酯化反应第二章

U se of Tin and Other Metal Alkoxides
159
2 T he oxygen atom of metal alkoxides exhibits enhanced nucleophilicity due to the electropositive character of the metal. If the metal - o xygen bond is chemically labile, then the alkoxide should function well as a nucleophile. Tin alkoxides, especially organotin(IV) alkoxides, are extremely useful because the tin - o xygen bond is readily formed, thanks to its thermodynamic stability, while this bond is reactive enough to attack electrophiles. Because of its mildness and high selectivity, this procedure has found a wide range of applications, particularly in sugar chemistry, and this subject is therefore addressed in this chapter.
B u 3
S nOMe undergoes exothermic reaction with acid anhydrides and halides to give the corresponding esters [711] . This reactivity of Bu 2
S nO is utilized for the selective acylation of nucleosides (Scheme 2.1 )[712] .The 2 ′,3 ′-O -(dibutylstannylene) nucleosides are obtained by heating a methanolic suspension of the nucleosides
and an equimolar amount of Bu 2 S nO. It is postulated that Bu 2S n(OMe) 2 is initially
formed under these conditions. Treatment of the stannylene nucleosides with acetic or benzoic anhydride or chloride results in selective acylation at the 3 ′ - position, no acylation taking place on the primary alcohol. The stannylene inter-mediate does not need to be isolated, resulting in a one - p ot acylation: the addition
of 5 – 10 equiv. of Ac 2 O and Et 3
N to a solution of the stannylene prepared in metha-nol effects selective monoacetylation.
Esterifi cation. Methods, Reactions, and Applications. 2nd Ed. J. Otera and J. Nishikido Copyright © 2010 WILEY-VCH Verlag GmbH & Co. KGaA, Weinheim ISBN: 978-3-527-32289-3
E xperimental Pro cedure [712] S c heme 2.1 2′,3 ′-O -(Dibutylstannylene)uridine: A suspension of uridine (488 m g, 2 m mol) and dibutyltin oxide (500 m g, 2 m mol) in methanol (100 m L ) is heated under refl ux for 30 m in, and the resulting clear solution is then evaporated to dryness and dried i n vacuo .The resulting crystalline residue (915 m g, 96%) is analytically pure and has m.p. 232 –234 °.3′-O - B enzoyluridine: A solution of 2 ′,3 ′-O -(dibutylstannylene)uridine (2 m mol) in methanol (100 m L) is prepared i n situ as above. Triethylamine (1.4 m L, 10 m mol) and benzoyl chloride (1.2 m L, 10 m mol) are added, and the mixture is stirred at room temperature for 10 m in, at which point TL C (ethyl acetate/acetone 1 : 1) shows no remaining uridine. The solvent is evaporated i n vacuo and the residue is partitioned between ether (100 m L) and water, and fi ltered. The aqueous phase
160 2
Use of Tin and Other Metal Alkoxides
O
HO OH
B
HO
Bu
2Sn(OMe)2
Bu 2SnO + MeOH
O
O OH B HO
Bu 2Sn
OMe
O
O O B
HO
Sn Bu Bu
3
O
BzO OH
B
HO
can be isolated
B= Ur, Cy, Ad, Hx
S cheme 2.1 is concentrated to about 30
m L and allowed to crystallize. Recrystallization from aqueous ethanol gives pure (NMR and TLC) 3 ′-O -b enzoyluridine (570 m g, 78%) as the dihydrate.
M ethyl α-D
- h exopyranosides undergo selective acylation at the 2 - p osition by the stannylene method [713] .While 4,6 -O -b enzylidene D -h exopyranosides are con-verted into the corresponding stannylene derivatives, which undergo acylation at the 2 - p osition upon treatment with acyl halides in dioxane in the presence of Et 3N , the unprotected sugars are also successfully transformed into the C2 monoesters in one - p ot fashion without isolation of the stannylene intermediates (Scheme 2.2 ).
The C2 esters of methyl α-D -g luco -,α-D -a llo -,and α-D
-g alactopyranosides are obtained by this procedure.
E xperimental Pro cedure S c heme 2.2 [713] M ethyl 2,3 -O -D ibutylstannylene -α -
D -g lucopyranoside: Dibutyltin oxide (12.50 g , 50 m mol) is added to a solution of methyl α-D -g lucopyranoside (9.7 g , 50 m mol) in methanol (200 m L
), and the resulting milky solution is heated at refl ux until it becomes homogeneous and clear (45 m in). After further heating at refl ux for an additional 0.5 h , the solvents are evaporated i n vacuo to leave a white solid, m.p. range 105 –115 °C . M ethyl 2 -O -B enzoyl -α - D -g lucopyranoside: Triethylamine (1.54 m L , 11 m mol) is added to a magnetically stirred, slightly cloudy solution of methyl 2,3 - O -
2 Use of Tin and Other Metal Alkoxides
161
Me O
HO Me
HO
Me
Me
OCH3 HO
Me
OH
Me
O
HO
Me
O
Me
Me
OCH3
O
Me
OH
Bu2SnO
Sn
Bu
Bu PhCOCl
NEt
Me
O
HO
Me
HO
Me
Me
OCH3
BzO
Me
OH
S cheme 2.2
O
OH
HO
HO
HO
OMe
32
O
OH
HO
HO
O
O
O
OR4
R3O
R2O
R1O
OMe
Me
Bu3Sn
R1= R4= Bz, R2= R3= H (81%)
R1= R2= R4= Bz, R3= H (18%) S cheme 2.3
d ibutylstannylen
e -α-D-g lucopyranoside (4.25 g, 10 m mol) in dioxane (75 m L),
followed by slow addition of benzoyl chloride (1.32 m L, 11 m mol). The solution
becomes clear upon addition of the benzoyl chloride, but a white precipitate starts
to form after about 2 m in. TLC examination of the solution (ethyl acetate, silica gel
G) after 1 h shows the presence of a major spot at R f0.50 and a minor spot at R f
0.70. The salts are fi ltered off and washed with dioxane (20 m L), and the combined
fi ltrates are evaporated i n vacuo to leave a syrup. This is fractionated on a column
of silica gel G (120 g) with ethyl acetate as eluent. The fi rst compound eluted from
the column is methyl 2,6 -d i -O-b enzoyl -α-D-g lucopyranoside (0.08 g, ∼2%). The
second compound eluted from the column is the desired material (2.05 g, 70%).
E xperimental Pro cedure S c heme 2.3 [714]M ethyl α-D-g lucopyranoside
(283 m g, 1.46 m mol) is stannylated with (Bu 3S n) 2O(1.3 g, 2.19 m mol) in toluene
(23 m L). A solution of benzoyl chloride (600 m g, 4.4 m mol) in toluene (5 m L) is
then added dropwise to the cooled solution over 5 m in at −10 °C. The mixture
is stirred for 4 h at −10 °C and then left for 17 h at −5°C. Acetic acid (0.2 m L) is
added and the solvent is evaporated i n vacuo to give an oily residue, which is
triturated with diisopropyl ether to afford the crystalline product (588 m g, 95%).
R egioselective acylation of sugars through the use of (Bu 3S n) 2O is also feasible
[714] . In this case, the selectivity is governed by a monoalkoxytin intermediate coordinated by the proximate hydroxy group. For example, stannylation of methyl
α-D-g lucopyranoside with two equiv. of (Bu 3S n) 2O followed by treatment with
benzoyl chloride at 20 °C provides the 2,6 -d i -O-b enzoyl ester (81%) and the 2,3,6 -t ri -
O-b enzoyl ester (18%) (Scheme 2.3 ). When the reaction is conducted at −10 °to
−5°C,the dibenzoate is obtained in 95% yield.
162 2 Use of Tin and Other Metal Alkoxides
T
he regioselectivity in monoacylation of secondary hydroxy groups in monosac-charides can be controlled by the stannylene technique (Scheme 2.4 ) [715] . Use of one equiv. of strong base such as N - m ethylimidazole results in the formation of the equatorial 3 - b enzoate in a yield of more than 90%.
O
O
Ph
HO OMe
OH O
O O
Ph
BzO
OMe
OH Bu 2SnO
O
O O Ph
O
OMe
O
Sn
Bu Bu
BzCl
N-methylimidazole benzene
> 90%
S cheme 2.4 O
O O
O O O BEt 2
BEt 2BEt 2
Et 2B
Et 2B
Et 2B OH
BzO OH
OH HO
OH +
1. Bu 3Sn(acac)3. MeOH
BzCl
S cheme 2.5 E xperimental Pro cedure S c heme 2.5 [716] A solution of hexa -O -d iethylboryl derivative (234 m g, 0.4 m mol) in toluene is treated with tributyltin acetylaceto-nate (0.5 m mol), and N - m ethylimidazole and benzoyl chloride are then added at −5°C . The reaction mixture is stirred at 5 °C for 10 h . After conventional workup the mixture is purifi ed by column chromatography on silica gel (chloroform/methanol, 3 :1). S elective O - a cylation and - a lkylation are feasible, as shown in Scheme 2.6 [717] and Scheme 2.7 [718] . B orylated carbohydrates are quantitatively O -s tannylated by transmetalation with tributyltin acetylacetonate. This methodology is applicable to O -a cylation of m yo -i nositol (Scheme 2.5 )[716] . The standard stannylene procedure is not effective for acylation because of the poor solubility of the stannylene intermediate, whereas the hexa -O - d iethylboryl derivative prepared by treatment with excess Et 3 B is soluble in hexane, and treatment of this compound with tributyltin acetylacetonate furnishes a partially borylated - s tannylated intermediate. Treatment of this com-pound with benzoyl chloride in the presence of N -m ethylimidazole affords 1 -O -b enzoyl -m yo -i nositol.
2 Use of Tin and Other Metal Alkoxides 163
OH
OH
OH OH OH OBn OBn
OAc OAc OAc
233. Ac 2O, Py
S cheme 2.6 O
Ph
HO
HO
OMe
Bu 2SnO,Bu 4NBr
Br
NO 2
+
O O O Ph
HO
RO
OMe
O O O Ph RO
HO
OMe
+
2O,Py
O O
O Ph
AcO
RO
OMe
R=2-NO 2C 6H 4CH 2
S cheme 2.7 R OH R
OH
Bu 2SnO, toluene
MS 4A, reflux
O
SnBu 2
O R R
R OCOR'R
OH
R'COCl
R'=
R= OCOMe (80%; 90% de )R= Ph (69%; 8% de )
S cheme 2.8 OH OH OH
O O
OH
Bu 2SnO, CH
2Cl 2MS 4A
SnBu 2
R*COCl
OCOR*
OH OH
R*=
OH
O O
*
*
Z
*
S cheme 2.9 T
he use of chiral acid halides in the stannylene approach allows asymmetric acylation of m eso -1,2 -d iols. Thus, treatment of m eso -d imethyl tartrate with Bu 2S nO followed by (1 S ) - k etopinic acid chloride exclusively affords the monoacylation product in high yield and with high diastereoselectivity (Scheme 2.8 ) [719] .
O
ptically active glycerol acetonide can be prepared analogously from achiral glycerol (Scheme 2.9 )[720] .
164 2 Use of Tin and Other Metal Alkoxides
E xperimental Pro cedure S c heme 2.10 [721] S odium carbonate (1.5 m mol)
base is suspended in HF (5 m L) containing racemic alcohol (1 m mol), water (100 µl, 5.5 m mol), and organotin catalyst (0.25 m ol%). Benzoyl chloride
(0.5 m mol) is then added to the suspension at −10 °C, and the resulting
solution is stirred at that temperature for 14 h. After conventional workup, a mixture of primary monobenzoate (86% e e, 38% yield) and recovered racemic alcohol (46% e e, 58% yield) is obtained, with a trace amount of secondary monobenzoate.
Ph
OH
OH
catalyst,Na2CO3
THF / H2O
+BzCl
+
Ph
OH
OBz
Ph
OH
OH
+
(±)
2
catalyst=
S cheme 2.10
W hen the treatment of unsymmetrical diols by the stannylene procedure is
accompanied by i n situ quenching with chlorosilane or oxalic acid, acylation takes
place on the more substituted hydroxy group (Scheme 2.11 )[722, 723] . This
method can be applied to 1,2 -,1,3 -,and 1,4 -d iols of primary -s econdary, primary -
t ertiary, and secondary -t ertiary natures. Benzoyl chloride and other acid chlorides
are employable, but acid anhydrides are of no use.
E xperimental Pro cedure S c heme 2.11 [723] G eneral Acylation Procedure: A
portion of the diol (1.5 m mol) is dissolved or suspended in toluene (30 m L),
and, after the addition of dibutyltin oxide in 5% molar excess, water is separated
by azeotropic distillation in a Dean -S tark apparatus for a variable length of
time, depending on the substrate. After evaporation of the solvent, the residue
is dried under vacuum, dissolved under nitrogen in anhydrous CHCl 3
(30 m L), and cooled to 0 –5°C. An equimolar amount of the appropriate acylat-
ing reagent in the same solvent (1 m L) is added dropwise to the stirred solution
by syringe through a septum cap, and the reaction mixture is allowed to react
at room temperature for 1 h, and then quenched by one of two different
methods.
K inetic resolution of chiral 1,2 -d iols is effected by use of an organotin catalyst
with a binaphthyl moiety as a chiral source (Scheme 2.10 )[721] . Addition of
sodium carbonate and a small amount of water improves the selectivity.
2 Use of Tin and Other Metal Alkoxides 165
R
OH (CH 2)n OH
+
Bu 2SnO
toluene
R
O
(CH 2)n O
SnBu 2
1. R'COCl, CHCl 3
2. Me 3SiCl or (COOH)2
R OCOR'(CH 2)n OSiMe 3
R
OSiMe 3(CH 2)n OCOR'
+
(or OH)
(or OH)63 : 37~98 : 2
S cheme 2.11 M ethod A – Quenching with Trialkylsilyl Chlorides: A solution of the appropri-ate silyl chloride (5% molar excess) in anhydrous CHCl 3(1 m L) is added dropwise by syringe to the cooled solution (0 – 5 ° C ), and the mixture is then allowed to react
at room temperature for 1 – 2 h . The mixture obtained is then analyzed by
1
H NMR spectroscopy. M ethod B – Quenching with Oxalic Acid: The solvent is evaporated under
vacuum, and the residue is dissolved in anhydrous CH 3C N (8 m L
). The solution is cooled to 0 –5°C , oxalic acid (0.75 m mol) in CH 3C N (3.5
m L) is added, and the mixture is stirred at room temperature for 20 h . The resulting suspension is fi l-tered under nitrogen, and the solid is washed several times with CH 3C N. The residue obtained after evaporation of the solvent under vacuum is dissolved in
CDCl 3 , and the mixture is analyzed by 1
H NMR spectroscopy. M
icrowave irradiation is useful not only for shortening the time required to prepare the stannylene intermediates but also for rendering the procedure cata-lytic. As shown in Scheme 2.12 , if Bu
2
S n(OH)Cl is successfully transformed to non-selective benzoylation
Bu 2SnO
O
O
SnBu 2
BzCl,
base
SnBu 2Cl
Bu 2Sn(OH)Cl
base,
S cheme 2.12
166 2 Use of Tin and Other Metal Alkoxides
(CH2)n R OH R'OH +BzCl(CH
2
)n
R OBz
R'OH
0.01~0.1eq.Me2SnCl2
2 eq.K2CO3,rt
S cheme 2.13
HO
OH
(CH2n
O O
2
n= 3 (42%)
n= 4 (28%)
n= 5 (35%)
n= 6 (35%)
n= 7 (53%)
n= 8 (65%)
CH2CH2
O
Bu2SnBu2
O
O
CH2CH2
3
)n S cheme 2.14
Bu 2S nO in the presence of a base, the organotin species can be recycled. Under normal conditions, however, in which heating is necessary to prepare stannylate diols, the base promotes the reaction between benzoyl chloride and diols. However, no such direct reaction occurs under microwave conditions, thus allowing the catalytic cycle to complete.
T he catalytic process is also achievable through the use of Me 2S nCl 2in the pres-ence of K 2C O 3, although the mechanism is not clear (Scheme 2.13 )[724] . A variety of cyclic and acyclic diols, 1,2 -d iols in particular, are selectively monobenzoylated in good yield.
E xperimental Pro cedure S c heme 2.13 [724] A catalytic amount of dimethyltin dichloride (0.01 m mol), solid K 2C O 3(2.0 m mol), and benzoyl chloride (1.2 m mol) are successively added at room temperature to a TH
F (5 m L) solution of t rans-1,2 -c yclohexanediol (1 m mol). After the mixture has been stirred at room tem-perature until t rans-1,2 -c yclohexanediol has disappeared (checked by thin layer chromatography), the mixture is poured into water and the organic portion is extracted with CH 2C l 2. After evaporation of the solvent, a residue is obtained, and this is confi rmed by NMR to be pure monobenzoylated product ( >99%).
C yclic stannoxanes made up of dibutylstannylene and 1, n -d ialkoxy units func-tion as covalent templates in reaction with acid dihalides to give macrocycles (Scheme 2.14 )[725, 726] . Acid anhydrides are also employable, and the use of chiral tin templates affords diastereomeric macrocyles (Scheme 2.15 )[727, 728] . N-(Trifl uoroacetyl) -g lutamic and -a spartic anhydrides provide macrocylces with an
2 Use of Tin and Other Metal Alkoxides 167
+Bu 2Sn(OEt)2
O SnBu 2
O Me
(±)
HO
OH
Me
Cl
O
O )5
Me HC Me
O
O SnBu 2
O
O
Bu 2Sn Me
Me
dimeric complexes of stannoxanes
S cheme 2.15 O O O
H
N
F 3C
O Bu 22+
CH 2CH 2
O C
O CH
F 3COCHN CH 2
O
C
O HC NHCOCF 3CH 2CH 2CH 2
O
O
O
O
CHCl 3 (boiling)
S cheme 2.16 O 2CH O Bu 2Sn
SnBu 2O
O
2CH O O O O
N
Me
or +
O
O O or
S cheme 2.17 amino residue on the ring (Scheme 2.16 ). Treatment of the distannoxane with a cyclic carboxy - c arbonate derived from glycolic acid or isatoic anhydride results in ring opening (Scheme 2.17 )[729] . T in(II) alkoxides are also effective. Reactions between 1,1 ′-d imethylstannocene and alcohols readily occur at room temperature, and the resulting tin(II) alkoxides
168 2 Use of Tin and Other Metal Alkoxides
provide esters upon treatment with acid halides (Scheme 2.18 ) [730] . When this reaction is carried out in the presence of a chiral amine ligand, asymmetric desym-metrization of 2 - O - p rotected glycerols is feasible, furnishing monoesters with up to 84% e e (Scheme 2.19 )[731] .
+
Sn
R'COCl, toluene R'COOR 60~94%
ROH
S cheme 2.18 SnCl
+R=Ph,o -ClC 6H 4,1-naphthyl,PhCH=CH,cHex
S cheme 2.19 E xperimental Pro cedure S c heme 2.18 [730] 3-P henylpropanol (125 m g, 0.921 m mol) in toluene (1.5 m L) is added at room temperature, under an argon atmosphere, to a toluene solution (2 m L) of 1,1 ′-d imethylstannocene (153 m g, 0.552 m mol). After the mixture has been stirred for 30 m in, hexamethylphos-phoric triamide (1 m L ) and benzoyl chloride (155 m g, 1.11 m mol) in toluene (1.5 m L) are successively added. The mixture is kept stirring at room tempera-ture for 2 h and quenched with pH 7 phosphate buffer. The aqueous phase is extracted three times with ether and the combined extracts are washed with
brine and dried over anhydrous Na 2S O 4
. After evaporation of the solvent, the resulting crude product is purifi ed by silica - g el thin layer chromatography to afford 3 -p henylpropyl benzoate (200 m g, 90%). T he stannylene technique has been successfully applied to synthesis of ( – ) - i nte-gerrimine (Scheme 2.20 )[732] and ( –)-s enecionine (Scheme 2.21 )[733] .
M etallacycles with metals other than tin also react with acid halides. When an arsole or a stibole is treated with one equiv. of acid halides with subsequent hydrolysis, a monoester is produced (Scheme 2.22 ) [734] . On the other hand, treatment with two equiv. of acid halides affords the corresponding diesters.
2 Use of Tin and Other Metal Alkoxides
169
N
OH
HO
H Bu 2SnO, benzene N
O
H O
Sn Bu Bu O
O
O
Me OCH 2SCH 3Me
H
N
O
H benzene, 5°C
O
O OH Me H OCH 2SCH 3
Me
N O
O H
O
O Me H
OH Me (-)-Integerrimine
HO
S cheme 2.20 O
OCH 2SCH 3
H
Bu 2SnO, MS
benzene
N
HO
OH
H
N
O
H O
Bu 2Sn O
H O
HOOC Me
H
OCH 2SCH 3
Me
N O
O
H O
OH
Me
O
Me H
(-)-Senecionine
S cheme 2.21 O
MCl O R R'
R
R'
R
OCOR''
R'
OMCl 2OCOR''
OCOR''H 2O
R OCOR''R'
OH
M= As, Sb
S cheme 2.22
170 2 Use of Tin and Other Metal Alkoxides
Cl
(CH 2)n
O
Cl
O R
R O
Sb O
Cl benzene, reflux O
O R
R O
O
(CH 2)n (CH 2)n O O O O
R
R
18~36%
n= 1, 3, 5, 7, 8
S cheme 2.23 O R H H Ph
O O O
R AcO
H OH
H Ph
O
O
R HO H OAc
H Ph
O O
R AcO
H OAc
H Ph
+
+
+
2 eq. NaH, THF 2
Chiral
Chiral
Chiral
Chiral a: R= SC 2H 5 (74%)b: R= SePh (81%)c: R= OPh (63%)
a: 0%b: 0%c: 19%
a: 21%b: 3%c: 0%
AcCl
S cheme 2.24 Macrocyles can be obtained by the treatment of stiboles with diacid dihalides (Scheme 2.23 )[735] . C opper(II) also functions as a template. Regioselective C3 O - a cylation is achieved by treatment of sodium salts of 4,6 - O -b enzylidene -g lucopyranosides (prepared by
addition of NaH) with CuCl 2 followed by acid halides (Scheme
2.24 ) [736] . S i(OMe) 4 acts as a catalyst/reagent in the selective methylation of 2 -h ydroxycar-boxylic acids (Scheme 2.25 ) [737] . 2 - H ydroxy acids play a crucial role: the hydroxy acid attaches to silicon through the alkoxy group and subsequently through the carboxy group in an intramolecular rearrangement to form an unstable and reac-tive cyclic intermediate. This intermediate may accelerate methylation of the car-boxylic acid via nucleophilic attack of MeOH at the carbonyl group. B(OBu) 3acts similarly for butylation of dicarboxylic acids (Scheme 2.26 ) [738] . Heating of a mixture of dicarboxylic acid and B(OBu) 3in a 3 :2ratio affords the desired diester in good yield.
2 Use of Tin and Other Metal Alkoxides 171
I n transesterifi cation, a tetranuclear zinc cluster, Zn 4(OCOCF 3)6 O , acylates alco-hols in the presence of free amine [739] , in contrast to the conventional reactivity, by which amines are more reactive than alcohols due to their stronger nucle-ophilicity. In this sense, the zinc cluster is similar to lipase. With this catalyst, various amino alcohols are transformed into the corresponding esters without violating the amine function (Scheme 2.27 ).
Si(OMe)4
3
O Si O X O
OMe
OMe -
+
O Si
O X O
OMe OMe
O Si O
OMe OMe -+MeOH
-H O Si +MeOH
++H +;-MeOH
+OMe OH
OMe -MeOH
S cheme 2.25 3 HOOC 2B(OBu)3
3H 3BO 3
2+
+
BuOOC Z COOH
Z COOBu
S cheme 2.26 Zn 4(OCOCF 3)6O
i -Pr 2O,reflux
>82
<18
+:
H 2N H 2N +
Z OH
Z OCOPh
PhCONH Z OCOPh
S cheme 2.27。