First enantioselective total synthesis of (-)-tejedine

Article abstract of DOI:10.1021/ol0261635

(Matrix presented) The first enantioselective total synthesis of (-)-tejedine (1) is reported. Tejedine is a seco-bisbenzyltetrahydroisoquinoline isolated in 1998 as a minor component from Berberis vulgaris. The synthesis was achieved using a strategy employing four key steps, including a chiral auxiliary-assisted diastereoselective Bischler-Napieralski cyclization.

Full text of DOI:10.1021/ol0261635

ORGANIC
LETTERS
2002
Vol. 4, No. 16
2675-2678
First Enantioselective Total Synthesis of
(−)-Tejedine
You-Chu Wang and Paris E. Georghiou*
Department of Chemistry, Memorial UniVersity of Newfoundland,
St. John’s, Newfoundland and Labrador, Canada A1B 3X7
parisg@mun.ca
Received May 9, 2002
ABSTRACT
The first enantioselective total synthesis of (−)-tejedine (1) is reported. Tejedine is a seco-bisbenzyltetrahydroisoquinoline isolated in 1998 as
a minor component from Berberis vulgaris. The synthesis was achieved using a strategy employing four key steps, including a chiral auxiliary-
assisted diastereoselective Bischler−Napieralski cyclization.
(-)-Tejedine (1), first reported in 1998 by the group of Suau
et al.,1 is a minor component of Berberis Vulgaris. It is an
example of a “Type VI” seco-bisbenzyltetrahydroisoquino-
line,2 a relatively rare group of compounds within the larger
and diverse group of bisbenzylisoquinoline alkaloids.3 Te-
jedine, whose biological properties have not been reported,
is structurally very closely related to baluchistanamine (2),
which was reported by Shamma et al.4 in 1974.
bamate synthon, 3. In turn, 3 can be constructed using a base-
mediated SNAr diaryl ether coupling of 4 with 5. An
Scheme 1
These two alkaloids possess only a single stereogenic
center, but when the complexity of the substituents on the
tetrahydroisoquinoline and dihydroisoquinolone subunits is
also taken into consideration, they are synthetically relatively
challenging. We herein report the first enantioselective total
synthesis of (-)-tejedine.
The retrosynthetic plan in Scheme 1 outlines the synthetic
approach taken. The first disconnection envisioned a ring
closure to form the tetrahydroisoquinoline unit via a car-
(1) Suau, R.; Rico, R.; Lopez-Romfro, J. M.; Najera, F.; Cuevas, A.
Phytochemistry 1998, 49, 2545-2549.
10.1021/ol0261635 CCC: $22.00 © 2002 American Chemical Society
Published on Web 07/11/2002

enantioselective Bischler-Napieralski5 disconnection sug-
gested that 4 could be constructed via the reaction of
synthons 6 with 7. Synthon 7 itself requires a diaryl ether
coupling disconnection. Vanillin (8) was chosen as the
starting compound for 6 (Scheme 2): bromination, followed
Scheme 3a
Scheme 2a
a Reagents and conditions: (a) Br2/CHCl3, rt 12 h (55%); (b)
i-PrBr, DMSO, K2CO3, 55 °C, 12 h (94%); (c) NaBH4, THF/MeOH,
rt, 2 h (98%); (d) TBSCl, imidazole, DMF, rt, 12 h (95%); (e)
n-BuLi/THF, -78 °Cfrt, 12 h; H2O2, rt, 24 h (14, 82%); (f) 14 +
15, Cu(OAc)2, py, CH2Cl2, 4 Å mol sieves, rt, 48 h (16, 57%); (g)
16, LiOH, 1:3:1 MeOH/THF/H2O, rt, 2 h (quant); (h) Tf2O, 2,6-
lutidine, CH2Cl2, -40 °C, (98%); (i) bis(pinacolato)diboron,
PdCl2(dppf), KOAc, dioxane, 80 °C, (19, 85%); (j) diethanolamine,
2-propanol, Et2O, (78%); (k) aq 1 M HCl, THF, rt (15, 85%).
a Reagents and conditions: (a) Br2, AcOH, rt, 1 h (94%); (b)
(CH3)2SO4, NaOH, Adogen 464R, CH2Cl2, rt, 15 h (89%); (c)
NaBH4, THF/MeOH, 2 h; (d) TBSCl, imidazole, DMF, rt, 12 h
(92%); (e) n-BuLi, -78 °C 1 h; B(OCH3)3, 12 h, -78 °Cfrt; H2O2,
rt, 12 h (78%); (f) BnBr, K2CO3, acetone, reflux, 12 h (75%); (g)
Bu4NF, THF, 0 °C, 2 h (quant); (h) SOCl2, benzene, rt, 12 h (88%);
(i) NaCN, DMSO/benzene, rt, (89%); (j) NaOH (4 M), EtOH,
reflux, 20 h (98%); (k) (COCl)2, benzene, rt, 2 h; (l) (S)-R-
methylbenzylamine, aq 5% NaOH/CH2Cl2 (1.5:1), rt, 1 h (90%);
(m) B2H6‚THF/BF3‚Et2O, THF, reflux; (n) aq 20% HCl (98%).
sequence. An isopropyl group7 was employed as the protect-
ing group since this allowed for selectivity in the removal
of protecting groups in the final step of the total synthesis.
Cu(OAc)2-mediated8 diaryl ether coupling of 14 with boronic
acid 15 afforded 16, which was hydrolyzed to the free
carboxylic acid synthon 7, using conditions that did not affect
the other two protecting groups.
by methylation, NaBH4 reduction, and protection of the
resulting primary alcohol as the TBS ether afforded 9 (92%).
Lithiation of 9 was followed by transmetalation to form the
arylboronate, which was quenched with hydrogen peroxide
to form the corresponding phenol.
Boronic acid 15 was synthesized via conversion of methyl
(4-hydroxyphenyl)acetate (17) to the triflate 18, followed by
PdCl2(dppf)-catalyzed coupling with bis(pinacolato)diboron9
to form the intermediate arylboronate 19. Conversion to 15
could only be efficiently accomplished using a procedure
similar to that described by Jung and Lazarova:9 reaction of
19 with diethanolamine formed the corresponding cyclic
aminoboronate intermediate, which could be more easily
hydrolyzed than 19, under acidic conditions, to 15 (Scheme
3).
Diastereoselective6 Bischler-Napieralski cyclization to
form synthon 4 was accomplished by the reactions shown
in Scheme 4: the chiral auxiliary-bearing synthon 6 con-
densed smoothly with 7 using HOBt/EDCI conditions10 to
form amide 20. A four-step sequence converted 20 into 22b
in 60% overall yield. Cyclization of 22b using typical
Bischler-Napieralski conditions, with POCl3 in benzene,
Protection of the phenolic group as the benzyl ether 10
was followed by homologation to the trisubstituted phenyl-
acetic acid 11. The readily available (S)-R-methylbenzy-
lamine6 was found to be the most efficient chiral auxiliary
to effect a diastereoselective Bischler-Napieralski cycliza-
tion at a subsequent stage. Reaction of 11 with (S)-R-
methylbenzylamine using Schotten-Baumann conditions
resulted in the amide 12 (90%), which was converted to
synthon 6.
Synthesis of the diaryl ether 7 was achieved in 40% overall
yield, using the reactions shown in Scheme 3: 4-hydroxy-
benzaldehyde (13) was converted to 14 via a five-step
(2) For reviews, see: (a) Guha, K. P.; Mukherjee, B.; Mukherjee, R. J.
Nat. Prod. 1979, 42, 1-84. (b) Schiff, P. L., Jr. J. Nat. Prod. 1983, 46,
1-43. (c) Schiff, P. L., Jr. J. Nat. Prod. 1987, 50, 529-599. (d) Schiff, P.
L., Jr. J. Nat. Prod. 1991, 54, 645-749. (e) Schiff, P. L., Jr. J. Nat. Prod.
1997, 60, 934-953.
(7) Banwell, M. G.; Flynn, B. L.; Stewart, S. G. J. Org. Chem. 1998,
63, 9139-9144.
(8) (a) Evans, D. A.; Katz, J. L.; West, T. R. Tetrahedron Lett. 1998,
39, 2937-2940. (b) Chan, D. M. T.; Monaco, K. L.; Wang, R. P.; Winters,
M. P. Tetrahedron Lett. 1998, 39, 2933-2936. (c) Lam, P. Y. S.; Clark, C.
G.; Saubern, S.; Adams, J.; Winters, M. P.; Chan, D. M. T.; Combs, A.
Tetrahedron Lett. 1998, 39, 2941-2944.
(3) Bentley, K. W. The Isoquinoline Alkaloids; Harwood Academic
Publishers: Amsterdam, 1998; Vol. 1, pp 59-92.
(4) Shamma, M.; Foy, J. E.; Miana, G. A. J. Am. Chem. Soc. 1974, 96,
7809-7811.
(5) Whaley, W. M.; Govindachari, T. R. Org. React. 1951, 6, 74-206.
(6) Polniaszek, R.; Kaufman, C. R. J. Am. Chem. Soc. 1989, 111, 4859-
4863.
(9) Jung, M. E.; Lazarova, T. I. J. Org. Chem. 1999, 64, 2976-2977.
(10) Evans, D. A.; Wood, M. R.; Trotter, B. W.; Richardson, T. I.;
Barrow, J. C.; Katz, J. L. Angew. Chem., Int. Ed. 1998, 37, 2700-2704.
2676
Org. Lett., Vol. 4, No. 16, 2002

Scheme 4a
Figure 1. ORTEP X-ray structure of 26.
that included the high-yield six-step nitro to methoxy group
transformation,13 followed by a two-step removal of the Boc
group and N-methylation to form 3. These steps were
conducted in a “one-pot” reaction, not requiring purification
of the intermediates. The penultimate step, in which 3 was
cyclized to form the corresponding isoquinolone, was ef-
fected using Banwell’s procedure.14 Chemoselective removal
of the isopropyl protecting group on the cyclized product
using AlCl3 gave 1, which was identical in all respects with
a sample of authentic (-)-tejedine.15
a Reagents and conditions: (a) HOBt/EDCI, DMF, 0 °C, 48 h
(73%); (b) TBAF, THF, 0 °C, 1 h, (quant); (c) Dess-Martin
periodinane oxidation, 1 h; (d) NaClO2, Na2HPO4, resorcinol,
DMSO, rt, 12 h; (e) TMSCHN2, MeOH, benzene, rt, 1 h (60%
from 20a); (f) POCl3, benzene, reflux, 12 h; (g) NaBH4/MeOH,
-78 °C, 5 h (23, 45%; 24, 40%); (h) H2, Pd/C, EtOH, EtOAc, aq
HCl, rt, 15 h; (i) (Boc)2O, Et3N, -78 °Cfrt, 12 h (4, 80%).
followed by NaBH4 reduction afforded a pair of regioisomers
23 and 24 in 45 and 40% yields, respectively. The regio-
isomer 24, which was required for the synthesis of (-)-
tejedine, was formed in approximately 99% de, as determined
Scheme 5a
1
by H NMR spectroscopy. Pd/C-catalyzed hydrogenation
effected smooth removal of both the chiral auxiliary and the
benzyl groups. The secondary amine of the tetrahydroiso-
quinoline was then selectively protected as the Boc derivative
to afford 4.
Supporting evidence that the new stereogenic center in
24 had the same configuration as that in the target (-)-
tejedine came from a model study: reaction of bromoarene
25 under the Bischler-Napieralski/NaBH4 conditions gave
26 as the major diastereomer in 94% de. Its X-ray crystal
structure11 (Figure 1) established that the configuration of
the new stereogenic center was the desired one.
a Reagents and conditions: (a) 12 M, HCl, reflux 15 h (92%);
(b) (COCl)2, DMF, benzene, rt, 2 h; (c) MeNH3+Cl-, aq 5% NaOH,
rt, 2 h (80%); (d) B2H6‚THF/BF3‚Et2O, THF, reflux, 5 h; (e)
ClCO2Et, aq satd NaHCO3, CH2Cl2/H2O, rt, 12 h (80%); (f) 4 +
5: CsF, DMSO, rt, (90%); (g) H2/Pd-C, MeOH; (h) HBF4,
i-amylONO, CH3CN, -20 °C, 0.5 h; aq satd KI, -45 °Cfrt, 2 h;
i-PrMgCl, THF, -60 f -40 °C, 2 h; B(OCH3)3, from -60 f
-40 °C, 1 h; H2O2, aq 1 M NaOH, -20 f 0 °C, 1 h (85% from
28); (i) CH3I, DMF, 0 °C/TFA, THF; (j) aq 37% HCHO,
NaBH3CN, (95%); (k) Tf2O, DMAP, CH2Cl2, 0 °Cfrt, 12 h (80%);
(l) AlCl3, CH2Cl2, rt, 48 h, (56%).
Synthon 5 was synthesized via a five-step synthetic
sequence from 4-fluoro-3-nitroacetonitrile (27)12 (Scheme 5).
Base-mediated SNAr coupling of 5 with 4 produced 28, which
was transformed into the carbamate synthon in a sequence
Org. Lett., Vol. 4, No. 16, 2002
2677

Acknowledgment. We thank the Prime Pharmaceutical
Corporation, Toronto, Ontario, and the Natural Sciences and
Engineering Research Council of Canada for a CRD grant.
Genesis Group and the Department of Chemistry, Memorial
University, are also thanked for financial support.
Supporting Information Available: 1H NMR spectra
(500 MHz) of synthetic and authentic tejedine and of the
key intermediates 3-7. This material is available free of
charge via the Internet at http://pubs.acs.org.
OL0261635
(12) Beugelmans, R.; Singh, G. P.; Bois-Choussy, M.; Chastanet, J.; Zhu,
J. J. Org. Chem. 1994, 59, 5535-5542.
(11) C33H34O3NBr: monoclinic, space group P21 (#4), a ) 10.814 (2)
Å, b ) 9.818 (1) Å, c ) 13.573 (2) Å, â ) 97.61 (1)o, V ) 1428.3 (4) Å3,
Z ) 2, Dcalcd ) 1.331 g/cm3. Intensity data were measured at 299 "1 K on
a Rigaku AFC6S diffractometer with graphite-monochromated Mo KR
radiation (λ ) 0.71069 Å) to 2θmax (deg) 55.1°. A total of 7336 reflections
were measured of which 3496 (Rint ) 0.056) were unique. The final cycle
of full-matrix least-squares refinement on F was based on 2284 observed
reflections (I > 2.00σ(I)) and 343 variable parameters and converged with
unweighted and weighted agreement factors of: R ) 0.038 Rw ) 0.038,
GOF ) 1.42. We thank David O. Miller, X-ray Crystallography Unit,
Department of Chemistry, Memorial Univerity of Newfoundland for these
measurements.
(13) Nicolaou, K. C.; Takayanagi, M.; Jain, N. F.; Natarajan, S.;
Koumbis, A. E.; Bando, T.; Ramanjulu, J. M. Angew. Chem., Int. Ed. 1998,
37, 2717-2719.
(14) (a) Banwell, M. G.; Cowden, C. J.; Gable, R. R. J. Chem. Soc.,
Perkin Trans. 1 1994, 3515-3518. (b) Banwell, M. G.; Bissett, B. D.;
Busato, S.; Cowden, C. J.; Hockless, D. C. R.; Holman, J. W.; Read, R.
W.; Wu, A. W. J. Chem. Soc., Chem. Commun. 1995, 2551-2553.
(15) We thank Professor Rafael Suau of the University of Malaga, Spain
for a sample of (-)-tejedine. The spectral and optical properties of
synthetically derived tejedine and those of the sample provided by Professor
Suau were identical.
2678
Org. Lett., Vol. 4, No. 16, 2002