Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical Cyclization: Application in the Synthesis of ent-Tadalafil

Article abstract of DOI:10.1002/adsc.202100506

An enantioselective synthesis of 1-substituted tetrahydroisoquinolines from L–Dopa methyl ester through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of (S)-2-amino-3-(2-bromo-4,5-dimethoxyphenyl)propanoate followed by condensation with various aldehydes to afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating conditions (ⁿBu₃SnH/AIBN) cyclizes via 6-endo mode to afford cis-1-substituted tetrahydroisoquinolines exclusively in 99% ee. The utility of this synthetic protocol is demonstrated in the synthesis of (6S, 12aS) Tadalafil (5 steps, 21%, 99% ee). (Figure presented.).

Full text of DOI:10.1002/adsc.202100506

RESEARCH ARTICLE
doi.org/10.1002/adsc.202100506
Diastereospecific Synthesis of Tetrahydroisoquinolines via Radical
Cyclization: Application in the Synthesis of ent-Tadalafil
Wei-Jung Chiu,a Yan-Liang Lin,a Indrajeet J. Barve,a, c and Chung-Ming Suna, b,*
a
Department of Applied Chemistry,
National Chiao-Tung University,
Hsinchu 300-10, Taiwan
E-mail: cmsun@nctu.edu.tw
Department of Medicinal and Applied Chemistry,
b
Kaohsiung Medical University,
Kaohsiung 807-08, Taiwan
Department of Chemistry,
c
MES Abasaheb Garware College,
Pune, India
Manuscript received: April 24, 2021; Revised manuscript received: June 11, 2021;
Version of record online: ■■■, ■■■■
Supporting information for this article is available on the WWW under https://doi.org/10.1002/adsc.202100506
Abstract: An enantioselective synthesis of 1-substituted tetrahydroisoquinolines from L–Dopa methyl ester
through intramolecular aryl radical cyclization is demonstrated. The strategy consists of bromination of (S)-2-
amino-3-(2-bromo-4,5-dimethoxyphenyl)propanoate followed by condensation with various aldehydes to
afford bromoimidate ester. Aryl radicals generated from bromoimidate ester under the radical generating
conditions (nBu3SnH/AIBN) cyclizes via 6-endo mode to afford cis-1-substituted tetrahydroisoquinolines
exclusively in 99% ee. The utility of this synthetic protocol is demonstrated in the synthesis of (6S, 12aS)
Tadalafil (5 steps, 21%, 99% ee).
Keywords: diastereospecific synthesis; isoquinolines; radical cyclization; Tadalafil; tetrahydroisoquinolines
Introduction
Commercial drug quinisocaine as a topical anesthetic
utilized to reduce pruritus (Figure 1).[8]
Tetrahydroisoquinolines, particularly 1-substituted tet-
Most of the tetrahydroisoquinolines present in plant
rahydroisoquinolines exist in naturally occurring alka- alkaloids and pharmaceutical agents have a chiral
loids and pharmaceutical agents. For example, Higen- center at the C-1 position. Traditionally, Pictet-
amine is an alkaloid isolated from the roots of the
aconitum japonicum plant. It acts as a β2 adrenorecep-
tor agonist and shows vasodilating activity.[1] Solifena-
cin, a M3 selective receptor blocker is used to treat
urinary incontinence.[2] Naturally occurring alkaloid
noscapine isolated from papaver somniferum plant is
used as a cough-suppressing medicine.[3] The com-
pound MY336-1 was isolated from streptomyces
gabonae and utilized in the treatment of hypertension
and cardiac arrhythmias.[4] Salsolidine acts as a human
monoamine oxidase A inhibitor and displays antide-
pressant activity.[5] Emetine commonly found in the
ground roots of uragoga ipecacuanha has been used in
the therapy of amebiasis.[6] Isoquinoline-based alkaloid
Figure 1. Biologically active 1-substituted tetrahydroiso quino-
lines and isoquinolines.
papaverine shows an antispasmodic activity and is
useful in the treatment of smooth muscle spasm.[7]
Adv. Synth. Catal. 2021, 363, 1–7
1
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
Spengler condensation and Bischler-Napieralski reac- limitations such as low to moderate enantioselectivity,
tion of phenethylamines with aldehydes is an eminent low substrate scope and the necessity to use expensive
strategy for the construction of a tetrahydroisoquino- chiral catalysts. Since the synthesis of chiral 1-
line scaffold.[9,10] However, these methods are limited substituted
tetrahydroisoquinolines
remains
a
to the substrates containing electron-rich phenethyl challenge,[19] and in this regard, there is an utmost need
aromatic rings. Moreover, the stereochemical outcome to develop a synthetic protocol for the synthesis of 1-
of the transformation ends up with a mixture of substituted tetrahydroisoquinolines (THIQs) which
stereoisomers.[9,11] Hence, various synthetic strategies could be efficient and enantioselective. Herein we
and modifications of the traditional methods aimed at report the highly enantioselective synthesis of 1-
the asymmetric synthesis of 1-substituted tetrahydroi- substituted THIQs from L-Dopa through a radical
soquinolines (Scheme 1). For example, Zhang’s group intramolecular cyclization.
reported iridium-catalysed asymmetric hydrogenation
of 1-aryl-substituted dihydroisoquinolines to access
Results and Discussion
chiral 1-aryl-substituted tetrahydroisoquinolines.[12]
Ward found that enzyme norcoclaurine synthase can The requisite radical precursor bromoimidate ester 5a
efficiently catalyze Pictet-Spengler reaction to afford was prepared from commercially available L-3,4-
chiral disubstituted tetrahydroisoquinolines.[13] Bismuth dihydroxyphenylalanine methyl ester via bromination
(III) trifluoromethanesulfonate catalyzed chiral syn- followed by imination with various aldehydes. The
thesis of 1-substituted tetrahydroisoquinolines was Boc-protected methyl ester amine 1a was obtained
documented by Uenishi and colleagues.[14] Meyers’s from L-Dopa through series of functional group
group reported asymmetric alkylation of C-1 carbon of transformations.[20] Esterification of L-Dopa and the
tetrahydroisoquinoline in the presence of oxazoline subsequent protection of amino group gave Boc-
chiral auxiliary to give chiral tetrahydroisoquinoline protected L-Dopa methyl ester. Next, methylation and
derivatives.[15] Park developed asymmetric intramolec- bromination of 1a afforded 2a.[21] Removal of the Boc
ular cyclization of β-phenethylamine with chiral group gave methyl (S)-2-amino-3-(2-bromo-4,5-
aldehydes or ketones.[16] Recently, Kallman’s group dimethoxyphenyl) propanoate 3a. The desired imine
described a stereoselective Pictet-Spengler cyclization intermediate 5a was obtained when 3a was treated
of N-(phenylsulfonyl)alkyloxazolidinone in the pres- with an aldehyde (Scheme 2).
ence of Lewis acid.[17] Dalpozzo reviewed an enantio-
selective synthesis of 1-substituted tetrahydro-β-carbo- mixture of AIBN and Bu3SnH to 5a (0.01 M) in
Our study began with syringe-pump addition of a
n
lines by reacting 2-acyl-3-indoleacetic acid with chiral toluene under an argon atmosphere. The reaction
amino acid.[18]
afforded tetrahydroisoquinoline 6a-cis regioselectively
Despite the synthetic strategies mentioned above via 6-endo closure to the C-atom in only 54% yield
being useful and elegant, they possess multiple along with isoquinoline 7a (Table 1, entry 1). The
Scheme 1. Methods for the synthesis of chiral 1-substituted tetrahydroisoquinolines.
Adv. Synth. Catal. 2021, 363, 1–7
2
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
(Scheme 3). Accordingly, for cis-1,2,3-substituted tet-
rahydroisoquinolines, the bulky substituents at C1 and
C3 and N-substitution prefer pseudoequatorial position
which ultimately forces the newly formed tetrahydroi-
soquinoline ring in the most stable distorted half-chair
conformation. Next, we attempted to improve the
reaction yield. Accordingly, when the same reaction
n
was carried out using 2.5 equivalents of Bu3SnH, the
yield of 7a did not improve (Table 1, entry 2). The
yield of 7a was decreased when the amount of
nBu3SnH was increased up to 3 equivalents (Table 1,
entry 3). Subsequently, we tried the reaction at a
slightly higher reactant concentration and lower tem-
Scheme 2. Synthesis of methyl (S)-2-(benzylideneamino)-3-(2-
bromo-4,5-dimethoxyphenyl)propanoate 5a.
1
stereochemistry of 6a-cis was assigned by H NMR perature. In view of that, radical cyclization at 0.05 M
°
and NOE. A singlet at δ 5.09 ppm for C1-H proton concentration of 5a at 60 C furnished 6a-cis in a
appeared in proton NMR. Correlation between C1-H slightly lower yield, but the formation of 7a was
and C3-H protons was established through NOESY drastically suppressed (Table 1, entry 4). An increase
°
(See SI, S28). A highly competitive 1-phenylindoline in the reaction temperature to 70 C significantly
8a formation through 4-exo ring closure to the N-atom increased the reaction yield (Table 1, entry 5). To our
was not observed in this case. The stereoselectivity in delight, when the same reaction was carried out for
the cyclization could be reasoned on the basis of 2 h, the tetrahydroisoquinoline 6a-cis was obtained in
conformational[22] and molecular modeling analysis good yield (70%) with 99% ee along with the oxidized
Table 1. Optimization of reaction conditions.[a]
Entry
Initiator (equiv)
Additive
(equiv.)
Conc.
(M)
Temp
Yield (%)[b]
6a-cis
ee
(%)
°
( C)
7a
1
2
3
4
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
AIBN (1.5)
BPO (1.5)
DTBP (1.5)
Et3B (2.5)
–
nBu3SnH (2.2)
nBu3SnH (2.5)
nBu3SnH (3)
0.01
0.01
0.01
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.05
0.01
0.01
70
70
100
60
70
70
70
80
70
90
25
25
25
25
25
54
55
44
50
66
72
46
17
25
–
–
–
30
–
–
15
18
30
7
12
10
32
62
48
50
55
–
60
43
12
50
99
99
85
90
33
–
–
–
20
–
–
nBu3SnH (2.2)
nBu3SnH (2.2)
nBu3SnH (2.2)
nBu3SnH (2.2)
nBu3SnH (2.2)
(TMS)3SiH (2.2)
nBu3SnH (2.2)
nBu3SnH (2.2)
nBu3SnH (2.2)
Bis(tributyltin) (2.2)
Et3N (10)
5
6[c]
7[d]
8
9
10
11
12
13[e]
14[f],[g]
15[g]
10
46
42
–
AIBN (1.5)
nBu3SnH (2.5)
[a] Reaction conditions: 5a (1 equiv) 0.01 M, a radical initiator, additive, toluene (10 mL), syringe pump addition at a rate of 2 mL/
h, under argon atmosphere for 5 h.
[b] Isolated yield.
[c] Reaction for 2 h.
[d] Benzene as a solvent was used.
[e] Benzene, UV irradiation (254 nm).
[f] CH3CN as a solvent was used.
[g] UV irradiation (254 nm).
Adv. Synth. Catal. 2021, 363, 1–7
3
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
Scheme 3. A plausible radical mechanism for the formation of 6-cis and isoquinoline 7.
Table 2. The substrate scope for the synthesis of tetrahydroiso-
quinolines 6 and isoquinolines 7.[a]
product 7a (Table 1, entry 6). Changing the reaction
solvent to benzene reduced the efficiency of intra-
molecular radical cyclization and increased the iso-
quinoline product 7a (32%) (Table 1, entry 7). Eleva-
°
tion of the temperature to 80 C did not improve the
yield and the chiral HPLC analysis revealed partial
racemization of the product (Table 1, entry 8). The use
of (TMS)3SiH as a H-donor in the reaction instead of
nBu3SnH afforded 6a-cis in poor yield (Table 1,
entry 9). Incorporation of initiators like benzoyl
peroxide (BPO), di-tert-butyl peroxide (DTBP) or
triethylborane other than AIBN in the reaction yielded
either only isoquinoline 7a or no reaction at all
(Table 1, entries 10–12). We also tried to drive this
reaction by irradiating the reaction mixture with a UV
lamp (254 nm) in the presence of bis(tributyltin) in
benzene. The reaction afforded desired product in only
30% yield along with 7a (10%) and the starting
material (Table 1, entry 13). When the reaction was
performed in the presence of triethylamine under UV
irradiation, oxidized product 7a was obtained exclu-
sively (Table 1, entry 14). No desired product was
observed when the reaction was conducted using 1.5
[a] Reaction conditions:
5 (1 equiv.), AIBN (1.5 equiv.),
nBu3SnH (2.2 equiv.), dry toluene, syringe pump addition,
n
equiv. of AIBN and 2.5 equiv. of Bu3SnH under the
UV irradiation (Table 1, entry 15).
With the optimized conditions in hand, the scope
and generality of the intramolecular radical cyclization
reaction were investigated (Table 2). Accordingly, a
°
70 C, 5 h. All the reactions were carried out at 0.05 M
reactant concentration.
variety of aromatic aldehydes bearing electron-donat- the radical transformation. The substituent groups had
ing and electron-withdrawing groups were subjected to little influence on the reaction and the corresponding
Adv. Synth. Catal. 2021, 363, 1–7
4
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
products were obtained in good yield (6b-cis, 6c-cis,
6j-cis and 6k-cis). Besides, heteroaromatic aldehydes
were also examined. The use of furan-2-carboxalde-
hyde and thiophene-2-carboxaldehyde furnished the
desired products in moderate yield (6d-cis and 6e-cis).
The impact on the yields could be attributed to the
decomposition of the starting material owing to the
instability of the aldimine group during the reaction.
Pleasingly, aldimine generated from pyridine-2-carbox-
aldehyde was stable and in this case, 6f-cis was
obtained in good yield. However, when aliphatic
aldehydes were employed in the reaction, the desired
products (6g-cis and 6h-cis) did not obtain. When
hydroxyl groups of substrates were protected by
formation of ether, they needed a longer time for
reaction completion (6i-cis, 6j-cis and 6k-cis). Nota-
bly, bromo aldimine obtained from tryptophan methyl
ester underwent this transformation smoothly to afford
6l-cis in good yield.
Scheme 4. A radical synthesis of ent-Tadalafil.
The possible mechanism for the formation of provided imine 11. Next, the crude imine 11 was
tetrahydroisoquinoline 6-cis in a regio- and stereo subjected to the optimized condition of intramolecular
selective manner has been proposed in Scheme 3. radical cyclization in toluene to deliver tetrahydro-1H-
Initially, the decomposition of AIBN forms isobutyr- pyrido[3,4-b] indole-3- carboxylate 12 in 62% yield
n
onitrile radicals which then react with Bu3SnH to and methyl 1-(benzo[d][1,3]dioxol-5-yl)-9H-pyrido
generate tributyltin radicals. Removal of the Br atom [3,4-b] indole-3-carboxylate 7m in 18% yield. Acyla-
of 5 by tributyltin radical in a chain-propagating step tion of 12 with chloroacetyl chloride under basic
gives intermediate 5 A. Subsequent intramolecular conditions yielded intermediate 13 in 90% yield.
addition of aryl radical through 6-endo closure to the Lastly, the diketopiperazine ring was constructed via
C-atom furnishes intermediate 5B having a chair-like double nucleophilic substitution using methylamine to
six-membered transition state where C1 and C3 furnish ent-Tadalafil (5 steps, 21%) with 99% ee.
substituents possess pseudoequatorial positions (path
a). This mode of cyclization proceeds in preference to
either the formation of indoline 8 through intermediate
Conclusion
5c by 5-exo closure to the N-atom (path b) or In conclusion, we have demonstrated a method for the
diastereomer 6-trans via chair like intermediate 5B’ synthesis of enantiomerically pure cis-1-substituted
comprising 1,3-diaxial interactions. Lastly, tetrahydroi- tetrahydroisoquinolines 6. The sp2 aryl radical of
soquinoline 6-cis is formed by the abstraction of H bromoimidate ester subsequently cyclized via intra-
atom from nBu3SnH.
molecular 6-endo attack. The conformational prefer-
Based on the literature reports[23] and experimental ence for a chair-like six-membered transition state
observations, the formation of isoquinoline 7 from where bulky substituents at C1 and C3 require
tetrahydroisoquinoline 6-cis is proposed. The isobutyr- pseudoequatorial positions rationalizes cis selectivity.
onitrile radical abstracts C3-H hydrogen of 6-cis to Whereas, a conformer that could lead to trans-1-
form tetrahydroisoquinolinyl radical 6-cisA. Subse- substituted tetrahydroisoquinolines possess 1,3-diaxial
quent abstraction of the C4-H hydrogen of 6-cisA by interactions between substituents at C1 and C3. This
another isobutyronitrile radical generates dihydroiso- protocol also provides an alternative route towards a
quinoline 6B. Lastly, aerobic oxidation of 6B in the privileged scaffold-isoquinoline 7. The practicality of
presence of air (O2) as an oxidant yields isoquinoline this method was shown in the preparation of ent-
7.
Tadalafil in 21% (overall yield) with 99% ee.
Finally, the synthetic utility was demonstrated in
the stereoselective synthesis of the enantiomer of
Tadalafil which is a cGMP specific type V phospho-
Experimental Section
diesterase (PDE 5) inhibitor (Scheme 4). Our initial General Methods
efforts to brominate D-tryptophan methyl ester 9 by N-
1H NMR (400 MHz) and 13C NMR (101 MHz) spectra were
recorded on 400-MR automated spectrometer. Chemical shifts
are reported in parts per million (ppm) on the δ scale from an
internal standard (TMS). Analytical thin-layer chromatography
bromosuccinimide gave a mixture of 2-bromo trypto-
phan methyl ester 10 (45%), 2,5- and 2,6-dibromo-
tryptophan methyl esters.[24] In the next step, condensa-
tion of 10 with piperonal in dehydrating condition
Adv. Synth. Catal. 2021, 363, 1–7
5
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
asc.wiley-vch.de
(TLC) was performed using 0.25 mm silica gel-coated Kiselgel
60 F254 plates. Flash chromatography was performed using the
indicated solvent and silica gel 60 (Merck, 230–400 mesh).
High-resolution mass spectra (HRMS) were recorded in ESI
mode using TOF mass spectrometer. All materials were
purchased from commercial sources and used without further
purification.
Chang, H. S. Yun-Choi, Bioorg. Med. Chem. Lett. 2008,
18, 4110–4114.
[2] R. Basra, C. Kelleher, Ther. Clin. Risk Manag. 2008, 4,
117–128.
[3] A. DeBono, B. Capuano, P. J. Scammells, J. Med. Chem.
2015, 58, 5699–5727.
[4] H. Kase, H. Fujita, J. Nakamura, K. Hashizume, J. Goto,
K. Kubo, K. Shutto, J. Antibiot. 1986, 39, 354–363.
[5] M. E. Bembenek, C. W. Abell, L. A. Chrisey, M. D.
Rozwadowska, W. Gessner, A. Brossi, J. Med. Chem.
1990, 33, 147–152.
[6] R. Knight, J. Antimicrob. Chemother. 1980, 6, 577–593.
[7] Y. J. Gao, S. Stead, R. M. K. W. Lee, Life Sci. 2002, 70,
2675–2685.
[8] C. L. Gentry, R. J. Lukas, Pharm. Exp. Ther. 2001, 299,
1038–1048.
[9] E. D. Cox, J. M. Cook, Chem. Rev. 1995, 95, 1797–1842.
[10] R. D. M. Davis, J. H. Pink, J. S. Scott, A. Bailey,
Tetrahedron Lett. 2018, 59, 2917–2920.
[11] a) A. Couture, E. Deniau, P. Grandclaudon, S. Lebrun, S.
Léonce, P. Renard, B. Pfeiffer, Bioorg. Med. Chem. 2000,
8, 2113–2125; b) H. Suzuki, S. Aoyagi, C. Kibayashi,
Tetrahedron Lett. 1995, 36, 6709–6712.
[12] a) M. Perez, Z. Wu, M. Scalone, T. Ayad, V. Ratovelo-
manana-Vidal, Eur. J. Org. Chem. 2015, 6503–6514;
b) H. Nie, Y. Zhu, X. Hu, Z. Wei, L. Yao, G. Zhou, P.
Wang, R. Jiang, S. Zhang, Org. Lett. 2019, 21, 8641–
8645.
[13] a) B. R. Lichman, J. Zhao, H. C. Hailes, J. M. Ward, Nat.
Commun. 2017, 8, 14883; b) B. R. Lichman, E. D.
Lamming, T. Pesnot, J. M. Smith, H. C. Hailes, M. J.
Ward, Green Chem. 2015, 17, 852–855.
[14] N. Kawai, R. Abe, M. Matsuda, J. Uenishi, J. Org.
Chem. 2011, 76, 2102–2114.
A Representative Procedure for the Synthesis of
Methyl (1S,3S)-6,7-Dimethoxy-1-Phenyl-
1,2,3,4-Tetrahydroisoquinoline-3-Carboxylate (6a-
cis)
To the stirred solution of methyl (S,E)-2-(benzylideneamino)-3-
(2-bromo-4,5-dimethoxyphenyl)
propanoate
5a
(0.3 g,
0.6 mmol) in degassed toluene (5 mL) was added a mixture of
AIBN (0.1 g, 0.7 mmol) and nBu3SnH (0.4 g, 1.4 mmol) in
degassed toluene (10 mL) via syringe-pump (2 mL/h) under an
°
argon atmosphere while heating at 80 C for 2 h. After
completion, toluene was evaporated under reduced pressure.
The crude product was purified by flash column chromatog-
raphy (35-40% ethyl acetate in hexanes) to obtain methyl
(1S,3S)-6,7-dimethoxy-1-phenyl-1,2,3,4-tetrahydroisoquinoline-
3-carboxylate 6a-cis as a white solid (0.14 g, 70%) and methyl
6,7-dimethoxy-1-phenylisoquinoline-3-carboxylate 7a as a yel-
low solid (0.024 g, 12%).
Methyl (1S,3S)-6,7-dimethoxy-1-phenyl-1,2, 3,4-tetrahydroiso-
1
quinoline-3-carboxylate 6a-cis: H NMR (400 MHz, acetone-
d6) δ 7.48–7.22 (m, 5H), 6.75 (s, 1H), 6.18 (s, 1H), 5.09 (d, J=
1.9 Hz, 1H), 3.85–3.81 (m, 1H), 3.78 (s, 3H), 3.73 (s, 3H), 3.49
(s, 3H), 3.01 (s, 1H), 2.99 (s, 1H); HRMS (ESI) calcd. for
C19H22NO4 328.1549; found 328.1548; HPLC analysis: (25% i-
PrOH/hexanes, 0.3 mL/min, 256 nm); 99% ee: tR = 24.0 min.
Methyl 6,7-dimethoxy-1-phenylisoquinoline-3-carboxylate 7a:
1H NMR (400 MHz, acetone-d6) δ 8.45 (s, 1H), 7.78 (d, J=
7.6 Hz, 2H), 7.66–7.50 (m, 4H), 7.47 (s, 1H), 4.06 (s, 3H), 3.92
(s, 3H), 3.87 (s, 3H) ; 13C NMR (101 MHz, C3D6O) δ 166.1,
157.8, 153.4, 152.1, 140.0, 139.7, 133.4, 129.7, 128.4, 128.2,
123.9, 121.5, 106.6, 105.2, 55.5, 55.1, 51.4. MS (ESI): m/z
324.2.
[15] A. I. Meyers, D. A. Dickman, J. Am. Chem. Soc. 1987,
109, 1263–1265.
[16] Y. S. Lee, D. J. Cho, S. N. Kim, J. H. Choi, H. Park, J.
Org. Chem. 1999, 64, 9727–9730.
[17] N. A. Magnus, J. Y. Buser, M. C. Embry, N. J. Kallman,
J. Org. Chem. 2020, 85, 7510–7514.
[18] R. Dalpozzo, Mol. 2016, 21, 699.
[19] W. Liu, S. Liu, R. Jin, H. Guo, J. Zhao, Org. Chem.
Front. 2015, 2, 288–299.
Acknowledgments
The authors thank the Ministry of Science and Technology
(MOST) of Taiwan for financial assistance and the authorities
of the National Chiao Tung University for providing laboratory
facilities.
[20] E. García, S. Arrasate, E. Lete, N. Sotomayor, J. Org.
Chem. 2005, 70, 10368–10374.
[21] P. K. Chhattise, A. V. Ramaswamy, S. B. Waghmode,
Tetrahedron Lett. 2008, 49, 189–194.
[22] A. F. Ibañez, G. Y. M. Iglesias, J. M. Delfino, J. Hetero-
cycl. Chem. 1996, 33, 265–270.
[23] M. J. Tomaszewski, J. Warkentin, N. H. Werstiuk, Aust.
J. Chem. 1995, 48, 291–321.
[24] F. Y. Miyake, K. Yakushijin, D. A. Horne Angew. Chem.
Int. Ed. 2004, 43, 5357–5360; Angew. Chem. 2004, 116,
5471–5474.
References
[1] a) H. S. Yun-Choi, M. K. Pyo, K. M. Park, K. C. Chang,
D. H. Lee, Planta Med. 2001, 67, 619–622; b) M. K.
Pyo, D. H. Lee, D. H. Kim, J. H. Lee, J. C. Moon, K. C.
Adv. Synth. Catal. 2021, 363, 1–7
6
© 2021 Wiley-VCH GmbH
��
These are not the final page numbers!

RESEARCH ARTICLE
Diastereospecific Synthesis of Tetrahydroisoquinolines via
Radical Cyclization: Application in the Synthesis of ent-
Tadalafil
Adv. Synth. Catal. 2021, 363, 1–7
W.-J. Chiu, Y.-L. Lin, I. J. Barve, C.-M. Sun*