Asymmetric synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives: Via sequential palladium and copper catalysis

Article abstract of DOI:10.1039/c6sc01724j

We present a full account detailing the development of a sequential catalysis strategy for the synthesis of chiral β-alkynyl carbonyl and sulfonyl derivatives. A palladium-catalyzed cross coupling of terminal alkyne donors with acetylenic ester, ketone, a

Full text of DOI:10.1039/c6sc01724j

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Asymmetric Synthesis of Chiral βꢀAlkynyl Carbonyl and Sulfonyl Derivatives via
Sequential Palladium and Copper Catalysis
Barry M. Trost*, James T. Masters, Benjamin R. Taft, and JeanꢀPhilip Lumb
*Corresponding Author Eꢀmail: bmtrost@stanford.edu
Abstract
We present a full account detailing the development of a sequential catalysis
strategy for the synthesis of chiral βꢀalkynyl carbonyl and sulfonyl derivatives. A
palladiumꢀcatalyzed cross coupling of terminal alkyne donors with acetylenic ester,
ketone, and sulfone acceptors generates stereodefined enynes in high yield. These
compounds are engaged in an unprecedented, regioꢀ and enantioselective copperꢀ
catalyzed conjugate reduction. The process exhibits a high functional group tolerance,
and this enables the synthesis of a broad range of chiral products from simple, readily
available alkyne precursors. The utility of the method is demonstrated through the
elaboration of the chiral βꢀalkynyl products into a variety of different molecular
scaffolds. Its value in complex molecule synthesis is further validated through a concise,
enantioselective synthesis of AMG 837, a potent GPR40 receptor agonist.
Introduction
Conjugate addition reactions are fundamental bond forming processes that are
widely employed in the synthesis of functionalized molecules. 1 As a result, the
development of efficient methods for asymmetric conjugate addition remains of
paramount importance in modern organic synthesis. Transition metal catalysis is a wellꢀ
established means of effecting the conjugate addition of a carbon nucleophile,2 and such
catalytic processes often enable the rapid assembly of molecular complexity in a highly
atom economic3 fashion.
The asymmetric addition of a terminal alkyne to an activated olefin—for example,
to an α,βꢀunsaturated ester, ketone, sulfone, aldehyde, or a synthetic equivalent thereof—
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is a conjugate addition reaction that has attracted significant attention. Novel methods
involving the activation of a terminal alkyne as a more nucleophilic boron,4 aluminum,5
or zinc 6 acetylide have been developed toward this end (Scheme 1A). However,
strategies based on transition metal catalysis have the potential to improve functional
group tolerance while avoiding the generation of stoichiometric metal waste.
Over the past several years, numerous methods for the transition metalꢀcatalyzed
asymmetric conjugate addition of a terminal alkyne to an activated olefin have been
described (Scheme 1B). Carreira and coꢀworkers reported the Cuꢀcatalyzed addition of
aryl acetylenes to Meldrum’s acid alkylidenes with high yields and enantioselectivities,7
with an example of an alkyl acetylene addition that proceeded with more modest yield
(29%) and enantioselectivity (68% ee).7a Shibasaki and coꢀworkers disclosed the Cuꢀ
catalyzed addition of various terminal alkynes to α,βꢀunsaturated thioamides.8 Hayashi
and Fillion have reported the asymmetric conjugate addition of silyl acetylenes to enones,
enals, and Meldrum’s acid alkylidenes under Rh9 and Co10 catalysis. Very recently, the
asymmetric addition of triisopropylsilylacetylene to select α,βꢀunsaturated lactone and
lactam
substrates
was
accomplished
using
Rh
catalysis,
with
diphenyl[(triisopropylsilyl)ethynyl]methanol serving as the alkynylating reagent.9e Blay
and Pedro have reported asymmetric additions of primarily aryl acetylenes to
arylidenediketones,11 coumarins,12 βꢀtrifluoromethylꢀα,βꢀunsaturated enones,13 and other
electronꢀdeficient enones14 under Zn or Cu catalysis. Mascareñas and coꢀworkers recently
described the Pdꢀcatalyzed addition of various terminal alkynes to enones, enals, and
acrylates in a racemic fashion, but investigations toward an asymmetric variant of the
process were met with modest success (38ꢀ39% ee). 15 In a similar vein, Ito and
Nishiyama have reported racemic additions of terminal alkynes to different activated
olefins using Ru pincer catalysts.16 These conditions were extended to one example of an
asymmetric addition, the reaction of phenylacetylene with 3ꢀpentenꢀ2ꢀone (49% yield,
82% ee).
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Scheme 1: Strategies for the Asymmetric Conjugate Addition of Alkynes to Activated
Olefins.
These reports illustrate how transition metal catalysis can be effective for the
asymmetric conjugate addition of select types of alkynes to certain activated olefins.
However, they also demonstrate how such direct approaches can be limited in terms of
substrate scope. As these examples illustrate, the highest levels of reactivity are often
observed when aryl or silyl acetylenes are employed as donors. Major restrictions
regarding the scope of the acceptor olefin are also apparent. Significantly, no general
strategy currently exists for the catalytic asymmetric addition of a terminal alkyne to an
acyclic α,βꢀunsaturated ester. The catalytic asymmetric conjugate alkynylation of an α,βꢀ
unsaturated sulfone is, similarly, unknown.
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A procedure to effect the formal asymmetric conjugate addition of a broad set of
terminal alkynes to various acceptor olefins would complement these strategies.
Importantly, the products obtained—chiral βꢀalkynyl carbonyl or sulfonyl derivatives—
are valuable both on their own and as precursors to more functionalized molecules. For
example, enantioenriched βꢀaryl, βꢀalkynyl carboxylic acids have been identified as
potent pharmacophores and have been investigated for the treatment of Type II
diabetes. 17 In addition, chemoselective18 functional group manipulations that engage
either the alkyne group or the carbonyl group are possible. In an early illustration of this
concept, Hayashi and coꢀworkers reported the conversion of a βꢀalkynyl ketone to a
1,2,3ꢀtriazole through a Cuꢀcatalyzed azideꢀalkyne cycloaddition; this transformation
proceeded in high yield and without interference by the carbonyl moiety.9b The prospect
of converting βꢀalkynyl carbonyl derivatives into different heterocyclic scaffolds via such
catalytic processes is attractive, and it further motivates interest in a general method for
the synthesis of these compounds.
Recognizing the need for a broadly applicable method for the synthesis of chiral
βꢀalkynyl carbonyl and sulfonyl derivatives—and cognizant of the rich synthetic utility
associated with these products—we considered a new approach. We envisioned that the
subject compounds might be accessible through a sequential catalysis process involving:
(a) a Pdꢀcatalyzed cross coupling of alkynes to generate stereodefined enynes, and (b) a
regioꢀ and enantioselective CuHꢀcatalyzed asymmetric conjugate reduction of these
intermediates (Scheme 1C).
Our research group has established that combinations of palladium acetate and
tris(2,6ꢀdimethoxyphenylphosphine) (TDMPP, 1) can efficiently promote the cross
coupling of a diverse set of terminal alkynes 2 with various acceptor alkynes 3 (EWG =
CO2R, COR, SO2Ph).19 In this completely atomꢀeconomic addition reaction, the
enyne products 4 are typically formed in very high yields. Except in certain rare cases,20
this reaction proceeds with complete regioꢀ and stereoselectivity, yielding solely the
enyne isomer shown. The ability to generate stereodefined olefins in this manner is
crucial to the proposed second stage of transition metalꢀcatalyzed conjugate reduction, as
a reduction reaction performed using a mixture of olefin isomers would be expected to
result in poor enantioselectivity.21
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Although CuHꢀcatalyzed asymmetric conjugate reductions of α,βꢀunsaturated
esters, ketones, and sulfones are known,22 the extended πꢀsystem borne by an activated
enyne of the type 4 presents a critical issue of regioselectivity. Such a substrate has the
potential to undergo an undesired 1,6ꢀreduction of the alkyne group in competition with
the desired 1,4ꢀreduction event. Indeed, previous research has revealed that Cuꢀmediated
conjugate addition and reduction reactions of activated enynes typically proceed with
high selectivity for the 1,6ꢀpathway.23 A 1,4ꢀselective asymmetric conjugate reduction of
an activated enyne would thus constitute a reversal of typical reaction trends, and it
would provide direct access to the chiral βꢀalkynyl product of interest. Combining such a
selective reduction event with the Pdꢀcatalyzed coupling of alkynes would thus provide
efficient access to a broad range of chiral βꢀalkynyl carbonyl and sulfonyl derivatives
starting from simple alkyne precursors.
We previously reported preliminary results toward this end, highlighting the
utility of dual Pd and CuH catalysis in the synthesis of selected examples of chiral βꢀ
alkynyl esters.24 Herein, we provide a comprehensive account describing not only the
development of that process but also further progress in this area. These subsequent
studies have enabled significant expansions in both the scope and the synthetic utility of
this sequential catalysis strategy. Specifically, the detailed reaction optimization efforts
that revealed the critical influence of ligand selection on the regioselectivity of the
reduction event are presented. The application of the optimized reaction conditions to the
synthesis of many new chiral βꢀalkynyl esters bearing valuable functionality to truly
highlight the selectivity now demonstrates the very broad breadth of the methodology.
We show, for the first time, the introduction of further structural diversity at the enyne
stage via Pd(0) catalyzed allylic alkylation followed by the asymmetric reduction.
Moreover, efficient syntheses of chiral βꢀalkynyl ketones and sulfones via the sequential
catalysis approach are reported here for the first time. The chemoselective elaboration of
these latter products provides access to new chemical scaffolds that are not readily
accessible from the corresponding βꢀalkynyl esters. In addition, the value of the method
in a more complex molecular setting is demonstrated through a concise, asymmetric
synthesis of a βꢀalkynyl, βꢀaryl carboxylic acid derivative of pharmaceutical relevance.
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Results and Discussion
Reaction Optimization. Our reaction discovery efforts began with the
preparation of a model enyne via the Pdꢀcatalyzed alkyneꢀalkyne coupling reaction.
Given the lack of known methods for the direct asymmetric addition of alkynes to acyclic
α,βꢀunsaturated esters, we were attracted to propiolates as acceptor alkynes. The Pdꢀ
catalyzed alkyneꢀalkyne coupling was thus performed using 4ꢀphenylꢀ1ꢀbutyne (6a) as
the donor alkyne and methyl 2ꢀnonynoate (7a) as the acceptor alkyne (Scheme 2).19b
Ynenoate 8aa was obtained as a single regioꢀ and stereoisomer in excellent yield (96%).
Scheme 2: Pd-catalyzed Alkyne-Alkyne Coupling to Generate a Model Substrate.
The asymmetric conjugate reduction stage was then explored, using 8aa as the
substrate of interest. Drawing on prior reports of CuHꢀcatalyzed reductions,
Cu(OAc)2•H2O was selected as the Cu preꢀcatalyst, diethoxymethylsilane was used as the
stoichiometric reductant, and the reactions were conducted in toluene at 4 °C.22 In
addition, tertꢀbutanol was included in the reaction mixture, as it had been reported that
this additive could improve the rate of conjugate reduction reactions.22c,d We anticipated
that the steric and electronic properties of the bisphosphine ligand might significantly
impact the regioselectivity of the process. To this end, the nature of the ligand was
systematically varied in these optimization experiments, which were assayed in terms of
reaction conversion and regioselectivity (Table 1 and Figure 1).
Table 1: Optimization of the Asymmetric CuH-catalyzed Conjugate Reduction of Ynenoate
8aa to β-Alkynyl Ester 9aa.
1,4:Σ1,6 Selectivityb
Entry
Ligand
Conversion (%)a
1
2
3
91
58
71
1.3:1
1:8.6
1:5.1
10
11
12
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4
5
92
93
1:1.3
1.1:1
13
14
15
16
17
18
19
6
60
1:3.7
7
80
1:4.6
8
> 95
10
> 19:1 (99% ee)
N. D.
9
10
11
N. D.
a Conversion was determined by 1H NMR analysis of the crude reaction mixture relative to mesitylene as an
internal standard. b Determined by 1H NMR analysis of the crude reaction mixture. N. D. = not determined.
Figure 1: Ligands Examined in the CuH-catalyzed Conjugate Reduction of Ynenoate 8aa.
The use of the achiral ligand 1,2ꢀbis(diphenylphosphino)benzene (10)25 led to
high conversion of ynenoate 8aa, but the 1,4ꢀreduction product—βꢀalkynyl ester 9aa—
was obtained with only moderate selectivity (entry 1). The mass balance comprised an
1
intractable mixture of compounds, the H NMR spectra of which were consistent with
1,6ꢀreduction byproducts. When axially chiral, C2ꢀsymmetric ligands such as BINAP22b
(11) or DTBMꢀSEGPHOS (12)22d were employed, significant decreases in both
conversion and 1,4ꢀselectivity were observed (entries 2 and 3). The complexity of these
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product mixtures, together with the fact that the various products were inseparable via
chromatography, precluded a determination of the enantioselectivity of the 1,4ꢀreduction
event. The use of ferroceneꢀderived JOSIPHOS ligands26 led to more promising results.
Specifically, both tertꢀbutylꢀ and xylylꢀderived ligands 13 and 14 delivered high
conversion, and they provided the highest levels of regioselectivity observed among the
chiral ligands examined up this point (entries 4 and 5).
The fact that xylylꢀsubstituted ligand 14 delivered a greater level of 1,4ꢀselectivity
than did tertꢀbutylꢀsubstituted ligand 13 suggested that aromatic substitution on the
eastern portion of the bisphosphine might be beneficial for 1,4ꢀselectivity. It was
therefore postulated that modulation of this specific aromatic subunit might yield
improved 1,4ꢀselectivity. To this end, various commercially available ligands of the
related WALPHOS ligand family (15ꢀ19) were examined. Relative to the JOSIPHOS
ligands, the WALPHOS series offers greater variation in terms of aromatic substituents
on the easternmost phosphine. However, these ligands differ from those in the
JOSIPHOS family in that the western portion of the ferrocene unit is not bonded directly
to the phosphorous atom but is, instead, annealed onto the 2ꢀposition of a
triphenylphosphino unit. This gross structural change on its own was sufficient to direct
the reduction event toward the 1,6ꢀpathway (entry 6 vs. entry 5). That effect was
magnified upon replacement of this eastern phenyl substituent with a xylyl unit (entry 7
vs entries 5 and 6). However, a significant electronic influence was observed within the
WALPHOS series: the use of the 3,5ꢀbis(trifluoromethyl) WALPHOS ligand 17
delivered quantitative reaction conversion, essentially complete 1,4ꢀselectivity, and
excellent enantioselectivity (99% ee, entry 8).
One possible explanation for this result is that the electronꢀwithdrawing nature of
ligand 17 generates a more Lewis acidic Cu catalyst, one that is better able to coordinate
to the carbonyl oxygen atom of ynenoate 8aa. Such secondary binding could help to
promote the 1,4ꢀreduction event by increasing the electrophilicity of the βꢀcarbon or by
directing hydride delivery to this position through a template effect.
It is noteworthy that both the western triphenylphosphino substituent and the
eastern bis(3,5ꢀbis(trifluoromethyl)phenyl) groups of ligand 17 were necessary for
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reactivity: the use of the related bis(dicyclohexyl)phosphino ligands 18 and 19 resulted in
low levels of reaction conversion (entries 9 and 10).
Synthesis of Chiral β-Alkynyl Esters. With the optimized conditions for the
asymmetric conjugate reduction stage established, the scope of this new synthesis of
chiral βꢀalkynyl esters was investigated. A range of donor alkynes 6 was examined, using
methyl 2ꢀnonynoate (7a) as the acceptor alkyne (Table 2). In addition to alkyl alkyne 6a,
various aryl alkyne donors reacted successfully, including electronꢀneutral, electronꢀrich,
and electronꢀdeficient examples. Of particular note is the fact that pꢀ
bromophenylacetylene (6d) underwent both the PdIIꢀcatalyzed alkyneꢀalkyne coupling
and the CuIꢀcatalyzed reduction without competitive oxidative addition. Silyl substituted
donor alkynes were also compatible, with both benzyldimethylsilylacetylene (6e) and
trimethylsilylacetylene (6f) reacting smoothly. In the latter case, the corresponding
trimethylsilylacetyleneꢀderived βꢀalkynyl ester (9fa) was identified after the reduction
stage (1H NMR analysis of an aliquot), but the crude product was treated with TBAF to
liberate the terminal alkyne. The latter was isolated in very good yield after column
chromatography. The more sterically encumbered donor alkyne 6g was also employed
without complication.
To further probe the regioselectivity of the reduction stage, an ynenoate bearing
an extended (1,7ꢀ) πꢀsystem was prepared using enynyl donor alkyne 6h. The CuHꢀ
catalyzed reduction of this substrate maintained excellent regioselectivity, delivering 1,4ꢀ
reduction product 9ha in high yield and with excellent enantioselectivity.
To further assess reaction robustness and scalability, each stage was examined on
larger scale using a reduced catalyst loading. A 15 mmolꢀscale coupling between donor
6a and acceptor 7a was performed using 1.5 mol % Pd(OAc)2/TDMPP, and this
delivered ynenoate 8aa in 98% yield. A 10 mmolꢀscale conjugate reduction of the latter
compound was performed using 2.5 mol % Cu(OAc)2•H2O/17, and this furnished ester
9aa in 91% yield and 99% ee. Importantly, these results meet or exceed those obtained
on smaller scale (1.0 mmol and 0.30 mmol, respectively) and with higher catalyst
loadings.
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Table 2: Substrate Scope in the Synthesis of β-Alkynyl Esters (Donor Alkynes)a
a Reaction conditions: (i) 6a-h:7a ratio = 1.25–1.75:1.0, 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23
°C for 1–18 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), tꢀBuOH (2 equiv), 0.20 M in PhMe
at 4 °C for 14ꢀ20 h. Yields are of isolated products after chromatography. Enatiomeric excesses were
b
determined by chiral HPLC analysis. Result obtained from a 15 mmolꢀscale reaction using 1.5 mol %
Pd(OAc)2/TDMPP. c Result obtained from a 10 mmolꢀscale reaction using 2.5 mol % Cu(OAc)2 mol %
d
Cu(OAc)2•H2O/17 The crude reduction product was treated with TBAF (1 M in THF), and the
e
corresponding terminal alkyne (R1 = H) was isolated after chromatography. The ee was determined after
conversion of the product into a diastereomeric mixture of amides using (S)ꢀαꢀmethylbenzylamine (> 95:5
dr observed).
Attention next turned to the scope of the process with regard to other propiolate
acceptors, using 4ꢀphenylꢀ1ꢀbutyne (6a) as the donor alkyne (Table 3). The steric bulk
around the ester unit could be increased without ill effect: in addition to the methyl ester
examples shown previously, ethyl and benzyl esters reacted smoothly in both stages and
delivered excellent enantioselectivity. The sterically demanding, cyclopropylꢀderived
acceptor 7d also underwent the alkyneꢀalkyne coupling in high yield. When the resulting
ynenoate (8ad) was subjected to the conjugate reduction stage, the reaction reached 80%
conversion and delivered a 4:1 mixture of 1,4ꢀ to 1,6ꢀreduction products from which pure
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9ad was isolated in 54% yield. Importantly, the enantioselectivity of the event remained
high (99% ee). In addition to these hydrocarbonꢀsubstituted acceptor alkynes, a
propiolate bearing a primary alkyl chloride was prepared and was found to react
smoothly in both stages.
Table 3: Substrate Scope in the Synthesis of β-Alkynyl Esters (Acceptor Alkynes)a
a Reaction conditions: (i) 6a:7b-e ratio = 1.25:1.0, 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C for
1–18 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), tꢀBuOH (2 equiv), 0.20 M in PhMe at 4
°C for 14ꢀ20 h. Yields are of isolated products after chromatography. Enantiomeric excess were determined
by chiral HPLC analysis. b The reaction reached 80% conversion (1H NMR) and produced a mixture of 1,4ꢀ
and 1,6ꢀreduction products (4:1 1,4:Σ1,6, 1H NMR analysis of the crude reaction mixture), from which pure
9da was isolated in 54% isolated yield.
The fact that the conjugate reduction of βꢀcyclopropylꢀsubstituted ynenoate 8ad
proceeded with slight decreases in efficiency and regioselectivity can be understood in
terms of the increased steric clash associated with the coordination of the Cu catalyst to
this more sterically congested olefin. These interactions could be expected to retard the
rate of hydride addition, and they also could cause hydride addition across the less
sterically demanding alkyne unit to become more favorable.27 A more surprising change
in regiochemical outcome came during the examination of ynenoates bearing alkyl
groups of different chain lengths at their βꢀpositions (Table 4). When methyl substituted
propiolate 7f was coupled with phenylacetylene (6b) and the resulting ynenoate was
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subjected to the standard reduction conditions, 2.3:1 1,4:Σ1,6 regioselectivity was
observed. The conjugate reduction of the βꢀethyl congener (8bg) led to a similar outcome
(2.7:1 1,4:Σ1,6). However, a marked increase in regioselectivity (12.5:1 1,4:Σ1,6) was
observed in the reaction of the βꢀnꢀpropyl analogue (8bh). As previously described,
excellent regioselectivity (> 19:1) was observed upon moving to longer chain lengths
(e.g., the reactions of βꢀchloropropyl substrate 8ae or βꢀhexyl compound 8aa). While a
detailed explanation for this phenomenon remains elusive, a trend of increasing 1,4ꢀ
selectivity with increasing chain length clearly emerges from these data.
Table 4: Substrate Scope in the Synthesis of β-Alkynyl Esters (Acceptor Alkynes of
Different Chain Lengths at the β-Position).a
a Reaction conditions: (i) 6b:7f-h ratio = 1.25:1.0, 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C for
1–6 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), tꢀBuOH (2 equiv), 0.20 M in PhMe at 4 °C
for 14ꢀ16 h. Yields are of isolated products after chromatography. Ratios of 1,4:1,6 selectivity were
determined by 1H NMR analysis of the crude reaction mixture. Enantiomeric excesses were determined by
chiral HPLC analysis. b Isolated yield of analytically pure 1,4ꢀreduction product 9bf obtained from the
crude 2.3:1 mixture of regioisomeric products. c Quantitative reaction conversion and yield were obtained,
d
but 1,4ꢀreduction product 9bg could not be separated from the various 1,6ꢀreduction products. Isolated
yield of 9bh (> 90 % purity) from the crude 12.5:1 mixture of regioisomeric products.
As shown in Table 2, the conjugate reduction of an ynenoate derived from an
enynyl alkyne donor maintained excellent 1,4ꢀselectivity. To further study the behavior
of extended πꢀsystems in the method, enynyl alkyne acceptor 7i was prepared (Scheme
3). This compound reacted smoothly with 4ꢀphenylꢀ1ꢀbutyne (6a), delivering ynenoate
8ai. To our surprise, the reduction of the latter substrate using ligand 17 generated,
exclusively and in high yield, (Z)ꢀenyne 20. The same product was obtained when the
reaction was performed using 1,2ꢀbis(diphenylphosphino)benzene (10) as the ligand. The
outstanding regioꢀ and stereoselectivity observed in this case is remarkable, and it may be
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the result of a multiꢀdentate coordination event involving the Cu catalyst and both the
alkyne and olefin subunits of this unique, crossꢀconjugated substrate.
Scheme 3: Regio- and Stereoselective Reduction of a Substrate Featuring an Extended π-
System.
a
Conditions: (i) 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C for 16 h. (ii) 5 mol %
Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), tꢀBuOH (2 equiv), 0.20 M in PhMe at 4 °C for 16 h.
Propiolate acceptors bearing heteroatom substitution were next examined. Initial
efforts focused on the reaction of carbonateꢀbearing propiolate 7j with different donor
alkynes (Table 5). Cross couplings between this acceptor and 4ꢀphenylꢀ1ꢀbutyne (6a),
phenylacetylene (6b), and benzyldimethylsilylacetylene (6e) all proceeded in good to
very good yields. The ynenoates so obtained were smoothly reduced to the corresponding
βꢀalkynyl esters in high yield, with > 19:1 regioselectivity, and in 99% ee. Notably, there
was no indication that competitive ionization or reduction of the propargylic or allylic
carbonates occurred during either of the two transition metalꢀcatalyzed reaction stages.
Table 5: Synthesis of β-Alkynyl Esters Bearing Carbonate Functionality.a
a Reaction conditions: (i) 6:7j ratio = 1.25ꢀ1.75:1.0, 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C
for 5ꢀ18 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), tꢀBuOH (2 equiv), 0.20 M in PhMe at
4 °C for 16ꢀ20 h. Yields are of isolated products after chromatography. Enantiomeric excesses were
determined by chiral HPLC analysis.
To explore the use of nitrogenꢀbearing acceptors in the method, propargylamine
derivative 7k was prepared. Coupling reactions between this acceptor and donor alkynes
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6a, 6b, and 6e all proceeded smoothly, even when performed with a lower catalyst
loading (1.5 mol %) and under shorter reaction times (1ꢀ3 h, Table 6).28 However, the
conjugate reduction of the resulting ynenoates using the standard conditions (with ligand
17) furnished βꢀalkynyl esters with more modest regioꢀ and enantioselectivity. As a
representative example, the reduction of ynenoate 8ak yielded ester 9ak with 9:1
1,4:Σ1,6 selectivity and 70% ee. A survey of different ligands led to the discovery that
JOSIPHOS ligand 13 was particularly well matched for the reduction of these ynenoates:
when it was used in place of ligand 17, excellent regioselectivity (> 19:1) and
enantioselectivity (≥ 92% ee) were obtained for the range of substrates. The decreased
selectivity associated with the electronꢀdeficient WALPHOS ligand 17 may have resulted
from secondary interactions between the copper catalyst and the Lewis basic carbamate
group, interactions that may have been disfavored when the more electronꢀrich and
sterically encumbered JOSIPHOS ligand 13 was used.
Table 6: Synthesis of Nitrogen Substituted β-Alkynyl Esters.a
a Reaction conditions: (i) 6:7k ratio = 1.25ꢀ1.75:1.0, 1.5 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C
for 1ꢀ3 h. (ii) 2 mol % Cu(OAc)2•H2O/13, (EtO)2MeSiH (1.5 equiv), tꢀBuOH (1.5 equiv), 0.20 M in PhMe
at 4 °C for 4 h. Yields are of isolated products after chromatography. Enantiomeric excesses were
determined by chiral HPLC analysis.
Synthesis of Chiral β-Alkynyl Esters via the Pd-catalyzed Allylic Alkylation
of an Ynenoate. As noted, carbonateꢀsubstituted ynenoate 8aj underwent both the PdIIꢀ
and CuIꢀcatalyzed reaction stages without competitive ionization. However, we
questioned whether this ionization event could be intentionally induced under Pd0
catalysis, with the concomitant formation of a πꢀallylpalladium complex. Subsequent
trapping of this complex with a heteroatom nucleophilic would generate a new ynenoate,
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itself a candidate for asymmetric reduction. This catalytic allylic alkylation process
would thus provide a convenient means for the convergent synthesis of additional,
valuable ynenoates and chiral βꢀalkynyl esters.29
In pursuit of this, compound 8aj was reacted with pyrrole nucleophile 21a in the
presence of Cs2CO3 and catalytic amounts of [(η3ꢀC3H5)PdCl]2 and
diphenylphosphinoferrocene (dppf) in 1,2ꢀdichloroethane (Scheme 4).30 To our delight,
desired allylic alkylation product 22a was successfully formed as a mixture of olefin
isomers (9:1 Z:E), and pure (Z)ꢀ22a was isolated in very good yield after
chromatography. Following conjugate reduction using ligand 17, βꢀalkynyl ester 23a was
obtained in high yield and enantioselectivity. Allylic substitution with phenol nucleophile
21b likewise yielded oxygenꢀsubstituted ynenoate 22b, in this case as a single olefin
isomer (> 19:1 Z:E). The asymmetric conjugate reduction of 22b was similarly effective,
giving rise to oxygenꢀsubstituted βꢀalkynyl ester 23b.
Scheme 4: A Pd-AA Approach to Heteroatom-substituted β-Alkynyl Esters.
Synthesis of Chiral β-Aryl, β-Alkynyl Esters: Total Synthesis of AMG 837.
Recognizing the biological relevance of, specifically, β-aryl, βꢀalkynyl carboxylic acid
derivatives, we were motivated to apply the present method to the synthesis of a
representative compound within this subclass. As a target of interest, we selected AMG
837 (24), a GPR40 receptor agonist developed by Amgen, Inc.17c,31 The requisite acceptor
alkyne was expediently prepared via the alkylation of known phenol 2532 with known
bromide 2631a (Scheme 5). Silylꢀsubstituted acetylenes were chosen as alkyne coupling
partners, as it was anticipated that the ethynylsilane moiety could be converted to the
propynyl group of the target via desilylation and alkylation. To this end, the alkyneꢀ
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alkyne coupling between trimethylsilylacetylene and propiolate 27 was performed, and
this furnished ynenoate 28a with > 95% conversion. However, the conjugate reduction of
this intermediate using ligand 17 delivered predominantly 1,6ꢀreduction products (1:1.6
1,4:Σ1,6 selectivity, entry 1). We suspected that this might have been a consequence of
the increased steric hindrance around the βꢀcarbon of this substrate, analogous to that
observed in the reaction of βꢀcyclopropyl substrate 8ad. We questioned whether a
corresponding increase in steric demand around the alkyne unit might serve to disfavor
1,6ꢀreduction and redirect reactivity back toward the 1,4ꢀpathway. Thus, the alkyne
coupling reaction was performed using triisopropylsilylacetylene, delivering ynenoate
28b in 92% isolated yield. Gratifyingly, the reduction of this compound using ligand 17
proceeded with 13:1 regioselectivity in favor of the 1,4ꢀpathway and with 86% ee, albeit
with only 26% conversion (entry 2). Further ligand evaluation led us to discover that
reactions promoted by JOSIPHOS ligands 13 and 14 proceeded with > 95% conversion,
maintained high regioselectivity, and, in the latter case, provided satisfying
enantioselectivity (82% ee, entries 3 and 4).
Scheme 5: Synthesis of β-Alkynyl Esters 29a and 29b en route to AMG 837 (24).
The reaction conditions of Scheme 5, entry 4 were incorporated into a oneꢀpot
conjugate reductionꢀalkyne desilylation process (Scheme 6). The conjugate reduction
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was carried out to completion, and then the reaction mixture was directly treated with
tetrabutylammonium fluoride to effect alkyne desilylation. This sequence delivered
terminal alkyne 30 in 74% yield from 28b (82% ee). Alkyne methylation using Pd and
Cu coꢀcatalysis in the presence of NHC ligand 318b, 33 furnished βꢀalkynyl ester 32.
Hydrolysis of the ethyl ester moiety of 32 proceeded smoothly, and AMG 837 (24) was
obtained in 83% yield.
The brevity and efficiency of this synthesis, which was completed in five steps
and 31% yield from compound 25, stemmed from the use of a propiolate as a coupling
partner. By directly employing an esterꢀderived acceptor, the need to unmask an ester
equivalent (e.g., a Meldrum’s acid alkylidene) during the synthetic sequence was
avoided. Moreover, the successful synthesis of this target highlights the applicability of
the present method toward the specific subclass of β-aryl, βꢀalkynyl esters.
Scheme 6: Completion of the Synthesis of AMG 837 (24).
Synthesis of Chiral β-Alkynyl Ketones. The success achieved in the synthesis of
chiral βꢀalkynyl esters from terminal alkynes and propiolates prompted us to examine
other classes of activated alkynes as acceptors. Ketoneꢀderived acceptors (ynones) were
readily engaged as partners in the alkyneꢀalkyne coupling, giving rise to a range of
ynenone products (Table 7). These compounds were then exposed to the reduction
conditions developed for ynenoates, with one modification: tertꢀbutanol was omitted as
an additive, as it has been shown to promote 1,2ꢀreduction in reactions of enones.22e
Under these modified conditions, asymmetric hydrosilylation of the ynenone substrates
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occurred, giving rise to silyl enol ether intermediates. The addition of either
tetrabutylammonium fluoride or methanolic HCl rapidly effected desilylation, and the
corresponding βꢀalkynyl ketones were isolated in good yields and with excellent levels of
enantioselectivity. Alkyl, aryl, and silyl donor alkynes were all compatible with this
process, as were ynone acceptors bearing methyl, ethyl, and cyclohexyl substituents.
Table 7: Synthesis of β-Alkynyl Ketones via Sequential Catalysis.a
a Reaction conditions: (i) 7:6 ratio = 1.5ꢀ2.0:1.0, 5 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C for
14 or 24 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2 equiv), 0.20 M in PhMe at 23 °C for 0.25ꢀ2 h,
followed by quenching with TBAF (1.0 M in THF, 3.5 equiv). Yields are of isolated products after
b
chromatography. Enantiomeric excesses were determined by chiral HPLC analysis. The coupling was
performed using a 2.0:1.0 ratio of 6i:7l c The reduction was conducted at 0 °C, and the silyl enol ether was
quenched using 1% HCl in MeOH instead of TBAF.
Synthesis of Chiral β-Alkynyl Sulfones. Alkyneꢀalkyne couplings employing
acetylenic sulfones as acceptors were particularly successful. Reactions between terminal
alkynes 6a, 6b, and 6i and sulfone 7o proceeded in high yields, setting the stage for the
conversion of the resulting enynyl sulfones to synthetically valuable βꢀalkynyl sulfones
via conjugate reduction (Table 8). This process was initially investigated using the
conditions developed for ynenoate reduction: namely, the use of catalytic Cu(OAc)2•H2O,
ligand 17, and diethoxymethylsilane in toluene with added tertꢀbutanol. Although the
desired βꢀalkynyl sulfones were obtained with complete regioꢀ and stereoselectivity,
reaction conversion was limited (< 20% conversion after 24 h at room temperature). A
report from Charette and Desrosiers22g describing the asymmetric conjugate reduction of
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α,βꢀunsaturated sulfones in mixed organic/aqueous media encouraged us to examine
water as a reaction additive. We soon discovered that reactions performed using water in
place of the tertꢀbutanol additive proceeded to high conversion. When conducted at 50°C,
these transformations consistently proceeded to completion within 6 h. The
corresponding alkylꢀ, arylꢀ, and silylꢀsubstituted βꢀalkynyl sulfones were isolated in high
yields. Excellent enantioselectivity (98ꢀ99% ee) was still uniformly observed, despite this
introduction of water and this increase in reaction temperature.
Table 8: Synthesis of β-Alkynyl Sulfones via Sequential Catalysis.a
a Reaction conditions: (i) 6:7o ratio = 1.25:1.0, 3 mol % Pd(OAc)2/TDMPP, 1.0 M in PhMe at 23 °C for 17ꢀ
22 h. (ii) 5 mol % Cu(OAc)2•H2O/17, (EtO)2MeSiH (2.0 equiv), H2O (5.0 equiv), 0.20 M in PhMe at 50 °C
for 2.5ꢀ6 h. Yields are of isolated products after chromatography. Enantiomeric excesses were determined
by chiral HPLC analysis.
One-pot β-Alkynyl Ester Synthesis. To further assess the robustness and
operationally simplicity of the method, a oneꢀpot, sequential alkyneꢀalkyne
coupling/conjugate reduction process was investigated (Scheme 7). In this event, the
coupling was carried out using donor 6a and a slight excess of acceptor 7k. Following
complete consumption of the donor alkyne, the reaction vessel was cooled to 0 °C. A preꢀ
formed solution of the copper catalyst was introduced, and then the silane and tertꢀ
butanol were added. Under these conditions, asymmetric conjugate reduction occurred
smoothly, and ester 9ak was obtained in 78% isolated yield and 92% ee.
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Scheme 7: One-pot Sequential Alkyne-Alkyne Coupling/Conjugate Reduction.
Synthetic Utility. The βꢀalkynyl compounds so produced were readily converted
into a range of other chiral small molecules through chemoselective transformations.
Carbonateꢀbearing compound 9aj was hydrolyzed to furnish alcohol 33 (Scheme 8, Eqn.
A). Treatment of the latter compound with Otera’s esterification catalyst34 effected
cyclization of the oxygen atom onto the ester group, furnishing chiral lactone 34 in 78%
yield. Alternatively, cyclization onto the alkyne group was possible using gold and
Brønsted acid coꢀcatalysis, leading to chiral tetrahydrofuran 35. 35 Nitrogenꢀbearing
substrate 9bk was similarly converted to pyrrolidinone 36 via trimethylaluminumꢀ
mediated lactamization (Eqn. B). Upon exposure to Pd(OAc)2, LiBr, and acrolein,
compound 9bk underwent a tandem 5ꢀendoꢀdig cyclization/reductive Heckꢀtype addition,
generating chiral dihydropyrrole 37.36 It was also possible to engage both the carboxylate
group and the alkyne moiety of a substrate in a single bondꢀforming event: when βꢀ
alkynyl ester 9ca was hydrolyzed to acid 38 and the latter compound was treated with
catalytic Pd(PhCN)2Cl2 and Et3N in refluxing MeCN, cycloisomerization occurred to
generate chiral lactone 39 (Eqn. C).37
Scheme 8: Chemoselective Elaboration of β-Alkynyl Esters.
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In addition to these cycloisomerization processes, addition reactions involving βꢀ
alkynyl carbonyl and sulfonyl derivatives were also possible (Scheme 9). In the presence
of a catalytic amount of copper thiopheneꢀ2ꢀcarboxylate (CuTC), the terminal alkyne
group of ester 9fa underwent cycloaddition with tosyl azide (40) to deliver 1,2,3ꢀtriazole
41 in quantitative yield (Eqn. A).38 Fokin and coꢀworkers have described such tosylꢀ
substituted triazoles as efficient precursors to azavinyl carbenes,39 and this highꢀyielding,
catalytic asymmetric synthesis of 41 provides an efficient entry into a new series of these
compounds. The asymmetric addition of the terminal alkyne group of 9fa to transꢀ
cinnamaldehyde (42) under ZnꢀProPhenol catalysis40 likewise proceeded smoothly and
with complete diastereocontrol, delivering tertiary alcohol 43 in high yield (85%).
In a further display of chemoselectivity, βꢀalkynyl sulfone 9ao was engaged in an
alkylation/reductive desulfonylation sequence (Eqn. B). Following deprotonation of this
substrate with nꢀbutyllithium, alkylation with benzyl bromide occurred cleanly.
Treatment of the crude product with sodiumꢀmercury amalgam in buffered
MeOH/THF22g delivered chiral hydrocarbon 44 in high yield (83% for two steps).
Notably, competitive reduction of the alkyne moiety was not observed during this
process.
Scheme 9: Addition Reactions of β-Alkynyl Carbonyl and Sulfonyl Derivatives.
Determination of the Absolute Stereochemistry. βꢀAlkynyl ester 9bf, which
was prepared from ynenoate 8bf via conjugate reduction using WALPHOS ligand 17,
was hydrogenated to aliphatic compound 45 (Scheme 10). The optical rotation exhibited
by this product was of comparable magnitude but opposite sign to that reported by
Feringa and coꢀworkers for the known (S)ꢀenantiomer. 41 The product is therefore
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assigned as the (R)ꢀenantiomer, and the stereochemical assignments of the remaining βꢀ
alkynyl esters, ketones, and sulfones prepared using ligand 17 are assigned by analogy.
Scheme 10: Catalytic Hydrogenation of β-Alkynyl Ester 9bf.
Asymmetric conjugate reductions performed using JOSIPHOS ligand 13 have
been reported to proceed with the opposite sense of absolute stereoinduction relative to
those performed using WALPHOS ligand 17.22f,j As a result, the βꢀalkynyl esters
prepared using ligand 13 (e.g., compounds 9ak, 9bk, and 9ek) are assigned as depicted:
enantiomeric to the set of products obtained using ligand 17. Entirely consistent with
these reports, the conjugate reduction of ynenoate 28b using WALPHOS ligand entꢀ17
furnished the same major enantiomer of product as did the reduction of 28b using either
JOSIPHOS ligand 13 or JOSIPHOS ligand 14 (Cf. Scheme 5). The preceding data
suggest that the product, βꢀalkynyl ester 29b, would bear (S)ꢀstereochemistry. This
assignment was verified upon completion of the synthesis of AMG 837 (24) from 29b:
the optical rotation data obtained for the latter were in agreement with prior reports
25
(observed [α]D
CHCl3)31b).
=
4.4° (c = 0.9, CHCl3); lit. [(S)ꢀenantiomer]: + 7.2° (c = 0.5,
Conclusions
We present a full account describing a sequential catalysis strategy for the
asymmetric synthesis of chiral βꢀalkynyl carbonyl and sulfonyl derivatives from simple
alkyne precursors. A Pdꢀcatalyzed alkyneꢀalkyne cross coupling generates, with complete
regioꢀ and stereoselectivity, enyne intermediates that are reduced under CuH catalysis. A
detailed assessment of ligand effects in the latter stage led to the identification of
WALPHOS ligand 17 and JOSIPHOS ligands 13 and 14 as highly effective for the regioꢀ
and enantioselective reduction of a broad range of activated enynes.
Relative to our initial report in this area, the substrate scope has been significantly
expanded. Fourteen new, sterically and electronically diverse chiral βꢀalkynyl esters have
been prepared. Additionally, the scope of the sequential catalysis approach has been
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expanded to encompass ynones and acetylenic sulfones as acceptor alkynes. To this end,
new and previously unreported syntheses of chiral βꢀalkynyl ketones and sulfones are
described.
The transformations described herein demonstrated high levels of robustness.
Excellent results (> 90% yield and 99% ee) were obtained when the reactions were
executed on gram scale. A oneꢀpot βꢀalkynyl ester synthesis was also developed, one that
furnished the target in high yield without sacrificing selectivity.
In contrast to other methods for the synthesis of these targets, such as the direct
addition of an alkyne to an activated olefin, the process described herein displays a
significant breadth of scope. Alkyl, silyl, and arylꢀsubstituted alkynes were all engaged as
donors, and ester, ketone, and sulfoneꢀderived acceptors all proved compatible. This
ability to directly employ esterꢀbased acceptors is especially noteworthy, given the
paucity of methods for the catalytic asymmetric alkynylation of acrylates.
The method tolerates oxygen and nitrogen substitution, and this enabled the
preparation of six different heterocyclic scaffolds from the corresponding βꢀalkynyl
compounds. In addition, a new Pdꢀcatalyzed allylic alkylation reaction was developed to
enable the convergent introduction of heteroatom functionality to the ynenoate
intermediate. This expanded the scope of the method even further, as the ynenoates so
prepared responded well to the conjugate reduction conditions. Upon further reaction
optimization, the substrate scope was expanded to include βꢀaryl ynenoates. This
facilitated a concise synthesis of AMG 837, a chiral βꢀalkynyl carboxylic acid of
pharmaceutical interest.
In a further demonstration of the synthetic utility of the process, the βꢀalkynyl
products were engaged in efficient addition reactions. These included a catalytic,
stereocontrolled addition of a terminal alkyne to an aldehyde. The versatility of the
sulfone substituent in the product via an alkylationꢀdesulfonylation sequence involving
the βꢀalkynyl sulfone provides tertiary propargylic all carbon stereocenters. Further,
given the flexibility of the alkyne beyond semiꢀhydrogenation bot to Zꢀ and E- olefins as
well as full saturation truly becomes enabling in creating structural diversity. The ability
to access such diverse products from simple alkyne precursors highlights the utility of the
method in complex molecule synthesis.
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Acknowledgements
We thank the National Science Foundation (CHEꢀ1360634) and the National Institutes of
Health (GM033049) for their generous support of our programs. J.T.M. acknowledges
support from an Abbott Laboratories Stanford Graduate Fellowship. B.R.T. and J.ꢀP.L.
are grateful for NIH postdoctoral fellowships (CA137999 and GM083428, respectively).
We warmly thank Solvias for gifts of chiral bisphosphine ligands and JohnsonꢀMatthey
for gifts of palladium salts.
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24 A portion of these results were disclosed in a preliminary Communication: B. M. Trost,
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32
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