Merging Asymmetric Henry Reaction with Organocatalytic Cascade Reaction for the Construction of a Chiral Indolizidine Alkaloid Skeleton

Article abstract of DOI:10.1021/jo502379v

A sequential reaction combining the copper-catalyzed asymmetric Henry reaction with the organocatalytic Michael addition-hemiacetalization cascade reaction was developed. The C₁-symmetric chiral diamine L1-copper complex was responsible for the first highly enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective organocatalyst for the second cascade reaction between chiral β-nitro alcohol and α,β-unsaturated aldehydes. Via rational design and combination of the two independent catalytic systems, good yields and excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis strategy for chiral indolizidine alkaloid and its analogues.

Full text of DOI:10.1021/jo502379v

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Article
Merging Asymmetric Henry Reaction with Organocatalytic Cascade
Reaction for the Construction of Chiral Indolizidine Alkaloid Skeleton
Yirong Zhou, Qin Yang, Jian Shen, Xin Chen, Yiyuan Peng, and Yuefa Gong
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/jo502379v • Publication Date (Web): 06 Jan 2015
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Merging Asymmetric Henry Reaction with Organocatalytic Cascade
Reaction for the Construction of Chiral Indolizidine Alkaloid
Skeleton
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Yirong Zhou,*,† Qin Yang,† Jian Shen,† Xin Chen,† Yiyuan Peng,*,† and Yuefa Gong‡
† Key Laboratory of Small Fuctional Organic Molecule, Ministry of Education, Jiangxi Normal
University, 99 Ziyang Road, Nanchang, Jiangxi 330022, China
‡ School of Chemistry and Chemical Engineering, Huazhong University of Science and
Technology, 1037 Luoyu Road, Wuhan 430074, China
Eꢀmail: zhouyirong@jxnu.edu.cn; yypeng@jxnu.edu.cn
Abstract
Cat II system
Michael cascade reaction
A
N
HN
L1
H
OH
O
Ph
O
Ph
Ph
O
H
N
H
OH
NO2
N
O
NO2
CHO
or
MeO2C
MeO2C
HO
Ph
CO2Me
L1/CuCl2
Ph
Two useful chiral core structures
Cat I system
Henry reaction
N
OTMS
H
A
A
sequential reaction combining copperꢀcatalyzed asymmetric Henry reaction with
organocatalytic Michael additionꢀhemiacetalization cascade reaction was developed. The
C1ꢀsymmetric chiral diamine L1ꢀcopper complex was responsible for the first highly
enantioselective Henry reaction, while diphenylprolinol silyl ether A acted as effective
organocatalyst for the second cascade reaction between chiral βꢀnitroalcohol and α,βꢀunsaturated
aldehydes. Via rational design and combination of the two independent catalytic systems, good
yields, excellent enantioselectivities and diastereoselectivities were achieved for a broad substrate
scope under mild reaction conditions. The synthetic utility of this sequential catalytic asymmetric
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cascade reaction was demonstrated as an alternative and straightforward stereoselective synthesis
strategy for chiral indolizidine alkaloid and its analogues.
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Introduction
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Indolizidine alkaloids can be found in a large family of important naturally occurring molecules
which have wide biological, pharmacological and medicinal applications.1ꢀ4 The core structure of
this bicyclic system is symbolized as fused fiveꢀ and sixꢀnumbered rings bearing a bridgehead
tertiary amine nitrogen atom.1ꢀ4 For instance, coniceine,5 containing the simplest unsubstituted
skeleton, was obtained from the hemlock alkaloid coniine. An important class is plantꢀderived
polyhydroxylated indolizidines, such as swainsonine6,7 and lentiginosinee,8,9 which served as
selective glycosidase inhibitors exhibiting diverse biological activities. 5ꢀIndolizidione10ꢀ12 had
been used as a valuable intermediate for the assembly of many kinds of different indolizidine
alkaloids. Esculeoside B13 as a novel steroidal alkaloid glycoside was isolated from the red
colorꢀtype tomato which was further identified having antiꢀcancer activity. As a consequence,
tremendous effort has been devoted to the development of various synthetic methods for this kind
of privileged fragment.14ꢀ17 Although great success has been achieved for the construction of these
useful alkaloids, there are some limitations for most of the established strategies. For example, the
starting materials were tedious and restricted to natural amino acids,18ꢀ27 sugars28ꢀ33 or other chiral
synthon,34ꢀ44 and chiral auxiliaries were usually required for chiral induction.45ꢀ48 In particular, the
reported examples always suffered from long synthesis routes with low efficiency and
atomꢀeconomy. Very recently, Shenvi and coꢀworkers illustrated an impressive chemoselective
hydroamination of simple unsaturated amines to prepare indolizidines with excellent
diastereocontrol.49ꢀ50 However, there were only few examples involved catalytic enantioselective
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approaches.51ꢀ59 Thus, asymmetric catalytic stepꢀeconomical access to indolizidine alkaloids
bearing multiple chiral centers is highly desirable.
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OH
OH
HO
HO
H
N
H
H
N
H
N
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HO
HO
N
(ꢀ)ꢀconiceine
(ꢀ)ꢀlentiginosine
(ꢀ)ꢀperhydroꢀ8ꢀindolizinol
(ꢀ)ꢀswainsonine
HN
O
H
R
OH
H
OGlc
OH
N
O
LycO
5ꢀindolizidinone, R=H or Me
Esculeoside B
H
Figure 1. Selected examples of indolizidine alkaloids.
For the last decade, asymmetric organocatalytic cascade reaction has emerged as one of the
most promising approaches for natural products total syntheses.60ꢀ68 Nitro compounds bearing
another reactive moiety such as hydroxyl, amine or carbonyl, have been wellꢀcoupled in the
tandem cyclization with various enals, which were always initiated by nucleophlic Michael
addition.69ꢀ81 Recently, Hayashi and our group have independently demonstrated that
nitroethanol,79 racemic βꢀsubstituted βꢀnitroethanols80 as well as 1ꢀnitromethylcycloalkanol81 can
serve as suitable partners for the organocatalytic asymmetric Michael additionꢀhemiacetalization
cascade reaction of α,βꢀunsaturated aldehydes, providing polysubstituted chiral tetrahydropyrans
which can be further transformed into vast and assorted useful core architectures by various
derivations. Although excellent enantioselectivities were achieved, diastereoselectivities were
rather moderate. Considering asymmetric Henry reactions can deliver chiral βꢀnitroalcohol
adducts, we envisioned that these chiral βꢀnitroalcohols could act as potential starting material for
the above cascade reaction. With the assistance of the adjacent chiral centre of βꢀnitroalcohol, the
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diastereoselectivity may be improved. Recently, we have developed a series of C1ꢀsymmetric
chiral diamine ligands and found successful application in highly enantioselective
copperꢀcatalyzed Henry reactions82ꢀ86 and organocatalytic Michael additions.87ꢀ88 According to
retrosynthetic analysis illustrated in Scheme 1, we realized a possible construction of chiral fused
bicyclic indolizidine alkaloid via sequential asymmetric Henry reaction and Michael
additionꢀhemiacetalization cascade process.
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Scheme 1. Retrosynthetic Analysis for Indolizidine Alkaloid and its Homologues
OH
Ph
O
Ph
H
N
Ph
Reduction
aminolysis
H
N
NO2
O
or
HO
CO2Me
O
6a
O
TM 8 and 9
Organocatalytic
cascade reaction
Copper catalyzed
Henry reaction
OH
CHO
NO2
MeO2C
MeO2C
1q
Results and Discussion
Toward this end, Sꢀ2ꢀnitroꢀ1ꢀphenylethanol 1a82 was chosen as the model substrate to react with
cinnamaldehyde 2a. For ease of NMR and chiral HPLC analysis, the hemiacetal product 3a was
directly converted into 4a by subsequent dehydroxylation. To our delight, only single diastereomer
was detected for the 1H NMR analysis of the rural product of 4 when diphenylprolinol silyl ether
A was used as catalyst. To figure out the stereochemistry outcome of this sequential reaction,
NMR HSQC analysis of 4a was performed to determine the exact locations of all the three
continuous chiral hydrogen atoms. Moreover, NOE experiment of 4a showed that all the three
continuous stereocenters were in cisꢀrelationship which was in consist with our previous
observation.80,81 This assignment in the stereochemistry was further conformed by Xꢀray
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crystallographic analysis of 4h, and its absolute configuration was determined to be (2S, 3S, 4R).89
Therefore, the chirality of Sꢀβꢀnitroalcohol had remained during the tandem procedure. In addition,
the diastereoselectivity was greatly improved relative to the previous experimental results,79,80
which indicates the matching role of the adjacent chiral centre of βꢀnitroalcohol.
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A series of commonly used chiral secondary amines were then screened as small organic
catalysts using benzoic acid as the coꢀcatalyst in chloroform at room temperature. As shown in
Table 1, satisfied results were obtained by several different Dꢀdiphenylprolinol silyl ethers (AꢀC),
and the steric hindrance effects of the silyl ethers protection groups were not noticeable (entries
1ꢀ3). However, simple unprotected diphenylprolinol D provided poor diastereoselectivity albeit
with good yield and high enantioselectivity (Table 1, entry 4). Dꢀproline could also facilitate the
process but the efficiency decreased sharply. Even when the reaction time was extended to 48
hours, the transformation did not accomplish yet (Table 1, entry 5). In contrast, Dꢀprolinamide
showed no catalytic activity at all (Table 1, entry 6). In addition, 5 mol% catalyst loading was
sufficient for the transformation went to completion smoothly within 30 hours (Table 1, entry 7).
Table 1. Catalyst Screeninga
Ph
Ph
OH
NO2
Ph
NO2
Ph
CHO
3 equiv of Et3SiH/BF3—Et2O
CH2Cl2, 0 oC to rt
NO2
10 mol% cat./PhCOOH
CHCl3, rt
+
HO
O
3a
O
4a
1a
2a
O
O
Ph
Ph
OR
A: R=TMS
B: R=TES
C: R=TPS
D: R=H
N
N
H
OH
NH2
N
H
H
Dꢀprolinamide
Dꢀproline
entry
catalyst
time (h)
yield (%)b
drc
ee (%)d
99
1
2
20
24
96
90
>19:1
>19:1
A
B
99
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7f
C
30
24
48
48
30
91
>19:1
1:1
99
99
99
nde
99
82
D
Dꢀproline
Dꢀprolinamide
A
53
1:1
trace
95
nde
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>19:1
aReaction conditions for step 1: 0.2 mmol scale of 1a with 1.2 equiv of 2a, in the presence of 10 mol% catalyst and
benzoic acid as additive, in 1 mL CHCl3 at room temperature. Reaction conditions for step 2: Dissolved lactol 3a
(0.2 mmol) into 2 mL CH2Cl2, then added 3 equiv of Et3SiH and BF3·Et2O successively at 0 oC, next the reaction
mixture was warmed to rt and stirred for several hours. bYield of isolated product 3a. Yields for step 2 (4a) were in
range of 80% to 85%. cDetermined by 1H NMR spectroscopy analysis on the rural product of 4a. dThe ee value of
4a was determined by chiral HPLC analysis. eNot determined. f5 mol% catalyst A and benzoic acid were used.
Then a set of organic achiral and chiral acids as well as organic bases were tested as additives
as exploratory efforts to improve the efficiency, but none of them could afford better outcomes
than benzoic acid. The results are presented in Table 2. In the absence of acid additive, the reaction
efficiency declined sharply, while the enantioselectivity was not influenced (Table 2, entry 1).
Other substituted benzoic acids delivered similar ee values, in spite of a little slower reaction rate
(Table 2, entries 3–6). 1ꢀnaphthoic acid and acetic acid could give the comparable results (Table 2,
entries 7 and 8). Some other chiral acids including Lꢀtartaric acid and protected proline made the
process become sluggish (Table 2, entries 9–11). When much stronger camphorsulfonic acid was
used, the transformation did not occur at all (Table 2, entry 12). Then a group of organic bases
were investigated. Among them, only imidazole and 1ꢀMeꢀimidazole could promote the reaction
(Table 2, entries 13–15).
Table 2. Additive Screeninga
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Ph
Ph
OH
NO2
4
5
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7
NO2
Ph
CHO
NO2
10 mol% A/additive
3 equiv of Et3SiH/BF3—Et2O
CH2Cl2, 0 oC to rt
+
CHCl3, rt
HO
O
3a
Ph
O
4a
1a
2a
8
9
entry
1
additive
none
time (h)
35
yield (%)b
75
drc
ee (%)d
99
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9:1
2
benzoic acid
20
96
>19:1
9:1
99
3
pꢀnitrobenzoic acid
pꢀiodobenzoic acid
oꢀiodobenzoic acid
salicylic acid
30
72
99
4
24
93
9:1
99
5
24
80
9:1
99
6
35
77
9:1
99
7
1ꢀnaphthoic acid
acetic acid
24
94
>19:1
>19:1
9:1
99
8
24
91
99
9
Lꢀtartaric acid
30
65
99
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11
12
13
14
15f
CbzꢀLꢀproline
48
74
>19:1
>19:1
nde
99
CbzꢀDꢀproline
camphorsulfonic acid
imidazole
48
85
99
48
trace
81
nde
99
30
9:1
1ꢀMeꢀimidazole
Other organic bases
30
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9:1
99
48
trace
nde
nde
aReaction conditions for step 1: 0.2 mmol scale of 1a with 1.2 equiv of 2a, in the presence of 10 mol% catalyst A
and additive, in 1 mL CHCl3 at room temperature. Reaction conditions for step 2 were the same to Table 1. bYield
of isolated product 3a. Yields for step 2 (4a) were in range of 80% to 85%. cDetermined by 1H NMR spectroscopy
analysis on the rural product of 4a. dThe ee value of 4a was determined by chiral HPLC analysis. eNot determined.
fOther organic bases used here including DMAP, DABCO, TEA DIPEA, DBU and cinchonine, etc.
Solvent effect on this asymmetric cascade process was next investigated. The results are
disclosed in Table 3. Alcohols were not good choice because of the slow reaction rate (Table 3,
entries 1–3). Halogenated solvents such as chloroform, dichloromethane and 1,2ꢀdichloroethane
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(DCE) proved to be the most proper one in terms of yield, diastereoselectivity and
enantioselectivity (Table 3, entries 4–6). Acetonitrile and tetrahydrofuran (THF) just provided
inferior outcomes (Table 3, entries 7 and 8). Toluene provided a good result, but needed a rather
long reaction time (Table 3, entry 9). Aprotic polar solvent DMF owned low efficiency and gave
poor diastereoselectivity (Table 3, entry 10). It should be noticed that the reaction could not
proceed in dioxane (Table 3, entry 11).
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Table 3. Solvent Screeninga
Ph
Ph
OH
NO2
Ph
NO2
Ph
CHO
NO2
10 mol% A/PhCOOH
3 equiv of Et3SiH/BF3—Et2O
CH2Cl2, 0 oC to rt
+
solvent, rt
HO
O
3a
O
4a
1a
2a
entry
1
solvent
MeOH
EtOH
time (h)
48
yield (%)b
72
drc
ee (%)d
99
9:1
2
30
77
9:1
99
3
iPrOH
CHCl3
CH2Cl2
DCE
30
86
9:1
99
4
20
96
>19:1
>19:1
>19:1
>19:1
9:1
99
5
24
93
99
6
24
92
99
7
MeCN
THF
40
83
99
8
40
65
99
9
Toluene
DMF
35
94
>19:1
3:1
99
10
11
40
60
99
Dioxane
48
trace
nde
nde
aReaction conditions for step 1: 0.2 mmol scale of 1a with 1.2 equiv of 2a, in the presence of 10 mol% catalyst A
and benzoic acid, in 1 mL solvent at room temperature. bYield of isolated product 3a. Reaction conditions for step
c
1
d
2 were the same to Table 1. Determined by H NMR spectroscopy analysis on the rural product of 4a. The ee
value of 4a was determined by chiral HPLC analysis. eNot determined.
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On the basis of the above systematical optimization of reaction parameters, the substrate
scope of enals was subsequently investigated under the established conditions. The results are
listed in Table 4. Generally, a variety of α,βꢀunsaturated aldehydes could work well with 1a to
give the corresponding products in good yields with excellent enantioselectivities and
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1
diastereoselectivities. In most cases, the H NMR analysis of the rural product of 4 showed that
only single diastereomer was detected. Chiral HPLC analysis indicated that most of the expected
products 4 were obtained in greater than 99% ee. On one hand, the position of substituents owned
some effect on the outcomes of the catalytic transformation. Especially, orthoꢀsubstituted enals
always gave lower yields compared with other analogues (Table 4, entries 2, 5 and 7). However,
no matter whether orthoꢀ, metaꢀ or paraꢀpositions had been taken or not, all the variants could be
tolerated well and the enantioselectivities and diastereoselectivities were not affected (Table 4,
entries 2ꢀ9). On the other hand, the electronic nature of the substituents also did not influence the
course of the asymmetric catalytic process. For instance, 4k bearing electronꢀdonating methoxyl
group worked the same well as the wide range of electronꢀwithdrawing halogen groups (Table 4,
entry 11). Interestingly, heterocyclic substrate containing furan ring delivered excellent ee value
albeit with moderate yield (Table 4, entry 12).
Table 4. Substrate Scope of the Enalsa
R
NO2
Ph
OH
1). 5 mol% A/PhCOOH, CHCl3, rt
CHO
NO2
+
R
Ph
2). 3 equiv of Et3SiH/BF3—Et2O,
CH2Cl2, 0 oC to rt
O
2
1a
4
single diastereomer
entry
R (Product 4)
Ph (4a)
yield 1 (%)b
yield 2 (%)c
ee (%)d
99
1
2
95
76
83
82
2ꢀMePh (4b)
99
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3ꢀMePh (4c)
4ꢀMePh (4d)
2ꢀClPh (4e)
4ꢀClPh (4f)
2ꢀBrPh (4g)
3ꢀBrPh (4h)
4ꢀBrPh (4i)
4ꢀFPh (4j)
88
91
80
89
81
88
87
93
91
89
95
91
82
86
89
88
99
99
99
99
98
99
99
99
99
99
4
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8
9
10
11
12
4ꢀMeOPh (4k)
2ꢀfuryl (4l)
96
78
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aReactions conditions for step 1: 0.3 mmol of 1a and 0.36 mmol (1.2 equiv) of 2 were added to a mixture of 5
mol% catalyst A and benzoic acid in 2 mL CHCl3 at room temperature for 30 to 48 hours. Reactions conditions for
step 2: Dissolved lactol 3 (0.2 mmol) into 2 mL CH2Cl2, then added 3 equiv of Et3SiH and BF3·Et2O successively
o
b
c
at 0 C, next the reaction mixture was warmed to rt and stirred for several hours. Yield for step 1 (3). Yield for
step 2 (4). dThe ee value of 4 was determined by chiral HPLC analysis.
Having achieved the above results, we turned our attention to the reactivity and generality
of diverse chiral βꢀnitroalcohols. The data listed in Table 5 showed that this catalytic cascade
reaction was a useful and practical protocol for a wide rang of nitroalcohols, all of the tested
substrates could react well with cinnamaldehyde 2a to provide single diastereomer of desired
product 5. In general, either the substituent locations or their electronic properties exerted any
evident influence on the cascade process. For all the substrates employed, extremely high
enantioselectivities and diastereoselectivities were afforded while the yields verified at a slightly
different levels. It was noteworthy that chiral nitroalcohol 1m derived from pꢀtrifluoromethyl
benzaldehyde was suitable for this system and gave excellent results (Table 5, entry 13). The
trifluoromethyl group was a useful moiety and had been found in a variety of drug and pesticide
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molecules. Moreover, heterocyclic nitroalcohol 1n could also work well and delivered the desired
product with moderate yield and high ee value (Table 5, entry 14). Furthermore, cinnamaldehyde
derivative 1o can be tolerated and the double carbonꢀcarbon bonds did not influence the process
(Table 5, entry 15). Additionally, aliphatic substrate 1p was examined and comparable good result
was obtained (Table 5, entry 16).
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Table 5. Substrate Scope of the Chiral βꢀNitroalcoholsa
Ph
OH
NO2
R
1). 5 mol% A/PhCOOH, CHCl3, rt
CHO
+
NO2
Ph
R
2). 3 equiv of Et3SiH/BF3—Et2O,
CH2Cl2, 0 oC to rt
O
1
2a
5
single diastereomer
entry
1
R (Product 5)
2ꢀMePh (5a)
3ꢀMePh (5b)
4ꢀMePh (5c)
2ꢀCl Ph (5d)
3ꢀClPh (5e)
4ꢀClPh (5f)
2ꢀBrPh (5g)
3ꢀBrPh (5h)
4ꢀBrPh (5i)
4ꢀFPh (5j)
yield 1 (%)b
yield 2 (%)c
ee (%)d
99
91
84
88
90
94
89
90
87
91
88
94
96
91
93
91
84
93
91
90
93
2
99
3
99
4
97
5
99
6
99
7
98
8
99
9
99
10
11
12
13
14
15
16
99
3ꢀNO2Ph (5k)
4ꢀNO2Ph (5l)
4ꢀCF3Ph (5m)
93
87
85
81
99
98
95
73
85
89
85
81
79
92
99
2ꢀthiophenyl (5n)
PhCHCH (5o)
99
99
PhCH2CH2 (5P)
99
c
aIdentical reaction conditions (see footnote a in Table 4). bYield for step 1 (3). Yield for step 2 (5). dThe ee value
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of 5 was determined by chiral HPLC analysis.
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9
After finishing the exploration of generality and limitation of the substrate scope, we kept on
going to probe the synthetic utility of this sequential catalytic asymmetric cascade reaction. A
successful application to prepare valuable chiral indolizidine alkaloid skeleton 9 was depicted in
Scheme 2. In the presence of chiral L1/copper complex I, 4ꢀoxobutyric acid methyl ester accessed
easily from commercially available 1,4ꢀbutyrolactone, reacted well with nitromethane to afford
optically pure βꢀnitroalcohol 1q with 98% ee. Then, diphenylprolinol silyl ether A could
efficiently promote the Michael addition of 1q to cinnamaldehyde 2a and
(E)ꢀ3ꢀpꢀtolylacrylaldehyde 2d, providing fiveꢀdisubstituted tetrahydropyran lactol 6a and 6b.
Treatment of 6a and 6b with 10 equivalent of zinc powder in glacial acetic acid at ambient
temperature provided 9a and 9b, which means that the reduction of nitro group and successive
intramolecular reductive amination and aminolysis would occur. Firstly, the nitro group can be
readily reduced to amino motif. Subsequently, the resulting free primary amine would attack
hemiacetal to form imine, which was immediately reduced to secondary amine in situ. Following
intramolecular aminolysis completed the construction of chiral indolizidine alkaloid framework 9
stereoselectively. On the other hand, lactol 6a can firstly be dehydroxylated by treatment with 3
equivalent of BF3·Et2O and Et3SiH in dichlormethane (DCM) to afford 7. Then, though the same
manipulation for 9, the target fused bicyclic lactam 8 was yielded via the reduction of nitro group
and followed by the intramolecular aminolysis reaction. This practical useful and simple operation,
avoiding costly protecting groups and timeꢀconsuming purification procedures for the
intermediates, delivered the final expected core structures in high yields without any evident
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erosion in enantiomeric purities.
Scheme 2. Synthesis of Indolizidine Alkaloid and Its Relative Heterocycles
7
8
9
N
HN
L1
OH
H
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2a or 2d
NO2
CHO
+ MeNO2
MeO2C
MeO2C
5 mol% cat. A
2.5 mol% L1/CuCl2
1q, 90% yield, 98% ee
R
OH
R
H
N
NO2
10 eq Zn, HOAc
9a, R = Ph, 91% yield, 96% ee
9b, R = 4ꢀMePh, 83% yield, 99% ee
HO
O
CO2Me
6a, R = Ph, 91% yield
6b, R = 4ꢀMePh, 86% yield
O
R
R
R
H
H
OH
OH
NH2
N
N
H
MeO2C
MeO2C
HO
O
CO2Me
Ph
O
Ph
O
Ph
O
H
NO2
N
O
NO2
3 eq Et3SiH/BF3—Et2O
88% yield,
CO2Me
10 eq Zn, HOAc
95% yield,
HO
CO2Me
98% ee
98% ee
8
7
6a
Conclusion
In conclusion, this work provided an alternative and straightforward stereoselective synthesis
of chiral indolizidine alkaloid and its analogues by combining copperꢀcatalyzed asymmetric Henry
reaction and organocatalytic Michael additionꢀhemiacetalization cascade reaction together for the
first time. By using low to 2.5 mol% C1ꢀsymmetric chiral diamineꢀcopper complex, the first step
enantioselective direct Henry reaction was rendered to provide optical pure βꢀnitroalcohols in high
yields. Diphenylprolinol silyl ether as an effective chiral secondary amine organocatalyst can
promote the second Michael addition cascade reaction between chiral βꢀnitroalcohols and
α,βꢀunsaturated aldehydes. Though rational design and combination of the above two independent
catalytic systems, satisfying results including good yields, excellent enantioselectivities and
diastereoselectivities as well as high functional group compatibility, atomꢀeconomy and
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stepꢀeconomy were achieved under mild reaction conditions without any special precautions to
exclude air or moisture. Further investigations focusing on the applications of this developed
methodology are currently in progress in our laboratory.
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Experimental Section
General Experimental Methods. THF was dried over Na and distilled prior to use. Nitromethane
was dried over anhydrous CaCl2 and distilled prior to use. All the chiral catalysts L1, and AꢀD
were prepared according to our previous work or literature. All the chiral βꢀnitroalcohols were
prepared though asymmetric Henry reaction according to our previous work. Reactions were
monitored by TLC analysis using Silica Gel 60 Å Fꢀ254 thin layer plates. Flash column
chromatography was performed on silica gel 60 Å, 10ꢀ40 ꢁm. Optical rotations were measured by
1
polarimeter in the solvent indicated. H NMR spectra were recorded on instruments (400 MHz).
Chemical shifts are reported in ppm from tetramethylsilane with the solvent resonance as the
internal standard (CDCl3, d=7.26). Data are reported as follows: chemical shift, multiplicity (s =
singlet, d = doublet, t = triplet, q = quartet, m = multiplet, br = broad), coupling constants (Hz) and
integration. 13C NMR spectra were recorded on instruments (100 MHz) with complete proton
decoupling. Chemical shifts are reported in ppm from the tetramethylsilane with the solvent
resonance as internal standard (CDCl3, d=77.0). HRMS was measured on a Fourier transform ion
cyclotron resonance (FTICR) mass spectrometer equipped with an EI or ESI source in the
positiveꢀion mode. Enantiomer ratios were determined by chiral HPLC analysis on Chiralcel
ADꢀH, ODꢀH, IA and IDꢀ3 in comparison with the authentic racemates. Retention times are given
in minutes. The absolute configuration of 4h was determined to be (2S, 3S, 4R) by Xꢀray
crystallographic analysis. The same stereochemistry was assumed for assigning the absolute
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configuration of the rest of the compounds.
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Preparation of Racemic Products. All the racemic nitrolalcohols were obtained by the racꢀHenry
reaction which was catalyzed by 30 mol% of triethylamine with 20 equiv of nitromethane in
dichloromethane at room temperature. For the Michael addition cascade reaction, racmeic
diphenylprolinol silyl ether was used as catalyst under the same conditions starting from racemic
nitrolalcohols.
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General Procedure and Characterization of the Products. Step 1. A vial equipped with a
stirring bar was charged with chiral βꢀnitroalcohol 1 (0.3 mmol), benzoic acid (1.8 mg, 0.015
mmol, 5 mol %), and neat chloroform (2.0 mL). After addition of enal 2 (0.36 mmol, 1.2 equiv.)
and diphenylprolinol trimethylsilyl ether A (4.8 mg, 0.015 mmol, 5 mol %), the reaction mixture
o
was stirred at room temperature (about 25 C) for 30 to 48 hours. The reaction was monitored by
TLC, when it finished, the mixture was quenched by NaHCO3 aqueous, extracted by ethyl acetate,
dried over Na2SO4 anhydrous, then concentrated and purified by silica gel column
chromatography, eluting with petroleum ether and ethyl acetate to afford the corresponding
product 3.
(4R,5S,6S)ꢀtetrahydroꢀ5ꢀnitroꢀ4,6ꢀdiphenylꢀ2Hꢀpyranꢀ2ꢀol (3a). White solid (Table 1, entry 7,
57 mg, 95% yield). m.p. 164−166 oC; the ratio of major isomer to minor isomer was 9:1 according
1
to H NMR analysis; major isomer: 1H NMR (400 MHz, DMSO–d6, 25 °C, TMS): δ 7.42 – 7.25
(m, 10H), 6.77 (d, J = 3.2 Hz, 1H), 5.70 (s, 1H), 5.66 (d, J = 2.4 Hz, 1H), 5.38 (t, J = 3.4 Hz, 1H),
3.98 (dt, J = 13.6, 4.0 Hz, 1H), 2.85 (t, J = 12.2 Hz, 1H), 1.77 (dd, J = 13.2, 4.0 Hz, 1H); 13C
NMR (100 MHz, DMSO–d6, 25 °C, TMS): δ 139.4, 137.9, 129.0, 128.6, 128.3, 127.8, 127.6,
126.2, 91.1, 90.3, 68.8, 36.2, 28.4; minor isomer: 1H NMR (400 MHz, DMSO–d6, 25 °C, TMS): δ
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7.42 – 7.25 (m, 10H), 7.14 (d, J = 6.4 Hz, 1H), 5.70 (s, 1H), 5.22 (d, J = 0.8 Hz, 1H), 5.09(t, J =
6.8 Hz, 1H), 3.76 (dt, J = 13.6, 4.0 Hz, 1H), 2.60 (t, J = 11.2 Hz, 1H), 1.93 (d, J = 12.8 Hz, 1H);
HRMS (ESI): m/z calcd for C17H17NO4Na [M + Na]+: 322.1050; found: 322.1053; HPLC
(Chiralcel ADꢀH, hexane/isopropanol 70/30, 0.5 mL/min, UV λ = 210 nm): tR(major) = 22.31 min,
tR(minor) = 23.81 min.
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Step 2. A vial equipped with a stirring bar was charged with lactol 3 (0.2 mmol) in dry
dichloromethane (2.0 mL). To the mixture 3 equiv of Et3SiH and BF3·Et2O were added dropwise
o
successively at 0 C. Then the reaction was allowed to warm to room temperature naturally. The
reaction was monitored by TLC, when it finished, the mixture was quenched by NaHCO3 aqueous,
extracted by ethyl acetate, dried over Na2SO4 anhydrous, then concentrated and purified by silica
gel column chromatography, eluting with petroleum ether and ethyl acetate to afford the
corresponding product 4 or 5.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2,4ꢀdiphenylꢀ2Hꢀpyran (4a). White solid (Table 4, entry 1, 85
mg, 95% yield for step 1; 47 mg, 83% yield for step 2, 99% ee). m.p. 214−216 oC; [α]D23 = –46.94
(c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.24 (m, 10H), 5.06 (t, J =
3.4 Hz, 1H), 4.85 (d, J = 2.8 Hz, 1H), 4.55 (dd, J = 11.4, 4.4 Hz, 1H), 3.82 (td, J = 12.0, 2.4 Hz,
1H), 3.43 (dt, J = 13.2, 4.4 Hz, 1H), 3.07 (qd, J = 13.2, 4.8 Hz, 1H), 1.77 (dt, J = 13.6, 2.0 Hz,
1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.3, 136.7, 128.9, 128.6, 128.5, 127.9, 127.1,
125.4, 90.1, 79.4, 68.5, 43.8, 23.9; HRMS (ESI): m/z calcd for C17H17NO3Na [M + Na]+:
306.1101; found: 306.1108; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV
λ = 210 nm): tR(major) = 29.58 min, tR(minor) = 25.06 min.
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4a minor diastereomer. 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.31 – 7.27 (m, 6H), 7.22 –
7.18 (m, 4H), 4.71 – 4.65 (m, 2H), 4.23 – 4.20 (m, 1H), 3.81 (td, J = 12.0, 2.4 Hz, 1H), 3.56 –
3.49 (m, 1H), 2.11 (dtd, J = 17.2, 12.6, 4.8 Hz, 1H), 2.00 – 1.96 (m, 1H).
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(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ4ꢀoꢀtolylꢀ2Hꢀpyran (4b). White solid (Table 4, entry 2,
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71 mg, 76% yield for step 1; 49 mg, 82% yield for step 2, 99% ee). m.p. 167−169 C; [α]D
=
–141.36 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.38 – 7.28 (m, 5H),
7.17 – 7.16 (m, 4H), 4.97 (s, 1H), 4.86 (d, J = 2.4 Hz, 1H), 4.56 (dd, J = 11.6, 4.4 Hz, 1H), 3.86
(td, J = 12.0, 2.0 Hz, 1H), 3.64 (dt, J = 13.2, 4.0 Hz, 1H), 3.13 (qd, J = 13.2, 4.8 Hz, 1H), 2.44 (s,
3H), 1.65 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 136.6, 136.1, 135.1,
130.8, 128.6, 128.4, 127.7, 126.9, 126.4, 125.4, 88.1, 79.3, 68.8, 40.1, 24.2, 19.4; HRMS (ESI):
m/z calcd for C18H19NO3Na [M + Na]+: 320.1257; found: 320.1262; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 27.27 min, tR(minor) = 14.97
min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ4ꢀmꢀtolylꢀ2Hꢀpyran (4c). White solid (Table 4, entry 3,
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83 mg, 88% yield for step 1; 54 mg, 91% yield for step 2, 99% ee). m.p. 152−154 C; [α]D
=
–49.71 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.34 – 7.26 (m, 5H), 7.20
(t, J = 3.4 Hz, 1H), 7.05 (t, J = 9.2 Hz, 3H), 5.05 (t, J = 3.2 Hz, 1H), 4.83 (d, J = 2.4 Hz, 1H), 4.53
(dd, J = 11.4, 4.6 Hz, 1H), 3.79 (td, J = 12.2, 2.4 Hz, 1H), 3.38 (dt, J = 13.2, 4.2 Hz, 1H), 3.04 (qd,
J = 13.0, 4.8 Hz, 1H), 2.31 (s, 3H), 1.74 (d, J = 13.2 Hz, 1H) ; 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 138.4, 138.3, 136.7, 128.7, 128.6, 128.5, 128.4, 127.8, 125.3, 124.0, 90.2, 79.3, 68.4,
43.5, 23.8, 21.4; HRMS (ESI): m/z calcd for C18H19NO3Na [M + Na]+: 320.1257; found:
320.1261; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm):
t
R(major) = 26.57 min, tR(minor) = 20.30 min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ4ꢀpꢀtolylꢀ2Hꢀpyran (4d). White solid (Table 4, entry 4,
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85 mg, 91% yield for step 1; 53 mg, 89% yield for step 2, 99% ee). m.p. 195−198 C; [α]D
=
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–59.40 (c = 1.2 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.25 – 7.19 (m, 5H), 7.04
(s, 4H), 4.95 (t, J = 3.4 Hz, 1H), 4.75 (d, J = 2.4 Hz, 1H), 4.45 (dd, J = 11.2, 4.4 Hz, 1H), 3.71 (td,
J = 12.0, 2.4 Hz, 1H), 3.30 (dt, J = 13.2, 4.4 Hz, 1H), 2.95 (qd, J = 13.2, 4.8 Hz, 1H), 2.21 (s, 1H),
1.66 (dd, J = 13.6, 2.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 137.5, 136.7, 135.3,
129.6, 128.5, 128.4, 126.9, 125.3, 90.2, 79.3, 68.5, 43.3, 23.9, 21.0; HRMS (ESI): m/z calcd for
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C18H19NO3Na [M
+
Na]+: 320.1257; found: 320.1264; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 26.24 min, tR(minor) = 20.71
min.
(2S,3S,4R)ꢀ4ꢀ(2ꢀchlorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4e). White solid (Table
4, entry 5, 80 mg, 80% yield for step 1; 60 mg, 95% yield for step 2, 99% ee). m.p. 135−137 oC;
[α]D23 = –164.12 (c = 1.2 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.40 – 7.29 (m,
5H), 7.24 – 7.19 (m, 4H), 5.23 (t, J = 3.2 Hz, 1H), 4.89 (d, J = 2.4 Hz, 1H), 4.54 (dd, J = 11.2, 4.0
Hz, 1H), 3.93 (dt, J = 13.2, 4.2 Hz, 1H), 3.86 (td, J = 12.2, 2.4 Hz, 1H), 3.10 (qd, J = 13.2, 4.8 Hz,
1H), 1.65 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 136.5, 135.2, 133.5,
129.7, 129.1, 128.5, 128.4, 128.2, 127.6, 125.3, 87.3, 79.1, 68.4, 40.3, 23.6; HRMS (ESI): m/z
calcd for C17H16ClNO3Na [M + Na]+: 340.0711; found: 340.0717; HPLC (Chiralcel ODꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 29.07 min, tR(minor) = 26.96
min.
(2S,3S,4R)ꢀ4ꢀ(4ꢀchlorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4f). White solid (Table
4, entry 6, 89 mg, 89% yield for step 1; 58 mg, 91% yield for step 2, 99% ee). m.p. 248−250 oC;
[α]D23 = –56.70 (c = 0.7 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.34 – 7.26 (m,
7H), 7.20 – 7.18 (m, 2H), 5.03 (t, J = 3.2 Hz, 1H), 4.86 (d, J = 2.4 Hz, 1H), 4.56 (dd, J = 11.2, 4.0
Hz, 1H), 3.82 (td, J = 12.2, 2.4 Hz, 1H), 3.42 (dt, J = 13.2, 4.2 Hz, 1H), 3.03 (qd, J = 13.0, 4.8 Hz,
1H), 1.77 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 136.8, 136.4, 133.9,
129.2, 128.6, 128.6, 128.5, 125.3, 89.9, 79.4, 68.4, 43.2, 23.9; HRMS (ESI): m/z calcd for
C17H16ClNO3Na [M
+
Na]+: 340.0711; found: 340.0719; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 210 nm): tR(major) = 27.36 min, tR(minor) = 19.85
min.
(2S,3S,4R)ꢀ4ꢀ(2ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4g). White solid (Table
4, entry 7, 92 mg, 81% yield for step 1; 59 mg, 82% yield for step 2, 98% ee). m.p. 134−137 oC;
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[α]D23 = –162.83 (c = 1.2 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.58 (dd, J =
8.0, 0.8, 1H), 7.37 – 7.21 (m, 7H), 7.16 – 7.11 (m, 1H), 5.25 (t, J = 3.2 Hz, 1H), 4.89 (d, J = 2.8
Hz, 1H), 4.55 (dd, J = 12.0, 3.6 Hz, 1H), 3.93 – 3.83 (m, 2H), 3.10 (qd, J = 13.2, 4.8 Hz, 1H), 1.67
(d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 136.7, 136.5, 133.1, 129.5,
128.9, 128.5, 128.4, 128.3, 128.2, 125.9, 125.3, 124.4, 87.4, 79.2, 68.4, 42.9, 23.8; HRMS (ESI):
m/z calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found: 384.0209; HPLC (Chiralcel ODꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 29.91 min, tR(minor) = 26.49
min.
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(2S,3S,4R)ꢀ4ꢀ(3ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4h). White solid (Table
4, entry 8, 100 mg, 88% yield for step 1; 62 mg, 86% yield for step 2, 99% ee). m.p. 172−174 oC;
[α]D23 = –61.39 (c = 1.0 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.40 – 7.28 (m,
7H), 7.21 – 7.18 (m, 2H), 5.04 (t, J = 3.4 Hz, 1H), 4.84 (d, J = 2.4 Hz, 1H), 4.54 (dd, J = 11.8, 4.6
Hz, 1H), 3.80 (td, J = 12.0, 2.2 Hz, 1H), 3.39 (dt, J = 13.2, 4.2 Hz, 1H), 3.03 (qd, J = 13.0, 4.8 Hz,
1H), 1.76 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 140.6, 136.4, 131.0,
130. 5, 128.6, 128.5, 125.9, 125.6, 125.3, 122.9, 89.7, 79.3, 68.2, 43.2, 23.7; HRMS (ESI): m/z
calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found: 384.0208; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 210 nm): tR(major) = 22.64 min, tR(minor) = 19.72
min.
(2S,3S,4R)ꢀ4ꢀ(4ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4i). White solid (Table
4, entry 9, 98 mg, 87% yield for step 1; 64 mg, 89% yield for step 2, 99% ee). m.p. 230−232 oC;
[α]D23 = –49.66 (c = 0.8 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.46 (d, J = 8.4
Hz, 2H), 7.34 – 7.31 (m, 5H), 7.14 (d, J = 8.4 Hz, 2H), 5.03 (t, J = 3.4 Hz, 1H), 4.86 (d, J = 2.8 Hz,
1H), 4.56 (dd, J = 11.6, 4.0 Hz, 1H), 3.82 (td, J = 12.0, 2.0 Hz, 1H), 3.40 (dt, J = 13.2, 4.0 Hz, 1H),
3.03 (qd, J = 13.2, 4.8 Hz, 1H), 1.77 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 137.3, 136.4, 132.1, 128.8, 128.6, 128.6, 125.3, 122.0, 89.8, 79.4, 68.3, 43.2, 23.8;
HRMS (ESI): m/z calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found: 384.0214; HPLC
(Chiralcel ADꢀH, hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 210 nm): tR(major) = 28.92 min,
tR(minor) = 21.38 min.
(2S,3S,4R)ꢀ4ꢀ(4ꢀfluorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4j). White solid (Table
4, entry 10, 88 mg, 93% yield for step 1; 53 mg, 88% yield for step 2, 99% ee). m.p. 238−240 oC;
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[α]D23 = –54.58 (c = 1.0 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.29 (m,
5H), 7.23 (dd, J = 8.6, 5.4 Hz, 1H), 7.02 (t, J = 8.6 Hz, 1H), 5.02 (t, J = 3.4 Hz, 1H), 4.86 (d, J =
2.8 Hz, 1H), 4.56 (dd, J = 11.8, 3.8 Hz, 1H), 3.82 (td, J = 12.0, 2.4 Hz, 1H), 3.42 (dt, J = 13.2, 4.4
Hz, 1H), 3.03 (qd, J = 13.2, 4.8 Hz, 1H), 1.77 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ 136.5, 134.1, 134.1, 128.8, 128.7, 128.6, 128.5, 125.3, 116.0, 115.8, 90.1, 79.4,
68.4, 43.1, 24.1; HRMS (ESI): m/z calcd for C17H16FNO3Na [M + Na]+: 324.1006; found:
324.1016; HPLC (Chiralcel ADꢀH, hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 210 nm):
tR(major) = 24.32 min, tR(minor) = 18.27 min.
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(2S,3S,4R)ꢀtetrahydroꢀ4ꢀ(4ꢀmethoxyphenyl)ꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4k). White solid
(Table 4, entry 11, 95 mg, 96% yield for step 1; 58 mg, 93% yield for step 2, 99% ee). m.p.
o
155−158 C; [α]D23 = –39.06 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ
7.32 – 7.22 (m, 5H), 7.15 (d, J = 8.8 Hz, 2H), 6.83 (d, J = 8.4 Hz, 1H), 5.01 (t, J = 3.4 Hz, 1H),
4.81 (d, J = 2.8 Hz, 1H), 4.51 (dd, J = 11.6, 4.0 Hz, 1H), 3.81 – 3.76 (m, 1H), 3.73 (s, 3H), 3.36
(dt, J = 12.8, 4.2 Hz, 1H), 3.00 (qd, J = 13.2, 4.8 Hz, 1H), 1.72 (d, J = 13.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ 136.5, 134.1, 134.1, 128.8, 128.7, 128.6, 128.5, 125.3, 116.0,
115.8, 90.1, 79.4, 68.4, 43.1, 24.1; HRMS (ESI): m/z calcd for C18H19NO4Na [M + Na]+:
336.1206; found: 336.1215; HPLC (Chiralcel ADꢀH, hexane/isopropanol 80/20, 0.5 mL/min, UV
λ = 210 nm): tR(major) = 28.49 min, tR(minor) = 23.74 min.
(2S,3S,4S)ꢀ4ꢀ(furanꢀ2ꢀyl)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenylꢀ2Hꢀpyran (4l). White solid (Table 4,
o
entry 12, 68 mg, 78% yield for step 1; 39 mg, 71% yield for step 2, 99% ee). m.p. 133−136 C;
[α]D23 = –3.95 (c = 0.7 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.34 – 7.29 (m,
6H), 6.29 (dd, J = 3.2, 2.0 Hz, 1H), 6.15 (d, J = 3.2 Hz, 1H), 5.23 (t, J = 3.2 Hz, 1H), 4.82 (d, J =
2.4 Hz, 1H), 4.50 (dd, J = 12.2, 4.2 Hz, 1H), 3.81 (td, J = 12.6, 2.8 Hz, 1H), 3.55 (dt, J = 12.0, 4.0
Hz, 1H), 2.86 (qd, J = 13.2, 4.8 Hz, 1H), 1.89 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ 152.2, 142.2, 136.4, 128.6, 128.5, 125.3, 110.5, 106.5, 87.1, 78.8, 68.1, 37.9, 23.2;
HRMS (ESI): m/z calcd for C15H15NO4Na [M + Na]+: 296.0893; found: 296.0901; HPLC
(Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 30.64 min,
tR(minor) = 22.68 min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2ꢀoꢀtolylꢀ2Hꢀpyran (5a). White solid (Table 5, entry 1,
o
23
85 mg, 91% yield for step 1; 56 mg, 94% yield for step 2, 99% ee). m.p. 177−179 C; [α]D
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–7.20 (c = 0.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.42 – 7.39 (m, 1H), 7.31
– 7.22 (m, 5H), 7.15 – 7.11 (m, 3H), 4.99 – 4.97 (m, 2H), 4.49 (dd, J = 11.4, 4.6 Hz, 1H), 3.77 (td,
J = 12.0, 1.6 Hz, 1H), 3.36 (dt, J = 12.8, 4.0 Hz, 1H), 3.09 (qd, J = 12.8, 4.8 Hz, 1H), 2.31 (s, 3H),
1.72 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.4, 134.8, 133.1, 130.1,
128.8, 128.1, 127.7, 127.0, 126.5, 125.5, 87.9, 76.5, 68.5, 43.4, 23.9, 19.0; HRMS (ESI): m/z
calcd for C18H19NO3Na [M + Na]+: 320.1257; found: 320.1260; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 20.87 min, tR(minor) = 18.28
min.
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(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2ꢀmꢀtolylꢀ2Hꢀpyran (5b). White solid (Table 5, entry 2,
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79 mg, 84% yield for step 1; 57 mg, 96% yield for step 2, 99% ee). m.p. 130−133 C; [α]D
=
–59.84 (c = 1.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.31 – 7.05 (m, 9H), 5.03
(s, 1H), 4.78 (s, 1H), 4.50 (dd, J = 11.6, 4.8 Hz, 1H), 3.76 (t, J = 12.0 Hz, 1H), 3.38 (dt, J = 13.2,
4.0 Hz, 1H), 3.02 (qd, J = 13.2, 4.8 Hz, 1H), 2.29 (s, 3H), 1.72 (d, J = 13.2 Hz, 1H); 13C NMR
(100 MHz, CDCl3, 25 °C, TMS): δ 138.4, 138.1, 136.5, 129.1, 128.8, 128.3, 127.8, 127.0, 125.9,
122.3, 90.1, 79.2, 68.3, 43.5, 23.8, 21.3; HRMS (ESI): m/z calcd for C18H19NO3Na [M + Na]+:
320.1257; found: 320.1253; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV
λ = 210 nm): tR(major) = 26.85 min, tR(minor) = 19.67 min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2ꢀpꢀtolylꢀ2Hꢀpyran (5c). White solid (Table 5, entry 3,
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83 mg, 88% yield for step 1; 54 mg, 91% yield for step 2, 99% ee). m.p. 187−189 C; [α]D
=
–36.42 (c = 0.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.22 (m, 7H), 7.15
– 7.13 (m, 2H), 5.04 (t, J = 3.6 Hz, 1H), 4.84 (d, J = 2.4 Hz, 1H), 4.55 (dd, J = 11.4, 3.8 Hz, 1H),
3.82 (td, J = 12.0, 2.4 Hz, 1H), 3.42 (dt, J = 13.2, 4.0 Hz, 1H), 3.07 (qd, J = 13.4, 5.2 Hz, 1H),
2.31 (s, 3H), 1.78 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.4, 133.6,
129.3, 128.9, 127.9, 127.1, 125.8, 125.2, 90.2, 79.4, 68.5, 43.8, 23.9, 21.1; HRMS (ESI): m/z
calcd for C18H19NO3Na [M + Na]+: 320.1257; found: 320.1263; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 29.17 min, tR(minor) = 22.86
min.
(2S,3S,4R)ꢀ2ꢀ(2ꢀchlorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5d). White solid (Table
5, entry 4, 90 mg, 90% yield for step 1; 59 mg, 93% yield for step 2, 97% ee). m.p. 180−182 oC;
[α]D23 = 34.65 (c = 1.3 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.49 (dd, J = 7.0,
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2.2 Hz, 1H), 7.37 – 7.30 (m, 3H), 7.29 – 7.22 (m, 5H), 5.32 (t, J = 3.2 Hz, 1H), 5.19 (d, J = 2.4 Hz,
1H), 4.55 (dd, J = 11.4, 4.6 Hz, 1H), 3.87 (td, J = 12.4, 2.4 Hz, 1H), 3.45 (dt, J = 13.2, 4.2 Hz, 1H),
3.12 (qd, J = 13.0, 4.8 Hz, 1H), 1.80 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 138.3, 134.2, 130.9, 129.6, 129.0, 128.9, 127.8, 127.6, 127.4, 127.1, 87.1, 76.4, 68.6,
43.2, 23.8; HRMS (ESI): m/z calcd for C17H16ClNO3Na [M + Na]+: 340.0711; found: 340.0715;
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17.15 min, tR(minor) = 15.74 min.
=
(2S,3S,4R)ꢀ2ꢀ(3ꢀchlorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5e). White solid (Table
5, entry 5, 94 mg, 94% yield for step 1; 58 mg, 91% yield for step 2, 99% ee). m.p. 165−167 oC;
[α]D23 = –62.03 (c = 1.3 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.36 – 7.20 (m,
9H), 5.03 (t, J = 3.4 Hz, 1H), 4.77 (d, J = 2.4 Hz, 1H), 4.50 (dd, J = 11.6, 4.0 Hz, 1H), 3.75 (td, J
= 12.0, 2.2 Hz, 1H), 3.38 (dt, J = 13.2, 4.2 Hz, 1H), 3.00 (qd, J = 13.2, 4.8 Hz, 1H), 1.73 (d, J =
13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.7, 138.1, 134.4, 129.7, 128.9,
128.5, 127.9, 127.0, 125.7, 123.5, 89.8, 78.3, 68.3, 43.4, 23.6; HRMS (ESI): m/z calcd for
C17H16ClNO3Na [M
+
Na]+: 340.0711; found: 340.0705; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 31.30 min, tR(minor) = 25.82
min.
(2S,3S,4R)ꢀ2ꢀ(4ꢀchlorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5f). White solid (Table
5, entry 6, 89 mg, 89% yield for step 1; 53 mg, 84% yield for step 2, 99% ee). m.p. 216−217 oC;
[α]D23 = –49.85 (c = 1.3 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.34 – 7.29 (m,
6H), 7.25 – 7.24 (m, 3H), 5.03 (t, J = 3.2 Hz, 1H), 4.84 (d, J = 2.4 Hz, 1H), 4.55 (dd, J = 11.6, 4.0
Hz, 1H), 3.82 (td, J = 12.0, 2.4 Hz, 1H), 3.42 (dt, J = 13.2, 4.4 Hz, 1H), 3.05 (qd, J = 13.2, 5.2 Hz,
1H), 1.78 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.1, 135.2, 134.3,
129.0, 128.8, 128.0, 127.1, 126.8, 89.9, 78.6, 68.5, 43.7, 23.8; HRMS (ESI): m/z calcd for
C17H16ClNO3Na [M
+
Na]+: 340.0711; found: 340.0720; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 40.78 min, tR(minor) = 30.80
min.
(2S,3S,4R)ꢀ2ꢀ(2ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5g). White solid (Table
5, entry 7, 102 mg, 90% yield for step 1; 67 mg, 93% yield for step 2, 99% ee). m.p. 188−190 oC;
[α]D23 = 60.67 (c = 1.2 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.50 (dd, J = 22.0,
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7.8 Hz, 2H), 7.35 – 7.22 (m, 5H), 7.16 (t, J = 7.6 Hz, 1H), 5.36 (t, J = 3.0 Hz, 1H), 5.14 (d, J = 2.0
Hz, 1H), 4.54 (dd, J = 11.6, 4.8 Hz, 1H), 3.86 (td, J = 12.0, 2.0 Hz, 1H), 3.44 (dt, J = 13.2, 4.0 Hz,
1H), 3.12 (qd, J = 13.2, 4.8 Hz, 1H), 1.79 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ 138.3, 135.7, 132.3, 129.9, 128.9, 128.0, 127.9, 127.8, 127.1, 120.9, 87.0, 78.6,
68.6, 43.2, 23.8; HRMS (ESI): m/z calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found:
384.0214; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm):
tR(major) = 17.32 min, tR(minor) = 14.87 min.
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(2S,3S,4R)ꢀ2ꢀ(3ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5h). White solid (Table
5, entry 8, 98 mg, 87% yield for step 1; 66 mg, 91% yield for step 2, 99% ee). m.p. 168−170 oC;
[α]D23 = −49.47 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.52 (s, 1H),
7.41 (d, J = 7.6 Hz, 1H), 7.35 – 7.15 (m, 7H), 5.05 (t, J = 3.2 Hz, 1H), 4.81 (d, J = 2.0 Hz, 1H),
4.54 (dd, J = 11.8, 3.8 Hz, 1H), 3.80 (td, J = 12.0, 2.4 Hz, 1H), 3.41 (dt, J = 13.2, 4.2 Hz, 1H),
3.04 (qd, J = 13.2, 4.8 Hz, 1H), 1.77 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 138.8, 138.1, 131.6, 130.1, 129.0, 128.7, 128.0, 127.1, 124.0, 122.7, 89.7, 78.4, 68.5,
43.7, 23.8; HRMS (ESI): m/z calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found: 384.0211;
HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major)
35.73 min, tR(minor) = 26.99 min.
=
(2S,3S,4R)ꢀ2ꢀ(4ꢀbromophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5i). White solid (Table
5, entry 9, 103 mg, 91% yield for step 1; 65 mg, 90% yield for step 2, 99% ee). m.p. 223−224 oC;
[α]D23 = −42.94 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.46 (d, J = 8.4
Hz, 2H), 7.35 – 7.32 (m, 2H), 7.28 – 7.22 (m, 5H), 5.03 (t, J = 3.4 Hz, 1H), 4.82 (d, J = 2.4 Hz,
1H), 4.55 (dd, J = 11.6, 3.6 Hz, 1H), 3.82 (td, J = 12.2, 2.4 Hz, 1H), 3.42 (dt, J = 13.2, 4.2 Hz, 1H),
3.05 (qd, J = 13.2, 4.8 Hz, 1H), 1.78 (d, J = 14.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 138.1, 135.7, 131.7, 129.0, 128.0, 127.1, 127.0, 122.5, 89.8, 78.6, 68.5, 43.6, 23.8;
HRMS (ESI): m/z calcd for C17H16BrNO3Na [M + Na]+: 384.0206; found: 384.0200; HPLC
(Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 43.36 min,
tR(minor) = 33.97 min.
(2S,3S,4R)ꢀ2ꢀ(4ꢀfluorophenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5j). White solid (Table
5, entry 10, 84 mg, 88% yield for step 1; 56 mg, 93% yield for step 2, 99% ee). m.p. 178−180 oC;
[α]D23 = −38.29 (c = 0.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.31 (m,
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4H), 7.28 – 7.23 (m, 3H), 7.05 – 7.00 (m, 2H), 5.03 (t, J = 3.4 Hz, 1H), 4.85 (d, J = 2.4 Hz, 1H),
4.55 (dd, J = 11.2, 4.2 Hz, 1H), 3.83 (td, J = 12.2, 2.4 Hz, 1H), 3.43 (dt, J = 13.2, 4.2 Hz, 1H),
3.07 (qd, J = 13.2, 4.8 Hz, 1H), 1.79 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 138.2, 132.5, 132.4, 129.0, 128.0, 127.2, 127.1, 127.0, 115.7, 115.5, 90.1, 78.8, 68.5,
43.7, 23.8; HRMS (ESI): m/z calcd for C17H16FNO3Na [M + Na]+: 324.1006; found: 324.1012;
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HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major)
43.08 min, tR(minor) = 27.73 min.
=
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀ(3ꢀnitrophenyl)ꢀ4ꢀphenylꢀ2Hꢀpyran (5k). White solid (Table 5,
o
entry 11, 96 mg, 93% yield for step 1; 56 mg, 85% yield for step 2, 99% ee). m.p. 153−155 C;
[α]D23 = −48.89 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 8.26 (s, 1H),
8.14 – 8.12 (m, 1H), 7.70 (d, J = 8.0 Hz, 1H), 7.49 (t, J = 8.0 Hz, 1H), 7.34 – 7.24 (m, 5H), 5.14 (t,
J = 3.4 Hz, 1H), 4.96 (d, J = 2.4 Hz, 1H), 4.57 (dd, J = 11.6, 4.0 Hz, 1H), 3.84 (td, J = 12.4, 2.4
Hz, 1H), 3.48 (dt, J = 13.0, 4.4 Hz, 1H), 3.05 (qd, J = 13.2, 4.8 Hz, 1H), 1.81 (d, J = 13.6 Hz, 1H);
13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 148.2, 138.8, 137.9, 131.5, 129.6, 129.0, 128.0,
127.0, 123.3, 120.8, 89.6, 77.9, 68.4, 43.4, 23.6; HRMS (ESI): m/z calcd for C17H16N2O5Na [M +
Na]+: 351.0951; found: 351.0961; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min,
UV λ = 210 nm): tR(major) = 21.07 min, tR(minor) = 19.69 min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀ(4ꢀnitrophenyl)ꢀ4ꢀphenylꢀ2Hꢀpyran (5l). White solid (Table 5,
o
entry 12, 90 mg, 87% yield for step 1; 53 mg, 81% yield for step 2, 99% ee). m.p. 182−184 C;
[α]D23 = −42.88 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 8.20 (d, J = 8.8
Hz, 2H), 7.55 (d, J = 8.8 Hz, 2H), 7.36 – 7.25 (m, 5H), 5.11 (t, J = 3.4 Hz, 1H), 4.98 (d, J = 2.4 Hz,
1H), 4.59 (dd, J = 11.8, 4.8 Hz, 1H), 3.86 (td, J = 12.2, 2.4 Hz, 1H), 3.48 (dt, J = 13.0, 4.2 Hz, 1H),
3.07 (qd, J = 13.0, 4.8 Hz, 1H), 1.83 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C,
TMS): δ 148.2, 138.8, 137.9, 131.5, 129.6, 129.0, 128.0, 127.0, 123.3, 120.8, 89.6, 77.9, 68.4,
43.4, 23.6; HRMS (ESI): m/z calcd for C17H16N2O5Na [M + Na]+: 351.0951; found: 351.0954;
HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major)
35.91 min, tR(minor) = 21.14 min.
=
(2S,3S,4R)ꢀ2ꢀ(4ꢀ(trifluoromethyl)phenyl)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyran (5m). White
solid (Table 5, entry 13, 105 mg, 95% yield for step 1; 60 mg, 85% yield for step 2, 99% ee). m.p.
o
229−230 C; [α]D23 = −50.94 (c = 0.8 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ
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7.59 (d, J = 8.0 Hz, 2H), 7.48 (d, J = 8.0 Hz, 2H), 7.36 – 7.23 (m, 5H), 5.09 (t, J = 3.2 Hz, 1H),
4.91 (s, 1H), 4.57 (dd, J = 11.6, 4.4 Hz, 1H), 3.83 (td, J = 12.2, 2.2 Hz, 1H), 3.45 (dt, J = 13.0, 4.2
Hz, 1H), 3.06 (qd, J = 13.0, 4.8 Hz, 1H), 1.80 (d, J = 12.8 Hz, 1H); 13C NMR (100 MHz, CDCl3,
25 °C, TMS): δ 140.5, 138.0, 129.0, 128.1, 127.1, 125.9, 125.57, 125.54, 125.50, 125.46, 89.7,
78.6, 68.5, 43.7, 23.8; HRMS (ESI): m/z calcd for C18H16F3NO3Na [M + Na]+: 374.0974; found:
374.0982; HPLC (Chiralcel ADꢀH, hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm):
tR(major) = 32.32 min, tR(minor) = 26.44 min.
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(2R,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2ꢀ(thiophenꢀ2ꢀyl)ꢀ2Hꢀpyran (5n). Light yellow solid
(Table 5, entry 14, 67 mg, 73% yield for step 1; 47 mg, 81% yield for step 2, 99% ee). m.p.
117−120 C; [α]D23 = −37.64 (c = 1.5 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ
o
7.36 – 7.24 (m, 6H), 7.02 (d, J = 3.2 Hz, 1H), 6.97 (dd, J = 5.0, 3.8 Hz, 1H), 5.11 (s, 2H), 4.54 (dd,
J = 11.8, 4.6 Hz, 1H), 3.85 (td, J = 12.4, 2.4 Hz, 1H), 3.43 (d, J = 12.8 Hz, 1H), 3.04 (qd, J = 13.2,
4.8 Hz, 1H), 1.77 (d, J = 13.6 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.9, 138.0,
129.0, 128.0, 127.1, 126.8, 125.4, 123.9, 89.8, 76.3, 68.7, 43.5, 23.8; HRMS (ESI): m/z calcd for
C15H15NO3SNa [M
+
Na]+: 312.0665; found: 312.0660; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 40.70 min, tR(minor) = 32.26
min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2ꢀstyrylꢀ2Hꢀpyran (5o). White solid (Table 5, entry 15,
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83 mg, 85% yield for step 1; 49 mg, 79% yield for step 2, 99% ee). m.p. 175−177 C; [α]D
=
−45.77 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.23 (m, 10H),
6.79 (d, J = 16.0 Hz, 1H), 6.11 (dd, J = 16.0, 5.4 Hz, 1H), 4.94 (s, 1H), 4.46 (dd, J = 11.6, 4.8 Hz,
1H), 3.74 (t, J = 12.0 Hz, 1H), 3.32 (dt, J = 12.8, 4.0 Hz, 1H), 3.00 (qd, J = 12.8, 4.8 Hz, 1H), 1.73
(d, J = 12.0 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 138.3, 135.9, 133.2, 128.9,
128.5, 128.1, 127.9, 127.1, 126.7, 123.3, 88.9, 77.5, 68.1, 43.3, 23.9; HRMS (ESI): m/z calcd for
C19H19NO3Na [M
+
Na]+: 332.1257; found: 332.1261; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 77.27 min, tR(minor) = 42.14
min.
(2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ2ꢀphenethylꢀ4ꢀphenylꢀ2Hꢀpyran (5p). White solid (Table 5,
o
entry 16, 87 mg, 89% yield for step 1; 57 mg, 92% yield for step 2, 99% ee). m.p. 100−101 C;
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[α]D23 = −86.69 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.33 – 7.18 (m,
10H), 4.76 (s, 1H), 4.39 (dd, J = 11.6, 4.8 Hz, 1H), 3.63 – 3.57 (m, 2H), 3.18 (dt, J = 13.0, 4.2 Hz,
1H), 2.97 (qd, J = 13.0, 4.8 Hz, 1H), 2.89 – 2.82 (m, 1H), 2.80 – 2.72 (m, 1H), 1.90 – 1.76 (m,
2H), 1.69 (d, J = 13.2 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 140.8, 138.4, 128.9,
128.6, 128.5, 127.8, 127.1, 126.1, 88.8, 75.8, 68.1, 43.3, 33.8, 31.4, 24.1; HRMS (ESI): m/z calcd
for C19H21NO3Na [M + Na]+: 334.1414; found: 334.1416; HPLC (Chiralcel ADꢀH,
hexane/isopropanol 90/10, 0.5 mL/min, UV λ = 210 nm): tR(major) = 24.72 min, tR(minor) = 17.54
min.
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Synthesis of indolizidine alkaloid and characterization of the derivatives.
(S)ꢀmethyl 4ꢀhydroxyꢀ5ꢀnitropentanoate (1q). Ligand L1 (6 mg, 0.025 mmol, 2.5 mol %) and
CuCl2·2H2O (4.2 mg, 0.025 mmol, 2.5 mol %) were added to a round bottle containing absolute
THF (4 mL). The solution was stirred for 1 h at room temperature to give a green solution. To the
resulting solution, 4ꢀoxobutyric acid methyl ester (0.116 g 1 mmol), the nitromethane (0.54 mL,
10 mmol, 10 equiv) and DIPEA (0.174 mL, 1 mmol, 1 equiv) were added successively and the
o
tube was introduced in a bath at –20 C without special precautions to exclude moisture or air.
Then the reaction was monitored by TLC, when it finished, the mixture was quenched by 2 M HCl
aqueous, extracted by ethyl acetate, dried over Na2SO4 anhydrous, then concentrated and purified
by silica gel column chromatography, eluting with petroleum ether and ethyl acetate to afford the
corresponding product 1q as colorless oil (0.159 g, 90% yield, 98% ee). [α]D23 = –8.13 (c = 1.0 in
EtOH); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 4.47 – 4.38 (m, 3H), 3.70 (s, 3H), 3.42 (br s,
1H), 2.55 (t, J = 7.0 Hz, 2H), 1.90 – 1.77 (m, 2H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ
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173.9, 80.42, 67.7, 51.9, 29.7, 28.4; HPLC (Chiralcel IA, hexane/isopropanol 90/10, 0.5 mL/min,
UV λ = 210 nm): tR(major) = 30.86 min, tR(minor) = 32.67 min.
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6a and 6b were prepared according to the General Procedure, Step 1 by using 1q to react with
2a and 2d respectively.
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Methyl 3ꢀ((2S,3S,4R)ꢀtetrahydroꢀ6ꢀhydroxyꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyranꢀ2ꢀyl)propanoate (6a)
White solid (84 mg, 91% yield). m.p. 110−112 oC; the ratio of major isomer to minor isomer was
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87:13 according to H NMR analysis; major isomer: H NMR (400 MHz, DMSO–d6, 25 °C,
TMS): δ 7.34 – 7.23 (m, 5H), 6.94 (d, J = 6.8 Hz, 1H), 5.12 (s, 1H), 4.82 (t, J = 7.2 Hz, 1H), 3.93
(s, 1H), 3.53 (dt, J = 13.6, 4.0 Hz, 1H), 2.47 – 2.42 (m, 3H), 1.83 – 1.73 (m, 2H), 1.67 – 1.49 (m,
1H); 13C NMR (100 MHz, DMSO–d6, 25 °C, TMS): δ 173.1, 139.2, 128.9, 127.6, 127.5, 96.4,
1
87.6, 73.6, 51.7, 41.5, 31.8, 30.1, 27.3; minor isomer: H NMR (400 MHz, DMSO–d6, 25 °C,
TMS): 7.34 – 7.23 (m, 5H), 6.58 (d, J = 3.2 Hz, 1H), 5.43 (s, 1H), 4.92 (t, J = 12.0 Hz, 1H), 4.38
(s, 1H), 3.71 (dt, J = 14.4, 4.4 Hz, 1H), 2.73 (t, J = 14.0 Hz, 1H), 2.47 – 2.42 (m, 2H), 1.83 – 1.73
(m, 2H), 1.67 – 1.49 (m, 1H); HRMS (ESI): m/z calcd for C15H19NO6Na [M + Na]+: 332.1105;
found: 332.1108.
Methyl 3ꢀ((2S,3S,4R)ꢀtetrahydroꢀ6ꢀhydroxyꢀ3ꢀnitroꢀ4ꢀpꢀtolylꢀ2Hꢀpyranꢀ2ꢀyl)propanoate (6b)
o
Light yellow solid (83 mg, 86% yield) . m.p. 107−109 C; the ratio of major isomer to minor
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isomer was 1:1 according to H NMR analysis; H NMR (400 MHz, DMSO–d6, 25 °C, TMS): δ
7.18 – 7.12 (m, 4H), 6.93 (d, J = 6.8 Hz, 0.5H), 6.57 (d, J = 3.2 Hz, 0.5H), 5.43 (s, 0.5H), 5.10 (t,
J = 4.6 Hz, 1H), 4.82 (t, J = 7.2 Hz, 0.5H), 4.39 (t, J = 3.8 Hz, 0.5H), 3.93 (s, 0.5H), 3.67 (dt, J =
13.6, 4.0 Hz, 0.5H), 3.60 (s, 3H), 3.48 (dt, J = 13.6, 4.0 Hz, 0.5H), 2.71 (t, J = 13.4 Hz, 0.5H),
2.48 – 2.37 (m, 2.5H), 1.80 – 1.47 (m, 3H); 13C NMR (100 MHz, DMSO–d6, 25 °C, TMS): δ
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173.2, 136.8, 136.7, 136.5, 136.1, 129.53, 129.51, 127.4, 96.3, 90.5, 88.6, 87.5, 73.3, 66.0, 51.86,
51.83, 40.9, 35.6, 31.6, 29.9, 28.9, 27.2, 27.1, 21.0; HRMS (ESI): m/z calcd for C15H19NO6Na [M
+ Na]+: 346.1261; found: 346.1267.
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Methyl 3ꢀ((2S,3S,4R)ꢀtetrahydroꢀ3ꢀnitroꢀ4ꢀphenylꢀ2Hꢀpyranꢀ2ꢀyl)propanoate (7) was
prepared in 77 mg, 88% yield and 98% ee according to the General Procedure, Step 2 starting
o
from 6a (0.3 mmol scale). White solid. m.p. 68−70 C; [α]D23 = −167.85 (c = 0.6 in CH2Cl2);1H
NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.35 – 7.31 (m, 2H), 7.27 (d, J = 7.2 Hz, 1H), 7.22 (d, J
= 7.2 Hz, 2H), 4.85 (t, J = 3.0 Hz, 1H), 4.34 (dd, J = 11.6, 4.8 Hz, 1H), 3.79 (dt, J = 9.6, 3.0 Hz,
1H), 3.69 (s, 3H), 3.61 (td, J = 12.0, 3.0 Hz, 1H), 3.24 (dt, J = 13.2, 4.4 Hz, 1H), 2.96 (qd, J =
13.0, 4.8 Hz, 1H), 2.56 – 2.49 (m, 2H), 1.96 – 1.88 (m, 1H), 1.78 – 1.69 (m, 2H); 13C NMR (100
MHz, CDCl3, 25 °C, TMS): δ 173.3, 138.3, 128.8, 127.8, 127.1, 88.6, 75.8, 68.1, 51.6, 43.2, 29.5,
27.3, 24.0; HRMS (ESI): m/z calcd for C15H20NO5 [M + H]+: 294.1336; found: 294.1341; HPLC
(Chiralcel ADꢀH, hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 210 nm): tR(major) = 16.45 min,
tR(minor) = 19.02 min.
(4R,4aS,8aS)ꢀhexahydroꢀ4ꢀphenylꢀ2Hꢀpyrano[3,2ꢀb]pyridinꢀ6(7H)ꢀone (8). A vial equipped
with a stirring bar was charged with 7 (59 mg, 0.2 mmol) in acetic acid (3.0 mL). To the mixture
10 equiv of zinc powder were added portionwise, then it was stirred at room temperature (about
25 oC) for 60 hours. The reaction was monitored by TLC, when it finished, the excess zinc powder
was removed by filtration. The filtrate was concentrated under reduced pressure to remove the
excess acetic acid. The remaining mixture was neutralized by saturated NaHCO3 aqueous solution
until pH=10 and subsequently extracted with CH2Cl2 for three times. The combined organic phase
was dried over anhydrous Na2SO4, and evaporated under reduced pressure. The crude product was
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=
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9
−109.26 (c = 1.0 in CH2Cl2); 1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.38 (t, J = 7.6 Hz, 2H),
7.29 (t, J = 7.6 Hz, 1H), 7.23 (d, J = 7.6 Hz, 2H), 5.06 (br s, 1H), 4.19 – 4.16 (m, 1H), 3.89 (d, J =
2.0 Hz, 1H), 3.69 – 3.64 (m, 2H), 3.14 (dt, J = 13.2, 3.2 Hz, 1H), 2.60 (ddd, J = 18.0, 13.2, 6.8 Hz,
1H), 2.29 – 2.12 (m, 3H), 1.83 (tdd, J = 13.8, 6.4, 1.8 Hz, 1H), 1.63 (dd, J = 13.2, 1.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3, 25 °C, TMS): δ 172.5, 139.2, 129.2, 127.5, 127.2, 70.7, 67.6, 55.1, 43.7,
26.5, 26.4, 23.2; HRMS (ESI): m/z calcd for C14H18NO2 [M + H]+: 232.1332; found: 232.1332;
HPLC (Chiralcel IA, hexane/isopropanol 80/20, 0.5 mL/min, UV λ = 254 nm): tR(major) = 21.38
min, tR(minor) = 20.32 min.
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(1R,8S,8aS)ꢀhexahydroꢀ8ꢀhydroxyꢀ1ꢀphenylindolizinꢀ5(1H)ꢀone (9a) was prepared in 42 mg,
91% yield and 96% ee according to the above operation for 8 (0.2 mmol scale). White solid. m.p.
173−174 oC; [α]D23 = 28.48 (c = 1.0 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.37
– 7.25 (m, 5H), 3.94 (d, J = 1.6 Hz, 1H), 3.73 – 3.57 (m, 3H), 3.46 – 3.36 (m, 2H), 2.60 – 2.51 (m,
1H), 2.35 (dd, J = 18.0, 7.6 Hz, 1H), 2.25 (dt, J = 12.2, 6.2 Hz, 1H), 2.11 – 2.02 (m, 2H), 1.77 (td,
J = 12.2, 7.8 Hz, 1H); 13C NMR (100 MHz, CDCl3, 25 °C, TMS): δ 169.3, 139.1, 128.7, 127.7,
127.2, 68.7, 61.6, 45.2, 44.9, 29.9, 28.2, 26.2; HRMS (ESI): m/z calcd for C14H18NO2 [M + H]+:
232.1332; found: 232.1329; HPLC (Chiralcel IA, hexane/isopropanol 90/10, 0.5 mL/min, UV λ =
210 nm): tR(major) = 37.70 min, tR(minor) = 41.99 min.
(1R,8S,8aS)ꢀhexahydroꢀ8ꢀhydroxyꢀ1ꢀpꢀtolylindolizinꢀ5(1H)ꢀone (9b) was prepared in 41 mg,
83% yield and 99% ee according to the above operation for 8 (0.2 mmol scale). Colorless Oil.
[α]D23 = 30.21 (c = 0.9 in CH2Cl2);1H NMR (400 MHz, CDCl3, 25 °C, TMS): δ 7.22 – 7.13 (m,
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