Highly regiocontrolled and stereocontrolled syntheses of polysubstituted aminocyclohexanes: mild inverse-electron-demand Diels–Alder cycloadditions of electrophilic 2-pyridones

Article abstract of DOI:10.1016/j.tetlet.2016.06.068

Strongly electrophilic N-arenesulfonyl-2-pyridone-3-carboxylate methyl esters complex with zinc dibromide and then react with nucleophilic benzyl vinyl ether or benzyloxyallene to achieve inverse-electron-demand Diels–Alder (IEDDA) cycloadditions. These cycloadducts are produced on gram scale and in 77–89% yields, importantly without the use of high pressure. These 4+2 cycloadditions strongly favor regioselective and stereoselective formation of endo bicyclic lactams as established by X-ray crystallography. These bicyclic lactams undergo useful reactions, including reductive cleavage of the N-sulfonyl group, exo-syn-dihydroxylations, and lactam ring-opening to produce a variety of aminocyclitols.

Full text of DOI:10.1016/j.tetlet.2016.06.068

Tetrahedron Letters 57 (2016) 3344–3348
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Highly regiocontrolled and stereocontrolled syntheses of
polysubstituted aminocyclohexanes: mild inverse-electron-demand
Diels–Alder cycloadditions of electrophilic 2-pyridones
⇑
Ryan C. Conyers, Jennifer R. Mazzone, Maxime A. Siegler, Gary H. Posner
Department of Chemistry, School of Arts and Sciences, Johns Hopkins University, 3400 N. Charles Street, Baltimore, MD 21218, United States
a r t i c l e i n f o
a b s t r a c t
Article history:
Strongly electrophilic N-arenesulfonyl-2-pyridone-3-carboxylate methyl esters complex with zinc
dibromide and then react with nucleophilic benzyl vinyl ether or benzyloxyallene to achieve inverse-elec-
tron-demand Diels–Alder (IEDDA) cycloadditions. These cycloadducts are produced on gram scale and in
Received 13 May 2016
Revised 9 June 2016
Accepted 14 June 2016
Available online 16 June 2016
77–89% yields, importantly without the use of high pressure. These 4+2 cycloadditions strongly favor
regioselective and stereoselective formation of endo bicyclic lactams as established by X-ray crystallogra-
phy. These bicyclic lactams undergo useful reactions, including reductive cleavage of the N-sulfonyl group,
exo-syn-dihydroxylations, and lactam ring-opening to produce a variety of aminocyclitols.
Ó 2016 Elsevier Ltd. All rights reserved.
Keywords:
Gram scale 4+2 cycloadditions
Inverse electron demand Diels–Alder
cycloadditions
Regiocontrolled and stereocontrolled
cycloadditions
Diels–Alder cycloadditions are among the most useful
transformations in organic chemistry. Such [4+2] cycloadditions
are characterized usually by high control of regiochemistry and
stereochemistry and by producing cycloadducts rich in
functionality.
Diels–Alder cycloadditions often convert simple reactants in
one step into much more complex and therefore much more
valuable building blocks.
O
O
O
Br
O
Br
O
O
CH Cl , sealed tube, 90 °C
O
2
2
6
3%
O
Scheme 1. Example of cycloaddition reactions using 3-bromo-2-pyrone.
2
-Pyrones cycloadd under mild conditions to form isolable
lactones without extruding carbon dioxide, which would result in
the loss of much stereochemical information. For example,
O
O
S
O
O
O
O
3
-bromo-2-pyrone cycloadds to electron-rich dienophiles to form
OMe
NO2
S
OMe
9
0 °C
0%
Tol
N
Tol
N
1,2
versatile cycloadducts (Scheme 1). Also, 3,5-dibromo-2-pyrone
has been used insightfully in Diels–Alder cycloadditions as a key
step in total synthesis of several natural products.3
+
ref . 7
8
NO2
Scheme 2. [4+2] Cycloaddition using an electron-rich 3-methoxy-2-pyridone.
2
-Pyridones, being considerably more aromatic than
4
,5
2
-pyrones, do not enter easily into Diels–Alder dearomatizing
cycloadditions, whereas several examples exist of [4+2]
cycloadditions of electron-rich 2-pyridones (Scheme 2), very few
6
7
O
O
O
O
O
O
O O
S
5
5
Kbar
0 °C
examples exist of [4+2] cycloadditions of electron-poor 2-pyridones
S
S
OBn
S(O)
Tol
even under high pressure (Scheme 3).8
–10
Noteworthy is that in
Tol
N
Tol
2
Tol
N
+
ref . 8
Scheme 3 inverse-electron-demand Diels–Alder (IEDDA) adducts
were formed as a 7:1 mixture of endo:exo diastereomers. We have
56 h
8%
:1 endo:exo
OBn
7
7
Scheme 3. IEDDA cycloaddition using an electron-deficient 2-pyridone.
⇑
Corresponding author. Tel.: +1 410 516 4670.
E-mail address: ghp@jhu.edu (G.H. Posner).
http://dx.doi.org/10.1016/j.tetlet.2016.06.068
040-4039/Ó 2016 Elsevier Ltd. All rights reserved.
0

R. C. Conyers et al. / Tetrahedron Letters 57 (2016) 3344–3348
3345
O
O
O
O
a. NaH
O
O
O
O
H SO , MeOH
b. ArS(O) Cl
S
2
4
2
HN
OH
HN
OMe
Ar
N
OMe
reflux, 48h
0%
CH Cl
2 2
5
0 °C
rt
1
2
3a-d
Compound
Ar
Yield
78%
3
a
b
Me
O N
3
2
81%
50%
80%
NO2
3
c
d
O N
2
Cl
Cl
3
F3C
Scheme 4. Preparation of N-arenesulfonyl pyridones.
now developed one approach to mild, regiocontrolled and
stereocontrolled IEDDA cycloadditions using easily prepared very
electron-poor N-arenesulfonyl-2-pyridone-3-carboxylate esters.
In an effort to develop mild IEDDA cycloaddition reactions,
while circumventing any undesired N- to O-sulfonyl group
electron-rich benzyl vinyl ether slowly at 60–100 °C, unfortunately
forming a considerable amount of the undesired N- to O-sulfonyl
rearranged product. Additionally, the high reaction temperatures
resulted in significant polymerization of the benzyl vinyl ether.
In dramatic contrast, in the presence of zinc-based Lewis acids,
highly electron-poor dinitrobenzenesulfonamide pyridone 3c and
migration,
a series of increasingly electron-poor N-sulfonyl
pyridones was synthesized. Fischer esterification of commercially
available 2-pyridone-3-carboxylic acid (1) produced 2-pyridone
methyl ester 2 (Scheme 4). Subsequent N-sulfonylation of pyridone
methyl ester 2 was accomplished using commercially available
arenesulfonyl chlorides yielding N-sulfonyl-2-pyridone methyl
esters 3a–d.
especially
dichlorinated
trifluoromethylbenzenesulfonamide
pyridone 3d underwent IEDDA cycloaddition at room temperature
with benzyl vinyl ether, which resulted in a mixture of endo-4d
and exo-4d bicyclic lactam diastereomers with cycloadduct endo-
4d predominating (Table 1). A crucial aspect for the success of
the IEDDA cycloaddition involved exposing pyridone 3d to zinc
dibromide in dichloromethane solvent for 1 h before adding benzyl
N-(2,4-dichlorobenzyl)-2-pyridone-3-carboxylic acid methyl
ester and benzyl vinyl ether failed to undergo IEDDA cycloaddition
1
vinyl ether. During that first hour, H NMR spectroscopic analysis
1
1
even in the presence of various Lewis acids, such as ZnBr
2
,
revealed the following changes: exposure of pyridone 3d to zinc
dibromide in the absence of benzyl vinyl ether produced a complex
evident by new broadened proton resonances and the absence of
11
12,13
14
15
12
ZnCl
2
,
Zn(OTf)
2
,
FeCl
2
,
TiCl
4
,
CuCl
2 2
, Cu(OTf) , Eu
Therefore, we examined even
1
6
17
18
(
hfc)
3
, Eu(fod)
3
, and Pr(fod) .
3
more electron-deficient N-tosyl-2-pyridone 3a and N-(p-nitroben-
zenesulfonyl)-2-pyridone 3b, which could be coaxed to cycloadd to
starting material 3d, which suggests
a
zinc–pyridone
1
3,19,20
complex.
Upon addition of benzyl vinyl ether, new proton
Table 1
Optimization of benzyl vinyl ether IEDDA cycloaddition reaction conditions
O
O
O
S
O
O
O
O
S
O
O O
a. Lewis Acid
OBn (5 equiv)
CH Cl
COOMe
S
COOMe
OBn
Ar
N
OMe
Ar
N
Ar
N
+
b.
OBn
2
2
3
a-d
endo-4d
exo-4d
endo-4db,c (%)
Entry
Pyridone
Lewis acid (equiv)
Temp (°C)
Time (h)
endo:exod
a
1
2
3
4
5
6
7
8
9
3a
3b
3b
3c
3c
3c
3d
3d
3d
3d
3d
3d
None
100
80
60
40
0 ? 21
21
21
21
21
40
48
48
48
24
24
36
24
24
24
24
24
24
52
50
45
85
75
90
33
82
88
87
91
89
—
—
—
18:1
38:1
32:1
a
None
a
None
ZnBr
ZnBr
ZnBr
2
2
2
(0.2 equiv)
(0.2 equiv)
(1 equiv)
e
Zn(OTf)
ZnI (1 equiv)
2
(1 equiv)
na
2
10:1
12:1
18:1
50:1
55:1
ZnBr
ZnBr
ZnBr
2
2
2
(1 equiv)
1
1
0
1
(0.2 equiv)
(0.2 equiv)
(0.2 equiv)
21
0 ? 21 °C
12
ZnBr
2
a
b
c
Reaction was run without Lewis acid.
Isolated yield of chromatographically pure endo-4d.
Isolation and identification of exo-4d was accomplished by 1H NMR spectroscopy (characteristic resonances at 2.65 ppm for endo-4d and 6.29 ppm for exo-4d).
d
e
1
Ratio of diastereomers was established by H NMR spectroscopic analysis of the crude reaction mixture.
Incomplete conversion to endo-4d.

3
346
R. C. Conyers et al. / Tetrahedron Letters 57 (2016) 3344–3348
O
O
O
O
O
S
O O
O
S
O
cat. OsO4
NMO
cat. TsOH
DMP
Ar
HO
HO
Ar S
COOMe
COOMe
COOMe
Ar
N
N
N
O
O
OBn
THF:H
2
O
OBn
52%
over 2 steps
OBn
8
°C, 18 h
6
d
Ar = 2,6-Cl -4-CF Ph
exo-syn-diol 5d
2
3
endo-4d
O
L-Selectride
THF
COOMe
6
d
HN
O
O
-
78 °C - rt
OBn
50%
7
d
Scheme 5. Functionalization of endo-bicyclic lactam 4d.
resonances associated with endo-4d were observed. Identification
of the major cycloadduct endo-4d and the minor cycloadduct
exo-4d was accomplished by isolation and characterization by 1
H
NMR spectroscopy. Additionally the relative stereochemistry of
exo-4d was confirmed via X-ray crystallography. Optimization
of the reaction conditions revealed that decreasing the amount of
zinc dibromide (from 1.0 to 0.2 equiv) significantly increased the
diastereomeric ratio of products. Most noteworthy was exposing
pyridone 3d to 0.2 equiv of zinc dibromide at 0 °C for 1 h followed
by the addition of benzyl vinyl ether (5 equiv) followed by slow
warming to 21 °C for 24 h to produce, on gram scale and in 89%
isolated yield, desired cycloadduct endo-4d in a stunning 55:1 ratio
of endo:exo diastereomers (Table 1, entry 12).
Toward the goal of synthesizing various pentasubstituted cyclo-
hexane building blocks, endo-bicyclic lactam 4d was functionalized
(Scheme 5). syn-Dihydroxylation of the alkene unit within the
Figure 1. X-ray structure of desulfonylated lactam 7d.
bicyclic lactam core of 4d was achieved under standard osmium
Table 2
Optimization of benzyloxy allene IEDDA cycloaddition reaction conditions
O
O
O
O
a. ZnBr
b.
2
O O
O
S
O
O
S
O
S
COOMe
COOMe
OBn
Ar
N
Ar
N
OMe
H
Ar
N
OBn
(4 equiv)
OBn
solvent
H
Pyridone
endo-8d
exo-8d
3
d
Entry
Solvent
ZnBr
2
(equiv)
Temp (°C)
Time
endo-8db,c (%)
endo:exod
1
2
3
4
5
6
7
8
9
CH
CH
CH
CH
CH
CH
CH
THF
2 2
ClCH CH Cl
MeNO
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
1,4-Dioxane
2
2
2
2
2
2
2
Cl
Cl
Cl
Cl
Cl
Cl
Cl
2
2
2
2
2
2
2
1.0
0.9
0.9
0.2
0.1
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.3
0.1
0.2
0
21
48 h
36 h
48 h
48 h
96 h
48 h
48 h
7 days
48 h
48 h
48 h
72 h
24 h
24 h
24 h
24 h
26
51
26
67
naf
5:1
f
À20
na
0
9:1
—
e
0
0
—
65
56
46
47
45
35
52
55
51
77
13:1
14:1
13:1
7:1
10:1
16:1
12:1
12:1
17:1
17:1
6:1
À10
À10 ? 55
À10
À10
21
55
80
80
80
10
11
12
13
14
2
15
a
g
1
6
—
80
—
a
b
c
d
e
f
Reaction was run without Lewis acid.
Isolated yield of chromatographically pure endo-8d.
Isolation and identification of exo-8d was accomplished by 1H NMR (characteristic resonances at 5.63 ppm for endo-8d and 6.35 ppm for exo-8d).
1
Ratio of diastereomers was established by H NMR analysis of the crude reaction mixture.
Only starting material present in crude NMR.
Incomplete conversion to endo-8.
g
Reaction mixture was not purified, only crude 1H NMR spectrum obtained.

R. C. Conyers et al. / Tetrahedron Letters 57 (2016) 3344–3348
3347
O
O
O
O
S
O
O
O
O O
cat. OsO4
NMO
cat. TsOH
DMP
COOMe
S
COOMe
OH
S
COOMe
Ar
N
Ar
N
Ar
N
O
OBn
THF:H O
50%
over 2 steps
2
4
°C
Ar = 2,6-Cl -4-CF Ph
OH
OBn
O
OBn
2
3
24 h
9d
10d
endo-8d
O
O
O
O
O
O
2
.0 equiv
DIBAL
cat. OsO
NMO
S
4
Ar
S
OH
Ar
N
OH
N
HO
10d
O
HO
O
CH
2 2
Cl
THF:H O
2
-
78 °C - rt
4
5 °C
11d
O
OBn
O
OBn
4
h
2
4 h
0%
12d
6
5%
8
Scheme 6. Functionalization of endo-bicyclic lactam 8d.
tetraoxide and N-methylmorpholine-N-oxide (NMO) reaction
products. Also, solvent choice and reaction temperature were key
factors in increasing the yield and diastereomeric ratio of products.
Most noteworthy was exposing pyridone 3d in 1,4-dioxane to
0.2 equiv of zinc dibromide at room temperature for 1 h followed
by the addition of benzyloxy allene (4 equiv) followed by heating
to 80 °C for 24 h produced, on gram scale and in 77% isolated yield,
2
1
conditions to produce exclusively exo-syn-diol 5d. Purification of
exo-syn-diol 5d on silica gel resulted however in a loss of desired
product, and thus a two-step protocol was developed. The crude
reaction mixture containing exo-syn-diol 5d was immediately
subjected to catalytic toluene sulfonic acid in 2,2-dimethoxypro-
pane (DMP) solvent at room temperature for 18 h, which produced
acetonide 6d. The acid lability of acetonide 6d was overcome by
desired cycloadduct endo-8d in
diastereomers (Table 2, entry 15). Formation of cycloadduct
endo-8d represents successful stereocontrolled and
a 17:1 ratio of endo:exo
neutralization of the silica gel (1% Et
matographic purification, affording 52% yield of pure exo-acetonide
d over 2 steps. No evidence of the corresponding endo-diol was
3
N in hexanes) prior to chro-
a
regiocontrolled synthesis of a cyclohexane ring with each carbon
atom of the ring being functionalized.
6
found. Desulfonylation of sulfonamide 6d was achieved using
lithium tri-sec-butylborohydride (L-selectride) solution to form
sulfur-free pentasubstituted cyclohexane 7d, with relative
stereochemistry unambiguously determined using X-ray
crystallography (Fig. 1).
Toward the goal of synthesizing hexasubstituted cyclohexane
building blocks, dichlorinated trifluoromethylbenzenesulfonamide
pyridone 3d underwent IEDDA cycloaddition with benzyloxy
allene, which resulted in a mixture of endo-8d and exo-8d bicyclic
lactam diastereomers (Table 2). Optimization of the reaction
conditions revealed that decreasing the amount of zinc dibromide
Continuing with our goal of synthesizing highly substituted
aminocyclohexane building blocks, endo-bicyclic lactam 8d was
functionalized (Scheme 6). Chemoselective syn-dihydroxylation of
only the exocyclic double bond of diene 8d with osmium tetraoxide
and N-methylmorpholine-N-oxide (NMO) produced diol 9d. The
crude reaction mixture containing diol 9d was immediately sub-
jected to catalytic toluenesulfonic acid in 2,2-dimethoxypropane
(DMP) solvent at room temperature for 18 h, which produced
acetonide 10d. Acetonide 10d was purified on neutralized silica
3
gel (1% Et N in hexanes), affording 50% yield of pure acetonide
10d over 2 steps. Reduction of the ester group in acetonide 10d with
diisobutylaluminum hydride (DIBAL) gave primary alcohol
acetonide 11d in 65% yield. Dihydroxylation of the alkene unit of
(
from 1.0 to 0.2 equiv) increased the diastereomeric ratio of
1
1d was achieved under standard osmium tetraoxide and
N-methylmorpholine-N-oxide (NMO) reaction conditions and
heated to 45 °C for 24 h to produce triol 12d. In addition to full
spectroscopic characterization of triol synthon hexasubstituted
cyclohexane 12d, its relative stereochemistry was confirmed using
X-ray crystallography (Fig. 2). Lactam sulfonamide 11d was treated
with excess sodium hydroxide in methanol to give fully substituted
ring opened product 13d (Scheme 7).
In summary, electrophilic dichlorinated trifluoromethylben-
zenesulfonamide pyridone 3d complexes with zinc dibromide
and then reacts with nucleophilic benzyl vinyl ether or
nucleophilic benzyloxyallene to achieve IEDDA cycloadditions.
These cycloadducts are produced on gram scale and in good yield.
O
O
O
O
S
MeO
OH
OBn
OH
Ar
N
NaOH
O
O
MeOH
rt, 3 h
O
O
NH
1
1d OBn
6
0%
Ar
O
S
13d
O
Figure 2. X-ray structure of triol lactam 12d.
Scheme 7. Lactam ring-opening of 11d.

3
348
R. C. Conyers et al. / Tetrahedron Letters 57 (2016) 3344–3348
These [4+2] cycloadditions strongly favor regioselective and
stereoselective formation of endo bicyclic lactams, which undergo
useful reactions including dihydroxylation, reductive cleavage of
the N-sulfonyl group, and lactam ring-opening to produce highly
substituted aminocyclohexane building blocks for biologically
2. Afarinkia, K.; Vinader, V.; Nelson, T. D.; Posner, G. H. Tetrahedron 1992, 48,
111–9171.
9
3
4
.
.
Chung, S.-I.; Seo, J.; Cho, C.-G. J. Org. Chem. 2006, 71, 6701–6704.
Gilchrist, T. L. Heterocyclic Chemistry; Pitman: London, 1985; p 27.
5. Aihara, J. J. Am. Chem. Soc. 1976, 98, 2750–2758.
6.
7.
8.
9.
Gompper, T.; Schmidt, A. Angew. Chem., Int. Ed. Engl. 1980, 19, 463–464.
Posner, G. H.; Vinader, V.; Afarinkia, K. J. Org. Chem. 1992, 57, 4088–4097.
Posner, G. H.; Switzer, C. J. Org. Chem. 1987, 52, 1642–1644.
2
2
active aminocyclitols.
Harmata, M. Advances in Cycloaddition; JAI Press Inc.: Connecticut, 1999; p 47.
1
1
1
0. Jiang, X.; Wang, R. Chem. Rev. 2013, 113, 5515–5546.
Acknowledgments
1. Lee, H.; Lee, S.-I.; Yang, S.-I. Bioorg. Med. Chem. Lett. 1998, 8, 2991–2994.
2. Takacs, J. M.; Lawson, E. C.; Reno, M. J.; Youngman, M. A.; Quincy, D. A.
Tetrahedron: Asymmetry 1997, 8, 3073–3078.
We thank Prof. Kou Hiroya (Musashino University, Japan) for
sharing some of his IEDDA cycloadditions prior to publication.
We thank the Johns Hopkins University for financial support on
this project. ESI Mass spectral data were obtained at Old Dominion
University Mass Spectrometry Center.
2
3
13. Wang, P.; Feng, L.-W.; Wang, L.; Li, J.-F.; Liao, S.; Tang, Y. J. Am. Chem. Soc. 2015,
37, 4626–4629.
1
1
4. Furukawa, T.; Kawazoe, J.; Zhang, W.; Nishimine, T.; Tokunaga, E.; Matsumoto,
T.; Shiro, M.; Shibata, N. Angew. Chem., Int. Ed. 2011, 50, 9684–9688.
5. Tietze, L. F.; Schneider, C. Synlett 1992, 755–756.
6. Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983, 105, 6968–6969.
7. Bednarski, M.; Danishefsky, S. J. Am. Chem. Soc. 1983, 105, 3716–3717.
1
1
1
Supplementary data
18. Passarella, D.; Lesma, G.; Martinelli, M.; Silvani, A.; Cantó; Hidalgo, J.
Tetrahedron 2000, 56, 5205–5208.
1
9. Merino, P.; Anoro, S.; Cerrada, E.; Laguna, M.; Moreno, A.; Tejero, T. Molecules
001, 6, 208–220.
20. Capaccio, C. A. I.; Varela, O. Tetrahedron Lett. 2003, 44, 4023–4026.
Supplementary data (experimental details and the characteriza-
tion data, X-ray crystal structure data for 7d, CCDC No. 1473170
and X-ray crystal structure data for 12d, CCDC No. 1473171)
associated with this article can be found, in the online version, at
http://dx.doi.org/10.1016/j.tetlet.2016.06.068.
2
2
2
1. VanRheene, V.; Kelly, R. C.; Cha, D. Y. Tetrahedron Lett. 1976, 23, 1973–1976.
2. Knapp, S.; Patel, D. V. J. Am. Chem. Soc. 1983, 105, 6985–6986. and references
therein.
23. Hiroya, K.; Kawamoto, K.; Inamoto, K.; Sakamoto, T.; Doi, T. Tetrahedron Lett.
009, 50, 2115–2118.
2
References and notes
1
.
Posner, G. H.; Nelson, T. D.; Kinter, C. M.; Afarinkia, K. Tetrahedron Lett. 1991, 32,
295–5298.
5