Stereoselective synthesis of 3,3-diarylacrylonitriles as tubulin polymerization inhibitors

Article abstract of DOI:10.1021/jo800428b

(Chemical Equation Presented) A series of 3,3-diarylacrylonitriles were synthesized stereo-selectively as tubulin polymerization inhibitors for potential use in cancer chemotherapy. This synthetic route features stannylcupration and palladium-catalyzed St

Full text of DOI:10.1021/jo800428b

interfere with microtubule/tubulin dynamic equilibrium have
antimitotic activity. These drugs modulate microtubule assembly
either by inhibition of tubulin polymerization or by blocking
microtubule disassembly. On the basis of their mechanisms of
action, these drugs are classified as tubulin polymerization
inhibitors or microtuble stabilizers.3 Some common tubulin
polymerization inhibiting anticancer drugs derived from natural
sources include colchicine (Figure 1), the cryptophycins, vin-
cristine, combretastatin A4, and vinblastine. Well-known mi-
crotubule stabilizing anticancer drugs include paclitaxel (Taxol),
docetaxel (Taxotere), discodermolide, the epothilones, the
eleutherobins, and laulimalide.4 These small molecules bind to
different sites on tubulin and thereby exert diverse effects on
microtubule dynamics. However, all of these compounds have
limitations resulting from high toxicity, poor oral bioavailability,
difficulty of synthesis or isolation from natural sources, and drug
resistance.5 Therefore, there is current interest in the develop-
ment of new synthetic compounds with both improved oral
bioavailability and lower toxicity. Recently, researchers at
Celgene Corp. reported a novel synthetic tubulin polymerization
inhibitor, the 3,3-diarylacrylonitrile CC-5079 (Figure 1), for
potential use in cancer chemotherpy.6
Stereoselective Synthesis of
3,3-Diarylacrylonitriles as Tubulin Polymerization
Inhibitors
Zhenglai Fang,† Yunlong Song,† Taradas Sarkar,‡
Ernest Hamel,‡ William E. Fogler,§ Gregory E. Agoston,§
Phillip E. Fanwick,# and Mark Cushman*,†
Department of Medicinal Chemistry and Molecular
Pharmacology, School of Pharmacy and Pharmaceutical
Sciences, and the Purdue Cancer Center, Purdue UniVersity,
West Lafayette, Indiana 47907, Toxicology and
Pharmacology Branch, DeVelopmental Therapeutics
Program, DiVision of Cancer Treatment and Diagnosis,
National Cancer Institute at Frederick, National Institutes of
Health, Frederick, Maryland 21702, EntreMed, Inc.,
RockVille, Maryland 20850, and Department of Chemistry,
Purdue UniVersity, West Lafayette, Indiana 47907
cushman@pharmacy.purdue.edu
ReceiVed February 21, 2008
FIGURE 1. Colchicine and synthetic tubulin polymerization inhibitor
CC-5079.
3,3-Diarylacrylonitriles bind to tubulin at the colchicine-
binding site.6 In the Celgene study, compound CC-5079 was
tested for biological activity as a mixture of E and Z isomers.
Methods that would allow the synthesis of the E and Z isomers
are needed so that either one can be prepared in stereochemically
pure form, thus eliminating the need for the difficult and time-
consuming separation of the final products. To explore the
structure-activity relationships associated with 3,3-diarylacry-
lonitrile tubulin polymerization inhibitors, a set of compounds
derived from the general structures (E)-1 and (Z)-1 were
considered (Figure 2), and a versatile synthesis that would allow
the incorporation of a variety of substituents was therefore
needed. This led to the decision to explore the Stille cross-
coupling reaction as a possible solution of this problem (Figure
2).7
A series of 3,3-diarylacrylonitriles were synthesized stereo-
selectively as tubulin polymerization inhibitors for potential
use in cancer chemotherapy. This synthetic route features
stannylcupration and palladium-catalyzed Stille cross-
coupling chemistry, allowing both E and Z isomers of 3,3-
diarylacrylonitriles to be prepared in a very short sequence
of reactions.
Microtubules, made of heterodimeric R- and ꢀ-tubulin
subunits with highly dynamic behavior,1 are fundamental
components of cellular structure. They participate in a wide
variety of critical cellular functions, such as motility, division,
shape maintenance, and intracellular transport.2 Drugs that
The target compounds (E)-1 and (Z)-1 can be disconnected
retrosynthetically into the aromatic halides or the triflate 4 and
(3) (a) Li, Q.; Sham, H. L. Exp. Opin. Ther. Pat. 2002, 12, 1662–1702. (b)
Prinz, H. Exp. ReV. Anticancer Ther. 2002, 2, 695–708. (c) Beckers, T.;
Mahboobi, S. Drugs Future 2003, 28, 767–785.
† Department of Medicinal Chemistry and Molecular Pharmacology, School
of Pharmacy and Pharmaceutical Sciences, and the Purdue Cancer Center, Purdue
University.
(4) Kavallaris, M.; Verills, N. M.; Hill, B. T. Drug Resist. Updates 2001, 4,
392–401.
(5) Wood, K. W.; Cornwell, W. D.; Jackson, J. R. Curr. Opin. Pharmacol.
2001, 1, 370–377.
‡ National Institutes of Health.
§ EntreMed, Inc.
(6) Zhang, L. H.; Wu, L.; Raymon, H. K.; Chen, R. S.; Corral, L.; Shirley,
M. A.; Narla, R. K.; Gamez, J.; Muller, G. W.; Stirling, D. I.; Bartlett, J. B.;
Schafer, P. H.; Payvandi, F. Cancer Res. 2006, 66, 951–959.
(7) Merkushev, E. B. Synthesis 1998, 923–937.
# Department of Chemistry, Purdue University.
(1) Jordan, M. A. Curr. Med. Chem.: Anti-Cancer Agents 2002, 1, 1–17.
(2) Downing, K. H.; Nogales, E. Curr. Opin. Cell Biol. 1998, 10, 16–22.
10.1021/jo800428b CCC: $40.75
Published on Web 05/01/2008
2008 American Chemical Society
J. Org. Chem. 2008, 73, 4241–4244 4241

3-(trialkylstannyl)acrylonitriles 2 or 3. Despite several attempts,
stannylcupration of propionitrile 8 failed to produce vinylstan-
nane intermediates 2 or 3.
Stannylcuprates are also known to undergo substitution
reactions with 3-iodo-2-enones,14 enol triflates of cyclic ꢀ-ke-
toesters,15 and 2-enoates containing good leaving groups (such
as Cl or I) at the ꢀ-position.16 These substitution reactions are
believed to proceed through a conjugate addition-elimination
pathway or by direct substitution. Based on this precedent,
conjugated enol triflate (Z)-11 was synthesized in two steps,
and its structure was determined by X-ray crystallography
(Figure 3). Compound (Z)-11 was then converted to (Z)-3 and
(E)-3. The optimal conditions we found for this reaction used
(Bu3Sn)2Cu(CN)Li2 at -50 °C for 10 min (entry 7 in Table 1).
FIGURE 2. Retrosynthetic analysis of 3,3-diarylacrylonitriles 1.
the possible vinylstannane intermediates 2 or 3 (either E or Z
isomers). Intermediates of general structure 4 are commercially
available or can be prepared easily by halogenation of aromatic
rings7 or triflation of substitued phenols.8
There are many efficient methods for the synthesis of
vinylstannanes reported in the literature.9 For example, vinyl-
stannanes can be prepared by hydrostannation of alkynes either
under radical conditions10 or catalyzed by transition metal
complexes like Pd(PPh3)4.11 However, when propiolonitrile 8
was treated with Bu3SnH under either of these two conditions,
only the undesired vinylstannane intermediate 9 with the
incorrect regiochemistry was obtained (Scheme 1).
FIGURE 3. X-ray structure of 11 and stereochemical assignment for
vinylstannane for intermediates 3.
SCHEME 1. Failed Hydrostannation or Stannyl Cupration
Attempts for the Synthesis of Vinylstannanes 2 or 3
TABLE 1. Syntheses of 2 or 3 via Substitution of Conjugated
Enol Triflate by Stannylcupratesa
temp
(°C)
time
(min)
product
(% yield)
Therefore, these unsuccessful attempts to generate compounds
2 or 3 led us to consider another well-developed method for
the preparation of vinylstannanes: stannylcupration of alkynes.12
Stannylcuprates are known to react in a Michael fashion with
2-ynoates to afford 3-trialkylstannyl-2-enoates.13 Although there
is no literature precedent, we attempted to extend this chemistry
to the direct stannylcupration of propionitrile 8 to afford
entry
reagent
Bu3SnCu
Bu3SnCu(PhS)Li
Bu3SnCu(PhS)Li
Bu3SnCu(CN)Li
E/Z
1
2
3
4
5
6
7
8
-50
-78
-50
-78
-50
-78
-50
-20
-20
-20
-20
10
10
10
10
10
30
10
10
10
10
10
3 (0)
3 (0)
3 (0)
3 (0)
3 (0)
3 (<5)
3 (80)c
3 (35)
2 (0)
2 (0)
2 (0)
N/A
N/A
N/A
N/A
N/A
1:1
Bu3SnCu(CN)Li
(Bu3Sn)2Cu(CN)Li2
(Bu3Sn)2Cu(CN)Li2
(Bu3Sn)2Cu(CN)Li2
(Me3Sn)2Cu(CN)Li2
Me3SnCu(PhS)Lib
3:2
4.6:1
N/A
N/A
N/A
(8) Stang, P. J.; Hanack, M.; Subramanian, L. R. Synthesis 1982, 85–126.
(9) Davies, A. G. Organotin Chemistry, 2nd ed.; Wiley-VCH Verlag Gmbh
& Co German KGaA:. Weinheim, Germany, 2004; Chapter 8, pp 114.
(10) Corey, E. J.; Wollenberg, R. H. J. Am. Chem. Soc. 1974, 96, 5581–
5583.
b
9
10
11
b
(Me3Sn)2Cu(PhS)Li2
a All reactions were carried out with 1 mmol of 11 and 1.1 mmol of
stannylcuprates in THF. b 5.0 mmol of stannylcuprates was used. c This
reaction was done on 10 mmol scale.
(11) (a) Smith, N. D.; Mancuso, J.; Lautens, M. Chem. ReV. 2000, 100, 3257–
3282. (b) Ferri, F.; Alami, M. Tetrahedron Lett. 1996, 37, 7971–7974.
(12) (a) Fleming, I. Organocopper Reagents: A Practical Approach; Taylor,
R. J. K., Ed.; Oxford University Press: Oxford, UK, 1994; Chapter 12, p 257.
(b) Piers, E.; Rogers, C. Encylopedia of Reagents for Organic Synthesis; Paquette,
L. A., Ed.; Wiley: Chichester, UK, 1995; Vol. 7, pp 5328. (c) Piers, E.; Rogers,
C. Encylopedia of Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley:
Chichester, UK, 1995; Vol. 7, p 5024. (d) Piers, E.; Rogers, C. Encylopedia of
Reagents for Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, UK,
1995; Vol. 5, p 3157. (e) Piers, E.; Rogers, C. Encylopedia of Reagents for
Organic Synthesis; Paquette, L. A., Ed.; Wiley: Chichester, UK, 1995; Vol. 3,
p 1965.
(14) Piers, E.; Morton, H. E.; Chong, J. M. Can. J. Chem. 1987, 65, 78–87.
(15) (a) Lipshutz, B. H.; Sharma, S.; Reuter, D. C. Tetrahedron Lett. 1990,
31, 7253–7256. (b) Piers, E.; Tse, H. L. A. Can. J. Chem. 1993, 71, 983–994.
(c) Houpis, I. N.; DiMichele, L.; Molina, A. Synlett 1993, 5, 365–366. (d) Piers,
E.; McEachern, E. J.; Romero, M. A.; Gladstone, P. L. Can. J. Chem. 1997, 75,
694–701. (e) Piers, E.; Boehringer, E. M.; Yee, J. G. K. J. Org. Chem. 1998,
63, 8642–8643. (f) Gilbertson, S. R.; Challener, C. A.; Bos, M. E.; Wulff, W. D.
Tetrahedron Lett. 1988, 29, 4795–4798.
(13) (a) Piers, E.; Morton, H. E. J. Org. Chem. 1980, 45, 4263–4264. (b)
Piers, E.; Chong, J. M.; Morton, H. E. Tetrahedron Lett. 1981, 22, 4905–4908.
(c) Piers, E.; Chong, J. M. J. Org. Chem. 1982, 47, 1602–1604. (d) Cox, S. D.;
Wudl, F. Organometallics 1983, 2, 184–185. (e) Piers, E.; Tillyer, R. D. J. Org.
Chem. 1988, 53, 5366–5369.
(16) (a) Seitz, D. E.; Lee, S.-H. Tetrahedron Lett. 1981, 22, 4909–4912. (b)
Imanieh, H.; MacLeod, D.; Quayle, P.; Zhao, Y.; Davis, G. M. Tetrahedron
Lett. 1992, 33, 405–408.
4242 J. Org. Chem. Vol. 73, No. 11, 2008

No desired product was detected with other stannylcuprates tried,
rather elimination product 8 was obtained. Compound 8 is most
likely formed due to the competing elimination reaction with
the cuprates acting as a base.
Stille reactions were stereospecific. None of the undesired
isomers were detected.
The final compounds 1 were tested for inhibition of tubulin
assembly and inhibition of colchicine binding to tubulin, as well
as for their inhibitory properties against three cell lines: MDA-
MB-231, LLC, and HUVEC. The biological results are shown
in Table 3. Most of the compounds 1 had good activity against
tubulin polymerization, especially (Z)-1a and (Z)-1b. The (Z)-1
isomers are generally more potent inhibitors of tubulin polym-
erization. Likewise, the same stereochemical trend holds for the
in vitro cytotoxicity and endothelial cell proliferation assays.
A computer modeling study was performed to find a possible
binding model of 3,3-diarylacrylonitriles with tubulin. The X-ray
structure of the colchicine-tubulin complex (PDB code: 1SA0)
was downloaded and the structure of colchicine was deleted.22
Then (Z)-1a was docked into the empty colchicine cavity by
using GOLD software (BST, v3.0, 2005). The postdocking
energy minimization was performed by using the MMFF94s
force field and MMFF94 charges within Sybyl 7.3. The resulting
structure is displayed in Figure 4. According to the model, the
1,2-dimethoxyphenyl group occupies the cavity that is distal to
the GTP. This puts the nitrile of (Z)-1a in proximity of the
Tyr224 phenol, with formation of a hydrogen bond in (Z)-1a.
The geometric configurations of the vinylstannanes (E)-3 and
(Z)-3 were determined by their NMR coupling constants
between the R-olefinic proton and the tin atom (117Sn, 119Sn) of
the Bu3Sn group (Figure 3). It is well-known that when a
trialkylstannyl group and a proton are vicinal on a CdC double
bond, the 3JSn-H values are much larger when the moieties are
trans than when they are cis.17 As shown below in Figure 3,
3
the JSn-H values of (E)-3 and (Z)-3 are 46.4 and 89.0 Hz,
respectively. According to selective transient 1D NOE studies,
there is a significant 1H NOE between the vinyl proton and the
1
aromatic protons in (Z)-3, while there is a significant H NOE
between the vinyl proton and the methylene protons in the Bu3Sn
group in (E)-3 (Figure 3). These corroborating observations
provide strong evidence for the assignment of stereochemistry
for both (E)-3 and (Z)-3.
TABLE 2. Stille Coupling Reaction of Vinylstannane 3 and X-ray
Structure of (Z)-1a
entry
3
ArX
conditionsa
prod (% yield)
1
2
3
4
5
6
7
8
Z
Z
Z
Z
Z
E
Z
E
Z
E
Z
Z
E
4a
4a
4a
4a
4a
4a
4b
4b
4c
4c
4d
4d
4d
Pd(PPh3)4, CuI, CSF, rt
Pd(PPh3)4, CuI, CSF, 60 °C
Pd2(dba)3, AsPh3, CuI, CSF, 60 °C (Z)-1a (0)
Pd2(dba)3, AsPh3, CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd(dppf), CSF, 60 °C
Pd2(dba)3, PtBu3, CSF, 60 °C
Pd2(dba)3, PtBu3, CSF, 60 °C
(Z)-1a (0)
(Z)-1a (0)
(Z)-1a (45)
(Z)-1a (85)
(E)-1a (81)
(Z)-1b (76)
(E)-1b (70)
(Z)-1c (73)
(E)-1c (65)
(Z)-1d (0)
9
10
11
12
13
(Z)-1d (68)
(E)-1d (71)
FIGURE 4. Hypothetical model for the binding of (Z)-1a to tubulin.
a All reactions were done in a sealed tube with anhydrous DMF,
which was degassed with argon.
In summary, a series of 3,3-diarylacrylonitriles were synthe-
sized stereoselectively. This synthetic route utilizes a stannyl-
cuprate-mediated substitution of a conjugated enol triflate
followed by a Stille cross-coupling reaction. The biological
studies demonstrated that 3,3-diarylacrylonitriles are effective
tubulin polymerization inhibitors and are good inhibitors of
endothelial cell proliferation and cytotoxic agents with the Z
isomers being more potent than corresponding E isomers.
Vinylstannanes (E)-3 and (Z)-3 were then coupled with a
variety of aryl and heteroaromatic halides under Stille cross-
coupling conditions (Table 2). Several catalytic systems were
studied, and we found that Pd(dppf) as the catalyst with CsF as
promoter in DMF worked best with aryl iodides and activated
aryl bromides.18 For unactivated (hetero)aryl bromides, the
Pd2(dba)3/PtBu3/CsF catalytic system was optimal.19 For aryl
iodides (entries 5-8) and activated aryl bromide (entries 9 and
10), the Stille reactions were completed at 60 °C in 4 and 6 h,
respectively. For the unactivated aryl bromide (entries 12 and
13), the reactions were completed at 60 °C in 24 h. All of the
Experimental Section
Syntheses of (Z)-3-(3,4-Dimethoxyphenyl)-3-(tributylstanny-
l)acrylonitrile ((Z)-3) and (E)-3-(3,4-Dimethoxyphenyl)-3-(tribu-
tylstannyl)acrylonitrile ((E)-3). Bu3SnH (3.51 mL, 13.2 mmol)
(20) Hamel, E. Cell Biochem. Biophys. 2003, 38, 1–21.
(21) Verdier-Pinard, P.; Lai, J.-Y.; Yoo, H.-D.; Yu, J.; Marquez, B.; Nagle,
D. G.; Nambu, M.; White, J. D.; Falck, J. R.; Gerwick, W. H.; Day, B. W.;
Hamel, E. Mol. Pharmacol. 1998, 53, 62–76.
(22) (a) Ravelli, R. B. G.; Gigant, B.; Curml, P. A.; Jourdain, I.; Lachkar,
S.; Sobel, A. Nature 2004, 428, 198–202. (b) Gigant, B.; Curmi, P. A.; Martin-
Barbey, C.; Charbaut, E.; Lachkar, S.; Lebeau, L. Cell 2000, 102, 809–816. (c)
Lowe, J.; Li, H.; Downing, K. H.; Nogales, E. J. Mol. Biol. 2001, 313, 1045–
1057.
(17) Leusink, A. J.; Budding, H. A.; Marsamn, J. W. J. Organomet. Chem.
1967, 9, 285–294.
(18) Mee, S. P. H.; Lee, V.; Baldwin, J. E. Angew. Chem., Int. Ed. 2004, 43,
1132–1136.
(19) Littke, A. F.; Schwarz, L.; Fu, G. C. J. Am. Chem. Soc. 2002, 124,
6343–6348.
J. Org. Chem. Vol. 73, No. 11, 2008 4243

TABLE 3. Cytotoxicities and antitubulin activities of 3,3-Diarylacrylonitriles 1
cytotoxicity (IC50 in nM)a
inhibition of tubulin assembly
(IC50, µM) ( SDb
inhibition of colchicine binding
compd
MDA-MB-231
LLC
22.1
595
15.5
2320
73.6
97100
>10000
118000
HUVEC
(% ( SD)
c d
,
(Z)-1a
(E)-1a
(Z)-1b
(E)-1b
(Z)-1c
(E)-1c
(Z)-1d
(E)-1d
CSA4
17.6
680
18.0
1750
79.1
17.3
320
8.66
1760
82.4
1.6
78 ( 0.1
40 ( 4
86 ( 3
27 ( 6
23 ( 7
4.2 ( 0.3
1.0d
5.8 ( 0.5
6.5 ( 0.4
70000
>100000
186000
151000
>10000
164000
1.2 ( 0.1
98 ( 0.3
a The cytotoxicity IC50 values are the concentrations corresponding to 50% growth inhibition. b Tubulin concentration was 1.0 mg/mL (10 µM). Assay
c
performed as described previously.20 Tubulin concentration was 1.0 µM, [3H]colchicine and inhibitor concentrations, 5.0 µM. Assay performed as
described previously.21 d Same value obtained in all experiments.
was added to LDA (15.6 mmol, 8.67 mL, 1.80 M solution) in
anhydrous THF (100 mL) under argon at -60 to -78 °C. The
reaction mixture was stirred for 20 min. CuCN (592 mg, 6.60 mmol)
was added and the solution was slowly warmed to -50 °C. The
solid CuCN dissolved, resulting in a green-yellow solution.
Compound 11 (2.03 g, 6.0 mmol) in THF (50 mL) was added
dropwise and the color of the solution changed to red-orange. After
10 min of further stirring, the reaction was quenched with saturated
aqueous NH4Cl solution. The reaction mixture was extracted with
EtOAc and washed with H2O and brine. The organic solution was
dried over Na2SO4 and the solvent was removed under reduced
pressure. Flash column chromatography on SiO2 eluting with pure
dichloromethane afforded the desired products (Z)-3 (0.92 g, less
polar which came out of column first) and (E)-3 (1.38 g, more polar
which came out of column last) both as pale yellow oils in a yield
of 80%.
6 H), 1.35-1.24 (m, 6 H), 1.02 (t, J ) 8.1 Hz, 6 H), 0.87 (t, J )
7.3 Hz, 9 H); 13C NMR (75 MHz, CDCl3) δ 176.4, 149.2, 148.9,
134.8, 119.8, 116.7, 111.2, 109.7, 104.3, 56.0, 28.9 (JSn-C ) 10.0
Hz), 27.3 (JSn-C ) 29.0 Hz), 13.7, 11.0. Anal. Calcd for
C23H37NO2Sn: C, 57.76; H, 7.80; N, 2.93. Found: C, 57.94; H, 7.78;
N, 2.95.
General Procedure for the Synthesis of 3,3-Diarylacryloni-
triles by the Stille Cross-Coupling Reaction of (Z)-3 or (E)-3
with Aromatic Iodides or Bromides. A mixture of (Z)-3-(3,4-
dimethoxyphenyl)-3-(tributylstannyl)acrylonitrile ((Z)-3) or (E)-3-
(3,4-dimethoxyphenyl)-3-(tributylstannyl)-acrylonitrile ((E)-3) (0.1
mmol, 1.0 equiv), aryl halide (1.20 equiv), cesium fluoride (2.20
equiv), and Pd(dppf) (5.0 mol%) or Pd2(dba)3 (2.5 mol%) and PtBu3
(5.0 mol%) in anhydrous DMF (1.0 mL, degassed by freeze-pump-
thaw-pump method) was stirred in the dark under argon at 60 °C
for the indicated time. The reaction mixture was then cooled to
room temperature and filtered through a short column of silica gel
(5 g), and the column was washed with ethyl acetate. The solvent
was removed under reduced pressure and purified by column
chromatography on SiO2 eluting with EtOAc-hexanes.
Compound (Z)-3: IR (film) 2954, 2922, 2207, 1511, 1462, 1259,
1140, 1026, 804 cm-1; EIMS m/z (rel intensity) 479 (M+, 14), 422
(100), 366 (30), 308 (50); 1H NMR (300 MHz, CDCl3) δ 6.85 (d,
J ) 8.3 Hz, 1 H), 6.67 (dd, J ) 2.2, 8.6 Hz, 1 H), 6.62 (d, J ) 2.2
3
Hz, 1 H), 6.02 (s, JSn-H ) 89 Hz, 1 H), 3.89 (s, 3 H), 3.88 (s, 3
H), 1.59-1.45 (m, 6 H), 1.38-1.25 (m, 6 H), 1.17 (t, J ) 8.2 Hz,
6 H), 0.87 (t, J ) 7.2 Hz, 9 H); 13C NMR (75 MHz, CDCl3) δ
176.8, 149.5, 149.0, 137.2, 119.2, 119.1, 111.2, 109.3, 108.4, 56.1,
56.0, 29.1, 27.3 (JSn-C ) 30.2 Hz), 13.8, 11.6. Anal. Calcd for
C23H37NO2Sn: C, 57.76; H, 7.80; N, 2.93. Found: C, 57.90; H, 7.79;
N, 2.92.
Acknowledgment. This investigation was conducted in a
facility constructed with the financial support of a Research
Facilities Improvement Program grant, No. C06-14499.
Supporting Information Available: Experimental proce-
dures, NMR spectra for all compounds, the selective transient
1D NOE for 3, and the X-ray coordinates for 11 and (Z)-1a.
This material is available free of charge via the Internet at
http://pubs.acs.org.
Compound (E)-3: IR (film) 2955, 2928, 2870, 2851, 2205, 1597,
1509, 1463, 1410, 1259, 1140, 1073, 1026, 863, 799, 762, 667
cm-1; EIMS m/z (rel intensity) 479 (M+, 15), 422 (100), 366 (33),
1
308 (50), 188 (95); H NMR (300 MHz, CDCl3) δ 6.89 (d, J )
8.3 Hz, 1 H), 6.86 (d, J ) 2.0 Hz, 1 H), 6.81 (dd, J ) 2.0, 8.3 Hz,
1 H), 5.54 (s, 3JSn-H ) 46.6 Hz, 1 H), 3.91 (s, 6 H), 1.54-1.40 (m,
JO800428B
4244 J. Org. Chem. Vol. 73, No. 11, 2008