Asymmetric synthesis of corsifuran A by an enantioselective oxazaborolidine reduction

Article abstract of DOI:10.1021/ol800239q

(Chemical Equation Presented) Corsifuran A has been prepared in an enantiomerically pure form for the first time by an asymmetric reduction procedure, allowing confirmation of the absolute stereochemistry of the natural product as (R).

Full text of DOI:10.1021/ol800239q

ORGANIC
LETTERS
2008
Vol. 10, No. 7
1457-1460
Asymmetric Synthesis of Corsifuran A
by an Enantioselective Oxazaborolidine
Reduction†
Harry Adams, Nathan J. Gilmore, Simon Jones,* Mark P. Muldowney,‡
Stephan H. von Reuss,§ and Ramesh Vemula
Department of Chemistry, UniVersity of Sheffield, Dainton Building, Brook Hill,
Sheffield S6 1XD, U.K.
simon.jones@sheffield.ac.uk
Received February 1, 2008
ABSTRACT
Corsifuran A has been prepared in an enantiomerically pure form for the first time by an asymmetric reduction procedure, allowing confirmation
of the absolute stereochemistry of the natural product as (R).
Corsifuran A (1) is one of a group of three corsifurans,
composed of a 4′,5-dioxygenated-2-arylbenzofuran skeleton,
recently isolated from the Mediterranean liverwort Corsinia
coriandrina (Figure 1).1 The corsifuran skeleton is thought
to be constructed biogenetically from a stilbenoid precursor
and the naturally occurring material has shown to be of high
enantiomeric purity.
Corsifuran A has been prepared twice in racemic form.
The first synthesis involved a cycloaddition of 4-methoxy-
styrene with p-quinone to yield corsifuran B, which when
methylated gave racemic corsifuran A in an overall yield of
Figure 1. Biogenetic pathway for corsifuran A (stilbenoid unit
drawn in bold).
around 50%.1 The second route involved an anodic oxidation
of a phenol and styrene, which provided the target in 57%
yield.2
At the outset of this work the absolute configuration of
corsifuran A had not been identified. Our strategy for
installing the lone O-stereocenter of corsifuran A would entail
us applying our recently reported “one-pot” oxazaborolidine
methodology to ketol 3 to generate 2.3
Our approach to the dihydrofuran ring would involve a
metal-catalyzed cycloetherification being applied to enan-
tiomerically pure alcohol 2 (Scheme 2). A Friedel-Crafts
reaction would provide the ketone 3, and carboxylic acid 4
and anisole 5 would serve as its possible precursor.
2-Bromo-5-methoxyphenylacetic acid 4 was obtained from
carboxylic acid 6 in essentially quantitative yield (Scheme
2).4 Adaptation of an existing literature procedure5 allowed
† Dedicated to the memory of the late Dr. David R. Kelly, School of
Chemistry, Cardiff University, Cardiff, U.K.
‡ Shasun Pharma Solutions Ltd., Dudley, Northumberland NE23 7QG,
U.K.
§ Institute Fu¨r Organische Chemie, Universita¨t Hamburg, Martin-Luther-
King-Platz 6, D-29146 Hamburg, Germany.
(2) Gates, B. D.; Dalidowicz, P.; Tebben, A.; Wang, S.; Sweton, J. S. J.
Org. Chem. 1992, 57, 2135.
(1) von Reuss, S. H.; Ko¨nig, W. A. Phytochemistry 2004, 65, 3113.
(3) Gilmore, N. J.; Jones, S.; Muldowney, M. P. Org. Lett. 2004, 6, 2805.
10.1021/ol800239q CCC: $40.75
© 2008 American Chemical Society
Published on Web 03/13/2008

Scheme 1. Retrosynthesis of Corsifuran A
acid 4 to be coupled with anisole. The key ketone 3 was
isolated in 89% yield after chromatography. Asymmetric
With the key alcohol 2 in hand, cycloetherification was
attempted with various palladium catalysts in conjunction
with popular ligands and bases (Scheme 3, Table 1). Previous
work has shown that the choice of ligand is extremely
important in accelerating the rate of the desired reductive
elimination pathway and hence obtaining high yields of
product.6 2,2′-Bis(diphenylphosphino)-1,1′-binaphthalene (BI-
NAP) 9 was chosen as a benchmark ligand for comparison
purposes, and 2-di-tert-butylphosphino-2′-(N,N-dimethylami-
no)biphenyl 10, which has been shown to be a useful
phosphine for Pd-catalyzed etherification, was also employed.
Scheme 2. Preparation of Alcohol 2
The desired corsifuran A 1 was only produced in two
reactions, neither of which gave satisfactory results. Pd-
(OAc)2, BINAP, and t-BuONa (entry 1) gave poor yields
and did provide the target compound in high ee. By way of
contrast, a simple change of the Pd source gave a complete
conversion to product (entry 4). However, extensive race-
mization had occurred. Cs2CO3 led to no reaction (entries 2
and 5), and in certain circumstances (entries 1, 2, 3, and 6)
varying quantities of unreacted starting material 2, debro-
minated starting material 7, and ketones 3 and 8 were also
obtained in each case, the identities of which were confirmed
by independent syntheses. However, even with the drop of
enantioselectivity, we were able to conclude that the absolute
configuration of naturally occurring corisfuran A 1 was
indeed (R) by comparison of the chiral phase GC with that
of the authentic natural product and by comparison of the
optical rotation {[R]D -11.5 (c 1, CHCl3), lit.7 -11.1 (c 0.1
CDCl3), ee 92%}.
reduction of this ketone 3 with either the B-OMe oxazaboro-
lidine derived from (1R,2S)- or (1S,2R)-cis-1-amino-indan-
2-ol gave the S and R enantiomers of the alcohol 2 in 76%
and 78% ee, respectively. Recrystallization to >99% enan-
tiomeric purity allowed confirmation of the absolute con-
figuration through comparison of the Flack parameter
obtained by single-crystal X-ray crystallography.
Corsifuran A obtained from natural sources has a high
enantiomeric purity and has been shown to be configuration-
ally stable in air. Storage in dichloromethane in the presence
Scheme 3. Preparation of Corsifuran A by Pd-Catalyzed Intramolecular Etherification of Alcohol (R)-2a
a
Reactions performed as described in Table 1.
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Org. Lett., Vol. 10, No. 7, 2008

Table 1. Optimization of Pd-Catalyzed Intramolecular Etherificationa
conversion (%)b [ee (%)]c
entry
Pd source (3 mol %)
ligand (3.5 mol %)
base (1.5 equiv)
1d
2
7
3
8
1
2
3
4
5
6
Pd(OAc)2
Pd(OAc)2
Pd(OAc)2
Pd2(dba)3
Pd2(dba)3
Pd2(dba)3
9
9
9
10
10
10
NaOt-Bu
Cs2CO3
KOt-Bu
NaOt-Bu
Cs2CO3
KOt-Bu
5 [100]
0
0
100 [45]
0
0
0
5 [40]
3
0
0
0
0
5
87
3
100
0
0
95
97 [100]
0
0
100 [100]
0
0
0
0
0
0
a Reactions performed in toluene at reflux for 24 h under a nitrogen atmosphere. b Based on comparison of ratios of integrals of appropriate signals in the
1H NMR spectrum of the crude reaction mixture. c Values for ee determined by chiral phase GC analysis (see Supporting Information for further details).
d Refers to isolated product.
of an acidic ion-exchange resin (Amberlyst 15) for 1 h does,
however, cause complete racemization.7 Therefore, given the
reaction conditions, any loss in enantioselectivity most
probably occurs by the reversible formation of a palladium
hydride species formed by â-hydride elimination from the
palladium(II) aryl oxide intermediate. (Scheme 4). A similar
chloride catalyzed etherification of aryl halides, with only
minor quantities of byproducts being formed.8
Additionally, Buchwald et al. have reported a related
intermolecular copper-catalyzed etherification with enantio-
merically pure 1-phenylethanol that proceeded with retention
of configuration.9 Thus, this system was applied to the
preparation of corsifuran A in order to evaluate the intramo-
lecular variant and obtain a high yield of enantiopure
compound. When heated at reflux for 24 h corsifuran A 1
was obtained in 76% yield as essentially one enantiomer,
confirming that this method preserves the stereochemical
integrity (Scheme 5).
Scheme 4. Racemization by â-Hydride Elimination
Scheme 5. Corsifuran A by Copper-Catalyzed Intramolecular
Etherification
process has been reported in a Pd-catalyzed amination
process.6b This was supported by analysis of the ee of
dehalogenated alcohol 7 (entry 1, Table 1), which revealed
a significant reduction in enantioselectivity, alcohol 7 being
recovered in 40% ee.
As an alternative approach to circumvent the racemization
process, a copper-catalyzed intramolecular etherification was
considered. Such reactions have been reported in the
literature, with high yields being obtained for the copper(I)
Etherification reactions of this type are thought to proceed
via a catalytic cycle in which the copper coordinates initially
to the alkoxide before oxidative addition to the Ar-X bond.
Reductive elimination then yields the desired coupled
product.
In summary, we have achieved a synthesis of enantio-
merically enriched corsifuran A 1 by two routes: one in low
yield/high ee (5%, 100% ee, Pd route), the other in high
yield and high ee (76%, 100% ee, Cu route). We have
thereby established the absolute configuration of the natural
product. We have also demonstrated that copper-catalyzed
(4) Lebegue, N.; Bethegnies, G.; Berthelot, P. Synth. Commun. 2004,
34, 1041.
(5) Percec, V.; Zuber, M. J. Polym. Sci. Part A: Polym. Chem. 1992,
30, 997.
(6) (a) Kuwabe, S.-I.; Torraca, K. E.; Buchwald, S. L. J. Am. Chem.
Soc. 2001, 123, 12202. (b) Wagaw, S.; Rennels, R. A.; Buchwald, S. L. J.
Am. Chem. Soc. 1997, 119, 8451.
(7) Personal communication; von Reuss, S. H. Institute Fu¨r Organische
Chemie, Universita¨t Hamburg. Martin-Luther-King-Platz 6, D-29146
Hamburg, Germany.
(8) (a) Zhu, J.; Price, B. A.; Zhao, S. X.; Skonezny, P. M. Tetrahedron
Lett. 2000, 41, 4011. (b) Fagan, P. J.; Hauptman, E.; Shapiro, R.;
Casalnuovo, A. J. Am. Chem. Soc. 2000, 122, 5043. (c) Beletskaya, I. P.;
Cheprakov, A. V. Coord. Chem. ReV. 2004, 248, 2337.
(9) Wolter, M.; Nordmann, G.; Job, G. E.; Buchwald, S. L. Org. Lett.
2002, 4, 973.
Org. Lett., Vol. 10, No. 7, 2008
1459

intramolecular etherifications lead to significantly higher
yields and no racemization compared to their palladium
counterparts.
Supporting Information Available: Experimental pro-
cedures, full spectroscopic data for all new compounds and
X-ray data of compounds (R)- and (S)-2. This material is
available free of charge via the Internet at http://pubs.acs.
org.
Acknowledgment. We would like to thank the EPSRC
(NJG, RV) and Shasun Pharma Solutions Ltd. for funding
(N.J.G.).
OL800239Q
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Org. Lett., Vol. 10, No. 7, 2008