Classics in Asymmetric Synthesis

1
Chapter 13: Olefinations

13.1. Introduction

Ever since Georg Wittig back in 1953 pioneered the first olefination of
a carbonyl compound,
1
the synthesis of alkenes has become an indispensable
strategic tool for the construction of complex molecules. While alkenes can be
obtained by functional group transformations, most notably by selective
hydrogen transfer to alkynes, the most powerful olefination reactions proceed by
concurrent carbon-carbon formation.
There are three general strategies that allow the synthesis of alkenes
with a broad structural variety and functional group tolerance, which each
emerged approximately two decades apart from each other. The reaction of
carbanions 3, being stabilized by an electron withdrawing group LG that acts at
the same time as a good leaving group, with aldehydes or ketones 2 has been for
more than 50 years a most reliable tool for alkene synthesis (Scheme 1, strategy
A).
2
Depending on the group LG, these transformations are known as Wittig
reaction (LG = PR
3
),
3
for which the Nobel Prize was awarded in 1960, Horner-
Wittig reaction (LG = P(O)Ph
2
), Horner-Wadsworth-Emmons (HWE) reaction
(LG = P(O)(OR)
2
),
4
Julia Olefination (LG = SO
2
R),
5
or Peterson Olefination
(LG = SiR
3
).
6
Related to this strategy are carbonyl olefination reactions with
metal carbene, carbenoid or gem-dimetal complexes, making use e.g. of titanium
(Tebbe reagent), zinc, chromium, or zirconium. Reductive coupling reactions of
carbonyl compounds using low valent titanium, most notably the McMurry
reaction, have also seen a spectacular development over the years, beginning
with the synthesis of symmetrical, unfunctionalized alkenes up to complex
applications in natural product synthesis with high functional group tolerance.
7


R
3
R
2
R
1
R
4
O
R
2
R
1
+ LG
R
4
R
3
R
3
R
2
Y
R
4
R
1
X
+
R
2
R
1
+
R
3
R
4
1
2 3
4 5
6 7
LG = PR
3
, P(O)R
2
, SO
2
R, SiR
3
X = Hal, OTf, N
2
, OP(OR)
3
Y = H, BR
2
, SnR
3
, Hal
A
B
C


Scheme 1. Widely used strategies for olefinations

In the seventies, transition metal catalyzed cross coupling reactions with
alkenes 5 entered the synthetic arena (Scheme 1, strategy B).
8
Direct coupling of
alkenes (Heck reaction: Y = H) or alkenyl metals (Stille reaction: Y = SnR
3
;
Suzuki-Miyaura reaction: Y = BR
2
; Negishi reaction Y = ZnR) with appro-
priately activated aryl, alkenyl or even alkyl substrates 4 has been developed
into most economic processes, which have found not only manifold examples as
R
2
R
1
R
2
R
1
R
1
R
2
Li, NH
3
Pd/C, BaSO
4
, H
2
(Lindlar Catalyst)
Oliver Reiser
2
key steps in natural product synthesis but are used in industrial large scale
applications for common intermediates such as styrenes as well.
With the discovery of robust and readily available catalysts, about a
decade ago molybdenum (Schrock) and especially ruthenium (Grubbs),
catalyzed metathesis reactions (Scheme 1, strategy C) initiated a change in
paradigm not only for the synthesis of alkenes, but also for the assembly of
complex structures such as carbo- and heterocycles.

13.2. Olefination of carbonyl compounds with phosphorus reagents

13.2.1. The Wittig reaction

The reaction of phosphonium ylides with carbonyl compounds named
after its inventor the Wittig reaction is one of the most reliable methods for the
synthesis of alkenes. It occurs with complete regioselectivity, i.e. the carbonlyl
group of the substrate is replaced by the alkene group without that double bond
isomerizations occur, and also the double bond geometry can be controlled to a
large extend.
There has been a heated debate on the mechanism of the Wittig reaction,
which is still ongoing even today. The controversy is centered around the
intermediate that is formed after addition of the ylide to the carbonyl compound,
i.e. if the betaine plays a role along the reaction pathway, or if the phospha-
oxetan is directly formed in a formal [2+2]cycloaddition. Based on low
temperature
31
P NMR studies and calculations, and also supported through X-
ray structures of phosphaoxetanes the scales have been tipped over in favor of
the latter not only as being the decisive intermediate prior to alkene formation
through elimination of phosphinoxide.
Thus, the currently accepted mechanism for the Wittig reaction is the formation
of the phosphaoxetanes 10 and 12, which stereospecifically collapse to the Z- or
E-alkenes 11 and 13 (Scheme 2). The sterically more crowded cis-
phosphaoxetane 10 is apparently kinetically favored over the trans-phopha-
oxetane 12 for reasons not yet fully understood. Consequently, non-stabilized
ylides 9 will follow a kinetically controlled pathway via 10 to give preferentially
rise to (Z)-alkenes 11. With stabilzed ylides an equilibration of the diastereo-
meric phosphaoxetanes 10 and 12 is reached via back reaction to 8 and 9, thus
ultimately favoring the formation of (E)-alkenes 13 via the sterically less
crowded 12 under thermodynamic control (Table 1). As a notable exception, !-
alkoxyaldehydes give rise to Z-alkenes, especially when the reaction is carried
out in protic solvents.

O
R
s
R
L
+ PPh
3
R
8 9
PPh
3
O
R
L
R
PPh
3
O
R
L
R

R R
L
R
R
L
10
12
11
13
PPh
3
O
PPh
3
O
R
s
R
s
R
s
R
s


Scheme 2. The mechanism of the Wittig reaction
PPh
3
RCH
2
X
RCH
2
PPh
3
X
Base
RCH PPh
3
R
1
CHO
PPh
3
O
R
1
R
PPh
3
O
R
1
R
betaine phosphaoxetane
Chart 1. Definition of stabilized
and non-stabilized ylides

RCH PPh
3
non-stabilized ylides:
R = H, Alkyl, Aryl
salt free (M!Li)
generated in situ
react with aldehydes and ketones
stabilized ylides:
R = electronwithdrawing group
e.g. CO
2
R, COR, CN
can be isolated and subsequently
reacted with aldehydes
M X
RCH
2
PPh
3
X
M Base

Classics in Asymmetric Synthesis
3
Table 1. Wittig reaction of aldehydes 8 with phosphonium ylides 9

8: R
L
/R
S
9: R MX/solvent 11:13 (E/Z) Yield (%) Ref.
(CH
2
)
8
OAc/H n-Pent NaHMDS/THF 2:98 79 9a

O
OHC
MeO
O
O


CO
2
Et
DMF
CHCl
3
MeOH
86:14
60:40
8:92


9b



Nevertheless, the synthesis of (E)-alkenes from non-stabilized ylides can be
achieved using the Schlosser modification,
10
which calls for the presence of
lithium salts to form the betaine, followed by a deprotonation/reprotonation
sequence under kinetically controlled conditions in order to drive the reaction
the trans-phosphaoxetane trans-15.

PPh
3
R
14
PPh
3
O
R
1
R
(cis)-15
Br
1) PhLi
2) R
1
CHO
LiBr H R
1
OLi
H R
Ph
3
P
PhLi
H R
1
O
Ph
3
P R
Li
Br
Li
Br
(syn)-16 17
H
+
H R
1
OLi
Ph
3
P R
H
(anti)-16
PPh
3
O
R
1
R
(trans)-15
R
1
R
18


Scheme 3. The Schlosser modification of the Wittig reaction

A very useful extension of this variant is to trap 17 with formaldehyde,
resulting in the formation of Z-configurated allylic alcohols (Scheme 4).
11
It is
important to note that only the secondary alkoxide in 19 forms an oxaphos-
phetane that subsequently eliminates triphenylphosphine oxide to yield the
alkene 20.


H R
1
O
Ph
3
P R
Li
Br
Li
17
O
H H
H R
1
O
Ph
3
P R
Li
19
LiO
Ph
3
PO
R
1
R
HO
20


Scheme 4. Synthesis of Z-allylic alkenes from aldehydes

The synthesis of alkenes with perfluoroalkyl groups is usually not
possible by direct Wittig reaction, since such substituents in !-position are
Chart 2. Factors that control
the alkene geometry in the
Wittig reaction

E-alkenes
stabilized Ylides
aprotic solvents
catalytic amounts PhCO
2
H
Schlosser modification

Z-alkenes
non-stabilized ylides
salt free conditions (M!Li)
sterically bulky aldehydes
sterically bulky ylides
!-alkoxy aldehydes, methanol
Chart 3. Examples for the
Schlosser modification of the
Wittig reaction (cf. Scheme 3)

R R
1
Y
(%)
E/Z
Me n-Pent 70 99:1
n-Pent Me 60 96:4
n-Pr n-Pr 72 98:2
Me Ph 69 99:1
Et Ph 72 97:3

Oliver Reiser 11/7/04 2:56 PM
Comment: Check authors of reference 10
Oliver Reiser
4
stabilizing the ylide too strongly to render it nucleophilic enough to react with
carbonyl compounds. Perfluoralkylated "-ketophosphonium ylides, however,
provide a solution for the synthesis of such alkenes, demonstrating in an
interesting way alternative applications of commonly employed phosphor ylides
(Scheme 4).
12
Thus, ylides 21 can be acylated with perfluoroalkyl substituted
acid anhydrides to yield "-ketophosphonium salts 22, which have a sufficiently
high carbonyl reactivity to be attacked by nucleophiles to form alkenes 23 with
generally high (E)-selectivity.
13

PPh
3
R
21 22 23
(R
f
CO)
2
O
R
Ph
3
P
R
f
O
R
1
R
f
R R
1
R
1
R
f
= CF
3
, C
2
F
5
, n-C
3
F
7
R, R
1
= alkyl, aryl, allyl, benzyl
R
2
= Ph, n-Bu, alkynyl
R
2
R
2
Li


Scheme 5. Synthesis of perfluoralkyl substituted alkenes

Despite the great synthetic versatility there is one significant
disadvantage that has hampered the application of the Wittig reaction on
industrial scale: As a byproduct triphenylphosphine oxide is formed, disfavoring
this transformation under the aspect of atom economy. A convincing solution for
large-scale applications of the Wittig reaction was developed by BASF AG in
the synthesis of 26 as a precursor towards Vitamin A. Triphenylphosine oxide
(27) is recycled by chlorination with phosgene, followed by reduction of the
resulting dichloride (29) with aluminum metal to give back triphenylphospine
(28) along with aluminumtrichloride that is further used as a catalyst for Friedel-
Crafts acylations of aromatic compounds.

O PPh
3
PPh
3
COCl
2
PPh
3
Cl
Cl
Al
AlCl
3
25 26
27
28 29
OHC OAc
PPh
3
OAc
1) RBr
2) NaOH


Scheme 6. Synthesis of the Vitamine A precursor 26

13.2.2. The Horner-Wadsworth-Emmons reaction

An analogous olefination of carbonyl compounds can be achieved if
phosphonates instead of phosphonium ylides are used (Horner-Wadsworth
Emmons HWE reaction) are used, however, distinct differences to the Wittig
Chart 4. Atom economy in
the Wittig reaction

Ph
3
P CH
2
+ RCHO
R
OPPh
3
278g/mol


In a Wittig reaction for each
mol product one mole tri-
phenylphospine oxide (278g)
waste is produced.
Classics in Asymmetric Synthesis
5
reaction previously described exist. Carbanions obtained upon deprotonation of
a phosphonate are generally much more reactive than phosphonium ylides, so
that they need to be stabilized by an electron withdrawing substituents in order
to give useful yields in a subsequent reaction with either an aldehyde or a
ketone. As byproduct water soluble phosphates are formed which greatly
facilitates the workup of the products. The stereoselectivity of the HEW-reaction
can be controlled by the steric and electronic properties of the alcohol groups R
2

in the phosphonate: While alkyl groups, especially bulky ones like i-Pr,
generally result in high E-alkenes, trifluoroethyl or aryl groups or the use of
cyclic phosphonates will lead preferentially to Z-alkenes.

H
RO
CH
3
O
a, b or c
H
RO
CH
3
CO
2
R
1
H
RO
CH
3
R
1
O
2
C
+
30 (E)-32 (Z)-32
CO
2
R
1
P
O
R
2
O
R
2
O
31
31a: R
2
= CH
2
CH
3
; 31b: R
2
= CH
2
CF
3
, R
2
=
H
3
C
31a: 92 8
31b: 9 91
31c: 1 99


Scheme 7. Reagents and Conditions: (a) 31a, NaH, THF, 83%; (b) 31b, KH, THF, 84%;
(c) 31c, NaH, NaI, 88%.

A remarkable control of stereoselectivity with !-fluorinated
phosphonates 34 has been reported solely by a combination of the appropriate
choice of the group R and the base used for its deprotonation.

O
H
a or b
CO
2
R P
O
R
2
O
R
2
O
34
F
H
F CO
2
R
33
H
RO
2
C F
+
(Z)-35 (E)-35
R = H 99 1
R = Et 6 94


Scheme 8. Reagents and Conditions: (a) 34 (R = H), Pr
i
MgBr, 84%; (b) 34 (R = Et),
Bu
n
Li, 83%.

Masamune and Roush first developed a very useful variant that allows
carrying out the HWE-reaction with phosphonates 31 under mild basic
conditions. Chelation of the carbonyl and the phosphonate oxygen with LiCl of
MgBr
2
activates 31 sufficiently to allow its deprotonation with weak bases such
as triethylamine, and subsequent reactions with aldehydes yields predominantly
E-alkenes.
14
The activation by Lewis acids is not even necessary if the reaction
is carried out at high pressure.
15

Chart 5. The HWE-reaction

R
1
H
O
+
X P
O
R
2
O
R
2
O
base
R
1
H
X
X = CO
2
R, C(O)R, CN



E-alkenes
Bulky alkyl groups R
2

Bulky groups X

Z-alkenes
R
2
= CH
2
CF
3
(Still-Genari)
R
2
= Ar; (Ando)
Cyclic phosponates
Chart 6. Common methods for
the synthesis of phosponates

(RO)
3
P + R
1
CH
2
X
(RO)
2
P(O)CH
2
R
1
a) Michaelis-Arbuzov Reaction
(EtO)
2
P
O
CH
3
1) Bu
n
Li
2) CuX
3) RCOCl
(EtO)
2
P
O O
R
b) Alkylation of phosphonates
c) Acylation of phosphonates
1) NaH
2) R
1
X
(EtO)
2
P
O O
OR
(EtO)
2
P
O O
OR
R
1

Oliver Reiser
6

13.2.3. The Horner-Wittig reaction

Phosphine oxides are yet another class of phosphorus reagents that can
be used for carbonyl olefinations, a process that is known as Horner-Wittig
reaction. Mechanistically similar to the Wittig and the HWE reaction, an
important difference is the possibility to isolate the intermediate "-hydroxy
phosphine oxides, when lithium bases and low temperatures are employed.
Subsequently, 37 and 39 can be individually transformed after separation by
chromatography to the Z-alkene 38 or the E-alkene 40, respectively.


R P
O
Ph
Ph
36
1) Bu
n
Li
2) R
1
CHO
3) H
+
Ph
2
(O)P
R R
1
OH
Ph
2
(O)P
R R
1
OH
R
R
1
R
1
R
38
40
37
39
base
base


Scheme 9. Lithium bases in the Wittig-Horner reaction.

Like the Schlosser variation in the Wittig reaction, there is also the
possibility to obtain preferentially E-alkenes 40 from non-stabilized phosphine
oxides. Oxidation of the mixture of 37/39 to "-ketophosphine oxides 41, being
also accessible directly from 36 by a Claisen type ester condensation, followed
by reduction with NaBH
4
preferentially gives rise to 39, which can be explained
by applying the Felkin-Anh-model.
16
Complementary to this, if the reduction is
carried out using CeCl
3
/NaBH
4
(Luche reduction) 37 is preferentially obtained
via chelate control, which collapses to the Z-alkene 38.

36
37/39
PDC
1) Bu
n
Li
2) R
1
CO
2
Me
R
O
R
1
Ph
2
(O)P
NaBH
4
NaBH
4
/CeCl
3
39
37
40
38
P(O)Ph
2
H
R
O
R
1
BH
4
40
R
P
H
R
1
O
BH
4
38
O
Ph
Ph
Ce
3=
41


Scheme 10. Warren variation of the Horner-Wittig reaction.

There are numerous examples for the application of Wittig-type
olefinations in natural product synthesis.
17
A particular impressive example can
Chart 7. Factors that control
the alkene geometry in the
Wittig-Horner reaction

E-alkenes
R anion stabilizing, moderate
temperatures, non-Li base,
thermodynamic control "
one-step protocol

Z-alkenes
R not anion stabilizing, low
temperatures, Li base, kinetic
control " two-step protocol
Classics in Asymmetric Synthesis
7
be found in the synthesis of the antibiotic aurodox (42) from the Nicolaou group,
in which in a total of six olefination reactions all three Wittig variants were
applied.

Me
Me
OH
OH
OH
H
N
O
OMe
Me
O
H H
HO OH
Me
N
OH
O
Me
O Me
Horner-Wittig Horner-Wadsworth-Emmons Wittig 42


13.2.4 Asymmetric Wittig-type reactions

On a first glance, one might think that asymmetric olefination reactions
are a contradiction in terms since no chiral centers are created by alkenylating a
carbonyl group. However, by symmetry-breaking strategies, either by differen-
tiating meso-compounds or, in a kinetic resolution, racemic carbonyl compounds
asymmetric processes can be developed.
18
Most successfully, asymmetric
Horner-Wadsworth-Emmons reactions have been developed, making use of
three principle strategies to render a phosphonate chiral: (a) Introducing a C
2
-
symmetrical, chiral auxiliary in place of the alkoxy groups in the phosphonate;
(b) introducing a non C
2
-symmetrical, chiral auxiliary in place of the alkoxy
groups in the phosphonate, thus making the phosphorus atom itself a chiral
center; (c) introducing a chiral auxiliary in the part of the phosphonate that is
subsequently transfered to the carbonyl compound.
Phosphonates, being rendered chiral by BINOL
19
or the corresponding
phosphonic acid bis(amides)
20
bearing C2-chiral 1,2-diamines instead of diols
are particularly effective for the desymmetrization of prochiral carbonyl
compounds. Thus, upon deprotonation with KHMDS and subsequent reaction
with 43, the alkene 45 is obtained. Zinc chloride was found to be an effective
additive, ensuring in general high yields and selectivities in such
transformations.

H H
O O
O
H H
O O
O
O
P
O
CO
2
Me
CO
2
Me
KHMDS, ZnCl
2
43
44
45
82%
91% ee

Scheme 11. Asymmetric HWE-reaction with phosphonates bearing a C
2
-symmetrical
chiral auxiliary

The camphorquinone modified phosporamidate 47 also promotes
olefinations with high selectivity (Scheme 11).
21
The better enantioselectiviy
obtained in the transformation of cyclohexanone 46 to 48 in comparison to the
use of 44 might very well reflect the greater proximity of the chiral information
to the reaction centers, being manifested in a stereogenic phosphorus atom in 47.

Chart 8. Strategies for asymme-
tric olefination reactions

O R R
R
1
*
R R
*
O
O O
R
O
R
H
1. Prochiral carbonyl group differentiation
2. Enantiotopic carbonyl group differentiation
3. Kinetic resolution

Oliver Reiser
8
O
Bu
t
Bu
t
CO
2
Me
KHMDS
N
O
P
O
CO
2
Me
46
47
48 (78%, 86%ee)
(ent)-48 (98%, 79% ee)
44, KHMDS, ZnCl
2

Scheme 12. Asymmetric HWE-reaction with phosphonates bearing a non C
2
-
symmetrical chiral auxiliary and a stereogenic phosphorus center

Racemic !-chiral aldehydes have been successfully applied in
asymmetric HWE-reactions using the strategy of kinetic resolutions.
20,22
With
configurationally labile substrates even dynamic kinetic resolutions can be
carried out if the base used for the deprotonation of the phosphonate is
sufficiently strong to racemize the aldehyde by protonation/deprotonation
sequences via its enolate.
23
Thus, alkenylation of !-aminoaldehyde 49 with the
phosphonate 50 in the presence of KHMDS/18-crown-6 gave rise to 51 in good
yield and selectivity.
23b
The stereochemical outcome of this reaction can be
rationalized by a transition state 52, in which the chiral auxiliary dictates the
face of the phosphonate Z(O)-enolate that is attacked, the R groups on the
phosphonate dictate the relative configuration between C2 and C3, and finally
selection of the aldehyde enantiomer occurs in accordance with the Felkin-Anh
model. Support for this model comes from the fact that in this type of kinetic
resolutions the other aldehyde enantiomer reacts preferentially under chelating
conditions.
24


O
H
N
Bn p-Ts
Ph
+
P
O
O O
(CF
3
CH
2
O)
2
Ph
1.3 equiv 1.0 equiv
KHMDS (1.2 equiv)
18-crown-6
N
Bn p-Ts
Ph
CO
2
R*
49 50 51(77%, 90%de)
O
P(O)(OR
2
)
NR
2
O
H
Bn
H
53
R
2
N
Ph
P(O)(OR
2
O
CO
2
R*
52
Felkin-Anh
(Z)-selective
phosphonate


Scheme 13. Dynamic kinetic resolution of !-aminoaldehydes by an asymmetric HWE-
reaction

13.3. The Peterson Olefination

Conceptually quite similar to the Wittig type reactions but quite
different in scope and limitation are alkenylations that proceed through "-
Classics in Asymmetric Synthesis
9
hydroxysilanes, the so-called Peterson olefination. Most commonly, an !-
silylated carbanion is added to a carbonyl compound to give rise to two
diastereomeric "-hydroxysilanes, which can be isolated analogous to the
previouls discussed Horner-Wittig reaction and separately transformed further to
alkenes. In distinct contrast, however, by careful control of the reaction
conditions either alkene geometry can be obtained from each individual "-
hydroxysilane. Under basic conditions, a syn-elimation of the silyl and hydroxy
group takes place, presumably through a pentacoordinated intermediate, which
is formed by attack of the deprotoanted oxygen onto silicon. On the other hand,
under acidic conditions protonation of the hydroxyl group followed by an E2-
elimination occurs, reversing the stereochemical outcome with respect to the
base variant.
Based on this mechanistic rational it is possible to synthesize selectively
E-alkenes by utilizing the different reaction rates of the diastereomeric "-
hydroxysilanes in the elimination step. Upon sulfur-lithium exchange of 54 and
reaction with an aldehyde, only 57 undergoes is converted at low temperature to
(E)-56, while syn-elimination of 55 is hampered due to steric hindrance between
R and Ar. Subsequent addition of acid then converts 55 in an anti-elimination to
(E)-56 as well.
25

Me Me
Me
SPh Me
3
Si
R
1) LDMAN
2) ArCHO
O
Me
3
Si
Ar
R
H
H
O
Me
3
Si
Ar
H
R
H
78C
fast
slow R Ar
R
Ar
syn
syn
3) AcOH
anti
54
55 (Z)-56
57 (E)-56 (68%)
x
OBn
OBn
Ar =


Scheme 14. Stereoconvergent Peterson reaction

Many methods have been utilized to generate !-silyl carbanions, which
were subsequently reacted with carbonyl compounds to yield alkenes, but the
most valuable strategies are those, which will form "-hydroxysilanes diastereo-
selectively, thus making their separation or the combination of different work up
protocols superfluous in order to arrive at geometrically pure products.
Peterson reagents being stabilized by electron withdrawing substituents
such as aldehydes, ketones or esters, preferentially give rise to (E)-alkenes upon
deprotonation with a lithium base without isolation of the intermediate "-
hydroxysilanes. The origin of this stereoselectivity has not been extensively
explored, but it appears plausible that similar arguments as previously discussed
for stabilized Wittig ylides. For example, in the synthesis of maytansine, the
trisubstituted alkene 60 was synthesized as a single diastereomer using 59, in
which the aldehyde functionality is masked as an imine.

Chart 9. The Peterson olefination

R
2
R
3
CO
R
1
SiMe
3
R
2
R
2
Me
3
Si OH
R
4
R
1
R
3
R
2
Me
3
Si OH
R
3
R
1
R
4
base
Me
3
SiOH
(syn)
base
Me
3
SiOH
(syn)
H
=
Me
3
SiOH
(anti)
R
3
R
4
R
2
R
1
R
4
R
3
R
2
R
1
+

Chart 10. Common methods
for the generation of !-silyl
carbanions.
1. Deprotonation

SiMe
3
R
Lithiumbase SiMe
3
R Li
R = Ar, CO
2
R, CN, OMe, N(Me)=CNR,
Hal, SR, S(O)R, SO
2
R, P(O)(OR)
2


2. Heteroatom Substitution

SiMe
3
X
Lithiumnaphthalid SiMe
3
Li
X = SR, SeMe, SnBu
3
or n-BuLi


3. Nucleophile Addition to
Vinylsilanes
SiMe
3
RLi
SiMe
3
R
or RMgBr
R
1
R
1
M

Oliver Reiser
10
Cl
MeO N
CH
3
OMe
OHC CH
3
OMEM
COCF
3
S
S
NBu
t
H
CH
3
Li
SiMe
3
82%
OHC CH
3
CH
3
OMEM
59
58 60


Scheme 15. Stereoselective Peterson olefination in the synthesis of maytansine.

Alternatively, when non-enolizable alhdeydes are employed,
alkenylation can be induced with fluoride, giving rise to (E)-alkenes with high
stereoselectivity.
26

In contrast, N,N-dibenzyl-(triphenylsilyl)acetamide has been reported to
yield with high selectivity (Z)-alkenes upon metallation with LDA followed by
reaction with aromatic aldehydes.
27


SiPh
3
O
NBn
2
1) LDA
2) ArCHO
NBn
2
O Ar
60 61


Scheme 16. Stereoselective synthesis of (Z)-configurated !,"-unsaturated amides.

Allyltrimetylsilanes 62 can readily be deprotonated with s-BuLi,
however, upon reaction with an aldehyde 4-hydroxy-1-alkenylsilanes by attack
on the #-position in 63 and not Peterson products, which would require attack on
the !-position are often obtained. However, transmetallation of lithium by
titanium, boron or magnesium changes the regioselectivity to the !-position, and
moreover, anti "-hydroxysilanes are obtained with high diastereoselectivity,
which is best explained by a Zimmerman-Traxler type transition state model.
Acid or base induced elimination can then be carried out to yield either Z,E or
E,E-dienes.

Classics in Asymmetric Synthesis
11
Me
3
Si R
62
s-BuLi
Me
3
Si R
63
Li
R
1
CHO
Me
3
Si R
64
HO R
1
1) MX
2) R
1
CHO
O
M
R
1
Me
3
Si
R
R
1
R
OH
SiMe
3
KH
H
2
SO
4
R
R
1
R
R
1
65 66
67
68
M = MgBr
2
, B(OMe)
3
, Ti(OPr
i
)
4
, R = SiMe3, SMe, R
1
= alkyl, Ph
90-94%
91-95%


Scheme 17. Stereoselective synthesis of 1,3-dienes

References

1

2
Modern Carbonyl Olefination; Takeda, T., Ed.; Wiley-VCH: Weinheim,
2004.
3
(a) Maryanoff, B. E.; Reitz, A. B. Chem. Rev. 1989, 89, 863; (b) Vedejs, E.;
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9
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Oliver Reiser
12

18
(a) Rein, T.; Reiser, O. Acta Chem. Scand. 1996, 50, 369; (b) Tanaka, K.;
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24
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25
Huang, W.; Tidwell, T. T. Synthesis 2000, 457-470.
26

27