Highly efficient asymmetric vinylogous Mannich reaction induced by O-pivaloylated d-galactosylamine as the chiral auxiliary

Article abstract of DOI:10.1039/c0ob01048k

The diastereospecific formation of β-N-glycoside-linked α-amino-2(5H)-furanone has been achieved with high yield via a vinylogous Mannich reaction. The reaction was performed by using O-pivaloylated galactosylamine 1 as a chiral template and ZnCl₂·Et ₂O as a promoter in Et₂O. Imines 3 of aromatic compounds and trimethylsiloxyfuran 4 were converted to N-galactosyl α-amino-2(5H)- furanone 5, giving ratios of diastereomers higher than 20:1. This procedure provides rapid access to biologically important γ-butenolide derivatives.

Full text of DOI:10.1039/c0ob01048k

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PAPER
Highly efficient asymmetric vinylogous Mannich reaction induced by
O-pivaloylated D-galactosylamine as the chiral auxiliary†
Jipan Yu, Zhiwei Miao* and Ruyu Chen*
Received 18th November 2010, Accepted 1st December 2010
DOI: 10.1039/c0ob01048k
The diastereospecific formation of b-N-glycoside-linked a-amino-2(5H)-furanone has been
achieved with high yield via a vinylogous Mannich reaction. The reaction was performed by using
O-pivaloylated galactosylamine 1 as a chiral template and ZnCl2·Et2O as a promoter in Et2O.
Imines 3 of aromatic compounds and trimethylsiloxyfuran 4 were converted to N-galactosyl
a-amino-2(5H)-furanone 5, giving ratios of diastereomers higher than 20 : 1. This procedure
provides rapid access to biologically important g-butenolide derivatives.
of carbohydrates as chiral templates to promote Mannich-type
reactions and the stereoselective synthesis of a-amino-phosphonic
Introduction
acid derivatives is reported.9 We have developed a convenient and
efficient synthetic protocol for preparation of a-aminophosphinic
acid derivatives in high yields and high enantiostereoselec-
tivity, utilizing SnCl4 as the promoter and O-pivaloylated D-
galactosylamine as the chiral auxiliary by means of Mannich-
type reactions.10 Herein we report the first example of chiral
auxiliary asymmetric vinylogous Mannich reaction of aldimines
with TMSOF under mild conditions to afford the corresponding
adducts in moderate to good diastereomeric excesses and high
yields as well as good diastereoselectivities for the production of
chiral g-butenolide derivatives.
Asymmetric Mannich reactions are among the most fundamental
carbon–carbon bond forming reactions in organic chemistry, and
the reaction products are versatile intermediates in the synthesis
of chiral, enantiomerically enriched amines.1 On the other hand,
the vinylogous Mannich reaction has gained increasing attention
because in principle, it offers facile access to complicated and
highly functionalized d-amino compounds.2 In recent years, the
asymmetric Mannich-type reaction of trimethylsiloxyfuran with
aldimines has proven to be a powerful synthetic protocol to pre-
pare chiral g-butenolide derivatives bearing an amine functionality
in good yields and moderate to good enantiomeric excesses.3
This synthetic approach allows us to obtain a,b-unsaturated g-
lactone via a regio- and diastereoselective four-carbon elongation
of suitable imines with trimethyl siloxyfuran (TMSOF).4
Results and discussion
In 1999, Martin and Lopez reported the first example of
the catalytic asymmetric addition of trialkylsilyloxyfurans to
the aldimines.3f Hoveyda and Snapper also reported a silver(I)-
based catalyst using a 2-methyloxyphenyl group as an aldimine
substituent, leading to the product of asymmetric vinylogous
Mannich reaction of trimethylsiloxyfuran with aldimine in excel-
lent diastereo- and enantioselectivity.5 However, to the best of our
knowledge, the chiral auxiliary asymmetric vinylogous Mannich
reaction of aldimine with TMSOF has not been disclosed thus far.
Carbohydrates are valuable as enantiomerically pure starting
materials in chiral pool syntheses of many chiral natural products
and drugs.6 Carbohydrate derivatives are efficient auxiliaries for
stereo-differentiation in many stereoselective chiral syntheses.7–8
A notable example is the paper by Kunz, in which the use
The synthesis of b-N-glycosidically linked a-amino-2(5H)-
furanone started with the condensation of arylaldehyde 2 and
2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosylamine 1. The for-
mation of the corresponding N-galactosylaldimines 311 proceeded
smoothly at room temperature under dehydrating conditions.
Higher temperature and longer reaction time led preferentially
to the formation of the undesired conjugated enamines.12 In a
Lewis acid catalyzed Mannich-type reaction, the aldimines 3 were
reacted with trimethylsiloxyfuran 4 at low temperature to form
N-galactosyl a-amino-2(5H)-furanone 5 (Scheme 1).
We initially investigated the reaction of O-pivaloylated N-
galactosylimine 3h (R = p-ClC6H4) with trimethylsiloxyfuran 4
in Et2O without the aid of a Lewis acid and no product 5h was
detected (Table 1, entry 1). Since the electrophilicity of imines
is only moderate, the reaction between TMSOF 4 and imines
requires activation by a Lewis acid to proceed. In this sense, various
Lewis acids were tested in the reaction of the N-galactosylimine
3h with 4 in Et2O. The results revealed that CuCl, CuBr, CuI,
AgOTf and LiClO4 only caused anomerization of the Schiff base
3h, and no product of 5h was observed (Table 1, entries 2–6).
State Key Laboratory and Institute of Elemento-Organic Chemistry, Nankai
University, Tianjin, 300071, China. E-mail: miaozhiwei@nankai.edu.cn;
Fax: +86 2350 2351; Tel: +86 2350 4783
† Electronic supplementary information (ESI) available. CCDC reference
number 783107. For ESI and crystallographic data in CIF or other
electronic format see DOI: 10.1039/c0ob01048k
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Table 1 Survey of the conditions for the formation of 5h according to Scheme 1a
Entry
Lewis acid (equiv.)
Solvent
Time
Yields (%)b
drc
1
2
3
4
5
6
7
8
—
CuCl (1)
CuBr (1)
CuI (1)
AgClO4 (1)
LiClO4 (1)
FeCl3 (1)
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
Et2O
THF
toluene
CH2Cl2
MTBE
EDCe
Et2O
Et2O
Et2O
2 d
2 d
2 d
2 d
2 d
2 d
2 d
2 d
2 d
2 h
2 h
2 h
n.r.d
n.r.
trace
n.r.
trace
n.r.
78
83
11
92
81
87
85
89
86
92
87
80
91
—
—
—
—
—
—
74 : 26 : 0 : 0
63 : 37 : 0 : 0
56 : 40 : 4 : 0
78 : 22 : 0 : 0
89 : 11 : 0 : 0
86 : 14 : 0 : 0
84 : 12 : 4 : 0
91 : 9 : 0 : 0
69 : 31 : 0 : 0
77 : 23 : 0 : 0
68 : 32 : 0 : 0
62 : 38 : 0 : 0
62 : 38 : 0 : 0
93 : 7 : 0 : 0
88 : 12 : 0 : 0
84 : 16 : 0 : 0
AlCl3 (1)
9
Mg(ClO4)2 (1)
Cu(OTf)2 (1)
Zn(OTf)2 (1)
BF3·Et2O (1)
SnCl4 (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1)
ZnCl2·Et2O (1.5)
ZnCl2·Et2O (2.0)
ZnCl2·Et2O (0.5)
10
11
12
13
14
15
16
17
18
19
20
21
22
2 h
18 h
72 h
20 h
5 h
72 h
4 h
12 h
7 h
60 h
90
88
82
a Unless otherwise noted all the reactions were performed with 0.3 mmol of 3, 0.6 mmol TMSOF in 2 mL solvent at -78 ◦C. b After purification by
chromatography. c Diastereomeric ratio (dr) values were determined by HPLC of unpurified products. d no reaction. e EDC = 1,2-dichloroethane.
Scheme 1 Reaction of aldimines with trimethylsiloxyfuran.
Other Lewis acids tested (e.g., FeCl3, AlCl3, Mg(ClO4)2, Cu(OTf)2,
Zn(OTf)2, BF3·Et2O, SnCl4 and ZnCl2·Et2O) were able to promote
the addition (Table 1, entries 7–14). Since ZnCl2·Et2O gave the
higher diastereoselectivity (d.r. = 91 : 9 : 0 : 0) compared with other
Lewis acids, it was used in further investigations. The ratio of
diastereomers 5h was determined by HPLC.
With the best Lewis acid ZnCl2·Et2O being identified, we next
carried out the asymmetric vinylogous Mannich reaction of 3h
with 4 in different solvents to determine the best solvent for this
reaction. The results showed that THF, toluene, CH2Cl2, methyl
tert-butyl ether (MTBE) and 1,2-dichloroethane were providing
5h in lower yields and diastereomeric ratio (Table 1, entries 15–
19). Therefore, the tentatively optimized reaction conditions were
determined to use Et2O as the solvent in further investigations.
To determine the optimal conditions, imine 3h was reacted
with two equivalents of trimethylsiloxyfuran 4 in the presence
of different concentrations of ZnCl2·Et2O in Et2O at -78 ◦C. An
increase in the concentration of Lewis acid (1.5 equiv) resulted in
a higher yield of 5h and a slight increase in the diastereoselectivity.
A further increase in the concentration (2 equiv) had no significant
effect on the yield or the selectivity. The reaction time will extend
to 60 h when the catalyst concentration decreases to 0.5 equivalent
(Table 1, entries 20–22).
Under these optimum conditions, we next examined the gener-
ality of this reaction with various aldimines 3 with siloxyfuran
4 and the results were summarized in Table 2. It was found
that O-pivaloylated N-galactosylimine 3, bearing both electron-
rich and electron-poor aromatic groups, gave the corresponding
asymmetric vinylogous Mannich products 5b–n in good to high
yields and diastereoselectivities (Table 2, 5b–n). As for the aldimine
in which R was a phenyl group, relatively lower yield and di-
astereoselectivity was realized under identical conditions (Table 2,
5a). Particularly, this process was efficient for cinnamaldehyde
and afforded the desired product with 54% diastereoselectivity
in 76% yield (Table 2, 5o). Notably, the aldimine derived from
heteroaromatic aldehydes gave the adducts in good yields with high
diastereoselectivities (Table 2, 5p–q). Furthermore, the reaction of
Schiff base 3 of aliphatic aldehyde with trimethylsiloxyfuran 4
led to the product in very poor yield, only anomerization and
decomposition occurred.
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Scheme 2 Synthesis of (S)-5-((R)-amino(4-chlorophenyl) methyl)-5H-furan-2-one 8b.
Table 2 The vinylogous Mannich reaction of N-(2,3,4,6-tetra-O-
pivaloylated-D-galactosyl)aldimines 5a–q
Product
R
Time (h) Yield (%)a
drb
de(%)c
5a
5b
5c
5d
5e
5f
5g
5h
5i
5j
5k
5l
5m
5n
5o
5p
5q
C6H5
36
18
24
18
18
24
16
12
54
87
72
83
75
88
73
90
66
94
60
84
66
88
76
63
54
61 : 39 : 0 : 0 22
95 : 5 : 0 : 0 90
80 : 17 : 3 : 0 60
87 : 13 : 0 : 0 74
o-CH3C6H4
o-ClC6H4
o-BrC6H4
m-ClC6H4
m-FC6H4
m-CH3C6H4
p-ClC6H4
p-OCH3C6H4 96
p-FC6H4
p-NO2C6H4
p-BrC6H4
p-CH3C6H4
p-CF3C6H4
93 : 7 : 0 : 0
94 : 6 : 0 : 0
86
88
89 : 11 : 0 : 0 78
93 : 7 : 0: 0 86
69 : 13 : 8 : 10 38
97 : 3 : 0 : 0 94
90 : 10 : 0 : 0 80
26
108
44
12
24
98 : 2 : 0 : 0
90 : 5 : 5 : 0
94 : 6 : 0 : 0
96
80
88
Fig. 1
phCH CH 12
2-furyl
3-pyridyl
77 : 23 : 0 : 0 54
shows that the relative configuration of b-N-glycoside-a-amino-
2(5H)-furanone main product can be assigned as bRS.
18
12
86 : 8 : 6 : 0
93 : 7 : 0 : 0
72
86
The possible mechanism for the reactions is shown in Fig. 2.
The preferred formation of the configured diastereomer of 5
can be rationalized by an attack of trimethylsiloxyfuran from
the Si side of N-galactosylaldimines 3. In the transition state,
the zinc atom has tetra-coordination of which the sites are
occupied by the imine nitrogen and carbonyloxygen (C-2) of the
pivaloyloxy group respectively, and one of the two chlorines may
be removed when trimethylsiloxyfuran was introduced. According
to this rationalization, the SN2¢-type attack of trimethylsiloxyfuran
from the back side of the plane of C N is initiated. Based
on these results, this hypothesis would explain the course of
the main isomer synthesis. The mechanism indicates that the
pivaloyl group in the aldimines 3 plays a significant role in
controlling the diastereoselective addition of trimethylsiloxyfuran
to N-galactosylaldimines 3.
a After purification by chromatography. b Diastereomeric ratio determined
from the crude product by HPLC. c Reference 8c.
The ratio of the obtained diastereomers 5 was determined
by HPLC from the crude mixture of the reaction. It should be
noted that because of the anomeric carbon and one stereogenic
centre created at the a-position of the 2(5H)-furanone, the eight
diastereomers were bSS, bRS, aSS, aRS, bSR, bRR, aSR and
aRR. The determination of the diasteriomeric ratios (dr) from
HPLC illustrated that the aldimines derived from arylaldehydes
with electron-withdrawing groups afforded moderate to good
diastereoselectivities. The experimental results showed that only
the corresponding b-anomers were obtained in this reaction. The
mixture 5h was treated with 1 M hydrogen chloride in methanol
at room temperature giving the easily separable carbohydrate
template 6 and the enantiomerically pure (S)-5-((R)-amino(4-
chlorophenyl)methyl)-5H-furan-2-one hydrochloride 7h in quan-
titative yield. The diastereomers 7h could be hydrolyzed by using
saturated NaHCO3 to give the g-butenolide 8h with (-)-optical
1
rotations in 90% yield. The H NMR spectrum of 8h showed
that the two diastereomers of 5h (ratio 93 : 7, Table 2) contain
enantiomers of the g-butenolide 8h (Scheme 2).
In order to determine the absolute configuration of the main iso-
mer of the trimethylsiloxyfuran addition to N-galactosylaldimines
3, a single crystal X-ray diffraction study of 5h was performed.
The molecular structure of 5h is shown in Fig. 1, and the structure
Fig. 2
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C(CH3)3), 2.33 (d, 3JH–H = 11.4 Hz, 1H, NH), 3.63 (t, 3JH–H = 6.0 Hz,
1H, CH), 3.88 (dd, 3JH–H = 11.4 Hz, 3JH–H = 6.0 Hz, 2H, 2CH), 4.00
(dd, 3JH–H = 10.2 Hz, 3JH–H = 7.2 Hz, 1H, CH), 4.51 (s, 1H, CH),
Conclusion
In conclusion, we have developed a new efficient synthetic
protocol for preparation of chiral g-butenolide derivatives in high
yields and high enantiostereoselectivity, utilizing ZnCl2·Et2O as
the promoter and O-pivaloylated D-galactosylamine 1 as chiral
auxiliary via vinylogous Mannich reactions. The O-pivaloylated
galactosylamine 1 is an effective chiral template in the synthesis
of chiral N-galactosyl a-amino-2(5H)-furanone 5. ZnCl2·Et2O
can form the tetra-coordination intermediate inducing the S
3
4.96–5.07 (m, 3H, 3CH), 5.41 (d, JH–H = 7.2 Hz, 1H, CH), 5.96
3
(d, JH–H = 4.4 Hz, 1H, CH), 7.19–7.31 (m, 6H, Ph); 13C-NMR
(75 MHz, CDCl3): d = 26.07, 26.18, 26.21, 26.26, 37.66, 37.69,
37.77, 38.06, 52.50, 58.60, 66.19, 67.62, 70.17, 70.70, 85.05, 85.59,
121.79, 127.09, 127.67, 127.99, 134.90, 152.13, 171.45, 175.89,
176.11, 176.50, 176.80; ESI-MS: 710.8 ([M + Na]+); HRMS calcd
for C37H53NO11: 710.3511 [M + Na]+. found: 710.3514.
configuration at the Ca centre by attack at the Si-side of the C
N
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
plane of the imine carbon atom. (S)-5-((R)-amino(phenyl)methyl)-
5H-furan-2-one 8 can be detached easily from the carbohydrate
template, which can be recycled.
amino(2-methylph◦enyl)methyl)-5H-furan-2-one
(5b). White
solid; Mp 71–72 C; [a]2D5 = -48.4◦ (c = 0.5, CH2Cl2); H-NMR
(400 MHz, CDCl3): d = 1.02 (s, 9H, C(CH3)3), 1.07 (s, 9H,
1
C(CH3)3), 1.09 (s, 9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.19 (d,
Experimental
3
3JH,H = 10.9 Hz, 1H, NH), 2.30 (s, 3H, CH3), 3.60 (t, JH,H
=
=
3
6.6 Hz, 1H, CH), 3.82–3.92 (m, 2H, 2CH), 3.97 (dd, JH,H
General remarks
10.9 Hz, 3JH,H = 6.6 Hz, 1H, CH), 4.84 (s, 1H, CH), 4.97–4.99 (m,
3
All reactions were carried out under an inert atmosphere and in
heat-dried glassware. Anhydrous Et2O was obtained by distillation
from sodium. Flash column chromatography was performed on
silica gel (particle size 10–40 mm, Ocean Chemical Factory of
2H, 2CH), 5.02 (s, 1H, CH), 5.27 (s, 1H, CH), 6.03 (d, JH,H
=
5.2 Hz, 1H, CH), 7.13–7.15 (m, 3H, Ph), 7.30–7.31 (m, 2H, Ph,
CH); 13C-NMR (75 MHz, CDCl3): d = 18.47, 26.07, 26.12, 26.16,
26.21, 37.64, 37.70, 37.78, 38.06, 53.43, 60.21, 66.03, 67.71, 70.13,
70.60, 84.04, 85.32, 121.99, 125.31, 126.22, 127.13, 130.04, 132.89,
135.49, 151.91, 171.34, 175.84, 176.09, 176.40, 176.80; ESI-MS:
724.9 ([M + Na]+); HRMS calcd for C38H55NO11: 724.3667 [M +
Na]+. found: 724.3674.
Qingdao, China). H and 13C NMR spectra were recorded on
1
Brucker-400 (400 MHz for 1H, 75 MHz for 13C). Chemical shifts
were reported in ppm downfield from internal Si(CH3)4. The
crystal structure was determined on a Bruker SMART 1000
CCD diffractometer. Mass spectra were recorded on a LCQ
advantage spectrometer with ESI resource. HR-MS were recorded
on APEXII and ZAB-HS spectrometers. Melting points were
determined on a T-4 melting point apparatus (uncorrected). Op-
tical rotations were recorded on a Perkin Elemer 241 Polarimeter.
HPLC analyses were recorded on a C18 column.
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(o-chlorophenyl)methyl)-5H-furan-2-one (5c). White solid;
◦
Mp 87–89 C; [a]D25 = -22.5◦ (c = 0.5, CH2Cl2); 1H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 18H, 2C(CH3)3), 1.10 (s, 9H,
C(CH3)3), 1.21(s, 9H, C(CH3)3), 2.57 (dd, 3JH–H = 11.1 Hz, 3JH–H
=
3
4.8 Hz, 1H, NH), 3.75 (t, JH–H = 6.8 Hz, 1H, CH), 3.90 (dd,
General procedure for the preparation of O-pivaloyiated N-
Galactosylimines 3 of Aromatic Aldhydes. To a solution of
2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosylamine 1 (0.515 g,
1 mmol) and aldehyde 2 (1.3 mmol) in 2-propanol (2.5 ml), 2–
3 drops of acetic acid were added and the mixture was stirred at
room temperature for about 0.5 h. The appearance of a precipitate
from the solution indicated the formation of 3, after the precipitate
was filtered off, then washed with ice cold 2-propanol and dried in
vacuum, N-galactosylaldimines 3 was isolated as a colorless solid.
3JH–H = 11.1 Hz, 3JH–H = 7.0 Hz, 1H, CH), 3.96–4.02 (m, 2H, 2CH),
3
5.00–5.07 (m, 3H, 3CH), 5.31 (s, 2H, 2CH), 5.88 (dd, JH–H
=
3
5.6 Hz, JH–H = 1.4 Hz, 1H, CH), 7.13–7.19 (m, 2H, Ph), 7.25
3
(d, JH–H = 5.6 Hz, 1H, CH), 7.32–7.37 (m, 2H, Ph); 13C-NMR
(75 MHz, CDCl3): d = 26.07, 26.16, 26.20, 26.25, 37.66, 37.71,
37.78, 38.07, 54.76, 60.34, 66.06, 67.45, 70.11, 70.76, 84.12, 86.72,
121.83, 125.98, 128.33, 128.50, 128.53, 132.18, 132.88, 151.55,
171.34, 175.89, 176.12, 176.54, 176.84; ESI-MS: 744.9 ([M + Na]+);
HRMS calcd for C37H52ClNO11: 744.3121 [M + Na]+. found:
744.3126.
General procedure for the synthesis of b-N-glycosidic linkages
c-butenolide derivatives 5. A solution of N-galactosylaldimines
3 (0.3 mmol) in Et2O (2 ml) was cooled to -78 ◦C, and trimethyl-
siloxy furan (0.094 g, 0.6 mmol) and ZnCl2·OEt2 (0.45 mL,
0.45 mmol) were added. The mixture was stirred for corresponding
time at -78 ◦C. The mixture was hydrolyzed with saturated
aqueous NH4Cl (5 ml). The aqueous phase was extracted with
Et2O (3 ¥ 10 ml), and the organic layers were dried with anhydrous
MgSO4, filtered, and concentrated in vacuo to yield the crude
products 5, which were purified by flash column chromatography
on silica gel [petroleum ether/ethyl acetate, 5 : 1(v/v)] to provide
pure products 5.
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(o-bromophenyl)methyl)-5H-furan-2-one (5d). White solid;
◦
Mp 64–66 C; [a]D25 = -22.6◦ (c = 0.5, CH2Cl2); 1H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 18H, 2C(CH3)3), 1.10 (s, 9H,
C(CH3)3), 1.22 (s, 9H, C(CH3)3), 2.53 (dd, 3JH–H = 4.0 Hz, 3JH–H
=
=
3.3 Hz, 1H, NH), 3.74 (t, 3JH–H = 6.9 Hz, 1H, CH), 3.91 (dd, 3JH–H
3
3
10.8 Hz, JH–H = 7.6 Hz, 2H, 2CH), 4.01 (dd, JH–H = 10.8 Hz,
3JH–H = 6.9 Hz, 1H, CH), 4.99–5.04 (m, 3H, 3CH), 5.27–5.31 (m,
2H, 2CH), 5.89 (dd, 3JH–H = 5.7 Hz, 3JH–H = 1.5 Hz, 1H, CH), 7.08
(t, 3JH–H = 7.7 Hz, 1H, Ph), 7.16–7.25 (m, 1H, Ph), 7.33 (d, 3JH–H
7.7 Hz, 1H, Ph), 7.36 (d, 3JH–H = 5.7 Hz, 1H, CH), 7.45 (d, 3JH–H
=
=
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosyl)-
am◦ino(phenylmethyl)-5H-furan-2-one (5a). White solid; Mp 64–
68 C; [a]2D5 = -2.6◦ (c = 0.5, CH2Cl2);1H-NMR (400 MHz, CDCl3):
d = 1.02 (s, 9H, C(CH3)3), 1.09 (s, 18H, 2C(CH3)3), 1.21 (s, 9H,
7.7 Hz, 1H, Ph); 13C-NMR (75 MHz, CDCl3): d = 26.10, 26.19,
26.22, 26.26, 37.68, 37.73, 37.79, 38.08, 57.30, 60.22, 66.00, 67.49,
70.09, 70.74, 84.06, 86.59, 121.88, 122.89, 126.58, 128.68, 128.73,
131.91, 134.36, 151.42, 171.33, 175.90, 176.16, 176.55, 176.88;
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ESI-MS: 788.9 ([M + Na]+); HRMS calcd for C37H52BrNO11:
788.2616 [M + Na]+. found: 788.2614.
C(CH3)3), 1.10 (s, 9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.39 (dd,
3JH,H = 11.8 Hz, 3JH,H = 2.9 Hz, 1H, NH), 3.65 (t, 3JH,H = 6.8 Hz, 1H,
3
3
CH), 3.86–3.90 (m, 2H, 2CH), 4.00 (dd, JH,H = 11.8 Hz, JH,H
=
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
6.8 Hz, 1H, CH), 4.46 (t, 3JH,H = 2.9 Hz, 1H, CH), 4.98–5.05 (m,
2H, 2CH), 5.12 (t, 3JH,H = 1.7 Hz, 1H, CH), 5.29 (d, 3JH,H = 1.7 Hz,
1H, CH), 5.96 (dd, 3JH,H = 5.7 Hz, 3JH,H = 1.7 Hz, 1H, CH), 7.13
(d, 3JH,H = 8.3 Hz, 2H, Ph), 7.23–7.26 (m, 3H, Ph, CH); 13C-NMR
(75 MHz, CDCl3): d = 26.07, 26.08, 26.17, 26.20, 37.66, 37.70,
37.77, 38.06, 58.11, 60.43, 66.10, 67.51, 70.06, 70.76, 84.65, 85.61,
122.06, 127.83, 128.46, 133.28, 133.47, 151.71, 171.15, 175.85,
176.07, 176.52, 176.78; ESI-MS: 744.9 ([M + Na]+); HRMS calcd
for C37H52ClNO11: 744.3121 [M + Na]+. found: 744.3121.
amino(m-chlorophenyl)methyl)-5H-furan-2-one
(5e). White
◦
solid; Mp 83–85 C; [a]2D5 = -37.5◦ (c = 0.5, CH2Cl2); H-NMR
1
(400 MHz, CDCl3): d = 1.03 (s, 1H, C(CH3)3), 1.10 (s, 18H,
3
2C(CH3)3), 1.21 (s, 1H, C(CH3)3), 2.36 (d, JH–H = 10.7 Hz, 1H,
NH), 3.66 (t, 3JH–H = 7.0 Hz, 1H, CH), 3.89 (dd, 3JH–H = 10.7 Hz,
3
3
3JH–H = 6.7 Hz, 2H, 2CH), 3.99 (dd, JH–H = 11.3 Hz, JH–H
=
7.0 Hz, 1H, CH), 4.47 (s, 1H, CH), 4.98–5.05 (m, 2H, 2CH), 5.11
3
3
(t, JH–H = 1.7 Hz, 1H, CH), 5.29 (s, 1H, CH), 5.99 (dd, JH–H
=
3
3
5.6 Hz, JH–H = 1.7 Hz, 1H, CH), 7.09 (d, JH–H = 5.9 Hz, 1H,
Ph), 7.19–7.24 (m, 3H, Ph), 7.27 (d, JH–H = 5.6 Hz, 1H, CH);
3
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
13C-NMR (75 MHz, CDCl3): d = 26.07, 26.15, 26.21, 26.30, 37.67,
37.70, 37.79, 38.07, 58.02, 60.45, 66.09, 67.44, 70.06, 70.81, 84.57,
85.45, 122.11, 125.34, 127.00, 128.97, 133.70, 137.22, 151.56,
171.08, 175.88, 176.11, 176.54, 176.82; ESI-MS: 722.9 ([M + H]+);
HRMS calcd for C37H52ClNO11: 744.3121 [M + Na]+. found:
744.3125.
amino(4-methoxyphenyl)methyl)-5H-furan-2-one
(5i). White
◦
solid; Mp 80–82 C; [a]2D5 = -20.2◦ (c = 0.5, CH2Cl2); H-NMR
1
(400 MHz, CDCl3): d = 1.02 (s, 9H, C(CH3)3), 1.10 (s, 18H,
3
2C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.26 (d, JH,H = 1.4 Hz, 1H,
NH), 3.61 (t, 3JH,H = 6.7 Hz, 1H, CH), 3.74 (s, 3H, CH3), 3.87–3.91
3
3
(m, 2H, 2CH), 3.99 (dd, JH,H = 11.1 Hz, JH,H = 6.7 Hz, 1H,
CH), 4.48 (s, 1H, CH), 4.95–5.03 (m, 2H, 2CH), 5.08 (s, 1H,
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(m-fluorophenyl)methyl)-5H-furan-2-one (5f). White solid;
3
3
CH), 5.27 (d, JH,H = 1.7 Hz, 1H, CH), 5.96 (dd, JH,H = 5.8 Hz,
3
◦
3JH,H = 1.7 Hz, 1H, CH), 6.80 (d, JH,H = 6.4 Hz, 2H, Ph), 7.11
Mp 79–81 C; [a]D25 = -31.5◦ (c = 0.5, CH2Cl2); 1H-NMR
3
3
(d, JH,H = 6.4 Hz, 2H, Ph), 7.26 (d, JH,H = 5.8 Hz, 1H, CH);
13C-NMR (75 MHz, CDCl3): d = 26.08, 26.16, 26.20, 26.27,
37.66, 37.69, 37.77, 38.06, 54.26, 57.83, 60.47, 66.17, 67.56, 70.14,
70.68, 85.15, 85.32, 113.06, 121.80, 126.42, 128.26, 152.11, 158.62,
171.46, 175.90, 176.12, 176.46, 176.81; ESI-MS: 740.9 ([M +
Na]+); HRMS calcd for C38H55NO12: 740.3617 [M + Na]+. found:
740.3623.
(400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.09 (s, 18H,
2C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.35 (s, 1H, NH), 3.64 (t, 3JH–H
=
3
3
6.7 Hz, 1H, CH), 3.89 (dd, JH–H = 11.4 Hz, JH–H = 6.6 Hz, 2H,
3
3
2CH), 3.99 (dd, JH–H = 11.4 Hz, JH–H = 6.7 Hz, 1H, CH), 4.49
3
(d, JH–H = 3.2 Hz, 1H, CH), 4.98–5.05 (m, 2H, 2CH), 5.12 (d,
3JH–H = 2.1 Hz, 1H, CH), 5.29 (s, 1H, CH), 5.99 (dd, JH–H
=
3
3
5.7 Hz, JH–H = 2.1 Hz, 1H, CH), 6.92–6.99 (m, 3H, Ph), 7.21–
7.29 (m, 2H, Ph, CH); 13C-NMR (75 MHz, CDCl3): d = 26.07,
26.11, 26.17, 26.21, 37.68, 37.72, 37.79, 38.08, 58.12, 60.45, 66.11,
67.49, 70.08, 70.83, 84.60, 85.55, 113.86, 114.09, 114.43, 114.64,
122.08, 122.79, 129.23, 129.32, 137.71, 137.77, 151.60, 160.65,
163.11, 171.11, 175.89, 176.13, 176.57, 176.83; ESI-MS: 728.9
([M + Na]+); HRMS calcd for C37H52FNO11: 728.3417 [M + Na]+.
found: 728.3418.
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(4-fluoro◦phenyl)methyl)-5H-furan-2-one (5j). White solid;
Mp 133–135 C; [a]D25 = -40.0◦ (c = 0.5, CH2Cl2); 1H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.08 (s, 9H,
C(CH3)3), 1.10 (s, 9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.36 (d,
3JH,H = 11.7 Hz, 3JH,H = 2.5 Hz, 1H, NH), 3.64 (t, 3JH,H = 6.6 Hz, 1H,
CH), 3.88 (dd, 3JH,H = 11.7 Hz, 3JH,H = 7.2 Hz, 2H, 2CH), 4.00 (dd,
3JH,H = 11.1 Hz, 3JH,H = 6.6 Hz, 1H, CH), 4.47 (t, 3JH,H = 2.5 Hz, 1H,
CH), 4.97–5.05 (m, 2H, 2CH), 5.12 (s, 1H, CH), 5.29 (s, 1H, CH),
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(m-methylphenyl)methyl)-5H-furan-2-one
(5g). White
5.96 (dd, 3JH,H = 5.8 Hz, 3JH,H = 1.3 Hz, 1H, CH), 6.96 (t, 3JH,H
=
◦
solid; Mp 69–72 C; [a]2D5 = -37.4◦ (c = 0.5, CH2Cl2); H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.10 (s, 18H,
2C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.23 (br, 1H, NH), 2.27 (s, 1H,
CH3), 3.62 (t, 3JH,H = 6.6 Hz, 1H, CH), 3.87–3.93 (m, 2H, 2CH),
1
3
8.4 Hz, 2H, Ph), 7.16–7.19 (m, 2H, Ph), 7.26 (d, JH,H = 5.8 Hz,
1H, CH); 13C-NMR (75 MHz, CDCl3): d = 26.07, 26.16, 26.20,
26.32, 37.66, 37.70, 37.76, 38.06, 58.01, 60.41, 66.08, 67.49, 70.04,
70.73, 84.81, 85.59, 114.51, 114.73, 122.01, 128.69, 128.77, 130.61,
151.77, 160.33, 162.79, 171.21, 175.86, 176.10, 176.51, 176.80. ESI-
MS: 728.9 ([M + Na]+); HRMS calcd for C37H52FNO11: 728.3417
[M + Na]+. found: 728.3411.
4.00 (dd, 3JH,H = 11.1 Hz, 3JH,H = 6.6 Hz, 1H, CH), 4.49 (t, 3JH,H
=
3.4 Hz, 1H, CH), 4.92–5.03 (m, 2H, 2CH), 5.08 (d, 3JH,H = 1.3 Hz,
1H, CH), 5.27 (d, 3JH,H = 2.3 Hz, 1H, CH), 5.97 (d, 3JH,H = 5.8 Hz,
3
1H, CH), 7.00 (d, JH,H = 7.5 Hz, 1H, Ph), 7.03 (s, 1H, Ph), 7.05
(d, 3JH,H = 6.9 Hz, 1H, Ph), 7.16 (t, 3JH,H = 7.5 Hz, 1H, Ph), 7.26
(d, 5.8 Hz, 1H, CH); 13C-NMR (75 MHz, CDCl3): d = 20.41,
26.07, 26.16, 26.21, 26.28, 37.67, 37.70, 37.78, 38.07, 58.27, 60.50,
66.18, 67.59, 70.14, 70.70, 85.09, 85.34, 121.76, 124.17, 127.58,
127.63, 128.31, 134.75, 137.43, 152.05, 171.43, 175.94, 176.16,
176.41, 176.84; ESI-MS: 724.9 ([M + Na]+).]+); HRMS calcd for
C38H55NO11: 724.3667 [M + Na]+, found: 724.3669.
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(4-nitrop◦henyl)methyl)-5H-furan-2-one (5k). White solid;
Mp 177–179 C; [a]D25 = -49.1◦ (c = 0.5, CH2Cl2); 1H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.08 (s, 9H,
C(CH3)3), 1.10 (s, 9H, C(CH3)3), 1.22 (s, 9H, C(CH3)3), 2.61 (dd,
3JH,H = 11.5 Hz, 3JH,H = 3.7 Hz, 1H, NH), 3.68 (t, 3JH,H = 6.6 Hz, 1H,
3
3
CH), 3.84–3.95 (m, 2H, 2CH), 4.00 (dd, JH,H = 11.5 Hz, JH,H
=
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(4-chlorophenyl)methyl)-5H-furan-2-one (5h). White solid;
6.6 Hz, 1H, CH), 4.53 (t, 3JH,H = 3.7 Hz, 1H, CH), 5.00–5.08 (m,
2H, 2CH), 5.31 (s, 1H, CH), 5.96 (d, 3JH,H = 5.4 Hz, 1H, CH), 7.28
(d, 3JH,H = 5.4 Hz, 1H, CH), 7.37 (d, 3JH,H = 8.3 Hz, 2H, Ph), 8.12
(d, 3JH,H = 8.3 Hz, 2H, Ph); 13C-NMR (75 MHz, CDCl3): d = 26.06,
◦
Mp 96–98 C; [a]D25 = -37.9◦ (c = 0.5, CH2Cl2); 1H-NMR
(400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.08 (s, 9H,
1760 | Org. Biomol. Chem., 2011, 9, 1756–1762
This journal is
The Royal Society of Chemistry 2011
©

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26.15, 26.20, 26.25, 37.68, 37.72, 37.80, 38.07, 58.58, 60.30, 65.94,
67.35, 69.90, 70.86, 84.20, 86.08, 122.41, 122.66, 128.03, 142.67,
146.87, 151.22, 170.72, 175.79, 176.08, 176.66, 176.79; ESI-MS:
755.9 ([M + Na]+); HRMS calcd for C37H52N2O13: 755.3362 [M +
Na]+. found: 755.3358.
176.09, 176.59, 176.81; ESI-MS: 778.9 ([M + Na]+); HRMS calcd
for C38H52F3NO11: 778.3385 [M + Na]+. found: 778.3381.
(S)-5-((R,E)-(2,3,4,6-tetra-O-pivaloyl-b-D-galactopyranosyl)-
1-amin◦o-3-phenylallyl)-5H-furan-2-one (5o). White solid; Mp
◦
1
54–57 C; [a]2D5 = -29.9 (c = 0.5, CH2Cl2); H-NMR (400 MHz,
CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.09 (s, 9H, C(CH3)3), 1.11 (s,
9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.13 (s, br, 1H, NH), 3.79
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D -galactopyranosyl)-
amino(4-bromophenyl)methyl)-5H-furan-2-one (5l). White solid;
3
3
3
(dd, JH–H = 13.0 Hz, JH–H = 6.3 Hz, 1H, CH), 3.91 (dd, JH–H
=
◦
Mp 171–173 C; [a]D25 = -60.8◦ (c = 0.5, CH2Cl2); 1H-NMR
11.1 Hz, 3JH–H = 7.1 Hz, 1H, CH), 4.01–4.08 (m, 2H, 2CH), 4.12
(400 MHz, CDCl3): d = 1.10 (s, 9H, C(CH3)3), 1.16 (s, 9H,
C(CH3)3), 1.17 (s, 9H, C(CH3)3), 1.28 (s, 9H, C(CH3)3), 2.42
3
3
(d, JH–H = 8.4 Hz, 1H, CH), 5.01 (q, JH–H = 8.4 Hz, 1H, CH),
5.06 (dd, 3JH–H = 10.4 Hz, 3JH–H = 3.3 Hz, 1H, CH), 5.11 (t, 3JH–H
=
3
3
3
(dd, JH,H = 12.3 Hz, JH,H = 3.5 Hz, 1H, NH), 3.70 (t, JH,H
=
3
1.5 Hz, 1H, CH), 5.33 (d, JH–H = 3.3 Hz, 1H, CH), 5.78 (dd,
3
3
6.8 Hz, 1H, CH), 3.94 (dd, JH,H = 11.1 Hz, JH,H = 6.9 Hz, 2H,
2CH), 4.07 (dd, JH,H = 11.1 Hz, JH,H = 6.8 Hz, 1H, CH), 4.51
3JH–H = 15.9 Hz, 3JH–H = 8.4 Hz, 1H, CH), 6.08 (dd, 3JH–H = 5.8 Hz,
3
3
3JH–H = 1.8 Hz, 1H, CH), 6.55 (d, JH–H = 15.9 Hz, 1H, CH),
3
3
(t, JH,H = 3.5 Hz, 1H, CH), 5.03–5.09 (m, 2H, 2CH), 5.16–5.19
3
3
7.22–7.29 (m, 5H, Ph), 7.36 (dd, JH–H = 5.8 Hz, JH–H = 1.4 Hz,
1H, CH); 13C-NMR (75 MHz, CDCl3): d = 26.06, 26.09, 26.11,
26.19, 37.69, 37.73, 37.87, 38.05, 57.37, 60.42, 66.08, 67.49, 70.13,
70.69, 84.77, 86.28, 122.02, 122.98, 125.48, 127.35, 127.73, 134.06,
134.68, 152.17, 171.48, 175.90, 176.10, 176.41, 176.81; ESI-MS:
736.9 ([M + Na]+); HRMS calcd for C39H55NO11: 736.3667 [M +
Na]+. found: 736.3659.
(m, 1H, CH), 5.36 (3JH,H = 2.4 Hz, 1H, CH), 6.04 (dd, JH,H
=
3
3
3
5.8 Hz, JH,H = 1.0 Hz, 1H, CH), 7.14 (d, JH,H = 8.4 Hz, 2H,
3
3
Ph), 7.30 (dd, JH,H = 5.8 Hz, JH,H = 1.5 Hz, 1H, CH), 7.48 (d,
3JH,H = 8.4 Hz, 2H, Ph); 13C-NMR (75 MHz, CDCl3): d = 26.07,
26.18, 26.20, 26.33, 37.66, 37.69, 37.77, 38.06, 58.12, 60.40, 66.06,
67.48, 70.01, 70.77, 84.54, 85.55, 121.47, 122.12, 128.75, 130.82,
133.90, 151.56, 171.11, 175.85, 176.08, 176.52, 176.79; ESI-MS:
788.9 ([M + Na]+); HRMS calcd for C38H55NO11: 788.2616 [M +
Na]+. found: 788.2612.
(S)-5-((S)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
ami◦no(2-furyl)methyl)-5H-furan-2-one (5p). White solid; Mp 39–
42 C; [a]2D5 = -11.9◦ (c = 0.5, CH2Cl2); H-NMR (400 MHz,
1
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.06 (s, 9H, C(CH3)3), 1.11 (s,
3
amino(p-methylph◦enyl)methyl)-5H-furan-2-one
(5m). White
9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.23 (dd, JH,H = 12.7 Hz,
solid; Mp 75–77 C; [a]2D5 = -36.6◦ (c = 0.5, CH2Cl2); H-NMR
(400 MHz, CDCl3): d = 1.02 (s, 9H, C(CH3)3), 1.10 (s, 18H,
2C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.24 (s, br, 1H, NH), 3.28 (s,
3JH,H = 4.7 Hz, 1H, NH), 3.71 (t, JH,H = 7.1 Hz, 1H, CH), 3.90
1
3
3
3
3
(dd, JH,H = 12.7 Hz, JH,H = 11.9 Hz, 2H, 2CH), 4.24 (t, JH,H
=
6.3 Hz, 1H, CH), 4.55 (t, 3JH,H = 4.5 Hz, 1H, CH), 4.93–5.04 (m,
2H, 2CH), 5.19 (s, 1H, CH), 5.30 (s, 1H, CH), 6.03 (d, JH,H
3
3
3
3H, CH3), 3.60 (t, JH–H = 6.8 Hz, 1H, CH), 3.88 (dd, JH–H
=
=
3
3
11.1 Hz, JH–H = 6.8 Hz, 2H, 2CH), 3.99 (dd, JH–H = 11.0 Hz,
5.4 Hz, 1H, CH), 6.21–6.32 (m, 2H, 2CH), 7.21 (s, 1H, CH), 7.41–
7.48 (m, 1H, 1CH); 13C-NMR (75 MHz, CDCl3): d = 26.04, 26.06,
26.17, 26.19, 37.67, 37.69, 37.83, 38.04, 53.26, 60.31, 66.05, 67.32,
70.14, 70.66, 83.55, 86.10, 108.34, 109.47, 121.67, 141.57, 148.92,
152.60, 171.37, 175.85, 176.07, 176.44, 176.76; ESI-MS: 700.33
([M + Na]+); HRMS calcd for C35H51NO12: 700.3298 [M + Na]+.
found: 700.3303.
3
3JH–H = 6.8 Hz, 1H, CH), 4.49 (d, JH–H = 3.7 Hz, 1H, CH),
3
4.94–5.00 (m, 2H, 2CH), 5.08 (t, JH–H = 7.0 Hz, 1H, CH), 5.27
3
3
3
(d, JH–H = 2.2 Hz, 1H, CH), 5.97 (dd, JH–H = 5.7 Hz, JH–H
=
1.7 Hz, 1H, CH), 7.07–7.11 (m, 4H, Ph), 7.25 (d, 3JH–H = 5.7 Hz,
1H, CH); 13C-NMR (75 MHz, CDCl3): d = 20.10, 26.08, 26.14,
26.17, 26.22, 37.67, 37.71, 37.78, 38.07, 58.15, 60.51, 66.21, 67.61,
70.18, 70.72, 85.12, 85.35, 121.81, 127.03, 128.40, 131.63, 137.33,
152.04, 171.42, 175.92, 176.13, 176.45, 176.83; ESI-MS: 724.9
([M + Na]+); HRMS calcd for C38H55NO11: 724.3667 [M + Na]+.
found: 724.3667.
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
amino(◦3-pyridyl)methyl)-5H-furan-2-one (5q). White solid; Mp
◦
1
67–69 C; [a]2D5 = -11.4 (c = 0.5, CH2Cl2); H-NMR (400 MHz,
CDCl3): d = 1.10 (s, 9H, C(CH3)3), 1.12 (s, 9H, C(CH3)3), 1.18
(s, 9H, C(CH3)3), 1.29 (s, 9H, C(CH3)3), 2.12 (d, 3JH,H = 10.1 Hz,
(S)-5-((R)-(2,3,4,6-tetra-O-pivaloyl-b -D-galactopyranosyl)-
3
1H, NH), 3.77 (t, JH,H = 6.6 Hz, 1H, CH), 3.98–4.06 (m, 2H,
amino(p-trifluoromethylphenyl)methyl)-5H-furan-2-one
(5n).
3
3
2CH), 4.32 (d, JH,H = 5.2 Hz, 1H, CH), 4.53 (d, JH,H = 3.3 Hz,
1H, CH), 5.08–5.12 (m, 2H, 2CH), 5.30 (s, 1H, CH), 5.35 (d,
3JH,H = 3.0 Hz, 1H, CH), 6.02 (d, 3JH,H = 5.8 Hz, 1H, CH), 7.39 (t,
◦
White solid; Mp 160–161 C; [a]2D5 = -41.2◦ (c = 0.5, CH2Cl2);
1H-NMR (400 MHz, CDCl3): d = 1.03 (s, 9H, C(CH3)3), 1.08 (s,
9H, C(CH3)3), 1.10 (s, 9H, C(CH3)3), 1.21 (s, 9H, C(CH3)3), 2.46
(d, 3JH–H = 8.8 Hz, 1H, NH), 3.65 (t, 3JH–H = 6.8 Hz, 1H, CH), 3.88
3JH,H = 5.8 Hz, 2H, Ph), 7.71 (d, JH,H = 6.5 Hz, 1H, CH), 8.47–
3
8.68 (m, 2H, Ph); 13C-NMR (75 MHz, CDCl3): d = 26.07, 26.09,
26.13, 26.23, 37.69, 37.72, 37.78, 38.08, 56.96, 60.31, 65.99, 67.35,
69.93, 70.88, 84.49, 86.32, 122.49, 122.72, 127.83, 129.89, 131.31,
135.66, 151.47, 170.77, 175.80, 176.08, 176.71, 176.81; ESI-MS:
689.3 ([M + H]+); HRMS calcd for C36H52N2O11: 711.3460 [M +
Na]+. found: 711.3463.
(dd, 3JH–H = 11.1 Hz, 3JH–H = 6.8 Hz, 2H, 2CH), 4.00 (dd, 3JH–H
=
3
3
11.1 Hz, JH–H = 6.7 Hz, 1H, CH), 4.52 (d, JH–H = 3.8 Hz, 1H,
3
3
CH), 4.99–5.06 (m, 2H, 2CH), 5.16 (dd, JH–H = 3.8 Hz, JH–H
=
3
1.3 Hz, 1H, CH), 5.29 (d, JH–H = 2.1 Hz, 1H, CH), 5.97 (dd,
3JH–H = 5.8 Hz, 3JH–H = 2.0 Hz, 1H, CH), 7.26 (dd, 3JH–H = 5.8 Hz,
3JH–H = 1.3 Hz, 1H, CH), 7.33 (d, 3JH–H = 8.1 Hz, 2H, Ph), 7.53 (d,
3JH–H = 8.1 Hz, 2H, Ph); 13C-NMR (75 MHz, CDCl3): d = 26.06,
26.14, 26.20, 26.24, 37.67, 37.71, 37.78, 38.07, 58.47, 60.37, 66.03,
67.47, 69.99, 70.81, 84.45, 85.76, 121.47, 122.22, 124.17, 124.56,
124.60, 127.49, 129.58, 129.91, 139.26, 151.44, 170.99, 175.85,
General Procedure for the synthesis of (S)-5-((R)-amino(phenyl)-
methyl)-5H-furan-2-one 8.
A
solution of compound 5h
(0.2 mmol) in dry methanol (2 ml) was treated with freshly
prepared (1 M) solution of HCl/MeOH (0.5 ml). The solution
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was stirred for 1.5 d (TLC control). Then methanol was evaporated
in vacuo and the remaining residue dissolved in 0.5 M HCl (5 ml)
and extracted with pentane (3 ¥ 10 ml). The aqueous solution was
neutralized using saturated NaHCO3 aqueous solution until a pH
value of 7 was achieved for the solution. Then, CH2Cl2 (5.0 ml)
was added, the organic layer was separated, and the aqueous layer
was washed with CH2Cl2 (3 ¥ 5 ml). The combined organic layers
were dried over anhydrous MgSO4 and the solvent evaporated,
giving 8h as yellow oil.
Soc., 2006, 128, 6048; (j) Y. Chi and S. H. Gellman, J. Am. Chem. Soc.,
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4 Catalytic asymmetric synthesis of functionalized g-butenolide skeleton:
For a review, see: (a) G. Casiraghi and F. Zanardi, Chem. Rev., 2000, 100,
1929; For selected examples, see: (b) D. A. Evans, M. C. Kozlowski, J. A.
Murry, C. S. Burgey, K. R. Campos, B. T. Connell and R. J. Staples,
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(S)-5-((R)-amino(4-ch◦lorophenyl)methyl)furan-2(5H)-one (8h).
Yellow oil; [a]2D5 = -92.9 (c = 0.5, CH2Cl2); 1H-NMR (400 MHz,
3
CDCl3): d = 1.70 (bs, 2H, NH2), 4.33 (d, JH–H = 4.4 Hz, 1H,
3
3
CH), 5.11 (t, JH–H = 2.1 Hz, 1H, CH), 6.06 (dd, JH–H = 2.4 Hz,
3JH–H = 5.6 Hz, 1H, CH), 4.51 (s, 1H, CH), 7.20–7.23 (m, 3H, Ph,
CH), 7.27–7.29 (d, 3JH–H = 8.4 Hz, 2H, Ph); 13C-NMR (75 MHz,
CDCl3): d = 55.61, 85.61, 122.40, 127.12, 127.97, 132.99, 136.95,
151.93, 171.50; ESI-MS: 206.5 (M+ - NH3); HRMS calcd for
C38H52F3NO11: 224.0473 [M + H]+. found: 224.0476.
Acknowledgements
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We thank the National Natural Science Foundation of China
(21072102), Project 973 of the Ministry of Science and Technology
of China (2007CB914800) and State Key Laboratory of Elemento-
Organic Chemistry in Nankai University for financial support.
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