Diastereoselective Povarov-like reaction involving O-pivaloylated D-galactosylimine

Article abstract of DOI:10.1002/adsc.201200761

A diastereoselective Povarov-like reaction using O-pivaloylated β-D-galactosylamine as the chiral auxiliary is described. The three-component reaction of chiral aldimines, cyclic enol ethers and nucleophiles afforded the desired products in good yields and high content of the main isomer. This procedure provides an efficient method to obtain multifunctional molecules carrying three contiguous chiral centers in high stereoselectivity.

Full text of DOI:10.1002/adsc.201200761

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DOI: 10.1002/adsc.201200761
Diastereoselective Povarov-Like Reaction Involving
O-Pivaloylated d-Galactosylimine
Gang Wang,a Boyu Li,a,b Qinghua Lou,a Zhongjun Li,a,* and Xiangbao Menga,*
a
State Key Laboratory of Natural and Biomimetic Drugs, Department of Chemical Biology, School of Pharmaceutical
Sciences, Peking University, Beijing 100191, Peopleꢀs Republic of China
Fax : (+86)-10-8280-5496; e-mail: zjli@bjmu.edu.cn or xbmeng@bjmu.edu.cn
Current address: MC 101-20, Chemistry and Chemical Engineering, California Institute of Technology, Pasadena, CA
b
91125, USA
Received: August 24, 2012; Published online: January 9, 2013
Supporting information for this article is available on the WWW under http://dx.doi.org/10.1002/adsc.201200761.
Abstract: A diastereoselective Povarov-like reac-
tion using O-pivaloylated b-d-galactosylamine as
the chiral auxiliary is described. The three-compo-
nent reaction of chiral aldimines, cyclic enol ethers
and nucleophiles afforded the desired products in
good yields and high content of the main isomer.
This procedure provides an efficient method to
obtain multifunctional molecules carrying three
contiguous chiral centers in high stereoselectivity.
derivatives,[1] a representative example was reported
by Jacobsen.[1e] In recent years, reactions trapping the
oxocarbonium intermediate by an internal[2] (Eq. 2)
or external[3] (Eq. 3) nucleophile have been devel-
oped, which are called Povarov-like reactions. Multi-
component reactions (MCRs) have many advantages,
such as operational simplicity, atom economy, high ef-
ficiency of bond formation, and the access to molecu-
lar complexity from simple starting materials.[4] The
multicomponent Povarov-like reactions have been
used as powerful synthetic approches to prepare
structurally diverse oxacyclic scaffolds in good yields
and moderate to excellent diastereomeric selectivity.[5]
For example, 4-aminobenzopyran derivatives were ob-
tained in moderate to excellent stereoselectivity using
this strategy.[6] However, the optimal reaction condi-
tions of Povarov-like reactions in the presence of an
Keywords: asymmetric synthesis; carbohydrate aux-
iliary; multicomponent reactions; Povarov-like re-
actions; scandium triflate [ScACTHNURTGNENG(U OTf)3]
The Povarov reaction, the condensation of an imine external nucleophile have not been systematically in-
with an activated olefin, (Scheme 1, Eq. 1), has been vestigated so far.
widely used in the synthesis of tetrahydroquinoline
Carbohydrate moities have been used as effective
chiral auxiliaries in many asymmetric syntheses.[7]
A
remarkable example is the O-pivaloylated b-d-galac-
tosylamine, which has been used in a variety of reac-
tions such as Strecker reaction,[8] Ugi reaction,[9] Man-
nich reaction,[10] and hetero-Diels–Alder reaction.[11]
Chiral homoallyl amines,[12] a-aminophosphonic acid
derivatives,[13]
AHCTUNGTRENNUNG
and
a-aminoACTHNGUTERN(UNG phenyl)methyl-
(phenyl)phosphinic acids[14] were synthesized with the
assistance of this chiral amine. Previous reports[15,16]
also demonstrated that O-pivaloylated b-d-galactosyl-
amine could be used for the induction of crucial
chiral centers in alkaloids through domino Mannich–
Michael reactions. Recently, the asymmetric aza-Frie-
del–Crafts reaction of indoles assisted by O-pivaloy-
lated b-d-galactosylamine has been reported with ex-
cellent yield and diastereoselectivity.[17] The use of O-
pivaloylated b-d-galactosylamine as chiral template to
promote high enantioselectivity has been well de-
fined.
Scheme 1. Povarov and Povarov-like reactions.
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Gang Wang et al.
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Table 1. Optimization of the reaction conditions for the three-component Povarov-like reaction.
Entry[a]
2a [equiv.]
3a [equiv.]
Sc
(OTf)3 [equiv.]
Yield [%][b]
Content [%][c]
1
2
3
4
5
2
5
1
1
1
3
0.2
0.2
0.2
0.5
1.0
59
55
59
76
76
–
–
89.0
87.5
84.8
7.5
1.5
1.5
1.5
[a]
All reactions were carried out with 0.15 mmol of 1a (1 equiv.), at À788C in 1 mL dry dichloromethane for 72 h.
Isolated yield by column chromatography.
Content of the main product was determined by HPLC.
[b]
[c]
Herein, we describe the optimal reaction conditions was carried out in chloroform at À408C, the yield in-
of a Povarov-like three-component reaction of an O- creased to 82% (Table 2, entry 11). We also decreased
pivaloylated b-d-galactosylimine, a cyclic enol ether, the reaction temperature from À408C to À608C and
and an alcoholic nucleophile.
increased the reaction time from 24 h to 48 h; the re-
We initially investigated the reaction of O-pivaloy- action proceeded smoothly with a slight decrease of
lated N-galactosylimine 1a (R1 =NO2), 3,4-dihydro- yield (Table 2, entry 12). But there was no significant
2H-pyran (2a) and an excess of methanol (3a) difference in the contents of the main product ob-
(Scheme 1). Various ratios of 1a, 2a and 3a were in- tained at À408C and À608C (Table 2, entries 11 and
vestigated. The reactions were carried out at À788C 12). Considering reaction time, yield and diastereose-
with the catalysis by ScACHTUNRGTNEUNG(OTf)3. The results revealed lectivity, the optimal conditions were defined as
that good yield (76%) and high stereoselectivity 0.5 equiv. Sc
(main product content 87.5%) were obtained when chloroform at À408C for 24 h.
1.0 equivalent of 2a, 1.5 equivalents of 3a and Under the optimized conditions, the generality of
0.5 equivalents of Sc(OTf)3 were used (Table 1, this method was examined with various aldimines,
ACHTUNGRTEN(NUNG OTf)3, 1.0 equiv. 2 and 1.5 equiv. 3 in dry
AHCTUNGTRENNUNG
entry 4). We found that increased amounts of 2a and cyclic enol ethers and nucleophiles. The results are
3a resulted in lower yields (Table 1, entries 1 and 2). summarized in Table 3. We found that O-pivaloylated
When the catalyst loading was increased to 0.5 equiv., b-d-galactosylimine 1, bearing electron-withdrawing
the yield increased obviously but the diastereoselec- groups such as nitro-, cyano- and halogen element
tivity decreased slightly (Table 1, entry 4). However, groups, produced the corresponding asymmetric prod-
the yield did not increase and the diastereoselectivity ucts in moderate to good yields and good to high dia-
decreased slightly when the catalyst was increased to stereoselectivity. When an external nucleophile, meth-
1.0 equiv. (Table 1, entry 5).
anol, was used, a relatively low content of the main
After optimizing the ratios of reaction components, isomer was obtained under the optimized conditions
we next identified the most suitable Lewis acid cata- (Table 3, entries 2 and 3). However, when isopropyl
lyst for the reaction of 1b, 2a and 3a. The results alcohol was used as the nucleophile, higher yields and
showed that iron trichloride, zinc triflate, copper tri- diastereoselectivity were observed (Table 3, entries 4
flate, stannic chloride and indium trichloride provided and 5), which indicated that the steric hindrance of
lower yields of the product 4ba than Sc
(Table 2, entries 1–6). Therefore, Sc(OTf)3 was the selectivity. Particularly, this reaction was efficient
most suitable Lewis acid to catalyze the reaction. We when dihydrofuran was used.
ACHTUNGRTEN(NNUG OTf)3 the nucleophiles had a significant effect on diastereo-
AHCTUNGTRENNUNG
then optimized the solvent and temperature for the
The content of the main isomer of the desired prod-
reaction. The results indicated that reactions in di- uct 4 was determined by HPLC after purification by
chloromethane, acetonitrile, 1, 2-dichloroethane and chromatography. Three chiral centers are created
tetrahydrofuran produced 4ba in very low yields even during the reaction. There are eight possible diaste-
when the temperature was increased to À408C reomers, which are RRR, SRR, SSR, SSS, SRS, RRS,
(Table 2, entries 7–10). Fortunately, when the reaction RSR and RSS. Diastereomerically pure product, for
304
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Diastereoselective Povarov-Like Reaction Involving O-Pivaloylated d-Galactosylimine
Table 2. Optimization of reaction conditions for the three-component reaction.
Entry[a]
Solvent
Time [h]
Lewis Acid
FeCl3
Temperature [8C]
Yield [%][b]
1
2
3
4
5
6
7
8
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH3CN
96
72
72
72
72
72
24
24
24
24
24
48
À78
À78
À78
À78
À78
À78
À40
À40
À35[c]
À40
À40
À60
17
Zn
Cu
U
trace
trace
28
34
41
45
35
49
SnCl4
InCl3
Sc
Sc
Sc
Sc
Sc
Sc
Sc
N
9
Cl
N
10
11
12
THF
CHCl3
CHCl3
25
82[d]
80[e]
[a]
All reactions were carried out with 0.15 mmol of 1b, 1 equiv. of 2a, 1.5 equiv. of 3a and 0.5 equiv. of Lewis acid in 1 mL
dry solvent.
Isolated yield by column chromatography.
[b]
[c]
[d]
[e]
The melting point of ClCH2CH2Cl is À408C.
Content of the main product among the eight possible isomers is 83.6% determined by HPLC.
Content of the main product among the eight possible isomers is 85.3% determined by HPLC.
Table 3. The three-component Povarov-like reaction of O-pivaloylated b-d-galactosylimines.
Entry[a]
n
R1
R2
Yield [%][b]
Content [%][c]
1
2
3
4
5
6
7
8
2
2
2
2
2
2
2
2
1
1
1
1
1
NO2
F
Cl
F
Cl
Me (4aa)
Me (4ca)
Me (4ba)
i-Pr (4fa)
i-Pr (4ea)
i-Pr (4ga)
i-Pr (4da)
i-Pr (4ha)
Me (4ab)
i-Pr (4db)
i-Pr (4fb)
i-Pr (4eb)
i-Pr (4gb)
85
74
82
87
84
86
80
81
90
82
76
73
77
90.2
86.1
83.6
94.7
95.7
94.7
Br
NO2
CN
NO2
NO2
F
92.4 (>99[d])
96.7
9
90.7
96.1
91.9
99.1
10
11
12
13
Cl
Br
98.6
[a]
All reactions were carried out with 0.15 mmol of 1, 1 equiv. of 2, 1.5 equiv. of 3 and 0.5 equiv. of Sc
Isolated yield by column chromatography.
Content of the main product among the eight possible isomers is determined by HPLC.
Content was determined by HPLC after simple recrystallization.
ACHTUNGTREN(NUNG OTf)3 in 1 mL dry CHCl3.
[b]
[c]
[d]
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Gang Wang et al.
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Figure 2. Proposed reaction transition state.
Scheme 2. Release of the chiral auxiliary.
state as shown in Figure 2.[20] Avoiding the steric hin-
drance of the pivaloyl group in aldimine 1, the cyclic
example 4da (Table 3, entry 6), could be obtained enol ether attacks the imine carbon from the Si face
after a simple recrystallization from ethanol and of the C=N plane. The generated oxocarbonium inter-
water.
mediate is subsequently attacked by the alcohol from
To prepare the final product, we tested different the backside of the oxygen heterocycle, which leads
methods to remove the auxiliary. The typical method to the preferred formation of diastereomer 4. The
with hydrochloric acid in methanol was not successful. proposed mechanism indicates that the pivaloyl group
We later used acetic acid-water after treatment with plays a critical role in controlling the stereochemistry
sodium methoxide in methanol[13,17] (Scheme 2) which of the reaction.
generated the desired products 5ea with high yields
and without racemization. The enantiomeric ratio (er) ditions of three component Povarov-like reactions
was determined by chiral HPLC. and developed an efficient method for the prepara-
X-Ray diffraction analysis of a single crystal of 4aa tion of chiral 2-alkoxy-3-phenyl(amino)methyl-
tetrahydro-2H-pyran (or furan) derivatives with Sc-
(OTf)3 as catalyst and using O-pivaloylated-b-d-galac-
In conclusion, we have optimized the reaction con-
AHCTUNGTRENNUNG
was performed to determine the absolute configura-
ACHTUNGTRENNUNG
tion of the main isomer. The crystal structure of 4aa
ACHTUNGTRENNUNG
(Figure 1) shows that the absolute configuration of tosylimine as a chiral auxiliary. High yield and diaste-
the main diastereomer, 2-methoxy-3-[4-nitrophenyl- reoselectivity were obtained with yields up to 90%
(2,3,4,6-tetra-O-pivaloyl-b-d-galactosylamino)methyl]- and contents of the main isomer up to 99%. The octa-
tetrahydro-2H-pyran, is bSRS.[19]
hedral coordination intermediate, which is formed
Based on these results, a possible reaction mecha- with Sc(OTf)3, controls the configuration of the reac-
AHCTUNGTRENNUNG
nism (Figure 2) was proposed. The preferred forma- tion product.
tion of diastereomer 4 can be explained by the postu-
lated transition state. The scandium atom should
adopt an octahedral coordination in the transition
Experimental Section
General Procedure for the Three-Component
Povarov-Like Reaction
An oven-dried, 10-mL vial was charged with O-pivaloylated
b-d-galactosylimine
(0.15 mmol)
and
ScACHTUNGTRENNUNG(OTf)3
(0.075 mmol). After the vessel was treated with alternating
vacuum and nitrogen purge, 1 mL of dry choroform was
added via a syringe, and the mixture was stirred under nitro-
gen at À408C for 15 min before 3,4-dihydro-2H-pyran or
2,3-dihydro-2H-furan (0.15 mmol) and methanol or isopro-
pyl alcohol (0.225 mmol, 1.5 equiv.) were added. The result-
ing solution was stirred for the indicated time until the reac-
tion was complete as shown by TLC (usually 24 h). Then
three drops of triethylamine were added and the mixture
was gradually warmed to room temperature. After extrac-
tion with dichloromethane, the organic layer was washed
with saturated aqueous sodium bicarbonate, dried over mag-
nesium sulphate, filtered, and the volatiles were removed
under vacuum. The residue was purified by column chroma-
tography on silica gel (petroleum ether/ethyl acetate=15/1),
yielding the corresponding compounds 4aa–gb as a mixture
Figure 1. X-ray structure of the product 4aa.[18]
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Adv. Synth. Catal. 2013, 355, 303 – 307

Diastereoselective Povarov-Like Reaction Involving O-Pivaloylated d-Galactosylimine
of 4–8 diastereomers (clean NMR spectra were obtained for
11 of 13 products).
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ral Science Foundation of China (NSFC) (No. 21072017,
20732001).
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