Download Chapter 1 Organoaluminum Reagents for Selective Organic

Chapter 1 Organoaluminum Reagents for Selective Organic
Transformation
1.1. Epoxide – Allylic Alcohol Rearrangement
The reaction of epoxides with a strong base constitutes a well-known synthetic
method for the preparation of allylic alcohols. In his early days at Kyoto, Yamamoto
demonstrated the reaction proceeded stereo- and regioselectively with organoaluminum
amides [29].
N Al
DATMP
O
90%
OH
DATMP
O
78%
OH
The method was used for his straightforward synthesis of trans-α-farnesene
and juvenile hormone from farnesol [26].
OR
OR
OR
O
HO
O
OR
OH
OR
COOMe
O
HO
O
OH
HO
HO
OH
OH
O
Cecropia juvenile hormone
In 1974, Yamamoto synthesized humulene in a highly stereoselective manner.
This is the first example of palladium catalyzed medium ring cyclization. Another key
step of the synthesis is the base catalyzed elimination of oxetane, a similar
transformation using aluminum amide reagent to that described above [39].
Pd(PPh 3)4
O
1 LAH
2 TsCl, base
O
O
OAc
COOMe
COOMe
1 Oxid.
2 WK
Et2AlNMePh
Humulene
OH
1.2. Aldol Synthesis
Complexes of organoaluminum compounds and ketones led to a variety of
reactions. An example is the reaction of haloketone and aldehyde developed by
Yamamoto. The critical part of the process is the coupled attack of the α-haloketone
by diakylakuminum chloride and zinc dust which generates an aluminum enolate
regioselectively. The method was used for short synthesis of medium and large ring
compounds [43].
O
+
Br
O
O
PhCHO
O
Br
Me
O
Zn / Et2 AlCl
Ph
100%
68%
OH
O
O
OH
Me
1.3. Beckmann Rearrangement Using Organoaluminum Reagent
The Beckmann rearrangement is the skeletal rearrangement of ketoximes in the
presence of certain acids under aqueous conditions to give amides or lactams.
Reexamination of this reaction using organoaluminum reagents under aprotic conditions
led to the abstraction of the sulfonyl group, followed by capture of the intermediary
iminocarbocation or alkylidyneammonium ion with the nucleophilic group (X; R2AlX
(X = R, SR’, SeR’)) on the aluminum. Thus, aluminum reagents act not only as a
2
Lewis acid but also as a base [73].
R2
R1
N
R1 N C R2
R2AlX
R1
N
X
R1 N C R2
OSO2R'
R2
X
This method opens a new synthetic entry to a variety of alkaloides such as
Pumiliotoxin C [60].
H
1) n-Pr3 Al
2) DIBAL
H
O
N OTs
H
60%
N
H H H
Pumiliotoxin C
The intermediary iminocarbocation or alkylidyneammonium ion generated by
an organoaluminum can also be trapped intramolecularly with olefinic groups [71] .
This interesting rearrangement–cyclization sequence can be extended to an efficient
synthesis of muscopyridine [72].
R
N
O
Me
S
O
O
R
1) Et2AlCl
2) DIBAL
N
H
O
88%
N
1.4. Nucleophilic Aromatic Substitution
3
Muscopyridine
Muscone
Arylhydroxyamines behave in a different manner from alkylhydroxyamines on
treatment with organoaluminum compounds [80].
The highly oxygenophilic
organoaluminum reagent can cleave the N–O bond heterolytically to yield a
phenylaminyl cation, which undergoes nucleophilic attack by an alkylaluminum at the
ortho or para position of the aromatic ring.
N
OAc
Me3 Al
N
N
Ph
N
Ph
Ph
Ph
+
NH
NH
71% (3:2)
Ph
Ph
The synthetic potential of this novel reaction has been demonstrated by the
synthesis of indol derivatives [80].
SiMe3
F
N
Me
1.5.
OSiMe3
(Me 3SiC C)3Al
F
N
Ph
Me
H
Ph
F
CuI-CaCO3
N
DMF
83%
Me
96%
Ph
Hydroalumination of Olefins Catalyzed by Organoborane
Phenylboric acid catalyzed hydroalumination of Cl2AlH to various olefins in high
yields. Regio- and chemoselectivity of the reaction is exceedingly high [119].
catalytic R B
C C
Cl2AlH
H C C AlCl2
E+
H C C E
1.6.
Biomimetic Heterolysis of Allyl Phosphates
Reactions of dialkyl phosphates of a variety of terpene alcohols were exposed to
organoaluminum reagents. After careful investigation of these systems, Yamamoto
achieved biomimetic synthesis of many terpenes with this technology [34].
Chapter 2. Development of Designer Lewis Acids
4
Classical Lewis acids activate a wide variety of functional groups of substrates,
and the reactions usually proceed efficiently but with relatively low stereo-, regio-, and
chemoselectivities. Relatively simple design of the ligands of these Lewis acids leads
to monomeric Lewis acids in organic solvent and consequently to high Lewis-acidity
and reactivity. Furthermore, upon coordination with designed ligand(s), the well
designed Lewis acid exhibits new selectivity.
Classical Organic Synthesis
(Carbon-Carbon Bond Formation)
Diels-Alder Reaction
Aldol Synthesis
Ene Reaction
Friedel-Crafts Reaction
Lewis Acid Catalysts
(AlCl3 , AlR3 , RAlCl2 , R2 AlCl)
Modification
of Ligands
Modern Organic Synthesis
Designer Lewis Acid Catalysts
(MAD, MABR, ATPH, ATPH-Br)
Stereo-, Regio- and Chemoselective
Reactions
Introduction
of Chiral Ligand
Asymmetric Synthesis
Chiral Lewis Acid Catalysts
In the early 1970’, Yamamoto, together with H. Nozaki, reported the first and a
variety of examples of such designer Lewis acid catalysts using organoaluminum
reagents [44]. These results encouraged further work by a large number of scientists in
various laboratories worldwide and Yamamoto’s principle is now accepted as one of the
fundamental chemical means of organic synthesis.
2.1. Preparation of Various Aluminum Phenoxides
Several bulky aluminum reagents can be prepared from sterically hindered
phenols. Most aluminum reagents in solution exist as dimeric, trimeric, or higher
oligomeric
structures.
In
contrast,
methylaluminum
bis(2,6-di-tert-butyl-4-methylphenoxide)(MAD)
and
aluminum
tris(2,6-diphenylphenoxide)(ATPH) are monomeric in organic solvent. Lewis-acidity
5
of these reagents decreases with the coordination of more electron-donating aryloxides,
but this can be compensated for by loosening of the aggregation. Compared with
classical Lewis acids, the steric effect of our aluminum reagents also plays an important
role in selective organic synthesis [R-27, 28, 323].
Thus, MAD, ATPH, methylaluminum bis(4-bromo-2,6-di-tert-butylphenoxide)
(MABR) and methylaluminum bis(2,6-diphenylphenoxide)(MAPH) are readily
prepared by treatment of Me3Al with a corresponding amount of the phenol in toluene
(or in CH2Cl2) at room temperature for 0.5~1 hour with rigorous exclusion of air and
moisture. The reactivity of a phenol toward Me3Al largely depends on the
stereochemistry of the phenol.
For example, treatment of 3 equiv of
2,6-di-tert-butyl-4-methylphenol with Me3Al in CH2Cl2 at room temperature under
argon results in the generation of bisphenoxide MAD together with the unreacted
phenol. In contrast, 3 equiv of 2,6-diphenylphenol completely reacts with 1 equiv of
Me3Al to produce the trisphenoxide ATPH.
R1
OH
Me3Al
(1/2 equiv)
toluene
or
CH2Cl 2
R1
O
1
O
R
Al
Me
MAD : R 1 = Me
MABR : R 1 = Br
Ph
R2
OH
Me3Al
(1/3 equiv)
toluene
or
CH2Cl 2
Ph
R2
O
Ph
Ph
toluene
Me3Al
or
(1/2 equiv)
CH2Cl 2
R2
Ph
Al
Me
O
Al
O
Ph
Ph
ATPH
: R2 = H
ATPH-Br : R2 = Br
R2
O
O
R2
R2
Ph
Ph
Ph
Ph
Ph
2
MAPH : R = H
6
2.2. Structural Features of ATPH
The X-ray crystal structure of the N,N-dimethylformamide-ATPH complex
[251] disclosed that three arene rings of ATPH form a propeller-like arrangement around
the aluminum center, and hence ATPH has a cavity with C3 symmetry. By contrast, the
X-ray crystal structure of the benzaldehyde-ATPH complex shows that the cavity
surrounds the carbonyl substrate upon complexation with slight distortion from C3
symmetry. A particularly notable structural feature of these aluminum-carbonyl
complexes is the Al-O-C angles and Al-O distances, which clarify that the size and the
shape of the cavity change flexibly depending on the substrates. According to these
models, the cavity should be able to differentiate carbonyl substrates, which when
accepted into the cavity should exhibit unprecedented reactivity under the steric and
1
electronic environment of the arene rings.
H NMR measurement of
crotonaldehyde-ATPH complex (300 MHz, CD2Cl2) revealed that the original chemical
shifts of the aldehydic proton (Ha) at δ 9.50, and the α- and β-carbon protons (Hb and
Hc) at δ 6.13 and δ 6.89, were significantly shifted upfield to δ 6.21, δ 4.92 and δ 6.40,
respectively. The largest ∆δ value of Ha of 3.29 ppm suggests that the carbonyl is
effectively shielded by the arene rings of the cavity. This observation is in contrast to
the resonance frequencies of the crotonaldehyde-Et2AlCl complex at -60 °C ( Ha: δ
9.32; Hb: δ 6.65; Hc: δ 7.84), and those of crotonaldehyde complexes with other
ordinary Lewis acids.
7
2.3. Molecular Recognition with Bulky Aluminum Reagents
The monomeric aluminum phenoxides have sufficient Lewis-acidity and thus
bind with polar functionalities. The complexation heavily depends on the structural
features of these functional groups. Thus, functional groups outside a molecule bind to
bulky aluminum reagents rather tightly and functional groups inside a molecule cannot
form stable complexes. In other words, the steric bulk of aluminum reagents appears to
play a crucial role in discriminating among structurally or electronically similar
substrates.
2.3.1. Discrimination of Two Different Ethers with MAD
The 125-MHz 13C NMR measurement of a mixture of 1 equiv each of MAD,
methyl 3-phenylpropyl ether, and ethyl 3-phenylpropyl ether in CDCl3 (0.4 M solution)
at -50 °C showed that the original signal of methyl ether at δ 58.7 shifted downfield to δ
60.1, whereas the signal of the α-methylene carbon of ethyl ether remained unchanged.
The unusual selectivity could not be observed with other Lewis acids as shown below.
This method could be extended to the use of a polymeric aluminum aryloxide in
complexation chromatography: heteroatom-containing solutes can be separated by
complexation with stationary, insolubilized organoaluminum polymer [174].
Ph
O
+ Ph
Lewis acid
O
LA
Ph
O
LA
+
Ph
O
MAD
i-Bu3 Al
SnCl4
: >99 : 1
: 4:1
: 2 equiv of ethers coordinated
to SnCl4 to form a 2 : 1 complex
BF3 •OEt2 : no complexation
BEt3
: 5:3
2.3.2.
Discrimination of Two Different Ketones with MAD
Selective reduction of more hindered or electronically less polarizable ketones
can be accomplished using MAD as a selective stabilizer of the carbonyls of less
hindered or electronically more polarizable ketones [138, 140].
8
O
O
+
MAD
O
MAD
(1 equiv)
O
MAD
+
>99 : 1
OH
DIBAL
(1 equiv)
OH
+
toluene
-78 °C
66 % (1 : 10)
2.3.3. Discrimination of two Different Esters with MAD
Discrimination of two different ester carbonyls can be similarly achieved with
MAD [201, 222]. For example, reaction of tertbutyl methyl fumarate with 1.1 equiv of
MAD in CH2Cl2 at -78 °C gave new organoaluminum fumarate exclusively, the
structure of which was rigorously established by low-temperature 13C NMR
spectroscopy. Diels-Alder reaction of a complex with cyclopentadiene gave a single
isomer, predominantly with endo orientation of the methoxycarbonyl group. Thus, the
methyl ester coordinated with the aluminum reagent gave us high endo-selectivity of the
Diels-Alder reaction.
CO2 Me
RO2C
R = Bu
t
MAD
OMe
MAD
CH2 Cl2
O
OR
8
MAD
R = But :
CO2 R
-78 °C
O
+
O
OMe
O
OR
>99 : 1
CO2 Me
+
CO2Me
CO2R
t
R = Bu : 86 % (>99 : 1)
i
= Pr : 90 % (89 : 11)
= Et : 66 % (71 : 29)
2.3.4.
Discrimination of Two Different Aldehydes with MAPH and ATPH
ATPH can discriminate between structurally similar aldehydes, thereby
facilitating the selective functionalization of the less hindered aldehyde carbonyl.
Treatment of an equimolar mixture of valeraldehyde and cyclohexane-carboxaldehyde
with 1.1 equiv of ATPH in CH2Cl2 at -78 °C, followed by addition of Danishefsky’s
9
diene at this temperature proceeded hetero-Diels-Alder selectively. It should be noted
that the complexed aldehyde could only react with the diene [258].
CHO +
ATPH
CHO
+
O
CH2 Cl2
OSiMe 3
ATPH
OSiMe 3
-78 °C
-78 °C
OH O
O
ATPH
OMe
O
+
OH O
O
75 % (>99 : 1)
O
+
O
87 % (>99 : 1)
Obviously, the coordinated aldehyde is electronically activated but sterically
deactivated with bulky aluminum reagents. The selective functionalization of more
sterically hindered aldehydes was accomplished by the combined use of MAPH and
alkyllithiums (RLi; R= n-Bu or Ph) [218] In this system, MAPH acted as a carbonyl
protector of a less hindered aldehyde [175, 226], and therefore the carboanions
preferentially react with more hindered carbonyl groups.
MAPH
CHO +
CHO
CH 2Cl2
-78 °C
reagent
O Al
+
OH
+
n-Bu
: 31 % (2.5 : 1)
n-BuTi(OPri) 3 (1 eq.)
MAPH (1 eq.)/ n-BuLi (1 eq.) : 76 % (1 : 6.5)
MAPH (2 eq.)/ n-BuLi (2 eq.) : 45 % (1 :14)
10
CHO
OH
n-Bu
Chapter 3. Bulky Aluminum Reagents for Selective Organic Synthesis
In chapter 2 we discussed several excellent methods of discriminating various
functional groups using bulky aluminum reagents. In this section we focus on the
reactions promoted with bulky aluminum reagents which could not be achieved with
ordinary Lewis acid catalysts.
The following is a typical example which shows the potential of a bulky
aluminum reagent for a new selectivity. When MAD was mixed with the carbonyl
compound 4-tert-butylcyclohexanone, MAD gave a stable 1:1 complex. This complex
was treated with methyllithium at low temperature to yield an equatorial alcohol, the
stereochemistry of which was opposite that of the product from reaction of
cyclohexanone with methyllithium. The equatorial selectivity achieved with MAD was
found to be perfect [102, 139].
O
t-Bu
1)
OH
Al
2) MeLi
Me
Me + t-Bu
t-Bu
OH
equatorial alcohol
axial alcohol
: 85% (79:21)
MeLi
MAD/MeLi : 84% (1:99)
Such complexation also allows inversion of nucleophilic addition to chiral
aldehydes. While ethylmagnesium bromide, on reaction with 2-phenylpropanol, obeys
Cram’s rule, the opposite mode is largely favored in the presence of MAD [102, 139].
Me
Ph
CHO
Me-M
Me
Me
Me
Ph
OH
Cram
+
Ph
Me
OH
anti- Cram
EtMgBr
: 78% (84:16)
MAD/EtMgBr : 90% (25:75)
3.1. Stereoselective Claisen Rearrangement
Claisen rearrangement is accelerated significantly by bulky aluminum reagents
[151, 167]. With MABR, the rearrangement of 1-substituted-2-propenyl vinyl ether
derivatives takes place in a few seconds even at -78 °C to give the 4-(Z)-alkenols after
reduction with NaBH4. When MABR is replaced by MAPH, (E)-isomers are formed
11
preferentially.
Al
R
NaBH4
CH2Cl 2
O
R = i-Bu
vinyl
allyl
+
R
OH
(E)
MABR
R = i-Bu ; 64 % (7 : 93)
vinyl ; 97 % (24 : 76)
allyl ; 40 % (7 : 93)
R
(Z)
OH
MAPH
85 % (97 : 3)
91 % (90 : 10)
97 % (95 : 5)
This stereochemical reversal observed with MABR and MAPH can be
accounted for by two possible chair-like transition state structures, which was proposed
by the absolute configuration of the double bonds and the allylic carbons of the
produced aldehydes.
Aromatic side chains
prevent the R group from
axial orientation
A-strain because of the
bulky aluminum reagent
R
Me
O
Al
R
O
Me
(ax)
(eq)
MABR
MAPH
Me
R
Al
Me
CHO
R
(Z)
CHO
(E)
3.2. Stereoselective ene-Reaction
Intramolecular ene reactions of α-substituted-δ,ε-unsaturated aldehydes were
achieved in a stereoselective manner using MABR [180].
The reaction shows
unprecedented trans-selectivity, in contrast to the cis-selectivity frequently observed in
the type II ene reaction with other ordinary Lewis acids.
12
MABR
+
CH2 Cl2
-40 °C
O
trans
OH
cis
OH
85% (17:1)
3.3.
Stereoselective Epoxide Rearrangement
Two different rearrangement modes of β-siloxy epoxides gave distinct β-siloxy
aldehydes using MABR as a key reagent depending on the substrate employed [160,
Since optically pure α-siloxyepoxides are easily accessible by the
185].
Katsuki–Sharpless asymmetric epoxidation, this rearrangement protocol is very useful
to obtain optically pure β-siloxyaldehydes which are often key building blocks in
natural product syntheses.
MABR
O
Ph
MABR
OSiMe 2t-Bu
Ph3SiO
CH2 Cl2
-78 °C
OSiMe 2t-Bu
O
OSiMe 2t-Bu
Ph
MABR
O
MABR
Ph3SiO
O
Ph
CHO
Ph3SiO
H
CHO
H
toluene
-40 °C
87%
88%
eryrhro/threo = 1:100
3.4. Primary α-Alkylation of Carbonyl Compounds
Primary α-alkylation of carbonyl compounds proceeded with silyl enol ethers,
MABR and alkyltriflates under non-basic conditions.
This is tolerated by
base-sensitive functional groups [207].
R
MABR, ROTf
OSiMe 3
CH2 Cl2, -40 °C
O
R = Me (84%); Et (73%); Hexyl (80%)
OSiMe 3
MABR, MeOTf
Me
CH2 Cl2, -40 °C
CHO
55%
3.5. Conjugate Addition to α,β-Unsaturated Carbonyl Compounds
Organocuprates are the most widely used reagents for Michael addition to
13
α,β-unsaturated ketones, and for one of the most powerful and important carbon-carbon
bond-forming reactions. ATPH can be used as a carbonyl protector upon complexation,
which facilitates 1,4-addition to even α,β-unsaturated aldehydes for which 1,4-addition
is virtually unexplored [251]. Complexation of cinnamaldehyde with 1.1 equiv of
ATPH in CH2Cl2 at -78 °C, followed by subsequent addition of 1.5 equiv of
n-butylmagnesium bromide (n-BuMgBr), gave the 1,4-addition product preferentially.
The alkylation of cinnamaldehyde with MAD and n-BuMgBr gave unsatisfactory
results (95 %; 1,4/1,2-adduct ratio = 7 : 93). The combination of MAPH with the same
butylating agent gave an equal mixture of 1,4- and 1,2-adducts (98 %; ratio = 49 : 51).
Replacing organomagnesium reagents with organocalcium, strontium, and barium
enhanced 1,4-selectivity.
Ph
CHO
C ßCSiMe3
Me3SIC ßCLi
DME
90 %
Ph
17
CHO
ATPH
CH2 Cl2
Ph
[1,4]
RM
ether
-78 °C
O Al
[1,2]
LiTMP/THF
-78 ~ 25 °C
86%
Ph
CHO
Ph
CHO +
R
OH
R
1,2-adduct
1,4-adduct
RM = n-BuLi
n-BuMgCl
n-BuCaI
n-BuSrI
n-BuBaI
Ph
:
:
:
:
:
92 % (49 : 51)
99 % (90 : 10)
88 % (98 : 2)
60 % (95 : 5)
97 % (97 : 3)
Cl
One advantage of this method over organocopper-mediated conjugate addition
is the availability of lithium alkynides and thermally unstable lithium carbenoids as
Michael donors. With alkynides, raising the reaction temperature after the Michael
addition afforded cyclopropanation to give a sole diastereomer.
Selective 1,6-addition of alkyllithiums to aromatic carbonyl substrates such as
benzaldehyde or acetophenone was achieved with ATPH to give functionalized
cyclohexadienyl compounds [285].
According to the molecular structure of the
benzaldehyde-ATPH complex, it is obvious that the para- position of benzaldehyde is
deshielded by the three arene rings, which effectively block the ortho- position as well
as the carbonyl carbon from nucleophilic attack.
14
OH
CHO
+
CHO
CHO
OLi
CO2Bu
t
t
CHO 1) Me3 Si
CO2Bu
MePh2Si
t
OBu
Bu Li
OLi
Ph2MeSiLi
ATPH
O
OBu t
CHO
Li
2) TBAF/MeOH
t
OLi
Li
Li
OMe
CHO
CHO
CHO
CO2Me
CO2 H
The values in parentheses is the ratio of 1,6- and 1,4-adducts.
90% (15:1)
CO2H
t-Bu
(13:1)
i-Pr
71%
CO2Me
O
(>99:1)
Ph
MgCl
PhLi
96%
MgBr
CO2Me
Li
(8.5:1)
53%
OLi
Cl
Ot-Bu
t-BuO
CO2H
O
78%
CO2Me
Li
ATPH
68%
(3.4:1)
(7.9:1)
OLi
LiO
OMe
CO2H
OLi
72%
OLi
75%
O
(>99:1)
CO2H
41%
MeO
O
46%
CO2H
(>99:1)
O
(>99:1)
O
CO2H
(>99:1)
Unfortunately, however, conjugate addition to the ATPH–PhCHO complex did
not proceed effectively with smaller nucleophiles.
15
Yamamoto and his colleagues
recently illustrated that ATPH–ArCOCl is superior to ATPH–PhCHO for the
nucleophilic dearomatic functionalization. Several analytical and spectral data showed
that the ATPH–PhCOCl complex was more reactive than ATPH–PhCHO[367].
X-ray crystal structure (space-filling model) of the
ATPH-benzaldehyde complex, which shows more facile
nucleophilic attack at the para-position.
The 1,4-addtion process was the key step of the synthesis of jasmonates. The
synthesis involves the combined use of: (1) organolithium reagent (RLi); (2) aluminum
tris(2,6-diphenylphenoxide) (ATPH)-cyclopentenone complex; and (3) 2,5-dihydrofuran
(DHF)–BCl3 complex[387].
Al
RLi +
O
ATPH
-
BCl3
+
Li+
O
Al
Ln M
O
OML n-1
O
O
R
R
O
O
CO2Me
CO2H
trans-jasmonic acid
cis-methyl jasmonate
3.6. Exo-Selective Diels-Alder Reaction
One characteristic stereochemical feature of the Diels-Alder reaction is
endo-selectivity. The origin of the endo-preference in Diels-Alder reactions can be
ascribed to “secondary orbital interactions”. If the carbonyl functions of dienophilic
16
α,β-unsaturated carbonyl substrates are effectively shielded by complexation with ATPH,
secondary interaction is decreased, thereby disfavoring the hitherto preferred endo
transition state.
R1
Lewis Acid (LA)
R1
O LA
O
R
R
endo transition state
+
R
R
R1
endo isomer
R
O Al
O
ATPH( Al
)
O
1
R
R1
exo transition state
exo isomer
As expected, precomplexation of α,β-unsaturated ketone with ATPH in CH2Cl2
at -78 °C, followed by cyclization with cyclopentadiene, resulted in the stereochemical
reversal to furnish exo-adduct as a major product [269].
O
1
R
1) ATPH/CH2Cl2
R
COR
2)
R1
exo
-78 °C
R1
+
COR
endo
R = Ph, R1 = H ; 81 % (73 : 27)
R = Ph, R1 = Me : 81 % (96 : 4)
: 87 % (87 : 13)
R = R1 = Me
3.7. Stereoselective Claisen Rearrangement
Claisen rearrangement is believed to proceed via a six-membered transition
state. The preferential conformation of the reactant in the transition state might be due
to the shape and the size of the cavity of ATPH. This hypothesis can be verified by
treatment of 1-butyl-2-propenyl vinyl ether with ATPH at 0 °C to give isomeric
rearrangement products in 87% yield in a ratio of 16 : 1 [273].
Al
Bu
O
CH2 Cl2
0 °C
NaBH 4
+
Bu
OH
17
Bu
OH
MAPH : 75 % (5 : 1)
ATPH : 87 % (16 : 1)
3.8. Selective Alkylation at the α-Carbon of Unsymmetrical Ketones
An unsymmetrical dialkyl ketone can form two regioisomeric enolates upon
deprotonation under either kinetic or thermodynamic control. Ideal conditions for the
kinetic control of less-substituted enolate formation are those in which deprotonation is
irreversible using lithium diisopropylamide (LDA). On the other hand, at equilibrium,
the more substituted
enolate
is
the
dominant
species
with
moderate
selectivity. A hitherto unknown method, i.e., the kinetically controlled generation of
the more substituted enolate, was realized by the combined use of ATPH and LDA
[306].
O
OLi
O
Me
LDA
Me
MeX
Me
Me
alkylation at the
less hindered site
ATPH
ATPH
O
ATPH
ATPH
Me
O
OLi
O
Me
LDA
Me
Me
Me
MeOTf
alkylation at the
more hindered site
Precomplexation of ATPH with 2-methylcyclohexanone at -78 °C in toluene
was followed by treatment with LDA in tetrahydrofuran (THF), and the mixture was
O
1) ATPH/toluene
O
stirred for 1 h. Subsequent treatment with methyl trifluoromethanesulfonate furnished
2) LDA/THF
2,2-dimethylcyclohexanone and
2,6-dimethylcyclohexanone
in an isolated yield of
3) OctOTf
Oct
53 % in a ratio of 32 : 1. Similarly, highly89%
regiocontrolled
alkylation
of unsymmetrical
( > 99 % selectivity
)
ketones with octyl triflate proceeded selectively as shown below (>99 : 1).
O
1) ATPH/toluene
O
Oct
2) LDA/THF
3) OctOTf
71% ( >99 % selectivity )
18
Generation of the kinetically deprotonated more substituted enolate can be
explained in terms of the effect of ATPH on the inherent coordination preference of
unsymmetrical ketones.
Most likely, the bulky aluminum reagent ATPH prefers
coordination with one of the lone pairs anti to the more hindered α-carbon of the
unsymmetrical ketones. As a consequence, the aluminum reagent surrounds the less
hindered site of the carbonyl group, thus obstructing the trajectory of the nucleophilic
attack of LDA.
Space-filling model of the ATPH-methylcyclohexanone complex.
LDA attacking is more feasible at the more substituted α-carbon
3.9.
New Directed Aldol Condensation between two Different Carbonyl
Compounds
The mixed aldol condensation between two different carbonyl compounds
which present several possible sites for enolization is very difficult including proton
transfer and over-alkylation.
Recent progress has been made in the directed mixed
crossed aldol condensation of two different carbonyl compounds which involves the
control of reactivity and selectivity of the activated enolates using ATPH [R-34, 329].
Precomplexation of PhCHO and crotonaldehyde with ATPH was followed by treatment
with LDA to give γ-aldol adduct in 99% yield. The reaction generally proceeds even
with other carbonyl substrates with high E and γ selctivity.
19
O
ATPH
CHO (2.2 eq)
toluene
-78 °C
CHO
+
ATPH
ATPH
O
OH
LDA
(1.2 eq)
+
CHO
THF
-78 °C
H
yield 99%
E:Z = >99:1
γ:α = >99:1
deprotonation
However,
when
β,β-disubstituted-α,β-unsaturated
carbonyl
compounds
complexed with ATPH were subjected to the alkylation reaction with an aldehyde in the
presence of LDA or LTMP, different selectivity was observed depending on the
carbonyl functionality employed: the predominant alkylation site was at the (Z)–γ
position of methyl 3-methyl-2-butenoate,
whereas senecialdehyde gave the
(E)–γ-addition product exclusively. This could be ascribed to a specific complexation
of ATPH with a different carbonyl compound by molecular recognition, which was
rigorously ascertained by X-ray crystal analysis and NOE measurement.
"(Z)–γ"
OMe
CHO
"(E)–γ"
+
α
O
1) ATPH (2.2 eq)
toluene, -78 °C
Ph
HO
Z
2) LTMP (1.2 eq)
THF, -78 °C
Ph
OMe +
E
HO
O
OMe
O
91% (13:1)
Ph
CHO
+
1) ATPH (3.3 eq)
toluene, -78 °C
H
O
HO
2) LDA (2.3 eq)
THF, -78 °C
Z
H
Ph
+
O
HO
E
H
O
99% (1:>99)
3.10. Remarkable Enhancement of Catalyst Activity of Trialkylsilyl Sulfonates on
the Mukaiyama Aldol Reaction
Yamamoto and his colleagues disclosed the remarkable rate enhancement on
the trialkylsilyl triflate-catalyzed Mukaiyama aldol reaction of silyl enol ethers by using
a bulky organoaluminum reagent, i.e., MAD or MABR, as a cocatalyst [334]. Thus, a
more strongly Lewis acidic species forms from two different Lewis acids of the bulky
organoaluminum reagent and Me3SiOTf in the presence of an aldehyde.
20
Me
O Al O
Br
Br
Me 3SiOTf
Highly reactive Lewis acid catalyst
3.11. Chiral Aluminum Reagents in Asymmetric Synthesis
Biomimetic synthetic approach involving the organoaluminum-accelerated
cyclization of chiral alkoxides to limonene was highlighted by chiral leaving group
strategy [79]. A modfied aluminum reagent which has a bulky phenoxy ligand and a
strong electron-withdrawing group (-OTf) was devised to obtain high reactivity and
selectivity.
The reaction of (R)-(+)-binaphthol mononeryl ether with this bulky
aluminum reagent proceeded via effective activation of the allyl ether and subsequent
elimination of binaphthol to give D-limonene in 77% ee.
OH
OH
O
Al
OTf
O
OH
O
O
Al
D-limonene
58% (77% ee)
(R)-(+)-binaphthol
Asymmetric hetero-Diels-Alder reaction was found to be catalyzed by the
optically pure bulky aluminum reagent [134].
Thus, treatment of a mixture of
benzaldehyde and siloxydiene under the influence of catalytic amount of binaphthol
derived reagent furnished cis-dihydropyrone in 93% yield with 97% diastereoselectivity
and 97% ee. The same catalyst was used as in the first asymmetric ene reaction.
SiR 3
O
O
Me 3SiO
+
OMe
PhCHO
21
R = Xylyl
Al Me
SiR 3
H+
97% de
97% ee
O
Ph
O
The same optically pure aluminum reagent is an excellent promoter for the
asymmetric Claisen rearrangement of allyl vinyl ethers which possess bulky
substituents such as trialkylsilyl- or trialkylgermanium groups [176].
SiAr3
Ph
O
2
O
AlMe
AlMe
O
SiAr3
Ar3 = t-BuPh2
MAPH
Ph
O
Ph
catalyst
(1.1 ~ 1.2 eq.)
R
CH2 Cl2
-78 ¨ -40 °C
R = SiMe 3
= GeMe3
O
R
R = SiMe3 : 76 % (90 %ee)
= GeMe3 : 68 % (93 %ee)
Based on the structure of ATPH, an optically active catalyst, aluminum
tris((R)-1-α-naphthyl-3-phenyl-2-naphthoxide)((R)-ATBN), was synthesized, and was
subjected to the asymmetric Claisen rearrangement of to give the corresponding
aldehydes
elaborate
in moderate
enantioselectivities (>60% ee).
(R)-ATBN
In contrast, the more
analogue,
tris((R)-1-α-naphthyl-3-p-fluorophenyl-2-naphthoxide)
products of up to 92% ee [273].
22
((R)-ATBN-F),
aluminum
generated
Ar
Ph
O
3
O
Al
: (R )-ATBN
Ar = Ph
= p-F-Ph : (R )-ATBN-F
ATPH
R
O
R = Ph
c-hexyl
t-Bu
Me3Si
Al
3
Al
R
(1.1 ~ 1.2 eq.)
toluene
-78 °C
O
R = Ph : (R )-ATBN
: (R )-ATBN-F
: 93 % (61 %ee)
: 97 % (76 %ee)
R = c-hexyl : (R )-ATBN-F
: (R )-ATBN-F
t-Bu
Me3 Si : (R )-ATBN-F
: 85 % (86 %ee)
: 70 % (91 % ee)
: 78 % (92 % ee)
It is reasonable to anticipate that certain chiral ketones may discriminate
between racemic organoaluminum reagents by diastereoselective complexation:
preferential formation of one of the diastereomers.
Indeed, the Lewis acidic
enantiomer that in situ remained intact promoted the asymmetric hetero-Diels-Alder
reaction of several aldehydes with substituted Danishefsky diene in high
enantioselectivity [155]. The so-called concept of “chiral poisoning” of one of two
active enantiomers triggers the selective and relative activation of another enantiomer.
Similar approaches using this strategic chiral poisoning for asymmetric synthesis have
also been reported.
23
SiPh3
O=CR*R'*
O
O
SiPh3
O
SiPh3
O=CR*R'*
Al
Me
O
+
O
SiPh3
Al Me
SiPh3
(R)/ketone complex
Al Me
(S)
O
SiPh3
SiPh3
SiPh3
( })
O
O=CR'*R*
enantiomer of
O=CR*R'*
O
Al Me
O
+
O
O=CR'*R*
Al
Me
SiPh3
SiPh3
(S)/ketone complex
(R)
O
O
Ph
OSiMe 3
+
H
(10 mol%)
Br
( })-cat (10 mol%)
MeO
CH2Cl 2
-78 °C
Me
O
O
Ph
Me
75%, 82% ee
24
Chapter 4. Enantioselective Synthesis Using Chiral Lewis Acids
In 1985 Yamamoto and his colleagues reported the first logically designed
chiral Lewis acid catalyst for asymmetric synthesis: an asymmetric cyclization took
place efficiently using chiral zinc reagent derived dimethylzinc and optically active
binaphthol. The reaction proceeds smoothly at low temperature to generate the
cyclization product in reasonable asymmetric induction. Since then, a great number of
chiral Lewis acid catalysts have been reported in the literature and the resulting process
is now an essential tool for many asymmetric syntheses [98].
O
Zn
O
CHO
OH
CH2Cl2, -78~0 °C
91% yield
90% ee
4.1. Chiral (Acyloxy)boranes (CAB)
Yamamoto and his colleagues found that the action of a controlled amount of
diborane on a carboxylic acid leads to an (acyloxy)borane RCO2BR'2 which behaves as
a Lewis acid: the chiral (acyloxy)borane (CAB) complex that is formed in situ from
monoacyl tartaric acid and diborane [147]. Yamamoto and his colleagues has achieved
highly enantioselective carbo-Diels–Alder [147, 156, 165, 215, 240, 243],
hetero-Diels–Alder [206, 246], aldol [182, 193, 239], and allylation [194, 241] reactions
using a common CAB catalyst.
The CAB (R’ = Me, R = H) is an excellent asymmetric catalyst for the
Diels–Alder reaction between cyclopentadiene and acrylic acid [147] or methacrolein
[156, 240]. The reaction with acrylic acid deserves special attention, since usually it is
not a good component in Diels–Alder reactions. The α-substituent on the α,β-enals
increased the enantioselectivity. When there was a β-substitution on the α,β-enals, the
cycloadduct was almost racemic, but for a substrate having substituents at both α- and
β-positions, high ee's were observed.
According to NOE studies of the
CAB-coordinated methacrolein and crotonaldehyde, the effective shielding of the
si-face of the coordinated α,β-enal arises from π-stacking of 2,6-dialkoxybenzene ring
25
and the coordinated aldehyde [243].
OR' O
O
CO2H
O
OR'
BR
O
O
CAB
Diels–Alder adducts (10 mol%)
CHO
CO2H
exo/endo: 4/96
endo: 78% ee
CHO
exo/endo: 89/11 exo/endo: 4/96
exo: 96% ee
exo: 92% ee
A little later Yamamoto and his colleagues reported that CAB (R’ = i-Pr, R = H)
is also an excellent catalyst for the Mukaiyama condensation of simple enol silyl ethers
of achiral ketones with various aldehydes [182]. Furthermore, the reactivity of aldol
reactions can be improved without reducing the enantioselectivity by using CAB (R =
3,5-(CF3)2C6H3 or R = o-PhOC6H4) [239]. The CAB-catalyzed aldol process allows
the formation of adducts in a highly diastereo- and enantioselective manner (up to 99%
ee) under mild reaction conditions. Another aldol-type reaction of ketene silyl acetal
derived from phenyl esters with achiral aldehydes also proceeds smoothly with 2 and
can furnish erythro β-hydroxy esters with high optical purity [193]. Regardless of the
stereochemistry of enol silyl ethers, syn aldols are highly selectively obtained via the
acyclic extended transition-state mechanism. Judging from the product configurations,
CAB catalyst (from natural tartaric acid) should effectively cover the si face of carbonyl
following its coordination.
R 1CHO
OTMS
+
R2
R3
1) CAB (10~20 mol%)
EtCN, -78 °C
HO
O
R1
2) 1N HCl or TBAF
R3
2
R
HO
O
Ph
(83%), 97% ee syn
syn:anti=>95:5
(R=3,5-(CF3) 2C6H 3)
HO
Ph
O
HO
OPh
92% ee syn
syn:anti=79:21
(R' = iPr; R = H)
Ph
O
HO
Ph
(92%), 96% ee syn
syn:anti=99:1
(R=3,5-(CF3)2 C6H3)
26
Pr
O
OPh
97% ee syn
syn:anti=96:4
(R' = iPr, R = H)
R3
TMSO
anti
R1
TMSO
H
H
R2
O
CAB
<
R
3
R1
H
H
R2
O
syn
CAB
Extended Transition-State Model
Yamamoto and his colleagues found for the first time that chiral Lewis acid
catalyzed the Sakurai-Hosomi reaction asymmetrically. Thus, CAB has a powerful
activity for the reaction to furnish homoallylic alcohols in excellent enantiomeric excess
[194]. Alkyl substitution at the olefin moiety of allylsilanes increases the reactivity,
permitting a lower reaction temperature with improved asymmetric induction.
γ-Alkylated allylsilanes exhibit excellent diastereo- and enantioselectivities affording
erythro homoallylic alcohols of higher optical purity. Regardless of the geometry of
starting allylsilanes, the predominant isomer in this reaction had erythro configuration.
The observed preference for relative and absolute configurations for the adducts is
predicted on the basis of an extended transition-state model similar to that for the
CAB-catalyzed aldol reaction. The boron substituent of 3 has strong influence on the
chemical yield and the enantiomeric excess of allylation adduct, and the
3,5-bis(trifluoromethyl)phenyl group is most effective [241].
R3
1
R CHO
+
2
R
TMS
OH
1) CAB (10~20 mol%)
EtCN, -78 °C
R2
OH Et
Ph
92% ee syn
syn:anti=96:4
96% ee syn
syn:anti=97:3
3
R
R1
2) TBAF
Ph
OH
OH
Ph
89% ee syn
syn:anti=92:8
(CAB, R =3,5-(CF3 )2C6 H3)
CAB was also effective in catalyzing the hetero Diels-Alder reaction of aldehydes
with a Danishefsky diene to produce dihydropyrone derivatives of high optical purity
(up to 98%ee) [206]. The extent of asymmetric induction is largely dependent on the
structure of the boronic acid.
In general, bulky phenylboronic acid
(Ar=2,4,6-Me3C6H2, o-MeOC6H4) results in excellent asymmetric induction [246].
Judging from the product configuration, CAB (from natural tartaric acid) should
27
effectively cover the si face of carbonyl when coordinated, and the selective approach of
nucleophiles from the re face should agree well with the results of other CAB-catalyzed
asymmetric reactions.
OMe
1) CAB (20 mol%)
R'
EtCN, -78 °C
R'
+
R"CHO
2) CF3CO2H
TMSO
O
O
R"
R'
R'=H or Me
R'
O
O
O
O
O
98% ee, >99% cis
(Ar=o -MeOC6H 4)
O
Ph
O
Ph
97% ee, >99% cis
95% ee
(Ar=o-MeOC6 H4) (Ar=2,4,6-Me3C6 H2)
The mechanism of CAB-catalyzed asymmetric Diels-Alder reaction has been
α-Substituted methacrolein favors s-trans
studied carefully using NMR [243].
conformation in the transition-state assembly independent of the steric feature of
boron-substituent.
On the other hand, the sp2-sp2 conformational preference of
α-nonsubstituted acrolein and crotonaldehyde are reversed by altering the structure of
the boron-substituent: s-trans conformation is preferred when the boron substituent is
small, while s-cis conformation is preferred when it is bulky.
Me
H
H
O
B
O
O
i-PrO
H
O
HO2C
O
O
H
B
O
H
O
H
H
H
H
Oi-Pr
H
O
H
HO2C
methacrolein
Me
H
H
O
H
H
O
i-PrO
O
H
Oi-Pr
crotonaldehyde
4.2. Chiral Helical Lewis Acid
Chiral helical titanium reagents have been prepared and as an efficent chiral
template for asymmetric Diels-alder reaction with dienes, regardless of reaction
temperature and structure of dienophiles [225].
28
SiR3
R
O
O
Ti
O
O
CHO
CHO
SiR3
95-96% ee exo
exo:endo=85:15
Me
94% ee exo
exo:endo=>99:1
4.3. Enantioselective Synthesis Using Chiral Brønsted–Lewis Acids
4.3.1. Brønsted Acid-assisted Chiral Lewis Acids (BLA)
Yamamoto and his colleagues found that Brønsted acid assisted chiral Lewis acid:
BLA achieved high selectivity through the double effect of intramolecular hydrogen
binding interaction and attractive π−π donor-acceptor interaction in the transition-state
[249, 330]. Extremely high enantioselectivity (>99 to 92% ee) and exo selectivity (>99
to 97% exo) are obtained for cycloadditions of α-substituted α,β-enals with dienes in
the presence of BLA. The absolute stereopreference in the reaction can be easily
understood in terms of the most favorable transition-state assembly. The coordination
of a proton of 2-hydroxyphenyl group with an oxygen of the adjacent B-O bond in
complex should play an important role in asymmetric induction; this hydrogen binding
interaction via Brønsted acid would cause Lewis acidity of boron and π-basicity of
phenoxy moiety to increase.
O
O - +
BH
O
O
O
O B
O H O
O
R
BLA (5~10 mol%)
BnO
CHO
Br
>99% ee exo
exo:endo=>99:1
CHO
Non-Helical Transition-State
Br
94% ee exo
exo:endo=>99:1
29
Diels–Alder reactions of α-unsubstituted α,β-enals with BLA as well as most
chiral Lewis acids exhibit low enantioselectivity and/or reactivity. Yamamoto and his
colleagues developed a new type of BLA, which was prepared from a chiral triol and
3,5-bis(trifluoromethyl)benzeneboronic acid [291, 331]. This catalyst was extremely
effective in enantioselective cycloaddition of both α-substituted and α-unsubstituted
Ph
CF3
CF3
O
B
O
OH
CF3 Diene
CF 3
R
O B
O O
O
H
2
H
Ph
1
R
R2
BLA
Proposed Transition State Model
CHO
CHO
95% ee (S)
99% ee (S)
OHC
CO2Et
CHO
95% ee (R)
CHO
95% ee (S)
80% ee (R)
α,β-enals with various dienes. The Brønsted acid in the new BLA catalysts clearly
accelerates the cycloaddition.
Yamamoto and his colleagues reported the first example of an enantioselective
reaction of dienes and acetylenic aldehydes catalyzed by chiral Lewis acids and an ab
initio study which supports the predominance of an exo-transition structure, thus
clarifying the origin of the enantioselectivity observed upon catalysis [305]. The
reaction catalyzed by BLA proceeded with good enantioselectivity and conversion,
although the use of CAB or BLA gave higher enantioselectivity in some cases.
CHO
CAB or BLA
(CH2) n +
(CH2)n
CHO
R
CHO
I
85% ee (BLA)
R
CHO
CHO
CO2 Et
CO2Et
95% ee (BLA)
86% ee (CAB)
30
CHO
89% ee (CAB)
The absolute stereochemical outcomes attained in these reactions can be
explained in terms of the anti-exo-transition-state models which are analogous to those
previously proposed for the reaction of dienes and olefinic dienophiles. Simple ab
initio molecular orbital calculations at the RHF/6-31G* level identified the transition
structures of the processes: acid-free and BF3-promoted reactions of cyclopentadiene
and propynal. As expected, the calculations showed that the exo-transition structures
are more stable than the endo structures by 0.8 kcal/mol for the former reaction and by
2.0 and 2.4 kcal/mol for anti and syn pairs, respectively, for the latter.
F3C
CF3
CF 3
O
O
O
H
CF3
O
Bi-PrO
O
O
HO2C
O B
OO
HO
O
OH
Ph
O
B
O
O
Oi-Pr
Proposed anti-exo-transition structures.
The aza-Diels-Alder reaction with a Danishefsky diene is promoted by another
boron catalyst which was prepared from optically active binaphthol and traiarylborate
[209, 220, 221, 223].
O
BOAr
O
N
1
R
OTMS
Bn
+
H
Bn
(1 equiv)
2
R
CH2 Cl2
-78 °C
OMe
Bn
Ph
R1
Bn
N
O
R2
N
N
O
R2
O
Ar=Ph: (75%), 82% ee
Ar=3,5-Me2C 6H3: (82%), 86% ee
31
N
Ar=Ph: (71%), 90% ee
The same catalyst was effective for the stereoselective aldol-type reaction of
aldimines with ketene silyl acetals [217, 233, 234, 253]. This method can be
effectively applied to the preparation of β-lactam compounds including thienamycin and
related carbapenems.
N
R1
Ph +
OTMS
HN
Ph
CH2Cl 2, -78 °C
CO2t-Bu
(50~60%)
R1
74-94%ee
Ot-Bu
H
BLA, which is prepared from a 1:2 molar ratio mixture of a trialkylborate and
optically pure binaphthol, is also an excellent chiral promoter for the aza Diels-Alder
reaction of imines with Danishefsky dienes [265].
O
B- H+
O
O
O
N
Ph
OTMS
R
(1 equiv)
R
CH 2Cl2
-78 °C
Ph
+
H
OMe
N
O
R=Bn: 86% ee (78%)
R=(S)-PhMeCH: >99% ee (64%)
The same BLA is very useful in the double stereodifferentiation of aldol-type
reactions of chiral imines [265]. The aldol-type reaction with trimethylsilyl ketene
acetal
derived
from
tert-butyl
acetate
using
yellow
crystals
of
(R)-9·(S)-benzylidene-α-methylbenzylamine·PhOH proceeds with unprecedented
diastereoselectivity.
N
Ph
Ph
H
+( R)- BLA+PhOH
+
OTMS
HN
Ot-Bu
Ph
CO2t-Bu
Ph
(65%), >99% de
Yellow crystal
Based on the above results, Yamamoto developed the first method of
32
enantioselective synthesis of chiral β-amino acid esters from achiral imines and ketene
silyl acetals using BLA [265, 271].
CHPh 2
N
+
Ar
H
Ar=Ph: 96% ee (R)
Ar=p -MeC6H 4: 97% ee
OTMS
BLA
(1 equiv)
HN
Ot-Bu toluene-CH 2Cl2 Ar
(1 : 1)
(35~58%)
CHPh2
CO2 t-Bu
Ar=p -ClC6H4: 98% ee
Ar=2,4-Cl2 C6H3: 95% ee
Ar=p -AcOC6H4: 98% ee Ar=2-naphthyl: 96% ee
4.3.2. Lewis Acid-assisted Chiral Brønsted Acids (LBA)
Enantioselective protonation of prochiral silyl enol ethers is a very simple but
attractive route for preparing optically active carbonyl compounds. However, it is
difficult to achieve high enantioselectivity using simple chiral Brønsted acids because of
the conformational flexibility in the neighborhood of the proton. The coordination of a
Lewis acid to a Brønsted acid would restrict the direction of the proton and increase its
acidity. In 1994, Yamamoto and his colleagues found that the Lewis acid assisted
chiral Brønsted acid (LBA) is a highly effective chiral proton donor for the
enantioselective protonation [266, 304].
LBA is generated in situ from optically pure binaphthol and tin tetrachloride in
toluene, and is stable in the solution even at room temperature. In the presence of a
stoichiometric amount of (R)-LBA, the protonation of the TMS enol ether derived from
2-phenylcyclohexanone proceeded at -78 °C to give the (S)-isomer with 97% ee. This
reagent is applicable to various ketene bis(trialkylsilyl) acetals derived from
α-arylcarboxylic acids. The observed absolute stereopreference can be understood in
terms of the proposed transition state assembly. The trialkylsiloxy group is directed
opposite to the binaphthyl moiety in order to avoid any steric interaction, and the aryl
group stacks on this naphthyl group.
33
H
O
SnCl4
O
H
OTMS
Ph
Another example:
O
MeO
O
Ph
(0.1~1 equiv)
OH
toluene, -78 °C
92% ee (S)
naproxen
>95%, 97% ee (S)
R1
OSiR3
R2
O
HO
Cl
overlap each other
H
Sn
Cl
Cl
Cl
The Proposed Transition State Assembly
In further studies, Yamamoto and his colleagues succeeded in the enantioselective
protonation using a stoichiometric amount of an achiral proton source and a catalytic
amount of LBA [302].
Me
O
SnCl 4
O
H
OTMS
Ph
OTMS
(addition over 1 h)
BINOL-Me (10 mol%)
SnCl4 (8 mol%)
2,6-dimethylphenol (110 mol%)
toluene, -80 °C
100% conv.
34
O
Ph
OH
94% ee
The regio- and stereoselective isomerization of a “kinetic” silyl enol ether to a
“thermodynamic” one was catalyzed by LBA [336]. “Kinetic” TBDMS enol ethers
were isomerized to the “thermodynamic” ones in the presence of catalytic amounts of
the coordinate complexes of tin tetrachloride and the monoalkyl ethers of BINOL or
biphenol. For the various structurally diverse substrates, the isomerization cleanly
proceeded in the presence of 5 mol% of the achiral LBA.
H
O
SnCl4
O
R1
i-Pr
OTBDMS
R3
(5 mol%)
R2
toluene
-78 °C, 1-5 h
OTBDMS
98% rs
OTBDMS
1
R
2
R
OTBDMS
96% Z
99% rs
OTBDMS
R3
OTBDMS
99% rs
Despite
extensive
studies
on
acid-catalyzed
diastereoselective
polyene-cyclizations, their enantioselective processes have not yet been reported. Very
recently, Yamamoto and his colleagues succeeded in the first enantioselective
biomimetic cyclization of polyprenoids catalyzed by LBA [341].
Cyclization of o-geranylphenol with the monobenzoyl ester of (R)-BINOL
((R)-BINOL-Bz)-SnCl4 complex in dichloromethane at –78 °C was completed within 1
day, and the transfused tricyclic compound was obtained as a major diastereomer (95%
ds) in good yield with moderate induction of 54% ee. The same tricyclic ether was
obtained with much better selectivity from geranyl phenyl ether. Surprisingly, the
reaction proceeded smoothly even in the presence of 20 mol% of this LBA to give the
desired compound with 77% ee and 98% ds. Geranyl phenyl ether is more reactive
than o-geranylphenol due to the lack of a hydroxy group.
35
(R)-BINOL-Bz–SnCl4
(0.2 or 1 equiv)
CH 2Cl2, –78 °C
>99% conv.
O
LBA (1 eq), 1 day
LBA (0.2 eq), 4 days
[1,3]-Rearrangement
O
O
+
H
81% yield
78% yield
H
98 (69% ee)
98 (77% ee)
2
2
:
:
H
O
It is surmised that this reaction takes place via a [1,3]-rearrangement and
subsequent cyclization,. The use of this LBA without exception resulted in the high
enantioselectivity (up to 90%ee) and diastereoselectivity.
To demonstrate the effectiveness of the LBA-promoted enantioselective
cyclization, the biomimetic synthesis of (–)-chromazonarol, a minor constituent of the
brown Pacific seaweed., was performed. The cyclization of 4-benzyloxyphenyl
farnesyl ether with (S)-LBA gave the desired tetracyclic compound as the major
diastereomer.
OAc
O
( S)-BINOL-i -Pr–SnCl4
(1 equiv)
OBn
CH2Cl 2, -78 °C
3 days
1. H2, Pd/C
EtOH
O
2. Ac2 O
Et3 N, DMAP
CH2 Cl2, rt
H
H
ca. 40% overall yield, 44% ee
(–)-Ambrox® was synthesized via the enantioselective cyclization of
(E,E)-homofarnesyl
triethylsilyl
ether
with
tin(IV)
chloride-coordinated
(R)-2-(o-fluorobenzyloxy)-2’-hydroxy-1,1’-binaphthyl
((R)-BINOL-o-FBn)
subsequent diastereoselective cyclization with CF3CO2H•SnCl4 as key steps [391].
36
and
OSiEt3
1. (R)-BINOL-o-FBn•SnCl4
toluene, –78 °C, 1 day
O
2. Et 3SiCl, imidazole, DMF
3. CF3 CO2H•SnCl4
EtNO 2, –78 °C, 1 day
76% ds, 75% ee
54% yield
The optimized structure of a BIPOL–SnCl4 complex was determined at the
B3LYP/LANL2DZ level to understand the absolute stereochemical outcome of the
cyclizations. It is noteworthy that two acidic protons are probably located at
pseudo-axial sites parallel to the apical axis of the tin atom, and an electrostatic
interaction between the acidic protons and the apical chlorines is expected.
H
H
2.602 Å
H
111.6°
H
H
H
H
O
O
Sn
Cl4
H
H
H
O
Cl
H
2.366 Å
2.331 Å
2.325 Å
O
H
Sn
Cl
Cl
Cl
Optimized geometry of a biphenol–SnCl4 complex
Nonenzymatic enantioselective polyene cyclization of homo(polyprenyl)arenes
is an attractive application of the new method. Yamamoto and his colleagues have
demonstrated the effectiveness of chiral LBAs for absolute stereocontrol in the initial
cyclization step of homo(polyprenyl)arenes to form an A-ring and the importance of the
nucleophilicity of the internal terminator in homo(polyprenyl)arenes for the relative
stereocontrol in the subsequent step.
For example, a tetracyclic polyprenoid from
Eocene Messel shale (Germany) was synthesized with 77% ee in good yield by using
the LBA-induced enantioselective cyclization as a key step.
37
H
O
SnCl 4
O
F
toluene, –78 °C
H
BF3•Et2O
H
MeNO2 , rt
H
77% ee, 65% overall yield
4.3.3. Enantioselective SEM Addition Reaction Using SnCl4–BINOL(SEM)2
Yamamoto and his colleagues developed the enantioselective alkoxymethylation
of silyl enol ethers by introducing suitable carbon-electrophiles in place of the
activated-protons of LBA [348]. Thus, the reaction of the trimethylsilyl enol ether
derived from 2-phenylcyclohexanone with the bis[trimethylsilyl(ethoxy)methyl (SEM)]
ether of (R)-BINOL was promoted in the presence of SnCl4, and the (R)-α-SEM ketone
was obtained in 91% yield with up to 94% ee.
OSiMe 3
2
R
R1
R3
+
OSEM
OSEM
SnCl 4
(1.1 equiv)
PrCl or CH2 Cl2
O
R1
2
* R
SEM
R3
O
HF-pyridine
THF, rt
>95% yield
R1
2
* R OH
R3
up to 94%ee
4.3.4. Asymmetric Synthesis of (R)-Limonene Using a Chiral Leaving Group
A six-membered monocyclic terpene, (R)-limonene have been synthesized by
new enantioselective intramolecular cyclization reactions of neryl ether using an
(R)-1,1’-binaphthyl-2-benzoxy-2’-oxy auxiliary as a chiral leaving group in the
presence of tin(IV) chloride [377, 393].
38
O
SnCl 4 (1 equiv)
2,4,6-collidine
CH2 Cl2, –97 °C, 4 h
reflux, 8 h
*
+
OR
81:19
90% yield, 93% ee
4.4. Catalytic Asymmetric Allylation and Aldol Reaction with Aldehydes Using a
Chiral Silver(I) Complex
Yamamoto and his colleagues found that a BINAP·silver(I) complex also
catalyzes the asymmetric allylation of aldehydes with allylic stannanes, and high γ-,
anti-, and enantioselectivities are obtained by this method [R-27, R-30, R-31, 296, 308,
321]. The chiral phosphine-silver(I) catalyst can be prepared simply by stirring an
equimolar mixture of chiral phosphine and silver(I) compound in THF at room
temperature. Treatment of benzaldehyde with allyltributyltin under the influence of 5
mol % of (S)-BINAP·silver(I) triflate in THF at -20 ˚C provides the corresponding
(S)-enriched homoallylic alcohol in 88% yield with 96% ee. The reaction furnishes
high yields and remarkable enantioselectivities not only with aromatic aldehydes but
also with α,β-unsaturated aldehydes and aliphatic aldehydes [296]. Enantioselective
addition of methallyltributylstannane to aldehydes can also be achieved using this
method [308].
SnBu3 + PhCHO
(S)-BINAP·AgOTf
(0.05 eq)
OH
THF, -20 ÞC
88%
Ph
96% ee (S)
4.4.1. Enantioselective Addition of Allylic Trimethoxysilanes to Aldehydes Catalyzed
by p-Tol-BINAP·AgF [349]
Treatment of benzaldehyde with allyltrimethoxysilane in MeOH under the
influence of (R)-BINAP·AgF complex (10 mol %) at -20 ˚C for 4 h gave the
corresponding (R)-enriched homoallylic alcohol in 72% yield with 91% ee. It should
be noted that, when (R)-BINAP·AgOTf complex was used as a catalyst, a racemic
homoallylic alcohol was obtained in only 5% yield. After careful investigation to
optimize the reaction conditions and the allylation proceeded in higher yield and
enantioselectivity when only 3 mol % of (R)-p-Tol-BINAP was present.
39
Si(OMe) 3 + PhCHO
1.5 equiv
OH
(R)-p-Tol-BINAP (3 mol%)
AgF (5 mol%)
CH3OH, -20 ÞC, 4 h
Ph
80%, 94% ee (R)
The BINAP·AgF-catalyzed reaction of (E)- and (Z)-crotyltrimethoxysilane
with benzaldehyde gave remarkable γ- and anti selectivities for the reaction with
crotylsilanes, irrespective of the configuration at the double bond. Thus, addition of
(E)-enriched crotyltrimethoxysilane (E/Z = 83/17) to benzaldehyde in the presence of 6
mol % of (R)-BINAP and 10 mol % of AgF in MeOH at -20 ˚C ~ r.t. exclusively gives
the γ-adducts with an anti/syn ratio of 92/8. The anti-isomer indicates 96% ee with a
1R,2R configuration. Use of (Z)-crotyltributyltin (E/Z < 1/99) or a nearly 1:1 mixture
of the (E)- and (Z)- crotyltrimethoxysilane also results in a similar anti/syn ratio and
enantioselectivity.
γ
α
Si(OMe)3 + PhCHO
1.5 equiv
OH
(R)-BINAP (6 mol%)
AgF (10 mol%)
OH
γ
Ph
CH3OH
-20 ÞC(7 h) ~ RT (17 h)
anti (1R, 2R)
+ Ph
γ
syn (1R, 2S)
E/Z ratio
Yield (%)
anti (% ee)/syn (% ee)
83/17
<1/99
45/55
77
82
99
92 (96)/8 (62)
94 (94)/6 (60)
93 (94)/7 (60)
4.4.2. Enantioselective Aldol Reaction of Tin Enolates with Aldehydes Catalyzed by
BINAP·Silver(I) Complex [R-27, 324]
The aldol reaction of tributyltin enolates with aldehydes is catalyzed by a
BINAP·silver(I) complex with high diastereo- and enantioselectivities. The catalytic
aldol reaction of a variety of tributyltin enolates with typical aromatic, α,β-unsaturated,
and aliphatic aldehydes was obtained in up to 95% ee. Addition of substituted enol
stannanes to aldehydes also proceeds to furnish high diastereo- and enantioselectivities
using this chiral catalyst. For example, treatment of the tributyltin enolate of
cyclohexanone (1 equiv) with benzaldehyde (1 equiv) under the influence of 10 mol %
of (R)-BINAP·AgOTf complex in dry THF at -20 ˚C gives the optically active anti aldol
product preferentially with an anti/syn ratio of 92/8. The anti-isomer indicates 93% ee
with a 2S,1’R configuration. In contrast, the Z-enolate derived from tert-butyl ethyl
ketone provides the syn aldol adduct nearly exclusively with 95% ee. These results
40
show that the diastereoselectivity depends on the geometry of enol stannane and that
six-membered cyclic transition-state structures A and B are probable models.
OSnBu3
+ PhCHO
O
(R)-BINAP·AgOTf
(10 mol%)
O
OH
Ph +
THF, -20 ÞC
94%
Ph
syn
anti
E-enolate
anti/syn = 92 (93% ee)/8 (25% ee)
OSnBu3
t-Bu
OH
+ PhCHO
(R)-BINAP·AgOTf
(10 mol%)
THF, -20 ÞC
Z-enolate
O
OH
O
Ph +
t-Bu
81%
OH
t-Bu
Ph
syn
anti
anti/syn < 1/99 (95% ee)
*
*
H
2
R
P
R1
H
SnBu 3
O
R3
H
O
E
H
P
Ag+
A
P
P
Ag+
R1
O
Z
R2
anti
SnBu3
O
R3
B
syn
Probable cyclic transition-state structures.
4.4.3.
Enantioselective Aldol Reactions Catalyzed by Tin Methoxide and
BINAP·Silver(I) Complex [351]
Since the aldol process has the disadvantage of requiring the stoichiometric use
of toxic trialkyltin compounds [324], Yamamoto and his colleagues achieved the aldol
reaction using a catalytic amount of tin enolate and the asymmetric version with
BINAP·silver(I) catalyst. Thus, treatment of benzaldehyde with the aforementioned
enol trichloroacetate in the presence of (R)-BINAP·AgOTf complex (5 mol %),
tributyltin methoxide (5 mol %), and MeOH (200 mol %) in dry THF at -20 ˚C for 8 h
and then at room temperature for 12 h gave a 92:8 mixture of optically active anti and
syn aldol adduct in 82% combined yield. The anti isomer showed 95% ee with
(2S,1’R)-configuration, a level of enantioselectivity similar to that observed for a
BINAP·silver(I) catalyzed aldol reaction of tributyltin enolates.
41
(R)-BINAP·AgOTf (5 mol%)
Bu3SnOMe (5 mol%)
MeOH (200 mol%)
OCOCCl3
+ PhCHO
O
OH
Ph +
THF, -20 ÞC (8 h) ~ r.t. (12 h)
O
OH
Ph
anti
syn
82% [anti/syn = 92 (95% ee)/ 8 (17% ee)]
A possible catalytic cycle of this aldol reaction is shown below. First,
Bu3SnOMe reacts with an enol trichloroacetate A to generate the trialkyltin enolate B
and methyl trichloroacetate. Subsequently, the tin enolate B can be added to
benzaldehyde to give the aldol adduct C. Finally, protonolysis of the alkoxide C by
MeOH produces the product D and regenerates the tin methoxide. The rate of
methanolysis is regarded as the key to success in the catalytic cycle.
O
4
R CHO
R1
OSnR3
R1
B
2
OSnR3
R2
R3
R4
MeOH
C
R
R3
MeOCOCCl3
O
R3 SnOMe
OH
1
R
OCOCCl 3
R2
1
R
3
A R
2
3
R
4
R R
D
A possible catalytic cycle.
4.4.4 Enantioselective Aldol Reaction of Trimethoxysilyl Enol Ethers with Aldehydes
Catalyzed by p-Tol-BINAP·AgF Complex
Recently, Yamamoto and his colleagues has achieved novel and practical
asymmetric aldol reaction with trimethoxysilyl enol ethers catalyzed by
p-Tol-BINAP·AgF complex. The procedure can be performed without any difficulty
employing readily available chemicals and can provide various optically active
β-hydroxy ketones with high enantioselectivity up to 97% ee. Furthermore, remarkable
syn selectivity was observed for the reaction independent of the E/Z stereochemistry of
the silyl enol ethers.
42
OSi(OMe)3
+ PhCHO
chiral phosphine·AgF
(10 mol%)
O
OH
Ph
MeOH
90% syn selective
up to 93%ee
4.4.5 Enantioselective Addition of Allyltrimethylsilane to Aldehydes Catalyzed by
BINAP·AgOTf, KF, and 18-Crown-6
More recently, Yamamoto and his colleagues have achieved an asymmetric
Sakurai-Hosomi allylation of aldehydes with allylic trimethoxysilanes catalyzed by
BINAP·AgOTf complex, KF, and 18-crown-6. He attempted KF and 18-crown-6 as
co-catalysts for the reaction anticipating that the fluoride ion would activate the allylic
silanes. Treatment of benzaldehyde with 3 equiv of allyltrimethoxysilane in THF
under the influence of (R)-BINAP (3 mol%), AgOTf (5 mol%), KF (5 mol%), and
18-crown-6 (5 mol%) at -20 ˚C for 4 h gave the corresponding (R)-enriched homoallylic
alcohol in 91% yield with 96% ee .
Si(OMe)3 + PhCHO
OH
( R)-BINAP (3 mol%), AgOTf (5 mol%)
KF (5 mol%), 18-crown-6 (5 mol%)
Ph
91%, 96% ee (R)
THF, -20 ÞC, 4 h
4.4.6 Enantioselective Aldol Reaction of Trimethylsilyl Enol Ethers with Aldehydes
Catalyzed by BINAP·AgOTf, KF, and 18-Crown-6
The new chiral catalytic system (BINAP·AgOTf/KF/18-crown-6) described
above was further successfully applied to the catalytic asymmetric aldol condensation of
trimethoxysilyl enol ethers with aldehydes. Treatement of trimethoxysilyl enol ether of
cyclohexanone (1 equiv) with benzaldehyde (1 equiv) in the presence of (R)-BINAP (3
mol%), AgOTf (5 mol%), KF (5 mol%), and 18-crown-6 (5 mol%) in dry THF at -20 ˚C
gave the optically active anti aldol product preferentially with an anti/syn ratio of 92/8.
The anti-isomer indicates 93% ee with a 2S,1’R configuration.
OSi(OMe)3
+ PhCHO
(R)-BINAP (3 mol%), AgOTf (5 mol%)
KF (5 mol%), 18-crown-6 (5 mol%)
O
OH
Ph
THF, -20 ÞC, 4 h
anti
52% [anti/syn = 92 (93% ee)/8]
43
Chapter 5 Other New Synthetic Reactions
5.1. Allylbarium and Related Allylmetal Reagents for Organic Synthesis
5.1.1 Allylbarium in Organic Synthesis: α-Selective and Stereospecific Allylation of
Carbonyl Compounds [R-22, R-23, R-31]
The allylic organometallic compounds of heavier alkaline-earth metals have
found little application in organic synthesis, since they do not offer any particular
advantages over simple Grignard reagents. Yamamoto and his colleagues have been
interested in using barium or strontium reagents with the anticipation that such species
would exhibit stereochemical stability markedly different from that of the ordinary
magnesium reagents. Allylic barium reagents, generated from the corresponding
allylic chlorides and reactive barium, undergo reaction with carbonyl compounds with
high α-selectivity and stereospecificity.
5.1.2 Allylbarium Reagents: Regio- and Stereoselective Allylation Reactions of
Carbonyl Compounds [197, 211, 230, 255]
The first direct preparation of allylbarium reagents by reaction of in situ
generated reactive barium with various allylic chlorides, and their new and unexpected
selective allylation reactions of carbonyl compounds are disclosed. Highly reactive
barium was readily prepared by the reduction of barium iodide with 2 equiv of lithium
biphenylide in dry THF at room temperature. A variety of carbonyl compounds reacted
with barium reagents generated from (E)- or (Z)-allylic chlorides in THF at -78 °C [197,
255].
R1 γ
R2
α
Ba*
Cl
THF, -78 ÞC
R1
R2
α
BaCl
R3COR4
R1
-78 ÞC
89% yield
(α/γ = 94/6, E/Z = 2/98)
OH
OH
n-C5H 11
82% yield
(α/γ = 98/2, E/Z = 97/3)
44
n-C5H 11
n-C7 H15
75% yield
(α/γ = 86/14, E/Z = 2/98)
3
R
Ph
Ph
n-C7H15
α
R2
OH
OH
90% yield
(α/γ = 92/8, E/Z = 98/2)
OH
R
4
All reactions resulted in high yields with remarkable selectivities not only with
aldehydes but also with ketones. The double bond geometry of the starting allylic
chloride was completely retained in each case.
β,γ-Unsaturated carboxylic acids and their derivatives are valuable synthetic
intermediates of various natural products. One straightforward way to obtain
β,γ-unsaturated acids is by the carboxylation of an allylmetal. In the substituted allylic
series, the reaction usually occurs at the more sterically hindered terminus. However,
carboxylation of allylic barium reagent shows α-selectivity without loss of the double
bond geometry [211, 230, 255].
Mg
R1
γ
R1
Cl
R2
THF
Ba*
5.1.3
[153]
R2
1
α
CO2H
γ
R2
γ-carboxylation
BaCl
R2
R1
CO2
α
R
γ
THF
MgCl
CO2
1
R
CO2H
α
R2
α-carboxylation
Double Alkylation of α,β-Unsaturated Acetals. An Inverse Polarity Approach
Yamamoto and his colleagues have found that an α,β-unsaturated acetal
undergoes rapid metallation upon treatment with allylic zinc reagents in the presence of
a nickel catalyst.
Copper or nickel-catalyzed reaction of Grignard reagent with α,β-unsaturated
acetals was reported to produce only the corresponding Michael-type addition
(β-alkylation) products in moderate yields. In some cases, the more reactive allylic
Grignard reagent reacts with nonactivated double bonds. Allylic zinc reagents, in
contrast, are relatively unreactive toward alkenic bonds. Treatment of 1 equiv of the
α.β−unsaturated acetal with a solution of prenylzinc bromide (3.5 equiv) under the
influence of catalytic NiBr2(PBu3)2 (10 mol %) at 40 °C for 30 min gave an α-adduct
almost exclusively.
45
ZnBr + β
α
OR
cat. NiBr 2(PBun3 )2
CH2Cl 2
OR
OR
α -adduct
β
+
OR
OR
β-adduct
ZnBr
α
O
O
(CH3 )2C=CHCH2ZnBr
O
n
cat. NiBr2(PBu 3)2
O
E
E+
O
O
E+ = CH3I (50%), H2C=CHCH2I (45%), HC≡ CCH 2Br (30%)
5.1.4. γ-Selective Nucleophilic Substitution Reaction of Allylmetal Reagents: A New
Cross-Coupling of Diphenylphosphates with Allylic Grignard Reagents [227]
The highly γ-selective cross-coupling reaction of allylic Grignard reagent was
achieved using diphenylphosphate as electrophile. Yamamoto and his colleagues
examined the various kinds of leaving groups and the diphenylphosphate ester revealed
this
unique
regioselectivity.
For
example,
treatment
of
(E)-2-decenyl-1-diphenylphosphate with 2-cyclopentylideneethylmagnesium chloride in
THF at -20 °C afforded the γ-alkylated product in 86% yield with an γ/α ratio of 99/1.
In contrast, the dimethylthiophosphates, for which the longer P-S bond would be
expected, showed entirely different results and afforded the α-coupling product nearly
exclusively.
46
γ
MgCl
α
n
+ C 7H15
OPO(OPh)2
THF, -20 ÞC
n
C 7H15
γ
86% yield (γ/α = 99/1)
γ
MgCl
α
+
n
C3H7
OPS(OMe)2
THF, 20 ÞC
α
C3H7n
55% yield (α/γ = 98/2)
The reason for these striking features in regioselectivity may be the fact that, in
the normal alkylation of an allyl metal to an alkyl halide, an acyclic transition structure
With
is formed that brings a mixture of α- and γ-alkylation products.
diphenylphosphates, on the other hand, bidentate leaving groups coordinate with
magnesium metal to produce a γ-alkylation product selectively via a rigid bicyclic
transition structure.
R' γ
R
α
O
PhO
MgCl
P
O
OPh
5.1.5. Transition Metal-Catalyzed Substitution Reaction of Allylic Phosphates with
Grignard Reagents [R-31, 242, 248]
Transition metal-catalyzed substitution reaction of alkyl halides with Grignard
reagents is generally described as the Kharasch reaction. In the cross-coupling reaction
of allylic substrates, the regioselectivity has been actively studied with a variety of
leaving groups but to a lesser extent with phosphate leaving groups. Yamamoto and his
colleagues examined the transition metal catalysts most suitable for the regioselective
coupling of allylic phosphates with Grignard reagents and found that iron, nickel, and
copper compounds showed remarkable catalytic activities. In addition, nearly
exclusive SN2-regioselectivities were obtained using Fe and Ni catalysts, while SN2'-
47
regioselectivity was observed for CuCN-2LiCl.
cat. Ni or Fe
n -C7H 15
n -BuMgCl
+
OPO(OPh) 2
THF, -78 ÞC, 1 h
cat. CuCN·2LiCl
n-C7H15
n -Bu
SN2 product
n -C7H 15
THF, -78 ÞC, 1 h
Fe(acac)3 :
Ni(acac)2:
CuCN·2LiCl:
n -Bu
S N2' product
94% yield, S N2/SN2' = 99:1
73% yield, S N2/SN2' > 99:1
98% yield, S N2/SN2' = 1:99
5.1.6. Direct Insertion of Alkali (Alkaline-Earth) Metals into Allylic Carbon-Halogen
Bonds Avoiding Stereorandomization [R-22, R-23, R-31, 188, 255]
Allylic alkali and alkaline-earth metal compounds are popular allylating
reagents that exhibit high reactivity toward various functional groups of organic
molecules. However, these allylic organometallics readily isomerize between the Eand Z-isomers. If the stereo-randomization of an allylic metal is due to rapid
isomerization through metallotropic 1,3-rearrangements that are temperature dependent,
a stereochemically pure allylic metal should be generated from the corresponding allylic
halide by its reaction with reactive metal below the isomerization temperature. Thus,
Yamamoto and his colleagues investigated the temperature dependence of the E/Z ratio
of geranyl, neryl, and 2-decenylmetals (Mg, Li, Na, and K), directly prepared from the
corresponding allylic halides and reactive metals. The result was that extremely high
stereoretention was observed below -95 °C for geranyl and neryl magnesium chloride.
In contrast, the double bond geometry of the alkali allylmetals was retained even at
higher temperature. The versatility of stereochemically homogeneous mono- and
disubstituted allylmetals in synthesis is noteworthy, as is their complementary
relationship to other key functional groups. Stereochemically pure allylic silanes can
be prepared easily from the corresponding Grignard or lithium derivatives. Deuteration
can be accomplished smoothly and selectively. Reaction of carbonyl derivatives
selectively produced the stereochemically homogeneous homoallylic alcohols.
48
CH2D
(Metal, temp, Yield, α/γ, E/Z )
(Li, -75 ÞC, 69%, 98/2, >99/1)
D 2O
R'
X
R"
R'
M*/THF
low temp.
M
TMS
(Mg, -95 ÞC, 80%, >99/1, >99/1)
Me3 SiCl (Z-isomer: Mg, -95 ÞC, 65%, >99/1, <1/99)
R"
TMS
(Li, -95 ÞC, 64%, >99/1, >99/1)
(Z-isomer: Li, -95 ÞC, 52%, 93/7, 1/99)
1) RCOTIPS
2) F
n
C5H11
OH
(Li, -75 ÞC, 69%, 97/3, 99/1)
( Z-isomer: Li, -75 ÞC, 51%, >99/1, <1/99)
5.1.7. Highly Chemoselective Allylation of Carbonyl Compounds with Tetraallyltin in
Acidic Aqueous Media [229]
Yamamoto and his colleagues has found a novel allylation reaction of carbonyl
compounds by tetraallyltin in acidic aqueous media which shows exclusive
chemoselectivity toward aldehydes. Reaction of 4 equiv of benzaldehyde with
tetraallyltin (1 equiv) in a 1:8 mixture of 2N HCl (1 equiv) and THF at 20 °C
exclusively afforded the corresponding homoallyl alcohol.
Sn
4
1 eq
O
+
OH
aq. HCl (1 eq)/THF
Ph
H
4 eq
20 ÞC, 1 h
Ph
88% yield
Noteworthy is the fact that tetraallyltin decomposes relatively slowly in acidic aqueous
media and four of the allyl groups on tin metal reacted with carbonyl compounds in the
presence of 1 equiv of hydrochloric acid. None of the organic tin compound was
produced and thus the work-up of the reaction proceeded quite smoothly.
Ketone was inert under the standard reaction conditions except for
cyclohexanone, which showed a relatively high reactivity. The above results suggested
a possibility of chemoselective addition of tetraallyltin to aldehydes in the presence of
ketones. Indeed, in a competitive reaction of benzaldehyde and acetophenone with
tetraallyltin, only the aldehyde adduct was obtained with 99.98% selectivity.
49
Intramolecular discrimination of carbonyl groups is also possible with tetraallyltin
under acidic media. Thus, reaction of keto-aldehyde with tetraallyltin resulted in
complete chemoselectivity (>99%) towards aldehyde. Water-soluble aldehyde was used
without any difficulty and treatment of an aqueous solution of glutaraldehyde with
tetraallyltin in the presence of excess acid afforded the diallylated product in 94% yield.
Sn
4 (1 eq)
O
H
Ph
O
4 eq
O
aq. HCl (1 eq)/THF
Ph
98% yield
Sn
4 (1 eq)
O
H
H
1 eq (50 wt% in H2O)
O
aq. HCl (10 eq)/THF
OH
OH
OH
94% yield
5.2. Selective Cleavage of Acetals
5.2.1. Cleavage of C-O and C-N Bond
Organoaluminum has strong Lewis acidity and thus strongly coordinates with
heteroatoms such as N or O. This characteristic advantage was used elegantly for the
cleavage of aminals or acetals. DIBAL is an effective and selective reducing agent that
cleanly
converts
1-heptyl-2-hexyl-2,3-dihydropyrimidine
to
1,8-bis(heptylamino)naphthalene in a high yield [57].
DIBAL
NH2 NH
HN
N
NH NH
88%
Optically active acetals were cleaved regio- and stereoselectively by
organoaluminum reagents [90]. Chiral unsaturated acetals derived from tartaric acid
undergoes ring-opening alkylation in the presence of a trialkylaluminum to give 1,4and 1,2-adduct in high optical purity.
50
CONMe2
O
CONMe 2
O
O
O
CONMe 2
O
Me 3Al
n-PrCl
CONMe 2
O
91% ee
CONMe 2
O
+
O
CONMe 2
96% (6.5:1)
5.2.2. Diastereoselective Synthesis Using Chiral Acetals
Diastereoselective Simmons-Smith reactions of α,β-unsaturated acetals derived
from chiral dialkyl tartarate or (2R,4R)-2,4-pentanediol were developed [105, 122].
Treatment of the acetal with diethylzinc and methylene iodide gives a cyclopropane
with high diastereoselectivity. The acetal group is readily transformed to the aldehyde
or the ester group.
In addition, the method is successfully applied to the
enantioselective synthesis of 5,6-methanoleukotriene A4, a stable and selective inhibitor
of leukotriene biosynthesis.
H
R
R
CHO
CHO
H
H
88~94% ee
CO2H
H
R
O
O
H
CO2R' Et2Zn–CH 2I2
CO2R'
R
O
H
O
(5R,6R)-5,6-Methanoleukotriene A4
CO2R'
CO2R'
Chiral acetals derived from aldehydes and (2R,4R)-2,4-pentanediol are cleaved
selectively by organoaluminum reagents [78 , 89, 95, 111, 112, 172]. The reaction
proceeds via the retentive-alkylation process with >95% selectivities in most cases.
Trialkylaluminum reagent is utilized for higher alkyl transfers, but for smaller alkyl
transfers, a new reagent system, combining trialkylaluminum and the halophenols such
as pentafluorophenol and 2,4,6-trichlorophenol is employed [185, 237]. Chiral acetals
derived from aldehydes and 1,3-butanediol are cleaved selectively by trialkylaluminum,
even for smaller alkyl transfers.
The reaction of acetals derived from
(2R,4R)-2,4-pentanediol and ketones in the presence of a catalytic amount of aluminum
pentafluorophenoxide produces reductively cleaved products with high
diastereoselectivity. The reaction is a new means of diastereoselective cleavage of
acetals:
an intramolecular Meerwein-Ponndorf-Verley reductive and Oppenauer
51
oxidative reaction on an acetal template [219].
In contrast, alkylative cleavage of the
same chiral acetals using Lewis acid-alkylmetal systems and reductive cleavage of the
same acetals using Lewis acid-trialkylsilane or dialkylsilane systems occur inversely
[112, 123, 130, 157, 171].
R3Al-C6 F5OH
or
(DIBAH or X2 AlH)
(H)R O
1
OH
O
retentive
2
R
R
RLi, RMgX, or R2Zn-TiCl4
or
(R 3SiH or R2SiH2-TiCl 4)
(H)R O
O
1
invertive
2
R R
R1
>
1
(H)R OH
2
R1
R
R
R
R
R2
(H)R OH
1
OH
2
(C8H 17)3 Al–C6F5 OH
O
BnO
toluene, 25 °C
O
R2
O
OH
BnO
retentive:invertive=97:3
OH
HO2C
(+)-8-Hydroxypalmitic acid
O
O
R1 R 2
O
Al(OC6F5) 3 (5 mol%)
CH2Cl 2
O
R1
R2
OH
aq. K2CO3
R1
R2
(-)-Lardolure has been synthesized elegantly by intramolecular cyclization of
vinyl ether alcohol derived from spiroacetal via triisobutylaluminium [150] and further
ring enlargement of the afforded bicyclic hemiacetals [173, 278, 294]. The same
method was utilized for new stereospecific ring enlargement to yield medium and large
rings from simple ketones [173, 278, 294].
52
O
O
i-Bu 3Al
O
OH
Tf2 O
HO
O
PhI(OAc)2
i-Pr2 EtN
I2, hv
O
O
I
OCHO
(–)-Lardolure
Lewis Acid-Catalyzed Esterification and Amidation
5.3.1. Esterification
Scandium trifluoromethanesulfonate (triflate), which is commercially available, is
a practical and useful Lewis acid catalyst for acylation of alcohols with acid anhydrides
or the esterification of alcohols by carboxylic acids in the presence of p-nitrobenzoic
anhydrides. The remarkably high catalytic activity of scandium triflate can be used to
assist the acylation by acid anhydrides of not only primary alcohols but also
sterically-hindered secondary or tertiary alcohols. The method presented is essentially
effective for selective macrolactonization of ω-hydroxy carboxylic acids [274, 299].
R2OH
+
(R CO)2O
1
R2OH
+
R1CO2H
cat. Sc(OTf)3
CH3 CN
cat. Sc(OTf)3
(p -NO2C6 H4CO)2 O
CH 3CN
1
2
R CO2 R
R1CO2 R2
In order to promote atom efficiency in synthesis and to avoid the generation of
environmental waste, the use of stochiometric amounts of condensing reagents or
excess substrates should be avoided. In esterification, excesses of either carboxylic
acids or alcohols are normally needed. Yamamoto and his colleagues showed that the
direct condensation of equimolar amounts of carboxylic acids and alcohols can be
achieved with the use of hafnium(IV) salts such as commercially available hafnium(IV)
chloride and hafnium(IV) tert-butoxide.
He also synthesized polyesters by
polycondensing ω-hydroxycarboxylic acids and aliphatic diols in the presence of 0.2
mol% of HfCl4•(THF)2 in o-xylene with the removal of water for 1 day. In most cases,
polycondensation proceeded quantitatively [ 371].
53
R1CO2 H + R2OH
(1 equiv) (1 equiv)
HfCl4•(THF) 2 (0.1~0.2 mol%)
R1CO2 R2
toluene, azeotropic reflux
O
quantitative yield
O
HO
O
O
H
>200
Mn = >27000
1 Amidation [297, 359,384]
Trifluorophenylboronic acid is a highly effective amidation catalyst between
carboxylic acids and amines [297]. In the presence of a catalytic amount of catalyst the
condensation proceeds in almost quantitative yields.
F
cat. F
B(OH) 2
F
R1CO2H + R2 R3NH
R 1CONR2 R3
Polyamides are used in the production of synthetic fibers and engineering resins.
Aromatic polyamides are particularly well-known as high-performance polymers due to
their excellent thermal, mechanical, and chemical properties. Direct polycondensation
that produces only a stoichiometric amount of water as a byproduct is the most ideal
route, both environmentally and industrially. However, it is difficult to obtain aromatic
polyamides with a high molecular weight by molten polycondensation. This has been
explained primarily by the low reactivity of aromatic amines compared with that of
aliphatic
amines
because
of
the
resonance
effect
of
phenyl
groups.
3,45-Trifluorophenylboronic acid was for the first time shown to be a highly effective
catalyst for the direct polycondensation to aramids, semiaromatic nylons, and
polyimides [359].
54
3,4,5-F 3C6 H2B(OH)2 (10 mol%)
CO2H + H2N(CH2 )9NH 2
HO2C
(1 equiv)
m -terphenyl:NBP=10:1
200 °C to 300 °C
(1 equiv)
O
HO C
H
CONH(CH2) 9N H
n
94% yield, Mw=229200
3,5-Bis(perfluorodecyl)phenylboronic acid has been synthesized based on the
direct coupling of perfluorodecyl iodide with 1,3-diiodobenzene [384]. This new
boronic acid is shown to be a fluorous catalyst for the direct amide condensation
reaction by virtue of the strong electron-withdrawing effect and the immobility in the
fluorous recyclable phase of the perfluorodecyl group.
C10F 21
B(OH)2
C10F 21
Fluorous esterification catalyst
R1 CO2H
HNR 2R3
cooling to
azeotropic
1
room temp. R C N
R3
reflux
(–H2 O)
cat. (solid)
(heterogeneous, rt)
(homogeneous, reflux) (heterogeneous, rt)
decantation
flask
R1 CO2H
HNR 2R3
toluene or o-xylene
O R2
(heterogeneous, rt)
O R2
C N
R3
toluene or o-xylene
R1
Recovery of a catalyst by decantation and its reuse without isolation
55
5..3.3 Synthesis of Nitrile
Yamamoto and colleagues have found rhenium(VII) oxo complexes as extremely
active catalysts (1 mol%) for dehydration of not only primary amides but also
aldoximes to the corresponding nitriles. The reaction proceeds under essentially
neutral conditions, and the present method is mild and simple to conduct. This
protocol can be readily applied to large-scale processes with high efficiency and
selectivity, making it an economical and environmentally benign process for the
preparation of nitriles.
RCONH2 or RCH=NOH
(HO)ReO 3 (1 mol%)
RCN
toluene etc.
azeotropic reflux with removal of water
5.4. Templated Cyclization of Polyamino Compounds [58, 288, 330]
Tris(dimethylamino)borane is effective for the metal-templated cyclization of
triamino esters to give macrocyclic spermidine alkaloids such as
(+)-(S)-dihydroperiphylline and celacinnine.
CO2 Me
Ph
N
H
NH2
N
H
B(NMe2) 3
toluene
azeotropic reflux
EtO
O
N
O
H
N
B
N
H
N
Ph
Ph
N
H
N
O
Ph
(+)-( S)-Dihydroperiphyline
Antimony(III) ethoxide is also effective for the metal-templated cyclization of
tetramino esters to give the macrocyclic spermine alkaloids buchnerine, verbacine,
verbaskine, and verbascenine. The accelerated rates and high regioselectivities of
therse polyamino systems suggest a mechanism in which the acyclic tri and tetramino
esters are covalently or coordinately attached to the boron or antimony before the final
cyclization step.
56
CO2Et
p -MeOC6H 4
N
H
H
N
N
H
toluene
azeotropic reflux
O
HN
EtO
Sb(OEt)3
NH2
O
N
(H)
N(H) N(H)
N
H
Sb
p-MeOC 6H4
R
N
H
N
H
N
H
Buchnerine
5.5. Cooperative Blocking Effect
In the study of the influence of concave-convex topological features on
asymmetric Diels-Alder
deserve reinvestigations
underestimated. Indeed,
orgnoaluminum reagent
reaction, readily available dimenthyl fumarate appears to
since its primitive topological features seem have been
a series of dienes was subjected to Diels-Alder reaction with
and all the attempted reaction proceeded with excellent
stereoselection [115].
ROOC
COOR
Bu 2AlCl
COOR +
COOR
R = menthyl
95%ee
The observed rigorous selectivity in the present system can adequately prove
the concept of cooperative blocking which is working effectively even for the dianion
alkylative cyclizations [99].
ROOC
N
Li
COOR
R = menthyl
CH2BrCl
H
COOR
H
COOR
99%ee
5.6. Stereoselective Catalytic Shapiro Reaction
Shapiro reaction is one of the most powerful techniques for regioselective
preparation of alkenes. Yamamoto and his colleagues disclosed an excellent regio- and
stereoselectivity obtained using the combination of ketone phenylaziridinylhydrazone as
arenesulfonylhydrazone equivalents with a catalytic amount of lithium amide. The
57
preparation proceeded with highly regio-(>98%) and stereoselectivities (cis/trans
96-99%) [292].
R1
R2
N
cat. LDA
N
Ph
R1
R2
>98% regio, 96-99% stereoselectivity
5.7. New Cross coupling Reaction Using Aryllead
5.7.1. Aryl-aryl Coupling Reaction Using Aryllead Compounds - Asymmetric
Coupling of Phenols with Arylleads
The asymmetric coupling of various phenol derivatives with aryllead
triacetates was investigated for the first time using optically active amines including
strychnine and brucine. Yamamoto and his colleagues found that conformationally
restricted tertiary amines, as well as the effect of lithium aryloxides and molecular
sieves are essential for accelerating the rate of this coupling process. Consequently, the
reaction can be carried out at a low temperature, giving a high degree of diastereo- and
enantioselectivities [345].
OH
OLi
BuLi
toluene
0 °C
Pb(OAc) 3
brucine
-40 °C~-20 °C
OH
yield 93%
83% ee
Ph
Ph
5.7.2. Asymmetric Coupling of Anilines with Arylleads
Although Barton pointed out that no reaction occurred between amines and
organolead derivatives alone, simple magnesation of anilines proved to be effective for
transmetallation and subsequent arylation with aryllead compounds. This finding was
extended to an asymmetric version of this novel process using brucine.
58
Pb(OAc) 3
NH2 t-BuMgCl
toluene
rt, 3h
NH2
brucine
-78 °C, 12h
-40 °C, 3h
yield 90%
41% ee
5.8. Polyhalomethyllithium as a Useful Synthetic Reagents
Dihalomethyllithium can be generated from dihalomethane with LDA or
butylllithium. However, generation of this highly useful reagent required the
conditions of very low temperature and careful temperature control. Yamamoto
reported an easy in-situ generation method which is now widely used for many
synthetic transformations of this reagent [25].
O
CH 2Cl2
OH
LDA. 0°C
89%
CH2Cl 2
The technique was used for ring enlargement reaction including synthesis of
muscone [28, 36].
O
CH2 Br 2
O
BuLi
OH
CHBr2
LDA
5.9. Asymmetric Propargylation using Chiral Allenylboronic Esters
Yamamoto reported condensations of aldehydes with chiral allenylboronic
esters to provide β-acetylenic alcohols with a high degree of enantioselectivity. Similar
reagents derived from allylboronic ester and dalkyl tartrate are now widely used for
asymmetric allylation processes [69, 114].
H
H
C C C
B(OH)2
H
COOR
Dialkyl tartrate
H
H
C C C
O
B
H
RCHO
O
COOR
R
HO H
95%ee
5.10. Peterson Olefination for Stereoselective Synthesis
In his early research at Kyoto, Yamamoto reported an efficient silicon-mediated
59
alkene synthesis which directly produces Z-alkenyl derivatives [24, 59].
Me 3SiCH2COOEt
1) R2 NLi
2) R1 R2C=O
R1
R2
COOEt
HR3 SiC C CMSiMe 3
CHO
97% Z
Me3 Si
5.11. Enantioselective Protonation of Simple Enolates: Chiral Imide as a Chiral
Proton Source [R-25, R-33, 245, 332]
Asymmetric protonation of prochiral metal enolates is an effective route to
produce optically active carbonyl compounds. Although a number of groups have
made important contributions to the continuing progress in this process, most of these
are the reactions of enolates having polar groups including amino, hydroxyl, or phenyl
groups, and there have been few satisfactory reports on the asymmetric induction of
enolates of simple ketones such as 2-methylcyclohexanone. New chiral proton sources
possessing an asymmetric 2-oxazoline ring, (S,S)-imide and related imides, were
synthesized from Kemp's triacid and optically active 2-amino alcohols. With these
chiral imides, various lithium enolates of α-monoalkylated cycloalkanones were
effectively protonated with excellent to moderate enantioselectivity.
Ph
Ph
S
S
H N
O N
O
O
OLi
OSiMe3
O
(S,S)-imide
MeLi·LiBr
Et2O, 0 ÞC
R
THF, -78 ÞC, 2 h
86% yield (87% ee)
1.3. Novel
α-Amino
Acid-based
Hydroxamic
Acid
Ligand
Vanadium-Catalyzed Asymmetric Epoxidation of Allylic Alcohols
60
for
Irrational and facile design of acyclic chiral hydroxamic acid ligands for
asymmetric epoxidation has been achieved. In a study on asymmetric epoxidation of
allylic alcohols the catalyst structure optimization was carried out step by step with
varying structure of the ligand, i.e., three components of α-amino acid, N-protecting
group, and hydroxylamine. As a result of the above screening, the new structure was
discovered to be the best ligand whose vanadium complex reaches unprecedented
catalytic performance of productivity and selectivity. For instance, in the presence of
new catalyst (0.1 mol%) a mixture of (E)-2,3-diphenyl-2-propenol and
tert-butylhydroperoxide in toluene was stirred at 25 °C for 15 h to afforded the
corresponding epoxide in high yield and good selectivity (99% yield, 86% ee).
O
N
O
Ph
Ph
O
N
OH
VO(O-i-Pr)3 (1 mol%)
Hydroxamic acid (1.5 mol%)
OH
TBHP, toluene, 0 °C
Ph
Ph
O
OH
93-96%. 95-96%ee
The new chiral catalytic system described above was further successfully applied
to the catalytic asymmetric epoxidation of homoallylic alcohols.
The asymmetric
epoxidation of a variety of 3-substituted homoallylic alcohols was obtained in up to
91% ee. Using this catalyst concise synthesis of (–)-Bisabolol was achieved.
61
VO(O-i-Pr)3 (2 mol %)
Ph3COOH (1.5 equiv)
toluene, 0 °C, 10 h
OH
O
N
O
(CH2 O)n
Me 2AlCl
OH
OH
O
Ph
VO(O-i-Pr) 3 (2 mol %)
Ph3COOH (1.5 equiv)
toluene, 0 °C, 10 h
O
39%
O
N
O
OH
Ph
84%, 90% de
N
Ph
OH
(6 mol %)
O
HO
3 steps
65%
77%, 90% ee
N
Ph
OH
(6 mol %)
CHCl3
(S)-Limonene
O
(–)-(4S, 8S)-α-Bisabolol
5.13. Regioselective Nucleophilic Addition to Nitrosobenzen Catalyzed by Lewis
Acid
Yamamoto and his colleagues found that the nucleophilic attack by enol silyl
ethers to nitroso compounds was regioselectively occurred in the presence of Lewis acid.
For instance, N-hydroxy-2-aminoketone and 2-aminooxyketone were obtained using 10
mol % of AgF·(±)-BINAP and 5 mol % of Et3SiOTf, respectively. Especially, the
regioselective nucleophilic attack by various enol silyl ethers in the presence of 5 mol %
of Et3SiTOf was obtained with high selectivities to give 2-aminooxyketone. The
process of the reaction using Me3SiTOf was pursued by ReactIR, and suggested that the
dimerization of nitrosobenzene was promoted by Me3SiTOf.
OSiMe 3
+
O OH
N
PhN=O
AgF·(±)-BINAP (10 mol %)
MeOH, 0 °C, 2 h
Et3SiOTf (5 mol %)
(CH2 Cl)2, 0 °C, 1 h
62
O
+
91% (>99 : 1)
88% (1 : >99)
O
N
H
Ph
5.14. The Me3SiNTf2-induced Carbon–Carbon Bond-forming Reactions of Silyl
Nucleophiles with Carbonyl Compounds
Yamamoto and colleagues have demonstrated the efficiency of Me3SiNTf2
(0.3~1.0 mol%) as a strong Lewis acid catalyst for the Mukaiyama aldol and
Sakurai–Hosomi allylation reactions, and that the slow addition of carbonyl compounds
to a solution of acid catalyst and Me3Si–Nu is very important for suppressing side
products; this may be widely accepted as a common and reasonable general procedure
for the Lewis acid-induced reaction of Me3Si–Nu with carbonyl compounds [388].
OSiMe 3
3
R
R4
(1.1 equiv)
1. HNTf2 (1.0 mol%)
Et 2O, –78 °C, 15 min
2. Addition of R1 R2C=O
(1 equiv) at –78 °C over 2 h
R1
3. Stirred at –78 °C, 15 min
4. 1 M HCl–THF (1:1) or Bu4NF/THF
OH
O
OH O
Ph
92% (syn:anti=70:30)
SiMe 3
R2
R4
R3
OH O
Ph
(1.5 equiv)
OH O
87%
Ph
Ph
92%
(step 3: –40 °C, 0.5 h)
1. HNTf2 (0.5 mol%), CH2Cl2 , rt, 0.5 h
2. Addition of R1 R2C=O (1 equiv)
at –78 °C over 2 h
OH
R1
3. Stirred at –78 °C, 15 min
4. 1 M HCl–THF (1:1)
R2
OH
OH
89%
91%
The Me3SiX-induced Mukaiyama aldol reaction proceeds through each catalytic
cycle under the influence of X–: the silyl group of Me3SiNTf2 does not release from
–
NTf2 and that of silyl enol ether intermolecularly transfers to the product, while the
silyl group of Me3SiOTf remains in the product and that of the silyl enol ether becomes
the catalyst for the next catalytic cycle . These findings may provide a basis for the
63
future development of not only chiral silyl Lewis acid catalysts but also other chiral
metal catalysts for carbon–carbon bond-forming reactions of silyl nucleophiles with
carbonyl compounds
O
R1
X
SiMe 3
OSiR3
+
R2
3
R
H
Intramolecular transfer of OTf
X
Me 3Si
O
O
X=OTf
SiR3
Me3SiO
R2 + R3SiX
R1
2
R1
O
3
R
R
3
R
X=NTf 2
or
CTf3
R1CHO
+
SiR 3-induced cascade process
R1
X
Me 3Si
δ+
O
H
SiR
δ+
3
O
O
R2
R1
R1
OSiR3
R2
R3
X
Me 3Si
R3SiO
O
R1
O
δ+O
SiR3
R2
1
R CHO
X
Me 3Si
O R3
1
2
R
R
R3
3
R
R1
R3SiO
O
R2
R1
3
R
64
OSiR3
R2
3
R
δ+ SiR3
R3SiO
O
O
R1
O R3
R2
R3
R2
H
Chapter 6 Development of Designer Brønsted Acid
6.1.
Polystyrene-Bound Tetrafluorophenylbis(triflyl)methane as an Organic
Solvent-Swellable and Strong Brønsted Acid Catalyst
The trifluoromethanesulfonyl (triflyl, Tf) group is one of the strongest neutral
electron-withdrawing groups. In particular, it greatly increases the acidity of hydrogen
atoms at α-positions. For example, bis(triflyl)methane (pKa in water = –1) and
phenylbis(triflyl)methane (pKa in MeCN = 7.83). The steric and electronic factors of
the aromatic ring on arylbis(triflyl)methanes are expected to greatly influence their
Brønsted acidity and their catalytic activity and selectivity for organic reactions. We
have developed new strong carbon Brønsted acids, pentafluorophenylbis(triflyl)methane
and polystyrene-bound tetrafluorophenylbis(triflyl)methane [389]. The synthesis of the
resin-bound Brønsted acid has been accomplished by using the nucleophilic
para-substitution reaction of lithium pentafluorophenylbis(triflyl)methide with lithiated
polystyrenes as a key step. To the best of our knowledge, this is the first example of a
highly acidic heterogeneous Brønsted acid catalyst that is effectively swollen by
non-polar organic solvents, and its catalytic activities are superior to those of Nafion®
SAC-13. Organic solvent-swellable superacids should make a great contribution to
green chemistry and the growth of the chemical industry.
65
F
F
F
Br
F
F
CF3 SO2Na
cat. Bu4NI
1. t-BuLi
2. Tf2O
EtCN, reflux
3. 4 M HCl
F
F
Tf
H
Tf
F
F
F
superacid
F
Li
F
Tf
H
Tf
F
F
Organic solvent-swellable
solid strong acid
esterification
CO2Me
Ph
PS-C6F4CHTf 2 vs. Nafion®SAC-13
1 mol%: 94% vs. 39%
F
benzoylation
Mukaiyama aldol
OH O
F
Ph
Tf
H
Tf
F
OBz
3 mol%: >99% vs. >99%
F
Sakurai-Hosomi allylation
OH
i-Pr
Ph
3 mol%: 71% vs. 0%
Friedel-Crafts acylation
MeO
O
1 mol%: 54% vs. 25%
Ph
Michael addition
O
3 mol%: 89% vs. 2%
acetalization
CO2Me
3 mol%: 77% vs. <1%
MeO OMe
Ph
0.5 mol%: >99% vs. 16%
Recently, Yamamoto and colleagues [384] demonstrated that perfluorocarbon
solvent isn’t essential for fluorous biphasic catalysis: the perfluorocarbon solvent can
be skipped by designing fluorinated catalysts that themselves have a
temperature-dependent phase miscibility–that is solubility–in ordinary organic solvents.
We
have
developed
a
fluorous
super
Brønsted
acid
catalyst,
4-(1H,1H-perfluorotetradecanoxy)-2,3,5,6-tetrafluorophenylbis(trifluoromethanesulfon
yl)methane . The fluorous catalyst can be recycled based upon liquid/solid phase
separation without fluorous solvents. Now, perfluorocarbon solvent isn’t essential for
fluorous biphasic catalysis..
66
NaH (3 equiv)
1. C6 F5Tf2Li (1 equiv),
70 ÞC,1 day
CF3 (CF2) 12CH2OH
(3 equiv)
pyridine:(C 4F9)3 N 2. 4 M HCl
=2:1
rt to 70 ÞC, 1 h
PhCHO HO
catalyst (1 mol%)
OH
cyclohexane
Ph
azeotropic reflux, 3h
F
CF3(CF 2)12 CH2O
F
F
84% yield, 62 wt %F
O
O
86% yield; recovery of a catalyst: 96%
67
F
Tf
H
Tf