Nondynamic and dynamic kinetic resolution of lactones with stereogenic centers and axes: Stereoselective total synthesis of herbertenediol and mastigophorenes A and B

Article abstract of DOI:10.1021/ja001455r

The stereoselective total synthesis of the sesquiterpene herbertenediol (3) and of its naturally occurring dimers, mastigophorenes A [(P)-1] and B [(M)-1], is described. Following the 'lactone concept', the configuration at the biaryl axis was atropo-dive

Full text of DOI:10.1021/ja001455r

J. Am. Chem. Soc. 2000, 122, 9127-9133
9127
Nondynamic and Dynamic Kinetic Resolution of Lactones with
Stereogenic Centers and Axes: Stereoselective Total Synthesis of
Herbertenediol and Mastigophorenes A and B†
Gerhard Bringmann,*,‡ Thomas Pabst,‡ Petra Henschel,‡ Ju1rgen Kraus,‡ Karl Peters,§
Eva-Maria Peters,§ David S. Rycroft,| and Joseph D. Connolly|
Contribution from the Institut fu¨r Organische Chemie, UniVersita¨t Wu¨rzburg, Am Hubland,
D-97074 Wu¨rzburg, Germany, Max-Planck-Institut fu¨r Festko¨rperforschung, Heisenbergstrasse 1,
D-70506 Stuttgart, Germany, and Department of Chemistry, UniVersity of Glasgow G12 8QQ,
Scotland, U.K.
ReceiVed April 26, 2000
Abstract: The stereoselective total synthesis of the sesquiterpene herbertenediol (3) and of its naturally occurring
dimers, mastigophorenes A [(P)-1] and B [(M)-1], is described. Following the “lactone concept”, the
configuration at the biaryl axis was atropo-divergently induced to be P or, optionally, M, by stereocontrolled
reductive ring cleavage (diastereomeric ratio up to 97:3) of the configurationally unstable joint biaryl lactone
precursor 17 using the oxazaborolidine-borane system, through dynamic kinetic resolution. Mechanistic
considerations of the lactone coupling suggested interference by a methoxy group next to the halogen substituent
and led to an improvement of the coupling yield from 39 to 87% (to give the lactone 37). As a new, likewise
highly efficient variant of the lactone method, we report for the first time thesnow nondynamicskinetic
resolution of a structurally related, but centrochiral “aliphatic-aromatic” lactone, (rac)-10. Its highly efficient
(krel > 300) enantiomer-differentiating Corey-Bakshi-Shibata reduction delivers the centrochiral building
block (R,R)-10 in good chemical yield and with excellent stereochemical purity (enantiomeric excess > 99.9%;
enrichment of the starting matrial). The new synthesis of natural herbertenediol (3) confirms its absolute
stereostructure as well as that of its dimers, (P)-1 and (M)-1.
Introduction
the atropo-enantioselective construction of the biaryl axis. An
application of the biomimetic strategy to a simple derivative of
the authentic monomeric half, 3, led to the first formal total
synthesis of (P)-1 and (M)-1, albeit with moderate asymmetric
inductions.7 During our ongoing work, Meyers et al. published
a synthetic pathway to (P)-1 and (M)-1, involving a first
enantioselective route to (-)-herbertenediol (3) and an atropo-
diastereoselective Ullmann coupling of chiral aryloxazolines.8
We report on our highly stereoselective total synthesis of
mastigophorenes A [(P)-1] and B [(M)-1] by a 2-fold application
of the lactone method:6 first, the novel nondynamic kinetic
resolution of “aromatic-aliphatic” lactones for the enantiose-
lective synthesis of the centrochiral molecular “half”, her-
bertenediol (3), and second, the dynamic kinetic resolution of
a configurationally unstable biaryl lactone for the directed,
atropo-diastereodivergent construction of the biaryl array to give,
optionally, the M- or the P-configured product, in high atropo-
diastereomeric ratios.
The natural products mastigophorene A [(P)-1] and B [(M)-
1] are representatives of a group of axially chiral “dimeric”1
sesquiterpenes exhibiting nerve growth stimulating activity.2
Such nonpeptidyl neurotrophic substances are regarded as
promising potential therapeutic agents for degenerative diseases
of the central nervous system such as Parkinson and Alzheimer.3
Therefore the total synthesis of (P)-1 and (M)-1 is an attractive
target, even more so because the interesting, C2-symmetric
structures involve elements of both axial and centro chirality.
In our investigations, we published two different strategies for
the construction of the simplified analog 2,4 the first one by
a (nonstereoselective) biomimetic oxidative phenolic coupling,
leading to the likewise neurotrophic5 mastigophorene analog
2,4 and the second one using our “lactone methodology”6 for
† Part 87 of the series “Novel Concepts in Directed Biaryl Synthesis”.
For part 86 see ref 18.
* To whom correspondence should be addressed (Tel: +49 931 888
5323; Fax: +49 931 888 4755; E-mail: bringman@chemie.uni-wuerzburg.de).
‡ Universita¨t Wu¨rzburg.
(7) Bringmann, G.; Pabst, T.; Rycroft, D. S.; Connolly, J. D. Tetrahedron
Lett. 1999, 40, 483.
(8) Degnan, A. P.; Meyers, A. I. J. Am. Chem. Soc. 1999, 121, 2762.
(9) Fukuyama, Y.; Kiriyama, Y.; Kodama, M. Tetrahedron Lett. 1996,
37, 1261.
§ Max-Planck-Institut, Stuttgart.
| University of Glasgow.
(1) Strictly speaking such “dimers” should be described as “dehy-
drodimers”.
(2) Fukuyama, Y.; Asakawa, Y. J. Chem. Soc., Perkin Trans. 1 1991,
2737.
(3) Skaper, S. D.; Walsh, F. S. Mol. Cell. Neurosci. 1998, 12, 179.
(4) Bringmann, G.; Pabst, T.; Busemann, S.; Peters, K.; Peters, E.-M.
Tetrahedron 1998, 54, 1425.
(5) Gille, G.; Pabst, T.; Bringmann, G.; Janetzky, B.; Reichmann, H.;
Rausch, W.-D. Drug DeV. Res. 2000, 50, 153.
(6) Bringmann, G.; Breuning, M.; Tasler, S. Synthesis 1999, 525.
(10) Weeratunga, G.; Jaworska-Sobiesiak, A.; Horne, S.; Rodrigo, R.
Can. J. Chem. 1987, 65, 2019.
(11) Shiba, T.; Cahnmann, H. J. J. Org. Chem. 1964, 29, 3061.
(12) Bringmann, G.; Schneider, S. Synthesis 1983, 139.
(13) Kla¨rner, F.-G.; Adamsky, F. Chem. Ber. 1983, 116, 299. The
elimination step to ethyl 1,2-dimethyl-cyclopent-2-enoate was done by
azeotropic removal of water with toluene and p-toluenesulfonic acid.
Subsequent hydrolysis as described gave (rac)-8 in 72% yield (2 steps).
10.1021/ja001455r CCC: $19.00 © 2000 American Chemical Society
Published on Web 09/07/2000

9128 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bringmann et al.
Scheme 1
Scheme 2
Results and Discussion
Our concept for the enantioselective synthesis of herbertene-
diol (3) was related to a synthetic pathway previously developeds
albeit in a racemic formsby Fukuyama et al.9 (Scheme 1). In
that approach the chiral quaternary carbon center had been built
up by a diastereoselective intramolecular Heck coupling of
(rac)-4 to give lactone (rac)-5, which was then converted to
(rac)-3, including introduction of the second phenolic oxygen
function.
For the directed synthesis of enantiomerically pure 3, with
its two oxygen functions, we modified this synthetic concept
in two respects. First, to avoid the subsequent introduction of
the second phenolic function, we started directly from the
dioxygenated aromatic building block 7 (Scheme 2), which
might be prepared either according to a method described in
the literature10 or, more easily, from the known11 5-iodovanilline
(6), by reaction with NaBH4 and reductive deoxygenation via
the corresponding bromide.4,12 Esterification of 7 with the
known13 acid (rac)-8 using dicyclohexylcarbodiimide (DCC)
as the condensation agent gave (rac)-9. This iodo ester was,
similar to (rac)-4 in the literature, diastereoselectively cyclized
by a palladium-catalyzed Heck reaction, to afford, after hydro-
genation, the cis-configured lactone (rac)-10 in racemic form
(of which Scheme 2 arbitrarily shows the R,R-enantiomer). The
cis-configuration, which could not be assigned by nuclear
Overhauser effect (NOE) experiments, was clearly established
by X-ray structure analysis of (rac)-10 (see Scheme 2). This
analysis further showed the methyl group â to the carbonyl
function to be in an axial position, and the R-methyl group in
an equatorial position. This conformation avoids 1,3-allylic strain
between the â-CH3 group and the aromatic hydrogen.
The second, even more significant improvement of the
synthetic pathway to 10 was development of a route to
enantiomerically pure material. The acid 8, however, which
would thus be required in stereochemically homogeneous form,
had been synthesized only in an insufficient enantiomeric purity
(enantiomeric excess (ee) ) 90%) in the literature.9 Therefore,
given our good results with atropisomer-selective cleavage
reactions of biaryl lactones, a kinetic resolution at the level of
the aromatic-aliphatic lactone (rac)-10 seemed to offer an ideal
extension of our lactone method. For this purpose, the rigid
structure of 10 might indeed provide a good precondition for
efficient stereodifferentiation of the two enantiomers. Given the
mostly excellent results with oxazaborolidine-mediated borane
reductions (Corey-Bakshi-Shibata (CBS) reaction)14 in the
kinetic resolution of configurationally unstable6sor stable15s
Scheme 3
biaryl lactones, we then tried this method also for 10, i.e., for
the first time in the enantiomer-differentiating reduction of
nonbiarylic chiral lactones. Initial reduction experiments with
(rac)-10 on an analytical scale, even when an excess of 11 was
used, revealed the system to be too unreactive to be reduced
completely to the diol 14 and the reaction stopped at the lactol
12 (obtained as a diastereomeric mixture) (Scheme 3). Fortu-
nately, this reduction was found to proceed with perfect
enantiomer-differentiating selectivity: After 51.5% conversion,16
the starting material 10 was enriched to an ee > 99%; the other
lactone enantiomer was no longer detectable by HPLC analysis
on a Chiralcel OD-H phase. Attempts to run the reaction with
(14) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. Engl. 1998, 37,
1986.
(15) Bringmann, G.; Hinrichs, J. Tetrahedron: Asymmetry 1997, 8, 4121.
(16) The conversion and the relative rate krel were calculated according
to (a) Kagan, H. B.; Fiaud, J. C. Top. Stereochem. 1988, 18, 249. (b) Chen,
C.-S.; Fujimoto, Y.; Girdaukas, G.; Sih, C. J. J. Am. Chem. Soc. 1982,
104, 7294.

Kinetic Resolution of Lactones
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9129
Figure 2. Comparison of the experimental CD spectrum of 10 with
the spectra calculated for its two possible enantiomeric forms.
Scheme 4
Figure 1. Rationalization of the observed stereodifferentiation and
prediction of the stereoisomer expected to be reduced.
catalytic amounts of the oxazaborolidine 11, however, failed:
With 0.1 equivalents of 11, only 8.4% conversion was observed.
Nevertheless, to perform the reaction as economically as possible
with respect to the chiral reagent, we used 0.6 equivalents of
11 in preparative reactions and then isolated enantiopure 10 (ee
> 99.9%, krel > 300!)16 in an excellent 48% chemical yield ()
96% based on the maximum possible yield for that enantiomer).
For a directed synthesis of the correct enantiomer of natural
herbertenediol (3), independent of a “late” assignment of the
product configuration at the level of the stereochemically
known17 monomeric target molecule 3, the absolute product
configuration was already determined for the enantiopure lactone
10.
Scheme 5
From model considerations (Figure 1) based on previous
experimental and computational investigations14,18,19 but also
on the crystal structure of 10 (see above), a distinctly preferred
attack of the N-activated borane to the B-activated carbonyl
function of 10 should occur from a conformation related to
(R,R)- or, (S,S)-13a [) (S)-11‚BH3‚10], thus avoiding a strong
heteroallylic strain as, for example, in (R,R)-13b. Of the two
isomers of 13a, (S,S)-13a should react much more easily,
because here (assuming a conformation of the lactone part
similar to that of 10 in the crystal) the quasi-intramolecular
hydride attack would occur syn to the equatorial methyl group,
but anti to the propylene bridge, which is axial in the R-position
next to the carbonyl function. For (R,R)-13a, by contrast, the
attack would have to occur syn to that axial part of the propylene
bridge, so that this isomersand thus (R,R)-10 - should remain
unreacted with (S)-11‚BH3.
that obtained with (S)-11. Conversely, with the ultimate outcome
of the synthesis (see below), the CD calculations confirm the
absolute centrochiral S-configuration for both herbertenediol (3)
and the mastigophorenes A [(P)-1] and B [(M)-1] as established
earlier.2,17
Starting from (R,R)-10, enantiomerically pure herbertenediol
(3) was synthesized by analogy to the procedure described for
racemic material by Fukuyama et al.9 Reduction with LiAlH4
(LAH) gave the diol 14 (see Scheme 4), which was converted
to the still O,O-dimethylated herbertenediol precursor 15 by
O-protection with Me2SO4, Swern oxidation, and Wolff-
Kishner reduction. Deprotection with BBr3 led to herbertenediol
(3), which was found to be enantiopure by HPLC analysis on
a Chiralcel OD-H phase, and was fully identical to natural
material by its physical, chiroptical, and spectroscopic data.17
This assumption was confirmed by quantum chemical circular
dichroism calculations.20 Thus, the circular dichroism (CD)
spectrum calculated for (R,R)-10 shows good agreement with
the experimental spectrum of the product 10 that remained
unreacted with (S)-11, whereas the spectrum calculated for (S,S)-
10 is virtually opposite to the experimental spectrum (Figure
2), clearly indicating that the product (R,R)-10 needed for the
synthesis of natural i.e., S-configured, herbertenediol (3), was
Another approach to enantiomerically pure 3, recently
described in preliminary form,7 is its partial synthesis from the
natural aldehyde 16 (Scheme 5), which co-occurs with her-
bertenediol (3) in the liverwort Herbertus aduncus and was
isolated as described previously.21 Protection of the phenolic
functions of 16 with Me2SO4 and reduction of the aldehyde
function with LAH led to the corresponding alcohol, whose
reductive deoxygenation via the corresponding bromide12 gave
the dimethyl ether 15, which was deprotected with BBr3 to
afford (-)-herbertenediol (3). This partial synthesis of 3
simultaneously confirms the S-configuration of 16, which had
so far been assumed only from its slightly negative RD.21
(17) Matsuo, A.; Yuki, S.; Nakayama, M. J. Chem. Soc., Perkin Trans.
1 1986, 701.
(18) Bringmann, G.; Hinrichs, J.; Kraus, J.; Wuzik, A.; Schulz, T. J.
Org. Chem. 2000, 65, 2517.
(19) Bringmann, G.; Vitt, D. J. Org. Chem. 1995, 60, 7674.
(20) Bringmann, G.; Busemann, S. In Natural Product Analysis; Schreier,
P., Herderich, M., Humpf, H.-U., Schwab, W., Eds.; Vieweg: Braunschweig,
1998; pp 195-212.
(21) Buchanan, M. S.; Connolly, J. D.; Rycroft, D. S. Phytochemistry
1996, 43, 1245.

9130 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bringmann et al.
Scheme 6
With enantiopure herbertenediol (3) in hand by partial and
by total synthesis, we could now start building its natural dimers,
mastigophorenes A [(P)-1] and B [(M)-1], based on previous
experience from our model studies.4 Using our lactone method,6
both (P)-1 and (M)-1, optionally, should be synthesizable from
the same biaryl lactone 17 (Scheme 6), by atropo-diastereo-
selective ring cleavage. This key intermediate, expected to be
configurationally unstable,6 should best22 be synthesized via an
intramolecular biaryl coupling of the carboxylic ester 18, and
thus from the phenol 19 and the acid 20, both ultimately arising
from herbertenediol (3).
Still better diastereoselectivities and the option of producing
either of the two atropisomers, (P)- or (M)-21, highly selectively
from the same configurationally unstable lactone precursor 17,
within a now dynamic kinetic resolution, were attained using
Scheme 7
The acid 20 was synthesized from herbertenediol dimethyl
ether (15) by bromination and cobalt-catalyzed oxidation with
O2 (Scheme 7). Alternatively, a second approach to 20sby
partial synthesisssucceeded by bromination of the natural21
aldehyde 16, protection with Me2SO4, and oxidation with
NaClO2. The phenolic precursor 19 was obtained7 from 3 by
selective benzylation of the less hindered oxygen at C-1 and
subsequent methylation of the second phenolic function at C-2.
Hydrogenolysis of the benzyl group then generated the monophe-
nolic building block 19.
From the phenol 19 (via its phenolate) and the acid 20 (via
its acid chloride) the bromo ester 18 was obtained and submitted
to a Pd0-catalyzed intramolecular biaryl coupling reaction, to
give the desired key biaryl lactone 17, in 39% yield (subse-
quently improved, see later), together with 41% of recovered
substrate. Longer reaction times did not lead to higher yields,
but rather to decomposition of the product already formed. As
expected, 17 consists of two rapidly interconverting atropo-
diastereomers (P)-17 h (M)-17 in solution, as required for a
dynamic kinetic resolution in the ring cleavage reaction. In the
crystal however, it occurs as theslike-configuredsP-atropiso-
mer, exclusively, as shown by an X-ray structure analysis (see
Scheme 7).
In accordance with the predominance of (P)-17 in the crystal
is the observation that LAH reduction of 17 gave the corre-
sponding diols (P)-21 and (M)-21 in favor of the P-configured
product (diastereomeric ratio (dr) 77:23). Rapid reduction by
addition of crystalline 17 to a 1 M solution of LAH in
tetrahydrofuran (THF) (-100 f -30 °C) gave an even better
dr of 81:19.
(22) For the synthesis of relatedsalbeit sterically less hinderedsbiaryl
lactones by other methods, see: (a) Wang, W.; Snieckus, V. J. Org. Chem.
1992, 57, 424. (b) Davies, D. I.; Waring, C. J. Chem. Soc. C 1967, 1639
and references cited therein. (c) de Frutos, O.; Echavarren, A. M.
Tetrahedron Lett. 1996, 37, 8953.

Kinetic Resolution of Lactones
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9131
Scheme 8
Scheme 9
structure analysis of the tetramethyl ether (P)-22 of mastigo-
phorene A [(P)-1] (see Figure 3). From the relative configuration
of (P)-22 in the crystal, together with the known17 S-configu-
ration in the cyclopentyl residue, as determined above again
by the CD calculations, the absolute axial configuration could
be established directly to be P, which confirms the configura-
tional assignment by Fukuyama et al. based on the exciton
chirality rule.2
The synthetic approach to the mastigophorenes A [(P)-1] and
B [(M)-1] presented here is most flexible and efficient, with
the exception of the coupling step to the lactone 17. Unexpect-
edly and in contrast to so many other related coupling reactions,
which gave excellent yields,6 even against highest steric
hindrance (e.g., with a tert-butyl group next to the axis),18 no
further optimization was possible by variation of the catalyst,
the solvent, or other reaction conditions. The search for a reason
for this failure led us to compare the substrate structures of
successful coupling reactions in the literature6,23,24 with those
of 17 and others that had previously given insufficient coupling
yields.4,25,26 Strikingly, all the unsuccessful coupling substrates
had a methoxy group ortho to the halogen. Indeed, previous
investigations by Dyker et al.27 had shown that Pd0-catalyzed
reactions of substrates such as 23 (Scheme 9) give “trimeric”
products of type 24, apparently by CH activation of the
O-methyl group of 25, leading to the five-membered pallada-
cycle 26, followed by the addition of a second substrate
molecule to give 27. Ring closure and involvement of a third
molecule of 23 ultimately produce the observed product 24.
These results suggested that, in our reaction, intermediates
such as 28 and 29 (Figure 4) might play a role and be
responsible for the poor coupling yield. However, there was no
evidence for such intermediates and consequent byproducts.
Therefore, we performed the reaction with the simplified
carboxylic ester 30, i.e., in the absence of an intramolecular
coupling partner (Scheme 10), thus increasing the chance of
detecting possibly relevant CH activation products in our system.
Indeed, with Pd(OAc)2 as the catalyst, 30 gave the cyclic biaryl
ether 31 in 10% yield, consistent with initial oxidative addition
techniques developed previously within the lactone methodol-
ogy.6 Thus, reaction of (P)-17 h (M)-17 with (S)-11 gave (P)-
21 with an excellent dr of 97:3 (Scheme 8). But even the
M-configured atropisomer of 21 (less readily produced using
achiral reagents, see above) could be obtained with a good dr
of 92:8 by using (R)-11, thus overcoming the molecule-inherent
P-preference by a strong external asymmetric induction exerted
by the CBS system. In both cases diastereomerically pure
compounds were obtained by column chromatography.
Further transformation of (P)- and (M)-21 to mastigophorenes
A [(P)-1] and B [(M)-1], respectively (Scheme 8), followed
protocols developed previously for related model compounds.4
Protection of the phenolic function of (P)- and (M)-21 by
O-methylation, and reductive benzylic deoxygenation12 (via the
corresponding bromide) provided the tetra-O-methylmastigo-
phorenes (P)- and (M)-22, respectively. Deprotection with BBr3
gave (P)-1 and (M)-1, which proved to be identical in all respects
with the data published2 for the natural products.
Within this stereoselective synthesis of the mastigophorenes,
their axial configuration was proved rigorously by an X-ray
(23) Bringmann, G., Saeb, W.; Ru¨benacker, M. Tetrahedron 1999, 55,
423.
(24) Bringmann, G.; Ochse, M.; Go¨tz, R. J. Org. Chem. 2000, 65, 2069.
(25) Bringmann, G.; Walter, R.; Weirich, R. Angew. Chem., Int. Ed. Engl.
1990, 29, 977.
(26) Rao, A. V. R.; Chakraborty, T. K.; Joshi, S. P. Tetrahedron Lett.
1992, 33, 4045.
(27) (a) Dyker, G. Chem. Ber./Recl. 1997, 130, 1567. (b) Dyker, G.
Angew. Chem., Int. Ed. Engl. 1999, 38, 1698. (c) Dyker, G. Chem. Ber.
1994, 127, 7, 739.
Figure 3. X-ray crystal structure of tetra-O-methylmastigophorene A
[(P)-22].

9132 J. Am. Chem. Soc., Vol. 122, No. 38, 2000
Bringmann et al.
Scheme 11
Figure 4. Possible intermediates in the Pd-assisted intramolecular
coupling of 18.
Scheme 10
should be achieved very easily, by hydrogenolysis, even at the
level of the sensitive lactone 37.
The required acetal-protected bromo acid 35 31 was synthe-
sized from herbertenediol (3), by reaction with Ph2CCl2,
bromination, and cobalt-catalyzed oxidation with O2. Subsequent
DCC activation and reaction with the phenol 19 gave the desired
bromo ester 36. Its coupling was now highly efficient under
the standard reaction conditions and our considerations presented
above were confirmed. The lactone was obtained with an
excellent yield of 87% and no side products or even hints of
decomposition were observed.
Unexpectedly however, and in contrast to results from the
literature,29,30,32 cleavage of the diphenylmethylene acetal group
was more difficult than anticipated. Thus, upon attempted
hydrogenolysis with H2 in THF with Pd/C as the catalyst29 or
by acid-catalyzed hydrolysis,32 no reaction was observed. Only
after further optimization did deprotection succeed hydro-
genolytically using THF/concentrated H2SO4 (10:1) as the
solvent, followed by renewed protection with MeI, to give the
lactone 17 in low yield.
of Pd0 and subsequent cyclometalation by CH activation at the
neighboring methoxy group to give 32. Addition of a second
molecule of 30 and reductive elimination, with formation of
the biaryl axis, apparently then lead to the intermediate 33,
whose ring closure with decarboxylation would produce the
ether bridge in 31. The constitution of 31 was proved, inter
alia, by a series of nuclear Overhauser enhancement spectros-
copy
(NOESY) interactions. In addition, dynamic nuclear magnetic
resonance (DNMR) investigations showed the expected splitting
of the signals of the diastereomeric protons in the ether bridge
(below ca. -35 °C), and thereby confirmed the chiral (though,
at room temperature, configurationally unstable) biaryl structure
of 31.28
This experiment demonstrates that in the bromobenzoic acid
18, it is likely that, after oxidative addition, a CH-activating
interaction of Pd with the adjacent ortho-methoxy group will
indeed play an important role in diminishing the yield of the
desired coupling product. As a consequence of these results, a
methoxy group (or any other protecting group that might
undergo such CH activation) should be avoided in the immediate
neighborhood of the halogen substituent. This condition had
been satisfied for our successful substrates, e.g., for 1-bro-
monaphthalene-2-carboxylic acids and for many precursors of
numerous biaryl alkaloid syntheses.6,24 Therefore, a better
coupling substrate than 18 should, for example, be the modified
bromo ester 36 (Scheme 11), in which the ortho-methoxy group
of 18 is replaced by a diphenylmethylene acetal group for the
simultaneous protection of both phenolic hydroxy functions, so
that the critical ortho-OCH moieties are absent; moreover,
according to experience in the literature,29,30 its deprotection
Although the overall yield of the total synthesis could not
thus be improved, this does not diminish the value of our finding
that avoiding an OCH unit next to the palladation site will
increase the coupling yields dramatically. This important result
should find further applications in other syntheses.
Conclusions
The work presented describes a new synthetic pathway to
highly enantiopure herbertenediol (3) and its rational conversion
to mastigophorene A [(P)-1] or, optionally, mastigophorene B
[(M)-1] in high diastereoselectivities. Although for the construc-
(30) (a) Lu¨tolf, W. L.; Prewo, R.; Jost, H.; Ru¨edi, P.; Eugster, C. H.
HelV. Chim. Acta 1985, 860. (b) Kawase, M.; Sinhababu, A. K.; McGhee,
E. M.; Milby, T.; Borchardt, R. T. J. Med. Chem. 1990, 33, 2204.
(31) This reaction sequence was first optimized with a simplified model
system, bearing a tert-butyl group instead of the chiral cyclopentyl residue;
for the characterization of these compounds see the Supporting Information.
(32) (a) Feldman, K. S.; Quideau, S.; Appel, H. M. J. Org. Chem. 1996,
61, 6656. (b) Horie, T.; Tsukayama, M.; Kourai, H.; Nakayama, Y.;
Nakayama, M. Chem. Pharm. Bull. 1986, 34, 30. (c) Bachi, M. D.; Klein,
J. J. Chem. Soc., Perkin Trans. 1 1983, 1925.
(28) Line-shape analyses of the 1H NMR spectra at different low
temperatures gave the corresponding rate constants k and the activation
parameters ∆Hq ) 43.5 ( 1.7 kJ mol-1, ∆Sq ) -20.8 ( 7.2 J K-1 mol -1
,
and ∆Gq ) 49.7 kJ mol-1
.
298
(29) Feldman, K. S.; Ensel, S. M. J. Am. Chem. Soc. 1994, 116, 3357.

Kinetic Resolution of Lactones
J. Am. Chem. Soc., Vol. 122, No. 38, 2000 9133
stirring, the reaction was quenched with 2 N HCl, the solvent was
removed in vacuo, and the remaining aqueous layer was extracted with
diethyl ether. HPLC analysis gave a dr of 97:3. Purification of the dried
(MgSO4) extract by column chromatography on silica gel (petroleum
ether/diethyl ether 10:1) gave 34.2 mg (55%) of (P,1′′S,1′′′S)-2-hydroxy-
6′-hydroxymethyl-3,2′,3′-trimethoxy-6-methyl-4,4′-di-(1,2,2-trimethyl-
cyclopentyl)biphenyl [(P)-21] (dr > 99.9:0.1) and (as a late fraction
from column chromatography) 4.00 mg (6%) of a mixture of (P)- and
(M)-21 (dr ) 89:11).
Improved Coupling Reaction to (1′S,1′′S)-4-Methoxy-3,8-di-
(1,2,2-trimethylcyclopentyl)-1-methyl-9,10-(diphenylmethylidene-
dioxy)-dibenzo[b,d]pyran-6-one (37). In 50 mL of freshly distilled
(over CaH) dimethylacetamide (DMA) 36 (518 mg, 703 µmol), Pd-
(PPh3)2Cl2 (49.3 mg, 70.3 µmol), NaOAc (115 mg, 1.41 mmol), and
PPh3 (14.2 mg, 70.3 µmol) were dissolved under N2. After heating
(130 °C), the reaction mixture was stirred for 16 h, the solvent was
removed under reduced pressure, and the residue obtained was purified
by column chromatography on silica gel (petroleum ether/diethyl ether
10:1). Crystallization from dichloromethane/petroleum ether gave 402
mg (87%) of 37 as colorless crystals.
tion and atropo-diastereodivergent oxazaborolidine-assisted
cleavage of the biaryl lactone 17, the lactone concept was
applied for establishing axial chirality, this methodology was
extended here for the first time to the synthesis of enantiomeri-
cally pure centrochiral compounds, by highly selective (krel
>
300) kinetic resolution of the aromatic-aliphatic lactone 10. A
further improvement of the lactone methodology described here
was to recognize and avoid possible side reactions arising from
a 2-bromo-3-methoxy benzoate precursor; the methoxy group
was replaced by a unit without the critical OCH entity, here a
benzylidene acetal, by which the coupling yield was increased
from 39 to 87%.
Experimental Section
Kinetic Resolution of (rac)-10. From a solution of (S)-11 (9.24 mL,
9.24 mmol, 1 M in toluene) the solvent was removed in vacuo and the
residue was dissolved under argon in dry THF (50 mL). Then BH3‚
THF (15.4 mL, 15.4 mmol, 1 M in THF) was added and the solution
was stirred for 30 min. This solution was added slowly to a cooled
(-78 °C) solution of (rac)-10 (4.00 g, 15.4 mmol) in dry THF (200
mL) under argon. This mixture was stirred for 20 h at -78 °C, then
acidified with 2 N HCl and the solvent was removed after warming to
room temperature. The white precipitate was filtered off and washed
with diethyl ether. The filtrate was extracted with diethyl ether, the
extract was dried (MgSO4), and the solvent was evaporated. Column
chromatography on silica gel (petroleum ether/diethyl ether 2:1)
afforded (3aR,9bR)-cyclopentyl[d]-3a,9bH-6-methoxy-cis-(3a,9b),8-tri-
methylcoumarin (R,R-10) (1.91 g, 48%, ee > 99.9%, HPLC) and (S,S)-
12 (1.90 g) as a diastereomeric mixture. Reduction of a small sample
of (S,S)-12 with LAH gave (S,S)-14 with an ee ) 94% (HPLC). (R,R)-
Acknowledgment. We thank Dr. M. Heubes for carrying
out the DNMR investigations. For making available samples
of natural (P)-1 and (M)-1, we thank Professor L. J. Harrison,
National University of Singapore. This work was supported by
the Deutsche Forschungsgemeinschaft (SFB 347 “Selektive
Reaktionen Metall-aktivierter Moleku¨le”) and by the Fonds der
Chemischen Industrie.
Supporting Information Available: Detailed experimental
procedures and characterization data for all new compounds
(including unnumberd intermediates), X-ray crystallographical
data of (rac)-10, (P)-17, (P)-22, NOESY correlations of 31, and
characterization of the model compounds of 34-37 (PDF). This
material is available free of charge via the Internet at
http://pubs.acs.org.
10: mp 108 °C; [R]23 ) -23.8 (c 0.73, CHCl3); CD (ethanol): λmax
D
(∆ꢀ) 203 (+42), 220 (-34), 251 (+4), 287 (+6).
Atroposelective Ring Opening of 17 with (S)-11‚BH3. From 500
µL (500 µmol) of a 1 M solution of (S)-11 in toluene, the solvent was
removed in vacuo and the residue was dissolved in 2 mL dry THF.
After addition of 400 µL (400 µmol) of BH3 (1 M solution in THF)
and 30 min stirring, this solution was added to a solution of the lactone
17 (62.0 mg, 119 µmol) in 3 mL dry THF at 0 °C. After 4 days of
JA001455R