Tetrahedron: Asymmetry 25 (2014) 1061–1090
Contents lists available at ScienceDirect
Tetrahedron: Asymmetry
journal homepage: www.elsevier.com/locate/tetasy
Tetrahedron: Asymmetry Report Number 152
Recent advances in the application of the Oppolzer camphorsultam
as a chiral auxiliary
Majid M. Heravi ⇑, Vahideh Zadsirjan
Department of Chemistry, School of Science, Alzahra University, Vanak, Tehran, Iran
a r t i c l e
i n f o
Article history:
Received 22 May 2014
Accepted 3 July 2014
a b s t r a c t
Oppolzer’s camphorsultam has attracted much attention as an efficient chiral auxiliary, and is one of the
most powerful synthetic tools in asymmetric synthesis. The sultam chiral auxiliary can be applied in a
variety of different reactions such as alkylations, allylations, 1,3-dipolar cycloadditions, cyclopropanation,
reductions, Diels–Alder, aldol and ene reactions. These applications have been highly successful in the
stereoselective construction of a number of important natural products via total synthesis. The present
review is focused on the utility and versatility of the sultam in various asymmetric reactions.
Ó 2014 Elsevier Ltd. All rights reserved.
Contents
1.
2.
3.
Introduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Examples of the application of the sultam in various reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.1.
Allylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.2.
Alkylation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.3.
1,3-Dipolar cycloaddition . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.4.
Cyclopropanation. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.5.
Ene reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.6.
Reduction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.7.
Halohydrin reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.8.
[3+2] Cycloaddition reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.9.
[4+2] Cycloaddition reaction. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.10. Aldol and nitroaldol reactions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.11. Diels–Alder reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.12. 1,4-Addition. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.13. Oxidative cyclization. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.14. Epoxidation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.15. Acylation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
2.16. Aza-Darzen reaction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Conclusions. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
Acknowledgements . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
References . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . .
1. Introduction
Camphorsultam, which is also known as bornanesultam, is a
crystalline solid and in both enantiomers in its exo form (1R)-(+)⇑ Corresponding author. Tel.: +98 129121329147; fax: +98 2188041344.
E-mail address: mmh1331@yahoo.com (M.M. Heravi).
http://dx.doi.org/10.1016/j.tetasy.2014.07.001
0957-4166/Ó 2014 Elsevier Ltd. All rights reserved.
1061
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1070
1075
1076
1078
1079
1080
1081
1081
1083
1083
1084
1085
1086
1087
1088
1089
1089
2,10-camphorsultam 1 and (1S)-()-2,10-camphorsultam 2, are
commercially available (Fig. 1). However it is relatively expensive
and since several of the intermediates are also commercially
available, its synthesis can be readily accomplished. First and
foremost, it has been utilized as a chiral auxiliary for the asymmetric synthesis of useful chemicals for which a preferred specific
stereoselectivity is desired.1
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
NH
HN
S
O2
S
O2
(1R)-(+)-2,10-camphorsultam 1
(1S)-(-)-2,10-camphorsultam 2
Figure 1.
Initially, the camphorsultam moiety was synthesized via a catalytic hydrogenation of camphor sulfonylimine using Raney Nickel
as a suitable catalyst.2 However, more suitable and contemporary
syntheses involves the use of lithium aluminum hydride as a
reducing agent.3 Both reductions were found to be stereoselective.
In these reductions, although the formation of both the endo and
exo diastereomeric forms are theoretically feasible, only the exo
isomer is produced, because of the steric effects of one of the
methyl groups.2 Camphorsultam is also known as Oppolzer’s
sultam reference, who originally developed and used the lithium
aluminum hydride for the reduction of camphor sulfonylimine1
and initially applied it in a fruitful asymmetric synthesis.3 As illustrated in Scheme 1, the sultam can be easily synthesized by starting from camphorsulfonyl chloride.1 Both enantiomers can be
prepared in the same way, by using different natural camphor
enantiomers to obtain both camphorsulfonyl chlorides.
Over the past few years, the applications of Oppolzer camphorsultam 1 has grown rapidly and nowadays is considered to be one
of the most useful and suitable chiral auxiliaries for asymmetric
synthesis. It is the chiral auxiliary of choice, especially when thermal reactions in the absence of metals are required. Oppolzer has
also extended the application of the sultam as a powerful auxiliary
for various types of metal catalyzed reactions.2 Oppolzer’s camphorsultam was first reported. in 1984;1 this sultam in the presence of metals (enolate alkylations, conjugate additions, and
Lewis acid catalyzed Diels–Alder reactions) has been largely investigated by Oppolzer et al.5 Back to back papers by Oppolzer et al.6
and continuous reports by others7 proved the usefulness of the sultam for controlling stereochemistry in the absence of any chelating
metals. Since then, much attention has been paid to the thermal
chemistry of acryloyl derivatives of Oppolzer’s sultam.8 Due to its
capability of being derivatized through its nitrogen atom and the
unique structural inflexibility of its skeleton, the camphorsultam
is frequently used in asymmetric reactions as a chiral auxiliary to
direct a selected reaction to proceed with the desired stereoselectivity. In the synthesis of Manzacidin B, a camphorsultam is used
for achieving the preferred stereoselected product.9 In a Michael
reaction or a Claisen rearrangement, camphorsultam grants a high
level of stereoselectivity. It allows more control during reactions
and the formation of highly specific products.10,11 camphorsultam
is also useful in determining the absolute stereochemistry of certain compounds. Thus, it is frequently referred to as a ‘chiral probe’.
SO 2Cl
2. Examples of the application of the sultam in various
reactions
2.1. Allylation
The diastereoselective addition of allylic reagents to chiral
a-ketoimides obtained from Oppolzer’s sultam has attracted much
attention. Jurczak et al. reported on a diastereoselective addition of
chiral a-ketoimides obtained from Oppolzer’s sultam to various
allylic reagents.25 The asymmetric addition of allylic reagents 5–7
to N-glyoxyloyl-(2R)-bornane-10,2-sultams provides a synthetic
path to the syntheses of different natural products. The diastereoselectivity in the allylation reaction of chiral a-ketoimides 3 and
4 creates tertiary stereogenic centers. N-Methyl- 326 and Nphenylglyoxyloyl-(2R)-bornane-10,2-sultam 4 were treated with
allylic Grignard reagent 5 and allyl bromide 6 in the presence of
zinc dust and silane 7 using BF3Et2O as Lewis acid to provide the
main products (14R)-8 and (14S)-9, respectively (Scheme 2). These
reactions were achieved with various Lewis acids under different
conditions. The results of the experiments are shown in Table 1.
The major products (14R)-8 and (14S)-9 were obtained from the
reaction of silane 7 with a-ketoimides 3 and 4, due to the predominance of nonchelated conformer A (Fig. 2). Similar results were
obtained for the reaction mediated by SnCl4 and are the result of
the predominance of a-chelated conformer B. High diastereoselection in these reactions was observed. A change in the direction of
the asymmetric induction was observed when allyltrimethyl
silane/TiCl4 was used. This was due to the formation of c-chelated
conformer C (Fig. 2). As a result, the development of tertiary stereogenic centers was controlled by means of using various reaction
H+
NH4OH
O
Oppolzer’s camphorsultam is currently on the market at almost
identical prices for each enantiomer. It is generally introduced to
an organic fragment by typical acylation reactions. Since it is a
sulfonamide, its removal via a reductive or hydrolytic reaction is
relatively easy, giving it another advantage. The recovery of this
auxiliary after removal is also convenient.8
Herein we report on the application of the sultam as a chiral
auxiliary in asymmetric synthesis.8,12 In 1987, Oppolzer presented
a comprehensive review entitled, camphor derivatives as chiral
auxiliaries in asymmetric syntheses. In 1993, Kim et al. published
a review on asymmetric thermal reactions with Oppolzer’s
camphorsultam.
In a continuation of our interests in asymmetric synthesis13–16
and the applications of named reactions in total syntheses,17–23
and encouraged by the interest of asymmetric synthetic chemists
on a review concerning applications of oxazolidinones as a chiral
auxiliary in asymmetric aldol reactions applied in total syntheses24
and due to the large number of published articles on the application of sultams in asymmetric syntheses, we submit a new report
of the entitled that is up to date and shows the versatility of this
chiral auxiliary in different asymmetric syntheses.
LiAlH4
O
NH
S N
SO2NH2
O
O
S
O
O
2,10-camphorsultam
Scheme 1.
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
R +
N
O
O
3: R = Me
4: R = Ph
5: X = MgCl
6: X = Br
7: X = SiMe3
N
R
HO
S
O
O
+
N
O
S
O
X
R
S
OH
O
O
(14S)-8 R = Me
(14R)-9 R = Ph
(14R)-8 R = Me
(14S)-9 R = Ph
Scheme 2.
Table 1
Entry
Substrate
Reagent
Solvent
Temperature (°C)
Time (h)
Yield (%)
Diastereoisomer ratio
Configuration
1
2
3
4
5
6
7
8
9
10
11
12
13
14
3
4
3
4
3
4
3
4
3
4
3
4
3
4
AllMgCl
AllMgCl
AllMgCl, ZnBr2
AllMgCl, ZnBr2
AllBr, Zn
AllBr, Zn
AllBr, Zn, NH4Claq
AllBr, Zn, NH4Claq
AllSiMe3, BF3Et2O
AllSiMe3, BF3Et2O
AllSiMe3, SnCl4
AllSiMe3, SnCl4
AllSiMe3, TiCl4
AllSiMe3, TiCl4
THF
THF
THF
THF
THF
THF
THF
THF
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
78
78
78
78
78
78
rt
rt
rt
rt
20
20
20
20
1
0.5
1
0.5
48
24
48
20
17
70
1
48
1
48
50
74
50
87
60
80
90
20
17
70
84
82
75
82
93:7
87:23
73:27
95:5
52:48
86:14
74:26
88:12
63:37
91:9
62:38
70:30
62:38
63:37
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
(R)
(S)
BF3. Et2O
O
R
N
O
SnCl4
O
O
O
R
N
S
O
A
N
R
O
S
S
O
O
O
O
O
B
TiCl4
C
Figure 2.
conditions such as reagents and catalysts. The results obtained
demonstrate that control of the diastereoselectivity of allylation
of a-ketoimides 3 and 4, leading to the formation of tertiary stereogenic centers can be carried out by changing the reaction
conditions.
The synthesis of a-hydroxy acids in enantiomerically pure form
has attracted much attention, due to their various biological activities and their application as chiral building blocks with them
being used as precursors in total syntheses. As shown in Scheme 3,
a highly diastereoselective indium catalyzed allylation of chiral
a-ketoimides obtained from Oppolzer’s sultam in good yields and
with high diastereomeric excess. That is an invaluable procedure
for the formation of enantiopure a-hydroxy acids. Indiummediated allylation onto N-phenylglyoxyloyl-(2R or 2S)-bornane10,2-sultam 4a and 4b with different allyl bromides 10 was
accomplished to give the desired homoallylic alcohols 11 and 12,
respectively (Scheme 3 and Table 2).27
Allylations of N-thiophenylglyoxyloyl-(2R)-bornane-10,2-sultam 13a and N-furylglyoxyloyl-(2R)-bornane-10,2-sultam 13b
were carried out to provide products 14a and 14b (Scheme 4 and
Table 3). The diastereoselectivity decreased when the substituent
of the a-ketoimides was changed from a phenyl to a thiophenyl
or furyl group. The diastereoselectivity was enhanced by changing
the solvent to aqueous ethanol. The lower diastereoselectivity of
thiophenyl and furyl a-ketoimides in comparison with the phenyl
derivatives can be attributed to the chelation of the sulfur or oxygen atom of the heterocycles with indium, resulting in a disturbance of the chelation of the carbonyl with the indium.27
R
O
HO
OH
R'
10: R'Br
Xc
In. aq. THF, r.t.
O
Xc
Xc
O
10:RBr
In, aq. THF, r.t.
4a: Xc = (+)-sultam
4b: Xc = (-)-sultam
12
Xc = (-)- Sultam
R=
R' =
Scheme 3.
O
11
Xc = (+)-Sultam
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 2
Substrate
1
2
4a
4b
11a
12a
97
98
>99:1
>1:99
(R)
(S)
3
4a
11b
86
>99:1
(R)
4
4b
12b
96
5
6
4a
4b
11c
12c
7
8
4a
4b
11d
12d
O
R
Product
R0
Entry
RBr, In
X
N
S
O
O
X
OH
R'
N
S
solvent, r.t.
O O
O
O
14a: X = O
14b: X = S
13a: X = O
13b: X = S
R=
R' =
Scheme 4.
Table 3
Entry
R
Product (R0 )
Solvent
Yield (%)
dr
1
25% aq THF
90% aq EtOH
81
89
72:28
95:5
2
25% aq THF
90% aq EtOH
89
95
92:8
95:5
3
25% aq THF
90% aq EtOH
77
62
75:25
84:16
4
25% aq THF
90% aq EtOH
56
No reaction
99:1
—
2.2. Alkylation
A novel non-hydrolyzable phosphotyrosine analogue, L-2,3,5,6tetrafluoro-4-(phosphonomethyl) phenylalanine (F4Pmp), and its
N-Fmoc protected derivative were prepared, by employing an
enantioselective synthetic pathway, using a camphorsultam as
the chiral auxiliary.28 The chiral synthon 17 was reacted with
n-BuLi under an argon atmosphere and alkylated with 15 or 16.
Subsequent warming of the mixture to ambient temperature
provided monoalkylphosphonate 18 or 19. Only a trace amount
of dialkylphosphonate was detected in the ether extract. The
hydrolysis of 18 was performed at ambient temperature; upon
evaporation of the THF, the aqueous residue was washed with
ethyl acetate and lyophilized to afford crude 20, which was
subsequently hydrolyzed. Next, camphorsultam was removed
from compounds 20 and 21 to provide compounds 22 and 23
Yield (%)
dr (R:S at C2)
Configuration
>1:99
(S)
55(69)
54(70)
>99:1
>1:99
(R)
(S)
82
84
>99:1
>1:99
(R)
(S)
(Scheme 5). This synthesis also appears to be very suitable for
the large-scale preparation of Fmoc-L-F2Pmp-OH.
Chassaing et al. reported on the asymmetric syntheses of
(S)-Boc-N-methyl-p-benzoyl-phenylalanine 26 via the alkylation
of a sultam Boc-sarcosinate.29 It should be noted that the levorotatory sultam led to (S)-Boc-N-methyl amino acids with excellent
enantiomeric purity. This acid is a photoreactive amino acid
and was included into the sequence of a Substance P peptide
antagonist. The preparation of enantiomerically pure Boc-Nmethyl amino acids using a short route (4 steps) including an alkylation of the chiral substrate 29 as the key step was accomplished.
The protected N-methylated amino acid was created in order to
avoid the N-methylation step and a final racemization. The chiral
synthon 29 can be prepared after Boc protection from sarcosine
27 and activation with isobutyl chloroformate. Oppolzer’s
sultam,30 as its sodium salt, was treated with the carboxylic function of 28, after being activated with isobutyl chloroformate. The
lithiated chiral precursor was then activated in THF/HMPT. The
NMR data indicated that the alkylation by benzyl bromide or
p-benzoyl-benzyl bromide was extremely diastereoselective
(>99%). Finally, the sultam moiety was cleaved by phase transfer
catalysis in acetonitrile to create product 31 and consequently
the sultam was recovered. The absolute configuration of the acarbon on compound 31a was characterized by comparison of
the specific rotation with a commercial sample of (S)-Boc-Nmethyl-phenylalanine. (S)-Boc-N-methyl-phenylalanine 31a can
be synthesized from the levorotatory enantiomer of the sultam
while the contrary (+)-sultam afforded (R)-Boc-N-methylphenylalanine.
As depicted in Scheme 6, the photoreactive amino acid 31b can
be constructed from the chiral precursor 29 after alkylation by
p-benzoyl-benzylbromide (for the alkylation step, the diastereoisomeric excess was over 98% and the yield 67%). Finally, the sultam
was removed via hydrolysis to form (S)-Boc-N-methyl-p-benzylphenylalanine 31b. The design of a photoreactive peptidic antagonist of Substance P, a photosensitive reporter that is part of the
chromophore which imparts antagonist properties to the peptide,
was also attempted.
In 2001, the synthesis of a series of 5,5-diaryl-2-amino-4-pentenoates (new amino acid derivatives) as a new class of biologically
active molecules targeted toward the recently cloned glycine reuptake transport system were reported by Isaac et al.31 In this synthesis, the authors used Oppolzer’s sultam as the chiral auxiliary to
give distinct substrates. Using Oppolzer’s bornane-10,2-sultam as
the chiral auxiliary, the sultam-derived N-(diphenyl-methylene)glycinate 1732 was obtained, which upon reaction with an
activated organic bromide gave the monoalkylated intermediate
33 with excellent diastereoselectivity in which only one isomer
was detected. Regioselective hydrostannation provided intermediate 34. In the following 2 steps, trifluoroacetic acid catalyzed
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
CH3
Ph
N
F
N
SO2
Ph
O
F X4
N
17
N
CY2PO3R2
THF, HMPA, - 78 oC
S
O2
r.t., overnight
15: X = F, Y = H, R = Me
CY2PO3RH
O
18 : X = F, Y = H, R = Me
16: X = H, Y = F, R = Et
19: X = H, Y = F, R = Et
NH2
1) HCl / THF
X4
LiOH
N
S
O2
2) LiOH / dioxane, r.t.
CY2PO 3RH
O
20: X = F, Y = H, R = Me
21: X = H, Y = F, R = Et
9M HCl
NH2
F
L-F4Pmp
F
HO
Fmoc-NH
CH2PO3MeH
O
F
F
F
Fmoc-OSu
F
CH2PO 3MeH
HO2C
22
F
F
9 M HCl or
24
NH2
NH2
3 M HCl
CO2H
HO2C
HO
CF2PO 3EtH
O
25
23
L-F2Pmp
TMSl
Scheme 5.
O
O
(Boc)2O
HO
N
CH3
H
NaHCO 3
EtOH
O
DME, NMM, ClCOOiBu
HO
N
N
O
CH3
O
27
S
O2
N-Na+
N
O
O
29
S
O2
28
CH3
i) THF/HMPT
-78°C, BuLi
ii) RX
a: R=CH2Ph
b: R=CH2C6H4COPh
O
O
+
NH
S
O2
CH3CN, LiOH, LiBr
(Bu)4N+Br-
H
S
O2
R
HO
N
O
R
CH3
O
26: R=CH2C6H4COPh
31: R=CH2Ph
Scheme 6.
N
O
O
30
CH3
H
N
1066
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
deprotection of compound 35 and lithium hydroxide-mediated
hydrolysis of the chiral auxiliary provided the lithium salt of 32
as a pure (S)-enantiomer (Scheme 7). The key part of this synthetic
strategy is the palladium-catalyzed stereoselective hydrostannylation of the highly functionalized intermediates to give product 32
in good overall yield.
Kirk et al. reported on a novel, convenient, and extremely efficient method for the synthesis of 2-, 5-, and 6-fluoro-L-DOPA,
and 2,6-difluoro-L-DOPA analogues 36a–d.33 Among the methods
reported for the preparation of the enantiomers of a-amino acids,
including both enantioselective and diastereoselective strategies,34
this was considered to be a diastereoselective method. Alkylation
was accomplished under phase transfer conditions of the chiral
glycine synthon 17 (generated from the commercially available
Oppolzer chiral sultam which was developed by Chassaing et al.32b)
and fluorinated analogues of 3,4-dimethoxybenzyl chloride 37a–d
to provide 38a–d with high diastereoselectivity. The chiral auxiliary was then easily removed from 39a–d by the reaction with
LiOH/THF to yield amino acid 40c. Compound 40c was heated in
HBr causing hydrolysis of the methyl ethers. After conventional
work-up, the free amino acids were obtained. The amino acids
were obtained in excellent overall yield and with high enantiomeric purity (Scheme 8).
One of the key steps for the stereoselective synthesis of
(3S,5S,6S)-tetrahydro-6-isopropyl-3,5-dimethylpyran-2-one 41, a
C5-epimer of a component of the natural sex pheromone of the
Me
Me
Ph
O
N
i) LDA, THF, HMPA, - 78 °C,
N
N
S
O O
Ph
Bu3SnH, PdCl2 (PPh3)2, THF
Br
, -78 °C to r.t.
Ar1
ii)
Ph
COOXc
Ph
Ar2
33
Ar1 = 2,4-difluorophenyl, Ar2 = 4-isopropylphenyl
17
Ph
COOXc
N
Ph
COOXc
F
Ph
Bu3Sn
Ar2
Ar
34
COO -Na+
NH2
Ph
N
1
Ar
2
F
35
32
Xc =
N
S
O
O
Scheme 7.
O
R1
O
Ph
Ph
K2CO 3,
cat. Bu4NBr, CH3CN, 50°C
MeO
N
N
Ph
S
O2
Cl
+
R3
MeO
N
N
Ph
R1
S
O2
R2
17
OMe
R2
37a:R1 = F, R2 =R3 = H
37b: R2 = F, R1 = R3 = H
37c: R3 = F, R1= R3 = H
37d: R1= R3 = F,R2 = H
O
N
S
O2
Ph
N
LiOH,
H2O/THF, 0°C
R1
O
R2
OMe
39a: 2-F (83%)
39b: 5-F (99%)
39c: 6-F (86%)
39d: 2,6-diF (87%)
R1
MeO
OH
MeO
OMe
OMe
38a: 2-F (88%)
38b: 5-F (98%)
38c: 6-F (92%)
38d: 2,6-diF (87%)
Ph
R1
R3
1 M HCl, CH2Cl2, r.t.
R3
R
R
3
48% HBr, 145°C
OH
NH2
2
O
HO
R3
HO
NH2
R2
40a: 2-F (80%)
40b: 5-F (77%)
40c: 6-F (82%)
40d: 2,6-diF (74%)
36a: 2-F (70%)
36b: 5-F (99%)
36c: 6-F (66%)
36d: 2,6-diF (99%)
43% for 36c and
similar yields for 36a, b, d
Scheme 8.
1067
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
CO2H
45: EtCOXC
NaHMDS, Bu4NI, HMPTA,
Br
NH2
OTHP
43
44
XC
THF, 5 h, 77%
OTHP
O
46
i) H2O 2, LiOH, 12 h;
ii) extraction of 1, CHCl3, 89%;
O
iii) HCl, H2O, 1 h,
84% over two synthetic steps
O
XC =
N
42
90% de
S
O
O
Scheme 9.
wasp Macrocentrus grandii, is the diastereoselective alkylation of
Oppolzer’s (N-propionyl)-(2R)-bornane-10,2-sultam. The first stereoselective synthesis of (3S,5S,6S)-tetrahydro-6-isopropyl-3,5dimethylpyran-2-one 41 was achieved from the easily available
natural amino acid L-valine 43 via the work of Matiushenkov
et al.,35 in which the C2–C3 carbon fragment of lactone 41 was created via a diastereoselective alkylation of Oppolzer’s N-acylsultam.36 The diastereoselective alkylation of the sodium enolate
obtained from Oppolzer’s N-propionylsultam 45 with the alkyl bromide 44 with HMPTA and TBAI36 provided imide 46. Imide 46 was
hydrolyzed under mild conditions with the sequential extraction of
the chiral auxiliary (AuxH) 1 with chloroform, the acid-catalyzed
removal of the THP-protecting and one-pot lactonization provided
the unsaturated d-valerolactone 42 with high de (Scheme 9).
Hydrogenation of the exocyclic double bond in lactone 42 using
conventional catalysts such as palladium on carbon or platinum
black under 1 atm pressure of H2 accompanied with the reductive
cleavage of the CAO bond at the allyl position afforded (2S,4RS)2,4,6-trimethylheptanoic acid 47 (Scheme 10).
Fluorinated amino acids have attracted much attention both in
the field of pharmaceuticals and supramolecular sciences.37 b-Perfluoroalkyl a-amino acids have strong potential to create novel
functional compounds due to their unique properties, for instance
their hydrophobic bulkiness.38 Chiral b-perfluoroalkyl a-amino
acids were prepared via a method using Oppolzer’s camphorsultam
as the chiral auxiliary to induce high stereoselectivity. This reaction can be also applied to N-phthalimide dehydroamino acids
and the product was transformed into the corresponding amino
acid and a peptide derivative. As depicted in Scheme 11, the diastereoselective reaction of a methacrylic acid derivative containing a
camphorsultam as the chiral auxiliary can be achieved to give
hydroperfluoroalkylated product 49 as a single stereoisomer with
high stereoselectivity. The excellent selectivity can be attributed
to the bulkiness of TTMSS.39
For the synthesis of chiral fluorinated amino acids, dehydroamino acid 51 with both phthalimide and camphorsultam moieties
were reacted with various perfluoroalkyl iodides. Phthalimide
phtalimide, PPh3
CH2Cl2, r.t., 15 h
N
O
S
O2
H2, catalyst
r.t., 1 atm
O
OH
47
Scheme 10.
C6F 13l
hυ, TTMSS
N
C6F13
Na2S3O3 aq.
CH2Cl2
S
O2
N
S
O2
O
O
49
76% (>98% de)
48
Scheme 11.
was added in the a-addition40 to the already prepared N-propioloyl
derivatives of Oppolzer’s camphorsultam4150 to afford the dehydroamino acid 51 in good yield. The hydroperfluoroalkylation of 51
proceeded smoothly to afford the required products 52a–e in good
yield and with high stereoselectivity. The sultam auxiliary was
then removed via hydrolysis of compounds 52a and 52e to yield
carboxylates 53a and 53e in good yields, respectively, which were
then treated with hydrazine hydrate to yield the b-perfluoroalkylated amino acids 54a and 54e, respectively. As a result, by using
the (+)-camphorsultam, the corresponding (S)-amino acid was
formed. The N-Boc protected compound 56 can be obtained in
good yield in two steps from 53a. The trifluoromethylated product
53e was transformed into a dipeptide via EDC condensation with
phenylalanine methyl ester. No loss of enantiopurity was observed
in this reaction (Schemes 12 and 13).
N
S
O2
O
Rf
O
N
N
Na2S3O3 aq.
CH2CI2
O
O
52a-e
50
O
41
Rf I
hυ, TTMSS
O
O
42
O
N
O
+
O
51a-e
99%
Scheme 12.
Rf = C6F13 52a: (84%, d.r. = >99:1)
t-C4F9 52b: (51%, d.r. = >99:1)
C3F 7 52c: (79%, d.r. = >92:8)
i-C3F7 52d: (79%, d.r. = >99:1)
CF 3 52e: (90%, d.r. = >92:8)
S
O2
1068
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Rf
O
S
O2
O
O
OH
N
LiOH-H2O,H2O2
N
N
Rf
O
Rf
THF / H2O
H2N
o
EtOH, 80 C
O
52a: R = C6F13
52e: R = CF3
OH
NH2NH2-H2O
O
O
54a: R = C6F 13
54e:R = CF3 (66%)
53a: R = C6F 13 (81%)
53e:R = CF 3 (96%)
H2N
CO 2Me
Boc2O,NaOH aq.
dioxane / H2O
EDC , HOBt
TEA, CH2CI2
55
C6F13
CF3
O
H
N
CO2Me
N
OH
BocHN
O
O
O
56
(60% for two steps)
57
Scheme 13.
O2
S
O2
S
O
N
O
N
RMgX, THF, -78 °C
N
S
O2
O2
S
O
N
O
+
R
N
O
S
O2
58
N
R
O
S
O2
60
59
Scheme 14.
Asymmetric conjugate addition is one of the most useful methods for the stereoselective synthesis of b-substituted products.42
For this type of addition, chirality was introduced using the sultam
as an efficient chiral auxiliary to provide a wide variety of optically
active organic compounds. The diastereoselective conjugate addition of Grignard reagents to N-enoylsultams2 was first reported
by Oppolzer et al.43 In 2004, Robins et al. reported on the diastereoselective conjugate addition of Grignard reagents to N,N0 -fumaroyl
bis[(2R)-bornane-10,2-sultam] 58 obtained from fumaroyl chloride
and (2R)-()-2,10-camphorsultam.44 The C2 symmetrical fumaramide 58 with two Oppolzer camphorsultam moieties has previously been employed in reactions such as cycloaddition and
dihydroxylation reactions.45,46 As shown in Scheme 14, the fumaramide 58 was reacted with a number of Grignard reagents,
obtained from the corresponding alkyl bromides and chlorides, to
yield a mixture of diastereomers 59 and 60 (Table 4).
Succinamides 59 and 60 were treated with lithium aluminum
hydride to give a mixture of diol 61 and camphorsultam, which
Table 4
Entry
RMgX
1
2
3
4
5
6
7
8
9
10
R = ethyl
R = isopropyl
R = propyl
R = butyl
R = cyclohexyl
R = octyl
R = benzyl
R = isobutyl
R = hexyl
R = cyclohexyl methyl
Yield (%)
76
89
69
76
87
62
78
87
80
75
N
N
S
O2
de (%)
62
32
36
54
34
52
N/A
44
53
38
was then separated by column chromatography. It should be noted
that the camphorsultam was recovered in high yields and showed
no loss of appreciable enantiomeric excess and so could be reused
(Scheme 15 and Table 5).
O2
S
O
dr (major/minor)
81:19
66:34
68:32
77:23
66:34
76:24
N/A
72:28
76:24
69:31
LiAIH4, THF,
0 °C, 38-85%
NH
S
O2
R
O
90-95%
1
59 and 60
Scheme 15.
+
HO
OH
R
61
1069
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 5
Table 6
Entry
2-Substituted diol
1
2
3
4
5
6
7
8
9
Ethyl
Isopropyl
Propyl
Butyl
Cyclohexyl
Octyl
Bezyl
Isobutyl
Hexyl
Yield (%)
ee (%)
44
43
46
56
38
79
75
85
75
Configuration
73
29
36
56
33
54
90
50
60
(R)
(R)
(R)
—
(R)
—
—
—
—
Entry
2-Substituted diacid
1
2
3
4
5
Ethyl
Propyl
Butyl
Benzyl
Hexyl
Yield (%)
65
71
67
71
65
ee (%)
Configuration
63
52
72
92
37
(R)
(R)
(R)
(R)
(R)
O2
S
O
O
N
NH
LiOH, H2O, H2O2,
N
S
O2
aq. THF, 0 °C, 65-76%
R
O
S
O2
+
HO
OH
O
R
62
ee 92%
1
59 and 60
Scheme 16.
On the other hand, saponification of succinamides 59 and 60
formed the desired enantiomerically enriched substituted succinic
acids 62 with an (R)-configuration, with high ee thus indicating
that the addition of the Grignard reagents had occurred selectively
on the re-face of 58 (Scheme 16 and Table 6). Substituted succinic
acids 62 are essential intermediates in organic synthesis and building blocks for the preparation of enantiomerically pure b-substituted b-amino acids,47 a common scaffold for some natural
products.48 Hence, this methodology can be extended and applied
for the asymmetric synthesis of a variety of substituted butane1,4-diols and substituted succinic acids with moderate enantiomeric excess. However, (2R)-benzylsuccinic acid was obtained
with high ee; note that (2R)-benzylsuccinic acid proved to be an
inhibitor of carboxypeptidase A.49
The addition of organometallic reagents to a,b-unsaturated
carbonyl compounds is one of the most general synthetic methodol-
ogies for the introduction of a new stereogenic center at the
b-position of carbonyl compounds.42 Grignard reagents are among
the most popular and extensively used organometallic reagents.
Oppolzer et al. reported on the diastereoselective conjugate addition
of various Grignard reagents43 and organocuprates, Gilman reagents
(R2CuLi),12 to N-enoylsultams. The asymmetric conjugate addition
of inexpensive and easily synthesized Grignard reagents to aryl
substituted a,b-unsaturated carbonyl compounds 63 occurred with
high regioselectivity and good to excellent diastereoselectivity
(Table 7). These compounds can be transformed into chiral ketones,
alcohols, aldehydes, and carboxylic acids, which are significant and
valuable intermediates for the total synthesis of natural and medicinal products. The asymmetric conjugate addition of Grignard
reagents to N-enoylsultam 63 which is generated via acylation of
the camphorsultam with acyl chlorides50 afforded a mixture of
1,4-addition product 64 and 1,2-addition product 65 (Scheme 17).51
Table 7
Entry
Ar
RMgX
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
21
22
23
Ph
4-FPh
4-ClPh
4-MePh
Ph
4-FPh
4-MePh
4-ClPh
Ph
4-FPh
4-ClPh
4-MePh
Ph
4-ClPh
Ph
Ph
4-FPh
Ph
4-FPh
Ph
4-FPh
4-MePh
4-MePh
EtMgBr
EtMgBr
EtMgBr
EtMgBr
n-PrMgBr
n-PrMgBr
n-PrMgBr
n-PrMgBr
i-PrMgCl
i-PrMgCl
n-BuMgBr
n-BuMgBr
n-BuMgBr
n-BuMgBr
BnMgBr
BnMgBr
Cyclohexyl-MgC
MeMgI
Allyl MgBr
Allyl MgBr
Vinyl MgBr
Vinyl MgBr
4-MePhMgBr
Yield (%)
83
85
78
85
87
85
92
88
59
64
81
84
85
87
81
75
62
77
98
97
75
73
84
Product
64a
64b
64c
64d
64e
64f
64g
64h
64i
64j
64k
64l
64m
64 n
64o
64p
64q
65r
65s
65t
65u
65v
65x
Configuration of 64a
(3R)
(3R)
(3R)
(3R)
(3R)
(3R)
(3R)
(3R)
(3R)
(3S)
(3R)
(3R)
(3R)
(3R)
(3R)
(3R)
(3S)
1,4-/1,2-Product
ee of 66c
1,4-Product dr
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
>20:1
<1:20
<1:20
<1:20
<1:20
<1:20
<1:20
90
82
90
88
94
90
88
84
60
68
86
88
98
88
68
52
56
95:5
91:9
95:5
94:6
97:3
95:5
94:6
92:8
80:20
84:16
93:7
94:6
>99:1
94:6
84:16
76:24
78:22
1070
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
R
Ar
N
O
Ar
Ar
1,4-product
de: 52-98%
S
O
o
R
N
S
RMgX
N
+
O
O
64
O
- 78 C
S
O
R= ethyl, n-propyl, n-butyl, cyclohexyl, i-propyl, benzyl
O
63
OH
O
or
Ar
R
1,2-product
R
R
R = methyl, allyl
Ar
65
R = vinyl, allyl
Scheme 17.
Under optimized conditions, the asymmetric conjugate addition
of Grignard reagents to N-enoylsultam 63 afforded the 1,4-addition
product 64 in excellent regioselectivities (>20:1) and with good to
excellent diastereoselectivities. Compound 64 was then reduced
upon treatment with NaBH4 to provide the desired compound
66. Due to the steric hindrance of the camphor skeleton, most of
the Grignard reagents produced 1,4-addition products, except for
the methyl, allyl, vinyl, and aryl Grignard reagents. The nucleophilicity and steric properties of the Grignard reagents played an
important role with regard to the control of the regioselectivities
and diastereoselectivities of the conjugate addition reaction
(Scheme 18). In summary, the use of inexpensive and easily available Grignard reagents to provide excellent stereocontrol in conjugate addition reactions was demonstrated. These reactions provide
easy access to highly valuable building blocks for natural products
and important medicinal intermediates.
The hydroxyalkyl furan (S)-2-(20 -furyl)propan-1-ol (S)-67, an
essential building block for the synthesis of a range of natural
products,52 can be synthesized by employing Oppolzer’s camphorsultam.53 The sodium salt of (2R)-sultam 1 was acylated with
furan-2-yl-acetyl chloride to afford mixed imide 68, which was
methylated with high diastereoselectivity to afford 69. Lastly, the
corresponding (S)-67 form in virtually enantiopure was obtained
O
O
N
Ar
2.3. 1,3-Dipolar cycloaddition
Nitrones are multipurpose intermediates in the total synthesis
of alkaloids. They show an interesting dual reactivity either as electrophiles55 or 1,3-dipoles in 1,3-dipolar cycloaddition reactions for
the synthesis of five membered heterocycles.56 The intramolecular
1,3-dipolar cycloaddition of nitrones and olefins is especially
significant, since it gives an opportunity for the efficient access to
alkaloids containing a spirocyclic motif.57 Marine alkaloids from
cylindricine and lepadiformine families contain a remarkable
spirotricyclic skeleton. An intramolecular nitrone/olefin 1,3-dipolar
cycloaddition reaction was employed to generate their spirocyclic
1-azaspiro[4.5]decane core with acceptable regio- and stereoselectivities. The precursor for the cyclization was synthesized by
applying an asymmetric electrophilic hydroxyamination of the
enolate.58 In this pathway, intermediate 70 was directly
transformed into the terminal alkyne 71 via the addition of t-BuLi.
However, the expected product was not detected even in trace
amounts and instead t-butylketone 72 was obtained. To circumvent this problem, coupling of the bornane-10, 2-sultam chiral
O
R
RMgX
N
S
O
using a reductive cleavage of 69 in the presence of lithium aluminum hydride (Scheme 19).54
Ar
O
R
NaBH4
+
N
Ar
O
O
66
O
63
64
Scheme 18.
i) NaH, toluene , r.t.;
N
NH
ii) furan-2-yl-acetyl chloride, r.t., 76%
S
O2
S
O2
O
68
N
O
LiAlH4, THF, r.t., 89%
OH
O
O
(S)-67
69
Scheme 19.
i) NaN(SiMe3)2, THF, -78 °C
ii) MeI, HMPA, -78 °C to r.t.
iii) recrystallization,
87% 69 (>99% de.)
O
1
S
O2
Ar
HO
S
S
O
R
1071
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
O
Br
O
O
i) 1, AlMe3,PhMe, 70 °C
MeO
O
XC
Br
ii) t-BuLi, then Me3SiCl
70
NaN(SiMe3)2,THF, -78 °C, then 73
X
SiMe3
N+
O-
O
64%
71
SiMe3
74
NO
O
O
NH
XC =
CI
O
S
1
O
O
72
73
Scheme 20.
auxiliary 11, by employing a standard protocol taking advantage of
steric hindrance around the carbonyl group and the high acidity of
a-hydrogens was attempted.59 This sequence proved to be successful, and the desired alkynylsilane 74 was obtained in 50% yield via
the addition of t-BuLi and quenching the reaction with TMSCl. Electrophilic hydroxyamination was achieved via treatment of the
amide enolate with 1-chloro-1-nitrosocyclohexane 74.60 Acidic
hydrolysis allowed the hydrolysis of the initial cyclohexylnitrone
and an unmasked ketone was liberated with simultaneous cyclization to afford a single diastereoisomer of the nitrone 74. In this
manner, the spirocyclic skeleton of marine alkaloids, such as the
cylindricines or lepadiformine could be achieved via a stereoand regioselective 1,3-dipolar cycloaddition reaction (Scheme 20).
Tuning of the geometric and electronic properties of the
dipolarophile was crucial for achieving the desired selectivity.
Oppolzer et al. accomplished the asymmetric synthesis of
1-azaspiro[4.5]decanes,61 intermediates for the total synthesis of
cylindricine alkaloids using intramolecular 1,3-dipolar cycloadditions of nitrones with the bornane-10,2-sultam chiral auxiliary.
The intramolecular 1,3-dipolar cycloaddition of a cyclic nitrone
generated by an asymmetric electrophilic enolate hydroxyamination using the (2R)-bornane-10,2-sultam as the chiral auxiliary
was accomplished to afford bridged and fused cycloadducts with
total diastereocontrol. In this method, trimethylaluminum catalyzed the acylation of (2R)-bornane-10,2-sultam with methyl
undecenoate 75 was carried out to create the amide linkage of
the (undecenoyl)bornane-10,2-sultam 76 in good yield. After
i) AIMe3, toluene
deprotonation, trapping the (Z)-enolate with a hydroxyaminating
agent such as 1-chloro-1-nitroso-cyclohexane as the electrophile,62
with subsequent acid-catalyzed hydrolysis of the protected acetal
led to in situ cyclodehydration to produce nitrone 77 in high yield
as an enantiomerically pure diastereoisomer. Chiral nitrone 77 was
then subjected to an intramolecular cycloaddition. From this reaction, the two new products, fused 78 and bridged 79 cycloadducts
were separated by flash chromatography. The (2R)-bornane-10,
2-sultam was responsible for the stereocontrol at the spirocyclic
and bridgehead chiral centers (Scheme 21). The regiochemistry of
the cycloaddition limits the efficiency of this protocol for the syntheses of natural products. The formation of bridged and fused
adducts in the intramolecular cycloaddition of cyclic nitrones
was employed. Although the regioselectivity of this strategy was
unsatisfactory, the study validated the potential of this protocol
for the asymmetric synthesis of 1-azaspiro[4.5]decanes. The
bornane-10,2-sultam auxiliary induced the stereochemistry of
the nitrone a-center and thus controlled the stereochemistry of
the intramolecular dipolar cycloaddition, which generated the
spirocyclic stereogenic center. Subsequent efforts have been carried out to control the regiochemistry of the nitrone cycloaddition
via the introduction of extra substituents onto the dipolarophilic
tether.
Pyroglutamic acids, the cyclic forms of glutamic acids 80 and
their derivatives have been used extensively in organic synthesis.63
In its protected form, compound 80 has been used in the total
syntheses of a number of natural and pharmaceutical products.64
O
O
i) NaHMDS, THF, -78 °C
O
NH
ii)
S
O2
O
O
ii) 1-chloro-1-nitrosocyclohexane
iii) concentrated HCI, 80%
O
MeO 2C
76
60 °C, 78%
1
H
toluene, heat
*X
*XC
N
N+
O
O-
77
O
*XC
N
+
O
O
O
H
78, 41%
Scheme 21.
79, 49%
1072
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
O
N
TBDPSO
CO2Et
O
82
O
XC
N
+
O
TBDPSO
O
O
O
O
O
O
83
81
XC
N
TBDPSO
O
sealed tube
O
EtO 2C
EtO2C
XC
O
84
OTBDMS
XC =
EtO2C
N
S
O
N
Boc
O
85
O
Scheme 22.
The 1,3-dipolar cycloaddition of a chiral nitrone derived from
glyoxylic acid and protected D-ribosyl hydroxylamine 81 with the
acrylamide of Oppolzer sultam 82 gives a perfectly stereoselective
reaction resulting in protected (2R,4R)-4-hydroxy-D-pyroglutamic
acid 83.65 Nitrone 81 was synthesized in situ66 treated with the
Oppolzer sultam derived acrylamide 8213 to afford 84 in a 20:1
ratio, which can be separated (Scheme 22). As a result, protected
4-hydroxy-D-pyroglutamic acid 85 was synthesized via a five-step
sequence, using the Oppolzer sultam. The Oppolzer sultam was
recovered from compound 84 in approximately 60% yield. This
pathway resulted in the synthesis of the desired compound
(protected (2S,4R)-4-hydroxypyroglutamic acid) in a highly
efficient approach (dr = 20:1). This synthesis require a very low
temperature or difficult purifications, and avoided oxidation, thus
making it suitable and amenable for large-scale and even pilot
plant preparation.
The preparation of enantiomerically pure functionalized
derivatives of pyroglutamic acids has continued due to their
applications in both the synthesis of peptide-based drugs and as
synthons in asymmetric synthesis.67 The 1,3-dipolar cycloaddition
of D-glyceraldehyde nitrones with the Oppolzer sultam acrylamide
have been investigated extensively. The adducts obtained from the
cycloaddition reactions have been used as precursors in the stereoselective syntheses of protected 4-hydroxy pyroglutamic acids.68
The (2S,4S)-isomer, prepared from the major adducts of the
cycloadditions is especially useful. Accordingly, the first enantioselective syntheses of the cis-isomer ent-86b formally derived from
D-pyroglutamic acid, by using an Oppolzer sultam as the chiral
auxiliary and the furan ring as an efficient carboxyl group equivalent, was reported. Enantiomerically pure protected derivatives of
86b were synthesized via a diastereoselective strategy using
D-glyceraldehyde derived nitrones 87 and acrylates 82 as starting
materials.69 A literature survey on stereoselective nitrone cycloadditions with a-alkoxy nitrones revealed that substituents at both
the nitrone nitrogen and the dipolarophile have a large effect on
the steric control of the reaction (Scheme 23).70 The stereoselective
1,3-dipolar cycloaddition of D-glyceraldehyde-derived nitrones
87a–e with methyl acrylate and other dipolarophiles was achieved
to give the corresponding cycloadducts 88–92. The aforementioned methodology represents an easy and practical procedure for
the stereoselective syntheses of protected (2S,4S)-4-hydroxy
pyroglutamic acids.
In 2005, the Oppolzer (2R)-bornane-10,2-sultam 93 was used
for the synthesis of novel aldoxime 94, which is easily prepared
in high chemical yields via oximation of the desired glyoximide
using hydroxylamine hydrochloride (Scheme 24).71 From the
NMR spectra and X-ray crystallographic structural measurements,
the anti-configuration of the above aldoxime was established.
Aldoximes are very suitable substrates for the preparation of
nitroalkanes, and upon treatment with trifluoroperoxyacetic acid
(generated by 90% H2O2) were converted into nitroalkanes 95 in
good yields.72 Using di-tert-butyl dicarbonate and DMAP,
nitroalkane 95 was transformed into the nitrile oxides, and subjected to 1,3-dipolar cycloaddition with 3-E-hexene 97 to provide
2-isoxazoline 98 in reasonable yields, although only moderate
stereoselectivities were achieved. It was observed that chiral
aldoxime 94 in the presence of a 15-fold excess of MnO2 reacted
relatively sluggishly to afford the expected 2-isoxazolines in only
reasonable yields. The usual formation of aldehydes as by-products
of oxidation was not observed in this case (Scheme 25 and Table 8).
The asymmetric synthesis of chiral piperazinylpropylisoxazoline analogues (R)-(+)-99, 100, and (S)-()-99, 100 as potent
ligands for dopamine receptors was completed in seven steps
involving a 1,3-dipolar cycloaddition using Oppolzer’s chiral
sultams as a chiral auxiliary. This step is the most crucial and plays
a key role in this multi-step synthesis (Scheme 26).73 Asymmetric
1,3-dipolar cycloaddition of nitrile oxides 101 (3,4-dimethoxybenzaldehyde oxime 101) and acryloyl derivatives 82a and 82b
(1S)-()-2,10-camphorsultam a and (1R)-(+)-2,10-camphorsultam
b afforded diastereomeric mixtures of cycloadducts 102a and
102b in 58–65% yields. Compounds (R)-102a and (S)-102b were
then reduced with L-Selectride to produce (R)-103 and (S)-103 in
high yields. In this investigation, the asymmetric induction was
more promising when camphorsultams were used as chiral auxiliaries instead of oxazolidinones. Chiral ligands (R)-(+)-99, 100
showed a higher binding affinity as well as selectivity for the D3
receptor over the D4 receptor, compared with (S)-()-99 and 100
ligands.
An efficient method for the stereocontrolled syntheses of
4,5-dihydroisoxazoles,74 offering wide applications for the preparation of various pharmaceuticals75 and natural products,76 is the
asymmetric 1,3-dipolar cycloaddition of nitrile oxides. The
intermolecular diastereoselective cycloadditions of achiral nitrile
oxides to optically active dipolarophiles,77 using acryloyl
derivatives of chiral auxiliaries such as chiral sultams78 has
attracted the interest of asymmetric synthetic chemists. Recently,
Jurczak et al. reported on a useful procedure for the preparation
of the chiral nitrile oxide79 derived from N-glyoxyloyl-(2R)-bornane-10,2-sultam 93, using linear olefins as dipolarophiles via
1,3-dipolar cycloaddition,80 which provided 2-isoxazolines in both
moderate yields and diastereoselectivities. Asymmetric 1,3-dipolar
cycloadditions of a chiral carboxyloyl nitrile oxide derived from
1073
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
R1
R1
R
O
R1
1
R1
R3
O
O
R1
O
O
H
O
O
+
COR3
COR3
82a-c
N
N
-O + R2
reflux
O
R2
O
R2
87a-e
N
O
CO 2Me
O
+
89
88
N
Bn
O
1
R
R1
R1
3
82a R = OMe
82b R3 = OtBu
92
R1
O
+
O
O
O
N
S
R2
O
O
H
N
-O +
Ph
O
O
O
H
H
N
-O +
N
-O +
Ph
Ph
Ph
Ar
87b
O
H
N
-O +
Ar
N O
91
O
H
87a
R2
O
O
O
N
-O +
N
90
O
O
O
COR3
COR3
82c R3 =
87d
87c
87e
Ar: p-methoxyphenyl
OH
HO2C
N
H
O
ent-86b
Scheme 23.
Table 8
O
O
H
XC
NH2OH.HCI
O
H
CF3COOOH
XC
XC
NO2
Product
N
O
93
94
89-93%
OH
Yield (%)
98a
98b
98c
98d
98e
95
70-85%
de (trans)
58
55
59
68
70
15
13
10
Not determined
Not determined
NH
XC =
S
O2
(2R)-bornane-10,2-sultam to cycloalkenes was also achieved to
construct the corresponding 2-isoxazoline in both moderate yields
and diastereoselectivities. Then various alcohols obtained from the
corresponding compounds (Scheme 27, Table 9).
Scheme 24.
O
H
XC
94
MnO 2
CH2CH3
N
O
OH
O
CH3CH2
N
97
XC
N
O
O
NO2
XC
95
O
XC
Boc2O
96
DMAP
Scheme 25.
98
1074
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
+
R
OH
1
O
NaOCl, 0°C,
CH2Cl2, 58-65%
N
O
101
N
O
ii) (S)-(+)-MTPA-Cl, DMAP,
0°C, toluene, 90-92%.
N
N
103
102 a-e
XC =
R1
*
HO
XC
82 a-e
i) L-selectride,
R1 0 °C, THF, 80-85%;
*
XC
R1=
H3CO
S
O
O
OCH3
Scheme 26.
OH
O
H
XC
NH2OH HCI
MnO2
N
XC
O
OH
O
O
.
OH
CH2CI2
N
NaBH4
+
O
N
94
O
93
n
O
n
O
XC
n=1
n=2
n=3
n=4
(R,R)-112
(R,R)-113
(R,R)-114
(R,R)-115
O
N
104,
105,
106,
107,
N
O
108, 109, 110 or 111
XC
N
O
+ XC
XC =
n
Scheme 27.
In this reaction, compound 94 can be easily prepared via oximation of the corresponding precursor 93 and the chiral nitrile oxide,
which came from aldoxime 94 through mild oxidation with MnO2,
and trapped in situ with cycloalkenes 104–107 to form 2-isoxazolines 108–111 in moderate to good yields. Cycloadducts 108–111
were then converted into alcohols 112–115, respectively, through
a simple reduction. The configuration of the major cycloadducts
109 was proven to be (R,R) by comparison of the chiral GC analysis
of alcohol 113, obtained from either a single diastereoisomer or
from the reaction mixtures (Scheme 28). As a result, only modest
diastereoselectivities were achieved. These results open the way
for further studies, including the use of more sterically challenging
olefins, more operative and effective chiral auxiliaries and less
polar solvents.
The 1,3-dipolar cycloaddition between a nitrone and an alkene
is considered the method of choice for accessing a number of nitrogen containing compounds. The isoxazolidines synthesized via this
reaction, are among the most important intermediates in organic
and heterocyclic synthesis.81 In 2013, a diastereoselective
asymmetric 1,3-dipolar cycloaddition of N-(alkoxycarbonylmethyl) nitrones derived from amino acids (glycine, alanine and
phenylalanine) was reported by Merino et al. Asymmetric induction was observed when using an Oppolzer sultam acrylamide
which preferentially provided the (3R,5R)-isomer (Scheme 29).82
The isoxazolidines are readily converted into the desired 5-substi-
Table 9
Cycloadduct
1
2
3
4
108
109
110
111
Yield (%)
Alcohol
52
45
52
61
Yield (%)
112
113
114
115
de (%)
92
90
95
95
Abs configuration
39
45
48
50
O
N
S
O
EtO 2C
+
N
O-
(S,S)-112
(S,S)-113
(S,S)-114
(S,S)-115
Scheme 28.
109
Entry
n=1
n=2
n=3
n=4
N
S
O2
n
108
n
O
O
82a
N
R2
toluene, sealed tube, 80 °C, 16h
116 a-e
O
R2
O N
S
O
CO2Et
117a-e
R1 = H, Me
R2 = i-Pr, Ph, 2-Furyl, BnOCH2, BocHNCH2
116a ; R1 = H, R2 = i-Pr
116b: R1 = H, R2 = Ph
116c: R1 = H, R2 = 2-Furyl
116d: R1 = H, R2 = BnOCH2
116e: R1 = H, R2 = BocHNCH2
Scheme 29.
(R,R)
(R,R)
(R,R)
(R,R)
1075
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 10
Entry
R1
R2
Nitrone
Alkene
Isoxazolidine
1
2
3
4
5
H
H
H
H
H
i-Pr
Ph
2-Furyl
BnOCH2
BocHNCH2
116a
116a
116a
116a
116a
82a
82a
82a
82a
82a
117a
117a
117a
117a
117a
2.4. Cyclopropanation
The Oppolozer sultam chiral auxiliary is highly efficient in
inducing valuable and practical diastereoselectivity in the stepwise cyclopropanation of sulfur ylides with an acyclic substrate.
This strategy affords chiral 2-(4-imidazolyl) cyclopropyl derivatives, which are invaluable intermediates in the synthesis of
chiral histamine H3 receptor agents. Phillips et al. reported on
the diastereoselective synthesis of trans-2-(1-triphenylmethyl1H-imidazol-4-yl)cyclopropane carboxylic acids. In this multi-step
synthesis, the 3:1 diastereoselective cyclopropanation of (5R)trans-4-aza-10,10-dimethy-3-thia-4-(3-(1-triphenymethy-1H-imi-
O
O H
OH
N
CDI, DBU
H
H
O
O
N
H
CH3
CH3
N
97%
N
N
O
O H
CH3
S
H
N
O
O
Tr
O
122
121
O
H
N
NH2
H
N
H
123
N
120
CH3
N
+
H
N
H
O
H
NH2
H
OH
N
H
OH
N
H
N
N
N
H
124
Tr
125
Tr
126
Scheme 30.
CH3
S
N
S
H
CH3
O
Tr
O H
DMSO / THF
Tr
N
96%
O
H
80%
TrCI,TEA, CHCl3
CH3
N
50
61
80
80
75
O H
119
Tr
CH3
S
sulfur ylide
CH3
N
N
118
>98:2:0:0
>98:2:0:0
>98:2:0:0
>98:2:0:0
>98:2:0:0
CH3
S
N
Tr
Yield (%)
dazol-4-yl)prop-2-enoyl) tricyclo[5.2.1.0<l,5>]decane-3,3-dione83
using trimethylsulfoxonium ylide in the key step plays an important role. These cyclopropanes are key intermediates for the
development of potent and chiral histamine H3 receptor
agents.84 For the preparation of chiral Michael acceptor 120, urocanic acid was reacted with 1,10 -carbonyldiimidazole, followed
by the addition of (1R)-(+)-2,10-camphorsultam and DBU. The
acryloyl derivative 119 can be prepared in high yields from
N-acylation of the (1R)-(+)-2,10-camphorsultam. (5R)-trans-4-Aza10,10-dimethyl-3-thia-4-(3-(1H-imidazol-4-yl)prop-2-enoyl)tricyclo[5.2.1.0<l,5>]decane-3,3-dione 119 is trityl protected in the
presence of triethylamine to afford 120 in high yield. The cyclopropanation of sultam 120 using trimethylsulfoxonium iodide in
DMSO/THF was accomplished to form a 3:1 mixture of (1S,2S)cyclopropane-sultam 122 and (1R,2R)-cyclopropane-sultam 121,
respectively. The N-acryloyl derivative 120 was transformed into
a diastereomeric mixture of cyclopropanes 121 and 122 in 80%
isolated chemical yield. The major diastereoisomer 122 was
separated by the flash chromatography of the mixture of cyclopropanes and recrystallized from ethanol. Similarly, the cyclopropanation reaction of the (lS)-(+)-2,10-camphorsultam chiral
auxiliary was also achieved. The major cyclopropane
diastereoisomer 122 was reacted with LiOH in THF/H2O to give
(1S,2S)-trans-2-(1-triphenylmethyl-1H-imidazol-4-yl)cyclopropanecarbocyclic acid 123 in high yield. In the same way, compound
121 afforded (1R,2R)-trans-2-(1-triphenylmethyl-1H-imidazol-4yl)cyclopropanecarboxylic acid 124. Cyclopropanecarboxylic acid
123 was also converted into (1S,2S)-trans-2-(1H-imidazol4yl)cyclopropylamine 125 and 126 and then used subsequently
to construct (1R,2R)-trans-2-(1H-imidazol-4-yl)cyclopropylamine
126 (Scheme 30).
tuted-3-hydroxypyrrolidin-2-ones. The cycloaddition reaction of
compound 116a–e with N-acryloyl-(2R)-bornane-10,2-sultam
82a as a dipolarophile was carried out with complete regio-(3,5),
(trans) diastereo- and enantioselectivity (3R,5R). Only one product
was characterized from the reaction mixtures. The results are
listed in Table 10. As a result, the diastereoselective 1,3-dipolar
cycloadditions of achiral N-(alkoxycarbonylmethyl)nitrones with
Oppolzer sultam acrylamide was achieved in which regio- and diastereoselectivity was complete toward the 3,5-trans-disubstituted
isoxazolidines. Furthermore the asymmetric induction leads to
the (3R,5R)-isomers. The use of the Oppolzer’s sultam acrylamide
as a dipolarophile has the advantage of affording only one isomer.
In conclusion, and in accordance with previously reported dipolar
cycloadditions with such a dipolarophile, the Oppolzer’s sultam
was established as an excellent chiral auxiliary. It is worthy that
for this type of 1,3-dipolar cycloaddition, it is more desirable and
appropriate to position the chiral group on the dipolarophile rather
than on the nitrone nitrogen atom.
N
dr
O
O
1076
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
H
CH2N2
N
S
O2
R
of an achiral catalyst Rh2(OAc)4 was achieved with high yields
and stereoselectivities. These results are a considerable improvement in the case of 132a, even though the sultam derivative
provides the only source for chiral induction in the cyclopropanation. Cyclopropanation of 132a with 131 afforded two transdiastereomers 133a in 81% diastereomeric excess (de) and 65%
yield along with some of the cis-isomer (Table 11).
N
Pd(OAc)2
S
O2
O
128
R
H
O
129
a: R= Ph, 73% yield, 99% de
b: R= tert-Bu, no reaction
Table 11
H
HO
H
132
R1
R2
Yield (%)
a
b
c
tert-Bu
Me
Ph
H
Me
H
85
83
67
trans:cis
trans de %
cis de %
81
90
67
>98
76:24
—
68:32
70
127
Scheme 31.
The cyclopropanation of olefins with carbenoids is an important
reaction and offers a suitable method for the stereoselective
preparation of substituted cyclopropanes.85 The stereoselective
cyclopropanation of alkenes using the Oppolzer sultam carbenoid
was first investigated by Haddad et al. in 1997.86 The addition reaction was accomplished in high yields on substituted alkenes and
gave an access to the stereoselective synthesis of di- and tri-substituted cyclopropanes. This method can be applied to the stereoselective syntheses of 127. In this research, the stereoselective
cyclopropanation of chiral alkene 128a with diazomethane87 was
performed, providing 129a in excellent yield and with high de.
However, the addition of diazomethane to 128b was unsuccessful
(cyclopropanation did not occur, probably because of steric hindrance). Applying this method in the syntheses of tri-substituted
alkenes,88 gave low yields while the separation was tedious
(Scheme 31).
To circumvent these problems, an alternative method for the
preparation of sterically hindered cyclopropanes, based on the
addition of the a-diazoamide derivative of Oppolzer sultam 131
to olefins was performed. As shown in Scheme 32, diazoacetamide
131 can be generated from the reaction of glyoxylchloride-p-tosylhydrazone 130 and bornane-10,2-sultam (Oppolzer sultam).89
Cyclopropanation of the sultam carbenoid with 3,3-dimethylbutene 132a, isopropylene 132b, and styrene 132c in the presence
SO2NHN=CHCOCI
N,N-dimethylaniline, Et3N
CHN2
N
S
O2
O
90%
Me
130
NH
S
O2
131
1
R1
N
S
O2
CHN2 +
R2
O
131
O
H
H
127
133
Scheme 33.
2.5. Ene reaction
As shown in Scheme 34 N-glyoxyloyl-(2R)-bornane-10,2-sultam 9391–95 can be prepared from the Oppolzer (2R)-bornane10,2-sultam.10
The asymmetric ene reaction of N-glyoxyloyl-(2R)-bomane10,2-sultam 93 and its hemiacetal 134 with 1-pentene 135 and
1-hexene 136 was accomplished in the presence of various Lewis
acids (SnCl2, TiCl4, ZnBr2, BF3Et2O, AlCl3, EtAlCl2, Eu(fod)3) as the
catalyst to afford diastereoisomeric mixtures of olefins 137 and
138 or 139 and 140 with the preferred formation of the products
with an (S) absolute configuration on the newly generated stereogenic center. The best results with regard to the diastereoisomeric
excess were observed when the reactions of 93 and 135 (80% de)
and 136 (78% de) were performed under ZnBr2 catalysis (Scheme 35
and Table 12).96
S
O2
O
R2
O
O
O
H
H
N
XC
+ MeOH
- MeOH
O
O
S
O
Scheme 32.
HO
84%
S
O2
133
R1 = tert-Bu, Me, Ph
R2 = H, Me
LiAIH4
R1
N
132
H
H
N
H
Rh2(OAc)4
55%
de 95.55%
From crystallization of the mixture, the major isomer of trans133a was obtained in good yield and with high de. Finally,
compound 133a was reduced by LiAIH4 to form the desired cyclopropane 127 in high yield (Scheme 33). For the development of
tri-substituted cyclopropanes, the sultam carbenoid was added to
isobutylene 132b to obtain 133b in 90% de and 83% yield. Lastly,
cyclopropanation of styrene 132c was carried out with moderate
stereoselectivity. Isomer 133c was identified by its comparison
(GC–MS) with that of an authentic sample of trans-133c90 and
the corresponding cis/trans isomers of 127, prepared by the reduction of 133c using tetradecane as an internal standard. An
improved selectivity is expected in the addition of the sultam
carbenoid to alkenes if a chiral catalyst of matched double chiral
induction is used.
25
O
Scheme 34.
OH
XC
H
OMe
134
1077
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
O
R
+
H
Lewis acid
R
XC
XC
+
XC
R
OH
OH
O
135: R = Et
136: R = n-Pr
93
(14R)-138 R =Et
(14R)-140 R= n-Pr
(14S)-137 R =Et
(14S)-139 R= n-Pr
Scheme 35.
Table 12
Entry
Enophile
Ene
Catalyst (equiv)
Solvent
Temperature (°C)
Time (h)
Yield (%)
Diastereoisomeric composition (S):(R)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
17
18
19
20
93
93
93
93
93
134
134
93
134
134
134
93
134
93
134
134
134
134
134
134
135
135
135
135
136
136
136
136
136
136
136
135
135
136
136
136
136
136
136
135
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (1.1)
SnCl4 (3.0)
TiCl4 (1.1)
TiCl4 (1.1)
TiCl4 (2.0)
TiCl4 (3.0)
ZnBr2 (1.1)
ZnBr2 (1.1)
ZnBr2 (1.1)
ZnBr2 (1.1)
ZnBr2 (1.1)
BF3Et2O (1.1)
AlCl3 (2.0)
EtAlCl2 (2.0)
Eu(fod)3 (0.02)
CH3NO2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
5
5
20
78
78
78
78
78
78
78
78
5
5
5
5
20
5
5
5
5
36
8
2
48
48
48
48
24
48
48
48
48
54
48
60
48
80
80
80
120
95
89
86
77.8
93.3
94.6
96
42
40
63
57
50
46
43
43
46
65
78
42
87
55:45
71:29
66:34
84:16
75:25
69:31
78:22
83:17
79:21
77:23
77:23
90:10
88:12
89:11
85:15
82:18
65:35
84:16
76:24
83:17
O
ZnBr2
+
R
R = Ph 141
Me 142
i-Pr 143
t-Bu 144
OH
N
S
O
O
H
OMe
+
N
OH
O
O
R
N
S
O
O
R
CH2Cl2
S
(S)-141a
(S)-142a
(S)-143a
(S)-144a
134
OH
O
O
(R)-141a
(R)-142a
(R)-143a
(R)-144a
O
O
ZnBr2
N
+
n
+
CH2Cl2
S
O
n = 1 145
n = 2 146
OH
O
(S)-145a
(S)-146a
N
S
n
O
OH
O
n
(S)-145a
(S)-146a
Scheme 36.
In the following, the application of an N-glyoxyloyl camphorpyrazolidinone in the reaction with 1,1-disubstituted olefins in the
presence of Sc(OTf)3 as the catalyst with stereoselectivities of typically more than 74% (up to 94%)97 was reported by Chen et al.97
The ene reaction of olefins with glyoxylates is one of the most useful strategies for synthesizing a-hydroxy acids with a double bond
at the c,d-position, which upon reduction give the corresponding
1,2-diols. Such enantiomerically pure ene products are of great
synthetic usefulness as intermediates in total syntheses.98 The
application of the ene reaction is one of the most effective methods
for the asymmetric synthesis of 1,2-diols. The diastereoselective
carbonyl-ene reaction of a variety of 1,1-disubstituted olefins with
chiral glyoxylic acid derivatives of Oppolzer sultam 134 auxiliaries,
prepared by the ozonolysis of N-crotonoyl-(2R)-bornane-10,2-sultam, catalyzed by ZnBr2 was achieved in good yields and with high
to excellent de.99 The use of hemiacetal 134 is desirable since the
products are often crystalline. Among catalysts used for the ene
reaction with the Oppolzer sultam-derived hemiacetal 134, ZnBr2
was found to be the catalyst of choice and showed many advantages over the use of SnCl4 and Sc(OTf)3. Remarkably, all of the products were typically crystalline and could be readily purified by
crystallization from a suitable solvent (Scheme 36 and Table 13).
The products obtained with the hemiacetal of N-glyoxyloyl(2R)-bornane-10,2-sultam 134 catalyzed by ZnBr2 have the (20 S)absolute configuration, which was confirmed by reduction of the
ene products using Oppolzer sultams 141a–146a auxiliaries to
the corresponding 1,2-diols 141c–146c, and re-confirmed via chromatographical comparison on chiral phases (Scheme 37). According to this approach, chiral a-hydroxy-acids esters containing a
double bond in the c,d-position, were established as compounds
of synthetic interest, and which can be obtained in good to high
diastereomeric purity (72% up to 94% de).
1078
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 13
Entry
Alkene
1
2
141
ZnBr2 (equiv)
Temperature (°C)
Time (h)
Product
Yield (%)
de (%)
1
1
20
0–5
5
5
141a
141a
96
92
77
82
0.2
1
0.2
20
0–5
20
60
2
20
141a
142a
142a
75
93 (49)
50
75
86
86
0–5
5
143a
5
144a
85
72
Ph
3
4
5
142
6
143
7
144
8
9
145
1
0.2
0–5
5–20
5
20
145a
145a
89
84
94
81
10
146
1
0–5
5
146a
92(45)
82
1
Pri
1
But
20
92(55) 79
(Regioselectivity: 90:10)
O
OH
O
R
R
LiAIH4
N
O
OH
Et2O
OH
S
HO
HO
O
R = Ph
Me
i-Pr
t-Bu
OH
145a or 145b
146a or 146b
MeOH
OH
HO
147a: R = Me
147b: R = Ph
Ph
O
n
OH
Et2O
O
S
O2
HO
149
R
N
141a-144a
LiAIH4
O
10% Na2CO3. aq
141c
142c
143c
144c
150
n= 1 145c
n=2 146c
Scheme 39.
Scheme 37.
conditions, higher diastereoselectivities in each direction of asymmetric induction were observed. As shown in Scheme 38, the
asymmetric reduction of 3 and 4 was achieved using a platinum
catalyzed hydrogenation. Hydrogenation of 3 resulted in an equimolar mixture of diastereomers 147 and 148, which were separated chromatographically. In a similar procedure, compound 4
was hydrogenated using Adam’s catalyst to yield a diastereomeric
mixture of alcohols 147 and 148 in which crystalline 147 was
found to be the major diastereomer.103
The hydrolysis of both crystalline products 147 and 148 was
achieved in the presence of sodium carbonate in methanol to
remove the sultam auxiliary and give (S)-lactic 149 and (S)-mandelic 150 acids, respectively (Scheme 39). It has been found that
readily available (2R)-bornane-10,2-sultam is a highly effective
chiral auxiliary in the reduction of its a-ketoacyl derivatives. It
has also been established that by simply changing the reduction
conditions, high diastereoselectivities in each direction of asymmetric induction can be achieved. Furthermore, the removal of
the auxiliary is extremely easy and its regeneration is quantitative.
Butane-1,4-diols, recognized as useful four-carbon building
blocks in organic chemistry, are precursors for the preparation of
2.6. Reduction
Optically active a-hydroxy acids can also be applied as chiral
building blocks in the total syntheses of natural products.100 For
the synthesis of chiral a-keto acids, diastereoselective reduction
was selected as a competitive approach. The application of a chiral
auxiliary in this case is a common method. A (2R)-bornane-10,2sultam4 can be employed as an extremely efficient chiral auxiliary
for various stereoselective transformations.101 N-Methylglyoxyloyl-3 and N-phenylglyoxyloyl-4102 derivatives of (2R)-bornane-10,
2-sultam were selected as model substrates for diastereoselective
reductions. The asymmetric reduction of N-methylglyoxyloyl-3
and N-phenylglyoxyloyl-(2R)-bornane-10,2-sultam 4 can be
achieved, using different reducing conditions [H2/Pt, H2/Pd-C,
H2/Ir-Al2O3, H2/RhCl(PPh3)3, L-Selectride, Super-H, NaBH4, and
Zn(BH4)2] to create mixtures of two diastereoisomeric alcohols.
Significantly, the reaction conditions resulted in an excess of both
the (S)- and (R)-configurations at the newly generated stereogenic
center of the product. As a result, by only changing the reduction
O
N
S
O2
3a: R = Me
4b: R = Ph
OH
R
O
OH
[H]
N
S
O2
147a: R = Me
147b: R = Ph
Scheme 38.
R
+
R
N
O
S
O2
148a: R = Me
148b: R = Ph
O
1079
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O2
S
O
O
N
N
N
+
N
S
O2
R
O
O2
S
O
O2
S
H2, 10% Pd/C
N
7 bar, 25 oC, dry toluene
S
O2
151
a: R = Me
b: R = Et
c: R = Pr
d: R = hexyl
e: R = octyl
f: R = phenylethyl
g: R = isopentyl
h: R = isopropyl
i: R = isobutyl
j: R = cyclohexylethyl
R
O
R
N
S
O2
O
153
152
LiAIH4
OH
HO
R
154
Scheme 40.
many pyrrolidine natural products.104 The Oppolzer camphorsultam is a most useful chiral auxiliary and can be used for the asymmetric synthesis of such chiral compounds. The reduction of
prochiral unsaturated reactants has attracted much attention.
The diastereoselective hydrogenation of N-enoylsultams has been
reported by Oppolzer et al.;105 the asymmetric syntheses of 2substituted butane-1,4-diols was achieved by the hydrogenation
of homochiral fumaramides 151 derived from the (2R)-Oppolzer
sultam. The succinamides were reduced by LiAlH4 to afford the
desired (2S)-butane-1,4-diols; it was established that the addition
of hydrogen had occurred selectively on the re-face of the fumaramides 151. Robins et al. reported on the diastereoselective hydrogenation of various novel fumaramide derivatives 151a–i including
N,N0 -bis[(2R)-bornane-10,2-sultam]-fumaramide.106 The reduction
of some compounds was achieved in the presence of LiAlH4 to
afford 2-substituted butane-1,4-diols 154a–e. Using this strategy,
a series of pyrrolidine natural products were obtained from the
enantiomer of the methyl derivative 154. It is noteworthy that
the synthesis of the novel fumaramide derivatives 151a–j could
be started from the corresponding 2-substituted fumaric acids.
These were synthesized by following already known procedures.107 Modification of one of the reported procedure107 led to
an improvement of the yields by 10–20%. Coupling of the acids
to commercially available (2R)-()-2,10-camphorsultam was performed either by reacting the acid chloride with the camphorsultam in the presence of sodium hydride or by employing DCC and
DMAP as conventional coupling reagents with the diacid and the
camphorsultam. The optimization conditions with regard to the
solvent, catalyst, temperature, and pressure for the catalytic hydrogenation of 151a had a great effect on the outcome of the reaction.
The use of dry toluene with Pd/C as a catalyst under 7 bar pressure
was found to be the best combination of the reaction conditions
(Scheme 40).
This asymmetric heterogeneous hydrogenation procedure has
been developed for the syntheses of enantiomerically pure 2substituted butane-1,4-diols. The method has also been applied
in the total synthesis of natural products such as the pyrrolidine
alkaloids.
2.7. Halohydrin reactions
The 1,2-halo functionalization of olefins such as halohydrination (halohydroxylation and haloalkoxylation) is a common and
important reaction in organic chemistry. Regioselective and
asymmetric syntheses leading to halohydrin formation from
a,b-unsaturated carboxylic acids can afford different chiral carboxyhalohydrins and a-halo-b-hydroxy/alkoxy carboxylic acids.
These are often used as versatile and useful synthetic intermediates due their ability to be converted into a variety of important
organic compounds via easy transformations. Asymmetric halohydrin reactions such as halohydroxylation and halomethoxylation of chiral a,b-unsaturated carboxylic acid derivatives108
were accomplished in the presence of a Lewis acid as a catalyst
using N-halosuccinimide (NXS; X = Br, I) as the halogen source.
In this reaction, by using Oppolzer’s sultam as the chiral auxiliary regio and anti-selectivities of 100% and diastereoselectivities
of up to 82:18 were achieved in good yields.109 It is important to
note that the majority of metal halides and acetates were not
suitable catalysts for the halohydrin reactions, but metal triflates
especially Yb(OTf)3 exhibited excellent catalytic activity for the
development of a,b-unsaturated carbonyl products via halohydrination. Bromohydrin reactions of alkenoyl, cinnamoyl, and moderately electron-rich cinnamoyl compounds with NBS under
Yb(OTf)3 catalysis were achieved successfully, whereas the more
electron-rich cinnamoyl substrates undergo iodohydrin reactions
with NIS preferably. However, the cinnamoyl substrates carrying
electron-withdrawing substituents on the aromatic ring did not
react via Lewis acid catalyzed halohydrin reaction with either
NCS, NBS or NIS. Notably, bromohydroxylation using the oxazolidinone chiral auxiliary under the action of Yb(OTf)3 was
achieved with low diastereoselectivity, and as a result of the
bromohydroxylation of a,b-unsaturated carboxylic acid derivatives containing an Oppolzer sultam chiral auxiliary. Lewis acid
Yb(OTf)3 mediated bromohydroxylation of (2R)-N-cinnamoylbornanesultam 63 provided a-halo-b-hydroxycarbonyl compounds 155 and 156 with moderate diastereoselectivity and
good yields. This reaction was successful for a range of cinnamoyl substrates involving electron donating and withdrawing substituents on the aromatic ring that were reacted with various
alkenoyl substrates (Schemes 41 and 42 and Table 14).
a-Halo-b-methoxycarboxylic acid derivatives are important
precursors for the synthesis of b-methoxyamino acids109 (a rather
unusual amino acid constituent of some biologically active compounds). The catalytic asymmetric halomethoxylation of various
(2R)-N-enoylbornanesultam substrates 63a–l with NBS was performed using Yb(OTf)3 as the catalyst at room temperature to
afford the corresponding bromomethoxycarbonyl compounds in
moderate yield. The iodomethoxylation of 63a under identical con-
1080
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
N
5% aqueous CH3CN (v/v), 25 °C
R
X
S
O
O
R1
1
N
R2
R
S
O
63
HO
O
Yb(OTf)3, NBS
N
R2
S
O
HO
O
1
R
O
155
2
X
O
156
X = Br, I, Cl /Br/I
Scheme 41.
O
O
HO
Br
MeO
ii) MeOH , n-BuLi, -78 °C
81%
N
S
O
i) K2CO 3, acetone, 25°C
OMe
OMe
O
O
157
109
Scheme 42.
Table 14
Entry
Substrate
R1
R2
1
2
3
4
5
6
7
8
9
10
11
12
13
63a
63b
63c
63d
63e
63f
E-63g
63h
63i
63j
63k
63l
E-63m
C6H5
4-MeOC6H4
4-BnOC6H4
3,4-MeOC6H3
4-BnO-3-MeOC6H3
3,4,5-MeOC6H4
4-MeOC6H4
2-Naphthyl
2-ClC6H4
2-NO2C6H4
CH3
C6H13
C6H13
H
H
H
H
H
H
CH3
H
H
H
H
H
CH3
Time (h)
ditions (NIS instead of NBS) resulted in the formation of iodomethoxycarbonyl compounds in good yield with moderate diastereoselectivity. Compound 158a was the major isomer and could be
converted into the N-protected syn-b-methoxyphenylalanine
which is the unusual amino acid part of the cyclomarins.109 The
electron-rich cinnamoyl substrate and the b-(2-naphthyl)enoyl
substrate showed moderate to good diastereoselectivities in
bromomethoxylation and the more electron-rich cinnamoyl substrates were subjected to iodomethoxylation with NIS preferably.
The electron-deficient cinnamoyl substrates did not respond to
halomethoxylation and halohydroxylation even under more vigorous reaction conditions (Scheme 43 and Table 15). This protocol is
an alternative route for the synthesis of chiral a-halo-b-hydroxy/
8
2
3
1.5
3
3
6
10
48
48
36
36
36
R1
N
MeOH , 25 C
X
S
S
O
63
O
158a
1
R = C6H5, 4-MeOC6H4, 4-BnOC6H4,
3,4-MeOC6H3, 4-BnO-3-MeOC6H3, 2-Naphthyl,
2-ClC6H4, 2-NO2C6H4, CH3, C6H13
R1
N
+
X
S
OMe
O
OMe
Yb(OTf)3, NBS
O
80(12)
93
91
94
90
71
95
88
78(20)
81(10)
80(12)
Pandey et al. reported110 on a general procedure for the production of X-azabicyclo[m.2.1]alkane frameworks111 in enantiomerically pure form found, as in epibatidine (X = 7, m = 2),111 cocaine
alkaloids (X = 8, m = 3),112 and anatoxines X = 9, m = 4)113using
an asymmetric [3+2]-cycloaddition reaction of cyclic azomethine
o
O
Yield (%)
2.8. [3+2] Cycloaddition reactions
O
R1
dr (155:156)
64:36
72:28
74:26
75:25
76:24
78:22
82:18
65:35
NR
NR
72:28
68:32
70:30
methoxy carboxylic acid derivatives by employing readily available N-halosuccinimide as the common halogen source. The diastereoselectivity of this process has been improved upon and this
concept has also been applied to other catalytic 1,2-halo functionalizations of olefins.
O
N
X
Br
Br
Br
I
I
I
Br
Br
Cl/Br/I
Cl/Br/I
Br
Br
Br
O
O
158b
X = Br, I, Cl /Br /I
Scheme 43.
1081
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 15
Entry
Substrate
R1
1
2
3
4
5
6
7
8
9
10
11
63a
63a
63b
63c
63d
63e
63h
63i
63j
63k
63l
C6H5
C6H5
4-MeOC6H4
4-BnOC6H4
3,4-MeOC6H3
4-BnO-3-MeOC6H3
2-Naphthyl
2-ClC6H4
2-NO2C6H4
CH3
C6H13
Time (h)
7
8
3
4
2
2
9
48
48
24
24
X
dr (158a:158b)
Br
I
Br
Br
I
I
Br
Cl/Br/I
Cl/Br/I
Br
Br
65:35
67:33
78:22
75:25
79:21
75:25
63:37
NR
NR
66:34
62:38
R
n
N
R
O
n
+
N
O
n
H
+
DCM
S
O2
N
H
N
S
O2
160
161
82
71(10)
78(8)
N
Ag(I)F
TMS
52
87
98
91
97
90
90
R
N
TMS
Yield (%)
O
162
S
O2
i) LiOH, MeOH:H2O (2:1)
ii) SOCI2, dry MeOH
R
R
N
N
O
EWG*
n
n
OMe
H
159
163
Scheme 44.
Table 16
Substrate 161
R
a, n = 1
b, n = 2
c, n = 3
PhCH2
Me
PhCH2
Yield (%)
62
58
68
161:162
98:2
80:20
95:5
cycloaddition reaction.115 In contrast to the application of other
auxiliaries,116 a strong effect and a correlation between the
increasing solvent polarity and p-facial selectivity was found during the uncatalyzed cycloaddition of ()-164b to cyclopentadiene
in the aforementioned protocol (Scheme 45).
2.10. Aldol and nitroaldol reactions
ylides containing an Oppolzer acryloyl camphorsultam. Several
compounds possessing X-azabicyclo[m.2.1]alkane in enantiomerically pure form 159 were synthesized from precursors 160 via
Oppolzer chiral acryloyl sultam 82 through a [3+2]-cycloaddition
strategy using cycloadducts 161 and 162. The chiral auxiliary
was removed from the major cycloadduct 161 by heating with
LiOH in MeOH/H2O (2:1) and with subsequent treatment with
SOCl2 to afford the desired methyl ester 163 (Scheme 44 and
Table 16). In conclusion, an efficient strategy for the synthesis of
X-azabicyclo[m.2.1]alkanes in enantiomerically pure form using a
[3+2]-cycloaddition reaction of a cyclic azomethine yilde with
Oppolzer’s chiral acryloyl camhor sultam, has been performed.
2.9. [4+2] Cycloaddition reaction
(2R)-Bornane-10,2-sultam was as an efficient and multi-purpose chiral auxiliary in the [4+2] cycloaddition of cyclopentadiene
to N,N0 -fumaroyl derivatives. Jurczak et al. observed114 complete pfacial selectivity when using cyclopentadiene, N-fumaroyl mono
and bis[(2R)-bornane-10, 2-sultam] in a TiCl4-catalyzed [4+2]
One of the basic strategies for the development of carbon–carbon bonds117 is the nitroaldol additions reaction (Henry reaction)
in which nitroalcohols are constructed and provide a simple access
to diverse intermediates such as 2-aminoalcohols, 2-nitroketones,
nitroalkenes etc.118,119 These intermediates are effective in the
preparation of biologically important compounds.120 The derivative of glyoxylic acid containing a (2R)-bornane-10,2-sultam as
the chiral auxiliary is a very useful substrate for the construction
of enantiomerically pure nitroalcohols via nitroaldol reactions
and note that nitroalcohols can be applied as the starting materials
in the synthesis of diverse natural products. N-Glyoxyloyl-(2R)bornane-10,2-sultam 9313 was treated with simple nitroalkanes
(nitromethane 168, 1-nitrohexane 169 and 2-nitroacetaldehyde
diethyl acetal 169) to construct diastereomeric nitroalcohol 168
with high asymmetric induction. Significantly, the glyoximide 93
is an extremely efficient chiral inducer. Finally, for the major diastereoisomer, the absolute configuration (2S) and relative configuration (syn) were confirmed. These reactions were examined under
different conditions such as by using neutral Al2O3, activated
Al2O3, tetrabutylammonium fluoride trihydrate (TBAF3H2O) or
1082
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
C(O)R
OH
OH
C(O)R
(2R,3R)-167a R=OH
(2R,3R)-167b R=CI
(2S.3S)-166
iii) LiOH, THF/H2O
R1
ii) NaBH4, MeOH/H2O
o
i) Solvent, 20 C,
1,3-cyclopentadiene
R1
R1
+
O
O
O
XC
XC
XC
(-)-164a R1= CO2Me; XC = (2R)-bornane-10,2-sultam
(-)-164b R1= C(O)XC ; XC = (2R)-bornane-10,2-sultam
(3'S)-165a-d
(3'R)-165a-d
(2R)-bornane-10,2-sultam = XC =
N
SO2
Scheme 45.
anhydrous TBAF (Scheme 46 and Table 17).121 In conclusion, it was
found that the derivative of glyoxylic acid carrying a (2R)-bornane10,2-sultam can be used as a readily available chiral auxiliary for
the synthesis of enantiomerically pure nitroalcohols.
Jurczak et al. continued this method and selected five other
nitro compounds among others as representatives of simple aliphatic, benzylic or other functional groups, such as 1-nitrohexane
169a, 2-nitroacetaldehyde diethyl acetal 169b, 1-nitro-1-phenylmethane 169c, 2-nitro-1-phenylethane 169d and ethyl nitroacetate 169e.122 N-Glyoxyloyl-(2R)-bornane-10,2-sultam was treated
with simple nitro compounds 169a–e to afford the diastereoisomeric nitroalcohols with high asymmetric induction. The absolute
(2S)-configuration at the center bearing the hydroxy group and the
relative syn-configuration of the major diastereoisomers were also
determined. The configuration of the minor diastereoisomer 173aa
was determined by comparison of the specific rotations and NMR
spectra of two nitrodiols 176a and 176b which were obtained via
reductive hydrolysis of the sultam from diastereoisomeric diols
(2S)-172aa and 173aa (Scheme 47). Nitrodiols 176a and 176b were
diastereoisomeric, meaning that the relative configuration of compound 173aa was anti. The configuration of the major adduct
172ab was determined by an X-ray crystal structure, and confirmed to have an absolute (2S)-hydroxy-(3R)-nitro configuration,
which in turn meant a relative syn-configuration.
The asymmetric aldol reaction plays a significant role in the
synthesis of complex natural products, especially those containing
multiple contiguous stereogenic centers.123 Perlmutter et al. determined that Et2BOTf improves the anti-selective aldol addition
using an Oppolzer sultam in the synthesis of (+)-nonactic acid124
and oxatropanes.125 An excess of diethylboron triflate in the aldol
additions using Oppolzer sultam to both aliphatic and aromatic
+ CH3NO2
168
O
O
XC
NO2
+
XC
NO2
OH
OH
170
171
O
H
XC =
XC
N
O
S
O2
93
+ RCH2NO2
O
XC'
169a: R = C5H11
169b: R = (C2H5O)2CH
169c: R = Ph
169d: R = CH2Ph
169e: R = COOC2H5
O
NO2
169
R
+
XC
R
OH
OH
173 a-e
172 a-e
O
O
NO2
XC
R
+
NO2
XC
R
OH
OH
174a-e
NO2
175 a-e
Scheme 46.
aldehydes resulted in high anti diastereoselectivity (up to 98:2).
It should be noted that an excess of Et2BOTf is essential to advance
and impose the anti-selective aldol addition. Propionyl sultam 45
Table 17
Entry
Aldehyde
Nitro compound
Methoda used
1
2
3
4
5
6
7
8
93
93
93
93
93
93
93
93
169a
169a
169a
169a
169b
169b
169b
169b
A
A0
B
B0
A
A0
B
B0
Time (h)
26
8
2
2.5
26
1
5
2.5
Yield (%)
Diastereoisomeric ratio 172:173:174:175
5
93
29
58
60
0
78
45
74:26:0:0
68:14:12:6
90:10:0:0
51:35:7:7
62:22:10:6
—
64:16:15:5
100:0:0:0
a
Method A: 3 equiv of neutral Al2O3, 1.5 equiv of nitro compound, THF, rt; method A0 : 3 equiv of activated Al2O3; method B: 0.5 equiv of TBAF3H2O, 1.5 equiv of nitro
compound, THF, 78 °C; method B0 : 0.5 equiv of anhydrous TBAF.
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 18
O
O
NO2
NaBH4
N
HO
R
S
O2
NO 2
R
OH
OH
172aa
173aa
172ac
173ac
174ac
R = C5H11
R = C5H11
R = Ph
R = Ph
R = Ph
176a
176b
177a
177b
177c
Entry
R
180:181
1
2
3
4
5
Me
Et
nPr
iPr
Ph
88:12
97:3
97:3
91:9
96:4
Yield (%)
75
84
66
64
51
Scheme 47.
was reacted with iPr2NEt and Et2BOTf, after which a variety of
aldehydes 179a–e were added to the resulting solution to provide
the anti aldol adducts 180a–e and 181a–e (Scheme 48). As
depicted in Scheme 49, the aldol addition of unsaturated acyl sultam 182 to TMS propargylic aldehyde 184 afforded the aldol
adduct 185 in good yield and with 93:7 anti:syn diastereoselectivity which can be utilized in more complex substrates (Table 18).126
In conclusion, It has been shown that Et2BOTf causes anti addition
of acylated Oppolzer’s sultams to various aliphatic, aromatic and
propargylic aldehyes with good to excellent diastereoselectivities.
This strategy also offers practical advantages, since it (a) avoids
the need to precomplex the aldehyde, which can cause undesired
side reactions promoting the generation of unwanted side products, and (b) it introduces the Lewis acid in situ.
OBEt 2
O
Et2BOTf
XC
XC
i-Pr2NEt
178
45
O
H
XC =
N
R
179a-e
S
O2
O
O
OH
+
R
XC
OH
R
XC
anti
180a-e
syn
181a-e
Scheme 48.
O
OBEt2
Et 2BOTf
XC
XC
i-PrNEt 2
183
182
O
H
TMS
184
O
OH
O
XC
+
OH
XC
TMS
185
TMS
186-syn
2.11. Diels–Alder reaction
Ethyl 5-iodo-2-methylcyclohexanecarboxylate 187, recognized
as the Mediterranean fruit fly attractant ceralure B1, and its (2)(1R,2R,5R)-enantiomer 187 can be easily prepared from commercially available racemic trans-6-methyl-3-cyclohexenecarboxylic
acid 188 or its (1R,6R) enantiomer 188.127 One of the key steps in
the total syntheses of this natural product is an asymmetric
Diels–Alder reaction using a sultam auxiliary. Khrimian et al.
reported on a new, amenable approach to both 187 and (2)-ceralure B1 187 in which they used the commercially available (2)-bornane-10,2-sultam as an appropriate chiral auxiliary in the
Diels–Alder reaction to prepare (2)-siglure acid 188. For the acylation of the amides, and particularly the crotonylation of sultam 1,
usually a base such as sodium hydride was used.
As shown in Scheme 50 (2)-bornane-10,2-sultam 1 was directly
crotonylated using trans-crotonyl chloride to afford 4 in high
yield.128 A Lewis acid catalyzed Diels–Alder reaction of 189 with
butadiene was accomplished by employing a strategy which was
amended in a way to avoid the polymerization of the diene via
the addition of galvinoxyl as a radical inhibitor.129 For the conversion of 190 to 188, adduct 190 was initially reduced using lithium
aluminum hydride to afford sultam 1 and intermediate 6-methyl3-cyclohexen methanol. The latter was then oxidized in situ with
pyridinium dichromate in DMF130 to afford 188.The organic products were first separated by extraction and purified by chromatography to provide (2)-siglure acid 188 plus recovered 1 for further
use.
The isoquinuclidine ring system, a 2-azabicyclo[2.2.2]octane
ring, is commonly found in iboga-type indole alkaloids. Among
them (+)-catharanthine is of particular interest; it also is an invaluable synthetic precursor in the total synthesis of the antitumor
alkaloids vinblastine and vincristine.131 The catalyzed Lewis
acid Diels–Alder reaction of the 1,2-dihydropyridine derivatives
(1-phenoxycarbonyl-1,2-dihydropyridine 192 or 1-methoxycarbonyl-1,2-dihydropyridine 194 with N-acryloyl (1S)-2,10-camphorsultam (1S)-82 {or N-acryloyl (1R)-2,10-camphorsultam
(1R)-82} was accomplished. Various Lewis acids, such as titanium
tetrachloride, zirconium tetrachloride, and hafnium tetrachloride
can be used for these reactions to provide the endo-cycloaddition
product, 2-azabicyclo[2.2.2]octane derivatives, in good yields and
with excellent de. The absolute configuration of the endo-cycloaddition product (1S)-193a starting from N-acryloyl (1S)-2,10-camphorsultam (1S)-82 was proven to be (1S,4R,7S) and therefore a
plausible mechanism was proposed for this reaction132
(Scheme 51). In this reaction, the chelation of the Lewis acid with
N-acryloyl (1S)-2,10-camphorsultam 82 {or N-acryloyl (1R)-2,10camphorsultam 82} is an efficient method providing the corresponding cycloaddition products.
2.12. 1,4-Addition
185-anti
54%
93:7 anti : syn
Scheme 49.
The 1,4-conjugate addition of alkenylzirconocene chloride complexes to a,b-enones, a,b-enoic acid esters, and a,b-enoic acid
amides was carried out by employing [RhCl(cod)]2 as the catalyst.
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
trans-CH3CH = CHCOCl/Cu2+, reflux
NH
CH2=CHCH=CH2, EtAlCl2, - 50 to 0oC
N
92%
SO2
85%; > 98% de
SO2
O
189
1
CO 2H
LiAlH4, THF, r.t.
N
SO2
OH
1 +
O
PDC, DMF, r.t.
(82%)
(82%)
190
188 (71%; > 98% ee)
H2O2, LiOH, THF/H2O, r.t.
H
N
+
1 (34%) + 188 (23%)
O
HO3S
191
Scheme 50.
PhO 2C N
CO2Ph
O
N
Lewis acid
O2
N S
O
+
S
O2
+ exo-(1S)-193b
CH2Cl2, MS-4Å
N
endo-(1S)-193a
(1S)-82
192
Scheme 51.
A high diastereoselectivity (95% yield, 90% de) was achieved via the
reaction of a,b-enoic acid amide derived from the Oppolzer sultam
and 2-butenoyl chloride. In this reaction the use of Evans chiral
oxazolidinone as a chiral auxiliary, instead of Oppolzer sultam,
afforded a poor diastereoselectivity (98% yield, 26% de) thus showing the better versatility and usefulness of sultams over oxazilidinone in this example. The 1,4-addition of organometallic reagents
is an important and useful reaction in organic syntheses. A range of
organometallic reagents and catalysts to provide excellent selectivity for the 1,4-addition have been designed. An efficient Rh(I)-catalyzed 1,4-conjugate addition of alkenylzirconocene chlorides 196
to electron deficient olefin a,b-enoic acid amides, and the diastereoselective 1,4-addition onto chiral acid amide derivatives are
particularly noteworthy (Scheme 52).133 The facile and effective
additions of 196 to a,b-enoic acid amides under the aforementioned conditions led the diastereoselective 1,4-addition of 196
to chiral a,b-enoic acid amides 197. The diastereoselective 1,4additions of 196 to chiral a,b-enoic acid amides 197 derived from
2-butenoyl chloride and chiral amine derivatives are demonstrated
O
ZrCp2Cl
R
+
O
[RhCl(cod)]2
XC
dioxane, r.t.
R
XC
XC = nitrogen
196
197
Scheme 52.
Table 19
XC
197
R
198
197a
197a
t-Bu
n-Bu
198a
198b
Yield (%)
92
95
de (%)
88
90
N
S
O2
in Scheme 52. The application of Oppolzer’s sultam 197c,134
imposed high diastereoselectivity to afford adducts 198c and
198d in high chemical yield (Table 19). The absolute configuration
of the new stereocenter of the major isomer of 198d was
determined as being an (S)-configuration by transforming and
comparing it with the already known methyl (3S)-3-methyl-4-oxobutanoate.135 It has been shown that the highly efficient conjugate
addition reactions of alkenylzirconocene chlorides to a,b-enones,
-enoic acid esters, and -enoic acid amides can be performed by
using Rh(I) as an effective catalyst. Extending this to a,b-enoic acid
chiral amides proved that Oppolzer’s sultam was an excellent chiral auxiliary in terms of diastereoselectivity and chemical yield and
once again confirms its versatility.
2.13. Oxidative cyclization
198
The permanganate promoted oxidative cyclizations of 1,6dienes exclusively affords cis-2,6-bis-hydroxyalkyl-tetrahydropy-
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
O
O
S
O
H
N
H
OH
O
O
N
S
OH
KMnO4 , adogen 464, AcOH,
O
201 (20%)
CH2Cl2, -60 oC
+
O
O
O
S
O
199
OH
N
H
H
OH
202 (3%)
O
O
O
S
H
O
OH
O
O
N
S
O
N
H
OH
203
KMnO 4, AcOH:acetone (2:3), -15 oC
+
O
O
O
S
O
N
H
H
OH
OH
200
204
16:17 = 4: 1 (24%)
Scheme 53.
rans.136 When a dienoyl sultam is used, good levels of asymmetric
induction are achieved in this reaction. The oxidative cyclization of
the other 1,6-dienes 199 and 200137,138 was also achieved using the
above conditions to obtain the desired THP diols in moderate
yields but with good diastereoselectivity (Scheme 53). It is worthwhile to mention that the camphorsultam auxiliary can be
employed to obtain enantiomerically pure THP diol-containing
motifs, which are useful and required in the total synthesis of
the products; a simple permanganate-mediated oxidative cyclization of 1,6-dienes to obtain cis-2,6-disubstituted THP diols with
excellent stereoselectivity has been developed. The control of the
absolute stereochemistry obtained from the camphorsultam provides the direction of the initial attack of MnO
4 onto one face of
the more reactive enoyl olefin bond. Moreover, the potential of this
reaction for the synthesis of enantiomerically enriched THP fragments containing up to four new stereocenters was confirmed.
OMe
O
S
O
OAc
MeO
N
O
OMe
(2R,3S)-(-)-206
NMe2. HCl
205
Cl
Me
207
O
O
O
Cl
Cl
Me
208
Cl
Me
Cl
Cl
209
Figure 3.
2.14. Epoxidation
Hajra et al. were interested in the asymmetric epoxidation of
chiral cinnamic acid derivatives,139 generally, epoxides and in particular, chiral epoxy cinnamoyl compounds, which are important
precursors in the synthesis of many biologically active compounds
either synthetic or natural products. For example, methyl (2R,3S)3-(4-methoxyphenyl) glycidate 206 is a key intermediate in the
total synthesis of diltiazem hydrochloride 205. The latter is one
of the most potent calcium antagonists that is prescribed as a drug
for the treatment of angina and extensively as an anti-hypertensive
(Fig. 3). Effective epoxidation of chiral cinnamic acid derivatives
has been carried out by the in situ formation of dioxiranes of chloroacetones with good to high diastereoselectivity (dr up to 90:10)
and high chemical yields. Interaction of cinnamic acid derivatives
with a chiral auxiliary with chloroacetones–monochloroacetone
207 (MCA), 1,1-dichloroacetone 209 (DCA), 1,1,1-trichloroacetone
208 (TCA) and Oxone™ has been investigated. It has been found
that both the Oxone™ loading and the reaction time were reduced
when the amount of chlorine atoms in the acetone is increased.
The use of 1.1 equiv of TCA was very effective in the epoxidation
of cinnamate substrates and increased the reaction rate up to
4–10-fold in comparison with acetone. It also allowed the Oxone™
loading amount to be decreased. This procedure afforded methyl
(2R,3S)-3-(4-methoxyphenyl)glycidate ()-206, as a key intermediate in the synthesis of diltiazem hydrochloride with >99% enantiomeric purity (Scheme 54). With the aim of developing an
asymmetric epoxidation and to study the reactivity of the
substrates along with diastereoselectivity, the epoxidation of
a,b-unsaturated carboxylic acid derivatives containing Oppolzer’s
sultam as the chiral auxiliary was performed (Table 20). The rate
of epoxidation of 63 with a camphorsultam chiral auxiliary was
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
ketone
O
O
OxoneTM , NaHCO3
S
S
63
O
O
Ar
N
CH3CN/H2O, 25 C
Ar
N
O
o
O
O
210
210a: Ar = 4-MeOC6H4, 210b: Ar = Ph
63a: Ar = 4-MeOC6H4, 63b: Ar = Ph
O
O
O
O
MeOH, n-BuLi
N
-78 oC, 79%
S
O
MeO
OMe
OMe
O
(2R,3S)-(-)-206
210a
Scheme 54.
Table 20
Entry
Substrate
Ketone
Oxone™ (equiv)
1
2
3
4
5
6
7
8
9
10
11
12
210a
210a
210a
210a
210a
210a
210b
210b
210b
210b
210b
210b
Acetone
208
208
209
209
209
Acetone
Acetone
208
208
209
209
1.5
1.5
2.5
1.5
2.5
2.5
1.5
5.0
1.5
5.0
1.5
5.0
also enhanced by increasing the amount of chlorine atoms in the
acetone. The configuration of the obtained major epoxide 210
was determined by comparing it with the literature data given
for epoxide 210b.140 The formation of glycidate ()-206 via epoxidation of 210a was also reported, using MeOLi which is usually
generated in situ via the addition of n-BuLi to MeOH. The chiral
auxiliary also plays a key role in the reactivity and selectivity of
the epoxidation by in situ created dioxiranes. Cinnamoyl substrates containing an oxazolidinone chiral auxiliary readily
undergo asymmetric epoxidation under mild conditions to provide
moderate diastereoselectivity (up to 65:35). However, substrates
containing a sultam chiral auxiliary undergo epoxidation and
require longer times, but provide better diastereoselectivity (up
to 85:15). The reactivity of cinnamic acid derivatives decreases
for the substrates containing an oxazolidine or oxazolidinone when
sultam chiral auxiliaries are used. This method gave ()-methyl-3(4-methoxyphenyl)glycidate ()-206 with >99% enantiomeric
purity.
2.15. Acylation
The synthesis of the two pairs of enantiomers
(+)-(3aS,4R,6aS)-/()-(3aR,4S,6aR)-3-hydroxy-3a,4,6,6a-tetrahydropyrrolo[3,4-d]isoxazole-4-carboxylic acid [(+)-HIP-A and ()-HIPA]
and
(+)-(3aS,6S,6aS)-/()-(3aR,6R,6aR)-3-hydroxy-3a,4,6,
6a-tetrahydro-pyrrolo[3,4-d]isoxazole-6-carboxylic acid [(+)-HIPB and ()-HIP-B], was reported and their inhibitory activities
at EAATs were also investigated extensively.141 A mixture of
Base (equiv)
3.5
3.5
6.0
3.5
4.7
11
3.5
12
3.5
12
3.5
12
Time (h)
4
3
3
2
2
2
12
12
12
12
12
12
dr
Conv. (%)
Not determined
Not determined
85:15
20
54
82
85
100
100 (92)
<10
18
27
30
36
55 (51)
Not determined
Not determined
Not determined
Not determined
Not determined
Not determined
82:18
acids (3aR,4S,6aR)-211f and (3aS,6S,6aS)-212f and (1S)-()-2,
10-camphorsultam38 in the presence of dimethylaminopyridine
(DMAP) and o-(benzotriazol-1-yl)-N,N,N0 ,N0 -tetramethyluronium
hexafluorophosphate (HBTU), was reacted to afford a mixture
of amides ()-(3aR,4S,6aR)-215 and ()-(3aS,6S,6aS)-216 in high
yields. These derivatives could only be separated by flash chromatography and could then be converted into amino acids ()HIP-A (11% overall yield) and (+)-HIP-B (13% overall yield),
respectively, upon treatment with a sodium hydroxide solution
with subsequent removal of the N-Boc as protective group
(Scheme 55). In this case, treatment with an alkali did not disturb the stereochemical integrity. As a result, the four enantiomerically pure amino acids (+)-HIP-A, ()-HIP-A, (+)-HIP-B,
()-HIP-B were employed and their ability to interact with rat
glutamate transporters was evaluated. The biological outcome,
as well as docking experiments, vividly illustrate that the
absolute configuration of the stereogenic centers plays an
important role in the interactions with the target proteins: in
both cases, the eutomer is characterized as the (S)-configuration
around the a-amino acidic carbon, that is, ()-HIP-A and
(+)-HIP-B.
In 2001, Orlandi et al. reported on the stereoselective bimolecular radical coupling of enantiopure phenylpropenoidic phenols,
starting from enantiopure amidic derivatives of ferulic acid (generated from ferulic acid with an Oppolzer camphorsultam).142 This
chiral auxiliary induces the significant levels of diastereoselectivity
to such bimolecular coupling reactions of phenoxyl radicals, and
consequently these are conveyed to enantioselectivity in the
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M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
COXC
Br
N
N
N
Boc
N
Br
COOH
Br
N
+
N
Boc
(-)-215
Br
80%
O
O
Boc
O
(1S)-(-)-2,10-camphorsultam/
DM Ap-HBTU-CH2Cl2
COOH
N
211f
N
Boc
O
212f
COXC
(-)-216
COXC
Br
Br
COOH
N
N
Boc
N
Br
+ N
N
Boc
Boc
(-)-217
O
O
N
O
(1S)-(-)-2,10-camphorsultam/
DMAP-HBTU-CH2Cl2
80%
Br
COOH
213
N
214
N
Boc
O
COXC
CH3
H3C
(-)-218
H
XC =
H
S
O2
(-)-215
(-)-216
(-)-217
N
i) 1 M NaOH/H2O - dioxane, 60 oC;
ii) 30% CF 3COOH/CH2Cl2
(-)-(3aR,4S,6aR)-HIP-A
i, ii
(+)-(3aS,6S,6aS)-HIP-B
i, ii
(+)-(3aS,4R,6aS)-HIP-A
i, ii
(-)-218
(-)-(3aR,6R,6aR)-HIP-B
Scheme 55.
desired products. This strategy provides a new route for the construction of invaluable lignans. O-Acetylferulic acid chloride
219143 was reacted with Oppolzer sultam37 as a chiral auxiliary
to construct intermediate 220. Derivative 221 can be obtained by
deacetylation of intermediate 220144 (Scheme 56). For the preparation of diastereoisomers 222 and 223, compound 221 was coupled
oxidatively via two different pathways (i) enzymatically, using
HRP/H2O2 obtaining 40% yield; and (ii) chemically, using silver
oxide145,146 obtaining an identical yield. Upon dimerization and
subsequent separation of the pure diastereoisomers 222 and 223
using preparative RP-HPLC, the absolute configuration of the newly
generated stereogenic centers of the major diastereoisomer 223
was assigned by chemical means. The camphorsultam auxiliary
of phenylcoumaran 223 was removed via reduction using LiAlH4/
THF and enantiomerically pure dehydrodiconiferyl alcohol (DDA)
224 was obtained. Comparison of 224 (using chiral HPLC) with
authenticated specimens of both enantiomers of dehydrodiconiferyl alcohol36 established the absolute configuration to be (2S,3R).
These results show that chiral auxiliaries induce remarkable levels
of diastereoselection in bimolecular coupling reactions of phenoxyl
radicals, and this is reflected in the enantioselectivity in the final
product. As expected, this method can be extended to various
related structures thus presenting a new approach to the synthesis
of precious lignans.
2.16. Aza-Darzen reaction
One of the most important intermediates in organic synthesis is
the aziridine. Asymmetric aziridine syntheses via aza-Darzens
(‘ADZ’) reactions of N-diphenylphosphinyl (‘N-Dpp’) imines with
chiral enolates obtained from oxazolidinones and a camphorsultam was described by Sweeney et al. in 2006. As shown in
Scheme 57, (2R)-N-bromoacetylcamphorsultam 225 can be prepared in good yield.147
Using LiHMDS, compound 225 was deprotected to provide an
a-bromo lithioenolate 226, which was immediately added to a
THF solution of N-diphenylphosphinylbenzaldimine (Scheme 58
and Table 21). After aqueous work-up, the aziridinyl sultam 227
was obtained.
The aziridinyl sultams were then reacted smoothly with lithium
hydroxide monohydrate to yield the desired N-Dpp aziridine carboxylates 229 in good yield (Table 22). As a result, the hydrolytic
cleavage of the auxiliary from (aziridinyl) acyl sultams occurred.
These heterocycles are excellent precursors to a variety of aziridine
esters or other invaluable compounds of interests both from synthetic and biological points of view. Thus, the synthesis of N-bromoacylcamphorsultams as efficient precursors of a range of cisN-Dpp-aziridine-2-carboxylates via a two-step process has been
reported (Scheme 59).
1088
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
O
Cl
O
O
N
MeONa
NaH
+
HN
N
SO2
SO2
MeOH
toluene
SO2
OMe
OMe
OMe
OAc
OH
OAc
219
2
221
220
O
O
R*
R*
XC
O
HO
XC
O
HO
OH
HO
HO
O
O
MeO
O
MeO
OMe
MeO
OMe
222
OMe
223
XC =
224
N
S
O2
Scheme 56.
3. Conclusions
n-BuLi,BrCH2C(O)Br,
THF, -78 oC
NH
S
O2
75%
S
O2
1
In conclusion, in this report, we have tried to highlight the
recent applications of the sultam as a chiral auxiliary in a wide
range of asymmetric synthetic reactions, usually for the synthesis
of valuable intermediates that are used in the total synthesis of
biologically natural products, pharmaceuticals, and other useful
complex molecular targets. In these reactions, the auxiliary
controlled processes are crucial tools for creating the desired
Br
N
O
225
Scheme 57.
LiHMDS, THF, -78 oC
N
S
O
O
Br
N
O
Br
S
OLi
O O
225
226
PhCH=NP(O)Ph2,THF,-78 oC
Dpp
H
H
N
S
O
O
O
227
71%
Scheme 58.
N
+
NH
S
Ph
O
O
1
8%
M. M. Heravi, V. Zadsirjan / Tetrahedron: Asymmetry 25 (2014) 1061–1090
Table 21
1089
References
Entry
R
Yield 227 (%)
1
2
3
4
5
6
7
8
9
10
11
12
13
14
15
16
Ph
4-NO2-C6H4
4-MeO-C6H4
2-NO2-C6H4
4-Br-C6H4
2-Naphthyl
2-Fluorenyl
2-Furyl
tBu
Ph
4-F-C6H4
2,6-Cl2-C6H4
3-Br-C6H4
4-MeO-C6H4
2-Pyridyl
CH2@CH
cis:trans
dr
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
100:0
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
>95:<5
Aziridine
configuration
Yield 229 (%)
227a: 71
227b: 75
227c: 78
227d: 70
227e: 60
227f: 72
227g: 67
227h: 68
227i: 40
227j: 71
227k: 57
227l: 60
227m: 60
227n: 60
227o: 67
227p: 47
Table 22
Entry
R
Sultam
configuration
1
2
3
4
5
6
7
8
9
Ph
4-NO2-C6H4
2-NO2-C6H4
4-Br-C6H4
2-Naphthyl
tBu
3-Br-C6H4
2,6-Cl2-C6H3
2-Pyridyl
(R)
(R)
(R)
(R)
(R)
(R)
(S)
(S)
(S)
(20 R,30 R)
(20 R,30 R)
(20 R,30 R)
(20 R,30 R)
(20 R,30 R)
(20 R,30 R)
(20 S,30 S)
(20 S,30 S)
(20 S,30 S)
229a: 64
229b: 60
229c: 67
229d: 61
229e: 67
229f: 47
229g: 80
229h: 45
229i: 100
Dpp
N
Dpp
i) LiOH,THF/H2O,r.t.
XC
ii) 2 M HCl
R
O
228
N
HO2C
R
229
Scheme 59.
stereogenic centers. The commercial availability of both enantiomers having known a synthetic procedure, the ease of removal,
compatibility with a wide variety of stereoselective reactions and
tolerance of different functional groups, are noteworthy advantages of this auxiliary. They are enough to make the sultam an ideal
chiral auxiliary for asymmetric synthetic chemists. Since the first
realization that such a privileged and accessible chiral organic molecules such as sultam, could induce high stereoselectivities during
CAC bond formatting reactions, a wave of interest has been stirred
up among organic chemists and the key reactions such as aldol
condensations, alkylations, Diels–Alder reactions, and many other
aforementioned reactions have been investigated and performed
using this auxiliary. By recognition of the benefits of the use of this
relatively small molecule as a chiral auxiliary, these processes have
become a vibrant area of study for sophisticated stereoselective
CAC bond formation.
Acknowledgements
The authors are thankful to the Alzahra Research Council for
support.
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