From dynamic to non-dynamic kinetic resolution of lactone-bridged biaryls: Synthesis of mastigophorene B

Article abstract of DOI:10.1055/s-2001-9760

The atroposelective ring cleavage of configurationally unstable biaryl lactones, by dynamic kinetic resolution, is an efficient tool for the stereoselective synthesis of axially chiral biaryl target molecules. The recent extension of this methodology to the kinetic resolution of configurationally stable biaryl lactones and its application to natural product synthesis is described herein, exemplarily for the preparation of the nerve-growth stimulating dimeric sesquiterpene mastigophorene B.

Full text of DOI:10.1055/s-2001-9760

FEATURE ARTICLE
155
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged
Biaryls: Synthesis of Mastigophorene B†
Gerhard Bringmann,*a Jürgen Hinrichs,a Thomas Pabst,a Petra Henschel,a Karl Peters,b Eva-Maria Petersb
a Institut für Organische Chemie, Universität Würzburg, Am Hubland, 97074 Würzburg, Germany
Fax +49(931)8884755; E-mail: bringman@chemie.uni-wuerzburg.de
b Max-Planck-Institut für Festkörperforschung, Heisenbergstr. 1, 70506 Stuttgart, Germany
Received 31 July 2000; revised 2 September 2000
Dedicated to Prof. Max Schmidt, on the occasion of his 75th birthday.
Me
HO OMe
Abstract: The atroposelective ring cleavage of configurationally
R
HO
M
unstable biaryl lactones, by dynamic kinetic resolution, is an effi-
cient tool for the stereoselective synthesis of axially chiral biaryl
target molecules. The recent extension of this methodology to the
kinetic resolution of configurationally stable biaryl lactones and its
application to natural product synthesis is described herein, exem-
plarily for the preparation of the nerve-growth stimulating dimeric
sesquiterpene mastigophorene B.
N
R
H
OH Me
Me
MeO
P
Me
HO
R
1
R
N
H
Me
OH
HO
Me
O
2
Key words: axial chirality, biaryl natural products, lactone-bridged
biaryls, kinetic resolution, total synthesis
H
R
N
R
OH
Me
Me
O
M
*
OH OMe
OMe
Introduction and Background
MeO
Me
M
MeO HO
Rotationally hindered, stereogenic biaryl axes are, besides
stereocenters, the most commonly found and utilized ele-
ments of chirality. During the past years, stereochemically
pure biaryl compounds have become increasingly impor-
tant as effective chiral reagents and catalysts in stereose-
lective synthesis1 and as widespread natural products.2
Such naturally occurring biaryls constitute a large class of
structurally most divergent substances, among them
antimalarial3 naphthylisoquinoline alkaloids4,5 like dion-
copeltine A (1)6 and dioncophylline C (2),7 the anti-HIV
quateraryl alkaloid michellamine B (3),8 the insect anti-
feedant bicoumarin (+)-isokotanin A (4),9 the antimalarial
phenylanthraquinone knipholone (5),10 and the nerve-
growth stimulating biphenyl mastigophorene A (6a)11
(Figure 1).
Me
Me
Me
MeO
P
*
HO
OMe
R
3
N
R
H
O
4
OH Me
O
HO
O
OH
S
Me
Me
O
Me
M
OH
Me
HO
P
OH
5
OH
OH
S
MeO
O
OH
6a
= configurationally unstable
= configurationally stable
*
Figure 1 Axially chiral biaryl natural products with pronounced
biological activities
Due to the increasing importance of axially chiral biaryls,
the availability of atropo-enantio- or -diastereomerically
pure material is a challenging task. For the elaboration of
efficient methods for the stereoselective synthesis of such
biaryl target molecules, quite a couple of methods have
been developed based on oxidative,12,13 ‘redox-neu-
tral’,14,15 or reductive16 coupling reactions, following in-
ter- and intramolecular strategies.17 Still, many of these
methods suffer from low chemical and/or optical yields as
soon as sterically crowded target molecules are in-
The Basic ‘Lactone Concept’: Atropisomer-Selective
Cleavage of Configurationally Unstable Biaryl Lac-
tones with Dynamic Kinetic Resolution
volved.15,17,18 Moreover, most of them do not permit an at- For the regio- and stereoselective construction of even
ropo-enantio- or -diastereo-divergent synthesis, i.e., the sterically highly hindered biaryls, we have developed a
directed preparation of any desired atropisomeric product fundamentally novel approach, the ‘lactone concept’.20 It
from a joint general precursor, and thus few applications differs from the other existing coupling methods in solv-
to natural products biaryl synthesis have as yet been ing the two formal partial goals of atropisomer-selective
described in the literature.19
synthesis: the C,C-bond formation, and the asymmetric
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156
G. Bringmann et al.
FEATURE ARTICLE
Biographical Sketches
From left to right:
Bringmann, Henschel, Hinrichs, Pabst
Gerhard Bringmann was born in syntheses of acetogenic isoquinoline tional natural products chemistry,
1951. He studied chemistry in alkaloids (1984), he was offered some particular fields being mono-
Gießen und Münster, where he ob- chairs in Vienna (1986) and and dimeric naphthylisoquinoline al-
tained his diploma in 1975. In addi- Würzburg (1987), and has since been kaloids, bioassay-guided search for
tion, he performed a basic study of a full professor and director at the In- new bioactive compounds from trop-
biology ('Vordiplom', 1977). He re- stitute of Organic Chemistry of the ical medical plants, novel concepts in
ceived his Ph.D. with B. Franck University of Würzburg. In 1998, he regio- and stereoselective biaryl syn-
(1978), for research in the field of received a call for a chair of natural thesis, computational chemistry in-
porphyrin chemistry and related cy- products chemistry at the Institute of cluding the calculation of structures,
clic and linear oligopyrroles. From Plant Biochemistry (a Gottfried Wil- dynamics, and chemical reactivities
1978 to 1979, he worked as a post- helm Leibniz Institute) in Halle. He of molecules and the prediction of
doctoral fellow with Sir Derek H. R. was awarded, i.a. the 'Otto Klung CD spectra as well as QSAR investi-
Barton's group in Gif-sur-Yvette Prize' in 1988 and the Prize for Good gations, and ‘endogenous alkaloids
(France) studying radical-induced Teaching by the Bavarian Ministry in Man’, their in vivo formation, me-
hydrodeamination reactions of rele- of Culture and Research in 1999. His tabolism, and medicinal relevance
vance to aminoglycoside chemistry. research interests lie in the fields of for neurodegeneration.
After his 'habilitation' on biomimetic analytical, synthetic, and computa-
Petra Henschel, born in 1970, re- Akademie Prof. Dr. Grübler in Isny, ytical fields, likewise involving cell
ceived her education as a technical Germany. She joined the Bringmann tissue culture techniques.
assistant from 1991 to 1993 at the group in 1993 and has since then
Naturwissenschaftlich-Technische
worked in various synthetic and anal-
Jürgen Hinrichs, born in 1970, re- gow, Scotland, and spent three phorene B. From 1997 to 1999 he
ceived his diploma in 1996 under the months (Autumn, 1998) as an intern was supported by a fellowship of the
supervision of Prof. Bringmann at the at Merck in Rahway, NJ, where he State of Bavaria. He was also among
University of Würzburg. His re- developed an automated protocol for the prize winners at Drug Discovery
search interests are the development the rapid screening of new catalysts. 99 held by Pfizer. After receiving his
of new methodologies in stereoselec- For his Ph. D. thesis, he examined the Ph.D., he recently joined Professor
tive organic synthesis and their appli- kinetic resolution of configurational- Nicolaou's group at Scripps as a post-
cations to the preparation of complex ly stable biaryl lactones and prepared doctoral fellow.
natural products. He received part of the axially chiral target molecules,
his undergraduate education in Glas- (+)-isokotanin
A
and mastigo-
Thomas Pabst, born in 1969, re- methodology for stereoselective oxi- growth stimulating mastigophorenes
ceived his diploma in 1996 under the dative biaryl coupling by using car- A and B, as well as structurally sim-
guidance of Prof. Bringmann at the bohydrates as chiral templates. He plified analogs, via configurationally
University of Würzburg for work fo- received his Ph. D. in 2000 for the at- labile biaryl lactones.
cused on the development of a new roposelective synthesis of the nerve-
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FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
157
induction, separately. Firstly, and independent of the final And finally, even minor atropisomeric byproducts are not
axial chirality, the coupling is achieved intramolecularly, lost, but can be re-used; literally a recycling by re-cycliza-
after pre-fixation of the two aromatic portions via an ester tion back to the configurationally unstable lactone, and re-
bridge as in 7 (Scheme 1). This bridge is of manifold cru- newed stereocontrolled ring cleavage.24,25
cial importance within the concept:
This lactone method is not only conceptually novel and
It brings together the reaction partners, i.e., the two aro- thus of intellectual and mechanistic interest, but has prov-
matic rings, thus guaranteeing the coupling to 6-mem- en its efficiency and practicability already in the total syn-
bered lactones of type 8 to be achieved in excellent yields, thesis of more than 25 natural biaryl target molecules,
even against highest steric hindrance (e.g., R = t-Bu).
among them all of the natural products shown in Figure
1.25-30 Furthermore, quite a series of useful axially chiral
reagents and ligands like the aminophenol (P)-1331 (Fig-
ure 2), the monodentate phosphine reagent (P)-14,32 and
the as yet unprecedented C3-symmetric tripod ligand
(M,M,M)-15,33 which has three homochiral biaryl axes,
have been prepared by this efficient methodology.
Moreover, by dramatically lowering the atropisomeriza-
tion barrier at the newly created biaryl axis, it allows the
establishment of the required axial configuration sepa-
rately, by atropisomer-selective cleavage of lactone 8, for
which a variety of different nucleophilic reagents can be
used. For this purpose, the bridge with its reactive C=O
group again provides the site of stereocontrolled attack The target molecules to be prepared by the lactone meth-
and thus constitutes a useful “Achilles’ heel” for the di- odology do not necessarily have to be equipped with C1-
rected opening of the lactone ring of 8. This cleavage can and O-substituents next to the axis because of the possibil-
be brought about with high stereocontrol; atropo-diastere- ity of further modifying the substitution pattern after the
oselectively to esters or amides 9 using O- or N-nucleo- ring cleavage reaction. Besides subsequently transform-
philes21,22 (e.g., sodium 8-phenylmentholate (11), giving ing the phenolic oxygen function into hydrogen (cf. struc-
drs of up to > 99:1), or atropo-enantioselectively with H- ture 2) or into a phosphorous substituent (cf. 14), the C1-
nucleophiles23,24 (e.g., with borane activated by the oxaza- ‘bridgehead’ can be used to build up further ring systems
borolidine (S)-12, to provide alcohols 10 with up to er (cf. 3), or it can be replaced by an oxygen function, or
98.5:1.5 (Scheme 1). In each case, the other respective at- again just by hydrogen.34
ropisomer can be obtained, too, just by the use of the other
reagent enantiomer, starting from the same ‘late’ lactone
precursor 8, in the sense of an atropisomer-divergent pro-
cedure.
Biographical Sketches
Karl Peters, born in 1940, received direction of H. G. von Schnering. Stuttgart, and his research interests
his doctorate degree in inorganic Since 1975 he has been a senior re- concentrate on the application of X-
chemistry for work on single-crystal search associate at the Max-Planck- ray crystallography.
structure determinations, under the Institut für Festkörperforschung in
Eva-Maria Peters, born in 1948, ex- Max-Planck-Institut für Festkörper-
tended her chemical profession to the forschung, where she has been work-
computational management of crys- ing since 1975.
tal structure determinations at the
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158
G. Bringmann et al.
FEATURE ARTICLE
‘Non-Dynamic’ Kinetic Resolution of Configuration-
ally Stable Lactones
O
Br
R
R
O
More recently, the lactone method has been further ex-
tended to the atropisomer-selective ring cleavage of con-
figurationally stable lactones,35,36 which have thus proved
to be valuable substrates for such enantiomer-differentiat-
ing reactions, too. Configurational stability for lactone-
bridged biaryls can be attained in two different ways: by
placing even more steric hindrance into the ortho-position
next to the biaryl axis (which is easily tolerated in the cou-
pling step), or by utilizing a bridge that will not, as in the
previous cases, lead to a 6-membered lactone, but to a 7-
membered one. The first of these two cases is exemplified
by the tert-butyl substituted lactone 8d. The fact that it
can, as all the other (less hindered) lactones of type 8,
again be prepared by the intramolecular coupling of the
corresponding bromo ester, despite the now enormous
steric hindrance, emphasizes the efficiency of this cou-
pling step, which provides 8d in more than 80% yield.36
Lactone 8d is a drastically distorted, helicene-like chiral
molecule,37 and of course initially racemic. Application of
the reductive cleavage reactions as above leads to a ‘here
non-dynamic’ kinetic resolution. Due to the strain-in-
duced enhanced reactivity of 8d, this resolution can be
performed even at -78 °C, now proceeding with a nearly
immeasurably high relative rate constant krel > 20036
(Scheme 2). The remaining unreactive atropisomer, (P)-
8d, in the case of the S-configured oxazaborolidine (S)-12
can again be recycled, this time not in situ, but separately,
R
H
OMe[a] Me tBu
7
7 - 10
a
b
c
d
O
O
fast[b]
M
P
°
°
O
R
O
R
R
(M)-8
R
(P)-8
Nu ML
*
HML
n
*
n
dr up to > 99 : 1
er up to 98.5 : 1.5
OH
Nu
*
*
O
*
HO
R
HO
R
R
10
R
9
Nu ML = chiral O- or N-nucleophiles,
HML = chiral H-nucleophiles,
e.g.
*
*
n
n
e.g.
H
Ph
Ph
Ph
NaO
R
S
N
O
B
, BH THF
3
(R)-11
(S)-12
Me
[a]Note that for formal reasons of the CIP denotation, biaryls with R = OMe
have opposite descriptors compared to those with R = H or alkyl
-20oC
O
O
M
P
O
tBu
O
tBu
[b]Due to the large ortho substituent, lactone 8d (R = tBu) is configuration-
ally stable at room temperature
Scheme 1 The basic principle of the ‘lactone concept’ for the atro-
poselective synthesis of axially chiral biaryls like 9 or 10: the dyna-
mic kinetic resolution of configurationally unstable biaryl lactones
820
tBu
tBu
(M)-8d
(P)-8d
H
S
Ph
Ph
NnBu2
krel > 200 !
N
O
Me
PPh2
B
P
P
Me
Me
OH
(S)-12
, BH THF
3
Me
(P)-13
(P)-14
Me
Me
OH
O
M
P
+
tBu
tBu
O
HO
N
M
M
Me
Me
HO
HO
M
OH
Me
tBu
tBu
(M)-10d
(P)-8d
(M,M,M)-15
Me
Me
Scheme 2 Highly efficient non-dynamic kinetic resolution of the
configurationally stable biaryl lactone 8d using oxazaborolidine-ac-
tivated borane36
Figure 2 A selection of useful biaryl ligands already prepared by
the lactone methodology31-33
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FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
159
by thermal equilibration, followed by renewed reduction
Application of the 7-Membered Lactone Methodolo-
of the racemic lactone; a most efficient pathway to even gy to Natural Product Synthesis: Preparation of
highly hindered biaryls, proceeding in excellent chemical Mastigophorene B (4)
and optical yields.36
With this new methodology in hand, the synthesis of mas-
tigophorene B (6b), the atropo-diastereomer of mastigo-
phorene A (6a), via a configurationally stable biaryl
lactone was envisaged and is described herein. Reaction
Turning from 6-membered lactones of type 8 to larger,
e.g., to 7-membered rings as in 16, the atropisomerization
barrier at the axis is less efficiently lowered by the bridge:
thus, in contrast to its 6-membered analog,38 16 is config-
conditions were first optimized for a simplified analog 23
urationally stable up to well above 120 °C (Scheme 3).
(vide infra), in which the two chiral cyclopentyl residues
This makes a dynamic kinetic resolution impossible, but
of 6 are replaced by tert-butyl groups. Previous studies
under reductive conditions using borane activated by the
had shown that, like the mastigophorenes 6 themselves,11
oxazaborolidine (S)-12, the diol (M)-17 is obtained
this model compound also has neurotrophic properties.39
through a ‘normal’ kinetic resolution, again with high rel-
Starting from the known28 ester 18, the required lactone
ative rate constants (up to krel = 50).35 During the reaction,
22 was obtained in five smooth reaction steps as outlined
(P)-16 is enriched up to complete optical purity.
in Scheme 4. Ullmann coupling of 18 gave racemic 19,
whose structure was fully confirmed by X-ray structure
analysis;40 reduction of 19 and oxidation of the resulting
O
O
O
O
M
P
CO Me
2
Br
OMe
(M)-16
(P)-16
OMe
a
18
90%
H
Ph
Ph
S
krel = 50
N
O
R
B
R
(S)-12
, BH THF
3
Me
M/P
OMe
*
OMe
OMe
19
(X-ray)
OMe
O
(rac)-19 R = CO2Me
(rac)-20 R = CH2OH
b
OH
87%
M
P
O
+
c
98%
OH
OHC
OHC
(M)-17
(P)-16
M/P
OMe
Scheme 3 Another successful example of the new principle: kinetic
resolution of the 7-membered lactone 16 with two C1 units next to the
biaryl axis35
*
OMe
OMe
21
OMe
(rac)-21
(X-ray)
d,e 89%
Configurative instability at the axis and the resulting pos-
sibility of achieving dynamic kinetic resolutions has to be
considered as a major advantage when using 6-membered
lactones, while 7-membered lactones can be cleaved only
by a normal, non-dynamic kinetic resolution and thus re-
quire a separate recycling of the unreacted enantiomer. On
the other hand, the 7-membered lactones bear the inherent
advantage of complementing the substitution pattern ini-
tially attained in the primary ring cleavage process of 6-
membered lactones (one C1- and one O-substituent) by
producing molecules with two C1-units next to the biaryl
axis, which is a valuable enrichment of the basic lactone
methodology.
O
O
M/P
OMe
*
OMe
OMe
OMe
(rac)-22
22
(X-ray)
Reagents and conditions: (a) Cu, DMF, 160 °C, 48 h (90%);
(b) LiAlH4, THF, 2 h (87%); (c) MnO2, CH2Cl2, 3 days (98%);
(d) KOH, EtOH, reflux, 24 h; (e) DCC, DMAP, CH2Cl2, reflux, 4 h
(89%, two steps)
Scheme 4 Preparation of the configurationally stable model lac-
tone 22
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160
G. Bringmann et al.
FEATURE ARTICLE
diol 20 yielded the dialdehyde 21,40 which was trans- essary to use the enantiomerically enriched unreacted
formed into the corresponding hydroxy acid under Can- lactone (P)-2241 for further transformations. Reduction of
nizzaro conditions. Ring closure with DCC gave the key (P)-22 with LiAlH4 yielded the alcohol (P)-20 without
lactone 22.
significant loss of stereochemical purity.
This lactone-bridged biaryl 22 was found to be configura- In order to avoid unnecessary tedious separation work on
tionally stable at room temperature by HPLC on a chiral synthetic intermediates, the final steps in the synthesis of
stationary phase (Chiralcel OF, Daicel Chem. Ind.). An X- the mastigophorene A analog (P)-23, the hydroxy-bromo
ray crystallographic analysis of 22 (Scheme 4)40 revealed exchange, the LiAlH4 reduction, and the subsequent re-
that the lactone bridge as compared to that of the 6-mem- moval of the protecting groups were all achieved in situ,
bered lactones 837 is long enough to let the two molecular yielding (P)-23 in an overall 73% yield, fully identical
portions adopt a ‘relaxed’, near-orthogonal position, with- with material previously prepared.42
out distortion of the aromatic rings, which, besides addi-
This procedure was then applied to the total synthesis of
tional steric interactions in the atropisomerization
the related authentic natural product mastigophorene B
transition state,36 results in the observed higher rotational
(6b). As a starting material, we chose herbertenediol dim-
barrier. Kinetic resolution under the conditions previously
ethyl ether (26),28 which had previously been obtained by
optimized for lactone 1635 proceeded with moderate se-
a novel modification of the lactone method, as outlined in
Scheme 6: by an again – non-dynamic – kinetic resolution
lectivity (krel = 12) in this case (Scheme 5), making it nec-
of a configurationally stable lactone, here the ‘aliphatic-
aromatic’ 24, with borane activated by oxazaborolidine
(S)-12, resulting in a highly efficient (krel > 300!) enanti-
O
O
omer-differentiating reduction, which underlines that the
extension of the basic lactone concept described here is
not limited to biaryl lactones. This high selectivity made
it possible to obtain unreacted, stereochemically pure
(R,R)-24 (ee > 99.9%) already after less than 52% conver-
sion.28 Standard transformations of (R,R)-24 then gave
herbertenediol dimethyl ether (26), the O-protected
‘monomer’ of the mastigophorenes 6.
O
O
P
M
OMe
OMe
OMe
OMe
OMe
OMe
OMe
OMe
(M)-22
(P)-22
a
H
Ph
Ph
S
krel = 12
N
O
B
Me
(S)-12
Me
65% conversion
OMe
Me
OH
cis
O
O
HO
O
(rac)-24
O
P
M
OMe
+
S
OMe
OMe
OMe
OMe
H
Ph
OMe
OMe
Ph
OMe
26
S
krel > 300 !
OMe
OMe
N
O
B
(M)-20
er = 76 : 24
(P)-22
er = 98 : 2
92%
(S)-12
, BH THF
3
Me
51.6% conversion
b
Me
O
Me
OH
Me
HO
Me
+
c-d
OMe
OMe
S
S
P
R
R
P
OMe
OH
OH
O
73%
OMe
OMe
(S,S)-25
(R,R)-24
O
OH
OH
(P)-23
OH
OMe
ee > 99.9%
ee = 96%
(P)-20
er = 97 : 3
Scheme 6 Another efficient extension of the lactone methodology:
the highly selective (krel > 300) production of the enantiomerically
pure ‘monomer’, herbertenediol dimethyl ether (26), by reduction of
the ‘aliphatic-aromatic’ lactone 24 with kinetic resolution28
.
Reagents and conditions: (a) (S)-12, BH3 THF, THF, -20°C, 3 h [33%
(P)-22 and 58% (M)-20]; (b) LiAlH4, THF, 2 h (92%); (c) (CBrCl2)2,
PPh3, CH2Cl2, 4 h, then LiAlH4, CH2Cl2/Et2O, 24 h; (d) BBr3, CH2Cl2,
1 h (73%, three steps)
Scheme 5 Kinetic resolution of lactone 22 by enantiomer-differen-
tiating reduction and further transformation of (P)-22 to give the ma-
stigophorene A analog (P)-23
Bromination of 26 according to the literature28 gave com-
pound 27 (Scheme 7), which was oxidized in a three-step
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FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
161
procedure (74% overall yield) to furnish the bromo alde- sible of the minor (‘wrong’) (P)-isomer of lactone 31,
hyde 29, fully identical to material previously obtained by through reduction to the corresponding alcohol by kinetic
semisynthesis from a natural precursor.28 In an improve- resolution. For this, by analogy to the stereochemical out-
ment compared to the synthesis of the mastigophorene A come of previous ring cleavage reactions (see i.a. above),
analog (P)-23 presented above, aldehyde 29 was directly the (R)-oxazaborolidine enantiomer, (R)-12, should be the
subjected to the Ullmann coupling conditions; not as its required reagent of choice. The resulting enriched (M)-
ester derivative. Although this gave rise to the biaryl dial- enantiomer of the unreacted lactone (M)-31 would then be
dehyde 30 in an only moderate yield (53%), it reduced the used for completing the synthesis of mastigophorene B
number of steps significantly. Cannizzaro reaction of 30 (6b), which is likewise (M)-configured.
and ring closure with DCC gave the 7-membered biaryl
lactone 31 as a mixture of its two configurationally stable
atropisomers, in a diastereomeric ratio of 58:42.
O
OMe
O
P
Me
OMe
H
Me
OMe
OMe
MeO
(P)-32
28
Br
lit.
Figure 3 Biaryl lactone (P)-32, an axially chiral compound from
the synthesis of (+)-isokotanin A (4)30
OMe
OMe
S
S
OMe
26
27
57%
(plus 26% 29)
a,b
Following this strategy, partial reduction of (M/P)-31 with
(R)-12◊BH3 gave stereochemically enriched lactone (M)-
31 with a diastereomeric ratio of 81:19. Further reduction
of (M)-31 with LiAlH4 (85% yield) and application of the
above three-step procedure; reduction of the two benzylic
alcohol functions in (P)-33 to methyl groups and subse-
quent removal of the protecting groups gave stereochem-
ically pure mastigophorene B (6b) after chromatographic
purification, in an overall yield of 5.1% starting from the
herbertenediol derivative 26 (Scheme 8). It proved to be
identical in all respects with the natural product 6b,11 by
which the previous assumption (see above) that the (M)-
atropisomer of lactone 31 had been formed predominately
in the coupling step, was confirmed.
OH
O
Br
Br
c
85%
OMe
OMe
S
S
OMe
OMe
29
28
d
53%
S
S
O
OHC
OHC
O
e,f
51%
M/P
M/P
OMe
OMe
Although the atropisomer-differentiating selectivity in the
resolution step is only moderate, the strategy elaborated
here represents the as yet shortest and most convergent
synthesis of mastigophorene B (6b), compared both to
Meyers’ oxazoline approach43 and to our previous synthe-
sis via a configurationally unstable six-membered lac-
tone.28
OMe
OMe
OMe
OMe
S
S
OMe
OMe
30
31
Reagents and conditions: (a) NBS, (t-BuO)2, CHCl3, reflux, 4 h;
(b) CaCO3, H2O/dioxane, reflux, 16 h (57% and 26% 29, two steps);
(c) MnO2, CH2Cl2, 1 day (85%); (d) Cu, DMF, 165 °C, 16 h (53%);
(e) KOH, EtOH, reflux, 1.5 h; (f) DCC, DMAP, CH2Cl2, 8 h (51%,
two steps)
Conclusion
Scheme 7 Preparation of the configurationally stable lactone 31, a
key intermediate in the synthesis of mastigophorene B (6b)
The kinetic resolution of configurationally stable lac-
tones, both biarylic and ‘aliphatic-aromatic’ ones, has
proven to provide an efficient pathway to both axially
chiral and centrochiral compounds. The new protocol has
been used for the first time in a diastereomer-differentiat-
ing reaction, for a short synthesis of the nerve-growth
stimulating bis-sesquiterpene mastigophorene B (6b). In
comparison to our lactone method via configurationally
unstable biaryl lactones, it is especially well-suited for
constitutionally symmetric biaryls, since it avoids the need
of first building up two different aryl compounds (a bro-
mo acid and a phenolic portion) for the construction of a
6-membered lactone, thus significantly reducing the num-
ber of required reaction steps.
Comparison of the CD spectrum of this mixture with that
of the related lactone (P)-32, a compound from the syn-
thesis of the configurationally well known natural prod-
uct, (+)-isokotanin A (4)30 (Figure 3), clearly revealed that
(M)-31 must be the predominant atropisomer in the mix-
ture. This made it rewarding to pursue the following strat-
egy: Since the enantiomer-differentiating selectivities in
the model studies (see above) had been unexpectedly
moderate, the remaining, stereochemically enriched lac-
tone, in that case (P)-22, was used for further transforma-
tions. For the actual mastigophorene synthesis, it thus
seemed desirable to rather try to remove as much as pos-
Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

162
G. Bringmann et al.
FEATURE ARTICLE
THF was freshly distilled from K, Et2O from Na wire, DMF from
CaH2, and CH2Cl2 from P2O5. All air or moisture sensitive reactions
were carried out with dry glassware under N2 or Ar atm. Column
chromatography was performed on silica gel 63-200 mm (Merck).
Oxazaborolidines (S)-12 and (R)-12 (1 M in toluene, which was re-
S
S
O
O
O
O
P
M
OMe
OMe
.
moved in vacuo prior to use) and BH3 THF (1 M in THF) were ob-
tained from Aldrich.
OMe
OMe
OMe
OMe
S
S
OMe
OMe
Ph
HPLC analyses were carried out with a combination of a Waters
HPLC pump 510, a 20 µl injection loop and Chiralcel OF and OD-
H columns (0.46 ¥ 25 cm, Daicel Chem. Ind.) with UV detection at
254 nm. The atropisomers of lactone 22 were separated on the OF
column with hexane/i-PrOH (85:15; 1.0 mL/min) as the eluent, the
tR for (P)-22 and (M)-22 were 11 and 15 min, respectively. For diol
20, the OD-H column was used with hexane/i-PrOH (98:2; 1.0 mL/
min) as the eluent, with tR of 9 and 15 min for (M)-20 and (P)-20,
respectively. The diastereomeric ratios of compounds 31 and 33
were determined by 1H NMR.
(P)-31
(M)-31
H
Ph
a
R
N
O
46% conversion
B
(R)-12
Me
OH
S
S
O
HO
(rac)-Dimethyl 4,4¢-Di-tert-butyl-5,5¢,6,6¢-tetramethoxy-1,1¢-bi-
phenyl-2,2¢-dicarboxylate (19)
O
P
M
+
A mixture of methyl 2-bromo-5-tert-butyl-3,4-dimethoxybenzoate
(18)28 (3.00 g, 9.06 mmol) and activated copper44 (4.40 g) in DMF
(10 mL, degassed) was heated to 160 °C for 48 h under N2. After the
mixture had cooled to r.t., the copper was filtered off and washed
with CH2Cl2, and the solvent was removed in vacuo. Column chro-
matography (petroleum ether/Et2O 10:1) gave 19 (2.05 g, 4.08
mmol, 90%) as colorless crystals from petroleum ether, mp 161-
165 °C.
OMe
OMe
OMe
OMe
OMe
OMe
S
S
OMe
OMe
(M)-31
dr = 81 : 19
(P)-33
dr = 65 : 35
b
85%
IR (KBr): n = 2980, 2930, 2890, 2840 (C-H), 1710 (C=O), 1300,
1040 cm-1.
1H NMR (250 MHz, CDCl3): d = 1.43 [s, 18H, C(CH3)3], 3.55, 3.56,
OH
S
S
3.90 (3 ¥ s, each 6H, each OCH3), 7.75 (s, 2H, 3-H, 3¢-H).
Me
Me
HO
c-d
13C NMR (63 MHz, CDCl3): d = 30.36 [C(CH3)3], 35.12 [C(CH3)3],
51.59, 59.50, 59.84 (OCH3), 123.8, 124.4, 132.1, 142.3, 150.8,
155.9, 167.4 (C=O).
M
M
OMe
OH
59%
OMe
OMe
OH
OH
S
S
MS (70 eV): m/z (%) = 502 (21) [M+], 455 (20) [M+-CH3OH-
OMe
OH
+
CH3], 149 (100), 57 (47) [C4H9 ].
(M)-33
mastigophorene B (6b)
Anal. Calcd for C28H38O8 (502.60): C, 66.91; H, 7.62. Found: C,
66.64; H, 7.52.
Reagents and conditions: (a) (R)-12, BH3◊THF, THF, -20 °C, 2 h
[51% (M)-31 and 43% (P)-33]; (b) LiAlH4, THF, 2 h (85%);
(c) (CBrCl2)2, PPh3, CH2Cl2, 4 h, then LiAlH4, CH2Cl2/Et2O, 4 h;
(d) BBr3, CH2Cl2, 1 h (59%, three steps).
(rac)-4,4¢-Di-tert-butyl-6,6¢-dihydroxymethyl-2,2¢,3,3¢-tetra-
methoxy-1,1¢-biphenyl (20)
At 0 °C under Ar, a solution of diester 19 (2.00 g, 3.98 mmol) in
THF (50 mL) was treated with LiAlH4 (605 mg, 15.9 mmol) in por-
tions. After 2 h, the reaction mixture was carefully hydrolyzed by
slow addition of H2O (10 mL) and 2 N HCl (20 mL), the organic sol-
vent was removed in vacuo, and the aqueous phase was extracted
with Et2O. The organic phase was dried (MgSO4), the solvent evap-
orated, and the residue crystallized from Et2O/petroleum ether to
give colorless crystals of 20 (1.54 g, 3.45 mmol, 87%), mp 183-
185 °C.
Scheme 8 kinetic – here diastereomeric – resolution of 31 by oxa-
zaborolidine-assisted borane reduction and final steps of the synthe-
sis of mastigophorene B (6B).
Experimental
Mps were determined on a Reichert-Jung Thermovar hot-stage ap-
paratus and are uncorrected. IR spectra were recorded using a Per-
kin-Elmer 1420 spectrometer and are reported in wave numbers
(cm-1). Optical rotations were measured on a Perkin-Elmer 241
MC polarimeter. CD spectra were taken on a Jasco J-715 spectropo-
larimeter, using EtOH as solvent. 1H and 13C NMR spectra were re-
corded on Bruker AC 200 (200 and 50 MHz), AC 250 (250 and 63
MHz), and AMX 400 (400 and 101 MHz) machines. Chemical
shifts (d) are reported in ppm and coupling constants (J) in Hz. As
the internal reference, the solvent signal [1H: d (CDCl3) = 7.26, 13C:
d (CDCl3) = 77.01] was used. EI mass spectra (70 eV) were mea-
sured on Finnigan MAT 90 and MAT 8200 mass spectrometers, the
relative intensities are given in brackets. Microanalyses were per-
formed by the microanalytical laboratory of the Inorganic Institute
of the University of Würzburg, Germany (Leco CHNS-932).
IR (KBr): n = 3420 (OH), 2980, 2940, 2850 (C-H), 1370, 1290,
1220, 1000 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.43 [s, 18H, C(CH3)3], 3.62 (s,
6H, 2- and 2¢-OCH3), 3.87 (s, 6H, 3- and 3¢-OCH3), 4,17 (s, 4H,
CH2OH), 7.21 (s, 2H, 5-H, 5¢-H).
13C NMR (50 MHz, CDCl3): d = 30.53 [C(CH3)3], 35.14 [C(CH3)3],
59.91 (OCH3), 63.76 (CH2OH), 123.3, 128.1, 134.3, 143.7, 150.6,
152.2.
MS (70 eV): m/z (%) = 446 (10) [M+], 428 (100) [M+-H2O ], 57
+
(81) [C4H9 ].
Anal. Calcd for C26H38O6 (446.58): C, 69.93; H, 8.58. Found: C,
69.46; H, 8.40.
Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
163
(rac)-4,4¢-Di-tert-butyl -5,5¢,6,6¢-tetramethoxy-1,1¢-biphenyl-
2,2¢-dicarbaldehyde (21)
13C NMR (63 MHz, CDCl3): d = 30.27, 30.38 [C(CH3)3], 35.18,
35.38 [C(CH3)3], 60.10, 60.21, 60.23 (OCH3), 69.99 (CH2), 121.6,
123.9, 126.3, 126.5, 126.7, 130.8, 144.1, 144.6, 151.0, 152.8, 153.6,
155.6, 170.5 (C=O).
A solution of compound 20 (1.54 g, 3.45 mmol) in CH2Cl2 (50 mL)
was stirred with MnO2 (3.00 g, 34.5 mmol) for 3 days at 30 °C with
ultrasonic assistance. The mixture was filtered over silica (2 cm
Celite on top of column). After evaporation of the solvent, the crude
product (1.49 g, 3.37 mmol, 98%) was obtained, which was used in
the next step without purification. An analytical sample was crystal-
lized from petroleum ether, mp 181-182 °C.
MS (70 eV): m/z (%) = 442 (100) [M+], 427 (25) [M+-CH3], 397
(18) [M+-CO2H], 383 (32), 341 (55).
Anal. Calcd for C26H34O6 (442.55): C, 70.56; H, 7.74. Found: C,
70.56; H, 7.46.
IR (KBr): n = 2980, 2940, 2840, 2800 (C-H), 1670 (C=O), 1290,
Kinetic Resolution of (rac)-3,9-Di-tert-butyl-1,2,10,11-tetra-
methoxydibenzo[c,e]oxepin-5(7H)-one (22)
1220, 1040 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.45 [s, 18H, C(CH3)3], 3.56 (s,
6H, 5- and 5¢-OCH3), 3.95 (s, 6H, 6- and 6¢-OCH3), 7.81 (s, 2H, 3-
H, 3¢-H), 9.61 (s, 2H, CHO).
13C NMR (50 MHz, CDCl3): d = 30.22 [C(CH3)3], 35.44 [C(CH3)3],
59.70, 60.15 (OCH3), 122.3, 129.6, 130.0, 144.7, 151.2, 157.9,
190.6 (CHO).
To a solution of oxazaborolidine (S)-12 (133 mg, 480 µmol) in THF
(4 mL), BH3∑THF (1 M in THF, 640 µl, 640 µmol) was added at
0 °C under an Ar atm. After stirring for 30 min at r.t., the solution
was cooled to -20 °C and added dropwise during 5 min to a solu-
tion of lactone 22 (71.0 mg, 160 µmol) in THF (4 mL) at -20 °C.
After 3 h, the mixture was hydrolyzed by careful addition of H2O
(5 mL) and acidified with 2 N HCl (5 mL). After removal of the
organic solvent in vacuo, the mixture was extracted with CH2Cl2.
The organic phase was dried (Na2SO4), the solvent was removed
in vacuo, and the residue was chromatographed on silica gel
(petroleum ether/Et2O, 1:2), leading to alcohol (M)-20 [41.8 mg,
93.6 µmol, 58%, er = 76:24; after crystallization: enrichment to
er = 90:10 in the mother liquor] and lactone (P)-22 (23.2 mg,
52.4 µmol, 33%, er = 98:2). The relative rate constant Krel was
determined45 to be 12 (65% conversion).
MS (70 eV): m/z (%) = 442 (56) [M+], 413 (41) [M+-CHO], 385
+
(73), 57 (100) [C4H9 ].
Anal. Calcd for C26H34O6 (442.55): C, 70.56; H, 7.74. Found: C,
70.15; H, 7.64.
(rac)-4,4¢-Di-tert-butyl-2¢-hydroxymethyl-5,5¢,6,6¢-tetra-
methoxy-1,1¢-biphenyl-2-carboxylic Acid (22)
A mixture of dialdehyde 21 (1.49 g, 3.37 mmol) and KOH (2.80 g,
50.6 mmol) in EtOH (100 mL) was refluxed for 24 h. The solvent
was removed in vacuo, H2O (20 mL) was added, and the mixture
was acidified with 2 N HCl. Extraction with Et2O (drying with
MgSO4) gave the hydroxy acid 22 as a colorless solid, which was
used in the next step without purification. An analytical sample was
crystallized from EtOAc, mp 189-191 °C.
(M)-4,4¢-Di-tert-butyl-6,6¢-dihydroxymethyl-2,2¢,3,3¢-tetra-
methoxy-1,1¢-biphenyl [(M)-20]
Colorless needles, mp 182-184 °C (CH2Cl2/petroleum ether).
[a]23D -54.7° (c 0.20, CHCl3).
CD (EtOH): De194 +29.8, De218 -14.4.
IR (KBr): n = 3400 (OH), 2980, 2920, 2840 (C-H), 1690 (C=O),
(P)-3,9-Di-tert-butyl-1,2,10,11-tetramethoxydibenzo[c,e]oxepin-
5(7H)-one [(P)-22]
1290, 1240 cm-1.
Colorless crystals, mp 198 °C (CH2Cl2/petroleum ether).
[a]24D = +23.3° (c 0.95, CH2Cl2).
1H NMR (200 MHz, CDCl3): d = 1.41 [s, 18H, C(CH3)3], 3.50, 3.57
(2 ¥ s, each 3H, 6-OCH3, 6¢-OCH3), 3.78, 3.91 (2 ¥ s, each 3H, 5-
OCH3, 5¢-OCH3), 4.21, 4.22 (2 ¥ br s, each 1H, CHHOH, CHHOH),
7.15, 7.75 (2 ¥ s, each 1H, 3-H, 3¢-H).
CD (EtOH): De196 +12.3, De212 -7.1, De228 +2.7, De266 -4.0.
13C NMR (50 MHz, CDCl3): d = 30.25, 30.53 [C(CH3)3], 35.08,
35.20 [C(CH3)3], 59.40, 59.73, 59.85, 60.24 (OCH3), 64.40
(CH2OH), 122.9, 124.9, 125.0, 128.5, 131.1, 132.8, 143.1, 143.3,
150.5, 150.9, 152.1, 156.6, 171.3 (CO2H).
(P)-4,4¢-Di-tert-butyl-6,6¢-dihydroxymethyl-2,2¢,3,3¢-tetra-
methoxy-1,1¢-biphenyl [(P)-20]
LiAlH4 (3.87 mg, 102 µmol) was added in portions at 0 °C to a so-
lution of (P)-22 (37.9 mg, 85.6 µmol) in THF (6 mL) under Ar atm.
After stirring for 2 h at r.t., the reaction was quenched by addition
of 2 N HCl (1 mL), the organic solvent was removed in vacuo, and
H2O (10 mL) was added. This mixture was extracted with CH2Cl2,
the combined organic layers were dried (Na2SO4), and the solvent
was removed in vacuo. The residue was purified by column filtra-
tion (petroleum ether/Et2O, 1:2). Crystallization from Et2O/petro-
leum ether gave (P)-20 (35.2 mg, 78.8 µmol, 92%, er = 97:3) as
colorless crystals, mp 182-183 °C.
MS (70 eV): m/z (%) = 460 (47) [M+], 442 (100) [M+-H2O], 427
+
(28) [442-CH3], 57 (87) [C4H9 ].
Anal. Calcd for C26H36O7 (460.57): C, 67.80; H, 7.88. Found: C,
67.51; H, 7.94.
(rac)-3,9-Di-tert-butyl-1,2,10,11-tetramethoxydibenzo[c,e]oxe-
pin-5(7H)-one (22)
To a solution of crude hydroxy acid 22 (vide supra) in CH2Cl2 (150
mL), DCC (832 mg, 4.04 mmol) and DMAP (206 mg, 1.68 mmol)
were added, and the mixture was refluxed. After 4 h, the solvent was
removed in vacuo and the residue was purified by column chroma-
tography (petroleum ether/Et2O, 5:1). Crystallization from Et2O/pe-
troleum ether gave the lactone 22 (1.33 g, 3.01 mmol, 89% over two
steps) as colorless crystals, mp 196-197 °C.
[a]23D +64.1° (c 0.93, CHCl3).
CD (EtOH): De197 -21.3, De221 +14.8, De240 +2.1.
(P)-4,4¢-Di-tert-butyl-2,2¢,3,3¢-tetrahydroxy-6,6¢-dimethyl-1,1¢-
biphenyl [(P)-23]
Under an atm of dry Ar, 1,2-dibromotetrachloroethane [(CBrCl2)2,
67.7 mg, 208 µmol] and PPh3 (54.6 mg, 208 µmol) were added to
(P)-20 (33.1 mg, 74.1 µmol) in CH2Cl2 (3 mL). After stirring for 4
h at r.t., Et2O (3 mL) and LiAlH4 (11.8 mg, 311 µmol) were added,
and the reaction was stirred at r.t. for 1 day. After addition of H2O
(8 mL) and 2 N HCl (4 mL), extraction (CH2Cl2, drying over
Na2SO4), and removal of the solvent in vacuo gave a colorless resi-
due,46 which was dissolved in CH2Cl2 (4 mL) and treated with BBr3
(49.1 µL, 519 µmol) at 0 °C under Ar. After stirring for 1 h at r.t.,
IR (KBr): n = 2960, 2920, 2840 (C-H), 1690 (C=O), 1360, 1220,
1140, 1040 cm-1.
1H NMR (200 MHz, CDCl3): d = 1.41, 1.43 [2 ¥ s, each 9H, each
C(CH3)3], 3.56, 3.64 (2 ¥ s, each 3H, 1-OCH3, 11-OCH3), 3.93, 3.94
(2 ¥ s, each 3H, 2-OCH3, 10-OCH3), 4.80 (d, 1H, J = 11.8 Hz,
CHH), 4.96 (d, 1H, J = 11.9 Hz, CHH), 7.11, 7.56 (2 ¥ s, each 1H,
4-H, 8-H).
Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

164
G. Bringmann et al.
FEATURE ARTICLE
excessive BBr3 was destroyed by addition of MeOH (1 mL), and the
solvent was removed in vacuo. Purification of the residue by col-
umn chromatography (cyclohexane/EtOAc, 5:1) yielded (P)-23,
which was obtained from EtOAc/cyclohexane as colorless crystals
(19.5 mg, 54.4 µmol, 73% over three steps), identical to material
was filtered off and washed with CH2Cl2 and the solvent was re-
moved in vacuo. Column chromatography (cyclohexane/EtOAc,
8:1) gave 30 (36.8 mg, 66.8 µmol, 53%, drM:P = 54:46) as a colorless
solid, along with (1¢S)-3,4-dimethoxy-5-(1¢,2¢,2¢-trimethylcyclo-
pentyl)benzaldehyde28 (19.6 mg, 70.9 µmol, 28%). The atropiso-
mers (M)-30 and (P)-30 could not be separated at this point and
were thus characterized as a diastereomeric mixture.48
obtained previously,42 mp 244 °C (Lit.42: mp 242-243 °C); [a]23
-
D
33.6° (c 0.53, CHCl3) [Lit.42: [a]23D -33.3° (c 0.61, CHCl3)]. During
this reaction, Ph3P.BBr347 was formed, which could be easily sepa-
rated by column chromatography. On contact with air, Ph3P.BBr3
slowly hydrolyzed, so that, after treatment of the recovered adduct
with H2O and extraction with Et2O, PPh3 (47.2 mg, 180 µmol, 86%)
could be recycled.
IR (KBr): n = 3090 (Ar-H), 2930, 2835, 2805 (C-H), 1675 (C=O),
1570 (C=C), 1285 cm-1.
1H NMR (400 MHz, CDCl3) [(M)-30]: d = 0.71, 1.18, 1.44 (3 ¥ s,
each 6H, each CH3), 1.51-1.90 (m, 10H, 3¢¢-H, 4¢¢-H, 5¢¢-CHH),
2.63-2.72 (m, 2H, 5¢¢-CHH), 3.46, 3.89 (2 ¥ s, each 6H, each
OCH3), 7.91 (s, 2H, 3-H, 3¢-H), 9.67 (s, 2H, CHO).
1H NMR (400 MHz, CDCl3) [(P)-30]: d = 0.74, 1.18, 1.45 (3 ¥ s,
each 6H, each CH3), 1.49-1.92 (m, 10H, 3¢¢-H, 4¢¢-H, 5¢¢-CHH),
2.61-2.74 (m, 2H, 5¢¢-CHH), 3.55, 3.90 (2 ¥ s, each 6H, each
OCH3), 7.87 (s, 2H, 3-H, 3¢-H), 9.60 (s, 2H, CHO).
13C NMR (101 MHz, CDCl3): d = 20.41/20.43 (CH2), 23.49/23.82,
25.26/25.38, 27.00/27.02 (CH3), 39.21/39.36, 41.06/41.20 (CH2),
44.91/44.94, 51.95/51.96 (C-1¢¢, C-2¢¢), 59.34/59.70, 60.27/60.31
(OCH3), 124.3/124.7, 128.9/129.2, 129.2/129.9, 142.0/142.2,
151.2/151.5, 158.2/158.4, 190.5/190.8 (C=O).
MS (70 eV): m/z (%) = 550 (100) [M+], 535 (6) [M+-CH3], 521 (18)
[M+-CHO], 520 (18) [M+-CH2O], 519 (44) [M+-CH3O], 492 (29),
480 (9) [M+-C5H10], 468 (4) [M+-C6H10].
(1¢S)-2-Bromo-3,4-dimethoxy-5-(1¢,2¢,2¢-trimethylcyclopent-
yl)phenyl-1-methanol (28)
Bromo compound 2728 (150 mg, 440 µmol) was refluxed with NBS
(156 mg, 876 µmol) and (t-BuO)2 (50 µL) in CHCl3 (10 mL). After
2 h, another portion of NBS (117 mg, 657 µmol) and (t-BuO)2 (50
µL) was added to ensure complete consumption of the starting ma-
terial. The reaction was stirred at reflux for another 2 h. After cool-
ing to r.t., H2O (10 mL) was added, and the mixture was extracted
with CH2Cl2. The organic phase was dried (MgSO4) and the solvent
was removed in vacuo. The resulting solid was dissolved in H2O/di-
oxane (9 mL each) and refluxed with CaCO3 (222 mg, 2.22 mmol)
overnight. After acidification with 2 N HCl, the mixture was ex-
tracted with CH2Cl2, the combined organic extracts were dried
(MgSO4) and evaporated. The resulting residue was purified by
column chromatography (petroleum ether/Et2O, 5:1), yielding, be-
sides the aldehyde 29 (40.0 mg, 113 µmol, 26%), the bromo alcohol
28 (90.0 mg, 252 µmol, 57%) as a colorless oil.
HRMS: m/z calcd for C34H46O6: 550.3294. Found: 550.3291.
(1¢S)-3,9-Bis(1¢,2¢,2¢-trimethylcyclopentyl)-1,2,10,11-tetra-
methoxydibenzo[c,e]oxepin-5(7H)-one (31)
[a]23D -13.9° (c 0.75, CHCl3).
A solution of dialdehyde 30 (35.3 mg, 64.1 µmol) in EtOH (3 mL)
was treated with KOH (119 mg, 2.12 mmol) at reflux for 1.5 h. The
solvent was removed in vacuo, H2O (10 mL) was added, and the
mixture was acidified with 2 N HCl. Extraction with CH2Cl2 (dry-
ing with Na2SO4) gave the corresponding hydroxy acid as a color-
less solid, which was used without purification for the next step: It
was dissolved in CH2Cl2 (8 mL), together with DCC (19.8 mg, 96.0
µmol) and DMAP (3.92 mg, 32.1 µmol), and stirred for 8 h at r.t.
under Ar. Then the solution was washed with H2O (20 mL) and
brine (20 mL), the organic phase was dried (Na2SO4), and the sol-
vent was removed in vacuo. The residue was purified by column
chromatography (petroleum ether/Et2O, 3:1) to yield lactone 31
(17.9 mg, 32.5 µmol, 51% over two steps, drM:P = 58:42) as a slight-
ly yellow oil. The inseparable atropisomers (M)-31 and (P)-31 were
characterized as a diastereomeric mixture.49
CD (EtOH): De195 -3.3, De208 +7.8, De234 -4.9.
IR (KBr): n = 3090 (Ar-H), 2920, 2845, 2805 (C-H), 1535 (C=C),
1375, 1020, 1005 cm-1.
1H NMR (400 MHz, CDCl3): d = 0.68, 1.12, 1.34 (3 ¥ s, each 3H,
each CH3), 1.44-1.84 (m, 5H, 3¢-H, 4¢-H, 5¢-CHH), 2.51-2.63 (m,
1H, 5¢-CHH), 3.81, 3.83 (2 ¥ s, each 3H, each OCH3), 4.68 (br s, 2H,
CH2OH), 7.21 (s, 1H, 6-H).
13C NMR (101 MHz, CDCl3): d = 20.34 (CH2), 23.88, 25.23, 26.84
(CH3), 39.12, 40.96 (CH2), 44.83, 51.68 (C-1¢, C-2¢), 59.87, 60.27
(OCH3), 65.46 (CH2OH), 115.7, 124.5, 133.9, 140.5, 150.8, 153.4.
MS (70 eV): m/z (%) = 358/356 (100/100) [M+], 327/325 (13/22)
[M+-CH3O], 288/286 (62/61) [M+-C5H10], 277 (7) [M+-Br], 276/
274 (62/76) [M+-C6H10], 275/273 (65/89) [M+-C6H11], 259 (51),
245/243 (46/55).
IR (KBr): n = 3080 (Ar-H), 2930, 2845 (C-H), 1705 (C=O), 1570
Anal. Calcd for C17H25BrO3 (357.29): C, 57.15; H, 7.05. Found: C,
56.89; H, 7.18.
(C=C), 1380, 1360 cm-1.
1H NMR (400 MHz, CDCl3) [(M)-31]: d = 0.74, 0.74, 1.16, 1.18,
1.41, 1.42 (6 ¥ s, each 3H, each CH3), 1.50-1.94 (m, 10H, 3¢-H, 4¢-
H, 5¢-CHH), 2.54-2.71 (m, 2H, 5¢-CHH), 3.51, 3.52, 3.86, 3.91 (4
¥ s, each 3H, each OCH3), 4.80 and 4.96 (AB system, 2H, 2J = 11.9
Hz, OCH2), 7.15 (s, 1H, 8-H), 7.65 (s, 1H, 4-H).
1H NMR (400 MHz, CDCl3) [(P)-31]: d = 0.72, 0.74, 1.15, 1.17,
1.39, 1.43 (6 ¥ s, each 3H, each CH3), 1.48-1.92 (m, 10H, 3¢-H, 4¢-
H, 5¢-CHH), 2.53-2.74 (m, 2H, 5¢-CHH), 3.55, 3.63, 3.85, 3.87 (4
¥ s, each 3H, each OCH3), 4.78 and 4.96 (AB system, 2H, 2J = 11.9
Hz, OCH2), 7.15 (s, 1H, 8-H), 7.64 (s, 1H, 4-H).
13C NMR (101 MHz, CDCl3) [(M)-31]: d = 20.36, 20.44 (CH2),
23.97, 24.13, 25.26, 25.32, 26.83, 26.96 (CH3), 39.05, 39.30, 40.95,
41.09 (CH2), 45.14, 45.15, 51.76, 51.88 (C-1¢, C-2¢), 60.12, 60.23,
60.30, 60.35 (OCH3), 70.18 (OCH2), 123.6, 125.8, 126.1, 126.3,
126.4, 126.5, 130.2, 141.8, 142.1, 153.2, 154.0, 156.2, 170.6 (C=O).
(1¢S)-2-Bromo-3,4-dimethoxy-5-(1¢,2¢,2¢-trimethylcyclopent-
yl)benzaldehyde (29)
To a solution of benzyl alcohol 28 (74.5 mg, 209 µmol) in CH2Cl2
(10 mL), MnO2 (72.7 mg, 836 µmol) was added, and the mixture
was stirred at r.t. for 1 day. After removal of the insolubles by filtra-
tion, the solvent was evaporated and the residue was subjected to
column chromatography (petroleum ether/Et2O, 5:1), to give 29
(63.2 mg, 178 µmol, 85%) as a colorless oil, identical to material
previously obtained by semisynthesis,28 [a]23 -38.5° (c 1.26,
D
CHCl3) [Lit.28: [a]23D -37.6° (c 1.01, CHCl3)].
(1¢¢S)-5,5¢,6,6¢-Tetramethoxy-4,4¢-bis(1¢¢,2¢¢,2¢¢-trimethylcyclo-
pentyl)-1,1¢-biphenyl-2,2¢-dicarbaldehyde (30)
Bromo aldehyde 29 (89.7 mg, 252 µmol) was dissolved in degassed
DMF (0.25 mL) and treated with activated copper44 (176 mg) under
Ar at 165 °C for 16 h. After the mixture had cooled to r.t., the copper
13C NMR (101 MHz, CDCl3) [(P)-31]: d = 20.29, 20.78 (CH2),
23.82, 23.95, 25.10, 25.29, 27.09, 27.12 (CH3), 39.10, 39.26, 40.86,
Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
165
41.12 (CH2), 44.84, 44.92, 51.90, 51.97 (C-1¢, C-2¢), 60.11, 60.14,
60.21, 60.39 (OCH3), 70.15 (OCH2), 123.8, 125.5, 125.8, 126.1,
126.3, 126.4, 130.3, 141.2, 141.7, 153.1, 154.0, 156.2, 170.6 (C=O).
MS (70 eV): m/z (%) = 550 (100) [M+], 535 (7) [M+-CH3], 532
(18), 519 (20) [M+-CH3O], 501 (20), 480 (9) [M+-C5H10], 468 (8)
[M+-C6H10], 467 (6) [M+-C6H11], 419 (13).
After stirring for 2 h at r.t., the mixture was acidified by addition of
2 N HCl (1 mL), H2O (5 mL) was added, and this mixture was ex-
tracted with CH2Cl2. The combined organic layers were dried
(Na2SO4), and the solvent was removed in vacuo. The residue was
purified by column chromatography (cyclohexane/EtOAc, 2:1).
Crystallization from EtOAc/cyclohexane gave (M)-33 (6.41 mg,
11.6 µmol, 85%, dr = 78:22) as colorless crystals, mp 192-193 °C.
HRMS: m/z calcd for C34H46O6: 550.3294. Found: 550.3296.
[a]23D -60.7° (c 0.25, CHCl3).
CD (EtOH): De202 +6.1, De221 -13.0.
Kinetic Resolution of (1¢S)-3,9-Bis(1¢,2¢,2¢-trimethylcyclopent-
yl)-1,2,10,11-tetramethoxydibenzo[c,e]oxepin-5(7H)-one (31)
To a solution of oxazaborolidine (R)-12 (23.9 mg, 86.2 µmol) in
THF (2 mL), BH3∑THF (1 M in THF, 115 µL, 115 µmol) was added
at 0 °C under Ar. After stirring for 30 min at r.t., the solution was
cooled to -20 °C and added dropwise during 5 min to a solution of
the above prepared diastereomeric mixture of lactone 31 (15.8 mg,
28.7 µmol) in THF (2 mL) at -20 °C. After 2 h, the mixture was
hydrolyzed by careful addition of H2O (4 mL) and acidified with
2 N HCl (4 mL). This mixture was extracted with CH2Cl2, the or-
ganic phase was dried (Na2SO4), the solvent was removed in vacuo,
and the residue was chromatographed over silica gel (petroleum
ether/Et2O, 3:1 Æ 1:2), leading to alcohol (P)-33 (colorless oil,
6.92 mg, 12.5 µmol, 43%, dr = 65:35) and lactone (M)-31 (colorless
oil, 8.10 mg, 14.7 µmol, 51%, dr = 81:19). The atropisomers (M)-
33 and (P)-33 could not be separated and were thus characterized as
a diastereomeric mixture.50
Mastigophorene B (6b)
Under an atm of dry Ar, 1,2-dibromotetrachloroethane [(CBrCl2)2,
8.05 mg, 24.7 µmol] and PPh3 (6.48 mg, 24.7 µmol) were added to
(M)-33 (4.90 mg, 8.83 µmol, dr = 78:22) in CH2Cl2 (2 mL). After
stirring for 4 h at r.t., Et2O (2 mL) and LiAlH4 (1.41 mg, 37.2 µmol)
were added, and the reaction was stirred at r.t. for 4 h. After addition
of H2O (4 mL) and 2 N HCl (2 mL), extraction (CH2Cl2, drying over
Na2SO4) and removal of the solvent in vacuo gave a colorless resi-
due, which was dissolved in CH2Cl2 (3 mL) and treated with BBr3
(5.85 µL, 61.9 µmol) at 0 °C under an Ar atm. After stirring for 1 h
at r.t., excess BBr3 was destroyed by addition of MeOH (1 mL), the
solvent was removed in vacuo, and the residue purified by prepara-
tive TLC [1 mm plates (Merck), hexane/CH2Cl2, 1:1], to yield enan-
tio- and diastereomerically pure mastigophorene B (6b) (2.43 mg,
5.21 µmol, 59% over three steps) as a colorless oil, fully identical
spectroscopically with the natural product,11 [a]23D -38.8° (c 0.11,
CHCl3) [Lit.11: [a]19D -39.1° (c 0.35, CHCl3)].
(M,1¢S)-3,9-Bis(1¢,2¢,2¢-trimethylcyclopentyl)-1,2,10,11-tetra-
methoxydibenzo[c,e]oxepin-5(7H)-one [(M)-31]
dr = 81:19; [a]23D ¢-19.1° (c 0.76, CHCl3).
CD (EtOH): De192 -7.5, De212 +4.7, De236 -3.3, De269 +5.8, De308
-1.7.
Acknowledgement
This work has been supported by the Deutsche Forschungsgemein-
schaft (SFB 347 ‘Selektive Reaktionen Metall-aktivierter Molekü-
le’) and by the Fonds der Chemischen Industrie. J. H. thanks the
Freistaat Bayern for a generous fellowship.
(P,1¢¢S)-6,6'-Dihydroxymethyl-2,2¢,3,3¢-tetramethoxy-4,4¢-bis-
(1¢¢,2¢¢,2¢¢-trimethylcyclopentyl)-1,1¢-biphenyl [(P)-33]
dr = 65: 35
IR (KBr): n = 3370 (OH), 3075 (Ar-H), 2920, 2895, 2835 (C-H),
1580 (C=C), 1445, 1375, 1285 cm-1.
References
1H NMR (400 MHz, CDCl3) [(M)-33]: d = 0.74, 1.15, 1.42 (3 ¥ s,
each 6H, each CH3), 1.51-1.91 (m, 10H, 3¢¢-H, 4¢¢-H, 5¢¢-CHH),
2.74-2.85 (m, 2H, 5¢¢-CHH), 3.57, 3.80 (2 ¥ s, each 6H, each
OCH3), 4.18 and 4.22 (AB system, 4H, 2J = 11.5 Hz, CH2OH), 7.29
(s, 2H, 5-H, 5¢-H).
1H NMR (400 MHz, CDCl3) [(P)-33]: d = 0.70, 1.17, 1.45 (3 ¥ s,
each 6H, each CH3), 1.52-1.89 (m, 10H, 3¢¢-H, 4¢¢-H, 5¢¢-CHH),
2.55-2.67 (m, 2H, 5¢¢-CHH), 3.57, 3.82 (2 ¥ s, each 6H, each
OCH3), 4.17 and 4.23 (AB system, 4H, 2J = 11.4 Hz, CH2OH), 7.29
(s, 2H, 5-H, 5¢-H).
13C NMR (101 MHz, CDCl3) [(M)-33]: d = 20.39 (CH2), 24.40,
25.06, 26.96 (CH3), 38.75, 40.70 (CH2), 44.99, 51.75 (C-1¢¢, C-2¢¢),
59.82, 60.28 (OCH3), 63.81 (CH2OH), 126.0, 128.0, 133.7, 140.7,
150.8, 152.7.
13C NMR (101 MHz, CDCl3) [(P)-33]: d = 20.42 (CH2), 23.54,
25.43, 26.99 (CH3), 39.21, 41.07 (CH2), 44.99, 51.74 (C-1¢¢, C-2¢¢),
59.82, 60.05 (OCH3), 64.22 (CH2OH), 126.1, 127.7, 134.2, 141.1,
150.5, 152.7.
†
Part 89 of the series “Novel Concepts in Directed Biaryl
Synthesis”. For part 88; see ref. 13.
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Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

166
G. Bringmann et al.
FEATURE ARTICLE
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Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York

FEATURE ARTICLE
From Dynamic to Non-Dynamic Kinetic Resolution of Lactone-Bridged Biaryls
167
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Gee, W.; Shaw, R. A.; Smith, B. C. J. Chem. Soc. 1964, 4180.
Muylle, E.; van der Kelen, G. P.; Eeckhaut, Z. Spectrochim.
Acta, Part A 1975, 31A, 1039.
Peters, K.; Peters, E. -M.; von Schnering, H. G.; Bringmann,
G.; Hartung, T. Z. Kristallogr. 1992, 202, 275.
(38) Oi, S.; Kawagoe, K.; Miyano, S. Chem. Lett. 1993, 79.
Bringmann, G.; Schöner, B.; Schupp, O.; Peters, K.; Peters, E.
-M.; von Schnering, H. G. Liebigs Ann. Chem. 1994, 91.
(39) Gille, G.; Pabst, T.; Bringmann, G.; Janetzky, B.; Reichmann,
H.; Rausch, W. -D. Drug Dev. Res. 2000, 50, 153.
(40) In the crystals of 19, 21 and 22, both helimeric forms are
found; for reasons of clarity, only the (M)-configured
atropisomers are shown. Crystal data for 19: C28H38O8,
monoclinic, space group P21; unit cell parameters:
a = 927.16(7), b = 1143.30(9), c = 1402.0(1) pm;
ß = 106.38(7)°; V = 1425.9(2).106 pm3.
Weller, F.; Möhlen, M.; Dehnicke, K. Z. Kristallogr. NCS
1997, 212, 159.
Crystal data for 21: C26H34O6, monoclinic, space group P21/c;
unit cell parameters: a = 829.7(1), b = 1176.9(2),
c = 2561.9(4) pm; ß = 94.05(1)°; V = 2495.2(7).106 pm3.
Crystal data for 22: C26H34O6, monoclinic, space group P21/c;
unit cell parameters: a = 1175.9(3), b = 1054.9(3),
c = 2017.5(8) pm; ß = 101.10(1)°; V = 2455.6(1).106 pm3.
Further details of the structure investigations are available on
request from the Cambridge Crystallographic Data Centre, on
quoting the depository numbers CCDC-147219 (for 19),
CCDC-147220 (for 21) or CCDC-147221 (for 22), the names
of the authors and the journal citation.
Goetze, R.; Nöth, H. Z. Naturforsch. B: Chem. Sci. 1975, 30b,
343.
(48) Due to the prevalence of (M)-30, the 1H NMR signals could be
attributed to each diastereomer.
(49) Due to the prevalence of (M)-31 in the next step (kinetic
resolution), the NMR signals could be attributed to each
diastereomer.
(50) Due to the prevalence of (M)-33 in the next step, the NMR
signals could be attributed to the two diastereomers.
Article Identifier:
1437-210X,E;2001,0,01,0155,0167,ftx,en;Z07100SS.pdf
Synthesis 2001, No. 1, 155–167 ISSN 0039-7881 © Thieme Stuttgart · New York