Asymmetric hydroformylation of Z -Enamides and enol esters with rhodium-bisdiazaphos catalysts

Article abstract of DOI:10.1021/ja507701k

Asymmetric hydroformylation (AHF) of Z-enamides and Z-enol esters provides chiral, alpha-functionalized aldehydes with high selectivity and atom economy. Rh-bisdiazaphospholane catalysts enable hydroformylation of these challenging disubstituted substrates under mild reaction conditions and low catalyst loadings. The synthesis of a protected analog of l-DOPA demonstrates the utility of AHF for enantioselective, atom-efficient synthesis of peptide precursors.

Full text of DOI:10.1021/ja507701k

Article
pubs.acs.org/JACS
Asymmetric Hydroformylation of Z‑Enamides and Enol Esters with
Rhodium-Bisdiazaphos Catalysts
M. Leigh Abrams, Floriana Foarta, and Clark R. Landis*
Department of Chemistry, University of WisconsinMadison, 1101 University Avenue, Madison, Wisconsin 53706, United States
S
* Supporting Information
ABSTRACT: Asymmetric hydroformylation (AHF) of Z-
enamides and Z-enol esters provides chiral, alpha-function-
alized aldehydes with high selectivity and atom economy. Rh-
bisdiazaphospholane catalysts enable hydroformylation of
these challenging disubstituted substrates under mild reaction
conditions and low catalyst loadings. The synthesis of a
protected analog of L-DOPA demonstrates the utility of AHF
for enantioselective, atom-efficient synthesis of peptide
precursors.
INTRODUCTION
■
Chiral aldehydes are versatile building blocks in organic
synthesis. Although the conversion of simple, terminal alkenes
into aldehydes by hydroformylation with rhodium catalysts
constitutes a long-standing commodity process, applications to
the synthesis of chiral aldehydes are less common.1 The
emergence of new chiral catalysts that effect rapid,
enantioselective, and regioselective hydroformylation of mono-
susbtituted and, to a lesser extent, disubstituted alkenes
provides new opportunities for efficient syntheses of chiral
aldehydes. In this paper, we demonstrate that disubstituted
Figure 1. BDP ligand used for hydroformylation.
alkenes comprising Z-enol esters and Z-enamides undergo
efficient hydroformylation with excellent selectivity and func-
tional group tolerance using rhodium catalysts in the presence
of the (S,S,S)-bisdiazaphos ligand, 1.
than other C−C bond forming reactions. An excellent example
is provided by Burke’s recent report of a highly efficient
synthesis of Patulolide C that features AHF of the Z-enol ester
2 (Scheme 1).8e Additional examples include the enantiose-
lective synthesis of Garner’s aldehyde9 and Leighton’s synthesis
of Dictyostatin.10
Effective, modern asymmetric hydroformylation (AHF)
technology began with the development of the Rh-
(BINAPHOS) catalyst system.2 Applications of this catalyst
demonstrated that useful regio- and enantioselectivities could
be effected for a variety of alkenes, especially monosubstituted
alkenes. Following these initial demonstrations, several notable
ligand systems for AHF have been reported. These ligands
include diphosphites such as Chiraphite,3 mixed phosphine-
phosphoramidites such as Yanphos,4 mixed phosphine-
phosphite ligands with small bite angles,5 Duphos-related
diphosphines such as Ph-BPE,6 and so-called scaffolding
monophosphine ligands.7 Rhodium complexes of the bisdiaza-
phospholane (BDP; see Figure 1) class of ligands exhibit
unusual activity and selectivity in AHF reaction for a broad
range of alkene substrates. High (>90% ee) enantioselectivities
have been achieved with aryl alkene, 1,3-diene, vinyl acetate,
and N-vinyl acetamide, dihydrofuran, and other substrates using
BDP-derived catalysts.8
Scheme 1. AHF in the Synthesis of (+)-Patulolide C
Many simple, terminal alkenes have been converted into
chiral aldehydes with high selectivity by asymmetric hydro-
formylation. However, selective AHF of more complex
substrates requires effective transformation of more highly
substituted alkenes. Prior examples of enantioselective AHF of
Effective AHF with disubstituted alkene substrates would
expand the strategies available for complex molecule synthesis
because AHF provides a fundamentally different disconnection
Received: August 8, 2014
Published: September 22, 2014
© 2014 American Chemical Society
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Table 1. Some Representative Examples of AHF of 1,1- and 1,2-Disubstituted Alkenes
a
Run with 15 mol % ligand (6.7:1 substrate:ligand) and 0.05 mol % pTsOH as an additive.
Table 2. Asymmetric Hydroformylation of para-Substituted Z-Enol Esters (run with 100 mg alkene)
a
a
c
entry
R =
conc. alkene (M)
conv.
α:β
isolated yield
% ee
b
,e
1
2
3
4
5
6
7
H
1.5
1.3
1.8
1.3
1.3
1.5
>99%
>99%
>99%
>99%
>99%
94%
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
>50:1
92%
84%
85%
88%
82%
78%
82%
97
96
90
96
92
92
99
f
OMe
SMe
Cl
Br
d
CH2Cl
OH
1.3
93%
a
b
c
d
1
Determined by H NMR of crude reaction mixture. Run with 1 g alkene. The ee determined by SFC or HPLC after NaBH4 reduction. 0.5%
e
f
catalyst loading. [α]20D = −14.7 (S), (c = 1.24, CHCl3). The configuration is S as determined by LAH reduction to the diol and comparison of the
optical rotation with the previously assigned diol.
disubstituted alkenes with enantioselectivities that exceed 90%
ee are given in Table 1.
groups, such as acetoxy- or acetamido-substituents, generally
yield high regioselectivity and good activity.8c With the
exception of particularly electron-deficient alkenes, AHF of
1,1-disubstituted alkenes is sluggish.11 A small set of data
indicates that the geometry of the double bond of 1,2-
disbustituted alkenes also impacts AHF selectivity, with Z-
alkenes giving higher regio- and enantioselectivities and faster
rates.2b,8c Such observations suggest that AHF can be
particularly effective for 1,2-disubstituted alkenes comprising
(Z)-enol esters and enamides.
Application of AHF to 1,2-disubstituted alkenes requires
controlling the regioselectivity of CO insertion between two
positions that are less sterically differentiated than in
monosubstituted or 1,1-disubstituted alkenes. To date, control
of regioselectivity has been addressed most effectively for allyl
amines and alcohols that are amenable to scaffolding catalysis.7
Hydroformylation of disubstituted alkenes commonly requires
long reaction times and/or high catalyst loading in order to
overcome the substrate bulkiness. With Rh-BDP catalysts, AHF
of alkenes substituted with inductively electron-withdrawing
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enantiopure amino acids of opposite chirality undergo AHF
with high diastereoselectivity that is predominately catalyst-
controlled, with little match-mismatch effect (Table 4, entries 2
and 3). Trifluoroacetyl enol esters also were investigated, but
these undergo undesirable elimination of trifluoroacetic acid
under catalytic conditions and give low conversion (37−60%)
to the desired product.
AHF of Enamides. Z-Enamides can be synthesized by Ru-
catalyzed coupling of primary amides to alkynes.14 These
substrates also undergo AHF with high selectivity for the α-
amino aldehyde product. The AHF of enamides is slower than
that of the corresponding enol esters (Figure 2), and complete
conversion within a day requires higher catalyst loading (1%) at
65 °C.
RESULTS AND DISCUSSION
■
AHF of Enol Esters. Enol ester substrates are attractive
candidates for AHF because the two carbons of the alkene are
well-differentiated electronically. Benzoyloxy-substituted al-
kenes are synthetically accessible as the Z isomer via Ru-
catalyzed addition of alkynes to carboxylic acids.12,13 Hydro-
formylation of these alkenes in the presence of 1 and
Rh(acac)(CO)2, where acac = acetylacetonate, produces only
the alpha-substituted, 2-benzoyloxy aldehyde with excellent
enantioselectivity (90−99% ee) at low catalyst loadings (0.3%)
(Table 2). Results obtained on the gram scale (Table 2, entry
1) are similar to small scale results (Table 2, entries 2−7).
Hydroformylation is tolerant of a wide variety of functional
groups, including potential catalyst poisoning groups such as
thioether, benzylic chloride, and free phenol (Table 2, entries 3,
6, and 7). The substituent in the para position has little effect
on the hydroformylation activity and all substrates tested give
high regio- and enantioselectivity under the screening
conditions.
While the results in Table 2 incorporate 24 h reaction times,
many substrates go to complete conversion at 60 °C in under
16 h. Significantly, at higher temperatures the reaction time is
reduced with no effect on the enantio- or regioselectivity. For
(Z)-hex-1-en-1-yl 4′-methoxybenzoate, AHF is complete within
1.5 h at 100 °C, and the resultant aldehyde is produced in 96%
ee (Table 3, entry 3). The enantioselectivity only drops
modestly when the temperature is further increased to 120 °C.
Table 3. Selectivity of AHF Is Maintained at Higher
Temperatures (run with 100 mg alkene)
Figure 2. AHF of enamide N-((Z)-1-hexen-1-yl)benzamide with time.
a
a
b
entry
temp (°C)
time (h)
conv.
α:β
% ee
Both E- and Z-enamides were tested under standard AHF
conditions of 65 °C and 150 psig CO/H2 (Table 5, entries 1
and 2). Consistent with prior results for propenamide, the Z-
enamide gives both higher enantioselectivity and faster rates.
Under standard conditions, the AHF of most enamides
proceeds with high selectivity and excellent functional group
tolerance, including groups that often react with metal catalysts,
such as alkyl chlorides and nitriles (Table 5, entries 4 and 5).
Important limitations of AHF with bisdiazaphos catalysts are
revealed by entries 10 and 11. The α−β unsaturated substrate
ethyl-(2-benzamido)ethenoate not only undergoes hydro-
1
2
3
4
60
80
24
5
>99%
>99%
>99%
>99%
>50:1
>50:1
>50:1
>50:1
96
96
95
89
100
120
1.5
0.5
a
b
Determined by 1H NMR of crude reaction mixture. The ee
determined by HPLC after NaBH4 reduction.
AHF of enol esters is effective with both acetates and
benzoates (Table 4, entry 1). Enol esters derived from
Table 4. AHF of Other Enol Esters (run with 150 psig H2/CO)
a
b
c
d
1
Determined by H NMR of crude reaction mixture. ee determined by HPLC after NaBH4 reduction. Run with (R,R,R)bisdiazaphos. The
configuration is S as determined by LAH reduction to the diol and comparison of the optical rotation with the previously assigned diol.
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Table 5. Asymmetric Hydroformylation of Enamides (run with 100 mg alkene)
a
b
c
Determined by 1H NMR of crude reaction mixture. ee determined by HPLC after NaBH4 reduction. [α]20D = −103.1 (S), (c = 1.29, EtOH) for
d
alpha isomer. The absolute configuration was assigned as S after reduction to the alcohol with sodium borohydride and comparison with the
previously assigned alcohol.
formylation but also shows extensive hydrogenation of the
double bond and degradation of starting material (entry 10).
Second, the tertiary amide N-4-phenyl-1-butenylpyrrolidinone
hydroformylates at much slower rates than other enamides
giving only 27% conversion to aldehyde in 24 h, with extensive
isomerization to the E alkene (entry 11).
(trifluoroacetamido vs benzamido) improves the regioselectiv-
ity at a given syngas pressure and the trend of increasing regio-
and enantioselectivity with increased syngas pressure persevere.
Such results demonstrate the importance of manipulating
reaction conditions to control selectivity in the hydro-
formylation of styrenyl substrates.
The N-styryl enamides examined undergo hydroformylation
with lower regioselectivity than that seen for enamides with
pendant alkyl chains. Presumably this reflects competition
between the aryl (which directs formyl insertion in the β
position) vs carboxamido (which directs formyl insertion in the
α position) directing effects. Because styrene exhibits strong
CO-pressure-dependent selectivity, we examined the hydro-
formylation of N-((Z)-2-phenylvinyl) benzamide as a function
of pressure (Figure 3).
Synthesis of a L-DOPA Building Block. AHF provides
more atom efficient and direct access to highly enantioenriched
α-amino aldehydes than methods involving multiple-step
reactions and multiple changes in oxidation state to reach the
desired aldehyde functionality.15 Although alpha-substituted
aldehydes potentially are susceptible to racemization via
enolization, the intrinsically neutral conditions unique to
aldehyde synthesis by hydroformylation obviate racemization
even at temperatures in excess of 100 °C.16 As a demonstration
of the practical utility of AHF, the synthesis of a protected L-
DOPA aldehyde was performed (Scheme 2). While the acid
form is accessible through various synthetic methods (the most
As seen for simple styrenes, the regio- and enantioselectivity
of (Z)-styreneamides decrease with decreased syngas pressure.
Increasing the electron-withdrawing nature of the carboxamide
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CONCLUSION
■
AHF provides a direct, catalytic, and atom-efficient route to
useful chiral building blocks, including unnatural amino
aldehydes. A variety of Z-enol esters and enamides undergo
asymmetric hydroformylation in the presence of 1 and
Rh(acac)(CO)2 to produce α-chiral aldehydes with high
regio- and enantioselectivity. Five of the products were
determined to have the S configuration by comparison of
optical rotations of known compounds; all data are consistent
with S configurations for all aldehydes reported herein. These
studies highlight critical attributes of the bisdiazaphos hydro-
formylation catalysts: high intrinsic reactivity (with complete
conversion and >90% ee in just 90 min at 0.3 mol % catalyst
loading in simple pressure bottles), reliably high enantiose-
lectivities (>90% ee) for a variety of Z-enol esters and
enamides, and tolerance of functional groups such as phenols,
thioethers, aryl bromides, and benzylic chlorides. For 1,2-
disubstituted alkenes with competing regiodirecting substitu-
ents, such as styrenyl enamides, increased pressure can effect
increased regio- and enantioselectivities for the α-carboxamido
aldehyde. Overall, these results significantly expand efficient
access to chiral α-functionalized aldehydes.
EXPERIMENTAL DETAILS
■
General Method for Hydroformylation. Inside a N2-purged
glovebox, an oven-dried 15 mL Ace Glass pressure bottle equipped
with a magnetic stir bar was charged with THF stock solutions of
Rh(acac)(CO)2 and BDP ligand 1 using 1000 and 200 μL Eppendorf
pipets. The pressure bottle was attached to a pressure reactor and
removed from the glovebox, placed in a fume hood, subjected to 5
pressurization (140 psig)/depressurization (15 psig) cycles with
syngas to ensure replacement of the dinitrogen atmosphere with
syngas, then filled to the appropriate syngas pressure. The solution was
allowed to stir at high speed to ensure gas mixing for 30−60 min in an
oil bath at the reaction temperature. The reaction vessel was then
removed from the oil bath and allowed to cool for 5 min, then the
pressure was reduced to <10 psig, and the olefin was injected with a
gastight syringe with a 12 in. needle. Solid olefins were injected as a
solution in THF. Reactions were run at 0.8−1.3 M final concentration
of olefin. The reaction was then repressurized to the reaction pressure
after additional pressurization/depressurization cycles and replaced in
the oil bath. Upon completion of the reaction, the pressure bottle was
removed from the oil bath, allowed to cool to room temperature, and
vented in a fume hood. NMR spectra are initially obtained of the crude
reaction mixture by adding NMR solvent directly to the reaction
mixture. Enantiomeric excess of the hydroformylation product was
determined by chiral SFC or HPLC after reduction to the alcohol with
NaBH4.
Figure 3. Pressure effects on AHF of styrenyl enamides.
Scheme 2. AHF of Enamides Applied to the Synthesis of
a
Protected analog of L-DOPA Aldehyde
a
The ee determined by HPLC after NaBH4 reduction to the alcohol.
ASSOCIATED CONTENT
■
S
* Supporting Information
notable of which is Knowles’ asymmetric hydrogenation), the
aldehyde form is a valuable intermediate for formation of
peptides and analogs.17
Detailed experimental procedures, spectral characterization of
new compounds, and conditions for determination of
enantiomeric excess. This material is available free of charge
via the Internet at http://pubs.acs.org.
The desired Z-enamide was synthesized by Ru-catalyzed
coupling of benzamide to an alkyne derived from vanillin.18
Asymmetric hydroformylation of this substrate proceeds cleanly
to produce the aldehyde with 98% ee and 15.4:1 branch
selectivity. The improved selectivity relative to the styrenyl
enamides in Figure 3 is likely due to the electron-donating
methoxy substituents on the aryl ring disfavoring acyl formation
at the β position.8b
AUTHOR INFORMATION
■
Corresponding Author
landis@chem.wisc.edu
Notes
The authors declare no competing financial interest.
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ACKNOWLEDGMENTS
■
We thank Yicong Ge for his synthetic contributions. We are
grateful to Prof. Tehshik Yoon and co-workers for access to
SFC instrumentation. We thank the Dow Chemical Company
for their generous donation of Rh(acac)(CO)2 and Merck &
Co. (Dr. Neil Strotman) and Vertex Pharmaceuticals (Dr.
William Nugent) for resolution of tetracarboxylic acid BDP. We
also acknowledge the NSF for funding the NMR facilities
(CHE-9208463 and CHE-0342998) and some of the reactor
equipment (CHE-0946901). The research described herein
received funding from the NSF (CHE- 1152989) and the
University of Wisconsin.
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