Alternative synthesis of the PDE5 inhibitor RWJ387273 (R290629)

Article abstract of DOI:10.1055/s-2007-970769

An alternative synthesis of a PDE5 inhibitor is reported using a highly diastereoselective Pictet-Spengler reaction. Georg Thieme Verlag Stuttgart.

Full text of DOI:10.1055/s-2007-970769

LETTER
709
Alternative Synthesis of the PDE5 Inhibitor RWJ387273 (R290629)
Synthesis of th
é
e
P
DE5 Inh
b
ibitor RWJ3
a
87273 (R2
s
90629) tien Lemaire,a Bert Willemsens,b István E. Markó*a
a
Université Catholique de Louvain, Unité de Chimie Organique et Médicinale, Place Louis Pasteur, 1, 1348 Louvain-la-Neuve, Belgium
Fax +32(10)472788; E-mail: marko@chim.ucl.ac.be
b
Chemical Process Research, Johnson & Johnson Pharmaceutical Research & Development, Turnhoutseweg 30, 2340 Beerse, Belgium
Received 22 November 2006
CO2Me
CO2Me
Abstract: An alternative synthesis of a PDE5 inhibitor is reported
using a highly diastereoselective Pictet–Spengler reaction.
Bn
N
Bn
N
ArCHO (2)
Key words: Pictet–Spengler reaction, b-tetrahydrocarboline oxida-
tion, Buchwald–Hartwig coupling, PDE5 inhibitor
H
i
Ar
N
N
H
H
Ar =
1
3
O
During the past few years, phosphodiesterase 5 (PDE5)
inhibitors have been the focus of interest due to their
ability to enhance penile erection.1 Indeed, the first market
introduction of a PDE5 inhibitor, Viagra® (sildenafil)2 has
been a worldwide commercial success. Recently, several
other products, Levitra® (vardenafil)3 and Cialis® (tadala-
fil),4 have been developed. Eventually, new chemical
entities, such as the pyrroloquinolones, have emerged as
potent and selective inhibitors of PDE5. Medicinal chem-
ists at Johnson & Johnson have identified RWJ387273 as
a potent and selective PDE5 inhibitor (Figure 1).5 In order
to provide sufficient quantities of this new compound for
clinical trials, a novel synthesis has been devised.6 In this
report, we present an alternative synthesis of the API
using a highly diastereoselective Pictet–Spengler reaction
as the key step.
Scheme 1 Reagents and conditions: (i) 10 mol% PTSA, toluene,
Dean–Stark, 22 h, 73%.
Based upon the work of Cox and Cook,9 it was decided to
use L-tryptophan derivatives as cheap sources of chiral
materials. Moreover, it was anticipated that Pictet–Spen-
gler cyclisation of 1 would give the desired trans product.
When the N-benzyl-L-tryptophan methyl ester (1) and a
stoichiometric amount of the aromatic aldehyde 2 are
refluxed in toluene in a Dean–Stark apparatus, in the
presence of a catalytic amount of PTSA (10 mol%), a
complete conversion to the b-tetrahydrocarboline 3 is
achieved after 22 hours. We were delighted to observe the
formation of the trans product 3 as a single diastereo-
isomer (as measured by NMR in the crude reaction
mixture).10,11,15 Crystallisation from t-BuOMe affords
pure product 3 in a 73% yield (Scheme 1).
O
N
In order to obtain the key b-tetrahydrocarboline 5, the
ester function of compound 3 has to be removed
(Scheme 2). Initially, it is converted into the cyano func-
tion in three steps: saponification of the methyl ester in
alkaline media affords the corresponding carboxylic acid
intermediate (not shown). Then, without purification, the
amide derivative is formed by treatment with ammonium
carbonate and EEDQ as coupling agent.12 Finally, treat-
ment of the primary amide with POCl313 leads to its dehy-
dration and to the formation of the cyano derivative 4 in
50% yield (over three steps and after crystallisation from
t-BuOMe).16 The cyano group is then substituted by a
hydride in an ethanol–pyridine mixture by treatment with
an excess of NaBH4.13,14,17 The (R)-b-tetrahydrocarboline
5 is isolated in 97% yield with an enantiomeric ratio (er)
of 95.7:4.3 as measured by chiral HPLC. The benzyl
group is removed by hydrogenolysis in the presence of
catalytic amounts of palladium on charcoal. At room
temperature, the debenzylated product 6 is isolated in
82% yield without loss of enantiomeric purity.18 How-
ever, when the hydrogenolysis is performed at 50 °C, the
er drops to 83.5:16.5 at complete conversion.
N
N
H
MeSO3H
O
RWJ387273
Figure 1 Potential PDE5 inhibitor
In the original route developed by the discovery chemists,
the b-tetrahydrocarboline 6 (Scheme 2) is obtained by a
racemic
Pictet–Spengler
condensation
between
tryptamine and the aromatic aldehyde 2. A chiral prepar-
ative liquid chromatography5 or a resolution by diastereo-
meric salt formation7 enabled the separation of the two
enantiomers from the racemic mixture. Asymmetric Pict-
et–Spengler reactions have been reported using a chiral
auxiliary linked to the nitrogen atom of the tryptamine.8
SYNLETT 2007, No. 5, pp 0709–0712
Advanced online publication: 08.03.2007
1
6.
0
3.
2
0
0
7
DOI: 10.1055/s-2007-970769; Art ID: D35406ST
© Georg Thieme Verlag Stuttgart · New York

710
S. Lemaire et al.
LETTER
CN
N
CO2Me
Bn
Bn
Bn
i–iii
N
v
iv
N
Ar
Ar
N
H
N
H
Ar
N
H
3
4
5
O
COCF3
N
NH
Ar
vi
vii
N
COCF3
N
H
Ar
N
H
N
H
O
Ar
6
7
8
Scheme 2 Reagents and conditions: (i) NaOH 15% w/w, MeOH–THF 1:1, 28 h, r.t.; (ii) (NH4)2CO3, EEDQ, CH2Cl2, 16 h, r.t.; (iii) POCl3,
DMF, 2 h, 0 °C, 50% from 3; (iv) 2 × 5 equiv NaBH4, pyridine–EtOH 1:2, 24 h, 70 °C, 97%; (v) H2 (3 atm.), 5% w/w Pd/C 10%; cat. HCl,
MeOH, r.t., 82%; (vi) 1.1 equiv (CF3CO)2, Et3N, 1 h, 0 °C, >95%; (vii) acetone, oxone®, NaHCO3, 0 °C then MCPBA, 60%.
O
O
The oxidation of the b-tetrahydrocarboline 6 into 9 has
already been described using potassium superoxide.7
However, we have recently reported on the hazardous
behaviour of this oxidation especially on large scale.6 The
oxidation of trifluoroacetamide 719 by dimethyldioxirane,
generated in situ, followed by addition of MCPBA leads
to compound 8 in 60% yield in a safe and scalable
manner.20
i
N
COCF3
NH
Ar
N
H
N
H
O
Ar
8
9
O
N
ii, iii
N
N
H
Treatment of the nine-membered heterocycle 8 with two
equivalents of KOH in ethanol affords the N-deprotected
pyrroloquinolone 9 in 90% yield (Scheme 3).21 At that
stage, compound 9 could be enantioselectively enriched to
>99.5:0.5 either by chiral preparative HPLC or by enanti-
oselective crystallisation of the HCl salt.22 Finally the de-
sired PDE5 inhibitor RWJ387273 is obtained in 90%
yield by the coupling of the secondary amine 9 with 2-bro-
mopyridine under palladium catalysis in THF at 60 °C.23
The temperature range for the coupling is relatively small:
(1) in refluxing THF or in higher boiling solvent such as
1,4-dioxane, epimerisation of the stereogenic centre is ob-
served; (2) below ca. 45 °C, the conversion is slow due to
the poor solubility of the starting material. Crystallisation
of the methanesulfonate salt of RWJ387273 from metha-
nol leads to final API in >99.5:0.5 er24 and 80.5% yield.
MeSO3H
O
RWJ387273
er > 99.5:0.5
Scheme 3 Reagents and conditions: (i) 2 equiv KOH, EtOH, 16 h,
r.t., 90%; (ii) 2-bromopyridine, t-BuONa, Pd(dba)2, BINAP, THF,
60 °C, 9 h, 90%; (iii) MeSO3H, MeOH, 20 °C, 20 h, 80.5%.
M.; Coste, H.; Kirilovsky, J.; Linget, J.-M.; Hyafil, F.;
Labaudiniere, R. J. Med. Chem. 2003, 46, 4533.
(5) (a) Jiang, W.; Alford, V.; Qiu, Y.; Bhattacharjee, S.; John, Y.
M.; Haynes-Johnson, D.; Kraft, P. J.; Lundeen, S. G.; Sui, Z.
Bioorg. Med. Chem. 2004, 12, 1505. (b) Lanter, J.; Sui, Z.;
Macielag, M. J.; Fiordeliso, J.; Jiang, W.; Qiu, Y.;
Bhattacharjee, S.; Kraft, P.; John, T. M.; Haynes-Johnson,
D.; Craig, E.; Clancy, J. J. Med. Chem. 2004, 47, 656.
(c) Jiang, W.; Sui, Z. WO 2004000842, 2003. (d) Qiu, Y.;
Bhattacharjee, S.; Kraft, P.; John, T. M.; Craig, E.; Haynes-
Johnson, D.; Guan, J.; Jiang, W.; Macielag, M.; Sui, Z.;
Clancy, J.; Lundeen, S. Eur. J. Pharmacol. 2003, 472, 73.
(e) Jiang, W.; Sui, Z. WO 2003042213, 2003. (f) Jiang, W.;
Sui, Z.; Macielag, M.; Walsh, S. P.; Fiordeliso, J. J.; Lanter,
J. C.; Guan, J.; Qiu, Y.; Kraft, P.; Bhattacharjee, S.; Craig,
E.; Haynes-Johnson, D.; John, T. M.; Clancy, J. J. Med.
Chem. 2003, 46, 441. (g) Jiang, W.; Sui, Z.; Chen, X. Org.
Lett. 2003, 5, 43. (h) Jiang, W.; Sui, Z.; Chen, X.
Tetrahedron Lett. 2002, 43, 8941. (i) Sui, Z.; Guan, J.;
Macielag, M.; Jiang, W.; Zhang, S.; Qiu, Y.; Kraft, P.;
Bhattacharjee, S.; John, T. M.; Hyanes-Johnson, D.; Clancy,
J. J. Med. Chem. 2002, 456, 4094. (j) Sui, Z.; Macielag, M.;
Guan, J.; Jiang, W.; Lanter, J. C. WO 2001087882, 2001.
(k) Jiang, W.; Guan, J.; Macielag, J. M.; Zhang, S.; Qiu, Y.;
Kraft, P.; Bhattacharjee, S.; John, T. M.; Haynes-Johnson,
D.; Lundeen, S.; Sui, Z. J. Med. Chem. 2005, 48, 2126.
In conclusion, we have developed a scalable, safe and
highly enantioselective synthesis of RWJ387273 based
upon a diastereoselective Pictet–Spengler reaction start-
ing from a cheap amino acid derivative. The synthesis
consists of a 12-step sequence and delivers the final
product with an enantiomeric ratio of >99.5:0.5.
References and Notes
(1) Corbin, J. D.; Francis, S. H. J. Biol. Chem. 1999, 274, 13729.
(2) For Viagra®(sildenafil), see: Brook, G. Drugs Today 2000,
26, 125.
(3) For Levitra®(vardenafil), see: Sorbera, L. A.; Martin, L.;
Rabasseda, X.; Castaner, J. Drugs Future 2001, 26, 141.
(4) (a) For Cialis®(tadalafil), see: Sorbera, L. A.; Martin, L.;
Leeson, P. A.; Castaner, J. Drugs Future 2001, 26, 15.
(b) For discovery of tadalafil, see: Daugan, A.; Grondin, P.;
Ruault, C.; Gouville, A.-C. L. M.; Coste, H.; Kirilovsky, J.;
Hyafil, F.; Labaudinière, R. J. Med. Chem. 2003, 46, 4525.
(c) Daugan, A.; Grondin, P.; Ruault, C.; Gouville, A.-C. L.
Synlett 2007, No. 5, 709–712 © Thieme Stuttgart · New York

LETTER
Synthesis of the PDE5 Inhibitor RWJ387273 (R290629)
711
(6) (a) Willemsens, B.; Vervest, I.; Ormerod, D.; Aelterman,
W.; Fannes, C.; Mertens, N.; Markó, I. E.; Lemaire, S. Org.
Process Res. Dev. 2006, 10, 1275. (b) Li, X.; Lemaire, S.;
Markó, I.; Willemsens, B. WO 2006093719, 2006.
(7) Li, X.; Branum, S.; Russel, R. K.; Jiang, W.; Sui, Z. Org.
Process Res. Dev. 2005, 9, 640.
solvent was evaporated under reduced pressure. 1H NMR
(200 MHz, CDCl3): d = 7.72–7.64 (m, 2 H), 7.40–7.15 (m, 8
H), 6.90–6.64 (m, 4 H), 5.60 (br s, 1 H), 4.90 (s, 1 H), 4.52
(t, 2 H, J = 9 Hz), 3.90 (m, 1 H), 3.88 (AB, 1 H, J = 4 Hz),
3.66 (AB, 1 H, J = 4 Hz), 3.15 (m, 2 H), 3.07 (t, 2 H, J = 9
Hz). The obtained primary amide (1 equiv) was dissolved in
dry DMF (10 L/mol) at 0 °C. After addition of pyridine (0.7
L/mol), POCl3 (1.2 equiv) was added dropwise to the
reaction mixture. After a 2 h stirring period at 0 °C, the
reaction mixture was quenched with a CuSO4 aq solution
and extracted with CH2Cl2. After evaporation of the organic
solvent, the obtained solid was purified by crystallization
from t-BuOMe to afford compound 4 in 50% yield. 1H NMR
(200 MHz, CDCl3): d = 7.62–7.58 (m, 1 H), 7.47–7.16 (m,
11 H), 6.84 (d, 1 H, J = 11 Hz), 4.96 (s, 1 H), 4.76 (t, 2 H,
J = 11 Hz), 4.19 (AB, 1 H, J = 18 Hz), 3.60 (AB, 1 H, J = 18
Hz), 3.46–3.20 (m, 2 H). 13C NMR (50 MHz, CDCl3): d =
160.4, 137.4, 136.4, 134.3, 131.4, 129.0, 128.6, 128.5, 128.1,
127.7, 126.6, 125.3, 121.9, 119.5, 118.1, 117.2, 110.9,
109.3, 104.8, 71.4, 61.9, 55.4, 48.4, 29.4,25.5. IR: 3388,
2848, 2219, 1612, 1489, 1467, 1453, 1302, 1234 cm–1.
MS (EI, 70 eV): m/z = 404.4, 260.1, 233.1, 169.1, 91.5.
(17) Procedure for Compound 5 (1.23 mmol scale).
Compound 4 (1 equiv) was dissolved in EtOH–pyridine (5
L/mol, 2:1) at r.t. Then, NaBH4 (5 equiv) was added and the
reaction mixture was heated to 70 °C for 12 h. A second
portion of NaBH4 (5 equiv) was added and the reaction
mixture was stirred for additional 12 h at 70 °C. After
completion, aq NH4Cl (5 L/mol) and CH2Cl2 (5 L/mol) were
added. The organic layers were separated and the organic
solvent was evaporated under reduced pressure to afford
compound 5 in 97% yield; er 95.7:4.3. 1H NMR (200 MHz,
CDCl3): d = 7.56–7.03 (m, 11 H), 6.81 (d, 1 H, J = 8 Hz),
4.64 (t, 3 H, J = 9 Hz), 3.92 (AB, 1 H, J = 14 Hz), 3.42 (AB,
1 H, J = 14 Hz), 3.35–3.19 (m, 3 H), 3.00–2.61 (m, 3 H). MS
(EI, 70 eV): m/z = 380.1, 355.1, 261.2, 260.1, 184.1, 91.0,
73.1. IR: 3406, 1614, 1488, 1307, 1241, 981 cm–1.
(8) Jiang, W.; Sui, Z.; Chen, X. Tetrahedron Lett. 2002, 43,
8941.
(9) Cox, E. D.; Cook, J. M. Chem. Rev. 1995, 95, 1797.
(10) To confirm the stereochemistry of compound 3, the two
diastereoisomers trans-3 and cis-3 were prepared in a two-
step sequence. Treatment of unprotected L-tryptophan
methyl ester with aldehyde 2 leads to the quantitative
formation of the corresponding carbolines in a 45:55
cis:trans ratio. An NMR study allowed the identification of
both diastereoisomers without ambiguity. After separation
by chromatography, each isomer was benzylated leading to
pure compounds cis-3 and trans-3 used as references to
assess the trans stereochemistry of compound 3 obtained
from tryptophan derivative 1.
(11) For the attribution of the cis:trans ratio, see: (a) Ungemach,
F.; Soerens, D.; Weber, R.; DiPierro, M.; Campos, O.;
Mokry, P.; Cook, J. M.; Silverton, J. V. J. Am. Chem. Soc.
1980, 102, 6976. (b) Bailey, P. D.; Hollinshead, S. P.;
McLay, N. R. Tetrahedron Lett. 1987, 5177.
(12) (a) Josse, O.; Labar, D.; Marchand-Brynaert, J. Synthesis
1999, 404. (b) For the mechanism: Belleau, B.; Martel, R.;
Lacasse, G.; Menard, M.; Weinberg, N. L.; Perron, Y. G. J.
Am. Chem. Soc. 1968, 823. (c) Belleau, B.; Malek, G. J. Am.
Chem. Soc. 1968, 1651.
(13) Peng, S.; Guo, M.; Winterfeldt, E. Liebigs Ann. Chem. 1993,
137.
(14) Peng, S.; Zhang, L.; Cai, M.; Winterfeldt, E. Liebigs Ann.
Chem. 1993, 141.
(15) Procedure for Compound 3 (65 mmol scale).
In a round-bottomed flask charged with toluene (6 L/mol),
N-benzyl-L-tryptophan methyl ester (1 equiv) and the
aromatic aldehyde 2 (1.05 equiv) were added at r.t. Finally,
PTSA (0.1 equiv) was added and the reaction mixture was
refluxed in a Dean–Stark apparatus for 22 h. After cooling to
r.t., sat. aq NaHCO3 (0.2 L/mol) was added. After 15 min of
stirring and then separation of the two phases, the organic
solvent was evaporated under vacuum. The obtained crude
product was purified by crystallisation from t-BuOMe (3 L/
mol) to afford compound 3 in 73% yield. 1H NMR (300
MHz, CDCl3): d = 7.51–7.07 (m, 12 H), 6.72 (d, 1 H, J = 8
Hz), 5.39 (s, 1 H), 4.53 (t, 2 H, J = 9 Hz), 3.94 (m, 1 H), 3.80
(m, 2 H), 3.61 (s, 3 H), 3.19 (m, 2 H), 3.13 (t, 2 Hz, J = 9 Hz).
13C NMR (75 MHz, CDCl3): d = 173.7, 160.0, 139.7, 136.5,
135.6, 134.0, 128.9, 128.5, 128.3, 127.7, 127.1, 127.0, 125.3,
121.5, 119.3, 118.2, 110.8, 108.9, 71.4, 60.4, 56.1, 54.2,
51.3, 29.6, 24.5. IR: 3388, 1732, 1601, 1488, 1451 cm–1.
MS (EI, 70eV): m/z = 438.3, 379.4, 347.1, 184.2.
(16) Procedure for Compound 4 (46 mmol scale).
Compound 3 (1 equiv) was dissolved in MeOH–THF (6 L/
mol; 1:1) at r.t. Then, aq NaOH (3 L/mol, 15% w/w) was
added in one portion. After 28 h of stirring at r.t., the organic
mixture was acidified to pH 6–7 and extracted by CH2Cl2 (5
L/mol). 1H NMR (300 MHz, CDCl3): d = 8.20 (br s, 1 H),
7.60 (s, 1 H), 7.43 (d, 1 H, J = 8 Hz), 7.21–6.94 (m, 10 H),
6.58 (d, 1 H, J = 14 Hz), 5.22 (s, 1 H), 4.40 (t, 2 H, J = 9 Hz),
3.88 (m, 1 H), 3.85 (AB, 1 H, J = 14 Hz), 3.74 (AB, 1 H,
J = 14 Hz), 3.13 (d, 2 H, J = 5 Hz), 3.00 (t, 2 H, J = 9 Hz).
Then, at r.t., (NH4)2CO3 (3 equiv) and EEDQ (1.1 equiv)
were added to the CH2Cl2 phase. After a 16 h stirring period,
the organic phase was filtered over dicalite. Then the organic
layer was washed with H2O (3 L/mol) and the organic
(18) Procedure for Compound 6 (2.95 mmol scale).
See ref. 5f and 6b: 1H NMR (200 MHz, CDCl3): d = 7.63–
7.52 (m, 2 H), 7.25–7.02 (m, 5 Hz), 6.73 (d, 1 H, J = 8 Hz),
5.08 (s, 1 H), 4.55 (t, 2 H, J = 8 Hz), 3.35 (m, 1 H), 3.12 (t,
2 H, J = 8 Hz), 3.08 (m, 1 H), 2.85 (m, 2 H), 1.80 (s, 1 H).
(19) Procedure for Compound 7 (69 mmol scale).
Compound 6 (1 equiv) was partially dissolved in CH2Cl2 (5
L/mol) at r.t. After cooling at 0 °C, Et3N (1.5 equiv) was
added followed by the dropwise addition over 10 min of
(CF3CO)O (1.2 equiv) in CH2Cl2 (1 L/mol). After a 0.5 h
stirring period, the reaction mixture was quenched with sat.
NaHCO3. The organic layer was evaporated under reduced
pressure to afford compound 7 in >95% yield.1H NMR (300
MHz, CDCl3): d = 7.90 (br s, 1 H), 7.54 (d, 1 H, J = 7 Hz),
7.32–7.02 (m, 5 H), 6.82 (s, 1 H), 6.69 (d, 1 H, J = 8 Hz),
4.55 (t, 2 H, J = 9 Hz), 4.08 (m, 1 H), 3.55 (m, 1 H), 3.13 (t,
2 H, J = 9 Hz), 2.98 (m, 2 H). 13C NMR (150 MHz, CDCl3):
d = 160.5, 136.3, 130.4, 130.3, 128.9, 127.8, 126.2, 125.6,
122.5, 119.9, 118.2, 111.2, 109.4, 109.2, 71.5, 53.6, 45.9,
29.4, 22.2. 19F NMR (300 MHz, CDCl3): d = –68.64.
(20) Procedure for Compound 8 (44 mmol scale).
Confer ref. 6a, mixture of tautomers: 1H NMR (600 MHz,
DMSO-d6): d = 10.94 (s, 1 H, 90%), 10.68 (s, 1 H, 10%),
7.62 (m, 1 H), 7.43 (m, 2 H), 7.30 (m, 1 H), 7.06 (s, 1 H),
6.89 (d, 1 H, J = 8 Hz), 6.73 (m, 1 H), 6.13 (s, 1 H, 90%),
6.02 (s, 1 H, 10%), 4.51 (t, 2 H, J = 9 Hz), 4.42 (m, 1 H), 3.55
(m, 1 H), 3.16 (m, 2 H), 3.02 (m, 1 H), 2.93 (m, 1 H). 13
C
NMR (150 MHz, DMSO-d6): d = 202.2, 168.4, 159.5, 137.9,
136.4, 132.5, 128.0, 127.6, 127.0, 126.7, 126.3, 125.4,
123.9, 108.6, 71.2, 61.8, 44.0, 43.3, 39.8, 39.6, 39.3, 3.09,
29.1.
Synlett 2007, No. 5, 709–712 © Thieme Stuttgart · New York

712
S. Lemaire et al.
LETTER
another 15 min. The two layers were separated and the
(21) Procedure for Compound 9 (12 mmol scale).
Compound 8 (1 equiv) was dissolved in EtOH (10 L/mol) at
r.t. Then, KOH (2 equiv) dissolved in H2O was added to the
reaction mixture. After a 16 h stirring period at r.t., sat.
NH4Cl was added and the reaction mixture was extracted
with EtOAc. The evaporation of the organic layer under
reduced pressure afforded compound 9 in 90% yield. 1H
NMR (400 MHz, DMSO): d = 11.58 (s, 1 H), 8.13 (d, 1 H,
J = 7.81 Hz), 7.61–7.53 (m, 2 H), 7.29 (ddd, 1 H, J = 8.12,
5.85, 2.14 Hz), 7.17 (s, 1 H), 7.07 (dd, 1 H, J = 8.31, 1.76
Hz), 6.73 (d, 1 H, J = 8.31 Hz), 5.38 (br s, 1 H), 4.50 (t, 2 H,
J = 9.06 Hz), 4.18 (dd, 1 H, J = 12.97, 2.90 Hz), 4.02 (dd, 1
H, J = 12.97, 1.38 Hz), 3.60 (br s, 1 H), 3.13 (t, 2 H, J = 8.69
Hz). 13C NMR (100 MHz, DMSO): d = 173.5, 159.3, 153.9,
140.7, 134.5, 131.0, 127.6, 127.4, 125.2, 124.7, 124.3,
122.7, 118.4, 118.0, 108.6, 71.0, 66.3, 48.9, 29.0.
organic layer was discarded. Then, EtOAc (5.4 L/mol) was
added to the aqueous layer, followed by the addition of aq
NH3 50% w/w (0.26 L/mol). After stirring for 30 min, the
aqueous layer was removed and the organic phase was
evaporated to dryness. The desired pyrroloquinolone 2
(yield = 135%) was obtained with a quality of 66.1%,
corresponding to an active yield of 89.2%. The ee of the
R-enantiomer was 99%. The product contained 2530 ppm of
residual Pd.
The obtained pyrroloquinolone was dissolved in MeOH (80
L/mol) at r.t. After heating to 60 °C, the mixture was stirred
for 1 h at this temperature. Then, Norit A Supra (35 g/mol)
and dicalite (3.5 g/mol) were added. The mixture was stirred
for another 20 min and thereafter filtered. The cake was
washed with MeOH (1.7 L/mol). The solvent was reduced to
10%, at 50 °C. Subsequently, MsOH (1.02 equiv), dissolved
in MeOH (0.3 L/mol) was added over 10 min to the mixture.
Finally, the solution was cooled down to 20 °C and stirred
for 20 h. The mixture was filtered and the cake was washed
with MeOH (0.5 L/mol). After drying for 45 h, R290629
were obtained (yield 80.5%) with a HPLC quality of 100%
and >99.5:0.5 er. The amount of residual Pd was below 10
ppm.
(22) Enantioselective Enrichment of Compound 9 (33.35 mol
scale).
Compound 9 (1 equiv) was dissolved in H2O (2 L/mol) at r.t.
Then, aq HCl 34.5% w/w (0.09 L/mol) was dropwise added
to the heterogeneous mixture. Afterwards, the reaction
mixture was heated at 60 °C and 2-PrOH (0.54 L/mol) was
added dropwise. After 30 min, the reaction mixture was
cooled down to r.t. and stirred overnight. The reaction
mixture was filtered and dried under reduced pressure. The
obtained HCl salt was dissolved in EtOH (4 L/mol) at r.t. and
aq NH3 50.5% w/w (0.1 L/mol) was added dropwise. After
addition of H2O (2 L/mol) and seeding with compound 9, the
reaction mixture was stirred for 16 h at r.t. The desired
compound 9 was obtained by filtration with an er >99.5:0.5
in 59% yield.
Free base: 1H NMR (400 MHz, CD3OD): d = 8.30 (d, 1 H,
J = 9.3 Hz), 8.02 (m, 1 H), 7.35 (m, 4 H), 7.10 (m, 3 H), 6.55
(m, 2 H), 4.85 (d, 1 H, J = 22.0 Hz), 4.54 (d, 1 H, J = 22.0
Hz), 4.40 (t, 2 H, J = 9.5 Hz), 2.92 (t, 2 H, J = 9.5 Hz).
(24) Analytical Method.
The progress of the reaction and the purity of the products
were measured by HPLC, employing (Method A: LCC01/
209/01/01) a 10 cm Hypersil BDS column (4.0 mm I.D., 3
mm spherical material, UV wavelength of 254 nm) at r.t. The
elution gradient was 5% MeCN/95% NH4OAc (0.5% in
H2O) ramping to 95% MeCN/5% NH4OAc (0.5% in H2O)
over 16 min, at a flow rate of 1.2 mL/min, then kept 95%
MeCN/5% NH4OAc (0.5% in H2O) for 3 min. Optical
purities were measured by Capillary Electrophoresis
employing (Method B: CEO 01/211/01/01) a 57 cm
uncoated fused silica column (75 mm I.D., 375 mm O.D., UV
wavelength of 200 nm) at 20 °C. The mobile phase consisted
of a 50 mM phosphate buffer, at pH 3.0; the chiral selector
of 10 mM DM-b-CD. Each run lasted 30 min.
(23) Procedure for RWJ387273 (2.5 mol scale).
In degassed THF (10 L/mol) under inert atmosphere,
Pd2(dba)3 (0.04 equiv) was added followed by the addition
of ( )-BINAP (0.09 equiv) at r.t. After stirring for 30 min, 2-
bromopyridine (1.2 equiv) was added over 10 min. Finally,
pyrroloquinolone 1 (1 equiv) and t-BuONa (2.5 equiv) were
added and the mixture was allowed to warm up to 60 °C and
kept at that temperature for 5 h. After cooling to r.t., dicalite
(20 g/mol) was added and the mixture was filtered. The cake
was washed with THF (2 L/mol). Then, H2O (8 L/mol) was
added to the organic mixture, followed by aq HCl 34.5%
w/w (0.275 L/mol). After stirring for 30 min at r.t., EtOAc
(4.3 L/mol) was added and the mixture was stirred for
Synlett 2007, No. 5, 709–712 © Thieme Stuttgart · New York

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