Journal of Organometallic Chemistry 661 (2002) 31 /47

www.elsevier.com/locate/jorganchem

The lactone concept* a novel approach to the metal-assisted

/

atroposelective construction of axially chiral biaryl systems

Gerhard Bringmann a,*, Matthias Breuning a, Robert-M. Pfeifer a, Wolfdieter
A. Schenk b, Ken Kamikawa c, Motokazu Uemura c
a
Institut für Organische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
b
Institut für Anorganische Chemie, Universität Würzburg, Am Hubland, D-97074 Würzburg, Germany
c
Department of Chemistry, Faculty of Integrated Arts and Sciences, Osaka Prefecture University, Sakai, Osaka 599-8531, Japan

Received 24 April 2002; accepted 30 July 2002

Dedicated to Dr. Waldemar Adam on the occasion of his 65th birthday.

Abstract

The atroposelective synthesis of axially chiral biaryls via configurationally unstable, lactone-bridged biaryls is reviewed. These key
molecules are easily accessible by regioselective intramolecular cross-coupling of ester-linked, even sterically hindered aromatic
portions and can be cleaved highly atropo-enantio- or -diastereoselectively by three principal options, either (a) by using a wide
range of chiral metalated nucleophiles (usually with external asymmetric induction), (b) after Lewis acid activation of the lactone
C
/O function using uncharged chiral or achiral nucleophiles, or (c) with internal asymmetric induction, using the stereoelement of
planar chirality originating from h6-coordination (typically involving Cr or Ru complexes). The resulting ring-opened
configurationally stable biaryls are obtained in mostly excellent chemical and optical yields. By the choice of the respective
enantiomer of the nucleophile, the method allows the atropo-divergent synthesis of both atropisomers from the same immediate
biaryl precursor and, if required, a recycling of the undesired minor atropisomer is possible, too. Such advantages are otherwise
well-known for the stereoselective preparation of centrochiral compounds.
# 2002 Elsevier Science B.V. All rights reserved.

Keywords: Biaryls; Stereoselective synthesis; Atropisomers; Axial chirality; Ring opening; Dynamic kinetic resolution

1. Introduction vancomycin (2) [3], show a broad structural variety and

frequently offer attractive pharmacological profiles [4].
The presence of an axially chiral biaryl axis is the Despite the increasing importance of axial chirality,
structurally dominating feature of a steadily growing only few methods (for three selected examples, see Fig.
number of chiral auxiliaries and natural products. As an 2) exist that permit an efficient regio- and stereoselective
example, binaphthyl-derived systems like BINAP (1) [1] construction of biaryl compounds under mild conditions
(Fig. 1) provide a rigid framework for numerous chiral [5 /8]. Most of them, however, suffer from low chemical
transition metal complexes, which are highly stereo- and/or optical yields in the cross coupling of more
differentiating catalysts successfully applied in almost sophisticated and sterically hindered aryl moieties. Also,
any area of asymmetric synthesis [2]. Axially chiral there is often no possibility for the optional, ‘atropo-
biaryls from nature, among them the famous antibiotic divergent’ preparation of both rotational isomers from
the same precursor, in particular if the chiral auxiliary is

Novel Concepts in Directed Biaryl Synthesis, part 101. For part attached to one or two of the coupling partners. The
100, see Ref. [75]. recently published enantioselective coupling protocols
* Corresponding author. Tel.: /49-931-888-5323; fax: /49-931- [9] using chirally modified Pd-catalysts are restricted to
888-4755 only few substrates and are not (or not yet) generally
E-mail address: [email protected] (G.
Bringmann). applicable.

0022-328X/02/$ - see front matter # 2002 Elsevier Science B.V. All rights reserved.
PII: S 0 0 2 2 - 3 2 8 X ( 0 2 ) 0 1 8 0 4 - 1
32 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

Fig. 1. Structures of the synthetic auxiliary BINAP (1) and the naturally occurring antibiotic vancomycin (2).

The obvious need for efficient procedures that permit that they have to perform two difficult tasks simulta-
the atroposelective construction of axially chiral biaryls, neously: The C /C-bond formation to create the axis
led us to face this challenging problem and to focus on and the introduction of the chiral information. Our idea
the development of a method that fulfills the following was to solve these two problems consecutively, i.e. to
demands: it should provide high chemical and optical achieve a non-stereoselective, but chemically highly
yields and should be broadly applicable, i.a. to the efficient (since intramolecular) coupling reaction leading
regioselective cross coupling even of sterically severely to a stereochemically not yet fixed biaryl, which would
hindered biaryl fragments; it should tolerate virtually subsequently be converted into the axially chiral target
any substitution pattern in the starting materials and molecule of any configuration. The possibility to reverse
should be compatible with usual functional groups. this process would permit the re-use of undesired
Furthermore, it should include the principle of atropo- atropisomers. To reach such a stereochemically unde-
divergence, i.e. the directed preparation of both atropi- fined intermediate, the two aryl moieties had to be
somers from the same immediate precursor, and should forced to lie ‘in plane’, or */at least */to adopt a slightly
provide the option for a recycling of undesired stereo-
distorted and thus chiral arrangement, yet with a low
isomeric by-products possibly likewise formed. With the
isomerization barrier (see below), which can be achieved
‘lactone concept ’ presented in this paper, we have tried
by connecting them by a short bridge. Thus, in contrast
to meet all these requirements [10 /12]. Selected exam-
to many known methods (cp. Fig. 2), our strategy [10]
ples of applications of the strategy in the atroposelective
does not use the bridge as a chiral auxiliary in the
synthesis of axially chiral biaryl auxiliaries and concrete
naturally occurring target molecules will be reviewed in coupling step, but*/besides bringing the coupling
the following article [13]. partners close together */rather as a tool that prevents
the formation of a configurationally stable axis. This
concept was realized as outlined in Scheme 1, with
benzonaphthopyranones of type 11 [14] as the key
2. The basic principle of the ‘lactone concept’ intermediates.
In esters of type 10, easily synthesized from simple
A major problem of most of the known techniques for aromatic compounds like 8 and 9, the two biarylic
the stereoselective biaryl coupling results from the fact portions are prefixed at a short distance to each other */

Fig. 2. A brief selection of methods for the stereoselective construction of axially chiral biaryls [6,7,9].
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 33

an ideal precondition for the following intramolecular helically distorted */severely for R /t Bu and also for
biaryl coupling step (100/11), which proceeds with a R /Me, but even for R /H (Fig. 4).
reliable regioselectivity with respect to the bromine and The optional preparation of either the M - or the P -
the ortho -positions of the phenolic part. Using configured ring opening product from the same lactone
Pd(OAc)2 or, even better, the more temperature-stable can thus only be brought into line with their configura-
palladacycle 13 [15] as catalyst, the desired lactones 11 tional instability. Again in agreement with quantum
are obtained in good to excellent yields (Fig. 3) [16,17]. chemical calculations [18,22], the halflife of this process
In this way, a set of useful, structurally diverse biaryl was determined experimentally by racemization of
lactones 11a/f has been prepared, equipped with steric enantiomerically enriched samples or by DNMR experi-
hindrance at the biaryl axis which ranges from low (11a: ments on derivatives equipped with ethyl or isopropyl
R /H) to very high (11f: R /t Bu). Subsequent cleavage groups as stereochemical probes (Scheme 2) [23]. For
of the lactone function can be performed stereoselec- small substituents R ortho to the axis like H or OMe,
tively, leading to the now axially chiral target biaryls 12. and even for R /Me, the interconversion occurs very
These possess a hydroxy group and a C1-unit next to the rapidly at room temperature (t1/2 B/1 s). The process
axis */a useful structural array found in many naturally slows down with increasing size of R (e.g. R /Et: t1/2 /
occurring axially chiral biaryls [4,10,13], which is, if ca. 1 min, i Pr: t1/2 /ca. 30 min) and is eventually
required, also open for further transformations. (almost) frozen for R /t Bu (t1/2 /2 day). From these
findings, the ring opening of 11 must follow the
principle of a dynamic kinetic resolution, by which the
enantiomer that gets consumed more rapidly, is con-
3. Structure and dynamics of the biaryl lactones stantly provided from the less reactive one, by the fast
equilibrium (M)-11X/(P )-11, while the configuration-
Among the two key steps of the procedure, the C /C- ally stable lactone 11f (R /t Bu) is an excellent substrate
bond formation through intramolecular biaryl coupling for ‘normal’ (i.e. non-dynamic) kinetic resolutions (see
and the ring cleavage reaction, the latter was found to be Section 7.2).
the stereochemically decisive one, since it is usually this
step that establishes the ultimate configuration at the
axis. The simplest explanation for this atropo-diver- 4. Different options for the metal-assisted ring opening of
gence in the ring opening reaction would be that the the lactones
lactones are flat and thus achiral, and that the chiral ring
cleavage reagent, with transient pyramidalization of the For the cleavage of the configurationally unstable
lactone carbonyl function, opens the ring with a defined biaryl lactones (9), with external or internal asymmetric
‘twisting’ at the previously planar-substituted axis. This, induction, three fundamentally different strategies have
however, cannot be the case, because quantum chemical been elaborated (Fig. 5).
calculations [18,19] as well as experimental investiga-
tions like X-ray structure analyses [17,20,21] and NMR 4.1. Method I
[23] clearly show that all of the lactones of type 11 are
Using chiral anionic nucleophiles like metalated
amines, alcohols, hydride transfer reagents etc. for the
cleavage of the lactone bridge of 11; this method
provides the most direct approach to axially chiral
biaryls (see Section 5).

4.2. Method II

Fig. 3. Yields of the PdII-catalyzed coupling 100/11 and structure of By Lewis acid activation of the lactone function of 11,
the binary Pd-catalyst 13 [15]. allowing to perform the ring opening even with un-

Fig. 4. Crystal structures (X-ray) of the helically distorted biaryl lactones 11.
34 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

All three methods are idealized borderline cases,

which in reality will act more or less cooperatively.
For example, a bifunctional catalyst or a Lewis acidic
transition metal as the counter ion will not only activate
the nucleophile, but also coordinate to the carbonyl
group and, thus, enhance the electrophilicity of the
lactone function (combination of methods I and II; for
specific examples see Sections 5.2 and 5.5).

5. Atroposelective ring opening reactions with metalated

nucleophiles (Method I)

5.1. Lactone cleavage with chiral N -nucleophiles

First experiments were performed with the lactones

11b and 11c as the standard substrates, using the cheap
and simple (S )-phenylethylamine [(S )-14 (M /H)] as
Scheme 1. The basic strategy of the lactone concept.
the N -nucleophile (Scheme 3) [25]. While no reaction
occurred with the free amine, ring cleavage with the
alkali metal activated derivatives (S )-14 (M /Li, Na, K)
proceeded smoothly, leading to the biaryl amides 15 in
good yields of 70/99%. In these reactions, a strong
dependence of the asymmetric induction from the
counter ion became evident: Whereas with Li  a low
stereo-differentiation (dr B/60:40) was observed, Na 
and, in particular, K  delivered excellent diastereomeric
Scheme 2. Dynamic behavior of the biaryl lactones 9 (note that for
stereochemically identical lactones 11a,c /f, the CIP descriptors at the ratios of up to 95:5. The degree of steric hindrance at the
biaryl axis are opposite to those of 11b [24]).

charged nucleophiles; in this case, the stereochemical

information can be provided either by using a chiral
Lewis acid or a chiral nucleophile; both options have
been evaluated and are discussed in Section 9.

4.3. Method III

By h6-coordination of a transition metal fragment to

one of the aromatic rings of the biaryl 11, leading to an
activated species whose lactone bridge can be cleaved
with simple achiral nucleophiles, with internal asym-
metric induction through the stereoelement of planar
Scheme 3. Atropo-diastereoselective amidolyses of 11b,c with the
chirality and, possibly, by additional stereocenters (see
metalated (S )-1-phenylethylamides (S )-14.
Section 10).

Fig. 5. Three principal options for the metal-assisted ring opening of the biaryl lactones 11.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 35

biaryl axis [11b (R /OMe) versus 11c (R /Me)] had no

major effect on the asymmetric induction. Diastereo-
merically pure biaryl amides, e.g. (P ,S )-15c, were
obtained by chromatographic separation or, more
conveniently for larger-scale preparations, by crystal-
lization from the crude product mixtures [25].
For the ring opening of the biaryl lactone 11c with
other enantiopure N -nucleophiles like the sterically
more demanding and also commercially available (S )-
1-naphthylethylamine [(S )-16] or the 2,3,4-trimethoxy
derivative (S )-17 [26] of (S )-1-phenylethylamine
(Scheme 4) [25], the activating alkali metal had a similar
influence on the asymmetric induction as observed with
(S )-14 (vide supra), thus delivering the best diastereo-
meric ratios with the potassium amides K /(S )/16 [0/
(P ,S )-18c: dr 90:10] and K /(S )/17 [0/(P,S )-19c: dr
93:7]. With these more differentiated N -nucleophiles,
improved stereoselectivities were not obtained, though.

Scheme 5. Alcoholysis of 11 with metalated (R )-menthoxides as the O-

5.2. Ring opening with chiral alcoholates nucleophiles.

The ring cleavage of 11 with chiral O -nucleophiles in ether (Scheme 5, right table) [27]: Not only did the
leads to configurationally stable esters, which are ring opening in this case proceed with a higher degree of
versatile precursors for the construction of functiona- stereo-differentiation, reaching, dr’s of up to 94:6, but it
lized axially chiral biaryls since they offer manifold also provided an inverse asymmetric induction to give
possibilities for further transformations. Moderate to (P ,R )-21b [and (M ,R )-21c] as the major diastereomers!
good asymmetric inductions were achieved in the This is one of the rare cases in which both stereoisomers
alcoholysis of 11b, c, using the alkali menthoxides (R )- can be prepared from a single precursor and with the
20 (Scheme 5, left table) [27]. In this case, the depen- same reagent (even with the same enantiomer) */just by
dence of the diastereomeric ratio on the counter ion was slightly changing the reaction conditions (here: solution
opposite to that observed for the N -nucleophiles (cf. vs. suspension).
Section 5.1), the highest dr of 14:86 being obtained with The best stereocontrol with O -nucleophiles was
the more covalently N -bonded Li  as the activating achieved with sodium (R )-8-phenylmenthoxide [Na /
metal ion. (R )/22], in which, compared with sodium (R )-menth-
An unexpected result was achieved if sodium menth- oxide [Na /(R )/20], the isopropyl substituent is replaced
oxide [Na /(R ) /20] was not used in solution, but in by the more bulky dimethylphenyl group (Scheme 6).
suspension as formed by deprotonation of (R )-menthol Alcoholysis of 11 with Na /(R ) /22 gave exclusively the
biaryl ester (M ,R )-23c in 95% yield, the other atropo-
diastereomer not being detectable [27].
A first successful approach to a directly enantioselec-
tive variant of the method was achieved with Seebach’s
(i PrO)2Ti-TADDOLate (24) [28], which serves both as a
chiral Lewis acid and as the O -nucleophile (Scheme 7).
Treatment of 11c with 24 delivered the ester (P )-25c [29],
albeit as yet with a moderate er of 79:21 [30].

Scheme 4. Amidolyses of 11c with the arylethylamides (S )-16 and (S )- Scheme 6. Ring opening of 11c with sodium (R )-8-phenylmenthoxide
17. [(R )-22].
36 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

Scheme 7. Atropo-enantioselective alcoholysis of 11c with the

(i PrO)2Ti-TADDOLate 24.

5.3. Less efficient: the use of chiral S -nucleophiles

Different from the highly stereo-differentiating N -

and O -nucleophiles (vide supra), chiral lithiated thiols
like (S )-26 (Scheme 8) have so far cleaved the lactone
bridge of 11c with disappointingly low asymmetric
inductions (dr B/60:40) [31]. The resulting thioesters
(here 27c) are configurationally stable under neutral
conditions, but easily cyclize back to the lactone 11c
Scheme 9. Preparation of the non-racemic alcohol (P )-31c by ring
under basic conditions. Thus, it is not clear whether the opening of 11c with the lithiated sulfoxide (R )-28, ‘stereo-focusing’ by
unsatisfying diastereoselectivities obtained are due to an crystallization, followed by rapid desulfonylation and C -methylation.
insufficient stereocontrol in the ring opening step or
whether they are the result of a subsequent loss of [23]), the subsequent alkylation of which gave the now
stereochemical homogeneity through equilibration via configurationally stable alcohol (P)-31c, still with an er
11, e.g. (M )-27cX/11X/(P )-27c (for a detailed discus- of 86:14 [12].
sion on such ‘stereochemical leakages’, see Section 8).
5.5. Atropo-enantioselective lactone reductions
5.4. Ring cleavage with extension of the carbon
framework: by reaction with C -nucleophiles The atropo-enantioselective cleavage of lactones 11
with chiral hydride transfer reagents proved to be
The ring opening of the lactones 11 with chiral C - particularly successful (Scheme 10). Treatment of 11
nucleophiles should be particularly attractive, in com- with Noyori’s BINAL-H [(M )-32] [33] gave the alcohols
bining the introduction of the stereogenic information at 33 with an er of up to 94:6 and in /90% yield [34];
the biaryl axis with an extension of the C-skeleton. reduction of 11 with borane-THF in the presence of
Practically, however, a severe problem, arises from the Corey’s CBS-reagent (S )-34 [35] delivered 33 in even
configurational instability of the products [11,12]. As an higher chemical (/95%) and optical yields (er of up to
example, treatment of 11c with the chiral lithiated 98.5:1.5) [36,37] Since the substrates for these atropose-
sulfoxide (R )-28 (Scheme 9) delivered the diastereomeric lective reductive ring cleavage reactions are lactones,
b-keto sulfoxides (M,R )-29c and (P ,R )-29c as a 1:1
mixture, as a consequence of the interconversion of the
two atropisomers at room temperature (t1/2 /1.5 h) [12].
In this particular case, the problem was overcome by
converting essentially the entire material of 29c into
(P ,R )-29c by fractional crystallization [23,32]. Rapid
reductive desulfurization of now stereochemically
homogeneous (P ,R )-29c led to the likewise configur-
ationally unstable ketone (P )-30c (t1/2 /7 h at 25 8C

Scheme 8. Cleavage of 11c with lithiated (S )-26 as a chiral S - Scheme 10. Reduction of 11 with BINAL-H [(M )-32] and with the
nucleophile. CBS-reagent (S )-34.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 37

with diminished carbonyl reactivities as compared with enantiomers of 34 are commercially available, both
ketones (for which the CBS-system has originally been atropo-enantiomers of 33c can be prepared from 11c
developed), usually three equivalents of (S )-34 are used. atropo-divergently just by using (R )-34 [leading to (P )-
Still, with only slightly smaller asymmetric inductions 33c] or, optionally, (S )-34 [leading to (M )-33c]. The
also reductions of 11c with borane/THF in the presence small amount of nearly racemic alcohol rac -33c as
of 10 mol% (S )-34 are possible, leading to (M )-33c with recovered from the mother liquor after crystallization,
an er of 94:6 */a truly catalytic atropo-enantioselective can be re-used by re-oxidation and recyclization back to
biaryl synthesis [37]. In each case, the biaryl alcohol was the lactone 11c and renewed ring cleavage, following the
obtained in enantiopure form by a single crystallization principle of chiral economy [39]. These two advantages
step. are quite generally applicable to all the biaryls resulting
from the ring opening reactions of 11 and related
lactones (see Section 5).

6. Atropo-divergence and chiral economy /two *

characteristic advantages of the lactone methodology
7. Expansion of the lactone concept to other substrates
For an efficient stereoselective transformation, two
crucial requirements have to be fulfilled: (1) it must
allow an optional preparation of any of the two 7.1. Configurationally unstable biaryl hydroxy aldehydes
atropisomers from the same immediate precursor, and
(2) it has to permit a recycling of an undesired The strategy elaborated is not restricted to biaryl
stereoisomer possibly formed as a side product, in lactones as the substrates, but can be extended to other
particular for the use of the method for ‘precious’ configurationally unstable biaryls. Such a remarkable
substrates resulting from multi-step syntheses. These case is the enantioselective reduction of biaryl hydroxy
two fundamental demands, which are well known from aldehydes of type 35 (Scheme 12), which are, although
the field of centrochiral compounds, can, however, not not being bridged biaryls as such, configurationally
(yet) be fulfilled [5 /9] in the synthesis of axially chiral unstable too, since they can atropisomerize via their
biaryls by other methods [38]. The basic principle of the bridged lactol tautomers (for an explicit discussion of
lactone concept, however, the dynamic kinetic resolu- this mechanism, see Section 9) [40 /42].
tion of configurationally unstable lactone precursors, is The CBS-reduction of 35 in the presence of a
suited to meet these demands perfectly. This is demon- stoichiometric amount of (S )-34 and with catecholbor-
strated in Scheme 11, exemplarily for the catalytic ane as the achiral reductant showed a strong dependence
enantioselective reduction of the lactone 11c with the of the enantiomeric ratio on steric hindrance at the axis
CBS-catalyst 34 [37] (see also Section 5.5): Since both [43]: While the less hindered derivative 35g (R /H) was
obtained with a high er of 92:8, the stereoselectivity was
less significant with more bulky groups (R /OMe, Me)
next to the axis (Scheme 12). Nevertheless, at least for
sterically less hindered biaryl hydroxy aldehydes, CBS-
reduction of 35 is a valuable complement to the lactone
method, which, by contrast, delivered the best optical
yields for sterically more hindered derivatives (optimum

Scheme 11. Additional advantages of the lactone strategy: atropo-

divergent biaryl synthesis and chiral economy, as exemplified for the
catalytic enantioselective reduction of 11c with (S )-34 and (R )-34. Scheme 12. CBS-reduction of the biaryl hydroxy aldehydes 35.
38 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

ture (t1/2 /2 day, see Section 3) [21,23]. Thus, 11f is

clearly not suited for a dynamic kinetic resolution, but
might be a useful substrate for a normal, i.e. non-
dynamic kinetic resolution (Scheme 14). This was
confirmed by its CBS-reduction, which proceeded highly
atroposelectively, with a relative rate constant krel /200
[47,48]! Depending on the degree of conversion, either
Scheme 13. Catalytic enantioselective addition of Et2Zn to 35c.
the alcohol (M )-33f or the lactone (P )-11f [49] can be
obtained in almost enantiopure form (er /99.5:0.5).
for R /Me, see Section 5.5); for an application to
Furthermore, if high quantities of (M )-33f are wanted,
natural product synthesis, see Ref. [44].
the unreacted lactone 11f, enriched with the ‘wrong’
With the hydroxy aldehyde 35c, we also succeeded in
enantiomer (P )-11f, can be re-used by thermal racemi-
performing the first catalytic atropo-enantioselective
zation, and can then be re-submitted to the enantiomer-
addition of a C -nucleophile to a configurationally
unstable biaryl (Scheme 13) [11]. Treatment of 35c differentiating reduction. At low conversions, small
with diethylzinc in the presence of 10 mol% (/)- portions of the now configurationally stable hydroxy
DBNE (36) [45] gave the secondary alcohol (P ,R )-37c, aldehyde (M )-35f, the intermediate of the reduction
albeit with a moderate asymmetric induction (dr / 11f 0/33f, can be isolated with high enantiopurity (er /
63:37, er/80:20) [46]. This reaction proceeded with 98:2), too.
double stereo-differentiation, simultaneously establish- Likewise successful was the kinetic resolution of the
ing the configuration at the axis and at the stereocenter. again, configurationally stable seven-membered ring
These initial investigations already reveal that the lactone 38 [50,51] (Scheme 15). In this case, a krel of
hydroxy aldehydes are versatile precursors for the 50 was found [52].
atroposelective construction of axially chiral biaryls,
making a further evaluation of the potential of this class
of precursors a rewarding task.

7.2. Non-dynamic kinetic resolution of configurationally

stable lactones

In contrast to the rapidly atropisomerizing biaryls

discussed in the preceding chapters, the lactone 11f,
equipped with a voluminous tert-butyl group next to the Scheme 15. Kinetic resolution of the configurationally stable seven-
axis is configurationally nearly stable at room tempera- membered lactone 40.

Scheme 14. Kinetic resolution of the configurationally stable lactone 11f.

 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 39

Scheme 16. The proposed mechanistic course of the lactone cleavage; for reason of simplicity, metalated species drawn in a purely anionic form.

8. The stereochemical course of the ring opening reaction atropo-diastereomer (P ,R )-40! If both (M ,R )-40 and
(P ,R )-40 open with equal rates, any stereochemical
An intriguing question is where the high asymmetric information initially achieved will be lost and 41 will
inductions obtained by the lactone method come from, be formed as a racemic mixture. Furthermore, if the
i.e. what the stereochemical principle is. The fast product initially formed, e.g. (M)-41, cyclizes back, both
equilibrium between the two lactone enantiomers (M )- to (M ,R )-40 and (M ,S )-40, again a complete loss of the
11 X/(P )-11 (see Section 3) forms the basis for the ring stereochemical input might result via the whole ‘outer
cleavage reaction to proceed according to the principle circle’ (M )-41X/(M ,R )-40 X/(P ,R )-40 X/(P )-41X/
of a dynamic kinetic resolution (Scheme 16). In princi- (P ,S )-40 X/(M ,S )-40X/(M)-41. So, the decisive ques-
ple, each helimer of 11, (M )-11 and (P )-11, can be tion is: Under which conditions or with which type of
attacked in an equatorial or axial fashion, but quantum nucleophile does which pathway prevail?
chemical calculations indicate the latter mode of In the ring cleavage of 11 with metalated O - and N -
approach to be preferred leading to (M,R )-40 and nucleophiles, the intermediates 40 are the (likewise
(P ,S )-40, respectively, [22,53]. A chiral nucleophile deprotonated and metalated) ortho-esters, which indeed
that can differentiate between the atropo-enantiomers will rapidly (and largely irreversibly) burst open, due to
(M )-11 and (P )-11 will thus ideally give only one of the the electron push of the exocyclic heteroatoms. This
four possible intermediates, e.g. only (M ,R )-40, which, process may be further accelerated by the presence of
if it opens immediately, will deliver the target biaryl bulky substituents ortho to the axis as an additional
(M )-41, exclusively. By this way, given the rapid driving force. Thus, in the case of O - and N -nucleo-
interconversion (M )-11 X/(P )-11, the entire racemic philes, an intermediate of type 40, once formed in the
starting material can be converted into a single, stereo- attack on lactone 11, should spontaneously open, with-
chemically uniform product. out any significant isomerization at the biaryl axis, so
This reaction pathway, however, bears the inherent that in this case a direct pathway, e.g. (M )-11 0/(M ,R )-
risk of ‘stereochemical leakage’ [40,42] at the level of 40 0/(M )-41, is pursued without major risk of stereo-
intermediates 40, viz if (M,R )-40 has a sufficient life chemical leakage. Once achieved, high levels of asym-
time or if it gets steadily rebuilt via an equilibrium with metric induction resulting from the initial attack on the
the product (M )-41. As a bridged biaryl, (M,R )-40 lactone 11 will be transmitted to the product. Due to the
might, similar to the lactones 11, helimerize to give its comparably low chemical reactivity of the resulting ester
40 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

and (in particular) of the amide function, the product 35. These protonated analogs of 41 (Nu /H), however,
will not cyclize back and will thus be configurationally gave high asymmetric inductions only for the less
stable. sterically hindered derivative 35a (R /H) (cf. Section
This direct, simple pathway may, however, no longer 7.1), thus indicating that for sterically more hindered
apply if the lactones 11 are cleaved with C - or H - lactones 11 (e.g. with R /OMe, Me) it is the initial
nucleophiles. That is, the initially resulting, far more attack on 11 that establishes the ultimate configuration
reactive intermediate ketone or aldehyde phenolates 41 at the biaryl axis (Section 8.1).
(Nu /H or alkyl) can easily atropisomerize ‘chemically’,
via the lactolates 40 [40,41,53,54] and, thus, may ‘fall’
into the stereochemical leakage. The consequence is that 9. Ring opening of biaryl lactones activated by Lewis
any asymmetric information introduced in the primary acids (method II)
attack on 11 gets lost, which is indeed observed in the
ring cleavage of 11c with the chiral C -nucleophile (R )-28
(cf. Section 5.4). This configurational instability of the 9.1. Lactones modified by a chiral rhenium complex
hydroxy aldehydes 35 can in turn be utilized by their fragment
atropo-enantioselective reduction with dynamic kinetic
resolution (cf. Section 7.1). An alternative approach that does not have to rely on
In contrast to the chiral C -nucleophiles, reductive an activation of the nucleophile is the activation of the
cleavage reactions on the lactones 11 deliver excellent lactones 11 themselves, by coordination of a Lewis-
levels of asymmetric induction. Initial attack on 11 acidic transition metal, which in addition can serve as
probably occurs highly stereoselectively as proven at the chiral auxiliary for the ring opening step.
least for the (non-dynamic) kinetic resolution of lactone First experiments in this direction were performed
11f, and as also seen from the configurationally stable with lactone 11c, complexed with the chiral rhenium
hydroxy aldehyde 35f obtained in high optical yield (see fragment Re*Cp(NO)(PPh3) [55] (Scheme 17) [56].
Section 7.2). For the subsequent steps, however, two Reduction of 43c with the achiral hydride K-Selectride
completely different mechanistic explanations are ima- (KsBu3BH) delivered the lactolate 44c, which was ring-
ginable, depending on the degree of steric hinderance opened with CaO to give the aldehyde 45c, yet in a
ortho to the axis: moderate diastereomeric ratio of 75:25. In contrast to
the configurationally unstable free hydroxy aldehydes
8.1. Route a (35) (see Sections 7.1 and 7.2), this metal-‘protected’
derivative was sufficiently configurationally stable such
The lactolate stereoselectively formed, e.g. (M,R )-40 that the reduced and decomplexed alcohol (M)-33c
(Nu /H), immediately bursts open to give the aldehyde could be obtained without considerable loss of atropi-
phenolate (M )-41, which is trapped at once by a rapid someric purity.
second hydride shift. Thus, the asymmetric information
introduced in the first attack on the lactone 11 is fully 9.2. Atropo-diastereoselctive ring opening of chiral
conserved in the resulting configurationally stable thionolactone /ruthenium complexes
diolate (M )-42, without isomerization at the level of
the intermediate species (M ,R )-40 and (M )-41, thus Better results were obtained with the respective
circumventing stereochemical leakage. ruthenium thionolactones of type 46 (Scheme 18) [57],

8.2. Route b

As the other extreme, there is a rapid equilibrium

between all the isomeric species 40 and 41 (Nu /H) of
the ‘outer circle’ of Scheme 16, leading to the loss of any
stereochemical information possibly attained in the
initial step. Consequently, it must be the second hydride
transfer step, 410/42, that is stereochemically decisive in
this case, i.e. a dynamic kinetic resolution at the level of
the intermediate aldehydes 41: Ideally, only one of the
two enantiomers (M )-41 and (P )-41 gets reduced,
delivering the stereochemically highly enriched diolate
experimentally found, e.g. (M )-42. The existence of this
route b is substantiated by the successful enantioselec- Scheme 17. Atroposelective reduction of the rhenium-complexed
tive CBS-reduction of the (racemic!) hydroxy aldehydes biaryl lactone 43c.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 41

Scheme 18. Synthesis and atropo-diastereomeric equilibrium ratios of the biaryl-thionolactone complexes 50, and, exemplarily for 50c, crystal
structure (hydrogen atoms and the BF4 anion omitted for reason of clarity).

activated and chirally modified by the coordinatively of 48c is perfectly shielded from the si -side by one of the
unsaturated complex fragment {CpRu[(S,S )- phenyl groups of the (S ,S )-CHIRAPHOS ligand. It is
CHIRAPHOS)]}  [(S ,S )-CHIRAPHOS /(2S,3S )- thus tempting to hope that nucleophiles will add from
bis(diphenylphosphino)butane)] [58,59]. The key com- the re -side with high diastereoselectivities, provided that
pounds 48a /f were synthesized in excellent yields from the structure in solution resembles that in the solid state.
the highly reactive thiophene complex 47a [60] and the An important clue to that comes from the observation
thionolactones 46a /f (Scheme 18), which in turn had of two fairly different 3J (P,C) couplings of the C
/S
been obtained from the corresponding ‘standard’ lac- group for the two diastereomeric forms of 48b /f,
tones 11 by treatment with Lawesson’s reagent. indicating that the two dihedral angles C /S /Ru /P
As in the corresponding oxolactones 11, the biaryl remain unequal in solution, too. Furthermore, the M -
axis is configurationally unstable in the ruthenium diastereomer must have a similar structure with a near-
complexes 48a/f, and again, the diastereomerization coplanar arrangement of C, S, Ru, and P. This can be
rate (M )-48 X/(P )-48 depends strongly on the size of the deduced unequivocally from the fact that in the room
substituent R next to the axis (see also Section 3) [57]. temperature NMR spectra of 48a and 48b the 13C signal
The borderline cases are marked by 48a (R/H), which, of the thionolactone group still appears as a doublet of
even at 210 K, exists as a mixture of rapidly equilibrat- doublets with two unequal couplings. If the inversion of
ing atropo-diastereomers, and 48c/f (R /Me, Et, i Pr, the biaryl axis was accompanied by a rotation of the
t
Bu), whose 31P-NMR spectra up to 380 K exhibit two Ru /S bond such as to expose the si -side for nucleophilic
separate sets of signals for the two rotational diaster- attack, then the two couplings 3J(P,C) of the diaster-
eomers. Biaryl (48b) (R /OMe) shows two sets of eomers should become equal and make the signal at d/
signals at 210 K in a 55:45 ratio, which coalesce at 263 200 appear as a triplet. The conclusion then is that for
K (DG " /11 kcal mol 1). 1H-NMR spectra of 48c and both diastereomers of the thionolactone complexes 48a/
48d, if recorded immediately after dissolution at 253 K, f, re-addition should be strongly favored over a si-
gave distinctly higher diastereomeric ratios, which, attack.
however, decreased within a short time indicating that The stereochemical outcome of the reduction of 48a /f
the atropo-diastereomerization process has a halflife in with lithium triethylborohydride to give the thiolacto-
the range of a few minutes at this temperature. Never- late complexes 49a/f (Scheme 19) was found in perfect
theless, the influence of the stereogenic centers at the agreement with these assumptions. At room tempera-
metal on the atropisomeric ratio in the thermodynamic ture, compounds 49a /f are present as mixtures of two
equilibrium was relatively small. (49a, b) or four (49c /f) diastereomers. The 31P-NMR
An X-ray structure determination of complex 48c spectrum of 49b consists of two broad signals, which
shows that the biarylic thionolactone ligand preferen- upon cooling to 270 K decoalesce into two AX spin
tially adopts the P -configuration in the solid state (vide systems due to a slowed atropisomerization at the biaryl
supra, Scheme 18) [57]. The thiolactone carbonyl atom axis. The X-ray structure determination of the major
42 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

Scheme 20. Twofold hydride addition to the biaryl-thionolactone

Scheme 19. Hydride addition to biaryl-thionolactone complexes 48,
proton-induced ring opening of 49 to give 50, and the crystal structure complexes 48 and stepwise decomplexation of the Ru-thiolates 51 to
of (P )-49a; hydrogen atoms (except for the acetalic one) omitted. give the enantiomerically enriched biaryl compounds 54.

diastereomer of 49a shows the expected S -configuration

at the newly formed acetalic stereocenter at C70, while 18). The decomplexation sequence occurs with full
the biaryl axis has a fixed P -configuration in the crystal. retention of configuration at the biaryl axis.
While the diastereoselectivity of the hydride addition to For further experiments with other chelating phos-
48 exceeded 80%, the atropisomeric ratio [(M)-49:(P )- phine ligands as chiral auxiliaries [61], the thionolactone
49], which is thermodynamically controlled, was dis- complexes 55a /c (enantiomerically pure) and 56a/c
appointingly low, apparently due to only faint energetic (racemic) were synthesized (Scheme 21).
differences between the two diastereomers. It is thus not Ruthenium complexes 55a and 56a were reacted with
surprising that the proton-induced ring opening gives lithium triethylborohydride to give 57a and 58a (Scheme
the thioaldehyde complexes 50a/f in very low diaster- 22). Chirality transfer from (2S ,4S)-bis(diphenylpho-
eoselectivities. sphino)pentane (dr /91:9) was comparable to that of
The acid-induced ring opening 49 0/50 can be re- (S ,S )-CHIRAPHOS (dr /93:7, see Scheme 19),
versed [57]: Addition of sodium carbonate to deep whereas the binaphthol-derived bis(phosphinite) ligand
purple solutions of 50c,d led to a color change back to gave a somewhat inferior result (dr /79:21).
yellow, with quantitative formation of 49c,d. Overall, As expected, full reduction of 55b,c and 56b,c with
this step constitutes a stereochemical leakage as dis- LiAlH4 in THF yielded the thiolate complexes 59b,c and
cussed in Section 9. Nevertheless, if the thioaldehyde
intermediate 50 could be reductively trapped by a
second hydride addition before an isomerization at the
biaryl axis occurs, then it might be possible, despite this
stereochemical leakage, to preserve the possibly high
asymmetric induction attained in the initial attack on
the thionolactone 50. Indeed, treatment of 48a /f with
lithium aluminum hydride in THF gave, as expected, the
configurationally stable thiolate complexes 51a /f in
good yields and in some cases quite good diastereos-
electivities (Scheme 20). Exemplarily for 51a/c, the
chiral ruthenium fragment was removed by alkylation
with methyl iodide giving the thioether complexes 52a/
c. By heating in benzene, these were cleaved to the
enantiomerically enriched free thioethers 54a /c and the Scheme 21. Synthesis of the chiral biaryl /thionolactone complexes 55
iodo complex 53, which can thus be re-used (see Scheme and 56.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 43


10. Ring opening of h6-complexed planar /chiral biaryl
lactones (Method III) (Section 4.3)

10.1. Substrates for highly diastereoselective ring

cleavage reactions: h6-Cr complexes

A third option to activate the lactones 11 is given by

the h6-coordination of a transition metal fragment,
which adds an additional element of planar chirality to
the system. As an example, coordination of a tricarbo-
nyl chromium unit to the phenolic part of 11c delivered
the (here still racemic) h6-complex 62c (Scheme 24) [63].
Scheme 22. Single and double hydride addition to biaryl /thionolac- The complexation site of the chromium fragment and
tone complexes 57 and 58.
the dynamic behavior of 62c has been rationalized by
density functional (DF) methods [64]. The calculated
structural data of exo -62c are in good agreement with
60b,c. In the case of 61b,c, the stereoselectivity was still
those from its X-ray analysis. Like the ‘free’ lactone 11c,
insufficient. However, 59b was formed in an excellent
its complex 62c is configurationally unstable and exists
diastereomeric ratio of 94:6. This is particularly en- as a 56:44-mixture of the two (again racemic) atropo-
couraging since the ring opening of the analogous diastereomeric forms exo-62c X/endo -62c in solution.
methoxy-substituted thionolactone complex 48b accord- Out of this equilibrium, ring cleavage of 62c with
ing to Scheme 20 was achieved with only very low sodium borohydride proceeds highly stereoselectively,
stereocontrol, which again emphasizes the importance yielding the biaryl alcohol exo-63c exclusively. Its
of the proper choice of chiral auxiliary. formation is in agreement with an axial attack of the
hydride transfer reagent anti to the large Cr(CO)3
fragment.
9.3. Atropo-enantioselective ring cleavage of ‘achiral’
thionolactone /ruthenium complexes with chiral H - 10.2. Even more efficient and with a different
nucleophiles regioselectivity: complexation with RuCp*

As an alternative to the sequence described above, h6-Complexation of 11b with Cp* /ruthenium, how-
also an achiral ruthenium fragment in combination with ever, led to 64b, with the sterically more demanding
a chiral hydride source can be used. This has been most metal fragment now located on the distal naphthalene
successfully exemplified in the atropo-enantioselective (Scheme 25) [65], i.e. on the sterically better accessible,
yet less electron-rich ring as compared with the phenolic
reduction of the dppe-complex 61c [60] with (M )-
part (which, in turn, had been the site of coordination in
BINAL-H [(M)-32] (Scheme 23). After decomplexation,
the case of the less bulky Cr(CO)3 fragment; vide supra).
the thioether (M )-54c was obtained in almost quantitive
By contrast to the Cr(CO)3 complex 62c, in which the
yield and with an excellent enantiomeric ratio of 92:8
two atropisomers exo -62c X/endo -62c are nearly equally
[62], showing that further investigations along this [(56:44), see above] populated, the corresponding equili-
approach are highly rewarding for the future. brium in the RuCp* complex 64b is entirely pushed
towards the sterically less constrained atropo-diastereo-

Scheme 23. Enantioselective reductive cleavage of the ‘achiral’ (more

exactly: helical, but rapidly enantiomerizing) ruthenium complex 61c Scheme 24. Atropo-diastereoselective reduction of the (still racemic)
with (M )-BINAL-H [(M )-32]. h6-complexed lactone 62c with NaBH4.
44 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

Scheme 25. Ring opening of the racemic Cp* /ruthenium-complexed

lactone exo- 64b with NaOMe.
Scheme 26. Highly diastereoselective synthesis of the enantiopure Cp /
mer exo -64b. [66] In agreement with this array and with ruthenium complexed biaryl lactones (P ,R ,Sp)-69a and (M ,R ,Sp)-69b
an axial attack of the nucleophile anti to the RuCp* (note that the change in the stereochemical denotation from 69a to 69b
fragment, ring cleavage of exo -64b (racemic) even with is only due to the formalism of the CIP-denotation [24]).
NaOMe as a small and simple O -nucleophile thus gave
the biaryl ester exo -65b, exclusively. As previously for the relative stereo array established P-configuration at
the Cr(CO)3 complexes (see above), all the experimental the biaryl axis and Sp-configuration for the planar /
observations matched with the results of DF-calcula- chiral stereo-element, so that the full stereostructure is
tions, here using the Fukui function [65]. P ,R ,Sp [70]. Surprisingly, the (M ,R ,Sp)-atropo-diaster-
eomer of 69a was not observed in solution, indicating a
strong energetic differentiation between the two isomers.
10.3. Enantiopure RuCp complexes with stereocontrol for This fact is supported by ab initio calculations (B3LYP
planar and axial chirality hybrid density function theory), which predict (P ,R ,Sp)-
69a to be thermodynamically more stable by 2.1 kcal
The excellent diastereoselectivities achieved in the ring mol 1.
cleavage reactions of the h6-complexed and thus The methoxy substituted analog (M ,R ,Sp)-69b, which
planar /chiral (albeit still racemic) biaryl lactones 62c was prepared in a similar way, was likewise obtained as
and 64b encouraged us to extend this strategy to the use a single regio- and diastereomer. In both cases, the Cp /
of enantiomerically pure material and to develop ruthenium fragment was directed to the electron-rich
methods for the stereoselective coordination of a hydroxymethyl and methoxy substituted arene ring,
transition metal fragment. Based on earlier investiga- possibly assisted by an attractive interaction with the
tions [69], the plan was to use a chiral benzylic alcohol of benzylic oxygen, permitting both the remarkable regio-
known absolute configuration, which should facilitate and stereoselectivity, to give (P ,R ,Sp)-69a and
the regioselective coordination of the metal to that arene (M ,R ,Sp)-69b (same stereoarray; opposite axial descrip-
ring and, at the same time, allow a differentiation tors only for formal reasons) with the ruthenium
between the two (now diastereotopic) arene faces. This fragment attached to one face of the arene.
concept was realized as shown in Scheme 26 [70]. Cleavage of the lactone bridge of 69 with achiral
Intramolecular Pd-catalyzed coupling of (R )-66a nucleophiles proceeded with complete stereocontrol
(er /98:2), as prepared from the corresponding ketone (Scheme 27) [70]. Treatment of the ruthenium complexes
by CBS-reduction [35], delivered the biaryl lactone (R )- (P ,R ,Sp)-69a and (M ,R ,Sp)-69b with sodium methano-
67a in 69% yield. Despite the (expected) presence of (R )-
67a as an atropo-diastereomeric mixture, its treatment
with [CpRu(CH3CN)3]PF6 (68) in refluxing dichlor-
oethane gave the desired centro-, axial- and planar/
chiral Cp /ruthenium complex 69a as a single regio-
and stereoisomer in 51% yield. The absolute axial and
planar configuration of 69a was determined by X-ray
crystallography. With the configuration of the second-
ary benzylic alcohol known to be R , the elucidation of Scheme 27. Atroposelective ring cleavage and demetalation of 69.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 45

late in methanol followed by photo-oxidative demetala-

tion using an Hg lamp gave the enantiopure, ortho -
tetrasubstituted biaryl esters (P ,R )-70a and (M ,R )-70b
in 93% yield, while reductive cleavage of (M,R ,Sp)-69b
succeeded with sodium borohydride (or also with
lithium aluminium hydride) and subsequent demetala-
tion delivered the chiral biaryl triol (M,R )-71b in 99%
yield, again as a single diastereomer.
These results impressively prove the potential of
planar /chirally modified biaryl lactone h6-transition
metal complexes in the atropo-stereoselective synthesis
of axially chiral biaryls within the lactone concept.
Scheme 29. Further enlargement of the spectrum of axially chiral
biaryl molecules, by subsequent modification of the ortho -C1- and the
oxygen-substituents originally present after the atroposelective ring
cleavage.
11. Concluding remarks
exemplarily for the P- isomer) can be converted, e.g.
The lactone methodology constitutes an efficient
via 75a, into the bromides 75b, which can be further
novel tool [37] for the stereoselective preparation of
reduced down to the methyl group as in 75c, or can
axially chiral biaryls (Scheme 28). The key step is the
readily undergo substitution reactions with several
dynamic kinetic resolution of the configurationally
nucleophiles (for selected examples see 75d and e [71]).
unstable lactones of type 73, which are easily accessible
Furthermore the hydroxymethylene group of 75a, as
by intramolecular coupling of appropriately substituted
also obtained directly from 73 by using H-nucleophiles
bromoesters (72), leading to the ring-opened and, thus,
for the ring cleavage, can be converted into a phenolic
configurationally stable axially chiral biaryls (74) in high
OH group like in 76a, by oxidation to the corresponding
chemical and optical yields.
aldehyde, followed by Baeyer /Villiger rearrangement
The lactone method thus does fulfill the demands
and, via the respective O -triflate, [72] into numerous
mentioned in Section 1 to a very high degree. It permits
other groups, exemplarily shown for the reduction to
the regioselective cross coupling of 72 in mostly excellent
76b (Scheme 29). The same applies to the phenolic OH
chemical yields, even for derivatives with severe steric
group of the ‘lower’ ring of 74, which has been
hindrance, and the mild coupling and ring cleavage
transformed into phosphanes like 78 [73] or can be
conditions are compatible with a variety of common
reductively eliminated as in 77 [74].
functional groups. The method provides atropo-diver-
Of even greater importance, however, is the fact that
gent access to any of the two atropisomers, (M)-74 or,
the lactone method does not only work for the model
optionally, its (P )-isomer from the same immediate
systems described here, but has also proven its applic-
precursor 73, and, last but not least, the recycling of
ability in the synthesis of a broad series of (even highly
an undesired minor atropisomer, formed to any extent is
functionalized) natural products and useful chiral aux-
possible by its re-cyclization back to the lactone.
iliaries. This is reviewed in the following article [13].
The scope of the lactone method is further extended
by the fact that it gives rise to biaryls not only with the
typical immediate substitution pattern: a C1 unit and an
oxygen function next to the axis, but also to a series of
Acknowledgements
biaryls bearing different substituents. The previous
carbonyl carbon atom of the lactones (73) may be
For generous financial support of this work, we thank
transformed into a variety of functionalities. The
the Deutsche Forschungsgemeinschaft (SFB 347 ‘Selec-
obtained ring-opened products (74) (in Scheme 29
tive Reactions of Metal-Activated Molecules’ and
Normalverfahren), the Freistaat Bayern (FLUEGGE
program), and the Fonds der Chemischen Industrie
(followship to MB and supplies). We are especially
grateful to all those coworkers who have developed this
field of research with great engagement, enthusiasm, and
skill, and to our scientific cooperation partners */their
names can be seen from the literature cited. Particular
thank is due to Professor Helmut Werner, for doing a
wonderful job as the speaker of our Sonderforschungs-
Scheme 28. The basic strategy of the lactone concept. bereich for the full period of 12 years.
46 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47

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(f) G. Bringmann, R. Walter, R. Weirich, Angew. Chem. Int. Ed. [18] G. Bringmann, H. Busse, U. Dauer, S. Güssregen, M. Stahl,
Engl. 29 (1990) 977; Tetrahedron 51 (1995) 3149.
(g) K.A. Lutomski, A.I. Meyers, in: J.D. Morrison (Ed.) [19] (a) G. Bringmann, U. Dauer, O. Schupp, M. Lankers, J. Popp, U.
Asymmetric Synthesis, vol. 3, Academic Press, New York, 1984, Posset, A. Weippert, W. Kiefer, Inorg. Chim. Acta 222 (1994)
pp. 213. 247;
[6] A.I. Meyers, A. Meier, D.J. Rawson, Tetrahedron Lett. 33 (1992) (b) G. Bringmann, U. Dauer, J. Mol. Model 1 (1995) 88;
853. (c) G. Bringmann, U. Dauer, M. Lankers, J. Popp, U. Posset, W.
[7] (a) B.H. Lipshutz, F. Kayser, Z.-P. Liu, Angew. Chem. 106 (1994) Kiefer, J. Mol. Struct. 349 (1995) 431;
1962; (d) G. Bringmann, U. Dauer, J. Kraus Tetrahedron 54 (1998)
(b) B.H. Lipshutz, F. Kayser, Z.-P. Liu, Angew. Chem. Int. Ed. 12265.
Engl. 33 (1994) 1842; [20] K. Peters, E.-M. Peters, H.G. von Schnering, G. Bringmann, T.
(c) B.H. Lipshutz, P. Müller, D. Leinweber, Tetrahedron Lett. 40 Hartung, O. Schupp, Z. Kristallogr. 202 (1992) 271.
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Chem. 111 (1999) 3743; [22] G. Bringmann, S. Güssregen, D. Vitt, R. Stowasser, J. Mol.
(b) B.H Lipshutz, J.M. Keith, Angew. Chem. Int. Ed. Engl. 38 Model 4 (1998) 165.
(1999) 3530; [23] G. Bringmann, M. Heubes, M. Breuning, L. Göbel, M. Ochse, B.
(c) A.I. Meyers, J. Heterocycl. Chem. 35 (1998) 991; Schöner, O. Schupp, J. Org. Chem. 65 (2000) 722.
(d) T. Watanabe, M. Uemura, J. Chem. Soc. Chem. Commun. [24] For the now recommended M /P denotation for axial chirality,
(1998) 871; see: G. Helmchen, in: G. Helmchen, R.W. Hoffmann, J. Mulzer,
(e) T. Sugimura, H. Yamada, S. Inoue, A. Tai, Tetrahedron E. Schaumann (Eds.), Methods of Organic Chemistry (Houben
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(f) R.W. Baker, S. Liu, M.V. Sargent, B.W. Skelton, A.H. White, [25] G. Bringmann, M. Breuning, S. Tasler, H. Endress, C.L.J. Ewers,
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(g) K.S. Feldman, R.S. Smith, J. Org. Chem. 61 (1996) 2606; (h) [26] G. Bringmann, J.-P. Geisler, T. Geuder, G. Künkel, L. Kinzinger,
K. Kamikawa, T. Watanabe, M. Uemura, J. Org. Chem. 61 Liebigs Ann. Chem. (1990) 795.
(1996) 1375; [27] G. Bringmann, M. Breuning, R. Walter, A. Wuzik, K. Peters, E.-
(i) M. Uemura, A. Daimon, Y. Hayashi, J. Chem. Soc. Chem. M. Peters, Eur. J. Org. Chem. (1999) 3047.
 G. Bringmann et al. / Journal of Organometallic Chemistry 661 (2002) 31 /47 47

[28] For the use of 24 in the enantioselective ring opening of meso - [51] For the synthesis of further 7-membered biaryl lactones see: G.
anhydrides and -sulfonylimides see: (a) D. Seebach, G. Jaeschke, Bringmann, J. Hinrichs, P. Henschel, K. Peters, E.-M. Peters,
Y.M. Wang, Angew. Chem. 107 (1995) 2605; Synlett 12 (2000) 1822.
(b) D. Seebach, G. Jaeschke, Y.M. Wang, Angew. Chem. Int. Ed. [52] G. Bringmann, J. Hinrichs, Tetrahedron Asymm. 8 (1997) 4121.
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(c) D.J. Ramon, G. Guillena, D. Seebach, Helv. Chim. Acta 79 [54] G. Bringmann, B. Schöner, K. Peters, E.-M. Peters, H.G. von
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[29] K. Peters, E.-M. Peters, H.G. von Schnering, M. Breuning, G. [55] F. Agbossou, E.J. O’Connor, C.M. Garner, N. Quirós Méndez,
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Schnering, J. Organomet. Chem. 438 (1992) 117;
53 (1997) 7539.
(b) T.S. Ertel, S. Hückmann, H. Bertagnolli, G. Bringmann, O.
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Schupp, Inorg. Chim. Acta 222 (1994) 27.
[32] K. Peters, E.-M. Peters, G. Bringmann, B. Schöner, Z. Kristal-
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(b) G. Bringmann, T. Hartung, Angew. Chem. Int. Ed. Engl. 31
Int. Ed. Engl. 33 (1994) 1609;
(1992) 761; (c) W.A. Schenk, J. Frisch, M. Dürr, N. Burzlaff, D. Stalke, R.
(c) G. Bringmann, T. Hartung, Tetrahedron 49 (1993) 7891; Fleischer, W. Adam, F. Prechtl, A.K. Smerz, Inorg. Chem. 36
(d) See also G. Bringmann, T. Hartung, T. Synthesis (1992) 433. (1997) 2372;
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[38] For a very special exception occurred in the syntheses of [62] G. Bringmann, A. Wuzik, J. Kümmel, W.A. Schenk, unpublished
vancomycin (2, see Fig. 1), in which the initially ‘wrong’ results.
configuration at the biaryl axis was corrected by thermodynami- [63] G. Bringmann, L. Göbel, K. Peters, E.-M. Peters, H.G. von
cally controlled atropo-diastereomeric equilibration as achieved Schnering, Inorg. Chim. Acta 222 (1994) 255.
by heating, due to the low steric hindrance in the proximity of the [64] (a) G. Bringmann, R. Stowasser, D. Vitt, J. Organomet. Chem.
axis; see: (a) D.A. Evans, M.R. Wood, B.W. Trotter, T.I. 520 (1996) 261;
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(b) D.A. Evans, M.R. Wood, B.W. Trotter, T.I. Richardson, J.C. [65] G. Bringmann, A. Wuzik, R. Stowasser, C. Rummey, L. Göbel, D.
Barrow, J.L. Katz, Angew. Chem. Int. Ed. Engl. 37 (1999) 2700. Stalke, M. Pfeiffer, W.A. Schenk, Organometallics 18 (1999) 5017.
[39] (a) Q. Branca, A. Fischli, Helv. Chim. Acta 60 (1977) 925; [66] A related case in which */now due to the presence of stereogenic
(b) A. Fischli, Chimia 30 (1976) 4. centers */an atropo-diastereomeric equilibrium is fully on the side
[40] G. Bringmann, D. Vitt, J. Kraus, M. Breuning, Tetrahedron 54 of one particular atropisomer, occurred in the syntheses of the
(1998) 10691. naphthylisoquinoline alkaloids ancistrocladine and dioncophyl-
[41] G. Bringmann, T. Hartung, Liebigs Ann. Chem. (1994) 313. line C, see Refs. [67,68,11].
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(1986) 917;
M. Peters, Tetrahedron 54 (1998) 10677.
(b) G. Bringmann, J.R. Jansen, H.-P. Rink, Angew. Chem. Int.
[43] G. Bringmann, M. Breuning, Synlett (1998) 634.
Ed. Engl. 25 (1986) 913.
[44] G.Bringmann,W.Saeb,M.Rübenacker,Tetrahedron55(1999)423.
[68] G. Bringmann, J. Holenz, R. Weirich, M. Rübenacker, C. Funke,
[45] (a) K. Soai, S. Yokoyama, K. Ebihara, T. Hayasaka, J. Chem.
M.R. Boyd, R.J. Gulakowski, G. François, Tetrahedron 54
Soc. Chem. Commun. (1987) 1690.;
(1998) 497.
(b) K. Soai, Y. Kawase, A. Oshio, J. Chem. Soc. Perkin Trans. 1
[69] M. Uemura, T. Kobayashi, K. Isobe, T. Minami, Y. Hayashi, J.
(1991) 1613.
Org. Chem. 51 (1986) 2859.
[46] The absolute configuration of (P ,R )-39c was determined by
[70] K. Kamikawa, M. Furusho, T. Uno, Y. Sato, A. Konoo, G.
oxidative degradation: G. Bringmann, M. Münchbach, M.
Bringmann, M. Uemura, Org. Lett. 3 (2001) 3667.
Michel, Tetrahedron Asymm. 11 (2000) 3167. [71] G. Bringmann, M. Breuning, Tetrahedron Asymm. 10 (1999) 667.
[47] G. Bringmann, J. Hinrichs, J. Kraus, A. Wuzik, T. Schulz, J. Org. [72] G. Bringmann, G. Prasuna, unpublished results.
Chem. 65 (2000) 2517. [73] G. Bringmann, A. Wuzik, M. Breuning, P. Henschel, K. Peters,
[48] For accompanying quantumchemical calculations see ref. [47]. E.-M. Peters, Tetrahedron Asymm. 10 (1999) 3025.
[49] K. Peters, E.-M. Peters, H.G. von Schnering, G. Bringmann, T. [74] G. Bringmann, J. Holenz, R. Weirich, M. Rübenacker, C. Funke,
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[50] (a) G. Bringmann, T. Hartung, O. Kröcher, K.-P. Gulden, J. (1998) 497.
Lange, H. Burzlaff, Tetrahedron 50 (1994) 2831; [75] G. Bringmann, D. Menche, J. Kraus, J. Mühlbacher, K. Peters,
(b) K. Peters, E.-M. Peters, H.G. von Schnering, G. Bringmann, E.-M. Peters, R. Kaminsky, R. Brun, M. Bezabih, B.M. Abegaz,
T. Hartung, Z. Kristallogr. 209 (1994) 738. J. Org. Chem. 67 (2002) 5595.