Stereoselective synthesis of atropisomeric korupensamines A and B utilizing planar chiral arene chromium complex

Article abstract of DOI:10.1021/jo049600x

Naphthyl tetrahydroisoquinoline alkaloids, atropisomeric korupensamines A and B and entkorupensamine B, were synthesized by syn-selective cross-coupling of a planar chiral arene chromium complex with naphthylboronic acid and subsequent axial isomerization or tricarbonylchromium migration to the inverted arene face as a key step. Palladium(0)-catalyzed cross-coupling of planar chiral arene chromium complex 12 with naphthylboronic acid 9 gave syn-biaryl coupling product 13. syn-Biaryl chromium complex 13 was heated in 1:1 mixture of di-n-butyl ether and 1,2-dichloroethane to give a face-inverted anti-biaryl chromium complex 14 without axial isomerization. Korupensamine A was synthesized from the syn-biaryl chromium complex 13 via o-formyl syn-biaryl chromium complex 10, and ent-korupensamine B was prepared from the face-inverted anti-biaryl chromium complex 14. On the other hand, difluoro-substituted syn-biaryl chromium complex 40 with a formyl group afforded anti-biaryl chromium complex 41 containing a rotated central bond by heating in xylene. The chromium-complexed fluorine atom was easily substituted with an isopropoxy group by nucleophilic substitution. Use of these reactions allowed (+)-2-bromo-3,5-difluorobenzaldehyde chromium complex (37) as a single chiral source to be converted to atropisomeric korupensamines A and B, respectively.

Full text of DOI:10.1021/jo049600x

Ster eoselective Syn th esis of Atr op isom er ic Kor u p en sa m in es A a n d
B Utilizin g P la n a r Ch ir a l Ar en e Ch r om iu m Com p lex
Takashi Watanabe,† Yoshie Tanaka,† Ryohei Shoda,† Ryota Sakamoto,† Ken Kamikawa,†,‡ and
Motokazu Uemura*,†,‡
Department of Chemistry, Faculty of Integrated Arts and Science, Osaka Prefecture University,
Sakai, Osaka 599-8531, J apan, and Research Institute for Advanced Science and Technology,
Osaka Prefecture University, Sakai, Osaka 599-8570, J apan
uemura@ms.cias.osakafu-u.ac.jp
Received March 11, 2004
Naphthyl tetrahydroisoquinoline alkaloids, atropisomeric korupensamines A and B and ent-
korupensamine B, were synthesized by syn-selective cross-coupling of a planar chiral arene
chromium complex with naphthylboronic acid and subsequent axial isomerization or tricarbonyl-
chromium migration to the inverted arene face as a key step. Palladium(0)-catalyzed cross-coupling
of planar chiral arene chromium complex 12 with naphthylboronic acid 9 gave syn-biaryl coupling
product 13. syn-Biaryl chromium complex 13 was heated in 1:1 mixture of di-n-butyl ether and
1,2-dichloroethane to give a face-inverted anti-biaryl chromium complex 14 without axial isomer-
ization. Korupensamine A was synthesized from the syn-biaryl chromium complex 13 via o-formyl
syn-biaryl chromium complex 10, and ent-korupensamine B was prepared from the face-inverted
anti-biaryl chromium complex 14. On the other hand, difluoro-substituted syn-biaryl chromium
complex 40 with a formyl group afforded anti-biaryl chromium complex 41 containing a rotated
central bond by heating in xylene. The chromium-complexed fluorine atom was easily substituted
with an isopropoxy group by nucleophilic substitution. Use of these reactions allowed (+)-2-bromo-
3,5-difluorobenzaldehyde chromium complex (37) as a single chiral source to be converted to
atropisomeric korupensamines A and B, respectively.
In tr od u ction
tramolecular coupling of a tethered nonracemic chiral
compound is also elaborated.5 Atrop-enantioselective
biaryl synthesis as a unique method has been achieved
by stereocontrolled torsion of flat achiral lactone precur-
sors by means of optically active nucleophiles.6 Other
interesting methods, including catalytic asymmetric cou-
pling,7 have been reported for optically active axially
chiral biaryls.
Axially chiral biaryls are of importance not only as
chiral ligands or auxiliaries in asymmetric reaction but
also for biologically active natural products. There is
considerable current interest in the development of
efficient methodologies for the synthesis of axial biaryls
in an enantiomerically pure form.1 Nucleophilic displace-
ment of an ortho-methoxy group of chiral aryl oxazolines
by aryl Grignard reagents has been widely employed in
asymmetric biaryl syntheses.2 Copper-mediated Ullmann
homocoupling reaction has been reported for biaryl
coupling of the chiral ortho-bromo phenyloxazolines.3
Nucleophilic aromatic substitution to the arene ring
activated with other functional groups, e.g., ester and
imine, has been also achieved for the preparation of chiral
biaryl compounds.4 Cyanocuprate-mediated biaryl in-
(η6-Polysubstituted arene)chromium complexes exist in
two enantiomeric forms based on planar chirality when
the arene ring is substituted at the ortho or meta position
(3) For intermolecular Ullmann homocoupling, see: (a) Nelson, T.
D.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 3061. Nelson, T. D.;
Meyers, A. I. J . Org. Chem. 1994, 59, 2577 and 2655. (b) Nelson, T.
D.; Meyers, A. I. Tetrahedron Lett. 1994, 35, 3259. (c) Degnan, A. P.;
Meyers, A. I. J . Am. Chem. Soc. 1999, 121, 2762. For intramolecular
Ullmann cross-coupling, see: (a) Miyano, S.; Fukusima H.; Hanada,
S.; Ito, H.; Hashimoto, H. Bull. Chem. Soc. J pn. 1988, 61, 3249. (b)
Miyano, S.; Hanada, S.; Ito, H.; Hashimoto, H. Bull. Chem. Soc. J pn.
1984, 57, 1943. (c) Miyano, S.; Tobita, M.; Hashimoto, H. Bull. Chem.
Soc. J pn. 1981, 54, 3522. (d) Spring, D. R.; Krishnan, S.; Blackwell,
H. E.; Schreiber, S. L. J . Am. Chem. Soc. 2002, 124, 1354. (e) Lin,
G.-Q.; Zhong, M. Tetrahedron: Asymmetry 1997, 8, 1369.
(4) (a) Hattori, T.; Hotta, H.; Suzuki, T.; Miyano, S. J . Bull. Chem.
Soc. J pn. 1993, 66, 613. (b) Baker, R. W.; Pocock, G. R.; Sargent, M.
V.; Twiss, E. Tetrahedron: Asymmetry 1993, 4, 2423. (c) Shindo, M.;
Koga, K.; Tomioka, K. J . Am. Chem. Soc. 1992, 114, 8732. (d) Hattori,
T.; Hayashizaka, N.; Miyano, S. Synlett 1995, 41. (e) Hattori, T.;
Takeda, A.; Yamabe, O.; Miyano, S. Tetrahedron 2002, 58, 233.
(5) Lipshutz, B. H.; Liu, Z.-P.; Kayser, F. Tetrahedron Lett. 1994,
35, 5567.
† Faculty of Integrated Arts and Science.
‡ Research Institute for Advanced Science and Technology.
(1) For some representative reviews: (a) Bringmann, G.; Walter,
R.; Weirich, R. Angew. Chem., Int. Ed. Engl. 1990, 29, 977. (b)
Lutomski, K. A.; Meyers, A. I. Asymmetric Synthesis via Chiral
Oxazolines. In Asymmetric Synthesis; Morrison, J . D., Ed.; Academic
Press, Inc.: New York, 1984; Vol. 3, p 213. (c) Gant, T. G. Meyers, A.
I. Tetrahedron 1994, 50, 2297. (d) Bringmann, G.; Menche, D. Acc.
Chem. Res. 2001, 34, 615. (e) Lloyd-Williams, P.; Giralt, E. Chem. Soc.
Rev. 2001, 30, 145.
(2) (a) Meyers, A. I.; Lutomsky, K. A. J . Am. Chem. Soc. 1982, 104,
879. (b) Moorlang, H.; Meyers, A. I. Tetrahedron Lett. 1993, 34, 6989.
(c) Warshawsky, A. M.; Meyers, A. I. J . Am. Chem. Soc. 1990, 112,
8090. (d) Neuville, L.; Bois-Choussy, M.; Zhu, J . Tetrahedron Lett. 2000,
41, 1741.
(6) (a) Brigmann, G.; Hartung, T. Synthesis 1992, 433. (b) Bring-
mann, G.; Reuscher, H. Angew. Chem., Int. Ed. Engl. 1989, 28, 1672.
10.1021/jo049600x CCC: $27.50 © 2004 American Chemical Society
Published on Web 05/18/2004
4152
J . Org. Chem. 2004, 69, 4152-4158

Synthesis of Atropisomeric Korupensamines A and B
with different substituents. This fact, in concert with
ability of the tricarbonylchromium function to effectively
block one face of the arene ring, has allowed the use of
(arene)chromium complexes as synthetic intermediates,
chiral auxiliaries, and ligands for the asymmetric reac-
tions.8,9 As part of our asymmetric exploration of the
planar chiral arene chromium complexes, we have de-
veloped diastereoselective synthesis of axially chiral
biaryls in enantiomerically pure form.10 In this paper,
we report full details of total syntheses of korupen-
samines A and B and ent-korupensamine B using ste-
reoselective palladium(0)-catalyzed cross-coupling of pla-
nar chiral arylhalide chromium complexes with arylboronic
acid and subsequent axial isomerization or stereoselective
migration of the tricarbonylchromium fragment to an
inverted arene face.
F IGURE 1. Axially chiral naphthyltetrahydroisoquinoline
alkaloids.
Lipshutz et al. reported15 that palladium(0)-catalyzed
atropselective cross-coupling was achieved using a prop-
erly positioned internal phosphine group in the tetrahy-
droisoquinoline part as a coordinating ligand to afford a
single biaryl atropisomer for korupensamine A. The other
method for induction of the axial chirality other than
central bond formation developed by Bringmann et al.
is an attractive procedure for stereoselective synthesis
of korupensamines A and B from a common precursor
by a divergent lactone cleavage method with a chiral
reducing agent.16 As a further extension for the stereo-
selective axial bond formation utilizing the planar chiral
(arene)chromium complex, we investigated total synthe-
Resu lts a n d Discu ssion
Syn th esis of Kor u p en sa m in e A a n d en t-Kor u p en -
sa m in e B fr om a Com m on Ar en e Ch r om iu m Com -
p lex. Michellamine B, dimerization product of atropdi-
astereomeric korupensamines A and B, was found to be
fully protective against both HIV-1- and HIV-2-infected
CEMSS cells and identified by NCI for preclinical devel-
opment.11 These alkaloids have been isolated from the
tropical liana Ancistrocladus korupensis in Cameroon and
have a naphthyltetrahydroisoquinoline skeleton with
axial chirality between the naphthalene and tetrahy-
droisoquinoline rings (Figure 1).12 These alkaloids have
been previously synthesized via construction of the axial
bond between the naphthalene and tetrahydroisoquino-
line rings as a key step. However, palladium(0)-catalyzed
cross-coupling13 of two arene rings or nucleophilic addi-
tion14 of aryl Grignards to the chiral o-methoxyaryl
oxazoline compounds for the formation of the central
bond of the naphthalene and tetrahydroisoquinoline rings
usually gave various ratios of an atropisomeric mixture.
(11) (a) Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H., II; McMahon,
J . B.; Pannell, L. L.; Cragg, G. M.; Boyd, M. R. J . Med. Chem. 1991,
34, 3402. (b) Boyd, M. R.; Hallock, Y. F.; Cardellina, J . H., II; Manfredi,
K. P.; Blunt, J . W.; McMahon, J . B.; Buckheit, R. W., J r.; Bringmann,
G.; Scha¨ffer, M.; Cragg, G. M.; Thomas, D. W.; J ato, J . G. J . Med. Chem.
1994, 37, 1740. (c) McMahon, J . B.; Currens, M. J .; Gulacowski, R. J .;
Buckheit, R. W., J r.; Lackman-Smith, C.; Hallock, Y. F.; Boyd, M. R.
Antimicrob. Agents Chemother. 1995, 39, 484. Korupensamines have
antimalarial activity: (d) 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. (e) Manfredi, K. P.; Blunt, J . W.; Cardellina, J . H., II; McMahon,
J . B.; Pannell, L. L.; Cragg, G. M.; Boyd, M. R. J . Med. Chem. 1991,
34, 3402. (f) Hallock, Y. F.; Manfredi, K. P.; Dai, J . R.; Cardellina, J .
H., II; Gulakowski, R. J .; McMhon, J . B.; Scha¨ffer, M.; Stahl, M.;
Gulden, K. P.; Bringmann, G.; Franc¸ois, G.; Boyd, M. R. J . Nat. Prod.
1997, 60, 677. (g) Bringmann, G.; Pokorny, F. In The Alkaloids; Cordell,
G. A., Ed.; Academic Press: New York, 1995; Vol. 46, p 127.
(12) (a) 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. (b)
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.
(13) (a) Bringmann, G.; Go¨tz, R.; Harmsen, S.; Holenz, J .; Walter,
R. Liebig Ann. 1996, 2045. (b) 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. (c) Hoye, T. R.; Chen, M.; Hoang, B.;
Mi, L.; Priest, O. J . Org. Chem. 1999, 64, 7184. (d) Hoye, T. R.; Chen,
M. J . Org. Chem. 1996, 61, 7940. (e) Hobbs, P. D.; Upender, V.;
Dawson, M. I. Synlett 1997, 965. (f) Hobbs, P. D.; Upender, V.; Dawson,
M. I. Synlett 1997, 965. (g) Hoye, T. R.; Chen, M. Tetrahedron Lett.
1996, 37, 3099. (h) de Koning, C. B.; Michael, J . P.; van Otterlo, W. A.
L. Tetrahedron Lett. 1999, 40, 3037. (i) Rao, A. V.; Gurjar, M. K.;
Ramana, D. V.; Chheda, A. K. Heterocycles 1996, 43, 1. (j) Kelly, T. R.;
Garcia, 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. (k) Bringmann, G.; Hamm, A.; Schraut, M. Org. Lett. 2003,
5, 2805.
(7) (a) Hayashi, T.; Hayashizaki, K.; Kiyoi, T.; Ito, Y. J . Am. Chem.
Soc. 1988, 110, 8153. (b) Hayashi, T.; Niizuma, S.; Kamikawa, T.;
Suzuki, N.; Uozumi, Y. J . Am. Chem. Soc. 1995, 117, 9101. (c) Hayashi,
T. J . Organomet. Chem. 2002, 653, 41. (d) Spring, D. R.; Krishman,
S.; Blackwell, H. E.; Schreiber, S. L. J . Am. Chem. Soc. 2002, 124,
1354. (e) Yin, J .; Buchwald, S. L. J . Am. Chem. Soc. 2000, 122, 12051.
(f) Castanet, A.-S.: Colobert, F.; Broutin, P.-E.; Obringer, M. Tetra-
hedron: Asymmetry 2002, 13, 659. (g) Cammidge, A. N.; Cre´py, K. V.
L. Chem. Commun. 2000, 1723. (h) Herrbach, A.; Marinetti, A.;
Baudoin, O.; Gue´nard, D.; Gue´ritte, F. J . Org. Chem. 2003, 68, 4897.
(8) For some representative reviews: (a) Solladie´-Cavallo, A. In
Advances in Metal-Organic Chemistry; Liebeskind, L. S., Ed.; J AI
Press: Greenwich, CT, 1989; Vol. 1, p 99. (b) Davies, S. G.; Coote, S.
J .; Goodfellow, C. L. In Advances in Metal-Organic Chemistry; Liebe-
skind, L. S., Ed.; J AI Press: Greenwich, CT, 1991; Vol. 2, p 1. (c)
Uemura, M. In Advances in Metal-Organic Chemistry; Liebeskind, L.
S., Ed.; J AI Press: Greenwich, CT, 1991; Vol. 2, p 195. (d) Semmelhack,
M. F. In Comprehensive Organometallic Chemistry II; Abel, E. D.,
Stone, F. G. A., Wilkinson, Eds.; Pergamon Press: Oxford, 1995; Vol.
12, p 979. (e) Davies, S. G.; McCarthy, T. D. In Comprehensive
Organometallic Chemistry II; Abel, E. D., Stone, F. G. A., Wilkinson,
Eds.; Pergamon Press: Oxford, 1995; Vol. 12, p 1039.
(9) Some representative references: (a) Bolm, C.; Muniz, K. Chem.
Soc. Rev. 1999, 28, 51. (b) Uemura, M.; Miyake, R.; Nakayama, K.;
Shiro, M.; Hayashi, Y. J . Org. Chem. 1993, 58, 1238. (c) J ones, G. B.;
Huber, R. S.; Chapman, B. J . Tetrahedron: Asymmetry 1997, 8, 1797.
(d) Son, S. U.; J ang, H.-Y.; Lee, I. S.; Chung, Y. K. Organometallics
1998, 17, 3236.
(10) (a) Uemura, M.; Kamikawa, K. J . Chem. Soc., Chem. Commun.
1994, 2697. (b) Kamikawa, K.; Watanabe, T.; Uemura, M. J . Org.
Chem. 1996, 61, 1375. (c) Kamikawa, K.; Uemura, M. Synlett 2000,
938. (d) Kamikawa, K.; Watanabe, T.; Daimon, A.; Uemura, M.
Tetrahedron 2000, 56, 2325.
(14) (a) Chau, P.; Czuba, I. R.; Rizzacasa, M. A. J . Org. Chem. 1996,
61, 7101. (b) Rizzacasa, M. A.; Sargent, M. V. J . Chem. Soc., Perkin
Trans. 1 1991, 845. (c) Leighton, B. N.; Rizzacasa, M. A. J . Org. Chem.
1995, 60, 5702.
(15) Lipshutz, B. H.; Keith, J . M. Angew. Chem. 1999, 111, 3743.
Lipshutz, B. H.; Keith, J . M. Angew. Chem., Int. Ed. 1999, 38, 3530.
J . Org. Chem, Vol. 69, No. 12, 2004 4153

Watanabe et al.
TABLE 1. Dia ster eoselective Lith ia tion of Meth yl
r-Glu cop yr a n osid e Ch r om iu m Com p lex 5a
SCHEME 1. Retr osyn th esis of Kor u p en sa m in es A
a n d B fr om Id en tica l P la n a r Ch ir a l Ar en e
Ch r om iu m Com p lex.
solvent
yield 6 (%)b
% ee 6
1
2
THF
ether
38 (76)c
57 (98)
78
94
a
Conditions for reaction depicted: (a) n-BuLi, solvent, 78 ˚C;
(b) BrCF2CF2Br; (c) 50% aq H2SO4/acetone (1:1), reflux, 30 min.
b
Yield in parentheses is for the bromination product before the
hydrolysis step. c p-Bromination product was obtained in 15%
yield.
TABLE 2. Dia ster eoselective Lith ia tion of Ch r om iu m
Com p lex 7a
sis of both atropisomeric korupensamines A and B
starting from an identical planar chiral arene chromium
complex. Our synthetic plan of atropisomeric korupen-
samines A and B is illustrated in Scheme 1. Planar chiral
3,5-dialkoxy-2-bromobenzaldehyde chromium complex 2
would produce syn-biaryl chromium complex 3 by pal-
ladium(0)-catalyzed cross-coupling with naphthylboronic
acid under kinetic conditions. The obtained syn coupling
product 3 would be isomerized to the corresponding
thermodynamically stable anti isomer 4 with central
bond rotation under thermal conditions.10,17 The syn- and
anti-biaryl chromium complexes, 3 and 4, would be
converted to korupensamines A and B, respectively, by
stereoselective conversion of the formyl group to a tet-
rahydroisoquinoline skeleton.
Initially, an optically pure tricarbonyl(2-bromo-3,5-
diisopropoxybenzaldehyde)chromium complex as a cou-
pling partner was synthesized by diastereoselective ortho
lithiation (Tables 1, 2).18 According to reported proce-
dure,19 a tricarbonylchromium complex of chiral 3,5-
diisopropoxybenzaldehyde acetal 5 was prepared from
methyl R-D-glucopyranoside and 3,5-diisopropoxybenzal-
dehyde dimethylacetal in good yield. Directed lithiation
of the complex 5 with n-BuLi in THF followed by
quenching with 1,2-dibromo-1,1,2,2-tetrafluoroethane gave
an ortho-brominated chromium complex in 76% yield
along with 15% yield of a para bromination product
solvent
yield 8 (%)b
% ee 8
1
2
THF
ether
58 (90)
64 (92)
94
96
Conditions for reaction depicted: (a) n-BuLi, solvent, 78 °C;
(b) BrCF2CF2Br; (c) TiCl4, ether, 78 C. Yield in parentheses is
for the bromination product before the hydrolysis step.
a
°
b
(Table 1). Hydrolysis of the bromination product was
carried out with 50% aqueous sulfuric acid in refluxing
acetone, and the yield of hydrolysis was 45-50% yield
along with de-chromium tricarbonyl compound. The
optical purity of (-)-(1R,2S)-tricarbonyl(2-bromo-3,5-di-
isopropoxybenzaldehyde)chromium complex (6) was found
to be 78% ee by HPLC with Chiralcel OJ -H. Thus, the
directed lithiation of 5 occurred at the Hb-position via
chelation of the lithium metal with the nearby methoxy
oxygen of the sugar moiety followed by regioselective
removal of one of the diastereotopic ortho-hydrogens. Use
of diethyl ether instead of THF as a solvent in the
lithiation reaction increased both the diastereoselectivity
and the yield of the bromination product. Thus, lithiation
of 5 in ether followed by bromination and acidic hydroly-
sis gave the bromination product 6 in 57% overall yield
with 94% ee without formation of the bromination
product at the 4-position. The low diastereoselectivity of
ortho lithiation of 5 in THF would be attributed to the
competitive coordinative ability of THF oxygen with the
lithium atom. We next investigated the diastereoselec-
tivity in the directed lithiation of chiral benzaldehyde
acetal chromium complex 7 derived from (S)-1,2,4-bu-
tanetriol as the chiral auxiliary (Table 2). Directed
lithiation of 7 with n-BuLi at -78 °C followed by
quenching with 1,2-dibromo-1,1,2,2-tetrafluoroethane was
carried out under the same conditions. Hydrolysis of the
bromination product was achieved by treatment with 1
equiv of titanium tetrachloride in ether at -78 °C, since
(16) (a) Bringmann, G.; Ochse, M. Synlett 1998, 1294. (b) Bring-
mann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525. (c) Bringmann,
G.; Ochse, M.; Go¨tz, R. J . Org. Chem. 2000, 65, 2069. (d) Bringmann,
G.; Breuning, M.; Pfeifer, R.-M.; Schenk, W. A.; Kamikawa, K.;
Uemura, M. J . Organomet. Chem. 2002, 661, 31. (e) Bringmann, G.;
Menche, D.; Kraus, J .; Mu¨hlbacher, J .; Peters, K.; Peters, E.-M.; Brun,
R.; Bezabih, M.; Abegaz, B. M. J . Org. Chem. 2002, 67, 5595.
(17) Kamikawa, K.; Watanabe, T.; Uemura, M. Synlett 1995, 1040.
(18) Watanabe, T.; Shakadou, M.; Uemura, M. Inorg. Chim. Acta.
1999, 296, 80.
(19) Han, J . W.; Son, S. U.; Chung, Y. K. J . Org. Chem. 1997, 62,
8264. Other diastereoselective ortho lithiation of benzaldehyde acetal
chromium complexes: (a) Aube´, J .; Heppert, J . A.; Milligan, M. L.;
Smith, M. J .; Zenk, P. J . Org. Chem. 1992, 57, 3563. (b) Uemura, M.;
Daimon, A.; Hayashi, Y. J . Chem. Soc., Chem. Commun. 1995, 1943.
(c) Green, J . R.; Kondo, Y.; Ho, J . J . Org. Chem. 1993, 58, 6182. (d)
Kondo, Y.; Green, J . R.; Ho, J . J . Org. Chem. 1991, 56, 7199.
4154 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Atropisomeric Korupensamines A and B
SCHEME 2 a
product. The low yield in the palladium(0)-catalyzed
cross-coupling and unsatisfactory axial isomerization
under thermal conditions might be attributed to the
thermal lability of the chromium-complexed naphthyl
benzaldehyde 10. Therefore, the formyl group of 8 was
reduced to a hydroxymethyl group. The planar chiral
benzyl alcohol chromium complex 12 was coupled with
naphthylboronic acid 9 under the same conditions to give
22
syn coupling product 13 (([R]D -105° (c 0.50, CHCl3))
in 88% yield. Oxidation of 13 with TFAA/DMSO afforded
the syn-formyl complex 10 in 80% yield. The peri protons
(H8) of the naphthalene ring of the tricarbonylchromium-
complexed syn-biaryls, 10 and 13, appeared at 8.29 and
8.65 ppm, respectively. The low field shift was attributed
to an anisotropic effect of the tricarbonylchromium frag-
ment.22 The syn coupling product 13 was next heated in
xylene for central bond rotation. However, (xylene)Cr-
(CO)3 was only obtained without formation of the corre-
sponding anti isomer. Therefore, a nonaromatic solvent
was next employed for thermal isomerization. Heating
of the syn-biaryl chromium complex 13 in 1:1 mixture of
di-n-butyl ether and 1,2-dichloroethane at 120 °C for 30
min gave thermally isomerized chromium-complexed
biaryl 14 ([R]D22 -89.2° (c 0.50, CHCl3)) in 80% yield. The
stereochemistry of the thermal isomerized product 14
was easily presumed to be an anti isomer from the chem-
ical shift (H8; 6.68 ppm) of the corresponding peri proton
of the naphthalene ring. However, the thermally isomer-
ized anti-chromium complex 14 was found not to be the
axially isomerized anti-biaryl chromium complex. Optical
rotation of a de-tricarbonylchromium compound derived
from the syn-coupling product 13 was consistent with
that of a photooxidative demetalation product from the
thermally isomerized anti-biaryl chromium complex 14.23
This result obviously indicates that thermal isomeriza-
tion of 13 afforded stereoselective migration of the tricar-
bonylchromoium fragment to the reversed arene face
giving anti-biaryl complex 14 without formation of the
expected anti-biaryl complex with central bond rotation.24
This stereoselective Cr(CO)3 migration to the inverted
arene face is an interesting reaction and would be useful
for further asymmetric reactions utilizing the planar
chirality. The face-inverted anti-chromium complex 14
was also oxidized to the anti-formyl chromium complex
a
Reagents and conditions: (a) 9, 5 mol % Pd(PPh3)4, 1 M aq
Na2CO3/MeOH (1/10), 75 °C, 10-30 min (38% for 10, 88% for 13);
(b) NaBH4, MeOH/CH2Cl2 (2/1), 0 °C, 30 min (99%); (c) n-Bu2O/
ClCH2CH2Cl (1/1), 120 °C, 30 min (80%); (d) (CF3CO)2O, DMSO,
CH2Cl2, -78 °C, then Et3N (80% for 10, 93% for 15).
the hydrolysis with aqueous sulfuric acid resulted in poor
yield. The obtained benzaldehyde chromium complex 8
was an antipode (+)-isomer. In this case, directed lithia-
tion took place at the Ha-position of 7. In this way, both
enantiomers of a planar chiral bromobenzaldehyde chro-
mium complex were obtained by diastereoselective lithia-
tion of 3,5-diisopropoxybenzaldehyde chiral acetal chro-
mium complexes 5 and 7. Of both enantiomers, (+)-3,5-
diisopropoxybenzaldehyde chromium complex 8 was
employed as a coupling partner for synthesis of koru-
pensamines, since the overall chemical yield and the
diastereoselectivity of ortho lithiation were superior to
those of 6.
29
15 ([R]D -341° (c 0.26, CHCl3)). In this way, the key
Palladium(0)-catalyzed cross-coupling of planar chiral
(+)-2-bromo-3,5-diisopoxybenzaldehyde chromium com-
plex (8) with 4-benzyloxy-5-methoxy-7-methylnaphthyl-
boronic acid (9)20 in the presence of sodium carbonate
under heating at 75 °C in aqueous MeOH for 10 min gave
intermediates 10 and 15 for synthesis of korupensamine
A and ent-korupensamine B were stereoselectively pre-
pared from identical planar chiral arene chromium
complex 8 in enantiomerically pure form in good yields.
We next designed stereoselective addition of an acyl
anion equivalent to the formyl group of the axial biaryl
chromium complex 10 for construction of the dimethyl
tetrahydroisoquinoline skeleton of korupensamine A
(Scheme 3). Reaction of the syn-biaryl chromium complex
28
a kinetically controlled syn coupling product 10 ([R]D
+108° (c 0.25, CHCl3)) in 38% yield without formation of
the corresponding anti isomer (Scheme 2).21 The axial
stereochemistry of the syn cross-coupling product 10 is
identical with that of korupensamine A. Toward the
synthesis of atropisomeric korupensamine B, the axial
isomerization of the syn coupling product 10 to anti-biaryl
chromium complex 11 was next examined under thermal
conditions. Unfortunately, refluxing of 10 in xylene gave
a de-tricarbonylchromium biaryl compound as the major
(22) (a) Uemura, M.; Nishimura, H.; Kamikawa, K.; Shiro, M. Inorg.
Chim. Acta 1994, 222, 63. (b) Bringmann, G.; Go¨bel, L.; Peters, K.;
Peters, E.-M.; Schnering, H. G. Inorg. Chim. Acta 1994, 222, 255.
20
(23) Optical rotation ([R]D +49 (c 1.0, CHCl3)) of de-tricarbonyl-
chromium compound derived from thermally isomerized anti-biaryl
chromium complex 14 by air oxidation was completely identical with
that of de-tricarbonylchromium compound of the syn-biaryl complex
13.
(20) Naphthylboronic acid 9 was prepared by a modified procedure
of the following reference: Hoye, T. R.; Mi, L. J . Org. Chem. 1997, 62,
8586.
(24) (a) Kamikawa, K.; Sakamoto, T.;Uemura, M. Synlett 2003, 516.
(b) Tanaka, Y.; Sakamoto, T.; Kamikawa, K.; Uemura, M. Synlett 2003,
519. (c) Kamikawa, K.; Sakamoto, T.; Tanaka, Y.; Uemura, M. J . Org.
Chem. 2003, 68, 9356.
(21) Watanabe, T.; Shakadou, M.; Uemura, M. Synlett 2000, 1141.
J . Org. Chem, Vol. 69, No. 12, 2004 4155

Watanabe et al.
chemistry according to Barton’s procedure,28 followed by
desilylation provided monoalcohol 21. Conversion of the
(S)-hydroxyl group of 21 to azide with stereochemical
inversion was achieved under Mitsunobu conditions.29
Thus, treatment with (PhO)2PON3 in the presence of
DEAD and PPh3 gave (R)-azido compound 22, which was
converted into amide 24 by reduction and subsequent
acetylation. Cyclization of 24 followed by reduction with
LiAlH4 in the presence of trimethylaluminum30 afforded
predominantly trans-dimethyl naphthyltetrahydroiso-
quinoline 26 along with the corresponding cis isomer in
a ratio of 76:24 and then 27 after protection of NH with
benzyl bromide. Deprotection of the isopropoxy and
O-benzyloxy groups of 27 with BCl3 gave N-benzyl
korupensamine A (28) in 35% yield along with a mixture
of regioisomeric monoisopropyl ethers of N-benzyl koru-
pensamine A (in 33% yield). Compound 28 was com-
pletely consistent with reported N-benzylkorupensamine
A12a in the spectral data, including optical rotation, and
converted to korupensamine A by treatment with Pd/C
under a hydrogen atmosphere. Moreover, a regioisomeric
mixture of the monoisopropyl ether of N-benzyl koru-
pensamine A was treated with isopropyl bromide in the
presence of CsCO3 to give the triisopropyl ether of
N-benzyl korupensamine A. The obtained triisopropyl
ether of N-benzyl korupensamine A was finally converted
to korupensamine A using a reported procedure, and all
spectral data of the synthetic product were consistent
with those of natural korupensamine A.12a
SCHEME 3 a
Similarly, the thermally isomerized anti-biaryl chro-
mium complex 15 was converted to ent-korupensamine
B by the same reaction sequence (Scheme 4). Synthetic
korupensamine B was found to be ent-korupensamine B.
Thus, optical rotation of the synthetic korupensamine B
was -63° (c 0.09, MeOH), while natural korupensamine
B shows a plus value of optical rotation.31 In this way,
korupensamine A and ent-korupensamine B were syn-
thesized via a stereoselective Pd(0)-mediated cross-
a
Reagents and conditions: (a) CH2dC(OEt)Li, THF, -78 °C;
(b) 10% aq HCl/THF (1/5), 25 °C, in air (79% from 10); (c) Zn(BH4)2,
THF, ether, -78 °C (99%); (d) ButMe2SiOTf, Et3N (95%); (e) NaH,
CS2, MeI, THF (90%); (f) nBu3SnH, AIBN, toluene, 100 °C, 15 min
(94%); (g) nBu4NF (87%); (h) (PhO)2PON3, DEAD, PPh3, THF, 0
°C (94%); (i) SnCl2‚2H2O, MeOH; (j) Ac2O, pyr (86% from 22); (k)
POCl3, MeCN, reflux (97%); (l) LiAlH4, Me3Al, THF, -78 to 0 °C;
(m) BnBr, K2CO3, acetone, (64% from 25); (n) BCl3, CH2Cl2 (35%);
(o) 10% Pd/C, H2, MeOH (90%).
(26) Some representative references: (a) Pache, S.; Romanens, P.;
Ku¨ndig, E. P. Organometallics 2003, 22, 377. (b) Wang, Q.; Foerster-
ling, F. H.; Hossain, M. M. Organometallics 2002, 21, 2596. (c) Tanaka,
Y.; Taniguchi, N.; Uemura, M. J . Org. Chem. 2002, 67, 9227. (d) Gibson,
S. E.; Ibrahim, H. Chem. Comm. 2002, 21, 2465. (e) Rose-Munch, F.;
Rose, E. Eur. J . Inorg. Chem. 2002, 1269. (f) Tanaka, Y.; Taniguchi,
N.; Uemura, M. Org. Lett. 2002, 4, 835. (g) Netz, A.; Polborn, K.;
Mu¨eller, T. J . J . Am. Chem. Soc. 2001, 123, 3441. (h) Baldoli, C.; Del
Buttero, P.; Perdicchia, D.; Pilati, T. Tetrahedron 1999, 55, 14089. (i)
Rose-Munch, F.; Rose, E. Curr. Org. Chem. 1999, 3, 445. (j) Han, J .
W.; Son, S. U.; Chung, Y. K. J . Org. Chem. 1997, 62, 8264. (k) Fretzen,
A.; Ku¨ndig, E. P. Helv. Chim. Acta 1997, 80, 2023. (l) Alexakis, A.;
Kanger, T.; Mangeney, P.; Rose-Munch, F.; Perrotey, A.; Rose, E.
Tetrahedron: Asymmetry 1995, 6, 2135. (m) Baldoli, C.; Del Buttero,
P. J . Chem. Soc., Chem. Comm. 1991, 982. (n) Baldoli, C.; Del Buttero,
P.; Licandro, E.; Maiorana, S.; Papagni, A. J . Chem. Soc., Chem. Comm.
1987, 762. (o) Schmalz, H.-G.; Siegel, S. In Transition Metals for Fine
Chemicals and Organic Synthesis; Bolm, C., Beller, M., Eds.; VCH:
Weinheim, 1998; Vol. 1.
10 with R-ethoxy vinyllithium25 followed by acidic hy-
drolysis under air gave a single demetalated (R)-R-
hydroxy methyl ketone derivative 16 in 79% overall yield.
Extremely high diastereoselectivity (>99:<1 dr) in the
addition of vinyllithium would be attributed to an op-
posite face attack of the nucleophile to a preferred
conformation of a chromium-complexed benzaldehyde
from a tricarbonylchromium fragment, in which the
carbonyl oxygen of the formyl group is well-known to be
in anti orientation to the ortho substituent due to
stereoelectronic effect.8,26 Subsequent reduction of the
ketone 16 with zinc borohydride produced erythro-(R,S)-
diol 17 as a single product via a chelation-controlled
transition state.27 Regioselective protection of homo-
benzylic alcohol with tert-butyldimethylsilyl triflate fol-
lowed by reduction of the benzylic hydroxyl via xanthate
(27) (a) Nakata, T.; Tanaka, T.; Oishi, T. Tetrahedron Lett. 1983,
24, 2653. (b) Oishi, T.; Nakata, T. Acc. Chem. Res. 1984, 17, 338.
(28) Barton, D. H. R.; McCombie, S. W. J . Chem. Soc., Perkin Trans.
1 1975. 1574.
(29) Mitsunobu, O. Synthesis 1981, 1.
(30) (a) Bringmann, G.; J ansen, J . R.; Rink, H.-P. Angew. Chem.
1986, 98, 917. Bringmann, G.; J ansen, J . R.; Rink, H.-P. Angew. Chem.,
Int. Ed. Engl. 1986, 25, 913. (b) Bringmann, G.; Weirich, R.; Reusher,
H.; J ansen, J . R.; Kinzinger, L.; Ortmann, T. Liebigs. Ann. Chem. 1993,
877. (c) Maruoka, K.; Yamamoto, H. Angew. Chem. 1985, 97, 670.
Maruoka, K.; Yamamoto, H. Angew. Chem., Int. Ed. Engl. 1985, 24,
668.
(25) Braish, T. F.; Saddler, J . C.; Fuchs, P. L. J . Org. Chem. 1988,
53, 3647.
(31) Optical rotation of natural korupensamine B is [R]D +65 (c 0.76,
MeOH): see ref 11d.
4156 J . Org. Chem., Vol. 69, No. 12, 2004

Synthesis of Atropisomeric Korupensamines A and B
SCHEME 4 a
SCHEME 5. Axia l Isom er iza tion of syn -Bia r yl
Ch r om iu m Com p lexes
a
Reagents and conditions: (a) CH2dC(OEt)Li, THF, -78 °C;
(b) 10% aq HCl/THF (1/5), 25 °C, in air (84% from 15); (c) Zn(BH4)2,
THF, ether, -78 °C (99%); (d) ButMe2SiOTf, Et3N, CH2Cl2 (92%);
(e) NaH, CS2, MeI, THF (97%); (f) nBu3SnH, AIBN, toluene, 100
°C, 15 min (99%); (g) nBu4NF (88%); (h) (PhO)2PON3, DEAD, PPh3,
THF, 0 °C (98%); (i) SnCl2.2H2O, MeOH; (j) Ac2O, pyr, 94% from
31; (k) POCl3, MeCN, reflux (95%); (l) LiAlH4, Me3Al, THF, -78
to 0 °C; (m) BnBr, K2CO3, acetone, 65% from 32; (n) BCl3, CH2Cl2,
(30%); (o) 10% Pd/C, H2, MeOH (94%).
complex 33a was heated in xylene to give the expected
anti-biaryl chromium complex 34a , containing a rotated
central bond, in 70% yield (Scheme 5). Similarly, syn-
biphenyl complex 33b afforded axial isomerization prod-
uct 34b in 60% yield by refluxing in xylene. These syn-
biaryl chromium complexes 33 are substituted with a
phenyl ring instead of the naphthalene ring as the central
bond. Construction of the functionalized-naphthalene
ring for the korupensamine skeleton by conversion from
the methyl-substituted phenyl ring of 33 and 34 is not
so easy. Therefore, we next studied thermal isomerization
of the syn-biaryl chromium complex with a naphthalene
fragment. syn-Biaryl complex 35, devoid of a p-methoxy
group at the chromium-complexed arene ring, was heated
in xylene to afford axially isomerized anti-biaryl chro-
mium complex 36 in 56% yield. The progress of the axial
isomerization of 35 is in sharp contrast to the syn-biaryl
chromium complex 10, which was a thermally labile
complex. These results indicate that the thermal stability
of the syn-biaryl chromium complexes with the formyl
group would be attributed to an electronic effect on the
arene ring. An electron-donating group of the chromium-
complexed arene ring would destabilize the syn-biayl
chromium complexes under thermal conditions. There-
fore, the syn-biaryl chromium complex with an electron-
withdrawing fluorine atom would be expected to be a
thermally stable chromium complex for the axial isomer-
ization.
coupling and subsequent tricarbonylchromium migration
to the inverted arene face under thermal conditions
starting from the identical planar chiral arene chromium
complex 8.
Syn th esis of Atr op isom er ic Kor u p en sa m in es A
a n d B fr om Com m on Ar en e Ch r om iu m Com p lex.
As described above, we have succeeded in the total
synthesis of korupensamine A and ent-korupensamine B
from common planar chiral arene chromium complex by
diastereoselective cross-coupling of 2-bromo-3,5-diisopro-
poxybenzaldehyde chromium complex 8 with naphthyl-
boronic acid 9 and subsequent face inversion under
heating in a mixture of di-n-butyl ether and 1,2-dichlo-
roethane. Thermal isomerization of the syn-biaryl chro-
mium complex 13 with a hydroxymethyl group gave anti-
biaryl chromium complex 14 with inversion of planar
chirality by stereoselective migration of the tricarbonyl-
chromium fragment without central bond rotation as
shown in Scheme 2. For the achievement of total syn-
thesis of atropisomeric korupensamines A and B from an
identical arene chromium complex, the axial isomeriza-
tion of the syn-biaryl chromium complex should be
required. From our previous results,24 the ortho-formyl
group is essential for the axial isomerization of syn-biaryl
chromium complexes under thermal conditions. However,
the syn-biaryl chromium complex 10 with an ortho-formyl
group was a thermally labile chromium complex to give
a decomposition product by heating in xylene. Therefore,
further investigation of the axial isomerization was
directed toward the total synthesis of both korupen-
samines A and B from an identical planar chiral arene
chromium complex. 2-Formyl-substituted syn-chromium
In line with this idea, we selected enantiomerically
pure 2-bromo-3,5-difluorobenzaldehyde chromium com-
plex (37)32 ([R]D +890° (c 0.06, CHCl3)) as a coupling
24
partner. Furthermore, the chromium-complexed fluorine
(32) Enantiomerically pure (+)-2-bromo-3,5-difluorobenzaldehyde
chromium complex (37) was obtained by optical resolution of the
diastereomers prepared from the corresponding racemic chromium
complex and L-valinol with column chromatography according to
reported procedure: (a) Davies, S. G.; Goodfellow, C. L. J . Chem. Soc.,
Perkin Trans 1 1989, 192. (b) Davies, S. G.; Goodfellow, C. L. J . Chem.
Soc., Perkin Trans 1 1990, 393. (c) Bromley, L. A.; Davies, S. G.;
Goodfellow, C. L. Tetrahedron Asymmetry 1991, 2, 139.
J . Org. Chem, Vol. 69, No. 12, 2004 4157

Watanabe et al.
SCHEME 6 a
and NaH in the presence of 18-crown ether-6 at room
temperature gave diisopropoxy biaryl chromium complex
13 in 93% yield. Optical rotation ([R]D -105° (c 0.50,
22
CHCl3)) was identical with that of the syn-biaryl chro-
mium complex prepared by cross-coupling of planar chiral
(-)-2-bromo-3,5-diisopropoxybenzyl alcohol chromium
complex (12) with naphthylboronic acid 9 as shown in
Scheme 2. The syn complex 13 was already converted to
korupensamine A via formyl-substituted syn-biaryl chro-
mium complex 10 as shown in Scheme 3. We next studied
the axial isomerization of a difluoro-substitituted syn-
biaryl complex. The hydroxymethyl group of 39 was
initially oxidized to the formyl group. Heating of syn-
23
biaryl chromium complex 40 ([R]D +193.8° (c 0.26,
CHCl3)) in xylene at 120 °C for 1 h gave the expected
anti-biaryl chromium complex 41 containing a rotated
central bond ([R]D25 +490.4° (c 0.34, CHCl3)) in 65% yield
along with de-chromium tricarbonyl product (25%). Peri
H8 proton of the syn-biaryl complex 40 appeared at 8.07
ppm, while the corresponding proton of the axially
isomerized anti-complex 41 showed at 6.74 ppm. Protec-
tion34 of the formyl group of the anti-biaryl chromium
complex 41 as dimethyl acetal, followed by nucleophilic
substitution with 2-propanol and finally acidic hydrolysis,
22
afforded 11 ([R]D +338° (c 0.05, CHCl3)). The obtained
anti-biaryl chromium complex 11 is an antipode of anti-
biaryl chromium complex 15; thus, the chromium com-
plex 11 would be converted to korupensamine B by the
same reaction sequence. In conclusion, we have demon-
strated the total synthesis of korupensamines by dias-
tereoselective cross-coupling of a planar chiral arene
chromium complex with naphthylboronic acid and sub-
sequent axial isomerization of the syn coupling product
or stereoselective tricarbonyl chromium migration to the
inverted arene face as key steps.
a
Reagents and conditions: (a) NaBH4, MeOH (79%); (b) 9,
Pd(PPh3)4, 0.1 M aq K3PO4, toluene, 95 °C (74%); (c) i-PrOH, NaH,
18-crown ether-6, benzene, rt (93%); (d) TFAA, DMSO, CH2Cl2,
then Et3N (87%); (e) xylene, 120 °C, 1 h (65%); (f) CH(OMe)3,
p-TsOH, rt, 3 h (78%); (g) i-PrOH, NaH, 18-crown ether-6, benzene,
rt (73%); (h) 50% aq H2SO4, acetone, 0 °C, 15 min (46%).
atom could be easily converted to alkoxybenzene by
nucleophilic substitution.8d Since cross-coupling of (+)-
difluoro-bromobenzaldehyde chromium complex 37 with
naphthylboronic acid 9 under various conditions resulted
in formation of complex mixtures, the formyl group was
reduced to a hydroxymethyl group. Palladium(0)-cata-
lyzed cross-coupling of 2-bromo-3,5-difluorobenzyl alcohol
chromium complex 38 ([R]D23 +28.6° (c 0.21, CHCl3)) with
9 in aqueous methanol gave a complicated mixture.
However, use of a mixture of toluene and water instead
of methanol at 95 °C gave the desired syn-biaryl coupling
Ack n ow led gm en t. This work was financially sup-
ported by a Grant-in-Aid for Scientific Research from
the Ministry of Education, Science, Sports and Culture,
J apan. We thank Prof. Bringmann for a gift of natural
korupensamines A and B.
Su p p or tin g In for m a tion Ava ila ble: Experimental de-
tails for preparation of the all compounds. This material is
available free of charge via the Internet at http://pubs.acs.org.
23
product 3933 ([R]D -7.3° (c 0.49, CHCl3)) in 74% yield.
The syn stereochemistry was confirmed by 1H NMR
spectra (peri H8 proton; δ 8.42 ppm). Treatment of the
syn-difluoro arene chromium complex 39 with 2-propanol
J O049600X
(34) Nucleophilic substitution reaction of the fluoro atom of 41 with
sodium isopropoxide gave a complex mixture. The formyl group of 41
disappeared in this nucleophilc substitution reaction. Furthermore,
nucleophilic substitution of an anti-difluorobenzyl alcohol chromium
complex obtained from 41 by sodium borohydride reduction gave a
monoisopropoxy-substituted chromium complex under the same condi-
tions with syn-biaryl chromium complex 39. The ortho-fluorine atom
of the anti-biaryl chromium complex did not reacted with the nucleo-
phile due to steric hindrance.
(33) Reflux of difluoro-substituted syn-biaryl chromium complex 39
in a mixture of di-n-butyl ether and dichloroethane resulted in recovery
of the starting material without tricarbonylchromium migration to the
inverted arene face despite the benzyl alcohol function. This result
would be attributed to the strong electron-withdrawing ability of the
fluorine atom: see ref 24.
4158 J . Org. Chem., Vol. 69, No. 12, 2004