Asymmetric Catalysis with Ethylene. Synthesis of Functionalized Chiral Enolates

Article abstract of DOI:10.1021/jacs.5b10364

Trialkylsilyl enol ethers are versatile intermediates often used as enolate surrogates for the synthesis of carbonyl compounds. Yet there are no reports of broadly applicable, catalytic methods for the synthesis of chiral silyl enol ethers carrying latent functionalities useful for synthetic operations beyond the many possible reactions of the silyl enol ether moiety itself. Here we report a general procedure for highly catalytic (substrate:catalyst ratio up to 1000:1) and enantioselective (92% to 98% major enantiomer) synthesis of such compounds bearing a vinyl group at a chiral carbon at the β-position. The reactions, run under ambient conditions, use trialkylsiloxy-1,3-dienes and ethylene (1 atm) as precursors and readily available (bis-phosphine)-cobalt(II) complexes as catalysts. The silyl enolates can be readily converted into novel enantiopure vinyl triflates, a class of highly versatile cross-coupling reagents, enabling the syntheses of other enantiomerically pure, stereodefined trisubstituted alkene intermediates not easily accessible by current methods. Examples of Kumada, Stille, and Suzuki coupling reactions are illustrated.

Full text of DOI:10.1021/jacs.5b10364

Communication
pubs.acs.org/JACS
Asymmetric Catalysis with Ethylene. Synthesis of Functionalized
Chiral Enolates
Souvagya Biswas, Jordan P. Page, Kendra R. Dewese, and T. V. RajanBabu*
Department of Chemistry and Biochemistry, The Ohio State University, 100 West 18th Avenue, Columbus, Ohio 43210, United
States
S
* Supporting Information
Scheme 1. Enantioselective 1,4-Addition as a Route to Chiral
Silyl Enol Ethers
ABSTRACT: Trialkylsilyl enol ethers are versatile inter-
mediates often used as enolate surrogates for the synthesis
of carbonyl compounds. Yet there are no reports of
broadly applicable, catalytic methods for the synthesis of
chiral silyl enol ethers carrying latent functionalities useful
for synthetic operations beyond the many possible
reactions of the silyl enol ether moiety itself. Here we
report a general procedure for highly catalytic (sub-
strate:catalyst ratio up to 1000:1) and enantioselective
(92% to 98% major enantiomer) synthesis of such
compounds bearing a vinyl group at a chiral carbon at
the β-position. The reactions, run under ambient
conditions, use trialkylsiloxy-1,3-dienes and ethylene (1
atm) as precursors and readily available (bis-phosphine)-
cobalt(II) complexes as catalysts. The silyl enolates can be
readily converted into novel enantiopure vinyl triflates, a
class of highly versatile cross-coupling reagents, enabling
the syntheses of other enantiomerically pure, stereodefined
trisubstituted alkene intermediates not easily accessible by
current methods. Examples of Kumada, Stille, and Suzuki
coupling reactions are illustrated.
ketones and not the more synthetically useful, regioselectively
trapped enolates. Highly specialized silyl enolate products are
formed, but never isolated, in some asymmetric metal-catalyzed
reactions including hetero-Diels−Alder reactions of siloxy-1,3-
dienes.5 Here we report a general procedure for highly catalytic,
chemo-, regio- and enantioselective synthesis of silyl enol ethers
that carry a vinyl-bearing chiral center at the β-position (6,
Scheme 2). The reactions, which proceed under ambient
conditions, couple siloxy-1,3-dienes (5) and ethylene (1 atm),
use as little as 0.001−0.05 equiv of readily available cobalt
complexes, and give products in high yield (>90%) and
rialkylsilyl enol ethers are among the most widely used
Tnucleophilic reagents in organic synthesis because of the
ease of their preparation and the facile reactions they undergo
with a broad range of electrophiles to form highly functionalized
carbonyl compounds.1 Many of these reactions exhibit exquisite
reagent- and catalyst-dependent selectivities at every level
chemo-, regio-, and stereoselectivityin the bond-forming
processes.2 Development of highly efficient and enantioselective
protocols for the synthesis of functionalized silyl enol ethers
would considerably expand the utility of these venerable
intermediates. The closest precedent for a catalytic reaction
that results in the regio- and stereoselective synthesis of a silyl
enol ether involves a Rh(L*)-catalyzed enantioselective
conjugate addition (Scheme 1) of an alkenylorganozirconium
reagent to a cycloalkenone (1) followed by a difficult (large
excess of four reagents, long reaction times) in situ silylation of
the weakly reactive zirconium-enolate 2 (see step 2).3 The
reaction shows poor selectivity for the preparation of acyclic
derivatives (e.g., 4).3 While similar catalytic asymmetric
conjugate alkenylation of enones using alkenyl boronates4a,b
and alkenyl aluminum reagents4c,d is known, no such reaction has
been reported for simple vinyl (H2CCH−) additions. In all
these cases, the products of addition are almost invariably the
Scheme 2. Co(II)-Catalyzed Asymmetric Hydrovinylation of
Siloxydienes (this work)
Received: October 4, 2015
© XXXX American Chemical Society
A
DOI: 10.1021/jacs.5b10364
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Journal of the American Chemical Society
Communication
a
exceptionally high enantioselectivity (92−98% ee). The silyl
enolates can be readily converted into nearly enantiopure vinyl
triflates (7), which are potentially valuable precursors for a
variety of cross-coupling reactions.
Table 1. Scope of Hydrovinylation of 2-Siloxy-1,3-dienes
Our studies started with an examination of the hydrovinylation
of a prototypical trimethylsiloxy-1,3- diene, 8a, under conditions
described in eq 1, which was arrived at in initial optimization
studies. In these experiments,6 carried out using cobalt(II)
chloride-complexes of 1,n-bis-diphenylphosphinoalkane ligands
and various promoters, we recognized that trimethylaluminum, a
Lewis acidic alkylating agent which we had successfully used
previously,7gave unacceptable yields of the expected hydro-
vinylation product (9a). Alternate procedures using Zn/ZnI2 in
place of the aluminum reagents8 also gave unsatisfactory results.
The major product in these reactions arises from simple
decomposition of the sensitive silyloxydiene 8a to regenerate
the enone from which this substrate was prepared. On the other
hand, a relatively weaker alkylating agent, methylaluminoxane
(MAO), which is an easily handled solid reagent,9 gave excellent
yields of the addition products. In all cases, the major product
was identified as the branched 1,4-adduct (E)-9.10 A minor side-
product that is observed in some of the reactions is the linear 1,4-
adduct 10a. Among the cobalt complexes, (dppp)CoCl2 [dppp
=1,3-bis-diphenylphosphinopropane] gave an exceptionally
clean reaction to yield the product (E)-9a in quantitative yield.
Likewise, the corresponding triethylsilyl and t-butyldimethylsi-
lyloxy dienes, 8b and 8c, also gave the respective adducts (9b and
9c) in excellent yields and exquisite E-selectivity (eq 1).
The hydrovinylation reaction has a broad scope as illustrated
by the examples 8a−8p in Table 1. Under the optimized
conditions, the reactions of the 2-trimethylsiloxydienes 8a−8p
proceed at room temperature giving excellent yields of the
hydrovinylation products. In all cases except 8k (entry 9), the
hydrovinylation favors the branched product in which the
hydrogen is attached to the terminal, unsubstituted carbon, C1,
and the vinyl group to the C4 of the original diene. When the
trialkylsiloxy group is on C3 (e.g., 8h compared to 8a where it is
on C2 by this numbering scheme), proportionally more linear
product 10h (up to 25%) is also formed (entry 6). Dienes with
bulkier substituents (R) at the C4 position (8f, R = t-Bu, and 8g,
R = i-Pr) take up to 20 h to give moderate yields of the products.
An enantiopure siloxydiene derived from (−)-citronellal, 8j,
undergoes the reaction giving excellent yield of the expected
product as a mixture of 1:1 diastereomers (at C4) with the achiral
(dppp)CoCl2 complex (entry 8). A diene with a phenyl
substituent in the C4-position (8k) does not give any of the
expected products. Instead a linear 1,4-adduct, (Z)-6-phenyl-1,4-
hexadiene (10k), is formed in 80% yield (entry 9). Entries 10−14
show a class of substrates where one of the double bonds of diene
is embedded in a cycloalkene, which allows for the regio- and
stereoselective preparation of 1,2-dialkylated cycloalkanes. The
substrates for these reactions are readily prepared from the
corresponding cycloalkanones in two steps using the Meyer−
a
b
c
SI for details. No other products detected by GC. After hydrolysis
d
to ketone. Only a 1,4-linear product 10k is formed.
Schuster rearrangement11 as the key step.10 The siloxydienes 8l−
8p, derived from C6−C8 cycloalkanones, lead to exclusive
formation of the branched 1,4-hydrovinylation products (9l−
9p) with the vinyl group attached to a ring carbon. No trace of
the alternate achiral linear 1,4-adduct or the 1,2-adduct was
observed in any of the reactions. As shown in entries 12 and 13,
B
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Journal of the American Chemical Society
Communication
a
the triethylsiloxy- and t-butyldimethylsiloxy derivatives (8n and
8o) engage in the reaction just as well as the trimethylsiloxy
derivative (8m), giving comparable yields of the expected
products. The t-butyldimethylsiloxy-adduct, 9o, is hydrolytically
stable and is readily purified by column chromatography on silica
gel.
Next, we turned our attention to asymmetric variants of these
reactions. Asymmetric hydrovinylations of prototypical silox-
ydienes 8a−8c were attempted using various Co(II)-complexes
of several commercially available chiral bisphosphines in the
presence of MAO as a promoter. Based on the initial
observations, 2,3-O-isopropylidene-2,3-dihydroxy-1,4-bis-
(diphenylphosphino)butane (DIOP) and 2,3 bis-
(diphenylphosphino)pentane (BDPP) were chosen for further
study under conditions shown in eq 2. As is the case with the
Table 2. Asymmetric Hydrovinylation of 1,3-Siloxydienes
b
c
entry diene
cat. (equiv), time (h)
0.05, 0.5
product
yield (%) ee (%)
1
8a
8a
8b
8c
8d
8d
8e
8f
(S)-9a
(R)-9a
(R)-9b
(R)-9c
(S)-9d
(R)-9d
(S)-9e
(S)-9f
(S)-9g
>95
95
84
d
2
0.05, 0.17
98
d
3
0.05, 0.17
>90
>90
>95
96
>95
>95
80
d
4
0.05, 0.17
5
0.05, 0.5
d
6
0.05, 0.17
97
7
0.05, 0.5
0.20, 24
0.05, 20
0.05, 0.25
0.05, 0.5
0.01, 2
93
97
8
0
−
9
8g
8h
8l
88
>95
e
10
11
12
13
14
15
16
17
18
(S)-9h
>90
90
94
(R)-9l
92
8m
8m
8n
8o
8p
8j
(R)-9m
(R)-9m
(R)-9n
>90
93
96
0.001, 36
0.05, 0.25
0.05, 0.25
0.05, 20
96
>90
93
g
(R)-9o
78
87
(R)-9p
68
91
92
98
d
h
h
0.05, 0.25
9j [C4(R)]
9j [C4(S)]
97:3
96:4
f
8j
0.05, 0.25
a
See SI for further details. Using [(S,S)-BDPP]CoCl2 except entries 2,
b
3, 4, 6, 17 where the (S,S)-DIOP complex is used. See Table 1 for
structures of siloxydienes and the corresponding products. Deter-
mined by CSP GC. Using [(S,S)-DIOP]CoCl2. 10h (9%) also
formed. Using [(R,R)-DIOP]CoCl2. Isolated by column chromatog-
c
d
e
f
g
h
raphy. Diastereomeric (at C4) ratio.
96% ee (entry 12). Indeed this reaction can be run with as little as
0.001 equiv (substrate:catalyst 1000:1, 2.5 mmol scale) of the
catalyst (entry 13).12 Since the enantiopure siloxydiene 8j
showed no inherent selectivity in the formation of the newly
created chiral center in the HV reaction with the achiral catalyst
[(dppp)CoCl2] (Table 1, entry 8, diastereomeric ratio 1:1), we
examined the reaction of this substrate with enantiomeric
[DIOP]CoCl2 complexes. As shown in entries 17 and 18 the
enantiomeric complexes [(R,R)-DIOP]CoCl2 and [(S,S)-
DIOP]CoCl2 exert excellent catalyst control in the hydro-
vinylation reaction, and the adducts are formed in diastereomeric
ratios [at C4 (S): C4 (R)] 96:4 and 3:97 in the respective cases.
Conversion of silyl enolates to suitable precursors for cross-
coupling would considerably expand the utility of this chemistry.
For this we turned to alkenyl triflates which could be formed via
the lithium enolates and subsequent trapping by PhN(Tf)2
(Scheme 3).13 The conversions of the silyl enolates to the
structurally analogous complex (dppp)CoCl2, the enantioselec-
tive reaction of 8a using the [(S,S)-BDPP]CoCl2 complex is very
facile and proceeds to completion in <30 min at room
temperature with 0.05 equiv of the catalyst. The configuration
of the product was established by converting the adduct 9a to the
known saturated ketone 11a via hydrolysis of the enol ether to a
β-vinylketone and subsequent hydrogenation of the alkene using
Wilkinson’s catalyst [RhCl(PPh3)3(cat)/CH2Cl2/25 °C/16
h)].10 In a preparative scale reaction (5 g), using 0.01 equiv of
[(S,S)-DIOP]-CoCl2 catalyst, 90% yield of the product (R)-9a
(98% ee) was isolated after bulb-to-bulb distillation. To our
delight, we find that the [(S,S)-DIOP] CoCl2 complex also gave
excellent yields (>90%) and enantioselectivities (>95% ee) for
the triethylsiloxy- and the t-butyldimethylsiloxy dienes 8b and 8c
(see eq 1 for structures).
Further scope of the enantioselective transformation was
explored using the siloxydienes previously listed in Table 1, and
the results are shown in Table 2. Since the cobalt(II)-BDPP-
complex gave acceptable yields and enantioselectivities for most
of the substrates, our studies were largely limited to this catalyst.
However, substrates 8a and 8d gave relatively lower selectivities
(entries 1 and 5) with this complex. Gratifyingly, asymmetric
hydrovinylation of these substrates using the cobalt(II)-DIOP-
complex gave excellent yields and >97% ee for the expected
products (Table 2, entries 2 and 6). The sterically demanding 4-t-
butyl-2-trimethylsiloxy-1,3-butadiene (8f) failed to react even
under more forcing conditions. The corresponding i-propyl-
derivative 8g reacts sluggishly (20 h, 0.05 equiv of catalyst), yet
giving very high ee for the expected product, 9g (entry 9). The
siloxydienes derived from cylic ketones 8l−8p (see Table 1 for
structures) are also excellent substrates for the asymmetric
hydrovinylation, giving excellent yields of the expected product
in very high enantioselectivities (entries 11−16). A preparative
scale run on 2.5 mmol scale of the substrate 8m uses only 0.01
equiv of the catalyst (2 h, rt) to give >90% yield of the product in
Scheme 3. Synthesis of Enol Triflates and Cross-Coupling
Products
C
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Communication
(c) May, T. L.; Dabrowski, J. A.; Hoveyda, A. H. J. Am. Chem. Soc. 2011,
133, 736. (d) McGrath, K. P.; Hoveyda, A. H. Angew. Chem., Int. Ed.
2014, 53, 1910.
(5) See for example: (a) Mikami, K.; Aikawa, K. Asymmetric ene
reactions and cycloadditions. Catalytic Asymmetric Synthesis; Ojima, I.,
Ed.; John Wiley: Hoboken, NJ, 2010; pp 725−733. (b) Kawasaki, M.;
Yamamoto, H. J. Am. Chem. Soc. 2006, 128, 16482. (c) For an
enantioselective intramolecular addition of a siloxydiene to an alkyne
leading to a chiral silyl enol ether, see ref 2g.
(6) For details of the optimization studies, see SI Tables 1 and 2.
(7) (a) Timsina, Y. N.; Sharma, R. K.; RajanBabu, T. V. Chem. Sci.
2015, 6, 3994. (b) Sharma, R. K.; RajanBabu, T. V. J. Am. Chem. Soc.
2010, 132, 3295. (c) For the first report of a Co-catalyzed asymmetric
hydrovinylation, see: Grutters, M. M. P.; Muller, C.; Vogt, D. J. Am.
Chem. Soc. 2006, 128, 7414. (d) For recent reviews of hydrovinylation,
see: RajanBabu, T. V.; Smith, C. R. Enantioselective Hydrovinylation of
Alkenes. Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.;
Elsevier: London, 2012; Vol. 5, pp 355−398. (e) Hilt, G. Eur. J. Org.
Chem. 2012, 2012, 4441.
vinyl triflates (12−17) and their subsequent cross coupling
reactions (typical examples of products: 18−20) proceed with
complete retention of configuration at the double bond and
preservation of the vinyl-bearing stereogenic center. Examples of
Kumada, Stille, and Suzuki coupling reactions of a prototypical
vinyl triflate (12) are included in the Supporting Information
(SI). The reactivity difference between the monosubstituted and
the stereodefined trisubstituted double bonds in these 1,4-
skipped diene products14 should make these almost enantiopure
intermediates valuable components for further synthesis. Further
applications of the silyl enol ethers and the enol triflates are the
subject of ongoing investigations.
ASSOCIATED CONTENT
■
S
* Supporting Information
The Supporting Information is available free of charge on the
ACS Publications website at DOI: 10.1021/jacs.5b10364.
(8) Kersten, L.; Hilt, G. Adv. Synth. Catal. 2012, 354, 863.
(9) Reddy, S. S.; Radhakrishnan, K.; Sivaram, S. Polym. Bull. 1996, 36,
165.
Experimental details; typical reaction conditions for the
hydrovinylation reactions; chromatographic and spectro-
scopic data for all compounds (PDF)
(10) See SI for full experimental details.
(11) Engel, D. A.; Dudley, G. B. Org. Biomol. Chem. 2009, 7, 4149.
(12) The siloxydienes are significantly more reactive compared to the
corresponding unsubstituted dienes. For example, with 0.001 equiv.
catalyst, there is practically no reaction under otherwise identical
conditions for comparable substrates without the siloxy substituent.
Page, J. P.; RajanBabu, T. V. J. Am. Chem. Soc. 2012, 134, 6556−6559.
(13) Stang, P. J.; Mangum, M. G.; Fox, D. P.; Haak, P. J. Am. Chem. Soc.
1974, 96, 4562.
AUTHOR INFORMATION
Corresponding Author
*rajanbabu.1@osu.edu
Notes
■
The authors declare no competing financial interest.
(14) For two recent applications and a list of more extensive references,
see: (a) Macklin, T. K.; Micalizio, G. C. Nat. Chem. 2010, 2, 638.
(b) Huang, Y.; Fananas-Mastral, M.; Minnaard, A. J.; Feringa, B. L.
Chem. Commun. 2013, 49, 3309.
ACKNOWLEDGMENTS
■
Financial assistance for this research provided by US NSF (CHE-
1362095) and NIH (R01 GM108762) is gratefully acknowl-
edged. This paper is dedicated to Dr. William A. Nugent in
recognition of his many seminal contributions to synthetic
chemistry.
REFERENCES
■
(1) (a) Wyatt, P.; Warren, S. Organic Syntheis: Strategy and Control;
John Wiley and Sons: Chichester, 2007. (b) Carey, F. A.; Sundberg, R. J.
Advanced Organic Chemistry Parts A and B, 5th ed.; Springer: New York,
2007.
(2) For example, see: (a) Alkylation: Stoltz, B. M.; Bennett, N. B.;
Duquette, D. C.; Goldberg, A. F. G.; Liu, Y.; Loewinger, M. B.; Reeves,
C. M. Alkylations of Enols and Enolates. In Comprehensive Organic
Synthesis II, 2nd ed.; Knochel, P., Ed.; Elsevier: Amsterdam, 2014; pp 1−
55. (b) Additon to carbonyl compounds: Kobayashi, S.; Yoo, W. J.;
Yamashita, Y. C-C Bond Formation using Lewis Acids and Silicon
Enolates. Comprehensive Chirality; Carreira, E. M., Yamamoto, H., Eds.;
Elsevier: Amsterdam, 2012; pp 168−197. (c) Cα-Hetero-atom bond
formation: Chen, B.-C.; Zhou, P.; Davis, F. A.; Ciganek, E. α-
Hydroxylation of Enolates and Silyl Enol Ethers. Organic Reactions; John
Wiley: Hoboken, NJ, 2004; Vol. 62, pp 1−356. (d) Smith, A. M. R.; Hii,
K. K. Chem. Rev. 2011, 111, 1637. (e) Aromatic substitution:
RajanBabu, T. V.; Reddy, G. S.; Fukunaga, T. J. Am. Chem. Soc. 1985,
107, 5473. (f) Ir-Catalyzed allylation: Graening, T.; Hartwig, J. F. J. Am.
Chem. Soc. 2005, 127, 17192. Catalyzed addition to alkynes: (g) Brazeau,
J.-F.; Zhang, S.; Colomer, I.; Corkey, B. K.; Toste, F. D. J. Am. Chem. Soc.
2012, 134, 2742.
(3) Westmeier, J.; Pfaff, C.; Siewert, J.; von Zezschwitz, P. Adv. Synth.
Catal. 2013, 355, 2651. For another example of a β-vinylation of an
acyclic enone using a vinylboronate nucleophile giving low selectivity
(42% ee), see: Duursma, A.; Boiteau, J. G.; Lefort, L.; Boogers, J. A. F.;
de Vries, A. H. M.; de Vries, J. G.; Minnaard, A. J.; Feringa, B. L. J. Org.
Chem. 2004, 69, 8045.
(4) (a) Wu, T. R.; Chong, J. M. J. Am. Chem. Soc. 2007, 129, 4908.
(b) Okamoto, K.; Hayashi, T.; Rawal, V. H. Org. Lett. 2008, 10, 4387.
D
DOI: 10.1021/jacs.5b10364
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