Chemoenzymatic total synthesis and reassignment of the absolute configuration of ribisin C

Article abstract of DOI:10.1021/ol403220t

The enantiomerically pure and enzymatically derived cis-1,2-dihydrocatechol 5 has been converted, by two related pathways, into compounds 3 and ent-3. As a result, it has been determined that the true structure of the natural product ribisin C is represen

Full text of DOI:10.1021/ol403220t

Letter
pubs.acs.org/OrgLett
Chemoenzymatic Total Synthesis and Reassignment of the Absolute
Configuration of Ribisin C
Ping Lan, Martin G. Banwell,* Jas S. Ward, and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra ACT 0200, Australia
S
* Supporting Information
ABSTRACT: The enantiomerically pure and enzymatically
derived cis-1,2-dihydrocatechol 5 has been converted, by two
related pathways, into compounds 3 and ent-3. As a result, it
has been determined that the true structure of the natural
product ribisin C is represented by ent-3.
While a number of naturally occurring dibenzofurans have
been reported,4 the highly oxygenated nature of the ribisins and
the presence of sp3-hybridized carbons within their frameworks
makes them a structurally quite distinctive group of
compounds. Given such features and their intriguing biological
properties we have initiated synthetic studies in the area and
these have revealed, as detailed below, that the true structure of
ribisin C is represented by ent-3 rather than by 3 (Figure 1).5
The assembly of the structure, 3, proposed for ribicin C was
the initial focus of our efforts and the ultimately successful
reaction sequence used for this purpose is shown in Scheme 1.
Thus, the enantiomerically pure and stereochemically well-
defined cis-1,2-dihydrocatechol 5, which is readily obtained
through the whole-cell biotransformation of bromobenzene
using a genetically engineered form of E. coli JM109,6 was first
converted, via acetonide 6,7 into the well-known7 epoxy
acetonide 7. Treatment of the last compound with aqueous
hydrochloric acid resulted in the formation of the previously
reported7 trans-diol 8 that was subjected to a 2-fold
O‑methylation reaction using methyl iodide in the presence
of sodium hydride. The acetonide moiety associated with the
ensuing bis-ether 9 (90%) was cleaved with aqueous acetic acid
and thus providing the cis-diol 10 (90%). In a pivotal step of
the reaction sequence, compound 10 was subjected to Suzuki−
Miyaura cross-coupling with the commercially available
o‑hydroxyphenylboronic acid pinacol ester (11)8 in the
presence of PdCl2(dppf)·CH2Cl2 and triethylamine and thereby
affording a chromatographically separable mixture of the biaryl
12 (41%)9 and the hoped for tetrahydrodibenzofuran 13
(24%). Product 13 presumably arises by a process in which the
phenolic hydroxyl group associated with the initial cross-
coupling product displaces the allylic hydroxyl group with
inversion of configuration and so establishing the illustrated
stereochemistry at C-4a. However, this assignment must be
considered a tentative one since it is conceivable that other
ecently, Fukuyama and co-workers reported the isolation
Rof the benzofuran-type natural products ribisins A−D (1−
́
4, Figure 1) from Phellinus ribis (Schmach.) Quel. (Hyme-
nochaetaceae),1 a white-rot fungus found in various East Asian
countries and the fruiting bodies of which are used in the
traditional medicines of the region for the treatment of
gastrointestinal cancer and for enhancing immunity.2,3 The
structures of the ribisins, including relative stereochemistries,
were assigned on the basis of extensive and multidimensional
NMR spectroscopic as well as mass spectrometric studies, while
their absolute configurations were proposed based on the
application of CD exciton chirality methods to the chemically
derived p-bromobenzoates.1 The positive and dose-dependent
effects of compounds 1−4 on the neurite outgrowth of PC12
cells were shown to be exerted at rather low concentrations
(viz. in the range of 1−30 μM) with ribisin C being the most
active member of the series. As such it has been suggested1 that
these natural products could serve as useful lead candidates for
the development of new treatments of certain neurodegener-
ative diseases.
Received: November 7, 2013
Published: December 16, 2013
Figure 1. Ribisins A−D (1−4, respectively) and ent-3.
© 2013 American Chemical Society
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Organic Letters
Letter
Scheme 1
cyclization pathways proceeding with retention of configuration
could be involved. The precise sequence of events leading to
the formation of compound 12 remains unclear at the present
time but necessarily involves the loss of the elements of
methanol and water at some stage.
reported for ribisin C established that they were a good match.
However, while the specific rotations of the two compounds
were of similar magnitude they were of opposite sign13 and thus
suggesting that the absolute configuration of ribisin C had been
incorrectly assigned with the true structure of this natural
product being represented by ent-3.
In anticipation of the need to carry out a late-stage oxidation
of a yet to be introduced hydroxyl group within the developing
ribisin C framework, alcohol 13 was converted into the
corresponding α-chloroacetate 14 by treating the former
compound with α-chloroacetyl chloride in the presence of
triethylamine and 4-(N,N-dimethylamino)pyridine (DMAP).
Ester 14 was exposed to m-chloroperbenzoic acid (m-CPBA) in
dichloromethane, and by such means the rather sensitive
polyoxygenated tetrahydrodibenzofuran 15 was obtained as a
single diastereoisomer in 49% yield (from 13). This product
presumably arises through spontaneous rearrangement of the
initially formed β-epoxide, a process that is driven, at least in
part, by the creation of the aromatic benzofuran substructure.
The assignment of the illustrated β-stereochemistry at C-1 in
compound 15 remains tentative but is based on the observation
that the vicinal proton−proton couplings J1,2 and J3,4 observed
In view of the outcomes of the studies detailed above, and
because of the desire to obtain biologically active material for
further evaluation, we sought to prepare compound ent-3. We
were able to do so by using the reaction sequence shown in
Scheme 2 and that started with the same enantiomerically pure
cis-1,2-dihydrocatechol, 5, as used earlier. Thus, treatment of
this starting material with N-bromosuccinimide (NBS) in wet
THF lead to a previously reported10b bromotriol that was
immediately converted into the corresponding acetonide 17
(73% from 5) under standard conditions. Reaction of this last
compound with sodium methoxide in methanol then provided,
presumably through a ring-closure/epoxide ring-opening
sequence,14 the alcohol 18 (90%) that was subjected to
O‑methylation using methyl iodide in the presence of sodium
hydride and thus delivering the bis-ether 19 (97%). Hydrolysis
of the acetonide residue within this last compound was readily
achieved using aqueous acetic acid at 70 °C and the resulting
diol 20 (93%) subjected to reaction with p-methoxybenzalde-
hyde dimethyl acetal (p-MBDMA) in the presence of
p‑toluenesulfonic acid (p-TsOH). The p-methoxyphenyl acetal
so-formed was subjected to reductive cleavage with diisobutyl-
aluminum hydride (DIBAl-H) and the tris-ether 21 (57%)
thereby obtained.15 Compound 21 readily participated in a
PdCl2(dppf)·CH2Cl2-catalyzed Suzuki−Miyaura cross-coupling
reaction with aryl boronate ester 11 in the presence of
triethylamine and so delivering compound 22 (83%) as the
only isolable product of reaction. Thus, while none of the
anticipated cyclization product 23 was observed, this
compound was readily formed, in 89% yield, by subjecting
phenol 22 to an intramolecular Mitsunobu reaction using
1
in the 400 MHz H NMR spectrum of this material are very
similar (3.6 and 3.5 Hz, respectively) and the knowledge that a
trans-relationship must exist between the H-3 and H-4.
Subjection of alcohol 15 to Swern oxidation conditions
afforded the corresponding ketone 16 (66%) that represents
the α-chloroacetate derivative of the structure assigned to
ribisin C. Finally, treatment of compound 16 with Zn(OAc)2 in
methanol at 18 °C10,11 effected cleavage of the ester residue and
thereby providing compound 3 in 71% yield. All of the
spectroscopic data acquired on this product were consistent
with the illustrated structure but final confirmation of it
followed from a single-crystal X-ray analysis,12 details of which
are presented in the Supporting Information. A comparison
1
(Table 1) of the 13C and H NMR spectral data acquired on
the synthetically derived samples of compound 3 with those
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Organic Letters
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Table 1. Comparison of the 13C and 1H NMR Data Recorded for Synthetically Derived Compound 3 with Those Reported for
Ribisin C
δC
δH
a
b
c
d
synthetically derived compound 3
ribisin C
synthetically derived compound 3
ribisin C
189.9
165.9
155.7
126.2
124.8
123.0
122.4
114.6
111.8
83.8
189.9
165.9
155.7
126.1
124.8
123.0
122.3
114.6
111.8
83.8
8.07, 1H, dm, J = 7.3 Hz
7.56, 1H, dm, J = 7.3 Hz
7.42−7.34, 2H, complex m
8.07, 1H, ddd, J = 7.4, 1.6, and 0.6 Hz
7.55, 1H, ddd, J = 7.4, 1.3, and 0.6 Hz
7.39, 1H, td, J = 7.4 and 1.6 Hz
7.37, 1H, td, J = 7.4 and 1.3 Hz
4.99, 1H, ddd, J = 8.3, 4.3, and 0.7 Hz
3.99, 1H, dd, J = 6.1 and 4.3 Hz
3.97, 1H, dd, J = 6.1 and 0.7 Hz
3.61, 3H, s
4.98, 1H, ddd, J = 8.9, 4.1, and 0.9 Hz
4.01−3.95, 2H, complex m
3.60, 3H, s
3.58, 3H, s
3.59, 3H, s
3.36, 1H, d, J = 8.9 Hz
3.41, 1H, d, J = 8.3 Hz
82.8
82.9
66.1
66.1
59.7(4)
59.7(3)
59.8
59.8
a
b
c
Data recorded in CDCl3 at 100 MHz. Data obtained from the Supporting Information of ref 1 and recorded in CDCl3 at 150 MHz. Data
d
recorded in CDCl3 at 400 MHz. Data obtained from ref 1 and recorded in CDCl3 at 600 MHz.
Scheme 2
triphenylphosphine (Ph3P) in the presence of diethyl
azodicarboxylate (DEAD).16 Treatment of compound 23 with
m-CPBA gave a rather unstable product that was immediately
oxidized under Swern conditions to afford the ketone 24 in
48% yield. Cleavage of the p-methoxybenzyl ether (p-MB)
residue within the latter compound was achieved using 2,3-
dichloro-5,6-dicyano-1,4-benzoquinone (DDQ) and thus pro-
viding C-4-epi-ribisin C (25) in 85% yield. Subjection of
compound 25 to an intermolecular Mitsunobu reaction using
Ph3P/DEAD and α‑chloroacetic acid as the nucleophile10b gave
the anticipated ester 26 (84%) that could be methanolyzed in
the presence of Zn(OAc)2 and thereby affording the targeted
and crystalline compound ent-3 in 82% yield. Once again, all
the NMR spectral data acquired on the latter compound were
in accord with the assigned structure17 and matched those
recorded for both compound 3 and ribisin C. Significantly, the
specific rotation of compound ent-3 {[α]24 −10.8 (c 0.5,
D
MeOH)} was a good match, both in terms of magnitude and
sign, with that reported1,13 for ribisin C.
The implications of the present study in terms of whether or
not the absolute configurations of ribisins A, B, and D (1, 2,
and 4, respectively) have also been assigned incorrectly remain
unclear. It is hoped the present studies will provide the means
for clarifying this matter and for generating analogues of these
fascinating natural products for biological evaluation. In
addition, this report further highlights the synthetic utility of
the enzymatically derived cis-1,2-dihydrocatechols such as 5 as
chiral, nonracemic starting materials for chemical synthesis.6,18
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Organic Letters
Letter
L. J. Chem. Soc., Perkin Trans. 1 1997, 1779. (b) Vo, Y.; Banwell, M. G.;
Willis, A. C. Chem.Asian J., in press. DOI: 10.1002/asia.201301233
(15) For related reaction sequences leading to the selective
monoprotection of cis-vicinal diols, see: (a) Banwell, M. G.; Darmos,
P.; McLeod, M. D.; Hockless, D. C. R. Synlett 1998, 897. (b) Banwell,
M. G.; McRae, K. J.; Willis, A. C. J. Chem. Soc., Perkin Trans. 1 2001,
2194. (c) Banwell, M. G.; McLeod, M. D.; Riches, A. G. Aust. J. Chem.
2004, 57, 53.
(16) For an example of an intramolecular Mitsunobu reaction
involving a pendant phenolic group acting as the nucleophile see:
Hodgetts, K. J. Tetrahedron 2005, 61, 6860.
(17) The structure (including relative stereochemistry) of compound
ent-3 was confirmed by single-crystal X-ray analysis. Details are
presented in the Supporting Information.
ASSOCIATED CONTENT
* Supporting Information
Full experimental procedures; ORTEPs and data derived from
■
S
the single-crystal X-ray analyses of compounds 3, ent-3, and 12
(CCDC Nos. 969616−969618, respectively); and H and 13C
1
NMR spectra of compounds 3, 9, 10, 12, 13, and 15−26. This
material is available free-of-charge via the Internet at http://
pubs.acs.org.
AUTHOR INFORMATION
Corresponding Author
■
*E-mail: martin.banwell@anu.edu.au.
Notes
(18) For a recent study using these chirons that has allowed for the
determination of the correct absolute configuration of another class of
natural product, see: Ma, X.; Banwell, M. G.; Willis, A. C. J. Nat. Prod.
2013, 76, 1514.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
■
We thank the Australian Research Council and the Institute of
Advanced Studies for financial support. P.L. is the grateful
recipient of a CSC PhD Scholarship provided by the
Government of the People’s Republic of China.
REFERENCES
■
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resulted in its decomposition.
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5 and the reaction sequence used.
(13) The optical rotation reported for ribisin C is [α]24 −11.4 (c
D
0.5, MeOH) while that obtained on synthetically derived compound 3
is [α]24 +11.1 (c 0.25, MeOH). It was not possible to prepare a 5.0
D
mg/mL solution of compound 3 in methanol because of its limited
solubility in this solvent.
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231
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