A Concise and Practical Semisynthesis of Ecteinascidin 743 and (–)-Jorumycin

Article abstract of DOI:10.1002/ejoc.201601409

Ecteinascidin 743 is an antitumor drug used to treat specific soft-tissue sarcomas (STS). In this paper, we present a concise and practical semisynthesis of ecteinascidin 743 starting from safracin B. The strategy involves the direct conversion of an aliphatic amino group into an acetoxy group. By this approach, ecteinascidin 743 was synthesized in 14 steps and 1.5 % overall yield. The synthetic approach also provided access to other tetrahydroisoquinoline alkaloids, such as (–)-jorumycin (a promising anticancer candidate). (–)-Jorumycin was prepared in six steps and 24.1 % overall yield from safracin B.

Full text of DOI:10.1002/ejoc.201601409

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A Journal of
Accepted Article
Title: A Concise and Practical Semi-synthesis of Ecteinascidin 743 and
(-)-Jorumycin
Authors: Shanghu Xu, Guan Wang, Jinjin Zhu, Chuang Shen, Zhezhou
Yang, Jun Yu, Zhong Li, Tanghuan Lin, Xun Sun, and Fuli
Zhang
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To be cited as: Eur. J. Org. Chem. 10.1002/ejoc.201601409
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A Concise and Practical Semi-synthesis of Ecteinascidin 743 and
(-)-Jorumycin
Shanghu Xu,**[a, b] Guan Wang,**[b, c] Jinjin Zhu,[b] Chuang Shen,[b] Zhezhou Yang,[b] Jun Yu,[b] Zhong
Li,[b] Tanghuan Lin,[c] Xun Sun*[a] and Fuli Zhang*[a, b]
Because of the unique structures and the remarkable biological
Abstract: Ecteinascidin 743 is an antitumor drug used to treat
activities, 1 and 2 are attractive synthetic targets for chemists.
specific soft tissue sarcomas (STS). Herein, a concise and practical
7-10
Four total syntheses
and one semi-synthesis6 of 2 had been
semi-synthesis of Ecteinascidin 743 starting from Safracin B is
presented by the strategy of directly converting an aliphatic amino
group to the acetoxyl group. Through this strategy, Ecteinascidin
743 was synthesized via 14 steps with 1.5% overall yield. The
synthetic approach also provided access to other tetrahydro-
isoquinoline alkaloids, such as (-)-Jorumycin (a promising anticancer
candidate). (-)-Jorumycin was prepared in six steps and 24.1%
overall yield from Safracin B.
reported. For 1, Corey’s group initially published a total
synthesis involving 36 steps with an overall yield of
0.72%11.Then Fukuyama12, 13 and Zhu14, respectively, reported
16
its synthetic routes. Meanwhile, other groups15,
studied its
formal total synthesis. In 2000, based on Corey’s synthesis, a
semi-synthetic process for 1 starting from Cyanosafracin B
(compound 5) was developed as an industrial route, which took
21 steps in 1.0% overall yield reported by Cuevas and co-
workers17.
Compound 3 was a key intermediate in Corey’s synthetic route
(Figure 1)11. Cuevas et al. reported several routes to prepare 3
and its derivatives17-21. The essential issue for the semi-
synthesis of 3 and its derivatives was how to convert the
aliphatic amino group at C22 to the hydroxyl group. Four
different strategies were developed for this issue17-21, and the
best strategy is outlined in Scheme 1. In this strategy,
intermediate 8 (a derivative of 3) was achieved in 13 steps and
Introduction
Ecteinascidin 743 and (-)-Jorumycin
Ecteinascidin 743 (Trabectedin, compound 1, Figure 1), a
tetrahydro-isoquinoline alkaloid, is a marine-derived antitumor
drug isolated by Rinehart and co-workers1, 2. (-)-Jorumycin
(compound 2, an analogue of 1, Figure 1) is a promising
candidate for new anticancer drugs that was isolated from
Jorunna funebris in 20003. Both of 1 and 2 displayed significantly
cytotoxic2-6. In 2015, 1 was approved for the treatment of specific
soft tissue sarcomas (STS).
5.7% overall yield from 5 20
.
Figure 1. The structures of Ecteinascidin 743 (1), (-)-Jorumycin (2), and
compounds 3 and 4
Scheme 1. The semi-synthesis of intermediate 820
Although wonderful work were accomplished by Cuevas and co-
workers, there are still some drawbacks needed to be resolved
for the semi-synthesis of 8, such as long steps (13 steps), many
protective groups and the use of poisonous reagent (n-Bu3SnH).
Based on the work of Cuevas et al. we developed a more
concise and practical synthesis of 4 (a derivative of 8) in 9 steps
with 9.1% overall yield, by directly converting an aliphatic amino
group to an ester group. Moreover, this synthetic approach also
provided access to (-)-Jorumycin.
[a]
Department of Natural Products Chemistry, School of Pharmacy,
Fudan University
826 Zhangheng Road, Shanghai 201203, P. R. of China
E-mail: zhangfuli1@sinopharm.com, sunxunf@shmu.edu.cn
Shanghai Institute of Pharmaceutical Industry, China State Institute
of Pharmaceutical Industry
285 Gebaini Road, Shanghai 201203, P. R. of China.
Zhejiang Hisun Pharmaceutical Co.LTD
46 Waisha Road, Zhejiang 318000, P. R. of China
* Corresponding author
** These authors contributed equally to this study and share first
authorship
[b]
[c]
Finally, we prepared Ecteinascidin 743 in 14 steps and
synthesized (-)-Jorumycin through the new route in six steps.
Electronic Supplementary Information (ESI) available: analytical data
for the reported compounds
Retrosynthetic analysis
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10.1002/ejoc.201601409
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unstable and would slowly convert to a stable intermediate
(compound 11, Scheme 2)19, 22
.
Interestingly, a salt of 10 (amine hydrochloride 14) was obtained
after Edman degradation in our experiment. And amine
hydrochloride 14 was stable. Then we optimized our strategy,
which is outlined in Scheme 3. Inspired by the method of directly
converting an aliphatic amino group to an ester group by
diazotization23-25, compound 15 (an analogue of 12) was
designed as an appropriate intermediate for the synthesis of 4
(Scheme 3), since the hydroxyl group of 15 had been protected
and the protection of phenol group would not be affected.
There are several advantages for this strategy, listed as follows:
1) We shifted the primary amine’s diazotization from the ninth
step to the fourth step, making the route more economical,
because the yield of primary amine’s diazotization was low17-21
;
2) the conversion of the amino group to the ester group was
carried out in one step, and the ester group could be
deprotected when the methoxy-p-quinone was hydrolyzed under
basic condition, so none of steps would be increased for the
hydroxyl group’s protection and deprotection at C22 (Scheme 3);
and 3) (-)-Jorumycin could be synthesized from 15 (Scheme 3).
Scheme 2. The synthetic strategy for 1 via compound 12
Results and Discussion
For the synthesis of 1, we considered shifting the Edman
degradation and diazotization to the earlier steps to optimize the
route (Scheme 2). However, two synthetic challenges appeared:
1) It was difficult to selectively protect the phenol group of 12
(Scheme 2), because the reactivity of the phenol group and the
hydroxyl group was very similar; and 2) the intermediate 10 was
The synthesis of key intermediate 15
Our synthesis started from Safracin
B (13, Scheme 4).
Compound 13 is an antibiotic of bacterial origin, which is
available through fermentation of the bacteria Pseudomonas
fluorescence and can be obtained in kilogram scale26, 27. The
synthesis of 15 from amine 13 is outlined in Schemes 4 and 5.
Scheme 4. The synthesis of intermediate 14
The amino group of Safracin B was reacted with phenyl
isothiocyanate to give the thiourea 1621, 28. Then the hydroxyl
group of 16 was substituted by the cyano group (NaCN,
CH3COOH) 7, followed by Edman degradation21 (TMSCl, MeOH)
to furnish the amine hydrochloride 14 in 80% overall yield for the
three steps without column chromatography. The amine
Scheme 3. The retrosynthetic analysis of 1 and 2
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10.1002/ejoc.201601409
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hydrochloride 14 was directly precipitated from the reaction
solution. Its free base (intermediate 10, Scheme 5) would slowly
convert to compound 11 （Scheme 2）, which was previously
reported19, but amine hydrochloride 14 was stable at 0 °C for
long-term storage.
Scheme 6. The synthesis of (-)-Jorumycin
The synthesis of Ecteinascidin 743 from intermediate 15
To synthesize Ecteinascidin 743, intermediate 15 was protected
with MOM (MOMBr, NaH). Then the methoxy-p-quinone and the
ester group were hydrolyzed with LiOH in H2O/THF in one pot to
give 20 (96% yield for the two steps without column
chromatography, Scheme 7)21. Intermediate 20 was reduced by
10% Pd/C, then immediately treated with CH2BrCl /Cs2CO3 in
DMF to form a five-member cycle to obtain 21 (44% yield)17.
Scheme 5. The synthesis of intermediate 15
With the stable intermediate 14 in hand, we considered
converting the amino group at C22 to the acetoxyl group
(Scheme 5). Firstly, the amine hydrochloride 14 was treated with
NaHCO3 in CH2Cl2/H2O at 0 °C to give its free base (10’s
methylene chloride solution), since the chloride ion in
intermediate 14 was a good nucleophile and it would react with
17 to produce by-product. Then, to convert amino group at C22
to the acetoxyl group, a great amount of NaOAc (6.8 eq) was
added as a competitive nucleophile of water for the selective
synthesis of 15 (Scheme 5). Finally, 10 was treated with NaNO2
and NaOAc under acidic condition in CH2Cl2/H2O at -5 °C to give
15 (45% yield). Although 15 was obtained, we wondered why
the diazotization was not affected in our experimental condition.
We concluded that this was due to the following reasons: 1) the
acetic acid was massive (60 eq) in the condition of diazotization,
and 10 was converted into a salt which was unfavourable for the
formation of 11 under acidic condition; 2) the reaction was
Scheme 7. The synthesis of intermediate 21
carried out in
a two-phase solution (CH2Cl2/H2O) which
contained a large amount of water, making the dehydration of 10
more difficult29; and 3) the temperature of the reaction was low
(-5~0°C).
With 21 in hand, we conceived ester condensation of 21 with 22
to gain 23, and then oxidized 23 with (PhSeO)2O to obtain 4
(Scheme 8). During the synthesis of 23, the major product was a
by-product. The by-product was monitored by mass
spectrometry, and the results showed that 21 was reacted with 2
eq of 22. And Jia31 reported the phenol group at C5 was more
active than the hydroxyl at C22 for esterification (Scheme 8). So
we proposed another method to prepare 4. Directly oxidizing the
phenol group of 21 with (PhSeO)2O in THF, followed by ester
condensation (EDCI, DMAP) with 22 to give 4 in 60% overall
The synthesis of (-)-Jorumycin from intermediate 15
To synthesize (-)-Jorumycin, intermediate 15 was oxidized by
salcomine in air9, 30 and the cyano group was substituted by a
hydroxyl group (AgNO3, ACN/H2O) to obtain (-)-Jorumycin (2,
Scheme 6).
yield for the two steps (Scheme 8)11
.
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