5 Organolithium reagents 45
1.1.6 Organomagnesium reagents 63
1.1.7 Organozinc reagents 67
1.1.8 Allylic organometallics of boron, silicon and tin 71
1.2 Transition-metal chemistry 75
1.2.1 Organocopper reagents 75
1.2.2 Organochromium chemistry 81
1.2.3 Organocobalt chemistry 85
1.2.4 Organopalladium chemistry 89
Problems 101
2 Formation of carbon–carbon double bonds 105
2.1 ␤-Elimination reactions 105
2.2 Pyrolytic syn eliminations 111
2.3 Fragmentation reactions 118
2.4 Alkenes from hydrazones 120
2.5 Alkenes from 1,2-diols 123
2.6 Alkenes from alkynes 125
2.7 The Wittig and related reactions 132

v
vi Contents

2.8 Alkenes from sulfones 144

2.9 Alkenes using titanium or chromium reagents 148
2.10 Alkene metathesis reactions 151
Problems 155
3 Pericyclic reactions 159
3.1 The Diels–Alder cycloaddition reaction 159
3.1.1 The dienophile 162
3.1.2 The diene 174
3.1.3 Regiochemistry of the Diels–Alder reaction 185
3.1.4 Stereochemistry of the Diels–Alder reaction 188
3.1.5 Intramolecular Diels–Alder reactions 193
3.1.6 The retro Diels–Alder reaction 199
3.1.7 Asymmetric Diels–Alder reactions 202
3.2 [2+2] Cycloaddition reactions 211
3.3 Cycloaddition reactions with allyl cations and allyl anions 219
3.4 1,3-Dipolar cycloaddition reactions 222
3.5 The ene reaction 231
3.6 [3,3]-Sigmatropic rearrangements 238
3.6.1 The Cope rearrangement 239
3.6.2 The Claisen rearrangement 244
3.7 [2,3]-Sigmatropic rearrangements 253
3.8 Electrocyclic reactions 259
Problems 264
4 Radical and carbene chemistry 268
4.1 Radicals 268
4.1.1 Radical abstraction reactions 269
4.1.2 Radical addition reactions 280
4.2 Carbenes 299
Problems 312
5 Functionalization of alkenes 315
5.1 Hydroboration 315
5.1.1 Reactions of organoboranes 322
5.2 Epoxidation and aziridination 331
5.2.1 Epoxidation 331
5.2.2 Asymmetric epoxidation 337
5.2.3 Aziridination 346
 Contents vii

5.3 Dihydroxylation 349

5.3.1 Dihydroxylation with osmium tetroxide 349
5.3.2 Other methods of dihydroxylation 355
5.3.3 Amino-hydroxylation 358
5.4 Oxidative cleavage 360
5.5 Palladium-catalysed oxidation of alkenes 365
Problems 367
6 Oxidation 370
6.1 Oxidation of hydrocarbons 370
6.1.1 Alkanes 370
6.1.2 Aromatic hydrocarbons 371
6.1.3 Alkenes 374
6.2 Oxidation of alcohols 378
6.2.1 Chromium reagents 378
6.2.2 Oxidation via alkoxysulfonium salts 381
6.2.3 Manganese reagents 384
6.2.4 Other metal-based oxidants 386
6.2.5 Other non-metal-based oxidants 389
6.2.6 Oxidation to carboxylic acids or esters 392
6.3 Oxidation of ketones 394
6.3.1 ␣,␤-Unsaturated ketones 394
6.3.2 ␣-Hydroxy-ketones 396
6.3.3 Baeyer–Villiger oxidation of ketones 398
Problems 402
7 Reduction 405
7.1 Catalytic hydrogenation 405
7.2 Reduction by dissolving metals 422
7.3 Reduction by hydride-transfer reagents 434
7.3.3 Derivatives of lithium aluminium hydride and sodium
borohydride 443
7.3.4 Mixed lithium aluminium hydride–aluminium chloride
reagents 444
7.3.5 Diisobutylaluminium hydride (DIBAL-H) 445
7.3.6 Sodium cyanoborohydride and sodium
triacetoxyborohydride 446
7.3.7 Borane and derivatives 449
viii Contents

7.4 Other methods of reduction 454

7.4.1 Enzyme catalysed 454
7.4.2 Wolff–Kishner reduction 457
7.4.3 Reductions with diimide 459
7.4.4 Reductions with trialkylsilanes 460
Problems 462
Answers to problems 466
Index 487
 1
Formation of carbon–carbon single bonds

Formation of carbon–carbon single bonds

Table 1.1. Approximate acidities of some activated

compounds and common reagents

Compound pKa Compound pKa

CH3 CO2 H 5 C6 H5 COCH3 19
CH2 (CN)CO2 Et 9 CH3 COCH3 20
CH2 (COCH3 )2 9 CH3 CO2 Et 24
CH3 NO2 10 CH3 CN 25
CH3 COCH2 CO2 Et 11 ((CH3 )3 Si)2 NH 26
CH2 (CO2 Et)2 13 CH3 SO2 CH3 31
CH3 OH 16 CH3 SOCH3 35
(CH3 )3 COH 19 ((CH3 )2 CH)2 NH 36

(e.g. sulfide) and decreased by alkyl groups.

O O O O
C OEt C OEt C OEt C OEt
base
H2C H C H C H C (1.1)
C OEt C OEt C OEt C OEt
O O O O

O O O

R C base R C R C
C R' C R' C R'
H2
H H

O O
(1.2)
H H H H
C R C C C
X R'' C R' R'' C R'
H R H

X = leaving group, e.g. Br

O OH

R C R C
C R' C R' (1.3)
H2
H

– – (1.4)
CH2(CO2Et)2 + B CH(CO2Et)2 + BH
 OSO2Me CH(CO2Et)2
CsF
+ CH2(CO2Et)2 (1.5)
CO2Et CO2Et
68%

CH2(CO2Et)2
+ (1.6)
NaOEt, EtOH
Cl CH(CO2Et)2 CH(CO2Et)2

CO2Et
NaOEt
Br n Br + CH2(CO2Et)2 n (1.7)
EtOH CO2Et

n = 0–4

CO2Et
Br
NaNH2 –
CH(CO2Et)2 CO2Et
PhCH(CO2Et)2 (1.8)
liq. NH3 50%

CN CN CN
NaOEt
(1.9)
EtOH
CO2Et CO2Et CO2Et

MeI

CN

CO2Et
Me

NaOEt, EtOH i, NaOH

CH2(CO2Et)2 RCH(CO2Et)2 RCH2CO2H (1.10)
R–X ii, H3O+, heat
LiCl
DMF

RCH2CO2Et

i, LiNiPr2 (LDA) i, LDA

CO2Me
THF, –78 °C
CO2Me
THF, –78 °C
CO2Me (1.11)
ii, Br ii, EtBr

90%

O OMnX O

Me
ˆ LDA or LHMDS MeI
(1.12)
MnCl2 or MnBr2 76%
 O O O
KOH, Bu4NBr
Ph Ph + Ph Me
MeI
(1.13)
95% Me 100 : 0

Ph

i, LDA, THF
MEMO2C CO2Me MEMO2C CO2Me (1.14)
ii, PhCH2Cl

1 57%

MEM = CH3OCH2CH2OCH2–

Table 1.2. Composition of enolate anions generated from the ketone and a base

Ketone Base (conditions) Enolate anion composition (%)

O O– O–
Me Me Me

LDA, DME, −78 ◦ C 1 99

(kinetic control)
Ph3 CLi, DME, −78 ◦ C 9 91
(kinetic control)
Ph3 CLi, DME 90 10
(equilibrium control)
t-BuOK, t-BuOH 93 7
(equilibrium control)
O O– O–

LDA, THF, −78 ◦ C 0 100

(kinetic control)
Ph3 CLi, DME 87 13
(equilibrium control)

O O O O
Me
NaOEt CO2Et NaOEt CO2Et Me
EtOH EtOH HCl, heat (1.15)
CO(OEt)2 MeI or
LiCl, DME

´
 O O
H H
Me
t BuOK, t BuOH

MeI
(1.16)
H H
major product
i, NaOEt, EtOH
HCO2Et
ii, BuSH, TsOH

O O O
H Me Me
CHSBu CHSBu
t BuOK KOH
t BuOH H2O
MeI ethylene
H H glycol, reflux H

O O O O O O
2 equiv. KNH2 C4H9Br

NH3 (l) then H3O+

O
OTHP
O i, 1 equiv. NaH CO2Et
THF, HMPA several O
CO2Et
ii, 1 equiv. BuLi steps
iii, O O

OTHP Br 4
3
i, 2 equiv. LDA
ii, C6H5SeBr
THP =
O
O O

O H2O2, CH2Cl2 O

O O

SePh
6 5

O Li

NO2 2 equiv. BuLi N C6H5CH2Br NO2

O (1.19)
then H3O+
Li
53% Ph
7

O OSiMe3 OSiMe3

Me Me Me
iPr
2NMgBr
+
Et3N, Me3SiCl

97 : 3
 O OSiMe3 OSiMe3

Me Me Me
LDA, -78 °C
+
Me3SiCl

1 : 99

OSiMe3 OLi O O
Me
Me Me Me
CH3Li C6H5CH2Br Ph Ph
+
DME

84% 7%

OSiMe3 O
i, t C4H9Cl, TiCl4
CH2Cl2, –23 °C

ii, Na2CO3 (aq)

(1.21)
48%
8 9

Cl
O i, LDA, THF Me3SiO
–78 °C 10
(1.22)
ii, Me3SiCl ZnBr2, CH2Cl2
O
80%

SPh
H H H

ClCH2SPh i, NaIO4, 0 °C
OSiMe3 O O (1.23)
O ZnBr2, CH2Cl2 O ii, CCl4, 80 °C O
H H H

OTMS O OTMS
LDA LDA
(1.24)
THF THF/HMPA
OEt OEt OEt
Me3SiCl Me3SiCl
E:Z 85:15 E:Z 0:100

Et3SiH

O
0.5 mol% (Ph3P)3RhCl
Et3SiO
(1.25)
50 °C H
92%

H H H
nC
4H9
t BuOK nC
4H9I

t BuOH
O O O
H H H

H H (1.26)
nC
2 equiv. Li 4H9I

O 1 equiv. t BuOH O O
NH3 H H
11 n
C4H9
 O O O

Me
n Bu2CuLi excess MeI
(1.27)
THF, –78 °C THF/HMPA, –30 °C
n n
Bu Bu
99%
trans:cis 7:1

O O O O

PhSe
Ph Me2CuLi Ph PhSeBr Ph H2O2 Ph
CH2Cl2 (1.28)
reflux
88%
12

O O O

R R R" R
α
base R"X
α'
(1.29)
γ β

R' R' 13 R'

base

O O O
R"
R" R R" R R" R
or

R' R' R'

Me Me
slightly less than
one equiv. of LDA Li

N THF c
C6H11N

14
MeI
(1.30)
Me Me

MeCO2H
H2O, reflux cC
O 6H11N

Me Me

O HO NR"2 NR"2 HO NR"2

R"2NH - H2O
R' R' R' (1.31)
R R R R

R'

N N

C C (1.32)
C C
 H
O N H N

Me Me Me
TsOH
+
PhH
+ (1.33)
N
H
85 : 15

t
Bu
N i, LDA O
DME, –60 °C
(1.34)
ii, CH3I
iii, H3O+

NMe2 NMe2
N N O
Me Me Me Me Me
i, LDA NaIO4
(1.35)
ii, CH3I MeOH, H2O
95%
97% trans
O
CO2Et

α OEt NaOEt
EtO2C CO2Et + EtO2C CO2Et
EtOH
β Ph
Ph
73%
15 16
NaOEt

CO2Et CO2Et
EtO2C CO2Et 15
EtO2C CO2Et EtO2C CO2Et

Ph Ph
17 18

O O O
CO2Et CO2Et
CO2Et
NaH, THF PhMe
SOPh heat
SOPh

50% 60%
19 20 21

CO2Me i, LDA, THF, –78 °C

CO2Me
ii, CO2Et
CO2Et
NC
CN
22 23
90%

O O
Me
Me CO2Me t BuOK
+ (1.39)
t BuOH CO2Me

24
 N O

Me CN NC Me
EtOH, reflux (1.40)
+
+
then H3O

25 26

OMe
OMe

Ar

OH
HO
+
N O 120 °C N O

Me Me
27 OMe
OMe (1.41)

Ar

N 56% N O
O
Me Me
mesembrine
O

O Me O Me
N H H
NO2 NO2 NO2
i, Et2O (1.42)
+ +
ii, EtOH, HCl
Me
99 : 1
28 29

Me Me
t BuO2C COt Bu
LDA t BuO2C COt Bu t BuO2C COt Bu
+ +
Me
THF, –78 °C (1.43)
Me Me Me

30 syn 95 : 5 anti

O O Me O
OSiMe3 H

Me TiCl4 Me
+ (1.44)
CH2Cl2, –78 °C
Me
31 32 major

O OSiEt3
OSiEt3
HgI2
MeO
+ (1.45)
74% CO2Me
t BuMe SiO t BuMe SiO
2 2

33 34 cis : trans 95 : 5
 O O O O O Ph O
N
i, Et , Sn(OTf)2
O N Me O N Me
+
ii, TMSCl, CH2Cl2
Me Me
Ph
78%
syn : anti 29 : 71

O
OSnBu3 O O

OMe 0.1 equiv. Bu4NBr

Ph +
THF
Ph OMe (1.47)
>99% 35

CO2Et
H
CO2Et
K2CO3
O O
EtOH
O
89% H
36 37

Me Me Me
H H
O
CONMe2 CONMe2
LDA i, LiBH4
THF, –78 °C ii, Amberlyst 15 O
CO2Me CO2Me
68% H
Me Me Me

38 39 iridomyrmecin

H
H
CONMe2
Me OLi (1.50)
Me
H OMe

R
O CO2Et O
H CO2Et
N
R H H
CH3COOH (1.51)
THF, heat
Me Me

40 R = Me 78% 41
R = NHCOMe 85%
R R
R
acid
+
or
O O base O O O

42 43

i, PhH, heat
+
N ii, AcOH, NaOAc
O O
H2O
Me Me
45%
 O OH O
base
R CHO +
R' R R'

base

O O O O

R H R' R R'

M M
O O O O OH O
base CH3CHO H3O+

O OLi O OH
LDA i, nPrCHO
THF, –78 °C ii, H3O+

65% 44

OSiMe3 O OH
Me
Me
PhCHO
Ph
CH2Cl2, TiCl4

45

R"2B
O O O OH
R"2BOTf R'CHO
iPr NEt R then oxidative R R'
2
Et2O work-up

O O O

base
OEt OEt (1.59)
room temp.
R R R

O O
O O
pyridine
O +
TiCl4
O O
O O

N
O OH O
N
RCHO +
OEt (DABCO) R OEt
 O OH O OH O
base
RCHO +
R' R R'
+
R R'
(1.62)
R" R" R"

syn anti

OM OH O

RCHO + R"
R' R R'

46 cis- or Z-enolate R"

(1.63)
OM OH O

RCHO +
R' R R'

R" R"
47 trans- or E-enolate

H
R'
R'
M OH O
R O
OM RCHO
H
O R R'
R"
R" R"
46 48
H (1.64)
R' OH O
M
R' R O
RCHO
R" R R'
R" O
OM
H R"

47 49

O OLi OLi O OH O OH
LDA PhCHO
Me + +
R THF, –78 °C R R R Ph R Ph

Me Me Me Me

R cis : trans syn : anti

Et 30 : 70 64 : 36
t
Bu >98 : <2 >98 : <2

O OBR2 OBR2 O OH O OH
PhCHO
Me + +
–78 °C Ph Ph
Me Me Me Me Me Me Me Me Me

Conditions cis : trans syn : anti

Bu2BOTf, iPr2NEt >97 : <3 >97 : <3

Et2O, –78 °C

(cC6H11)2BCl, Et3N 5 : 95 5 : 95
pentane, 0 °C
 t Bu Me
O OH O OH O
i, LDA
+ (1.67)
O ii, PhCHO Ph OAr Ph OAr

Me t Bu Me Me
syn : anti
<3 : >97

O Bu2BO OH O
Bu2BOTf n PrCHO

St Bu iPr St Bu St Bu
2NEt
Me Me Me

syn : anti 10 : 90

B
O O OH O
9-BBNOTf n PrCHO
Me
SPh iPr SPh SPh
2NEt
Me Me

syn : anti 97 : 3

OM Me O OH O OH

Me + Ph + Ph
R Ph CHO R R

Me Me Me Me
cis-enolate
2,3-syn, 3,4-syn 2,3-syn, 3,4-anti

OM Me O OH O OH

+ Ph + Ph
R Ph CHO R R

Me Me Me Me Me
trans-enolate
2,3-anti, 3,4-anti 2,3-anti, 3,4-syn

OLi Me Me Me Me
Me H
+ ArO + ArO
O OHC Ph Ph Ph
Me O OH O OH

anti, syn 80 : 20 anti, anti

‘Felkin’ product
50

H
Ph
H OAr O Me
Li
Me O
Ph
O
Me
H H H Nu

51 52
 O O

HN O HN O (1.71)

Me Ph

53 54

O O O O

N O i, LDA, THF, –78 °C N O

ii, Br

71%

55 98:2 (96% d.e.)

(1.72)
O O O O

N O i, LDA, THF, –78 °C N O

ii, Br

Me Ph Me Ph
75%

Me3Si Me3Si56 98:2 (96% d.e.)

OH OH

Me
57 O 58
i, PCC
61% ii, t BuCOCl,HN O LiBH4 74% (1.73)
Et3N

Me3Si O O Ph Me3Si O O

NaN(SiMe3)2
N O N O
THF, –78 °C
Me
then MeI
69%
Ph Ph

N N
O N N
OMe OMe
i, LDA, Et2O
(1.74)
ii, n PrI, –110 °C
N
NH2 OMe
O3, CH2Cl2
59 or i, MeI; ii, H3O+

O
 t BuCHO H i, LDA Me H3O+ Me
O O
N CO2H H+ N ii, MeI N N CO2H
H H
O O
t t
Bu Bu

60 61

Me O Me OLi

Ph NH2 H2O 3.2 equiv. LHMDS Ph NH2

N N
3.2 equiv. LiCl
OH Me THF, 0 °C OLi Me

62 63

RX

O Me O

NH2 H2O Ph NH2

HO N
heat
R OH Me R

64

O O

N Ph 50% KOH, PhMe, CHCl3 N Ph

t BuO t BuO
PhCH2Br, 0 °C
Ph 1 mol% 66 Ph
Ph
65 95% 67 97% ee

N Br

R =
N O
R R

66
Me Me

Me
O Ph N Ph NH O
Me
Me Ph NH2 Me Me
68 CO2Me
CO2Me
(1.78)
81%

69 90% ee
O O

MeO2C CO2Me 0.1 mol% 70

+
0.09 mol% t BuOK, THF CO2Me

H
CO2Me
91% >99% ee

O O
Al
O O
Li

(R)-70
O O OH O O

N O i, Bu2BOTf, iPr2NEt N O
Ph
ii, PhCHO

88%

ratio of two syn stereoisomers >99 : 1 (1.80)

O Ph
O O OH O O O
H N Me

N O i, Bu2BOTf, iPr2NEt N O Ph BBu2

Ph O
ii, PhCHO H O

Me Ph Me Ph Me
89% 71
ratio of two syn stereoisomers >99 : 1

O O OH O O

N O 10 mol% MgCl2 N O
Ph (1.81)
Et3N, TMSCl, PhCHO
then CF3CO2H

Ph Ph
91%
ratio of major (anti) to other stereoisomers 32 : 1

O OH O

i, iPr2NEt
Me B Me + SCEt3 Ph SCEt3
ii, PhCHO, –78 °C
OTf

72 71% anti 99.8% ee (anti:syn 97:3)

Ph Ph
O OH O

N N i, iPr2NEt
ArO2S B SO2Ar + SPh Ph SPh (1.83)
ii, PhCHO, –78 °C
Br
90% syn 97% ee (anti:syn 1:99)
73
Ar = 3,5-bis(trifluoromethyl)phenyl

O OH O

i, iPr2NEt, 73
OBut Ph OBut
ii, PhCHO, –78 °C

89%
anti 94% ee (anti:syn 96:4)

O OH O

i, (–)-(Ipc)2BOTf, iPr
2NEt

ii, Me

CHO
74
78% syn 91% ee (anti:syn 2:98)
t
Bu But
Si
O O OPMB O OPMB O OH OPMB O OH
i, L2BOTf
i
Pr2NEt
+ (1.85)
ii, EtCHO

75 76 77

L2BOTf ratio
n
Bu2BOTf 67 : 33
(–)-(Ipc)2BOTf 92 : 8
(+)-(Ipc)2BOTf 12 : 88

CHO
OSiMe3 OH O

Sn(OTf)2,
SEt SEt (1.86)
N
HN
Me
71% >98% ee (anti:syn 0:100)
78

OSiMe3 i, 2 mol% 80 OH
Et2O, RCHO
CO2Me
OMe ii, Bu4NF, THF R

79
72-98% 94-97% ee
t
Bu

N
O
O Ti Br
O
O
O
t Bu

t
Bu
80

30 mol%
O N CO2H O OH
OHC H
+
DMSO, room temp. (1.88)

97% 81 96% ee

Me2N NMe2

TMEDA

Et2O
CH3(CH2)3Br + 2 equiv. Li CH3(CH2)3Li + LiBr

2 equiv. t BuLi
R I R Li (1.90)
pentane-Et2O, –78 °C
¨
 H NBn2 H NBn2 H NBn2
+ MeLi Me + Me (1.91)
Me CHO Me Me
91%
HO H H OH

82, Bn = CH2Ph 83 84

anti 91 : 9 syn

O Me

Bn2N

Me–Li
H H

85

OMe OMe

O O
i, n C5H11Li
H H H H (1.92)
ii, H2O
CHO

OH OH OH

86 87
O

CO2H CO2Li
Me

MeLi MeLi
(1.93)
THF, 0 °C then Me3SiCl
then H3O+

85%

Li E
t BuLi
20 °C E+
–78 °C (1.94)
Me I Me Li Me Me

88 89 cis:trans 10 : 1

t t Bu
Bu
N Li N
t BuLi i, PhCH2Br
Me Ph
Me2NH NHMe
N N
–78 °C ii, KOH, MeOH/H2O
Me Me
90 91
i, PhCHO
ii, KOH, MeOH/H2O

Ph
NHMe

OH

92
MeO MeO

N i, t BuLi, –78 °C NH
BnO BnO (1.96)
ii, ArCH2Br, –100 °C
N BnO
iii, NH2NH2, EtOH, AcOH

t BuO
MeO
93 94 97% ee

s BuLi, -78 °C E+

TMEDA
N N Li N E

Boc Boc Boc

95
E+ = MeI, DMF, PhSSPh, Bu3SnCl, etc.

H
N i, s BuLi, –78 °C ii, Ph2CO Ph
N N (–)-sparteine 96 N N Ph
Li
H
Boc Boc OH
tBuO O
96 77% 90% ee

R R

Boc i, n BuLi, –78 °C Boc CAN

Ph N Ph N Ph NHBoc
(–)-sparteine 96
Ar Ar
ii, R–OTf
97 98 99 93-96% ee

Ar = p-MeOC6H4 R = Me, Et, allyl, benzyl

Tf = SO2CF3

nBuLi,
–78 °C E+
and/or
N SnBu3 N Li N E N E

Me Me Me Me

100 101

(–)-sparteine

O Li O Bu3Sn O
n BuLi, –78 °C Bu3SnCl
O NiPr2 O NiPr2 O NiPr2
(1.101)
(–)-sparteine 96

102 103 104 90% ee

i, Ti(OiPr)4
ii, Bu3SnCl

Bu3Sn OCONiPr2

105 95% ee
 Li

PhS PhS
n BuLi, –78 °C

Cl

(1.102)
SPh

Li, EtNH2

59%

NaH
Me2S CH3 I Me2S CH2

106
(1.103)
hν
Ph2S + N2C(CO2Me)2 Ph2S C(CO2Me)2
or Cu, heat
O
107 Me S CH2
2 O
SMe2
O
(1.104)
O 72%
O
109 110
108
O
O O
Me2S CH2
(1.105)
Ph Ph Ph Ph

111 112
TBSO TBSO
i, n BuLi, THF, –78 °C OH Me

Me
MeO MeO
ii, OHC
SO2Ph SO2Ph O O
O O
113 115 C6H4-p-OMe
C6H4-p-OMe

114

TBSO
O Me

MeO

O O

116 C6H4-p-OMe
 S S
i, n BuLi, THF Hg2+ OHC
(1.107)
S ii, Br S H3O+

117 118 119

H H
O O
i, n BuLi, THF Me Me
O HgO O
S S H
S
Me BF •OEt Me (1.108)
O 3 2 OHC
ii, Me O O O
OH H Me OH H Me
Me S

O O
H Me 121 122
120

O
OSiMe3 OSiMe3
Me3SiCN LDA i, PhCOMe Ph
PhCHO Ph Ph (1.109)
ii, H2O Ph
CN CN
HO Me

Br
OMe OMe OMe
t BuLi

Li
(1.110)

i, OHC
dilute HCl
ii, H3O+

63% 74%
O O

OH

NO2 O NO2

(1.111)
iPr O
2NH, CHCl3

TiCl3, H2O
dimethoxyethane
O
O

i, base
ii, H2, catalyst O

cis-Jasmone

OTHP
i, n BuLi, THF
H (1.112)
OTHP Br
ii,
123

¨
THP =
O

CN
H
i, n BuLi, THF N OH
O CN
(1.113)
O ii,
N H
OBn
O
124 CHO O
H
OBn

125 85% 4:1

Me Me
n BuLi
Me Me
Br Li

Br Li
n BuLi
Me Me
Me Me

n BuLi
Bu3Sn OCH2SMe Li OCH2SMe (1.115)

126

OH
H
OCH2SMe
CHO OSiMe2t Bu
MEMO
OSiMe2t Bu
MEMO

127

X = SO2NR2, OCONR2, CONR, CONR2, OCH2OMe (OMOM), OMe, NCO2R (1.116)

CONEt2 CONEt2
i, s BuLi, –78 °C
(1.117)
THF/TMEDA
ii, MeI Me

77% 128

O
CONHMe
i, 2 equiv. n BuLi
O
THF/TMEDA
ii, Ph2CO
Ph
OMe OMe Ph

129 65%
O

CONEt2
i, LDA O
(1.119)
ii, PhCHO
Me Ph

128
 OCONEt2 OCONEt2
i, s BuLi, –78 °C
THF/TMEDA
ii, DMF CHO

73% 130

OCONEt2 OH
s BuLi, –78 °C
(1.121)
THF/TMEDA
then warm to r.t. CONEt2

75%

i, n BuLi, Et2O, heat

Ph
ii, PhCHO
O O
OH
98% 131 (1.122)

i, n BuLi, Et2O, r.t.

ii, n BuBr
S S

47% 132

HO
Br O
n
i, BuLi
O (1.123)
ii, OHC
O O
O
O

60%
OMe

Br
i, n BuLi
OSiiPr3
ii, OMe
OH
OMOM
OSiiPr3 OMOM
O
133 134 135

70%
i, 2.2 equiv. n BuLi (1.124)
ii, CO2

OMe OMe

i, Ac2O
OH ii, HCl, Et2O OSiiPr3

O OLi
iii, Bu4NF
CO2Li

OH O OMOM

phyllodulcin
 O Bu OH HO Bu
nC
7H15
BuMgBr nC
7H15
nC
7H15
Me Me + Me
THF
H OMOM H OMOM H OMOM

>95% 136 >99 : 1

Mg2+
MOMO
O

C7H15
BrMg–Bu H Me

137
O
O O
O
O MeMgBr OH OH
R* + R*
O O
–78 °C
H
Me H H Me

138 86% 99.7 : 0.3

R*OH = 8-phenylmenthol

BrMg
O HO H
+
(1.127)
H

Me O Me iPr OH Me HO H Me OH
iPrMgBr
N N + N + N
Ph Me Ph Me Ph Me Ph Me (1.128)
H Me H Me H Me Me

139 140 24% 141 43% 142 30%

O O O O
CO2Me Me CO2Me
n C H MgBr
6 13
N (1.129)
OMe 0 °C
O O
70%
143 144

MgBr
Ti(OiPr)4 Br
Br HO
Me

excess MeCO2Et

64%
Ti(OiPr)4

i OiPr
PrO
(iPrO)2Ti Ti
R R'CO2Et
Ti(OiPr)2 O
R
R
EtO R'
 O OSiMe3
MgBr
Me Me

CuI, TMSCl
THF, HMPA
89%

O O Ph O O Ph O
PhMgBr LiOH, H2O2
Me N O Me N O Me OH
CuBr.SMe2 H2O, THF

Ph 90% 98 : 2 Ph

OH

Br CO2Me Zn CO2Me
PhCHO + Ph (1.133)
PhH, heat
Me Me

80% syn : anti 63 : 37

CO2Et CO2Et

Br Zn ZnBr PhCHO
Ph O
25 °C O

145 88% 146

CN CN CN
i, ZnCl2
Li naphthalenide PhCOCl
Br Cu(CN)ZnBr COPh (1.135)
ii, CuCN•2LiBr 0 °C

98%

i, Zn O
I (1.136)
ii, CuCN•2LiCl
H H Ph Me
iii, Ph O

Me3SiCl Me
95%

CO2Bn i, Zn CO2Bn
I (1.137)
ii, CuCN•2LiCl
NHBoc Ph NHBoc
iii, Ph Cl

48%

Me Me

i, Zn OHC Ph
AcO I AcO Cu(CN)ZnI AcO Ph (1.138)
ii, CuCN•2LiCl BF3•OEt2
OH
147 148 77% 149 syn : anti 83 : 17

O
O 4 mol%
ZnI TfO Pd(PPh3)4
+ Ph
Ph 40 °C

150 151 67% 152

 O 4 mol% O

ZnI Bu Pd(PPh3)4 Bu
Ph
+
I 40 °C Ph (1.140)

150 153 77% 154

O 10 mol% O
Br Ni(acac)2 OCOt Bu
t BuCOO(CH +
2)4ZnI Ph Ph
3 equiv. Bu4NI
20 mol%

73%

Ph Ph

O NHSO2CF3
Me OH
Ph Me
NMe2
Me
O
OH (1.142)
OH NHSO2CF3
HO NBu2
Ph Ph
(–)-DIAB (+)-DBNE TADDOL 155

OH

2 mol% (–)-DIAB
PhCHO + Et2Zn Ph (1.143)
98% 99% ee

OH

CHO Zn 8 mol% 155

+ PivO
2 Ti(OiPr)4
Br Br
PivO
88% > 96% ee

OH
20 mol% Zn(OTf)2
CHO OSiMe2t Bu PhMe, Et3N, 60 °C
+ H OSiMe2t Bu
22 mol%
Ph Me

HO NMe2 88% 90% ee

OH OH

R MLn
R'CHO + R' + R'

R R

H
OH
O BLn
PhCHO Ph O
Me B Ph
O Me
80%
Me
H
E : Z 93 : 7 anti : syn 94 : 6
(1.147)
H
OH
O
BLn
PhCHO Ph O
B Ph
O H 80%
Me
Me
Me
E : Z 5 : 95 anti : syn 5 : 95
 OH OH

Me SnBu3 200 °C
PhCHO + Ph + Ph (1.148)
Me Me
E : Z 92 : 8 anti 87 : 13 syn

OH OH

iPrCHO Me SiMe3 TiCl4 i i

+ Pr + Pr
CH2Cl2
–78 °C Me Me
156 92% syn 97 : 3 anti

Me3Si H Me

H H
H
H O
R

CO2Me OH OH

158 SiMe3 BnO BnO

BnO CHO CO2Me + CO2Me
BF3•OEt2
CH2Cl2, –78 °C Me Me

157 68% 159 87 : 13 160

Me3Si Me Me

H H
H (1.152)
MeO2C O
OBn

OH OH
OHC OMe H OMe H OMe
O O O
SiMe3
+ (1.153)
Lewis acid
O O O O O O

161 BF3•OEt2 80% >20 : 1

TiCl4 89% 1 : 20

OH
B
2 EtCHO
(1.154)
-78 °C

162 71% 163 86% ee

OH
OH iPrCHO
SnBu3
(1.155)
OH 10 mol% Ti(OiPr)4
10 mol% BINOL 164
–20 °C
165 96% ee

(R)-BINOL 164 89%

 MeLi + CuI Et2O MeLi
MeCu Me2CuLi

Me
Me Me
OCOMe OCOMe
Me2CuLi
(1.157)
Et2O, 0 °C
O O
H H

Bu2CuLi
(1.158)
BF3•OEt2
O O
Et2O, –70 °C

53%

O O

2
Cu(CN)Li2
(1.159)
Et2O, –50 °C

88%

O
O
R Li R

(R2CuLi)2 + Cu Cu

R Li R
(1.160)
OLi•R2CuLi OLi•R2CuLi•RCu O

R2Cu R R

O OLi O
Me
Cu Li Br
(1.161)
THF
69%

166 167

O Br
O O
Me
Me
Me
Me2CuLi
0 °C (1.162)
Br
Me Me

168

C7H15 CO2Me C7H15 CO2Me

Me2CuLi H3O+
C7H15 CO2Me (1.163)
–78 °C
Me Cu Me
 O O
Ph
O
Et2Zn, 2.5 mol% Cu(OTf)2
P N
O
(1.164)
5 mol% 169
Ph

169 >98% ee

Bu2CuLi
OTs C10H22 (1.165)
Et2O, –75 °C

98%

Me OH Me OH
H H
Me2CuLi
(1.166)
Et2O, –15 °C
H Me H Me
57%
Br Me
Br Me

I
2
Cu(CN)Li2
(1.167)
THF, 0 °C

90%

BuMgCl
3 mol% Li2CuCl4
Br CO2Et Bu CO2Et
THF, NMP
(1.168)
86%

NMP = O
N
Me

H Br Ph2CuLi Ph H
(1.169)
Et2O-THF

Ph Me2CuLi Ph
(1.170)
Br Et2O, 0 °C Me

OTf Me

MeMgBr
(1.171)
CuI, THF

96%
MeO2C CO2Me MeO2C CO2Me

170 171
¨
I
2 HC CH
Et2CuLi
Et 2 CuLi HMPA Et (1.172)
63% 95% Z
 I
ZnBr2
+
5 mol% Pd(PPh3)4
(1.173)
2 CuLi
C5H11 THF, –25 °C C5H11

96% 99.5% E

MeO2C Cl Bu2CuLi MeO2C Bu

(1.174)
Et2O, –78 °C
O O
172 85% 173

n
Pr
O OH
nPr
2Cu(CN)Li2
(1.175)
THF, 0 °C

174 86% 175

Cr(CO)6
R + 3 CO
heat
(1.176)
Cr
OC CO
CO

EtO2C CO2Et

CO2Et
F
F
EtO2C CO2Et CO2Et
(1.177)
Cr Cr Cr
OC CO OC CO OC CO
CO CO CO

176

S
Me S
Me S
Li Me
S Me
F (1.178)
then H+
Me
Cr 62%
OC CO
CO Me

CO2But
Li CO2But CO2But
OMe +
then excess I2
(1.179)
OMe OMe
Cr 86%
OC CO
CO 94 : 6
O
O
Li
nBuLi O O
F F F
(1.180)
O– O
Cr Cr Cr
OC CO OC CO OC CO Cr(CO)3
CO CO CO 177
 n
BuLi
Me3Si Me3Si Me (1.181)
MeI
MeO OMe MeO OMe H
Cr 95% Cr
OC CO OC CO
CO CO

MeLi
Me (1.182)
O OH
Cr Cr
OC CO OC CO
CO CO

OH
Br OHC CrCl2
+ CO2Me CO2Me (1.183)
THF

75%

O O

CrCl2
+ PhCHO (1.184)
DMF Ph
I
91%
OH

OH
I OHC 0.1 equiv. CrCl3
+ OPMB OPMB
(1.185)
0.1 equiv. 180
Et3N, TMSCl
178 179 Mn, THF 59% 181 75% ee

N N

t OH HO t
Bu Bu

t t
Bu Bu
180

H
OMe OMe
MeO

182, R=Ph (1.186)

R Cr(CO)5
THF, heat
Cr
(CO)4
182 88% OH 183

R R'
heat
R R' + [Co2(CO)8] (1.187)
(CO)3Co Co(CO)3
¨
184
RL RL
RS RS
[Co2(CO)8]
RS RL + R O + O (1.188)
¨ heat
R
R
¨
185 186
 RS RL RS RL RS RL

(1.189)
(CO)3Co Co(CO)3 (CO)2Co Co(CO)3 Co Co(CO)3
R (CO)2

RS RL RL
Co(CO)3Co(CO)3
RL RS Co(CO)3 RS Co(CO)3
185 Co(CO)3 Co(CO)3

O
R R
O
R

Ph Ph
H Ph
PhMe
+ SMe
90 °C
O + O (1.190)
(CO)3Co Co(CO)3
61% 95 : 5
SMe
SMe

H H

Me [Co2(CO)8] Me Me

Me Me
O +
Me
O (1.191)
Me heptane
t 110 °C
BuMe2SiO t BuMe2SiO Me t BuMe2SiO Me
65% 186 77 : 23

EtO2C CH2Cl2 EtO2C

EtO2C
O (1.192)
EtO2C Me3NO
0 °C
Co2(CO)6
187 81% 188

3 mol% [Co2(CO)8]
EtO2C 1 atm. CO EtO2C
O (1.193)
EtO2C PhH, 70 °C EtO2C

R' 189 50% R' 188

R OH R
R'
HBF4 Nu–
R (1.194)
(CO)3Co Co(CO)3 (CO)3Co Co(CO)3 then CAN, or
Nu
Fe(NO3)3 or
Me3NO
CAN = ceric ammonium nitrate

SiMe3

O H
O O O
BF3•OEt2 PhH
CH2Cl2 CO (1.195)
Co(CO)3 Co(CO)3 60 °C

(CO)3Co (CO)3Co
75% 85%
O

190 191 192

 O OBBu2 Et O O Et

Me MeO SiMe3 Bu2BOTf

O N + O N
then CAN
Me SiMe3
(1.196)
(CO)3Co Co(CO)3
94%

193 194 >98 : 2 syn : anti

SiMe3
CpCo(CO)2
n n
CoCp n
(1.197)
Me3Si SiMe3
SiMe3

195 196
CHO
CN CN

OTf CHO
3 mol% Pd(PPh3)4
+ (1.198)
dioxane, LiCl, heat
Me3Sn
80%

OTf CO2Et
CO2Et 8 mol% Pd2(dba)3
+ Bu3Sn
AsPh3, THF, heat NHAc (1.199)
NHAc
47%

MEMO O Me O MEMO O Me

P Pd(PPh3)4
O O

Bu3Sn
heat (1.200)
MEMO I MEMO O
54%
197 198

R X
Pd(0)

Reductive Elimination Oxidative Addition

R
(1.201)
Pd PdX

199

R–M
Transmetallation
M–X

Me Me Me Me O

OTf Pd(PPh3)4
+ SiMe3
Me3Sn CO, THF, LiCl
(1.202)
SiMe3
Me 87% Me
 Ph Ph
O C4H9 Pd(PPh3)4
Br + B C4H9
PhH, NaOEt, heat (1.203)
O
86%

Pd2(dba)3
TfO Cl + (HO)2B TfO (1.204)
P(t Bu)3, THF
room temp.
Me Me
95%

O
CO2Me
CO2Me i, 9-BBN
(1.205)
ii, [PdCl2(dppf)]
Ph3As, Cs2CO3
DMF, THF, H2O OSiMe2t Bu
O
200 I
70% 202

t BuMe2SiO 201

Cl
B
5 mol% [Pd2(dba)3]
+
20 mol% PCy3
(1.206)
CsOH•H2O
dioxane, 90 °C
OSiMe2t Bu OSiMe2t Bu

203 204 73% 205

Pd(PPh3)2Cl2
I + H SiMe3 SiMe3 (1.207)
CuI, Et2NH, 30 °C

NH2 68% NH2

OTHP OTHP
Cl
¨ 3)4
Pd(PPh H SiMe3
+ H (1.208)
CuI, BuNH2 Pd(PPh3)4
Cl OTHP Cl
CuI, BuNH2
72% 90% SiMe3

206
THP =
O

Br Br
Pd(OAc)2
+ CO2Me
Et3N, 100 °C (1.209)
I CO2Me
68%

Br Ph
Pd(OAc)2
+ Ph (1.210)
P(o-MeC6H4)3
N N
100 °C

78%
 R–X
Pd(0)
H–X

Reductive Elimination Oxidative Addition

H–Pd(II)–X R–Pd(II)–X (1.211)

R
R' Pd(II)–X R'
R
R'
β-hydride elimination Carbopalladation

Pd–X
Ph Ph
PhI
OH OH O
5 mol% Pd(OAc)2 (1.212)
KOAc, DMF, 60 °C 88%
207 208 209

O O

O
I 10 mol% Pd(OAc)2
(1.213)
O PPh3, Ag2CO3
H O
NHCO2Me THF, 56 °C
NHCO2Me
70%
O O

O O
210 211

N N

I 30 mol% Pd(OAc)2
OSiMe2t Bu (1.214)
Bu4NCl, K2CO3
DMF, 70 °C
N N H OH
H then HCl, THF H

O 71% O
212 213

Me
MeO Me MeO
I CHO
10 mol% Pd2(dba)3•CHCl3
OSiiPr3 (1.215)
23 mol% (S)-BINAP O
N N
R3N, MeCONMe2, 100 °C
O
Me then HCl, THF Me
96% ee
214 84% 215

PPh2

PPh2
(S)-BINAP
 Me Me

EtO2C 3 mol% Pd(PPh3)4 EtO2C

EtO2C Et3N, MeCN, reflux EtO2C

(1.216)
I

76%

Me
Me
I CO2Me
5 mol% Pd2(PPh3)2Cl2
CO (1 atm), MeOH
N
(1.217)
N Tl(OAc), 65 °C
SO2Ph SO2Ph
91%

Me

Br Me
LHMDS, PhMe, 80 °C CO2t Bu
+
3 mol% Pd(OAc)2
(1.218)
CO2t Bu
MeO 6.3 mol% 216 MeO

74%

PCy2
NMe2

216

X [Pd(0)L4] Nu
Nu–
(1.219)
[Pd(0)L4]

+
Nu

Nu–
Pd(II) Pd(0)
L L L L
217

OCOMe
Pd(PPh3)4
Br Br CO2Et
NaCH(CO2Et)2 (1.220)
THF
CO2Et
218

CO2Me CO2Me
Pd(PPh3)4
NaCH(CO2Me)2

OCOMe CH(CO2Me)2
(1.221)
CO2Me CO2Me
Pd(PPh3)4
NaCH(CO2Me)2

OCOMe CH(CO2Me)2
 Pd2(dba)3•CHCl3 HO
CO2Me
O
+
CO2Me
(1.222)
Ph2PCH2CH2PPh2
MeO2C CO2Me
55%
219 220 221

CO2Me
Me Me
OCOMe
Me Me SO2Ph
Pd(PPh3)4
(1.223)
NaCH(CO2Me)SO2Ph

222 223

MeO2C CO2Me
OCOMe
[Pd(η3-C3H5)Cl]2
Ph Ph Ph Ph (1.224)
CH2(CO2Me)2, KOAc

98% 98% ee
O

Ph2P N

224
Me
Me

H
AcO H
1 mol% Pd(PPh3)4
(1.225)
AcOH, 70 °C
N N

Boc 58% Boc

225 226

OAc AcO Me
Me Pd
Pd
H H

N N

Boc Boc
 O OH O

i, 2 equiv. TiCl4, Bu4NI

Me C6H13 Me
ii, C6H13CHO
iii, H3O+ I

80% 1

O O OH O O

Me CHO Me
+ N O N O

Me 92% Me
Me Ph Me Ph

O OMe O OMe
O Me2S Cl OTf O

DBU
Ph O Ph O

O Cl CHO

Me

Li O OMe + ?
Ph CHO

N
Ph Me
Me Me iPr OH Me HO H
iPrMgBr
N + N
Ph Me Ph Me
H Me H Me H Me

4 5 6
 Problems

OH OH
N N s BuZnBr
N
i, LiTMP

ii, OHC [PdCl2(dppf)]

N Cl I N Cl N OMOM N Cl OMOM

OMOM
iii, LiTMP
7 8
iv, I2

LiTMP = Li N

O Ph
Zn
+ Br ?
N Ph THF

Boc

Ph Ph
i, Et2BH

ii, iPr2Zn
iii, CuCN•2LiCl
iv, Br
9

CrCl2, NiCl2 PDC

11
DMF, room temp.
O Br

10 cis-jasmone
MeO2C
O

CO2Me
O [Co2(CO)8] TiCl4
12

Bu 13 Bu

Me3Si Pd(PPh3)4
+ OSO2CF3
SnMe3

CONHEt

B(OH)2
Pd(PPh3)4
+
Br
S

Br Pd(PPh3)2Cl2
+
OH Ph
CuI, Et2NH

CO2Et
H CO2Et
EtO2C CO2Et 5 mol% Pd(OAc)2
+
Ph3P, NaH, THF

H
O
Br HO
14
 TYPE 333

B
H
E2
C C C C
X

B
H H
E1
C C C C C C (2.1)
X

B
H
E1cB
C C C C C C
X X

CH3
NaOEt
CH2 CH CH3CH CHCH3 + CH3CH2CH CH2
EtOH
H3C Br 81 : 19
(2.2)
CH3
KOH, H2O
CH2 CH C2H5CH CHCH3 + C2H5CH2CH CH2
–
130 °C
C2H5 NMe3 I 2 : 98

CH3 H CH3 CH3

CH3 base
CH2 C C C + CH2 C (2.3)
H3C C Cl H3C C CH3 H3C C CH2
CH3 CH3 CH3
H3C H3C H3C
1
19 : 81

CH3
H+ CH3

CH3 (2.4)
OH CH3

2 3

H
Me3N H Ph H H

Ph NaOEt Ph
≡
Ph Me Ph
Ph fast
Me H NMe3 Me
syn
(2.5)
H
H NMe3 Ph
H Ph
Ph NaOEt Ph
Ph ≡ H
Me Ph slow
Me H Me
NMe3
anti
 H Me
H Cl
i
Pr H NaOEt iPr
Me Cl H H Me
slow
H H
H H H i
Pr
only
4
(2.6)
H
H
iPr NaOEt
Me iPr + Me iPr
Me H
fast
H
H Cl
25 : 75
5

D
H
NMe3
H HO– H
H

OHC 6 OHC
CO2Me CO2Me
PhH
N N OMe OMe
MsO
OMe OMe
6 7 Ms = SO2Me 8

O OH
LiNEt2
(2.9)
Et2O-hexane
reflux
9 84%

OH
LDA, DBU (6)
O (2.10)
THF, 0 °C

NH 91% 96% ee
N

5 mol% 10

O O OH O
NaOEt
+ PhCHO (2.11)
Ph CH3 EtOH Ph Ph Ph
90% Ph

O O O
R"2NH
+ CH2O
R R NR"2 R
(2.12)
R' R' R'

11
H H Me OSiMe2t Bu
O H
O +
H2C=NMe2 I –

t BuMe Et3N, CH2Cl2

2SiO O
Me H H O H CHO
H 90%
H CHO
12
 C C O
xanthate heat
C C + HS
elimination H O
S SR

SR
(2.14)

C C heat
selenoxide
C C + RSeOH
elimination H Se R
O

Me
Ph H
O 400 °C
C C
O D
H Ph
C C 61%
Ph H
H Ph
13 14 (2.15)
Me
Ph D
O 400 °C
C C
O H
H Ph
C C 74%
Ph D
H Ph
15 16

OCOMe

500 °C

(2.16)
47%
OCOMe
17

O Me heat Me Me
+ Me + Me
Me
Me Me
57 : 28 : 15

CO2Et 435 °C
H CO2Et

OCOMe

18
(2.18)
H

CO2Et 435 °C
OCOMe CO2Et

19
 Me Me
H CO2Et H CO2Et

Me O 200 °C Me O
(2.19)
O O
H 94% H
O
S
20 21
SMe

O–

NMe2 140 °C

61%

H
H
i
Pr 100-180 °C iPr + iPr
Me NMe2 Me Me
H O–
H H 85% 65 : 35

22

H
(2.21)
H
iPr 90-160 °C i
Me H Me Pr
H
H NMe2 77%
–
O
23 (only)

Me

1-methylcyclohexene methylenecyclohexane

H Me Me
Ph 80 °C Ph
Ph Ph
–O S H H
Ph

24
O O O O
OH
i, TsOH, HO
OMe ii, LiNR2, THF, –78 °C OMe (2.23)
iii, MeSSMe SMe
iv, H3O+
69% i, NaIO4
ii, PhMe, 110 °C
86%
O O

OMe
 O O O

i, Ph2CuLi SePh H2O2

ii, PhSeBr 10 °C

Ph 72% Ph

OMe OMe

i, LDA
O O (2.25)
SePh ii, Br
O H O H
O iii, H2O2 O

65%
SePh
H2O2

25 °C
OH OH
98%

Me
H H H
i, LDA SePh
ii, PhSeSePh H2O2
O O O (2.27)
O iii, LDA O 0 °C O
H iv, MeI H H
25 26

SePh Me
H H
i, LDA Me
ii, MeI H2O2
O O O + 26
O iii, LDA O 0 °C O
H iv, PhSeSePh H 90 : 10
27 28

SePh Ph
Se
C7H15 SOCl2 C7H15
C5H11 C7H15 C5H11 (2.28)
Et3N, CH2Cl2
HO H 25 °C C5H11 H 80% H
29

O
base
X O (2.29)
H R
R B

X = leaving group, e.g. OSO2Me

OTs
H H
OTs
t BuOK
≡ O
H
OH > 90%
OH
30
(2.30)
 OTs
H
OTs
t BuOK
≡ H

H
90%
OH OH
O
31

OTs
H H
H

≡
OTs
OH OH

32

Me Me
OH Me OH

NaH, THF
Me
20 °C
TsO
OH O
Me 100%
Me
i, MeLi, Et2O
(2.31)
33
ii, TsCl, pyridine

Me Me Me Me
OTs
Me
NaH, THF
Me O Me
HO
80% Me
OMs
Me Me
35 OMs 34
B2H6 HO –
Me H Me Me Me
(2.32)
H
Me H Me Me
B
36 37

HO –

H
N N
O Ts N Ts N

Me TsNHNH2 Me base Me
O O O
AcOH
Me Me Me
38

¨ (2.33)
Ts

N
N
Me
O
O Me
Me
O–
O Me Me 91% Me
exo-brevicomin
 N
NHSO2Ar N SO2Ar
N N N
NaOMe heat H
R R
R R
R' R'
R' R' R'
39

H H

t
BuMe2SiO NaOMe tBuMe
2SiO (2.35)
diglyme
H heat H
N
NHTs

Ts = SO2C6H4-p-Me

NHSO2Ar N SO2Ar N Li
N N N Li E
2 BuLi E
R R R R R

R' R' 2 Li R' R' R'

40 41

2 BuLi
Ph Ph (2.37)
C6H14, TMEDA
N D
NHTs then D2O

74%

N SO2Ar
H N I
N S
O2 2 BuLi BuLi
N (2.38)
–60 °C 0 °C
then then I2
OMe OMe
I OMe
77%

NHTrisyl Li E
N
2.1 t BuLi E+
(2.39)
hexane–TMEDA
–78 °C to 0 °C e.g. E+ = DMF
H H
E = CHO, 61%

0.1 equiv. LDA

Et2O

N
N 89%
Ph

42
 H
H N Ts N
NNHTs N H N H
NaBH4
CH3CO2H

43 44

NNHTs D

NaBD4
CH3CO2H

75%
(2.42)
NNHTs D

NaBH4
CH3CO2D

72%
OH OH

Ti(0)
(2.43)
no reaction
OH OH
Ti(0) can be
45 46 47 generated
from TiCl3
and K metal
CH3
N
Cl P Ph
H3C O OCH3 S H3C O OCH3 N H3C O OCH3
Cl CH3
(2.44)
CH2Cl2, 0 °C CHCl3, 40 °C
BnO OH BnO O BnO
OH O 75%
S
48 49 50

OH
Ph Ph
Ph i, Cl2C=S
Ph
ii, Me
OH N
PPh
N 76%
Me
OH (2.45)
Ph
Ph i, Cl2C=S
Ph
ii, Me
OH N Ph
PPh
N 89%
Me

OH
i, S=CCl2
(2.46)
trans ii, (MeO)3P
hydroxylation OH
100-130 °C

75% 99% E
 HO OH

(2.47)
Me Me Me Me

PhCHO
H+ 71% 100% Z
96%

Ph Ph Li

O O O O
n
BuLi
pentane
Me Me Me Me

CH3(CH2)7 (CH2)7CO2H
H2
CH3(CH2)7 C C (CH2)7CO2H C C
Lindlar's catalyst
H H
EtOAc

C3H7 H
i, Na, NH3
C3H7 C C (CH2)7OH C C
ii, NH4Cl
H (CH2)7OH

NaNH2 C3H7 H
i, Na, NH3
C3H7C≡C(CH2)4C≡CH C3H7C≡C(CH2)4C≡C Na C C
NH3 ii, NH4Cl
H (CH2)4C≡CH

75%

R2B R
O
B H R H + R2B OCOR'
O H
O
O
R'
51

Me Me

Et Et Et Et
Me 2 BH CH3CO2H
Et C C Et C C C C (2.52)
25 °C
H B(C5H11)2 H H

82% 99% Z

C4H9 C4H9 C6H11

(C6H11)2BH I2, NaOH
C4H9 C C H (2.53)
B(C6H11)2

52 99% Z

anti
elimination

I I H
B

C4H9 C4H9
B C6H11 H C6H11

X C6H11
 H3C CH3 H3C C2H5
I2, NaOMe
(2.54)
–78 °C
B(C2H5)2 CH3

53 71%

O
B H
O C6H13 C6H13
i, NaOH
C6H13 C C H (2.55)
51 ii, I2
B(OH)2 I
then H2O
80% >99% E

O
B H
O C6H13 i, Br2 C6H13 Br
C6H13 C C H (2.56)
51 ii, NaOMe
B(OH)2
then H2O
85% 99% Z
H

O Cp2(Cl)Zr O
I [Cp2Zr(H)Cl] I
(2.57)
THF, 0 °C
Et3SiO Et3SiO
O O

54 55
Me
Me O Me O
[Cp2Zr(H)Cl] I
(2.58)
Me then I2
HO Me HO Me
65%
56 57

i Bu C4H9 C4H9
2AlH i, I2, THF
C4H9 C C H
ii, H3 O+
Ali Bu2 I
74%

H CH3 H CH3
Li[i Bu2Al(H)Me] i, CO2
H3C C C CH3
ii, H3O+
H3C Ali Bu2 H3C CO2H
H3C Li 72%

H3C CH3 H3C CH3

i, i Bu2AlH i, CO2
H3C C C CH3 (2.61)
ii, MeLi ii, H3O+
Et2O, –30 °C H Ali Bu2 H CO2H
H3C Li 76%
 i, LiAlH4 R H ii, I2, –78 °C R
R C C CH2
NaOMe, THF
OH Al I OH
O

i, LiAlH4
AlCl3, THF R I
R C C CH2
ii, I2, –78 °C
(2.63)
OH OH

i, LiAlH4 Me
NaOMe, THF
OH
ii, I2
OH iii, Me2CuLi

HO HO Me HO Me
Bu3SnH
Me +
[Pd(PPh3)4]
Bu3Sn SnBu3
84% 83 : 17

C4H9 C4H9
Et3SiH
H C4H9 +
[H2PtCl6]
Et3Si SiEt3
100% 82 : 18

CO2Me
(EtO)3SiH, CH2Cl2
CO2Me (2.67)
1 mol% [Cp*Ru(MeCN)3]PF6
then Bu4NF, CuI

Cp* = pentamethylcyclopentadienyl anion 83%

Me
CuBr•SMe2 C3H7 C C H
MeMgBr MeCuMgBr2•SMe2 CuMgBr2•SMe2 (2.68)
Et2O, –45 °C C3H7

Me O Me

CuMgBr2•SMe2 OH
C3H7 C3H7
78%

Me3Al Me2Al Me I2 I Me
H C C C5H11
Cp2ZrCl2
C5H11 C5H11
58 83%

R1 R3 R1 R3
O + R3P R3P O (2.70)
R2 R4 R2 R4
 R3P R3P
R' R'

R4
R1 R3
R3P R3 R1 R3 (2.71)
O + R3P + R3P O 60 R4
O R3P
R2 R4 R2 R2 R4 R3
R1

59 O R2
R1

CO2Et

CHO Ph3P CO2Et

PhH, heat

80%
(2.72)
CO2Et
O
Ph3P CO2Et

PhH, heat

25%

H R2 R2 R2
R3P R3P
O + R3P +
O O
R1 H R1 R1

PR3 H
R2 R2
O
cis oxaphosphetane
R1
R1 R1
R2 H

CO2Et Me
Me Me Me Me
O Ph3P O
O CHO O CO2Et
Me
PhCO2H (cat.)
Ph O OTBS Ph O OTBS
H PhH, 50 °C H

90%
TBS = SiMe2t Bu
(2.74)

Me Me Me Me
OHC O OBn O OBn
TBSO PPh3 I – TBSO

NaHMDS
TBSO O OBn TBSO O OBn
H Me THF, 0 °C H Me

99%
 OMe
O CHO

MeO PPh3 Br – H3O+ (2.75)

NaH, DMSO

67%

Br
n
CBr4, Ph3P, Zn BuLi
RCHO R E (2.76)
then E+
R Br

PPh3 Br t BuOK
R
or NaOMe
NHCOR N
PhMe, heat H

R S R
(2.77)
S
CHO
heat
N PPh3 N
O O

CO2R' CO2R'

1 equiv. 2 equiv.
Ph3P CH2 Ph3P CHLi Ph3P CH3 X – (2.78)
t BuLi s BuLi

61 62

O CH2
Ph3P CHLi

then t BuOH

87% 63

Br –
O O
(EtO)3P + BrCH2CO2Et P CO2Et P CO2Et
EtO EtO
EtO EtO

(2.79)
O
O O O
NaH CO2Et
P CO2Et P CO2Et + P
EtO EtO EtO
DME O– Na+
EtO EtO EtO
Na+ 70%
64 65
 O O
O
MeO2C P
MeO
LiCH2P(OMe)2
MeO
O O OSiMe2t Bu O O OSiMe2t Bu

96%

O (2.80)
i, NaH, DME

ii, CHO
OBn O O O O OSiMe2t Bu
OBn O O

94%

O O
DBU, LiCl, MeCN
N P(O)(OMe)2 N CO2Me (2.81)
O O
Boc O Boc O
OHC CO2Me
DBU

84% 66 93% e.e.

N N

O
KN(SiMe3)2
PhCHO +
CF3CH2O
P CO2Me (2.82)
THF Ph CO2Me
CF3CH2O 18-crown-6

>95% Z:E >50:1

O
NaH
C7H15CHO +
PhO
P CO2Et (2.83)
THF C7H15 CO2Et
PhO

100% Z:E 9:1

O
O
R
Ph2P R
P R i, BuLi, THF, –78 °C NaH
Ph
ii, R'CHO DMF
Ph
R'
R' OH

i, BuLi, THF, –78 °C anti predominates

ii, R'CO2Et
[O]

O O
R
Ph2P R Ph2P R
NaBH4 NaH
DMF
R'
R' O R' OH

syn predominates
 O
O
Ph2P
Ph2P i, BuLi, THF, –78 °C NaBH4
(2.85)
ii, O
OH
O
O 85%

81%
O

Ph2P
NaH OH
DMF
OH
HO
90% 67

SiMe3 Me3Si O C3H7

C3H7 KH, THF
C3H7 H C3H7
syn elimination C3H7 H C3H7
OH
96% 95% E

(2.86)
SiMe3 Me3Si H
C3H7
C3H7 BF3•OEt2, CH2Cl2
C3H7 H
anti elimination C3H7 O BF3 C3H7 C3H7
OH
H 99% 94% Z

OSiMe2t Bu OSiMe2t Bu
O O O
i, Me3SiCH2MgCl
Et2O
ii, KH, THF

62%
RO RO

SiMe2Ph SiMe2Ph SiMe2Ph

i, Mg, Et2O, heat MeLi
C4H9 C4H9
C5H11 Cl ii, CuBr•SMe2 C5H11 C5H11

iii, C4H9COCl O HO Me

68 69

SiMe2Ph

C4H9 C4H9 Me
C5H11 C5H11 + C5H11
HO Me Me C4H9
KH 61% 95 : 5
69
TsOH 60% 5 : 95
 O Me3Si OH
m-ClC6H4CO3H (C3H7)2CuLi
(2.89)
Me3Si C3H7 Me3Si C3H7 Et2O, –78 °C C3H7 C3H7

OAc OAc OAc

CO2Me HO CO2Me HO CO2Me

OsO4 TsOH
t
(2.90)
BuOH, acetone, H2O PhH, heat
O HO
SiMe3 SiMe3 98%
N
Me O

SO2Ph PhO2S
i, BuLi i, MeSO2Cl
Me ii, Me OH ii, Na-Hg Me
OHC
EtOH
80%

(2.91)
CHO

H H
i, BuLi, THF, –78 °C
then 70
SO2Ph ii, Ac2O
H H
BzO iii, Na-Hg BzO
EtOAc, MeOH
70
58%

PhO2S R' R' R'

••
Na-Hg H
H (2.92)
R OAc R OAc R

71

SO2Ph
BuMgBr

C9H19 Pd(acac)2, Bu3P Me C9H19

83%
72 73 98.5% Z

OMe
OMe OMe
OMe PivO
PivO O O
O N
O
N N
N
N
N
N S N KHMDS
O2
Ph
O (2.94)
O 74

OHC 85%

74 75 76
E:Z 91:9
 S N S N

R'
O 2S O O 2S O
(2.95)
R
R R' R R'

77

O2
O2 S R
R S R' base R – SO2
(2.96)
R'
X R'

X = Cl, Br, I

Cl

t BuOK
O2S
n n

n = 3-8 32-52%

78 79

BnO BnO
O O Ph
KOH–Al2O3
BnO SO2CH2Ph BnO (2.98)
CF2Br2
t BuOH, CH2Cl2
BnO OBn BnO OBn

94% Z:E 88:12

TiCl3, K
CHO
THF, reflux

77% E:Z 70:30

O O O O
2e
2 2

OH
CHO TiCl3(DME)2
(2.101)
CHO Zn-Cu
DME, r.t. OH

85%

¨
 O CHO

TiCl3(DME)1.5
(2.102)
Zn-Cu
O DME, reflux O
H H
OAc OAc
80 32%

TiCl3, LiAlH4
O DME, reflux (2.103)
H
EtO2C O

81 38% 82

O
83
Cp2Ti AlMe2 Ph Ph
Cl OEt PhMe, THF OEt

O 83 90%
H H
TiCl4, Zn, CH2Br2
(2.105)
THF
OH OH

MeO2C O MeO2C O
O 90% O

OMe
TiCl4, Zn, TMEDA
PhCO2Me + RCHBr2 R (2.106)
THF Ph

R = Me 86% Z:E 92:8

SPh

Cp2Ti[P(OEt)3]2
Ph CO2Et + Ph SPh Ph Ph
THF (2.107)
OEt

75% Z:E 86:14

CHO CHI3, CrCl2 I

MeO2C MeO2C
THF
OAc OBn OAc OBn

80% E:Z 98:2

O O

CHI3, CrCl2
CHO I (2.109)
THF

75% E:Z 81:19

 [LnM=CHR']
2 RCH CH2 RCH CHR + H2C CH2 (2.110)

Ar Mes N N Mes
PCy3 Ph N Ph
Cl Ph Cl
Ru Mo Ru
Cl Me(F3C)2CO Cl
PCy3 Me(F3C)2CO PCy3

84 85 86
Cy = cyclohexyl
Ar = 2,6-diisopropylphenyl
Mes = 2,4,6-trimethylphenyl

R
R
LnM H2C CH2

¨ 87

[LnM=CH2] [LnM=CHR] (2.111)

R R

RCH CHR
LnM R

H H H
10 mol% 84 i, H2, Pd(OH)2
(2.112)
N ClCH2CH2Cl N ii, LiAlH4 N
room temp.
O O
89%
88 89 90

Me Me Me
Me 5 mol% 86

45 °C

EtO2C CO2Et CO2Et

CO2Et
90%
91 92

Me
OSiMe3 OH
Me
3 mol% 85
(2.114)
hexane, 55 °C
then Bu4NF H
Me Me Me
Me Me
Me 92%

93 94
 S S
HO 10 mol% 84 HO
N N (2.115)
O CH2Cl2 O
room temp.
O OSiR3 O O OSiR3 O

95 96 46%

SiR3 = SiMe2t Bu

HO S

+
N
O

O OSiR3 O

97 39%

5 mol% 86
AcO n
+ CO2Me AcO n CO2Me
CH2Cl2
room temp.
98

94%

Problems (answers can be found on page 469)

1. Explain why the two diastereomeric amine N-oxides 1 give, on heating, two different
major regioisomeric alkene products.

NMe2
heat
+

Ph Ph Ph

1
syn 98 : 2
anti 15 : 85

2. Explain the formation of the Z-,-unsaturated ester 2.

OH
CO2Me TiCl4, iPr2NEt MsCl, pyridine
n CO2Me
C5H11CHO + n
C5H11 n
C5H11 CO2Me
SePh CH2Cl2 CH2Cl2
SePh
2

3. Draw a mechanism to account for the formation of methyl chrysanthemate by the trans-
formation shown below.

CH3
S
N
P Ph
O O N
H CH3
CO2Me CO2Me
40 °C
H

methyl chrysanthemate
 4. Suggest a method to prepare the allylic alcohol 3 as a single stereoisomer.

Me

OH

MeO2C

3
5. Suggest two methods for the conversion of the alkyne 4 into the Z-alkene 5, which was
hydrolysed to the anticancer compound combretastatin A-1.

MeO MOMO OMOM OMOM

MeO OMe MeO OMOM

MeO MeO OMe OMe

4 5

6. Suggest a reagent and conditions to convert the lactol 6 to the alkene 7.

PMBO PMBO

CO2H
OH
O OH

6 7

7. Account for the formation of the pyrrolizine 8.

NaH
CHO N
N
H PPh3 Br

8. Explain the formation of the adduct 9.

O CH2
Ph3P CHLi

then t BuOH

9 agent pinnaic acid. Suggest

9. The diene 11 was used in a synthesis of the anti-inflammatory
a method to prepare the alkenyl stannane 10 and reagents for the steps from 10 to the
diene 11.
CHO i CO2Et ii CO2Et
Bu3Sn Bu3Sn I

Me Me
10

R iii
iv

BocN
H CO2Et
R
R = Me
H Me
t
BuPh2SiO 11
 Problems

10. Suggest reagents for the conversion of the silane 12 to the alkene 13 and of the
silane 12 to the alkene 14. Explain the regioselectivity of the elimination in each
case.
SiMe2Ph

HO OH HO OH

or
HO OBn HO OBn HO OBn

OBn OBn OBn

12 13 14

11. Explain the following chemistry, used in a synthesis of the anti-cancer agent zampano-
lide.
t BuMe SiO Me
2

OSiMe2t Bu
O2
Br Me S N Br Me
N
H H KHMDS, THF, –78 °C H H
O N O
Ph then
t BuMe
2SiO Me

OSiMe2t Bu

CHO

12. Draw the structure of the product from double ring-closing metathesis of the tetra-ene
15.

PhMe, 80 °C
?
1 mol%
N
COCF3
Mes N N Mes
Ph
Cl
Ru
Cl
15 PCy3

13. Alkene–alkene metathesis reactions are a valuable method to construct cyclic com-
pounds (see Section 2.10). Alkene–alkyne reactions can also be effective. Explain the
formation of the bicyclic product 16.
O
Me O
CH2Cl2, 40 °C

5 mol%
Me
Mes N N Mes
Ph
Cl
Ru
Cl
PCy3
 3
Pericyclic reactions

cycloaddition
+ (3.1)
reaction

sigmatropic
(3.2)
rearrangement

electrocyclic
(3.3)
reaction

ψ3
ψ2
LUMO HOMO ψ2

(3.4)

ψ2
HOMO ψ1 LUMO ψ2

diene dienophile

Cl Cl
190 °C
+

Cl
Cl
(3.5)
Cl
190 °C
+
Cl
Cl
Cl
O
maleic anhydride

O
 Table 3.1. Rates of reaction of dienophiles with cyclopentadiene
and 9,10-dimethylanthracene

Cyclopentadiene 9,10-Dimethylanthracene
Dienophile 105 k/mol–1 s–1 105 k/mol−1 s−1
Tetracyanoethene (NC)2 C C(CN)2 c. 43 000 000 c. 13 000 000 00
Tricyanoethene (NC)2 C CHCN c. 480 000 c. 590 000
1,1-Dicyanoethene H2 C C(CN)2 45 500 12 700
Acrylonitrile H2 C CHCN 1.04 0.089
MeO2C
Dimethyl fumarate CO2Me 74 215
Dimethyl acetylene MeO2C CO2Me 31 104
dicarboxylate

9,10-dimethylanthracene Me

Me

CHO CHO
+ (3.6)

1
CO2H
CO2H
+ (3.7)
CO2H
CO2H
2
O O O

+ (3.8)

O O O

O O
Me
Me
100 °C
+ (3.9)
MeO MeO
H
O 86% O
 200 °C H3O+
+ (3.10)
O 400 °C CHO CHO
OR O OR

OMe

O O
O O
OMe 5 °C
O H
+ (3.11)
O
CHO
48% CHO
3 4

Ph

N
H

Ph N MeOH Et
+ (3.12)
N reflux
N
Me CO2Me CO2Me
Et 55% Me

5 6

H
0 °C
+ +
H

97% 37% (3.13)

7 8

Ph Ph

+ O O (3.14)

Ph 91%
Ph

9
F

Br Mg

CO2
+ other products (3.15)
N2

N benzyne
N
S
O2
 SO2Ph
SO2Ph Na–Hg

135 °C
76%
94%

i, base
ii, PhCH2Br (3.16)

SO2Ph

Ph Na–Hg Ph

85%

OMe OMe OMe

Cl Cl
CN O
CN Na2S•9H2O
CHCl3, 61 °C EtOH
50% 80%

O OEt BnO BnO

S S
Tol Et3O BF4 Tol OBn

–30 °C
BF4
then NaOH (3.18)
S O
Tol
10 60% O 11

>96% de >96% ee

H CO2R
C H
TiCl2(OPri)2
+ C
–20 °C CO2R
CH2
CH2 (3.19)
12 98% 13

tBu 99% de
O
R =

Me Me PPh3 Br Me CHR
PPh3 Br i, LDA
ii, RCHO (3.20)
145 °C
Me Me Me

92%

Me O
O O
Me
cat. H+ OH O
O Me
(3.21)
CH2Cl2, <0 °C
Me

14 65% 15
 OEt OEt

O 180 °C O
+
C
H H
(3.22)
OMe OMe

O 20 °C O
+
C
H CO2Bu CO2Bu

OMe OMe
Me Me Me
O ZnCl2 O CF3CO2H O
+ (3.23)
C 25 °C
TMSO H C5H11 TMSO C5H11 O C5H11

Me Me Me

16 17

NMe2 NMe2

O CH2Cl2 O CH3COCl O
+
C
(3.24)
25 °C
t
BuMe2SiO H R t
BuMe2SiO R O R

R = Ph 86%
18 19 R = C5H11 73%

O HO
O
O
O H
H ZnCl2 H O
+
C PhH, 25 °C O
(3.25)
TMSO OMe
H O HO OH

72% O

20 21 22 23

Ts
N PhH Ts
+ N (3.26)
room temp. CO2Bu
CO2Bu

84%
24

N Ph DMF, TFA N Ph
+ (3.27)
cat. H2O
Me EtO2C Me CO2Et
room temp.

43%

OSIMe2t Bu OSIMe2t Bu t BuMe SiO

2
H

heat
N N N (3.28)
CO2Me CO2Me CO2Me
O H O O
OAc
82%
25 26
 O EtOH, 0 °C O
+
N N
Ph Ph
95%

Br O OH
Br
O
O Bu4NIO4 O
Ar NHOH Al(Hg)
+
THF
(3.30)
O O
O O
80% N 91%
COAr
NHCOAr
27 28 29 30

O Br
(via Ar N )
O Ar =
O O

H H

Pr4NIO4
NHOH N N
Bu O Bu
Bu
O 82% O

31 32 gephyrotoxin 223AB

O O O ROH O
+
N N N NH2

Cl
Cl Cl Cl
RO
+ RO

H2
N Cl NH2
O OAc
OAc Cl OH
EtOH
+ N
–20 °C
(3.33)
OAc O OH
OAc
87%
OH
conduramine F1

O OH
O
O2, hν H2, Pt
(3.34)
sensitizer

OH
 cisoid

O O
H
100 °C
+ O O (3.35)
PhH

H
O O

2,3-di-tert- 1,3-di-tert- Z-1,3-

butylbutadiene butylbutadiene pentadiene

OMe Me OMe
Me Me
CHO CHO H3O+ CHO

heat
Me3SiO Me3SiO O

20 33

OMe O O
O O
O CO2Me CO2Me CO2Na O
PhS OMe
OMe
i, 9-BBN
CO2Na
100 °C ii, NaOH,
Me3SiO then AcOH O MeOH HO

20 34

(3.37)
OMe MeO OMe OMe
CO2Me
CO2Me CO2Me
OMe heat
+

Me3SiO Me3SiO HO

35

(3.38)
NHCO2Bn NHCO2Bn
HN
CHO CHO H
110 °C
+ (3.39)
H
Me 61% Me
Me

36 37 38
 O N O N
H
230 °C
(–)-38 (3.40)
H

Me Me
60%

39 40

O
SPh SPh SPh
CO2Me CO2Me CO2Me
MeO2C
120 °C i, mCPBA
+ O O O O
ii, (MeO)3P
HO
H H H
R R R R

41 42 43

R= O

MeO OMe

OAc OAc OAc

CO2Me CO2Me CO2Me

xylene
+ + (3.42)
heat

80%
SiMe3 SiMe3 9 : 1 SiMe3

44

OAc OAc
HO CO2Me HO CO2Me HO CO2H
OsO4 TsOH
44

96% HO 98% HO
SiMe3 OH
45 Shikimic acid

Me CO2Na Me CO2H Me CO2H

H Me H CHO
Me Me CHO Me CHO Me Me
H2O
+ + (3.43)

85%

46 47 4.7 : 1 48

OCOMe
O
+
OAc

49 50
 O O
O

O
O + O (3.45)
H O
O H
51

CO2Me
O O CO2Me
200 °C CO2Me
+ (3.46)
O
84% CO2Me
CO2Me CO2Me

O O

100 °C
+ (3.47)
77%
O O

52
Z Z
+

53
O

OH OH O
OH H

PhH O

heat
(3.48)
H
75% O

54 55

O TBSO O
OTBS H
Me Me
90 °C
+
CO2CH2CH2TMS CO2CH2CH2TMS
OTBS OH OH
H
TBSO O 90% TBSO TBSO O

56 57 58

TBS = SiMe2But
 O
O OMe Br O OMe O OMe O
Me
NaI Me
70 °C
(3.50)
75%
O OMe Br O OMe O OMe

59 60 61

F–
Me Me CO2Me Me

CO2Me
SiMe3 Bu4NF MeO2C

MeCN
(3.51)
NMe3
50 °C CO2Me

Me Me Me

62 63 64

Me Me

10 mol% 66
+ (3.52)
THF, –78 °C
EtO2C O OEt EtO2C O OEt
89%

65 Me Me 67 >99% ee
O O

N N
Cu
t
Bu (OTf)2 But

66

O OMe O OMe O OMe

Me Me Me
PhH air
+
room
(3.53)
N temp. N N
NMe2 O NMe2 O O
62%

Me CO2Me
Me CO2Me
MeCN
+ (3.54)
N –20 °C N
CO2Me
NMe2 CO2Me
58%

O O
H
Me3SiO O
CHCl3
+ O O (3.55)
N 20 °C HN
then MeOH
H
Ph O Ph O
92%

68
 H
O O O O
N SnCl4 N
+ (3.56)
CH2Cl2, –78 °C
H
Ph Ph
93%

69

R R R

CO2R' CO2R'
+ + (3.57)
CO2R'

R R' Temp. (°C) Ratio of 1,2- : 1,3- adducts

NEt2 Et 20 100 : 0
Me Me 20 95 : 5
CO2H H 70 100 : 0
CO2Na Na 220 50 : 50

R CO2Me R R CO2Me
+ + (3.58)
CO2Me

R Temp. (°C) Ratio of 1,4- : 1,3- adducts

OEt 160 100 : 0
Ph 150 82 : 18
CN 95 100 : 0

CO2H CO2H
CO2H CO2H

(3.59)

HOMO LUMO

Ph Ph

(3.60)
CO2Me CO2Me

HOMO LUMO
Me Me Me CHO
+ + (3.61)
CHO CHO

PhMe, 120 °C, no catalyst 59 : 41

PhH, 25 °C, SnCl4•5H2O 96 : 4

O O
MeO MeO O
Me heat Me Me
+

PhS PhS Me
75%

70 71 ~4:1 in favour of carvone

this regioisomer

O O O

90 °C Bu3SnH
+ (3.63)
O2N
NO2 80%
Me Me Me

72 73
CO2Me H CO2Me
+ +
H CO2Me
CO2Me CO2Me H
CO2Me H
74 75

(3.64)
MeO2C CO2Me
+
H
CO2Me H
CO2Me
76

R R

R' R'
(3.65)
R R

+
R'

R'
 O H
H
O H
O
O H O
O
77 endo (3.66)

O O
H
O H
H O
H
O
exo furan fulvene
O

CO2H O HO2C O
H

PhH
+ (3.67)

H
O O

78

R CO2H R CO2H
+ + (3.68)
CO2H R

R endo exo
H 75 : 25
Me 35 : 65
Et 0 : 100
Ph 60 : 40
Br 30 : 70

CO2H CO2H CO2H

CO2H CO2H CO2H

+ +

Temp. (°C)) endo exo

75 100 : 0
90 88 : 12
100 82 : 18
110 67 : 33
130 50 : 50
Possible explanations for endo selectivity

H
H

...................
and/or
(3.70)

O O
..... secondary orbital interaction electrostatic interaction
favours endo transition state disfavours exo transition state

H H

H H
+ (3.71)
CO2Me CO2Me
CO2Me

79 150 °C 65% 80 60 : 40 81
EtAlCl2, 23 °C 60% 100 : 0

H
´
180 °C H
(3.72)
CO2Me

CO2Me
82 81

(3.73)

O O
PhMe, 155 °C 70-80%
Et2AlCl, –70 °C 90%

130 °C H
(3.74)
CO2R'
CO2R'
~70%
RO RO

83 84

R = SiPh2t Bu or CH2OCH2CH2OMe
R' = Me or Et

H
H

H .... H ...

(3.75)
.... ....
R'O2C R'O2C

RO RO
 Me Me

Me 200 °C

OSiMe3 then H3O+ OH

H H
Me Me Me
88%
87 88 89

CO2Me CO2Me
H

N PhMe N
R R (3.77)
heat
O N O N
Boc Boc
68%
OSiPh2t Bu OSiPh2t Bu

90 91

R = (CH2)5OSiPh2t Bu

O SiPh2 O SiPh2 OH
O O
H
160 °C HCl, MeOH
O (3.78)
CO2Me
H
Me CO2Me 87% Me 35% Me O

92 93 94

OH O OH
Mg
i, BuLi, THF 80 °C
(3.79)
ii, MgBr then H2O

Me Me ~70% Me

95

OBn OBn OBn OBn

H H
HCHO(aq)
+ (3.80)
H2N 65 °C N N N

96 82% 97 1.6 : 1 98
 O O
O O
O
SiMe3
N
N N
Cl O xylene
(3.81)
0 °C reflux

53%
99

OBn OBn OBn

H H H
HO
i, Swern
oxidation AcOH
HO N N (3.82)
ii, NH3 NH4OAc
25 °C

90% (from 100)

100 101 102

OSiMe2t Bu OSiMe2t Bu OSiMe2t Bu

Me Me Me

H
213 °C
(3.83)
SO2 H H
NC NC NC

103 104 80% 105

O
PhS
SPh O
N PhS N
N
i
Pr2NEt, PhCl, heat Et

O O
Et (3.84)
Me N
N Et N
EtO O
CO2Me CO2Me CO2Me
107
106 108 58% 109

MeO2C H H CO2Me

+ (3.85)
CO2Me
O O

110 111 112

650 °C, 0.02 mm Hg

MeO2C H

113
 H
O OR
H OR
O
O
RO KH, dioxane
+ (3.86)
35 °C, 12 h
O
HO
OR O

114 115
R = CH2OCH2Ph

OAc O

N 180 °C N OAc
O + OAc PhCN + O

Ph Ph 90%

CO2Et Me CO2Et

Me
N N 25 °C N
+ N
N
EtO2C EtO2C
Br 50%
EtO2C EtO2C
Br
116 117 118

OH O
O OH

119 120

TiCl2(OiPr)2 LiAlH4
+ (3.90)
CH2Cl2, –20 °C
CO2R*
CO2R*
96% OH

121 96% endo 122

99.4% d.e.

O
O s-trans
O
TiLn

123

TiCl4 LiOH
+
O O
(3.91)
0 °C
CO2R* CO2H
O O 73%

124 86% d.e. 125

O
O
s-cis O
Ti O
Ln

126
 O O
COXN*
Et2AlCl i, crystallize OH
+ N O
ii, LiOBn
(3.92)
CH2Cl2, –100 °C
iii, MeMgBr
Ph 85%

127 90% d.e. 128

O AlEt2
O Et2AlCl2
N
O
Ph
129

COXN*
H
EtAlCl2
N (3.93)
S
O2 O 75%
H

94% d.e.

Ph O OH R*COO O OH
O H

OMe B(OAc)3
+ (3.94)
0 °C
H
O 98% O

130 131 >97% d.e.

O NH • HCl
O
O
O O O N MeOH
O + (3.95)
–70 °C
Cl

132 133 >96% e.e.

O
2+ 2+
Me Me Me Me
N
O O O O O O
O N Cu
2 OTf – 2 SbF6–
O N
N N N N (3.96)
Cu Cu
t Bu t Bu t Bu t Bu

66 134 135 Re face

Me O O Me O O

N O 10 mol% 134 N O
+ (3.97)
CH2Cl2, 25 °C

89%

83:17 cis:trans cis: 94% ee

 O O O

N O 5 mol% 134
O + O (3.98)
CH2Cl2, –78 °C

97% O N O

136 80% endo 97% ee

OSiMe2t Bu OH
i, LiSEt i, OsO4, NMO HO
ii, MeOH, Cs2CO3 ii, Bu4NF
136
iii, LHMDS OMe iii, TMSOK OH
then TBDMSOTf HO

O O

137 ent-shikimic acid

OMe
O Me
Me 0.05 mol% 66 CO2Me
+ OMe
THF, –78 °C O
Me3SiO O then TFA O

90%
20 138 98.4% ee

O O
Me
N O 15 mol% 140
+ O (3.100)
PhMe, –16 °C
Me
94% O N O

139 87% endo

88% ee

Me Attack on Re face favoured

Ar Ar
+
O Ar N
O O
Me
TiCl2 O
Me Ti O O Cl –
O O O
Cl
Ar Ar Ar

140, Ar = 2-naphthyl 141

 O
TiCl2
Me Me
O
O O
H
30 mol% 143
+ (3.101)
PhMe, room temp.

>65% H
O OSiMe2t Bu O OSiMe2t Bu

142 144 87% ee

O O
B
O
OH

CHO
CHO
20 mol% 145
+ (3.102)
CH2Cl2, –78 °C
I
I
72% 146 85% ee

OH

OH
OMe

20 mol% Ti(OiPr)4 O
PhCHO + (3.103)
PhMe, 0 °C
OSiMe3 then CF3CO2H Ph O

20 92% 147 97% ee

NH

N O
Ts B
Bu CHO
Br CHO
5 mol% 148
+
CH2Cl2, –78 °C Br (3.104)

95% 96% exo 99% ee

Ph
N Ph
H B O

TfO–

CO2Et
20 mol% 149
+
CO2Et
(3.105)
CH2Cl2, –20 °C

94% 97% endo 98% ee

 Me

H H

N O
Cr
O SbF6
O
5 mol% 150 O
+ OSiMe2 t Bu
room temp. OSiMe2t Bu
(3.106)
H
Et3SiO Et3SiO
61%
98% ee

O O O O
H H H Me
Me
hν
+ + +
hexane
Me Me Me Me
H Me H Me H

151 26.5% 6.5% 6%

O O
H CN
NC
hν
+
Me CH2Cl2 Me
Me
Me Me Me H
85%
152 153

O O
Me Me Me
Me i, Ph3P=CH2
hν DMSO
ii, TsOH
(3.109)
hexane Me
Me PhH
Me Me
Me 77% Me

154 155 isocomene

Me Me
O O
H Me
Me
O hν
(3.110)
O CH2Cl2
O
81% O
O Me
O
O
Me

O
156 157 97 : 3

Me O
Me
Me

hν O
+ O
O
(3.111)
OH
Me OH Me
78% Me

158 159
 Me Me
O Me O O
Me
Me
hν H i, LHMDS H
hexane ii, MeI
(3.112)
OCOPh iii, KOH
OCOPh O
98%

160 161

Me O Me
Me Me Me Me
H

H H
O Me

162 epi-precapnelladiene

O O
H H
R
R

N
hν
N R N O (3.113)
Boc Boc Boc
N N
N
H H H

163 164 165

Ar
H H
O
A B
N N OH
pyridine Boc R D C

AcOH N N
H H
20% from 163
E

R = (CH2)2CH=CH(CH2)4OH 166 manzamine A

Ar = β-carbolin-1-yl

H H

hν
O ` ¨ O
+
PhCHO
N C9H19 Ph C9H19 Ph C9H19
N N
H H
CO2Me CO2Me CO2Me
65%

167 168 4.4 : 1 169

HO

N C9H19
Ph Me preussin
 C8H17
C8H17
H H

hν ` ¨ O
O
C8H17CHO
O O O O O
H H
98%
170 avenaciolide

Me Me
Me OnPr Me OnPr Me OnPr
room temp.
C O + +
Et2O
Me Me O Me O Me

Z-171 89% cis-172 99 : 1 trans-172

(3.116)
Me Me
Me OnPr Me OnPr Me OnPr
room temp.
C O + +
Et2O
Me Me O Me O Me

E-171 60% cis-172 1 : 99 trans-172

H H
O
O
Et3N i, Zn, AcOH
+ Cl2CH–COCl Cl O (3.117)
ii, H2O2

H Cl H
72%

173

Ph

N O Ph
R'
R EtO
OEt O
EtO N O
hν i, mCPBA
(CO)5Cr O (3.118)
R
CO, CH2Cl2 ii, 2 × Bu4NF
O
O O
76%

174 175 176

R = CH2CH2C≡CSiiPr3
R' = CH2CH2C≡CH

O
t BuMe SiO O t BuMe SiO O
2 2
O
H C EtAlCl2 C6H13
+ H SiMe3 (3.119)
C5H11 Et2O C5H11
Me3Si C6H13
91%

177 178 179 (9:1 1,3-diastereoselectivity)

 O CO2Me
PhthN CO2Me
O Et3N
N + N
CH2Cl2
(3.120)
N
Cl
O Ar
O MeO 61%

181 182
180

H
O
Et2O, –20 °C
+ ClSO2N=C=O (3.121)
then Na2SO3, K2HPO4 NH

H
52%
183

(3.122)

OMe OMe

Me N N
LDA
N N (3.123)
THF N
H
N

184 85% 185 trans : cis 95 : 5

O
O

O O
Ar Ar
O O
O nBuLi
+ (3.124)
THF
N SnBu3
O then H2O N N
H H H H
5 : 1
186 74%

Me
CF3CO2Ag
+ I (3.125)
Me

30% 187
 SiMe3
SPh SPh
H H
HO SPh
Tf2O
+ (3.126)
CH2Cl2
2,6-lutidine
H H
10 : 1
188 65% 189 190

O
O
O O Me Me
Zn-Cu
Me Me Me Me O (3.127)
or Fe2(CO)9
or Et2Zn
Br Br

191 192 193

O O
O
i, LDA, CF3SO2Cl
O (3.128)
ii, LiClO4, Et2O, Et3N

58%
194 195

O
O O O
O
O O R
O
O
(3.129)
R R
ozonide

R' R'

N N
N N N N N R N O
O (3.130)
R R
R R

azides diazoalkanes nitrile oxides nitrones azomethine ylides

Me N
Me
Me NO2 PhNCO Me O
Me C N O
Et3N
Me Me

(3.131)
N
Ph
Ph NOH Et3N Ph H O
Ph C N O
Et2O
Cl Ph
 N NH OH NH2 OH
R
O H2, catalyst H2
(3.132)
R R' R R'
R'
H2O

O OH

R R'

O
O O2N
O O
O O O LiAlH4
PhNCO, Et3N O
O N
58% 94%
196
(3.133)
HO
O O
O
O HCl
O HO OH

OH NH2
NH3 Cl
197 major stereoisomer

NO2 N O O OH O

p-ClC6H4NCO H2, Raney Ni MeSO2Cl

H
Et3N, PhH, 25 °C MeOH, H2O Et3N, 0 °C
CO2Et CO2Et AcOH CO2Et CO2R
55% 97% 100%
198 199 200 201

O O O O O O
N N N
OH NaOCl
O + O (3.135)
CH2Cl2, H2O, 0 °C
PhCO2 PhCO2 PhCO2
65% H H
OMEM OMEM OMEM

202 203 3.6 : 1 204

Me LiAlH4 OH
PhMe, 110 °C
H H (3.136)
N N N Me
53% H
O O
Me
205 206 sedridine
 C9H19
H (3.137)
145 °C
Me N Me N Me N (CH2)10Me
81% H
O O
C9H19
207 208 solenopsin

Ph Ph
Me N O N O
OHC
Ph N Ph + (3.138)
20 mol% 209 Me Me
O Ph Ph
MeCN, H2O
–20 °C CHO CHO

98% 94% ee 94 : 6

Me O
N
Me O
N Ph
N
Ph
N
H • HClO4

Me
209 210

Me
H
Me
MeNHOH Me
CHO
O (3.139)
PhMe, heat O
N N
55% H
Me Me

211 212

NHOH Me
H
N N
CH2=O Me Me
O (3.140)
PhMe, heat
Me
H O
89%

213 214 luciduline

C5H11 C5H11
C5H11 RCHO PhMe
N N
R
(3.141)
CH2Cl2 R heat
NHOH O O
MgSO4
89%
215 R = (CH2)3OAc 216 217
 O OSiMe2t Bu
O Me
CO2Me
175 °C Me OSiMe2t Bu
N CO2Me (3.142)
N PhMe CO2Me
N

Ph 69%
Ph
Ph
218 219 220

Ph
Ph
O O O Ph
N H
N N
Ph N 325 °C Ph N Ph N

78% H OMe

MeO OMe MeO OMe

OMe
221 222 223

(3.143)

O O CO2Et O CO Et
H 2
CO2Et H
NH2 N N
Ph N CH2=O Ph N Ph N
PhMe
heat
78% H OBn
OBn OBn

224 225 226

(3.144)

H
MeNH CO2Et
CO2Et CO2Et (3.145)
xylene, heat N
CHO H
camphor sulfonic acid N S SH
S S S S Me
Me 60%

227 228 229

MeO2C
Me Me MeO2C
Et3N, MeCN
Ph N CO2Me AgOAc or LiBr Ph N CO2Me Me (3.146)
Ph N CO2Me
M H
80-90%
230 231 232

CF3 CO2Et
For X = OC5H11
CO2Et
CF3COOH CF3
N (3.147)
X N SiMe3 CH2Cl2
room temp. N
Ph
Ph
80% Ph
X = OMe, CN, Bt, etc 233
 CO2Me

N2 MeO2C
O O MeO2C CO2Me O
Rh2(OAc)4
Me O
PhH
Me O Me O (3.148)
room temp.

88%
234 235 236

(3.149)
H H H

O O
Me Me
170 °C
+ O O (3.150)
H
80%
O O

CO2Me
Me
CO2Me
EtAlCl2
+ (3.151)
Me 25 °C Me

Me Me
40%

CO2Me
CO2Me
170–190 °C
+ (3.152)
H CO2Me
CO2Me 80%

237

Me OH

Me2AlCl Me
+ MeCHO (3.153)
CH2Cl2, 25 °C
Me Me
65% 238

NHTs
CO2Bu
Me SnCl4 Me
+ CO2Bu (3.154)
NTs CH2Cl2, 0 °C

90%

239 Ts = p-MeC6H4SO2
 O OH
10 mol% (iPrO)2TiCl2
+ OMe OMe (3.155)
H 10 mol% (R)-BINOL
4 Å molecular sieves
O CH2Cl2, –30 °C O

82% 240 97% ee

OH
(R)-BINOL =
OH

O OH
Me 0.5 mol% (iPrO)2TiCl2
+ OMe OMe (3.156)
H 0.5 mol% (R)-BINOL PhSe
PhSe 4 Å molecular sieves
O CH2Cl2, –30 °C O

95% >99% ee

SiMe2t Bu
i, MgBr
O Me OH Me
i, t BuMe SiOTf cat. Ni(0)
2

ii, DIBAL PhSe Me ii, Bu4NF Me

iii, Ph3P=CMe2

57% 73% (–)-ipsdienol

H H
Et2AlCl
(3.157)
or SnCl4
O OH
H H
Me Me
241 242

CO2Et
Me
Me CO2Et Me CO2H
Me
130 °C
OSiMe2t Bu PhMe OSiMe2t Bu (3.158)
N N N CO2H
H
Boc Boc
75%
243 244 245

Me Me Me

90 °C H2O
(3.159)
Mg SiMe3 Mg SiMe3 SiMe3
Cl Cl
77%
246 247

n
C6H13
ZnBr 60 °C
+ n
C6H13 SiMe3 (3.160)
THF
then I2 I SiMe3

83%
248 Z : E 85 : 15
 Me Me Me
H
MgCl
60 °C
THF, Et2O OH
(3.161)
then
H H
Me Me OHC Me Me Me Me H

57%
249 250 ∆9(12)-capnellene

MgCl

H H Me H Me
Me Me Me
60 °C i, CO2
Me THF ii, H3O+ (3.162)
MgCl CO2H
O O
H H H
O O O

85%
251 252

ZnBr
ZnBr
i, s BuLi
THF, –40 °C
• SiMe3 (3.163)
H
ii, ZnBr2, 20 °C H
SiMe3
SiMe3

253 254 255

Me
OZnBr
i, LDA, Et2O
N (3.164)
ii, ZnBr2, 20 °C H OMe N CO2Me
N CO2Me iii, H3O+ H
Ph 60%
Ph Ph

256 257 258

MeO2C CO2Me MeO2C CO2Me CO2Me CO2Me

H CO2Me H CO2Me
7 mol%
[Pd(PPh3)4]
AcOH, 75 °C
AcO LnPd
H H
84%
LnPd
259 260

(3.165)

Cope
rearrangement

(3.166)
Claisen
O rearrangement O
 EtO2C Me EtO2C Me
EtO2C 200 oC, 8 h
EtO2C
(3.167)

90%
261 262

Me Me Me
Ph Ph
6 mol% [PdCl2(PhCN)2]
+ (3.168)
THF, 25 °C, 24 h Ph

263 87% 264 93 : 7 265

n
Bu
n nBu
Bu
15 oC

266 267 268

R O R OSiMe3 O
R

LDA
iPr SiO THF, HMPA iPr
3 3SiO
Me –78 °C Me
iPr
3SiO Me
then Me3SiCl
269 270 74% 271

O
R = (3.170)
O

OH O

220 oC, 3 h
(3.171)
H
90%

272 273

Me Me Me Me
KH Me Me
K O Me
THF, 18-crown-6 OHC
HO Me room temp. Me

68-75% (3.172)
Me Me Me Me
KH Me Me
Me K O
THF, 18-crown-6 OHC
HO room temp. Me
Me
 OMe

Me

MeO H
KH O
HO
Me (3.173)
diglyme, 110 oC

77%
274 275 96 : 4

Me Li Me Me
H

Me Me KH, 25 oC
(3.174)
THF, –78 oC THF, 18-crown-6
Me O Me Me
OH O

Me Me 73% Me Me

N N
(3.175)
R R

CHO O

OH
Me Me
N
(3.176)
CSA, PhH, 80 °C
N
MeHN
Me
84% N
276 277 trans:cis 1:1

OH O H
Me

Me
N N

Me Me
N N

278 279
Ar

O
OH H Ar
Ar O
HCHO(aq) BF3•OEt2
CSA
(3.177)
CH2Cl2, –20 °C
NHBn Na2SO4 N N
H Bn H
81% 97% Bn

280 281

O
Ar =
O
O O

N Ar N Ar
Bn Bn
H H
 Ot Bu

(CH2O)n
Ar (3.178)
N
H MeCN, Na2SO4, 80 °C
O
HO 98% Ot Bu

Ar

282

R1 R1
heat R1
O
(3.179)
O O
R2

R2 R2

R2 = H, alkyl, OR, OSiR3, NR2

CHO
OH O
Me Me Me
OEt 196 °C
Hg(OAc)2
(3.180)
O reflux O O
H H H
Me Me Me Me Me Me
70% 75%
283 284

CO2Me CO2Me
CO2Me Me Me
Me
MeC(OMe)3 Me Me
Me
PhMe, 100 °C Me O O
OH EtCO2H
MeO OMe OMe
285
(3.181)
Me Me
Me Me
CO2Me
HO
OH
73% CO2Me
286
95% E

Me
Me
143–160 oC 160–190 oC Me
O O O Me
Me
Me
287
(3.182)
Me
Me
145–170 oC 145–165 oC
Me Me
O O O
Me
Me
288
 Me Me
O
heat
+ O H
PhCOO EtCO2H O (3.183)
PhCOO
OH EtO OEt
80%
289 290

O
O
R OMe O
O
MeO OMe MeO2C O
MeO2C O
xylene, 160 °C (3.184)
H
R
OH CO2Me
59%

291 292

nBu nBu
(ArO)3Al

CH2Cl2, –78 °C O

Ph 62% E : Z >200 : 1

Ar = Br

Ph

O O

O Me OH Me
10 mol% Ho(fod)3
(3.186)
CHCl3, 60 °C

Me Me
84%
100% chirality transfer; E-isomer only

O O
Ho(fod)3 = holmium
C3F7 CMe3
3

Ph
O
Ph 5 mol% Cu(OTf)2
O Me (3.187)
CH2Cl2, 25 °C CO2iPr

Me
CO2iPr
98%
syn : anti 93:7
 Me
Me Me Me
LDA, THF, -78 °C 65 °C
Me +
O then t BuMe2SiCl O then HCl, THF
Me HO2C Me HO2C Me
O OSiMe2t Bu 79% 87 : 13
(3.188)
°C Me
Me LDA, -78 Me Me
THF / 23% HMPA, 65 °C
+
O then t BuMe2SiCl O then HCl, THF
Me Me HO2C Me HO2C Me
O OSiMe2 t Bu
73% 19 : 81

OLi NH O NR O OLi
Li Li
R
H H
(3.189)
OR' R H OR'
OR' OR'

E-enolate 293 294 Z-enolate

Me Me

Me
Me
CO2H
O
Me Me O Me Me

295 296

O O
R
O O O
2.5 eq. LDA, THF
1.1 eq. ZnCl2, –78 °C
(3.191)
O N
BnO2CN to room temp. BnO2C O BnO2CN CO2H
H Zn H
O
92%
297 298 299

Me Me
Me
300, Et3N –20 °C
Me CO2H
O PhMe-hexane O
Me Me

O OBL*2 65% 80% de, 96% ee

(3.192)
Me Me
Me
300, iPr2NEt –20 °C
CO2H
O CH2Cl2 O
Me Me Me
O OBL*2 75% 98% de, >97% ee
 Ph Ph

O2S N N SO2
B

F3C Br CF3

CF3 F3C

300

O O HO

MeO MeO MeO

190 °C
decalin
Br Br Br
91%
Me Me Me

301 302

Me Ph Me
OMe HN OMe
O PhNHNH2 N HN OMe
+ N
H H
OMe OMe
OMe
303

(3.194)
H

[3,3]-sigmatropic NH2
OMe
rearrangement HN Ar
N N
HN Ar H H
OMe
304

Me Me O
Me
TiCl4•(THF)2 N
+ EtCOCl
N CH2Cl2, iPr2NEt N
23 °C O Me Me O
O 92% syn:anti >99:1
O
(3.195)

CCl3 CCl3

OH HN O HN O
KH, THF xylene
Ph Ph Ph (3.196)
Me then Cl3CCN, Et2O Me reflux Me
0 °C to 23 °C
94% 72%
 OBn O OBn O

O O
H i, NaH, THF H
OBn OBn (3.197)
O then Cl3CCN 74% O
H H
ii, 100 °C
OH 0.1 mm Hg 56% HN

COCCl3

R R' R' R R'

X
X R Y (3.198)
Y Y X

SiMe3 OH
H
BuLi
(3.199)
t BuMe THF, –78 °C t BuMe
2SiO 2SiO
O SiMe3
66%
305 306

Me Me

Me
O
Me BuLi O
Me Me
(3.200)
THF–pentane
O –78 °C HO

88%

307 308

iPr
i i
Pr Me Pr Me
BuLi/KOt Bu
O Me
Me
+
Me
(3.201)
THF
HO HO
–78 °C to 0 °C
Me
87%
309 310 97 : 3 311
¨

RE
H
RZ
O
RE
G = hydrocarbon
G OH
RZ G in exo orientation
(3.202)
G RE
O
RE
G = acyl
G OH
H H in endo orientation
 Me Me Me
Me Me Me
N Me N Me N
LDA
Me O + (3.203)
O THF, –78 °C O O

OH OH
80%
312 313 84 : 16 314

Me Me OR

BuLi
Me (3.204)
THF, –78 °C
O O
Me Me Me
83%
SnBu3 Li
315 316 317, R=H

Br

Me2N Me2N
S Br S Me2N S
Me Me NaH Me

N Me acetone N Me DMF-PhH N Me
(3.205)
O O O
CO2Me CO2Me CO2Me
80% 75%
318 319 320

Me Me S Me Me Me Me
S S
S BuLi

S THF, –78 °C S

Br Br
321 322
(3.206)
Me Me S Me Me
CHO
20 °C S hydrolysis

80%
323 γ-cyclocitral
SPh

Me Me
CH2I2
¨ (3.207)
Me Et2Zn Me
SPh
PhH, 55 °C

78%
324 325

O 2 mol% O O
Cu[CH(COCF3)2]2
´ (3.208)
N2 CH2Cl2
Me O Me O Me O
reflux
68%

326 trans:cis 77:23

 I Me
NMe2 CsF NMe2
+ Ph (3.209)
HMPA, DBU NMe2
SiMe3 room temp.

327 65% 328 84 : 16 329

NMe2

NMe2

Ph O PhS OH
S O (MeO)3P
MeOH, 25 °C Me
(3.210)
Me Me
74%

O SPh
OH OH
i, LDA
i, BuLi THF, –60 °C (MeO)3P
O
O MeOH
ii, PhSCl S ii, MeI S
Me Ph Me
Ph

330 331 332 333

(3.211)

Me Me Me Me
H2O2
Me NMe2 Me NMe2

(3.212)
Me Me Me Me
40 °C Zn, AcOH
Me Me
ultrasound
O OH
NMe2
linalool

Cl
Cl
140–150 °C
conrotatory
Cl
85%
Cl
(3.213)
Cl
Cl
181 °C
conrotatory
Cl
Cl
80%
Cl Cl

HOMO ψ2 Conrotatory Disrotatory

 OCOPh OCOPh
H H
CHO OCOPh
C6H13 TPAP C6H13
NMO C6H13 (3.214)
OH CH2Cl2, 0 °C CHO
75%

334 335 336

O O
Me Me
Me O
H
Me3Si Me3Si Me3Si
decane
H H
174 °C
Me3Si Me3Si Me3Si

95%
337 338 339

(3.215)

Me
Me
pentane
132 °C
Me
Me

340 341 (3.216)

Me
Me Me
hexane
Me +
178 °C
Me Me

342 343 344

OMe OMe OMe

210 °C 5% Pd–C
Me Me Me
decalin
N N N
48%
H Ph H Ph H Ph
345 346

hν I2, air

C6H12
H H 73%

O N O O N O
Me Me
OMe OMe
OMe O hν OMe O
(3.219)
OMe CH2Cl2 OMe
I2

O OMe O OMe
30%
OMe OMe

347 348
 O OH OH O

H3PO4
HCO2H
80 °C 50%

O
Me Me Me Me H O Me Me H OTf
Me3Sn
BF3•OEt2 LiBHs Bu3 SiMe3

PhMe, 100 °C then Tf2NPh [Pd(PPh3)4], CO

Me SiMe3
70% Me 76% Me 86%

(3.221)
O O
Me Me H SiMe3 Me Me H H Me Me H H

BF3•OEt2 i, H2, Pd/C

PhMe, 25 °C ii, Ph3P=CH2
H H
Me 88% Me Me

349

OBF3 OSiEt3 O
O
Me Me Me Me Me Me
Me Me BF3•OEt2 HCl
Et3SiH (3.222)
Ph Ph Ph Ph Ph Ph 98% Ph Ph

350

Problems

Me Me Me
Me

NO2 Bu3SnH
RO RO
1
80 °C PhMe, AIBN

O Me O Me

NaSEt
R = Me

R = H, frondosin B

3. Explain the formation of the cycloadduct 2, used in a synthesis of hybocarpone.

Me
OMe OMe OH
Me CHO Me CO2Me
hν
Me
MeO Me CO2Me MeO

OMe OMe

2
 Problems
O
O
O
Boc
HN N N

N N Boc2O N N 265 °C
MeO 4
N N DMAP N N

SMe SMe SMe

5. Draw the structure of the cycloadduct 5 and explain why the preparation of this compound
is best carried out as a one-pot procedure, rather than by isolation of the diene and separate
heating with the dienophile in toluene.

O
7 mol%
PCy3 Ph O
Cl
Ru
Cl
PCy3 O
5
CH2Cl2 heat
N N

Ac Ac

6. Draw the structure of the major stereoisomer of the cycloadduct 6. (Hint: use the Felkin–
Anh model to explain the stereochemistry.)

Bn OMe
N
ZnI2
+ 6
BnO H MeCN
OBn OSiMe3

7. Draw the structure of the intermediate 7 and explain its formation.

OMe OMe

MeO MeO
O
Et3N Zn
N + Cl Cl 7 N
MeO CF3CH2OH NH4Cl, MeOH MeO
Cl

O O

8. Explain the formation of the isoxazoline 8, formed in the following cycloaddition

reaction.
 Pericyclic reactions

OH
N N O
i, t BuOCl
Me
t BuMe SiO ii, Me t BuMe
2 2SiO

Me Me OH
OH
EtMgBr
CH2Cl2, iPrOH 8

9. Explain the formation of the pyrrolidine 10, prepared by heating a mixture of the
aldehyde 9 and N-methyl-glycine.

Me
O N
H
H
N CO2H heat
H + Me Et3N, DMF H

N N
Ts Ts

9 10

10. Draw a mechanism to explain the transformation given below.

Ot Bu

(CH2O)n
Ar
N
H MeCN, Na2SO4, 80 °C
O
HO Ot Bu

Ar

11. Suggest reagents for the conversion of the alcohol 11 to the ester 12.

OH
OCO2Me OCO2Me
MeO2C

O O O O

11 12

12. Explain the formation of the aldehyde 14 on treatment of the ether 13 with potassium
hydride. (Hint: two consecutive sigmatropic rearrangements are involved.)
 Problems
Ph
KH
O Ph CHO
18-crown-6, THF

13 14

13. Explain the formation of the enone 16, from the triene 15.
OMe O

i, 215 °C
ii, HCl(aq), EtOH
CO2Me CO2Me

15 16
 4
Radical and carbene chemistry

Radicals
R3C R3C R3C R2C
(4.1)
carbanion carbon radical carbocation carbene
(or carbenium ion)

O O

O Ph t1/2 ≈ 1 h at 95 °C
Ph O 2 Ph O 2 Ph + 2 CO2
or hν
O

(4.2)
NC
t1/2 ≈ 1 h at 85 °C
N N 2 CN + N2
or hν
CN

AIBN 1

H
Bu 3SnH + CN Bu 3Sn + CN (4.3)

R X SnBu3 R + XSnBu3
(4.4)
R H SnBu3 R H + SnBu3

Cl Cl H Cl
F3COC F3COC
N Bu3SnH, AIBN N NaOMe N
N N N
PhH, reflux
Br

95% 96%
2 3

BnO BnO BnO

PhSeCN Bu3SnH, AIBN
(4.6)
Bu3P PhMe, 105 °C
OH THF OH OH
HO PhSe >93%
4 5
 S
SnBu3
ROH R S
O R'
R
6 O R'

AIBN SnBu3
Bu3SnH Bu3Sn (4.7)
S

O R'

R–H
Bu3SnH

O O O

Ph O Ph O Ph O

OH O SMe
NaH, CS2 Bu3SnH, AIBN
(4.8)
then MeI S PhMe, 110 °C
O O O
OSiMe2t Bu 87% OSiMe2t Bu 72% OSiMe2t Bu

O O O

N N + N
O R O R O

S S S
R R

9 R R + CO2

O O
N
O
N
Cl O t BuSH
SNa

S PhH, reflux
+ N (4.10)
CO2Me CO2Me CO2Me
S
95% St Bu
10 + CO2

NaBH4
R–HgX R–HgH R R–H

OBn OBn OBn

RO O RO RO
Hg(O2CCF3)2 O NaBH4 O
NMe2
THF
(4.12)
O2
HN room temp. N NMe2 N NMe2
CF3CO2Hg HO
69%
11 12 13

R = SiMe2t Bu
 H X H H X' H
Y –X Y Y X' Y

¨
Cl H R
H R Cl R
N H+ N NaOH N

heat or hν

H H
R' Cl R R' H R R' R' Cl
N hν N NH2R NH2R

i, H2SO4, 140 °C
(4.16)
N ii, NaOH N
Br

14 δ-coneceine

N N (4.17)
Br Me Me
N N

nicotine

Me Me H2SO4
N +
Me (4.18)
95 °C Me N N
H D Cl D
Me Me
43%
15 16 22 : 78 17

H2SO4
N (4.19)
heat Me N
Cl
C4H9
18

Me
Me
Cl N ¨ N Me
Me Me
H H
Me H i, H2SO4, hν Me H
ii, NaOH
(4.20)
H H H H

Me2N 79% Me2N

H H

19

¨
 I2, PhI(OAc)2
(4.21)
N cyclohexane N
H hν, 25 °C
O O
82%

20

PO(OPh)2 (PhO)2OP
HN
N
O I2, PhI(OAc)2 O
MeO MeO (4.22)
CH2Cl2
room temp.
MeO MeO
65%

21

O OH

H NO H N H N H
O hν O OH NO O O
(4.23)
– NO

O OAc O OAc
NO
18
Me Me
HO O
19
Me H Cl–N=O Me H hν
pyridine PhMe
H H H H
21%
O O

22
(4.24)
OH
O OAc HO O OAc
N
HO O

Me H AcOH Me H

NaNO2 (aq)
H H H H

O O

23 24

O OAc O OAc

Me Me
HO HO

H H
22 (4.25)
H H H H

O O
NOH
25
 4.1 Radicals

hν TsCl
pyridine
(4.26)
O OH NH OH
NO 20% N

OH O
26 27 28

H Cl H Cl H O
O hν O OH O
(4.27)

Cl
O O O
hν R
R R + (4.28)
R" R" R"
R'
R' R'

R Cl

R'

Me C8H17 Me C8H17

Me H I2, PhI(OAc)2 H

cyclohexane
H H hν, 40 °C O H

AcO AcO
H 90% H
OH

29 30

O
Ph
N I
OBn OBn O OBn
HO O
O
(4.30)
hν
OBn OBn OBn OBn

64%
31 32

Bu3Sn

I2, PhI(OAc)2 O
O (4.31)
cyclohexane
HO Me O Me
hν, 40 °C
H H
Me O Me O
70%
O O
33 34
 Radical and carbene chemistry

NHCO2t Bu CO2t Bu

O OH N OMe
I2, PhIO
(4.32)
CH2Cl2
MeO OMe room temp. OHC O OMe

OMe OMe
68%

NHCO2t Bu NHCO2t Bu NHCO2t Bu

O O O O O
CHO

MeO OMe MeO OMe MeO OMe

OMe OMe OMe

Z
Z
+ (4.33)

Z k (relative)
H 1
Ph 65
CO2Me 450
CHO 2300

OBn
OBn
O O Me
Me O
O
Me Me Me
O O Me
Me Bu3SnH, AIBN
(4.34)
O O
PhH, heat
I
53% Me

35 36 37

Me Me
O O O O
Me
Bu3SnH
I + (4.35)
Me N O Yb(OTf)3 Me N O
Me
–78 °C
Ph Ph

Ph Ph
90% 25 : 1
 R–I + Bu3Sn R + Bu3SnI

R + Z Z
R (4.36)

Z Z
R + Bu3SnH R + Bu3Sn

I CN
CN 0.2 Bu3SnCl
+ (4.37)
1.3 NaBH4
EtOH, 25 °C

95% 38

R + + Bu3Sn
SnBu3 R SnBu3 R

O O
OBn OBn
AIBN
+ SnBu3
PhMe, 80 °C
+ Bu3SnBr (4.39)
Br
MeO O MeO O
76%
39 40

O OBn O OBn
S
SnBu3

PhO O AIBN, 80 °C
O O
O 80% O

41 42

OH OH OH

CO2Et SnBu3
CO2Et CO2Et Me
Me Me
+
Me O
(4.41)
AIBN
H AlMe2
SePh O
O
Et
43 no additive 98% 63 : 37
Bu3Sn 44
Me3Al 97% 95 : 5

EtO AIBN EtO

Br + CO2Et CO2Et + Bu3SnBr
PhMe, 86 °C
OEt SnBu3 OEt
52%
45

EtO2S Cl
H H H

Cl
O O + O (4.43)
heptane, PhCl
O O O
lauroyl peroxide Cl Cl
H H H
I reflux

Cl Cl
64% 85 : 15

´
lauroyl peroxide =
(C11H23COO)2
 Ph
I Bu3SnH, AIBN
Ph
PhH, reflux
OAc
OAc

46 94% 47

O S O S N

O Me hν Me
Me N +
CH2Cl2
Me (4.45)
O O O
68%
48 49

Hg(OAc)2 HgOAc NaBH(OAc)3 CO2Me

NHCO2Bn N N i, H2, Pd N
CO2Me
CO2Bn CO2Bn ii, LiAlH4

50 64% δ-coniceine

SmI2
O O
SmI2 CO2Et
R O
(4.47)
R R' THF, room temp. R R'
R' O

51

CO (10 atm)
I
AIBN, PhH, 80 °C
O Me
SnBu3
Me
52

C8H17 C8H17
C8H17 SnBu3
O O Me

80 °C
t BuO N N Ot Bu 2 t BuO + N2
(4.49)
t BuO + Bu3SnSnBu3 t BuOSnBu + Bu3Sn
3

H H H
3 equiv. PhSO2N3
O O + O (4.50)
Bu3SnSnBu3
O t BuON=NOt Bu O O
H H H
I PhH, 80 °C N3 N3

53 55% 84 : 16
 4.1 Radicals

Bu3SnH
+ (4.51)
AIBN
Br
0.08 M

+ +

17% 81% 2%

Me
Me Me

54 major minor
(4.52)

+
Me
Me Me

55 major minor

EtO2C

Me Me CO2Et Me CO2Et
O O O
Me Bu3SnH Me Me
+
O AIBN O O
Br

OCOPh OCOPh OCOPh

56 57 91 : 9 58

Me Me
Br
Bu3SnH
(4.54)
AIBN

OH OH
CN CN
70%
59 60
 O O O O
Cl Cl

Me Br Bu3SnH Me

AIBN
PhH, reflux

61

O
(4.55)
O
Cl
O
O Cl Me
Me

75%
H

62

I
Me H Me
Me Me
Bu3SnH
Me Me
AIBN
PhH, reflux
H H H H

63 ~80% hirsutene

OEt OEt

I
O O

0.1–0.2 equiv. Bu3SnCl SiMe3

(4.57)
2 equiv. NaBH3CN
THF, hν, room temp.
t BuMe t BuMe
2SiO 7 equiv. SiMe3 2SiO O

64 65
O
O
O
N
N
I Me3SnSnMe3 N
O
O PhNC
PhH, 70 °C, hν
OH O
OH O
63% camptothecin

(4.58)

O O
N N

N
Ph N O O

OH O OH O
 PhS

Br

N N
Bu3SnH SO2Ph
SO2Ph (4.59)
AIBN
N PhH, reflux N
COPh OBn COPh OBn
95%

66 67

OMe H
N O
SPh
O H
O O
Bu3SnH O
O NMe N
AIBN O Me N (4.60)
PhH, reflux O Me
O
OMe CO2Et
64%
CO2Et
68 gelsemine

O
O

SePh (Me3Si)3SiH
BnO CO2Me (4.61)
BnO CO2Me Et3B, O2
O
O –78 °C

69 92% 70

HO Me
O
2.2 equiv. SmI2 E
Me
(4.62)
THF, HMPA
room temp.
then E+
71 72

E+ = PhSSPh, E = SPh 77%

E+ = Ac2O, E = COMe 74%

I2Sm I2Sm
SmI2 O Me O Me
O
SmI2
Me

SPh

HO
R
CHO R SmI2
Me (4.63)
Me THF, HMPA
Me –78 °C Me
OSiMe2t Bu OSiMe2t Bu
78%
 4.1 Radicals
OMe OMe OMe OMe

Me Me Me Me
Mn(OAc)3
AcOH
(4.64)
O or MeOH O O O
Me Me H H
CO2R CO2R RO2C Me RO2C Me

50–56%
73, R=Et or 8-phenylmenthyl 74

O O O O

Hg(OAc)2 NaBH(OMe)3
AcOH CH2Cl2 H H

HgOAc 58%

OAc OAc OAc

75 76

Br

HO NOBn HO NHOBn
Bu3SnH
(4.66)
AIBN, PhMe
O O O O
75%

77 78

Ph

Ph
N O O
Bu3SnH, AIBN
N (4.67)
then TsOH, MeOH
O
H
45%

O
S
79 83
SMe

Ph
Ph
Ph O O
N O Ph
N N O O
O N

N2 +
PhCH=CHPh
80 81 82
 4.1 Radicals

H H
Cl
Bu3SnH, AIBN O O
(4.68)
N O PhMe, reflux N N
H
Ph 92% Ph
Ph
84 85 86

Cl
Bu3SnH, AIBN
(4.69)
N O PhMe, reflux
N O N O
50%
Ph
Ph Ph
87 88 89

O
O O O
N OMe Bu3SnH, AIBN N
(4.70)
O Br PhH, 80 °C O
OMe
OMe

61%
OMe

lennoxamine

HO
NHOBn
CHO
NOBn
SmI2, HMPA
(4.71)
N THF, t BuOH N

Boc Boc
46% (+7% cis)
90

Me Me
H

Bu3SnH, AIBN
(4.72)
PhH, 80 °C O
O O
Me Me
68%
O Br

91 92
 O O

O
I
Bu3SnH, AIBN
+ C11H23 (4.73)
PhH, 80 °C

93 94 63% 95 22%

Carbenes
R
R R
R R
(4.74)
R

lowest singlet triplet triplet

heat
N2CH–CO2Et CH–CO2Et + N2

base
CHCl3 CCl3 CCl2 + Cl (4.75)

BuLi
R2CBr2 R2CBrLi R2C + LiBr

N
NHSO2Tol NSO2Tol
N N N
base
R R' (4.76)
R R' R R' R R'

O Cu, PhH, reflux O

or Ag(I), THF, 45 °C
N2
97% 96
 O
O (4.77)
CO2Me
[Rh2(OAc)4] CO2Me
N2
CH2Cl2

55%

97 98

O O OH

Me N2 [Rh2(OAc)4] Me Me

CH2Cl2
(4.78)
O O O
OBn NMe3 Cl
OBn 47%

99 100 (8:1 cis:trans) muscarine

O 1 mol%
O
N2 OMe (4.79)
O
O N CO2Me OMe
4
Rh Rh
62% 101 91% ee
[Rh2(5S-MEPY)4]

Ph
N2
1 mol% CO2Me
+
Ph CO2Me
(4.80)
O
N Rh
PhSO2 O
4 Rh 80% 95% ee
[Rh2(S-DOSP)4]

R (4.81)
R

O
O O C8H17 OH
O O O
O N2CHSiMe3 O
BuLi, THF
(4.82)
–78 to 0 °C O

72%

102 malyngolide
 MeO OMe

Cl

KN(SiMe3)2
BnO (4.83)
Et2O
BnO
MeO 85%
OMe
103 104

O
O
cat. [Rh2(OAc)4]
(4.84)
80 °C
C6H13 OH N2 PO(OEt)2 C6H13 O PO(OEt)2

54%

105 106

OH OH
H H O H H
cat. [Rh2(OAc)4]
O (4.85)
80 °C
NH CO2CH2Ar N
O N2 O
100% CO2CH2Ar

107 Ar = C6H4-p-NO2 108

Me Me
Me Me CHBr3, t BuOK

H H Br Br
70%
109 110

CH2N2, CuCl

85%

H H i, CH2I2, Zn–Cu
ii, NaOH, H2O
C8H17 (CH2)7CO2Me C8H17 (CH2)7CO2H
51%
111

CH2I2, Zn–Cu
(4.89)
Et2O
OH OH
 CH2I2, Et2Zn
Ph OH Ph OH
(4.90)
DME, CH2Cl2, –10 °C
Me2NOC CONMe2

O O
B
112 98% 93% ee
Bu

CH2I2, Et2Zn
OH OH
HO CH2Cl2, ent-112, 0 °C HO

89% 97% ee

CH2I2, Et2Zn
OH OH
HO HO (4.91)
CH2Cl2, ent-112
DME, –10 °C

93% O
H O NH
N
N O

O
HO OH
FR-900848

OMe
THF Bu OMe
+ Bu
(CO)5Cr Ph

75%
Ph

113 114 72% de

[Rh2(OAc)4]
Ph +
N2 CO2Et
+ (4.93)
Ph CO2Et Ph CO2Et
93%

115 1.4 : 1 116

0.1 mol% CuOTf

+ CO2Et
N2 0.1 mol% CO2Et

O O
91% 118 99% ee
N N
t t
Bu Bu
117

O
O CO2Me

CO2Me CuSO4

N2
58% H

119 120
 O
O H

N2 0.1 mol%
O O (4.96)

O N CO2Me H
4
Rh Rh
75% 121 95% ee

O O
CuSO4

CO2Me
CO2Me
N2
54% OH

122 123 cycloeudesmol

NNH2 MnO2 N2 CuI

(4.98)
H

124 125 sesquicarene

N2 Cu(acac)2 580 °C
CuSO4
O O (4.99)
CO2Et
EtO2C
61% EtO2C 57%

126

N2 BF3•OEt2
O
O

127 128

N2 O (4.100)

O CF3CO2H

MeO O

129 130
 O O
CH2N2 R'OH
RCOCl N2 RCH=C=O RCH2CO2R' (4.101)
R R CH

NHCO2Bn NHCO2Bn NHCO2Bn

i, EtOCOCl, Et3N PhCO2Ag
Ph Ph Ph CO2Me (4.102)
CO2H ii, CH2N2 N2 Et3N, MeOH

76% O 89%

O MeOH
hν
(4.103)
N2 CO2Me

1 mol% O
[Rh2(OAc)4] PhCHO
Ph N2
20 mol% S Ph Ph
95%
Ph trans:cis >98:2
S

131 132

Na+ 1 mol% O
NTs BnEt3N+Cl– [Rh2(OAc)4]
Ph N Ph N2
MeCN, 40 °C 5 mol% Ph Ph
S

PhCHO 82% 94% ee

Me
Me CO2Me
CuSO4 Bu
Bu +
N2 CO2Me (4.106)
SPh MeO2C SPh
MeO2C E:Z 9:1

O O O

[Rh2(OAc)4]
O
N2 heat O (4.107)
H
CO2Et
65%
OEt EtO

133 134
 Problems of the lesson
1. Suggest reagents and conditions for the decarboxylation of the carboxylic acid 1 to
give 2.
OH OH

MeO2C CO2H MeO2C

N N

Boc Boc

1 2

2. Explain the formation of the alcohol 4 from the epoxide 3.

OBn
H

Bu3SnH
O
OBn AIBN, PhH

OH

3 4

3. Explain (using the benzoyl radical and N-hydroxy-phthalimide) the formation of the
ketone 5.
CO2Et cat. (PhCOO)2 O CO2Et
PhMe, 80 °C
CHO +
CO2Et cat. O CO2Et

N OH 5

4. Draw the structures of the intermediate radicals to explain the formation of the three
ketones 7–9 on treatment of the iodide 6 with a trialkyltin hydride.

H O
Me O Me O Me
O H
Me R3SnH
+ +
Me Me
Me Me
Me Me
I Me
Me
6 7 8 9

5. Suggest a mechanism for the formation of the cyclohexanones 10 that involves a

phenylthio radical catalyst.
O
Ph
O Ph PhSSPh
+ + Ph2C=O
O AIBN, PhCl
CO2t Bu
CO2t Bu

10
6. Draw the structure of the products resulting from Wittig alkenylation of the ketone 11,
and subsequent treatment with sodium hexamethyldisilazide (NaHMDS). Note that the
base NaHMDS promotes the formation of the alkylidene carbene.
Me

O Me Ph3P=CHCl alkene NaHMDS C–H insertion

Me
product product
O 77%
OBn

11

7. Draw the structure of the cyclopropane intermediate and explain the formation of the
cycloheptadiene in the following reaction. Explain the stereochemistry of the product by
drawing an appropriate three dimensional conformation of the transition state.
CO2Me CO2Me

N2 [Rh2(OAc)4] cyclopropane
intermediate
OAc
Me 67%
Me
O O
OAc

8. Explain the formation of the lactam product 13 on treatment of the diazoketone 12 with
silver(I) benzoate.
O
N2 PhCO2Ag
NHTs O N
Et3N
Ts
12 13

9. A synthesis of the pine beetle pheromones exo- and endo-brevicomin makes use of
the following reaction. Draw the structure of the intermediate ylide and explain the
regiochemistry of the cycloaddition reaction (don’t worry about the stereochemistry – a
mixture of the exo and endo isomers is formed).
Me Me
O
N2 Me [Rh2(OAc)4] EtCHO O O
ylide O + O
O Et Et
60%
O O
 5
Functionalization of alkenes

H B
C C + H B C C (5.1)

δ δ
H B
(5.2)
C C

CH3 CH3 CH3

BH3•THF H2O2
(5.3)
THF NaOH
2 BH OH

85%

H3C CH3
B2H6
[(CH3)2CHCH(CH3)]2BH
25 °C
H3C
1

(5.4)
H3C CH3
B2H6
[(CH3)2CHC(CH3)2]BH2
25 °C
H3C CH3
2

H
B

B2H6
≡ HB
25 °C
(5.5)

EtO Cl
CH3CH CHC(CH3)3

6% 94% 2% 98% 19% 81% 40% 60% 58% 42%

 CH3 CH3 CH3 B(C5H11)2
H3C CH3 (C5H11)2BH 1
+
H3C CH3 H3C CH3 (5.7)
B(C5H11)2
4 3 : 97

9-BBN
(5.8)

5 6

H2B
2
B (5.9)

H2B B B CO2Et
2 CO2Et
H
(5.10)

CH3 CH3
Br2BH•SMe2 BBr2•SMe2

(5.11)
CH3 CH3
(C5H11)2BH 1
(C5H11)2B

O
B H
TESO O TESO
8 HO
(5.12)
3 mol% Rh(PPh3)3Cl
OMe OPMB room temp. OMe OPMB
then H2O2, NaOH
 OH OH OH

OH + OH (5.13)

9 8, Rh(PPh3)3Cl 79% 81 : 19
9-BBN 91% 17 : 83

OH

OH
Ph Ph + Ph CH3

BH3•THF 82 18
8, Rh(PPh3)3Cl 90 10
8, [Rh(COD)2]BF4, PPh3 <1 : >99

BH BH2
2

10 11

OH
i, (–)-(Ipc)2BH 10
(5.15)
ii, CH3CHO
O O
iii, H2O2, HO–

92% 12 100% ee

(+)-(Ipc)BH2 11 HCl
O
then H2O2, HO–
O
THF, H2O
(5.16)
OH O
O O
71% 74%
13 70% ee (+)-cryptone

O
B H
O OH
PPh2
8
PPh2 Ph Ph CH3 (5.17)
2 mol% [Rh(COD)2]BF4
2 mol% (R)-BINAP
DME, –78 °C 91% 96% ee
(R)-BINAP
then H2O2, NaOH

O
B H
OH
N O
8
PPh2
1 mol% [Rh(COD)2]BF4
(5.18)
1 mol% 14
PhMe, room temp. 78% 96% ee
14 then H2O2, NaOH
 R2B R

R2B OCOEt + RH (5.19)

O H
O
Et

SMe i, BH3•THF SMe

(5.20)
ii, EtCO2H

78%

H2O2
R3B 3 ROH + B(OH)3
NaOH

R
HOO B 2 HOO
R3B R O R2B–OR B(OR)3 (5.21)
R
OH HO
HO

OH
2 HO
B(OH)3 + 2 RO (RO)2B–OH B
RO OR
RO
RO

B OH

B2H6 H2O2
(5.22)
NaOH

cis-myrtanol

Me Me
H 2B Me Me
2
TrO OTr (5.23)
OH then H2O2, NaOH
TrO OTr OH OH OH

15 75% 16

Hydroboration of 15
is thought to occur
via the conformation Me
with the allylic R
hydrogen atom HO
eclipsing the alkene
H
(compare with OTr Tr = CPh3
reactions of allylic
derivatives in Section
1.1.8)
 Me Me Me

BH OH
NaBH4 2 Oxone
(5.24)
BF3•OEt2 H2O
N N N
THF, 0 °C

Ph Ph 92% Ph

17 18

i, (C5H11)2BH 1 CHO
(5.25)
ii, PCC, CH2Cl2

71%

NH2
i, BH3•THF
(5.26)
ii, NH4OH, NaOCl(aq)

91%

O
B H
O BMe2 NH2
8 NH2OSO3H
Ph Ph CH3 Ph CH3 (5.27)
1 mol% [Rh(COD)(acac)]OTf
1 mol% ent. 14, THF
then MeMgCl, THF 54% 87% ee

OH OH

MeO2C Me (c-C6H11)2BH Me
MeO2C (5.28)
then HCl
N3 N
72% H
19 20

CO H2O2
R3B R3B C O R 2B C R RB CR2 OB CR3 HO CR3
HO
O O
(5.29)

CO H2O2
R3B RB CR2 R R (5.30)
H2O HO
HO OH
O
 H2B B B CO2Et
2 CO2Et
H
(5.31)
THF, 0 °C

i, CO, H2O
50 °C, 70 atm. 84%
ii, H2O2, NaOAc

CO2Et

O
H H
H2 B i, CO, H2O
2 B
50 °C, 70 atm.
(5.32)
ii, HOO –
H H

21

O
B H O
O Cl B(OR)2 CO2H
O
B
8 LiCHCl2 NaClO2
Ph Ph CH3 (5.33)
[Rh(COD)2]BF4 Ph CH3 Ph CH3
(R)-BINAP
then pinacol 97% 93% ee 87% 93% ee

i, 9-BBN
CO2Et (5.34)
ii, BrCH2CO2Et
t BuOK, t BuOH

53%

Ph Ph Ph Ph
iPr Zn
Et2BH 2 i, CuCN•2LiCl
(5.35)
25 °C 25 °C THF, –78 °C
BEt2 ZniPr
ii, Br

46% 98:2 trans : cis

 CO2Me

MeO2C

HN
BocHN BocHN
i, 9-BBN CF3CO2H
(5.36)
Me ii, Me Me
I CO2Me 23 77%
H H overall H
[Pd(dppf)Cl2]
t BuPh2SiO t BuPh2SiO t BuPh2SiO
AsPh3, Cs2CO3
DMF, H2O
22

CHO

B Me CHO
Me 3
Me (5.37)
then H2O
Me Me Me

95%

CHO R3B
s s s OBR2
Bu Bu Bu
Me Me

O
O O O
B H
O B
O
8
(5.38)
CH2Cl2 O2, DMPU
Me2NCOMe, heat CH2Cl2, H2O
room temp. 24

94%

O R

H O
O O O R
+ H (5.39)
O

mCPBA O

OOH

Cl
 Me Me
mCPBA
O
CHCl3
Me Me
80% (5.40)
OMe OMe
O

mCPBA

CH2Cl2

O 75% O

25

CH3(CH2)7 (CH2)7CO2H PhCO3H CH3(CH2)7 (CH2)7CO2H

CH2Cl2
O
26 27
(5.41)

CH3(CH2)7 PhCO3H CH3(CH2)7 (CH2)7CO2H

CH2Cl2
(CH2)7CO2H O

28 29

OCOMe OCOMe OCOMe

mCPBA
O + O
CH2Cl2, 0 °C

90% 40 : 60
(5.42)
OH OH OH

mCPBA
O + O
CH2Cl2, 0 °C

98% 92 : 8

O
mCPBA
BnO BnO (5.43)
CH2Cl2
Me Me
OH OH
92%
30 (+ 4% other diastereomer) 31

[O]

BnO
OH
H
Me
32
 t BuOOH O

OH OH
(5.44)
cat. VO(acac)2
PhH, heat

93% 33

t BuOOH O O
+ (5.45)
OH cat. VO(acac)2 OH OH
PhH, heat

34 90 : 10
but mCPBA 52 : 48

OH O OH
t BuOOH

cat. VO(acac)2
CH2Cl2, room temp.

35 83% 36
(5.46)
OH t BuOOH OH

cat. Mo(CO)6
PhH, heat
O
37 90% 98% cis

O
30% H2O2 (aq)
(5.47)
0.3 mol% MeReO3
2 mol% 3-cyanopyridine
CH2Cl2, 24 °C 38

98%

F3C F3C F3C

OH H2O2 OH
O or (5.48)
OH OOH
F3C F3C F3C

39

O O
Me 39 Me
Me Me
O (5.49)
ClCH2CH2Cl
O O
Na2HPO4, heat

83% 40
Me Me Me
KHSO5 O OSO3H O
O (5.50)
O O
Me Me Me

DMDO

BnO BnO
O O
DMDO
BnO BnO (5.51)
CH2Cl2, 0 °C
O
BnO 99% BnO

41 20:1 α:β

30 mol% CF3COMe O
(5.52)
H2O2, MeCN
K2CO3, 0 °C

89%

O O
KHSO5 42
N X N X (5.53)
MeCN, H2O

42

TfO
N CF3 O
10 mol% 43, KHSO5
Ph Ph
Ph MeCN, H2O Ph (5.54)

43 89%

D-(–)-tartrate
[O]

R2
R1
(5.55)
R3 OH

[O]
L-(+)-tartrate
 t BuOOH,

5 mol% Ti(OiPr)4
O
7.3 mol% (+)-DET OH
4 Å mol. sieves
CH2Cl2, –40 °C
45

OH
77% 93% ee (5.56)

t BuOOH,
44
5 mol% Ti(OiPr)4
O
7.3 mol% (–)-DET OH
4 Å mol. sieves
CH2Cl2, –40 °C
46
70% 92% ee
EtO2C CO2Et
(+)-DET = (+)-diethyl tartrate =
HO OH

t BuOOH
O
5 mol% Ti(OiPr)4
C8H17 OH C8H17 OH
6 mol% (+)-DET
4 Å mol. sieves
CH2Cl2, –10 °C

78% 94% ee (5.57)

t BuOOH

C8H17 5 mol% Ti(OiPr)4 C8H17

OH OH
6 mol% (+)-DET
O
4 Å mol. sieves
CH2Cl2, –12 °C

63% 83% ee

t BuOOH

C5H11 1 equiv. Ti(OiPr)4 C5H11

OH OH (5.58)
1.2 equiv. (–)-DIPT
O
CH2Cl2, –25 °C

47 90% 48 86% ee

DIPT = di-isopropyl tartrate

t BuOOH O O

O OH O OH
+
O OH (5.59)
Ti(OiPr)4
O O O

49 50 51

no ligand 2.3 : 1
(–)-DIPT 90 : 1
(+)-DIPT 1 : 22
 D-(–)-tartrate D-(–)-tartrate
[O] slow [O] fast

R2 R2
R1 R1
R3
R
R3
H (5.60)
OH OH

H R

[O] [O]
L-(+)-tartrate fast L-(+)-tartrate slow

OH OH OH
t BuOOH, O O
Ti(OiPr)4
H H + H (5.61)
C6H11 (+)-DIPT, –20 °C C6H11 C6H11
fast
(S)-52 53 98 : 2

OH OH OH
t BuOOH, O O
Ti(OiPr)4
C6H11 C6H11 + C6H11 (5.62)
H (+)-DIPT, –20 °C H H
slow
(R)-52 62 : 38

0.5 equiv. PhC(Me)2OOH O

1 equiv. Ti(OiPr)4
(5.63)
OH 1.2 equiv. (–)-DIPT OH
OSiPh2t Bu CH2Cl2, –20 °C OSiPh2t Bu

54 45% 55 96% ee

OH OH
H H O
O 1.3 equiv. t BuOOH O
i
1 equiv. Ti(O Pr)4
O O OH Me O O OH Me
H H 1.2 equiv. (+)-DIPT H H
Me O 4 Å mol. sieves, –20 °C Me O

70%
56 57

(5.64)

E
OR O

RO O O
Ti E Ti E
R'
O O O

O O
t Bu

RO
 Ph Me
N N Ph Me NaOCl, CH2Cl2, 4 °C
Mn
t O O t 4 mol% 58
Bu Bu O
Cl
t t
Bu Bu 81%
58 59 92% ee
(5.66)

Ph Me

O
Ph Me
N N 59 (5.67)
Mn
t O O t
Bu Bu O
Mn(IV)salen
t t
Bu Bu

60 61

N O
O
C2F5 C2F5 C2F5 OH
NaOCl, CH2Cl2 2-piperidone
(5.68)
O 0.1 mol% 58, 4 °C, 2 h O
t BuOK O
0.1 mol%

62 87% 94% ee BRL-55834

N
O

0.55 equiv. H2O

N N O THF, 0 °C to room temp. O
Co Cl Cl (5.69)
t t
Bu O O Bu 0.5 mol% 63
OAc
t t
Bu Bu
(±) 41% 99% ee
63

KHSO5 O
Me Me (5.70)
Ph Ph
O
O
O
94% 96% ee
O O
O
64

O
CO2Me KHSO5 CO2Me
(5.71)
64
Me Me

89% 94% ee
 HO
O O O O
HOO O
R R R R R R
(5.72)

O O
O
Ph Ph t BuOOH, Ph Ph (5.73)
THF
5 mol% La(OiPr)3, 66
65 4 Å mol. sieves 99% 96% ee
15 mol% Ph3P=O

KOCl, PhMe
10 mol% 67 96% 93% ee
–40 °C

poly-L-leucine
urea–H2O2 85% >95% ee (opposite enantiomer)
DBU, THF

Br

N
OH
OH OBn
N

(R)-BINOL 66 67

i, mCPBA, CH2Cl2 88%

NH (5.74)
ii, NaN3, MeOH 93%
iii, Ph3P, MeCN 91%
OH OH

68 71

mCPBA Ph3P

N3
NaN3
O

OH

OH OH

69 70
 Ts

PhI=NTs, MeCN, 25 °C N
Ph Ph (5.75)
5 mol% Cu(OTf)2

92% 72

TsNClNa, MeCN, 25 °C
N Ts
10 mol% PhNMe3 Br3

86%
(5.76)
Ts
N
TsNClNa, MeCN, 25 °C
OH OH
10 mol% PhNMe3 Br3

97%

Ts

PhI=NTs, PhH N
CO2t Bu CO2t Bu (5.77)
Ph 5 mol% CuOTf Ph

6 mol% Me Me
73 O O 60% 96% ee

N N
Ph Ph

OH
syn dihydroxylation
CO2H CO2H
HO2C HO2C

OH
(5.78)
OH
HO2C syn dihydroxylation
CO2H
HO2C
CO2H
OH

O
O
O Os OH
OsO4 O OH
R R R (5.79)
¨
osmate ester
 OH
CO2Et 0.2 mol% OsO4 CO2Et
NMO, t BuOH, H2O
room temp. OH
MeO MeO
then Na2SO3(aq)

74 88%

NMO O

N
Me O

OH OH OH

OH OH
cat. OsO4
+ (5.81)
NMO
OH OH

94% 75 12 : 1 76

OBn OBn OH OBn OH

cat. OsO4
BnO BnO + BnO (5.82)
NMO

OH OH

77 78 7.6 : 1 79

OsO4

BnO

H
BnO

80

OH OH OH

OH OH
1 equiv. OsO4
+
TMEDA
CH2Cl2, –78 °C OH OH

98% 75 1 : 9 76

OH
0.2 mol% [K2OsO4•2H2O]
1 mol% (DHQD)2PHAL
[K3Fe(CN)6], K2CO3 OH
MeSO2NH2, t BuOH, H2O, 0 °C
97% ee
(5.84)
¨ OH

CO2Et 0.2 mol% [K2OsO4•2H2O] CO2Et

1 mol% (DHQ)2PHAL
[K3Fe(CN)6], K2CO3 OH
MeSO2NH2, t BuOH, H2O, 0 °C
96% ee
 N N N N
N N
N O O O O N

OMe MeO
MeO OMe
N N N N

(DHQ)2PHAL 81 (DHQD)2PHAL 82

OsO4

RS RM

RL H

OsO4
DHQ ligand

OH
OsO4, [K3Fe(CN)6]
OH OH (5.86)
7 (DHQD)2PHAL 7

MeSO2NH2, t BuOH, H2O OH

83 71% 84 94% ee

N O OH N O OH N O

AcO AcO + AcO (5.87)

OAc OAc OH OAc OH

85 86 87

10 mol% OsO4, 3 equiv. NMO, THF, H2O 83% 76 : 24

8 mol% [K2OsO4•2H2O], 3 equiv. [K3Fe(CN)6]

82% 98 : 2
(DHQD)2PHAL, MeSO2NH2, t BuOH, H2O
8 mol% [K2OsO4•2H2O], 3 equiv. [K3Fe(CN)6]
85% 5 : 95
(DHQ)2PHAL, MeSO2NH2, t BuOH, H2O
 OH

Ph OsO4, [K3Fe(CN)6] Ph
Ph Ph (5.88)
Ligand 88
OH

91% 99% ee

O
O O
MeO n
O
O DHQD
O
N
N
N
N
O
O DHQD
MeO O
O O
m
O
88

R R

OH
Pseudomonas putida
(5.89)
OH

OH
Br Br
HO OH
OH O H
i, Me2C(OMe)2, TsOH
O
OH
(5.90)
ii, PhI=NTs, Cu(acac)2 H
OH O
TsN NH
O

90 91 OH O pancratistatin

OH
KMnO4, H2O, NaOH
BnMe3N+ Cl–, 0 °C
OH

50% 92
¨

OCOPh
I2, AgOCOPh
CCl4
OCOPh

(5.92)
OAc
I2, AgOAc
AcOH, H2O
OH
 O R
RCOO
Ag+
I I Ag+ I
O
OCOR I

O O O
R R R
O O O

93

O OCOR
anhydrous conditions
R (5.93)
O OCOR
RCOO

93

O O OCOR
H2O R
R
OH
O O OH

93

Amino-hydroxylation
1 mol% OsO4 OH
TsNClNa•3H2O

BnNMe3+ Cl–, 60 °C
NHTs
CHCl3, H2O

74%

Ts = SO2C6H4-p-Me O NTs
Os
O
O

NHCO2Bn OH
3 equiv. BnO2CNCl Na
OH NHCO2Bn
4 mol% [K2OsO4•2H2O]
+
5 mol% (DHQ)2PHAL
BnO nPrOH, H O, 20 °C BnO BnO
2

95 90% 96 4 : 1 97

94% ee

(5.95)

MeCONHBr, LiOH NHCOMe NH2•HCl

CO2iPr 1.5 mol% [K2OsO4•2H2O] CO2iPr HCl, H2O CO2H
Ph Ph 100 °C Ph
1 mol% (DHQ)2PHAL
t BuOH, H2O, 4 °C OH OH

71% 98 99% ee 96%

 Oxidative cleavage

O O R'
R' O3 R' H2O2
R RCO2H + O
R O R"
R" R"

ozonide
(5.97)
O O R'
R' O3 R' Me2S
R RCHO + O
R O R"
R" R"

OSiPh2t Bu OSiPh2t Bu
O3, CH2Cl2 CHO
then Me2S

O O
R R O O
O O O O
O3 R R
+ (5.99)
R R R R R R R R R O R
R R
99 100

O O
R R OH
MeO O
R R
O O R R

101 102

O O Me Me O O
Me Me
O3 O3 Me H
Me Me C5H12 C5H12
(5.100)
O O Me Me Me O H
H2C=O

O3, MeOH CO2H

then H2O2 CO2Hv

85%

O3, –78 °C OMe

CH2Cl2, MeOH OOH NaHCO3 CHO
(5.102)
then TsOH OMe then Me2S CH(OMe)2
room temp. OMe
93%
 OMe
O3, MeOH CO2Me

Me2S, –78 °C
Me Me OH
then NaBH4

103 >52% 104

CO2H
O
Me Me

O3, AcOH
H H (5.104)
then H2O2
H H
Me Me Me Me

105 90% 106

H O
O OH
R R'
R O R O O
R' O3 O
O + + (5.105)
H2O O O HO R'

R R R R
R R O
OsO4 IO4
2 + IO3
R H2O
R HO OH R R

O O
cat. OsO4 CHO
NaIO4
(5.107)
N N
Cl OSiMe2t Bu THF, H2O
Cl OSiMe2t Bu

107 70% 108

Me Me Me
OHC
cat. OsO4 NaOH(aq)

Me OAc NaIO4 Me OAc MeOH OH

dioxane, H2O
H H H
O Me Me O Me Me O Me Me

109 75% 110 90% 111

(5.108)

Boc Me Boc Me
N N
cat. RuCl3, NaIO4
Ph Ph (5.109)
CCl4, MeCN, H2O CO2H

OCH2OMe OCH2OMe
80%
 cat. RuCl3, Oxone®
MeO2C MeO2C
NaHCO3 CHO
MeCN, H2O

94%

(5.110)

5.5 Palladium-catalysed oxidation of alkenes

H2C CH2 + PdCl2 + H2O CH3CHO + Pd + 2 HCl

Pd + 2 CuCl2 PdCl2 + 2 CuCl (5.111)

2 CuCl + 0.5 O2 + 2 HCl 2 CuCl2 + H2O

R O R
H2O Pd2+Cl–2 + Pd + 2 HCl
Me

R
HO R HO R HO Pd+Ln
Pd+Ln
Pd+Ln H H

112

O
cat. PdCl2
OAc Me OAc (5.113)
O2, CuCl
DMF, H2O

113 90%

Me

H H
t BuPh t BuPh SiO
2SiO 2 O
cat. PdCl2
O O (5.114)
O2, CuCl
DMF, H2O
H H
CN CN

114 86%
 Me Me Me

O O
cat. PdCl2 Me KOH
O
O2, CuCl MeOH
O
DMF, H2O heat
H
Me Me Me
115 80% 116 82% 117

75% LiN(SiMe3)2
then Br

Me
Me
O H
Me
Me
Me

Me H

pentalenene

O
cat. PdCl2
Me OBn Me OBn
O2, CuCl
DMF, H2O, 50 °C

67% 119

Problems
1. Explain the regio- and stereoselectivity in the formation of the organoborane 2 from the
alkene 1.

BH
BH3•SMe2 2

1 2

2. Explain the formation of the pyrrolidine 3, R H, used in a synthesis of the unnatural

enantiomer of nicotine 3, R Me.

(c-C6H11)2BH
N3 then MeOH N
R
N N
3, R=H

3. Draw the structures of the intermediates in the carbonylation of cyclohexene to give the
aldehyde 4.
 Functionalization of alkenes

CHO
i, 9-BBN-H
ii, CO, K+(iPrO)3BH–
iii, H2O2, NaOH
4

4. Suggest reagents for the asymmetric epoxidation of the allylic alcohol 5 to give the
epoxide 6.
O
OH OH
BnO BnO

5 6

5. Explain the selective formation of the epoxide 8 from 1,4-pentadien-3-ol 7.

OH OH
t BuOOH, Ti(OiPr)4

(+)-DIPT O

7 8

6. Suggest reagents and conditions for the asymmetric synthesis of the epoxide 9, used in
a synthesis of the HIV protease inhibitor indinavir.
O

7. Suggest reagents and conditions for the synthesis of the two diastereomeric diols syn
and anti 10.
OH

OH
syn-10

OH

OH
anti-10

8. Suggest reagents and conditions for the formation of the exo-cis-diol and reagents and
conditions for the formation of the endo-cis-diol product by oxidation of the alkene 11.
 Problems

OH

OH OR
OH
11 exo endo OH

9. Suggest reagents, including an appropriate chiral ligand, and conditions for the forma-
tion of the chiral 1,2-amido-alcohol 12, used in a synthesis of the antibiotic vancomycin.
OH

CO2Et CO2Et

NHCO2Bn
BnO BnO
12 87% ee

10. Unexpected products sometimes arise on ozonolysis of alkenes bearing allylic het-
eroatoms. Draw the structure of the ozonide from the reaction of the allylic alcohol 13
with ozone and suggest an explanation for the formation of the product 14, used in a
synthesis of grandisol.
Me Me
Me
O3 CO2H
O
Me EtOAc
H OH H
Me Me

13 14

11. Suggest reagents for the conversion of the alkene 15 to the ester 16.

CO2Me

N O N O

Ph Ph

15 16

12. Draw the structures of the compounds 17 and 18, and suggest reagents for the conversion
of 17 to 18 and for 18 to the cyclopentenone 19.

17 18 O

19
 6
Oxidation

OCOCF3
CF3CO2H, CH2Cl2
30% AcOOH, 1 mol% RuCl3 77%
or 30% aq. H2O2 80%
1

adamantane

HO

Sphingomonas sp. HXN-200

O O
N N

Ph 68% Ph

>99% ee

6.1.2 Aromatic hydrocarbons

In the absence of activating hydroxy or amino substituents, benzene rings are
attacked only slowly by oxidizing agents such as chromic acid or permanganate,

CH3 CO2H C8H17 CO2H

Na2Cr2O7 CrO3, AcOH

(6.3)
aq. H2SO4 aq. H2SO4

NO2 86% NO2 50%

CH3 CHO CH3 CHO

CrO3, Ac2O CrO2Cl2, CCl4

(6.4)
aq. H2SO4 then H2O

CH3 52% CHO Br 80% Br

 O
O
IBX t BuOOH, PhH
Ph Ph (6.5)
DMSO, 80 °C 1 mol% RuCl2(PPh3)3

72% Cl 73% Cl

IBX HO O
I
O

Me Me
Me Me
O

(KSO3)2NO CAN
Me Me
acetone, H2O H THF, H2O H
Me Me
OMe O
OH OH 81% OH O 40%

juglone
avarone
MeO O

(6.6)

OH CHO O CHO O OH
MeO MeO N
(KSO3)2NO
(6.7)
N CO2Et acetone, H2O N CO2Et N
Me O Me O Me OH
73%
2 3 EO9

OMe MeO OMe OH O

H H
N O N O
PhI(OAc)2 PhI(OCOCF3)2
(6.8)
O MeOH O MeCN, pyridine

64% 59% O
OMe O

4 5 6 OH 7

HO O OMe

OAc
I Me
H N
OAc
CONHMe CONHMe
O
CF3CH2OH
O O
O
(6.9)
H
N CH2Cl2 N N
O COCF3 O COCF3 O
82%
O
C6H4-p-OH
8 9 plicamine
 Alkenes

OH OH OH

Se H Se Se
O ene O OH – H2O O
OH R
R
H R reaction

(6.10)
OH
Se
[2,3]-sigmatropic HO R
O R
rearrangement

10 mol% SeO2 HO
OAc t BuOOH OAc (6.11)
CH2Cl2, 25 °C

50% (+ 5% aldehyde) 10

OAc O OAc O
3 equiv. pyH+CrO3Cl–
(6.12)
Ph py, CH2Cl2, reflux Ph

OAc OAc OAc OAc

68%
11

OAc OCOC6H4-p-NO2

t BuOOH p-O2NC6H4CO3t Bu
(6.13)
CuCl, AcOH CuPF6, MeCN
13, –20 °C

88% 12 44% 96% ee

13 Me Me
O O

N N
Ph Ph
NHSES
SES
N S
H N S N H
SES
O O
SES
O O
N PhMe N
H H
Boc Boc

14 15 (6.14)
Br Me
H H OH
O O H N
NaBH4
O O N O
N N N
H
S N
H
Boc >90% HN
H
Boc NH H H

SESN H SES SES O

16 17 agelastatin A

SES = SO2CH2CH2SiMe3
 PhSeOH

CH2Cl2 Se
Ph

OH H H OH OH
t BuOOH

SePh Se
O Ph 88%

PhSeOH
OMe OMe (6.16)
then t BuOOH HO

87% 18

Me Me Me Me

OH H2CrO4 O

acetone

Me 84% Me

O
H2CrO4 O slow
OH Cr
OH O (6.18)
H
O

O excess CrO3•py2 O
MeO2C
OH
MeO2C CHO
(6.19)
CH2Cl2, 23 °C

19 96% 20

Me Me

HO HO Me Me O O Me Me
Me 3 equiv. O O
Me
MeCHO CrO3•py2
Me Me Me
(6.20)
H+
OH OH O
21 22 88% 23

OH O
1.5 equiv. pyH+CrO 3Cl
–
t BuMe
2SiO Me t BuMe
2SiO Me (6.21)
CH2Cl2
Me Me

80%

t BuOCO t BuOCO

O 1.4 equiv. (pyH+)Cr2O72– O

HO OEt O OEt (6.22)
CH2Cl2

84%
 Oxidation via alkoxysulfonium salts

Me H Me Me H Me
O
Me +
2.1 equiv. pyH CrO3Cl – Me
(6.23)
CH2Cl2, Al2O3
H OH H
64%
24 25

O O
Me Me
HN HN

HO O N O N
dicyclohexylcarbodiimide OHC
O O (6.24)
DMSO, H3PO4, 25 °C

OCOMe 90% OCOMe

26

Me Me Me Me
DMSO, (COCl)2 CHO
Me OH Me (6.25)
CH2Cl2, –50 °C
then Et3N

95%

Me Me Me Me

O O O O

Me DMSO, (COCl)2 Me CHO

OH (6.26)
CH2Cl2, –78 °C
Me then Et3N Me

98%

NHBoc NHBoc
DMSO, (COCl)2
Ph OH Ph
CHO
(6.27)
CH2Cl2, –63 °C
then Et3N

95–100%

O O
H3C H3C H3C
CH2Cl2, –60 °C –CO2, –CO
S O + (COCl)2 S O Cl Cl S Cl Cl
H3C H3C H 3C
27 28
(6.28)
H3C H3C R
RCH(OH)R' S O Cl base S O Cl Me2S + O
–HCl R R
H3C H2C
R' R' R'
H H

29 30
 Me Me OH Me Me OH
Me2S, NCS
t BuMe SiO
t BuMe
2SiO OH 2 (6.29)
CH2Cl2, –20 °C CHO
then Et3N

NCS O 31 95% 32

N Cl

OSiEt3 OSiEt3

MnO2 OHC
HO I I (6.30)
CH2Cl2
Me Me Me Me Me Me Me Me

90%
33 34

H H
O O
MeO MnO2 MeO
(6.31)
OH acetone OH

CHO
97%
OH

35 36

Boc Boc
N N
10 equiv. MnO2 (6.32)
O O CO2Me
Ph3P=CHCO2Me
OH
CHCl3, reflux

37 70% 38

HO O

Ag2CO3 on celite
CO2Me PhH, reflux CO2Me

OSiMe2t Bu OSiMe2t Bu

39 86% 40

O
H
O O
OH Ag2CO3 on celite
O (6.34)
OH PhH, reflux
O O
H
65%

OH O
Ag2CO3 on celite
OH OH (6.35)
PhH, reflux

80%
 OBn OBn
Me Me

t BuPh t BuPh
2SiO 2SiO
cat. TPAP, NMO

MeCN, 25 °C OHC
(6.36)
O O
HO
O Me 95% O Me
NMO O Me Me
41 42
N
Me O

NMe3RuO4 CHO
OH
CH2Cl2, room temp.
Cl N Cl N
95%

5 mol% Pd(II)-hydrotalcite CHO

OH
10 1 atm. air, 65 °C 10
PhMe, pyridine

91%
(6.38)
5 mol% Pd(II)-hydrotalcite

1 atm. O2, 80 °C
PhMe, pyridine CHO
OH
89%

OH O OH

5 mol% Pd(norbornadiene)Cl2

1 atm. O2, PhMe, 80 °C

+ (6.39)
20 mol% (–)-sparteine

43 55% conversion 44 44% 43 99% ee

H
N

N
H
norbornadiene (–)-sparteine

O AcO OAc
OH
I I I OAc
KBrO3 Ac2O
O O (6.40)
H2SO4 TsOH
CO2H
O O

IBX 45 46
 O O
O O
1.3 equiv. 46
(6.41)
OH CH2Cl2, 0 °C
MeO MeO CHO

47 70%

C5H11 C5H11

HN HN
1.5 equiv. 46
(6.42)
CH2Cl2, room temp.
C4H9 C4H9

OH O
87%
48 49

OH
CHO

1.1 equiv. IBX

DMSO, room temp.
N N
H H
98% 50

Me N Me Me N Me
Me Me Me Me
O O

TEMPO, 51 52

t BuCOO OH t BuCOO OH

Me OH 1 mol% TEMPO Me
CHO (6.44)
CH2Cl2, –5 °C
N OH NaOCl N OH
Ph2C Ph2C

53 96% 54

OiPr
R R R
Al(OiPr)3
R H Al
OH O O + OiPr (6.45)
OiPr O
R H Al R Me
Me Me
OiPr
O
Me
 COMe COMe
Me Me

Me Al(OiPr)3 Me
(6.46)
cyclohexanone
PhMe, heat
HO O
83%

(COCl)2 NaClO2
R OH
R CHO R CO2H (6.47)
DMSO H2O2, MeCN
then Et3N H2O, NaH2PO4

Br Br

CO2H
OH 7 mol% TEMPO
(6.48)
Me MeCN, 35 °C Me
2 equiv. NaClO2
2 mol% NaOCl
OMe OMe
92% 55

Br Me Br Me
RuCl3•H2O
Me NaIO4 Me O
t BuMe SiO O t BuMe O
2 CCl4, MeCN 2SiO
pH 7 buffer

56 70% 57

O i, LDA, O O O
THF, –78 °C NaIO4 15–25 °C
Ph ii, PhSeBr Ph MeOH, H2 O H Ph Ph (6.50)
SePh Se 89%
O Ph

i, LDA,
CO2Me THF, –78 °C CO2Me
(6.51)
ii, PhSeBr
iii, NaIO4

80%

O O O
i, Me2CuLi H2O2
Ph ii, PhSeBr Ph Ph (6.52)
SePh 85%

¨
 O O
HIO3
Ph DMSO, 50 °C Ph

88%
(6.53)

O O
i, LDA,
Ph THF, –70 °C HO Ph
(6.54)
ii, MoOPH
–70 to 0 °C
iii, H2O

70%

O O
i, LDA,
OH
THF, –78 °C
ii, O
(6.55)
N
H Ph SO2Ph H
59
For reaction of oxaziridines
58 72% 60 or oxaziridinium salts with
alkenes, see Section 5.2

OSiMe2t Bu O

Me AD-mix-β Me
(6.56)
MeSO2NH2
OH
MeO
t BuOH, H2O, 0 °C MeO
then Na2SO3

94% 99% ee

I
O
O O
CO2H (6.57)
KOH, MeOH
then H3O+ OH

81%
H3O+

O MeO MeO OMe

O
MeO MeO

I OH
HO Ar

10 mol%
NHPh
CO2H O OH
N NaBH4
Ph H
CHO
Ph Ph OH (6.58)
PhN=O, CHCl3 CHO then H2, Pd/C

95% 97% ee 98% ee

 O O
PhCO3H hydrolysis
PhOH
Ph Me CHCl3 PhO Me
O (6.59)
O
OH

Me mCPBA O LiAlH4
HO Me
CHCl3 Et2O
Me

O R"
O O
R"CO3H, H+ H O O
R R' R OR'
+ R"CO2H (6.60)
R R'

PhCO3H
Ph Ph O
CHCl3
O

O MeCO3H O
AcOH
O
61 100%
(6.61)

MeCO3H
AcOH O
O
O
62 94%

O
MeO MeO
CO2H
mCPBA NaOH
CH2Cl2, 0 °C
(6.62)
OMe
O O CHO
O HO AcO
63 >95% 64

O O

mCPBA
CH2Cl2 O

65 89%
(6.63)
O O

Me3SiOOSiMe3 O
BF3, CH2Cl2

65 44%
66
 O O
cyclohexanone
monooxygenase O
(6.64)

Me Me
80% >98% ee

OH
OH O O O OH

CHO OCHO OH
H2O2, NaOH O

~100%

(6.65)

Problems
1. Suggest a method for the preparation of naphthaquinone.
O

naphthaquinone
O

2. Draw the structures of the intermediates in the following allylic amination reactions and
hence explain the difference in the outcome of these two reactions.

(i) Ts
N S N NHTs
Ts

CH2Cl2
then (MeO)3P

(ii) CO2Et
N N NHCO2Et
EtO2C

SnCl4, CH2Cl2
then Li, NH3(I)

¨
 3. Suggest a two-step method for the conversion of the diol 1 to the
,-unsaturated ketone
2.
OH

OH O

H H

1 2

4. Explain the formation of the products 4 and 5, formed from the alcohol 3 in the presence
or absence of a base.

OH
DMSO CHO
(COCl)2, –60 °C
then Et3N
3 4

DMSO
(COCl)2, –60 °C
then 0 °C

Cl

5. Suggest a reagent for the selective oxidation of the diol 6 to the ketol 7.

OH O

MeO MeO
OH OH

MeO MeO

6 7

6. Draw the structure of the product 9 from oxidation of the diol 8 with silver carbonate on
celite.

OH Ag2CO3 on celite
9
HO
PhH, reflux
8
 7. Suggest reagents for the conversion of the alcohol 10 to the carboxylic acid 11.

OH
Ph Ph CO2H

10 11

8. Suggest reagents for the conversion of undecanal [CH3 (CH2 )9 CHO] to undecenal.

9. Draw the structures of the products 12 and 13 from oxidation of the following ketones:
O O

Ph PhCO3H Ph MeCO3H
12 13
OMe NO2

10. Suggest reagents for the formation of the phenol 15 from the aldehyde 14.
CHO OH

Cl Cl

OH OH
14 15
 7
Reduction
O O
H H H
Ph O N N H2, 10% Pd/C H2N N
N N (7.1)
H MeOH H
O
OMe OMe
100%

CO2Me CO2Me

1 atm. H2, PtO2

CO2Me CO2Me (7.2)
N MeOH N

Ph H Ph H
87%
Me Me
1 2 dr 95:5

H2, CuCr2O4 H2, Raney Ni

PhCH2OH PhCO2Et CO2Et (7.3)
160 °C, 250 atm. 50 °C, 100 atm.

Table 7.1. Approximate order of reactivity of functional groups

in catalytic hydrogenation

Functional group Reduction product

R COCl R CHO, R CH2 OH
R NO2 R NH2
H H
R C C R C C , RCH2CH2R
R R
R CHO R CH2 OH
R CH CH R RCH2 CH2 R
R CO R R CH(OH) R, R CH2 R
C6 H5 CH2 OR C6 H5 CH3 + ROH
R C N R CH2 NH2
Polycyclic aromatic hydrocarbons Partially reduced products
R CO2 R R CH2 OH + R OH
R CONHR R CH2 NHR

R CO−
2 Na
+
inert
 OAc OAc
H H

O OAc H2, 10% Pd/C O OAc

(7.4)
EtOH
H
H

MeO2C 74% MeO2C

Ph N 5 atm. H2, 5% Pd/C(en) Ph N

N THF N
Cbz Cbz

4 93% (7.5)

en = H N NH2
2

O OH O OH
H2, 5% Rh–Al2O3
(7.6)
EtOH
O O

5 6

Me

(7.7)

Me Me

7 8

O O

H2, Pd/C
Ph Ph (7.8)
MeOH

9 90% 10
 Me
H H
Ph 1 atm. H2, Pd
Ph
Ph Me
Me Me Ph

11 98% (±)-12 (7.9)

Ph
H H
Ph 1 atm. H2, Pd
Me
Ph Ph
Me Me Me

13 98% meso-14

Me Me Me Me
CO2H
CO2H H2, PtO2
CH3CO2H

15 90% 16
(7.10)

Me Me OH Me
O
H2, PtO2
Me Me + Me OH
CH3CO2H
Me Me Me

17 83% 17%

O H O H O
H2, Pd
O O + O
MeOCH2CH2OH
MeO R MeO R MeO R
cis + trans
18 R = CH2OH 95 : 5
R = CO2Me 15 : 85

(7.11)
H H
H2, Pd/C
+ (7.12)
CH3CO2H

H H

19 21% 79%

Me Me Me
+ (7.13)
Me Me Me

20 H2, Pd 16% 46%

CH3CO2H

H2, PtO2 82% 18%

CH3CO2H
 H
H H H H H H H
H

catalyst surface 21 23

(7.14)
H
H H H H

H H
22
H
24
H
25

OH
OH
OH
H2, Pt
(7.15)

CH3(CH2)7 (CH2)7CO2H
H2
CH3(CH2)7 C C (CH2)7CO2H C C
Lindlar catalyst
H H
26 27

OH O

Me i, 55 atm. H2, EtOH Me

5% Rh–Al2O3, AcOH
(7.17)
ii, CrO3, H2SO4
acetone, H2O
Me Me
71%
(+10–15% trans) 28

OH OH
H2, Rh–Al2O3
CO2H CO2H

29
(7.18)

OH
H2, Pd/C
CO2H CO2H
 H2, Pd/C
NO2 NH2 (7.19)
Ph EtOH, H2SO4, 25 °C Ph

R R
H2 H2
R C N C NH C NH2
cat. cat. H
H H
(7.20)
R H2 N R R R
H2
C NH N NH
– NH3 cat.
H R R

H2, PtO2
(7.21)
N CN EtOH NH CN N

OH OH
H2, [(Ph3P)3RhCl]
(7.22)
PhH

30 80% 31

O O
H2, [(Ph3P)3RhCl]
(7.23)
PhH

32 33

NO2 H2, [(Ph3P)3RhCl] NO2

Ph Ph (7.24)
PhH

CO2Bn H2, [(Ph3P)3RhCl] CO2Bn

Ph Ph
(7.25)
SPh H2, [(Ph3P)3RhCl] SPh

93%

H
PPh3 H H
H2 H
Ph3P H Ph3P PPh3
[(Ph3P)3RhCl] Rh Rh Ph3P
Cl H Cl H Rh
PPh3 Ph3P – RhLn
Cl H

(7.26)
 Me Me

H2, [Ir(COD)py(PCy3)]PF4
(7.27)
OH OH
H

34 35
OH OH
Me Me

H2, [Ir(COD)py(PCy3)]PF4

O O
H
36 37
(7.28)
OH OH
Me Me

H2, [Ir(COD)py(PCy3)]PF4

O O
H
38 39

Ph
P OMe P
PPh2 PPh2 O
O PPh2
P NMe2
P
PPh2 P PPh2 O
Ph PPh2 O
OMe

(S)-BINAP 40 41 42 43 44 (S)-MonoPhos 45

CO2H H2, [Rh(NBD)]+ClO4– CO2H

Ph Ph (7.29)
(S,S)-42, THF
NHCOPh NHCOPh

99% ee
NBD = norbornadiene

CO2H 135 atm. H2, MeOH CO2H

(7.30)
0.5 mol% [Ru(OAc)2], (S)-40
MeO MeO

92% 46 97% ee

O OH
0.5 mol% [Ru(cymene)Cl2]2

0.5 mol% (S,S)-48

iPrOH, KOH, 28 °C
Me3Si Me3Si
47 99% 49 98% ee
(7.31)

O OH
0.25 mol% [Ru(cymene)Cl2]2
NHBoc NHBoc
Ph 0.5 mol% (R,R)-48 Ph
HCO2H, Et3N

(S,S)-48 Ph NHTs 50 86% 51 99% ee

Ph

NH2
 O O Ph Ph
Na, NH3 (l) Ph Ph
(7.32)
Ph Ph Ph Ph
O O
52

EtOH

OH Ph Ph
Ph Ph

Ph Ph
HO OH

53

Na

OH OH

Ph Ph Ph Ph

54

Reduction

Table 7.2. Ratio 55:56 by reduction of

2-methylcyclohexanone

Reagent Ratio 55:56

Na–alcohol 99 : 1
LiAlH4 82 : 18
NaBH4 69 : 31
Al(Oi-Pr)3 42 : 58
catalyst + H2 ∼30 : 70

O OH OH

+
(7.33)
Me Me Me

55 56

O
Na O R'OH OH
R R R

Na (7.34)

R'OH
OH OH
R R
 TiCl3•(DME)2
(7.35)
CHO Zn–Cu, DME
CHO
OH
OH

57 46% 58

O
CO2Et Na
(7.36)
CO2Et xylene, heat
then H3O+ OH

59 63% 60

OH
CO2Me
Na, NH3 (l) O
CO2Me (7.37)
Et2O

MeO MeO
61 91% 62

O
Zn, HCl
(7.38)
Ph 14
Ph 14

88%

AcOZn
O O O
Zn
OCOMe
Zn AcOH
(7.39)

NH3 (l)
M M (NH3) e (NH3)

Na, NH3 (l)

 Li, NH3 (l), Et2O
O then NH4Cl O
H

57 92% 58
(7.42)

Li, NH3 (l)

O EtOH HO
H

57 80% 59

Li NH3
O HO
(or 1 equiv.
t BuOH)

O
57 60 61 (7.43)

Li
HO O O
H H

62 63 58

H H H

Na, NH3 (l)

+ (7.44)
O O O
H H

64 99% 65 1%

3D conformation of 65 H

O
H

Li, NH3 EtOH Li, NH3 EtOH

(7.45)

OMe OMe O O

Li, NH3 mild H+ H3O+

EtOH
(7.46)
 O O
CO2H CO2 CO2H

Na, NH3 H3O+

(7.47)
EtOH
90%

OMe OMe O OMe O O

C7H15 C7H15
CO2H CO2 CO2H C7H15
Na O C7H15Br HCl(aq)
NH3

66 67 68

(7.48)
OH OH

Li, NH3
EtOH

98%

OMe OMe
O O

i, K, NH3, t BuOH
N N
ii, EtI
OMe OMe

69 100% 70 dr >100:1

OMe OMe

i, Na, NH3
N N
O ii, MeI O
O O
OMe OMe

71 87% 72 dr 30:1

OH CO2H OH
Na, NH3
CO2H (7.52)
THF, –33 °C

80%

2e 2 H+
A B A + + B AH + BH (7.53)
 O O
H H
O N O N
N CO2H N CO2H
H H
O S Na, NH3 SH
(7.54)
Ph O N CO2H Ph H2N CO2H
H
71 72

O O O O O O

i, Li, NH3 Li, EtNH2

t BuOH
(7.55)
O ii, (EtO)2POCl O
H H
P
EtO O
EtO
73 74 90% 75

Al(OiPr)2 Al(OiPr)2
OH
O O O H3O+
O
R
R H R

O OH

Br i Br
Al(O Pr)3
iPrOH

85% 76

O
O AlH3
O
O
H H 2 AlH2
Al
H H O
(7.58)
O

OH
H3O+
O O
4 Al 3 AlH
 Reduction

Table 7.3. Common functional groups reduced by

lithium aluminium hydride

Functional group Reduction product

RCHO RCH2 OH
R2 C O RCH(OH)R
RCO2 R RCH2 OH + R OH
RCO2 H RCH2 OH
RCONHR RCH2 NHR
RCONR 2 RCH2 NR 2 or RCH(OH)NR 2 (→ RCHO +
R 2 NH)
RC N RCH2 NH2 or RCH NH (→ RCHO)
RCH NOH RCH2 NH2
RNO2 RNH2
ArNO2 ArNHNHAr or ArN NAr
RCH2 Br RCH3
RCH2 OSO2 Ar RCH3
O OH
C CH2 C
R
CH3
H R H

OH
CHO LiAlH4
O N THF, 0 °C O N

O 98% O

Ph Ph

LiAlH4
H 2N CO2H THF, heat H 2N

OH
100%

LiAlH4
N O Et2O, 20 °C N

Me Me
75%
OMe OMe

CHO LiAlH4
Ph Ph OH
Et2O, 35 °C

CHO LiAlH4
Ph Ph OH
Et2O, –10 °C
or NaBH4
 H 2H
2HOR
O
Ph Al Ph OH
Ph
O

77 78

O OH

CO2Et NaBH4 CO2Et

EtOH
O OH (7.62)
CO2Et LiAlH4
OH
Et2O

OH
HO , H+

O
O O
i, LiAlH4
CO2Et
OH
ii, H3O+

O OH OH

NaBH4
+ (7.63)
MeOH

no CeCl3 59 : 41
CeCl3•7H2O 99 : 1

O OH

NaBH4, CeCl3•7H2O

CHO EtOH, –15 °C CHO

64%

O OH
H

NaBH4, CeCl3•7H2O

EtOH, H2O, –15 °C

CHO CHO

78%
 O OH

NMe3BH4

CH2Cl2, MeOH
NO2 room temp. NO2
Cl N Cl N
79 89% 80

O H OH HO H
LiAlH4
+ (7.66)
Me Me Me
Me H Me H Me H

81 72 : 28

O M HO M

L L H (7.67)
H R S
R S

H2 H2
O −
Al Al HO H H OH
O O H AlH3 O O
Ph LiAlH4 Ph Ph
Me Me + Me (7.68)
Ph Ph Me
H OH H Me H H H OH H OH

82 83 80 : 20

OH
O
LiAlH4
OH + (7.69)

84 90 : 10

OH
O
OH + (7.70)

85 LiAlH4 45 : 55 86
or LiBH(s Bu)3 <1 : >99

OH
LiAlH4 NaBH3CN
O (7.71)
BF3•OEt2
OH
88 87 89
 HO HO HO
H H H
O O O
HO O TsO O O
TsCl LiAlH4
pyridine THF
(7.72)
O O O O O O
room temp.

90 89% 91 86% 92

O O O
O O O
OHC
LiAlH(Ot Bu)3 HO Amberlite resin O
(7.73)
MeO2C THF, –10 °C MeO2C PhH
O
O O O

93 94 93%

COCl CHO
LiAlH(Ot Bu)3 (7.74)
–78 °C
NC NC
80%

i, LiAlH(OEt)3
CONMe2 CHO
ii, H3O+

85%

3 LiAlH4 + AlCl3 3 LiCl + 4 AlH3

LiAlH4 + AlCl3 LiCl + 2 AlH2Cl (7.76)

LiAlH4 + 3 AlCl3 LiCl + 4 AlHCl2

LiAlH4–AlCl3 (1:1) OH
CO2Et (7.77)
Et2O
Br Br
93%

Ph NMe2 LiAlH4–AlCl3 (3:1) Ph NMe2

(7.78)
Et2O
O
94%
(0% using LiAlH4)
 Diisobutylaluminium hydride (DIBAL-H)

O O
DIBAL-H
O OH (7.79)
PhMe, –78 °C

94%

CO2Me DIBAL-H CHO

O O (7.80)
CH2Cl2, –78 °C
MeO MeO
85%

H H
CN CHO
DIBAL-H
(7.81)
hexane, –70 °C

96%

Boc Boc

Ph N DIBAL-H Ph N OH
CO2Et (7.82)
PhMe, –78 °C

95 67% 96

Boc = CO2tBu

NaBH3CN
RCHO + HNR'2 R NR'2 R NR'2 (7.83)

Ph Ph

N N N
i
H , CH2Cl2, Ti(O Pr)4
H H (7.84)
O then NaBH3CN, MeOH N
N N

Bn 83% Bn

Me
H
N CH2O (37% in water) N
(7.85)
NaBH3CN, MeCN
F F
93%

O O
H2N Ph
O NH (7.86)
O NaBH(OAc)3 O Ph
ClCH2CH2Cl, AcOH

98%
 O NH2

HCOONH4
0.1 mol% [RhCp*Cl2]2
(7.87)
MeOH, 70 °C

95%

(Cp* = pentamethylcyclopentadienyl anion)

OH O OH OH

CO2CH2CH2CH2Ph Me4NBH(OAc)3 CO2CH2CH2CH2Ph

(7.88)
MeCN, AcOH, –40 °C

92% anti:syn 95:5

H p-TsNHNH2, TsOH H
DMF, sulfolane
H H
(7.89)
O then NaBH3CN, 100 °C O

O H O H
55%
97 98

AcO AcO
p-TsNHNH2, AcOH
(7.90)
O then NaBH3CN, 70 °C

72%

99 100

AcO AcO
H
N Ts N
N N
H
H

101 102
 Reduction

Table 7.4. Functional groups reduced by borane

Functional group Reduction product

RCO2 H RCH2 OH

B
RCH CHR R
R
RCHO RCH2 OH
R2 C O RCH(OH)R
RC N RCH2 NH2
RCONR 2 RCH2 NR 2
RCO2 COR RCH2 OH
O OH
R
C CH2
R
H
RCO2 R RCH2 OH + R OH (slow rate of reaction)
RCOCl no reaction
RNO2 no reaction

BH3
O O H O BH2
+ BH3 (7.91)

OEt BH3•THF OEt

HO HO
THF, –18 °C
O O

103 88% 104

Ph O Ph

HO BH3•THF HO
N CO2t Bu N CO2t Bu (7.93)
THF, room temp.
Me Ph Me Ph

105 67% 106

 [H–]
O L
OH O B H OH OH
O B
O L
O
(7.94)
THF, –10 °C

82% 107 syn:anti 90:10

O OH OH

+ (7.95)
SO2Ph SO2Ph SO2Ph
BH3•pyridine, TiCl4
CH2Cl2, –78 °C 85% 87 : 13
LiBHEt3, CeCl3
THF, –78 °C 85% <1 : >99

OMe OMe

B2H6, LiBH4
O (7.96)
THF, 0 °C OH
N OMe N OMe

OMe 82% OMe

O OH
(+)-(Ipc)2BCl
Cl Cl
–25 °C
(7.97)

F F
108 90% 109 98% ee

110
Ipc
Cl
B
O
H
RS
RL

O OH

Br BH3•SMe2, THF, –15 °C Br

5 mol%
(7.98)
Ph
N Ph 99% 96% ee
B O
Me
111

112
Ph
N Ph
H3B B O
Me
 O PhN(Et)iPr•BH3 OH
THF, 25 °C
OSO2Tol OSO2Tol (7.99)
Ph 10 mol% Ph

Ph
N Ph 99% 99% ee
B O
Me
111

Ph
Me
Ph
111 B
O
Ph N Ph (7.100)
N
H RS H2B B O
O
B H O
H H Me
RL
H RS
RL

113

O O OH O
Baker's yeast
OEt OEt (7.101)
water, sucrose, 30 °C

60–80% >90% ee

O OH

Immobilized Baker's yeast

(7.102)
CO2Et water, sucrose, 30 °C CO2Et
N N

CO2Bn CO2Bn

114 85% 95% ee 115

O O OH O
Baker's yeast
Cl Cl (7.103)
OEt OEt
water, sucrose, 30 °C

55% ee

O OH
Rhodococcus ruber
(7.104)
phosphate buffer, iPrOH

116 67% 99% ee

 H H H+
CONH2 O HO H

R R' R R'
N enzyme
O O H H (7.105)
O–
O P NH2 CONH2 CONH2
O
O– OH HO N
O P N
N N
O N N
O
NADPH NADP+

OH O
PO3H
formate
NADPH dehydrogenase
CO2 HCOO–

H H
O OH
HLADH
(7.106)
O cat. NADH, EtOH O
H phosphate buffer, 20 °C H

117 64% >98% ee 118

NH2NH2•H2O
(HOCH2CH2)2O, 180 °C
O (7.107)
then Na, (HOCH2CH2)2O, 180 °C, 4 h
HO HO

119 69% 120

NH2
O N
NH2NH2 KOH
Ph Me Ph Me Ph Me (7.108)
PhMe, microwave microwave, 25 min

96% 75%

NH2 NH
N N H N N H H H
HO
R R' R R' R R' R R' R R'

N2
121 122

CHO NH2NH2•H2O
(7.110)
NaOEt, EtOH, 200 °C

80%

O NH2NH2
N (7.111)
N
H
 OH
O
NH2NH2•HCl
Et3N, MeCN
(7.112)
O room temp.

123 71% 124

S
O SH
HS Raney nickel
S (7.113)
BF3•OEt2 EtOH, heat

95% 82%

O2 or H2O2
NH2NH2 HN NH
Cu(II)

heat
TsNHNH2 HN NH (7.114)

KO2C
AcOH
N N HN NH
CO2K

S TsNHNH2 S
(7.115)
glycol, heat

93–100%

O O OH
O O
KO2CN NCO2K
OH
(7.116)
AcOH, DME, 45 °C
MeO MeO MeO
77%
125 126 127

H H (7.117)
H H H H
N N N N N N

Et3SiH
COCl CHO
10% Pd/C
(7.118)

83%

NHBoc NHBoc
Et3SiH
MeO2C COSEt MeO2C CHO (7.119)
10% Pd/C
acetone
128 93% 129
 O Et3SiO O
CO2Me CO2Me CO2Me

Et3SiH K2CO3 (aq)

(7.120)
[(Ph3P)3RhCl] MeOH
H H H
91% 88%
130

O O
5 mol% CuCl
1.05 equiv. PMHS
(7.121)
5 mol% (S)-p-Tol-BINAP
CO2Me 5 mol% NaOt Bu CO2Me

86% 92% ee

MeO Et3SiH MeO

OH OH (7.122)
CF3CO2H
NHSO2Ph NHSO2Ph
MeO 45 °C MeO

131 81% 132

Ph O BnO
O Et3SiH O
O HO
BnO BnO (7.123)
BF3•OEt2
BnO BnO
OMe CH2Cl2 OMe

133 83% 134

t BuO C
2
t BuO C OH
2

O Et3SiH O
(7.124)
N BF3•OEt2 N
OSiPh3 OSiPh3
CH2Cl2
O O
135 91% 136

Problems
1. Draw the structure of the product from the following reaction.
CO2Me
N
H2, Pd
?
Ph EtOAc, AcOH

NHCO2Bn
 Problems

2. Explain the formation of the product pumiliotoxin C (as its hydrochloride salt) in the
following reaction.

Me O Me
H
H2, Pd/C

EtOH, HCl
NHCO2Bn N
H H

pumiliotoxin C

3. Draw the structure of the product from the following reaction.

Me
Me

Me H2, [(Ph3P)3RhCl]
?

4. Explain the formation of the product from the following reaction.

O N O N

H2, [Ir(COD)py(PCy3)]PF4

Me Me
H

5. Draw the structure of the product from the following reaction.

Br

Zn, AcOH
?
Br
O

6. Draw the structures of the resonance forms of the intermediate radical anion from addition
of an electron to the dienone below. (Hint: compare with structure 60, Scheme 7.43.)
Addition of a second electron gives a dianion, which leads (after aqueous work-up)
exclusively to the stereoisomer shown. Provide an explanation for the stereoselectivity
in this reaction.
 Reduction

O O

Li, NH3

OH OH

7. Suggest reagents to effect the transformation shown below.

OH
CHO

CHO
OH

8. Explain the formation of the product from the following reaction.

i, Na, NH3

ii, MeI
N Ts N Me
PhS
O O

9. Draw a mechanism to explain the formation of the primary alcohol from treatment of
cyclohexanecarboxaldehyde with LDA.

O OH

H Li–NiPr2

(LDA)

10. Suggest a reagent for the selective reduction of the aldehyde shown below.

OH
CHO

O O

11. Draw the structure of the major enantiomer of the product from reduction of the ketone
shown below, used in a synthesis of fredericamycin A.
 Problems
O

BH3•SMe2
?
catalytic

Ph
N Ph
B O
Me

12. Explain the formation of the allylic alcohol product from the reaction shown below.
OH
O
NHTs nBuMgBr, Et2O
O N O
O O