Expansion of Thieles Acid Chemistry in Pursuit of a Suite of Conformationally Constrained Scaffolds

Article abstract of DOI:10.1021/acs.joc.5b01332

The Diels-Alder dimer of cyclopentadiene carboxylate, Thieles acid has conformational properties that make it attractive as a molecular scaffold for applications in supramolecular and biological chemistry. However, a lack of known reaction methodology for derivatives of Thieles acid (or the corresponding esters) has hampered its utilization in these fields. We describe an improved preparation of Thieles esters and survey the chemistry of these versatile intermediates. As part of this effort, we also describe the synthesis of a suite of Thieles acid (or ester) analogues spanning a broad range of cleft angles.

Full text of DOI:10.1021/acs.joc.5b01332

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Expansion of Thiele’s Acid Chemistry in Pursuit of a Suite of
Conformationally Constrained Scaffolds
Jun Chen,† Brenden Kilpatrick,† Allen G. Oliver,‡ and Jeremy E. Wulff*,†
†Department of Chemistry, University of Victoria, P.O. Box 3065 STN CSC, Victoria, BC V8W 3V6, Canada
‡Molecular Structure Facility, Department of Chemistry and Biochemistry, University of Notre Dame, 251 Nieuwland Science Hall,
Notre Dame, Indiana, 46556, United States
S
* Supporting Information
ABSTRACT: The Diels−Alder dimer of cyclopentadiene
carboxylate, Thiele’s acid has conformational properties that
make it attractive as a molecular scaffold for applications in
supramolecular and biological chemistry. However, a lack of
known reaction methodology for derivatives of Thiele’s acid
(or the corresponding esters) has hampered its utilization in
these fields. We describe an improved preparation of Thiele’s
esters and survey the chemistry of these versatile intermedi-
ates. As part of this effort, we also describe the synthesis of a
suite of Thiele’s acid (or ester) analogues spanning a broad
range of cleft angles.
formula C14H16O4Br4.1 This early publication therefore
provided a critical indication that productive chemical trans-
formations could occur both at the two carbonyl functions and
at the two olefins in what is otherwise a relatively
unfunctionalized, rigid alkane scaffold.
From a structural perspective, Thiele’s acid (or ester
INTRODUCTION
Well over a century ago, Johannes Thiele reported that the
reaction of cyclopentadienyl anion with carbon dioxide resulted
■
in the formation of a dimeric product with the molecular
formula C12H12O4.1,2 Subsequent studies revealed this product
to be a mixture of regioisomeric Diels−Alder dimers, of which
the major isomer produced was compound 3 (Scheme 1).3
derivatives thereof; colloquially referred to as Thiele’s esters)
can be viewed as a molecular cleft: a rigid molecule containing a
chemically inert backbone that projects functionality outward
Scheme 1. Thiele’s 1901 Synthesis of a Diacid and Diester
from its central core at a well-controlled angle.8 It might be
supposed, therefore, that products derived from 3 could find
application in supramolecular systems (alongside better studied
brethren like dibenzonorbornadienes,9 terpyridines,10 Kagan’s
ether,11 and Troger’s base12), as a template for the preparation
̈
of ß-hairpin peptidomimetics13 (akin to tetrahydrothiazolopyr-
idinone,14 amino(oxo)piperidinecarboxylate,15 phenoxathiin,16
or dibenzofuran17 derivatives), or even as conformationally
constrained enzyme inhibitors.18
A survey of the relevant literature, however, reveals three
obstacles to the use of Thiele’s acid and esters in these
applications.
The first difficulty is that Thiele’s acid itself is not terribly
Diacid 3, which Thiele was able to purify by repeated
easy to access in pure form. Thiele’s initial preparation suffered
crystallizations, is the result of an endo Diels−Alder coupling
from low yields and required a series of recrystallizations to
between two regioisomers of cyclopentadiene carboxylate, 2b
access pure 3. Indeed, the purest compound was only obtained
and 2c, which may coexist with a third isomer, 2a, in an
after esterification to 4a and subsequent ester hydrolysis.1
Marchand and Watson described a modified procedure that
resulted in an improved yield (80% on 55 g scale) but noted
that the product was contaminated with regioisomers even after
equilibrating mixture.4,5 Compound 3 is now known as Thiele’s
acid and represents a challenging test of the predictive power of
mechanistic models used to forecast the outcomes of
cycloaddition chemistry.6,7
Thiele’s initial report went on to describe the conversion of
diacid 3 to the corresponding diester 4a, which could in turn be
reacted with bromine to afford a tetrabromide derivative of
Received: June 12, 2015
© XXXX American Chemical Society
A
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recrystallization.19 A subsequent publication from the same
group indicated that selection of the major regioisomer
required esterification, followed by recrystallization of diester
4a.20 Likewise, a report from the Smith group described the use
of sodium sand for the initial deprotonation of cyclopentadiene,
but the crude acid appears to have once again been taken on in
impure form to the next step in the synthetic sequence.21 In
other cases, regioisomeric mixtures were inconsequential for
the intended application, and so it appears that no effort was
made to purify 3 to homogeneity.22,23 Adding to this
purification challenge is the fact that Thiele’s acid is highly
insoluble, an observation highlighted by the fact that despite
over a century of chemistry on compound 3 we were unable to
find any NMR spectral data for the pure compound in the
literature.24
a
Scheme 3. Dive’s Salt Route to 4a
a
The structures shown for 7a′ and 8a′ are those assigned by Dive. See
below for a re-interpretation of the structural assignments.
Esterification of 3 to 4a prior to final purification might seem
like it ought to be a fairly trivial exercise. However, two separate
groups have reported the formation of unexpected addition
products, either in the conversion of the acid to the methyl
ester21 or in the subsequent saponification of the ester back to
the desired acid.20
An obvious strategy to avoid these difficulties would be to
form the ester prior to dimerization. Indeed, methyl cyclo-
pentadiene-1-carboxylate (5a) was reported by Peters to
dimerize spontaneously to Thiele’s ester 4a at room temper-
ature (Scheme 2).25 However, this result obscures the fact that
addition of 4a was shown by Dunn and Donohue to afford the
corresponding cyclobutane,3 which was subsequently utilized
by Marchand in the synthesis of a larger cage structure.28 In
addition, Deslongchamps and co-workers converted the diacid
3 to the corresponding ketone, en route to a synthesis of
triquinacene;29 the route was later repeated by the Paquette
group to prepare a series of triquinacene derivatives for
absorption and circular dichroism studies.30 Notwithstanding
these seminal contributions, however, very little (nonphoto-
chemical) reactivity has been described for the two alkenes 3 or
4, aside from Thiele’s initial description of perbromination of 31
and Peters’ report of hydrogenations and epoxidations
occurring at both alkenes of 4.31 However, in neither of these
cases were the structures of the products established.
Scheme 2. Direct Access to Thiele’s Ester from the
Corresponding Cyclopentadiene
The third barrier to the use of Thiele’s acid in supramolecular
or medicinal applications is that the cleft angle (i.e., the
difference between the vectors of projection for the two
carbonyl functions in 3) has not been shown to be tunable.
In the current work, we sought to address each of these
obstacles by (1) establishing an improved, scalable route to
regioisomerically pure 3 and 4, (2) exploring the fundamental,
nonphotochemical reaction chemistry of compound 4, focusing
particularly on selective transformations of the two alkenes, and
(3) synthesizing and structurally characterizing a suite of
derivatives of 4 containing a range of cleft angles.
the monomeric ester itself is both volatile and unstable. The
difficulty in accessing 5a directly is highlighted by the fact that
Peters actually generated this compound by depolymerization of
4a! We attempted to prepare Thiele’s methyl and benzyl esters
(4a and 4b) directly by reaction of lithium or sodium
cyclopentadienide and the appropriate chloroformate26 but
found that we consistently obtained yields of <10% over two
steps. Minor regioisomers (separated from 4 by column
chromatography) accounted for only a few additional percent,
indicating that most of the poor yield was attributable to
difficulties in handling 5.
A recent publication from Dive and co-workers described a
modification to this “ester first” approach,27 wherein the metal
salt of 5a (i.e., 6a, Scheme 3) was first isolated as a stable solid.
The intermediate salt was then exposed to ammonium chloride
to trigger reprotonation and subsequent dimerization.27
Although Dive’s experimental conditions did not afford
preparatively useful quantities of 4 in our hands, we nonetheless
found this to be an excellent starting point for optimization and
report here an improved synthetic protocol that provides gram-
scale quantities of regioisomerically pure Thiele’s ester.
The second obstacle to the use of Thiele’s acid or esters in
the applications described above is that a dearth of general
reaction chemistry has been reported for this system, although
the photochemically promoted intramolecular [2 + 2] cyclo-
RESULTS AND DISCUSSION
■
We began our studies by optimizing the preparation of Dive’s
salt (6a, Scheme 3). We found that an improved yield could be
obtained by using commercially available sodium cyclo-
pentadienylide (2.0 M in THF) and 5 equiv of dimethyl
carbonate (Scheme 4). The desired salt was isolated by partial
concentration of the reaction mixture, precipitation, and
vacuum filtration to provide a 94% yield of 6a on a 5.5 g
Scheme 4. Improved Preparation of the Intermediate Salt
B
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scale. Although somewhat air and moisture sensitive, we found
6a to be relatively stable under an argon atmosphere.
Exposure of 6a to the conditions described by Dive (aqueous
ammonium chloride in dichloromethane) provided a 40%
isolated yield of 4a after column chromatography, together with
a further 22% of an approximately 1:1 mixture of regioisomers
7a and 8a.
Seeking to further optimize the synthesis of 4a, we explored
the effect of different solvents, temperature, reaction time and
acid source on the yield of the reaction. As shown in Table 1,
Relatively poor yields were found with DMSO or acetic acid as
solvent, while aprotic solvents generally supported a higher
incidence of unwanted regioisomers 7a and 8a.
Hindered alcohols were best for the reaction, with 2-
propanol (entry 16) outperforming methanol (entry 5). 2-
Pentanol was better still (entry 17), but the greater cost for this
solvent led us to select 2-propanol as the medium of choice for
the transformation.
We briefly re-examined the effect of the acid promoter but
once again found no significant difference between acetic acid
(entry 18) and sulfuric acid (entry 16). Addition of p-
toluenesulfonic acid (entry 19) was associated with a reduced
yield. The use of elevated temperatures (refluxing 2-propanol,
entry 20) gave no increase in yield while diminishing the purity
of the isolated product. Finally, we explored the effect of scale
and were pleased to find that the reaction could be run on 5 g
batches of 6a with no loss in yield (entry 22).
Table 1. Optimization of Thiele’s Ester Formation
Having achieved our initial goal of a scalable synthesis of
compound 4, we turned our attention to the characterization of
the minor regioisomers 7 and 8. The exact structures of these
products (or their acid analogues) have been a matter of some
disagreement, with several conflicting reports appearing in the
literature. For example, an early report by Peters (relying
mostly upon characterization by UV spectroscopy) tentatively
assigned the structure of a minor regioisomer arising from the
dimerization of cyclopentadiene carboxylate (2) as being the
diacid congener of 8a-A (Figure 2).31 Later work by
Marchand19 suggested that Peters had actually characterized
the precursor to 7a-A (Figure 1) but that the acid forms of both
8a-A and 7a-A were present in the reaction mixture, at 13% and
1%, respectively.19 Jaouen, on the other hand, proposed that
the most abundant minor reaction product arising from
dimerization of 2 was actually the diacid analogue of 7a-C.5
Most recently, Dive reported that the dimerization of the
cyclopentadiene methyl ester (6a) gave two products in
addition to the target compound 4a. For one of these
(shown as 7a′ in Scheme 3), the position of the conjugated
ester was left undefined (i.e., the proposed structure was either
7a-A or 7a-B). For the other regioisomer (shown as 8a′ in
Scheme 3) the structure 8a-C was suggested.27
The multigram-scale synthesis of 4a shown in Table 1
provided us with ample quantities of the two minor
regioisomers 7a and 8a, which were spectroscopically identical
to those isolated by Dive. Looking to establish once and for all
the identity of these compounds, and to address any possibility
that the dimerization of the ester 6a might actually give rise to a
different collection of regioisomers from that reported for the
dimerization of 2, we collected an extensive series of 1D and
2D NMR spectra for each isolated compound (1H, 13C, COSY,
NOESY, HSQC, HMBC, TOCSY) and also performed DFT
calculations32 to calculate likely chemical shifts for each of the
four possible structures for each isolated product (7a-A−7a-D
and 8a-A−8a-D) shown in Figures 1 and 2.
isolated
a
scale
temp
crude ratio yield of
solvent
MeCN
(mg)
acid
(°C)
4a: 7a: 8a
4a (%)
j
j
h
b
1
500
250
250
250
250
250
250
250
250
250
250
250
250
250
250
250
250
500
500
500
1750
5000
AcOH
AcOH
rt
100:21:22
100:24:21
100:18:13
100:17:14
100:15:13
n.d.
39
g
2
MeCN
MeOH
MeOH
MeOH
MeOH
toluene
toluene
DMSO
d
50
53
j
i
b
3
NH4Cl
rt
27
b
k
k
k
i
4
H2SO4
H2SO4
H2SO4
rt
38
g
5
50
48
46
42
i
6
50
j
g
7
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
AcOH
50
100:31:36
n.d.
j
c
,
g
h
g
e
8
110
50
50
50
50
rt
0
j
j
j
j
j
j
j
g
i
9
100:26:36
100:50:19
n.d.
28
33
38
41
10
11
12
13
14
15
16
17
18
19
20
21
22
g
g
i
AcOH
THF
n.d.
b
Et2O
100:32:42
100:33:38
100:35:44
100:19:18
100:23:21
100:22:24
100:24:27
100:13:9
n.d.
41
c
,
CH2Cl2
EtOAc
iPrOH
2-pentanol
iPrOH
iPrOH
iPrOH
iPrOH
iPrOH
40
50
50
50
50
50
83
50
50
49
52
56
60
56
48
g
g
g
g
g
k
k
H2SO4
H2SO4
j
AcOH
j
p-TsOH
k
c
,
f
H2SO4
<58
k
g
g
H2SO4
63
64
k
H2SO4
n.d.
a
b
Mass of 6a used. Calculated yield, accounting for minor impurities
c
d
in the isolated product. Reflux temperature for the solvent. This
e
reaction was conducted in the absence of additional solvent. Extensive
f
decomposition precluded the isolation of any pure compound. This
g
product contained an unidentified impurity. The reaction was run for
16 h. The reaction was run for 48 h. The reaction was run for 72 h.
1.05 equiv of the acid source was used. 0.55 equiv of the acid source
h
i
j
k
was used.
the use of a somewhat elevated temperature (50 °C) provided a
modest benefit to the yield and purity of the isolated
compound (e.g., compare entry 1 with entry 2 or entry 4
with entry 5). However, more extreme temperatures (e.g., entry
8) led to extensive decomposition. We therefore selected 50 °C
as the optimal temperature for our other trials.
The acid source had little evident effect on the outcome of
the reaction (e.g., compare entries 1, 3, and 4), while longer
reaction times provided no increase in yield (compare entry 6
with entry 5). We found that the dimerization proceeded in
several different solvents (entries 9−15), with modest but
significant differences in both yield and product distribution.
For the first minor regioisomer, 7a, the NMR analysis was
made significantly more challenging by the number of long-
range couplings arising from the rigidity of the molecule
(particularly the 4J couplings in the HMBC data), but we were
ultimately able to determine the compound’s identity as 7a-A.
Each of the other possible structures could be ruled out by the
observation of at least one conflicting correlation in the HMBC
spectrum, while 7a-C and 7a-D could be further eliminated on
the basis of comparison to the calculated 13C chemical shift
data, wherein the expected shifts for C3a and C7a were >10
C
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Figure 2. Structural assignment for 8a: blue, 13C chemical shifts; red,
1H chemical shifts; green, COSY correlations; cyan, NOE correlations;
mauve, HMBC correlations. Only the most significant correlations are
shown from each data set. Crosses indicate data that would be
incompatible with the proposed structures. Regions circled in green
would be expected to contribute to couplings and peak shapes
1
different from those observed in the H NMR spectrum.
using dibenzyl carbonate in place of dimethyl carbonate
furnished the corresponding benzyl ester 4b (entry 1 of
Table 2). However, the intermediate cyclopentadienylide salt
Figure 1. Structural assignment for 7a: blue, 13C chemical shifts; red,
1H chemical shifts; green, COSY correlations; cyan, TOCSY
correlations; solid mauve, 3J HMBC correlations: dashed mauve, 4J
HMBC correlations. Only the most significant correlations are shown
from each data set. Crosses indicate data that would be incompatible
with the proposed structures.
Table 2. Additional Thiele’s Esters and Ketones
ppm away from the observed signals (see Scheme 6 for atom
numbering). Our assignment of 7a-A as the correct structure
for the first isolated regioisomer was further supported by the
collection of X-ray data for an isolated crystal (inset to Figure
1). While this structure is of low quality due to internal
disorder, it is nonetheless sufficient to confirm that the two
ester functions exist on opposite faces of the molecule.
Turning to the second regioisomer, structures 8a-B and 8a-C
could be quickly ruled out on the basis of HMBC data, but it
was more difficult to unambiguously distinguish between
structures 8a-A and 8a-D. Ultimately, however, 8a-D was
ruled out on the basis of the peak shape of the vinyl proton at
1
6.58 ppm in the H NMR spectrum. This signal appears as an
approximate quartet with a ∼2 Hz coupling. Such a coupling
pattern is inconsistent with the calculated geometry-optimized
structure for 8a-D, where at least one larger coupling (>5 Hz)
would be expected for the proton attached to the conjugated
olefin. The preponderance of evidence therefore supports 8a-A
as the correct structure for the second isolated regioisomer. An
NOE interaction between the methylene proton at 1.94 ppm
and the alkene proton at 6.09 ppm confirmed that this structure
was also an endo adduct.
a
Method A: the intermediate salt (6) was isolated by vacuum filtration,
washed with ether, and dried prior to acidification in 2-propanol.
Method B: the intermediate salt (6) was used directly in the
acidification step. Refer to the Experimental section for details.
Returning to our target dimer 4, we next sought to apply our
method to the synthesis of additional analogues. We found that
D
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(6b) was in this case too unstable to be isolated. In order to
achieve a satisfactory yield of 4b, we therefore adopted a
modified procedure (method B) in which the intermediate salt
was directly acidified to provide rapid conversion to the desired
Diels−Alder product.
osmium tetraoxide-mediated dihydroxylation provided a 52%
yield of the heavily functionalized product 11 as a single
diastereomer.
Bis-alkene 4a also reacted smoothly under dihydroxylation
conditions to provide tetraol 12. Once again focusing on
transformations capable of distinguishing between the two
similarly functionalized halves of the molecular framework, we
were pleased to find that acetonide formation took place more
rapidly at the Eastern diol of 12 to provide 13 in acceptable
yield (after removal of overprotected product). Alternatively,
the use of superstoichiometric concentrations of the acid
catalyst (accompanied by a switch from p-toluenesulfonic acid
to camphorsulfonic acid) afforded an excellent yield of the fully
protected compound 14. Hydrolysis of 14 was selective for the
C2′ carboxyl group, providing 15 as an orthogonally function-
alized scaffold.
We were able to prepare crystals of bis-ester 14 suitable for
X-ray analysis. The resulting structure (inset to Scheme 6)
provided a useful contrast to the known X-ray structure of 4a
(CCDC 704728).38 As shown in Figure 3, the most striking
effect of the sp2 → sp3 hybridization change at C2 and C6 was
to push the two ester functions inward, substantially narrowing
the cleft angle between them (Figure 3).
Because our primary interest is in using these Thiele’s ester
derivatives as scaffolds for various applications, we particularly
desired to access compounds containing functional group
handles for subsequent derivatization. In this vein, we were
gratified to be able to access 4c (containing terminal olefins for
subsequent cross-metathesis reactions) and 4d (containing
primary alcohols for subsequent esterification reactions) in
serviceable yields from diallyl carbonate and ethylene
carbonate, respectively (entries 2 and 3). Using similar
protocols, we also prepared two representative ketones, 4e
and 4f (entries 4 and 5).33 Unfortunately, attempts to use
carbamates as electrophiles (to directly access the correspond-
ing Thiele’s amides) were not successful.
Hydrolysis and Fischer esterification of 4a and 3,
respectively, have previously been reported to suffer from
competing conjugate addition reactions.20,21 We found that by
conducting the hydrolysis reaction in a hindered solvent
(Scheme 5) we could achieve high yields of regioisomerically
The fact that 14 enforces a ca. 180° turn between the two
carbonyl groups suggests that it could find application in the
design of peptide β-turn mimics. At the same time, the
difference in cleft angle between 4a and 14 is quite large, and we
wondered if we might be able to access compounds supporting
intermediate angles in order to establish a more broadly
applicable family of molecular scaffolds. Positing that the
installation of 3-membered rings (formally sp5 hybridized)39
into the Thiele’s acid structure would enforce a geometry at C2
and C6 that is midway between that of compounds 4a (sp2)
and 14 (sp3), we conducted a computational study to identify
potentially valuable target compounds.
For the purpose of comparison (and to remove any
conformational issues associated with the methyl ester groups
in 4a and 14), we opted to conduct our study on diacids A−D
(Table 3; red arrows indicate vectors of projection of the
carboxyl groups from the central core). DFT calculations40
indicated that calculated structure A (i.e., the in silico rendering
of compound 3) had a somewhat broader cleft angle (123°)
than was observed for the solid-state structure of diester 4a
(133°). By contrast, calculated structure D (i.e., the in silico
rendering of the diacid of 14) had a somewhat narrower cleft
angle (189°) than was observed for the solid-state structure of
14 (176°). These differences between our gas-phase calcu-
lations and solid-state structures may be at least partly due to
packing effects in the crystals of 4a and 14.41
As hypothesized, structures B (incorporating a single
cyclopropane) and C (incorporating two cyclopropanes)
occupied structural space midway between the two extremes
represented by A and D. We therefore adopted these molecules
(or the corresponding half esters) as our final targets for
synthesis.
As shown in Scheme 6, nucleophilic cyclopropanation of 4a
using the Corey−Chaykovsky protocol42 exhibited the same
level of selectivity as that shown in our previous conjugate
addition reaction, taking place exclusively at the electrophilic
C5−C6 alkene to afford compound 16 as a single regioisomer
and single diastereomer. Saponification resulted in selective
hydrolysis at the C2′ carboxyl group (analogous to our earlier
result with 14) to provide the desired target compound 17.
Scheme 5. Access to Regioisomerically Pure Thiele’s Acid
for Characterization by NMR Spectroscopy and Proof of
Principle for Esterification
pure Thiele’s acid (3). Notably, our NMR data (see Supporting
Information) constitute the first complete spectral character-
ization for this century-old compound.34 We also explored
esterification from 3 back to 4 and found that prior formation
of the corresponding bis-acyl chloride provided the desired
ester in better yield and purity than the previously reported
Fischer esterification strategy.
With scalable access to Thiele’s acid and various ester
derivatives well established, we next explored the reaction
chemistry of 4a (Scheme 6). We were particularly interested in
identifying transformations that permitted the differentiation of
the two conjugated alkenes (C2−C3 and C5−C6; see Scheme
6 for numbering) and of the two carbonyl functions (at C2′ and
C6′).
Conjugate addition using benzylamine as a representative
nucleophile proceeded solely at the C5−C6 alkene.35,36 As
expected, the nucleophile exclusively approached from the less-
hindered face of the alkene, but the protonation step was less
selective, affording a mixture of anti (9) and syn (10) addition
products. Exposure of 9 to more DBU and higher temperature
facilitated isomerization to the more stable 10, although some
elimination of benzylamine was also observed under these
conditions. Repeated attempts to add nucleophiles to the C2−
C3 alkene of 4a or 10 were unsuccessful, leading us to suspect
that this second alkene function does not experience the same
degree of conjugation to the associated carbonyl group.20,37
This observation is in good accord with previously reported
computational studies21 and indicated that functionalization of
the Eastern portion of the molecule might be better achieved
under electrophilic conditions. In the event, exposure of 10 to
E
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Scheme 6. Chemo- and Regioselective Derivatizations of Thiele’s Ester in Pursuit of Scaffolds of Varying Cleft Angle
reduction to provide compound 19 could be achieved by
limiting the number of equivalents of reducing agent in the
reaction mixture. Alternatively, when a larger excess of LiAlH4
was added, complete reduction to diol 20 could be achieved in
high yield.
Installation of the second cyclopropyl motif, to access our
final target, C, was more challenging. Once again, the C2−C3
alkene proved resilient to the addition of nucleophiles, even
under forcing conditions. Guided therefore by our earlier
transformation of 10 to 11 under electrophilic dihydroxylation
conditions, we explored the conversion of diol 20 to 21 using
an electrophilic cyclopropanation (Scheme 7). Gratifyingly, we
found that Simmons−Smith conditions43 provided compound
21 in high yield, after which reoxidation of the two primary
alcohols allowed access to the target diacid 22 (i.e., compound
C).
Before completing our synthetic study, we wanted to address
a limitation that we perceived for our methodology: the
Figure 3. Comparison of X-ray data for 4a and 14.
difficulty in hydrolyzing the C6′ ester (e.g., in 15 or 17). While
the reduction/reoxidation sequence that provided diacid 22 is
always an option, it may not be sufficiently step-economical for
some applications. An alternative route to a diacid product
could be the hydrogenolysis of a benzyl ester precursor. Since
we had ready access to compound 4b (by two separate routes,
described above), we sought to explore the synthetic utility of
hydrogenolysis of a functionalized intermediate. We therefore
converted 4b to intermediate 23 (Scheme 7) using the same
transformation that we had previously employed to access 16.
Fortuitously, 17 was amenable to the production of X-ray
quality crystals; the solved solid-state structure (inset to
Scheme 6) confirmed the identity of the target compound
and showed a cleft angle of 149°, nearly identical to that
predicted for structure B in Table 3.
With significant quantities of intermediate 16 on hand, we
also briefly explored other regioselective transformations. We
found that Grignard addition took place exclusively at the C2′
carbonyl to afford compound 18 and that a partially selective
F
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Featured Article
C2−C3 alkene could be reacted with electrophiles. Conversely,
the C2′ ester function was much more reactive than the C6′
ester, although the use of benzyl ester intermediates permits
dual reactivity when desired.
Table 3. Calculated Cleft Angles for Representative Scaffolds
Along the way, we made important contributions to the
structural assignment and characterization of the core Thiele’s
ester and acid building blocks: refining the structure of 7a,
revising the structure of 8a, and recording the first NMR
spectra for purified 3.
Most significantly, we employed a combination of structure-
based design (aided by both DFT calculations and X-ray
crystallography) and strategic synthesis to establish a new suite
of molecular scaffolds incorporating a broad range of cleft
angles. We hope that the combination of easy synthetic access
and structural tunability will lead these scaffolds to be employed
in a diverse range of applications.
EXPERIMENTAL SECTION
■
General Methods. All reactions were performed in single-neck,
flame-dried, round-bottom flasks fitted with rubber septa under a
positive pressure of argon, unless otherwise noted. Liquid reagents
were transferred via glass microsyringe. Solvents were transferred via
syringe with a stainless steel needle. Organic solutions were
concentrated at 40 °C by rotary evaporation under vacuum. Analytical
thin-layer chromatography (TLC) was performed using aluminum
plates precoated with silica gel (0.20 mm, 60 Å pore-size, 230−400
mesh, Macherey-Nagel) impregnated with a fluorescent indicator (254
nm). TLC plates were visualized by exposure to ultraviolet light. Flash-
column chromatography was performed over silica gel 60 (63−200
μM, Caledon).
a
b
See ref 40 for details. Angles α and β are defined as illustrated in
c
Figure 3. The cleft angle is defined as = 360° − (α + β), such that a
perfect reverse turn has a cleft angle of 180°.
Commercial solvents and reagents were used as received with the
following exceptions. Tetrahydrofuran was dried by distillation over
sodium and benzophenone. Dichloromethane was dried by passage
through alumina in a commercial solvent purification system (SPS).
Proton nuclear magnetic resonance spectra (1H NMR) were
recorded at 300 or 500 MHz at ambient temperature. Proton chemical
shifts are expressed in parts per million (ppm, δ scale) downfield from
tetramethylsilane and are referenced to residual protium in the NMR
solvent (CDCl3, δ 7.26; D2O, δ 4.79; DMSO-d6, δ 2.50; MeOD, δ
3.31; acetone-d6, δ 2.05). Carbon nuclear magnetic resonance spectra
(13C NMR) were recorded at 75 or 125 MHz at ambient temperature.
Carbon chemical shifts are reported in parts per million downfield
from tetramethylsilane and are referenced to the carbon resonances of
the solvent (CDCl3, δ 77.16; DMSO-d6, δ 39.52; MeOD, δ 49.00;
acetone-d6, δ 29.84). Infrared (IR) spectra were obtained using an FT-
IR spectrometer referenced to a polystyrene standard. Accurate masses
were obtained using an ion trap MS. Melting points were obtained
using a Mel-Temp II apparatus and are uncorrected.
Scheme 7. Access to Additional Scaffolds
General Procedure A. A flame-dried round-bottom flask fitted
with an oven-dried condensor was charged with sodium cyclo-
pentadienylide solution (2 M in THF, 1.0 equiv). To this solution was
added the desired electrophile in THF at room temperature with
stirring. The reaction mixture was heated to reflux for 6 h, cooled to
room temperature, and concentrated in vacuo. The resulting solid was
suspended in ether and collected by vacuum filtration. The collected
solid was washed with ether until the washings became colorless and
then dried in vacuo to give intermediate salt 6 as a tan-brown air-
sensitive solid. In a separate step, the partially purified salt 6 (1 equiv)
was added to a fresh round-bottom flask, where it was combined with
iPrOH (to 0.33 M) and sulfuric acid (0.55 equiv) at room temperature
with stirring. Acidification was marked by a brown to orange color
change. The solution was heated to 50 °C overnight. The reaction
mixture was concentrated in vacuo, and the resulting oil was dissolved
in toluene and loaded onto a silica gel column. Elution with hexanes−
ethyl acetate provided the desired Thiele’s ester.
As anticipated, standard hydrogenolysis conditions rapidly
transformed both ester functions to the corresponding
carboxylic acids while also reducing the remaining olefin.
Diacid 24 was thus accessed in high yield.
CONCLUSIONS
■
Building upon existing synthetic methods, we have identified an
improved protocol for the scalable synthesis of a variety of
Thiele’s esters, including novel structures like 4c and 4d that
incorporate synthetic handles for the attachment of additional
functionality. In addition, we have greatly expanded the
repertoire of fundamental reaction chemistry for Thiele’s
esters, focusing particularly on selective transformations that
permit one to discriminate between the two similarly
functionalized halves of the scaffold structure. Generally
speaking, we found the C5−C6 alkene to be amenable to a
variety of selective nucleophilic transformations, after which the
General Procedure B. A flame-dried round-bottom flask fitted
with an oven-dried condensor was charged with sodium cyclo-
pentadienylide solution (2 M in THF, 1.0 equiv). To this solution was
G
DOI: 10.1021/acs.joc.5b01332
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Featured Article
added the desired electrophile in THF at room temperature with
stirring. The reaction mixture was heated to reflux for 6 h and then
cooled to room temperature. The supernatant was transferred by
cannula to a fresh round-bottom flask and concentrated in vacuo. To
the resulting solid was added iPrOH (to 0.33 M) and sulfuric acid
(0.55 equiv) at room temperature with stirring. Acidification was
marked by a brown to orange color change. The solution was heated
to 50 °C overnight. The reaction mixture was concentrated in vacuo,
and the resulting oil was dissolved in toluene and loaded onto a silica
gel column. Elution with hexanes−ethyl acetate provided the desired
Thiele’s ester.
Compound 4a. Prepared according to general procedure A using
20 mL of sodium cyclopentadienylide (2 M in THF, 40 mmol), 16.8
mL of dimethyl carbonate (100 mmol, in 20 mL THF), and 1.17 mL
of H2SO4 (22 mmol, in 120 mL iPrOH). Chromatography (hexanes−
ethyl acetate, 20:1) afforded 3.18 g (65%) of 4a as a pale yellow solid
(mp = 189−191 °C): 1H NMR (300 MHz, CDCl3) δ 6.83 (d, J = 3.1
Hz, 1H), 6.49 (q, J = 2.2 Hz, 1H), 3.71 (s, 3H), 3.65 (s, 3H), 3.44−
3.52 (m, 1H), 3.32−3.37 (m, 1H), 3.10−3.14 (m, 1H), 2.91−3.01 (m,
1H), 2.47 (ddt, J = 17.9, 10.4, 2.0 Hz, 1H), 2.00 (ddt, J = 17.9, 4.0, 2.0
Hz, 1H), 1.67 (dt, J = 8.6, 1.7 Hz, 1H), 1.41 (dq, J = 8.8, 1.1 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 165.6, 165.4, 147.4, 142.8, 139.0, 138.1,
54.5, 51.6, 51.4, 51.0, 47.4, 46.8, 41.2, 33.1; IR (cm−1, film) 2950,
1718, 1633, 1597, 1272, 1093, 765; HRMS (ESI) calcd for [M + Na]+
C14H16O4Na 271.0941, found 271.0940.
Compound 4e. Prepared according to general procedure B from 5
mL of sodium cyclopentadienylide (2 M in THF, 10 mmol), 2.4 mL of
methyl acetate (30 mmol, in 5 mL of THF), and 293 μL of H2SO4
(5.5 mmol, in 10 mL of iPrOH). Chromatography (hexanes−ethyl
1
acetate, 1:1) afforded 545 mg (51%) of 4e as a brown oil: H NMR
(300 MHz, CDCl3) δ 6.73 (d, J = 3.3 Hz, 1H), 6.43 (q, J = 2.1 Hz,
1H), 3.52−3.60 (m, 1H), 3.42−3.48 (m, 1H), 3.17−3.22 (m, 1H),
2.86−2.93 (m, 1H), 2.39 (ddt, J = 18.0, 10.4, 2.0 Hz, 1H), 2.17 (s,
3H), 2.16 (s, 3H), 1.85 (dtd, J = 18.1, 3.9, 2.0 Hz, 1H), 1.64 (dt, J =
8.7, 1.9 Hz, 1H), 1.42 (dq, J = 8.6,0.9 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 196.6, 195.7, 148.3, 147.5, 147.1, 142.6, 55.0, 50.5, 47.9,
45.6, 40.6, 32.6, 27.0, 25.7; IR (cm−1, film) 2939, 1702, 1664, 1641,
1372, 1272, 950; HRMS (ESI) calcd for [M + Na]+ C14H16O2Na
239.1042, found 239.1040.
Compound 4f. Prepared according to general procedure B from 5
mL of sodium cyclopentadienylide (2 M in THF, 10 mmol), 3.8 mL of
methyl benzoate (30 mmol, in 5 mL of THF), and 293 μL of H2SO4
(5.5 mmol, in 15 mL of iPrOH). Chromatography (hexanes−ethyl
1
acetate, 5:1) afforded 584 mg (35%) of 4f as a yellow oil: H NMR
(300 MHz, CDCl3) δ 7.58−7.63 (m, 2H), 7.51−7.56 (m, 2H), 7.44−
7.50 (m, 2H), 7.30−7.37 (m, 4H), 6.62 (d, J = 3.3 Hz, 1H), 6.23 (q, J
= 2.2 Hz, 1H), 3.66−3.73 (m, 2H), 3.27−3.32 (m, 1H), 3.03−3.14 (m,
1H), 2.70 (ddt, J = 18.2, 10.3, 1.9 Hz, 1H), 2.38 (dtd, J = 18.0, 3.8, 2.0
Hz, 1H), 1.82 (dt, J = 8.7, 1.7 Hz, 1H), 1.54 (dd, J = 8.8,0.8 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 193.7, 193.3, 150.4, 146.8, 146.3, 144.7,
138.8, 138.7, 131.9, 131.8, 129.1, 128.7, 128.6, 128.3, 128.2, 125.4,
55.4, 50.6, 48.6, 47.0, 40.8, 33.9; IR (cm−1, film) 3060, 2938, 1687,
1636, 1578, 1446, 1353, 1277, 918; HRMS (ESI) calcd for [M + Na]+
C24H20O2Na 363.1355, found 363.1357.
Compound 7a. Isolated as a yellow solid from the preparation of 4a
described above (540 mg; 11% yield; mp = 73−77 °C): 1H NMR (300
MHz, CDCl3) δ 6.85 (dd, J = 3.2, 1.3 Hz, 1H), 5.56 (dt, J = 5.7, 2.4
Hz, 1H), 5.48 (dt, J = 5.7, 2.3 Hz, 1H), 3.71 (s, 3H), 3.70 (s, 3H),
3.30−3.35 (m, 2H), 3.21−3.28 (m, 1H), 2.40 (ddt, J = 18.3, 9.9, 2.2
Hz, 1H), 1.78 (dq, J = 18.3, 2.4 Hz, 1H), 1.65 (t, J = 1.5 Hz, 2H); 13C
NMR (75 MHz, CDCl3) δ 175.8, 165.7, 147.9, 139.7, 134.9, 130.0,
70.3, 52.3, 51.6, 51.3, 49.1, 46.9, 46.0, 34.6; IR (cm−1, film) 2954,
1733, 1717, 1653, 1559, 1436, 1272, 1089, 773; HRMS (ESI) calcd for
[M + Na]+ C14H16O4Na 271.0941, found 271.0941.
Compound 4b. Prepared according to general procedure B using
2.5 mL of sodium cyclopentadienylide (2 M in THF, 5 mmol), 1.83 g
of dibenzyl carbonate (7.5 mmol, in 5 mL THF), and 147 μL of
H2SO4 (2.75 mmol, in 15 mL of iPrOH). Chromatography (hexanes−
1
ethyl acetate, 5:1) afforded 540 mg (54%) of 4b as a yellow oil: H
NMR (300 MHz, CDCl3) δ 7.37−7.27 (m, 10H), 6.90 (d, J = 3.1 Hz,
1H), 6.55 (q, J = 2.1 Hz, 1H), 5.15 (s, 2H), 5.10 (q, J = 12.8, 6.0 Hz,
2H), 3.46−3.54 (m, 1H), 3.36−3.41 (m, 1H), 3.11−3.16 (m, 1H),
2.91−3.01 (m, 1H), 2.51 (ddt, J = 17.9, 10.4, 2.0 Hz, 1H), 2.10 (ddt, J
= 17.9, 3.9, 2.1 Hz, 1H), 1.69 (dt, J = 8.8, 1.7 Hz, 1H), 1.41 (dq, J =
8.5, 0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 165.0, 164.7, 148.0,
143.3, 138.9, 138.2, 136.5, 136.4, 128.6, 128.1, 128.0, 127.9, 66.1, 65.9,
54.5, 50.9, 47.5, 46.8, 41.2, 33.2; IR (cm−1, film) 2944, 1708, 1454,
1268, 1231, 1074, 749; HRMS (ESI) calcd for [M + H]+ C26H25O4
401.1748, found 401.1748.
Compound 8a. Isolated as a white solid from the preparation of 4a
1
Compound 4c. Prepared according to general procedure A from 2
mL of sodium cyclopentadienylide (2 M in THF, 4 mmol), 580 μL of
diallyl carbonate (4 mmol, in 2 mL THF), and 117 μL of H2SO4 (2.2
mmol, in 3 mL of iPrOH). Chromatography (hexanes−ethyl acetate,
described above (880 mg; 18% yield; mp = 98−102 °C): H NMR
(300 MHz, CDCl3) δ 6.58 (q, J = 2.2 Hz, 1H), 6.09 (dd, J = 5.7, 2.7
Hz, 1H), 6.05 (d, J = 5.6, 2.7 Hz, 1H), 3.77 (s, 3H), 3.68 (s, 3H),
3.60−3.67 (m, 1H), 2.96−3.05 (m, 2H), 2.45 (ddt, J = 17.6, 9.9, 2.1
Hz, 1H), 1.94 (dtd, J = 17.6, 3.6, 2.0 Hz, 1H), 1.77 (dd, J = 8.3, 1.8 Hz,
1H), 1.67 (d, J = 8.2 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 174.4,
165.4, 142.2, 138.5, 134.6, 133.6, 61.2, 59.0, 53.5, 52, 51.5, 46.9, 42.7,
33.8; IR (cm−1, film) 2955, 1734, 1718, 1653, 1559, 1275, 1096, 736;
HRMS (ESI) calcd for [M + Na]+ C14H16O4Na 271.0941, found
271.0941.
1
10:1) afforded 186 mg (31%) of 4c as a yellow oil: H NMR (300
MHz, CDCl3) δ 6.88 (d, J = 3.2 Hz, 1H), 6.54 (q, J = 2.2 Hz, 1H),
5.82−5.98 (m, 2H), 5.27 (dm, J = 17.3 Hz, 2H), 5.20 (dq, J = 10.4, 1.4
Hz, 2H), 4.63 (dq, J = 5.2, 1.5 Hz, 2H), 4.54−4.59 (m, 2H), 3.46−
3.54 (m, 1H), 3.36−3.40 (m, 1H), 3.11−3.17 (m, 1H), 2.91−3.02 (m,
1H), 2.50 (ddt, J = 17.9, 10.4, 2.0 Hz, 1H), 2.06 (dtd, J = 17.9, 4.1, 2.2
Hz, 1H), 1.69 (dt, J = 8.8, 1.8 Hz, 1H), 1.36 (dd, J = 8.8,1.0 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 164.8, 164.6, 147.8, 143.1, 139.0, 138.2,
132.6, 132.5, 117.9, 117.8, 65.0, 64.9, 54.5, 50.9, 47.5, 46.8, 41.2, 33.2;
IR (cm−1, film) 2939, 1717, 1701, 1268, 1231, 1087, 765; HRMS
(ESI) calcd for [M + Na]+ C18H20O4Na 323.1254, found 323.1254.
Compound 4d. Prepared according to general procedure A from 5
mL of sodium cyclopentadienylide (2 M in THF, 10 mmol), 890 mg
of ethylene carbonate (10 mmol, in 5 mL THF), and 293 μL of H2SO4
(5.5 mmol, in 7 mL iPrOH). Chromatography (hexanes−ethyl acetate,
Compound 3. To a solution of Thiele’s ester 4a (270 mg, 1.1
mmol) in iPrOH (4 mL) was added KOH (10% solution, 4 mL)
dropwise. After 5 h, iPrOH was removed in vacuo. The mixture was
acidified to pH = 1 by addition of HCl (2 M) and extracted twice with
ethyl acetate. The combined organic layers were dried over MgSO4
and concentrated in vacuo to afford Thiele’s acid 3 as a white powder
1
without further purification (184 mg, 76%; mp >200 °C): H NMR
(300 MHz, D2O) δ 6.60 (d, J = 3.1 Hz, 1H), 6.21 (q, J = 1.9 Hz, 1H),
3.39−3.48 (m, 1H), 3.13−3.20 (m, 1H), 3.04- 3.09 (m, 1H), 2.87−
2.97 (m, 1H), 2.36 (ddt, J = 17.3, 10.5, 1.9 Hz, 1H), 1.88 (ddt, J =
17.3, 4.0, 2.0 Hz, 1H), 1.58 (dt, J = 8.4, 1.7 Hz, 1H), 1.36 (d, J = 8.4
Hz, 1H); 13C NMR (75 MHz, D2O) δ 174.7, 174.3, 143.8, 142.8,
139.6, 53.8, 50.3, 47.0, 46.9, 40.9, 34.0; IR (cm−1, film) 2976, 2868,
1685, 1676, 1420, 1295, 1244, 949; HRMS (ESI) calcd for [M + Na]+
C12H12O4Na 243.0628, found 243.0629.
1
2:1) afforded 786 mg (51%) of 4d as a yellow oil: H NMR (300
MHz, CDCl3) δ 6.89 (d, J = 3.3 Hz, 1H), 6.54 (q, J = 2.1 Hz, 1H),
4.25−4.33 (m, 3H), 4.11 (ddd, J = 11.9, 4.8, 4.1 Hz, 1H), 3.77−3.84
(m, 4H), 3.49−3.56 (m, 1H), 3.37−3.41 (m, 1H), 3.15−3.20 (m, 1H),
2.91−3.01 (m, 1H), 2.61 (br, 2H), 2.48 (ddt, J = 17.9, 10.3, 2.0 Hz,
1H), 2.15 (dtd, J = 18.0, 3.9, 2.2 Hz, 1H), 1.68 (dt, J = 8.7, 1.8 Hz,
1H), 1.42 (dq, J = 8.5,0.9 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
165.7, 165.5, 148.5, 143.7, 138.3, 137.9, 66.2, 65.8, 61.6, 61.3, 54.3,
50.3, 47.5, 46.8, 41.0, 33.1; IR (cm−1, film) 3416, 2943, 1707, 1630,
1272, 1235, 1068, 766; HRMS (ESI) calcd for [M + Na]+
C16H20O6Na 331.1152, found 331.1148.
Compounds 9 and 10. To a solution of Thiele’s ester 4a (100 mg,
0.40 mmol) in MeCN (3 mL) were added benzylamine (129.6 mg,
1.21 mmol) and DBU (61.4 mg, 0.80 mmol). The mixture was heated
to 70 °C and stirred overnight. After being cooled to room
temperature, the reaction was quenched by the addition of saturated
H
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Featured Article
NH4Cl and extracted twice with ethyl acetate. The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
Chromatography (hexanes−ethyl acetate, 4:1) afforded 75 mg of 9
(53%) and 27 mg of 10 (19%). For compound 9 (brown solid; mp =
83−85 °C): 1H NMR (300 MHz, CDCl3) δ 7.27−7.32 (m, 4H) 7.20−
7.25 (m, 1H), 6.60 (q, J = 2.0 Hz, 1H), 3.74 (d, J = 12.8 Hz, 1H), 3.73
(s, 3H), 3.65 (d, J = 12.8 Hz, 1H), 3.62 (s, 3H), 3.25−3.30 (m, 1H),
3.24 (dd, J = 4.9, 1.7 Hz, 1H), 2.76 (t, J = 4.0 Hz, 1H), 2.70 (tt, J =
10.6, 4.0 Hz, 1H), 2.48−2.39 (m, 3H), 2.27 (ddt, J = 18.4, 3.1, 1.6 Hz,
1H), 1.86 (dt, J = 10.0, 1.4 Hz, 1H), 1.48 (dq, J = 10.0, 1.5 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 173.6, 165.3, 143.1, 140.7, 136.6, 128.4,
128.3, 127.0, 57.9, 54.6, 52.8, 52.1, 51.6, 51.5, 45.8, 44.3, 41.8, 40.5,
31.0; IR (cm−1, film) 3436, 2959, 1720, 1639, 1438, 1273, 1081;
HRMS (ESI) calcd for [M + H]+ C21H26NO4 356.1857, found
356.1860. For compound 10 (brown oil): 1H NMR (300 MHz,
CDCl3) δ 7.22−7.33 (m, 5H), 6.61 (q, J = 2.0 Hz, 1H), 3.76 (d, J =
12.3 Hz, 1H), 3.75 (s, 3H), 3.68 (s, 3H), 3.66 (d, J = 12.3 Hz, 1H),
3.22−3.28 (m, 1H), 2.98 (dd, J = 8.1, 1.2 Hz, 1H), 2.69 (dd, J = 8.1,
1.2 Hz, 1H), 2.63 (ddt, J = 9.9, 4.2, 2.7 Hz, 1H), 2.53 (ddt, J = 17.5,
9.9, 2.5 Hz, 1H), 2.48 (d, J = 5.7 Hz, 1H), 2.37−2.44 (m, 2H), 2.07
(dt, J = 10.7, 1.6 Hz, 1H), 1.44 (dt, J = 10.6, 1.5 Hz, 1H); 13C NMR
(75 MHz, CDCl3) δ 174.0, 165.4, 144.1, 140.7, 136.4, 128.4, 128.0,
127.0 60.6, 52.8, 52.5, 51.6, 51.5, 46.3, 44.2, 44.1, 41.6, 37.7, 31.4; IR
(cm−1, film) 3419, 2950, 1717, 1633, 1436, 1274, 1094; HRMS (ESI)
calcd for [M + H]+ C21H26NO4 356.1857, found 356.1853.
Compounds 13 and 14. To a solution of 12 (64 mg, 0.20 mmol)
in 3 mL of acetone were added 2,2-dimethoxypropane (0.4 mL) and p-
toluenesulfonic acid (32 mg, 0.16 mmol). The reaction was stirred at
room temperature overnight. Solvent was removed in vacuo, and the
residue was purified by chromatography (hexanes−ethyl acetate, 1:1)
to afford 13 (28 mg, 40%) and 14 (38 mg, 48%) as colorless oils. For
1
compound 13: H NMR (300 MHz, CDCl3) δ 5.05 (d, J = 1.9 Hz,
1H), 4.30 (t, J = 8.7 Hz, 1H), 3.80 (s, 3H), 3.78 (s, 3H), 3.49 (s, 1H),
2.68−2.82 (m, 1H), 2.43−2.55 (m, 3H), 2.17 (d, J = 10.3 Hz, 1H),
2.12 (d, J = 9.0 Hz, 1H), 1.71 (dd, J = 14.5, 9.3 Hz, 1H), 1.53 (dd, J =
14.5, 10.4 Hz, 1H), 1.48 (s, 3H), 1.32 (s, 3H); 13C NMR (75 MHz,
CDCl3) δ 174.0, 172.7, 110.4, 88.9, 85.8, 79.8, 74.1, 53.0, 52.6, 47.9,
47.0, 42.3, 40.7, 39.5, 32.3, 26.2, 25.8; IR (cm−1, film) 3445, 2992,
2955, 1737, 1654, 1437, 1258, 1070, 731; HRMS (ESI) calcd for [M +
H]+ C17H25O8 357.1544, found 357.1544. For compound 14: 1H
NMR (300 MHz, CDCl3) δ 5.09 (d, J = 5.0 Hz, 1H), 4.93 (d, J = 1.9
Hz, 1H), 3.79 (s, 3H), 3.73 (s, 3H), 2.93−3.05 (m, 1H), 2.70 (dt, J =
12.8, 5.1 Hz, 1H), 2.49−2.56 (m, 2H), 2.10−2.17 (m, 2H), 1.51 (s,
3H), 1.47−1.55 (m, 1H), 1.47 (s, 3H), 1.40 (d, J = 10.5 Hz, 1H)1.30
(s, 3H), 1.29 (s, 3H); 13C NMR (75 MHz, CDCl3) δ 172.8, 172.1,
113.1, 110.7, 96.5, 89.1, 82.1, 79.1, 52.6, 52.4, 51.7, 47.6, 44.5, 41.5,
40.1, 33.1, 29.2, 27.5, 26.4, 26.0; IR (cm−1, film) 2990, 2953, 1742,
1457, 1373, 1256, 1072, 1036, 749; HRMS (ESI) calcd for [M + Na]+
C20H28O8Na 419.1676, found 419.1674.
Direct Access to Compound 14 from 12. To a stirred solution of
12 (90 mg, 0.28 mmol) in 4 mL of dichloromethane were added 2,2-
dimethoxypropane (0.8 mL) and camphorsulfonic acid (160 mg, 0.68
mmol) at 0 °C. The reaction was allowed to warm to room
temperature with stirring. After 16 h, the reaction mixture was cooled
to 0 °C, and the reaction was quenched by the addition of aqueous
NaHCO3. The resulting mixture was extracted twice with dichloro-
methane, and the combined organic layers were dried over NaSO4 and
concentrated in vacuo. Chromatography (hexanes−ethyl acetate, 6:1)
afforded 14 (103 mg, 88%) as a colorless oil with spectral properties
identical to those reported above.
Isomerization of 9 to 10. To a solution of 9 (40 mg, 0.11 mmol) in
toluene (3 mL) was added DBU (31 μL, 0.22 mmol). The mixture was
heated to 110 °C and stirred for 2 d. After being cooled to room
temperature, the reaction was quenched by the addition of saturated
NH4Cl and extracted twice with ethyl acetate. The combined organic
layers were dried over MgSO4 and concentrated in vacuo.
Chromatography (hexanes−ethyl acetate, 4:1) afforded 10 as a
brown oil (21 mg, 52%). Spectral details were identical to those
provided above.
Compound 11. To a solution of 10 (50 mg, 0.14 mmol) in 3 mL of
acetone were added 4-methylmorpholine N-oxide (25.7 mg, 0.22
mmol) and OsO4 (4% in H2O, 45 μL, 0.007 mmol) at 0 °C. The
mixture was warmed to room temperature and stirred for 6 h. The
reaction was quenched by the addition of aqueous Na2S2O3, and
acetone was removed in vacuo. The resulting mixture was extracted
twice with ethyl acetate, and the combined organic layers were dried
over Na2SO4 and concentrated in vacuo. Chromatography (hexanes−
ethyl acetate, 1:1) afforded 11 as a yellow oil (28 mg, 52%): 1H NMR
(300 MHz, CDCl3) δ 7.13−7.29 (m, 5H), 4.07 (d, J = 8.6 Hz, 1H),
3.80 (d, J = 13.3 Hz, 1H), 3.77 (s, 3H), 3.69 (d, J = 13.3 Hz, 1H), 3.67
(s, 3H), 3.38 (dd, J = 8.3, 1.3 Hz, 1H), 2.94 (dd, J = 8.2, 1.4 Hz, 1H),
2.66 (ddd, J = 21.8, 9.4, 4.1 Hz, 1H), 2.28−2.40 (m, 3H), 2.22 (dt, J =
10.4, 1.8 Hz, 1H), 1.80 (dd, J = 14.1, 9.6 Hz, 1H), 1.70 (dd, J = 14.1,
9.6 Hz, 1H), 1.56 (d, J = 10.6 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
175.5, 173.6, 140.5, 128.4, 128.0, 127.0, 86.2, 74.9, 58.9, 53.2, 52.9,
51.5, 50.8, 46.6, 42.3, 42.0, 41.1 33.4; IR (cm−1, film) 3436, 2954,
1726, 1642, 1452, 1275, 1171, 1083, 748; HRMS (ESI) calcd for [M +
H]+ C21H28NO6 390.1911, found 390.1908.
Compound 15. To a stirring solution of 14 (44 mg, 0.11 mmol) in
1 mL of MeOH was added NaOH (10% solution, 1 mL) slowly. The
reaction was stirred overnight. MeOH was removed in vacuo, and the
mixture was acidified to pH = 1 by addition of aqueous HCl (2 M),
extracted twice with ethyl acetate, dried over MgSO4, and
concentrated in vacuo to afford 15 as a white solid (41 mg, 96%,
1
mp = 161−162 °C): H NMR (300 MHz, CDCl3) δ 5.07 (d, J = 4.9
Hz, 1H), 4.93 (d, J = 1.9 Hz, 1H), 3.75 (s, 3H), 2.93−3.06 (m, 1H),
2.71 (dt, J = 12.8, 5.0 Hz, 1H), 2.57 (d, J = 4.4 Hz, 1H), 2.51 (d, J =
4.4 Hz, 1H), 2.11−2.23 (m, 2H), 1.61 (dd, J = 16.2, 8.7 Hz, 1H), 1.53
(s, 3H), 1.47 (s, 3H), 1.42 (d, J = 11.9 Hz, 1H), 1.36 (s, 3H), 1.31 (s,
3H); 13C NMR (75 MHz, CDCl3) δ 175.4, 173.0, 113.6, 110.9, 96.3,
89.2, 82.3, 79.0, 52.8, 51.8, 47.6, 44.6, 41.6, 40.2, 33.2, 29.2, 27.7, 26.5,
26.1; IR (cm−1, film) 3056, 2978, 2941, 1716, 1639, 1598, 1578, 1447,
1353, 1277, 732; HRMS (ESI) calcd for [M + Na]+ C19H26O8Na
405.1520, found 405.1521.
Compound 16. To a stirred solution of trimethylsulfoxonium
iodide (273 mg, 1.24 mmol) and DBU (341 mg, 2.24 mmol) in
MeCN (5 mL) was added Thiele’s ester 4a (140 mg, 0.56 mmol) in 1
mL of MeCN. The reaction mixture was heated to 60 °C for 36 h and
then returned to room temperature. The resulting mixture was diluted
with ethyl acetate, filtered through filter paper, and dried over MgSO4.
The solvent was removed in vacuo, and the residue was purified by
chromatography (hexanes−ethyl acetate, 4:1) to afford 16 as a white
Compound 12. To a solution of Thiele’s ester 4a (400 mg, 1.61
mmol) in 20 mL of acetone were added 4-methylmorpholine N-oxide
(565 mg, 4.83 mmol) and OsO4 (4% in H2O, 1.02 mL, 0.16 mmol) at
0 °C. The reaction was quenched by the addition of aqueous Na2S2O3,
and acetone was removed in vacuo. The resulting mixture was
extracted twice with ethyl acetate, and the combined organic layers
were dried over Na2SO4 and concentrated in vacuo. Chromatography
(5% methanol in dichloromethane) afforded 12 as a yellow oil (382
1
solid (91 mg, 62%): H NMR (300 MHz, CDCl3) δ 6.63 (q, J = 2.0
Hz, 1H), 3.68 (s, 3H), 3.57 (s, 3H), 3.19−3.27 (m, 1H), 2.62−2.75
(m, 3H), 2.53−2.58 (m, 1H), 2.40 (ddt, J = 18.7, 10.5, 2.7 Hz, 1H),
1.35 (dd, J = 7.7, 4.0 Hz, 1H), 1.22 (dt, J = 11.0, 1.6 Hz, 1H), 1.12 (dd,
J = 5.1, 4.6 Hz, 1H), 0.89 (dd, J = 11.0, 1.2 Hz, 1H), 0.56 (dd, J = 7.7,
5.4 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ 175.4, 165.4, 142.7, 137.4,
53.8, 51.5, 51.4, 44.5, 40.4, 39.8, 31.1, 30.9, 25.2, 21.5, 13.6; IR (cm−1,
film) 2954, 1707, 1442, 1293, 1230, 1150, 1095, 951; HRMS (ESI)
calcd for [M + H]+ C15H19O4 263.1278, found 263.1276.
1
mg, 75%): H NMR (300 MHz, MeOD) δ 4.60 (d, J = 2.1 Hz, 1H),
4.25 (d, J = 8.7 Hz, 1H), 3.73 (s, 3H), 3.72 (s, 3H), 2.65−2.79 (m,
1H), 2.39−2.51 (m, 2H), 2.35 (dt, J = 10.3, 1.7 Hz, 1H), 2.16−2.21
(m, 1H), 1.43−1.63 (m, 3H); 13C NMR (75 MHz, MeOD) δ 175.3,
175.0, 87.2, 81.3, 75.6, 71.4, 52.7, 52.6, 51.0, 50.3, 46.2, 41.5, 41.3,
34.9; IR (cm−1, film) 3408, 2959, 1728, 1644, 1439, 1273, 1073, 728;
HRMS (ESI) calcd for [M + Na]+ C14H20O8Na 339.1050, found
339.1049.
Compound 17. To a stirring solution of 16 (41 mg, 0.16 mmol) in
1 mL of MeOH was added NaOH (10% solution, 1 mL) slowly. The
I
DOI: 10.1021/acs.joc.5b01332
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The Journal of Organic Chemistry
Featured Article
reaction was stirred overnight. MeOH was removed in vacuo, and the
mixture was acidified to pH = 1 by addition of aqueous HCl (2 M),
extracted twice with ethyl acetate, dried over MgSO4, and
concentrated in vacuo. Chromatography (hexanes−ethyl acetate,
2:1) afforded 17 as a white solid (38 mg, 97%, mp = 193−196 °C):
1H NMR (300 MHz, CDCl3) δ 6.79 (q, J = 1.9 Hz, 1H), 3.61 (s, 3H),
3.22−3.31 (m, 1H), 2.65−2.79 (m, 3H), 2.59−2.62 (m, 1H), 2.43
(ddt, J = 18.6, 10.2, 2.6 Hz, 1H), 1.38 (dd, J = 7.7, 4.3 Hz, 1H),1.25
(dt, J = 11.0, 1.7 Hz, 1H), 1.15 (t, J = 5.0, Hz, 1H), 0.93 (dd, J = 11.1,
1.0 Hz, 1H), 0.60 (dd, J = 7.8, 5.3 Hz, 1H); 13C NMR (75 MHz,
CDCl3) δ 175.5, 169.6, 145.5, 137.0, 54.0, 51.7, 44.6, 40.4, 39.9, 31.1,
30.6, 25.3, 21.6, 13.6; IR (cm−1, film) 2935, 1710, 1673, 1423, 1295,
1129, 1116, 749; HRMS (ESI) calcd for [M + H]+ C14H17O4
249.1122, found 249.1121.
Compound 18. To a solution of 16 (40 mg, 0.15 mmol) in THF (6
mL) was added MeMgBr (3.0 M in THF, 0.1 mL, 0.3 mmol)
dropwise. The reaction was stirred overnight. The mixture was
quenched by the addition of saturated NH4Cl and extracted with
ether. The aqueous layer was washed with brine, dried over MgSO4,
and concentrated in vacuo. Chromatography (hexanes−ethyl acetate,
4:1) afforded 18 as a colorless oil (34 mg, 70%): 1H NMR (300 MHz,
CDCl3) δ 5.43 (q, J = 1.9 Hz, 1H), 3.67 (s, 3H), 3.07−3.16 (m, 1H),
2.58−2.70 (m, 2H), 2.38−2.48 (m, 2H), 2.30 (ddt, J = 18.2, 10.1, 2.7
Hz, 1H), 1.81 (br, 1H), 1.43 (dd, J = 7.9, 4.6 Hz, 1H), 1.36 (s, 3H),
1.18−1.26 (m, 4H), 1.16 (t, J = 4.7 Hz, 1H), 0.91 (dd, J = 10.7, 1.0 Hz,
1H), 0.55 (dd, J = 7.6, 5.3 Hz, 1H); 13C NMR (75 MHz, CDCl3) δ
177.0, 152.8, 123.0, 70.0, 53.2, 51.9, 44.4, 40.4, 39.5, 31.4, 30.3, 29.6,
28.3, 25.6, 21.4, 14.2; IR (cm−1, film) 3429, 2974, 1701, 1647, 1439,
1292, 1157, 750; HRMS (ESI) calcd for [M + Na]+ C16H22O3Na
285.1461, found 285.1456.
0.6 mL, 0.6 mmol) and CH2I2 (48 μL, 0.6 mmol) was added, and the
reaction was heated to 40 °C overnight. The following day, the
reaction was cooled to room temperature and quenched by the
addition of saturated NH4Cl. The resulting mixture was extracted
twice with dichloromethane, washed with brine, dried over NaSO4,
and concentrated in vacuo to afford 21 as a colorless oil with no
1
further purification (63 mg, 97%). H NMR (300 MHz, CDCl3) δ
4.34 (d, J = 11.4 Hz, 1H), 3.68 (d, J = 4.0 Hz, 1H), 3.65 (d, J = 4.0 Hz,
1H), 3.48 (d, J = 11.3 Hz, 1H), 2.26−2.44 (m, 5H), 1.72 (dd, J = 14.1,
9.6 Hz, 1H), 1.36 (d, J = 7.4 Hz, 1H), 1.20−1.27 (m, 2H), 0.84 (dd, J
= 5.0, 2.5 Hz, 1H), 0.73 (d, J = 10.5 Hz, 1H), 0.66 (ddd, J = 8.6, 4.2,
1.2 Hz, 1H), 0.05 (dd, J = 7.2, 2.8 Hz, 1H), −0.02 (dd, J = 7.2, 5.3 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 68.0, 66.4, 52.5, 50.6, 41.7, 40.8,
37.1, 33.6, 30.6, 26.4, 24.1, 20.1, 16.2, 8.0; IR (cm−1, film) 3324, 2933,
1456, 1261, 1024, 913; HRMS (ESI) calcd for [M − H]− C14H19O2
219.1390, found 219.1383.
Compound 22. To a solution of 21 (30 mg, 0.14 mmol) in a
mixture of CCl4 (0.5 mL), MeCN (0.5 mL), and water (0.75 mL)
were added NaIO4 (584 mg, 2.74 mmol) and RuCl3·XH2O (5.7 mg).
The reaction mixture was stirred overnight and then was partitioned
between aqueous HCl (10%) and ethyl acetate. The aqueous layer was
extracted with ethyl acetate twice, and the combined organic layers
were dried over Na2SO4 and concentrated in vacuo. Chromatography
(dichloromethane−methanol, 20:1) afforded 22 as a white solid (33
1
mg, 99%): H NMR (300 MHz, D2O) δ 2.50−2.55 (m, 1H), 2.32−
2.48 (m, 4H), 1.80 (dd, J = 9.1, 5.1 Hz, 1H), 1.65−1.75 (m, 2H), 1.26
(d, J = 10.4 Hz, 1H), 1.19 (dd, J = 9.1, 3.0 Hz, 1H), 1.14 (t, J = 4.4 Hz,
1H), 0.83 (d, J = 11.0 Hz, 1H), 0.44 (dd, J = 7.7, 5.0 Hz, 1H), 0.37
(dd, J = 5.0, 3.8 Hz, 1H); 13C NMR (75 MHz, D2O) δ 185.7, 184.9,
51.3, 48.2, 41.1, 41.0, 39.7, 32.2, 29.2, 28.0, 27.6, 24.0, 17.9, 12.8; IR
(cm−1, film) 3351, 1685, 1540, 1423, 830; HRMS (ESI) calcd for [M +
Na]+ C14H16O4Na 271.0941, found 271.0940.
Compounds 19 and 20. To a solution of 16 (162 mg, 0.62 mmol)
in ether (10 mL) was added LiAlH4 (58.7 mg, 2.48 mmol) at 0 °C.
After addition, the reaction was warmed to room temperature and
stirred overnight. The next day, the reaction was quenched by the
addition of water, and extracted with ethyl acetate. The organic layer
was dried over MgSO4 and concentrated in vacuo. Chromatography
(hexanes−ethyl acetate, 1:1 to 1:3) afforded 19 (72 mg, 50%) and 20
(49 mg, 39%). For 19 (colorless oil): 1H NMR (300 MHz, CDCl3) δ
5.48−5.52 (m, 1H), 4.16 (dd, J = 12.7, 3.6 Hz, 1H), 3.90- 3.99 (m,
1H), 3.67 (s, 3H), 3.07−3.17 (m, 1H), 2.60−2.70 (m, 2H), 2.42−2.47
(m, 1H), 2.38 (d, J = 18.5 Hz, 1H), 2.20 (dd, J = 18.1, 9.7 Hz, 1H),
1.66 (dd, J = 8.2, 4.0 Hz, 1H), 1.43 (dd, J = 8.0, 4.6 Hz, 1H), 1.22 (dt,
J = 11.0, 1.7 Hz, 1H), 1.14 (t, J = 5.1 Hz, 1H), 0.91 (dd, J = 11.0, 1.2
Hz, 1H), 0.53 (dd, J = 7.9, 5.2 Hz,1H); 13C NMR (75 MHz, CDCl3) δ
177.0, 145.7, 126.7, 62.2, 53.0, 51.9, 44.8, 40.4, 39.3, 31.7, 31.3, 25.5,
21.4, 14.0; IR (cm−1, film) 3427, 2950, 1705, 1438, 1294, 1164, 1017,
923, 751; HRMS (ESI) calcd for [M + Na]+ C14H18O3Na 257.1148,
found 257.1148. For 20 (pale yellow crystalline solid, mp =105−110
Compound 23. To a stirred solution of trimethylsulfoxonium
iodide (99 mg, 0.45 mmol) and DBU (69 mg, 0.45 mmol) in MeCN
(5 mL) was added 4b (90 mg, 0.225 mmol) in MeCN (1 mL). The
reaction was heated to 60 °C for 36 h. The resulting mixture was
diluted with ethyl acetate, filtered through filter paper, dried over
MgSO4, and concentrated in vacuo. The residue was purified by
chromatography (hexanes−ethyl acetate, 2:1) to afford 23 as a yellow
1
oil (67 mg, 72%): H NMR (300 MHz, CDCl3) δ 7.13−7.29 (m,
10H), 6.67 (q, J = 2.2 Hz, 1H), 5.10 (d, J = 12.7 Hz, 1H), 4.95 (d, J =
12.7 Hz, 1H), 4.89 (d, J = 12.6 Hz, 1H), 4.78 (d, J = 12.6 Hz, 1H),
3.13−3.23 (m, 1H), 2.69−2.80 (m, 2H), 2.58−2.68 (m, 1H), 2.48-
2.53 (m, 1H), 2.39 (ddt, J = 18.2, 10.3, 2.7 Hz, 1H), 1.36 (dd, J = 7.6,
4.2 Hz, 1H), 1.17 (dt, J = 10.7, 1.7 Hz, 1H), 1.08 (dd, J = 5.4, 4.5 Hz,
1H), 0.84 (dd, J = 10.9, 1.0 Hz, 1H), 0.54 (dd, J = 7.7, 5.3 Hz, 1H);
13C NMR (75 MHz, CDCl3) δ 164.8 (2C), 143.3, 137.5, 136.4, 136.2,
128.6, 128.5, 128.1, 128.0, 66.3, 65.9, 53.9, 44.5, 40.4, 39.9, 31.2, 31.0,
25.5, 21.7, 13.8; IR (cm−1, film) 2955, 1714, 1630, 1455, 1280, 1230,
1135, 746; HRMS (ESI) calcd for [M + Na]+ C27H26O4Na 437.1723
found 437.1723.
1
°C): H NMR (300 MHz, CDCl3) δ 5.57 (s, 1H), 4.14 (s, 2H), 4.07
(dd, J = 11.6, 1.0 Hz, 1H), 3.22 (d, J = 11.6 Hz, 1H), 3.07−3.16 (m,
1H), 2.54−2.69 (m, 2H), 2.27−2.44 (m, 3H), 1.83 (br, 2H) 1.19 (dt, J
= 10.7, 1.8 Hz, 1H), 0.77−0.85 (m, 3H), −0.12 (dd, J = 6.9, 5.0 Hz,
1H); 13C NMR (75 MHz, CDCl3) δ 144.8, 127.1, 66.6, 62.1, 52.9,
45.6, 40.5, 39.1, 33.5, 32.1, 25.3, 17.7, 9.3; IR (cm−1, film) 3407, 1645,
1260, 1016; HRMS (ESI) calcd for [M-H]− C13H17O2: 205.1234,
found 205.1235.
Compound 24. To a solution of 23 (68 mg, 0.17 mmol) in 10 mL
of MeOH was added Pd/C 10% (∼30 mg). The reaction mixture was
pressurized inside a Parr reactor to 200 psi of H2 and was stirred for 16
h. The product mixture was filtered through cotton and then
concentrated in vacuo. The residue was purified by chromatography
(hexanes−ethyl acetate, 2:1) to afford 24 as a white solid (30 mg, 75%,
Direct Access to Compound 20 from 16. To a solution of 16 (96
mg, 0.36 mmol) in ether (5 mL) was added LiAlH4 (140 mg, 3.66
mmol) at 0 °C. After addition, the reaction was warmed to room
temperature and stirred overnight. The next day, the reaction was
quenched by the addition of water, and extracted with ethyl acetate.
The organic layer was dried over MgSO4 and concentrated in vacuo.
Chromatography (hexanes−ethyl acetate, 1:1 to 1:3) afforded 20 (75
mg, 99%) as a pale yellow crystalline solid, with spectral properties
identical to those reported above.
Compound 21. To a solution of 20 (61 mg, 0.28 mmol) in
dichloromethane (3 mL) was added Et2Zn (1 M in hexane, 0.6 mL, 0.6
mmol) at 0 °C. After 15 min, CH2I2 (48 μL, 0.6 mmol) was injected
into the mixture. The reaction was then heated to 40 °C for 18 h and
then returned to room temperature. Additional Et2Zn (1 M in hexane,
1
mp >200 °C): H NMR (300 MHz, D2O) δ 2.56−2.67 (m, 1H),
2.44−2.49 (m, 1H), 2.37−2.44 (m, 2H), 2.19−2.24 (m, 1H), 1.54−
1.82 (m, 4H), 1.39 (d, J = 10.7 Hz, 1H), 1.23−1.34 (m, 1H), 1.19 (t, J
= 4.6 Hz, 1H), 1.04 (d, J = 11.1 Hz, 1H), 0.52 (dd, J = 7.7, 4.9 Hz,
1H); 13C NMR (75 MHz, D2O) δ 185.7, 185.0, 52.8, 47.3, 46.2, 39.4,
38.8, 34.2, 31.7, 28.7, 28.7, 18.7, 12.7; IR (cm−1, film) 3421, 2926,
1701, 1560, 1438, 1295; HRMS (ESI) calcd for [M + Na]+
C13H16O4Na 259.0941, found 259.0941.
J
DOI: 10.1021/acs.joc.5b01332
J. Org. Chem. XXXX, XXX, XXX−XXX

The Journal of Organic Chemistry
Featured Article
(16) (a) Feigel, M. J. Am. Chem. Soc. 1986, 108, 181−182.
(b) Winningham, M. J.; Sogah, D. Y. J. Am. Chem. Soc. 1994, 116,
11173−11174.
(17) Díaz, H.; Espina, J. R.; Kelly, J. W. J. Am. Chem. Soc. 1992, 114,
8316−8318.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/acs.joc.5b01332.
1H NMR and 13C NMR spectra for all new compounds,
2D NMR data for 7a and 8a, computational results and
crystallographic data(PDF)
X-ray data for compound 7a (CIF)
X-ray data for compound 14 (CIF)
(18) Brant, M. G.; Wulff, J. E. Org. Lett. 2012, 14, 5876−5879.
(19) Marchand, A. P.; Namboothiri, I. N. N.; Lewis, S. B.; Watson,
W. H.; Krawiec, M. Tetrahedron 1998, 54, 12691−12698.
(20) Watson, W. H.; Marchand, A. P.; Sivappa, R. ARKIVOC 2004,
66−73.
(21) Minter, D. E.; Smith, W. B.; Marchand, A. P.; Etukala, J. R.;
Sivappa, R. J. Phys. Org. Chem. 2004, 17, 174−179.
X-ray data for compound 17 (CIF)
(22) Gansauer, A.; Fleckhaus, A.; Lafont, M. A.; Okkel, A.; Kotsis, K.;
̈
Anoop, A.; Neese, F. J. Am. Chem. Soc. 2009, 131, 16989−16999.
(23) Murphy, E. B.; Bolanos, E.; Schaffner-Hamann, C.; Wudl, F.;
Nutt, S. R.; Auad, M. L. Polym. Reprints 2008, 49, 976−977.
(24) For a detailed analysis of the NMR spectra associated with the
diester derivative, see: Minter, D. E.; Marchand, A. P.; Lu, S.-P. Magn.
Reson. Chem. 1990, 28, 623−627.
AUTHOR INFORMATION
■
Corresponding Author
*E-mail: wulff@uvic.ca.
Notes
(25) Peters, D. J. Chem. Soc. 1961, 1042−1048.
The authors declare no competing financial interest.
(26) Scapens, D.; Adams, H.; Johnson, T. R.; Mann, B. E.; Sawle, P.;
Aqil, R.; Perrior, T.; Motterlini, R. Dalton Trans. 2007, 4962−4973.
(27) Dive, G.; Robiette, R.; Chenel, A.; Ndong, M.; Meier, C.;
Desouter-Lecomte, M. Theor. Chem. Acc. 2012, 131, 1236.
(28) Marchand, A. P.; Zhao, D.; Ngooi, T.-K.; Vidyasagar, V.;
Watson, W. H.; Kashyap, R. P. Tetrahedron 1993, 49, 2613−2620.
(29) Deslongchamps, P.; Cheriyan, U. O.; Lambert, Y.; Mercier, J.-
C.; Ruest, L.; Russo, R.; Soucy, P. Can. J. Chem. 1978, 56, 1687−1704.
(30) Paquette, L. A.; Kearney, F. R.; Drake, A. F.; Mason, S. F. J. Am.
Chem. Soc. 1981, 103, 5064−5069.
ACKNOWLEDGMENTS
■
We are grateful to the Cancer Research Society of Canada for
operating funds (17396) and the Michael Smith Foundation for
Health Research (CI-SCH-03064) and the Canada Research
Chairs program (950-226685) for salary support to J.W. and
incentive funds used to support this research. We also thank the
Office of the Vice President of Research at the University of
Notre Dame for financial support for the purchase of the
copper microfocus source used in this research as well as Dr.
Ori Granot and the UVic Genome BC Proteomics Centre for
mass spectrometry support.
(31) Peters, D. J. Chem. Soc. 1959, 1761−1765.
(32) NMR calculations were performed with Spartan ’14 using EDF2
functionals with a 6-31G* basis set.
(33) Alberto also reported the formation of a ketone under similar
conditions, although the connectivity of the isolated product was not
established; see: Liu, Y.; Spingler, B.; Schmutz, P.; Alberto, R. J. Am.
Chem. Soc. 2008, 130, 1554−1555.
(34) A small amount of aqueous KOH was used to bring 3 into D2O
for NMR analysis.
(35) Similar regioselectivity was observed during the unwanted
additions of methanol during esterification and saponification of 3 and
4. See refs 20 and 21.
(36) Peters also reported a conjugate addition of dimethylamine to
4a; however the stereochemical outcome was not established. See ref
25.
(37) Namboothiri, I. N. N.; Rastogi, N.; Ganguly, B.; Mobin, S. M.;
Cojocaru, M. Tetrahedron 2004, 60, 1453−1462.
(38) N’Dongo, H. W. P.; Liu, Y.; Can, D.; Schmutz, P.; Spingler, B.;
Alberto, R. J. Organomet. Chem. 2009, 694, 981−987.
(39) de Meijere, A. Angew. Chem., Int. Ed. Engl. 1979, 18, 809−886.
(40) Structural calculations were performed with Spartan ’14 using
B3LYP functionals with a 6-31G* basis set.
(41) The presence or absence of the methyl group appears to make
no significant difference to the cleft angle: the DFT-optimized
structure of 4a had a cleft angle identical to that of structure A (123°).
Similarly, the DFT-optimized structure of 14 had a cleft angle (189°)
identical to that determined for structure D, although the individual
angles α and β varied slightly in this case.
REFERENCES
■
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DOI: 10.1021/acs.joc.5b01332
J. Org. Chem. XXXX, XXX, XXX−XXX