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

Article abstract of DOI:10.1021/jo0611364

The first total synthesis of ancistrocladidine, a rare 7,3′-linked naphthylisoquinoline alkaloid, has been completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl linkage by ortho-arylation of a naphthol with

Full text of DOI:10.1021/jo0611364

Total Synthesis of the 7,3′-Linked Naphthylisoquinoline Alkaloid
Ancistrocladidine
Christopher J. Bungard‡ and Jonathan C. Morris*,†
School of Chemistry and Physics, UniVersity of Adelaide, Adelaide, SA, Australia, and Department of
Chemistry, UniVersity of Canterbury, Christchurch, New Zealand
jonathan.morris@adelaide.edu.au
ReceiVed June 4, 2006
The first total synthesis of ancistrocladidine, a rare 7,3′-linked naphthylisoquinoline alkaloid, has been
completed, with the key feature of the synthesis being the formation of the extremely hindered biaryl
linkage by ortho-arylation of a naphthol with an aryllead triacetate. Initial efforts were focused on the
generation of a heteroaryl lead species, which would have allowed a convergent synthesis to be developed.
However, it was not possible to generate such a lead species. A simpler aryl lead triacetate was prepared
and reacted. The resulting biaryl aldehyde was 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.
Introduction
The naphthylisoquinoline alkaloids are a large group of
natural products whose only known sources are the Ancistro-
cladaceae and the closely related Dioncophyllaceae plant
families.1 Extracts from the tropical Ancistrocladaceae and
Dioncophyllaceae plant families have been used in traditional
medicines for the treatment of malaria and dysentery.2 More
recently, bioassay-directed isolation has led to the discovery of
many structurally related compounds with biological activities
such as antimalarial,3 antifeedant,4 molluscidal,5 insect growth-
retarding,6 and anti-HIV activity.7 Accordingly, structure-
activity guided modifications, coupled with chemical syntheses
of the natural products, has been a fruitful area of investigation
for the development of more selective and active drugs.2b
These structurally unique alkaloids are characterized by a
naphthalene group, linked to either a dihydro- or tetrahydroiso-
quinoline moiety, as exemplified by the examples shown in
Figure 1. As a result of the hindered nature of the biaryl bond,
restricted rotation dictates that many of these compounds exist
FIGURE 1. Representative examples of naphthylisoquinoline alkaloids.
as thermally stable atropisomers.8 These natural products can
be grouped according to the position of the biaryl bond linking
the naphthalene and isoquinoline structural entities, with the
5,1′- and 7,1′-linkages being the most common. Ancistrocladi-
dine (1a),9 ancistroheynine B (1b),10 ancistrotectorine (2a),11
and ancistrotanzanine C (2b)12 are some of the more unusual
† University of Adelaide.
‡ University of Canterbury.
(1) Bringmann, G.; Pokorny, F. In Alkaloids; Academic Press: New
York, 1995; p 127.
(2) (a) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phy-
tochemistry 1992, 31, 3821-3825. (b) Bringmann, G.; Francois, G.; Ake
Assi, L.; Schlauer, J. Chimia 1998, 52, 18-28.
10.1021/jo0611364 CCC: $33.50 © 2006 American Chemical Society
Published on Web 08/19/2006
7354
J. Org. Chem. 2006, 71, 7354-7363

Total Synthesis of Ancistrocladidine
members of the naphthylisoquinoline family because of the
presence of the highly hindered 7,3′-biaryl linkage.
The challenging architecture of the naphthylisoquinoline
alkaloids, combined with their interesting biological activity,
has led to considerable interest from the synthetic community.13
The most successful strategy for the synthesis of these natural
products is Bringmann’s lactone method,14 which provides ready
access to the 5,1′- and 7,1′- linked members of the family in an
atroposelective manner. Direct coupling of the appropriate
naphthalene and isoquinoline moieties, under palladium cataly-
sis, has also proved to be a rewarding approach.13g,15 However,
little synthetic attention16 has been focused on 7,3′-linked
systems such as that found in ancistrocladidine 1a as the highly
hindered biaryl system presents a significant challenge to
existing methods for the synthesis of the naphthylisoquinoline
alkaloids.
FIGURE 2. Retrosynthetic analysis.
coupling methodology for the formation of the 7-3′ linkage of
ancistrocladidine was sought.
The ortho-arylation of phenols with aryllead tricarboxylates
is a reaction that is known to proceed on hindered substrates in
an efficient manner.21 Furthermore, Yamamoto and co-workers
have extended this ortho-arylation methodology even further
to allow asymmetric coupling.22 This ortho-arylation chemistry
has far-reaching implications with regards to a synthetic
approach to a 7-3′ naphthylisoquinoline alkaloid (Figure 2).
The possibility exists for direct functionalization of naphthol
3,23 which would circumvent the need for preparation of a
difficult-to-access naphthalene precursor. In this paper, we
present full details of this synthetic strategy and its application
to the total synthesis of ancistrocladidine.24
Although numerous palladium-catalyzed biaryl cross-cou-
plings have been utilized in the synthesis17 of biaryls possessing
one, two, or three ortho-substituents, a common trend in such
reactions is a lowering in the yield of coupled product upon an
increase in the steric bulk surrounding the resulting biaryl
bond.18,19 For this reason there are only a few examples of
couplings resulting in products that contain four ortho-substit-
uents, although recent work by Buchwald has begun to rectify
this situation.19 Perhaps more importantly, synthesis of an
appropriate naphthalene precursor for the cross-coupling would
not be a trivial process.20 For these reasons, an alternative biaryl
Results and Discussion
(3) (a) Francois, G.; Bringmann, G.; Phillipson, J. D.; Assi, L. A.; Dochez,
C.; Ru¨ebenacker, M.; Schneider, C.; We´ry, M.; Warhurst, D. C.; Kirby, G.
C. Phytochemistry 1994, 35, 1461. (b) Bringmann, G.; Goetz, R.; Franc¸ois,
G. Tetrahedron 1996, 52, 13419. (c) Bringmann, G.; Koppler, D.; Wiesen,
B.; Franc¸ois, G.; Narayanan, A. S. S.; Almeida, M. R.; Schneider, H.;
Zimmermann, U. Phytochemistry 1996, 43, 1405. (d) Bringmann, G.; Saeb,
W.; Koppler, D.; Franc¸ois, G. Tetrahedron 1996, 52, 13409. (e) Hallock,
Y. F.; Caredellina, J. H., II; Scha¨ffer, M.; Stahl, M.; Bringmann, G.;
Franc¸ois, G.; Boyd, M. R. Tetrahedron 1997, 53, 8121. (g) Francois, G.;
Timperman, G.; Eling, W.; Assi, L. A.; Holenz, J.; Bringmann, G.
Antimicrob. Agents Chemother. 1997, 41, 2533-2539. (h) Bringmann, G.;
Holenz, J.; Weirich, R.; Ru¨benacker, M.; Funke, C.; Boyd, M. R.;
Gulakowski, R. J.; Franc¸ois, G. Tetrahedron 1998, 54, 497. (i) Bringmann,
G.; Saeb, W.; God, R.; Scha¨ffer, M.; Franc¸ois, G.; Peters, K.; Peters, E.-
M.; Proksch, P.; Hostettmann, K.; Assi, L. A. Phytochemistry 1998, 49,
1667. (j) Bringmann, G.; Teltschik, F.; Michel, M.; Busemann, S.; Ru¨ckert,
M.; Haller, R.; Ba¨r, S.; Robertson, S. A.; Kaminsky, R. Phytochemistry
1999, 52, 321. (k) Bringmann, G.; Saeb, W.; Wohlfarth, M.; Messer, K.;
Brun, R. Tetrahedron 2000, 56, 5871. (l) Bringmann, G.; Saeb, W.; Kraus,
J.; Brun, R.; Franc¸ois, G. Tetrahedron 2000, 56, 3523. (m) Bringmann, G.;
Gu¨nther, C.; Saeb, W.; Mies, J.; Wickramasinghe, A.; Mudogo, V.; Brun,
R. J. Nat. Prod. 2000, 63, 1333. (n) Stiefl, N.; Bringmann, G.; Rummey,
C.; Baumann, K. J. Comput.-Aided Mol. Design, 2003, 17, 347-365. (o)
Bringmann, G.; Holzgrabe, U.; Hoerr, V.; Stich, A. Pharmazie 2003, 58,
343-346.
Our initial efforts focused on the attractive possibility of
preparing ancistrocladidine 1a in a convergent fashion by
generating a lead reagent 4 whereby the entire heterocyclic
moiety of ancistrocladidine is present (Figure 2). This would
allow us to investigate Yamamoto’s methodology to control the
atroposelectivity.
Organolead compounds may be prepared by two routes, either
by direct plumbation or by transmetalation.21c,f,25 The latter
method is the more general route as it exhibits a greater tolerance
(8) Eliel, E. L.; Wilen, S. H.; Mander, L. N. In Stereochemistry of
Organic Compounds; John Wiley & Sons: New York, 1994; p 1142.
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Phytochemistry 1990, 29, 2750.
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R. Phytochemistry 2004, 65, 2903-2907.
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J.; Cox, P. J.; Funayama, S.; Cordell, G. A. J. Nat. Prod. 1985, 48, 529.
(b) Bringmann, G.; Gu¨nther, C.; Busemann, S.; Scha¨ffer, M.; Olowokudejo,
J. D.; Alo, B. D. Phytochemistry 1998, 47, 37.
(4) Bringmann, G.; Gramatzki, S.; Grimm, C.; Proksch, P. Phytochemistry
1992, 31, 3821.
(5) Bringmann, G.; Holenz, J.; Assi, L. A.; Zhao, C. X.; Hostettmann,
K. Planta Med. 1996, 62, 556.
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P. J. Nat. Prod. 1997, 60, 342. (b) Hallock, Y. F.; Cardellina, J. H., II;
Scha¨ffer, M.; Bringmann, G.; Franc¸ois, G.; Boyd, M. R. Bioorg. Med. Chem.
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B.; Pannell, L. L.; Cragg, G. M.; Boyd, M. R. J. Med. Chem. 1991, 34,
3402. (b) Upender, V.; Pollart, D. J.; Liu, J.; Hobbs, P. D.; Olsen, C.; Chao,
W.; Bowden, B.; Crase, J. L.; Thomas, D. W.; Pandey, A.; Lawson, J. A.;
Dawson, M. I. J. Heterocycl. Chem. 1996, 33, 1371. (c) Zhang, H.;
Zembower, D. E.; Chen, Z. Bioorg. Med. Chem. Lett. 1997, 7, 2687. (d)
Hoye, T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P. J. Org. Chem.
1999, 64, 7184. (e) Boyd, M. R.; Hallock, Y. F.; Cardellina, J. H., II;
Manfredi, K. P.; Blunt, J. W.; McMahon, J. B.; Buckheit, R. W., Jr.;
Bringmann, G.; Scha¨effer, M.; Cragg, G. M.; Thomas, D. W.; Jato, J. G. J.
Med. Chem. 1994, 37, 1740.
(12) Bringmann, G.; Dreyer, M.; Faber, J. H.; Dalsgaard, P. W.; Strk,
D.; Jaroszewski, J. W.; Ndangalasi, H.; Mbago, F.; Brun, R.; Christensen,
S. B. J. Nat. Prod. 2004, 67, 743.
(13) (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) Chau, P.; Czuba, I. R.; Rizzacasa, M. A.;
Bringmann, G.; Gulden, K.-P.; Scha¨ffer, M. J. Org. Chem. 1996, 61, 7101-
7105. (d) Rizzacasa, M. A. In Studies in Natural Product Synthesis, Structure
and Chemistry, Part F; Atta-ur-Rahman, Ed.; Elsevier: Amsterdam, 1998;
Vol. 20, pp 407-455 and references therein. (e) Bringmann, G.; Breuning,
M.; Tasler, S. Synthesis 1999, 525-558 and references therein. (f) Lipshutz,
B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999, 38, 3530-3533. (g) Hoye,
T. R.; Chen, M.; Hoang, B.; Mi, L.; Priest, O. P. J. Org. Chem. 1999, 64,
7184-7201. (h) Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M.
Tetrahedron 2000, 56, 2325-2337. (i) Bringmann, G.; Menche, D. Acc.
Chem. Res. 2001, 34, 615-624 and references therein.
J. Org. Chem, Vol. 71, No. 19, 2006 7355

Bungard and Morris
SCHEME 1a
a Reagents and conditions: (a) (EtO)2POCH2CO2Et, NaH, benzene, 0 °C to rt, 100%; (b) DIBAL, CH2Cl2, 0 °C, 80%; (c) VO(acac)2, t-BuOOH, CH2Cl2,
rt, 91%; (d) TsCl, NEt3, DMAP, CH2Cl2, 0 °C, 95%; (e) DIBAL, CH2Cl2, -20 °C to rt, 94%. (f) phthalimide, PPh3, DEAD, THF, 0 °C to rt, 81%; (g)
MeNH2, H2O/EtOH, reflux; (h) HCl (g), ether, 0 °C, 91% for 2 steps; (i) CH3COCl, NEt3, CH2Cl2, 0 °C to rt, 96%; (j) POCl3, 2,4,6-collidine, CH3CN,
reflux, 89%. (k) t-BuLi, THF, -95 °C, ClSnBu3, -95 °C to rt, 83%. (l) Pb(OAc)4, cat. Hg(OAc)2, CHCl3.
of functionality. This metal-metal exchange route is normally
achieved using either a tin or boron species in the presence of
catalytic amounts of mercuric(II) salts.25c,d Tin-lead exchange
has proven to be the method of choice in many cases because
of the ease of purification of the resulting organolead com-
pounds. With this in mind, synthesis of stannane 5 was our first
concern (Figure 2). To generate this compound, we required
7-iododihydroisoquinoline 6. With the Bischler-Napieralski
reaction being the standard method26 for preparing dihydroiso-
quinolines, access to amphetamine 7 was necessary. Although
there are several excellent syntheses26,27 of such compounds en
route to dihydroisoquinolines, the majority are not compatible
with the iodo moiety due to the strong reducing agents utilized.
(14) (a) Bringmann, G.; Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.;
Kamikawa, K.; Uemura, M. J. Organomet. Chem. 2002, 661, 31-47. (b)
Bringmann, G.; Tasler, S.; Pfeifer, R.-M.; Breuning, M. J. Organomet.
Chem. 2002, 661, 49-65 and references therein. (c) Bringmann, G.; Pfeifer,
R.-M.; Schreiber, P.; Hartner, K.; Schraut, M.; Breuning M. Tetrahedron
2004, 60, 4349-4360 and references therein.
Investigations into the Preparation of Heterocyclic Lead
Triacetates. Rao and co-workers13a have reported a synthesis
that utilizes mild conditions, which we felt would be amenable
to the preparation of the iodide 6. Furthermore, it would allow
for the preparation of chiral material. However, our initial efforts
were focused on the preparation of 7 in a racemic form. Starting
from aldehyde 8,29 the required allylic alcohol 9 was readily
prepared in 80% yield by first forming the R,â-unsaturated ester
10 by Horner-Wadsworth-Emmons reaction and then reduc-
tion with DIBAL-H (Scheme 1). Treatment of allylic alcohol 9
with catalytic vanadyl acetylacetonate and t-BuOOH in dichloro-
methane gave epoxide 11 in 91% yield after chromatography.28
Conversion of this epoxide to the secondary alcohol 12 was
achieved utilizing a method reported by Chong.30 Tosylate 13
was readily prepared from epoxyalcohol 11 in 95% yield.
(15) (a) Bringmann, G.; Hamm, A.; Schraut, M. Org. Lett. 2003, 5,
2805-2808. (b) Bringmann, G.; Guenther, C. Synlett 1999, 216-218. (c)
Watanabe, T.; Tanaka, Y.; Shoda, R.; Sakamoto, R.; Kamikawa, K.; Uemura,
M. J. Org. Chem. 2004, 69, 4152-4158.
(16) Comber, M. F.; Morris, J. C.; Sargent, M. V. Aust. J. Chem. 1998,
51, 19-22.
(17) (a) Stanforth, S. P. Tetrahedron 1998, 54, 263-303. (b) Metal-
Catalyzed Cross-Coupling Reactions; Diederich, F., Stang, P. J., Eds.;
Wiley-VCH: New York, 1998. (c) Bringmann, G.; Price Mortimer, A. J.;
Keller, P. A.; Gresser, M. J.; Garner, J.; Breuning, M. Angew. Chem., Int.
Ed. 2005, 44, 5384-5427.
(18) (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.
(19) Barder, T. E.; Walker, S. D.; Martinelli, J. R.; Buchwald, S. L. J.
Am. Chem. Soc. 2005, 127, 4685-4696.
(20) For example, 2-bromo-3-methyl-8-methoxy-1-naphthol has been
prepared by Nishiyama and Kameoka via an eight-step sequence, in 7.5%
overall yield, from (3-methoxyphenyl)-2-propanone. Although useful, the
sequence required many purification steps and included a poor-yielding
bromination step (23%). Nishiyama, T.; Kameoka, H. Chem. Express 1991,
6, 109.
(25) (a) Bell, H. C.; Kalman, J. R.; Pinhey, J. T.; Sternhell, S. Aust. J.
Chem. 1979, 32, 1521. (b) Kozyrod, R. P.; Pinhey, J. T. Tetrahedron Lett.
1983, 24, 1301-1302. (c) Kozyrod, R. P.; Morgan, J.; Pinhey, J. 1985, 38,
1147. (d) Morgan, J.; Pinhey, J. T. J. Chem. Soc., Perkin Trans. 1 1990,
715.
(26) (a) Rizzacasa, M. A.; Sargent, M. V.; Skelton, B. W.; White, A. H.
Aust. J. Chem. 1990, 43, 79-86. (b) Bringmann, G.; Weirich, R.; Reuscher,
H.; Jansen, J. R.; Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993,
877-888.
(27) (a) Bringmann, G.; Jansen, J. R.; Rink, H.-P. Angew. Chem., Int.
Ed. Engl. 1986, 25, 913. (b) Hoye, T. R.; Chen, M. Tetrahedron Lett. 1996,
37, 3099. (c) Lipshutz, B. H.; Keith, J. M. Angew. Chem., Int. Ed. 1999,
38, 3530. (d) Davis, F. A.; Mohanty, P. K.; Burns, D. M.; Andemichael,
Y. W. Org. Lett. 2000, 2, 3901-3903.
(28) The aldehyde 8 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.
(29) Tanaka, S.; Yamamoto, H.; Nozaki, H.; Sharpless, K. B.; Michael-
son, R. C.; Cutting, J. D. J. Am. Chem. Soc. 1974, 96, 5254.
(30) Chong, J. M. Tetrahedron Lett. 1992, 33, 33-36.
(21) 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. (e) Pinhey, J. T. In ComprehensiVe
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson, G.,
Eds.; Pergamon: Oxford, 1995; Vol. 11, p 461. (f) For an excellent overview
of aryllead chemistry, see: Elliott, G. I.; Konopelski, J. P. Tetrahedron
2001, 57, 5683-5705.
(22) (a) Saito, S.; Kano, T.; Muto, H.; Nakadai, M.; Yamamoto, H. J.
Am. Chem. Soc. 1999, 121, 8943 and references therein. (b) Kano, T.;
Ohyabu, Y.; Saito, S.; Yamamoto, H. J. Am. Chem. Soc. 2002, 124, 5365-
5373.
(23) (a) Watanabe, M.; Hisamatsu, S.; Hotokezaka, H.; Furukawa, S.
Chem. Pharm. Bull. 1986, 34, 2810-2820. (b) Bungard, C. J.; Morris, J.
C. J. Org. Chem. 2002, 67, 2361-2364.
(24) A preliminary communication of this work has been published:
Bungard, C. J.; Morris, J. C. Org. Lett. 2002, 4, 631-633.
7356 J. Org. Chem., Vol. 71, No. 19, 2006

Total Synthesis of Ancistrocladidine
SCHEME 2a
Subsequent reduction with DIBAL-H in dichloromethane gave
alcohol 12 in 94% yield after chromatography.
Reaction of alcohol 12 with triphenylphosphine, phthalimide,
and diethyl azodicarboxylate in THF gave imide 14 in 81%
yield. Deprotection of the phthalmide was readily accomplished
by refluxing 14 in an ethanolic solution of aqueous methylamine
to give the amine 7, which was isolated in 91% yield as its
hydrochloride salt 15. Hydrochloride 15 was smoothly acetylated
using acetyl chloride and triethylamine in dichloromethane to
give acetamide 16 in 96% yield. However, the ensuing Bis-
chler-Napieralski cyclization was problematic. Exposure of 16
to the standard cyclization conditions of phosphorus oxychloride
in acetonitrile, at reflux, resulted in varying degrees of deiodi-
nation. Addition of 1 equiv of 2,4,6-collidine to the reaction,
as reported by Lipshutz and Keith,26c afforded the desired
dihydroisoquinoline 6 in 89% yield.
The stannane 5 was readily prepared in 83% yield by
treatment of iodide 6 with t-BuLi at -95 °C in THF, followed
by addition of tributyltin chloride. The standard preparation of
aryl lead triacetates involves stirring the stannane with freshly
purified Pb(OAc)4 in the presence of a catalytic amount of Hg-
(OAc)2. Unfortunately, exposure of stannane 5 to these condi-
tions resulted in a complex mixture, from which only starting
material could be isolated. The reaction was repeated at room
temperature, and it was noted that upon addition of 5 to a
solution of Pb(OAc)4, red coloration and precipitation of material
resulted. The precipitated material appeared to dissolve in water,
but no useful information could be gathered from the resulting
1H NMR spectrum run in D2O. On the assumption that the Pb-
(OAc)4 and/or Hg(OAc)2 were reacting with the imine group,
it was decided to investigate whether the tetrahydroisoquinoline
may be a more suitable compound for the generation of an aryl
lead triacetate. Tetrahydroisoquinoline 17 was selected as it is
the same as the tetrahydroisoquinoline moiety present in the
other 7-3′-linked naphthylisoquinoline alkaloid, ancistrotecto-
rine 2a, and thus could be utilized in a total synthesis.
It is well documented that reduction of 3,4-dihydroisoquino-
lines with sodium borohydride in methanol gives cis-configured
tetrahydroisoquinolines.26b These can be converted into their
N-methyl derivatives by preparation of the carbamate, followed
by lithium aluminum hydride reduction.13c However, the iodide
functionality is not compatible with such a reducing agent, and
therefore an alternative method was sought. Rizzacasa and
Sargent have shown that upon N-methylation of dihydroiso-
quinoline 18, reduction of the resulting tetrahydroisoquinolinium
salt, with sodium borohydride, affords a 2:1 mixture of
tetrahydroisoquinolines in favor of the trans-isomer.26a As
ancistrotectorine contains a cis arrangement of the methyl
groups, an alternative reducing agent was required. There was
evidence to suggest that reduction of isoquinolinium salts with
the bulkier diisobutylaluminum hydride should give the desired
cis-selectivity.31 Accordingly, N-methyldihydroisoquinoline 19
was readily prepared by treating a solution of dihydroisoquino-
line 6 in acetone with iodomethane (Scheme 2). The so-obtained
salt was reduced with DIBAL-H in dichloromethane at -78
°C to afford a 9:1 ratio of diastereoisomers, which after
chromatography afforded the cis-diastereoisomer 20 in 85%
yield. The relative configuration was confirmed by deiodination,
using t-BuLi then H2O, which gave the tetrahydroisoquinoline
cis-21, which had previously been prepared by Sargent and
a Reagents and conditions: (a) MeI, acetone, rt; (b) DIBAL, CH2Cl2,
-78 °C to rt, 85% for 2 steps; (c) t-BuLi/H2O, THF, -78 °C; (d) t-BuLi,
THF, -95 °C, ClSnBu3, - 95 °C to rt, 83%.
Rizzacasa.26a The observed stereoselectivity for the reduction
of the isoquinoline could be explained in terms of the bulky
reducing agent delivering a hydride from the opposite face with
respect to the methyl group at 3-position.
Stannane 22 was prepared in 56% yield from iodide 20 by
halogen/metal exchange, followed by addition of tributyltin
chloride. Stirring a solution of the stannane 22, Pb(OAc)4, and
Hg(OAc)2 at room temperature gave only recovered starting
material and a small amount of demetalated material 21.
Repeating the reaction, but at 40 °C resulted in complete
demetalation to form 21. Barton and co-workers have observed
that aryllead reagents can be demetalated by arylamines via an
oxidation mechanism.32 Two potential solutions to this problem
were considered at this stage. First, in situ trapping of the
aryllead species 17 with naphthol 3, which may be a faster
process than the proposed oxidation, or second, an electron-
withdrawing group could be attached to the nitrogen atom of
the tetrahydroisoquinoline, thus decreasing the basicity of the
lone pair of electrons and slowing the undesired nucleophilic
addition to lead. Unfortunately, conducting the plumbation
reaction in the presence of naphthol 3 and pyridine resulted in
a complex mixture from which only starting materials and
demetalated species could be isolated. No trace of a ortho-
arylated naphthol was found.
Carbamate 23 was chosen as the precursor to aryllead species
24 as the carbamate group would provide significant withdrawal
of electron density from the nitrogen and still be readily
converted into an N-methyl derivative as is required for the
synthesis of ancistrotectorine 2a (Scheme 3). Thus, stannane 5
was readily reduced with sodium borohydride in methanol to
give amine 25 in 96% yield. Carbamate 23 was prepared in
77% yield by reacting amine 25 with methyl chloroformate in
dichloromethane, in the presence of triethylamine. Interestingly
the aliphatic CH signals were significantly broadened in the 1H
(31) Martens, J. In Methods of Organic Chemistry, workbench ed. E21;
Georg Thieme Verlag: Stuttgart, 1996; Vol. 7, p 4220.
(32) Barton, D. H.; Donnelly, D. M. X.; Finet, J.-P.; Guiry, P. J. J. Chem.
Soc., Perkin Trans. 1 1991, 2095.
J. Org. Chem, Vol. 71, No. 19, 2006 7357

Bungard and Morris
SCHEME 3a
SCHEME 4a
a Reagents and conditions: (a) NaBH4, MeOH, rt, 96%; (b) ClCO2Me,
NEt3, CH2Cl2, rt, 77%; (c) Pb(OAc)4, cat. Hg(OAc)2, CHCl3
NMR spectrum of 23. This may arise from a slowing of the
rate of pyramidal inversion at nitrogen by the electron-
withdrawing carbamate group
a Reagents and conditions: (a) 1,2-ethanediol, cat. TsOH, benzene,
Dean-Stark, 99%. (b) t-BuLi, Bu3SnCl, THF, -95 °C - rt, 85%; (c)
Pb(OAc)4, cat. Hg(OAc)2, CH2Cl2, rt, 24 h, 93%; (d) 3, pyridine, CH2Cl2,
24 h, rt; (e) 3% v/v aqueous H2SO4, THF, 1 h, rt, 67% yield from 3.
Unfortunately, stirring of 23 with Pb(OAc)4 and Hg(OAc)2
in chloroform at room temperature gave only recovered starting
material and a small amount of demetalated material. Conduct-
ing the reaction at 40 °C resulted in an increase in the amount
of demetalated material.
Using the standard Sharpless conditions,33 the epoxide 31 was
obtained in 80% yield and 90% de.34 This reaction generates
diastereomers with respect to the biaryl linkage, but they were
not observable. The epoxide was recrystallized from toluene/
petroleum ether to provide material with >95% de (63% yield).
Tosylation of 31 gave the tosylate 32 in 83% yield. Concomitant
cleavage of the tosylate and ring opening of the epoxide to afford
alcohol 33, in 94% yield, was achieved by reaction of tosylate
32 with LiAlH4 in Et2O. Transformation of the alcohol 33 into
the amine 29 was achieved, in 81% overall yield, by reaction
of 33 with phthalimide as described earlier, followed by
hydrolysis of the phthalimide group with aqueous ethanolic
methylamine. Acetylation of the resulting amine 29 with CH3-
COCl gave the acetamide 34 in 97% yield. Bischler-Napieralski
cyclization was readily achieved by reaction of 34 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 1a was isolated, along with the
atropisomer 35, in a 1:1 ratio, in 74% overall yield. Separation
of the atropisomers was readily achieved by recrystallization
as the non-natural atropisomer 35 proved to be noncrystalline.
While comparison with an authentic sample of ancistrocladidine
is not possible as the natural product is no longer available,
synthetic ancistrocladidine matches all the reported data for the
natural product.9
The inability of stannanes 4, 22, and 23 to form an aryllead
species could be due to a number of factors. The presence of a
nitrogen atom containing a basic lone pair of electrons could
be detrimental, as it has been shown that nitrogen-containing
species such as pyridine interact strongly with aryllead triacetates
in solution. A possible steric argument can also be considered
when discussing aryllead tricarboxylate 4. A steric clash between
the C8 methoxy group and the C1 methyl group in 4 could cause
a subtle compression of the steric environment between the
methoxy groups resulting in an inability to form a lead-species.
It is possible to remove the issues associated with the nitrogen
atom and those associated with steric crowding by investigating
the synthesis of aryllead tricarboxylate 25.
Preparation of an Aryl Lead Triacetate. Iodide 26 was
prepared by acetalization of iodobenzaldehyde 828 with ethylene
glycol (99%) (Scheme 4). Conversion to the stannane 27 was
achieved by halogen-lithium exchange of iodide 26 with t-BuLi
and subsequent quenching with Bu3SnCl.
To our delight, stirring the stannane 27 with freshly purified
Pb(OAc)4 in the presence of a catalytic amount of Hg(OAc)2
provided aryllead triacetate 25 in 93% yield. Formation of the
key biaryl linkage using the Pinhey-Barton methodology was
readily achieved by reaction of the lead species 25 with naphthol
3 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 28, in 67%
yield from 3.
In summary, the first total synthesis of a 7,3′-linked naph-
thylisoquinoline 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 an aryllead
triacetate. Future work will involve the application of this
strategy to other members of the naphthylisoquinoline alkaloid
family, with the ultimate goal being the generation of such
compounds as single atropoisomers.
Completion of the Synthesis of Ancistrocladidine. With
the successful establishment of the hindered biaryl linkage,
aldehyde 28 was then elaborated to the chiral amine 29, with
the Katsuki-Sharpless asymmetric epoxidation being used to
set the stereochemistry at C3 (Scheme 5).13a The required allylic
alcohol 30 was prepared in three steps from biaryl aldehyde 28
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-Wadsworth-Emmons reaction, and (iii) reduc-
tion with DIBAL-H.
(33) Gao, Y.; Hanson, R. M.; Klunder, J. M.; Ko, S. Y.; Masamune, H.;
Sharpless, K. B. J. Am. Chem. Soc. 1987, 109, 5765-5780.
(34) The diasteromeric excess of this reaction was determined by the
method described in Dale, J. A.; Dull, D. L.; Mosher, H. S. J. Org. Chem.
1969, 34, 2543-2549. Details are provided in Supporting Information.
7358 J. Org. Chem., Vol. 71, No. 19, 2006

Total Synthesis of Ancistrocladidine
SCHEME 5a
a Reagents and conditions: (a) MOM-Cl, NaH, THF, rt, 81%; (b) NaH, (EtO)2POCH2CO2Et, C6H6, 0 °C - 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 - rt, 97%; (j) POCl3, 2,4,6-collidine, CH3CN, reflux, 4 h, 74% (1:1 mixture of 1a and 35).
Experimental Section35
mg, 1.6 mmol) and VO(acac)2 (8 mg, 3.1 µmol) in dry CH2Cl2 (5
mL). The reaction was stirred for 1 h at room temperature, diluted
with CH2Cl2, and filtered through a plug of Celite. The solvent
was removed under reduced pressure, and the residue was purified
by flash chromatography, eluting with 70% EtOAc/petroleum ether,
to give the title compound as a white solid (480 mg, 91%). Mp:
99-100 °C. 1H NMR (500 MHz, CDCl3): δ 1.82 (d, J ) 7.8 Hz,
1H), 3.17 (m, 1H), 3.82 (m, 1H), 3.88 (s, 6H), 3.94 (d, J ) 2.0 Hz,
1H), 4.06 (m, 1H), 6.44 (s, 2H). 13C NMR (75 MHz, CDCl3): δ
55.3, 56.5, 60.9, 62.6, 76.8, 101.1, 139.3, 159.5. IR (KBr): 3412
cm-1. HRMS: calcd for C11H13IO4 (M+) 335.9857, found 335.9859.
(E)-3-(4-Iodo-3,5-dimethoxyphenyl)-acrylic Acid Ethyl Ester
(10). Triethyl phosphonoacetate (1.58 mL, 7.94 mmol) was added
to a suspension of prewashed NaH (208 mg, 8.67 mmol) in dry
benzene (20 mL) at 0 °C. The reaction was stirred for 15 min, and
then a solution of the aldehyde 828 (2.11 g, 7.22 mmol) in dry
benzene (30 mL) was slowly added. The reaction was stirred for 1
h at 0 °C, then 30 min at room temperature, following which H2O
was added. The aqueous layer was extracted with EtOAc (×4) and
the combined organic extracts were washed with H2O (×2).
Removal of the solvent under reduced pressure gave the title
compound as a white solid (2.62 g, 100%). Mp: 135-136 °C. 1H
NMR (500 MHz, CDCl3): δ 1.34 (t, J ) 7.3 Hz, 3H), 3.92 (s,
6H), 4.27 (q, J ) 7.3 Hz, 2H), 6.47 (d, J ) 16 Hz, 1H), 6.63 (s,
2H), 7.62 (d, J ) 16 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
14.2, 56.4, 60.5, 80.2, 103.2, 118.9, 136.1, 143.7, 159.5, 166.5. IR
(KBr): 1703 cm-1. HRMS: calcd for C13H15IO4 (M+) 362.0014,
found 362.0015.
(E)-3-(4-Iodo-3,5-dimethoxyphenyl)prop-2-en-1-ol (9). Neat
DIBAL-H (2.88 mL, 16.2 mmol) was added dropwise to a solution
of the ester 10 (2.34 g, 6.47 mmol) in dry CH2Cl2 (40 mL) at 0 °C.
The reaction was stirred at 0 °C for 1 h and quenched by dropwise
addition of H2O until coagulation occurred. The suspension was
diluted with 1 M aqueous HCl solution and extracted with EtOAc
(×4). Removal of the solvent under reduced pressure and purifica-
tion of the residue by flash chromatography, eluting with 70%
EtOAc/petroleum ether, gave the title compound as a white solid
(1.65 g, 80%). Mp: 122-123 °C. 1H NMR (500 MHz, CDCl3): δ
3.89 (s, 6H), 4.34 (d, J ) 4.9 Hz, 2H), 6.41 (dt, J ) 16, 5.4 Hz,
1H), 6.53 (s, 2H), 6.58 (dd, J ) 16, 1.5 Hz, 1H). 13C NMR (75
MHz, CDCl3): δ 56.4, 63.1, 76.5, 102.1, 129.5, 130.1, 138.6, 159.2.
IR (film): 3209 cm-1. HRMS: calcd for C11H13IO3 (M+) 319.9908,
found 319.9910.
(2S*,3R*)-Toluene-4-sulfonic Acid 3-(4-Iodo-3,5-dimethoxy-
phenyl)oxiranyl-methyl Ester ((13). Dry NEt3 (1.69 mL, 12.2
mmol) was added to a solution of the alcohol 11 (0.816 g, 2.43
mmol) and DMAP (0.297 g, 2.43 mmol) in dry CH2Cl2 (25 mL) at
0 °C. A solution of TsCl (0.510 g, 2.67 mmol) in dry CH2Cl2 (3
mL) was slowly added. The reaction was stirred at 0 °C for 1 h,
diluted with CH2Cl2, and washed in turn with 1 M aqueous HCl
solution and saturated aqueous NaHCO3 solution. Removal of the
solvent under reduced pressure gave the title compound as a fluffy
1
white solid (1.13 g, 95%). Mp: 48-49 °C. H NMR (500 MHz,
CDCl3): δ 2.45 (s, 3H), 3.19 (m, 1H), 3.80 (d, J ) 2.0 Hz, 1H),
3.86 (s, 6H), 4.15 (dd, J ) 12, 4.2 Hz, 1H), 4.33 (dd, J ) 12, 3.4
Hz, 1H), 6.37 (s, 2H), 7.35 (d, J ) 8.3 Hz, 2H), 7.81 (d, J ) 8.3
Hz, 2H). 13C NMR (75 MHz, CDCl3): δ 21.5, 56.0, 56.4, 58.5,
69.0, 77.2, 101.0, 127.8, 129.8, 132.3, 138.1, 145.1, 159.4.
HRMS: calcd for C18H19IO6S (M+) 489.9946, found 489.9947.
1-(4-Iodo-3,5-dimethoxyphenyl)-propan-2-ol ((12). Neat DIBAL
(1.23 mL, 6.91 mmol) was added dropwise to a solution of the
tosylate 13 (1.13 g, 2.30 mmol) in dry CH2Cl2 (35 mL) at 15 °C.
The resulting solution was stirred for 2 h at 15 °C and then allowed
to warm to room temperature overnight. The reaction was quenched
by dropwise addition of H2O, till coagulation occurred. The
suspension was diluted with 1 M aqueous HCl solution and then
extracted with EtOAc (×4). The combined organic extracts were
washed with saturated aqueous NaHCO3 solution. Removal of the
solvent under reduced pressure and purification by flash chroma-
tography, eluting with 60% EtOAc/petroleum ether, gave the title
(2S*,3R*)- (3-[4-Iodo-3,5-dimethoxyphenyl]oxiranyl)-metha-
nol ((11). Anhydrous TBHP solution (6.1 M, 67.2 mmol) in CH2-
Cl2 (0.52 mL) was added to a solution of the allylic alcohol 9 (500
(35) General procedures are detailed in Supporting Information.
J. Org. Chem, Vol. 71, No. 19, 2006 7359

Bungard and Morris
compound as a colorless viscous oil (693 mg, 94%). 1H NMR (500
MHz, CDCl3): δ 1.25 (d, J ) 6.4 Hz, 3H), 2.65 (dd, J ) 13, 8.3
Hz, 1H), 2.76 (dd, J ) 14, 4.4 Hz, 1H), 3.87 (s, 3H), 4.01 (m,
1H), 6.36 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 22.7, 45.8, 56.3,
CDCl3): δ 21.6, 25.7, 34.6, 51.3, 56.5, 61.9, 82.4, 105.9, 117.3,
142.5, 159.0, 160.2, 161.7. HRMS: calcd for C13H16INO2 (M+)
345.0225, found 345.0226.
6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl-3,4-dihydroiso-
quinoline ((5). A solution of t-BuLi in pentane (1.5 M, 0.707 mL,
1.06 mmol) was added dropwise to a solution of the iodide 6 (154
mg, 0.424 mmol) in dry THF (4 mL) at -95 °C. The reaction was
stirred at -95 °C for 15 min, then ClSnBu3 (0.288 mL, 1.06 mmol)
was slowly added, and the reaction allowed to warm to room
temperature overnight. The resulting solution was poured into
saturated aqueous NaHCO3 solution and extracted with EtOAc (×4).
Removal of the solvent under reduced pressure and purification
by flash chromatography on alumina, eluting with 15% EtOAc/
petroleum ether, gave the title compound as a colorless oil (179
mg, 83%). 1H NMR (500 MHz, CDCl3): δ 0.88 (m, 9H), 1.07 (m,
6H), 1.32 (m, 6H), 1.39 (d, J ) 6.8 Hz, 3H), 1.51 (m, 6H), 2.33
(dd, J ) 16, 14 Hz, 1H), 2.43 (d, J ) 2.0 Hz, 3H), 2.60 (dd, J )
16, 4.4 Hz, 1H), 3.32 (m, 1H), 3.56 (s, 3H), 3.77 (s, 3H), 6.44 (s,
1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 13.6, 22.0, 25.5, 27.3,
29.1, 35.2, 51.6, 55.2, 63.1, 104.5, 117.0, 121.0, 144.0, 163.2, 164.9,
165.9. HRMS: calcd for C25H43NSnO2 (M+ - Bu) 452.1612, found
452.1612.
68.4, 74.1, 105.1, 140.9, 159.0. IR (film): 3385, 3547 cm-1
HRMS: calcd for C11H15IO3 (M+) 322.0066, found 322.0065.
.
2-(2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethyl)isoindole-
1,3-dione ((14). DEAD (0.422 mL, 0.570 mmol) was added to a
solution of the alcohol 12 (693 mg, 2.15 mmol), PPh3 (0.705 g,
2.69 mmol), and phthalimide (0.396 g, 2.69 mmol) in dry THF
(20 mL) at 0 °C. The reaction was protected from light and allowed
to warm to room temperature overnight. Saturated aqueous NaHCO3
solution was added, and the product was extracted with EtOAc
(×4). The combined organic extracts were washed with saturated
aqueous NaHCO3 solution. The solvent was removed under reduced
pressure, and purification by flash chromatography, eluting with
25% EtOAc/petroleum ether, gave the title compound as a white
1
solid (786 mg, 81%). Mp: 124-125 °C. H NMR (500 MHz,
CDCl3): δ 1.55 (d, J ) 6.8 Hz, 3H), 3.06 (dd, J ) 14, 6.4 Hz,
1H), 3.37 (dd, J ) 10, 14 Hz, 1H), 3.76 (s, 6H), 4.70 (m, 1H),
6.32 (s, 2H), 7.67 (m, 2H), 7.75 (m, 2H). 13C NMR (75 MHz,
CDCl3): δ 18.4, 39.8, 47.8, 56.3, 74.9, 104.7, 122.9, 131.6, 133.8,
140.7, 159.1, 168.2. IR (KBr): 1705 cm-1. HRMS: calcd for
C19H18INO4 (M+) 451.0279, found 451.0281.
(1R*,3S*)-7-Iodo-6,8-dimethoxy-1,2,3-trimethyl-1,2,3,4-tet-
rahydroisoquinoline ((20). Iodomethane (212 µL, 3.40 mmol)
was added to a solution of the dihydroisoquinoline 6 (235 mg, 0.680
mmol) in dry acetone (7 mL), followed by stirring at room
temperature for 48 h. The solvent was removed under reduced
pressure and the residue dissolved in dry CH2Cl2 and cooled to
-78 °C. Neat DIBAL (145 µL, 0.816 mmol) was added, and the
reaction allowed to warm to room temperature overnight. The
reaction was quenched by dropwise addition of H2O till coagulation
occurred. The suspension was diluted with 1 M aqueous HCl
solution, stirred for 5 min, and then neutralized with 1 M aqueous
NaOH solution. The product was extracted with CH2Cl2 (×4), and
the solvent was removed under reduced pressure. Purification by
flash chromatography on alumina, eluting with 15% EtOAc/
petroleum ether, gave the title compound as a pale yellow solid
2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethylammonium Chlo-
ride ((15). 40% Aqueous MeNH2 solution (33 mL) was added to
a solution of the imide 14 (0.786 g, 1.74 mmol) in absolute EtOH
(50 mL). The reaction was heated at reflux for 1 h, and then most
of the EtOH was removed under reduced pressure. H2O was added,
the product was extracted with Et2O (×4), and the combined organic
extracts were concentrated to a volume of ca. 25 mL. The resulting
solution was cooled to 0 °C and purged with gaseous HCl for 15
min. The resulting white precipitate was collected by filtration and
dried under reduced pressure to give the title compound as a white
solid (566 mg, 91%). Mp: 230-231 °C dec. 1H NMR (500 MHz,
CD3OD): δ 1.30 (d, J ) 6.4 Hz, 3H), 2.86 (dd, J ) 14, 7.8 Hz,
1H), 2.95 (dd, J ) 14, 6.8 Hz, 1H), 3.59 (m, 1H), 3.87 (s, 6H),
6.52 (s, 2H). 13C NMR (75 MHz, CD3OD): δ 18.9, 42.2, 50.4,
1
(209 mg, 85%). Mp: 79-80 °C. H NMR (500 MHz, CDCl3): δ
57.4, 76.8, 106.6, 140.2, 161.5. IR (KBr): 1415, 3431 cm-1
.
1.23 (d, J ) 6.4 Hz, 3H), 1.40 (d, J ) 6.8 Hz, 3H), 2.44 (m, 1H),
2.45 (s, 3H), 2.59 (dd, J ) 16, 2.9 Hz, 1H), 2.67 (dd, J ) 10, 16
Hz, 1H), 3.68 (q, J ) 6.4 Hz, 1H), 3.79 (s, 3H), 3.85 (s, 3H), 6.38
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 21.3, 23.2, 38.3, 41.4,
55.0, 56.4, 57.5, 60.5, 81.2, 106.6, 126.7, 138.5, 157.0, 157.6.
HRMS: calcd for C14H19INO2 (M+) 360.0459, found 360.0461.
(1R*,3S*)-6,8-Dimethoxy-1,2,3-trimethyl-7-tributylstannanyl-
1,2,3,4-tetrahydroisoquinoline ((22). A solution of t-BuLi in
pentane (1.5 M, 0.489 mL, 0.734 mmol) was added dropwise to a
solution of the iodide 20 (0.106 g, 0.293 mmol) in dry THF (3
mL) at -95 °C. The reaction was stirred at -95 °C for 15 min
then ClSnBu3 (0.200 mL, 0.734 mmol) was slowly added, and the
reaction was allowed to warm to room temperature overnight. The
resulting solution was poured into saturated aqueous NaHCO3
solution and extracted with EtOAc (×4). The solvent was removed
under reduced pressure and purification by flash chromatography
on alumina, eluting with 5% EtOAc/petroleum ether, gave the title
HRMS: electrospray calcd for C11H17INO2 (M+) 322.0304, found
322.0319.
N-(2-(4-Iodo-3,5-dimethoxyphenyl)-1-methylethyl)aceta-
mide ((16). Dry NEt3 (0.722 mL, 5.18 mmol) was added to a
suspension of the hydrochloride 15 (842 mg, 2.35 mmol) in dry
CH2Cl2 (20 mL) at 0 °C. Freshly distilled acetyl chloride (194 µL,
2.71 mmol) was slowly added, and the reaction was warmed to
room temperature overnight. The resulting solution was diluted with
CH2Cl2 and washed with 1 M aqueous HCl solution (×3). Removal
of the solvent under reduced pressure gave the title compound as
1
a white solid (817 mg, 96%). Mp: 142-143 °C. H NMR (500
MHz, CDCl3): δ 1.12 (d, J ) 6.4 Hz, 3H), 1.94 (s, 3H), 2.65 (dd,
J ) 14, 7.8 Hz, 1H), 2.87 (dd, J ) 14, 5.4 Hz, 1H), 3.86 (s, 6H),
4.26 (m, 1H), 5.33 (d, J ) 7.3 Hz, 1H), 6.33 (s, 2H). 13C NMR (75
MHz, CDCl3): δ 19.8, 23.2, 42.5, 45.8, 56.3, 74.8, 105.1, 140.5,
159.0, 169.2. IR (KBr): 1570, 1630, 3076, 3242 cm-1. HRMS:
calcd for C13H19INO3 (M+) 364.0410, found 364.0411.
1
compound as a colorless oil (87 mg, 56%). H NMR (500 MHz,
CDCl3): δ 0.88 (m, 9H), 1.07 (m, 6H), 1.23 (d, J ) 6.4 Hz, 1H),
1.32 (m, 6H), 1.41 (d, J ) 6.4 Hz, 3H), 1.51 (m, 6H), 2.44 (m,
1H), 2.45 (s, 3H), 2.58 (dd, J ) 16, 2.6 Hz, 1H), 2.71 (dd, J ) 16,
11 Hz, 1H), 3.62 (s, 3H), 3.63 (m, 1H), 3.72 (s, 3H), 6.34 (s, 1H).
13C NMR (75 MHz, CDCl3): δ 11.2, 13.7, 21.4, 23.3, 27.4, 29.2,
39.0, 41.4, 55.0, 55.2, 57.6, 61.8, 104.9, 119.7, 125.4, 139.3, 162.8,
163.5. HRMS: calcd for C26H47NSnO2 (M+ - CH3) 510.2394,
found 510.2394.
(1R*,3S*)-6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl-
1,2,3,4-tetrahydroisoquinoline ((25). NaBH4 (78 mg) was added
to a solution of the dihydroisoquinoline 5 (179 mg, 0.353 mmol)
in MeOH (35 mL). The reaction was stirred for 30 min at room
temperature, following which the solvent was removed under
7-Iodo-6,8-dimethoxy-1,3-dimethyl-3,4-dihydroisoquinoline
((6). 2,4,6-Collidine (173 µL, 1.30 mmol) was added to a solution
of the amide 16 (429 mg, 1.18 mmol) in dry CH3CN (6 mL).
Freshly distilled POCl3 (121 µL, 1.30 mmol) was added, and the
reaction was heated at reflux for 3 h. The resulting solution was
poured into saturated aqueous NaHCO3 solution and extracted with
EtOAc (×4). The solvent was removed under reduced pressure,
and purification by flash chromatography on alumina, eluting with
30% EtOAc/petroleum ether, gave the title compound as a light
1
tan solid (364 mg, 89%). Mp: 91-92 °C. H NMR (500 MHz,
CDCl3): δ 1.37 (d, J ) 6.8 Hz, 3H), 2.30 (dd, J ) 16, 13 Hz, 1H),
2.45 (d, J ) 2.0 Hz, 3H), 2.61 (dd, J ) 16, 4.4 Hz, 1H), 3.33 (m,
1H), 3.73 (s, 3H), 3.90 (s, 3H), 6.47 (s, 1H). 13C NMR (75 MHz,
7360 J. Org. Chem., Vol. 71, No. 19, 2006

Total Synthesis of Ancistrocladidine
reduced pressure. The residue was dissolved in CH2Cl2 and filtered
through a plug of Celite. Removal of the solvent under reduced
pressure gave the title compound as a colorless oil (173 mg, 96%).
1H NMR (500 MHz, CDCl3): δ 0.87 (m, 9H), 1.04 (m, 6H), 1.21
(d, J ) 6.4 Hz, 3H), 1.30 (m, 6H), 1.48 (d, J ) 5.9 Hz, 3H), 1.50
(m, 6H), 2.48 (dd, J ) 16, 11 Hz, 1H), 2.69 (dd, J ) 16, 2.4 Hz,
1H), 2.91 (m, 1H), 3.57 (s, 3H), 3.70 (s, 3H), 4.25 (q, J ) 6.4 Hz,
1H), 6.32 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 11.2, 13.7, 22.4,
22.6, 27.3, 29.2, 39.8, 48.3, 50.1, 55.0, 60.7, 105.8, 120.2, 125.3,
139.6, 162.8, 164.2. HRMS: calcd for C17H45NO2Sn (M+ - Bu)
454.1768, found 454.1768.
(1R*,3S*)-6,8-Dimethoxy-1,3-dimethyl-7-tributylstannanyl-
3,4-dihydro-1H-isoquinoline-2-carboxylic Acid Methyl Ester
((23). NEt3 (190 µL, 1.36 mmol) was added to a solution of the
amine 25 (178 mg, 0.339 mmol) in dry CH2Cl2 at 0 °C. Methyl
chloroformate (53 µL, 0.678 mmol) was added slowly added, and
the reaction was allowed to warm to room temperature overnight.
The resulting solution was diluted with CH2Cl2 and washed with
water. The solvent was removed under reduced pressure, and the
residue was purified by flash chromatography, eluting with 15%
EtOAc/petroleum ether, to give the title compound as a colorless
oil (148 mg, 77%). 1H NMR (500 MHz, CDCl3): δ 0.87 (m, 9H),
1.08 (m, 6H), 1.31 (m, 6H), 1.38 (d, J ) 6.4 Hz, 3H), 1.44 (d, J )
7.3 Hz, 3H), 1.50 (m, 6H), 2.88 (dd, J ) 16, 8.8 Hz, 1H), 2.96
(dd, J ) 16, 6.8 Hz, 1H), 3.67 (s, 3H), 3.71 (s, 3H), 3.72 (s, 3H),
4.16 (br m, 1H), 5.54 (br m, 1H), 6.41 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ 11.1, 13.5, 22.0 (br), 24.0(br), 27.3, 29.2, 35.6, 46.5,
47.3, 52.3, 55.1, 62.6, 105.4, 120.0, 125.0 (br), 137.0, 156.1 (br),
162.2, 163.5. IR (KBr): 1699 cm-1. HRMS: calcd for C27H47-
NO4Sn (M+ - Bu) 512.1823, found 512.1823.
under high vacuum to give the title compound as a light yellow
solid (2.98 g, 93%), which was used immediately in the next
reaction. H NMR (500 MHz, CDCl3): δ 2.08 (s, 9H), 3.90 (s,
6H), 4.03-4.10 (m, 4H), 5.81 (s, 1H), 6.82 (s, 2H).
1
3,5-Dimethoxy-4-(1-hydroxy-8-methoxy-3-methylnaphthalen-
2-yl)benzaldehyde (28). Dry pyridine (1.34 mL) was added
dropwise to a solution of the aryllead compound 25 (2.98 g, 5.02
mmol) and the naphthol 3 (0.945 g, 5.02 mmol) in dry CH2Cl2 (50
mL). The reaction was stirred at room temperature, protected from
light, for 24 h. After this time saturated aqueous NH4Cl solution
was added, and the aqueous layer was extracted with EtOAc (×4).
The combined organic extracts were washed with 1 M aqueous
HCl solution. The solvent was removed under reduced pressure,
and the residue was dissolved in THF (100 mL). A solution of 3%
v/v aqueous H2SO4 solution (25 mL) was added, and the reaction
was stirred vigorously for 1 h. The resulting solution was diluted
with 1 M aqueous HCl solution and extracted with EtOAc (×4).
Removal of the solvent under reduced pressure and purification
by flash chromatography, eluting with 40% ethyl acetate/petroleum
ether, gave the title compound as pale yellow solid (1.18 g, 67%).
1
Mp: 196-197 °C. H NMR (500 MHz, CDCl3): δ 2.09 (s, 3H),
3.81 (s, 6H), 3.98 (s, 3H), 6.71 (d, J ) 7.8 Hz, 1H), 7.22 (s, 2H),
7.24 (s, 1H), 7.27 (m, 1H), 7.35 (d, J ) 8.3 Hz, 1H), 9.41 (s, 1H),
10.01 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 55.8, 56.1,
103.1, 105.3, 113.2, 116.0, 118.5, 121.1, 122.0, 125.5, 136.1, 137.1,
137.2, 150.7, 156.0, 158.5, 191.9. IR (KBr): 1697, 3500 cm-1
HRMS: calcd for C21H20O5 (M+) 352.1311, found 352.1311.
.
(E)-3-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-meth-
ylnaphthalen-2-yl)-phenyl)prop-2-en-1-ol (30). (a) A solution of
the naphthol 28 (1.18 g, 3.34 mmol) in dry THF (45 mL) was added
to a suspension of prewashed NaH (0.160 g, 6.68 mmol) in dry
THF (10 mL). The reaction was stirred for 1 h at room temperature,
resulting in a turbid red solution. MOM-Cl (1.27 mL, 16.7 mmol)
was added dropwise, and the reaction was stirred at room
temperature overnight. The reaction was poured into saturated
aqueous NaHCO3 solution and extracted with EtOAc (×4). The
solvent was removed under reduced pressure and the residue
purified by flash chromatography, eluting with 50% EtOAc/
petroleum ether, to give 3,5-dimethoxy-4-(8-methoxy-1-meth-
oxymethoxy-3-methylnaphthalen-2-yl)benzaldehyde as a white solid
(1.08 g, 81%). Mp: 177-178 °C. 1H NMR (500 MHz, CDCl3): δ
2.09 (s, 3H), 2.80 (s, 3H), 3.79 (s, 6H), 3.95 (s, 3H), 4.86 (s, 2H),
6.80 (d, J ) 6.8 Hz, 1H), 7.19 (s, 2H), 7.34 (dd, J ) 8.3, 7.8 Hz,
1H), 7.38 (dd, J ) 8.3, 1.5 Hz), 1H), 7.52 (s, 1H), 10.01 (s, 1H).
13C NMR (75 MHz, CDCl3): δ 20.0, 55.9, 56.0, 56.1, 100.3, 104.8,
104.9, 118.6, 120.4, 122.9, 124.3, 126.0, 126.1, 136.1, 136.9, 137.1,
149.7, 155.8, 158.9. IR (KBr): 1693 cm-1. HRMS: calcd for
C23H24O6 (M+) 396.1573, found 396.1573.
2-(4-Iodo-3,5-dimethoxy-phenyl)-(1,3)-dioxolane (26). A solu-
tion of the aldehyde 8 (3.42 g, 11.7 mmol), 1,2-ethanediol (0.98
mL, 17.6 mmol), and p-toluenesulfonic acid (40 mg, 0.21 mmol)
in benzene (80 mL) was heated at reflux under Dean-Stark
conditions for 20 h. After this time Et2O (100 mL) and saturated
aqueous NaHCO3 solution were added. The organic extract was
washed with water, and the solvent was removed under reduced
pressure to give the title compound as a white solid (3.89 g, 99%).
1
Mp: 82-83 °C. H NMR (300 MHz, CDCl3): δ 3.91 (s, 3H),
4.00-4.17 (m, 4H), 5.80 (s, 1H), 6.64 (s, 2H). 13C NMR (75 MHz,
CDCl3): δ 56.6, 65.3, 78.2, 102.0, 103.1, 140.3, 159.4. HRMS:
calcd for C11H13IO4 (M+) 335.9857, found 335.9859.
Tributyl-(4-(1,3)-dioxolan-2-yl-2,6-dimethoxy-phenyl)stan-
nane (27). A solution of t-BuLi in pentane (1.5 M, 10.2 mL, 15.2
mmol) was added dropwise via syringe to a stirred solution of the
iodide 26 (2.05 g, 6.10 mmol) in dry THF (60 mL) at -95 °C. The
resulting solution was stirred at -95 °C for 15 min, then ClSnBu3
(4.13 mL, 15.2 mmol) was slowly added, and the reaction was
allowed to warm slowly to room temperature overnight. The
resulting solution was poured into saturated aqueous NaHCO3
solution and extracted with EtOAc (×4). Evaporation of the solvent
under reduced pressure gave the crude product, which was purified
by flash chromatography on alumina, eluting with 5% ethyl acetate/
petroleum ether, to give the title compound as colorless oil (2.58
g, 85%). 1H NMR (500 MHz, CDCl3): δ ?0.87 (m, 9H), 1.01 (m,
6H), 1.30 (m, 6H), 1.48 (m, 6H), 3.75 (s, 3H), 4.00-4.17 (m, 4H),
5.80 (s, 1H), 6.62 (s, 2H). 13C NMR (75 MHz, CDCl3): δ 11.2,
13.7, 27.3, 29.1, 55.1, 65.2, 100.9, 103.7, 117.8, 140.8, 165.1.
HRMS: calcd for C23H40O4120Sn (M+ - Bu) 443.1245, found
443.1244.
(b) Triethyl phosphonoacetate (592 µL, 2.98 mmol) was added
to a suspension of prewashed NaH (78 mg, 3.25 mmol) in dry
benzene (8 mL) at 0 °C. The reaction was stirred for 15 min, and
then a solution of the aldehyde (1.08 g, 2.71 mmol) in dry benzene
(15 mL) was slowly added. The reaction was stirred for 1 h at 0
°C, warmed to room temperature, and stirred for a further 30 min,
following which H2O was added. The aqueous layer was extracted
with EtOAc (×4) and the combined organic extracts were washed
with H2O (×2). Removal of the solvent under reduced pressure
gave (E)-3-(3,5-dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-
methylnaphthalen-2-yl)-phenyl)acrylic acid ethyl ester as a white
1
solid (1.26 g, 100%). Mp: 181-182 °C. H NMR (500 MHz,
4-[(1,3)-Dioxolan-2-yl]-2,6-dimethoxyphenyl Lead Triacetate
(25). Pb(OAc)4 (95%, 3.02 g) was protected from light and stirred
under high vacuum for 30 min. A solution of the stannane 27 (2.69
g, 5.39 mmol) and Hg(OAc)2 (86 mg, 0.27 mmol) in dry CH2Cl2
(55 mL) was added via cannula, and the reaction was stirred at
room temperature for 24 h. After this time the solution was diluted
with CH2Cl2 and rinsed through a plug of Celite. The solvent was
removed under reduced pressure to give a residue, which was
washed with petroleum ether (×4). The resulting solid was dried
CDCl3): δ 1.37 (t, J ) 7.1 Hz, 3H), 2.12(s, 3H), 2.84 (s, 3H),
3.74 (s, 6H), 3.94 (s, 3H), 4.30 (q, J ) 7.1 Hz, 2H), 4.86 (s, 2H),
6.50 (d, J ) 16 Hz, 1H), 6.78 (d, J ) 7.3 Hz, 1H), 6.83 (s, 2H),
7.32 (dd, J ) 8.3, 7.3 Hz, 1H), 7.35 (d, J ) 7.3 Hz, 1H), 7.51 (s,
1H), 7.73 (d, J ) 16 Hz, 1H). 13C NMR (75 MHz, CDCl3): δ
14.1, 20.0, 55.6, 55.7, 55.9, 60.3, 100.0, 103.3, 104.7, 117.8, 118.3,
118.6, 120.3, 124.0, 125.7, 126.4, 134.9, 136.5, 136.7, 144.8, 149.6,
155.6, 158.4, 166.7. IR (KBr): 1709 cm-1. HRMS: calcd for
C27H30O7 (M+) 466.1992, found 466.1992.
J. Org. Chem, Vol. 71, No. 19, 2006 7361

Bungard and Morris
(c) Neat DIBAL-H (1.00 mL, 5.61 mmol) was added dropwise
to solution of the ester (1.05 g, 2.24 mmol) in dry toluene (25 mL)
at -78 °C. The reaction was stirred for 15 min at this temperature.
After this time EtOAc (100 mL) was added, and the solution was
allowed to warm to room temperature. Saturated aqueous NaHCO3
solution was added, and the solution swas tirred vigorously for 5
min, followed by filtration and separation of the layers. The aqueous
layer was further extracted with EtOAc (×3), and the organic
extracts combined. Removal of the solvent under reduced pressure
and purification by flash chromatography, eluting with 60% EtOAc/
petroleum ether, gave the title compound 30 as a white solid (844
7.8 Hz, 1H), 7.36 (d, J ) 7.8 Hz), 7.38 (d, J ) 8.3 Hz, 2H), 7.49
(s, 1H), 7.85 (d, J ) 8.3 Hz, 2H). 13C NMR (75 MHz, CDCl3): δ
20.1, 21.5, 55.7, 56.1, 56.6, 58.6, 69.2, 99.9, 100.6, 101.0, 104.7,
116.0, 118.7, 120.3, 124.1, 125.7, 126.7, 127.8, 129.9, 132.4, 136.6,
136.7, 136.8, 145.1, 149.6, 155.7, 158.3, 158.4. HRMS: calcd for
C32H35O9 (M+ + H) 595.2002, found 595.1981.
(-)-(2R)-1-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-
3-methylnaphthalen-2-yl)-phenyl)-propan-2-ol (32). A solution
of LiAlH4 (1.0 M, 1.55 mL, 1.55 mmol) in THF was added
dropwise to a solution of the tosylate 33 (307 mg, 0.516 mmol) in
dry Et2O (50 mL) at 0 °C. The reaction was stirred for 2 h at 0 °C,
then 30 min at room temperature. The resulting solution was diluted
with EtOAc and washed with saturated aqueous NaHCO3 solution.
Removal of the solvent under reduced pressure and purification
by flash chromatography, eluting with 80% EtOAc/petroleum ether,
gave the title compound as a fluffy white solid (206 mg, 94%).
[R]20D -14.0 (c 4.10, CHCl3). Mp: 94-95 °C. 1H NMR (500 MHz,
CDCl3): δ 1.29 (d, J ) 6.4 Hz, 3H), 2.11 (s, 3H), 2.73 (dd, J )
13, 8.3 Hz, 1H), 2.85 (dd, J ) 13, 4.9 Hz, 1H), 2.88 (s, 3H), 3.70
(s, 6H), 3.94 (s, 3H), 4.07 (m, 1H), 4.84 (s, 2H), 6.51 (s, 2H), 6.78
(d, J ) 7.3 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J ) 7.8 Hz, 1H), 7.51
(s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.2, 22.6, 46.5, 55.8,
55.9, 56.1, 68.9, 99.9, 104.6, 104.7, 104.8, 113.9, 118.9, 120.4,
124.1, 125.6, 127.1, 136.7, 137.1, 139.5, 149.5, 155.8, 158.2, 158.3.
IR (film): 3427 cm-1. HRMS: calcd for C25H30O6 (M+) 426.2042,
found 426.2042.
1
mg, 89%). Mp: 154-155 °C. H NMR (500 MHz, CDCl3): δ
2.11 (s, 3H), 2.87 (s, 3H), 3.72 (s, 6H), 3.94 (s, 3H), 4.36 (d, J )
4.9 Hz, 2H), 4.84 (s, 2H), 6.42 (m, 1H), 6.65 (d, J ) 16 Hz, 1H),
6.69 (s, 2H), 6.77 (d, J ) 6.8 Hz, 1H), 7.31 (m, 1H), 7.36 (d, J )
7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1,
55.6, 55.7, 56.1, 63.1, 99.8, 101.9, 104.6, 115.2, 118.7, 120.3, 124.0,
125.6, 127.0, 128.5, 130.9, 136.6, 136.9, 137.5, 149.4, 155.6, 158.1.
IR (KBr): 3500 cm-1. HRMS: calcd for C25H28O6 (M+) 424.1886,
found 424.1886.
(+)-(2S,3R)-{3-(3,5-Dimethoxy-4-(8-methoxy-1-meth-
oxymethoxy-3-methyl-naphthalen-2-yl)-phenyl)-2,3-oxiranyl}-
methanol (31). Ti(OiPr)4 (20 µL, 0.068 mmol) was added to a
solution of diisopropyl-D-tartrate (19 mg, 0.081 mmol) and
powdered 4 Å molecular sieves (40 mg) in dry CH2Cl2 (5 mL) at
-20 °C. An anhydrous solution of TBHP in dry CH2Cl2 (6.1 M,
439 µL, 2.69 mmol) was added at a rate that maintained the internal
temp at -20 °C. The reaction was stirred for 30 min at this
temperature, following which a solution of the allylic alcohol 30
(568 mg, 1.34 mmol) in dry CH2Cl2 (6 mL), previously stirred over
4 Å sieves for 30 min, was added at a rate as to maintain the internal
temperature between -15 and -20 °C. The reaction was stirred
for 5 h at -20 °C, and then 10% aqueous NaOH solution, saturated
with brine, was added, followed by Et2O (15 mL). The solution
was warmed to room temperature, and then dry MgSO4 (2.6 g)
and Celite (0.33 g) were added. The suspension was stirred for 15
min, diluted with CH2Cl2, and filtered through a pad of Celite,
eluting with CH2Cl2. Removal of the solvent under reduced pressure
and purification by flash chromatography, eluting with 60% EtOAc/
petroleum ether, gave the title compound as a white solid (474 mg,
80%, 90% de). Recrystallization from toluene/petroleum ether gave
material (372 mg, 63%) of >95% de. [R]20D +13.8 (c 3.99, CHCl3).
Mp: 174-175 °C. 1H NMR (500 MHz, CDCl3): δ 1.83 (m, 3H),
2.09 (s, 3H), 2.86 (s, 3H), 3.25 (m, 1H), 3.71 (s, 6H), 3.85 (m,
1H), 3.94 (s, 3H), 3.99 (d, J ) 2.0 Hz, 1H), 4.09 (m, 1H), 4.83 (s,
2H), 6.585 (s, 1H), 6.590 (s, 1H), 6.78 (d, J ) 7.3 Hz, 1H), 7.31
(m, 1H), 7.36 (d, J ) 7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75
MHz, CDCl3): δ 20.1, 55.7, 56.0, 56.1, 61.20, 61.25, 62.5, 99.8,
100.8, 104.7, 115.5, 118.7, 120.3, 124.1, 125.6, 126.8, 136.6, 136.8,
137.9, 149.4, 155.6, 158.2. IR (KBr): 3485 cm-1. HRMS:
electrospray calcd for C25H28O7 (M+ + Cl) 475.1524, found
475.1524.
(+)-(1S)-2-(3,5-Dimethoxy-4-(8-methoxy-1-methoxymethoxy-
3-methylnaphthalen-2-yl)-phenyl)-1-methylethylamine (29). (a)
DEAD (90 µL, 0.570 mmol) was added to a solution of the alcohol
32 (194 mg, 0.456 mmol), PPh3 (0.149 g, 0.570 mmol), and
phthalimide (84 mg, 0.570 mmol) in dry THF (6 mL) at 0 °C. The
reaction was protected from light and allowed to warm to room
temperature overnight. Saturated aqueous NaHCO3 solution was
added, and the product extracted with EtOAc (×4). The combined
organic extracts were washed with saturated aqueous NaHCO3
solution. The solvent was removed under reduced pressure, and
the residue was passed through a short column of alumina, eluting
with 25% EtOAc/petroleum ether. Removal of the solvent under
reduced pressure and purification of the residue by flash chroma-
tography, eluting with 40% EtOAc/petroleum ether, gave (1S)-2-
{2-(3,5-dimethoxy-4-(8-methoxy-1-methoxymethoxy-3-methyl-
naphthalen-2-yl)-phenyl)-1-methylethyl}isoindole-1,3-dione as a
white solid (207 mg, 82%). [R]20D +120 (c 3.05, CHCl3). Mp: 82-
1
85 °C. H NMR (500 MHz, CDCl3): δ 1.60 (d, J ) 5.9 Hz, 3H),
1.88 (s, 3H), 2.61 (s, 3H), 3.12 (dd, J ) 14, 5.9 Hz, 1H), 3.43 (dd,
J ) 11, 14 Hz, 1H), 3.54 (s, 3H), 3.60 (s, 3H), 3.90 (s, 3H), 4.70-
4.80 (overlapping m, 2H and 1H), 6.44 (s, 1H), 6.47 (s, 1H), 6.74
(d, J ) 7.3 Hz, 1H), 7.27 (dd, J ) 7.8, 7.3 Hz, 1H), 7.32 (d, J )
7.8 Hz, 1H), 7.43 (s, 1H), 7.67 (m, 2H), 7.75 (m, 2H). 13C NMR
(75 MHz, CDCl3): δ 18.5, 19.8, 40.1, 48.2, 55.5, 55.6, 55.7, 55.8,
99.6, 104.0, 104.4, 104.5, 113.6, 118.6, 120.2, 122.7, 123.9, 125.4,
126.9, 131.6, 133.7, 136.5, 136.9, 139.2, 149.4, 155.6, 157.7, 157.8,
168.1. IR (KBr): 1709, 1770 cm-1. HRMS: calcd for C33H33O7
(M+) 555.2257, found 555.2257.
(+)-(2S,3R)-Toluene-4-sulfonic Acid 3-(3,5-Dimethoxy-4-(8-
methoxy-1-methoxy-methoxy-3-methyl-naphthalen-2-yl)-phen-
yl)-2,3-oxiranylmethyl Ester (33). Dry NEt3 (433 µL, 3.12 mmol)
was added dropwise to a solution of the epoxy alcohol 31 (275
mg, 0.623 mmol) and DMAP (76 mg, 0.623 mmol) in dry CH2Cl2
(6 mL) at 0 °C. A solution of TsCl (131 mg, 0.686 mmol) in dry
CH2Cl2 (2 mL) was slowly added, and the reaction was stirred at
0 °C for 1 h. Saturated aqueous NaHCO3 solution was added, and
the product was extracted with EtOAc (×4). The combined organic
extracts were washed with saturated aqueous NaHCO3 solution.
Removal of the solvent under reduced pressure gave the title
compound as a fluffy white solid (307 mg, 83%). [R]20D +29.3 (c
(b) A 40% aqueous MeNH2 soution (8 mL) was added to a
solution of the phthalimide (234 mg, 0.420 mmol) in abs EtOH
(10 mL). The reaction was heated at reflux for 1 h, following which
most of the EtOH was removed under reduced pressure. Saturated
aqueous NaHCO3 solution was added, and the product was extracted
with EtOAc (×4). Removal of the solvent under reduced pressure
gave amine (29) as a white solid (179 mg, 100%). [R]20D +13.8 (c
1
3.58, CHCl3). Mp: 45-46 °C. H NMR (500 MHz, CDCl3): δ
1.18 (d, J ) 6.4 Hz, 3H), 2.11 (s, 3H), 2.60 (dd, J ) 13, 8.3 Hz,
1H), 2.78 (dd, J ) 13, 5.4 Hz, 1H), 2.88 (s, 3H), 3.26 (m, 1H),
3.70 (s, 6H), 3.94 (s, 3H), 4.84 (s, 2H), 6.49 (s, 1H), 6.50 (s, 1H),
6.77 (d, J ) 7.3 Hz, 1H), 7.30 (m, 1H), 7.36 (d, J ) 7.8 Hz, 1H),
7.50 (s, 1H). 13C NMR (75 MHz, CDCl3): δ 20.1, 23.0, 46.8, 48.4,
55.6, 55.7, 56.0, 99.7, 104.4, 104.5, 104.6, 113.5, 118.8, 120.3,
124.0, 125.5, 127.1, 136.5, 137.0, 140.4, 149.4, 155.7, 157.9, 158.0.
1
2.39, CHCl3). Mp: 80-81 °C. H NMR (500 MHz, CDCl3): δ
2.07 (s, 3H), 2.47 (s, 3H), 2.84 (s, 3H), 3.29 (m, 1H), 3.685 and
3.687 (s, 3H), 3.84 (d, J ) 2.0 Hz, 2H), 3.94 (s, 3H), 4.16 (dd, J
) 11, 5.4 Hz, 1H), 4.39 (dd, J ) 11, 3.4 Hz, 1H), 4.82 (s, 2H),
6.51 (s, 1H), 6.53 (s, 1H), 6.77 (d, J ) 7.8 Hz, 1H), 7.31 (t, J )
7362 J. Org. Chem., Vol. 71, No. 19, 2006

Total Synthesis of Ancistrocladidine
IR (KBr): 3416, 3551 cm-1. HRMS: electrospray calcd for C25H31-
NO5 (M+ - CH3OH) 393.1940, found 393.1940.
-136 (c 1.84, CHCl3). Mp: 253-254 °C dec (lit.9a 245-247 °C
dec; lit.9b 255-258 °C dec). 1H NMR (500 MHz, CDCl3): δ 1.42
(d, J ) 6.8 Hz, 3H), 2.16 (s, 3H), 2.45 (dd, J ) 15, 13 Hz, 1H),
2.48 (d, J ) 2.0 Hz, 3H), 2.68 (dd, J ) 15, 4.4 Hz, 1H), 3.37 (s,
3H), 3.43 (m, 1H), 3.75 (s, 3H), 4.01 (s, 3H), 6.63 (s, 1H), 6.72 (d,
J ) 7.3 Hz, 1H), 7.25 (s, 1H), 7.28 (dd, J ) 8.3, 7.3 Hz, 1H), 7.36
(d, J ) 8.3 Hz, 1H), 9.61 (s, 1H). 13C NMR (126 MHz, CDCl3):
δ 20.5, 22.0, 26.9, 35.2, 51.5, 55.8, 56.0, 60.9, 103.1, 105.9, 113.3,
116.9, 117.1, 118.7, 118.8, 121.1, 125.6, 136.2, 137.8, 141.3, 151.3,
156.1, 157.7, 159.2, 163.1. IR (KBr): 3361 cm-1. HRMS: calcd
for C25H27NO4 (M+) 405.1940, found 405.1940.
Concentration of the mother liquor gave atropisomer 35 as a
colorless gum shown to be 90% diastereomerically pure by 1H NMR
spectroscopy. [R]20D +40.4 (c 0.292, CHCl3). 1H NMR (500 MHz,
CDCl3): δ 1.44 (d, J ) 6.8 Hz, 3H), 2.19 (s, 3H), 2.43 (dd, J )
15, 14 Hz, 1H), 2.47 (d, J ) 2.0 Hz, 3H), 2.67 (dd, J ) 16, 4.4
Hz, 1H), 3.41 (s, 3H), 3.41 (m, 1H), 3.76 (s, 3H), 4.01 (s, 3H),
6.64 (s, 1H), 6.73 (d, J ) 7.3 Hz, 1H), 7.27 (s, 1H), 7.29 (dd, J )
8.3, 7.3 Hz, 1H), 7.37 (d, J ) 8.3 Hz, 1H), 9.59 (s, 1H). 13C NMR
(126 MHz, CDCl3): δ 20.6, 22.4, 26.6, 35.3, 51.5, 55.9, 56.0, 61.2,
103.1, 105.9, 113.3, 117.0, 117.3, 118.8, 118.9, 121.3, 125.6, 136.2,
138.0, 141.5, 151.1, 156.1, 157.7, 159.3, 163.2. IR (film): 3381
cm-1. HRMS: calcd for C25H27NO4 (M+) 405.1940, found
405.1940.
(+)-(1S)-N-{2-(3,5-Dimethoxy-4-(8-methoxy-1-meth-
oxymethoxy-3-methyl-naphthalen-2-yl)-phenyl)-1-methylethyl}-
acetamide (34). Dry NEt3 (129 µL, 0.924 mmol) was added to a
solution of the amine 29 (179 mg, 0.420 mmol) in dry CH2Cl2 at
0 °C. Freshly distilled AcCl (36 µL, 0.504 mmol) was added
dropwise, and the reaction was allowed to warm slowly to room
temperature overnight. The resulting solution was diluted with CH2-
Cl2 and washed with saturated aqueous NaHCO3 solution. Removal
of the solvent under reduced pressure gave the title compound as
a white solid (191 mg, 97%). [R]20 +16.7 (c 1.10, CHCl3). Mp:
D
200-202 °C. 1H NMR (500 MHz, CDCl3): δ1.15(d, J ) 6.8 Hz,
3H), 1.96 (s, 3H), 2.09 (s, 3H), 2.68 (dd, J ) 14, 7.8 Hz, 1H), 2.87
(s, 3H), 2.94 (dd, J ) 13, 5.4 Hz, 1H), 3.69 (s, 3H), 3.70 (s, 3H),
3.94 (s, 3H), 4.30 (m, 1H), 4.84 (m, 2H), 5.35 (d, J ) 7.8 Hz, 1H),
6.46 (s, 1H) and 6.49 (s, 1H), 6.77 (d, J ) 6.8 Hz, 1H), 7.31 (m,
1H), 7.36 (d, J ) 7.3 Hz, 1H), 7.50 (s, 1H). 13C NMR (75 MHz,
CDCl3): δ 19.7, 20.1, 23.3, 43.2, 46.2, 55.7, 55.7, 56.1, 83.2, 99.8,
104.6, 104.6, 104.7, 113.7, 118.8, 120.3, 124.0, 125.5, 127.1, 136.6,
137.0, 139.2, 149.4, 155.7, 157.9, 158.0, 169.2. IR (KBr): 1568,
1636, 3061, 3242, 3416 cm-1. HRMS: calcd for C27H33NO6 (M+)
467.2308, found 467.2308.
(-)-M-(3S)-2-(6,8-Dimethoxy-1,3-dimethyl-3,4-dihydroiso-
quinolin-7-yl)-8-methoxy-3-methyl-naphthalen-1-ol (1a) and (+)-
P-atropisomer (35). 2,4,6-Collidine (58 µL, 0.437 mmol) was
added to a solution of the amide 34 (186 mg, 0.397 mmol) in dry
CH3CN (2 mL). Freshly distilled POCl3 (41 µL, 0.437 mmol) was
added, and the reaction was heated at reflux for 4 h. The resulting
solution was cooled to room temperature, poured into saturated
aqueous NaHCO3 solution, and extracted with EtOAc (×4).
Removal of the solvent under reduced pressure and purification
by flash chromatography on alumina, eluting with 50% EtOAc/
petroleum ether, gave the title compound as a 1:1 mixture of
diastereoisomers (119 mg, 74%). The mixture was crystallized from
toluene/petroleum ether. Concentration of the mother liquor and
repeated crystallization gave a further crop of crystals. The
combined crops of crystals from above were recrystallized from
Acknowledgment. We thank the University of Canterbury
and the University of Adelaide for financial assistance and Mr.
Bruce Clark for mass spectrometry experiments. J.C.M. thanks
the ARC Centre of Excellence for Free Radical Chemistry and
Biotechnology for support for a period of study leave at the
RSC, The Australian National University.
Supporting Information Available: Characterization data for
natural ancistrocladidine, synthetic ancistrocladidine, and atro-
pisomer 35. Experimental details on the determination of diaster-
1
eomeric excess. Copies of H and 13C NMR spectra of all new
compounds. This material is available free of charge via the Internet
at http://pubs.acs.org.
toluene/petroleum ether to give ancistrocladidine (1a) as a single
1
diastereoisomer as determined by H NMR spectroscopy. [R]20
JO0611364
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J. Org. Chem, Vol. 71, No. 19, 2006 7363