Stereospecific cross-coupling reactions of aryl-substituted tetrahydrofurans, tetrahydropyrans, and lactones

Article abstract of DOI:10.1021/ja5076426

The stereospecific ring-opening of O-heterocycles to provide acyclic alcohols and carboxylic acids with controlled formation of a new C-C bond is reported. These reactions provide new methods for synthesis of acyclic polyketide analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic template is utilized to control relative configuration; subsequent stereospecific nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type coupling with a range of Grignard reagents to furnish acyclic alcohols with high diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an antidyslipidemia agent is demonstrated. (Chemical Equation Presented)

Full text of DOI:10.1021/ja5076426

Article
pubs.acs.org/JACS
Stereospecific Cross-Coupling Reactions of Aryl-Substituted
Tetrahydrofurans, Tetrahydropyrans, and Lactones
Emily J. Tollefson, David D. Dawson, Charlotte A. Osborne, and Elizabeth R. Jarvo*
Department of Chemistry, University of California, Irvine, California 92697-2025, United States
*
S Supporting Information
ABSTRACT: The stereospecific ring-opening of O-heterocycles to provide acyclic
alcohols and carboxylic acids with controlled formation of a new C−C bond is
reported. These reactions provide new methods for synthesis of acyclic polyketide
analogs with complex stereochemical arrays. Stereoselective synthesis of the cyclic
template is utilized to control relative configuration; subsequent stereospecific
nickel-catalyzed ring-opening affords the acyclic product. Aryl-substituted
tetrahydrofurans and tetrahydropyrans undergo nickel-catalyzed Kumada-type
coupling with a range of Grignard reagents to furnish acyclic alcohols with high
diastereoselectivity. Enantioenriched lactones undergo Negishi-type cross-coupling
with dimethylzinc to afford enantioenriched carboxylic acids. Application in a two-step enantioselective synthesis of an anti-
dyslipidemia agent is demonstrated.
INTRODUCTION
Scheme 1. Stereoselective Ring-Opening and C−C Bond
Formation Strategy
■
The discovery and asymmetric synthesis of novel polyketides
and their unnatural analogs fuel the development of new
therapeutic agents. The structural complexity of this class of
molecules has inspired and tested synthetic organic chem-
1
−3
istry.
One challenge is control of relative configuration
during construction of acyclic fragments. Woodward pioneered
the use of cyclic stereocontrol followed by ring-opening to
4
reveal a single diastereomer of an acyclic target. For example,
in the first synthesis of erythromycin A, a dithiadecalin template
was employed to control relative stereochemistry of ensuing
reactions; subsequent ring-opening provided a highly sub-
stituted acyclic polyketide. This general strategy has been5
applied successfully to the synthesis of many natural products.
Ring-opening reactions of tetrahydrofurans and tetrahydro-
6
pyrans have been developed; however, there are few examples
7
,8
3
3
sp
that occur with formation of a new C −C bond. Panek
sp
and co-workers have achieved diastereoselective ring-opening
reactions of tetrahydropyrans with cyanide in the presence of a
Lewis acid (Scheme 1a). The stereochemical course is
7a
1
,3
12,13
consistent with a stereoablative reaction; minimization of A
coupling of ethers (Scheme 1c).
We anticipated that
strain in a carbocation intermediate and attack of cyanide on
the least hindered face provides the major diastereomer.
A complementary approach to control of relative stereo-
chemistry is via a stereospecific reaction, where stereochemical
information is conserved throughout the transformation.
Hoveyda and co-workers demonstrated that unsaturated cyclic
ethers activated by pendant alcohols undergo stereospecific
cross-coupling would proceed with inversion at the electro-
philic carbon. Therefore, by appropriate choice of diastereomer
of starting material 5, either the syn or anti diastereomer of 6
could be obtained selectively. This work would harness
diastereoselective synthesis of tetrahydrofurans and tetrahy-
dropyrans to provide complex acyclic fragments. The products
would contain a free alcohol that could be further utilized in
synthetic sequences. This method would provide stereospecific
incorporation of a benzylic methyl substituent, a common motif
S 2′ reactions with Grignard reagents to yield enantioenriched
N
9
acyclic products (Scheme 1b). We sought to expand
14
in medicinal agents. In addition, strategic use of extended
stereospecific ring-opening reactions to include saturated cyclic
1
0,11
ethers that are not activated by ring strain.
We envisioned
stereospecific nickel-catalyzed ring-opening reactions of cyclic
ethers, based on our enantiospecific Kumada-type cross-
Received: July 31, 2014
©
XXXX American Chemical Society
A
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alkyl or aryl Grignard reagents would allow for the generation
of a wide range of unnatural polyketide analogs for biological
testing. In this manuscript, we report the stereospecific
Kumada-type cross-coupling of tetrahydrofurans and tetrahy-
dropyrans with a range of Grignard reagents. We also report
stereospecific Negishi-type cross-coupling reactions of benzylic
lactones with dimethyl zinc to provide enantioenriched
carboxylic acids.
Scheme 3. Diastereoselective Cross-Coupling Reactions
RESULTS AND DISCUSSION
■
Determination of Reaction Stereospecificity. To
establish nickel-catalyzed ring-opening of cyclic ethers and
determine the stereospecificity of the reaction, we designed
model substrate (R)-7 based on our prior experience
developing Kumada-type cross-coupling reactions of benzylic
ethers. We chose to first examine coupling with methyl
Grignard reagent, as incorporation of “magic” methyl groups is
an established strategy to increase potency of certain
14
pharmaceutical agents. Naphthyl-substituted tetrahydropyran
Table 1. Absence of Match/Mismatch Effect
(
R)-7 is straightforward to prepare in high enantiomeric excess
15
(ee) utilizing the Corey−Bakshi−Shibata (CBS) reduction.
We were pleased to see that in the presence of a nickel catalyst
and Grignard reagent, (R)-7 provided acyclic alcohol (S)-8 with
cross-coupling at the benzylic center (Scheme 2). The reaction
Scheme 2. Enantiospecific Nickel-Catalyzed THP Opening
was highly enantiospecific, providing the product in 96% ee and
1
6,17
>99% enantiospecificity (es).
No reaction occurs in the
presence of Grignard reagent in the absence of nickel catalyst.
We envisioned that the most powerful application of this
method would be in ring-opening reactions of heterocycles
containing multiple stereogenic centers. To test our hypothesis
that the nickel-catalyzed ring opening would occur with
inversion at the electrophilic carbon, irrespective of the
presence of other stereogenic centers, we examined both
diastereomers of substituted tetrahydrofuran 9. In the presence
a
b
1
Isolated yield after column chromatography. Determined by H
NMR.
reaction, then one enantiomer of BINAP should provide
diminished or inverted diastereoselectivity. In reactions of
tetrahydrofuran cis-11 both enantiomers of BINAP afforded
acyclic syn-12 in similar yield and 20:1 dr (entries 1 and 2).
Either enantiomer of ligand provided the same diastereomer of
product. Similarly, use of either enantiomer of BINAP in
reactions of trans-11 provided anti-12 in good yield and 20:1 dr
(entries 3 and 4). Therefore, we conclude that there is no
match/mismatch between the chirality of the catalyst and
substrate. All reactions proceed strictly with inversion without
influence by the chirality of the catalyst. These results are
consistent with our previous observations of robust substrate
control in stereospecific Kumada and Negishi coupling
reactions.
of Ni(cod) and DPEphos each diastereomer underwent cross-
2
coupling with clean inversion at the site of oxidative addition
1
8
(
Scheme 3). Tetrahydrofuran trans-9 (dr >20:1) afforded
acyclic anti-10 in 93% and a dr of >20:1. The other
diastereomer, cis-9 (dr >20:1), afforded syn-10 in 93% yield
and >20:1 dr. The relative configuration of tetrahydrofuran cis-
9
was determined by X-ray crystallographic analysis. The
relative configuration of both diastereomers of acyclic 10 was
assigned based on analysis of chemical shifts in the H NMR
1
spectra, based on the pioneering strategy of Kishi for
assignment of relative configuration of acyclic polyketide
19
fragments using the Breit model for 1,3-deoxypropionates.
To determine whether or not there is a match/mismatch
effect in reactions employing chiral catalysts, we examined ring-
opening of both diastereomers of tetrahydrofuran 11 with each
enantiomer of BINAP (Table 1). If the reaction proceeds
strictly with inversion, regardless of the catalyst chirality, then
both enantiomers of BINAP would provide similar results in
the ring-opening reactions. However, if the chiral catalyst
influences the stereochemical outcome of the cross-coupling
Scope of the Reaction: Tetrahydrofurans. We next
examined the application of the methodology to a series of
substituted tetrahydrofurans with a broad array of substituent
patterns and stereochemical relationships found in polyke-
20
tides. Our starting materials were 2-aryltetrahydrofurans, a
motif at the core of natural products such as the lignans
21
sesaminone and pinoresinol. As such, there are outstanding
methods for diastereoselective synthesis of highly substituted 2-
B
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2
2
aryltetrahydrofurans. Furthermore, development of methods
for their direct derivatization could have application in natural
Table 2. Scope of Cross-Coupling Reaction of THFs
2
3
product editing. We prepared substrates using the general
strategy outlined in Scheme 4, employing Lewis-acid catalyzed
Scheme 4. Synthesis of Substituted THFs
24
cyclization of the requisite diols (see SI for full details). This
synthesis typically provides access to both diastereomers,
important for interrogation of the influence of additional
stereogenic centers on the stereochemical course of the cross-
coupling reactions. The relative configuration of starting
materials and products could be assigned using well established
methods typically employed for polyketides, including NOE
1
experiments, analysis of H NMR spectra, and X-ray
2
5
crystallography.
We continued our studies with 2,4-disubstituted tetrahy-
drofurans, as ring-opening provides the 1,3-dimethyldeoxypro-
pionate fragment (e.g., 9 to 10, Scheme 3). To determine the
stereochemical course of the reaction, we examined reactions of
both diastereomers of tetrahydrofuran 11 (Table 2, entries 1
2
6
and 2). Under Kumada-type coupling conditions, tetrahy-
drofuran trans-11 (dr >20:1) afforded acyclic anti-12 in 82%
27
and >20:1 dr (entry 1). The diastereomer, cis-11, (dr 9:1)
gave syn-12 in 86% and 9:1 dr (entry 2). Rigorous assignment
of the relative configuration of the starting materials and
products demonstrates that the Kumada-type couplings
proceeded with inversion.
We next examined introduction of a substituent at the 5-
position, to determine whether the method would be amenable
to synthesis of secondary alcohols. Both diastereomers of 2,5-
disubstituted tetrahydrofuran 13 were synthesized by the
Stetter reaction, reduction of the ketones and diol cyclization.
Tetrahydrofuran cis-13 (dr 9:1) underwent cross-coupling in
a
b
1
Isolated yield after column chromatography. Determined by H
2
8
c
NMR. Reaction performed using DPEphos (10 mol %) instead of rac-
BINAP. Nap = 2-naphthyl.
8
2% yield with inversion to yield syn-14 (dr 9:1, entry 3). The
diastereomer trans-13 (dr 8:1), afforded anti-14 with high
stereospecificity and in a slightly lower yield of 61% (entry 4).
This lower yield is presumably due to steric interactions with
the pseudo axial C5 methyl that would be present in the trans
diastereomer but not in the cis diastereomer.
Vicinal methyl-bearing stereogenic centers are motifs in
natural products such as kalkitoxin and nordihydroguaiaretic
acid. We envisioned accessing this motif from 2,3-
disubstituted tetrahydrofurans. Starting materials trans-15 and
trans-17 were prepared in 9:1 dr using the Nozaki−Hiyama−
Kishi reaction as a key step. Using DPEphos as the ligand,
trans-15 afforded syn-16 in 65% yield and 9:1 dr (entry 5). We
also found that heteroaromatic substituents are well tolerated.
In addition to benzofuran-substituted tetrahydrofuran 9,
benzothiophene-substituted trans-17 (dr 9:1) afforded syn-18
in good yield and 9:1 dr (entry 6). While coupling reactions of
both 15 and 17 proceed with inversion, more modest yields are
likely an impact of steric crowding near the site of oxidative
addition.
drofurans trans-19 and cis-19 underwent the reaction to afford
good yields and excellent transfer of stereochemical information
(entries 7 and 8). We attribute slightly diminished yields with
both diastereomers of 19 to formation of an allylic ether via β-
hydride elimination, which further reacted to a mixture of
32
products under the reaction conditions.
Scope of Reaction: Tetrahydropyrans. To further
expand the scope and utility of this method to include
synthesis of 5-substituted alcohols, we next turned our
attention to tetrahydropyrans. We chose to examine cis-
(±)-2,4-disubstituted tetrahydropyrans, subunits of the calyxin
2
9
30
33
family of natural products. Such cross-coupling reactions
would provide synthetic access to syn-3,5-disubstituted alcohols.
There are several elegant methods for the diastereoselective
34
synthesis of highly substituted tetrahydropyrans. For example,
these tetrahydropyrans are easily accessed by diastereoselective
35
Prins cyclization reactions, as outlined in Scheme 5a. Clay-
mediated Prins cyclization of 2-napthaldehyde with 4-buten-1-
ol in benzene provided cis-(±)-21 in a single step with high
36
We examined 4-methoxytetrahydrofurans for synthesis of a
diastereoselectivity and reasonable yield.
1
,3-disubstituted ether unit as found in FK-506 and
We developed an alternative two-step diastereoselective
strategy to prepare tetrahydropyrans containing a broad range
3
1
geldanamycin. We found that methoxy-substituted tetrahy-
C
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Scheme 5. Diastereoselective Synthesis of Tetrahydropyrans
Table 3. Scope of Cross-Coupling Reaction of THPs
a
(
a) Montmorillonite K10 (1.1 equiv), MeOH, C H , reflux, 18 h; (b)
6 6
p-TSA (1.0 equiv), MgBr (1.1 equiv), CH Cl , rt, 18 h; (c) Ni(cod)
2
2
2
2
(
(
10 mol %), bathophenanthroline (BPhen) (20 mol %), ArB(OH)2
1.2 equiv), KOtBu (1.6 equiv), s-BuOH, 60 °C, 24 h.
of aryl substituents at the C4 position (Scheme 5b). 4-
Bromotetrahydropyran 22 is easily synthesized as a 2:1 mixture
of diastereomers under mild conditions via a MgBr and p-
2
37
TsOH-promoted Prins cyclization. To further derivatize 22,
we employed a nickel-catalyzed Suzuki-type cross-coupling
3
8
reaction. Based on the seminal work of Fu, we hypothesized
that the coupling would be stereoconvergent and afford the
39
more stable diastereomer, cis-23. Indeed, cross-coupling of 22
with a range of commercially available aryl boronic acids
afforded a wide variety of 4-aryltetrahydropyrans in high
diastereoselectivity. These results are consistent with a
stereoablative cross-coupling reaction that proceeds through a
40
radical intermediate, with a strong preference for formation of
the thermodynamic product. The relative configuration of these
cis-2,4-diaryl tetrahydropyrans was assigned by X-ray crystallo-
graphic analysis and NOE NMR experiments (see SI for
details).
As with the tetrahydrofuran substrates, we examined the
transfer of stereochemical information in the cross-coupling
reaction by comparing the diastereomeric ratios of the starting
materials to those of the acyclic products. We observed that
employing a catalyst loading of 15 mol % resulted in good to
excellent yields with high diastereomeric ratios (Table 3).
Tetrahydropyran 21 (dr >20:1) afforded syn-24 in 84% yield
and >20:1 dr (entry 1) indicating the complete transfer of
stereochemical information in the cross-coupling. We found
that both electron-rich and electron-poor aryl substituents at
the C4 position of the tetrahydropyran are well tolerated in the
reaction (entries 2 and 3). To further challenge the
tetrahydropyran ring-opening, we sought to incorporate
biologically relevant moieties in our substrates. For example,
the cross-coupling of tetrahydropyran cis-29 proceeded in 81%
yield and >20:1 dr to form benzodioxane-substituted product
syn-30 (entry 4). 1,4-Benzodioxanes are present in a range of
a
b
1
Isolated yield after column chromatography. Determined by H
c
d
41
NMR. Calculated yield; see SI for details. Reaction performed using
Ni(acac) (10 mol %) and DPEphos (10 mol %) instead of rac-
BINAP. Nap = 2-naphthyl.
pharmaceutical agents such as piperoxan and idazoxan. We
were also pleased to see that 3-furan-substituted tetrahydropyr-
an cis-31 was well tolerated in the reaction. Product syn-32 was
formed in high yield and dr and contains a furan substituent
that can be readily derivatized by oxidation or cycloaddition
2
C4, and C6 positions can be easily altered by the use of
commercially available aldehydes, arylboronic acids, and
homoallylic alcohols, respectively.
We set out to determine the compatibility of the reaction
conditions with silylethers, common protecting groups. 4-
Hydroxytetrahydropyrans are straightforward to prepare in high
diastereoselectivity by Prins cyclization employing trifluoro-
4
2
reactions (entry 5).
To challenge the method with synthesis of a stereotriad, we
examined Kumada coupling of 2,4,6-trisubstituted tetrahydro-
pyran cis-33. Subjecting cis-33 to the reaction conditions
afforded the secondary alcohol syn-34, containing three
stereogenic centers, as a single diastereomer and with good
yield (entry 6). This strategy provides a modular three-step
synthesis of polyketide analogs where substituents in the C2,
43
acetic acid. Using DPEphos, we found that benzofuran- and
benzothiophene-substituted tetrahydropyrans 35 and 37
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afforded the acyclic products in good yields and >20:1 dr
Table 4. Scope with Respect to Grignard Reagent
(entries 7 and 8). To further challenge the ring-opening
reaction, we employed a substrate activated by a simple
aromatic substituent. 3-Furan-substituted tetrahydropyran cis-
3
9 formed syn-40 in high yield and >20:1 dr (entry 9).
Grignard Reagent Scope. The ability of a synthetic
method to easily provide access to analogs with a range of
substituent patterns is critical for the discovery of new
therapeutics as well as for conducting structure−activity
relationship (SAR) studies. We next wanted to examine the
scope with respect to the transmetallating agent, which would
provide access to a variety of benzylic substituents in the acyclic
products. Our laboratory has recently demonstrated that
Ni(dppe)Cl is a broadly applicable catalyst for cross-coupling
2
12d
of alkyl and aryl Grignard reagents with benzylic ethers. To
examine the generality of conditions for a range of Grignard
reagents, we applied this catalyst system to the cross-coupling
reactions of a representative series of tetrahydropyrans and
tetrahydrofurans (Table 4).
We began with n-propylmagnesium iodide, a representative
alkyl Grignard reagent. Cross-coupling with tetrahydrofuran 19
afforded the desired product in 75% yield and high dr (entry 1).
3-Phenylpropylmagnesium bromide reacted smoothly with
tetrahydropyran 37 to form alcohol 42 in good yield and
high dr (entry 2).
We also examined aryl Grignard reagents for synthesis of
complex diarylalkanes. Phenylmagnesium bromide underwent
successful cross-coupling with tetrahydrofuran 9 and tetrahy-
dropyran 21 (entries 3 and 4). In order to confirm that the
reaction proceeded with inversion at the benzylic position, both
trans-19 and cis-19 were prepared and subjected to the Kumada
couplings with phenylmagnesium bromide. As with methyl-
magnesium bromide, the products were afforded in good yield
and in high dr (entries 5 and 6). The relative configurations of
anti-45 and syn-45 were assigned by the preparation of
crystalline derivatives that were subjected to X-ray crystallo-
graphic analysis (see SI for details). 4-Methoxyphenylmagne-
sium bromide underwent smooth cross-coupling with tetrahy-
drofuran 9 and tetrahydropyran 21. Products 46 and 47 were
formed in high yield and dr (entries 7 and 8, respectively).
We have previously demonstrated that diarylalkanes
containing a thiophene moiety provide lead compounds with
12d
selective anti-breast cancer activity.
We therefore also
examined our methodology with 2-thiophenylmagnesium
bromide as the nucleophile. With both 2,4-disubstituted
tetrahydropyran 21 and tetrahydrofuran 11 the desired product
was afforded in excellent yield and dr (entries 9 and 10).
Negishi-Type Cross-Coupling of Lactones. We hy-
pothesized that a similar cross-coupling could be applied to
benzylic lactones, based on our recently reported Negishi-type
44
nickel-catalyzed cross-coupling of benzylic esters. Sawama
and co-workers have recently demonstrated that aryl
substituted lactones undergo Lewis acid-catalyzed ring-opening
a
b
1
Isolated yield after column chromatography. Determined by H
c
NMR. Calculated yield; see the SI for details. Nap = 2-naphthyl.
7
b
with allylsilane. However, to the best of our knowledge,
stereoselective ring-opening of lactones with carbon-based
nucleophiles has not been reported. As a further benefit, alkyl
zinc reagents provide increased functional group tolerance as
compared to Grignard reagents. The resulting enantioenriched
product would contain a benzylic stereocenter with a distal
carboxylic acid. As with the alcohols obtained from the
Kumada-type opening of cyclic ethers, this carboxylic acid
affords a convenient synthetic handle that can be used for
further derivatization. Enantioselective synthesis of lactones
provides straightforward access to the requisite starting
materials.
We prepared enantioenriched lactones for cross-coupling by
45
CBS reduction of the benzylic ketones and cyclization of the
46
corresponding 1,5-diols. The absolute configuration of the
lactones were assigned as R by the accepted CBS model of
15
selectivity of the intermediate alcohols (see SI for details).
After examining a series of bidentate ligands and nickel
precatalysts, we determined that Ni(acac)2 and Xantphos
E
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4
7
afforded the highest yield of cross-coupled carboxylic acid.
Scheme 6. Diels−Alder Reaction of Furan 57
Commercially available lactone 50 afforded the cross-coupled
product with excellent es (Table 5, entry 1), as did benzofuran-
substituted lactone 52 and indole-substituted lactone 54
48
(entries 2 and 3, respectively).
Table 5. Cross-Coupling Reaction of Lactones
a
1
Yield determined by H NMR based on comparison to PhTMS as
b
internal standard. Isolated yield after column chromatography.
Synthesis of Anti-dyslipidemia Agent 61. Dyslipidemia,
a serum lipoprotein level disorder, is implicated in cardiovas-
5
3
cular diseases and is often treated with niacin. Anti-
dyslipidemia agent 61 was disclosed as part of a campaign for
54
discovery of niacin receptor agonists with reduced side effects.
Amide 61 was previously synthesized in seven steps and used
chiral chromatography to separate the enantiomers.
We applied our methodology to the asymmetric synthesis of
niacin receptor agonist 61 from commercially available lactone
55
(
R)-59 (Scheme 7). Utilizing our optimized cross-coupling
a
Scheme 7. Enantiospecific Synthesis of Anti-Dyslipidemia
Agent 61
a
b
Isolated yield after column chromatography. Determined by
c
supercritical fluid chromatography. Enantiospecificity (es) =
d
(
eeproduct/eesubstrate) × 100%. Reaction performed using DPEphos
(
20 mol %) instead of Xantphos. Nap = 2-naphthyl.
Furan-substituted δ-valerolactones such as 56 are found in
natural products such as ricciocarpin A and salvinorin B;
a
49
(a) Ni(acac) (10 mol %), Xantphos (20 mol %), ZnMe (3.0 equiv),
2 2
PhMe, rt, 24 h; (b) (i) (COCl) (1.3 equiv), C H , rt, 2 h; (ii)
anthranilic acid (1.1 equiv), C H , rt, 3 h.
2
6
6
methods for their ring-opening would provide a strategy for
6
6
23
synthesis of analogs for biological testing. We anticipated that
lactone 56 would undergo straightforward nickel-catalyzed
Negishi-type cross-coupling. Our laboratory has observed a
strong dependence of the rate of cross-coupling on the identity
of the aryl substituent. We hypothesize that arenes possessing
conditions, carboxylic acid (S)-60 was afforded in 76% yield
with >99% es. A subsequent amide coupling directly affords
enantioenriched anti-dyslipidemia agent 61 in 75% yield. The
other enantiomer can easily be accessed by using (S)-59.
Therefore, using our method either enantiomer of anti-
dyslipidemia agent 61 can be prepared in two steps and 57%
overall yield from commercially available starting material.
50
lower aromatic stabilization energy are better ligands for the
nickel catalyst and stabilize the transition state for oxidative
addition. Benzylic ethers and esters activated by extended
aromatic rings such as naphthalene and benzofuran are
5
1
sufficiently reactive, as are those activated by furan.
CONCLUSIONS
Furthermore, the incorporation of the furan moiety affords a
■
product with two functional group handles: the carboxylic acid
In summary, we have developed the nickel-catalyzed, stereo-
specific ring-opening cross-coupling reactions of aryl-substi-
tuted tetrahydrofurans, tetrahydropyrans, and lactones.
Through judicious choice of starting materials, cyclic ether
intermediates have been utilized to set the desired relative
stereochemical relationships and allow for the selective
synthesis of syn- and anti- deoxypropionate subunits. We have
demonstrated the high stereospecificity of the reaction, where
the dr of the product matches the dr of the starting O-
heterocycles. The Negishi-type cross-coupling of benzylic
lactones has allowed for the enantiospecific synthesis of
42
and the furan itself. Therefore, we evaluated a 3-furan-
substituted lactone and found that (R)-56 underwent the cross-
coupling with 84% yield and >99% es (Table 5, entry 4).
To take advantage of the furan’s utility for further
manipulations, we derivatized product (S)-57 by a Diels−
42b,52
Alder reaction (Scheme 6).
The cycloaddition furnished
the enantioenriched bicyclic acid 58 in 64% yield as a 1:1
mixture of diastereomers. Based on Woodward’s analysis of the
thermodynamic product of the reaction, the Diels−Alder
52
reaction is anticipated to be highly exo selective.
F
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enantioenriched carboxylic acids, which can be further
derivatized. Using this methodology, we report the two-step,
enantiospecific synthesis of an anti-dyslipidemia agent with easy
access to either enantiomer. We are currently investigating the
application of these methods toward the implementation of
natural product editing to generate a library of unnatural
polyketides for SAR studies.
A.; Homoto, Y.; Harada, T. Chem. Lett. 1986, 1495. (d) Christensen,
S. H.; Holm, T.; Madsen, R. Tetrahedron 2014, 70, 4942.
(
8) For examples of allylic substitution reactions that open
dihydropyrans and lactones, see: (a) Sawama, Y.; Sawama, Y.;
Krause, N. Org. Lett. 2009, 11, 5034. (b) Matsushita, H.; Negishi,
E.-i. J. Chem. Soc., Chem. Commun. 1982, 160.
(9) (a) Heron, N. M.; Adams, J. A.; Hoveyda, A. H. J. Am. Chem. Soc.
1
997, 119, 6205. (b) Adams, J. A.; Heron, N. M.; Koss, A.-M.;
Hoveyda, A. H. J. Org. Chem. 1999, 64, 854. (c) The Hoveyda group
has also reported enantioselective, catalyst controlled ring-opening of
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ASSOCIATED CONTENT
Supporting Information
Experimental procedures and characterization data for all new
compounds, including X-ray crystallographic data. For supple-
mentary crystallographic data see CCDC 1017411, 1017412,
■
*
S
(
10) For nickel-catalyzed cross-coupling of dihydrofurans with
Grignard reagents, see: Cornella, J.; Martin, R. Org. Lett. 2013, 24,
298.
11) For examples of nickel-catalyzed addition to strained hetero-
1
017413, and 1017414. This material is available free of charge
via the Internet at http://pubs.acs.org.
6
(
cycles, e.g., epoxides and aziridines, see: (a) Molinaro, C.; Jamison, T.
F. J. Am. Chem. Soc. 2003, 125, 8076. (b) Lin, B. L.; Clough, C. R.;
Hillhouse, G. L. J. Am. Chem. Soc. 2002, 124, 2890. (c) Nielsen, D. K.;
Doyle, A. G. Angew. Chem., Int. Ed. 2011, 50, 6056. (d) Nielsen, D. K.;
Huang, C.-Y.; Doyle, A. G. J. Am. Chem. Soc. 2013, 135, 13605.
AUTHOR INFORMATION
Corresponding Author
erjarvo@uci.edu
■
Notes
(
2
e) Jensen, K. L.; Standley, E. A.; Jamison, T. F. J. Am. Chem. Soc.
014, 136, 11145. (f) Takeda, Y.; Ikeda, Y.; Kuroda, A.; Tanaka, S.;
Minakata, S. J. Am. Chem. Soc. 2014, 136, 8544.
12) (a) Taylor, B. L. H.; Swift, E. C.; Waetzig, J. D.; Jarvo, E. R. J.
The authors declare no competing financial interest.
ACKNOWLEDGMENTS
(
■
Am. Chem. Soc. 2011, 133, 389. (b) Taylor, B. L. H.; Harris, M. R.;
Jarvo, E. R. Angew. Chem., Int. Ed. 2012, 51, 7790. (c) Greene, M. A.;
Yonova, I. M.; Williams, F. J.; Jarvo, E. R. Org. Lett. 2012, 14, 4293.
This work was supported by NIH NIGMS (R01GM100212),
NIH NCI (F31CA177212 to C.A.O.), and the University of
California (Chancellor’s Fellowship and Graduate Opportunity
Fellowship to E.J.T.). Dr. Joseph Ziller is acknowledged for X-
ray crystallographic data. Dr. John Greaves is acknowledged for
mass spectrometry data. Dr. Elizabeth Swift performed
preliminary experiments of Negishi-type coupling of lactone
(
d) Yonova, I. M.; Johnson, A. G.; Osborne, C. A.; Moore, C. E.;
Morrissette, N. S.; Jarvo, E. R. Angew. Chem., Int. Ed. 2014, 53, 2422.
13) For a recent review of nickel-catalyzed reactions, see: Tasker, S.
Z.; Standley, E. A.; Jamison, T. F. Nature 2014, 509, 299.
14) For a review, see: Barreiro, E. J.; Kummerle, A. E.; Fraga, C. A.
M. Chem. Rev. 2011, 111, 5215.
15) Corey, E. J.; Helal, C. J. Angew. Chem., Int. Ed. 1998, 37, 1986.
(
(
̈
5
0. We thank Frontier Scientific for donations of boronic acids.
(
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H
dx.doi.org/10.1021/ja5076426 | J. Am. Chem. Soc. XXXX, XXX, XXX−XXX