First total synthesis of the 7,3′-linked naphthylisoquinoline alkaloid ancistrocladidine

Article abstract of DOI:10.1021/ol017258u

(formula presented) (-)-Ancistrocladidine (1) The first total synthesis of the rare 7,3′-linked naphthylisoquinoline alkaloid, ancistrocladidine, has been completed. The key feature of the synthesis is the formation of the extremely hindered biaryl linkag

Full text of DOI:10.1021/ol017258u

ORGANIC
LETTERS
2002
Vol. 4, No. 4
631-633
First Total Synthesis of the 7,3′-Linked
Naphthylisoquinoline Alkaloid
Ancistrocladidine
Christopher J. Bungard and Jonathan C. Morris*
Department of Chemistry, UniVersity of Canterbury, Christchurch, New Zealand
j.morris@chem.canterbury.ac.nz
Received December 18, 2001
ABSTRACT
The first total synthesis of the rare 7,3′-linked naphthylisoquinoline alkaloid, ancistrocladidine, has been completed. The key feature of the
synthesis is the formation of the extremely hindered biaryl linkage by Pinhey−Barton ortho-arylation of a naphthol with an aryllead triacetate.
The biaryl aldehyde formed is elaborated in 10 steps to form a 1:1 mixture of ancistrocladidine and its atropisomer. Recrystallization of the
mixture afforded ancistrocladidine, which was identical in all respects to the reported data.
Extracts from the tropical Ancistrocladaceae and Dionco-
phyllaceae plant families have been used in traditional
medicines for the treatment of malaria and dysentery.1 Recent
examination of these extracts has revealed that the profound
biological activity is due to the presence of naphthyliso-
quinoline alkaloids. These structurally unique alkaloids are
characterized by a naphthalene group, linked to either a
dihydro- or tetrahydroisoquinoline moiety as exemplified in
the examples shown in Figure 1.2 While significant advances
have been made in the syntheses3 of 5,1′-, 7,1′-, and 5,8′-
linked naphthylisoquinoline alkaloids, little synthetic atten-
(1) (a) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phyto-
chemistry 1992, 31, 3821-3825. (b) Bringmann, G.; Francois, G.; Ake Assi,
L.; Schlauer, J. Chimia 1998, 52, 18-28.
(2) Bringmann, G.; Pokorny, F. In The Alkaloids; G. Cordell, Ed.;
Academic Press: New York, 1995; Vol. 46, pp 127-271.
(3) (a) Rao, A. V. R.; Gurjar, M. K.; Ramana, D. V.; Chheda, A. K.
Heterocycles 1996, 43, 1-6. (b) Hobbs, P. D.; Upender, V.; Dawson, M.
I. Synlett 1997, 965-967. (c) Rizzacasa, M. A. In Studies in Natural Product
Synthesis, Structure and Chemistry (Part F); Atta-ur-Rahman, Ed.; Else-
vier: Amsterdam, 1998; Vol. 20, pp 407-455 and references therein. (d)
Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525-558 and
references therein. (e) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed.
1999, 38, 3530-3533. (f) Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest,
O. P. J. Org. Chem. 1999, 64, 7184-7201. (g) Kamikawa, K.; Watanabe,
T.; Daimon, A.; Uemura, M. Tetrahedron 2000, 56, 2325-2337. (h)
Bringmann, G.; Menche, D. Acc. Chem. Res. 2001, 34, 615-624 and
references therein.
Figure 1. Representative examples of naphthylisoquinoline alka-
loids.
tion4 has been focused on 7,3′-linked systems such as that
found in ancistrocladidine 1.5 The 7,3′-biaryl bond in
10.1021/ol017258u CCC: $22.00 © 2002 American Chemical Society
Published on Web 01/16/2002

ancistrocladidine represents a particular challenge to con-
temporary cross-coupling methods as a result of the presence
of four ortho substitutents. Despite the many advances6 in
transition metal catalyzed cross-coupling methodology,
relatively few biaryl linkages with four ortho-substituents
have been synthesized in this way.7 In this Letter, we report
a new strategy that has resulted in the first total synthesis of
ancistrocladidine.
Scheme 2a
An overview of our retrosynthetic analysis is depicted in
Scheme 1 and is based on the formation of the key biaryl
t
a Reagents: (a) BuLi, Bu3SnCl, THF, -95 °C to rt, 85%; (b)
Pb(OAc)4, cat. Hg(OAc)2, CH2Cl2, rt, 24 h, 93%; (c) 2, pyridine,
CH2Cl2, 24 h, rt; (d) 3% v/v aqueous H2SO4, THF, 1 h, rt, 67%
yield from 3.
Scheme 1
Stirring the stannane 6 with freshly purified Pb(OAc)4 in
the presence of a catalytic amount of Hg(OAc)2 provided
aryllead triacetate 3 in 93% yield. Formation of the key biaryl
linkage using the Pinhey-Barton methodology was readily
achieved by reacting the lead species 3 with naphthol 211 in
the presence of pyridine and CH2Cl2 at room temperature.
Hydrolysis of the crude reaction mixture with 3% v/v
aqueous H2SO4 in THF gave the desired biaryl aldehyde 4,
in 67% yield from 3.
With the successful establishment of the hindered biaryl
linkage, aldehyde 4 was then elaborated to the chiral amine
5 (R ) MOM) by use of the Katsuki-Sharpless epoxida-
tion12 (Scheme 3).
The required allylic alcohol 8 was prepared in three steps
from biaryl aldehyde 4 in 71% overall yield: (i) protection
of the naphthol as its MOM ether, (ii) elaboration of the
aldehyde to the R,â-unsaturated ester by Horner-Wads-
worth-Emmons reaction, and (iii) reduction with DIBAL-
H.
Epoxide 9 was obtained in 80% yield and 90% de14 using
the standard Sharpless catalytic conditions.15 Tosylation of
9 gave the primary tosylate 10 in 83% yield. Concomitant
cleavage16 of the tosylate and ring opening of the epoxide
to afford alcohol 11, in 94% yield, was achieved by reaction
of tosylate 10 with LiAlH4 in Et2O.Transformation of the
alcohol 11 into the amine 5 (R ) MOM) was achieved, in
81% overall yield, by reaction of 11 with phthalimide under
Mitsunobu conditions,17 followed by hydrolysis of the
linkage by Pinhey-Barton ortho-arylation8 of naphthol 2
with aryllead triacetate 3. Elaboration of the biaryl 4 to
amphetamine 5 would allow for the use of a Bischler-
Napieralski cyclization to form the 3,4-dihydroisoquinoline
ring system.9
In light of these plans, our initial goal was the synthesis
of aryllead triacetate 3. While there are a variety of methods8c
for the preparation of aryllead triacetates, perhaps the most
general method involves a tin-to-lead transmetalation using
Pb(OAc)4 in the presence of a catalytic amount of a mercury
salt. Accordingly, stannane 6 was prepared in 85% yield by
halogen-lithium exchange of iodide 710 with t-BuLi and
subsequent quenching with Bu3SnCl (Scheme 2).
(4) Comber, M. F.; Morris, J. C.; Sargent, M. V. Aust. J. Chem. 1998,
51, 19-22.
(5) (a) Govindachri, T. R.; Parthsarathy, P. C.; Desai, H. K. Indian J.
Chem. 1973, 11, 1190. (b) Govindachri, T. R.; Parthsarathy, P. C.;
Rajagopalan, T. G.; Desai, H. K.; Lee, E. J. Chem. Soc., Perkin Trans. 1,
1975, 2134-2136. (c) Meksuriyen, D.; Ruangrungsi, N.; Tantivatana, P.;
Cordell, G. A. Phytochemistry, 1990, 29, 2750-2752.
(10) Iodide 7 is prepared by acetalization of 3,5-dimethoxy-4-iodobenz-
aldehyde with ethylene glycol (99%). The aldehyde is readily available from
3,5-dihydroxybenzoic acid as described in (a) Gray, J. S.; Martin, G. C. J.;
Rigby, W. J. Chem. Soc. C 1967, 2580-2587. (b) Kompis, I.; Wick, A.
HelV. Chim. Acta 1977, 8, 3025-3034.
(6) (a) Stanforth, S. P. Tetrahedron, 1998, 54, 263-303. (b) Metal-
catalyzed Cross-coupling Reactions, Diederich, F.; Stang, P. J. (Eds), Wiley-
VCH: NY, 1998.
(11) Watanabe, M.; Hisamatsu, S.; Hotokezaka, H.; Furukawa, S. Chem.
Pharm. Bull. 1986, 34, 2810-2820.
(12) For a related example, see ref 3a. For other methods for the
introduction of chirality into biaryl systems, see refs 3e, 3g, and 13.
(13) (a) Bringmann, G.; Jansen, J. R.; Rink, H. P. Angew. Chem., Int.
Ed. Engl. 1986, 25, 913-915. (b) Hoye, T. R.; Chen, M. Tetrahedron Lett.
1996, 37, 3099-3100.
(14) This reaction generates diastereomers with respect to the biaryl
linkage, but they are not observable. The epoxide was recrystallized from
toluene/petroleum ether to provide material with >95% de, as determined
by the method described in Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org.
Chem. 1969, 34, 2543-2549.
(15) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(16) Chong, J. M. Tetrahedron Lett. 1992, 33, 33-36.
(7) (a) Johnson, M. G.; Foglesong, R. J. Tetrahedron Lett. 1997, 38,
7001-7002. (b) Saa´, J. M.; Martorell, G. J. Org. Chem. 1993, 58, 1963-
1966.
(8) The groups of Pinhey and Barton have shown that this is an efficient
method for the generation of extremely hindered biaryl linkages: (a) Bell,
H. C.; Pinhey, J. T.; Sternhell, S. Aust. J. Chem. 1979, 32, 1551-1560. (b)
Morgan, J.; Hambley, T. W.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1
1996, 2173-2177. (c) Pinhey, J. T. Aust. J. Chem. 1991, 44, 1353-1382.
(d) Barton, D. H. R.; Donnelly, D. M. X.; Guiry, P. J.; Finet, J.-P. J. Chem.
Soc., Perkin Trans. 1 1994, 2921-2926.
(9) Bringmann, G.; Weirich, R.; Reuscher, H.; Jansen, J. R.; Kinzinger,
L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877-888.
632
Org. Lett., Vol. 4, No. 4, 2002

Scheme 3a
a Reagents: (a) MOM-Cl, NaH, THF, rt, 81%; (b) NaH, (EtO)2POCH2CO2Et, C6H6, 0 °C to rt, 99%; (c) DIBAL-H, toluene, -78 °C,
15 min, 89%; (d) 5 mol % Ti(OiPr)4, 6 mol % D-diisopropyltartrate, TBHP, CH2Cl2, -20 °C, 5 h, 80%, 90% ee; (e) TsCl, NEt3, DMAP,
CH2Cl2, 1 h, 0 °C, 83%; (f) LiAlH4, Et2O, 0 °C, 2 h, 94%; (g) phthalimide, DEAD, PPh3, THF, rt, 16 h, 82%; (h) 40% aq MeNH2, EtOH,
reflux, 1 h, 99%; (i) CH3COCl, NEt3, CH2Cl2, 0 °C to rt, 97%; (j) POCl3, 2,4,6-collidine, CH3CN, reflux, 4 h, 74% (1:1 mixture of 1 and
13).
phthalimide group with aqueous ethanolic methylamine.
Acetylation of the amine 5 (R ) MOM) with CH3COCl gave
the acetamide 12 in 97% yield. Bischler-Napieralski cy-
clization was readily achieved by reaction of 12 with POCl3
in the presence of 1.1 equiv of 2,4,6-collidine. During the
course of this reaction, the MOM protecting group was
cleaved in situ, and thus ancistrocladidine 1 was isolated,
along with the atropisomer 13, in a 1:1 ratio, in 74% overall
yield. Separation of the atropisomers was readily achieved
by recrystallization from toluene/petroleum ether. Compari-
son with an authentic sample of ancistrocladidine is not
possible as the natural product is no longer available, but
synthetic ancistrocladidine matches all the reported data for
the natural product.5a,5c,18
an aryllead triacetate. The formation of such a hindered bond
under very mild conditions, coupled with the recent report
that this chemistry can be carried out in an atroposelective
fashion,19 indicates that this new strategy could be applied
to the synthesis of other members of the naphthylisoquinoline
alkaloid family.
Acknowledgment. We thank the University of Canter-
bury for financial assistance, Mr. Bruce Clark for mass
spectrometry experiments, and Profs. Peter J. Steel and Andy
J. Phillips for helpful discussions.
Supporting Information Available: Characterization
data for natural ancistrocladidine, synthetic ancistrocladidine,
and atropisomer 13, and copies of 1H and 13C NMR spectra
of all new compounds. This material is available free of
charge via the Internet at http://pubs.acs.org.
In summary, the first total synthesis of a 7,3′-linked
naphthylisoquinoline alkaloid has been completed. The key
feature of our synthesis is the formation of the extremely
hindered biaryl linkage by ortho-arylation of a naphthol with
OL017258U
(17) Hughes, D. L. Org. React. (N.Y.) 1992, 42, 335-656.
(18) Professor Geoffrey Cordell (Illinois) has indicated that the 1.8 Hz
coupling constant reported for the signal at δ 2.42 (dd, J ) 15.5, 1.8 Hz,
1H) is a misprint in the original paper (ref 5c). (Personal communication)
(19) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J. Am.
Chem. Soc. 1999, 121, 8943-8944.
Org. Lett., Vol. 4, No. 4, 2002
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