Chemoenzymatic total syntheses of ribisins A, B, and D, polyoxygenated benzofuran derivatives displaying NGF-potentiating properties

Article abstract of DOI:10.1021/jo500210k

Total syntheses of the structures, 1, 2, and 4, assigned to the biologically active natural products ribisins A, B, and D, respectively, have been achieved using the microbially derived and enantiomerically pure cis-1,2-dihydrocatechol 5 as starting material. Key steps include Suzuki-Miyaura cross-coupling, intramolecular Mitsunobu, and tandem epoxidation/rearrangement reactions. As a result of these studies, the structures of ribisins A and D have been confirmed while that of congener B was shown to be represented by 31 rather than 2.

Full text of DOI:10.1021/jo500210k

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pubs.acs.org/joc
Chemoenzymatic Total Syntheses of Ribisins A, B, and D,
Polyoxygenated Benzofuran Derivatives Displaying NGF-
Potentiating Properties
Ping Lan, Martin G. Banwell,* and Anthony C. Willis
Research School of Chemistry, Institute of Advanced Studies, The Australian National University, Canberra, ACT 0200, Australia
S
* Supporting Information
ABSTRACT: Total syntheses of the structures, 1, 2, and 4,
assigned to the biologically active natural products ribisins A,
B, and D, respectively, have been achieved using the
microbially derived and enantiomerically pure cis-1,2-dihy-
drocatechol 5 as starting material. Key steps include Suzuki−
Miyaura cross-coupling, intramolecular Mitsunobu, and
tandem epoxidation/rearrangement reactions. As a result of
these studies, the structures of ribisins A and D have been
confirmed while that of congener B was shown to be
represented by 31 rather than 2.
INTRODUCTION
■
In late 2012, Fukuyama and co-workers reported1 the outcomes
of an investigation of the active principals associated with
́
Phellinus ribis (Schmach.) Quel (Hymenochaetaceae), a white-
rot fungus found in several East Asian countries and the fruiting
bodies of which have been exploited in traditional medicines for
promoting immunity and for the treatment of gastrointestinal
cancer.2 In particular, they described the isolation (in milligram
amounts) and structural assignment of four novel polyoxy-
genated benzofuran derivatives, namely ribisin A (1), ribisin B
(2), ribisin C (3), and ribisin D (4). Their structures, including
relative stereochemistries, were proposed on the basis of
1
various spectroscopic analyses, particularly those involving H
of ribisin C had been incorrectly assigned and is, in fact,
represented by structure ent-3. As a consequence, we also
developed3 a 14-step total synthesis of compound ent-3 from
the same starting material, viz. cis-1,2-dihydrocatechol 5, and
thereby clearly established the true structure of ribisin C. Of
course, this sequence also provided biologically active material
for further testing. These preliminary results prompted us to
pursue total syntheses of the remaining members of the ribisin
family, namely congeners A, B, and D in order to either confirm
their structures or establish the correct ones. Herein we detail
the outcome of these studies that, inter alia, provide the means
for obtaining all of the ribisins in quantities suitable for
comprehensive biological evaluation.
and 13C NMR studies, while the illustrated absolute
configurations followed from the application of CD exciton
chirality methods to the readily derived p-bromobenzoates.
Ribisins A − D were shown1 to enhance neurite outgrowth in
nerve growth factor (NGF)-mediated PC12 cells in a dose-
dependent way and in the micromole range with ribisin C being
the most active member of the series. The variation in activity
of these compounds as a function of changes in both
stereochemistry and substituent suggests that they could
represent novel leads for creating drugs that reduce neuronal
damage as a result of stroke and other trauma and might even
have application in the development of new therapeutic agents
for the treatment of Alzheimer’s disease.1
As a result of their novel structures and interesting biological
properties, we embarked on a program to develop syntheses of
the ribisins so as to generate material for extended biological
evaluation. The outcomes of our initial studies in the area,3
which culminated in a 10-step synthesis of compound 3 from
the microbially derived and enantiomerically pure cis-1,2-
dihydrocatechol 5,4 revealed that the absolute stereochemistry
RESULTS AND DISCUSSION
■
The key features of our recently reported3 total synthesis of
ribisin C (ent-3) were a Suzuki−Miyaura cross-coupling
Received: January 28, 2014
Published: February 18, 2014
© 2014 American Chemical Society
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Given the structural similarities between the various ribisin
structures, the above-mentioned synthetic protocols would
seem suitable for deployment in syntheses of the targeted
members of the family, namely compounds 1, 2, and 4. In many
respects, then, a major focus of the present work was the
manipulation of the nonhalogenated double bond within the
starting diene 5 in ways that allowed for the introduction of the
relevant functionalities at C2 and C3 in the title compounds.
Details of the successful implementation of these protocols are
provided in the following sections.
Total Synthesis of Ribisin A. The reaction sequence
leading to the preparation of ribisin A (1) is presented in
Scheme 1. Thus, a dichloromethane solution of the starting diol
5 maintained at 0 °C was treated with p-methoxybenzaldehyde
dimethyl acetal (p-MBDMA) in the presence of (+)-camphor-
sulfonic acid (CSA), and the previously reported6 p-
methoxyphenyl (PMP) acetal 6 was thereby obtained as a
single diastereoisomer. Immediate subjection of the latter
compound to reaction with diisobutylaluminum hydride
(DIBAl-H) resulted in regioselective cleavage of the acetal
moiety and formation of the known6,7 p-methoxybenzyl (PMB)
ether 7, which was obtained in 74% yield over the two steps
involved. Treatment of compound 7 with N-bromosuccinimide
(NBS) in wet THF resulted in the selective formation of the
previously unreported bromohydrin 8 (76%) that was
immediately treated with sodium methoxide in methanol. It is
presumed that the initial product of reaction is the epoxide 9,
but this reacts, in situ, to give, via nucleophilic ring-opening at
reaction between a dimethoxy-substituted derivative of
compound 5 and the commercially available 2-(4,4,5,5-
tetramethyl-1,3,2-dioxaborolan-2-yl)phenol. This was followed
by the immediate engagement of the product of this process in
an intramolecular Mitsunobu reaction with the pendant
phenolic hydroxyl group serving as an internal nucleophile.
The resulting 2,3,4,4a-tetrahydrodibenzo[b,d]furan was treated
with m-chloroperbenzoic acid (m-CPBA), and the epoxide thus
formed underwent a spontaneous isomerization to give the
corresponding allylic alcohol now incorporating a fully aromatic
benzofuran substructure. Oxidation of the associated hydroxyl
then allowed for introduction of the necessary C1-carbonyl
moiety (see structure 1 for atom numbering). Another
important feature of our earlier work3 was the use of an α-
chloroacetate group to protect the C4-hydroxyl group since this
can be cleaved under exceptionally mild conditions so as to
reveal the seemingly rather fragile polyoxygenated cyclo-
hexenone-type substructure associated with the final target.5
Attempts to cleave the corresponding acetate using potassium
carbonate in methanol only resulted in a complex mixture of
products.
Scheme 1. Total Synthesis of Ribisin A (1)
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Table 1. Comparison of the 13C and 1H NMR Data Recorded for Synthetically Derived Compound 1 with Those Reported for
Ribisin A
13C NMR (δC)
f1H NMR (δH)
a
b
c
d
compd 1
ribisin A
compd 1
ribisin A
193.1
169.3
157.4
127.1
125.9
124.3
122.8
116.1
112.7
87.1
193.1
169.2
157.4
127.1
125.9
124.3
122.8
116.1
112.7
87.1
7.99 (broad dd, J = 7.5 and 1.2 Hz, 1H)
7.61 (broad d, J = 7.5 Hz, 1H)
7.46−7.35 (complex m, 2H)
7.97 (ddd, J = 7.5, 1.4, and 0.7 Hz, 1H)
7.52 (ddd, J = 7.5, 1.0, and 0.7 Hz, 1H)
7.40 (td, J = 7.4 and 1.4 Hz, 1H)
7.36 (td, J = 7.5 and 1.0 Hz, 1H)
4.97 (d, J = 7.5 Hz, 1H)
5.00 (d, J = 7.3 Hz, 1H)
4.04 (d, J = 9.8 Hz, 1H)
4.01 (d, J = 9.8 Hz, 1H)
4.00 (dd, J = 9.8 and 7.3 Hz, 1H)
3.74 (s, 3H)
3.97 (dd, J = 9.8 and 7.5 Hz, 1H)
3.71 (s, 3H)
signals due to OH protons not observed
78.8
78.8
70.3
70.3
60.8
60.8
a
b
c
d
Recorded in CD3OD at 100 MHz. Obtained from ref 1 and recorded in CD3OD at 150 MHz. Recorded in CD3OD at 400 MHz. Obtained from
ref 1 and recorded in CD3OD at 600 MHz.
the allylic carbon, the diol 10 in 82% yield and as the only
isolable product. Suzuki−Miyaura cross-coupling of this last
compound with 2-(4,4,5,5-tetramethyl-1,3,2-dioxaborolan-2-
yl)phenol (11)8 using PdCl2(dppf)·CH2Cl2 as the source of
catalyst and triethylamine as base afforded the anticipated
product 12 in 80% yield. Interestingly, and in contrast to our
experience3 when carrying out the analogous cross-coupling
reaction en route to compound 3, no biaryl(s) arising from
elimination of the elements of methanol and water within the
primary coupling product was (were) observed in this instance.
Treatment of compound 12 with diethyl azodicarboxylate
(DEAD) in the presence of triphenylphosphine resulted in an
intramolecular Mitsunobu reaction with the phenolic OH
group serving as the internal nucleophile, thus affording the
benzofuran isomer 13 in 88% yield and so establishing the
tricyclic framework of target 1. The illustrated β-configuration
at C4a (ribisin numbering) within this product, which is of no
consequence in terms of the overall synthesis, was assigned on
the basis of the well-known propensity of the Mitsunobu
reaction to proceed with inversion of configuration at the
center undergoing substitution.9 The alcohol 13 was protected
as the corresponding β-methoxyethoxymethyl (MEM) ether 14
(80%) under standard conditions and the latter compound
subjected to reaction with m-CPBA. This resulted in the
formation of the benzofuran 15, presumably through
spontaneous rearrangement of the initially formed epoxide (a
process driven by cleavage of the strained three-membered ring
and accompanying formation of an aromatic ring system). The
illustrated α-orientation of the C1-hydroxy group within
compound 15, a rather unstable material, is tentatively assigned
on the basis that the initial epoxidation reaction will proceed
from that face of the alkene opposite to the allylically
positioned and β-configured methoxy group. Oxidation of
alcohol 15 under Swern conditions afforded compound 16
(70% from 14), the PMB group of which was cleaved using
DDQ to afford the γ-hydroxy ketone 17 in 81% yield. The last
compound was engaged in an intermolecular Mitsunobu
reaction using α-chloroacetic acid as the nucleophile and thus
affording the ester 18 in 85% yield. The MEM ether residue
within compound 18 was cleaved using zinc(II) bromide in
dichloromethane10 and the product diol monoester 19 treated
with zinc acetate dihydrate in methanol,11 thereby affording the
target compound 1 in 50% yield over the two steps.
All the spectroscopic data acquired on compound 1 were in
complete accord with the assigned structure but final
confirmation of this followed from a single-crystal X-ray
analysis, details of which are provided in the Experimental
Section and Supporting Information. Furthermore, the 13C and
1H NMR spectral data recorded for this material compared
favorably (see Table 1) with those reported1 by Fukuyama and
co-workers for ribisin A.
Since the specific rotations were also a good match {[α]20
D
−24.9 (c 1.2, methanol) for synthetically derived 1 vs [α]25
D
−21.9 (c 1.0, methanol) reported for ribisin A}, we conclude
that the structure of this natural product has been correctly
assigned. This outcome agrees with that of Du and co-workers
who have very recently completed a synthesis of the same
compound starting from methyl α-D-glucopyranoside.12
Total Synthesis of the Structure Assigned to Ribisin B.
The next structure targeted for synthesis was that assigned to
ribisin B, namely the all-cis and dimethoxylated system 2. In the
early stages of the synthetic sequence (Scheme 2), the well-
known acetonide derivative (20)13 of the starting diol 5 was
subjected to a completely facially selective cis-dihydroxylation of
the nonhalogenated double bond under Upjohn conditions,14
thereby affording the previously reported13,15 diol 21 in 75%
yield (from 5). Two-fold O-methylation of the last compound
was achieved using methyl iodide in the presence of sodium
hydride, and the bis-ether 22 (98%) thus obtained subjected to
treatment with aqueous acetic acid at 70 °C for 14 h. A
dichloromethane solution of the diol 23 so-formed (97%) was
exposed to p-MBDMA in the presence catalytic quantities of p-
TsOH and the ensuing PMP-acetal immediately subjected to
reductive cleavage using DIBAl-H and thereby delivering the
alcohol 24 (50% from 23). Suzuki−Miyaura cross-coupling of
the last compound with arylboronate ester 11 then afforded the
expected product 25 (81%) that could be engaged in an
intramolecular Mitsunobu reaction to give the tricyclic
compound 26 in 89% yield. Reaction of alkene 26 with m-
CPBA gave, via in situ rearrangement of the initially formed
epoxide, benzofuran 27 that, because of its instability, was
immediately oxidized under Swern conditions to afford the
enone 28 (61% from 26), the PMB ether residue of which was
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Scheme 2. Total Synthesis of Compound 2, the Structure Incorrectly Assigned to Ribisin B
cleaved with DDQ to afford alcohol 29 (85%). Subjection of
the last compound to an intermolecular Mitsunobu reaction
using α-chloroacetic acid as the nucleophile then gave the all-
cis-configured ester 30 (71%) that on methanolysis in the
presence of the dihydrate of zinc acetate afforded the targeted
structure 2 in 82% yield.
of which are presented below, we have concluded that the true
structure of ribisin B is represented by 31 and not by 2.
All of the spectral data acquired on compound 2 were in
accord with the assigned structure, but final confirmation of this
followed from a single-crystal X-ray analysis. Details are
provided in the Experimental Section and Supporting
Information. However, in contrast to the case of ribisin A (as
detailed above), the spectral data acquired on compound 2 did
not match those reported for the natural product ribisin B.
For the sake of completeness, the synthetic route employed
in our earlier studies3 for the purpose of obtaining compound
31 (and, thereby, ribisin C) is reproduced in Scheme 3. Thus,
the starting diol 5 was reacted with NBS in wet THF and so
forming, in a regio- and diastereo-selective process, a
bromohydrin that was immediately converted into the
acetonide 32 (73%) under standard conditions. Treatment of
the latter material with sodium methoxide in methanol then
lead, in a manner analogous to that involved in the sequence 8
→ 9 → 10 (Scheme 1), to compound 33 (90%). Manipulation
of alcohol 33 in a similar fashion to that associated with the
early stages of the synthesis of compound 2 (Scheme 2) lead,
via compounds 34 (97%) and 35 (93%), to the conduritol 36
(57%). This last compound was then engaged in a Suzuki−
Miyaura cross-coupling reaction with boronate ester 11 to give
the arylated cyclohexene 37 (83%). Subjection of compound
37 to the now familiar sequence involving an intramolecular
Mitsunobu reaction (leading to tricycle 38 in 89% yield),
epoxidation/rearrangement then Swern oxidation (delivering
1
Thus, the 13C and H NMR spectral data (see the Supporting
Information) were quite different. The same was true for the
specific rotations {[α]20 +51.9 (c 0.4, methanol) for
D
synthetically derived 2 vs [α]25 −91.1 (c 0.4, methanol)
D
reported1 for ribisin B}. These results clearly suggest that ribisin
B is a diastereoisomer or, perhaps (even), a structural isomer of
compound 2. The fortuitous identification of the true structure
of this natural product is described in the following section.
Identification of the True Structure of Ribisin B. While
examining the 13C NMR spectral data obtained on the various
intermediates generated during the course of our synthesis of
the true structure, ent-3, of ribisin C we noted that those due to
its C4-epimer, viz. compound 31, displayed essentially identical
chemical shifts to those reported1 for ribisin B. On the basis of
further comparisons of the relevant sets of spectral data, details
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Scheme 3. Total Synthesis of Compound 31, the True Structure of Ribisin B
Table 2. Comparison of the 13C and 1H NMR Data Recorded for Synthetically Derived Compound 31 with Those Reported for
Ribisin B
13C NMR (δC)
1H NMR (δH)
a
b
c
d
compd 31
ribisin B
compd 31
ribisin B
190.2
165.2
155.7
126.0
124.8
123.0
122.2
115.2
111.7
81.8
190.2
165.2
155.8
126.1
124.9
123.0
122.3
115.3
111.8
81.8
8.05 (dm, J = 7.5 Hz, 1H)
7.53 (dm, J = 7.5 Hz, 1H)
7.39−7.32 (complex m, 2H)
8.07 (ddd, J = 7.4, 1.6, and 0.6 Hz, 1H)
7.55 (ddd, J = 7.4, 1.3, and 0.6 Hz, 1H)
7.39 (td, J = 7.4 and 1.6 Hz, 1H)
7.37 (td, J = 7.4 and 1.3 Hz, 1H)
5.30 (dd, J = 7.0 and 4.1 Hz, 1H)
4.16 (d, J = 6.6 Hz, 1H)
5.29 (dd, J = 6.9 and 4.0 Hz, 1H)
4.14 (d, J = 7.5 Hz, 1H)
3.98 (dd, J = 6.9 and 4.0 Hz, 1H)
3.60 (s, 3H)
4.00 (dd, J = 6.6 and 4.1 Hz, 1H)
3.62 (s, 3H)
3.60 (s, 3H)
3.62 (s, 3H)
3.17 (d, J = 6.9 Hz, 1H)
3.05 (d, J = 7.0 Hz, 1H)
81.6
81.6
63.7
63.7
59.7
59.7
59.4
59.4
a
b
c
d
Recorded in CD3OD at 100 MHz. Obtained from ref 1 and recorded in CD3OD at 150 MHz. Recorded in CD3OD at 400 MHz. Obtained from
ref 1 and recorded in CD3OD at 600 MHz.
compound 39 in 48% yield) and then cleavage of the PMB
ether (once again using DDQ) afforded compound 31 (85%).
Comparisons of the 13C and 1H NMR spectral data recorded
on compound 31 with those reported for ribisin B are
presented in Table 2 and reveal good matches and thus
suggesting they are one and the same compound. Disappoint-
ingly, and despite strenuous efforts, we have been unable to
grow crystals of compound 31 suitable for X-ray analysis. The
specific rotation of the synthetically derived material was of the
same sign but considerably larger magnitude than that reported
Total Synthesis of Ribisin D. In order develop a synthesis
of the structure, 4, proposed by Fukuyama and co-workers for
the natural product ribisin D a new boronate ester building
block was required. The one identified as being most
appropriate for this purpose was compound 40 because of
the prospects of being able to cleave aryl isopropyl ethers under
mild conditions16 and thus revealing a phenolic hydroxyl group
as required at C6 in target 4.
for the natural product {[α]20 −168.5 (c 0.6, methanol) vs
D
[α]25D −91.1 (c 0.4, methanol) reported1 for ribisin B}, and this
discrepancy is attributed to the presence of impurities in the
latter which was only isolated in 1.6 mg quantities (more than
200 mg of synthetic material was obtained).
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The reaction sequence employed in preparing aryl boronate
40 is shown in Scheme 4 and involved initial monoisopropy-
lation of catechol 41 under conditions described by Waldmann
and co-workers and thus affording phenol 4217 (45%).
Electrophilic aromatic bromination of the latter compound
using molecular bromine in the presence of tert-butylamine
afforded the 1,2,3-trisubstituted arene 4317 (81%), and this was
immediately protected, under conventional conditions, as the
corresponding and previously unreported methoxymethyl
(MOM) ether 44 (96%). Treatment of compound 44 with n-
BuLi in THF at −78 °C and trapping of the resulting lithiated
arene with triisopropyl borate gave, after warming of the
reaction mixture to 18 °C and quenching it with water, the
anticipated boronic acid 45. After removing the associated
MOM protecting group using NaI/TMSCl in acetonitrile, the
last compound was immediately treated with pinacol in
refluxing benzene in an apparatus fitted with a Dean−Stark
trap, thus providing, after conventional workup, the boronate
ester 40 (45% from 44). All the spectroscopic data acquired on
ester 40 were in complete accord with the assigned structure.
With building block 40 to hand its exploitation in the
synthesis of compound 4 could be pursued. The ultimately
successful reaction sequence used for this purpose is shown in
Scheme 5 and involved initial Suzuki−Miyaura cross-coupling
of compounds 36 and 40, thereby generating the arylated
cyclohexene 46 in 92% yield. This last compound readily
participated, under the usual reaction conditions, in an
intramolecular Mitsunobu reaction to deliver the cyclo-
dehydration product 47 (94%), and this was subjected to an
epoxidation/rearrangement sequence and so delivering an
allylic alcohol that was immediately oxidized under Swern
conditions to give the ketone 48 (58% over two steps).
Cleavage of the associated PMB ether moiety within the last
compound was achieved using DDQ and the resulting free
alcohol 49 (84%) subjected to an intermolecular Mitsunobu
reaction using α-chloroacetic acid, thus providing ester 50 in
84% yield. Methanolysis of this ester under the usual conditions
then gave compound 51, the isopropyl ether of target
compound 4. The cleavage of the aryl isopropyl ether
Scheme 4. Synthesis of Boronate Ester 40
Scheme 5. Total Synthesis of Ribisin D (4)
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Table 3. Comparison of the 13C and 1H NMR Data Recorded for Synthetically Derived Compound 4 with Those Reported for
Ribisin D
13C NMR (δC)
1H NMR (δH)
a
b
c
d
compd 4
ribisin D
compd 4
ribisin D
192.8
168.7
146.2
144.1
126.8
126.0
116.4
113.6
113.4
88.7
192.8
168.7
146.4
144.5
126.9
7.39 (dd, J = 7.7 and 1.0 Hz, 1H)
7.24 (t, J = 7.7 Hz, 1H)
6.83 (dd, J = 7.7 and 1.0 Hz, 1H)
5.04 (d, J = 7.5 Hz, 1H)
4.08 (d, J = 9.7 Hz, 1H)
3.69 (s, 3H)
7.41 (dd, J = 7.7 and 1.0 Hz, 1H)
7.16 (t, J = 7.7 Hz, 1H)
6.83 (dd, J = 7.7 and 1.0 Hz, 1H)
5.06 (d, J = 7.6 Hz, 1H)
4.11 (d, J = 9.8 Hz, 1H)
3.71 (s, 3H)
e
125.9
116.4
113.7
113.0
88.8
3.69 (s, 3H)
3.71 (s, 3H)
3.67 (dd, J = 9.7 and 7.5 Hz, 1H)
3.69 (dd, J = 9.8 and 7.6 Hz, 1H)
signals due to hydroxyl group not observed
86.9
87.0
69.8
69.9
61.5
61.5
61.0
61.0
a
b
c
d
Recorded in CD3OD at 100 MHz. Obtained from ref 1 and recorded in CD3OD at 150 MHz. Recorded in CD3OD at 400 MHz. Obtained from
e
ref 1 and recorded in CD3OD at 600 MHz. Calculated from inspection of the 13C NMR spectrum shown in the Supporting Information associated
with ref 1; we believe the tabulated value of δC for C9a of 125.4 in ref 1 is an error.
associated with the former compound proved challenging. So,
for example, exposure of it to AlCl3 in dichloromethane at 18
°C had no effect while the use of the more reactive BCl3 under
essentially the same conditions resulted in the formation of
various and thus far incompletely characterized but evidently
fully aromatic products. Eventually it was established that
reaction of substrate 51 with BBr3 in dichloromethane at −78
°C for 2 h resulted in its partial conversion into target 4 (36%
from 50). Attempts to “push” this conversion to completion
only resulted in the rapid formation of fully aromatic products
as observed earlier.
explore how much variation in spectroscopic properties might
be observed as a result of changing the stereochemistry in
compound 4. Accordingly, we deliberately sought to generate
its C4-epimer. This was readily achieved (Scheme 6) by
cleaving the isopropyl ether residue associated with compound
49 (an intermediate en route to ribisin D) using BBr3 in
dichloromethane at −78 °C. By such means the desired
compound, 52, was obtained in 57% yield. The spectroscopic
data for the synthetic material were entirely consistent with
assigned structure C4-epi-ribisin D (52), and distinct from the
data for ribisin D. A comparison (see Supporting Information)
1
of the derived 13C and H NMR data with those reported for
Despite the difficulties associated with carrying out the final
step of the above-mentioned reaction sequence, sufficient
quantities of compound 4 could be accumulated so as to allow
for its complete spectroscopic characterization. All of the data
thus acquired were in complete accord with the assigned
structure and final confirmation of this followed from a single-
crystal X-ray analysis, details of which are presented in the
Experimental Section and the Supporting Information. A
ribisin D reveal, for example, ΔδC values of up to 5.9 ppm, thus
leaving no doubt that these are different compounds.
Scheme 6. Synthesis of C4-epi-Ribisin D (52)
1
comparison (Table 3) of the 13C and H NMR spectral data
acquired on compound 4 with those reported1,18 for ribisin D
reveals a good but not a perfect match. In particular, the signals
due to the aromatic carbons C5, C6, and C9 (see bolded values
in Table 3, assignments due to Fukuyama et al.1) had ΔδC
values of >0.1 ppm (146.2 vs 146.4, 144.1 vs 144.5 and 113.4 vs
113.0, respectively). As a result of carrying out a range of
relevant experiments (see Table S3 in the Supporting
Information), we attribute these differences to variations in
pH between the samples rather than, for example, to variations
in concentration. As was the case earlier, the specific rotation of
the synthetically derived material was of the same sign but
considerably larger magnitude than that reported for the natural
product {[α]20 −39.3 (c 0.8, methanol) vs [α]24 −22 (c 0.2,
CONCLUSION
■
The work detailed above, when considered in conjunction with
our earlier studies,3 has clearly established that ribisins A−D are
represented by 1, 31, ent-3, and 4, respectively. Accordingly, in
all instances these natural products possess the 2S,3R
configurations with variations only being observed in the
degree of O-methylation, the extent of oxygenation on the
aromatic ring and/or the stereochemistry at C4.
The synthetic protocols used to obtain the title natural
products and certain analogues seem to be robust ones that
should provide the capacity to generate a significant number of
variants if that becomes a worthwhile pursuit. Our current
efforts are focused on undertaking a comprehensive biological
evaluation of the various compounds we have produced to date.
Results will be reported in due course.
D
D
methanol) reported1 for ribisin D}. Once again, this
discrepancy is attributed to the presence of impurities in the
latter which was only isolated in 1.4 mg quantities (more than
40 mg of synthetic material was obtained).
Synthesis of C4-epi-Ribisin D. Given the minor
discrepancies in 13C NMR chemical shifts mentioned
immediately above and highlighted in Table 3, we sought to
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Featured Article
(20), 121 (100); HRMS M+• calcd for C14H1679Br2O4 405.9415, found
405.9400.
Compound 10. A magnetically stirred solution of bromohydrin 8
(1.10 g, 2.70 mmol) in methanol (20 mL) maintained at 18 °C was
treated with freshly prepared sodium methoxide (730 mg, 13.5 mmol)
and the resulting solution stirred at 18 °C for 6 h and then
concentrated under reduced pressure. The residue thus obtained was
dissolved in ethyl acetate (100 mL) and the solution so-formed
washed with NH4Cl (1 × 30 mL of a saturated aqueous solution). The
separated organic layer was then dried (Na2SO4) before being filtered
and concentrated under reduced pressure. The ensuing light yellow oil
was subjected to flash chromatography (silica, 1:1 v/v ethyl acetate/
hexane elution), and concentration of the appropriate fractions (Rf =
0.6) afforded alcohol 10 (800 mg, 82%) as a clear, colorless oil: [α]20
D
−60.8 (c 0.8, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.4
Hz, 2H), 6.89 (d, J = 8.4 Hz, 2H), 6.26 (d, J = 3.4 Hz, 1H), 4.78 (d, J
= 11.2 Hz, 1H), 4.67 (d, J = 11.2 Hz, 1H), 4.25 (dd, J = 8.7 and 4.4
Hz, 1H), 3.98 (dd, J = 4.2 and 1.8 Hz, 1H), 3.94−3.91 (complex m,
2H), 3.81 (s, 3H), 3.43 (s, 3H), 2.95 (d, J = 8.8 Hz, 1H), 2.82 (d, J =
4.5 Hz, 1H); 13C NMR (100 MHz, CDCl3) δ 159.6, 129.8, 129.7,
128.2, 127.1, 114.0, 79.5, 76.5, 73.2, 71.4, 71.1, 57.3, 55.3; IR νmax
3434, 2932, 2834, 1611, 1514, 1463, 1344, 1302, 1249, 1175, 1094,
1033, 967, 827 cm−1; MS (EI, 70 eV) m/z 360 and 358 (M+•, both 1),
137 (10), 122 (20), 121 (100); HRMS M+• calcd for C15H1979BrO5
358.0416, found 358.0413.
EXPERIMENTAL SECTION
■
General Experimental Procedures. Unless otherwise specified,
proton (1H) and carbon (13C) NMR spectra were recorded at room
temperature in either base-filtered CDCl3 or in CD3OD on a
spectrometer operating at 400 MHz for proton and 100 MHz for
1
carbon nuclei. H NMR data are recorded as follows: chemical shift
(δ) [multiplicity, coupling constant(s) J (Hz), relative integral] where
multiplicity is defined as: s = singlet; d = doublet; t = triplet; q =
quartet; m = multiplet or combinations of the above. The signal due to
residual CHCl3 and CD3OD appearing at δH 7.26 and 3.30,
respectively, and the central resonance of the CDCl3 “triplet”
appearing at δC 77.0 or that of the CD3OD “multiplet” centered at
δC 49.0 were used to reference 1H and 13C NMR spectra, respectively.
Samples were analyzed by infrared spectroscopy (νmax) as thin films on
KBr plates. Low-resolution ESI mass spectra were recorded on a single
quadrupole liquid chromatograph−mass spectrometer, while high-
resolution measurements were conducted on a time-of-flight instru-
ment. Low- and high-resolution EI mass spectra were recorded on a
magnetic-sector machine. Melting points are uncorrected. Analytical
thin-layer chromatography (TLC) was performed on aluminum-
backed 0.2 mm thick silica gel 60 F254 plates. Eluted plates were
visualized using a 254 nm UV lamp and/or by treatment with a
suitable dip followed by heating. These dips included phosphomolyb-
dic acid: ceric sulfate: sulfuric acid (conc.): water (37.5 g: 7.5 g: 37.5 g:
720 mL) or potassium permanganate: potassium carbonate: 5%
sodium hydroxide aqueous solution: water (3 g: 20 g: 5 mL: 300 mL).
Flash chromatographic separations were carried out following
protocols defined by Still et al.19 with silica gel 60 (40−63 μm) as
the stationary phase and using the AR- or HPLC-grade solvents
indicated. Starting materials, reagents, drying agents and other
inorganic salts were generally commercially available and were used
as supplied. Tetrahydrofuran (THF), methanol and dichloromethane
were dried using a solvent purification system that is based upon a
technology originally described by Grubbs et al.20 Where necessary,
reactions were performed under a nitrogen atmosphere.
Compound 12. A magnetically stirred solution of alcohol 10 (1.90
g, 5.29 mmol), 2-hydroxyphenylboronic acid pinacol ester (11) (1.40
g, 6.40 mmol), PdCl2dppf·CH2Cl2 (360 mg, 0.44 mmol), and
triethylamine (10 mL) in THF/water (36 mL of a 9:1 v/v mixture)
was purged with nitrogen for 0.5 h and then heated at 70 °C for 1 h
before being cooled, poured into water (50 mL), and extracted with
ethyl acetate (3 × 30 mL). The combined organic phases were washed
with brine (1 × 40 mL) before being dried (Na2SO4), filtered, and
concentrated under reduced pressure. The ensuing light yellow oil was
subjected to flash chromatography (silica, 2:3 v/v ethyl acetate/hexane
elution), and concentration of the relevant fractions (Rf = 0.3) afforded
phenol 12 (1.60 g, 80%) as a clear, colorless oil: [α]20 −12.4 (c 0.3,
D
CHCl3); 1H NMR (400 MHz, CDCl3) δ 9.06 (broad s, 1H), 7.31 (d, J
= 8.5 Hz, 2H), 7.24−7.20 (complex m, 1H), 7.09 (dd, J = 7.6 and 1.6
Hz, 1H), 6.92−6.87 (complex m, 3H), 6.85−6.81 (complex m, 1H),
6.07 (d, J = 4.3 Hz, 1H), 4.71 (d, J = 11.0 Hz, 1H), 4.62 (d, J = 11.0
Hz, 1H), 4.50 (m, 1H), 4.23 (m, 1H), 4.01 (m, 1H), 3.83 (m, 1H),
3.79 (s, 3H), 3.47 (s, 3H), 3.19 (broad s, 1H) (signal due to one
proton obscured or overlapping); 13C NMR (100 MHz, CDCl3) δ
159.6, 154.6, 139.8, 130.6, 129.9, 129.8, 129.5, 127.4, 127.0, 119.7,
117.2, 114.0, 78.3, 73.5, 70.9, 69.8, 68.1, 57.6, 55.3; IR νmax 3291, 2933,
1611, 1513, 1485, 1357, 1301, 1248, 1175, 1091, 1032, 963, 826, 755
cm−1; MS (EI, 70 eV) m/z 372 (M+•, 2), 160 (15), 122 (20), 121
(100); HRMS M+• calcd for C21H24O6 372.1573, found 372.1572.
Compound 13. A magnetically stirred solution of Ph3P (420 mg,
1.61 mmol) in dry THF (10 mL) was treated with DEAD (250 μL,
1.61 mmol), the resulting solution stirred at 18 °C for 0.17 h, and then
a solution of phenol 12 (600 mg, 1.61 mmol) in THF (5 mL) was
added dropwise. The ensuing mixture was stirred at 18 °C for 1 h
before being concentrated under reduced pressure, and the resulting
light yellow oil was subjected to flash chromatography (silica, 1:3 v/v
ethyl acetate/hexane elution). Concentration of the appropriate
fractions (Rf = 0.4) afforded compound 13 (500 mg, 88%) as a
clear, colorless oil: [α]20D −65.2 (c 0.7, CHCl3); 1H NMR (400 MHz,
CDCl3) δ 7.37 (m, 3H), 7.22 (m, 1H), 6.94−6.90 (complex m, 4H),
5.86 (t, J = 3.1 Hz, 1H), 5.26 (dt, J = 8.9 and 2.3 Hz, 1H), 4.95 (d, J =
11.3 Hz, 1H), 4.72 (d, J = 11.3 Hz, 1H), 4.17 (m, 1H), 4.03 (m, 1H),
3.83 (m, 1H), 3.82 (s, 3H), 3.45 (s, 3H), 2.59 (d, J = 1.4 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 162.9, 159.4, 139.3, 130.6, 130.1, 129.7,
124.7, 121.5, 121.2, 113.9, 113.0, 110.9, 83.8, 80.2, 76.7, 72.1, 69.9,
57.8, 55.3; IR νmax 3434, 2904, 1610, 1513, 1462, 1303, 1249, 1083,
1032, 952, 818, 751 cm−1; MS (EI, 70 eV) m/z 354 (M+•, 1), 295
(10), 233 (10), 175 (25), 174 (100), 131 (20), 122 (20), 121 (85);
HRMS M+• calcd for C21H22O5 354.1467, found 354.1464.
Compound 8. A magnetically stirred mixture of alcohol 76,7 (1.20
g, 3.86 mmol) in THF/water (20 mL of a 4:1 v/v mixture) maintained
at 0 °C was treated, in small portions, with NBS (690 mg, 3.88 mmol)
over 0.17 h. The resulting solution was warmed to 18 °C over 6 h and
then diluted with Na2S2O3 (20 mL of a saturated aqueous solution).
The mixture thus obtained was extracted with ethyl acetate (2 × 40
mL), and the combined organic phases were washed with brine (1 ×
50 mL) before being dried (Na2SO4), filtered, and concentrated under
reduced pressure. The resulting light yellow oil was subjected to flash
chromatography (silica, 1:3 v/v ethyl acetate/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.2),
bromohydrin 8 (1.20 g, 76%) as an amorphous, white powder: [α]20
D
−44.0 (c 0.6, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.30 (d, J = 8.7
Hz, 2H), 6.91 (d, J = 8.7 Hz, 2H), 6.27 (d, J = 3.6 Hz, 1H), 4.75 (d, J
= 10.9 Hz, 1H), 4.63 (d, J = 10.9 Hz, 1H), 4.42 (dd, J = 6.0 and 4.2
Hz, 1H), 4.28−4.26 (complex m, 2H), 3.87−3.84 (complex m, 1H),
3.82 (s, 3H), 2.72 (d, J = 6.0 Hz, 1H), 2.66 (d, J = 7.8 Hz, 1H); 13C
NMR (100 MHz, CDCl3) δ 159.9, 131.5, 130.1, 128.4, 125.3, 114.2,
77.9, 73.6, 72.6, 69.7, 55.3, 50.8; IR νmax 3393, 2904, 1611, 1513, 1463,
1303, 1248, 1175, 1106, 1035, 871, 820, 743 cm−1; MS (EI, 70 eV) m/
z 410, 408, and 406 (M+•, 1, 2, and 1, respectively), 137 (18), 122
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Compound 14. A magnetically stirred solution of alcohol 13 (300
mg, 0.85 mmol) in dry THF (10 mL) maintained at 0 °C was treated
with NaH (51 mg of a 60% suspension in mineral oil, 1.27 mmol).
After 0.5 h, the reaction mixture was treated with β-methoxyethox-
ymethyl chloride (146 μL, 1.27 mmol) and then stirred at 18 °C for 16
h before being quenched with water (30 mL; CAUTION: evolution of
hydrogen gas). The separated aqueous layer was extracted with ethyl
acetate (3 × 40 mL), and the combined organic phases were washed
with brine (1 × 50 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The resulting light yellow oil was subjected to
flash chromatography (silica, 1:3 v/v ethyl acetate/hexane elution) to
afford, after concentration of the appropriate fractions (Rf = 0.4 in 1:3
v/v ethyl acetate/hexane), tris-ether 14 (300 mg, 80%) as a clear,
reduced pressure. The resulting light yellow oil was subjected to flash
chromatography (silica, 3:2 v/v ethyl acetate/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.3 in 1:1 v/v
ethyl acetate/hexane), alcohol 17 (380 mg, 81%) as a clear, colorless
1
oil: [α]20 −31.9 (c 0.92, CHCl3); H NMR (400 MHz, CDCl3) δ
D
8.06 (m, 1H), 7.55 (m, 1H), 7.40−7.32 (complex m, 2H), 5.40 (dd, J
= 6.9 and 3.6 Hz, 1H), 4.95 (d, J = 7.5 Hz, 1H), 4.91 (d, J = 7.5 Hz,
1H), 4.32 (d, J = 6.9 Hz, 1H), 4.26 (dd, J = 7.5 and 3.6 Hz, 1H), 4.22
(d, J = 7.5 Hz, 1H), 3.86 (m, 1H), 3.76 (m, 1H), 3.63 (s, 3H), 3.62−
3.56 (complex m, 2H), 3.42 (s, 3H); 13C NMR (100 MHz, CDCl3) δ
190.4, 165.7, 155.8, 126.0, 124.8, 123.1, 122.3, 115.5, 111.7, 97.0, 82.1,
81.3, 71.6, 68.2, 64.4, 59.9, 59.0; IR νmax 3400, 2896, 2830, 1683, 1603,
1483, 1448, 1245, 1200, 1096, 1044, 1022, 978, 844, 754 cm−1; MS
(ESI, +ve) m/z 359 [(M + Na)+, 100]; HRMS (M + H)+ calcd for
C17H20O7 337.1287, found 337.1288.
colorless oil: [α]20 −75.2 (c 1.4, CHCl3); 1H NMR (400 MHz,
D
CDCl3) δ 7.37−7.34 (complex m, 3H), 7.20(m, 1H), 6.93−6.87
(complex m, 4H), 5.81 (m, 1H), 5.35 (dm, J = 9.2 Hz, 1H), 4.95 (d, J
= 6.9 Hz, 1H), 4.88 (d, J = 11.5 Hz, 1H), 4.84 (d, J = 6.9 Hz, 1H), 4.69
(d, J = 11.5 Hz, 1H), 4.24 (m, 1H), 4.03 (m, 1H), 3.89 (dd, J = 9.2 and
2.5 Hz, 1H), 3.80 (s, 3H), 3.76−3.73 (complex m, 2H), 3.54−3.48
(complex m, 2H), 3.43 (s, 3H), 3.37 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 162.9, 159.1, 140.9, 130.5, 129.3, 125.0, 121.4, 121.0, 113.7,
112.8, 110.9, 95.7, 84.0, 79.3, 76.3, 74.1, 71.9, 71.6, 67.1, 59.0, 57.8,
55.2 (signal due to one carbon obscured over overlapping); IR νmax
2904, 2890, 2835, 1674, 1611, 1514, 1463, 1362, 1303, 1248, 1081,
1019, 947, 820, 752 cm−1; MS (EI, 70 eV) m/z 442 (M+•, <1%), 268
(5), 198 (10), 174 (27), 162 (15), 122 (19), 121 (100); HRMS (M +
Na)+ calcd for C25H30O7 465.1889, found 465.1890.
Compound 16. Step i. A magnetically stirred solution of
compound 14 (900 mg, 2.03 mmol) in dry dichloromethane (40
mL) maintained at 0 °C was treated, in portions, with m-CPBA (550
mg of ca. 77% material, 2.43 mmol) and the resulting mixture warmed
to 18 °C over 14 h and then diluted with NaHCO3 (50 mL of a
saturated aqueous solution). The separated aqueous phase was
extracted with dichloromethane (3 × 30 mL), and the combined
organic phases were then dried (Na2SO4) before being filtered and
concentrated under reduced pressure. The resulting light yellow oil
(presumed to be comprised largely of alcohol 15) was immediately
subjected to the next step of the reaction sequence.
Compound 18. A magnetically stirred solution of alcohol 17 (200
mg, 0.59 mmol) in dry THF (10 mL) was treated with Ph3P (190 mg,
0.71 mmol), α-chloroacetic acid (67 mg, 0.71 mmol), and DEAD (110
μL, 0.71 mmol). The resulting solution was stirred at 18 °C for 1 h
and then concentrated under reduced pressure. The light yellow
residue thus obtained was subjected to flash chromatography (silica,
1:3 v/v ethyl acetate/hexane elution) to afford, after concentration of
the relevant fractions (Rf = 0.3), α-chloroacetate 18 (210 mg, 85%) as
an amorphous, white powder: [α]20D +98.9 (c 0.65, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 8.07 (m, 1H), 7.54 (m, 1H), 7.44−7.36
(complex m, 2H), 6.38 (d, J = 6.5 Hz, 1H), 4.94 (s, 2H), 4.38 (dd, J =
6.6 and 8.4 Hz, 1H), 4.34 (d, J = 15.4 Hz, 1H), 4.26 (d, J = 15.4 Hz,
1H), 4.01 (d, J = 8.4 Hz, 1H), 3.77 (m, 1H), 3.70 (s, 3H), 3.68 (m,
1H), 3.58−3.55 (complex m, 2H), 3.40 (s, 3H); 13C NMR (100 MHz,
CDCl3) δ 189.5, 166.8, 160.7, 156.1, 126.7, 125.1, 122.5, 122.4, 116.9,
111.9, 97.0, 84.6, 79.3, 71.6, 69.2, 68.1, 60.7, 59.1, 40.7; IR νmax 2925,
2887, 1764, 1688, 1449, 1241, 1172, 1132, 1048, 1013, 957, 855, 763
cm−1; MS (ESI, +ve) m/z 437 and 435 [(M + Na)+, 30 and 100];
HRMS (M + Na)+ calcd for C19H2135ClO8 435.0823, found 435.0826.
Compound 1. Step i. A magnetically stirred solution of α-
chloroacetate 18 (170 mg, 0.41 mmol) in dry dichloromethane (15
mL) was treated with zinc bromide (920 mg, 4.10 mmol). The
resulting solution was stirred at 18 °C for 16 h and then quenched by
NaHCO3 (20 mL of a saturated aqueous solution). The separated
aqueous layer was extracted with dichloromethane (3 × 20 mL), and
the combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting light yellow oil,
presumed to contain compound 19, was immediately subjected to the
next step of the reaction sequence.
Step ii. Dimethyl sulfoxide (1.10 mL, 15.5 mmol) was added
dropwise to a magnetically stirred solution of oxalyl chloride (650 μL,
7.75 mmol) in dry dichloromethane (10 mL) maintained at −78 °C.
The ensuing mixture was stirred at this temperature for 0.08 h, and
then a solution of the oil obtained from step i in dichloromethane (20
mL) was added. The ensuing mixture was stirred at −78 °C for a
further 0.33 h, treated with triethylamine (6.5 mL, 46.7 mmol), and
allowed to stir for a further 0.66 h before being poured into brine (50
mL) and extracted with dichloromethane (3 × 40 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure, and the ensuing light yellow oil was subjected to
flash chromatography (silica, 1:3 v/v ethyl acetate/hexane elution).
Concentration of the relevant fractions (Rf = 0.2) afforded ketone 16
Step ii. A magnetically stirred solution of product obtained from
step i in methanol (20 mL) was treated with zinc acetate dihydrate
(110 mg, 0.49 mmol) and the ensuing mixture stirred at 18 °C for 6 h
and then concentrated under reduced pressure. The resulting white
solid was subjected to flash chromatography (silica, 2:1 v/v ethyl
acetate/hexane elution) to afford, after concentration of the relevant
fractions (Rf = 0.6), compound 11,12 (51 mg, 50% from 18) as an
amorphous, white powder: [α]20 −24.9 (c 1.2, MeOH) [lit.1 [α]25
(650 mg, 70% from 14) as a clear, colorless oil: [α]20 −131.4 (c 0.4,
D
D
D
1
CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.08 (m, 1H), 7.55 (m, 1H),
7.40−7.33 (complex m, 4H), 6.92−6.89 (complex m, 2H), 5.07 (d, J =
3.6 Hz, 1H), 4.90−4.79 (complex m, 4H), 4.35 (dd, J = 7.9 and 3.6
Hz, 1H), 4.25 (d, J = 7.9 Hz, 1H), 3.81 (s, 3H), 3.70−3.67 (complex
m, 2H), 3.65 (s, 3H), 3.51−3.48 (complex m, 2H), 3.37 (s, 3H); 13C
NMR (100 MHz, CDCl3) δ 190.8, 165.6, 159.6, 155.8, 129.9, 129.8,
129.2, 126.0, 124.9, 123.1, 122.4, 113.9, 111.6, 95.7, 82.7, 77.2, 72.6,
71.6, 69.9, 67.2, 60.3, 59.0, 55.3; IR νmax 2904, 2896, 2834, 1687, 1612,
1514, 1448, 1361, 1302, 1248, 1116, 1097, 1031, 844, 754 cm−1; MS
(ESI, +ve) m/z 479 [(M + Na+), 100]; HRMS (M + Na)+ calcd for
C25H28O8 479.1682, found 479.1682.
−21.9 (c 1.0, MeOH)]; H NMR (400 MHz, CD3OD) see Table 1;
13C NMR (100 MHz, CD3OD) see Table 1; IR νmax 3512, 3228, 2945,
2912, 2878, 2842, 1682, 1591, 1483, 1352, 1279, 1133, 1024, 1003,
948, 861, 750 cm−1; MS (ESI, +ve) m/z 271 [(M + Na)+, 100];
HRMS (M + Na)+ calcd for C13H12O5 271.0582, found 271.0583.
A sample of this material suitable for single-crystal X-ray analysis
was grown from a dichloromethane/methanol solution, mp 220−222
°C.
Compound 22. A magnetically stirred mixture of cis-diol 2113,15
(5.70 g, 21.5 mmol) in dry THF (100 mL) maintained at 0 °C was
treated with NaH (2.60 g of a 60% suspension in mineral oil, 64.5
mmol) and, after 0.5 h, with iodomethane (6.70 mL, 107.5 mmol).
The ensuing mixture was stirred at 18 °C for 1 h and then quenched
with water (100 mL) (CAUTION: evolution of hydrogen gas). The
separated aqueous layer was extracted with ethyl acetate (3 × 40 mL),
and the combined organic phases were washed with brine (1 × 50 mL)
before being dried (Na2SO4), filtered, and concentrated under reduced
pressure. The residue thus obtained was subjected to flash
Compound 17. A magnetically stirred mixture of ketone 16 (640
mg, 1.40 mmol) in dichloromethane/water (42 mL of a 20:1 v/v
mixture) was treated with DDQ (380 mg, 1.68 mmol) and stirring
continued at 18 °C for 20 h. After this time, the reaction mixture was
poured into water (20 mL) and extracted with dichloromethane (3 ×
30 mL). The combined organic phases were washed with brine (1 ×
40 mL) before being dried (Na2SO4), filtered, and concentrated under
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chromatography (silica, 1:4 v/v ethyl acetate/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.7 in 3:1 v/v
under reduced pressure. The ensuing light yellow oil was subjected to
flash chromatography (silica, 1:3 v/v ethyl acetate/hexane elution),
and concentration of the relevant fractions (Rf = 0.3) afforded phenol
25 (1.60 g, 81%) as a clear, colorless oil: [α]20D −29.7 (c 1.6, CHCl3);
1H NMR (400 MHz, CDCl3) δ 9.07 (s, 1H), 7.30 (d, J = 8.7 Hz, 2H),
7.22 (m, 1H), 7.03 (dd, J = 7.6 and 1.7 Hz, 1H), 6.91 (dd, J = 8.1 and
1.0 Hz, 1H), 6.82−6.78 (complex m, 3H), 6.11 (d, J = 5.1 Hz, 1H),
4.84 (d, J = 10.6 Hz, 1H), 4.53 (d, J = 10.6 Hz, 1H), 4.28 (broad s,
1H), 4.12 (dd, J = 5.1 and 4.2 Hz, 1H), 4.07 (dd, J = 3.7 and 1.8 Hz,
1H), 3.94 (m, 1H), 3.83 (m, 1H), 3.67 (s, 3H), 3.62 (s, 3H), 3.56 (s,
3H); 13C NMR (100 MHz, CDCl3) δ 159.4, 154.7, 139.4, 130.7,
129.9, 129.7(3), 129.7(0), 127.4, 119.6, 117.1, 113.9, 77.6, 76.0, 74.0,
73.5, 69.7, 58.7, 58.2, 55.1 (signal due to one carbon obscured or
overlapping); IR νmax 3204, 2934, 2824, 1613, 1575, 1514, 1486, 1466,
1287, 1250, 1120, 1090, 1019 cm−1; MS (EI, 70 eV) m/z 386 (M+•,
1), 192 (13), 160 (20), 122 (16), 121 (100); HRMS M+• calcd for
C22H26O6 386.1723, found 386.1729.
ethyl acetate/hexane), acetonide 22 (6.20 g, 98%) as a clear, colorless
1
oil: [α]20 −64.5 (c 0.55, CHCl3); H NMR (400 MHz, CDCl3) δ
D
6.26 (d, J = 3.5 Hz, 1H), 4.63 (d, J = 5.8 Hz, 1H), 4.48 (t, J = 5.8 Hz,
1H), 3.97 (m, 1H), 3.76 (dd, J = 5.8 and 3.3 Hz, 1H), 3.53 (s, 3H),
3.45 (s, 3H), 1.45 (s, 3H), 1.40 (s, 3H); 13C NMR (100 MHz, CDCl3)
δ 129.7, 123.7, 109.9, 78.0, 76.8, 75.5, 74.8, 59.3, 57.5, 27.6, 25.9; IR
νmax 2986, 2933, 2827, 1645, 1455, 1382, 1371, 1234, 1198, 1118,
1081, 1042, 1008, 935, 870, 849 cm−1; MS (EI, 70 eV) m/z 294 and
292 (M+•, both 1), 279 and 277 (both 5), 115 (100); HRMS M+•
calcd for C11H1779BrO4 292.0310, found 292.0307.
Compound 23. Acetonide 22 (1.20 g, 4.1 mmol) was treated with
acetic acid/water (50 mL of a 7:3 v/v mixture) and the resulting
solution heated at 70 °C for 14 h and then cooled and concentrated
under reduced pressure. The light yellow residue thus obtained was
subjected to flash chromatography (silica, ethyl acetate elution) to
afford, after concentration of the relevant fractions (Rf = 0.5), diol 23
Compound 26. A magnetically stirred solution of Ph3P (1.05 g, 4.0
mmol) in dry THF (5 mL) was treated with DEAD (620 μL, 4.0
mmol), the resulting solution was stirred at 18 °C for 0.17 h, and then
a solution of phenol 25 (1.30 g, 3.37 mmol) in THF (15 mL) was
added dropwise. The ensuing reaction mixture was stirred at 18 °C for
2 h before being concentrated under reduced pressure. The resulting
light yellow oil was subjected to flash chromatography (silica, 1:4 v/v
ethyl acetate/hexane elution) to afford, after concentration of the
appropriate fractions (Rf = 0.7 in 1:3 v/v ethyl acetate/hexane),
(1.00 g, 97%) as a clear, colorless oil: [α]20 −175.3 (c 1.0, CHCl3);
D
1H NMR (400 MHz, CDCl3) δ 6.35 (d, J = 4.7 Hz, 1H), 4.40 (d, J =
4.7 Hz, 1H), 4.20 (dd, J = 9.0 and 4.3 Hz, 1H), 4.01 (t, J = 4.3 Hz,
1H), 3.65 (dd, J = 9.0 and 3.8 Hz, 1H), 3.50 (s, 3H), 3.46 (s, 3H), 3.11
(broad s, 1H), 3.05 (broad s, 1H); 13C NMR (100 MHz, CDCl3) δ
129.3, 126.8, 77.2, 73.7, 71.8, 68.1, 58.1, 57.8; IR νmax 3401, 2917,
2827, 1643, 1196, 1097, 1001, 916, 864 cm−1; MS (ESI, +ve) m/z 277
and 275 [(M + Na)+, 100 and 95]; HRMS (M + Na)+ calcd for
C8H1379BrO4 274.9895, found 274.9898.
compound 26 (1.10 g, 89%) as a clear, colorless oil: [α]20 −89.5 (c
D
Compound 24. Step i. A magnetically stirred solution of diol 23
(3.00 g, 11.9 mmol) in dichloromethane (30 mL) maintained at 0 °C
was treated with p-methoxybenzaldehyde dimethyl acetal (2.20 mL,
13.0 mmol) and p-toluenesulfonic acid monohydrate (80 mg, 0.42
mmol). The resulting solution was stirred at 0 °C for 2 h and then
treated with NaHCO3 (30 mL of a saturated aqueous solution). The
separated aqueous layer was extracted with dichloromethane (2 × 20
mL), and the combined organic phases were then dried (Na2SO4),
filtered, and concentrated under reduced pressure. The resulting light
yellow oil, containing the PMP-acetal derived from substrate 23, was
immediately subjected to the next step of the reaction sequence.
Step ii. The acetal prepared as described above was immediately
dissolved in anhydrous dichloromethane (100 mL) and the resulting
magnetically stirred solution cooled to −78 °C while being maintained
under nitrogen and then treated with a solution of DIBAl-H (60 mL of
a 1 M solution in hexanes, 60 mmol). The mixture thus obtained was
stirred at −78 °C for 6 h before being treated with potassium sodium
tartrate (100 mL of saturated aqueous solution). The mixture so-
formed was stirred at 18 °C for 14 h, and then the separated aqueous
phase was extracted with dichloromethane (3 × 50 mL). The
combined organic phases were dried (Na2SO4), filtered, and
concentrated under reduced pressure, and the ensuing oil was
subjected to flash chromatography (silica, 1:3 v/v ethyl acetate/
hexane elution) to afford, after concentration of the relevant fractions
1.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.40 (d, J = 8.3 Hz, 2H),
7.37 (m, 1H), 7.22 (m, 1H), 6.94−6.89 (complex m, 4H), 6.04 (t, J =
3.2 Hz, 1H), 4.93 (ddd, J = 7.4, 3.2, and 1.5 Hz, 1H), 4.89 (d, J = 8.8
Hz, 1H), 4.83 (d, J = 8.8 Hz, 1H), 4.13 (m, 1H), 3.97 (t, J = 7.4 Hz,
2H), 3.81 (s, 3H), 3.54 (s, 3H), 3.52 (s, 3H), 3.51 (m, 1H); 13C NMR
(100 MHz, CDCl3) δ 162.9, 159.2, 138.8, 130.7, 130.6, 129.6, 124.3,
121.5, 121.2, 113.8, 113.7, 110.9, 87.3, 81.3, 79.0, 76.6, 73.1, 58.8, 57.9,
55.3; IR νmax 2931, 2833, 1611, 1513, 1463, 1302, 1248, 1174, 1118,
1086, 1031 cm−1; MS (EI, 70 eV) m/z 368 (M+•, 1), 295 (10), 194
(20), 174 (40), 122 (20), 121 (100); HRMS M+• calcd for C22H24O5
368.1624, found 368.1622.
Compound 28. Step i. A magnetically stirred solution of
compound 26 (300 mg, 0.81 mmol) in dry dichloromethane (10
mL) maintained at 0 °C was treated, in portions, with m-CPBA (180
mg of ca. 77% material, 0.81 mmol), and the resulting mixture was
warmed to 18 °C and then stirred at this temperature for 14 h before
being diluted with NaHCO3 (15 mL of a saturated aqueous solution).
The separated aqueous phase was extracted with dichloromethane (3
× 20 mL), and the combined organic phases were dried (Na2SO4),
filtered, and concentrated under reduced pressure. The resulting light
yellow oil, presumed to contain allylic alcohol 27, was immediately
subjected to the next step of the reaction sequence.
Step ii. Dimethyl sulfoxide (440 μL, 6.2 mmol) was added dropwise
to a magnetically stirred solution of oxalyl chloride (260 μL, 3.1
mmol) in dry dichloromethane (4 mL) maintained at −78 °C. The
ensuing mixture was stirred at this temperature for 0.08 h, and then a
solution of the product obtained from step i in dichloromethane (10
mL) was added. The ensuing mixture was stirred at −78 °C for a
further 0.33 h and then treated with triethylamine (2.60 mL, 18.7
mmol) and allowed to stir for a further 0.66 h before being poured
into brine (30 mL) and extracted with dichloromethane (3 × 20 mL).
The combined organic layers were dried (Na2SO4), filtered, and
concentrated under reduced pressure, and the ensuing light yellow oil
subjected to flash chromatography (silica, 1:3 v/v ethyl acetate/hexane
elution). Concentration of the relevant fractions (Rf = 0.4) afforded
(Rf = 0.4), compound 24 (2.20 g, 50%) as clear, colorless oil: [α]20
D
−81.7 (c 1.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.27 (d, J = 8.6
Hz, 2H), 6.89 (d, J = 8.6 Hz, 2H), 6.28 (d, J = 4.2 Hz, 1H), 4.72 (d, J
= 11.2 Hz, 1H), 4.62 (d, J = 11.2 Hz, 1H), 4.30 (t, J = 5.5 Hz, 1H),
4.03 (dd, J = 8.1 and 4.4 Hz, 1H), 3.95 (m, 1H), 3.81 (s, 3H), 3.67 (m,
1H), 3.50 (s, 3H), 3.43 (s, 3H), 2.83 (d, J = 5.5 Hz, 1H); 13C NMR
(100 MHz, CDCl3) δ 159.6, 129.7, 129.6, 129.2, 126.8, 114.0, 77.0,
76.1, 75.3, 73.7, 70.8, 59.1, 57.6, 55.3. IR νmax 3434, 2934, 2835, 1612,
1586, 1514, 1463, 1302, 1248, 1175, 1102, 1033 cm−1; MS (ESI, +ve)
m/z 397 and 395 [(M + Na)+, 100 and 97]; HRMS (M + Na)+ calcd
for C16H2179BrO5 395.0470, found 395.0475.
Compound 25. A magnetically stirred solution of tris-ether 24
(1.90 g, 5.1 mmol), 2-hydroxyphenylboronic acid pinacol ester (11)
(1.10 g, 5.1 mmol), PdCl2dppf·CH2Cl2 (290 mg, 0.35 mmol), and
triethylamine (10 mL) in THF/water (36 mL of a 9:1 v/v mixture)
was purged with nitrogen for 0.5 h and then heated at 70 °C for 2 h
before being cooled, poured into water (50 mL), and extracted with
ethyl acetate (3 × 30 mL). The combined organic phases were washed
with brine (1 × 40 mL), dried (Na2SO4), filtered, and concentrated
ketone 28 (190 mg, 61% from 26) as a clear, colorless oil: [α]20
D
−116.9 (c 3.2, CHCl3); 1H NMR (400 MHz, CDCl3) δ 8.08 (m, 1H),
7.55 (m, 1H), 7.40−7.36 (complex m, 4H), 6.92 (d, J = 8.7 Hz, 2H),
4.95−4.75 (complex m, 3H), 4.40 (d, J = 2.4 Hz, 1H), 4.07 (dd, J = 4.3
and 2.4 Hz, 1H), 3.82 (s, 3H), 3.65 (s, 3H), 3.49 (s, 3H); 13C NMR
(100 MHz, CDCl3) δ 190.3, 164.8, 159.6, 155.9, 129.8, 129.2, 125.9,
124.7, 123.1, 122.3, 116.1, 114.0, 111.6, 83.1, 82.4, 73.0, 71.0, 59.6,
59.4, 55.2; IR νmax 2934, 2834, 1701, 1612, 1587, 1514, 1483, 1447,
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1303, 1251, 1174, 1131, 1110, 1076, 1034 cm−1; MS (EI, 70 eV) m/z
382 (M+•, 10), 294 (20), 261 (20), 245 (20), 173 (30), 121 (100);
HRMS M+• calcd for C22H22O6 382.1416, found 382.1415.
being quenched with water (100 mL, CAUTION: evolution of
hydrogen gas). The separated aqueous layer was extracted with diethyl
ether (3 × 40 mL), and the combined organic phases were washed
with brine (1 × 50 mL), dried (Na2SO4), filtered, and concentrated
under reduced pressure. The residue thus obtained was subjected to
flash chromatography (silica, 5:95 v/v diethyl ether/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.8), bromide
44 (16.0 g, 96%) as a clear, colorless oil: 1H NMR (400 MHz, CDCl3)
δ 7.12 (d, J = 7.8 Hz, 1H), 6.92−6.84 (complex m, 2H), 5.18 (s, 2H),
4.54 (septet, J = 6.0 Hz, 1H), 3.67 (s, 3H), 1.34 (d, J = 6.0 Hz, 6H);
13C NMR (100 MHz, CDCl3) δ 151.7, 144.5, 125.1, 124.9, 118.1,
114.8, 98.6, 71.4, 58.0, 22.2; IR νmax 2977, 2931, 1581, 1465, 1384,
1288, 1261, 1231, 1206, 1159, 1111, 1072, 963, 879 cm−1; MS (EI, 70
eV) m/z 276 and 274 (M+•, 99 and 100), 234 and 232 (38 and 41),
204 (67), 202 (83), 189 and 187 (both 60), 153 (50), 51 (57); HRMS
M+• calcd for C11H1579BrO3 274.0205, found 274.0198.
Compound 29. A magnetically stirred mixture of ketone 28 (380
mg, 0.99 mmol) in dichloromethane/water (21 mL of a 20:1 v/v
mixture) maintained at 18 °C was treated with DDQ (250 mg, 1.09
mmol), and the resulting mixture was stirred at 18 °C for 24 h, poured
into water (20 mL), and extracted with dichloromethane (3 × 30 mL).
The combined organic phases were washed with brine (1 × 40 mL)
before being dried (Na2SO4), filtered, and concentrated under reduced
pressure. The resulting light yellow oil was subjected to flash
chromatography (silica, 1:2 v/v ethyl acetate/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.1 in 1:3 v/v
ethyl acetate/hexane), alcohol 29 (220 mg, 85%) as a clear, colorless
1
oil: [α]20 −131.9 (c 0.47, CHCl3); H NMR (400 MHz, CDCl3) δ
D
8.04 (m, 1H), 7.53 (m, 1H), 7.40−7.38 (complex m, 2H), 5.30 (d, J =
6.0 Hz, 1H), 4.25 (broad s, 1H), 3.90 (m, 1H), 3.60 (s, 3H), 3.57 (s,
3H), 3.00 (broad s, 1H); 13C NMR (100 MHz, CDCl3) δ 189.5, 165.8,
155.9, 126.1, 124.9, 123.0, 122.2, 115.4, 111.7, 84.6, 81.7, 65.8, 59.1,
58.9; IR νmax 3412, 2934, 2832, 1693, 1599, 1483, 1447, 1280, 1204,
1106, 1072, 1024 cm−1; MS (EI, 70 eV) m/z 262 (M+•, 35), 247 (30),
230 (53), 229 (50), 201 (30), 174 (100), 153 (60), 146 (80), 145
(47); HRMS M+• calcd for C14H14O5 262.0841, found 262.0843.
Compound 30. A magnetically stirred solution of alcohol 29 (150
mg, 0.57 mmol) in dry THF (10 mL) was treated with Ph3P (180 mg,
0.69 mmol), α-chloroacetic acid (65 mg, 0.69 mmol), and DEAD (110
μL, 0.69 mmol). The resulting solution was stirred at 18 °C for 1 h
and then concentrated under reduced pressure. The light yellow
residue thus obtained was subjected to flash chromatography (silica,
1:4 v/v ethyl acetate/hexane elution) to afford, after concentration of
the relevant fractions (Rf = 0.4 in 1:3 v/v ethyl acetate/hexane), α-
chloroacetate 30 (140 mg, 74%) as a clear, colorless oil: [α]20D +101.0
(c 1.0, CHCl3); 1H NMR (400 MHz, CDCl3) 8.04 (m, 1H), 7.51 (m,
1H), 7.41−7.34 (complex m, 2H), 6.52 (d, J = 3.8 Hz, 1H), 4.40 (dd, J
= 3.8 and 2.2 Hz, 1H), 4.30 (s, 2H), 4.11 (m, 1H), 3.71 (s, 3H), 3.59
(s, 3H); 13C NMR (100 MHz, CDCl3) δ 189.3, 166.9, 160.3, 155.9,
126.4, 125.0, 122.8, 122.3, 116.8, 111.7, 84.4, 81.2, 68.1, 61.1, 59.9,
40.6; IR νmax 2938, 2837, 1756, 1698, 1590, 1483, 1448, 1254, 1163,
1138, 1098, 1055 cm−1; MS (EI, 70 eV) m/z 340 and 338 (M+•, 3 and
10), 275 (20), 261 (70), 245 (90), 229 (60), 174 (55), 173 (60), 153
(100), 105 (62); HRMS (M + Na)+ calcd for C16H1535ClO6 361.0455,
found 361.0455.
Compound 40. Step i. A magnetically stirred mixture of bromide
44 (4.0 g, 14.5 mmol) in dry THF (50 mL) maintained at −78 °C was
treated with a n-BuLi solution (11.0 mL of a 1.6 M solution in THF,
17.6 mmol). After 1 h, the reaction mixture was treated with
triisopropyl borate (6.70 mL, 29.0 mmol) and then stirred at 18 °C for
14 h before being quenched with HCl (20 mL of a 10% w/v aqueous
solution). The separated aqueous layer was extracted with ethyl acetate
(3 × 50 mL), and the combined organic phases were washed with
brine (1 × 50 mL) before being dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained,
which is presumed to contain boronic acid 45, was subjected directly
to step ii of the reaction sequence.
Step ii. A magnetically stirred mixture of the product obtained from
step i in dry CH3CN (40 mL) maintained at 0 °C was treated with
sodium iodide (2.17 g, 14.5 mmol) and chlorotrimethylsilane (1.84
mL, 14.5 mmol). The resulting solution was warmed to 18 °C over 4 h
and then treated with Na2S2O3 (50 mL of a saturated aqueous
solution). The separated aqueous layer was extracted with ethyl acetate
(3 × 50 mL), and the combined organic phases were washed with
brine (1 × 50 mL) before being dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
immediately subjected to step iii of the reaction sequence.
Step iii. A magnetically stirred mixture of the product obtained from
step ii in benzene (50 mL) was treated with pinacol (3.44 g, 29.0
mmol), and the solution thus obtained heated at reflux for 2 h in an
apparatus fitted with a Dean−Stark trap. The cooled reaction was
treated with water (20 mL) and the separated aqueous layer extracted
with ethyl acetate (3 × 40 mL). The combined organic phases were
washed with brine (1 × 50 mL), dried (Na2SO4), filtered, and
concentrated under reduced pressure. The residue thus obtained was
subjected to flash chromatography (silica, 1:5 v/v diethyl ether/hexane
elution) to afford, after concentration of the relevant fractions (Rf =
Compound 2. A magnetically stirred solution of α-chloroacetate
30 (140 mg, 0.32 mmol) in methanol (15 mL) was treated with zinc
acetate dihydrate (110 mg, 0.50 mmol) and the ensuing mixture
stirred at 18 °C for 12 h then concentrated under reduced pressure.
The resulting white solid was subjected to flash chromatography
(silica, 1:2 v/v ethyl acetate/hexane elution) to afford, after
concentration of the relevant fractions (Rf = 0.6 in 1:1 v/v ethyl
0.6), boronic acid pinacol ester 40 (1.80 g, 45% from 44) as an
1
amorphous, white powder: [α]20 −64.5 (c 0.55, CHCl3); H NMR
acetate/hexane), compound 2 (90 mg, 81%) as an amorphous, white
D
1
powder: [α]20 +51.9 (c 0.36, MeOH) or −54.5 (c 1.2, CHCl3); H
(400 MHz, CDCl3) δ 7.66 (s, 1H), 7.21 (m, 1H), 6.98 (dd, J = 7.5 and
1.4 Hz, 1H), 6.79 (t, J = 7.5 Hz, 1H), 4.50 (septet, J = 6.1 Hz, 1H),
1.33(8) (s, 12H), 1.33(6) (d, J = 6.1 Hz, 6H); 13C NMR (100 MHz,
CDCl3) δ 154.2, 145.2, 127.7, 120.2, 119.5, 84.3, 71.5, 24.8, 22.1
(signal due to one carbon obscured or overlapping); IR νmax 3436,
2978, 2933, 1615, 1577, 1456, 1368, 1308, 1272, 1243, 1167, 1113,
1076, 985, 896, 856, 839, 826, 745, 678 cm−1; MS (EI, 70 eV) m/z 278
(M+•, 30), 180 (21), 179 (100), 178 (50), 136 (40); HRMS M+• calcd
for C15H2311BO4 278.1689, found 278.1689.
D
NMR (400 MHz, CDCl3) δ see Table S1 (Supporting Information);
13C NMR (100 MHz, CDCl3) δ see Table S1 (Supporting
Information); IR νmax 3304, 2991, 2940, 2837, 1693, 1588, 1481,
1447, 1138, 1115, 1101, 1081, 1051, 1029, 1010 cm−1; MS (EI, 70 eV)
m/z 262 (M+•, 10), 174 (20), 153 (100), 105 (50); HRMS M+• calcd
for C14H14O5 262.0841, found 262.0841.
A sample of this material suitable for single-crystal X-ray analysis
was grown from a dichloromethane/methanol solution, mp 166−168
°C.
Compound 46. A magnetically stirred solution of compound 36
(2.00 g, 5.36 mmol), ester 40 (1.80 g, 6.70 mmol), PdCl2dppf·CH2Cl2
(310 mg, 0.38 mmol), and triethylamine (10 mL) in THF/water (36
mL of a 9:1 v/v mixture) was purged with nitrogen for 0.5 h and then
heated at 70 °C for 1 h before being cooled, poured into water (50
mL), and extracted with ethyl acetate (3 × 30 mL). The combined
organic phases were washed with brine (1 × 40 mL), dried (Na2SO4),
filtered, and concentrated under reduced pressure. The ensuing light
yellow oil was subjected to flash chromatography (silica, 1:2 v/v ethyl
acetate/hexane elution) and concentration of the relevant fractions (Rf
= 0.7 in 1:1 v/v ethyl acetate/hexane) afforded phenol 46 (2.20 g,
Compound 31. The title compound was prepared as previously
described3 from diol 5 using the 12-step reaction sequence show in
Scheme 3. The spectral data obtained on compound 31 have been
presented elsewhere3 and compared favorably (see Table 2) with those
reported1 for the natural product ribisin C.
Compound 44. A magnetically stirred mixture of phenol 4317
(14.0 g, 60.6 mmol) in dry THF (150 mL) maintained at 0 °C was
treated with NaH (2.90 g of a 60% suspension in oil, 72.7 mmol).
After 0.5 h, the reaction mixture was treated with chloromethyl methyl
ether (4.90 mL, 64.5 mmol) and then stirred at 18 °C for 48 h before
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92%) as a clear, colorless oil: [α]20D −117.0 (c 0.5, CHCl3); 1H NMR
(400 MHz, CDCl3) δ 7.31 (d, J = 8.6 Hz, 2H), 7.20 (broad s, 1H),
6.87 (d, J = 8.6 Hz, 2H), 6.81−6.73 (complex m, 3H), 5.94 (d, J = 3.3
Hz, 1H), 4.79−4.73 (complex m, 3H), 4.54 (septet, J = 6.1 Hz, 1H),
4.13 (m, 1H), 4.05 (m, 1H), 3.80 (s, 3H), 3.65 (m, 1H), 3.54 (s, 3H),
3.47 (s, 3H), 1.35 (d, J = 6.1 Hz, 6H) (signal due to one proton
obscured or overlapping); 13C NMR (100 MHz, CDCl3) δ 159.2,
145.1, 144.6, 140.3, 130.4, 129.5, 126.7, 125.4, 122.4, 119.2, 113.8,
113.7, 81.8, 77.1, 75.0, 72.2, 71.6, 68.2, 58.7, 57.1, 55.2, 22.2(0),
22.1(9); IR νmax 3504, 2976, 2932, 1611, 1582, 1513, 1464, 1464,
1354, 1247, 1173, 1110, 972, 824 cm−1; MS (EI, 70 eV) m/z 444
(M+•, 5), 122 (22), 121 (100); HRMS M+• calcd for C25H32O7
444.2148, found 444.2150.
(35), 189 (20), 122 (20), 121 (100); HRMS M+• calcd for C25H28O7
440.1835, found 440.1826.
Compound 49. A magnetically stirred mixture of ketone 48 (600
mg, 1.36 mmol) in dichloromethane/water (21 mL of a 20:1 v/v
mixture) was treated with DDQ (340 mg, 1.59 mmol). The ensuing
mixture was stirred at 18 °C for 20 h and then was poured into water
(20 mL) and extracted with dichloromethane (3 × 30 mL). The
combined organic phases were washed with brine (1 × 40 mL) before
being dried (Na2SO4), filtered, and concentrated under reduced
pressure. The resulting light yellow oil was subjected to flash
chromatography (silica, 1:2 v/v ethyl acetate/hexane elution) to
afford, after concentration of the relevant fractions (Rf = 0.4 in 1:1 v/v
ethyl acetate/hexane), alcohol 49 (370 mg, 84%) as a white foam:
1
[α]20 −132.9 (c 0.85, CHCl3); H NMR (400 MHz, CDCl3) δ 7.64
Compound 47. A magnetically stirred solution of Ph3P (1.42 g, 5.4
mmol) in dry THF (10 mL) was treated with DEAD (850 μL, 5.4
mmol), the resulting solution was stirred at 18 °C for 0.17 h, and then
a solution of phenol 46 (2.0 g, 4.5 mmol) in THF (15 mL) was added
dropwise. The ensuing reaction mixture was stirred at 18 °C for 1 h
before being concentrated under reduced pressure. The resulting light
yellow oil was subjected to flash chromatography (silica, 1:4 v/v ethyl
acetate/hexane elution) to afford, after concentration of the
appropriate fractions (Rf = 0.5 in 1:3 v/v ethyl acetate/hexane),
compound 47 (1.80 g, 94%) as a clear, colorless oil: [α]20D −303.6 (c
0.3, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.37 (d, J = 8.7 Hz, 2H),
7.00 (m, 1H), 6.87 (d, J = 8.7 Hz, 2H), 6.84−6.77 (complex m, 2H),
5.79 (m, 1H), 5.37 (m, 1H), 4.94 (d, J = 11.7 Hz, 1H), 4.72 (d, J =
11.7 Hz, 1H), 4.63 (septet, J = 6.1 Hz, 1H), 4.01 (m, 1H), 3.88 (dd, J
= 9.2 and 2.3 Hz, 1H), 3.80 (s, 3H), 3.72 (m, 1H), 3.57 (s, 3H), 3.41
(s, 3H), 1.33 (d, J = 6.1 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ
159.1, 153.1, 143.1, 141.3, 130.8, 129.3, 126.8, 121.6, 119.9, 114.6,
113.7, 112.6, 84.5, 79.5, 78.3, 76.9, 72.6, 72.1, 59.5, 57.6, 55.3, 22.4; IR
νmax 2976, 2931, 1612, 1586, 1513, 1464, 1302, 1248, 1174, 1111,
1063, 989, 824 cm−1; MS (EI, 70 eV) m/z 426 (M+•, 12), 273 (30),
121 (100); HRMS M+• calcd for C25H30O6 426.2042, found 426.2041.
Compound 48. Step i. A magnetically stirred solution of
compound 47 (1.00 g, 2.34 mmol) in dry dichloromethane (30 mL)
maintained at 0 °C was treated, in portions, with m-CPBA (630 mg of
ca. 77% material, 2.81 mmol) and the resulting mixture warmed to 18
°C and stirred at this temperature for 14 h before being diluted with
NaHCO3 (30 mL of a saturated aqueous solution). The separated
aqueous phase was extracted with dichloromethane (3 × 30 mL), and
the combined organic phases were then dried (Na2SO4), filtered, and
concentrated under reduced pressure. The resulting light yellow oil,
presumed to contain the alcohol precursor to ketone 48, was
immediately subjected to the next step of the reaction sequence.
Step ii. Dimethyl sulfoxide (1.10 mL, 15.5 mmol) was added
dropwise to a magnetically stirred solution of oxalyl chloride (0.65 mL,
7.75 mmol) in dry dichloromethane (10 mL) maintained at −78 °C.
The ensuing mixture was stirred at this temperature for 0.08 h, then a
solution of the product obtained from step i in dichloromethane (30
mL) was added. The resulting mixture was stirred at −78 °C for a
further 0.33 h, treated with triethylamine (6.50 mL, 46.7 mmol), and
allowed to stir for a further 0.66 h before being poured into brine (20
mL) and extracted with dichloromethane (3 × 30 mL). The combined
organic layers were dried (Na2SO4), filtered, and concentrated under
reduced pressure and the ensuing light yellow oil subjected to flash
chromatography (silica, 1:3 v/v ethyl acetate/hexane elution).
Concentration of the relevant fractions (Rf = 0.1) afforded ketone
48 (600 mg, 58% from 47) as a pale yellow oil: [α]20D −265.3 (c 0.67,
CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.67 (d, J = 7.8 Hz, 1H), 7.42
(d, J = 8.2 Hz, 2H), 7.28 (m, 1H), 6.96−6.92 (complex m, 3H), 5.08
(d, J = 3.5 Hz, 1H), 4.89 (d, J = 11.7 Hz, 1H), 4.83−4.76 (complex,
2H), 4.36 (d, J = 8.7 Hz, 1H), 3.88 (dd, J = 8.7 and 3.6 Hz, 1H), 3.84
(s, 3H), 3.75 (s, 3H), 3.55 (s, 3H), 1.46 (d, J = 6.0 Hz, 6H); 13C NMR
(100 MHz, CDCl3) δ 190.9, 164.8, 159.5, 146.3, 143.5, 130.0, 129.2,
125.7, 124.9, 116.8, 114.5, 113.8, 112.2, 82.5, 81.9, 72.4, 72.0, 68.4,
60.6, 58.8, 55.3, 22.2(3), 22.19(2); IR νmax 2978, 2933, 2833, 1687,
1612, 1514, 1494, 1464, 1302, 1276, 1248, 1175, 1112, 1068, 1033,
920, 821 cm−1; MS (EI, 70 eV) m/z 440 (M+•, 20), 352 (10), 231
D
(d, J = 7.8 Hz, 1H), 7.28 (m, 1H), 6.93 (d, J = 7.8 Hz, 1H), 5.33 (d, J
= 3.7 Hz, 1H), 4.82 (septet, J = 6.0 Hz, 1H), 4.19 (d, J = 7.0 Hz, 1H),
3.98 (dd, J = 7.0 and 3.7 Hz, 1H), 3.65 (s, 3H), 3.64 (s, 3H), 3.13
(broad s, 1H), 1.44 (d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3)
δ 190.3, 164.8, 146.0, 143.6, 125.7, 124.9, 115.8, 114.1, 111.6, 82.0,
81.7, 71.6, 63.6, 59.9, 59.4, 22.0(9), 22.0(8); IR νmax 3430, 2979, 2934,
2832, 1686, 1624, 1600, 1494, 1464, 1385, 1374, 1277, 1192, 1140,
1112, 1059, 1022, 988, 914, 820, 794 cm−1; MS (EI, 70 eV) m/z 320
(M+•, 80), 278 (30), 246 (46), 245 (50), 232 (43), 190 (100), 162
(50), 134 (37); HRMS M+• calcd for C17H20O6 320.1260, found
320.1262.
Compound 50. A magnetically stirred solution of alcohol 49 (310
mg, 0.97 mmol) in dry THF (20 mL) was treated with Ph3P (280 mg,
1.06 mmol), α-chloroacetic acid (100 mg, 1.06 mmol), and DEAD
(170 μL, 1.06 mmol). The resulting solution was stirred at 18 °C for 2
h and then concentrated under reduced pressure, and the light yellow
residue thus obtained was subjected to flash chromatography (silica,
1:4 v/v ethyl acetate/hexane elution). Concentration of the relevant
fractions (Rf = 0.4 in 1:3 v/v ethyl acetate/hexane) then afforded α-
chloroacetate 50 (320 mg, 84%) as an amorphous, white powder:
[α]20D +15.4 (c 0.85, CHCl3); 1H NMR (400 MHz, CDCl3) δ 7.63 (d,
J = 7.7 Hz, 1H), 7.26 (t, J = 7.7 Hz, 1H), 6.92 (d, J = 7.7 Hz, 1H), 6.32
(d, J = 5.4 Hz, 1H), 4.75 (septet, J = 6.0 Hz, 1H), 4.24−4.23 (complex
m, 2H), 4.00−3.95 (complex m, 2H), 3.68 (s, 3H), 3.62 (s, 3H), 1.41
(d, J = 6.0 Hz, 6H); 13C NMR (100 MHz, CDCl3) δ 189.6, 166.6,
160.4, 146.3, 143.6, 126.0, 124.5, 117.2, 114.3, 112.6, 84.3, 82.4, 72.1,
68.4, 60.4(4), 60.4(3), 40.6, 22.1(2), 22.1(1); IR νmax 2978, 2935,
2837, 1768, 1691, 1624, 1600, 1494, 1318, 1277, 1188, 1143, 1110,
1080, 1010, 921, 852, 789 cm−1; MS (EI, 70 eV) m/z 398 and 396
(M+•, 23 and 50%), 277 (60), 261 (100), 245 (60), 190 (62), 189
(60); HRMS M+• calcd for C19H2135ClO7 396.0976, found 396.0973.
Compound 4. Step i. A magnetically stirred solution of α-
chloroacetate 50 (180 mg, 0.45 mmol) in methanol (15 mL) was
treated with zinc acetate dihydrate (120 mg, 0.54 mmol) and the
ensuing mixture stirred at 18 °C for 4 h then concentrated under
reduced pressure. The resulting white solid was treated with ethyl
acetate (50 mL), and the suspension thus obtained was filtered
through a short plug of TLC-grade silica gel and the filtrate
concentrated under reduced pressure. The white solid thus obtained
and presumed to contain compound 51, was immediately subjected to
the next step of the reaction sequence.
Step ii. A magnetically stirred solution of the product obtained from
step i in dry dichloromethane (20 mL) maintained at −78 °C was
treated with BBr3 (0.5 mL of a 1 M solution in dichloromethane, 0.5
mmol). The resulting solution was stirred at −78 °C for 0.33 h, and
then a further three aliquots of BBr3 (3 × 0.5 mL of a 1 M solution in
dichloromethane, 0.5 mmol) were added at 0.33 h intervals. A further
1 h after the addition of the last aliquot of BBr3, the reaction mixture
was quenched by careful addition of water (10 mL), the resulting
mixture was warmed to 18 °C, and then the separated aqueous phase
was extracted with dichloromethane (3 × 30 mL). The combined
organic phases were then dried (Na2SO4), filtered, and concentrated
under reduced pressure, and the light yellow residue thus obtained
subjected to flash chromatography (silica, 3:2 v/v ethyl acetate/hexane
elution). Concentration of the relevant fractions (Rf = 0.6) then
afforded compound 41 (45 mg, 36% from 50) as an amorphous, white
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Featured Article
powder: [α]20 −39.3 (c 0.8, MeOH) {lit.1 [α]D −22.0 (c 0.2,
24
40, 44, 46−50, and 52. This material is available free-of-charge
D
MeOH)}; H NMR (400 MHz, CD3OD) δ see Table 3; 13C NMR
1
via the Internet at http://pubs.acs.org.
(100 MHz, CD3OD) δ see Table 3; IR νmax 3306, 2942, 1679, 1597,
1493, 1332, 1250, 1178, 1142, 1110, 1050, 1018, 850, 789 cm−1; MS
(EI, 70 eV) m/z 278 (M+•, 50), 248 (38), (246 (36), 245 (40), 190
(100), 162 (70), 134 (60); HRMS M+• calcd for C14H14O6 278.0790,
found 278.0789.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: martin.banwell@anu.edu.au.
A sample of this material suitable for single-crystal X-ray analysis
was grown from a hexane/dichloromethane/methanol solution, mp
194−196 °C.
Notes
The authors declare no competing financial interest.
Compound 52. A magnetically stirred solution of alcohol 49 (0.10
g, 0.31 mmol) in dry dichloromethane (10 mL) maintained at −78 °C
was treated with BBr3 (0.35 mL of a 1 M solution in dichloromethane,
0.35 mmol), and then a further three aliquots of BBr3 (3 × 0.5 mL of a
1 M solution in dichloromethane, 0.5 mmol) were added at 0.33 h
intervals. A further 1 h after the addition of the last aliquot of BBr3, the
reaction mixture was quenched by careful addition of water (10 mL),
the resulting mixture was warmed to 18 °C, the separated aqueous
phase was extracted with dichloromethane (3 × 30 mL), and the
combined organic phases dried (Na2SO4), filtered, and concentrated
under reduced pressure. The light yellow residue thus obtained was
subjected to flash chromatography (silica, 3:2 v/v ethyl acetate/hexane
elution) to afford, after concentration of the relevant fractions (Rf =
0.6), compound 52 (50 mg, 57%) as a white foam: [α]20D −78.1 (c 1,
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 Ph.D. Scholarship provided by the
Government of the People’s Republic of China.
REFERENCES
■
(1) Liu, Y.; Kubo, M.; Fukuyama, Y. J. Nat. Prod. 2012, 75, 2152.
(2) (a) Lee, I.-K.; Lee, J.-H.; Yun, B.-S. Bioorg. Med. Chem. Lett. 2008,
18, 4566. (b) Liu, Y.; Wang, F. Carbohydr. Polym. 2007, 70, 386.
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(4) For reviews on methods for generating cis-1,2-dihydrocatechols
such as 5 by microbial dihydroxylation of the corresponding aromatics,
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1
MeOH); H NMR (400 MHz, CD3OD) δ see Table S2 (Supporting
Information); 13C NMR (100 MHz, CD3OD) δ see Table S2
(Supporting Information); IR νmax 3339, 2932, 2838, 1680, 1599,
1493, 1334, 1178, 1098, 1052, 1021, 841, 801 cm−1; MS (EI, 70 eV)
m/z 278 (M+•, 60%), 246 (50), 245 (50), 190 (100), 162 (70), 134
(60); HRMS M+• calcd for C14H14O6 278.0790, found 278.0789.
Crystallographic Studies. Crystallographic Data. Compound 1:
C13H12O5·H2O, M = 266.25, T = 200 K, orthorhombic, space group
P212121, Z = 4, a = 5.1685(2) Å, b = 10.4961(4) Å, c = 21.9445(7) Å;
McLeod, M. D.; McRae, K. J.; Stewart, S. G.; Vogtle, M. Pure Appl.
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50, 2821.
V = 1190.47(8) Å3, Dx = 1.485 g cm−3, 1615 unique data (2θmax
=
55°), R = 0.037 [for 1234 reflections with I > 2.0σ(I)]; Rw = 0.084 (all
data), S = 0.99.
(5) Certain structurally related γ-hydroxycyclohexenones are
reported to be unstable. See: (a) Paddock, V. L.; Phipps, R. J.;
Conde-Angulo, A.; Blanco-Martin, A.; Giro-Manas, C.; Martin, L. J.;
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White, A. J. P.; Spivey, A. C. J. Org. Chem. 2011, 76, 1483.
Compound 2: C14H14O5, M = 262.26, T = 200 K, monoclinic, space
group P21, Z = 2, a = 10.2259(6) Å, b = 4.7596(3) Å, c = 13.9296(8)
Å; β = 108.834(3)°; V = 641.67(7) Å3, Dx = 1.357 g cm−3, 1278
unique data (2θmax = 50°), R = 0.040 [for 1106 reflections with I >
2.0σ(I)]; Rw = 0.091 (all data), S = 1.02.
(b) Palframan, M. J.; Kociok-Kohn, G.; Lewis, S. E. Chem.Eur. J.
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2012, 18, 4766.
Compound 4: C14H14O6·H2O, M = 296.28, T = 200 K,
orthorhombic, space group P212121, Z = 4, a = 4.7511(5) Å, b =
13.5474(10) Å, c = 20.9950(18) Å; V = 1351.3(2) Å3, Dx = 1.456 g
cm−3, 1412 unique data (2θmax = 49.8°), R = 0.071 [for 914 reflections
with I > 2.0σ(I)]; Rw = 0.126 (all data), S = 1.01.
(6) (a) Matveenko, M.; Banwell, M. G.; Willis, A. C. Tetrahedron
2008, 64, 4817. (b) Findlay, A. D.; Gebert, A.; Cade, I. A.; Banwell, M.
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Structure Determinations. Images were measured on a CCD
diffractometer (Mo Kα, graphite monochromator, λ = 0.71073 Å) and
data extracted using the DENZO package.21 Structure solutions were
by direct methods (SIR92).22 The structures of compounds 1, 2, and 4
were refined using the CRYSTALS program package.23 Atomic
coordinates, bond lengths and angles, and displacement parameters for
compounds 1, 2, and 4 have been deposited at the Cambridge
Crystallographic Data Centre (CCDC nos. 981971, 981972, and
981973 for compounds 1, 2, and 4, respectively). These data can be
obtained free-of-charge via www.ccdc.cam.ac.uk/data_request/cif.
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1141.
ASSOCIATED CONTENT
■
S
* Supporting Information
Crystallographic data (CIFs), anisotropic displacement ellip-
soid plots derived from the single-crystal analyses of
compounds 1, 2, and 4; Tables S1 and S2 (comparison of
1
the 13C and H NMR data recorded for compounds 2 and 52
(17) Kissau, L.; Stahl, P.; Mazitschek, R.; Giannis, A.; Waldmann, H.
J. Med. Chem. 2003, 46, 2917.
with those reported for ribisins B and D, respectively) and
Table S3 (comparison of the 13C NMR data recorded for
synthetically derived compound 4 at varying pH with those
reported for ribisin D); 13C and 1H NMR spectra for
compounds 1, 2, 4, 8, 10, 12−14, 16−18, 22−26, 28−30,
1
(18) We assume the 13C and H NMR data reported for ribisin D
were obtained using CD3OD rather than CDCl3 as solvent (see Table
2 vs the Experimental Section and the Supporting Information within
ref 1).
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(19) Still, W. C.; Kahn, M.; Mitra, A. J. Org. Chem. 1978, 43, 2923.
(20) Pangborn, A. B.; Giardello, M. A.; Grubbs, R. H.; Rosen, R. K.;
Timmers, F. J. Organometallics 1996, 15, 1518.
(21) DENZO−SMN. Otwinowski, Z.; Minor, W. Processing of X-ray
diffraction data collected in oscillation mode. In Methods in
Enzymology; Carter, C. W., Jr.; Sweet, R. M., Eds.; Academic Press:
New York, 1997; Vol. 276: Macromolecular Crystallography, Part A,
pp 307−326.
(22) SIR92. Altomare, A.; Cascarano, G.; Giacovazzo, C.; Guagliardi,
A.; Burla, M. C.; Polidori, G.; Camalli, M. J. Appl. Crystallogr. 1994, 27,
435.
(23) Betteridge, P. W.; Carruthers, J. R.; Cooper, R. I.; Prout, K.;
Watkin, D. J. J. Appl. Crystallogr. 2003, 36, 1487.
NOTE ADDED AFTER ASAP PUBLICATION
Scheme 5 contained an error in the version published ASAP
February 28, 2014; the correct version reposted March 4, 2014.
■
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