A new and general synthetic pathway to strychnos indole alkaloids: total syntheses of (-)-dehydrotubifoline and (-)-tubifoline by palladium-catalyzed asymmetric allylic substitution.

Article abstract of DOI:10.1021/ol0159571

[see reaction]. A novel procedure for the synthesis of an indole skeleton was developed. Treatment of a cyclohexenol derivative having a silyloxymethyl group at the 2-position with N-tosyl-o-bromoaniline in the presence of Pd2dba3*CHCl3 and (S)-BINAPO gav

Full text of DOI:10.1021/ol0159571

ORGANIC
LETTERS
2001
Vol. 3, No. 12
1913-1916
A New and General Synthetic Pathway
to Strychnos Indole Alkaloids: Total
Syntheses of (−)-Dehydrotubifoline and
(−)-Tubifoline by Palladium-Catalyzed
Asymmetric Allylic Substitution
Miwako Mori,* Masato Nakanishi, Daisuke Kajishima, and Yoshihiro Sato
Graduate School of Pharmaceutical Sciences, Hokkaido UniVersity,
Sapporo 060-0812, Japan
mori@pharm.hokudai.ac.jp
Received April 7, 2001
ABSTRACT
A novel procedure for the synthesis of an indole skeleton was developed. Treatment of a cyclohexenol derivative having a silyloxymethyl
group at the 2-position with N-tosyl-o-bromoaniline in the presence of Pd2dba3‚CHCl3 and (S)-BINAPO gave compound 6a with 84% ee in 75%
yield. Compound 6a was converted into 11, which was treated with Pd(OAc)2 and Me2PPh in the presence of Ag2CO to give indoline derivative
3
12. From 12, we succeeded in the total syntheses of (−)-dehydrotubifoline and (−)-tubifoline.
There are many alkaloids having an aromatic ring connected
to a cyclohexane ring. Palladium-catalyzed asymmetric
allylic substitution is a very attractive procedure for the
synthesis of these alkaloids. We have already reported the
syntheses of (-)-mesembrane,1a (-)-mesembrine,1a (+)-
crinamine,1b (-)-haemanthidine,1b and (+)-pretazetine1b
from 2-arylcyclohexenylamine derivatives 3 prepared by
palladium-catalyzed asymmetric allylic substitution.1 It is
expected that intramolecular allylic substitution of 1a using
Pd(0) would afford indoline derivative 3a. However, there
is no functional group in 3a except the double bond, and
the synthesis of a natural product from 3a would therefore
be difficult. Thus, we made an alternative plan for the
synthesis of indole alkaloids. If cyclohexenol derivative 4
having a functional group at the 2-position were reacted with
o-bromoaniline derivative 5a in the presence of a palladium
catalyst with a chiral ligand,2 compound 6 would be obtained
as a chiral form. Treatment of 6 with Pd(0) would give
indoline derivative 7, which should be a useful precursor
for the synthesis of indole alkaloids.
At first, we selected 2-carboethoxycyclohexenol derivative
4a.3 When methyl carbonate 4a was reacted with allyl
tosylamide 8 (1.1 equiv) in the presence of 2.6 mol % of
Pd2(dba)3‚CHCl3 and 5.2 mol % of (S)-BINAPO4 in DMF
at room temperature for 3 h, allylamine derivative 9a was
obtained in 40% yield, but the ee of 9a was only 5%5 (Table
(2) After we reported the palladium-catalyzed asymmetric allylic sub-
stitution of a 2-arylcyclohexenol derivative, similar reactions were reported
by two groups: (a) Trost, B. M.; Toste, F. D. J. Am. Chem. Soc. 2000,
122, 11262. (b) Hamada, Y.; Sakaguchi, K.; Hatano, K.; Hara, O.
Tetrahedron Lett. 2001, 42, 1297.
(3) Graff, M.; Al Dilaimi, A.; Seguineau, P.; Rambaud, M.; Villeras, J.
Tetrahedron Lett. 1986, 27, 1577.
(4) Grubbs, B. H.; DeVries, R. A. Tetrahedron Lett. 1977, 18, 1879.
(5) Conversion of 9a into 9c was carried out by treatment with LiAlH4.
The ee of 9c was determined by HPLC analysis using DAICEL CHIRAL-
PAK AD (hexane/iPrOH 9:1).
(1) (a) Mori, M.; Kuroda, S.; Zhang, C.-S.; Sato, Y. J. Org. Chem. 1997,
62, 5265. (b) Nishimata, T.; Mori, M. J. Org. Chem. 1998, 63, 7586. (c)
Nishimata, T.; Yamaguchi, K.; Mori, M. Tetrahedron Lett. 1999, 40, 5713.
10.1021/ol0159571 CCC: $20.00 © 2001 American Chemical Society
Published on Web 05/17/2001

Subsequently, N-tosylaniline 5b (X ) H) was used as a
nucleophile, and 6b was obtained in 85% yield (Table 2,
run 1).
Scheme 1. Our Plan for the Synthesis of an Indole Skeleton
Table 2. Reaction with Aniline Derivatives
run
R
5, X temp (°C) time (h)
yield (%) ee (%)
1
2
3
4
Me
Me
4e
4e Br
H
rt
rt
0
3
7
21
6b
6a
6a
6a
85
78
75
67
76
80
84
83
CHdCH2 4h Br
CHdCH2 4h Br
-20
168
1, run 1). Treatment of 4b and 4c with 8 in the presence of
a palladium catalyst did not afford the desired product (runs
2 and 3). In the case of 4c, palladium black was precipitated
during the reaction and none of the product was formed
except the starting material. However, when cyclohexenol
derivative 4d having a benzyloxymethyl group at the
2-position was reacted with 8 in the presence of a palladium
catalyst, the desired product 9d was obtained in 49% yield
and the ee showed 34%.6 The result was very encouraging,
and the silyl group was chosen as a protecting group. When
compound 4e (R ) CH2OSitBuMe2) was treated with 2.6
mol % of Pd2(dba)3‚CHCl3 and 5.2 mol % of (S)-BINAPO
in THF at room temperature for 100 h, 9e with 78% ee was
obtained in 53% yield.6 The use of DMF as a solvent
enhanced the reaction rate, and 9e was obtained in 70% yield
after only 3.5 h (run 5). Various silyl groups were examined,
and in each case, the ee was almost same (runs 6-8).
The use of N-tosyl-o-bromoaniline 5a gave a desired
compound 6a in 78% yield, and the ee7 was 80% (run 2).
To enhance the reactivity of the leaving group, vinyl
carbonate 4h was used,8 and the reaction was carried out at
0 °C to give 6a with 84% ee in 75% yield (run 3). The lower
reaction temperature did not affect the ee of 6a (run 4).
Next, we tried to synthesize an indoline derivative from
6a using a palladium catalyst. When a DMF solution of 6a
was warmed at 90 °C for 24 h in the presence of Pd(OAc)2
9
(5 mol %), PPh3 (10 mol %), and Ag2CO3 (1 equiv), we
were pleased to find that indoline derivatives 10a and 10b
were obtained in 50% yield in a ratio of 5.3 to 1. The result
of an NOE experiment of 10a showed that the stereochem-
istry of the fused five-six-membered ring was a cis-
configuration. As a ligand, dimethylphenylphosphine gave
10 in high yield, although the ratio of 10a to 10b was 3 to
1 (run 3). Isomerization product 10b was not found when
DMSO was used as a solvent (run 5).
Table 1. Asymmetric Allylic Substitutiona
On the basis of these results, we focused on a total
synthesis of Strychnos alkaloids, which include (-)-tubifo-
line, (-)-tubifolidine, and (-)-strychnine. Our target mol-
ecule was (-)-tubifoline,10 which has been synthesized by
several groups,11 as a racemic11a-d or a chiral form.11e
A
retrosynthetic analysis of (-)-tubifoline is shown in Scheme
2. (-)-Tubifoline would be synthesized from I, which would
be obtained from tetracyclic compound II. The synthesis of
indoline derivative III from IV has already been demon-
(6) The ee’s of 9d and 9e were determined after conversion into 9c.5
(7) The ees of 6a and 6b were determined by HPLC analyses using
DAICEL CHIRALCEL OJ-R (CH3CN/H2O 9:1) and DAICEL CHIRAL-
CEL OJ (hexane/iPrOH 9:1) after desilylation by treatment with 4 N HCl,
respectively.
(8) Mori, M.; Nishimata, T.; Nagasawa, Y.; Sato, Y. AdV. Synth. Catal.
2001, 343, 34.
(9) The use of silver salts suppressed alkene isomerization in the Heck
reaction: Abelman, M. M.; Oh, T.; Overman, L. E. J. Org. Chem. 1987,
52, 4130.
(10) For the isolation and structural elucidation of this alkaloid, see:
Kump, W. G.; Patel, M. B.; Rowson, J. M.; Schmid, H. HelV. Chim. Acta
1964, 47, 1497.
a All reactions were carried out using Pd2(dba)3‚CHCl3 (2.6 mol %) and
(S)-BINAPO at room temperature.
1914
Org. Lett., Vol. 3, No. 12, 2001

NOE experiment showed that the ring junction of the fused
five-six-membered ring was also cis.
Table 3. Synthesis of an Indoline Derivative
Treatment of 12 with LiAlH4 followed by protection of
nitrogen gave 13 in 66% yield. Allylic oxidation of 13 with
Pd(OAc)2 in the presence of benzoquinone and MnO212 gave
the expected tetracyclic compound 14 in 77% yield. The
amide nitrogen attacked the double bond on the cyclohexene
ring coordinated to Pd(II) to produce 14. Regioselective
hydroboration of 14 with 9-BBN proceeded smoothly at 50
°C followed by treatment with H2O2 and NaOH to give the
alcohol, which was oxidized to give ketone 15 in 70% yield.
Treatment of 15 with potassium hexamethyldisilazide and
then PhNTf2 afforded the enol triflate,13 which was converted
into olefin 16 by treatment with HCO2H and iPr2NEt in the
run
ligand
PPh3
PMePh2
PMe2Ph
PMe2Ph
PMe2Pha
solvent
10a (%)
10b (%)
6a (%)
14
presence of Pd(OAc)2 and PPh3 in 64% yield.
1
2
3
4
5
DMF
DMF
DMF
C3H7CN
DMSO
42
52
56
17
47
8
13
19
1
33
29
20
71
38
Scheme 4. Total Syntheses of (-)-Dehydrotubifoline and
(-)-Tubifolinea
0
a Reaction temperature: 105 °C.
strated. Thus, for the synthesis of II, compound IV (R1 )
CN) would be suitable.
Scheme 2. Retrosynthetic Analysis of Tubifoline
Compound 6a was converted into 11, which was treated
with 2 mol % of Pd(OAc)2 and 4 mol % of PMe2Ph in the
presence of Ag2CO3 (1 equiv) in DMSO at 90 °C for 17 h
to give indoline derivative 12 in 87% yield (Scheme 3). No
olefin isomerization product was produced. The result of an
a (i) LiAlH4; (ii) Boc2O; (iii) 10 mol % Pd(OAc)2, 40 mol %
benzoquinone, MnO2 (2 equiv) AcOH, 50 °C, 20 h; (iv) 9-BBN,
50 °C, then H2O2; (v) Swern oxidation; (vi) PhNTf2, KHMDS; (vii)
Pd(OAc)2, PPh3, HCO2H, iPr2NEt; (viii) Na-naphthalenide. (ix)
CF3CO2H; (x) 18, K2CO3; (xi) 10 mol % Pd(OAc)2, Bu4NCl (1
equiv) K2CO3 (5 equiv) DMF, 60 °C, 3 h. (xii) H2, PtO2, EtOH, rt.
Scheme 3. Synthesis of an Indoline Derivativea
Deprotection of the tosyl group of 16 with sodium
naphthalenide followed by treatment with CF3CO2H gave
(11) (a) Danson, B. A.; Harley-Mason, J.; Foster, G. H. Chem. Commun.
1968, 1233. (b) Takano, S.; Hirama, M.; Ogasawara, K. Tetrahedron Lett.
1982, 23, 881. (c) Ban, Y.; Yoshida, K.; Goto, I.; Oishi, T.; Takeda, E.
Tetrahedron 1983, 39, 3657. (d) Amat, M.; Linares, A.; Bosch, J. J. Org.
Chem. 1990, 55, 6299. (e) Amat, M.; Coll, M.-D.; Bosch, J.; Espinosa, E.;
Molins, E. Tetrahedron: Asymmetry 1997, 8, 935.
a (i) 4 N aqueous HCl; (ii) PBr3; (iii) NaCN; (iv) 2 mol %
Pd(OAc)2, 4 mol % Me2PPh, Ag2CO3 (1 equiv), DMSO, 90 °C,
17 h.
(12) Hansson, S.; Heumann, A.; Rain, T.; A° kermark, B. J. Org. Chem.
1990, 55, 975.
Org. Lett., Vol. 3, No. 12, 2001
1915

diamine. Monoalkylation with 1815a in the presence of K2-
CO3 proceeded smoothly to give 17 in 49% yield from 16.
Intramolecular Heck reaction using a palladium catalyst15a,16
result indicated that the absolute configuration of the product
6a, which was obtained by asymmetric allylic substitution,
was S. Thus, we succeeded in the total synthesis of (-)-
dehydrotubifoline and (-)-tubifolin from allylamine deriva-
tive 6a, which was synthesized by palladium-catalyzed
asymmetric allylic substitution, via 16 steps. All steps for
the ring constructions were achieved using the palladium
catalysts.
1
gave a pentacyclic compound in 59% yield, whose H and
13C NMR spectra agreed with those of (-)-dehydrotubifoline
reported in the literature.15 However, the [R]D value of (-)-
dehydrotubifoline is not known. Thus, hydrogenation of (-)-
dehydrotubifoline with PtO2 in EtOH was carried out to give
1
(-)-tubifoline, whose [R]D value17 and H and 13C NMR
spectra agreed with those reported in the literature.10,18 The
Further studies on the asymmetric synthesis of Strychnos
alkaloids are now in progress.
(13) (a) Stang, P. J.; Dueber, T. E. Org. Synth. 1974, 54, 79. (b) McMurry,
J. E.; Scott, W. J. Tetrahedron Lett. 1983, 24, 979.
(14) Cacchi, S.; Morera, E.; Orter, G. Tetrahedron Lett. 1984, 25, 4821.
(15) (a) Rawal, V. H.; Michoud, C.; Monestel, R. F. J. Am. Chem. Soc.
1993, 115, 3030. (b) Crawley, G. C.; Harley-Mason, J. Chem. Commun.
1971, 685. (c) Angle, S. R.; Fevig, J. M.; Knight, S. D.; Marquis, R. W.,
Jr.; Overman, L. E. J. Am. Chem. Soc. 1993, 115, 3966.
Supporting Information Available: Experimental pro-
cedure and spectral data of 4h, 9a, 9d-f, 6a,b, 10a, 11-
17, (-)-dehydrotubifoline, and (-)-tubifoline. This material
is available free of charge via the Internet at http://pubs.acs.org.
(16) Jeffery, T. Tetrahedron Lett. 1985, 26, 2667.
(17) 84% ee, [R]22 -311 (c 0.236, AcOEt).
D
(18) Schumann, D.; Schmid, H. HelV. Chim. Acta 1963, 46, 1996.
OL0159571
1916
Org. Lett., Vol. 3, No. 12, 2001