A convergent total synthesis of the michellamines

Article abstract of DOI:10.1021/jo971495m

A convergent total synthesis of the anti-HIV michellamines (1) is described. The tetraaryl skeleton of the michellamines was constructed by formation first of the inner (nonstereogenic) biaryl axis and subsequently of the two other (stereogenic) axes in a highly convergent manner. The key transformation features a double Suzuki-type cross-coupling reaction between binapthalene ditriflate 26 and isoquinolineboronic acid 35. Ditriflate 26 is synthesized in six steps starting from diene 6 and 2,6-dibromobenzoquinone (9) in 21% overall yield. For large scale production of 26, a substantially shortened version of an existing procedure for the preparation of bisnaphthoquinone 13 was also developed, which allows for the preparation of 13 from benzoquinone and diene 6 in five steps and 67% overall yield. Binaphthoquinone 13 was subsequently converted into ditriflate 26 in three steps and 67% overall yield. By the described synthetic strategy, michellamines A (1a) and B (1b) are produced (1a:1b = 1:2.5) in 24.6% overall yield from diene 6. Curiously, none of the nonnaturally occurring atropoisoner 1c is formed.

Full text of DOI:10.1021/jo971495m

1090
J . Org. Chem. 1998, 63, 1090-1097
A Con ver gen t Tota l Syn th esis of th e Mich ella m in es|
Gerhard Bringmann,*,† Roland Go¨tz,† Paul A. Keller,† Rainer Walter,† Michael R. Boyd,‡
Fengrui Lang,§ Alberto Garcia,§ J ohn J . Walsh,§ Imanol Tellitu,§ K. Vijaya Bhaskar,§ and
T. Ross Kelly*,§
Institut fu¨r Organische Chemie, Universita¨t Wu¨rzburg, Am Hubland, D-97074 Wu¨rzburg, Germany,
Laboratory of Drug Discovery Research and Development, National Cancer Institute, Building 1052,
Room 121, Frederick, Maryland 21702-1201, and Department of Chemistry, Eugene F. Merkert Chemistry
Center, Boston College, Chestnut Hill, Massachusetts 02167-3860
Received August 12, 1997
A convergent total synthesis of the anti-HIV michellamines (1) is described. The tetraaryl skeleton
of the michellamines was constructed by formation first of the inner (nonstereogenic) biaryl axis
and subsequently of the two other (stereogenic) axes in a highly convergent manner. The key
transformation features a double Suzuki-type cross-coupling reaction between binaphthalene
ditriflate 26 and isoquinolineboronic acid 35. Ditriflate 26 is synthesized in six steps starting from
diene 6 and 2,6-dibromobenzoquinone (9) in 21% overall yield. For large scale production of 26, a
substantially shortened version of an existing procedure for the preparation of bisnaphthoquinone
13 was also developed, which allows for the preparation of 13 from benzoquinone and diene 6 in
five steps and 67% overall yield. Binaphthoquinone 13 was subsequently converted into ditriflate
26 in three steps and 67% overall yield. By the described synthetic strategy, michellamines A (1a )
and B (1b) are produced (1a :1b ) 1:2.5) in 24.6% overall yield from diene 6. Curiously, none of
the nonnaturally occurring atropoisomer 1c is formed.
In tr od u ction
sible atropisomer named michellamine C (1c) was also
isolated, but was later found to be an artifact formed
under too harsh isolation conditions.3,7
The lack of effective drugs for the treatment of AIDS
led the United States National Cancer Institute to
initiate in the late 1980s a major effort to discover novel
HIV (human immunodeficiency virus) inhibitory agents
from natural sources.1 In 1991, Boyd et al.2,3 reported
the isolation of two anti-HIV alkaloids, michellamines A
and B, from the tropical plant Ancistrocladus korupensis
native to Cameroon. Michellamine B, the more potent
and abundant of the naturally occurring michellamines,
aborted viral replication and virus-induced cell killing
across an unusually broad range of HIV strains and
isolates in diverse human host-cell types.3
By a combination of spectroscopic and degradative
studies2-6 michellamines A and B were assigned struc-
tures 1a and 1b, respectively, with the relative and
absolute configurations shown. Initially, the third pos-
| Part 102 in the series Acetogenic Naphthylisoquinoline Alkaloids
(from the University of Wu¨rzburg). For part 101, see: Bringmann, G.;
Saeb, W.; Wenzel, M.; Franc¸ois, G.; Schlauer, J . Pharm. Pharmacol.
Lett., submitted. Part 47 in the series: HIV-Inhibitory Natural
Products (from the National Cancer Institute). For part 46, see:
Hallock, Y. F.; Cardellina, J . H., II; Scha¨ffer, M.; Bringmann, G.; Boyd,
M. R. BioMed. Chem. Lett., submitted.
† Institute fu¨r Organische Chemie.
‡ National Cancer Institute.
§ Boston College.
(1) Boyd, M. R. In AIDS Etiology, Diagnosis, Treatment and Preven-
tion; De Vita, V. T., J r., Hellman, S., Rosenberg, S. A., Eds.; Lippin-
cott: Philadelphia, 1988, p 305.
(2) Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H., II; MacMahon,
J . B.; Pannell, L. L.; Gordon, M. C.; Boyd, M. R. J . Med. Chem. 1991,
34, 3402.
(3) Boyd, M. R.; Hallock, Y. F.; Cardellina, J . H., II; Manfredi, K.
P.; Blunt, J . W.; MacMahon, J . B.; Buckheit, R. W.; Bringmann, G.;
Scha¨ffer, M.; Cragg, G. M.; Thomas, D. W.; J ato, J . G. J . Med. Chem.
1994, 37, 1740.
(4) Bringmann, G. In The Alkaloids; Brossi, A., Ed.; Academic
Press: New York, 1986; Vol. 29, pp 141-184.
(5) Bringmann, G.; Zagst, R.; Scha¨ffer, M.; Hallock, Y. F.; Cardellina,
J . H., II; Boyd, M. R. Angew. Chem., Int. Ed. Engl. 1993, 32, 1190.
(6) Bringmann, G.; Gulden, K.-P.; Hallock, Y. F.; Manfredi, K. P.;
Cardellina, J . H., II; Boyd, M. R.; Kramer, B.; Fleischhauer, J .
Tetrahedron 1994, 50, 7807.
The isolation of michellamine C (1c) apparently results
from the fact that the michellamines can be intercon-
verted by epimerization under basic conditions.3 At
equilibrium the ratio of michellamines A, B, and C is ∼3:
3:1. Although michellamine C (1c) is thermodynamically
(7) Bringmann, G.; Harmsen, S.; Holenz, J .; Geuder, T.; Go¨tz, R.;
Keller, P. A.; Walter, R.; Hallock, Y. F.; Cardellina, J . H., II; Boyd, M.
R. Tetrahedron 1994, 50, 9643.
S0022-3263(97)01495-3 CCC: $15.00 © 1998 American Chemical Society
Published on Web 01/27/1998

Convergent Total Synthesis of the Michellamines
J . Org. Chem., Vol. 63, No. 4, 1998 1091
Sch em e 1
Sch em e 2
The second synthesis,12 which was completed only a
few months later, follows the complementary pathway
(B), by first establishing the central bond to result in a
dimeric naphthalene unit, which is then connected with
the corresponding isoquinoline parts by a double Suzuki-
type cross-coupling reaction.
Since then, additional syntheses have been published
from the laboratories of Hoye13 and Dawson14 following
pathway A, the central axis again being built up by
oxidative dimerization using Ag2O13 or by Suzuki-type
cross-couplings.14 These and other15-17 synthetic efforts
to build up both mono- and dimeric naphthylisoquinoline
alkaloids strongly underline the worldwide interest in
this promising field of research.
We originally reported the present synthesis in a brief
communication in 1994.12 We now provide greater detail
and experimental procedures and also describe some of
the ancillary studies that facilitated the synthesis’s
achievement.
Resu lts a n d Discu ssion
The first stage of the synthesis required the prepara-
tion of the binaphthalene synthon 5. To that end, we
undertook the synthesis of bromonaphthoquinone 11
since dimerization of 11, or derivatives thereof, would
afford access to the carbon skeleton of 5.
less stable than the other two atropisomers, the reason
for the apparent total absence of 1c in nature is un-
known.
The pronounced biological activity as well as the
structural novelty of the michellamines has attracted
much interest from synthetic chemists, especially after
the U.S. National Cancer Institute published8 an an-
nouncement encouraging the research community to
pursue synthetic and/or other studies aimed at the
production of michellamine B. In principle, the michel-
lamines can be most efficiently dissected retrosyntheti-
cally in two manners (Scheme 1). One retrosynthesis
leads to a biomimetic pathway (A) that involves the
construction of the naphthalene/isoquinoline bonds prior
to the formation of the central naphthalene/naphthalene
axis. By contrast, the complementary pathway (B) would
have the central axis established first, with the two
isoquinoline moieties being added subsequently.
The first synthesis of the michellamines was achieved
in 1994 following the biomimetic concept.7,9,10 In this
approach, the monomeric halves of the michellamines,
korupensamines A (2, R ) H, X ) H, axis, P-configured)
and B (3, R ) H, Y ) H, axis, M-configured), which also
occur in A. korupensis,11 were synthesized9,10 and then
homo- or cross-coupled by biomimetic oxidative dimer-
ization of appropriately protected 2 and/or 3 using
silver(I) oxide.7,10
Brassard18 reported that chloronaphthoquinone 8 can
be prepared regioselectively in 74% overall yield from the
known diene 618,19 and 2,6-dichloro-1,4-benzoquinone (7)
by a Diels-Alder reaction followed by aromatization of
the adduct on silica gel and final O-methylation (Scheme
2).
Since bromides are generally more reactive than
chlorides in metal-catalyzed coupling reactions, the bro-
mo analogue 11 was prepared from 9. Using 2,6-
dibromo-1,4-benzoquinone (9)20 as the dienophile and
618,19 as diene, bromoquinone 10 was synthesized in 70%
(11) Hallock, Y. F.; Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H.,
II; Scha¨ffer, M.; Gulden, K.-P.; Bringmann, G.; Lee, A. Y.; Clardy, J .;
Franc¸ois, G.; Boyd, M. R. J . Org. Chem. 1994, 59, 6349.
(12) Kelly, T. R.; Garc´ıa, A.; Lang, F.; Walsh, J . J .; Bhaskar, K. V.;
Boyd, M. R.; Go¨tz, R.; Keller, P. A.; Walter, R.; Bringmann, G.
Tetrahedron Lett. 1994, 35, 7621.
(13) Hoye, T. R.; Chen, M.; Mi, L.; Priest, O. P. Tetrahedron Lett.
1994, 35, 8747.
(14) Hobbs, P. D.; Upender, V.; Liu, J .; Pollart, D. J .; Thomas, D.
W.; Dawson, M. I. J . Chem. Soc., Chem. Commun. 1996, 923. Hobbs,
P. D.; Upender, V.; Dawson, M. I. Synlett 1997, 965.
(15) (a) Hoye, T. R.; Mi, L. Tetrahedron Lett. 1996, 37, 3097. (b)
Hoye, T. R.; Chen, M.; Tetrahedron Lett. 1996, 37, 3099.
(16) 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 . Heterocyc. Chem. 1996, 33, 1371.
(17) (a) Rama Rao, A. V.; Gurjar, M. K.; Ramana, D. V.; Cheda, A.
K. Heterocycles 1995, 43, 1. (b) Gable, R. W.; Martin, R. L.; Rizzacasa,
M. A. Aust. J . Chem. 1995, 48, 2013. (c) Watanabe, T.; Kamikawa, K.;
Uemura, M. Tetrahedron Lett. 1995, 36, 6695.
(8) Anon. J . Nat. Prod. 1992, 55, 1018.
(9) Bringmann, G.; Go¨tz, R.; Keller, P. A.; Walter, R.; Henschel, P.;
Scha¨ffer, M.; Sta¨blein, M.; Kelly, T. R.; Boyd, M. R. Heterocycles 1994,
39, 503.
(10) Bringmann, G.; Go¨tz, R.; Harmsen, S.; Holenz, J .; Walter, R.
Liebigs Ann. Chem. 1996, 2045.
(18) Savard, J .; Brassard, P. Tetrahedron 1984, 40, 3455.
(19) Casey, C. P.; J ones, C. R.; Tukeda, H. J . Org. Chem. 1981, 46,
2089.

1092 J . Org. Chem., Vol. 63, No. 4, 1998
Bringmann et al.
Sch em e 3
Sch em e 5
Sch em e 4
tion of 11 to 13 could be realized in a similar yield (43%)
by an Ullmann coupling reaction with copper bronze in
the presence of tetrakis(triphenylphosphine)palladium-
(0) in DMF,22 but the current Stille-type23 coupling route
is preferred (Scheme 4).
The binaphthoquinone 13 had been synthesized before
by Laatsch24,25 via an oxidative coupling as shown in
Scheme 5. Although our four-step synthesis of 13 is
several steps shorter than the one in Scheme 5, we also
explored the possibility of improving the latter route. To
that end, we first developed an improved synthesis of
19.24-26 The new synthesis starts with the Diels-Alder
reaction between diene 618,19 and benzoquinone (16),
which affords the adduct 24 cleanly. Desilylation of 24
in methanol with aqueous HCl and subsequent aroma-
tization gave the desired product 19 in 41% overall yield.
When excess benzoquinone (16) was used in the Diels-
Alder reaction, the leftover 16 could serve as the oxidant
for the aromatization, which avoided the use of PCC in
the original procedure.
We were pleased with this modified synthesis because
it was shorter than the literature sequence, but it was
not a perfect solution. For although the Diels-Alder
reaction was fast and clean, the cleavage of ketal 24 only
afforded naphthoquinone 19 in a moderate yield. And
an O-methylation step was still needed for the prepara-
tion of 20.
yield (Scheme 3). Methylation of 10 by refluxing in
methyl iodide in the presence of silver (I) oxide gave the
desired methyl ether 11 in 97% yield.
Bromoquinone 11 was converted into stannane deriva-
tive 12 in 71% yield by heating at 100 °C in dioxane with
Bu6Sn2 and bis(triphenylphosphine)palladium(II) chlo-
ride.21 A second palladium-promoted reaction,21 utilizing
the same catalyst, coupled stannane 12 and bromo-
quinone 11 to afford binaphthoquinone 13. Because 13
is light sensitive, it was usually converted without
purification to 14 by reductive acetylation. The yield of
14 from 12 is 65% (Scheme 4).
Since the two consecutive coupling reactions leading
to 13 use the same reaction conditions, it proved possible
to make 13 in a single step. Thus, when half an
equivalent of Bu6Sn2 was used in the reaction of 11, after
reductive peracetylation, tetraacetate 14 was isolated in
40% yield. We previously reported12 that the dimeriza-
(20) Prepared in 52% yield using the procedure of Hodgson, H. H.;
Nixon, J . J . Chem. Soc. 1930, 1085. The crude product was purified
by passing a CH2Cl2 solution of it through a column of silica gel. A
number of preparations of 9 have been reported in the literature, but
we found this method (the oxidation of 2,4,6-tribromophenol using 90%
fuming nitric acid) to be the most reliable one.
(21) For recent reviews, see: (a) Farina, V. In Comprehensive
Organometallic Chemistry II; Abel, E. W., Stone, F. G. A., Wilkinson,
G., Eds.; Pergamon: Oxford, 1995; Vol. 12 (Hegedus, L. S., Ed.), p 161.
(b) Knight, D. W. In Comprehensive Organic Synthesis; Trost, B. M.,
Fleming, I., Eds.; Pergamon Press: Oxford, 1991; Vol. 3 (Pattenden,
G., Ed.), Chapter 2.3. (c) Bringmann, G.; Walter, R.; Weirich, R. Angew.
Chem., Int. Ed. Engl. 1990, 29, 977.
(22) Shimizu, N.; Kitamura, T.; Watanabe, K.; Yamaguchi, T.;
Shigyo, H.; Ohta, T. Tetrahedron Lett. 1993, 34, 3421.
(23) Stille, J . K. Angew. Chem., Int. Ed. Engl. 1986, 25, 508.
(24) Laatsch, H. Liebigs Ann. Chem. 1980, 1321.
(25) (a) Krohn, K. Tetrahedron Lett. 1980, 21, 3557. (b) Krohn, K.;
Broser, E. J . Org. Chem. 1984, 49, 3766.
(26) Ro¨sner, A.; Tolkiehn, K.; Krohn, K. J . Chem. Res. (M) 1978,
3831.

Convergent Total Synthesis of the Michellamines
J . Org. Chem., Vol. 63, No. 4, 1998 1093
Sch em e 6
Sch em e 7
To further improve the synthesis, we sought to opti-
mize the cleavage of ketal 24. Since an acid milder than
HCl might give a cleaner reaction, acetic acid was tested
and the result was most rewarding. Thus, after the
Diels-Alder reaction between diene 6 and benzoquinone
(16) in CH2Cl2 was complete, acetic acid was added to
the reaction solution. Evaporation of the solvent gave,
surprisingly, the desired methyl ether 20 instead of the
expected phenol 19 as the product (Scheme 6). The
reason why 20 is formed instead of 19 is unclear, but
the one-pot reaction provides 20 in 85% overall yield
based on diene 6.
Compound 20 was then converted to 13 using the
previously reported24 procedures (Scheme 5). The syn-
thesis of 13 via 20 still has more steps than the route
via 11, but the synthesis of 13/14 via 20 is easier and
faster, and better suited for large-scale production.
As already mentioned, quinone dimer 13 is light
sensitive, so it was usually not purified but instead
reductively peracetylated27 directly to afford tetraacetate
14. The transformation is conveniently carried out at
room temperature by stirring a mixture of crude 13, zinc
powder, acetic anhydride, sodium acetate, and 4-(di-
methylamino)pyridine (DMAP) in CH2Cl2 overnight. The
conversion of 13 to 14 proceeds cleanly: With a pure
sample of 13, 14 was obtained in 95% yield.
Tetraacetate 14 contains the entire carbon skeleton of
the binaphthalene synthon 5, but it is not properly
functionalized for biaryl coupling with the isoquinoline
units. Refunctionalization began with a selective bis-
deacetylation at the less hindered sites with DBU in
methanol28 to give diacetate 25; without purification, 25
was subsequently converted29 into ditriflate 26 using
trifluoromethanesulfonic anhydride (Tf2O) and 2,6-luti-
dine in CH2Cl2. The two-step sequence gave 26 in 70%
yield from 14 (Scheme 7). Ditriflate 26 was also con-
verted into the distannanes 27a and 27b and diiodide30
28 (Scheme 7) so that three different types of binaph-
thalene units were available for coupling with various
isoquinoline synthons.
We anticipated steric hindrance31 to be the major
obstacle in the coupling reaction between the naphtha-
lene and isoquinoline units to give the michellamine
skeleton. The isoquinoline unit 4 can be considered a
benzene ring with two substituents ortho to the coupling
position, while naphthalene 5 () 26-28) can be regarded
as a benzene ring with one substituent ortho to the
coupling position. It is very congested at the coupling
positions. For elaboration of the best coupling conditions,
we decided to carry out model coupling studies in order
to save the precious enantiomerically pure isoquinoline
unit 34.
Orcinol derivatives 29, 30, and 31 were used as models
because they are similar to the isoquinoline unit in both
steric and electronic respects. The stannane derivatives
30 were prepared30 by first lithiation of the corresponding
bromide 29 followed by reacting with Bu3SnCl (Scheme
8). The boronic acids32 31 were prepared by lithiation of
29 and subsequent reaction with triisopropyl borate as
shown in Scheme 8. After various permutations of
potential coupling partners were examined (26-28 with
(27) For a leading reference, see: Ulrich, H.; Richter, R. In Methoden
de Organische Chemie (Houben-Weyl): Chinone; Georg Thieme Ver-
lag: Stuttgart, 1977; Teil I, p 652.
(28) Baptistella, L. H. B.; dos Santos, J . F.; Ballabio, K. C.; Marsaioli,
A. J . Synthesis 1989, 436.
(29) Stang, P. J .; Hanack, M.; Subramanian, L. R. Synthesis 1982,
85.
(30) Ingham, R. K.; Rosenberg, S. D.; Gilman, H. Chem. Rev.
(Washington, D.C.) 1960, 60, 459.
(31) (a) Thompson, W. J .; Gaudino, J . J . Org. Chem. 1984, 49, 5237.
(b) Saa´, J . M.; Martorell, G.; Garcia-Raso, A. J . Org. Chem. 1992, 57,
678. (c) Fu, J .-m.; Snieckus, V. Tetrahedron Lett. 1990, 31, 1665.
(32) For a leading reference, see: Hevesi, L. In Comprehensive
Organic Functional Group Transformations; Katritzky, A. R., Meth-
Cohn, O., Rees, C. W., Eds.; Pergamon: Oxford, 1995; Vol. 2 (Ley, S.
V., Ed.), p 899.

1094 J . Org. Chem., Vol. 63, No. 4, 1998
Bringmann et al.
Sch em e 8
Sch em e 10
Sch em e 9
spheric pressure for 14 h. The two acetates in the
naphthalene unit were finally taken off in the last step
of the synthesis using methanolic HCl.
The resulting mixture of atropisomers was separated
by preparative HPLC to give michellamine A (1a ) and
michellamine B (1b) (1a : 1b ) 1:2.5). The synthetic 1a
and 1b were shown to be identical, by direct comparison,
to authentic, naturally derived materials. However, we
were unable to detect any michellamine C (1c) in the
synthetic mixture even though we had a sample of 1c as
a TLC/HPLC standard. The question of why 1c is not
detectable in either the natural source or our synthetic
mixture is intriguing. Atropisomer 1c is a stable com-
pound3 (although slightly underrepresented in a ther-
modynamically dictated mixture of 1a , 1b, and 1c) and
has been synthesized previously.10 While its absence in
plant material presumably has to do with the high
specificity of the dimerization enzyme, which has recently
been isolated,36 at least one of the two coupling steps in
our synthesis must proceed with a high diastereoselec-
tivity. Of great interest would be the axial configuration
of the intermediate monocoupled product, which would
indicate the degree of asymmetric induction by the
stereocenters present in 35 and would thus allow an
estimation of the additional degree of asymmetric induc-
tion exerted by the first-generated biaryl axis on the
second coupling step. Regretably, all attempts to isolate
or at least detect such a monocoupled intermediate in
the reaction of 35 and 26 failed.
29-31), it was determined that Suzuki-type33,34 cross-
coupling reactions between ditriflate 26 and boronic acids
31 gave the best yield for the desired coupling. Coupling
reactions between ditriflate 26 and boronic acids 31 were
carried out in the presence of tetrakis(triphenylphos-
phine)palladium(0) and barium hydroxide34 to afford 32a
and 32b in 88% and 94% yields, respectively.
With a method established for making the final biaryl
bonds, we turned to the synthesis of the michellamines
themselves. Preparation of the specifically protected key
heterocyclic building block 34 (Scheme 9) in a stere-
ochemically homogeneous form, was done as described
previously.9,10,35
The subsequent conversion of 34 into the isoquinoline
boronic acid 35 was achieved in 89% yield by the same
method used above for preparation of the orcinol-derived
boronic acids 31 (Scheme 10). Boronic acid 35 was then
coupled with ditriflate 26 under the same conditions
elaborated for the model compounds to give 36 as a
mixture of atropisomers. Deprotection of the benzyl
groups was carried out by catalytic hydrogenation; all six
benzyl protecting groups were removed by hydrogenation
with 10% palladium on charcoal in ethanol at atmo-
Biologica l Eva lu a tion of Syn th etic 1a /1b. The
antiviral activity of the synthetic michellamines was
indistinguishable from that previously reported2,3 for the
natural compounds (data not shown).
(33) Miyaura, N.; Yanagi, T.; Suzuki, A. Synth. Commun. 1981, 11,
513.
(34) (a) Watanabe, T.; Miyaura, N.; Suzuki, A. Synlett 1992, 207.
(b) Suzuki, A. Pure Appl. Chem. 1994, 213.
(35) Bringmann, G.; Weirich, R.; Reuscher, H.; J ansen, J . R.;
Kinzinger, L.; Ortmann, T. Liebigs Ann. Chem. 1993, 877.
(36) Schlauer, J .; Wiesen, B.; Ru¨ckert, M.; Ake´Assi, L.; Haller, R.
D.; Ba¨r, S.; Fro¨hlich, K.-U.; Bringmann, G. Arch. Biochem. Biophys.
1998, 350, 87.

Convergent Total Synthesis of the Michellamines
J . Org. Chem., Vol. 63, No. 4, 1998 1095
Con clu sion . The convergent synthesis described
herein provides the michellamines in an overall yield of
24.6% from diene 6.
was added solid benzoquinone 16 (2.61 g, 24.0 mmol) over
5 min. The resulting dark greenish solution was stirred
at room temperature for 18 h. An aliquot of the solution
was evaporated to dryness and analyzed by NMR spec-
troscopy, which showed the formation of the Diels-Alder
adduct 24. 24: 1H NMR (CDCl3, 400 MHz) δ 0.20 (9H,
s), 1.79 (3H, s), 2.01 (1H, dd, J ) 5.7, 12.8 Hz), 2.85 (1H,
d, J ) 12.8 Hz), 3.04 (3H, s), 3.12 (1H, d, J ) 5.7 Hz),
3.23 (1H, m), 5.53 (1H, s), 6.62 (1H, d, J ) 8.4 Hz), 6.74
(1H, d, J ) 8.4 Hz). Then 1.5 mL of acetic acid was added
to the reaction mixture and the solvent was evaporated
to dryness at room temperature under reduced pressure
overnight. A dark, greenish-yellow solid was formed. The
solid was mixed with 100 mL of MeOH, and a yellow solid
was observed at the bottom of the flask. The solvent was
evaporated to dryness and the residue purified by flash
column chromatography on silica gel (petroleum ether/
ethyl acetate ) 3:2) to afford 2.18 g (85%) of 20 as a
yellow solid, mp 164-166 °C (lit.24 mp 166 °C).
2,2′-Bis(1,4-d ia cet oxy-8-m et h oxy-6-m et h yln a p h -
th a len e) (14). (A) F r om Cou p lin g of 11 a n d 12. In
a sealed tube covered with aluminum foil (13 is light
sensitive), a solution of 11 (210 mg, 0.76 mmol), tribu-
tylstannane 12 (373 mg, 0.76 mmol), and (PPh3)2PdCl2
(80 mg, 15 mol %) in 10 mL of anhydrous dioxane was
heated under argon at 110 °C overnight. After cooling,
the mixture was poured onto a stirred mixture of Zn dust
(497 mg, 7.60 mmol), 4-(dimethylamino)pyridine (371 mg,
3.04 mmol), NaOAc (623 mg, 7.60 mmol), and Ac2O (2
mL) in 35 mL of CH2Cl2, and the new reaction mixture
was stirred in the dark overnight. For the workup, the
solution was first filtered through Celite, washed with
H2O (3 × 25 mL), dried over Na2SO4, and concentrated
under vacuum to afford, after chromatography (petro-
leum ether/ethyl acetate ) 1:1), tetraacetate 14 as a light
brown oil (283 mg, 65%).
(B) F r om Dim er iza tion of 11. In a sealable tube
covered with aluminum foil, bromoquinone 11 (438 mg,
1.56 mmol), Sn2Bu6 (0.39 mL, 0.78 mmol), and (PPh3)2-
PdCl2 (164 mg, 15% mol) were dissolved in 15 mL of
anhydrous dioxane under argon. The tube was sealed
and heated at 110 °C for 24 h. After being cooled to room
temperature, the mixture was poured onto a stirred
mixture of Zn dust (1.02 g, 15.6 mmol), 4-(dimethylami-
no)pyridine (762 mg, 6.24 mmol), NaOAc (1.28 g, 15.6
mmol), and Ac2O (3 mL) in 50 mL of CH2Cl2, and the
new reaction mixture was stirred in the dark at room
temperature for 15 h. For the workup, the solution was
filtered through Celite, washed with H2O, dried over Na2-
SO4, and concentrated under vacuum. Flash column
chromatography on silica gel (petroleum ether/ethyl
acetate ) 1:1) afforded 14 (178 mg, 40%) as a light brown
oil.
(C) F r om P u r e 13. A mixture of binaphthoquinone
13 (2.01 g, 5.00 mmol), dichloromethane (200 mL), zinc
dust (10 g), sodium acetate (10 g), acetic anhydride (10
mL), and DMAP (6 g) was stirred in the dark at room
temperature for 20 h. Then the mixture was filtered
through Celite and the solids were washed with dichlo-
romethane (100 mL). The filtrate and wash were com-
bined and evaporated at reduced pressure and elevated
temperature (up to 80 °C) to get rid of the acetic
anhydride. The crude product was filtered through a
short column of silica gel using dichloromethane as
eluent. The filtrate was evaporated to dryness, giving
2.72 g (95%) of 14 as an off-white solid, which was
Exp er im en ta l Section 37
2-Br om o-8-h yd r oxy-6-m et h yl-1,4-n a p h t h oq u in -
on e (10). To a solution of 2,6-dibromobenzoquinone20 (9)
(11.65 g, 43.8 mmol) in 70 mL of dry THF at 0 °C under
a nitrogen atmosphere was added dropwise via a syringe
pump over 1 h a solution of diene 6 (9.07 g, 48.7 mmol)
in 40 mL of dry THF. The resulting solution was stirred
at room temperature for 3 h. Then 250 g of 230-400
mesh silica gel was added, and the mixture was shaken
until it appeared homogeneous and allowed to stand at
room temperature for 48 h. Subsequently, the reaction
mixture was put directly onto a silica gel column (4 in. x
10 in.) and purified by eluting with petroleum ether/ethyl
acetate (7:3) to give 8.18 g (70%) of bromoquinone 10 as
an orange red solid, mp 186-187 °C: IR (KBr) ν 3438,
1
1638 cm-1; H NMR (CDCl3, 400 MHz) δ 2.45 (3H, s),
7.10 (1H, s), 7.45 (1H, s), 7.46 (1H, s), 11.69 (1H, s); 13C
NMR (CDCl3, 100 MHz) δ 22.9, 112.6, 122.0, 125.0, 132.1,
140.2, 141.6, 150.0, 163.0, 182.6, 182.9. Anal. Calcd for
C11H7O3Br: C, 49.47; H, 2.64. Found: C, 49.40; H, 2.57.
In addition, 1.27 g (10%) of methyl ether 11 was obtained
as a yellow solid.
2-Br om o-8-m et h oxy-6-m et h yl-1,4-n a p h t h oq u in -
on e (11). A mixture of 5.38 g of 10 (20 mmol), 6.98 g of
Ag2O powder, and 100 mL of iodomethane was refluxed
for 1 h. Then the mixture was filtered through Celite
and the Celite and the solid were washed with CH2Cl2.
The filtrate and the wash were combined and evaporated
to give 5.49 g (97%) of bromonaphthoquinone 11 as a
yellow solid. The crude product was used in the next
reaction without further purification. An analytical
sample of 11 was obtained by recrystallization from
ethanol as a yellow solid, mp 175-177 °C: IR (CH2Cl2) ν
1667, 1597 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.48 (3H,
s), 4.00 (3H, s), 7.10 (1H, s), 7.41 (1H, s), 7.54 (1H, s);
13C NMR (CDCl3, 100 MHz) δ 23.0, 57.1, 117.1, 119.2,
121.1, 134.4, 138.8, 143.5, 147.9, 161.3, 176.5, 183.5;
HRMS calcd for C12H9BrO3 279.9735, found: 279.9767.
Anal. Calcd for C12H9BrO3: C, 51.27; H, 3.23. Found:
C, 51.17; H, 3.15.
2-(Tr ibu tylsta n n yl)-8-m eth oxy-6-m eth yl-1,4-n a p h -
th oqu in on e (12). A solution of bromonaphthoquinone
11 (370 mg, 1.31 mmol), hexabutylditin (0.730 mL, 1.45
mmol), and bis(triphenylphosphine)palladium(II) chloride
(Aldrich, 138 mg, 15 mol %) in 25 mL of anhydrous
dioxane was heated at reflux under a nitrogen atmo-
sphere for 1 h. After cooling, the solution was evaporated
under vacuum to yield a brown oil which was purified
by flash column chromatography on silica gel (petroleum
ether/ethyl acetate ) 7:3) to afford 12 as a yellow oil (495
mg, 71%): 1H NMR (CDCl3, 400 MHz) δ 0.85 (9H, t, J )
7.2 Hz), 1.10 (6H, t, J ) 7.2 Hz), 1.28-1.36 (6H, m), 1.48-
1.51 (6H, m), 2.47 (3H, s), 3.99 (3H, s), 7.07 (1H, s), 7.10
(1H, s), 7.53 (1H, s). Stannane 12 was converted to 13
and 14 without further characterization.
5-Meth oxy-7-m eth yl-1,4-n a p h th oqu in on e (20). To
a solution of diene 618,19 (2.37 g, 12.7 mmol) in 100 mL of
CH2Cl2 under an argon atmosphere at room temperature
(37) For general procedures and protocols, see: (a) Kelly, T. R.; Lang,
F. J . Org. Chem. 1996, 61, 4633. (b) Reference 10.

1096 J . Org. Chem., Vol. 63, No. 4, 1998
Bringmann et al.
sufficiently pure for carrying out the next step without
further purification.
s), 7.19-7.31 (15H, m). Anal. Calcd for C32H34BNO4
(HBr salt): C, 65.33; H, 6.00; N, 2.38. Found: C, 64.93;
H, 6.02; N, 2.36.
Crystallization of partially purified 14 from CH2Cl2/
hexanes gave 14 as a white solid, mp 228-230 °C: IR
(CH2Cl2) ν 1759 cm-1; 1H NMR (CDCl3, 400 MHz) δ 2.10
(6H, br s), 2.44 (6H, s), 2.49 (6H, s), 3.89 (6H, s), 6.73
(2H, s), 7.11 (2H, br s), 7.22 (2H, s); 13C NMR (CDCl3,
100 MHz) δ 21.3, 21.7, 23.0, 56.8, 110.0, 113.7, 119.3,
121.3, 122.5, 126.7, 130.4, 138.2, 142.2, 143.7, 156.4,
169.9; HRMS calcd for C32H30O10 574.1839, found
574.1820. Anal. Calcd for C32H30O10: C, 66.89; H, 5.26.
Found: C, 66.54; H, 5.20.
5′,5′′-O-Dia cet yl-N,N-d ib en zyl-6,6′′′,8,8′′′-t et r a -O-
ben zylm ich ella m in e (36). Into a dry Schlenk flask
were placed under argon 60.0 mg (0.11 mmol) of iso-
quinolineboronic acid 35, 37.8 mg (0.050 mmol) of ditri-
flate 26, 6.0 mg (0.003 mmol) of tetrakistriphenylphos-
phinepalladium(0), 29.0 mg (0.16 mmol) of barium
hydroxide, 3 mL of dimethoxyethane, and 1.5 mL of
degassed water. The reaction was heated at 80 °C for 8
h and cooled to room temperature, and volatiles were
removed under vacuum. The residue was subjected to
preparative thin-layer chromatography on deactivated37b
silica gel plates using a 2:1 mixture of petroleum ether/
ethyl acetate as eluent to give 51.0 mg (74%) of 35 in the
2,2′-Bis((1-a cetoxy-8-m eth oxy-6-m eth yl-4-tr iflu o-
r om eth a n esu lfon yl)oxy)n a p h th a len e) (26). To a so-
lution of tetraacetate 14 (2.80 g, 4.90 mmol) in 65 mL of
CH2Cl2 and 65 mL of MeOH was added 1,8-diazabicyclo-
[5.4.0]undec-7-ene (3.50 mL, 23.4 mmol) at room tem-
perature. After 15 min, the solvent was evaporated at
reduced pressure and 50 mL of water was added to the
mixture. The mixture was then extracted with CH2Cl2,
and the organic layer was separated and dried over Na2-
SO4. Evaporation of the solvent gave crude diacetate 25
which was used without purification in the next reaction.
The crude 25 was dissolved in 80 mL of CH2Cl2 at 0 °C,
2,6-lutidine (1.0 mL, 8.5 mmol) was added, and then
trifluoromethanesulfonic anhydride (1.26 mL, 7.50 mmol)
was added dropwise over 3 min. The reaction mixture
was stirred at room temperature for 10 min. The solvent
was evaporated under vacuum, and the resulting oil was
purified by flash column chromatography on silica gel
(CH2Cl2) to give 2.55 g (70% from 14) of 26 as a white
solid. An analytical sample of 26 was obtained by
recrystallization from CH2Cl2/hexane as white flakes, mp
1
form of a light brown solid. Evaluation of the H NMR
spectrum is not worthwhile due to substantial peak
broadening (due to hindered rotation) and overlap: IR
(KBr, HBr salt) ν 3500-3200, 2940, 2900, 1700, 1650,
1570 cm-1. Anal. Calcd for C92H88N2O10 (HBr salt): C,
79.97; H, 6.42; N, 2.03. Found: C, 79.34; H, 6.44; N, 2.16.
Mich ella m in es A (1a ) a n d B (1b). The mixture 36
(50 mg) was dissolved in 2 mL of absolute ethanol and
hydrogenated over 5.0 mg of 10% Pd/C for 14 h at room
temperature and 1 atm of hydrogen. Catalyst was
removed by filtration through a short pad of silica gel,
and the filtrate was heated at reflux for 8 h in MeOH
that had been saturated in the cold with gaseous HCl.
After evaporation of the filtrate, the residue was taken
up in MeOH and chromatographed on LH-20 Sephadex,
eluting with MeOH. The fractions containing mixtures
of 1a and 1b were combined and evaporated. The two
atropoisomers were separated on an HPLC equipped with
a 254 mm detector, using a 2.1 × 25 cm Rainin Dynamax
amine phase column. The crude 1a /1b mixture was
dissolved in 7 mL of 87:13 chloroform/methanol, and 0.25-
mL aliquots were injected and eluted with the same
solvent mixture at a flow rate of 12 mL/min to give a
total of 6.6 mg (21%) of michellamine A (1a ) and 16.5
mg (53%) of michellamine B (1b) which were identical
with authentic samples of naturally derived 1a and 1b.
1
190-191 °C: IR (CH2Cl2) ν 1766, 1421, 1205 cm-1; H
NMR (CDCl3, 400 MHz) δ 2.07 (6H, br s), 2.56 (6H, s),
3.93 (6H, s), 6.83 (2H, s), 7.40 (2H, br s), 7.48 (2H, s); 13
C
NMR (CDCl3, 100 MHz) δ 21.0, 23.1, 56.9, 110.9, 113.4,
119.4 (q, J ) 320 Hz) 119.6, 120.7, 121.9, 125.9, 130.3,
140.5, 142.7, 144.7, 156.3; HRMS calcd for C30H24S2O12F6
754.0613, found 754.0608. Anal. Calcd for C30H24S2O12F6:
C, 47.75; H, 3.21. Found: C, 47.66; H, 3.18.
(1R,3R)-N-Ben zyl-6,7-bis(ben zyloxy)-1,3-d im eth yl-
1,2,3,4-tetr a h yd r oisoqu in olin e-5-bor on ic Acid (35).
A solution of 120 mg (0.22 mmol) of bromoisoquinoline
349,10,35 in 10 mL of dry THF under argon was cooled to
-78 °C. Over the course of 10 min, 0.16 mL (0.24 mmol)
of a 1.5 M solution of n-BuLi in hexanes was added and
the reaction mixture was stirred 50 min, resulting in an
orange solution. Freshly distilled (from sodium) tri-
methyl borate (0.12 mL, 1.11 mmol) was added, and the
reaction mixture was allowed to warm to room temper-
ature overnight. Ten milliliters of water was added, and
the mixture was extracted five times with 10-mL portions
of CH2Cl2. The combined organic extracts were dried
over MgSO4 and evaporated under vacuum. The residue
was chromatographed on deactivated (7.5% NH3)37b silica
gel using 4:1 petroleum ether/ethyl acetate to give, after
recrystallization from ethanol/petroleum ether, 100 mg
(89%) of boronic acid 35 as a colorless solid, mp 106-
1a : [R]23 ) -8.3 (c ) 0.4 in MeOH) (lit.2 -10.5, c )
D
0.83 in MeOH); CD ∆ꢀ209 -98.3, ∆ꢀ242 +24.6, ∆ꢀ258 +17.4;
IR (KBr, diacetate) ν 3550-3100, 2960, 2910, 1690, 1600
cm-1; 1H NMR (d4-MeOH, 500.1 MHz) δ 1.21 (6H, d, J )
6.5 Hz), 1.63 (6H, d, J ) 6.5 Hz), 2.12 (2H, m), 2.34 (6H,
s), 2.81 (2H, m) 3.64 (2H, m), 4.10 (6H, s), 4.74 (2H, q, J
) 6.5 Hz), 6.43 (2H, s), 6.75 (2H, s), 6.85 (2H, s), 7.30
(2H, s); 13C NMR (d4-MeOH, 125.0 MHz) δ 18.4, 19.3,
22.1, 33.1, 45.1, 49.4, 57.0, 102.0, 108.0, 113.1, 115.2,
119.1, 120.4, 124.2, 133.1, 134.7, 136.7, 137.5, 152.2,
155.5, 156.9, 159.1.
1b: [R]23 ) -16.2 (c ) 0.72 in MeOH) (lit.2 -14.8, c )
D
0.74 in MeOH); CD ∆ꢀ209 -53.8, ∆ꢀ214 -53.8; IR (KBr,
HBr salt) ν 3600-3150, 2960, 2910, 1600 cm-1; 1H NMR
(d4-MeOH, 500.1 MHz) δ 1.16 (3H, d, J ) 6.0 Hz), 1.19
(3H, d, J ) 6.5 Hz), 1.59 (3H, d, J ) 6.5 Hz), 1.63 (6H, d,
J ) 6.5 Hz), 2.03 (1H, dd, J ) 18.5, 11.5 Hz), 2.25 (1H,
dd, J ) 18.5, 4.5 Hz), 2.33 (3H, s), 2.36 (3H, s), 2.42 (1H,
dd, J ) 18.5, 11.3 Hz), 2.69 (1H, dd, J ) 18.5, 4.0 Hz),
3.48-3.55 (2H, m), 4.09 (3H, s), 4.10 (3H, s), 4.62 (1H, q,
J ) 6.0 Hz), 4.66 (1H, q, J ) 6.0 Hz), 6.41 (2H, s), 6.75
108 °C: [R]23 ) +49.3 (c ) 1.5 in MeOH); IR (KBr) ν
D
3600-3100, 3010, 2920, 2910, 2840 cm-1 1H NMR
;
(CDCl3, 200.1 MHz) δ 1.30 (3H, d, J ) 6.6 Hz), 1.35 (3H,
d, J ) 6.7 Hz), 2.79 (1H, dd, J ) 18.0, 11.3 Hz), 3.13 (1H,
dd, J ) 18.0, 4.6 Hz), 3.33 (1H, d, J ) 14.1 Hz), 3.45-
3.56 (1H, m), 3.85 (1H, d, J ) 14.1 Hz), 4.08 (1H, q, J )
6.7 Hz), 5.02 (2H, s), 5.04 (2H, s), 5.92 (2H, s), 6.42 (1H,
(1H, s), 6.84-6.85 (3H, m), 7.26 (1H, s), 7.30 (1H, s); 13
C
NMR (d4-MeOH, 125.0 MHz, diacetate) δ 13.1, 19.1, 20.1,
20.2, 22.1, 22.2, 30.7, 30.7, 33.9, 34.9, 44.5, 44.6, 56.9,

Convergent Total Synthesis of the Michellamines
J . Org. Chem., Vol. 63, No. 4, 1998 1097
57.0, 101.8, 101.9, 108.3, 114.8, 115.1, 115.2, 118.9, 119.0,
119.2, 119.3, 120.3, 120.4, 124.4, 124.5, 134.6, 134.7,
135.1, 135.2, 136.6, 136.7, 137.4, 137.5, 152.1, 152.2,
155.5, 155.6, 156.3, 156.4, 158.0, 158.1, 180.2, 180.2.
ander von Humboldt Foundation, respectively, for post-
doctoral fellowships.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails concerning model studies and other compounds (19, 27a ,
27b, 28, 29b, 30a , 30b, 31a , and 31b) not directly related to
the final synthetic sequence (6 pages). This material is
contained in libraries on microfiche, immediately follows this
article in the microfilm version of the journal, and can be
ordered from the ACS; see any current masthead page for
ordering information.
Ack n ow led gm en t. This work was supported by the
National Institutes of Health (Grant CA65093 to T.R.K.),
the Deutsche Forschungsgemeinschaft (SFB 251 “O¨ kol-
ogie, Physiologie und Biochemie pflanzlicher und
tierischer Leistung unter Stress”), and the Fonds der
Chemischen Industrie (financial support and fellowship
to R.G.). A.G. and P.A.K. thank NATO and the Alex-
J O971495M