Ni(II) Tol-BINAP-catalyzed enantioselective Michael reactions of β-ketoesters and unsaturated N-acylthiazolidinethiones

Article abstract of DOI:10.1021/ja053820q

The enantioselective addition of β-ketoesters to unsaturated N-acylthiazolidinethiones catalyzed by Ni(II) Tol-BINAP Lewis acid complexes is reported. Notable features of this reaction are its operation simplicity, the obviated need for the addition of an

Full text of DOI:10.1021/ja053820q

Published on Web 07/19/2005
Ni(II) Tol-BINAP-Catalyzed Enantioselective Michael Reactions of â-Ketoesters
and Unsaturated N-Acylthiazolidinethiones
David A. Evans,* Regan J. Thomson, and Francisco Franco
Department of Chemistry and Chemical Biology, HarVard UniVersity, Cambridge, Massachusetts 02138
Received June 10, 2005; E-mail: evans@chemistry.harvard.edu
Table 1. Scope of the â-Ketoester Addition to Crotonyl Thione 2aa
The Michael reaction ranks as one of the most useful C-C bond
constructions, and the development of catalytic enantioselective
variants has become an important endeavor.1 Previously, our
research group has reported selective Mukaiyama-Michael reac-
tions of silylketene acetals to alkylidene malonates and unsaturated
N-acyloxazolidinones, catalyzed by Cu(II) bisoxazoline complexes.2
More recently, we reported a Ni(II)-catalyzed direct addition of
malonates and â-ketoesters to nitroalkenes.3 Here we wish to report
an operationally simple, direct addition of â-ketoesters to unsatu-
rated N-acylthiazolidinethiones, catalyzed by Ni(II) p-Tol-BINAP
Lewis acid complexes 1b and 1c.4 The products are readily
converted into dihydropyrone derivatives (eq 1), which are useful
substrates for further stereoselective bond constructions (eq 2).
entry
3 (R)
time (h)
yield 4 (%)b
yield 5 (%)b
ee (%)c
1
2
3
4
5
6
7d
Me (a)
Et (b)
n-Pr (c)
i-Bu (d)
C6H11 (e)
Ph (f)
12
14
14
24
24
12
12
89
92
86
78
97
85
95
84
80
85
72
94
94
94
93
94
93
91
90
83
91
Ph (f)
a 0.25 mmol 2a, 1.5 equiv of 3, 0.2 M in EtOAc, 0 °C. b Isolated yield.
c Determined by chiral HPLC. d 10 mol % catalyst 1c.
Table 2. Scope of the Thiazolidinethione Michael Acceptor 2a
entry
2 (R)
time (h)
yield 6 (%)b
yield 7 (%)b
ee (%)c
Kanemasa has reported the enantioselective Michael addition of
1,3-diketones and related nucleophiles to unsaturated acylpyrazoles
and oxazolidinones, using a combination of a chiral Ni-based Lewis
acid and an appropriate amine base.5 Similar experiments by us,
utilizing the readily available complex 1b,6 afforded little or no
desired product. However, we have found that 1b (10 mol %)
catalyzes the addition of tert-butyl acetoacetate (3a) to crotonyl
thiazolidinethione 2a,7 in the absence of an amine base, to afford
4a as a 1:1 mixture of diastereomers. Treatment of 4a with DBU
(20 mol %) resulted in the formation of enantioenriched dihydro-
pyrone 5a.8 A solvent survey indicated that ethyl acetate is the
preferred reaction medium in terms of reaction rate and enantio-
selectivity (Table 1, entry 1).
With effective conditions for the t-butyl acetoacetate9 reaction
in hand, additions of other â-ketoester nucleophiles were evalu-
ated.10 Generally, unbranched and branched ketoester substrates
afford good yields (78-97%) and enantioselectivities (Table 1,
entries 1-5). The use of the tetrafluoroborate catalyst 1c affords
slightly better enantioselectivity for 3f (Table 1, entry 7); however,
this trend has not yet been evaluated for all cases.
The scope of the thione Michael acceptor is summarized in Table
2. While the triflate complex was an excellent catalyst for Michael
acceptor 2a (R ) Me), the tetrafluoroborate complex 1c is superior
as its derived substrate complexes are generally more soluble, while
maintaining similar reactivity to 1b. Thiones 2a-2c generated the
desired Michael adducts in good yield and with high enantio-
selectivity (Table 2, entries 1-3). Substitution at the δ-position
results in a marked decrease in reactivity and selectivity (Table 2,
entry 4), a common attribute for this and related reactions. For
1
2
3
4d
5
6
7
Me (a)
Et (b)
12
14
14
24
72
12
24
95
88
91
67
-
84
89
75
72
10e
97
-
93
95
95
84
70
97
-
n-Pr (c)
i-Bu (d)
i-Pr (e)
CO2Et (f)
Ph (g)
87
nrf
a 0.25 mmol 2, 1.5 equiv of 3a, 0.2 M in EtOAc, 0 °C. b Isolated yield.
c Determined by chiral HPLC. d 0.8 M in EtOAc. e From unpurified 6e.f No
reaction.
γ-branched substrate 2e (R ) i-Pr), the reaction is prohibitively
slow (Table 2, entry 5). Alternatively, the fumarate derivative 2f
(R ) CO2Et) afforded the desired Michael adduct in high yield
and 97% enantiomeric excess (Table 2, entry 6).
The Michael adducts are readily converted to the corresponding
acyclic ketoester derivatives by treatment with K2CO3 in methanol
followed by acidic decarboxylation. Representative examples are
illustrated in eq 3.11
There are two plausible roles that the Ni catalyst could play in
promoting this reaction: (a) generation of a Ni-bound ketoester
enolate and (b) Lewis acid activation of the thiazolidinethione
Michael acceptor. The first mechanism would be analogous to our
recently reported addition of â-ketoesters to conjugated nitro-
alkenes.3 However, the failure of complexes 1a-1c to catalyze such
a reaction provides some circumstantial evidence against such a
proposal. The absolute sense of asymmetric induction observed in
these reactions is the same as that observed for the 1b-catalyzed
enantioselective Diels-Alder reaction of 2a with cyclopentadiene
(eq 4).12 Both of these results are consistent with addition of the
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J. AM. CHEM. SOC. 2005, 127, 10816-10817
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C O M M U N I C A T I O N S
high yield. No loss of stereochemical integrity was observed during
any of these ring-opening processes.
The present study is complementary to a recent enantioselective
addition-cyclization sequence reported by Kanemasa.5a The method
detailed in this communication provides a practical approach to
the enantioselective construction of monocyclic dihydropyrone
derivatives.14 These adducts afford useful options for the stereo-
selective construction of vicinal alkyl stereocenters in both dia-
stereochemical variants (Scheme 1). These stereochemical options
are complementary to the Claisen rearrangement for the construction
of either syn or anti vicinal carbon substituents on bis-functionalized
carbon chains.15
Figure 1. Stereochemical model for Michael reaction.
nucleophile/diene to the thiazolidinethione bound to a distorted
square planar Ni center, as represented by structure 10 (Figure 1).13
We suggest that the nucleophile is most likely a reactive enol
tautomer of the â-ketoester, formed at equilibrium concentrations
under the reaction conditions.
Acknowledgment. Support has been provided by the National
Science Foundation and the National Institutes of Health (GM-
33328-18). F.F. acknowledges support from the Fundacion Ramon
Areces.
Supporting Information Available: Experimental procedures,
spectral data for all compounds, crystallographic data, and stereochem-
ical proofs (CIF, PDF). This material is available free of charge via
the Internet at http://pubs.acs.org.
References
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10475.
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Soc. 1999, 121, 8675-8676.
(6) Prepared in situ from 1a and 2.0 equiv of AgOTf. 1c was prepared in an
analogous fashion using AgBF4.
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The product pyrones 5 are excellent substrates for further enolate-
based stereoselective transformations (Scheme 1). For example, the
lithium enolate derived from 5b may be selectively alkylated with
benzyl bromide to provide the anti lactone 11. Alternatively, aldol
condensation of 5b with benzaldehyde provides R,â-unsaturated
lactone 13. Hydrogenation of 13 (10% Pd/C, toluene) afforded the
syn-substituted product 14 with excellent diastereoselectivity. Both
the anti and syn adducts may be transformed into their derived
Weinreb amides 12 and 15, respectively, without loss of stereo-
chemistry after TFA-induced decarboxylation. Dihydropyrone 5b
may also be hydrolyzed to its derived carboxylic acid 16 (R ) H)
upon exposure to aqueous LiOH in THF and subsequent decar-
boxylation (eq 5). In a similar manner, treatment of 5b with sodium
methoxide affords the corresponding methyl ester 17 (R ) Me) in
Scheme 1. Stereoselective Elaboration of Dihydropyrone 5ba
(8) For the synthesis of related structures, see: Katritzky, A. R.; Deniski, O.
V. J. Org. Chem. 2002, 67, 3104-3108. See also ref 5a.
(9) Other alkyl acetoacetates were also effective; Me: 86% ee, Et: 91% ee,
Bn: 93% ee. See Supporting Information for full details.
(10) (a) Oikawa, Y.; Sugano, K.; Yonemitsu, O. J. Org. Chem. 1978, 43, 2087-
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(11) 8b and 8f are known compounds and allowed the assignment of the
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(12) See Supporting Information for full details.
(13) Model generated from the X-ray structure of [Ni((S)-BINAP)]Cl2 by
docking the thiazolidinethione to the Ni center, followed by PM3
minimization. See Supporting Information for X-ray structure.
(14) An enantioselective hydrogenation of pyrone derivatives to 5,6-dihydro-
2-pyrones has been reported. See: Fehr, M. J.; Consiglio, G.; Scalone,
M.; Schmid, R. J. Org. Chem. 1999, 64, 5678-5776 and references
therein.
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a Reagents and conditions: (a) LiHMDS (1 equiv), BnBr (5 equiv); (b)
i. LiHMDS (1.5 equiv), PhCHO (1.5 equiv), -78 °C, THF; ii. MsCl (2
equiv), Et3N (2.5 equiv), CH2Cl2, rt; iii. DBU (2 equiv), toluene, rt, 81%
(three steps); (c) H2, 10% Pd/C, toluene, 100%; (d) i. Me(OMe)NH‚HCl
(5 equiv), i-PrMgCl (9 equiv), THF, -20 °C; ii. TFA, CH2Cl2, rt, 80%.
JA053820Q
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