An enantioselective approach to 2-alkyl substituted tetrahydroquinolines: Total synthesis of (+)-angustureine

Article abstract of DOI:10.1039/c5ra05987a

A simple and highly efficient synthetic approach to enantiopure 2-alkyl substituted tetrahydroquinoline 1 skeleton from aldehydes as starting materials and its application to the total synthesis of (+)-angustureine 2 is described. Key transformations incl

Full text of DOI:10.1039/c5ra05987a

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An enantioselective approach to 2-alkyl substituted
tetrahydroquinolines: total synthesis of
(+)-angustureine†
Cite this: RSC Adv., 2015, 5, 38846
Received 3rd April 2015
Accepted 23rd April 2015
*
Yuvraj Garg, Suraksha Gahalawat and Satyendra Kumar Pandey
DOI: 10.1039/c5ra05987a
www.rsc.org/advances
A simple and highly efficient synthetic approach to enantiopure 2-alkyl aminoxylation, Corey–Fuchs protocol, palladium catalyzed
substituted tetrahydroquinoline 1 skeleton from aldehydes as starting Sonogashira coupling, and Mitsunobu reaction as key steps.
materials and its application to the total synthesis of (+)-angustureine
2 is described. Key transformations include proline catalyzed amino-
xylation, Corey–Fuchs protocol, Sonogashira coupling and intra-
molecular Mitsunobu reactions.
Introduction
Quinoline and tetrahydroquinoline alkaloids are found abun-
dantly in nature and most of them exhibit interesting biological
activity.1 Enantiomerically pure 2-alkyl substituted tetrahy-
droquinoline alkaloids 1 from which angustureine 2, galipeine
3, cuspareine 4, and galipinine 5 were rst extracted from the
Fig. 1 Some naturally occurring 2-alkyl substituted tetrahydroquino-
line alkaloids.
bark of the Galipea officinalis Hancock shrub tree found in the
mountains of Venezuela (Fig. 1).2
These alkaloids exhibits anti-malarial, anti-tuberculous,
cytotoxic, and antiplasmodial activities.3 Galipea species have
also been used in folk medicine for the treatment of dysentery,
Results and discussion
Our retrosynthetic approach for the synthesis of 2-alkyl
dyspepsia, chronic diarrhea, spinal motor nerve problems and
substituted tetrahydroquinolines 1 including (+)-angustureine 2
fevers.4 Enantiomerically pure 2-alkyl substituted tetrahydro-
quinoline alkaloids have synthetic target of considerable
interest due to their wide range of important biological activi-
ties and with an array of functionalities. Various methods for
the synthesis of (+)-angustureine 2 and others 3–5 have been
documented in the literature.5 Very recently, M. Yus and co-
is outlined in Scheme 1. We envisioned that the aryl nitro-
alkyne derivative 6 from which 2-alkyl substituted tetrahydro-
quinolines 1 and (+)-angustureine 2 could be synthesized via
hydrogenation, Mitsunobu intramolecular ring closer in SN2
fashion followed by alkylation. The aryl nitro-alkyne derivative 6
could be obtained from the monoprotected alkyne derivative 7
workers reported the synthesis of the (+)-angustureine 2 using
through palladium catalyzed Sonogashira coupling reaction
diastereoselective addition of an allylic indium intermediate to
with suitable aromatic nitro-halides. The alkyne derivative 7 in
chiral O-bromophenyl N-tert-butylsulnyl aldimines.5v Herein,
turn could be obtained by means of Corey–Fuchs protocol from
we wish to report a new, general and highly efficient synthetic
the aldehyde synthesized from oxidation of monoprotected
approach for enantiopure 2-alkyl substituted tetrahydroquino-
alcohol 8. Enantiomerically pure monoprotected alcohol 8
lines 1 and its application to the total synthesis of (+)-angus-
could be obtained from the commercially available aldehydes 9
tureine
2
employing proline catalyzed asymmetric
via proline catalyzed aminoxylation followed by standard
organic transformation. The (S)- and (R)-conguration of the
2-alkyl substituted tetrahydroquinolines 1 and (+)-angustureine
2 could be manipulated by simply changing the D-proline and
L-proline, respectively, during organocatalytic step.
School of Chemistry and Biochemistry, Thapar University, Patiala 147001, India.
E-mail: skpandey@thapar.edu; Fax: +91-175-236-4498; Tel: +91-175-239-3832
† Electronic supplementary information (ESI) available: Copies of 1H and 13C
NMR spectra of compounds 2 and 11–16. See DOI: 10.1039/c5ra05987a
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presence of catalytic amount of PPTS, which furnished
1,2-benzylidene acetal 12 in 89% yield.7 Regioselective reductive
opening of 1,2-benzylidene acetal 12 with DIBAL-H afforded
monobenzyl protected alcohol 13 in 93% yield. Oxidation of
alcohol 13 under Swern conditions8 and subsequent treatment
with CBr4/TPP followed by treatment with n-BuLi under Corey–
Fuchs protocol9 afforded the terminal alkyne 14 in 86% yield.
The terminal alkyne 14 under Sonogashira coupling condi-
tions10 with commercially available 1-iodo-2-nitro benzene in
the presence of Et3N as a base afforded the 2-nitrobenzene-
alkyne derivative 15 in excellent yield (95%). Concomitant
reduction of the triple bond, nitro group to amine and depro-
tection of benzyl group of 2-nitrobenzene-alkyne derivative 15
was achieved in one pot via hydrogenation under 1 atm. pres-
sure in presence of catalytic amount of Pd/C (10%) which fur-
nished the key intermediate amino alcohol 16 in 96% yield.
Cyclization of amino alcohol 16 under Mitsunobu conditions11
(DEAD, PPh3, CH2Cl2, rt) afforded the tetrahydroquinoline
(norangustureine), and subsequent methylation using reductive
amination with formaldehyde in presence of Na(CN)BH3
afforded the target compound (+)-angustureine 2 in 88% yield
{[a]2D5 +7.6 (c 0.4, CHCl3) [Lit.5t +7.5 (c 0.4, CHCl3)}. The physical
and spectroscopic data were in full agreement with those
documented in literature.
Scheme 1 Retrosynthetic approach to 2-alkyl substituted tetrahy-
droquinolines 1 and (+)-angustureine 2.
The synthesis of (+)-angustureine 2 started from the
commercially available n-heptanal 10, which on treatment
with nitrosobenzene in the presence of catalytic amount of
L-proline (10 mol%) in DMSO at room temperature afforded
a-aminoxylated aldehyde which on subsequent reduction with
NaBH4/CH3OH followed by benzylamine cleavage with
CuSO4$5H2O afforded the required diol 11 in 71% yield over
three steps with >99% ee.6 {[a]D25 ꢀ14.4 (c 1, CH3OH)}. The
physical and spectroscopic data were in full agreement with
those reported in literature (Scheme 2).
With enantiomerically pure diol 11 in hand, we then sub-
jected it to protection with benzaldehyde dimethyl acetal in
Conclusions
In conclusion, a simple, exible and highly efficient synthetic
approach for 2-alkyl substituted tetrahydroquinolines 1 and its
application to the total synthesis of (+)-angustureine 2 has been
developed. The overall yield for alkaloid (+)-angustureine 2 was
41% in ten steps. The merits of this synthesis are high enan-
tioselectivity with high yielding reaction steps. The synthetic
strategy described has signicant potential for stereochemical
variation and further extension to 2-alkyl substituted tetrahy-
droquinolines derived natural products with interesting phar-
macological activities.
Experimental
The solvents and chemicals were purchased from Merck and
Sigma Aldrich chemical company. Progress of the reactions
was monitored by TLC using precoated aluminium plates of
1
Merck kieselgel 60 F254. H and 13C NMR spectra were recor-
ded in CDCl3 (unless otherwise mentioned) on JEOL ECS
operating at 400 and 100 MHz, respectively. Chemical shis are
reported in d (ppm), referenced to TMS. IR spectra were
recorded on Agilent resolution Pro 600 FT-IR spectrometer,
tted with a beam-condensing ATR accessory. HRMS were
recorded using Electron Spray Ionization. Optical rotations
were measured on Automatic polarimeter AA-65. Column
Scheme 2 Reagents and conditions: (a) (i) nitrosobenzene, L-proline,
DMSO, rt, 12 h, (ii) NaBH4, CH3OH, 0 ꢁC, 15 min, (iii) CuSO4$5H2O,
CH3OH, 0 ꢁC to rt, 12 h, 71% (one pot, three steps) (b) PhCH(OMe)2,
C6H6, PPTS, reflux, 1 h, 89% (c) DIBAL-H, CH2Cl2, ꢀ40 ꢁC to rt, 2 h, 93% chromatography was performed on silica gel (60–120 and 100–
(d) (i) (COCl)2, DMSO, Et3N, CH2Cl2, –78 ꢁC to ꢀ60 ꢁC, 2 h, (ii) CBr4,
200 mesh) using a mixture of hexane and ethyl acetate. All
reactions were carried out under argon or nitrogen in oven-
dried glassware using standard glass syringes, cannulas and
septa. Solvents and reagents were puried and dried by stan-
PPh3, CH2Cl2, 0 ꢁC, 30 min, (iii) n-BuLi, THF, ꢀ78 ꢁC to rt, 3 h, 86% (over
three steps) (e) 1-iodo-2-nitrobenzene, 2 mol% Pd(PPh3)2Cl2, 1 mol%
CuI, Et3N, DMF, reflux, 3 h, 95% (f) H2, Pd/C (10%), EtOAc, rt, 24 h, 96%
(g) (i) PPh3, DEAD, CH2Cl2, rt, 12 h, (ii) HCHO, Na(CN)BH3, AcOH,
CH3CN, rt, 10 h, 88% (over two steps).
dard methods prior to use.
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1
1609, 1505, 772 cmꢀ1; H NMR (CDCl3, 400 MHz) d: 7.33–7.36
(m, 5H), 4.56 (s, 2H), 3.8 (m, 1H), 3.5 (m, 1H), 3.3 (m, 1H), 2.4 (s,
1H), 1.28–1.43 (m, 8H), 0.9 (t, 3H, J ¼ 6.4 Hz); 13C NMR (CDCl3,
100 MHz) d: 137.9, 128.4, 127.8, 127.7, 74.6, 73.3, 70.4, 33.0,
31.8, 25.2, 22.5, 14.0. HRMS (ESI) m/z calcd for C14H22O2Na [M +
Na+] 245.1512; found 245.1510.
(R)-Heptane-1,2-diol, 11
To a DMSO solution (60 mL) of L-proline (168 mg, 1.46 mmol)
was added n-heptanal 10 (5.0 g, 43.86 mmol) and nitro-
sobenzene (1.56 g, 14.6 mmol) successively at room tempera-
ture. Aer stirring the reaction mixture for 12 h, MeOH (20 mL)
and NaBH4 (835 mg, 22 mmol) were added and the reaction
mixture was stirred for 15 min at 0 ꢁC. The reaction was
quenched with aqueous saturated NH4Cl solution, extracted
with ethyl acetate (3 ꢂ 10 mL), dried over anhydrous Na2SO4,
and concentrated in vacuo.
The residue thus obtained above was dissolved in MeOH
(15 mL) and subjꢁected to treatment with CuSO4$5H2O (913 mg,
3.65 mmol) at 0 C and warm to room temperature over 12 h.
Aer completion of reaction as monitored by TLC, it was
quenched with aqueous saturated NH4Cl solution. The organic
layer was separated and the aqueous phase extracted with
EtOAc (3 ꢂ 20 mL). The combined organic phase was dried over
anhydrous Na2SO4, concentrated in vacuo, and puried by silica
gel column chromatography (EtOAc/hexanes 1 : 1 v/v) to afford
the desired diol 11 (1.35 g, 71%). {[a]2D5 ꢀ14.4 (c 1, CH3OH) [Lit.12
ꢀ14.1 (c 1, CH3OH)]}; IR (CH2Cl2) n: 3359, 2941, 2853, 1462,
1312, 1062, 927 cmꢀ1; 1H NMR (CDCl3, 400 MHz) d: 3.6 (m, 2H),
3.4 (m, 1H), 2.67 (bs, 2H), 1.29–1.43 (m, 8H), 0.9 (t, 3H, J ¼ 6.4
Hz); 13C NMR (CDCl3, 100 MHz) d: 72.3, 66.8, 33.1, 31.8, 25.2,
22.5, 14.0; HRMS (ESI) m/z calcd for C7H16O2Na [M + Na+]
155.1043; found 155.1041.
(R)-((Oct-1-yn-3-yl-oxy)methyl)benzene, 14
To a solution of oxalyl chloride (1.63 g, 1.1 mL, 12.84 mmol) in
dry CH2Cl2 (30 mL) at ꢀ78 ꢁC was added dropwise DMSO
(2.07 g, 1.9 mL, 26.53 mmol) in CH2Cl2 (10 mL) over 15 min. The
reaction mixture was stirred for 30 min and a solution of
monobenzyl protected alcohol 13 (1.9 g, 8.56 mmol) in CH2Cl2
(20 mL) was added dropwise over 15 min. The reaction mixture
was stirred for 30 min at ꢀ60 ꢁC and then Et3N (3.80 g, 5.20 mL,
37.7 mmol) was added dropwise and stirred for 1 h. The reac-
tion mixture was poured into saturated solution of NaHCO3
(50 mL) and the organic layer separated. The aqueous layer was
extracted with CH2Cl2 (3 ꢂ 20 mL) and the combined organic
layer was washed with brine, dried over Na2SO4 and concen-
trated in vacuo to give the crude aldehyde, which was used as
such for the next step without further purication.
To a solution of CBr4 (5.68 g, 17.12 mmol) in dry CH2Cl2
(30 mL) at 0 ꢁC was added PPh3 (8.97 g, 34.24 mmol) and stirred
for 15 min at 0 ꢁC. To this reaction mixture, a solution of crude
aldehyde obtained above in dry CH2Cl2 (20 mL) was added
ꢁ
dropwise and stirred for 15 min at 0 C. The reaction mixture
was quenched with water and aqueous layer was extracted with
CH2Cl2 (3 ꢂ 20 mL). The combined organic layer was washed
with brine, dried over Na2SO4 and concentrated in vacuo to give
the crude dibromoolen, which was used as such for the next
step without further purication. To a solution of above crude
dibromoolen in dry THF (30 mL) at ꢀ78 ꢁC was added n-BuLi
(6.85 mL, 17.12 mmol, 2.5 M in hexane). The reaction mixture
was stirred for 1 h at ꢀ78 ꢁC and 2 h at 0 ꢁC. The reaction
mixture was quenched with saturated aqueous solution of
NH4Cl and extracted with ethyl acetate (3 ꢂ 20 mL). The
combined organic layer was washed with brine, dried over
Na2SO4 and concentrated in vacuo. Silica gel column chroma-
tography of the crude product using EtOAc/hexane (1 : 19 v/v) as
eluent furnished the corresponding terminal alkynes 14 (1.59 g,
86% over three steps) as a pale yellow oil. [a]2D5 +34.2 (c 1,
CHCl3); IR (CH2Cl2) n: 3302, 2952, 2851, 2125, 1610, 1512,
1102 cmꢀ1; 1H NMR (CDCl3, 400 MHz) d: 7.26–7.36 (m, 5H), 4.8
(m, 1H), 4.5 (m, 1H), 4.0 (m, 1H), 2.46 (d, 1H, J ¼ 1.84 Hz),
1.28–1.78 (m, 8H), 0.9 (t, 3H, J ¼ 6.88 Hz); 13C NMR (CDCl3, 100
MHz) d: 137.9, 128.4, 128.0, 127.7, 83.0, 73.7, 70.5, 68.5, 35.6,
31.4, 24.9, 22.5, 14.0; HRMS (ESI) m/z calcd for C15H21O [M + 1]
217.1587; found 217.1587.
(4R)-4-Pentyl-2-phenyl-1,3-dioxolane, 12
To a benzene solution (50 mL) of diol 11 (1.35 g, 10.4 mmol) was
added benzaldehyde dimethylacetal (1.58 g, 10.4 mmol) and
catalytic amount of PPTS (260 mg, 1.04 mmol). The mixture was
then heated to reux with a Dean–Stark apparatus. Aer 1 h,
triethylamine (1 mL) was added to the mixture, and the solvent
was removed under reduced pressure. The resulting residue was
puried by silica gel chromatography (EtOAc/hexanes 1 : 99 v/v)
to afford the 1,2-benzylidene acetal 12 (2.0 g, 89%). [a]2D5 ꢀ11.5
(c 1, CHCl3); IR (CH2Cl2) n: 1478, 1366, 1260, 1120, 1015 cmꢀ1
;
1H NMR (CDCl3, 400 MHz) d: 7.35–7.48 (m, 5H), 5.92 (s, 1H), 4.2
(m, 2H), 3.59–3.67 (m, 1H), 1.31–1.75 (m, 8H), 0.9 (t, 3H, J ¼ 6.9
Hz); 13C NMR (CDCl3, 100 MHz) d: 138.4, 129.0, 128.3, 126.4,
103.0, 70.8, 33.3, 31.8, 25.4, 22.5, 14.0; HRMS (ESI) m/z calcd for
C
14H21O2 [M + 1] 221.1536; found 221.1537.
(R)-2-(Benzyloxy)heptan-1-ol, 13
To a solution of 1,2-benzylidene acetal 12 (2.0 g, 9.2 mmol) in
dry CH2Cl2 (30 mL) at ꢀ40 ꢁC was added dropwise DIBAL-H
(6.3 mL, 11.1 mmol, 1.75 M in toluene) through a syringe. The
reaction mixture was allowed to warm at room temperature over
a period of 2 h, then re-cooled to 0 ꢁC and treated with saturated
aqueous solution of potassium sodium tartrate. The solid
material was ltered through a pad of Celite and concentrated
(R)-1-(3-(Benzyloxy)oct-1-enyl)-2-nitrobenzene, 15
A
mixture of 1-iodo-2-nitrobenzene (1.67 g, 6.7 mmol),
in vacuo. Silica gel column chromatography of the crude Pd(PPh3)2Cl2 (94 mg, 0.134 mmol, 2 mol%), CuI (13 mg,
product using EtOAc/hexane (3 : 7 v/v) as eluent furnished 0.067 mmol, 1 mol%), Et3N (60 mL) and 14 (1.45 g, 6.7 mmol) in
monobenzyl protected alcohol 13 (1.9 g, 93%) as a pale yellow 20 mL DMF was purged with nitrogen for 10 min. The resulting
oil. [a]2D5 ꢀ44.7 (c 1, CHCl3); IR (CH2Cl2) n: 2957, 2902, 2820, mixture was then stirred at 100 C for 3 h. It was then
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concentrated, diluted with water, extracted with ether, dried Na2SO4, and concentrated in vacuo. Silica gel column chroma-
over sodium sulfate and concentrated in vacuo. Silica gel tography of the crude product using EtOAc/hexane (1 : 99 v/v) as
column chromatography of the crude product using EtOAc/ eluent furnished the target compound (+)-angustureine 2
hexane (1 : 19 v/v) as eluent gave the coupled product 15 (2.15 (345 mg, 88% over two steps) as pale yellow oil. {[a]2D5 +7.6 (c 0.4,
g, 95%) as a yellow oil. [a]2D5 ꢀ121.3 (c 1, CHCl3); IR (CH2Cl2) n: CHCl3) [Lit.5t +7.5 (c 0.4, CHCl3); IR (CH2Cl2) n: 2930, 2860, 950,
3275, 1540, 1341, 2205, 870 cmꢀ1; 1H NMR (CDCl3, 400 MHz) d: 750 cmꢀ1; 1H NMR (CDCl3, 400 MHz) d: 7.1 (t, 1H, J ¼ 7.2 Hz),
8.0 (m, 1H), 7.6 (m, 2H), 7.26–7.42 (m, 6H), 4.9 (d, 1H, J ¼ 11.5 6.9 (d, 1H, J ¼ 7.2 Hz), 6.57 (t, 1H, J ¼ 7.2 Hz), 6.52 (d, 1H, J ¼
Hz), 4.6 (d, 1H, J ¼ 11.9 Hz), 4.3 (t, 1H, J ¼ 6.8 Hz), 1.84–1.88 (m, 7.2 Hz), 3.2 (m, 1H), 2.92 (s, 3H), 2.66 (m, 1H), 2.62 (m, 1H), 1.8
2H), 1.5 (m, 2H), 1.3 (m, 4H), 0.9 (t, 3H, J ¼ 6.8 Hz); 13C NMR (m, 2H), 1.56 (m, 1H), 1.25–1.3 (m, 7H), 0.9 (t, 3H, J ¼ 6.84 Hz);
(CDCl3, 100 MHz) d: 149.8, 137.9, 134.9, 132.8, 128.7, 128.4, 13C NMR (CDCl3, 100 MHz) d: 145.3, 128.6, 127.0, 121.8, 115.1,
128.2, 127.7, 124.6, 118.3, 97.0, 81.1, 70.8, 69.1, 35.5, 31.5, 25.0, 110.3, 58.9, 37.9, 32.0, 31.1, 25.7, 24.3, 23.5, 22.7, 14.0; HRMS
22.5, 14.0; HRMS (ESI) m/z calcd for C21H24NO3 [M + 1] (ESI) m/z calcd for C15H24N [M + 1] 218.1902; found 218.1902.
338.1779; found 338.1780.
Acknowledgements
(R)-1-(2-Aminophenyl)octan-3-ol, 16
Y.G. and S.G. thank UGC and CSIR, respectively, New Delhi for
To a solution of 15 (1.0 g, 2.96 mmol) in EtOAc (12 mL) was
research fellowships. S.K.P. is thankful to University Grant
added catalytic amount of HCl followed by addition of 10%
Commission, New Delhi, for generous funding of the project
Pd/C (150 mg, 5 mol%). The reaction mixture was subjected to
[Grant no. F.20-40(12)/2013(BSR)]. We are grateful to Prof.
hydrogenation under 1 atmosphere pressure for 24 h. Aer this
Prakash Gopalan for his support and encouragement.
time, a solution of saturated Na2CO3 was added to the reaction
mixture, ltered through a pad of Celite and washed with
additional EtOAc (30 mL) and organic layer separated. The
Notes and references
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2.6 (m, 2H), 2.1 (bs, 1H), 1.7 (m, 2H), 1.25–1.28 (m, 8H), 0.87 (t,
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droquinolone (norangustureine), which was used as such for
next step without further purication.
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w/w in H2O, 1.5 mL, 18 mmol), sodium cyanoborohydride
(1.13 g, 18 mmol) and acetic acid (1 mL, 18 mmol) and stirred
for 10 h at room temperature. TLC monitoring showed
complete conversion {hexane/ethyl acetate 19 : 1 v/v, Rf ¼ 0.60}.
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layer was extracted with diethyl ether (3 ꢂ 10 mL). The
combined organic layer was washed with brine, dried over
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