Synthetic study toward ecteinascidin 743: Concise construction of the diazabicyclo[3.3.1]nonane skeleton and assembly of the pentacyclic core

Article abstract of DOI:10.1021/jo100788j

(Figure Presented) Synthesis of the pentacyclic core of ecteinascidin 743 is described. This synthesis features concise construction of the diazabicyclo[3.3.1]nonane skeleton using gold(I)-catalyzed one-pot keto amide formation, acid-promoted enamide formation, and oxidative Friedel-Crafts cyclization as the key steps.

Full text of DOI:10.1021/jo100788j

pubs.acs.org/joc
Synthetic Study toward Ecteinascidin 743: Concise
Construction of the Diazabicyclo[3.3.1]nonane
Skeleton and Assembly of the Pentacyclic Core
Taro Enomoto,† Yoshizumi Yasui,‡ and
Yoshiji Takemoto*,†
†Graduate School of Pharmaceutical Sciences, Kyoto
University, Yoshida, Sakyo-ku, Kyoto 606-8501, Japan, and
‡WPI Advanced Institute for Materials Research, Tohoku
University, Aoba, Sendai 980-8577, Japan
takemoto@pharm.kyoto-u.ac.jp
Received April 21, 2010
FIGURE 1. Ecteinascidin 743 and saframycins.
recently approved and sold as Yondelis for use in Europe,
Russia, and South Korea for the treatment of advanced soft
tissue sarcoma. It is also undergoing clinical trials for breast,
prostate, and pediatric sarcomas. The antiproliferative acti-
vity of Et-743 is greater than that of paclitaxel, camptothecin,
mitomycin C, and cisplatin. Et-743 is structurally similar to
the saframycin family.1 A significant difference is that the C-4
carbon of Et-743 possesses a higher oxidation state than that
in saframycins. Its remarkable biological activity, the scarcity
of the natural product from tunicates, and its complex mole-
cular structure render Et-743 an attractive target for synthesis.
To date, three total syntheses have been accomplished by the
groups of Corey,5 Fukuyama,6 and Zhu,7 and the groups of
Danishefsky8 and Williams9 have each developed formal total
syntheses. A semisynthesis from cyanosafracin B has also
been developed by Cuevas, Manzanares, and co-workers at
PharmaMar.10 Additionally, other synthetic approaches have
been reported by several research groups.11 We describe here a
concise alternative approach to the diazabicyclo[3.3.1]nonane
skeleton and assembly of the core (ABCDE ring system) that
can be applied to the synthesis of Et-743.
Synthesis of the pentacyclic core of ecteinascidin 743 is
described. This synthesis features concise construction
of the diazabicyclo[3.3.1]nonane skeleton using gold(I)-
catalyzed one-pot keto amide formation, acid-promoted
enamide formation, and oxidative Friedel-Crafts cycli-
zation as the key steps.
(5) (a) Corey, E. J.; Gin, D. Y.; Kania, R. S. J. Am. Chem. Soc. 1996, 118,
9202. (b) Martinez, E. J.; Corey, E. J. Org. Lett. 2000, 2, 993.
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Danishefsky, S. J. Angew. Chem., Int. Ed. 2006, 45, 1754.
(9) Fishlock, D.; Williams, R. M. J. Org. Chem. 2008, 73, 9594.
Tetrahydroisoquinoline alkaloids, which comprise a large
family of biologically active natural products, have received
considerable attention due to their potent biological acti-
vities and structural diversity.1 In particular, ecteinascidin 743
(Et-743, 1; Figure 1), which was isolated from the Caribbean
tunicate Ecteinascidia turbinate,2 possesses potent cytotoxic
activities against several tumor cell lines, several rodent
tumors, and human tumor xenografts in vitro.3,4 It was
ꢀ
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(10) Cuevas, C.; Perez, M.; Martın, M. J.; Chicharro, J. L.; Fernandez-
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Chem. 2005, 70, 4397. (g) Gonzalez, J. F.; Salazar, L.; Cuesta, E.; Avendano,
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4876 J. Org. Chem. 2010, 75, 4876–4879
Published on Web 06/17/2010
DOI: 10.1021/jo100788j
r
2010 American Chemical Society

Enomoto et al.
JOCNote
SCHEME 1. Retrosynthesis
SCHEME 2. Synthesis of Phenylglycinol Derivative 8a
aConditions: (a) (i) Boc2O, THF, (ii) TBAF, two steps 75%; (b) NaH,
BnBr, TBAI, DMF/THF, 78%; (c) (i) 4 M HCl aq, MeOH/dioxane, (ii)
Boc2O, CH2Cl2/satd NaHCO3 aq; (d) MsCl, DIPEA, CH2Cl2; (e) TFA,
anisole, CH2Cl2, 4 steps 99%.
SCHEME 3. Synthesis of Phenylalanine Derivative 9a
aConditions: (a) K2CO3, MeOH; (b) H2, Pd/C, Boc2O, MeOH, two
steps 85%; (c) NBS, MeCN, 88%; (d) BnBr, K2CO3, TBAI, DMF, 92%;
(e) AcCl, MeOH (3 M HCl), CH2Cl2; (f) propargyl bromide, LiOH H2O,
3
MS4A, DMF, two steps 81%; (g) TrocCl, CH2Cl2/NaHCO3 aq, 93%;
(h) AcBr, SnBr2, CH2Cl2, 94%; (i) LiOH, MeOH/H2O/THF.
MOM ether to the mesylate, we converted 11 into amine 8 in
good yield by the usual protection and deprotection protocol.
The synthesis of alkynoic acid 9, a highly functionalized (S)-
bromophenylalanine derivative, is depicted in Scheme 3. Start-
ing from Cbz-carbamate 12, which was synthesized by Zhu’s
method,13 we removed the acetyl group, and subsequent con-
version of the Cbz moiety to the Boc group afforded phenol 13,
which was then subjected to regioselective bromination with
N-bromosuccinimide (NBS) to give bromide 14 in 88% yield.
After the hydroxyl group of 14 was masked with benzyl bro-
mide, successive deprotection of the Boc group, N-propargyla-
tion,14 and N-Troc protection provided alkynyl ester 15 in
69% yield in four steps. Conversion of the benzyl ether to the
acetate and simultaneous hydrolysis of the methyl ester and
acetate moieties furnished the desired alkynoic acid 9, which
was used for the next reaction without any purification.
At this stage, two requisite fragments 8 and 9 were incor-
porated into keto amide 6 by means of a one-pot sequence,
which consisted of the gold(I)-catalyzed 6-exo-dig intramole-
cular hydro-oxycarbonylation of 915 and a coupling reaction
Our retrosynthesis of Et-743 is illustrated in Scheme 1. We
envisioned that Pomeranz-Fritsch-type cyclization of ap-
propriately protected dimethyl acetal 3 would afford the
desired synthetic intermediate 2, which has all of the requisite
functionalities for the pentacyclic core of Et-743. The acetal 3
could be obtained from exo-enamide 4 through a sequence of
hydroxylation, oxidation, and acetalization according to
Fukuyama’s method.6 The key intermediate 4, which bears
a diazabicyclo[3.3.1]nonane system, is derived from endo-
enamide 5 by the oxidative Friedel-Crafts-type cyclization
developed in our group for the synthesis of saframycin B.12
By the acid-promoted intramolecular condensation of the
amide and ketone moieties, the desired enamide 5 would be
prepared from keto amide 6. The requisite product 6 can be
transformed from (R)-phenylglycinol derivative 8 and cyclic
enol ester 7, which is easily prepared by a 6-exo-dig cycliza-
tion of alkynoic acid 9.
The synthesis of (R)-phenylglycinol derivative 8was achieved
as described in Scheme 2. The one-pot N-Boc protection and
desilylation of O-TBDPS amine 10, prepared by the reported
procedure,6 was followed by regioselective benzylation to give
the desired product 11. To switch the protecting group from the
(13) Demoulin, N.; Zhu, J. Synlett 2009, 466.
(14) Cho, J. H.; Kim, B. M. Tetrahedron Lett. 2002, 43, 1273.
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^
J.-P.; Michelet, V. J. Am. Chem. Soc. 2006, 128, 3112. (b) Uchiyama, M.;
Ozawa, H.; Takuma, K.; Matsumoto, Y.; Yonehara, M.; Hiroya, K.;
Sakamoto, T. Org. Lett. 2006, 8, 5517. (c) Harkat, H.; Weibel, J.-M.; Pale,
P. Tetrahedron Lett. 2006, 47, 6273. (d) Marchal, E.; Uriac, P.; Legouin, B.;
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73, 5206.
J. Org. Chem. Vol. 75, No. 14, 2010 4877

Enomoto et al.
JOCNote
SCHEME 4. Construction of Diazabicyclo[3.3.1]nonane systema
TABLE 1. Investigation of Oxidative Friedel-Crafts Cyclization
entry
conditionsa
yieldb (%)
1
2
3
4
5
6
NBS (0.95 equiv)
NBS (0.95 equiv), MgSO4 (30 equiv)
NBS (0.95 equiv), MS 3A
31
36
56
55
17
70
AcNHBr (0.95 equiv), MS 3A
N-bromosaccharin (0.95 equiv), MS 3A
PhNMe3 Br3 (0.95 equiv), MS 3A
3
aReactions were carried out at room temperature for 15 min and then
at 60 °C for 1 h. bIsolated yields of 4
SCHEME 5. Assembly of the Pentacyclic Core of Et-743a
aConditions: (a) AuCl(PPh3) (1 mol %)/AgNTf2 (1 mol %), CH2Cl2;
(b) 8, CH2Cl2, three steps, 80% based on 16; (c) anhydrous TsOH, MgSO4,
toluene, 75%; (d) see Table 1.
of the resulting enol ester 7 with amine 8 (Scheme 4). In fact,
treatment of alkynoic acid 9 with a dichloromethane solution
of 1 mol % of AuCl(PPh)3/AgNTf2 followed by the addition
of 8 led to the formation of keto amide 6 in 80% yield.
Condensation is an elementary organic transformation.16
However, to the best of our knowledge, intramolecular con-
densation between an amide and a ketone has rarely been
applied to the synthesis of a highly functionalized enamide.17
Indeed, the intramolecular condensation of 6 resulted in for-
mation of the desired enamide 5 in low yields due to recovery
or decomposition of the starting material under a variety of
aConditions: (a) BnBr, K2CO3, KI, DMF, 91%; (b) (i) DMDO, MeOH/
acetone, (ii) CSA; (c) NaBH3CN, TFA/THF, three steps, 86%; (d) Dess-
Martin periodinane, CH2Cl2; (e) PTSA, (MeO)3CH/MeOH, two steps,
60%; (f) TMSOK, MeCN, 75%; (g) 5 M HCl, dioxane/H2O, 82%.
corresponding bromide 5 to suppress the undesired cyclization.
In fact, treatment of enamide 5 with an acetonitrile solution
of NBS12 gave the desired tricyclic product 4 in 31% yield
(Table 1, entry 1). The promising result with NBS prompted us
to optimize the reaction conditions. As a result, we found that
the addition of dehydrating agents such as MgSO4 and acti-
vated MS 3A improved the reaction efficiency (entries 2 and 3).
Moreover, while the reaction of 5 with AcNHBr or N-bromo-
saccharin did not give good results, the use of trimethylpheny-
lammonium tribromide and MS 3A significantly increased the
yield of 4 (entries 4-6). On the basis of these studies, it appears
that MS 3A acts not only as a dehydrating agent but also as an
acid scavenger.
Our final goal was to reach the ABCDE ring system of
Et-743. Toward this end, after the hydroxyl group of 4 was
subjected to benzylation, it was subsequently transformed to
alcohol 17 by epoxidation with dimethyldioxirane, ring-open-
ing with MeOH, and reduction with NaBH3CN according
to Fukuyama’s total synthesis (Scheme 5).6 Subsequently,
alcohol 17 was oxidized to the corresponding aldehyde with
Dess-Martin periodinane,19 which was followed by acetali-
zation to give dimethyl acetal 18 in 60% yield. To elaborate B
ring formation by Pomeranz-Fritsch cyclization, both the
mesyl and N-Troc groups of 18 were cleaved by reaction with
TMSOK,20 and treatment of the resulting product 19 with
Lewis acidic conditions [TiCl4-Et3N,17d HfCl4 (THF)2,18
3
BF3 OEt2, Zn(OTf)2]. Therefore, various Brønsted acids
3
were next examined for use in intramolecular condensation.
After many experiments under a variety of reaction condi-
tions, we finally found that the use of anhydrous TsOH (1.0
equiv) and MgSO4 (50 equiv) in toluene at 90 °C improved
the yield to give the desired product 5 in 75% yield.
The next challenge in the synthesis is the construction
of the diazabicyclo[3.3.1]nonane system. For this purpose,
we explored the oxidative Friedel-Crafts cyclization of phe-
nolic enamides such as 5. We first examined the reaction of
nonbrominated compound of 5, which provided the product
that was exclusively cyclized at the para position of the
phenol ring, not at the desired ortho position, due to the
high reactivity of the para position. We then synthesized the
(16) (a) Ingold, C. K. Structure and Mechanism in Organic Chemistry, 2nd
ed.; Cornell University Press: Ithaca, NY, 1969; p 1129. (b) March, J. Advanced
Organic Chemistry, 3rd ed.; Wiley-Interscience: New York, 1985; p 335.
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Synth. Commun. 2000, 30, 3171. (c) Reiner, J. E.; Siev, D. V.; Araldi, G.-L.;
Cui, J. J.; Ho, J. Z.; Reddy, K. M.; Mamedova, L.; Vu, P. H.; Lee, K.-S. S.;
Minami, N. K.; Gibson, T. S.; Anderson, S. M.; Bradbury, A. E.; Nolan,
T. G.; Semple, J. E. Bioorg. Med. Chem. Lett. 2002, 12, 1203. (d) Liu, J.;
Liang, F.; Liu, Q.; Li, B. Synlett 2007, 156. (e) Yamazaki, Y.; Mori, Y.; Oda,
A.; Okuno, Y.; Kiso, Y.; Hayashi, Y. Tetrahedron 2009, 65, 3688.
(18) (a) Ishihara, K.; Ohara, S.; Yamamoto, H. Science 2000, 290, 1140.
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2002, 58, 8179.
(19) Dess, D. B.; Martin, J. C. J. Org. Chem. 1983, 48, 4155.
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3095.
4878 J. Org. Chem. Vol. 75, No. 14, 2010

Enomoto et al.
JOCNote
excess aqueous HCl in 1,4-dioxane afforded the pentacyclic
product 20 in 82% yield. Unfortunately, we could not obtain
the desired product 2, which bears a stereogenic center at C3,
but we did achieve a concise synthesis of the important
synthetic intermediate 20 for the total synthesis of Et-743.
In summary, we have developed an efficient route to
pentacyclic segment 20 of Et-743. Our strategy features easy
access to the diazabicyclo[3.3.1]nonane system by gold(I)-
catalyzed one-pot keto amide formation, acid-promoted
enamide formation, and oxidative Friedel-Crafts cycliza-
126.86, 118.5, 116.8, 115.3, 113.4, 113.2, 112.2, 101.5, 95.0, 74.5,
72.0, 70.7, 60.4, 59.3, 56.0, 47.7, 37.6, 35.2, 26.0, 16.2, 9.0; IR
(ATR) ν 3370, 3305, 3027, 2940, 2869, 1727, 1680, 1091 cm-1; MS
(FAB+) m/z 895 [M + H]+ (15), 815 (10), 488 (8), 391 (67), 149
(100); HRMS (FAB+) calcd for C35H39BrCl3N2O12S [M + H]+
895.0473, found 895.0483.
Enamide 4. To a mixture of enamide 5 (200 mg, 0.228 mmol),
activated molecular sieves 3A (685 mg), and MeCN (9.0 mL)
was added a solution of trimethylphenylammonium tribromide
(77.7 mg, 0.207 mmol) in MeCN (2.4 mL) at room temperature.
After being stirred at room temperature for 15 min, the reaction
mixture was heated at 60 °C and additionally stirred for 1 h. To
the reaction mixture was added an aqueous saturated Na2SO3
solution at 0 °C. The resultant mixture was extracted with
AcOEt, and the combined organic extracts were washed with
brine, dried over Na2SO4, filtered, and concentrated in vacuo.
The residue was purified by preparative thin-layer chromatog-
raphy (silica gel) (hexane/AcOEt = 1.5/1) to afford enamide 4
tion under newly developed conditions (PhNMe3 Br3, MS
3
3A, MeCN, room temperature, then 60 °C). Further research
directed toward the total synthesis of Et-743 is in progress.
Experimental Section
Keto Amide 6. To a solution of ester 16 (389 mg, 0.678 mmol)
in a mixture of MeOH (9.2 mL), H2O (2.3 mL), and THF (2.3 mL)
was added lithium hydroxide (73.1 mg, 3.05 mmol) at 0 °C. After
being stirred at room temperature for 20 h, the reaction mixture
was diluted with benzene and concentrated in vacuo. The residue
was dissolved with H2O, and to the resultant mixture was added a
saturated aqueous KHSO4 solution at 0 °C. The resultant suspen-
sionwasextractedwithAcOEt,andthe combinedorganic extracts
were washed with brine, dried over Na2SO4, filtered, and concen-
trated in vacuo to afford the corresponding carboxylic acid 9 as a
colorless amorphous material, which was used in the next step
without further purification. To a solution of carboxylic acid 9 in
dichloromethane (1.5 mL) was added a mixture of AuCl(PPh3)
(3.5 mg, 0.0071 mmol), AgNTf2 (2.7 mg, 0.0070 mmol), and di-
chloromethane (0.5 mL) at room temperature. After being stirred
at room temperature for 3.5 h, to the reaction mixture was added a
solution of amine 8 (270 mg, 0.712 mmol) at room temperature,
and the resultant mixture was additionally stirred for 22 h. After
the reaction mixture was diluted with a saturated aqueous NaH-
CO3 solution, the resultant mixture was extracted with CHCl3.
The combined organic extracts were washed with brine, dried over
Na2SO4, filtered, and concentrated in vacuo. The residue was
purified by silica gel column chromatography (hexane/AcOEt =
(139 mg, 70%) as a colorless foam: [R]22 +54 (c = 1.25,
D
1
CHCl3); H NMR (500 MHz, DMSO-d6, 388 K) δ 9.12 (br,
1H), 7.30-7.20 (m, 3H), 7.08 (d, 2H, J = 7.0 Hz), 6.59 (s, 1H),
5.98 (dd, 1H, J = 3.1, 2.6 Hz), 5.86 (d, 1H, J = 1.0 Hz), 5.78 (dd,
1H, J = 8.1, 6.2 Hz), 5.73 (dd, 1H, J = 1.0 Hz), 5.05-5.01 (m,
1H), 4.92 (d, 1H, J = 12.6 Hz), 4.84 (d, 1H, J = 12.6 Hz), 4.83
(d, 1H, J = 1.7 Hz), 4.52 (d, 1H, J = 1.7 Hz), 4.32(d, 1H, J =
12.5 Hz), 4.25 (d, 1H, J = 12.5 Hz), 4.14 (dd, 1H, J = 10.3, 6.2
Hz), 4.07 (dd, 1H, J = 10.3, 8.1 Hz), 3.60 (s, 3H), 3.22 (s, 3H),
3.05- 3.03 (m, 2H), 2.23 (s, 3H), 2.08 (s, 3H); 13C NMR (126
MHz, CDCl3) mixture of carbamate rotamers δ 168.2, 167.8,
151.9, 151.3, 146.8, 145.2, 144.9, 144.24, 144.18, 143.1, 142.62,
142.58, 139.9, 137.7, 131.3, 128.5, 128.3, 128.1, 127.4, 127.3,
127.2, 119.5, 119.3, 117.6, 117.4, 116.3, 116.1, 113.71, 113.65,
113.3, 113.1, 101.71, 101.66, 96.3, 96.0, 95.1, 95.0, 75.11, 75.06,
72.86, 72.84, 67.8, 67.6, 61.2, 54.1, 53.6, 53.3, 52.6, 51.9, 50.9,
37.3, 34.3, 33.9, 29.6, 16.7, 9.8; IR (ATR) ν 3360, 3020, 2932,
1720, 1680, 1634, 1424, 1364 cm-1; MS (FAB+) m/z 897 [M +
Na]+ (12), 875 [M + H]+ (22), 797 (20), 769 (37), 91 (100);
HRMS (FAB+) calcd for C35H34BrCl3N2O11S [M]+ 874.0132,
found 874.0126.
1.5/1 to 2/1) to afford amide 6 (484 mg, 80% in three steps) as a
Acknowledgment. This work was supported in part by a
Grant-in-Aid for Scientific Research (B) (Y.T.) and “Tar-
geted Proteins Research Program” from the Ministry of
Education, Culture, Sports, Science and Technology of
Japan.
1
white amorphous material: [R]28 -37 (c = 1.00, CHCl3); H
D
NMR (500 MHz, DMSO-d6, 388 K) δ 8.85 (br, 1H), 8.36 (s, 1H),
7.32-7.27 (m, 2H), 7.27-7.22 (m, 3H), 6.84 (s, 1H), 6.71 (s, 1H),
6.04 (d, 1H, J = 1.0 Hz), 5.99 (d, 1H, J = 1.0 Hz), 5.17 (dd, 1H,
J = 13.9, 6.0 Hz), 4.73-4.56 (m, 3H), 4.50 (d, 1H, J = 12.2 Hz),
4.47 (d, 1H, J = 12.2 Hz), 4.26 (d, 1H, J = 18.4 Hz), 3.92 (br, 1H),
3.74-3.65 (m, 2H), 3.69 (s, 3H), 3.30 (br, 1H), 3.29 (s, 3H), 3.05
(dd, 1H, J = 14.4, 9.4 Hz), 2.26 (s, 3H), 2.13 (s, 3H), 2.03 (s, 3H);
13C NMR (126 MHz, DMSO-d6, 388 K) δ 168.0, 152.9, 148.5,
146.0, 145.3, 142.4, 142.1, 137.9, 132.0, 130.9, 127.7, 126.92,
Supporting Information Available: Detailed experimental
procedures and product characterization data for all new com-
pounds prepared. This material is available free of charge via the
Internet at http://pubs.acs.org.
J. Org. Chem. Vol. 75, No. 14, 2010 4879