A concise and efficient synthesis of tetrahydroquinoline alkaloids using the phase transfer mediated Wittig olefination reaction

Article abstract of DOI:10.1016/j.tetlet.2017.07.044

The present study describes the total synthesis of 1,2,3,4-tetrahydroquinoline alkaloids (±)-galipinine, (±)-cuspareine, (±)-galipeine and (±)-angustureine, in three steps and high yields (78%, 76%, 74%, and 66%, respectively) from common aldehyde and the ylide respectives. The key step of this approach is based on an unusual Wittig reaction by using the phase transfer medium (aq. NaOH/CH₂Cl₂ 1:1 or t-BuOK/t-BuOH/CH₂Cl₂ 1:1), affording olefinic intermediates in high yields.

Full text of DOI:10.1016/j.tetlet.2017.07.044

Accepted Manuscript
A Concise and Efficient Synthesis of Tetrahydroquinoline Alkaloids Using the
Phase Transfer Mediated Wittig Olefination Reaction
Gaspar Diaz-Muñoz, Raquel Geralda Isidorio, Izabel Luzia Miranda, Gabriel
Nunes de Souza Dias, Marisa Alves Nogueira Diaz
PII:
S0040-4039(17)30890-0
DOI:
http://dx.doi.org/10.1016/j.tetlet.2017.07.044
TETL 49126
Reference:
Tetrahedron Letters
To appear in:
Received Date:
Revised Date:
Accepted Date:
20 May 2017
2 July 2017
10 July 2017
Please cite this article as: Diaz-Muñoz, G., Isidorio, R.G., Miranda, I.L., de Souza Dias, G.N., Diaz, M.A.N., A
Concise and Efficient Synthesis of Tetrahydroquinoline Alkaloids Using the Phase Transfer Mediated Wittig
Olefination Reaction, Tetrahedron Letters (2017), doi: http://dx.doi.org/10.1016/j.tetlet.2017.07.044
This is a PDF file of an unedited manuscript that has been accepted for publication. As a service to our customers
we are providing this early version of the manuscript. The manuscript will undergo copyediting, typesetting, and
review of the resulting proof before it is published in its final form. Please note that during the production process
errors may be discovered which could affect the content, and all legal disclaimers that apply to the journal pertain.

A Concise and Efficient Synthesis of Tetrahydroquinoline Alkaloids
Using the Phase Transfer Mediated Wittig Olefination Reaction
Gaspar Diaz-Muñoz1*, Raquel Geralda Isidorio1, Izabel Luzia Miranda1, Gabriel Nunes
de Souza Dias,2 and Marisa Alves Nogueira Diaz3
1Departament of Chemistry, Universidade Federal de Minas Gerais, Belo Horizonte,
Minas Gerais 31270-901, Brazil
2Aquaculture-Veterinay School, Universidade Federal de Minas Gerais, Belo
Horizonte, Minas Gerais 31270-901, Brazil
3Departament of Biochemistry and Molecular Biology, Universidade Federal de Viçosa,
Minas Gerais 36570-900, Brazil
*Correspondence should be addressed to Gaspar Diaz-Muñoz: gaspardm@qui.ufmg.br.
Abstract
The present study describes the total synthesis of 1,2,3,4-tetrahydroquinoline alkaloids
(±)-galipinine, (±)-cuspareine, (±)-galipeine and (±)-angustureine, in three steps and
high yields (78%, 76%, 74%, and 66%, respectively) from common aldehyde and the
ylide respectives. The key step of this approach is based on an unusual Wittig reaction
by using the phase transfer medium (aq. NaOH/CH2Cl2 1:1 or t-BuOK/t-BuOH/CH2Cl2
1:1), affording olefinic intermediates in high yields.
Keyword: Wittig reaction, phase transfer medium, tetrahydroquinoline alkaloids,
Galipea officinalis.
3

Tetrahydroquinoline alkaloids
1,2,3,4-Tetrahydroquinoline (THQ) alkaloids are important pharmacological
structures that are currently among the most popular targets for the development of new
synthetic methodologies.1 Among the natural alkaloids containing the 1,2,3,4-
tetrahydroquinoline nucleus, angustureine and its congeners – galipinine, cuspareine,
and galipeine – stand out (Figure 1).
12
2'
O
O
OCH3
OCH3
1'
6'
3'
N
N
11
CH3
CH3
4'
5'
galipinine
cuspareine
5
8
4
9
6
7
3
2
1
N
OH
10
N
11
15
CH3
CH3
OCH3
angustureine
galipeine
Figure 1. Structures of THQ alkaloids galipinine, cuspareine, galipeine, and
angustureine.
These alkaloids were isolated from the stem bark of Galipea officinalis Hancock, a
South American shrub known as angostura and characterized for the first time by
Jacquemond-Collet et al.2 and Rakotoson et al.3 Extracts of the stem bark of this shrub
have been used in Venezuelan folk medicine to treat various diseases, including
dyspepsia, dysentery, and diarrhea, and symptoms such as fever.4 Additional biological
assessments of alkaloids also revealed a prominent in vitro antimalarial activity (IC50
0.09-38 g mL-1) against chloroquine-resistant (CQR) strains.5
In this context, these compounds have emerged as reference standards for the
application of new methodologies to prepare tetrahydroquinoline-type structures. In the
literature, there are more than 24 publications to date concerning the synthesis of these
tetrahydroquinolinic alkaloids,6 in addition to a recent review covering this subject.1
4

A Wittig reaction
The Wittig reaction is one of the most versatile synthetic methods for the preparation
of olefins from carbonyl compounds. This reaction classically requires the use of
hydrides or organometallic bases, anhydrous aprotic organic solvents, and an inert
atmosphere.
However, in recent years, the use of water instead of the use of organic solvents,
whether totally or partially, in various organic reactions, especially in the Wittig
reaction, have become increasingly popular. These studies have contributed to the
development of new environmentally benign chemical methodologies. Some
representative examples on this topic can be seen in the works of Wu, J. & Yue, C.; and
Bergdahl et al.; among others.7
Inserted in a research program for the synthesis of natural products with remarkable
biological activities, which allows for advances in the bioprospecting of new drugs,
mainly against neglected tropical diseases (leishmaniasis, Chagas disease, and
schistosomiasis), the present study seeks to describe a new approach to the racemic
synthesis of 2-alkyl-substituted tetrahydroquinolinic alkaloids: galipinine, cuspareine,
galipeine, and angustureine. The preparation of these compounds was facilitated by the
use of a phase transfer medium in the Wittig reaction, applied as a new protocol, to
prepare the olefin intermediates for the synthesis of these alkaloids. Our main interest
focused on a simple, direct, and environmentally friendly approach that would allow for
the synthesis of these alkaloids.
From our point of view, the key reaction in alkaloid synthesis, according to the
retrosynthetic analysis shown in Scheme 1, is the Wittig olefination between
quinaldehyde 7 and phosphorus ylides (phosphoranes) 11, 17, 25, and 30 (prepared in
situ from the respective phosphonium salts by treatment with a base). Quinaldehyde 7
can be readily obtained from the commercially available quinaldine acid (5). The Wittig
salts 10, 16, 24, and 29, which are phosphorane precursors, can be prepared from the
piperonyl alcohol (8), 3,4-dimethoxybenzyl alcohol (14), 3-benzyloxy-4-
methoxy)benzyl alcohol (22), and bromobutane (28), respectively.
5

Wittig olefination
R
reduction
OR2
OR1
Ph3P
+
H
N
N
R
N
N-methylation
12 or 18 or 26 or 31
Me
O
7
11, R1,R2 = -CH2-
17, R1 = R2 = CH3
O
R =
(±)-galipinine (1),
(±)-cuspareine (2),
O
25, R1 = CH3, R2 = Bn
OMe
R =
30, Ph3P
OH
OMe
OH
N
O
quinaldic acid (5)
(±)-galipeine (3), R =
OMe
R =
(±)-angustureine (4),
Scheme 1. Retrosynthetic analysis of the THQ alkaloids (±)-galipinine, (±)-cuspareine,
(±)-galipeine and (±)-angustureine.
Synthesis of quinaldehyde 7 and the benzyl alcohol 22
Our synthesis started with the preparation of aldehyde 7 and (3-benzyloxy-4-
methoxy)benzyl alcohol (22). The sequence of esterification followed by reduction with
DIBAL at 78 oC from the quinaldine acid (5), led to aldehyde 7 in 83% yield (2 steps)
(Scheme 2). Benzyl alcohol 22 was obtained in a two-step one-pot synthesis from
isovanillic acid (20). The protection of phenolic hydroxyl and simultaneous
esterification of 20, was done by treatment with benzyl bromide and K2CO3 in DMF.
Reduction of the ester function with DIBAL at 21, with no purification, afforded
alcohol 22 in 98% yield (2 steps).
DIBAL, CH2Cl2
iodoethane, K2CO3
78 oC, 1.5 h
H
OH
OEt
N
N
N
quantitative
82%
O
O
O
quinaldine acid (5)
6
7
O
O
DIBAL, CH2Cl2
0 oC, 2 h
BrBn, K2CO3, DMF
60 oC, 24 h
OBn
OH
OBn
HO
HO
BnO
98% (2 steps)
OCH3
OCH3
isovanillic acid (20)
OCH3
21
22
6

Scheme 2. Preparation of aldehyde 7 and benzyl alcohol 22.
Synthesis of Wittig's salts 10, 16, 24, and 29
Treatment with PBr3 in CH2Cl2 of benzyl alcohols 8, 14, and 22, produced bromides
9, 15, and 23, respectively (Scheme 3). These bromides, which are very unstable when
exposed to chromatographic column purification, were treated with Ph3P immediately
after their preparation, producing Wittig's salts 10 and 16 in 83% yield (2 steps) after
recrystallization with ethanol, and Wittig's salt 24 in 89% yield (2 steps) after
purification by column chromatography. However, Wittig's salt 29 was prepared
directly from bromobutane (28) by treatment with Ph3P, affording salt 29 in 85% yield
after purification by column chromatography.
PBr3, CH2Cl2
0 oC to r.t., 2.0 h
Ph3P, CH3CN
reflux, overnight
83-89% (2 steps)
OR2
OR1
OR2
OR1
OR2
OR1
HO
BrPh3P
Br
10, R1,R2 = -CH2-
9 or 15 or 23
piperonyl alcohol (8), R1,R2 = -CH2-
3,4-dimethoxybenzyl alcohol (14), R1 = R2 = CH3
16, R1 = R2 = CH3
(3-benzyloxy-4-methoxy)benzyl alcohol (22), R1 = CH3, R2 = Bn
24, R1 = CH3, R2 = Bn
Ph3P, CH3CN
reflux, overnight
Br
BrPh3P
85%
bromobutane (28)
29
Scheme 3. Synthesis of the Wittig salts 10, 16, 24 and 29.
Synthesis of THQ alkaloids galipinine, cuspareine, galipeine, and angustureine
With the quinoline aldehyde (7) and the respective phosphonium salts 10, 16, 24, and
29, we attempted to carry out the Wittig olefination reaction between these substrates. It
was believed that it would be a simple task; however, exhaustive attempts, employing
conventional methods (PhLi/Et2O,8 n-BuLi/hexanes, NaHMDS/THF,10 t-BuOK/THF,11
t-BuOK/toluene,12 etc) led to fruitless results (yields of less than 5% and obtaining
unwanted products).
7

In light of these results, we rationalized that the problem could be a consequence of
the low solubility of the phosphonium salts in the organic solvents used to conduct this
study. Hence, another Wittig olefination attempt between 7 and 10, employing
NaHMDS and a mixture of solvents THF/dioxane/DMF (1:1:1) (Method A), led to the
olefination product 12, in 75% yield (Table 1 and Scheme 4).
To verify the above hypothesis, we performed another Wittig olefination attempt
between aldehyde 7 and salt 10, this time using aqueous NaOH and CH2Cl2, known as
the phase transfer medium (Table 1: Method B and Scheme 4). In this case, the ylide
derived from benzo[1,3]dioxol-5-ylmethyl-triphenylphosphonium bromide 10, as it
does not have a global charge, can change from the aqueous phase to the organic phase.
In addition, the hydroxide ion and the phosphonium salt preferably remain in the
aqueous phase, while the aldehyde and the olefin produced preferably remain in the
organic phase (Table 1; Method B). To our surprise, this attempt produzed olefin 12 in
a high yield (95%) in a mixture of E/Z isomers (1:3) according to the 1H NMR spectrum
analysis obtained from an aliquot of the crude sample. The latter result confirms our
initial suspicions, suggesting that the problem in obtaining Wittig olefination products
in low yields is due to the low solubility of Wittig salts in organic solvents, although the
literature reports otherwise. This new protocol was consolidated with the reproduction
of other olefination products 18, 26, and 31 in high yields (85-94%) from the aldehyde
7 and the salts 16, 24, and 29, respectively. However, a solution of t-BuOK/t-
BuOH/CH2Cl2 (1:1), under reflux (Method C) to produce the Wittig olefination between
aldehyde 7 and the aliphatic Wittig salt 29, was required for the preparation of the
olefin intermediate 31. This change was necessary, since using the B method, under
reflux with these substrates, produced olefin 31 with low yields (<10%). Note: It is
worth mentioning that this is the first time that a phase transfer medium has been used
to perform the Wittig olefination reaction with these substrates.
Table 1. Wittig olefination and synthesis of THQ alkaloids 1, 2, 3, and 4.
Wittig
olefination A: NaHMDS,
THF/dioxane/DMF (1:1:1), 0
Yield
(%)
Reduction
(%)
N-Methylation:
Method:
THQ alkaloids (%)
8

oC 10 min to r.t., 24 h
B: aq. NaOH/CH2Cl2 (1:1),
r.t., 3 h
C: t-BuOK/t-BuOH/CH2Cl2
(1:1), reflux, 24 h
Conventional
0-5
-
-
7 + 10
7 + 10
7 + 10
7 + 16
7 + 24
7 + 29
12 (75)
12 (95)
18 (94)
26 (92)
31 (85)
-
A
B
B
B
C
-
13 (92)
19 (91)
27 (89)
32 (92)
1 (90)
2 (88)
3 (90)
4 (85)
OR2
Method A
from 10
BrPh3P
E/Z (1:3)
H
+
OR1
10, R1,R2 = -CH2- or
N
N
R
Method B
from 10, 16 and 24
O
12 or 18 or 26 or 31
7
16, R1 = R2 = CH3 or
Method C
from 29
24, R1 = CH3, R2 = Bn
or
BrPh3P
29
PtO2, H2
Iodomethane, K2CO3
CH3OH, 8 h
78-87% (2 steps)
DMF, r.t., 24 h
from 13, 19 and 32
85-90%
N
R
N
R
H
Me
13 or 19 or 27 or 32
O
(±)-galipinine (1), R =
O
HCHO, NaBH3CN
AcOH, MeCN, t.a.
from 27
OMe
(±)-cuspareine (2), R =
(±)-angustureine (4), R =
90%
OMe
OH
OMe
N
Me
(±)-galipeine (3)
Scheme 4. Synthesis of THQ alkaloids (±)-galipinine, (±)-cuspareine, (±)-galipeine,
and (±)-angustureine.
9

To complete the synthesis of the THQ alkaloids, the double bonds of crude olefinic
adducts 12, 18, 26, and 31 were simultaneously hydrogenated by treatment with PtO2
and hydrogen atmosphere, in turn, reducing both the endocyclic quinoline ring as well
as the exocyclic double bonds, in addition to promoting debenzylation in olefin 26 in
order to produce (±)-nor-galipinine (13), (±)-nor-cuspareine (19), (±)-nor-galipeine
(27), and (±)-nor-angustureine (32) in 78-87% yields (2 steps). Finally, N-methylation
with iodomethane and K2CO3 in DMF of 13, 19, and 32, and under reductive amination
conditions of 27, using HCHO/AcOH and NaBH3CN, produced, respectively, (±)-
galipinine (1), (±)-cuspareine (2), (±)-angustureine (4), and (±)-galipeine (3) in yields of
85-90%. It proved to be impossible to control the chemosseletively N-methylation from
nor-galipeine (27), which possesses the free amine and hydroxyl phenolic functions,
using CH3I, to produce galipeine (3). This protocol has always indirectly produced
cuspareine (2) as the simultaneous product of N- and O-methylation, even when using
an eq. of CH3I. The chemoselective N-methylation of 27, in a single step, was only
possible by treatment with HCHO/NaBH3CN (reductive N-methylation) to afford (±)-
galipeine (3) in 90% yield.
1
13
Characterizations of the compounds were made from the analysis of IR, H and C
NMR and mass spectra. However, there are some discrepancies with the 13C NMR data
13
described in the literature for the first two alkaloids: galipinine and cuspareine.2 For C
NMR, some signals of the side chain aromatic rings of our synthetic products galipinine
(1) and cuspareine (2) do not match to those published for the natural products.2 For
example, the signals of the C-2' and C-5' carbons (Table 2) in products 1 and 2 from our
study appear in 108.7 and 111.7 ppm, respectively, while the signals of these same
carbons in natural products 1 and 2 appear, surprisingly, at 111.6 and 108.8 ppm, a
difference of approximately 3 ppm for each chemical shift of these carbons. Trying to
understand these discrepancies, we performed a careful re-evaluation of all of the
compounds’ the spectral data, mainly from the HSQC and HMBC spectra of 1 and 2,
which allowed us to conclude that the attributions of chemical shifts of these carbon
atoms are unequivocal.
In this context, performing a new evaluation and careful comparison between the 13C
NMR data of the natural and synthetic alkaloids 1 and 2, allowed us to conclude that
10

there was, probably, an involuntary inversion of these data by the authors. This can be
verified by exchanging the data for the natural compounds 1 and 2 and by comparing
them again with the synthetic ones, this time observing a perfect correlation between
these values, except for the presence of two signals of the methoxy groups in compound
2 rather than the signal of the methylenedioxy group present in compound 1. Table 2
shows the data of the 13C NMR signals of the synthetic products 1, 2, 3, and 4 obtained
in this work as compared to those from natural sources.
Table 2. 13C NMR (CDCl3, 100 MHz) chemical shifts of natural and synthetics
galipinine (1), cuspareine (2), galipeine (3), and angustureine (4).
Carbon
1
1
2
2
3
3
4
4
synthetic natural3 synthetic natural3 synthetic natural2 synthetic natural2
NCH3
2
38.0
58.2
24.4
23.6
110.6
127.1
115.4
128.6
121.7
145.3
33.2
32.0
-
38.1
58.4
24.4
23.6
110.7
127.1
115.4
128.7
122.7
145.3
33.1
31.9
-
38.0
58,3
24.4
23.5
110.6
127.0
115.4
128.6
121.7
145.3
33.0
31.9
-
38.1
58.3
24.4
23.6
110.7
127.2
115.5
128.7
121.8
145.4
33.2
32.1
-
38.2
58.4
24.6
23.8
110.8
127.3
115.6
128.8
122.0
145.5
33.1
31.8
-
38.2
58.5
24.4
23.6
110.7
127.2
115.4
128.8
121.8
145.4
33.2
32.1
-
38.1
59.2
26.0
23.8
110.6
127.2
115.4
128.8
122.1
145.6
31.4
24.7
32.2
22.9
14.2
-
38.2
59.3
26.1
23.9
110.7
127.4
115.5
128.9
122.0
145.7
31.5
24.8
32.4
23.0
14.4
-
3
4
5
6
7
8
9
10
11
12
13
14
15
1’
-
-
-
-
-
-
-
-
-
-
-
-
135.8
108.7*
147.6
145.6
108.1*
120.9
-
134.7
111.6
148.9
147.2
111.3
120.1
-
134.6
111.7*
148.9
147.2
111.4*
120.0
55.9
55.8
135.9
108.8
147,6
145.7
108.2
121.0
55,9
55,9
135.5
110.9
144.9
145.7
114.7
119.7
56.2
134.0
110.8
143.7
146.5
114.3
120.9
56.0
-
2’
-
-
3’
-
-
4’
-
-
5’
-
-
6’
-
-
OCH3
OCH3
-
-
-
-
-
-
11

OCH2O
100.7
100,8
-
-
-
-
-
* Original assignments in galipinine and cuspareine synhetics.
In summary, the use of the phase transfer medium (aq. NaOH/CH2Cl2 1:1 or t-
BuOK/t-BuOH/CH2Cl2 1:1) in the Wittig olefination reaction established a significant
advance for this reaction. This new protocol involves an environmentally friendly
method, whose mild conditions, operational simplicity and high yields make this
approach a highly attractive method for the synthesis of 2-alkyltetrahydroquinoline
alkaloids. Additional tests are also being performed using the t-BuOK/t-BuOH/CH2Cl2
(1:1) system with chiral aldehydes in the Wittig reaction. The objective of these tests
was to verify if these conditions avoid or minimize the racemization rate of the chiral
aldehydes, in the generation of ylides, as well as to generalize the reach of the
methodology for chiral substrates. These results will be published on another occasion.
Acknowledgments
We would like to thank FAPEMIG for a grant awarded to G.D.-M. (APQ-01061-14)
and PRPq-UFMG for a scholarship awarded to G.N.S.D. We thank Research Center
René Rachou - Fiocruz-MG for the mass spectra.
Supplementary data
Supplementary data (general experimental procedures, NMR and mass spectra)
associated with this article can be found at http://dx.doi.org/......
References
1. Diaz-Muñoz, G.; Dudley, G. B. Org. Prep. Proced. Int. 2015, 47, 179-206.
2. Jacquemond-Collet, I.; Hannedouche, S.; Fabre, N.; Fourast, I.; Moulis, C.
Phytochemistry 1999, 51, 1167-1169.
12

3. Rakotoson, J. H.; Fabre, N.; Jacquemond-Collet, I.; Hannedouche, S.; Fourasté, I.;
Moulis, C. Planta Med. 1998, 64, 762-763.
4. Mester, I. Fitoterapia 1973, 44, 123-152.
5. Jacquemond-Collet, I.; Benoit-Vical, F.; Valentin, M. A.; Stanislas, E.; Mallie, M.;
Fouraste, I. Planta Med. 2002, 68, 68-69.
6. (a) Wang, W.-B.; Lu, S.-M.; Yang, P.-Y.; Han, X.-W.; Zhou, Y.-G. J. Am. Chem.
Soc. 2003, 125, 10536-10537.; (b) Avemaria, F.; Vanderheiden, S.; Braese, S.
Tetrahedron 2003, 59, 6785-6796.; (c) Lin, X.-F.; Li, Y.; Ma, D.-W. Chin. J. Chem.
2004, 22, 932-934.; (d) Theeraladanon, C.; Arisawa, M.; Nakagawa, M.; Nishida, A.
Tetrahedron: Asymmetry 2005, 16, 827-831; Lu, S.-M.; (e) Wang, Y.-Q.; Han, X.-
W.; Zhou, Y.-G. Angew. Chem., Int. Ed. 2006, 45, 2260-2263.; (f) Rueping, M.;
Antonchick, A. P.; Theissmann, T. Angew. Chem., Int. Ed. 2006, 45, 3683-3686.; (g)
Ryu, J.-S. Bull. Korean Chem. Soc. 2006, 27, 631-632.; (h) Patil, N. T.; Wu, H.;
Yamamoto, Y. J. Org. Chem. 2007, 72, 6577-6579.; (i) O’Byrne, A.; Evans, P.
Tetrahedron 2008, 64, 8067-8072.; (j) Shahane, S.; Louafi, F.; Moreau, J.; Hurvois,
J.-P.; Renaud, J.-L.; van de Weghe, P.; Roisnel, T. Eur. J. Org. Chem. 2008, 4622-
4631.; (k) Fustero, S.; Moscardó, J.; Jiménez, D.; Pérez-Carrión, M. D.; Sánchez-
Roselló, M.; del Pozo, C. Chem. Eur. J. 2008, 14, 9868-9872.; (l) Wang, Z.-J.; Zhou,
H.-F.; Wang, T.-L.; He, Y.-M.; Fan, Q.-H. Green Chem. 2009, 11, 767-769.; (m)
Kothandaraman, P.; Foo, S. J.; Chan, P. W. H. J. Org. Chem. 2009, 74, 5947-5952.;
(n) Chen, B.-L.; Wang, B.; Lin, G.-Q. J. Org. Chem. 2010, 75, 941-944.; (o) Cruz-
Lopez, O.; Nunez, M. C.; Conejo-Garcia, A.; Kimatrai, M.; Campos, J. M. Curr.
Org. Chem. 2011, 15, 869-887.; (p) Bentley, S. A.; Davies, S. G.; Lee, J. A.;
Roberts, P. M.; Thomson, J. E. Org. Lett. 2011, 13, 2544-2547.; (q) Wang, T.; Zhuo,
L.-G.; Li, Z.; Chen, F.; Ding, Z.; He, Y.; Fan, Q.-H.; Xiang, J.; Yu, Z.-X.; Chan, A.
S. C. J. Am. Chem. Soc. 2011, 133, 9878-9891.; (r) Satyanarayana, G.; Pflästerer, D.;
Helmchen, G. Eur. J. Org. Chem. 2011, 6877-6886.; (s) Ye, K.-Y.; He, H.; Liu, W.-
B.; Dai, L.-X.; Helmchen, G.; You, S.-L. J. Am. Chem. Soc. 2011, 133, 19006-
19014.; (t) Taylor, L. L.; Goldberg, F. W.; Hii, K. K. Org. Biomol. Chem. 2012, 10,
4424-4432.; (u) Tummatorn, J.; Diaz-Muñoz, G.; Dudley, G. B. Tetrahedron Lett.
2013, 54, 1312-1314.; (v) Dousová, H.; Horák, R.; Ruzicková, Z.; Simunek, P.
13

Beilstein J. Org. Chem. 2015, 11, 884-892.; (w) Garg, Y.; Gahalawat, S.; Pandey, S.
K. RSC Adv. 2015, 5, 38846-38850.
7. (a) Wu, J.; Yue, C. Synth comm. 2006, 36, 2939-2947.; (b) El-Batta, A.; Jiang, C.;
Zhao, W.; Annes, R.; Cooksy, A. L.; Bergdahl, M. J. Org. Chem. 2007, 72, 5244-
5259.
8. Wittig, G.; Geissler, G. Liebigs Ann. 1953, 580, 44-57.
9. Corey, E. J.; Yamamoto, H. J. Am. Chem. Soc. 1970, 92, 226-228.
10. Karatholuvhu, M. S.; Sinclair, A.; Newton, A. F.; Alcaraz, M-L.; Stockman, R. A.;
Fuchs, P. L. J. Am. Chem. Soc. 2006, 128, 12656-12657.
11. Nagaoka, H.; Kishi, Y. Tetrahedron 1981, 37, 3873-3888.
12. Taber, D. F.; Sheth, R. B. J. Org. Chem., 2008, 73, 8030-8032.
14

 The total synthesis of 1,2,3,4-tetrahydroquinoline alkaloids, was carry out in
three steps and high yields.
 The key step of this approach is based on an unusual Wittig reaction by using
the phase transfer medium.
 This protocol is compatible with chiral aldehydes.
Graphical Abstract
A Concise and Efficient Synthesis of Tetrahydroquinoline Alkaloids
Using the Phase Transfer Mediated Wittig Olefination Reaction
Gaspar Diaz-Muñoz, Raquel Geralda Isidorio, Izabel Luzia Miranda, Gabriel Nunes de Souza
Dias, Marisa Alves Nogueira Diaz
THQ alkaloids
N
R
OR2
OR1
CH3
BrPh3P
Using the Phase Transfer
Medium Wittig Reaction
O
H
+
(±)-galipinine (1), R =
N
7
O
10, R1,R2 = -CH2-
O
OCH3
16, R1 = R2 = CH3
E/Z (1:3)
(±)-cuspareine (2), R =
(±)-galipeine (3), R =
(±)-angustureine (4), R =
24, R1 = CH3, R2 = Bn
OCH3
OH
N
R
29,
BrPh3P
12 or 18 or 26 or 31
OCH3
15