Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold from Chiral α-Hydroxyaldehyde Derivatives by the Aza-Prins Reaction

Article abstract of DOI:10.1021/acs.joc.7b01291

(R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane in a highly diastereoselective manner through an unexpected intramolecular nucleophilic attack. Our work has opened a new route toward the asymmetric synthesis of 7-(alkyl or aryl)-6-oxa-2-azabicyclo[3.2.1]octane derivatives from chiral α-hydroxyaldehyde derivatives in one step.

Full text of DOI:10.1021/acs.joc.7b01291

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Article
Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane
Scaffold from Chiral #-Hydroxyaldehyde Derivatives by Aza-Prins Reaction
Alejandro Mahia, Ramon Badorrey, Jose Antonio Galvez, and Maria Dolores Diaz-De-Villegas
J. Org. Chem., Just Accepted Manuscript • DOI: 10.1021/acs.joc.7b01291 • Publication Date (Web): 17 Jul 2017
Downloaded from http://pubs.acs.org on July 18, 2017
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Diastereoselective Construction of the 6-Oxa-2-azabicyclo[3.2.1]octane Scaffold
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from Chiral α-Hydroxyaldehyde Derivatives by Aza-Prins Reaction
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Alejandro Mahía,a,b Ramón Badorrey, a José A. Gálvez, a,* and María D. Díaz-de-
Villegasa,*
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a Instituto de Síntesis Química y Catálisis Homogénea (ISQCH), CSIC -
Universidad de Zaragoza, Departamento de Química Orgánica, Pedro Cerbuna 12,
50009 Zaragoza, Spain.
b Present address, Instituto de Biocomputación y Física de Sistemas Complejos
(BIFI), Mariano Esquillor, Edificio I + D Campus Río Ebro, Universidad de
Zaragoza, 50018 Zaragoza, Spain.
Corresponding Author: * jagl@unizar.es, loladiaz@unizar.es
Abstract
R1
N
H
Ts
p-TsOH·H2O
H
O
R1
+
+
*
O
MeCN, rt, 3h
NH
Ts
O
Ts
R1
N
OBn
H
major compound
from R aldehydes
major compound
from S aldehydes
dr from 79/21 to 87/13
(R)-2,3-Di-O-benzylglyceraldehyde and N-tosyl homoallylamine undergo aza-Prins
cyclization to afford (1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-
azabicyclo[3.2.1]octane in a highly diastereoselective manner through an
unexpected intramolecular nucleophilic attack. Our work has opened a new route
toward
the
asymmetric
synthesis
of
7-(alkyl
or
aryl)-6-oxa-2-
azabicyclo[3.2.1]octane derivatives from chiral α-hydroxyaldehyde derivatives in
one step.
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INTRODUCTION
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Among the different routes that are available to prepare piperidines, the aza-Prins
cyclization, together with its alkyne, silyl and acyliminium variants, provides
straightforward access to this heterocyclic system1−3 and this method has been
successfully applied to the synthesis of several natural products and analogs.4
The classical aza-Prins reaction is a three-component coupling of an aldehyde, a
homoallylic amine and a nucleophile that it is usually promoted by a Lewis5−9 or
Brønsted10−13 acid and takes place through the formation of an iminium
intermediate, which is trapped by the nucleophile. Different 2,4-disubstituted
piperidines have been obtained depending on the reaction conditions (Scheme 1).
Scheme 1. Aza-Prins Reaction
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Nu
Lewis or Bronsted
acid
H
+
Nu-
NH
R1
N
R2
R2
O
R1
There are examples in the literature concerning the use of different acidic catalysts,
nucleophiles, N-homoallylamines and carbonyl compounds but, to the best of our
knowledge, a study on the use of chiral aldehydes for the synthesis of chiral 2,4-
disubstitued piperidines in a diastereoselective manner has not been performed to
date. In recent years we have been interested in the development of versatile
synthetic methodologies for the synthesis of chiral nitrogen-containing heterocycles
using chiral imines that are readily available from renewable sources as starting
materials. In this context, imines derived from conveniently protected (R)-
glyceraldehyde, obtained from inexpensive D-mannitol, have proven to be
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excellent precursors for the construction of the piperidine heterocyclic ring.14−16 As
a consequence, we decided to study the behavior of conveniently protected
glyceraldehyde as the carbonyl compound in the aza-Prins cyclization directed at
the asymmetric synthesis of 2,4-disubstituted piperidines. The first reaction was
carried out between N-(but-3-en-1-yl)-4-methylbenzenesulfonamide17 1a (1 equiv)
and (R)-2,3-di-O-benzylglyceraldehyde 2a (1 equiv) in benzene at room
temperature using BF3·OEt2 (1.1 equiv) as the Lewis acid as a means to obtain
chiral 4-arylpiperines 3 through an aza-Prins-Friedel–Crafts reaction18 (Scheme 2).
However, trapping by the arene was not observed and a 74/24 mixture of
diastereomeric 6-oxa-2-azabicyclo[3.2.1]octanes 4a and 5a, formed by
intramolecular quenching, was obtained in 77% yield.
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Scheme 2. Aza-Prins Reaction of (R)-2,3-di-O-Benzylglyceraldehyde 2a
Ph
H
BF3.OEt2
X
Benzene
+
OBn
O
OBn
NH
Ts
N
OBn
2a
Ts
OBn
H
1a
3
O
H
O
BF3.OEt2
Benzene
+
N
OBn
N
OBn
Ts
Ts
4a
5a
Both diastereoisomers were isolated by silica gel chromatography and their
1
corresponding structures and stereochemistries were determined by H NMR
spectroscopy and NOE experiments, as detailed below.
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The 6-oxa-2-azabicyclo[3.2.1]octane scaffold is present in biologically relevant
molecules and natural products such as stemona alkaloids19 or scopoline20 (Figure
1) and it has served as an intermediate in the synthesis of azasugars.21
Figure 1. Structures of some natural products based on 6-oxa-2-
azabicyclo[3.2.1]octane scaffold
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Me
Me
OMe
Me
OMe
Me
O
O
O
O
N
N
O
O
O
O
Stemofoline
Asparagamine A
N
Me
OH
O
(-) Scopoline
The
reported
procedures
for
the
construction
of
the
6-oxa-2-
azabicyclo[3.2.1]octane skeleton are based on intramolecular nucleophilic
displacement of a leaving group at C-6 by an amino group at C-2 on an
aminomannofuranoside,21 reaction of tetrahydropyridines with formaldehyde in the
presence of manganese dioxide22 or Pd-catalyzed N,O-bicyclization of an
aminoalkenitol.23 In all cases the reported procedure led to a defined compound,
usually as a racemic mixture, and the methodology was not extended to different
substrates. Due to the lack of a versatile methodology for the preparation of 6-oxa-
2-azabicyclo[3.2.1]octane derivatives, and given the potential of the observed
cyclization for the asymmetric synthesis of 7-substituted derivatives from chiral α-
hydroxyaldehydes in only one step, we decided to study this reaction in more detail
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in order to optimize the formation of the bicyclic ring and to explore the scope of
this transformation.
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RESULTS AND DISCUSSION
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We began our study by testing the effect of the solvent on the formation of the 6-
oxa-2-azabicyclo[3.2.1]octane skeleton (Table 1). The reaction did not work
efficiently when it was conducted in ethereal solvents (entries 2,3). The use of
other polar aprotic solvents gave yields in the range 69–77% and the best result as
far as yield and diastereoselectivity are concerned was obtained when the reaction
was performed in acetonitrile (entry 5).
Table 1. Solvent Screening of the Aza-Prins Reaction of 1a and 2aa
entry
solvent
Benzene
Et2O
yield (%)b
4a/5ab
74/26
60/40
-
1
2
3
4
5
6
77
35
0
THF
CH2Cl2
MeCN
Toluene
69
79
70
70/30
86/14
79/21
a
All reactions were carried out under the following conditions: aldehyde (0.33
mmol), tosylamine (0.3 mmol), BF3·OEt2 (0.33 mol), dry solvent (5 mL), room
b
1
temperature, 20 h, under Ar. Determined from the crude reaction mixture by H
NMR using 1,3,5-trimethoxybenzene as internal standard.
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To identify the best catalyst for the reaction, a series of Lewis acids and Brønsted
acids were screened in both dry acetonitrile and dry toluene (Table 2). On using
Lewis acids the reaction did not work with Zn2+ salts, which are considered
borderline acids according to the HBSA theory24 (entries 1–3). On using Lewis
acids with a higher hardness the reaction worked to a greater or lesser extent and
the diastereoselectivity was in the range 67/33–87/13 diastereomeric ratio. In many
cases the diastereoselectivity and yield were higher in acetonitrile than in toluene.
Scandium triflate was found to give the best results and this gave an 85/15
diastereomeric mixture of 6-oxa-2-azabicyclo[3.2.1]octanes 4a and 5a in 91% yield
in dry acetonitrile (entry 8). On using Brønsted acids the reactivity depended on
acidity, with stronger acids giving higher yields. The best results were obtained on
using p-toluensulfonic acid in dry acetonitrile, i.e., 86% yield and 86/14
diastereomeric ratio (entry 17).
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Table 2. Catalyst Screening for the Aza-Prins Reaction of 1a and 2a in
Acetonitrile (A) and Toluene (B)a
entry
acid
ZnCl2
yield A (%)b
yield B (%)b
4a/5a Ab
4a/5a Bb
1
2
3
4
5
6
0
0
0
0
-
-
ZnI2
-
-
Zn(OTf)2
BiCl3
0
0
-
-
28
80
24
12
48
36
82/18
85/15
79/21
67/33
77/23
69/31
Bi(OTf)3
Yb(OTf)3
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In(OTf)3
Sc(OTf)3
FeCl3·6H2O
FeBr3
78
91
69
16
51
49
54
0
52
0c
57
61
74
0
87/13
85/15
83/17
81/19
80/20
82/28
83/17
-
71/29
-
8
9
74/26
75/25
70/30
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AlCl3
BBr3
-
TiCl4
74
0
74/26
HOAc
-
TFA
27
83
86
0
78/22
81/19
86/14
-
73/27
-
MsOH
p-TsOH
66
0c
a
All reactions were carried out under the following conditions: aldehyde (0.33
mmol), tosylamine (0.3 mmol), catalyst (0.33 mol), dry solvent (5 mL), room
b
1
temperature, 20 h, under Ar. Determined from the crude reaction mixture by H
c
NMR using 1,3,5-trimethoxybenzene as internal standard. The catalyst was not
soluble in toluene.
Taking as a reference the results obtained with scandium triflate in dry acetonitrile
at room temperature, the reaction conditions were re-investigated in an effort to
improve the diastereoselectivity (Table 3). The use of a lower reaction temperature
did not improve the reaction efficiency (cf. entries 2 and 3 vs 1). We proceeded to
test the evolution of the reaction and after only 3 hours similar results were
obtained (entry 4). Rigorously anhydrous conditions were not required (entry 5) but
the presence of water as a co-solvent25 led to a decrease in the yield to 57% (entry
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6). Finally, the use of a substoichiometric amount of scandium triflate was
investigated. It was observed that reaction occurred – albeit to a lesser extent
(entry 7), even on prolonging the reaction time (entry 8). From this study a ratio
1.1/1/1 aldehyde/amine/scandium triflate in acetonitrile at room temperature for 3
hours without an argon atmosphere were selected as the optimal reaction
conditions. In this way an 86/14 diastereomeric mixture of 6-oxa-2-
azabicyclo[3.2.1]octanes 4a and 5a was obtained in 85% yield (entry 9). Under
these new conditions the replacement of scandium triflate by the cheaper p-
toluensulfonic acid monohydrate led to similar results, i.e., 83% yield, 84/16
diastereomeric ratio (entry 10). The yield could be improved to 92% by increasing
slightly the excess of p-toluensulfonic acid monohydrate (entry 11).
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Table 3. Optimization of Aza-Prins Reaction Conditions for 1a and 2aa
entry T (ºC) t (h)
solvent
dry MeCN
dry MeCN
dry MeCN
dry MeCN
MeCN
acid
yield (%)b 4a/5ab
1
2
rt
0
20
20
20
3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
Sc(OTf)3
91
80
85
81
88
57
48
37
85
85/15
85/15
85/15
85/15
85/15
82/18
83/17
84/16
86/14
3
–40
rt
4
5
rt
20
20
20
72
3
6
rt
MeCN/H2O (9:1)
dry MeCN
dry MeCN
MeCN
7c
8c
9d
rt
rt
rt
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10d
11d,e
12d,f
rt
rt
rt
3
3
3
MeCN
MeCN
MeCN
p-TsOH·H2O
p-TsOH·H2O
p-TsOH·H2O
83
92
92
84/16
84/16
84/16
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a The model reaction was carried out under the following conditions: aldehyde (0.33
b
mmol), tosylamine (0.3 mmol), acid (0.33 mol), solvent (5 mL), under Ar.
Determined from the crude reaction mixture by 1H NMR using 1,3,5-
trimethoxybenzene as internal standard. c 20 mol% of Sc(OTf)3. d Without an argon
atmosphere. e 1.3 equiv of p-TsOH·H2O. f 1.5 equiv of p-TsOH·H2O.
The scope and limitation of this reaction were investigated next. Although both the
reaction yield and diastereoselectivity were worse than with the N-
tosylhomoallylamine 1a, the reaction also worked with other N-protecting groups
that are capable of increasing the electrophilicity of the iminium intermediate, such
as the benzyloxycarbonyl or diphenylphosphoryl groups (Table 4). The reaction of
benzyl but-3-en-1-ylcarbamate 1b (1 equiv) with (R)-2,3-di-O-benzylglyceraldehyde
2a (1.1 equiv) in acetonitrile at room temperature using p-toluensulfonic acid
monohydrate (1.3 equiv) as the Brønsted acid provided a 70/30 diastereomeric
mixture of 6-oxa-2-azabicyclo[3.2.1]octanes 4b and 5b in 50% yield. Similarly,
reaction of diphenyl but-3-en-1-ylphosphoramidate 1c (1 equiv) with (R)-2,3-di-O-
benzylglyceraldehyde 2a (1.1 equiv) in acetonitrile at room temperature using p-
toluensulfonic acid monohydrate (1.3 equiv) as the Brønsted acid provided an
80/20 diastereomeric mixture of 6-oxa-2-azabicyclo[3.2.1]octanes 4c and 5c in
44% yield.
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Table 4. Scope of the Aza-Prins Reaction, Homoallylamine Derivative
Screeninga
7
8
9
O
H
H
O
H
p-TsOH·H2O
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11
12
13
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+
+
OBn
O
NH
R
MeCN, rt, 3h
N
OBn
N
OBn
OBn
2a
R
R
5a-c
1a-c
entry
R
Tosylamine
Products
4a, 5a
yield (%)b
4/5 b
84/16
70/30
80/20
1
2
3
Ts
1a
1b
1c
92
50
44
Cbz
4b, 5b
4c, 5c
P(O)(OPh)2
a
All reactions were carried out under the following conditions: aldehyde (0.33
mmol), tosylamide (0.3 mmol), p-TsOH (0.39 mol%), acetonitrile (5 mL), room
b
1
temperature, 3 h. Determined from the crude reaction mixture by H NMR using
1,3,5-trimethoxybenzene as internal standard.
The reaction of more highly substituted alkenyl homoallylic tosylamines 1d–f with
(R)-2,3-di-O-benzylglyceraldehyde 2a was also investigated. As a general trend,
the presence of additional substituents on the C=C moiety led to complex mixtures
of compounds with a markedly reduced yield in the formation of the 6-oxa-2-
azabicyclo[3.2.1]octane ring.
On using homoallylic tosylamine 1d as the substrate, in addition to a 87/13 mixture
of diastereomeric 6-oxa-2-azabicyclo[3.2.1]octanes 4d and 5d (43% isolated yield),
octahydroisoquinolines 6 and 7 were isolated from the reaction mixture (Scheme
3).
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Scheme 3. Aza-Prins Reaction of (R)-2,3-di-O-Benzylglyceraldehyde 2a with
5
6
Alkene 1d
7
8
9
O
H
H
p-TsOH·H2O
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OBn
OBn
+
+
+
OBn
O
MeCN, rt, 3h
NH
Ts
N
H
N
N
OBn
2a
OBn
Ts
Ts OBn
Ts OBn
1d
4d/5d
43%, dr = 87/13
6
7
12%
12%
On using homoallylic tosylamine 1e as a substrate, the formation of 6-oxa-2-
azabicyclo[3.2.1]octanes 4e and 5e was significantly reduced (28% combined
yield). Furthermore, an 87/13 mixture of two diastereomeric (piperidin-4-
yl)acetamides 8 was also isolated from the reaction mixture in around 36% yield
(Scheme 4).
Scheme 4. Aza-Prins Reaction of (R)-2,3-di-O-Benzylglyceraldehyde 2a with
Alkene 1e
Me
Me
Me
NHAc
Me
H
O
O
H
H
p-TsOH·H2O
+
+
+
OBn
O
MeCN, rt, 3h
OBn
NH
Ts
N
N
N
OBn
OBn
OBn
2a
Ts
Ts
Ts
OBn
1e
4e
5e
8
36%
dr = 87/13
28%
4e/5e = 14/86
The use of homoallylic tosylamine 1f in the reaction led to the formation a 60/40
mixture of two diastereomeric of pyrrolidines 9 in 55% combined yield and the
formation of 6-oxa-2-azabicyclo[3.2.1]octanes was not detected (Scheme 5).
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Scheme 5. Aza-Prins Reaction of (R)-2,3-di-O-Benzylglyceraldehyde 2a with
5
6
Alkene 1f.
7
8
9
Me
Me
Me
NHAc
Me
H
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
33
34
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51
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53
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55
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59
60
p-TsOH·H2O
+
OBn
O
MeCN, rt, 3h
OBn
NH
N
OBn
2a
OBn
Ts
Ts
1f
9
55%, dr = 60/40
The absolute configurations of compounds 6, 7, 8 and 9 were not determined. The
use of other substituted alkenyl homoallylic tosylamines was ruled out due to the
disappointing
results
in
the
formation
of
the
desired
6-oxa-2-
azabicyclo[3.2.1]octanes observed with tosylamines 1d–e.
The use of other α-hydroxyaldehyde derivatives was subsequently explored (Table
5). 2-Benzyloxyaldehydes 2b–d, with alkyl and aryl substituents at C2, were
successfully employed as substrates in the Aza-Prins reaction promoted by p-
toluensulfonic acid monohydrate to give the corresponding mixture of 6-oxa-2-
azabicyclo[3.2.1]octanes in reasonable yields and diastereoselectivities. On using
aldehydes 2c–d of opposite configuration, 6-oxa-2-azabicyclo[3.2.1]octanes with
opposite configuration at C1 and C5 were obtained preferentially.
Table 5. Scope of the Aza-Prins Reaction, Aldehyde Screeninga
O
O
H
H
H
p-TsOH·H2O
+
R2
R2
+
R1
O
NH
Ts
MeCN, rt, 3h
N
N
Ts
Ts
5a,f-g
2a-f
4a,f-g
1a
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entry
1
Aldehyde
Products
R2
yield (%)b,c
92 (77)
4/5b
H
9
OBn
O
O
O
O
O
O
10
11
12
13
14
15
16
17
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19
20
21
22
23
24
25
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27
28
29
30
31
32
33
34
35
36
37
38
39
40
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42
43
44
45
46
47
48
49
50
51
52
53
54
55
56
57
58
59
60
4a, 5a
CH2OBn
84/16
OBn
2a
H
H
H
H
H
Bn
2
3
4
5
6
4f, 5f
4g, 5g
4h, 5h
4g, 5g
4i, 5i
CH2Bn
Me
69 (52)
76 (42)
69 (40)
25
86/14
21/79
13/87
24/76
66/44
OBn
2b
Me
OBn
2c
Ph
Ph
OBn
2d
Me
Me
OTBS
2e
O
CH2OH
59
O
2f
All reactions were carried out under the following conditions: aldehyde (0.33
a
mmol), tosylamide (0.3 mmol), p-TsOH (0.39 mol%), acetonitrile (5 mL), room
b
1
temperature, 3 h. Determined from the crude reaction mixture by H NMR using
c
1,3,5-trimethoxybenzene as internal standard. The yield of the major compound
isolated is in brackets.
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9
Finally, the use of a different protecting group on the hydroxy moiety was
investigated. Although the reactions showed complete consumption of the starting
aldehyde, low yields of 6-oxa-2-azabicyclo[3.2.1]octanes were observed with O-
tert-butyldimethylsilyl α-hydroxyaldehyde 2e (25% yield, entry 5 Table 5) and 2,2-
dimethyl-1,3-dioxolane-4-carbaldehyde 2f (59% yield, entry 6 Table 5) bearing
more labile protecting groups in acidic media. The use of aldehyde 2f led to a
diastereoselectivity that gave only a 66/34 diastereometic ratio.
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60
The structures and stereochemistries of compounds 4 and 5 were established on
1
1
the basis of their H NMR spectra26 and NOESY experiments (Figure 2). In the H
NMR spectra of all compounds it was possible to assign unambiguously the H3a
signal due to the presence of two large coupling constants, which is indicative of
the axial disposition of this proton. Clear cross-peaks were observed between H3a
and the corresponding resonance of the vicinal nuclei of the substituent at C7 in the
spectra of compounds 4a–f,i, which were obtained from aldehydes with an R-
configuration. These cross-peaks clearly indicate a close spatial disposition, which
1
is only possible for the (1R,5S) stereoisomers. In the H NMR spectra of
compounds 5a–f,i, obtained from aldehydes of R-configuration, the presence of
clear cross-peaks between H3a and H7 resonances clearly indicates the close
spatial disposition of these two nuclei, which is only possible for the (1S,5R)
stereoisomers. For compounds 4g,h and 5g,h, which were obtained from
aldehydes of S-configuration, NOESY cross-peaks were observed between the H3a
and H7 resonances or those for H3a and the group at C7, respectively, thus
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confirming the absolute configuration. Furthermore, the structure of 4a was
confirmed by X-ray crystallography.
7
8
9
Figure 2. Diagnostic nOe cross-peaks for the unambiguous determination of
the configurations of compounds 4 and 5
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nOe
nOe
H3e
H3a
H7
R
H3a
H3e
H3a
R
H3a
N
N
Ts
nOe
Ts
nOe
O
H7
H3e
Ts
O
H3e
Ts
O
O
R
H7
N
N
H7
4a-f,i
R
5a-f,i
4g,h
5g,h
Mechanistically, it has been proposed17,27,28 that the Aza-Prins reaction proceeds
through the formation of an N-sulfonyl iminium ion. Theoretical calculations have
demonstrated that E-imimiun cations are more stable than Z-imimiun cations.17,29
The iminium ion undergoes cyclization with an olefin to afford an intermediate
carbocation, which is trapped by a nucleophile present in the reaction medium to
afford 4-substituted piperidines. On using aldehyde 2a, intramolecular trapping of
the resulting carbocation by the oxygen of the secondary benzyloxy moiety would
result in the formation of the observed 6-oxa-2-azabicyclo[3.2.1]octanes.
Depending on the absolute configuration of the chiral aldehyde, 6-endo trig
cyclization occurs with preferential iminium top face approach of the alkene (a) or
iminium bottom face approach of the alkene (b) to produce 6-oxa-2-
azabicyclo[3.2.1]octane 4a or 5a in excess (Scheme 6).
This model can be used to rationalize the results obtained. The presence of
internal substituents on the olefin moiety would make intramolecular quenching of
the intermediate carbocation difficult and this could evolve in a different way.17 An
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elimination reaction would explain the formation of alkenes 6 and 7 when
homoallylic tosylamine 1d was used as the substrate. Intermolecular trapping with
acetonitrile through a Ritter sequence7,30 would explain the formation of acetamide
8 when homoallylic tosylamine 1e was used as the substrate. Dobbs et al.
observed the exclusive formation of pyrrolidines when trisubstituted homoallylic
amine 1f was used in the Aza-Prins reaction with aliphatic aldehydes due to the
preferential formation of a tertiary carbocation upon cyclization to a five-membered
ring.17 In our case, Ritter reaction of the tertiary carbocation with acetonitrile used
as solvent would explain the formation of compound 9.
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Scheme 6. Possible Model for the Aza-Prins reaction of 2a
E-iminium ion top face approach
a
N+
H
Ts
N
H
Ts
4a
major
H2O
BnOH
BnOCH2
O+
O
BnCH2O
TsHN
Bn
H
H
Bn
- H2O
+
E-iminium ion bottom face approach
Bn
H
O+
Bn
O+
H
H
O
H
R
BnOCH2
Ts
BnOCH2
Ts
5a
minor
N+
N
H2O
BnOH
H
H
b
Cleavage of the N-tosyl group was performed by heating compound 4a under
reflux with an excess of magnesium turnings (20 equiv) in methanol for 4 hours.31
Under these conditions compound 10 was obtained in 83% yield. Alternatively,
tosyl cleavage by reduction with magnesium turnings in anhydrous methanol under
ultrasound conditions at room temperature was tested.32 On using 5 equiv of
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9
magnesium the tosyl group in 4a remained unaltered after sonication for 20 hours.
Efficient deprotection under ultrasound conditions required a larger excess of
magnesium (20 equiv) and sonication under reflux. In this way compound 10 was
obtained in 92% yield after 4 hours (Scheme 7).
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Scheme 7. Cleavage of the Tosyl Group
O
H
O
H
Mg (20 equiv.)/MeOH
CH2OBn
CH2OBn
N
N
, Δ, 4h
Ts
H
10
4a
92%
In summary, we have shown that the aza-Prins reaction of N-(but-3-en-1-yl)-4-
methylbenzenesulfonamide 1a with chiral α-hydroxyaldehyde derivatives takes
place by intramolecular nucleophilic attack to form compounds with a 6-oxa-2-
azabicyclo[3.2.1]octane moiety. This structural motif is present in compounds with
interesting biological properties. Optimization of the reactions conditions allowed
the development of a new and efficient procedure for the asymmetric synthesis of
6-oxa-2-azabicyclo[3.2.1]octanes with different substituents at C7 in one step using
p-toluenesulfonic acid monohydrate as a promoter and without the need to employ
strictly anhydrous conditions.
EXPERIMENTAL SECTION
General Details. Unless otherwise specified, all reagents were obtained from
commercial suppliers and were used without purification. For anhydrous
conditions, reactions were carried out under Ar in solvents dried using a Solvent
Purification System (SPS). TLC was performed on precoated silica gel polyester
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plates and products were visualized using UV light (254 nm) and ninhydrin,
anisaldehyde or potassium permanganate solutions followed by heating. Column
chromatography was performed on silica gel (60, 40−63 µm) with air pressure.
Sonication treatment was performed in an ultrasonic cleaner (ultrasonic frequency
45 Hz, HF effective power 80 W) with an integrated heater up to 80 ºC.
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Melting points were determined in open capillary tubes and are not corrected. FT-
IR spectra were recorded as thin films on NaCl plates, νmax values expressed in
cm–1 are given for the main absorption bands. Optical rotations were measured on
a digital polarimeter at λ 589 nm and 25 ºC in cells with 1 or 10 cm path length, [α]D
values are given in 10–1 deg·cm2·g–1 and concentrations are given in g/100 mL. 1H
NMR and 13C NMR spectra were acquired in deuterated solvent at room
temperature unless otherwise stated at 400 and 100 MHz, respectively using a 5-
mm probe. All chemical shifts (δ) are reported in parts per million (ppm) with the
solvent resonance as the internal standard,33 and coupling constants (J) in hertz
(Hz). NOESY spectra were acquired in the phase sensitive mode with gradient
pulses in the mixing time as 2048 x 256 hipercomplex files with 8 transients for 256
time increments. A mixing time of 900 ms was used and processing was carried
out using a sine-bell squared function shifted by π/2 and a states-TPPI method.
Special precautions such as degassing of the sample were not taken. High-
resolution mass spectra were recorded from methanolic solutions on a
MICROTOF-Q (quadrupole time-of-flight) micro instrument using the positive
electrospray ionization mode (ESI+). The X-ray diffraction data were collected at
room temperature on a four-circle diffractometer, using graphite-monochromated
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Mo-Kα radiation (λ = 0.71073 Å). The following N-protected alkenyl homoallylic
amines were synthesized according to previously published procedures: 1a,34 1b,35
1d,36 1e17 and 1f.17 The following α-hydroxyaldehyde derivatives were synthesized
according to previously published procedures: 2c,37,38 2d,39 2e,40 2f.41
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60
Diphenyl but-3-en-1-ylphosphoramidate (1c)42
To an ice-cold solution of phenol (376 mg, 4.0 mmol) in CH2Cl2 (60 mL) were
added sequentially POCl3 (307 mg, 2.0 mmol) and Et3N (1.4 mL, 10.0 mmol). After
stirring for 0.5 h at 0 ºC but-3-en-1-amine (142 mg, 2.0 mmol) was added and
stirring was continued first for 1 h at 0 ºC and then for 16 h at room temperature.
Solvent was evaporated in vacuo and CH2Cl2 (30 mL) and water (30 mL) were
added. The aqueous layer was separated and extracted with CH2Cl2 (2 × 15 mL).
The combined organic layers were dried over anhydrous MgSO4, filtered and
concentrated in vacuo. Purification of the residue by silica gel column
chromatography (Et2O/hexanes, 1:1) afforded 455 mg (75% yield) of compound 1c
1
as a yellowish oil. IR (nujol) 3223, 1591, 1491; H NMR (400 MHz, CDCl3) δ
7.40−7.15 (m, 10H), 5.69 (ddt, J = 17.2, 10.4, 6.8 Hz, 1H), 5.11−5.01 (m, 2H),
3.22−3.11, (m, 3H), 2.27−2.19 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 150.8 (d, J =
6.7 Hz), 134.6, 129.7, 124.9 (d, J = 0.9 Hz), 120.2 (d, J = 5.0 Hz), 117.9, 40.7 (d, J
= 0.4 Hz), 35.5 (d, J = 6.4 Hz).
(R)-2,3-Bis(benzyloxy)propanal (2a)
To a solution of 1,2,5,6-tetra-O-benzyl-D-mannitol43 (1.90 g, 3.5 mmol) in dry THF
(18 mL) was added solid NaIO4 (1.50 g, 7.0 mmol). Then water (1.8 mL) was
added dropwise with stirring to dissolve the NaIO4 and the solution was vigorously
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stirred at 35 ºC for 1 h. Solvents were evaporated in vacuo and the solid residue
was washed with Et2O (3 × 15 mL). The combined filtrates were concentrated in
vacuo and the residue purified by silica gel column chromatography
(hexanes/Et2O, 1:1) to afford 1.77 g (94% yield) of compound 2a as a colorless oil.
Spectroscopic and physical data are in good agreement with those reported in the
literature.44
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(R)-2-(Benzyloxy)-4-phenylbutanal (2b)
To a solution of ethyl (R)-2-hydroxy-4-phenylbutanoate (208 mg, 1.0 mmol) and of
O-benzyl-2,2,2-trichloroacetimidate (505 mg, 2.0 mmol) in dry hexane-CH2Cl2 7:1
v/v (5 mL) at room temperature under argon atmosphere was added dropwise
trifluoromethanesulfonic acid (15 mg, 0.1 mmol). After stirring for 72 h at room
temperature the reaction mixture was filtered to remove the white precipitate, which
is washed with hexane. The combined organic filtrates were washed with a
saturated aqueous solution of NaHCO3 (15 mL). The aqueous layer was extracted
with hexane (15 mL). Combined organic layers were dried over MgSO4, filtered,
and evaporated under reduced pressure. Purification of the residue by silica gel
column chromatography (hexanes/Et2O, 9:1) afforded 210 mg (70% yield) of ethyl
(R)-2-benzyloxy-4-phenylbutanoate as a yellowish oil. [α]D25 = 55.0 (c 1.02, CHCl3);
1
IR (neat) 1745; H NMR (400 MHz, CDCl3) δ 7.42−7.23 (m, 7H), 7.21−7.12 (m,
3H), 4.72 (d, J = 11.6 Hz, 1H), 4.40 (d, J = 11.6 Hz, 1H), 4.26−4.14 (m, 2H), 3.92
(dd, J = 7.6, 5.2 Hz, 1H), 2.81 (ddd, J = 13.6, 8.8, 6.4 Hz, 1H), 2.75−2.65 (m, 1H),
13
2.16−2.00 (m, 2H), 1.28 (t, J = 7.6 Hz, 3H); C NMR (100 MHz, CDCl3) δ 172.8,
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141.1, 137.5, 128.5, 128.4, 128.4, 128.1, 127.9, 126.0, 77.3, 72.3, 60.8, 34.6, 31.4,
14.3.
7
8
9
To a solution of the obtained ethyl (R)-2-benzyloxy-4-phenylbutanoate (151 mg,
0.51 mmol) in dry Et2O in (5 mL) at – 78 ºC under argon atmosphere was added
dropwise while stirring a 1M solution of DIBAL-H in hexane (0.77 mL, 0.77 mmol)
and stirring is continued for 1.5 h at the same temperature. Upon complete
consumption of the ester a 4N aqueous solution of HCl (5 mL) was added and the
reaction mixture was left to reach room temperature. The aqueous layer was
separated and extracted with Et2O (3 × 5 mL). The combined organic layers were
dried over anhydrous MgSO4, filtered and concentrated in vacuo to afford 120 mg
(93% yield) of compound 2b as a yellowish oil. Spectroscopic and physical data
are in good agreement with those reported in the literature for ent-2b.45
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General procedure A: Optimization of Aza-Prins reaction of (R)-2,3-di-O-
benzylglyceraldehyde with N-tosyl-homoallyl amine. To a solution of N-(but-3-
en-1-yl)-4-methylbenzenesulfonamide 1a (67.5 mg, 0.30 mmol) and (R)-2,3-di-O-
benzylglyceraldehyde 2a (89 mg, 0.33 mmol) in the selected dry solvent (5 mL) at
room temperature under argon atmosphere was added the corresponding Lewis or
Brønsted acid (0.33 mmol). The resulting solution was stirred for the required time
at room temperature. The crude product was concentrated under reduced
pressure, then diluted in CH2Cl2 (20 mL), and washed with a saturated aqueous
solution of NaHCO3 (20 mL). The aqueos layer was extracted with CH2Cl2 (20 mL).
Combined organic layers were dried over MgSO4, filtered, and evaporated under
reduced pressure. The reaction was concentrated in vacuo and the residue was
1
analyzed by H NMR using 1,3,5-trimethoxybenzene as internal standard46 to
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determine the reaction yield and diastereoselectivity. Purification of the residue
was performed by column chromatography.
7
8
9
General procedure B: Aza-Prins reaction of hydroxyaldehyde derivatives with
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N-tosyl-homoallyl
amine.
To
a
solution
of
N-(but-3-en-1-yl)-4-
methylbenzenesulfonamide 1a (67.5 mg, 0.30 mmol) and α-hydroxyaldehyde
derivative (0.33 mmol) in acetonitrile (5 mL) at room temperature was added p-
toluensulfonic acid monohydrate (74.2 mg, 0.39 mmol). The resulting solution was
stirred for 3 h at room temperature. The crude product was concentrated under
reduced pressure, then diluted in CH2Cl2 (20 mL), and washed with a saturated
aqueous solution of NaHCO3 (20 mL). The aqueos layer was extracted with CH2Cl2
(20 mL). Combined organic layers were dried over MgSO4, filtered, and evaporated
under reduced pressure. The crude product was purified by column
chromatography to give 6-oxa-2-azabicyclo[3.2.1]octanes.
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(1R,5S,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane (4a)
and (1S,5R,7S)-7-[(benzyloxy)methyl]-2-tosyl-6-oxa-2-azabicyclo[3.2.1]octane
(5a).
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Following general procedure B with N-(but-3-en-1-yl)-4-methylbenzenesulfonamide
1a (67.5 mg, 0.30 mmol), (R)-2,3-di-O-benzylglyceraldehyde 2a (89 mg, 0.33
mmol) and p-toluensulfonic acid monohydrate (74.2 mg, 0.39 mmol), purification by
column chromatography (Et2O/hexanes, 3:2) afforded 89 mg (77% yield) of
compound 4a as a white solid and 17 mg (15% yield) of compound 5a as a
yellowish oil. 4a: mp 101–102 ºC; [α]D25 = 7.44 (c 1.00, CHCl3); IR (nujol) 1159; 1H
NMR (400 MHz, C6D6) δ 7.70−7.65 (m, 2H), 7.39−7.34 (m, 2H), 7.24−7.18 (m, 2H),
7.14−7.07 (m, 1H), 6.83−6.78 (m, 2H), 4.50−4.47 (m, 1H), 4.40 (d, J = 12.1 Hz,
1H), 4.36 (d, J = 12.1 Hz, 1H), 4.06 (ddd, J = 8.7, 5.7, 3.0 Hz, 1H), 4.01 (ddd, J =
6.2, 4.6, 1.3 Hz, 1H), 3.75−3.65 (m, 2H), 3.51 (ddd, J = 13.4, 7.4, 1.8 Hz, 1H), 3.20
(ddd, J = 13.4, 10.5, 5.9 Hz, 1H), 1.93 (s, 3H), 1.39−1.30 (m, 1H), 1.30−1.19 (m,
1H), 1.09−1.02 (m, 1H), 0.95−0.84 (m, 1H); 13C NMR (100 MHz, C6D6) δ 142.7,
139.2, 138.9, 129.7, 128.5, 127.6, 127.3, 81.6, 73.7, 73.3, 69.3, 56.2, 40.2, 36.6,
305, 21.1; HRMS(ESI+) m/z [M+Na]+ calcd for C21H25NO4SNa 410.1397, found
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410.1413. 5a: [α]D = 49.8 (c 0.92, CHCl3); IR (neat) 1164; H NMR (400 MHz,
CDCl3) δ 7.57−7.53 (m, 2H), 7.34−7.00 (m, 7H), 4.48−4.32 (m, 4H), 3.68−3.60 (m,
1H), 3.44 (dd, J = 6.6, 5.1 Hz, 1H), 3.19 (dd, J = 9.8, 5.1 Hz, 1H), 3.09 (dd, J = 9.8,
6.6 Hz, 1H), 2.82−2.73 (m, 1H), 2.31 (s, 3H), 1.94−1.85 (m, 1H), 1.71 (d, J = 11.7
Hz, 1H), 1.67−1.60 (m, 2H); 13C NMR (100 MHz, CDCl3) δ 143.4, 137.8, 135.1,
129.6, 128.4, 127.7, 127.7, 127.6, 78.1, 74.5, 73.4, 71.0, 57.9, 40.2, 36.0, 30.7,
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21.5; HRMS(ESI+) m/z [M+Na]+ calcd for C21H25NO4SNa 410.1397, found
410.1385.
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Benzyl (1R,5S,7S)-7-[(benzyloxy)methyl]-6-oxa-2-azabicyclo[3.2.1]octane-2-
carboxylate (4b) and benzyl (1S,5R,7S)-7-[(benzyloxy)methyl]-6-oxa-2-
azabicyclo[3.2.1]octane-2-carboxylate (5b).
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Following general procedure B with benzyl but-3-en-1-ylcarbamate 1b (61.5 mg,
0.30 mmol), (R)-2,3-di-O-benzylglyceraldehyde 2a (89 mg, 0.33 mmol) and p-
toluensulfonic acid monohydrate (74.2 mg, 0.39 mmol), purification by column
chromatography (Et2O/hexanes, 3:2) afforded 35 mg (32% yield) of compound 4b
as a yellowish oil and 15 mg (14% yield) of compound 5b as a yellowish oil. 4b:
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[α]D = 10.6 (c 1.42, CHCl3); IR (neat) 1699; H NMR (400 MHz, C7D8, 383 K)
δ 7.26−7.00 (m, 10H), 5.09 (d, J = 12.4 Hz, 1H), 5.04 (d, J = 12.4 Hz, 1H),
4.78−4.63 (m, 1H), 4.37 (d, J = 13.0 Hz, 1H), 4.33 (d, J = 13.0 Hz, 1H), 4.16−4.10
(m, 1H), 3.98 (ddd, J = 5.6, 5.6, 2.8 Hz, 1H), 3.70−3.55 (m, 3H), 3.17 (ddd, J =
13.2, 9.6, 7.0 Hz, 1H), 1.64−1.55 (m, 1H), 1.50−1.42 (m, 1H), 1.31 (d, J = 12.0 Hz,
13
1H), 1.23−1.12 (m, 1H); C NMR (100 MHz, C7D8, 383 K) δ 155.7, 139.6, 138.1,
128.6, 128.5, 128.2, 128.0, 127.6, 82.2, 74.2, 73.9, 69.8, 67.5, 55.1, 39.3, 37.3,
31.2; HRMS(ESI+) m/z [M+Na]+ calcd for C22H25NO4Na 390.1676, found 390.1675.
5b: [α]D25 = 25.4 (c 0.42, CHCl3); IR (neat) 1700; 1H NMR (400 MHz, CDCl3, 333 K)
δ 7.37−7.27 (m, 10H), 5.17 (d, J = 12.6 Hz, 1H), 5.14 (d, J = 12.6 Hz, 1H),
4.81−4.73 (m, 1H), 4.59−4.48 (m, 3H), 4.23 (dd, J = 5.4, 5.4 Hz, 1H), 4.02−3.93
(m, 1H), 3.48 (dd, J = 10.0, 5.4 Hz, 1H), 3.41−3.35 (m, 1H), 3.31 (ddd, J = 13.6,
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11.2, 5.6 Hz, 1H), 2.01−1.91 (m, 1H), 1.81−1.72 (m, 1H), 1.68−1.56 (m, 2H) ; C
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NMR (100 MHz, CDCl3, 333 K) δ 154.7, 138.2, 137.0, 128.5, 128.4, 128.0, 127.8,
127.6, 81.2, 74.9, 73.6, 71.7, 67.2, 56.0, 38.6, 35.7, 31.3; HRMS(ESI+) m/z
[M+Na]+ calcd for C22H25NO4Na 390.1676, found 390.1675.
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Diphenyl [(1R,5S,7S)-7-[(benzyloxy)methyl]-6-oxa-2-azabicyclo[3.2.1] octan-2-
yl]phosphonate (4c) and diphenyl [(1S,5R,7S)-7-[(benzyloxy)methyl]-6-oxa-2-
azabicyclo[3.2.1]octan-2-yl]phosphonate (5c).
Following general procedure B with diphenyl but-3-en-1-ylphosphoramidate 1c
(90.9 mg, 0.30 mmol), (R)-2,3-di-O-benzylglyceraldehyde 2a (89 mg, 0.33 mmol)
and p-toluensulfonic acid monohydrate (74.2 mg, 0.39 mmol), purification by
column chromatography (Et2O/hexanes, 2:1) afforded 42 mg (30% yield) of
compound 4c as a yellowish oil and 6 mg (4% yield) of compound 5c as a
yellowish oil. 4c: [α]D25 = 1.31 (c 0.80, CHCl3); IR (neat) 1590, 1488, 1192; 1H NMR
(400 MHz, C6D6) δ 7.42−7.32 (m, 6H), 7.21−7.16 (m, 2H), 7.12−7.06 (m, 1H),
7.05−6.96 (m, 4H), 6.88−6.80 (m, 2H), 4.43−4.36 (m, 1H), 4.34 (d, J = 12.1 Hz,
1H), 4.27 (d, J = 12.1 Hz, 1H), 4.14−4.08 (m, 2H), 3.71 (dd, J = 10.1, 6.0 Hz, 1H),
3.62 (dd, J = 10.1, 5.4 Hz, 1H), 3.52−3.43 (m, 1H), 3.29−3.18 (m, 1H), 1.49−1.38
13
(m, 1H), 1.38−1.29 (m, 1H), 1.14−1.08 (m, 1H), 1.07−0.97 (m, 1H); C NMR (100
MHz, C6D6) δ 151.7 (d, J = 3.3 Hz), 151.6 (d, J = 3.1 Hz), 139.2, 129.9, 129.8,
128.5, 127.7, 127.5, 125.0 (d, J = 0.9 Hz) , 124.9 (d, J = 0.9 Hz), 120.8 (d, J = 5.0
Hz), 120.7 (d, J = 5.1 Hz), 82.0 (d, J = 5.0 Hz), 74.1 (d, J = 0.4 Hz), 73.2, 69.1, 55.6
(d, J = 4.1 Hz), 39.6 (d, J = 1.4 Hz), 38.4 (d, J = 2.0 Hz), 31.0 (d, J = 5.3 Hz);
HRMS(ESI+) m/z [M+H]+ calcd for C26H29NO5P 466.1778, found 466.1789. 5c:
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[α]D = 12.4 (c 0.27, CHCl3); IR (neat) 1590, 1488, 1192; H NMR (400 MHz,
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C6D6) δ 7.45−7.39 (m, 4H), 7.27−7.22 (m, 2H), 7.17−7.12 (m, 2H), 7.11−7.06 (m,
1H), 7.04−6.96 (m, 4H), 6.87−6.80 (m, 2H), 4.56 (dd, J = 7.8, 3.9 Hz, 1H),
4.22−4.16 (m, 3H), 4.10 (dd, J = 5.4, 5.4 Hz, 1H), 3.62−3.53 (m, 1H), 3.28 (dd, J =
9.9, 4.3 Hz, 1H), 3.24−3.14 (m, 1H), 3.06 (dd, J = 9.9, 7.0 Hz, 1H), 1.68−1.56 (m,
1H), 1.39−1.30 (m, 1H), 1.28−1.23 (m, 1H), 1.11−0.98 (m, 1H). 13C NMR (100
MHz, C6D6) δ 151.7 (d, J = 4.8 Hz), 151.5 (d, J = 5.1 Hz), 138.8, 129.9, 129.8,
128.6, 128.3, 127.5, 124.9 (d, J = 0.9 Hz), 124.8 (d, J = 0.8 Hz), 120.8 (d, J = 5.1
Hz), 120.6 (d, J = 5.3 Hz), 81.2 (d, J = 4.0 Hz), 74.8 (d, J = 0.6 Hz), 73.3, 71.7, 57.0
(d, J = 3.2 Hz), 39.4 (d, J = 2.2 Hz), 36.3 (d, J = 2.9 Hz), 31.5 (d, J = 5.8 Hz);
HRMS(ESI+) m/z [M+H]+ calcd for C26H29NO5P 466.1778, found 466.1766.
(1R,4aS,8aR,10S)-10-[(Benzyloxy)methyl-2-tosyloctahydro-2H-4a,1-
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(epoxymethano)isoquinoline (4d), (1S,4aR,8aS,10S)-10-[(benzyloxy)methyl-2-
tosyloctahydro-2H-4a,1-(epoxymethano)isoquinoline
(5d),
1-[(S)-1,2-
bis(benzyloxy)ethyl]-2-tosyl-1,2,3,4,6,7,8,8a-octahydroisoquinoline (6) and 1-
[(S)-1,2-bis(benzyloxy)ethyl]-2-tosyl-1,2,3,4,5,6,7,8-octahydroisoquinoline (7).
Following
general
procedure
B
with
N-(2-(cyclohex-1-en-1-yl)ethyl)-4-
methylbenzenesulfonamide 1d (83.8 mg, 0.30 mmol), (R)-2,3-di-O-
benzylglyceraldehyde 2a (89 mg, 0.33 mmol) and p-toluensulfonic acid
monohydrate (74.2 mg, 0.39 mmol), purification by column chromatography
(hexanes/Et2O, 4:1) afforded 19 mg (ca. 12% yield) of slightly unpurified compound
6 as a brown solid and 19 mg (ca. 12% yield) of compound slightly unpurified 7 as
a yellowish oil. Further elution (Et2O/hexanes, 2:1) provided 57 mg (43% yield) of a
87/13 diastereomeric mixture compounds 4d/5d as a yellowish oil. 4d (from the
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87/13 diastereomeric mixture): IR (neat) 1346; 1H NMR (400 MHz, C6D6)
δ 7.73−7.69 (m, 2H), 7.36−7.32 (m, 2H), 7.21−7.14 (m, 2H), 7.12−7.05 (m, 1H),
6.81−6.76 (m, 2H), 4.55−4.52 (m, 1H), 4.40−4.30 (m, 4H), 3.74 (dd, J = 10.0, 5.8
Hz, 1H), 3.68 (dd, J = 10.0, 5.2 Hz, 1H), 3.61 (ddd, J = 13.4, 7.6, 1.6 Hz, 1H), 3.21
(ddd, J = 13.4, 10.5, 6.0 Hz, 1H), 1.89 (s, 3H), 1.78−1.71 (m, 1H), 1.40−1.28 (m,
3H), 1.27−1.15 (m, 3H), 1.12−1.01 (m, 1H), 0.89−0.62 (m, 3H); 13C NMR (100
MHz, C6D6) δ 142.7, 139.1, 139.1, 129.7, 128.5, 127.8, 127.6, 127.3, 80.4, 79.8,
73.4, 70.2, 61.9, 47.5, 40.9, 37.5, 33.4, 25.5, 24.1, 21.3, 21.1; HRMS(ESI+) m/z
[M+H]+ calcd for C25H32NO4S 442.2047, found 442.2052. 6 (from the mixture): IR
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(nujol) 1340, 1165, 1114; H NMR (400 MHz, CDCl3) δ 7.60−7.70 (m, 2H),
7.40−7.18 (m, 12H), 5.26 (bs, 1H), 4.81 (d, J = 11.6 Hz, 1H), 4.55 (d, J = 11.6 Hz,
1H), 4.50 (d, J = 12.0 Hz, 1H), 4.46 (d, J = 12.0 Hz, 1H), 4.20 (dd, J = 6.8, 2.8 Hz,
1H), 4.06−4.01 (m, 1H), 3.80 (dd, J = 10.2, 12.0 Hz, 1H), 3.74 (dd, J = 10.2, 6.4
Hz, 1H), 3.75−3.68 (m, 2H), 2.41 (s, 3H), 2.35−2.24 (m, 1H), 2.08−2.01 (m, 1H),
1.97−1.89 (m, 2H), 1.89−1.79 (m, 2H), 1.76−1.40 (m, 3H); 13C NMR (100 MHz,
CDCl3) δ 143.0, 138.9, 138.9, 138.3, 134.3, 129.7, 128.4, 127.9, 127.8, 127.6,
127.1, 127.0, 127.0, 120.7, 79.6, 73.5, 73.3, 73.1, 58.2, 43.7, 38.1, 31.9, 26.0,
25.2, 22.2, 21.5; HRMS(ESI+) m/z [M+Na]+ calcd for C32H37NNaO4S 554.2336,
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found 554.2341. 7 (from the mixture): IR (neat) 1335, 1158, 1089; H NMR (400
MHz, CDCl3) δ 7.66−7.62 (m, 2H), 7.42−7.17 (m, 12H), 4.72 (d, J = 11.6 Hz, 1H),
4.64 (d, J = 11.6 Hz, 1H), 4.56 (d, J =11.6 Hz, 1H), 4.49 (d, J = 11.6 Hz, 1H),
4.14−4.09 (bs, 1H), 3.97−3.74 (m, 5H), 2.40 (s, 3H), 1.97−1.83 (m, 1H), 1.76−1.32;
13C NMR (100 MHz, CDCl3) δ 142.9, 138.9, 138.6, 138.0, 129.6, 129.1, 128.3,
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128.1, 127.8, 127.5, 127.4, 127.4, 127.1, 124.5, 79.0, 73.8, 73.6, 72.8, 58.5, 41.0,
30.0, 27.8, 27.0, 22.8, 22.5, 21.4; HRMS(ESI+) m/z [M+Na]+ calcd for
C32H37NNaO4S 554.2336, found 554.2354.
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(1R,5S,7S)-7-[(Benzyloxy)methyl]-5-methyl-2-tosyl-6-oxa-2-
azabicyclo[3.2.1]octane (4e), (1S,5R,7S)-7-[(benzyloxy)methyl]-5-methyl-2-
tosyl-6-oxa-2-azabicyclo[3.2.1]octane
(5e)
and
N-{2-[(S)-1,2-
bis(benzyloxy)ethyl]-4-methyl-1-tosylpiperidin-4-yl}acetamide (8).
Following
general
procedure
B
with
mg,
4-methyl-N-(3-methylbut-3-en-1-
0.30 mmol), (R)-2,3-di-O-
yl)benzenesulfonamide
1e (71.8
benzylglyceraldehyde 2a (89 mg, 0.33 mmol) and p-toluensulfonic acid
monohydrate (74.2 mg, 0.39 mmol), partial purification by column chromatography
(hexanes/Et2O, 3:2) afforded 16 mg of compound 5e slightly unpurified with
unreacted 1e and 2a (5e/2a/1e = 79/14/7), and 7 mg of compound 4e unpurified
with 5e and unreacted 2a (4e/5e/2a = 72/25/3). Further elution (EtOAc) provided
59 mg (36% yield) of compound 8 as a 83/17 mixture of diastereoisomers as a
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yellowish oil. 4e (from the mixture): IR (neat) 1349; H NMR (400 MHz, CDCl3)
δ 7.71−7.66 (m, 2H), 7.41−7.23 (m, 7H), 4.58−4.53 (m, 1H), 4.53 (d, J = 12.0 Hz,
1H), 4.44 (d, J = 12.0 Hz, 1H), 4.24 (ddd, J = 7.0, 4.4, 3.2 Hz, 1H), 3.71 (dd, J =
13.6, 7.2 Hz, 1H), 3.58 (dd, J = 10.0, 7.0 Hz, 1H), 3.50 (dd, J = 10.0, 4.4 Hz, 1H),
3.37−3.23 (m, 1H), 2.42 (s, 3H), 1.82−1.69 (m, 2H), 1.62−1.52 (m, 1H), 1.48−1.42
(m, 1H), 1.32 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.3, 138.0, 137.6, 129.8,
128.3, 127.7, 127.6, 126.9, 81.4, 80.3, 73.4, 68.9, 57.6, 42.6, 40.9, 35.8, 25.6,
21.5; HRMS(ESI+) m/z [M+Na]+ calcd for C22H27NNaO4S 424.1553, found
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424.1559. 5e (from the mixture): IR (neat) 1342; H NMR (400 MHz, CDCl3)
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δ 7.65−7.61 (m, 2H), 7.41−7.28 (m, 5H), 7.18−7.12 (m, 2H), 4.57−4.53 (m, 1H),
4.48 (d, J = 12.0 Hz, 1H), 4.44 (d, J = 12.0 Hz, 1H), 3.76−3.69 (m, 1H), 3.48 (dd, J
= 6.8, 4.8 Hz, 1H), 3.26 (dd, J = 9.6, 4.8 Hz, 1H), 3.16 (dd, J = 9.6, 6.8 Hz, 1H),
2.86 (ddd, J = 11.6, 11.6, 5.2 Hz, 1H), 2.39 (s, 3H), 1.83−1.65 (m, 2H), 1.63−1.55
(m, 2H), 1.29 (s, 3H); 13C NMR (100 MHz, CDCl3) δ 143.4, 138.0, 135.2, 129.6,
128.4, 127.7, 127.6, 127.6, 80.6, 78.6, 73.3, 71.3, 59.5, 41.4, 40.7, 36.4, 25.0,
21.5; HRMS(ESI+) m/z [M+Na]+ calcd for C22H27NNaO4S 424.1553, found
424.1547. 8 (major compound from the 83/17 diastereomeric mixture): IR (neat)
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3370, 1676; H NMR (400 MHz, CDCl3) δ 7.66−7.60 (m, 2H), 7.30−7.14 (m, 12H),
6.47 (bs, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.51 (d, J = 11.8 Hz, 1H), 4.40 (d, J = 11.8
Hz, 1H), 4.36 (d, J = 11.2 Hz, 1H), 4.16 (dd, J = 6.8, 6.8 Hz, 1H), 3.87 (ddd, J =
6.8, 4.0, 3.6 Hz, 1H), 3.71 (dd, J = 10.8, 3.6 Hz, 1H), 3.71−3.62 (m, 1H), 3.56 (dd,
J = 10.8, 4.0 Hz, 1H), 3.24−3.13 (m, 1H), 2.40−2.39 (m, 1H), 2.32 (s, 3H),
1.91−1.84 (m, 1H), 1.27 (s, 3H), 1.10−1.01 (m, 1H), 1.06 (s, 3H), 0.77 (ddd, J =
13
13.6, 13.6, 4.4 Hz, 1H); C NMR (100 MHz, CDCl3) δ 169.8, 143.4, 138.1, 137.7,
137.4, 129.8, 128.6, 128.4, 128.0, 127.9, 127.8, 127.6, 126.9, 79.1, 73.5, 71.9,
68.8, 51.9, 49.5, 39.3, 35.3, 31.0, 27.5, 23.8. 21.4; HRMS(ESI+) m/z [M+H]+ calcd
for C31H39N2O5S 551.2574, found 551.2592.
N-{2-[2-[(S)-1,2-Bis(benzyloxy)ethyl]-1-tosylpyrrolidin-3-yl]propan-2-yl}
acetamide (9)
Following general procedure
B
with 4-methyl-N-(4-methylpent-3-en-1-
yl)benzenesulfonamide 1f (76 mg, 0.30 mmol), (R)-2,3-di-O-benzylglyceraldehyde
ACS Paragon Plus Environment