Total synthesis of (-)-serotobenine

Article abstract of DOI:10.1021/ja807676v

The efficient total synthesis of (?)-serotobenine (1) has been achieved by constructing an optically active dihydrobenzofuran ring via a rhodium carbenoid mediated intramolecular C?H insertion reaction, which was developed by our group. Then the possibili

Full text of DOI:10.1021/ja807676v

Published on Web 11/19/2008
Total Synthesis of (-)-Serotobenine
Yasuaki Koizumi,† Hideki Kobayashi,‡ Toshiyuki Wakimoto,† Takumi Furuta,§,†
Tohru Fukuyama,*,‡ and Toshiyuki Kan*,†
School of Pharmaceutical Sciences, UniVersity of Shizuoka and Global COE Program, 52-1 Yada,
Suruga-ku, Shizuoka 422-8526, Japan, and Graduate School of Pharmaceutical Sciences, UniVersity of Tokyo,
7-3-1 Hongo, Bunkyo-ku, Tokyo 113-0033, Japan
Received October 8, 2008; E-mail: kant@u-shizuoka-ken.ac.jp; fukuyama@mol.f.u-tokyo.ac.jp
Scheme 1. Preparation of trans-Dihydrobenzofuran 12a
Serotobenine (1), which is a pentacyclic indole alkaloid, was initially
isolated from safflower seeds (Carthamus tinctorius L.) by Sato and
co-workers in 1985.1 The unique heterocyclic structure of 1, which
includes an indole, dihydrobenzofuran, and eight-membered lactam
and should be a significant structure in medicinal chemistry, has
prompted us to investigate its total synthesis. Furthermore, natural 1
has been isolated as the racemic form, although structurally related
decursivine (2)2 has been isolated in the optically active form from
Rhaphidophora decursiVa. Because the biosynthesis of both 1 and 2
appear to be similar, a special mechanism for racemization of 1 might
exist during biosynthesis. Hence, to clarify the possibility of racem-
ization of 1, we started to synthesize serotobenine (1) in an optically
active form. Recently, we developed a novel methodology to construct
optically active dihydrobenzofuran rings by rhodium carbenoid medi-
ated intramolecular C-H insertion reaction.3 We envisioned that
applying this strategy for 3 would provide an optically active
a Reagents and conditions: (a) allyl bromide, K2CO3, DMF; (b)
Me2NCH(OMe)2, pyrrolidine, DMF, 100 °C; (c) Zn, AcOH, CH2Cl2, 0 °C;
(d) TsCl, NaOH, CH2Cl2, 75% (4 steps); (e) Et2NPh, 160 °C; (f) 7, K2CO3,
acetone, reflux, 74% (2 steps); (g) OsO4, NMO, acetone/H2O; (h) Pb(OAc)4,
K2CO3, benzene, 80% (2 steps); (i) NaClO2, NaH2PO4, 2-methyl-2-butene, THF/
t-BuOH/H2O, 92%; (j) 10, EDCI, DMAP, CH2Cl2, 95%; (k) p-ABSA, DBU,
MeCN, 80%; (l) Rh2(S-DOSP)4 (0.3 mol%), CH2Cl2 (92%, 93% de).
dihydrobenzofuran ring of 1 as shown in Figure 1. Herein we report
efficiently to give a bicyclo[3.3.0]octane skeleton.7 Thus, chiral alcohol
10 was incorporated into carboxylic acid 9, and the subsequent
diazotransfer reaction was conducted by treating with p-acetamido-
benzenesulfonyl azide (p-ABSA) and DBU to provide C-H insertion
precursor 11. Upon treating 11 with 0.3 mol% of Davies catalyst,8
the C-H insertion reaction proceeded smoothly to afford exclusively
trans-dihydrobenzofuran 12 in 92% yield in a completely stereose-
lective manner.9 In this C-H insertion reaction, combining the
mandelate chiral auxiliary10 and Rh2(S-DOSP)4 provided an excellent
result; asymmetric induction strongly depended on the chiral auxiliary
rather than the catalyst.
With desired optically active dihydrobenzofuran 12 in hand, we then
focused on constructing the eight-membered macrolactam ring. Due
to instability of 12 under both acidic and basic conditions, a cross
coupling reaction should be suitable for the alkylation at the 3-position
of indole. Thus, incorporating a bromine atom into the 3-position of
12 was achieved by treating with NBS. After numerous efforts using
Pd mediated reactions, a Stille type reaction11 of 13 was found to be
suitable. Upon treating 13 with allyltributyltin and 30 mol% of
Pd(dppf)Cl2 ·CH2Cl2, the cross coupling reaction proceeded smoothly
to provide desired 14. The allyl group was converted to ethyl azide
15 via a five-step sequence involving dihydroxylation, oxidative
cleavage with Pb(OAc)4, reduction of the aldehyde, mesylation of the
alcohol, and displacement of the mesylate with NaN3. Removing
the chiral auxiliary of 15 by hydrolysis and subsequent condensation
of the resultant carboxylic acid with pentafluorophenol gave ester 16.
Figure 1. Structures of (-)-Serotobenine (1) and (-)-Decursivine (2).
a total synthesis of (-)-serotobenine (1) as well as corroborative
evidence for the racemization of 1.
As shown in Scheme 1, the indole skeleton of 1 was synthesized
by the Leimgruber-Batcho procedure.4 O-Allylation of 3-methyl-4-
nitrophenol (4), an enamine formation in the presence of pyrrolidine,
and subsequent reduction of the nitro group provided 5-allyloxy-1H-
indole (5). After protecting 5 with a Ts group, a regioselective Claisen
rearrangement5 proceeded under thermal conditions to give 6. In this
reaction, rearrangement at the C6-position was not observed even at
the sterically less hindered site. Incorporating benzyl halide derivative
7 to resultant phenol 6 was carried out under basic conditions to give
8. Oxidative cleavage of the olefin was performed in a stepwise
manner, including dihydroxylation, treatment with Pb(OAc)4, and
oxidation of the resulting aldehyde by NaClO26 to furnish carboxylic
acid 9.
Recently, we clarified that the C-H insertion reaction of diazoesters
possessing piperidinyl mandelate as a chiral auxiliary proceeded
† University of Shizuoka and Global COE Program.
‡ University of Tokyo.
§ Current address: Institute for Chemical Research, Kyoto University, Uji, Kyoto
611-0011, Japan.
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16854 J. AM. CHEM. SOC. 2008, 130, 16854–16855
10.1021/ja807676v CCC: $40.75
2008 American Chemical Society

C O M M U N I C A T I O N S
Scheme 2. Completion of Synthesis of (-)-Serotobenine (1) a
drobenzofuran ring proceeded to afford p-quinonemethide intermediate
21 as shown in Scheme 3. Furthermore, the acidic R-proton of the
amide of 21 should enable 21 and 22 to equilibrate. On the other hand,
the methylenedioxy bridge likely prevents conversion from 2 to the
p-quinonemethide intermediate,14 which may be the reason 2 is
optically active, whereas natural 1 exists as a racemic mixture.15 Further
investigation into the discrepancy of the optical activity of 1 and 2 is
currently underway in our laboratory.
In conclusion, an efficient total synthesis of (-)-serotobenine (1)
was accomplished by a Rh-catalyzed C-H insertion reaction developed
by our group. The C-H insertion precursor, 4,5-disubstituted indole,
was efficiently synthesized by the Leimgruber-Batcho protocol and
a regioselective Claisen rearrangement. The racemization of 1 is
suggested by the p-quinonemethide intermediate of 21.
Acknowledgment. We thank Professor Hiroshi Sato (Hokkaido
Agricultural Laboratory for Business Development) for providing
19 derived from natural product 1. This work was financially
supported by Takeda Science Foundation, Naito Foundation, Nagase
Science and Technology Foundation, and a Grant-in-Aid for
Scientific Research on Priority Areas 12045232 from the Ministry
of Education, Culture, Sports, Science and Technology (MEXT)
of Japan.
a Reagents and conditions: (a) NBS, CH2Cl2, 96%; (b) allyltributyltin,
Pd(dppf)Cl2 · CH2Cl2, toluene, 90 °C, 95%; (c) OsO4, NMO, acetone/
H2O; (d) Pb(OAc)4, K2CO3, benzene; (e) NaBH4, MeOH, 0 °C, 62% (3
steps); (f) MsCl, Et3N, CH2Cl2, 0 °C; (g) NaN3, DMF, 50 °C, 70% (2
steps); (h) LiOH · H2O, THF/MeOH/H2O; (i) Pfp-OH, EDCI, DMAP,
CH2Cl2, 82% (2 steps); (j) PPh3, MeCN/H2O, 50 °C, 95%; (k) Cs2CO3,
THF/MeOH, 64 °C, 96%: for 17, 82%: for 1, 79%: for 20; (l) 10%
Pd/C, H2, THF/MeOH, 97%; (m) Ac2O, pyridine, 0 °C, 97%.
Upon treating azide 16 with PPh3 in the presence of H2O, reduction
to the amine and simultaneous macrolactam formation proceeded to
provide eight-membered lactam 17 in excellent yield. Removing the
Ts group12 and cleaving the benzyl ether under hydrogenolysis
condition yielded (-)-serotobenine (1), the spectral data of which (1H,
13C NMR, IR, and HRMS) fully agreed with those of the natural
product,1,2 except for the optical rotation. Enantiomeric excess was
confirmed by comparing the behavior on a chiral HPLC of its acetate
19 derived from 1.13
Because natural serotobenine (1) was reported as a racemic form,
we examined the stability of optically active 1 under several conditions.
Neither racemization nor epimerization occurred upon treating 1 under
acidic and/or basic conditions.13 On the other hand, treating N-Ts
derivative 20 with Cs2CO3 decreased the enantiomeric excess to 15%
ee13 because incorporating the Ts group promoted the leaving ability
of 5-hydroxy indole. Thus, the ring opening reaction of the dihy-
Supporting Information Available: Experimental details and
spectroscopic data. This material is available free of charge via the
Internet at http://pubs.acs.org.
References
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Scheme 3. Our Hypothesis for Racemization of 20
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(9) The detailed selectivity by employment with other catalysts was described
in supporting information.
(10) In the total synthesis of ephedradine-A, a similar dihydrobenzofuran ring
was constructed via a lactamide auxiliary; see ref 3b. As expected, changing
the corresponding methyl group to a bulky phenyl derivative increased the
selectivity.
(11) Tilley, J. W.; Clader, J. W.; Zawoiski, S.; Wirkus, M.; LeMahieu, R. A.;
O’Donnell, M.; Crowley, H.; Welton, A. F. J. Med. Chem. 1989, 32, 1814.
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(13) Detailed data are described in the Supporting Information.
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(15) During the course of isolating decursivine (2), Professor Fong detected
serotobenine (1) from the same natural source; see ref 2a. Although they
did not verify the optical purity of 1, biosynthesis of 2 would be derived
from 1.
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