Effects of nitrogen and alkene substitution on the PtCl2 catalyzed cycloisomerization of N-tethered 1,6-enyne precursors to the triple reuptake inhibitor GSK1360707

Article abstract of DOI:10.1016/j.tetlet.2011.05.005

The effects of nitrogen and alkene substitution on the cycloisomerization of N-tethered 1,6-enynes into 3-azabicyclo[4.1.0]heptene precursors to the triple reuptake inhibitor GSK1360707 are described. In general, electron donating substituents proved bene

Full text of DOI:10.1016/j.tetlet.2011.05.005

Tetrahedron Letters 52 (2011) 3518–3520
Contents lists available at ScienceDirect
Tetrahedron Letters
journal homepage: www.elsevier.com/locate/tetlet
Effects of nitrogen and alkene substitution on the PtCl2 catalyzed
cycloisomerization of N-tethered 1,6-enyne precursors to the triple
reuptake inhibitor GSK1360707
⇑
Vassil Elitzin , Bing Liu, Matthew Sharp, Elie Tabet
Product Development, API Chemistry and Analysis, GlaxoSmithKline, 5 Moore Drive, Research Triangle Park, NC 27709, USA
a r t i c l e i n f o
a b s t r a c t
Article history:
The effects of nitrogen and alkene substitution on the cycloisomerization of N-tethered 1,6-enynes into 3-
azabicyclo[4.1.0]heptene precursors to the triple reuptake inhibitor GSK1360707 are described. In gen-
eral, electron donating substituents proved beneficial both in terms of the reaction rate and
chemoselectivity.
Received 6 April 2011
Revised 28 April 2011
Accepted 2 May 2011
Available online 8 May 2011
Ó 2011 Elsevier Ltd. All rights reserved.
Keywords:
1,6-Enyne cycloisomerization
Pt(II) catalysis
Au(I) catalysis
Nitrogen substitution effect
Alkene substitution effect
1. Introduction
both in terms of the protecting group on nitrogen, as well as the
alkene substitution pattern. From the point of view of large-scale
The cycloisomerization of 1,n-enynes and related compounds
has rapidly emerged as a powerful tool for the synthesis of com-
plex polycyclic compounds of structural1 and biological interest2
and has been the subject of a number of mechanistic3,4 and compu-
tational studies.5 For substrates where the reactive partners are
tethered by a nitrogen atom, the latter is typically protected as
the p-toluenesulfonamide (tosylate, p-Ts).6 Depending on other
functionality present in the molecule, however, the N-tosyl pro-
tecting group can be difficult to cleave selectively.7 Thus, while
ideal for methodology development purposes, it can prove prob-
lematic should its removal be required. To the best of our knowl-
edge, the effect of the nitrogen protecting group on reaction rate,
chemoselectivity or further processing post-cycloisomerization
has not been studied systematically for this class of substrates.
Moreover, examples where the alkene fragment bears a hetero-
atom substituent are relatively rare.
drug substance synthesis, we sought operationally facile transfor-
mations that maximize yield, minimize impurity formation, and
increase material throughput. Thus, our substrate selection was
guided by the potential for straightforward ultimate conversion
to GSK1360707. Herein, we wish to report our findings regarding
nitrogen and select alkene substituent effects on the enyne cyclo-
isomerization reaction.
The former objective was readily accomplished by first cleaving
the 2-nitrobenzenesulfonamide group in 1a (Scheme 1, synthesized
in three steps as reported previously) using modified Fukuyama
Cl
Cl
Cl
Cl
2. Results and discussion
O
O
N
S O
During the course of developing an enyne cycloisomerization
route8 to the triple reuptake inhibitor GSK13607079 (2, Scheme
1), we were interested in exploring the scope of this key reaction,
N
H
O
ref . 8
NO2
2
, GSK1360707
1a
⇑
Corresponding author. Tel.: +1 919 483 9068; fax: +1 919 315 8735.
E-mail address: vassil.i.elitzin@gsk.com (V. Elitzin).
Scheme 1. Our previously reported enyne cycloisomerization approach to
GSK1360707.
0040-4039/$ - see front matter Ó 2011 Elsevier Ltd. All rights reserved.
doi:10.1016/j.tetlet.2011.05.005

V. Elitzin et al. / Tetrahedron Letters 52 (2011) 3518–3520
3519
3-azabicyclo[4.1.0]heptenes), suggesting that with these substrates
any competing interaction between the carbonyl oxygen and the al-
kyne is reversible. Reaction of the N-acetyl substrate 1h led to sev-
eral products (entry 8).12 As with the carbamate series, we reasoned
that this was perhaps due to interference by the amide carbonyl
group. Thus, switching to the more electron withdrawing (i.e., less
Lewis basic) trichloroacetyl (TCA, 1i) and trifluoroacetyl (TFA, 1j)
protecting groups (entries 9 and 10), we found that the predomi-
nant reaction pathway was once again the desired one, although
the reaction rate dropped off significantly. This was a rather general
observation—the more electron withdrawing the protecting group,
the slower the reaction rate, likely due to reduced electron density
on the alkyne and/or alkene through inductive effects. Additionally,
reduced availability of the nitrogen lone pair would presumably
lead to lower migratory propensity by the propargyllic hydrogens,
a proposed mechanistic step in the process.13 Substrates in which
the nitrogen lone pair was not engaged through conjugation, such
as substrates 1k (entry 11) and 3 (no protecting group on nitrogen,
Scheme 2) led to decomposition.
Cl
Cl
LiOH, HS(CH2)2CO2H
1a
DMF, 80%
O
N
H
3
Cl
Cl
1b
, R = 4-Ns
1c, R = p-Ts
1d
, R = Boc
1e, R = Cbz
Conditionsa
1f
, R = EtOCO
1g, R = PhOCO
1h, R = Ac
O
1i
, R = TCA
N
R
1j, R = TFA
1k
, R = PMB
Au(I) catalysis proved effective in accelerating the reaction, par-
ticularly for substrates such as 1j. Thus, reaction of 1j at room tem-
perature in dichloromethane with 10 mol % AuClPPh3/AgSbF6 led
to the formation of 4j in less than 2 h.
Scheme 2. Synthesis of various N-protected enynes. aReaction conditions (all in
CH2Cl2, 2 h, rt): 1b, c, e–i RCl, TEA; 1d: (Boc)2O, TEA; 1j: TFAA, TEA; 1k:
p-MeOPhCHO, NaBH(OAc)3.
In studying the effect of the substitution pattern on the alkene
fragment, we were once again particularly interested in exploring
substrates that would yield products easily convertible to
GSK1360707. Thus, enynes 6a–d, synthesized in analogous fashion
to 1a, were subjected to the same reaction conditions as those
described in Table 1. All substrates, with the exception of 6d,14 pro-
ceeded to give the desired products (Table 2). Relatively electron
rich olefins, such as 6a (entry 1) gave good reaction rates (reaction
completion in ꢀ1 h), while enoate 6c required 72 h for complete
conversion (entry 3). We were also pleased to find that the free
hydroxyl group in 6b (entry 2) did not interfere with the desired
cycloisomerization pathway.15 For our purposes, we ultimately
chose allyl methyl ether 1a which was the most suitable
GSK1360707 precursor.8
Table 1
Protecting group comparisona
Cl
Cl
Cl
Cl
4a
Cl
, R = 2-Ns
Cl
O
4b, R = 4-Ns
4c, R = p-Ts
4d
, R = Boc (minor)
O
4e, R = Cbz
4f
O
O
, R = EtOCO
4g, R = PhOCO
4h
N
N
R
N
R
, R = Ac (minor)
4i, R = TCA
4j
5
, R = TFA
4k, R = PMB (trace)
O
1a-k
4a-k
Substrate
In conclusion, we have investigated the effects of nitrogen and al-
kene substituents on the cycloisomerization of 1,6-enynes into 3-
azabicyclo[4.1.0]heptenes, with the ultimate goal of developing an
Entry
Major product
Time (h)
Yieldb (%)
1
2
3
4
5
6
7
8
1a
1b
1c
1d
1e
1f
1g
1h
1i
4a
4b
4c
5
4e
4f
4g
7
94
93
96
83
91
90
88
N/A
91
90
N/A
12
4.5
2.5
3
3
3.5
3
16
48
5
Table 2
Effect of alkene substituentsa
Mult. prod.
Cl
9
10
11
4i
4j
Cl
Cl
1j
1k
Cl
Decomp.
a
Reaction conditions: 10 mol % PtCl2, toluene (10 ml/g 1), 80 °C.
HPLC percent area under the curve (AUC), excluding toluene peak.
b
R2
PtCl2 (10 mol %)
Toluene, 80 o
R2
conditions (LiOH, HS(CH2)2CO2H, DMF).10 The resulting secondary
amine was then derivatized with a variety of protecting groups,
as shown in Scheme 2.
C
N
R1
N
R1
The above enynes were then subjected to cycloisomerization
conditions (10 mol % PtCl2, toluene, 80 °C, see Table 1) until com-
plete disappearance of starting material was observed by HPLC.
We found that substrates bearing substituted benzenesulfona-
mides (1a–c, entries 1–3) gave the cleanest reactions, with the tos-
ylate giving the fastest reaction. Switching to carbamate protecting
groups, we found that 1d gave predominantly oxazolidinone 5 (en-
try 4, alkene geometry not determined). Based on previous litera-
ture reports,11 5 is presumably the product of 5-exo-dig attack on
the alkyne by the carbonyl oxygen followed by loss of isobutene.
Interestingly, the other carbamates screened (1e–g, entries 5–7)
gave mostly the desired enyne cycloisomerization products (i.e.,
7a
, R1 = p-Ts, R2 = CH2Si(CH3)3
6a, R1 = p-Ts, R2 = CH2Si(CH3)3
6b
7b, R1 = 2-Ns, R2 = CH2OH
, R1 = 2-Ns, R2 = CH2OH
6c, R1 = p-Ts, R2 = C(O)OEt
6d
7c
, R1 = p-Ts, R2 = C(O)OEt
7d, R1 = p-Ts, R2 = CH2Cl
, R1 = p-Ts, R2 = CH2Cl
Entry
Substrate
Time (h)
Yieldb (%)
1
2
3
4
6a
6b
6c
6d
1
96
8
81
72
89
No reaction
N/A
a
Reaction conditions: 10 mol % PtCl2, toluene (10 ml/g 6), 80 °C.
HPLC percent area under the curve (AUC), excluding toluene peak.
b

3520
V. Elitzin et al. / Tetrahedron Letters 52 (2011) 3518–3520
4. (a) Fürstner, A.; Davies, P.; Gress, T. J. Am. Chem. Soc. 2005, 127, 8244; (b)
Fürstner, A.; Szillat, H.; Gabor, B.; Mynott, R. J. Am. Chem. Soc. 1998, 120,
8305.
5. (a) Lee, Y. T.; Kang, Y. K.; Chung, Y. K. J. Org. Chem. 2009, 74, 7922; (b) Nieto-
Oberhuber, C.; Munoz, M.; Bunuel, E.; Nevado, C.; Cardenas, D.; Echavarren, A.
M. Angew. Chem., Int. Ed. 2004, 43, 2402.
6. Examples: (a) Fürstner, A.; Szillat, H.; Stelzer, F. J. Am. Chem. Soc. 2000, 122,
6785; (b) Fürstner, A.; Stelzer, F.; Szillat, H. J. Am. Chem. Soc. 2001, 123,
11863; (c) Monnier, F.; Castillo, D.; Derien, S.; Toupet, L.; Dixneuf, P. Angew.
Chem., Int. Ed. 2003, 42, 5474; (d) Marion, F.; Coulomb, J.; Courillon, C.;
Fensterbank, L.; Malacria, M. Org. Lett. 2004, 6, 1509–1511; (e) Shibata, T.;
Kobayashi, Y.; Maekawa, S.; Toshida, N.; Takagi, K. Tetrahedron 2005, 61,
9018; (f) Kim, S.; Lee, S.; Chung, Y. Org. Lett. 2006, 8, 5425; (g) Nishimura, T.;
Kawamoto, T.; Nagaosa, M.; Kumamoto, H.; Hayashi, T. Angew. Chem., Int. Ed.
2010, 49, 1638.
7. For an excellent summary of p-toluenesulfonamide desulfonation
methodology, see: Nandi, P.; Redko, M. Y.; Petersen, K.; Dye, J. L.; Lefenfeld,
M.; Vogt, P. F.; Jackson, J. E. Org. Lett. 2008, 10, 5441–5444. and ref. therein.
8. Deschamps, N. M.; Elitzin, V. I.; Liu, B.; Mitchell, M. B.; Sharp, M. J.; Tabet, E. A. J.
Org. Chem. 2011, 76, 712–715.
9. (a) Bertani, B.; Di Fabio, R.; Micheli, F.; Tedesco, G.; Terreni, S. PCT Int.
Appl.WO2008031772, 2008.; (b) Micheli, F.; Cavanni, P.; Andreotti, D.; Arban,
R.; Benedetti, R.; Bertani, B.; Bettati, M.; Bettelini, L.; Bonanomi, G.; Braggio, S.;
Carletti, R.; Checchia, A.; Corsi, M.; Fazzolari, E.; Fontana, S.; Marchioro, C.;
Merlo-Pich, E.; Negri, M.; Oliosi, B.; Ratti, E.; Read, K. D.; Roscic, M.; Sartori, I.;
Spada, S.; Tedesco, G.; Tarsi, L.; Terreni, S.; Visentini, F.; Zocchi, A.; Zonzini, L.;
Di Fabio, R. J. Med. Chem. 2010, 53, 4989–5001; (c) Elitzin, V. I.; Harvey, K. A.;
Kim, H.; Salmons, M.; Sharp, M. J.; Tabet, E. A.; Toczko, M. A. Org. Process Res.
Dev. 2010, 14, 912–917.
10. Fukuyama, T.; Jow, C.-K.; Cheung, M. Tetrahedron Lett. 1995, 36, 6373–6374.
11. For related examples, including a proposed mechanism, see: Robles-Machin,
R.; Adrio, J.; Carretero, J. C. J. Org. Chem. 2006, 71, 5023–5026.
12. For a related example involving the reaction participation of pendant esters,
see: Zheng, H.; Zheng, J.; Yu, B.; Chen, Q.; Wang, X.; He, Y.; Yang, Z.; She, X. J.
Am. Chem. Soc. 2010, 132, 1788.
efficient synthetic route to the triple reuptake inhibitor
GSK1360707.16 In general, electron-donating moieties gave faster
and higher yielding reactions in both cases. A number of different
substrates were well tolerated, with the exception of those where
pendant functional groups (i.e., nitrogen lone pair, electron-rich car-
bonyl oxygen, or chloride) presumably compete irreversibly for
either the catalyst or the alkyne.
3. General cycloisomerization procedure
The N-tethered 1,6-enyne (2 mmol, 1 equiv), toluene (10 ml per
gram of substrate), and PtCl2 (53 mg, 0.2 mmol, 0.1 equiv) were
heated to ꢀ80 °C in a sealed vial. The reaction progress was mon-
itored by reverse-phase HPLC using a mixture of water and aceto-
nitrile as mobile phase (gradient at a flow rate of 1.0 ml/min and
UV detection at 220 nm). After completion, the reaction was cooled
to room temperature, filtered through celite and concentrated.
Acknowledgments
We are thankful to Mark Mitchell, Nicole Deschamps and
Robert Yule for useful discussions, and to Kim Harvey for analytical
support.
References and notes
1. Selected reviews: (a) Aubert, C.; Fensterbank, L.; Garcia, P.; Malacria, M.;
Simonneau, A. Chem. Rev. 2011, 111, 1954; (b) Fürstner, A. Chem. Soc. Rev. 2009,
38, 3208; (c) Michelet, V.; Toullec, P. Y.; Genet, J.-P. Angew. Chem., Int. Ed. 2008,
47, 4268–4315; (d) Zhang, L.; Sun, J.; Kozmin, S. A. Adv. Synth. Catal. 2006, 348,
2271; (e) Ma, S.; Yu, S.; Gu, Z. Angew. Chem., Int. Ed. 2006, 45, 200–203; (f)
Aubert, C.; Buisine, O.; Malacria, M. Chem. Rev. 2002, 102, 813.
2. Recent examples: (a) Molawi, K.; Delpont, N.; Echavarren, A. M. Angew. Chem.,
Int. Ed. 2010, 49, 3517–3519; (b) Trost, B. M.; Dong, G. Nature 2008, 456, 485–
488; (c) Veitch, G. E.; Beckmann, E.; Burke, B. J.; Boyer, A.; Maslen, S. L.; Ley, S.
V. Angew. Chem., Int. Ed. 2007, 46, 7629–7632.
13. Soriano, E.; Marco-Contelles, J. J. Org. Chem. 2005, 70, 9345.
14. Allylic chloride 6d gave no reaction even when a stoichiometric amount of
PtCl2 was used. Unreacted starting material was recovered after celite filtration
and solvent removal, suggesting that the formation of a Pt(IV) p–allyl complex
can be ruled out. Rather, the formation of a relatively labile yet unproductive
substrate–PtCl2 complex appears likely. Heating to >100 °C led to slow
decomposition.
15. For an alternate transformation involving a related substrate, see: Yeh, M.-C. P.;
Lin, M.-N.; Chang, W.-J.; Liou, J.-L.; Shih, Y.-F. J. Org. Chem. 2010, 75, 6031.
16. For example, 4j was cleanly converted to GSK1360707 upon treatment with
NaBH4 in MeOH. See also Ref. 8.
3. Ferrer, C.; Raducan, M.; Nevado, C.; Claverie, C.; Echavarren, A. M. Tetrahedron
2007, 63, 6306. and references therein.