Concise synthesis of the CDE ring system of tetrahydroisoquinoline alkaloids using carbophilic lewis acid-catalyzed hydroamidation and oxidative friedel-crafts cyclization

Article abstract of DOI:10.1021/jo800898k

(Chemical Equation Presented) A concise synthesis of the CDE ring system of the tetrahydroisoquinoline antitumor alkaloids such as saframycins, renieramycins, and ecteinascidins has been developed. Both Au(I)-catalyzed intramolecular hydroamidation of alkynylamide and NBS-mediated oxidative Friedel-Crafts cyclization of the resulting 2-ketopiperazine were utilized as key reactions.

Full text of DOI:10.1021/jo800898k

Concise Synthesis of the CDE Ring System of
Tetrahydroisoquinoline Alkaloids Using
Carbophilic Lewis Acid-Catalyzed
Hydroamidation and Oxidative Friedel-Crafts
Cyclization
Shingo Obika,† Yoshizumi Yasui,† Reiko Yanada,‡ and
Yoshiji Takemoto*,†
Graduate School of Pharmaceutical Sciences, Kyoto
UniVersity, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan, and
Faculty of Pharmaceutical Sciences, Hiroshima International
UniVersity, Hirokoshingai, Kure, Hiroshima 737-0112, Japan
takemoto@pharm.kyoto-u.ac.jp
ReceiVed April 25, 2008
FIGURE 1. Biologically active tetrahydroisoquinoline alkaloids.
A concise synthesis of the CDE ring system of the tetrahy-
droisoquinoline antitumor alkaloids such as saframycins,
renieramycins, and ecteinascidins has been developed. Both
Au(I)-catalyzed intramolecular hydroamidation of alkynyl-
amide and NBS-mediated oxidative Friedel-Crafts cycliza-
tion of the resulting 2-ketopiperazine were utilized as key
reactions.
alkaloids possess potent antitumor, antibiotic, and antimicrobial
activities through the inhibition of RNA, DNA, and protein
synthesis.4 In particular, ecteinascidin 743 (Et 743) is currently
undergoing phase II/III clinical trials for the treatment of ovarian,
endometrial, and breast cancer.5 The antiproliferative activity
of Et 743 is greater than that of taxol, camptothecin, mitomycin
C, or cisplatin. However, the development of these compounds
as antitumor drugs has been limited by their natural scarcity.
Thus, total synthesis of these compounds presents a formidable
and urgent challenge to the synthetic chemists in terms of the
complexity of molecular architecture, the remarkable biological
activities, and the restricted natural availability. Although, to
date, a number of elegant synthetic studies on these pentacyclic
alkaloids have been developed,1–3,6 most of these approaches
were based on a similar strategy with use of either double aldol
condensation of 2,5-diketopiperazine and appropriate aryl al-
dehydes or stepwise Pictet-Spengler cyclization for the con-
Tetrahydroisoquinoline alkaloids are a broad family of
biologically active natural products, which include saframycins,1
renieramycins,2 and ecteinascidins3 as shown in Figure 1. These
† Kyoto University.
‡ Hiroshima International University.
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5206 J. Org. Chem. 2008, 73, 5206–5209
10.1021/jo800898k CCC: $40.75 2008 American Chemical Society
Published on Web 06/05/2008

SCHEME 1. Retrosynthetic Analysis of
Tetrahydroisoquinoline Antitumor Alkaloids
SCHEME 2. The Lewis Acid-Catalyzed 6-Exo
Hydroamination of Alkynylamides 1a-d
2). Both Lewis acids gave the same product 2a as a single (Z)-
isomer in a similar chemical yield, but the Au(I)-catalyzed
reaction took place under milder reaction conditions than that
of PtCl2. Therefore, the latter reactions of 1b-d were carried
out in the presence of 10 mol % of AuCl(PPh3)/AgNTf2
(Scheme 2).Although the reaction of amine derivative 1b
provided no desired product 2b, carbamate 1c underwent the
hydroamidation to give the cyclic adduct (Z)-2c in 84% yield.
In contrast to 1a, the same reaction of secondary PMB amide
1d as primary amide 1a proceeded slowly to furnish the desired
product 2d in only 30% yield as an (E)-isomer together with a
large amount of the recovered starting material (65%). The low
yield of 2d and the isomerization of (Z)-2d into (E)-2d might
be attributed to the steric hindrance between N-PMB and phenyl
groups on the trisubstituted olefin of 2d. To improve the
chemical yield of 2d, other Lewis acids10 such as In(OTf)3,
NiCl2, PdCl2, AgNTf2, and Cu(OTf)2 were investigated for the
hydroamidation of 1d, but no good results could be obtained.
The configuration of the double bond of 2a-d was determined
to be Z by NOE experiment between the vinylic proton and the
methylene proton of the C-5 position. The reaction demonstrated
excellent stereoselectivity and none of E-isomer was detected.
Having accomplished the structural optimization of alkynyl-
amides 1 for the hydroamidation, our attention was next directed
toward the synthesis of the requisite alkynylamide 13. For the
purpose, alkynylaldehyde 5 was prepared from aryl iodide 311
and alkyne 4 by Sonogashira cross-coupling reaction and
subsequent TPAP oxidation (Scheme 3).
struction of the AB and DE tetrahydroisoquinoline ring
systems.1,2c–e,3a–c,6c–f
Therefore, we planned to develop an alternative assembly
for installation of the CDE ring system A as shown in Scheme
1. From our retrosynthetic analysis, both oxidative Friedel-Crafts
cyclization (B to A) and intramolecular hydroamidation (C to
B) would be key steps for success of this approach. The requisite
compound C to test the key reactions can be synthesized by
the reductive condensation of amino acid derivative D and
alkynyl aldehyde E, which are easily accessible from F and G
in the usual manner. Herein, we describe the concise synthesis
of tricyclic fragment A of tetrahydroisoquinoline alkaloids by
using Au(I)-catalyzed hydroamidation and NBS-mediated
Friedel-Crafts cyclization as key reactions.
We have already reported that the Au(I)-catalyzed intramo-
lecular hydroamidation of N-Boc(2-alkynylaryl)methylamine
and N-Boc-2-(2-alkynylaryl)ethylamine in 1,2-dichloroethane
(DCE) proceeded smoothly even at room temperature to give
the corresponding hydroisoquinolines in good yields.7 On the
basis of these results, we first examined the 6-exo hydroami-
dation of N-Ns(alkynyl)amides 1a in the presence of carbophilic
Lewis acids such as PtCl28 and AuCl(PPh3)/AgNTf29 (Scheme
Another coupling component 11 was synthesized from aryl
alcohol 612 by a 7-step sequence. After conversion of alcohol 6
into bromide 7, successive treatment of 7 with imino ester 8
under the phase-transfer-catalyzed conditions and then with citric
acid provided amino acid derivative 9 in good yield.13 The
resulting carboxylic acid, which was obtained from 9 via
carbamate 10 by the protection and deprotection protocol, was
transformed into the desired primary amide 11 by the mixed
anhydride procedure with ammonia.
At this stage, we next undertook the coupling of two
synthesized fragments 5 and 11 into 12. Subjection of Cbz
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111, 2353.
J. Org. Chem. Vol. 73, No. 13, 2008 5207

SCHEME 3. Synthesis of 5 and 11a
SCHEME 4. Synthesis of Tricyclic Product 17a
a Reagents and conditions: (a) 4, PdCl2(PPh3)2, CuI, Et3N; (b) TPAP,
NMO, MS4A, CH2Cl2; (c) CBr4, PPh3, CH2Cl2; (d) 8, Bu4NHSO4, 50% aq
KOH, CH2Cl2; (e) 15% citric acid, THF; (f) CbzCl, Et3N, CH2Cl2; (g) TFA,
CH2Cl2; (h) EtOCOCl, Et3N, CH2Cl2; (i) aq NH3.
adduct 11 to hydrogenolysis with Pd(OH)2 and reductive
alkylation with aldehyde 5 afforded the coupling product 12 in
71% yield in two steps. After the carbamoylation of 12, the
key hydroamidation of 13 was carried out under the same
conditions. As expected, the reaction occurred with excellent
regio- and stereoselectivity to give the desired cyclized adduct
14 in 85% yield as a single isomer.
a Reagents and conditions: (a) H2 (1 atm), Pd(OH)2, MeOH; (b) 5, MeOH,
then NaBH4; (c) i-PrOCOCl, i-Pr2NEt, CH2Cl2; (d) AuCl(PPh3), AgNTf2,
CH2Cl2; (e) BnBr, NaH, DMF; (f) NBS, CH3CN.
Having succeeded in construction of the C ring of tetrahy-
droisoquinoline alkaloids, we finally explored the oxidative
Friedel-Crafts cyclization of 14 into tricyclic compounds such
as 15 and 17. The initial attempts were directed to the oxidation
and halogenation of 14 with CAN, DDQ, NBS, and RuCl2(PPh3)3/
t-BuO2H.14 However, all attempts resulted in a complex mixture
and failed to yield the desired product 15. Then, our attention
was next focused on the reactivity of benzyl adduct 16, which
has no proton on the nitrogen of the amido group. In contrast
to 14, the desired tricyclic compound 17 was produced in 15%
yield along with 2,5-diketopiperazine 18 (15% yield), when 16
was subjected to the single-electron oxidation with CAN in
methanol and then heating at 60 °C in the presence of HCO2H
(Scheme 4). Further elaboration of the oxidative Friedel-Crafts
cyclization finally led to discovery of NBS15 as the best oxidant,
enhancing the chemical yield of 17 up to 70%. In both cases,
we observed the isomerization of the enamide moiety from Z-
to E-configuration, giving 17 as a single isomer.1b,6d The
obtained product 17 is a known compound, from which total
synthesis of saframycin B has been achieved by Kubo’s group
in 1988.1b The synthetic compound 17 was identical with the
NMR, IR, and MS). Therefore, this means that we have
succeeded in a formal synthesis of saframycin B.
In conclusion, a concise synthesis of the CDE ring system
of tetrahydroisoquinoline alkaloids such as saframycins,
renieramycins, and ecteinascidins was established by using
Au(I)-catalyzed intramolecular hydroamidation and NBS-
mediated oxidative Friedel-Crafts cyclization as key reac-
tions. Furthermore, we have also demonstrated a formal
synthesis of saframycin B starting from alkynylamide C
bearing two aryl substituents.
Experimental Section
Au(I)-Catalyzed Cyclization of 13 to 14. To a solution of 13
(60 mg, 0.10 mmol) in CH2Cl2 (0.5 mL) were added AuCl(PPh3)
(5.0 mg, 0.010 mmol) and AgNTf2 (4.8 mg, 0.010 mmol), and the
mixture was stirred at room temperature for 6 h. After being
quenched with an aqueous NaHCO3 solution (0.5 mL), the mixture
was extracted with CHCl3 (3 × 1 mL) and the combined organic
layers were dried over Na2SO4 and then concentrated in vacuo.
The residue was purified by column chromatography on silica gel
reported authentic sample from all spectral data (1H NMR, 13
C
1
(hexane/AcOEt ) 3/1 to 1/1) to give 14 (48 mg, 85%). H NMR
(14) (a) Murahashi, S.; Naota, T.; Kuwabara, T.; Saito, H.; Kumobayashi,
S.; Akutagawa, A. J. Am. Chem. Soc. 1990, 112, 7820. (b) Aubry, S.; Pellet-
Rostaing, S.; Lemaire, M. Eur. J. Org. Chem. 2007, 5212. (c) Yamaura, M.;
Suzuki, T.; Hashimoto, H.; Yoshimura, J.; Okamoto, T.; Shin, C. Bull. Chem.
Soc. Jpn. 1985, 58, 1413.
(500 MHz, CDCl3) δ 6.67 (s, 1H), 6.61 (s, 1H), 5.27 (s, 1H),
4.96-4.86 (m, 2H), 4.18-4.00 (m, 2H), 3.98-3.84 (m, 4H), 3.81
(s, 3H), 3.79 (s, 3H), 3.78 (s, 3H), 3.68 (s, 3H), 3.66 (s, 3H), 3.33
(s, 3H), 2.21 (s, 3H), 2.19 (s, 3H), 1.34-1.26 (m, 6H); 13C NMR
(126 MHz, CDCl3) δ 173.2, 155.7, 150.8, 149.1, 149.0, 148.3,
146.7, 133.5, 126.9, 126.2, 125.2, 124.9, 111.5, 110.9, 110.5, 77.2,
(15) (a) Shin, C.; Nakano, T.; Sato, Y.; Kato, H. Chem. Lett. 1986, 1453.
(b) Flanagan, M. E.; Williams, R. M. J. Org. Chem. 1995, 60, 6791. (c) Annett,
B.; Peter, G. J.; Ju¨rgen, L. Synthesis 2003, 67.
5208 J. Org. Chem. Vol. 73, No. 13, 2008

69.6, 61.3, 60.7, 60.4, 60.2, 60.1, 56.0, 55.8, 44.8, 29.5, 22.0, 9.5,
9.3; IR (CHCl3) 3235, 2983, 2840, 1772, 1700, 1635 cm-1; MS
(FAB) m/z 573 (MH+, 8), 529 (5), 485 (10), 346 (10), 321 (10),
271 (15), 219 (55), 195 (100), 181 (17), 165 (15), 91 (25); HRMS
(FAB) calcd for C30H41N2O9 (MH+) 573.2812, found 573.2766.
Synthesis of 17. To a solution of 16 (33 mg, 0.050 mmol) in
MeCN (0.10 mL) was added NBS (11 mg, 0.060 mmol), and the
mixture was stirred at 60 °C for 15 min. After being quenched
with an aqueous NaHCO3 solution (0.5 mL), the mixture was
extracted with CHCl3 (3 × 1 mL) and the combined organic layers
were dried over Na2SO4 and concentrated in vacuo. The residue
was purified by column chromatography on silica gel (hexane/
AcOEt ) 3/1 to 1/1) to give 17 (23 mg, 70%). 1H NMR (500 MHz,
CDCl3) δ 7.52 (s, 1H), 7.11-6.99 (m, 3H), 6.79 (s, 1H), 6.72-6.62
(m, 2H), 6.08 (s, 1H), 5.71 (d, J ) 14.9 Hz, 1H), 5.33-5.19 (m,
1H), 5.12-4.93 (m, 1H), 4.55 (d, J ) 15.5 Hz, 1H), 3.99 (s, 3H),
3.79 (s, 3H), 3.69 (s, 3H), 3.45 (s, 3H), 3.39 (d, J ) 17.2 Hz, 1H),
3.14-3.03 (m, 1H), 2.98 (s, 3H), 2.88 (s, 3H), 2.19 (s, 3H), 2.17
(s, 3H), 1.33 (d, J ) 5.7 Hz, 3H), 1.28 (d, J ) 5.7 Hz, 3H); 13C
NMR (126 MHz, CDCl3) δ 168.3, 152.9, 152.7, 150.7, 150.3, 149.2,
146.8, 146.4, 136.3, 134.6, 128.4, 126.7, 126.1, 125.4, 125.2, 125.1,
124.7, 121.7, 110.2, 107.6, 77.2, 69.6, 60.3, 60.1, 59.9, 59.5, 59.0,
56.5, 53.4, 45.8, 43.7, 28.2, 22.2, 9.3, 9.2; IR (CHCl3) 2936, 2830,
1698, 1672, 1639 cm-1; MS (FAB) m/z 661 (M+, 100), 575 (5),
278 (22), 234 (33), 204 (15), 91 (22); HRMS (FAB) calcd for
C37H45N2O9 (M+) 660.3047, found 660.3027.
Acknowledgment. This work was supported by grants from
the 21st Century COE Program “Knowledge Information
Infrastructure for Genome Sciences” and Grant-in-Aid for
Scientific Research on Priority Areas from MEXT (18032039),
and JSPS. KAKENHI (19390005). S.O. thanks the JSPS for a
fellowship.
Supporting Information Available: Detailed experimental
procedures and product characterization data for all new
compounds prepared. This material is available free of charge
via the Internet at http://pubs.acs.org.
JO800898K
J. Org. Chem. Vol. 73, No. 13, 2008 5209