C-C BOND FORMATION 72

Carbon- Carbon Bond Formation

1. Alkylation of enolates, enamines and hydrazones
C&S: Chapt. 1, 2.1, 2.2 problems Ch 1: 1; 2; 3, 7; 8a-d; 9; 14 Ch. 2: 1; 2; 4)
Smith: Chapt. 9
2. Alkylation of heteroatom stabilized anions C&S :Chapt. 2.4 - 2.6)
3. Umpolung Smith: Chapt. 8.6
4. Organometallic Reagents
C&S: Chapt. 7, 8, 9 problems ch 7: 1; 2; 3, 6; 13 Ch. 8: 1; 2
Smith: Chapt. 8
5. Sigmatropic Rearrangements . C&S Chapt. 6.5, 6.6, 6.7 # 1e,f,h,op
Smith Chapt. 11.12, 11.13
Enolates Comprehensive Organic Synthesis 1991, vol. 2, 99.
- α-deprotonation of a ketone, aldehyde or ester by treatment with a strong non-
nucleophillic base.
- carbonyl group stabilizes the resulting negative charge.

O O O-
B:
H H - H
R R R
H
H H H

- Base is chosen so as to favor enolate formation. Acidity of C-H bond must be greater
(lower pKa value) than that of the conjugate acid of the base (C&S table 1.1, pg 3)
O
MeO- pKa = 15 unfavorable enolate
pKa = 20 concentration
H 3C CH3 tBuO- pKa = 19
O O more favorable
H 3C CH2 OEt
pKa = 10 enolate concentration

- Common bases: NaH, EtONa, tBuOK, NaNH2, LiNiPr2, M N(SiMe3)2,

Na CH2S(O)CH3

Enolate Formation:
- H+ Catalyzed (thermodynamic)
O
OH
H+

- Base induced (thermodynamic or kinetic)

O O- +
:B B:H
H

Regioselective Enolate Formation Tetrahedron 1976, 32, 2979.

- Kinetic enolate- deprotonation of the most accessable proton (relative rates of
deprotonation). Reaction done under essentially irreversible conditions.

O O - Li+
LDA, THF, -78°C
 C-C BOND FORMATION 73
typical conditions: strong hindered (non-nucleophilic) base such as LDA
R2NH pKa= ~30
Li
N

Ester Enolates- Esters are susceptible to substitution by the base, even LDA can be
problematic. Use very hindered non-nucleophillic base (Li isopropylcyclohexyl amide)
O O

OR' LDA, THF, -78°C

N
R E+
R

O O- Li+
N
OR' Li R
OR'
R THF, -78°C

- Thermodynamic Enolate- Reversible deprotonation to give the most stable enolate:

more highly substituted C=C of the enol form
O - K+ O O - K+
tBuO- K+, tBuOH

kinetic thermodynamic

typical conditions: RO- M+ in ROH , protic solvent allows reversible enolate

formation. Enolate in small concentration (pKa of ROH= 15-18 range)

- note: the kinetic and thermodynamic enolate in some cases may be the same
- for α,β-unsaturated ketones
O
thermodynamic kinetic
site site

Trapping of Kinetic Enolates

- enol acetates
1) NaH, DME
2) Ac2O Ph
Ph Ph + O
O kinetic O
O
O isolatable
separate & purify

CH3Li, THF CH3Li, THF

Regiochemically
Ph Ph
pure enolates
O- Li+ O- Li+
 C-C BOND FORMATION 74
- silyl enolethers Synthesis 1977, 91. Acc. Chem. Res. 1985, 18, 181.
1) LDA
2) Me3SiCl Ph
Ph Ph + OTMS
O kinetic OTMS
isolatable
separate & purify

CH3Li, THF CH3Li, THF

-or-
Bu4NF -or- TiCl4

Geometrically Ph Ph
pure enolates O- M+ O- M+

- tetraalkylammonium enolates- "naked" enolates

- TMS silyl enol ethers are labile: can also use Et3Si-, iPr3Si- etc.
- Silyl enol ether formation with R 3SiCl+ Et3N gives thermodyanamic silyl
enol ether

- From Enones
1) MeLi
1) Li, NH3
2) TMS-Cl 2) E+

O TMSO O
H H
E

OSiMe3 O OSiMe3

TMS-Cl, Et3N TMS-OTf

Et3N

O OSiMe3

Li, NH3, tBuOH

TMS-Cl

- From conjugate (1,4-) additions

O
O- Li+ O
(CH3)2CuLi E+ E

Trap or use directly

- From reduction of α-halo carbonyls

O
Zn or Mg O- M+
Br

Alkylation of Enolates (condensation of enolates with alkyl halides and epoxides)

Comprehensive Organic Synthesis 1991, vol. 3, 1.
1° alkyl halides, allylic and benzylic halides work well
2° alkyl halides can be troublesome
3° alkyl halides don't work
 C-C BOND FORMATION 75
O O
a) LDA, THF, -78°C Me
b) MeI

- Rate of alkylation is increased in more polar solvents (or addition of additive)

O O O O
NMe2
(Me2N)3P O S
R NMe2 H 3C CH3 CH3N CH3N NCH3
HMPA R= H DMF Me2N
DMSO
R-CH3 DMA
TMEDA
Mechanism of Enolate Alkylation: SN2 reaction, inversion of electrophile stereochemistry
X
C
180 °

M+ -O

Alkylation of 4-t-butylcyclohexanone:
O O
E
R
R

equitorial anchor

E H
A E
H tBu
A favored Chair
tBu R
O
R
B O- M+
H
E O
tBu Twist Boat
B R

E
on cyclohexanone enolates, the electrophile approaches from an "axial" trajectory. This
approach leads directly into a chair-like product. "Equitorial apprach leads to a higher
energy twist-boat conformation.

Alkylation of α,β-unsaturated carbonyls

O- M+ O
R1 R2 E
R1 R2

O Kinetic H E H
R1 R2

H H O- M+ O
E
R1 R2 R1 R2

H H E
Thermodynamic
 C-C BOND FORMATION 76
Stork-Danheiser Enone Transposition:
- overall γ-alkylation of an α,β-unsaturated ketone

O O
LDA HO CH3 CH3
+
PhCH2OCH2Cl CH3Li H3O
PhO PhO PhO
OMe OMe OMe O
J. Org. Chem. 1995, 60, 7837.

Chiral enolates- Chiral auxilaries.

D.A. Evans JACS 1982, 104 , 1737; Aldrichimica Acta 1982,15 , 23.
Asymmetric Synthesis 1984, 3, 1.
- N-Acyl oxazolidinones
O O
H 2N OH
R
N O
Me Ph
Me Ph norephedrine
O O
R H 2N OH
N O

valinol
O O O O
O
R LDA, THF R LiOH, H2O, THF R
N O N O
OH
Et-I
Me Ph Me Ph Complimentary Methods
major product for enantiospecific alkylations
(96:4)
O O O
O O Diastereoselectivity: 92 - 98 %
R LDA, THF
N O R
N O
LiOH, H2O, THF R for most alkyl halides
OH
Et-I

major product
(96:4)

Enolate Oxidation Chem. Rev. 1992, 92, 919.

O O O O
NaN(SiMe3)2, R
R THF, -78°C
N O N O
O OH
N (88 - 98 % de)
Ph SO2Ph

1) HO-
O O
2) CH2N2 O
LDA, THF R
N O 3) TFA
R
O Boc N 4) Raney Ni OMe
N OtBu NH2
tBuO N HN (94 - 98 % de)
O Boc
 C-C BOND FORMATION 77
Bu Bu
O O B O O
R Bu2BOTf, Et3N O O NBS N3-
N O R
R N O
N O
Br

Ph
Ph
Ph
O O
1) LiOH O
R 2) H2, Pd/C
N O R
OH
N3
NH2

Ph D- amino acids

O O O O
R KN(SiMe3)2, THF R
N O N O
N3
SO2N3
Ph Ph

Oppolzer Camphor based auxillaries Tetrahedron, 1987, 43, 1969.

diastereoselectivities on the order of 50 : 1

SO2Ph
R
N Ar
Ar N O R
O SO2Ph
R O O N
O
O SO2N(C6H11)2 S O
O2
R

H
LDA, NBS H
Et2Cu•BF3 H
O O
O
Br HO
O O NH2
SO2N(C6H11)2 SO2N(C6H11)2 O
SO2N(C6H11)2 O

Asymmetric Acetate Aldol

O S O
TIPSO O
1) Br H
N O J. Am. Chem. Soc. 1998, 120, 591
Sn(OTf)2, CH2Cl 2, Br NH2 J. Org. Chem. 1986, 51, 2391
R3N, -40°C
2) TIPS-OTf, pyridine 85 %, 19:1 de
3) NH3

Chiral lithium amide basess

CH3 CH3
Ph N OMe
MeO MeO
Li

CO2Et THF, -78°C O

(CH3)2C=O
OMe OMe O
(72% ee)
 C-C BOND FORMATION 78

H
N Ph OTMS
O But H N Ph
N
N O Li
Li N
THF, HMPA (97 % ee)
TMSCl N tBu
tBu Me

Lewis Acid Mediated Alkylation of Silyl Enolethers- SN1 like alkylations

OTMS tBu-Cl, TiCl4, O
CH3
CH2Cl2, -40°C note: alkylation with a
C(CH3)3 3° alkyl halide
(79%)
ACIEE1978, 17, 48
SPh O SPh O TL 1979, 1427
OTMS
Raney Ni
R Cl R R
TiCl4, CH2Cl2, -40°C (95 %)
(78%)

Enamines Gilbert Stork Tetrahedron 1982, 38, 1975, 3363.

- Advantages: mono-alkylation, usually gives product from kinetic enolization
O O

N N can not become coplanar

"Kinetic" "Thermodynamic"

O O
O
O +
••
N N N O
H R-I H2O
R E
H+, (-H2O)

enamine

-Chiral enamines
O
N
E

Imines Isoelectronic with ketones

Me
Ph O
Li
OMe Ph O E = -CH3, -Et, Pr,
N N 1) E
PhCH2-, allyl-
LDA, THF, -20°C 2) H3O+ E
ee 87 - 99 %
 C-C BOND FORMATION 79
Hydrazones isoelectronic with ketones Comprehensive Organic Synthesis 1991, 2, 503

N N
O N N
N
-N
Me2N-NH2 LDA, THF
-
+
H , (-H2O)

N
N O
E+ hydrolysis
E E

- Hydrazone anions are more reactive than the corresponding ketone or aldehyde
enolate.
- Drawback: can be difficult to hydrolyze.
- Chiral hydrazones for asymmetric alkylations (RAMP/SAMP hydrazones- D. Enders
"Asymmetric Synthesis" vol 3, chapt 4, Academic Press; 1983)
OMe MeO
N N
NH2 H 2N

SAMP RAMP

N N
LDA O3 O
N OMe N OMe
H
I OTBS

(95 % de) TBSO

TBSO
1) LDA
N 2) Ts-CH3, THF
N -95 - -20 °C O
OMe 3) MeI, 2N HCl
CH3

(100 % ee)
Me
O
Li •• MeO
R1 N N R1 N N
E (C,C) R2 R2 H
H Z (C,N)
E

Aldol Condensation Comprehensive Organic Synthesis 1991, 2, 133, 181.

O a) LDA, THF, -78°C O OH β-hydroxyl aldehyde
b R'CHO (aldol)
R
H H R'
R

- The effects of the counterion on the reactivity of the enolates can be important
Reactivity Li+ < Na+ < K+ < R4N+ addition of crown ethers
 C-C BOND FORMATION 80
- The aldol reaction is an equilibrium which can be "driven" to completion.
M
O- M+ O O O OH
work-up
R + RCHO H H R'
R'
R' R
R

In the case of hindered enolates, the equillibrium favors reactants. Mg2+ and Zn2+
counterions will stabilize the intermediate β-alkoxycarbonyl and push the equillibrium
towards products. (JACS 1973, 95, 3310)

O- M+ O OH

PhCHO, THF Ph M= Li 16% yield

M= MgBr 93% yield

- Dehydration of the intermediate β-alkoxy- or β-hydroxy ketone can also serve to drive
the reaction to the right.
O O
O

tBuO- Na +, tBuOH
JACS 1979, 101 , 1330
O O
H H
O O

Enolate Geometry
- two possible enolate geometries
O O - Li+ O - Li+
LDA, THF, -78°C H
+
H
E - enolate Z - enolate

- enolate geometry plays a major role in stereoselection.

OM O OH
Z -enolate
R2 R3CHO erythro
1 1 3
R R R (syn)
H R2

E -enolate OM O OH
R3CHO threo
H
R
1
R 1
R 3 (anti)
R2 R
2

- Zimmerman-Traxler Transition State : Ivanov condensation

JACS 1957, 79 , 1920.
+
O MgBr H Br
O O
- - + Mg
Ph H + PHCHCO2 MgBr Ph

Ph OMgBr
H

"pericyclic" T.S.
 C-C BOND FORMATION 81
Analysis of Z-enolate stereoselectivity
R2 R2
R3 R2 O M O O
O O R3 O OH
R3 M M
O R1 R3
H H
H H R1
H R1 H R2
R1
erythro (syn)
favored

R2 H R2 O M R2
O O O O O OH
H M H M
O
H R1 R3
H H R3
R3 R1 R3 R1 R2
R1
threo (anti)
disfavored

Analysis of E-enolate stereoselectivity

H
H R3 H O M O O
3 O OH
O O R M
R3 M O
R2 R1 R3
R2 R2 H R1
H
H R1 R1 R2
threo (anti)
favored

H H
O O H H O M O O
H M H M
O OH
2 O R2
R R1 R3
R1 R2 R3 R3 R1
R3
R1 erthro (syn) R2
disfavored

Analysis of Boat Transition State for Z-Enolates

R2 R3
O O O
M O HO
R3 H
O M
R1 R3 R2
H
H R1 R2
H R1
Favored Chair
Boat
H
R2 O
O O O HO R3
M O M
H R2
R1 R3 staggered
H R2
R3 R1 H R1
Boat: R1-R2
Disfavored Chair 1,3-interaction is gone
 C-C BOND FORMATION 82
Analysis of Boat Transition State for E-Enolates
H R3
O O O
M O HO
R3 H
O M
R2 R1 R3 H
H R1 R2
R2 R1
Favored Chair
Boat
H
H O
O O O HO
M R3
H O M
R1 R3 H
staggered
R2 R2
R3 R1 R1
R2
Disfavored Chair Boat: R1-R2
1,3-interaction is gone

Summary of Aldol Transition State Analysis:

1. Enolate geometry (E- or Z-) is an important stereochemical aspect. Z-Enolates
usually give a higher degree of stereoselection than E-enolates.
2. Li+, Mg 2+, Al3+= enolates give comparable levels of diastereoselection for kinetic
aldol reactions.
3. Steric influences of enolate substituents (R1 & R2) play a dominent role in kinetic
diastereoselection.
O- M+ O HO
Path A
R2
R1 R1 R3
H Path R2
B

O- M+ O HO
H
R1 R1 R3
Path A
R2 R2
When R1 is the dominent steric influence, then path A proceeds. If R2 is the dominent
steric influence then path B proceeds.
4. The Zimmerman-Traxler like transition state model can involve either a chair or boat
geometry.

Noyori "Open" Transition State for non-Chelation Control Aldols

Absence of a binding counterion. Typical counter ions: R4N+, K+/18-C-6, Cp2Zr2+
- Non-chelation aldol reactions proceed via an "open" transition state to give syn aldols
regardless of enolate geometry.
Z- Enolates:
R1 O-
R1 O-
R1 O-
O HO
Favored R3 H
H R2 R3 H R1 R3
R3 H H R2
H R2 R2
O O
O
Syn Aldol
Favored
R1 O-
R1 O-
R1 O-
O HO
Disfavored H R3
H R2 H H R R2 R1 R3
H R3 3
H R2 R2
O O
O
Disfavored Anti Aldol
 C-C BOND FORMATION 83
E- Enolate:
- - O R1
O R1 - R1
O O HO
favored R3 H
H R2 H R1 R3
R3 H R2
R3 H R2
H R2
O O
O Syn Aldol
favored
-
-
O R1 -
O R1
O R1 O HO
disfavored H R3
H R2 H H R3 R2 R1 R3
H R3
H R2 R2
O O
O
disfavored Anti Aldol

NMR Stereochemical Assignment.

Coupling constants (J) are a weighted average of various conformations.
H
O O
HB Syn Aldol
R1 R3 JAB = 2 - 6 Hz
R2 HA

60 ° 60 °
HA HA HA
O HB HB R3 R3 OH
H
O R1 O
R2 R2 R2
R1 R3 O O R1 HB
H
non H-bonded

H
O OH
B Anti Aldol
R1 R3 JAB = 1 - 10 Hz
R2 HA

60 ° 60 °
HA HA HA
O R3 R3 HB HB OH
H
O R1 O
R2 R2 R2
R1 HB O O R1 R3
H
non H-bonded

Boron Enolates: Comprehensive Organic Synthesis 1991, 2, 239. Organic Reactions 1995, 46, 1;
Organic Reactions 1997, 51, 1. OPPI 1994, 26, 3.
- Alkali & alkaline earth metal enolates tend to be aggregates- complicates
stereoselection models.
- Boron enolates are monomeric and homogeneous
- B-O and B-C bonds are shorter and stronger than the corresponding Li-O abd Li-C
bonds (more covalent character)- therefore tighter more organized transition state.
Generation of Boron Enolates:

O R2B-X OBR2
X= OTf, I
R= Bu, 9-BBN
iPrEtN
 C-C BOND FORMATION 84
R3N: H _ OBL2
+ BL2OTf R2
R1 O R1
H R2
Z-enolate

R3N: H _ OBEt2
+ BL2OTf
R1 O R1

R2 H R2
E-enolate

O
R 3B OBR2

OSiMe3 OBR2
R2B-X
+ Me3 Si-X

O R' 3B OBR'2
N2 R' Hooz Reaction
R R

Diastereoselective Aldol Condensation with Boron Enolates

O OBEt2 O OBEt2
RCHO
Ph Ph Ph R
pure
Z-enolate 100% Syn Aldol
OBEt2 O OH
R3CHO generally
R2 R1 R3 > 95 : 5
R1 syn : anti
Z-enolate R2

OBEt2 O OH
R3CHO generally
R1 R3 ~ 75 : 25
R1 anti : syn
R2 R2
E-enolate

Asymmetric Aldol Condansations with Chiral Auxilaries-

D.A. Evans et al. Topics in Stereochemistry, 1982, 13 , 1-115.
- Li+ enolates give poor selectivity (1:1)
- Boron and tin enolates give much improved selectivity
Bu Bu

O O B OH O O
Bu2BOTf, O - O +
Me EtNiPr2 , -78° RCHO
N O R N O
N O
Me

> 99:1 erythro

O O
1) Bu2BOTf, OH
Me EtNiPr2 , -78° O
N O
2) RCHO R X
Ph Me
 C-C BOND FORMATION 85

L L H L L L L
B
_ + B
_ B +
O O R O O O _ O
+ O O

N O N O R N O
RCHO

H L L L L
B B +
R O _ O O _ O
+

N R N
O O
O O
preferred conformation

R2 R2
R3
O O
H H
L O R3 L O R3
B B
N N
H
L O L
O
O O

Favored Disfavored

O O OH O O OH

O N R3 O N R3
R2 R2

Oppolzer Sultam
L 2B OH
O O O
R2 R2 R3CHO
N N N R3

S S S R2
O2 O2 O2

1) LDA
2) Bu3SnCl

R3
Sn OH
O R3CHO O
R2
O N R3
N
S R2
S
O2
O
 C-C BOND FORMATION 86
Chiral Boron

O BOTf OH O OH O
StBu Ph StBu + Ph StBu
iPrEt2N,
PhCHO,-78°C
when large, 1 : 33
higher E-enolate (> 99 % ee)
selectivity
Ph Ph

O ArO2SN NSO2Ar OH O
B OH O
R Br
SPh Ph SPh + Ph SPh
iPrEt2N, R R
PhCHO,-78°C > 95 : 5
(> 95 % ee)

• In general, syn aldol products are achievable with high selectivity, anti aldols are
more difficult

Mukaiyama-Aldol- Silyl Enol Ethers as an enolate precursors.

Lewis acid promoted condensation of silyl ketene acetals (ester enolate equiv.) with
aldehydes: proceeds via "open" transition state to give anti aldols starting from either
E- or Z- enolates.

RCHO, TiCl4, OH OH
OSiMe3 CH2Cl2, -78°C
CO2Et + CO2Et
R R
OEt CH3 CH3

R= iPr (anti : syn) = 100 : 0

C6H11 94 : 6
Ph 75 : 25

RCHO, TiCl4, OH
OSiMe3 OH
CH2Cl2, -78°C
CO2Et + CO2Et
R R
OEt CH3 CH3

R= iPr (anti : syn) = 52 : 48

C6H11 63 : 37
Ph 67 : 33

Asymmetric Mukiayama Aldol:

RCHO, TiCl4, OH O OH O
Ph O
CH2Cl2, -78°C
R Rc +
OSiMe3 R Rc
H 3C NMe2
(90-94% de)

syn : anti = 85 : 15
selectivity insenstivie to enolate geometry
 C-C BOND FORMATION 87

Ph iPrCHO, TiCl4, O HO
N SO Ph CH2Cl2, -78°C 96 % de
2 Rc anti : syn = 93 : 7
O OSitBuMe2 CH3

RCHO, TiCl4, O HO
CH2Cl2, -78°C + Syn product
O Rc
CH3
OSitBuMe2
SO2N(C6H11)2
E-Enolate
R= Ph % de= 90 anti : syn = 91 : 19
nPr 85 94 : 6
iPr 85 98 : 2

Z-Enolate
R= iPr % de= 87 anti : syn = 97 : 7

Mukaiyama-Johnson Aldol- Lewis acid promoted condensation of silyl enol ethers with acetals:
OSiMe3 O OH
TiCl4 or SnCl4 Mukaiyama-Johnson Aldol
R
RCHO or RCH(OR')2
via Ti or Sn enolate
CH2Cl2, -78°C

O O

TiCl4, CHCl2, -78 °C

O O

O HO
O O

O
OTMS

+
O
O Cl4Ti O
Cl4Ti O+ OSiMe3

OTMS TiCl4,
(CH3)2C(OEt)2 O OEt

Ph (78 %) Ph

Fluoride promoted alkylation of silyl enol ethers Acc. Chem. Res. 1985, 18, 181
OSiMe3 O

nBu4NF, THF, MeI

 C-C BOND FORMATION 88
Meyer's Oxazolines:
1) RCHO
O (ipc)2BOtf 2) 3N H2SO4 H 3C H 3C
iPrEt2N, Et2O O 3) CH2N2
N R + R
CO2Me CO2Me
N (~ 30%)
OH OH
(ipc)2B
Ester R= nPr %ee (anti) = 77 anti : syn = 91 : 9
equiv.
C6H11 84 95 : 5
tBu 79 94 : 6

Anti-Aldols by Indirect Methods:

SePh
O 1) (C5H7)2BOTf 1) HF
R3N OTBS 2) [O] CO2Me
PhSe C6H11
R R
C6H11 3) NaIO4 CO2Me R
2) RCHO
OTBS 4) CH2N2
HO O HO
HO
chiral syn
auxillary aldol

1) TBS-Cl CH3 CH3

2) DiBAl-H O3 Anti Aldol
R R Product
3) TsCl CHO
4) Ba(CN)BH3 OTBS OTBS

CO2Me O OH
1) LDA, THF, 1) HIO6
-78 °C O 2) CH2N2 MeO2C
N R
2) RCHO CH3
N R
CH3 Anti Aldol

MOMO O HO

N CH3 syn : anti

O O O O KBEt3H, Et2O, 1 : 99
MOMO -78 °C
MeO 1) LDA, THF, CH3
N -78 °C N CH3 OMOM

2) RCOCl CH3
O
OMOM MOMO O HO
MeO
Zn(BH4)2 N CH3 syn : anti
97 : 3
CH3
OMOM

Syn Aldols by Indirect Methods:

O O
1) LDA, THF, O O O O O OH
-78 °C Zn(BH4)2
O N
O N R O N R
2) RCOCl syn : anti = 100 : 1
CH3 CH3
 C-C BOND FORMATION 89
Aldol Strategy to Erythromycin:
O
9
10
8 4 3 2 1
11 7

12
OH 6
CO2H Erythromycin
15 5
seco acid
13 O 4
OH OH OH O OH OH
14 1 3
O 2
OH
[O] [O]
syn
Erythromycin aldol 3
aglycone

CHO CO2H
OH O OH OH
syn syn
aldol 4 aldol 1

CHO + CHO +
CHO CO2H
O OH

syn
aldol 2

CHO +
CHO
O

OH OH O OH OH
1
HO2C
3 5 9 11 13

1) Zn(BH3)2
O O LDA, O O O TiCl4, iPr 2EtN, O O O OH 2) (H3C)2C(OMe)2
CH3CH 2COCl CH2Cl2 CSA
O N O N 1 O N 5
83%, (96:4) (100%)
Ph CHO
Ph 90% (> 99:1) Ph

O 1) 9-BBN, THF O O O O
O O O
2) Swern oxid.
CHO
O N O N
3 5 73% (85:15)

Ph Ph

1) Na BH(OAc)3
O OH OTBS
O O O O OH 2) TBS-OTf, 2,6-lutidine
O O Sn(OTf)2, 3) AlMe3, (MeO)MeNH•HCl MeO
Et3N, CH2Cl2 N
O N O N 9 11 13
CH3CH 2CHO 72% (>99:1) CH3

84% (> 96:4)

Ph Ph
O OH OTBS 1) PMBC(NH)CCl3 PMBO
TfOH TMSO OTBS
EtMgBr
11 13 2) (PhMe2Si)2NLi,
86% 8 TMS-Cl
48 %
 C-C BOND FORMATION 90
X X
L
H3C H
H O O O OH L O
Sn H CH3
O L Ti
X R H
L O O
CH3 CH3 L Disfavored
H O
CH3 H
CH3 anti-syn CH3
X CH3
H L X
H3C J. Am. Chem. Soc.
O CH3 O O OH O 1990,112, 866
Sn L
H H
O X R Ti L
H
O L CH3 CH3 O
H O L
H3C H
Disfavored anti-syn
CH3 H3C
CH3

PMBO PMBO
O O O O BF3•OEt2, O O O O OH O OTBS
TMSO OTBS
CH 2Cl2, -78 °C
CHO
O N 3 5 7 + 11 13 83% (95:5)
O N
3 5 7 9 11 13
8

p-MeOC 6H4
Ph Ph
O O O O OH O O OTBS
1) Zn(BH3)2 1) NaH, CS2, MeI
2) DDQ 2) nBu3SnH, AIBN
O N
95% 70%

Ph
p-MeOC 6H4 p-MeOC 6H4
Cl3C6H2COCl
O O O O O O OTBS 1) LiOOH O O O O O OH
2) TBAF
iPr2EtN, DMAP
O N HO
63% 13 (86%

Ph p-MeOC 6H4 O
O 9

10 9 1) Pd(OH)2, iPrOH
11
8 2) PCC
11 7 3) 1M HCl, THF OH
O 5
12 6
5 58 % 13 O OH
13 O O 1 3
4
1 3 O OH
O 2 O

Michael Addition
- 1,4-addition of an enolate to an α,β-unsaturated carbonyl to give 1,5-dicarbonyl
compounds
O O O
- +
O M
R Ph
Ph
R

Organometallic Reagents
Grignard reagents:
O
Mg(0) OH
R-Br R-MgBr
THF R
O
O
OH
often a mixture of
+
R-MgBr R 1,2- and 1,4-addition
THF
R
 C-C BOND FORMATION 91
O
OH

R-MgBr R 1,2-addition
THF, CeCl3
O O

R-MgBr 1,4-addition
CuI,THF, -78C
R

Organolithium reagents
- usually gives 1,2-addition products
- alkyllithium are prepared from lithium metal and the corresponding alkyl halide
- vinyl or aryl- lithium are prepared by metal-halogen exchange from the
corresponding vinyl or aryl- haidide or trialkyl tin with n-butyl, sec-butyl or t-
butyllithium.
Li(0)
R-Br R-Li
Et2 O
X Li
nBu-Li
X= Br, I, Bu3Sn
Et2 O
Organocuprates
Reviews: Synthesis 1972, 63; Tetrahedron 1984, 40 , 641; Organic Reactions 1972, 19 , 1.
- selective 1,4-addition to α,β-unsaturated carbonyls
CuI, THF
2 R-Li R2CuLi

O O

R2CuLi

- curprate "wastes" one R group- use non transferable ligand

MeO
_
Cu MeO
Cu R Li+
R-Li

non-transferable
ligand
Other non transferable ligands
_ _ _ _
+ +
Bu3P Cu R Li Me2S Cu R Li+ NC Cu R Li F3B Cu R Li+

2-

+ Mixed Higher Order Cuprate

Cu R 2Li
S B. Lipshutz Tetrahedron 1984, 40 , 5005
CN Synthesis 1987, 325.

Addition to Acetals Tetrahedron Asymmtetry 1990, 1, 477.

n-C6 H13 CH3 1) PCC
O R (n-C6H13)2CuLi
2 NaOEt n-C6 H13 CH3
H3C TL 1984, 25, 3087
BF3•OEt 2 O
O OH
R OH
Chiral axulliary is destroyed 99 % ee
LA
LA O
O O
R O CH3 H
R O
R O
H CH3
Nu: H
Nu
 C-C BOND FORMATION 92
TMS
O 1) TiCl4
JACS 1984, 106, 7588
O 2) [O]
3) TsOH OH
98 % ee

Stereoselective Addition to Aldehydes

- Aldehydes are "prochiral", thus addition of an organometallic reagent to an aldehydes
may be stereoselective.
- Cram's Rule JACS 1952, 74 , 2748; JACS 1959, 84 , 5828.
empirical rule
O - OH
M M
1) "R2 - "
S R1 S
R 1
* 2) "H + " R 2

L L

O OH
M S M S

L R1 R2 -
R
1
R
2
L

- Felkin-Ahn TL 1968, 2199; Nouv. J. Chim. 1977, 1 , 61.

based on ab initio calculations of preferred geometry of aldehyde which considers the
trajectory of the in coming nucleophile (Dunitz-Burgi trajectory).
O O
S
M vs.
L
L R2 - R2 -

1
S M 1
R R

better worse
- Chelation Control Model- "Anti-Cram" selectivity
- When L is a group capable
+
of chelating a counterion such as alkoxide groups
M OH
O S
2 M
OR' R
1
R1 R
*
M OR' "Anti-Cram" Selectivity
S

M+
OR'
O OR' HO R2

R2 -
M S
M S R1
1
R
Umpolung - reversal of polarity Aldrichimica Acta 1981, 14, 73; ACIIE 1979, 18, 239.
i.e: acyl anion equivalents are carbonyl nucleophiles (carbonyls are usually electophillic)
O O
usually
- +
R R

Benzoin Condensation Comprehensive Organic Synthesis 1991, 1, 541.

KCN O- OH HO O- -O OH O OH
PhCHO
PhCHO
H
Ph CN Ph - CN Ph Ph Ph Ph Ph Ph
CN CN
Cyanohydrin anion Benzoin
 C-C BOND FORMATION 93
Thiamin pyrophosphate- natures acyl anion equivalent for trans ketolization reactions
NH2 H
NH2 _
+ +
N N S
N N S

H 3C N OPO3PO3
H 3C H 3C N OPO3PO3
H 3C
Thiamin pyrophosphate
H 2C OH
CHO H 2C OH
O
H OH O CHO
thiamin-PP HO H
H OH + H OH H OH
+
H OH
H OH H OH H 2C OPO3
H OH
H 2C OPO3 H 2C OPO3
H OH
glyceraldehyde-3-P
D-ribose-5-P D-ribulose-5-P (C3 aldose) H 2C OPO3
(C5 aldose) (C5 ketose)
sedohepulose-7-P
(C7 ketose)

Trimethylsilycyanohydrins
O TMS-CN TMSO CN TMSO CN acyl anion
LDA, THF
R H R
_ equivalent
R H

NC O
OMs
NaHMDS, OEE
THF, -60°C CSA, tBuOH
CN Tetrahedron Lett. 1997, 38, 7471
(72%)
OEE O
O O O
O O

Dithianes

B:, THF R'-I Hg(II) O

S S S S S S
R - R R'
R H R R'
Aldehyde Hydrazones
H B:
N tBu N tBu
N O
N E+
R E R E
R H H

Heteroatom Stabilized Anions (Dithiane anion is an example)

Sulfones
O R'
_ OH R' OH
Ph R'
Al(Hg)
Ph LDA, THF R' R' R'
R S R S
Ph
O O O O R S R
O O

Sulfoxides
O R'
_ OH
R' OH
Ph Ph R' R' R' Raney Ni
LDA, THF R S R'
R S Ph
O R S
O
R
O
 C-C BOND FORMATION 94
Epoxide Opening Asymmetric Synthesis 1984, 5, 216.
Basic (SN2) Condition
Nu:
R R Nu
Steric Approach Control
O HO
Acid (SN1-like) Condition
R Nu: attachs site that best
R OH
O+ stabilizes a carbocation
Nu Nu
H

OH
O
OH OH + OH
BnO BnO BnO TL 1983, 24, 1377
OH
Me2CuLi 6:1
AlMe3 1:5
OH
Me3Al
O JACS 1981, 103, 7520

S S
_ OH S JOC 1974, 3645
O
S

O
OH
S S + S S
_ Ph
Ph (69 %)

1) TBS-Cl O OH
2) MeI, CaCO 3, H+
Ph Tetrahedron Lett. 1992, 33, 931

Cyclic Sulfites and Sulfates (epoxide equivalents) Synthesis 1992, 1035.

O O O
OH S S
SOCl2, Et3N O O RuCl3, NaIO4 O O
R2
R1
R1 R2 R1 R2
OH
sulfite sulfate
O O O -

S S
H2O HO H
O O Nu: O H

R2 R2
R1 R2 R1 Nu R1 Nu

H2O

O O O
O-
S O S
O O Nu: Nu: H H
O H
Nu2 R
R1 R2 R1
R2 R1 Nu1 2
Nu
 C-C BOND FORMATION 95
CO2Me
MeO2C CO2Me
O SO2
CO2Me
R2
R1 R1 R2
O NaH

O
O SO2 OTBS
1) H2, Rh
1) (CH3)2CuLi 2) HF
CO2Me O carpenter Bee
CO2Me
pheromone
O 2) TBS-Cl
CH3

OBn MeO OMe

OMe OBn
OMe H
O SO2 N OMe 1) Ac2O
H3C OMe NCH3 2) HCl

∆
O
MeO OH
MeO
OBn
meso OBn
HO OBn OBn
MeO OMe MeO OMe
NCH3 NCH3

BnO BnO
OAc

Irreversible Payne Rearrangement

OH
O
OH
O
O SO2
Bu 4NF OH
OTBS
O O
Payne Rearrangement of 2,3-epoxyalcohols Aldrichimica Acta 1983, 16, 60

Sigmatropic Rearrangements Asymmetric Synthesis 1984, 3, 503.

Nomenclature:
2 3 R 2 3 R
1 1
σ bond ∆ σ bond
[3,3]-rearrangement
that breaks that forms
1 3 R 1 3 R
2 2

3 3
2 4 2 4
∆
1 1 5 [1,5]-Hydogen migration
R H 5 R H
1 1
σ bond σ bond
that breaks that forms

3,3-sigmatropic Rearrangements
Cope Rearrangemets- requires high temperatures Organic Reaction 1975, 22, 1

∆
R R
 C-C BOND FORMATION 96
Chair transition state:
CH3 CH3 Z
220 °C
H 3C H H 3C

H E

E,Z (99.7 %) E,E (0.3 %) Z,Z (0 %)

CH3
H
H 3C HH
H 3C
CH3
H

CH3 Z
E
H 3C
H 3C
E Z
H 3C

E,Z (0 %) E,E (90 %) Z,Z (10 %)

"Chirality Transfer"
H
Ph R E S
Ph CH3
CH3
CH3 (87 %)
Diastereomers
Ph
Ph Z
H 3C
H 3C CH3
R R
E H (13 %)
CH3
R R
Ph E
Z Ph H
CH3
CH3
Diastereomers

Ph
Ph Z
H 3C
H
H 3C R
S
Z CH3

- anion accelerated (oxy-) Cope- proceeds under much milder conditions (lower
temperature) JACS 1980, 102 , 774; Tetrahedron 1978, 34, 1877; Organic Reactions 1993, 43,
93; Comprehensive Organic Synthesis 1991, 5, 795. Tetrahedron 1997, 53, 13971.
 C-C BOND FORMATION 97
OMe O
OH
KH, DME, 110°C

OMe

KH
OH
O- O

Ring expansion to medium sized rings

OH O
KH, ∆
9-membered
ring

Claisen Rearrangements - allyl vinyl ether to an γ,δ-unsaturated carbonyl

Chem. Rev. 1988, 88, 1081.; Organic Reactions 1944, 2, 1.; Comprehnsive Organic Synthesis
1991, 5, 827.
∆
O O

O
OH CHO

O
220 °C

Hg(OAc)2 JACS 1979, 101 , 1330

O
O H O
H H
O
O O

Chair Transition State for Claisen

E-olefin
R O O
R
H X X

X=H E/Z = 90 : 10
X= OEt, NMe2, etc E/Z = > 99 : 1

R O X 1,3-diaxial
interaction Z-olefin
R X R
X
H
O
O

new stereogenic
centers
R O
old stereogenic O
center H X R
X
 C-C BOND FORMATION 98
- Chorismate Mutase catalyzed Claisen Rearrangement- 105 rate enhancement over
non-enzymatic reaction
CO2H HO2C CO2H
Chorismate
mutase O J. Knowles
JACS 1987, 109, 5008, 5013
O CO2H
OH OH

Chorismate Prephenate

- Claisen rearrangement usually proceed by a chair-like T.S.

H HO2C H

HO2C H O H
O Chair
CO2H
T.S

OH OH
Opposite
H stereochemistry
H H CO2H
CO2H Boat
O H
CO2H T.S O
CO2H

OH OH

OH OH OH
+

O O
J. Org. Chem. 1976, 41, 3497, 3512 +
J. Org. Chem. 1978, 43, 3435

O
R R
O

H H

O
s CH3 R H
O
R s
H CH3

CH3 O

CH3 OH CH3 OH

CH3 O CH3 CH3

CO2R
H
CH3 OH CH3 OH
Tocopherol
94 - 99 % ee

hydrophobically accelerated Claisen - JOC 1989, 54, 5849

 C-C BOND FORMATION 99
Johnson ortho-ester Claisen:
EtO OEt OEt OEt

OH O ∆ O [3.3]
H3C-C(OEt)3 O
H+ - EtOH

Ireland ester-enolate Claisen. Aldrichimica Acta 1993, 26, 17.

OTMS
O OH
LDA, THF
TMS-Cl O [3.3]
O O

O
OBn LDA, THF Me
O TMS-Cl
CO2H JOC 1983, 48, 5221
Me
Me Me
OBn

Eschenmoser
NMe2
R
EtO OEt O ∆ O
OH
BF3 NMe2 NMe2
R R
"Chirality Transfer"
R R
R aldehyde
O N
N N O oxidation state

Ph O
Ph Ph
R= Et, Bn, iPr, tBu (86 - 96 % de)

[2,3]-Sigmatropic Rearrangement Comprehensive Organic Synthesis 1991, 6, 873.

Z H H
H H E
:X Y X Y:
R Y: R :X Y
X
R R
R1
R R1 R
X Y:

H Y
:X

-Wittig Rearrangement Organic Reactions 1995, 46, 105 Synthesis 1991, 594.

_
O base
HO

BuLi _
O SnR3 O
 C-C BOND FORMATION 100
TBDPSO KH, 18-C-6, TBDPSO TBDPSO
Me3SnCH2I nBuLi
H H H
MeO O MeO O MeO O
OH O O
J. Am. Chem. Soc.
SnMe3 Li 1997, 119, 10935
TBDPSO
TBDPSO

H +
H
MeO O
MeO O
OH
(58%) (42%)

CH3 H3C CH3

H3C Ph
O
_
OH (87 %)
H Ph

CH3 CH3

CH3 (13 %)
H _ H3C
O Ph Ph OH
Sulfoxide Rearrangement
R R
S S (MeO) 3P
O
-
O HO

O O
CO2Et CO2Et
(MeO) 3P

S
Ph HO
O-

Ene Reaction Comprehensive Organic Synthesis 1991, 5, 1; Angew. Chem. Int. Ed. Engl. 1984, 23,
876; ; Chem. Rev. 1992, 28, 1021.

H H

- Ene reaction with aldehydes is catalyzed by Lewis Acids (Et2AlCl)

R R
H
O O
H
H

OH
CHO
Et2AlCl JOC 1992, 57, 2766

CH2Cl2 -78°C

O O
Ph Ph
O OH
O O 99.8 % de
H SnCl4

O
Ph
OH
O
SnCl4 + syn isomer
H3C
(94 : 6)
 C-C BOND FORMATION 101

O
TiCl2
O
O OH Tetrahedron Lett.
(97% ee)
+ 1997, 38, 6513
H CO2Me CO2Me

OH
O OH
+ +
PhS PhS CO2Me
R H CO2Me CO2Me
PhS R
R
(9 : 1)
anti (99 % ee) syn (90 % ee)

- Metallo-ene Reaction Angew. Chem. Int. Ed. Engl. 1989, 28, 38

CH3 CH3
C6H13 C6H13
H2O
C6H13
CH3 H 3C (10 %)
ClMg

C6H13 C6H13
Cl MgCl H2O
H 3C
H 3C H 3C
ClMg (> 1%)

intramolecular

BrMg
+ (11 : 1)
+
MgBr

BrMg

CH3
1) Mg(0), Et2 )
1) Li 2) 60 °C MgCl

CHO 2) SOCl2 MgCl

Cl

CH3 CH3
O Cl 1) Mg(0), Et2 )
SOCl2 2) 60 °C
OH

CH3 CH3
MgCl O2

H H
MgCl OH

1) PCC CH3 H3C

4) KOH
2) MeLi 5) H2
3) O3 CHO 6) Ph3 P=CH2
H
H
O Capnellene
 C-C BOND FORMATION 102

Synthesis of Phyllanthocin A. B. Smith et al. J. Am. Chem. Soc. 1987, 109, 1269.
O O O O
1) LAH
(Me3Si)2 NLi 2) BnBr
O N O N
Br

Ph CH3 Ph CH3

BnO
1) O3
2) H2, Lindlar's BnO MeAlCl

CHO

BnO 1) MEM-Cl
H 2) O3
BnO BnO
CH3
O H
OH CHO
OMEM

O O O
O
1) ZnCl2 O
1) BnO +
- O
2) H O
O BnO (CH3 )2S(O)CH 2-
2) H3O + O
MEMO O
3) Swern

O CH 1) DBU
O O 1) LDA, TMSCl O 3
2) H2, Pd/C
2) BnMe3 NF, MeI
O O
BnO BnO 3) RuO4
O O

O O
O
O CH3 O CH3
O Ph Phyllanthocin
O MeO2C O
HO2C
O