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First Atropo-Enantioselective Ring Opening of Achiral Biaryls Containing Lactone Bridges with Chiral Hydride-Transfer Reagents Derived from Borane.

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[4] a ) J. T. Kauer, S. Erickson-Vitanen, H. R. Wolfe, W. F. De Grddo, J B d .
Chrm. 1986.261. 10695, b) W. T. Miller, E. T. Kaiser. Proc. Nurl. Arud. Sci.
U S A 1988, K S , 5429. c) T. Tao. C. J. Schemer, M. Lamkin. 5io~liemistr.v
1986.2.7. 7633.
[5] a ) R. Breslow, Acr. Chrm. Res. 1980, 13, 170, b) C . Helene, Phofochem.
Pholohiol. 1972, 16. 519.
[6] G. W. Anderson, J. E. Zimmerman. F. M. Gallahan, J. Am. Cheni. Sor.
1964. K6. 1839.
[7] A section of a silica substrate bearing nitroveratryloxycarbonyl(NV0C)protected amino groups was photodeprotected [3] and then derivatized
uith the NHS ester of 3-benzoylbenzoic acid. A second section of the
substrate was then deprotected and derivatized with the NHS ester of
biotin. Any unreacted sites in the first section (due to incomplete coupling
of benzophenone) will also react with the biotin NHS ester. The entire
surface was then treated with fluorescein-streptavidin (Molecular Probes
lnc.. Eugene. O R (USA)). The coupling efficiency of benzophenone was
then determined by comparison of the fluorescence intensities of the two
[8] Zeiss Axioskop 20, 488 nm excitation from an argon ion laser, SpectraPhysics model 2025. Fluorescence emission above 520 nm was detected
with a cooled photomultiplier (Hamamatsu-943-02).
[9] I. Pilz. E. Schwarz. W. Palm, Eur. J. Biochem. 1977, 75, 195.
[lo] The use of acetylated or nonacetylated support did not significantly affect
the degree of nonspecific antibody binding.
[ I l l A caged biotin analogue has recently been shown useful for noncovalent
photolithographic immobilization of biopolymers: S . Sundberg, R. Barrett. C. Holmes. Biophvs. J. 1992. 61. 1171.
had in most cases been developed for chemoselective reduction, for example, of ketones, their tendency to function
simultaneously as N-nucleophiles, and the mediocre selectivities (in the most favorable case, 88: 12 and not attainable for
all substrates), as well as the laborious workup. We now report atropo-enantioselective biaryl syntheses by stereoselective reduction of achiral biaryl lactones with modified boranes.
For this purpose, we selected the oxazaborolidines developed by Itsuno et al.[9iand Corey et al.r’O1of the type 3.BH3
and 4.BH, , which had already been extremely successfully
applied for the enantioselective reduction of ketones. where
they gave excellent optical and chemical yields, and required
very short reaction times;[’. ‘I even a catalytic reaction procedure (“CBS” procedure,”’] “molecular robot’”’ ‘I) was possible. The B-alkylated compounds 3 b and 3c were first prepared,[”] analogously to the synthesis of 4 b and 4c.[”3 1 3 , 14]
= CH3
First Atropo-Enantioselective Ring Opening
of Achiral Biaryls Containing Lactone Bridges
with Chiral Hydride-Transfer Reagents Derived
from Borane**
By Gerhard Bringmann* and Thomas Hurtung
Dedicuted to Professor Gerhurd Quinkert
on the occasion of his 65th birthday
Rotationally restricted biaryl compounds from natural
and synthetic sources have attracted ever more attention
because of their biological activity but also as chiral auxiliaries. For the regio- and stereocontrolled construction of
even extremely sterically congested biaryl systems, the lactone-bridged biaryls have proved to be very useful intermediates.”. *I They are easily accessible through Pd-catalyzed intramolecular aryl coupling of the molecular halves, which
are joined by an ester linkage.[3,4JMost of these bridged
biaryls (if containing ortho substituents of “normal” size) are
not differentiated into stable atropisomers, since at room
temperature they undergo a rapid “hehrnerizdti~n”.[~.
This suggests the possibility of cleaving the lactone bridge
atropisomer-selectively to form the configuratively stable
ring-opened products. By utilizing achiral H- or O-nucleophiles for chiral substrates (i.e., under internal asymmetric
induction) or chiral 0- and N-nucleophiles for achiral substrates (i.e., under external asymmetric induction),[’I we performed this reaction atropodiastereoselectively and demonstrated its application in natural product synthesis. Recently
we extended this principle to the atropo-enantioselective ring
opening of achiral lactones with chirdl H-nucleophiles using
chirally modified aluminum hydrides.[81The major problems
were the lack of chemical reactivity of the reagents, which
Prof. Dr G . Bringmann, DipLChem. T. Hartung
Institut fur Organische Chemie der Universitit
Am Hubland, D-W-8700 Wurzburg (FRG)
[**I Novel Concepts in Directed Biaryl Synthesis, Part 12. This work was
supported by the Deutsche Forscbungsgemeinschaft (SFB 347: Selective
Reactions of Metal-Activated Molecules) and by the Fonds der Chemischen Industrie. Part 11 : Reference [2].
Angew. Climr Int. Ed. Engl. 31 (f9Y2J No. 6
0 VCH VerlugsgessellschafimhH,
r i a
= OCH3
= CH3
R = H
R = H
R = CH3
= CH3
R = nBu
= nBu
As substrates we used the configuratively labile, axially prostereogenic bridged biaryls 1 and 2, which can easily be synthesized by esterification and intramolecular aryl
from I-bromo-2-naphthoic acid and 3,s-dimethoxy- or -dimethylphenol. The results of the ring-opening experiments are
summarized in Table 1.
The efficiency of the process can be seen in the good results
already obtained for the monocyclic derivatives 3a-c, but in
particular for the excellent atropisomeric ratios attained with
the bicyclic reagents 4a-4c, which are at least 90: 20 for pracW-6940 Weinheim, 19Y2
Oj70-0833/92/0606-0761 $ 3 . 5 0 + 2 S i O
tically quantitative yields in all cases. By far the highest asymmetric induction is obtained with the B-methyl and B-n-butyl
derivatives 4b and 4c, independent of the lactone used.
Table 1. Ratios for the atropisomers on reduction of 1 and 2 with the chirally
modified boranes 3.BH, and 4.BH3 in THF at 30°C [a].
Ratio [b]
5a:5b or
84: 16
88: 12
98.5: 1.5
[a] All transformations were conducted on an analytic scale (0.03 mmol lactone) in the lactone/oxazaborolidine/BH,.THF ratio of 1/3/4. [b] The ratio of
atropisomers was determined by analytic HPLC on a chiral stationary phase.
5 4 b:I8' Chiralcel OF (Daicel), petroleum ether (b.p. 56- 64"C)/z€'rOH/
HC0,H = 85/15/0.05; the alcohol eluted first is 5b. 6a/b:"'] Chiralcel OD
(Daicel), petroleum ether (b.p. 56-64 'C)/zl)rOH = 90jlO; the alcohol eluted
first is 6a.
(11 G. Bringmann, R. Walter, R. Weirich, Angew. Chem. 1990, 102, 10061019; Angew. Chem. I n l . Ed. Eng/. 1990, 29, 977-991.
[2] G. Bringmann, R. Walter, R. Weirich, Melhods Org. Chem. (Houhm
WeyI), 4th. Ed. 1952 -, Vol. E 22, C2, in press.
[3] D. E. Ames, A. Opalko. Tetrahedron 1984, 40, 1919-1925.
[4] G. Bringmann, T. Hartung, L. Gobel. 0. Schupp, C. L. J. Ewers, B.
Schoner, R. Zagst, K. Peters, H. G. von Schnering, C. Burschka, Liebigs
Ann. Chem. 1992, 225-232.
[5] G. Bringmann, H. Reuscher, Angew. Chem. 1989, IUf, 1725-1726; Angew.
Chem. Int. Ed. Engl. 1989, 28, 1672-1673.
[6] G. Bringmann, J. R. Jansen. Synthesis 1991, 825-827.
[7] G. Bringmann, R. Walter, C. Ewers, Sjnlett 1991, 581-583.
181 G. Bringmann, T. Hartung, Synthesis, 1992. 433-435.
[9] S. itsuno. K. Ito, J. Org. Chem. 1984,49, 555-557; S. Itsuno, M. Nakano.
K. Miyazaki, H. Masudo, K. Ito, A. Hirao, S. Nakahama, J. Chem. SOC.
Perkin Trans. I 1985, 2039-2044.
[lo] E. J. Corey, R. K . Bakshi. S. Shibata, J. Am. Chem. Soc. 1987,109,55515553; E. J. Corey, R. K. Bakshi, S. Shibata, C.-P. Chen, V. K. Singh, ibid.
1987,109,7925-7926; E. J. Corey, S. Shibata, R. K. Bakshi, J. Org, Chem.
1988,53, 2861 -2863.
[Ill E. J. Corey, Angew. Chem. 1991, 103, 469-479; Angew. Chenr. Int. Ed.
Engl. 1991, 30, 455-465.
1121 All new compounds were completely characterized by 'H NMR, IR. and
mass spectra, as well as elemental analysis.
[13] E.J. Corey, R. K. Bakshi, Tetrahedron Leu. 1990, 31, 611-614.
[I41 D. J. Mathre, T. K. Jones, L. C. Xavier, T. J. Blacklock, R. A. Reamer,
J. J. Moban, E. T. Turner Jones, K. Joogsteen, M. W Baum, E. J. J.
Grabowski, J. Org. Chem. 1991,56, 751 -762.
Matrix-Assisted Laser Desorption Mass
Spectrometry of Lignins**
The practicality of this stereoselective synthesis is increased by the discovery that when the reaction is performed
on a preparative scale, the atropisomeric ratios achieved (e.g.,
98.5: 1.5 for the reduction of 2 with 4b) can be improved still
further by a simple crystallization step that effortlessly yields
enantiomerically pure material (6a:6b > 99.9:O.l).
Experimental Procedure
3b: A solution of (5')-(-)-2-amino-3-methyl-1,l-diphenylbutan-l-ol(510 mg,
2.0 mmol) 191 in dry toluene (10 mL) was treated with trimethylboroxine
(190 pL, 171 mg, 1.36 mmol) and stirred for 0.5 h at 20 "C. Thereafter the solution was concentrated to 2 mL, and twice treated with 5 mL of toluene and
destilled. After removal of the solvent, colorless crystals of3 b"'l were obtained
-221.8 (c =1.66, THF).
in quantitative yield. M.p. 99.5-101 "C,
3 c : A solution of (S)-(-)-2-amino-3-methyl-l,1-diphenylbutan-l-ol
(510 mg,
2.0 mmol) and n-butylboronicacid (205 mg, 2.01 mmol) in toluene (30 mL) was
heated for 24 h under reflux; water was removed with a Dean-Stark trap.
Workup analogous to that of 3 b gave a quantitative yield of 3~"'' as colorless
- 185.7 (c = 1.89, THF).
6 a (preparative atropo-enantioselective ring opening of 2 with 4b): A solution
of BH,.THF (0.80 mmol in 4 mL, 0.2M) was treated with a 0.2M solution of
oxazaborolidine 4b (3 mL, 0.60 mmol) in THF at 0 "C under argon. After the
addition the mixture was warmed to 30"C, and a solution of the lactone 2 in
T H F (0.20 mmol, 55 mg in 6 mL) was added dropwise over 10 min. The reaction solution was stirred for a further 30min at 30"C, upon which it was
hydrolyzed by addition of water ( 5 ml) and HCI (2m, 2 mL). After extraction
into ether, the organic phase was dried over MgSO,, and the solvent destilled
off in vacuum. Chromatography of the residue on a short silica gel column
(CH,CI,) afforded the alcohol 6 a [I21 (6a:6b = 98.5:1.5), yield 52.5mg
(94%), m.p. 141-142 "C. [a]," -31.6 (c = 0.51, CH,OH). A subsequent crystallization from dichloromethane/petroleum ether furnished enantiomerically
pure material (6a:6b 199.9:O.l).
Received: December 27, 1991 [Z5089IE]
German version: Angew. Chem. 1992, f04,782
CAS Registry numbers:
1,138435-70-8; 2,138435-72-0; 3a, 117349-13-0; 3b, 140834-48-6; 3.2, 14083449-7; 4a, 110205-59-9; 4b, 112022-81-8; 4c, 129145-37-5; 5a, 140834-50-0; Sb,
140834-51-1; 6a, 140834-52-2; 6b, 140834-53-3; (S)-( -)-2-Amino-3-methyl1,I-diphenylbutan-1-01, 78603-95-9; Trimethylboroxine, 823-96-1; n-Butylboronic acid, 4426-47-5.
0 VCH Ver/ugsgese//schaftmhH, W-6940
Weinheim, 1992
By Jiirgen 0. Metzger,* Christine Bicke, Oskar Faix,
Wilfried Tuszynski, Raimond Angermann, Michael Karas,
and Kerstin Strupat
As component of the lignocelluloses, the skeletal substance
of terrestrial plants, lignin is the most common biopolymer
besides the polysaccharides cellulose and hemicelluloses. As
side product of the cellulose recovery over 50 million tons of
technical lignins is produced yearly worldwide, and its use as
renewable raw material with a view to protecting the environment is a challenge for chemists. Knowledge about lignins
is still fragmentary.['-31 It is certain that its monomeric precursor in conifers is predominantly coniferyl alcohol (1a); in
deciduous trees sinapyl alcohol (I b) is an additional precursor, as is p-cumaryl alcohol (lc) in grasses and herblike dicotyledons.['] According to Fre~denberg,'~]
these alcohols
polymerize to give lignin, by a radical mechanism. However,
the biosynthesis path from the monomers to the macromolecule has not yet been unambiguously elucidated.r21At
any rate lignin is fundamentally different from other biopolymers like proteins, nucleic acids, and polysaccharides, in
[*I Prof. Dr. J. 0. Metzger
Fachbereich Chemie der Universitat
Carl-von-Ossietzky-Strasse 9- 11, D-W-Oldenburg (FRG)
Dip].-Chem. C. Bicke, Priv. Doz. Dr. 0. Faix
Bundesforschungsanstalt fur Forst- und Holzwirtschaft, Hamburg (FRG)
Dr. W. Tuszynski, Dip].-Phys. R. Angermann
Fachbereich Physik der Universitit Oldenburg
Dr. M. Karas, K. Strupat
Institut fur Medizinische Physik der Universitst Munster
OS70-0833/92/0606-0762$3.50+ .2S/U
Angen. Chenr. Int. Ed. Engl. 31 (1992) N o . 6
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reagents, lactones, bridge, achiral, ring, enantioselectivity, chiral, containing, first, opening, transfer, biaryl, hydride, derived, boranes, atropa
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