An enyne cycloisomerization approach to the triple reuptake inhibitor Gsk1360707F

Article abstract of DOI:10.1021/jo102098y

The triple reuptake inhibitor GSK1360707F was synthesized via an efficient and scalable route that features an enyne cycloisomerization reaction catalyzed by either Pt(II) or Au(I). Key aspects of this work such as the choice of the nitrogen protecting gr

Full text of DOI:10.1021/jo102098y

pubs.acs.org/joc
Transition metal-catalyzed enyne cycloisomerizations have
An Enyne Cycloisomerization Approach to the Triple
Reuptake Inhibitor GSK1360707F
emerged as powerful tools for the synthesis of carbocyclic
and heterocyclic compounds.4,5 In particular, we were intrigued
by the possibility of isomerizing appropriately functionalized
1,6-enynes to arrive at the 3-azabicyclo[4.1.0]heptane6 ske-
leton of GSK1360707F. Several recent examples of this type
of transformation have appeared in the literature, typically
utilizing Pt(II) or Au(I) catalysts. We were also encouraged
by the likelihood of conducting these reactions in enantio-
selective fashion.7
Nicole M. Deschamps, Vassil I. Elitzin,* Bing Liu,
Mark B. Mitchell, Matthew J. Sharp, and Elie A. Tabet
Chemical Development, GlaxoSmithKline, 5 Moore Dr.,
Research Triangle Park, North Carolina 27709, United States
vassil.i.elitzin@gsk.com
We initially focused our attention on identifying a suitable
nitrogen protecting group that would enable the synthesis
and cycloisomerization of the desired enyne, and allow for
ultimate conversion to GSK1360707F. While the vast ma-
jority of similar cyclization substrates in the literature em-
ploy p-toluenesulfonyl (p-Ts) nitrogen protecting groups, we
reasoned (and later confirmed) that the late-stage removal of
an N-tosylate would be difficult to accomplish chemoselec-
tively. On the other hand, we surmised that a 2- or 4-nitro-
benzenesulfonyl protecting group would meet our criteria.
To that end, reaction of propargyl amine with 2-nitroben-
zenesulfonyl chloride gave propargyl sulfonamide1(Scheme1).
Sonogashira coupling8 with 1,2-dichloro-4-iodobenzene
generated 2 with no detected PCBs (by HPLC analysis).
Allylation with 2-methoxymethylallyl chloride 39 furnished
the requisite cycloisomerization precursor 4. Gratifyingly,
heating 4 in toluene at 80 °C in the presence of catalytic PtCl2
afforded the desired product 5 in high yield. Racemic
GSK1360707F was then obtained after enamine reduction
with TFA-triethylsilane,10,11 protecting group removal under
Received October 26, 2010
The triple reuptake inhibitor GSK1360707F was synthe-
sized via an efficient and scalable route that features an
enyne cycloisomerization reaction catalyzed by either
Pt(II) or Au(I). Key aspects of this work such as the
choice of the nitrogen protecting group and initial en-
antioselectivity studies are discussed.
(5) Related examples with;Palladium: (a) Trost, B. M.; Lautens, M. J.
Am. Chem. Soc. 1985, 107, 1781. (b) Trost, B. M.; Tanoury, G. H. J. Am.
Chem. Soc. 1988, 110, 1636. Platinum: (c) Chatani, N.; Morimoto, T.; Muto,
GSK1360707F is a potent serotonin, noradrenaline, do-
pamine reuptake(triplereuptake) inhibitorunderdevelopment
at GlaxoSmithKline1 for the treatment of major depressive
disorder (MDD).2 We recently disclosed our first generation
route for the multikilogram scale synthesis of (-)-GSK-
1360707F,3 which took advantage of a novel double alkylation
with a dihalomethane to construct the cyclopropane ring.
While this route was utilized for the supply of 15 kg of drug
substance, it had some potential long-term drawbacks, namely,
the formation of polychlorinated biphenyl (PCB) byproducts
in the Suzuki coupling, high cost of goods (COGs), and low
atom efficiency. To address these issues, we have been exploring
alternative approaches to the synthesis of GSK1360707F.
€
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W.; Xiao, W.-J.; Zhou, Y.-G. Org. Lett. 2009, 11, 1119–1122.
(11) Efficient removal of the platinum catalyst from the previous step was
required to suppress competitive reduction of the nitro group.
(1) (a) Bertani, B.; Di Fabio, R.; Micheli, F.; Tedesco, G.; Terreni, S. PCT
Int. Appl. WO 2008031772, 2008. (b) Micheli, F.; Cavanni, P.; Andreotti, D.;
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Published on Web 12/21/2010
DOI: 10.1021/jo102098y
r
2010 American Chemical Society

Deschamps et al.
JOCNote
SCHEME 1. Synthesis of GSK1360707Fa
TABLE 1. D-Optimal Screening for Enantioselective Cycloisomeriza-
tiona
Au:Ag
molar ratio
% area
(5)
entry ligand
AgX
solvent
eeb
1
2
3
4
5
6
7
8
9
A
H
C
B
J
AgSbF6 CH2Cl2
AgSbF6 CH2Cl2
AgSbF6 CH2Cl2
AgSbF6 CH2Cl2
AgSbF6 CH2Cl2
AgSbF6 toluene
AgSbF6 toluene
AgSbF6 toluene
AgSbF6 toluene
AgSbF6 toluene
1:1
1:2
1:1
1:2
1:1
1:2
1:1
1:1
1:2
1:2
1:1
1:2
1:2
1:2
1:1
1:2
1:1
1:1
1:1
1:2
1:2
1:2
1:2
1:1
1:1
1:2
1:1
1:1
1:1
1:2
2:3
2:3
100
63
17
99
97
66
97
18
0
37
21
100
92
37
16
43
36
0
0
5
21
-4
2
5
-51
0
F
I
E
G
D
F
I
D
B
J
A
H
E
C
G
H
E
C
G
D
F
I
10
11
12
13
14
15
16
17
18
19
20
21
22
23
24
25
26
27
28
29
30
31
32
8
14
-48
19
-7
-7
33
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgOTf
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
AgBF4
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
CH2Cl2
toluene
toluene
toluene
toluene
toluene
toluene
toluene
-12
0
14
100
100
100
100
100
80
100
86
13
40
37
36
-1
-1
-2
-6
-3
0
13
-59
33
-5
-8
-8
-6
aNs = 2-nitrobenzenesulfonyl.
A
B
J
J
J
modified Fukuyama conditions,12 and phosphate salt for-
mation. The overall yield for this route was 58%.
aLigands: A (R)-Xylyl-P-Phos, B (R)-(S)-NMe2-P(3,5-CF3Ph)2-Man-
dyphos, C (R)-(S)-NMe2-Pcy2-Mandyphos, D catASium MNXyl(R), E
(R)-(R)-Ph2PPhFCHCH3PPh2-Walphos, F (R)-MONOPHOS, G (R,
R)-BDPP, H (R)-(S)-PPF-PtBu2, I (R)-Tol-BINAP, J (S)-(þ)-(3,5-
dioxa-4-phosphacyclohepta[2,1-a;3,4-a0]dinapthalen-4-yl)[(1R)-1-pheny-
lethyl]amine. bPlus ee indicates the fast eluting peak is in excess. For the
purpose of this initial screen, the absolute configuration of 5 that relates
to the respective peak by chiral HPLC was not determined. All the
evaluated ligands may be procured in both antipodes allowing access to
either enantiomer of 5.
Parallel reaction screening techniques were employed to
investigate the enantioselective cycloisomerization of 4 with
Au(I) catalysis.13 Ligand, solvent, silver salt, and Ag/Au
stoichiometry were assessed using a D-optimal experimental
design. Statistical main effects indicated that (R)-tol-BINAP
(I) was essential for good conversion and enantioselectivity.
None of the remaining factors studied had significant impact
upon the observed enantioselectivity. However, it was found
that CH2Cl2 and AgBF4 were beneficial to conversion overall.
The highest ee observed was 59% with (R)-tol-BINAP as
ligand (Table 1, entry 27).
no PCBs were detected during the incorporation of the
dichlorophenyl fragment.
In conclusion, we have demonstrated an efficient new
route for the synthesis of GSK1360707F. This approach
takes advantage of a highly selective enyne cycloisomerization
reaction that elegantly assembles the 3-azabicyclo[4.1.0]heptane
framework of the molecule, and offers the possibility of
obtaining the product in enantioselective fashion. Additionally,
Experimental Section
2-Nitro-N-2-propyn-1-ylbenzenesulfonamide (1).In a 1 L jacketed
laboratory reactor were charged triethylamine (91.9 g, 0.908 mol,
1 equiv), dichloromethane (994 g, 750 mL, 11.7 mol), and propar-
gylamine (50 g, 0.908 mol, 1 equiv). The solution was cooled to
about 0 °C and then treated with 2-nitrobenzenesulfonyl chloride
(191.1 g, 0.862 mol, 0.95 equiv) portionwise over 15 min. The
reaction was warmed to about 25 °C over 15 min, stirred for 3 h,
and quenched with 1 M HCl (95 mL). The layers were separated.
The organic layer was washed with water (200 mL) and saturated
(12) Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36,
6373–6374.
(13) Analogous enantioselectivity screens on a closely related substrate
(4-nitrobenzenesulfonamide) with Pt(II) catalysts exhibited slow reaction
rates at elevated temperatures.
J. Org. Chem. Vol. 76, No. 2, 2011 713

Deschamps et al.
JOCNote
aqueous NaHCO3 (100 mL) and then concentrated under vacuum.
The solids obtained were dried under vacuum at 40 °C for 12 h to
give 201 g of 1 (97% yield). 1H NMR (400 MHz, CDCl3) δ 8.22-
8.18 (m, 1H), 7.93-7.90 (m, 1H), 7.76 (J=Hz, 2H), 5.70 (s, 1H),
4.02 (dd, J=6.1, 2.4 Hz, 2H), 1.97 (t, J=2.5 Hz, 1H); 13C NMR
(100.6 MHz, CDCl3) δ 134.2, 134.1, 133.2, 131.8, 125.8, 73.5, 33.6;
IR (ATR) 3319 (w), 3296 (m), 1535 (s), 1415 (m), 1366 (m), 1330
(s), 1156 (s), 1127 (s), 1070 (s), 929 (w), 855 (w), 783 (s), 742 (s);
HRMS m/z 241.0276 [(Mþ); calcd for C9H9N2O4S 241.0278]; mp
90-92 °C.
N-[3-(3,4-Dichlorophenyl)-2-propyn-1-yl]-2-nitrobenzenesul-
fonamide (2). In a 1 L jacketed laboratory reactor were charged
2-nitro-N-2-propyn-1-ylbenzenesulfonamide 1 (60 g, 0.250 mol,
1 equiv), 3,4-dichloroiodobenzene (62.02 g, 0.227 mol, 0.91 equiv),
and DMF (397 g, 420 mL, 5.43 mol). After all the solids were
dissolved, triethylamine (27.8 g, 0.275 mol, 1.1 equiv), PdCl2-
(PPh3)2 (3.51 g, 0.005 mol, 0.02 equiv), and copper(I) iodide (1.9 g,
0.01 mol, 0.04 equiv) were added. Once the reaction was deemed
complete, it was treated with MTBE (600 mL), 1 N HCl (100 mL),
and water (200 mL). After separation of the layers, the aqueous
layer was back extracted with MTBE (200 mL). The combined
organic layers were washed with water (200 mL) and 1:1 water:
saturated aqueous NaHCO3 (300 mL). The organic layer was
then partially concentrated to about 400 mL and the resulting
slurry stirred at room temperature for about 72 h. The solid was
filtered and dried at 40 °C under vacuum for 12 h to give 71 g of 2
(81% yield). 1H NMR (400 MHz, CDCl3) δ 8.24-8.22 (m, 1H),
7.89-7.87 (m, 1H), 7.73-7.67 (m, 2H), 7.29 (d, J = 8.2 Hz, 1H),
6.99 (d, J=2 Hz, 1H), 6.88 (dd, J=8.4, 2 Hz, 1H), 5.78 (s, 1H),
4.24 (d, J=2.2 Hz, 2H); 13C NMR (100.6 MHz, CDCl3) δ 134.6,
134.0, 133.5, 133.3, 133.2, 132.7, 131.8, 130.7, 130.6, 125.7, 121.7,
111.5, 85.1, 83.2, 34.4; IR (ATR) 3310 (w), 1534 (s), 1432 (m),
1337 (s), 1165 (s), 1125 (m), 1067 (s), 886 (w), 819 (w), 782 (s), 738
(s), 652 (s); HRMS m/z 384.9812 [(Mþ); calcd for C15H11Cl2N2-
O4S 384.9812]; mp 122-124 °C.
N-[3-(3,4-Dichlorophenyl)-2-propyn-1-yl]-N-{2-[(methyloxy)-
methyl]propen-1-yl}-2-nitrobenzenesulfonamide (4). In a 2 L round-
bottomed flask were charged N-[3-(3,4-dichlorophenyl)-2-propyn-
1-yl]-2-nitrobenzenesulfonamide 2 (50 g, 0.130 mol, 1 equiv),
DMF (378 g, 400 mL, 5.17 mol), and K2CO3 (19.7 g, 0.143 mol,
1.1 equiv). The reaction was stirred for 20 min followed by the
addition of 3-chloro-2-[(methyloxy)methyl]-1-propene (3) (17.22g,
0.143 mol, 1.1 equiv). After 2 h, the reaction was quenched with
water (400 mL) and toluene (400 mL) and the layers were separated.
The organic layer was washed successively with water (200 mL)
and 1:1 water:saturated NaHCO3 (200 mL). After concentration
under vacuum, the material was purified by chromatography
(gradient of 10 to 60% ethyl acetate/heptane) to give 49 g of oil
4 (80% yield). 1H NMR (400 MHz, CDCl3) δ 8.10-8.07 (m, 1H),
7.70-7.61 (m, 3H), 7.31 (d, J=8.4 Hz, 1H), 7.20 (d, J=2.0 Hz,
1H), 7.02 (dd, J=8.2, 1.8 Hz, 1H), 5.27 (d, J=23.5 Hz, 2H), 4.34 (s,
2H), 4.09 (s, 2H), 3.86 (s, 2H), 3.26 (s, 3H); 13C NMR (100.6 MHz,
CDCl3) δ 148.5, 139.6, 134.1, 133.5, 133.4, 132.9, 132.7, 131.9,
131.5, 130.9, 130.6, 124.4, 122.1, 117.3, 84.4, 83.6, 73.0, 58.5, 49.9,
36.9; IR (ATR) 2926 (w), 1541 (s), 1464 (m), 1357 (s), 1163 (s),
1125 (s), 1086 (s), 1032 (m), 906 (S), 851 (m), 820 (m), 774 (s), 740
(s), 683 (m); HRMS m/z 469.0383 [(Mþ); calcd for C20H19Cl2N2-
O5S 469.0387].
6-(3,4-Dichlorophenyl)-1-[(methyloxy)methyl]-3-[(2-nitrophenyl)-
sulfonyl]-3-azabicyclo[4.1.0]hept-4-ene (5). In a 250 mL round-
bottomed flask were charged N-[3-(3,4-dichlorophenyl)-2-pro-
pyn-1-yl]-N-{2-[(methyloxy)methyl]propen-1-yl}-2-nitrobenze-
nesulfonamide 4(10 g, 0.0213 mol, 1 equiv), toluene (43.3 g, 50 mL),
and PtCl2 (0.142 g, 0.5 mmol, 0.025 equiv). The reaction was
heated to ∼80 °C for 19.5 h. An additional charge of PtCl2 (0.07 g,
0.26 mmol) was performed since the reaction did not reach
completion. The reaction was stirred for another 2.5 h at which point
it had reached completion. After cooling to room temperature,
the reaction was filtered through Celite and concentrated.
Purification by chromatography (ethyl acetate) through a plug
of silica gel afforded 10 g of 5 as a yellow foam (100% yield). 1H
NMR (400 MHz, CDCl3) δ 8.05-8.02 (m, 1H), 7.77-7.67 (m,
3H), 7.36-7.34 (m, 2H), 7.09 (dd, J=8.4, 2.2 Hz, 1H), 6.44 (d,
J=8.0 Hz, 1H), 5.35 (d, J=8 Hz, 1H), 4.10 (d, J=12.3 Hz, 1H),
3.38 (d, J=12.3 Hz, 1H), 3.08 (s, 3H), 3.07 (d, J=8.4 Hz, 1H),
2.90 (d, J=10.4 Hz, 1H), 1.36 (d, J=5.5 Hz, 1H), 1.19 (d, J=5.3 Hz,
1H); 13C NMR (100.6 MHz, CDCl3) δ 148.3, 140.9, 134.3, 132.4,
132.1, 131.7, 131.6, 131.2, 131.19, 130.4, 129.0, 124.6, 121.1,
116.8, 74.8, 59.0, 43.7, 36.8, 27.4, 22.4; IR (ATR) 2924 (w), 1541
(s), 1470 (m), 1397 (w), 1356 (s), 1287 (w), 1172 (s), 1128 (m),
1096 (s), 1030 (w), 978 (w), 956 (m), 851 (m), 756 (m), 742 (s), 681
(s); HRMS m/z 469.0382 [(Mþ); calcd for C20H19Cl2N2O5S
469.0387].
6-(3,4-Dichlorophenyl)-1-[(methyloxy)methyl]-3-[(2-nitrophenyl)-
sulfonyl]-3-azabicyclo[4.1.0]heptane (6). 6-(3,4-Dichlorophenyl)-
1-[(methyloxy)methyl]-3-[(2-nitrophenyl)sulfonyl]-3-azabicyclo[4.1.0]-
hept-4-ene 5 (8 g, 0.017 mol, 1 equiv) was dissolved in toluene (69 g,
80 mL). After addition of 5 wt % aqueous cysteine (40 mL), the
mixture was heated to 60 °C for about 2 h and then cooled to room
temperature. Toluene (40 mL), 1 N HCl (20 mL), and water (20 mL)
were then added followed by phase separation. After the organic
layer was washed with 1:1 water:saturated aqueous NaHCO3
(100 mL), the aqueous layers were combined and extracted with
toluene (100 mL). The combined organic layers were washed with
water (100 mL), filtered, and then concentrated under vacuum to
oil. The oil was dissolved in toluene (35 g, 40 mL) and then treated
with triethylsilane (1.98 g, 2.72 mL, 1 equiv) and TFA (15.55 g,
10.1 mL, 8 equiv). After being stirred for 2 h, the reaction was
quenched with 2 N NaOH (70 mL) and toluene (40 mL). After
phase separation, the organic layer was washed with water (80 mL)
and concentrated under vacuum. Purification by column chroma-
tography (gradient of 30 to 40% ethyl acetate/heptane) gave 6.8 g
of 6as a yellow foam (84.8% yield). 1H NMR (400 MHz, CDCl3) δ
8.04-8.02 (m, H), 7.73-7.69 (m, H), 7.64-7.62 (m, H), 7.35 (s, H),
7.33 (d, J=5.7Hz,H),7.10(dd,J=8.2,2Hz,H),3.67(t,J=13.5 Hz,
H), 3.37-3.21 (m, H), 3.10 (s, H), 2.99 (d, J=10.0 Hz, H), 2.83 (d,
J=10.0 Hz, H), 2.15-1.99 (m, H), 1.07 (d, J=5.7 Hz, H), 1.05 (d,
J=5.7 Hz, H); 13C NMR (100.6 MHz, CDCl3) δ148.4, 144.1, 133.9,
132.4, 132.3, 131.9, 131.4, 131.3, 130.9, 130.6, 128.9, 124.3, 76.06,
58.9, 46.8, 43.0, 32.7, 28.7, 26.4, 19.1; IR (ATR) 2922 (m), 2853 (m),
1541 (s), 1467 (m), 1372 (s), 1343 (s), 1163 (s), 1128 (m), 1097 (s),
1059 (w), 1030 (w), 953 (m), 908 (w), 851 (m), 824 (w), 733 (s);
HRMS m/z 471.0533 [(Mþ); calcd for C20H21Cl2N2O5S 471.0543].
(()-GSK1360707F. In a 250 mL round-bottomed flask were
charged 6-(3,4-dichlorophenyl)-1-[(methyloxy)methyl]-3-[(2-nitro-
phenyl)sulfonyl]-3-azabicyclo[4.1.0]heptane 6 (4 g, 0.0085 mol,
1 equiv), DMF (32.1 g, 34 mL), 3-mercaptopropionic acid (1.35 g,
1.11 mL, 0.0127 mol, 1.5 equiv), and LiOH (0.61 g, 0.0255 mol,
3 equiv). The reaction was stirred for 1 h and then quenched with
MTBE (100 mL) and H2O (50 mL). After phase separation, the
organic layer was washed with 1 N NaOH (50 mL) and then H2O
(50 mL). Following concentration under vacuum, 1-propanol
(17.7 g, 22 mL) was added. The solution was heated to about 80 °C
and then treated with concentrated H3PO4 (0.53 mL, 0.0076 mol,
0.9 equiv). The slurry was then cooled to 25 °C over 5 h, and
filtered. The wet solid was then dried at 60 °C under vacuum for
72 h to give 2.07 g of racemic GSK1360707F as a white solid
(85% yield). The sample was identical by 1H NMR to a sample
of (-)-GSK1360707F, as reported previously.3
Enantioselective Isomerization of 4 to 5. D-Optimal Reaction
Screen. To each of 32 individual 1.5 mL HPLC filter vials equipped
with stir bars and assembled in a microtiter plate format were
added AuCl(SMe2) (3.8 mg, 0.013 mmol, 0.1 equiv) and 25 mg of
ultra-activated charcoal, using a solid dispensing robot. To each
vial were added the appropriate ligand (0.1 equiv for monodentate
or 0.05 equiv for bidentate phosphines) and silver salt, using the
714 J. Org. Chem. Vol. 76, No. 2, 2011

Deschamps et al.
JOCNote
solid dispensing robot followed by 750 μL of either toluene or
CH2Cl2 as given in Table 1. The vials were sealed with parafilm
and stirred at 25 °C for 1 h. The stir bars were now removed and
a filter insert placed in each vial and depressed, transferring each
filtrate to a fresh 1.5 mL HPLC vial equipped with a stir bar. To
each vial was added a 0.5 M stock solution of 4 (250 μl, 0.13 mmol,
1 equiv) in either toluene or CH2Cl2 as given in Table 1. The vials
were crimp sealed and stirred at 25 °C for 5 h. The conversion
and enantioselectivity after this time were determined by HPLC
and are reported in Table 1.
Acknowledgment. We are grateful to Kim Harvey, Mark
Saulter, Andrew Wolters, and David Black for analytical
support, and to Robert Yule for useful discussions regarding
the purification of chloride 3.
Supporting Information Available: Experimental data, co-
pies of spectra, and chromatograms for all new compounds.
This material is available free of charge via the Internet at http://
pubs.acs.org.
J. Org. Chem. Vol. 76, No. 2, 2011 715