Enantioselective Suzuki reactions: Catalytic asymmetric synthesis of compounds containing quaternary carbon centers

Article abstract of DOI:10.1002/anie.200352648

Prochiral ditriflates can act as substrates in asymmetric Suzuki couplings by using an enantioselective desymmetrization strategy. The products are obtained with selectivities up to 86% ee and contain a quaternary carbon center and a synthetically useful

Full text of DOI:10.1002/anie.200352648

Angewandte
Chemie
Suzuki coupling reactions to produce axially chiral sys-
tems.[3–5] Hayashi et al. have developed a metal-catalyzed
asymmetric biaryl synthesis; a desymmetrization approach
was employed to allow palladium- and nickel-catalyzed
enantioselective Kumada couplings to generate axially
chiral systems with high selectivities.[6] A similar approach
has also been employed to prepare systems containing planar
chirality.[7] Herein, we utilize a desymmetrization strategy to
detail the first report on the intermolecular enantioselective
Suzuki couplings that produce compounds containing stereo-
defined sp3 carbon centers.[8]
An important consideration with desymmetrization strat-
egies is that the meso- or the achiral substrates are readily
available and do not require laborious synthetic sequences.[9]
For this reason we were drawn to the use of ditriflates 1,
derived from the corresponding cyclic 1,3-diketones, as
attractive and readily available desymmetrization substrates
(Scheme 1). We reasoned that the reaction of the triflates
Asymmetric Catalysis
Enantioselective Suzuki Reactions: Catalytic
Asymmetric Synthesis of Compounds Containing
Quaternary Carbon Centers**
Michael C. Willis,* Luke H. W. Powell,
Christelle K. Claverie, and Simon J. Watson
Palladium-catalyzed coupling reactions are some of the most
widely used and reliable transformations available to organic
chemists, and it is therefore not surprising that the efforts
taken to adapt these key transformations to asymmetric
processes are ongoing.[1] The use of enantiomerically pure
palladium catalysts in inter- and intramolecular Heck reac-
tions is well established and has been applied to a number of
successful total syntheses.[2] The systems studied in Heck
reactions generally involve carbon–carbon double bond
transposition, thus resulting in the stereoselective formation
of a new sp3 center. The development of enantioselective
cross-coupling reactions, such as Suzuki and Stille couplings,
is more complex, in that generally the reactions result in the
union of two sp2 centers with no stereogenic sp3 centers being
produced. An elegant solution, reported recently by the
research groups of both Buchwald and Cammidge, is to use
Scheme 1. Desymmetrization-based enantioselective palladium cou-
plings. Tf=trifluoromethanesulfonyl.
such as 1 with a chiral palladium catalyst should allow
selective oxidative addition to produce enantiomerically
enriched vinyl–palladium species 2. Coupling of intermediate
2 with a nucleophilic partner should deliver the enantiomeri-
cally enriched desymmetrized products 3 containing a defined
quaternary stereocenter. Intermediates similar to 2 are
common in many cross-coupling processes and variation in
the coupling partner should allow a range of enantioselective
palladium-catalyzed coupling reactions to be developed. The
wide availability, low toxicity, and good tolerance towards
oxygen and water of boronic acids and esters prompted us to
focus our initial study on the development of an enantiose-
lective Suzuki reaction.[10]
[*] Dr. M. C. Willis,L. H. W. Powell,C. K. Claverie
Department of Chemistry
University of Bath
Bath,BA2 7AY (UK)
Fax: (+44)1225-386231
E-mail: m.c.willis@bath.ac.uk
We focused on the coupling of a five-membered ditriflate
1a and boronic acid 4 as a platform to evaluate conditions for
the proposed Suzuki couplings.[11,12] Experiments revealed
that the optimal catalyst for this coupling was generated from
S. J. Watson
Novartis Horsham Research Centre
Wimblehurst Road
À
MeO MOP (MOP = (diphenylphosphanyl)-2’-methoxy-1,1’-
Horsham,RH12 4AB (UK)
binaphthyl) and Pd(OAc)2 using dioxane as the reaction
solvent (Scheme 2).[13] Under these conditions, the coupled
product could be obtained with 77% ee.
[**] This work was supported by the EPSRC,the University of Bath,and
Novartis Pharmaceuticals. The EPSRC Mass Spectrometry service
at the University of Wales Swansea is also thanked for their
assistance. Dr. Alastair Denholm is thanked for his helpful
discussions.
With optimized conditions for the selective union of 1a
and 4 in hand, we further explored the tolerance of the
process towards a range of boronic acids (Table 1).[15] Both
the para- and the meta-substituted acetylbenzene boronic
Supporting information for this article is available on the WWW
under http://www.angewandte.org or from the author.
Angew. Chem. Int. Ed. 2004, 43, 1249 –1249
DOI: 10.1002/anie.200352648
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Communications
The enantioselective synthesis of quaternary carbon
centers remains a considerable challenge;[16] the presence of
such centers in the monocoupled products, obtained above,
together with the remaining triflate group results in these
compounds being useful synthetic intermediates. To demon-
strate their utility we elaborated the remaining triflate
functionality by a series of palladium-catalyzed reactions
(Scheme 3). Monotriflate 6 was initially subjected to a second
Scheme 2. Desymmetrization of the ditriflate 1a.
Table 1: Enantioselective Suzuki coupling of the ditriflate 1a with
representative boronic acids.[a]
entry
Ar
Yield [%][b]
ee [%][c]
1
2
3
4
5
6
7
8
9
4-C6H5C(O)Me
3-C6H5C(O)Me
2-C6H5C(O)Me
4-C6H5CHO
3-C6H5CHO
2-C6H5CHO
4-C6H5-OH
46
51
<5
47
57
41
43
53
66
77
86
–
Scheme 3. Functionalization of the monotriflate 6. Reagents: a) KOH,
73[d]
80[d]
82
74
72
85
N-phenylsulfonyl-3-indoleboronic acid,Pd(OAc) (10 mol%),PPh 3
2
(22 mol%),THF,room temperature,1 h; b) Pd(OAc) (10 mol%),
2
PPh3 (22 mol%),NBu 3,HCO 2H,DMF,60 8C,1 h; c) Pd(OAc) 2
(15 mol%),PPh 3 (30 mol%),NBu 3,DMF,60 8C,1 h. Bs =benzenesul-
fonyl. Bn=benzyl
3-furyl
3-N-Bs-indolyl[e]
[a] For all the reactions: 10 mol% Pd,11 mol% ligand,2.0 equiv base,
2.0 equiv boronic acid. [b] Yield of the isolated pure material. [c] Deter-
mined by chiral HPLC analysis using a Chiracel OD,OA,or OJ column.
[d] ee values were determined (chiral HPLC) on a derivative,see
Supporting Information for details. [e] Bs= benzenesulfonyl.
Suzuki coupling to provide bisaryl 7 in 93% yield. The triflate
functionality present in 6 could also undergo palladium-
catalyzed reduction (HCO2H, NBu3) to yield alkene 8 in 85%
yield. Finally, the triflate functionality of 6 could be exploited
À
in an intramolecular C Hcoupling procedure to deliver
acids performed well, and provided the coupled products in
77 and 86% ee, respectively (entries 1 and 2). However, the
corresponding ortho-substituted boronic acid displayed poor
reactivity, presumably because of steric factors (entry 3). All
the three positional isomers of formylbenzene boronic acid
performed well (entries 4–6). The hydroxy functionality is
compatible with the reaction conditions, thus allowing 4-
hydroxybenzene boronic acid to deliver the product with
74% ee (entry 7). Finally, heterocyclic boronic acids are also
tolerated well, with 3-furyl- and N-phenylsulfonyl-3-indole
boronic acids providing the coupled products with enantio-
selectivities of 72 and 85%, respectively (entries 8 and 9). The
enantiopurity of the products can be improved by simple
recrystallization. For example, the enantioselectivity of the
material obtained in entry 1 can be increased from 77 to
97% ee by a single recrystallization from a dichloromethane/
hexane mixture (31% yield). The relatively close enantiose-
lectivities obtained over a range of boronic acids are
consistent with the oxidative addition being the enantiode-
termining step; the variations observed are most likely as a
consequence of differing reactivities between the boronic
acids. The moderate to good yields obtained are a reflection
on the catalystꢀs lifetime, with starting material (15%–25%)
being recovered in all cases.
tricylic 9 in quantitative yields.[17]
In conclusion, we have demonstrated that the use of a
desymmetrization strategy allows highly enantioselective
Suzuki coupling reactions that can deliver compounds
containing stereodefined quaternary carbon centers. The
process can tolerate a variety of functionalized boronic
acids and also delivers products containing vinyl triflate
units that can be functionalized by a range of palladium-
catalyzed reactions. The enantioselectivities obtained are
good and represent the highest that have been achieved for a
Suzuki coupling in which stereogenic carbon centers are
created.
Experimental Section
Dry degassed 1,4-dioxane (2 mL) was added to a mixture of ditriflate
1a (93.20 mg, 0.20 mmol), the relevant boronic acid (0.40 mmol),
À
Pd(OAc)2 (4.50 mg, 0.02 mmol, 10 mol%), (S)-MeO MOP
(10.30 mg, 0.022 mmol, 10 mol%), and cesium fluoride (91.40 mg,
0.60 mmol). The reaction mixture was stirred for 6–10 h at room
temperature. EtOAc (10 mL) and water (8 mL) were added and the
aqueous layer was extracted using EtOAc (2 ” 10 mL). The combined
organic phases were dried (MgSO4), filtered, and concentrated under
reduced pressure. The residue was purified by flash chromatography
(gradient elution 1–40% diethyl ether:hexane) to give the monotri-
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Chemie
flate products. See the Supporting Information for complete data for
all novel compounds.
(SEMI-ESPHOS; 36, 16% ee) were more encouraging although
À
MeO MOP (33, 55% ee) performed best. The use of
À
[Pd2(dba)3]/MeO MOP
(dba = trans,trans-dibenzylideneace-
tone) and CsF, dioxane conditions resulted in 30% yield and
51% ee.
Received: August 13, 2003
Revised: October 23, 2003 [Z52648]
[14] S. Breeden, D. J. Cole-Hamilton, D. F. Foster, G. J. Schwarz, M.
Wills, Angew. Chem. 2000, 112, 4272 – 4274; Angew. Chem. Int.
Ed. 2000, 39, 4106 – 4108.
[15] The absolute configuration of compound 5 was established by X-
ray diffraction analysis of the recrystallized material (97% ee).
The absolute configurations of the remaining adducts are
assigned by analogy.
[16] For reviews detailing the enantioselective construction of
quaternary centers, see: a) J. Christoffers, A. Mann, Angew.
Chem. 2001, 113, 4725 – 4732; Angew. Chem. Int. Ed. 2001, 40,
4587 – 4591; b) E. J. Corey, A. Guzman-Perez, Angew. Chem.
1998, 110, 402 – 415; Angew. Chem. Int. Ed. 1998, 37, 388 – 401;
c) K. Fuji, Chem. Rev. 1993, 93, 2037 – 2066.
Keywords: asymmetric catalysis · cross-coupling ·
enantioselectivity · palladium
.
[1] For reviews of enantioselective palladium-catalyzed coupling
reactions, see: a) T. Hayashi in Comprehensive Asymmetric
Catalysis, Vol. 2 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto),
Springer, Berlin, 1999, pp. 887 – 907; b) M. Ogasawara, T. Hay-
ashi in Catalytic Asymmetric Synthesis, 2nd ed. (Ed.: I. Ojima),
Wiley, New York, 2000, pp. 651 – 674; c) C. G. Frost in Rodd's
Chemistry of Carbon Compounds, Vol. 5, 2nd ed. (Ed.: M.
Sainsbury), Elsevier, Amsterdam, 2001, pp. 315 – 350.
[2] For recent reviews of enantioselective Heck reactions, see: a) M.
Shibasaki, E. M. Vogl in Comprehensive Asymmetric Catalysis,
Vol. 1 (Eds.: E. N. Jacobsen, A. Pfaltz, H. Yamamoto), Springer,
Berlin, 1999, pp. 457 – 487; b) M. Shibasaki, E. M. Vogl, J.
Organomet. Chem. 1999, 576, 1 – 15; c) O. Loiseleur, M. Hayashi,
M. Keenan, N. Schmees, A. Pfaltz, J. Organomet. Chem. 1999,
576, 16 – 22; d) Y. Donde, L. E. Overman in Catalytic Asymmet-
ric Synthesis, 2nd ed. (Ed.: I. Ojima), Wiley, New York, 2000,
pp. 675 – 697.
[17] M. C. Willis, C. K. Claverie, M. F. Mahon, Chem. Commun.
2002, 832 – 833.
[3] J. Yin, S. L. Buchwald, J. Am. Chem. Soc. 2000, 122, 12051 –
12052.
[4] A. N. Cammidge, K. V. L. CrØpy, Chem. Commun. 2000, 1723 –
1724.
[5] For the application of an antropo-enantioselective Suzuki
reaction to the synthesis of the analogues of rhazinilam, see:
A. Herrbach, A. Marinetti, O. Baudoin, D. GuØnard, F. GuØritte,
J. Org. Chem. 2003, 68, 4897 – 4905.
[6] a) T. Hayashi, K. Hayashizaki, T. Kiyoi, Y. Ito, J. Am. Chem. Soc.
1988, 110, 8153 – 8156; b) T. Hayashi, S. Niizuma, T. Kamikawa,
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c) T. Kamikawa, T. Hayashi, Tetrahedron 1999, 55, 3455 – 3466.
[7] a) M. Uemura, H. Nishimura, T. Hayashi, J. Organomet. Chem.
1994, 473, 129 – 137. For a palladium-catalyzed carbonylation
route to planar chiral systems, see: b) B. Gotov, H.-G. Schmalz,
Org. Lett. 2001, 3, 1753 – 1756.
[8] For a desymmetrization-based enantioselective intramolecular
Suzuki coupling that delivers products with selectivities up to
31% ee, see: S. Y. Cho, M. Shibasaki, Tetrahedron: Asymmetry
1998, 9, 3751 – 3754.
[9] For a review of enantioselective desymmetrization, see: M. C.
Willis, J. Chem. Soc. Perkin Trans. 1 1999, 1765 – 1784.
[10] For reviews of Suzuki reactions, see: a) N. Miyaura, A. Suzuki,
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[11] For the synthesis of 1a and its use in achiral Suzuki couplings,
see: M. C. Willis, C. K. Claverie, Tetrahedron Lett. 2001, 42,
5105 – 5107.
[12] For the use of substrates related to 1a in enantioselective
intramolecular Heck reactions, see: S. Bräse, Synlett 1999, 1654 –
1656.
[13] Initial catalyst evaluation was conducted using a KOH–THF
combination at room temperature; bidentate ligands such as 2,2’-
bis(diphenylphosphanyl)-1,1’-binaphthyl (BINAP), O-isopropy-
lidene-2,3-dihydroxy-1,4-bis(diphenylphosphanyl)butane
(DIOP), and 2,3-bis(diphenylphosphanyl)butane (CHIRA-
PHOS) produced inactive catalysts. 4,12-Bis(diphenylphos-
phanyl)-[2,2]paracyclophane (PHANEPHOS; 36, 12% ee), neo-
menthyldiphenylphosphane (29, 6% ee), and 1-(2-methoxy-
phenyl)-2-phenylhexahydropyrrolo[1,2-c][1,3,2]diazaphosphole[14]
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