Table 1. Screening of Achiral Proton Donorsa
Scheme 1. Pd-Catalyzed Enantioselective Decarboxylative
Allylation and Protonation of Racemic Allyl â-Ketoesters
basis of kinetic and mechanistic studies carried out in our
laboratories as well as computational studies performed in
collaboration with the W. A. Goddard group at Caltech,7 we
believe that in the course of the reaction a chiral Pd-enolate
is generated in solution. We chose to explore a proton
electrophile to take further advantage of this valuable
intermediate for the preparation of tertiary stereocenters.8 As
a result of these studies, we reported a highly enantioselective
catalytic system for the decarboxylative protonation of
racemic allyl â-ketoesters in the presence of Pd(OAc)2, (S)-
t-Bu-PHOX (1), 4 Å molecular sieves (MS), and HCO2H
(Scheme 1).9 Although this protocol is capable of generating
cycloalkanones with excellent ee, each substrate required
optimization of the amounts of 4 Å MS and HCO2H in
order to suppress competitive allylation and maximize
product ee. Moreover, the heterogeneous nature of the
reaction hinders investigation of the mechanism of proto-
nation. In response, we have sought substantially different
protonation conditions to allow further development of a
practical synthetic process. Herein, we report a highly
enantioselective, general homogeneous catalytic system for
the facile synthesis of tertiary stereocenters by protonation
of ketone enolates.
a Reactions performed with 0.1 mmol of (()-2 at 0.033 M in p-dioxane.
b Measured by 1H NMR spectroscopy. c Measured by chiral HLPC. d Reac-
tion performed at 23 °C. e Reaction performed at 0 °C in THF solvent.
f Reaction performed with 90 mg of 4 Å MS.
moderate (entry 1). Acetoacetic esters (entries 2 and 3)
provided 3 in significantly higher ee than the malonate case,
but at the expense of conversion. Acetylacetone derivatives
(entries 4-6) were very reactive, with the more acidic
analogues providing higher ee products. Noting that the more
acidic compounds increased the rate of reaction dramatically,
we chose next to explore other highly acidic organic proton
donors. Ketosulfones (entries 7-9) led to protonated product
3 in very high ee, although conversion was sometimes slow.
However, commercially available Meldrum’s acid10 led to
extremely rapid formation of 3 with good enantioselectivity
(entry 10). Given the rapid reaction at 40 °C, we attempted
the transformation at ambient temperature (23 °C) and
observed a significant increase in product ee (entry 11).
Further lowering of the temperature required changing the
solvent to THF, and although the ee was excellent, reactivity
dropped sharply (entry 12). Notably, addition of MS to the
reaction had a severe impact on the ee (entry 13).
The combination of reactivity, selectivity, and availability
prompted us to choose the Meldrum’s acid scaffold for our
further studies (Table 2). It was found that, in general, large
substituents between the carbonyls of the proton source
decrease the enantiopurity of 3, although smaller groups (e.g.,
CH3) are tolerated (entries 1-5). In contrast to the acyclic
case, addition of a third resonance withdrawing group (e.g.,
acetyl) severely decreased reactivity and product ee (cf. Table
1, entry 5, and Table 2, entry 5). Electronic perturbation by
substituting dimedone as the proton source led to only trace
To achieve a homogeneous enantioselective protonation,
the racemic allyl â-ketoester (()-2 was exposed to Pd2(dba)3,
(S)-t-Bu-PHOX (1), and a variety of achiral organic proton
donors (Table 1). Gratifyingly, the use of dimethyl malonate
did indeed lead to protonated product 3, although the ee was
(7) Keith, J. A.; Behenna, D. C.; Mohr, J. T.; Ma, S.; Marinescu, S. C.;
Oxgaard, J.; Stoltz, B. M.; Goddard, W. A., III. J. Am. Chem. Soc. 2007,
129, 11876-11877.
(8) To our knowledge, there are three other groups that have reported
related Pd-catalyzed systems that produce similar enantioenriched products.
(a) Henin, F.; Muzart, J. Tetrahedron: Asymmetry 1992, 3, 1161-1164.
(b) Aboulhoda, S. J.; Henin, F.; Muzart, J.; Thorey, C.; Behnen, W.; Martens,
J.; Mehler, T. Tetrahedron: Asymmetry 1994, 5, 1321-1326. (c) Abouldoda,
S. J.; Letinois, S.; Wilken, J.; Reiners, I.; Henin, F.; Martnes, J.; Muzart, J.
Tetrahedron: Asymmetry 1995, 6, 1865-1868. (d) Baur, M. A.; Riahi, A.;
Henin, F.; Muzart, J. Tetrahedron: Asymmetry 2003, 14, 2755-2761. (e)
Sugiura, M.; Nakai, T. Angew. Chem., Int. Ed. Engl. 1997, 36, 2366-2368.
(f) Hamashima, Y.; Somei, H.; Shimura, Y.; Tamura, T.; Sodeoka, M. Org.
Lett. 2004, 6, 1861-1864.
(10) (a) For the initial synthesis of this compound, see: Meldrum, A.
N. J. Chem. Soc. 1908, 93, 598-601. (b) For the correct structural
assignment, see: Davidson, D.; Bernhard, S. A. J. Am. Chem. Soc. 1948,
70, 3426-3428. (c) For a highlight of recent chemistry based on Meldrum’s
acid, see: Bonifa´cia, V. D. B. Synlett 2004, 1649-1650.
(9) Mohr, J. T.; Nishimata, T.; Behenna, D. C.; Stoltz, B. M. J. Am.
Chem. Soc. 2006, 128, 11348-11349.
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Org. Lett., Vol. 10, No. 6, 2008