A general copper-BINAP-catalyzed asymmetric propargylation of ketones with propargyl boronates

Article abstract of DOI:10.1021/ja2028958

An operationally simple copper-BINAP-catalyzed, highly enantioselective propargylation of ketones is presented. The methodology was developed as an enantioselective process for methyl ethyl ketone and shown to be applicable to a wide variety of prochiral

Full text of DOI:10.1021/ja2028958

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A General CopperÀBINAP-Catalyzed Asymmetric Propargylation
of Ketones with Propargyl Boronates
Keith R. Fandrick,* Daniel R. Fandrick, Jonathan T. Reeves, Joe Gao, Shengli Ma, Wenjie Li,
Heewon Lee, Nelu Grinberg, Bruce Lu, and Chris H. Senanayake
Chemical Development, Boehringer Ingelheim Pharmaceuticals Inc., 900 Ridgebury Road/P.O. Box 368, Ridgefield, Connecticut
06877-0368, United States
S Supporting Information
b
propargylations of aldehydes with trimethylsilyl (TMS)-propar-
gyl boronates.14 The need for a practical and general asymmetric
ABSTRACT: An operationally simple copperÀBINAP-
catalyzed, highly enantioselective propargylation of ketones
is presented. The methodology was developed as an en-
antioselective process for methyl ethyl ketone and shown to
be applicable to a wide variety of prochiral ketones. The
resulting homopropargyl adducts are versatile latent carbonyls
from which γ-butyrolactones, β-hydroxy methyl ketones,
and β-hydroxycarboxylates are readily obtained.
catalytic propargylation of prochiral aliphatic ketones encour-
aged us to investigate this reaction further, focusing on the most
challenging of prochiral aliphatic ketones, MEK. Herein we
report a general copper alkoxide-catalyzed, highly enantioselec-
tive propargylation of ketones employing the commercially
available BINAP ligand.
With MEK as a challenging model substrate, initial attempts
at the asymmetric propargylation employing our previously
reported copper(II) isobutyrateÀMeO-BIBOP14 catalyst system
provided the desired homopropargylic alcohol 3a with moderate
enantioselectivity (69% ee; Table 1, entry 1). Attempts to im-
prove the facial discrimination with this catalyst system were not
successful,15 and an extensive ligand, solvent, and catalyst
survey15 revealed copper(II) isobutyrateÀBINAP-type catalysts
to be superior for the facial discrimination, providing the adduct
in 79À83% ee. Furthermore, decreasing the temperature of the
reaction to À83 °C provided the desired product in 83% isolated
yield with 95% enantiomeric excess for this challenging substrate.
After the optimal reaction parameters had been established,
structurally diverse prochiral ketones were surveyed for the pro-
pargylation (Table 2). This methodology was found to be effective
for prochiral ketones other than MEK, including cyclopropyl
methyl ketone (3b). It was also amenable to a wide variety of
acetophenone derivatives, providing the corresponding adducts
in 93À98% yield with high enantioselectivity (94À96% ee)
(entries 7À11). The chemistry was shown to display wide
functional-group tolerance, as an ester (1l), pyridine (1n) and
an N-tosyl indole (1o) were well-tolerated, providing the corre-
sponding adducts in high yields (87À95%) with 91À95%
enantiomeric excess. The methodology was not readily affected
by the electronic nature of the acetophenone substrate, as both
p-methoxyacetophenone (1j) and p-nitroacetophenone (1i) pro-
vided the corresponding addition products with high enantioin-
duction (95 and 93% ee, respectively). However, the reaction
with benzofuran methyl ketone (1p) required a catalyst loading
of 10 mol % and 35 h to reach complete conversion and pro-
ceeded with a decrease in enantiocontrol (84% ee).
he synthesis of chiral tertiary alcohols represents a major
T
challenge in asymmetric catalysis.1 One of the most challen-
ging substrates in this area is methyl ethyl ketone (MEK), for
which there is minimal steric differentiation of the carbonyl’s
prochiral faces. To date, only low enantiocontrol has been realized
with small-molecule catalysis (Figure 1).2 Although enzymatic
processes have been able to address this substrate, the enantio-
control is only moderate in view of the fact that enzymatic
processes normally proceed with excellent stereoinduction.3
With this challenge in mind, we set out to develop a practical
asymmetric catalytic propargylation focusing on MEK.
Chiral homopropargylic alcohols are valuable synthons because
of the synthetic versatility provided by the alkyne moiety.4 The
asymmetric propargylation of aldehydes has seen significant
development through the use of stoichiometric chiral reagents,5
Barbier-type processes,6 and the catalytic chiral Lewis acid-7 and
base-type8 methodologies. Limited success9 had been realized
with the corresponding asymmetric propargylations of prochiral
ketones until Soderquist and co-workers10 were able to imple-
ment their chiral allenyl borolane reagents. Recently, Shibasaki
and co-workers11 developed copperÀboron exchange into a
highly enantioselective catalytic allylation of aldehydes and imines
with chiral catalytic bis(phosphine)copper complexes. Further-
more, they implemented this concept for the asymmetric allyla-
tions and propargylations of ketones with allenyl boronates.12
Although high enantioselectivity can be achieved in asymmetric
propargylations of acetophenones with the use of their modular
chiral bisphosphine ligands, only moderate enantiocontrol
is realized with aliphatic prochiral ketones.12 The development
of a general highly enantioselective propargylation of aliphatic
prochiral ketones as well as acetophenones is still needed.
Recently, we showed that copper alkoxideÀMeO-BIBOP13
complexes are competent catalysts for highly enantioselective
The acetylene component of the chiral homopropargylic
alcohol is a versatile functional group.12 However, the acetylene
can also be considered as a latent carbonyl, thus making this
methodology an attractive alternative to the homoacetate and
Received: March 30, 2011
Published: June 03, 2011
r
2011 American Chemical Society
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Table 2. Substrate Survey for the CuÀBINAP Asymmetric
Propargylationa
Figure 1. Highest reported enantioselective catalytic carbonyl additions
with MEK.
Table 1. Initial Development of the Asymmetric Propargy-
lation with Methyl Ethyl Ketone (1a)a
a Typical reaction conditions: 1.2 mmol of ketone, 1.7 mmol of
propargyl boronate, 3 mL of THF. b Complete conversion was observed
upon GC analysis. c Absolute stereochemistries; reported as enantiomeric
excess as determined by chiral HPLC analysis. d Isolated yield 81%.
e Isolated yield 83%
acetate aldol reactions.2a,16 Treatment of chiral homopropargylic
alcohol 3f with catalytic palladium and stoichiometric copper17
furnished γ-butyrolactone 4 in 92% isolated yield without
erosion of the chiral center (eq 6 in Figure 2). The correspond-
ing β-hydroxy methyl ketone 6 could also be accessed in 75%
yield via terminal acetylene 5 by gold-catalyzed hydration (eq 7
in Figure 2).18 Although ruthenium oxide-catalyzed oxidative
a Typical reaction conditions: 1.2 mmol of ketone, 1.7 mmol of
propargyl boronate, 3 mL of THF. b Determined by chiral HPLC
analysis. c 10 mol % catalyst, 35 h.
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Figure 2. Derivatization of homopropargylic tertiary alcohols into
homoacetate and acetate aldol products.
Figure 3. Stereochemical model of the propargylation of MEK with
CuÀ(R)-BINAP.
Scheme 1. Proposed Catalytic Cycle for the Propargylation
of Ketones with Propargyl Borolane 2
exchange with propargyl borolane 2, intermediate A is regener-
ated to complete the catalytic cycle.
In conclusion, focusing on MEK as the paramount prochiral
aliphatic ketone for the initial development of the enantioselective
propargylation enabled the development of this methodology
into a general system amenable not only to prochiral aliphatic
ketones but also to a variety of acetophenones. The homopro-
pargylic products have been shown to be versatile latent carbonyls,
making this methodology a practical alternative to the asymmetric
homoacetate and acetate aldol reactions.
’ ASSOCIATED CONTENT
S
Supporting Information. Optimization studies, experi-
b
mental procedures, characterization data (1H NMR and 13C
NMR spectra for all products), chiral HPLC data and copies of
chromatograms, and determination of absolute stereochemis-
tries. This material is available free of charge via the Internet at
http://pubs.acs.org.
cleavage is precedented for terminal acetylenes,19 the corre-
sponding cleavage with TMS-acetylene 3a under the standard
conditions (acetonitrile/water solvent system) was highly exo-
thermic and gave a poor yield (40%). Performing the oxidative
cleavage with a biphasic isopropyl acetate/water solvent system
(eq 8 in Figure 2) offered the necessary control to provide the
corresponding β-benzoate carboxylic acid 8 in 97% yield, thus
allowing access to this challenging substrate2a,20 with high
enantiomeric excess (93% ee).
’ AUTHOR INFORMATION
Corresponding Author
keith.fandrick@boehringer-ingelheim.com
’ REFERENCES
(1) For a recent review of asymmetric catalysis, see: Carreira, E. M.;
Kvaerno, L. Classics in Stereoselective Synthesis; Wiley-VCH: Weinheim,
Germany, 2009.
Scheme 1 presents a proposed catalytic cycle based on a
previously demonstrated copper-alkoxide B/Cu exchange12 with
propargyl borolane 2 to form allenylcopper intermediate A.14
After complexation with a ketone to form B, the stereochemically
defining intermolecular propargylation14 occurs, affording copper
alkoxide C. A stereochemical model of B based on the copperÀ
(R)-BINAP crystal structure of Anslyn21 is presented in Figure 3,
with the BINAP ligand represented as a space-filling model. The
allenyl and ketone moieties are appended on the two available
sites in the distorted tetrahedral copperÀligand complex. The
ketone is oriented to position the more sterically demanding
substituent away from the ligand, exposing the Re face for the
intramolecular propargylation.22 Following subsequent Cu/B
(2) For selected examples of asymmetric catalytic additions to
MEK, see: (a) Lewis base-catalyzed aldol addition of trichlorosilyl
ketene to MEK (32% ee): Denmark, S. E.; Fan, Y.; Eastgate, M. D.
J. Org. Chem. 2005, 70, 5235–5248. (b) Aminothiourea-catalyzed
cyanosilylation of MEK (11% ee): Zuend, S.; Jacobsen, E. N. J. Am.
Chem. Soc. 2007, 129, 15872–15883. (c) Enantioselective phenylation of
MEK (6% ee): Forrat, V. J.; Prieto, O.; Ramꢀon, D. J.; Yus, M. Chem.—
Eur. J. 2006, 12, 4431–4445. (d) Asymmetric allylation of MEK
(40% ee): Harper, K. C.; Sigman, M. S. Proc. Natl. Acad. Sci. U.S.A.
2011, 108, 2179–2183.
(3) For selected examples of asymmetric enzymatic catalysis
with MEK, see: (a) Cabirol, F. L.; Tan, P. L.; Tay, B.; Cheng, S.;
Hanefeld, U.; Sheldon, R. A. Adv. Synth. Catal. 2008, 350, 2329–2338.
(b) Nanda, S.; Kato, Y.; Asano, Y. Tetrahedron 2005, 61, 10908–10916.
10334
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COMMUNICATION
(c) Effenberger, F.; H€orsch, B.; Weingart, F.; Ziegler, T.; K€uhner, S.
Tetrahedron Lett. 1991, 32, 2605–2608.
(21) Nieto, S.; Lynch, V. M.; Anslyn, E. V.; Kim, H.; Chin, J. Org.
Lett. 2008, 10, 5167–5170.
(4) For selected examples of the use of chiral homoprogargylic
alcohols in natural product syntheses, see: (a) Carter, R. G.; Weldon,
D. J. Org. Lett. 2000, 2, 3913–3916. (b) O’Sullivan, P. T.; Buhr, W.;
Fuhry, M. A. M.; Harrison, J. R.; Davies, J. E.; Feeder, N.; Marshall, D. R.;
Burton, J. W.; Holmes, A. B. J. Am. Chem. Soc. 2004, 126, 2194–2207.
(c) Trost, B. M.; Dong, G. Nature 2008, 456, 485–488. (d) Liu, S.; Dong,
C.-G.; Kishi, Y. Org. Lett. 2009, 11, 4520–4523. (e) Francais, A.; Leyva,
A.; Etxebarria-Jardi, G.; Ley, S. V. Org. Lett. 2010, 12, 340–343.
(5) For selected examples of stoichiometric chiral-reagent-based
propargylations of aldehydes, see: (a) Haruta, R.; Ishiguro, M.; Ikeda,
N.; Yamamoto, H. J. Am. Chem. Soc. 1982, 104, 7667–7669. (b) Corey,
E. J.; Yu, C.-M.; Lee, D.-H. J. Am. Chem. Soc. 1990, 112, 878–879.
(c) Lee, K.-C.; Lin, M.-J.; Loh, T.-P. Chem. Commun. 2004, 2456–2457.
(d) Lai, C.; Soderquist, J. A. Org. Lett. 2005, 7, 799–802.
(22) The stereochemical model was generated by replacing the
appended counterions on the CuÀBINAP crystal structure with MEK
and the TMS-allene unit. The BINAP ligand and the position of the
carbonyl oxygen of MEK and C1 of the TMS-allene were frozen as found
in the crystal structure. The distance between the terminus of the allene
and the carbonyl carbon of MEK was constrained as 3.0 Å, after which a
single-point energy minimization was performed using Spartan ’08
(version 1.1.1).
(6) For selected examples, see: (a) Boldrini, G. P.; Tagliavini, E.;
Trombini, C.; Umani-Ronchi, A. J. Chem. Soc., Chem. Commun. 1986,
685–686. (b) Inoue, M.; Nakada, M. Org. Lett. 2004, 6, 2977–2980. (c)
Hirayama, L. C.; Dunham, K. K.; Singaram, B. Tetrahedron Lett. 2006,
47, 5173–5176. (d) Naodovic, M.; Xia, G.; Yamamoto, H. Org. Lett.
2008, 10, 4053–4055. (e) Liu, S.; Kim, J. T.; Dong, C.-G.; Kishi, Y. Org.
Lett. 2009, 11, 4520–4523.
(7) For selected examples of Lewis acid-catalyzed propargylations of
aldehydes with allenylmetal reagents, see: (a) Keck, G. E.; Krishnamurthy,
D.; Chen, X. Tetrahedron Lett. 1994, 35, 8323–8324. (b) Minowa, N.;
Mukaiyama, T. Bull. Chem. Soc. Jpn. 1987, 60, 3697–3704. (c) Yu, C.-M.;
Yoon, S.-K.; Choi, H.-S.; Baek, K. Chem. Commun. 1997, 763–764.
(d) Yu, C.-M.; Yoon, S.-K.; Baek, K.; Lee, J.-Y. Angew. Chem., Int. Ed.
1998, 37, 2392–2395. (e) Evans, D. A.; Sweeny, Z. K.; Rovis, T.;
Tedrow, J. S. J. Am. Chem. Soc. 2001, 123, 12095–12096. (f) Hanawa, H.;
Uraguchi, D.; Konishi, S.; Hashimoto, T.; Maruoka, K. Chem.—Eur. J.
2003, 9, 4405–4413.
(8) Denmark, S. E.; Wynn, T. J. Am. Chem. Soc. 2001, 123,
6199–6200.
ꢀ
(9) Justicia, J.; Sancho-Sanz, I.; Alvarez-Manzaneda, E.; Oltra, J. E.;
Cuerva, J. M. Adv. Synth. Catal. 2009, 351, 2295–2300.
(10) Hernandez, E.; Burgos, C. H.; Alicea, E.; Soderquist, J. A. Org.
Lett. 2006, 8, 4089–4091.
(11) For selected examples, see: (a) Wada, R.; Oisaki, K.; Kanai, M.;
Shibasaki, M. J. Am. Chem. Soc. 2004, 126, 8910–8911. (b) Wada, R.;
Shibuguchi, T.; Makino, S.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2006, 128, 7687–7691. (c) Kanai, M.; Wada, R.; Shibuguchi,
T.; Shibasaki, M. Pure Appl. Chem. 2008, 80, 1055–1062.
(12) Shi, S.-L.; Zu, L.-W.; Oisaki, K.; Kanai, M.; Shibasaki, M. J. Am.
Chem. Soc. 2010, 132, 6638–6639.
(13) Tang, W.; Qu, B.; Capacci, A.; Rodriguez, S.; Wei, X.; Haddad,
N.; Narayanan, B.; Ma, S.; Grinberg, N.; Yee, N. K.; Krishnamurthy, D.;
Senanayake, C. H. Org. Lett. 2010, 12, 176–179.
(14) Fandrick, D. R.; Fandrick, K. R.; Reeves, J. T.; Tan, Z.; Tang,
W.; Capacci, A. G.; Rodriguez, S.; Song, J. J.; Lee, H.; Yee, N. K.;
Senanayake, C. H. J. Am. Chem. Soc. 2010, 132, 7600–7601.
(15) See the Supporting Information for full details.
(16) For selected examples of enantioselective acetate aldol reac-
tions, see: (a) Singer, R. A.; Brock, J. R.; Carreira, E. M. Helv. Chim. Acta
2003, 86, 1040–1044. (b) Crimmins, M. T.; Shamszad, M. Org. Lett. 2007,
9, 149–152. (c) Zhang, Y.; Phillips, A. J.; Sammakia, T. Org. Lett. 2004,
6, 23–25. (d) Kanwar, S.; Trehan, S. Tetrahedron Lett. 2005, 46, 1329–1332.
(17) Yasui, H.; Hirai, K.; Yamamoto, S.; Takao, K.; Tadano, K.
Heterocycles 2006, 67, 123–128.
(18) Marion, N.; Ramꢀon, R. S.; Nolan, S. P. J. Am. Chem. Soc. 2009,
131, 448–449.
(19) Chang, W.-W.; Zhang, D.-W.; Chen, F.; Dong, Z.-M.; Yang, D.
Synlett 2009, 3159–3162.
(20) For the auxiliary-based method via the formation of the
intermediate 1,3-perhydrooxazin-4-one (33% ee), see: Bandini, E.;
Martelli, G.; Spunta, G.; Bongini, A.; Panunzio, M. Synlett 1999,
1735–1738.
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