Concise synthesis of chiral 2(5H)-furanone derivatives possessing 1,2,3-triazole moiety via one-pot approach

Article abstract of DOI:10.1016/j.tet.2012.01.092

Combining three bioactive units, such as 2(5H)-furanone, 1,2,3-triazole, and amino acid together into one potential drug molecule with polyfunctional groups, a series of new chiral 2(5H)-furanone derivatives containing 1,2,3-triazole moiety have been designed and synthesized from (5S)-5-alkoxy-3,4-dibromo-2(5H)-furanones, amino acids, propargyl bromide, and organic azides via the sequential three steps, including asymmetric Michael addition-elimination, substitution, and click reaction. The latter two steps, substitution and click reaction could proceed smoothly in a one-pot process. Furthermore, the target products could be directly synthesized via a four-component one-pot approach.

Full text of DOI:10.1016/j.tet.2012.01.092

Tetrahedron 68 (2012) 2827e2843
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Concise synthesis of chiral 2(5H)-furanone derivatives possessing 1,2,3-triazole
moiety via one-pot approach
,
,
*
Yue-He Tan a, Jian-Xiao Li a b, Fu-Ling Xue a, Ji Qi a, Zhao-Yang Wang a
a School of Chemistry and Environment, South China Normal University, Guangzhou 510006, PR China
b School of Chemistry and Chemical Engineering, South China University of Technology, Guangzhou 510640, PR China
a r t i c l e i n f o
a b s t r a c t
Article history:
Combining three bioactive units, such as 2(5H)-furanone, 1,2,3-triazole, and amino acid together into one
potential drug molecule with polyfunctional groups, a series of new chiral 2(5H)-furanone derivatives
containing 1,2,3-triazole moiety have been designed and synthesized from (5S)-5-alkoxy-3,4-dibromo-
2(5H)-furanones, amino acids, propargyl bromide, and organic azides via the sequential three steps,
including asymmetric Michael additioneelimination, substitution, and click reaction. The latter two
steps, substitution and click reaction could proceed smoothly in a one-pot process. Furthermore, the
target products could be directly synthesized via a four-component one-pot approach.
Ó 2012 Elsevier Ltd. All rights reserved.
Received 11 December 2011
Received in revised form 18 January 2012
Accepted 31 January 2012
Available online 6 February 2012
Keywords:
2(5H)-Furanone
1,2,3-Triazole
Polyfunctional groups
One-pot synthesis
Asymmetric synthesis
1. Introduction
Though more and more methods for 2(5H)-furanones with
polyfunctional groups have been reported in the researches on
Molecules possessing 2(5H)-furanone moiety, a kind of
a
,
b
-
2(5H)-furanone, these synthetic methods can be divided into two
categories according to different synthetic strategies. One is that
introducing substituents first and then producing 2(5H)-furanone
ring via cyclization.4e7 The other is that taking simple furanones or
other oxygen-containing five-membered cyclic compounds as
starting materials and then introducing various substituents as
required to synthesize a series of derivatives.8,9 No matter which
approach, the synthesis of 2(5H)-furanones with polyfunctional
groups has been a challenge for a long time due to the instability of
2(5H)-furanone ring under certain conditions and the particularity
of various functional groups.4e9 Besides, the reported methods had
some deficiencies, especially the starting materials were not easily
available,4,6 or the process was lengthy,7 or the catalysts were
precious and not easily obtainable.5,6,9
unsaturated lactone substructure frequently found in natural
products (Fig. 1), have received considerable interest due to their
significant biological activities, such as antifungal, anti-bacterial,
anti-inflammatory, and anti-tumor.1 At the same time, many
2(5H)-furanone compounds are important organic intermediates.2
These made the researches on 2(5H)-furanone chemistry become
very intensive recently.3
As an important pharmacophore, 1,2,3-triazole nitrogen
heterocycle plays an significant role in the anti-bacterial,10 anti-
tumor,11 anti-inflammatory,12 anti-HIV,13 and anti-platelet aggre-
gation.14 This makes many medicinal chemists and biochemists
have increasing emphasis on the synthesis of 1,2,3-triazoles with
polyfunctional groups.15 However, the studies on combination
1,2,3-triazole into 2(5H)-furanone compounds via different bio-
active amino acids as building blocks16 have not been reported
before. Herein, we tried to combine three bioactive units, such as
2(5H)-furanone, 1,2,3-triazole, and amino acid to design and
synthesize potential bioactive chiral compounds 6 containing
Fig. 1. Some biologically active natural products bearing 2(5H)-furanone moiety.
* Corresponding author. Tel.: þ86 20 3931 0258; fax: þ86 20 3931 0187; e-mail
addresses: wangwangzhaoyang@tom.com, wangzy@scnu.edu.cn (Z.-Y. Wang).
0040-4020/$ e see front matter Ó 2012 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tet.2012.01.092

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Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
polyfunctional groups, e.g., butenolide ring, amino, ester, 1,2,3-
triazole, and halogen (Scheme 1). Meanwhile, based on the mild,
simple, economical three-step synthetic method, we further in-
vestigated their efficient syntheses via a multi-component one-pot
approach.
the influences of the kinds and dosage of the catalyst, and solvent
on the yield of 6afa (Table 1).
Firstly, the influences of different catalysts were evaluated
(entries 1e5). Obviously, when Cu(OAc)2$H2O/Cu was used as
a catalytic system, a satisfactory yield was obtained (entry 2).
However, the base PMDETA19 was not conducive to the reaction
here (entry 1). If the catalytic system was replaced by CuBr (or
CuBr/Cu), some by-products could be detected according to the
monitoring by TLC, and the yield dropped (entries 4 and 5).
The solvent also affected the reaction significantly (entries 2 and
6e10). The monitoring by TLC showed that the reaction could be
smoothly carried out in CH3CN, and the reaction time could be
shortened from 10 h to 4 h, even the yield was higher (entries 2
and 6). However, in DMF, if the reaction time was reduced to 4 h, the
yield was significantly reduced (entries 2 and 7). Similarly, changing
other solvents while maintaining the same reaction time (4 h), the
results indicated that CH3CN was the best solvent of all (entry 6).
Especially, though t-BuOH/H2O (1:1)17 or THF/H2O (1:1)20 was
suitable solvent system for other click reactions, here they were not
suitable due to their bad solubility or polarity for the substrates.
Furthermore, the influences of catalyst system on the yield were
investigated (entries 6, 11 and 12). Increasing the ratio of Cu in the
component of catalyst system gave higher yield (entry 11). If
keeping the higher ratio of Cu unchangeable, even the catalyst
dosage was wholly reduced to half, the yield was almost un-
changeable (entry 12). Thus, suitable catalyst system should be
0.05 equiv Cu(OAc)2$H2O and 0.1 equiv Cu.
Scheme 1. Synthetic route of target compounds 6.
2. Results and discussion
2.1. Synthesis of target compounds by fractional-step method
Therefore, when choosing 1 equiv N-[(5S)-5-menthyloxy-2(5H)-
furanonyl] 6-aminohexanoic acid propargyl ester 4af and 1.5 equiv
benzyl azide 5a as the model substrates, the optimized reaction
conditions could be summarized in the following: CH3CN as the
solvent, 0.05 equiv Cu(OAc)2$H2O and 0.1 equiv Cu as the catalytic
Based on the synthesis of the intermediates N-[(5S)-5-alkoxy-
2(5H)-furanonyl] amino acids 31k,3t and N-[(5S)-5-alkoxy-2(5H)-
furanonyl] amino acid propargyl esters 4,3u we investigated the
fractional-step method in preparation the target compounds
starting from propargyl esters 4. According to the most literature on
click chemistry,15,17,18 all reactions in our experiments were carried
out at room temperature. Choosing N-[(5S)-5-menthyl-oxy-2(5H)-
furanonyl] 6-aminohexanoic acid 4af and benzyl azide 5a as the
model substrate, we optimized experimental conditions, including
system, room temperature for
4 h. Under these conditions,
changing substrates, more new chiral 2(5H)-furanone derivatives
containing 1,2,3-triazole moiety have been designed and success-
fully synthesized with satisfactory yields (mostly equal to or over
67%) except for 6bha and 6bhb (Table 2).
Table 1
Condition optimization for click reaction of N-[(5S)-5-menthyloxy-2(5H)-furanonyl] 6-aminohexanoic acid propargyl ester 4af with benzyl azide 5a
Entrya
Catalyst
Solvent
Time (h)
Yieldb (%)
1c
2
3
4
5
6
7
8
9
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/sodium ascorbate
CuBr/Cu
DMF
DMF
DMF
DMF
DMF
CH3CN
DMF
t-BuOH/H2O (1:1)
THF/H2O (1:1)
CH2Cl2
CH3CN
CH3CN
10
10
10
10
10
4
4
4
4
4
11
66
63
58
57
68
21
0
CuBr
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
Cu(OAc)2$H2O/Cu
0
10
11d
11e
31
71
71
4
4
a
Reaction conditions: rt, N-protected amino acid propargyl ester 4af (1 mmol), benzyl azide 5a (1.5 equiv), catalyst (all components 0.1 equiv except for special
explanations).
b
c
Isolated yield.
1,1,4,7,7-Penta-methyldiethylenetriamine (PMDETA) (0.2 equiv) was used as an additive.
Cu(OAc)2$H2O 0.1 equiv, Cu 0.2 equiv.
Cu(OAc)2$H2O 0.05 equiv, Cu 0.1 equiv.
d
e

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2829
Table 2
The yields of target compounds 6 using N-protected amino acid propargyl esters 4 and organic azides 5 as materials
Entry
Propargyl esters 4
Azides 5
Compounds 6 a
Yieldb (%)
1
77
5a
4aa
6aaa
2
3
4
5
6
5a
5a
5a
5a
5a
63
70
75
67
71
4ab
4ac
4ad
4ae
6aba
6aca
6ada
6aea
4af
6afa
7
5a
80
4ag
6aga
(continued on next page)

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Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
Table 2 (continued )
Entry
Propargyl esters 4
Azides 5
Compounds 6 a
Yieldb (%)
8
5a
54
4ah
6aha
9
5a
5a
5a
5a
62
74
61
82
4ba
6baa
10
11
12
4bb
4bc
6bba
6bca
4bd
6bda
13
5a
57
4be
6bea
14
5a
67
4bf
6bfa
15
5a
76
4bg
6bga

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2831
Table 2 (continued )
Entry
Propargyl esters 4
Azides 5
Compounds 6 a
Yieldb (%)
16
5a
32
4bh
6bha
17
18
19
20
21
4aa
4ab
4ac
4ad
4ae
75
5b
6aab
5b
76
71
73
74
6abb
5b
5b
5b
6acb
6adb
6aeb
22
4af
5b
85
6afb
23
4ag
5b
83
6agb
(continued on next page)

2832
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
Table 2 (continued )
Entry
Propargyl esters 4
Azides 5
Compounds 6 a
Yieldb (%)
24
25
4ah
4ba
5b
5b
57
6ahb
76
77
6bab
26
27
4bb
4bc
5b
5b
6bbb
6bcb
67
75
28
4bd
5b
6bdb
29
4be
5b
82
6beb
30
31
4bf
4bg
4bh
5b
5b
5b
77
70
34
6bfb
6bgb
32
6bhb
a
Reaction conditions: N-protected amino acid propargyl esters 4 1 mmol, organic azides 5 1.5 equiv, Cu(OAc)2$H2O 0.05 equiv, Cu 0.1 equiv, solvent CH3CN, rt, 4 h.
Isolated yield.
b

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2833
2.2. Synthesis of target compounds via three-component
one-pot approach
When the amount of Cu(II) and Cu increased to 1.05 equiv and
1.1 equiv of the K2CO3 dosage, respectively, the one-pot reaction
gave the product 6aga with the yield of 14% after 12 h. Encouraged
by this positive result, we continued to study the experiment.
When the reaction time was prolonged to 24 h, and the amount of
Cu(II) and Cu increased to 1.2 equiv and 1.5 equiv of the K2CO3
dosage, respectively, the monitoring by TLC showed the reaction
was completed with a greatly increased yield. And the isolated
yield of 6aga was 57%, which was higher than the corresponding
cumulative yield (54%) by fractional-step method. Thus, we ex-
amined a variety of other substrates in the next experiments
(Table 3).
The results showed that different organic azides 5 could easily
take part in the three-component reaction (Table 3). For the sub-
strates N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acids 3, whether
the main chain of amino acid was long or short, and the side chain
of amino acids was alkyl or aryl, the reaction could proceed
smoothly, and most of the isolated yields of target compounds
reached the middle level (equal to or over 50%). Compared with
their corresponding cumulative yields of fractional-step method,
three-component one-pot method wholly gave a roughly similar
yield. However, the one-pot method didn’t need the separation of
intermediate products, N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino
acid propargyl esters 4, and had greater advantages due to sim-
plifying the experimental procedure.
How to improve synthetic efficiency and reduce labor intensity is
an important goal of synthetic method study. Especially for the
synthesis of chiral compounds, it is of great significance to in-
vestigate the multi-component one-pot synthesis,21 and the one-
pot three-component reaction involving in the studies of azides
has been investigated recently.22 The above optimized conditions
for click reaction showed that CH3CN was the best solvent, which
was the same as the best solvent in the substitution reaction.3t This
made us believe that to synthesize the target compounds via
a three-component one-pot approach using N-[(5S)-5-alkoxy-
2(5H)-furanonyl] amino acids 3, propargyl bromide, and organic
azides 5 as starting materials should be possible.
Choosing
N-[(5S)-5-menthyloxy-2(5H)-furanonyl]-4-amino-
butyric acid 3ag, propargyl bromide, and benzyl azide 5a as the
model substrates for the three-component one-pot reaction
(Scheme 2), once the substitution reaction was completed, the
catalytic amount of Cu(OAc)2$H2O and Cu was added to the ace-
tonitrile system, hoping that Cu(I) generated in situ could catalyze
the subsequent click reaction. However, there was no any target
product obtained in the end. The reason might be that catalytic
amount Cu(OAc)2$H2O was destroyed by the residual K2CO3 via
hydrolysis in the presence of a little water produced in the step of
substitution reaction.
2.3. Synthesis of target compounds via four-component one-
pot approach
In the whole fractional-step method (Scheme 1), N-[(5S)-5-
alkoxy-2(5H)-furanonyl] amino acids 3 were prepared under
alkaline conditions, and a neutralization process was needed after
the Michael additioneelimination reaction. At the same time,
N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters 4
were also prepared under alkaline conditions. Therefore, the
combination of Michael additioneelimination and substitution
Scheme 2. Synthesis of target compound 6aga via three-component one-pot
approach.
Table 3
A yield comparison between three-component one-pot method and fractional-step method both using N-protected amino acids 3 as starting material
Entry
N-Protected amino acids 3
Azides 5
Compounds 6
Yield of one-pota (%)
Yield of
fractional-stepb (%)
1
5a
6aaa
54
44
3aa
2
5a
6aba
61
53
3ab
3
5a
6aca
53
58
3ac
(continued on next page)

2834
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
Table 3 (continued )
Entry
N-Protected amino acids 3
Azides 5
Compounds 6
Yield of one-pota (%)
Yield of
fractional-stepb (%)
4
5
6
7
8
9
5a
6ada
39
59
55
52
54
28
39
3ad
5a
5a
5a
5a
5a
6aea
6afa
6aga
6aha
6baa
50
52
57
32
39
3ae
3af
3ag
3ah
3ba
10
11
5a
5a
6bba
6bca
65
48
55
51
3bb
3bc
12
5a
6bda
62
67
3bd

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2835
Table 3 (continued )
Entry
N-Protected amino acids 3
Azides 5
Compounds 6
Yield of one-pota (%)
Yield of
fractional-stepb (%)
13
5a
6bea
68
46
3be
14
15
16
5a
5a
5a
6bfa
6bga
6bha
58
54
31
54
57
18
3bf
3bg
3bh
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
3aa
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
5b
6aab
6abb
6acb
6adb
6aeb
6afb
6agb
6ahb
6bab
6bbb
6bcb
6bdb
6beb
6bfb
6bgb
6bhb
50
56
43
62
59
50
43
33
56
57
51
56
47
53
51
30
43
64
59
58
61
63
57
30
48
57
56
61
65
52
52
15
3ab
3ac
3ad
3ae
3af
3ag
3ah
3ba
3bb
3bc
3bd
3be
3bf
3bg
3bh
a
Isolated yield under the reaction conditions: N-protected amino acids 3 1 mmol, K2CO3 1.5 equiv, propargyl bromide 2 equiv, CH3CN, 40 ꢀC, 8 h; then, organic azides 5
2 equiv, Cu(OAc)2$H2O 1.8 equiv, Cu 2.2 equiv, rt, 24 h.
b
The cumulative yield is based on the isolated yield of two steps according to Scheme 1 using N-protected amino acids 3 as starting material.
together was also possible. Encouraged by the success of three-
component one-pot approach, we hoped to synthesize the target
compounds 6 in a one-pot three-step process with four compo-
nents. Taking the synthesis of products 6afb from the substrate 1a
as an example, we investigated the reaction conditions (Table 4).
It could be seen that, even the twice catalytic amount of
Cu(OAc)2$H2O and Cu were added to the reaction system, the re-
action couldn’t proceed (entry 1). As mentioned above, may be the
small amount of Cu(OAc)2$H2O was ineffective for its reacting with
K2CO3 in the presence of a little water. When the amount of Cu(II)
was increased to 1.2 equiv of the K2CO3 dosage, the reaction only
gave the desired product with the yield of 10% after 72 h (entry 2).
This may be related to the base KOH, and KOH dosage was related to
the dosage of amino acid. When controlling the feed ratio of amino
acid 2f and (5S)-5-menthoxy-3,4-dibromo-2(5H)-furanone 1a as
1:1, we found that the yield indeed had an increase (entry 3). And
further reducing the dosage of base K2CO3 made the yield increase
to 17% finally (entry 4).
Even so, this result was still very disappointing. Monitored by
TLC, we observed that the reaction proceeded very slowly, espe-
cially in the later two steps it was difficult to react completely.
Compared with the above three-component one-pot reaction, we
thought that in this one-pot four-component process the solvent
EtOH added in the first step of Michael additioneelimination re-
action might seriously affect the consecutive two steps, and the
subsequent results proved this guess.
Firstly, if only EtOH was as the solvent, there was no target
product generated (entry 5). The failure was due to that no click

2836
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
Table 4
Condition optimization for four-component one-pot method
Entrya
1a/2f/K2CO3/Cu(II)/Cu
Solvent (EtOH/CH3CN, volume ratio)
Yieldb (%)
1
2
3
4
5
6
7
8
1.0:1.5:1.0:0.1:0.2
1.0:1.5:1.0:1.2:1.5
1.0:1.0:1.0:1.2:1.5
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1.0:1.0:0.5:0.6:0.75
1:1
1:1
1:1
1:1
1:0
0:1
1:4
1:8
1:10
1:8
1:8
0
10
13
17
0
0
25
40
40
37
44
9
10c
11d
a
Reaction conditions: (5S)-5-menthoxy-3,4-dibromo-2(5H)-furanone 1a 1.0 mmol, KOH 1.3 equiv of 2f, propargyl bromide 1.0 equiv, hexyl azide 5b 1.5 equiv.
Isolated yield.
Molecular sieves (4 Ǻ) were used as an additive.
Tetrabutyl ammonium bromide (TBAB) (0.2 equiv) was used as an additive.
b
c
d
reaction proceeded in the last step according to the monitoring
yield dropped slightly (entry 10). At the same time, in consideration
of involving a variety of substances in the reaction system, espe-
cially some inorganic compounds, which may be disadvantageous
for the final cycloaddition reaction, TBAB as phase-transfer agent
was added, and it played a certain role (entry 11).
In these cases, the appropriate conditions for this four-
component one-pot reaction can be summarized below: (5S)-5-
menthoxy-3,4-dibromo-2(5H)-furanone 1a 1 equiv, amino acid 2f
1 equiv, K2CO3 0.5 equiv, Cu(OAc)2$H2O 0.6 equiv, Cu 0.75 equiv,
additive TBAB 0.2 equiv, and using mixed solvent EtOH/CH2Cl2/
CH3CN (1:2:8, volume ratio).
Under the optimized conditions, the reactions of some repre-
sentative substrates were examined (Table 5). It could be seen that,
most of isolated yields were equal to or over 38%. Compared with
the fractional-step method, some yields of one-pot method were
basically equal to the corresponding cumulative yields. However, it
was obvious that the four-component one-pot method was ad-
vantageous to effectively improve the yields for the cases that
fractional-step method gave the lower cumulative yields.
by TLC. So, it was not appropriate to choose EtOH as solvent for
this one-pot four-component process. However, the test of using
pure CH3CN as solvent also failed (entry 6), because amino acid
2f and KOH added in the first step could not dissolve in this
solvent, and Michael additioneelimination reaction couldn’t take
place.
Therefore, the process of adding CH3CN into the reaction system
after the first step reaction was completed and the selection of the
mixed solvent should be necessary in the one-pot reaction. It could
be seen from the entries 4 and 7e9, the higher the ratio of CH3CN in
mixed solvent (EtOH/CH3CN), the higher the yield of the product.
While the ratio of CH3CN further increased, the yield would not
continue to improve. Thus, we chose the mixed solvent (EtOH/
CH3CN¼1:8) as the best solvent system (entry 8).
Because water was disadvantageous for the substitution,3u but
small amount of water was generated in the first step of the one-
pot reaction, a little 4 Ǻ molecular sieve was added to avoid the
interference of water. However, the effect was not obvious, even the
Table 5
A yield comparison between four-component one-pot method and fractional-step method both using (5S)-5-alkoxy-3,4-dibromo-2(5H)-furanones 1 and amino acids 2 as
starting materials
Entry
1
(5S)-5-Alkoxy-2(5H)-furanones 1
Amino acids 2
Compounds 6
Yield of one-pota (%)
Yield of fractional-stepb (%)
6aab
28
14
2a
1a
2
3
1a
6abb
6acb
44
45
35
42
2b
1a
2c

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2837
Table 5 (continued )
Entry
(5S)-5-Alkoxy-2(5H)-furanones 1
Amino acids 2
Compounds 6
Yield of one-pota (%)
44
Yield of fractional-stepb (%)
4
1a
6afb
41
15
2f
5
6
2a
6bab
6bdb
28
33
1b
1b
36
2d
7
8
1b
1b
6beb
6bfb
42
38
44
39
2e
2f
9
1b
6bgb
41
26
2g
a
Isolated yield under the reaction conditions: 5-alkoxy-3,4-dibromo-2(5H)-furanones 1 1 mmol, amino acids 2 1 equiv, KOH 1.3 equiv, 1 mL, 40 ꢀC, 24 h; then, K2CO3
0.5 equiv, propargyl bromide 1 equiv, TBAB 0.2 equiv, CH3CN 8 mL, 40 ꢀC, 24 h; finally, hexyl azide 5b 1.5 equiv, Cu(OAc)2$H2O 0.6 equiv, Cu 0.75 equiv, rt, 24 h.
b
The cumulative yield is based on the isolated yield of three steps according to Scheme 1 using 5-alkoxy-3,4-dibromo-2(5H)-furanones 1 and amino acids 2 as starting
materials.
3. Conclusion
All reagents and solvents were commercially available and used
as received. The intermediates N-[(5S)-5-alkoxy-2(5H)-furanonyl]
amino acids 3 and N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acid
propargyl esters 4 were prepared according to the literature.1k,3se3u
In summary, a series of novel chiral 2(5H)-furanone derivatives
containing 1,2,3-triazole moiety with potential biological activity
were designed and synthesized from available (5S)-5-alkoxy-3,4-
dibromo-2(5H)-furanones, amino acids, propargyl bromide, and
organic azides through an asymmetric Michael additioneelimina-
tion, substitution, and cycloaddition under mild conditions with
economical catalysts. They also could be generated via a simple and
efficient multi-component one-pot approach. Due to the diversity
of 5-alkoxy-3,4-dihalo-2(5H)-furanones,1k,3s amino acids, and or-
ganic azides, these serial investigations provide a theoretical and
practical basis for the combination of three bioactive units, which is
very advantageous for the synthesis of more 2(5H)-furanone de-
rivatives, especially chiral 2(5H)-furanone compounds with poly-
functional groups. Future efforts will continue to focus on their
biological evaluation and the new development of other diverse
and functionalized libraries.
4.2. General procedure for the synthesis of target compounds
6 from propargyl esters 4 (fractional-step method)
A flame-dried 25-mL round-bottomed flask was charged with
N-[(5S)-5-alkoxy-2(5H)-furanonyl] amino acid propargyl esters 4
(1 mmol) organic azides 517 (1.5 mmol), copper acetate mono-
hydrate [Cu(OAc)2$H2O] (5% mmol), and copper powder (10%
mmol) in CH3CN (5 mL). The mixture was stirred at room tem-
perature, and the reaction was monitored by TLC. After the com-
pletion of the reaction (about 4 h), the reaction mixture was
quenched with a saturated aqueous solution of NH4Cl (20 mL) and
extracted with ethyl acetate (3ꢂ30 mL). Then, the organic layer was
dried over anhydrous MgSO4, filtered, and concentrated in vacuo.
The purification of the residue by silica gel column chromatography
yielded the desired compounds 6 in 32e85% isolated yields (mostly
equal to or over 67%, Table 2, entries 1e32).
4. Experimental section
4.1. General
4.3. General procedure for the synthesis of target compounds
6 via three-component one-pot approach
All the melting points were determined on an X-5 digital
melting points apparatus and were uncorrected. Infrared spectra
were recorded on a Bruker Vector 33 FT-IR instrument by liquid
A flame-dried flask was charged with N-[(5S)-5-alkoxy-2(5H)-
furanonyl] amino acids 3 (1 mmol) and anhydrous K2CO3
film method in the absorption range of 4000e400 cmꢁ1. 1H and 13
C
NMR spectra were obtained in CDCl3 on a Varian DRX-400 MHz
spectrometer and tetramethylsilane (TMS) was used as an internal
standard. UV absorption peaks were measured by Shimazu UV-
2550 ultraviolet absorption detector with dichloromethane as
a solvent. Optical rotations were determined with an Autopol IV
polarimeter in C2H5OH in a 10 cm cell. Elemental analysis was
performed on a Thermo Flashea TM 112 elemental analyzer. The
mass spectra (MS) were recorded on Thermo LCQ DECA XP MAX
mass spectrometer.
(1.5 mmol) in CH3CN (5 mL). The mixture was stirred for 30 min
under N2 atmosphere. Then, propargyl bromide (2 mmol) was
added, and the resulting mixture was stirred at 40 ꢀC. After 8 h, the
chiral synthon 3 had been consumed according to the monitoring
by TLC. At last, organic azides
5 (2 mmol), Cu(OAc)2$H2O
(1.8 mmol), and Cu (2.2 mmol) were added in order, and the mix-
ture was stirred at room temperature and monitored by TLC. Once
the reaction was completed (about 24 h), the reaction mixture was
quenched with a saturated aqueous solution of NH4Cl (20 mL) and

2838
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
extracted with ethyl acetate (3ꢂ30 mL). The organic layer was dried
over MgSO4, and concentrated in vacuo. The residue was purified
by column chromatography using the mixture of petroleum
ether and ethyl acetate as eluent to obtain the target compounds 6
in 30e68% isolated yields (mostly equal to or over 50%, Table 3,
entries 1e32).
UVevis (CH2Cl2) lmax: 269 nm; 1H NMR (400 MHz, CDCl3)
d, ppm:
0.82 (d, J¼8.0 Hz, 3H), 0.84e0.96 (m, 13H), 0.97e1.12 (m, 2H),
1.30e1.44 (m, 2H), 1.60e1.71 (m, 2H), 2.08e2.28 (m, 3H), 3.51e3.60
(ddd, J1¼4.0 Hz, J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.77 (b, 1H), 5.23 (d,
J¼8.0 Hz, 1H), 5.27e5.35 (m, 2H), 5.49e5.58 (m, 2H), 5.70 (s, 1H),
7.26e7.31 (m, 5H), 7.60 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm:
15.67, 17.23, 17.87, 20.87, 22.07, 22.71, 25.78, 31.50, 32.13, 33.86,
42.22, 47.88, 54.18, 58.54, 59.64, 77.38, 83.20, 99.83, 124.00, 128.04,
4.4. General procedure for the synthesis of target compounds
6 via four-component one-pot approach
128.82, 129.10, 134.31, 142.10, 157.27, 167.66, 170.43; IR (film) n,
cmꢁ1: 3379, 3060, 2956, 2929, 2868, 1745, 1652, 1520, 1454, 1328,
1191, 1133.09, 955, 746, 697, 557; ESI-MS m/z (%): 603 ([MþH]þ, 63),
625 ([MþNa]þ, 96); Anal. Calcd for C29H39BrN4O5: C 57.71, H 6.51, N
9.28, found: C 57.46, H 6.76, N 8.99.
A solution of (5S)-5-alkoxy-3,4-dibromo-2(5H)-furanones 1
(1 mmol) in dichloromethane (2 mL) was added in dropwise with
vigorous stirring into a solution of amino acids 2 (1 mmol) and KOH
(1.3 mmol) in ethanol (1 mL), and the mixture was stirred at 40 ꢀC
for 24 h under N2 atmosphere. Then, propargyl bromide (1 mmol),
K2CO3 (0.5 mmol), tetrabutyl ammonium bromide (0.2 mmol), and
solvent CH3CN (8 mL) were added, and the reaction continued for
4.5.4. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-4-methylpentanoate (6ada). Yellowish oil,
24 h. Finally, organic azides
5
(1.5 mmol), Cu(OAc)2$H2O
yield 75%. ½a 2D0
ꢃ
40.4 (c 0.069, CH3CH2OH); UVevis (CH2Cl2) lmax:
(0.6 mmol), and Cu (0.75 mmol) were added to the flask, and the
resulting mixture was stirred at room temperature until the mon-
itoring by TLC showed almost complete conversion of the substrate
(about 24 h). Then, according to the procedure mentioned above,
the reaction mixture was treated to obtain some representative
target compounds 6 in 28e48% isolated yields (mostly equal to or
over 38%, Table 5, entries 1e9).
268 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.80 (d, J¼8.0 Hz, 3H),
0.82e0.96 (m,13H), 0.97e1.10 (m, 2H),1.28e1.45 (m, 2H),1.59e1.75
(m, 5H), 2.06e2.25 (m, 2H), 3.51e3.62 (ddd, J1¼4.0 Hz, J2¼4.0 Hz,
J3¼4.0 Hz, 1H), 4.69e4.90 (m, 1H), 5.21e5.35 (m, 3H), 5.53 (s, 2H),
5.73 (s, 1H), 7.26e7.41 (m, 5H), 7.63 (s, 1H); 13C NMR (100 MHz,
CDCl3) d, ppm: 15.83, 20.93, 21.81, 22.09, 22.62, 22.75, 24.56, 25.79,
31.47, 33.85, 42.06, 42.22, 47.88, 54.12, 58.41, 58.64, 77.48, 82.39,
99.10, 124.06, 128.05, 128.77, 129.08, 134.34, 142.11, 157.80, 167.77,
4.5. Characterization data for compounds 6
171.67; IR (film) n
, cmꢁ1: 3302, 3066, 2956, 2923, 2874, 1748, 1649,
1556, 1454, 1328, 1188, 1128, 958, 7468, 700, 576; ESI-MS m/z (%):
619 ([MþH]þ, 58), 641 ([MþNa]þ, 100); Anal. Calcd for
C30H41BrN4O5: C 58.34, H 6.69, N 9.07, found: 58.08, H 6.92, N 9.29.
4.5.1. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl
2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)acetate (6aaa). Yellow oil, yield 77%. ½a D20
ꢃ
150.1 (c 0.059, CH3CH2OH); UVevis (CH2Cl2) lmax: 269 nm; 1H NMR
4.5.5. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
(400 MHz, CDCl3)
d
, ppm: 0.79 (d, J¼4.0 Hz, 3H), 0.82e0.95 (m, 7H),
0.96e1.12 (m, 2H), 1.30e1.42 (m, 2H), 1.61e1.71 (m, 2H), 2.04e2.26
(m, 2H), 3.50e3.64 (m, 1H), 4.33 (s, 2H), 5.31 (s, 2H), 5.48 (b, 1H),
5.53 (s, 2H), 5.74 (s, 1H), 7.26e7.46 (m, 5H), 7.59 (s, 1H); 13C NMR
dihydrofuran-3-ylamino)-3-phenylpropanoate
(6aea). Yellowish
105.8 (c 0.093, CH3CH2OH);
, ppm:
solid, yield 67%. Mp 58.3e58.9 ꢀC; ½a D20
ꢃ
UVevis (CH2Cl2) lmax: 272 nm; 1H NMR (400 MHz, CDCl3)
d
(100 MHz, CDCl3)
33.88, 42.25, 44.51, 48.00, 54.25, 58.81, 77.33, 82.36, 98.97, 123.98,
d
, ppm: 15.71, 21.03, 22.10, 22.73, 25.60, 31.56,
0.70 (d, J¼4.0 Hz, 3H), 0.74e0.91 (m, 7H), 0.92e1.07 (m, 2H),
1.19e1.39 (m, 2H), 1.53e1.70 (m, 2H), 1.85e2.15 (m, 2H), 3.04e3.24
(m, 2H), 3.34e3.54 (m, 1H), 5.09 (b, 1H), 5.28 (s, 2H), 5.32e5.44 (m,
1H), 5.51 (s, 3H), 6.97e7.25 (m, 5H), 7.26e7.46 (m, 5H), 7.56 (s, 1H);
128.16, 128.91, 129.17, 134.16, 141.98, 158.30, 167.53, 168.85; IR (film)
n
, cmꢁ1: 3357, 3046, 2954, 2923, 2852, 1753, 1652, 1528, 1454, 1331,
1191, 1128, 936, 744, 697, 549; ESI-MS m/z (%): 561 ([MþH]þ, 34),
583 ([MþNa]þ, 94); Anal. Calcd for C26H33BrN4O5: C 55.62, H 5.92, N
9.98, found: C 55.55, H 5.98, N 10.08.
13C NMR (100 MHz, CDCl3)
d, ppm: 15.51, 21.02, 22.13, 22.61, 25.40,
31.50, 33.88, 39.82, 42.23, 47.83, 54.16, 56.08, 58.89, 77.56, 82.86,
99.38, 124.24, 127.53, 128.18, 128.65, 128.84, 129.13, 129.49, 134.34,
141.84, 156.91, 167.52, 170.08; IR (film) n
, cmꢁ1: 3374, 3027, 2951,
4.5.2. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)propanoate (6aba). Yellow oil, yield 63%.
2923, 2868, 1750, 1652, 1517, 1495, 1454, 1325, 1182, 1122, 955, 744,
700, 562; ESI-MS m/z (%): 653 ([MþH]þ, 54), 675 ([MþNa]þ, 100);
Anal. Calcd for C33H39BrN4O5: C 60.83, H 6.03, N 8.60, found: C
61.01, H 6.10, N 8.32.
½
a 2D0
ꢃ
89.3 (c 0.073, CH3CH2OH); UVevis (CH2Cl2) lmax: 269 nm; 1H
NMR (400 MHz, CDCl3)
d
, ppm: 0.82 (d, J¼4.0 Hz, 3H), 0.83e0.97
(m, 7H), 0.98e1.13 (m, 2H),1.29e1.42 (m, 2H),1.50 (d, J¼4.0 Hz, 3H),
1.59e1.73 (m, 2H), 2.05e2.26 (m, 2H), 3.51e3.62 (ddd, J1¼4.0 Hz,
J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.80 (b, 1H), 5.26e5.35 (m, 2H),
5.36e5.44 (m, 1H), 5.53 (s, 2H), 5.72 (s, 1H), 7.27e7.45 (m, 5H), 7.62
4.5.6. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl
6-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)hexanoate (6afa). Yellow oil, yield 71%.
½
a 2D0
46.5 (c 0.073, CH3CH2OH); UVevis (CH2Cl2) lmax: 273 nm; 1H
ꢃ
(s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 15.87, 20.26, 20.89,
NMR (400 MHz, CDCl3)
d
, ppm: 0.80 (d, J¼8.0 Hz, 3H), 0.86e0.98
22.07, 22.91, 25.88, 31.52, 33.88, 42.22, 47.89, 50.79, 54.18, 58.86,
82.63, 99.10, 104.99, 123.95, 128.10, 128.83, 129.11, 134.26, 141.99,
(m, 7H), 1.00e1.15 (m, 2H), 1.31e1.43 (m, 4H), 1.57e1.72 (m, 6H),
2.08e2.28 (m, 2H), 2.34 (t, J¼8.0 Hz, 2H), 3.37e3.52 (m, 2H),
3.53e3.62 (ddd, J1¼4.0 Hz, J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.84 (s, 1H),
5.19 (s, 2H), 5.53 (s, 2H), 5.74 (s, 1H), 7.26e7.45 (m, 5H), 7.53 (s, 1H);
157.08, 167.62, 171.76; IR (film) n
, cmꢁ1: 3374, 3065, 3028, 2951,
2923, 2868, 1750, 1649, 1523, 1493, 1454, 1325, 1196, 1130, 955, 744,
697, 576; ESI-MS m/z (%): 577 ([MþH], 23), 599 ([MþNa]þ, 100);
Anal. Calcd for C27H35BrN4O5: C 56.35, H 6.13, N 9.74, found: C
56.30, H 6.05, N 9.68.
13C NMR (100 MHz, CDCl3)
d, ppm: 15.86, 21.08, 22.13, 22.73, 24.23,
25.39, 25.71, 30.16, 31.53, 33.69, 33.88, 42.35, 43.59, 48.04, 54.11,
57.42, 77.42, 81.57, 98.46, 123.70, 128.07, 128.74, 129.06, 134.39,
142.95, 159.82, 168.00, 173.06; IR (film) n
, cmꢁ1: 3346, 3072, 3026,
4.5.3. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-3-methylbutanoate (6aca). Yellow solid,
2918, 2852, 1734, 1638, 1495, 1454, 1314, 1155, 1119, 933, 744, 694,
574; ESI-MS m/z (%): 619 ([MþH]þ, 18), 641 ([MþNa]þ, 100); Anal.
Calcd for C30H41BrN4O5: C 58.34, H 6.69, N 9.07, found: 58.20, H
6.75, N 9.13.
yield 70%. Mp 118.2e119.0 ꢀC; ½a D20
ꢃ
75.9 (c 0.057, CH3CH2OH);

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2839
4.5.7. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)butanoate (6aga). Yellow oil, yield 80%.
4-((S)-4-bromo-2-
4.5.11. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-
5-oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-
2,5-dihydrofuran-3-ylamino)-3-methylbutanoate (6bca). Yellow oil,
½
a 2D0
ꢃ
88.9 (c 0.049, CH3CH2OH); UVevis (CH2Cl2) lmax: 273 nm; 1H
yield 61%. ½a 2D0
ꢃ
ꢁ141.8 (c 0.049, CH3CH2OH); UVevis (CH2Cl2) lmax
:
NMR (400 MHz, CDCl3)
d
: 0.77 (d, J¼4.0 Hz, 3H), 0.81e0.95 (m, 7H),
269 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.71e0.94 (m, 15H),
0.96e1.13 (m, 2H), 1.26e1.41 (m, 2H), 1.59e1.70 (m, 2H), 1.89e1.99
(m, 2H), 2.10e2.27 (m, 2H), 2.43 (t, J¼8.0 Hz, 2H), 3.46e3.64 (m,
3H), 5.19 (s, 2H), 5.52 (s, 2H), 5.64 (s, 1H), 5.78 (s, 1H), 7.26e7.44 (m,
1.10e1.34 (m, 4H), 1.63e1.75 (m, 2H), 2.13e2.29 (m, 2H), 3.96 (d,
J¼8.0 Hz, 1H), 4.53 (b, 1H), 5.24e5.36 (m, 3H), 5.54 (s, 2H), 5.68 (s,
1H), 7.26e7.44 (m, 5H), 7.60 (s, 1H); 13C NMR (100 MHz, CDCl3)
d,
5H), 7.60 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
, ppm: 15.80, 21.11,
ppm: 13.89, 17.26, 18.16, 18.75, 19.57, 26.40, 27.86, 32.14, 36.97,
44.77, 47.52, 49.41, 54.14, 58.52, 60.16, 77.42, 87.97, 99.58, 124.01,
128.00, 128.79, 129.08, 134.35, 142.12, 158.83, 167.52, 170.47; IR
22.15, 22.72, 25.10, 25.34, 30.89, 31.53, 33.89, 42.33, 43.03, 48.06,
54.15, 57.75, 77.44, 81.56, 98.43, 123.70, 128.11, 128.78, 129.09,
134.36, 142.71, 159.73, 168.08, 172.74; IR (film)
3039, 2951, 2923, 2868, 1742, 1646, 1525, 1498, 1454, 1325, 1166,
1122, 947, 746, 697, 582; ESI-MS m/z (%): 589 ([MþH]þ, 44), 611
([MþNa]þ, 100); Anal. Calcd for C28H37BrN4O5: C 57.05, H 6.33, N
9.50, found: C 57.17, H 6.44, N 9.48.
n
, cmꢁ1: 3324, 3069,
(film) n
, cmꢁ1: 3321, 3074, 2953, 2877, 1748, 1649, 1523, 1455, 1329,
1195, 1134, 956, 745, 696, 545; ESI-MS m/z (%): 601 ([MþH]þ, 33),
623 ([MþNa]þ, 100); Anal. Calcd for C29H37BrN4O5: C 57.90, H 6.20,
N 9.31, found: C 57.82, H 6.27, N 9.29.
4.5.12. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-
5-oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-
2,5-dihydrofuran-3-ylamino)-4-methylpentanoate (6bda). Yellow
4.5.8. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-2-phenylacetate (6aha). Yellow oil, yield
oil, yield 82%. ½a D
ꢃ
20 102.1 (c 0.019, CH3CH2OH); UVevis (CH2Cl2) lmax
:
54%. ½a D
ꢃ
20 90.8 (c 0.054, CH3CH2OH); UVevis (CH2Cl2) lmax: 269 nm;
270 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.84 (s, 6H), 0.86 (s, 3H),
1H NMR (400 MHz, CDCl3)
d, ppm: 0.78 (d, J¼8.0 Hz, 3H), 0.82e0.97
0.92 (d, J¼4.0 Hz, 6H), 1.08e1.32 (m, 4H), 1.60e1.75 (m, 5H),
2.14e2.27 (m, 1H), 3.95 (d, J¼8.0 Hz, 1H), 4.65 (b, 1H), 5.18e5.34 (m,
3H), 5.53 (s, 2H), 5.68 (s, 1H), 7.26e7.44 (m, 5H), 7.57 (s, 1H); 13C
(m, 7H), 0.98e1.17 (m, 2H), 1.23e1.39 (m, 2H), 1.57e1.78 (m, 2H),
2.05e2.33 (m, 2H), 3.48e3.62 (m, 1H), 5.17e5.37 (m, 2H),
5.40e5.55 (m, 2H), 5.56e6.06 (m, 3H), 7.06e7.74 (m, 11H); 13C NMR
NMR (100 MHz, CDCl3) d, ppm: 13.85, 18.76, 19.59, 21.86, 22.71,
(100 MHz, CDCl3)
33.88, 42.10, 47.98, 54.17, 58.49, 59.36, 83.29, 85.38, 100.21, 123.66,
126.45, 126.80, 128.06, 128.86, 129.14, 129.27, 134.24, 135.57, 141.91,
d
, ppm: 15.83, 21.01, 22.09, 22.82, 25.78, 31.54,
24.65, 26.37, 27.88, 37.10, 42.24, 44.78, 47.55, 49.40, 54.22, 54.54,
58.68, 77.33, 88.03, 99.43, 123.90, 128.09, 128.88, 129.16, 134.25,
142.18, 158.12, 167.17, 171.66; IR (film) n
, cmꢁ1: 3313, 3071, 2951,
163.44, 167.58, 169.85; IR (film)
n
, cmꢁ1: 3374, 3028, 2951, 2923,
2874,1748,1649,1556,1454,1331,1144,1130, 958, 746, 697, 573; ESI-
MS m/z (%): 617 ([MþH]þ, 67), 639 ([MþNa]þ, 100); Anal. Calcd for
C30H39BrN4O5: C 58.54, H 6.39, N 9.10, found: 58.47, H 6.32, N 9.07.
2868, 1750, 1652, 1512, 1495, 1454, 1317, 1169, 1125, 958, 746, 697,
576; ESI-MS m/z (%): 637 ([MþH]þ, 41), 659 ([MþNa]þ, 100); Anal.
Calcd for C32H37BrN4O5: C 60.28, H 5.85, N 8.79, found: C 60.31, H
5.78, N 8.82.
4.5.13. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-
5-oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-
4.5.9. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-oxo-
2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-2,5-
dihydrofuran-3-ylamino)acetate (6baa). Yellowish oil, yield 62%.
2,5-dihydrofuran-3-ylamino)-3-phenylpropanoate
(6bea). White
93.7 (c 0.078, CH3CH2OH);
, ppm:
solid, yield 57%. Mp 62.8e64.4 ꢀC; ½a D20
ꢃ
UVevis (CH2Cl2) lmax: 270 nm; 1H NMR (400 MHz, CDCl3)
d
½
a 2D0
ꢃ
49.1 (c 0.024, CH3CH2OH); UVevis (CH2Cl2) lmax: 267 nm; 1H
0.81 (s, 3H), 0.82 (s, 3H), 0.83 (s, 3H), 1.10e1.30 (m, 4H), 1.59e1.72
(m, 2H), 2.03e2.23 (m, 1H), 2.92e3.22 (m, 2H), 3.72e3.87 (m, 1H),
4.74 (b, 1H), 5.22e5.35 (m, 3H), 5.53 (s, 3H), 7.02e7.10 (m, 2H),
7.17e7.25 (m, 3H), 7.26e7.45 (m, 5H), 7.51 (s, 1H); 13C NMR
NMR (400 MHz, CDCl3)
d, ppm: 0.85 (s, 9H), 1.22e1.28 (m, 4H),
1.65e1.79 (m, 2H), 2.20e2.29 (m, 1H), 3.91e3.99 (m, 1H), 4.28 (s,
2H), 5.32 (s, 2H), 5.34e5.40 (m, 1H), 5.53 (s, 2H), 5.71 (s, 1H),
7.27e7.45 (m, 5H), 7.56 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm:
(100 MHz, CDCl3) d, ppm: 13.98, 18.74, 19.60, 26.46, 27.91, 36.84,
13.96, 18.77, 19.60, 26.55, 27.94, 36.98, 44.67, 44.80, 47.61, 49.42,
54.30, 58.78, 77.26, 87.84, 99.28, 123.96, 128.19, 128.97, 129.21,
39.88, 44.77, 47.53, 49.37, 54.25, 56.55, 58.89, 77.35, 88.10, 99.38,
124.04, 127.70, 128.16, 128.89, 128.93, 129.19, 129.41, 134.22, 141.97,
134.12, 141.98, 158.58, 167.25, 168.90; IR (film)
n
, cmꢁ1: 3346, 3072,
157.55, 167.12, 170.23; IR (film) n
, cmꢁ1: 3357, 3055, 3033, 2951,
3034, 2945, 2923, 2852, 1753, 1649, 1528, 1492, 1454, 1320, 1188,
1130, 952, 746, 697, 576; ESI-MS m/z (%): 561 ([MþH]þ, 100), 583
([MþNa]þ, 94); Anal. Calcd for C26H31BrN4O5: C 55.82, H 5.59, N
10.01, found: C 55.75, H 5.52, N 9.97.
2923, 2852, 1751, 1649, 1521, 1495, 1454, 1322, 1177, 1128, 955, 744,
700, 560; ESI-MS m/z (%): 649 ([MþH]þ, 36), 671 ([MþNa]þ, 100);
Anal. Calcd for C33H37BrN4O5: C 61.02, H 5.74, N 8.63, found: C
61.30, H 5.46, N 8.38.
4.5.10. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-
5-oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-
2,5-dihydrofuran-3-ylamino)propanoate (6bba). Yellow oil, yield
4.5.14. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 6-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-2,5-
dihydrofuran-3-ylamino)hexanoate (6bfa). Yellow oil, yield 67%.
74%. ½a 2D0
ꢃ
117.5 (c 0.046, CH3CH2OH); UVevis (CH2Cl2) lmax
:
½
a 2D0
ꢃ
55.0 (c 0.068, CH3CH2OH); UVevis (CH2Cl2) lmax: 273 nm; 1H
269 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.84 (s, 6H), 0.86 (s, 3H),
NMR (400 MHz, CDCl3) d, ppm: 0.85 (s, 6H), 0.88 (s, 3H), 1.14e1.33
1.18e1.27 (m, 4H), 1.50 (d, J¼8.0 Hz, 3H), 1.63e1.77 (m, 2H),
2.18e2.28 (m, 1H), 3.95 (d, J¼12.0 Hz, 1H), 4.72 (b, 1H), 5.30 (s, 2H),
5.38e5.47 (m, 1H), 5.54 (s, 2H), 5.71 (s, 1H), 7.26e7.43 (m, 5H), 7.58
(m, 4H), 1.34e1.44 (m, 2H), 1.62e1.91 (m, 6H), 2.18e2.28 (m, 1H),
2.32 (t, J¼8.0 Hz, 2H), 3.35e3.57 (m, 2H), 3.99 (d, J¼8.0 Hz, 1H), 5.17
(s, 2H), 5.53 (s, 2H), 5.78 (s, 2H), 7.26e7.41 (m, 5H), 7.64 (s, 1H); 13C
(s, 1H); 13C NMR (100 MHz, CDCl3)
d
, ppm: 13.85, 18.76, 19.59, 20.12,
NMR (100 MHz, CDCl3) d, ppm: 13.92, 18.78, 19.60, 24.23, 25.77,
26.49, 27.91, 37.06, 44.78, 47.58, 49.41, 51.10, 54.26, 58.85, 77.32,
87.61, 99.28, 123.87, 128.12, 128.90, 129.16, 134.19, 142.07, 157.44,
26.54, 27.97, 30.15, 33.70, 37.00, 43.90, 44.78, 47.48, 49.37, 54.07,
57.40, 77.54, 87.21, 99.14, 123.81, 128.05, 128.70, 129.03, 134.45,
167.32, 171.79; IR (film)
n
, cmꢁ1: 3313, 3071, 3035, 2951, 2923, 2854,
142.92, 160.19, 168.08, 173.10; IR (film) n
, cmꢁ1: 3313, 3066, 3029,
1750, 1649, 1557, 1496, 1454, 1325, 1199, 1141, 958, 744, 700, 554;
ESI-MS m/z (%): 573 ([MþH]þ, 30), 595 ([MþNa]þ, 100); Anal. Calcd
for C27H33BrN4O5: C 56.55, H 5.80, N 9.77, found: C 56.61, H 5.74,
N 9.82.
2951, 2874, 1742, 1646, 1540.72, 1495, 1454, 1320, 1155, 1128, 955,
741, 697, 579; ESI-MS m/z (%): 617 ([MþH]þ, 35), 639 ([MþNa]þ,
100); Anal. Calcd for C30H39BrN4O5: C 58.54, H 6.39, N 9.10, found: C
58.47, H 6.41, N 9.06.

2840
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
4.5.15. (1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 4-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-2,5-
dihydrofuran-3-ylamino)butanoate (6bga). Yellowish oil, yield 76%.
4.5.19. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-3-methylbutanoate (6acb). Yellow oil,
½
a 2D0
ꢃ
87.5 (c 0.034, CH3CH2OH); UVevis (CH2Cl2) lmax: 272 nm; 1H
yield 71%. ½a 2D0
ꢃ
ꢁ103.4 (c 0.046, CH3CH2OH); UVevis (CH2Cl2) lmax
:
NMR (400 MHz, CDCl3)
d, ppm: 0.85 (s, 6H), 0.87 (s, 3H), 1.17e1.32
269 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.85 (d, J¼4.0 Hz, 3H),
(m, 4H), 1.64e1.86 (m, 2H), 1.92e2.02 (m, 2H), 2.20e2.29 (m, 1H),
2.45 (t, J¼8.0 Hz, 2H), 3.44e3.60 (m, 2H), 3.98 (d, J¼8.0 Hz,1H), 5.20
(s, 2H), 5.53 (s, 2H), 5.58 (b, 1H), 5.73 (s, 1H), 7.26e7.43 (m, 5H), 7.56
0.86e1.01 (m, 16H), 1.02e1.14 (m, 2H), 1.23e1.45 (m, 8H), 1.61e1.73
(m, 2H), 1.84e1.97 (m, 2H), 2.08e2.30 (m, 3H), 3.52e3.62 (ddd,
J1¼4.0 Hz, J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.37 (t, J¼8.0 Hz, 2H), 4.79 (b,
1H), 5.21e5.42 (m, 3H), 5.72 (s,1H), 7.65 (s,1H); 13C NMR (100 MHz,
(s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.99, 18.79, 19.61, 25.27,
26.58, 27.97, 31.07, 37.02, 43.39, 44.81, 47.56, 49.42, 54.21, 57.80,
77.33, 87.52, 99.15, 123.61, 128.14, 128.85, 129.13, 134.32, 142.74,
CDCl3) d, ppm: 13.91, 15.69, 17.27, 17.88, 20.87, 22.05, 22.36, 22.74,
25.82, 26.03, 30.18, 31.05, 31.53, 32.19, 33.87, 42.24, 47.91, 50.44,
58.64, 59.74, 77.31, 83.15, 99.76, 123.87, 141.61, 157.32, 167.71,
159.78, 167.78, 172.86; IR (film) n
, cmꢁ1: 3313, 3060, 2951, 2879,
1742, 1646, 1528, 1495, 1454, 1322, 1166, 1130, 949, 746, 697, 576;
ESI-MS m/z (%): 589 ([MþH]þ, 66), 611 ([MþNa]þ, 100); Anal. Calcd
for C28H35BrN4O5: C 57.24, H 6.00, N 9.54, found: C 57.15, H 5.96,
N 9.58.
170.53; IR (film) n
, cmꢁ1: 3319, 3083, 2956.04, 2929, 2868, 1745,
1652, 1525, 1465, 1328, 1193, 1136, 955, 664; ESI-MS m/z (%): 599
([MþH]þ, 100), 621 ([MþNa]þ, 99); Anal. Calcd for C28H45BrN4O5: C
56.28, H 7.59, N 9.38, found: C 56.32, H 7.65, N 9.41.
4.5.16. (S)-(1-Benzyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bro-mo-
5-oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-
2,5-dihydrofuran-3-ylamino)-2-phenylacetate (6bha). Yellow oil,
4.5.20. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-4-methylpentanoate (6adb). Yellow oil,
yield 32%. ½a 2D0
ꢃ
130.5 (c 0.053, CH3CH2OH); UVevis (CH2Cl2) lmax
:
yield 73%. ½a 2D0
ꢃ
ꢁ132.1 (c 0.050, CH3CH2OH); UVevis (CH2Cl2) lmax
:
269 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.79e0.95 (m, 9H),
268 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.82 (d, J¼8.0 Hz, 3H),
1.21e1.30 (m, 4H), 1.63e1.86 (m, 2H), 2.11e2.31 (m, 1H), 3.83e3.99
(m, 1H), 5.22e5.36 (m, 2H), 5.40e5.53 (m, 2H), 5.54e5.73 (m, 2H),
0.83e0.99 (m, 16H), 1.00e1.13 (m, 2H), 1.24e1.44 (m, 8H), 1.59e1.79
(m, 5H), 1.84e1.96 (m, 2H), 2.06e2.26 (m, 2H), 3.53e3.64 (ddd,
J1¼4.0 Hz, J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.37 (t, J¼8.0 Hz, 2H), 4.82 (b,
1H), 5.15e5.38 (m, 3H), 5.75 (s, 1H), 7.67 (s, 1H); 13C NMR (100 MHz,
6.05 (b, 1H), 7.05e7.59 (m, 11H); 13C NMR (100 MHz, CDCl3)
d, ppm:
14.27, 18.76, 19.62, 26.63, 27.96, 36.80, 44.81, 47.52, 49.49, 54.22,
58.47, 59.45, 77.24, 87.83, 99.57, 123.51, 126.47, 126.82, 128.05,
128.92, 129.17, 129.29, 134.16, 135.44, 141.97, 157.74, 167.26, 169.96;
CDCl3) d, ppm: 13.89, 15.79, 20.88, 21.81, 22.03, 22.33, 22.59, 22.74,
24.57, 25.81, 26.01, 30.13, 31.00, 31.48, 33.83, 42.15, 42.22, 47.86,
50.39, 54.14, 58.72, 77.38, 82.58, 99.10, 123.90, 141.61, 157.68, 167.67,
IR (film) n
, cmꢁ1: 3368, 3060, 3027, 2951, 2923, 1753, 1649, 1495,
1454, 1317, 1169, 1128, 958, 746, 694, 557; ESI-MS m/z (%): 637
([MþH]þ, 20), 659 ([MþNa]þ, 100); Anal. Calcd for C32H35BrN4O5: C
60.47, H 5.55, N 8.82, found: C 60.54, H 5.49, N 8.78.
171.74; IR (film) n
, cmꢁ1: 3302, 3084, 2956, 2929, 2868, 1748,
1649,1558, 1462, 1325, 1188, 1128, 958, 667; ESI-MS m/z (%): 611
([MþH]þ, 100), 633 ([MþNa]þ, 80); Anal. Calcd for C29H47BrN4O5: C
56.95, H 7.75, N 9.16, found: C 57.03, H 7.72, N 9.22.
4.5.17. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl
2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
4.5.21. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-3-phenylpropanoate (6aeb). Yellow oil,
dihydrofuran-3-ylamino)acetate (6aab). Yellow oil, yield 75%. ½a D20
ꢃ
170.5 (c 0.046, CH3CH2OH); UVevis (CH2Cl2) lmax: 268 nm; 1H NMR
(400 MHz, CDCl3)
d
, ppm: 0.70 (d, J¼8.0 Hz, 3H), 0.72e1.10 (m,12H),
yield 74%. ½a 2D0
ꢃ
92.6 (c 0.040, CH3CH2OH); UVevis (CH2Cl2) lmax:
1.11e1.38 (m, 8H), 1.50e1.64 (m, 2H), 1.73e1.89 (m, 2H), 1.98e2.17
(m, 2H), 3.43e3.55 (ddd, J1¼4.0 Hz, J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.26
(t, J¼8.0 Hz, 4H), 5.24 (s, 2H), 5.62 (s, 1H), 5.70 (s, 1H), 7.60 (s, 1H);
272 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.72 (d, J¼8.0 Hz, 3H),
0.81 (d, J¼8.0 Hz, 3H), 0.84e0.95 (m, 7H), 0.96e1.11 (m, 2H),
1.21e1.39 (m, 8H), 1.56e1.71 (m, 2H), 1.86e1.94 (m, 2H), 2.07e2.41
(m, 2H), 3.07e3.26 (m, 2H), 3.37e3.50 (m, 1H), 4.36 (t, J¼8.0 Hz,
2H), 4.81e5.17 (m, 2H), 5.33 (s, 3H), 7.01e7.12 (m, 2H), 7.24e7.33
13C NMR (100 MHz, CDCl3)
d, ppm: 13.88, 15.67, 21.00, 22.06, 22.32,
22.69, 25.51, 26.02, 30.13, 31.01, 31.51, 33.85, 42.23, 44.51, 47.99,
50.44, 58.81, 77.37, 82.13, 98.86, 123.95, 141.49, 158.55, 167.57,
(m, 3H), 7.60 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.93,
168.90; IR (film)
n
, cmꢁ1: 3357, 3099, 2956, 2923, 2868, 1753, 1654,
15.48, 20.97, 22.07, 22.36, 22.59, 25.41, 26.07, 30.16, 31.05, 31.51,
33.85, 39.96, 42.22, 47.83, 50.42, 55.99, 58.96, 77.40, 82.96, 98.67,
124.09, 127.54, 128.66, 129.49, 134.31, 141.38, 156.84, 167.44, 170.14;
1527, 1454, 1325, 1191, 1125, 936, 691; ESI-MS m/z (%): 557
([MþH]þ, 48), 579 ([MþNa]þ, 100); Anal. Calcd for C25H39BrN4O5: C
54.05, H 7.08, N 10.09, found: C 53.94, H 7.16, N 9.97.
IR (film) n
, cmꢁ1: 3374, 3092, 3072, 3031, 2951, 2929, 2863, 1750,
1652, 1516, 1495, 1454, 1322, 1182, 1117, 955, 744, 700, 571; ESI-MS
m/z (%): 647 ([MþH]þ, 98), 669 ([MþNa]þ, 100); Anal. Calcd for
C32H45BrN4O5: C 59.53, H 7.03, N 8.68, found: C 59.48, H 6.97,
N 8.62.
4.5.18. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)propanoate (6abb). Yellow oil, yield 76%.
½
a 2D0
1H NMR (400 MHz, CDCl3)
ꢃ
72.7 (c 0.066, CH3CH2OH); UVevis (CH2Cl2) lmax: 268 nm;
d, ppm: 0.84 (d, J¼8.0 Hz, 3H),
4.5.22. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl
6-((S)-4-bromo-2-
0.86e0.95 (m, 10H), 0.98e1.13 (m, 2H), 1.27e1.39 (m, 8H), 1.52 (d,
J¼8.0 Hz, 3H), 1.61e1.73 (m, 2H), 1.82e1.97 (m, 2H), 2.01e2.26 (m,
2H), 3.48e3.66 (ddd, J1¼4.0 Hz, J2¼4.0 Hz, J3¼8.0 Hz, 1H), 4.37 (t,
J¼8.0 Hz, 2H), 4.82 (s, 1H), 5.17e5.47 (m, 3H), 5.74 (s, 1H), 7.67 (s,
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)hexanoate (6afb). Yellow oil, yield 85%.
½
a D
ꢃ
20 165.2 (c 0.059, CH3CH2OH); UVevis (CH2Cl2) lmax: 273 nm; 1H
NMR (400 MHz, CDCl3)
d, ppm: 0.64e1.01 (m, 13H), 1.02e1.17 (m,
1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.88, 15.86, 20.30, 20.87,
2H), 1.18e1.49 (m, 10H), 1.53e1.79 (m, 6H), 1.83e1.99 (m, 2H),
2.10e2.28 (m, 2H), 2.30e2.46 (m, 2H), 3.38e3.57 (m, 2H),
3.58e3.70 (m, 1H), 4.28e4.49 (m, 2H), 5.21 (s, 2H), 5.71 (s, 1H), 5.84
22.02, 22.34, 22.91, 25.91, 26.03, 30.13, 31.02, 31.53, 33.88, 42.23,
47.90, 50.45, 50.80, 58.90, 77.32, 82.70, 99.11, 123.82, 141.51,
157.08, 167.56, 171.82; IR (film)
n
, cmꢁ1: 3324, 3091, 2951, 2923,
(s, 1H), 7.71 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.86, 15.78,
2863, 1750, 1652, 1557.35, 1518, 1454, 1328, 1199, 1133, 958, 672;
ESI-MS m/z (%): 569 ([MþH]þ, 37), 591 ([MþNa]þ, 100); Anal.
Calcd for C26H41BrN4O5: C 54.83, H 7.26, N 9.84, found: C 54.87, H
7.19, N 9.80.
21.02, 22.08, 22.27, 22.66, 24.20, 25.23, 25.68, 25.95, 29.52, 30.08,
30.97, 31.43, 33.66, 33.83, 42.28, 43.43, 47.99, 50.28, 57.38, 77.51,
81.31, 98.36, 123.66, 142.36, 159.66, 168.15, 173.02; IR (film)
3242, 3093, 2951, 2923, 2863, 1734, 1649, 1457, 1317, 1166, 1125,
n :
, cmꢁ1

Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
2841
938, 664; ESI-MS m/z (%): 613 ([MþH]þ, 19), 635 ([MþNa]þ, 100);
171.84; IR (film)
n
, cmꢁ1: 3297, 3093, 2951, 2929, 2873, 1750, 1649,
Anal. Calcd for C29H47BrN4O5: C 56.95, H 7.75, N 9.16, found: C 57.04,
H 7.81, N 9.20.
1561, 1523, 1454, 1328, 1199, 1144, 955, 658; ESI-MS m/z (%): 569
([MþH]þ, 97), 591 ([MþNa]þ, 100); Anal. Calcd for C26H39BrN4O5: C
55.03, H 6.93, N 9.87, found: C 54.98, H 7.04, N 9.82.
4.5.23. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl
4-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
4.5.27. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-oxy)-2,5-
dihydrofuran-3-ylamino)-3-methylbutanoate (6bcb). Yellowish oil,
dihydrofuran-3-ylamino)butanoate (6agb). Yellowish solid, yield
83%. Mp 115.0e115.6 ꢀC; ½a D20
ꢃ
69.1 (c 0.080, CH3CH2OH); UVevis
, ppm: 0.79 (d,
(CH2Cl2) lmax: 273 nm; 1H NMR (400 MHz, CDCl3)
d
yield 67%. ½a 2D0
ꢃ
132.5 (c 0.024, CH3CH2OH); UVevis (CH2Cl2) lmax
:
J¼4.0 Hz, 3H), 0.81e1.00 (m, 10H), 1.01e1.17 (m, 2H), 1.24e1.44 (m,
8H), 1.61e1.74 (m, 2H), 1.84e1.93 (m, 2H), 1.94e2.04 (m, 2H),
2.11e2.28 (m, 2H), 2.46 (t, J¼8.0 Hz, 2H), 3.43e3.65 (m, 3H), 4.36 (t,
J¼8.0 Hz, 2H), 5.23 (s, 2H), 5.46 (s, 1H), 5.78 (s, 1H), 7.63 (s, 1H); 13C
270 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.63e1.06 (m, 18H),
1.12e1.40 (m, 10H), 1.63e1.75 (m, 2H), 1.86e1.97 (m, 2H), 2.16e2.32
(m, 2H), 3.97 (d, J¼8.0 Hz, 1H), 4.36 (t, J¼8.0 Hz, 2H), 4.60 (b, 1H),
5.22e5.40 (m, 3H), 5.69 (s, 1H), 7.64 (s, 1H); 13C NMR (100 MHz,
NMR (100 MHz, CDCl3)
d, ppm: 13.92, 15.79, 21.09, 22.11, 22.36,
CDCl3) d, ppm: 13.88, 17.26, 18.32, 18.71, 19.53, 22.33, 26.00, 26.40,
22.73, 25.36, 25.39, 26.07, 30.18, 30.96, 31.06, 31.57, 33.89, 42.35,
43.12, 48.07, 50.42, 57.86, 77.33, 81.65, 98.50, 123.53, 142.22, 159.79,
27.85, 30.15, 31.02, 32.19, 36.98, 44.79, 47.52, 49.41, 50.40, 58.58,
60.31, 77.33, 87.99, 99.53, 123.88, 141.59, 157.93, 167.17, 170.51; IR
167.89,172.81; IR (film)
n
, cmꢁ1: 3324, 3090, 2951, 2923, 2868,1742,
(film) n
, cmꢁ1: 3324, 3085, 2956, 2929, 2868, 1748, 1649, 1551, 1462,
1649, 1525, 1457, 1322, 1166, 1122, 947, 667; ESI-MS m/z (%): 585
([MþH]þ, 66), 607 ([MþNa]þ, 100); Anal. Calcd for C27H43BrN4O5: C
55.57, H 7.43, N 9.60, found: C 55.62, H 7.37, N 9.55.
1331, 1193, 1136, 955, 675; ESI-MS m/z (%): 597 ([MþH]þ, 12), 619
([MþNa]þ, 100); Anal. Calcd for C28H43BrN4O5: C 56.47, H 7.28, N
9.41, found: C 56.51, H 7.36, N 9.38.
4.5.24. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-2-
((1R,2S,5R)-2-isopropyl-5-methylcyclohexyloxy)-5-oxo-2,5-
dihydrofuran-3-ylamino)-2-phenylacetate (6ahb). Yellow oil, yield
4.5.28. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-oxy)-2,5-
dihydrofuran-3-ylamino)-4-methylpentanoate (6bdb). Yellow oil,
57%. ½a D
ꢃ
20 72.9 (c 0.071, CH3CH2OH); UVevis (CH2Cl2) lmax: 268 nm;
yield 75%. ½a 2D0
ꢃ
130.5 (c 0.062, CH3CH2OH); UVevis (CH2Cl2) lmax
:
1H NMR (400 MHz, CDCl3)
d
, ppm: 0.81 (d, J¼8.0 Hz, 3H), 0.83e1.01
270 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.58e1.06 (m, 18H),
(m, 10H), 1.02e1.17 (m, 2H), 1.19e1.48 (m, 8H), 1.58e1.75 (m, 2H),
1.78e1.94 (m, 2H), 2.05e2.37 (m, 2H), 3.51e3.85 (ddd, J1¼4.0 Hz,
J2¼4.0 Hz, J3¼4.0 Hz, 1H), 4.30 (t, J¼8.0 Hz, 2H), 5.13e5.43 (m, 2H),
5.53e6.14 (m, 3H), 7.22e7.76 (m, 6H); 13C NMR (100 MHz, CDCl3-
1.07e1.47 (m, 10H), 1.62e1.79 (m, 5H), 1.85e1.97 (m, 2H), 2.15e2.32
(m, 1H), 3.98 (d, J¼8.0 Hz, 1H), 4.37 (t, J¼8.0 Hz, 2H), 4.74 (b, 1H),
5.32 (s, 2H), 5.57e5.68 (m, 1H), 5.75 (s, 1H), 7.71 (s, 1H); 13C NMR
(100 MHz, CDCl3) d, ppm: 13.71, 13.88, 18.69, 19.51, 21.72, 22.31,
TMS)
d
, ppm: 13.93, 15.80, 20.96, 22.05, 22.35, 22.78, 25.74, 26.00,
22.69, 24.58, 25.97, 26.29, 27.84, 30.12, 30.99, 37.03, 42.00, 44.73,
47.44, 49.31, 50.34, 54.61, 58.67, 77.46, 87.78, 99.54, 123.90, 141.59,
30.11, 31.03, 31.51, 33.86, 42.08, 47.96, 50.36, 58.49, 59.43, 83.22,
85.26, 100.18, 123.60, 126.46, 129.11, 129.24, 135.62, 141.37, 162.65,
169.60,171.64; IR (film)
1748, 1652, 1512, 1454, 1317, 1166, 1122, 958, 746, 697, 653; ESI-MS
m/z (%): 633 ([MþH]þ, 95), 655 ([MþNa]þ, 100); Anal. Calcd for
C31H43BrN4O5: C 58.95, H 6.86, N 8.87, found: C 59.03, H 6.91,
N 8.85.
158.52, 167.42, 171.65; IR (film) n
, cmꢁ1: 3286, 3085, 2956, 2929,
n
, cmꢁ1: 3357, 3072, 3036, 2951, 2923, 2863,
2868, 1750, 1649, 1559, 1465, 1333, 1144, 958, 678; ESI-MS m/z (%):
611 ([MþH]þ, 92), 633 ([MþNa]þ, 96); Anal. Calcd for
C29H45BrN4O5: C 57.14, H 7.44, N 9.19, found: C 57.08, H 7.51, N 9.23.
4.5.29. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-oxy)-2,5-
dihydrofuran-3-ylamino)-3-phenylpropanoate (6beb). Yellow oil,
4.5.25. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicy-clo[2.2.1]heptan-2-yloxy)-2,5-
yield 82%. ½a 2D0
ꢃ
73.2 (c 0.053, CH3CH2OH); UVevis (CH2Cl2) lmax
:
dihydrofuran-3-ylamino)acetate (6bab). Yellow oil, yield 76%. ½a D20
ꢃ
270 nm; 1H NMR (400 MHz, CDCl3)
d, ppm: 0.66e0.98 (m, 12H),
159.5 (c 0.021, CH3CH2OH); UVevis (CH2Cl2) lmax: 270 nm; 1H NMR
1.03e1.45 (m, 10H), 1.59e1.74 (m, 2H), 1.85e1.96 (m, 2H), 2.10e2.26
(m, 1H), 2.95e3.28 (m, 2H), 3.70e3.88 (m, 1H), 4.36 (t, J¼8.0 Hz,
2H), 4.70 (b, 1H), 5.04e5.53 (m, 4H), 7.02e7.15 (m, 2H), 7.20e7.33
(400 MHz, CDCl3) d, ppm: 0.65e1.03 (m, 12H), 1.15e1.41 (m, 10H),
1.60e1.76 (m, 2H), 1.80e1.94 (m, 2H), 2.20e2.36 (m, 1H), 3.97 (d,
J¼12.0 Hz, 1H), 4.32 (s, 2H), 4.36 (t, J¼8.0 Hz, 2H), 5.34 (s, 2H), 5.77
(m, 3H), 7.60 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.94,
(s, 2H), 7.68 (s, 1H); 13C NMR (100 MHz, CDCl3)
d
, ppm: 13.88, 13.92,
13.95, 18.71, 19.56, 22.37, 26.08, 26.43, 27.89, 30.19, 31.06, 36.84,
39.88, 44.75, 47.50, 49.35, 50.44, 57.64, 58.94, 77.37, 88.06, 100.06,
124.03, 127.66, 128.87, 129.43, 134.79, 141.46, 158.73, 167.13, 170.25;
18.74, 19.56, 22.36, 26.06, 26.51, 27.92, 30.17, 31.05, 36.96, 44.67,
44.78, 47.57, 49.38, 50.49, 58.76, 77.31, 87.73, 99.30, 123.99, 141.49,
158.80, 167.43, 169.00; IR (film)
n
, cmꢁ1: 3346, 3091, 2951, 2929,
IR (film) n
, cmꢁ1: 3313, 3092, 3060, 3030, 2951, 2929, 2868, 1753,
2868, 1756, 1652, 1529, 1454, 1438, 1322, 1188, 1130, 952, 568; ESI-
MS m/z (%): 555 ([MþH]þ, 14), 577 ([MþNa]þ, 100); Anal. Calcd for
C25H37BrN4O5: C 54.25, H 6.74, N 10.12, found: C 54.30, H 6.69,
N 10.08.
1652, 1526, 1496, 1454, 1322, 1177, 1130, 955, 744, 700, 560; ESI-MS
m/z (%): 645 ([MþH]þ, 38), 667 ([MþNa]þ, 100); Anal. Calcd for
C32H43BrN4O5: C 59.72, H 6.73, N 8.71, found: C 59.76, H 6.67,
N 8.65.
4.5.26. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-oxy)-2,5-
dihydrofuran-3-ylamino)propanoate (6bbb). Yellow oil, yield 77%.
4.5.30. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 6-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-2,5-
dihydrofuran-3-ylamino)hexanoate (6bfb). Yellow oil, yield 77%.
½
a D
ꢃ
20 129.3 (c 0.048, CH3CH2OH); UVevis (CH2Cl2) lmax: 270 nm; 1H
½
a 2D0
ꢃ
25.3 (c 0.051, CH3CH2OH); UVevis (CH2Cl2) lmax: 273 nm; 1
H
NMR (400 MHz, CDCl3)
d, ppm: 0.67e1.03 (m, 12H), 1.09e1.45 (m,
NMR (400 MHz, CDCl3) d, ppm: 0.68e0.99 (m, 12H), 1.03e1.51 (m,
10H), 1.53 (d, J¼8.0 Hz, 3H), 1.62e1.73 (m, 2H), 1.78e1.93 (m, 2H),
2.18e2.29 (m, 1H), 3.97 (d, J¼12.0 Hz, 1H), 4.37 (t, J¼8.0 Hz, 2H),
4.75 (b,1H), 5.34 (s, 2H), 5.43e5.58 (m,1H), 5.75 (s,1H), 7.66 (s,1H);
12H), 1.52e1.81 (m, 6H), 1.84e1.94 (m, 2H), 2.17e2.29 (m, 1H), 2.35
(t, J¼8.0 Hz, 2H), 3.35e3.61 (m, 2H), 4.00 (d, J¼8.0 Hz, 1H), 4.37 (t,
J¼8.0 Hz, 2H), 5.20 (s, 2H), 5.81 (s, 1H), 5.97 (b, 1H), 7.72 (s, 1H); 13C
13C NMR (100 MHz, CDCl3)
d
, ppm: 13.83, 13.91, 18.74, 19.57, 20.14,
NMR (100 MHz, CDCl3) d, ppm: 13.80, 13.86, 18.69, 19.51, 22.27,
22.36, 26.05, 26.48, 27.91, 30.16, 31.04, 37.06, 44.79, 47.57, 49.41,
50.46, 51.11, 58.93, 77.32, 87.62, 99.28, 123.82, 141.57, 157.62, 167.36,
24.20, 25.75, 25.95, 26.46, 27.90, 30.09, 30.97, 33.67, 36.93, 43.94,
44.72, 47.40, 49.29, 50.28, 57.39, 77.55, 87.09, 99.07, 123.68, 142.38,

2842
Y.-H. Tan et al. / Tetrahedron 68 (2012) 2827e2843
Pharm. Pharm. Sci. 2011, 3, 225e228; (k) Mo, Y.-Q.;Wang, Z.-Y.;Mei, W.-J.;Fu,J.-H.;
160.53, 167.98, 173.06; IR (film) n
, cmꢁ1: 3319, 3087, 2951, 2929,
2868, 1742, 1646, 1536, 1457, 1320, 1155, 1130, 952, 672; ESI-MS m/z
(%): 611 ([MþH]þ, 100), 633 ([MþNa]þ, 77); Anal. Calcd for
C29H45BrN4O5: C 57.14, H 7.44, N 9.19, found: C 57.26, H 7.50, N 9.13.
Tan, Y.-H.; Luo, S.-H. Monatsh. Chem. 2012, 143, 443e453.
2. (a) Paquette, L. A.; Wang, T.-Z.; Sivik, M. R. J. Am. Chem. Soc. 1994, 116,
2665e2666; (b) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 1999, 121, 3543e3544;
(c) Martin, S. F.; Barr, K. J.; Smith, D. W.; Bur, S. K. J. Am. Chem. Soc. 1999, 121,
6990e6997; (d) Bernardelli, P.; Moradei, O. M.; Friedrich, D.; Yang, J.; Gallou, F.;
Dyck, B. P.; Doskotch, R. W.; Lange, T.; Paquette, L. A. J. Am. Chem. Soc. 2001, 123,
9021e9032; (e) Trost, B. M.; Crawley, M. L. J. Am. Chem. Soc. 2002, 124,
9328e9329; (f) Alibes, R.; De March, P.; Figueredo, M.; Font, J.; Racamonde, M.;
Parella, T. Org. Lett. 2004, 6, 1449e1452; (g) Huang, Q.-H.; Rawal, V. H. Org. Lett.
2006, 8, 543e545; (h) Doroh, B.; Sulikowski, G. A. Org. Lett. 2006, 8, 903e906;
4.5.31. (1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 4-((S)-4-bromo-5-oxo-
2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yloxy)-2,5-
dihydrofuran-3-ylamino)butanoate (6bgb). Yellow oil, yield 70%.
½
a 2D0
ꢃ
65.7 (c 0.113, CH3CH2OH); UVevis (CH2Cl2) lmax: 272 nm; 1H
ꢀ
ꢀ
ꢀ
(i) Perez, M.; Perez, D. I.; Martínez, A.; Castro, A.; Gomez, G.; Fall, Y. Chem.
Commun. 2009, 3252e3254; (j) Huang, H.-C.; Yu, F.; Jin, Z.-C.; Li, W.-J.; Wu, W.-
B.; Liang, X.-M.; Ye, J.-X. Chem. Commun. 2010, 5957e5959; (k) Gassama, A.;
Ernenwein, C.; Hoffmann, N. Green Chem. 2010, 12, 859e865; (l) Ube, H.; Shi-
mada, N.; Terada, M. Angew. Chem., Int. Ed. 2010, 49, 1858e1861; (m) Hickmann,
V.; Kondoh, A.; Gabor, B.; Alcarazo, M.; Furstner, A. J. Am. Chem. Soc. 2011, 133,
13471e13480; (n) Flores, R.; Rustullet, A.; Alibes, R.; Alvarez-Larena, A.; de
March, P.; Figueredo, M.; Font, J. J. Org. Chem. 2011, 76, 5369e5383; (o) Da-
lencon, S.; Youcef, R. A.; Pipelier, M.; Maisonneuve, V.; Dubreuil, D.; Huet, F.;
Legoupy, S. J. Org. Chem. 2011, 76, 8059e8063; (p) Benz, A.; Cardona, F.; Goti, A.
Synlett 2011, 231e234; (q) Wang, X.-J.; Xu, H.-W.; Guo, L.-L.; Zhang, E.; Chen, G.-
W.; Guo, X.; Liu, H.-M. Heterocycles 2011, 83, 1005e1012; (r) Saitman, A.; Rul-
liere, P.; Sullivan, S. D. E.; Theodorakis, E. A. Org. Lett. 2011, 13, 5854e5857.
3. (a) Park, K. H.; Kim, S. Y.; Chung, Y. K. Org. Biomol. Chem. 2005, 3, 395e398; (b)
Zhang, J.; Das Sarma, K.; Curran, T. T.; Belmont, D. T.; Davidson, J. G. J. Org. Chem.
2005, 70, 5890e5895; (c) Roginskaya, M.; Razskazovskiy, Y.; Bernhard, W. A.
Angew. Chem., Int. Ed. 2005, 44, 6210e6213; (d) Paddon-Row, M. N.; Kwan, L. C.
H.; Willis, A. C.; Sherburn, M. S. Angew. Chem., Int. Ed. 2008, 47, 7013e7017; (e)
Gendrineau, T.; Chuzel, O.; Eijsberg, H.; Genet, J.-P.; Darses, S. Angew. Chem., Int.
Ed. 2008, 47, 7669e7672; (f) Feng, C.-G.; Wang, Z.-Q.; Tian, P.; Xu, M.-H.; Lin, G.-
Q. Chem.dAsian J. 2008, 3, 1511e1516; (g) Du, Y.; Xu, L.-W.; Shimizu, Y.; Oisaki,
K.; Kanai, M.; Shibasaki, M. J. Am. Chem. Soc. 2008, 130, 16146e16147; (h) Trost,
B. M.; Hitce, J. J. Am. Chem. Soc. 2009, 131, 4572e4573; (i) Luo, Y.; Carnell, A. J.
Angew. Chem., Int. Ed. 2010, 49, 2750e2754; (j) Luo, J.; Wang, H.-F.; Han, X.; Xu,
L.-W.; Kwiatkowski, J.; Huang, K.-W.; Lu, Y.-X. Angew. Chem., Int. Ed. 2011, 50,
1861e1864; (k) Berhal, F.; Esseiva, O.; Martin, C.-H.; Tone, H.; Genet, J.-P.; Ayad,
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L.; Ji, J.; Xie, M.-S.; Liu, X.-H.; Feng, X.-M. Org. Lett. 2011, 13, 3056e3059; (m)
Berhal, F.; Wu, Z.; Genet, J.-P.; Ayad, T.; Ratovelomanana-Vidal, V. J. Org. Chem.
2011, 76, 6320e6326; (n) Jahjah, R.; Gassama, A.; Dumur, F.; Marinkovic, S.;
Richert, S.; Landgraf, S.; Lebrun, A.; Cadiou, C.; Selles, P.; Hoffmann, N. J. Org.
Chem. 2011, 76, 7104e7118; (o) Yu, J.-P.; Miao, Z.-W.; Chen, R.-Y. Org. Biomol.
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ueredo, M. Eur. J. Org. Chem. 2011, 3888e3895; (q) Yang, J.-J.; Huang, H.-C.; Jin,
Z.-C.; Wu, W.-B.; Ye, J.-X. Synthesis 2011, 1984e1987; (r) Gondela, E.; Walczak,
K. Z. Molecules 2011, 16, 1011e1020; (s) Li, J.-X.; Liang, H.-R.; Wang, Z.-Y.; Fu, J.-H.
Monatsh. Chem. 2011, 142, 507e513; (t) Tan, Y.-H.; Wang, Z.-Y.; Hao, Z.-F.; Li, J.-X.
Chin. J. Org. Chem. 2011, 31, 1222e1229; (u) Tan, Y.-H. ; Wang, Z.-Y. ; Qi, J.; Xiong,
J.-F. ; Lv, M.-X. Res. Chem. Intermed. 2012, 38, 925e936.
NMR (400 MHz, CDCl3)
d
, ppm: 0.76e0.96 (m, 12H), 1.12e1.43 (m,
10H), 1.61e1.76 (m, 2H), 1.86e1.94 (m, 2H), 1.95e2.05 (m, 2H),
2.20e2.30 (m, 1H), 2.43e2.53 (m, 2H), 3.45e3.64 (m, 2H), 4.00 (d,
J¼8.0 Hz,1H), 4.36 (t, J¼8.0 Hz, 2H), 5.22 (s, 2H), 5.79 (s,1H), 5.96 (b,
1H), 7.68 (s, 1H); 13C NMR (100 MHz, CDCl3)
d, ppm: 13.87, 13.90,
18.73, 19.55, 22.31, 25.31, 26.02, 26.50, 27.93, 30.13, 31.01, 36.94,
43.24, 44.76, 47.46, 49.34, 50.37, 57.78, 77.45, 87.30, 99.13, 123.62,
142.20, 160.20, 168.02, 172.81; IR (film) n
, cmꢁ1: 3319, 3095, 2951,
2929, 2868, 1742, 1649, 1526, 1460, 1322, 1166, 1130, 952, 675; ESI-
MS m/z (%): 583 ([MþH]þ, 72), 605 ([MþNa]þ, 100); Anal. Calcd for
C27H41BrN4O5: C 55.76, H 7.11, N 9.63, found: C 55.81, H 7.17, N 9.56.
4.5.32. (S)-(1-Hexyl-1H-1,2,3-triazol-4-yl)methyl 2-((S)-4-bromo-5-
oxo-2-((1S,2R,4S)-1,7,7-trimethylbicyclo[2.2.1]heptan-2-yl-oxy)-2,5-
dihydrofuran-3-ylamino)-2-phenylacetate (6bhb). Yellow oil, yield
34%. ½a 2D0
ꢃ
174.6 (c 0.015, CH3CH2OH); UVevis (CH2Cl2) lmax
:
271 nm; 1H NMR (400 MHz, CDCl3)
d
, ppm: 0.77e0.98 (m, 12H),
1.20e1.34 (m, 10H), 1.63e1.71 (m, 2H), 1.82e1.91 (m, 2H), 2.14e2.32
(m, 1H), 3.85e4.01 (m, 1H), 4.21e4.37 (m, 2H), 5.26e5.42 (m, 2H),
5.55e5.87 (m, 2H), 6.07 (b, 1H), 7.27e7.49 (m, 6H); 13C NMR
(100 MHz, CDCl3) d, ppm: 13.95, 14.29, 18.76, 19.60, 22.39, 26.05,
26.63, 27.96, 30.15, 31.07, 36.81, 44.82, 47.52, 49.49, 50.43, 58.50,
59.56, 77.21, 87.88, 99.58, 123.45, 126.51, 129.22, 129.32, 135.54,
141.47, 160.84, 167.10, 170.04; IR (film) n
, cmꢁ1: 3357, 3058, 3034,
2951, 2923, 2852, 1753, 1652, 1515, 1454, 1320, 1166, 1130, 955, 744,
694, 557; ESI-MS m/z (%): 629 ([MþH]þ, 36), 651 ([MþNa]þ, 100);
Anal. Calcd for C31H41BrN4O5: C 59.14, H 6.56, N 8.90, found: C
59.24, H 6.55, N 9.02.
Acknowledgements
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We thank the National Natural Foundation of China (No.
20772035), the Third Talents Special Funds of Guangdong Higher
Education (No. Guangdong-Finance-Education[2011]431) and
Guangdong Natural Science Foundation (No. S2011010001556) for
financial support.
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Supplementary data
Experimental procedures, spectroscopic data for all new com-
pounds 6aaae6bhb, and copies of 1H NMR and 13C NMR spectra for
6aaae6bhb are provided and can be found in the online version.
Supplementary data related to this article can be found online at
doi:10.1016/j.tet.2012.01.092.
References and notes
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