Practical syntheses of (2S)-R207910 and (2R)-R207910

Article abstract of DOI:10.1002/ejoc.201001720

Concise and practical syntheses of (2S)-R207910 (3a) and (2R)-R207910 (3b) have been achieved in high overall yield of 12 % in 10 steps for each isomer starting from a known intermediate following Sharpless asymmetric epoxidation, regioselective epoxide opening, modified allylzinc bromide addition as key reactions. Copyright

Full text of DOI:10.1002/ejoc.201001720

FULL PAPER
DOI: 10.1002/ejoc.201001720
Practical Syntheses of (2S)-R207910 and (2R)-R207910
Srivari Chandrasekhar,*[a] G. S. Kiran Babu,[a] and Debendra K. Mohapatra[a]
Keywords: Medicinal chemistry / Tuberculosis / Total synthesis / Asymmetric synthesis / Epoxidation
Concise and practical syntheses of (2S)-R207910 (3a) and
(2R)-R207910 (3b) have been achieved in high overall yield
of 12% in 10 steps for each isomer starting from a known
intermediate following Sharpless asymmetric epoxidation,
regioselective epoxide opening, modified allylzinc bromide
addition as key reactions.
of M. tuberculosis but not on other bacterial ATP systems,
which explains its high specificity for mycobacteria.[13–15] In
the mouse model, 2-month treatment regimes containing
R207910 and PZA led to sterilization, which shows the po-
tential for reduction of treatment time to two months.[16]
Introduction
Tuberculosis (TB) is a deadly infectious disease caused
by Mycobacterium tuberculosis. It is primarily an infirmity
of the respiratory system and is spread through air via co-
ughing and sneezing of the infected person. In conjunction
with the spread of HIV infection,[1] tuberculosis is today
amongst the worldwide health intimidations.[2–8] As a result,
TB has become a major health and socioeconomic problem
in most of the countries. Currently, a major problem in TB
treatment is the development of multidrug-resistant tuber-
culosis strains (MDR-TB), which can be defined as strains
that show resistance towards at least isoniazid (1)[9] and ri-
fampicin (2),[10] two important first-line drugs used in TB
treatment. Another serious problem, in the context of
MDR-TB, is the emergence of extensively drug-resistant tu-
berculosis (XDR-TB), which are strains resistant to first-
and second-line anti-TB drugs.[11]
In this context, a search for new entities led to the quin-
oline nucleus, which constitutes an important class of
heterocyclic compounds found in many synthetic and natu-
ral products with a wide variety of important pharmacolog-
ical activities. R207910 (TMC 207) (Figure 1) is one such
compound structurally dissimilar to isoniazid and rifampi-
cin and consisting of diarylquinoline scaffold. This com-
pound was developed at Johnson & Johnson Pharmaceuti-
cal Research and Development,[12] and possess a new
mechanism of action based on the interaction with the en-
zyme adenosine triphosphate (ATP) synthase. It is active
against both drug-resistant and drug-susceptible M. tuber-
culosis, as well as other mycobacterial species. It has a rela-
tively longer half life in plasma and tissues, of nearly 24 h.
The compound stops the energy production by acting on
the proton pump of adenosine triphosphate (ATP) synthase
Figure 1. Structures of isoniazid (1), rifampicin (2), (2S)-R207910
(3a) and (2R)-R207910 (3b).
It’s fascinating biological activity interested us to develop
an asymmetric and practical synthesis of R207910. There is
no asymmetric synthesis reported on R207910 except a re-
cent publication by Shibasaki et al. which appeared during
the completion of our work.[17] Herein, we report an ef-
ficient synthesis of (2S)-R207910 (3a) and (2R)-R207910
(3b) in 10 linear steps starting from a known compound
with 12% overall yield for each.
[a] Organic Chemistry Division-I, Indian Institute of Chemical
Technology, CSIR,
Hyderabad 500607, India
Fax: +91-40-27160512
According to our retrosynthetic analysis, 3a could be ob-
tained from 4a in two steps (Scheme 1). The stereocenter at
the tetrasubstituted C atom was introduced by chelation-
E-mail: srivaric@iict.res.in
Supporting information for this article is available on the
WWW under http://dx.doi.org/10.1002/ejoc.201001720.
Eur. J. Org. Chem. 2011, 2057–2061
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
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S. Chandrasekhar, G. S. K. Babu, D. K. Mohapatra
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controlled Barbier-type reaction. The enantiomerically en- Reduction of compound 9 with DIBAL-H at 0 °C furnished
riched ketone 6 could be obtained by Sharpless epoxidation allyl alcohol 10. Reaction of 10 with sodium methoxide
followed by ring opening with PhMgBr.
gave 2-methoxy derivative 11.[19]
The next operation was the Sharpless asymmetric epox-
idation[20] which was carried out with (+)-DIPT, Ti(OiPr)4,
TBHP at –20 °C to afford epoxy alcohol 7 in 86% yield
(95% ee). Subsequent exposure of the epoxide to PhMgBr
in the presence of CuCN furnished diol 12 in 86% yield.[21]
Diol 12 was oxidatively cleaved with NaIO4 impregnated
over silica gel[22] to furnish aldehyde 13. The crude aldehyde
was treated with 1-naphthylmagnesium bromide[23] to ob-
tain secondary alcohol 14 as a mixture of isomers which
on oxidation with Dess–Martin periodinane[24] afforded the
keto derivative 6 in 81% yield with high enantiomeric pu-
rity (95% ee). Our next concern was to construct the tetra-
substituted carbon center through allylation of carbonyl
group present in 6. In accordance with Shibasaki et al. ob-
servation, our attempts to introduce the tetrasubstituted
carbon through conventional nucleophiles like allylmagne-
sium, allylaluminium, allylindium, allylboronate, and allyl-
stannane derivatives were not successful. In all the attempts,
the starting material was recovered from the reaction mix-
ture. A recent development of solvent free addition reaction
of allylzinc bromide to carbonyl compound developed by
Wang et al. attracted our attention in this regard.[25] Thus,
addition of allylzinc bromide by a modified protocol, in
which compound 6 in THF was added to allylzinc bromide
to afford the required homoallyl alcohol 5a and 5b as an
inseparable mixture in 2:3 ratio in favor of unwanted dia-
stereomer (Scheme 3). To improve the ratio towards the de-
sired isomer, different chelating agents like CuBr, CuCN,
CuI, CuBr·Me2S were tried. Only in the case of CuBr·Me2S,
Scheme 1. Retrosynthetic analysis of (2S)-R207910 (3).
Results and Discussion
The synthesis commenced with a known intermediate 6-
bromo-2-chloroquinoline-3-carbaldehyde 8,[18a] prepared
from 4-bromo-acetanilide following Vilsmeier–Haack
modified protocol (Scheme 2). It was subjected to Horner–
Wadsworth–Emmons olefination using lithium enolate of
the phosphonate [(OEt)2P(O)CH2CO2Et] to afford α,β-un-
saturated ester 9 in 89% yield with complete E-selectivity.
Scheme 2. Reagents and conditions: (a) (EtO)2P(O)CH2CO2Et,
LiHMDS, THF, 0 °C to room temp., 2 h, 89%; (b) DIBAL-H,
CH2Cl2, 0 °C to room temp., 2 h, 84%; (c) NaOMe, MeOH, reflux,
8 h, 92%; (d) (+)-DIPT, Ti(OiPr)4, TBHP, CH2Cl2, –20 °C, 4 h,
86%; (e) PhMgBr, CuCN, THF, –40 °C, 4 h, 86%. LiHMDS = lith-
ium hexamethyldisilazide, THF = tetrahydrofuran, DIBAL = diiso-
butylaluminum hydride, DIPT = diisopropyl tartrate, TBHP = tert-
butyl hydroperoxide.
Scheme 3. Reagents and conditions: (a) NaIO4, CH2Cl2, 0 °C to
room temp., 1 h, 98%; (b) 1-naphthylmagnesium bromide, Et2O,
0 °C, 1 h, 92%; (c) DMP, CH2Cl2, 3 h, 87%; (d) allylzinc bromide,
neat, room temp., 1 h, 90%. DMP: Dess–Martin periodinane.
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Practical Syntheses of (2S)-R207910 and (2R)-R207910
the ratio changed to almost equal amounts of diastereomers first in this area. There is no report till date of creating
(by HPLC).
crowded asymmetric centers using Sharpless asymmetric
Having 5a and 5b in hand, the next task was to achieve epoxidation strategy. Furthermore, our protocol has great
chromatographic separation of the mixture obtained from potential for the generation of R207910 analogues. The pro-
further reactions of 5a and 5b which was not practical at cess described herein is in the (unpatented) public domain
this stage. Thus, we proceeded further without separation and can be utilized for bulk scale production.
of diastereomers.
Oxidative cleavage[26] of olefin using OsO4/NaIO4 in
presence of 2,6-lutidine afforded aldehyde 15a and 15b. The
Experimental Section
General Remarks: Air- and/or moisture-sensitive reactions were car-
ried out in anhydrous solvents under an atmosphere of argon in an
oven or flame-dried glassware. All anhydrous solvents were distilled
prior to use: THF, benzene, toluene and diethyl ether from Na and
benzophenone; CH2Cl2, quinoline, Et3N from CaH2; MeOH, EtOH
from Mg cake. Commercial reagents were used without purification.
Column chromatography was carried out by using silica gel (60–
120 mesh). Specific optical rotations [α]D are given in 10–1
deg cm2g–1. Infrared spectra were recorded in CHCl3/neat (as men-
tioned) and reported in wave number (cm–1). 1H and 13C NMR
mixture of aldehydes was treated with NaBH4 in methanol
at 0 °C to obtain the diol 4a and 4b in 82% yield over two
steps. Finally, O-mesylation followed by displacement of the
mesylate group in 16a and 16b with dimethylamine fur-
nished (2S)-R207910 (3a) and (2R)-R207910 (3b) in 79%
yield over two steps (Scheme 4).[27] The products were sepa-
rated easily by silica gel column chromatography (ethyl
acetate:hexane = 1:6). The spectral and analytical data of
3a [α]2D5 = –165.2 (c = 0.8, DMF); ref.[12] [α]2D5 = –166.98 (c
= 0.5, DMF) was in good agreement with the reported chemical shifts are reported in ppm downfield from tetramethylsilane
(TMS) and coupling constants (J) are repo rted in Hertz [Hz]. The
following abbreviations are used to designate signal multiplicity: s
singlet, d doublet, t triplet, q quartet, m multiplet, br. broad.
data.
Ethyl (E)-3-(6-Bromo-2-chloroquinolin-3-yl)acrylate (9): To a stirred
solution of phosphonate (EtO)2P(O)CH2CO2Et (32.2 g, 140 mmol)
in THF (200 mL) was added LiHMDS (138.0 mL, 38.0 mmol, 1.0 m)
at 0 °C slowly for 30 min and stirred further for 30 min at room
temperature. The above solution was cannulated to a solution of 8
(30.0 g, 11 mmol) in THF (50 mL) dropwise and stirred for 2 h. The
reaction was quenched with water (100 mL). The organic layer was
separated and the aqueous layer extracted with ethyl acetate
(2ϫ100 mL). The combined organic layers were washed with brine,
dried with Na2SO4 and concentrated under reduced pressure. The
crude product was silica gel chromatographed (eluent: ethyl acetate/
hexane = 1:19) to give 9 as a white solid (33.2 g, 89%); m.p. 175 °C.
1H NMR (300 MHz, [D6]DMSO): δ = 8.98 (s, 1 H, H4), 8.28 (d, J
= 1.5 Hz, 1 H, H8), 8.03–7.86 (m, 3 H, H7, H5, H11), 6.83 (d, J =
16.0 Hz, 1 H, H12), 4.26 (q, J = 7.1 Hz, 2 H, H13), 1.29 (t, J =
7.1 Hz, 3 H, H14) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 165.2,
148.1, 145.6, 137.9, 136.6, 134.7, 130.3, 129.7, 128.0, 127.3, 123.4,
120.6, 60.5, 14.0 ppm. IR (KBr): ν = 1701 cm–1. HRMS (ESI) calcd.
˜
for C14H12BrClNO2 [M + H]+ 339.9734; found 339.9739.
(E)-3-(6-Bromo-2-chloroquinolin-3-yl)prop-2-en-1-ol (10): DIBAL-
H (125.0 mL, 170.0 mmol, 1.4 m in hexane) was added slowly to
α,β-unsaturated ester 9 (30.0 g, 88.0 mmol) in CH2Cl2 (150 mL) at
0 °C, and the resulting mixture was stirred at room temperature for
2 h. The reaction mixture was carefully quenched with saturated
aqueous Rochelle’s salt (150 mL) at 0 °C and the resulting suspen-
sion was stirred vigorously for 4 h. The reaction mixture was fil-
tered and the two layers separated. The aqueous layer was further
extracted with CH2Cl2 (3ϫ150 mL). The combined organic layers
were dried with Na2SO4 and concentrated under reduced pressure.
The crude product was silica gel chromatographed (eluent: AcOEt/
hexane = 1:5) to afford 10 as a pale yellow solid (22.0 g, 84%);
m.p. 130 °C. 1H NMR (500 MHz, [D6]DMSO): δ = 8.62 (s, 1 H,
H4), 8.30–8.24 (m, 1 H, H8), 7.89–7.83 (m, 2 H, H7, H5), 6.94 (td,
J = 15.6, 1.9 Hz, 1 H, H11), 6.64 (td, J = 15.6, 3.9 Hz, 1 H, H12),
5.16 (t, J = 4.8 Hz, 1 H, OH), 4.26 (br. s, 2 H, H13) ppm. 13C
NMR (75 MHz, [D6]DMSO): δ = 149.4, 144.4, 137.5, 133.7, 133.2,
Scheme 4. Reagents and conditions: (a) NaIO4, 2,6-lutidine, OsO4,
dioxane/H2O (3:1), room temp., 2 h; (b) NaBH4, MeOH, 0 °C to
room temp., 82% over two steps; (c) MsCl, Et3N, CH2Cl2, 0 °C to
room temp., 3 h, 88%; (d) Me2NH, THF, 45 °C, 24 h, 90%. Ms =
methylsulfonyl, THF = tetrahydrofuran.
Conclusions
In conclusion, we have achieved the synthesis of (2S)-
R207910 (3a) and (2R)-R207910 (3b) in overall yield of
12% each in 10 steps. The key steps involved are Sharpless
asymmetric epoxidation, regioselective epoxide opening and
modified allylzinc bromide addition. Optimization of the
allylation reaction would enable the approach amenable for
scale up at affordable cost as Sharpless asymmetric epoxid-
130.4, 129.8, 129.6, 128.5, 122.0, 120.2, 61.0 ppm. IR (KBr): ν =
˜
3285 cm–1. HRMS (ESI) calcd. for C12H10BrClNO [M + H]+
ation is a commercially viable process and our attempt is 297.9629; found 297.9616.
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S. Chandrasekhar, G. S. K. Babu, D. K. Mohapatra
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(E)-3-(6-Bromo-2-methoxyquinolin-3-yl)prop-2-en-1-ol (11): To
a
(m, 1 H, H13), 3.43 (m, 1 H, H13Ј), 2.82 (br. s, 1 H, OH), 2.50 (br.
s, 1 H, OH) ppm. 13C NMR (75 MHz, CDCl3): δ = 160.8, 143.8,
139.7, 135.0, 132.1, 129.3, 128.5, 128.4, 126.9, 126.7, 126.4, 117.1,
solution of 10 (39.4 g, 130 mmol) in MeOH (150 mL), was added
NaOMe (35.6 g, 650 mmol) and the resulting suspension was re-
fluxed at 80 °C for 8 h. The solvent was evaporated under reduced
pressure to give a crude solid which was quenched with water
(100 mL) and extracted with ethyl acetate (3ϫ150 mL). The com-
bined organic layers were dried with Na2SO4 and rotary evapo-
rated. The crude product was silica gel chromatographed (eluent:
AcOEt/hexane = 1:5) to furnish 11 as a pale yellow solid (35.1 g,
73.3, 64.8, 53.7, 47.4 ppm. IR (KBr): ν = 3374, 2924 cm–1. HRMS
˜
(ESI) calcd. for C19H19BrNO3 [M + H]+ 388.0543; found 388.0540.
(2R)-3-(6-Bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-
phenylethanol (14): To a solution of 12 (19.0 g, 49 mmol) in CH2Cl2
(400 mL) was added NaIO4 impregnated over silica (20% w/w on
silica, 150 g) and stirred for 1 h. The suspension was filtered and
washed with CH2Cl2 (100 mL). The filtrate was evaporated under
reduced pressure to give crude 13 (17.0 g, 98%) which was used
immediately for the next reaction.
1
92%); m.p. 134 °C. H NMR (300 MHz, [D6]DMSO): δ = 8.32 (s,
1 H, H4), 8.10 (d, J = 1.7 Hz, 1 H, H8), 7.75–7.64 (m, 2 H, H7,
H5), 6.8 (d, J = 16.0 Hz, 1 H, H11), 6.63 (td, J = 16.0, 4.5 Hz, 1
H, H12), 5.04 (br. s, 1 H, OH), 4.21 (br. s, 2 H, H13), 4.04 (s, 3 H,
H14) ppm. 13C NMR (75 MHz, [D6]DMSO): δ = 159.5, 143.4,
135.4, 133.0, 131.9, 129.3, 128.4, 126.6, 122.7, 121.1, 116.5, 61.4,
To a solution of 13 (16.5 g, 46 mmol) in diethyl ether (100 mL) at
0 °C was added freshly prepared naphthyl Grignard reagent (230 mL,
0.6 m in Et2O, 139.0 mmol) and stirred for 1 h. The reaction was
quenched with saturated aqueous solution of NH4Cl and the aque-
ous layer extracted with diethyl ether (2ϫ150 mL). The combined
organic layers were washed with water, brine, dried with Na2SO4,
and concentrated under reduced pressure. The inseparable mixture of
diastereomers were silica gel chromatographed (eluent: ethyl acetate/
hexane = 1:10) to give 14 as an off white solid (20.4 g, 92%).
53.5 ppm. IR (KBr): ν = 3258 cm–1. HRMS (ESI) calcd. for
˜
C13H13BrNO2 [M + H]+ 294.0124; found 294.0120.
[(2S,3S)-3-(6-Bromo-2-methoxyquinolin-3-yl)oxiran-2-yl]methanol
(7): Ti(OiPr)4 (2.0 mL, 0.68 mmol) in CH2Cl2 (20 mL) was added
to a suspension of molecular sieves (4 Å, 7.0 g, 30% w/w based on
substrate) in CH2Cl2 (20 mL). The mixture was cooled to –20 °C
and l-(+)-diisopropyl tartrate (2.1 mL, 10 mmol) in CH2Cl2
(10 mL) was added and stirred for 30 min followed by 11 (20.0 g,
68.0 mmol) in CH2Cl2 (200 mL). The resulting suspension was
stirred for 40 min at the same temperature. After this time anhy-
drous tert-butyl hydroperoxide in toluene (68.2 mL, 270 mmol,
4.0 m) was added dropwise and stirring continued for 4 h. After
warming up to 0 °C, water (100 mL) was added and the mixture
was stirred for 1 h. 20 % Aqueous NaOH saturated with NaCl
(50 mL) was added and stirring continued for 1.5 h. The slurry was
filtered through a plug of Celite and rinsed thoroughly with
CH2Cl2. The organic layer was separated and the aqueous layer
extracted with CH2Cl2 (2ϫ150 mL). The combined organic layer
was washed with brine, dried with Na2SO4, and rotary evaporated.
The crude product was silica gel chromatographed (eluent: AcOEt/
hexane = 1:5) to obtain 7 as a white solid (18.1 g, 86 %); m.p.
(R)-2-(6-Bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-2-phen-
ylethanone (6): To a solution of 14 (20.3 g, 40.0 mmol) in CH2Cl2
(150 mL) was added Dess–Martin periodinane (25.4 g, 60.0 mmol).
After being stirred at room temperature for 3 h, the reaction mix-
ture was quenched with saturated aqueous Na2S2O3 (50 mL) and
saturated aqueous NaHCO3 (50 mL). The organic layer was sepa-
rated and the aqueous phase was extracted with CH2Cl2
(2ϫ100 mL). The combined organic extracts were washed with
brine (150 mL), dried with Na2SO4 and rotary evaporated. The
crude product was silica gel chromatographed (eluent: AcOEt/hex-
ane = 1:10) to furnish 6 as a white solid (17.7 g, 87%); m.p. 168 °C.
[α]2D8 = +217.9 (c = 0.5, CHCl ). IR (KBr): ν = 1684 cm–1. 1H
˜
3
NMR (400 MHz, CDCl3): δ = 8.55 (d, J = 8.4 Hz, 1 H, H20), 8.04
(d, J = 7.2 Hz, 1 H, H8), 7.95 (d, J = 8.3 Hz, 1 H, H7), 7.85 (d, J
= 7.6 Hz, 1 H, H17), 7.75 (d, J = 2.1 Hz, 1 H, H5), 7.71 (d, J =
8.9 Hz, 1 H, H16), 7.64 (dd, J = 8.9, 2.1 Hz, 1 H, H14), 7.60–7.33
(m, 9 H, H4, H19, H18, H15, Ph), 6.22 (s, 1 H, H11), 3.97 (s, 3 H,
H23) ppm. 13C NMR (75 MHz, CDCl3): δ = 200.9, 160.0, 144.3,
136.8, 136.0, 135.4, 133.9, 132.6, 132.3, 130.5, 129.6, 129.5, 129.3,
128.4, 128.3, 127.9, 127.8, 127.6, 126.8, 126.5, 126.4, 125.7, 124.2,
117.1, 57.2, 53.8 ppm. HRMS (ESI) calcd. for C28H21BrNO2 [M +
H] + 4 8 2 . 0 75 0; fo un d 4 82 . 0 73 8; HP LC [C hi ra lp ak IC
(250ϫ4.6 mm, 5 µ), IPA/hexane, 1:10, flow 1.0 mL]: tR = 5.0 min
(major), 6.2 min (minor) 95% ee.
153 °C. [α]3D1 = –41.8 (c = 0.5, CHCl ). IR (KBr): ν = 3377, 3281
˜
3
cm–1. 1H NMR (300 MHz, [D6]DMSO): δ = 8.16 (d, J = 1.8 Hz, 1
H, H8), 7.99 (s, 1 H, H4), 7.78–7.67 (m, 2 H, H7, H5), 5.09 (t, J
= 5.8 Hz, 1 H, OH), 4.11 (d, J = 1.7 Hz, 1 H, H11), 4.06 (s, 3 H,
H14), 3.83 (ddd, J = 12.6, 5.4, 2.6 Hz, 1 H, H13), 3.61 (m, 1 H,
H13Ј), 3.21–3.17 (m, 1 H, H12) ppm. 13C NMR (75 MHz, [D6]-
DMSO): δ = 160.1, 143.7, 133.0, 132.3, 129.6, 128.4, 126.1, 123.3,
116.6, 62.8, 60.3, 53.6, 50.3 ppm. HRMS (ESI) calcd. for
C13H13BrNO3 [M + H]+ 310.0073; found 310.0088; HPLC [Chi-
ralpak IC (250ϫ4.6 mm, 5 µ), IPA/hexane, 1:10, flow 1.0 mL]: tR
= 10.8 min (minor), 15.4 min (major) 95% ee.
(1R)-1-(6-Bromo-2-methoxyquinolin-3-yl)-1-(naphthalen-1-yl)-1-
phenylpent-4-en-2-ol (5a and 5b): To a catalytic solution of
CuBr·DMS in THF (50 mL) was added freshly prepared allylzinc
bromide (14.9 g, 80.0 mmol) at room temperature and stirred for
10 min. Compound 6 (20.0 g, 40.0 mmol) was then added to it.
After 30 min, the reaction was quenched with saturated aqueous
NH4Cl solution (100 mL). The organic layer was separated and
the aqueous layer extracted with ethyl acetate (2ϫ100 mL). The
combined organic extracts were washed with brine, dried with
Na2SO4 and rotary evaporated. The crude product was silica gel
chromatographed (eluent: AcOEt/hexane = 1:19) to give 5a and 5b
(2R,3R)-3-(6-Bromo-2-methoxyquinolin-3-yl)-3-phenylpropane-1,2-
diol (12): To a suspension of CuCN (23.0 g, 250 mmol) in THF
(150 mL) at –40 °C, PhMgBr (258.2 mL, 510 mmol, 2.0 m in Et2O)
was added. After stirring for 1 h, solution of 7 (16.0 g, 51.0 mmol)
in THF (50 mL) was added dropwise via cannula. After 3 h, the
reaction was quenched with a saturated aqueous solution of NH4Cl
(100 mL), diluted with ethyl acetate (100 mL) and allowed to stir
for 3 h. The layers were separated and the aqueous layer extracted
with ethyl acetate (3ϫ100 mL). The combined organic layers were
washed with water, brine, dried with Na2SO4, and concentrated un-
der reduced pressure. The crude mixture was silica gel chromato-
graphed (eluent: AcOEt/hexane = 1:4) to afford diol 12 as an off
white solid (17.1 g, 86%); m.p. 110 °C. [α]2D6 = –133.5 (c = 0.5,
as a white solid (19.4 g, 90%) (racemic). IR (KBr): ν = 3363 cm–1.
˜
HRMS (ESI) calcd. for C31H27BrNO2 [M + H]+ 524.1220; found
524.1223.
1
CHCl3). H NMR (300 MHz, CDCl3): δ = 8.01 (s, 1 H, H4), 7.86
(4R)-4-(6-Bromo-2-methoxyquinolin-3-yl)-3-(naphthalen-1-yl)-4-
phenylbutane-1,3-diol (4a and 4b): To a solution of 5a and 5b
(d, J = 1.7 Hz, 1 H, H8), 7.67–7.58 (m, 2 H, H7, H5), 7.29–7.14
(m, 5 H, Ph), 4.47 (br. s, 2 H, H11, H12), 3.99 (s, 3 H, H14), 3.57 (14.0 g, 26.0 mmol) in dioxane/water (3:1, 100 mL) were added 2,6-
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Practical Syntheses of (2S)-R207910 and (2R)-R207910
lutidine (6.1 mL, 52.0 mmol), OsO4 (27.2 mL, 0.4 mmol, 0.5% in
(s, 3 H, H30), 2.49 (td, J = 14.3, 3.0 Hz, 1 H, H27), 2.26 (dt, J =
toluene) and NaIO4 (22.8 g, 106.0 mmol). After 2 h, water (20 mL) 12.2, 3.2 Hz, 1 H, H27Ј), 2.14–1.90 (m, 9 H, H28, H28Ј, H29) ppm.
and CH2Cl2 (30 mL) were added. The layers were separated and
the aqueous layer was extracted with CH2Cl2 (2ϫ100 mL). The
combined organic extracts were washed with brine, dried with
Na2SO4 and concentrated under reduced pressure. The crude 15a
and 15b was used for the next reaction without purification.
13C NMR (75 MHz, CDCl3): δ = 160.4, 143.2, 141.6, 141.1, 137.8,
134.6, 131.2, 130.0, 129.6, 129.5, 128.1, 128.0, 127.9, 127.6, 127.4,
127.1, 126.5, 126.4, 125.4, 124.9, 124.8, 124.3, 116.2, 81.5, 56.1,
52.7, 50.9, 44.5, 34.1, 29.6 ppm. HRMS (ESI) calcd. for
C32H32BrN2O2 [M + H]+ 555.1642; found 555.1659.
Supporting Information (see footnote on the first page of this arti-
To a stirred solution of 15a and 15b in MeOH (150 mL) was added
NaBH4 (1.2 g, 28.0 mmol) at 0 °C and stirred at room temperature
for 2 h. The reaction was quenched with water (50 mL) and meth-
anol was removed under reduced pressure. The aqueous layer was
extracted with ethyl acetate (3ϫ100 mL). The combined organic
layers were washed with brine, dried with Na2SO4 and rotary evap-
orated. The crude product was silica gel chromatographed (eluent:
AcOEt/hexane = 1:10) to obtain 4a and 4b as a white solid (11.2 g,
1
cle): Copies of H and 13C NMR spectra for new compounds.
Acknowledgments
This work was financially supported by Department of Science and
Technology (DST), New Delhi (GAP-0154). G. S. K. B. is thankful
to Council of Scientific and Industrial Research (CSIR), New Delhi
for a research fellowship.
82% over 2 steps). IR (KBr): ν = 3420 cm–1. HRMS (ESI) calcd.
˜
for C30H27BrNO3 [M + H]+ 528.1169; found 528.1177.
[1] Y. L. Janin, Bioorg. Med. Chem. 2007, 15, 2479.
[2] A. J. Lenaerts, M. A. Degroote, I. M. Orme, Trends Microbiol.
2008, 16, 48.
[3] H. Tomioka, Curr. Pharm. Des. 2006, 12, 4047.
[4] K. J. Williams, K. Duncan, Curr. Mol. Med. 2007, 7, 297.
[5] E. Check, Nat. Med. 2007, 13, 266.
[6] J. A. Salomon, J. O. Llyod-Smith, W. M. Getz, S. Resch, M. S.
Sanchez, T. C. Porco, M. W. Borgdorff, PloS. Med. 2006, 3,
e273.
[7] M. C. Freire, World Hosp. Health Serv. 2006, 42, 34.
[8] M. Spigelman, S. Gillespie, Lancet 2006, 367, 945.
[9] A. Lilienkampf, J. Mao, B. Wan, Y. Wang, S. G. Franzblau,
A. P. Kozikowski, J. Med. Chem. 2009, 52, 2109 and references
cited therein .
(4R)-4-(6-Bromo-2-methoxyquinolin-3-yl)-3-hydroxy-3-(naphth-
alen-1-yl)-4-phenylbutylmethane-Sulfonate (16a and 16b): To a solu-
tion of 4a and 4b (10.6 g, 20.1 mmol) in CH2Cl2 (70 mL) were
added Et3N (5.4 mL, 40.2 mmol) and methanesulfonyl chloride
(2.0 mL, 26.1 mmol) sequentially at 0 °C. After stirring for 3 h at
room temperature, water (40 mL) was added to quench the reac-
tion. The reaction mixture was diluted with CH2Cl2 (50 mL). The
organic layer was separated and the aqueous layer extracted with
CH2Cl2 (2ϫ50 mL). The combined organic extracts were washed
with brine, dried with Na2SO4 and concentrated under reduced
pressure. The crude product was silica gel chromatographed (elu-
ent: AcOEt/hexane = 1:5) to afford 16a and 16b as a white solid
(10.5 g, 88%). IR (KBr): ν = 3432 cm–1. HRMS (ESI) calcd. for
˜
[10] F. Meng, P. Marek, K. J. Potter, C. B. Verchere, D. P. Raleigh,
Biochemistry 2008, 47, 6016.
C31H29BrNO5S [M + H]+ 606.0944; found 606.0955.
[11] http://www.who.int/tb/challenges/mdr/en/index.html.
[12] a) J. F. E. van Gestel, J. E.G. Guillemont, M. G. Venet, H. J. J.
Poignet, L. F. B. Decrane, F. C. Odds, U. S. Patent 2005/
0148581; b) The overall yield of this route was less than 1%.
[13] W. J. Bruman, S. Goldberg, J. L. Johnson, G. Muzanye, M. En-
gle, Am. J. Respir. Crit. Care Med. 2006, 174, 331.
[14] S. T. Cole, P. M. Alzari, Science 2005, 307, 214.
[15] S. Petrella, E. Cambau, A. Chauffour, K. Andries, V. Jarlier,
Antimicrob. Agents Chemother. 2006, 50, 2853.
[16] M. Ibrahim, K. Andries, N. Lounis, A. Chaufour, C. Truffot-
Pernot, Antimicrob. Agents Chemother. 2007, 51, 1011.
[17] Y. Saga, R. Motoki, S. Makino, Y. Shimizu, M. Kanai, M.
Shibasaki, J. Am. Chem. Soc. 2010, 132, 7905. The overall yield
was 5 % .
(1R,2S)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-
2-(naphthalen-1-yl)-1-phenylbut-an-2-ol (3a): A solution of 16a and
16b (6.0 g, 10.2 mmol) in Me2NH (200 mL, 8.0 m in THF) was
stirred at 45 °C for 24 h. The solution was filtered and the filtrate
concentrated under reduced pressure to afford the crude product
which on purification by silica gel column chromatography (eluent:
ethyl acetate/hexane = 1:6) furnished 3a and 3b as white solids
(4.8 g, 90%) (1:1 w/w). 3a: M.p. 104 °C. [α]2D5 = –165.2 (c = 0.8,
1
DMF). H NMR (300 MHz, CDCl3): δ = 8.89 (s, 1 H, H4), 8.61
(d, J = 8.6 Hz, 1 H, H20), 7.96 (d, J = 2.0 Hz, 1 H, H5), 7.92 (d,
J = 7.4 Hz, 1 H, H14), 7.87 (d, J = 8.1 Hz, 1 H, H17), 7.72 (d, J
= 8.8 Hz, 1 H, H8), 7.68–7.56 (m, 3 H, H7, H16, H19), 7.48 (t, J
= 7.6 Hz, 1 H, H18), 7.30 (t, J = 7.7 Hz, 1 H, H15), 7.17–7.10 (m,
2 H, H24), 6.93–6.83 (m, 3 H, H25, H26), 5.89 (s, 1 H, H11), 4.21
(s, 3 H, H30), 2.60–2.51 (m, 1 H, H27), 2.18–2.02 (m, 2 H, H27Ј,
H28), 1.99 (s, 6 H, H29), 1.95–1.85 (m, 1 H, H28Ј) ppm. 13C NMR
(75 MHz, CDCl3): δ = 161.3, 143.7, 141.6, 140.5, 138.7, 134.6,
131.9, 129.9, 129.8, 129.7, 128.4, 128.1, 127.8, 127.3, 127.1, 126.8,
125.7, 125.2, 125.1, 125.0, 124.4, 116.9, 82.4, 56.2, 54.1, 49.5, 44.6,
[18] a) M. M. Ali, Tasneem, K. C. Rajanna, P. K. Sai Prakash, Syn-
lett 2001, 251–253; b) O. Meth-Cohn, B. Narine, B. Tarnowski,
J. Chem. Soc. Perkin Trans. 1 1980, 1520.
[19] R. Pathak, S. Madapa, S. Batra, Tetrahedron 2007, 63, 451.
[20] Y. Gao, R. M. Hanson, J. M. Klunder, S. Y. Ko, H. Masamune,
K. B. Sharpless, J. Am. Chem. Soc. 1987, 109, 5765.
[21] H. Palandoken, J. K. Wyatt, S. R. Hitchcock, M. M. Olmstead,
M. H. Nantz, J. Organomet. Chem. 1999, 579, 338.
[22] Y.-L. Zhong, T. K. M. Shing, J. Org. Chem. 1997, 62, 2622.
[23] R. Tsuji, K. Komatsu, Y. Inoue, K. Takeuchi, J. Org. Chem.
1992, 57, 636.
[24] D. B. Dess, J. C. Martin, J. Org. Chem. 1983, 48, 4155.
[25] Y. Zhang, X. Jia, J.-X. Wang, Eur. J. Org. Chem. 2009, 2983.
[26] W. Yu, Y. Mei, Y. Kang, Z. Hua, Z. Jin, Org. Lett. 2004, 6,
3217.
33.4, 29.6 ppm. IR (KBr): ν = 3441 cm–1. HRMS (ESI) calcd. for
˜
C32H32BrN2O2 [M + H]+ 555.1642; found 555.1671.
(1R,2R)-1-(6-Bromo-2-methoxyquinolin-3-yl)-4-(dimethylamino)-
2-(naphthalen-1-yl)-1-phenylbutan-2-ol (3b): M.p. 145 °C. [α]2D5
=
1
+41.2 (c = 0.31, DMF). H NMR (300 MHz, CDCl3): δ = 8.58 (s,
1 H, H4), 8.48 (d, J = 8.7 Hz, 1 H, H20), 7.99 (dd, J = 7.4, 0.9 Hz,
1 H, H14), 7.88 (d, J = 7.3 Hz, 2 H, H24), 7.82–7.75 (m, 2 H, H17,
H5), 7.60–7.50 (m, 2 H, H19, H16), 7.47–7.32 (m, 4 H, H8, H25,
H7, H18), 7.30–7.21 (m, 2 H, H26, H15), 5.73 (s, 1 H, H11), 3.25
[27] A. Tam, R. T. Raines, Bioorg. Med. Chem. 2009, 17, 1055.
Received: December 23, 2010
Published Online: March 3, 2011
Eur. J. Org. Chem. 2011, 2057–2061
© 2011 Wiley-VCH Verlag GmbH & Co. KGaA, Weinheim
www.eurjoc.org
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