Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines, important 5-HT2C agonist precursors

Article abstract of DOI:10.1016/j.tetlet.2018.04.030

Asymmetric syntheses of N-protected (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines, advanced intermediates for the synthesis of highly potent and selective 5-HT_2C agonists, are described. The key transformation involves ring opening of N-protected bicyclic sulfamidate (R)-hexahydro-3H-pyrazino[1,2-c][1,2,3]oxathiazine 1,1-dioxide with (4-halo-2-fluoropyridin-3-yl)lithiums or (3-bromo-5-fluoropyridin-4-yl)lithium. In situ hydrolyses of the resultant sulfamic acids and subsequent intramolecular nucleophilic aromatic substitutions (S_NAr) produce the enantiopure tricycles. The two step procedure represents new methodology for the stereoselective syntheses of tetrahydronaphthyridines.

Full text of DOI:10.1016/j.tetlet.2018.04.030

Accepted Manuscript
Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazi-
no[1,2-a][1,n]naphthyridines, important 5-HT2C agonist precursors
Thomas O. Schrader, Xiuwen Zhu, Michelle Kasem, Sufang Li, Chunyan Liu,
Albert Ren, Chunrui Wu, Graeme Semple
PII:
S0040-4039(18)30487-8
https://doi.org/10.1016/j.tetlet.2018.04.030
TETL 49893
DOI:
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
23 February 2018
11 April 2018
12 April 2018
Please cite this article as: Schrader, T.O., Zhu, X., Kasem, M., Li, S., Liu, C., Ren, A., Wu, C., Semple, G.,
Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines, important 5-
HT2C agonist precursors, Tetrahedron Letters (2018), doi: https://doi.org/10.1016/j.tetlet.2018.04.030
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Asymmetric synthesis of (R)-4-halo-6,6a,7,8,9,10-
hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines,
important 5-HT2C agonist precursors
Leave this area blank for abstract info.
Thomas O. Schrader, Xiuwen Zhu, Michelle Kasem, Sufang Li, Chunyan Liu, Albert Ren, Chunrui Wu, and
Graeme Semple

1
Tetrahedron Letters
Asymmetric syntheses of (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-
a][1,n]naphthyridines, important 5-HT2C agonist precursors
Thomas O. Schrader a,, Xiuwen Zhu a, Michelle Kasema, Sufang Li b, Chunyan Liu b, Albert Rena,
Chunrui Wu b, and Graeme Semple a
a Department of Medicinal Chemistry, Arena Pharmaceuticals, 6154 Nancy Ridge Drive, San Diego, CA, 92121, USA
bWuXi AppTec (Wuhan) Co Ltd., 666 Gaoxin Road, East Lake High-tech Development Zone, Wuhan 430075, China
ARTICLE INFO
ABSTRACT
Article history:
Received
Received in revised form
Accepted
Asymmetric syntheses of N-protected (R)-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-
a][1,n]naphthyridines, advanced intermediates for the synthesis of highly potent and selective 5-
HT2C agonists, are described. The key transformation involves ring opening of N-protected
bicyclic sulfamidate (R)-hexahydro-3H-pyrazino[1,2-c][1,2,3]oxathiazine 1,1-dioxide with (4-
halo-2-fluoropyridin-3-yl)lithiums or (3-bromo-5-fluoropyridin-4-yl)lithium. In situ hydrolyses
of the resultant sulfamic acids and subsequent intramolecular nucleophilic aromatic substitutions
(SNAr) produce the enantiopure tricycles. The two step procedure represents new methodology
for the stereoselective syntheses of tetrahydronaphthyridines.
Available online
Keywords:
5-HT2C agonists
asymmetric synthesis
Lorcaserin
2009 Elsevier Ltd. All rights reserved.
sulfamidate
tetrahydronaphthyridines
Agonists of the 5-HT2C receptor, a centrally expressed G-
protein coupled receptor (GPCR), have therapeutic potential
across a range of conditions including obesity,1 addiction,2
urinary incontinence,3 sexual dysfunction,4 and psychiatric
disorders.5 The identification of 5-HT2C receptor agonists which
possess high receptor selectivity is of critical importance, as
agonism of related receptor subtypes 5-HT2A and 5-HT2B has
been linked to hallucinations6 and cardiac side effects7
Our synthetic strategy toward compounds 4 and 5 was based
on a previous report from these laboratories detailing the
stereoselective synthesis of (R)-3-benzyl-7-bromo-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a]quinolines (6, Scheme 2),9 a
chemical precursor to a class of structurally related tricyclics
which are differentiated from the tetrahydronaphthyridine based
5-HT2C agonists (2 and 3) by the absence of a pyridyl ring
nitrogen.10 Our convergent route to 6 involved the addition of (2-
bromo-6-fluorophenyl)lithium (8) to optically pure aldehyde 7
and subsequent Swern oxidation which delivered
o-fluorophenone 9. After Boc-deprotection (to give 10), a base-
promoted intramolecular SNAr reaction followed by ketone
removal with TFA and Et3SiH produced the desired tricycle 6 in
a respectable 84% yield (3 steps). The proposed route to
tricycles 4 and 5 further exploits this methodology and includes
modifications inspired Moss et al.11 who described preparation of
functionalized 5,6,7,8-tetrahydropyrido[2,3-d]pyrimidines via the
ring opening of cyclic sulfamidates with magnesiated
respectively. In 2012 the anti-obesity medication lorcaserin8 (1,
Belviq®, Scheme 1) became the first selective 5-HT2C receptor
agonist to receive regulatory approval. As part of a program to
identify additional agents for this clinically validated target, a
number of selective (R)-4-substituted-6,6a,7,8,9,10-hexahydro-
5H-pyrazino[1,2-a][1,8]naphthyridine (2, scheme 1) and (R)-4-
substituted-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-
a][1,7]naphthyridine 5-HT2C agonists (3) were discovered.
Asymmetric syntheses of the chemically unique fused tricyclic
precursors (4 and 5) of these agonists are reported herein.
heterocycles and subsequent intramolecular SNAr reaction. We
envisioned coupling of the optically pure bicyclic sulfamidate 11
with a 3-metallo-2,4-dihalopyridine (12) to produce ring opened
sulfamic acid 13, which could be hydrolyzed in situ to the
cyclization precursor 14. Chemoselective intramolecular SNAr
substitution at the 2-position of pyridine 14 would yield the
desired tricycles (4 and 5). It is noteworthy that in contrast to o-
fluorophenone 10 which required a conjugated exocyclic ketone
to promote SNAr reaction, oxygenation at the benzylic position of
14 would not be required for cyclization. This is a key feature of
Scheme 1. Selective 5-HT2C agonists lorcaserin (1) and tricyclic
pyrazinonaphthyridines (2 and 3) with synthetic precursors 4 and 5.
———
 Corresponding author. Tel.: +1-858-401-0212; fax: +1-858-453-7210; e-mail: tschrader619@gmail.com

2
Tetrahedron
Table 1. Synthesis of (R)-8-benzyl-4-halo-6,6a,7,8,9,10-hexahydro-5H-
the proposed synthesis of 4 and 5, as the oxidation-reduction
pyrazino[1,2-a][1,8]naphthyridine (4) and (R)-3-benzyl-7-chloro-2,3,4,4a,5,6-
hexahydro-1H-pyrazino[1,2-a][1,6]naphthyridine (17).
sequence utilized in the previous route would be eliminated.
Entry
1
Nucleophilec
4 (% yield)d
17 (% yield)d
Additivee
-
2
3
4
5
6
7
-
-
-
-
Scheme 2. Previously reported stereoselective synthesis of (R)-3-benzyl-7-
bromo-2,3,4,4a,5,6-hexahydro-1H-pyrazino[1,2-a]quinoline (6) and proposed
synthesis of (R)-8-benzyl-4-halo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-
a][1,n]naphthyridines 4 and 5.
-
-
Synthesis of the requisite 6,6-bicyclic sulfamidate 11 is shown
in Scheme 3. The differentially protected piperazine alcohol 15
was prepared in 5 steps from commercially available Boc-
Asp(OBn)-OH (16) in 71% yield by optimization of a known
procedure.12 After Boc-deprotection, treatment with thionyl
chloride and DIEA in DCM gave the intermediate sulfamidite.
Oxidation to the sulfamidate was accomplished using catalytic
(0.5 mol %) ruthenium chloride and sodium periodate as the
stoichiometric oxidant which gave 11 in 38% yield (3 steps).
-
-
-
HMPA
HMPA
Scheme 3. Synthesis of bicyclic sulfamidate 11.
Investigations of the arylation of sulfamidate 11 with 2,4-
dihalo-3-metallopyridines is shown in Table 1. In an initial
experiment (entry 1) the lithium anion 12a (1.5 equiv), generated
by deprotonation of 2-bromo-4-chloropyridine13 with LiTMP at
-78 °C in THF, was treated with sulfamidate 11 (1.0 equiv) at
-78 °C and the reaction mixture was immediately warmed to 0 °C
and stirred for 1 h to generate the ring opened sulfamic acid
intermediate (13). Hydrolysis of the crude sulfamic acid (13)
was accomplished upon addition of 1N aq. HCl diluted with
MeOH and microwave heating at 60 °C for 2 h. Gratifyingly, the
tricyclic products 4a (39%) and 17a (26%) were generated under
the acidic conditions without the need for an additional
8
-
HMPA
aTypical reaction conditions for arylation step (0.3 – 2.0 mmol scale):
sulfamidate (1.0 equiv), 2,4-dihalo-3-metallopyridine (1.5 - 2.0 equiv), THF
(0.1 M). Reactions performed at -78 °C followed by immediate warming to 0
°C, stirring was continued while warming to rt over 18 h with the exception
of entries 1 and 5 which were stirred while warming to rt for 1 h and 2 h
respectively.
bHydrolysis conditions: 1 N aq. HCl /MeOH (1 : 1, 0.2M), 60 °C (microwave
irradiation), 2 h.
cAryllithiums 12a-c,e,f (entries 1-3, 5-7) were generated by deprotonation of
the corresponding 2,4-dihalopyridines with LiTMP at -78 °C.
Arylmagnesium reagent 12d (entries 4 and 8) was generated from 4-bromo-2-
fluoropyridine by treatment with TMPMgCl·LiCl at 0 °C.
dIsolated yields of product as a single isomer.
cyclization step. However, the observed chemoselectivity was
not optimal as there was only a slight preference for ring closure
at the pyridyl 2-position (4a : 17a = 1.5 : 1). To bias the system
to favor SNAr at the pyridyl 2-position
eFor reactions performed with additive, 5.0-5.5 equiv of HMPA was used.

3
we attempted arylation of 11 with aryllithium 12b, containing
a 2-fluoro substituent (entry 2). Although the reaction produced
solely the desired regioisomer (4b), the overall reaction
efficiency was poor (6%). A similar result was also observed
with the lithium anion (12c) generated from 4-bromo-2-
chloropyridine (entry 3). Arylation of 11 under conditions
reported by Moss et al.11 (entry 4) which involved a counterion
switch to the magnesium anion 12d (entry 4) was also
namely the Boc-protected 6,6,6 tricyclic (20) and 6,6,7-tricyclic
(21) systems shown in Scheme 5. Synthesis of Boc-sulfamidates
22 and 23 was performed using an optimized two step sequence
that involved treatment of amino alcohols 2416 and 2517 with
N,N′-sulfinylbisimidazole formed in situ, followed by oxidation
with wet silica gel-supported RuCl3/NaIO417 to furnish the
desired sulfamidates in satisfactory yields (85% for 22 and 51%
for 23). Arylation of the 6,6-bicyclic sulfamidate 22 with
aryllithium 12b successfully gave the ring opened intermediate
26. In order to prevent Boc-deprotection, hydrolysis of the
sulfamic acid and intramolecular SNAr reaction were
accomplished by heating the intermediate (26) in acetic acid and
water at 80 °C for 18 h to deliver the Boc-protected tricycle 20 in
41% yield. Similarly, the highly unique 6,6,7-tricyclic
compound 21 was prepared from 23, albeit in slightly reduced
yield (16%). The improved yield observed for the synthesis of
sulfamidate 22 (85%) and the compatibility of the Boc-protecting
group in the tandem arylation/intramolecular SNAr reaction
sequence suggests the utility of these methodologies can be
expanded and may warrant further exploration.
ineffective, affording only trace amounts of tricycle 4b.
Successful coupling of sulfamidate 11 with (2,4-dichloropyridin-
3-yl)lithium (12e, entry 5) was achieved, unfortunately the 2-
position chlorine atom did not significantly increase the
selectivity for product 4a over 17b (compare with entry 1). A
breakthrough was made when a literature search revealed
reactivities of certain lithium acetylides in the ring opening of
cyclic sulfamidates were improved when HMPA was used as a
cosolvent.14 Indeed, addition of HMPA (5.0 equiv) in the ring
opening of sulfamidate 11 with (4-bromo-2-fluoropyridin-3-
yl)lithium (12b) gave tricycle 4b exclusively in 66% isolated
yield (entry 6). A similar result was observed with anion 12f
which gave the desired chloro adduct 3a in 66% yield (entry 7).
This indicates that ring closure in these systems occurs
preferentially at the 2-fluoro position regardless of which
substituent (bromo or chloro) is in the 4-position. When the ring
opening of sulfamidate 11 with magnesium anion 12d was re-
examined with HMPA as cosolvent (entry 8), product 4b was
obtained in a slightly improved 23% overall yield (compare with
entry 4). This result suggested superior performance of
aryllithium 12b (versus 12d) toward ring opening of 11 but
incomplete metallation of 4-bromo-2-fluoropyridine could not be
ruled out.11 The diverse behavior of the various metallate species
(12a-f) and the role of HMPA in these reactions is intriguing.15
However, it was beyond the scope of this work to identify the
basis for these discoveries as the focus was to identify useful
synthons for our drug discovery program. Ultimately, the
reaction was performed on multi-gram scale to give sufficient
amounts of (R)-8-benzyl-4-bromo-6,6a,7,8,9,10-hexahydro-5H-
pyrazino[1,2-a][1,8]naphthyridine (4b), a key intermediate for
the preparation of a number of advanced preclinical selective 5-
HT2C agonists (2).
Scheme 5. Syntheses of the Boc-protected-6,6,6-tricycle 20 and Boc-
protected-6,6,7-tricycle 21.
In conclusion, the asymmetric syntheses of (R)-4-halo-
6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-a][1,n]naphthyridines
have been accomplished using a two-step procedure which
involved arylations of an optically pure bicyclic sulfamidates and
subsequent intramolecular SNAr reactions. This methodology
was useful for preparing important preclinical selective 5-HT2C
agonists. Structure activity relationships (SARs) and biological
activities of these unique tricyclic amines will be the subject of
future reports from these laboratories.
With optimized conditions established for the synthesis of
tricycle 4, the methodology was extended toward the synthesis of
(R)-8-benzyl-4-bromo-6,6a,7,8,9,10-hexahydro-5H-pyrazino[1,2-
a][1,7]naphthyridine (5), a synthon for the preparation of the
structurally isomeric series of 5-HT2C agonists (3). In this case,
sulfamidate 11 was coupled with (3-bromo-5-fluoropyridin-4-
yl)lithium (18) to generate free amine 19 after acidic quench of
the reaction mixture. The intramolecular SNAr reaction was
accomplished using DIEA in THF at reflux for 52 h to generate
tricycle 5 in 48% yield. No product that would have resulted
from ring closure on the less electrophilic carbon atom at the
3-bromo position (of 19) was obtained under these basic
conditions.
References and notes
1.
(a) Halford, J. C.; Harrold, J. A. Handb. Exp. Pharmacol. 2012,
349−356. (b) Burke, L. K.; Heisler, L. K. J. Neuroendocrinol.
2015, 27, 389-398.
2.
3.
Higgins, G. A.; Fletcher, P. J. ACS Chem. Neurosci. 2015, 6,
1071-1088.
(a) Mbaki, Y.; Ramage, A. G. Br. J. Pharmacol. 2008, 155, 343-
356. (b) Andrews, M. D.; Fish, P. V.; Blagg, J.; Brabham, T. K.;
Brennan, P. E.; Bridgeland, A.; Brown, A. D.; Bungay, P. J.;
Conlon, K. M.; Edmunds, N. J.; af Forselles, K.; Gibbons, C. P.;
Green, M. P.; Hanton, G.; Holbrook, M.; Jessiman, A. S.;
McIntosh, K.; McMurray, G.; Nichols, C. L.; Root, J. A.; Storer,
R. I.; Sutton, M. R.; Ward, R. V.; Westbrook, D.; Whitlock, G. A.
Bioorg. Med. Chem. Lett. 2011, 21, 2715−2720.
4.
5.
Giuliano, F. Trends Neurosci. 2007, 30, 79-84.
Di Giovanni, G.; De Deurwaerdere, P. Pharmacol.Ther. 2016,
157, 125-162.
Scheme 4. Synthesis of (R)-8-benzyl-4-bromo-6,6a,7,8,9,10-hexahydro-5H-
pyrazino[1,2-a][1,7]naphthyridine (5).
6.
7.
Halberstadt, A. L. Behav. Brain Res. 2015, 277, 99-120.
(a) Cheng, J.; Kozikowski, A. P. ChemMedChem 2015, 10, 1963-
1967. (b) Hutcheson, J. D.; Setola, V.; Roth, B. L.; Merryman, W.
D. Pharmacol.Ther. 2011, 132, 146-157.
The scope of the two step sulfamidate ring opening-
intramolecular SNAr reaction methodology was expanded to
include the preparation of other useful 5-HT2C agonist synthons,

4
Tetrahedron
8.
(a) www.belviq.com. (b) Smith, B. M.; Smith, J. M.; Tsai, J. H.;
Schultz, J. A.; Gilson, C. A.; Estrada, S. A.; Chen, R. R.; Park, D.
M.; Prieto, E. B.; Gallardo, C. S.; Sengupta, D.; Dosa, P. I.; Covel,
J. A.; Ren, A.; Webb, R. R.; Beeley, N. R. A.; Martin, M; Morgan,
M.; Espitia, S.; Saldana, H. R.; Bjenning, C.; Whelan, K. T.;
Grottick, A. J.; Menzaghi, F.e; Thomsen, W. J. J Med. Chem.
2008, 51, 305-313.
9.
Schrader, T. O.; Kasem, M.; Sun, Q.; Wu, C.; Ren, A.; Semple, G.
Tetrahedron Lett. 2016, 57, 4730-4733.
10. Schrader, T. O.; Kasem, M.; Ren, A.; Feichtinger, K.; Al Doori,
B.; Wei, J.; Wu, C.; Dang, H.; Le, M.; Gatlin, J.; Chase, K.; Dong,
J.; Whelan, K. T.; Sage, C.; Grottick, A. J.; and Semple, G.
Bioorg. Med. Chem. Lett. 2016, 26, 5877-5882.
11. Moss, T. A.; Hayter, B. R.; Hollingsworth, I. A.; Nowak, T.
Synlett 2012, 23, 2408-2412.
12. Ernst, G.; Frietze, W.; Jacobs, R.; Phillips, E. WO 2005061510,
2005. Alternatively, compound (R)-2-(4-benzylpiperazin-2-
yl)ethanol (des-Boc-15) could be prepared from H-N-Asp(OMe)-
OMe.HCl in three steps. See Supporting Information for details.
13. The ring opening of the cyclic sulfamidate tert-butyl 1,2,3-
oxathiazolidine-3-carboxylate 2,2-dioxide with (2-bromo-4-
chloropyridin-3-yl)lithium has been previously reported, see:
Behnke, D.; Carcache, D.; Ertl, P.; Koller, M.; Orain, D. WO
2014030128, 2014.
14. Eskici, M.; Karanfil, A.; Özer, M. S.; Sarikürkcü, C. Tetrahedron
Lett. 2011, 52, 6336-6341.
15. Reich, H. J. J. Org. Chem. 2012, 77, 5471-5491.
16. This compound was prepared in two steps from (R)-2-(4-
benzylpiperazin-2-yl)ethanol. See Supporting Information for
details.
17. This compound was prepared in two steps from (R)-2-(4-benzyl-
1,4-diazepan-2-yl)ethanol. See Supporting Information for
details. For the synthesis of (R)-2-(4-benzyl-1,4-diazepan-2-
yl)ethanol see ref. 10.
18. Röennholm, P.; Söedergren, M.; Hilmersson, G. Org. Lett. 2007,
9, 3781−3783.
Supplementary Material
Supplementary data (experimental procedures and compound
characterization data) associated with this article can be found, in
the online version, at: .

5
Highlights:
 Novel chiral tricyclic
tetrahydronaphthyridine-based tricyclic
amines are described
 Compounds are valuable synthetic
precursors to potent and selective 5-HT2C
agonists
 Ring opening of fused bicylic sulfamidate
with dihalopyridinyllithiums
 Chemoselective intramolecular SNAr
reaction