Chapter 1 Organoaluminum Reagents for Selective Organic...
67
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]. The method was used for his straightforward synthesis of trans-α-farnesene and juvenile hormone from farnesol [26]. 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]. O N Al DATMP OH O DATMP OH 90% 78% OR OR O O OR HO OH OR HO OH O O OR HO OH HO OH COOMe O Cecropia juvenile hormone
Transcript of 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].
The method was used for his straightforward synthesis of trans-α-farnesene and juvenile hormone from farnesol [26].
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].
O
N Al
DATMP
OH
O
DATMP
OH
90%
78%
OR OR
O
O
OR
HOOH
OR
HOOHO
OOR
HOOHHO
OH
COOMe
O
Cecropia juvenile hormone
2
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].
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
COOMeOAc
O O
COOMe
OH
O
1 LAH2 TsCl, base
Et2AlNMePh1 Oxid.2 WK
Pd(PPh3)4
Humulene
O
Br + PhCHOZn / Et2AlCl
OPh
OH100%
O
O Me
OHO
O Me
OBr
68%
3
Lewis acid but also as a base [73].
This method opens a new synthetic entry to a variety of alkaloides such as
Pumiliotoxin C [60].
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].
1.4. Nucleophilic Aromatic Substitution
R1 R2
NOSO2R'
R2AlXR1 N C R2
R1 N C R2
XN
R2
X
R1
O N
H
HOTs
1) n-Pr3Al
2) DIBAL
H
HNH H
60%
Pumiliotoxin C
NSO
O
Me
1) Et2AlCl
2) DIBAL
RNH
R
O Muscone
O
88%
NMuscopyridine
4
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.
The synthetic potential of this novel reaction has been demonstrated by the
synthesis of indol derivatives [80].
1.5. 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].
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
NOAc
Ph
Me3Al
N
Ph
N
Ph
N
Ph
NH
Ph
NH
Ph
+ 71% (3:2)
C Ccatalytic R B
Cl2AlHH C C AlCl2
E+H C C E
F
NOSiMe3
Me Ph
(Me3SiC C)3AlF
NH
Me Ph
SiMe3
CuI-CaCO3
DMF N
MePh
F
96%
83%
5
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.
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
Lewis Acid Catalysts(AlCl3, AlR3, RAlCl2, R2AlCl)
Designer Lewis Acid Catalysts (MAD, MABR, ATPH, ATPH-Br)
Introduction of Chiral Ligand
Chiral Lewis Acid Catalysts
Modification of Ligands
Classical Organic Synthesis(Carbon-Carbon Bond Formation)
Diels-Alder ReactionAldol SynthesisEne Reaction
Friedel-Crafts Reaction
Modern Organic SynthesisStereo-, Regio- and Chemoselective
Reactions
Asymmetric Synthesis
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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.
OHR1 OR1 O R1
Al
Me
OH
Ph
Ph
O
Ph
Ph OPh Ph
O
Ph
Ph
Al
: R1
: R1
R2
toluene or
CH2Cl2
Me3Al(1/2 equiv)
R2
R2
R2
toluene or
CH2Cl2
MADMABR
toluene or
CH2Cl2
= Me= Br
Me3Al(1/2 equiv)
O
Ph
Ph
R2
ATPHATPH-Br
O
Ph
Ph
R2
Al
: R2
: R2
Me
= H= Br
= H: R2 MAPH
Me3Al(1/3 equiv)
7
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 electronic environment of the arene rings. 1H 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.
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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].
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].
OPhOPh
OPhOPh
Lewis acid
LA
+
+
LA
MADi-Bu3AlSnCl4
BF3•OEt2BEt3
: >99 : 1: 4 : 1: 2 equiv of ethers coordinated to SnCl4 to form a 2 : 1 complex: no complexation: 5 : 3
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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.
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
O O O OMAD
+
MAD(1 equiv) +
OH
>99 : 1
OHDIBAL(1 equiv)
toluene+
MAD
66 % (1 : 10)
-78 °C
CO2MeRO2C
OO
OMe
OR MAD
OO
OMe
OR
MAD
CO2Me
CO2R
CO2R
CO2Me
MAD+
+
: 86 % (>99 : 1): 90 % (89 : 11): 66 % (71 : 29)
>99 : 1
CH2Cl2
-78 °C
R = But :
= But
= Pri= Et
R
R = But8
10
diene at this temperature proceeded hetero-Diels-Alder selectively. It should be noted that the complexed aldehyde could only react with the diene [258].
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.
CHO CHO
OSiMe3
OMe
O
O
O
O
OOATPH ATPH
OSiMe3
ATPH
OH O +OH O
+
87 % (>99 : 1)
CH2Cl2+
-78 °C-78 °C
+
75 % (>99 : 1)
CHO CHO+ O Al
OH
n-Bun-Bu
OH
MAPH+
+
CH2Cl2-78 °C
n-BuTi(OPri)3 (1 eq .)MAPH (1 eq.)/ n-BuLi (1 eq.)MAPH (2 eq.)/ n-BuLi (2 eq.)
: 31 % (2.5 : 1): 76 % (1 : 6.5): 45 % (1 :14)
reagent
CHO
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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].
t-BuO 1) Al
2) MeLit-Bu
Me
OHt-Bu
OH
Me +
MeLi MAD/MeLi
: 85% (79:21) : 84% (1:99)
axial alcohol equatorial alcohol
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].
Ph CHO
MeMe-M
Ph
Me
+Me
OHPh
MeMe
OHCram anti- Cram
EtMgBr MAD/EtMgBr
: 78% (84:16) : 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
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preferentially.
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.
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.
Al
R RCH2Cl2
NaBH4 +
i-Buvinylallyl
MABR MAPH; 64 % (7 : 93); 97 % (24 : 76); 40 % (7 : 93)
85 % (97 : 3)91 % (90 : 10)97 % (95 : 5)
R =
(E) (Z)OR OH OH
i-Buvinylallyl
R =
OO
AlAl
RR
RCHO
Me Me
Me
CHO
Me
R
(Z) (E)
(ax) (eq)
MABR MAPH
A-strain because of the bulky aluminum reagent
Aromatic side chains prevent the R group from axial orientation
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O
MABR
CH2Cl2-40 °C OHOH
+
85% (17:1)trans cis
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,
185]. Since optically pure α-siloxyepoxides are easily accessible by the
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.
Ph3SiOO MABR
toluene-40 °C
Ph3SiO
CHO 88%Ph3SiO
O
MABR
H
H
eryrhro/threo = 1:100
PhO
OSiMe2t-BuMABRCH2Cl2-78 °C
PhO
OSiMe2t-Bu
MABR
Ph CHO
OSiMe2t-Bu
87%
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].
OSiMe3
MABR, MeOTf
CH2Cl2, -40 °C CHOMe 55%
OSiMe3
MABR, ROTf
CH2Cl2, -40 °C
R = Me (84%); Et (73%); Hexyl (80%)O
R
3.5. Conjugate Addition to α,β-Unsaturated Carbonyl Compounds
Organocuprates are the most widely used reagents for Michael addition to
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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.
PhCHO Ph
O AlPh
CHOR
Ph OH
R
ATPHCH2Cl2
[1,4] [1,2]
+RM
RM =
ether-78 °C
1,4-adduct: 92 % (49 : 51): 99 % (90 : 10): 88 % (98 : 2): 60 % (95 : 5): 97 % (97 : 3)
PhCHO
C�ßCSiMe3
PhCHO
Cl
LiTMP/THF-78 ~ 25 °C
86%
1,2-adduct
Me3SIC�ßCLiDME90 %
n-BuLin-BuMgCln-BuCaIn-BuSrIn-BuBaI
17
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.
15
Unfortunately, however, conjugate addition to the ATPH–PhCHO complex did
not proceed effectively with smaller nucleophiles. Yamamoto and his colleagues
OATPH
LiCHO
OMeOLi
OButOLi
OButOLi
Me3Si
Li Li
CHO
CHOCHO
CO2Me
CHO
CO2But
CHO
CO2But
CHO
MePh2Si
CHO OH
2) TBAF/MeOH
Ph2MeSiLiButLi
+
1)
O
ClATPH
MgCl
MgBr
Ot-Bu
OLi
PhLi
OLi
LiO OMe OLi
OLi
Li
Li
t-Bu
CO2H
90%
Ph
CO2H
CO2Me
CO2Me
CO2H
O
CO2HOCO2H
O
CO2Me
i-Pr
CO2H
t-BuO
O
CO2H
MeO
O
41% 46%
72%75%
78%
71%
68%
53%
(>99:1)
96%
(15:1)
(13:1)
(7.9:1)
(>99:1)
(>99:1) (>99:1)
(>99:1)
(3.4:1)
(8.5:1)
The values in parentheses is the ratio of 1,6- and 1,4-adducts.
16
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].
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].
O
Al
RLi O
Al
R
Li+-
OBCl3
+ + OLnM O
R
OMLn-1
O
CO2H
trans-jasmonic acid
O
CO2Me
cis-methyl jasmonate
ATPH
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
X-ray crystal structure (space-filling model) of the ATPH-benzaldehyde complex, which shows more facile
nucleophilic attack at the para-position.
17
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 R
O
OR
R1R1
OR
LA
AlOR
R1R1
OR
Al
endo transition state
exo transition state exo isomer
endo isomer+
Lewis Acid (LA)
ATPH( )
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].
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].
R
O
CORCOR
1) ATPH/CH2Cl22)
-78 °C
+
; 81 % (73 : 27)
exo
R1
R = Ph, R1 = H
R1
R1
R = Ph, R1 = Me R = R1 = Me
: 81 % (96 : 4): 87 % (87 : 13)
endo
OBu
Al
Bu BuCH2Cl20 °C
+
MAPHATPH
: 75 % (5 : 1): 87 % (16 : 1)
NaBH4
OH OH
18
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].
Precomplexation of ATPH with 2-methylcyclohexanone at -78 °C in toluene
was followed by treatment with LDA in tetrahydrofuran (THF), and the mixture was
stirred for 1 h. Subsequent treatment with methyl trifluoromethanesulfonate furnished
2,2-dimethylcyclohexanone and 2,6-dimethylcyclohexanone in an isolated yield of
53 % in a ratio of 32 : 1. Similarly, highly regiocontrolled alkylation of unsymmetrical
ketones with octyl triflate proceeded selectively as shown below (>99 : 1).
OMe
OATPH
OMe
ATPH
OLiMe
OLiMe
ATPH
OMe
OMe
Me
Me
LDA
ATPH
LDA
MeX
MeOTfMe
alkylation at theless hindered site
alkylation at themore hindered site
O
O
89% ( > 99 % selectivity )
71% ( >99 % selectivity )
1) ATPH/toluene O
2) LDA/THFOct3) OctOTf
1) ATPH/toluene
2) LDA/THF3) OctOTf
OOct
19
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.
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.
Space-filling model of the ATPH-methylcyclohexanone complex. LDA attacking is more feasible at the more substituted α-carbon
20
CHOCHO
OH
+CHOO O
ATPH ATPH
H
ATPH(2.2 eq)
LDA(1.2 eq)
+
deprotonation
toluene-78 °C
THF-78 °C
yield 99%E:Z = >99:1
γ:α = >99:1
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.
O
H
O
HPh
HO+
O
H1) ATPH (3.3 eq)toluene, -78 °C
Ph
HO
2) LDA (2.3 eq)THF, -78 °C
+
α
"(Z)–γ"
"(E)–γ"
99% (1:>99)
O
OMe
O
OMePh
HO
+
O
OMe1) ATPH (2.2 eq)toluene, -78 °C
Ph
HO2) LTMP (1.2 eq)
THF, -78 °C
+
91% (13:1)
Z E
Z E
CHO
CHO
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.
21
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.
OHOH
(R)-(+)-binaphthol
OOH
AlO
OTf O
OAl
D-limonene58% (77% ee)
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.
OO
Al
SiR3
SiR3
Me
Me3SiO
OMe
+ PhCHOO
PhOR = Xylyl
H+
97% de97% ee
Br O AlMe
BrO Me3SiOTf
Highly reactive Lewis acid catalyst
22
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].
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 in moderate enantioselectivities (>60% ee). In contrast, the more
elaborate (R)-ATBN analogue, aluminum
tris((R)-1-α-naphthyl-3-p-fluorophenyl-2-naphthoxide) ((R)-ATBN-F), generated
products of up to 92% ee [273].
SiAr3
SiAr3
O
OAlMe
O
Ph
O AlMe
-78 � ̈-40 °C
2
Ph
R O
Ph
MAPH
R
R = SiMe3= GeMe3
Ar3 = t-BuPh2
: 76 % (90 %ee): 68 % (93 %ee)
catalyst(1.1 ~ 1.2 eq.)
CH2Cl2
R = SiMe3= GeMe3
23
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.
c-hexylt-BuMe3Si
: 85 % (86 %ee): 70 % (91 % ee): 78 % (92 % ee)
R =
Ar
O
Ph
O AlAl
3
Ar
3
ATPH : (R)-ATBN: (R)-ATBN-F
= Ph= p-F-Ph
O
R
(1.1 ~ 1.2 eq.)toluene-78 °C O
RAl
: 93 % (61 %ee): 97 % (76 %ee)
: (R)-ATBN: (R)-ATBN-F
: (R)-ATBN-F: (R)-ATBN-F: (R)-ATBN-F
R =
Phc-hexylt-BuMe3Si
R = Ph
24
O
OAl Me
SiPh3
SiPh3
O
OAl
Me
SiPh3
SiPh3
O
OAl
Me
SiPh3
SiPh3
O=CR*R'*
O
OAl Me
SiPh3
SiPh3
O
OAl Me
SiPh3
SiPh3
O=CR'*R*
+
+
(�})
(R)/ketone complex
(S)/ketone complex
O=CR'*R*
O=CR*R'*
enantiomer ofO=CR*R'*
(R)
(S)
Ph H
O
MeO
OSiMe3
O
BrO
O
Me(10 mol%)
MePh
+ (�})-cat (10 mol%)
75%, 82% ee
CH2Cl2-78 °C
25
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].
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
OZn
O
OHCHO
90% ee
91% yield
CH2Cl2, -78~0 °C
26
and the coordinated aldehyde [243].
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.
CHODiels–Alder adducts (10 mol%)
exo/endo: 4/96exo: 92% ee
exo/endo: 4/96endo: 78% ee
exo/endo: 89/11exo: 96% ee
CO2HO
OR'
OR'
OO BR
O
O
CO2HCHO
CAB
Ph
HO O
PhPh
OHO
OPh
OHO
Ph OPh
OHO
Pr
(92%), 96% ee synsyn:anti=99:1
(R=3,5-(CF3)2C6H3)
R2R3
OTMS
(83%), 97% ee synsyn:anti=>95:5
(R=3,5-(CF3)2C6H3)
92% ee synsyn:anti=79:21
(R' = iPr; R = H)
97% ee synsyn:anti=96:4
(R' = iPr, R = H)
R1CHO +R3
OHO
R1
R2
1) CAB (10~20 mol%) EtCN, -78 °C
2) 1N HCl or TBAF
27
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].
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
TMSOH
O
R3H
R1 CAB
HR2 OCAB
R1
R2TMSO H
R3<anti syn
Extended Transition-State Model
R2 TMSR3
R1
R3
R2
OH
OH
Ph
OH Et
Ph
96% ee synsyn:anti=97:3
92% ee synsyn:anti=96:4
1) CAB (10~20 mol%) EtCN, -78 °C
2) TBAFR1CHO +
89% ee synsyn:anti=92:8
(CAB, R =3,5-(CF3)2C6H3)
Ph
OH
28
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.
The mechanism of CAB-catalyzed asymmetric Diels-Alder reaction has been
studied carefully using NMR [243]. α-Substituted methacrolein favors s-trans 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.
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].
+ R"CHO
1) CAB (20 mol%) EtCN, -78 °C
2) CF3CO2H
R'=H or Me
98% ee, >99% cis(Ar=o-MeOC6H4)
97% ee, >99% cis(Ar=o-MeOC6H4)
95% ee(Ar=2,4,6-Me3C6H2)
R'TMSO
R'OMe
R"
O
O
R'
R'
O
OO
O
PhO
O
O Ph
methacrolein crotonaldehyde
i-PrO H
H
HH
MeH
Oi-PrO
Oi-Pr
H
B
H
O
HO2CO
H
O
O
O
B
OHO2C
O
HO
H
Oi-Pr
HO
O
O
H
H
Me
H
H
H
29
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
OOO
B-H+
Br
CHO
Br
CHO
BnO
BLA (5~10 mol%)
>99% ee exoexo:endo=>99:1
94% ee exoexo:endo=>99:1
O HO
OOB
O
R
Non-Helical Transition-State
O
OOO
Ti
CHO95-96% ee exoexo:endo=85:15
SiR3
SiR3Me
CHO
94% ee exoexo:endo=>99:1
R
30
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
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.
R2
OO
B
CF3
CF3
Ph
OHO
O
PhO
B
CF3
CF3
HO
R1
H
R2
OHCCHO
CHO CHO
BLA
99% ee (S) 95% ee (S)CHO
CO2Et
95% ee (S) 80% ee (R)95% ee (R)
Diene
Proposed Transition State Model
CHO
CO2Et
CHO
I
85% ee (BLA)
CHO
CO2Et
86% ee (CAB)
CHO
89% ee (CAB)95% ee (BLA)
R
CHO
+(CH2)n
CHO
R
(CH2)nCAB or BLA
31
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.
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 HO
OOB
OO
O
PhO
B
CF3
CF3
HO
i-PrO
O
O
O
B
OHO2C
O O
H
Oi-Pr
CF3F3C
Proposed anti-exo-transition structures.
R1 H
NBn
R2
OTMS
OMe
N
O
Bn
R1
R2
N
O
Bn
Ph
(1 equiv)
CH2Cl2-78 °C
Ar=Ph: (75%), 82% eeAr=3,5-Me2C6H3: (82%), 86% ee
Ar=Ph: (71%), 90% ee
N
O
Bn R2
N
+
O
OBOAr
32
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.
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].
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.
Based on the above results, Yamamoto developed the first method of
R1
N
H
PhOt-Bu
OTMS
R1
HN Ph+CO2t-BuCH2Cl2, -78 °C
(50~60%)74-94%ee
O
OB-H+
O
O
Ph H
NR
OTMS
OMe
N
O
R
Ph
R=Bn: 86% ee (78%)R=(S)-PhMeCH: >99% ee (64%)
+(1 equiv)
CH2Cl2-78 °C
+(R)-BLA+PhOH
N
Ph H
Ph
Ot-Bu
OTMS
PhCO2t-Bu
HN Ph
Yellow crystal(65%), >99% de
+
33
enantioselective synthesis of chiral β-amino acid esters from achiral imines and ketene silyl acetals using BLA [265, 271].
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.
+
Ar=p-ClC6H4: 98% eeAr=p-AcOC6H4: 98% ee
N
Ar H Ot-Bu
OTMS
ArCO2t-Bu
HNCHPh2
BLA(1 equiv)
toluene-CH2Cl2(1 : 1)
(35~58%)
Ar=Ph: 96% ee (R)Ar=p-MeC6H4: 97% ee
CHPh2
Ar=2,4-Cl2C6H3: 95% eeAr=2-naphthyl: 96% ee
34
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].
OTMS O
O
OSnCl4
H
H
Ph Ph
92% ee (S)naproxen
OH
OMeO
(0.1~1 equiv)
toluene, -78 °C
>95%, 97% ee (S)
Another example:
O
SnHO
ClCl
ClCl
R1
OSiR3
H
R2overlap each other
The Proposed Transition State Assembly
PhOTMS
OTMSPh
OH
O
94% ee
BINOL-Me (10 mol%)SnCl4 (8 mol%)
2,6-dimethylphenol (110 mol%)
toluene, -80 °C
100% conv.(addition over 1 h)
O
OSnCl4
Me
H
35
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.
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.
R2
OTBDMSR3
R2
OTBDMSR3
O
OSnCl4
H
i-Pr
R1 R1(5 mol%)
toluene-78 °C, 1-5 h
96% Z98% rs 99% rs
OTBDMS
99% rs
OTBDMS OTBDMS OTBDMS
36
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.
(–)-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) and subsequent diastereoselective cyclization with CF3CO2H•SnCl4 as key steps [391].
O
::
(R)-BINOL-Bz–SnCl4(0.2 or 1 equiv)
CH2Cl2, –78 °C>99% conv.
O
H
O
H
+
[1,3]-Rearrangement OH
22
98 (69% ee)98 (77% ee)
LBA (1 eq), 1 dayLBA (0.2 eq), 4 days
81% yield78% yield
(S)-BINOL-i-Pr–SnCl4(1 equiv)
CH2Cl2, -78 °C3 days
1. H2, Pd/C EtOH
2. Ac2O Et3N, DMAP CH2Cl2, rt
O
OBn
ca. 40% overall yield, 44% ee
O
OAc
H
H
37
1. (R)-BINOL-o-FBn•SnCl4 toluene, –78 °C, 1 day
2. Et3SiCl, imidazole, DMF3. CF3CO2H•SnCl4 EtNO2, –78 °C, 1 day 76% ds, 75% ee
54% yield
OSiEt3 O
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.
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.
HH
H
H
H
H
Cl
H
O
H
H O
H
Sn
Cl
Cl
Cl
Optimized geometry of a biphenol–SnCl4 complex
2.366 Å2.325 Å
2.331 Å
111.6°2.602 Å
O OSnCl4
H H
38
H
H
H
O
OSnCl4
H
F
toluene, –78 °C
BF3•Et2O
MeNO2, rt
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.
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].
R1 R2OSiMe3
R3
SnCl4(1.1 equiv)
PrCl or CH2Cl2R1 R2
O
R3SEM+ OSEM
OSEM
HF-pyridine
THF, rt>95% yield
R1 R2O
R3OH* *
up to 94%ee
39
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].
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.
SnBu3Ph
OH(S)-BINAP·AgOTf (0.05 eq)
88%THF, -20 ÞC
96% ee (S)
+ PhCHO
2,4,6-collidine
reflux, 8 hO
OR
+SnCl4 (1 equiv)
CH2Cl2, –97 °C, 4 h*
90% yield, 93% ee81:19
40
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.
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
Si(OMe)3Ph
OH
1.5 equiv 80%, 94% ee (R)
PhCHO+CH3OH, -20 ÞC, 4 h
(R)-p-Tol-BINAP (3 mol%)AgF (5 mol%)
CH3OH-20 ÞC (7 h) ~ RT (17 h)
+ PhCHO
(R)-BINAP (6 mol%)AgF (10 mol%)
+αγ
1.5 equiv
E/Z ratio anti (% ee)/syn (% ee)83/17 92 (96)/8 (62)
Yield (%)syn (1R, 2S)
γ γ
anti (1R, 2R)
77
45/5582 94 (94)/6 (60)<1/9999
Si(OMe)3
93 (94)/7 (60)
Ph
OH
Ph
OH
41
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.
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.
t-Bu
OSnBu3
t-Bu
O
Ph
OH
t-Bu
O
Ph
OH(R)-BINAP·AgOTf
+
81%
PhCHO
syn THF, -20 ÞC
(10 mol%)
Z-enolate
anti/syn < 1/99 (95% ee)
+
anti
OSnBu3 O
Ph
OH O
Ph
OH(R)-BINAP·AgOTf
PhCHO+
syn THF, -20 ÞC
(10 mol%)
E-enolate anti/syn = 92 (93% ee)/8 (25% ee)
+
anti 94%
ZE
anti
*
B
Probable cyclic transition-state structures.
A syn
*
O
SnBu3OR2
H
R3
Ag+
O
SnBu3O
H
R3
Ag+R1 R1
H
H
R2
P P P P
42
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.
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.
R4R1
OHO
R1
OCOCCl3
R3
R2
R2 R3
R1
OSnR3
R3
R2
R4R1
OSnR3O
R2 R3R4CHO
MeOH
R3SnOMe
A possible catalytic cycle.
MeOCOCCl3
A
B
C
D
++ PhCHO
(R)-BINAP·AgOTf (5 mol%)Bu3SnOMe (5 mol%)MeOH (200 mol%)
THF, -20 ÞC (8 h) ~ r.t. (12 h)anti syn
OCOCCl3
Ph
O OH
Ph
O OH
82% [anti/syn = 92 (95% ee)/ 8 (17% ee)]
43
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 .
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.
Si(OMe)3 PhCHO Ph
OH
91%, 96% ee (R)
+THF, -20 ÞC, 4 h
(R)-BINAP (3 mol%), AgOTf (5 mol%)KF (5 mol%), 18-crown-6 (5 mol%)
OSi(OMe)3 O
Ph
OH
MeOH+ PhCHO
chiral phosphine·AgF(10 mol%)
90% syn selectiveup to 93%ee
+
(R)-BINAP (3 mol%), AgOTf (5 mol%)KF (5 mol%), 18-crown-6 (5 mol%)
THF, -20 ÞC, 4 h
anti
OSi(OMe)3
Ph
O OH
52% [anti/syn = 92 (93% ee)/8]
PhCHO
44
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 Cl
R2
R1 BaCl
R2
R1
R2R4
OH
R3
Ba*
THF, -78 ÞC
R3COR4
αγ
α-78 ÞCα
90% yield(α/γ = 92/8, E/Z = 98/2)
Ph
OH
89% yield(α/γ = 94/6, E/Z = 2/98)
Ph
OH
82% yield(α/γ = 98/2, E/Z = 97/3)
n-C7H15n-C5H11
OH
75% yield(α/γ = 86/14, E/Z = 2/98)
n-C5H11
OH
n-C7H15
45
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].
5.1.3� Double Alkylation of α,β-Unsaturated Acetals. An Inverse Polarity Approach [153] 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.
γ
α
α-carboxylation
γ-carboxylation
γ α
THF
THF
Ba*
R2
MgCl
R1 Cl
R2
R1
R1 BaCl
R2
R1CO2H
R2
R2
CO2HR1
Mg
CO2
CO2
αγ
46
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.
ZnBr cat. NiBr2(PBun3)2+ β α
OR
ORCH2Cl2
OR
OROR+
α-adduct β-adduct
cat. NiBr2(PBun3)2
βα
O
O
(CH3)2C=CHCH2ZnBr O
O
ZnBr
E+O
O
E
E+ = CH3I (50%), H2C=CHCH2I (45%), HC≡CCH2Br (30%)
47
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 is formed that brings a mixture of α- and γ-alkylation products. With 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.
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'-
THF, -20 ÞC+
γ
α
86% yield (γ/α = 99/1)γ
nC7H15
MgClnC7H15 OPO(OPh)2
α
α
γ
55% yield (α/γ = 98/2)
+THF, 20 ÞC
OPS(OMe)2MgCl nC3H7
C3H7n
γ α
OMgCl
R'
R
PO
OPhPhO
48
regioselectivity was observed for CuCN-2LiCl.
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 E- and 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.
cat. CuCN·2LiCl+
cat. Ni or Fe
SN2 product
SN2' product
n-BuMgCl
n-C7H15 OPO(OPh)2
n-C7H15 n-Bu
n-C7H15
n-Bu
THF, -78 ÞC, 1 h
THF, -78 ÞC, 1 h
Fe(acac)3:Ni(acac)2:CuCN·2LiCl:
94% yield, SN2/SN2' = 99:173% yield, SN2/SN2' > 99:198% yield, SN2/SN2' = 1:99
49
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.
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.
R'
R"
M
CH2D
TMS
TMS
OH
nC5H11
(Li, -75 ÞC, 69%, 98/2, >99/1)
1) RCOTIPS2) F-
(Li, -75 ÞC, 69%, 97/3, 99/1)(Z-isomer: Li, -75 ÞC, 51%, >99/1, <1/99)
(Z-isomer: Li, -95 ÞC, 52%, 93/7, 1/99)(Li, -95 ÞC, 64%, >99/1, >99/1)
(Z-isomer: Mg, -95 ÞC, 65%, >99/1, <1/99)(Mg, -95 ÞC, 80%, >99/1, >99/1)
Me3SiCl
D2O
(Metal, temp, Yield, α/γ, E/Z )
R'
R"
X M*/THF
low temp.
20 ÞC, 1 h
aq. HCl (1 eq)/THF+
4
SnPh H
O
Ph
OH
1 eq 4 eq 88% yield
50
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.
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].
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 1,4- and 1,2-adduct in high optical purity.
PhH
O
Oaq. HCl (1 eq)/THF
4
Sn
4 eq
(1 eq)Ph
O
OH98% yield
H H
O
aq. HCl (10 eq)/THF
4
Sn
1 eq (50 wt% in H2O)
(1 eq)
94% yield
O OH OH
NH2 NH HN NDIBAL
NH NH 88%
51
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.
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
O
OCONMe2
CONMe2 O
OCONMe2
CONMe2
O
Me3Al
96% (6.5:1)
+O
OCONMe2
CONMe2
O
n-PrCl
91% ee
RCHO
RCHO
H
H
O
O
RCO2R'
CO2R'
Et2Zn–CH2I2 O
O
RCO2R'
CO2R'H
H
88~94% ee CO2HH
H
(5R,6R)-5,6-Methanoleukotriene A4
52
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].
(-)-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].
BnOO
O(C8H17)3Al–C6F5OH
toluene, 25 °C BnOO OH
HO2C
OH
(+)-8-Hydroxypalmitic acid
retentive:invertive=97:3
O O
R1 R2R1 R2
O
OAl(OC6F5)3 (5 mol%)
CH2Cl2 aq. K2CO3 R1 R2
OH
O O
R1 R2
R3Al-C6F5OHor
(DIBAH or X2AlH)
retentive
RLi, RMgX, or R2Zn-TiCl4or
(R3SiH or R2SiH2-TiCl4)
invertive
R1 > R2
R1 R2
(H)R O OH
R1 R2
(H)R O OH
R1 R2
(H)R OH
R1 R2
(H)R OH
53
�� 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].
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].
R2OH R1CO2H+cat. Sc(OTf)3
(p-NO2C6H4CO)2OCH3CN
R1CO2R2
R2OH (R1CO)2O+cat. Sc(OTf)3
CH3CNR1CO2R2
OO O OHi-Bu3Al Tf2O
i-Pr2EtN
OHO
PhI(OAc)2
I2, hv
OO
OCHO(–)-Lardolure
I
54
R1CO2H + R2OH R1CO2R2HfCl4•(THF)2 (0.1~0.2 mol%)
toluene, azeotropic reflux
HO O
O OO
H>200
Mn = >27000
(1 equiv) (1 equiv) quantitative yield
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.
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].
F
F
F
B(OH)2
R1CO2H + R2R3NH
cat.
R1CONR2R3
55
3,4,5-F3C6H2B(OH)2 (10 mol%)
m-terphenyl:NBP=10:1200 °C to 300 °C(1 equiv) (1 equiv)
HO2C CO2H H2N(CH2)9NH2
C CONH(CH2)9NO
HO HH
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.
CO
NR1R2
R3
azeotropic
reflux(–H2O)
(homogeneous, reflux)
cooling to
room temp.
decantation
R1CO2HHNR2R3
toluene or o-xylenetoluene or o-xylene
Recovery of a catalyst by decantation and its reuse without isolation
R1CO2HHNR2R3
(heterogeneous, rt) (heterogeneous, rt)
CO
NR1R2
R3
(heterogeneous, rt)
flask
cat. (solid)
C10F21
C10F21
B(OH)2
Fluorous esterification catalyst
56
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 RCH=NOH(HO)ReO3 (1 mol%)
toluene etc.azeotropic reflux with removal of water
RCNor
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.
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.
N N
HNO B
EtO
Ph
B(NMe2)3
toluene azeotropic reflux N
HPh
NH
O
Ph NH
NH
NH2
CO2Me
(+)-(S)-Dihydroperiphyline
N
PhO
57
5.5. Cooperative Blocking Effect
In the study of the influence of concave-convex topological features on asymmetric Diels-Alder reaction, readily available dimenthyl fumarate appears to deserve reinvestigations since its primitive topological features seem have been underestimated. Indeed, a series of dienes was subjected to Diels-Alder reaction with orgnoaluminum reagent and all the attempted reaction proceeded with excellent stereoselection [115].
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].
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
ROOCCOOR +
COOR
COOR
95%ee
Bu2AlCl
R = menthyl
ROOCCOOR
NLi
CH2BrClCOOR
H
H
COOR
99%eeR = menthyl
N(H) N(H)
N(H)
HNO
SbEtO
R
Sb(OEt)3
toluene azeotropic reflux N
HNH
p-MeOC6H4
NH
NH
O
p-MeOC6H4 NH
NH
HN NH2
CO2Et
Buchnerine
58
preparation proceeded with highly regio-(>98%) and stereoselectivities (cis/trans 96-99%) [292].
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].
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.
OLi Pb(OAc)3OH
Ph Phbrucine
-40 °C~-20 °C
yield 93%83% ee
OH
BuLitoluene0 °C
R1 R2N
N
Ph
cat. LDA R1 R2
>98% regio, 96-99% stereoselectivity
59
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].
The technique was used for ring enlargement reaction including synthesis of muscone [28, 36].
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]. �
5.10. Peterson Olefination for Stereoselective Synthesis
In his early research at Kyoto, Yamamoto reported an efficient silicon-mediated
OCH2Cl2LDA. 0°C
OH
CH2Cl289%
O OHCHBr2
OBuLiCH2Br2
LDA
Pb(OAc)3
NH2
brucinetoluenert, 3h
NH2
yield 90% 41% ee
-78 °C, 12h-40 °C, 3h
t-BuMgCl
C C CHH
B(OH)2H
Dialkyl tartrate RCHO R
HO H95%ee
C C CHH
BH
O
OCOOR
COOR
60
alkene synthesis which directly produces Z-alkenyl derivatives [24, 59].
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.
1.3. Novel α-Amino Acid-based Hydroxamic Acid Ligand for
Vanadium-Catalyzed Asymmetric Epoxidation of Allylic Alcohols
OO N
PhPh
N O
(S,S)-imide
HSS
Et2O, 0 ÞC THF, -78 ÞC, 2 h
OSiMe3 OLi ORMeLi·LiBr
86% yield (87% ee)
Me3SiCH2COOEt
1) R2NLi2) R1R2C=O
R2
R1
COOEt
CHOHR3SiC C CMSiMe3
Me3Si
97% Z
61
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).
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.
OHPh
PhOHPh
PhO
VO(O-i-Pr)3 (1 mol%)Hydroxamic acid (1.5 mol%)
TBHP, toluene, 0 °C
NN
O
OHO
O
93-96%. 95-96%ee
62
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.
OSiMe3
PhN=O
Et3SiOTf (5 mol %)(CH2Cl)2, 0 °C, 1 h
O
NOH O
O NH
Ph+ +
AgF·(±)-BINAP (10 mol %)MeOH, 0 °C, 2 h
91% (>99 : 1)
88% (1 : >99)
OH
N N Ph
Ph
OH
O
O
O
OH
N N Ph
Ph
OH
O
O
O
HO
OHO
OHO
VO(O-i-Pr)3 (2 mol %)Ph3COOH (1.5 equiv)
toluene, 0 °C, 10 h
(6 mol %)
(S)-Limonene
(CH2O)nMe2AlCl
CHCl339%
VO(O-i-Pr)3 (2 mol %)Ph3COOH (1.5 equiv)
toluene, 0 °C, 10 h
(6 mol %)
84%, 90% de
(–)-(4S, 8S)-α-Bisabolol3 steps
65%
77%, 90% ee
63
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].
R4
OSiMe3R3
Ph
OH O
Ph
OH O
PhPh
OOH
R1 R4
OH O
R2R3(1.1 equiv)
1. HNTf2 (1.0 mol%) Et2O, –78 °C, 15 min2. Addition of R1R2C=O (1 equiv) at –78 °C over 2 h
3. Stirred at –78 °C, 15 min4. 1 M HCl–THF (1:1) or Bu4NF/THF
87% 92%(step 3: –40 °C, 0.5 h)
92% (syn:anti=70:30)
SiMe3
1. HNTf2 (0.5 mol%), CH2Cl2, rt, 0.5 h2. Addition of R1R2C=O (1 equiv) at –78 °C over 2 h
3. Stirred at –78 °C, 15 min4. 1 M HCl–THF (1:1)
(1.5 equiv)R1
OH
R2
OH
89%
OH
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
64
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
R1 H
OSiMe3
X
R2
R3
OSiR3
R1 R2
R3
O OSiR3Me3Si
X
R1 R2
R3
Me3SiO O+ R3SiX
R1 R2
R3
O OSiR3Me3Si
X O
R1
Hδ+
δ+ R2
R3
OSiR3
R1 R2
R3
R3SiO OSiR3
R1 R2
R3
O OMe3Si
X
R1 R2
R3
O OMe3Si
XR1 R2
R3
R3SiO OSiR3
O
R1
Hδ+
δ+
R1 R2
R3
R3SiO O
R2
R3
OSiR3
R1CHO
R1CHO
Intramolecular transfer of OTf
+SiR3-induced cascade process
+
X=OTf
X=NTf2or
CTf3
65
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.
66
F F
F
F FBr
CF3SO2Nacat. Bu4NI
EtCN, reflux
1. t-BuLi 2. Tf2O
3. 4 M HCl
F F
F
F FTf
TfH
superacid
LiF
F
F
F
Tf
TfH
Organic solvent-swellable solid strong acid
F F
FF
Tf
TfH
PhCO2Me
1 mol%: 94% vs. 39%
esterification
OBzi-Pr
3 mol%: 71% vs. 0%
benzoylation
MeO
O1 mol%: 54% vs. 25%
Friedel-Crafts acylationO
CO2Me
3 mol%: 77% vs. <1%
Michael addition
Ph
MeO OMe
0.5 mol%: >99% vs. 16%
acetalization
Ph
OH
3 mol%: 89% vs. 2%
Sakurai-Hosomi allylation
Ph Ph
OH O
3 mol%: >99% vs. >99%
Mukaiyama aldolPS-C6F4CHTf2 vs. Nafion®SAC-13
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(trifluoromethanesulfonyl)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..
67
CF3(CF2)12CH2OH(3 equiv)
84% yield, 62 wt %F
NaH (3 equiv)
pyridine:(C4F9)3N=2:1
rt to 70 ÞC, 1 h
1. C6F5Tf2Li (1 equiv), 70 ÞC, 1 day
2. 4 M HClCF3(CF2)12CH2O
Tf
TfH
F F
FF
PhCHO HO OHcatalyst (1 mol%)
cyclohexaneazeotropic reflux, 3h
O
OPh
86% yield; recovery of a catalyst: 96%
