Stereoselective synthesis and some properties of new chlorodiorganotin- substituted macrodiolides

Article abstract of DOI:10.1021/om200987t

Radical tandem addition of dialkyltin chlorohydrides, R2SnHCl (R = n-Bu, neophyl, Ph), to TADDOL's substituted diacrylates (47) led to the corresponding products of cyclohydrostannation. The new optically active chlorodialkyltinsubstituted 11-membered macrodiolides were obtained in very good yields and with much higher stereoselectivity than that achieved with the corresponding monohydrides, R3SnH. Thus, the cyclohydrostannation of diacrylate 4 and dimethacrylate 5 lead to just one diastereomer in the first case and to an easily separable mixture of two diastereomers in the second. Reduction of the new organotin macrocycles with LiAlH4 afforded optically active organotin derivatives structurally related to glutaric acid. Oxidation of the new chlorodiorganotin-substituted macrocycles with 30% hydrogen peroxide gave the new 11-membered macrocycles 30 and 31 free of tin in an average total yield of 43.4% from TADDOL. Full ¹H, ¹³C, and 119Sn data are also reported.

Full text of DOI:10.1021/om200987t

Article
pubs.acs.org/Organometallics
Stereoselective Synthesis and Some Properties of New
Chlorodiorganotin-Substituted Macrodiolides
Darío C. Gerbino,†,‡ Jimena Scoccia,†,‡ Liliana C. Koll,*,†,‡ Sandra D. Mandolesi,†
and Julio C. Podesta*,†,‡
́
†Instituto de Química del Sur (INQUISUR, UNS-CONICET), Departamento de Química, Universidad Nacional del Sur, Avenida
Alem 1253, 8000 Bahía Blanca, Argentina
‡Consejo Nacional de Investigaciones Científicas y Tec
́
nicas (CONICET), Buenos Aires, Argentina
S
* Supporting Information
ABSTRACT: Radical tandem addition of dialkyltin chlorohy-
drides, R2SnHCl (R = n-Bu, neophyl, Ph), to TADDOL’s sub-
stituted diacrylates (4−7) led to the corresponding products of
cyclohydrostannation. The new optically active chlorodialkyltin-
substituted 11-membered macrodiolides were obtained in very
good yields and with much higher stereoselectivity than that
achieved with the corresponding monohydrides, R3SnH. Thus,
the cyclohydrostannation of diacrylate 4 and dimethacrylate 5 lead to just one diastereomer in the first case and to an easily
separable mixture of two diastereomers in the second. Reduction of the new organotin macrocycles with LiAlH4 afforded opti-
cally active organotin derivatives structurally related to glutaric acid. Oxidation of the new chlorodiorganotin-substituted macro-
cycles with 30% hydrogen peroxide gave the new 11-membered macrocycles 30 and 31 free of tin in an average total yield of
1
43.4% from TADDOL. Full H, 13C, and 119Sn data are also reported.
INTRODUCTION
RESULTS AND DISCUSSION
■
■
Natural products containing macrolides, i.e., macrolactones
with rings that contain eight or more members, are found in
plants, insects, and bacteria. Because of their biological and
medicinal activity, macrolides are very important target
molecules in synthetic studies. Though many of the antibiotic
macrolides have highly substituted complex structures, also
simple macrolides have properties that make them worth
studying.1 A number of synthetic strategies and methodologies
have been developed for macrolide synthesis.2 However, due to
the fact that most of these syntheses involve many steps, the
global yields are very low.3 In the area of free radical
macrocyclizations, the studies of Porter enabled defining
conditions wherein intramolecular addition of carbon radicals
to electron-deficient alkenes provides an effective tool for the
synthesis of 11−20-membered carbocycles.4a,b We have
recently reported a new approach based upon the fact that
free radical addition of triorganotin hydrides to unsaturated
diesters of TADDOL leads via a tandem cyclohydrostannation
to mixtures of 11-membered organotin-substituted macro-
diolides in high yields and with very good diastereoselectivity.5
However, we could not separate these mixtures. We considered
it possible to improve the utility of these reactions by carrying
out the cyclohydrostannations with diorganotin halohydrides,
which should lead to better stereoselectivities.6
The addition of di-n-butyltin chlorohydride (3) to the
unsaturated diesters of TADDOL, 4−7,7 was carried out
under argon at rt (Scheme 1). In first place, two methods were
Scheme 1. Hydrostannation of TADDOL Diesters 4−7 with
n-Bu2SnHCl
used: method A, where the stirred mixture of chlorohydride
and unsaturated diester in dry toluene was irradiated until total
reaction of the substrate or disappearance of the νSn−H band in
the IR spectrum; and method B, where the mixture of
In this article, we report our studies on the synthesis of 11-
membered organotin-substituted macrolactones via free radical
cyclohydrostannation of unsaturated diesters of TADDOL
with di-n-butyl- (3), dineophyl- (16), and diphenyltin chloro-
hydride (17).
Received: October 14, 2011
Published: January 3, 2012
© 2012 American Chemical Society
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Table 1. Addition of n-Bu2SnHCl to TADDOL Unsaturated Diesters 4−7
a
b
c
d
e
f
h
no.
method (time, h)
ratio subs/Sn−H
yield (%)
119Sn NMR (δ, ppm)
D (%)
100
[α]20 (c, g/mL)
D
8
A (1)
1:1.3
1:1.5
1:1.4
1:1.3
85
89
79
80
67.4
−79 (0.76)
B (48)
C (12)
A (1)
9a,b
52.5 (9a)
88.3
11.7
−87 (0.77)
i
47.5 (9b)
g
ND
g
g
9a−,b
9a
B (48)
C (12)
A (12)
1:1.5
1:1.4
1:1.3
87
75
60
52.5
100
−87° (0.77)
i
10a−d
25.2 (10a)
20.6 (10b)
43.3 (10c)
ND
i
ND
i
32.7 (10a)
32.4 (10b)
31.3 (10c)
25.3 (10d)
ND
i
10.9 (10d)
ND
g
i
10a−d
10a−d
B (72)
C (12)
1:1.5
1:1.3
65
65
ND
i
21.1 (10a)
15.0 (10b)
55.4 (10c)
10.4 (10d)
10.5 (11a)
14.9 (11b)
59.4 (11c)
ND
i
ND
i
ND
i
ND
i
11a−d
A (12)
1:1.3
62
ND
i
ND
i
36.7 (11a)
29.6 (11b)
27.5 (11c)
26.1 (11d)
ND
i
15.2 (11d)
ND
g
i
11a−d
11a−d
B (72)
C (12)
1:1.5
1:1.3
68
68
ND
i
7.0 (11a)
10.9 (11b)
71.8 (11c)
10.2 (11d)
ND
i
ND
i
ND
i
ND
a
b
Compounds 8−11 in Scheme 1. Method A: irradiation of the mixture of n-Bu2SnHCl and substrate in toluene at rt. Method B: the mixture of n-
Bu2SnHCl, AIBN, and substrate in toluene left at rt. Method C: to the mixture of n-Bu2SnHCl and substrate in toluene at −78 °C was added Et3B in
c
d
e
f
hexane. Ratio substrate (subs) (4−7)/n-Bu2SnHCl (Sn−H). After chromatographic purification. In CDCl3; in ppm with respect to Me4Sn. D =
g
h
i
% of diastereomer in the mixture (from 119Sn NMR spectra). Same proportions as using method A. In CHCl3. Not determined (mixture of
products).
chlorohydride 3, azobis(isobutyronitrile) (AIBN) as radical
initiator, and the unsaturated diester in dry toluene was stirred
until total reaction of the substrate. Under these reaction
conditions, using method A, the addition of chlorohydride 3 to
TADDOL diacrylate 4 in toluene in a ratio 3/4 = 1.3 (tin
hydride concentration = 0.073 M) leads to macrocycle 8 as the
only reaction product (Table 1). Following method B, after 48 h
and using a ratio 3/4 = 1.5 (tin hydride concentration = 0.085 M)
the reaction leads also to 8 as the only product.
di(2-methyl-3-phenyl)- (6) and di(2,3-diphenyl)acrylates (7)
with chlorohydride 3 using methods A and B showed them to
consist in each case of mixtures of only four diastereomers
(10a−d and 11a−d), even though the creation of four new
stereocenters could lead to 16 stereoisomers.
With the aim of improving the stereoselectivity, we carried
out the cyclohydrostannations at lower temperature. The
reactions between chlorohydride 3 and the unsaturated diesters
of TADDOL 4−7 at −78 °C, using triethylborane as free
radical initiator (method C), led to a dramatic increase in the
stereoselectivity. Thus, in two out of the four cases studied the
cyclohydrostannation proceeded with complete diastereoselec-
tivity (reaction with esters 4 and 5), leading to just one
diastereomer, while in the other two cases (addition to diesters
6 and 7) also a significant increase of the diastereoselectivity
was observed. The results obtained are also summarized in
Table 1.
The 119Sn NMR spectrum of the reaction crude product
showed it to consist of only one organotin adduct. Taking into
account that from the creation of one new stereogenic center at
C-7 two diastereomers should be expected, this result clearly
demonstrates that the reaction takes place with complete
diastereoselectivity. The product was purified by column
chromatography, giving 8 in 85% and 89% yield depending
on the method used (Table 1). It should be noted that the 13
C
In order to determine whether a change of diorganotin
halohydride would affect the steric course of the cyclo-
hydrostannation, we carried out similar studies on the reactions
of TADDOL’s unsaturated diesters 4−7 with dineophyl- (16)
and diphenyltin (17) chlorohydrides, according to Scheme 2.
Taking into account the previous results, we considered that
method A, i.e., irradiation of the mixture of R2SnHCl and
substrate in toluene at rt, was the more convenient due to the
shorter times of reaction.
NMR spectrum of this compound presents two CO signals,
one of them showing 3J(13C,119Sn) coupling constants (Scheme 1,
C-6).
When hydride 3 was added to TADDOL dimethacrylate 5,
the 119Sn NMR spectrum of the crude product obtained using
methods A and B showed that instead of the expected mixtures
of four diastereomerscreation of two new stereogenic
centersthe mixtures contained only two diastereomers in
different proportions (Table 1, compounds 9a,b), thus
confirming that free radical addition of n-Bu2SnHCl (3) is
more stereoselective than that of tri-n-butyltin hydride.5
On the other hand, the 119Sn NMR spectra of the crude
products resulting from the cyclohydrostannation of TADDOL
We found that the 119Sn NMR spectra of the crude products
resulting from the addition of dineophyltin chlorohydride (16)
and diphenyltin chlorohydride (17) to TADDOL diacrylate 4
indicated again the formation of just one of the two possible
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Even though the chlorodiorganotin macrocycles 8, 9a, 18,
19a, and 21a were obtained as crystalline solids, unfortunately
the crystals proved to be unsuitable for X-ray structure analysis.
However, using a crystal of the chlorodiphenyltin derivative 20
it was possible to carry out an X-ray analysis, which showed that
the structure might be the one depicted in Figure 2 (see X-ray
data in Supporting Information).
Scheme 2. Hydrostannation of TADDOL Diesters 4 and 5
with Chlorohydrides 16 and 17
Figure 2 shows the intramolecular coordination between the
CO and the Sn atom, and also that the configuration of the
asymmetric carbon α (C-7) is R.
1H and 13C NMR data of compound 20 (Tables 3 and 4)
also support the structure shown in Figure 2. The use of the
Karplus-type relationship existing between the dihedral angle
and the value of 3J(13C,119Sn) and 3J(1H,119Sn) coupling
constants enabled us to confirm the structure of 20. Thus,
the 3J(Sn,CO) coupling constant of 20 with a value of 14.1 Hz
is in agreement with the existence of a dihedral angle close
to 60° between the CO group and the organotin moiety.9b
diastereomeric organotin macrolides in both cases (compounds
18 and 20, respectively, Table 2).
3
Similarly, the J(Sn,C-8) coupling constant for 20 is 20.1 Hz
(Table 3), indicating a dihedral angle of about 60°. On the
1
other hand, the H NMR spectra of compound 20 show that
Table 2. Addition of Chlorohydrides 16 and 17 to
TADDOL’s Unsaturated Diesters 4 and 5 under Method A
Conditions (irradiation at rt)
3
the J(Sn−C−C−H) coupling constant between the proton
attached to C-7 and the organotin substituent has a value of
101.7 Hz (Table 4), which is consistent with a dihedral angle
close to 160°. Taking into account the previous discussion, it is
possible to conclude that the structure of compound 8 could be
represented as in Figure 3 (structure A).
119Sn
R (in
D
NMR (δ, yield
[α]20 (c,
D
b
c
d
e
f
no.
R2SnHCl) substrate (%)
ppm)
(%)
g/mL)
a
18
neophyl
neophyl
4
5
100
61
67
69
−92 (0.75)
−97 (0.71)
In the case of compound 19a the analysis of the 3J(13C,119Sn)
coupling constants also helps to establish the absolute
configuration of C-7. Thus, the 3J(Sn,CO) coupling constant
of 19a is 45.5 Hz, suggesting a dihedral angle of 20°, indicating
that the Sn moiety and the CO group are closer than in the
other cases. The 3J(Sn,C-8) and 3J(Sn,C-14) are 20.9 and 15.9 Hz,
respectively, values consistent with angles close to 120° in both
cases, suggesting that the conformation is almost eclipsed. These
dihedral angles suggest that the structure of compound 19a
could be close to structure B of Figure 3.
a
19a
19b
20
92
8
72
g
53
b
Ph
4
5
100
60
40
−65
−72
−61
73
−72 (0.75)
−78 (0.73)
b
21a
21b
Ph
71
g
a
b
c
Irradiation time: 14 h. Irradiation time: 1 h. D = % of diastereomer
d
in the mixture (from 119Sn NMR spectra). In CDCl3; in ppm with
e
f
respect to Me4Sn. After chromatographic purification. In CHCl3.
Could not be obtained pure.
g
In Table 5 are summarized the dihedral angles associated
We also determined that the addition of chlorohydride 16 to
TADDOL dimethacrylate 5 led to a mixture of two
diastereomers, compounds 19a (92%) and 19b (8%), and
that the cyclohydrostannation of 5 with hydride 17 led to a
mixture of macrocycles 21a (60%) and 21b (40%).
3
3
with the J(119Sn,13C) and J(119Sn,1H) coupling constants of
compounds 8, 9a, 18, 19a, 20, and 21a.9b
Using the values included in Table 5, it could be deduced
that whereas the structures of the macrocycles derived from
TADDOL diacrylate (8, 18, and 20) are close to structure A,
the macrocycles derived from TADDOL dimethacrylate (9a,
19a, and 21a) are closer to structure B of Figure 3.
We found that chlorohydrides 16 and 17 did not react with
unsaturated diesters 6 and 7 under the conditions of methods
A−C. Also, neither dineophyltin chlorohydride (16) nor
diphenyltin chlorohydride (17) reacted with substrates 4 and
5 after 48 h under method B and C conditions. The results
obtained are collected in Table 2.
The previous discussion suggests that, in agreement with the
X-ray analysis, the configuration of C-7 in compounds 8, 9a, 18,
19a, and 21a should be R, as depicted in structures A and B
(Figure 3). It should be noted that in the case of compound 9a,
the HSQC experiment (included in the Supporting Informa-
tion) shows that the methyl group corresponding to C-14 has a
chemical shift of 29.30 ppm, but we were not able to detect the
1H and 13C NMR characteristics are summarized in Tables 3
and 4. The 13C NMR chemical shifts (Table 1) were assigned
through the analysis of the multiplicity of the signals by means
of DEPT experiments, in some cases using HSQC experiments,
3
corresponding J(Sn,C-14) coupling constant. However, taking
n
and taking into account the magnitude of J(1H,119Sn) and
into account that the 3J(Sn,C-6) and 3J(Sn,C-8) coupling
constants of compound 9a (11.4 and 60.0 Hz) indicate dihedral
angles of around 60° and 180°, respectively, it could be
considered that in this compound the configuration of C-7 is
also R (structure B, Figure 3).Unfortunately, as stated before,
we could not obtain the X-ray structure of any of these
macrocycles, and therefore we are unable to give the absolute
configuration of C-9 in compounds 9a, 19a, and 21a.
nJ(13C,119Sn) coupling constants.
In macrocycles 8−11 and 18−21 the carbonyl of one of the
ester groups is intramolecularly coordinated with the tin atom
that has been made more electropositive because of the tin−
chloro bond, as shown in Figure 1.8 The existence of
intramolecular coordination is demonstrated by the fact that
the carbonyl stretching frequency of the IR spectra of
compounds 8 and 9a is the same when it was measured both
in the solid state (KBr) and in acetonitrile solution (10%).
We have previously proposed for these reactions a tandem
mechanism similar to the one shown in Scheme 3.5 In the case
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Article
a
Table 3. 13C NMR Spectra of Compounds 8, 9a, 18, 19a, 20, and 21a
b
c
d
e
f
g
8
9a
18
19a
110.15
20
21a
110.23
C-2
110.45
110.55
110.13
110.50
C-2a
27.03 and 27.10
76.04 and 76.95
87.29 and 89.66
180.37 (12.2)
44.06 (25.1)
30.09 (39.2)
33.70
26.90 and 27.34
75.92 and 76.81
86.95 and 90.17
180.96 (11.4)
46.52 (22.6)
46.58 (60.0)
36.12
27.30 and 27.33
76.81 and 76.94
87.38 and 87.42
175.31 (43.2)
43.07 (13.7)
29.92 (26.0)
34.76
27.29 and 27.33
76.81 and 76.94
87.39 and 87.43
174.61 (45.5)
42.91 (14.0)
29.77 (20.9)
34.61
26.87 and 26.90
76.78 and 76.80
87.32 and 90.00
179.17 (14.1)
43.08 (28.0)
31.80 (20.1)
27.29
27.46 and 27.72
75.88 and 77.11
87.00 and 90.16
181.02 (17.2)
46.56 (29.2)
46.11 (76.8)
35.70
C-3a and C-12a
C-4 and C-12
C-6 [3J(Sn,C)]
C-7 [2J(Sn,C]
C-8 [3J(Sn,C)]
C-9
C-10
170.49
175.26
170.92
170.77
171.16
175.17
C-13 [1J(Sn,C)]
C-14 [3J(Sn,C)]
C-15
21.10 (439.1)
26.65 (423.3)
29.13 (ND)
18.79
15.70 (291.1)
15.55 (291.3)
18.42 (15.9)
27.08
29.73 (440.0)
26.93 (ND)
29.30 (13.6)
19.07
a
In CDCl3; chemical shifts, δ, in ppm with respect to TMS; nJ(Sn,C) coupling constants, in Hz (in brackets); ND = not determined. Other signals:
b
13.78; 14.03; 16.92; 19.77; 26.51 (417.9); 27.81 (28.9); 28.22 (29.4); 126.75; 126.81; 127.25; 127.51; 127.62; 127.67; 127.81; 127.85; 128.17;
c
128.72; 129.82; 129.91; 139.66; 140.41; 143.62; 144.71. 13.61; 13.92; 18.01 (423.0); 18.89 (439.4); 27.72 (29.2); 28.13 (28.5); 29.61; 126.72,
127.12; 127.26; 127.51, 127.65; 127.81; 128.13; 129.60; 129.94; 139.81; 140.41; 142.73; 144.51. 31.13 (316.0); 33.34 (34.7); 33.64 (36.3); 125.52;
125.66; 126.83; 127.27; 127.31; 127.55; 127.61; 127.64; 128.25; 128.61; 128.63; 130.36; 140.65; 140.90; 144.86; 144.94; 151.39 (18.5). 30.97
d
e
(316.0); 33.18 (34.9); 33.47 (36.4); 38.13 (18.3); 125.53; 125.67; 126.83; 127.11; 127.16; 127.39; 127.45; 127.49; 128.09; 128.45; 128.48; 130.23;
f
140.49; 140.73 (27.0); 144.70; 144.78; 151.23 (18.6). 125.66; 131.86; 133.00; 133.42; 135.63; 136.10; 136.68; 139.30; 139.75; 144.44; 144.48.
g
126.86; 127.10; 127.25; 127.45; 127.72; 127.93; 128.35; 128.68; 129.03; 129.48; 135.43 (49.7); 136.68 (47.2); 139.83; 139.95; 140.84; 141.56;
143.02; 144.98.
a
1
Table 4. H NMR Spectra of Compounds 8, 9a, 18, 19a, 20, and 21a
a
b
no.
chemical shifts (δ, in ppm) [C-No.]
8
0.12−0.40 (m, 2H) [C-α, n-Bu]; 0.59 (s, 3H) and 0.67 (s, 3H)[C-2a]; 0.79 (t, 3H) and 0.92 (t, 3H) [C-δ, n-Bu]; 1.00−1.90 (m, 12H)
3 3
[C-α′, β, δ, and C-13]; 1.92−2.61 (m, 4H) [C-8 and 9]; 2.95 (m, JH,Sn 94.8 Hz, 1H) [C-7]; 5.44 (d, JH,H 7.5 Hz, 1H) [C-3a or C-12a];
3
5.51 (d, JH,H 7.5, 1H) [C-3a or C-12a]; 7.18−7.35 (m, 20H) [phenyl groups]
9a
18
run "i:/template/macmillan/npgeqn.3m0.03−0.16 (m, 1H) and 0.21−0.35 (m, 1H) [C-α, n-Bu]; 0.46 (s, 3H) and 0.70 (s, 3H) [C-2a];
0.75−0.97 (m, 10H) [C-δ, n-Bu, C-13, C-15]; 1.08 (s, 3H) [C-14]; 1.10−2.00 (m, 12H) [C-β and γ, n-Bu, C-8, C-13];
3
3
2.35−2.75 (m, 2H) [C-8 and C-9]); 5.48 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]; 5.56 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]
0.61 (s, 3H) [C-2a]; 0.63 (s, 3H) [C-2a]; 0.81 (s, 4H) [neophyl]; 1.37 (s, 12H) [neophyl]; 1.58 (d, 2H) [C-13]; 1.60−2.10 (m, 4H);
3
3
3
2.57−2.60 (m, JH,Sn 102.4 Hz, 1H) [C-7]; 5.53 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]; 5.56 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a];
7.09−7.27 (m, 30H) [phenyl groups]
2
19a
20
0.59 (s, 2H) [C-13]; 0.91 (s, JSn,H 48.5 Hz, 4H) [neophyl]; 1.05 (d, 2H) [C-8]; 1.21 (s, 3H) [C-14]; 1.29 (s, 6H) [C-2a]; 1.34 (d, 3H) [C-15];
1.37 (s, 12H) [neophyl]; 2.69 (m, 1H) [C-9]; 5.21 (d, JH,H 7.3 Hz, 1H) [C-3a or C-12a]; 5.35 (d, JH,H 7.3 Hz, 1H) [C-3a or C-12a]
3
3
3
0.50 (d, 2H) [C-13)]; 1.22 (s, 6H) [C-2a]; 1.92 (t, 2H) [C-9]; 2.32 (m, JH,Sn 101.7 Hz, 1H) [C-7]; 2.81−3.05 (m, 2H)
3
3
[C-8]; 5.25 (d, JH,H 7.1 Hz, 1H) [C-3a or C-12a]; 5.42 (d, JH,H 7.1 Hz, 1H) [C-3a or C-12a]; 7.05−7.91 (m, 30H)
21a
0.55 (s, 2H) [C-13]; 0.91 (s, 3H) [C-14]; 1.05 (d, 3H) [C-15]; 1.29 (s, 3H) [C-2a]; 1.31 (s, 3H) [C-2a]; 2.61 (m, 2H) [C-8];
3
3
2.92−3.03 (m, 1H) [C-9]; 5.42 (d, JH,H 7.2 Hz, 1H) [C-3a or C-12a]; 5.61 (d, JH,H 7.2 Hz, 1H) [C-3a or C-12a]; 6.95−7.92 (m, 30H)
a
b
In CDCl3; multiplicity and J values in Hz (in parentheses). Carbon to which the protons are attached.
of diesters 4−7 the two factors that dominate the rate of
addition to the olefins, i.e., electronic and steric, are both
favorable: the alkene substituent (ester group) is electron
withdrawing and the β-carbon of the unsaturated diesters is
either unsubstituted (4 and 5) or monosubstituted (6 and 7),
and therefore there is no steric hindrance or, at least, it is lower
than in the disubstituted α-carbon. Taking into account the
configuration of compound 19 shown in Figure 2, the possible
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Similarly, the fact that the addition of hydride 3 to diester 5
led to a mixture of two diastereomers (9a,b)using methods A
and Bas well as that the addition to ester 5 of hydrides 16
and 17 using method A also led to mixtures of only two
diastereomers (19a,b, and 21a,b), could as well be associated
with the existence of intramolecular coordination between the
CO of the ester group and the Sn atom.
Figure 1. Intramolecular coordination between the tin atom and the
carbonyl group.
Here again, intramolecular coordination would favor the
formation of an intermediate alkyl radical with a preferred
conformation, which will add to the second olefinic group to
give the product of endo cyclization, i.e., a cyclic alkyl radical
similar to II (Scheme 3). Then, chlorohydrides R2SnHCl (R =
n-Bu, neophyl, and Ph) will effect transfer of a hydrogen
atom to a preferred conformation of the cyclic radical as
shown by the fact that one of the diastereomers is formed in
much higher proportion (9a, 19a, and 21a) than the other (9b,
19b, and 21b).
On the other hand, radical addition of n-Bu2SnHCl (3) to
diester 5 initiated by Et3B at −78 °C (method C) leads to the
formation of diastereomer 9a as the only reaction product. This
result could be due to the fact that at −78 °C (method C) the
rate of hydrogen transfer is slower than at rt, and therefore, the
attack should become much more selective. The formation at rt
of the second diastereomer (9b) could be attributed to the
increase in the rate of hydrogen transfer from the tin
chlorohydride to the cyclic radical, which enables the hydrogen
attack to both faces of the cyclic type II radical (Scheme 3).
The formation of mixtures of only four macrocyclic
diastereomers when chlorohydride 3 was added to TADDOL
di(2-methyl-3-phenyl)- (6) and di(2,3-diphenyl)acrylates (7)
under methods A (12 h), B (72 h), and C (12 h) could also be
ascribed to the existence of intramolecular coordination. Thus,
taking into account the previous discussion on the hydro-
stannation of esters 4 and 5 with n-Bu2SnHCl, it should be
possible that also in this case intramolecular coordination could
lead to cyclic alkyl radicals stabilized in preferred conformations
that would attack stereoselectively (endo) the C-β of the second
olefinic system. Then, the resulting radicals on C-9 could again
accept the hydrogen transfer from n-Bu2SnHCl to any of its
two faces. It should be added that the hydrostannations of
unsaturated diesters 6 and 7 with chlorohydrides 16 and 17 do
not take place due probably to steric factors.
In order to determine some chemical properties of the new
organotin-substituted macrodiolides, we carried out a series of
studies. In the first place, taking into account that in β-
halodialkylstannyl esters intramolecular coordination prevents
the addition of a Grignard reagent to the CO of the ester
group, which instead alkylates the tin atom,8c we investigated
the reactions between some of the new organotin-substituted
macrodiolides and RMgX (R = n-Bu, neophyl, Ph; X = Cl, Br)
using ratios Grignard reagent/macrodiolides = 1.1 as shown in
Scheme 4 (eq 1).
Figure 2. X-ray structure of chlorodiphenyltin-substituted macrocycle 20.
Figure 3. Configuration of C-7 resulting from the dihedral angles
obtained in the analysis of the 3J(119Sn,13C) and 3J(119Sn,1H) coupling
constants of compounds 8, 9a, 18, 19a, 20, and 21a.
mechanism and stereochemistry of the cyclohydrostannation of
TADDOL diacrylate 4 could be the one depicted in Scheme 3.
The same should apply for the cyclohydrostannations of
diesters 4 and 5 with diorganotin chlorohydrides 16 and 17.
The very high stereoselectivity observed in these reactions
could be explained as follows. The addition of chlorohydrides 3,
16, and 17 to TADDOL diacrylate 4 generates a new
stereogenic center (C-7), and this should lead to the formation
of two diastereomeric macrocycles. The formation of only one
macrocycle in each case, compounds 8, 18, and 20, respectively,
using methods A, B, and C could reasonably be attributed to
the existence of intramolecular coordination. The latter would
favor the formation of an alkyl radical (I, Scheme 3) with a
preferred conformation that will add to the other unsaturated
group, leading to the cyclic radical II.4a Then, the
chlorohydrides R2SnHCl (R = n-Bu, neophyl, and Ph) would
effect hydrogen transfer to II, leading to the corresponding
organotin-substituted macrocyclic lactones III. This is con-
firmed by the fact that in the case of the addition of R3SnH
(R = n-Bu, neophyl, and Ph) to diester 4, where the inter-
mediate radical is not stabilized by intramolecular coordination,
two diastereomeric macrocycles are obtained.5
These reactions lead in good yields to the new triorganotin-
substituted macrodiolides 22−24 and to the known 25 and 26
reported earlier (ref 5), thus demonstrating the existence of
intramolecular coordination in the starting substrates. Two
points should be noted: in the first place the 119Sn NMR
spectra clearly demonstrate that compounds 22−26 are the
diastereomers present in higher proportion in the inseparable
mixtures of triorganotin-substituted macrocycles obtained
previously in the additions of triorganotin monohydrides
(R3SnH, R = n-Bu, neophyl, Ph) to the unsaturated TADDOL
diesters 4 and 5.5 Second, whereas in the case of the addition of
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a
3
3
Table 5. Dihedral Angles and J(119Sn,13C) and J(119Sn,1H) Coupling Constants of Compounds 8, 9a, 18, 19a, 20, and 21a
b
macrocycle
δ (ppm) [3J(Sn,R1), Hz]
δ (ppm) [3J(Sn,C-6), Hz)]
δ (ppm) [3J(Sn,C-8), Hz]
8
2.95 (94.8)
0/150°
29.13 (ND)
180.37 (12.2)
65/105°
180.96 (11.4)
65/105°
175.31.12 (43.2)
20/140°
174.61 (45.5)
20/140°
30.09 (39.2)
35/130°
46.58 (60.0)
180°
29.92 (26.0)
45/130°
29.77 (20.9)
60/120°
DA
9a
DA
18
2.59 (102.4)
160°
18.42 (15.9)
60/120°
2.32 (101.7)
160°
29.30 (13.6)
DA
19a
DA
20
179.17 (14.1)
60/110°
181.02 (17.2)
31.80 (20.1)
60/120°
46.11(76.8)
DA
21a
DA
60/120°
60/120°
180°
a
b
From Tables 3 and 4; DA = dihedral angles from ref 9b. R1 can be either H (8, 18, 20) or methyl group (9a, 19a, 21a), i.e., C-14.
Scheme 3. Mechanism of the Cyclohydrostannation of Diester 4 with Chlorohydrides 3, 16, and 17
Grignard reagents to β-chlorodialkylstannyl open-chain esters
care should be taken in using the ratio ester/Grignard = 1:1.1 in
order to avoid the formation of products of nucleophilic
addition to the ester group,8d in the case of the alkylation of
esters 8, 9a, 18, 20, and 21a we found that even when using 5-
fold excesses of Grignard reagents, the addition leads in all
cases only to the products of tin atom alkylation. These results
could be connected with the high steric hindrance generated by
the phenyl groups attached to carbons C-4 and C-12 of the
macrocycles.
The reduction of compounds 23, 25, and 26 with LiAlH4
according to eq 2 (Scheme 4) led to the organostannylated
diols 27−29, structurally related to glutaric acid. These
reactions also enabled confirming the structure of compound
28 previously reported.5 The mixtures of optically active diols
and TADDOL thus obtained were separated by column
chromatography (silica gel 60), leading to the optically active
stannylated diols 27, 28, and 29 in 56%, 75%, and 73% yield,
respectively.
We were also able to obtain organotin-free macrodiolides
with 11-membered rings via oxidation at room temperature of
macrocycles 8, 9a, 18, and 19a, with 30% hydrogen peroxide
and KHCO3 according to eq 3, Scheme 4.10 The new optically
active macrodiolides 30 and 31 were obtained pure by column
chromatography (silica gel 60) in 66−75% yield, as shown in
Scheme 4.
In conclusion, in the case of TADDOL’s unsaturated diesters
the use of diorganotin chlorohydrides leads to much more
stereoselective cyclohydrostannations than those carried out
using triorganotin hydrides. As a result of this, a new and
stereoselective two-step synthesis of organotin-substituted 11-
membered macrodiolides starting from the commercially avail-
able TADDOL has been developed. The organotin macrocycles
were obtained with an average total yield of 63% (from TADDOL).
Another important point is that this synthetic route could also be
applied to the synthesis of organotin-free 11-membered macro-
diolides in three steps (from TADDOL) in an average total
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Scheme 4. Some Reactions of Chlorodiorganotin-Substituted Macrodiolides
the 119Sn NMR spectrum of the crude product showed that the only
product of reaction was macrocycle 8. The crude product thus obtained
was directly purified by column chromatography using silica gel 60. The
cyclic adduct 8 (0.62 g, 0.74 mmol, 85%) was eluted with hexane/
yield of 43.4%, i.e., a shorter route with much higher total yield
than most macrolide syntheses.2
diethyl ether (80:20) as a yellow solid, mp 132−134 °C. [α]20 = −79
EXPERIMENTAL SECTION
■
D
(c 0.76, CHCl3). IR (KBr): 3055; 3021; 2945; 2850; 1717; 1672; 1602;
1485; 1450; 1243; 1155; 848; 747; 690 cm−1. HRMS (ESI): calcd for
C45H53ClO6Sn 844.2553, found 844.2548 Anal. Calcd for
C45H53ClO6Sn: C, 64.03; H, 6.33. Found: C, 64.08; H, 6.29.
NMR spectra were recorded on a Bruker ARX 300 instrument, using
CDCl3 as solvent; chemical shifts (δ) are reported in ppm with respect
1
to TMS, H NMR, and 13C NMR, and with respect to Me4Sn in the
case of 119Sn NMR spectra. IR spectra were recorded on a FT-IR
Nicolet Nexus 470/670/870 spectrophotometer. Mass spectra were
obtained using a Finnigan MAT Incos 50 Galaxy System (DIP-MS).
High-resolution mass spectra (HRMS) were recorded on a Finnigan
Mat. 900 (HR-EI-MS). Irradiations were conducted in a reactor
equipped with four 250 W lamps with peak emission at 350 nm, water-
cooled. Specific rotations were measured with a Polar L-μP, IBZ
Messtechnik instrument. Elemental analyses (C, H) were performed in
a Carlo Erba instrument. The melting points were determined with a
Kofler hot stage apparatus and are uncorrected. All the solvents and
reagents used were analytical reagent grade. Dineophyltin dichloride
was prepared by disproportion reaction from neophylmagnesium
chloride and tin tetrachloride.8e Di-n-butyl- (3), dineophyl- (16), and
diphenyltin chlorohydride (17) were prepared by reduction of the
corresponding dichloride with lithium aluminum hydride,11 and the
starting TADDOL unsaturated diesters were prepared as described
previously.7
Using the same method, the reaction of 5 (0.50 g, 0.83 mmol) with
n-Bu2SnCl2 (0.18 g, 0.58 mmol) and n-Bu2SnH2 (0.14 g, 0.58 mmol)
was studied in dry toluene (10 mL) as solvent. The crude product was
purified by column chromatography using silica gel 60. The cyclic
adduct 9a (0.58 g, 0.66 mmol, 80%) was eluted with hexane/diethyl
ether (95:5) as a white solid, mp 121−123 °C. [α]20 = −87 (c 0.77,
D
CHCl3). IR (KBr): 3060; 3024; 2955; 2923; 1719; 1676; 1605; 1492;
1448; 1239; 1160; 850; 757; 696 cm−1. HRMS (ESI): calcd for
C47H57ClO6Sn 872.2866, found 872.2872 Anal. Calcd for
C47H57ClO6Sn: C, 64.80; H, 6.48. Found: C, 64.89; H, 6.52.
Diastereoisomer 9b could not be separated pure.
Under the same conditions, the reaction of 6 (0.66 g, 0.87 mmol)
with n-Bu2SnCl2 (0.19 g, 0.62 mmol) and n-Bu2SnH2 (0.14 g, 0.62 mmol)
in dry toluene (4 mL) as solvent took 12 h. The crude product
was purified by column chromatography using silica gel 60. The mix-
ture of cyclic adducts (10a−d) (0.53 g, 0.52 mmol, 60%) was eluted
with hexane/diethyl ether (95:5) as a yellow solid. 1H NMR (CDCl3):
δ 0.61 (t, 4H); 0.82 (t, 6H); 1.23 (d, 3H); 1.33 (s, 6H); 1.30 (s, 3H);
1.34−1.61 (m, 8H); 2.52 (m, 1H); 2.81 (m, 1H); 3.62 (d, 1H); 5.25
(d, 3JH,H 7.3 Hz, 1H); 5.31 (d, 3JH,H 7.3 Hz, 1H); 7.05−7.51 (m, 30H).
13C NMR (CDCl3): δ 13.91; 14.13; 17.62 (167.5); 18.24 (226.8);
19.91; 21.25; 21.33; 27.12; 27.31; 29.65 (22.6); 29.82 (24.9); 52.21
(18.2); 52.31 (27.3); 79.23; 79.65; 80.40; 80.71; 89.92; 90.05; 91.22;
91.45; 109.62; 109.71; 127.96; 128.04; 128.13; 128.21; 128.42; 128.82;
128.91; 129.32; 129.85; 130.51; 130.92; 135.43; 135.51; 138.81;
138.81; 138.92; 139.53; 139.61; 142.76; 142.91; 143.33; 143.42;
143.45; 143.51; 169.15; 171.22; 180.59 (7.5); 181.53 (12.9). IR
(KBr): 3050; 3031; 2949; 2852; 1720; 1675; 1600 1490; 1451; 1245;
1150; 847; 750; 695 cm−1.
All hydrostannations were carried out under an argon atmosphere.
Reactions were monitored by thin-layer chromatography on silica gel
plates (60F-254) visualized under UV light and/or using 5%
phosphomolybdic acid in ethanol.
Method A: Cyclohydrostannations Initiated by Irradiation at
rt. (a) Synthesis of Chlorodi-n-butyltin-Substituted Macrocycles 8, 9a,b,
10a−d, and 11a−d. (−)-(3aR,7R,12aS)-7-((Dibutylchlorostannyl)-
methyl)-2,2-dimethyl-4,4,12,12-tetraphenyltetrahydro-3aH-[1,3]-
dioxolo[4,5-c][1,6]dioxacycloundecine-6,10(4H,7H)-dione (8). Di-n-
butyltin dichloride (2) (0.18 g, 0.60 mmol) was dissolved in dry
toluene (5 mL), and di-n-butyltin dihydride (1) (0.12 g, 0.60 mmol)
was added. The mixture was stirred for about 30 min, with monitoring
of the reaction by IR spectroscopy. A toluene (10 mL) solution of
diester 4 (0.50 g, 0.87 mmol) was added to the mixture. The reaction
mixture was irradiated for 1 h, with monitoring by TLC and IR spectros-
copy. The solvent was then distilled off under reduced pressure, and
Under the same conditions the reaction of 7 (0.20 g, 0.23 mmol)
with n-Bu2SnCl2 (0.046 g, 0.15 mmol) and n-Bu2SnH2 (0.035 g,
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0.15 mmol) in dry toluene (4 mL) also took 12 h. The crude product
obtained was purified by column chromatography using silica gel 60.
The mixture of cyclic adducts (11a−d) (0.16 g, 0.14 mmol, 62%) was
pressure, and the product was purified by column chromatography on
silica gel.
Using method B, the reactions with n-Bu2SnHCl led to macrocycles
8 (48 h, 89% yield), 9a,b (48 h, 87%), 10a−d (72 h, 65%), and 11a−d
(72 h, 68%), in the same proportions as using method A.
Hydrostannation at −78 °C Initiated by Et3B (Method C).
Dialkyltin dihydride (0.12 mL, 0.60 mmol) was added to a solution of
dialkyltin dichloride (0.18 g, 0.60 mmol) in dry toluene (5 mL) at 0
°C. After being stirred for 20 min, the mixture was cooled to −78 °C.
A solution of diester (0.9 mmol) in toluene (4 mL) was added to the
mixture. After 5 min, Et3B (1.0 M in hexane, 0.10 mL, 0.10 mmol) was
added. The mixture was stirred at −78 °C for 6 h and then 6 h at rt,
with monitoring by TLC and IR spectroscopy. The solvent was
distilled off under reduced pressure, and the crude product was
purified by column chromatography on silica gel.
1
eluted with hexane/diethyl ether (94:6) as a yellow solid. H NMR
(CDCl3): δ 0.90 (t, 4H); 0.96 (t, 6H); 1.31 (s, 6H); 1.35−1.45 (m,
8H); 3.61 (d, 1H); 3.82 (d, 1H); 4.12 (m, 1H); 5.21 (d, 3JH,H 7.4 Hz,
3
1H); 5.3 (d, JH,H 7.4 Hz, 1H); 6.97 −7.38 (m, 40H). 13C NMR
(CDCl3): δ 13.92; 14.02; 16.21 (205.2); 16.61 (201.3); 18.22; 18.71;
19.53; 19.71; 26.22; 26.70; 47.64 (26.5); 47.74 (27.3); 64.10 (27.1);
65.94 (18.6); 78.81; 79.42; 79.66; 80.12; 88.20; 88.31; 90.61; 90.71;
109.70; 109.79; 123.62; 126.12; 126.31; 126.44; 126.51; 126.57,
126.67; 126.91; 127.13; 127.32; 127.41; 127.71; 128.02; 128.71;
128.89; 139.49; 140.84; 142.49; 142.55; 142.73; 142.91; 143.15;
143.56; 143.77; 172.20; 173.91; 178.82 (14.1); 179.42 (4.2). IR
(KBr): 3048; 3027; 2950; 2850; 1718; 1670; 1601 1495; 1450; 1250;
1151; 848; 749; 690 cm−1.
Using method C, the reactions with n-Bu2SnHCl led to macrocycles
8 (12 h, 79% yield), 9a (12 h, 75%), 10a−d (72 h, 65%), and 11a−d
(72 h, 68%).
(b) Synthesis of Chlorodineophyl-Substituted Macrocycles 18
and 19a,b. Following the same procedure the reaction of diester 4
(0.55 g, 0.96 mmol) with dineophyltin dichloride (0.30 g, 0.65 mmol)
and dineophyltin dihydride (0.25 g, 0.65 mmol) in dry toluene
(18 mL) needed 14 h of irradiation. The crude product thus obtained
was directly purified by column chromatography using silica gel 60.
Cyclic adduct 18 (0.66 g, 0.66 mmol, 69%) was eluted with hexane/
diethyl ether (85:15) as a white solid, mp 151−153 °C. [α]20D = −92
(c 0.75, CHCl3). IR (KBr): 3053; 3019; 2943; 2912; 1720; 1675;
1601; 1490; 1454; 1227; 1157; 855; 755; 691 cm−1. HRMS (ESI):
calcd for C57H61ClO6Sn 996.3179, found 996.3165 Anal. Calcd for
C57H61ClO6Sn: C, 68.72; H, 6.17. Found: C, 68.67; H, 6.11.
Alkylation of Organotin Macrodiolides 8, 9a, 18, 20, and
21a. (−)-(3aR,7R,12aS)-7-((Tributylstannyl)methyl)-2,2,7,9-tetra-
methyl-4,4,12,12-tetraphenyltetrahydro-3aH-[1,3]dioxolo[4,5-c]-
[1,6]dioxacycloundecine-6,10(4H,7H)-dione (23). The reaction was
carried out under an argon atmosphere; n-butylmagnesium chloride
(1.8 M in diethyl ether, 2.40 mL, 4.37 mmol) was added with stirring
to a solution of 9a (0.38 g, 0.44 mmol) in dry diethyl ether (6 mL).
The reaction mixture was heated under reflux for 2 h. After cooling,
water was added (1 mL), and the solution was acidified with diluted
hydrochloric acid (10%). The organic layer was separated and then
dried on MgSO4. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography using
silica gel 60. The cyclic adduct 23 (0.29 g, 0.34 mmol, 78%) was eluted
with hexane/diethyl ether (99:1) as a white solid, mp 101−103 °C.
Under the same experimental conditions, the reaction of 5 (0.55 g,
0.91 mmol) with Neoph2SnCl2 (0.30 g, 65 mmol) and Neoph2SnH2
(0.25 g, 0.65 mmol) in dry toluene (8 mL) as solvent took place in 14 h.
The crude product was purified by column chromatography using
silica gel 60. The cyclic adduct 19a (0.67 g, 0.65 mmol, 72%) was
eluted with hexane/diethyl ether (90:10) as a white solid, mp 170−
[α]20 = −116 (c 0.70, CHCl3). IR (KBr): 3035; 3010; 2945; 2858;
D
1740; 1602; 1485; 1450; 1235; 1152; 860; 745; 692 cm−1. HRMS
(ESI): calcd for C51H65O6Sn 893.3803, found 893.3808. Anal. Calcd
for C51H65O6Sn: C, 68.61; H, 7.34. Found: C 68.66; H 7.29.
173 °C. [α]20 = −97 (c 0.71, CHCl3). IR (KBr): 3043; 3021; 2940;
D
2915; 1722; 1673; 1600; 1489; 1456; 1225; 1160; 857; 750; 695 cm−1.
HRMS (ESI): calcd for C59H65ClO6Sn 1024.3492, found 1024.3483
Anal. Calcd for C59H65ClO6Sn: C, 69.18; H, 6.40. Found: C, 69.25; H,
6.50.
Using the same procedure for the reaction of 8 (0.25 g, 0.29 mmol)
with n-butylmagnesium chloride (1.75 M in diethyl ether, 0.17 mL,
0.29 mmol), the crude product obtained was purified by column
chromatography using silica gel 60. The cyclic adduct 22 (0.21 g,
0.24 mmol, 83%) was eluted with hexane/diethyl ether (97:3) as a white
(c) Synthesis of Chlorodiphenyl-Substituted Macrocycles 20 and
21a,b. Following the same protocol, the reaction of 4 (1 g, 1.74 mmol)
with Ph2SnCl2 (0.42 g, 1.21 mmol) and Ph2SnH2 (0.33 g, 1.21 mmol)
occurred in dry toluene (10 mL) as solvent; the irradiation time was 1 h.
The crude product obtained was purified by column chromatography
using silica gel 60. The cyclic adduct 20 (1.12 g, 1.27 mmol, 73%) was
eluted with hexane/diethyl ether (93:7) as a white solid, mp 107−109 °C.
solid, mp 112−115 °C. [α]20 = −78 (c 0.70, CHCl3). IR (KBr):
D
3030; 3011; 2950; 2910; 2862; 1745; 1605; 1490; 1451; 1242; 1150;
850; 749; 690 cm−1. HRMS (ESI): calcd for C49H62O6Sn 866.3568,
found 866.3575. Anal. Calcd for C49H62O6Sn: C, 67.98; H, 7.22. Found:
C, 67.91; H, 7.28.
[α]20 = −72 (c 0.75, CHCl3). IR (KBr): 3053; 3025; 2950; 2913;
Following the same protocol for the reaction between 18 (0.30 g,
0.30 mmol) and neophylmagnesium chloride (1.80 M in diethyl ether,
0.16 mL, 0.30 mmol), the crude product obtained was purified by
column chromatography using silica gel 60. The cyclic adduct 24 (0.25 g,
0.23 mmol, 79%) was eluted with hexane/diethyl ether (98:2) as a
white solid, mp 107−109 °C. [α]20D = −88 (c 0.75, CHCl3). IR (KBr):
3031; 3015; 2950; 2912; 2860; 1743; 1600; 1495; 1455; 1240; 1151;
853; 749; 691 cm−1. HRMS (ESI): calcd for C67H74O6Sn 1094.4507,
found 1094.4515 Anal. Calcd for C67H74O6Sn: C, 73.56; H, 6.82.
Found: C, 73.61; H, 6.87.
In the case of the reactions using phenylmagnesium halides the
procedure was slightly different. Thus, phenylmagnesium bromide
(1.6 M in THF, 1.4 mL, 2.2 mmol) was added with stirring to a solu-
tion of 21a (0.34 g, 0.37 mmol) in THF (0.8 m L). The reaction mixture
was heated under reflux for 24 h. After cooling NH4Cl (4 mL) was
added to quench the reaction. The aqueous layer was extracted with
AcOEt. The combined extracts were washed with brine and dried on
magnesium sulfate. The solvent was removed under reduced pressure,
and the crude product was purified by column chromatography using
silica gel 60. The cyclic adduct 26 (0.27 g, 0.28 mmol, 75%) was eluted
with hexane/AcOEt (96:4) as a white solid, mp 106−110 °C, which
was identified by comparison with an authentic sample (ref 5).
Similarly, the crude product obtained in the reaction of 20 (0.40 g,
0.45 mmol) with phenylmagnesium bromide (1.60 M in THF, 1.7 mL,
D
1720; 1673; 1602; 1490; 1444; 1235; 1140; 860; 750; 691 cm−1.
HRMS (ESI): calcd for C49H44ClO6Sn 883.1848, found 883.1853
Anal. Calcd for C49H44ClO6Sn: C, 66.65; H, 5.02. Found: C, 66.70;
H, 6.62.
Under the same experimental conditions, the reaction of 5 (1 g,
1.66 mmol) with Ph2SnCl2 (0.40 g, 1.16 mmol) and Ph2SnH2 (0.32 g,
1.16 mmol) occurred in dry toluene (10 mL) as solvent; the
irradiation time was 1 h. The crude product obtained was purified by
column chromatography using silica gel 60. The cyclic adduct 21a
(1.07 g, 1.18 mmol, 71%) was eluted with hexane/diethyl ether (94:6)
as a white solid, mp 115−117 °C. [α]20 = −78 (c 0.73, CHCl3). IR
D
(KBr): 3045; 3014; 2951; 2902; 1717; 1675; 1600; 1482; 1440; 1229;
1157; 852; 758; 693 cm−1. HRMS (ESI): calcd for C51H48ClO6Sn
911.2161, found 911.2156. Anal. Calcd for C51H48ClO6Sn: C, 67.23;
H, 5.31. Found: C, 67.18; H, 5.35. Diastereoisomer 21b could not be
separated pure.
Method B: Cyclohydrostannations at rt Initiated by AIBN.
Dialkyltin dichloride (0.6 mmol) was dissolved in dry toluene (6 mL).
Then the dialkylltin dihydride (0.6 mmol) was added, and the mixture
was stirred for 1 h. A solution of diester (0.8 mmol) in toluene
(10 mL) and AIBN (ca. 4 mg, 0.025 mmol) was added, and the reac-
tion mixture was kept stirring for 48−72 h, with monitoring by TLC
and IR spectroscopy. The solvent was distilled off under reduced
669
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Organometallics
Article
a
Table 6. 13C NMR Spectra of Compounds 22−24
b
c
d
compound no.
22
110.08
27.31
23
110.72
27.48
24
110.07
C-2
C-2a
27.26 and 27.30
76.76 and 76.90
87.33 and 87.38
175.18 (45.0)
42.99 (13.9)
29.92 (21.4)
34.63
C-3a and C-12a
C-4 and C-12
C-6 [3J(Sn,C)]
C-7 [2J(Sn,C]
C-8 [3J(Sn,C)]
C-9
76.85 and 76.90
87.49 and 87.51
175.61 (34.3)
43.83 (15.5)
30.69 (25.1)
35.07
76.02 and 77.01
87.14 and 90.27
181.12 (11.3)
46.74 (60.7)
46.68 (23.0)
36.25
C-10
170.85
175.35
170.90
C-13 [1J(Sn,C)]
C-14 [3J(Sn,C)]
C-15
12.51 (279.0)
18.99 (441.1)
27.05 (15.7)
18.96
15.61 (290.1)
a
n
In CDCl3; chemical shifts, δ, in ppm with respect to TMS; J(Sn,C) coupling constants, in Hz (in brackets); NO = not observed. Other signals:
b
9.82 (327.4); 13.89; 27.50 (55.2); 29.32 (20.0); 126.82; 126.85; 127.28; 127.30; 127.53; 127.54; 127.58; 127.61; 128.61; 128.72; 130.43; 140.71;
c
140.87; 144.84; 144.87. 13.51; 13.78; 18.17 (421.9); 26.28 (83.4); 27.90 (27.84); 28.33 (27.84); 126.88; 127.31; 127.34; 127.69; 127.75; 127.94;
128.26; 129.75; 130.03; 139.82; 140.52; 142.86; 144.67. 31.07 (316.3); 33.32 (35.9); 33.62 (37.8); 38.23 (18.7); 125.47; 125.62; 126.78; 127.21;
d
127.27; 127.51; 127.55; 127.62; 128.20; 128.56; 128.60; 130.34; 140.60; 140.84 (27.5).
a
1
Table 7. H NMR Spectra of Compounds 22−24
a
b
no.
chemical shifts (δ, in ppm) [C-No.]
22
n-Bu groups: 0.62−0.66 (m, 6H); 0.81 (t, 9H); 1.13−1.40 (m, 12H). Protons of the cycle: 0.53 (s, 2H) [C-13]; 1.48 (s, 6H) [C-2a]; 1.96−2.62 (m, 5H)
3 3
[C-7, C-8, C-9]; 5.53 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]; 5.59 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]. Phenyl groups: 7.13−7.29 (m, 20H).
n-Bu groups: 0.55−0.69 (m, 6H); 0.93 (t, 9H); 1.29−1.39 (m, 6H); 1.41−1.49 (m, 6H). Protons of the cycle: 0.42−0.45 (m, 2H) [C-13]; 0.81 (s, 3H)
23
3
3
[C-14]; 1.01 (d, JH,H 6.8 Hz, 3H) [C-15]; 1.07 (s, 6H) [C-2a]; 2.55−2.61 (m, 3H) [C-8, C-9]; 5.56 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a];
3
5.83 (d, JH,H 7.6 Hz, 1H) [C-3a or C-12a]. Phenyl groups: 7.22−7.49 (m, 20H).
2
24
Neophyl groups: 0.81 (s, J(Sn,H) 49.0 Hz, 6H); 1.07 and 1.08 (two superimposed picks, 18H). Protons of the cycle: 0.19 (d, 1H) and 0.24 (d, 1H)
[C-13]; 0.61 (s, 3H) and 0.64 (s, 3H) [C-2a]; 1.60−1.79 (m, 2H) [C-9]; 1.98−2.22 (m, 2H) [C-8]; 2.24−2.40 (m, 1H) [C-7];
3
3
5.52 (d, JH,H 7.8 Hz, 1H) [C-3a or C-12a]; 5.57 (d, JH,H 7.8 Hz, 1H) [C-3a or C-12a]. Phenyl groups: 7.04−7.31 (m, 35H).
a
b
In CDCl3; multiplicity and J values in Hz (in parentheses). Carbon to which the protons are attached.
2.7 mmol) was purified by column chromatography using silica gel 60.
The cyclic adduct 25 (0.32 g, 0.34 mmol, 76%) was eluted with
hexane/diethyl ether (90:10) as a white solid, mp 96−98 °C, and was
identified by comparison with an authentic sample (ref 5).
1.27−1.37 (m, 2JH,Sn 29.3 Hz, 8H); 1.45−1.51 (m, 3JH,Sn 31.2 Hz, 6H);
1.66−1.69 (m, 1H, H4); 3.15−3.37 (m, 2H, H1/H5)); 3.45−3.57 (m,
2H, H1/H5). 13C NMR (CDCl3): δ 10.44 (316.3); 13.65; 19.93
(296.1); 20.09 (195.6); 27.45 (57.6) (C-2); 27.78 (19.4); 29.19
(19.6); 30.84 (C-6); 38.73 (18.0) (C-4); 42.89 (30.0); 69.27 (C-5);
70.99 (44.2) (C-1). IR (film): 3324, 2955, 2925, 2868, 1465, 1372,
1034 cm−1. HR-MS (EI): calcd for C20H44O2Sn 436.2363, found
436.2358. Anal. Calcd for C20H44O2Sn: C, 55.19; H, 10.19. Found: C,
55.15; H, 10.24.
Reduction of Macrodiolides 23, 25, and 26 with LiAlH4.
Synthesis of (+)-2,4-Dimethyl-2-[(tributylstannyl)methyl]pentane-
1,5-diol (27). To a solution of 23 (0.18 g, 0.22 mmol) in ether (4.0 mL)
was added lithium aluminum hydride (0.055 g, 1.44 mmol) at room
temperature. After stirring for 4 h, the reaction was quenched with
HCl (2 N, 0.8 mL) and the aqueous layer was extracted with ether. The
combined extracts were washed with brine and dried over magnesium
sulfate. The organic solvent was distilled off under reduced pressure to
give an oily residue, which was purified by column chromatography
(silica gel 60). The stannylated alcohol 27 (0.052 g, 0.12 mmol, 56%)
Under the same experimental conditions, the reduction of cyclic
adduct 25 gave diol 28 as a colorless oil in 75% yield. We have already
reported the physical characteristics of 28 (see ref 5).
Under the same experimental conditions, the reduction of cyclic adduct
26 gave diol 29 as a colorless oil in 73% yield. [α]20 = −3.4 (c 0.70,
D
was eluted with hexane/AcOEt (90:10) as a colorless oil. [α]20
+2.4 (c 0.70, CHCl3). H NMR (CDCl3): δ 0.84−1.04 (m, 23H);
=
CHCl3). 1H NMR (CDCl3): δ 0.88 (d, 3H, H6); 1.03 (s, 3H, H8); 1.23−
D
1
2
1.28 (m, 3H); 1.59 (s, JH,Sn 59.8 Hz, 2H, H7); 3.24−3.32 (m, 2H);
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Organometallics
Article
3.38−3.47 (m, 2H); 7.38−7.39 (m, 9H, HAr); 7.59−7.61 (m, 6H, HAr).
13C NMR (CDCl3): δ 19.75 (C-6); 22.61 (291.9) (C-7); 27.32 (89.0)
Foundation (Germany) are acknowledged. The generous help
of Dr. Jorg-Martin Neudorfl (University of Cologne, Germany)
̈
̈
(C-8); 29.71 (C-4); 38.93 (20.5) (C-2); 42.90 (37.4) (C-3); 71.22 (41.2)
(C-1); 69.23 (C-5); 128.41; 128.63 (10.7); 136.90 (35.6). IR (film):
3370, 3075, 2919, 1605, 1475, 1449, 1429, 1378, 1070, 1019, 722,
691 cm−1. HR-MS (EI): calcd for C26H32O2Sn 496.1424, found.
496.1429. Anal. Calcd for C26H32O2Sn: C, 63.06; H, 6.51. Found: C,
63.10; H, 6.56.
Oxidation of Organotin Macrocycles 8, 9a, 18, and 19a.
Synthesis of (−)-(3aR,7R,12aS)-7-(Hydroxymethyl)-2,2-dimethyl-
4,4,12,12-tetraphenyltetrahydro-3aH-[1,3]dioxolo [4,5-c][1,6]-
dioxacycloundecine-6,10 (4H,7H)-dione (30). To a solution of 8
(0.20 g, 0.23 mmol) in methanol (1.5 mL) and THF (1.5 mL) was
added KHCO3 (70 mg, 0.70 mmol) and 30% H2O2 (0.12 mL, 1.15
mmol) at rt, and the mixture was stirred for 48 h. The mixture was
quenched with a 5% aqueous sodium sulfite solution and extracted
with ethyl acetate. The organic layer was washed with brine, dried, and
then concentrated in vacuo to give an oil, which was purified by
column chromatography on silica gel 60. Alcohol 30 (0.089 g, 0.15 mmol,
́
and Dr. Lucia Riera (University of Zaragoza, Spain) concerning
X-ray experiments and advice is gratefully acknowledged.
REFERENCES
■
(1) Omura, S., Ed. Macrolides Antibiotics: Chemistry, Biochemistry, and
Practice, 2nd ed.; Academic Press: New York, 2002.
(2) Nakata, T. Chapter 4 in ref 1.
(3) Shindo, M. Top. Heterocycl. Chem. 2006, 5, 179, and references
therein.
(4) (a) Porter, N. A.; Chang, V. H.-T. J. Am. Chem. Soc. 1987, 109,
4976. (b) Porter, N. A.; Lacher, B.; Chang, V. H.; Magnin, D. R. J. Am.
Chem. Soc. 1989, 111, 8309. (c) Boyce, R. J.; Pattenden, G.
Tetrahedron Lett. 1996, 37, 3501. (d) Patterson, I.; Lombart, H. G.;
Allerton, C. Org. Lett. 1999, 1, 19. (e) White, J. D.; Jackson, R.;
Hanselmann, R. Chem. Commun. 1998, 79.
(5) Gerbino, D. C.; Koll, L. C.; Mandolesi, S. D.; Podesta,
Organometallics 2008, 27, 660.
(6) Thiele, M. C.; Mitchell, T. N. Eur. J. Org. Chem. 2004, 337.
(7) Gerbino, D. C.; Koll, L. C.; Mandolesi, S. D.; Podesta, J. C.
Synthesis 2005, 2491.
(8) (a) Podesta, J. C.; Chopa, A. B. J. Organomet. Chem. 1982, 229,
223. (b) Chopa, A. B.; Koll, L. C.; Savini, M.; Podesta, J. C.; Neumann,
W. P. Organometallics 1985, 4, 1036. (c) Podesta, J. C.; Ayala, A. D.;
Chopa, A. B.; Giagante, N. N. J. Organomet. Chem. 1989, 364, 39.
(d) Faraoni, M. B.; Koll, L. C.; Vitale, C. A.; Chopa, A. B.; Podesta,
J. C. Main Group Met. Chem. 199, 22, 289. (e) Zuniga, A. E.; Fidelibus,
́
J. C.
66%) was eluted with hexane/ethyl acetate (80:20) as a white solid,
1
mp 157−159 °C. [α]20 = −86 (c 0.71, CHCl3). H NMR (CDCl3):
D
δ 1.21 (s, 6H, H2a), 2.23−2.31 (m, 4H, H8/H15), 2.60−2.72 (m, 1H,
́
H14), 3.61 (d, 2H, H13), 4.10 (s, 1H, H16), 5.43 (d, 3JH,H 7.5 Hz, 1H,
3
H3a/H12a), 5.51 (d, JH,H 7.5 Hz, 1H, H3a/H12a), 7.12−7.33 (m,
́
20H). 13C NMR (CDCl3): δ 19.50 (C-8), 26.22 (C-2a), 26.55 (C-2a),
33.41(C-9), 50.80 (C-7), 62.12 (C-13), 75.53 (C-3a/C-12a), 76.81
(C-3a/C-12a), 79.71(C-4/C-12), 108.42 (C-2), 126.21, 126.65,
126.73, 127.85, 141.40, 142.01, 172.15 (C-10), 173.72 (C-6). IR (KBr):
3615, 3025, 3011, 2950, 2910, 2865, 1744, 1600, 1485; 1451; 1243; 1155;
852; 750; 691 cm−1. HRMS (ESI): calcd for C37H36O7 592.2461, found
592.2467. Anal. Calcd for C37H36O7: C, 74.98; H, 6.12. Found: C, 75.01;
H, 6.15.
́
́
́
́
̃
P. M.; Mandolesi, S. D.; Podesta,
1547.
́
J. C. J. Organomet. Chem. 2011, 696,
(9) (a) Doddrell, D.; Burfitt, I.; Kitching, W.; Lee, C.-H.; Mynott,
R. J.; Considine, J. L.; Kuivila, H. G.; Sarma, R. H. J. Am. Chem. Soc.
Using the same procedure, the oxidation of 9a led to compound 31.
The product was purified by column chromatography (silica gel 60),
and macrodiolide 31 (71%) was eluted with hexane/ethyl acetate
1974, 96, 1640. (b) Mitchell, T. N.; Podesta,
Chopa, A. B. Magn. Reson. Chem. 1988, 26, 497.
́
J. C.; Ayala, A. D.;
(85:15) as a white solid, mp 141−143 °C. [α]20 = −98 (c 0.77,
D
(10) (a) Yamamoto, M.; Itoh, K.; Kishikawa, K.; Kohmoto, Sh. Chem.
Lett. 1997, 1035. (b) Ochiai, M.; Iwaki, Sh.; Ukita, T.; Matsuura, Y.;
Shiro, M.; Nagao, Y. J. Am. Chem. Soc. 1988, 110.
(11) Kerk, G. J. M.; Noltes, J. G.; Luijten, J. G. A. J. Appl. Chem.
1957, 7, 366.
CHCl3). 1H NMR (CDCl3): δ 1.12 (d, 3H, H15), 1.21 (s, 3H, H14),
1.28 (s, 6H, H2a), 1.63 (d, 2H, H8), 2.71−2.82 (m, 1H, H9), 3.74 (s,
3
2H, H13), 4.31 (s, 1H, H16), 5.35 (d, JH,H 7.4 Hz, 1H, H3a/H12a),
5.41 (d, 3JH,H 7.4 Hz, 1H, H3a/H12a), 7.08−7.18 (m, 20H, HAr). 13
C
NMR (CDCl3): δ 19.22 (C-15), 22.50 (C-14), 26.33 (C-2a), 26.81
(C-2a), 37.51(C-7), 38.22 (C-9), 38.80 (C-8), (C-13), 75.50 (C-3a/
C-12a), 76.13 (C-3a/C-12a), 78.41 (C-4/C-12), 108.74 (C-2), 126.13,
126.51, 126.74, 127.60, 140.52, 141.61, 174.13 (C-10), 174.91 (C-6).
IR (KBr): 3610; 3030; 3010; 2945; 2912; 2861; 1741; 1605; 1487;
1452; 1240; 1158; 850; 751; 695 cm−1. HRMS (ESI): calcd for
C39H40O7 620.2774, found 620.2769. Anal. Calcd for C39H40O7: C,
75.46; H, 6.50. Found: C, 75.51; H, 6.55.
The oxidation of organotin macrodiolides 18 and 19a under the
same reaction conditions afforded the same alcohols 30 (72%) and 31
(75%), respectively.
ASSOCIATED CONTENT
■
S
* Supporting Information
Copies of 1H, 13C, and 119Sn NMR spectra as well as
crystallographic data for compound 19. This material is
available free of charge via the Internet at http://pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
*E-mail: jpodesta@uns.edu.ar; lckoll@criba.edu.ar.
■
ACKNOWLEDGMENTS
■
This work was supported by CONICET (Capital Federal,
Argentina; PIP 112-200801-02272), ANPCyT (Capital Federal,
Argentina; PICT 2006-02467), and Universidad Nacional del
́
Sur (Bahia Blanca, Argentina; PGI 24/Q024). A travel grant to
J.C.P. and a fellowship (D.C.G.) from the Alexander von Humboldt
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dx.doi.org/10.1021/om200987t | Organometallics 2012, 31, 662−671